key: cord- - s g wvd authors: zheng, guoping; huang, lanfang; tong, haijiang; shu, qiang; hu, yaoqin; ge, menghua; deng, keqin; zhang, liuya; zou, bin; cheng, baoli; xu, jianguo title: treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study date: - - journal: respir res doi: . / - - - sha: doc_id: cord_uid: s g wvd background: recent studies have demonstrated that mesenchymal stem cells (mscs) modulate the immune response and reduce lung injury in animal models. currently, no clinical studies of the effects of mscs in acute respiratory distress syndrome (ards) exist. the objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived mscs in ards patients and second to determine potential efficacy of mscs on ards. methods: twelve adult patients meeting the berlin definition of acute respiratory distress syndrome with a pao( )/fio( ) ratio of < were randomized to receive allogeneic adipose-derived mscs or placebo in a : fashion. patients received one intravenous dose of × ( ) cells/kg of body weight or saline. possible side effects were monitored after treatment. acute lung injury biomarkers, including il- , il- and surfactant protein d (sp-d), were examined to determine the effects of mscs on lung injury and inflammation. results: there were no infusion toxicities or serious adverse events related to mscs administration and there were no significant differences in the overall number of adverse events between the two groups. length of hospital stay, ventilator-free days and icu-free days at day after treatment were similar. there were no changes in biomarkers examined in the placebo group. in the mscs group, serum sp-d levels at day were significantly lower than those at day (p = . ) while the changes in il- levels were not significant. the il- levels at day showed a trend towards lower levels as compared with day , but this trend was not statistically significant (p = . ). conclusions: administration of allogeneic adipose-derived mscs appears to be safe and feasible in the treatment of ards. however, the clinical effect with the doses of mscs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ards. trial registration: clinical trials.gov, nct acute respiratory distress syndrome (ards) is a major cause of acute respiratory failure and is often associated with multiple organ failure. clinical disorders such as pneumonia, sepsis, aspiration of gastric contents, and major trauma can precipitate ards. the pathogenesis of ards involves lung endothelial injury, alveolar epithelial injury, and the accumulation of protein-rich fluid and cellular debris in the alveolar space [ ] . even with the current advances in lung-protective ventilation and fluid management, patient mortality rate remains high. a clinical diagnosis of ards is associated with large financial burdens due to long hospitalization and icu stays, a poor survival rate, and an increased use of health services after hospital discharge. most patients who survive an episode of ards will sustain some degree of permanent physical disability as well as reduction in their quality of life. in addition, survivors often have long-term neuromuscular, cognitive, and psychological symptoms [ ] . to decrease the occurrence of these life-changing consequences, alternative therapeutic options are needed that can reduce lung injury while facilitating and enhancing lung repair. in the past decade, the preclinical and clinical studies of mscs have boosted the expectations of both patients and physicians for mscs as a treatment modality. unlike embryonic stem cells, the procurement and use of mscs is less controversial. there are multiple mechanisms responsible for the protective effects of mscs, including the secretion of multiple paracrine factors capable of modulating the immune response and restoring epithelial and endothelial integrity [ ] . moreover, their immunomodulatory capacity, coupled with low immunogenicity, have opened up possibilities for their allogeneic use, consequently broadening the possibilities for their application. allogeneic mscs have been applied to treat graft-versus-host diseases [ ] , myocardial infarction [ ] , autoimmune diseases [ ] , and inflammatory bowel diseases [ ] . in may , canadian health regulators approved prochymal tm , the first allogeneic mscs-based drug, for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. bone marrow (bm)-mscs are the most widely used mscs in clinical trials. unfortunately, the harvest of bm is a highly invasive procedure. furthermore, the number, differentiation potential, and maximal life span of mscs from bm decline with increasing age [ , ] . due to their ease of procurement and cell banking, the adipose-derived mscs have received significant attention over the past few years [ ] . many studies, including publications from our group [ , ] , have demonstrated compelling evidence of the benefits of mscs from both bone marrow [ ] [ ] [ ] and adipose tissues [ ] [ ] [ ] in animal models for lung injury and ards. we hypothesized that allogeneic adipose-derived mscs serve as a potential therapeutic agent for the treatment of ards. in this randomized, placebo-controlled phase i clinical trial, the primary goal was to evaluate the safety and feasibility of systemic administration of allogeneic adipose-derived mscs in ards patients. secondary goals were to determine potential efficacy and the effect of mscs on biomarkers for ards. this was a single-center, randomized, double-blind, and placebo-controlled study. the study protocol complied with the declaration of helsinki and was approved by the research ethics committee at shaoxing second hospital (clinical trials.gov identifier: nct ). written informed consent was obtained from the patient or legally authorized representative before enrolling each patient. study enrollment occurred between january and april . ards was defined and classified according to the berlin definition [ ] . in the new berlin definition, diagnostic criteria for ards rely on categories: ( ) timing: within week of a known clinical insult or new or worsening respiratory symptoms; ( ) radiography: bilateral opacitiesnot fully explained by effusions, lobar/lung collapse or nodule; ( ) origin of lung edema: respiratory failure not fully explained by cardiac failure or fluid overload, and ( ) oxygenation impairment: subdivided into categories according to the degree of hypoxemia severity (mild, moderate and severe). the berlin definition eliminated the concept of acute lung injury, which now falls in the category of mild ards. eligible patients were at least years of age and diagnosed within hours with a pao /fio ratio of < . exclusion criteria included pre-existing severe disease of any major organs, pregnancy, pulmonary hypertension, malignant disease, human immunodeficiency virus (hiv) infection or if informed consent could not be obtained. patients were randomized upon study enrollment. for all patients, a negative fluid balance was maintained by diuretics and fluid restriction. ards network low tidal volume protocol was adopted for standardized ventilator management, targeting a tidal volume of ml/kg of the patient's ideal body weight and a plateau pressure less than mmhg [ ] . per the requirement of research ethics committee at shaoxing second hospital, frozen mscs with dmso and fetal bovine serum were not allowed to be infused to patients directly. for the mscs group, frozen cells were immediately thawed, cultured with patient's own serum and harvested in - hours. freshly harvested mscs, at a dose of × cells/kg body weight, were suspended in ml normal saline for peripheral intravenous infusion and administered over hour within hours of enrollment. for the placebo group, a bag of ml normal saline was infused at similar time point. after administration of the mscs or placebo at day , patients were assessed daily at days , , , , , and (or until hospital discharge or death, whichever occurred first). patients who were discharged from the hospital before day were asked to return to the study site for assessment. all other aspects of the therapeutic management of the patients were left to the discretion of the clinical team. the primary endpoint was the occurrence of adverse events. secondary efficacy endpoints included the following: pao /fio ratio, hospital indices (length of hospital stay, ventilator-free days and icu-free days at day ), and serum biomarkers of ards including il- , il- and sp-d. normal human adipose-derived mscs were purchased from atcc (cat # pcs- - , lot , passage , manassas, va). the donor of the mscs was a year-old female of hispanic origin. mscs were certified to be negative for hiv, hbv, hcv, bacteria, yeast and mycoplasma. after purchase, sterility, viral, and endotoxin tests of the mscs were performed at the pathology lab of shaoxing second hospital to confirm the certificate of analysis. cells were then resuspended in expansion media containing dulbecco's modified eagle's medium (dmem) -low glucose supplemented with penicillin and streptomycin and % fetal bovine serum (fbs) (life technologies, grand island, ny) plus egf and fgf (r&d systems, minneapolis, mn) at a density of cells/cm . cultures were maintained at °c in a humidified atmosphere containing % co in mm dishes (life technologies, grand island, ny). when the cultures reached near confluence (> %), the cells were detached by treatment with trypsin/edta and replated at a density of cells/cm . mscs were passaged up to a maximum of four times. after sufficient mscs were expanded, cells were harvested and cryopreserved in % culture media, % fetal bovine serum and % dmso. sterility, viral, and endotoxin tests were carried out again after the expansion. right after each enrollment, ml of peripheral blood was collected and serum harvested from the patients. if a patient was randomized to mscs treatment, cryopreserved mscs were immediately thawed, washed with phosphatebuffered saline (pbs), and cultured with the same expansion media above except supplemented with % of the patient's own serum at a density of cells/cm for - hours. cells were harvested with trypsin/edta and quantitated with a hemocytometer. viral and endotoxin tests were performed prior to the infusion. all cell culture procedures were carried out in good manufacturing practice (gmp) conditions by personnel who had received formal training in gmp within a facility with highly controlled temperature, room air, pressure, etc. morphology was monitored twice a week throughout the culture period by light microscopy. immunophenotyping of cultured mscs was performed using flow cytometry. the following markers were analyzed: cd , cd , cd , cd , cd , and human leukocyte antigen (hla)-dr (bd biosciences, franklin lakes, new jersey). the samples were analyzed on a facscalibur using cellquest pro software (bd biosciences). for osteogenic differentiation of the expanded mscs, cells were further cultured with osteogenic medium containing % fbs, . mm l-ascorbic acid -phosphate and . m β-glycerophosphate in dmem. after - weeks, the cultures were stained for alkaline phosphatase (alp) a b sixteen c bl/ male mice aged - week-old were randomized into study groups: short term mscs ( days), short term placebo, long term mscs ( days), and long term placebo. animal studies were approved by the institutional animal care and use committee at zhejiang university. mice received one high dose of intravenous infusion of × expanded cells/kg of body weight or normal saline at day . mice were sacrificed at day or day . at the sacrifice, serum was harvested for monitoring renal function, liver function, cardiac enzymes, and pancreatic enzymes. kidney, liver and lung samples were paraffin-fixed for histopathological analysis. five milliliters (ml) of peripheral blood were collected from patients immediately before mscs or saline treatment (day ) and day after treatment. serum samples were collected by centrifugation at , g for minutes and stored at - °c until assay at the end of the trial. il- , il- and sp-d levels were determined by commercial enzyme-linked immunosorbent assays (elisa) (r&d systems, minneapolis, mn). continuous variables were expressed as mean ± standard deviation (sd). comparisons of continuous variables between two groups were performed by using unpaired student's t-test. comparisons within groups were performed by using paired t-test. differences were deemed statistically significant at p < . . kidney liver lung figure histology of kidneys, liver and lungs after mscs treatment. mice were administered intravenously with one dose of × mscs/kg of body weight or placebo. after days, kidney, liver and lung samples were harvested for h&e staining. adipose-derived mscs were spindle-shaped with a fibroblast-like morphology and were attached to the plate during cell culture. these characteristics were well preserved during subculture for a total of passages before harvest. for phenotypic characterization of mscs, surface protein expression at the end of expansion was examined by flow cytometry. the mscs were positive for cd ( . %), cd ( . %), and cd ( . %), but were negative for cd ( . %), cd ( . %), and hla-dr ( . %). the expanded mscs preserved the abilities of osteogenesis as determined by alkaline phosphatase staining ( figure a ) and adipogenesis as assayed by oil red o staining ( figure b ). after administering one high dose of × mscs/kg or normal saline at day via intravenous infusion, no mouse death was observed during the -day study period. there were no significant differences in liver (alanine aminotransferase and total bilirubin) and kidney (creatinine and blood urea nitrogen) function between the two groups on both day and day (table ) . mscs treatment did not alter cardiac enzymes, pancreatic enzymes and body weight (data not shown). mice treated with mscs did not show any histopathological changes in the liver, lungs, or kidneys at both day ( figure ) and day (data not shown). a total of ards patients were screened for enrollment in the study. of this number, patients were not enrolled because of the exclusion criteria or refusal to participate the study. the study population is comprised of patients randomized to the mscs group and patients to the placebo group. baseline demographics with no statistically significant differences between the study groups are summarized in table . within hours of randomization, patients received one dose of × cells/kg body weight or saline as a single intravenous infusion over minutes. study drugs were well tolerated. no adverse events were recorded during infusions. one patient from each group presented with diarrhea one day after study drug treatment and resolved within hours. one patient in the mscs group developed rash in the chest area after the infusion and resolved spontaneously over hours. during the study period, one patient in the mscs group died of multiple organ failure. deaths occurred in two patients in the placebo group with one multiple organ failure and the other sepsis. none of the deaths were considered to be related to the study drugs by the clinical investigators and were consistent with the patients' existing disease processes. all the remaining patients completed the -day follow-up period. there were no other adverse events or serious adverse events. as part of the safety and efficacy assessment, an evaluation of the oxygenation index and patient outcomes was conducted. significant improvements in oxygenation index (pao /fio ) from baseline were observed in all data points in the mscs group. in the placebo group, there were no significant improvements at days (p = . ) and (p = . ) as compared to baseline. the pao /fio did not differ significantly between mscs and placebo groups at all time points (figure ). assessment of hospital indices did not reveal significant differences in length of hospital stay, ventilator-free days and icu-free days at day between the two study groups (table ) . there were no statistically significant differences in serum sp-d, il- or il- levels between the mscs and placebo groups at both day and day (table ). in the placebo group, sp-d, il- or il- levels were similar between day and day ( figure b, d, f) . these findings are in agreement with those reported in other ards studies which showed no changes in biomarkers during the first week of ards development [ , ] . in the mscs group, serum sp-d levels at day were significantly lower than those at day (p = . ) ( figure a ). the il- levels at day showed a trend towards lower levels as compared with day , but this trend was not statistically significant (p = . ) ( figure e ). although the mean value for il- at day was much lower than that of day (table ) , the difference was not statistically significant due to the variation of the data (p = . ) ( figure c ). animal studies from our research group and others have showed that mscs from both bone marrow [ ] [ ] [ ] [ ] [ ] and adipose tissues [ ] [ ] [ ] the anti-inflammatory/immunomodulatory effect of mscs provides a therapeutic rationale for ards. it has been reported that the pathogenesis of ards involves procoagulant and inflammatory mechanisms as well as damage to the epithelial and endothelial compartments [ ] . biomarkers that reflect inflammation (il- , il- ) [ ] , coagulation (plasminogen activator inhibitor- , protein c, thrombomodulin) [ ] , endothelial cell injury (von willebrand factor) [ ] , and epithelial cell injury [sp-d and receptor for advanced glycosylation end products (rage)] [ ] , have all been linked to increased disease severity and poorer clinical outcomes in patients with ards. our results suggest that the mscs may be effective in decreasing epithelial cell injury as evidenced by reduced sp-d levels at day after mscs treatment. the levels for pro-inflammatory cytokine il- were decreased with only marginal significance (p = . ) in mscs group. therefore, the present data are not sufficient to support a conclusion that mscs exert their effects through alleviating lung inflammation. in the present study, mscs were administered through peripheral intravenous infusion. intravenous delivery of mscs is especially advantageous to lung diseases. other studies showed that the majority of administered stem cells were initially trapped in the lungs. infrared imaging revealed stem cells evenly distributed over all lung fields ventilator-free days at study day . ± . . ± . . data are presented as mean ± sd. p values were calculated using student's t-test. [ ] . systemic administration of mscs was recently reported in chronic obstructive pulmonary disease (copd). there were no significant differences in the overall number of adverse events, frequency of copd exacerbations, or worsening of disease in mscs-treated patients. pulmonary function testing and quality of life indicators remained the same after mscs treatment. for patients who had elevated c-reactive protein levels at study entry, an early significant decrease in the levels of circulating c-reactive protein was demonstrated in mscs-treated group [ ] . adipogenic precursors were first isolated from human adipose tissue by plastic adherence [ ] . adipose-derived mscs were identified and characterized in human fat tissue by zuk et al. in [ ] , and this led to the recognition of adipose tissue as an alternative to bm for mscs. bm-mscs reside in the bone marrow stroma in relatively small quantities. it has been estimated that they comprise about . %- . % of the total marrow nucleated cells [ ] , whereas the proportion of adipose-derived mscs is approximately % of all nucleated cells of adipose tissue [ ] . this difference is particularly relevant for making adipose-derived mscs more suited for clinical applications due to their ease of accessibility. adipose-derived mscs have other advantages as compared with bm-mscs. it was initially shown that both bm-mscs and adipose-derived mscs exhibit immunosuppressive properties in vitro [ ] . adipose-derived mscs can be more effective suppressors of immune response. they were significantly better than bm-mscs in inhibiting both the differentiation of blood monocytes into dendritic cells as defined by cd expression and the expression of co-stimulatory molecules (cd , cd ) on the surface of mature monocyte-derived dendritic cells. adipose-derived mscs were more powerful than bm-mscs at stimulating data are presented as mean ± sd. sp-d = surfactant protein d (ng/ml); il- = interleukin (pg/ml). il- = interleukin (pg/ml). p values were calculated using unpaired student's t-test. the secretion of immunosuppressive cytokine il- by dendritic cells [ ] . it has been demonstrated that adipose-derived mscs show a significantly greater angiogenic potential compared with bm-mscs [ ] , and may be more effective in cardiovascular pathologies associated with ischemia. allogeneic bm-mscs, prochymal tm , has been approved in canada and new zealand for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. allogenic adipose-derived mscs have been tested to treat several diseases. an open-label, singlearm clinical trial was conducted for crohn's disease. twenty-four patients were administered intralesionally with million adipose-derived mscs in each draining fistula tract. a subsequent administration of million adipose-derived mscs was followed if fistula closure was incomplete at week . no safety concerns were revealed at months follow-up. at week , . % of the patients showed a reduction in the number of draining fistulas with . % of the patients achieving complete closure of the treated fistula [ ] . vanikar et al. administered allogeneic adipose-derived mscs along with hematopoietic stem cells intraportally in patients with insulin-dependent diabetes and followed the patients for months. clinical parameters improved significantly as evidenced by a decreased exogenous insulin requirement, reduced levels of glycosylated hemoglobin, elevated serum c-peptide levels, and resolved diabetic ketoacidosis events [ ] . allogenic adipose-derived mscs have been explored as a salvage therapy of patients with severe steroid-resistant acute graft-versus-host diseases [ ] . complete response was achieved in patients, of them were still alive after a median follow-up of months. all survivors were in good clinical condition and in remission of hematological malignancy [ ] . with the application of mscs in the clinical setting, there is no standard protocol regarding how to expand these cells with gmp. most existing expansion protocols use dmem supplemented with fbs. however, fbs is a source of xenogeneic antigens and carries the risk of transmitting animal viruses and prions [ ] . immunological reactions and anti-fbs antibodies have been observed after transplantation in allogeneic hematopoietic stem cell recipients [ ] . as an alternative for fbs, platelet lysate [ ] , both autologous [ ] and allogeneic human serum [ ] , and serum-free medium have been tested for mscs expansion [ ] . to mitigate the allergic reactions in seriously ill ards patients and meet the requirements of the research ethics committee at shaoxing second hospital, mscs were cultured in autologous human serum for - hours after enrollment in the present study. this delay in mscs administration may have reduced the effect of mscs in ards. our pilot study is limited primarily by the small sample size. the current sample size limits the statistical rigor and power of our findings and, thus, our conclusions regarding safety and efficacy. another limitation is that the follow-up period was only days. longer follow-up periods are essential in evaluating the long-term effects of the cells. finally, our study lacked data regarding the time-response relationship and the dose-response relationship for mscs. what remains unknown is how often or how many mscs should be administered in ards. due to the small sample size, only limited effects can be observed in this preliminary study. nevertheless, the findings demonstrated that infusion of allogeneic adipose-derived mscs was safe and there were no significant adverse events related to the mscs in ards. the change in ards biomarker, sp-d, after treatment may suggest the protective effect of mscs. additional large studies with a long follow-up period are necessary to confirm the safety and efficacy profile of mscs in ards and to establish the best strategy for their administration, including concomitant medication and dosage. the acute respiratory distress syndrome acute respiratory distress syndrome: epidemiology and management approaches mesenchymal stem cells: a promising therapy for the acute respiratory distress syndrome co-infusion of ex vivo-expanded, parental mscs prevents life-threatening acute gvhd, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation a randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction double allogenic mesenchymal stem cells transplantations could not enhance therapeutic effect compared with single transplantation in systemic lupus erythematosus expanded allogeneic adipose-derived stem cells (eascs) for the treatment of complex perianal fistula in crohn's disease: results from a multicenter phase i/iia clinical trial age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells human bone marrow and adipose tissue mesenchymal stem cells: a user's guide bone marrow-derived mesenchymal stem cells in repair of the injured lung prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice prevention of lps-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model human mesenchymal stem cells overexpressing the il- antagonist sst attenuate endotoxin-induced acute lung injury systemic human orbital fat-derived stem/stromal cell transplantation ameliorates acute inflammation in lipopolysaccharide-induced acute lung injury acute respiratory distress syndrome: the berlin definition ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: the acute respiratory distress syndrome network nichol ad: a randomised controlled trial of an open lung strategy with staircase recruitment, titrated peep and targeted low airway pressures in patients with acute respiratory distress syndrome bronchoalveolar and systemic cytokine profiles in patients with ards, severe pneumonia and cardiogenic pulmonary oedema pathogenetic and predictive value of biomarkers in patients with ali and lower severity of illness: results from two clinical trials network nardsct: lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury national heart l, blood institute acute respiratory distress syndrome clinical trials n: pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome significance of von willebrand factor in septic and nonseptic patients with acute lung injury acute respiratory distress syndrome n: plasma surfactant protein levels and clinical outcomes in patients with acute lung injury pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect a placebo-controlled, randomized trial of mesenchymal stem cells in copd cytological and enzymological characterization of adult human adipocyte precursors in culture multilineage cells from human adipose tissue: implications for cell-based therapies mesenchymal stromal cells adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (mystromalcell trial): study design adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease n-glycolylneuraminic acid xenoantigen contamination of human embryonic and mesenchymal stem cells is substantially reversible no alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients platelet lysate from whole blood-derived pooled platelet concentrates and apheresis-derived platelet concentrates for the isolation and expansion of human bone marrow mesenchymal stromal cells: production process, content and identification of active components autologous serum for isolation and expansion of human mesenchymal stem cells for clinical use in vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability development of fully defined xeno-free culture system for the preparation and propagation of cell therapy-compliant human adipose stem cells submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution the authors declare that they have no competing interests. we would like to give special thanks to dr. mauricio rojas, university of pittsburgh school of medicine, for his very helpful comments and suggestions. we would also like to thank tingting li, wei wang, xiaojiao yang, and xuezhi ye from shanghai biomed union for their support in gmp production of mscs. this work was supported by the national natural science foundation of china ( ) and shaoxing plan to jx, and the national natural science foundation of china ( ) and the zhejiang province science and technology program ( c ) to qs. key: cord- -ec qzurk authors: devaney, james; contreras, maya; laffey, john g title: clinical review: gene-based therapies for ali/ards: where are we now? date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: ec qzurk acute lung injury (ali) and acute respiratory distress syndrome (ards) confer substantial morbidity and mortality, and have no specific therapy. the accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ali/ards, suggest that the disease may be amenable to gene-based therapies. ongoing advances in our understanding of the pathophysiology of ali/ards have revealed multiple therapeutic targets for gene-based approaches. strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ali/ards have all demonstrated promise in preclinical models. despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ali/ards remains to be realized. multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene-based approaches for ali/ards to the clinical setting. gene-based therapy involves the insertion of genes or smaller nucleic acid sequences into cells and tissues to replace the function of a defective gene, or to alter the production of a specifi c gene product, in order to treat a disease. gene therapy can be classifi ed into germline and somatic gene therapies. germline approaches modify the sperm or egg prior to fertilization and confer a stable heritable genetic modifi cation. somatic gene approaches use gene therapy to alter the function of mature cells. commonly used somatic gene therapy strategies include the overexpression of an existing gene and/or the insertion of smaller nucleic acid sequences into cells to alter the production of an existing gene. ali/ards may be suitable for gene-based therapies as it is an acute but relatively transient process [ ] , requiring short-lived gene expression, obviating the need for repeated therapies and reducing the risk of an adverse immunological response. th e distal lung epithelium is selectively accessible via the tracheal route of administration, allowing targeting of the pulmonary epithelium [ ] . th e pulmonary vasculature is also relatively accessible, as the entire cardiac output must transit this circulation. antibodies that bind antigens selectively expressed on the pulmonary endothelial surface can be complexed to gene vectors to facilitate selective targeting following intravenous administration [ ] . it is also possible to use gene-based strategies to target other cells central to the pathogenesis of ali/ards, such as leuko cytes and abstract acute lung injury (ali) and acute respiratory distress syndrome (ards) confer substantial morbidity and mortality, and have no specifi c therapy. the accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ali/ ards, suggest that the disease may be amenable to gene-based therapies. ongoing advances in our understanding of the pathophysiology of ali/ards have revealed multiple therapeutic targets for genebased approaches. strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ali/ards have all demonstrated promise in preclinical models. despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ali/ ards remains to be realized. multiple barriers to eff ective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection effi ciency of nonviral delivery methods. defi cits remain in our knowledge regarding the optimal molecular targets for genebased approaches. encouragingly, recent progress in overcoming these barriers off ers hope for the successful translation of gene-based approaches for ali/ards to the clinical setting. fi bro blasts [ ] . furthermore, gene-therapy-based approaches off er the potential to selectively target diff erent phases of the injury and repair process. th e potential to target specifi c aspects of the injury and repair processes such as epithelial-mesenchymal transition, fi brosis, fi brinolysis, coagulopathy and oxidative stress with these approaches is also clear. gene therapy requires the delivery of genes or smaller nucleic acid sequences into the cell nucleus using a carrier or vector. th e vector enables the gene to overcome barriers to entry into the cell, and to make its way to the nucleus to be transcribed and translated itself or to modulate transcription and/or translation of other genes. both viral and nonviral vector systems have been developed (table ) . viral vectors are the most eff ective and effi cient way of getting larger nucleic acid sequences, particularly genes, into cells (table ) . th e viral genome is modifi ed to remove the parts necessary for viral replication. th is segment is then replaced with the gene of interesttermed a transgene -coupled to a promoter that drives its expression. th e modifi ed genome is then encapsulated with viral proteins. following delivery to the target site, the virus binds to the host cell, enters the cytoplasm and releases its payload into the nucleus (figure ). th e size of trans gene that can be used depends on the capsid size. a number of diff erent viral vectors have been used in preclinical lung injury studies to date. adenoviruses have double-stranded dna genomes, have demonstrated promise in preclinical models [ , ] and are well tolerated at low to intermediate doses in humans [ , ] . advantages include their ease of production, the high effi ciency at which they can infect the pulmonary epithelium [ , ] and that they can deliver relatively large transgenes. a disadvantage of adenoviruses is their immunogenicity, particularly in repeated doses [ ] . newer adenoviral vectors, in which much of the immuno genicity has been removed, hold promise [ ] . while adenovirus-mediated gene transfer in the absence of epithelial damage is relatively ineffi cient [ ] , this may be less of a problem in ali/ards that is characterized by widespread epithelial damage. adeno-associated viruses (aavs) are single-stranded dna parvoviruses that are replication defi cient [ ] . a substantial proportion of the human population has been exposed to aavs but the clinical eff ects are unknown. aav vectors have a good safety profi le, and are less immunogenic compared with other viruses, although anti bodies do develop against aav capsid proteins that can compromise repeat administration. aav vectors can insert genes at a specifi c site on chromosome . th e packaging capacity of the virus is limited to . kb, restricting the size of the transgene that can be used. aavs are less effi cient in transducing cells than adenoviral vectors. successful aav vector gene transfer has been demon strated in multiple lung cell types including lung progenitor cells, in both normal and naphthaleneinduced ali lungs [ ] . aav serotypes have specifi c tissue tropisms, due to diff erent capsid proteins that bind to specifi c cell membrane receptors. aav- [ ] and avv- [ ] exhibit enhanced tropism for the pulmonary epi thelium [ , ] . aavs can transduce nondividing cells and result in long-lived transgene expression. aav vectors have been used in clinical trials in cystic fi brosis patients, underlining their safety profi le [ , ] . th ese rna viruses can transfect nondividing cells such as mature airway epithelial cells [ ] . th e virus stably but randomly integrates into the genome and expression is likely to last for the lifetime of the cell (~ days). th e transgene can be transmitted post mitosis, and there is also a risk of tumorigenesis if the transgene integrates near an oncogene. th e development of leukemias in children following gene therapy for severe combined immunodefi ciency highlights this risk [ , ] . while lentiviral vectors may be useful to correct a gene defi ciency associated with increased risk of ali, the long-lived gene expression of lentiviral delivered genes may be more suitable for chronic diseases than for ali/ards. nonviral delivery systems, while generally less effi cient than viral vectors in transfecting the lung epithelium, are increasingly used to deliver smaller dna/rna molecules (table ). strategies include the use of dna-lipid and dna-polymer complexes and naked dna/rna oligonucleotides, such as sirna [ ] , decoy oligo nucleo tides [ ] and plasmid dna [ ] . nonviral delivery systems are less immunogenic than viral vector-based approaches, and can be generated in large amounts at relatively low cost. plasmid vectors are composed of closed circles of doublestranded dna. as naked and plasmid dna contain no proteins for attachment to cellular receptors, there is no specifi c targeting to diff erent cell types and thus it is essential that the dna is placed in close contact with the desired cell type. th ese limitations make this approach less relevant clinically. th e therapeutic dna is held within a sphere of lipids, termed a lipoplex, or within a sphere of polymers, such as polyethyleneimine, termed a polyplex. lipoplexes and polyplexes act to protect the dna, facilitate binding to the target cell membrane and also trigger endocytosis of the complex into the cell, thereby enhancing gene expression. th ese systems can be modifi ed to include a targeting peptide for a specifi c cell type, such as airway epithelial cells [ ] . th ese complexes effi ciently and safely transfect airway epithelial cells [ ] , and they have demonstrated promise in human studies [ ] . sirnas are dsrna molecules of to nucleotides that can regulate the expression of specifi c genes. specifi c sirnas reduce infl ammation-associated lung injury in table . viral vector-delivered gene therapy relatively easily produced immunogenic [ ] adenoviral transfer of genes for a surfactant (dsdna genome) effi ciently transfect lung enzyme [ ] , angiopoietin- [ ] , hsp- [ ] , epithelium [ , ] apolipoprotein a- [ ] , and na + ,k + -atpase pump can deliver larger genes [ ] genes attenuate experimental ali well tolerated in lower doses [ , ] adenoviral delivery of il- gene attenuates zymosan ali at low doses, but is harmful at high doses [ ] adeno-associated virus good safety profi le; less limited transgene size aav vector gene transfer demonstrated in multiple vectors (ssdna genome) immunogenic diffi cult to produce in large lung cell types including progenitor cells in both inherently replication defi cient quantities normal lungs and following naphthalene-induced aav- and aav- lung epithelial ali [ ] tropism [ , ] transduce nondividing cells long-lived gene expression used in clinical trials for cf [ , ] lentivirus vectors transduce nondividing cells [ ] oncogenesis risk due to lentiviral transfer of shrna to silence cd gene (rna genome) integrate stably but randomly integration into genome expression suppresses silica-induced lung fi brosis into the genome [ , ] in the rat [ ] nonviral gene-based strategies plasmid transfer (closed easily produced at low cost no specifi c cell targeting electroporation-mediated gene transfer of the dsdna circles) very ineffi cient na + ,k + -atpase rescues endotoxin-induced lung injury [ ] nonviral dna complexes complexes protect dna less effi cient than viral vectors cationic lipid-mediated transfer of the na + ,k + -(lipoplexes or polyplexes) complexes facilitate cellular atpase gene ameliorated high-permeability targeting [ ] pulmonary edema [ ] lipoplex-delivered il- gene decreased clp-induced ali [ ] systemic cationic polyethylenimine polyplexes incorporating indoleamine- , -dioxygenase decreased ischemia-reperfusion ali [ ] dna and rna easily produced at low cost no specifi c cell targeting specifi c sirnas reduce infl ammation-associated oligonucleotides (sirna, smaller molecules that can lung injury in humans [ ] and in animal models shrna, decoy easily enter cells [ , ] oligonucleotides) target regulation of specifi c genes shrna-based approaches have reduced lung injury in animal models [ , ] cell-delivered gene therapy humans [ ] and in animal models [ , ] . shrna is a single strand of rna that, when introduced into the cell, is reverse transcribed and integrated into the genome, becoming heritable. during subsequent transcription, the sequence generates an oligonucleotide with a tight hairpin turn that is processed into sirna. shrnas have reduced lung injury in animal models [ , ] . decoy oligonucleotides are double-stranded dna molecules of to nucleo tides, which bind to specifi c transcription factors to reduce expression of targeted genes, and have been successfully used in animal models [ , ] . an alternative approach is to use systemically delivered cells to deliver genes to the lung. th is approach has been used to enhance the therapeutic potential of stem cellssuch as mesenchymal stem/stromal cells, which demon strate promise in preclinical ali/ards models [ ] . fibroblasts have also been used to successfully deliver genes to the lung to attenuate ali [ ] . preliminary data from a clinical trial in pulmonary hypertension show that endothelial progenitor cells overexpressing endothelial nitric oxide synthase (nos ) decrease pulmonary vascular resistance [ ] , highlighting the potential of cell-delivered gene therapy for ali/ards. nebulization of genetic material into the lung is eff ective [ ] , safe and well tolerated [ , , ] . th e integrity of aav vectors [ , ] and adenoviral virus vectors [ ] are maintained post nebulization, as are cationic lipid vectors [ ] and dna and rna oligonucleotides [ ] . a number of gene therapy clinical trials have utilized nebulization to deliver the transgene to the lung [ , ] , but without clear clinical benefi t to date [ , ] . intravascular delivery approaches target the lung endothelium. th ese approaches have been successfully used in preclinical studies of cell-based gene therapies [ , ] , and also with vectors that incorporate components such as antibodies to target antigens on the lung endothelium [ ] . successful gene-based therapies require the delivery of high quantities of the gene or oligonucleotide to the pulmonary epithelial or endothelial surface, require effi cient entry into the cytoplasm of these large and insoluble nucleic acids, which then have to move from the cytoplasm into the nucleus, and activate transcription of its product. multiple barriers exist that hinder this process, not least the natural defense mechanisms of the lung, and additional diffi culties that exist in transducing the acutely injured lung (table ). limitations regarding delivery technologies and defi ciencies in our knowledge regarding the optimal molecular targets also reduce the effi cacy of these approaches. th e lung has evolved eff ective barriers to prevent the uptake of any inhaled foreign particles [ ] . while advantageous in minimizing the potential for uptake of external genetic material (for example, viral dna), these barriers make it more diffi cult to use gene-based therapies in the lung. barriers to entry of foreign genetic material into the lung include airway mucus and the epithelial lining fl uid, which traps and clears inhaled material. th e glycocalyceal barrier hinders contact with the cell membrane, while the tight intercellular epithelial junctions and limited luminal endocytosis further restrict entry of foreign material into the epithelial cells. transducing the acutely injured lung may be diffi cult, due to the presence of pulmonary edema, consolidated or collapsed alveoli, and additional extracellular barriers such as mucus. gene-based therapies targeted at the pulmonary epithelium may be less eff ective where there is extensive denudation of the pulmonary epithelium, as may occur in primary ards. encouragingly, there is some evidence to suggest that ali may not substantially impair viral gene transfer to the alveolar epithelium [ ] . th e key limitation of nonviral vector approaches has been their lack of effi ciency in mediating gene transfer and transgene expression in the airway epithelium. viral vectors are immunogenic, due to the protein coat of the viral vector, and the immune response is related to both vector dose and number of administrations. th e potential to limit administration to a single dose in ali/ards may reduce this risk. however, the development of an infl amma tory response resulting in death following administration of a fi rst-generation adenoviral vector highlights the risks involved [ ] . additional limitations of viral vectors include transgene size, which is limited by the size of the capsid that encloses the viral genes. th e therapeutic potential of gene therapy for ali/ards is underlined by a growing body of literature demon strating effi cacy in relevant preclinical models. in considering the clinical implications of these studies, it is important to acknowledge that animal models of ards do not fully replicate the complex pathophysiological changes seen in the clinical setting. th is is highlighted by the fact that many pharmacologic strategies demonstrating considerable promise in preclinical studies were later proven ineff ective in clinical trials. nevertheless, these studies provide insights into the clinical potential of these strategies. adenovirus-mediated transfer of a gene that enhances surfactant production improves lung function and confers resistance to pseudomonas aeruginosa infection ( figure ) [ ] . adenovirus-delivered superoxide dismutase and catalase genes protected against hyperoxic-induced, but not ischemia-reperfusion-induced, lung injury [ ] . more recent studies have demonstrated the therapeutic potential of overexpression of a number of genes, including angio poietin- [ ] , hsp- [ ] , apolipo protein a- [ ] , defensin β [ ] and the na + ,k + -atpase pump [ ] . in contrast, overexpression of il- β can directly cause ali [ ] , while overexpression of suppressor of cytokine signal ing- worsens immune-complex-induced ali [ ] . intriguingly, intra tracheal administration of adenoviral vector incor porating il- , prior to zymosan-induced lung injury, improved survival at a lower dose but was ineff ective and even harmful at higher doses [ ] . an early murine study demonstrated that cationic lipidmediated transfer of the na + ,k + -atpase gene ameliorated high-permeability pulmonary edema [ ] . electroporationassisted gene transfer of plasmids encoding for na + ,k + -atpase reverses endotoxin-induced lung injury [ ] . th e lipoplex-delivered il- gene decreased lung and systemic organ injury induced by cecal ligation and puncture in mice [ ] . systemically administered cationic polyethyleni mine polyplexes incorporating indoleamine- , -dioxyge nase transduced pulmonary endo thelial cells and decreased lung ischemia-reper fusion injury [ ] . nf-κb decoy oligonucleotides, incorporated into viral vectors, attenuate systemic sepsis-induced lung injury when administered intravenously (figure ) [ ] . in animal models, both intratracheal [ , ] and intra venously [ , ] administered sirna successfully silence their target genes. shrna-based approaches have been used to suppress silica-induced lung fi brosis [ ] and to ameliorate lung ischemia-reperfusion-induced lung injury [ ] . more recently, aerosolization of sirna that targets respiratory syncytial virus viral replication was safe and potentially eff ective in patients post lung transplant with respiratory syncytial virus infection [ ] , clearly illustrating the therapeutic potential of these approaches for ali/ards. mei and colleagues enhanced the effi cacy of mesen chymal stem/stromal cells in endotoxin-induced ali by transducing them to overexpress angiopoeitin- (figure ) [ ] . mesenchymal stem/stromal cells overexpressing il- decreased alveolar infi ltration of cd and cd t cells following lung ischemia-reperfusion injury [ ] . bone marrow stem cells expressing keratinocyte growth factor attenuate bleomycin-induced lung injury [ ] . non stem cells can also be used to deliver genes to the injured lung [ ] . fibroblasts overexpressing angiopoeitin- attenuate endotoxin-induced lung injury [ ] , while fi broblasts overexpressing vascular endothelial growth factor and endothelial nitric oxide synthase can attenuate or even reverse endotoxin-induced ali [ ] . advances in the identifi cation of therapeutic targets, improvements in viral and nonviral vector technologies, and regulation of gene-based therapies by temporal and spatial targeting off er the potential to translate the therapeutic promise of gene-based therapies for ali/ ards to the clinical setting (table ) . viral vectors remain the focus of intensive research to optimize their effi ciency, to minimize their immuno genicity and to enhance their tissue specifi city [ , , , ] . strategies to develop less immunogenic vectors have focused on modifying the naturally occurring proteins in the viral coat [ ] . much research has been devoted to searching and characterizing both naturally occurring [ ] and engineered capsid variants from mammalian species [ ] . capsid protein modification has also been used to enhance tissue specifi city [ ] . envelope protein pseudotyping involves encapsulating the modifi ed genome from one virus, such as simian immuno defi ci ency virus, with envelope proteins from another virus, such as vesicular stomatitic virus. th is encapsu lation can enhance the therapeutic potential of viral vectors, by combining the advantages of one viral genome (for example, bigger payload or site-specifi c integration) with the tissue tropism of another virus. strategies to enhance the eff ectiveness of the lipoplexes used to deliver plasmids and other dna/rna oligonucleotides involve manipulation of the lipoplex lipid content and the use of targeting peptides. th e choice of lipid infl uences expression effi ciency by enhancing release of the genetic material within the target cell [ , ] . targeting peptides increases transfection effi ciency by directing the lipid to a particular cell membrane or cell type [ ] . physical methods of plasmid delivery such as electroporation [ ] and ultrasound can enhance gene transfer by bringing the plasmid dna into closer proximity with the cell membrane and/or causing temporary disruption of the cell membrane. other physical methods can also be used to increase in vivo gene transfer, including pressurized vascular delivery, laser, magnetic fi elds and gene gun delivery. th ese systems enable plasmid-based gene delivery to reach effi ciencies close to that achieved with viral vectors. successful gene therapy relies upon being able to target the injury site, and to control the duration and levels of gene expression. modifying the transgene dna to exclude nonmethylated cpg motifs, typical of bacterial dna, decreases the immune response and may increase transgene expression [ , ] . high-effi ciency tissue-specifi c promoters may improve the effi ciency and specifi city of transgene expression. lung-specifi c promoters include surfactant promoters [ ] such as the surfactant protein c promoter [ ] , a ciliated cell-specifi c promoter foxj [ ] , the cytokeratin promoter [ ] , and the clara cell -kda protein [ ] . promoters can also be used to target a specifi c phase of illness, switching on when required to produce an eff ect at the optimal time point. a related approach is the development of promoters that allow for transfected genes to be turned on and off . currently, the tetracycline-dependent gene expression vector [ ] is the most widely used regulated system as it has a good safety profi le. tetracycline is rapidly metabolized and cleared from the body, making it an ideal drug to control gene expression. however, the potential for an activator such as tetracycline to modulate the lung injury should be borne in mind. new-generation transactivators, with no basal activity and increased sensitivity, have now been developed [ ] . in an ards context, conditional regulation of gene expression by the combined use of a lung-specifi c promoter and the tetracycline-dependent gene expression system may be a useful approach [ ] . capsid protein modifi cation to reduce immunogenicity [ ] capsid protein modifi cation to enhance tissue specifi city [ ] envelope protein pseudotyping manipulation of lipoplex lipid content to enhance cellular uptake [ , ] use of targeting peptides on lipoplexes and polyplexes [ ] strategies to enhance gene transfer; for example, electroporation, ultrasound, gene gun delivery modifying transgene dna to eliminate bacterial motifs [ , ] development of high-effi ciency tissue-specifi c promoters [ ] [ ] [ ] [ ] development of promoters that regulate gene expression [ ] enhanced therapeutic targeting nebulization technologies [ ] strategies to target the pulmonary endothelium [ ] improved cellular uptake of vector surface active agents to enhance vector spread [ ] reduce ubiquitination of viral capsid proteins [ ] better therapeutic targets enhancement or restoration of lung epithelial and/or endothelial cell function [ ] strengthening lung defense mechanisms against injury [ ] speeding clearance of infl ammation and infection enhancement of the repair process following ali/ards [ ] . an advantage of gene-based strategies is the ability to target specifi c cells within an organ; for example, the epithelial cells of the lung. novel nebulization technologies, which facilitate the delivery of large quantities of undamaged vector to the distal lung, demonstrate considerable promise in this regard [ ] . alternative approaches to spatial targeting include targeting specifi c receptors that are plentiful on the target cell to increase transfection effi ciency. an interesting development in this regard is the targeting of systemically administered therapies to the pulmonary endothelium using antibodies to proteins expressed preferentially on these cells ( figure ) [ ] . in these studies, the antioxidant enzyme catalase was conjugated with antibodies to the adhesion molecule pecam, which is widely expressed on pulmonary endothelial cells, and to a nonspecifi c igg antibody. th e anti-pecam/catalase conjugate, but not the igg/catalase conjugate, bound specifi cally to the pulmonary endothelium and attenuated hydrogen peroxide injury. specifi c strategies have been developed to maximize uptake of vector into alveolar epithelial cells. it is possible to enhance lung transgene expression with the use of surface-active agents such as perfl urocarbon, which enhances the spread of vector and mixing within the epithelial lining fl uid [ ] . agents that reduce ubiquitination of aav capsid proteins following endocytosis, such as tripeptide proteasome inhibitors, dramatically augment (> , -fold) aav vector transduction in airway epithelia [ ] . ultimately, the success or failure of gene-based therapies for ali/ards is likely to rest on the identifi cation of better gene targets. ongoing advances in our understanding of the pathophysiology of ali/ards continue to reveal novel therapeutic targets for gene-based approaches. promising potential approaches include strate gies to enhance or restore lung epithelial and/or endothelial cell function [ ] , to strengthen lung defense mechanisms against injury [ ] , to speed clear ance of infl ammation and infection, and to enhance the repair process following ali/ards [ ] . ali/ards may be a particularly suitable disease process for gene-based therapies (table ). th is is supported by increasing evidence from relevant preclinical ards models for the effi cacy of gene-based therapies that enhance or restore lung epithelial and/or endothelial cell function, strengthen lung defense mecha nisms against injury, speed resolution of infl ammation and infection, and enhance the repair process following ali/ards. despite this promising preclinical evidence, the potential for gene based approaches to ali/ards in the clinical setting remains to be realized. multiple barriers exist to the successful use of gene-based therapies in the lung, which limit the effi cacy of these approaches. future research approaches should focus on overcoming these barriers, by developing more eff ective and less immunogenic vector delivery systems, developing strategies to focus gene expression on specifi c injury zones of the lung for defi ned time periods, and identifying better molecular targets that can take advantage of these potentially very powerful therapeutic approaches. abbreviations aav, adeno-associated virus; ali, acute lung injury; ards, acute respiratory distress syndrome; il, interleukin; nf, nuclear factor; shrna, small hairpin rna; sirna, small interfering rna. the authors declare that they have no competing interests. epidemiology of acute lung injury incidence and outcomes of acute lung injury one-year outcomes in survivors of the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network pulmonary-artery versus central venous catheter to guide treatment of acute lung injury prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis elbourne d: effi cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial the acute respiratory distress syndrome optimized aerosol delivery to a mechanically ventilated rodent pecamdirected delivery of catalase to endothelium protects against pulmonary vascular oxidative stress adenoviral augmentation of elafi n protects the lung against acute injury mediated by activated neutrophils and bacterial infection aerosol delivery of a β-galactosidase adenoviral vector to the lungs of rodents adenovirusmediated persistent cystic fi brosis transmembrane conductance regulator expression in mouse airway epithelium airway epithelial cftr mrna expression in cystic fi brosis patients after repetitive administration of a recombinant adenovirus analysis of risk factors for local delivery of low-and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions modifi cation of nasal epithelial potential diff erences of individuals with cystic fi brosis consequent to local administration of a normal cftr cdna adenovirus gene transfer vector a phase i study of adenovirus-mediated transfer of the human cystic fi brosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fi brosis aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fi brosis. i. methods, safety, and clinical implications recent developments in adeno-associated virus vector technology analysis of adeno-associated virus progenitor cell transduction in mouse lung adeno-associated virus type (aav ) but not aav binds to the apical surfaces of airway epithelia and facilitates gene transfer adeno-associated virus type (aav ) vectors mediate effi cient transduction of airway epithelial cells in mouse lungs compared to that of aav vectors repeated adeno-associated virus serotype aerosol-mediated cystic fi brosis transmembrane regulator gene transfer to the lungs of patients with cystic fi brosis: a multicenter, double-blind, placebo-controlled trial safety and biological effi cacy of an adeno-associated virus vector-cystic fi brosis transmembrane regulator (aav-cftr) in the cystic fi brosis maxillary sinus lentivirus vectors pseudotyped with fi loviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha gene therapy of human severe combined immunodefi ciency (scid)-x disease cavazzana-calvo m: insertional oncogenesis in patients after retrovirus-mediated gene therapy of scid-x rna interference for α-enac inhibits rat lung fl uid absorption in vivo eff ect of antisense oligonucleotides to nuclear factor-κb on the survival of lps-induced ards in mouse electroporation-mediated transfer of plasmids to the lung results in reduced tlr signaling and infl ammation a receptor-targeted nanocomplex vector system optimized for respiratory gene transfer cationic lipid-mediated cftr gene transfer to the lungs and nose of patients with cystic fi brosis: a double-blind placebo-controlled trial rna interference therapy in lung transplant patients infected with respiratory syncytial virus in vivo gene silencing (with sirna) of pulmonary expression of mip- versus kc results in divergent eff ects on hemorrhage-induced, neutrophil-mediated septic acute lung injury silencing cd gene expression results in the inhibition of latent-tgf-β activation and suppression of silica-induced lung fi brosis in the rat prevention of lung ischemia-reperfusion injury by short hairpin rna-mediated caspase- gene silencing nuclear factor-κb decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis eff ects of intratracheal administration of nuclear factor-κb decoy oligodeoxynucleotides on long-term cigarette smokeinduced lung infl ammation and pathology in mice prevention of lpsinduced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin cell-based angiopoietin- gene therapy for acute lung injury stem cells and cell therapies in lung biology and lung diseases calculating expected lung deposition of aerosolized administration of aav vector in human clinical studies repeated aerosolized aav-cftr for treatment of cystic fi brosis: a randomized placebo-controlled phase b trial aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fi brosis. ii. transfection effi ciency in airway epithelium inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance gene transfer to the lung: lessons learned from more than decades of cf gene therapy acute lung injury does not impair adenoviral-mediated gene transfer to the alveolar epithelium fatal systemic infl ammatory response syndrome in a ornithine transcarbamylase defi cient patient following adenoviral gene transfer adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury gene therapy for oxidant injury-related diseases: adenovirus-mediated transfer of superoxide dismutase and catalase cdnas protects against hyperoxia but not against ischemiareperfusion lung injury angiopoietin- increases survival and reduces the development of lung edema induced by endotoxin administration in a murine model of acute lung injury enhanced expression of -kilodalton heat shock protein limits cell division in a sepsis-induced model of acute respiratory distress syndrome human apoa-i overexpression diminishes lps-induced systemic infl ammation and multiple organ damage in mice protection against pseudomonas aeruginosa pneumonia and sepsisinduced lung injury by overexpression of β-defensin- in rats overexpression of the na-k-atpase α -subunit improves lung liquid clearance during ventilation-induced lung injury interleukin- β causes acute lung injury via αvβ and αvβ integrin-dependent mechanisms adenoviral-mediated overexpression of socs enhances igg immune complex-induced acute lung injury dose-dependent improvements in outcome with adenoviral expression of interleukin- in a murine model of multisystem organ failure pretreatment with cationic lipid-mediated transfer of the na + k + -atpase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema electroporation-mediated gene transfer of the na + ,k + -atpase rescues endotoxin-induced lung injury interleukin- gene transfer: prevention of multiple organ injury in a murine cecal ligation and puncture model of sepsis nonviral gene delivery with indoleamine , -dioxygenase targeting pulmonary endothelium protects against ischemia-reperfusion injury silencing of fas, but not caspase- , in lung epithelial cells ameliorates pulmonary apoptosis, infl ammation, and neutrophil infl ux after hemorrhagic shock and sepsis caveolin- sirna increases the pulmonary microvascular and alveolar epithelial permeability in rats interleukin- delivery via mesenchymal stem cells: a novel gene therapy approach to prevent lung ischemia-reperfusion injury bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fi brosis cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer tetracycline-inducible transgene expression mediated by a single aav vector effi cient transfection of non-proliferating human airway epithelial cells with a synthetic vector system tailoring the aav vector capsid for gene therapy artifi cial evolution with adeno-associated viral libraries analysis and optimization of the cationic lipid component of a lipid/ peptide vector formulation for enhanced transfection in vitro and in vivo stabilized integrin-targeting ternary lpd (lipopolyplex) vectors for gene delivery designed to disassemble within the target cell cpg-free plasmids confer reduced infl ammation and sustained pulmonary gene expression toll-like receptor expression reveals cpg dna as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with cd ligand to induce high amounts of il- targeting type ii and clara cells for adenovirus-mediated gene transfer using the surfactant protein b promoter development of lentiviral vectors with regulated respiratory epithelial expression in vivo expression of cftr from a ciliated cell-specifi c promoter is ineff ective at correcting nasal potential diff erence in cf mice a human epithelium-specifi c vector optimized in rat pneumocytes for lung gene therapy tight control of gene expression in mammalian cells by tetracycline-responsive promoters use of a new generation reverse tetracycline transactivator system for quantitative control of conditional gene expression in the murine lung construction of an rtta (s)-m / tts(kid)-based transcription regulatory switch that displays no basal activity, good inducibility, and high responsiveness to doxycycline in mice and non-human primates adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats ubiquitination of both adeno-associated virus type and capsid proteins aff ects the transduction effi ciency of recombinant vectors gp -stat regulates epithelial cell migration and is required for repair of the bronchiolar epithelium spatial and temporal expression of surfactant proteins in hyperoxia-induced neonatal rat lung injury intrapulmonary tnf gene therapy reverses sepsis-induced suppression of lung antibacterial host defense clinical review: gene-based therapies for ali/ards: where are we now? the present work was supported by funding from the health research board key: cord- -aj nxi x authors: wang, chen yu; calfee, carolyn s.; paul, devon w.; janz, david r.; may, addison k.; zhuo, hanjing; bernard, gordon r.; matthay, michael a.; ware, lorraine b.; kangelaris, kirsten neudoerffer title: one-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: aj nxi x purpose: advances in supportive care and ventilator management for acute respiratory distress syndrome (ards) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. our objective was to quantify the difference between short-term and long-term mortality in ards and to identify risk factors for death and causes of death at year among hospital survivors. methods: this multi-intensive care unit, prospective cohort included patients with ards enrolled between january and february . we determined the clinical characteristics associated with in-hospital and -year mortality among hospital survivors and utilized death certificate data to identify causes of death. results: of patients hospitalized with ards, mortality at year was substantially higher ( %, % ci – %) than in-hospital mortality ( %, % ci – %), p < . . among patients who survived to hospital discharge, the ( %) who died in the subsequent year were older (p < . ) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at year (p < . ). important predictors of death among hospital survivors were comorbidities present at the time of ards, and not living at home prior to admission. ards-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors. conclusions: despite improvements in short-term ards outcomes, -year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ards. electronic supplementary material: the online version of this article (doi: . /s - - - ) contains supplementary material, which is available to authorized users. abstract purpose: advances in supportive care and ventilator management for acute respiratory distress syndrome (ards) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. our objective was to quantify the difference between shortterm and long-term mortality in ards and to identify risk factors for death and causes of death at year among hospital survivors. methods: this multi-intensive care unit, prospective cohort included patients with ards enrolled between january and february . we determined the clinical characteristics associated with in-hospital and -year mortality among hospital survivors and utilized death certificate data to identify causes of death. results: of patients hospitalized with ards, mortality at year was substantially higher ( %, % ci - %) than in-hospital mortality ( %, % ci - %), p \ . . among patients who survived to hospital discharge, the ( %) who died in the subsequent year were older (p \ . ) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at year (p \ . ). important predictors of death among hospital survivors were comorbidities present at the time of ards, and not living at home prior to admission. ards-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors. conclusions: despite improvements in short-term ards outcomes, -year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ards. the last decade has seen many advancements in care for patients with acute respiratory distress syndrome (ards) including improvements in ventilator management [ , ] , noninvasive mechanical ventilation strategies [ ] [ ] [ ] , sepsis management [ ] , and intensive care unit system changes [ , ] . more patients with ards are now surviving to hospital discharge, a phenomenon that has been reported in both observational studies and randomized trials [ ] [ ] [ ] . for example, -day mortality decreased from % in the traditional tidal volume arm of the ards network arma study published in to % in the most recent ards network trial published in , in spite of increased severity of illness and more comorbidities in the more recent trial [ , ] . however, less is known about the epidemiology of long-term survival in ards, particularly in the context of increasing severity of illness and comorbidities among icu patients today [ ] . initial studies of long-term outcomes in ards found that in-hospital survival from ards provided a good estimate of long-term survival [ ] [ ] [ ] [ ] ; however, these populations are not reflective of ards patients in modern practice. in-hospital mortality in these studies was higher at - %, as these cohorts predated widespread implementation of low tidal volume ventilation. furthermore, patients who survived to hospital discharge and were selected for these studies were young (mean age mid- s), had few coexisting conditions, and lower severity of illness on presentation. more recent data demonstrate a widening difference between ards survival at discharge and long-term follow-up [ , , ] . this ''survival gap'' suggests that while modern icu interventions have resulted in short-term improvements in ards survival, the overall survival after ards may not have improved. temporal changes in icu patient characteristics including increased severity of illness and more comorbid illnesses may explain some of the changes in trajectory of illness following discharge [ ] . although factors that predict short-term mortality have been well described [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , a better understanding of predictors of long-term mortality in ards is required for improved prognostication and a better understanding of the effects of icu interventions on long-term outcomes [ ] . a small study predating low tidal volume ventilation found that comorbidities, ards risk factor, and age were most highly associated with mortality months following ards diagnosis [ ] , but the influence of increased severity of illness over time has not been assessed. a more recent study found that the survival benefits of adherence to low tidal volume ventilation persisted at years follow-up, suggesting that modern changes in clinical practice may provide long-standing improvements in survival [ ] . however, this study excluded sicker patients with cancer or life-limiting diseasediagnoses that are frequent in patients presenting with ards. the predictors and causes of death in a broad sample of patients surviving to hospital discharge with ards are not known. the purpose of the current study was to ( ) quantify the gap between in-hospital and -year ards mortality in modern practice, ( ) identify the most influential risk factors for death at year among hospital survivors in a large, multi-icu prospective cohort study of patients with ards, and ( ) examine causes of death among patients dying in the year after diagnosis of ards. some of these data have previously been presented in the form of an abstract [ ] . the study subjects were drawn from the validation of biomarkers in acute lung injury diagnosis (valid) study, an ongoing prospective, multi-icu cohort study of critically ill patients at vanderbilt university medical center, a tertiary medical center in nashville, tn. the inclusion criteria and exclusion criteria of valid have been reported previously and are described in the supplemental appendix [ ] . specifically, patients with severe chronic lung disease were excluded, but patients with other underlying comorbidities including advanced cancer and hiv were not excluded. the study was approved by the vanderbilt university institutional review board. for this analysis, we included patients enrolled between january and february who had or developed acute lung injury (ali)/ards during the first days after admission to the icu. during the study period, there were a total of , total patients enrolled in valid of whom, , had at least one risk factor for ards. of these, the current study focused on the who met the american european consensus conference (aecc) criteria for ali/ards [ ] . data collection and definitions have been described previously [ ] . diagnosis of ali/ards was defined by the aecc definition (pao /fio b mmhg for ali and pao /fio b mmhg for ards) [ ] , and could be established at any time during the first days in the icu. both mechanically ventilated (defined as invasive mechanical ventilation within days of aecc ali/ ards diagnosis) and not mechanically ventilated patients meeting aecc criteria were included in our primary analysis. in a sensitivity analysis, we also considered the berlin definition for ards [ , ] . berlin severity levels were defined as mild ( mmhg \pao / fio b mmhg with peep or cpap c cmh o), moderate ( mmhg \pao /fio b mmhg with peep c cmh o), and severe (pao /fio b mmhg with peep c cmh o). for both aecc and berlin definitions, the ratio of pulse oximetric saturation to fraction of inspired oxygen (spo /fio ) was used as a validated surrogate for pao /fio among patients without an arterial blood gas measurement at the time of ali/ ards diagnosis: spo /fio = ? . (pao / fio ) [ ] . the discharge location for patients who survived hospitalization was categorized as home, rehabilitation hospital, nursing home, hospice, or other acute care hospital. the lung injury score [ ] , brussels organ failure [ ] , and definitions for sepsis, pneumonia, aspiration, and trauma are included in the supplemental appendix. all patients were followed until death or for at least year after study enrollment. short-term mortality was defined as all-cause mortality during hospitalization. long-term mortality was defined as all-cause mortality year following enrollment in valid in patients who survived to hospital discharge. patient deaths were identified by medical record review and query of the social security death index (ssdi) [ ] . causes of death were determined by review of death certificate data obtained from the tennessee vital records office of the tennessee department of health. underlying causes of death were categorized as infection, malignancy (primary, metastatic, or hematologic), cardiovascular, respiratory, gastrointestinal/hepatic, trauma, or other causes (listed in supplemental appendix) based on icd- coding of the primary cause of death on the death certificate. we used t tests, chi-squared tests, and fisher's exact tests as appropriate to compare baseline demographics and clinical risk factors across groups. descriptive statistics and mcnemar's were used to compare in-hospital and -year mortality. since all events were accounted for over the year of follow-up, logistic regression was used to analyze associations between candidate risk factors and mortality. kaplan-meier survival plots demonstrate the time from discharge to death in hospital survivors and the log-rank test was used to estimate differences according to discharge location. clinical characteristics associated with -year mortality with p \ . on bivariable analysis were entered into a stepwise elimination model to retain potential risk factors if they remained associated at a p value of less than . . because of the modest number of outcomes, the forward stepwise elimination was used to maintain model parsimony. in a sensitivity analysis, we analyzed only patients meeting the berlin definition of ards [ ] . analyses were performed using stata version (stata corp, college station, tx). statistical significance was defined as a two-tailed p \ . for all analyses. among patients with ali/ards, the proportion of patients who died increased from % (n = , % ci - %) during hospitalization to % (n = , % ci - %) during the year after discharge (p \ . ). one-year mortality was higher than inhospital mortality regardless of ali/ards etiology (supplemental fig. ). in the subset of patients with -year outcomes available (n = , %), the -year cumulative incidence of death was % (n = , % ci - %, p = . ). in a sensitivity analysis of patients meeting the berlin definition of ards [ ] (excluded patients: non-mechanically ventilated in first days of enrollment; two patients with missing peep; two patients with peep \ cmh o; and four patients not meeting hypoxemia criteria on day otherwise meeting all berlin criteria) we found similar rates of hospital and -year mortality (supplemental table ). severity of ards defined by berlin levels (mild, moderate, severe) was associated with in-hospital mortality but not with mortality at -year among hospital survivors. comparison of baseline characteristics by hospital and -year outcomes demographics, comorbidities, and initial clinical characteristics did not differ substantially between those who died early (in hospital) and those who died over the subsequent year (table ) . patients who died in the hospital (n = ) were more likely to have a hematologic malignancy and less likely to have copd or metastatic cancer than patients who died after surviving hospitalization but were otherwise demographically similar. in addition, there was no difference in underlying cause of ali/ards although patients who died during hospitalization had a lower p/f ratio and a higher incidence of hepatic failure compared to those dying after hospitalization. by contrast, compared to patients who died in the year following hospital discharge (n = ), survivors at year (n = ) were younger, were more likely to have been admitted through the emergency department and had substantially fewer comorbidities such as copd, hiv, diabetes, chronic heart failure, chronic kidney disease, or malignancy (table ). in addition, patients who were alive at year were more likely to have trauma and less likely to have sepsis as the cause of ali/ards. increased severity of illness on presentation was associated with higher -year mortality among patients who survived hospitalization: respiratory rate, apache ii score, presence of coagulation failure, renal failure, and circulatory failure were all significantly associated with death after discharge ( table ) . comparison of hospital course between hospital survivors who were dead or alive at year among patients with ali/ards who survived hospitalization, those who survived to year had significantly shorter time from hospital admission to icu admission, lower creatinine at discharge, and were more likely to be discharged home or to a rehabilitation facility and less likely to be discharged to a nursing home or hospice facility (table ) . specifically, discharge destination among hospital survivors was strongly associated with long-term mortality (fig. ) (p \ . ). there were no differences in icu length of stay (p = . ) or duration of mechanical ventilation (p = . ) between hospital survivors that died and survived at -year follow-up. stepwise elimination identified several baseline characteristics as independent predictors of mortality among hospital survivors. these included age and severe comorbidities: hiv, metastatic cancer, hematologic malignancy, non-metastatic cancer, and chronic renal disease (table ) . trauma as a cause of ards and living at home prior to hospitalization were strong independent predictors of decreased odds of mortality at year. increased length of hospital stay was the only characteristic of hospitalization that was independently associated with increased odds of death at year among hospital survivors. severity of illness measures including lis, apache ii, organ failure, and pao /fio did not emerge as independent predictors of mortality in survivors. the c-statistic for the final adjusted model was . . predictors of -year mortality among survivors were similar after excluding patients discharged to hospice, and characteristics associated with -year mortality among those surviving the hospitalization were similar to those associated with overall -year mortality (data not shown). death certificate data was available for ( %) of the patients who died within year of enrollment. overall, the most common underlying cause of death both in the hospital and among hospital survivors was malignancy (fig. ) . seventy-two percent of patients with known malignancy at the time of ards were found to have malignancy as the underlying cause of death at year. there were no significant differences in underlying cause of death between patients who died in the hospital and patients who died after discharge. short-term mortality in ards has declined over the last decade owing to improvements in supportive care and of the use of protective ventilator strategies [ , ] . we sought to quantify the survival gap between short-and long-term ards mortality and identify risk factors for death and causes of death at year for hospital survivors. in this study of a broad, heterogeneous cohort of critically ill patients with ali/ards, overall hospital mortality was %, concordant with short-term mortality rates of ali/ards mortality reported in the era of low tidal volume ventilation [ , ] , and -year mortality was substantially higher at %, consistent with other recent studies [ , , ] . this finding did not vary according to etiology of ards or in the presence of sepsis. furthermore, in a large subgroup of patients followed for years, we found that more than half of the patients with ali/ ards had died. disposition after hospitalization was highly associated with -year mortality, suggesting that functional status after discharge may be an important contributing factor to long-term mortality after ards. the independent predictors of death at year were age, living somewhere other than home prior to admission, and serious comorbidities. although several measures of severity of illness and characteristics of hospital course were associated with long-term mortality among hospital survivors, only length of hospital stay remained an independent predictor of long-term mortality in a stepwise elimination model. restriction of the analysis to patients meeting the berlin definition for ards did not change the findings, and berlin level of severity of ards did not predict long-term mortality in hospital survivors. this study provides several insights into recent reports of declines in ards mortality. although short-term mortality in ards has decreased in the last decade, our findings expand upon other recent studies demonstrating a widening survival gap between ards survival at discharge and long-term follow-up [ , , ] . this gap suggests that while modern icu interventions have improved short-term outcomes in ards, other factors contribute to a persistently high long-term mortality in ards. one possible explanation is the temporal changes in characteristics of icu patients over the last several decades. large studies have demonstrated that older age, the number of comorbidities, and the severity of illness have increased both in the general icu population and in ards patients specifically [ , ] . icu treatment cannot address the underlying comorbidities and increasing age that ultimately contribute to high long-term mortality in icu patients today. although a recent study found that adherence to low tidal volume ventilation in ards was associated with a survival benefit up to years following hospitalization, these conclusions may only be generalizable to the most healthy of ards patients because those with significant comorbidities, poor social status, and life-limiting illnesses were excluded from enrollment in the observational study [ ] . our findings are consistent with prior studies focusing on long-term mortality in general critically ill patients, a finding that supports the hypothesis that long-term outcomes in ards are more related to the medical conditions and age of patients requiring icu care in general rather than the development of ards specifically [ ] . in a recent study of medicare patients, icu survivors had higher -year mortality than non-icu hospital survivors or non-hospitalized controls, and a separate study showed that critically ill patients have decreased ards acute respiratory distress syndrome, hiv human immunodeficiency virus, sd standard deviation, apache acute physiology and chronic health evaluation, lis lung injury score * p value compares values in patients who died in the hospital to those who survived hospitalization but died in the first year p value compares values in hospital survivors who died at year versus those alive at year a leukemia including chronic, acute, and following stem cell transplant b pao /fio missing in patients; spo /fio used as surrogate survival for up to years compared to age-and sexmatched population controls [ , ] . furthermore, predictors of long-term outcomes for critically ill patients are similar to those we observed in ards, with comorbidities as top predictors for subsequent re-hospitalization and death [ ] . one possible explanation for the persistently high risk of death in patients with critical illness includes a persistent pro-inflammatory state that may exacerbate or trigger other underlying inflammatory disorders including cardiovascular disease, recurrent infection, cancer, and renal failure-all common causes of death among patients in our study who survived to hospital discharge. this study has several strengths including the large sample size, broad patient population with few exclusion criteria, and the careful prospective phenotyping for ali/ ards, sepsis, and other important clinical variables. because there were very few exclusion criteria for enrollment in valid, the findings are likely to be generalizable. the study also has some limitations. first, it is a single-center study. however, this is counterbalanced by the broad spectrum of heterogeneous critically ill patients from four different intensive care units included. second, it is possible that we underestimated the -year mortality rate of ards survivors; although the ssdi has been shown to be a valuable tool for determining long-term outcomes [ ] , some patients without social security numbers may not be included. third, mortality does not capture the full burden of disease. long-term sequelae of ards, including impaired pulmonary function, neuromuscular weakness, and neuropsychiatric are well described [ , [ ] [ ] [ ] [ ] . however, these limitations would have led us to underestimate rather than overestimate the differences in survival across groups are statistically significant (p \ . ) driven by significantly increased -year mortality among patients discharged to hospice (p \ . ), nursing home (p \ . ), and other hospital (p = . ) compared to discharge to home long-term mortality is substantially higher than shortterm mortality in a broad sample of patients with ards. in spite of improvements in supportive care and significantly improved short-term outcomes, long-term outcomes remain poor. the top predictors of -year mortality in hospital survivors include non-modifiable factors including age and comorbidities, and the most common causes of death are malignancy and infection. these results underscore the importance of considering the interaction between comorbid illness and ards on the trajectory of long-term outcomes in hospital survivors of ards for testing new interventions and providing prognoses. researchers must measure whether effects of interventions can influence the overall trajectory of survival in ards patients who do and do not have major comorbidities. possible clinical applications of such research include improved guidance of initial discussions of prognosis and the benefits of full resuscitation for highrisk patients. for clinical trials, it is perhaps more realistic to target shorter-term endpoints such as -to -day mortality, since -year mortality will be driven primarily by comorbidities that cannot be reversed or influenced by treatments for increasing survival from ards such as lung protective or prone ventilation. this study, along with others, demonstrates that premorbid illnesses are the top predictors of long-term outcomes after ards in critically ill patients today. acknowledgments we thank all the patients who participated in the study and the research staff who assisted with the study. we are grateful to dr. underlying causes of death in patients with ali/ards who died during the hospital stay (gray bars) and those who survived hospitalization but died during the year following enrollment (black bars). in both groups, the most common cause of death was underlying malignancy. no difference is statistically significant ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome deadspace ventilation: a waste of breath! a multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure neurally adjusted ventilatory assist (nava) improves patient-ventilator interaction during non-invasive ventilation delivered by face mask early goaldirected therapy in the treatment of severe sepsis and septic shock interventions to reduce mortality among patients treated in intensive care units recommendations on basic requirements for intensive care units: structural and organizational aspects mortality rates for patients with acute lung injury/ards have decreased over time recent trends in acute lung injury mortality acute respiratory distress syndrome: nationwide changes in incidence, treatment and mortality over years randomized, placebo-controlled clinical trial of an aerosolized beta- agonist for treatment of acute lung injury changes in hospital mortality for united states intensive care unit admissions from quality-adjusted survival in the first year after the acute respiratory distress syndrome one-year outcomes in survivors of the acute respiratory distress syndrome twoyear outcomes, health care use, and costs of survivors of acute respiratory distress syndrome survivors of acute respiratory distress syndrome: relationship between pulmonary dysfunction and long-term health-related quality of life the effect of pulmonary artery catheter use on costs and longterm outcomes of acute lung injury lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study identification of patients with acute lung injury. predictors of mortality acute lung injury in the medical icu: comorbid conditions, age, etiology, and hospital outcome early predictive factors of survival in the acute respiratory distress syndrome. a multivariate analysis pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome causes and timing of death in patients with ards predictors of hospital mortality in a population-based cohort of patients with acute lung injury predictors of mortality in acute lung injury during the era of lung protective ventilation a simple clinical predictive index for objective estimates of mortality in acute lung injury a simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation spanish initiative for epidemiology s, therapies for an ( ) a universal definition of ards: the pao /fio ratio under a standard ventilatory setting-a prospective, multicenter validation study the effect of acute respiratory distress syndrome on long-term survival long term mortality in clinical acute lung injury is dramatically higher than hospital mortality (abstract) urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material comparison of the spo /fio ratio and the pao /fio ratio in patients with acute lung injury or ards an expanded definition of the adult respiratory distress syndrome a trial of antioxidants nacetylcysteine and procysteine in ards. the antioxidant in ards study group validation of the social security death index (ssdi): an important readily-available outcomes database for researchers three-year outcomes for medicare beneficiaries who survive intensive care determinants of longterm survival after intensive care neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome one-year trajectories of care and resource utilization for recipients of prolonged mechanical ventilation: a cohort study functional disability years after acute respiratory distress syndrome long-term outcomes in survivors of acute respiratory distress syndrome ventilated in supine or prone position key: cord- -vzn ub authors: thompson, b. taylor; ranieri, v. marco title: steroids are part of rescue therapy in ards patients with refractory hypoxemia: no date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: vzn ub nan rescue therapies for acute respiratory distress syndrome (ards) usually target patients with severe hypoxia and/ or hypercarbia refractory to conventional therapies and are considered when rapid deterioration in the patient's condition over a period of hours suggests an increased risk of death. under these circumstances conventional mechanical ventilation will almost certainly cause additional lung injury if "rescue therapies" are not implemented. inhaled nitric oxide, inhaled epoprostanol, high-frequency ventilation, prone positioning, or immediate cannulation for extracorporeal membrane oxygenation (ecmo) or extracorporeal carbon dioxide removal (ecco r) are often considerations in this setting. three thoughtful views on the value, if any, of rescue therapies were published in intensive care medicine last year [ ] [ ] [ ] . none of these expert commentaries recommended corticosteroids as a rescue option. should they have? are the known effects of corticosteroids on the injured lung likely to reverse or stabilize lung injury in these catastrophically ill patients in a timely way? when confronted with such dramatic cases clinicians should first ensure that the underlying cause of ards has been identified and effectively treatment started, such as appropriate antibiotics and source control for patients with sepsis and prompt management of volume overload for hypervolemic patients. because rescue therapies are, in essence, life support or lung protective measures that do not treat the underlying disease processes leading to these catastrophic cases, intensivists must consider specific causes of ards or ards mimics that may benefit from specific therapies, including corticosteroids. ards mimics should be suspected when no identifiable risk factors for ards are apparent [ ] . examples include severe ards from pneumocystis jiroveci pneumonia presenting as an aids-defining illness, diffuse alveolar hemorrhage from vasculitis, acute hypersensitivity pneumonitis, cryptogenic organizing pneumonia, or acute eosinophilic pneumonia. these uncommon diseases may rarely present with fulminate ards and have specific treatments, including corticosteroids (table ) [ ] [ ] [ ] [ ] . corticosteroids have not been systematically studied as rescue therapy for acute ards, so much of the evidence that bears on this question is indirect. four randomized trials of high-dose steroids for prevention of ards (methyprednisolone at, for example, mg/kg every h for h, or equivalent doses dexamethazone) showed no effect or harm of this therapeutic strategy and were the subject of a contemporary bayesean meta-analysis [ ] . this analysis determined that the probability for an odds ratio of ≥ for developing ards and for death was and %, respectively. these probabilities suggest steroids are ineffective for prevention and probably harmful-although the credible intervals both include . accordingly, treatment with high doses of corticosteroids for short periods early in the course of critical illness has largely been abandoned. recent meta-analyses and a systematic review of studies of lower dose corticosteroids for established ards show substantial heterogeneity of the pooled trials along with short-term improvement in lung physiology and outcomes, including earlier achievement of unassisted breathing [ , , reviewed in ] . additional studies of corticosteroids for patients with ards and sepsis are ongoing and needed (clinical trials.gov identifiers nct and nct ). do these short-term improvements in lung physiology with corticosteroids support their use as rescue therapies? to do so, a relevant improvement of physiological variables would need to be observed in a matter of minutes or hours to "rescue" a patient from fulminant ards. in a recently published study, meduri et al. carefully observed the patterns of response to corticosteroids in patients with established and presumed fibroproliferative ards [ ] . of the patients enrolled in their study, demonstrated a "rapid" response to corticosteroids. unfortunately "rapid" meant that in these responders the partial pressure of arterial oxygen/ fraction of inspired oxygen (pao /fio ) had improved on day following initiation of steroid therapy and that static respiratory system compliance had improved on day . one-third of the patients did not improve at all. similarly, the ards network noted improvement in pao /fio and plateau airway pressure after and days, respectively, of steroid therapy and more rapid liberation from mechanical ventilation [ ] . recent studies of steroids for community acquired pneumonia (cap) also document beneficial acute responses, but the time course is relatively slow for the purposes of immediate rescue. for example, in one study of patients with severe cap the median time to clinical stability was shorter in the steroid group [ . days, interquartile range (iqr) . - . days] than in the placebo group ( . days, iqr . - . days) [ ] , and in a second study of patients with cap, time to treatment failure was reduced but the difference appeared after days [ ] . these encouraging data suggest corticosteroids at lower doses early in the course of pneumonia or ards improve lung function but that the onset of action is too slow and inconsistent and the magnitude of the effect too small to be recommended as a reliable life-saving rescue therapy. furthermore, corticosteroids have been associated with late complications, such as secondary infections and new shock [ , ] . because of the modest, delayed, and inconsistent physiologic improvement observed with the use of corticosteroids for ards and cap and the concern for late complications, we do not recommend the use of corticosteroids as rescue therapy for patients with immediately life-threatening early ards. clinicians should remain vigilant for steroid-responsive diseases that may masquerade as ards, especially in patients without identifiable risk factors for the syndrome of ards. some of these patients will require corticosteroids and other diseasespecific treatments for optimal outcomes. table steroid-responsive conditions which may present with severe acute respiratory distress syndrome some diseases, such as granulomatosis with polyangiitis leading to diffuse alveolar hemorrhage, require additional immunosupressive treatment with cyclophosphamide or rituximab [ ] . other conditions require removal of the offending antigen [heat shock proteins (hsp); asparagine endopeptidase (aep)]. acute interstial pneumonia (hamman rich) is often treated with corticosteroids but efficacy has not been established ards acute respiratory distress syndrome acute eosinophilic pneumonia (aep) diffuse alveolar hemorrhage from vasculitis crytogenic organizing pneumonia acute hypersensitivity pneumonitis (hsp) pneumocystis jiroveci pneumonia complicating human immunodeficiency virus (hiv) nonspecific interstitial pneumonitis and pneumonitis associated with connective tissue disease rescue therapy for refractory ards should be offered early: yes rescue therapy for refractory ards should be offered early: no rescue therapy for refractory ards should be offered early: we are not sure acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome pathogenesis and treatment of anca-associated vasculitides corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ards) in adults: meta-analysis prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature steroids for acute respiratory distress syndrome? corticosteroid rescue treatment of progressive fibroproliferation in late ards. patterns of corticosteroid rescue treatment of progressive efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome adjunct prednisone therapy for patients with community acquired pneumonia: a multicentre, doubleblind, randomised, placebo-controlled trial effect of corticosteroids on treatment failure among hospitalized patients with severe communityacquired pneumonia and high inflammatory response: a randomized clinical trial hydrocortisone therapy for patients with septic shock key: cord- -n d fw f authors: ong, david s. y.; spitoni, cristian; klein klouwenberg, peter m. c.; verduyn lunel, frans m.; frencken, jos f.; schultz, marcus j.; van der poll, tom; kesecioglu, jozef; bonten, marc j. m.; cremer, olaf l. title: cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: n d fw f purpose: cytomegalovirus (cmv) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ards) and has been associated with increased mortality. however, it remains unknown whether this association represents an independent risk for poor outcome. we aimed to estimate the attributable effect of cmv reactivation on mortality in immunocompetent ards patients. methods: we prospectively studied immunocompetent ards patients who tested seropositive for cmv and remained mechanically ventilated beyond day in two tertiary intensive care units in the netherlands from to . cmv loads were determined in plasma weekly. competing risks cox regression was used with cmv reactivation status as a time-dependent exposure variable. subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. results: of ards patients, ( %) were cmv seropositive and reactivation occurred in ( %) of them. after adjustment for confounding and competing risks, cmv reactivation was associated with overall increased icu mortality (adjusted subdistribution hazard ratio (shr) . , % ci . – . ), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (hr) . , % ci . – . ) and a reduced successful weaning rate (indirect effect; cause specific hr . , % ci . – . ). these associations remained in sensitivity analyses. the population-attributable fraction of icu mortality was % ( % ci – ) by day (risk difference . , % ci . – . ). conclusion: cmv reactivation is independently associated with increased case fatality in immunocompetent ards patients who are cmv seropositive. electronic supplementary material: the online version of this article (doi: . /s - - -z) contains supplementary material, which is available to authorized users. abstract purpose: cytomegalovirus (cmv) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ards) and has been associated with increased mortality. however, it remains unknown whether this association represents an independent risk for poor outcome. we aimed to estimate the attributable effect of cmv reactivation on mortality in immunocompetent ards patients. methods: we prospectively studied immunocompetent ards patients who tested seropositive for cmv and remained mechanically ventilated beyond day in two tertiary intensive care units in the netherlands from to . cmv loads were determined in plasma weekly. competing risks cox regression was used with cmv reactivation status as a time-dependent exposure variable. subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling. results: of ards patients, ( %) were cmv seropositive and reactivation occurred in ( %) of them. after adjustment for confounding and competing risks, cmv reactivation was associated with overall increased icu mortality (adjusted subdistribution hazard ratio (shr) . , % ci . - . ), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (hr) . , % ci . - . ) and a reduced successful weaning rate (indirect effect; cause specific hr . , % ci . - . ). these associations remained in sensitivity analyses. the although the burden of cytomegalovirus (cmv) disease has been well established in immunocompromised patients [ ] , cmv viremia has also been described in intensive care unit (icu) patients without known prior immune deficiency. this almost exclusively results from systemic viral reactivation, and incidence rates of up to % have been reported in critically ill cmv seropositive subjects [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, cmv reactivation in critically ill patients has been associated with a prolonged duration of mechanical ventilation [ , , [ ] [ ] [ ] [ ] [ ] , an increased length of stay in the icu [ , , , , ] , and excess mortality [ , , [ ] [ ] [ ] . nevertheless, it remains uncertain whether these findings imply that cmv reactivation is a truly independent risk factor with respect to these observed poor clinical outcomes because most studies that have assessed these associations did not adequately account for all possible sources of bias. as a consequence, cmv viremia might merely be a marker of illness severity, contributing only little to the overall burden of disease. to achieve an accurate estimation of the true effect of cmv reactivation on clinical outcome, it is crucial in observational studies to adjust for the time-dependent occurrence of cmv reactivation and the evolution of disease severity prior to its onset. moreover, the presence of competing events should be taken into account when follow-up time is censored [ ] . for instance, when icu mortality is the outcome, then icu discharge is a competing risk that prohibits the event of interest from occurring first. patients with acute respiratory distress syndrome (ards) often have a long and complicated disease course in the icu, which portends a particular risk for viral reactivations [ , ] . despite the uncertainties regarding the clinical relevance of cmv disease in immunocompetent critically ill patients, it is etiologically plausible that virus reactivation adds to the pulmonary pathology in patients with ards. in experimental murine studies, cmv reactivation caused exacerbated and prolonged cytokine and chemokine expression in lung tissues, which eventually led to increased pulmonary fibrosis compared to controls [ ] . in a clinical study of open lung biopsies in ards patients with prolonged respiratory failure or in whom microbiological cultures remained negative, cmv pneumonia was found in % of cases [ ] . both findings suggest that cmv-related pulmonary pathology may be causally linked to the clinical disease course following ards onset, especially in the most severely ill patients who require prolonged mechanical ventilation. if cmv reactivation does contribute to poor clinical outcome in these patients, either prophylaxis or pre-emptive therapy with (val)ganciclovir may be considered. the aim of this study was to estimate the proportion of deaths that can be attributed to systemic reactivation of cmv in ards patients who are latent carriers of the virus. some results of this study have been previously reported in the form of an abstract [ ] . the present study was conducted within the framework of the molecular diagnosis and risk stratification of sepsis (mars) cohort (clinicaltrials.gov identifier: nct ) for which the institutional review board approved an opt-out method of informed consent (protocol number - c) [ ] . we prospectively included consecutive adults who presented with ards to the mixed icus of two tertiary care hospitals in the netherlands between january and december and required mechanical ventilation beyond day of icu admission. since data collection for our study started before publication of the berlin definition in , ards was defined according to the american-european consensus conference criteria [ ] : that is, the diagnosis required an acute onset of symptoms, the presence of bilateral infiltrates on chest radiography, a pulmonary artery occlusion pressure less than mmhg and/or the absence of left ventricular dysfunction, and pao /fio ratio (p/f) less than . we excluded patients who had received (val)ganciclovir, (val)acyclovir, cidofovir, or foscarnet in the week before icu admission and those with known immunodeficiency [ ] . immunodeficiency was defined as a history of solid organ or stem cell transplantation, infection with the human immunodeficiency virus, hematological malignancy, use of immunosuppressive medication (more than . mg prednisone per kilo for more than months, more than mg prednisone per day for more than week, or equivalent), chemotherapy/radiotherapy in the year before icu admission, and any known humoral or cellular immune deficiency. leftover plasma, which was harvested from blood samples obtained daily as part of routine patient care, was stored at - °c within h after blood draw. cmv serostatus was determined by an enzyme immunoassay (enzygnost cmv/igg, siemens healthcare diagnostic products, marburg, germany). subsequently, in seropositive patients only, viral loads in plasma were determined by real-time taqman cmv-dna polymerase chain reaction [ ] . cmv loads were determined on a weekly basis for a maximum of days following study inclusion (i.e., day of icu admission). for intermediary days, on which quantitative pcr was not performed, we estimated viral loads by log-linear imputation. cmv reactivation was defined as a viral load of at least international units per milliliter (iu/ml), as calibrated according to the cmv world health organization (who) standard. screening for cmv was not part of routine clinical practice in either participating hospital. neither serology results nor viral loads measured as part of our study were made available to the treating physicians, and none of the included patients therefore received antiviral treatment directed against cmv. mortality was the outcome of primary interest in this study and was defined as death on mechanical ventilation before day (i.e., day following study inclusion). successful weaning, which is a competing event of the primary outcome, was defined as complete liberation from mechanical ventilatory support on two or more consecutive days before day . we considered distal end points more likely to be amenable by pre-existing comorbidities, as well as specific end-of-life practices, bed availability, and other local factors. nonetheless, in a subsequent sensitivity analysis, we used discharge and death in icu as alternative end points. for our primary analyses we used cox proportional hazards modeling, in which mortality and successful weaning were considered as competing events and cmv reactivation status was fitted as a time-dependent variable. possible confounders that were screened included all patient characteristics and therapeutic interventions listed in table , and some markers of disease severity: acute physiology and chronic health evaluation apache acute physiology and chronic health evaluation, ards acute respiratory distress syndrome, copd chronic obstructive pulmonary disease, icu intensive care unit, peep positive end expiratory pressure, p/f partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio (apache) iv score, presence of septic shock, partial pressure of oxygen in arterial blood to fraction of inspired oxygen ratio, and positive end expiratory pressure (peep) setting. to account for possible confounding, we included baseline covariables that showed differences between the reactivated and non-reactivated groups at a p value of less than . , and changed the crude effect estimates for either mortality or weaning by more than %. we included only the strongest (possible) confounders by using these two criteria combined in order to avoid statistical overfitting (i.e., incorporating too many variables given the limited number of events). the two possible outcomes are interrelated as increased mortality may negatively impact the duration of mechanical ventilation. a competing risks analysis accommodates for this by providing two measures of association. first, the cause-specific hazard ratio (cshr) estimates the direct effects of cmv reactivation on each outcome of interest (i.e., mortality on the ventilator and successful weaning). second, the subdistribution hazard ratio (shr) estimates the risk of dying from reactivation at a given time-point, while accounting for the competing risk of successful weaning. to obtain direct estimates of cumulative risks in terms of the shr we used the fine and gray model [ ] . finally, to estimate the populationattributable fraction of mortality due to cmv reactivation, we used a multi-state model (fig. s ), which accounts for the time of reactivation [ ] . confidence intervals were calculated by bootstrap resampling [ , ] . despite these efforts to accurately assess the effect of cmv reactivation on clinical outcomes, residual confounding may still remain, because markers of illness at baseline (which we included in all multivariable analyses) may no longer be representative of the disease state at the time of reactivation onset. thus, we performed a sensitivity analysis using marginal structural modeling to adjust for the evolution of disease severity prior to the onset of cmv reactivation (see also supplementary material) [ , ] . such analysis first involves estimation of the daily probabilities of cmv reactivation using a multivariable logistic regression model that includes markers of disease severity on a daily basis. these probabilities are used to calculate an inversed probability weight that is then included as a summary measure of all relevant covariables in the final cox regression model. however, because marginal structural modeling requires many assumptions that are difficult to be checked, we considered this a sensitivity analysis only. data were analyzed with sas . (cary, nc, usa) and r . . software (r foundation for statistical computing, vienna, austria; packages ''etm'', ''mstate'', ''ipw''). we enrolled patients with ards who required mechanical ventilation for more than days (fig. s ). of these were excluded because of known prior immunocompromise or antiviral treatment and two were excluded because of missing samples. subsequently, ( %) patients tested seropositive for cmv and were thus included in the study. ards was of primary pulmonary origin in ( %) of these cases, whereas the remainder was of secondary etiology (e.g., associated with non-pulmonary sepsis, major surgery, or blood transfusion). cmv reactivation cmv reactivation occurred in ( %) of the included patients (table ). these patients more frequently hadat the time of icu admission-concurrent septic shock, higher apache iv scores, and renal insufficiency compared to patients who never had cmv reactivation. in addition, a larger proportion of these patients were receiving high dose corticosteroid therapy during the first days in icu. the median time from icu admission to onset of reactivation was . days (interquartile range (iqr) - ). within the subgroup of patients acquiring cmv reactivation the proportion of individuals having relatively high viral loads (at least iu/ml) increased over time (fig. ) . in a patient population that is selected by an icu stay of at least weeks, the proportion with cmv viremia is as high as of patients ( %). on day after study inclusion (this was days following icu admission) ( %) patients had died, the quantitative pcr results were calibrated according to the cmv who standard; viral loads greater than or equal to iu/ml were denoted 'high reactivation'. viral loads of - iu/ml were denoted 'low reactivation', and undetectable loads or viral loads below iu/ml were denoted 'no reactivation' ( %) were successfully weaned, and ( %) remained still on mechanical ventilation (table ). in crude analyses, patients with cmv reactivation had both a longer duration of mechanical ventilation ( (iqr - ) vs. (iqr - ) days; p \ . ) and higher mortality ( of ( %) vs. of ( %) patients; p \ . ) compared to subjects without reactivation. table shows the results of the various cox survival regression analyses. baseline variables associated with reactivation status (at p \ . ) which changed the crude effect estimate by more than % included the apa-che iv score, use of high dose corticosteroid therapy, and peep setting. in the primary multivariable adjusted analysis, cmv reactivation was no longer statistically associated with either increased mortality or a reduced rate of successful weaning. however, simultaneous effects on both the daily rates of death and weaning did reveal a significant association with overall mortality when competing risks were accounted for (shr . , % ci . - . ). as a post hoc sensitivity analysis, we then used marginal structural modeling to assess potential residual confounding by differences in the evolution of disease severity prior to cmv reactivation between both groups, but found very similar results (table ) . changing the definitions of our primary end points to include all deaths in the icu (irrespective of mechanical ventilation status) and discharge (rather than successful weaning) also did not change these findings (table s ). furthermore, the independent association with mortality remained among subgroups of patients receiving and not receiving high dose corticosteroid therapy; shr . ( % ci . - . ) and . ( % ci . - . ), respectively (table s ). corticosteroids were mostly used for the treatment of concurrent septic shock ( of cases). figure shows the predicted mortality in a hypothetical population of ards patients in which all cmv reactivation is prevented, compared to true (observed) mortality in the study population. the population-attributable fraction of icu mortality due to cmv reactivation was estimated at % ( % ci - %) by day , which translates into an absolute mortality difference of . % ( % ci . - . ). data are presented as hazard ratios with % ci. the causespecific hazard ratio (cshr) estimates the direct effect of cmv reactivation on clinical outcome (i.e., successful weaning or death on mechanical ventilation). the subdistribution hazard ratio (shr) is a summary measure of both separate cause-specific hazards and estimates the overall risk of dying from cmv reactivation while taking into account the competing event of successful weaning a apache iv score, use of high dose corticosteroid therapy, and peep setting b time-dependent covariables included the risk, injury, failure, loss and end-stage kidney disease (rifle) score, sequential organ failure assessment (sofa) score, presence of septic shock, and use of high dose corticosteroid therapy, which were all measured on a daily basis until h prior to reactivation onset in order to explore possible causal pathways for the observed association between cmv reactivation and death, we performed a post hoc descriptive analysis of the trajectories of organ dysfunction, pulmonary and inflammatory markers over time following reactivation. in short, we compared the patients having cmv reactivation with non-exposed patients who were matched on baseline characteristics and their length of stay in icu at the onset of reactivation (table s ). in summary, the total burden of organ dysfunction was slightly higher in patients at the start of cmv reactivation compared to matched non-exposed control subjects, although individual markers of pulmonary dysfunction and inflammation were similar. more importantly, there was a clear trend towards resolution of organ dysfunction over time in nonexposed subjects that was less pronounced in patients having cmv reactivation. however, it should be emphasized that these findings should be interpreted very carefully because of the presence of informative censoring (i.e., patients who die or get discharged do not further contribute to average scores on the group level). cmv reactivation in ards patients increased the overall risk of death on the ventilator through the combined effect of subtle alterations in both the daily rates of death and successful weaning. after accounting for multiple sources of confounding, the absolute mortality that can be attributed to cmv reactivation was estimated to be . % by day following study inclusion. previous findings of excess mortality have triggered debate whether antiviral prophylaxis should be used [ , ] . however, a greater understanding of pathophysiology and clinical risk factors is necessary to select the optimal target population for such strategies. in our study, reactivation rates were % in ards patients overall and % among those with concurrent septic shock. the latter finding might be explained by the increased severity and duration of immune suppression that may be observed in patients with septic shock, including a pronounced depletion of t cells [ , ] . indeed, a recent study investigating the potential use of antiviral prophylaxis based on the screening of ards patients for cmv seroprevalence found that such a strategy is unlikely to be beneficial overall, but suggested a possible benefit in a post hoc subgroup of patients with septic shock [ ] . as the proportion of patients with cmv reactivation increased in time, altering the minimal length of stay in the icu as a criterion may also improve the selection of a high-risk target population. until then, a pre-emptive treatment strategy (by which patients would be screened for cmv and treated only if reactivation occurs) seems more attractive because the number of patients exposed to the toxicity of (val)ganciclovir would be reduced by %. however, the effects of pre-emptive compared to prophylactic treatment on relevant patient outcomes are most likely lower, as treatment is initiated only after reactivation has already begun. intervention trials comparing prophylaxis, pre-emptive treatment, and wait-andsee strategies are necessary before any evidence-based recommendations regarding the clinical management of cmv reactivation in critically ill patients with ards can be made. our study has several strengths. first, observations were nested within a large prospective data collection initiative that included consecutive patients, thereby minimizing selection bias [ ] . all ards events were diagnosed by dedicated trained observers, which minimizes information bias. moreover, we used a highly sensitive method of quantitative real-time pcr for cmv detection. most importantly, we used advanced methodologies to account for both competing risks and timedependent information in an attempt to produce unbiased estimates of the independent association between cmv reactivation and clinical outcome. this methodological approach was mainly necessary because of two reasons. first, cox regression analysis requires that censoring of survival time must be non-informative, but in our study this was clearly not the case since ards patients who are weaned and discharged from the icu alive are in a better health state than those who remain on the ventilator beyond that time point [ , ] . furthermore, when icu mortality is the event of interest, then discharge must be regarded as a competing event as it precludes this outcome from being observed [ ] . the use of the subdistribution hazard model provides a general solution to this informative censoring. second, the median time to cmv reactivation in our cohort was . (iqr - ) days. if ignored, such delays may cause distortion (termed immortal time bias) as nonexposed time observed before the onset of reactivation will be wrongfully attributed to the exposed time at risk, resulting in underestimation of effects associated with cmv reactivation [ , ] . time-dependent fitting of cmv reactivation status in our regression models resolved this issue. our study also has several limitations. first, even the use of advanced methodology cannot rule out the possibility of unmeasured confounding in an observational study. therefore, it remains somewhat uncertain whether the excess mortality that we observed can be fully attributed to cmv reactivation, or whether other unknown factors-including other viral reactivations [ , ]-may also be involved. second, the principle of multivariable analysis to adjust for confounders is to statistically 'force' exposed and non-exposed patients to be similar in all aspects of disease aside from their reactivation status. however, in a dynamic icu setting, during which critically ill patients continuously deteriorate and improve over time, it is very difficult to verify whether such adjustment was successful. we performed marginal structural modeling as a sensitivity analysis to assess the possible impact of variations in the evolution of disease severity between patients on our effect estimates, yet found very similar results as in our primary analysis. third, we measured systemic cmv reactivation in plasma but did not collect information about concurrent viral loads in the lungs. this study, therefore, provides no insight into either the prevalence or relevance of pulmonary cmv reactivations. of note, previous studies have shown that pulmonary reactivation may occur without the concurrent viremia [ , , ] . furthermore, we focused exclusively on the occurrence of reactivation while patients were on mechanical ventilation (primary analysis) or in the icu (sensitivity analysis), as we considered these to be the most relevant time windows to potentially treat or prevent cmv reactivation in the icu. however, because of this deliberate focus we cannot provide information about possible episodes of reactivation that may have occurred later. likewise we did not investigate the occurrence of reactivations after day in the icu. thus, this study only provides insight into the short-term effects of systemic cmv reactivation in ards patients in settings in which screening or antiviral prophylaxis is not part of routine clinical practice. in conclusion, systemic reactivation of cmv in immunocompetent ards patients is common and independently associated with death in the icu. these findings support the need for future studies to better predict cmv reactivation as well as to evaluate the efficacy of treatment strategies directed against cmv reactivation in these patients. human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients virological and immunological features of active cytomegalovirus infection in nonimmunosuppressed patients in a surgical and trauma intensive care unit looking for biological factors to predict the risk of active cytomegalovirus infection in nonimmunosuppressed critically ill patients cytomegalovirus seroprevalence as a risk factor for poor outcome in acute respiratory distress syndrome pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice a contributive result of openlung biopsy improves survival in acute respiratory distress syndrome patients cytomegalovirus reactivation in critically ill patients with acute respiratory distress syndrome interobserver agreement of centers for disease control and prevention criteria for classifying infections in critically ill patients the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination diagnosing herpesvirus infections by real-time amplification and rapid culture a proportional hazards model for the subdistribution of a competing risk attributable mortality due to nosocomial infections. a simple and useful application of multistate models use of multistate models to assess prolongation of intensive care unit stay due to nosocomial infection the time-dependent bias and its effect on extra length of stay due to nosocomial infection marginal structural models and causal inference in epidemiology attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis treating hsv and cmv reactivations in critically ill patients who are not immunocompromised: pro treating hsv and cmv reactivations in critically ill patients who are not immunocompromised: con sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy transient cd -memory contraction: a potential contributor to latent cytomegalovirus reactivation adjusting for time-varying confounding in the subdistribution analysis of a competing risk modeling the effect of time-dependent exposure on intensive care unit mortality immortal time bias in critical care research: application of timevarying cox regression for observational cohort studies effectiveness of inhaled corticosteroids in chronic obstructive pulmonary disease: immortal time bias in observational studies coreactivation of human herpesvirus and cytomegalovirus is associated with worse clinical outcome in critically ill adults immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients detection of herpesvirus ebv dna in the lower respiratory tract of icu patients: a marker of infection of the lower respiratory tract? acknowledgments we thank huberta dekker (department of medical microbiology, university medical center utrecht, the netherlands) for her logistical support in this project, and the participating icus and research nurses of the two medical centers for their help in data acquisition. this work was supported by the center for translational molecular medicine (http://www.ctmm.nl), project mars (grant i- ). jk received a personal fee from becton-dickinson. the sponsor did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.the mars consortium also includes the following per- key: cord- -dj bxhwb authors: kao, kuo-chin; hu, han-chung; chang, chih-hao; hung, chen-yiu; chiu, li-chung; li, shih-hong; lin, shih-wei; chuang, li-pang; wang, chih-wei; li, li-fu; chen, ning-hung; yang, cheng-ta; huang, chung-chi; tsai, ying-huang title: diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: dj bxhwb introduction: diffuse alveolar damage (dad) is the pathological hallmark of acute respiratory distress syndrome (ards), however, the presence of dad in the clinical criteria of ards patients by berlin definition is little known. this study is designed to investigate the role of dad in ards patients who underwent open lung biopsy. methods: we retrospectively reviewed all ards patients who met the berlin definition and underwent open lung biopsy from january to january in a referred medical center. dad is characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury. clinical data including baseline characteristics, severity of ards, clinical and pathological diagnoses, and survival outcomes were analyzed. results: a total of patients with ards were identified and open lung biopsies were performed on patients ( . %) during the study period. of these patients, the severity of ards on diagnosis was mild of . %, moderate of . % and severe of . %. the hospital mortality rate was not significant difference between the three groups ( . % vs . % vs . %, p = . ). of the clinical ards patients with open lung biopsies, . % ( / ) patients had dad according to biopsy results. the proportion of dad were . % ( / ) in mild, . % ( / ) in moderate and . % ( / ) in severe ards and there is no significant difference between the three groups (p = . ). pathological findings of dad patients had a higher hospital mortality rate than non-dad patients ( . % vs . %, p = . ). pathological findings of dad (odds ratio: . , % ci, . – . ; p = . ) and sequential organ failure assessment score on the biopsy day (odds ratio: . , % ci, . – . ; p< . ) were significantly and independently associated with hospital mortality. the baseline demographics and clinical characteristics were not significantly different between dad and non-dad patients. conclusions: the correlation of pathological findings of dad and ards diagnosed by berlin definition is modest. a pathological finding of dad in ards patients is associated with hospital mortality and there are no clinical characteristics that could identify dad patients before open lung biopsy. in the american-european consensus conference (aecc) released its definitions of acute lung injury (ali) and acute respiratory distress syndrome (ards) [ ] . several studies had challenged the aecc criteria for the diagnosis of ards because of its many limitations [ ] [ ] [ ] [ ] [ ] [ ] . to provide a more reliable definition of ards, an expert panel revisited the aecc definition and released the berlin definition of ards [ ] . however, the pathological diagnosis of ards using lung biopsy was not included in the berlin definition because of the controversial definition of the pathology and concern about surgical complications [ ] . it is essential to clarify the diagnosis of ards and to initiate effective treatments such as low tidal volume and prone positioning to improve clinical outcome [ ] [ ] [ ] . the current clinical definition of ards reflects only nonspecific functional or physiological abnormalities rather than pathological abnormality. since ards may occur with other pathologic findings, it is uncertain if the same management should be applied to all patients. the heterogeneity of patients with ards included in therapeutic trials remains a challenge when interpreting results from such trials [ ] . therefore, open lung biopsy sometimes has been performed to better define the pathology and to guide therapeutic management of selected patients with ards [ ] [ ] [ ] [ ] . ards is a form of ali characterized by severe inflammation with increasing epithelial and endothelial permeability [ ] . the pathologic hallmark of ards is diffuse alveolar damage (dad) characterized by hyaline membrane formation, lung edema, inflammation, hemorrhage and alveolar epithelial cell injury [ , ] . a post mortem study showed that % of patients who met the aecc definition of ards had typical dad findings [ ] . another study reported that of the patients diagnosed as having ards using aecc criteria, % ( / ) had dad findings at autopsy [ ] . a large retrospective study in spain revealed that among patients who met the berlin definition of ards, % had dad at autopsy [ , ] . however, autopsy results are based on results of analysis of samples from deceased patients and thus, there might be differences to results of analysis in the living. the purpose of this study was to investigate the role of dad in patients with ards defined by the berlin definition on open lung biopsy. our study was approved by the institutional review board of chang gung memorial hospital which waived the need for informed consent due to the retrospective nature of the study. chang gung memorial hospital is a tertiary care referral center with a -bed general ward, and a -bed adult icu. the hospital charts of all patients with ards who underwent open lung biopsy from january to january were reviewed. all patients who were given a discharge diagnosis code of . (according to the international classification of diseases, ninth revision, clinical modification) were reviewed for possible inclusion in this study. using the berlin definition, ards was characterized as mild if the arterial partial pressure of oxygen/inspired oxygen fraction (pao /fio ) was between and mm hg, moderate if pao /fio was between and mm hg, and severe if pao /fio was less than or equal to mm hg, in all cases using either continuous positive airway pressure (cpap) or positive end-expiratory pressure (peep) of at least cm h o [ ] . a total of , patients with ards were identified by the chart sheets and open lung biopsies were performed on patients ( . %). those patients with a pao /fio < while on cpap, or those treated with another noninvasive ventilation approach classified as as having moderate or severe ards were excluded. the ards severity was characterized at the time of diagnosis. these patients included patients previously identified using the aecc definition of ards, but reanalyzed in this study according to the berlin definition of ards [ , ] . the results of cultures from blood, sputum, transtracheal aspiration, and pleural effusion were recorded. the location for bronchoalveolar lavage (bal) sampling was decided on the basis of findings from high-resolution computed tomography (hrct) of the chest or chest x-ray (cxr), if hrct was not available. each specimen was examined for bacteria including legionella, mycoplasma pneumoniae, pneumocystis jiroveci, and mycobacteria, and for fungi and viruses (including cytomegalovirus, influenza virus, parainfluenza virus, adenovirus, herpes simplex virus, respiratory syncytial virus, and coxsackie virus). specimens were also sent for cytology and iron stain analysis. bal results were deemed positive when at the minimum one microorganism had grown to a concentration greater than colony-forming units/ml. all specimen examinations were performed within hours of open lung biopsy. open lung biopsy was indicated when ards was suspected to be noninfectious, there was no obvious risk factor, and if there was a possible indication for corticosteroid therapy based on clinical presentation with rapid progression, relative symmetric distribution of infiltrates on cxr, and predominant ground-glass attenuation on hrct of the chest. informed consent for surgical lung biopsy was obtained from each patient's family before surgery. open lung biopsy was performed in an operating room or at the bedside in the icu. the lobe of the lung biopsy was chosen based on the presence of a new or progressive lesion identified on hrct of the chest or cxr. while under general anesthesia, open lung biopsy was performed using either video-assisted thoracoscopic surgery (vats) or a -cm thoracotomy, depending on the patient's tolerance. for vats and thoracotomy, an endoscopic stapler-cutter was used to secure the pulmonary margins. to avoid the risk of transfer to the operating room, the timing of bedside open lung biopsy was considered when the given fio reached with a peep above cm h o. each tissue specimen was cultured and examined by pathologists. pathological criteria for the diagnosis of pneumonia involved severe neutrophil infiltration in the interstitium and intra-alveolar spaces, particularly around terminal bronchioles. the pathological criteria for the diagnosis of ali and dad included the presence of pulmonary inflammatory infiltrates and presence of hyaline membrane formation and at least one of the following: intra-alveolar edema, alveolar type i cell necrosis, alveolar type ii cell proliferation progressively covering the denuded alveolar-capillary membrane, interstitial proliferation of fibroblasts and myofibroblasts, or organizing interstitial fibrosis [ , , ] . our strategy for mechanical ventilation of patients with ards consisted of an initial low tidal volume of to ml/kg of predicted body weight for either volumecontrolled or pressure-controlled ventilation. ventilatory adequacy was monitored by arterial blood gas measurements, with the ventilator settings changed as needed. the peep levels were set according to a lower peep and fio strategy or at least cm h o above the lower inflection point derived from the p-v tool maneuvers of the ventilator [ ] . the plateau airway pressure was maintained below cm h o combined the peep setting and low tidal volume strategy. pulse oximeter was used to monitor oxygen saturation and the fio was adjusted to maintain spo above %. the plateau airway pressure was tried to avoid raising above cm h o. the following data were collected from the hospital chart of each patient and analyzed: age, sex, underlying diseases, acute physiology and chronic health evaluation (apache) ii score on the day of icu admission [ ] , sequential organ failure assessment (sofa) score on the day of icu admission and the day of open lung biopsy [ ] , lung injury score (lis) [ ] , pao /fio ratio, peep, tidal volume, diagnostic procedures before open lung biopsy (hrct or bal), complications related to surgery (i.e., postoperative air leak, pneumothorax, subcutaneous emphysema, bleeding, and wound infection), pathological diagnosis, hospital mortality, and therapeutic alterations. postoperative therapeutic alterations indicated that the results of open lung biopsy had led to the addition of a new therapy, or the original therapy had been stopped. immunocompromised patients were defined as follows: presence of hiv infection, recipient of solid organ transplantation, recipient of hematopoietic stem cell transplantation (hsct), recipient of chemotherapy, and recipient of long-term systemic corticosteroids for more than weeks. all statistical analyses were performed using the spss statistical package (spss for windows, spss inc., chicago, il, usa). all values are reported as means ± sd. categorical data were tested using the chi-square test (or fisher's exact test when the expected number of events was fewer than five). risk factors for hospital mortality were analyzed by univariate analysis, and the variables statistically significant (p < . ) in the univariate analysis were included in the multivariate analysis by applying multiple logistic regression based on backward elimination of data. the hosmer-lemeshow goodness-of-fit test was used for calibration when evaluating the number of observed and predicted deaths in risk groups for the entire range of death probabilities. a p value < . was considered statistically significant. from january to january , patients were admitted to our icus with a diagnosis of ards, of whom had undergone open lung biopsy, and the overall hospital mortality rate was . % (fig. ). of the screened patients, patients were excluded because the symptom onset was more than week ago and had not met berlin criteria. among the patients who met the berlin definition for ards, most patients were classified as having moderate ards (n = , . %), followed by severe ards (n = , . %), and mild ards (n = , . %). the proportions of dad were . % ( / ) in mild, . % ( / ) in moderate and . % ( / ) in severe ards and there were no significant differences among these three groups (p = . ). according to the severity on the biopsy day, the proportions of dad were % ( / ) in mild, . % ( / ) in moderate and % ( / ) in severe ards and there were no significant differences among these three groups (p = . ). figure shows the pathological findings of diffuse alveolar damage in the acute phase and organizing phase. baseline characteristics of these patients are shown in table pneumonia, with invasive fungal infection, with staphyloccus aureus, with a viral infection and with mycobacterium tuberculosis), as having an interstitial lung pattern (both patients having organizing pneumonia) and were classified as having miscellaneous infection ( patients with metastatic adenocarcinoma and with vasculitis). forty-four patients did not have dad and of these patients were classified as having infection ( patient with pneumocystis jiroveci pneumonia and cytomegalovirus pneumonia, with pneumocystis jiroveci pneumonia, with viral pneumonia, with invasive fungal infection, with bacterial pneumonia and with mycobacterium tuberculosis), patients had interstitial lung patterns ( patients with usual interstitial pneumonia, with organizing pneumonia, with nonspecific interstitial pneumonia, with desquamative interstitial pneumonia, with hypersensitive pneumonitis and with unclassified interstitial pneumonitis), and patients were classified as having miscellaneous conditions ( patients with fibrosis, with leukemic infiltration, with metastatic adenocarcinoma, with vasculitis and with lung edema). there were pneumonia patients including patients with dad and patients without dad. the hospital mortality rate was significantly higher in patients with pneumonia and dad ( / ) than in those with pneumonia without dad ( / ) ( . % vs %, p = . ). according to the results of open lung biopsy, patients had alterations to their therapy ( . %). these alterations included patients who had steroid therapy introduced, patients whose antimicrobial agent was changed, patient who had chemotherapy introduced, and patients in whom certain medications were discontinued, including withdrawal of antibiotics in viral pneumonia and metastatic carcinoma, and withdrawal of corticosteroids in bacterial pneumonia. the hospital mortality rates were . % in mild ards, . % in moderate ards, and . % in severe ards and there was no significant difference between the three groups (p = . ). table shows the demographic and clinical characteristics of survivors vs non-survivors hyaline membrane (arrow) is seen lining the alveolar ducts (hematoxylin and eosin stain, × ). b diffuse alveolar damage in the organizing phase. the interstitium is thickened with organizing connective tissue. prominent type pneumocyte hyperplasia is seen (hematoxylin and eosin stain, × ) univariate analysis was used to identify variables that have prognostic value for hospital mortality, and multivariate logistic regression analysis was used to identify variables that did not have significant prognostic value ( table ). identification of dad on pathological examination (odds ratio . , % ci . , . ; p = . ) and sofa score on the biopsy day (odds ratio . , % ci . , . ; p < . ) were significantly and independently associated with hospital mortality. regression coefficients for these variables were used to calculate a natural logarithm of the odds (logit) of the probability of death (p) as follows: demographic and clinical characteristics of patients with ards with dad vs those without dad are shown in table . there were no clinical characteristics that could discriminate patients with dad from those without dad before open lung biopsy. patients with ards and a pathologic diagnosis of dad had a higher mortality rate than those without dad ( . % vs . %, p = . ). in our study, dad was found in . % of patients who had ards diagnosed using the berlin definition and who underwent open lung biopsy. the overall hospital mortality rate was . %. dad and sofa scores obtained by pathological examination on biopsy day were significantly associated with hospital mortality. demographic and clinical characteristics were not significantly different between patients with and without dad patients before open lung biopsy. the typical pathological finding of ards is dad but the correlation between clinical criteria for ards and dad is not well-understood [ , , , ] . in an autopsy series, of the patients who met the aecc criteria for ards, % ( / ) were found to have dad identified on pathological examination [ ] . in another study based on autopsy data, dad was documented in % ( / ) of patients who met the aecc criteria for ards [ ] [ ] . they found that . % ( / ) of patients had dad. in another study, papazian and coworkers prospectively studied patients with ards who fulfilled aecc criteria and who underwent open lung biopsy; % were identified to have dad on pathological examination [ ] . in patel's study of open lung biopsy in patients with ards, % ( / ) of patients had dad on pathologic examination [ ] . in our previous study, dad was found in . % ( / ) of patients with early-stage ards, who were receiving open lung biopsy [ ] . a recent study in non-resolving ards showed the dad was found in . % ( / ) patients who had open lung biopsy [ ] . in the present study of open lung biopsy, dad was noted in . % ( / ) of patients with ards in this study, we demonstrated that a dad identified on pathological examination correlated with increased mortality in patients with ards identified using the berlin definition. in a study by parambil et al., the hospital mortality rate in patients with dad was % in patients with ards compared to % in patients without ards [ ] . in a study of patients with ards (papazian et al.) , the factors predicting survival included female gender, organ system failure score on the day of biopsy, and biopsy result leading to the addition of a new drug [ ] . another open lung biopsy study was performed in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates to determine factors independently associated with survival [ ] . they found that the charlson agecomorbidity index score, number of organ dysfunctions, and the pao /fio ratio on the day of biopsy were associated with survival. a study in patients with non-resolving ards, who had open lung biopsy showed that the icu mortality rate was higher in patients with dad than in those without dad ( % vs %), but this was not significantly different [ ] . the present study demonstrated that patients with dad had significantly increased hospital mortality compared to those without dad ( . % vs . %, p = . ). the poor survival outcome in patients with dad may imply more severe lung injury in patients with ards with vs without dad. however, no clinical characteristic differentiated between patients with and without dad before open lung biopsy (table ). our study highlights the heterogeneity of patients with ards and discrepancy between the clinical and pathological definitions of ards. a distinct phenotype of patients with ards characterized by dad needs to be further addressed due to it having worse outcomes. a meta-analysis of open lung biopsy in patients with ards summarized that the surgical complication rate was %; the most common complication was prolonged air leak, but mortality resulting from surgery was infrequent [ ] . meanwhile, open lung biopsy could offer a specific diagnosis in % of patients and altered management in % of patients. our study revealed that the surgical complication rate was . % and management alteration rate was . % in these selected patients with ards. the survival advantage of open lung biopsy in ards is still not approved due to lack of a randomized controlled trial. practically, it is important to assess the balance between the potential risk of surgical complications and diagnosis or treatment benefit in deciding to perform open lung biopsy. there were several limitations of our study. first, it is a retrospective study in one referred medical center, which may limit the generalization to all other icus. given the patients included retrospectively from the charts, some patients with ards may have been missed. in addition, the icd- diagnosis code . excludes ards associated with trauma and surgery and includes all type of hypoxemic acute respiratory failure. some patients with trauma-associated or surgery-associated ards may be missed in our study. however, it is one of the largest studies in patients with ards having open lung biopsy. second, the decision to perform open lung biopsy was highly selective and only . % of patients with ards were referred for biopsy in this study. the results, therefore, are unlikely to be representative of all patients with ards. however, the potential for selection bias for patients with ards may be lower with open lung biopsy than with autopsy as the patients are alive. third, only % of patients had bal before open lung biopsy. some specific diagnoses may have been missed because their recognition depended on the availability of laboratory facilities. fourth, the lung specimens were assessed by one pulmonary pathologist only and so the possibility of individual interpretation bias should be considered. finally, there was no standard treatment for patients with some specific diagnoses, such as interstitial lung disease, after the biopsy result became available. specific treatments such as corticosteroid therapy might have influenced the survival outcome in these patients. this retrospective study demonstrated that . % of selected patients with ards based on the berlin definition and who underwent open lung biopsy were identified as having dad. as a result of the moderate agreement between clinical and pathological diagnosis of ards, open lung biopsy may be considered in some patients to exclude or to clarify the diagnosis. according to the results of pathological examination, patients with dad had poorer outcomes than patients without dad. however, there was no clinical characteristic that discriminated between patients with and without dad before open lung biopsy. in future studies of ards, the clinical therapeutic trial may focus on this subgroup owing to the high mortality among these patients. in addition to open lung biopsy, some non-invasive modalities such as serum biomarkers and hrct may be used to identify this distinct type of patient with ards. this retrospective study demonstrated that . % of selected patients with ards based on berlin definition, and who underwent open lung biopsy were found to have dad. the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination acute lung injury and acute respiratory distress syndrome current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial an early peep/fio trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome acute respiratory distress syndrome years later: time to revisit its definition are we able to optimize the definition and diagnosis of severe acute respiratory distress syndrome? acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material year in review in intensive care medicine : iii. noninvasive ventilation, monitoring and patient-ventilator interactions, acute respiratory distress syndrome, sedation, paediatrics and miscellanea the acute respiratory distress syndrome network. ventilation with lower tidal volumes for acute lung injury and the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome clinical trials in patients with the acute respiratory distress syndrome: burn after reading open-lung biopsy in patients with acute respiratory distress syndrome the role of open-lung biopsy in ards open lung biopsy in early-stage acute respiratory distress syndrome a contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients the acute respiratory distress syndrome diffuse alveolar damage-the role of oxygen, shock, and related factors: a review pulmonary pathology of acute respiratory distress syndrome comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings ards: a clinicopathological confrontation comparison of the berlin definition for the acute respiratory distress syndrome with autopsy chronology of histological lesions in acute respiratory distress syndrome with diff use alveolar damage: a prospective cohort study of clinical autopsies the utility of surgical lung biopsy in cancer patients with acute respiratory distress syndrome ards and diffuse alveolar damage: a pathologist's perspective effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure an expanded definition of adult respiratory distress syndrome causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy open lung biopsy in nonresolving ards frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management usefulness of open lung biopsy in mechanically ventilated patients with undiagnosed diffuse pulmonary infiltrates: influence of comorbidities and organ dysfunction surgical lung biopsy in adult respiratory distress syndrome: a meta-analysis this study was supported by grant cmrpg d from chang gung memorial hospital. the authors would like to thank chiu-hua wang, shin-wen bai and ya-hui hsu for data management and appreciate the patients and staff of icus at chang gung memorial hospital. patients with dad identified on pathological examination had significantly higher hospital mortality than patients without dad, and there was no clinical characteristic that differentiated between patients with and without dad before open lung biopsy. in future studies, the clinical therapeutic trial may focus on patients with ards and dad and investigate some non-invasive modalities to identify this subgroup of patients with ards. on behalf of all authors, the corresponding author states that there is no competing interest.authors' contributions kck took responsibility for the accuracy of the data analysis and drafting the manuscript. hch, chc, cyh, lcc, shl, swl, lpc were responsible for data collection. lfl, nhc and cty were responsible for primary data analysis. cww reviewed the pathological specimens. cch and yht were responsible for interpretation of the results. all authors contributed to completing the manuscript and have approved the final version.submit your next manuscript to biomed central and take full advantage of: key: cord- -uh q we authors: zhang, yi; sun, honglei; fan, lihong; ma, yuan; sun, yipeng; pu, juan; yang, jun; qiao, jian; ma, guangpeng; liu, jinhua title: acute respiratory distress syndrome induced by a swine h n variant in mice date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: uh q we background: acute respiratory distress syndrome (ards) induced by pandemic h n influenza virus has been widely reported and was considered the main cause of death in critically ill patients with h n infection. however, no animal model has been developed for ards caused by infection with h n virus. here, we present a mouse model of ards induced by h n virus. methodology principal findings: mice were inoculated with a/swine/shandong/ / (sd/ ), which was a h n influenza variant with a g d mutation in the hemagglutinin. clinical symptoms were recorded every day. lung injury was assessed by lung water content and histopathological observation. arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post-inoculation. mice infected with sd/ virus showed typical ards symptoms characterized by % lethality on days – post-inoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. conclusions/significance: these results suggested that we successfully established an ards mouse model induced by a virulent h n variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ards caused by h n virus. a novel influenza a (h n ) virus of swine origin emerged among humans in mexico during the spring of and rapidly spread worldwide [ ] . the pandemic prompted the world health organization (who) to raise the alert level to the highest rating of six, the pandemic phase, within months [ ] . in august , who officially declared that the disease was in the post-pandemic period [ ] ; however, it is still circulating among humans, together with seasonal viruses. although most influenza cases caused by h n virus infection typically display mild upper respiratory tract syndrome, some cases progress to severe pneumonia and acute respiratory distress syndrome (ards) [ , ] . many studies have shown that ards caused by h n virus results in . - % mortality [ , , , ] , which was regarded as the major cause of death by h n virus infection [ ] . ards is the result of acute injury to lung tissue, commonly resulting from sepsis, trauma, and severe pulmonary infections [ ] . infectious factors, most of which are viruses, have become one of the most important causes of ards in humans [ , , ] . clinical cases and established animal models have revealed that the pathogenesis and pathological features of ards induced by different viral pathogens are distinct [ , ] . however, knowledge of the pathogenesis of h n virus, especially ards induced by h n virus, is still limited and hinders therapeutic strategies. therefore, it is necessary to evaluate the pathogenesis of ards caused by h n virus infection in an appropriate animal model to assess potential therapies. mice are a good model for evaluating the pathogenesis and antiviral therapy of influenza pneumonia, due to the general fidelity of the illness in mice to the human disease [ ] . moreover, a mouse model of ards caused by highly pathogenic h n avian influenza virus infection has been well established [ ] . the typical h n virus, such as a/california/ / (ca/ ), can efficiently replicate in mouse lungs without prior host adaptation. however, it only causes moderate lung lesions and no mortality, even when inoculated at a high dose of pfu [ , ] . thus, such typical h n viruses may not be able to induce ards in a mouse model. in the present study, we used a virulent variant h n virus, which was isolated from a pig and possessed a virulenceassociated ha-d g mutation, to establish an ards mouse model. the model established here provides a useful tool to explore the mechanism of ards, as well as screening and therapeutic options. six-week-old female mice were infected intranasally (i.n.) with . pfu sd/ virus. some of the infected mice showed signs of illness, such as altered gait, inactivity, ruffled fur, and anorexia on day post-infection (p.i.). from day p.i., the body weight of most mice significantly decreased ( figure s ). by day p.i., most mice presented with more severe clinical signs of respiratory disease, including labored respiration and respiratory distress, and most mice lost almost % of their initial body weight. on day p.i., most mice were nearly unable to respond to exterior stimuli, and acute respiratory rates and labored respiration were observed (video s , and video s for control). approximately % of mice died between days and p.i. gross observation of infected mice showed that the lungs were highly edematous, with profuse areas of hemorrhage and consolidation. no obvious gross lesions were observed in the kidneys, liver, spleen or brain of infected mice. mice were infected i.n. with . pfu sd/ virus, and three mice were euthanized on days , , , , and p.i., and the virus titers in viscera were determined. as shown in figure a , the virus titer in the lung gradually increased between days and p.i., and reached a peak on day p.i. the virus titers in the lung gradually decreased from day p.i., and only one of three mice possessed detectable virus in the lungs on day p.i. no viruses were detected in other organs, including heart, spleen, liver, kidneys, blood and brain, at the indicated time. these results indicate that sd/ virus could replicate efficiently in mouse lung but did not cause systemic infection. as shown in figure b , the effect of sd/ viral infection on lung wet:dry weight ratio did not change significantly within days p.i. however, a dramatic increase was observed from day p.i., and reached a peak on day p.i., which was nearly twice that observed in control group lungs (p, . ). the change in lung wet weight:body weight ratio was similar to the change in lung wet:dry weight ratio ( figure c ). the results indicated that the sd/ virus could induce acute lung edema in mice. kinetic observation of lung lesions of sd/ -virus-infected mice is shown in figure . on day p.i., lung lesions were characterized by dropout of mucous epithelium and inflammatory cells adhering to the bronchiolar surface ( figure c , d). on day p.i., severe edema could be seen around blood vessels ( figure e ); interstitial pneumonia was also observed that showed interstitial edema and thickening of the alveolar walls; and the alveolar lumen was flooded with detached alveolar cells, erythrocytes, and inflammatory cells ( figure e , f). on day p.i., the virus caused more severe interstitial pneumonia and peribronchiolitis, characterized by edema and extensive of lymphocytes, neutrophils and plasma cells around the area of bronchiolitis ( figure g , h). lesions in the lungs of infected mice were still severe on day p.i., with extensive alveolar collapse, and remaining alveoli were filled with fibrin, desquamated alveolar cells, and inflammatory cells. lymphocytes and alveolar macrophages were the predominant inflammatory cells observed at high magnification ( figure j ). masson's stain revealed that alveolar walls and spaces were filled with collagen fibers ( figure a , b), indicating that proliferative fibroblastic lesions may develop. in comparison, lungs from mockinfected control mice had no apparent histological changes ( mice were inoculated i.n. with . pfu sd/ viruses; tissues were collected at indicated times p.i. and viruses were titrated in mdck cells. body weight, lung wet and dry weight were determined and recorded. the lung wet weight:body weight ratio and lung wet:dry weight ratio were calculated and used as an indicator of lung edema. *p, . , **p, . , ***p, . , comparison between ratios obtained from the virusinfected and control groups. bars represent means sd of data from three mice. doi: . /journal.pone. .g immunohistochemistry revealed viral antigens in the epithelial cells of the bronchioles ( figure d ), terminal bronchioles, and alveolar epithelial cells ( figure e ). these data indicated that sd/ virus could infect the epithelia of the lower airway and cause viral pneumonia in mice. as shown in table , virus-infected mice showed a slightly decreased partial pressure of arterial oxygen (pa o ), saturation of arterial oxygen (sa o ), and slightly increased partial pressure of arterial carbon dioxide (pa co ) from days to p.i. most infected mice presented with severe clinical signs of respiratory distress on day p.i., and blood gas analysis also showed that pa o and sa o dramatically decreased compared with the controls (p, . ). these results suggested acute respiratory dysfunction and severe hypoxemia in virus-infected mice. the number of leukocytes in balf from sd/ -infected mice showed an increase from day p.i. ( table ). the balf of virusinfected mice on day p.i contained . cells/ml and was significantly different from the . cells/ml observed for pbsinoculated mice (p, . ). these data indicate a dramatic increase in inflammatory cells in the lungs of sd/ -infected mice. to quantify the immune cell subpopulations responding to viral infection, we next determined cell differential counts in the infected lungs by wright staining. compared with pbs-inoculated animals, mice infected with sd/ virus exhibited an increase of neutrophils from days p.i., and the peak was -fold greater than that of the control group on day p.i. leukopenia was detected on day p.i., and was statistically significant on day p.i. (p, . ); the lowest value appeared on day p.i. (p, . ). furthermore, differential blood counts revealed that the number of lymphocytes sharply decreased in infected mice. the lowest number of lymphocytes observed occurred on day p.i. (figure b ), which dropped to , % of the control group number (p, . ). to determine the cytokine responses that occur after sd/ virus infection, we measured the levels of five cytokines and chemokines in lungs of infected mice on days , , , and p.i. as shown in figure , all five were significantly different between virus-infected and control mice. interleukin (il)- and il- in the virus-infected mice reached peak levels as early as day p.i. and were significantly higher than those of the control group (p, . ). interferon (ifn)-c, monocyte chemotactic protein (mcp)- , and tumor necrosis factor (tnf) dramatically increased in mouse lungs on days - p.i. (p, . ), consistent with the appearance of pulmonary lesions. these results showed that infection with sd/ viruses resulted in elevated amounts of proinflammatory chemokines and cytokines in the lungs of mice. in the spring of , a novel influenza a(h n ) virus rapidly spread worldwide, resulting in the first influenza pandemic of the st century [ ] . critically ill cases caused by h n virus retrospectively showed that most had progressed or died due to ards [ , ] . however, the pathogenesis and therapeutic intervention of ards caused by h n infection have still not been elucidated. animal models of disease are important for characterizing pathogenesis and developing the preclinical evidence for revised approaches to ventilating patients with ards [ ] . here, we present a mouse model for the study of ards induced by sd/ virus, a virulent h n variant. previous studies have indicated that typical h n viruses such as ca/ bind only to a- , -linked sialic acid (sa) receptor [ ] , but only the a- , -linked sa receptor is found in the mouse respiratory tract [ ] . therefore, such a typical h n virus may not be able to induce ards in mice. in fact, we used ca/ virus to induce ards in mice; however, animals inoculated with a high dose of ca/ virus ( . pfu) only showed moderate respiratory symptoms, and no lethality was observed (unpublished data). it has been shown that h n virus possessing a d g mutation in hemagglutinin (ha) could increase the pathogenicity in mice [ , ] and binding to the a- , sa receptor [ ] . moreover, clinical data indicate that such variants are only associated with severe h n human infection [ ] . therefore, we suggest that the variant possessing the d g mutation in ha can induce ards in a mouse model. the virus used in the present study was isolated from swine in , and sequence analysis revealed that all the eight genes of the isolate had a close relationship with the h n influenza virus circulating in humans. notably, the swine isolate, sd/ , had a d g mutation in ha. compared with ca/ virus (ld . pfu), sd/ showed significantly increased virulence in mice, with an ld of . pfu, which was nearly identical to that of the mouse-adapted strain a/hong kong/ md/ (ld = . pfu) [ , ] . mice infected i.n. with . pfu sd/ virus showed obvious respiratory symptoms, including visually prominent signs of respiratory distress and abdominal respiration, with approximately % mortality between days and p.i. the lungs of virus-infected mice were highly edematous, which was also demonstrated by dramatically increased lung wet:dry weight ratio. pathological changes presented a progressive pattern, typically diffuse alveolar damage, interstitial and alveolar edema, neutrophil and macrophage-dominant inflammatory cellular infiltration, and areas of hemorrhage and necrotizing bronchiolitis. arterial blood gas saturation is a key parameter of ards in humans [ ] . in the present mouse model, pao and sao of infected mice were significantly lower than in the control group from day p.i., especially on day p.i., where these parameters sharply decreased, and most virus-infected mice began to die. these changes in arterial blood gas demonstrated that most infected mice developed severe hypoxemia consistent with of the appearance of clinical signs and lung lesions of ards. previous studies showed that mice infected with typical h n virus only exhibited mild interstitial inflammatory infiltration and limited alveolitis [ , ] , whereas severe lung damage was found in the sd/ -infected mice, including severe edema around the blood vessels and bronchiolitis, and extensive inflammatory accumulation from to days p.i. at days p.i., the surviving mice developed an irreversible fibrosis involving collagen deposition in alveolar walls and spaces, which was similar to that observed in human ards patients with h n infection [ ] . our histopathological results were consistent with ards induced by other influenza viruses. mice infected with mouse-adapted virus of the a/puerto rico/ / (h n ), or high pathogenic h n virus also showed a progressive series of pathological changes from interstitial pneumonia to diffuse alveolar damage [ , ] . however, in contrast to highly pathogenic h n virus, mice infected with sd/ virus did not show viral spread to extrapulmonary organs. immunohistochemical examination revealed the presence of viral antigens in the bronchioles, terminal bronchiolar epithelium, and alveolar epithelial cells. perhaps sd/ virus infection of the alveoli, particularly type ii pneumocytes, rather than bronchioles, is a key to the development of ards. type ii pneumocytes are responsible for the production and secretion of surfactant to lower the surface tension of water and allow membrane separation, and insufficient pulmonary surfactant in the alveoli may result in alveolar collapse [ , ] . the pandemic h n and high pathogenic h n viruses preferentially infect type ii pneumocytes and alveolar macrophage in mice [ , ] . alveolar macrophages may play a critical role in disease pathogenesis, not through production of infectious virus but rather through the upregulation of proinflammatory cytokines that may further damage alveolar pneumocytes [ ] . these phenomena suggest that viral cell tropism may determine the processes of ards. pulmonary aberrant immune response is considered a significant feature of ards induced by h n virus [ , ] . in the present mouse model, the number of leukocytes observed in the balf of virus-infected mice significantly increased compared with the control mice on day p.i. different counts in balf showed that the proportion of neutrophils dramatically increased. these innate immune cells were capable of reducing the virus load in the lung [ ] ; however, they could cause lung injury through direct or indirect mechanisms. neutrophil oxidants and proteases can cause direct injury of cells in the alveolar-capillary membrane [ ] . neutrophils and macrophages can secrete copious amounts of chemokines and cytokines that can recruit more immune cells into lung tissues, and produce a ''cytokine storm'', one of the most important factors in the production of ards [ ] . a retrospective cohort study of h n patients found that higher levels of proinflammatory cytokines and chemokines in plasma were observed in the ards-death group compared with the survived-without-ards or the mild-disease groups [ ] . another study in critically ill patients with ards caused by h n virus infection has shown that the hallmarks of disease severity were elevated levels of il- , il- , il- and tnf-a [ ] . we examined the levels of five cytokines and chemokines in infected mouse lungs and found significant differences between the virus-infected and mock groups. it has proved that high levels of il- were able to mediate acute lung injury [ ] , and had a negative correlation with the pa o :fi o ratio in severely affected patients with h n virus infection [ ] . our data showed sd/ viral infection induced high levels of il- in mouse lung, which may also play an important role in the course of ards. hagau etc. found the levels of tnf-a increased significantly in the h n -related ards patients [ ] . in present study, tnf levels also dramatically increased in the lungs of virus-infected mice, and were consistent with the clinical symptoms and reached peak levels when mice began to die. in addition, high levels of il- , ifn-c and mcp- were also present in the virus-infected mouse lungs, similar to observations found in severely affected humans with h n infection [ ] . in summary, we successfully established an ards mouse model induced by a virulent h n variant, which demonstrated key human ards clinical and pathological features, such as respiratory distress, low pa o , exudative, proliferative and fibrotic lung, and high levels of inflammatory cells and cytokines. the mouse model may contribute to the study of the pathogenesis and therapy of ards induced by h n virus. to determine ld of sd/ virus, eight -week-old female balb/c mice per group were inoculated i.n. with - pfu ( ml) viruses and monitored for days. the value of mld was calculated using the spearman-karber method and expressed by pfu per mld [ ] . we evaluated the pathogenicity of the virus in mice and found that it could efficiently replicate in the lungs of mice with high lethality ( . pfu per mld ). to determine the optimal dose of inoculation, mice in each group were infected i.n. with . , . or . pfu viruses, and the signs, body weight, and mortality were monitored daily for each group for days. pilot experiments indicated that a dose of . pfu was optimal, because the course of the disease was prolonged and the mice presented with obvious signs of respiratory illness. balb/c mice were lightly anesthetized and inoculated i.n. with ml . pfu sd/ virus in pbs. mock-infected animals were inoculated i.n. with ml pbs. at the indicated time, infected mice were sacrificed, and the parameters that present the course of the disease were determined. twenty mice ( infected with sd/ virus and inoculated with pbs) were used to investigate clinical signs and mortality for days. three mice were euthanized on days , , , , and p.i. and their organs were collected. the collected tissues were weighed, and % homogenates were prepared in cold pbs. the homogenates were centrifuged at rpm for min to remove cell debris, and then the supernatants were -fold serially diluted for viral titer determination by plaque assay in mdck cells. virus titers were expressed as mean log pfu/g standard deviation (sd). three mice were euthanized on days , , , , and p.i., and the lungs were removed and weighed and then desiccated in an oven at uc for h. the lung wet weight:body weight ratio and lung wet:dry weight ratio were calculated and used as an indicator of lung edema, as previously described [ ] . three mice were euthanized on days , , and p.i. the lungs were fixed in % buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. lungs on day p.i. were also stained with masson's trichrome. lung tissue sections taken on day p.i. were stained for influenza a virus antigens. an anti-influenza nucleoprotein monoclonal antibody (aa h; abcam, hong kong) was used to identify influenza a virus nucleoprotein in sections. secondary antibody (millipore, billerica, ma, usa) against the primary antibody was labeled with horseradish peroxidase, and the color reaction was developed with a horseradish peroxidase reaction kit (diaminobenzidine-tetrahydrochloride; sigma, st. louis, mo, usa). blood gas analysis was performed as previously described [ , ] . three mice were anesthetized with zoletil (tiletamine-zolazepam; virbac; mg/g) on days , , , and p.i. arterial blood samples were withdrawn into a heparinized syringe by percutaneous left ventricular sampling of lightly anesthetized mice that were spontaneously breathing room air. blood gas analysis was immediately performed using a vetstat electrolyte and blood gas analyzer (idexx laboratories, westbrook, ma, usa). leukocyte counts in balf were performed as previously described [ , ] . briefly, three mice were euthanized on days , , and p.i., and the lungs were lavaged twice in situ with the chest cavity opened by midline incision with a total volume of . ml saline ( uc) inserted through an endotracheal tube. the rate of recovery of balf was not less than % for all animals tested. after the amount of fluid recovered was recorded, an aliquot of balf was diluted : with . % crystal violet and . % acetic acid for leukocyte staining and erythrocyte hemolysis. the number of leukocytes in the balf was counted with a hemacytometer under a microscope. for differential counts, the balf samples from each mouse were stained with wright stain, and the numbers of monocytes, neutrophil and lymphocytes were determined, on the basis of morphologic criteria, under a light microscope, with evaluation of at least cells per slide. all slides were counted twice by different observers blinded to the status of the animal. heparinized blood samples were collected on days , , and p.i. the total numbers of leukocytes and differential blood counts for three individual mice were analyzed using an automated hematology analyzer. il- , il- , tnf, ifn-c and mcp- levels were determined in lung homogenates using a cytometric bead array technique (bd cytometric bead array mouse inflammation kit; bd bioscience, san diego, ca, usa) according to the manufacturer's instructions. briefly, ml mouse inflammation capture bead suspension and ml pe detection reagent were added to an equal amount of sample standard dilution and incubated for h at room temperature in the dark. subsequently, samples were washed by adding ml wash buffer and centrifugation at g at room temperature for min. supernatants were discarded and ml wash buffer was added. samples were analyzed on a bd facsarray bioanalyzer (bd bioscience) according to the manufacturer's instructions. standard curves were prepared similar to the method above. data were analyzed using bd cba software (bd bioscience). finally, the chemokine or cytokine levels were recorded as pg/ml homogenate. data were analyzed by two-way analysis of variance using graphpad prism version . (graphpad software, san diego, ca, usa). when a significant effect was observed, pairwise comparisons were performed using the bonferroni post-hoc test. all data are reported as mean sd. influenza ( ) clinical aspects of pandemic influenza a (h n ) virus infection world now at the start of influenza pandemic world health organization. h n now in the post-pandemic period pandemic influenza a (h n ) in argentina: a study of patients on mechanical ventilation delayed clearance of viral load and marked cytokine activation in severe cases of pandemic h n influenza virus infection critical care services and h n influenza in australia and new zealand critically ill patients with influenza a (h n ) infection in canada extracorporeal membrane oxygenation for severe influenza a (h n ) acute respiratory distress syndrome: a prospective observational comparative study update: swine influenza a (h n ) infections-california and texas acute respiratory distress syndrome clinical issues and research in respiratory failure from severe acute respiratory syndrome clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome acute respiratory distress syndrome induced by avian influenza a (h n ) virus in mice innate immunity to pulmonary infection john wiley & sons, ltd influenza a strain-dependent pathogenesis in fatal h n and h n subtype infections of mice animal models for the study of influenza pathogenesis and therapy transmission and pathogenesis of swine-origin a (h n ) influenza viruses in ferrets and mice variations in the hemagglutinin of the h n pandemic virus: potential for strains with altered virulence phenotype? acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells d g mutation in hemagglutinin of pandemic influenza h n ( ) virus enhances virulence in mice a single-amino-acid substitution in the ha protein changes the replication and pathogenicity of the pandemic a (h n ) influenza viruses in vitro and in vivo virulence-associated substitution d g in the hemagglutinin of pandemic influenza a (h n ) virus affects receptor binding observed association between the ha mutation d g in the pandemic influenza a(h n ) virus and severe clinical outcome markers for predicting the development of acute respiratory distress syndrome radiological prognostic factors in patients with pandemic h n (ph n ) infection requiring hospital admission serial histopathological examination of the lungs of mice infected with influenza a virus pr strain pulmonary surfactant in health and human lung diseases: state of the art serial changes in surfactant-associated proteins in lung and serum before and after onset of ards genomic analysis of increased host immune and cell death responses induced by influenza virus induction of proinflammatory cytokines in human macrophages by influenza a (h n ) viruses: a mechanism for the unusual severity of human disease? lung pathology in fatal novel human influenza a (h n ) infection pathogenicity of influenza viruses with genes from the pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice pathogenesis of the adult respiratory distress syndrome. evidence of oxidant activity in bronchoalveolar lavage fluid preparing for the next pandemic clinical aspects and cytokine response in severe h n influenza a virus infection identification of oxidative stress and toll-like receptor signaling as a key pathway of acute lung injury th and th hypercytokinemia as early host response signature in severe pandemic influenza trimmed spearman-karber method for estimating median lethal concentrations in toxicity bioassays hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharideinduced lung injury the pulmonary circulation of homozygous or heterozygous enos-null mice is hyperresponsive to mild hypoxia respiratory reovirus /l induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on t lymphocytes role of p mitogen-activated protein kinase in a murine model of pulmonary inflammation the authors thank dr. yanxin hu and dr. deping han for technical assistance in histopathologic observation. key: cord- - zfz ns authors: zhang, xianming; wu, weiliang; zhu, yongcheng; jiang, ying; du, juan; chen, rongchang title: abdominal muscle activity during mechanical ventilation increases lung injury in severe acute respiratory distress syndrome date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: zfz ns objective: it has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ards), but the precise mechanism is not clear. the purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ards. methods: eighteen male beagles were studied under mechanical ventilation with anesthesia. severe ards was induced by repetitive oleic acid infusion. after lung injury, beagles were randomly assigned into spontaneous breathing group (bipap(sb)) and abdominal muscle paralysis group (bipap(ap)). all groups were ventilated with bipap model for h, and the high pressure titrated to reached a tidal volume of ml/kg, the low pressure was set at cmh( )o, with i:e ratio : , and respiratory rate adjusted to a paco( ) of – mmhg. six beagles without ventilator support comprised the control group. respiratory variables, end-expiratory volume (eelv) and gas exchange were assessed during mechanical ventilation. the levels of interleukin (il)- , il- in lung tissue and plasma were measured by qrt-pcr and elisa respectively. lung injury scores were determined at end of the experiment. results: for the comparable ventilator setting, as compared with bipap(sb) group, the bipap(ap) group presented higher eelv ( ± vs. ± ml) and oxygenation index ( ± vs. ± mmhg), lower levels of il- ( . ± . vs. . ± . pg/ml) and il- ( . ± . vs. . ± . pg/ml) in plasma, and lower express levels of il- mrna ( . ± . vs. . ± . ) and il- mrna ( . ± . vs. . ± . ) in lung tissues. in addition, less lung histopathology injury were revealed in the bipap(ap) group ( . ± . vs. . ± . ). conclusion: abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ards, so abdominal muscle paralysis might be an effective strategy to minimize ventilator-induce lung injury. eighteen male beagles were studied under mechanical ventilation with anesthesia. severe ards was induced by repetitive oleic acid infusion. after lung injury, beagles were randomly assigned into spontaneous breathing group (bipap sb ) and abdominal muscle paralysis group (bipap ap ). all groups were ventilated with bipap model for h, and the high pressure titrated to reached a tidal volume of ml/kg, the low pressure was set at cmh o, with i:e ratio : , and respiratory rate adjusted to a paco of - mmhg. six beagles without ventilator support comprised the control group. respiratory variables, end-expiratory volume (eelv) and gas exchange were assessed during mechanical ventilation. the levels of interleukin (il)- , il- in lung tissue and plasma were measured by qrt-pcr and elisa respectively. lung injury scores were determined at end of the experiment. for the comparable ventilator setting, as compared with bipap sb group, the bipap ap group presented higher eelv ( ± vs. ± ml) and oxygenation index ( ± vs. mechanical ventilation is the main therapy for patients suffering from ards, which will improve oxygenation, reduce the work of breathing and prevent muscle fatigue. however, mechanical ventilation itself might aggravate lung injury [ , ] . although there is a widely use of the mechanical ventilation strategies such as low tidal volume, lower airway plateau pressure, optimal positive end-expiratory pressure (peep), permissive hypercapnia, patients with ards still has a higher morbidity and mortality in the past two decades [ ] . invasive mechanical ventilation for patients with ards include preserving spontaneous breathing (sb)and controlled mechanical ventilation (cmv). whether sb should be preserved has been debated for many years. animal experiments [ , ] and clinical studies [ ] have reported that cmv may increase alveolar collapse and inhomogeneity of pulmonary parenchyma, and thus induce further lung injury. sb during mechanical ventilation results in better aeration and less atelectasis in lung dependent zones, and less hyperinflation in nondependent lung zones in ards [ ] . some researchers have claimed that, even in the most severe ards, preserving sb activity was associated with beneficial effects in pulmonary function, speeding of weaning, and discharge from the icu [ ] . however, in a recent multicenter trial, papazian et al [ ] found that, in patients with severe ards, muscle paralysis was associated with a lower adjusted days morbidity than patients that received placebo.yoshida et al [ ] also found that in animal with severe ards, muscle paralysis might be more protective for injured lung, and sb could worsen lung injury. however, the precise mechanism is unclear. until now, it is unknown whether the activity of abdominal muscles has any impact on vali. caironi et al [ ] has recently proved that the amount of lung cyclically recruitment and decruitment, but not lung stress and strain, leads to the increase of mortality in ards patients. expiration in mechanical ventilation, as well as in normal breathing, is a passive phenomenon produced due to the lung elastic recoil forces. however, in the presence of increased respiratory driving, expiratory muscles, especially the abdominal muscles may actively participate in breathing and increase intra-abdominal pressure. it has been proved that the increase of intraabdominal pressure even cmh o may have injurious impacts on organ functions [ ] and aggravate lung damage [ ] . therefore, we hypothesized that abdominal muscle activity during mechanically ventilation increases lung injury in severe acute respiratory distress syndrome. in this study we explored the hypothesis. this study was approved by the ethics committee of guangzhou medical university. experimental animals obtained from the kangda laboratory animals science & technology company of gaoyao city and the care and treatment of the animals were in compliance with the university standard. position and anesthetize with propofol by continuous infusion ( . - . mg/ kg/ h). paralysis was achieved with pancuronium(bolus = . mg /kg, followed by . mg /kg/ h). after orotracheal intubation with an . mm id cuff tube, lungs were ventilated with the ventilator evita (dräger medical ag, lübeck, germany). volume-controlled model with a tidal volume (vt) of ml/kg, peep cm h o, i:e ratio : , fio . and the respiratory rate(rr)was adjusted to maintain paco between and mmhg. intravenous fluid (lactated ringer ' s; ml /kg/ h) were administrated to maintain the mean arterial blood pressure more than mmhg. the right jugular vein and femoral artery were catheterized and connected to picco system for measure of core temperature, mean arterial blood pressure(mpa) and obtain artery blood sample for gas analysis. a multipair esophageal electrode-balloon combined catheter was put into the esophagus, and airway occlusion technique was used to check the proper position [ ] . airway pressure (paw), esophageal pressure (peso) and intragastric pressure (pgas) from a side tap was connected to the end tracheal. a mlt l respiratory flow head was used to measure airflow, and integrated airflow to obtain tidal volume. signal of paw, peso, pgas, airflow, diaphragmatic esophageal surface electromyography (emgdi) and abdominal muscles surface electromyography (emgab) were recorded by powerlab / sp and chart . software on a mac book computer. body temperature was constant throughout the whole experiment at °c with a heating pad. after obtaining baseline measurements and minute stabilization, lung injury was induced by the total dose of . ml/kg purified oleic acid. if necessary, additional injection oleic acid ( . ml each time) was given until pao /fio were below mmhg. a stable severe ards model was established when the pao /fio value remain less than mmhg within min [ , , ] . after obtaining the measurements at injury, ventilator mode switched to bipap mode and the animals were randomly divided into sb group (bipap sb group) and abdominal muscle paralysis group(bipap ap group). after muscles paralysis, the p high titrated to achieve a vt of ml/kg, p low was set at cm h o, with fio . , i:e was fixed at : to minimize changes in mean paw. the mandatory rr adjusted a paco of to mmhg. in bipap sb group, in order to recover sb, stopped the injection of pancuronium and gradually reduced the dose of propofol. according to previous studies, in order to ensure a strong effort of unsupported sb during bipap, the mandatory rr was adjusted to maintain the percentage of minute ventilation (mv) of unsupported sb to total mv > % (fig ) .other ventilator settings remained the same as the above setting. sb was monitored by online registration of the peso signal. the amount of sb was quantified by measuring minute volumes before and after neuromuscular blockade. in the bipap ap group, the abdominal muscles paralysis method was described as warner do [ ] , a flexible epidural catheter was placed percutaneous through the second coccygeal vertebra and advanced until the tip closed to the l or l vertebra in the epidural space as confirmed by visual observation and autopsy. through the epidural catheter, % lidocaine was injected in . ml increment until the emgab was abolished and followed by continuous infusion of ropivacaine hydrochloride - ml/h. all the other ventilator setting were totally same with bipap sb group. all variables were recorded continuously. mean paw for the bipap mode can be calculated as follows [ , ] : (p high × t high + p low × t low ) / (t high + t low ), where the t high is the length of time for p high ; t low : length of time during p low . if the ratio of t high : t low is fixed at : , then the mean paw could be kept constant when we changed the rr.using above method adjust ventilator, we could maintain the level of mean paw comparable in our study. the transpulmonary pressure (p l ) was calculated as paw-peso. peak paw were recorded. peso swings as the frequency per minute of each type of breathing cycle was used to calculate the total rr (s fig) . the product of inspiratory peso vs. time (ptp) were determined. eelv eelv at peep or p low was measured by simplified helium dilution method. a flexible tube inserted between endotracheal tube and the circuit y and clamped during an end-expiratory pause at peep. anesthesia balloon filled with . l known gas mixture of helium ( . %) in oxyge was then connected to the tube. after releasing the clamp, tidal volumes compressing were performed rhythmically to dilute the helium gas mixture with the gas contained in beagles lungs. concentration of the helium in the bag was then measured with the helium analyzer (c-square company, usa), the following formula was used to computed the eelv (ml) = viÂci cf -vi, where vi: initial gas volume in the bag; ci: initial helium concentration; and cf: the final helium concentration [ ] . a pressure differential pneumotachometer was used to measure end-tidal co (etco ). the alveolar dead space fraction (vd/vt) was calculated by [ ] : vd/vt = paco Àetco plasma samples was collected at baseline, lung injury and at the end of h mv. after centrifuged at , rpm for min,supernatant aliquots were frozen at - °c for analysis. plasma levels of il- and il- were measured using an elisa kit for dogs (genequick, guangzhou, china) according to manufacturer protocol. expression levels of il- and il- mrna in lung tissues were measured by qrt-pcr as previously described [ ] . gapdh primers were used as an internal control. the sense and antisense of the primers ( '- ') used for il- and il- were: il- f: tgaccactcctgacccaacc, r: tccagactccgcaggatgag; il f: acttccaagctggctgttgc, r: ctggcatcgaagttctgaactg. after hours of ventilation, all beagles were euthanized by intravenous injection of potassium chloride, and lung tissues were harvested (s fig). samples were obtained separately from the upper lobe, middle lobe and ventral, lateral and dorsal sections of the right lower lobe. samples were fixed in % formalin and were stained by he for histological analysis. all sections were examined by the same pathologist and were evaluated by the following lung injury scores system [ , ] : , minimal changes; , mild; , moderate; , severe; , maximal changes. for each slide including the following criteria: congestion, alveolar and interstitial edema, granulocytes, lymphocytes and erythrocytes infiltration, fibrinous exudates and micro thrombi. the sum of pathological score was calculated by adding the cumulative lung injury sub-scores (maximal value is ). all date were represented as means ± sds. normal distribution of the data were assessed by the kolmogorov-smirnov test. comparison of data between two experimental groups with each other was performed using the unpaired t test or mann-whitney tests as appropriate. comparison of the continuous date within the same group before and after the experiments were evaluated by paired t tests. anova or kruskal-wallis test were applied for multiple-group comparisons as appropriate. effects of time and group differences on respiratory variables were evaluated by repeated measures two-way anova. the lsd post-hoc test was used as appropriate. ibm spss statistics was used for statistical analyses. differences were considered to be statistically significant if p was less than . . shows tracing records of paw, pes, pgas, p l , airflow, emgab and emgdi for the two groups in representative animals. there were no difference in the value of mean paw, and the only difference was the absence of abdominal muscle activity in bipap ap group. sb occurred rarely at p high in the experimental groups. the average percentage of minute ventilation of unassisted sb relative to total minute ventilation in the bipap sb group was above %.after abdominal muscle paralysis, the percentage decreased from %- % to % - %. as shown in table , at baseline, there are no differences in hr、map between the groups during the entire experiment. there were also comparable mean paw between the experimental groups. the paco level was less than mmhg in all of the animals. due to activity of the diaphragm and abdominal muscles, the bipap sb group presented higher swing of pes, pgas and peak p l than bipap ap group. after abdominal muscle paralysis, bipap ap group presented lower swing of peso, pgas, peak p l , more even p l and longer time on p high (s table) . moreover, the bipap ap group resulted in a higher eelv ( ± ml) compared with the bipap sb group ( ± ml) (fig ) . meanwhile, bipap ap group showed a lower vd/vt than bipap sb group (fig ) . bipap ap group showed a trend toward improving pao /fio , but not in bipap sb group. the difference in pao /fio between two groups was statistically significant after h mv (p = . ). ptp decreased gradually from bipap sb group to bipap ap group. as shown in , and all experimental groups were higher than the control group. as shown in table , the sum of lung injury scores was lower in bipap ap group ( . ± . ) than that in bipap sb group ( . ± . ), but the sum of scores in the experimental groups was higher than that in the control group. the bipap ap group showed less congestion, alveolar edema, alveolar infiltration of neutrophils and interstitial, and less infiltration of lymphocyte. the bipap sb group showed increased alveolar collapse, alveolar congestion, infiltration of inflammatory cells, and interstitial edema with hyaline membrane formation (fig ) . in an oleic acid-induced model of experimental ards in beagles, our findings suggested that abdominal muscle activity during mechanically ventilation increases lung injury in severe acute respiratory distress syndrome. to our knowledge, no previous experimental study has investigated the effect of abdominal muscle on lung damage in ards. we used an oleic acid-induced experimental ards because this model has reproduced many basic characteristics of ards [ ] . for different animals, the same dose of oleic acid administered by the same route can induce a reasonably reproducible lung injury [ ] . different ventilated strategies have been proposed in ards. bipap mode was chosen because it can be easily modulated to maintain comparable levels of ventilator support in the three groups. by the methods of adjusting ventilator setting, the levels of mean paw were comparable, the only difference was with or without abdominal muscles activity which were visible from electromyogram. in our study, we used a super syringe method to make a static pressure-volume curve and our results showed that the lower inflection points were - cm h o for lung injury. so we set p low (peep) at cm h o for the three groups. with comparable ventilator setting, the oxygenation index were significantly higher in bipa-p ap group than bipap sb group after h mv. this outcome proved that abdominal muscle values are means ± sd. ards = acute respiratory distress syndrome; bipap sb = biphasic positive airway pressure with sb; bipap ap = biphasic positive airway pressure with abdominal muscles paralysis; sb = spontaneous breathing; mv = minute ventilation; paco = partial pressure of carbon dioxide; pao /fio = ratio of partial pressure of arterial oxygen to faction of inspired oxygen concentration; rr = respiratory rate; vtave = average tidal volume; p plat = plateau pressure; ptp = pressure time product; mean paw, = mean airway pressure; peak p l , = peak transpulmonary pressure; mean p l , = mean transpulmonary pressure; peso = esophageal pressure; pgas = intragastric pressure; Δpes = change of esophageal pressure, ptp = pressure time product *p < . ,bipap ap vs. bipap sb group at the same time. activity may worsen gas exchange. there were several reasons to explain this phenomenon: first, activity of the abdominal muscle was associated with decreased eelv. douglas and colleagues [ ] observed in their study that eelv was parallel to oxygenation. similarly, a better gas exchange was also observed after abdominal muscle paralysis. second, activity of the abdominal muscle was associated with increased ptp, which represented a decrease of total work of breathing and oxygen consumption.third, activity of the abdominal muscle resulted in an decreased p l on p high , which could recruit the collapse alveolar units and result in greater lung units available for oxygenation [ ] . fourth, abdominal muscle activity increase of intraabdominal pressure which is associated with the decrease of p l and respiratory compliance on t high , which can lead to a loss in lung volume and hypoxemia episodes [ ] . fifth, activity of the abdominal muscle resulted in worsen blood reperfusion to nondependent lung area, and led to a higher vd/vt and greater inhomogeneity of lung ventilation to perfusion. all the above factors can worsen gas exchange. ventilator-associated lung injury (vali) includes volutrauma, atelectrauma and biotrauma., and these injuries may eventually lead to severe systemic inflammatory response and multiple organ failure. no previous studies have proved the relationships between abdominal muscle and vali in ards. in an oleic acid-induced ards model, our study showed that bipap ap had lower mrna expression of il- and il- in lung tissues and less total cumulative histopathological lung injury scores compared with bipap sb group. these findings suggested that activity of the abdominal muscle during mechanically ventilation was one of the injurious factors in severe ards. various mechanisms may explain the findings:①activity of the abdominal muscle can increase the value of pes which has been shown to promote the formation of pulmonary edema and aggravate lung injury [ ] . ②activity of the abdominal muscle can increase end-expiratory alveolar pressure at the start of expiratory. ③activity of the abdominal muscle can increase intra-abdominal hypertension. it has been proved that activity of the abdominal muscles can increase iap by up to cmh o [ ] . when intra-abdominal hypertension existed, unopposed increase of intra-abdominal pressure by spontaneous expiratory can cause greater lung injury by reducing p l in dependent zones [ ] . ④activity of the abdominal muscle can decrease eelv, and make part of lung units breathing in the lower inflection point of the p-v curve and cause so-called "low volume injury" which is associated with the cyclic opening-closing of lung units and aggregates lung injury by interfacial forces. ⑤activity of the abdominal muscle allows peep to be bad controlled and resulting in increased "atelectrauma". ⑥activity of the abdominal muscle resulted in decreased p l which was presumed to aggravate lung injury. ⑦activity of the abdominal muscle resulted in decreased eelv, so lung strain, a major determinant of vali, might be further increased. there are several limitations in this study. first, the work was done in an oleic acid-induced ards model. therefore, we are not sure whether these results can be reproduced in the other ards models. second, due to protective strategy with a ltv used in this experiment, we cannot preclude the protective effects of abdominal muscle on a high tidal volume injurious ventilation. third, the rr and nervous distribution of canine may not be the same as human being, so we cannot guarantee our data can be used for patients and further studies are needed. finally, in bipap ap group, lidocaine and ropivacaine hydrochloride were used for epidural anesthesia to paralyze abdominal muscles, so we cannot rule out the possibility that these drugs affected pulmonary inflammatory response. in conclusion, in a canine model of oleic acid-induced severe ards, abdominal muscle activity during mechanically ventilation increases lung injury in severe acute respiratory distress syndrome, so abdominal muscles paralysis minimize ventilator-induced lung injury in early, severe patients with ards. supporting information table. representative data in different groups. (xlsx) spontaneous breathing activity in acute lung injury and acute respiratory distress syndrome ventilator-induced lung injury early airway pressure release ventilation prevents ards-a novel preventive approach to lung injury spontaneous breathing with biphasic positive airway pressure attenuates lung injury in hydrochloric acid-induced acute respiratory distress syndrome pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow spontaneous breathing during ventilatory support improves ventilation-perfusion distributions in patients with acute respiratory distress syndrome spontaneous breathing improves lung aeration in oleic acid-induced lung injury the impact of spontaneous breathing during mechanical ventilation neuromuscular blockers in early acute respiratory distress syndrome the comparison of spontaneous breathing and muscle paralysis in two different severities of experimental lung injury lung opening and closing during ventilation of acute respiratory distress syndrome intra-abdominal hypertension in the critically ill: it is time to pay attention effects of preserved spontaneous breathing activity during mechanical ventilation in experimental intra-abdominal hypertension a simple method for assessing the validity of the esophageal balloon technique partial liquid ventilation with perfluorocarbon improves gas exchange and decreases inflammatory response in oleic acid-induced lung injury in beagles chest wall disruption with and without acute lung injury: effects of continuous positive airway pressure therapy on ventilation and perfusion relationships overview of the pathology of three widely used animal models of acute lung injury chest wall motion during epidural anesthesia in dogs airway pressure release ventilation: theory and practice effect of spontaneous breathing on ventilator-induced lung injury in mechanically ventilated healthy rabbits: a randomized, controlled, experimental study lung volume in mechanically ventilated patients: measurement by simplified helium dilution compared to quantitative ct scan estimating alveolar dead space from the arterial to end-tidal co( ) gradient: a modeling analysis pumpless extracorporeal lung assist for protective mechanical ventilation in experimental lung injury animal models of acute lung injury improved oxygenation in patients with acute respiratory failure: the prone position airway pressure release ventilation: what do we know mechanisms of hypoxemia episodes in spontaneously breathing preterm infants after mechanical ventilation abdominal muscle activity and intraabdominal pressure after upper abdominal surgery the authors are thankful to ph.d. yuanda xu, dongming hua, for assistance in the experiments, to dr.ruibing wu, for pathological analysis, we also thank dr.zhimin lin,for excellent technical assistance, and dr. yuanzi hua for his careful review of the manuscript. key: cord- -absjerdt authors: hagau, natalia; slavcovici, adriana; gonganau, daniel n; oltean, simona; dirzu, dan s; brezoszki, erika s; maxim, mihaela; ciuce, constantin; mlesnite, monica; gavrus, rodica l; laslo, carmen; hagau, radu; petrescu, magda; studnicska, daniela m title: clinical aspects and cytokine response in severe h n influenza a virus infection date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: absjerdt introduction: the immune responses in patients with novel a(h n ) virus infection (nva(h n )) are incompletely characterized. we investigated the profile of th and th mediators and interferon-inducible protein- (ip- ) in groups with severe and mild nva(h n ) disease and correlated them with clinical aspects. methods: thirty-two patients hospitalized with confirmed nva(h n ) infection were enrolled in the study: patients with nva(h n )-acute respiratory distress syndrome (ards) and patients with mild disease. one group of patients with bacterial sepsis-ards and another group of healthy volunteers were added to compare their cytokine levels with pandemic influenza groups. in the nva(h n )-ards group, the serum cytokine samples were obtained on admission and days later. the clinical aspects were recorded prospectively. results: in the nva(h n )-ards group, obesity and lymphocytopenia were more common and ip- , interleukin (il)- , il- , tumor necrosis factor (tnf)α, il- , il- and il- were significantly increased versus control. when comparing mild with severe nva(h n ) groups, il- , il- , il- and tnfα were significantly higher in the severe group. in nonsurvivors versus survivors, il- and il- were increased on admission and remained higher days later. a positive correlation of il- , il- and il- levels with c-reactive protein and with > -day interval between symptom onset and admission, and a negative correlation with the pao( ):fio( )ratio, were found in nva(h n ) groups. in obese patients with influenza disease, a significant increased level of il- was found. when comparing viral ards with bacterial ards, the level of il- , il- and tnfα was significantly higher in bacterial ards and il- was increased only in viral ards. conclusions: in our critically ill patients with novel influenza a(h n ) virus infection, the hallmarks of the severity of disease were il- , il- , il- and tnfα. these cytokines, except tnfα, had a positive correlation with the admission delay and c-reactive protein, and a negative correlation with the pao( ):fio( )ratio. obese patients with nva(h n ) disease have a significant level of il- . there are significant differences in the level of cytokines when comparing viral ards with bacterial ards. originating from mexico and spreading initially in the united states and canada, a novel influenza a(h n ) virus infection (nva(h n )) of swine origin spread globally during spring to mid-february . rates of hospitalization and death have varied widely according to country [ ] . among hospitalized patients to % have been admitted to intensive care units (icus) where the rate of death was to % [ ] [ ] [ ] [ ] [ ] . in romania the pandemic wave lasted from september to february , reaching a peak in december. the romanian ministry of health reported , confirmed cases of nva(h n ) influenza, the death rate being . %. primary influenza pneumonia had a high mortality rate during pandemics not only in immune-compromised individuals and patients with underlying co-morbid conditions, but also in young healthy adults [ ] . during nva(h n ) virus infection, experimental and clinical studies have identified dysregulated systemic inflammation as an important pathogenetic mechanism correlating with severity and progression of the disease [ , ] . the role of most immune responses in controlling and clearance of h n influenza a or its contribution to severe respiratory compromise is not well known. to and colleagues found higher plasma levels of proinflammatory cytokines and chemokine in the group of patients with acute respiratory distress syndrome (ards) caused by viral a(h n ) influenza, throughout the initial days after symptom onset [ ] . bermejo-martin and colleagues found that mediators involved in the development of th cells (il- , il- , il- , il- ), th cells (tnfα, il- , il- p ) and type ii interferon (ifnγ) had high systemic levels in hospitalized patients with nva(h n ) influenza [ ] . the detrimental or beneficial role of these cytokines in severe illness is not known. the aim of our study was to further investigate the profile of th and th mediators and interferoninductible protein- (ip- ), an innate-immunity mediator, as early host response in a group of critical and noncritical hospitalized patients with nva(h n ) from cluj-napoca, romania, and to correlate them with the clinical aspects. the study was performed between october and february in the icus of the emergency county clinical hospital and of the teaching hospital of infectious diseases, cluj-napoca, romania. thirty-two patients hospitalized with nva(h n ) infection were enrolled in the study: patients with nva(h n )-ards, and patients with nva(h n )mild disease. additionally, patients with bacterial sepsis-ards were included and served to compare the cytokine levels between the nva(h n )-ards group and the bacterial sepsis-ards group. the study protocol was approved by the ethics committee for clinical research of the university of medicine and pharmacy 'iuliu hatieganu' cluj napoca and the hospital authority. informed consent was obtained from each patient or their legal representative. the inclusion criteria were age > years, symptoms compatible with influenza and confirmed nva(h n ) virus, bacterial severe sepsis with ards, and informed consent. the exclusion criteria were age < years, known infection by human immunodeficiency virus, patients with other respiratory viral infections, bacterial sepsis without ards-syndrome, and refusal to consent. the control group included healthy volunteers without chronic or acute disease. data were recorded prospectively by investigators at each hospital. the following data were recorded: age, sex, pregnancy, underlying diseases (chronic obstructive pulmonary disease, asthma, diabetes, chronic heart failure, chronic renal failure, cirrhosis, immunosuppression), obesity defined as body mass index > , and the time in days from symptom onset to hospital admission. hematological, biochemical and microbiological results were included in the database. the extension of lung infiltrates on chest x-ray scan was registered as the number of quadrants involved. the severity and prognosis of the illness was assessed in adults using the acute physiology and chronic health evaluation ii (apache ii) score and the sepsis-related organ failure assessment (sofa) score. ards was defined using the american-european consensus conference definitions [ ] . the pulmonary dysfunction score was based on the pao :fio ratio, ranging from to where grade represented a ratio less or equal to ; grade , a ratio ranging from to ; grade , a ratio ranging from to ; and grade , a ratio less or equal to [ ] . a(h n ) influenza virus presence was confirmed by testing nasopharyngeal swabs or bronchoalveolar lavage specimens with real-time pcr (commercial kits: full velocity sybr green qrt-pcr/superscript iii platinum one-step quantitative rt-pcr taqman; invitrogen corporation, carlsbad, california, usa) at the national influenza centre of cantacuzino institute, bucharest, romania. in patients with nva(h n )-mild disease, the serum samples were taken on hospital admission. in patients with nva(h n )-ards infection, the serum samples were taken on admission to the icu and days later to determine cytokine kinetics. the installation of ards, either viral or bacterial, in the course of the disease determined the time of admission to the icu. in patients with bacterial sepsis-related ards, the serum samples were taken on admission to the icu. the enrolled patients and the healthy volunteers gave whole blood, which was clotted for minutes at °c and stored at - °c until use. the resulting serum was used for cytokine determination. seven different serum cytokines (il- , il- , il- p , il- , il- , tnfα and ifn-γ) were measured with luminex (luminex corporation, austin, tx, usa) using a multiplex cytokine kit along with the assay performed in accordance with the manufacturer's instructions (r&d systems, minneapolis, mn, usa). additionally, we used elisa kits for quantitative determination of the two cytokines il- and ip- (quantikine; r&d systems). subjects were stratified into three groups: patients with nva(h n )-mild disease, patients with nva (h n )-ards, and patients with bacterial sepsis-ards. descriptive statistics included means and standard deviations or medians and interquartile ranges for continuous variables of normal and non-normal distributions. clinical and biochemical characteristics and cytokine levels were compared. the fisher exact test and the chi-square test were used for categorical variables. the mann-whitney u test was used for nonparametric variables. the wilcoxon test (nonparametric test) was used to compare two paired groups. the association between nonparametric variables was determined by the spearman correlation coefficient (r). any value of p < . was considered statistically significant. graphpad prism version . software for windows (graphpad software, la jolla, california, usa) was used. a total of patients with confirmed nva(h n ) infection and patients with bacterial sepsis-ards were enrolled over the study period. their demographic, co-morbidities and clinical characteristics are presented in table . patients in the nva(h n )-ards group were significantly older than those in the nva(h n )-mild disease group (median age years vs. years, p = . ). obesity was more common in the nva(h n )-ards group. the median interval between onset of illness and admission was days (interquartile range . to . ) in the nva(h n )-ards group and days (interquartile range to ) in the mild disease group (p < . ) ( table ). all the patients with nva(h n ) virus infection presented symptoms of acute respiratory viral infection on admission. the median length of hospital stay was higher in the nva(h n )-ards group compared with the mild disease group ( days vs. days, p < . ). all patients with nva(h n ) virus infection received oseltamivir on admission: the standard dose ( mg/day) was administered for patients with mild disease, and a higher dose ( mg/day) was used for nva(h n )-ards patients. during the icu hospitalization, critical patients with influenza virus infection (ards) received corticosteroid therapy (hydrocortisone or methylprednisolone). in agreement with our protocol, empirical antibiotics were started on admission. among patients with nva(h n )-ards, four developed acute renal failure requiring renal replacement therapy, two developed secondary bacterial pneumonia and three developed pneumothorax (table ). ten patients from the nva(h n )-ards group received non-invasive ventilation and patients received mechanical ventilation. pregnancy was another risk factor for nva(h n )-ards infection and icu admission ( / cases; table ). two pregnant women were in the third trimester and one was in the second trimester. no underlying disease was noted. the range interval after symptom onset and icu admission was to days. caesarean delivery was necessary in two cases. all pregnant women required respiratory support (two invasive and one noninvasive) during hospitalization and all survived. seven patients died in the nvh n -ards group. histopathological changes were similar in all cases: tracheitis, bronchitis with focal squamous metaplasia, necrotizing bronchiolitis, emphysema, extensive diffuse alveolar damage associated with alveolar hemorrhage and marked hyaline membrane formation, fibrosis and granulocyte pulmonary infiltrates. pulmonary thromboemboli with focal infarcts were observed in three cases. the lymphocyte count was significantly lower in the nva(h n )-ards group than in the mild disease group (p = . ) ( table ). comparing laboratory abnormalities on hospital admission we found that patients with nva(h n )-ards were more likely to have elevated levels of serum lactate dehydrogenase, alanine and aspartate aminotransferase (p < . , p = . and p < . , respectively) than patients with nva(h n )mild disease ( table ) . twenty patients with bacterial sepsis-ards were included to compare the cytokine levels in viral and bacterial ards. immune suppression (six patients with cancer) was more common in the bacterial sepsis-ards group (p = . ). the mean (standard deviation) apache ii score, sofa score and pao :fio ratio were similar in both groups ( table ). the leukocyte count, c-reactive protein and procalcitonin levels were higher in the bacterial ards group than in the nva (h n )-ards group (p = . , p = . and p < . , respectively) ( table ) . the results of the cytokine profile are shown in figure . at admission, only il- , il- , ip- and tnfα were significantly higher in the mild disease group than in the control group. except for il- and ifnγ, all cytokine levels were higher in critical patients with nva (h n )-ards than in the control group. compared with the mild disease group, significantly higher levels of il- , il- , il- and tnfα were found in the nva (h n )-ards group (p < . , p < . , p < . and p < . , respectively). compared with controls, the levels of il- , il- , il- , il- , il- , ip- and tnfα were significantly elevated in the bacterial sepsis-ards group. levels of il- , il- and tnfα were significantly higher in the bacterial-ards group versus the nva (h n )-ards group (p = . , p = . and p = . , respectively; figure ). patients with pandemic influenza virus (severe ards and mild disease) were stratified according to the interval between symptom onset and admission. levels of il- , il- , il- and ifnγ were significantly higher in patients with delayed admission, > days after symptom onset (p = . , p = . , p = . and p = . , respectively) ( table ). serum cytokine levels over time ( days after admission and antiviral treatment) showed a decrease of il- , ip- , tnfα, ifnγ and il- in critical patients with nva (h n )-ards (table ). serum cytokine levels over time in nva(h n )-ards survivors showed a significant decrease of il- , ip- and tnfα (table ). in nonsurvivors versus survivors from the nva(h n )-ards group, the levels of il- and il- on admission and days after were significantly higher ( table ). il- was higher in nonsurvivors days after admission (table ) . correlation between cytokine levels and clinical or laboratory characteristics in patients with confirmed nva(h n ) infection was determined by spearman correlation coefficient. we found significant correlation of il- , il- and il- levels with c-reactive protein (r = . , p < . ; r = . , p = . ; and r = . , p = . , respectively), with pao :fio ratio (r = - . , p = . ; r = - . , p < . ; and r = - . , p < . , respectively) and with interval between symptom onset and hospital admission (r = . , p = . ; r = . , p = . ; and r = . , p = . , respectively). il- was significantly higher (p = . ) in obese versus nonobese patients with nva(h n ) infection. in this study we presented the cytokine profiles following nva(h n ) infection in hospitalized patients ( mild and severe disease) and the cytokine profiles found in cases of bacterial sepsis. the patients with severe nva(h n ) disease were younger than the patients with bacterial sepsis (no statistical significance). similarly to other study groups, we found that obesity was more common in the nva (h n ) ards group, suggesting it may be a risk factor for complications and admission to the icu [ , , ] . laboratory findings in the same group of patients include lymphocytopenia and elevation in levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatinine -as in other patient groups with novel influenza virus infection [ , ] . in contrast, the bacterial-ards group presented no lymphocytopenia, lower elevation in serum liver enzymes and higher levels of c-reactive protein and procalcitonin. no significant differences were found between bacterial and viral ards groups in sofa and apache ii scores at admission. the pulmonary histopathological findings in nva(h n )-ards nonsurvivors were similar to other fatal cases of nva(h n ) virus infection [ , ] . installation of ards in the course of the disease was the moment of blood sampling for cytokine measurements. there was a difference regarding the time of symptom onset and hospital admission between the severe and mild groups of nva(h n ) disease that could affect the comparison of cytokine levels between the two groups. for this reason we not only compared the cytokine levels between mild and severe disease, but also mixed the patients with nva(h n )-mild and severe disease and compared the level of cytokines according to the interval between symptom onset and admission (first interval to days, second interval to days). we found that not all cytokines had the same behavior against the time of symptom onset and admission. the pattern of immune response in patients with nva (h n ) virus infection is incompletely characterized. cd + t cells are known to play an important role in the initiation of immune responses by providing help to other cells. t-helper cells could be divided into subsets: th , th and th . th cells mainly develop following infections by intracellular bacteria and some viruses [ ] . the mediators involved in the development of th are il- , ifnγ, il- , il- and tnfα. il- bridges the early nonspecific innate immunity and the subsequent antigen-specific adaptative immunity [ ] . il- was shown to inhibit apoptosis of t cells [ ] and of dendritic cells [ ] . alveolar macrophages have a functional il- receptor, and virus-infected macrophages in the presence of il- might be protected from apoptosis limiting viral clearance [ ] . apoptosis of virus-infected cells was shown to be an effective mechanism for viral clearance [ ] . bermejo-martin and colleagues reported more significant il- results in the critical a(h n ) group of patients [ ] . in our study, il- is significantly higher in the nva (h n )-mild disease group and in the nva(h n )-ards group versus the control group and is not significantly higher in the bacterial ards group. il- plays a critical role in protecting cd + t cells from apoptosis during the contraction phase following microbial infection [ , ] . the cd + t cells surviving in the presence of il- might be pathogenic in lung injury following highly pathogenic influenza a virus infection [ ] . il- activates the effector function of memory phenotype cd + cells [ ] . in our study, il- is significantly higher in the nva(h n )-ards group versus the nva(h n )-mild disease group, but without significant difference in the nva(h n )-ards versus bacterial-ards groups. similar to our results, il- was a hallmark of critical illness in the hong kong and spanish nva(h n ) cytokine studies [ , ] . il- is significantly higher at admission (p ) and days later (p ) in the nva(h n )-ards group for nonsurvivors versus survivors, so it might be pathogenic in lung injury influenza a virus infection. similarly, to and colleagues found il- significantly higher in critical a(h n ) patients and very significant in the a(h n )-ards death group [ ] . ifnγ is a cytokine of innate and adaptative immunity. its major functions are activation of macrophages, differentiation of th from t cells, inhibition of the th pathway and control of intracellular pathogens [ ] . bermejo-martin and colleagues found high systemic levels of ifnγ in hospitalized patients with nva(h n ) [ ] . in contrast, in the present study there were no differences between the control and study groups. the ifnγ level over time in the nva(h n ) ards group was higher at admission than days later, without significant difference between survivors versus nonsurvivors. tnfα is a cytokine of innate immunity. the principal cellular targets and biologic effects include activation of endothelial cells, neutrophil activation, fever, liver synthesis of acute phase proteins, muscle and fat catabolism, and apoptosis of many cell types. in our study, we found highly increased tnfα levels in the nva(h n )mild disease, nva(h n )-ards and bacterial ards groups compared to the control group. tnfα is significantly higher in nva(h n )-ards versus nva(h n )mild disease, with similar results being found by to and colleagues and bermejo-martin and colleagues [ , ] . this cytokine is also significantly increased in bacterial-ards versus nva(h n )-ards. for the groups of patients with nva(h n ), according to the time interval between symptom onset and hospital admission, there were no significant differences found for il- and tnfα levels, but there were significant differences for il- and ifnγ, levels being higher when the time interval was between and days. none of our patients were on oseltamivir medication between symptom onset and admission. th cells are effective in host defense against certain pathogens and tissue inflammation. th mediators for the development of th cells are il- , transforming growth factor beta, il- , il- , il- , il- and il- . il- is a cytokine of innate immunity, its principal targets being the liver cells, the β cells and the naïve t cells [ ] . despite the apparently beneficial role that macrophages play in controlling early viral replication, several reports have demonstrated a more deleterious effect of these cells in influenza a viral infections by excessive inflammation in the lung attributed to il- and tnfα [ ] . in our study, il- is increased in nva(h n )-ards versus nva(h n )-mild disease. similarly, il- and il- constituted a hallmark of critical illness in the hong kong and spanish nva(h n ) cytokine studies [ , ] . in the nva(h n )-ards group, the il- serum level is significantly higher at admission than days later. in the same group, il- is significantly higher in nonsurvivors versus survivors at admission and days later, which seems to further contribute to pulmonary damage and death. we found positive correlations between il- , il- and il- levels and a longer than days interval between symptom onset and admission, as well as with c-reactive protein, but a negative correlation with the pao :fio ratio, indicating the severity of the disease. il- is a chemokine of innate immunity. the chemokine's principal biologic effect is chemotaxis, being a major chemokine for neutrophil activation, and migration into tissues [ ] . in our study, il- is highly significant in the nva(h n )-ards and ards bacterial groups versus the control group, but is not significant in mild disease. in contrast, il- was increased in both critical and noncritical nva(h n ) hospitalized patients in the spanish and hong kong studies. in our study, il- is higher in nva(h n )-ards versus nva(h n )-mild disease and in bacterial ards versus nva(h n )-ards. the obese patients with nva(h n ) disease had a significant level of il- . plasma il- levels are increased in normoglycemic obese subjects, related to fat mass and the tnfα system [ ] . ip- is a chemokine of innate immunity, and macrophages and dendritic cells are the principal cell source. we found a higher level of ip- in nva(h n )-mild disease, nva(h n )-ards and bacterial-ards groups versus the control group, and no other differences between groups. in the nva(h n )-ards group, the ip- level is higher at admission than days after admission because of the survivors' cytokine profile. an increased level of ip- was found in the spanish group as early response to nva(h n ) infection in both hospitalized and mild patient disease, as in the present study, while in the hong kong group ip- was significantly higher in critical patients only. in our study, ip- levels in nva(h n )-ards nonsurvivors remained higher at admission and days later, being not significantly correlated with the clinical outcome. emphysema was one of our hystopathological findings and thus it might be speculated that a high level of ip- in nonsurvivors could be correlated with emphysema. ip- released by lung cd and cd t cells stimulates alveolar macrophage production of matrix metalloproteinase- , which digests lung elastin [ , ] . il- is a cytokine of adaptative immunity. principal cellular targets include endothelial cells with increased chemokine production and macrophages with increased chemokine and cytokine production. this cytokine's principal biologic effect is proinflammatory [ , ] . in the present study il- is significantly higher in the bacterial ards group versus the control group and is higher in the bacterial ards group versus the nva(h n )-ards group. no significant differences between nva(h n )-mild disease versus controls and between nva(h n )-ards versus controls were found. in the nva(h n )-ards group, il- was higher at admission and lower days later. in the spanish study the il- level was increased in hospitalized noncritical patients, and in the hong kong study no differences between groups were found, similar to the present study. il- , like il- , is a th cytokine that induces differentiation of th cells and has anti-inflammatory properties. il- is a cytokine of current interest associated with allergic th responses and is a key modulator of antiviral immunity [ ] . in our study il- is significantly higher in the h n -ards group versus the control group, and is not significantly increased in mild disease -in contrast to the spanish study, where il- was increased in both critical and noncritical hospitalized patients. regarding the behavior of th mediators in nva (h n ) groups of patients according to the time interval between symptom onset and admission, there were no differences for il- , il- and ip- and there were significant differences for il- and il- , the levels being higher when the interval was between and days. all our patients with ards disease were on corticosteroid treatment, because deficient corticosteroid-mediated downregulation of inflammatory cytokine transcription in ards patients is associated with disease progression and mortality. many studies reported that prolonged corticosteroid treatment was associated with a significant reduction in markers of systemic inflammation [ , ] . in the present study the blood samples for cytokine measurements were taken at admission for the bacterial-ards group of patients, and at admission and days later for the nva(h n ) group of patients -for this reason, corticosteroid could not significantly affect cytokine levels. the small number of patients enrolled in the mild disease group is one of our study limitations. among hospitalized patients with mild flu-like syndrome, only those with risk of severe complications and of secondary outbreaks in the exposed population were sampled for real-time pcr. on the contrary, the laboratory of the national influenza centre of cantacuzino institute, bucharest was overwhelmed, being the only centre for influenza pcr diagnosis. another limitation is the exclusion of children, an important group with nva (h n ) virus infection. in our critically ill patients with nva(h n ) virus infection we found increased levels of some cytokines: ip- , tnfα, il- , il- , il- , il- and il- . the hallmarks for the severity of the disease were il- , il- , il- and tnfα. we found a positive correlation of il- , il- and il- with the admission delay and c-reactive protein and a negative correlation with the pao :fio ratio. the obese patients with nva(h n ) disease had a significant level of il- . there were significant differences in the level of cytokines when comparing viral ards with bacterial ards. • in the influenza-related ards group, the levels of il- , il- , il- , il- , il- , ip- and tnfα are significantly increased versus the control group. in the bacterial sepsis-ards group, levels of il- , il- , il- , il- , il- , ip- and tnfα are also increased versus the control group. when comparing these two groups, the levels of il- , il- and tnfα are significantly higher in bacterial ards versus viral ards, and il- is increased only in viral ards whereas il- is increased only in bacterial ards. when comparing the mild nva (h n ) and critical ards influenza a groups, il- , il- , il- and tnfα are significantly higher in critical ards patients being hallmarks of disease severity. • the serum levels of il- , il- , il- and ifnγ according to the interval between symptom onset and admission in hospitalized nva(h n ) patients are significantly higher when this interval is longer than days. • in nonsurvivors versus survivors from the nva (h n )-ards group, il- and il- are increased at admission and stay higher days later -which seems to further contribute to pulmonary damage and death. • there is a positive correlation of il- , il- and il- levels with c-reactive protein and with > -day interval between symptom onset and hospital admission, and a negative correlation with the pao :fio ratio. • the obese patients versus nonobese patients with nva(h n ) infection have a significant level of il- . writing committee of the who consultation on clinical aspects of pandemic (h n ) influenza: clinical aspects of pandemic influenza a (h n ) virus infection h n ) working group: factors associated with death or hospitalization due to pandemic influenza a(h n ) infection in california pandemic influenza a (h n ) virus hospitalizations investigation team: hospitalized patients with h n influenza in the united states critically ill patients with influenza a(h n ) in mexico the anzic influenza investigators: critical care services and h n influenza in australia and new zealand critically ill patients with influenza a(h n ) infection in canada clinical review: primary influenza viral pneumonia pandemic h n study group: delayed clearance of viral load and marked cytokine activation in severe cases of pandemic h n influenza virus infection th and th hypercytokinemia as early host response signature in severe pandemic influenza definition, mechanisms, relevant outcome, and clinical trial coordination lung injury severity scoring in the era of lung protective mechanical ventilation: the pao /fio ratio pulmonary pathologic findings of fatal pandemic influenza a/h n viral infections lung pathology in fatal novel human influenza a(h n ) infection romagnani s: t-cell subsets (th versus th ) interleukin a key immunoregulatory cytokine in infection applications il- decreases activation-induced cell death in human naïve th cells costimulated by intercellular adhesion molecule- .i. il- alters caspase processing and inhibits enzyme function cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the bcl- family of proteins positive regulatory role of il- in macrophages and modulation by ifn-gamma influenza a virus-induced apoptosis in bronchiolar epithelial (nci-h ) cells limits pro-inflammatory cytokine release il- promotes the survival of naïve and memory phenotype cd + t cells il- regulates cd + t cell contraction during primary infection interleukin- is critical in the pathogenesis of influenza a virus-induced acute lung injury il- mimics t cell receptor crosslinking in the induction of cellular proliferation, gene expression, and cytotoxicity in cd + memory t cells interleukin- and type helper t cells th cells: effector t cells with inflammatory properties innate immune control and regulation of influenza virus infections plasma interleukin- concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-α system chronic obstructive pulmonary disease: molecular and cellular mechanisms an immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema il- regulates pathology during primary and memory responses to respiratory syncytial virus infection prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. evidence for inadequate endogenous glucocorticoid secretion and inflammationinduced immune cell resistance to glucocorticoids corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review clinical aspects and cytokine response in severe h n influenza a virus infection the present work was possible thanks to the financial support for reagent and kit acquisition, obtained from the university of medicine and pharmacy 'iuliu hatieganu' cluj-napoca, romania. the authors would like to thank to all of the nurses, residents and attendings for their special care to the patients with nva(h n ) influenza virus infection. authors' contributions nh and as designed the study, coordinated patient recruitment, supervised laboratory works and wrote the article. dng and so performed cytokine profiling and wrote the report. dsd, esb and mma collected clinical and laboratory data, and wrote the report. cc assisted in the design of the study and assisted in writing the paper. mml, rlg and cl supervised clinical aspects, participated in patient recruitment. rh contributed to the statistical analysis. mp provided pulmonary histopathological analysis. dms assisted in the design of the study, coordinated patient recruitment, analyzed and interpreted the data. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- - rmx j authors: korkmaz ekren, pervin; basarik aydogan, burcu; gurgun, alev; tasbakan, mehmet sezai; bacakoglu, feza; nava, stefano title: can fiberoptic bronchoscopy be applied to critically ill patients treated with noninvasive ventilation for acute respiratory distress syndrome? prospective observational study date: - - journal: bmc pulm med doi: . /s - - -y sha: doc_id: cord_uid: rmx j background: noninvasive ventilation (niv) is a cornerstone for the treatment of acute respiratory failure of various etiologies. using niv is discussed in mild-to-moderate acute respiratory distress syndrome (ards) patients (pao( )/fio( ) > ). these patients often have comorbidities that increase the risk for bronchoscopy related complications. the primary outcome of this prospective observational study was to evaluate the feasibility, safety and contribution in diagnosis and/or modification of the ongoing treatment of fiberoptic bronchoscopy (fob) in patients with ards treated with niv. methods: ards patients treated with niv and who require fob as the diagnostic or therapeutic procedure were included the study. intensive care ventilators or other dedicated niv ventilators were used. niv was applied via simple oro-nasal mask or full-face mask. pressure support or inspiratory positive airway pressure (ipap), external positive end expiratory pressure (peep) or expiratory positive airway pressure (epap) levels were titrated to achieve an expiratory tidal volume of to ml/kg according to ideal body weight, spo( ) > % and respiratory rate below /min. results: twenty eight subjects (mean age . ± . years, men, women, pao( )/fio( ) rate ± . at admission) were included the study. overall the procedure was well tolerated with only ( . %) patients showing minor complications. there was no impairment in arterial blood gas and cardiopulmonary parameters after fob. pao( )/fio( ) rate increased from . ± . to . ± . (p = . ). no patient was intubated within h after the bronchoscopy. . , . and . % of the patients required invasive mechanical ventilation after h, h and h, respectively. bronchoscopy provided diagnosis in ( . %) patients. appropriate treatment was decided according to the results of the bronchoscopic sampling in ( . %) patients. conclusion: fob under niv could be considered as a feasible tool for diagnosis and guide for treatment of patients with ards treated via niv in intensive care units. however, fob-correlated life-treathening complications in severe hypoxemia should not be forgotten. furthermore, further controlled studies involving a larger series of homogeneous ards patients undergoing fob under niv are needed to confirm these preliminary findings. noninvasive ventilation (niv) is defined as any form of ventilatory support applied without endotracheal intubation [ ] . application of niv is a cornerstone for the treatment of acute respiratory failure of various etiologies [ ] . it reduces intubation rate in patients with exacerbations of chronic obstructive pulmonary disease (copd) and acute cardiogenic pulmonary edema [ ] and in immunocompromised patients with hypoxemic respiratory failure [ , ] . using niv is discussed in mildto-moderate acute respiratory distress syndrome (ards) patients (pao /fio > ) [ ] . fiberoptic bronchoscopy (fob) may be required in some patients with acute respiratory failure in intensive care units (icu), mainly as diagnostic tool or to remove abundant secretions [ , ] . as a matter of fact it may also be applied to determine the cause of diffuse pulmonary infiltrates (infection, diffuse alveolar hemorrhage, organizing pneumonia) [ ] . other indications for fob in critically ill patients consist of atelectasis, hemoptysis and suspicion of lung neoplasia. patients in icu for acute respiratory failure often have comorbidities that increase the risk of bronchoscopy related complications. feasibility of bronchoscopy during niv in patients with respiratory failure was shown previously and niv was found to be superior to conventional oxygen supplementation for preventing gasexchange deterioration during fob [ , ] . in those studies, niv was used to facilitate bronchoscopy and niv was not required prior to bronchoscopy. however, there is limited data on the feasibility and usefulness of fob in patients who are already treated with niv for acute respiratory failure [ ] and in particular there is not enough evidence for using niv in patients with ards [ ] . therefore, we aimed to evaluate the feasibility and safety of fob in patients with ards ventilated with niv and its contribution in the diagnosis and/or modification of the ongoing therapy. the patients hospitalized in -bed icu at ege university medical school department of chest diseases were assessed in terms of ards, niv treatment and fob application. the decision both to initiate niv and to perform fob were made by the pulmonologist. this prospective observational study was approved by the ege university ethical and research project committee ( -tip- ). all study participants or legal representatives provided written informed consent before the procedures. the study population was obtained from the specified respiratory intensive care unit (january -december ). inclusion criteria were: . ards diagnosed by berlin criteria or the american-european consensus conference [ , ] , . age ≥ years, . treated with niv before the bronchoscopy . requiring fob with or without bronchoalveolar lavage (bal) for diagnostic or therapeutic apporach, . informed consent. exclusion criteria were: . refusal of niv, . presence of contraindications for niv such as facial deformity, upper gastrointestinal bleeding, upper airway obstruction, inability to protect the airway, significantly altered mental status, severe haemodynamic instability, respiratory or cardiac arrest and acute coronary syndromes, . tracheostomy or intubation before admission, . presence of contraindications for bronchoscopy procedure such as insufficient platelet number (< , cells/μl) and coagulation disorders, . patients with niv use at home prior to icu admission. demographic characteristics, comorbid diseases, presence of immunosuppression, acute physiology and chronic health evaluation ii (apache ii) score [ ] and radiologic and laboratory findings were recorded for each patient. acquired immunodeficiency syndrome, immunosuppressive medication, organ transplantation, high dose chemotherapy during the past days, absolute neutrophil count < /ml were defined as immunosuppression. standard microbiological diagnostic measures before fob and additional serological studies were ordered in immunosuppressed patients as indicated. heart and respiratory rates, blood pressures and arterial blood gases were assessed min before and h after the fob for this study. these measurements and ventilator settings were monitored during fob. all patients were on niv prior and throughout the bronchoscopic sampling in the icu. niv was applied via simple oro-nasal mask (af oro-nasal mask, philips respironics) or full-face mask (performax total face mask, philips respironics) (fig. ) and the ventilator settings were adjusted by the pulmonologist. icu ventilator (servo c, siemens) or dedicated niv ventilator (vivo , general electric) devices were set with the optimal required fio . pressure support or inspiratory positive airway pressure (ipap), external positive end expiratory pressure (peep) or expiratory positive airway pressure (epap) levels were titrated to achieve an expiratory tidal volume of to ml/kg according to ideal body weight, adjusted to maintain spo > % and respiratory rate below /min. throughout the niv treatment and bronchoscopy procedure electrocardiography, intra arterial blood pressure, pulse oximeter and ventilator parameters were monitored continuously. the icu bronchoscopy team was composed of two well-trained pulmonologists (fb, mst) and two nurses. all bronchoscopies were performed while patients were in upright position and in their own beds. % lidocaine spray solution and % lidocaine solution were used for topical anaesthesia of nasopharynx and tracheobronchial tree, respectively. a connector (bronchoscopy elbow, philips respironics) was used between the ventilator tubing and the mask for the insertion of fob (olympus bfu f) (fig. ). fiberoptic bronchoscopy was performed via nasal route. short term sedation was administered in some patients according to their respiratory and hemodynamic situations. sedation was started using mg midazolam at the beginning of the procedure. the patients who did not achieve stabilisation received repetitive applications of to mg midazolam. maximum total dose of midazolam was mg. patients were supplied with the necessary fio which provided spo > % during fob procedure (one or more of these procedures were performed in same fob application: bal, bronchoscopic brushings and biopsy, aspiration) under niv. the bronchoscopic samples were sent to microbiology and pathology laboratories. antimicrobial treatment was started empirically while the sampling was performed and, later treatment was adjusted according to microbiological results. primary outcomes were: . safety with the recording of any complications [such as fever, arrhythmia, hypoxemia (spo < %), hypotension (systolic and diastolic blood pressure below mmhg and mmhg, respectively), haemorrhage and pneumothorax]. . contribution of fob in diagnosis and/or modification of the ongoing treatment. . requirement for endotracheal intubation was specifically observed within two hours and eight hours after the fob. criteria of two and eight hour limit for endotracheal intubation were adopted from previous studies [ , ] . data management and analysis of all data were conducted via spss for windows . software (spss, version , chicago). kolmogorov-smirnov test was used to present the distribution of all recorded variables. arterial blood gases and haemodynamic parameters before and after fob were compared with wilcoxon test. statistical significance level was set at p < . . twenty eight subjects (mean age . ± . years, men, women) were included the study. patients ( . %) had immunosuppression. patients had hematologic malignancy, solid-organ tumor, renal transplantation, long-term corticosteroid treatment due to interstitial lung disease or connective tissue disease that caused immunosuppression. the most common admission diagnosis to icu was pneumonia ( table ). as shown on the median duration of niv prior to fob was h (range - h). vasopressor/inotropic agents before the fob application were begun in patients ( . %) due to hemodynamic instability. thirteen patients ( . %) received sedation for niv and/or fob. maximum duration of the bronchoscopy was min and fob application was performed only once for each patients. arterial blood gas analyses, pao /fio rates and cardiorespiratory parameters before and after fob were shown in table . there was no impairment in these parameters after bronchoscopy. pao /fio rate increased from . ± . to . ± . after procedure. pressure support, ipap, epap/ peep and fio levels did not change during fob. respiratory and hemodynamic variables were followed up very closely for the required intubation. complications other than endotracheal intubation developed in ( . %) patients within h after fob. fever (n = ), hypoxemia (n = ) and hypotension (n = ) occurred as complication of bronchoscopy. in one of these patients, hypotension developed within the first four hours. no other adverse effects were observed such as haemorrhage and pneumothorax. endotracheal intubation was not required within h after the bronchoscopy. intubation was performed only in three patients ( the study demonstrated that bronchoscopy under niv is feasible, safe and an effective diagnostic procedure, therapeutic approach and guide for treatment in ards patients. after the procedure, arterial blood gas values, pao /fio rate, and cardiac parameters did not change and none of the patients needed intubation within two hours after bronchoscopy. fiberoptic bronchoscopy can be performed safely without major complications in this group of patients. diagnostic or therapeutic bronchoscopy is necessary for some icu patients treated for acute respiratory failure, however it can be associated with various complications as well as mortality. because of these risks, fob can be challenging in these patients. bronchoscope covers - % of the tracheal lumen and may increase respiration efforts and decrease pao by - mmhg causing respiratory and cardiac complications [ ] . additionally, bal sampling may cause worsening of oxygen desaturation [ ] . the american thoracic society recommends avoiding fob and bal in patients with hypoxemia (pao < mmhg or oxygen saturation < % with supplemental oxygen) [ ] . although alternative approaches in these patients with higher-risk are empirical treatments or intubation for fob, the observational study and the randomized controlled trials have shown that niv may be an alternative to endotracheal intubation in these critically ill patients who are not previously ventilated [ , , ] . early etiological diagnosis in critically ill patients is important for appropriate treatment. baumann et al. [ ] showed that bal during niv yielded diagnostic information in % of the patients with acute respiratory failure. diagnostic success of fob was % in another study in which oxygen supplementation or niv application was used during the procedure [ ] . our immunosuppressed patient ratio was higher than the study population of bauman et al. and cracco et al. ( . % vs %, %, respectively). clouzeau et al. [ ] found that diagnostic or therapeutic information ratio was % in patients who underwent fob under niv. . % of their patients were immunocompromise. in our study, diagnostic accuracy of fob in ards patients was . %. high diagnostic rate in our study can be interpreted with the fact that we performed sampling with fob just as the patients apply to icu. at the same time, fob application allowed the therapeutic approaches such as aspiration. furthermore, agarwal et al. [ ] have shown that niv-assisted bronchoscopic lung biopsy is another diagnostic method in hypoxemic patients with diffuse lung infiltrates. azoulay et al. [ ] found that deterioration in respiratory status occurred in . % of patients who had bal with oxygen. but only . % of their patients underwent bal with niv. chiner et al. [ ] showed that there were no significant differences in arterial blood gas levels in patients with acute respiratory failure before fob and h after fob. another study showed a significant improvement in arterial blood gas levels of patients with acute decompensated copd due to community-acquired pneumonia second hour after fob with niv [ ] . secretion aspiration might lead to improvement. in our study, there were no significant changes in arterial blood gas analyses and cardiac parameters after fob. other complications such as cardiac arrhythmia, pneumothorax or hemoptysis did not occur in our study population. only three patients ( . %) were intubated within h after fob ( h, h and h, respectively). underlying diseases of these patients were interstitial lung disease and lung involvement due to connective tissue disease. the patients were receiving systemic corticosteroid therapy before admission to hospital and fob was applied to diagnose opportunistic infections. three patients died within h after the procedure. fob should not be considered in these cases, because they had severe underlying diseases and infections when they were admitted. identified mixt infectious agents had a major effect in their fast progression. cytomegalovirus and pneumocystis jiroveci in two patients, acremonium and cytomegalovirus in another patient were shown as opportunistic infectious agents. fiberoptic bronchoscopy usually causes alteration in gas exchange. in hypoxemic intubated patients, pao returns to baseline within h [ ] . none of the patients in the current study needed intubation within h after fob. based on this information, fob may not have led to intubation in three patients. baumann et al. [ ] found that patients required niv prior to the decision to use fob. four of them ( shown as risk factors for intubation [ ] . intubation rate in the current study is acceptable according to presented rates in the literature. intubation rate reached to % in patients with acute respiratory failure who received niv. also, niv failure ratio was % in moderate and % in severe ards [ ] . cases in the current study were not intubated due to sudden gas exchanges and hemodynamic deterioration after bronchoscopy. severe underlying diseases and infection situations should be taken into consideration for imv. the authors of this study aware of the discussions about using niv in patients with ards. but a recent study which assessed intubation rate and risk factors of niv failure in patients with non-hypercapnic acute hypoxemic respiratory failure showed significant differences for intubation rate among four groups (non-ards, mild ards, moderate ards, severe ards). however, the mortality rate was not statistically significant and the time to intubation had no effect on patient mortality [ ] . in patients with hematologic malignancies and acute respiratory failure, delayed (after niv failure) vs. immediate imv was associated with increased hospital mortality which was not statistically significant ( % vs. %) [ ] . early diagnosis and beginning time of true treatment in patients with immunosuppression may be as important as ards severity. the authors think that fob under niv treatment due to ards may be applied to patients whose pao /fio ratio is close to when their hemodynamic status is stable and procedure is performed in icu where all intubation equipment for emergency intubation exist. this study has some limitations. first, there are no control groups. enrolment of a control group was not possible due to ethical reasons, because treatment with niv requires in patients with acute respiratory failure. in other words, it is believed that intubation is not advisable solely for fob applications. second, the study population in the current study was small. third, the study population was composed of patients with hypoxemic and hypercapnic respiratory failure. fourth, the data about excluded patients was not given and limited number arterial blood gas analyses were assessed after fob. fifth, these results were from a single center. in conclusion, fob under niv may be safely and effectively applied for diagnosis and treatment of patients with ards in icu units that is adequately equipped and staffed for intubation. there are high risks associated with intubation during fob and after procedure. therefore, these patients should be closely followed up for ventilation and for other vital parameters. fob with niv may be considered in patients with ards for diagnosis and treatment, so intubation and its complications may be avoided in this patient group. more studies with large sample sizes are required to make a more thorough assessment of fob application under niv in patients with ards. abbreviations apache ii: acute physiology and chronic health evaluation ii; ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; copd: chronic obstructive pulmonary disease; epap: expiratory positive airway pressures; fob: fiberoptic bronchoscopy; icu: intensive care unit; ipap: inspiratory positive airway pressure; niv: noninvasive ventilation; peep: positive end expiratory pressure. the dataset of this article are stored in department of chest diseases of ege university medical faculty and can be made available upon request. authors' contributions pke participated in the design of the study, performed the statistical analysis and was the largest contributor to the manuscript. bba was involved in drafting the manuscript and the acquisition of the data. fb was the main designer of this study and revised the manuscript critically for important intellectual content. mst participated in the design of this study. ag was one of the designers of this study and was involved in drafting the manuscript. sn was the other main designer of this study and revised the manuscript critically for important intellectual content. all authors have read and approved the final manuscript. the european society of intensive care medicine, and the société de réanimation de langue française, and approved by ats board of directors non-invasive ventilation in acute respiratory failure noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure recent advances in mechanical ventilation in patients with acute respiratory distress syndrome unusual applications of noninvasive ventilation tratado de ventilación mecánica no invasiva. práctica clínica y metodológica. madrid: grupo aula médica acute respiratory failure in patients with severe community-acquired pneumonia. a prospective randomized evaluation of non-invasive ventilation noninvasive positive-pressure ventilation vs. conventional oxygen supplementation in hypoxemic patients undergoing diagnostic bronchoscopy continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. a randomized double-blind study using a new device fiber optic bronchoscopy in patients with acute hypoxemic respiratory failure requiring noninvasive ventilation -a feasibility study acute respiratory distress syndrome: the berlin definition the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination a severity of disease classification system fiberoptic bronchoscopy under noninvasive ventilation and propofol target-controlled infusion in hypoxemic patients safety and efficacy of bronchoalveolar lavage using a laryngeal mask airway in cases of acute hypoxaemic respiratory failure with diffuse lung infiltrates effects of transoral and transnasal fiberoptic bronchoscopy on oxygenation and cardiac rhythm cardiac arrhythmias. frequency during fiberoptic bronchoscopy and correlation with hypoxemia clinical role of bronchoalveolar lavage in adults with pulmonary disease fiberoptic bronchoscopy during nasal non-invasive ventilation in acute respiratory failure safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure bronchoscopic lung biopsy using noninvasive ventilatory support: case series and review of literature of niv-assisted bronchoscopy diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data early fiberoptic bronchoscopy during noninvasive ventilation in patients with decompensated chronic obstructive pulmonary disease due to community-acquired-pneumonia fiberoptic bronchoscopy in ventilated patients. evaluation of cardiopulmonary risk under midazolam sedation non-invasive ventilation for acute hypoxemic respiratory failure: intubation rate and risk factors italian group for the evaluation of interventions in intensive care medicine). noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: a -year multicenter observational survey the authors except sn declare no conflict of interest. sn has conflict of interest: advisory board for philips and breas, speaking fee from philips and resmed, travel grants from weinman. not applicable. this study was approved by the ege university ethical and research project committee ( -tip- ).• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- - yu di g authors: fujishima, seitaro title: pathophysiology and biomarkers of acute respiratory distress syndrome date: - - journal: j intensive care doi: . / - - - sha: doc_id: cord_uid: yu di g acute respiratory distress syndrome (ards) is defined as an acute-onset, progressive, hypoxic condition with radiographic bilateral lung infiltration, which develops after several diseases or injuries, and is not derived from hydrostatic pulmonary edema. one specific pathological finding of ards is diffuse alveolar damage. in , in an effort to increase diagnostic specificity, a revised definition of ards was published in jama. however, no new parameters or biomarkers were adopted by the revised definition. discriminating between ards and other similar diseases is critically important; however, only a few biomarkers are currently available for diagnostic purposes. furthermore, predicting the severity, response to therapy, or outcome of the illness is also important for developing treatment strategies for each patient. however, the pao( )/fio( ) ratio is currently the sole clinical parameter used for this purpose. in parallel with progress in understanding the pathophysiology of ards, various humoral factors induced by inflammation and molecules derived from activated cells or injured tissues have been shown as potential biomarkers that may be applied in clinical practice. in this review, the current understanding of the basic pathophysiology of ards and associated candidate biomarkers will be discussed. acute respiratory distress syndrome (ards) is defined as an acute-onset, progressive, hypoxic condition characterized by bilateral lung infiltration on chest x-ray or computed tomography [ ] . ards develops quickly after several conditions, traumas, or insults. however, it needs to be confirmed that the condition does not result from heart or renal failure or overhydration. diffuse alveolar damage (dad) is designated as a specific pathological finding for ards. for more than two decades, the definition set forth by the american-european consensus conference (aecc) has been used for the clinical diagnosis of ards [ ] , and a newer definition with better specificity has long been awaited. in , a draft of a revised definition was presented at the th annual congress of the european society of intensive care medicine in berlin, and its final version was published in jama in may [ ] . in the revised berlin definition, the term ards was redefined as a broader concept including a milder condition of lung injury; therefore, it became equivalent to acute lung injury (ali), which was the previous aecc definition. the revised ards definition was significantly improved by the inclusion of timing, underlying conditions, and the mandated determination of the pao /fio ratio under positive airway pressure. however, no new parameters or biomarkers were adopted. in this review, the current understanding of the basic ards pathophysiology and associated candidate biomarkers will be discussed. the essential pathophysiology of ards includes increased pulmonary microvascular permeability. the process of water passage from the capillaries to the alveoli is presented with several physical barriers, including endothelial and epithelial cell layers, the basement membrane, and the extracellular matrix. among these barriers, water passage (permeability) across endothelial and epithelial cell layers is actively regulated. increased vascular permeability in ards is the result of several independent mechanisms. first, tissue injury and the resultant destruction of the pulmonary microvascular architecture contribute to a direct leak of blood components from the capillaries to the alveoli. in addition, endothelial and epithelial permeability is dynamically regulated by a set of inter-and intracellular molecules, the dysregulation of which may also induce increased vascular permeability. in order to protect the lungs from pulmonary edema, the pulmonary lymphatic system and epithelial water channels play important roles in pumping water out of extravascular space. however, when vascular leakage surpasses the capacity of these compensating systems, clinical pulmonary edema develops. there are multiple mechanisms by which vascular permeability is regulated. sphingosine- phosphate (s p) binds to its receptor, s p , and regulates vascular permeability through non-muscle myosin light chain kinase (nmmlck) and the rho family gtpase pathway [ ] . in addition, angiopoietin- (ang- ) binds to its receptor, tie- , to stabilize the vasculature through the activation of syx and rho a [ ] . in contrast, angiopoietin- (ang- ) is produced by activated endothelial cells and competes with ang for tie binding to destabilize vascular junctional formation [ ] . the dysregulation of any of these mechanisms may lead to a change in vascular permeability; therefore, these factors may represent potential biomarkers for ards. acute inflammation of and neutrophil accumulation in the lungs are commonly observed in both patients with ards and animal models of the disease. extensive research has revealed the pathogenic roles of neutrophilmediated acute inflammation in ards development [ ] . neutrophils release cytotoxic molecules, including granular enzymes, reactive oxygen metabolites, bioactive lipids, and cytokines, and induce the formation of neutrophil extracellular traps (nets) [ ] . in addition to causing tissue necrosis, these cytotoxic molecules induce apoptosis and autophagy, each of which causes tissue injury and cell death, which are characteristic of ards [ ] . numerous proinflammatory cytokines play major roles in acute inflammation and the development of inflammatory lung diseases, including ards. among these, tumor necrosis factor alpha (tnfα) and interleukin beta (il- β) can induce ali when administered to animals, and their levels are also elevated in the lungs of ards patients. therefore, they are thought to be key pathogenic cytokines in ards. in addition, a neutrophil chemotactic chemokine, interleukin (il- , cxcl ), is important because its neutralizing antibody was protective against the development of ali in animal models, and il- levels are elevated in the lungs of ards patients [ ] . additional cytokines and chemokines are involved in the development of ards, including il- and il- , both of which, like il- β, are regulated by the inflammasome/caspase- pathway [ , ] . these cytokines may represent good targets for antimediator therapy for ards as well as become potential biomarkers of ards. recently, pattern recognition receptors (prrs) were demonstrated to play a key role in innate immunity [ ] . prrs are cell-surface or cytosolic proteins expressed by innate immune cells, and each is activated by a specific molecule (s). prr ligands are divided into two categories, namely, pathogen-associated molecular patterns (pamps) and damage (danger)-associated molecular patterns (damps). pamps are extrinsic molecules derived from various microorganisms, while damps are intrinsic molecules derived from injured cells or extracellular molecules. when these prrs are activated, nuclear factor (nf)-κb translocates to the nucleus, predominantly through a myeloid differentiation primary response gene (myd )-dependent mechanism. activation of prrs also leads to the transcription of proinflammatory cytokines such as tnfα, il- β, and il- . table lists the major prrs and their counterpart pamps and damps. infection, including severe sepsis and pneumonia, is the leading predisposing factor for ards. in this regard, the pathogenic roles of lipopolysaccharide (lps) have been thoroughly examined. because other pamps can induce proinflammatory reactions, it is reasonable to speculate that they also play important roles in the development and progression of ards. in addition, because tissue destruction (i.e., multiple trauma and burn injuries) is a major predisposing factor for ards, we can speculate that damps play critical roles in its onset and/ or progression. the high-mobility group box protein (hmgb ) was one of the earliest discovered nuclear binding proteins demonstrated to function as a damp [ ] . this protein not only leaks from damaged cells, but its production is also induced in activated dendritic cells and macrophages. hmgb can potently induce inflammation through its interaction with multiple receptors, including the receptor for advanced glycation end products (rage), toll-like receptor (tlr ), and toll-like receptor (tlr ). initially, a pathogenic role of hmgb was reported in association with sepsis; subsequently, its involvement in ards was also revealed [ , ] . histone, another nuclear binding protein, is released into the circulation after trauma and can induce inflammation and ali in animal models [ ] . further, mitochondrial dna can induce the production of il- and thus may play a role in ards as a damp [ ] . at present, however, little is known of the pathogenic roles of prrs, pamps, and damps in ards, and their involvement needs to be clarified in future studies. differentiating similar diseases or conditions from ards remains to be a matter of great importance. currently, only a few biomarkers are clinically available for this purpose. for example, brain natriuretic peptide (bnp) is used for differentiation between ards and hydrostatic pulmonary edema, although its usefulness remains controversial [ , ] . procalcitonin is increased in bacterial infection, but not in viral or fungal infection; it may be useful for discriminating between bacterial pneumonia and ards. however, because the sensitivity of procalcitonin is as high as % for bacterial pneumonia and because bacterial pneumonia and sepsis are common predisposing conditions for ards, its utility is limited [ ] . predicting the severity of illness is also important to develop a specific diagnostic strategy for each patient with ards, but the pao /fio ratio is the sole clinical parameter used for this purpose. the importance of biomarkers is underscored by the fact that they can also be utilized to predict response to therapy and prognosis. however, no ards-specific biomarkers are currently available for these purposes. as discussed above, various humoral factors have been identified as candidate biomarkers of ards (table ) . among the proinflammatory cytokines, tnfα, il- β, interleukin (il- ), and il- are elevated in the bronchoalveolar lavage fluid (balf) of ards patients, and their levels were reportedly higher in non-survivors than in survivors [ ] . we previously showed that il- levels in balf were higher in patients with ards and inhalation injury [ , ] . these levels were also able to predict the degree of lung oxygenation impairment in inhalation injury. recent secondary analysis of the ards clinical network's (ardsnet) activated protein c study, where various candidate biomarkers of ards were assessed, showed that plasma plasminogen activator inhibitor (pai- ) and il- were correlated with the oxygenation index (mean airway pressure × fio /pao ). furthermore, ventilator-free days were significantly shorter in patients with higher levels of il- , il- , and thrombomodulin, which were associated with poor patient outcomes [ ] . among these three molecules, the usefulness of il- in predicting the outcome of ards was confirmed by several additional studies [ , ] . a recent report from harvard demonstrated that il- is a new ards biomarker [ ] . this study was independently performed by three affiliated hospitals and showed a consistent increase in plasma il- levels in ards patients, while mortality was increased in direct proportion to plasma il- levels. several growth factors have been determined to be candidate biomarkers of ards. in this regard, the lung levels of vascular endothelial growth factor (vegf) and keratinocyte growth factor (kgf) were shown to correlate with the severity of illness and reflect patient outcome [ , ] . furthermore, secondary analysis of the ardsnet's fluid and catheter treatment (fact) study revealed that plasma levels of growth differentiation factor- (gdf- ) were increased in proportion to -day mortality [ ] . another recent study showed that ang- , a competitor of ang- and a regulator of vascular permeability (as mentioned earlier), could predict the prognosis of ards [ ] . as described, among inflammatory cells, neutrophils play dominant roles in inducing ards through the release of various cytotoxic substances and mediators, including granular enzymes, reactive oxygen species, bioactive lipids, cytokines, and nets. therefore, these neutrophil-derived molecules can be candidate biomarkers of ards. neutrophil elastase, a major granular enzyme with potent nonspecific tissue destruction activity, forms a complex with alpha -antitrypsin (ne-at) soon after release from activated neutrophils. we have previously shown that the levels of the ne-at complex were increased in ards patients and were significantly higher in a subgroup of patients with clinical deterioration after admission than in a subgroup without deterioration [ ] . leptin, a hormone involved in the regulation of energy intake and expenditure, was also shown to contribute to ards development. epidemiological data demonstrated the low incidence of ards among patients with diabetes mellitus; however, the reason for this is unknown [ , ] . recently, a decrease in leptin levels in these patients was shown as a potential key mechanism underlying this epidemiological finding. in an animal experiment, leptin induced the expression of transforming growth factor beta (tgf-β) and the production of collagen types i and ii in the presence of tgf-β, and leptin-deficient mice were resistant to the development of ali [ ] . furthermore, in non-obese patients with ards, leptin levels in balf correlated with tgf-β levels. the duration of artificial ventilation and icu stay was significantly longer in a subgroup of ards patients with higher leptin levels in balf than in those with lower leptin levels in balf [ ] . these results suggest that leptin can be a candidate biomarker of ards. substances derived from activated cells or injured tissues can also reflect the degree of inflammation or tissue injury and, consequently, the severity of ards. in addition to the earlier discussed pathogenic role of hmgb in ards, it was shown to be a candidate biomarker of ards, along with soluble rage [ ] . excessive formation and ineffective clearance of neutrophil extracellular trap in alveolar space would be responsible for the pathogenesis of ards. the increase in dna decorated with proteases and histone in balf was observed in cystic fibrosis [ ] and acute inhalation injuries [ ] . thus, dna in balf could also become the candidate as biomarker for ards. similarly, histone may be useful as an ards biomarker in patients with lungs subjected to multiple trauma [ ] . as the roles of damps in the pathophysiology of ards are revealed, their utility as biomarkers will also be clarified. among endothelial cell-derived molecules, plasma levels of soluble p-selectin and soluble intercellular adhesion molecule (sicam- ) were reported as candidate biomarkers. the potential of sicam- was demonstrated by multicenter studies [ , ] . additional epithelial cellderived molecules that represent candidate ards biomarkers include sialylated carbohydrate antigen krebs von den lungen- (kl- , a fragment of muc mucin), surfactant protein b (sp-b) [ ] , surfactant protein d (sp-d) [ , , ] , clara cell protein cc- [ ] , and the gamma- chain of laminin- (an extracellular matrix protein with cell adhesive properties) [ ] . in , an article that focused on a new meta-analysis of plasma biomarkers for ards was published [ ] . the authors analyzed studies and found that kl- , lactate dehydrogenase, soluble rage, and von willebrand factor are strongly associated with ards diagnosis in the at-risk population. for outcome prediction, they found that il- , il- , ang- , and kl- were most strongly associated with mortality from ards. in parallel with progress in the understanding of ards pathophysiology, several molecules have been shown to be candidate biomarkers of this disease, with the clinical usefulness of some being confirmed by large-scale or multicenter studies. however, none of these candidates have been clinically applied for diagnosis or prediction of disease severity, response to therapy, and prognosis in patients with ards. future studies, along with a search for new biomarker candidates, need to determine the potential application(s) of each candidate discussed here. this will lead to improved diagnosis and treatment strategies for patients with ards. update in acute respiratory distress syndrome definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition concepts in microvascular endothelial barrier regulation in health and disease regulation of vascular permeability by sphingosine -phosphate angiopoietin signaling in the vasculature neutrophil-mediated tissue injury and its modulation excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis interactions between mechanical and biological processes in acute lung injury a prominent role of il- in inflammatory lung diseases and multiple organ dysfunction syndrome human mesenchymal stem cells overexpressing the il- antagonist soluble il- receptor-like- attenuate endotoxin-induced acute lung injury inflammasome-regulated cytokines are critical mediators of acute lung injury innate immune recognition in infectious and noninfectious diseases of the lung hmg- as a late mediator of endotoxin lethality in mice increased levels of soluble receptor for advanced glycation end products (srage) and high mobility group box (hmgb ) are associated with death in patients with acute respiratory distress syndrome contributions of high mobility group box protein in experimental and clinical acute lung injury circulating histones are mediators of trauma-associated lung injury circulating mitochondrial damps cause inflammatory responses to injury diagnostic utility of b-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study b-type natriuretic peptide in the assessment of acute lung injury and cardiogenic pulmonary edema usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia inflammatory cytokines in the bal of patients with ards. persistent elevation over time predicts poor outcome pathogenetic and predictive value of biomarkers in patients with ali and lower severity of illness: results from two clinical trials national heart blood, and lung institute acute respiratory distress syndrome network: use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients growth differentiation factor- and prognosis in acute respiratory distress syndrome: a retrospective cohort study plasma angiopoietin- predicts the onset of acute lung injury in critically ill patients neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients role of diabetes in the development of acute respiratory distress syndrome* diabetes, insulin, and development of acute lung injury leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferatoractivated receptor-{gamma} hartl d: cxcr mediates nadph oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation dna and inflammatory mediators in bronchoalveolar lavage fluid from children with acute inhalational injuries soluble intercellular adhesion molecule- and clinical outcomes in patients with acute lung injury soluble form of p-selectin in plasma is elevated in acute lung injury elevated plasma surfactant protein-b predicts development of acute respiratory distress syndrome in patients with acute respiratory failure acute respiratory distress syndrome network: plasma surfactant protein levels and clinical outcomes in patients with acute lung injury critical care research group of the quebec respiratory health network: outcome value of clara cell protein in serum of patients with acute respiratory distress syndrome laminin gamma fragments are increased in the circulation of patients with early phase acute lung injury plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis cite this article as: fujishima: pathophysiology and biomarkers of acute respiratory distress syndrome the author declares that he has no competing interest. key: cord- -psjyjvbu authors: zhou, yile; yang, yajie; liang, tao; hu, yan; tang, haihong; song, dongli; fang, hao title: the regulatory effect of microrna- a- p on the promotion of telocyte angiogenesis mediated by pi k (p α)/akt/mtor in lps induced mice ards date: - - journal: j transl med doi: . /s - - -z sha: doc_id: cord_uid: psjyjvbu background: telocytes (tcs) are newly identified interstitial cells that participate in tissue protection and repair. the present study investigated the mechanisms underlying the protective effect of tcs in a mouse model of respiratory distress. methods: the mouse model of acute respiratory distress syndrome (ards) was established by intratracheal instillation of lipopolysaccharide (lps). after instillation of tcs culture medium, lung injury was assessed, and angiogenesis markers, including cd and endothelial nitric oxide synthase (enos), were detected by immunofluorescence. bioinformatics analysis was used to screen significantly differentially expressed micrornas (mirnas) in cultured tcs stimulated with lps, and the regulation of downstream angiogenesis genes by these mirnas was analysed and verified. pi k subunits and pathways were evaluated by using a pi k p α inhibitor to study the involved mechanisms. results: in ards mice, instillation of tcs culture medium ameliorated lps-induced inflammation and lung injury and increased the protein levels of cd and enos in the injured lungs. a total of mirnas and mrnas were differentially regulated in tcs stimulated with lps. functional prediction analysis showed that the differentially expressed mrnas were enriched in angiogenesis-related processes, which were highly correlated with mir- a- p. culture medium from tcs with mir- a- p inhibition failed to promote angiogenesis in mouse models of lps-induced ards. in cultured tcs, lps stimulation upregulated the expression of mir- a- p, which further targeted the transcription factor e f and decreased notch protein expression. tcs culture medium enhanced hemangioendothelioma endothelial cells (eoma cells) proliferation, which was blocked by the mir- a- p inhibitor. the pi k p α inhibitor decreased vascular endothelial growth factor levels in lps-stimulated tcs and reversed the enhancing effect of tcs culture medium on eoma cells proliferation. conclusions: tcs exerted protective effects under inflammatory conditions by promoting angiogenesis via mir- a- p. the pi k p α subunit and transcriptional factor e f could be involved in this process. acute respiratory distress syndrome (ards) is a clinical syndrome characterised by acute progression of respiratory failure. according to an international multicentre research, the prevalence of ards was . % of icu admissions [ ] . inflammatory responses destroy underlying vascular endothelial cells and respiratory epithelial cells and impair the lungs' ability to exchange oxygen and carbon dioxide [ ] . therefore, decreasing inflammation and accelerating blood vessel repair are two key factors in the prevention and treatment of ards. since its severity and lack of effective pharmacologic treatments [ ] , it is of great significance to explore novel therapeutic strategies for ards. recently, cell therapy have been shown to have promising therapeutic potential. mesenchymal stem cells ameliorated ards due to paracrine mechanism [ ] . telocytes (tcs) are newly identified mesenchymal cells that play a role in providing nutrition to surrounding cells by cell-cell communication and have post-injury repair and regeneration functions [ ] [ ] [ ] . tcs contribute to angiogenesis within the myocardium [ ] . transplantation of cardiac tcs promotes post ischaemic myocardial repair [ ] . pulmonary tcs also assist with angiogenesis since they participate in forming the structure of the air-blood barrier [ ] . intratracheal administration of activated tcs has been reported to alleviate ventilator-induced lung injury in a mouse model by releasing angiogenic factors [ ] . however, the underlying mechanism remains unclear. class i phosphoinositide- -kinases (pi ks) or the four subtypes of catalytic subunit-p α, p β, p γ and p δ-are expressed in all mammalian cells. the catalytic subunits bind to p regulatory subunits, activate receptor tyrosine kinases (rtks), and transmit a variety of cell surface receptor signals, such as those from the epidermal growth factor receptor (egfr) or fibroblast growth factor receptor (fgfr), to promote cell growth [ ] . the pi k subunits p α and p δ were demonstrated to be associated with tissue repair; however, this function is mediated by different mechanisms. the activity of pi k p α can be enhanced by tyrosine kinase ligands, such as vascular endothelial growth factor (vegf) a, and can induce angiogenesis and vascular remodelling [ ] . moreover, p α regulates endothelial cell migration through the small gtpase rhoa, mediated by pi kcg, a gene encoding a p γ subunit, which has a protective effect on hypoxic-reoxygenated cardiomyocytes mediated by activation of the pi k/akt signalling pathway and inhibition of apoptosis [ ] . pi k (p δ)/ akt/mammalian target of rapamycin (mtor) signalling pathway mediates interferon-γ (ifn-γ) induced airway epithelial cell growth and proliferation through interaction with ceacam [ ] . micrornas (mirnas) are small, non-coding rnas that regulate the expression of target genes via posttranscriptional degradation of mrna and/or translational inhibition of protein expression. mir- a can influence cell proliferation, migration, invasion, apoptosis and tumour angiogenesis through the igf- /pi k/ akt signalling pathway in non-small cell lung cancer (nsclc) [ ] . mature mir- a- p was found to be secreted by lipopolysaccharide (lps)-activated macrophages in small vesicles, which were endocytosed and internalised by renal fibroblasts, thereby promoting the expression of fibrosis and inflammation markers in a mouse model of chronic renal allograft dysfunction (cad) in allogeneic kidney transplantation [ ] . antagonism of mir- a- p ameliorated cad in mouse model following kidney transplantation [ ] . in patients with renal allograft, elevation of urinary [ ] and plasma [ ] mir- level was correlated with interstitial fibrosis and tubular atrophy. the tcs line was established by transfection with simian vacuolating virus (sv ) and identified to maintain tcs morphology and immune characteristics [ ] . tcs proliferation was demonstrated to be regulated by transforming growth factor-β (tgf-β) and mediated by the pi k p α subunit and the pi k/akt/mtor signalling pathway [ ] . the present study was designed to investigate the underlying protective effect of tcs in a mouse model of respiratory distress. bioinformatics approaches were applied to analyse gene expression profiles in tcs challenged with lps. particular attention was devoted to the angiogenesis-related process. the protective mechanisms mediated by the pi k subunit in tcs were further examined in hemangioendothelioma endothelial cells (eoma cells) in vitro. the current study presents the theoretical bases of an alternative new potential therapeutic strategy for ards. both the mir- a- p inhibitor and nc were purchased from china ribobio (ribobio, guangzhou, china). tcs were transfected with the mir- a- p inhibitor and nc at a final concentration of nmol/l using a lipofectamine rnaimax transfection system (thermofisher scientific, carlsbad, ca) according to the manufacturer's protocol. cells were incubated with sirna in serum-free and antibiotic-free medium for h and then in normal growth medium for another h before the experiments were performed. gene expression profiling analysis of both mirna and mrna were performed with agilent microarray scanner (cat # g ca, agilent technologies, santa clara, ca). the data were normalised with the agimicrorna package [ ] . the gene expression files were analysed with r- . . software. differentially expressed genes (degs) were defined as those with an adjusted p-value of less than . . degs were further analysed with the limma package [ ] . heat maps were generated with the ggplot package [ ] . the online databases mirwalk [ ] and targetscan [ ] were used to screen potential mirna target genes. overlapping genes in the two databases were selected for further analysis. the online database string [ ] and the database for annotation, visualization and integrated discovery (david) v . [ ] were used to analyse gene function. the relationship between degs and mir-nas was further visualised with cytoscape . . [ ] . total rna was extracted from cultured tcs with trizol (takara, shiga, japan) according to the provided instructions. mirnas were reverse transcribed with a bulge-loop mirna qrt-pcr starter kit (ribobio, guangzhou, china), and mrnas were reverse transcribed to complementary dna (cdna) with a primescript rt reagent kit with gdna eraser (takara, shiga, japan). the expression levels of mir- a- p, mir- - p and mrnas were measured by quantitative real-time polymerase chain reaction (qpcr) on a bio-rad iq real-time pcr instrument, with u and gapdh used as the housekeeping genes for mirnas and mrnas, respectively. mirna pcr was performed with the bulge-loop mirna qrt-pcr starter kit, bulge-loop mmu-mir- a- p primer set and bulge-loop mmu-mir- - p primer set (ribobio, guangzhou, china). mrna primers were synthesised by sangon (shanghai, china). the following mouse-specific primers were used: gapdh sense primer: ′-gtt caa cgg cac agt caa g- ′, antisense primer: ′-gcc agt aga ctc cac gac at- ′; e f sense primer: ′-ctg ttt gca cga aca ctt atcag- ′, antisense primer: ′-gta ccg cgc tag gaa ttt gtg- ′; acvrl sense primer: ′-tga ttc ctg ttg ccg gcc t- ′, antisense primer: ′-cag tgt ggg ctc tca caa gt- ′; rbpj sense primer: ′-tgg cga gag ttt gtg gaa ga- ′, antisense primer: ′-agc act gtt tga tcc cct cg- ′; notch sense primer: ′-tgt ggc ttc ctt cta ctg cg- ′, antisense primer: ′-ctt tgc cgt tga cag ggt tg- ′; flt sense primer: ′-gtg agc act gcg gca aaa ag- ′, antisense primer: ′-act cat ttt ggg agg agc gt - ′; efnb sense primer: ′-cga ggt ggc aac aac aat gg- ′, antisense primer: ′-ata gtc ccc gct gac ctt ct - ′; thbs sense primer: ′-ctg cca atc ata acc agc g- ′, antisense primer: ′-ttc gtt aaa ggc cga gtg ct- ′; epas sense primer: ′-ctg agg aag gag aaa tcc cgt- ′, antisense primer: ′-tgt gtc cga agg aag ctg atg- ′; hypoxia inducible factor- α (hif- α) sense primer: ′-acc ttc atc gga aac tcc aaag- ′, antisense primer: ′-ctg ttg gct ggg aaa agt tagg- ′; pik ca sense primer: ′-cca cga cca tct tcg ggt g- ′, antisense primer: ′-acg gag gca ttc taa agt cacta- ′; pik cb sense primer: ′-cta tgg cag aca acc ttg acat- ′, antisense primer: ′-ctt ccc gag gta ctt cca act- ′; pik cd sense primer: ′-gta aac gac ttc cgc act aaga- ′, antisense primer: ′-gct gac acg caa taa gcc g- ′; and vegf sense primer: ′-gta cct cca cca tgc caa gt- ′, antisense primer: ′-tcc tat gtg ctg gct ttg gt- ′ . total protein was extracted from cultured tcs with lysis buffer ( mmol/l nacl, mmol/l edta, mmol/l naf, mmol/l dithiothreitol, μg/μl aprotinin, μg/ μl leupeptin, . mmol/l na vo , mmol/l phenylmethylsulfonyl fluoride (pmsf), and . % np- ). protein extracts ( μg) were separated by % sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes (merck millipore, darmstadt, germany). after blocking with % non-fat milk/tris-buffered saline containing . % tween at room temperature for one hour, membranes were incubated with primary antibodies [specific for gapdh ( - -ig, proteintech, wuhan, china), e f (ab , abcam, cambridge, uk), deltalike (dll )(ab , abcam, cambridge, uk), notch (sc- , santa cruz, dallas, tx), notch (sc- , santa cruz, dallas, tx), notch (sc- , santa cruz, dallas, tx), phosphatase and tensin homolog deleted on chromosome ten (pten)(ab , abcam, cambridge, uk), pi k ( t, cst, boston, ma), p-pi k ( t, cst, boston, ma), mtor ( t, cst, boston, ma), p-mtor ( t, cst, boston, ma), akt ( s, cst, boston, ma), p-akt ( s, cst, boston, ma), and p α ( t, cst, boston, ma)] overnight at °c. protein expression levels were normalised to those of gapdh with imagej (nih, bethesda, md). eoma cells proliferation was assessed with a colorimetric assay-cell counting kit- (cck , yeasen, shanghai, china)-following the manufacturer's protocol. approximately eoma cells/well were seeded in a -well plate. after adhesion, eoma cells were incubated for h with culture medium from tcs transfected with the mir- a- p inhibitor or nc in the presence of lps. the pgl reporter vector (promega, madison, wi) was used to generate the plasmids pgl -wt-e f - ′-utr and pgl -mut-e f - ′-utr. human embryonic kidney cells were co-transfected with pgl -e f - ′-utr (wt or mut) and the mir- a- p mimic or nc with lipofectamine reagent (thermofisher scientific, carlsbad, ca). after incubation for h, luciferase activity was assessed by the dual-luciferase reporter assay system (promega, madison, wi) according to the manufacturer's protocol. the concentration of vegf in the tcs culture medium was measured by a commercial vegf elisa kit (westang, shanghai, china) according to the manufacturer's protocol. live observation of eoma cells was performed with a cell-iq cell culture platform (chip-man technologies, tampere, finland) equipped with a phase contrast microscope (nikon cfi achromat phase contrast objective with magnification) and a camera (nikon, fukasawa, japan). the equipment was controlled by imagen software (chip-man technologies). each group contained replicates of visual fields. images were acquired at -h intervals for h. lung tissues were fixed with % formalin solution and embedded in paraffin. each tissue was sectioned at μm and stained with haematoxylin-eosin (he, beyotime, shanghai, china) according to the manufacturer's protocol. for immunofluorescence staining, an antigen retrieval protocol was carried out with incubation in . % h o for min and heating to boiling in a microwave in citrate buffer for min. after blocking with % goat serum in tris-buffered saline, sections were incubated with diluted primary antibodies [cd ( : , ab , abcam, cambridge, uk), endothelial nitric oxide synthase (enos) ( : , cat , bd biotechnology, san jose, ca)] overnight at °c and then with secondary antibodies and ′, -diamidino- -phenylindole (dapi), separately. data are expressed as the means ± sds and were analysed by one-way analysis of variance (anova) and tukey's multiple comparisons test. a p-value of < . was considered statistically significant. all statistical analyses were performed with graphpad prism . (graphpad, san diego, ca). the ability for tcs protection was first estimated in ards mouse models. lps stimulation caused inflammatory infiltration, alveolar wall widening, and vessel destruction (fig. a) . the production of inflammatory cytokines was elevated in ards mice (fig. b) . since substances, including molecules and exosomes, released by tcs could be important factors affecting adjacent cells, the effect of tcs culture medium was assessed. instillation of tcs culture medium reduced the inflammatory infiltration, reduced the alveolar interstitial width and decreased the levels of inflammatory cytokines. bio-behaviours of tcs were recorded by cell-iq to show the typical morphology of cultured cells (additional file : figure s ). as angiogenesis is essential in tissue repair, the induction of angiogenic factors in tcs after stimulation with lps was assessed. in ards mice, the expression of the angiogenesis-related marker cd and enos was downregulated. however, an increase in cd and enos expression was observed in the wt tcs treatment group but not in the group treated with medium from tcs with mir- a- p inhibition (fig. ) . to identify the critical mirnas in the regulation of angiogenesis by tcs, mirna and mrna profiles were generated, and the relationship of differentially expressed mirnas with downstream angiogenesis factor-associated mrnas were analysed in lps-stimulated tcs. in the mrna expression of inflammatory cytokines in mice lungs in the above four groups. *p < . vs control, # p < . vs lps, **p < . vs lps/tcs, n = . il- β interleukin- β, il- interleukin- , tnf-α tumour necrosis factor-α lps-stimulated tcs, six mirnas, including mir- - p, mir- a- p, mir- , mir- - p, mir- a- p and mir- a- p, were upregulated, and one mirna (mir- - p) was downregulated with an absolute fold change > ( fig. a and table ). by referring these results to two online databases (mirwalk and targetscan), target genes were predicted to be downstream targets of the differentially expressed mirnas. in total, mrnas- upregulated and downregulated-were differentially expressed in tcs after lps stimulation ( fig. b and table ). a total of genes overlapped with those from the online prediction (fig. c) . pulmonary tcs were reported to promote angiogenesis in a mouse model of ards [ ] ; thus, particular attention was devoted to angiogenesis in the gene ontology (go) functional analysis. according to the david online database, degs were enriched in the processes of blood vessel formation, angiogenesis, blood vessel morphogenesis, blood vessel remodelling, and sprouting angiogenesis. for further analysis, the degs were enriched in the string database. according to the string database, the degs were enriched in angiogenesis-related processes: angiogenesis, blood vessel morphogenesis, vasculature development, blood vessel remodelling, sprouting angiogenesis, venous blood vessel sprouting, venous blood vessel morphogenesis, regulation of angiogenesis, and positive regulation of angiogenesis (fig. d) . as most genes participated in at least biological processes, those involved in more than three processes-i.e. e f , notch , epas , rbpj, flt , acvrl , efnb and thbs -were selected for further research. mir- a- p, mir- - p, mir- a- p and mir- - p regulated these genes (fig. e) . we next assessed the mrna levels of angiogenesis factors. the mrna expression of e f , notch , epas , rbpj, flt , acvrl , efnb and thbs was measured in fig. differentially expressed genes in tcs with lps treatment. a heat map of differential expressed mirnas in cultured tcs stimulated with lps. b heat map of differential expressed genes in cultured tcs stimulated with lps. c relationship between differential expressed mirnas and their differential expressed target mrnas. yellow indicated mirnas, green indicated downregulated mrnas, and red indicated upregulated mrnas. d interaction of the angiogenesis-related proteins in string. different colours indicated the involvement of proteins in different processes. red indicated angiogenesis, pink indicated blood vessel morphogenesis, purple indicated vasculature development, brown indicated blood vessel remodelling, blue indicated sprouting angiogenesis, cyan indicated venous blood vessel sprouting, orange indicated venous blood vessel morphogenesis, green indicated regulation of angiogenesis, and yellow indicated positive regulation of angiogenesis. e angiogenesis related mirnas and their downstream genes. red indicated upregulated mirnas, green indicated downregulated mirnas, yellow indicated genes that were enriched in more than three processes in string, blue indicated other mrnas tcs after lps stimulation. after lps stimulation, e f , efnb , and epas were significantly downregulated, while flt was upregulated. given that mirnas usually negatively regulate downstream genes, e f , efnb , and epas were further studied. lps stimulation significantly increased mir- a- p and mir- - p expression in tcs compared with that in cells under control conditions. to clarify the relationship between mirnas and mrnas, mirna inhibitors were applied. mir- - p inhibition restored the expression of epas but not efnb , and mir- a- p inhibition restored the expression of e f but not epas . mir- had been reported to increase proliferation, migration and tube formation of human umbilical vein endothelial cells (huvecs) and induce angiogenesis by directly targeting pten [ , ] . moreover, mir- a- p and its downstream target e f were further studied. after h, the protein expression of e f was decreased in tcs challenged with lps and was restored by inhibition of mir- a- p. the dual luciferase reporter assay indicated that e f was the direct target of mir- a- p (fig. ). the transcription factors e f / were reported to regulate vessel branching via dll -notch approaches [ ] or hif- α/vegfa signalling [ ] . in the present study, lps stimulation reduced the protein expression of notch but not notch , notch or dll . inhibition of mir- a- p restored notch protein expression in tcs in the presence of lps. lps did not affect hif- α expression. however, lps increased the expression of vegfa at the mrna level, and this increase was reversed by mir- a- p inhibition in cultured tcs (fig. ). pi k, especially the class i catalytic isoforms, plays an important role in angiogenesis. to study the mechanisms underlying the effect of mir- a- p in tcs on angiogenesis induction, pi k subunit expression was first examined. the mrna levels of the class i pi k isoforms pik ca, pik cb, and pik cd did not significantly change with lps stimulation. however, the protein level of p α in tcs was significantly increased with lps stimulation and decreased with mir- a- p inhibitor co-treatment. the pi k signalling molecules akt, mtor, and pten were unaffected by either lps or mir- a- p. these results indicated that pi k signalling might participate in angiogenesis via the p α isoform (fig. ). the proliferation of eoma cells was then estimated after co-culture with tcs pre-treated with the mir- a- p or pi k p α inhibitor. culture medium from tcs stimulated with lps promoted eoma cells proliferation, as determined by the cck assay. compared with medium from nc tcs, culture medium from tcs with mir- a- p inhibition significantly reduced eoma cells proliferation (fig. a) . the effect of p α was examined by dynamic real-time cell observation. the proliferation assay indicated that eoma cells proliferation decreased with lps stimulation but was restored by co-culture with tcs. inhibition of mir- a- p or p α (with its inhibitor hs- ) weakened the protective effect of tcs (fig. b, d) . the scratch assay showed similar results (fig. c, e) . vegf protein expression was significantly elevated with lps stimulation, and this increase was reversed by inhibition of either mir- a- p or p α (fig. f ) . the results above indicated that vegf is regulated by both mir- a- p and p α. this study reports that tcs culture medium can alleviate ards in mice probably via angiogenesis-associated factors regulated by mir- a- p. tcs exposed to lps exhibited increased mir- a- p expression and vegf production, which further promoted vascular endothelial cell proliferation. the protective effects of tcs mediated by mir- a- p might be regulated through pi k (p α)/ akt/mtor signalling and the expression levels of the downstream targets e f and notch (fig. ) . endotoxin-induced ards has been reported to affect both respiratory epithelial cells and the underlying vascular endothelial cells [ ] . in the present study, lps stimulation induced severe vascular damage in the lungs, as shown by the reduced levels of cd and enos. tcs are distinct from mesenchymal stem cells and fibroblasts and have been reported to have specific roles in cell signalling, tissue remodelling and angiogenesis [ ] . in the present study, tcs culture medium exhibited great potential to reverse the angiogenic signalling that was reduced by lps-induced inflammation, supporting the observation that tcs alleviate lps-induced lung injury in mice by releasing angiogenic factors [ ] . non-coding mirnas are involved in several pathological processes, including angiogenesis [ , ] . mir- - p [ ] , mir- a- p [ ] , and mir- a- p [ ] [ ] [ ] are reported to be associated with the angiogenesis process. mir- a- p and mir- - p were demonstrated to be involved in the promotion of angiogenesis in tcs. as mir- a- p was more frequently reported on angiogenesis, it was further studied. mir- a- p knockdown fig. mir- a- p and p α mediated the promotion of tcs on eoma proliferation induced by lps. a cells proliferation rate of eoma treated with lps and/or tcs and mir- a- p inhibitor measured by cck assay. *p < . vs control, # p < . vs lps/tc. b, d cell proliferation of eoma treated with lps and/or tcs and mir- a- p inhibitor or p α inhibitor measured by cell-iq. *p < . vs control, # p < . vs lps, **p < . vs lps/ tc, n = . c, e cell movement of eoma treated with lps and/or tcs and mir- a- p inhibitor or p α inhibitor measured by cell-iq. f vegfa levels secreted by tcs treated with lps and/or mir- a- p inhibitor or p α inhibitor measured by elisa. *p < . vs control, # p < . vs lps, n = : in tcs reduced cd and enos expression in the lungs of ards mice in vivo. mir- a- p exerts its protective effects on injury repair by inducing angiogenesis-associated signalling pathways. for instance, mir- a- p activates the akt pathway and increases matrix metalloproteinase- (mmp- ) expression to reduce the extent of the infarcted region in heart ischaemia/reperfusion injury [ ] , inhibits pten and sprouty homolog (spry ) to heal soft tissue wounds [ ] , and upregulates vegf and activates the ang- /tie- axis in traumatic brain injury [ ] . in the current study, the p α isoform in pi k/akt/mtor signalling pathway was demonstrated to be involved in mir- a- p-mediated angiogenic factor induction in tcs. however, the alteration of other protein levels and hif- α in tcs treated with lps and the mir- a- p inhibitor indicated that more complex signalling pathways were involved in regulating the angiogenic function of tcs. culture medium from lps-induced tcs promoted eoma cells proliferation in vitro, accompanied by elevated levels of vegf mrna and secretion, which further demonstrated that the functional mir- a- p was generated by tcs. these data support the hypothesis that mir- a- p plays a role in angiogenesis and profoundly demonstrate the mechanisms mediated by pi k p α. the e f family was first reported to induce cell proliferation [ ] , and e f family members are essential transcriptional regulators of cell cycle progression [ ] , as well as apoptosis, metabolism and angiogenesis [ ] . e f is an atypical transcriptional repressor in the e f family since it contains domains that differ from the canonical domains [ ] . by forming homodimers or heterodimers with e f , e f reduces the excessive and destructive activation of e f [ ] . however, reports of e f in angiogenesis in the literature are controversial. e f / has been reported to positively regulate the formation of blood vessels during embryonic development via hif- α/vegfa signalling [ ] . on the other hand, e f / suppresses tumour angiogenesis via the induction of dll [ ] . in the present study, e f expression was reduced after lps stimulation in tcs and restored with mir- a- p inhibition, indicating that e f plays a negative role in angiogenesis under inflammatory conditions. the notch family, which contains several receptors and ligands, is fundamental in the regulation of blood vessel branching [ ] . dll , a notch ligand, has an inhibitory function in blood vessel branching [ ] that is compromised by jagged activation [ ] . notch positively regulates angiogenesis [ ] , while notch negatively regulates cell proliferation [ ] and angiogenesis [ ] . in the initial stage of angiogenesis, inhibition of notch promotes vascular endothelial cell proliferation, while activation of notch reduces endothelial cell responses to vegf [ , ] . in the present study, notch expression was mediated by mir- a- p. however, the relationship between the transcription factor e f and notch was not illustrated. further experiments should be conducted to confirm the signalling pathway of e f /notch in angiogenesis. tcs have been reported to be important in tissue repair and healing processes. via mouse models, bioinformatics approaches and molecular biological methods, the present study shows that activated tcs promote endothelial regeneration and angiogenesis through mir- a- p-pi k (p α)/akt/mtor signalling and further demonstrates the key roles of vegf in tcs. the e f /notch signalling might also participates in this process. these findings shed light on mir- a- p in tcs as a new therapeutic target for vessel protection. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries the acute respiratory distress syndrome acute respiratory distress syndrome: advances in diagnosis and treatment mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome: concise review. stem cells transl med cell-cell communication: old mystery and new opportunity telocyte implications in human pathology: an overview telocytes-a case of serendipity: the winding way from interstitial cells of cajal (icc), via interstitial cajal-like cells (iclc) to telocytes experimental acute myocardial infarction: telocytes involvement in neo-angiogenesis cardiac telocytes were decreased during myocardial infarction and their therapeutic effects for ischaemic heart in rat potential significance of telocytes in the pathogenesis of lung diseases telocytes promote vegf expression and alleviate ventilator-induced lung injury in mice ginsenoside rg inhibits angiogenesis in a rat model of endometriosis through the vegfr- -mediated pi k/akt/mtor signaling pathway ras interaction with pi k p alpha is required for tumor-induced angiogenesis protective effects of pi kcg gene on acute myocardial infarction interferon gamma induces inflammatory responses through the interaction of ceacam and pi k in airway epithelial cells effect of microrna- a on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the igf- /pi k/akt signaling pathway in non-small cell lung cancer antagonism of profibrotic microrna- improves outcome of murine chronic renal allograft dysfunction dysregulation of urinary mir- and mir- b associated with interstitial fibrosis and tubular atrophy (ifta) in renal transplant recipients differential expression of circulating mir- , mir- - p and mir- in renal transplant recipients with impaired graft function influence of gene modification in biological behaviors and responses of mouse lung telocytes to inflammation roles of tgfbeta in the expression of phosphoinositide -kinase isoform genes and sensitivity and response of lung telocytes to pi k inhibitors pre-processing and differential expression analysis of agilent microrna arrays using the agimicrorna bioconductor library limma powers differential expression analyses for rna-sequencing and microarray studies ggplot : elegant graphics for data analysis mirwalk: an online resource for prediction of microrna binding sites predicting effective microrna target sites in mammalian mrnas string v : protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets david: database for annotation, visualization, and integrated discovery cytoscape: a software environment for integrated models of biomolecular interaction networks ionizing radiation-inducible microrna- induces angiogenesis by directly targeting pten the role of the mir- / spry axis in modulating proangiogenic factors, epithelial phenotypes, and wound healing in corneal epithelial cells atypical e fs inhibit tumor angiogenesis e f and e f promote angiogenesis through transcriptional activation of vegfa in cooperation with hif animal models of acute lung injury genetic comparison of mouse lung telocytes with mesenchymal stem cells and fibroblasts angiomirs-key regulators of angiogenesis micrornas modulate the angiogenic properties of huvecs silencing microrna- / cluster suppresses glioblastoma angiogenesis by suppressor of cytokine signaling- -dependent jak/stat pathway exogenous mirna- a enhances the therapeutic efficacy of human mesenchymal stem cells by increasing vascular endothelial growth factor secretion in the ischemia/ reperfusion-injured heart exosomes from human umbilical cord blood accelerate cutaneous wound healing through mir- - p-mediated promotion of angiogenesis and fibroblast function microrna expression in response to murine myocardial infarction: mir- regulates fibroblast metalloprotease- via phosphatase and tensin homologue mir- improves the neurological outcome after traumatic brain injury in rats the e f transcription factor is a cellular target for the rb protein the broken cycle: e f dysfunction in cancer emerging roles of e fs in cancer: an exit from cell cycle control structural insights into the dna-binding specificity of e f family transcription factors synergistic function of e f and e f is essential for cell survival and embryonic development blockade of dll inhibits tumour growth by promoting non-productive angiogenesis molecular regulation of angiogenesis and lymphangiogenesis notch signaling in osteogenesis, osteoclastogenesis, and angiogenesis endothelium-specific cyp j overexpression improves cardiac dysfunction by promoting angiogenesis via jagged /notch signaling a receptorspecific function for notch in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor b minar is a notch -binding protein that inhibits angiogenesis and breast cancer growth knockdown mir- b alleviates lps-induced injury by targeting smad in c /i chondrocytic cells notch activation during endothelial cell network formation in vitro targets the basic hlh transcription factor hesr- and downregulates vegfr- /kdr expression publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank dr. dongli song supplementary information accompanies this paper at https ://doi. org/ . /s - - -z.additional file : figure s . the morphology of tcs. the pictures were gathered by cell-iq every h. the white arrow showed the typical telopode. not applicable. this study was approved by the ethics committee of the zhongshan hospital biomedical research department. not applicable. the authors declare that they have no competing interests. key: cord- -iryb v z authors: kao, kuo-chin; chang, ko-wei; chan, ming-cheng; liang, shinn-jye; chien, ying-chun; hu, han-chung; chiu, li-chung; chen, wei-chih; fang, wen-feng; chen, yu-mu; sheu, chau-chyun; tsai, ming-ju; perng, wann-cherng; peng, chung-kan; wu, chieh-liang; wang, hao-chien; yang, kuang-yao title: predictors of survival in patients with influenza pneumonia-related severe acute respiratory distress syndrome treated with prone positioning date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: iryb v z background: patients with influenza complicated with pneumonia are at high risk of rapid progression to acute respiratory distress syndrome (ards). prone positioning with longer duration and lung-protective strategies might reduce the mortality level in ards. the aim of this study is to investigate the survival predictors of prone positioning in patients with ards caused by influenza pneumonia. methods: this retrospective study was conducted by eight tertiary referral centers in taiwan. from january to march in , all of the patients in intensive care units with virology-proven influenza pneumonia were collected, while all of those patients with ards and receiving prone positioning were enrolled. demographic data, laboratory examinations, management records, ventilator settings and clinical outcomes were collected for analysis. results: during the study period, patients with severe influenza pneumonia were screened and patients met the diagnosis of ards. totally, patients receiving prone positioning were included for analysis. the -day survivors had lower acute physiology and chronic health evaluation (apache) ii score, pneumonia severity index (psi), creatinine level and lower rate of receiving renal replacement therapy than non-survivors ( . ± . vs. . ± . , p = . ; . ± . vs. . ± . , p = . ; . ± . mg/dl vs. . ± . mg/dl, p = . ; and % vs. %, p < . ). multivariate cox regression analysis identified psi (hazard ratio . , % confidence interval . – . ; p < . ), renal replacement therapy (hazard ratio . , % confidence interval . – . ; p < . ), and increase in dynamic driving pressure (hazard ratio . , % confidence interval . – . ; p = . ) which were independent predictors associated with -day mortality. conclusions: in the present study, in evaluating the effect of prone positioning in patients with influenza pneumonia-related ards, pneumonia severity index, renal replacement therapy and increase in dynamic driving pressure were associated with -day mortality in patients with influenza pneumonia-related ards receiving prone positioning. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. severe complicated influenza including pneumonia, myocarditis and neurologic complications are still a burden on intensive care units (icu) nowadays, especially viral or secondary bacteria pneumonia-induced acute respiratory distress syndrome (ards) [ , ] . during the winter season in , there was an outbreak of influenza in taiwan. totally, subjects were admitted to icus due to severe complicated influenza pneumonia according to the data from the centers for disease control of taiwan [ ] . patients with influenza pneumonia needing mechanical ventilation were at high risk of rapid progression to ards. for the pandemic h n virus infection, - % of patients admitted to icus had complications with ards [ , ] . there are several therapeutic options for refractory hypoxemia in patients with severe ards [ , ] , but only a few options have been confirmed with clinical validity by previous studies, including higher positive endexpiratory pressure (peep) [ , ] , lower tidal volume [ ] , neuromuscular blocking agents [ ] and prone positioning [ ] . prone positioning was first suggested in [ ] ; however, the clinical benefit of prone positioning in patients with ards was not confirmed until when the proseva study showed decreased -day and -day mortality and increased ventilator-free days only when it was started early and there were sufficiently long sessions [ ] . further, meta-analysis by cochrane database also revealed that prone positioning would reduce the mortality rate when used with lung-protective strategies and longer duration in patients with severe ards [ , ] . few studies have explored the effect of prone positioning focused on influenza pneumonia-related ards patients. xu et al. [ ] studied h n influenza patients with prone positioning, and decrease in carbon dioxide retention was noted, but no clinical outcome was mentioned. moreover, what factors that can predict the efficacy of prone positioning in severe ards are not entirely clear [ ] . the aim of this study is to investigate the survival predictors of prone positioning in patients with severe ards caused by influenza pneumonia. this multicenter retrospective cohort study was conducted by the taiwan severe influenza research consortium (tsirc), which included eight tertiary referral centers (four hospitals in northern taiwan, two hospitals in central taiwan and two hospitals in southern taiwan). over a period of months from january to march in , all patients with the virology-proven influenza infection who were admitted to icus due to severe complicated influenza in these eight hospitals were collected and their data were analyzed. all patients diagnosed as severe ards according to berlin definition and also receiving prone positioning were collected for investigation [ ] . the berlin definition of ards was defined by acute onset within week, bilateral lungs opacities, no evidence of cardiac failure-related hydrostatic edema by echocardiography, and pao /fio ratio < mm hg with positive end-expiratory pressure (peep) ≥ cm h o. the demographic and laboratory data, treatment record, mechanical ventilation settings, and clinical outcomes were analyzed from the electronic medical records with a standardized case report form in each hospital. university hospital rind, tri-service general hospital - - - ). the need for informed consent was waived, and patients' data were anonymized and de-identified prior to analysis. influenza infection was confirmed by one of the following tests revealing as positive including the rapid antigen test, nucleic acid reverse transcriptase polymerase chain reaction (rt-pcr), viral culture sampling from nasopharynx swab, throat swab, sputum or bronchoalveolar lavage and positive serum antibody serologic test (antibody titers increased more than times from acute to convalescent stages). the usual practice in the units was that patients be ventilated with lung-protective strategy by low tidal volume - ml/kg of predict body weight plus low positive endexpiratory pressure (peep)-oxygen fraction in air (fio ) table for pressure-controlled or volume-controlled ventilation [ ] . ventilation was monitored by arterial blood gas measurements, with ventilator settings changed as needed. pulse oximetry (spo ) was used to monitor oxygenation, and ventilatory settings were adjusted to maintain spo > % or pao > mm hg and to avoid raising the plateau pressure > cm h o. the method of prone positioning complied with the proseva study [ ] . doses of neuromuscular blocking agent with intravenous cisatracurium and sedatives with intravenous midazolam were adjusted to maintain synchrony between the ventilator and the patient's breathing, as well as hemodynamics. the criteria for stopping prone positioning were any of the following: improvement in oxygenation (defined as a pao /fio ratio ≥ mm hg, with a peep of ≤ cm h o and an fio ≤ . ), a decrease in the pao /fio ratio ≥ % or complications happening during prone positioning such as spo ≤ % or pao /fio ratio ≤ mm hg, severe cardiac arrhythmia, systolic blood pressure ≤ mm hg and any other life-threatening condition for which the intensivist decided to stop the prone positioning. the laboratory data including baseline characteristics, underlying disease, complete blood count, differential count and biochemistry data were obtained when the patient was admitted to the icu. the mechanical ventilator settings were recorded such as peak inspiratory pressure, peep, artery blood gas, partial pressure of oxygen in arterial blood (pao ), pao /fio ratio, tidal volume, dynamic driving pressure and dynamic compliance of the respiratory system before and day after the first prone positioning. the above physiological data were recorded before prone positioning on the supine position and day after first prone positioning on the prone position. the dynamic driving pressure and dynamic compliance were computed as peak pressure minus peep and tidal volume divided by peak pressure minus peep. the severity scores including pneumonia severity index (psi) [ ] , acute physiology and chronic health evaluation ii (apache ii) score [ ] , curb- (confusion, urea > mmol/l, respiratory rate ≥ /min, blood pressure [systolic < mm hg or diastolic ≤ mm hg] and age ≥ years) pneumonia severity score [ ] and sequential organ failure assessment (sofa) score [ ] were collected on the icu admission day. statistical analyses and database management were performed using spss version . . (spss inc., chicago, il). the data were presented as number (percentages) for nominal variables, and as mean ± standard deviation for continuous variables. the chi square test was used to compare the nominal variables, and the student's t test was used to compare the continuous variables. cox proportional hazard models were used with covariates significantly different between survivors and non-survivors at the threshold of . and mortality at day as the dependent variable. calibration was assessed using hosmer-lemeshow goodness-of-fit test (c statistic, goodness of fit was defined as a p value > . ), and discrimination was assessed by the area under the receiver operating curves. even though peak airway pressure, dynamic driving pressure, and compliance are mathematically coupled, we planned to formally test the collinearity within them and, if verified, to use a specific cox model for each. we also included those collinear variables two-by-two into three additional cox regression models [ ] , besides the other covariates. one model pertained to peak airway pressure and dynamic driving pressure, one to peak airway pressure and compliance, and one to dynamic driving pressure and compliance. if both variables in the couple lacked significance, the conclusion could be that the same information was carried by each component of the couple. if one of the variables in the couple remained significantly correlated with survival, this variable would be more informative than the other in the couple. univariate and multivariate cox proportional hazard regression models were used to estimate the hazard ratio (hr). in this study, we used the two-tailed test, and the definition of significance was p value < . . in total, patients with virology-proven severe influenza pneumonia were admitted to icus and screened during the study period. there were patients with influenza a (including h n in patients and h n in patients), patients with influenza b, and patients with undetermined influenza type. of these patients, patients ( %) met the diagnosis of severe influenza pneumonia-related ards. the rates of mild, moderate and severe ards were % ( / ), % ( / ) and % ( / ), respectively. of these patients with ards, patients ( %) receiving prone positioning were included for analysis (fig. ) . the rate of receiving prone positioning was % ( / ) in mild, % ( / ) in moderate and % ( / ) in severe ards, respectively (p = . ). the characteristics of the subjects according to the -day survivors and non-survivors are summarized in table . the mean age was . ± . years, and patients ( %) were male. the duration of prone positioning of survivors and non-survivors was not significantly different ( . ± . days vs. . ± . days, p = . ). the survivors had lower apache ii score, psi, creatinine level and lower rate of receiving renal replacement therapy than did non-survivors ( . ± . vs. . ± . , p = . ; . ± . vs. . ± . , p = . ; . ± . mg/dl vs. . ± . mg/dl, p = . ; and % vs. %, p < . ). regarding the oxygenation, the mean pao /fio ratio of these patients before prone positioning was . ± . mm hg. before prone positioning, there were no significant differences in the pao /fio ratio, paco , tidal volume, peep, peak airway pressure, dynamic driving pressure and dynamic compliance between surviving and non-surviving patients. the data regarding the gas exchange and lung mechanics were recorded before prone positioning and after -day prone positioning (table ) . for the -day survivors, there were no significant differences in these parameters compared with -day non-survivors except for peak airway pressure. after prone positioning, the -day survivors had decreased peak airway pressure (− . ± . cm h o) and the -day non-survivors had increased peak airway pressure ( . ± . cm h o). compared with -day non-survivors, the peak airway pressure and dynamic driving pressure were both decreased in -day survivors (− . ± . univariate analysis was used to identify variables that have prognostic value for -day mortality, and multivariate cox regression analysis was used to identify variables that did have significant predictive value (table ) . pneumonia severity index (hazard ratio . , % confidence interval . - . ; p < . ), renal replacement therapy (hazard ratio . , % confidence interval . - . ; p < . ) and increased dynamic driving pressure (hazard ratio . , % confidence interval . - . ; p = . ) were identified as significant and independent predictors associated with -day mortality. as the collinearity between Δ dynamic driving pressure, Δ peak airway pressure and Δ dynamic compliance was statistically significant, a cox model was constructed for each of these variables. after multiple adjustments of coupled variables, three additional cox models were performed (additional file ). when Δ dynamic driving pressure and Δ peak airway pressure were analyzed two-by-two, Δ dynamic driving pressure remained significant but Δ peak airway pressure did not (model in additional file ). when Δ dynamic driving pressure and Δ dynamic compliance were analyzed two-by-two, Δ dynamic driving pressure remained significant but Δ dynamic compliance did not (model in additional file ). when Δ peak airway pressure and Δ dynamic compliance were analyzed two-by-two, both did not reveal significant (model in additional file ). receiver operating curves analysis and c statistic of variables of predictors revealed . in psi ( % confidence interval, . - . , p = . ), . in renal replacement therapy ( % confidence interval, . - . , p = . ) and . ( % confidence interval, . - . , p = . ) in delta dynamic driving pressure (fig. ). the aim of this multicenter retrospective study was to evaluate the effect of prone positioning focusing on patients with influenza pneumonia-related ards. after multivariate cox regression analysis, psi, renal replacement therapy and increased dynamic driving pressure were associated with -day mortality in patients with influenza pneumonia-related ards receiving prone positioning. most of the studies evaluating the effect of prone positioning were in ards patients with heterogeneous risk factors [ , ] . for specific conditions such as burns, prone positioning has been demonstrated to safely implement and improve oxygenation (in burn patients with severe ards) in a burn intensive care unit [ ] . the present study was more homogenous and specific to patients with ards caused by influenza pneumonia. systematic review and meta-analysis studies in prone positioning have revealed decreased mortality in patients with severe acute hypoxemic respiratory failure, but not in less severe hypoxemia. survival benefits were noted using a range of pao /fio ratio thresholds up to approximately mm hg [ ] or less than mm hg [ ] . in the present study, the pao /fio ratio was . ± . mm hg before prone positioning. however, the pao /fio ratio was not significantly different between -day survivors and -day non-survivors ( . ± . mm hg vs. . ± . mm hg, p = . ). in terms of the response of prone positioning to ards, the different entities of the risk factor possibly produce different outcomes. in addition to severity of hypoxemia, further clinical trials would assist in clarifying the survival benefits of prone positioning in the specific risk factors. some studies have shown that acute kidney injury (aki) was common and an independent risk factor for mortality in patients with influenza a [ ] [ ] [ ] [ ] . in patients with severe ards caused by h n influenza pneumonia, a recent study also revealed aki was common and demonstrated significantly increased mortality [ ] . the % mortality rate among the patients requiring renal replacement therapy was significantly higher than the % mortality rate among the patients not requiring renal replacement therapy. the present study in patients receiving prone positioning caused by influenza pneumonia-related ards demonstrated that the requirement for renal replacement therapy had nearly times the mortality rate (hazard ratio . ) than patients not requiring renal replacement therapy. in order to reduce the mortality in patients with severe ards caused by h n influenza pneumonia, it is important to prevent development ards acute respiratory distress syndrome, bmi body mass index, apache ii acute physical and chronic health evaluation, sofa sequential organ function assessment, psi pneumonia severity index, curb- curb- for pneumonia severity, wbc white blood cell count, paco atrial pressure of carbon dioxide in arterial blood, pao atrial pressure of oxygen in arterial blood, fio oxygen fraction in air, pbw predict body weight, peep positive end-expiratory pressure all values are expressed as the number of patients (percentage) or mean ± sd *p < . : survivors versus non-survivors of aki and need for renal replacement therapy by avoiding nephrotoxic agents and supplying sufficient renal perfusion and oxygenation. amato and colleagues analyzed randomized controlled trials in ards patients and demonstrated that driving pressure was the strongest predictor of mortality [ ] . a secondary analysis of data from ards patients enrolled in two independent randomized controlled trials revealed that when ventilating patients with low tidal volume, driving pressure was a risk factor for death in ards patients, as was plateau pressure or compliance of respiratory system [ ] . airway driving pressure was significantly related to lung stress and could detect lung over-stress with acceptable accuracy (r = . p < . and r = . p < . at and cm h o of peep) in ards patients [ ] . furthermore, the apronet study on prone positioning of ards patients found that prone positioning was associated with low complication rates, significant increase in oxygenation, and a significant decrease in driving pressure [ ( - cm h o) to [ ] [ ] [ ] [ ] [ ] [ ] [ ] cm h o, p = . ] [ ] . our previous study for severe ards patients with ecmo revealed that higher dynamic driving pressure [hazard ratio . ( . - . ), p = . ] during the first days of ecmo was one of the factors independently associated with icu mortality [ ] . the present study in influenza pneumonia-related ards patients receiving prone positioning also found that increased dynamic driving pressure (hazard ratio . , % confidence interval . - . ; p = . ) was identified as ards acute respiratory distress syndrome, Δ change between before and after prone positioning day, pao partial pressure of oxygen in arterial blood, paco atrial pressure of carbon dioxide in arterial blood, one of the independent predictors associated with -day mortality. it was suggested that ventilatory support with lung-protective strategy with low tidal volume and optimal peep level be applied, and these be then adjusted according to the driving pressure, ideally less than cm h o, although this limit should be addressed in future studies [ ] . despite some studies associating driving pressure with physiological and clinical outcomes, it is necessary to evaluate the driving pressure as a primary end point during ventilatory setting in ards patients in the near future. the lung safe study showed that the use of prone positioning actually depended on the severity of hypoxemia, from % in mild to . % in moderate and to . % in severe ards [ ] . a prospective international prevalence study (the apronet study, ards prone position network) found that the rates of prone positioning were up to . %, . % and . % in mild, moderate and severe ards [ ] . in our study, the rates of prone positioning were %, % and % in mild, moderate and severe ards, respectively. the substantially different rates in the use of the prone positioning may reflect the management bias of prone positioning in patients with ards between the different studies. furthermore, among our eight involved hospitals, the rate of prone positioning varied from % ( / ) to % ( / ) and the bias even existed between different hospitals in the same study. it is important to be homogenous on the indication and management in the selected prone position as one of the standard interventions in severe ards. this study has some limitations. firstly, since this study is retrospective, some patients or data might be missing. secondly, the primary end point of this study was -day mortality, and the value of computed power was . . this was a retrospective study, and patients with severe ards receiving prone positioning were analyzed. although more patients were needed to increase the power of this study, the limitation was from the nature of retrospective study within a -month period. thirdly, prone positioning is not a routine intervention in the management of ards and has no standard procedure such as how many hours a day, how to perform it or how to protect the patients. in this study, even though every patient had prone positioning for more than h a day, the exact duration showed little difference between each hospital. fourthly, the change in physiological measurements pertains to a difference between supine and prone position, and hence, the impact of chest wall is not taken into account. finally, in this study, we focused on influenza-related ards patients, and whether the result can be extrapolated to all patients with ards is unknown, requiring further investigation. to confirm the benefit of prone positioning in ards especially in influenza this study was designed to evaluate the effect of prone positioning in influenza pneumonia-related ards patients. after multivariate cox regression analysis, it was found that psi, renal replacement therapy and increased dynamic driving pressure were associated with -day mortality in patients with influenza pneumoniarelated ards receiving prone positioning. h n : viral pneumonia as a cause of acute respiratory distress syndrome pathogenesis of influenzainduced acute respiratory distress syndrome taiwan national infectious disease statistics system. taiwan centers for disease control critical care services and h n influenza in australia and new zealand critically ill patients with influenza a(h n ) infection in canada the berlin definition of ards: an expanded rationale, justification, and supplementary material european society of intensive care medicine, and society of critical care medicine an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome conference on the scientific basis of respiratory therapy. pulmonary physiotherapy in the pediatric age group. comments of a devil's advocate prone position for acute respiratory failure in adults effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis a multicenter retrospective review of prone position ventilation (ppv) in treatment of severe human h n avian flu treatment of ards with prone positioning acute respiratory distress syndrome: the berlin definition a prediction rule to identify lowrisk patients with community-acquired pneumonia apache ii: a severity of disease classification system defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine effect of driving pressure on mortality in ards patients during lung protective mechanical ventilation in two randomized controlled trials prone positioning improves oxygenation in adult burn patients with severe acute respiratory distress syndrome prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis prone position for acute respiratory distress syndrome: a systematic review and meta-analysis writing committee of the who consultation on clinical aspects of pandemic (h n ) influenza influenza a infection and acute kidney injury: incidence, risk factors, and complications acute kidney injury among critically ill patients with pandemic h n influenza a in canada: cohort study acute kidney injury in criticallyill adult patients with seasonal influenza infection outcomes of acute kidney injury in patients with severe ards due to influenza a(h n ) pdm virus driving pressure and survival in the acute respiratory distress syndrome airway driving pressure and lung stress in ards patients a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study dynamic driving pressure associated with mortality in acute respiratory distress syndrome with extracorporeal membrane oxygenation driving pressure: a marker of severity, a safety limit, or a goal for mechanical ventilation? epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries we thank professor meng-chih lin, the president of the taiwan society of pulmonary and critical care medicine, who organized and coached the tsirc team. on behalf of all authors, the corresponding author states that there is no conflict of interest. not applicable. not applicable. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - kw v rm authors: vuillard, constance; pineton de chambrun, marc; de prost, nicolas; guérin, claude; schmidt, matthieu; dargent, auguste; quenot, jean-pierre; préau, sébastien; ledoux, geoffrey; neuville, mathilde; voiriot, guillaume; fartoukh, muriel; coudroy, rémi; dumas, guillaume; maury, eric; terzi, nicolas; tandjaoui-lambiotte, yacine; schneider, francis; grall, maximilien; guérot, emmanuel; larcher, romaric; ricome, sylvie; le mao, raphaël; colin, gwenhaël; guitton, christophe; zafrani, lara; morawiec, elise; dubert, marie; pajot, olivier; mentec, hervé; plantefève, gaëtan; contou, damien title: clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-mda- dermato-pulmonary syndrome: a french multicenter retrospective study date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: kw v rm background: anti-synthetase (as) and dermato-pulmonary associated with anti-mda- antibodies (amda- ) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. we undertook a -year retrospective multicenter study in french icus in order to describe the clinical presentation and the outcome of patients admitted to the icu for acute respiratory failure (arf) revealing as or amda- syndromes. results: from to , patients ( males; median age [ st– rd quartiles – ] years, no comorbidity %) were admitted to the icu for arf revealing as (n = , %) or amda- (n = , %) syndromes. muscular, articular and cutaneous manifestations occurred in patients ( %), ( %) and ( %) patients, respectively. seventeen of them ( %) had no extra-pulmonary manifestations. c-reactive protein was increased ( [ – ] mg/l), whereas procalcitonine was not ( . [ . – . ] ng/ml). proportion of patients with creatine kinase ≥ n was % (n = / ). forty-two patients ( %) had ards, which was severe in %, with a rate of % (n = / ) of extra-corporeal membrane oxygenation requirement. proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were %, %, %, % and %, respectively. icu and hospital mortality rates were % (n = / ) and % (n = / ), respectively. patients with amda- dermato-pulmonary syndrome had a higher hospital mortality than those with as syndrome (n = / , % vs. n = / , %; p = . ). conclusions: intensivists should consider inflammatory myopathies as a cause of arf of unknown origin. extra-pulmonary manifestations are commonly lacking. mortality is high, especially in amda- dermato-pulmonary syndrome. identifying the cause of acute respiratory distress syndrome (ards) is a crucial step for initiating a targeted treatment and improving prognosis [ , ] . however, two recent studies [ , ] showed that % of patients with ards according to the berlin criteria [ ] lacked exposure to "common" risk factors (e.g., pneumonia, acute pancreatitis, aspiration of gastric content or extra-pulmonary sepsis) with no etiology eventually retrieved in % of them [ ] . for such atypical ards, a comprehensive diagnostic work-up, including specific immunologic tests, is recommended [ ] so that to identify immune causes, typically amenable to specific therapeutic interventions (e.g., corticosteroids). yet, an ancillary analysis [ ] of an international, multicenter, prospective cohort study [ ] reported that such immunological examinations were performed in only % of ards without common risk factors. anti-synthetase (as) and anti-melanoma differentiation-associated gene (amda- ) syndromes are near one of the other autoimmune inflammatory myopathies [ ] potentially responsible for rapidly progressive interstitial lung disease leading to acute respiratory failure and ards [ ] [ ] [ ] [ ] . as and amda- dermatopulmonary syndromes may be clinically indistinguishable one from another, with almost three-quarter of patients with amda- dermato-pulmonary syndrome exhibiting the clinical attributes of the as syndrome [ ] . when arf is the initial presentation of as or amda- syndromes [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] or when extra-respiratory manifestations, such as muscular, cutaneous or articular signs are lacking [ , [ ] [ ] [ ] [ ] [ ] , the diagnosis is challenging, especially in the intensive care unit (icu) setting, where many other reasons of acute respiratory failure (arf) can be discussed. to the best of knowledge, a number of case reports of arf revealing autoimmune inflammatory myopathies have been previously reported, but an extended case series has not been published as yet. therefore, we undertook this retrospective study in order to: ( ) describe the clinical features and the outcome of patients admitted to the icu for arf revealing either an as or an amda- dermato-pulmonary syndrome, and; ( ) identify predictive factors of hospital mortality. we conducted a -year multicenter retrospective noninterventional study in icus in france from january , , to december , . all patients older than years were included if they met the following criteria: ( ) admitted to the icu for arf not related to cardiogenic pulmonary edema; ( ) no common ards risk factor, among pneumonia, acute pancreatitis, aspiration of gastric content, extra-pulmonary sepsis, multiple transfusions, major trauma, pulmonary vasculitis, drowning, severe burns, identified according to the berlin definition [ ] ; ( ) immunologic test performed during icu stay, which was positive for anti-synthetase (jo- , pl , pl , oj, ej, ks, zo, yrs/tyr/ha) or anti-mda- autoantibodies; and ( ) no alternative diagnosis for arf. it is worth notifying that in the present study the diagnosis of as or amda- dermato-pulmonary syndromes had to be made during the icu stay. therefore, those who had a diagnosis of as or amda- made before icu admission were not included. the investigator of each participating center was responsible for the identification of the patients, either from the hospital medical reports, using the function "research the files in which the key words mda- or antisynthetase or myositis occurs" of microsoft windows ® , or through a search using the international classification of diseases ( th revision) following codes: m (autoimmune myositis), m (myositis), m (polymyositis) and m (dermatomyositis). the clinical charts of all identified patients were anonymized before sending to the main investigators (dc and cv). clinical charts were reviewed in order to check the inclusion criteria. the following data were collected on a standardized anonymized case record form: demographic characteristics (age, gender), severity scores upon icu admission (sequential organ failure assessment [ ] and simplified acute physiology score ii [ ] ), main comorbidities, delay between first respiratory sign and icu admission, clinical examination (respiratory and extra-respiratory manifestations) and laboratory findings at the time of icu admission (blood leukocytes and platelets counts, serum procalcitonine, c-reactive protein, creatine kinase and creatinine levels, pao /fio with fio calculated according to the following formula [ , ] : fio = oxygen flow in liter per minute × . + . when standard oxygen was used), radiological findings on chest x-ray and ct scan, cytological and bacteriological analyses of broncho-alveolar lavage (bal) fluid, type of positive autoantibodies (jo- , pl , pl , oj, ej, ks, zo, yrs/tyr/ ha or amda- ), immunosuppressive treatments received (corticosteroids, cyclophosphamide, rituximab, basiliximab, tacrolimus, cyclosporine, methotrexate, intravenous immunoglobulins or plasma exchange), organ supports in the icu (invasive mechanical ventilation, extra-corporeal membrane oxygenation (ecmo), renal replacement therapy, vasopressors), icu and hospital length of stay, icu and hospital mortality. written reports of chest ct scan performed at the time of icu admission were sent to the main investigators (dc and cv) in order to individualize elementary lesions (ground-glass attenuation, alveolar consolidation, septal thickening, pleural effusion, pneumothorax, pneumomediastinum and mediastinal lymphadenopathy) and their location (lower or upper lobe predominance). signs of lung fibrosis (honeycombing, traction bronchiectasis and reticulations) were also collected. cytological analyses of bal fluid collected at the time of icu admission were reported, as well as results of open lung, skin or muscle biopsies, if performed. continuous variables are reported as median [ st- rd quartiles] and compared by the mann-whitney u test. categorical variables are reported as counts and percentage points in groups and compared by using the fisher's exact test. survival curves of patients with amda- and as syndromes were drawn using the kaplan-meier method and compared using the log-rank test. all tests were two-sided, with p < . indicating statistical significance. the statistical analysis was performed by using the rstudio software version . . (www.rstud io.com). from january , , to december , , patients fulfilled the inclusion criteria, including ( %) with as syndrome (jo- n = / ( %); pl n = / ( %); pl n = / ( %); ej n = / ( %)) and ( %) with amda- dermato-pulmonary syndrome. all the patients with amda- dermato-pulmonary syndrome were admitted after january , . demographical characteristics, main comorbidities and clinical manifestations are given in table . most of the patients had no comorbidity (n = / , %). median sapsii and sofa scores at the time of icu admission were and [ ] [ ] [ ] [ ] [ ] [ ] , respectively. the median delay between first respiratory sign and icu admission was days. most of the patients had central temperature > °c (n = / , %). myalgia, arthralgia/arthritis and cutaneous manifestations occurred in % (n = / ), % (n = / ) and % (n = / ) of patients, respectively. about one-third of patients (n = / , %) had no extra-pulmonary manifestation, in a similar proportion in amda- and as groups. biological data at the time of icu admission and radiological findings are reported in table . c-reactive protein levels (n < mg/l) were increased ( mg/l), while procalcitonine levels (n < . ng/ml) were not ( . [ . - . ] ng/ml). the rate of patients having creatine kinase plasma levels greater than times the upper limit of normal laboratory range was % (n = / ) in the whole population, and only % (n = / ) in the as group. the median pao /fio ratio at icu admission was [ - ] mmhg. most patients (n = / , %) had bilateral condensations on chest x-ray, with a predominantly lower location (n = / , %) ( table ). all patients underwent a lung ct scan, which showed ground-glass attenuation in % (n = / ) and alveolar condensation in % (n = / ). signs of lung fibrosis were observed in % (n = / ), while % (n = / ) had mediastinal lymphadenopathies. bal fluid analyses were available in % (n = / ) of patients and are summarized in table . the cell count was [ - ] × /ml, and percentages of lymphocytes, neutrophils and macrophages were % , % and % , respectively. bal was performed before antibiotic therapy in only / ( %) patients and was negative for lung infection in every patient. there was no correlation between bal findings and elementary lesions observed on chest ct scan. in particular, the proportion of patients with > % bal neutrophils did not differ between patients with or without elementary lesions of lung fibrosis on chest ct scan (n = / , % vs. n = / , %, p = . ). an open lung biopsy was performed in ( %) patients and depicted findings consistent with organizing pneumonia (n = ), usual interstitial pneumonitis (n = ) and diffuse alveolar damage (n = ) ( table ). a total of patients ( %) had a muscle (n = ) or a skin (n = ) biopsy performed during the icu stay. all muscle biopsies revealed findings consistent with an inflammatory myositis, while skin biopsies were either normal (n = ) or revealed findings consistent with lichenoid dermatitis (n = ) or with dermatomyositis (n = ) ( table ) . most patients (n = / , %) received an antimicrobial therapy upon icu admission (table ). all patients received steroids, after a median delay of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days following the icu admission. other immunosuppressive treatments administered are reported in table . almost all patients (n = / , %) had ards, categorized as severe (pao /fio ≤ mmhg with peep ≥ mmh o) in % (n = / ), with % (n = / ) of them requiring ecmo. icu and hospital mortality rates were % (n = / ) and % (n = / ), respectively. patients with amda- dermato-pulmonary syndrome had a higher icu mortality than those with as syndrome (n = / , % vs. n = / , %; p < . ). among the icu survivors, ( %) were diagnosed with a cancer (colorectal n = , pharyngeal n = , melanoma n = ) during the [ - ] days post-icu stay follow-up. compared to patients who survived at the hospital discharge, those who died were more likely to have an amda- autoantibody (n = / , % vs. n = / , %; p = . ), had a higher rate of ground-glass attenuation table demographical and clinical manifestations of patients with acute respiratory failure revealing anti-synthetase syndrome or dermato-pulmonary syndrome associated with anti-mda- antibodies amda- anti-mda- antibodies, as anti-synthetase, arf acute respiratory failure, hiv human immunodeficiency virus, icu intensive care unit, iqr inter-quartile range, saps simplified acute physiology score, sofa sepsis-related organ failure assessment chronic respiratory failure ( ) ( ) ( ) . congestive heart failure ( ) ( ) ( ) . chronic kidney failure active solid cancer or malignant hemopathy ( ) ( ) ( ) . table ). after adjustment on syndrome (anti-synthetase or amda- dermato-pulmonary syndrome), the presence of ground-glass attenuations on chest ct scan was no longer associated with in-hospital mortality (p = . ). the kaplan-meier graph showed a lower probability of survival days after icu admission in patients with amda- antibody than in patients with as antibody (fig. ; p < . log-rank test). we are herein reporting the first large cohort of patients admitted to icu for arf revealing either as or amda- dermato-pulmonary syndrome. the main findings are: ( ) clinical manifestations may be nonspecific with the absence of extra-pulmonary manifestations of inflammatory myositis in one-third of patients; ( ) hypoxemia is severe with a high rate of severe ards and rescue maneuvers; and ( ) hospital mortality is high, especially in dermato-pulmonary syndrome associated with amda- autoantibodies. as and amda- -associated dermato-pulmonary syndromes are two near each of the other inflammatory myopathies that may be responsible for severe acute interstitial lung diseases [ ] [ ] [ ] . the diagnosis is easy to consider when extra-pulmonary manifestations are present. in as syndrome, the main extra-pulmonary manifestations include myositis with elevated creatine kinase levels, non-erosive arthritis, raynaud's phenomenon and thick cracked skin over the tips and sides of the fingers called "mechanic's hands" [ ] [ ] [ ] [ ] [ ] [ ] . however, there is a wide heterogeneity in clinical manifestations depending on the causative as autoantibody [ , ] . in amda- -associated dermato-pulmonary syndrome, the cutaneous manifestations (skin ulcerations or necrosis, facial erythema, mechanic's hands, periungual telangiectasia, gottron's papules, raynaud's phenomenon) are in the forefront [ , , ] and usually contrast with the absence of clinical signs of myositis (clinically "amyopathic myositis"). demographical and clinical findings in our patients were in line with those recently reported in non-icu patients with as [ , , ] or with amda- dermato-pulmonary syndromes [ ] . both in as and amda- dermato-pulmonary syndromes, extra-pulmonary manifestations may be lacking [ , ] rendering the diagnosis difficult to make. in our series, more than one-third of patients had no extra-pulmonary manifestations with a similar proportion in as and amda- patients. this rate contrasts with the % rate recently reported [ ] in patients with amda- dermato-pulmonary syndrome, reflecting the lack of training of intensivists for the clinical assessment of these patients and highlighting the need for a multidisciplinary approach. considering the high proportion of patients lacking extra-pulmonary manifestations, the clinical presentation may mimic that of a "bilateral pneumonia without microbiological documentation. " hence, % of our patients received antibiotic therapy at icu admission. the presence of an intense inflammatory syndrome with increased c-reactive protein levels contrasting with the lack of elevation of serum procalcitonine could help intensivists appreciating the probability of an infectious process, this dissociation being highly suggestive of a non-infectious inflammatory process. in our series, bal was performed in % of patients. unlike a recent work [ ] showing that a lymphocytic bal fluid was associated with better icu survival in ards patients with no common risk factor, our study failed to identify any predictive role of bal cytology on hospital survival. bal fluid analysis does not seem a useful diagnostic tool for as or amda- dermato-pulmonary syndromes, but should nevertheless be performed to rule out an alternative diagnosis, such as diffuse alveolar hemorrhage or active infection. all included patients underwent chest ct scan. interestingly, ct chest findings predominate in the lower lobes, which is consistent with a previous report [ ] . ct scan signs of lung fibrosis have been recently shown to be associated with a poor outcome in patients with arf related to interstitial lung diseases [ ] . in our study, ct scan signs of lung fibrosis were not associated with hospital mortality, probably because of a lack of adequate power. while ground-glass opacities are usually considered as potentially reversible lung lesions during idiopathic pulmonary fibrosis [ , ] , these lesions were associated with in-hospital mortality in our study, probably because they were more frequently observed during amda- dermato-pulmonary syndromes. indeed, this association was no longer observed after adjustment on the type of positive antibody (anti-synthetase or amda- ). our series underlines the severity of as and amda- dermato-pulmonary syndrome, since % of patients fulfilled the berlin criteria for ards [ ] , categorized as severe (pao /fio ≤ mmhg with peep ≥ mmh o) in % of cases. anti-mda- dermato-pulmonary syndromes exhibited a significantly higher mortality than as syndromes, with almost all these patients dying in the icu of refractory ards despite a high rate of ecmo ( %). moreover, amda- patients had a much higher mortality than those with severe ards included in the lung safe study [ ] , highlighting the irreversibility of lung lesions despite immunosuppressive treatments. these results are in line with previous series, showing that refractory ards is the leading cause of mortality in amda- patients [ ] . whether our patients had a true ards (i.e., presence of diffuse alveolar damage (dad), the histological hallmark of ards) or simply fulfilled the berlin criteria while having a non-dad histology is unknown. in fact, the berlin definition of ards is not fully reliable for diagnosing dad, and several non-dad histological entities (such as lung fibrosis, organizing pneumonia, diffuse alveolar hemorrhage or lung tumoral infiltration) have been reported in patients fulfilling the clinical and radiological criteria for ards [ , [ ] [ ] [ ] . regarding the onset of lung injury, the berlin definition of ards stipulates that "respiratory signs should occur (or worsen) within days after an exposure to a common ards risk factor" (e.g., pneumonia, acute pancreatitis, aspiration of gastric content or extra-pulmonary sepsis). in our patients, the absence of a common risk factor for ards according to the berlin definition together with delay between first respiratory sign and icu admission exceeding days ( days) advocate more for an ards mimicker rather than for a real ards. however, a recent histological study revealed that % of patients with an acute decompensation of as syndrome due to jo- autoantibody exhibited histological lesions of dad [ ] . in non-icu patients, the prognosis of inflammatory myopathies depends on the severity of lung involvement [ , , , ] . treatment of interstitial lung disease associated with as and amda- dermato-pulmonary syndromes is not standardized and based on case reports. numerous immunosuppressive therapies are available (e.g., cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, rituximab, basiliximab, intravenous immunoglobulins or plasma exchange) [ , , , , , ] , but high-dose corticosteroids remain the first-line therapy. our study underlines the wide variations in the choice of immunosuppressive treatment even if the association corticosteroids-cyclophosphamide was administered in almost over patients. patients with amda- received significantly more immunosuppressive drugs highlighting a higher severity. of note, % of icu survivors developed cancer, in line with previous series of as patients [ ] . our study suffers from several limitations. first, we included a limited number of patients, inherent to the rarity of the disease. however, this is the first series on arf revealing as or amda- syndromes in an icu context and our findings are consistent with previous reports. this limited number of patients precluded performing multivariable analyses and thus did not allow for adjusting the observed association between some variables and mortality with potential confounders. second, the relationship between positive as or amda- autoantibody and arf is not proven. we therefore cannot exclude that some patients had a fortuitously positive autoantibody and that inflammatory myopathy was not the cause of arf. however, this hypothesis appears unlikely since an alternative diagnosis for arf had to be excluded, and all patients were treated with immunosuppressive therapies underlining the high degree of clinician's suspicion. third, because the patients were recruited over a -year period in centers, icu procedures were inevitably heterogeneous. fourth, the prevalence of amda- dermato-pulmonary syndromes may have been underestimated during the study period since detection of amda- autoantibody was first described in [ ] and was therefore routinely available only from in most of participating centers. last, several classical predictors of mortality related to ventilation (tidal volume or driving pressure [ ] ) were not available as a result of a long-term retrospective design. considering the high proportion of patients lacking extra-pulmonary manifestations and the nonspecific presentation mimicking that of a bilateral communityacquired pneumonia, we believe that arf related to autoimmune inflammatory myopathies may be underdiagnosed. hence, de prost et al. recently showed that the diagnostic work-up performed in ards patients with no common risk factor was not comprehensive, with only % of patients having immunological tests [ ] . the lack of screening for as or amda- autoantibodies is probably one of the reasons why these diseases are underestimated. therefore, when the etiology of arf appears unclear, we recommend a more aggressive diagnostic work-up [ ] , including immunological tests in order to identify patients amenable to specific therapies. a careful assessment of extra-pulmonary manifestations, such as cutaneous or articular signs, is crucial. while the presence of extra-pulmonary manifestations is highly suggestive, the -week delay between first respiratory signs and icu admission, the absence of an obvious etiology for arf, the presence of bi-basal consolidations on chest x-ray with an intense inflammatory process, contrasting with a low procalcitonin level together with the lack of microbiological documentation are the main clues to consider the diagnosis of as or amda- syndromes in a patient without extra-pulmonary manifestation. to better assess the relevance of these signs, further prospective studies aiming at systematically screen for autoantibodies in ards without risk factors are needed. once the diagnosis is made, the management is difficult and requires a multidisciplinary approach involving intensivists, pulmonologists, internists and rheumatologists in order to decide the best-individualized therapeutic strategy. intensivists should consider inflammatory myopathies, such as anti-synthetase syndrome and dermato-pulmonary syndrome associated with anti-mda- antibodies, as a cause of acute respiratory failure when the etiology appears unclear. extra-pulmonary manifestations are commonly lacking and an isolated lung involvement may reveal the disease. hospital mortality is high, especially in amda- dermato-pulmonary syndrome. abbreviations ards: acute respiratory distress syndrome; arf: acute respiratory failure; as: anti-synthetase; amda- : anti-mda- autoantibody; bal: broncho-alveolar lavage; dad: diffuse alveolar damage; ecmo: extra-corporeal membrane oxygenation; icu: intensive care unit. dc had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. dc made substantial contribution to the study design, data collection and analysis and manuscript writing. cv contributed to data collection and interpretation, and drafting of the manuscript. mpc, ndp, ad, j-pq, sp, gl, mn, gv, mf, rc, gd, em, nt, yt-l, fs, mg, eg, rl, sr, rlm, gc, cg, lz and em contributed to patients identification in each center, data collection and manuscript writing. md contributed to the data analysis, statistical analysis and manuscript revision. ndp, cg, op, hm and gp contributed to the manuscript writing and revision, and provided important intellectual content. all authors read and approved the final manuscript. service de réanimation, centre hospitalier universitaire de grenoble alpes, avenue maquis du grésivaudan, la tronche, france. service de réanimation médico-chirurgicale, centre hospitalier universitaire avicennes -assistance publique hôpitaux de paris, rue de stalingrad, bobigny, france. service de réanimation service de réanimation médico-chirurgicale service de réanimation médico-chirurgicale, centre hospitalier du mans, avenue rubillard, le mans, france. service de réanimation médicale unité de réanimation et de surveillance continue, service de pneumologie et réanimation médicale, groupe hospitalier pitié-salpêtrière, - bd de l'hôpital a contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients do we need ards? acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicenter study acute respiratory distress syndrome: the berlin definition diagnostic workup for ards patients epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries anti-melanoma differentiation-associated protein -associated dermatomyositis: expanding the clinical spectrum interstitial lung disease and anti-jo- antibodies: difference between acute and gradual onset dermato-pulmonary syndrome associated with mda- antibodies a novel dermato-pulmonary syndrome associated with mda- antibodies: report of cases and review of the literature. medicine (baltimore) interstitial pneumonia with autoimmune features: an additional risk factor for ards? ann intensive care acute interstitial lung disease revealing antisynthetase syndrome acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus acute respiratory distress syndrome as the initial clinical manifestation of an antisynthetase syndrome adult respiratory distress syndrome in polymyositis patients with the anti-jo- antibody severe respiratory failure as a presenting feature of an interstitial lung disease associated with anti-synthetase syndrome (ass) interstitial lung disease with autoantibodies against aminoacyl-trna synthetases in the absence of clinically apparent myositis clinical profiles and prognosis of patients with distinct antisynthetase autoantibodies two cases of interstitial pneumonia with anti-jo- antibodies in the absence of myositis pulmonary fibrosis with predominant cd lymphocytic alveolitis and anti-jo- antibodies clinical manifestations of anti-synthetase syndrome positive for antialanyl-trna synthetase (anti-pl ) antibodies: a retrospective study of cases the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine a new simplified acute physiology score (saps ii) based on a european/north american multicenter study delivered oxygen concentrations using low-flow and high-flow nasal cannulas early identification of acute respiratory distress disorder in the absence of positive pressure ventilation: implications for revision of the berlin criteria for acute respiratory distress syndrome interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past years? antisynthetase syndrome clinical and serological aspects of patients with anti-jo- antibodies-an evolving spectrum of disease manifestations myositis specific autoantibodies: changing insights in pathophysiology and clinical associations polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-trna synthetase enzymes clinical manifestations and outcome of anti-pl positive patients with antisynthetase syndrome sensitivity and specificity of anti-jo- antibodies in autoimmune diseases with myositis comparison of long-term outcome between anti-jo -and anti-pl /pl positive patients with antisynthetase syndrome the mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to mda (cadm- ): a retrospective study clinical features and outcomes of interstitial lung disease in anti-jo- positive antisynthetase syndrome acute respiratory failure in critically ill patients with interstitial lung disease idiopathic pulmonary fibrosis: predicting response to therapy and survival idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography comparison of the berlin definition for acute respiratory distress syndrome with autopsy the role of open-lung biopsy in ards open lung biopsy in nonresolving acute respiratory distress syndrome commonly identifies corticosteroid-sensitive pathologies, associated with better outcome the pulmonary histopathologic manifestations of the anti-jo- trna synthetase syndrome interstitial lung disease in polymyositis and dermatomyositis the diagnosis and treatment of antisynthetase syndrome basiliximab may improve the survival rate of rapidly progressive interstitial pneumonia in patients with clinically amyopathic dermatomyositis with anti-mda antibody antisynthetase syndrome and malignancy: our experience autoantibodies to a -kd polypeptide, cadm- driving pressure and survival in the acute respiratory distress syndrome the authors declare that they have no competing interests. the study was approved by institutional review board of the french society for respiratory medicine in september (cepro - ), which waived informed consent. this study did not receive funding from external or internal sources. key: cord- - myqgme authors: yoon, byung woo; lee, seung hyeun title: possible therapeutic effect of orally administered ribavirin for respiratory syncytial virus-induced acute respiratory distress syndrome in an immunocompetent patient: a case report date: - - journal: j med case rep doi: . /s - - -x sha: doc_id: cord_uid: myqgme background: human respiratory syncytial virus usually causes self-limiting upper respiratory infection and occasionally causes pneumonia in immunocompromised hosts. respiratory syncytial virus-induced severe pneumonia or acute respiratory distress syndrome in immunocompetent adults has been rarely described. unfortunately, optimal treatment has not been established for this potentially fatal condition. we report a case of respiratory syncytial virus-induced acute respiratory distress syndrome occurring in a previously healthy man successfully treated with orally administered ribavirin. case presentation: an -year-old previously healthy korean man presented with cough, dyspnea, and febrile sensation. he had hypoxemia with diffuse ground glass opacity evident on chest radiography, which progressed and required mechanical ventilation. all microbiological tests were negative except multiplex real-time reverse transcriptase polymerase chain reaction using respiratory specimen, which was positive for human adenovirus. under the diagnosis of respiratory syncytial virus-induced acute respiratory distress syndrome, orally administered ribavirin was administered and he recuperated completely without complications. conclusion: this case demonstrates the potential usefulness of orally administered ribavirin as a therapeutic option for severe respiratory syncytial virus infection, at least in an immunocompetent host. human respiratory syncytial virus (rsv) is an enveloped ribonucleic acid (rna) virus belonging to the family paramyxoviridae. rsv is a major pathogen causing lower respiratory tract infection in babies and young children, leading to hospitalization and death [ ] . in adults, it usually causes upper respiratory infection that is self-limiting. however, with recent increases in hematopoietic stem cell and solid organ transplantation, rsv infection is attracting clinical attention as a key pathogen of opportunistic infections which is associated with high mortality and morbidity [ ] . rsv-induced severe pneumonia or acute respiratory distress syndrome (ards) in immunocompromised patients is not uncommon. however, it has been rarely described in immunocompetent adults. here we report a case of ards due to rsv occurring in a previously healthy adult successfully treated with orally administered ribavirin. he denied any previous medical histories. he stopped smoking tobacco years ago, and never drank alcohol in recent years. his vital signs were: blood pressure / mmhg, heart rate beats/minute, respiratory rate breaths/minute, and body temperature . °c. on physical examination, crackle was noted in both lungs. laboratory tests revealed a white cell count of / mm with slight left shift (neutrophils . %), c-reactive protein (crp) level of . mg/dl (normal < . mg/ dl), total bilirubin level of . mg/dl, and alanine transaminase and aspartate transaminase levels of and iu/l, respectively. his sodium level was meq/ml. in arterial blood gas analysis, which was checked in ambient conditions, ph, partial pressure of carbon dioxide in arterial blood (paco ), partial pressure of oxygen in arterial blood (pao ), bicarbonate, and oxygen saturation levels were . , mmhg, mmhg, . mmol/l, and %, respectively. the result of a test for human immunodeficiency virus was negative. serologic tests for mycoplasma and chlamydia were negative. streptococcal and legionella urinary antigens were negative. antinuclear and anti-neutrophilic cytoplasmic antibodies were negative. a chest x-ray revealed diffuse haziness dominant in his right lung field (fig. a) . chest computed tomography revealed ground glass opacity in both lungs with small amounts of pleural effusion dominant in the right hemithorax (fig. b) . with an initial assessment of community-acquired pneumonia, we administered nasal oxygen at l/minute and empirical antibiotics with a respiratory quinolone. at hospital day , thoracentesis was conducted in the right hemithorax and a turbid yellowish fluid was obtained. pleural fluid analysis revealed lymphocyte-dominant exudate with white cell count of /mm and adenosine deaminase level of . iu/l. on the same day, opacities were found on chest x-ray and hypoxemia rapidly progressed to require high flow oxygen supply with fraction of inspired oxygen (fio ) . at a flow rate of l/minute (fig. a) . at hospital day , he had to be intubated and mechanically ventilated due to worsening hypoxemia. the initial pao /fio after application of mechanical ventilator was , which was compatible with the definition of "severe" ards [ ] . potential cardiac dysfunction was ruled out using transthoracic echocardiography. antibiotics were escalated to carbapenem. multiplex real-time reverse transcriptase polymerase chain reaction (rt-pcr) was conducted using advansure tm respiratory virus real-time rt-pcr kit (lg life sciences, seoul, korea) to detect respiratory viruses using tracheal aspirate. results revealed positive for human rsv type b. under the diagnosis of rsv-induced ards based on the berlin definition [ ] , we started antiviral therapy of orally administered ribavirin mg every hours with concomitant intravenously administered methylprednisolone mg every hours. after treatment, hypoxemia and lung lesions gradually improved. at hospital day , he was extubated and we tapered methylprednisolone to orally administered prednisolone mg. finally, his chest x-ray cleared and he was discharged on hospital day without any complications or drug-related adverse events (fig. b ). orally administered ribavirin was maintained until his discharge. we summarized the whole clinical course with the drugs administered in fig. . rsv pneumonia in adults occurs mostly in immunocompromised patients and is characterized by rapid clinical deterioration often leading to death. however, ards due to rsv in previously healthy adults is extremely rare and only two cases have been reported to date [ , ] . of note, patients in those cases were treated without ribavirin or with inhaled ribavirin. to the best of our knowledge, this is the first case that reports successful treatment of rsvinduced ards using orally administered ribavirin in an immunocompetent patient. rsv has been considered a less significant pathogen in adults as it usually causes mild and self-limiting upper respiratory tract infection. the clinical significance of rsv infection in adults has been acknowledged in recent years. a study has estimated that rsv infects to % of adults annually and it may be associated with to % of community-acquired pneumonia [ ] . in a retrospective cohort study, rsv infection was complicated with pneumonia in two thirds of infected patients from which one tenth required mechanical ventilation, and the mortality rate was as high as to % comparable to that of seasonal influenza [ ] . in that study, severe rsv-related lower respiratory tract infections occurred mostly in elderly patients and those with major medical comorbidities [ ] . in this case, the patient denied previous medical history and had no relevant comorbidities. therefore, the severe rsv infection may be attributable to his advanced age. similar to other viral diseases, rsv pneumonia is difficult to diagnose. its respiratory symptoms are nonspecific, and laboratory and radiologic findings are usually indistinguishable from other respiratory viral infections. definitive diagnosis of rsv can be confirmed by identification of typical plaque morphology with syncytium formation using immunofluorescent staining. however this is time consuming and costly. nucleic acid detection using multiplex real-time rt-pcr test is used in clinical practice as it enables rapid detection with increased sensitivity [ ] . in this case, atypically rapid deterioration of clinical manifestations led us to suspect infections caused by atypical pathogen including viral pneumonia. therefore, we conducted the multiplex real-time rt-pcr test. although diagnostic performances of different multiplex real-time rt-pcr assays for respiratory viral infections can vary depending on devices used [ , ] , the assay used for diagnosis of our case had revealed relatively high sensitivity and specificity for respiratory viral pathogens with performance that is comparable to other commercial assays despite shorter turnaround time [ ] . in a previous study, rogers et al. reported the clinical impact of multiplex rt- pcr test for respiratory viruses on clinical outcome using more than children patients including rsv pneumonias [ ] . they demonstrated that the use of a multiplex rt-pcr test was associated with decreased duration of antibiotic use, length of in-patient stay, and duration of isolation of patients admitted for acute respiratory infections. in addition, rappo et al. using a retrospective cohort (n = ) had compared clinical outcomes for adult patients diagnosed by multiplex rt-pcr for respiratory viruses with those diagnosed by conventional methods at a tertiary care center [ ] . in that study, influenza ( % from all isolates) and rsv ( %) were the predominant viruses identified. they found a significantly lower rate of admission, length of hospital stay, duration of antimicrobial use, and number of chest radiographs, after adjusting potential confounders in the multiplex rt-pcr group [ ] . taken together, multiple rt-pcr tests are clinically useful methods for early detection of viral pathogens for respiratory tract infection and for cost effectiveness during treatment. our case was compatible with the berlin definition of ards, defined by the timing (within week of clinical insult or onset of respiratory symptoms), radiographic changes (bilateral opacities not fully explained by effusions, consolidation, or atelectasis), and origin of edema (not fully explained by cardiac failure or fluid overload). the severity of our case corresponded to "severe" [ ] . there is debate about the use of corticosteroids for patients with ards, and current data do not support routine use of corticosteroids in those patients [ ] . however, several studies suggested that low-dose corticosteroids ( to mg/kg per day of intravenously administered methylprednisolone) may be beneficial in terms of short-term mortality for patients with ards which is less than days after onset [ , ] . our case was compatible with the definition of ards and duration of onset was less than days, thus we started mg of methylprednisolone intravenously. a current guideline states that a low dose of systemic steroid used in the early stage may improve hypoxemia and reduce the period of mechanical ventilation, length of intensive care unit (icu) stay, and mortality [ ] . optimal treatment duration of corticosteroids has not been established, as corticosteroids were used for different durations at different trials. we maintained the initial dose of methylprednisolone by the time of his extubation and slowly tapered it until his discharge. the clinical benefits of corticosteroids for respiratory virus-associated ards as well as their optimal dose or treatment duration need to be elucidated. of note, pathogens other than rsv could have contributed to the development of his ards and a spontaneous resolution could have contributed to the outcome. however, his atypical clinical presentation and no evidence of other disease or infectious pathogen except rsv after vigorous microbiologic examination led us to suspect rsv-related ards. optimal treatment for rsv pneumonia has not been established. oral neuraminidase inhibitors have been widely used in severe influenza infection, however, they failed to show efficacy against paramyxoviridae family viruses including rsv. aerosolized ribavirin, a nucleoside analogue with broad antiviral activity, has been reported to be effective in preventing severe pneumonia in non-influenza respiratory viral infections in babies and children [ ] . however, there is concern about its use due to its high cost, teratogenicity, and potentially administered risk of lung function decline. in addition, intravenously administered or aerosolized ribavirin unfortunately is not readily available in our country because we can acquire this agent only through the korea orphan & essential drug center (koedc), which may cause delay in the start of treatment. meanwhile, orally administered ribavirin is relatively safe and economic, and several reports have suggested that it is associated with favorable clinical outcomes in rsv infection [ , ] . thus, we selected orally administered ribavirin with systemic corticosteroids for our case. our treatment is supported by a previous study reporting that orally administered ribavirin and corticosteroid were a well-tolerated and cost-effective regimen for lung and heart/lung transplant recipients with paramyxovirus infection [ ] . this case suggests that orally administered ribavirin may be an option, although not optimal treatment, even for cases of severe rsv, especially in a situation where other forms of ribavirin are not readily available. rsv-induced ards is very uncommon but can be lethal in immunocompetent patients. the present case highlights the significance of early clinical suspicion and active use of multiplex real-time rt-pcr test. in addition, this case suggests that orally administered ribavirin could be a therapeutic option even for severe pneumonia or ards due to rsv, at least in immunocompetent hosts, especially if other antiviral agents are unavailable. future studies are needed to determine its efficacy for selected patients. global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis respiratory syncytial virus infection in recipients of allogeneic stem-cell transplantation: a retrospective study of the incidence, clinical features, and outcome clinical practice guideline of acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition respiratory syncytial virus infection: a cause of respiratory distress syndrome and pneumonia in adults inhaled ribavirin therapy in adult respiratory syncytial virus-induced acute respiratory distress syndrome respiratory syncytial virus infection in adults high morbidity and mortality in adults hospitalized for respiratory syncytial virus infections rapid diagnosis of respiratory syncytial virus infections in immunocompromised adults multiplex pcr point of care testing versus routine, laboratory-based testing in the treatment of adults with respiratory tract infections: a quasi-randomised study assessing impact on length of stay and antimicrobial use respiratory syncytial virus infection control challenges with a novel polymerase chain reaction assay in a comparison of the advansure real-time rt-pcr and seeplex(®) rv ace assay for the detection of respiratory viruses impact of a rapid respiratory panel test on patient outcomes impact of early detection of respiratory viruses by multiplex pcr assay on clinical outcomes in adult patients use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis steroid treatment in ards: a critical appraisal of the ards network trial and the recent literature respiratory viruses other than influenza virus: impact and therapeutic advances oral ribavirin therapy for lower respiratory tract infection of respiratory syncytial virus complicating bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation successful treatment of parainfluenza virus pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections an -year-old korean man visited our out-patient clinic complaining of cough, dyspnea, and febrile sensation. the present study was not funded. the dataset supporting the conclusions of this article are included within the article.authors' contributions bwy contributed to diagnoses and management, collected data, and wrote and reviewed the manuscript. shl contributed to the study design and reviewed the manuscript. both authors read and approved the final manuscript.ethics approval and consent to participate this case report was performed in accordance with international ethical rules. written informed consent was obtained from the patient for publication of this case report and any accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal. the authors declare that they have no competing interests.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- -hgx bfbz authors: chen, chaolei; huang, xiaomin; ying, zhaojian; wu, dengmin; yu, yani; wang, xiangdong; chen, chengshui title: can glypican- be a disease-specific biomarker? date: - - journal: clin transl med doi: . /s - - - sha: doc_id: cord_uid: hgx bfbz background: glypican- (gpc ) is a cell surface-bound proteoglycan which has been identified as a potential biomarker candidate in hepatocellular carcinoma, lung carcinoma, severe pneumonia, and acute respiratory distress syndrome (ards). the aim of our review is to evaluate whether gpc has utility as a disease-specific biomarker, to discuss the potential involvement of gpc in cell biology, and to consider the changes of gpc gene and protein expression and regulation in hepatocellular carcinoma, lung cancer, severe pneumonia, and ards. results: immunohistochemical studies have suggested that over-expression of gpc is associated with a poorer prognosis for hepatocellular carcinoma patients. expression of gpc leads to an increased apoptosis response in human lung carcinoma tumor cells, and is considered to be a candidate lung tumor suppressor gene. increased serum levels of gpc have been demonstrated in ards patients with severe pneumonia. conclusions: glypican- could be considered as a clinically useful biomarker in hepatocellular carcinoma, lung carcinoma, and ards, but further research is needed to confirm and expand on these findings. acute respiratory distress syndrome (ards) is a lifethreatening syndrome characterized by the acute onset of pulmonary edema of non-cardiogenic origin, along with bilateral pulmonary infiltrates and reduction in respiratory system compliance in the seriously ill patient. ards is a complex response of the lung to direct and indirect insults associated with high morbidity and mortality, with current treatments mainly being supportive, without accurate targeted therapies [ , ] . directions of research are concentrating on identifying potential biomarkers or genetic markers to facilitate diagnosis, and to assist in prediction of outcome and treatment response. recently, our group found that the serum level of glypican- (gpc ), a proteoglycan anchored to cell surface by glycosyl-phosphatidylinositol, was significantly higher in the circulation of patients with severe pneumonia, as compared with healthy control, and increased even more significantly in patients with severe pneumonia accompanied with ards than those with severe pneumonia alone [ ] . we proposed that the circulating level of glypican- may correlate with the severity of pneumonia as potential biomarker to predict the occurrence of ards. gpc has been recently reported and suggested as a novel potential oncofetal biomarker for diagnosis in a number of cancer diseases such as hepatocellular carcinoma [ ] . it has previously been demonstrated that gpc was over-expressed in human hepatocellular carcinoma measured by cdna microarrays, and gpc protein was found in serum from % of patients with hepatocellular carcinoma, but not in serum from patients with liver cirrhosis, chronic hepatitis, and healthy donors [ ] . therefore, gpc was proposed as a useful tumor marker for cancer-diagnosis for patients with hepatocellular carcinoma. specific role of gpc in cancer and inflammatory disease at different times seems to have a clear and reasonable disease control, e.g., severe pneumonia with or without ards, or virus-infected patients with hepatocellular carcinoma compared with other liver diseases [ , ] . the significant open access increases in expression of gpc in hepatocellular carcinoma and ards raise the question whether gpc has utility as a biomarker of disease or disease severity [ ] [ ] [ ] [ ] . the present commentary calls for further research into the molecular biology, disease-specific associations, and potential value as a biomarker of gpc . glypican- , also called oci- , dgsx, gtr - , mxr , sdys, sgb, sgbs, and sgbs , was identified in a rare undifferentiated epithelial cell line oci- [ ] . it is a cell surface heparan sulfate proteoglycan belonging to the glypican-related integral membrane proteoglycan family [ ] , which includes six members (gpc -gpc ). according to the homogeneity and heterogeneity of gene sequences, these six members are divided into two subfamilies; one group is gpc and gpc which show % sequence homology, while the other group contains gpc , gpc , gpc , and gpc [ ] . gpc is encoded at chromosome xp adjacent to gpc , and spans more than kilobases. four isoforms have been reported, of which isoform (genbank accession no.: np_ ), which encodes a -kda precursor core protein with amino acids, is the most commonly expressed [ ] . glypicans are composed of a - kda size membrane-associated core protein, a variable number of heparan sulfate glycosaminoglycan polysaccharide side chains, and a glycosyl-phosphatidylinositol linkage. the core protein is predicted to form a conserved globular tertiary structure because of several intramolecular disulfide bridges caused by conserved cysteine residues domains. heparan sulfate chains bind to serine residues of core protein carboxyl terminal protein [ ] , and approximate the core protein to the cell membrane. a glycosyl-phosphatidylinositol linkage anchor becomes the final connecting link between the core protein and the cell membrane. gpc has one -kda amino terminal protein and one -kda membrane-bound carboxyl terminal protein. the amino acid sequences for the two different terminal proteins are arg and ser , which can be enzymatically lyzed releasing a soluble form of gpc (sgpc ). sgpc can be specifically detected in the circulating blood of patients with hepatocellular carcinoma [ ] . secreted gpc can also be cleaved by notum, a secreted enzyme, into a released form in the extracellular environment [ ] . the notum's cleavage site and glycosyl-phosphatidylinositol linkage-phospholipase c, the glycosyl-phosphatidylinositol linkage anchor of gpc , are two distinct soluble gpc forms, each having different functions. glypican- gene is weakly expressed in the placenta and lung, kidney, ovarian, breast, and skin tissue, but not in normal adult liver, heart, brain, spleen, stomach, intestine, testicles, and bladder tissue [ ] . gpc plays important roles in tissue morphogenesis and homeostasis during development, e.g., developmental outgrowth and dysplastic kidneys of simpson-golabi-behmel syndrome [ ] , via wnt/jnk signaling [ ] or fgf signaling pathways [ ] , in the processes of chondrogenesis and osteogenesis via the morphogenetic protein signaling pathway [ ] , and several malignancies as a cancer suppressor gene through a suppression of pi k/akt pathways and a stimulation of p /mapk pathway [ ] (fig. ) . gpc contributes to cell proliferation and survival, and regulates breast cancer cell growth [ ] . increasing evidence suggests soluble gpc as a novel diagnostic candidate marker in hepatocellular carcinoma [ ] . gpc is expressed in % of hepatocellular carcinomas, but not in neuroendocrine tumor metastatic to the liver, and cholangiocarcinoma, measured by liver cancer tissue microarrays which were constructed from hepatocellular carcinoma, neuroendocrine tumor, and cholangiocarcinoma samples [ ] . the high positive rate of gpc in hepatocellular carcinoma indicates the specificity of gpc in hepatocyte-origin carcinogenesis. gpc was considered as important as alpha-fetoprotein in a fast and effective cell sorting strategy to specifically identify hepatocellular carcinoma circulating cells [ ] . the positive rate of hepatocellular carcinoma circulating cells was above % in combination of gpc with alpha-fetoprotein. the hepatocellular carcinoma cells positive to both gpc and cytokeratin were found to have the highest risk of multifocality, microvascular invasion, regional lymph node involvement, shortest recurrence time, and distant metastasis in a retrospective study of immunohistochemical staining [ ] . the combination of gpc and cytokeratin expression in the cancer tissue was suggested as an independent prognostic indicator in patients with hepatocellular carcinoma. glypican- was recently suggested to be a critical part of molecular mechanisms by which the proliferation and invasion of hepatocellular carcinoma are regulated and controlled. microrna- b is a small non-coding rna which targets sirt s, suppressing its expression in hepatocellular carcinoma cells, increasing the proliferation and invasion of hepatocellular carcinoma cells through the activation of e-cadherin expression, and repressing expression of gpc and the anti-apoptotic proteins (bcl- , bcl-xl, and mcl- ) [ ] . it is questioned whether the gpc /wnt β-catenin signal pathway is mir- b/ sirt -specific regulation or is the hepatocellular carcinoma cell-specific and/or dominated mechanism. a clinical trial of codrituzumab, a humanized monoclonal antibody against gpc , was recently performed in a randomized phase ii trial in advanced hepatocellular carcinoma patients who had failed prior systemic therapy [ ] . it was proposed that gpc could interact with cd / fcγriiia and trigger antibody-dependent cytotoxicity in hepatocellular carcinoma cells. patients with vascular invasion and/or extra-hepatic metastasis were treated with sorafenib and then with codrituzumab or placebo. this particular study with patients with codrituzumab failed to show any significant improvement of the median progression-free survival and overall survival, even though those patients had high cd /fcγriiia expression on peripheral immune cells and gpc expression in the tumor. oligonucleotide microarray analysis demonstrated that gpc is over-expressed in tissues harvested from smokers with lung adenocarcinoma [ ] . the importance of gpc was furthermore validated in lung cancer cell lines. it was proposed that the over-expression of gpc may be induced by smoking, although no direct evidence to support this has been reported. high expression of gpc was noticed in lung cancer tissues, particularly in lung squamous cell carcinoma. gpc protein and mrna expression were positive in % of squamous cell carcinoma versus % of adenocarcinoma, but negative in normal lung tissues [ ] . the suggestion that gpc was suggested as a potential candidate marker for early detection of lung squamous cell carcinoma should be questioned, since about half of patients with lung squamous cell carcinoma have negative gpc staining, and because it is hard to access the lung tissue at the early stage of the disease. when comparing the sensitivity of tissue markers using immunostaining [ ] , the positive staining of p was about % in both lung squamous cell carcinoma and adenocarcinoma, followed by high-molecular-weight cytokeratin (hmck) ( %), cytokeratin / ( %), sry-related hmg-box ( %), thrombomodulin ( %), desmocollin- ( . %), s a ( %), s a ( . %), and gpc ( %), while desmocollin- in lung squamous cell carcinoma alone was %, followed by cytokeratin / ( %), sry-related hmg-box ( %), gpc ( %), s a ( %), thrombomodulin ( %), s a ( %), p ( %), and hmck ( %). thyroid transcription factor- (ttf- ) expression was observed in . % of lung adenocarcinoma cases and . % of squamous cell lung carcinoma cases. when analyzing only poorly differentiated tumors, hmck was the most sensitive marker for squamous cell lung carcinoma ( %), followed by p ( . %), ck / ( . %), sox ( . %), thrombomodulin ( . %), desmocollin- ( . %), s a ( %), glypican- ( . %), and s a ( . %). desmocollin- was the most specific marker for poorly differentiated squamous cell lung carcinoma ( %), followed by ck / ( . %), glypican- ( . %), sox ( . %), s a ( %), s a ( . %), thrombomodulin ( . %), p ( . %), and hmck ( . %). the study by tsuta et al. demonstrated that a number of molecules could be altered according to disease subtypes, differentiations, durations, and severities. the cytokeratin / was suggested as the best marker for differentiating lung squamous carcinoma and lung adenocarcinoma, although gpc and others were also differentially expressed compared with controls. in addition, an early study demonstrated an increased apoptosis response caused by ectopic expression of gpc in human lung carcinoma tumor cell, and gpc would be a candidate lung tumor suppressor gene [ ] , although little has been known on accurate mechanisms of gpc in the carcinogenesis of lung cancer. the specificity of gpc as disease biomarkers should be carefully examined and validated in large cohorts, in a comparison among multiple diseases, and in cases of different stages, duration, and severity. gpc was firstly reported as a disease-specific biomarker for ards [ ] . gpc was identified by integrating proteomic profiles of inflammatory mediators with clinical bioinformatics [ ] . in the research by chen et al., plasma was collected from the healthy persons as controls or from patients with severe pneumonia infected by bacteria or from patients with severe pneumonia-associated ards on day of the admission, day , and day [ ] . expression of gpc in peripheral circulation of severe pneumoniaassociated ards patients progressively increased over time (admission day, day , day ) compared with healthy persons or severe pneumonia patients alone. the investigators further showed that circulating levels of gpc were increased in ards induced by severe pneumonia as a model of infection-dominated disease, as well as in ards induced by acute pancreatitis as a model of non-infection-based disease. it seems that altered gpc may be more dependent upon the disease stage and severity, rather than the properties of associated pathogens or initiates. in acute liver injury models induced by lipopolysaccharide, expression of gpc genes increased over time after induction, and even more significantly when bone marrow-derived mesenchymal stem cells were transplanted [ ] . the mechanism by which gpc influences ards is unknown. based on the known gpc -related signaling pathways [ ] [ ] [ ] , we propose a possible hypothesis that the gpc -wnt pathway may play a significant role in the development and progression of ards (fig. ) . gpc has opposite effects on the canonical and non-canonical wnt signaling pathways, suppressing canonical wnt/βcatenin signaling while activating non-canonical wnt signaling pathway (wnt/jnk) [ ] . the wnt/β-catenin signaling pathway can induce transformation of mesenchymal stem cells to alveolar epithelial cells [ ] . thus, a suppression of wnt/β-catenin signaling pathway by gpc may destroy cell integrity, change alveolar epithelial permeability, and aggravate lung edema. on the other hand, an enhancement of wnt/jnk signaling pathway caused by gpc may induce nf-κb activation, which is a classic proinflammatory transcription factor in many inflammatory diseases including ards [ ] . we therefore hypothesize that gpc may be involved in the tissue/cell-associated auto-defensive processes, repair and recovery, or regeneration. glypican- is involved in the inhibition of cell proliferation and modulation of cell survival during development process of the organ. it may have value as a biomarker of hepatocellular carcinoma, lung carcinoma, severe pneumonia, and ards. gpc was recently selected and proposed as a biomarker in patients with severe pneumonia and ards [ ] . the potential of gpc as a disease biomarker needs further study in different diseases in particular in lung diseases, such as ards, and in cancers including lung and liver cancer. these studies should involve large cohorts with a variety of disease durations and severity, and in the case of ards, of inducing factors. the biological functions and roles of gpc require further investigation to understand the molecular mechanisms underpinning the associations of gpc with disease. we aim to further evaluate the utility of gpc as a biomarker, in order to enable producing more precise and accurate medicine. potential mechanisms of gpc in acute lung injury. wnt/β-catenin signaling pathway shows its ability to transform the mesenchymal stem cells to alveolar epithelial cells. the suppression of wnt/β-catenin signaling pathway by gpc may destroy cell integrity, change alveolar epithelial permeability, and aggravate lung edema. on the other hand, gpc can enhance wnt/jnk signaling pathway which may create an increase transcription of nf-κb acute respiratory distress syndrome: the berlin definition epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries disease-specific dynamic biomarkers selected by integrating inflammatory mediators with clinical informatics in ards patients with severe pneumonia glypican- , overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker network biomarkers, interaction networks and dynamical network biomarkers in respiratory diseases biomarkers of early chronic obstructive pulmonary disease (copd) in smokers and former smokers. protocol of a longitudinal study application of clinical bioinformatics in lung cancer-specific biomarkers opportunities and challenges of disease biomarkers: a new section in the journal of translational medicine isolation of a cdna corresponding to a developmentally regulated transcript in rat intestine mutations in gpc , a glypican gene, cause the simpson-golabi-behmel overgrowth syndrome the molecular diversity of glycosaminoglycans shapes animal development glypican- : a new target for cancer immunotherapy identification of soluble nh -terminal fragment of glypican- as a serological marker for early-stage hepatocellular carcinoma processing by proprotein convertases is required for glypican- modulation of cell survival, wnt signaling, and gastrulation movements mammalian notum induces the release of glypicans and other gpi-anchored proteins from the cell surface expression pattern of glypican- (gpc ) during human embryonic and fetal development gpc expression correlates with the phenotype of the simpson-golabi-behmel syndrome the loss of glypican- induces alterations in wnt signaling glypican- modulates bmp-and fgf-mediated effects during renal branching morphogenesis boning up on glypicans-opportunities for new insights into bone biology overexpression of gpc inhibits hepatocellular carcinoma cell proliferation and invasion through induction of apoptosis glypican- reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating pi k/akt and p mapk signaling pathways liver metastases of neuroendocrine tumors rarely show overlapping immunoprofile with hepatocellular carcinomas biofunctionalized magnetic nanospheres-based cell sorting strategy for efficient isolation, detection and subtype analyses of heterogeneous circulating hepatocellular carcinoma cells ck and glypican expression profiling in the prognostic indication for patients with hcc after surgical resection microrna- b inhibits hepatocellular carcinoma cell progression by targeting sirt randomized phase ii placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma glypican- is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma utility of immunohistochemical markers including novel markers (desmocollin- , glypican , s a , s a , and sox- ) for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung the heparan sulfate proteoglycan gpc is a potential lung tumor suppressor bone marrow-derived mesenchymal stem cells inhibits hepatocyte apoptosis after acute liver injury glypican- promotes the growth of hepatocellular carcinoma by stimulating canonical wnt signaling glypican- regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through wnt signaling modulation glypican- binds to frizzled and plays a direct role in the stimulation of canonical wnt signaling activation of wnt/beta-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice protective effect of ginkgo biloba leaves extract, egb , on endotoxininduced acute lung injury via a jnk-and akt-dependent nfkappab pathway not applicable. authors' contributions cc drafted the whole idea of this review. cc completed the manuscript writing. xh, zy, dw, and yy participated in manuscript preparation. cc and xw reviewed and edited the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. this work was supported by the national nature science foundation of china (the molecular mechanisms of glypican -wnt signal pathways mediated airway local inflammation in acute lung injury, award number: ; dialogue between the immediate early protein cyr /ccn with pi k signaling regulates the development of acute lung injury, award number: ), and wenzhou science technology department foundation (the role and mechanism of gpc in acute lung injury, award number: y ). springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -daxz yhp authors: haeberle, helene; prohaska, stefanie; martus, peter; straub, andreas; zarbock, alexander; marx, gernot; zago, manola; giera, martin; koeppen, michael; rosenberger, peter title: therapeutic iloprost for the treatment of acute respiratory distress syndrome (ards) (the thilo trial): a prospective, randomized, multicenter phase ii study date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: daxz yhp background: acute respiratory distress syndrome (ards) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. the treatment of ards to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ards, iloprost treatment resulted in improved oxygenation. therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ards. methods: the therapeutic iloprost during ards trial (thilo trial) is a multicenter, randomized, single blinded, clinical phase ii trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ards in critically ill patients. one hundred fifty critically ill patients suffering from acute ards will be treated either by nebulized iloprost or nacl . % for days. blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. mechanical ventilation will be standardized. in follow-up visits at days and as well as months after enrollment, functional status according to the barthel index and a health care-related questionnaire, and frailty (vulnerable elders survey) will be evaluated. the primary endpoint is the improvement of oxygenation, defined as the ratio of pao( )/fio( ). secondary endpoints include -day all-cause mortality, sequential organ failure assessment scores during the study period up to day , the duration of mechanical ventilation, the length of intensive care unit (icu) stay, ventilator-associated pneumonia, delirium, icu-acquired weakness, and discharge localization. the study will be conducted in three university ards centers in germany. discussion: the results of the thilo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ards, resulting in the improvement of outcome parameters in patients with ards. trial registration: eudra-ct: - - . registered on april . clinicaltrials.gov: nct . registered on june . acute respiratory distress syndrome (ards) is defined as pulmonary compromise with bilateral pulmonary infiltrates associated with moderate to severe hypoxemia [ ] . the public health impact of ards is considerable, and it is estimated that approximately , cases of ards occur annually in germany. the estimated mortality ranges from to % and depends on the severity of the associated hypoxemia [ ] . patients surviving ards treatment also show reduced functional capacity in their everyday life following hospitalization [ , ] . therefore, there is a pressing need to develop further ards treatment strategies with a view to ultimately improving patient outcomes. the bilateral pulmonary infiltrates that can be identified on chest radiography reflect the diffuse inflammatory changes within the lung that are caused by acute inflammation within the pulmonary tissue and the alveolar space. the initial inflammatory process is induced by the activation of the innate immune response by the binding of microbial products (pathogen-associated molecular patterns [pamps]) or cell injury-associated endogenous molecules (danger-associated molecular patterns [damps] ) to pattern recognition receptors (prrs). therefore, the common causes of ards are trauma, sepsis, pneumonia, blood transfusion, or aspiration into the lungs. after the initial activation of the innate immune response, innate immune effector mechanisms, such as the formation of neutrophil extracellular traps (nets), are activated, which further aggravate the alveolar injury [ ] . the resulting increased permeability of the microvascular barrier results in the extravascular accumulation of protein-rich fluid that accumulates within the alveolar space. the increased permeability is also linked to the transfer of leukocytes (mostly neutrophil granulocytes) and erythrocytes into the alveolar space in ards, as well as to the presence of proinflammatory-regulated cytokines that increase the inflammatory burden within the lung [ ] . as a result, dysregulated inflammation, the accumulation of leukocytes and platelets, and altered permeability of alveolar barriers remain the central pathophysiologic problems in ards [ , ] . the treatment of ards to date is focused on the prevention of further iatrogenic damage of the lung through lung-protective mechanical ventilation, neuromuscular blockade, and conservative fluid management [ ] . recent clinical trials have focused on the role of ventilation strategies in the prevention or treatment of ards using noninvasive ventilation devices or prone positioning [ , ] . although these strategies have shown a positive effect on patient oxygenation and symptoms, they do not interfere with the underlying pathophysiological changes of ards. several interventions have tried to use a potential anti-inflammatory strategy for the treatment of the existing intra-alveolar inflammation or to intervene in the development of intra-alveolar inflammation. for this, patients were treated with aspirin, simvastatin, and surfactant, but the tested treatments failed and did not have any significant effect [ ] [ ] [ ] . considerable evidence in preclinical models shows that the use of iloprost for the treatment of ards and pulmonary inflammation might be of significant benefit. in small animal models, investigators showed that iloprost improves endothelial barrier function and reduces the detrimental signs of pulmonary edema [ ] . it also reduces the pulmonary sequestration of leukocytes and platelets, which is a central disease mechanism underlying the development of ards [ ] . this evidence could be transferred into different models of lung injury, showing positive evidence for the reduction of pulmonary inflammation in a pressure-induced model of lung injury [ ] . the anti-inflammatory effect was attributed to the cyclooxygenase- (cox- ) system and the involvement of lipoxin a [ ] . ras-related protein (rap- ) might also be involved in the protective role of iloprost [ ] . this positive anti-inflammatory effect of iloprost on the pulmonary tissue was also demonstrated in several models of ischemia-reperfusion (ir) injury. furthermore, ir injury can also result in ards and pulmonary failure. iloprost was able to reduce this pulmonary compromise in several preclinical studies [ ] [ ] [ ] [ ] . the anti-inflammatory effect of iloprost was also shown in large animal models of lung injury using porcine models of ards [ ] [ ] [ ] . here, again, iloprost showed an anti-inflammatory effect. in addition, the shunt fraction could be reduced, which resulted in improved oxygenation and improved pulmonary dynamics, which is essential for the reinstitution of spontaneous ventilation during and following ards [ , , [ ] [ ] [ ] . this shows that the preclinical data identified a beneficial effect of iloprost on ards. so far, only one study on inhaled iloprost in adult patients with ards has been conducted, although an application of inhaled iloprost is noted in the guidelines of the association of the scientific medical societies (awmf) for the treatment of ards [ ] . the awmf guidelines indicate that the use of ards can be considered, especially in patients with severe ards who are mechanically ventilated and not selfconsenting [ ] . thilo is a multicenter, randomized, single blinded clinical phase ii trial assessing the efficacy of inhaled iloprost in the development and progression of ards in critically ill patients. based on the risk of pulmonary hemorrhage, which is very rare-especially in patients with ards-the study medication was unblended. for safety reasons, after treatment of patients (day after last dose investigational medicinal product [imp] patient ) within the study, an interim analysis for an increased risk for pulmonary hemorrhage ≥ grade iii according to common terminology (toxicity) criteria for adverse events (ctcae) version . in the treatment (iloprost) arm will be performed and the results discussed with the data and safety monitoring board (dsmb). the study was ap- the target population for this clinical trial is adult critically ill patients with ards. patients will be included in the trial if they present with ards as defined by the berlin definition (table and [ ] ) and meet the inclusion criteria. the trial population will consist of both sexes. one hundred fifty intensive care patients with ards will be included in the study at the department of anesthesiology, eberhard karls university tübingen, germany; the department of intensive care and intermediate care, university hospital rwth aachen, germany; and the department of anesthesiology, university hospital münster (ukm), münster, germany. patients meeting the following criteria will be included: age ≥ years, pao /fio ≤ , bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph, need for positive pressure ventilation via an endotracheal tube or noninvasive ventilation and no clinical signs of left atrial hypertension detected via echocardiography, or if measured, a pulmonary arterial wedge pressure (pawp) less than or equal to mmhg. the term "acute onset" is defined as follows: the durations of the hypoxemia criterion and the chest radiograph criterion must be ≤ h at the time of randomization. patients must be enrolled within h of ards onset and no later than days from the initiation of mechanical ventilation. the exclusion criteria are defined as follows: subject age < years; time interval more than days since the initiation of mechanical ventilation; more than h since the onset of ards; patient, surrogate, or physician not committed to full intensive care support; positive pregnancy test at the time of screening; and contraindications against iloprost. these are defined as conditions in which the effects of iloprost on platelets might increase the risk of hemorrhage (e.g., active peptic ulcers, trauma, intracranial hemorrhage), severe coronary heart disease, myocardial infarction (within the last months), decompensated heart failure, severe arrhythmias, unstable angina pectoris, pulmonary arterial hypertension caused by the occlusion of pulmonary veins, cerebrovascular events (e.g., transient ischemic attack, stroke) within the last months, and congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension. patients who received iloprost treatment for any indication within h prior to enrollment in the clinical trial or patients who were on thrombin inhibitors or nitric oxide (no) within the previous h before study randomization were also excluded. additionally, patients dependent on the sponsor, investigator, or their employees were not included in the study. the imp is iloprost (ventavis®; drug code sub mig; atc code b ac ), manufactured by berlimed s.a., madrid, spain (for bayer pharma ag, germany). it will be used as a concentrate for use in nebulizers and will be administered by inhalation three times a day ( μg per administration). the administration of the drug will occur at the same time each day ± h. in cases of severe adverse effects, the dosage will be reduced to μg once a day (morning). other dose modifications or temporary cessation of the study drug will not be allowed. iloprost is usually dissolved in . % sodium chloride (nacl), which is used to keep the ventilator circuit moist as standard of care. therefore, in the control group, nacl . % will be used to keep the airway circuit moist, which is the standard of care for the treatment of patients with pulmonary insufficiency [ ] . considering the pharmacokinetic and dynamic profile of iloprost, we have suggested an approach of an application of three times per day, with a dose of μg, which seems to be an average dose in the trials reported up to now. the rationale behind this was that iloprost also exerts an anti- inflammatory effect that may last up to h [ ] [ ] [ ] [ ] [ ] . therefore, an administration of iloprost three times a day would allow a significant time frame per day to be covered by anti-inflammation due to this drug. the duration of days was included in the trial because the pathophysiology of ards develops within the first few days and is progressive during that period. randomization lists will be generated at the biostatistical center. based on these lists, numbered envelopes will be provided and used for randomization. relevant additional medications and treatments such as vasopressors, inotropes, anti-infective agents, inhalative therapy or sedation, steroids, and immunosuppressive therapy administered to the subjects on entry to the trial or at any time during the trial are regarded as concomitant medications and treatments and must be documented on the appropriate pages of the case report form (crf); these data will be grouped according to class of medication. depending on the substance, the documentation varies in details (e.g., dosing). this study will consist of the following consecutive phases: study entry, treatment, and follow-up. the time points and trial procedures are listed in table . all patients included in this trial will receive standard care for ards according to the ards network, with special consideration of lung-protective ventilation strategies. in this trial, patients with ards present an emergency situation, such as the diagnosis of ards requiring intensive care unit (icu) admission and ventilation therapy, which does not allow for any delay of diagnostic workup or therapy. additionally, due to severe symptoms, the vast majority of patients who meet the eligibility criteria for the trial are assumed to be unable to give consent in the acute admission phase, and legally authorized representatives (lars) might not be available in most cases. this is also in line with local regulations: e.g., § of the german drug law allows the start of a treatment in an emergency situation without prior consent if the immediate treatment is necessary to save the patient's life, recover the patient's health, or ease the patient's suffering. in this situation the consent of an independent physician not directly involved in the study conduct will be sought before the beginning of any study-related activity. the consent has to be obtained as soon as the patient is able to give consent or a lar is available. independently, personal consent will be obtained from each patient after recovering consciousness and competence for decisionmaking or by a legal representative in cases recovering is not achieved during the study duration (i.e., day ). when possible, however, the patient or his legal representative is to be informed both in writing and verbally by the investigator before any study-specific procedure is iloprost or nacl . % (control) x x x x x clinical assessment including outcome x x x x x x x x x laboratory testing x x x x x x x x adverse/serious adverse event monitoring x x x x x x x plasma biomarkers x x x x x x barthel index x x x x sofa score x x x x x x x x health-related questionnaire x ves x performed. each patient or his legal representative will be informed about the modalities of the clinical study in accordance with the provided patient information. informed consent from the patient will be obtained using a form approved by the ethics committee (ec) of the universitätsklinikum tübingen or the local ec if the patient is treated in a collaborating institution. the treatment group will receive μg of nebulized iloprost three times per day for days in addition to standard care. iloprost will be measured in blood samples to determine the serum levels within this setting. the control group will receive nebulized . % nacl with an equal volume three times per day for days. after days, the trial treatment will be complete (fig. ) . blood samples will be drawn at defined time points for a variety of biomarkers to better assess the associations among coagulation, inflammation, and iloprost treatment. key cointerventions (infection control, aspiration precautions, fluids, and transfusion) will be standardized across all patients. mechanical ventilation will be standardized (see additional file ). hospital survivors will undergo a brief follow-up phone survey to assess functional status (barthel index), a health-related questionnaire, and the vulnerable elders survey (ves) to assess frailty months after enrollment. the patients will be visited daily until day or until discharge from the icu, which could be beyond day . if discharged, the next visit will be on day ; if patients are still in the icu, there will still be daily visits until this time point. data will be collected according to the study procedure until then. each visit will consist of a clinical examination, a blood sample, assessment of the functional capacity through the barthel index, and assessment of the severity of illness through the sequential organ failure assessment (sofa) score. all data will be recorded on an electronic case report form (ecrf); this will be used as a visit diary. blood samples will be drawn at defined visits for a variety of biomarkers to better assess the associations among coagulation, inflammation, and iloprost treatment (table ) . the primary objective and endpoint is to assess the effect of iloprost on the improvement of oxygenation (pao /fio ratio) in patients with ards. as secondary objectives, the absolute incidence of the following parameters will be determined: fig. trial protocol and intervention scheme. after screening and determination of eligibility, patients will be included after a maximum of h after the onset of ards. within this time period, screening, consent, and randomization will be initialized. in addition, lung-protective ventilation will be instituted. after randomization, iloprost × μg (intervention) or nacl . % (control) will be administered for days through a standard ultrasound nebulizer. daily recordings will be made with respect to the development of the pao /fio ratio and the severity of ards, organ failure, lung injury, and potential adverse events. the treatment with iloprost or nacl ( . %) will be stopped after days. the follow-up period will then continue up to days and months to determine the outcome, quality of life, and pulmonary/secondary organ function overall survival in the -day follow-up period ( day all-cause mortality) duration of mechanical ventilation support icu length of stay ventilator-associated pneumonia pulmonary hemorrhage gastrointestinal hemorrhage pulmonary embolism hospital discharge or d laboratory testing blood count x a x a x a x a x a x a x b x c x x procalcitonin x a x a x a x a x a x a x b x c x x il- x a x a x a x a x a x a x b x c x x pao /fio x a x a x a x a x a x a x b x c hemoglobin x a x a x a x a x a x a x b x c x x hemostasis parameters x a x a x a x a x a x a x b x c x x renal parameters x a x a x a x a x a x a x b x c x x ventilation support including ventilation parameters x a x a x a x a x a x a x a prone positioning x a x a x a x a x a x a x a ecmo x a x a x a x a x a x a x a relaxation x a x a x a x a x a x a x a high-frequency ventilation x a x a x a x a x a x a x a tracheotomy hemodynamic parameters x a x a x a x a x a x a x b x x x vasopressor therapy x a x a x a x a x a x a x a inotrope therapy x a x a x a x a x a x a x a fluid balance x a x a x a x a x a x a x a transfusion of red blood cells x x x x x x x b x x x transfusion of thrombocytes x x x x x x x b x x x anticoagulation infection x x x x x x x b x x x anti-infective therapy x x x x x x x b x x x the exploratory objectives are -month survival, quality of life (qol) assessed with a short-form survey (sf ), functional status (barthel index), and frailty (ves) assessed by phone follow-up interview. the following parameters will be used to determine the treatment efficacy: improvement of oxygenation (pao /fio ) on a daily basis in relationship to baseline overall survival in the -day follow-up period decrease in duration and severity of ards sofa scores: to be calculated based on data in hospital records duration of mechanical ventilation support: documentation in hospital records icu length of stay: documentation in hospital records ventilator-associated pneumonia: documentation of microbiological findings in hospital records incidence of barotrauma: documentation of ventilator parameters in hospital records reduced morbidity assessed through sofa score, also according to the incidence of complications and increased functionality assessed through the barthel index delirium: documentation (e.g., confusion assessment method for the icu [cam-icu]) in hospital records icu-acquired weakness: documentation in hospital records discharge location: documentation in hospital records, phone call. the demographic parameters at enrollment include age, sex, race, icu admission diagnosis, and comorbidities (such as diabetes, existing malignancy, any kind of pre-existing pulmonary disease, and hypertension). the main clinical data obtained during the icu daily assessment are as follows: laboratory data: blood count, procalcitonin, interleukin (il)- , creatinine, urea, partial thromboplastin time (ptt), d-dimers, international normalized ratio (inr), aspartate aminotransferase (ast), alanine aminotransferase (alt), albumin, cholinesterase (che), brain natriuretic peptide (bnp) weekly assessments of the icu will include the following: differential blood count creatinine clearance ecmo post-oxygenator pao sofa score assessment at discharge chronic renal failure at discharge hepatic failure at discharge length of stay in the icu length of stay in the hospital discharge from hospital to a nursing home discharge from hospital to home discharge from hospital to a rehabilitation unit residence in nursing home at months the final assessment will consist of the following: days of ecmo support ventilator days tracheotomy need for mechanical ventilation at home incidence of pulmonary hemorrhage defined by an indication for blood transfusion, radiological finding, or a decrease in oxygenation incidence of barotrauma incidence of pleural drainage incidence of pulmonary embolism defined by the following parameters: new hypotension sign of right ventricular failure on echocardiography biomarkers computed tomography (ct) scan (optional) incidence of gastrointestinal bleeding defined by the following parameters: upper gastrointestinal bleeding, blood vomiting, lower gastrointestinal bleeding, melena, indication for blood transfusion, endoscopic diagnosis/intervention incidence of cerebral hemorrhage defined by the following parameters: impairment as measured by the glasgow coma scale, ct scan infections: incidence of positive blood culture, pneumonia, wound infection, peritonitis, surgical intervention due to infection, bacterial infection, fungal infection, viral infection, or multidrugresistant gram-negative bacteria (mrgn) infection anti-infective therapy: generic, duration, incidence of changing anti-infective therapy due to inadequate treatment incidence of surgical intervention. the trial case report form (crf) is the primary data collection instrument for the trial. for this project, electronic crfs (ecrfs) will be used. entered data will be subjected to plausibility checks directly implemented in the crf, monitoring, and medical review. the trial master file, the crfs, and other material supplied for the conduct of the study will be retained by the sponsor/ clinical research organization (cro) according to applicable regulations and laws. the investigator(s) will archive all trial data (source data and investigator site file [isf], including the subject identification list and relevant correspondence) according to the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ich) consolidated guideline on good clinical practice (gcp) and local laws or regulations. the study population will consist of the following: those to be assessed for eligibility (n = ); those to be assigned to the trial (n = ); those to be analyzed (n = in the intention-to-treat [itt] analysis, other endpoints n = ). the sample size and power consideration refers to evaluable patients, and it is assumed that the power will not be decreased in the analysis of the itt population using multiple imputation. furthermore, baseline adjustment will not be taken into account, which leads to a conservative sample size estimation. in a previous study on iloprost with patients, an increase from ± to ± was observed for the pao /fio , which was significant at the . level [ ] . recalculation shows that the intraindividual standard deviation must have been considerably smaller, as a p value of . corresponds to an effect size of . (intraindividually) and thus to an intraindividual standard deviation of approximately in this study. in our study, we can show effect sizes of . assuming error degrees of freedom, taking into account day for baseline adjustment and days for the study center (inquiry, power %, level of significance . , twosided t test). if we assume the recalculated standard deviation from the previous study in our study (which is still conservative due to the linear baseline adjustment used in our study), an (interindividual) effect size of . corresponds to a difference of approximately in the pao /fio ratio in the treatment arm compared to the control arm. this seems to be a reasonable and relevant effect. the primary endpoint of pao /fio at day after the baseline will be analyzed daily using a baseline adjusted analysis of covariance model with the last measurement of the pao /fio ratio before treatment as the baseline, with the study arm as a second-level factor. the study center will be included in the analysis as a nuisance factor. additionally, an interaction term between baseline and treatment will be included in the model if this term is significant. in the case of interaction, the main effect will be retrieved for the arithmetic mean of the baseline values using the centered variable for pao /fio . multiple imputation will be applied in the itt population of patients receiving at least one dose of treatment or the control. statistical analysis of the prespecified secondary endpoints will be performed with descriptive and exploratory statistical methods according to the scale and observed distribution (absolute and percentage frequencies, chi-square tests, logistic regression models for categorical variables; means and standard deviations, medians, and quartiles, or ranges with t tests or mann-whitney tests and linear regression models for continuous variables; kaplan-meier curves, log-rank tests, and cox proportional hazard models for censored data). the p values will be reported but should not be considered part of the confirmatory analysis. planned subgroup analyses will be performed according to the following: sex and race (only for subgroups larger than subjects) patients with increased pulmonary arterial pressure direct vs. indirect lung injury age stratified by decades. for safety reasons, after the enrollment of patients (day after last dose imp patient ), an interim analysis of the following will be performed: . an increased risk of pulmonary hemorrhage ≥ grade iii according to ctcae version . in the treatment (iloprost) arm . levels of imp in the serum. the results will be discussed with the dsmb. the dsmb has to assess whether the results allow continuation of the study as planned. moreover, after treatment of a total of patients (day after the last dose imp patient ), an interim analysis of an increased risk of pulmonary hemorrhage ≥ grade iii according to ctcae version . in the treatment (iloprost) arm will be performed, and the results will again be discussed with the dsmb. the dsmb must assess whether the results allow continuation of the study as planned. moreover, in the following situations, a premature termination of the trial must be considered: . substantial changes in risk-benefit considerations . new insights from other trials . insufficient recruitment rate. the biometric report will be delivered according to the sop bi of the statistical center (ikeab). in summary, the report will contain sections on the statistical methodology, preprocessing of data, and the descriptive, exploratory, and confirmatory analyses. it will be reviewed by the principal investigator (pi) before presenting the final version. to date, there is no pharmacologic intervention to treat or prevent the development of lung injury or ards. iloprost-containing medications are well recognized epidemiologically as an effective therapeutic agent for the treatment of moderate to severe pulmonary hypertension. iloprost has been shown to exert antiplatelet and anti-inflammatory actions in small clinical observation studies and several preclinical laboratory examinations. however, the use of iloprost for the treatment of ards is not novel; it has been used in small studies before. indeed, we propose in this study to systemically evaluate the application of iloprost in a randomized controlled trial (rct) to identify the potential use and benefit of iloprost in ards. the composite endpoint was chosen, as it is likely to be more sensitive than just -day mortality to detect an effect signal. although it is not a double-blinded strategy, the recorded objectives will help support or refute our hypothesis that iloprost reduces lung inflammation during early ards. this study includes some possible pitfalls, like the single-blinded design. however, due to randomization and based on the close data acquisition, we will be able to minimize bias. however, in addition to the effect of iloprost on lung inflammation, this study will also be a resource for information about clotting issues in terms of the systemic and local anticoagulation effects of iloprost in lung tissue, and also in other compartments besides the lung. although iloprost is used frequently in pulmonary hypertension, there are currently no data about iloprost concentration in the blood after inhalative treatment. in addition, iloprost may have a positive effect on lung compliance during acute ards as well as during resolution, since it has been shown to have a lasting positive effect on fibrosis in the lung and other tissues in animal models [ , ] . in one-lung ventilation, iloprost seems to reduce intrapulmonary shunts, resulting in better oxygenation [ , ] . in this context, the analysis of ventilator-free days or time on ecmo may reveal important information. further on, intravenous application of iloprost may improve microcirculation, resulting in better kidney recovery in patients with sepsis [ , ] . patients with ards frequently show multiorgan failure. therefore, the comparison of incidence and time frame for extracorporeal therapy may give insights on the effect of inhaled iloprost on microcirculation in other organs. therefore, iloprost may positively influence the outcome of ards patients by at least one of the effects described above. this study will be the first to describe the effects of iloprost on inflammation, fibrosis, bleeding events, and oxygenation organ failure and anticoagulation during a continuous time frame of at least days in critically ill patients. the berlin definition of ards: an expanded rationale, justification, and supplementary material the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination long-term outcomes after ards long-term assessment of lung function in survivors of severe ards the acute respiratory distress syndrome the acute respiratory distress syndrome leitlinie invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial prone positioning improves survival in severe ards: a pathophysiologic review and individual patient meta-analysis effect of aspirin on development of ards in at-risk patients presenting to the emergency department: the lips-a randomized clinical trial simvastatin in the acute respiratory distress syndrome rosuvastatin for sepsis-associated acute respiratory distress syndrome iloprost improves endothelial barrier function in lipopolysaccharide-induced lung injury iloprost attenuates traumarelated pulmonary sequestration of leucocytes and platelets lung endothelial barrier protection by iloprost in the -hit models of ventilator-induced lung injury (vili) involves inhibition of rho signaling protective role of cyclooxygenase (cox)- in experimental lung injury: evidence of a lipoxin a -mediated effect rap mediates protective effects of iloprost against ventilator-induced lung injury the effects of iloprost on lung injury induced by skeletal muscle ischemia-reperfusion iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary et- balance protective effects of levosimendan and iloprost on lung injury induced by limb ischemia-reperfusion: a rabbit model effects of alprostadil and iloprost on renal, lung, and skeletal muscle injury following hindlimb ischemia-reperfusion injury in rats donor pretreatment using the aerosolized prostacyclin analogue iloprost optimizes post-ischemic function of non-heart beating donor lungs inhalative pre-treatment of donor lungs using the aerosolized prostacyclin analog iloprost ameliorates reperfusion injury cardiopulmonary effects of iloprost in experimental acute lung injury preischemic iloprost application for improvement of graft preservation: which route is superior in experimental pig lung transplantation: inhaled or intravenous? aerosolized iloprost for severe pulmonary hypertension as a bridge to heart transplantation iloprost improves gas exchange in patients with pulmonary hypertension and ards aerosolized prostacyclins for acute respiratory distress syndrome (ards) the effects of iloprost and alprostadil on ischemia-reperfusion injury in preventing inflammation, tissue degeneration, and apoptosis in rat skeletal muscle increased neutrophil mediator release in patients with pulmonary hypertension-suppression by inhaled iloprost assessment of the vasodilator response in primary pulmonary hypertension. comparing prostacyclin and iloprost administered by either infusion or inhalation pharmacokinetics and pharmacodynamics of the prostacyclin analogue iloprost in man effects of hyperbaric oxygen and iloprost on intestinal ischemia-reperfusion induced acute lung injury iloprost reverses established fibrosis in experimental right ventricular failure effects of iloprost on bleomycin-induced pulmonary fibrosis in rats compared with methyl-prednisolone the effects of iloprost on oxygenation during one-lung ventilation for lung surgery: a randomized controlled trial iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat intravenous iloprost to recruit the microcirculation in septic shock patients? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations supplementary information accompanies this paper at https://doi.org/ . /s - - - . authors' contributions pr and hah drafted the current manuscript. mg, az, mk, pm, and sp critically reviewed and revised the draft report. all authors have read and approved the final version, which was also approved by the sponsor. this study is financed by the akf (applied clinical research) program ( - - ) for the faculty of medicine of the university of tübingen. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the thilo trial protocol was approved by the ethics committee of the university of tübingen, germany (protocol number / amg ) on june . the local ethics committee at each site will approve the study protocol (approvals already in place are shown in additional file ). any modifications to the protocol will be immediately communicated to all responsible authorities. all patients, or their legal representative, must give written informed consent. not applicable. the authors declare that they have no competing interests. key: cord- -flo j authors: andrews, peter; azoulay, elie; antonelli, massimo; brochard, laurent; brun-buisson, christian; dobb, geoffrey; fagon, jean-yves; gerlach, herwig; groeneveld, johan; mancebo, jordi; metnitz, philipp; nava, stefano; pugin, jerome; pinsky, michael; radermacher, peter; richard, christian; tasker, robert; vallet, benoit title: year in review in intensive care medicine, . i. respiratory failure, infection, and sepsis date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: flo j nan respiratory monitoring measurement of lung volume has always been a concern in patients receiving mechanical ventilation (mv), and complex methods have been proposed for clinical investigation. patroniti et al. [ ] described a simplified helium dilution technique to measure end-expiratory lung volume and compared it to computed tomography (ct) in mv patients. the authors specifically studied the accuracy and precision of the method. a simple rebreathing gas was used to deliver at least ten usual tidal volumes. the agreement between the two methods was found very acceptable for clinical purposes. it was noted, however, that the higher the amount of hyperinflated tissue, the greater was the underestimation of lung volume by the helium dilution method. it has been well demonstrated that a frequent cause of repeated lung volume loss is endotracheal suctioning. this can induce derecruitment in patients with acute respiratory distress syndrome (ards). the effects of such maneuver were tested in ten patients with only mild to moderate lung failure by fernandez et al. [ ] . three techniques were compared with or without preoxygenation. the authors found that reduction in lung volume during suctioning was similar with the quasiclosed and closed systems but significantly higher with the open system. they also observed that in these patients without severe lung disease these changes were transient and rapidly reversible within min. alveolar consolidation is best diagnosed by ct. lichtenstein et al. [ ] , continuing their assessment of the usefulness of lung ultrasound examination in the icu, assessed its value in patients in whom ct had confirmed alveolar consolidation. only were not diagnosed by ultrasound; conversely, ultrasound was positive in only one of control patients without alveolar consolidation on ct. at least in the author's hands, this technique seems to constitute a reliable tool for this diagnosis. measurement of respiratory mechanics usually describes the respiratory system in terms of elastance, compliance and time constant. in an elegant study, kondili et al. [ ] divided tidal expiration in different phases based on the analysis of expiratory flow-volume curves in ten patients with acute exacerbation of chronic obstructive pulmonary disease (copd). they showed that the end of expiration is characterized by a lengthening of time constants, and that the addition of external positive endexpiratory pressure decreases resistance at the end of expiration and shortens time constants, thus facilitating equilibration between the external pressure and the alve-olar pressure. although we already knew the effects of external positive end-expiratory pressure in such patients, this new method of exploration sheds new light on its mechanisms. a part of expiratory resistances can be caused by the endotracheal tube itself. in many cases its contribution is not huge. however, more and more studies suggest that over the course of mv the inner diameter of the tube may progressively decrease due to the permanent deposits of secretions. using the acoustic reflectometry method boquØ et al. [ ] prospectively assessed the inner volume reduction of endotracheal tubes, used in patients, and found this reduction to be extremely frequent. in almost one-fourth of the patients the real diameter of the tube was smaller than mm. the clinical implications of such findings may be important, and further studies are needed on this topic. intra-abdominal hypertension may have important clinical consequences in terms of both respiratory function and intra-abdominal organs function its prevalence, however, is not known. it is thus the great merit of this multicenter collaborative -day prevalence study by malbrain et al. [ ] in icus of six countries to evaluate its frequency in a cohort of patients. based on a definition of abnormal intra-abdominal pressure of mmhg or higher, its prevalence was %, while % of the patients had abdominal compartment syndrome with a pressure of mmhg or higher. the only risk factor was the body mass index, while the effects of massive fluid resuscitation and renal and coagulation impairment were at the limit of statistical significance. last, intrahospital transport poses an important risk to icu patients. continuous monitoring as well as presence of qualified staff and well maintained equipment are probably essential to minimize incidents. the australian incident monitoring study in intensive care received reports describing incidents over a -year period [ ] . they tried to identify all contributing factors, of which % were system-based and the others were humanbased. in % of the incidents there were significant adverse outcomes. a number of factors were also identified as having prevented or limited harm. these problems are often underestimated or underreported and deserve great attention. an editorial by shirley and bion [ ] accompanied this paper. acute respiratory distress syndrome epidemiological characteristics and outcomes from acute lung injury (ali) vary across studies. this variability depends on definitions, subpopulations included in studies, comorbidities, and the severity of the disease per se. brun-buisson and coworkers [ ] studied the current occurrence and causes of ali and ards, the relationships and respective outcome of mild ali (pao /fio between and mmhg) and ards (pao /fio equal to or below mmhg), and the factors associated with survival. a -month inception cohort (february-march ) of individuals with ali among , patients who were admitted for at least h in an intensive care unit (icu) was scrutinized. data pertain to ten european countries and icus. among patients initially having mild ali ( %) went on to ards. there were with mild ali while had ards. crude icu and hospital mortality rates were . % and . % (p< . ) for mild ali and . % and . % (p= . ) for ards. initial mean tidal volume and positive end-expiratory pressure were . € . ml/kg and . € . cmh o in ards patients. air leaks were detected in . % of subjects. in multivariate analysis mortality was associated with age, immunoincompetence, simplified acute physiology score (saps) ii, logistic organ dysfunction score, and early air leak. the authors concluded that ali is frequent, that there is a continuum between ali and ards, and that there is a substantial difference in mortality, being much higher in ards. an editorial comment by rubenfeld and christie [ ] accompanies this article, which also has an erratum [ ] . a pao /fio ratio below mmhg is one of the diagnostic criteria of ards according to the american-european consensus conference, yet this ratio is affected by a number of factors such as ventilator settings and fio per se. ferguson and colleagues [ ] analyzed the impact on enrollment in a trial of high-frequency oscillatory ventilation and the potential effects on study outcome when screened ards patients were placed on standard ventilator settings. these settings were pressure control ventilation to achieve a tidal volume - ml/kg predicted body weight ensuring peak inspiratory pressures below cmh o, fio and positive end-expiratory pressure cmh o. forty-one consecutive patients were included. after institution of standard settings, in patients ( %) the pao /fio was persistently below mmhg and the remainder ( patients, %) had a pao /fio above mmhg min after the changes were implemented. the change in fio was the main reason for these changes in pao /fio . the icu mortality rate was significantly greater in those with persistent ards than in those with the transient form, . % vs. . % respectively (p= . ). the authors concluded that their findings are important for trial design because of the observed differences in outcome, and proposed the use of standardized ventilator settings for patient enrollment. china has seen enormous economic growth, yet the country's demographic characteristics differ substantially from those in the western world. the epidemiological characteristics of ards in china are largely unknown. lu and coworkers [ ] performed a -month survey ( ) ( ) in icus in university hospitals in shanghai. the aim was to investigate the incidence, causes, and outcome of ards in adult patients who were treated in the icu for at least h. a total of , admissions were registered during this period, and patients ( %) were diagnosed as having an ards. the most common predisposing factors for ards were pneumonia ( %) and sepsis of nonpulmonary origin ( %). twenty-seven patients were not intubated. in those who received invasive mv the most frequently used ventilatory mode was synchronized intermittent mandatory ventilation ( %). in hospital mortality rate for ards patients was . %. the majority of ards patients who died ( %) did so because of multiple organ dysfunction, whereas % died because of refractory respiratory failure. the authors concluded that reassessment of respiratory and intensive care management and implementation of effective therapeutic interventions are required. severe acute respiratory syndrome severe acute respiratory syndrome epidemics, whose causative agent is a coronavirus, carries a mortality rate of about - % in young patients and about % in the elderly. gomersall and coworkers [ ] undertook a retrospective, observational cohort study of the first patients who were admitted to the icu of a hong kong university hospital because of respiratory failure. the aim was to describe the clinical course and outcome of these patients and to investigate factors associated with prognosis. their median acute physiology and chronic health evaluation (apache) ii score was (interquartile range - ). at days patients ( %) were alive and not undergoing mv, ( . %) were receiving mv, and had died ( . %). seven of ventilated patients ( . %) developed barotrauma despite a low tidal volume (mean tidal volume . € . ml/kg predicted body weight) and low-pressure strategy (mean positive end-expiratory pressure . € . cmh o, and peak airway pressures of . € . cmh o in those who did not develop barotrauma and . € . cmh o in those who did not develop it). variables associated with poor outcome on univariate analysis were age, severity of illness, lymphocyte count, decreased steroid dose, positive fluid balance, chronic disease or immunosuppresion, and nosocomial sepsis. the authors concluded that mortality is high for this syndrome, it causes severe respiratory failure with little organ failure, and there is a high incidence of barotrauma in those requiring mv. endotracheal extubation is the final step in weaning from mv. a failed tracheal extubation entails a worse prognosis. traditional weaning indices are poor predictors of extubation outcomes. data suggest that patients with neurological diagnoses, lack of adequate cough, and fre-quent endotracheal suctioning are at increased risk of extubation failure. salam and coworkers [ ] objectively assessed the impact of neurological status, cough strength, and volume of endotracheal secretions on extubation outcomes. in patients who had passed a spontaneous breathing trial they measured cough peak flow, endotracheal secretions and ability to complete four simple tasks (open eyes, follow with eyes, grasp hand, and stick out tongue). fourteen patients ( . %) failed the first extubation. patients with a cough peak flow equal to or below l/min were more likely to fail extubation than those with a cough peak flow higher than l/min [risk ratio (rr) . , % confidence interval (ci) . - . ]. patients with secretions of more than . ml/h were more likely to fail than those with fewer secretions (rr , % ci - . ). patients unable to complete the tasks were more likely to fail than those who completed the commands (rr . , % ci . - . ) . the presence of any two of those risk factors had a sensitivity of % and specificity of % in predicting extubation failure. the authors concluded that these simple, inexpensive, and reproducible methods provide a useful clinical approach to guide the extubation process. an editorial by epstein [ ] comments further on this article. periextubation pain has received little attention in icu patients. acute pain arouses clinical manifestations related to sympathetic system activation, and can lead to deleterious cardiovascular effects. gacouin and coworkers [ ] assessed the intensity of pain at extubation time using a visual analogue scale in of a total of extubated patients for a period of year. pain was significantly associated with a saps ii above (p= . ), duration of mv of days or more (p= . ) and intubation not performed in the operating room (p= . ). severe pain was reported by % of patients. pain resolved within h after extubation in the majority of patients. duration of mv for days or longer was the only independent risk factor for pain of at least moderate intensity [odds ratio (or) . , % ci . - . , p= . ]. the authors concluded that periextubation pain is frequent and should be considered for treatment. unplanned, deliberate self-extubation of the trachea may affect patients' outcomes and clinical resources. moons and coworkers [ ] developed a risk assessment tool to categorize patients at risk of deliberate tracheal self-extubation. patients admitted in seven icus of a large referral tertiary center and who had been intubated for more than h were followed for months. in this period cases of unplanned extubations occurred. clinical and demographic characteristics were compared to those of randomly selected control patients. incidence of unplanned extubations was . % (density incidence . per ventilation days). incidence was lower in surgical icus ( . %) compared with medical icus ( . %). fifteen cases ( . %) required reintubation. multiple logistic regression indicated that patients with a low sedation level and higher degree of consciousness were at higher risk for deliberate self-extubation. the authors concluded that appropriate reduction in sedation when patients are weaned, a timely extubation, and increased surveillance when high risk is recognized may reduce the number of unplanned extubations. the recent international consensus conference in intensive care medicine on the use of niv in acute respiratory failure [ ] clearly stated that, "the addition of nppv to standard medical treatment of patients with acute respiratory failure may prevent eti, and reduce the rate of complications and mortality in patients with hypercapnic "pump" failure." concerning episodes of "lung failure" the same document concluded that "the use of niv may be also an appropriate treatment in selected patient populations with acute "lung" failure. single studies have demonstrated noninvasive mv (niv) to be an adequate alternative to conventional ventilatory support or better therapeutic strategy than standard therapy plus oxygen in such patients. more studies are required to confirm these findings. in the year four studies were published in intensive care medicine to improve understanding of and perhaps expand the indications for niv and to highlight some methodological problems. continuous positive airway pressure (cpap) has been considered a very effective treatment of acute respiratory failure (arf) due to cardiogenic pulmonary edema (cpe). l'her et al. [ ] compared the physiological and clinical effects of cpap and those of standard medical therapy in a subset of very old patients (> years) in whom the application of any form of mv is sometimes denied. within h cpap led to decreased respiratory rate and improved oxygenation compared to baseline, whereas no differences were observed in the medical treatment group. seventeen patients of this latter group developed severe complications vs. only four of the cpap group. early -h mortality was significantly lower in the ventilated patients, but overall hospital mortality not. the authors concluded that cpap promotes early clinical and physiological improvement in elderly patients during episodes of arf due to cpe, without affecting overall mortality. while niv has been considered the first line treatment to prevent intubation in copd patients during an episode of hypercapnic arf, little is known about its effectiveness as "real" alternative to invasive mv when the criteria for emergency intubation are met. in a matched case control study performed in copd patients with very severe arf (ph . , paco mmhg) squadrone et al. [ ] , evaluated the efficacy of noninvasive (case) vs. invasive mv (control). mortality rate, duration of mv, and length of icu and hospital stay did not differ between the two groups, but the niv group had fewer complications and a tendency to be weaned earlier from ventilation. intubation rate in the case group was %, but this subset of patients had similar outcomes as those of the control group. those with successful niv had lower mortality rate and shorter icu and hospital stay than the patients who received intubation. in copd patients with very advanced hypercapnic arf niv thus has a high rate of failure but nevertheless provides some advantages compared to invasive ventilation. indeed a subgroup analysis suggested that the delay in intubation was not deleterious in the subset of patients who failed niv. patients with severe chronic pulmonary diseases often suffer from coexistent pathologies and are also likely to develop extrapulmonary complications. scala and coworkers [ ] assessed the impact of those comorbidity on short-and long-term outcomes of niv in hypercapnic arf of copd patients. they divided patients (ph . , paco mmhg) into failure (n= ) or success group (n= ) according to whether niv avoided intubation. the prevalence of chronic and acute comorbidities was, respectively, % and %, most of the cases being cardiovascular. both niv failure and -month mortality were greater in patients with than in those without comorbidities. multiple regression analysis predicted niv failure by acute comorbidity and forced expiratory volume in s, while death at months was predicted by having more than a single acute comorbidity of noncardiovascular origin and worst pre-existing activities of daily living. the presence of comorbidities is common in copd patients requiring niv, and their presence influences the outcomes of the patients. technical aspects of niv include not only the types of interfaces, ventilators, and ventilatory modes employed but also some "marginal factors" that may interfere with patient well-being. it is now clear, for example, that loud sounds can contribute to patient discomfort during the icu stay. cavaliere et al. [ ] studied the noise intensity in ten healthy volunteers undergoing niv with two different levels of pressure support ( and cmh o), using the helmet with and without heat and moisture exchanger filter, full face mask, and a nasal mask. inside the helmet the noise intensity exceeded db, which was significantly higher than that during facial and nasal ventilation ( db). noise intensity was not affected by the level of pressure applied or by the presence of filters. the level of discomfort was similar using the four different settings. the authors concluded that niv helmet is associated with significantly greater noise than nasal and facial masks, but that it is equally comfortable in the short-term setting. weaning and postextubation failure weaning difficulties occur in a relatively small percentage of ventilated patients; however, patients undergoing prolonged mv are more prone to develop complications and therefore dramatically increase the costs of care. great attention should be paid to early identification of patients who are likely to fail weaning and to predicting those who may develop postextubation respiratory failure. three studies assessed the causes of weaning failures or the effectiveness of physiological indices in predicting weaning or postextubation failure. paresis acquired during the icu stay (icuap) is recognized as a major event that often occurs during the management of patients with prolonged critical illness. it has also been shown that the duration of mv is an independent predictor of icuap. de jonghe et al. [ ] studied a prospective cohort of patients without preexisting neuromuscular disease and ventilated longer than days to determine whether icuap is an independent risk factor of prolonged weaning after awakening. the presence of icuap was defined as an medical research council score lower than . patients who developed icuap ( / , %), had a significantly longer weaning time ( days vs. days). in multivariate analysis the two independent predictors of prolonged weaning were icuap and the presence of copd. the authors concluded that icuap was the strongest independent predictor of prolonged mv, and that the prevention of icuap should result in shorter weaning time. only few of the studies that have investigated the utility and accuracy of some weaning indices were blinded. conti and coworkers [ ] evaluated the most popular weaning indices in a blinded fashion (i.e., the physicians making decisions about the weaning were always unaware of the predictive values). the study had two steps: patients' data were first used to select the cutoff values for weaning predictors (i.e., minimal false classification); these values were prospectively validated in a cohort of other patients. the variables recorded during the first min after discontinuation of ventilation were: vital capacity, tidal volume, pressure in the first ms of an occluded inspiration (p . ), minute ventilation, respiratory rate, maximal inspiratory pressure (mip), rapid shallow breathing index (f/vt), p . /mip, and p . f/vt. the receiving operating characteristic curve showed that the tests had no ability in discriminating between success and failure. the authors concluded that the most common evaluated indices are poor predictors of weaning outcome. the breathing pattern in normal persons displays a certain variability, which is maintained by a central neural mechanism and the feedback loops of arterial chemoreceptors and lung vagal sensory receptors. deviations in breathing pattern variability (bpv) from the normal level have been found in individuals under pathological con-ditions. bien et al. [ ] investigated whether potential changes in bpv predict weaning from mv in postoperative patients recovering from systemic inflammatory response syndrome (sirs). the analysis employed to assess the bpv during a -min period of pressure support ventilation at cmh o, was the pointcare plot, which is a scattergram that dynamically analyzes breathing pattern on real-time, breath-to-breath basis. the coefficient of variation and sd, indicators of the dispersion of data points in the plot, were significantly lower in the patients who failed the weaning attempt than in those who did not. a low bpv is associated with a high incidence of weaning failure, and this variability may potentially serve as a weaning predictor. p . has been proposed as a predictor of weaning parameter, despite results that have been somewhat controversial. fernandez and coworkers [ ] although catheter-related infection (cri) rates have decreased due to improved infection control techniques and devices, cri remains the major cause of nosocomial bacteremia in icus. preventive strategies and new devices opposing colonization continue to be tested. four randomized controlled trials (rct) on this topic have been published in intensive care medicine this year. langgartner et al. [ ] examined central venous catheters (cvcs) and investigated whether skin disinfection during cvc insertion with an alcohol plus chlorhexidine ( . %) solution followed by povidone-iodine provides greater protection against cvc colonization and infection than either one of the antiseptics alone. they found that catheter colonization rates were reduced fivefold (from % with povidone-iodine alone to . %) with the successive application of both antiseptics. mo-lecular typing of organisms confirmed that most cvc colonization originated from the skin insertion site. the sample size of this study was, however, too small to confirm a reduction in infection rates. in another rct including cvcs carrasco et al. [ ] compared heparin-coated triple-lumen catheters to chlorhexidine-sulfadiazine coated ones, a comparison which had not been performed previously. colonization was found in of heparin-coated catheters in of chlorhexidine and silver sulfadiazine coated catheters (p= . ). the incidence of cvc-related bloodstream infections (bsis) did not differ [ finally, brun-buisson et al. [ ] tested the new generation of antiseptic-coated catheters (with enhanced chlorhexidine-silver sulfadiazine coating on both the internal and external aspect of the cvc) vs. nonimpregnated cvcs in a rct enrolling patients. significant colonization of the catheter occurred in ( . %) and ( . %) patients, respectively, in the noncoated and coated groups ( vs. . per , catheter-days, p= . ), and cvc-related bsis occurred in ( ) and ( ) patients in the noncoated and coated groups, respectively ( . vs. per , catheter days, p= . ). in all these trials antimicrobial-impregnated catheters were associated with a significant reduction in catheter colonization and a trend to reduction in infection episodes, but not of bsi. it is noteworthy that all these trials have relatively low definite rates of cvc-related bsi in the control groups. in this context it is difficult to demonstrate efficacy of antimicrobial-impregnated catheters unless the sample size of the study is adequately powered. the potential for increased risk of colonization of antibiotic-impregnated catheters with candida spp. needs confirmatory evidence. safdar and maki [ ] provided additional evidence in support of the predominant pathogenesis of short-term cvc-related infection by analyzing the combined results of two trials ( , catheters) testing preventive strategies aimed at minimizing catheter colonization at the skin entry site. the pathogenesis of infection was confirmed by dna typing of organisms. the overall cvc-related bsi rate was . / , catheter-days. in the pooled control groups of the two trials cvc-related bsis occurred ( . per , catheter-days), in % of which infections were extraluminally acquired, % intraluminally derived, and % indeterminate. in contrast, cvc-related bsis in the treatment groups were most often intraluminally derived ( %, p= . ). the authors concluded that most cvc-related bsis were extraluminally acquired and derived from the cutaneous microflora. therefore strategies achieving successful suppression of cutaneous colonization can substantially reduce the risk of cvc-related bsi associated with short-term cvcs. it is noteworthy that about % of cvcs removed because of suspected infection prove not to be infected. to limit wasteful removal of catheters rijnders et al. [ ] tested in a small rct whether a "watchful waiting" strategy in which selected patients with low to moderate suspicion of cvc infection were observed without removal of the cvc is safe and allowed to retain the cvc. hemodynamically stable patients without proven bacteremia, insertion site infection, or intravascular foreign body were randomized to a standard-of-care group (in which all cvcs were changed as planned) or the watchful waiting group (in which cvcs were changed only when bacteremia or hemodynamic instability subsequently occurred). of patients with suspected cri, patients met exclusion criteria ( of whom were shown to be bacteremic, including , %, with cvc-related bsi), and ( %) were randomized. all cvcs were changed in the standard group vs. of in the watchful waiting group ( % reduction, p< . ), with no difference in bacteremia rate or outcome of patients. the authors concluded that the use of a simple clinical algorithm permits a substantial decrease in the number of unnecessarily removed cvcs, without increased morbidity. in an accompanying editorial, brun-buisson [ ] emphasizes the value of this conservative approach in selected patients with low/moderate suspicion of cvc infection and comments on the potential value of additional tests (skin site insertion swab culture, paired blood culture) to assist the clinical decision making in this conservative approach. to identify factors associated with hospital outcome of adult patients with infective endocarditis (ie) mourvilliers et al. [ ] retrospectively reviewed patients admitted over an -year period to their referral center icu. the overall hospital mortality rate was %. in patients with native valve ie (n= ) variables associated with outcome by multivariate analysis included septic shock (or . , % ci . - . , p= . ), cerebral emboli (or , % ci . - . , p= . ), immunocompromised state (or . , %ci . - . , p= . ), and cardiac surgery (or . , % ci . - . , p= . ). in those with prosthetic valve ie (n= ) the variables included septic shock (or . , % ci . - . , p= . ), neurological complications (or . , % ci . - . , p= . ), and immunocompromised state (or . , % ci . - . , p= . ). the authors concluded that ie is associated with a high mortality rate in patients requiring icu admission; although early complications make optimal medical and surgical management decisions often difficult, surgical treatment appears to improve outcome of patients. in a questionnaire survey of french intensivists azoulay et al. [ ] addressed the difficult and unresolved question of the interpretation of a lower respiratory secretion sample positive for candida spp. as expected, physicians' attitudes varied widely. although a majority felt that positive samples for candida reflect colonization only in nonimmunocompromised patients, one-fourth ( %) were inclined to provide antifungal therapy; a majority ( %) felt that repeating samplings at various sites to calculate the "colonization index" was necessary. the authors concluded that additional studies are needed to improve our understanding of respiratory tract candida colonization and infection in nonneutropenic mv patients and to determine the indications for preemptive antifungal therapy in this population. misset et al. [ ] report the results of a -year infection control quality improvement program, based on published guidelines to reduce nosocomial infection rates in their medical-surgical icu. mean device-related infection rates (per , procedure-days) were: ventilator-associated pneumonia (vap) . , urinary tract infection (uti) . , cvc colonization . , and cvc-related bsi . . during the -year study period there was a significant decline in uti and cvc-related infection rates and an increase in time to infection, but not of vap rates. the authors concluded that uti and cvc-related infections can be reduced through a continuous quality-improvement program based on surveillance of nosocomial infections. to identify factors associated with high use of antimicrobials, meyer et al. [ ] reported results from the first years in icus of the sari program, a surveillance system of antimicrobial use in a german icu network set up in . the mean antimicrobial use density (ad) was , ddd/ , patient-days and was correlated with length of stay. penicillins plus b-lactamase inhibitor (ad . ) and quinolones ( . ) were the antimicrobials most used. length of stay was an independent risk factor for an ad above the % percentile of the total amount of antimicrobials used (or . per day) as well as for higher use of carbapenems (or . per day) and extended-spectrum penicillins (or . per day). high use of glycopeptides and quinolones (ad > % percentile) was correlated with cvc. the authors suggested that the sari data could serve as a benchmark by which to improve the quality of antimicrobial drug administration in icus and for international comparison. two large epidemiological studies of severe sepsis syndromes were published this year. to provide an updated epidemiology of severe sepsis, brun-buisson et al. [ ] reported the results of a -week inception cohort study of severe sepsis and shock conducted in randomly selected french icus. of , patients admitted ( . %) had severe sepsis or shock, % of which cases were icu acquired. the median saps ii and sequential organ failure assessment (sofa) at onset of severe sepsis were and , respectively. mortality was % and . % at and days after sepsis, and . % of patients remained hospitalized at months. chronic liver and heart failure, acute renal failure and shock, saps ii at onset of severe sepsis and -h total sofa scores were the independent risk factors most strongly associated with death. the authors concluded that whereas the attack rate of severe sepsis has increased in french icus over the past decade, its mortality appears to have decreased, suggesting improved management of patients. finfer et al. [ ] reported a prospective populationbased, inception cohort, incidence study conducted in multidisciplinary icus of hospitals in australia and new zealand, including , consecutive icu admissions. a total of patients- . ( % ci . - . ) per icu admissions-had episodes of severe sepsis. the icu and -day mortality rates were . % and . %, respectively, and . % of patients died in hospital. the authors estimated the incidence of severe sepsis in adults treated in australian and new zealand icus at . ( . - . ) per , inhabitants and concluded that the population incidence found in this prospective study falls in the lower range of recent estimates from retrospective studies in the united states and the united kingdom. in an accompanying editorial moss [ ] highlights questions concerning the interpretation of epidemiological surveys and recent changes in the epidemiology of sepsis. finkielman et al. [ ] report a -year, single-center, retrospective study of patients (mean age years) with septic abortion, a relatively rare condition nowadays. their apache ii mean score was . on admission. acute renal failure developed in % ( of ) of patients, disseminated intravascular coagulation in % ( of ) , and septic shock in % ( of ) . blood cultures were positive in % ( of ). twelve patients died ( %). the authors concluded that, when requiring icu admission, this preventable event remains associated with high morbidity and mortality. the diagnostic value of c-reactive protein remains controversial. sierra et al. [ ] reexamined this question in a prospective observational study of patients with sirs ( having subsequently confirmed and without confirmed infection) and normal control subjects. median c-reactive protein values on day were lower in healthy subjects ( . mg/dl, % ci . - . ), patients with acute myocardial infarction ( . mg/dl, % ci . - . ), and those with noninfectious sirs ( . mg/dl, % ci . - . ), than in those with sepsis ( . , % ci . - . , p< . ). a c-reactive protein threshold value of mg/dl had a . % sensitivity and . % specificity for predicting sepsis. the authors concluded that determination of serum c-reactive protein can be used as an early indicator of infection in patients with sirs. to determine the clinical impact of the recently available highly active antiretroviral therapy (haart) on icu admissions and outcome in patients infected with human immunodeficiency virus (hiv) vincent et al. [ ] compared patients admitted during a pre-haart era ( - ; n= ) and the haart era ( - ; n= ) . during the latter % of patients admitted to the icu had not or only little benefited from the availability of haart: % had no history of antiretroviral therapy, and % had failed to respond to antiretroviral. the icu admission rate of hospitalized hiv-infected patients increased rather than decreased compared with the pre-haart era (haart . % vs. pre-haart . %, p= . ). after adjustment for significant prognostic covariates icu survival was unchanged between the two periods (adjusted or . , % ci . - . ), but month survival had improved (adjusted or . , % ci . - . , p= . ). the authors concluded that the icu admission rate of hiv-infected patients remains high in the haart era, possibly because of underutilization of therapy and limited access to health care. as indicated by yu and singh [ ] , "over studies have been published in peer-review journals in the past years dealing with management of ventilator-associated pneumonia (vap)." however, no consensus exists to date on the best way for identifying patients with true lung infection, for selecting early appropriate antimicrobial therapy, or for avoiding unnecessary use of antibiotics. controversies regarding the management of patients suspected of developing vap have been nourished by numerous studies comparing different bacteriological di-agnostic techniques, or clinical to bacteriological evaluation, and/or evaluating the clinical pulmonary infection score (cpis) recently proposed as the first step of a "clinical strategy" [ ] . elatrous et al. [ ] conducted a prospective study in patients clinically suspected of episodes of vap to compare quantitative cultures of endotracheal aspirates (eta) and plugged telescoping catheter. pneumonia was diagnosed on positive cultures (! cfu/ml) of the latter. the authors reported a good correlation between the two techniques for identifying bacterial species and differentiating between positive and negative cultures of the plugged telescoping catheter by using a diagnostic threshold for eta of cfu/ml. they calculated a sensitivity of % and a specificity of % for eta. with the usual and widely used threshold of cfu/ml for eta, results were less good, with a poor agreement between the two techniques (k= . ). the authors concluded that eta quantitative cultures are adequate techniques to identify pathogenic organisms in significant concentration in the lower respiratory tract but not to diagnose vap since quantitative cultures of the plugged telescoping catheter are not a "gold standard" and even not a "silver standard" to differentiate lung infection from heavy colonization of the lower respiratory tract. mentec et al. [ ] reported the results of a multicenter prospective study conducted in five french icus that enrolled patients with suspected vap, including with "confirmed" vap (based on the classification of the international consensus conference on the clinical investigation of vap [ ] ). four diagnostic techniques were compared: blind tracheal aspirates, blind protected telescoping catheter (blind ptc), bronchoscopic ptc, and bronchoscopic bronchoalveolar lavage (bal). the authors found that direct examination of secretions obtained with blind ptc, bronchoscopic ptc, and bal are of similar value for diagnosing vap and choosing appropriate initial treatment. in contrast, they underlined that blind and bronchoscopic ptc had diagnostic values comparable to that reported with bal only when the collected sample contains visible secretions; in the entire population, the areas under receiver operating characteristic curve were significant smaller with the three techniques ( . , p= . for blind tracheal aspirates; . , p= . for blind ptc; . , p= . for bonchoscopic ptc) than with bal ( . ). these two studies have the usual limitations of studies evaluating new diagnostic methods: the absence of clear and definitive definition of the disease, here the absence of a gold standard. several published studies have tried to determine such a gold standard-experimental studies, animal studies, postmortem studies [ ] -and suggested that only the combination of histological examination and quantitative cultures of lung tissue gives arguments strong enough to validate or eliminate the diagnosis of pneumonia in patients treated with mv for more than days. dupont et al. [ ] designed a study in patients with vaps to assess the impact on the duration of mv and the use of antibiotic treatment of the results of a diagnostic technique: the percentage of infected cells in liquid obtained with bal, i.e., the value of direct examination. in clinical practice the time of direct examination of pulmonary secretions is a very important issue since it corresponds to the time of the differentiation between infected and noninfected patients, the decision to treat or not, and the choice of initial antimicrobial therapy. the authors confirmed a strong relationship between the percentage of infected cells and the results of quantitative cultures of bal. they also found two factors negatively associated with the percentage of infected cells: the duration of mv before the onset of vap ( . € . % before the th day, . € . % between the th and the th day; and . € . % after days of mv; p= . ) and the ongoing use of antibiotics. they suggested that this diagnostic criteria should be analyzed with caution in patients receiving prior antibiotic therapy with clinical suspicion of late-onset vap. schurink et al. [ ] examined the accuracy of the cpis for diagnosing vap and evaluated interoberver variability in its calculation. they compared the scores of a slightly modified cpis with results of quantitative cultures of bal in patients suspected of vap. the diagnosis of vap was based on a positive bal (quantitative cultures growth ! cfu/ml). for patients the cpis was calculated by two investigators. vap was diagnosed in patients. when using cpis higher than to diagnose vap, the sensitivity of the score was % and the specificity only %. with a cutoff of points the diagnostic values were lower (sensitivity %, specificity %). in addition, a major limitations was identified by the authors, compromising the wide use of cpis in clinical practice, since the level of agreement between observers in measuring individual cpis ( vs. > ) was poor. they concluded that the low specificity and sensitivity of cpis, combined with a considerable interobserver variability, do not permit to base a diagnostic strategy on such a score. luyt et al. [ ] confirmed this observation in a retrospective cohort study conducted in patients included in the "invasive strategy" group of the french multicenter randomized trial comparing two strategies (invasive vs. clinical) in the management of patients suspected of having vap [ ] . cpis was calculated retrospectively with the data collected for the initial study on days and and was compared between patients with bacteriologically confirmed vap (n= ) or not (n= ). on day cpis was similar in the two groups ( . € . vs. . € . with and without vap, respectively, ns). on day the patients ( %) had a cpis higher than . based on the algorithm described by singh et al. [ ] these patients would have required prolonged antimicrobial therapy. compared with a strategy based on bronchoscopy, patients without bacteriologically confirmed vap would have been unnecessarily treated, and patients with vap would have not received antibiotics after day for a total of % of patients incorrectly managed. for more than years clinical evaluation including temperature, macroscopic aspect of tracheal secretions, leukocytosis, and chest radiography has been repeatedly identified as at least a nonoptimal way to diagnose pneumonia in patients treated with mv [ ] . cpis, which is no more than the quantification of a clinical evaluation, does indeed constitute significant progress, particularly when it is included in a management algorithm [ ] . as indicated by yu and singh [ ] in their editorial, the use of such an algorithm based on cpis resulted in limiting the number and duration of antibiotics, reducing incidence of infections due to multiresistant bacteria, shortening duration of stay, and lowering -day mortality rate. it is therefore possible to reduce antibiotic use without deleterious consequences for mv-treated patients treated with clinical signs suggesting the development of vap. furthermore the authors clearly stated that excessive broad-spectrum therapy leads to greater emergence of multiply-resistant organisms and increases mortality and morbidity. limiting the use of antibiotics in patients with cpis lower than is a very important first step of a "revisited" strategy. yu and singh reported important data concerning this strategy. during the years following the implementation of the singh protocol they had not experienced "a single case of a patient with an invasive infection leading to death in a patient with cpis < receiving day monotherapy." thus the relevant questions are: is this patient developing vap? does the patient require antibiotics? to answer to these questions, it is possible to propose at least two new randomized trials: first, according to the authors, a comparison of a shortcourse monotherapy vs. no antibiotics in patients with low (< ) cpis and, second, a comparison of the singh protocol with a bacteriological strategy already evidenced as superior to the "classic" clinical strategy [ ] . adequacy of initial antibiotic therapy is recognized as a major prognostic factor in patients with vap [ ] . this statement seems obvious; it is also the rationale for giving broad-spectrum antibiotics in all patients with clinical suspicion of vap, ignoring the risk of emergence of resistance, over morbidity and mortality associated with the absence of control of antibiotic prescriptions. thus the relationship between appropriateness of treatment and outcome needs to be clarified. clec'h et al. [ ] conducted a study in patients with bacteriologically confirmed vap to test the hypothesis of a link between adequacy of treatment, severity of illness at vap onset, and outcome. the rate of ade-quate antibiotic therapy was . % on day and % on day . no significant difference in mortality was observed with and without adequate initial treatment in the entire population. however, in patients ( %) with low severity level (defined by a logistic organ dysfunction score ), inadequate therapy was clearly associated with higher icu mortality ( %, vs. % in patients appropriately treated, p= . ). pending confirmatory studies these results potentially have major impact on the management of patients suspected of having vap: the appropriate choice of antibiotic(s) is of particular importance in the group of patients with low severity level at the time of the onset of clinical signs of infection. it is reasonnable to perform accurate bacteriological investigations in this population to guide the choice of initial treatment. development and correct evaluation of new antibiotics is one of the cornerstones for improving therapeutic management in patients with vap. one current and increasing difficulty is the treatment of infections due to multiresistant bacteria such as pseudomonas aeruginosa, acinetobacter spp., stenotrophomonas maltophilia, blactamase secretor enterobacteriaceae, and methicillinresistant staphylococcus aureus (mrsa). to date the treatment of mrsa is based on the use of glycopeptides. linezolid, a new oxazolidinone, is a potential alternative to vancomycin for the treatment of severe infections due to mrsa. kollef et al. [ ] reported the results of a retrospective analysis of a subgroup of patients enrolled in two randomized double-blind trials comparing mg linezolid to g vancomycin every h. among patients with suspected gram-positive vap, had vap due to mrsa. in this subgroup clinical cure rates were . % with linezolid (vs . % with vancomycin, p= . ), bacterial eradication rates . % (vs . %, p= . ), and survival rates . % (vs . %, p= . ). logistic regression analysis identified linezolid as one of the independent factors associated with survival in patients with mrsa vap (or . , p= . ), with apache ii score of or less, presence of pleural effusion, and absence of bacteremia. in their editorial ioanas and lode [ ] suggested that linezolid may already be a better choice than vancomycin in vap due to mrsa. the major reason is that vancomycin is a "modest drug" for the treatment of lung infection due predominantly to the extremely poor penetration of vancomycin in the epithelial lining fluid and to the frequent inadequate serum levels. however, linezolidresistant strains of s. aureus have already been reported in the united states and united kingdom. as a conclusion, the authors recommended that (a) linezolid be used with caution and (b) parallel strategies such as antibiotic rotations, restricted use of antibiotics, hygiene measures and cohorting be adapted to diminish antibiotic-selective pressure and to decrease infections by resistant s. aureus. to design strategies of prevention of vap, valles et al. [ ] conducted a study to identify routes and patterns of colonization with p. aeruginosa. ninety-eight intubated patients ventilated longer than days were investigated; authors collected samples from the tap water of the room, stomach, oropharynx, subglottic secretions, trachea, and rectum at the time of intubation and three times per week. they observed colonization in . % of patients and tracheal colonization in . %. ten patients had tracheal colonization at intubation, and four developed vap. p. aeruginosa was isolated in . % of samples of the room's tap water; however, identified pulsotypes were rarely associated with vap. the authors concluded that colonization with p. aeruginosa was endogenous and exogenous. as a consequence they suggested the combination of prophylactic measures avoiding airway colonization and infection control measures to reduce crosscontamination. subglottic suctioning and semirecubent positioning have been proposed to prevent vap [ ] . girou et al. [ ] designed a randomized trial to evaluate the impact of the two measures on tracheal colonization in patients receiving long-term mv. oropharyngeal and tracheal secretions were collected daily ( samples in the eight patients of the suctioning group and in the ten patients of the control group). comparing patients receiving these measures to patients receiving standard care and supine position, the authors identified no differences in bacterial counts in the trachea ( . log cfu/ml in the suctioning group vs. . log cfu/ml in the control group), colonization on day ( % vs. %, respectively), or in the daily bacterial count in the oropharynx and in the trachea. vap rate was similar in both groups. they concluded that continuous subglottic suctioning and semirecubent position do not reduce tracheal colonization in long-term mv patients. the true impact of such prophylactic measures needs to be evaluated more precisely. in contrast to community-acquired pneumonia, lung inflammatory response has been poorly investigated in patients with vap. millo et al. [ ] examined whether cytokine concentrations change in the lungs of patients with vap. they investigated the lungs by using nondirected bronchial lavage and performed serial cytokines and cytokine inhibitors measurements in patients with vap and patients without vap. they observed no modifications in plasma concentrations of cytokines and cytokine inhibitors. in nondirected bronchial lavage fluid the concentrations of tumor necrosis factor a, tumor necrosis factor a receptor , and interleukins a, b, and increased significantly in patients with vap. the authors concluded that cytokines and cytokine inhibitor production are compartmentalized in the lung of patients who develop vap. el-solh et al. [ ] evaluated the impact of inadequate antimicrobial therapy on procoagulant and fibrinolytic activity in patients with bacteriologically confirmed vap and control patients treated with mv. seven patients were not treated appropriately; thrombin-antithrombin complex, prothrombin activation fragment, and plasminogen activator inhibitor type levels were higher than in those who received adequate treatment. despite antibiotic adjustment on day thrombin-antithrombin complex levels remained elevated and were correlated with p/f ratio. such a procoagulant activity was accompanied by a local depression of fibrinolytic capacity. no correlation was found between the bacterial burden and the homeostatic derangements. the authors suggested that the lung inflammatory response in patients with inadequately treated vap induces a local procoagulant activity associated with hypoxemia. lung volume in mechanically ventilated patients: measurement by simplified helium dilution compared to quantitative ct scan changes in lung volume with three systems of endotracheal suctioning with and without preoxygenation in patients with mild-tomoderate lung failure ultrasound diagnosis of alveolar consolidation in the critically ill pattern of lung emptying and expiratory resistance in mechanically ventilated patients with chronic obstructive pulmonary disease endotracheal tube intraluminal diameter narrowing after mechanical ventilation. use of acoustic reflectometry prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study incidents relating to the intra-hospital transfer of critically ill patients. an analysis of the reports submitted to the australian incident monitoring study in intensive care intra-hospital transport of critically ill patients: minimising risk epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study the epidemiologist in the intensive care unit epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study screening of ards patients using standardized ventilator settings: influence on enrollment in a clinical trial a -months clinical survey of incidence and outcome of acute respiratory distress syndrome in shangai intensive care units short-term outcome of critically ill patients with severe acute respiratory syndrome neurologic status, cough, secretions and extubation outcomes putting it all together to predict extubation outcome. intensive care med assessment of peri-extubation pain by visual analogue scale in the adult intensive care unit: a prospective observational study. intensive care med development of a risk assessment tool for deliberate self-extubation in intensive care patients international consensus conferences in intensive care medicine: non-invasive positive pressure ventilation in acute respiratory failure. organised jointly by the american thoracic society, the european respiratory society, the european society of intensive care medicine, and the societe de reanimation de langue francaise, and approved by the ats board of directors noninvasive continuous positive airway pressure in elderly cardiogenic pulmonary edema patients noninvasive vs invasive ventilation in copd patients with severe acute respiratory failure deemed to require ventilatory assistance co-morbidity and acute decompensations of copd requiring non-invasive positive-pressure ventilation noise exposure during noninvasive ventilation with a helmet, a nasal mask, and a facial mask does icu-acquired paresis lengthen weaning from mechanical ventilation? a prospective, blinded evaluation of indexes proposed to predict weaning from mechanical ventilation breathing pattern variability: a weaning predictor in postoperative patients recovering from systemic inflammatory response syndrome extubation failure: diagnostic value of occlusion pressure (p . ) and p . -derived parameters combined skin disinfection with chlorhexidine/propanol and aqueous povidone-iodine reduces bacterial colonisation of central venous catheters. intensive care med evaluation of a triple-lumen central venous heparin-coated catheter versus a catheter coated with chlorhexidine and silver sulfadiazine in critically ill patients benefits of minocycline and rifampin-impregnated central venous cathetersa prospective, randomized, double-blind, controlled, multicenter trial central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections. a randomized, double-blind trial prevention of intravascular catheter-related infection with newer chlorhexidine-silver sulfadiazine-coated catheters: a randomized controlled trial the pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters watchful waiting versus immediate catheter removal in icu patients with suspected catheter-related infection: a randomized trial suspected central venous catheter-associated infection: can the catheter be safely retained? infective endocarditis in the intensive care unit: clinical spectrum and prognostic factors in consecutive patients practices in non-neutropenic icu patients with candida-positive airway specimens a continuous quality-improvement program reduces nosocomial infection rates in the icu surveillance of antimicrobial use and antimicrobial resistance in intensive care units (sari). i. antimicrobial use in german intensive care units. intensive care med episepsis: a reappraisal of the epidemiology and outcome of severe sepsis in french intensive care units adultpopulation incidence of severe sepsis in australian and new zealand intensive care units a global perspective on the epidemiology of sepsis the clinical course of patients with septic abortion admitted to an intensive care unit c-reactive protein used as an early indicator of infection in patients with systemic inflammatory response syndrome characteristics and outcomes of hiv-infected patients in the icu: impact of the highly active antiretroviral treatment era excessive antimicrobial usage causes measurable harm to patients with suspected ventilator-associated pneumonia shortcourse empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription diagnosis of ventilatorassociated pneumonia: agreement between quantitative cultures of endotracheal aspiration and plugged telescoping catheter blind and bronchoscopic sampling methods in suspected ventilatorassociated pneumonia. a multicentre prospective study patient selection for clinical investigation of ventilator-associated pneumonia. criteria for evaluating diagnostic techniques ventilatorassociated pneumonia variation of infected cell count in bronchoalveolar lavage and timing of ventilator-associated pneumonia clinical pulmonary infection score for ventilator-associated pneumonia: accuracy and inter-observer variability value of the clinical pulmonary infection score for the identification and management of ventilator-associated pneumonia invasive and non-invasive strategies for management of suspected ventilator-associated pneumonia. a randomized trial efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity clinical cure and survival in gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin linezolid in vap by mrsa: a better choice? intensive care med patterns of colonization by pseudomonas aeruginosa in intubated patients: a -year prospective study of : isolates using pulsed-field gel electrophoresis with implications for prevention of ventilator-associated pneumonia the prevention of ventilator-associated pneumonia airway colonisation in longterm mechanically ventilated patients. effect of semi-recumbent position and continuous subglottic suctioning compartmentalisation of cytokines and cytokine inhibitors in ventilator-associated pneumonia procoagulant and fibrinolytic activity in ventilator-associated pneumonia: impact of inadequate antimicrobial therapy key: cord- -e fbg i authors: liu, songqiao; zhao, zhanqi; tan, li; wang, lihui; möller, knut; frerichs, inéz; yu, tao; huang, yingzi; pan, chun; yang, yi; qiu, haibo title: optimal mean airway pressure during high-frequency oscillatory ventilation in an experimental model of acute respiratory distress syndrome: eit-based method date: - - journal: ann intensive care doi: . /s - - -z sha: doc_id: cord_uid: e fbg i background: high-frequency oscillatory ventilation (hfov) may theoretically provide lung protective ventilation. the negative clinical results may be due to inadequate mean airway pressure (mpaw) settings in hfov. our objective was to evaluate the air distribution, ventilatory and hemodynamic effects of individual mpaw titration during hfov in ards animal based on oxygenation and electrical impedance tomography (eit). methods: ards was introduced with repeated bronchoalveolar lavage followed by injurious mechanical ventilation in ten healthy male pigs ( . ± . kg). settings of hfov were hz (respiratory frequency), % (inspiratory time) and cmh( )o (∆pressure). after lung recruitment, the mpaw was reduced in steps of cmh( )o every min. hemodynamics and blood gases were obtained in each step. regional ventilation distribution was determined with eit. results: pao( )/fio( ) decreased significantly during the mpaw decremental phase (p < . ). lung overdistended regions decreased, while recruitable regions increased as mpaw decreased. the optimal mpaw with respect to pao( )/fio( ) was ( . – . ) cmh( )o, that is comparable to eit-based center of ventilation (eit-cov) and eit-collapse/over, . ( . – . ) and . ( . – . ), respectively (p = . ). eit-cov decreasing along with mpaw decrease revealed redistribution toward non-dependent regions. the individual mpaw titrated by eit-based indices improved regional ventilation distribution with respect to overdistension and collapse (p = . ). conclusion: our data suggested personalized optimal mpaw titration by eit-based indices improves regional ventilation distribution and lung homogeneity during high-frequency oscillatory ventilation. acute respiratory distress syndrome (ards) is common in icu characterized by diffuse endothelial and epithelial injury, inflammatory pulmonary edema, small lung, lung injury inhomogeneities and severe hypoxemia [ , ] . mechanical ventilation remains mainstay in the management of patients with ards [ ] . lung protective ventilation with low tidal volumes [ ] , positive end-expiratory pressure (peep) [ , ] and prone position [ ] may improve outcomes. nevertheless, the mortality of ards patients remains high, up to - % [ ] . high-frequency oscillatory ventilation (hfov) delivered high mean airway pressure (mpaw) and extremely small tidal volumes to prevent alveolar derecruitment/ overdistention as well as avoid the repeated opening/ closing of individual alveolar [ ] . clinical trials [ ] and large animal trials [ ] have demonstrated that hfov improves oxygenation, reduces lung inflammatory processes and histopathological damages, and attenuates oxidative lung injury compared with conventional mechanical ventilation (cmv). currently, clinical data do not support the use of hfov in patients of ards. two major multicenter, randomized trials (oscar and oscillate) failed to show improvement on -day mortality in moderate-to-severe ards patients [ ] [ ] [ ] . a meta-analysis found that hfov might not improve outcome compared with cmv [ ] . one possible reason may be the improper hfov protocols applied and inadequate hfov settings. the optimal mpaw titration is still a challenge during hfov. the selection of paw is usually guided by a static p-v curve or based on the oxygenation index [ ] ; however, either computed tomography scanning [ ] or frequent blood gas analysis is indispensable. recently, a study showed that hfov guided by transpulmonary pressure improved systemic hemodynamics, oxygenation, and lung overdistension compared with conventional hfov in animals [ ] . but the ventilation distribution and homogeneity remain unknown toward the methods mentioned above to titrate mpaw. electrical impedance tomography (eit) might allow the clinician to better adjust these ventilatory settings. eit is a bedside imaging technique that enables monitoring air distribution in the lungs [ ] . our previous study has showed the gi index may provide new insights into air distribution in cmv and may be used to guide ventilator settings [ , ] . eit might allow the clinician to better adjust ventilatory settings in hfov. it is possible that hfov would be safer and more effective with a more individualized approach to setting mpaw adjusted according to ventilation distribution bedside. in the present study, our objective was to evaluate the air distribution, ventilatory, and hemodynamic effects of individual mpaw titration in hfov based on oxygenation and eit. the study was approved by the science and technological committee and the animal use and care committee of the southeast university, school of medicine, nanjing, china. all animal procedures and protocols were performed according to the guidance for the care and use of laboratory animals [ ] . a total of ten healthy male pigs (body weight . ± . kg, mean ± sd) were included. pigs were anesthetized with an intramuscular injection of ketamine hydrochloride ( mg/kg), atropine ( mg/kg) and fentanyl citrate ( mg/kg), followed by a continuous intravenous infusion of propofol ( - mg/kg/h), fentanyl citrate ( . - . μg/kg/h), midazolam ( . mg/kg/h), and atracurium ( . mg/kg/h). after the induction of anesthesia, the pigs were placed in supine position, on a thermo-controlled operation table to maintain body temperature at about . ℃. with local anesthesia, a mid-line neck incision was performed and the trachea was secured using an -mm-id endotracheal tube. the animals received conventional mechanical ventilation (servo-i ventilator, solna, sweden) under volume-controlled mode (respiratory rate breaths per minute; inspiration-to-expiration time ratio : and peep cmh o; fraction of inspiration o (fio ) and tidal volume (v t ) . and ml/kg, respectively). a swan-ganz catheter (arrow international, reading, pa, usa) was inserted through the internal jugular vein to measure central venous pressure (cvp) and pulmonary arterial wedge pressure (pawp). a thermistor-tipped picco catheter (pulsion medical system, munich, germany) was advanced through the right femoral artery to monitor the mean arterial pressure (map) and cardiac output (co). in addition, arterial blood samples were collected from a picco catheter. a continuous infusion of a ml/(kg h) balanced electrolyte solution was administered during the experiment, and map was maintained above mmhg with rapid infusions of . % saline solution at up to ml/kg, if required. after the initial animal preparation, the pigs were stabilized for min and baseline measurements (t baseline ) were taken. ards was induced by repeated bilateral bronchoalveolar lavage with ml/kg of isotonic saline ( ℃). after stabilization, an arterial blood gas sample was obtained to verify that the ratio of partial pressure of arterial oxygen pao and fio decreased to less than mmhg, followed by h of injurious mechanical ventilation (peep cmh o and distending pressure cmh o in pcv). pao /fio remained less than mmhg for min (t ards ) with an increase of fio to . . the mechanical ventilation mode was then switched to hfov (fio . ; respiratory frequency hz; inspiratory time %; ∆pressure cmh o), and a recruitment maneuver was performed (mpaw of cmh o for s) after -min hfov ventilation. after recruitment, stepwise mpaw decrements were performed from to cmh o with a step of cmh o decrease every min. (flowchart of the study is showed in additional file : figure s ). cvp, pawp, map and co were recorded at every pressure level. all blood gas measurements were performed using an automated blood gas analyzer (nova m; nova biomedical, waltham, ma, usa). continuous eit measurements started after tracheostomy (pulmovista , dräger medical, lübeck, germany). an eit electrode belt with electrodes was placed around the thorax cm above the xyphoid level and one reference ecg electrode was placed at the abdomen. the frequency of injected alternating current was selected automatically according to the noise spectrum. the images were continuously recorded and reconstructed at hz. the eit data were reconstructed using a finite element method-based linearized newton-raphson reconstruction algorithm [ ] . baseline of the images was referred to the lowest impedance value measured during t ards . oscillatory impedance variations of every s were averaged to present the ventilation distribution. one-minute period at the end of each mpaw step was used for further eit analysis. optimal mpaw with respect to oxygenation was defined as mpaw in the step before the one at which pao dropped by > % compared to previous step (additional file : figure s ). the center of ventilation (cov) index showing the vertical distribution of ventilation was calculated [ , ] : i i denotes impedance value of pixel i. y i is the pixel height and pixel i is scaled so the most ventral row is and the most dorsal row is . optimal mpaw with respect to eit-cov was defined as mpaw associated with the cov values closest to %. eit-based cov index higher than % at high mpaw steps indicated ventilation distribution toward gravity-dependent regions. recruitable regions compared to the highest mpaw level and overdistended regions were calculated using a method that was published recently [ ] . during the analysis of hfov in the present study, the oscillatory impedance variation was too small to confirm overdistension. therefore, compared to the original method, the volume changes induced by mpaw changes were used. the differences of impedance between lower mpaw and higher mpaw were calculated. the regions with less than % changes were denoted as regions with limited volume changes. these regions with almost no pixels changes were considered to be overinflated, if they belonged to those image pixels that were showed in lung regions at lower mpaw step. regions were considered to be recruitable if they were included in the lung regions at end-expiration at the highest mpaw step but not at the current mpaw step. the lung regions at mpaw level n were defined as pixels with higher impedance value (i) than % of maximum changes compared to the lowest mpaw level r (reference level, the lowest mpaw level). subsequently, the maximum differences of impedance (i max-diff ) between lower mpaw (denoted as mpaw level n) and higher mpaw (mpaw level n + ) were calculated. the regions with less than % changes were denoted as regions with limited volume changes (for pixel k, k ∈ i, i k < % × i max-diff ). these regions k were compared to lung regions at mpaw level n (j n ). they were considered to be overinflated, if they belonged to lung regions at mpaw step n at the same time (k ∩ j n intersection of set k and set j n ). the numbers of pixels in these two regions were plotted against decremental mpaw. optimal mpaw with respect to recruitable and overdistended regions was defined as the step where these two-pixel curves intersected. if the curves not intersected, mpaw with the lowest sum of recruitable and overdistended regions was selected. with the nature of this method, no values could be calculated for the lowest mpaw step, since the calculation required a comparison with a lower mpaw step (eq. ). overdistension/recruitment ratio was defined as number of pixels in the overdistended regions over that in the recruitable regions. statistical analysis was performed with the mat-lab software package (matlab . statistic toolbox, the mathworks inc., natick, ma, usa). due to the limited number of subjects, results are presented as median ± interquartile range. one-way kruskal-wallis test was used to assess the significance of differences in hemodynamics and oxygenation among different mpaw, and differences in optimal mpaw estimated with various criteria. a p value lower than . was considered statistically significant. wilcoxon signed-rank test was applied for further comparison within groups and the significance levels were corrected for multiple comparisons using holm's sequential bonferroni method. ards was successfully induced by repeated bronchoalveolar lavages in all pigs. the induction of ards led to a significant decrease in pao /fio (p < . ). map and co increased while cvp and pawp decreased along with the decremental mpaw trial. hemodynamic data during the mpaw trial are plotted in additional file : table s . the effect of mpaw on the pao /fio and partial pressure of arterial carbon dioxide (paco ) during hfov are shown in additional file : figure s . during the decremental phase, significant decrease in pao /fio and increase in paco were found between the mpaw step of cmh o and cmh o (p < . ) (additional file : figure s left). the optimal mpaw calculated by individual animal with respect to pao /fio was ( . - . ) cmh o. cov decreased along with mpaw decrease revealing a redistribution of ventilation toward non-dependent regions (fig. , left) . the optimal mpaw with respect to eit-cov in all pigs was . ( . - . ) cmh o and the values among individuals varied a lot. eit-derived overdistended regions decreased as mpaw decreased (fig. , right, green circles) . at the same time, recruitable regions increased (black stars). the optimal mpaw using the approach based on the calculated eitcollapse/over was . ( . - . ) cmh o. the optimal mpaw with respect to pao /fio was ( . - . ) cmh o, that is comparable to eit-based center of ventilation (eit-cov) and eit-collapse/ over, . ( . - . ) and . ( . - . ), respectively (p = . ). the differences between the selected mpaw according to oxygenation and according to "eit-cov" and "eit-collapse/over" were compared with bland-altman plots (fig. ) . the differences in mpaw selection between oxygenation and eit-based methods could be as high as cmh o in some pigs. the optimal mpaw settings derived from oxygenation, eit-cov and eit-collapse/ over were compared (table ). in fig. , overdistended and recruitable regions at mpaw levels selected based on oxygenation were illustrated. in each pig, the optimal mpaw defined with oxygenation was given (x-axis). the mpaw titrated by eit-based indices improved regional air distribution with respect to overdistension and collapse (comparison among mpaw titration strategies, p = . ) ( table ) . in the present study, novel eit-based method titrating mpaw under hfov was proposed and evaluated in ards model. the titration results were compared with oxygenation method and the effects on lung homogeneity were examined. we found that the individual mpaw titrated by eit-based indices improved regional ventilation distribution with respect to overdistension and collapse and the suggested mpaw may not always match the ones proposed by oxygenation method. hfov may remain a tool in managing patients with severe ards and refractory hypoxemia and not the firstline treatment for ards patient. hfov with high mpaw values applied in both two trials [ , ] might contribute to negative clinical outcome on ards patients and canceled out the positive effects. hfov using paw set according to a static p-v curve [ ] , oxygenation, mean airway pressure during cmv [ ] , and transpulmonary pressure [ ] has been examined in clinical and animal studies, but the bedside monitoring base on ventilation distribution is lacking. in the present study, we provide new mpaw titration method in respect of regional ventilation distribution that improves lung homogeneity. the increased mpaw lead to more lung tissue hyperinflated, and the eit-cov decrease, which revealed redistribution toward non-dependent regions. a critical issue of this eit-based method was the pre-defined threshold used to identify lung regions. further studies are required to confirm if the threshold used in the present study is optimal for various subjects and conditions. the reliability of eit has been confirmed and eit has been used in clinic setting and adjust of cmv. eit has been used in peep titration and tidal volume setting by comparison with various conventional methods, such as ct [ ] , single-photon-emission computed tomography [ ] , positron emission tomography [ ] , and pneumotachography [ ] . previous studies have already shown that eit was able to monitor ventilation distribution during hfov in preterm infants and patients with chronic obstructive pulmonary disease [ , ] . the optimal settings based on oxygenation were comparable to eit-cov and eit-regional ventilation distribution. it was also observed that overdistended regions were large at the mpaw selected with oxygenation method in several pigs. pf ratio is an invasive method with a certain time delay in response to pressure changes. although the average values between eit-derived measures were not very different, individual differences could be large (up to cmh o, figs. and ) . hence, mpaw titration with eit-based indices improved regional ventilation distribution while titration aiming oxygenation was not always the case. besides, it is worth to note that eit is currently the only bedside non-invasive tool to assess overdistension. further investigation should be conducted in future clinical studies. number of pixels is presented as black asterisk (recruitable lung region) and red circles (overdistended lung region) with the optimal mpaw were defined with oxygenation (upper). the number of pixels is presented as black crosses (recruitable lung region) and red squares (overdistended lung region) with the optimal mpaw were defined with eit-based center of ventilation index (lower x-axis) as well (lower) our study has some limitations. first, as an experimental study, these data were obtained in animals and its clinical impact may be limited. therefore, the optimal mpaw selected in the present study might be not suitable with that in ards patients. second, hfov should not be employed in the absence of well-trained expertise because of its complexity. further validation study to assess the feasibility of such strategies in ards patients with proposed method should be conducted. our data provide personalized optimal mpaw titration in hfov with eit-based indices, which may provide a new insight of regional ventilation distribution and lung homogeneity during high-frequency oscillatory ventilation. acute respiratory distress in adults acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome higher peep improves outcomes in ards patients with clinically objective positive oxygenation response to peep: a systematic review and meta-analysis bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries high-frequency oscillatory ventilation for adult patients with high frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ards): systematic review and meta-analysis high-frequency oscillatory ventilation for early acute respiratory distress syndrome in adults highfrequency oscillation in early acute respiratory distress syndrome high-frequency oscillatory ventilation on shaky ground highfrequency oscillation for acute respiratory distress syndrome high-frequency oscillation for adult patients with acute respiratory distress syndrome. a systematic review and meta-analysis setting mean airway pressure during high-frequency oscillatory ventilation according to the static pressure-volume curve in surfactantdeficient lung injury: a computed tomography study high-frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the translational eit development study group evaluation of an electrical impedance tomography-based global inhomogeneity index for pulmonary ventilation distribution peep titration guided by ventilation homogeneity: a feasibility study using electrical impedance tomography guide for the care and use of laboratory animals electrical impedance tomography: functional lung imaging on its way to clinical practice? monitoring perioperative changes in distribution of pulmonary ventilation by functional electrical impedance tomography identification of regional overdistension, recruitment and cyclic alveolar collapse with electrical impedance tomography in an experimental ards model high-frequency oscillatory ventilation in adults with ards: past, present, and future high-frequency oscillatory ventilation: still a role? right ventricular function during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury detection of local lung air content by electrical impedance tomography compared with electron beam ct electrical impedance tomography compared to positron emission tomography for the measurement of regional lung ventilation: an experimental study imbalances in regional lung ventilation: a validation study on electrical impedance tomography changes in lung volume and ventilation during surfactant treatment in ventilated preterm infants publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. supplementary information accompanies this paper at https ://doi. org/ . /s - - -z.additional file : figure s . flowchart of the study. figure s . pao /fio (left) and paco (right) during mpaw decrements trial after having fully recruited the lungs.additional file : table s . hemodynamics characteristics during decremental hfov mpaw (n = ). the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study had the approval of the science and technological committee and the animal use and care committee of the southeast university, school of medicine, nanjing, china. the animals were handled according to the helsinki convention for the use and care of animals. all authors have read this paper and agreed with the submission. inez frerichs has received reimbursement of travel, meeting expenses and speaking fees from swisstom and dräger, respectively. zhanqi zhao receives a consulting fee from dräger medical. the remaining authors have disclosed that they do not have any potential conflicts of interest. the authors state that neither the study design, the results, the interpretation of the findings nor any other subject discussed in the submitted manuscript was dependent on support. key: cord- -mena g authors: chen, jiajia; wu, jie; hao, shaorui; yang, meifang; lu, xiaoqing; chen, xiaoxiao; li, lanjuan title: long term outcomes in survivors of epidemic influenza a (h n ) virus infection date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: mena g patients who survive influenza a (h n ) virus infection are at risk of physical and psychological complications of lung injury and multi-organ dysfunction. however, there were no prospectively individualized assessments of physiological, functional and quality-of-life measures after hospital discharge. the current study aims to assess the main determinants of functional disability of these patients during the follow-up. fifty-six influenza a (h n ) survivors were investigated during the -year after discharge from the hospital. results show interstitial change and fibrosis on pulmonary imaging remained months after hospital discharge. both ventilation and diffusion dysfunction improved, but restrictive and obstructive patterns on ventilation function test persisted throughout the follow-up period. for patients with acute respiratory distress syndrome lung functions improved faster during the first six months. role-physical and role-emotional domains in the -item short-form health survey were worse than those of a sex- and age-matched general population group. the quality of life of survivors with ards was lower than those with no ards. our findings suggest that pulmonary function and imaging findings improved during the first months especially for those with ards, however long-term lung disability and psychological impairment in h n survivors persisted at years after discharge from the hospital. chest radiography. chest radiography indicated ground-glass opacities and consolidation at the onset of disease, with the exception of . % ( / ) that showed minor changes. radiologic changes included linear fibrosis, isolated areas of pleural thickening, and small bullous cysts on cct at months. at months after discharge from the hospital, all patients showed improvement on cct; however, no marked change was evident after months. at the -month follow-up, . % ( / ) of patients were proximally normal, . % ( / ) had fibrosis and . % ( / ) had parenchymal opacification including ground-glass opacities (ggo) and reticular patterns. imaging abnormalities including bronchiectasis (n = ; . %), pneumatocele (n = ; . %), small bullous cysts (n = ; . %), nodules (n = ; . %), and pleural thickening (n = ; . %) were also identified. the radiologic findings of a -year-old female patient with hypertension were monitored from admission until the -month follow-up visit (fig. ) . lung function. forty seven of them were included in the analysis of the index of lung function. of the patients, were diagnosed with ards. their first visit's clinical and laboratory features were compared and summarized in table . the proportion of female gender was similar between the patients with ards and those without ards. however, the patients with ards were significantly older than those without ards. similarly, patients with ards had higher reported acute physiology and chronic health evaluation ii scores (apach ii) than the patients without ards. ards patients tended to stay longer in the hospital than non-ards patients. overall, lung function at the -month visit was better in patients without ards than in those with ards. both ventilation and diffusion dysfunction persisted throughout the follow up. the percentage of ventilation dysfunction in patients decreased from the first visit to the -month follow-up visit. the influence of ards on lung function during follow-up. the mean and % ci of parameters of lung function over time are plotted in fig. . estimated longitudinal effects on lung function from the mixed-effects regression models are shown in table . we observed general increases in forced expiratory volume in one second (fev ), dlco and forced vital capacity (fvc) for patients regardless of ards status. however, patients without ards consistently achieved higher fev , dlco and fvc scores over the study period (fig. , table ). the ratio of forced expiratory volume in one second to forced vital capacity score (fev /fvc) declined over the follow-up period, and was higher in ards patients than patients without ards (fig. , table ). the estimated improvement in fev for ards patients was . (p = . ), . (p < . ), . (p < . ), and . (p < . ) at the -, -, -and -month follow-up assessments compared to -month follow-up, respectively. for non-ards patients, the estimated improvement in fev was smaller ( table ) . the results were similar for other measures, such as fvc, dlco, and fev /fev. quality of life. the scores for all domains of the sf- did not change significantly from to months after discharge from the hospital. because the patients were residents in and near hangzhou, so we chose the sf- results of the residents in hangzhou as the control surveyed by wang, li et al. . the scores for role-physical (rp) and role-emotional (re) domains were significantly lower than those of the control population during the first year . rp remained lower than that of the controls, but there was no difference in re at the -month follow-up. social functioning (sf) and body pain (bp) were both lower than those of the controls; a significant difference was detected in the former at the -month follow-up and in the latter at the -and -month follow-up visits ( table ). the mean and % ci of parameters of quality of life over time are plotted in fig. . generally, patients with no ards reported higher scores on all the domains of quality of life except for re, which were comparable between patients with ards and patients without ards across the study period. hospitalized patients with h n virus infection usually present with fever and cough, with early sputum production, and the illness progresses rapidly to severe pneumonia, moderate-to-severe ards, and shock. the development of refractory hypoxemia is the usual cause of death . however, there are no previous reports on the quality of life of h n patients after hospital discharge. our study found that more than half of the survivors of h n virus infection had respiratory tract manifestations after discharge from the hospital. most symptoms improved within month (data not shown). six months after discharge, more than % of patients had returned to work, and the percentage of abnormal dlco was lowest. psychological impairment persisted throughout the follow-up period. all survivors were found to have lung involvement on hrct images, possibly due to diffuse alveolar damage with proteinaceous exudates, occasional cytomegaly, and intra-alveolar hemorrhage . imaging showed improvement in inflammation over time, especially during the first months after hospital discharge. however, no further significant changes in interstitial fibrosis or ground-glass opacities were detected at the -and -month visits. an autopsy study of patients with h n infection suggested that lung histology varied according to the duration of illness. after acute diffuse alveolar damage, post-inflammatory changes such as pulmonary pneumocyte hyperplasia and parenchyma fibroproliferation occurred during the later course of the disease . we speculate that changes during the -month convalescence period are irreversible. absorption occurred slowly and was coincident with clinical symptoms. in survivors of h n virus infection, radiologic abnormalities including ground-glass opacities with a reticular pattern remained evident at the -month follow-up visit . moreover, in a study of the long-term outcomes of pandemic h n -associated severe ards, the patients also had abnormal imaging findings, with mildly distorted septal lines, parenchymal bands, pneumatocele and distal bronchiectasis, at year post-icu discharge . at the -month visit, ground-glass opacities were evident in . % of patients . these features are generally similar to those of survivors of h n infection in this study. fibrosis ( . %) and parenchymal pacifications ( . %), which paralleled lung dysfunction, were common at the -year visit. parenchymal pacifications were more sensitive than ct imaging in the evaluation of fibrotic changes . pulmonary function has been reported to be near normal, with the exception of decreased diffusion capacity, in h n patients . in our study, approximately half of the survivors had ventilation dysfunction at months. hybrid patterns and restrictive ventilation dysfunction accounted for most types of dysfunction, which may be caused by muscle weakness and fatigue . . % of patients exhibited decreased dlco levels at the -year follow-up visit, which was higher than reported previously [ ] [ ] [ ] [ ] . the overall pattern of lung function impairment suggests impairment in the small airways and the alveolar diffusion pathway. furthermore, patients with ards had larger lung function changes at each follow-up time. the improvement between month and months after discharge was larger than the improvement between months and months, as was previously reported for ards . for example, patients with ards achieved . units of improvement in fev within months, but have only . units of improvement in the next months. a study of the long-term outcomes of survivors with ards reported a mild restrictive pattern on lung-function testing, with a mild-to-moderate reduction in carbon monoxide diffusion capacity at months; the median dlco improved by % of the predicted value from to months . in our study, the median dlco of the patients with ards improved by . - . % of the predicted value, which is considerably higher than the rates reported previously. these survivors stayed a long period of time in the hospital or icu and suffered from lung injury physically. they also suffered from the fear of death. when they went back home, they not only lacked of activities, but also were isolated by their relatives and neighbors because h n attack made people fear of infection and death. thus survivors have significantly lower hrqol than that of the general population and are likely to have social functioning and mental health deficits . similarly, h n survivors experience persistent hrqol decrements after discharge. thus, the disease affected hrqol mainly in the rp, bp, sf, and re domains compared with normal controls. a meta-analysis showed that recovery in the hrqol of ards survivors occurred during the first months after discharge , but no significant improvement was evident at the -year follow-up in our study. these findings suggest that the quality of life of survivors with ards was lower than that of those without ards. the severity of the diseases may influence the quality of life the patients. to our knowledge, this is the first prospective study of the physical and psychological health status of patients with influenza a(h n ) pneumonia during the convalescent period. this study had several limitations. first, most h n infections occurred in china between and the present. this was a single-center study involving a limited number of patients over a -year period in zhejiang province, china. second, follow-up visits were offered to all patients discharged from the hospital, but some refused to attend and some did not complete follow up. the follow-up rates for lft were %, %, % and % and those for hrqol were %, %, % and % at , , and months, respectively. although many indices did not change significantly after year, the study population may not be representative of the entire population of h n survivors. third, this was a prospective study on the impact of h n on the physical and psychological health of survivors. however, no information on the baseline lung function and quality of life of these patients was available. although some patients may have underlying pulmonary diseases, most of them received the medicine without further examination. so we cannot compare the index of lung function before and post infection of h n . in particular, this group of patients had pre-existing conditions, which may also have affected the hrqol results. patients who had suffered acute pathologies reported significant decreases in quality of life, whereas other patients with pre-existing conditions reported significant improvements in terms of reduced bp and improved mh, vt and sf scores . in our study, h n survivors had significantly higher vt and mh scores than the population norms. thus, those scores may have been higher at baseline, i.e., prior to admission. finally, after discharge from the hospital, there was no significant improvement; however, whether improvements in physical and mental health would have been detected had the follow-up duration been longer is unknown. thus, further expanded research is needed. in summary, long-term lung disability and psychological impairment in h n survivors persisted at years after discharge from the hospital. pulmonary function and imaging findings improved during the first months especially for those with ards. most survivors returned to work, but at the -year follow-up, more than half of survivors still had ventilation and blood-gas diffusion dysfunction. the h n survivors had impaired hrqol scores that were lower than those of a sex-and age-matched control population, and ards substantially influenced these scores. follow-up protocol. patients were evaluated in clinics at , , , and months after their discharge from the hospital. at each visit, computed tomography of the chest (cct) and lung function tests (lft) were performed. the -item short-form health survey (sf- ) (chinese version) of the medical outcome study assessing health-related quality of life (hrqol) was completed. patients who declined the face-to-face interview were telephoned to obtain survival information. statistical analysis. patients' characteristics were summarized with means ± standard deviation (m ± sd) for continuous variables or with frequency and proportion for categorical variables. baseline differences in ards status were assessed using student's t tests, fisher's exact tests or chi-square test, whenever is applicable. we plotted the means of lung function and quality of life and the corresponding % confidence intervals (cis) over time to graphically examine the changes in outcomes over time. we estimated mixed-effect models to fit lung function with patients' ards status as the main effect, visit ( , -, -, -, or -month follow-up), and the ards status-by-visit interaction. the models also included a first-order autoregressive covariance structure to account for repeated measures within each patient. we also assessed the estimated difference in the outcome measures at the -, -, -, or -month follow-up visits compared to those at -month visit according to ards status through model contrast. the estimated change in lung function relative to -month visit was assessed. one sample t tests were used to compare sf- scores at the -, -, -, or -month follow-up visits with that of the control group. data availability. the datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. ethical approval and informed consent. the study design was approved by the human ethics committee of the first affiliated hospital, school of medicine, zhejiang university. the methods were carried out in accordance with the relevant guidelines and regulations. informed consent was obtained from each patient included in the study. human infection with a novel avian-origin influenza a (h n ) virus clinical findings in cases of influenza a (h n ) virus infection human infections with the emerging avian influenza a h n virus from wet market poultry: clinical analysis and characterisation of viral genome assessing change in avian influenza a(h n ) virus infections during the fourth epidemic -china clinical features of pneumonia caused by influenza a(h n ) virus in beijing clinical features of human influenza a (h n ) infection in vietnam cumulative number of confirmed human cases for avian influenza a(h n ) reported to who development and psychometric tests of a chinese version of the sf- health survey scales the research on quality of life of civil residence in hangzhou with chinese version of the sf- questionaire. chinese journal of preventive medicine radiological features of lung changes caused by avian influenza subtype a h n virus: report of two severe adult cases with regular follow-up long-term outcomes of pandemic influenza a(h n )-associated severe ards follow-up study on pulmonary function and lung radiographic changes in rehabilitating severe acute respiratory syndrome patients after discharge one-year outcomes in survivors of the acute respiratory distress syndrome -year pulmonary function and health status in survivors of severe acute respiratory syndrome impact of severe acute respiratory syndrome (sars) on pulmonary function, functional capacity and quality of life in a cohort of survivors pulmonary function and exercise gas exchange in survivors of adult respiratory distress syndrome of survivors after the first outbreak of human infections with avian influenza a(h n ) virus in shanghai, china recovery of function in survivors of the acute respiratory distress syndrome health-related quality of life after acute lung injury quality of life after acute respiratory distress syndrome: a meta-analysis changes in quality of life after intensive care: comparison with normal data all authors contributed to the interpretation of results and approving the decision to submit the article for publication. l.j. li designed the study. j.j. chen, s.r. hao, m.f. yang were investigators in this study. x.q. lu, x.x. chen and j.j. chen collected the data. j.j. chen prepared the first draft of the article and j. wu completed the data analysis. all authors reviewed the manuscript. competing interests: the authors declare that they have no competing interests.publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- -fvrd w authors: herath, h. m. l. y.; jayasundara, j. m. h. d.; senadhira, s. d. n.; kularatne, s. a. m.; kularatne, w. k. s. title: spotted fever rickettsioses causing myocarditis and ards: a case from sri lanka date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: fvrd w background: spotted fever group of rickettsial infections are emerging in sri lanka. we describe a patient with rapidly progressing ards and myocarditis secondary to spotted fever caused by rickettsia conorii. ards and myocarditis are rare complications of rickettsia conorii infections and only a few cases are reported to date. case presentation: a years old manual worker presented with fever for days and a skin rash. he was in circulatory failure on admission and developed severe hypoxaemia with gross changes in chest radiograph by next day requiring assisted ventilation. he had myocarditis causing left ventricular failure and acute respiratory distress syndrome. he was confirmed to have spotted fever rickettsial infection with rising titre of indirect immunofluorescence antibodies to ricketssia conorii and made a complete recovery with appropriate antibiotic therapy and supportive care. conclusion: rickettsial infections can present with diverse manifestations. even the patients with severe organ involvements such as myocarditis and ards can be completely cured if timely identified and treated. emergence of spotted fever group of rickettsial infections in the hilly central province of sri lanka was first observed in early nineties [ ] . rickettsia conorii, the organism known to cause mediterranean spotted fever (msf) is the most prevalent organism causing spotted fever in sri lanka. few serologically confirmed cases of rickettsia honei and rickettsia japonica has also been reported [ , ] . usual presentation of spotted fever is with a prodrome of high grade fever, headache myalgia, arthralgia and anorexia. less common manifestations include frank arthritis, cough, abdominal pain, conjunctival injection and diarrhea [ ] . various neurological manifestations including confusion, hallucinations, tinnitus, hearing impairment and rarely coma are also seen [ ] . the characteristic skin rash is present only in about % of patients. typically, the rash is maculopapular with predominant involvement of limbs including palms and soles. in severe cases fern leaf type skin necrosis can occur. the typical eschar is rare to be found and often the patients are unaware of of tick bites [ , ] . on rare occasions patients present with fever and multiple organ dysfunction making it difficult for the clinician to find the exact diagnosis since many tropical diseases can cause a similar picture. indirect immunofluorescent antibody assay (ifa) is the reference serology method for the diagnosis. it is available in only a few laboratories in sri lanka. limited availability of ifa has led to underreporting of the cases with rickettsial infections. msf is usually a mild disease with a mortality rate around . %. elderly patients are prone to get more complications [ ] . mortality data regarding sri lankan patients are not available, except few fatal case reports. the following case report highlights myocarditis and acute respiratory distress syndrome (ards) as complications in a severely ill patient with spotted fever group of rickettsioses where timely diagnosis and intervention saved the life. a -year-old male was transferred from peripheral hospital hatharaliyadda (phh) to teaching hospital, kandy (thk) in a state of circulatory failure for specialized care. he was a previously well 'tree cutter' working close to his residence situated in a hilly terrain in the northern slope of central hills of sri lanka where rich lust green vegetations and tropical trees are in abundance. his routine was to cut trees in the tea estates in the area and to carry the logs to the closest motorable road. he developed fever with myalgia and headache days prior to the admission to phh. on the th day of fever he had noticed a rash over his body. as his condition deteriorated on the th day of the illness, he was transferred to thk. on admission, he was febrile and recorded temperature was °f. he had a generalized discrete erythematous macular rash in most areas of the body including palms and soles. also he had swelling of both ankle joints. he denied any tick bite prior to illness. there was no eschar found. he had neither lymphadenopathy nor splenomegaly. but the liver was palpable cm below costal margin. lungs were clear to auscultation. (fig. ) he had a thready pulse of /min with a blood pressure of / mmhg. he was initially resuscitated with intravenous normal saline and managed as septic shock. the presence of skin rash prompted to consider a spotted fever rickettsial infection. therefore, he was started on intravenous ceftriaxone and oral doxycycline. since his blood pressure did not improve with fluid resuscitation a central line was placed and intravenous norepinephrine infusion at a rate of . μg/kg/min was commenced along with septic dose of intravenous hydrocortisone mg/ hourly. his plasma random glucose was normal. initial electrocardiogram did not show st/t wave abnormalities and chest radiograph was normal. his serial investigations during the hospital stay are shown in table . with inotropic support, antibiotics and maintenance fluids he remained stable for the next h. his blood cultures, urine cultures and retroviral studies were negative. during the latter part of the second day of admission to thk he developed progressively worsening shortness of breath with hypoxemia and hypotension. blood gas analysis showed type respiratory failure with po /fio ratio of . . repeat chest radiograph showed bilateral alveolar and interstitial shadowing of both upper and mid zones. ecg revealed sinus tachycardia with no significant st/t wave changes. d echo cardiogram showed a ventricular ejection fraction of - % with global hypokinesia of myocardium suggestive of myocarditis. troponin-i titre was positive at . ng/ml (normal < . ng/ml) and ntprobnp (n-terminal pro b-type natriuretic peptide) value was elevated at pg/ml. at this juncture, elective intubation was done and the patient was transferred to the intensive care unit for assisted ventilation. (fig. ) . the management team identified some issues with regard to diagnosis and choosing the appropriate treatment for the patient. echocardiographic findings, elevated troponin titre and elevated bnp were consistent with myocarditis leading to heart failure causing pulmonary oedema and hypoxemia. the possibility of ards was considered based on clinical, blood gas and radiological evidence. spotted fever was considered to be the most likely diagnosis because of the presence of the typical rash. other differential diagnoses included leptospirosis with myocarditis and pneumonitis. but the rash and lack of liver and renal involvement was not in favor fig. skin rash. skin rash of the patient at the day of presentation. it was erythematous macular rash involving palms and soles with mild pedal edema of leptospirosis. streptococcal and staphylococcal toxic shock syndromes and meningococcal sepsis were also taken into consideration, but inability to fulfill diagnostic criteria and persistently negative cultures were against them. hemophagocytic lymphohistiocytosis (hlh) is also known to complicate many zoonoses including spotter fever infections [ , ] . however, absence of cytopenias and the splenomegaly made it less likely and further screening tests for hlh were not performed. considering the poor response to previous antibiotics, intravenous chloramphenicol mg hourly was added to the treatment regimen as authors personally had seen good response particularly in patients with severe disease. he required inotropes in increasing doses, including norepinephrine . μg/kg/min, dobutamine μg/kg/min and dopamine μg/kg min, to maintain the blood pressure for the next h. in view of myocarditis, iv hydrocortisone dose was increased to mg/ hourly. within h from starting chloramphenicol and increasing the dose of steroids, his clinical parameters started to improve. by next day tailing off of the inotropic support was possible. on the rd day in the intensive care unit, he was extubated and on the th day he was transferred back to the high dependency unit of the medical ward. the skin rash started to fade leaving few necrotic areas over the hands. all three antibiotics were stopped after the completion of days. he did not develop any treatment related complications. he was in two weeks' time, he was reviewed in the out-patient clinic and found to be completely asymptomatic. for the confirmation of diagnosis, st acute blood sample was tested for r. conorii indirect immunofluorescence antibodies (ifa) at the reference laboratory of university of peradeniya which showed moderately high positive titre ( / ). ten days later, nd blood sample was tested with ifa which showed rising titre ( / ) confirming the diagnosis. further species identification was not possible due to unavailability of facilities. unfortunately patient did not turn up for the follow up echocardiogram. we presented a middle aged man, a tree cutter in profession falling ill with fever, then collapsed on th day of illness due to myocarditis and became hypoxic due to ards. timely diagnosis of spotted fever and initiation of appropriate treatment saved his life. even though he denied a tick bite, it was likely that he had an unnoticed tick bite as his occupation carried a high risk of exposure. this case demonstrates a rather rare presentation of spotted fever rickettsial infection where patient deteriorated within short time leading to shock and ards. the development of myocarditis was rapid and severe enough to cause low left ventricular ejection fraction and hypotension. patients with myocarditis and ards are described in the literature in other types of rickettsial infections particularly with scrub typhus. myocarditis has been observed as an autopsy finding in fatal cases of rocky mountain spotted fever. other much rarer forms of tick borne rickettsial infections like sibirica mongolitimonae infections are also known to cause clinically significant myopericarditis [ ] . r. conorii related cardiac involvement is extremely rare and only about cases are described in the literature [ ] . severe forms of spotted fever rickettsioses is also known to be caused by some subspecies such as rickettsia conorii subsp. israelensis [ ] . unfortunately molecular diagnostic methods for identifications of subspecies is not yet available in sri lanka. myocarditis is caused mainly by viruses and also by leptospira spirochetes and toxins. in sri lanka myocarditis is an occasional complication in dengue infection and leptospirosis [ ] . it is not a diagnosis entertained in rickettsial infections despite its high prevalence. in myocarditis, patients usually develop undue tiredness, chest discomfort and dyspnoea which may progress to cardiogenic shock or development of arrhythmias. most often it is diagnosed clinically with ecg abnormalities such as t wave inversions, bundle branch blocks and presence or rhythm abnormalities. echocardiography and elevation of cardiac biomarkers can be used to diagnose myocarditis but these become evident mostly in severe cases. in the background of sepsis, transient cardiac dysfunction can occur due to sepsis induced cardiomyopathy. differentiation between the two diagnoses can only be achieved by endomyocardial biopsy. however, in acutely ill patients it is not justifiable do biopsy as it does not alter the management. further, in the available literature suggests that rickettsial infections related cardiac dysfunction is more likely to be due to myocarditis [ , , ] . newer methods including cardiac mri and segmented inversion recovery gradient-echocardiography pulse sequences have a better sensitivity in diagnosing acute myocarditis [ , ] . our patient had compatible symptoms and signs with global hypokinesia in d echocardiogram and elevated troponin and ntprobnp values to suggest the presence of myocarditis. differentiation between severe pulmonary oedema and ards is difficult both clinically and radiologically at the onset of the illness. but presence of prolonged severe hypoxia and persistent alveolar-interstitial shadows despite treatment with intravenous diuretics was more in favor of ards in our patient than pure pulmonary oedema. management of myocarditis and acute heart failure follow standard guidelines with diuretics, angiotensin converting enzyme inhibitors and beta blockers. place of steroid in acute myocarditis is debatable but it is commonly used by clinicians on empirical evidence and personal experience. european guideline on management of myocarditis recommends immunosuppression only in chronic virus negative myocarditis and inflammatory and autoimmune myocarditis [ ] . none of the reported patients with msf and myocarditis had received steroids. however, we believe that steroids helped in treating our patient. oral doxycycline is the recommended antibiotics for rickettsial infections [ ] . however, chloramphenicol which is a second line agent, is also widely used in many institutions in sri lanka. there are not many studies comparing the efficacy of chloramphenicol with other agents due to risk of major hematological adverse effects. in fact, cdc case report data suggest that patients with rocky mountain spotted fever treated with chloramphenicol are at higher risk for death than persons who received a tetracycline [ ] . in contrast to that our experience suggests that in severe spotted fever rickettsial infections, parenteral chloramphenicol can be used safely with good results like in this patient. out of the reported cases of msf with myocarditis, chloramphenicol was included in treatment regimens of two patients [ ] . limitations of the our report includes the unavailability of histological evidence of myocarditis and not identifying the species due to lack of resources. finally, this case highlights the need of prompt clinical diagnosis and treatment of spotted fever which can present with atypical features. emerging rickettsial infections in sri lanka: the pattern in the hilly central province seroepidemiology of rickettsioses in sri lanka: a patient based study a case series of spotted fever rickettsiosis with neurological manifestations in sri lanka cutaneous manifestations of spotted fever rickettsial infections in the central province of sri lanka: a descriptive study mediterranean spotted fever in spain, - : epidemiological situation based on hospitalization records secondary hemophagocytic lymphohistiocytosis in zoonoses. a systematic review haemophagocytic syndrome and rickettsial diseases acute myopericarditis associated with tickborne rickettsia sibirica mongolitimonae israeli spotted fever in sicily. description of two cases and minireview cardiac complications of a dengue fever outbreak in sri lanka cardiac involvement in a patient with clinical and serological evidence of african tick-bite fever diagnosis and treatment of viral myocarditis current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european society of cardiology working group on myocardial and pericardial diseases diagnosis and management of tickborne rickettsial diseases: rocky mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis -united states analysis of risk factors for fatal rocky mountain spotted fever: evidence for superiority of tetracyclines for therapy not applicable. none.availability of data and materials data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. all data contained within the article. abbreviations ards: acute respiratory distress syndrome; msf: mediterranean spotted fever; ntprobnp: n-terminal pro b-type natriuretic peptide; phh: peripheral hospital hataraliyadda; thk: teaching hospital kandy authors' contributions hmlyh, jmhdj, sdns managed the patient and did the literature review, gathering of data and writing of the initial manuscript. samk, wksk finalized the manuscript and gave expert opinion in management issues. all authors read and approved the final manuscript.ethics approval and consent to participate not applicable. informed written consent for the publication of details and pictures was obtained from the patient. consent form can be made available to the editor on request. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -q ydi authors: koyama, kansuke; katayama, shinshu; tonai, ken; shima, jun; koinuma, toshitaka; nunomiya, shin title: biomarker profiles of coagulopathy and alveolar epithelial injury in acute respiratory distress syndrome with idiopathic/immune-related disease or common direct risk factors date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: q ydi background: altered coagulation and alveolar injury are the hallmarks of acute respiratory distress syndrome (ards). however, whether the biomarkers that reflect pathophysiology differ depending on the etiology of ards has not been examined. this study aimed to investigate the biomarker profiles of coagulopathy and alveolar epithelial injury in two subtypes of ards: patients with direct common risk factors (dards) and those with idiopathic or immune-related diseases (iards), which are classified as “ards without common risk factors” based on the berlin definition. methods: this retrospective, observational study included adult patients who were admitted to the intensive care unit (icu) at a university hospital with a diagnosis of ards with no indirect risk factors. plasma biomarkers (thrombin–antithrombin complex [tat], plasminogen activator inhibitor [pai]- , protein c [pc] activity, procalcitonin [pct], surfactant protein [sp]-d, and kl- ) were routinely measured during the first days of the patient’s icu stay. results: among eligible patients with ards, were excluded based on the exclusion criteria (n = ) or other causes of ards (n = ). of the remaining patients, were identified as having dards and as having iards. among the iards patients, tat (marker of thrombin generation) and pai- (marker of inhibited fibrinolysis) were increased, and pc activity was above normal. in contrast, pc activity was significantly decreased, and tat or pai- was present at much higher levels in dards compared with iards patients. significant differences were also observed in pct, sp-d, and kl- between patients with dards and iards. the receiver operating characteristic (roc) analysis showed that areas under the roc curve for pc activity, pai- , pct, sp-d, and kl- were similarly high for distinguishing between dards and iards (pc . , p = . ; pai- . , p = . ; pct . , p = . ; and sp-d . , p = . vs. kl- . , respectively). conclusions: coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards. however, their biomarker profiles were significantly different between the two groups. the different patterns of pai- , pc activity, sp-d, and kl- may help in differentiating between these ards subtypes. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. acute respiratory distress syndrome (ards) comprises acute-onset respiratory failure, which is characterized by hypoxemia and radiographic bilateral lung opacities that result from various direct or indirect injuries to the pulmonary parenchyma or vasculature [ ] . the most recent berlin definition provides common risk factors for ards, which are classified as direct factors (e.g., pneumonia, aspiration of gastric contents) or indirect factors (e.g., nonpulmonary sepsis, major trauma, pancreatitis) [ ] . some patients presenting with ards, however, lack exposure to common risk factors, resulting in the condition called an ards "imitator" or "mimic" [ , ] . in a large cohort study, gibelin et al. reported a . % prevalence of ards without a common risk factor [ ] . a secondary analysis of the lung safe study confirmed that . % of ards patients had no common risk factors that were identified when ards was recognized [ ] . these ards patients who lacked exposure to common risk factors can be categorized as having immune, idiopathic, drug-induced, and malignant diseases [ , ] . connective tissue disease-associated interstitial lung disease (ctd-ild) is considered to be a main cause of immune-related forms of ards. ctd-ild may precede the clinical and laboratory manifestations of ctd and therefore could present as lone ards [ ] . acute onset or acute exacerbation of idiopathic interstitial lung diseases may refer to idiopathic forms of ards. although no risk factors or causes are identified in this subgroup of ards, recent studies have shown that many patients with idiopathic interstitial pneumonia have clinical features that suggest an underlying immune process, indicating that the pathobiology of idiopathic and immunerelated diseases may partially overlap [ , ] . early identification of these subsets of ards based on the pathophysiology is of clinical interest and may lead to the development of specific therapeutic intervention. however, the lesions of these idiopathic and immune-related ards may be mostly limited to the lung, and it is often difficult in the acute phase to distinguish between idiopathic/immune-related diseases and ards with common direct risk factors, based solely on the clinical findings. activation of coagulation and alveolar epithelial injury are the hallmarks of ards (fig. ) [ , ] . the biomarkers may reflect activation and injuries of different cell populations in the lung and thereby help to improve the understanding about pathogenic processes and to improve diagnostics. thrombin-antithrombin complex (tat) levels are increased in ards patients, reflecting tissue factor-and contact phase-mediated activation of coagulation cascade and excessive thrombin generation. thrombin and proinflammatory cytokines activate endothelial cells, leading to expression of plasminogen activator inhibitor (pai)- , which inhibits fibrinolysis. the levels of natural anticoagulants such as protein c (pc) are reduced because of increased consumption, impaired synthesis, and mostly capillary leakage that results from endothelial damage. surfactant protein (sp)-d and a membrane glycoprotein kl- are also increased in the plasma of ards patients, reflecting type ii alveolar cell injury [ , ] . the alterations in biomarkers that indicate thrombin generation, inhibited fibrinolysis, decreased anticoagulant, and epithelial injury are distinctive patterns of ards. however, whether these biomarker profiles may differ depending on the ards etiologies has not been examined. the aim of this study was to examine the profiles of the plasma biomarkers that reflect coagulopathy and alveolar epithelial injury in patients with idiopathic/immune-related ards (iards) and in those with common direct risk factors (dards). we investigated the baseline levels and time courses of hemostatic and type ii pneumocyte biomarkers and compared the discriminative ability of those biomarkers between iards and dards. we also evaluated the biomarkers in patients with unilateral pneumonia who were admitted during the same period for reference purposes. this single-center, retrospective, observational study was conducted at a -bed medicosurgical intensive care unit (icu) at jichi medical university hospital (tochigi, japan). medical records for all patients admitted to the icu between april and march were reviewed. adult patients admitted because of ards without indirect risk factors or unilateral pneumonia who underwent invasive mechanical ventilation within h of admission were included in the study. exclusion criteria were age < years, > week of respiratory disease progression before icu admission, previously known interstitial pneumonia or ipf, or a diagnosis of pneumocystis pneumonia. we also excluded patients with bone marrow failure, decompensated liver cirrhosis or failure, a history of chemotherapy, therapeutic anticoagulation, or blood transfusion during the preceding weeks. the institutional research ethics committee at jichi medical university approved this study and waived the requirement for informed consent because of the study's retrospective design. the ards without indirect risk factors was diagnosed according to the berlin definition with the following criteria: within week of new or worsening respiratory symptoms, bilateral lung opacities were found on chest radiography, and the pao /f i o ratio was ≤ mmhg with a positive end-expiratory pressure of ≥ cmh o. additionally, no cardiac failure or fluid overload and no common indirect risk factors for ards, such as nonpulmonary sepsis, major trauma, or pancreatitis could be found [ ] . direct lung injury risk factors were defined as pneumonia, aspiration of gastric contents, pulmonary contusion, inhalation injury, and near drowning, based on the berlin definitions. patients with vasculitis were classified as having ards without common risk factors because vasculitis is not pathologically characterized by diffuse alveolar damage (dad). the diagnosis of pneumonia was based on infectious diseases society of america/american thoracic society consensus guidelines combined with clinical data and microbiological diagnostic testing (including a blood culture, sputum culture, or culture of endotracheal aspirate, and a urinary antigen test for streptococcus pneumoniae and legionella pneumophila) [ , ] . bronchoalveolar lavage (bal) fluid for gram staining and culture, direct fluorescence assay for pneumocystis jirovecii, and a rapid influenza a/b diagnostic test (immunochromatographic assays for specific influenza viral antigens) were also performed, as needed. ards without common risk factors were separated into four etiological groups, as described below [ ] . idiopathic ards was defined as the absence of any ards etiology including common risk factors despite a comprehensive diagnostic work-up, or acute presentation of idiopathic interstitial pneumonia [ ] . immunerelated ards was defined as an acute presentation of ctd-ild as defined in accordance with established ctd criteria (e.g., american college of rheumatology criteria [ ] ) during hospitalization, or hypersensitive pneumonitis [ ] . malignancy-associated ards was defined as requiring cytological or pathological evidence of hematological or solid malignancy. drug-induced ards was defined as previous exposure to a drug that is known to be a pneumonia inducer in the absence of any other risk factor for ards [ ] . descriptive data (including demographic, diagnostic, clinical, and laboratory data) were collected from the electronic medical records of all eligible patients. initial severity indices, including the acute physiology and chronic health evaluation (apache) ii and simplified acute physiology score (saps) ii, were calculated on the day of icu admission [ , ] . sequential organ failure assessment (sofa) scores were calculated during the first days [ ] . clinical outcomes were assessed according to icu days, ventilator-free days, and allcause -and -day mortality. for the patients with idiopathic and immune-related ards, bal fluid cytological analysis and autoimmunity tests were extracted from the medical charts when available. at our institute, the biomarkers of coagulation and type ii pneumonocytes are routinely measured for the patients who are admitted to the icu with respiratory failure and/or with suspected sepsis. plasma biomarkers were measured at the time of icu admission (icu day ) and on icu days - . coagulation and fibrinolytic markers included global markers (platelet count, immature platelet fraction, prothrombin time-international normalized ratio [pt-inr], fibrin degradation product [fdp]), markers of thrombin generation (tat), markers of anticoagulant activity (pc activity), and markers of fibrinolytic activity (plasmin-α -plasmin inhibitor complex [pic], pai- ). global markers were assayed using an xe- hematology analyzer (sysmex, kobe, japan) and a cs- i automatic coagulation analyzer (sysmex). berichrom assays (siemens healthcare diagnostics, tokyo, japan) were used to assay pc activity. the tat/pic test f enzyme immunoassay (sysmex) was used to measure tat and pic levels. the pai- was measured using the tpai test (mitsubishi chemical medience, tokyo, japan). surfactant protein (sp)-d, kl- , c-reactive protein (crp), and procalcitonin (pct) were measured using the sp-d kit enzyme immunoassay (yamasa, chiba, japan), presto ii kl- chemiluminescent enzyme immunoassay (sekisui medical, tokyo, japan), crp-hg latex immunoassay (eiken kagaku, tokyo, japan), and brahms pct chemiluminescent enzyme immunoassay (roche diagnostic, tokyo, japan), respectively. differences in clinical characteristics and laboratory data among the groups were analyzed using the χ test or fisher's exact test for categorical variables and the wilcoxon rank-sum test or kruskal-wallis test with/without steel-dwass pairwise comparisons for continuous variables, as appropriate. changes in the biomarker concentrations over time in the groups were compared with multiple analysis of variance. a multivariate logistic regression model based on a forward stepwise method was used to identify the best combination of coagulation biomarkers to diagnose iards. receiver operating characteristic (roc) curve analysis was performed to calculate the area under the receiver operating characteristic curve (auc) of the biomarkers at day to evaluate the discriminative capacity between the two groups. all p values were two-tailed, and p < . was considered to indicate statistical significance. data were analyzed using jmp version (sas institute, tokyo, japan). overall, ards patients with no indirect risk factors were admitted to the icu during the study period. among them, were excluded based on the exclusion criteria: history of known interstitial pneumonia, ; pneumocystis pneumonia, ; hematological malignancy with bone marrow failure, ; liver failure, ; anticoagulation therapy, ; inconclusive diagnosis, ; and insufficient data, . data from the remaining patients were included in the study. in addition, patients who were admitted to the icu with unilateral pneumonia during the same period were enrolled for comparison. among the patients with pulmonary ards, had been exposed to direct lung injury risk factors and had not been exposed to any of the common risk factors. the direct risk factors of lung injury included pneumonia ( ; . %), aspiration ( ; . %), and drowning ( ; . %). the ards patients without common risk factors were classified as idiopathic ( ; . %), immunerelated ( ; . %), malignancy-associated ( ; . %), and drug-induced ( ; . %). table shows the baseline characteristics and outcomes of the study patients with iards and dards and those with unilateral pneumonia. patients with dards were more severely ill, with higher apache ii, saps ii, and sofa scores on icu admission compared with patients with iards. the pao /f i o ratio on admission and the severity of ards, however, were not different between patients with dards and those with iards. ventilator-free days, length of icu stay, and mortality were also similar for the two groups. the distribution of pathogens in patients with dards and those with pneumonia are shown in additional file : table s . in patients with dards, the most common causative microorganisms were klebsiella pneumoniae ( . %), followed by streptococcus pneumoniae ( . %) and methicillin-susceptible staphylococcus aureus ( . %). among the patients with iards, ( . %) were diagnosed with idiopathic ards and ( . %) with immune-related ards, which included the following: rheumatoid arthritis (n = ), dermatomyositis (n = ), systemic lupus erythematosus (n = ), scleroderma (n = ), microscopic polyangiitis (n = ), granulomatosis with polyangiitis (n = ), and hypersensitivity pneumonitis (n = ). table shows the bal findings and autoantibodies in patients with iards. in about half of these patients (idiopathic, . %; immune-related, . %), neutrophils and lymphocytes were both elevated in bal fluid, showing a mixed cellular pattern (defined as neutrophil > % and lymphocyte > % on bal differential cell counts). antinuclear antibody was positive (with > : titers) in . %, and anticyclic citrullinated peptide antibody was positive in . % of the patients with immune-related ards. notably, . % of the patients with idiopathic ards were positive for autoantibodies against aminoacyl-trna synthetase. data are expressed as the median (interquartile range) or n (%) ihd ischemic heart disease, chf chronic heart failure, copd chronic obstructive pulmonary disease, ckd chronic kidney disease, cvd cerebrovascular disease, apache acute physiology and chronic health evaluation, saps simplified acute physiology score, sofa sequential organ failure assessment, peep positive end-expiratory pressure *comparison between patients with direct risk factor-associated ards and idiopathic/immune-related ards **comparison among the three groups. italic numbers indicate statistical significance groups. the tat levels were increased in the three groups, but those levels were much lower in iards patients compared with dards patients on day ( . pct levels (marker of infection) on day were increased in the dards and pneumonia patients but were lower than the reference value for infection in patients with iards. however, levels of crp, a widely used marker of inflammation and mechanistically downstream of il- , were not different among the three groups. the markers of type ii pneumocyte injury, sp-d, and kl- were markedly increased in patients with iards compared with those with dards or pneumonia (figs. and ) . to compare the abilities of the plasma biomarkers to distinguish between ards subtypes, we conducted a roc curve analysis to calculate the aucs of biomarkers for coagulation, infection, and pneumocytes ( in this retrospective analysis of ards subtypes, we evaluated the changes in coagulation and alveolar epithelial cell biomarkers over time in patients with iards and dards. tat and pai- levels were increased in patients in both ards subgroups, but a significantly higher increase in those biomarkers were observed in patients with dards. additionally, pc activity decreased in dards, whereas that in iards was normal or even increased. there were also significant differences in pct, sp-d, and kl- levels between the two groups on the day of icu admission. these results suggest that each iards and dards may have its distinct patterns of plasma biomarkers, which could help to differentiate between these ards subgroups. alterations in coagulation and fibrinolytic abnormalities have been observed in animal models of lung injury and in human patients with ards or ild [ ] [ ] [ ] . chambers reported that uncontrolled activation of the coagulation cascade might contribute to the development of fibrosis in both ards and ipf, suggesting that coagulopathy is pivotal as a common pathophysiological factor in these diseases [ ] . in our study, increased coagulation (suggested by increased tat) and suppressed fibrinolysis (suggested by elevated pai- levels) were observed in patients with dards but were less prominent in iards patients. these results are in line with gunther et al.'s study that showed enhanced procoagulant and depressed fibrinolytic capacities were greater in patients with ards than in those with pneumonia or in healthy controls [ , ] . in addition, there were significant differences in coagulation inhibition or the levels of natural anticoagulant between dards and iards. to the best of our knowledge, this is the first study to show differences in the coagulation profile between ards with and without common risk factors, or ards mimics. the pathophysiology accounting for these different coagulopathic patterns has not been identified. one explanation might be that inflammation and coagulopathy fig. changes in coagulation biomarkers during days - in the intensive care unit (icu) for patients with iards, dards, or pneumonia. pt-inr, prothrombin time-international normalized ratio; fdp, fibrin degradation products; tat, thrombin-antithrombin complex; pic, plasmin-α plasmin inhibitor complex; pai- , plasminogen activator inhibitor- . data are expressed as the mean, with the % confidence interval shown by the error bars are relatively limited to the lung in iards, whereas dards is a more systemic disease. although the cause of dards is direct lung injury, indicators of systemic involvement, reflected in the apache ii or sofa scores, were significantly higher in patients with dards compared with those with iards. another possible mechanism might be explained by the different pathological findings of iards and dards. lorente et al. showed that ards patients with dad had higher pt-inr and lower platelet counts than ards patients without dad [ ] . pc activities were within the normal range or even increased in iards patients, whereas those in dards patients remained significantly decreased throughout the observational period. these results are somewhat consistent with the meta-analysis conducted by terpstra et al., which showed that the pc level was decreased in ards and was associated with increased odds for an ards diagnosis [ ] . in the presence of sepsis or ards, anticoagulation pathways, such as the pc system, are impaired because of increased consumption, decreased protein synthesis, extravasation from vessels, and degradation by several proteolytic enzymes. particularly, extravascular leakage resulting from endothelial damage may be the main mechanism during the acute phase [ , ] . decreased pc activity in dards patients, therefore, may reflect systemic endothelial dysfunction. in contrast, bargagli et al. reported that pc activity increased during acute exacerbation of usual ip but was normal in stable usual ip or nsip [ ] . they postulated that increased pc activity was associated with upregulation of the fibrinolytic response to a procoagulant state caused by fibrosis. although the pathophysiological mechanisms of altered pc activity in patients with ards have not been clarified, our findings indicate that the differences in the anticoagulant response to increased coagulation may be useful for distinguishing the ards etiologies. we analyzed idiopathic and immune-related ards within the same category, although these two disorders are classified as having different etiologies. idiopathic interstitial pneumonias (iips) are diffuse inflammatory lung diseases that are grouped together with similar clinical, radiological, and histopathological features. the diagnosis of an iip is based on the exclusion of known causes of ip, such as drugs, environmental exposure, or ctds [ ] . ctd-ilds are the lung manifestation of ctds, where the underlying mechanism is systemic autoimmunity. thus, the diagnosis is based on specific extra-thoracic features of ctds with/without the existence of autoantibodies. recent studies have shown, however, that some patients with ild have certain clinical features that suggest an underlying autoimmune process, although they do not fully meet the diagnostic criteria for any characterizable ctd. the european respiratory society/american thoracic society task force on undifferentiated forms of connective tissue disease-associated interstitial lung disease proposed the term "interstitial pneumonia with autoimmune features" for such diseases [ ] . in our study, approximately % of the idiopathic ards patients were diagnosed as having antisynthetase syndrome without myositis or arthritis and % were positive for anticyclic citrullinated peptide antibody. the biomarker profiles were similar in patients with idiopathic ards and those with immune-related ards, which indicates overlapping pathophysiology of coagulopathy and epithelial injury in these two subsets. sp-d and kl- , which are glycoproteins secreted by type ii alveolar epithelial cells, are widely used as potential surrogate markers of alveolar injury, or alveolitis. the roles of sp-d and kl- are well established for improving diagnostic accuracy, predicting the prognosis, or predicting the risk of acute exacerbation, especially in patients with nsip or ipf [ , , ] . sp-d and kl- are also known to be elevated in ards patients [ , ] , but no published reports have compared the biomarker levels according to different ards etiologies. using data from korea and the usa, park et al. showed that plasma sp-d levels were there were some potential limitations to our study. first, this was a retrospective, observational study conducted at a single center with a relatively small population. a large validation study is needed to confirm our results. second, we could not perform serological tests for non-influenza respiratory viruses, such as the respiratory syncytial virus or human metapneumovirus. although we ruled out the common ards risk factors and known causes of interstitial pneumonia (e.g., drugs, environmental agents, ctds) to diagnose idiopathic ards, we could not completely exclude the possibility of viral infections or environmental antigen exposures, which could subside spontaneously. third, we could perform bal for only about half of iards patients, which may not be generalizable to the whole population. finally, we did not measure the biomarkers in the bal fluid. although systemic markers are easier to obtain and the bal procedure may not always be possible because of the risk of respiratory and hemodynamic complications, the biomarkers in the bal fluid would more specifically reflect the regional pathophysiology in the alveoli. further studies are needed to evaluate the pathogenic processes of these biomarkers from the pulmonary compartment to the circulation. changes in the biomarkers of coagulopathy and alveolar epithelial injury were observed in both patients with dards and with iards, but those biomarker profiles were significantly different between the two groups. pai- and pc activity, as well as pct, sp-d, and kl- , discriminated well between dards and iards on the day of icu admission. these preliminary findings indicate that the biomarker profiles may help to understand the pathogenic processes and improve the prompt differentiation between ards subtypes. additional file : table s . distribution of microorganisms in patients with dards or pneumonia. (docx kb) acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome mimics: the role of lung biopsy acute respiratory distress syndrome without identifiable risk factors: a secondary analysis of the ards network trials acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicenter study rare respiratory diseases in the icu: when to suspect them and specific approaches serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features research statement: interstitial pneumonia with autoimmune features interstitial pneumonia with autoimmune features: an additional risk factor for ards? ann intensive care blood platelets and sepsis pathophysiology: a new therapeutic prospect in critical ill patients? ann intensive care a review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia comparative study of kl- , surfactant protein-a, surfactant protein-d, and monocyte chemoattractant protein- as serum markers for interstitial lung diseases plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis* management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias rheumatoid arthritis classification criteria: an american college of rheumatology/ european league against rheumatism collaborative initiative recent advances in hypersensitivity pneumonitis drugassociated acute lung injury: a population-based cohort study apache ii: a severity of disease classification system a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine acute respiratory distress syndrome and diffuse alveolar damage. new insights on a complex relationship coagulation, fibrinolysis, and fibrin deposition in acute lung injury tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. comparison with the acute respiratory distress syndrome acute respiratory distress syndrome in patients with and without diffuse alveolar damage: an autopsy study decreased plasma activity of antithrombin or protein c is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation decreased antithrombin activity in the early phase of trauma is strongly associated with extravascular leakage, but not with antithrombin consumption: a prospective observational study serum analysis of coagulation factors in ipf and nsip idiopathic pulmonary fibrosis: from epithelial injury to biomarkers--insights from the bench side pneumocyte biomarkers kl- and surfactant protein d reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia pathophysiology and biomarkers of acute respiratory distress syndrome plasma surfactant protein-d as a diagnostic biomarker for acute respiratory distress syndrome: validation in us and korean cohorts we appreciate the assistance of the nursing staff at the intensive care unit at jichi medical university hospital, tochigi, japan. we thank nancy schatken, bs, mt (ascp), and jodi smith, phd, from edanz group (http://www. edanzediting.com/), for editing a draft of this manuscript. authors' contributions kk contributed to the conception and design, data acquisition, analysis and interpretation of the data, and writing and drafting of the manuscript. sk and kt contributed to the patient recruitment, data acquisition, analysis, and review of the manuscript. tk and js helped review the draft manuscript. sn supervised the study and reviewed the manuscript. all authors read and approved the final manuscript. the study was not funded. the dataset generated and/or analyzed during the current study is not publicly available because of patient-related confidentiality, but is available from the corresponding author upon reasonable request. this study was approved by the institutional research ethics committee of jichi medical university. informed consent was waived based on the study's retrospective, observational design, which preserves the confidentiality of personal information. not applicable. the authors declare that they have no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -yp ehpeg authors: zhang, dong; qi, bo-yang; zhu, wei- wei; huang, xiao; wang, xiao-zhi title: crocin alleviates lipopolysaccharide-induced acute respiratory distress syndrome by protecting against glycocalyx damage and suppressing inflammatory signaling pathways date: - - journal: inflamm res doi: . /s - - -z sha: doc_id: cord_uid: yp ehpeg objective: to explore the mechanisms of crocin against glycocalyx damage and inflammatory injury in lipopolysaccharide (lps)-induced acute respiratory distress syndrome (ards) mice and lps-stimulated human umbilical vein endothelial cells (huvecs). methods: mice were randomly divided into control, lps, and crocin + lps ( , , and mg/kg) groups. huvecs were separated into eight groups: control, crocin, matrix metalloproteinase inhibitor (mmp- inhib), cathepsin l inhibitor (ctl inhib), lps, mmp- inhib + lps, ctl inhib + lps, and crocin + lps. the potential cytotoxic effect of crocin on huvecs was mainly evaluated through methylthiazolyldiphenyl-tetrazolium bromide assay. histological changes were assessed via hemotoxylin and eosin staining. lung capillary permeability was detected on the basis of wet–dry ratio and through fluorescein isothiocyanate-albumin assay. then, protein levels were detected through western blot analysis, immunohistochemical staining, and immunofluorescence. results: this study showed that crocin can improve the pulmonary vascular permeability in mice with lps-induced ards and inhibit the inflammatory signaling pathways of high mobility group box, nuclear factor κb, and mitogen-activated protein kinase in vivo and in vitro. crocin also protected against the degradation of endothelial glycocalyx heparan sulfate and syndecan- by inhibiting the expressions of ctl, heparanase, and mmp- in vivo and in vitro. overall, this study revealed the protective effects of crocin on lps-induced ards and elaborated their underlying mechanism. conclusion: crocin alleviated lps-induced ards by protecting against glycocalyx damage and suppressing inflammatory signaling pathways. acute respiratory distress syndrome (ards) is a wellknown disease with high morbidity and mortality. the main features of ards are lung endothelial cell injury, severe inflammatory responses, neutrophil adhesion or infiltration, and interstitial edema [ ] . at present, ards pathogenesis is complicated with lps-mediated sepsis being a common etiology [ ] . endothelial glycocalyx and inflammatory responses are crucial for the pathogenesis of ards. the endothelial glycocalyx, a layer of negatively charged gel-like substance, exists on surfaces of pulmonary vascular endothelial cells. heparan sulfate (hs) and syndecan- (sdc- ) are highly abundant in the glycocalyx [ , ] . the endothelial glycocalyx plays an important role in albumin exudation formation, leukocyte adhesion, and anticoagulation [ ] [ ] [ ] [ ] . however, the glycocalyx undergoes dynamic changes and is susceptible to various factors. enzymes are a key factor in glycocalyx degradation. glasner et al. [ ] reported that heparanase (hpa) and cathepsin l were connected with hs shedding in dengue virus non-structural protein -induced endothelial hyperpermeability. reine et al. [ ] reported that matrix metalloproteinase (mmp- ) was related to the degradation and shedding of sdc- in glomerular endothelial cells. excessive inflammation plays an important role in the development of ards. neutrophils are among the first inflammatory responders against acute bacterial inflammation. however, sepsis can induce changes in the deformation ability of neutrophils in pulmonary capillary and their retention on the surfaces of endothelial cells, thereby increasing the capillary permeability of alveoli and inducing and promoting the production of inflammatory cytokines [ ] . high mobility group box (hmgb- ), nuclear factor κb (nf-κb), and mitogen-activated protein kinase (mapk) signaling pathways are important and common inflammatory signaling pathways in lung injury [ ] [ ] [ ] . activation of the inflammatory signaling pathways promotes the production and release of high levels of pro-and anti-inflammatory factors. imbalance in the pro-and anti-inflammatory internal environment of the body leads to damage to vascular cells, cell dysfunction, adhesion or infiltration of inflammatory cells, and hemodynamic changes. crocin is an ester glycoside extracted from saffron. as one of the main active constituents of saffron, crocin has many pharmacological effects, such as anti-oxidation [ ] , anti-arteriosclerosis [ ] , anti-apoptosis [ ] , and anti-inflammatory [ ] . however, no studies have reported the effects of crocin on endothelial glycocalyx, hmgb- , nf-κb, and mapk signaling pathways in lps-induced ards mice and lps-stimulated huvecs. this study conducted an in-depth analysis of the protective effects and mechanisms of crocin on lps-induced ards. overall, the results of this study may provide a pharmacological basis for crocin in ards treatment. crocin (purity assay of ≥ %) was purchased from shanghai yuanye biological technology co., ltd. methylthiazolyldiphenyl-tetrazolium bromide (mtt), lps, , -diamidino- -phenylindole dihydrochloride (dapi), fluorescein isothiocyanate (fitc)-albumin, and dimethyl-sulfoxide (dmso) were obtained from sigma-aldrich. rabbit monoclonal antibody to hmgb (ab ), nf-κb p (ab ), iκbα (ab ), p-iκbα (ab ), jnk (ab ), erk (ab ), p (ab ), p-erk (ab ), p-jnk (ab ), p-p (ab ), laminb (ab ), mmp- (ab ), hpa (ab ), sdc- (ab ), ly g (ab ), β-actin (ab ), gapdh (ab ), mmp- inhibitor (mmp- inhib, ab ), and fitc (ab ) were acquired from abcam trading company ltd. mouse polyclonal antibody to cathepsin l (ctl) was purchased from santa cruz biotechnology. mouse polyclonal antibody to hs was purchased from ams biotechnology (switzerland, ma). thrombomodulin/bdca- was obtained from r&d systems (usa). hrp-conjugated goat anti-rabbit igg, goat anti-rabbit igg/alexa fluor , and rabbit anti-goat igg/alexa fluor were purchased from beijing biosynthesis biotechnology co., ltd. cathepsin l inhibitor (ctl inhib, cas - - ) was obtained from santa cruz biotechnology. huvecs were purchased from cell line bank (shanghai, china). huvecs were cultured in complete culture medium (allcells, shanghai, china) in an incubator with a humidified atmosphere of % air and % co at °c. cells at - % confluence were used for all assays. mtt assay, also known as mtt colorimetric assay, is a method used to detect cell survival and growth. the potential cytotoxic effect of crocin on huvecs was mainly evaluated by mtt assay. the concentration range of - µmol/l was randomly selected. as shown in fig. f , the concentration of - µmol/l crocin showed slight cytotoxicity to the huvecs. thus, µmol/l was selected as the pretreatment concentration of huvecs. for pretreatment, huvecs were separated into eight groups: control, crocin, mmp- inhibitor (mmp- inhib), ctl inhibitor (ctl inhib), lps, mmp- inhib + lps, ctl inhib + lps, and crocin + lps. in the control group, huvecs were only cultured in the complete culture medium without intervention. in the crocin group, huvecs were cultured in the complete culture medium with µm concentration of crocin. in the mmp- inhib group, huvecs were cultured in the complete culture medium with µm concentration of mmp- inhibitor. in the ctl inhib group, huvecs were cultured in the complete culture medium with µm concentration of ctl inhibitor. in the lps group, huvecs were cultured in the complete culture medium with µg/ml concentration of lps. in the mmp- inhib + lps group, huvecs were pretreated with µm concentration of mmp- inhibitor for h before the lps ( µg/ml) stimulation for h. in the ctl inhib + lps group, huvecs were pretreated with µm concentration of ctl inhibitor for h before the lps ( µg/ml) stimulation for h. in the crocin + lps group, huvecs were pretreated with µm concentration of crocin for h before the lps ( µg/ml) stimulation for h. male mice (c bl/ , - weeks old, weighing - g) were purchased from jinan animal feed center (shandong, china). all mice were housed in plastic cages with ± °c and supplied with clean food and purified water. the use of mice accorded with the national institute of health guide for the care and use of laboratory animals. the experimental mice were assorted into control, lps, and crocin + lps ( , , and mg/kg) groups. the doses and administration form of crocin were derived from the pre-experiments and previous reports [ , ] . the lps group mice were injected intraperitoneally with the lps ( mg/kg) for h to induce ards [ ] . for the crocin + lps groups, crocin at , , or mg/kg was administered intraperitoneally for days prior to intraperitoneal injection of the lps for h. at the same time, the control group mice were treated intraperitoneally with the same volume of normal saline. after anesthetizing with % chloral hydrate, lungs were collected and used for experiments. to assess the effect of crocin on the huvec viability, huvecs were cultured and treated with different concentrations ( - µmol/l, µl /well) of crocin for h and followed by lps stimulation ( µg/ml, µl /well). after h, the mtt ( µl, mg/ml) was added and incubated for h. supernatant was removed, and the formation of formazan was resolved with µl/well of dmso. optical density was measured at nm on a micro-plate reader. intraperitoneal injection of % chloral hydrate was conducted to anesthetize mice. mouse lungs were taken out and immersed in % paraformaldehyde for days. these portions were processed and embedded in paraffin. the lung sections ( µm thickness) were used for hematoxylin and eosin (he) staining. the lung injury score criteria were in accordance with the method described by aeffner et al. [ ] . the characteristics of lung injury were alveolar congestion, hemorrhage, infiltration, aggregation of neutrophils in the airspace or vessel wall, and thickness of the alveolar wall. the lung paraffin sections ( µm thickness) were treated via acetone-benzol dewaxing. then, the lung sections were placed in a microwave box with a certain ph . citrate buffer for the antigen retrieval. after the antigen retrieval, lung sections were washed with pbs and incubated with % h o at room temperature for min to block the activity of endogenous peroxidase. the lung sections were washed again with pbs and incubated with anti-ly g antibody at room temperature for h. then, the lung sections were incubated with secondary antibody and the dab solutions and hematoxylin. immunohistochemical images were observed and photographed with a microscope (olympus bx , japan). wet-dry (w-d) ratio was used as an indicator of lung tissue edema [ ] . intraperitoneal injection of % chloral hydrate was used to anesthetize mice; lungs were removed, washed, blotted dry, weighed to obtain the wet weight, and subsequently placed in an oven at °c for days to gain the dry weight. fitc-albumin osmosis analysis is a common method for measuring lung capillary permeability [ ] . mice were injected intraperitoneally with lps for h, followed by tail vein injection of fitc-albumin ( mg/ml). after h of the fitc-albumin blood circulation, intraperitoneal injection of % chloral hydrate was used to anesthetize mice. the lungs were removed and immersed in % paraformaldehyde for days. these portions were processed and embedded in paraffin and used for fitc-albumin osmosis analysis. after the lung sections had undergone retrieval antigen and purity antigen, the samples were incubated overnight with anti-bdca- and anti-fitc antibodies. the lung sections were washed with pbs ( min/each time) and incubated with fluorescent secondary antibodies for min. after the dapi staining, the lung sections were observed immediately under a fluorescent microscope (olympus, japan). finally, relative quantification of immunofluorescence was conducted by using imagej. to detect the contents of hs, sdc- , and ctl in huvecs, we seeded cells on coverslips in -well plates. after different pretreatments and treatments, the cells were fixed with % paraformaldehyde and permeabilized with . % triton x- . subsequently, the coverslips were incubated in serum blocking solution and then incubated with hs, sdc- , and ctl antibodies to overnight at °c. primary antibody binding was detected by using fitc-conjugated secondary antibodies. the cell nuclei were stained with dapi. finally, images were obtained by using a fluorescence microscope (olympus bx , japan). to detect the levels of hs, sdc- , and ctl in lungs, we deparaffinized, dehydrated, and treated for antigen retrieval in the -µm lung sections, and then, we permeabilized them with . % triton x- . the sections were washed with pbs and incubated with serum blocking solution and then treated with hs, sdc- , and ctl antibodies overnight at °c. thereafter, the sections were washed with pbs and fitc-conjugated secondary antibodies were incubated for min at room temperature. lastly, cell nuclei were stained with dapi. images were obtained by using a fluorescence microscope (olympus bx , japan). intraperitoneal injection of % chloral hydrate was used to anesthetize mice, whose lungs were removed and frozen in liquid nitrogen. the extraction of nuclear and cytoplasmic protein was performed with a protein extraction kit (beyotime, china), and its concentration was determined by the bca protein assay kit (beyotime, china). equal amounts of protein were loaded into each well and separated by % sodium dodecyl sulfate-polyacrylamide gel electrophoresis (sds-page) and transferred to polyvinylidene fluoride (pvdf) membranes. the pvdf membranes were washed by tris-buffered saline with tween (tbst) and incubated with % nonfat milk for h. the pvdf membranes were incubated with primary antibodies (hmgb , nf-κb p , iκbα, p-iκbα, p , p-p , jnk, p-jnk, erk, p-erk, laminb , mmp- , hpa, β-actin, and gapdh) overnight. the pvdf membranes were washed again with tbst and incubated with hrp-conjugated goat anti-rabbit igg at °c for h. the protein band at the pvdf membranes was visualized by the chemical exposure solution. all data are presented as the mean ± standard deviation (sd). the differences between groups were analyzed using student's t test and one-way anova followed by the snk test. p < . was considered to indicate statistical significance. all statistical analyses were performed using spss . (ibm corp.). as shown in fig. b -e, the lung tissues of the control group had complete alveolar structure and almost no neutrophil infiltration. however, the lung tissues of the lps group showed pulmonary congestion and edema, obvious infiltration of neutrophil cells, and alveolar collapse (fig. b-e) . compared with the lps group, lung structural damage and neutrophil infiltration significantly decreased with increased pretreatment concentration of crocin in crocin + lps groups (fig. b-e) . these data indicated that pretreatment with crocin can significantly decrease lung injury in lps-induced ards mice. vascular permeability increase is an important pathological change in ards. to study the effect of crocin on vascular permeability in lps-induced ards mice, lung w-d ratio and fitc-albumins were detected. the lung w-d ratio in the lps group was significantly higher than that of the control group (fig. c) . however, pretreatment with crocin significantly reduced the w-d ratio (fig. c) . the detection of fitc-albumin further indicated that vascular permeability in the lps group was significantly higher than that in the control group, and pretreatment with crocin significantly reduced albumin permeability (fig. a, b) . therefore, pretreatment with crocin can improve pulmonary vascular permeability in lps-induced ards mice. the results in vivo showed that sdc- and hs were significantly abscised after lps stimulation compared with the control group (fig. a-d) . in pretreatment with crocin groups, sdc- and hs abscission were significantly decreased (fig. a-d) . the results in vitro showed that hs and sdc- had no significant difference among the control, crocin, mmp- fig. a , lung permeability was determined by fitc-albumin osmosis analysis (a, magnification × , scale bar µm) and lung w-d ratio (c). b fluorescence intensity analysis of a. all data are presented as means ± sd of three independent experiments. # p < . vs. control group, *p < . vs. lps group inhibitor, and ctl inhibitor groups (fig. e-h) . after lps treatment, hs and sdc- showed significant shedding in vitro (fig. e-h) . pretreatment with mmp- inhibitor significantly reduced the shedding of sdc- but had no effect on the shedding of hs (fig. e-h) . pretreatment with ctl inhibitor significantly reduced the shedding of hs but had no effect on the shedding of sdc- ( fig. e-h) . however, hs and sdc- shedding with pretreatment crocin were significantly reduced (fig. e-h) . the preceding results indicated that crocin protected hs by inhibiting ctl and hpa and protected sdc- by inhibiting mmp- . the in vivo results showed that ctl and hpa were significantly expressed after lps stimulation compared with the control group (fig. a-d) . however, pretreatment with crocin, the expressions of ctl and hpa by lps stimulation were significantly inhibited (fig. a-d) . the results of ctl and hpa in vitro showed no significant difference among the control, crocin, and mmp- inhibitor groups (fig. e, g-i) . however, the expression of ctl and hpa was inhibited in the ctl inhibitor group (fig. e, g-i) . the expressions of ctl and hpa induced by lps were significantly inhibited in pretreatment with the ctl inhibitor group (fig. e, g-i) . after lps stimulation, pretreatment with the mmp- inhibitor had no significant inhibition on the expressions of ctl and hpa. however, pretreatment with ctl inhibitor significantly inhibited the expressions of ctl and hpa by lps stimulation (fig. e, g-i) . the preceding results indicated that crocin might inhibit the expression of hpa by inhibiting the upstream protein of ctl in lps-induced ards mice and lps-stimulated huvecs. the results in vivo showed that the expression of mmp- by lps stimulation was significantly increased compared with that of the control group (fig. c, d) . however, pretreatment with crocin significantly inhibited lps stimulation mmp- expression compared with lps treatment (fig. c, d) . mmp- expression in vitro showed no significant difference among the control, crocin, and ctl inhibitor groups (fig. h, i) . however, mmp- expression was suppressed in the mmp- inhibitor group (fig. h, i) . compared with ctl inhibitor treatment, the pretreatment with mmp- inhibitor significantly inhibited lps-stimulated mmp- expression (fig. h, i) . the preceding results indicated that crocin might protect against sdc- shedding by inhibiting lps-stimulated mmp- expression. mapk signaling pathway plays an important role in regulating the inflammatory response of lung injury. in this study, animal results showed that lps stimulation significantly enhanced the phosphorylation of p , erk, and jnk in lungs compared with the control group (fig. a, c) . pretreatment with crocin inhibited the phosphorylation of p , erk, and jnk, and the effect was more obvious with increased drug concentration (fig. a, c) . similarly, cell results showed that only crocin had no effect on the mapk signaling pathway compared with the control group. however, the significant phosphorylation of p , erk, and jnk was observed after lps stimulation (fig. b, d) . pretreatment with crocin inhibited the phosphorylation of p , erk, and jnk (fig. b, d) . these results suggested that crocin can inhibit the activation of mapk pathway in lps-induced ards mice and lps-stimulated huvecs. the hmgb and nf-κb signaling pathway also regulate lung injury of the inflammatory process. results in lungs showed that lps stimulation significantly enhanced iκbα phosphorylation, nf-κb p nuclear transfer, and hmgb cytoplasmic transfer compared with that of the control group (fig. a, c) . pretreatment with crocin can inhibit iκbα phosphorylation, nf-κb p nuclear transfer, and hmgb cytoplasmic transfer compared with that of the lps group (fig. a, c) . the inhibitory effect was more obvious with increased drug concentration (fig. a, c) . fig. effects of crocin on sdc- and hs in lps-induced ards mice and lps-stimulated huvecs. following the process shown in fig. a , immunofluorescence images of sdc- in mice (a) and huvecs (e) (magnification × , scale bar µm). g, b fluorescence intensity analysis of e, a, respectively. immunofluorescence images of hs in mice (c) and huvecs (f) (magnification × , scale bar µm). h, d fluorescence intensity analysis of f, c, respectively. all data are presented as means ± sd of three independent experiments. # p < . vs. control group, *p < . vs. lps group ◂ likewise, the results of cell experiments showed no significant changes in the crocin and control groups. however, lps stimulation significantly increased iκbα phosphorylation, nf-κb p nuclear transfer, and hmgb cytoplasmic transfer (fig. b, d) . pretreatment with crocin significantly inhibited iκbα phosphorylation, nf-κb p nuclear transfer, and hmgb cytoplasmic transfer (fig. b, d) . these results suggested that crocin can inhibit the activation of the nf-κb and hmgb inflammatory pathway in lps-induced ards mice and lps-stimulated huvecs. increased vascular permeability is one of the important pathological features of ards. the pulmonary edema associated with albumin leakage is closely related to the endothelial glycocalyx degradation [ ] . the endothelial glycocalyx acts not only as a physical barrier to prevent albumin exudation but also as an information molecule to fig. effects of crocin on ctl and hpa, mmp- in lps-induced ards mice and lps-stimulated huvecs. following the process shown in fig. a , the expression levels of ctl (a) and hpa, mmp- (c) in mice were detected (a, magnification × , scale bar: µm). d, b protein intensity analysis of c, a, respectively. the effect of crocin on cytotoxicity in huvecs was determined by mtt assay (f). the expression levels of ctl (e) and hpa, mmp- (h) in huvecs were detected (a, magnification × , scale bar µm). i, g protein intensity analysis of h, e, respectively. all data are presented as means ± sd of three independent experiments. # p < . vs. control group, *p < . vs. lps group ◂ fig. effects of crocin on mapk pathway activation in lps-induced ards mice and lps-stimulated huvecs. following the process shown in fig. a , the levels of phosphorylation and non-phosphorylation of p , erk, and jnk in lung tissues (a) and huvecs (b) were detected by western blot. c, d protein quantification of a, b, respectively. gapdh was used as internal control. all data are presented as means ± sd of three independent experiments. # p < . vs. control group, *p < . vs. lps group participate in hemodynamics [ ] [ ] [ ] [ ] ] . as shown in previous reports, crocin had an important protective effects in several diseases by affecting on cell apoptosis, arteriosclerosis, oxidation, and inflammation [ ] [ ] [ ] [ ] [ ] . the present study demonstrated that pretreatment with crocin effectively improved the pulmonary edema associated with albumin leakage by maintaining the integrity of glycocalyx in lps-induced ards mice. to our knowledge, this study is the first to reveal its protective effects and mechanisms of the endothelial glycocalyx. enzymatic degradation had been found to be involved in the endothelial glycocalyx degradation. as shown in previous reports, mmp- can directly cause the shedding of sdc- in lung endothelial cells or sdc- in glomerular endothelial cells [ , ] . additionally, ramani et al. [ ] found that the enzymatic hydrolysis of hs chain can promote sdc- shedding in the cell lines cag, thereby indicating that non-mmp mechanism is also involved in the process of sdc- shedding. in the present study, cathepsin l inhibitor did not alleviate lps-mediated sdc- fig. effects of crocin on hmgb and nf-κb pathway activation in lps-induced ards mice and lps-stimulated huvecs. following the process shown in fig. a , the levels of hmgb and nf-κb p as well as the phosphorylation and non-phosphorylation of iκbα in lung tissues (a) and huvecs (b) were detected by western blot. c, d protein quantification of a, b, respectively. gapdh or lamin b was used as internal control. all data are presented as means ± sd of three independent experiments. # p < . vs. control group, *p < . vs. lps group shedding, thereby suggesting that non-mmp mechanisms may not be involved in sdc- shedding. more importantly, the inhibition of mmp- expression by pretreatment with crocin is closely related to the reduction in sdc- shedding, and the inhibition of cathepsin l and hpa expression by pretreatment with crocin is closely related to the reduction in hs shedding. nf-κb and mapk are representative and important inflammatory pathways in the onset and development of ards pathogenesis, and they promote the production and secretion of inflammatory cytokines after activation [ , ] . otherwise, hmgb- as an important late inflammatory factor can trigger the intracellular nf-κb signaling pathway and aggravate serious injury [ ] . as shown in previous reports, crocin had a strong anti-inflammatory effect in diabetic nephropathy model [ ] . the results of this study also showed that crocin had the same strong anti-inflammatory effect in lps-induced ards cell and animal models. however, inflammatory injury also induces the production and release of glycocalyx shedding factors (such as mmp- and hpa) [ , ] . an incomplete glycocalyx may aggravate the inflammatory reaction and further spread inflammatory factors, resulting in persistent lung injury [ , ] . the present study showed that pretreatment with crocin effectively reduced glycocalyx damage, and this protective effect may be related to inhibiting the activation of inflammatory pathways. during the ards process, activated neutrophils release intracellular toxic components so as to amplify the inflammatory response by recruiting more inflammatory cells into the site of damage [ ] . additionally, ma et al. [ ] reported that neutrophils were involved in regulating the microvascular endothelial permeability. suzuki et al. [ ] reported that neutrophil elastase damaged the pulmonary endothelial glycocalyx in lps-induced endotoxemia. in the present study, pretreatment with crocin significantly improved the neutrophil adhesion or infiltration induced by lps in ards mice. the ability of crocin to alleviate glycocalyx damage may be closely related to the reduction in neutrophil retention. oxidative damage is another important factor in the pathogenesis of ards. oxidation/antioxidant imbalance can aggravate oxidative damage to tissues and cells [ ] . previous study reported that reactive oxygen species can damage the endothelial glycocalyx of the kidneys and lungs and modulate hpa expression of glomerular adriamycin nephropathy [ , ] . additionally, crocin has been reported to improve methotrexin-induced liver injury by inhibiting oxidative stress in rats [ ] . however, further studies are needed to determine whether crocin's protective effect on glycocalyx degradation of lps-induced ards mice and lps-stimulated huvecs is also related to oxidative injury. interestingly, how to repair the damaged endothelial glycocalyx is another important topic in the study of endothelial glycocalyx [ , ] . the present study did not involve how the endothelial glycocalyx was repaired, and further studies are needed to determine whether crocin promotes the repair of the endothelial glycocalyx. the full story is still incomplete. given the limitations of laboratory conditions, the pharmacokinetic and hemodynamic changes in mice were not analyzed in the present study. the complete analysis of the pharmacokinetic and hemodynamic changes in mice will provide additional insights into crocin and endothelial glycocalyx. overall, the present study demonstrated that crocin can protect against hs and sdc- degradation by inhibiting enzyme expression. enzyme inhibition may be related to the decrease in inflammatory responses or oxidative damage. these findings add new pharmacological functions to crocin, providing potential targets for new therapies to inhibit enzymes and potential pathways that lead to endothelial dysfunction and vascular leakage in ards, which may contribute to the treatment of this disease. β -na(+), k(+)-atpase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury , , '-tri-o-acetylresveratrol attenuates lipopolysaccharide-induced acute respiratory distress syndrome via mapk/sirt pathway. mediators inflamm fibroblast growth factor signaling mediates pulmonary endothelial glycocalyx reconstitution shedding of syndecan- promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice glycocalyx degradation induces a proinflammatory phenotype and increased leukocyte adhesion in cultured endothelial cells under flow role of the endothelial surface layer in neutrophil recruitment protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis the endothelial glycocalyx: an important regulator of the pulmonary vascular barrier dengue virus ns cytokine-independent vascular leak is dependent on endothelial glycocalyx components matrix metalloproteinase- mediated shedding of syndecan- in glomerular endothelial cells mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries propofol protects lung endothelial barrier function by suppression of high-mobility group box (hmgb ) release and mitochondrial oxidative damage catalyzed by hmgb effects of ceftaroline on the innate immune and on the inflammatory responses of bronchial epithelial cells exposed to cigarette smoke p /mapk contributes to endothelial barrier dysfunction via map phosphorylation-dependent microtubule disassembly in inflammation-induced acute lung injury evidence of crocin against endothelial injury induced by hydrogen peroxide in vitro antihyperlipidemic effect of crocin isolated from the fructus of gardenia jasminoides and its metabolite crocetin crocin protects against dexamethasone-induced osteoblast apoptosis by inhibiting the ros/ca + -mediated mitochondrial pathway crocin protects podocytes against oxidative stress and inflammation induced by high glucose through inhibition of nf-κb crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of nrf antioxidant system in preventing oxidative stress antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in lps-induced ards mouse models of acute respiratory distress syndrome: a review of analytical approaches, pathologic features, and common measurements alkannin attenuates lipopolysaccharide-induced lung injury in mice via rho/rock/ nf-κb pathway control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics endothelin- induces proteinuria by heparanase-mediated disruption of the glomerular glycocalyx the signaling mechanisms of syndecan heparan sulfate proteoglycans heparan sulfate chains of syndecan- regulate ectodomain shedding every cloud has a silver lining: proneurogenic effects of aβ oligomers and hmgb- via activation of the rage-nf-κb axis modulation of hmgb translocation and rage/nfκb cascade by quercetin treatment mitigates atopic dermatitis in nc/nga transgenic mice modulation of endothelial glycocalyx structure under inflammatory conditions the pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis glycocalyx and sepsis-induced alterations in vascular permeability a high admission syndecan- level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein c depletion, fibrinolysis, and increased mortality in trauma patients propensity of crocin to offset vipera russelli venom induced oxidative stress mediated neutrophil apoptosis: a biochemical insight role of neutrophil extracellular traps and vesicles in regulating vascular endothelial permeability neutrophil elastase damages the pulmonary endothelial glycocalyx in lipopolysaccharide-induced experimental endotoxemia lycium barbarum polysaccharide protects against lps-induced ards by inhibiting apoptosis, oxidative stress, and inflammation in pulmonary endothelial cells heparan sulfates mediate pressure-induced increase in lung endothelial hydraulic conductivity via nitric oxide/reactive oxygen species induction of glomerular heparanase expression in rats with adriamycin nephropathy is regulated by reactive oxygen species and the renin-angiotensin system crocin ameliorates methotrexate-induced liver injury via inhibition of oxidative stress and inflammation in rats therapeutic restoration of endothelial glycocalyx in sepsis acknowledgements this work was supported by funding from the national natural science foundation of china (no.: ). the authors declare no conflict of interest. key: cord- -x q f authors: pottecher, julien; noll, eric; borel, marie; audibert, gérard; gette, sébastien; meyer, christian; gaertner, elisabeth; legros, vincent; carapito, raphaël; uring-lambert, béatrice; sauleau, erik; land, walter g.; bahram, seiamak; meyer, alain; geny, bernard; diemunsch, pierre title: protocol for traumadornase: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: x q f background: acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. the incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the berlin definition, could be as high as %. its pathophysiology includes the release of damage-associated molecular patterns (damps), which propagate tissue injuries by triggering neutrophil extracellular traps (nets). nets include a dna backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. the structure of nets and many damps includes double-stranded dna, which prevents their neutralization by plasma. dornase alfa is a us food and drug administration-approved recombinant dnase, which cleaves extracellular dna and may therefore break up the backbone of nets and damps. aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. methods: traumadornase will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. the primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first days from % to % by providing aerosolized dornase alfa as compared to placebo. the secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. randomization of patients per treatment arm will be carried out through a secure, web-based system. statistical analyses will include a descriptive step and an inferential step using fully bayesian techniques. the study was approved by both the agence nationale de la sécurité du médicament et des produits de santé (ansm, on october ) and a national institutional review board (cpp, on november ). participant recruitment began in march . results will be published in international peer-reviewed medical journals. discussion: if early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. this treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. trial registration: clinicaltrials.gov, nct . registered on december . aerogen (ireland) will provide nebulizers to study centres at an estimated value of k€. after validation from its scientific committee, the traumadornase study is supported by a k€ grant from the french ministry of health (phrci- -s ). severe trauma remains a major socio-economic burden worldwide [ , ] . indeed, it is the third cause of fatality overall, the first cause of fatality and invalidity in the - age group and the first cause of disabilityadjusted life years (dalys). aside from civilian and military trauma cases, terrorist attacks have added new threats [ ] . while the first peak of trauma-associated mortality happens within the very first hours from exsanguination and severe central nervous system injuries, secondary deaths are triggered by multi-organ failure (mof) and acute respiratory distress syndrome (ards) in the intensive care unit (icu) [ ] . the taxonomy of ards was recently refined by the last berlin definition [ ] , which also distinguished three levels of increasing hypoxaemia severity (mild/moderate/ severe) based on the ratio of partial arterial oxygen tension (pao ) over inspired oxygen fraction (fio ). patients who develop moderate-to-severe ards in the icu have a worse prognosis compared to mild ards patients, including increased mortality rates ( % vs. %), impaired functional recovery, compromised quality of life and cognitive dysfunction [ ] . severe trauma definitely remains a significant risk factor for hypoxaemia, implicating both direct and indirect lung injuries [ ] . notwithstanding improvements in prehospital care, resuscitation and mechanical ventilation, the incidence of hypoxaemia in trauma patients has remained consistently high during the last years [ ] [ ] [ ] [ ] . in the most severely injured trauma patients (injury severity score (iss) [ ] above ) requiring blood transfusion, the incidence of hypoxaemia may exceed %. indeed, a recent analysis of the prommtt registry underlines that the incidence of moderate-to-severe hypoxaemia could be as high as % [ ] . in trauma patients, ards increases the duration of mechanical ventilation, icu and hospital lengths of stay, incidence of ventilation-acquired pneumonias, healthcare-associated costs and mortality [ ] . pathophysiology of trauma-associated hypoxaemia and acute respiratory distress syndrome as previously stated [ ] , severe trauma may contribute to hypoxaemia by both direct injuries (lung contusion, aspiration) and indirect injuries (non-thoracic trauma, musculoskeletal injuries, haemorrhagic shock, transfusionassociated acute lung injury [ , ] ). whatever the mechanism implicated, inflammation is a key player [ ] [ ] [ ] . indeed, tissue injury triggers a massive and short-lived release of damage-associated molecular patterns (damps) [ ] , which bind both toll-like receptors (tlrs) [ ] and receptors for advanced glycation end products (rage) [ , ] , which recruit and activate neutrophils, resulting in a widespread systemic inflammatory response [ ] . the molecular structure of damps is diverse but the most potent are made of double-stranded dna [ ] , either fully (e.g. mitochondrial dna [ ] [ ] [ ] ) or partly (e.g. nucleosomes [ ] , high mobility group box- (hmgb ), heat shock proteins (hsp)). once bound to neutrophils, damps induce profound conformational changes in these cells (netosis), which trigger both non-self pathogen killing [ ] and self tissue injury [ , ] . indeed, netosis refers to the release of neutrophil extracellular traps (nets), composed of a backbone (decondensed chromatin fibres) coated with antimicrobial granular and cytoplasmic proteins, such as myeloperoxidase, neutrophil elastase (ne) and αdefensins [ , ] . the detrimental effects of excessive net release are particularly important to ards, because nets can expand more easily in the pulmonary alveoli, causing extensive lung injury [ ] and hypoxaemia. moreover, while unbound ne is usually rapidly inactivated when released into plasma, dna-bound ne is protected from neutralization by plasma [ ] . double-stranded dna thus constitutes the backbone of both damps and nets, and prevents nets from plasma neutralization. extracellular dna is physiologically broken up by endogenous deoxyribonucleases (dnases [ , ] ), which may become overwhelmed by a massive influx of both damps and nets. this is exacerbated as the activity of endogenous dnases is reduced in severe trauma patients ( . ± . u/ml) compared to healthy controls ( . ± . u/ml; p < . [ ] ). however, an fda-approved recombinant dnase has been commercially available since (dornase alfa, pulmozyme; roche, basel, switzerland and genentech, san francisco, ca, usa) and prescribed for the treatment of pulmonary exacerbations in cystic fibrosis patients. as dornase alfa is usually administered via the intratracheal route (aerosols), its biological actions and pharmacokinetic properties could be an excellent prerequisite for a clinical breakthrough in trauma-induced hypoxaemia. indeed, dornase alfa was shown to reduce trauma-induced lung injury in mice [ ] , to fight against sepsis-induced ards [ , ] and to reduce mechanical ventilation-induced lung injury [ ] , which are traditional "second hits" for lung damage in ventilated trauma patients. in a small, randomized clinical trial, aerosolized dornase alfa was also shown to improve oxygenation in mechanically ventilated icu patients with lobar atelectasis [ ] . the primary objective of the traumadornase study is to demonstrate a reduction in the incidence of moderateto-severe hypoxaemia from % to % in severe trauma patients during the first icu days by providing aerosolized dornase alfa once during the first icu days as compared to equivalent provision of placebo (nacl . %). the secondary objectives are to demonstrate, using aerosolized dornase alfa as compared to placebo, an improvement in static lung compliance, a reduction in mechanical ventilation duration or an increase in ventilation-free icu days, a reduction in the length of icu stay, a reduction in the hospital length of stay, a reduction in the incidence of multi-organ failure, a reduction in the incidence of ventilator-associated pneumonia (vap) and a reduction in mortality at day . this will be an investigator-initiated, institution-led, multicentre, double-blinded, placebo-controlled, parallel-group, superiority, randomized trial in ventilated, trauma icu patients. randomization will be carried out through a secure web-based randomization system, stratified by the centre and the presence of severe traumatic brain injury (glasgow coma score < on scene). the study will be conducted in seven french participating hospitals, both university-affiliated and non-universityaffiliated. inclusion criteria will be checked before inclusion in the study. the inclusion criteria are as follows: the exclusion criteria are as follows: pregnancy or breast-feeding opposition from the patient or his/her relatives protected major (guardianship) contraindication to the use of dornase alfa known intolerance to dornase alfa patient whose life expectancy is less than h, according to the treating physician "do not resuscitate" order who will take informed consent? { a} inclusion will be feasible after patient approval, relative approval or emergency consent procedure (according to french law [ ] ). subsequent confirmation of consent will be obtained from the relatives and from the patient as soon as possible. the consent forms are available from the corresponding author on request. after primary haemostasis and emergent surgical interventions, patients will be randomized in the icu within h. in the case of emergent surgical intervention before icu admission, a maximum delay of h will be tolerated from hospital admission (trauma bay) to study drug administration. day will be considered the day of icu admission. additional consent will be required for the collection of biological specimens in ancillary studies, which will be stored for a maximum duration of years. the comparator will be normal saline (nacl . %, . ml, administered through the aerogen solo device). nacl is neutral regarding damps, nets and occurrence of either hypoxaemia or ards, and therefore is considered a placebo. treatment with either dornase alfa or placebo will be administered using aerosol (aerogen solo) in the ventilation circuit once per day (average treatment length: min) for the first days. the aerogen device was shown to optimize dornase alfa deposition in the distal lung airways [ , ] . dornase alfa has an excellent safety profile and aerosolized nacl . % has a neutral effect on lung physiology. the variables under study will be gathered every day and recorded on the electronic clinical research form (cleanweb; telemedicine technologies s.a.s., boulogne billancourt, france). for safety purposes, patient variables will be closely monitored before, during and within the first postadministration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. during the first days, at least one blood gas analysis and chest x-ray will be performed every day at : a.m. to compute the primary endpoint: presence or absence of ards and severity of hypoxaemia according to the berlin definition. additional blood gas analysis will be allowed and the worst daily pao /fio ratio will be considered. on days , and , additional blood samples ( ml on each day) will be drawn into edta tubes, centrifuged and stored (− °c) for subsequent analysis of damps (mitochondrial dna by qpcr; hmgb , hsp and srage by elisa) at the end of enrolment. whole blood samples will be drawn (days , and ) for extemporaneous quantification of nets on fresh blood using a flow cytometric assay [ ] in patients at the strasbourg centre. in the case of an adverse event following treatment administration (desaturation, bronchospasm, anaphylactic reaction), treatment will be immediately discontinued and the second treatment dose will not be given on day . in each centre, boxes containing both full and empty treatment vials will be returned to the pharmacy responsible for clinical studies. for every included patient, a sheet will be completed (date, hour, nurse in charge) and signed for every study treatment preparation, administration and clinical surveillance. for safety purposes, patient variables will be closely monitored before, during and within the first postadministration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. at least one blood gas analysis and chest x-ray will be performed every day at : a.m. to compute the primary endpoint: presence or absence of ards and severity of hypoxaemia according to the berlin definition. additional blood gas analysis will be allowed and the worst daily pao /fio ratio will be taken into account. daily care for the included patients will be protocolized according to good clinical practices, especially concerning respiratory care (semi-recumbent position, protective mechanical ventilation ( - ml/kg predicted body weight), peep > cmh o, plateau pressure < cmh o, close tracheal cuff pressure monitoring, early enteral feeding ( ml on day ), glucose control and protocolized sedation based on both cpot and rass scores [ ] ). adherence to guidelines will be checked in every centre for every patient. patients will be followed until day for the record of study outcomes. every concomitant care will be allowed except aerosols during study drug administration. post-trial care is not planned. patients who suffer harm from trial participation will be cared for in the intensive care unit. should prejudice linked to study participation occur, financial compensation will be provided by the insurance (société hospitalière d'assurances mutuelles-sham, rue edouard rochet, , lyon cedex , france; contract number: . ) contracted by the promotor (hôpitaux universitaires de strasbourg). at months, the respiratory status will be assessed using the modified mrc dyspnoea questionnaire [ , ] and a chest x-ray. the primary endpoint will be the incidence of moderate-to-severe hypoxaemia (pao /fio < , according to the berlin definition [ ] ) in severe trauma patients (iss > ) during the first icu days. the pao /fio ratio will be computed at least once daily ( : a.m.) together with the supine chest x-ray and the worst daily pao /fio value will be taken into account to define hypoxaemia severity. in ards patients, the severity of hypoxaemia allows for its classification according to the berlin definition and is strongly associated with mortality, length of recovery and quality of life [ , ] . the following secondary endpoints will be recorded: static lung compliance (ml/cmh o) (measured at least once daily at : a.m. during the first days) duration of mechanical ventilation (h) from icu admission to first extubation success (> h without reintubation) length of icu stay (h) length of stay in the hospital (days) incidence of multi-organ failure (a sofa score of or more in at least two organ systems [ ] ), assessed daily during the first days incidence of vap according to both the american thoracic society (ats) [ ] and the center for disease control and prevention (cdc) [ ] definitions, assessed daily during the first days the effects of dornase alfa and normal saline will be assessed according to the plasma concentrations of damps (mitochondrial dna, hmgb- , hsp , srage) and nets (strasbourg centre only) divided into quartiles at day , day and day . it is anticipated that trauma patients with the highest blood concentrations of either damps or nets will develop the most severe complications (including hypoxaemia and ards). the time course of damp and net blood concentrations will also be analysed according to treatment group to unveil a potential quicker decrease in patients randomized in the dornase alfa group. the total duration of participation in the study will be days. the forecast study duration is months from first to last patient recruitment (table ) . the sample size was determined to be subjects per arm (i.e. subjects in total). dornase alfa is expected to reduce the incidence of moderate-to-severe hypoxaemia from . to . . considering a reasonable standard deviation of . , and using bayesian techniques [ ] , subjects per arm were estimated to show a difference of more than . (instead of the expected . ). clinical examination includes physical examination (auscultation of the chest, central body temperature, positive end-expiratory pressure and inspired oxygen fraction levels) and recording of utstein criteria [ ] b diagnostic tests include arterial blood gases, chest x-ray, leukocyte and platelet counts, creatinine, blood urea nitrogen, bilirubin and quantitative lung bacteriologic samplings (bronchoalveolar lavage fluid or protected specimen brush) in the case of suspected lung infection c blood withdrawal: ml of blood on day , day and day d study treatment will be given on day and day assuming % loss to follow-up, this number was increased to subjects per arm, although these subjects will not be replaced. patients will be recruited in seven french participating hospitals, both university-affiliated and non-universityaffiliated and admitting severe trauma patients: taken as a whole, more than patients per year fulfil the inclusion criteria, allowing for an inclusion ratio of one patient included out of seven patients admitted to one of the participating centres. randomization will be conducted over a dedicated, password-protected, ssl-encrypted website (cleanweb; telemedicine technologies s.a.s.) to allow immediate and concealed allocation. allocation will also be stratified by centre and the presence of severe traumatic brain injury (glasgow coma score < on scene). the experimental study drug and placebo will be provided in identical boxes, allowing double-blind administration. the logistics of the trial fluid distribution to each of the seven participating centres that are anticipated to be recruiting will be coordinated by the pharmacy of the coordinating centre (hôpitaux universitaires de strasbourg). the allocation sequence will be computer-generated (cleanweb; telemedicine technologies s.a.s.). patients will be enrolled by registered investigators, who will also assign patients to a treatment consisting of either dornase alfa or placebo. trial participants, care providers, outcome assessors and data analysts will remain blinded after assignment to interventions, until the final analysis. unblinding is permissible whenever an adverse event occurs, via immediate request to the poison centre of the study coordinator hospital (hôpitaux universitaires de strasbourg) h per day and days per year. the procedure for revealing a participant's allocated intervention during the trial includes an explicit mention in the patient record. clinical research associates will ensure that patient inclusion, data collection, registry and rapport are in line with the protocol, and that the study is conducted in accordance with the good clinical practice guidelines. furthermore, clinical research associates will check the following variables: patient initials, date of birth, sex, signed consent form, eligibility criteria, date of randomization, treatment assignment, adverse events and study endpoints. the data monitoring committee is institution-based and independent from potential industrial sponsors. a dedicated card will be given to any included patient and participation in the traumadornase trial will be explicitly mentioned during transfer to another ward or hospital during handovers. data will be collected in each centre by clinical data technicians on an electronic case report form (cleanweb; telemedicine technologies s.a.s.) using double password-protected computers. pre-specified lists, range of values and drop-down menus in the electronic case report form will facilitate data entry and prevent writing errors. study documents will be deidentified, stored in each recruitment centre and kept for at least years in a locked, secure office, according to french law. all personnel involved in data analysis will be masked. only the principal investigators and the statisticians will have access to the final data set. people with direct access to the data will take all necessary precautions to maintain confidentiality. all data collected during the study will be rendered anonymous. only initials and inclusion number will be registered. plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use { } on days , and , additional blood samples ( ml on each day) will be drawn into edta tubes, centrifuged and stored (− °c) for subsequent analysis of damps (mitochondrial dna by qpcr; hmgb , hsp and srage by elisa) at the end of enrolment. in patients included in the strasbourg centre, whole blood samples will be drawn (days , and ) for extemporaneous quantification of nets on fresh blood using a flow cytometric assay [ ] . the remaining biological specimens will be stored in . -ml aliquots at "biomax" biobank, statistical analyses will include a descriptive step and an inferential step using fully bayesian techniques. the estimates will use markov chains to monte carlo integrations (mcmc), choosing prior distributions to be nearly conjugated situations. unless the diagnoses for convergence give clues to the contrary, we will use three markov chains with separated starting points, a burn-in of , for each chain and , more iterations with a thinning of for building a total sample of , iterations on which the monte carlo integrations are used to retrieve characteristics of posterior distributions. the analyses will be carried out using r software (with ad hoc packages) and openbugs. sensitivity analyses will be systematically conducted, considering three scenarios with different priors: a default non-informative prior (e.g. jeffreys prior), then an optimist prior and, finally, a pessimist prior. in the descriptive step, all of the variables collected will be summarized: number and frequency for qualitative variables (ordinal and categorical) and minimum, quantiles ( . , , , and . ), maximum, mean and standard deviation for quantitative variables (discrete and continuous). for variables gathered over time, these descriptions will be provided globally and at each time. this description will be enriched by inference to extrapolate the observed quantities on the sample. for quantitative variables, we will assume a normal likelihood combined with a normal prior on the mean (mean and variance ) and γ on the precision (inverse of variance) with parameters . and . , and therefore mean . and variance . for binary variables (for which one proportion needs to be estimated), we will assume a binomial likelihood and a β prior on the proportion (jeffreys prior with parameters . and . , and thus mean . and variance . ). for categorical variables with more than two categories, we will assume a categorical likelihood together with a dirichlet prior (jeffreys prior with all parameters at . ). the aim of this study is to show that the frequency of moderate-to-severe hypoxaemia is lower in the dornase alpha group than in the placebo group. the main variable is then dichotomous "moderate-to-severe hypoxaemia yes/no", modelled in a logistic mixed regression. we will assume that this variable is bernoulli distributed with parameter π. the logit of this parameter (linear predictor) is additively written as: where: α is a grand mean, with mean normal prior (the variance in this normal is , corresponding to a low informative prior) i(g i = ) is a dummy covariate coded for the group of subject i ( for the dornase alpha group and for the placebo group)the prior on the parameter of this covariate is the same normal as that for the grand mean β i is a (random) subject effect, on which is assumed a normal prior with mean and low variance (e.g. ) because the linear predictor is on the logit scale, the probability for moderate-to-severe hypoxaemia will be obtained by monitoring the back-transformation of the logit. this regression model without covariates except group will be completed for taking into account potential confounding variables. in the model, the entire set of these variables will be added and, secondly, selected using stochastic search variable selection (ssvs) [ ] . in such a model, the prior distribution on each parameter is a mixture of two mean normal distributions, one with low variance and the other with high variance: if the posterior weight on this second normal is strongly around , then the prior on the parameter is essentially driven by a normal distribution whose mean is centred on ; this is the clue for a "non-significant" parameter. the secondary analyses will be conducted as the main analysis with a regressive model, testing the difference of a parameter between the two groups. only the likelihood model will be changed to take into account the type of variable studied: γ distribution for continuous variables such as length of stay and duration of ventilation. dichotomous variables such as -day mortality will be studied with logistic regression. no statistical procedure for replacing missing values will be used. all variables and subjects will be considered in the descriptive analyses, but, for inference, % missing data or more will result in rejection of the variable or individual. an interim analysis will be performed after inclusion of the first patients. these preliminary data will be available to the data safety and monitoring board (see later for details), which will have the ability to stop the trial for either futility or harm. analyses will be performed in intention to treat. to verify the impact of possible deviations from the protocol, these analyses will be supplemented by an analysis per protocol. subgroup analyses will be conducted according to the glasgow coma scale on site (score either ≤ or > ). methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data { c} no statistical procedure for replacing missing values will be used. all variables and subjects will be considered in the descriptive analyses, but, for inference, % missing data or more will result in rejection of the variable or individual. plans to give access to the full protocol, participant-level data and statistical code { c} the protocol is available on the clinicaltrials.gov website (https://clinicaltrials.gov/ct /show/nct ?term= traumadornase&draw= &rank= ). study documents will be de-identified, stored in each recruitment centre and kept for at least years in a locked, secure office, according to french law. all personnel involved in data analysis will be masked. only the principal investigators and the statisticians will have access to the final data set. composition of the data monitoring committee, its role and reporting structure { a} the data safety and monitoring board (dsmb) will include dr laure peyro-saint paul (drug monitoring specialist), prof. bernard asselain (methodologist and biostatistician), prof. catherine paugam-burtz (anaesthesiologist and intensive care physician), prof. samir jaber (anaesthesiologist and intensive care physician) and prof. boris jung (intensive care physician). the dsmb, independent from the study sponsor and principal investigator, including three intensive care physicians, one methodologist and one drug safety specialist, will meet after inclusion of the first patients to assess the safety of dornase alfa administration in ventilated trauma patients. the safety variables under study are detailed in the "interventions" section. the dsmb will meet subsequently after further incremental inclusions of patients. the dsmb charter was signed by all of its members. adverse events and unintended effects of the trial intervention or trial conduct will be declared to the promotor within h of occurrence. moreover, the dsmb will meet after inclusion of the first patients to assess the safety of dornase alfa administration in ventilated trauma patients. the safety variables under study are detailed in the following. for safety purposes, patient variables will be closely monitored before, during and within the first post-administration hour: lowest spo , maximal value and maximal increase in peak inspiratory airway pressure, maximal value and maximal increase in plateau airway pressure, extreme values of heart rate and mean arterial pressure, skin erythema, urticaria and variations in central temperature exceeding °c. the dsmb will meet subsequently after further incremental inclusions of patients. in every centre, an audit will be performed by the direction de la recherche clinique des hôpitaux universitaires de strasbourg after inclusion of the first patient, then yearly and after enrolment of the last patient. plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) { } important protocol modifications will be communicated to investigators, irb and trial registries via e-mail. every protocol amendment will be first submitted to the irb and, after validation, transmitted to investigating centres, which will acknowledge receipt. the results of the study will be released to the participating physicians, referring physicians and medical community no later than year after the completion of the trial, through presentation at scientific conferences and publication in peer-reviewed journals. eligible authors will meet all four requirements of the icmje guidelines: substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data for the work drafting the work or revising it critically for important intellectual content final approval of the version to be published agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved to the best of our knowledge, traumadornase is the first large-scale study to evaluate the usefulness of inhaled dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in a population of severe trauma patients, who will also benefit from other lung-protective measures. the benefits are expected to include a reduction in both duration of mechanical ventilation and stay in the icu, lower costs of hospital stay, fewer days on mechanical ventilation and a reduction in the selective pressure on multidrug-resistant bacteria. in order to keep management practices as standardized as possible, we decided to limit the number of investigating centres to seven university-affiliated and non university-affiliated hospitals, all of which are recognized in the field of trauma care and treat more than severe trauma patients per year. these centres belong to the traumabase network (www.traumabase.eu), which promotes multicentre clinical research on trauma and ensures consistent recording of clinical data according to the traumabase registry guidelines. these seven centres also share the same standards of care and, except for pitié-salpêtrière centre, belong to the same region of france (grand est). from a translational point of view, the study will challenge the hypothesis that breaking up the doublestranded dna backbone of both damps and nets with dornase alfa may reduce inflammation and netinduced epithelial and endothelial cell injuries in the lungs of trauma patients. dornase alfa is a long-standingfda-approved mucolytic agent used in cystic fibrosis patients. its safety profile and limited side effects make it an appropriate candidate to curb damp-induced, net-mediated inflammation. as we will use high-end vibrating mesh nebulizers, which provide excellent lung deposition and drug bioavailability, we expect that dornase alfa will be deposited within the depth of the lung parenchyma, where it may be the most useful. the incidence of moderate-to-severe hypoxaemia is the primary study endpoint. a % basal incidence of moderate-to-severe hypoxaemia may appear overstated to some experts, but it must be underlined that only severe trauma patients will be included and that a % incidence was reported in the last randomized promtt trial [ ] , in the era of damage-control resuscitation [ ] . a % absolute reduction seems ambitious for a single intervention. however, previous studies using dornase alfa in animal lung injury models and in ventilated patients suffering atelectasis demonstrated striking results [ , [ ] [ ] [ ] [ ] ] . because fluid loading regimens and transfusion strategies are based on local written protocols, they may act as potential confounding variables. however, this will be controlled by the stratification of the randomization at the centre level and adjustment of statistical analyses in cases of differences between groups. in conclusion, this trial is the first multicentre, randomized controlled, double-blinded study adequately powered to test the hypothesis that aerosolized dornase alfa reduces the incidence of moderate-to-severe hypoxaemia in mechanically ventilated severe trauma patients. protocol version . was approved by the national institutional review board on november . the study started on march and is expected to last until september ( -month inclusion period plus month participation period). after validation from its scientific committee, the traumadornase study was funded by the french ministry of health. fédération hospitalo-universitaire omicare, centre de recherche d inserm umr_s neurophysiologie respiratoire expérimentale et clinique, ap-hp, groupe hospitalier pitié-salpêtrière charles foix, département d'anesthésie réanimation réanimation chirurgicale et traumatologique, samu , rue cognacq-jay, reims, france. hôpitaux universitaires de strasbourg, nouvel hôpital civil, laboratoire central d'immunologie, place de l'hôpital, strasbourg cedex service de physiologie et d'explorations fonctionnelles disability-adjusted life years (dalys) for diseases and injuries in regions, - : a systematic analysis for the global burden of disease study the toll of death and disability from traumatic injury in the united states-the "neglected disease" of modern society, still neglected after years icu specialists facing terrorist attack: the nice experience distribution of the probability of survival is a strategic issue for randomized trials in critically ill patients acute respiratory distress syndrome: the berlin definition functional disability years after acute respiratory distress syndrome acute respiratory distress syndrome incidence of adult respiratory distress syndrome in trauma patients: a systematic review and meta-analysis over a period of three decades clinical predictors of early acute respiratory distress syndrome in trauma patients the acute respiratory distress syndrome following isolated severe traumatic brain injury heterogeneous phenotypes of acute respiratory distress syndrome after major trauma the injury severity score revisited application of the berlin definition in prommtt patients: the impact of resuscitation on the incidence of hypoxemia acute lung injury and the acute respiratory distress syndrome in the injured patient potential contribution of mitochondrial (mt) dna damage associated molecular patterns (damps) in transfusion products to the development of acute respiratory distress syndrome (ards) after multiple transfusions transfusion-related acute lung injury: the work of damps a genomic storm in critically injured humans sterile inflammation: sensing and reacting to damage microbial recognition and danger signals in sepsis and trauma plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients toll-like receptors in the vascular system: sensing the dangers within the hmgb /rage axis triggers neutrophil-mediated injury amplification following necrosis the hmgb -rage inflammatory pathway: implications for brain injury-induced pulmonary dysfunction trauma surgery . advances and future directions for management of trauma patients with musculoskeletal injuries circulating mitochondrial damps cause inflammatory responses to injury clinical immunology: culprits with evolutionary ties elevated levels of plasma mitochondrial dna damps are linked to clinical outcome in severely injured human subjects plasma mitochondrial dna levels in patients with trauma and severe sepsis: time course and the association with clinical status circulating histones are mediators of trauma-associated lung injury neutrophil recruitment and function in health and inflammation neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones role of neutrophil extracellular traps following injury neutrophil extracellular traps in pulmonary diseases: too much of a good thing molecular mechanisms of net formation and degradation revealed by intravital imaging in the liver vasculature dnasei protects against paraquat-induced acute lung injury and pulmonary fibrosis mediated by mitochondrial dna reduced deoxyribonuclease enzyme activity in response to high postinjury mitochondrial dna concentration provides a therapeutic target for systemic inflammatory response syndrome targeting neutrophils to prevent malaria-associated acute lung injury/acute respiratory distress syndrome in mice mitochondrial dna damage associated molecular patterns in ventilatorassociated pneumonia: prevention and reversal by intratracheal dnase i mitochondrial dna damage-associated molecular patterns mediate a feedforward cycle of bacteria-induced vascular injury in perfused rat lungs mechanical ventilation induces neutrophil extracellular trap formation inhaled dornase alfa (pulmozyme) as a noninvasive treatment of atelectasis in mechanically ventilated patients french legal approach to clinical research aerosol delivery of recombinant human dnase i: in vitro comparison of a vibrating-mesh nebulizer with a jet nebulizer a technical feasibility study of dornase alfa delivery with eflow flow cytometric assay for direct quantification of neutrophil extracellular traps in blood samples hospital-acquired pneumonia in icu evaluation of clinical methods for rating dyspnea the body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (retic): a single-centre, parallelgroup, open-label, randomised trial infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia complications of mechanical ventilation-the cdc's new surveillance paradigm bayesian and mixed bayesian/likelihood criteria for sample size determination variable selection via gibbs sampling the prospective, observational, multicenter, major trauma transfusion (prommtt) study: comparative effectiveness of a time-varying treatment with competing risks local dornase alfa treatment reduces nets-induced airway obstruction during severe rsv infection publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors are greatly indebted to barbara jung and mathias candusso, clinical research associates, for writing the study draft. the authors thank jo-ann elicia west, msc, an independent consultant in cartigny l'epinay, france, for providing editorial support, which was funded by hôpitaux universitaires strasbourg, direction de la recherche clinique et des innovations, strasbourg, france in accordance with good publication practice (gpp ) guidelines (http://www.ismpp.org/gpp ). jp conceived the study, coordinated its design, drafted and wrote the manuscript. jp, en, mb, ga, sg, cm, eg, vl, rc, bu-l, es, wgl, sb, am, bg and pd read and were involved in critical appraisal and revision of the manuscript. es provided statistical expertise. all authors approved the final manuscript prior to submission. aerogen (ireland) will provide nebulizers to the study centres (estimated value: € , ). after validation from its scientific committee, the traumadornase study is supported by a € , grant from the french ministry of health (phrci- -s ). funders will have no role in the study's design, collection, management, analysis and interpretation of data, writing of the report and the decision to submit the report for publication conception or in the data analysis. name and contact information for the trial sponsor: ms nathalie portier, french ministry of health, girci est, chu de dijon, , rue paul gaffarel, bp , dijon cedex, france. only the principal investigators, the dsmb and the statisticians will have access to the final data set. the data sets used and analysed during the current study will be available from the corresponding author on reasonable request, after publication of the main core article. the clinical trial will adhere to the principles of the declaration of helsinki and to the clinical trials directive / /ec of the european parliament on the approximation of the laws, regulations and administrative provisions of the member states relating to the implementation of good clinical practices in the conduct of clinical trials on medicinal products for human use. ethical aspects of this research project have been approved by the french agence nationale de la sécurité du médicament et des produits de santé (ansm, on october ) and a national institutional review board (cpp, on november ), which covers all participant sites. the trial will be monitored by the research monitoring officers of strasbourg university hospital. significant changes to the protocol will be submitted for approbation by the national institutional review board. prior consent of the subject will not be possible in most cases due to traumatic brain injury, haemorrhagic shock or prehospital sedation requirements. therefore, consent of the subject's legally acceptable representative will be requested. a consent form specifically designed for the subject's legally acceptable representative will be provided with documented approval or favourable opinion of the institutional review board in order to protect the rights, safety and well-being of the subject and to ensure compliance with any applicable regulatory requirements. consent to participation in the study by the patient's relatives will be solicited, according to the requirements of the ethics committee. in cases where neither patient consent nor relative's consent is available within the -h inclusion timeline, the subject will be included following the emergency consent procedure (according to french law [ ] , code de la santé publique, article l - ). subsequent confirmation of consent will be obtained from the relatives and the patient as soon as possible. although it is not anticipated, owing to the trial design, publication of any personal information about a patient will require her/his consent. the authors declare that they have no competing interests. key: cord- -k t q q authors: hassett, patrick; curley, gerard f.; contreras, maya; masterson, claire; higgins, brendan d.; o’brien, timothy; devaney, james; o’toole, daniel; laffey, john g. title: overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury date: - - journal: intensive care med doi: . /s - - -y sha: doc_id: cord_uid: k t q q purpose: superoxide is produced by activated neutrophils during the inflammatory response to stimuli such as endotoxin, can directly or indirectly injure host cells, and has been implicated in the pathogenesis of acute lung injury (ali)/acute respiratory distress syndrome (ards). we wished to determine the potential for pulmonary overexpression of the extracellular isoform of superoxide dismutase (ec-sod) to reduce the severity of endotoxin-induced lung injury. methods: animals were randomly allocated to undergo intratracheal instillation of ( ) surfactant alone (vehicle); ( ) adeno-associated virus (aav) vectors containing a null transgene (aav-null); and ( ) adeno-associated virus vectors containing the ec-sod transgene (aav-ec-sod) and endotoxin was subsequently administered intratracheally. two additional groups were randomized to receive ( ) vehicle or ( ) aav-ec-sod, and to undergo sham (vehicle) injury. the severity of the lung injury was assessed in all animals h later. results: endotoxin produced a severe lung injury compared to sham injury. the aav vector encoding ec-sod increased lung ec-sod concentrations, and enhanced the antioxidant capacity of the lung. ec-sod overexpression decreased the severity of endotoxin-induced ali, reducing the decrement in systemic oxygenation and lung compliance, decreasing lung permeability and decreasing histologic injury. ec-sod attenuated pulmonary inflammation, decreased bronchoalveolar lavage neutrophil counts, and reduced interleukin- and cinc- concentrations. the aav vector itself did not contribute to inflammation or to lung injury. conclusions: pulmonary overexpression of ec-sod protects the lung against endotoxin-induced ali. electronic supplementary material: the online version of this article (doi: . /s - - -y) contains supplementary material, which is available to authorized users. acute lung injury (ali) and acute respiratory distress syndrome (ards) are life-threatening clinical conditions, for which there is no specific therapy [ ] . when ards occurs in the setting of multisystem organ failure, mortality rates over % have been reported, with significant morbidity in % of survivors [ ] [ ] [ ] . endotoxin is produced by gram negative bacteria and has been implicated in the pathogenesis of sepsis-induced ali/ ards, which is the commonest cause of ali/ards, and has the worst outcome [ ] [ ] [ ] . endotoxin may also contribute to ali/ards from other causes, such as major surgery, where alterations in mucosal permeability may permit access of gut-derived endotoxins to the systemic circulation [ ] . endotoxin binds the toll-like receptor- (tlr- ), which activates the innate immune response [ ] . neutrophil-derived reactive oxygen species such as superoxide contribute to lung damage and dysfunction in patients with ali/ards [ , ] . superoxide dismutase (sod) catalyses the dismutation of superoxide and is a key component of the antioxidant defences in the lung. pharmacologic strategies to directly augment the lung antioxidant defences via exogenous sod administration have demonstrated efficacy in preclinical models [ ] [ ] [ ] , but have not translated to the clinical setting. an alternative approach is to overexpress the gene encoding for superoxide in the lung epithelium, using intrapulmonary delivery of viral vectors encoding the gene. we wished to test the hypothesis that pulmonary overexpression of ec-sod would attenuate endotoxininduced ali. we used this model because of the role of endotoxin in the pathogenesis of ali/ards, and because this is a well-characterized model that closely mimics the clinical development of ards [ ] [ ] [ ] . a more detailed description of the methods and materials can be found in the online supplementary material. the ec-sod transgene was first ligated into the multiple cloning site of a p-aavmcs vector (agilent technologies inc., santa clara, ca, usa), product size was confirmed by gel electrophoresis, and the plasmid was sequenced to validate insert sequence integrity [ ] . plasmid dna and adeno-associated virus envelope for aav serotype was transfected into t cells. cells were harvested and lysed h later, the lysate was centrifuged and the clear lysate fraction loaded on an iodixanol gradient. following further purification of the viral particles by affinity column chromatography, particles were concentrated and desalted. viral vector particle titres were determined by quantitative real-time polymerase chain reaction (qrt-pcr). the process was then repeated for the synthesis of an empty aav vector with no gene product, termed aav-null. the aav particles were divided into aliquots of ll containing . dnaase-resistant particles (drp) per microlitre and stored at - °c. as required, an aliquot was thawed and added to ll of the porcine surfactant curosurf Ò ( mg/ml) (trinity-chiesi pharmaceuticals limited, cheadle, uk), to create a final instillate volume of ll. for those animals receiving vehicle only, the instillate was ll of curosurf Ò mixed with ll of phosphate-buffered saline (pbs). specific-pathogen-free adult male sprague-dawley rats ( - g) were used. the experimental model was based on those previously reported, with several modifications [ , ] . all work was approved by the national university of ireland, galway research ethics committee and conducted under licence from the department of health, ireland. animals were anaesthetised by inhalational induction with isoflurane and an intraperitoneal injection of mg kg - of ketamine (pfizer, kent, uk) [ , ] , and the trachea intubated with a size intravenous catheter (bd insyte Ò ; becton-dickinson ltd., oxford, uk). animals were randomized to intratracheal instillation of the surfactant/pbs mixture containing (a) vehicle alone; (b) . drp aav-null; or (c) . drp aav-ec-sod. subsequently, two additional groups were randomized to receive (d) vehicle or (e) aav-ec-sod instillation. the dose of aav-ec-sod used was determined to produce effective transgene expression in preliminary studies. following instillation in two aliquots, the animals were extubated, and allowed to recover from anaesthesia. five days following vector/vehicle instillation, the animals were re-anaesthetised and mg kg - of endotoxin derived from escherichica coli serotype :b (fluka, poole, uk) or vehicle was instilled intratracheally [ ] . twenty-four hours following endotoxin instillation, all animals were again anaesthetized as described above, intravenous access was secured via the dorsal penile vein and anaesthesia maintained with repeated intravenous boli of saffan Ò (alfaxadone . % and alfadadolone acetate . %; schering plough, welwyn garden city, uk) [ , ] . a tracheostomy tube ( -mm internal diameter) was then inserted and intra-arterial access ( -or -gauge cannulae; becton-dickinson, franklin lakes, nj, usa) was sited in the carotid artery. cis-atracurium besylate . mg kg - (glaxosmithkline, dublin, ireland) was administered intravenously and the lungs were mechanically ventilated (model ; harvard apparatus, holliston, ma, usa) at a respiratory rate of min - , tidal volume ml kg - and positive end-expiratory pressure of cmh o. to minimize lung derecruitment, a recruitment manoeuvre consisting of positive end-expiratory pressure cmh o for breaths was applied at the start of the protocol. all animals were ventilated with an inspired gas mixture of fio = . , and fin = . , for min. systemic arterial pressure, peak airway pressures and temperature were continuously measured, arterial blood samples were drawn for analysis (abl ; radiometer, copenhagen, denmark) and static inflation lung compliance measured [ ] . heparin ( iu kg - ) was administered intravenously and the animals were then killed by exsanguination under anaesthesia [ , ] . immediately post-mortem, the heart-lung block was dissected from the thorax and bronchoalveolar lavage (bal) collection performed [ , ] . total and differential cell counts were performed and the concentrations of cytokine-induced neutrophil chemoattractant- (cinc- ) and interleukin- (il- ) in the bal were determined using a quantitative sandwich elisa (r&d systems europe ltd., abingdon, uk) [ , ] . the micro bca tm protein assay kit (pierce, rockford, il, usa), was utilized to determine total bal protein levels [ ] . the left lung was isolated and fixed [ , ] , and the extent of histologic lung damage determined using quantitative stereological techniques [ ] . sod transgene expression was determined in lung homogenates by real-time rtpcr and western blotting as previously described [ , , ] . briefly, rna was extracted from lung tissue and cdna synthesis performed using the improm-ii tm reverse transcription system (promega, madison, wi, usa). quantitative pcr was performed for ec-sod gene, normalised against a gapdh control product. primer sequences (from mwg-biotech) used were as follows: gapdh sense: -ttgtgaagctcatttcctgg- , antisense: lung tissue western blot analysis for ec-sod was carried out as previously described [ ] . briefly, total cell protein was extracted, protein concentration was determined and samples were electrophoresed on an sds-page gel and transferred to nitrocellulose. primary goat anti-human ec-sod polyclonal antibody (santa cruz biotechnology, santa cruz, ca, usa) was used, with anti-goat antibody conjugated to horseradish peroxidase (cell signaling technology, danvers, ma, usa) as the secondary antibody. the membrane was subsequently incubated with a chemiluminescent substrate (supersignal west pico; pierce) and ec-sod protein detected at size . kda. lung homogenate sod activity was assessed utilizing a colorimetric sod activity assay kit (sigma aldrich, dorset, uk) in which the degradation of a tetrazolium salt produces a formazan dye upon reduction with a superoxide anion. the rates of reduction are inhibited by superoxide dismutase activity. lung tissue was flash-frozen in liquid nitrogen, cut into -lm-thick sections, fixed in acetone, washed, and nonspecific sites blocked with % (v/v) goat blocking serum. sections were then incubated with ec-sod primary antibody raised in goat (santa cruz), then incubated in rhodamine-conjugated donkey-anti-goat secondary antibody (santa cruz). fluorescence was subsequently imaged on an olympus ix microscope using cell^p Ò software (olympus europa gmbh, germany). results are expressed as mean ± standard deviation (sd) for normally distributed data, and as median (interquartile range, iqr) if non-normally distributed. data were analysed by repeated measures two-way anova or one-way anova as appropriate, followed by student-newman-keuls, t test or kruskal-wallis followed by mann-whitney u test with the bonferroni correction for multiple comparisons, as appropriate. a p value of less than . was considered statistically significant. forty-two animals were entered into this study. two animals were excluded prior to assessment of injury due to technical failures of the protocol, namely failure to deliver endotoxin intratracheally. the remaining animals were randomized to receive: ( ) sham injury plus vehicle treatment (sham-vehicle, n = ); ( ) sham injury plus ec-sod (sham-ec-sod, n = ); ( ) endotoxin injury plus vehicle (lps-vehicle, n = ); ( ) endotoxin injury plus null vector (lps-null, n = ); ( ) endotoxin injury plus ec-sod (lps-ec-sod, n = ). all animals survived vector and endotoxin instillation. one animal in each endotoxin injury group died following induction of anaesthesia for final injury assessment, immediately prior to assessment of physiologic indices of lung injury, due to the severity of their lung injury. all other data were collected from these animals. there were no differences between the groups in regard to arterial ph, paco , serum bicarbonate, serum lactate, base excess or mean arterial pressure (table ) . endotoxin-induced injury significantly decreased lung tissue ec-sod protein, and this decrease was fully restored by ec-sod overexpression (fig. a-b) . ec-sod protein was expressed throughout the lung tissue by immunohistochemical staining, with greater sod protein evident in animals that received the ec-sod transgene (fig. c-d) . these animals also demonstrated substantially greater lung expression of the ec-sod transgene (online fig. a) . there was no difference in lung ec-sod gene expression between the null vector and vehicle groups. lung tissue sod activity was significantly enhanced in the animals that received ec-sod in comparison to non-transduced animals and animals that received the null vector (online fig. a) . endotoxininduced lung injury did not appear to reduce ec-sod expression or activity. endotoxin instillation produced a severe lung injury, which was attenuated by ec-sod overexpression in comparison to animals that received vehicle or null vector. ec-sod abolished the fall in arterial oxygenation seen in vehicle and null gene transfected animals data are expressed as mean ± sd or median (interquartile range). final data are those collected upon completion of the experimental protocol bal bronchoalveolar lavage * significantly different from sham-vehicle and sham-ec-sod groups (p \ . by anova) significantly different from lps-null and lps-vehicle groups (p \ . by anova) following endotoxin instillation (fig. a) . ec-sod also abrogated the decrement in alveolar-arterial oxygen gradient following endotoxin-induced injury (table ) . ec-sod completely attenuated the decrease in static lung compliance (fig. b ) and the increase in peak airway pressure (fig. c) following endotoxin-induced injury. ec-sod attenuated the endotoxin-induced increase in pulmonary permeability, as assessed by protein leak into the bal fluid. bal protein concentrations were significantly greater in all endotoxin-injured animals, but were significantly lower in ec-sod animals ( table ) . ec-sod decreased the degree of histologic injury compared to both endotoxin-injured groups (online fig. b ). quantitative stereological analysis demonstrated that ec-sod overexpression attenuated the increase in acinar tissue volume fraction and the decrease in acinar airspace volume fraction induced by endotoxin (fig. a) . ec-sod overexpression attenuated the endotoxininduced inflammatory response. the endotoxin-induced bal neutrophil influx was attenuated by ec-sod overexpression (fig. b) . ec-sod overexpression also decreased endotoxin-induced bal interleukin- concentrations, although this was not statistically significant (table ) . ec-sod abolished the endotoxin-induced increase in bal cinc- concentrations (table ) . there was no evidence to suggest that the viral vector itself worsened the inflammatory response to endotoxin. specifically, animals that received empty vector did not demonstrate increases in bal il- , cinc- , or neutrophil counts compared to animals that received vehicle alone (fig. b, table ). these findings demonstrate the potential of antioxidant gene therapy to attenuate endotoxin-induced lung injury. intratracheal delivery of aav vectors encoding the ec-sod transgene resulted in expression of the ec-sod transgene, augmenting the antioxidant capacity of the lung. ec-sod overexpression reduced the severity of subsequent endotoxin-induced lung injury, reducing pulmonary inflammation and reducing physiologic and histologic indices of lung injury and damage. superoxide is produced by activated neutrophils during the immune response, and may cause injury directly, or via conversion to more damaging oxidant species, such as the hydroxyl radical and hypochlorous acid [ , ] . superoxide can also react with nitric oxide to produce the potent nitrating agent peroxynitrite [ ] . evidence of superoxide-mediated lung damage has been demonstrated in patients with ards [ , ] . strategies to augment the lung antioxidant potential have included exogenous sod fig. a densitometry of western blots demonstrating relative ec-sod protein concentrations in lung homogenates from each group. b representative western blots demonstrating relative ec-sod protein concentrations in lung homogenates from each group. *significantly different from sham-vehicle group (p \ . , anova). photomicrographs of representative confocal microscopy images of sections from lung tissue that received ec-sod (c) and null vector (d) respectively exposed to dapi nuclear stain and a stain for ec-sod. the extent of staining for ec-sod is greater in the lung sections from the animal that received ec-sod. the scale bar equals lm administration [ ] [ ] [ ] ; however, limitations regarding direct pharmacologic administration of sod have limited its therapeutic potential. in contrast, the extracellular sod isoform (ec-sod) may be a suitable candidate for gene therapy because it is a secreted product and therefore may protect adjacent cells against injury [ ] . in these studies, endotoxin-induced injury decreased pulmonary sod protein concentrations. intrapulmonary delivery of aav encoding ec-sod increased pulmonary ec-sod expression, and restored lung ec-sod protein concentrations, to the levels seen in uninjured lungs. of importance, the efficacy of the ec-sod vector was not affected by the subsequent endotoxin-induced lung injury. we chose aav serotype on the basis of preliminary data from our group demonstrating superior transduction with this serotype compared to aav serotypes or . increased total superoxide dismutase activity fig. a histogram representing mean (sd) arterial oxygen partial pressures following endotoxin injury in each group. b line graph representing mean (sd) static lung compliance following endotoxin injury in each group. c histogram representing mean (sd) peak airway pressures following endotoxin injury in each group. vehicle, animals that received intratracheal surfactant alone; null vector, animals that received intratracheal aav encoding no transgene; ec-sod, animals that received intratracheal aav encoding the ec-sod transgene. *significantly different from sham-vehicle group (p \ . , anova). significantly different from lps-vehicle and lps-null groups (p \ . , anova) was detected in lung homogenates of those animals who were treated with ec-sod using sod activity assays. whilst this assay is not specific for ec-sod, the relative increase in overall antioxidant activity in the ec-sod group is likely to be due to the increased ec-sod present in these animals. immunohistochemistry demonstrated that the ec-sod protein was expressed throughout the pulmonary tissue. this strategy significantly reduced endotoxin-induced lung injury, which is characterized by increased oxidant-induced injury. ec-sod overexpression significantly reduced endotoxin-induced lung inflammation, and reduced the increase in alveolar neutrophil counts and il- and cinc- concentrations. the reduction in alveolar neutrophil infiltration by ec-sod overexpression may be due, at least in part, to the reduction in alveolar concentrations of the potent neutrophil chemoattractant cinc- . of importance, there was no evidence to suggest that the viral vector itself worsened the inflammatory response to endotoxin. this is significant given concerns regarding the potential of viral vectors to produce a host immune response, a potentially deleterious effect in the setting of a generalized pro-inflammatory state such as ali/ards. ec-sod overexpression reduced endotoxin-induced lung injury, as evidenced by improved systemic arterial oxygenation, and lung static and dynamic compliance compared to untreated animals. ec-sod almost completely attenuated the endotoxin-induced decrement in these indices as evidence by the fact that these indices were not different from those in uninjured animals. in contrast, administration of empty vector did not exert any beneficial effects compared to administration of vehicle alone. ec-sod overexpression also reduced the extent of histologic injury, as evidenced by a greater preservation of alveolar airspace, and reduced alveolar tissue, compared to animals that received empty vector or vehicle alone. there are a number of limitations in regard to this study. firstly, this study involved the administration of vector prior to the onset of lung injury. in the clinical setting, lung injury is generally well established at presentation. it is not clear what effect ec-sod overexpression might have if introduced after the onset of lung injury. however, there are certain settings, such as major cardiovascular or intra-abdominal surgery, where an insult, such as the development of endotoxemia, is a frequent, and relatively predictable occurrence [ ] . a safe, low toxicity intervention, if proven effective in these settings, might confer substantial clinical benefit. secondly, intratracheal delivery of transgene following the development of ali/ards may be difficult, particularly where lung units are collapsed or filled with exudate, reducing the therapeutic utility of intrapulmonary delivered therapies. it is reassuring in these studies that endotoxin injury did not adversely affect transgene expression or activity. lastly, ali and ards generally have time courses significantly longer than the h assessed by this model. differences between groups that were not apparent at h might be very clear after a number of days. further experiments with a longer observation period, and which assess outcome, might be useful in giving insights into the likely clinical impact of pulmonary gene therapy for ards. in conclusion, intrapulmonary delivery of ec-sod decreased the severity of endotoxin-induced lung injury, demonstrating the potential beneficial effects of ec-sod overexpression in the setting of ali. more broadly, these findings suggest that gene therapy may have therapeutic potential for ali/ards. however, additional experimental work is needed over longer time periods to further clarify the therapeutic potential of pulmonary ec-sod overexpression in ali/ards. quality-adjusted survival in the first year after the acute respiratory distress syndrome epidemiology of acute lung injury one-year outcomes in survivors of the acute respiratory distress syndrome acute respiratory distress syndrome: frequency, clinical course, and costs of care risk factors for ards in the united states: analysis of the national mortality followback study acute lung injury in the medical icu: comorbid conditions, age, etiology, and hospital outcome the systemic inflammatory response to cardiac surgery: implications for the anesthesiologist endotoxin, toll-like receptor , and the afferent limb of innate immunity oxidative damage to proteins of bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome: evidence for neutrophilmediated hydroxylation, nitration, and chlorination contribution of reactive oxygen and nitrogen species to particulate-induced lung injury efficacy of adenoviral gene transfer with manganese superoxide dismutase and endothelial nitric oxide synthase in reducing ischemia and reperfusion injury mitigation of oxidant injury to lung microvasculature by intratracheal instillation of antioxidant enzymes transfection of a manganese-containing superoxide dismutase gene into hamster tracheal epithelial cells ameliorates asbestosmediated cytotoxicity hypercapnic acidosis attenuates endotoxin-induced acute lung injury intratracheal aerosolization of endotoxin (lps) in the rat: a comprehensive animal model to study adult (acute) respiratory distress syndrome gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes and hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism hypercapnic acidosis attenuates shock and lung injury in early and prolonged systemic sepsis differential effects of buffered hypercapnia versus hypercapnic acidosis on shock and lung injury induced by systemic sepsis l-arginine attenuates lipopolysaccharide-induced lung chemokine production tnf-alpha and il- beta are not essential to the inflammatory response in lps-induced airway disease measurement of protein using bicinchoninic acid chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation chronic airway infection leads to angiogenesis in the pulmonary circulation extracellular superoxide dismutase attenuates lung injury after hemorrhage delivery of cu/zn-superoxide dismutase genes with a viral vector minimizes liver injury and improves survival after liver transplantation in the rat hypercapnic acidosis attenuates pulmonary epithelial wound repair by an nf-kappab dependent mechanism oxidative damage to plasma proteins in adult respiratory distress syndrome key: cord- -vpzzsdld authors: thompson, kelly b.; krispinsky, luke t.; stark, ryan j. title: late immune consequences of combat trauma: a review of trauma-related immune dysfunction and potential therapies date: - - journal: mil med res doi: . /s - - - sha: doc_id: cord_uid: vpzzsdld with improvements in personnel and vehicular body armor, robust casualty evacuation capabilities, and damage control resuscitation strategies, more combat casualties are surviving to reach higher levels of care throughout the casualty evacuation system. as such, medical centers are becoming more accustomed to managing the deleterious late consequences of combat trauma related to the dysregulation of the immune system. in this review, we aim to highlight these late consequences and identify areas for future research and therapeutic strategies. trauma leads to the dysregulation of both the innate and adaptive immune responses, which places the injured at risk for several late consequences, including delayed wound healing, late onset sepsis and infection, multi-organ dysfunction syndrome, and acute respiratory distress syndrome, which are significant for their association with the increased morbidity and mortality of wounded personnel. the mechanisms by which these consequences develop are complex but include an imbalance of the immune system leading to robust inflammatory responses, triggered by the presence of damage-associated molecules and other immune-modifying agents following trauma. treatment strategies to improve outcomes have been difficult to develop as the immunophenotype of injured personnel following trauma is variable, fluid and difficult to determine. as more information regarding the triggers that lead to immune dysfunction following trauma is elucidated, it may be possible to identify the immunophenotype of injured personnel and provide targeted treatments to reduce the late consequences of trauma, which are known to lead to significant morbidity and mortality. in modern global conflicts, asymmetric warfare has led to a number of injuries in combat personnel that differ from prior conflicts. since the start of operation iraqi freedom (oif) in , the use of improvised explosive devices (ieds) and ambushes with rocket propelled grenades has led to an increase in the number of personnel wounded or killed by explosions and fewer casualties resulting from gunshot wounds compared to prior conflicts [ ] . during the vietnam conflict, % of injuries were in the head or neck region, and . % were in the thoracic area. oif witnessed a significant shift in the injury pattern, with more than % of injuries occurring in the head or neck region and only . % occurring in the thoracic region, a trend that continues in current conflicts due to improvements in personnel and vehicular body armor. armor use has also led to a decrease in the number of deaths as a result of gunshot wounds, which were down to . % [ , ] . in data examining the timing and causes of death for patients surviving transport to a forward deployed combat surgical hospital in iraq from to , head injury and truncal and/or extremity hemorrhage were the cause of death in % of all patients. most deaths occurred in the acute phase of care, with less than % occurring more than days after admission. of unexpectant deaths with higher preventability scores, hemorrhage was the leading cause of death ( %), followed by multi-organ dysfunction syndrome (mods) ( %), hypoxia ( %), and brain injury ( %). these patients had lower mean injury severity scores (iss) and were less likely to have severe head injuries; however, they had biochemical evidence of severe injuries as evidenced by significant acidosis, coagulopathy, and hypotension on presentation and the majority required massive transfusion (> units of red blood cells in h). the survival of combat-related injuries is in part due to the need for post-injury surgical care, where amputations accounted for % of all wounds, and % of all casualties suffered spinal cord injury [ ] . though there have been significant improvements in combat casualty care, with a focus on preventing deaths from hemorrhage, the relatively high incidence of surgical care and post-injury mods contributes to the burden of morbidity and mortality in those who survive the initial trauma [ ] . the associated morbidity and mortality is multifactorial, among which dysregulation of the immune system is an important contributing factor. immune dysregulation leads to an increased risk for late onset sepsis and infection, acute respiratory distress syndrome, and delayed wound healing in addition to late mods [ , ] . an important factor in the development of mods and immune dysregulation in the setting of trauma is the need for post-injury surgical intervention. given the increased incidence of explosive injuries in modern combat that lead to multiple injury patterns, it is useful to utilize explosive injuries as a model for understanding the complex nature of trauma-induced mods. primary blast injuries caused by the overpressure wave passing through the body lead to damage at the air-fluid interfaces of the tympanic membrane, the lungs, and intestine, and may lead to hollow viscus rupture and internal hemorrhage that can be difficult to identify upon initial triage [ ] . secondary blast injuries occur as a consequence of high-energy projectiles being released from the explosive, leading to extensive tissue injury or loss and wound contamination. tertiary blast injuries result from blunt trauma sustained when the casualty is blown back from the explosion into other objects. quaternary blast injuries involve injuries sustained due to the chemical nature of the blast, including burns and inhalation injuries, as well as when other objects are blown onto the casualty, leading to crush injuries and perhaps further penetrating injuries. injuries from explosives therefore present with numerous complex wounds that are likely to be contaminated and are associated with extensive tissue damage or loss and compounded by microvascular trauma as well. based on the nato triage doctrine, following initial stabilization and basic hemorrhage control by combat medics (role care), the injured are moved to role facilities at forward operating bases (fobs) for the provision of damage control resuscitation (dcr), which includes further hemorrhage control, decontamination or debridement of wounds, and limb or life-preserving surgeries, including exploratory laparotomy with temporary wound closure and the application of negative pressure wound therapy [ ] . administration of blood products and fluids is continued in a balanced manner to restore circulating volume and organ perfusion while allowing for "permissive hypotension". in recent conflicts, approximately to % of military casualties undergo massive transfusion, receiving more than units of blood in the first h after injury. such large volume transfusion has been associated with immune suppression, coagulopathy, acidosis, organ dysfunction and hypothermia [ , ] . these effects are further compounded by uncontrolled pain associated with the injuries of the wounded, which has been shown to induce an inflammatory state leading to hypercoagulation, an increased metabolic demand of tissues, and impaired immune function [ , ] . patients are then moved to a role forward-deployed level trauma-equivalent hospital where dcr is continued. the injured undergo further operations of their wounds and are managed in a critical care facility with the aim of restoring physiological function and limiting the effects of prolonged operative times, massive transfusion, and multiple complex injuries. it is here that the late effects of trauma may begin to develop. once stabilized enough for transport, typically within days after injury, patients are evacuated to role facilities for more definitive or specialized care and rehabilitation [ , , ] . within the first few weeks after injury, patients may undergo multiple surgeries, including initial surgeries for decontamination and hemorrhage control, followed by further debridement, grafting, amputations, primary closures and reconstructions. despite timely and appropriate medical and surgical care, the consequences of immune dysfunction after the initial trauma may persist and lead to further complications for survivors. the initial concepts of immune dysregulation and dysfunction came from a consensus meeting in describing the whole-body response to an infectious or injurious stimulus, which came to be known as the systemic inflammatory response syndrome (sirs) [ ] . these concepts later evolved to incorporate the response of counter-regulatory mechanisms designed to dampen the initial pro-inflammatory signal, termed the compensatory anti-inflammatory response syndrome (cars) [ ] . the temporal association of sirs and cars was initially conceptualized to happen in the sequence of sirs and then cars, but this belief has been challenged by a model demonstrating more overlap between the two responses [ ] . in addition, our more recent understanding of the complex integrated pro-and anti-inflammatory responses to injury has also led to the acknowledgement of a protracted form of immune dysregulation, termed persistent inflammation-immunosuppression and catabolism syndrome (pics) (fig. ) [ ] . while the clinical and temporal evolutions of sirs, cars and now pics have undergone revisions as our understanding of their associated immune phenotypes has evolved, the underlying concepts of pro-and anti-inflammatory responses have remained similar since they were first postulated. following the initial trauma, a host of immune mediators are released by various cells and tissues within the body to activate the immune system and promote a pro-inflammatory state through the expansion and recruitment of various cell lines with the goal of preventing or combating infection and eliminating dead or dying tissue. this pro-inflammatory state is carefully balanced with a compensatory anti-inflammatory response to limit further tissue damage, preserve organ function, and ultimately quiet the pro-inflammatory state and return the body to homeostasis. in severe trauma, there may be an exaggerated pro-inflammatory state, which leads to further injury and rapid multiple organ failure. this may be combined with or followed by an exaggerated and prolonged compensatory anti-inflammatory response, which is associated with immunosuppression through lymphocyte dysfunction and apoptosis, down-regulation of monocyte human leukocyte antigen (hla) receptors, monocyte deactivation, and unbalanced production of cytokines and anti-inflammatory mediators. these effects place injured patients at risk for late complications, secondary to susceptibility to infection and inability to clear infections [ ] . recent studies have suggested that damage-associated molecular patterns (damps) are key to the initiation and continuation of both sirs and cars and may play a critical role in both the "one-hit" and "two-hit" models for the development of mods as well as the subsequent development of pics [ ] . under these conditions, endogenous molecules, such as cytokines (tumor necrosis factor, interleukin- beta) or alarmins (interleukin- alpha, high mobility group box , s ), are released from activated or injured cells to promote a host response, and their presence has been linked to outcomes after trauma [ , ] . more specifically, cytokines are released when pattern recognition receptors, the typical receptors to which damps bind, are activated on immune cells, while alarmins, constitutively active molecules produced by somatic cells, are released when cells undergo necrosis or apoptosis [ ] . the release of alarmins, such as high mobility group box (hmgb ), has fig. temporal association of immune dysfunction syndromes. after an initial combat-related injury, there is the development of a hyper-inflammatory response, termed the systemic inflammatory response syndrome (sirs), and an immune suppressing response, termed the compensatory antiinflammatory response syndrome (cars). these two responses happen within minutes to days, occurring nearly simultaneously, and it is during these initial inflammatory phases that death from early multi-organ dysfunction syndrome (mods) may occur. as both the pro-inflammatory and antiinflammatory responses resolve, there is a period of resolution, typically within days to weeks, that allows for the return to homeostasis and survival after the injury. however, in a percentage of injured patients, the pro-inflammatory and/or anti-inflammatory responses never resolve, leading to a period of chronic critical illness termed persistent inflammatory-immunosuppressive and catabolic syndrome (pics). this occurs in patients who have been critically ill for longer than days with significant lymphopenia and chronic inflammation. pics may persist for months and lead to the risk of developing later mods and secondary infections with subsequent morbidity and late mortality been demonstrated to occur as soon as min after injury. this rapid release in response to trauma is in contrast to the delayed release demonstrated in the setting of severe infections [ ] [ ] [ ] . while the production and release of these molecules is intended to recruit cells to the site of injury and contain its effects, they also alter the response to later infectious or injurious challenges, termed immunotolerance [ ] . this tolerant phenotype was first described in trauma patients in the mid- s, where monocytes isolated from injured patients had a reduced cytokine response to ex vivo stimulation of endotoxins [ ] . though significant debate still exists regarding the mechanisms and effects of immunotolerance following injury or infection, population-based studies have demonstrated a correlation between the presence of endotoxin tolerance and the development of organ dysfunction [ , ] . one of the more important cytokines associated with an immunotolerant phenotype is interleukin- (il- ). this was first shown in il- knockout mice that demonstrated an impaired tolerant phenotype to repeated endotoxin challenge [ ] . persistently elevated il- levels in the plasma have also been correlated with a worse outcome in patients with sepsis and have been associated with the development of secondary complications after burn injury and trauma [ ] [ ] [ ] . more specific to combat-related injuries, higher il- levels have been shown in those who develop mods, as well as in non-survivors compared to survivors [ ] . similar to il- , elevated levels of transforming growth factor β (tgf-β), another anti-inflammatory cytokine, have been shown to correlate with the severity of injury and the development of secondary infections [ ] . comparatively, for those who survive the initial injury, an excessive predominance of pro-inflammatory markers compared to anti-inflammatory markers has been associated with poor wound healing, suggesting a temporal imbalance in immune function recovery and specific trauma-related outcomes [ ] . immune dysfunction after injury has been shown to impact both the innate immune system, which is able to immediately respond without reprogramming or differentiation, and the adaptive immune system, which requires secondary activation and programing via cell-cell contact [ ] . one classical feature of immune dysfunction after systemic inflammation is a reduced expression of human leukocyte antigen dr (hla-dr) on peripheral blood mononuclear cells, which are innate immune cells. this reduced hla-dr expression is associated with impaired antigen presentation [ ] . as early as the s, it was recognized that major trauma results in decreased expression of hla-dr on monocytes and was linked to an increased risk for infection during the recovery period, leading to late morbidity and mortality [ ] . these findings have been confirmed in multiple subsequent studies, which have suggested that both a more robust initial inflammatory reaction along with the inability to recover hla-dr expression predispose and prognosticate trauma patients to subsequent development of sepsis [ , ] . in addition, reduced hla-dr expression has been observed within h after surgery and can be restored through the application of granulocyte-macrophage colony stimulating factor (gm-csf) and interferon-gamma (ifn-γ) [ ] . continued suppression of monocyte hla-dr expression has also been correlated with a worse outcome in patients with sepsis [ ] . though monocytes and the tissue variant of monocytes, known as macrophages, have been the stereotypical innate immune cells to demonstrate immune dysfunction after trauma, other innate immune cells have been shown to have impaired activity, including neutrophils, dendritic cells and natural killer cells [ ] . the immunosuppressive phenotype displayed by these innate immune cells typically involves decreased phagocytosis, decreased cytokine production, decreased cytotoxic function and an overall susceptibility for apoptosis [ ] . the inactivation of monocytes after surgery, trauma, and infections further propagates immune dysfunction through alterations in t lymphocyte function. lymphopenia itself is known to occur after severe injury, and a lack of lymphocyte recovery is known to impact survival [ ] . beyond changes in lymphocyte number, circulating effector t lymphocytes also change from a pro-inflammatory th phenotype to an anti-inflammatory th phenotype [ ] . this change in phenotype is partly due to suppression by regulatory t cells, which are important mediators of il- and tgf-β production. the impairment of effector helper t lymphocytes after trauma also results in a reduction of interferon gamma (ifn-γ) production by th polarized cells [ ] . ifnγ serves a key function in stimulating increased antigen presentation and anti-pathogen activities of innate immunity cells [ ] . after major surgery, while the number of effector t cells decreases, the number of regulatory t cells remains relatively unchanged [ ] . these regulatory t cells express the receptor programmed death (pd- ), which can act as a negative regulator on other immune cells, particularly antigen-presenting cells expressing the programmed death ligand (pd-l ) [ ] . a high expression of pd- on t lymphocytes has been correlated with the severity of illness after major trauma [ ] . beyond t lymphocytes, b lymphocytes are also affected, resulting in impaired antibody production as well as apoptosis [ ] . a summary of the initial combat injury and the subsequent major pro-and anti-inflammatory responses is shown in fig. . while the proposed mechanisms of immune dysfunction mentioned here are not exhaustive and likely involve a complex and dynamic host of responses to curtail the integrated inflammatory response, it is increasingly clear that trauma and the necessary associated surgeries alter the immune system. in those injured personnel who develop more aberrant phenotypes of immune dysfunction, there is a higher risk of developing late complications of the initial injury. despite the early and aggressive medical management of patients as they are moved through various levels of care, alterations in immune function following trauma can place patients at risk for late complications of trauma. in addition, the inability to have sufficient resolution from sirs or cars can lead to the development of pics. the consequences of these altered immune phenotypes can lead to impaired wound healing, late onset sepsis, mods, and acute respiratory distress syndrome (ards) [ , ] . in a study from investigating the incidence of wound infections from wounded personnel arriving at a role facility week after injury from combat operations in afghanistan and iraq, approximately % of the wounds biopsied were infected or critically contaminated as defined by wound tissue biopsy cultures with greater than × cfu/g of biopsied tissue at admission. of infected wounds, gram-negative bacteria predominated, with acinetobacter baumannii being the most common pathogen throughout the study period. this finding was consistent with other reports of predominance in orthopedic wounds and osteomyelitis [ ] . in combat wounds treated at a referral facility within week of injury, nine wounds ( %) in five patients ( %) demonstrated impaired healing, including five delayed wound closures in three patients and four wound dehiscences in two patients, despite appropriate surgical debridement. delays in wound closure were made due to concerns about infection (n = ) or severe systemic illness (n = ). delayed wound healing was found to be associated with increased serum concentrations of multiple inflammatory mediators, including il- , il- , and matrix metalloproteinase- (mmp- ). increased effluent concentrations of il- , il- , and macrophage inflammatory protein alpha (mip α) were also predictive of critical contamination of wounds prior to closure. each of these bio-markers was also independently associated with wound outcome. many of these patients were critically ill on admission with a mean (±sd) iss of ± and a mean acute physiology and chronic health evaluation (apache) ii score of ± on admission. the critical interplay between systemic and local inflammation and wound bacterial burden likely contributes to wound outcome. the balance of chemokines, cytokines, fig. interactions of the innate and adaptive immune systems in response to trauma. immediately following injury, damaged tissues release damage-associated molecular patterns (damps) and in response, residing innate immune cells release pro-inflammatory cytokines. these signals help recruit other innate immune cells to the site of injury in an attempt to contain the deleterious effects of the injury. however, in severe injuries, the immune response goes beyond the local site of injury and leads to systemic inflammation. to reduce the impact of systemic inflammation, the adaptive immune system, primarily through the suppression of regulatory t cells (t reg ), releases anti-inflammatory cytokines and other signals that impede the immune system as it tries to continue the pro-inflammatory response. this manifests as apoptosis of innate immune cells and decreased antigen presentation (hla-dr on monocytes), as well as apoptosis and the anergy of helper t cells causing leukopenia. in the maladaptive state, preponderance of this anti-inflammatory, immune suppressing phenotype leads to the consequences of cars and pics. the general effect of a chronic inflammatory state on immune systems in response to injury is listed below their respective cell types. for a general review of the immune system and inflammation, the reader is referred to a review by spiering [ ] and matrix metalloproteinases that are necessary for appropriate wound healing may be altered by the presence of bacteria at the wound site. furthermore, this balance may be altered by a dysregulated immune response secondary to injury, with a higher risk of immunosuppression-associated infection or failure to clear the bacterial burden and chronic local inflammation at the tissue bed [ ] . although there is a high incidence of blast injuries sustained by combat personnel, only a small percentage ( to %) suffer burn injuries [ ] . despite this, infected burns are a difficult subset of wounds to manage as wound infection leading to sepsis is the most common cause of mortality in burn patients after burn injury and an important component to delayed wound healing. furthermore, due to the disruption of the protective epithelial layer of skin, burn patients are at risk for invasive bacterial and fungal infections. clinicians must have a high index of suspicion for infection as thermal injury-induced hyperpyrexia, immune suppression, and systemic inflammatory response syndrome may alter the typical presenting features of infection and make infection difficult to control [ ] . pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli and staphylococcus aureus are independent predictors of mortality, with s. aureus being a major cause of septicemia in burn patients [ ] . furthermore, the gram-negative p. aeruginosa, e. coli, and k. pneumoniae are also associated with failure to heal infected burn wounds [ ] . additionally, skin grafting is a common surgical procedure for the management of burns; however, given the presence of co-existing injuries, amputations, and the critical illness of patients, suitable donor sites are difficult to obtain and harvest, potentially leading to delayed healing and an increased risk of infection [ ] . sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection [ ] . sepsis is a major cause of morbidity and mortality after trauma, as alterations in immune function following trauma contribute to an increased susceptibility and impaired ability to combat infection through the modification of both the innate and adaptive immune functions. furthermore, the development of mods is often associated with infection and is the most common cause of late death in trauma patients who survive past the first to h of resuscitation [ ] . following major trauma, sirs is initiated by the activation of the innate immune response. this is often soon followed by cars, which is controlled by the adaptive immune system and was previously thought to occur approximately to days after trauma [ ] . however, more recent research has demonstrated that sirs and cars may occur at the same time with the robustness of each response dependent on a variable milieu of cytokines and other mediators [ , ] . massive trauma can lead to an accelerated and substantial inflammatory response and severe sirs, independent of infection, leading to a "one-hit" initiation of mods [ , ] . patients with less severe trauma may develop late mods due to new surgical stress, general anesthesia, transfusion of blood products, infection, or ischemia/reperfusion injury triggering the reactivation of the inflammatory response in a "two-hit" model of mods [ , ] . a key inciting event in the development of mods and sepsis may be the transfusion of blood products. studies have demonstrated that the transfusion of red blood cells to an already primed immune system leads to a significant increase in il- and tnf-α production by monocytes, which can have deleterious effects following injury or infection [ ] . these effects are likely a result of damps, residual white blood cells, and other soluble and insoluble mediators within the donor blood that contribute to a cascade of transfusion-related immunomodulation (trim), although the exact mechanisms remain difficult to elucidate. regardless, the transfusion of red blood cells has been associated with worsening organ dysfunction, increased rates of infection, and increased mortality [ , , ] . cars typically occurs in conjunction with late onset mods, as immunosuppression increases the potential for hospital acquired infections via immune-inflammatory dysregulation in which the balance of pro-inflammatory and anti-inflammatory mediators is disrupted [ ] . furthermore, it has been postulated that cytokines produced during this period of immune dysregulation may actually favor or promote the growth of bacteria [ ] . according to the trauma register of the german society of traumatology, more than % of civilian trauma patients with multiple injuries develop septic complications, with % of the patients developing multiple organ failure [ ] . among combat personnel admitted to a role facility during operation iraqi freedom, of ( . %) developed infections, with % of cases having wound infections followed by % with bacteremia and % with pneumonia. infection was more likely with those patients having had surgery prior to admission, higher iss, and injuries qualified as blast, abdominal, soft tissue, ≥ injury locations, or loss of limb. s. aureus, e. coli, p. aeruginosa and a. baumannii were the dominant causative organisms of infection, with many demonstrating multidrug resistance [ ] . sepsis and other nosocomial infections increase the risk of late onset mods, which carries a significant mortality burden. in another study of combat-related trauma patients with and without sepsis, of casualties with severe trauma who developed sepsis, developed mods and died. of the matched casualties with severe trauma and no evidence of sepsis, developed mods and died, demonstrating a . -fold higher mortality when trauma is complicated by sepsis [ ] . in combat-related burn patients, the presence of k. pneumoniae bacteremia was independently associated with an increased risk of mortality and increased ventilator days [ ] . according to the american burn association national burn repository, the primary cause of death in burn patients with sepsis is multi-organ failure ( . %), followed by pulmonary failure/sepsis ( . %) and burn wound sepsis ( %), with a higher total body surface area involvement associated with an increased risk of sepsis development and mortality [ ] . acute respiratory distress syndrome (ards) is the most frequent manifestation of mods following trauma, with to % of injured patients ultimately developing the syndrome. trauma patients who develop ards along with mods have mortality rates as high as to %; however, the attributable mortality to ards alone in this population has been difficult to delineate given the severity of co-existing injuries. additionally, ards causes significant morbidity in the trauma population, demonstrating increased rates of complications, longer hospital and icu lengths of stay, and increased hospital costs [ ] . ards has been shown to have varying patterns of onset within trauma cohorts with distinct risk factors for each pattern. in a study utilizing latent class analysis examining the timing of onset of ards in patients with trauma, major phenotypes were identified: early onset ards (occurring < h after trauma) and late onset ards (occurring > h after trauma). early onset ards was associated with an increased severity of thoracic trauma score, more severe early hypotension, and increased red blood cell transfusion during the initial resuscitation, suggesting that early onset ards may be characterized by higher iss and severe hemorrhagic shock necessitating the transfusion of blood products, which is consistent with a "one hit" model of mods and immune dysfunction. late onset ards was hypothesized to be associated with progressive mods and nosocomial infections consistent with the "two-hit" model of mods, in which dysfunction of the innate and adaptive immune systems plays a role in inappropriate immunosuppression, leading to an increased risk of nosocomial infections. despite the two phenotypes, there was no significant difference in mortality between early-and late-onset ards [ ] . in one study from , of mechanically ventilated us combat casualties from operation iraqi freedom/enduring freedom, ards was identified in . % and was associated with higher military-specific iss as well as hypotension and tachycardia at initial presentation. ards was also an independent risk factor for death (or . ) [ ] . additionally, large volumes of plasma and crystalloid infusion have been identified as independent risk factors for the development of ards in combat personnel [ ] . in a study examining the incidence and mortality of ards in combat-related burn patients, . % of mechanically ventilated burn patients developed ards with an overall mortality of . %. however, mortality increased in accordance with ards severity, with severe ards demonstrating . % mortality and a -fold increased odds of death. predictors for the development of moderate or severe ards were inhalation injury, higher iss, pneumonia, and the transfusion of fresh frozen plasma (ffp). [ ] . a recent study has demonstrated that the presence of mitochondrial dna (mtdna) damps from blood products is associated with the development of ards with ffp and platelets having the highest amounts of mtdna fragments prior to transfusion. following transfusion, patient serum concentrations of mtdna fragments increased linearly, with the serum quantity at h after transfusion being a predictor for the occurrence of ards ( . vs . ) [ ] . recently, with the advances provided by critical care medicine, more patients are surviving beyond the wellestablished sirs, cars, and early mods phenotypes and developing a chronic critical illness. this chronic critical illness is characterized by ongoing protein catabolism and a combination of inflammation and immunosuppression termed persistent inflammation-immunosuppression and catabolic syndrome (pics), which serves as a prolonged form of mods with late-term mortality [ ] . pics was characterized by gentile and moore et al. [ ] in as icu stay > days, c-reactive protein ≥ μg/dl, total lymphocyte count < . × /μl of blood, weight loss > % during hospitalization or body mass index < , creatinine height index < %, albumin level < . g/dl, prealbumin level < mg/dl, and retinol binding protein level < μg/dl. pics patients suffer from increased long-term mortality and have increased morbidity associated with manageable organ dysfunctions, poor wound healing, recurrent nosocomial infections, delirium, psychosocial stress, and prolonged rehabilitation needs with a decreased likelihood of returning to pre-insult functional status. recent research has demonstrated that sirs and cars may occur and proceed concurrently for prolonged periods of time leading to pics and that in addition to the mechanisms previously discussed, myeloid-derived suppressor cells (mdscs) may also play a critical role in the development of pics by augmenting both the immunosuppressed and pro-inflammatory state [ ] . following severe trauma or infection, granulocytes rapidly demarginate from the bone marrow and lymphocytes undergo massive apoptosis, creating space for hematopoietic progenitor production in an 'emergency myelopoiesis-granulopoiesis' [ ] . production in these disease states is shifted towards myelopoietic precursors, including mdscs, with the degree of expansion and persistence of mdscs being proportional to the severity of the inflammatory insult. mdscs are both pro-inflammatory and immunosuppressive through their interaction with t-cells and the production of various cytokines. though the precise incidence and evolution of pics after combat injury has not been studied, injured combat personnel may suffer from a milder form of pics as identified by chronic manageable organ dysfunction [ ] . stewart et al. [ ] demonstrated that of the combat injured personnel admitted to an icu, the iss at admission was consistently associated with an increased risk of development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease and at a higher rate than would be expected when compared to military controls. the development of these chronic diseases is likely, at least in part, driven by a chronic inflammatory response initiated by the initial injury and subsequent medical care, as a number of pro-inflammatory cytokines have been implicated in the development of hypertension, diabetes mellitus, coronary artery disease, and chronic kidney disease [ ] . despite the overwhelming presence of both systemic pro-inflammatory and compensatory anti-inflammatory responses after injury, treatment to curb the exaggerated phenotypes remains elusive. the reasons for the absence of targeted therapy are numerous; however, the crux of the issue lies in appropriately identifying the dynamic immunophenotype of a patient after injury. while the pro-inflammatory state happens immediately after injury, work from the late s showed that tolerance to endotoxin challenge could happen as soon as min after traumatic injury [ ] . while this may be an appropriate response to dampen the initial pro-inflammatory cascade, persistence of an anti-inflammatory phenotype after day of illness has been associated with higher mortality [ ] . thus, it seems reasonable to prevent or attempt to reverse the anti-inflammatory phenotype before the development of immune dysfunction. several therapies have been utilized, though the results have been mixed. granulocyte-macrophage colony stimulating factor and granulocyte colony stimulating factor gm-csf and granulocyte colony stimulating factor (g-csf) have been suggested as therapies to reverse the effects of immunosuppression. in a randomized, double-blinded trial of patients who had suffered traumatic brain injury or cerebral hemorrhage, the early application of g-csf ( μg/day) was associated with a reduced incidence of bacteremia, though not on other nosocomial infections or mortality [ ] . in another randomized control trial of patients with sepsis-induced immunosuppression, defined as reduced monocyte human leukocyte antigen-dr (mhla-dr) expression, patients received either a placebo or gm-csf ( μg/ kg/day) [ ] . those in the gm-csf group had a reduced duration of mechanical ventilation and an improved ex vivo monocyte cytokine response to bacterial endotoxin. though data on the use of g-csf during conflict is limited, it has been utilized to treat the myelosuppressive effects of mustard gas during the persian gulf war, suggesting that it could be offered in forward operating areas to aid in recovery [ ] . however, these results are tempered by a meta-analysis of both g-csf and gm-csf, demonstrating that while there was a quicker reversal of sepsis in patients who received therapy, there was no improvement in -day survival [ ] . ifn-γ is a cytokine important for the regulation of t cell function. early animal studies, such as one looking at infection mortality after hemorrhagic shock, showed that ifn-γ prophylaxis could reverse the immunosuppressive phenotype after injury [ ] . a later randomized, multicenter trial tested this hypothesis in severely injured patients through the preventive application of daily subcutaneous injections of ifn-γ ( μg) for days. while early mortality was not affected, mortality from infection was reduced in the ifn-γ treatment group after days [ ] . however, a later study in burn-injured patients receiving ifn-γ prophylaxis for days showed no difference in infection rates compared to placebo controls [ ] . though the application of ifn-γ after combat-related injuries has not been tested, issues could possibly arise from late complications related to the treatment, with a specific focus on wound healing, as animal studies have suggested that systemic ifn-γ treatment can impair wound healing [ ] . conversely, data showing that in dehisced wounds from combat-related injuries, ifn-γ expression is suppressed compared to wounds that heal appropriately, suggesting that either high or low levels of ifn-γ can alter the inflammatory response related to proper wound healing [ ] . the use of pooled intravenous immunoglobulin (ivig) has been proposed as an immunomodulator for some time. the concept behind its use is multifactorial, including receptor blockade, antigen binding, and opsonization. over the past several decades, numerous studies have been conducted examining the utility of either polyclonal or antigen-specific monoclonal ivig in the treatment of sepsis. in aggregate, systemic reviews and meta-analyses have led to no definitive conclusion about the efficacy of ivig in septic patients [ ] . however, within the more specific post-surgical population, the use of ivig has improved sepsis-mediated icu outcomes, especially when combined with appropriate antibiotic therapy [ , ] . in addition, one study examined the prophylactic application of ivig therapy in trauma patients. this randomized study tested the use of polyclonal ivig compared to albumin given in escalating doses ( to mg/kg/day) on hospital days , , and after admission for trauma. these patients also received penicillin prophylaxis on hospital days through . while there were no deaths related to infections in either group, the group that received ivig had a lower rate of nosocomial pneumonia and non-catheter infections [ ] . though the application of ivig after combat-related injuries to prevent immunologically induced organ dysfunction has not been tested, ivig has been used in deployed settings as a treatment for autoimmune diseases, suggesting the feasibility of such prophylactic use in combat areas [ ] . the feasibility of ivig use in deployed settings is further enhanced through the development of lyophilized ivig, which has a similar efficacy, yet a longer shelf life, that could be maintained within forward operating areas [ ] . interleukin- and transforming growth factor β despite the association of il- and tgf-β with an immunosuppressive phenotype, the application of il- antagonism to correct immunosuppression after trauma or injury has not been fully tested. animal models have suggested that the use of il- or tgf-β blocking antibodies can improve survival in polymicrobial sepsis [ ] . in addition, the combination receptor antagonism of il- and tgf-β has led to improved control of parasitic vectors similar to those observed in veterans who served in middle eastern conflicts, suggesting an additional potential benefit of il- and tgf-β antagonism to improve immune function [ , ] . currently, data supporting the clinical use of anti-il- antibodies are limited. its use has only been tested in a single pilot study looking at il- antagonism in patients with systemic lupus [ ] . this is in contrast to tgf-β blockade, which has received significant interest within cancer immunology, with several small molecule inhibitors and antibodies in development [ ] . the successful application of such therapeutics to combat-injured personnel to reverse immunosuppression remains unknown. while the application of the previously mentioned therapies has the largest amount of clinical evidence surrounding their use as immunomodulators in the post-injured or infected, other therapies are currently under investigation. one such therapy is interleukin- (il- ). this endogenous anti-apoptotic cytokine has a main function in supporting the proliferation and survival of effector t cells [ ] . preclinical studies have supported the use of recombinant il- as an immunostimulant to improve survival in animal models of sepsis [ , ] . this has led to a recent trial of human recombinant il- therapy to patients who had evidence of lymphopenia and persistent vasoactive medication requirements in the setting of sepsis [ ] . though the trial was underpowered to detect clinical differences, recovery in t cell counts and function was noted in the il- group, and this effect persisted for several weeks after the completion of therapy, suggesting that a limited early application may have longer-lasting effects. thymosin α is a peptide derived from thymic epithelial cells that has both immunostimulating and immunotolerizing effects on antigen presenting cells and t cells. its use in humans as an immunomodulator dates back to the s when it was used as a therapy to treat immunodeficiency in athymic patients [ ] . the immunomodulatory effects eventually led to its development as a commercially available therapy, called thymalfasin, which was tested as an adjuvant therapy in hepatitis and cancer [ , ] . its properties further led to the investigation of thymosin α as an adjuvant in sepsis. a recent systematic review of clinical trials demonstrated that thymosin α offered daily during sepsis showed benefits with regard to improved t cell counts, reduced cytokinemia, and a reduction in mortality risk ratio to . [ ] . there have been no studies examining the effectiveness of thymosin α in forward operating areas but given that it is supplied as a lyophilized powder that can be injected subcutaneously, its application in such areas would be testable. programmed death- and programmed death ligand- ameliorating t cell and macrophage dysfunction after injury has also been examined by targeting the programmed death- (pd- ) and programmed death ligand- (pd-l ) axis. using animal models of sepsis, the application of pd- or pd-l antibodies around sepsis initiation was associated with reduced leukopenia and improved survival [ ] [ ] [ ] . in humans, treatment of blood with anti-pd- or anti-pd-l antibodies from patients with sepsis or surgically mediated t cell suppression demonstrated decreased t cell apoptosis and increased ifn-γ production [ , ] . clinical trials of antibodies targeting pd- have been further employed in a variety of cancers as well as human immunodeficiency virus infection [ , ] . extrapolation of these efforts into treating patients with immunosuppression after sepsis led to a phase clinical trial using an anti-pd- antibody (#nct ); however, the trial was terminated in . though the pre-clinical data for modulating the pd- /pd-l axis is promising, further data are needed to determine its potential role in reversing the immunosuppressed phenotype after combat-related injuries. the asymmetric warfare of modern conflicts has led to an increased number of wounded combat personnel injured by blast injuries due to the increased utilization of improvised and rocket propelled explosive devices. patients who survive the initial trauma of injury and resuscitation are at risk for several late consequences of their injuries. among these consequences, delayed wound healing, late onset sepsis and infection, multi-organ dysfunction syndrome, acute respiratory distress syndrome, and persistent inflammation-immunosuppression and catabolic syndrome are significant in their association with the increased morbidity and mortality of wounded personnel. these late consequences of trauma have been shown to be associated with a dysregulated immune system that leads to an immunosuppressed state with variable immunophenotypes. promising research into determining the immune profiles of trauma patients to help personalize and target therapies may provide a potential avenue in preventing late complications and directing treatment [ , , ] . recent epigenetic work by scicluna et al. [ ] has demonstrated the ability to identify the immunophenotypes of sepsis patients according to the four molecular endotypes-mars , mars , mars , and mars . the mars endotype was associated with increased -day mortality and was characterized by decreased expression of promoter genes for both the innate and adaptive immune systems, indicative of an immunosuppressed phenotype. the mars and mars endotypes were associated with genes involved in pro-inflammatory and innate signaling, while the mars endotype was characterized by genes involved in the adaptive immune or t-cell pathways and was associated with the lowest risk of mortality. trauma, like sepsis, induces changes in gene expression in accordance with epigenetic gene regulation principles. these modifications in dna processing play a role in determining the immunophenotype of the injured [ ] . based on these results, pcr-based phenotype identification may soon be available for targeted treatment strategies [ ] . future research into immunomodulatory therapies and further advancements in resuscitation, including the use of artificial intelligence and machine learning to guide resuscitation efforts, will be necessary to improve the morbidity and mortality associated with the late consequences of trauma after combat-related injuries [ ] . incidence and epidemiology of combat injuries sustained during "the surge" portion of operation iraqi freedom by a u.s. army brigade combat team combat musculoskeletal wounds in a us army brigade combat team during operation iraqi freedom pelvic, spinal and extremity wounds among combat-specific personnel serving in iraq and afghanistan ( - ): a new paradigm in military musculoskeletal medicine an analysis of inhospital deaths at a modern combat support hospital early prevention of trauma-related infection/ sepsis inflammatory response is associated with critical colonization in combat wounds blast injuries: mechanics and wounding patterns negative pressure wound therapy in the management of combat wounds: a critical review challenges of treating modern military trauma wounds optimal use of blood in trauma patients the evolution of pain management in the critically ill trauma patient: emerging concepts from the global war on terrorism the majority of us combat casualty soft-tissue wounds are not infected or colonized upon arrival or during treatment at a continental us military medical facility triage in military settings definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis sir isaac newton, sepsis, sirs, and cars innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care the compensatory anti-inflammatory response syndrome (cars) in critically ill patients trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient the sterile inflammatory response cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. relation with subsequent adult respiratory distress syndrome and multiple organ failure alarmins: feel the stress hmgb is markedly elevated within hours of mechanical trauma in humans early release of high mobility group box nuclear protein after severe trauma in humans: role of injury severity and tissue hypoperfusion hmgb , a potent proinflammatory cytokine in sepsis tnf tolerance in monocytes and macrophages: characteristics and molecular mechanisms endotoxin tolerance after severe injury and its regulatory mechanisms endotoxin tolerance: is there a clinical relevance? an endotoxin tolerance signature predicts sepsis and organ dysfunction at initial clinical presentation interleukin- is a central regulator of the response to lps in murine models of endotoxic shock and the shwartzman reaction but not endotoxin tolerance antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (il)- receptor type ii, il- , and il- concentrations of cytokines il- and il- in plasma of burn patients: their relationship to sepsis and outcome relationship of interleukin- plasma levels to severity of injury and clinical outcome in injured patients immune cytokine response in combat casualties: blast or explosive trauma with or without secondary sepsis transforming growth factor-beta and major trauma: timedependent association with hepatic and renal insufficiency inflammatory biomarkers in combat wound healing primer on the immune system trauma-hemorrhage induces depressed splenic dendritic cell functions in mice depressed interferon gamma production and monocyte hla-dr expression after severe injury lack of recovery in monocyte human leukocyte antigen-dr expression is independently associated with the development of sepsis after major trauma early interleukin- and slope of monocyte human leukocyte antigen-dr: a powerful association to predict the development of sepsis after major trauma post-operative immune suppression is mediated via reversible, interleukin- dependent pathways in circulating monocytes following major abdominal surgery persisting low monocyte human leukocyte antigen-dr expression predicts mortality in septic shock sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern distinct mechanisms of immunosuppression as a consequence of major surgery depressed t cell-derived ifn-gamma following trauma-hemorrhage: a potential mechanism for diminished apc responses. langenbeck's arch surg interferon-gamma: an overview of signals, mechanisms and functions major surgical trauma differentially affects t-cells and apc overcoming t cell exhaustion in infection and cancer programmed death expression as a marker for immune and physiological dysfunction in the critically ill surgical patient the nature and extent of war injuries sustained by combat specialty personnel killed and wounded in afghanistan and iraq gram negative wound infection in hospitalised adult burn patients--systematic review and metanalysis burn injury: challenges and advances in burn wound healing, infection, pain and scarring surviving sepsis campaign: international guidelines for management of sepsis and septic shock immunosuppression following surgical and traumatic injury persistent inflammatory, immunosuppressed, catabolic syndrome (pics): a new phenotype of multiple organ failure evolving concepts in the pathogenesis of postinjury multiple organ failure augmented tnfalpha and il- production by primed human monocytes following interaction with oxidatively modified autologous erythrocytes mechanisms of red blood cell transfusion-related immunomodulation trauma-related infections in battlefield casualties from iraq outcomes of bacteremia in burn patients involved in combat operations overseas comparison of mortality associated with sepsis in the burn, trauma, and general intensive care unit patient: a systematic review of the literature acute respiratory distress syndrome after trauma: development and validation of a predictive model heterogeneous phenotypes of acute respiratory distress syndrome after major trauma incidence, risk factors, and mortality associated with acute respiratory distress syndrome in combat casualty care transfusion strategies and development of acute respiratory distress syndrome in combat casualty care acute respiratory distress syndrome in wartime military burns: application of the berlin criteria potential contribution of mitochondrial dna damage associated molecular patterns in transfusion products to the development of acute respiratory distress syndrome after multiple transfusions retrospective analysis of long-term outcomes after combat injury: a hidden cost of war the extent of traumatic damage determines a graded depression of the endotoxin responsiveness of peripheral blood mononuclear cells from patients with blunt injuries effect of prophylactic administration of recombinant human granulocyte colonystimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage. the filgrastim study group granulocyte-macrophage colony-stimulating factor to reverse sepsisassociated immunosuppression: a double-blind, randomized, placebocontrolled multicenter trial granulocyte colony stimulating factor (g-csf) for mustard-induced bone marrow suppression granulocyte-colony stimulating factor (g-csf) and granulocyte-macrophage colony stimulating factor (gm-csf) for sepsis: a meta-analysis interferon-gamma restores immune competence after hemorrhagic shock effect of interferon gamma on infection-related death in patients with severe injuries. a randomized, double-blind, placebo-controlled trial interferon-gamma in the prevention of severe burn-related infections: a european phase iii multicenter trial. the severe burns study group systemic administration of interferon-gamma impairs wound healing mantaring jb rd. intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock effect of adjuvant immunoglobulin therapy on infections in patients in an surgical intensive care unit. results of a randomized controlled study effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins guillain-barre variant in the deployed setting information for healthcare providers on general features of igiv with emphasis on differences between commercially available products neutralization of interleukin- or transforming growth factor-beta decreases the percentages of cd + cd + foxp + regulatory t cells in septic mice, thereby leading to an improved survival visceral infection caused by leishmania tropica in veterans of operation desert storm il- and tgf-beta control the establishment of persistent and transmissible infections produced by leishmania tropica in c bl/ mice clinical and biologic effects of anti-interleukin- monoclonal antibody administration in systemic lupus erythematosus novel tgf-beta inhibitors ready for prime time in onco-immunology il- administration alters the cd :cd ratio, increases t cell numbers, and increases t cell function in the absence of activation il- promotes t cell viability, trafficking, and functionality and improves survival in sepsis interleukin immunotherapy improves host immunity and survival in a two-hit model of pseudomonas aeruginosa pneumonia interleukin- restores lymphocytes in septic shock: the iris- randomized clinical trial thymosin activity in patients with cellular immunodeficiency thymalfasin in the treatment of hepatitis b and c thymosin alpha and cancer: action on immune effector and tumor target cells the efficacy of thymosin alpha as immunomodulatory treatment for sepsis: a systematic review of randomized controlled trials delayed administration of anti-pd- antibody reverses immune dysfunction and improves survival during sepsis pd-l blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction frontline science: anti-pd-l protects against infection with common bacterial pathogens after burn injury surgical trauma induces postoperative t-cell dysfunction in lung cancer patients through the programmed death- pathway targeting the programmed cell death : programmed cell death ligand pathway reverses t cell exhaustion in patients with sepsis development of pd- and pd-l inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations clinical trial of the anti-pd-l antibody bms- in hiv- infected participants on suppressive antiretroviral therapy metalloproteinase expression is associated with traumatic wound failure biomarkers for patients with trauma associated acute respiratory distress syndrome classification of patients with sepsis according to blood genomic endotype: a prospective cohort study immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach blood pressure and heart rate from the arterial blood pressure waveform can reliably estimate cardiac output in a conscious sheep model of multiple hemorrhages and resuscitation using computer machine learning approaches funding rjs was supported by national institutes of health grants, k -gm .availability of data and materials not applicable. authors' contributions kbt, ltk and rjs all contributed to writing the manuscript, with kbt creating the initial draft. all authors read and approved the final manuscript.ethics approval and consent to participate not applicable. not applicable. the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the air force, navy, the department of defense or the u.s. government (kbt, ltk). key: cord- -zdzeqc authors: agarwal, ritesh; gupta, dheeraj; aggarwal, ashutosh n.; behera, digamber; jindal, surinder k. title: experience with ards caused by tuberculosis in a respiratory intensive care unit date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: zdzeqc objective: acute respiratory distress syndrome (ards) is an important cause of morbidity and mortality in intensive care units. tuberculosis (tb) commonly causes respiratory failure in patients with extensive pulmonary parenchymal involvement, but it is a rare cause of ards. we report our experience of tb presenting with ards. methods: retrospective analysis of patients admitted with a diagnosis of ards over the previous years. data are presented in a descriptive fashion using mean±sd or median (range). results: nine ( . %) of patients had ards secondary to tuberculosis. all patients were mechanically ventilated. the diagnosis was made on clinico-radiological grounds and confirmed later using fiberoptic bronchoscopy and transbronchial biopsy in seven patients, and lymph node biopsy and examination of the joint aspirate in the remaining two. all patients were empirically started on anti-tubercular therapy with a median time to initiation of therapy being days (range – days). three patients had multi-organ dysfunction syndrome (mods) without any evidence of bacterial infection. seven of nine ( . %) patients survived; two died because of severe ards, mods, and respiratory failure. conclusions: tuberculosis is an uncommon but definite cause of ards, and in patients with ards of obscure aetiology where the clinical features suggest tuberculosis as the inciting cause, antitubercular therapy should be started empirically and the diagnosis actively pursued later. abstract objective: acute respiratory distress syndrome (ards) is an important cause of morbidity and mortality in intensive care units. tuberculosis (tb) commonly causes respiratory failure in patients with extensive pulmonary parenchymal involvement, but it is a rare cause of ards. we report our experience of tb presenting with ards. methods: retrospective analysis of patients admitted with a diagnosis of ards over the previous years. data are presented in a descriptive fashion using mean€sd or median (range). results: nine ( . %) of patients had ards secondary to tuberculosis. all patients were mechanically ventilated. the diagnosis was made on clinico-radiological grounds and confirmed later using fiberoptic bronchoscopy and transbronchial biopsy in seven patients, and lymph node biopsy and examination of the joint aspirate in the remaining two. all patients were empirically started on anti-tubercular therapy with a median time to initiation of therapy being days (range - days). three patients had multi-organ dysfunction syndrome (mods) without any evidence of bacterial infection. seven of nine ( . %) patients survived; two died because of severe ards, mods, and respiratory failure. conclusions: tuberculosis is an uncommon but definite cause of ards, and in patients with ards of obscure aetiology where the clini- acute respiratory distress syndrome (ards) is a common disorder in the intensive care unit (icu) and is associated with high mortality and morbidity [ ] . the common causes includes sepsis, pneumonia, aspiration, etc. tuberculosis (tb) remains a major public health problem in most of the developing world, and the epidemic of acquired immunodeficiency syndrome has resulted in a resurgence of tb the world over. tuberculosis is a disease of protean manifestations with lungs being the most commonly involved site. untreated pulmonary tb carries a mortality of % with the most common cause of death being extensive fibrocavitary disease and respiratory failure [ ] . tuberculosis can cause ards, and this usually occurs in the setting of disseminated disease such as miliary tb. there have been case reports and small case series describing association of ards and pulmonary tb [ , , , , ] ; however, tb is rarely recognized as a cause of ards. in fact, in none of the recent reviews does tb figure in the list of ards [ , ] . despite being a public health problem of significant magnitude in india [ ] , the largest series of tb and ards reported from india included only six cases of tb and ards over a -year period [ ] . although tb is a treatable illness, there has been a persistently high mortality ( - %) in patients with severe pulmonary tb and acute respiratory failure [ , ] . this is probably due to delayed recognition of the fact that tb can cause ards and acute respiratory failure [ ] . herein, we describe our experience with "tuberculous ards", and alert the clinicians that tuberculosis can cause ards and must figure in the differential diagnosis of "cryptic" ards. the records of patients admitted to the respiratory intensive care unit (ricu) with a diagnosis of ards between july to june were reviewed. patients of ards, where the underlying cause was diagnosed as tuberculosis, were selected. the original case records of the patients were then retrieved from the central registration department. demographic information, such as age and gender, underlying and/or concomitant diseases, and clinical status at admission to icu, including the details of organ failure, were recorded. details of the clinical manifestations and investigations, such as liver and renal function tests, arterial blood gases, hiv serology, complete blood count, and coagulation profile, were recorded. details of their stay in ricu and ventilator strategy, apache ii scores, treatment, and outcome were noted. at admission to the ricu, diagnosis of ards was established on the basis of acute onset respiratory distress, bilateral infiltrates on chest radiograph, pao/fio ratio < , and no clinical or radiological evidence of left atrial hypertension [ ] . all patients were mechanically ventilated (puritan bennett ae, hamilton amadeus). an informed consent was taken from all patients or their relatives as per protocol. activity and outcome parameters are presented in a descriptive fashion (mean€sd or median with range). there were admissions in the respiratory intensive care unit during this period and acute respiratory distress syndrome (ards) was diagnosed in ( . %) patients (table ) . infectious causes constituted the majority of cases of ards ( . %). nine of ( . %) patients (five males, four females) were finally diagnosed to have tuberculosis (tb) and ards. the mean age of these patients was . years (sd . years, range - years). the underlying comorbidities were post-renal transplant, alcoholism and diabetes mellitus in one patient each; one patient developed ards during pregnancy. serology performed for human immunodeficiency virus (hiv) was non-reactive in all the patients. the baseline characteristics, clinical presentations, radiological and laboratory parameters, investigations and the outcome of the patients are shown in table . the median acute physiology and chronic health evaluation ii (apache ii) scores were (range - ) and (range - ) for the tuberculous and non-tuberculous ards, respectively. although patients had fever, anorexia, weight loss and cough for a median duration of days (range - days), all had history of acute onset dyspnoea (duration < days). none of the patient had history of hemoptysis. physical exam-ination of the respiratory system was non-contributory; five patients had firm hepatosplenomegaly, two had cervical lymphadenopathy, three had clinical signs of meningitis and one patient had monoarticular arthritis. at admission, all patients had anaemia and hypoalbuminaemia; two patients had thrombocytopaenia, one leucopaenia, whereas none had coagulopathy. three patients had hyponatraemia, one had conjugated hyperbilirubinaemia and five had raised serum alkaline phosphatase. the mean pao /fio ratio was (sd . , range - ). all patients were started empirically on four drug [daily doses: isoniazid mg/kg (maximum mg); rifampicin mg/kg (maximum mg); pyrazinamide mg/kg (maximum gm); and ethambutol mg/kg (maximum . gm)] anti-tubercular therapy (given through nasogastric tube) based on clinical suspicion and diagnostic procedures were attempted as clinically feasible. the median time to initiation of anti-tubercular therapy was days (range - days). none of the patients received glucocorticoids. all patients were mechanically ventilated. the median duration of mechanical ventilation was days (range - days). radiology revealed miliary nodules in patients and consolidation in patient. tracheal aspirate sent for ziehl-neelsen staining did not reveal acid-fast bacilli in any of the patients. fiberoptic bronchoscopy and transbronchial lung biopsy (tbb) was performed in patients only once they were extubated, and was the most common method used for diagnosis. (the diagnosis in the remaining two patients was made on lymph node biopsy and joint aspirate; table ). the diagnosis was established with histopathological evidence of epithelioid granuloma and positive acid-fast bacilli on ziehl-neelsen stain. the overall mortality in patients with tuberculous ards was tuberculosis (tb) is an uncommon cause of acute respiratory distress syndrome (ards) associated with a very high mortality [ , , , , ] . lipoarabinomannan, a component of mycobacterial cell wall, acts in a manner similar to the antigens in bacterial sepsis, to activate the inflammatory cascade [ ] , and all features of mods with haemodynamic findings of septic shock have been described in patients with tb and ards who did not have any associated bacterial infection [ ] . in this study, the incidence of tuberculous ards was . % and could reflect referral bias or the high prevalence of tuberculosis in this country. eight of our patients had miliary shadows, whereas one had consolidation both of which can present with ards [ , , , , , ] . the demographic details and clinical features of our patients are similar to that described in the literature [ , ] . three of our patients had mods without any evidence of bacterial infection, although all of them were also given empiric antibiotics to cover for bacterial infection. the clinical clues, which pointed towards the diagnosis of tuberculosis, were the presence of longer history, lymphadenopathy, firm hepatosplenomegaly, miliary shadows on chest radiograph and raised alkaline phosphatase (suggesting granulomatous hepatitis). an elevated alkaline phosphatase is a useful clue and has been reported in up to % of patients with miliary tb [ ] . hyponatraemia has been described as a predictor of mortality in patients with miliary tb [ ] . in the present study, patients had hyponatraemia, of which one died from her illness. in our study, transbronchial biopsy (tbb) was performed only once the patients were extubated, as the diagnostic yield of tbb in a mechanically ventilated patients is generally poor because of its small size and yield of non-representative tissue [ ] . furthermore, it carries a significant risk of morbidity like bleeding and pneumothorax and the occurrence of pneumothorax and/or bronchopleural fistula in the seriously ill, mechanically ventilated patient requiring high levels of peep can be life threatening [ ] . tracheal aspirates sent for ziehl-neelsen staining for acid-fast bacilli and cultures were non-contributory, whereas tissue biopsies and histopathology were diagnostic in all patients. in our series, the overall mortality of patients with ards was . %, whereas it was . % in patients with tuberculosis and ards. the overall high mortality in this study for ards is because of obvious differences in case mix, delays in transfer of critically ill patients from emergency room to icu because of limited availability of beds, possible selection bias as sickest patients with multiple organ failure are admitted in the icu and other logistic reasons [ ] . the probable reason for better outcome of tuberculous ards in this study could be that the diagnosis was suspected clinically, and anti-tubercular therapy was instituted empirically (median time to initiation being days) based on clinical diagnosis. this can also account for the shorter duration of mechanical ventilation in our patients. also delayed treatment is known to contribute to mortality in icu patients with pulmonary tb and acute respiratory failure [ ] . however, this conclusion has limitations in that we cannot exclude the possibility that the decreased mortality is due to a selection bias. also the retrospective design of the study and small numbers makes it difficult to draw any firm conclusion. but our study does suggest that early clinical diagnosis and empiric therapy can improve the outcome of an uncommon but treatable cause of ards. in contrast to reports of patients with miliary tb being treated with antituberculous drugs and glucocorticoids, none of our patients received steroids. in conclusion, tuberculosis is an uncommon cause of ards. in regions where tuberculosis is common or in patients with ards of obscure aetiology, where the clinical features suggest tuberculosis as the inciting cause, antitubercular therapy should be started empirically and the diagnosis actively pursued later. the acute respiratory distress syndrome epidemiology tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation acute respiratory distress syndrome (ards) in miliary tuberculosis: a twelve-year experience delayed treatment contributes to mortality in icu patients with severe active pulmonary tuberculosis and acute respiratory failure miliary tuberculosis and acute respiratory distress syndrome patient mortality of active pulmonary tuberculosis requiring mechanical ventilation epidemiology and prognosis of acute respiratory distress syndrome definitions, mechanisms, relevant outcomes, and clinical trial coordination molecular biology, virulence, and pathogenicity of mycobacteria hemodynamic confirmation of septic shock in disseminated tuberculosis clinical and high-resolution computed tomographic findings in five patients with pulmonary tuberculosis who developed respiratory failure following chemotherapy clinical profile, laboratory characteristics and outcome in miliary tuberculosis indications of bal, lung biopsy, or both in mechanically ventilated patients with unexplained infiltrations adult respiratory distress syndrome in the tropics key: cord- -hx lkuj authors: morty, rory e.; eickelberg, oliver; seeger, werner title: alveolar fluid clearance in acute lung injury: what have we learned from animal models and clinical studies? date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: hx lkuj background: acute lung injury and the acute respiratory distress syndrome continue to be significant causes of morbidity and mortality in the intensive care setting. the failure of patients to resolve the alveolar edema associated with these conditions is a major contributing factor to mortality; hence there is continued interest to understand the mechanisms of alveolar edema fluid clearance. discussion: the accompanying review by vadász et al. details our current understanding of the signaling mechanisms and cellular processes that facilitate clearance of edema fluid from the alveolar compartment, and how these signaling processes may be exploited in the development of novel therapeutic strategies. to complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of alveolar edema fluid clearance in acute lung injury and acute respiratory distress syndrome. furthermore, it considers how what we have learned from these animal and organ models and clinical studies has suggested novel therapeutic avenues to pursue. acute lung injury (ali), and its more severe form, acute respiratory distress syndrome (ards), are important causes of morbidity and mortality in critically ill patients [ ] . one of the hallmarks of ali/ards is the accumulation of protein-rich edema fluid in the alveolar compartment of the lung [ ] , caused by increased fluid influx into the airspaces, and decreased fluid transport out of these airspaces. in the case of the latter, impaired alveolar fluid clearance (afc) is a key underlying cause of alveolar edema persistence [ , ] , and the ability of ali/ards patients to clear edema fluid is correlated with a shorter stay in the intensive care unit, and reduced mortality [ ] . much effort has therefore been focused on identifying pathogenic mechanisms underlying perturbed afc in ali/ards patients, and how we can potentiate afc, which may form the basis of novel or improved therapeu-tic strategies. the accompanying review by vadász et al. (http://dx.doi.org/ . /s - - - ) details our current understanding of the signaling mechanisms that facilitate afc. to complement that report this review focuses on how intact organ and animal models and clinical studies have facilitated our understanding of afc in ali/ards. we also discuss how some of these studies have led to novel therapeutic approaches. edema fluid is transported out of the alveolar airspaces into the interstitium, where it is cleared by the lymphatic drainage. alternatively, fluid can also be transported into the vasculature, where it is cleared by the circulation. maintenance of an optimum alveolar fluid volume results from a finely balanced influx of fluid into the lung, and fluid clearance out of the lung; therefore, endothelial and epithelial barrier integrity is essential for optimal fluid balance [ ] . in patients with ali/ards, the integrity of both the endothelial and epithelial barriers may be compromised, leading to accelerated fluid influx into the alveolar compartment and impaired afc [ ] . in healthy lungs the alveolar epithelium is considerably less permeable than the endothelium [ ] . approximately % of the alveolar epithelium surface area is composed of flat alveolar type i cells, with the remaining % accounted for by cuboidal type ii cells which produce surfactant and are progenitor cells that regenerate the epithelium after injury. historically, type ii cells are accredited with a key role in afc. it is widely accepted that afc is driven by sodium transport across the airway epithelium, which is affected by the concerted action of two sodium transport systems: the epithelial sodium channel (enac) [ ] and the na + , k + transporting adenosine- -triphosphatase (na,k-atpase) [ ] as well as the cystic fibrosis transmembrane conductance regulator (cftr; a chloride channel) [ ] and other, as yet uncharacterized channels [ ] . impaired function of any one of these ion transport systems can perturb afc. diffuse alveolar damage, including severe alveolar epithelial damage, is one of the hallmarks of ali/ards [ , ] , where extensive type i cell necrosis occurs, leaving an intact but denuded basement membrane which is repopulated by hyperplastic type ii cells that regenerate the alveolar epithelium [ ] . given the established importance of the type ii cell in afc [ ] and the emerging importance of the type i cell in afc with the recent discovery that type i cells also contain functional sodium and chloride channels [ ] , this epithelial damage fig. factors that cause impaired alveolar fluid clearance in ali/ards that have been investigated in animal and organ models and in clinical studies. anf, atrial natriuretic factor; enac, epithelial sodium channel; na,k-atpase, na + , k + transporting adenosine- triphosphatase, tgf-β, transforming growth factor β is likely to massively impact afc in ali/ards patients. this idea is strengthened by the observation that in patients with hydrostatic pulmonary edema, which may result from congestive heart failure or acute myocardial infarction, both the alveolar epithelial barrier and afc remain intact [ ] . animal and organ models have proved particularly useful to study afc, because the three-compartment (alveolar airspace-interstitium-vasculature) structure of the lung is preserved [ ] [ ] [ ] . studies in humans have relied heavily on the assessment of extravascular lung water (evlw) [ ] . more recently, nasal potential difference (npd) has been employed as a surrogate measurement for transepithelial ion transport [ ] , although this measurement is clearly limited in its usefulness when studying diseases that exclusively impair alveolar ion transport. the aspects of impaired afc in ali/ards that have been examined in animal or organ models and clinical studies are summarized in fig. . studies in live, anesthetized, ventilated sheep provided the first evidence that alveolar fluid relied on active ion transport, where clearance of salt and water occurred against an increase protein concentration in the alveolar lining fluid [ ] . supporting these data, fluid clearance was impeded at low temperature in in situ perfused goat lungs (maintained at °c) [ ] , and in isolated, perfused liquid-filled rat lungs [ ] consistent with the inhibition of an active transport process. active sodium transport in particular was implicated in afc, since amiloride, a potent and specific inhibitor enac inhibited - % of basal fluid clearance in sheep, rabbits, rats, mice, and in the human lung [ ] . o'brodovich and colleagues [ ] have further demonstrated that application of amiloride to newborn guinea pig lungs caused respiratory distress, hypoxemia and elevated extravascular lung water, implicating active sodium transport in afc in neonates. consistent with this idea, targeted deletion of both enacα alleles in mice caused death within h of birth as a consequence of impaired afc [ ] . transgenic overexpression of the enacα gene in an enacα -/null mouse background rescued this pulmonary phenotype [ ] . conversely, overexpression of enac in the mouse lower airways accelerated sodium absorption, and depleted the volume of fluid coating the airway epithelium [ ] . together, these data implicate both active transepithelial sodium transport and enac itself in afc. using small interfering rna directed against enacα applied to the airways of live rats, other non-enac type ion channels are also likely to play an important role in transepithelial sodium transport and fluid reabsorption, particularly baseline fluid reabsorption [ ] . while enac located on the apical surface of alveolar epithelial cells acts as a sodium channel, investigations in live animals and isolated organ models have revealed that the driving force behind enac-mediated sodium uptake is the na,k-atpase [ ] . ouabain, a potent and specific inhibitor of the na,k-atpase, inhibited afc in isolated, perfused fluid-filled mouse lungs [ ] . furthermore, adenoviral-mediated gene transfer of the na,k-atpase β subunit into the lungs of rats augmented afc [ ] . furthermore, overexpression of the na,k-atpase β subunit in the alveolar epithelium restored active transepithelial sodium transport and afc in a rat model of acute hydrostatic pulmonary edema [ ] . gene knockout strategies have also addressed a role for the two na,k-atpase α subunits in afc, where mice heterozygous for each of the na,k-atpase α subunits (α +/-/α +/-) exhibit reduced cyclic-adenosine monophosphate (camp) dependent afc [ ] . in addition to a role for sodium transport, it has recently emerged that chloride transport via the cftr channel also plays a role in afc. using glibenclamide, an inhibitor of potassium and cftr channels, fluid clearance from in situ perused and unperfused mouse lungs and ex vivo human lungs was impaired [ ] . these data were supported using a cystic fibrosis (∆f ) mouse in a model of acute hydrostatic edema, where chloride transport by the cftr channel was demonstrated to play a major role in afc [ ] . further supporting this idea, adenoviral-mediated transfer of the cftr gene into the lungs of live rats and mice significantly increased afc, an effect that was blocked in the presence the chloride channel blockers -nitro- -( phenylpropylamino) benzoic acid, bumetanide, and gliben-clamide [ ] . animal and organ models have thus confirmed invaluable in the identification of transepithelial active sodium transport as the basis of afc, and in the validation of enac and other channels and the na,k-atpase, as key components that drive this process. mechanisms of impaired fluid clearance in ali/ards: what we have learned from intact organ and animal models, and clinical studies hypoxia is a feature of both ards and high-altitude pulmonary edema (hape). in isolated, ventilated rat lungs perfused at constant pressure (therefore independent of pressure changes caused by adaptation to hypoxic pulmonary vasoconstriction), exposure to hypoxia ( . . these and other observations introduced the possibility of using gene therapy to augment afc and treat ali/ards. patients with ali/ards frequently require mechanical ventilation to facilitate breathing. however, mechanical ventilation can directly induce ali (ventilator-induced lung injury, vili), by promoting alveolo-capillary barrier permeability [ , ] , inducing proinflammatory cytokines [ ], or by directly inhibiting afc. supporting the latter idea, lecuona et al. [ ] demonstrated that ventilation of rats with high tidal volumes (v t ) of ml/kg and a peak airway pressure of cmh o rapidly impaired afc, accompanied by a significant decrease in activity (but not expression) of na,k-atpase. thus high v t ventilation can directly block afc by inhibiting na,k-atpase-driven sodium transport, and hence afc. mechanical ventilation can also worsen preexisting ali (ventilator-associated lung injury, vali). in a canine model of acid aspiration-induced ali corbridge et al. [ ] demonstrated that ventilation with high v t ( ml/kg) but a fixed, low positive end-expiratory pressure (peep; cmh o) increased evlw to a greater extent than did ventilation with lower v t ( ml/kg) but a fixed, higher peep ( cmh o). similar trends were observed in an acid aspiration-induced model of ali in rats, where a progressive reduction in v t from to to ml/kg, keeping peep fixed at to cm h o, was accompanied by a progressive decrease in evlw accumulation [ ] . in both instances a low v t /high peep strategy proved beneficial. thus in addition to reducing both permeability and proinflammatory cytokine release, a low v t /high peep ventilation strategy might also promote afc and has formed the basis of important advances in ventilation strategies for ali/ards patients that are in routine use today. hyperventilation and hypocapnic alkalosis are often found together in patients with ali/ards [ ] . in an isolated, buffer-perfused ventilated rabbit lung, exposure to hypocapnia (> h) increased vascular permeability, and hence promoted alveolar edema [ ] . further to this, using an isolated, perfused, fluid-filled rat lung, myrianthefs et al. [ ] demonstrated that hypocapnia dramatically impaired afc. this block was reversible upon restoration of normal co levels and was not induced by metabolic alkalosis. the afc block was attributed to impaired sodium transport resulting from decreased membrane abundance of the na,k-atpase in rat lungs [ ] . hypocapnia can therefore promote both the formation of alveolar edema and impair the resolution of this edema by blocking transepithelial sodium transport, and hence afc. procoagulant pathways are upregulated in ali/ards, while fibrinolysis is suppressed [ ] . coagulation proteases such as thrombin have well documented roles in the development of ali/ards where thrombin can directly increase vascular permeability and promote alveolar flooding [ ] . recent work by vadász et al. [ ] demonstrated that thrombin applied to the vascular compartment of isolated, ventilated and perfused rabbit lungs also impaired afc. this was attributed to a block in transepithelial sodium and hence fluid transport across the alveolocapillary barrier. it was subsequently demonstrated that thrombin promoted the endocytosis of the na,k-atpase, thereby reducing na,k-atpase activity (see the accompanying review by vadász et al. (http://dx.doi.org/ . /s - - - ). thus coagulation proteases play a dual role in impaired afc. in addition to causing a permeability edema, thrombin, by virtue of its signaling properties, directly blocks fluid reabsorption. in contrast to the thrombin-signaling effects on na,k-atpase trafficking, serine proteases can directly enhance β-adrenergic-stimulated enac activity in alveolar epithelial cells and enhance β-adrenergic-stimulated afc in live mice [ ] . thus serine proteases appear to have opposing effects on different components of the sodium transport machinery. infection and purified endotoxin promote vascular permeability and pulmonary edema by inflammatory mechanisms involving granulocytes [ ] . interestingly, afc was upregulated after intratracheal administration of endotoxin to live rats and in a rat model of septic shock [ ], possibly as a protective mechanism induced during septic shock to overcome alveolar flooding. however, both cell-surface enac expression and afc were downregulated in an experimental mycoplasma pneumoniae infection in live mice, an effect mediated by reactive oxygen-nitrogen intermediates [ ]. this phenomenon is not limited to bacterial pathogens, since in live rats, the influenza virus can directly impair enac activity by reducing the open probability (p o ) of the channel, and thus downregulate afc, independently of viral entry into the epithelium [ ] . thus it appears that lung infections can impair afc, although there appear to be multiple underlying causes. acute lung injury may develop rapidly in recipients of transfused whole plasma [ ] . this transfusion-associated acute lung injury (trali) is caused by biologically active lipids, and antileukocyte antibodies, which cause a pronounced vascular leak [ ] . in a new mouse model of trali looney et al. [ ] have demonstrated that afc is also impaired in trali, although the molecular mechanism has not been described. levels of proinflammatory factors are elevated in bronchoalveolar lavage fluids from ali/ards patients, including interleukin (il) β, il- , il- , tumor necrosis factor (tnf)-α, and transforming growth factor (tgf) β [ ]. based on studies in rats fukuda et al. [ ] demonstrated that different domains of tnf-α have opposing effects on sodium transport and afc, where interaction with the tnf-α receptor caused inflammation and increased permeability, while the tnf-α lectin-like domain directly activated enac and potentiated afc. in contrast, atrial natriuretic factor applied to the vasculature of isolated, perfused lungs [ ], and tgf-β applied intratracheally to live rats [ ] impaired transepithelial sodium transport and blocked afc. it was subsequently demonstrated that tgf-β downregulated enac gene expression [ ] . together these data indicate new and emerging roles for polypeptide growth factors and other hormones in the regulation of afc. targeting fluid clearance in ali/ards: what we have learned from intact organ and animal models, and clinical studies studies in animal models demonstrated that low v t and high peep ventilation strategies potentiated afc in acid aspiration-induced ali [ , ], suggesting a therapeutic benefit of this ventilation strategy in the management of ali/ards. several small phase iii clinical trials addressing the potential benefit of low v t (which is lung protective) vs. traditional higher v t (providing better oxygenation) yielded conflicting results (reviewed in [ ] ). a subsequent multicenter, randomized, controlled trial of patients conducted under the auspices of the national heart, lung and blood institute ards network demonstrated that a ml/kg v t ventilation strategy yielded a significant reduction in mortality compared with a ml/kg v t ventilation strategy (with a plateau pressure of < cmh o) [ ] . while evlw was not assessed in this trial, the ml/kg v t ventilation strategy also increased the number of ventilator-free days, indicative of improved lung function. to date this remains the only intervention with a confirmed benefit on clinical outcome, and clearly demonstrates how studies on ali/ards in animal and organ models have translated into a successful therapeutic strategy. catecholamine-stimulated transepithelial sodium transport is the most intensely explored possibility of manipulating afc in a therapeutic context. it was demonstrated in that epinephrine stimulated afc from the airspaces of newborn mammals [ ] , implicating β-adrenergic receptors in afc. both epinephrine and terbutaline stimulated afc in anesthetized sheep [ ] , and terbutaline stimulated transepithelial sodium transport in an isolated, buffer-perfused rat lung [ ] and dramatically enhanced alveolar fluid clearance in a resected human lung [ ] . β-adrenergic agonists also reduce high vascular pressureinduced vascular permeability in isolated rat lungs [ ] , indicating that β-adrenergic agonsist may influence both reduce barrier permeability and potentiate afc. the ability of β-adrenergic agonists to stimulate afc is attributed in part to recruitment from intracellular pools (a) of na,k-atpase to the basolateral membrane [ ] and (b) of enac to the apical membrane [ ] of alveolar epithelial cells (reviewed in [ ] ). furthermore, β-adrenergic stimulation can clear edema in hypoxia-induced ali [ ] and ventilator-associated lung injury [ ] in animals, suggesting a potentially exciting therapeutic potential for β-adrenergic agonists in the treatment of ali/ards. this idea was further supported by the observations that adenovirus-mediated transfer of β-adrenergic receptor genes to live rats improved afc due to increased sensitivity to endogenous catecholamines and consequent upregulation of na,k-atpase activity and enac protein expression the lung [ ] . more recently a role for the cftr channel in camp-stimulated afc has been proposed since afc in cystic fibrosis (∆f ) mice, which lack cftr activity was not stimulated with β-adrenergic agonists [ ] . furthermore, administration of a cftr inhibitor to live mice blocked camp-stimulated afc [ ] . these studies provide strong evidence of an important role for the cftr channel, along with the transepithelial sodium transport system, in β-adrenergic-stimulated afc. among the neurotransmitter catecholamines, dopamine stimulated afc in isolated, perfused rat lungs, by activation of the dopamine d receptor, which stimulated exocytosis of the na,k-atpase [ ] , and by activation of the d receptor, which induced na,k-atpase gene expression [ ] . dopamine also promoted edema clearance in rats when ali was induced either by hyperoxia or mechanical ventilation [ ] . although not assessed in animal or organ models, dopamine also exerted an enhancing effect on enac activity [ ] , where dopamine increased the p o of enac, without altering enac density on the apical surface of l cells. thus, separate from the β-adrenergic system, the dopamine system provides an alternative opportunity for the pharmacological manipulation of afc. some β-adrenergic agonists, for example, albuterol, can be deposited into the lungs of patients with pulmonary edema at therapeutic concentrations by aerosolization [ ] . in a double-blind, randomized, placebo-controlled study sartori et al. [ ] assessed the effect of inhalation of the β-agonist salmeterol ( µg every h) on the incidence of pulmonary edema in hape-prone subjects at high altitude. prophylactic salmeterol significantly reduced the incidence of hape by more than %, without any change in pulmonary hemodynamics. furthermore, this study demonstrated that transepithelial sodium transport in the nasal epithelium was reduced in hape-prone subjects. together, these data suggest a therapeutic benefit of inhaled β-agonists in the treatment of hape. the β-agonist lung injury trial (balti), a singlecenter, double-blind, randomized controlled trial, assessed the effect of sustained infusion of a β-agonist (in this case, µg/kg salbutamol per hour) on the resolution of pulmonary edema in ali/ards patients [ ] , using evlw as a primary endpoint. the balti trial demonstrated that sustained treatment with intravenous β-agonists was generally well tolerated, although patients receiving salbutamol exhibited a trend towards higher heart rates, and patients in the salbutamol group exhibited higher incidence ( % vs. % in the placebo group) of supraventricular arrhythmias. patients receiving salbutamol demonstrated a significant reduction in evlw in comparison to placebo-treated patients. the trial was not, however, powered to detect a mortality benefit. therefore a second multicenter, randomized, double-blind, placebo-controlled trial (balti- ; international standard randomized controlled trial number ) is currently underway to assess the influence of intravenous salbutamol in ards patients on -day mortality. although glucocorticoids have been employed in the management of ards to reduce inflammation (in the early phase), and fibrosis (in the late phase) [ ] , their use is controversial. the potential beneficial effects of glucocorticoid use are attributed in part to the ability of glucocorticoids to influence afc, by upregulating protein expression of the sodium transporting machinery. preterm infants with respiratory distress exhibit reduced expression of enac relative to healthy, full-term infants [ ] . administration of dexamethasone to these infants upregulated enac expression, restoring enac expression to levels observed in healthy infants [ ] . working in adult rats, noda et al. [ ] demonstrated that a single intraperitoneal injection of dexamethasone dramatically increased afc and reversed hypoxemia induced by an intratracheal fluid challenge, - h after dexamethasone administration. this was attributed to an increase in enac mrna levels. while na,k-atpase mrna levels were not altered, na,k-atpase activity was increased. these data suggest that glucocorticoids may be of use in the treatment of ards by potentiating afc. a number of clinical trials have addressed the use of glucocorticoids in early and late phase ards. notable among these, in a randomized, double-blind, placebocontrolled trial involving patients with unresolving ards, meduri et al. [ ] demonstrated that prolonged methlyprednisolone administration significantly improved lung function and reduced mortality. a larger randomized, multicenter, placebo-controlled trial of patients with unresolving ards (the "late steroid rescue study", lasrs) that used -day mortality as the primary endpoint did not support the use of methylprednisolone for unresolving ards [ ] . however, methylprednisolone did increase the number of ventilator-free days during the first days, accompanied by improved compliance and oxygenation. the evlw was not assessed in either study. several polypeptide growth factors can potentiate afc and protect against ali induced in experimental animal models, notable among them, keratinocyte growth factor (reviewed in [ ] ). keratinocyte growth factor upregulated alveolar fluid clearance in anesthetized, ventilated rats [ ] , and upregulated transepithelial sodium transport in isolated, ventilated, and perfused lungs from healthy rats as well as in rats in which ali has been induced with α-naphthylurea [ ] . this protective effect has been attributed to the ability of keratinocyte growth factor (kgf) to upregulate expression of components of the sodium transporting machinery, primarily the na,k-atpase, as well as its mitogenic properties on alveolar type ii cells, since the alveolar epithelium is may be denuded in ali/ards. an upregulation of afc attributable to elevated na,k-atpase levels has also been reported for epidermal growth factor (egf) instilled into lungs of live rats, where egf was proposed to upregulate expression levels of na,k-atpase [ ] . other nonpeptide hormones can also influence afc. for example, , , -triiodo-lthyronine upregulated afc in live adult rats, apparently by upregulation of transepithelial sodium transport [ ] . while no clinical trial has yet been initiated, recombinant human kgf and liposome-mediated kgf gene delivery into mouse lungs afforded significant protection against oleic acid induced lung injury by improving arterial oxygenation and lung compliance in comparison to the vehicle-treated group [ ] . it was not reported in that study, however, whether afc was improved in the kgf-treated group. however, given the ability of kgf upregulate afc in an isolated organ model, and to repop-ulate denuded areas of the alveolar epithelium by virtue of its mitogenic properties on type ii cells, further evaluation of the therapeutic potential of kgf appears warranted. the lectin-like domain of tnf-α enhanced afc in ventilated rats [ ] . mouse tnf-α promoted fluid reabsorption in wild-type mice and in mice deficient in both tnf-α receptors, indicating that the effect of tnf-α on afc was independent of both tnf-α receptors [ ] . intratracheal application of a synthetic peptide that was based on the lectinlike domain sequence to an isolated, ventilated, autologous blood-perfused rat lung model caused a significant reduction in lung water and improvement in lung compliance, in comparison to lungs treated with a scrambled peptide of the same length [ ] . thus at least two growth factors, kgf and the lectin-like domain of tnf-α, present us with novel opportunities for augmentation of afc. granulocyte-derived reactive oxygen and nitrogen species are believed to play an important role in ali/ards (reviewed in [ ] ), and increased levels of the stable byproducts of nitric oxide decomposition, nitrite, and nitrate are observed in edema fluid from patients with ali/ards [ ] . these and other data have suggested a therapeutic benefit of antioxidants, including nacetylcysteine (nac), procysteine, and albumin [ ] . antioxidant therapy could also augment afc. oxidants such as hydrogen peroxide suppress glucocorticoidinduced enac gene transcription, an effect reversed by reactive oxygen scavengers, including thioredoxin. in a rat model of hemorrhagic shock modelska et al. [ ] demonstrated that catecholamines were ineffective at upregulating afc. however, after either intravenous administration of nac, intratracheal administration of reduced glutathione or neutrophil depletion with vinblastine, the effect of catecholamines was restored. these data provided in vivo evidence that neutrophil-mediated oxidative injury impaired afc in ali. building on this study, lee et al. [ ] demonstrated that the induction of hemoxygenase i (ho- ), a potent antioxidant, restores normal afc after hemorrhagic shock by blocking inos-mediated no release. therefore with regard to edema resolution antioxidant therapy would most likely augment glucocorticoid or catecholamine-based efforts to upregulate afc. clinical trials involving antioxidants in ards have yielded equivocal results. in one randomized, placebocontrolled, double-blind trial of ards patients suter et al. [ ] demonstrated that intravenous nac ( mg/kg per day) improved systemic oxygenation and reduced the need for ventilatory support. in contrast, domenighetti et al. [ ] in a comparable trial (although employing a higher dose: mg/kg per day) demonstrated no improvement in systemic oxygenation or a reduction in the need for ventilatory support. neither study reported a survival benefit, nor was evlw assessed. clearly additional trials are warranted, although a recent, much larger phase iii double-blind, placebo-controlled, clinical trial evaluating procysteine in ali/ards was prematurely discontinued due to mortality concerns in the intervention group [ ] . to date, a single animal study has explored the effect of anticoagulation on afc, where the natural anticoagulant, activated protein c (apc) was applied in a pseudomonasinduced ali model in rats [ ] . in that study afc was potentiated in a tnfα-dependent manner; however, activated protein c did not enhance afc. given the recent report of vadász et al. [ ] which demonstrated that thrombin impaired afc by blocking transepithelial sodium transport mediated by na,k-atpase, it appears likely that anticoagulant therapy would improve edema resolution by upregulating na,k-atpase-mediated afc. to date, no randomized, placebo-controlled trials have been conducted with anticoagulants in ali/ards patients, although a randomized, phase ii clinical trial of apc is currently in progress at the university of california in san fransisco (clinicaltrials.gov identifier nct ), employing the number of ventilator-free days measured at day as the primary end-point. the lung is an organ that is particularly amenable to local delivery of dna, making it an attractive target for gene therapy studies. in the context of ali/ards this possibility is particularly attractive since ali/ards does not impair virus-mediated gene delivery to the alveolar epithelium [ ] . several studies have highlighted the potential benefit of augmenting afc by local delivery of genes into the lungs of live animals. the potential therapeutic benefit of upregulating na,k-atpase and cftr channels in the lung as well as the delivery of kgf and ho- to the lung have already been discussed. all four systems have been explored in the context of gene therapy for ali. adenovirus-mediated transfer of na,k-atpase genes to lungs of live rats increased afc [ ] . upregulation of na,k-atpase expression in the alveolar epithelium by gene transfer improved edema resolution in rat models of ali induced by elevated left arterial pressure [ ] and hyperoxia [ ] . furthermore, transfer of β -adrenergic receptor genes to the lungs of adult rats increased their sensitivity to exogenous catecholamines, and upregulated afc due to increased delivery of both enac and na,k-atpase to epithelial cell membranes [ ] . transfer of the ctfr gene to mouse and rat lungs also augmented afc and appeared to affect the expression and function of components of the sodium transport machinery [ ] . these data together suggest that the sodium transporting and β-adrenergic signaling systems in the lung are candidate targets for intervention by gene therapy in ali/ards. clearly, enough epithelial cells would have to be present in the damaged epithelium for gene therapy to be effective, therefore, regeneration of the damaged epithelium with growth factors such as kgf has also been addressed by gene therapy. liposome-mediated kgf gene delivery into mouse lungs afforded protection in an oleic-acid induced lung injury model [ ] . similarly, in the case of antioxidants adenovirus-mediated gene delivery of ho- into the lungs of live mice afforded significant protection against influenza virus-and lipopolysaccharide-induced methods of potentiating alveolar fluid clearance in ali/ards that have been validated in animal and organ models or in clinical studies. interventions involving gene therapy are indicated in the shaded box. cftr, cystic fibrosis transmembrane conductance regulator; d , dopamine d receptor; d , dopamine d receptor; egf, epidermal growth factor; enac, epithelial sodium channel; kgf, keratinocyte growth factor; na,k-atpase, na + , k + transporting adenosine - -triphosphatase; t , , , -triiodo-l-thyronine; tnf-α, tumor necrosis factor α ali [ ] . while afc was not specifically addressed in the kgf or ho- studies, the documented role of kgf and ho- in augmenting afc suggests that this phenomenon contributed to the beneficial effect observed. organ and animal models of ali together with clinical studies have helped us understand the contribution of impaired afc to the development and persistence of ali/ards (fig. ) . perturbations to the alveolo-capillary barrier can both promote the formation and prevent the resolution of alveolar edema associated with ali/ards. indeed, edema resolution is critical for the ali/ards patient to survive. animal and organ models of edema resolution and ali have proved irreplaceable in the development of novel therapeutic strategies that augment afc, the most obvious case being the low tidal volume ventilation strategy for the management of ards, a strategy that has now been validated in a large multicenter, randomized, controlled clinical trial. due to our focus on afc several other important ali/ards candidate therapies currently under evaluation have been omitted from this review, including other ventilation strategies, surfactant replacement, fluid management, inhaled vasodilators, and nonglucocorticoid anti-inflammatory agents. the reader is referred to other excellent reviews on these topics [ , ] . animal and organ models and clinical studies will no doubt continue to prove instrumental in the further development of several new and emerging ideas designed to augment afc in ali, notable among these are anticoagulation, stimulation of the β-adrenergic system, and local gene delivery to the alveolar epithelium. the acute respiratory distress syndrome alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome lung epithelial fluid transport and the resolution of pulmonary edema alveolar edema must be cleared for the acute respiratory distress syndrome patient to survive function of the alveolar epithelial barrier under pathologic conditions sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance invited review: lung edema clearance: role of na (+)-k (+)-atpase novel role for cftr in fluid absorption from the distal airspaces of the lung rna interference for alpha-enac inhibits rat lung fluid absorption in vivo alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia mechanisms of alveolar epithelial repair in acute lung injury-a translational approach functional ion channels in pulmonary alveolar type i cells support a role for type i cells in lung ion transport alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema alveolar epithelium: role in lung fluid balance and acute lung injury alveolar epithelial barrier functions in ventilated perfused rabbit lungs oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome? the measurement of lung water increased bioelectric potential difference across respiratory epithelia in cystic fibrosis differential liquid and protein clearance from the alveoli of anesthetized sheep effect of temperature on alveolar liquid and protein clearance in an in situ perfused goat lung active transport and passive liquid movement in isolated perfused rat lungs amiloride impairs lung water clearance in newborn guinea pigs early death due to defective neonatal lung liquid clearance in alpha-enac-deficient mice defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice increased airway epithelial na+ absorption produces cystic fibrosis-like lung disease in mice alveolar sodium and liquid transport in mice augmentation of lung liquid clearance via adenovirusmediated transfer of a na,k-atpase beta subunit gene na,k-atpase overexpression improves alveolar fluid clearance in a rat model of elevated left atrial pressure transforming growth factor-beta decreases expression of the epithelial sodium channel alphaenac and alveolar epithelial vectorial sodium and fluid transport via an erk / -dependent mechanism pharmacotherapy of acute lung injury and the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome the role of catecholamines in lung liquid absorption at birth beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep effects of terbutaline on sodium transport in isolated perfused rat lung alveolar fluid clearance in the resected human lung isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs isoproterenol increases na+-k+-atpase activity by membrane insertion of alpha-subunits in lung alveolar cells hypoxia and beta -agonists regulate cell surface expression of the epithelial sodium channel in native alveolar epithelial cells mechanisms of pulmonary edema clearance beta-adrenergic stimulation restores rat lung ability to clear edema in ventilator-associated lung injury beta ( )-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats the dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks dopamine regulates na-k-atpase in alveolar epithelial cells via mapk-erk-dependent mechanisms dopamine regulation of amiloride-sensitive sodium channels in lung cells aerosolized beta ( )-adrenergic agonists achieve therapeutic levels in the pulmonary edema fluid of ventilated patients with acute respiratory failure salmeterol for the prevention of high-altitude pulmonary edema the beta-agonist lung injury trial (balti): a randomized placebo-controlled clinical trial low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress single dexamethasone injection increases alveolar fluid clearance in adult rats effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair alveolar epithelial fluid transport can be simultaneously upregulated by both kgf and beta-agonist therapy keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs epidermal growth factor increases lung liquid clearance in rat lungs dexamethasone and thyroid hormone pretreatment upregulate alveolar epithelial fluid clearance in adult rats keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha oxidant-antioxidant balance in acute lung injury increased levels of nitrate and surfactant protein a nitration in the pulmonary edema fluid of patients with acute lung injury inhibition of beta-adrenergic-dependent alveolar epithelial clearance by oxidant mechanisms after hemorrhagic shock ho- induction restores c-amp-dependent lung epithelial fluid transport following severe hemorrhage in rats n-acetylcysteine enhances recovery from acute lung injury in man. a randomized, double-blind, placebo-controlled clinical study treatment with n-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study intravenous administration of activated protein c in pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response acute lung injury does not impair adenoviral-mediated gene transfer to the alveolar epithelium adenovirus-mediated transfer and overexpression of heme oxygenase cdna in lungs attenuates elastaseinduced pulmonary emphysema in mice integrating acute lung injury and regulation of alveolar fluid clearance acknowledgements. the authors are supported by the deutsche forschungsgemeinschaft (sfb "kardiopulmonales gefäßsystem" and klifo "lungenfibrose") and the european commission sixth european framework programme "pulmonary hypertension". key: cord- -h c novk authors: bos, lieuwe d. j.; paulus, frederique; vlaar, alexander p. j.; beenen, ludo f. m.; schultz, marcus j. title: subphenotyping acute respiratory distress syndrome in patients with covid- : consequences for ventilator management date: - - journal: ann am thorac soc doi: . /annalsats. - rl sha: doc_id: cord_uid: h c novk nan to the editor: guidance on the best provision of care for patients with coronavirus disease (covid- ) is urgently needed. recently a strong argument in defense of an evidence-based approach was made in annalsats ( ), and we fully support the given line of reasoning. most patients in the intensive care unit (icu) with severe covid- meet the criteria for acute respiratory distress syndrome (ards), and proven therapies for ards not related to covid- are likely effective in these patients as well. however, ards is known to be a heterogeneous syndrome. over the past decade, several biological, physiological, and morphological subphenotypes have been identified that may predict treatment effects and can be used as treatable traits ( ) . for example, patients with a focal lung morphology seem to respond better to prone positioning, but their lungs are not as recruitable as those of patients with a nonfocal lung morphology ( ) . it has been postulated that patients with covid- -related ards can develop typical ards (recently called "h type," characterized by high elastance, high shunt, and high lung weight) or have an atypical presentation (recently called "l type," characterized by low elastance, low shunt, and low lung weight) ( ). as with the abovementioned morphological subphenotypes, some investigators have speculated that these subphenotypes require different ventilator strategies. patients with h-type ards may benefit from lower tidal volumes and higher positive end-expiratory pressure (peep), and patients with l-type ards may benefit from higher tidal volumes and lower peep ( ) . several steps have to be taken before subphenotypedirected treatment can be implemented in clinical practice ( ) . the ultimate test would be a head-to-head comparison of subphenotype-directed treatment with standard of care in a randomized controlled trial. but before this step can be considered, it is important to validate the basic assumptions underlying the subclassification of patients. we hypothesized that patients with a low elastance (i.e., with a high respiratory system we conducted a retrospective analysis of the first patients with suspected covid- who were admitted to our icu. chest ct is performed in all hospitalized patients with suspected covid- . we had chest ct images for patients with proven covid- ( %) ( table ) , as the other patients were transferred from other hospitals to our icu or previously had a ct scan that supported the diagnosis of covid- pneumonia. crs was calculated shortly after intubation, during neuromuscular blockade (tidal volume/driving pressure). the ct scan was performed directly after intubation and before transport to our icu. we estimated the percentage consolidated area by summing the areas with a density of more than hu and expressing it as a quartile fraction ( %, %, %, %, or %). areas with this density are known to reflect poorly or nonaerated lung tissue ( ) and account for approximately , % of lung tissue in the l-phenotype and approximately % in the h-phenotype ( ) . lung morphology was classified as focal or nonfocal as described previously ( ). we did not perform a quantitative ct analysis at this point in time because it would have required segmentation of the ct scans, which takes hours of manual labor per scan to complete; however, a semiquantitative assessment of the percentage of affected lung ought to be sufficient to distinguish between the extremes of the spectrum. seventeen patients ( %) had a crs below ml/cm h o, which has been suggested as a cutoff ( ) , and seven patients ( %) had minor parenchymal involvement (figure ). there was no relation between crs and poorly aerated or nonaerated lung tissue (regression coefficient, . % per ml/cm h o; % confidence interval, . to . ; p = . ). most patients had a nonfocal lung morphology (n = , %). patients with a nonfocal lung morphology had more parenchymal involvement (p = . ) but did not have lower crs (p = . ) than patients with focal lung morphology. based on these preliminary data, we conclude that compliance and an estimation of lung weight do not correlate in patients with covid- -related ards. most patients could not be classified as either the h-or l-subphenotype, but showed mixed features. patients frequently showed extensive parenchymal involvement and a nonfocal morphology on chest ct imaging, which might suggest recruitable lung tissue. the crs was similar to that reported in other cohorts of patients with covid- ( - ) and with ards not related to covid- . h-or l-phenotype covid- related ards figure . association between compliance of the respiratory system (crs) and percentage of affected lung parenchyma. x-axis: crs; y-axis: percentage of lung that is poorly aerated or nonaerated, expressed semiquantitatively as quartiles. the boxplots indicate the distribution of the variables on the x-and y-axes. the red area and solid red symbols indicate patients with a consistent h-phenotype. the blue area and solid blue symbols indicate patients with a consistent l-phenotype. the solid gray symbols correspond to patients with a discordant phenotype. indicative computed tomography images for each area are shown on both sides. crs is not associated with an increase in poorly aerated/nonaerated lung tissue estimated by semiquantitative analysis in quartiles. regression coefficient for crs: . % per ml/cm h o ( % confidence interval, . to . ; p = . ). two patients met the criteria for the l-phenotype and patients met the criteria for the h-phenotype, leaving patients ( %) with discordant results and an unclear phenotype allocation. most patients had a nonfocal lung morphology (n = , %) rather than a focal lung morphology (n = , %). ards = acute respiratory distress syndrome; covid- = coronavirus disease. global impact of severe acute respiratory failure) study and other observational and interventional studies ( , , ) . our observations are limited by the absence of a quantitative ct analysis. however, given the urgent need for data, we used a semiquantitative surrogate that should capture the distinctions that were described in previous publications. another limitation is that we did not perform a formal evaluation of recruitability by performing ct imaging at different peep levels. we should acknowledge that the semiquantitative evaluation of ct images at a single level of peep is not even available for most clinicians caring for patients with covid- , and that most physicians will therefore resort to using the crs when these subphenotypes are applied in clinical practice. our data clearly indicate that the lung compliance alone does not correlate with the amount of lung parenchyma that is affected. although our sample size was small, there is no suggestion in our data that the "h-/l-phenotyping" schema accurately describes our patients with covid- . this study represents the first independent test of the proposed subphenotypes of covid- -related ards, and highlights that the features of the h-and l-subphenotypes are not mutually exclusive. we also validated the existence of heterogeneity in lung morphology known from non-covid- -related ards. we need data-driven approaches to evaluate the existence of treatable traits to improve patient-tailored care. until these data become available, an evidence-based approach extrapolating data from ards not related to covid- is the most reasonable approach for icu care ( ). in defense of evidence-based medicine for the treatment of covid- ards toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design azurea network. personalised mechanical ventilation tailored to lung morphology versus low positive endexpiratory pressure for patients with acute respiratory distress syndrome in france (the live study): a multicentre, single-blind, randomised controlled trial covid- pneumonia: different respiratory treatment for different phenotypes? intensive care med management of covid- respiratory distress phenotypes in acute respiratory distress syndrome: moving towards precision medicine lung recruitment in patients with the acute respiratory distress syndrome lung morphology predicts response to recruitment maneuver in patients with acute respiratory distress syndrome covid- pneumonia: ards or not? covid- does not lead to a "typical" acute respiratory distress syndrome covid- in critically ill patients in the seattle region: case series respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study lung safe investigators; esicm trials group. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome author disclosures are available with the text of this letter at www.atsjournals.org. key: cord- -h d v ga authors: ospina-tascón, gustavo a.; bautista, diego f.; madriñán, humberto j.; valencia, juan d.; bermúdez, william f.; quiñones, edgardo; calderón-tapia, luis eduardo; hernandez, glenn; bruhn, alejandro; de backer, daniel title: microcirculatory dysfunction and dead-space ventilation in early ards: a hypothesis-generating observational study date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: h d v ga background: ventilation/perfusion inequalities impair gas exchange in acute respiratory distress syndrome (ards). although increased dead-space ventilation (v(d)/v(t)) has been described in ards, its mechanism is not clearly understood. we sought to evaluate the relationships between dynamic variations in v(d)/v(t) and extra-pulmonary microcirculatory blood flow detected at sublingual mucosa hypothesizing that an altered microcirculation, which is a generalized phenomenon during severe inflammatory conditions, could influence ventilation/perfusion mismatching manifested by increases in v(d)/v(t) fraction during early stages of ards. methods: forty-two consecutive patients with early moderate and severe ards were included. peep was set targeting the best respiratory-system compliance after a peep-decremental recruitment maneuver. after min of stabilization, hemodynamics and respiratory mechanics were recorded and blood gases collected. v(d)/v(t) was calculated from the co( ) production ([formula: see text] ) and co( ) exhaled fraction ([formula: see text] ) measurements by volumetric capnography. sublingual microcirculatory images were simultaneously acquired using a sidestream dark-field device for an ulterior blinded semi-quantitative analysis. all measurements were repeated h after. results: percentage of small vessels perfused (ppv) and microcirculatory flow index (mfi) were inverse and significantly related to v(d)/v(t) at baseline (spearman’s rho = − . and − . , p < . ; r( ) = . , and . , p < . , respectively) and h after (spearman’s rho = − . , and − . ; p < . ; r( ) = . and . , p < . , respectively). other respiratory, macro-hemodynamic and oxygenation parameters did not correlate with v(d)/v(t). variations in ppv between baseline and h were inverse and significantly related to simultaneous changes in v(d)/v(t) (spearman’s rho = − . , p < . ; r( ) = . , p < . ). conclusion: increased heterogeneity of microcirculatory blood flow evaluated at sublingual mucosa seems to be related to increases in v(d)/v(t), while respiratory mechanics and oxygenation parameters do not. whether there is a cause–effect relationship between microcirculatory dysfunction and dead-space ventilation in ards should be addressed in future research. epithelial permeability, with subsequent loss of aerated lung tissue and increased lung stiffness [ ] . these alterations lead to imbalances between ventilation and perfusion relationships, which finally result in hypoxemia and impaired carbon dioxide clearance. an optimal ventilation-to-perfusion (v a /q) ratio ( . < v a /q < ) is necessary to ensure a normal gas exchange [ ] [ ] [ ] . typically, it has been considered that pulmonary perfusion in ards occurs in non-ventilated (v a /q < . ) or poorly ventilated ( . < v a /q < . ) lung units, which, in turn, results in vasoconstriction of perfusing arterioles [ ] . such v a /q mismatch in some lung regions in which perfusion largely exceeds ventilation, account for hypoxemia, which is the clinical hallmark of ards [ , , ] . nevertheless, distribution of ventilation to poorly perfused ( < v a /q < ), severely hypoperfused (v a /q > ) or non-perfused (v a /q ~ ∞) lung units might also occur in patients with ards [ ] and indeed, increases in v d /v t have been strongly related with adverse clinical outcomes [ ] [ ] [ ] . importantly, high v a /q and v a /q ~ ∞ ratios corresponding to lung regions where ventilation largely exceeds perfusion, account for carbon dioxide retention [ ] . increases in high v a /q and/or dead-space lung units have been classically attributed to alveolar overdistention with the subsequent compression of intra-alveolar vessels in the non-dependent lung areas [ , ] . nevertheless, increased dead-space ventilation has also been described in patients subjected to protective ventilation strategies with low plateau pressures [ , ] , which suggest that mechanisms different to alveolar overdistention should be implied. in normal conditions, the heterogeneity of systemic microcirculatory blood flow distribution is negligible [ ] . nevertheless, severe inflammation can induce microcirculatory alterations [ , ] determining alterations in oxygen extraction capabilities by the tissues and contributing to the development of multiple organ dysfunction [ ] . although there are many technical limitations to directly evaluate pulmonary microcirculation [ ] , heterogeneity of microvascular blood flow at pulmonary level could contribute to imbalances between ventilation and perfusion relationships. thus, considering microcirculatory dysfunction during inflammatory conditions as a generalized phenomenon, which may involve systemic and pulmonary vascular beds, we hypothesized that alterations in microvascular blood flow distribution evaluated at the sublingual mucosa as representative of an extra-pulmonary territory could be related to variations in dead-space ventilation v d /v t during early phases of moderate and severe ards. this prospective observational study was conducted in a -bed mixed icu from a university hospital. the local ethical and biomedical research committee approved the study (fundación valle del lili ebrc protocol number: ; approval number: - , ). a written informed consent was waived as no invasive procedures or new interventions were used. we daily screened all patients under mechanical ventilation in the icu during a -month period, searching for those with moderate and severe ards. to avoid the selection of cases with transitory hypoxemia simulating ards, patients were enrolled only after successfully completing a two-step selection process [ , ] : (a) first, patients mechanically ventilated through an endotracheal tube with a peep ≥ and fio ≥ . for at least h and meeting the moderate and severe ards criteria according to berlin consensus definitions [ ] were declared potentially eligible; (b) then, potential candidates were subjected to a fio trial at . while maintaining peep ≥ (to sustain a spo ≥ %, but ensuring peak inspiratory and plateau pressures < and cmh o, respectively) for at least min, after which, new arterial blood gases were collected. those patients maintaining a pao /fio ≤ after such peep/ fio trial and with < h of evolution of ards were finally included. the exclusion criteria were: < years of age, pregnancy state, history of neuromuscular diseases, moderate and severe copd (defined as fev < % predicted); history of intubation due to copd exacerbation, receiving domiciliary oxygen or long-term use of steroids because copd; history of congestive heart failure or any acute ischemic cardiac condition. a patient was also excluded when limitation of therapeutic effort orders were given. after fulfilling the two-step selection process, patients selected were connected to a mainstream co sensor and this in turn to a volumetric capnography module (infinity etco + respiratory mechanics module, dräger medical systems, telford, usa). mechanical ventilation parameters were adjusted after a stepwise alveolar recruitment maneuver, as it will be detailed later. after a min of stabilization period, we started capnography measurements while sublingual microcirculatory images were simultaneously acquired, such as detailed thereafter. a new set of measurements was obtained h after. arterial and mixed venous blood samples (when available) were drawn for gases analysis (abl , radiometer; copenhagen, denmark) at t and h after (t ). in all the cases, the attending physicians decided on the type of hemodynamic monitoring to use. complete respiratory and hemodynamic parameters were also registered simultaneously. at the time in which this study was performed, the local protocol included an initial recruitment maneuver to adjust peep in patients with severe ards. thus, patients were subjected to a stepwise recruitment maneuver with progressive peep increases until a peak pressure of cmh o while maintaining a driving pressure of cmh o, as described elsewhere [ , ] . once obtained the maximal peak pressure, it was sustained during min whereupon a decremental peep titration trial was conducted in steps of cmh o at min interval from to cmh o registering the corresponding compliance of the respiratory system (c rs ). after such a peep titration, a new alveolar recruitment was performed until a peak pressure of cmh o while maintaining a driving pressure of cmh o during min, to finally adjust the definitive ventilatory settings. definitive peep was set at the corresponding best c rs plus cmh o. if falls in c rs were observed in two consecutive downsteps, then the peep level was set at the highest compliance plus cmh o. according to the local protocol, the recruitment maneuver was stopped if one or more of following signs were observed: heart rate > or < bpm; decrease of mean arterial pressure < mmhg or systolic pressure < mmhg; acute atrial fibrillation, atrial flutter or ventricular tachycardia. thereafter, mechanical ventilation was set in volumecontrolled mode or in pressure-controlled, according to the selection of the attending physician. in the first case, ventilation was set at vt of ml/kg of predicted body weight maintaining plateau pressures < cmh o, flow of l/min, inspiratory pause of . s, i:e ratio of : to : , respiratory rate to match the minute ventilation previous to the recruitment maneuver, fio necessary for spo ≥ and ≤ % and peep adjusted as indicated above. if plateau pressures were > cmh o, then vt was reduced to a minimum of ml/kg of predicted body weight. for those ventilated in pressure-controlled mode, driving pressure was adjusted to maintain vt ml/kg of predicted body weight (or less if vt/c rs > ), i:e ratio : to : , minute ventilation matching that previous to the recruitment maneuver, peak inspiratory pressure ≤ cmh o, and fio and peep adjusted as indicated above. after an automatic purge and calibration procedure, a mainstream co sensor was placed between the ventilator circuit and the patient connection. this sensor was in turn connected to a volumetric capnography module (infinity etco + respiratory mechanics module, dräger medical systems, telford, usa). after selection of the ventilator settings, a min of stabilization period was allowed before to start the measurements. data trend for co production ( v co ) and exhaled minute ventilation (v e ) were averaged over min. v co measurements were obtained at standard temperature and pressure, and dry (stpd), whereby a correction factor of . mmhg l/ml was used to convert to body temperature, and pressure, saturated (btps). the fraction of exhaled co ( f eco ) was calculated dividing the v co by the v e (eq. ): exhaled co pressure ( p eco ) was then calculated as the product between the f eco and the barometric pressure minus the water vapor pressure (eq. ): where p b corresponds to the local barometric pressure (i.e., mmhg). subsequently, v d /v t was calculated by the enghoff modification of the bohr equation (eq. ): all measurements of v co performed by the module were automatically corrected for circuit compression, as described elsewhere [ ] . a sidestream dark-field (sdf) imaging device (micro scan; microvision medical, amsterdam, the netherlands) was used to explore the sublingual microcirculation simultaneously to dead-space fraction measurements, ventilatory mechanics and oxygenation parameters at both inclusion and h after. a cutoff value of μm was used to classify vessels as large or small. continuous flows were considered as normal while intermittent and stopped flows were considered as abnormal. according to the consensus for the evaluation of microcirculation, we calculated the proportion of small vessels perfused (ppv), the total vascular density (tcd) and the functional capillary density (fcd) [ ] . a heterogeneity index of microcirculatory blood flow was also calculated as the difference between maximal and minimal ppv values in five different mucosa areas divided by its own mean value (see additional file ). additionally, we reported the microvascular flow index (mfi). a detailed description about microcirculatory blood flow assessment is provided in additional file . ( ) sample size calculation is described in additional file . distribution of data was tested using the kolmogorov-smirnov test. non-parametric test for related samples were used to evaluate the differences on hemodynamic, respiratory, capnometry and microcirculatory blood flow parameters between baseline and h after. the relationships between the v d /v t , percentage of small vessels perfused (ppv), and microcirculatory blood flow index (mfi) were evaluated by the spearman rho test. other bivariate correlations between v d /v t , pao /fio , and respiratory mechanics were also performed using spearman rho test. additionally, simple linear regression models with linear and quadratic terms and their respective coefficients of determination (r ) were used to evaluate the relationship between each microcirculatory, respiratory mechanics or oxygenation parameter and the v d /v t at both baseline and h after. finally, we calculated the delta of variation of v d /v t and ppv measurements between baseline and h after. then, a spearman rho was used to evaluate the correlation between v d /v t and ppv dynamic variations from baseline to day- . furthermore, a simple linear regression model with quadratic term and its respective coefficient of determination (r ) was used to evaluate the relationship between variations in ppv and v d /v t from baseline to h after. data are presented as median [percentiles - ]. a p value ≤ . ( -tailed) was considered significant. a total of patients with moderate and severe ards were included in the study. a complete flowchart detailing the selection process is shown in additional file : figure s , while a strobe statement checklist for observational studies is provided in additional file : table s . mortality at day- and day- were % and . %, respectively. the icu length of stay was . [ . - . ] days. general characteristics are presented in table , while hemodynamics, respiratory mechanics, blood gases analysis, pulmonary dead-space fraction and microcirculatory blood flow parameters at baseline and h after are presented in table . we observed an inverse and significant relationship between ppv and v d /v t at both baseline (spearman rho = − . , p < . ; r = . , p < . ) and h after (spearman rho = − . , p < . ; r = . , p < . ) (fig. a, b) . similar findings were observed between v d /v t and the microcirculatory flow index at baseline (spearman rho = − . , p < . ; r = . , p < . ) and h after (spearman rho = − . , p < . ; r = . , p < . ) (fig. c, d) . there were no significant correlations between v d /v t and other respiratory mechanics and oxygenation parameters (fig. , additional file : table s ) . a significant relationship was observed between the variation in v d /v t and the percentage of variation of ppv from baseline measurements to h after (spearman rho = − . , p < . ; r = . , p < . ) (fig. , additional file : figure s ). additional information about survivors and non-survivors at day- is provided in additional file : table s . after simultaneous calculation of dead-space fraction by volumetric capnography and exploration of sublingual microcirculation by the sdf technique during the early stages of moderate and severe ards, we retrieved two hypothesis-generating observations: (a) v d /v t is inverse and significantly related with sublingual microcirculatory blood flow distribution, while peep levels, respiratory airway pressures, pao /fio and lung strain surrogates : (v t /c rs ) do not; (b) v d /v t variations were closely related with dynamic changes in the microcirculatory blood flow distribution observed at sublingual mucosa. other mechanisms unrelated to shunt-induced hypoxemia could be implicated in gas exchange abnormalities and in the onset of pulmonary and extra-pulmonary multiorgan dysfunction in ards. distribution of ventilation to poorly perfused ( < v a /q < ), severely hypoperfused (v a /q > ) or non-perfused, i.e., true dead-space ventilation (v a /q ~ ∞) lung units, can also contribute to gas exchange disturbances and it might be a key piece in the pathophysiology of ards. some studies in the past demonstrated the occurrence of increased pulmonary dead-space fraction in patients with acute hypoxemic respiratory failure [ , , ] , and highlighted the apparent relationship between high v d /v t and increased mortality [ ] . nevertheless, early studies included patients under non-lung-protective ventilation strategies, in which overinflation leading to capillary collapse could explain v a /q mismatching with the resultant increased v d /v t [ ] . remarkably, later studies in ards patients subjected to lung-protective ventilation, also demonstrated the occurrence of increases in v d /v t and confirmed its consistent relationship with worse clinical outcomes [ , , ] . in agreement with this, we observed increases in v d /v t at baseline and h after in patients with moderate and severe ards. importantly, we did not find any relationship between v d /v t and variables suggesting vascular collapse related to alveolar overdistention or increased pulmonary strain (e.g., v t /c rs ), although admittedly, fig. relationships between pulmonary dead-space fraction (v d /v t ) and the microcirculatory blood flow at baseline and h after. a scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the proportion of small vessels perfused at baseline. b scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the proportion of small vessels perfused h after. c scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and mfi at baseline. d scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and mfi h after. ppv: percentage of small vessels perfused; v d /v t : pulmonary dead-space fraction; hi: heterogeneity index of microcirculatory blood flow; mfi: microcirculatory blood flow index controlling airway pressures and v t /c rs (driving pressure) could not prevent alveolar overdistention because the inhomogeneous lung compromise in ards [ ] . relationships between microvascular blood flow and v d /v t have not been widely studied because of technical limitations to directly evaluate pulmonary microcirculation [ ] . our data suggest an apparent relationship between microcirculatory dysfunction and dead-space ventilation. admittedly, sublingual mucosa and pulmonary circulation are two dissimilar vascular beds with particular regulating mechanisms. nevertheless, during inflammatory conditions, microcirculatory dysfunction is a generalized phenomenon involving simultaneously most vascular beds [ ] , although with different effects depending on the territory studied [ ] . microcirculatory alterations have been described in autopsies and biopsies from lungs of patients with acute hypoxemic respiratory failure [ , ] and angiograms performed through pulmonary artery catheters demonstrated filling defects attributable to macro-and micro-emboli [ , ] . increases in v d /v t in our patients were well correlated with alterations in microcirculatory blood flow distribution detected in a non-pulmonary vascular bed. such observation could pose the hypothesis about heterogeneity of microvascular blood flow contributing to inequalities in v a /q relationships. indeed, variations of v d /v t from baseline to h after were closely related with dynamic changes in microcirculatory blood flow distribution at sublingual mucosa, which reinforce the strength of such relation. nevertheless, whether pulmonary microvascular alterations or other organ-specific microvascular blood flow can be evaluated or estimated through evaluation of an extra-pulmonary microvascular bed can result highly controversial [ ] . in normal conditions, heterogeneity of microvascular blood flow is negligible [ ] and matching of perfusion to metabolism usually improves during hypoxic or low-flow states [ ] . however, during inflammatory conditions, heterogeneity of microcirculation increases as consequence of the interruption of blood flow of individual capillaries causing derangements in the oxygen extraction capabilities, thus contributing to organ failure. in agreement with this, we observed important microcirculatory alterations consisting in decreased ppv, reduced fcd and increased heterogeneity of blood flow, which were in turn linked to more severe extra-pulmonary organ dysfunction quantified by sofa score (see additional file : table s ). pathophysiological mechanisms increasing v d /v t in ards are quite complex. an increased v d /v t reflects a global assessment of abnormal gas exchange, but not simply the contribution of discrete high v a /q regions and true anatomic dead space (v a /q ~ ∞). although the patchy pattern of vascular damage is a phenomenon clearly recognized in ards [ ] , no studies demonstrated that damaged areas necessarily receive substantial ventilation, as would be necessary to explain regions of high v a /q ratio. using the multiple inert gas elimination technique (miget) to evaluate the fractional contribution of each v a /q abnormality (shunt, mid-range v a /q heterogeneity, high v a /q, and anatomic dead space) on total v d /v t at progressively high peep levels, coffey et al. [ ] demonstrated similar v d /v t values at different peep levels mediated by very different physiologic abnormalities, although certainly, higher peep values were consistently related to high v a /q peaks. our results might add more complexity to the pathophysiology on increased v d /v t in ards suggesting the contribution of altered microcirculatory blood flow distribution on the increase of high v a /q units. routine assessment of pulmonary gas exchange in ards is based on analysis of oxygen and carbon dioxide partial pressures. these variables, although sensitive to intrapulmonary factors (e.g., shunt and v a /q matching), could be also altered by extra-pulmonary elements such as cardiac output, oxygen consumption, minute ventilation and inspired oxygen fraction. v d /v t values can widely vary according to the method used to estimate it [ ] . previous studies used the enghoff modification of the bohr equation (vd enghoff ) in patients with ards [ ] [ ] [ ] ] . nevertheless, this method could overestimate the real v d /v t when anatomic or intrapulmonary shunts are present as it assumes a perfect v a /q matching throughout all alveolar-capillary units [ , ] . (see figure on next page.) fig. relationships between pulmonary dead-space fraction (v d /v t ) and some respiratory mechanics and oxygen parameters at baseline and h after. a scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the pao /fio ratio at baseline. b scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the pao /fio ratio h after. c scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and peep levels at baseline. d scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and peep levels h after. e scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the v t /c rs at baseline. f scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and the v t /c rs h after. g scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and pm aw at baseline. h scatter plot depicting the correlation between pulmonary dead-space fraction (v d /v t ) and pm aw h after. pao /fio ratio: arterial oxygen partial pressure to oxygen inspiratory fraction; peep: positive end-expiratory pressure; v t /c rs : tidal volume-to-respiratory system compliance ratio (i.e., driving pressure); pm aw : mean pressure of the airway ospina-tascón et al. ann. intensive care ( ) : although we used the vd enghoff method, we computed v d /v t from the co production ( v co ) and co exhaled fraction ( f eco ) measurements by volumetric capnography, which can accurately reflect measurements by metabolic monitors [ ] . trying to exclude cases with transitory hypoxemia simulating ards, we completed a two-step selection previously described [ , ] . although breathing pure oxygen may influence the v a /q distribution [ ] , our definitive v d /v t measurements were performed min after return to the previous fio , thus causing the lowest impact on v a /q balance. also, we used a stepwise recruitment maneuver with progressive peep increases, which was part of the local protocol at the time in which patients were included. probably at present, such maneuver would not be used as recent evidence suggests that it can be harmful [ ] . nevertheless, such maneuver allowed us to standardize the selection of peep and ventilatory parameters. we recognize that our study has important limitations. first, many hemodynamic and respiratory coexisting factors can influence v d /v t measurements. indeed, combination of hypovolemia, vasoactive agents and/or inotropics, cardiac output variations, pulmonary resistances and flows, distribution of ventilation along the lungs and even local microthrombi formation, might influence v d /v t variations in one or other direction. thereby, identical v d /v t elevations might reflect simultaneous alterations in diverse physiological components. second, our study is not able to demonstrate a causal association between v d /v t and sublingual microcirculation and it was not registered as observational study. nevertheless, dynamic variations from baseline to h after merit exploration in future studies. third, whether pulmonary microvascular alterations occur in parallel to other extra-pulmonary microvascular beds is highly controversial. however, microcirculation studies reveal simultaneous alterations at different beds during shock or inflammatory conditions. fourth, the number of cases included in our study was relatively small. however, the fact that our patients were strictly selected and calculation of v d /v t used v co and exhaled fraction of co ( f eco ) measurements by volumetric capnography strengthens our results. increased heterogeneity of microcirculatory blood flow evaluated at sublingual mucosa seems to be related to increases in v d /v t independently of respiratory mechanics and oxygen parameters, thus suggesting that microcirculatory alterations could be implicated in ventilation/ perfusion mismatching during early ards. the inverse dynamic relationships observed between sublingual microcirculation and dead-space ventilation poses a hypothetical pathophysiological mechanism during moderate and severe ards that deserves future research efforts. supplementary information accompanies this paper at https ://doi. org/ . /s - - - . abbreviations ards: acute respiratory distress syndrome; co : carbon dioxide; copd: chronic obstructive pulmonary disease; c rs : compliance of the respiratory system; etco : end-tidal co ; fcd: functional capillary density; f eco : exhaled co fraction; mfi: microcirculatory flow index; p aco : arterial co partial pressure; p eco : exhaled co pressure; peep: positive end-expiratory pressure; ppv: percentage of small-vessels perfused; tcd: total capillary density; v a /q: ventilation-to-perfusion ratio; v co : co production; v d /v t : dead-space ventilation fraction; v e : exhaled minute ventilation; v t : tidal volume; v t /v rs : driving pressure. acute respiratory distress syndrome: the berlin definition ventilation-perfusion distributions in the adult respiratory distress syndrome distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome redistribution of pulmonary blood flow induced by positive end-expiratory pressure and dopamine infusion in acute respiratory failure fifty years of research in ards. gas exchange in acute respiratory distress syndrome an expanded definition of the adult respiratory distress syndrome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome pulmonary dead space fraction and pulmonary artery systolic pressure as early predictors of clinical outcome in acute lung injury lung injury etiology and other factors influencing the relationship between deadspace fraction and mortality in ards effects of positive end-expiratory pressure on gas exchange in dogs with normal and edematous lungs functional heterogeneity of oxygen supply-consumption ratio in the heart microvascular blood flow is altered in patients with sepsis monitoring the microcirculation in the critically ill patient: current methods and future approaches measuring microvascular blood flow in sepsis-a continuing challenge an early peep/fio trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome screening of ards patients using standardized ventilator settings: influence on enrollment in a clinical trial how large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome calculation of physiologic dead space: comparison of ventilator volumetric capnography to measurements by metabolic analyzer and volumetric co monitor how to evaluate the microcirculation: report of a round table conference pathologic features and mechanisms of hypoxemia in adult respiratory distress syndrome lung structure and function in different stages of severe adult respiratory distress syndrome redistribution of pulmonary blood flow in the dog with peep ventilation the association between physiologic dead-space fraction and mortality in subjects with ards enrolled in a prospective multi-center clinical trial lung inhomogeneity in patients with acute respiratory distress syndrome microvascular perfusion as a target for fluid resuscitation in experimental circulatory shock early bedside detection of pulmonary vascular occlusion during acute respiratory failure vascular obstruction causes pulmonary hypertension in severe acute respiratory failure alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia the pulmonary vascular lesions of the adult respiratory distress syndrome relationship between capillary and systemic venous po during nonhypoxic and hypoxic ventilation mechanisms of physiological dead space response to peep after acute oleic acid lung injury assessment of dead-space ventilation in patients with acute respiratory distress syndrome: a prospective observational study effect of anatomic shunt on physiologic deadspace-to-tidal volume ratio-a new equation rationale of dead space measurement by volumetric capnography effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank dr. fernando rosso (cic, fundación valle del lili-universidad icesi, cali, colombia) and dr. yuri takeuchi (universidad icesi -fundación valle del lili) for their unconditional support to this project. literature search: gaot, dfb and gh; data acquisition: gaot, dfb, jdv, wfb, and hjm; data analysis and interpretation: gaot, gh, hjm, jdv, wfb, eq, lect; critical review: gaot, gh, ab and ddb; conception, hypothesis delineation, and design of the study: gaot, and ddb. all authors read and approved the final manuscript. the current study received logistic support from the centro de investigaciones clínicas -fundación valle del lili, cali -colombia. the datasets generated and/or analyzed during the current study are not publicly available as recommended by the local ethical and research committee involving human beings (fundación valle del lili, cali, colombia) but these could be available from the corresponding author on reasonable request and under prior approval by such committee. the ethical and research committee involving human beings approved the current study (protocol number: ; approval number: - , , fundación valle del lili, cali, colombia). not applicable. key: cord- -a bspoii authors: roch, antoine; hraiech, sami; masson, elodie; grisoli, dominique; forel, jean-marie; boucekine, mohamed; morera, pierre; guervilly, christophe; adda, mélanie; dizier, stéphanie; toesca, richard; collart, fréderic; papazian, laurent title: outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: a bspoii purpose: patients with severe acute respiratory distress syndrome (ards) are candidates for extracorporeal membrane oxygenation (ecmo) therapy. the evaluation of organ severity is difficult in patients considered for cannulation in a distant hospital. this study was designed to identify early factors associated with hospital mortality in ards patients treated with ecmo and retrieved from referring hospitals. methods: data from consecutive ards patients equipped with ecmo by our mobile team and consequently admitted to our icu were prospectively collected and analyzed. results: the main ards etiologies were community-acquired bacterial pneumonia ( %), influenza pneumonia ( %) (with patients having been treated during the first half of the study period), and nosocomial pneumonia ( %). the median (interquartile range) time between contact from the referring hospital and patient cannulation was ( – ) h. ecmo was venovenous in ( %) patients. no complications occurred during transport by our mobile unit. forty-eight patients died at the hospital ( %). based on a multivariate logistic regression, a score including age, sofa score, and a diagnosis of influenza pneumonia was constructed. the probability of hospital mortality following ecmo initiation was % in the – score class (n = ) and % in the – score class (n = ). patients with an influenza pneumonia diagnosis and a sofa score before ecmo of less than had a mortality rate of %. conclusions: age, sofa score, and a diagnosis of influenza may be used to accurately evaluate the risk of death in ards patients considered for retrieval under ecmo from distant hospitals. abstract purpose: patients with severe acute respiratory distress syndrome (ards) are candidates for extracorporeal membrane oxygenation (ecmo) therapy. the evaluation of organ severity is difficult in patients considered for cannulation in a distant hospital. this study was designed to identify early factors associated with hospital mortality in ards patients treated with ecmo and retrieved from referring hospitals. methods: data from consecutive ards patients equipped with ecmo by our mobile team and consequently admitted to our icu were prospectively collected and analyzed. results: the main ards etiologies were community-acquired bacterial pneumonia ( %) , influenza pneumonia ( %) (with patients having been treated during the first half of the study period), and nosocomial pneumonia ( %) . the median (interquartile range) time between contact from the referring hospital and patient cannulation was ( ) ( ) ( ) ( ) h. ecmo was venovenous in ( %) patients. no complications occurred during transport by our mobile unit. forty-eight patients died at the hospital ( %). based on a multivariate logistic regression, a score including age, sofa score, and a diagnosis of influenza pneumonia was constructed. the probability of hospital mortality following ecmo initiation was % in the - score class (n = ) and % in the - score class (n = ). patients with an influenza pneumonia diagnosis and a sofa score before ecmo of less than had a mortality rate of %. conclusions: age, sofa score, and a diagnosis of influenza may be used to accurately evaluate the risk of death in ards patients considered for retrieval under ecmo from distant hospitals. the technique of extracorporeal membrane oxygenation (ecmo) for patients with severe acute respiratory distress syndrome (ards) involves placing them on a venovenous or venoarterial life-support circuit with a membrane oxygenator to temporarily take over the gas exchange and, sometimes, cardiac function [ ] . over the last two decades, the technique has progressed significantly, and several studies have reported encouraging survival rates using mainly venovenous ecmo in adults with ards [ ] [ ] [ ] [ ] [ ] [ ] [ ] . recently, an ecmo-based management protocol for selected ards patients transferred to a referral center was shown to improve -month disability-free survival [ , ] . however, owing to recent advances in the management of ards [ , ] , ecmo remains a salvage therapy in a limited number of patients with life-threatening hypoxemia or respiratory acidosis [ ] . moreover, because of its additional costs and the need for trained expertise [ , ] , a rational allocation of this limited resource is critical, and indications must be further explored. ecmo centers have developed and have long been associated with mobile units that retrieve patients from distant hospitals immediately after cannulation [ , ] . approximately half of the patients treated with ecmo for ards are cannulated in distant hospitals and transported on ecmo [ , , ] . for these patients, the decision to initiate ecmo is often made by phone and is based on the severity of respiratory failure, which is often evaluated by blood gas results or the lung injury score [ , ] . although some patients do not present with other organ failures, most of them present with septic shock and associated organ dysfunction. because they may contribute significantly to ecmo outcomes, an understanding of the impact of preexisting organ dysfunction on ecmo-associated mortality is helpful in modifying the current strategies of ecmo in the resuscitation of these high-risk patients [ ] . in the present study, we evaluated early prognostic factors in ards patients treated with ecmo in distant hospitals by our mobile team and brought to our center during a -year period. the goal was to establish simple decision rules that could aid the clinician in the decision regarding whether to treat patients with ecmo. marseille north hospital is a general acute-care, university hospital. it is a regional referral center for the treatment of severe respiratory infections. we established an ecmobased protocol in autumn that included a mobile unit that could initiate ecmo in referring hospitals of our region before transfer to our center [ , ] . we prospectively included all consecutive adult patients treated with ecmo in distant hospitals (a , -km region) by our mobile team and immediately brought to our center between october and march . only patients with ards were included. patients treated with ecmo as a bridge to or following lung transplantation or any surgery were not included. the protocol was approved by the local research ethics committee, who waived the need for informed consent, according to french legislation. referring hospitals were informed twice a year of ecmo criteria. the indication was discussed with one of three referees from our center who were contactable / through a hotline. a standardized form including ventilatory and blood gas parameters and sequential organ failure assessment (sofa) score parameters was prospectively completed. before consideration for ecmo, patients were all sedated using continuous neuromuscular blockade [ ] and ventilated with volume-controlled ventilation using a tidal volume (vt) of - ml/kg of predicted body weight. ecmo therapy was indicated if patients presented a pao to fio ratio of less than mmhg for at least h under an fio of and a peep level adjusted to obtain a plateau pressure (pplat) of cmh o, a pao to fio ratio of less than mmhg associated with a pplat value greater than cmh o, or respiratory acidosis with ph less than . despite a respiratory rate greater than /min. absolute contraindications included the following: any contraindication to heparin treatment, a chronic disease expected to be fatal within years, a sofa score greater than , and age over years. the sofa score [ ] was always precisely calculated before ecmo consideration. when feasible in the referring hospital, prone positioning was systematically performed before considering ecmo. relative contraindications were body mass index (bmi) greater than kg/m and duration of ards greater than days. venovenous ecmo was instituted using surgical cannulation, usually in a femoral-jugular configuration. echocardiography was performed in all patients before cannulation and each day under ecmo. this procedure enabled venoarterial cannulation to be performed initially or later in patients presenting with left heart failure on the basis of echocardiography, defined as a less than % left ventricular ejection fraction. we used centrifugal pumps (bio-console ; medtronic perfusion systems, minneapolis, mn, usa) with a flow of - l/min in all patients. circuits were heparin-coated and composed of quadrox d with bioline coating oxygenators (maquet, hirrlingen, germany), - fr cannulae (edwards lifesciences, irvine, ca, usa), and intersept polyvinyl chloride (pvc) class vi tubing (medtronic). initial ventilator settings were as follows: pplat, - cmh o; peep, - cmh o; respiratory rate, - breaths/min; and fio adjusted to obtain an arterial o saturation of - %, whereas the fio was set at on the oxygenator. the patients were transferred to our icu immediately after ecmo initiation by a team comprising one physician from our icu, the cardiac surgeon who cannulated the patient, and a perfusionist. continuous heparin infusion maintained the activated partial thromboplastin time (aptt) at - s. the triggering limits for transfusion were /ml for platelets and g/dl for hemoglobin. ecmo was continued until lung recovery or until irreversible multiorgan failure leading to death. patients were weaned from venovenous ecmo when the following criteria were met: pao to fio ratio greater than mmhg with peep less than cmh o, pplat less than cmh o with a vt of - ml/kg, fio of . on ecmo, blood flow of l/min, and gas flow of l/min. prospectively collected data included demographic data; presence of identified risk factors for ards and major co-morbidities; respiratory and hemodynamic parameters at admission, before ecmo initiation, and throughout ards evolution; duration of ecmo and of mechanical ventilation; complications; and outcome. icu and hospital mortality were recorded. the severity of the illness was assessed based on the simplified acute physiology score (saps) ii [ ] at icu admission and the sofa [ ] score before ecmo initiation and at days , , and of ecmo. the neurological score was calculated on the basis of the glasgow coma scale just before intubation. biological parameters were obtained in the h preceding cannulation for all patients. the number of ecmo-free days at day was defined as the number of days alive and free from ecmo at this time point. descriptive statistics included percentages for categorical variables and medians and interquartile ranges (iqrs) for continuous variables. comparisons were made using either the chi-square test or the fisher exact test for categorical variables and the student's t test or mann-whitney u test for continuous variables, according to their distribution. parameters significantly associated with hospital mortality on the basis of univariate analysis (p \ . ) were introduced into a logistic regression analysis. the final model expressed the odds ratios (or) and % confidence intervals (ci). to derive a simple and practical score to predict hospital mortality, we combined the logistic regression and the recursive partitioning analysis (rpa) [ , ] conducted using the rpart routine in r software [ ] . briefly, rpa accepts predictor and response values as the inputs. as the output, this function generates a decision tree using a recursive partitioning algorithm. each partitioning step selects the tree-branching criterion based on the predictor variables that will split the parent data set into two daughter data sets, with the daughter sets being as ''pure'' (homogeneous) as possible as approximated according to a heuristic. here, purity is measured with the gini statistic with respect to the response variable, such that the more homogeneous a daughter set, the higher the purity. partition steps are repeated, adding branches to the tree, until the subgroups reach a minimum size or until no improvement can be obtained. firstly, the significant variables in the multivariate logistic regression were selected into an rpa to build a decision tree. then the optimal cutoff in the tree associated with each variable was used to transform the continuous variables into categorical variables (named partial scoreps i ). with the aim to be as intuitive as possible, the score was constructed to give a result between and where is a lower risk of hospital mortality and a higher risk. the score can be calculated with the following formula: score = p ps i , where ps i is the partial score assigned to each categorical variable. the discriminative performance of the score was evaluated with a receiver operating characteristics (roc) curve and quantified by calculating the area under the curve and % ci. the best cutoff value was identified as the point with the highest sensitivity and specificity (youden index: se ? sp - ). lastly, kaplan-meier survival analysis was used to estimate the probability of survival after ecmo initiation for groups under and over the best cutoff value of the score. the log-rank test was used. statistical analysis was performed using the spss statistics software. during the study period, the referee from our center was contacted for consideration for ecmo by a referring hospital for patients with ards ( fig. ). among them, patients did not meet criteria for ecmo and were not referred and consecutive patients treated with ecmo were included. six of them had been included in a previous cohort study [ ] . patients' demographic characteristics are provided in table . no patient had a history of chronic heart, renal, or respiratory insufficiency. the main cause of ards was documented as communityacquired bacterial pneumonia (n = ). twenty patients presented with influenza pneumonia, of whom had been treated in the first half of the study period. the median (interquartile range) time between contact from the referring hospital and patient cannulation was ( - ) h; transfer to our center occurred within ( - ) h. no serious complications (including vascular or chest tube displacement, ecmo malfunction, cardiac arrest, or death) occurred during transport by our mobile unit. for venovenous ecmo, femoral-jugular vein cannulation was performed in patients, and femoral-femoral cannulation was performed in patients. femoral-femoral cannulation was performed in the eight patients treated with venoarterial ecmo. in all cases, venoarterial ecmo was used for left heart failure and severe shock complicating ards-associated disease. prior to ecmo, all patients had refractory hypoxemia, had a paco greater than mmhg, and had an arterial ph less than . . forty-eight patients died in the icu or at the hospital ( %). causes of death were multiorgan failure frequently associated with refractory hypoxemia (n = ); hemorrhagic complications secondary to cannulation (n = ); and intracerebral hemorrhage (n = ). forty-two nonsurvivors died during therapy after a median (range) of ( - ) days of ecmo, and of them died after successful ecmo weaning after a median (range) of ( - ) days of ecmo. survivors had a median (range) duration of ecmo therapy of ( - ) days and were mechanically ventilated for a median (interquartile range) duration of ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) days. after univariate analysis, factors potentially collected before ecmo that were associated with hospital mortality were age, sofa score, lactate level, and a diagnosis of influenza pneumonia ( table ). saps ii was not considered for multivariate analysis because it could not constantly be obtained at this time and because sofa score is easier to use at the bedside. age, sofa score, and a diagnosis of influenza pneumonia were introduced into the logistic regression analysis, which showed that these three parameters were independently associated with hospital mortality. mortality increased with age [or . , ci ( . ; . ), p = . ] and sofa score [or . , ci ( . ; . ), p = . ] whereas a diagnosis of influenza pneumonia was associated with a lower risk of death [or . , ci ( . ; . ), p = . ]. lactate level was not introduced into the multivariate analysis because it was not available for all patients in the h before considering ecmo. the distribution of sofa subscores just before ecmo is presented in fig. . hemodynamic and liver scores were higher in nonsurvivors (p = . and p = . , respectively). the score developed after transforming continuous into categorical variables is displayed in table . the optimal cutoff for the score was identified as . . finally, the probability of hospital mortality following ecmo initiation was % in the - score class (n = ) and % in the - score class (n = ) ( fig. ; p \ . ). the area under the roc curve of the performance of this scoring system was . , ic [ . ; . ], p \ . . during ecmo therapy, patients were treated with high-frequency oscillatory ventilation, with prone positioning, and with corticosteroids for ards ( table ) . sofa scores at day , , or of ecmo were higher in hospital nonsurvivors than in survivors. renal replacement therapy during ecmo was used more frequently in nonsurvivors than in survivors. hemorrhagic complications occurred in patients ( %) under ecmo. major hemorrhagic complications were retroperitoneal hematoma secondary to cannulation (n = ), intracerebral hemorrhage (n = ), and hemothorax due to fibrinolysis requiring ecmo weaning (n = ). other hemorrhagic complications were limited or moderate respiratory tract hemorrhage (n = ), epistaxis requiring nasal packing (n = ), and limited hemorrhage at cannulation sites (n = ). while under ecmo, patients were transfused with a median (iqr) of ( - ) units of red blood cells [ ( - ) u/day], ( - ) units of frozen plasma, and ( - ) unit of platelets. in eight cases, membrane exchange was required during ecmo therapy because of acute hemolysis. the results of the present study show that age, sofa score calculated in the h before ecmo, and a diagnosis of influenza pneumonia are independently associated with hospital mortality in ards patients retrieved under ecmo from distant hospitals and brought to our ecmo fig. distribution of sofa score and subscores before ecmo in survivors (white bars) and in nonsurvivors (black bars). the neurological score was and the respiratory score was in all patients center. these simple criteria can be included in a simple score to help clinicians make decisions regarding whether to treat patients with ecmo. our study is the first to analyze prognostic factors prior to ecmo in patients who have all been cannulated in distant hospitals. this population is likely to represent the majority of patients considered for ecmo in the future. those patients are often considered for ecmo under rescue conditions, and the decision to initiate ecmo is often difficult. our results show that simple criteria can be useful in predicting the prognosis in those patients despite the rapid evolution of their organ dysfunctions. another strength of the present study is that it only includes patients with ards. previous studies have frequently mixed patients with ards and cardiogenic shock [ , , [ ] [ ] [ ] , whereas these diseases are likely to affect different populations and to have different prognostic factors. most studies have shown that ecmo can be applied with encouraging survival rates [ ] [ ] [ ] [ ] [ ] [ ] [ ] . although the % mortality rate found in the present study is in agreement with most other studies, some studies have reported lower rates. in the cesar trial [ ] , % of patients treated with ecmo survived. of note, most of our patients had pneumonia with severe septic shock requiring vasopressors, and half of them required renal replacement therapy during the icu stay, which has been shown to have an important prognostic impact in ecmo patients [ , ] . moreover, mortality rate is most likely largely influenced by indications and contraindications defined by each center. in the present study, indications were quite liberal regarding the evolution of organ dysfunctions, making it possible to accurately evaluate their prognostic impact. to date, decision criteria given for ecmo initiation in guidelines and studies are still undefined. nevertheless, a recent study [ ] showed that the application of new criteria based on extracorporeal life support organization (elso) guidelines [ ] resulted in a higher mortality compared with previous criteria used at the same center, suggesting a strong influence of these criteria on the reported outcomes. studies, some with large numbers of patients, have identified early prognostic factors in patients treated with ecmo [ , , , , , , , ] . the analysis of the elso multicenter database has notably identified age as a pre-ecmo factor associated with prognosis in patients with acute respiratory failure [ ] . for this reason, only a few patients over years of age are treated with ecmo [ , , ] . recently, schmidt et al. [ ] reported that age over years was associated with a higher mortality. in the present study, we also observed that patients less than years old had a markedly better prognosis and that outcome was independent of other organ dysfunctions in those very young patients. this important finding suggests that ecmo should not be contraindicated on the basis of organ dysfunction in young patients. we found that the sofa score before ecmo was associated with mortality. the sofa score is simple to calculate and has been validated as a marker of organ dysfunction and of mortality in large multicenter studies in different patient populations [ ] . in a cohort of patients treated with ecmo for respiratory or heart failure, wu et al. [ ] suggested the prognostic value of sofa calculated before ecmo. recently, lindskov et al. [ ] showed that the sofa score calculated at day after ecmo initiation was predictive of death. in this latter study, a sofa score of or less was associated with % survival. in the study by wu et al. [ ] , the mean sofa score before ecmo was ± in ards patients, whereas it was ± in our study. however, as in the study by lindskov et al. [ ] , a higher score was associated with higher hospital mortality sofa sequential organ failure assessment fig. kaplan-meier estimates of cumulative probabilities of survival for patients with pre-ecmo score classes - (n = ), and - (n = ). ecmo extracorporeal membrane oxygenation sofa was not calculated in the same way as in the present study. notably, the glasgow coma scale score was set arbitrarily to points. no patient presented with impaired consciousness at the time of sedation in our study, resulting in a -point neurological score in all patients. pappalardo et al. [ ] proposed a prognostic score in patients with h n -associated ards treated with ecmo that was based on biological and clinical data similar to the data used to determine the sofa score. more recently, schmidt et al. [ ] proposed a prognostic score in ards patients treated with ecmo in which sofa had a quite similar weight to that in the present study. we found that a diagnosis of influenza-associated ards was associated with a better prognosis. our % mortality rate is in agreement with recent studies in patients with influenza h n -associated ards treated with ecmo [ , ] . our results also confirm those of previous observational studies suggesting that patients treated with ecmo for influenza pneumonia have a lower risk of death than patients presenting with other causes of ards [ ] . however, no study had previously clearly shown a protective effect of influenza in ecmo patients. unfortunately, the diagnosis of influenza is inconsistently confirmed but rather suspected at the time the ecmo decision is made. therefore, this parameter cannot be taken into account in all patients when making ecmo decisions. of note, all patients in our study who had confirmed influenza had been suspected of having influenza at ecmo initiation, and only three patients with suspected influenza were not confirmed. some studies have shown that the duration of mechanical ventilation before ecmo is associated with mortality [ , , , ] . in our study, the duration of mechanical ventilation prior to ecmo was not longer in nonsurvivors. however, it is notable that our duration of ventilation before ecmo was short. the analysis of the elso database showed that the duration of mechanical ventilation was no longer associated with mortality in the most recently treated patients [ ] , whereas the number of patients treated after days of mechanical ventilation decreased with time. further studies are necessary to clearly address this question. the present study is a single-center study, which could limit the translation of our results to other centers. however, our population has been stringently selected on the basis of predefined criteria and has benefited from protocolized treatments, including medical and technical maintenance of ecmo support. it is notable that the predefined indications that we used for ecmo based on gas exchange and ventilator pressure are not universally standardized and remain an important topic of discussion. in ards patients treated mainly with venovenous ecmo and retrieved after cannulation from referring hospitals, age, sofa score just before considering ecmo, and a diagnosis of influenza pneumonia can be used to aid the clinician in the decision about whether to initiate ecmo. prognosis is much less dependent on organ dysfunction in young patients. a diagnosis of influenza-associated ards is associated with a lower mortality rate. extracorporeal membrane oxygenation for respiratory failure in adults extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome extracorporeal life support for severe acute respiratory distress syndrome in adults extracorporeal membrane oxygenation for severe influenza a (h n ) acute respiratory distress syndrome: a prospective observational comparative study extracorporeal membrane oxygenation in adults with severe respiratory failure: a multi-centre database high survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation treatment of severe acute respiratory distress syndrome: role of extracorporeal gas exchange support timedependent outcome analysis for venovenous extracorporeal membrane oxygenation efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome what is the niche for extracorporeal membrane oxygenation in severe acute respiratory distress syndrome? extracorporeal life support organization ( ) elso guidelines for ecmo centers increased extracorporeal membrane oxygenation center case volume is associated with improved extracorporeal membrane oxygenation survival among pediatric patients interhospital transport of the patient on extracorporeal cardiopulmonary support inter-hospital transportation of patients with severe acute respiratory failure on extracorporeal membrane oxygenation-national and international experience extracorporeal membrane oxygenation in adult patients with severe acute respiratory failure predicting mortality risk in patients undergoing venovenous ecmo for ards due to influenza a (h n ) pneumonia: the ecmonet score contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era an expanded definition of the adult respiratory distress syndrome acute respiratory distress syndrome following h n virus pandemic: when ecmo come to the patient bedside the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine a new simplified acute physiology score (saps ii) based on a european/north american multicenter study an introduction to recursive partitioning using the rpart routines. mayo foundation, rochester evaluation of outcome scoring systems for patients on extracorporeal membrane oxygenation impact of preexisting organ dysfunction on extracorporeal life support for nonpostcardiotomy cardiopulmonary failure predictors of mortality in patients successfully weaned from extracorporeal membrane oxygenation prognosis of patients on extracorporeal membrane oxygenation: the impact of acute kidney injury on mortality is it possible to predict outcome in pulmonary ecmo? analysis of preoperative risk factors extracorporeal membrane oxygenation in acute adult respiratory distress syndrome mortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure the preserve mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome key: cord- -xna qve authors: zhou, yuqing; fu, xiaofang; liu, xiaoxiao; huang, chenyang; tian, guo; ding, cheng; wu, jie; lan, lei; yang, shigui title: use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: xna qve influenza-related severe pneumonia and acute respiratory distress syndrome (ards) are severe threats to human health. the objective of this study was to assess the effects of systematic corticosteroid therapy in patients with pneumonia or ards. the pubmed, embase, web of science and scopus databases were searched up to july, . nineteen studies including individuals were identified, and fifteen studies ( patients) were included in the meta-analysis of mortality. eighteen were observational studies and one was a randomized controlled trial (rct). the meta-analysis results showed that corticosteroid therapy was associated with significantly higher mortality (or . , % ci [ . , . ]) and incidence of nosocomial infection (or . , % ci [ . , . ]). subgroup analysis showed that among patients with unadjusted estimates, the odds of mortality were higher in patients receiving corticosteroid treatment (or . , % ci [ . , . ]), however, among patients with adjusted estimates, the result showed no statistically significant difference between corticosteroid group and control group (or . , % ci [ . , . ]). current data do not support the routine use of corticosteroids in patients with influenza severe pneumonia or ards. rcts are needed to provide more robust evidence. influenza is a viral infection that attacks the respiratory system. rapidly progressing viral pneumonia and acute respiratory distress syndrome are pulmonary manifestations that are commonly observed in patients with influenza and are associated with considerable mortality - , representing a severe threat and imparting a substantial financial burden worldwide . individuals with community-acquired pneumonia may benefit from systematic corticosteroid therapy, which may block the inflammatory cascade reaction . corticosteroids could improve the lung tissue damage induced by influenza pneumonia and decrease the risk of mortality in animal models with influenza infections , . many clinicians administer corticosteroids as an anti-inflammatory treatment for patients with severe influenza-related pneumonia to stop disease progression and improve clinical outcomes. a large cohort study of patients admitted to icus in spain found that the frequency of corticosteroid treatment by study period was . % in , . % in , % in , and . % in . recently, some studies have shown that corticosteroids may not be beneficial for patients with severe influenza and may even increase mortality [ ] [ ] [ ] . however, there is considerable uncertainty regarding whether patients with influenza-related ards or severe pneumonia can benefit from adjuvant corticosteroid therapy. we aimed to systematically review all experimental and observational studies on corticosteroid use in patients with influenza-related ards and severe pneumonia. the effect of corticosteroid treatment on clinical outcomes was investigated. search strategy and study selection. we comprehensively searched the pubmed, embase, web of science and scopus databases from inception to july . the core search terms were defined as those related to influenza-related pneumonia, ards, acute respiratory failure and corticosteroid use (for details on the search strategy in embase, refer to supplementary table s ). the references of eligible studies were screened, and two authors independently reviewed all citations that met the inclusion criteria. study selection was performed in stages: first, study title and abstract screening; second, full text examination. data extraction and quality assessment. outcome data were independently extracted from the included studies by two investigators using a previously piloted standardized pro forma. we obtained the following data: (a) characteristics of studies (design, setting, country, period, methodological details for quality assessment); (b) characteristics of participants (demographics, co-morbid illnesses, disease severity, numbers in each group, influenza virus type); (c) characteristics of interventions (type, dose, timing and duration of corticosteroid use); and (d) outcomes. the quality of each study was independently assessed by two individuals according to the cochrane risk of bias tool for rcts and the newcastle-ottawa scale for nonrandomized trials and comparative observational studies. three domains are assessed on the nos for observational studies : ( ) "selection bias", ( ) "comparability bias", and ( ) "outcome bias". disagreements at any stage were resolved through discussion with the other authors until consensus was reached. sensitivity analysis. we performed sensitivity analysis to assess the effect of the study design on clinical outcomes using stratification if the number of studies was sufficient. data analysis. odds ratios (ors) and their corresponding % confidence intervals (cis) were generated during the analysis of dichotomous outcome data, and mean differences or standardized mean differences and their corresponding % cis were generated during the analysis of normally distributed continuous data. ors or hazard ratios (hrs) for adjusted outcome estimates and their corresponding % cis were obtained and are presented in the pooled analyses. medians and interquartile ranges were generated in the analysis of continuous data that were not normally distributed. the i² test for inconsistency was used to analyse heterogeneity. if i² > %, the heterogeneity across studies was significant, and a random-effects model was used in the meta-analysis; otherwise, a fixed-effects model was used. subgroup analysis was performed in the following areas where possible: adult population versus child population; seasonal influenza versus outbreak influenza or pandemic influenza; icu versus inpatient; adjusted estimates versus unadjusted estimates; and corticosteroid dose, timing and duration. all statistical analyses were performed using cochrane systematic review software review manager (revman; version . . ; the nordic cochrane centre, the cochrane collaboration, copenhagen, ). a total of relevant articles were identified during the initial search. after the removal of duplicates, articles remained. after screening the titles and abstracts of those articles, articles were excluded because of irrelevance. of the full-text articles reviewed, were excluded for various reasons, and articles remained. details regarding the reasons for the exclusion of these studies are shown in fig. and supplementary table s . ultimately, studies were included in the meta-analysis of mortality, while studies reported outcomes other than mortality in association with corticosteroid use. the characteristics of the participants in the included studies are summarized in table and supplementary table s . the studies were published between and . eighteen of the studies had an observational design, while one had a randomized controlled trial design . outcome data were reported in studies ( individuals, including in corticosteroid group and in the non-corticosteroid group), while mortality data were reported in studies ( individuals). eight studies (n = ) included only icu patients. fourteen studies assessed individuals with h n pdm virus infection, study assessed individuals with h n virus infection, and study assessed individuals with inter-pandemic influenza virus infection. eight studies ( individuals) had useable data related to patients with ards , , [ ] [ ] [ ] [ ] [ ] [ ] . fourteen studies (n = ) reported mortality associated with adults only. the median ages varied from . to . years in all patients included. the proportion of male participants was higher than that of females ( . % versus . %) and range varied from . % to . % ( studies, individuals). obesity (bmi ≥ kg/m ) was common ( . %, / ) in the included studies ( studies, individuals), and the proportion of obese individuals ranged from . % to . %. disease severity at baseline was reported in seven studies and in studies ( individuals), the baseline disease severity was higher in individuals in the corticosteroid group than in those in the non-corticosteroid group [ ] [ ] [ ] . methylprednisolone ( . %, / ) was the most common steroid used in the corticosteroid group ( studies), and the median duration varied from . to . days. almost all patients ( . %, / ) received antiviral therapy (ranging from . % to %, studies), and . % ( / ) of participants received antibiotic therapy ( studies). the details of the therapies are described in table . because all studies included in the meta-analysis of mortality were observational cohort studies, selection bias was inevitable. the risk of bias identified in the included studies is shown in supplementary tables s a,b. the studies' nos scores varied from to , indicating that the quality of the included studies was high . however, most included studies had substantial comparability bias because we could not adequately adjust for disease severity, and individuals with greater diseases severity tended to use corticosteroids. overall mortality in the included studies. mortality data were reported in studies [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the pooled analysis of the crude results of the included studies ( individuals) suggested that those who used corticosteroids had a significantly higher mortality rate (or . , % ci [ . , . ], p < . ), and a moderate level of heterogeneity was observed (i² = %; supplementary fig. s ). five studies , , , , reported adjusted effect estimates of -day or inhospital mortality (adjusted or or adjusted hazard ratio (ahr), table ). the pooled analysis of the crude results of ten included studies and five adjusted effect estimates suggested that those who used corticosteroids had a significantly higher mortality rate (or . , % ci [ . , . ], i = %, p < . , fig. ). the subgroup analysis of unadjusted effect estimates showed a similar result (or . , % ci [ . , . ], i = %, p = . ). however, the subgroup analysis of the five adjusted estimates showed no association between mortality and corticosteroid use (hr . , % ci [ . , . ], i = %, p = . ). the test for subgroup differences between adjusted and unadjusted mortality was not statistically significant (p = . ). there was no clear indication of publication bias in the funnel plot analysis ( supplementary fig. s ). eight studies reported the mortality of patients with ards due to influenza (n = , supplementary table s ). meta-analysis of unadjusted and adjusted estimates suggested that the difference in mortality between the corticosteroid and control groups was not statistically significant (or . , % ci [ . , . ], i = %, p = . , fig. ). li et al. reported that corticosteroid use was associated with a decreased risk of mortality in patients with ards (pao /fio < mmhg) (ahr . , % ci [ . , . ]) . however, brun-buisson et al. and chawla et al. suggested that the risk of mortality was higher in corticosteroid group in the patients with ards. cao et al. reported that a low-to-moderate dose of corticosteroids had no statistically significant association with the risk of mortality in patients with ards (or . , % ci [ . , . ]), whereas a high dose was associated with greater mortality (or . , % ci [ . , . ]) . the other four studies , , , showed that corticosteroid use had no association with mortality ( fig. ) . considering the different management strategies for paediatric and adult patients, one study investigating paediatric patients was excluded www.nature.com/scientificreports www.nature.com/scientificreports/ with low statistical heterogeneity (i = %), and a similar result was found for mixed patient groups (or . [ . , . ], i = %) (supplementary fig. s ). three studies (n = ) have reported the results of mortality excluding patients who had potential indications (e.g., asthma, copd exacerbation, pregnancy/post-partum, shock or immunosuppressive conditions) for corticosteroid treatment that may have skewed the results , , . a pooled analysis of these three studies showed no statistically significant association between corticosteroid use and mortality (or . , % ci [ . , . ]), with a high level of heterogeneity (i² = %, p = . ). the number of studies was insufficient to perform subgroup analysis according to the various reported regimens. two studies compared early versus later/no corticosteroid treatment; one defined early treatment as within three days of mechanical ventilation , and the result suggested that early treatment with corticosteroids was associated with greater mortality (ahr . , % ci [ . , . ]); the other defined early treatment as within h of nais , and the result showed no statistically significant difference in mortality between patients receiving corticosteroids within h of nais and those who did. three studies categorized corticosteroid dose as low/low-to-moderate and high , . a large retrospective cohort study reported that a low-to-moderate dose ( - . another study reporting the result of patients with acute respiratory failure due to influenza showed no statistically significant difference between low dose and high dose corticosteroid therapy ( / versus / , p > . ) . two of the included studies reported outcomes related to children, but only one reported the risk of mortality (or . , % ci [ . , . ]) related to corticosteroid use . however, in that study, all children who received corticosteroids had ards, while the patients in the non-corticosteroid group had less severe disease conditions. another retrospective cohort study of children with pneumonia caused by the h n influenza virus only reported length of hospital stay and duration of fever and found a shorter length of stay and duration of fever in corticosteroid group (table ) . in four of these studies, corticosteroid use was associated with an increased risk of developing a nosocomial infection , , , , while the remaining two studies did not show a statistically significantly increased odds of developing infection , . overall, the pooled results revealed that the odds of nosocomial infection were significantly higher in patients who were administered corticosteroids than in those who were not (or . , % ci [ . , . ], p < . ), but a high level of heterogeneity was observed (i² = %) (fig. ) . three studies reported the common pathogens isolated from patients with nosocomial infection. one study reported that the most common bacteria isolated was acinetobacter baumannii ( . %) . in a study of patients with severe influenza pneumonia , patients had nosocomial infection, and the most commonly isolated pathogens were acinetobacter baumannii ( . %), pseudomonas aeruginosa ( . %), and staphylococcus aureus ( . %), while in another cohort study of patients with severe influenza pneumonia , streptococcus pneumoniae ( . %), pseudomonas aeruginosa ( . %), and staphylococcus aureus ( . %) were the most frequently isolated microorganisms. www.nature.com/scientificreports www.nature.com/scientificreports/ length of stay and length of mv. seven studies reported length of stay according to corticosteroid use; all were unadjusted for disease severity (table ) . six studies found no statistically significant difference between the groups. one study showed a longer length of icu stay associated with corticosteroid use, while the total length of hospital stays was not significantly different between the groups. notably, one of the five studies analysed the duration of hospital stay in people with influenza pneumonia treated with corticosteroid versus those receiving placebo, and found no significant difference between the groups (adjusted difference − . days, % ci [− . , . ]) . linko et al. reported a longer duration of mechanical ventilation in the group treated with corticosteroid therapy while brun-buisson et al. and moreno et al. found no statistically significant difference between the groups. (table ) . two studies reported the time to fever alleviation according to corticosteroid use , . kudo et al. found no statistically significant difference between the groups, while another cohort study of children with severe influenza pneumonia reported a shorter time to fever alleviation. notably, two studies found a shorter time to clinical stability in the corticosteroid group. the study of influenza a/h n found a significantly longer duration of viral shedding associated with corticosteroid treatment . the details of these outcomes are described in table . the overall findings of this meta-analysis indicated that patients with pneumonia or acute respiratory distress syndrome who were administered corticosteroids had significantly higher mortality and incidence of nosocomial infection but the use of corticosteroids did not influence the length of hospital stay. our studies suggested a deleterious effect of steroids on mortality and nosocomial infection. several factors need to be accounted for in interpreting these findings. first, most studies did not adjust the clinical outcomes for potential confounding factors. clinically, more severe cases tended to be treated with corticosteroids, which may obscure the real value of this treatment regarding mortality , . therefore, in this study, we preferred the use of adjusted estimates of the effect to minimize potential confounding between the treatment groups. however, five studies reported adjusted estimates of mortality, and their inclusion in the meta-analysis still revealed a higher odds of mortality related to steroids use. good evidences indicated that secondary bacterial pneumonia is an www.nature.com/scientificreports www.nature.com/scientificreports/ important cause of mortality related to influenza , . therefore, increasing risk of nosocomial infection due to corticosteroid treatment may partly account for the potential harm from corticosteroid use. two included studies , found that secondary bacterial pneumonia such as due to acinetobacter baumannii, pseudomonas aeruginosa, streptococcus pneumoniae, staphylococcus aureus or invasive fungal infection, were more common in corticosteroid-treated patients. several studies showed that prolonged viral shedding and delayed viral clearance were noted in corticosteroid-treated patients , , whereas slower clearance of virus loads was associated with higher mortality in patients with ards due to h n pdm virus infection . thus, prolonged viral shedding and delayed viral clearance may also contribute to higher mortality. second, most of the included observational studies did not explain why some patients received systemic corticosteroid therapy and others did not. the initial intentions of corticosteroid therapy were unclear (was it used as a rescue therapy or due to copd/asthma exacerbation or due to pneumonia/ards?). different indication may easily confound the effect of the corticosteroid. some evidences supported the use of corticosteroids for asthma or copd or septic shock in the context of influenza infection [ ] [ ] [ ] . in order to minimize the influences of different indications, subgroup analysis of the mortality in three studies (n = ) was performed after excluding patients receiving corticosteroids as rescue therapy or due to copd/asthma exacerbation, and found no statistically significant difference between the steroid therapy groups and control groups and the heterogeneity was high (i² = %). however, the high level of statistical heterogeneity may result in unstable estimates of the meta-analysis. therefore, well-designed clinical trials should be conducted to decrease the heterogeneity of patients and to provide more robust evidence. the results from clinical studies of corticosteroid therapy in patients with influenza are conflicting. many studies have shown a significant association between corticosteroid treatment and mortality in patients with influenza; however, several studies have reported that corticosteroids can provide benefits to patients under certain conditions , , , . an rct included in this review noted an association between adjuvant corticosteroid therapy ( mg of prednisone given orally for days) and decreased time to clinical stability. low-to-moderate doses of corticosteroids are beneficial in people with hypoxia ((pao /fio ) < mmhg), whereas high doses of corticosteroids showed no benefit in this group; however, low-to-moderate doses of corticosteroids may increase the -day mortality rate in those with pao /fio > mmhg . kil et al. reported that rapid (methylprednisolone, mg/kg/d) and short-term (tapered off within a week) corticosteroid treatment for children with severe pneumonia halted clinical exacerbation and possibly prevented progression to ards. however, in another study, compared with no treatment, administration (steroid therapy was initiated at a median daily dose equivalent to (iqr, - ) mg of hydrocortisone, and a median duration of (iqr, - ) days within the first days of mv was more strongly associated with an increased risk of death, whereas when administration was beyond the first days of mv, the association was no longer significant . considering the findings of the aforementioned studies, the condition of the patients' respiratory system and the dose, timing and duration of corticosteroids could be contributing factors that affect the effects of corticosteroids. several recent systematic reviews and meta-analyses concluded that corticosteroid therapy is significantly associated with mortality [ ] [ ] [ ] . however, in these studies, there were no special limitations on subject inclusion criteria, which means that the patients were very diverse. additionally, there was no subgroup analysis for these patients under different disease conditions. compared to patients in those previous studies, we focused only on patients with pneumonia or ards, which is more specific and makes the outcomes more targeted. our study observed a different outcome according to corticosteroid use in patients with ards due to influenza. this study has some limitations, including the lack of sufficient data on the dose, duration, timing and rationales of corticosteroid administration and the timing and duration of antiviral therapy. in addition, only one study included in this meta-analysis was an rct, and were observational in nature. thus, it is possible that selection bias or comparability bias could have affected the quality of the analysed evidence. there is insufficient evidence in this meta-analysis to make a firm determination about the effectiveness of corticosteroids for people with influenza-related pneumonia or ards. the small number of included studies and the small number of patients in the included studies might also make the effect size of some outcome indicators insufficient, and we were unable to analyse the effect of some factors on the outcome indicators by meta-regression or subgroup analysis. current data do not support the routine use of corticosteroids in patients with influenza pneumonia or ards. however, the data assessed in this meta-analysis were extracted from observational studies and only one rct; therefore, the limitations associated with study design are important to consider. there is a need for more robust evidence on the role of corticosteroids in the treatment of influenza-related ards and severe pneumonia before a firm recommendation for clinical practice can be made. update on avian influenza a (h n ) virus infection in humans critically ill patients with influenza a(h n ) infection in canada global mortality estimates for the influenza pandemic from the glamor project: a modeling study influenza cost and cost-effectiveness studies globally-a review effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial corticosteroid treatment ameliorates acute lung injury induced by swine origin influenza a (h n ) virus in mice combination anti-inflammatory and antiviral therapy of influenza in a cotton rat model corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection analytic strategy using propensity scores adjuvant corticosteroid treatment in adults with influenza a (h n ) viral pneumonia the influence of corticosteroid treatment on the outcome of influenza a(h n pdm )-related critical illness the newcastle-ottawa scale (nos) for assessing the quality of nonrandomised studies in meta-analyses pathogen-and antibiotic-specific effects of prednisone in community-acquired pneumonia early corticosteroids in severe influenza a/h n pneumonia and acute respiratory distress syndrome effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza a(h n )pdm viral pneumonia. influenza and other respiratory viruses hospitalized adult patients with influenza a(h n ) in beijing, china: risk factors for hospital mortality effects of corticosteroid and neuraminidase inhibitors on survival in patients with respiratory distress induced by influenza virus predictors of mortality and length of stay in hospitalized cases of influenza a (h n ): experiences of a tertiary care center corticosteroid therapy in intensive care unit patients with pcr-confirmed influenza a(h n ) infection in finland effect of immunomodulatory therapies in patients with pandemic influenza a (h n ) complicated by pneumonia predictors and outcomes of respiratory failure among hospitalized pneumonia patients with h n influenza in taiwan critical evaluation of the newcastle-ottawa scale for the assessment of the quality of nonrandomized studies in metaanalyses experience in the management of the severe form of human influenza a h n pneumonia in an intensive care unit lung function and organ dysfunctions in patients requiring mechanical ventilation during the influenza a (h n ) pandemic clinical and prognostic features of patients with pandemic influenza a (h n ) virus in the intensive care unit neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients predictors of mortality in hospitalized children with pandemic h n influenza in pune early corticosteroid treatment for severe pneumonia caused by h n influenza virus systemic corticosteroids and early administration of antiviral agents for pneumonia with acute wheezing due to influenza a(h n )pdm in japan risk factors associated with death among influenza a (h n ) patients surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock deaths from bacterial pneumonia during - influenza pandemic predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness viral loads and duration of viral shedding in adult patients hospitalized with influenza delayed clearance of viral load and marked cytokine activation in severe cases of pandemic h n influenza virus infection differences between asthmatics and nonasthmatics hospitalised with influenza a infection. the european respiratory journal surviving sepsis campaign: international guidelines for management of sepsis and septic shock seasonal influenza vaccination in patients with copd: a systematic literature review h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment multiphasic acute disseminated encephalomyelitis (adem) following influenza type a (swine specific h n ) the effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis shigui yang designed the study. yuqing zhou, xiaofang fu, xiaoxiao liu, chenyang huang, guo tian, cheng ding, jie wu, lei lan collected the data. yuqing zhou, xiaofang fu, xiaoxiao liu, guo tian, cheng ding and jie wu analyzed the data. yuqing zhou and shigui yang interpreted the results. yuqing zhou wrote the manuscript. yuqing zhou and shigui yang revised the manuscript from preliminary draft to submission. shigui yang supervised the study. the authors declare no competing interests. supplementary information is available for this paper at https://doi.org/ . /s - - - .correspondence and requests for materials should be addressed to s.y.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- -uf ls g authors: leclerc, f.; riou, y.; martinot, a.; storme, l.; hue, v.; flurin, v.; deschildre, a.; sadik, a. title: inhaled nitric oxide for a severe respiratory syncytial virus infection in an infant with bronchopulmonary dysplasia date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: uf ls g objective: to report the first case of ards in children treated with nitric oxide (no) inhalation. methods: a -months infant presented with bpd and severe hypoxemia related to rsv infection and ards. inhaled no was delivered in the ventilatory circuit of a continuous flow ventilator (babylog , dräger) in a concentration of – ppm for days. no and no( ) were continuously monitored (polyton draeger). respiratory mechanics were evaluated by using the method of passive inflation by the ventilator. results: no inhalation improved oxygenation (tcsao( )) and reduced respiratory system resistance without affecting arterial pressure. no( ) level remained below ppm, and methaemoglobin level below %. the child survived without neurologic sequela. conclusions: two mechanisms to explain oxygenation improvement can be suggested:selective improvement in perfusion of ventilated regions and bronchodilation. respiratory syncytial virus (rsv) causes lower respiratory tract infections (bronchiolitis and/or pneumonia) that are more often severe in children with bronchopulmonary dysplasia (bpd) [ , ] . profound respiratory failure related to rsv infection has been treated with aerosolized ribavirin [ ] , and extra corporeal membrane oxygenation [ ] . recently, adult respiratory distress syndrome (ards) has been treated with inhaled nitric oxide (no) [ ] , but to our knowledge, this therapy of ards has not been reported in children. we report here a child with severe bpd who presented with acute respiratory failure related to rsv infection. despite aggressive therapy (controlled ventilation and aerosolized ribavirin), he did not improve, and it was decided to try inhaled no. a male infant born at weeks of gestational age presented during the neonatal period a hyaline membrane disease complicated by a super in-correspondence to: f. leelerc fection due to staphylococcus epidermidis. he was treated, in the neonatal intensive care unit, with exogenous surfactant (one dose of curosurf, chiesi farmaceutici-italy), controlled ventilation ( days), and antibiotics. bpd subsequently developed, and he was discharged at months of age with nasal oxygen (fio : . ) and cisapride (gastrooesophageal reflux diagnosed by ph probe). he was readmitted at months of age for acute respiratory distress requiring weeks of controlled ventilation, and he was discharged with nasal oxygen (fio : . ). fifteen days later, he was admitted to our paediatric intensive care unit with a septicaemia due to escherichia coli, and a bronchitis requiring controlled ventilation and antibiotics. during the following weeks, several episodes of oxygen desaturation and hypercapnia were observed, and a tracheostomy was performed; he was then treated with nocturnal controlled ventilation and daytime oxygen. echocardiography and doppler did not show pulmonary hypertension. at months of age his condition deteriorated with bronchospasm and oxygen desaturation (capillary blood gas was ph . units, pco z mmhg). rsv antigen was detected in tracheal secretion by direct fluorescent antibody (clonatec-biosoft, france), treatment included intravenous salbutamol and aminophylline, controlled ventilation (pressure preset servoventilator siemens c, elema-sweden). three days later a chest radiograph was consistent with an ards, and tracheal aspiration remained positive for rsv antigen. aerosolized ribavirin (aerosol generator spag . icn pharmaceuticals. inc., costa mesa, usa) was delivered for days, salbutamol was stopped, and sedation (midazolam, fentanyl, pancuronium) was started. despite this treatment, his condition did not improve; with aggressive controlled ventilation (table ) tcsao was between and , and capillary blood gas was ph . units, pco mmhg. echocardiography and doppler did not show pulmonary hypertension. the probability of survival being poor, we decided to try inhaled no, with the aim of improving oxygenation and avoiding multiple organ failure. informed consent was obtained from parents. inhaled no, started at ppm, was delivered in the ventilator inspiratory circuit, between the y-piece and humidifier (continuous flow ventilator babylog , dr~tger, liabeck-germany, inspiratory flow /mim) from a tank of nitrogen with a no concentration of ppm (cfpo, meudon-france). no and no z concentrations were continuously monitored near the y-piece in the expiratory part of the circuit (potytron, dr~tger). ventilator settings, blood gases, and arterial pressures, recorded immediately before and during no inhalation, are shown in table . after no was breathed for rain, tcsao a increased from - %. respiratory mechanics measurements were performed using the passive inflation method as described previously [ ] . respiratory system resistance values (including resistance of the endotracheal tube no. . ) expressed in cm h / /sec. were as follows: just before no, after min; after min; and after min. respiratory system compliance values expressed in ml/cm h were as follows: . just before no, . after min, . after min, and . after min. after h of inhaled no at ppm, tcsao decreased to ~ no concentration was increased to ppm, and tcsao increased to %. after h of inhaled no (i h at ppm), peep was reduced from - cm h ; crepitations were noted and pip, peak inspiratory pressure; peep, positive end-expiratory pressure; *, fio delivered by the ventilator; tcsao , transcutaneous oxygen saturation (mean value of at least measurements during the period); sap and map, systolic and mean arterial pressures; nd, not determined pulmonary infiltrates worsened, suggesting pulmonary oedema, and leading to increase peep to i cm h . after h of no inhalation, the tank was empty, and no concentration fell to zero ppm; tcsao decreased to %, and rapidly increased to % with a new tank, while ventilator settings were not modified. after days of inhaled no at ppm, no concentration was progressively decreased to zero (by steps of ppm, between day and day ), without change in tcsao . at this time, resumption of inhaled no at ppm did not increase tcsao (not shown in table i ). during no inhalation, no level remained below ppm (maximum level: . ppm), and methaemoglobin (measured at h intervals) below %. then, his condition progressively improved; days after inhaled no withdrawal, daytime controlled ventilation could be stopped with oxygen ( l/rain into the tracheostomy tube) tcsao was %, and capillary blood gas was ph , units pco z mmhg. three months after this rsv infection, his condition was the same as that before ards and remained stable with oral aminophylline, salbutamol, and cisapride. there were no neurologic sequela, and eeg was normal. our child, who had typical features of ards, was treated with no in a concentration of - ppm for days; arterial oxygenation improved while systemic haemodynamics were not affected. no and methaemoglobin remained at low levels. the high no concentrations, chosen because hypoxaemia was profound, can be criticised, since the effect of lower no concentrations was not determined. the pulmonary oedema observed after h of inhaled no, is difficult to explain by these high no concentrations, as no levels, which may explain toxicity [ ] , were low ( . ppm) when it occurred. rossaint et al. have reported the successful use of no in adults with ards. in , no was inhaled at - ppm for - days [ ] . no reverses hypoxic pulmonary vasoconstriction [ ] . in patients with ards, inhaled no reduces intrapulmonary shunting by selectively improving the perfusion of ventilated regions [ ] . this is probably the main mechanism of action in our child. another mechanism of action of no can be suggested; inhaled no reverses bronchoconstriction in anaesthetised guinea pigs [ ] . respiratory system resistance was elevated in our child, and the decrease observed with inhaled no, suggests that bronchodilation participated in the oxygenation improvement. this potentially important mechanism of action needs further investigations. in our child with ards and severe hypoxemia, related to rsv infection, inhaled no was probably beneficial by significantly increasing saturation. collaborative studies are needed to confirm this efficacy, to exclude potential toxicity when used for several days, and to determine the exact mechanisms of action in this disease. respiratory syncytial virus puzzle: clinical features, pathophysiology, treatment, and prevention respiratory syncytial virus infection in children with bronchopulmonary dysplasia a controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection use of extracorporeal membrane oxygenation in the treatment of respiratory syncytial virus bronchiolitis: the national experience inhaled nitric oxide for the adult respiratory distress syndrome comparison of respiratory mechanics measurements during volume and pressure controlled ventilation in neonates inhaled nitric oxide. a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension bronchodilator action, of inhaled nitric oxide in guinea pigs we thank christophe raveau (cfpo, meudon france) for his technical assistance. key: cord- -wb n w authors: nieman, gary f.; gatto, louis a.; andrews, penny; satalin, joshua; camporota, luigi; daxon, benjamin; blair, sarah j.; al-khalisy, hassan; madden, maria; kollisch-singule, michaela; aiash, hani; habashi, nader m. title: prevention and treatment of acute lung injury with time-controlled adaptive ventilation: physiologically informed modification of airway pressure release ventilation date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: wb n w mortality in acute respiratory distress syndrome (ards) remains unacceptably high at approximately %. one of the only treatments is supportive: mechanical ventilation. however, improperly set mechanical ventilation can further increase the risk of death in patients with ards. recent studies suggest that ventilation-induced lung injury (vili) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and vili attenuated. a time-controlled adaptive ventilation (tcav) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. the goal of this review is to describe how the tcav method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. we present work from our group and others that identifies novel mechanisms of vili in the alveolar microenvironment and demonstrates that the tcav method can reduce vili in translational animal ards models and mortality in surgical/trauma patients. our tcav method utilizes the airway pressure release ventilation (aprv) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. time-controlled adaptive ventilation uses inspiratory and expiratory time to ( ) gradually “nudge” alveoli and alveolar ducts open with an extended inspiratory duration and ( ) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. the new paradigm in tcav is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. this novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. the outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection. globally more than three million patients per year develop acute respiratory distress syndrome (ards), accounting for % of all intensive care unit (icu) admissions. in the united states, up to , patients a year are diagnosed with ards and , of these patients die [ ] . current ards treatment is supportive: protective mechanical ventilation, typically using lower tidal volume ventilation (vt) and low-moderate positive end expiratory pressure (peep) [ ] . unfortunately, current protective ventilation strategies have not lessened ards mortality rate [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the determinant of vili is not the "mode" of ventilation, but the way parameters of the mechanical breath are set and combined. the goal of any protective mechanical breath should be maintaining functional residual capacity and increasing lung homogeneity. in this paper, we review the pathophysiology of ards in the microenvironment and identify how changes in alveolar micromechanics predispose the lung to a secondary vili. understanding how ards alters the dynamic alveolar inflation physiology enables us to adjust the mechanical breath profile (mb p -all airway pressures, volumes, flows, rates and the time at inspiration and expiration at which they are applied) necessary to minimize vili [ ] . variants of the airway pressure release ventilation (aprv) mode have been used for decades with many combinations of settings (fig. ) . in this review, we discuss the physiological impact of the time-controlled adaptive ventilation (tcav) method on ards-induced abnormal alveolar mechanics, efficacy in both translational animal models and in a retrospective clinical analysis. acute respiratory distress syndrome pathophysiology current falls into three categories: (a) normal nondependent tissue, (b) severely injured and collapsed dependent tissue, and (c) unstable tissue located between these two tissue types [ , ] . efforts to minimize vili, block progressive acute lung injury (ali), and reduce ards mortality have resulted in two current approaches: ( ) the ardsnet low vt (lvt) method is intended to protect the non-dependent normal lung tissue from overdistension (od) and reduce alveolar recruitment/ derecruitment (r/d) with positive end expiratory pressure (peep), while resting severely injured tissue by allowing it to remain collapsed throughout the ventilation cycle [ ] . however, this strategy has not further reduced ards mortality [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this suggests that our understanding of ards pathophysiology remains [ ] all using the airway pressure release ventilation (aprv) mode but with different methods: a stock et al. used a cpap phase that encompassed % of each breath, a release phase of . s and a respiratory rate (rr) of /min [ ] ; b davis et al. decreased the respiratory rate by prolonging both the cpap and release phase [ ] ; c gama de abreau et al. adjusted their cpap and release phase to values typical of a conventional breath [ ] ; d roy et al. minimized the release phase and extended cpap to occupy % of each breath, typical of the time-controlled adaptive ventilation (tcav) method [ ] . although these studies all used the aprv mode, each differs significantly in the application methods used to set the mode incomplete, particularly in the lung microenvironment [ , ] . indeed, the concept that the pulmonary parenchyma falls into three crudely differentiated categories according to the gravitational axis is being challenged. the current understanding is that open and collapsed tissues are not delineated into compartments, but are rather intermingled throughout the entire lung [ ] [ ] [ ] [ ] [ ] . the unchanged mortality associated with the lvt method may also reflect the fact that maintaining lung tissue collapse ("resting") may not be protective [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the atelectatic lung does not exchange gas, is susceptible to pneumonia, and may ultimately lead to collapse induration and fibrosis with the inability to re-inflate or epithelialize the airspace [ ] [ ] [ ] . using conventional ventilation strategies, the ola has not been shown to reduce alveolar r/d-induced atelectrauma [ , ] or improve survival [ ] . in a recent rct, the ola with maximal recruitment strategy and peep set to best compliance resulted in increased mortality [ ] . however, the lack of significant differences in compliance and driving pressure (∆p) between groups suggested that ( ) the lungs had not been well recruited, which is essential for the ola strategy to be effective; ( ) the lungs were overdistended by excessive strain following the maximal recruitment; or ( ) the chosen peep was not optimal to stabilize the newly recruited lung. other research has shown [ ] that ola could not be attained using peep up to cmh o and plateau pressure (pplat) limited to cmh o. while ola is theoretically lung protective, traditional recruitment maneuver (rm) + peep methods may not provide sustained recruitment, stability, and homogeneity [ , , [ ] [ ] [ ] . more recent studies suggest that the lung pathology compartmentalized by gravity (i.e., normal lung tissue adjacent to acutely injured tissue) is incorrect and that regional lung strain and inflammation throughout the entire lung is the main driver of vili [ , [ ] [ ] [ ] [ ] [ ] [ ] . regional strain is caused with each breath by ( ) alveolar and alveolar duct r/d [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ( ) stress-multiplication (s-m), which cause injury to open lung areas adjacent to collapsed or edema-filled tissue [ , , [ ] [ ] [ ] [ ] [ ] . retamal et al. used ct scans to generate volumetric strain maps revealing highly heterogeneous regional strains (caused by alveolar r/d and s-m), which suggests that there may not be a safe threshold for low vt [ ] . cereda et al. hypothesized that vili is not caused by overdistension of normal lungs, but rather develops in multiple areas of excessive regional strain located throughout the lung and caused by the primary insult [ ] . they showed that tissue adjacent to the primary lesion was most susceptible to secondary vili, an outcome supported by dynamic modeling of interdependent parenchyma during ali [ ] . this suggests that to effectively reduce vili at the bedside, the clinician needs to know how to adjust ventilator settings (e.g., vt, pplat, peep, inspiratory and expiratory duration) to reduce r/d and s-m [ ] [ ] [ ] . synchrotron phase-contrast imaging can measure r/d at acinar length scales over short time frames and has demonstrated that lung collapse in the microenvironment differs between normal and acutely injured lungs [ ] [ ] [ ] [ ] . scaramuzzo et al. first measured tissue collapse in the microenvironment of the normal lung with graded reductions in peep. they assessed the numerosity (asnum) and dimension (asdim) of airspaces during lung deflation and found that the primary mechanism by which the lung loses volume was reduced asnum secondary to alveolar and small airway derecruitment [ ] . in a subsequent paper, scaramuzzo showed in an ards model that the mechanism of lung deflation was reduced asdim, which differs from the mechanism of normal lung deflation (asnum) [ ] . broche et al. showed that "compliant collapse", which is described "as a structural collapse of the airway wall along a certain length" is the primary mechanism of airway closure in the acutely injured lung [ ] . "compliant collapse" suggests that fluid movement in the microenvironment would play a role in airway collapse and reopening. thus, the function of time during inspiration and expiration, and the opening and closing pressures, would be key components in keeping the lung open and stable [ ] . this work underscores the merits of an extended inspiratory duration and a brief expiratory duration to improve alveolar recruitment and stability in a rat ards model [ ] , lung protection in a neonatal piglet model [ ] , and reduced ards incidence and mortality in trauma patients [ ] . we postulate that as the lung opens, the increase in parenchymal tethering of airways [ ] and alveolar interdependence [ ] reduce lung pathology as a power-law function. hamlington et al. have shown that progressive lung injury advances in power-law fashion where alveolar r/d (atelectrauma) caused the initial holes in the epithelium and that high airway pressure (volutrauma) greatly expands these holes in a power-law or rich-get-richer fashion [ ] . lung protection also arguably follows a power-law function with reestablishment of parenchymal tethering, alveolar interdependence, and surfactant function all working together to accelerate recruitment and stabilization of adjacent tissue. alveoli are often misunderstood as elastic and modeled as rubber balloons with immediate size changes (volumetric distortion or strain) with application or removal of pressure (physical stress) during inspiration and expiration [ ] . in reality, alveoli behave in a viscoelastic rather than an elastic manner [ , [ ] [ ] [ ] . viscoelastic systems exhibit a time-dependent strain and can be conceptualized by the spring-and-dashpot model (fig. ) [ ] . figure illustrates the strain/time curve of elastic (spring), viscous (dashpot), and viscoelastic (spring-and-dashpot) behaviors. since the lung opens and collapses as a viscoelastic system, we use the spring and dashpot to illustrate lung recruitment during inspiration and derecruitment during expiration. the initial rapid opening or collapse (strain) of lung tissue followed by a continual opening or closing over an extended period time ( - s) is important. viscoelastic behavior of alveolar opening and collapse begins only after the critical opening or collapse pressure for that alveolus is reached. before these critical pressures are obtained, there is no alveolar strain. however, the opening and closing pressures are not static; instead, they are dependent upon the level of surfactant deactivation and the degree of mechanical interdependence between adjacent alveolar walls and parenchymal tethering on the walls of small airways [ ] . the original computational model of r/d by ma and bates was based on symmetrical bifurcations of the airway tree with each branch having an individual critical opening and collapse pressure [ ] . however, this computational model no longer supported the new biological evidence on r/d at the acinar level. an alveolar interdependence component was added to the model such that the closure of a unit will impact the critical opening and collapse pressures of adjacent units [ ] . fluid movement in the microenvironment during airway collapse and reopening suggests that the pressures necessary for opening and collapse are also a function of the time at which they are applied [ ] . thus, a long inspiratory time with a short expiratory time would open more alveoli and prevent more alveolar collapse, as compared to the same airway pressures applied for shorter or longer amounts of time [ ] . since alveoli recruit as a viscoelastic system, once critical opening and collapse pressures are reached, the longer the inspiration (fig. -red hold) , the more lung tissue recruited with each breath [ , [ ] [ ] [ ] [ ] . similarly, the shorter the expiratory duration (red release), the less lung tissue that will collapse. furthermore, the sustained inspiratory time causes both creep and stress relaxation, the most likely mechanism of which is redistribution of gas within the lung or opening of collapsed alveoli [ ] . we postulate that this information can be used to design an mb p that will open and stabilize the acutely injured lung. the longer the inspiratory time, the more alveoli recruited. we previously quantified in vivo alveolar recruitment in real-time in a rat ards study that involved mathematical modeling. initial recruitment after the applied breath did not begin until after the first second, followed by a rapid recruitment ( - s). the majority of recruitment occurred in s with continued gradual recruitment over the subsequent s (fig. ) [ ] . the absence of any inflation for the first second has clinical significance since inspiratory time in most conventional ventilator settings is . - . s. a brief inspiratory time confines ventilation to proximal conducting/convective airways rather than allowing the time-dependent gas distribution to reach and facilitate diffusion in the distal airspace [ ] . other investigators using ct scans combined with mathematical modeling also support this temporal lag in alveolar opening following an applied proximal airway pressure [ ] [ ] [ ] . the similarities between alveolar percent recruitment/time ( fig. ) coincide with the viscoelastic behavior strain/ time curves (fig. , inspiration-lung recruitment). derecruitment of alveoli is also viscoelastic in nature (fig. , expiration-lung derecruitment). the deflation strain/ time curve suggests that a ventilator strategy with a brief expiratory duration (red release) would minimize lung collapse, placing ventilation on the more favorable expiratory portion of the pressure-volume curve [ ] . there is no mechanistic evidence that current ola protocols using a rm and titrated peep actually achieve and sustain an open lung [ , , ] . the ardsnet method features a brief time at peak inspiration and an extended time at expiration (fig. , left) , producing an mb p that is antithetical to the tcav method (fig. , right) . conversely, the tcav method reconfigures time systems. an applied force (red arrows) generates a stress that results in a yield or strain once the force reaches critical opening pressure. upper left: the spring models elasticity with a rapid increase in strain leading to a plateau strain, which is distinctive of that spring. upper right: the dashpot models viscous strain, where movement of the dash progresses (dashed line) with flow of the fluid in the pot around the dash (brown arrows), which is distinctive of the viscosity of the fluid. bottom: viscoelastic behavior is modeled by the spring and dashpot, where force transfer from the spring to the dash results in a time-dependent strain with an initial rapid change in strain ( - s), which becomes gradual over time ( - s) . lung strain follows this behavior (fig. ) . bottom left: an extended inspiratory time (hold) optimizes lung recruitment once critical opening pressure is reached. bottom right: a short expiratory time (release) minimizes lung derecruitment if it is sufficiently fast to prevent reaching the critical collapse pressure (see figure on next page.) allocation to extend inspiration using a continuous positive airway pressure phase (cpap phase) with a brief (sub-second) release for exhalation (release phase). open valve cpap is used rather than closed valve to allow the patient to spontaneously inhale or exhale with little added resistance at any time in the breathing cycle. the short expiratory time does not allow the expiratory flow to reach zero flow, and therefore, the alveolar pressure is always above the set expiratory pressure (p low ), which itself is always set at cmh o. the cpap phase initiates before the lung fully depressurizes (fig. , right) , maintaining a positive end expiratory pressure determined by the peak expiratory flow, the expiratory duration, and the compliance of the respiratory system. the gas volume released (vr) during the release phase is analogous to vt in that it equals the volume delivered during the cpap phase (we use vt in place of vr in this review for consistency). however, tcav does not aim to achieve a target vt, but rather the vt changes depending on the release time (t low ), which is adjusted by changes in respiratory system compliance (c rs ): ↓c rs = ↓vt and ↑c rs = ↑vt alveolar recruitment is not only a function of the amount of pressure applied to the lung, but also of the time during which the pressure is applied because alveoli open and collapse as a viscoelastic system (fig. , viscoelastic behavior) . alveolar volume change is further influenced by alveolar micro-anatomy, including parenchymal tethering and shared alveolar walls, establishing alveolar interdependence. all the above components play an important role in alveolar recruitment and derecruitment [ , , [ ] [ ] [ ] . thus, the longer airway pressure is applied, the more alveoli recruited (fig. , viscoelastic behavior) [ ] . this time-dependent recruitment has been described by suki et al. as the "avalanche theory" of lung inflation [ ] . we conducted histological measurements of terminal airspace in a rat ards model [ ] and reported a redistribution of gas from alveolar ducts into alveoli with tcav, but not with a volume-controlled mode. stress relaxation occurs during the cpap phase because there is sufficient time for alveoli to be recruited. we postulate that gas is transferred from the more elastic ducts (fig. , viscoelastic behavior-rapid initial strain) into the more viscous alveoli (fig. , viscoelastic behavior-slow progressive strain over time) during the extended cpap phase. by comparison, the ardsnet brief inspiratory time (fig. , left, duration of inspiration) method would not effectively recruit viscoelastic alveoli, allow time for tissue creep, or result in redistribution of gas from the ducts into the alveoli [ , ] . this is supported by studies indicating that the ola, which uses occasional rms combined with a brief inspiratory duration (fig. , left) , has not been shown to reduce mortality. the likely reason for this lack of efficacy is that neither rms nor the brief fig. the ardsnet method using the volume assist-control ventilation mode (left) has an i:e ratio of : , which directs a short inspiration and a long expiration, and peep is arbitrarily set. conversely, the tcav method (right) has an i:e ratio of : , which directs a long inspiration (cpap phase) and a short expiration (release phase), not allowing the lung to fully depressurize and resulting in a time-controlled peep (tc-peep, red dashed line). time controlled-peep (tc-peep) is adaptive (not arbitrary) because it is determined in real-time according to compliance, which is measured in the preceding breath by the slope of the expiratory flow curve (slope fe ) (red arrowhead on right) (fig. ) inspiratory duration effectively opens the lung; therefore, alveolar heterogeneity and regional strain were not eliminated [ , , ] . to normalize the alveolar duct to alveolar volume distribution in the acutely injured lung, it is necessary to use a combination of an extended time at inspiration (cpap phase) and short expiratory duration (release phase) (fig. , right) . the physiologic impact of tcav on lung recruitment over time in a brain-dead organ donor is depicted in fig. a , top. displayed respiratory system compliance (c rs ), driving pressure (∆p = vt/c rs ), and vt measurements are after initial transition of the brain-dead donor to tcav (tcav = h) and then (tcav = h) and (tcav = h) hours on tcav. the prolonged inspiratory time (fig. , right) gradually "nudges" open the lung and normalizes gas distribution within the alveoli and ducts (fig. a -blue collapsed lung tissue converting to open tan tissue) and the brief expiratory time prevents these newly opened alveoli from re-collapsing (fig. , right) [ ] . although the ∆p was slightly elevated ( . cmh o) when tcav was first applied (t ) due to the low c rs ( ml/cmh o), it remained within the safe range due to the low vt ( . ml/kg). as the lung recruited over time, the vt increased (t = . ml/kg) without increasing ∆p, which fell into the normal lung range ( . cmh o) due to increased c rs ( ml/kg). continual reduction in ∆p occurred because c rs increased (t = ml/ cmh o) as the lung fully opened and ∆p fell into the normal range ( . cmh o) (fig. a, top) with a vt of . ml/ kg. these data indicate how the vt can only increase if c rs increases, which personalizes the vt to the pathophysiology of the patient's lung in real-time and normalizes the tidal volume to lung volume (fig. a, top) . figure b , bottom depicts the ventilator screen and the chest radiograph (cxr) from a brain-dead donor initially on controlled mechanical ventilation (cmv) and then converted to tcav. the progressive changes in ∆p and cxr at (tcav = h), (tcav = h) and (tcav = h) hours on tcav are displayed. the progressive decrease in ∆p as the lung recruits is identified by the reaeration of the lung on cxr. these data suggest that an extended cpap duration for a period of hours will "nudge" alveoli open with each breath, reducing c rs and allowing ventilation at a low ∆p even with a vt higher than ml/kg. the lung becomes time and pressure dependent when acutely injured, such that it will quickly collapse at atmospheric pressure [ , [ ] [ ] [ ] . in animal ards models, the majority of lung collapse occurred in the first s of exhalation with collapse as fast as . s [ ] . this suggests preventing collapse of alveoli with the fastest time constants, the expiratory duration must be less than . s. markstaller et al. had similar findings in an ards porcine model with lung collapse occurring in % of the lung within . s [ ] . lachmann was one of the first to suggest that stabilizing alveoli with heterogeneous collapse time constants could be accomplished by dramatically shortening expiratory time [ ] . together, these studies suggest it is possible to stabilize alveoli with fast collapse time constants by using a brief expiratory time [ , , ] . the slope of the expiratory flow curve (slope fe ) allows breath-by-breath assessment of changes in c rs (fig. ) [ ] . with progressive ali, edema and loss of surfactant function increases lung recoil force, causing (see figure on next page.) fig. optimizing recruitment with tcav allows the lung to accommodate increased tidal volumes, without increases in driving pressure, due to a concomitant increase in compliance. a tcav-induced lung recruitment over time ( - h) in a brain-dead organ donor. driving pressure (Δp) was calculated as tidal volume (vt) divided by respiratory system compliance (c rs ). the adaptive nature of tcav delivers low vt ( . ml/kg at h) with lung collapse and low c rs , but adjusts vt over time (vt = . ml/kg at h, vt = . ml/kg at h) as the lung opens and c rs increases. notably, Δp actually decreased despite increasing vt (a). b evolution of driving pressure (Δp) and chest x-ray (cxr) over time: a cmv (conventional mechanical ventilation) on a brain-dead organ donor ( kg) with baseline ventilator settings: vc-ac, vt , rate , peep cmh o with peak pressure cmh o, vt . ml/kg/predicted body weight (pbw), and Δp ml/cmh o. chest x-ray showed severe bilateral infiltrates. tcav = h: h after transition to tcav with settings: cpap phase pressure = cmh o, release set pressure = cmh o, cpap time = . s, release phase duration = . s. note the lower vt of ml ( . ml/kg/pbw), which gradually increased from a vt of . ml/kg/pbw when first transitioned to tcav (data not shown); both vts using the tcav protocol are lower than those on the conventional mode (cmv = ml, . ml/kg/pbw). the cxr demonstrates radiographic clearing of densities with significant recruitment and a reduction in Δp from to ml/cmh o. tcav = h: h on tcav, a new chest radiograph for line placement indicated continued recruitment, and the cpap phase pressure was subsequently decreased to cmh o. in addition, the angle of the expiratory flow curve became less acute (fig. ) , and the release phase duration was increased to . s. the cpap time was increased to . s because ventilation had improved. despite a lower p high , the vt continued to increase as did an improvement in c rs . the continued radiographic clearing of densities and reduction in Δp fell to ml/cmh o despite continued vt increase. tcav = h: the cpap phase pressure was further decreased to cmh o due to continued recruitment (cxr) with a Δp of ml/cmh o. the lungs and the heart, liver, and both kidneys from this organ donor were all successfully transplanted rapid lung collapse and decreased c rs . the collapse rate of the lung is manifested as a change in the slope of the expiratory flow curve (slope fe ), a measure of lung recoil, which is determined by c rs and both turbulent and viscous resistances [ ] . brody demonstrated that ( ) lung c rs could be calculated if both of these resistances are known; ( ) dynamic c rs must be a constant, independent of volume; and ( ) the inertia of the chest-lung system is negligible [ ] . the brief release phase is passive without muscular effort or added external resistance (i.e., peep) such that the slope fe can be used as a bedside monitor to analyze the mechanical properties of the respiratory system on a breath-to-breath basis [ ] . the release phase is protocolized using the tcav method for the expiratory flow to terminate (e ft ) at % of the expiratory flow peak (e fp ) (e fp × % = e ft ) (fig. a, b) [ ] . the formula e fp × % = e ft was first identified empirically at the bedside to be effective at stabilizing the lung [ ] and has been subsequently shown to be most effective at maintaining open and stable alveoli [ ] , normalizing alveolar/alveolar duct volume distribution [ ] , and resulting in homogeneously ventilated alveoli [ ] . in the example presented in fig. b , e fp is − l/min, so the expiratory flow is terminated (e ft ) at − . l/min (− l/min × % = − . l/min). to accomplish this at the bedside, the clinician sets the ventilator to terminate the expiratory flow when it reaches . l/min (fig. , right) , and the cpap phase is restored (fig. , right) . although slope fe is not directly measured, fig. personalizing the release phase using the slope of the expiratory flow curve (slope fe ). the release phase becomes briefer, directed by the slope fe with lung injury severity. a normal lung release phase is . s, with moderate ards of . s and severe ards of . s, all directed by changes in the slope fe . b the release phase duration is calculated by expiratory flow terminating (e ft ) at % of the expiratory flow peak (e fp ) (red arrow head). in this example, the e fp = − l/min, so flow will be terminated (e ft ) at − . l/min (− l/min × % = − . l/min). although the e ft is always at . l/min in our example, the release phase duration varies ( . , . , . s) due to changes in the slope fe (a, b) . we did not directly measure the slope of the expiratory flow curve, but by terminating expiration at % of the e ft , changes in the slope change the expiratory duration (a, b) . thus, the release phase is both personalized and adaptive as the patient's lungs become better or worse using the tcav method. c expiratory flow/ time graphics on a ventilator monitor from a brain-dead organ donor meeting berlin criteria for severe ards. the release phase was set using the equation: e fp × % = e ft . the slope fe when tcav was initially applied was . °, resulting in a release phase of . s. twenty-four hours on tcav and the slope fe increased to . °, resulting in a release phase of . s. the spike in the expiratory flow curve is an artifact due to compression of gas in the ventilator circuit variation in the slope causes a change in release phase duration: gradual slope = long release phase and steep slope = short release phase (fig. a, b, . , . , . s release phase times with changes in the slope fe ). figure c depicts two airway flow/time curves with the slope fe circled and the angle measured on the ventilator monitor in a brain-dead donor. the top curve shows the initial application of tcav, and the bottom curve is h later. with a steep slope ef , expressed as an angle ( . °), the expiratory time is short (t low . s), and as the slope ef increases (angle goes from . º to . °), the expiratory duration increases (t low . s). this illustrates that the duration of the release phase changes with changing lung pathology and thus is personalized and adaptive as the patient's lung mechanics becomes better or worse (fig. a, b ). with cpap, the vt is directly related to c rs (fig. a, top) . the adaptive quality of the tcav breath allows for unique personalization of vt based on changes in lung physiology in contrast to the prevailing "one size fits all" ml/kg method [ ] . further, the tcav method maintains a low Δp since vt decreases as c rs decreases (figs. a, top and ). figure presents gross lung photographs and the corresponding lung compliance (c rs ), tidal volume (vt), and driving pressure (Δp) calculated from a previously published paper [ ] . the animal model utilized was a clinically applicable porcine peritoneal sepsis and gut ischemia/ reperfusion (ps + i/r) ards model [ ] . two groups of animals were studied: ( ) ardsnet low vt (lvt) method applied after the animals desaturate and ( ) the tcav method applied immediately following ps + i/r injury. the time post-ps + i/r injury that these two protocols were applied matched the time of application on patients clinically (i.e., ardsnet method is applied to patients after oxygen desaturation [ ] and tcav is applied immediately upon intubation [ ] ). in the ardsnet group, c rs continually decreased over the -h study period, whereas in the tcav group, c rs remained similar to baseline at t (fig. c) . the Δp in the tcav group remained in the normal range even with elevated vt ( ml/kg) because c rs also increased (fig. d) . gross photos indicate that the tcav method (fig. a ) maintained an open homogeneously ventilated lung without edema, whereas the ard-snet method (fig. b) allowed the lung to develop severe atelectasis and both intra-lobule and airway pulmonary edema. given that the inspiration:expiration (i:e) ratio for tcav is approximately : , co retention could reasonably be a concern. because the tcav method is such an effective lung recruitment tool, there is seldom an issue with high blood levels of co once the lung is fully recruited. once recruited, there is a large surface area for co diffusion and thus high concentrations of co can be exhaled during the short release phase. the tcav method can be applied preemptively as soon as the patient is intubated, never giving the lung a chance to collapse and eliminating any problems with co retention [ ] , thus minimizing the risk of hypercapnia and eliminating the need for extracorporeal venovenous co removal (ecco r). in addition, if the patient is adequately hydrated, there is no negative impact on lung perfusion since lung recruitment reestablishes normal frc, which reduces pulmonary vascular resistance and right heart afterload [ , ] . no human rcts have yet utilized the tcav method, but several recent rcts have approximated many of the settings. zhou et al. first evaluated patients with a p/f less than mmhg who were intubated for less than h and randomized to receive either ardsnet lvt or aprv with tcav-like settings [ ] . the aprv group demonstrated a significant decrease in number of days on mechanical ventilation (from to ), length of icu stay , tracheostomy requirement ( . % to . %), and a . % absolute decrease in mortality ( . % to . %, p = . ), although the study was not sufficiently powered to show a difference in mortality. ganesan et al. conducted an rct using aprv and examined children under years old with ards who had been intubated for less than h and were randomized to receive either standard lvt strategy or aprv [ ] . unlike the zhou trial, the aprv arm performed significantly worse, necessitating early trial termination. the investigators, however, introduced two significant and synergistically harmful changes to the tcav protocol: setting and adjusting the p high pressure of the cpap phase based on vt and improper regulation of spontaneous breathing. by limiting p high to maintain a lower vt, the investigators never opened the lung to the point necessary to eliminate regional lung strain, the same mechanism hypothesized to explain the failed art rct. their initial mean airway pressure (pmaw) difference was only . cmh o despite setting p high at the pplat and then adding an additional cmh o. the authors even provide a table for guiding initial p high settings, which, based on the aprv arm's p/f ratio of mmhg, should have resulted in an initial pmaw difference closer to cmh o-an almost % increase from what was observed. lastly, hirshberg et al. conducted an rct in adults with acute hypoxic respiratory failure and attempted to keep the vt at about ml/kg. the study was stopped fig. gross lung photos with corresponding driving pressure (Δp), tidal volume (vt), and respiratory system compliance (c rs ) values over time [ ] . two protective mechanical ventilation strategies, the tcav method (a) and the ardsnet (lvt) method (b), were tested in a clinically applicable -h porcine ards model of peritoneal sepsis (ps) and gut ischemia/reperfusion (i/r) injury [ ] . the evolution of c rs , Δp, and vt with time in each group occurred over the -h study period (c, d). in the ardsnet lvt method group, Δp increased despite the reduction in vt because of worsening c rs . with the tcav method, Δp remained low despite vt = ~ ml/kg because c rs progressively increased (c, d). the personalized and adaptive vt based on lung c rs (i.e., high c rs = large vt and low c rs = small vt) was also seen in the brain-dead organ donor (fig. a) . gross lung photos illustrate that the tcav method (a) was lung protective, whereas the lvt method (b) resulted in severe acute lung injury. Δp was calculated retrospectively and was not in the publication by roy et al. [ ] early in part because the release volumes (i.e., vt) often exceeded ml/kg. using the tcav protocol an increasing vt indicates that the lung is reopening and is associated with improved crs, Δp, and cxr (see example, fig. b ). in addition, there was no evidence that the vt of ml/kg caused vili since there were no significant differences in pao /fio (p/f) ratio, sedation, vasoactive medications, pneumothorax, or outcome between groups [ ] . lastly, the t low was not set to a strict e fp × % = e ft . the aprv mode using different application methods has recently been shown in statistical reviews and meta-analyses of rcts to improved oxygenation, have a mortality benefit, and increase the number of ventilator-free days as compared to conventional ventilation strategies, without a higher risk of barotrauma or negative hemodynamic effects [ , ] . neither the current lung protect and rest nor ola ventilation strategies have been effective at reducing vili and ards-related mortality below that in the arma study. for a protective ventilation strategy to be effective, it must open and stabilize the lung. dynamic physiology of alveolar volume change suggests that the use of ventilation time can solve this heretofore intractable problem. the novel use of inspiratory and expiratory times to open and stabilize the acutely injured lung may accomplish the ola goals where traditional ventilation strategies have failed. specifically, the tcav method, which uses an extended time at inspiration to open alveoli and brief expiratory time to prevent alveolar re-collapse has been shown to effectively open and stabilize the lung in animal ards models. there is a sound physiological rationale for the efficacy of the tcav method, and deviations from this method may result in a significant loss of lung protection. the combination of basic science and clinical work has given this group a paradigm changing perspective. our approach focuses on veiled mechanisms that have been largely overlooked, such as understanding the time necessary for the alveolus to open or collapse or taking advantage of biological realities, such viscoelasticity, to manage the lung. the new paradigm in tcav is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. this novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. the outcome of this approach is an open and stable lung, which reduces regional strain and provides greater lung protection. abbreviations ards: acute respiratory distress syndrome; vili: ventilator-induced lung injury; aprv: airway pressure release ventilation; frc: functional residual capacity; tcav: time-controlled adaptive ventilation; cpap: continuous positive airway pressure; tc-peep: time controlled-positive end expiratory pressure; t low : time at low pressure; t high : time at high pressure; p high : pressure at inspiration; p low : pressure at expiration; peep: positive end expiratory pressure; e ft : expiratory flow termination; e fp : expiratory flow peak; rct : randomized controlled trial; ola: open lung approach; mb p : mechanical breath pattern; ct: computerized axial tomography. acute respiratory distress syndrome: advances in diagnosis and treatment ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries past and present ards mortality rates: a systematic review has mortality from acute respiratory distress syndrome decreased over time? a systematic review definition and epidemiology of acute respiratory distress syndrome current incidence and outcome of the acute respiratory distress syndrome lessons to learn from epidemiologic studies in ards outcome of acute respiratory distress syndrome in university and nonuniversity hospitals in germany mortality trends of acute respiratory distress syndrome in the united states from to outcomes of patients presenting with mild acute respiratory distress syndrome: insights from the lung safe study the -year evolution of airway pressure release ventilation (aprv) pressure-volume curve of total respiratory system in acute respiratory failure. computed tomographic scan study mechanical ventilation in adults with acute respiratory distress syndrome. summary of the experimental evidence for the clinical practice guideline looking beyond macroventilatory parameters and rethinking ventilator-induced lung injury airway pressure release ventilation reduces conducting airway micro-strain in lung injury visualizing the propagation of acute lung injury does regional lung strain correlate with regional inflammation in acute respiratory distress syndrome during nonprotective ventilation? an experimental porcine study stress distribution in lungs: a model of pulmonary elasticity alterations of mechanical properties and morphology in excised rabbit lungs rinsed with a detergent physiology in medicine: understanding dynamic alveolar physiology to minimize ventilator-induced lung injury alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis alveolitis and collapse in the pathogenesis of pulmonary fibrosis mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome opening pressures and atelectrauma in acute respiratory distress syndrome does high peep prevent alveolar cycling? effect of lung recruitment and titrated positive endexpiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial alveolar instability (atelectrauma) is not identified by arterial oxygenation predisposing the development of an occult ventilatorinduced lung injury effects of respiratory rate, plateau pressure, and positive end-expiratory pressure on pao oscillations after saline lavage a fibre optic oxygen sensor that detects rapid po changes under simulated conditions of cyclical atelectasis in vitro unstable inflation causing injury: insight from prone position and paired ct scans deterioration of regional lung strain and inflammation during early lung injury tidal changes on ct and progression of ards lung inhomogeneities and time course of ventilator-induced mechanical injuries mechanical breath profile of airway pressure release ventilation: the effect on alveolar recruitment and microstrain in acute lung injury effect of airway pressure release ventilation on dynamic alveolar heterogeneity mechanisms of surface-tensioninduced epithelial cell damage in a model of pulmonary airway reopening the influence of non-equilibrium surfactant dynamics on the flow of a semi-infinite bubble in a rigid cylindrical capillary tube biomechanics of liquid-epithelium interactions in pulmonary airways tidal ventilation at low airway pressures can augment lung injury airway closure in acute respiratory distress syndrome: an underestimated and misinterpreted phenomenon alveolar volume-surface area relation in air-and saline-filled lungs fixed by vascular perfusion influence of forced inflations on the creep of lungs and thorax in the dog alveolar micromechanics in bleomycin-induced lung injury lung inhomogeneity in patients with acute respiratory distress syndrome micromechanics of alveolar edema local strain distribution in real three-dimensional alveolar geometries stress concentration around an atelectatic region: a finite element model acute respiratory distress syndrome never give the lung the opportunity to collapse preemptive mechanical ventilation based on dynamic physiology in the alveolar microenvironment: novel considerations of time-dependent properties of the respiratory system last word on viewpoint: looking beyond macroventilatory parameters and rethinking ventilator-induced lung injury regional behavior of airspaces during positive pressure reduction assessed by synchrotron radiation computed tomography the effect of positive end-expiratory pressure on lung micromechanics assessed by synchrotron radiation computed tomography in an animal model of ards dynamic mechanical interactions between neighboring airspaces determine cyclic opening and closure in injured lung individual airway closure characterized in vivo by phase-contrast ct imaging in injured rabbit lung ventilator-induced lung injury and lung mechanics limiting ventilator-associated lung injury in a preterm porcine neonatal model early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ards literature alveolar leak develops by a rich-get-richer process in ventilatorinduced lung injury lung tissue viscoelasticity: a mathematical framework and its molecular basis lung parenchymal mechanics lung parenchymal mechanics in health and disease modeling the complex dynamics of derecruitment in the lung respiratory mechanics in anesthetized paralyzed humans: effects of flow, volume, and time differential susceptibility of diaphragm muscle fibers to neuromuscular transmission failure lung mechanics. an inverse modeling approach nunn's applied respiratory physiology stress relaxation of the human lung the role of time and pressure on alveolar recruitment effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury dynamics of lung collapse and recruitment during prolonged breathing in porcine lung injury what's new in respiratory physiology? the expanding chest wall revisited! intensive care med correlation between alveolar recruitment/derecruitment and inflection points on the pressurevolume curve ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial physiological effects of the open lung approach in patients with early, mild, diffuse acute respiratory distress syndrome: an electrical impedance tomography study airway-parenchymal interdependence. comprehensive micro-scale to meso-scale analysis of parenchymal tethering: the effect of heterogeneous alveolar pressures on the pulmonary mechanics of compliant airways a model of surfactant-induced surface tension effects on the parenchymal tethering of pulmonary airways avalanches and power-law behaviour in lung inflation viscoelastic properties of alveolar wall the effects of airway pressure release ventilation on respiratory mechanics in extrapulmonary lung injury early airway pressure release ventilation prevents ards-a novel preventive approach to lung injury predicting the response of the injured lung to the mechanical breath profile influence of inspiration to expiration ratio on cyclic recruitment and derecruitment of atelectasis in a saline lavage model of acute respiratory distress syndrome effect of tidal volume and positive end-expiratory pressure on expiratory time constants in experimental lung injury temporal dynamics of lung aeration determined by dynamic ct in a porcine model of ards open up the lung and keep the lung open mechanical compliance and resistance of the lung-thorax calculated from the flow recorded during passive expiration other approaches to open-lung ventilation: airway pressure release ventilation influence of state of inflation of the lung on pulmonary vascular resistance relation between lung volume and pulmonary vascular resistance early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome airway pressure release ventilation in pediatric acute respiratory distress syndrome: a randomized controlled trial randomized feasibility trial of a low tidal volume-airway pressure release ventilation protocol compared with traditional airway pressure release ventilation and volume control ventilation protocols airway pressure release ventilation in adult patients with acute hypoxemic respiratory failure: a systematic review and metaanalysis airway pressure release ventilation during acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials airway pressure release ventilation: a new concept in ventilatory support airway pressure release ventilation regional lung aeration and ventilation during pressure support and biphasic positive airway pressure ventilation in experimental lung injury publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. drafting of manuscript-lag, gfn, nmh, bd. critical revisions-gfn, pla, js, sjb, mm, lag, ha, mk, nmh. all authors read and approved the final manuscript. salary support for gfn, js, sjb, from nih r hl . not applicable. not applicable. not applicable. pla, gfn, mks, and nmh have presented and received honoraria and/or travel reimbursement at event(s) sponsored by dräger medical systems, inc., outside of the published work. pla, gfn, and nmh have lectured for intensive care online network, inc. (icon). nmh is the founder of icon, of which pla is an employee. nmh holds patents on a method of initiating, managing, and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same, but these patents are not commercialized, licensed, or royalty-producing. the authors maintain that industry had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. key: cord- - ezrjuq authors: li, hongqiang; zhou, runv; wang, chunmei; li, yusheng; zheng, guizhen; jiang, sen; dong, tiancao; bai, jianwen; xu, shumin title: t follicular regulatory cells infiltrate the human airways during the onset of acute respiratory distress syndrome and regulate the development of b regulatory cells date: - - journal: immunol res doi: . /s - - - sha: doc_id: cord_uid: ezrjuq t follicular regulatory (tfr) cell is a cxcr (+)foxp (+) subset of t regulatory (treg) cell with critical roles in regulating germinal center responses and modulating the immune environment in the lymph nodes. studies have shown that the proportion of tfr cells may increase during acute inflammation. in this study, we investigated the role of tfr cells in acute respiratory distress syndrome (ards). we found that tfr cells were significantly enriched in peripheral blood and in mini-bronchoalveolar lavage (bal) during the onset of ards. notably, tfr cells represented the majority of treg cells in the mini-bal samples. tfr cells also showed ctla- , il- , and tgf-β expression, but compared to the non-tfr treg cells, the ctla- and il- expression by tfr cells were slightly reduced. both tfr cells and non-tfr treg cells suppressed the proliferation of autologous cd (+)cd (−) t cells; however, the tfr cells displayed slightly reduced suppression capacity. subsequently, b cells were co-incubated with autologous tfr cells or non-tfr treg cells. interestingly, we found that the frequency of il- (+) breg cells was significantly higher following incubation with tfr cells than with non-tfr treg cells, which suggested that tfr cells were more potent at inducing il- (+) breg cells. together, these results demonstrated that tfr cells were a similar but distinctive subset of treg cells. given that tfr cells were strongly enriched in ards patients, especially in the lung infiltrates, they may exert critical ameliorating effects in ards. t follicular regulatory (tfr) cell is a recently discovered t regulatory (treg) cell subset with critical roles in regulating germinal center responses and modulating the immune environment in the lymph nodes [ ] . tfr cells present features of both t follicular helper (tfh) cells and treg cells, including cxcr , pd- , icos, ctla- , and foxp expression [ ] . currently, it is thought that tfr cells differentiate from treg cells that gain access to the b cell follicles in the spleen, lymph nodes, and peyer's patches [ , ] . following interaction with cognate b cells in the germinal center and the b cell follicles, these treg cells gain fully differentiated tfr phenotype with pd- and icos expression, and may stay in the b cell zones, exit the lymphoid tissues and enter circulation, or infiltrate the peripheral tissues [ , ] . representing approximately % of the total cd + t cells, and % of total treg cells in draining lymph nodes, tfr cells are a small but critical population in the development of antibody responses. in mice, tfr cell depletion resulted in elevated numbers of gc b cells, antigen-specific b cells, and plasma cells, and increased serum antibody titer [ , , ] . sorted human tfr cells (cd + cxcr + cd + cd − t cells) were shown to suppress antibody production in vitro [ ] . mechanistically, tfr cells can suppress tfh cell expansion and cytokine production in a ctla- -dependent fashion [ ] . interestingly, ctla- -deleted tfr cells promoted the production of low-affinity antibodies [ ] , suggesting that tfr cells likely improved the quality of the antibody response by hongqiang li and runv zhou contributed equally to this work. preventing overactive tfh-mediated antibody secretion. recently, studies demonstrated that tfr cells were dynamically regulated in acute and chronic virus infections. during influenza infection or lcmv infection, tfr cells in the lymphoid organs presented a drop in frequency, and it is possible that this drop was required for the generation of virus-specific antibodies [ ] . in contrast, tfr frequency appeared to increase in chronic hiv infections, as well as in chronic hepatitis b and hepatitis c patients [ , ] . the frequency and function of tfr cells in other settings have not been extensively investigated. acute respiratory distress syndrome (ards) is characterized by rapid-onset alveolar damage, hypoemia, interstitial and alveolar edema, fibrin deposition, and fibrocyte recruitment and proliferation in the lung [ ] . despite years of research, ards remains a life-threatening condition with only palliative treatments available [ ] . activation of effector immune cells and secretion of proinflammatory cytokines are found in the lung of ards patients, both of which can increase alveolar membrane permeability and coagulation in a perpetuating positive feedback loop [ ] . on the other hand, treg cells in humans and murine acute lung injury (ali) models can disrupt the proinflammatory process, reduce disease severity, promote injury resolution, and accelerate healing [ ] [ ] [ ] [ ] . in addition, we previously showed that early recruitment of il- -producing breg cells and elevated il- secretion could suppress the production of proinflammatory cytokines and predicted better survival in ards patients [ , ] . the role of tfr cells, on the other hand, has not been elucidated in ards patients. in this study, the tfr cells in ards patients were examined. all procedures of sample collection and experiment were approved by the shanghai east hospital ethics committee. peripheral blood and mini-bronchoalveolar lavage (bal) samples were collected from ten ards patients who provided written informed consent. diagnosis and treatment were performed at shanghai east hospital. all patients satisfied the american-european consensus for ards, including acute onset, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen less or equal to , bilateral infiltrates on frontal chest radiograph, pulmonary artery wedge pressure less or equal than mmhg, and no evidence of left atrial hypertension [ ] . ten age, sex, and bmi-matched healthy controls without prior history of pneumonia, ards, or other respiratory diseases donated peripheral blood samples. peripheral blood mononuclear cells (pbmcs) or mini-bal lymphocytes were harvested using standard ficoll-paque (ge healthcare) centrifugation method. a portion of fresh pbmcs and all mini-bal samples were used directly ex vivo. the remaining pbmcs were stored at − °c until further use. for sorting, pbmcs or mini-bal lymphocytes were incubated with anti-human cd (hit a), cd (a a ), cxcr (j d ), and cd (bc ; biolegend) monoclonal antibodies for min on ice. cells were then washed twice in sterile pbs supplemented with % fbs (gibco), and sorted in facsaria system (bd biosciences). for frequency analysis, pbmcs or mini-bal lymphocytes were incubated with anti-human cd , cd , cxcr , and cd monoclonal antibodies for min on ice, and washed twice. the foxp /transcription factor staining kit (ebioscience) and anti-human foxp monoclonal antibody (clone pch ; ebioscience) was then used according to the manufacturer's protocols. samples were analyzed in the lsr system (bd biosciences). greater than × events were acquired for pbmc samples, and greater than × events were acquired for mini-bal samples. following sorting, tfr and non-tfr treg cells were lysed and treated with the rneasy mini kit (qiagen) to collect total rna. cdna synthesis was then performed using high-capacity cdna reverse transcription kit (thermo fisher scientific) following protocol from the manufacturer. qpcr was performed in the abi prism system (applied biosystems) with pre-packaged taqman gene expression assays (thermo fisher scientific) for human ctla- (hs _m ), il- (hs _m ), tgf-β (hs _m ), and β microglobulin (hs _m ). three independent replicates were performed for each assay. tfr/treg suppression assay cd + cd − t cells were sorted from pbmcs and plated in well round-bottom plates at × cells per well. sorted tfr or non-tfr treg cells were then added to each well at numbers specified per experiment. cells were stimulated with t activator beads (thermo fisher scientific). after h incubation, cells were pulsed with . μci/ml tritiated thymidine (amersham biosciences) for h, and harvested. the amount of incorporated radioactive thymidine was examined using a beta counter. three independent replicates were performed for each assay. tfr/treg-b cell coculture b cells from ards pbmcs were sorted using human b cell enrichment kit (stemcell), and were incubated with sorted tfr cells or non-tfr treg cells at / b/t ratio in the presence of μg/ml seb (sigma). after h, cells were incubated with anti-human cd (biolegend), fixed and permeabilized using cytofix/cytoperm buffer (bd biosciences), and incubated with anti-human il- (biolegend). excess antibodies were removed by washing, and the samples were analyzed in the lsr system. data between two samples were compared using unpaired t test with welch's correction. data between multiple samples were compared using regular or repeated-measures (rm) oneway or two-way anova, as specified per experiment. twotailed p values smaller than . were considered significant. to investigate tfr cells, pbmcs from ten ards patients at day of disease onset, and from age, sex, and bmimatched healthy control volunteers were collected. the frequency of foxp + treg cells and foxp + cxcr + tfr cells was determined by flow cytometry (fig. a) . in healthy controls, the frequency of foxp + treg cells in cd + t cells was . % ± . % (mean ± s.d. for all results), and the frequency of foxp + cxcr + tfr cells in cd + t cells was . % ± . % (fig. b) . in ards patients, the frequency of foxp + treg cells in cd + t cells was . % ± . %, and the frequency of foxp + cxcr + tfr cells in cd + t cells was . % ± . %, both of which were significantly higher compared to that in healthy controls (p < . ). the frequency of non-tfr treg cells, calculated by the frequency of treg cells minus the frequency of tfr cells, was also slightly higher in ards patients than in healthy controls (p < . ). the expression level of foxp was not significantly different between tfr cells and non-tfr treg cells, and not significantly different between healthy controls and ards patients (p > . for all comparisons; fig. c ). in order to investigate the infiltration of treg and tfr cells in the affected lung tissue, mini-bal was performed on day , day , and day after ards onset. the frequency of treg cells and tfr cells was examined in the mini-bal samples by flow cytometry (fig. a) . first, we observed that the foxp expression level in mini-bal samples was not significantly different between tfr cells and non-tfr treg cells (fig. b) . also, the foxp expression by tfr cells from the pbmcs was not significantly different from the foxp expression by tfr cells from mini-bal samples (p > . for all comparisons). in most ards subjects, the frequencies of treg and tfr cells presented an increasing trend (fig. c) . for treg cells, the frequency in mini-bal increased from . % ± . % on day , . % ± . % on day , to . % ± . % on day . for tfr cells, the frequency in mini-bal increased from . % ± . % on day , . % ± . % on day , to . % ± . % on day . the non-tfr treg cells, on the other hand, were not different between day and day , but were elevated between day and day . notably, the tfr cells represented a minor subset in treg cells from pbmcs, but in mini-bal, tfr cells represented the major treg subtype. tfr cells expressed inhibitory molecules at similar or moderately reduced levels compared to non-tfr treg cells next, we sought to determine the function of tfr cells. both tfr (foxp + cxcr + cd + ) cells and non-tfr treg (foxp + cxcr − cd + ) cells presented high cd expression compared to foxp − cd + t cells (fig. a) . we sorted tfr cells as cd + cd + cxcr + t cells, and non-tfr treg cells as cd + cd + cxcr − t cells from pbmcs of healthy controls ards patients, and ards mini-bal samples were sorted using fluorescence activated cell sorting (facs). the cells were then lysed for the collection of mrna. the expression levels of ctla- , il- , and tgf-β were analyzed by rt-pcr. the expression of ctla- in non-tfr treg cells and tfr cells from ards pbmcs and ards mini-bal was significantly higher than the expression of ctla- in non-tfr treg cells and tfr cells from healthy control pbmcs (fig. b) . the ctla- expression in non-tfr treg cells and tfr cells from ards mini-bal was further increased compared to the ctla- expression in non-tfr treg cells and tfr cells from ards pbmcs. tfr cells from ards mini-bal presented lower ctla- expression than non-tfr treg cells. the il- expression by non-tfr treg cells and tfr cells was lower in healthy controls and significantly higher in ards pbmcs and ards mini-bal (fig. c) . non-tfr treg cells and tfr cells from ards mini-bal presented significantly higher il- expression than cells from ards pbmcs. in both ards pbmcs and ards mini-bal, the il- expression by tfr cells was lower than the il- expression by non-tfr treg cells. non-tfr treg cells and tfr cells from healthy controls presented significantly lower tgf-β expression than the non-tfr treg cells and tfr cells from ards patients (fig. d) . the non-tfr treg cells and tfr cells from ards mini-bal presented significantly higher tgf-β expression than the non-tfr treg cells and tfr cells from ards pbmcs. no significant differences between non-tfr treg cells and tfr cells in terms of tgf-β expression were observed. to further analyze tfr and non-tfr treg function, we sorted tfr cells as cd + cd + cxcr + t cells and non-tfr treg cells as cd + cd + cxcr − t cells from ards pbmcs. these cells were then incubated with autologous cd + cd − t cells in the presence of tcr (anti-cd /cd ) stimulation for h, and pulsed with tritiated thymidine for h. the capacity to suppress cd + cd − t cell proliferation was compared between tfr cells and non-tfr treg cells. both non-tfr treg cells and tfr cells were capable of suppressing the proliferation of autologous cd + cd − t cells (fig. ) . the tfr cells were less effective than non-tfr treg cells at high ( / ) regulatory-to-effector ratio. subsequently, the interactions between tfr cells, non-tfr treg cells, and b cells were examined. b cells from ards pbmcs were co-incubated with tfr (cd + cd + cxcr + ) cells or non-tfr treg (cd + cd + cxcr − ) cells in the presence of seb for h. the frequency of il- + breg cells was evaluated before and after stimulation by flow cytometry. the frequency of il- + b cells was significantly increased following incubation with both non-tfr treg cells and tfr cells (fig. ) . interestingly, tfr cells were significantly more potent at increasing il- + breg cell frequency than non-tfr treg cells. the current consensus suggests that treg cells promote ards resolution and recovery and may suppress fibroblast recruitment and proliferation [ , ] . hence, treg cells are considered a beneficial cell type in ards. in this study, we focused on a newly characterized subset of treg cells, the foxp + cxcr + tfr cells, and investigated their frequency and function. three major discoveries were made: first, both the treg cells and the tfr cells were significantly enriched in ards patients compared to in healthy controls; second, compared to the non-tfr treg cells, the tfr cells were slightly less effective in some, but not all, aspects of suppression; and third, compared to non-tfr treg cells, the tfr cells were more effective at promoting il- expression in b cells. overall, these results demonstrated that tfr cells presented similar, but different functions compared to non-treg cells. this study examined the tfr frequency in two distinctive samples, the circulating blood and the local lung infiltrates, represented by the mini-bal samples. a notable feature is that in mini-bal, the vast majority of treg cells were, in fact, tfr cells. in addition, tfr infiltration in the lung increased with the duration of disease onset. hence, the functional difference between non-tfr treg cells and tfr cells may become critical fig. the frequency of treg cells and tfr cells in the pbmcs from ards patients and healthy controls. a fresh pbmcs from ards patients and healthy controls were collected and examined using flow cytometry directly ex vivo. figures shown were pre-gated on cd + t cells from one representative ards patient and one representative healthy control. treg cells were gated as total foxp + cd + t cells, and tfr cells were gated as foxp + cxcr + cd + t cells. b the frequencies of treg cells, tfr cells, and non-tfr treg cells in the pbmcs from ten healthy controls and ten ards patients. c the mean fluorescence intensity (mfi) of foxp , compared between tfr cells and non-tfr treg cells in healthy controls and ards patients. unpaired t test with welch's correction. ***p < . . ns not significant in the determination of disease outcome. a number of mysteries remain. first, since there was no mini-bal sample from controls, it is yet unclear whether tfr cells also infiltrate healthy lungs. second, tfr frequency in mice increased significantly in the lung draining lymph nodes and in blood following influenza infection, which was another disease that involved significant inflammation in the respiratory tract and the lung [ ] . whether tfr upregulation is a general feature of lung inflammation requires further analysis. in order to investigate tfr function, we examined and compared the expression of inhibitory molecules in three samples, including the healthy pbmcs, the ards pbmcs, and the ards mini-bal. we found that the expressions of ctla- , il- , and tgf-β by healthy tfr and non-tfr treg cells were much lower than those by ards tfr and non-tfr treg cells. this unlikely indicated that the tfr or non-tfr treg cells from healthy individuals were defective, but rather, it was likely that tfr and non-tfr treg cells in ards samples were more activated and expressed more effector molecules. the higher il- and tgf-β in ards mini-bal compared to autologous pbmcs likely indicated that the tfr and non-tfr treg cells in the lung infiltrates were further activated. interestingly, although the expression of ctla- and il- , as well as the capacity to suppress cd + cd − t cell proliferation, were slightly reduced in tfr cells compared to non-tfr treg cells, the tfr cells presented higher capacity in inducing il- + breg cells than non-tfr treg cells. possibly, the common cxcr expression by tfr cells and b cells allowed both to localize close to each other, thus increasing interaction. whether tfr cells may represent a specialized breg-helper cell type requires further investigation. of note, the experiments were performed in vitro, where tfr cells, non-tfr treg cells and b cells were placed in the same tissue culture. in vivo, the requirement for common cxcr expression might be much higher for colocalization of t cells and b cells to occur. in chronic hepatitis b and hepatitis c patients, the frequencies of il- + breg cells and tfr cells were both upregulated [ ] . whether a common pathway upregulated both cell types, or one cell type promoted the upregulation of the other, still require further analysis. a number of limitations were present in this study. first, the samples, especially those from mini-bal, were limited in availability. as a result, the suppression studies were performed using tfr cells from pbmcs. since the tfr cells from fig. the frequency of treg cells and tfr cells in the mini-bal from ards patients at day , day , and day after disease onset. a fresh lymphocytes from mini-bal were collected and examined using flow cytometry immediately following isolation. figures shown were pre-gated on cd + t cells from day , day , and day of the same ards patient. treg cells were gated as total foxp + cd + t cells, and tfr cells were gated as foxp + cxcr + cd + t cells. b the mfi of foxp in tfr cells and non-tfr treg cells from the mini-bal. unpaired t test with welch's correction. c the frequencies of treg cells, tfr cells, and non-tfr treg cells in the mini-bal from ten ards patients. rm -way anova followed by tukey's test. *p < . . **p < . . ***p < . . ns not significant fig. the expression of inhibitory molecules by non-tfr treg cells and tfr cells from healthy controls and ards patients. a fresh pbmcs from healthy controls, pbmcs from ards patients, and fresh day mini-bal lymphocytes from ards patients were examined by flow cytometry directly ex vivo. the expression levels of cd by tfr (foxp + cxcr + cd + ) cells (solid black line), non-tfr-treg (foxp + cxcr − cd + ) cells (dotted black line), and foxp − cd + t cells (gray area) in one representative from each of the three samples were shown. b the tfr cells were sorted from each frozen-and-thawed sample as cd + cd + cxcr + t cells, and the non-tfr treg cells were sorted from each sample as cd + cd + cxcr − t cells. the expression levels of ctla- , il- , and tgf-β from each cell type from ten healthy control pbmcs, ten ards pbmcs, and ten ards day mini-bal are represented as ratios over β microglobulin (β m). two-way anova followed by sidak's test. *p < . . **p < . . ***p < . . ns not significant fig. tfr and non-tfr treg-mediated promotion of il- expression in b cells. from frozen-and-thawed ards pbmcs, the tfr cells were sorted as cd + cd + cxcr + t cells, and the non-tfr treg cells were sorted as cd + cd + cxcr − t cells. b cells were enriched using negative selection, and were incubated with tfr cells or non-tfr treg cells at / b/t ratio. after h incubation with seb, the frequency of il- + b cells was examined by flow cytometry. rm two-way anova followed by sidak's test. ***p < . . ns not significant. symbols directly above the datasets indicate the difference between the -h experiment and the -h control fig. tfr and non-tfr treg-mediated suppression of cd + cd − t cells. from frozen-and-thawed ards pbmcs, the tfr cells were sorted as cd + cd + cxcr + t cells, and the non-tfr treg cells were sorted as cd + cd + cxcr − t cells. the cd + cd − t cells (effector) were also sorted and incubated with tfr or non-tfr treg (regulatory) cells at the indicated ratios. after h in the presence of t activator beads (anti-cd / cd ), cells were pulsed for h with tritiated thymidine and harvested, and the amount of radioactive thymidine incorporation was examined. rm two-way anova followed by sidak's test. *p < . . ***p < . . ns not significant. symbols directly above the datasets indicate the difference between the labeled dataset and the no regulatory cell control ( / ) dataset mini-bal samples tended to present higher expressions of inhibitory molecules, it is possible that the tfr cells from mini-bal samples had more potent capacity to mediate suppression. also, our in vitro experiments need to be verified in animal models of ards to prove that tfr cell-mediated effects could ameliorate or prevent tissue damage mediated by inflammation. in addition, specific gene knockout experiments are necessary to investigate which inhibitory molecules are required for tfr cell-mediated suppression in vivo. conflict of interest the authors declare that they have no conflict of interest. ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. informed consent informed consent was obtained from all individual participants included in the study. t follicular regulatory cells t follicular regulatory cells in the regulation of b cell responses circulating t follicular regulatory and helper cells have memorylike properties the receptor pd- controls follicular regulatory t cells in the lymph nodes and blood association between chemotherapy-response assays and subsets of tumor-infiltrating lymphocytes in gastric cancer: a pilot study regulation of the germinal center reaction by foxp + follicular regulatory t cells human t-follicular helper and t-follicular regulatory cell maintenance is independent of germinal centers the coinhibitory receptor ctla- controls b cell responses by modulating t follicular helper, t follicular regulatory, and t regulatory cells hiv-infected spleens present altered follicular helper t cell (tfh) subsets and skewed b cell maturation increased numbers of cd +cd +cd dhighil- + bregs, cd +foxp + tregs, cd + cxcr +foxp + follicular regulatory t (tfr) cells in chb or chc patients acute respiratory distress syndrome: a clinical review epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management regulatory t cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment regulatory t cell dna methyltransferase inhibition accelerates resolution of lung inflammation cd +cd +foxp + tregs resolve experimental lung injury in mice and are present in humans with acute lung injury regulatory t cells contribute to the recovery of acute lung injury by upregulating tim- upregulation of cd +cd hicd hi regulatory b cells is associated with a reduced risk of acute lung injury in elderly pneumonia patients early recruitment of il- -producing b cells into alveoli improved the resolution of acute lung injury definitions, mechanisms, relevant outcomes, and clinical trial coordination key: cord- -csc lfbm authors: seeger, w.; günther, a.; walmrath, h. d.; grimminger, f.; lasch, h. g. title: alveolar surfactant and adult respiratory distress syndrome: pathogenetic role and therapeutic prospects date: journal: clin investig doi: . /bf sha: doc_id: cord_uid: csc lfbm the adult respiratory distress syndrome (ards) is characterized by extended inflammatory processes in the lung microvascular, interstitial, and alveolar compartments, resulting in vasomotor disturbances, plasma leakage, cell injury, and complex gas exchange disturbances. abnormalities in the alveolar surfactant system have long been implicated in the pathogenetic sequelae of this life-threatening syndrome. this hypothesis is supported by similarities in pulmonary failure between patients with ards and preterm babies with infant respiratory distress syndrome, known to be triggered primarily by lack of surfactant material. mechanisms of surfactant alterations in ards include: (a) lack of surface-active compounds (phospholipids, apoproteins) due to reduced generation/release by diseased pneumocytes or to increased loss of material (this feature includes changes in the relative composition of the surfactant phospholipid and/or apoprotein profiles); (b) inhibition of surfactant function by plasma protein leakage (inhibitory potencies of different plasma proteins have been defined); (c) “incorporation” of surfactant phospholipids and apoproteins into polymerizing fibrin upon hyaline membrane formation; and (d) damage/inhibition of surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids). alterations in alveolar surfactant function may well contribute to a variety of pathophysiological key events encountered in ards. these include decrease in compliance, ventilation-perfusion mismatch including shunt flow due to altered gas flow distribution (atelectasis, partial alveolar collapse, small airway collapse), and lung edema formation. moreover, more speculative at the present time, surfactant abnormalities may add to a reduction in alveolar host defense competence and an upregulation of inflammatory events under conditions of ards. persistent atelectasis of surfactant-deficient and in particular fibrin-loaded alveoli may represent a key event to trigger fibroblast proliferation and fibrosis in late ards (“collapse induration”). overall, the presently available data on surfactant abnormalities in ards lend credit to therapeutic trials with transbronchial surfactant administration. in addition to the classical goals of replacement therapy defined for preterm infants (rapid improvement in lung compliance and gas exchange), this approach will have to consider its impact on host defense competence and inflammatory and proliferative processes when applied in adults with respiratory failure. summary. the adult respiratory distress syndrome (ards) is characterized by extended inflammatory processes in the lung microvascular, interstitial, and alveolar compartments, resulting in vasomotor disturbances, plasma leakage, cell injury, and complex gas exchange disturbances. abnormalities in the alveolar surfactant system have long been implicated in the pathogenetic sequelae of this lifethreatening syndrome. this hypothesis is supported by similarities in pulmonary failure between patients with ards and preterm babies with infant respiratory distress syndrome, known to be triggered primarily by lack of surfactant material. mechanisms of surfactant alterations in ards include: (a) lack of surface-active compounds (phospholipids, apoproteins) due to reduced generation/ release by diseased pneumocytes or to increased loss of material (this feature includes changes in the relative composition of the surfactant phospholipid and/or apoprotein profiles); (b) inhibition of surfactant function by plasma protein leakage (inhibitory potencies of different plasma proteins have been defined); (c) °' incorporation" of surfacrant phospholipids and apoproteins into polymerizing fibrin upon hyaline membrane formation; and (d) damage/inhibition of surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids). alterations in alveolar surfactant function may well contribute to a variety of pathophysiological key events encountered in ards. these include decrease in compliance, ventilation-perfusion mismatch including shunt flow due to altered gas flow distribution (atelectasis, partial alveolar collapse, small airway collapse), and lung edema formation. moreover, more abbreviations." ards=adult respiratory distress syndrome; irds=infant respiratory distrss syndrome; pc=phosphatidylcholine; pg=phosphatidylglycerol; pe=phosphatidylethanolamine; ps = phosphatidylserine; pi = phosphatidylinositol; sph = spingomyelin; bal = bronchoalveolar lavage; tnf = tumor necrosis factor * dedicated to prof. dr. n. z ner on the occasion of his th birthday speculative at the present time, surfactant abnormalities may add to a reduction in alveolar host defense competence and an upregulation of inflammatory events under conditions of ards. persistent atelectasis of surfactant-deficient and in particular fibrin-loaded alveoli may represent a key event to trigger fibroblast proliferation and fibrosis in late ards (" collapse induration"). overall, the presently available data on surfactant abnormalities in ards lend credit to therapeutic trials with transbronchial surfactant administration. in addition to the classical goals of replacement therapy defined for preterm infants (rapid improvement in lung compliance and gas exchange), this approach will have to consider its impact on host defense competence and inflammatory and proliferative processes when applied in adults with respiratory failure. severe disturbances in gas exchange characterized by ventilation-perfusion mismatch and extensive shunt flow. this exudative phase may persist for days to weeks, and full recovery without persistent loss of lung function is well possible during this period of acute respiratory distress. new inflammatory events, such as recurrent sepsis or acquisition of secondary (nosocomial) pneumonia, may repetitively worsen the state of lung function and then progressively trigger proliferative processes with mesenchymal cell activation and rapidly ongoing lung fibrosis. thus, within a few weeks the lung architecture may become dominated by thickened fibrotic alveolar septae and large interposed airspaces ("honeycombing"). prognosis is very poor during this phase of ards, and only partial recovery of lung function may be achieved in the few survivors from this late phase of disease. the alveolar space of all mammalian lungs is covered by a complex surfactant system, which is essential to make alveolar ventilation and gas exchange feasible at physiological transpulmonary pressures. it is composed mainly of lipids (~ %) and proteins (~ %) [ , , , ] . apart from a minor amount of neutral lipids (~ - %), phospholipids (~ - %) represent the predominant class of lipids in this surface lining material. among those, phosphatidylcholine (pc; ~ - % of phospholipids, - % substituted with the saturated palmitic acid) and phosphatidylglycerol (pg; ~ % of phospholipids, bearing a large percentage of unsaturated fatty acids) represent the predominant classes; phosphatidylethanolamine (pe), phosphatidylserine (ps), phosphatidylinositol (pi), and sphingomyelin (sph) are regularly found in low percentages. about half of the protein mass of the alveolar lining layer represents the surfactant-specific apoproteins sp-a ( kda), sp-b ( kda), sp-c ( kda), and sp-d ( kda; all molecular weights given for reducing conditions; [ , , , , ] ). the predominant, and in some compounds exclusive, source of the different lipid and protein components of the alveolar surfactant system are the alveolar epithelial cells type ii [ , , ] . a complex and yet not fully understood interaction between phospholipids and surfactant apoproteins results in far-reaching reduction in the alveolar surface tension, approximating zero (mn/m) values at end expiration, with limited increase in surface tension upon alveolar surface enlargement during inspiration. such extremely low surface tension may only be achieved by dense "packing" of some rigid lipid material such as dipalmitoyl-pc in the surface film. however, characteristics of fluidity are similarly essential for removal of surface film compounds into the bulk phase during surface (over)-compression and rapid reentry and respreading of these compounds upon reexpansion of the surface area. tubular myelin, a unique morphological structure appearing in the alveolar subphase, appears to be of major functional importance in this context [ , , ] . studies focusing on the biophysical properties of individual surfactant compounds (for review see [ , , ] ) have underlined the importance of dipalmitoyl-pc and unsaturated pg and elaborated a key role of the highly hydrophobic low molecular weight apoproteins sp-b and sp-c for adsorption facilities and dynamic surface tension lowering properties [ , , , , , - , , , , ] . although several authors have reported on a cooperative effect of sp-a with the hydrophobic apoproteins on adsorption kinetics [ , , , , ] , the predominant function of this protein may be the regulation of the surfactant pool size in the alveolar space. sp-a binds to dipalmitoyl-pc, promotes the uptake of phospholipids into type ii cells via receptor-operated events, and inhibits secretion of surfactant compounds by this cell type [ , , ] . in addition, sp-d and sp-a might be involved in host defense mechanisms of the lower airw@s in vivo, as they function as opsonins for alveolar macrophage phagocytosis of bacteria and viruses in vitro [ ] [ ] [ ] ] . surfactant deficiency has been established as the primary cause of the respiratory distress syndrome in preterm infants (irds), and transbronchial administration of natural surfactant preparations has been proven to be beneficial in this disease [ , ] . surfactant abnormalities may also be involved in the sequelae of pathogenetic events in ards ; however, due to the diversity of underlying triggering mechanisms and the complexity of pathophysiological events in adrs, any evaluation of the role of surfactant in this disease is much less certain. this review focuses on two questions: (a) what is the present evidence for surfactant abnormalities in patients with ards? (b) which pathophysiological events encountered in the course of ards may be attributed to surfactant abnormalities? these aspects aim to provide a rational basis for the more general question of whether transbronchial surfactant administration may become a profitable therapeutic approach in patients with ards as it is in irds. in early postmortem investigations in lungs from patients who had died in ards, initial evidence for severe impairment of surfactant function was zmax t vmin, minimum surface tension; tmax, maximum surface tension ; * change as compared to normal volunteers a bal was centrifuged twice ( g, supernatant; g pellet) and was subjected to a discontinuous sucrose density gradient ( g). material between . and . m sucrose ("lipid-protein complex") was used b bal was separated from cells by centrifuged at further preparation bal was separated from cells by centrifugation supernatant was centrifuged at g, and the "crude surfactant pellet" was resuspended in saline for bubble measurements g, no at g, resulting and used (table ). in addition, the extent of impairment of biophysical surfactant function was correlated with the severity of ards (fig. ) . recently, elevated minimal surface tension values were also determined for surfactant samples obtained from patients at risk for ards [ ] . several factors may underlie such loss of surface activity in ards; those discussed below are the following: lack of surface-active compounds (phospholipids, apoproteins), change in phospholipid and apoprotein profiles, inhibition of surfactant function by plasma protein leakage, "incorporation" of surfactant in fibrin/hyaline membranes, and damage to surfactant compounds by inflammatory mediators (proteases, oxidants, nonsurfactant lipids, etc.). as summarized in table , clinical studies addressing the phospholipid composition of surfactant samples obtained from patients with ards have revealed three important features. first, the overall content of phospholipids was found to be de- [ ] b cell-free bal was concentrated by centrifugation at g; concentration given for "crude surfactant pellet;" from [ ] creased in two of the three studies performed to date. in addition, this decrease in total phospholipids appeared to be dependent on the severity of ards. second, the relative amounts of the two functionally most important phospholipids, pc and pg, were markedly depressed in all three studies. most strikingly, the pg levels decreased by over % in two of these studies; the decrease in the percentage of pc was more moderate in all three investigations. third, all studies demonstrated an increase in the relative amounts of pi, pe, and sph. due to the late detection and -in case of sp-b and sp-c -the extreme hydrophobic nature of the surfactant apoproteins, appropriate analytical techniques for measurement of these essential surfactant compounds have only recently become available; sp-c quantification in bal samples is still an unresolved problem. two recent studies measuring sp-a, one also measuring sp-b, in bal samples from patients with ards have demonstrated an impressive decline of these surfactant apoproteins (table ) . again, some decrease in these functionally important compounds was also observed in patients at risk for ards. the reported changes in lavage phospholipid and apoprotein contents in patients suffering from ards are very much reminiscent of biochemical profiles characterized in neonates with immature lungs and irds [ ] . they are thus likely to reflect injury of type ii pneumocytes with altered lipid and apoprotein metabolism and/or secretion by this cell type. in addition, the increase in pi, pe, and sph may be due to some surfactant "contamination" with membrane phospholipids from different injured cell types, and there may be leakage of plasma phospholipids under conditions of increased endothelial and epithelial permeability. finally, as discussed below, incorporation of phospholipids into hyaline membranes may also contribute to the alterations in phospholipid and apoprotein profiles. leakage of plasma proteins into the alveolar space may substantially contribute to surfactant alterations in ards. measurements of the protein content in bal samples from these patients persistently show markedly increased levels compared to normal controls. protein leakage is an early event in the sequence of pathogenetic events in ards and is related to the severity of the disease (see e.g., [ ] ; fig. ). experimental studies in vitro and in vivo have demonstrated that admixture of blood, serum, plasma, or alveolar washings obtained during states of plasma leakage may severe- biophysical measurements were undertaken in diluted surfactant material in the wilhelmy balance/langmuir trough system ( pg/ml phospholipids); the hysteresis of the surface tension-surface area relationship is given (arbitrary units). shaded area, mean -sd of hysteresis area of control surfactant without protein addition and of protein effects on pure saline. fibrinmonomers were first dissolved in a small volume in urea tris buffer and then bolus-admixed to the surfactant material; arising large fibrin strands (but not small fibrin oligomers) were removed from the soluble phase by centrifugation before measuring surface tension. [ (fig. ) . in contrast, concentrations of urokinase-type plasminogen activator, representing the predominant fibrinolysis pathway within the alveolar spaces [ , , , ] , were noted to be decreased in lavage fluids from patients with ards; concomitantly, increased levels of plasminogen activator inhibitor- and a -antiplasmin were detected [ , , , ] . moreover, surfactant phospholipid mixtures were found to inhibit plasrain-induced fibrinogenolysis, in particular when combined with the surfactant apoproteins sp-b and sp-c [ ] . thus, the hemostatic balance within the alveolar milieu appears to be shifted toward predominance of procoagulant and antifibrinolytic activity in acutely or chronically inflamed lung regions, in particular in ards. recent investigations performed by this group [ ] have demonstrated loss of surfactant phospholipids from the soluble phase due to binding to/within fibrin strands when the process of fibrin polymerization occurred in the presence of surfactant material. in parallel, virtually complete loss of surface activity was noted, with fibrin dose-effect curves ranging two orders of magnitude below the corresponding efficacy range of soluble fibrinogen. p nuclear magnetic resonance spectrum analysis has suggested membranelike, highly ordered arrangement of the fibrin-associated phospholipids. overall, these findings obviously suggest "incorporation" of phospholipids (and possibly hydrophobic apoproteins) into nascent fibrin strands. this phenomenon may cause severe loss of functionally important surfactant compounds in areas with alveolar fibrin and hyaline membrane formation. a variety of inflammatory processes are thought to underlie microcirculatory disturbances in ards, and mediator generation has also been demonstrated for the alveolar compartment. free elastase and collagenase activities were repeatedly detected in bal fluids of patients with ards [ , ] . [ , ] -induction of lipid peroxidation [ ] -decrease in surface activity [ ] -decrease in surface activity [ ] -degradation of sp-a [/ ] pases, proteases, oxygen radicals, free fatty acids, and activated granulocytes (via release of oxygen radicals), as summarized in table . presently, however, no data are available to quantify the contribution of such surfactant-inhibitory effects of inflammatory mediators to the impairment of surfactant function in patients with ards. as outlined above, there is strong evidence for severe impairment of the alveolar surfactant system under conditions of ards, and several mechanisms may underlie this finding. thus the question arises of whether and to what extent such surfactant alterations contribute to the sequence of pathogenetic events and the loss of lung functional integrity encountered in this disease. the main issues to be addressed in this context are the following: alteration of lung mechanics; impairment of gas exchange (ventilation/perfusion mismatch due to altered gas flow distribution, shunt flow) : lung edema formation (hydrostatic gradient, barrier characteristics); reduction in host defense competence (nosocomial pneumonia); up-regulation of inflammatory events; and "collapse induration", fibroblast proliferation and fibrosis. loss of alveolar surface activity increases surface tension and thereby causes alveolar instability and formation of atelectases. these features must be expected to result in a marked decrease in lung compliance. this basic finding was indeed described even in the very early reports on altered mechanics of postmortem analyzed lungs from patients dying from ards [ ] . in addition, in a variety of experimental approaches using animal models of ards, induction of acute lung injury resulted in significant decrease of compliance [ , , , , , , ] . accordingly, transbronchial administration of surfactant was shown to completely or partially restore physiological lung compliance in some of these models [ , , , , , ] . in patients with severe ards, however, reliable measurements of lung compliance are still difficult to perform, mostly because of uncertainties concerning lung volumes (at which part of the pressure-volume curve does the lung actually range?) and transpulmonary pressures. moreover, there is presently no reliable in vivo technique to differentiate the contribution of increased alveolar surface tension from that of interstitial congestion and on-going fibrosis to the reduction in lung compliance of ards patients. it is well conceivable that surfactant alterations predominate in the early phase of ards, whereas fibrotic events gain increasing importance in later states of the disease. future studies of transbronchial surfactant administration in ards patients using appropriate techniques to measure lung mechanics may help to determine the contribution of the alveolar surfactant system to altered lung mechanics in these patients. lack of surface active material has been established as primary cause of severe gas exchange disturbances in irds, and dramatic improvement in arterial oxygenation is achieved by transbronchial surfactant application under these conditions [ , ] . similarly, experimental approaches in adult animals with removal of alveolar surfactant (lung lavage models [ ] ) and subsequent transbronchial readministration of surface active material have also underscored the fundamental significance of the alveolar surfactant system for ventilation-perfusion matching in adult lungs [ , , ] . in more realistic models of ards, starting with induction of microvascular or alveolar injury, matters are more complex. shunt flow (perfusion of atelectatic regions) and blood flow through lung areas with low ventilation-perfusion ratios (partial closure of alveolar units or small airways) may well be related to acute impairment of the alveolar surfactant system in such experiments, and transbronchial surfactant administration was found to improve gas exchange conditions in models with protein-rich edema formation due to cervical vagotomy [ ] , acid aspiration [ , , ] , induction of pneumonia [ ] , hyperoxic lung injury [ ], and administration of n-nitroso-n-methylurethane [ , ] or oleic acid [ ] . the efficacy of surfactant replacement in these models with induction of lung inflammation is, however, lower than in models with primary surfactant depletion (lavage, preterm newborns), which is most probably attributable to inhibitory capacities of leaked plasma proteins and inflammatory mediators, as discussed above. [ , ] ; one example from this group is given in fig. . some more or less impressive improvement of gas exchange conditions was noted in these trials, suggesting that the use of larger amounts of surfactant material would be more promising. studies with long-term surfactant administration by use of aerosol techniques have been commenced in ards patients, but definite data are yet not available. further diagnostic and therapeutic approaches will be necessary to elucidate the contribution of impaired surfactant function to the gas exchange abnormalities in ards, to define whether this contribution is critically dependent on the phase of the disease (large impact in early ards, small impact in late ards with fibrosis?), and thereby to provide a rational basis for surfactant replacement trials aimed at acutely improving gas exchange conditions in ards patients. [ ] , cooling and ventilating at low functional residual capacity [ ] , or plasma lavage [ ] . moreover, the permeability characteristics of the epithelial membrane may be influenced by surfactant deficiencies. increased transepithelial passage of m t c -d p t a ( f r o m alveolar to intravascular space) and labeled albumin (from intravascular to alveolar space) was observed under experimental conditions of surfactant impairment, and the increased fluxes were reduced by transbronchial surfactant replacement [ , , ] . similarly, increased epithelial permeability for mtc-dpta is noted in neonates with irds [ ] . concerning patients with ards, there is presently no conclusive study to evaluate the impact of surfactant abnormalities on lung fluid balance and alveolar epithelial permeability characteristics. nosocomial pneumonia is a feared and frequent complication in ards. envolvement of the alveolar surfactant system in lung host defense mechanisms has long been suggested. direct cytolysis of several cocci upon in vitro incubation with lung lavage material was described in early reports and attributed primarily to free fatty acids in the surfactant material [ , ] . synthetic phospholipid mixtures and natural surfactant preparations (presumably lacking the hydrophilic apoproteins) were noted to suppress alveolar macrophage priming [ ] and phagocytosis as well as tumor necrosis factor (tnf) secretion [ ] ; this finding is possibly related to the down-regulation of inflammatory events in the alveolar compartment under physiological conditions [ ] . the pg fraction of the surfactant phospholipids was found to be particularly effective in this context [ ] [ ] [ ] . finally, the hydrophilic surfactant apoproteins sp-a and sp-d were recently noted to possess distinct immunological properties and may contribute substantially to the host defense mechanisms within the alveolar space (table ) [ ] [ ] [ ] ] . they apparently serve as opsonizing agents in this compartment and enhance bacterial and viral phagocytosis and killing. overall, these aspects are at best mosaics of a complex alveolar host defense system, which largely remains to be defined [ ] . studies directly addressing changes in host defense mechanisms due to surfactant alterations in ards patients are still lacking. the marked decrease in sp-a levels in these lungs (see above) may suggest loss of opsonizing capacity and increased susceptibility to nosocomial infections. one typical feature of ards is the perpetuation of inflammatory events in the microvascular and alveolar compartments, which may continue even after cessation of the primary noxious event (e.g., sepsis, shock, aspiration). similarly, as discussed for the host defense mechanisms, our knowledge of the regulation of inflammatory processes in the alveolar compartment is only fragmentary. alveolar cells such as macrophages, type ii pneumocytes, and invading granulocytes are rich sources of lipid mediators and cytokines when appropriate- ly stimulated, and intercellular cooperation in inflammatory mediator generation appears to be of major importance; an example for pulmonary capillary and alveolar leukotriene generation is depicted in fig. . interestingly, the "level" of leukotriene generation in this system of cell-cell cooperation may be largely up-regulated in the presence of free arachidonic acid (leukotriene precursor fatty acid) in the extracellular space, i.e., the alveolar surfactant system. such increase in lung tissue and surfactant free arachidonic acid content was indeed observed under conditions of experimental [ ] and clinical ards [ ] and may thus contribute to the perpetuation of inflammatory events. as another example of surfactant envolvement in inflammatory processes, allen et al. [ ] recently reported on suppression of interleukin-j and tnf release from human alveolar macrophages by natural surfactant material, without defining the contribution of single surfactant components to this finding. it is thus easily conceivable that alterations in surfactant composition may have multiple effects on inflammatory processes in the alveolar compartment. the proliferative phase of ards is characterized by progressive mesenchymal cell activation and proliferation, predominantly in atelectatic regions, and may result in widespread lung fibrosis and honeycombing within a few weeks. underlying mechanisms may well include a major role of the alveolar surfactant system and of alveolar fibrin deposition, as depicted schematically in fig. . a corresponding sequence of events was suggested for the pathogenesis of lung fibrosis in general by burkhardt [ ] and termed "collapse induration." basically, this concept starts with persistent atelectasis at sites of extensive loss of alveolar surfactant function, in particular regions with fibrin deposition. alveolar wall apposition and the fibrin matrix represent a nidus for fibroblast activation, and the concerned alveolar space is definitely lost by deposition of fibrous tissue (collapse induration). thus, thick indurated septae (or conglomerates of several septae) may exist adjacent to widened (remaining) alveoli to provide the typical morphological image of fibrosis and honeycombing [ , , ]. this concept does not deny an important role of inflammatory mediators, such as tnf, and growth factors for the induction of mesenchymal cell activation in late ards. however, it provides an explanation for the predominance of fibrosis at sites of persistent atelectasis and fibrin deposition. overall, there is good evidence for the assumption that significant surfactant abnormalities occur under conditions of ards, and a variety of mechanisms may contribute to this feature. it is thus conceivable that "classical" consequences of surfactant deficiency such as atelectasis formation and loss of compliance, ventilation-perfusion mismatch and shunt-flow, as well as lung edema formation may be related to such surfactant abnormalities in patients suffering from ards. however, the extent to which surfactant-related disturbances contribute to the overall pathophysiological events in ards cannot presently be quantified and may depend critically on the phase of the disease. moreover, surfactant abnormalities may have considerable impact on host defense mechanisms, inflammatory events, and fibrosis generation, but no definite evaluation of these aspects can currently be undertaken due to the scarcity of clinical data in these fields. there is, however, no doubt that all these aspects must be addressed when planning transbronchial surfactant administration as a new therapeutic approach in ards. final "design" of a surfactant to be administered under these conditions will have to use proper administration techniques (preferably some kind of aerosolization), aim at acut improvement in lung mechanics and gas exchange, and critically consider its impact on inflammation, host defense, and mesenchymal proliferation in the alveolar compartment. local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs increased surface tension favours pulmonary edema formation in anaesthetized dogs' lungs surfactant suppresses interleukin-i ¢/and tumor necrosis factor-c~ release by human alveolar macrophages identification of the immunosuppressive components of canine pulmonary surface active material immunosuppressive activity of canine pulmonary surface active material canine surface active material and pulmonary lymphocyte function studies with mixed-lymphocyte culture structural alterations of lung parenchyma in the adult respiratory distress syndrome mechanisms of damage to the lung surfactant system. u -trastructure and quantitation of normal and in vitro inactivated lung surfactant gas exchange and lung morphology after surfactant replacement in experimental adult respiratory distress syndrome induced by repeated lung lavage respiratory distress and surfactant inhibition following vagotomy in rabbits depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome high surface tension pulmonary edema alveolitis and collapse in the pathogenesis of pulmonary fibrosis abnormalities in pathways of alveolar fibrin turnover among patients with interstitiell lung disease role of plasminogen activator in degradation of extracellular matrix protein by live human alveolar macrophages alveolar macrophage urokinase receptors localize enzyme activity to the cell surface collagenase in the lower respiratory tract of patients with adult respiratory distress syndrome pathogenesis of the adult respiratory distress syndrome lysophosphatidylcholine sensitizes lipid extracts of pulmonary surfactant to inhibition by serum proteins pulmonary surfactant-associated protein a enhances the surface activity of lipid extract surfactant and reverses inhibition by blood proteins in vitro detection and partial characterization of antibacterial factor(s) in alveolar lining material of rats characterization of the extracellular bactericidal factors of rat alveolar lining material surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial persson a (t ) developmental expression of pulmonary surfactant protein d (sp-d) natural and artificial lung surfactant replacement therapy in premature lambs of baboons with diffuse alveolar damage serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome comparison of four surfactants: in vitro surface properties and responses of preterm lambs to treatment at birth lung albumin recovery in surfactant-treated preterm ventilated lambs pulmonary surfactant protein a enhances the host-defense mechanism of rat alveolar macrophages surfactant protein a is opsonin in phagocytosis of herpes simplex virus type by rat alveolar macrophages rat surfactant protein d enhances the production of oxygen radicals by rat alveolar macrophages idiopathic pulmonary fibrosis pulmonary epithelial permeability in hyaline-membrane disease neue medikament se behandlung im ards: effekt einer intrabronchialen xenogenen surfactantapplikation surfactant therapy for pulmonary edema due to intratracheally injected bile acid interaction of the lipid and protein components of pulmonary surfactant. role of phosphatidylglycerol and calcium lung lavage and surfactant replacement for hydrochloric acid aspiration in rabbits inactivation of exogenous surfactant by pulmonary edema fluid pulmonary surfactant apoprotein a structure and modulation of surfactant secretion by rat alveolar type ii cells surfactant replacement improves lung recoil in rabbit lungs after acid aspiration elastolytic activity in pulmonary lavage fluid from patients with adult respiratory distress syndrome nebulized vs. instilled exogenous surfactant in an adult injury model metabolism of exogenously administered surfactant in the acutely injured lungs of adult rabbits local activation of the coagulation and fibrinolysis systems in lung disease high surface tension pulmonary edema induced by detergent aerosol surfactant displacement by plasma lavage results in pulmonary edema biophysical activity of synthetic phospholipids combined with purified lung surfactant dalton apoprotein effect of fibrinogen degradation products and lung ground substance on surface function purification and biochemical characterization of cp (sp-d), a collagenous surfactant-associated protein abnormalities in lung elastic properties and surfactant function in adult respiratory distress syndrome surfactant abnormalities in patients with respiratory failure after multiple trauma proteolytic inactivation of dog lung surfactant-associated proteins by neutrophil elastase surfactant protein a (sp-a) is decreased in acute parenchymal lung injury associated with polytrauma a proposed nomenclature for pulmonary surfactant-associated proteins the lung: structure, function, and disease reconstitution of surfactant activity using purified human apoprotein and phospholipid measured in vitro and in vivo use of human surfactant low molecular apoproteins in the reconstitution of surfactant biologic activity pulmonary host defenses -state of the art surfactant-associated protein inhibits phospholipid secretion from type ii cells curstedt t ( ) the adult respiratory distress syndrome! first trials with surfactant replacement experimental evaluation of surfactants for replacement therapy phospholipid binding and biophysical activity of pulmonary surfaetant-associated protein (sap)- and its non-collagenous cooh-terminai domains inaktivierung von alveol/iren oberflfichenfilmen durch erniedrigung der oberfl/ichenspannung der hypophase binding and uptake of pulmonary surfactant protein (sp-a) by pulmonary type ii epithelial cells effects of activated polymorphonuclear leukocytes upon pulmonary surfacrant in vitro septic lung role of membrane lipids in the pulmonary vascuiar abnormalities caused by bacterial toxins alteration of surfactant function after exposure to oxidative stress and to oxygenated and native arachidonic acid in vitro alteration of surfactant function due to protein leakage: special interaction with fibrin monomer increased lung vascular permeability after arachidonic acid and hydrostatic challenge procoagulant activity in bronchoalveolar lavage of severly traumatized patients -relation to the development of acute respiratory distress surface properties and sensitivity to protein-inhibition of a recombinant apoprotein c-based phospholipid mixture in vitro comparison to natural surfactant differential sensitivity to fibrinogen-inhibition of sp-c versus sp-b based surfactants interactions of the low molecular weight group of surfactantassociated proteins (sp - ) with pulmonary surfactant lipids phagocytic functions and tumor necrosis factor secretion of human monocytes exposed to natural porcine surfactant (curosurf) pathology of the lung studies of the potential role of a semisynthetic surfactant preparation in an experimental aspiration trauma in rabbits reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant effect of surface active lipoprotein on clotting and fibrinolysis, and of fibrinogen on surface tension of surface active lipoprotein human pulmonary surfactant protein (sp-a), a protein structurally homologous to clq, can enhance fcr-and crl-mediated phagocytosis altered surface tension of lung extracts and lung mechanics intratracheal surfactant administration restores gas exchange in experimental adult respiratory distress syndrome associated with viral pneumonia surfactant replacement therapy improves pulmonary mechanics in end-stage influenza a pneumonia in mice the pulmonary surfactant system: biochemical aspects and functional significance biophysical inhibition of synthetic phospholipid-lung surfactant apoprotein admixtures by plasma proteins low molecular weight human pulmonary surfactant protein (sp ): isolation, characterization, and cdna and amino acid sequences hydrophobic surfactant-associated protein in whole lung surfactant and its importance for biophysical activity in lung surfactant extracts used for replacement therapy influence of septic shock upon phosphytidylcholine remodeling mechanism in rat lung changes in lipid structure produced by surfactant proteins sp-a, sp-b and sp-c tumor necrosis factoralpha inhibits expression of pulmonary surfactant protein reconstitution of surfactant activity by using the kda apoprotein associated with pulmonary surfactant comparative studies on the biophysical activities of the low-molecular-weight hydrophobic proteins purified from bovine pulmonary surfactant effects of aerosolized artificial surfactant on repeated oleic acid injury in sheep apoprotein-based synthetic surfactants inhibit plasmic cleavage of fibrinogen in vitro lung surfactant phospholipids associate with polymerizing fibrin -loss of surface activity key: cord- -bmigh rs authors: yener, nazik; Üdürgücü, muhammed title: airway pressure release ventilation as a rescue therapy in pediatric acute respiratory distress syndrome date: - - journal: indian j pediatr doi: . /s - - -w sha: doc_id: cord_uid: bmigh rs objectives: to describe experience with airway pressure release ventilation (aprv) in children with severe acute respiratory distress syndrome (ards) refractory to conventional low tidal volume ventilation. methods: this retrospective observational study was performed in an -bed, level pediatric intensive care unit. evaluation was made of pediatric patients receiving airway pressure release ventilation as rescue therapy for severe ards. results: patients were switched to aprv on an average . ± . d following intubation. when changed from conventional mechanical ventilation (cmv) to aprv, there was an expected increase in the spo( )/fio( ) ratio ( . ± . vs. . ± . ; p = . ). mean peak inspiratory pressure was significantly lower during aprv ( . ± . vs. . ± . , p < . ) compared to cmv prior to aprv but mean airway pressure (p(aw)) was significantly higher during aprv ( . ± . vs. . ± . , p < . ). hospital mortality in this study group was . %. conclusions: the results of this study support the hypothesis that aprv may offer potential clinical advantages for ventilatory management and may be considered as an alternative rescue mechanical ventilation mode in pediatric ards patients refractory to conventional ventilation. acute respiratory distress syndrome (ards) is the most severe form of acute respiratory failure, characterised by severe diffuse inflammation and hypoxemia that poses a significant threat to patients of all age groups. currently, lung-protective ventilation strategies, including open lung and low-tidal-volume, are among the major ards mechanical ventilation strategies to prevent ventilator-induced lung injury for both adults and children [ ] . despite advancements in our understanding of lung-protective low-tidal-volume ventilation, the mortality associated with pediatric ards remains high and has changed little in the last years ( - %) [ , ] . no consensus has been reached on the optimal mode of ventilation for pediatric ards patients refractory to conventional mechanical ventilation (cmv) using low tidal volume combined with sufficient positive end expiratory pressure (peep). over the past decades, such patients have commonly transitioned from cmv to high frequency oscillation ventilation (hfov) for refractory hypoxemia or to limit cyclic high peak pressures [ ] . unfortunately, there is a lack of relevant hfov research on pediatric populations as only one small cohort randomized controlled trial (rct) has been conducted [ ] . approximately y ago, airway pressure release ventilation (aprv) was introduced as a partial ventilatory mode for mechanical ventilation in clinical practice. however, until recently, it was not widely used as a rescue mode for the difficult-to-oxygenate patient with ards. as the name suggests, aprv mode has been described as a continuous positive airway pressure with a brief intermittent release phase allowing the release of only partial lung volume. in adult patients with ards, compared with other conventional ventilatory modes, aprv may improve oxygenation due to increased recruitment of lung volumes, length of stay in the intensive care unit and ventilator-free days [ , ] . until , pediatric research on aprv was restricted to case reports, case series and prospective crossover studies [ ] . a recent study by lalgudi ganesan et al. [ ] was the first randomised control trial (rct) of aprv as a primary ventilation strategy in children with ards. the trial was terminated early after % enrolment when the analysis demonstrated a trend toward higher mortality in the aprv group compared with the conventional low-tidal volume ventilation. however, there is a lack of data investigating the safety and efficacy of aprv as a rescue therapy in pediatric ards. the aim of this study was to describe authors' experience with aprv in children with severe ards refractory to conventional low tidal volume ventilation. this retrospective observational study was conducted in the -bed pediatric intensive care unit of ondokuz mayıs university hospital, a tertiary level hospital in turkey. approval for the study was granted by the university ethics committee. the study included patients aged between mo and y, receiving aprv ventilation during index admission to the picu and who fulfilled the diagnostic criteria of ards, according to the pallic definition and were refractory to conventional low tidal volume ventilation. determination of failure of cmv and the decision to employ alternative modes was left to the discretion of the attending intensive care physician. despite the lack of a standardized ventilator protocol, the authors' institutional practice for ards is to initiate cmv with a minimum of cm h o of positive end-expiratory pressure (peep), low tidal volume ( - ml/kg predicted body weight) and to attempt to wean fio to ≤ . . inability to wean fio prompts elevation level of peep ( - cm h o) with the goal of maintaining plateau airway pressure at no more than cmh o. prone positioning is a part of the authors' clinical practice if it is not possible to wean fio to ≤ . during conventional low tidal volume ventilation. the prone position and the other non-ventilatory co-interventions (inhaled nitric oxide or extracorporeal membrane oxygenation) for ards were not used during aprv. persistently elevated plateau pressures (≥ cm h o), or oxygenation difficulties (inability to wean fio ≤ . despite increasing peep) prompted consideration of changing the mode of ventilation. as there is no hfov ventilator in authors' clinic, aprv was used as a rescue mode in children with severe ards when cmv does not achieve a specific target level of oxygenation as previously described. patients receiving aprv for < h, or for an indication other than ards were excluded. all patients were ventilated with a servo-i (maquet, germany) ventilator and aprv parameters were initially adjusted by the attending intensive care physician. the authors' instutitional practice is personalized-setting aprv (p-aprv) where the low pressure (p low) is set at zero to facilitate rapid emptying and the brief expiratory time (t low) prevents full deflation of the lung end-expiratory pressure from reaching zero [ ] . data were retrieved from the medical records of eligible patients including the diagnosis on admission, demographic data, co-morbidities, date and time of intubation, mode of ventilation prior to initiation of aprvand date and time of aprv initiation, length of mechanical ventilation, length of stay in picu and survival to hospital discharge. a record was made of ventilator settings, the ph and venous co values, sedation and vasopressor use before and after aprv (at h) and evidence of pneumomediastinum or pneumothorax at any time on aprv. the oxygen saturation to fraction of inspired oxygen ratio (spo /fio ) was calculated before and after aprv, and the oxygen saturation index [osi = mean airway pressure (p aw ) × fio × ÷ spo ] was calculated prior to aprv. radiographic requirements for the diagnosis of ards were derived from the attending radiologist's final chest x-ray report. data obtained in the study were analysed statistically using ibm spss vn (spss inc., chicago, il, usa). data were expressed as mean ± standard deviation and as the median and interquartile ranges (iqr), or percentages. conformity of quantitative data to normal distribution was assessed with the shapiro-wilk test and the paired samples t-test was used in the comparisons of normally distributed variables. a value of p < . was accepted as statistically significant. of the patients ventilated with aprv between october and april , remained on aprv for more than h and patients met the study inclusion criteria. three patients were on aprv ventilation for < h, did not tolerate it and were placed back on cmv; of these, mortality was seen in with a diagnosis of drowning, and with sepsis survived. of the remaining patients who were on aprv ventilation for > h, patients were on aprv for non-ards reasons ( with cardiogenic pulmonary edema, with pulmonary hemorrhage) and were excluded. the median age of the patients enroled in the study was mo (iqr . - . ), % were younger than y old and % were infants. the demographic data and outcomes are presented in table . following a diagnosis of ards, all patients were ventilated with conventional low tidal volume and high peep ventilation with the synchronized intermittent mandatory ventilation mode with pressure support (simv+ps). ventilation measurements before and after transition to aprvare presented in table . mean maximum peep was ± . (range - ) during cmv. all patients had severe ards as per the pallic criteria, with mean osi . ( . - . ) prior to aprv. patients were switched to aprv on average . ± . d (range: - d) following intubation. during the observational period, all patients required sedation (including, benzodiazepines and narcotics). when changed from cmv to aprv, the sedation requirements increased in patients, decreased in and remained unchanged in all the others. at h after patients were switched to aprv there was an expected increase in the spo / fio ratio ( . ± . vs. . ± . , p = . ). mean peak pressure was significantly lower during aprv ( . ± . vs. . ± . , p < . ) compared to cvm prior to aprv but p aw was significantly higher during aprv (at h) ( . ± . vs. . ± . , p < . . mean mandatory breaths in aprv were . ± . ( - ). when changed from cmv to aprv, % of the patients received vasopressor. vasopressor requirement and the ph and venous co values were not significantly different before and after aprv. renal replacement therapy was given to six patients in the study group. patients were switched to simv+ ps as a weaning mode. after a weaning period of . ± . d, all patients were extubated with non-invasive ventilation (niv). mortality was seen in patients during aprv. the primary cause of death was worsening hypoxemia in patients and multi organ dysfunction in . in of these patients, there was a co-morbidity, and in , the cause of death was sepsis. all the patients with mortality were aged < y old and were < y old. of the patients who survived, ( %) were spontaneously breathing at d after extubation. two patients could not tolerate weaning from niv and were discharged home with niv. in patient with a history of reactive airway diseases, bilateral pneumothorax developed, which required bilateral chest tubes during aprv. these events occurred d post-aprv initiation and there was no associated early mortality. in-hospital mortality for the cohort was . % ( / ). aprv is an inverse ratio pressure control mode of mechanical ventilation that was first described and introduced into clinic practice more than two decades ago [ ] . although different mode names are used, aprv is now available in almost all critical care ventilators. the main findings of this study were that in a cohort of pediatric patients with severe ards, when cmv did not achieve a specific target level of oxygenation, initiation of aprv was able to significantly and sustainably improve oxygenation. inverse ratio ventilation (irv), hfov and aprv are non-conventional modes of ventilation considered as a rescue treatment for patients with moderate to severe ards who are refractory to cmv [ , ] . all these nonconventional modes increase oxygenation by increasing the average p aw [ ] . in the current study, when transfer was made from cmv to aprv mode, the average p aw increased significantly. as the inspiration duration is relatively much longer than the expirium duration in both irv and aprv, the duration at high pressure in the respiratory cycle is prolonged, causing elevation in the p aw values. it is thought that high p aw values increase oxygenation by opening the lungs [ ] . in the current study, there was a statistically significant decrease in peak airway pressure when cmv was switched to aprv. this decrease is thought to be protective against lung damage associated with the ventilator. in literature, there is no consensus on how the initial settings should be determined for aprv [ ] . in accordance with the findings of the current study, it could be considered appropriate to start with a lower p high than pip in cmv when determining the initial settings in the transfer to aprv from cmv as a rescue mode in children. the number of mandatory breaths in aprv is set much lower compared to cmv, but the patient can breathe spontaneously at each point of the ventilation cycle. a large part of the spontaneous respiration occurs in the longer inspirium duration. although spontaneous respiration has a positive effect on the protection of diaphragm functions, there is insufficient information about the effect on lung dynamics and vili formation of spontaneous breathing occurring in the long p high duration during aprv [ ] . in the current study, the mean number of mandatory breaths during aprv was determined as . ± . . although the results of a low number of breaths have not been investigated for direct aprv, previous animal experimental studies have shown that a high number of mandatory breaths during cmv, especially with high tv, led to additional damage in the lungs [ , ] . to increase patient compliance during both hfov and irv, heavy sedation and muscle blockage are often required [ ] . that the use of intense sedation and analgesia is not required in adults during aprv has been emphasised as an advantage in literature. in two different prospective studies of adults with trauma and cardiac surgery, controlled mechanical ventilation was compared with aprv and it was concluded that there was a reduced requirement for sedation and analgesia in aprv [ , ] . in the current study, there was no significant difference in the use of sedation and analgesia in the transition from cmv to aprv. nevertheless, in the current study, there was no requirement for the use of muscle blockage in any patient during both cmv and aprv. as the benefits of aprv are based on the spontaneous breathing component, the advantage of this method may be lost on patients who need heavy sedation or neuromuscular paralysis with lack of spontaneous breathing. possible contraindications to aprv include patients with obstructive lung disease (asthma or chronic obstructive pulmonary disease) who require prolonged exhalation time and conditions that may worsen with the elevation of the mean airway pressure, such as unmanaged increases of intracranial pressure and large bronchopleural fistulas. in addition, the limited research and experience with this form of ventilation can be a potential problem in certain facilities (neuromuscular disease) [ , ] . no consensus has been reached in literature on the subject of how weaning can be achieved in patients applied with aprv. while some authors have reduced p high until it is cpap mode, it is recommended that weaning is applied by increasing t high [ , ] . in the current study, first p high was reduced before starting weaning and when a sufficient drop was achieved, transition was made when tolerated to simv+ ps (peep = cmh o) mode, as this mode is well known by authors' team. following ventilation with simv+ps mode for mean . ± . d after aprv, all the surviving patients were extubated with niv. to minimise failure of extubation, prophylactic niv was applied immediately on extubation. of the patients of the current series who survived, were able to be discharged with spontaneous breathing. in the other patients, pulmonary damage developed, so niv was set and they were discharged home with niv. all the current study patients were applied with aprv in rescue mode, and all had been previously ventilated with lung-protective cmv (at mean peep) for mean . d. therefore, the ventilator-related lung damage that developed was not considered to be related to aprv alone. with the exception of patient with a history of reactive airway disease who developed pneumothorax, no significant complications were observed. although the number of cases in this study is low, aprv can be considered a safe ventilation method for children. a trend toward mortality benefit has only been shown in one small retrospective study as of patients: % in the aprv group, compared to % in the simv group (p < . ) [ ] . however, lalgudi ganesan et al. [ ] recently conducted the first rct of aprv in pediatric ards cases. the study had to be terminated after % enrolment ( children) as analysis showed higher mortality rates in the aprv group. it was concluded that the use of aprvas a primary ventilation strategy in children with ards resulted in higher mortality rates compared with conventional low tidal volume ventilation. in an rct by yehya et al., [ ] of immunocompromised and ards pediatric patients refractory to conventional ventilation, the mortality rate was % and did not differ between patients transitioned to aprv and hfov. hospital mortality in the current study group ( . %) was below the range of recently published mortality rates ( - %) in clinical trials of pediatric ards [ , ] . there are several limitations to this study. first, as this was a retrospective observational study, conducted with the intent of describing the outcomes of patients with severe ards refractory to cmv, who were then treated with aprv, there was no direct comparison with other conventional ventilation methods. second, the sample size was small so it may not have been of sufficient power to detect improvements in oxygenation before and after transition to aprv. third, the determination of failure of cmv and initiation of aprv were based on the decision of the intensive care physician rather than a unit guideline. in addition, as a sedation scale was not used, there could not be any evaluation of whether or not there was a difference in the requirement for sedation and analgesia. in conclusion, the results of this study demonstrated that in a cohort of pediatric patients with severe hypoxemic respiratory failure when cmv did not achieve a specific target level of oxygenation, initiation of aprv is associated with a significant and sustained improvement in oxygenation. these results support the hypothesis that aprv may offer potential clinical advantages for ventilatory management and may be considered as an alternative rescue mechanical ventilation mode in pediatric ards patients refractory to conventional ventilation. as aprv is commonly available on intensive care ventilators when hfov is not always accessible, this mode can be considered a relatively simple modality that can be implemented easily. pediatric acute lung injury consensus conference group. pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the pediatric acute lung injury consensus conference pediatric acute respiratory distress syndrome prospective, randomized comparison of highfrequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome airway pressure release ventilation in children airway pressure release ventilation in pediatric acute respiratory distress syndrome: a randomized controlled trial high frequency oscillation and airway pressure release ventilation in pediatric respiratory failure airway pressure release ventilation current role of high frequency oscillatory ventilation and airway pressure release ventilation in acute lung injury and acute respiratory distress syndrome severe hypoxemic respiratory failure: part : ventilatory strategies airway pressure release ventilation: what do we know? mean airway pressure: physiologic determinantsand clinical importance: part : clinical implications does airway pressure release ventilation offer important new advantages in mechanical ventilator support? respir care should airway pressure release ventilation be the primary mode in ards? respir care airwayv pressure release ventilation prevents ventilator-induced lung injury in normal lungs effects of respiratory rate on ventilator-induced lung injury at a constant paco in a mouse model of normal lung the influence of controlled mandatory ventilation (cmv), intermittent mandatory ventilation (imv) and biphasic intermittent positive airway pressure (bipap) on duration of intubation and consumption of analgesics and sedatives. a prospective analysis in patients following adult cardiac surgery long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury airway pressure release ventilation: an alternative mode of mechanical ventilation in acute respiratory distress syndrome other approaches to open-lung ventilation: airway pressure release ventilation airway pressure release ventilation: theory and practice practical use of airway pressure release ventilation for severe ards -a preliminary report in comparison with a conventional ventilatory support publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contribution ny: study design, literature search and manuscript preparation; mu: data collection, analysis of data and review of manuscript. ny is the guarantor fort his paper. conflict of interest none. key: cord- -danl io authors: jansen, oliver; kamp, oliver; waydhas, christian; rausch, valentin; schildhauer, thomas armin; strauch, justus; buchwald, dirk; hamsen, uwe title: extracorporeal membrane oxygenation in spina bifida and (h n )-induced acute respiratory distress syndrome date: - - journal: j artif organs doi: . /s - - - sha: doc_id: cord_uid: danl io acute respiratory distress syndrome (ards) is characterized as an acute hypoxemic and/or hypercapnic respiratory failure seen in critically ill patients and is still, although decreased over the past few years, associated with high mortality. furthermore, ards may be a life-threatening complication of h n pneumonia. we report on a -year-old spina bifida patient with confirmed h n influenza virus infection causing acute respiratory failure, who was successfully weaned from -day veno-venous extracorporeal membrane oxygenation (vv-ecmo) treatment with an excellent outcome. due to the physical constitution of spina bifida patients, we experienced challenges concerning cannula positioning and mechanical ventilation settings during weaning. acute respiratory distress syndrome (ards) is a severe respiratory condition characterized by diffuse inflammation of alveolar and vascular (capillary) lung structures leading to progressive hypoxemia and/or hypercapnia. the american-european consensus conference definition has been applied since its publication in and has helped to improve knowledge about ards. however, in , the european intensive medicine society agreed on the berlin definition, which is now widely applied and accepted in diagnosis of ards [ ] . in the management of patients with ards, extracorporeal membrane oxygenation (ecmo) has been successfully used as salvage therapy. ards severe enough to require ecmo therapy is estimated to occur in nearly - cases per million population per year [ ] . the effectiveness of ecmo in ards patients with pneumonia, influenza a (h n ), and/or trauma has recently been described and considered promising [ , ] , although is still associated with higher mortality [ ] . the addition of prone positioning therapy to ecmo may improve alveolar recruitment and, therefore, reduce ventilator-induced lung injury [ , ] . adding prone positioning therapy to ecmo patients is recommended by the guidelines for adult respiratory failure from the extracorporeal life support organization if radiological imaging shows posterior consolidation of the lung fields [ ] . a -year-old (height cm and kg bodyweight) chronic paraplegic patient due to spina bifida presenting an extraordinary kyphoscoliosis (see fig. ) was admitted to the intensive care unit (icu) after onset of an acute respiratory failure due to h n influenza. prior to ards onset, the patient underwent urologic treatment for pyelonephritis that had led to sepsis and required intensive medical care. as respiratory failure proceeded and pulmonary function could not be maintained despite extensive mechanical ventilation (mv), the patient met the criteria for extracorporeal membrane oxygenation (ecmo) and has, therefore, been transferred to our hospital (ecmo center). according to the patients' medical history, a magnetic resonance imaging (mri) conducted years ago showed no signs of chiari malformation. microbial testing revealed h n virus infection as the probable cause for the ongoing ards. his chest x-ray and computed tomography (ct) showed diffuse bilateral infiltration, and blood gas test showed a severe hypoxemia and hypercapnia refractory to the conventional mv (table ; fig. ). on the day of admission and after completion of diagnosis, we percutaneously (right jugular vein french size + right femoral vein french size) administered a veno-venous extracorporeal membrane oxygenation. cannula (maquet hls, rastatt, germany) positioning has been verified immediately using ultrasound, but was challenging due to a monstrous thoracic scoliosis. the cannulation is always performed in cooperation with the cardiotechnology following a standardized protocol. subsequently, mv settings were adjusted to ensure protective ventilation. because of the patients distinct physical constitution, the pump flow strongly depended on the positioning of the patient. very small positional changes (head tilt and rotation, hip flexion, or rotation) caused severe, recurrent, and prolonged episodes of decreased blood flow rate and increased negative pressure of the venous inflow, leading to an inadequate systemic oxygenation and to an increased risk of intraoxygenator blood clotting. therefore, patient and cannula positioning had to be adapted constantly. once the negative pressure exceeded a limit value and subsequently ecmo blood flow decreased, we immediately tried to ensure optimal suction of the ecmo cannula by small changes in the position of the body. in the event of persistent insufficient blood flow, we performed whole body position changes (e.g., head-low, legs-up, / / °). due to the enormous physical deformation, especially, whole body changes proved to be challenging and required partly improvised support aids. due to that there is no standardized protocol/regimen available, concerning ecmo therapy and positioning therapy in patients suffering challenging deformity, we adapted to incident by trial and error but agreed on the following scheme to solve the recurrent inflow pressure problems: st step checking for kinking of the cannules; nd step minimal body changes, e.g., head tilt and rotation, hip flexion, or rotation; rd step whole body position changes, e.g., head-low, legs-up, / / °. in the initial stage, moving the patients' body/body positioning therapy was conducted only to maintain or improve ecmo blood flow (see scheme above). on the th day of ecmo therapy as episodes of decreased blood flow rates persisted and one oxygenator already had to be replaced, the blood flow direction was reversed. although the pump flow remained strongly dependent on the patients position, the incidence and duration of decreased blood flow periods decreased. however, until termination of ecmo therapy and due to clotting, a total of three oxygenators had to be replaced as the patient highly depended on the extracorporeal oxygenation. meanwhile, the patients underwent percutaneous dilatational tracheostomy and as septic multi organ failure proceeded received continuous renal replacement. as ecmo blood flow could be reduced and, therefore, resulted in less inflow pressure problems and less dependency on the patients' position, we began to establish a regimen of intermittent prone positioning therapy to improve alveolar recruitment of the posterior consolidated lung fields and, therefore, pulmonary capacity (fig. ) . as the respiratory function improved, ecmo support was gradually decreased and terminated after days. prior to ecmo termination, blood flow has been lowered to two l/ min and oxygen flow down to l/min (withdrawal trial). days after ecmo removal, we transferred the patient at his own wish closer to his home to a clinic specialized on prolonged weaning from mv. at the time of discharge from our hospital, he was able to breath spontaneously for short periods of time depending after additional weeks, the patient was discharged to a rehabilitation center, breathing spontaneously and being able to mobilize himself in his wheelchair. severe kyphoscoliosis causing restrictive respiratory impairment may result or predispose acute respiratory failure [ ] . in addition, spinal cord injury (sci), due to several factors, e.g., reduction in respiratory muscle strength, fatigue (motor impairment), retention of secretions (ineffective coughing) [ ] aggravate the risk of respiratory failure. although pulmonary complications in sci patients are common, yet, there is insufficient evidence about their management; current practice is mainly based on clinical experience and expert opinion [ ] . ecmo is increasingly emerging into the icus and ards therapy. depending on the physical constitution of the patient, ecmo therapy and/or cannula positioning may be more challenging in patients suffering physical deformities. technical complications of ecmo therapy responsible for acute pump or circuit dysfunction are fortunately not common, but if so may cause devastating ecmo therapy failure [ ] . literature review on ecmo in sci, spina bifida, or severe kyphoscoliosis reveals a lack of evidence. to our knowledge, only one case series (n = ) of ecmo in sci addresses this specific issue [ ] . the intention was to provide the experiences of long-term ecmo therapy in a spina bifida patient. although the patient of this present case suffered severe technical complications due to spina bifida deformity, ecmo is feasible and the outcome was excellent. while experiencing recurrent episodes of increased negative pressure of the venous inflow and decreased blood flow rates in the initial stage, we applied positioning therapy (e.g., / and ° positioning) to resolve the inflow complications. alternatively, the addition of a second venous inflow cannula may significantly increase blood flow rate and decrease negative pressure (suction) of the venous inflow line [ ] . however, at the end of the ecmo treatment and once the patients' pulmonary function had been improved/partially restored and the patient showed less dependency on ecmo, we were able established a positioning therapy regimen including the prone position as an adjunct to ecmo without experiencing any technical problems. similarly, a systematic review by culbreth et al. also reported limited complications and highlighted the clinical efficacy, although evidence is still insufficient [ ] . however, both prone positioning and ecmo are well established in treating refractory hypoxemia in ards. combining these therapies may increase the potential risk of cannula dislodgement. this case report suggests that these therapy options can be used in tandem despite considerable physical deformities. acute respiratory distress syndrome: the berlin definition international ecmo network (ecmonet). position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome cesar trial collaboration. efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomized controlled trial mortality trends of acute respiratory distress syndrome in the united states from to prone positioning in severe acute respiratory distress syndrome prone position during ecmo is safe and improves oxygenation nocturnal mechanical ventilation improves exercise capacity in kyphoscoliostic patients with respiratory impairment extracor poreal life suppor t organization. guidelines for adult respiratory failure. . https:// w w w respiratory management during the first five days after spinal cord injury respiratory management following spinal cord injury: a clinical practice guideline for health-care professionals technical complications during veno-venous extracorporeal membrane oxygenation and their relevance predicting a system-exchangeretrospective analysis of cases extracorporeal lung support in patients with spinal cord injury: single center experience double-stage venous cannulation combined with avalon® cannula for potential prolongation of respiratory ecmo in end-stage pulmonary disease complications of prone positioning during extracorporeal membrane oxygenation for respiratory failure: a systematic review key: cord- -j ruj authors: dreyfuss, didier title: is it better to consent to an rct or to care?: Μηδεν αγαν (“nothing in excess”) date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: j ruj nan twenty-five years ago the belmont report [ ] established a formal distinction between care and research in order to protect patients. the legitimate fear that research might be conducted under the pretence of medical care regardless of whether this increased the risk to patients drove this effort toward clarification. a sound ethical foundation to medical research was deemed essential after the heinous nazi experiments and the abhorrent -year-long tuskegee syphilis study [ ] . at the time that the belmont report was issued randomized clinical trials (rcts) were coming into vogue. an rct is not routine clinical care, even when the treatments in both study arms are consonant with standard practice. thus both the ability of rcts to produce high-quality medical knowledge and the distinction between care and research were considered of paramount importance at the time of the belmont report [ ] . whether research should be incorporated into medical care remains controversial, however, as reflected by several recent and conflicting statements of opinion [ , , ] . i argue here that things have changed since the belmont report, and that a formal distinction between care and research may no longer serve medical or ethical principles in many situations, most notably in the area of critical care. this seemingly provocative position stems from three arguments. first, a large part of the "research" conducted in icu patients consists in evaluating practices or comparing two widely used procedures or treatments [ ] . second, the scientific value and the historical role of rcts may have been overemphasized and their socioeconomic impact misinterpreted. third, analysis of the informed consent process, a mandatory preliminary intended to ensure the autonomy of patients included in rcts, suggests that the cure may be worse than the disease. although informed consent was a major stride towards protecting the rights and dignity of patients, the process may in some instances be perverted into protecting the physicians rather than the patients. the tragic jesse gellsinger case ("teen dies undergoing experimental gene therapy," washington post, september ) reminds us that "informed consent" is not sufficient to protect patients during research [ ] . the informed consent process has many flaws stemming from the frequent complexity of consent forms [ ] , poor comprehension of information by many families who must draw on their limited scientific culture to unravel complicated issues at a time when they are struggling with severe anxiety about their loved one [ ] , and dearth of communication skills among physicians. thus, informed consent to research may be stressful for families and reassuring for physicians. this was not its original purpose. to overcome these problems a reform allowing informed consent to be waived under specific circumstances has been suggested [ ] . although the opinions expressed by the advocates of this approach are worthy of respect, they conflict with the principle of patient autonomy [ ] . a similar wish is expressed by some european physicians who seem very anxious about the putative threat on medical research in emergency that a new european directive supposedly poses [ , , ] . indeed, this directive [ ] does not allow the waiving of consent by proxies. another contention of the present paper is this [ ] : critical care physicians may still believe that rcts remain the best tool for improving knowledge and care, and in this case they must accept to use the means needed to achieve the end and therefore to insist on mandatory informed consent from the patient or proxy; or they may realize that the game is not worth the candle and they must then turn to other forms of research that are ranked less highly in the pyramid of evidence-based medicine [ ] . in so doing they give priority to the well-being of families and must seek the help of innovative methodologists who accept to deal with the real world. before discussing the problem of informed consent to research a critical appraisal of the scientific and ethical validity of rcts in critical care medicine is in order. the role of rcts was overemphasized from the outset many critical care physicians believe in the superiority of rcts over other types of clinical studies. this belief may not be supported by the evidence. before discussing objective data on the value of rcts in critically ill patients it is important to recall a number of historical facts. rcts emerged in the s as a tool for overcoming the drawbacks of anecdotal experience. although rcts initially met with considerable resistance, they undoubtedly contributed to making clinicians aware of the need for rigorous methods. however, the data obtained proved only that rcts are feasible, not that they are superior over other forms of well-conducted studies. this is best illustrated by the trials of streptomycin in tuberculosis in the united kingdom and of the salk polio vaccine in the united states. streptomycin was discovered in in the united states. the british government could not afford to purchase streptomycin for all patients with tuberculosis, and the effectiveness of the drug was not yet established. the words of d'arcy hart [ ] , a member of the medical research council scientific staff that conducted the streptomycin trial, are worth quoting: "the trial proceeded from . the small amount of streptomycin available made it ethically permissible for the control subjects to be untreated by the drug-a statistician's dream." this gives the two reasons for the trial: fair allocation of a limited resource and the determination of a brilliant statistician, sir austin bradford hill, to prove the validity of rcts. d'arcy hart [ ] further stated: "secondly, the trial heralded the general conversion of clinical scientists to randomisation." shortly after this brilliant demonstration of the feasibility of rcts the salk polio vaccine trial was interpreted as a triumph of the new rct method in the united states. the unique circumstances surrounding the vaccine trial deserve mention [ ] : there was a raging scientific controversy between salk and sabin regarding the type of vaccine that should be developed (salk was developing a killed virus vaccine, whereas sabin thought that only an attenuated living strain could be a suitable vaccine), and salk was under considerable pressure to perform the trial, both to stop the polio epidemic that was costing so many lives among children and to win the race against sabin. for the trial children in a number of states were randomly allocated to receive the vaccine or a placebo. the results proved the vaccine dramatically effective. this both improved medical care and propelled the rct to prominence as the gold standard design for clinical research. however, an observational study was conducted in states that refused the placebo-controlled trial [ ] . the results were similar to those of the rct, but only the results from the rct were considered statistically valid [ ] . interestingly, salk described the placebo-controlled study of his vaccine as "a beautiful... experiment over which the epidemiologist could become quite ecstatic but (which) would make the humanitarian shudder" [ ] . it seems that this rct was driven by statisticians rather than by clinicians, in order to counter sabin's criticism and gain the support of the leaders of the medical community [ ] . in brief, rcts were performed because they could be performed, not because they had been proved superior over other study designs. the same may still hold true in critical care research today. what is the socioeconomic role of rcts? henry k. beecher, a professor in anesthesia research at the massachusetts general hospital commenting years ago on the huge increase in funds for research, said "there is reason to fear that... these resources may be greater than the supply of responsible investigators," and "every young man knows that he will never be promoted to a tenure post, to a professorship in a major medical school, unless he has proved himself as an investigator" [ ] . these two sentences acknowledge an uncomfortable reality: money and careers are at the center of clinical research. the importance of rcts for drug companies large rcts are vital for drug companies. these trials are mandatory not only for proving the efficacy of new products but also for obtaining regulatory approval and marketing licenses for drugs. thus drug companies have good reason to argue that rcts offer unequalled methodological purity. however, drug company sponsored trials of both hematology treatments and nonsteroidal anti-inflammatory drugs usually showed superiority of the new drug [ ] . this finding obviously violates the principle of equipoise, under which one would expect only one-half of the studies to find better outcomes with the new drug [ ] . a similar bias has been reported with other studies funded by the pharmaceutical industry and ascribed to the use of an inappropriate comparator or to publication bias [ ] . the importance of rcts for medical journals although the editors of major medical journals have recently warned against the threat to objectivity posed by some forms of industry-sponsored research [ ] and stated that "the use of clinical trials primarily for marketing makes a mockery of clinical investigation," the potential for disseminating pharmacological breakthroughs makes them likely to accept most of the industry-sponsored trials. the recent controversy on the efficacy and safety of activated protein c in sepsis highlights the difficulties faced by editors in this area [ , ] . the ties that link drug companies to investigators and to prestigious academic centers pose a worrisome threat to academic medicine [ ] . money from advertising may also weigh on editorial policies. methodologists and statisticians are consulted by drug companies and by independent investigators at the studydesign stage and by editors at the peer-review stage. they developed the rules of "methodological validity," and these rules are likely to be the same at each step of the design and publication of a clinical trial. the grading system for the quality of evidence from clinical research, with rcts at the top, is akin to a self-fulfilling prophecy: young researchers and renowned experts alike comply with these "golden" rules to ensure publication of their findings in a prestigious journal. this compliance with artificial rules is taken as firm evidence of validity, thus spinning the wheel endlessly. as stated by knottnerus and dinant [ ] , "finally, in using strict criteria in reviewing manuscripts for publication, we should worry about risk avoidance by clinical researchers. they might focus their energies on topics where the methodological criteria of reviewers and editors can be most easily met, rather than studying real life clinical problems which present substantial methodological problems." the adage "publish or perish" still applies. all these interests shared by drug companies, investigators, methodologists, and journals concur both to overproduction of rcts and to overestimation of their contribution to medical progress. rcts tend to become an uncontrolled activity driven by forces foreign to scientific goals. this results in an inextricable tangle of so-called evidence. then, meta-analyses are performed, supposedly to clarify an issue that has been artificially obscured. they may merely add to the confusion, as discussed below. how useful are rcts in critically ill patients? the validity of conclusions of earlier studies on hepatitis and cirrhosis has been evaluated by poynard and coworkers [ ] under the provocative title of "truth survival in clinical research: an evidence-based requiem." in this study the -year survival rate of conclusions derived from meta-analyses was lower ( %) than that from nonrandomized studies ( %) or rcts ( %). more importantly, the truth survival rate was similar for studies of high and low methodological quality. examination of three important areas of critical care further indicates that challenging the usefulness of rcts is not necessarily sacrilegious. the acrimony of the debate on these three topics in medical journals and at international meetings is a strong indicator that rcts fail to provide the "definitive" answer expected from them. these three topics are mechanical ventilation in adult respiratory distress syndrome (ards), selective digestive decontamination (sdd), and prevention of gastrointestinal bleeding. controversy erupted after publication of the findings of the ards network study on tidal volume reduction during ards. although this remarkable work showed that a low tidal volume of ml/kg predicted body weight resulted in better outcomes than a higher tidal volume of ml/kg [ ] , it did not tell us how to ventilate these patients. decreases in mortality [ ] and tidal volume [ ] over time occurred well before the study was initiated. patients are usually ventilated with tidal volumes that are intermediate between the two arms of the ards network trial (and probably closer to the lower volume). there is no rct telling us whether ml/kg is better than the - ml/kg generally reported in international surveys [ , ] . the results of this trial will encourage clinicians to use smaller tidal volumes, a practice that has not yet gained sufficient acceptance [ , , ] . in that sense this rct will prove useful, but not more useful than the earlier experimental, physiological, and nonrandomized clinical trials that resulted in the use of gradually decreasing tidal volumes over time [ ] . it is merely one more brick in the wall, and not a gold one. similarly, the results of the recent alveoli randomized study that compared two peep levels will probably not change current practice [ ] . in this study peep levels higher than the moderate values used in most surveys [ , ] did not improve patient mortality. finally, will the lack of effect of prone positioning on mortality in rcts [ ] discourage clinicians from using this very inexpensive and effective maneuver to improve patient oxygenation, and will these clinicians continue to await an rct providing "proof" of efficacy [ ] ? ards mortality rates have decreased substantially over the years [ ] and are probably declining further still, yet this improvement is ascribable not to rcts but to patient-oriented research based on sound physiological thinking [ , , , ] . selective digestive decontamination meta-analyses of rcts indicate a clear survival advantage with sdd [ , ] . however, sdd is seldom used because of the legitimate fear that this practice may promote the emergence of resistant bacteria [ , ] . how many studies will be needed to convince clinicians to use a method they do not want to use? or shall we wait until the "final" meta-analysis is "negative" and "proves" that clinicians were right when they refused to use sdd despite the accumulation of so-called evidence? few fields in critical care have generated as many rcts and meta-analyses. a recent meta-analysis concluded that sucralfate and ranitidine failed to prevent gastrointestinal bleeding in critically ill patients [ ] . the authors noted that a previous meta-analysis [ ] found reduced bleeding rates with h antagonists but included several positive trials of cimetidine, which has since then been superseded by drugs with better safety profiles. in addition, the use of proton-pump inhibitors seems to be increasing in critically ill patients, although there is no proof that this practice is beneficial. finally, no one knows whether prophylaxis should be given, and this uncertainty has recently been exacerbated by an observational study in , patients showing no difference in bleeding rates between a cohort of patients given prophylaxis and a subsequent cohort not given prophylaxis at the same institution [ ] . additional rcts may be needed if the obsessive goal is to discover the illusive "truth," but their drawbacks should be weighed against their utility. this paper does not claim that all rcts are useless in critically ill patients. rcts may be helpful for evaluating a single and simple intervention (even if this intervention is technologically sophisticated) in patients with a welldefined disease. this is obviously the case for acute coronary syndromes. however, many conditions seen in icu patients stem from extraordinarily complex pathophysiological mechanisms that preclude simple trial designs and interpretations [ ] . a typical example is the patient with ards and septic shock, multiple indwelling catheters, and a high risk of nosocomial respiratory and systemic infections. it is difficult to conceive of a single therapeutic intervention capable of improving such a complex situation. a further obstacle to studies on such an intervention is the highly heterogeneous nature of the icu population. these issues relate to the internal and external validity of a trial. methodologists seek to maximize the internal validity of rcts to decrease the effects of confounders. however, as internal validity increases, external validity (i.e., generalizability) decreases [ ] . this problem may exist for the ards network trial on tidal volume reduction [ ] . indeed, because extremely stringent inclusion criteria were used, only % of ards patients admitted to the participating centers were included in the trial [ ] . what ethical problems do rcts raise in critically ill patients? some rcts may conflict with currently accepted principles of medical ethics [ ] : beneficence, nonmaleficence, autonomy, and justice [ , ] . in addition, rcts may conflict with the principle that what is not scientific is not ethical. it is of course difficult if not impossible to determine a priori that a research protocol has a favorable risk-benefit ratio. however, rcts should rest on a foundation of strong experimental or clinical concepts. this may not have been the case in all instances, most notably in studies of new treatments for sepsis [ ] . without seeking to fuel the debate on the failure of antimediator agents in sepsis, one cannot but wonder whether the huge financial and academic stakes were in part responsible for the apparent haste with which some trials were conducted. in addition, the quality of research oversight in several trials with high mortality rates has been challenged [ ] . it is difficult to ensure that the prerequisites for beneficence and nonmaleficence are met when there is a major influence of financial incentives and academic competition. thus we still encounter problems similar to those met by the salk vaccine trial: the process of virus inactivation was not fully mastered at all the vaccine production sites, and therefore active virus was inoculated into a number of children in whom poliomyelitis developed (http:// www.pbs.org/wgbh/aso/databank/entries/dm sa.html, accessed july ; http://www.polio-vaccine.com/fr/ histoire/vaccins_experience.html, accessed july ). another aspect of beneficence and nonmaleficence that does not seem well addressed during the conduct of rcts concerns proxies and are discussed below. most critically ill patients are too ill to deal with issues of consent. consent is therefore sought from a surrogate in the united states and most european countries. consent by a surrogate is usually considered the best means of protecting patients during research [ , ] , although studies have shown that the decisions made by surrogates do not always reflect the wishes of patients [ , ] . however, some states in the united states either do not accept surrogate consent for research or authorized this form of consent only after the end of the ards network study [ ] . in addition, mistrust is gaining ground in the public at large, and organizations such as the alliance for human research protection (ahrp), whose stated goal is to ensure that human rights are protected during research (http://www.researchprotection.org, accessed july ) , are opposed to surrogate consent. the ahrp contributed to drive the inquiry of the office for human research protection on the ards network trials [ ] . surrendering the principle of autonomy to the principle of beneficence is ethically acceptable only when there is a reasonable certainty of nonmaleficence. this degree of certainty is not usually obtainable, as discussed above. tremendous amounts of money are invested in clinical research, in principle in the best interest of patients. the above words of beecher [ ] on the discrepancy between the abundance of funds and the scarcity of responsible investigators deserve careful consideration. financial resources for healthcare and for research are limited [ ] , and their fair allocation is both a political and an ethical imperative. because rcts are far more expensive than observational studies [ ] , they should provide answers that cannot be given by observational studies. although the impressive work conducted by the ards network investigators is worthy of respect, its failure to achieve this goal must be acknowledged. millions of dollars were spent [ ] , but, as discussed above, this study [ ] is merely one among several (including physiological and observational studies [ ] ) showing that patients should be ventilated with less than ml/kg body weight. in addition, it failed to determine whether volumes smaller than the - ml/kg noted in observational studies should be used [ , ] . similarly, the alveoli trial [ ] randomized a large number of patients but simply ruled out a need for peep levels higher than those in observational studies [ , ] . what have these multimilliondollar trials contributed? in the words of the belmont report [ ] , "the term 'research' designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge." it is usually assumed that a nonscientific trial is unethical. but how generalizable are the data generated by rcts with excellent internal validity but limited external validity? as mentioned above, what makes the greatest contribution to clinical practice regarding the prevention of gastrointestinal bleeding in icu patients: "discordant" metaanalyses of multiple rcts [ , ] or a well conducted cohort study [ ] ? the informed consent dilemma this is a major ethical issue. as brilliantly discussed by several authors, informed consent by a proxy is a key safeguard for patients eligible for clinical trial inclusion [ , , ] . however, proxies may not consistently make the same choices as the patients or correctly interpret their best interests. in addition, the consent process can impose considerable suffering on the proxy. however, investigators are encouraged to disseminate the results of their work to the study participants [ ] , which is laudable. after the death of a loved one, a proxy might learn, for instance, that he or she consented to a clinical trial in which mortality was higher in the treatment arm. in that sense informed consent probably protects the icu patient and the physician in charge of the research project but not the proxy who is asked to provide consent. anxiety in patients asked to give their "full informed consent" to a study of a life-threatening disease has received attention [ ] . it has been rightly pointed out that this form of consent may be needlessly cruel [ ] . the same may hold true of "full informed consent" given by a proxy for a loved one. everyday practice teaches that proxies are highly vulnerable to distress and guilt when they are asked to provide consent to care for a critically ill patient (e.g., to a high-risk therapeutic procedure in a desperately ill patient). families of icu patients often exhibit major signs of anxiety and depression [ ] . the information that they receive in the name of the principle of autonomy may conflict with the principles of beneficence and nonmaleficence when proxies are asked to consent to research rather than to care. the primary focus of informed consent is risk disclosure [ ] , and the informed consent dilemma can be summarized as follows: if the consent form is to be reassuring for the family, it must fall short of providing honest information, and if the consent form is to be honest, as commendably proposed by the ards network investigators [ ] , it must supply information that is distressing to the family. surprisingly, most physicians fail to recognize that evaluation of the riskbenefit ratio, considered a requisite for ethical research [ ] , should not focus solely on the patient. the emotional risk to proxies should be balanced against the putative benefit (and risk) for the patient included in the rct [ ] . otherwise, proxies may be subjected to stress whose harmful effects exceed by far the objective benefits the patient may derive from participating in the study. does it make ethical sense to distress family members by asking them to consent to yet another study on sdd or on the prevention of gastrointestinal bleeding? informed consent documents and information sites for families of critically ill patients are sometimes so frightening that perhaps the door to the icu should bear the words inscribed on the gate to hell in dante alighieri's inferno (la divina commedia): "lasciate ogni speranza, voi ch'entrate!" ("abandon all hope, ye who enter here!"). two categories of solutions may be considered. some require no important qualitative changes in the system that governs clinical research but simply a tightening of research oversight procedures [ , , ] . other solutions would require a reshaping of many parts of the system, including the financial and academic incentives to publication, as well as a number of methodological dogmas. these two categories of solutions are not mutually exclusive. they both seek the best compromise between conflicting principles to protect the rights of patients and proxies and to improve scientific knowledge and quality of care, but not at the expense of scientific or ethical distortions. solutions that do not require significant changes in the system the protection of subjects who are unable to give or refuse consent must receive particularly close attention. there is little doubt that waiving of the requirement for consent should be reserved for highly unusual situations [ ] , which are described in detail in the united states code of federal regulations for the protection of human subjects [ ] . this text allows some forms of research in emergency situations without consent from the patient or surrogate provided certain conditions are met, including: the disorder is immediately life-threatening, available treatments are unsatisfactory, obtaining consent is not feasible, the research could not be carried out without the waiver, participation in the study holds the prospect of direct benefit, and the waiver of consent is given by an institutional review board. the situation is less clear in europe where research in emergency medicine can be performed without consent in some countries (including france) but not in others [ ] . however, the european parliament and council have issued a new directive that forbids research without consent, even in emergencies [ ] . this directive has been criticized as a serious potential threat to research in emergency situations [ , , , ] . before examining the magnitude of this threat, one must acknowledge the risk of overuse or abuse of waiving consent for emergency research in critically ill patients [ , ] . as recently argued by john luce, "few patients face true emergencies.... for example... studies of new modes of mechanical ventilation, novel therapies for sepsis... have a relatively long therapeutic window during which obtaining consent from patients or surrogates may be possible" [ ] . for research on true emergencies (e.g., treatment of cardiac arrest, acute brain injury) in the european union the directive and/or the research modalities will have to be modified, as discussed below. a strong argument that waiving consent may be appropriate for some rcts was put forward by truog and coworkers [ ] . they base their position on the frequently poor comprehension of the rct process and of informed consent documents by patients or surrogates. a waiver of consent could be obtained from an institutional review board provided the treatments offered in the trial are available outside the trial without the need for consent, the study carries only minimal additional risk, genuine equipoise exists among the studied treatments, and no reasonable person should have a preference for one treatment over any other. in the letters published in response to this thoughtful paper, the risk of jeopardizing patient autonomy was the principal argument against the contention by truog et al. [ ] . interestingly neither truog et al. nor their detractors questioned the validity of the opinion that governed their debate, namely, that rcts are useful under these special conditions. this is discussed below. solutions that require significant changes in the system from the above it clearly appears that the debate on informed consent to research stems primarily from two axioms that can be questioned: care and research are two separate activities, and rcts are superior to other forms of clinical research. investigators should acknowledge that they cannot have their cake and eat it too: they cannot both enjoy the putative methodological advantage of an rct and carry out their study without obtaining informed consent. consent is inherent in the rct process because it is needed to ensure compliance with basic ethical principles, most notably the principle of autonomy. except in the rare cases of true emergencies (see above), there is no obvious ethical justification of waiving consent to rcts. therefore if we want critical care to continue its amazing progress, we must rethink our research policies. first, the limited role (if any) of rcts in this progress must be acknowledged. second, the formal distinction between care and research must be reappraised. third, current methodological dogma must be challenged. as stated by miller and rosenstein [ ] in an article focusing mainly on rcts, "medical care is characterized by a convergence of the doctor's interests and the patient's interests.... by contrast, in clinical trials, the principal interests of the investigator and the participating patient may diverge." as mentioned above, the distinction between care and research was first made in the belmont report [ ] and should not be dismissed except in specific circumstances. critical care may be one of these circumstances, given the consensus that "there is instead a spectrum that extends from established, evidence-based interventions through unproved therapeutic innovations to formal rcts", as underlined by truog and colleagues [ ] in their response to the abundant correspondence generated by their publication [ ] . it is important to bear in mind that most if not all of the debate on the therapeutic misconception concerns the distinction between care and rcts [ , ] . this distinction is obviously valid. however, clinical research can also have an integral role in clinical care [ ] , most notably when the interventions are not allocated at random. this offers an opportunity for reconciling the interests of the patients and those of the physicians, provided adequate methodological changes are implemented. vandenbroucke and de craen [ ] wrote that "sometimes we accept the evidence from the randomized trial and overturn a theory-however beautiful it was-but at other times we stick with the theory and dismiss the evidence." there is no inviolable scientific reason to prefer rcts and their mandatory informed consent procedure to the well-being of patients and their proxies. there is, however, a moral obligation to improve the quality of critical care. therefore alternative methodological approaches that protect both the welfare and the autonomy of patients should be given preference. these approaches should "find ways of accommodating clinical reality, not ignoring it" [ ] , and should require acknowledgement that rcts can produce inconsistent results and can have limited external validity [ , ] . investigators will have to stop their obsessive quest for the so-called "absolute truth that can be given only by rcts" and acknowledge the subjective element in the evaluation of science [ ] . as underlined by jerome cornfield (inventor of both the odds ratio and logistic regression; cited in [ ] ), "good scientific practice... places the emphasis on reasonable scientific judgement and the accumulation of evidence and not on dogmatic insistence of the unique validity of a certain procedure." it is astonishing that physicians pressure institutional review boards (irbs) to accept waivers of consent and zealously lobby for changes in regulations that they feel may "impede research" [ , ] without questioning the validity of the diktats issued by a number of methodologists and journal editors. the real problem is not to obtain a waiver of consent to rcts from patients or proxies: the consent that we need is that of methodologists, from whom we seek creative study designs, and of medical journal editors, from whom we ask for greater openness to contributions that are less highly ranked in the pyramid of evidence-based medicine [ ] . trials with prerandomization. this design was introduced by zelen [ ] . patients are randomly preallocated to the conventional or new treatment before they are asked to consent to the study. in the patients allocated to the control arm no specific consent to research need be obtained. in contrast, informed consent is sought from the patients (or proxies) in the group allocated to the new treatment; when consent is refused, the patient receives the conventional treatment. this appealing design requires unblinded treatment administration, which is the case in many trials in icu patients (most notably on procedures). it has been used in pediatric trials of extracorporeal membrane oxygenation [ , ] . prerandomization may increase patient inclusion rates. studies have calculated the "price of autonomy," that is, the number of lives that may be lost if the inclusion rate is slower because prerandomization is not used, resulting in delayed implementation of a life-saving treatment [ , ] . however, ethical objections to prerandomization [ ] include denial of information, using people, denial of choice, and "overselling" of allocated treatments [ ] . observational studies. well-conducted observational cohort and case-control studies can provide the same level of internal validity as rcts [ , , ] . they are particularly well suited to research in the icu. indeed, as mentioned above, blinding is neither necessary nor feasible for most therapeutic interventions in the icu. in fact most of the major recent rcts were unblinded [ , , , , , , ] . why not evaluate new therapeutic interventions sequentially under conditions of genuine equipoise? in such conditions, rather than a detailed explanation of the randomization process, "such an elegant, reliable, sophisticated concept to the research clinician, but so brutal and harsh from the patient's view point" [ ] , only consent to general care [ ] and to the use of data obtained during usual patient care for research purposes [ ] would need to be obtained. renunciation of rcts in favor of observational studies does not imply that physicians have a free hand on their patients. irb approval and close monitoring of data quality and patient safety would still clearly be needed. in addition, cohort studies are probably the only option left for emergency research when legislation prohibits the waiving of consent, as may unfortunately become the case in the european union within the next few years [ , ] . interestingly, this approach was used in a recent study of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation [ ] . the cohort design deserves to be considered before the alarm is sounded for the questionable reason that research in emergencies may stop if rcts are no longer feasible [ , ] . these are among the most dangerous studies, as recently shown by the results published for several new drugs in icu patients [ ] . furthermore, by definition there is a risk of major conflicts of financial interest. it follows that patient protection should receive particularly careful attention, and that the studies must be completely free of potential methodological weaknesses and ethical flaws. clearly such studies must be randomized (which is mandatory anyway for obtaining regulatory approval). in addition to a thorough review of the research protocol by a completely independent irb, unblinded monitoring of adverse effects should be conducted, as recently suggested by freeman and coworkers [ ] . finally, the informed consent document should provide detailed information and receive careful scrutiny by the irb. for instance, a fair informed consent document on new therapies for sepsis should explain what physicians know, namely, that the pathophysiology of sepsis is incom-pletely understood, and that the animal models on which the clinical trial is based are not fully valid [ ] . in addition, if another new treatment was associated with increased mortality rates in other studies [ ] , this fact should be disclosed. finally, the amount of money received by the physicians or their institution per patient included should be indicated, as well as any financial interests linking the physicians to the drug company (e.g., shares owned or position as paid consultants), as suggested by organizations such as the alliance for human research protection (http://www.researchprotection.org/informedconsent/informedconsent.html, accessed july ). patient autonomy should not stop where potential financial profit begins. as pointed out by luce [ ] , stronger research oversight may be as important as informed consent in protecting patient welfare. since we contend that, provided investigators desist from performing rcts, formal consent to research need not be sought and consent to care and to the use of data is the rule, it also holds that research oversight must be reinforced [ , , , ] . research projects that do not require specific informed consent should be examined thoroughly by irbs, which should obtain the opinions of independent consultants if needed. the primary goal is not to make research easier for physicians but to increase the safety of patients and proxies. if greater ease of research occurs as a side effect, this will be welcome. in conclusion, rcts were born under a shroud of original sin consisting of financial, political, and academic pressure. this was summarized by yoshioka [ ] in a publication about the medical research council trial on streptomycin: "the innovation of centrally controlled randomisation can be attributed to a combination of scientific logic and political and social pressures on medical bureaucracy." this sin may have remained unredeemed, as suggested by the extraordinary controversy about the ards network study [ , ] . before deciding which clinical study design is best suited to critically ill patients, consideration should be given to several points: -many rcts in critical care generated heated pro-con debate during medical conventions yet failed to improve patient care. -respect for patients and their families requires that investigators refrain from using a plethora of informed consent documents which constitute a perversion of ethical principles but rather wield this two-edged sword with discernment. -clinical trials should be conducted not to achieve methodological purity but to improve patient management. -in clinical trials the best possible compromise should be sought between the ethical principle of beneficence to the patient and that of nonmaleficence to the proxy, who is asked to give consent while struggling with overwhelming distress. -clinical trials should be appraised according to the ethical principle of distributive justice: what cost for what result? -society is changing and may no longer be ready to accept what many persons may consider, rightly or wrongly, to be a manifestation of medical power. the effects of the aids epidemic on patient mentalities and the growing influence of organizations such as ahrp should be pondered. similarly, owing to widespread public concern about the adequacy of protection for human research subjects, litigation against investigators, irbs, and academic institutions is becoming increasingly common [ ] . then, nolens volens, clinicians may have to forbear conducting rcts for ethical, scientific, sociological, legal, and financial reasons. one solution may consist in giving preference to forms of clinical research that are tightly linked to care. clinicians should work closely with innovative methodologists to find new designs that are acceptable to all. clinicians serve patients. and methodologists serve clinicians, not the opposite. national commission for the protection of human subjects of biomedical and behavioral research ( ) belmont report: ethical principles and guidelines for the protection of human subjects of research. united states government printing office unraveling the tuskegee study of untreated syphilis the therapeutic orientation to clinical trials the integral role of clinical research in clinical care is informed consent always necessary for randomized, controlled trials? what makes clinical research ethical readability standards for informed-consent forms as compared with actual readability symptoms of anxiety and depression in family members of intensive care unit patients: ethical hypothesis regarding decisionmaking capacity is informed consent always necessary for randomized, controlled trials? non-therapeutic research in the eu in adults incapable of giving consent? a european directive for clinical research implications of the eu directive on clinical trials for emergency medicine directive / /ec of the european parliament and of the council to consent or not to consent, that is (not) the (sole) question evidence-based medicine. a new approach to teaching the practice of medicine a change in scientific approach: from alternation to randomised allocation in clinical trials in the s a calculated risk": the salk polio vaccine field trials of essai clinique. in: lecourt d (ed) dictionnaire de la pen-sØe mØdicale ethics and clinical research alternative medicine: a "mirror image" for scientific reasoning in conventional medicine pharmaceutical industry sponsorship and research outcome and quality: systematic review sponsorship, authorship, and accountability risks and benefits of activated protein c treatment for severe sepsis assessing the use of activated protein c in the treatment of severe sepsis is academic medicine for sale? medicine based evidence, a prerequisite for evidence based medicine truth survival in clinical research: an evidence-based requiem? ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome improved survival of patients with acute respiratory distress syndrome evidence-based medicine or fuzzy logic. what is best for ards management? characteristics and outcomes in adult patients receiving mechanical ventilation: a -day international study epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals are we really reducing tidal volume-and should we? barriers to providing lung-protective ventilation to patients with acute lung injury higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome effect of prone positioning on the survival of patients with acute respiratory failure intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats improved prognosis of acute respiratory distress syndrome years on searching for evidence: don't forget the foundations effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials selective digestive decontamination: for everyone, everywhere? selective decontamination of the digestive tract and its effect on antimicrobial resistance prevention of hospital-associated pneumonia and ventilator-associated pneumonia bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials stress ulcer prophylaxis in critically ill patients. resolving discordant meta-analyses clinically significant gastrointestinal bleeding in critically ill patients with and without stress-ulcer prophylaxis clinicians' approaches to mechanical ventilation in acute lung injury and ards the price of autonomy principles of medical ethics why immunomodulatory therapies have not worked in sepsis safeguarding patients in clinical trials with high mortality rates is the concept of informed consent applicable to clinical research involving critically ill patients? ethical considerations for research in critically ill patients do surrogate decision makers provide accurate consent for intensive care research? california's new law allowing surrogate consent for clinical research involving subjects with impaired decision-making capacity suspension of the nih ards network fluids and catheters treatment trial control group selection in critical care randomized controlled trials evaluating interventional strategies: an ethical assessment beyond randomised versus observational studies how best to ventilate? trial design and patient safety in studies of the acute respiratory distress syndrome informing clinical trial participants about study results bmj's present policy (sometimes approving research in which patients have not given fully informed consent) is wholly correct fully informed consent can be needlessly cruel influence of the law on risk and informed consent recommendations for informed consent forms for critical care trials. abstracts improving protection for research subjects protecting subjects with decisional impairment in research: the need for a multifaceted approach protection of human subjects: informed consent and waives of informed consent requirements in certain emergency research. final rules. title , code of federal regulations the european union directive and the protection of incapacitated subjects in research: an ethical analysis the effect of waiving consent on enrollment in a sepsis trial is informed consent always necessary for randomized controlled trials? a new design for randomized clinical trials extracorporeal circulation in neonatal respiratory failure: a prospective randomized study extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study informed consent. numbers inform the debate zelen randomization: attitudes of parents participating in a neonatal clinical trial should zelen prerandomised consent designs be used in some neonatal trials a comparison of observational studies and randomized, controlled trials randomized, controlled trials, observational studies, and the hierarchy of research designs a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. transfusion requirements in critical care investigators, canadian critical care trials group a trial of goal-oriented hemodynamic therapy in critically ill patients. svo collaborative group early goal-directed therapy in the treatment of severe sepsis and septic shock intensive insulin therapy in the critically ill patients improving the process of informed consent in the critically ill patients' consent preferences for research uses of information in electronic medical records: interview and survey data efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial ethics, science, and oversight of critical care research: the office for human research protections use of randomisation in the medical research council's clinical trial of streptomycin in pulmonary tuberculosis in the s metaanalysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes the rise of litigation in human subjects research key: cord- -uk wzk m authors: bachmann, d. c. g.; pfenninger, j. title: respiratory syncytial virus triggered adult respiratory distress syndrome in infants: a report of two cases date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: uk wzk m two infants with severe respiratory syncytial virus infection which resulted eventually in classical adult respiratory distress syndrome (ards) are presented. both infants had severe apneic spells, necessitating intubation and mechanical ventilation (mv). chest radiographs changed after a few days after institution of mv from initial bronchopneumonia like pattern to severe ards. assessment of respiratory system mechanics (single breath occlusion technique) revealed severe restrictive disease in both cases. the first patient recovered with residual restrictive changes determined during a follow-up . months later, whereas the second infant died because of ards, pulmonary interstitial emphysema and hypoxemic hypoxia. respiratory syncytial virus (rsv) is the single most frequent cause of acute viral infections of the lower respiratory tract in infants and young children [ ] . the clinical manifestations of rsv infections range from upper respiratory tract infection (rhinitis, otits media) to more serious involvement of lower airways and pulmonary parenchyma (bronchiolitis, pneumonia). there are data linking infection by this agent in early life and persistent obstructive lung disease [ ] . during the winter / we treated two infants in whom rsv infection triggered severe adult respiratory distress syndrome (ards). because of the scarcity of this complication we report the two cases. case a . -month old female infant was admitted to our icu because of fever, cough and severe apneic spells. the infant had been born after correspondence to: d. c.g. bachmann weeks of gestation and had suffered from mild neonatal respiratory distress syndrome, responding to supplemental oxygen. because of severe repeated apnea endotracheal intubafion was performed and mechanical . ventilation (mv) started. initial respiratory settings and arterial blood gases after stabilisation can be seen in table (day ). chest radiographs were suggestive of viral pneumonia, and rsv was demonstrated in nasopharyngeal secretions (antigen and culture positive). from day and onward the chest radiograph showed progressively typical signs of ards [ ] and respirator settings had to be increased considerably. assessment of respiratory system mechanics by the single breath occlusion method [ , ] revealed extremely severe restrictive changes (see table ). (for the physiological measurements the patients were supine and kept paralysed with either pancuronium or atracurium. at least measurements were performed not differing more than %. mean values are reported, and normal values are indicated at the bottom of table ). respiratory compliance (crs) started to improve on day , but respiratory system resistance (rrs) deteriorated. for this reason a trial bronchodilation with salbutamol was started on day with a net reduction of rrs from . - . cmh /ml/s and an increase of crs from . - . ml/cmh /kg [ ] . rapid weaning from the respirator was possible on the following days and extubation was performed on day . supplemental oxygen was stopped days later and salbutamol by inhalation on day . after discharge home the infant was seen . months after onset of ards for a follow-up: physical examination revealed normal psychomotor and somatic development and no abnormal respiratory signs except for slight tachypnea of /rain. transcutaneous oxygen saturation (stco ) was % in room air, capillary pco was mmhg. chest radiography showed mild increase of interstitial structures. repeated study of crs and rrs using same technique as before (i.e. after tracheal intubation) revealed moderate to severe restrictive changes, resistance however had improved (see table ). forced vital capacity using the deflation technique was ml/kg (normal - ml/ kg). a one-month-old, previously healthy male infant born at term was admitted to our icu because of cough, fever and severe apneic spells. he underwent emergency endotracheal intubation and mv was started [initial respirator settings and arterial blood gases (day t) can be seen in table ]. chest radiographs showed a mixture of pulmonary infiltrates, atelectasis and overinflation on both sides (see fig. ). viral pneumonia was suspected and eventually confirmed by demonstrating rsv in the tracheo-bronchial aspiration material. chest radiographs from day and onward showed classical signs of ards (see fig. ). assessment of respiratory system mechanics on day by single breath occlusion technique gave severe restrictive changes (see table ). in the following days a normal values: crs . - . ml/cmh /kg; rrs . - . cmh /ml/s mawp, mean airway pressure; peep, positive end-expiratory pressure; pip, plateau inspiratory pressure radiographic signs of ards worsened, and in addition pulmonary interstitial emphysema (pie) was evident. in order to minimise further iatrogenic lung injury inspiratory pressures were reduced, accepting high paco levels. on day poor respiratory mechanics were confirmed, and on the following day gas exchange worsened further. in this desperate situation a trial with high frequency ventilation was started, but the boy was critically dependent on high mean airway pressure (mawp) and fio . he died on day i due to refractory hypoxemic hypoxia. post-mortem lung biopsy was performed which showed a denudation of alveolar basement membranes, hyaline membrane formation, type ii pneumocyte and septal fibroblast proliferation. in addition there were signs of alveolitis with occasional multinucleated epithelial giant cells (syncytia). . apnea is one of the leading symptoms and is observed in approximately ~ of infants hospitalised for primary rsv infection [ ] . only two cases of rsv triggered acute hypoxemic failure ("ards") have been described in the literature [ ] , we report two additional cases with particular emphasis on respiratory system mechanics. it is of interest to note that both infants did not belong to a particular risk group (bronchopulmonary dysplasia, congenital heart disease etc.). ards is the manifestation of direct or indirect pulmonary injury with alveolo-capillary disruption, permeability pulmonary edema, hypoxemia and reduced compliance. our two patients with clearly documented rsv infection fulfilled the classical criteria of severe ards for infants and children as reported by pfenninger et al. [ ] , both had high lung injury scores as published by murray et al. (case : . , case : ) [ ] . few data are available on respiratory system mechanics in ards in the pediatric age group. stretton et al. using the same technique as in the present cases, reported mean crs values of . ml/cmh /kg in severe cases, with minimally increased rrs in the acute stage of the syndrome [ ] . these findings are slightly better than those in our two patients who had minimal mean crs of . ml/cmh /kg. as stated initially, rsv may lead to chronic obstructive pulmonary disease [ ] . in this respect it is interesting to note that patient showed transiently elevated rrs, beginning on day and responding to salbutamol. this finding is indicative of small airways hyperactivity. by its beta- -activity salbutamol decreased airway resistance and improved crs most likely by recruitment of lung volume [ ] . this infant had nearly normal rrs and still considerably reduced crs . months after ards. fanconi et al. have shown in children surviving severe ards that all had long-standing abnormal lung function [ ] . in conclusion two well-documented cases of rsv induced infantile ards are described. whereas the first infant survived with long-standing pulmonary abnormalities, the second died due to severe pulmonary involvement and pie. it remains unclear, if by early institution of antiviral treatment or extracorporeal membrane oxygenation the severity of the disease and outcome would have been modified [ , ] . acute lower respiratory tract infection in nonhospitalized children longterm prospective study in children after respiratory syncytial virus infection adult respiratory distress sydnrome in children passive respiratory mechanics in newborns and children lung mechanics and gas exchange in ventilated preterm infants during treatment of hyaline membrane disease with multiple doses of artificial surfactant (exosurf) respiratory response to salbutamol (albuterol) in ventilator-dependent infants with chronic lung disease: pressurized aerosol delivery versus intravenous injection apnea assoicated with respiratory syncytial virus infection in young infants acute hypoxemic respiratory failure in infants and children: clinical and pathologic characteristics an expanded definition of the aduk respiratory distress syndrome spirometry, lung volumes, flows and mechanics in the acute phase of ards in pediatric patients longterm sequelae in children surviving adult respiratory distress syndrome an rsvp to rsv (respiratory syncytical virus): declining mortality rates extracorporeal life support for pediatric respiratory failure key: cord- -hmv jjfl authors: peters, m. j.; tasker, r. c.; kiff, k. m.; yates, r.; hatch, d. j. title: acute hypoxemic respiratory failure in children: case mix and the utility of respiratory severity indices date: - - journal: intensive care med doi: . /s sha: doc_id: cord_uid: hmv jjfl objective: acute hypoxemic respiratory failure (ahrf) is a common reason for emergency pediatric intensive care. an objective assessment of disease severity from acute physiological parameters would be of value in clinical practice and in the design of clinical trials. we hypothesised that there was a difference in the best early respiratory indices in those who died compared with those who survived. design: a prospective observational study of consecutive ahrf admissions with data analysis incorporating all blood gases. setting: a pediatric intensive care unit in a national children’s hospital. interventions: none. results: mortality was / , % ( % confidence interval – %). there were no significant differences in the best alveolar-arterial oxygen tension gradient (a-ado( ), torr), oxygenation index (oi), ventilation index (vi), or pao( )/fio( ) during the first days of intensive care between the survivors and non-survivors. only the mean airway pressure (map, cm h( )o) used for supportive care was significantly different on days and (p≤ . ) with higher pressure being used in non-survivors. multiple logistic regression analysis did not identify any gas exchange or ventilator parameter independently associated with mortality. rather, all deaths were associated with coincident pathology or multi-organ system failure, or perceived treatment futility due to pre-existing diagnoses instead of unsupportable respiratory failure. when using previously published predictors of outcome (vi> and oi> ; a-ado( )> for h; a-ado( )> or map> ; or a-ado( )> ) the risk of mortality was overestimated significantly in the current population. conclusion: the original hypothesis was refuted. it appears that the outcome of ahrf in present day pediatric critical care is principally related to the severity of associated pathology and now no longer solely to the severity of respiratory failure. further studies in larger series are needed to confirm these findings. ( % confidence interval - % ). there were no significant differences in the best alveolar-arterial oxygen tension gradient (a-ado> torr), oxygenation index (oi), ventilation index (vi), or pao /fio during the first days of intensive care between the survivors and nonsurvivors. only the mean airway pressure (mar cm h;o) used for supportive care was significantly different on days and i (p _< . ) with higher pressure being used in non-survivors. multiple logistic regression analysis did not identify any gas exchange or ventilator parameter independently associated with mortality. rather, all deaths were associated with coincident pathology or multi-organ system failure, or perceived treatment futility due to pre-existing diagnoses instead of unsupportable respiratory failure. when using previously published predictors of outcome (vi > and oi > ; a-ado > for h; a-ado > or map > ; or a-ado > ) the risk of mortality was overestimated significantly in the current population. conclusion: the original hypothesis was refuted. it appears that the outcome of ahrf in present day pediatric critical care is principally related to the severity of associated pathology and now no longer solely to the severity of respiratory failure. further studies in larger series are needed to confirm these findings. acute hypoxemic respiratory failure (ahrf) remains a common reason for emergency pediatric intensive care. even with currently available ventilatory support it re-tains a significant morbidity and mortality with one subgroup, those with acute respiratory distress syndrome (ards), having a mortality rate of - % [ ] [ ] [ ] [ ] [ ] [ ] . however, it has also been suggested that much lower mortalities (< %) may occur in specific conditions such as respiratory syncytial virus-related ards [ ] . in this setting, promising new interventions, including permissive hypercarbia, exogenous surfactant, inhaled nitric oxide, high frequency oscillatory ventilation, extracorporeal membrane oxygenation and perfluorocarbon-assisted gas exchange have been described with the purpose of 'rescuing' potential survivors from severe pathology. in order to evaluate effectively such therapies, clinical trials have adopted assessments of disease severity for patient recruitment. such an approach is based on the hypothesis that the initial magnitude of acute severe physiological derangement equates with subsequent mortality. thereby warranting the experimental intervention as well as providing a measure for verifying the similarity between treatment patients and control patients. our experience from a retrospective study of children with severe ahrf [ ] questioned the usefulness of the previously reported respiratory predictors of outcome [ ] [ ] [ ] [ ] . rather, in common with sarnaik and colleagues [ ] , who found in their pediatric study that response to an intervention better predicted intensive care outcome, we reported that greater improvement in oxygenation to an intervention (a standard dose of inhaled nitric oxide) was associated with improved outcome [ ] . this suggests that with current clinical expertise, a test of potential ventilation-perfusion mismatch, shunt and lung injury reversibility is a more appropriate predictor of outcome than the status prior to any intervention. in an individual patient, such a response to intervention should be indicated by their best, rather than worst, measure of gas exchange, therefore, the purpose of the present prospective, single institution study of ahrf in children was to assess whether the best, early respiratory indices in non-survivors were significantly different from those who survived. approval for this observational study was obtained from our institution's ethics committee and patient data was stored according to the requirements of the data protection act. between august and march , all children older than month and less than years of age admitted to our pediatric intensive care unit (picu) were eligible for inclusion in this prospective study. inclusion criteria were modified from the american-european consensus conference diagnostic criteria for ards [ ] : a) acute onset of respiratory failure over less than h, b) evidence of a severe defect in oxygenation (arterial oxygen tension to fraction of inspired oxygen ratio (pao /fio ) of less than mmhg) for at least six consecutive hours on the day of picu admission, c) no evidence of left atrial hypertension and d) four quadrant interstitial shadowing on chest x-ray. children without the characteristic chest x-ray appearances of ards, but meeting the other criteria for ards, were described as cases of ahre details of the patients' acute diagnoses as well as any underlying conditions were recorded. an electronic patient charting sys-tem (carevue, hewlett packard) was reviewed daily and ventilator and physiological parameters recorded and stored on a separate data base. every blood gas analysis performed throughout the patients' admissions was reviewed and the oxygenation index (oi = mean airway pressure (map) x fio /pao ) , alveolar-arterial oxygen tension gradient (a-ado ), pao /fio ratio and ventilation index (vi = respiratory rate x paco x peak inspiratory pressure / ) were calculated for each blood gas measurement. analyses carried out used the best value obtained over the period under assessment. for the comparison with previously reported studies [ ] [ ] [ ] [ ] every blood gas was reviewed and the respective study criteria applied for patient selection. the ventilatory strategy employed in these patients was one of permissive hypercarbia (target pao _< kpa, provided ph > . ) with limitation of peak inspiratory pressure (< cmh ) while employing high maps to ensure maximum lung volume recruitment via the use of peak end expiratory pressure and inverse inspiratory : expiratory ratios. high frequency oscillatory ventilation was employed if oxygenation was inadequate with a map of cmh or greater. the use of inhaled nitric oxide therapy throughout the last months of the study was controlled by an institution approved multi-center randomisation protocol. extracorporeal membrane oxygenation was employed when no stability could be achieved with the above techniques. death or survival to discharge from the picu were the end points of the study. in children who died, the mode of death was recorded: failed resuscitation, limitation or withdrawal of support or brain death. the clinical course of patients with ahrf was categorised according to the severity of disrupted gas exchange and whether or not improvement occurred within days. the data were stored in a microsoft access . data base and analysed with microsoft excel . and statistical software (statistical package for social sciences . , spss inc.). comparisons between non-survivor and survivor data were performed with an independent sample t-test after transformation to normality if required. multiple logistic regression analysis was performed against survival for a range of respiratory parameters from days , and in those patients with available data for those days. parameters found to be significant in the univariate analysis were tested as well as those indices previously suggested to be associated with outcome from ards or ahrf [ ] [ ] [ ] [ ] . in addition, age, weight, multi-organ system failure (mosf) score [ ] and the presence of underlying immunodeficiency were also tested in the model. beta coefficients from significant independent predictors were converted to adjusted odds ratios with % confidence intervals. comparison with published series [ ] [ ] [ ] [ ] included a meta-analysis of reported results, calculation of the likelihood ratio for a positive test resuit, and the two-sample test for proportions. out of admissions to the picu, patients were admitted with ahrf over the months of the study. the median age was months (range - months), and weight . kg ( - kg). the median length of picu stay was days (range - days). the picu mortality was / , % ( % confidence interval - % ) in the non-ahrf cases, and significantly greater in the ahrf cases, / , % ( - %, p< . ). one patient with ahrf died within h of admission, having been inappropriately intubated and resuscitated: since treatment was limited from the time of admission, his respiratory indices data were excluded from analysis. fifty-two children who fulfilled the full criteria for ards in addition to ahrf had a significantly higher mortality in comparison to the non-ards, ahrf patients: . % ( / ) and . % ( / ), respectively (p < . ). the ventilatory strategy in these patients is reflected in the group median paco and map for survivors and non-survivors for each day of the study (fig. ). nonconventional or specialised intensive care treatments included extra-corporeal membrane oxygenation ( cases, death), high frequency oscillatory ventilation ( cases, deaths), artificial surfactant ( cases, deaths) and intention to use nitric oxide ( cases, deaths). outcome and acute physiological disturbance the range of physiological parameters most widely suggested to be associated with outcome are shown as a univariate analysis (table ) for the day of admission (day ), and the subsequent two complete days on the picu. on days and the eventual survivors do not differ significantly from non-survivors in terms of early a-ado , paojfio , oi or vi (when using the best values from all blood gases over the particular time period). by day , however, the a-ado just reached significance (p = . ). although it should be noted that up to this time there had been significant attrition in patient numbers with nine of the patients present on day not surviving and seven others improving to extubation, and therefore beyond the need for blood gas monitoring. in relation to the ventilatory parameters, there were significant differences between survivors and non-survivors in the maximum map employed on day and day , and the highest peak inspiratory pressures employed on day . in stepwise multiple logistic regression analysis, best and worst gas exchange parameters (a-ado , pao / fio> oi, vi, paco , peak inspiratory pressure, positive end expiratory pressure and map) were not independently associated with poor outcome on days , or of admission. the findings were not altered by correction for age, weight, mosf score or the presence of immunodeficiency. the association between ards and increased mortality noted on univariate analysis was not significant when corrected for the presence of mosf score _> . respiratory infection ( ) non-infective respiratory disease ( )* head injury ( ) • non-survivors all cases ( ) immunodefieicney ( )* ex-premature ( ) normal ( the acute diagnosis associated with admission and the mortality in each category is shown in fig. as well as the underlying or associated diagnosis. the presence of mosf (score _> ) was the only pattern of acute diagnosis associated significantly with death: % mortality rate ( / ) with an odds ratio ( % confidence interval) of . ( . - . ). of special note is the favorable outcome for previously healthy children with only deaths from cases ( . %) compared with the / ( . %) in cases with pre-existing disease (p < . ). as with previous reports [ , [ ] [ ] [ ] , the outcome for immunodeficient children who develop ahrf was significantly worse than for the rest of the study population: deaths from cases ( %) versus deaths from cases ( %), p < . ; odds ratio . ( % confidence interval . - . ). in the stepwise multiple logistic regression analysis, adjustment for gas exchange parameters (a-ado> pao /fio , oi, vi, paco , peak inspiratory pressure, positive end expiratory pressure and map) did not alter the association of mosf and immunodeficiency with non-survival. the clinical course of patients with ahrf was categorised according to the severity of the disruption of gas exchange. using the best daily a-ado (but the classification is identical if paojfio or oi are used), five distinct patterns of ahrf were identified (fig. ) . survivors follow one of three clinical patterns: a course of mild disease only (pattern a: n-- ), early improvement within days (pattern b: n = ) or later improvement longer than days (pattern c: n -- ). non-survivors die with persistent, severe, hypoxemic, respiratory failure (pattern d: n -- ) or during or following resolution of ahrf (pattern e: n -- ). the majority of deaths occur in children with persistently severe abnormal gas exchange (pattern d). of these children, none were previously healthy (ten were immunodeficient, three were ex-premature infants and the others had inherited metabolic disorders or major chromosomal abnormalities). further, only six of these patients died whilst receiving full supportive treatment including cardiopulmonary resuscitation, the remainder had either support withdrawn ( / ) or a limitation of intensive care therapy ( / ) because of the severity of the associated conditions or co-incident organ failure. therefore only six cases with ahrf reached a point of unsupportable respiratory failure, and none of these were previously normal children. the other children who died (pattern e) most frequently did so from severe cerebral injury ( / from brain death including the three previously normal children who died) with the other four cases having supportive treatment withdrawn or limited because of the severity of associated diseases. the principal observation in this preliminary report of ahrf in children is that associated or underlying diagnoses -case mix -have significant bearing on population outcomes. not surprisingly, children meeting criteria for ards had a poorer outcome. further, when using a defined ventilatory strategy, which in our practice emphasises permissive hypercarbia and lung volume recruitment, severity of ventilatory parameters (i. e., high map) rather than indices of gas exchange, reflected better the likelihood of poor outcome. most importantly, where the acute physiological parameters fail to differ between good and poor outcome patients, we propose that the presence of severe pre-existing disease or associated pathology, rather than severity of respiratory failure alone is associated with outcome in modern pediatric practice. this hypothesis should be tested in a larger series since, although we recruited patients, there were only deaths on which many of our conclusions are based. comparisons with previously published respiratory predictors of outcome from studies of ahrf and ards in childhood are shown in table . none of the proposed physiological correlates of outcome were applicable to our series. reviewing every blood gas and applying the published criteria we found in each case, the predictor overestimated our patients' risk of mortality, excepting the very severe criteria from the melbourne study in , which used a peak inspiratory pressure greater than cmh and a-ado more than mmhg [ ] . these were rarely achieved in our population ( cases) and hence the confidence intervals remain so wide ( - %) that no useful conclusion could be drawn. the largest study of pediatric ahrf [ ] , a multi-center retrospective study including cases from , identified an association between acute respiratory physiological disturbance and outcome. however, chil-dren who became brain dead or had treatment withdrawn because of perceived treatment futility -in the setting of severe neurological insult -were excluded from the subsequent analysis. such an approach (included because the study was principally designed to identify extra-corporeal membrane oxygenation candidates) would have excluded from our analysis all the normal children who died. since brain injury is a possible complication of severe hypoxemia or the disease processes that initiated hypoxemia, our view was that these patients should be included in our attempt to identify factors associated with outcome. the difference between our current findings and those of scores or predictors identified in the late s and early s may, in fact, relate to a fundamental change in ventilatory strategy. as shown in fig. , our median paco was - kpa instead of the . - kpa reported in the pediatric critical care study group multi-center retrospective study of children managed in [ ] . table comparison of previously published [ ] [ ] [ ] [ ] respiratory severity parameters with the present series (ppv positive predictive value for mortality, vi ventilation index, oi oxygenation index, pip peak inspiratory pressure (cmh ), a-ado alveolar arterial oxygen gradient (mmhg), map mean airway pressure (cmh ), lr + the likelihood ratio for a positive test result, i.e. the ratio of finding the predictor in non-survivors to finding it in survivors) * indicates intermediate to high diagnostic impact, ns not significant proposed ppv lr + ppv p predictors ( % confidence interval) in present study melbourne [ ] memphis [ ] salt lake city [ ] philadelphia [ ] vi pattern of disease and outcome the patients in our series exhibited one of five patterns in their clinical course. deaths amongst children admitted in ahrf can occur with active and progressive lung disease (pattern d) or in spite of resolving lung disease (pattern e). in children who survive, recovery may be slow or fairly rapid. on inspecting the data, it is apparent that there are similarities in the initial respiratory indices in children who survive despite severe, prolonged gas exchange disruption (pattern c) and those who die despite improving or improved gas exchange parameters (pattern e). the relative proportion of the patients with these patterns in a population being studied will clearly determine the utility of gas exchange parameters in predicting survival: conversely, as is our experience when including patients with underlying immunodeficiency or other associated diseases, these proportions may confound their use. of further note is the mode of death in children with persistently, severely abnormal gas exchange (pattern d): cases rarely reached a level of respiratory failure which was unsupportable by current techniques. instead, in the majority of cases ( / ) treatment was discontinued or limited as a result of other aspects of the clinical situation. worth re-emphasising in this context is the observation that no previously normal child died of unsupportable respiratory failure. observations from adult intensive care studies of lung injury have indicated that outcome is not necessarily related to the level of arterial oxygenation [ , ] . in contrast, many previous pediatric studies in defined populations have supported a contrary notion [ , [ ] [ ] [ ] [ ] [ ] . in the present pediatric study, we have observed that mortality from respiratory failure appears to be related to associated disease rather than the severity of initial gas exchange per se. the implications of such a hypothesis are wide. firstly, is there much to be gained by refining further the techniques of respiratory support when mortality is frequently determined by non-pulmonary factors? indeed, it has been suggested that mechanical ventilation should now be considered less a form of treatment than a form of organ support during disease resolution [ ] . secondly, can severity systems that solely employ acute pulmonary physiological parameters and do not incorporate underlying etiology be used to good effect, specifically in pediatric ahrf? perhaps the reported value of such pulmonary physiological predictors, with their institution specificity, are more a reflection of physician behavior, i. e. patient selection and local ventilatory strategy employed, than patient pulmonary pathophysiology. in this context, it is of interest that we found the presence or absence of ahrf in all picu patients to be a discriminator. more recently developed non-linear, multiple logistic regression models that predict the risk of death for children less than years of age (e. g., the 'pediatric risk of mortality iii'-prism ifi [ ] and the 'paediatric index of mortality' -pim [ ] ) may improve the outcome prediction since they incorporate both diagnostic and disease categories as well as acute physiological respiratory parameters. however, these two severity scoring systems do differ: not least in their ability, possibly, to be influenced by the ventilatory strategy employed. prism iii utilizes ph, pco , poz and fio and respiratory rate, whereas pim utilizes po and fio , and whether or not mechanical ventilation is being used. thirdly, how can clinical trials be designed to assess the impact of new respiratory therapies? it is possible that a comparison between heterogeneous treated and control groups using only early respiratory parameters to confirm similarity of disease severity is invalid. in keeping with other reports [ ] , the present series indicates that case mix should not be ignored, e.g., ahrf in an ex-premature infant with respiratory syncytial virus is not the same as ahrf in an infant with aspiration pneumonia -even if the respiratory indices suggest they are similar. therefore, is it not time to reconsider disease-specific stratification criteria in any future treatment evaluation, even though this will inevitably mean that studies will take much longer to recruit sufficient patients. finally, since death in a previously normal child is now an infrequent end point in ahrf, our data reiterates a previously discussed idea [ ] , that other markers sought. of ventilation-related outcome should be adult respiratory distress syndrome in a pediatric intensive care unit: predisposing conditions, clinical course and outcome predictors of mortality in children with respiratory failure: possible indications for ecmo alveolar-arterial oxygen gradient as a predictor of outcome in patients with non-neonatal respiratory failure mortality rates and prognostic variables in children with adult respiratory distress syndrome adult respiratory distress syndrome in children: associated diseases, clinical course and predictors of death fackler jc and the pediatric critical care study group and the extracorporeal life support organisation ( ) predicting death in pediatric patients with acute respiratory failure acute respiratory distress syndrome caused by respiratory syncytial virus early response to inhaled nitric oxide and its relationship to outcome in children with severe hypoxemic respiratory failure predicting outcome in children with severe acute respiratory failure treated with high-frequency ventilation the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes and clinicai trial coordination outcome of pediatric patients with multiple organ system failure arterial oxygenation does not predict the outcome of patients with acute respiratory failure needing mechanical ventilation is outcome from ards related to the severity of respiratory failure? outcome from mechanical ventilation prism iii: an updated pediatric risk of mortality score wilkinson k ( ) paediatric index of mortality (pim): a mortality prediction model for children in intensive care intensive care society's apache ii study in britain and ireland -i: variations in case mix of adult admissions to general intensive care units and impact on outcome should morbidity replace mortality as an end point for clinical trials in intensive care? key: cord- -fkh fzbr authors: bednarczyk, joseph m.; kethireddy, shravan; white, christopher w.; freed, darren h.; singal, rohit k.; bell, dean; ahmed, syed zaki; kumar, anand; light, bruce title: extracorporeal membrane oxygenation for blastomycosis-related acute respiratory distress syndrome: a case series date: - - journal: can j anaesth doi: . /s - - -z sha: doc_id: cord_uid: fkh fzbr purpose: blastomyces dermatitidis is a dimorphic fungus endemic to north america capable of causing fatal respiratory failure. acute respiratory distress syndrome (ards) complicates up to % of pulmonary blastomycosis in hospitalized patients and carries a mortality of - %. this report describes the clinical course of four consecutive patients with blastomycosis-related ards treated with venovenous extracorporeal membrane oxygenation (ecmo) during - . clinical features: four adults were referred from northwestern ontario, canada with progressive respiratory illnesses. all patients developed diffuse bilateral opacities on chest radiography and required mechanical ventilation within - hr. patients satisfied berlin criteria for severe ards with trough p(a)o( )/f(i)o( ) ratios of - on positive end-expiratory pressure of - cm h( )o. wet mount microscopy from respiratory samples showed broad-based yeast consistent with b.dermatitidis. despite lung protective ventilation strategies with maximal f(i)o( ) (patients a-d), neuromuscular blockade (patients a-d), inhaled nitric oxide (patients a and d), and prone positioning (patient d), progressive hypoxemia resulted in initiation of venovenous ecmo by hours - of mechanical ventilation with subsequent de-escalation of ventilatory support. in all four cases, ecmo decannulation was performed ( - days), mechanical ventilation was withdrawn ( - days), and the patients survived to hospital discharge ( - days). conclusion: this report describes the successful application of ecmo as rescue therapy in aid of four patients with refractory blastomycosis-associated ards. in addition to early appropriate antimicrobial therapy, transfer to an institution experienced with ecmo should be considered when caring for patients from endemic areas with rapidly progressive respiratory failure. conclusion this report describes the successful application of ecmo as rescue therapy in aid of four patients with refractory blastomycosis-associated ards. in addition to early appropriate antimicrobial therapy, transfer to an institution experienced with ecmo should be considered when caring for patients from endemic areas with rapidly progressive respiratory failure. objectif blastomyces dermatitidis est un champignon dimorphique endémique en amérique du nord, susceptible de provoquer une défaillance respiratoire fatale. le syndrome de détresse respiratoire aiguë (sdra) complique jusqu'à % des cas de blastomycose pulmonaire chez les patients hospitalisés avec un taux de mortalité de % à %. ce compte rendu décrit l'évolution clinique de quatre patients consécutifs atteints de sdra lié à une blastomycose et traités par oxygénation par membrane extracorporelle (ecmo) par voie veinoveineuse entre et . cliniques quatre adultes en provenance du nord-ouest de l'ontario (canada) ont été transférés pour des maladies respiratoires évolutives. tous les patients ont développé des opacités diffuses bilatérales sur les radiographies de thorax et une ventilation mécanique a été nécessaire dans un délai de à heures. les patients répondaient aux critères de berlin pour un sdra sévère avec des rapports minimums p a o /c i o de à sur une pression positive de fin d'expiration de à cm h o. un examen microscopique sur lame humide des échantillons respiratoires a montré une levure à base large compatible avec b. dermatitidis. en dépit de stratégies ventilatoires protégeant le poumon avec une f i o maximum (patients a à d), un bloc neuromusculaire (patients a à d), du monoxyde d'azote inhalé (patients a et d), et une position en procubitus (patient d), la progression de l'hypoxémie a nécessité l'instauration d'une ecmo veinoveineuse dans un délai de à heures après l'instauration de la ventilation mécanique, suivie d'une désescalade progressive du soutien ventilatoire. dans ces quatre cas, la décanulation de l'ecmo a pu avoir lieu (entre et jours), la ventilation mécanique a été retirée (entre et jours) et les patients ont survécu après leur congé de l'hô pital ( à jours). conclusion ce compte rendu décrit la réussite de l'utilisation de l'ecmo comme traitement de secours visant à aider quatre patients atteints d'un sdra réfractaire associé à une blastomycose. en plus du traitement antimicrobien adapté, le transfert des patients vers un établissement ayant l'habitude de l'ecmo doit être envisagé au cours de la prise en charge de patients vivant en zone d'endémie et présentant une défaillance respiratoire rapidement évolutive. blastomyces dermatitidis, a dimorphic fungus endemic to well-described regions in north america, is capable of causing life-threatening disease in young immunocompetent adults. , blastomycosis remains a rare disease, but incidence reaches seven cases per , annually in northwestern ontario. although % of affected patients have primarily pulmonary involvement, clinical manifestations vary widely. [ ] [ ] [ ] up to % of hospitalized patients with pulmonary blastomycosis develop acute respiratory distress syndrome (ards). , in contrast to ards of other etiologies, patients with blastomycosis-related ards have disproportionately high reported mortality ( - %) and may be more likely to die from early refractory respiratory failure. , , expert consensus supports early aggressive treatment; however, a specific strategy has yet to be developed. venovenous extracorporeal membrane oxygenation (ecmo) has been utilized for the management of severe ards to facilitate gas exchange, allow lung rest by deescalation of ventilatory support, and provide time for resolution of the underlying disease. extracorporeal membrane oxygenation is generally considered in ards patients with refractory hypoxemia or hypercapnia despite a lung protective ventilation strategy or in those where the maintenance of adequate gas exchange requires potentially injurious applied volumes or pressures. selective application of ecmo may have resulted in a reduction in mortality among patients with severe ards secondary to h n infection. [ ] [ ] [ ] nevertheless, uncertainty exists regarding the appropriateness of ecmo during disseminated fungal infection or septic shock in adults. we describe a case series of four critically ill patients with blastomycosis-related ards treated with venovenous ecmo. ethics approval was provided by the university of manitoba health research ethics board (registration number: university of manitoba h : , june, ), and informed consent was obtained in three of four cases in which contact information was available. a retrospective cohort study was performed on all patients with blastomycosis-related ards treated with ecmo at a single canadian site during - . the ecmo referral centre is a regional tertiary care -bed academic facility that performs approximately ten venovenous ecmo cannulations for respiratory failure annually. patient demographics, ecmo-related variables, and clinical data were obtained from the medical record. descriptive statistical analysis was performed with graphpad prism v . c (graphpad software inc., la jolla, ca, usa). four adults aged - were referred from northwestern ontario, canada with progressive respiratory symptoms, including coughing, sputum production, fever, and dyspnea. three of four patients were previously healthy and immunocompetent. one patient had complex comorbidities, including hemochromatosis, type diabetes mellitus, stiff person syndrome (a rare autoimmune disorder of progressive muscle rigidity), and addison's disease. all patients required tracheal intubation and mechanical lung ventilation for hypoxemic (patient c) or mixed hypoxemic/hypercapneic (patients a, b, d) respiratory failure. on admission to the intensive care unit, the patients were hemodynamically unstable requiring vasopressor support, with apache ii scores ranging from - . the patients initially received antimicrobial therapy for community-acquired bacterial pneumonia at local emergency departments or nursing stations. upon arrival at the tertiary facility, bronchoscopy with bronchoalveolar lavage was performed. wet mount microscopy of respiratory samples showed yeast morphology consistent with b. dermatitidis, subsequently confirmed by culture. accordingly, in patients a-c, liposomal intravenous amphotericin b mgÁkg - Áday - was initiated within the first hr of hospital care. patient d was given conventional amphotericin b infusion mgÁkg - Áday - commencing at hour . three of four patients received systemic corticosteroids (methylprednisone - mg every six hours) within the first hr of mechanical ventilation. additional baseline characteristics are summarized in table . patients developed four-quadrant airspace opacification on chest radiography ( fig. ) with murray lung injury scores of . - . berlin criteria for severe ards were satisfied with trough p a o /f i o ratios of - on positive end-expiratory pressure (peep) levels of - cm h o. positive end-expiratory pressure was titrated based on observation of gas exchange during bedside peep trials. a low tidal volume ventilation strategy ( - mlÁkg - of predicted body weight) with permissive hypercapnia was used. life-threatening hypoxemia, acidosis, and injurious airway pressures developed despite % f i o (patients a-d), neuromuscular blockade (patients a-d), inhaled nitric oxide at ppm (patients a and d), and prone positioning (patient d) ( table ). in two cases, these conditions prompted dispatch of an aeromedical ecmo transport team, consisting of a cardiothoracic surgeon, perfusionist, critical care nurse, and critical care fellow, to facilitate ecmo cannulation in the peripheral hospital. in the remaining cases, the cannulation procedure was performed on-site at the ecmo facility. patients were considered for ecmo support if they had ards and satisfied one of the following three conditions: (i) a p a o /f i o ratio \ on a peep of at least cm h o, (ii) a ph \ . or p a co [ mmhg despite an optimal lung protective ventilation strategy, or (iii) plateau pressures [ cm h o despite optimal ventilatory management; and if they were within seven days of the onset of ards. if strict inclusion criteria were not met but rapid clinical deterioration was apparent, patients could be considered for aeromedical ecmo retrieval from distant sites within the centre's catchment region at the discretion of the receiving intensivist and cardiothoracic surgeon. following informed consent by the substitute decision maker, venovenous peripheral ecmo cannulation was performed at the patient's bedside under sterile conditions. one of two circuit configurations was selected at the cardiothoracic surgeon's discretion ( table ). the bifemoral configuration consisted of drainage via the left common femoral vein (lcfv) with return via a long single-stage right common femoral vein cannula directed to the atrial-caval junction. the right internal jugular configuration consisted of a single fr bicaval duallumen catheter (avalon laboratories, rancho dominguez, ca, usa) capable of drainage via the superior and inferior venae cavae and return via the right atrial inlet. in either configuration, an additional venous drainage catheter could be added at an available site to achieve adequate flows and oxygenation, if required. the circuit was connected to a biomedicus Ò centrifugal pump (medtronic, minneapolis, mn, usa) and a maquet quadrox-id oxygenator/heat exchanger (maquet cardiovascular, san jose, ca, usa). the circuits were heparin coated and primed with lactated ringer's solution ml at room temperature. the cannula position was confirmed via transthoracic or transesophageal echocardiography and chest radiography. following confirmation of adequate flow and favourable gas exchange on ecmo, inspired f i o was weaned and lung rest settings were applied to facilitate peak inspiratory pressures \ cm h o, peep - cm h o, and respiratory rate * breathsÁmin - , as described in the cesar trial. weaning from extracorporeal support was considered after a global assessment of disease resolution based on chest radiography, respiratory mechanics and work of breathing, and adequacy of gas exchange while delivering a lung protective ventilation strategy. at this point, a weaning trial of extracorporeal f i o and/or ecmo blood flow was initiated prior to release from ecmo. use of ecmo resulted in rapid improvements in oxygenation, ventilation, and acid-base status (table ) . this facilitated reductions in tidal volume and peep which resulted in significantly lower airway pressures. vasopressor requirements, hemodynamic parameters, and serum lactate levels also improved within hr of ecmo support. in three cases, continuous venovenous hemodiafiltration was incorporated into the ecmo circuit due to acute kidney injury and volume overload. this facilitated achievement of a negative fluid balance and recruitment of the native lung. a timeline of in-hospital events is presented in fig. . the duration of ecmo ranged from seven to days (table ). patients a, b, and d were relieved of mechanical ventilation at - days and were subsequently discharged with a cerebral performance category score obtained via chart review. patient c sustained a -min cardiac arrest due to tension pneumothorax seven days after ecmo decannulation. despite targeted temperature management, the patient experienced an anoxic cerebral injury that required prolonged rehabilitation. three months later, the patient returned home and was independent with several activities table . two reports have previously described attempts to rescue patients with refractory blastomycosis-related ards with ecmo. , resch et al. reported a case of a -yr-old previously healthy male with blastomycosis-related ards in germany. venovenous ecmo was initiated on the fourth day of illness; however, bilateral pneumothoraces and multi-system organ failure resulted in death on ecmo at day . due to a delay in diagnosis, antifungal therapy was initiated only on the final days in the course of the illness. dalton et al. reported a case of a -yr-old male with blastomycosis-related ards in which veno-arterial ecmo was initiated at day five of mechanical ventilation. although amphotericin b was initiated after approximately seven days of hospital contact, the patient developed progressive pulmonary necrosis and sustained a cardiac arrest due to bilateral tension pneumothoraces on ecmo day . a single reported case of central venoarterial ecmo for blastomycosis-related septic shock in a -yr-old was similarly unsuccessful. post-mortem specimens from affected patients have shown the classic pathologic features of ards, but they have also shown severe necrosis, abscess formation, hemorrhagic cysts, and invasive parenchymal destruction. , this raises the possibility that blastomycosis-related ards may be a uniquely severe disease entity due to virulence factors of an organism, pronounced host inflammatory response, or late recognition and treatment of the disease. it is possible that previous applications of ecmo in refractory blastomycosis-related ards failed due to delays in diagnosis and antimicrobial therapy or late initiation of extracorporeal support. , in contrast to previous reports, this case series describes the successful application of ecmo as a rescue therapy in blastomycosis-related ards. all patients in this series had severely impaired gas exchange, reduced pulmonary compliance, and rapid deterioration despite respiratory support consistent with the standard of care. extracorporeal membrane oxygenation facilitated improved gas exchange, as evidenced by increased p a o /f i o ratios and normalization of ph and p a co , and allowed lung rest as shown by reductions in potentially injurious airway pressures. although the therapy was resource intensive and necessitated prolonged admissions to hospital and the intensive care unit, in all four cases, ecmo decannulation ards = acute respiratory distress syndrome; ecmo = extracorporeal membrane oxygenation; f i o = fraction of inspired oxygen; p a o = partial pressure of oxygen; p a co = partial pressure of carbon dioxide; pbw = predicted body weight; peep = positive endexpiratory pressure ast = aspartate aminotransferase; ecmo = extracorporeal membrane oxygenation; f i o = fraction of inspired oxygen; p a co = partial pressure of carbon dioxide; p a o = partial pressure of oxygen; pbw = predicted body weight; peep = positive end-expiratory pressure; pip = peak inspiratory pressure; pplateau = plateau pressure; s v o = central venous oxygen saturation was performed, mechanical ventilation was withdrawn, and the patients were discharged home with acceptable quality of life. these outcomes are exceptional given the uniquely high mortality of blastomycosis-related ards. indications for ecmo among patients with ards are evolving. , , in addition to providing rescue therapy for patients with refractory hypoxemia, hypercapnia, or acidosis, when instituted early, ecmo may prevent ventilator-induced lung injury by allowing de-escalation of mechanical ventilatory support. , observational trials of ecmo among patients with ards due to h n virus have shown survival rates as high as %, though data from high-quality randomized controlled trials are lacking. with its inherently severe clinical course, blastomycosisrelated ards has thus been considered a therapeutic target for ecmo. maintaining a lung protective ventilation strategy may have greater clinical importance in this setting due to the pathologic severity of blastomycosisrelated ards. several factors may have contributed to the favourable outcomes in our cohort. first, diagnoses were made relatively early due to high clinical suspicion and experienced laboratory personnel. accordingly, appropriate antimicrobial agents were instituted early in the clinical course. it is well established that the administration of early appropriate antimicrobials reduces mortality in septic shock. second, ecmo support was initiated within hr in all patients. extracorporeal membrane oxygenation may confer greater therapeutic benefit in ards when initiated within seven days. , in addition, three patients in this series received early systemic corticosteroids, a therapy which may limit the inflammatory response and possibly reduce mortality in the paucity of published attempts at ecmo rescue in this setting may reflect clinicians' reluctance to apply ecmo in the context of septic shock and possible fungemia, both of which are considered relative contraindications to the use of ecmo. , we observed a decline in vasopressor requirement within the first - hr of ecmo support. although ecmo flows upon peripheral cannulation were - lÁmin - , this would not have matched patients' cardiac output prior to cannulation in the setting of septic shock, nor would ecmo be expected to deliver direct improvement in hemodynamics in a venovenous configuration. thus, we speculate that ecmo indirectly improved hemodynamics by improving oxygen delivery to vital organs and restoring physiologic acid-base balance. accordingly, ecmo may still have a therapeutic role in the setting of primary pulmonary disease with concomitant septic shock. our findings should be interpreted with several considerations. the previously reported mortality of blastomycosis-related ards largely reflects case series predating the arma study, representing an era in which lung protective ventilation was not standard practice. thus, with modern ventilatory strategies and possibly prone positioning, it is possible that more patients with blastomycosis-related ards may be salvageable and not require ecmo rescue. , our case series was small, retrospective, and lacked a control group; however, no patients referred for ecmo for pulmonary blastomycosis were refused during the study period. last, our aeromedical transport team provided several patients with early aggressive care and extracorporeal support. we acknowledge that our findings may lack generalizability because many centres lack such a service. extracorporeal membrane oxygenation may be an effective treatment modality for patients with blastomycosis-related ards and refractory hypoxemia despite optimal mechanical ventilation. early application of ecmo and timely appropriate antimicrobial therapy may contribute to favourable patient outcomes. when blastomycosis-related ards is identified or suspected, transport to an ecmocapable centre should be considered. epidemiology and clinical spectrum of blastomycosis diagnosed at manitoba hospitals acute respiratory distress syndrome and blastomycosis: presentation of nine cases and review of the literature endemic blastomycosis in mississippi: epidemiological and clinical studies corticosteroids for blastomycosis-induced ards: a report of two cases and review of the literature overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome blastomycosis in northeast tennessee extracorporeal life support for adults with severe acute respiratory failure extracorporeal membrane oxygenation for ards in adults efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for, influenza a(h n ) acute respiratory distress syndrome extracorporeal lung support for patients who had severe respiratory failure secondary to influenza a (h n ) infection in canada extracorporeal membrane oxygenation resuscitation in adult patients with refractory septic shock extracorporeal membrane oxygenation (ecmo) for severe acute respiratory distress syndrome (ards) in fulminant blastomycosis in germany extracorporeal membrane oxygenation for overwhelming blastomyces dermatitidis pneumonia central extracorporeal membrane oxygenation support for disseminated blastomycosis septic shock a systematic review to inform institutional decisions about the use of extracorporeal membrane oxygenation during the h n influenza pandemic duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock the italian ecmo network experience during the influenza a(h n ) pandemic: preparation for severe respiratory emergency outbreaks continuous cardiac output in septic shock by simulating a model of the aortic input impedance: a comparison with bolus injection thermodilution ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network prone positioning in severe acute respiratory distress syndrome reliability of the cerebral performance category to classify neurological status among survivors of ventricular fibrillation arrest: a cohort study acknowledgement the authors gratefully acknowledge the contributions of louise dyck who provided quality assurance regarding the reporting of technical aspects of ecmo conduct and equipment. disclosures no funding sources, commercial or non-commercial affiliations, associations, or consultancies apply to the corresponding author or author group. key: cord- -byffqwjd authors: lewandowski, k.; bartlett, r. h. title: der alte mann und die „i sea u“: essay über vertrauen, schicksal und evidenz – im stil von hemingway date: - - journal: anaesthesist doi: . /s - - - sha: doc_id: cord_uid: byffqwjd robert bartlett, emeritus professor of surgery at the university of michigan in ann arbor, usa, transformed classical works of world literature (charles dickens: a christmas carol, lewis carroll: alice in wonderland) into teaching aids for advanced training in intensive care medicine. he recently turned his hand to the well-known work of ernest hemingway: the nobel prize winning novel the old man and the sea. subsequent to robert bartlett’s essay this article provides background information and comments on the current problems in modern intensive care medicine addressed in his essay. in der jugend hatte der mann beim boxen seine nase gebrochen. gelegentlich litt er unter nasenbluten, so auch diese nacht. es blutete stärker nach der lovenox-morgendosis. unmittelbar vor dem mittagessen erbrach er eine schale voll von etwas, das wie verfaulte weintrauben schmeckte und aussah wie kaffeesatz. die schwester rief dr. manolin, der eine endoskopie des oberen gastrointestinaltrakts anordnete. in der endoskopieabteilung war es kalt, und der boden war befleckt mit getrocknetem blut. er verspürte ein brennen in seinem arm und dann einen bitteren geschmack. eine halbe stunde später wachte er auf; sogleich erbrach er eine große menge salzigen wassers, vermischt mit blut und magensaft. wieder verspürte er ein brennen im arm, und er erwachte mit einem dicken plastikschlauch in seinem mund und in seiner luftröhre. jemand, den er nicht sehen konnte, zwang mit einem plastikbeutel luft in seine lungen. ein gesicht wurde erkennbar. "alter mann, ich bin dr. yungensmart. sie befinden sich auf der icu ["intensive care unit", intensivtherapiestation]. die gute nachricht ist: ihre endoskopie war unauffällig. die schlechte nachricht ist, dass sie erbrochenes in ihre lungen eingeatmet haben. aber wir haben alle mittel, die bewirken, dass es ihnen wieder bes-infobox biografie von hemingway am "aber ja. das ardsnet hat bewiesen, dass dies die beste beatmungsform bei ards ist." "verglichen mit was?" "verglichen mit einem doppelt so großen atemzugvolumen." "wäre ein vergleich mit druckkontrollierter beatmung nicht sinnvoller?" "das ist nicht nötig. die haben bewiesen, dass ml/kg bei volumenkontrollierter beatmung genau das richtige verfahren ist." "wäre es nicht besser, ihn aufzusetzen und auf der seite zu lagern? er liegt nun schon seit tagen flach auf dem rücken!" "keine evidenz." anecdotes as topic · evidence-based medicine · intensive care units · acute respiratory distress syndrome · sepsis "und wäre es nicht besser, ihn wach werden zu lassen und ihm spontanatmung zu ermöglichen?" "keine evidenz. es gibt sogar studien, die zeigen, dass es besser ist, die patienten zu relaxieren." "er ist ausgeprägt anämisch. sein hämoglobinwert ist nur halb so hoch wie der normalwert. sein arterieller sauerstoffgehalt beträgt nur ." "ich mache mir keine sorgen über den sauerstoffgehalt, solange der pao [arterieller sauerstoffpartialdruck] über ist. und es gibt keine evidenz dafür, dass eine anämie die letalität erhöht. eine studie bewies sogar, dass es besser ist, anämisch zu sein, wenn man schwer erkrankt ist. und übrigens, wie würden sie eine anämie behandeln? es gibt mehr als eine tonne schwerer evidenz, die belegt, dass je mehr man transfundiert, desto höher die sterblichkeitsrate." "aber das ist doch nur so, weil bluten die sterblichkeitsrate erhöht. transfusionen sind lediglich ein maß für die schwere der blutung." "kann ja sein, aber es gab eine studie, die belegt hat, dass die transfusion selbst nicht die Überlebensrate verbessert. einige patienten wurden von auf g% auftransfundiert und wurden nicht besser. ja, einigen ging es sogar schlechter." "aber damit werden doch nur verschiedene grade der anämie verglichen. und noch was: war das nicht die studie, in der uraltes blut transfundiert wurde?" "ja, aber es gibt nun mal diese evidenz, und wirhaltenuns daran. delirium der begriff delirium ist aus dem lateinischen abgeleitet: "delirare" bedeutet "aus der furche geraten", "irresein", "verwirrtheitszustand". das delir gehört zu den leitsymptomen organischer psychosen. es stellt keine eigene erkrankung dar, sondern ein syndrom mit einem breiten spektrum möglicher Ätiologien [ ] . die aktuelle . auflage des diagnostic and statistical manual of mental disorders (dsm- ) der "american psychiatric association" legt folgende diagnosekriterien fest [ [ ] . speziell die auf intensivtherapiestationen als sedativum häufig eingesetzten benzodiazepine erhöhen das delirrisiko [ ] , besonders dann, wenn sie als dauerinfusion und nicht als bolusinjektion verabreicht werden [ ] . als alternative bietet sich die kontinuierliche infusion von dexmedetomidin oder propofol an [ ] . wegen der komplexität des facettenreichen syndroms delir ist nicht zu erwarten, dass einzelne maßnahmen zu einer entscheidenden senkung seiner inzidenz führen. maßnahmenpakete jedoch, die mehrere der zurzeit als aussichtsreich geltenden optionen vereinen, erscheinen durchaus vielversprechend. so konnten beispielsweise balas et al. zeigen, dass eine kombination aus aufwachversuch, spontanatmungsversuch, monitoring und therapie des delirs sowie frühmobilisierung eine reduktion der beatmungsdauer und der delirinzidenz sowie auch eine bessere frühmobilisierung bewirkt als eine standardbehandlung [ ] . vor fast einem vierteljahrhundert wurde die evidenzbasierte medizin eingeführt (ebm) [ ] . die methode ist wie folgt definiert: kritiker befürchten aber, dass bei der generierung der evidenz der grundlagenmedizin und dem über jahre erworbenen medizinischen erfahrungsschatz der anwender zu wenig bedeutung zugemessen wird. sie fragen sich auch, ob die mit ebm gewonnenen ergebnisse auf individuelle patienten anwendbar sind. die krankheiten letzterer unterscheiden sich ja oft von den lehrbuchbeschreibungen, und auch die patienten sind nichtwie in den studien -streng selektiert. ardsnet [ ] . im laufe der letzten jahre hat dieses protokoll weite akzeptanz gefunden; es haben sich aber auch folgende neue sichtweisen und modifikationen ergeben: die grenzen für das oxygenierungsziel sind möglicherweise zu niedrig angesetzt. von den Überlebenden eines ards weisen % eine eingeschränkte kognitive funktion mit eingeschränktem erinnerungsvermögen sowie reduzierter aufmerksamkeits-und konzentrationsfähigkeit auf. diese veränderungen korrelieren mit häufigkeit und dauer der phasen von mithilfe der plethysmographie gemessenen sättigungswerten von < , < und < % [ ] . möglicherweise ist der während der akutphase gemessene pao ein besserer prognostischer parameter [ ] . beatmungsmodus: es ist bisher der nachweis nicht gelungen, dass die druckkontrollierte der volumenkontrollierten maschinellen ventilation überlegen ist [ , ] . die einstellung des vt, bezogen auf das ibw, berücksichtigt nicht das momentan tatsächlich für den gasaustausch verfügbare lungenvolumen. letzteres kann mithilfe apparativer methoden wie z. b. computertomographie oder lungenfunktionsuntersuchungen ermittelt werden. es gibt aber auch relativ einfach anwendbare bettseitige verfahren, wie z. b. die bestimmung der inspiratorischen kapazität (summe aus vt und inspiratorischem reservevolumen) [ ] . es wird infrage gestellt, ob der plateaudruck der geeignete parameter zur festlegung der beatmungsdrücke ist. eine mögliche alternative stellt der transpulmona-le druck (atemwegsdruck minus pleuradruck) dar. ziele sind ein transpulmonaler druck von cm h o in der endinspiration und ein positiver endexspiratorischer transpulmonaler druck von bis cm h o. zu seiner bestimmung ist allerdings die messung des Ösophagusdrucks (surrogatparameter für den pleuradruck) über eine spezielle magensonde erforderlich [ ] . bei auswahl hoher beatmungsfrequenzen ist zu berücksichtigen, dass sich ein relevanter auto-peep aufbauen kann [ ] . die flow-kurve sollte regelmäßig überprüft und der auto-peep wiederholt gemessen werden. die peep-tabelle ist hinterfragt worden, da lediglich der pulmonale gasaustausch, nicht aber zusätzlich hämodynamik und atemmechanik zur individuellen peep-titration herangezogen werden [ ] . unter recruitment versteht man die wiedergewinnung (eröffnung) nichtbelüfteter alveolen für den gasaustausch, unter derecruitment den verlust von vormals belüfteten alveolen durch kompressions-, resorptionsatelektasen, intraalveoläres Ödem oder konsolidierung. um einen möglichst guten pulmonalen gasaustausch zu erzielen, ist die parallele anwendung von recruitment-manövern (rm) und maßnahmen zur vermeidung von derecruitment erforderlich. recruitment-manöver waren im ursprünglichen ards-netzwerk-protokoll nicht vorgesehen, haben sich aber in der zwischenzeit als wichtige komponente einer lungenprotektiven beatmungsstrategie etabliert. allerdings ist ihre effizienz in der intensivmedizin nicht vollständig klar: zwar verbessern beatmungsstrategien, die rm als komponente beinhalten, oft den pulmonalen gasaustausch und die thorakopulmonale compliance günstig, ohne das risiko für das auftreten von barotraumen zu erhöhen. ein eindeutiger einfluss auf die Überlebensraten konnte aber noch nicht unstrittig nachgewiesen werden [ ] . eine mögliche klärung wird in der zukunft durch das "alveolar recruitment for ards trial" (art) [ ] erwartet. permissive hyperkapnie als bestandteil einer lungenprotektiven beatmungsstrategie wird bei patienten mit ards, status asthmaticus, chronisch obstruktiver lungenerkrankung und bei frühgeborenen mit atemversagen eingesetzt. es wird ein erhöhter wert des arteriellen kohlendioxidpartialdrucks (paco ) mit dem ziel akzeptiert, einen ventilatorinduzierten lungenschaden zu reduzieren. solch ein vorgehen kann die sterblichkeitsrate von ards-patienten senken [ , ] . die herausforderung für den intensivmediziner besteht nun darin, für jeden einzelnen patienten einen gelungenen kompromiss zwischen den vorteilen, die sich aus der anwendung kleiner vt und der hyperkapnie selbst ergeben, und auch den nachteilen der letzteren zu finden [ ] . zur vorsicht mahnt ein aktueller systematischer review, einschließlich einer netzwerkmetaanalyse, von wang et al. [ ] : bei einem vergleich von (sic!) beatmungsregimen schnitt die kombination aus permissiver hyperkapnie, rm und niedrigen atemwegsdrücken hinsichtlich ihres einflusses auf das Überleben am schlechtesten ab. der endgültige stellenwert der permissiven hyperkapnie kann noch nicht abschließend eingeschätzt werden, insbesondere da sich in den letzten jahrzehnten die verschiedenen spielarten des extrakorporalen gasaustausches zu einem effektiven und sicheren instrument der kohlenstoffdioxidelimination entwickelt haben. die anwendung kleiner vt in der größenordnung von ml/kgibw ist damit möglich [ ] . eine metaanalyse, die randomisierte, kontrollierte studien ("randomized controlled trial", rct) der gleichen arbeitsgruppe einschloss, ergab, dass die kurzzeitanwendung ( h) von cisatracurium bei ards-patienten zu einer verbesserung der krankenhaussterblichkeitsrate und zu einem niedrigeren risiko für die entwicklung eines barotraumas führt. das risiko für die entstehung einer "icu-acquired weakness" steigt nicht [ ] . aktuell werden neuromuskulär blockierende substanzen ("neuromuscular blocking agents", nmba) bei [ ] . eine unerwünschte folge kann sein, dass das vt im mittel , -mal/min werte von , ml/kgibw erreicht (statt der gewünschten von ml/kgibw) [ ] . an dieser stelle muss erwähnt werden, dass es in vielen fällen möglich sein sollte, durch veränderung von atemfrequenz, i:e-verhältnis, atemgasfluss, vt, anpassung der sedierung oder Änderung des kompletten beatmungsmodus die patient-respirator-dyssynchronie zu unterbrechen. weiterhin haben viele intensivmediziner konzeptionelle schwierigkeiten damit, in der akutphase des ards auf die positiven effekte der spontanatmung zu verzichten [ ] . gattinoni und marini sprechen sich dafür aus, nmba nicht als standardtherapie für alle ards-patienten zu verwenden, sondern nur für solche mit schweren verlaufsformen und ausgeprägter patient-respirator-dyssynchronie trotz tiefer sedierung [ ] . wen wundert es, dass diese ansicht nicht unwidersprochen bleibt [ ] ( ) die alleinige betrachtung des pao zur feststellung einer ausreichenden oxygenierung ist unzureichend. weltweit werden alljährlich mio. einheiten ek transfundiert [ ] . die transfusion von ek ist mit inhärenten risiken verbunden. hierzu zählen durch transfusion von blutprodukten übertragene infektionen ("transfusion transmitted infections", tti), wie z. b. syphilis, infektionen mit humanem immundefizienzvirus, humanem t-lymphotropem virus oder hepatitis-b-oder hepatitis-c-virus, eine schwächung der immunabwehr ("transfusionrelated immunomodulation", trim), transfusionsassoziierte volumenüberladung ("transfusion-associated circulatory overload", taco), transfusionsassoziierte lungeninsuffizienz nach ek-gabe ("transfusion-related acute lung injury", trali) sowie allergische und hämolytische transfusionsreaktionen [ ] . auch die einjahreslebensqualität nach operation und intensivstationsaufenthalt wird durch gabe von blutprodukten negativ beeinflusst [ ] . metaanalysen haben inzwischen gezeigt, dass restriktive transfusionsregime -im vergleich zu liberalen -von den patienten in den meisten klinischen situationen gut toleriert werden und auch tatsächlich einen geringeren verbrauch nach sich ziehen [ ] . uneinigkeit herrscht jedoch darüber, ob restriktive transfusionsregime für alle patientenkollektive empfohlen werden können. möglicherweise profitieren beispielsweise patienten mit akutem koronarsyn-drom, chronischen herzerkrankungen, maligner hämatologischer erkrankung oder knochenmarkinsuffizienz eher von liberalen transfusionsregimen [ ] . das in der geschichte angesprochene problem der transfusion von länger gelagerten ek konnte zwischenzeitlich aufgelöst werden: shah et al. kommen nach der analyse von rct mit patienten aus den fachgebieten intensivmedizin, kardiochirurgie, pädiatrie und solchen, die im krankenhaus ek erhielten, zu der schlussfolgerung, dass es für die bevorzugung "frischer" ek keine indikation gibt [ ] . für den unmittelbar am krankenbett tätigen intensivmediziner ist die entscheidung, ek zu transfundieren oder nicht zu transfundieren, nach wie vor schwierig. diese muss nach gründlicher evaluation des physiologischen zustands des kritisch kranken patienten erfolgen; sie kann nicht allein an einem bestimmten grenzwert für hämoglobin oder hämatokrit festgemacht werden [ ] . spinelli in den vergangenen jahren ist zunehmendes interesse am einsatz von β-rezeptoren-blockern bei sepsis zu beobachten. die hierzu gehörenden substanzen können sepsisinduzierte hämodynamische veränderungen günstig beeinflussen. die pathophysiologische rationale lässt sich wie folgt darstellen: in der akutphase der sepsis ist oft das hzv erhöht, es besteht eine tachykardie, der gefäßwiderstand ist erniedrigt und die myokardkontraktilität beeinträchtigt [ ] . der sympathikotonus ist hoch. die gabe von β-rezeptoren-blockern senkt die herzfrequenz, reduziert den myokardialen sauerstoffverbrauch, verlängert die diastole und verbessert die koronarperfusion. das risiko einer minderperfusion des myokards nimmt ab. weiterhin können β-rezeptoren-blocker auch vorteilhafte metabolische und immunologische veränderungen induzieren sowie die gerinnung modulieren [ ] . studien belegen, dass dieses therapieprinzip auch greift: morelli et al. verabreichten im rahmen einer rct patienten mit schwerem septischen schock den β-rezeptoren-blocker esmolol. verglichen mit der kontrollgruppe (standardtherapie des schweren septischen schocks) zeigten mit esmolol behandelte patienten gesteigerte schlagvolumina, einen unbeeinflussten arteriellen mitteldruck und einen reduzierten noradrenalinbedarf. es bestand kein erhöhter bedarf an positiv-inotropen substanzen. negative effekte auf verschiedene organfunktionen wurden nicht beobachtet. die -tage-sterblichkeitsrate war niedriger ( , % in der esmolol-vs. , % in der kontrollgruppe, bereinigte "hazard ratio" , ; %-konfidenzintervall [ %-ki] , - , ; p < , ) [ ] . christensen et al. verglichen kritisch kranke patienten mit einer β-rezeptoren-blocker-therapie, die schon vor aufnahme auf die intensivtherapiestation bestand, mit der gleichen patientenzahl, die keine β-rezeptoren-blocker erhalten hatte. die autoren dokumentierten eine niedrigere -tage-sterblichkeitsrate in der β-rezeptoren-blocker-gruppe ( [ ] . in folgeuntersuchungen konnten diese günstigen ergebnisse jedoch nicht reproduziert werden, sodass zur finalen klärung die studie "normoglycemia in intensive care evaluation -survival using glucose algorithm regulation" (nice-sugar) [ ] initiiert wurde. diese rct wurde in zentren durchgeführt und es nahmen kritisch kranke patienten an der studie teil. als ziele für die blutzuckereinstellung waren - mg/dl vs. - mg/dl vorgegeben. Überraschenderweise war die -tage-sterblichkeitsrate in der gruppe mit der strengen blutzuckereinstellung höher ( , % vs. , %, p = , ). schwere hypoglykämien (blutzuckerkonzentrationen ≤ mg/dl) traten bei , % der patienten mit strenger und bei , % mit liberaler blutzuckerkontrolle auf (p < , ). heute ist die frage nach der idealen blutzuckereinstellung weiter ungeklärt. folgende domänen, die interagieren, sind zu berücksichtigen: der zielwert von mg/dl soll nicht unterschritten werden blutzuckerkonzentrationen von - mg/dl können toleriert werden; bis blutzuckerkontrollen/tag. unter insulintherapie soll die Überwachungsfrequenz in abhängigkeit von der dosis erhöht werden being an essay on anemia, suffocation, starvation, and other forms of intensive care, after the manner of dickens being an essay on nonsense and common sense in the icu, after the manner of lewis carroll alice im intensivland. essay über unsinn und gesunden menschenverstand auf der intensivtherapiestation -im stil von lewis carroll the old man and the i sea u: being an essay on faith, fate, and evidence, after the manner of hemingway the complex interplay between delirium, sepsis and sedation concordance between dsm-iv and dsm- criteria for delirium diagnosis in a pooled database of prospectively evaluated patients using the delirium rating scale-revised- intensive care unit delirium: a review of the literature delirium in critically ill patients delirium in the intensive care unit: an under-recognized syndrome of organ dysfunction clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit benzodiazepine-associated delirium in critically ill adults effectiveness and safety of the awakening and breathing coordination, delirium monitoring/ management, andearlyexercise/mobility(abcde) bundle evidence based medicine. a new approach to teaching the practice of medicine evidence based medicine: a movement in crisis too much guidance? ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome theadultrespiratorydistresssyndromecognitive outcomes study. long-term neuropsychological function in survivors of acute lung injury pressurecontrolled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ali) or acute respiratory distress syndrome (ards) pressure-controlled vs volume-controlled ventilation in acute respiratory failure: a physiologybased narrative and systematic review mechanical ventilation in obese patients mechanical ventilation guided by esophageal pressure in acute lung injury ardsnet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome do the nih ards clinical trials network peep/fio tables provide the best evidence-based guide to balancing peep andfio settingsinadults effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis rationale, study design, and analysis plan of the alveolar recruitment for ards trial (art): study protocol for a randomized controlled trial effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome permissive hypercapnia: what to remember lung ventilation strategies for acute respiratory distress syndrome: a systematic review and network meta-analysis lower tidal volume strategy (≈ ml/kg) combined with extracorporeal co removal versus "conventional" protective ventilation (≈ ml/kg) in severe ards. the prospective randomized xtravent-study neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials impact of ventilator adjustment and sedation -analgesia practices on severe asynchrony in patientsventilatedinassist-controlmode excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury the impact of spontaneous breathing during mechanical ventilation prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: we are not sure prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: yes red blood cell transfusion: a clinical practice guideline from the aabb persistent effect of red cell transfusion on health-related qualityoflifeaftercardiacsurgery restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials and meta-analysis with trial sequential analysis effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a noncardiac surgery setting: systematic review and meta-analysis fresh versus old red cell transfusions: what have the recent clinical trials found? wissenschaftlicher beirat der bundesärztekammer ( ) querschnitts-leitlinien zur therapie mit blutkomponenten und plasmaderivaten -herausgegeben von der bundesärztekammer auf empfehlung ihres wissenschaftlichen beirats, . aufl. deutscher Ärzte-verlag anemia and transfusion in critical care: physiology and management ventricular dysfunction and dilation in severe sepsis and septic shock: relation to endothelial function and mortality beta-blocker use in severe sepsis and septic shock: a systematic review effectof heart rate control with esmolol on hemodynamic andclinicaloutcomesinpatientswithsepticshock. a randomized clinical trial preadmission beta-blocker use and -day mortality among patients in intensive care: a cohort study intensive insulin therapy in critically ill patients intensive versus conventional glucose control in critically ill patients glycemic control in the critically ill: what have we learned since nice-sugar? s -leitlinie der deutschen gesellschaft für ernährungsmedizin (dgem) in zusammenarbeit mit der geskes und der ake. besonderheiten der Überwachung bei künstlicher ernährung s e-leitlinie: lagerungstherapieundfrühmobilisation zur prophylaxe oder therapie von pulmonalen funktionsstörungen prone positioning in severe acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome therapie des akuten lungenversagens. umfrage an deutschen ards-zentren und wissenschaftliche evidenz a farewell to arms ernest hemingway: a psychological autopsy of a suicide inevitable suicide: a new paradigm in psychiatry the old man and the sea. herausgegebenvonhans-christianoeser der alte mann und das meer. aus dem englischen von werner schmitz, . aufl. rowohlt taschenbuch, reinbek bei hamburg bei kritisch kranken patienten, insbesondere bei solchen mit ards, hat die flache rückenlage zahlreiche ungünstige auswirkungen auf die hämodynamik und den pulmonalen gasaustausch. sie sollte daher gar nicht, oder bei zwingend notwendigen therapeutischen maßnahmen, so kurz wie möglich zugelassen werden [ ] .die maschinelle ventilation in bauchlage ist eine von in den beiden letzten dekaden entwickelten therapieoptionen, die die sterblichkeitsrate von ards-patienten günstig beeinflussen können [ ] . die beiden anderen sind: beatmung mit kleinen atemzugvolumina [ ] und gabe von nmba [ ] wolters kluwer health and its affiliates take no responsibility for the accuracy of any translation from the published english original and are not liable for any errors which may occur. key: cord- -mryrl s authors: raimondi, francesco; yousef, nadya; migliaro, fiorella; capasso, letizia; de luca, daniele title: point-of-care lung ultrasound in neonatology: classification into descriptive and functional applications date: - - journal: pediatr res doi: . /s - - - sha: doc_id: cord_uid: mryrl s lung ultrasound (lus) is the latest amongst imaging techniques: it is a radiation-free, inexpensive, point-of-care tool that the clinician can use at the bedside. this review summarises the rapidly growing scientific evidence on lus in neonatology, dividing it into descriptive and functional applications. we report the description of the main ultrasound features of neonatal respiratory disorders and functional applications of lus aiming to help a clinical decision (such as surfactant administration, chest drainage etc). amongst the functional applications, we propose safe (sonographic algorithm for life threatening emergencies) as a standardised protocol for emergency functional lus in critical neonates. safe has been funded by a specific grant issued by the european society for paediatric research. future potential development of lus in neonatology might be linked to its quantitative evaluation: we also discuss available data and research directions using computer-aided diagnostic techniques. finally, tools and opportunities to teach lus and expand the research network are briefly presented. the first report on the use of lung ultrasonography (lus) in adult medicine appeared in and lus has been rapidly gaining popularity, also in paediatrics and in neonatology. lus is a point-ofcare, easy-to-learn, radiation-free, bedside, quick and repeatable technique. lus signs vary little by age, which makes it especially suitable for use in the smallest patients and in the critical care setting. in the past years, there has been a notable increment in publications on the use of lus in neonatology (fig. ) , and even more in adult medicine. we demonstrated that launching a lus program in their neonatal intensive care unit (nicu) roughly halved the number of chest radiograms and significantly decreased the mean radiation dose/patient. we present a comprehensive review on lus in neonatology with an emphasis on pathophysiology and on a classification into descriptive (qualitative) and functional (semiquantitative) applications. lus is a powerful diagnostic technique and a noninvasive research tool to describe several neonatal respiratory disorders in a qualitative manner. international lus guidelines for adult critical care include a short chapter about applications in infants, based on the little data available in , and conclude that the use of descriptive lus may be of interest. many studies have been published since then, and we aim to review the knowledge available today. the main lus semiology patterns are illustrated in fig. and in the supplementary material s -s . the description of lus findings for each neonatal lung disorder is summarised in table . transient tachypnoea of the neonate the main pathophysiological feature of transient tachypnoea of the neonate (ttn) is delayed lung fluid re-absorption during the foetal life transition and this creates a mainly interstitial, ab extrinseco lung oedema. lus shows a high sensitivity and specificity to detect alveolar-interstitial oedema and to estimate extravascular lung water (evlw) in adults through the evaluation of b-lines, which are vertical dynamic artefacts arising at the fluid/ air interface. , b-lines may be sparse or confluent, creating a continuum that is generally referred to as an 'alveolar-interstitial pattern'. using lus, substantial liquid retention has been demonstrated at years of life in % of healthy neonates, while %, % and % of neonates had completed airway liquid clearance at , and h, respectively. moreover, it seems that neonates born by an elective caesarean section have higher fluid retention early after birth than those vaginally delivered. [ ] [ ] [ ] consistently, copetti and cattarossi showed that neonates with ttn have both interstitial oedema (represented by b-lines), and normal areas (represented by a-lines). a sharp increase in echogenicity was described in the lower lung fields of ttn neonates and the authors named this finding 'double lung' point. subsequent publications showed that the double lung point is not a perfect diagnostic tool for ttn, whose ultrasound appearance may include pleural line thickness, a more diffused alveolar-interstitial pattern and the presence of normally aerated areas. , this seems to be confirmed by the preliminary data of an ongoing multicentre, international study. despite the rich semiology and the absence of a unique diagnostic sign, the distinction between ttn and respiratory distress syndrome (rds) is relatively easy (see below), but it should be kept in mind that clinical and laboratory data must always be integrated with lus to refine the diagnosis. respiratory distress syndrome the typical lus appearance of respiratory distress syndrome (rds) consists of bilateral white lungs (i.e., the diffuse alveolar-interstitial pattern) with no spared areas reflecting decreased air/fluid ratio. other findings include 'sub-pleural' small consolidations and/or an irregular pleural line. these results have been confirmed by multiple studies. [ ] [ ] [ ] [ ] [ ] [ ] since rds is a more severe and diffuse condition than ttn, the absence of spared areas (with a-lines) seems the most noticeable sign and, contrary to ttn, in the absence of any treatment, lus appearance will not improve quickly. there is a high inter-observer agreement among physicians with different levels of lus expertise, which makes the differential diagnosis between rds and ttn reliable, irrespective of the operator. lus is also useful in diagnosing the complications of rds, such as pulmonary haemorrhage, pneumothorax (pnx) or atelectasis. , two pathophysiological aspects must be considered: ( ) clinical and laboratory data must always be integrated with lus to refine the diagnosis of rds, especially when it may coexist with other conditions, like pneumonia, early-onset sepsis or air leaks; ( ) mixed-type situations may exist where fluid retention is associated with partial surfactant deficiency, as this has been recently demonstrated by lamellar body count. interestingly, a semiquantitative lus score describing lung aeration (see below) correlated with lamellar body count. these mixed ttn/rds cases may last longer than classical ttn and may sometimes require noninvasive respiratory support or even a surfactant. unlike chest x-rays, lus appearance does not change shortly after surfactant administration, and this is intrinsically due to their different properties: lus detects lung fluid content, while xrays directly detect lung aeration. surfactant replacement unavoidably implies some fluid administration even with the more concentrated surfactant preparations. animal data demonstrate an almost total evlw clearance h after surfactant administration. however, the same process seems more variable and heterogeneous in human neonates, as lus appearance may be influenced by respiratory support, gestational age, fluid intake, pre-existing condition (pure rds or a more complex situation with superimposed lung inflammation and surfactant catabolism, such as acute respiratory distress syndrome (ards)) and the eventual simultaneous development of broncho-pulmonary dysplasia (bpd). neonatal ards ards is an acute, life-threatening respiratory failure, characterised by extensive lung tissue inflammation, endothelial injury and both quantitative and qualitative secondary surfactant dysfunction, leading to loss of lung aeration. neonatal ards shares the same biological and pathophysiological aspects of the syndrome in lung ultrasound semiology. the basic semiology patterns are illustrated: these patterns may be variably found in different respiratory disorders described in table . arrows indicate the sub-pleural consolidation, the border of a consolidation, the double lung point or the lung point. the size threshold to distinguish micro-consolidations (sub-pleural) from consolidations ( . cm) is arbitrary. some semiology patterns are also dynamically shown in the videos in supplementary material older patients: thus, signs on lung imaging are similar. lus findings in neonatal ards consist of bilateral diffuse loss of aeration, which may vary from a diffuse alveolar-interstitial to an irregular alveolar pattern with consolidations with bronchograms and/or atelectases. lung imaging is one of the diagnostic criteria included in the montreux definition of neonatal ards, but this officially requires x-ray findings (diffuse, bilateral and irregular opacities or infiltrates, or complete opacification of the lungs, which are not fully explained by local effusion, atelectasis, rds, ttn or congenital lung anomalies). nonetheless, lus has been used for the diagnosis of ards in adults and is considered suitable in neonates if sufficient clinical expertise exists for its interpretation. despite similarities with the syndrome in older patients, neonatal ards may also have different triggers, such as meconium aspiration syndrome (mas), lung haemorrhage, perinatal asphyxia or necrotising enterocolitis that are peculiar to newborn age. meconium aspiration syndrome meconium aspiration syndrome (mas) is the only ards-triggering condition for which lus findings have been formally described so far and they consist of a mix of normal lung areas, coalescent or sparse alveolar-interstitial pattern and consolidations with bronchograms. these signs are irregularly present all over the lungs and may change over time as the meconium-driven inflammation progresses; meconium plugs may also occur and create atelectases. these findings were confirmed in a larger study of neonates with mas and a dissociation between clinical severity and imaging findings may sometimes occur. in summary, lus signs in mas include all the possible findings ranging from normally aerated zones to a complete loss of aeration, and, when the injury is sufficiently severe and diffuse, the lesions may cause an important oxygenation impairment and qualify as neonatal ards. air leak syndromes lus signs of pnx (see supplementary material s and s ) are the absence of lung sliding and of any other sign other than a-lines; these findings are described in detail elsewhere. lus has a higher diagnostic accuracy than conventional radiology for the diagnosis of pnx in adults, as it has been demonstrated by a metaanalysis of studies. therefore, lus can potentially detect subclinical pnx that may go radiologically underdiagnosed and that does not require treatment. recently, a case report and two diagnostic accuracy studies suggest that lus may also be very useful in the diagnosis of neonatal pnx. [ ] [ ] [ ] in critically ill babies, lus can be used for rapid detection of life-threatening tension pnx: an international multicentre study confirmed that lus has an optimal diagnostic accuracy and is quicker than conventional radiology. lus also resulted more accurately than chest transillumination (which is also less accurate than conventional radiology). a case report described the use of lus to detect and follow up neonatal interstitial emphysema. no formal lus description of neonatal pneumomediastinum exists. however, pneumomediastinum has been detected in children as ( ) the absence of lung sliding on parasternal scan (with normal sliding in other chest areas); ( ) a parasternal 'still' lung point, since the air collection displaces the lungs laterally and reveals the border between the air-filled mediastinum and the displaced lung; this still lung point does not move with spontaneous breathing and it remains under the parasternal area; ( ) impossibility to obtain a normal parasternal heart view due to air artefact, regardless of the breathing cycle. , pneumonia lus typically shows pneumonia as the presence of consolidations with irregular borders and air bronchograms, associated with pleural line abnormalities, and alveolar-interstitial pattern in the adjacent areas if the inflammatory process is extended. the presence of these signs carries an optimal diagnostic accuracy according to a study performed on neonates with symptomatic pneumonia and controls. similar results were obtained in a larger cohort of chinese neonates, of whom were diagnosed with pneumonia by routine lus: among cases without any sign of lung disease by chest radiograms, there were cases with clinical and ultrasound evidence of pneumonia. these data are fully consistent with those obtained in older patients. in fact, a meta-analysis of eight diagnostic studies ( paediatric patients, including both neonates and children) yielded a sensitivity and a specificity of and %, respectively, which is superior to the accuracy of chest radiograms and comparable to that obtained combining radiology and laboratory exams. similarly, a meta-analysis of studies ( adults) showed that lus has a high accuracy (sensitivity %, specificity %) to diagnose pneumonia defined by the combination of radiological and clinical data. finally, a smaller metaanalysis of studies ( adults) showed lus to be more accurate than conventional radiology or computerised tomography (ct) alone. some points still deserve to be investigated. there are no specific data regarding pneumonia of different types (i.e. congenital, community-acquired or ventilator-associated), although lobar or haemilobar consolidations are useful to diagnose ventilatorassociated pneumonia in adults, when coupled with clinical diagnostic criteria. thresholds for the size of consolidations and exact measurement methods also need to be defined. bronchiolitis and other viral low tract respiratory infections bronchiolitis, often caused by respiratory syncytial virus (rsv), is essentially an airway inflammatory disease causing obstructive respiratory failure with possible secondary involvement of the alveolar tissue. therefore, from an ultrasound point of view, bronchiolitis presents as a nonhomogeneous pleural line abnormalities (pleural line thickening and/or irregularities), small 'subpleural' and/or larger consolidations or an alveolar-interstitial pattern, in the case of parenchymal involvement. for the sickest patients, consolidations may span across several intercostal spaces, due to associated atelectasis, viral alveolar injury or superimposed bacterial infection. if the lung injury is severe enough, patients may qualify for rsv-induced ards and this is characterised by a shift towards a mainly restrictive and severe respiratory failure with a greater loss of aeration, as described above. lus findings correlate with disease severity, with a higher proportion of hospitalised patients having positive findings compared to outpatients. moreover, findings gradually resolve with clinical improvement and the lung aeration correlates with the duration of oxygen therapy both in spontaneously breathing infants and in those needing noninvasive respiratory support. a good concordance among operators of different expertise has been reported for the ultrasound evaluation of bronchiolitis, similar to that reported for restrictive disorders. bronchiolitis findings are non-specific and shared with other viral low tract respiratory infections; thus, laboratory tests are warranted to clarify the aetiology and also rule out bacterial coinfection. only one study has evaluated lus during a h n outbreak suggesting moderate accuracy in distinguishing viral and bacterial pneumonias, as these were showing an interstitial pattern and consolidations, respectively. however, this study was performed during an outbreak and may be biased by the high disease prevalence. consistently, other case series in adults have shown nonspecific lus findings in influenza and measles. [ ] [ ] [ ] no specific neonatal studies are available in this field. broncho-pulmonary dysplasia early prediction of worsening respiratory conditions and bronchopulmonary dysplasia (bpd) is a potentially interesting application for lus, as other techniques have failed in this regard. , two studies published in the nineties addressed lus features of bpd using the trans-abdominal approach. the authors found that in bpd-developing babies, lus showed the persistence or the appearance of nonhomogeneous retro-diaphragmatic hyperechogenicity, which was not visible in controls. , . since then, ultrasound technology and our understanding of bpd have greatly improved. data on transthoracic lus and bpd are currently lacking. moreover, there are no lus data describing 'developing bpd' or the new concept of chronic pulmonary insufficiency of prematurity, that may provide new interesting areas of application for lus. malformations lus has been used to describe congenital pulmonary airway malformations (cpam), which have a variable appearance (a large or micro-cystic lesion or irregular consolidations) in line with the four histological types described in the most recent cpam classification. , the gold standard to diagnose lung malformations remains the ct-scan, though lus may allow to suspect cpam in the absence of an antenatal diagnosis. functional lung ultrasound lus may also be used in a more 'functional' way, to guide therapeutic interventions or to assist during invasive procedures. some examples of these applications already exist in the form of lus scores or decision-making protocols in adult critical care. , we shall review a few neonatal data and provide specific proposals for these applications in neonatology. scores for semi-quantitative lus a basic, three-stage classification can be set as coalescent b lines (i.e. the 'white lung image'), sparse b lines and the normal, diffuse a-line pattern. using this simple system, our group monitored the postnatal lung fluid clearance and predicted nicu admission in a cohort of late preterm and term infants. this information may be particularly valuable to healthcare providers in level i/ii perinatal centres. we also investigated the usefulness of lus linking a specific lus profile to a therapeutic decision: the presence of a bilateral severe alveolar-interstitial pattern reliably predicted the need for intubation in nicu-admitted preterm neonates (sensitivity . %, specificity %). similar results were found by other authors in a cohort of neonates older than weeks, arbitrarily classifying the lus findings as low (normal or ttn) or high risk (rds, mas, pneumothorax or pneumonia). these papers used descriptive lus to predict or guide clinical decision but did not quantify the lus findings. since lus detects the artefacts generated by the accumulation of fluid, and given that artefacts may be ranked according to the air/fluid ratio, it is possible to create scores inversely reflecting lung aeration. several semi-quantitative scores are available in adult critical care and their description is beyond our scope. nonetheless, all lus scores are based on the same semiology and, interestingly, they seem only useful in restrictive lung disorders. in fact, an obstructive condition will create air-trapping and this might not be distinguishable from a normally aerated lung at lus, as both present with a-lines. consistently, lus scores may well evaluate lung aeration, but they cannot detect over-distension, as it has been proven in ventilated adults. despite these limitations, lus scores offer the advantage of allowing serial semi-quantitative evaluations of the disease severity. we described the first lus score to be used in neonates with respiratory failure modifying a score already used in adult critical care. the main modifications were ( ) fewer lung areas to scan given the smaller chest size; ( ) use of a small linear or a microlinear 'hockey-stick' probe instead of a convex one. we were able to demonstrate that the lus score is suitable and inversely correlated to oxygenation. the score is based on three chest areas for each side (upper anterior, lower anterior and lateral) and a -to- score is given for each area: more details are shown in supplementary material s . the lus score is able to predict the need for surfactant treatment in preterm infants below weeks' gestation (area under the curve: . ( % ci: . - . ; p < . )), and in extremely preterm neonates affected by rds (area under the curve: . ( % ci: . - . ; p < . )). the diagnostic accuracy was lower in late preterm and term neonates since they may be affected by various lung disorders with different appearance and severity, such as rds and ttn, but also aspiration syndromes and sepsis or ards. lus score calculation has a high inter-observer agreement regardless of the ultrasonographers' experience. computer-aided image analyses provide an appealing approach for interpreting lus and different technologies are being developed. for instance, ultrasound lung texture analysis has already been used to examine the foetal lung and predict the need of respiratory support. we found a significant correlation between the lus score calculated by the ultrasonographer or by a supervised machine-learning approach and oxygenation indexes, while a lus score obtained with greyscale analysis, another computerised image analysis technique, did not correlate with oxygenation. computer technology is progressing fast and we speculate a future when ultrasound images will be processed free of subjective interpretation. in the meantime, available data demonstrate that a visually calculated lus score is a useful and easy tool to predict surfactant need in preterm neonates with rds, to evaluate lung aeration while titrating the respiratory support or to be used as a research outcome measure. lus score has its drawbacks (i.e. a semi-quantitative measure, impossibility to detect air-trapping) but is more easy and quickly available at the bedside than more complex techniques, such as electrical impedance tomography or respiratory inductance plethysmography. , semi-quantitative lus has not only been used for respiratory failure due to a primary pulmonary disorder, but also for neonates with heart defects causing cardiogenic lung oedema. the latter is much more common in adults and, in these cases, the lus score has been calculated simply by counting b-lines, provided that there was no consolidation due to a parenchymal process. neonates with congenital heart defects predisposing to pulmonary overflow have a higher b-line count than babies without overflow and the b-line score also correlates with the duration of ventilation. similar applications could be proposed to evaluate pulmonary overflow in the case of haemodynamically significant patent ductus arteriosus or to guide fluid management albeit specific studies are currently lacking. standardised protocol for functional lus: the safe algorithm there is a need for specific protocols integrating lus findings into diagnostic and/or operative flow-charts. formal lus protocols for the evaluation of trauma, ( ) pleural effusion. the algorithm only takes a few minutes and aims to help diagnosing the most urgent treatable complications whilst awaiting expert help. a paediatric cardiologist evaluation of congenital heart defects is included in the algorithm but only when the most urgent causes have been already ruled out. safe is designed for the average neonatologist and may be applied using any probe without losing time to change it commonly used in adult critical care. thus, lus needs to be integrated into appropriate decision-making algorithms in neonatology. point-of-care ultrasound is rapidly growing and guidelines about neonatologist-performed echocardiography have been already published, , but there are no formal algorithms for the use of lus in neonatology. a project in this direction has been specifically funded by a european society for paediatric research grant and aimed to create the 'safe protocol' (sonographic algorithm for life threatening emergencies) to standardise the use of lus in critically ill neonates. the safe protocol is designed for use in the case of unexpected and severe decompensation (bradycardia or severe desaturation requiring resuscitative manoeuvres or significantly increasing oxygen/ ventilator parameters to maintain stable oxygen saturation levels) in formerly stable infants in the nicu. it aims to help the diagnosis of the most urgent treatable complications: current knowledge on the ultrasound detection of the most critical neonatal complications was integrated into the algorithm and rapid diagnosis of unexpected and potentially fatal complications was prioritised. the safe protocol starts with an easy, subjective 'eyeball' assessment of myocardial contractility, which is comparable to other techniques which are more accurate but unsuitable during emergencies. , then, safe uses standardised items together with a simplified and rapid rule-in/rule-out approach to detect only three main life-threatening complications. as shown in fig. , the ultrasound algorithm is designed by order of urgency. hence, ruling out cardiac tamponade, which is a rare condition, is the first step in the decision tree since it may be rapidly fatal in the absence of prompt intervention followed by pneumothorax, and lastly, pleural effusion. the latter is also quite unusual, but it is associated to central venous lines often used in nicu care: current guidelines for adult critical care recommend the use of lus for the diagnosis of pleural effusion, as it outperforms chest x-rays. safe is designed for the average neonatologist, it requires only minimal training and can be performed with a single ultrasound probe, as it targets basic ultrasound signs. a preliminary evaluation of safe after basic training in an academic nicu has shown that the algorithm is quick and easy to perform, even for lesserexperienced clinicians. the safe protocol will need to be evaluated prospectively, as it has been done for similar algorithms (bedside lung ultrasound in emergency (blue) and fluid administration limited by lung sonography (falls)) presently used in adult critical care. [ ] [ ] [ ] moreover, although any probe can be used, the optimal probe needs to be determined with a specific study. further work to expand the safe protocol to include other organs is ongoing. lus-guided procedures lus has been used to guide invasive procedures in order to reduce associated complications. lus guidance is recommended for chest tube placement in adults, as this effectively reduces complications. there are no neonatal studies about these procedures, but it is highly probable that lus may provide similar advantages, also because of the smaller patients' size. we demonstrated that the lus detection of tension pnx is extremely accurate and quicker than using conventional radiology. other authors successfully performed a lus-guided drainage of a lifethreatening tension pneumomediastinum. even in the absence of specific studies, the use of lus is advisable in these situations, where enough expertise exists, as lus will likely assist the operator and make the procedure easier. lus has been shown to be effective for verifying endotracheal tube (ett) position in patients of different ages. this can be achieved by assessing the normal sliding on both hemithoraces that confirms ventilation; in turn, other studies have aimed to directly visualise the ett tip position. jaeel et al. recently performed a systematic review of neonatal studies on this topic. the studies report a successful visualisation of the tube tip in more than % of cases and this correlated with the position observed on chest radiograms in - % of cases. we must acknowledge that there were variations in techniques, calculations, probes and operators' expertise across the studies: lus visualisation of ett does not seem to be straightforward and is potentially subjected to erroneous interpretation. simpler techniques (such as digital palpation of the ett tip in the suprasternal notch) have also been proposed. unless convincing evidence is published, lus cannot be recommended as a routine technique to verify ett placement, while end-tidal co measurement is recognised as the gold standard. lus is relatively easy to learn in vivo and we have organised successful practical courses since . however, some interesting bench models have been created to mimic lus semiology and teach lus-guided procedures, although they may also be useful as an educational tool for descriptive lus. models have been created with plastic phantoms or a wet sponge with or without pork ribs, but also simply using a hand with a wet foam. [ ] [ ] [ ] [ ] conclusion there is a rapid growth in the use of lus in neonatology and an increasingly large body of evidence supporting its use in neonatal respiratory care. however, the knowledge available is still far from that acquired in adult critical care. methodological stringency and multicentre studies are needed. therefore, we have founded the neolus group (neonatal lung ultrasound for the neonate and the small infant): a dedicated research network currently counting more than members around the world and disposing of a dedicated page on social networks. this and other initiatives will contribute to the further development of lus in neonatology. a bedside ultrasound sign ruling out pneumothorax in the critically ill. lung sliding neonatal lung ultrasound exam guidelines lung ultrasound decreased radiation exposure in preterm infants in a neonatal intensive care unit international evidence-based recommendations for point-of-care lung ultrasound the comet-tail artifact. an ultrasound sign of alveolarinterstitial syndrome lung ultrasound predicts well extravascular lung water but is of limited usefulness in the prediction of wedge pressure lung ultrasound immediately after birth to describe normal neonatal transition: an observational study lung ultrasound during the initiation of breathing in healthy term and late preterm infants immediately after birth, a prospective, observational study delayed lung liquid absorption after cesarean section at term the 'double lung point': an ultrasound sign diagnostic of transient tachypnea of the newborn lung ultrasound accuracy in respiratory distress syndrome and transient tachypnea of the newborn lung ultrasonography to diagnose transient tachypnea of the newborn is the double lung point an accurate diagnostic marker fir transient tachypnoea of the neonate? a prospective international study clinical data are essential to validate lung ultrasound diagnosis of neonatal transient tachypnea and its differentiation from respiratory distress syndrome using lung ultrasound lung ultrasound in respiratory distress syndrome: a useful tool for early diagnosis diagnostic performance of point of care ultrasonography in identifying the etiology of respiratory distress in neonates neonatal lung sonography: interobserver agreement between physician interpreters with varying levels of experience use of lung ultrasound in detection of complications of respiratory distress syndrome lung ultrasonography of pulmonary complications in preterm infants with respiratory distress syndrome. ups surfactant deficiency in transient tachypnea of the newborn a noninvasive surfactant adsorption test predicting the need for surfactant therapy in preterm infants treated with continuous positive airway pressure continuous positive airway pressure and the burden of care for transient tachypnea of the neonate: retrospective cohort study surfactant administration for neonatal respiratory distress does not improve lung interstitial fluid clearance: echographic and experimental evidence the montreux definition of neonatal ards: biological and clinical background behind the description of a new entity imaging in acute respiratory distress syndrome hospital incidence and outcomes of the acute respiratory distress syndrome using the kigali modification of the berlin definition diagnosis of neonatal ards: is montreux closer to berlin than to kigali? authors' reply lung ultrasound findings in meconium aspiration syndrome lung ultrasonography to diagnose meconium aspiration syndrome of the newborn bedside ultrasonography for diagnosis of pneumothorax pleural ultrasonography versus chest radiography for the diagnosis of pneumothorax: review of the literature and meta-analysis lung ultrasound-guided emergency pneumothorax needle aspiration in a very preterm infant lung ultrasound diagnostic accuracy in neonatal pneumothorax lung ultrasonography to diagnose pneumothorax of the newborn lung ultrasound for diagnosing pneumothorax in the critically ill neonate lung ultrasound: an useful tool for the follow-up of neonatal localized interstitial emphysema pneumomediastinum as a sonographic mimic of pneumothorax the still lung point: new sonographic evidence for pneumomediastinum lung ultrasonography for the diagnosis of severe neonatal pneumonia routine application of lung ultrasonography in the neonatal intensive care unit lung ultrasound for the diagnosis of pneumonia in children: a meta-analysis systematic review and meta-analysis for the use of ultrasound versus radiology in diagnosing of pneumonia lung ultrasound for the diagnosis of pneumonia in adults: a metaanalysis accuracy and applications of lung ultrasound to diagnose ventilator-associated pneumonia: a systematic review lung ultrasound in bronchiolitis: comparison with chest x-ray can a simple lung ultrasound score predict length of ventilation for infants with severe acute viral bronchiolitis? acute respiratory distress syndrome caused by respiratory syncytial virus point-of-care lung ultrasound in young children with respiratory tract infections and wheeze lung ultrasound: a useful tool in diagnosis and management of bronchiolitis the role of lung ultrasound in viral lower respiratory tract infections prospective application of clinicianperformed lung ultrasonography during the h n influenza a pandemic: distinguishing viral from bacterial pneumonia dynamic assessment of lung injury by ultrasound in a case with h n influenza early recognition of the pandemic influenza a (h n ) pneumonia by chest ultrasound sonographic detection of radio-occult interstitial lung involvement in measles pneumonitis variables associated with the early failure of nasal cpap in very low birth weight infants reliability of cxr for the diagnosis of bronchopulmonary dysplasia sonographic prediction of chronic lung disease in the premature undergoing mechanical ventilation the value of ultrasound examination of the lungs in predicting bronchopulmonary dysplasia chronic pulmonary insufficiency of prematurity: developing optimal endpoints for drug development prenatal and postnatal management of congenital pulmonary airway malformation lung ultrasound findings in congenital pulmonary airway malformations blue-protocol and falls-protocol: two applications of lung ultrasound in the critically ill chest ultrasound in acute respiratory distress syndrome can neonatal lung ultrasound monitor fluid clearance and predict the need of respiratory support? use of neonatal chest ultrasound to predict noninvasive ventilation failure lung ultrasound as a predictor of mechanical ventilation in neonates older than weeks bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment lung ultrasound in the icu: from diagnostic instrument to respiratory monitoring tool lung ultrasonography score to evaluate oxygenation and surfactant need in neonates treated with continuous positive airway pressure point-of-care lung ultrasound in neonatology: classification into lung ultrasound score predicts surfactant need in extremely preterm neonates detection of abnormalities in ultrasound lung image using multi-level rvm classification fetal lung texture team. prediction of neonatal respiratory morbidity by quantitative ultrasound lung texture analysis: a multicenter study can we assess the severity of neonatal respiratory distress by ultrasound? a comparison of three methods noninvasive high-frequency ventilation and the errors from the past: designing simple trials neglecting complex respiratory physiology chest electrical impedance tomography examination, data analysis, terminology, clinical use and recommendations: consensus statement of the translational eit development study group evaluation of bedside pulmonary function in the neonate: from the past to the future usefulness of lung ultrasound in neonatal congenital heart disease (lusnehdi): lung ultrasound to assess pulmonary overflow in neonatal congenital heart disease assessment of extravascular lung water by ultrasound after congenital cardiac surgery: lung ultrasound after congenital cardiac surgery focused assessment with sonography for trauma (fast): results from an international consensus statement relevance of lung ultrasound in the diagnosis of acute respiratory failure: the blue protocol international federation for emergency medicine consensus statement: sonography in hypotension and cardiac arrest (shoc): an international consensus on the use of point of care ultrasound for undifferentiated hypotension and during cardiac arrest targeted neonatal echocardiography in the neonatal intensive care unit: practice guidelines and recommendations for training. writing group of the american society of echocardiography (ase) in collaboration with the european association of echocardiography (eae) and the association for european pediatric cardiologists (aepc) recommendations for neonatologist performed echocardiography in europe: consensus statement endorsed by european society for paediatric research (espr) and european society for neonatology (esn) techniques for comprehensive two dimensional echocardiographic assessment of left ventricular systolic function the search for intelligent quantitation in echocardiography: "eyeball," "trackball" and beyond the safe protocol: a sonographic algorithm for life-threatening emergencies in the neonatal intensive care unit recommendations on the use of ultrasound guidance for adult thoracentesis: a position statement of the society of hospital medicine ultrasound-guided thoracentesis: is it a safer method ultrasound guided percutaneous relief of tension pneumomediastinum in a -day-old newborn ultrasonography for endotracheal tube position in infants and children a role of end-tidal co( ) monitoring for assessment of tracheal intubations in very low birth weight infants during neonatal resuscitation at birth creating thoracic phantoms for diagnostic and procedural ultrasound training phantom model and scoring system to assess ability in ultrasound-guided chest drain positioning randomized, noninferiority study between video versus hand ultrasound with wet foam dressing materials to simulate b-lines in lung ultrasound: a consort-compliant article economical sponge phantom for teaching, understanding, and researching a-and bline reverberation artifacts in lung ultrasound the authors are grateful to the espr pulmonology section for their support. the authors are also indebted with philippe durand (md) for the cpam image. the authors also wish to thank samsung (seoul, south korea) for the technical assistance provided. videos in the supplementary material have been taken with samsung hm a or with general electrics ge logiq e , using a high-frequency linear probe. the development of the safe algorithm has been supported by the espr cure & care research grant (received by ny). the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -gipjuhhc authors: xu, jing; pan, tingting; qi, xiaoling; tan, ruoming; wang, xiaoli; liu, zhaojun; tao, zheying; qu, hongping; zhang, yi; chen, hong; wang, yihui; zhang, jingjing; wang, jie; liu, jialin title: increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine date: - - journal: respir res doi: . /s - - - sha: doc_id: cord_uid: gipjuhhc background: there is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ards). certain metabolites play a key role in ards and could serve as potential targets for developing therapies against this respiratory disorder. the present study was designed to determine such “functional metabolites” in ards using metabolomics and in vivo experiments in a mouse model. methods: metabolomic profiles of blood plasma from ards patients and healthy controls were captured using ultra-high performance liquid chromatography tandem mass spectrometry (uhplc-ms/ms) assay. univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ards patients and healthy controls to screen for “functional metabolites”, which were determined by variable importance in projection (vip) scores and p value. pathway analysis of all the metabolites was performed. the mouse model of ards was established to investigate the role of “functional metabolites” in the lung injury and mortality caused by the respiratory disorder. results: the metabolomic profiles of patients with ards were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ards patient pool. levels of phenylalanine, d-phenylalanine and phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ards. phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ards patients. in vivo animal experiments demonstrated that high levels of phenylalanine might be associated with the severer lung injury and increased mortality of ards. conclusion: increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine. trial registration: chinese clinical trial registry, chictr . registered april , http://www.chictr.org.cn/edit.aspx?pid= &htm= as a common cause of death in patients enrolled in intensive care units (icus), acute respiratory distress syndrome (ards) is associated with high morbidity ( . %) and mortality (ranging from to %) [ ] . unfortunately, despite many efforts made toward its diagnosis and treatment, the development of a drug treatment for ards remains challenging. to pursue the precise care of patients with ards, a better understanding of the mechanisms and accurate methods to prognosticate ards are required. to date, hundreds of biomarkers have been explored but very few of them have been able to successfully guide the diagnose and treatment of ards. metabolites are the downstream products of multiple intracellular biomolecules including genes and protein transporters, which enable metabolomics to serve as a remarkable tool that precisely describes "what is happening" within our body [ ] . previous studies have performed metabolomic analysis of plasma, pulmonary edema fluid and bronchoalveolar lavage fluid (balf) in ards patients, preliminarily results revealed a broad range of metabolites that could help in diagnosis and stratify ards [ ] [ ] [ ] [ ] . however, it is still unknown whether there exist any specific metabolites that not only help in identifying different phenotypes of ards but also have a crucial function in the disease process. ards is characterized by dysregulated immune response and diffused alveolar damage. it is well reported that some metabolites are capable of inducing inflammation and regulating the activation of immune cells [ , ] . kentaro tojo et al. have revealed that the enhancement of glycolysis attenuated the lung tissue injury by protecting alveolar epithelial cells from decline in energy [ ] . their results also indicated that metabolites played an important role in ards. therefore, our study aimed to find "functional metabolites" that could be potential therapeutic targets in ards. to this end, we conducted metabolomics analysis and in vivo experiments in a mouse model of ards. blood plasma samples of patients with ards and healthy controls were collected, and metabolomics analysis was conducted to find differential metabolites and altered pathways that are associated with the ards mortality. such functional metabolites were determined by selecting for the ones that were differentially expressed between ards patients and healthy controls and between the disease survivors and the non-survivors. moreover, the mouse model of ards was established to investigate the role of identified "differential metabolites" in ards mortality. the study received approval from ruijin hospital ethics committee of shanghai jiao tong university school of medicine. all patients who met the criteria for acute respiratory distress syndrome (ards) according to the berlin definition were considered for study enrollment [ ] . patients were excluded if: ) they were less than< years of age; ) they had any autoimmune diseases; ) they were on another clinical trial; ) they had chronic respiratory ailments; blood samples for metabolomic analysis were collected within h of ards diagnose. volunteers from the health center of the ruijin hospital of shanghai jiao tong university school of medicine were selected as healthy controls. altogether, a total of patients and healthy controls were enrolled in this study. blood samples that were each ml in volume were collected using heparin tube from ards patients and healthy controls. the samples were preserved as previously described [ ] . briefly, all samples were incubated at room temperature for min and then centrifuged at g, °c for min, the supernatant is obtained and stored at − °c till further use. this trial was registered with the chinese clinical trial registry under the identification number, chictr . the detail of methods for sample preparation referred to previous study [ ] . briefly, μl of sample was transferred to an eppendorf (ep) tube and vortexed for s with the addition of μl of methanol (containing μg/ml internal standard). to precipitate proteins, the sample was sonicated for min in ice-water bath and incubated for h at − °c. the sample was then centrifuged at rpm for min at °c. the resulting supernatant was transferred to a fresh glass vial for analysis. the quality control (qc) sample was prepared by mixing an equal volume of aliquot from the supernatant of each sample. for targeted uhplc-ms/ms, a μl aliquot of balf sample was transferred to an eppendorf tube. two hundred μl of extraction solution (acetonitrile-methanol, : , and containing isotopically-labelled internal standard mixture) was added and then the samples were vortexed for s, and sonicated for min in ice-water bath. the samples were incubated at − °c for hour and centrifuged at rpm at °c for min. an μl aliquot of the supernatant was transferred to an auto-sampler vial for uhplc-ms/ms analysis. ultra-high pressure liquid chromatography-mass spectrum/mass spectrum (uhplc-ms/ms) analysis was performed using an uhplc system ( , agilent technologies) with a uplc hss t column ( . mm × mm, . μm) coupled to q exactive mass spectrometer (orbitrap ms, thermo). the mobile phase a was consist of positive ( . % formic acid in water)and negative modes ( mmol/l ammonium acetate in water). the mobile phase b was acetonitrile. the lc method used for detailed metabolite profiling with higher resolution was as follows: column temperature °c, flow rate . ml/min, injected volume μl. the parameters for elution gradient was as follows: ~ . min, % b; . ~ . min, %~ % b; . ~ . min, % b; . ~ . min, %~ % b; . ~ min, % b. the qe mass spectrometer (orbitrap ms, thermo) was used to acquire ms/ms spectra data under the control of the acquisition software (xcalibur . . , thermo). in information-dependent acquisition (ida) mode, the acquisition software continuously evaluated the full scan ms spectrum. the esi source conditions were set as following: sheath gas flow rate as arb, aux gas flow rate as arb, capillary temperature °c, full ms resolution as , , ms/ms resolution as , , collision energy as / / ev in nce mode, spray voltage as . kv (positive) or − . kv (negative), respectively. to prepare the standard solution preparation, stock solutions were prepared by dissolving or diluting each standard substance to a final concentration of mmol/ l. an aliquot of the stock solutions was transferred to a ml flask to form a mixed working standard solution. a series of calibration standard solutions were then prepared by stepwise dilution of this mixed standard solution (containing isotopically-labelled internal standard mixture in identical concentrations with the samples). the uhplc system used was the same as described above, equipped with a waters acquity uplc beh amide column. an agilent triple quadrupole mass spectrometer (agilent technologies), equipped with an ajs electrospray ionization (ajs-esi) interface, was applied for assay development. the mrm parameters for each of the targeted analytes were optimized using flow injection analysis. several most sensitive transitions were used in the mrm scan mode to optimize the collision energy for each q /q pair. among the optimized mrm transitions per analyte, the q /q pairs that showed the highest sensitivity and selectivity were selected as 'quantifier' for quantitative monitoring. the additional transitions acted as 'qualifier' for the purpose of verifying the identity of the target analytes. agilent mass hunter work station software (b. . , agilent technologies) was employed for mrm data acquisition and processing. the raw data were converted to the mzxml format using proteowizard and processed by the xcms-based r-script for peak detection, extraction, alignment, and integration. then the kyoto encyclopedia of genes and genomes (kegg, http://www.genome.jp/kegg/) and human metabolome database (hmdb, http://www.hmdb.ca/) were applied in metabolite annotation. mouse model and survival curve c bl/ mice ( - weeks old) were intratracheally injected with pseudomonas aeruginosa [ × colonyforming units (cfu) of pao strain, atcc, manassas, va, usa] in μl phosphate-buffered saline (pbs) or just equal volume of pbs as a control. to determine the role of phenylalanine in the mortality of ards, mice were pretreated with phenylalanine (sangon biotech, shanghai, china; a - ) or pbs ( mg/ml in a total volume of ul by intravenous route) h before the intratracheal injection of pao , mortality was monitored for days and every h during the week the mice were administrated with another dose of phenylalanine or pbs until death. the mice were pretreated with phenylalanine h before the intratracheal injection of pao . every h the mice were given another dose of phenylalanine and then sacrificed h later after the infection. balf and lung tissue were obtained to determine the lung injury. the lungs were perfused with . ml of pbs ( times, . ml/perfusion) using a -gauge endotracheal catheter, followed by the collection of balf from the right lung (the left lung was ligated with string). the supernatant of balf samples was used to assess the protein concentration by bovine serum albumin protein assay (sigma-aldrich, st. louis, mo, usa) and the red blood cell in pellet was removed by lysis buffer (ack lysis buffer, gibco, grand island, ny, usa) and then assayed for white cell counts with a cell counter (jimbio, jimbio technology, jiangsu, china). the left lung of the mice was processed for hematoxylin and eosin (he) staining. univariate analysis and multivariate statistical analysis performed by metabo analyst (v . ) were used to discriminate significant metabolites between different groups. all data were normalized to sum and pareto scaled prior to further analysis. principle component analysis (pca) was applied to find the distribution features of the dataset. partial least square-discriminant analysis (pls-da) was used to determine the variable importance in projection (vip) of each compound, the models were validated by permutation test (n = ) to avoid over-fitting. cross validation was to determine the optimal number of components needed to build the pls-da mode. only compounds with a p value < . (student's t test) and vip value > . were considered significantly different between groups. the pathway analysis module was performed based on kegg database to identify the utmost affected pathway. receiver operating characteristic (roc) curve and area under the roc curve (auroc) performed by graphpad prism (version . ) were used to evaluate the prognostic value of potential biomarkers in patients with ards. the combined model of biomarkers was created by binary logistic regression analysis. the independent samples t-test and mann-whitney u-test were performed by spss . to compare normally or non-normally distributed data respectively. categorical data were compared using the chi-square or fisher's exact test. kaplan-meier plots and the log-rank test were used to compare survival between the groups treated with pbs or phenylalanine. all tests were two-tailed, p < . was considered to indicate statistical significance. between may and june , a total of patients who fulfilled the berlin definition of ards and healthy volunteers were included in this study. the patients of ards were divided into survivors and nonsurvivors based on intensive care unit (icu) mortality. table shows characteristics of each trial subject at the time of plasma collection including age, gender, risk factors of ards, severity scores of disease, laboratory results and outcomes. appropriate measures were taken to have no difference of age and gender between the ards patients and the healthy controls. compared to the survivors, the non-survivors of ards patients had a higher acute physiology and chronic health evaluation ii (apacheii) score, other than that, no significant differences were found between the two groups. we identified metabolites from the plasma samples using ultra-high performance liquid chromatography tandem mass spectrometry (uhplc-ms/ms) assay. see supplementary table s for the abundance and distribution of these metabolites in plasma samples from patients and healthy volunteers. the differential metabolomic profiles between the ards patients and the healthy controls, and between the survivors and the non-survivors from the patient pool were obtained via principal component analysis (pca) and partial least square-discriminant analysis (pls-da). these score plots displayed a significant separation between ards patients and healthy controls (fig. a) . cross validation showed that five components were optimal to build the model, based on which we calculated the related statistics (fig. c) . the r was ( . ) for the validity of pls-da model against over-fitting and the predictive ability was described by q ( . ). the permutation test (n = ) with a p value less than . indicated toward good predictive ability of pls-da models ( figure s ). statistically significant separation of metabolomic profiles was also observed between the survivors and non-survivors of ards (fig. b) , and pls-da served as a valid model for discriminating the metabolites (r = . , q = . ) (fig. d) . variable importance in the projection (vip) is a weighted sum of squares of the pls loadings taking into account the amount of explained y-variation, in each dimension (https://www.metaboanalyst.ca). the higher vip scores of the metabolites had, the more important contribution of it in the differences between groups. a vip plot generated from the pls-da models ranked individual metabolites for their power to discriminate ards from controls (fig. a) . it can be seen that phosphatidylcholine (pc) ( : / : ), isoleucine, d-phenylalnaine and l-gulose in the plasma were mainly contributed to the metabolic differences between ards patients and healthy controls (vip > . ). the differences in the metabolic profiles of the survivors and the non-survivors of ards patients are shown in fig. b . they were mainly attributed to d-phenylalanine, myristic acid and oleic acid in the plasma (vip > . ). the heatmap shows the abundance of top metabolites in all individuals based on vip scores. we found several glycerophospholipids like -linoleoylglycerophosphocholine, pc( , / : ), phosphatidylcholine lyso : , and lysopc : ( z, z, z, z) that were significantly downregulated in the ards patients compared to the healthy controls (fig. c) . the levels of d-phenylalanine and phenylalanine increased in the non-survivors compared to the survivors while a group of short peptides containing different amino acid residues downregulated in the non-survivors (fig. d) . screening of differentially expressed metabolites as potential mortality predictors for ards we next investigated the potential biomarkers and mortality predictors of ards patients. to preliminary screen the differential metabolites, we selected the metabolites that had a p value less than . (calculated by student's t-test) and a vip score greater than . (calculated using pls-da model). the differential metabolites between ards patients and healthy controls are displayed in table . similarly, the metabolites that were found to distinguish the non-survivors from the survivors of ards are shown in table . among all those selected compounds, phenylalanine, d-phenylalanine, phenylacetylglutamine and a short peptide (gly pro gly lys) were identified in both groups (ards vs healthy controls and survivors vs non-survivors) (fig. a) . as phenylalanine, d-phenylalanine and phenylacetylglutamine are all involved in the phenylalanine metabolism, we focused on these three metabolites. the box whisker plots showed that all of three compounds had significant higher concentration in the non-survivors compared to the survivors (fig. b-d) . phenylalanine and d-phenylalanine had higher levels in the ards patients compared to the healthy controls (fig. b-c) . we also compared these metabolites in ards patients with different severity (mild moderate and severe) according to berlin's definition. the levels of phenylacetylglutamine were markedly lower in moderate ards patients compared to severe ards patients ( figure s ). there was no significant difference among the concentration of phenylalanine and d-phenylalanine in three groups ( figure s ). to investigate the effect of these three differentially expressed metabolites in predicting the mortality of ards, we plotted a roc curve (fig. e) to assess the sensitivity and specificity. the area under the roc curve (auc) of phenylalanine, d-phenylalanine and phenylacetylglutamine is . , . and . , respectively, indicating that phenylalanine had the highest efficacy in predicting the mortality of ards. in the combined model the auc was . . pathway analysis reveals the phenylalanine pathway to be one of the most significantly altered pathways in ards patients to gain the functional interpretation of these numerous compounds in ards, we applied pathway analysis of the metabolites identified in our data. the pathways that altered between ards and healthy controls or between survivors and non-survivors were listed in table s . figure a and b display all matched pathways. we screened the quantitative data are presented as mean ± sd, qualitative data are presented as number (%), p-value for the survivors and non-survivors of ards; apache acute physiologic and chronic health evaluation, crp c-reactive protein, pct procalcitonin, ecmo extracorporeal membrane oxygenation; * p < . tested by student t test. # p < . tested by chi-square test pathways with an impact factor greater than and a p value less than . , the top pathways in the group of ards versus healthy controls were ) purine metabolism pathway, ) phenylalanine, tyrosine and tryptophan biosynthesis pathway, ) histidine metabolism pathway, ) phenylalanine metabolism pathway and ) glycerophospholipid metabolism pathway. in the survivors versus non-survivors group, only three pathways satisfied the standards of screening, they were ) d-glutamine and d-glutamate metabolism pathway, ) phenylalanine, tyrosine and tryptophan biosynthesis pathway, and ) phenylalanine metabolism pathway. figure c shows that in both the ards versus healthy controls group and the non-survivors versus survivors group, phenylalanine metabolism pathway, phenylalanine, tyrosine and tryptophan biosynthesis pathway were identified as the most significantly altered pathways. to visualize the change of metabolites in the most significantly altered pathways between non-survivors and survivors, the metabolic network was plotted (fig. d) , all the matched metabolites in our data that involved in the pathways were marked in red, yellow and green according to the different levels of significance. in phenylalanine metabolism pathway, five compounds were matched and three of them (phenylalanine, d-phenylalanine and phenylacetylglutamine) upregulated while tyrosine and hippurate were downregulated in the non-survivors compared to the survivors. in phenylalanine, tyrosine and tryptophan biosynthesis pathway, three metabolites were matched with our data, l-tryptophan and phenylalanine levels increased while tyrosine levels decreased in the non-survivors. in d-glutamine and dglutamate metabolism pathway, only one metabolites (glutamine) was matched and was found to be significantly downregulated in the non-survivors. the differential metabolites and pathway analysis indicated that phenylalanine, d-phenylalanine and phenylacetylglutamine might play a role in ards. d-phenylalanine and phenylacetylglutamine are products of phenylalanine, and the roc analysis showed that phenylalanine had the highest accuracy of predicting the mortality. therefore, we investigated whether phenylalanine increased the mortality of ards in a mouse model. the ards mouse model was established and phenylalanine was administrated by intravenous injection. as shown in fig. a , mice were pretreated with phenylalanine at h and received intratracheal injection of pseudomonas aeruginosa (pao ) at h. the ards mice and sham mice were administrated with either a dose of phenylalanine or pbs every h, following which the mice started to die at h after injection of pao . a significant increase of mortality rate was observed around h, at which time % of the mice injected with phenylalanine and % of mice injected with pbs found dead. at days after pao injection, the phenylalanine group had significantly lower survival rate ( %) compared to those treated with pbs ( %) (fig. b) . the same amount of phenylalanine was administrated in sham mice without ards every h for days and no death was observed during the period (fig. b) , confirming that the concentration of phenylalanine we used was not lethal in control mice. to determine the changes of phenylalanine and other related amid acids in balf after the phenylalanine injection, we performed targeted uhplc-ms/ms to assay phenylalanine, glutamine, tyrosine and tryptophan in sham mice after two doses of intravenous injection of phenylalanine. the phenylalanine in balf significantly increased after injection, whereas the tyrosine (downstream products of phenylalanine) did not change, indicating that intravenously injection of phenylalanine increased the levels of this amino acid in lung. we found the levels of glutamine and tryptophan (not significantly) in balf also increased after injection of phenylalanine ( figure s ). the lung injury of mice were assayed h post injection with pao , protein and white cell counts in bronchoalveolar lavage fluid (fig. b-c) increased in ards mice injected with phenylalanine compared to those treated with pbs, indicating that phenylalanine increased the recruitment of inflammatory cells and impairment of alveolar epithelial cells. the pathological changes in lungs of mice with ards assayed by hematoxylin-eosin (he) staining indicated severer destruction of alveoli and inflammation in phenylalanine group than that in pbs group (fig. e) . the lung injury in sham mice treated with phenylalanine and pbs had no significant differences. together, these results confirmed that phenylalanine administration increased the lung injury and mortality of ards mice but not in sham mice. in this study, we found that the global metabolomic profile of blood plasma from an ards patient was remarkably different than that of a healthy volunteer. striking difference in the metabolomic profile was also noticed between the survivors and the non-survivors of this disease. by metabolomics analysis, we uncovered metabolites differences as well as the altered pathways that attributed to the mortality of ards patients. of note, we showed that the level of phenylalanine increased in the non-survivors compared to the survivors and we confirmed using a mouse model that phenylalanine administration increased the lung injury and mortality of mice with ards. phenylalanine is an essential amino acid required for biosynthesis of neurotransmitters [ ] . the high serum phenylalanine is neurotoxic, producing intellectual disability, and other neurologic features [ ] . recently, the role of phenylalanine in acute inflammatory diseases has been increasingly investigated. it was found that the serum phenylalanine increased in patients post trauma or with sepsis [ ] and was associated with the activation of immune response [ , ] . in a recent study, shie-shian huang and et al. uncovered that high levels of serum phenylalanine was associated with high mortality risk in patients with severe infection [ ] . consistent with our findings of phenylalanine, akhila viswan and his colleagues reported that the relative concentration of phenylalanine increased in non-survivors of ards patients compared to survivors [ ] . another study also revealed the upregulation of phenylalanine metabolism in patients with more severe ards compared to those with less severity. although these studies provided supportive evidence of the associations between phenylalanine and the prognosis of ards, it is hard to determine whether the increased phenylalanine was just a phenotype reflecting the severity or it also played a role in the process of ards [ ] . through the injection of phenylalanine in ards mice, our study demonstrated that phenylalanine played a detrimental role of in ards. the accumulation of phenylalanine could be a consequence of reduced activity of phenylalanine hydroxylase (pha) and its cofactor , , , -tetrahydrobiopterin (bh ) [ ] . these enzymes convert phenylalanine into tyrosine. to be noted that, in our results, the levels of tyrosine decreased in the non-survivors compared to the survivors of ards patients (not a significant difference though), which means the turnover of phenylalanine into tyrosine in the non-survivors may be impaired. a number of studies have indicated that the deficiency of pha and bh in inflammatory disease may be due to the overwhelming production of reactive oxygen species (ros) [ , ] . therefore, it was possible but not conclusive that the increased phenylalanine in the non-survivors of ards was due to the deficiency of pha and bh induced by inflammation. the accumulated phenylalanine in turn amplified the already existing inflammation. a study found that intraperitoneal injection of phenylalanine increased il- secretion in early pregnancy mice, which implied that phenylalanine could sustain t cell proliferation and thereby enhance the adaptive immune in response [ ] . more recently, ming jiang et.al demonstrated that phenylalanine enhanced the innate immune response of the host [ ] . multiple immunological processes involving neutrophils, macrophages, and dendritic cells participate in mediating lung tissue injury in ards [ ] . thus the activation of immune response by phenylalanine may exert negative impact on ards. our data showed that phenylalanine increased the lung injury of mice with ards, which we speculated was associated with the role of phenylalanine in promoting inflammation. phenylacetylglutamine was recently reported to be a gut microbiota generated metabolite fermented from dietary phenylalanine [ ] . the levels of phenylacetylglutamine significantly decreased in human after a -day course of oral broad spectrum antibiotics cocktail. further investigation revealed microbial pora gene in clostridium facilitated the conversion of phenylalanine into phenylacetylglutamine [ ] . in our study, the levels of phenylacetylglutamine were lower in ards than that in controls, which was presumably due to the damage of gut microbiota caused by antibiotics use in ards patients. phenylacetylglutamine was demonstrated to enhance platelet activation-related phenotypes and thrombosis potential in animal models of arterial injury [ ] . pulmonary thrombosis is common in sepsis-induced ards shown by human and animal studies [ ] . platelets could promote pulmonary vascular damage in sepsis induced ards, thereby aggravating the lung injury [ ] . we found the non-survivors of ards had higher levels of phenylacetylglutamine than survivors, the mechanisms underlying may be related to the roles of phenylacetylglutamine in modulating platelets and thrombosis. in the last decades, a broad range of drug therapies emerged for improving ards, but none showed efficacy in phase ii and iii trials [ ] [ ] [ ] [ ] [ ] [ ] . given the high mortality rate of ards, even a small improvement can save many lives. nutritional input may be a good choice as a new adjuvant strategy for ards, since most metabolites can be manipulated by simply controlling the uptake from food. omega- fatty acids were once used for fig. pathway analysis reveals the phenylalanine pathway to be one of the most altered pathways in ards patients. a pathway analysis uncovered the altered pathways in ards patients vs healthy controls. b pathway analysis uncovered the altered pathways in the survivors vs non-survivors of ards. all matched pathways were shown according to p values from pathway enrichment analysis (y-axis) and all pathway impact values were according to pathway topology analysis (x-axis). the color and size of each circle are based on p values and pathway impact values, respectively. the deeper the red of the nod, the more significant alteration of the pathway is observed. small p value and big pathway impact circles indicate that the pathway is greatly influenced. c the pathways that are altered between ards and healthy controls (pink circle) or between survivors and non-survivors (blue circle). the pathways in the cross area were identified in both groups. d schematic diagram of metabolic pathway networks. the metabolites involved in the selected pathways (p < . ,impact factor > ) altered between the survivors and the non-survivors were marked in different colors. light blue means those metabolites are not in my data and are used as background for enrichment analysis; red (p < . ) and yellow (p > . ) means the metabolites are upregulated in the survivors deep green (p < . ) and light green (p > . ) mean that the metabolites are downregulated in survivors with different levels of significance. the metabolites in the box belong to the same pathway treatment of ards but ended up with a negative results, one of the reasons for this could be the failure of identifying specific metabolites in ards patients [ ] . however, with the development of metabolomics, we are able to screen the most specific metabolites that play a role in ards [ ] . our study has revealed that controlling the uptake of phenylalanine might be a novel strategy for treating ards. this would also open new avenues in the control of pathological inflammatory responses. sufficient (high-dose) protein was suggested to be provided in critically ill patients [ ] , nevertheless, eight essential amino acids including phenylalanine were indispensable the survival rate of ards mice (n = /group) and sham mice (n = /group) treated with phenylalanine or pbs. c the levels of phenylalanine and tyrosine in balf of sham mice treated with phenylalanine or pbs (n = - /group). d the protein concentration in bronchoalveolar lavage fluid (balf) (n = - /group). e the white cell counts in balf (n = - /group). f the hematoxylin and eosin staining of lung tissue (n = - /group) phe = phenylalanine. each value represents the mean ± sem of one of the three independent experiments. kaplan meier survival analysis and comparisons were performed by log-rank test in our commonly used parenteral and enteral nutrition. to reduce the uptake of phenylalanine, the phenylalaninerestricted diet designed for phenylketonuria patients might be a good choice. it is a feasible and easy approach that can be implemented in ards patients. the present study still has some limitations. the small samples size of our ards patients was the main one. however, the matched age and gender ratio as well as the strict screening standards by multivariate and univariate analysis minimized the artificial mistakes. secondly, the commonly used drugs in critically ill individuals could also be detected in our analysis. it was difficult to interpret the role of these metabolites, therefore, we didn't include them in our list of differential metabolites and focused only on the endogenous compounds. thirdly, the nutritional status of ards and control subjects was not controlled for, which could affected the results of metabolomics. lastly, the untargeted screening by metabolomics can only obtain relative concentrations of metabolites, quantitative metabolomics should be used in the future studies to confirm the absolute concentration of phenylalanine and its related metabolites in ards patients. in conclusion, our study revealed that the perturbance of phenylalanine metabolism was associated with the rate of mortality in ards. phenylalanine increased in the ards patients compared to the healthy controls, and in the nonsurvivors compared to the survivors of ards. moreover, our study is the first to demonstrate high levels of phenylalanine were associated with the aggravated lung injury and increased mortality of ards mice. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries metabolomics for investigating physiological and pathophysiological processes explore potential plasma biomarkers of acute respiratory distress syndrome (ards) using gc-ms metabolomics analysis distinct metabolic endotype mirroring acute respiratory distress syndrome (ards) subphenotype and its heterogeneous biology untargeted lc-ms metabolomics of bronchoalveolar lavage fluid differentiates acute respiratory distress syndrome from health profiling of ards pulmonary edema fluid identifies a metabolically distinct subset alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury acute respiratory distress syndrome: the berlin definition l-histidine, arachidonic acid, biliverdin, and l-cysteine-glutathione disulfide as potential biomarkers for cured pulmonary tuberculosis amino acids and immune response: a role for cysteine, glutamine, phenylalanine, tryptophan and arginine in t-cell function and cancer? phenylalanine ammonia lyase (pal): from discovery to enzyme substitution therapy for phenylketonuria serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations immune activation and inflammation in patients with cardiovascular disease are associated with higher phenylalanine to tyrosine ratios: the ludwigshafen risk and cardiovascular health study serum phenylalanine concentrations in patients with ovarian carcinoma correlate with concentrations of immune activation markers and of isoprostane- phenylalanine-and leucine-defined metabolic types identify high mortality risk in patients with severe infection chronic immune stimulation correlates with reduced phenylalanine turnover mechanisms of inflammation-associated depression: immune influences on tryptophan and phenylalanine metabolisms the immunologic and antioxidant effects of l-phenylalanine on the uterine implantation of mice embryos during early pregnancy phenylalanine enhances innate immune response to clear ceftazidimeresistant vibrio alginolyticus in danio rerio the acute respiratory distress syndrome: from mechanism to translation microbiota-derived phenylacetylglutamine associates with overall mortality and cardiovascular disease in patients with ckd the role of microvascular thrombosis in sepsis impact of thrombosis on pulmonary endothelial injury and repair following sepsis statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials the role of neutrophil elastase inhibitors in lung diseases matrix metalloproteinases and protein tyrosine kinases: potential novel targets in acute lung injury and ards emerging drugs for treating the acute respiratory distress syndrome anti-tnfα therapy in inflammatory lung diseases acute respiratory distress syndrome enteral omega- fatty acid supplementation in adult patients with acute respiratory distress syndrome: a systematic review of randomized controlled trials with meta-analysis and trial sequential analysis guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all the patients and guardians of those patients for their participation in the study we would also like to acknowledge the professors and colleagues from shanghai jiaotong university including the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the human study was approved by the ruijin hospital ethics committee shanghai jiao tong university school of medicine. this trial is registered with the chinese clinical trial registry under number chictr . the animal study was approved by the university committee for laboratory animals and was performed in accordance with the guidelines of the shanghai institutes for biological sciences council on animal care. not applicable. the authors declare that they have no competing interests. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . additional file . key: cord- -oxbquzeg authors: dwenger, a.; beychok, c.; schweitzer, g.; pape, h. c.; röllig, g.; nerlich, m. l.; jonas, e.; funck, m.; zimmermann, t.; albrecht, s.; schuster, r.; lauschke, g.; jaroß, w.; kaever, v.; schmitz, e.; resch, k.; brandl, h.; böhm, w. -d.; beckert, r.; köstler, e.; menschikowski, m.; kacian, d.; lawrence, t.; sanders, m.; putnam, j.; majlessi, m.; mcdonough, s.; ryder, t.; santana rodríguez, j. j.; sosa ferrera, z.; afonso perera, a.; gonzález díaz, v. title: bioluminescence, chemiluminescence date: journal: fresenius j anal chem doi: . /bf sha: doc_id: cord_uid: oxbquzeg nan in the recent years the essential role of granulocytes in the initiation and amplification of the pathomechanisms resulting in the adult respiratory distress syndrome (ards) has been documented [ , - ] . on the contrary, there is only little information about the participation of alveolar macrophages in the ards pathogenesis [ ] and no report on alterations of macrophage functions during the development of the ards. bronchoalveolar lavage fluid (balf) of multiply traumatized patients (injury severity score > points; ards and non-ards patients) and of controls (co) was centrifuged at x g, min, °c [ , ] . the supernatant was analysed for/ln-acetyl-gtucosaminidase (fl-nag) spectrofluorimetrically and for elastase by enzymeimmunoassay [ ] . the cell pellet was resuspended in phosphate buffered saline and the cell count was determined after staining with tfirk's solution and the cell pattern by the use of a cytospin [ ] . for the separation of granulocytes (pmnl) and alveolar macrophages (am ) the cell resuspension was centrifuged on percoll ( . g/ ml) at x g, min, ° c. from citrated blood granulocytes were isolated by a two-step discontinuous percoll gradient ( . / . g/ml) centrifugation at x g, min, ° c. the zymosan-induced and luminol-enhanced chemiluminescence response (cl) of granulocytes and macrophages, respectively, was determined with a six-channel biolumat lb [ , ] . urea was determined enzymatically in the plasma and the balf [ ] and the concentration of proteins/cells in the epithelial lining fluid (elf) was calculated according to cel f : cbalf " curea_plasma/curea_balf statistical analyses were performed by the student's nonpaired t-test. for calculation and graphical presentation the results of each days were combined. the posttraumatic courses of alveolar neutrophil and macrophage counts as well as the cell patterns of the bronchoalveolar lavage fluids for ards and non-ards patients are listed in table . figure depicts the chemiluminescence response of isolated blood and alveolar neutrophils (a) and alveolar macrophages (c) of multiply traumatized patients as well as the secretion activity of alveolar neutrophils (b) and alveolar macrophages (d) for ards and non-ards patients after multiple trauma. in the posttraumatic course the total alveolar cell count increased for ards patients and decreased for non-ards patients for up to days, predominantly caused by the neutrophil influx. there was an early (days / ) pathological elevation of the neutrophil fraction above normal values ( < % neutrophils) that further increased for ards patients and decreased for non-ards patients, whereas the alveolar macrophage fraction ( % for normals) exhibited the corresponding inverse behaviour. concerning the chemiluminescence response against zymosan, blood neutrophils were hyperactive and balf derived _+ sem n = (pmnl) n = (am~b), * p < . posttraumatic enzyme secretion activity ( + sem) of alveolar neutrophils b as gg elastase/ pmnl (calculated from gg elastase/ elf/pmnl count/ elf) and alveolar macrophages d as mu fl-nag/ amg~ (calculated from mu fl-nag/ elf/ am~b count/ elf) for ards and non-ards patients neutrophils were hypoactive from the beginning up to day after trauma, whereas alveolar macrophages developed a hyperactive state not before days or . on the contrary, alveolar macrophages were already active in enzyme secretion in the initial posttraumatic course (days / ), especially of ards patients. alveolar neutrophils showed an initially increased enzyme secretion, especially in non-ards patients. the secretory reactivity decreased for both cell types and for both patient groups up to days after trauma. after multiple trauma alveolar macrophages responded with different cellular reactions in different time courses, whereas alveolar neutrophils seemed to have lost most of their metabolic capacity before they invaded into the alveoli. polymorphonuclear leukocytes (pmnl, neutrophils) hyperactivated by multiple trauma release oxygen derived radicals and lyosomal enzymes. these inflammatory mediators can damage endothelial structures of capillaries and, therefore, contribute to the development of multi-organ failure including the adult respiratory distress syndrome (ards) [ , ] . one therapeutical approach to prevent the ards is based on the inhibition of neutrophil functions by prostaglandin e (pgei) [ ] . citrated blood was obtained from donors, pmnl were isolated by percoll gradient centrifugation [ , ] . the oxygen radical production was measured by luminol ( . mmol/ test) and/or lucigenin ( . retool/ test) enhanced chemiluminescence response (cl) (biolumat lb , berthold) in absence or in presence of different stimuli, n-formyl-l-methionyl-l-leucyl-l-phenylalanine (fmlp, sigma; . • - tool/ test), zymosan a (sigma; . mg/ml test), latex (unisphere latex , . gin, serva; gl/ml test), lipopolysaccharide (lps from e. coli serotype no. :b , sigma; ng/ml test), /~-phorbo /%myristate a-acetate (pma, sigma; • ] - tool/ test) and nylon fiber (from leuko-pak leukocyte filter, fenwal, travenol laboratories; rag/test) [ ] [ ] [ ] . all parameters have been measured in dependency on the pge concentration (alprostadil, schwarz pharma ag). the enzyme release was determined by the measurement of the intra-and extracellular elastase activity by the kinetical enzyme test with methoxysuccinyl-l-ala-l-ala-l-pro-l-val-pnitroanilide (bachem) as a substrate and of the /~-n-acetylglucosaminidase (/%nag) activity determined spectrofluorimetrically [ , ] . briefly, neutrophils were isolated from citrated blood and resuspended in minimal essential medium .) and cl response (%; g ..... q) of neutrophils in citrated blood in dependency on the pge concentration. stimulus: mg of nylon fiber (lucigenin-enhanced cl). ± sem; n = . % = cl response ( cpm/ pmnl of the peak maximum) in the presence of the lowest pge concentration. * p < . values vs % values (boehringer) with . % bovine serum albumin to ~ pmnl/ ml. pge was added ( ; ; , and ng/ml) and after min at °c the stimulation was started with fmlp ( . - - tool/ test). after rain at °c the reaction mixtures were centrifuged and the supernatants were analysed for elastase and fl-nag. additionally, an aliquot of the original pmnl suspension was lysed and the enzymes were determined [ , ] . the neutrophil count in blood and of isolated cells was performed by the use of a neubauer hemocytometer after staining with tiirks solution [ , ] . the significance between groups of values were tested by the tests according to wilcoxon and mann-whitney, respectively, and accepted if p < . . the dose-dependent inhibition by pgei of the cl response of isolated neutrophils after stimulation with different stimuli is shown in fig. i the dose-dependent inhibition by pgei of adherence and cl response is shown in fig. d. the correlation coefficient between adherence and cl values was r = . . the fmlp-induced enzyme release (elastase/fl-nag) was %/ . % without pge ; %/ % with ng/ml; . %/ . % with ng/ml; . %/ . % with ng pge /ml test volume ( % = total intracellular enzyme activities). the values represent the means of experiments. the production and the release of oxygen derived radicals and lysosomal enzymes from stimulated polymorphonuclear leukocytes were inhibited by prostaglandin e in a dose-dependent manner. furthermore, regarding the nylon fiber system as an artificial but relevant model for endothelial cell adherence [ ] the observed inhibition by pge of adherence and cl response seems to be of marked pathophysiological importance. since the contact activation/stimulation of neutrophils was inhibited and less inflammatory mediators were produced, less endothelial cell and tissue structure damage can be produced in an in vivo system. the good correlation of adherence and cl production in absence and in presence of pge indicated that the oxygen radical production is nearly exclusively caused by adherence-mediated stimulation and can be inhibited by pge . as a result, pgei may be a drug to prevent inflammationinduced damage of capillary endothelial structures in different disorders, e.g. the adult respiratory distress syndrome. the present study is based upon the theory that polymorphonuclear leukocytes (pmnl, neutrophils) play an important role in inflammatory reactions [ ] . further investigations hypothesize that affection of endothelial cells (ec), mediated by lipopolysac-% control charide (lps)-stimulated neutrophils, is rather caused by oxygen derived metabolites than by lysosomal enzymes [ , ] . in- vestigations, performed with endothelial cells, have shown a respiratory burst stimulation of neutrophils during adherence of neutrophils to ec and amplification of this process by previous lps-priming of neutrophils [ ] . the aim of the present study was to examine, if pge might influence injury to ec, caused by lps-primed neutrophils, and furthermore, if this effect could be explained by a diminished oxygen radical production, measured by chemiluminescence (cl). human umbilical cord vein endothelial cells were harvested according to [ ] . after reaching confluence in rm-medium containing % human serum, endothelial cells were trypsinized onto cover slips (lux scientific corporation) for measurement of chemiluminescence response and were split onto microtiter wells (greiner co) for measurement of cell injury. neutrophils. blood of healthy donors was preincubated for rain at °c with ng lps/ml blood (lps: e. coli serotype : b , sigma co). neutrophils were prepared using percoll density gradient centrifugation according to [ ] , and were resuspended in phosphate buffered saline. , neutrophils were added to , endothelial cells/test. varying concentrations of prostaglandin e (donation of schwarz pharma, monheim, frg) were prepared in . % nac solution. concentrations were , , , , and ng/ml test. chemilumineseenee measurements. production of oxygen derived metabolites by neutrophils was measured by lucigenin enhanced chemiluminescence, which has been measured simultaneously in a six channel biolumat (lb c, berthold, wildbad, frg). chemiluminescence measurements (cpm of peak maximum) of lps-primed neutrophils were performed in the absence and presence of varying concentrations of pge . injury assay. the evaluation for ec damage was based upon in_release from labeled endothelial cells, as described [ ] . statistical analysis. for statistical analysis u-test according to mann-whitney was used. values represent mean ÷/-sem of experiments performed in duplicate. ( l ( ) ( ) ]- the release of toxic oxygen metabolites from sensitised polymorphonuclear leukocytes is an important pathogenetic factor in a series of diseases (ards, mof, myocardial infarction). moreover, toxic oxygen metabolites seem also to play an important part in the formation of necroses in acute haemorrhagic-neerotising pancreatitis. kelemen et al. [ ] found excessive production of toxic oxygen metabolites (mda) accompanied by loss of tissue antioxidative capacity (sod, gsh) in experimentally induced haemorrhagic-necrotising pancreatitis in rats. besides the liver, the pancreas is known to surpass all other organs with respect to radical formation and its antioxidative potential. however, to what extent toxic oxygen metabolites are responsible for the development of mof as a consequence of acute pancreatitis has scarely been investigated as yet. the present study is intended to clarify the question, whether the activation of granulocytes takes place in the pancreas and whether these activated granulocytes are capable of releasing toxic oxygen metabolites which substantially contribute to endothelial cell damage in the respective organs (lung, kidney, liver, small intestine, heart). in addition, the antioxidative effect of mdtq-da was studied in a first in vitro test. following anaesthetization with pentobarbital (nembutal®), acute haemorrhagic-necrotising pancreatitis was induced in dogs by injection of , ml/kg bw of autologous bile. catheters for selective blood sampling were placed in the portal vein (via splenic vein) and in the coeliac artery (via femoral artery). samples were taken within min after placing the catheters, at the moment of bile injection and within , , , and h after the injection of bile. at these times cl response was determined in whole blood and separated granulocytes from the portal vein (i. e. after passage through the pancreas) and the coeliac artery as appears from fig. , whole blood and especially separated granulocytes from the portal vein (to a much lower degree also from the coeliac artery) show a sharp increase in spontaneous (only luminol-enhanced) cl already within i h after injection of bile. the maximum is reached within h after injection, with cl response being much higher in blood and granulocytes from the portal vein than in samples taken from the coeliac artery. within h after injection of bile cl response of granulocytes from the coeliac artery surpasses that of granulocytes from the portal vein. there was no difference in cl response between whole blood from the portal vein and the coeliac artery after h. stimulation with zymosan-activated plasma results in a -fold increase in cl response of whole blood and a , - , -fold increase in cl response of granulocytes. at the same time we found massive activation of complement in the blood, accompanied by the formation of complement split products and their deposition throughout the pancreas. addition of . gg of radical trap (mdtq-da) to each zymosan stimulated whole blood sample reduced cl response by - p.c. following induction of haemorrhagic-necrotising pancreatitis, high quantities of toxic oxygen metabolites are released from pancreatic tissue, contributing to the development of mof. granulocytes are obviously sensitised by activated complement deposited in excessive quantities in pancreatic parenchyma. later on, the release of toxic oxygen metabolites from activated granulocytes persists in a systemic circulation level and becomes independent of the inflammatory process in the pancreas. stimulating agents, such as zymosan, zymosan-activated plasma, or endotoxin drastically increase the release of toxic oxygen radicals from sensitised granulocytes, causing an even greater damage to the organs. that is why chemiluminescence response of granulocytes is much higher in systemic blood than in blood from the portal vein after h. our study gives rise to the assumption that complement-induced activation of granulocytes and the release of toxic oxygen metabolites are essential pathogenetic factors in the development of mof as sequela of acute pancreatitis. we believe that the prognosis of this disease can be considerably improved by therapeutic use of antioxidants. macrophages are crucially involved in the regulation of various immune reactions. they represent a heterogeneous group of cells not only due to their different tissue origin but even more attributable to distinct activation stages during which they acquire additional receptors, metabolic functions and capacities. reactive oxygen intermediates (roi) such as the superoxide anion radical (oy) or hydrogen peroxide (h oz) contribute to the development of cytotoxic and antimicrobial activities and also play an important role in inflammatory processes [ ] . the amount of roi production strongly correlates with macrophage activation where-at fully activated cells are the most effective producers after addition of appropriate stimuli [ , ] . roi decay leads to the emission of small amounts of light but this chemiluminescence (cl) is enormously intensified in the presence of chemical amplifiers such as luminol and lucigenin [ ] . in the report we describe a method for the determination of lucigeninenhanced cl of resident or in vivo preactivated mouse peritoneal macrophages using a -well microtiter system (amerlite research luminometer). resident macrophages were obtained by peritoneal lavage of untreated dba/ mice [ ] . elicited or fully activated cells were . in a total volume of gl x l s cells were preincubated in white well microtiter plates (microfluor ~, dynatech) with lucigenin ( , '-dimethyl-bis- , '-acridinium nitrate) (sigma) at a concentration of _ mol/ for min at °c. after addition of mg/ml of the phagocytic stimulus zymosan (sigma) cl was repeatedly measured in an amerlite research luminometer (amersham buchler) in the scan only program with a dwell time of s for each sample. figure i shows that by use of amerlite research luminometer the roi production of differentially preactivated macrophages could easily be measured. where-as thioglycolate-elicited or response to zymosan after about min no difference to background cl was observed with resident macrophages. addition of superoxide dismutase ( u/ml) during the preincubation time totally inhibited the zymosan-induced cl response (data not shown) indicating that the lucigenin- amplified cl predominantly resulted from o -production by nadph oxidase. the applied system seems suitable to study cl as a correlate of the macrophage activation stage. additionally, enhancing or inhibitory properties of drugs can effectively be determined in up to samples running in parallel with only small amounts of cells required. chemiluminescent systems based on luminol, acridine, phenanthridine, and lophine derivatives as well as singlet oxygen generating hypohalogenite-peroxy compound systems have been widely used in analytical biochemistry during the last two decades. ill contrast to this, there are only few reports on the application of the currently most efficient chemiluminescent system, the peroxyoxalate chemiluminescence (cl) with cl quantum yields up to . einstein/mol in aprotic solvents. oxalic acid esters or oxamides which are poorly soluble in protic environment and/or susceptible to solvolysis are predominantly used in micellar or reversed micellar systems for the detection (also as hplc-detector) of h or fluorescent compounds [ ] . moreover, there are attempts at using specially substituted dioxetanes as labels for cl-immunoassay technique [ ] . one of the most interesting recent papers describes the peroxyoxalate cl as an extraordinarily favourable alternative to the haematoporphyrin sensitized phototherapy for tumours without light in animal experiments [ ] . in the following the applicability of the cl system oxalic acid/fluorescer/dehydrator/peroxy compound is described with regard to biochemical analysis in protic solvents. in , rauhut described bright, strongly visible cl of an oxalic acid/carbodiimide/fluorescer/h system in aprotic solvents [ ] . our own experiments showed intensive short-time cl at ph = with a maximum within . s after the start of reaction also in protic environment (ethanol/h ). monoperoxyoxalate is formed as an intermediate which, f* ~ f + hv ( ) (f* = fluorescer in excited electronic singlet or triplet state). the quantification of oxalate, fluorescer and peroxy compound with the above-mentioned system is described in the following. all chemiluminometric measurements were made on a clinilumat lb (berthold, frg). dosed by injector, gl of a solution of bis(cyclohexyl)-carbodiimid (dcc) in abs. ethanol ( g/l) were added to ktl of aqueous sample adjusted to ph = . h was, if necessary, admixed to the sample ( t~ of a . mol/ aqueous solution of h ). the fluorescer was, depending on what was to be determined, either added to ethanol ( , -diphenylanthracene (dpa) in case of determina- fig. a, b . sensitization of the chemiluminescent system oxalic acid/dcc/hz by a free and b protein-bound rhodamineisothiocyanate contained in gl of sample ( mol/ oxalate solution, ph ) tion of oxalate and h ) or used together with the oxalate solution as sample, measurement was started immediately after injection and continued for s. quantification of oxalate in urine. we previously reported on chemiluminometric quantification of oxalate in urine after precipitation of calcium oxalate by means of a lkb luminometer [ ] . as further studies with the clinilumat lb have shown, oxalate concentration can be directly determined in native urine under optimized preanalytic conditions, concentration of reagents and timing of measurements, because all in-terfering organic substances in urine are inferior to oxalate by several orders of magnitude with regard to their reaction kinetics and cl quantum yield. a mol/ oxalic acid or alkali oxalate solution (adjusted with hc to ph = ) used as sample, a sensitization of the system by to orders of magnitude depending on the concentration of fluorescer can be achieved regarding the cl measuring signal. however, many of the common fluorescent dyes cannot be employed because of insufficient fluorescence quantum yield at ph = . apart from polycondensed carbohydrates (e.g. diphenylanthracene), brillant sulfoflavine, rhodamine and porphyrins (except complexes of metals with several stable valence states, e.g. iron and cobalt) are, among others, known as excellent sensitizers. covalent bounding to protein of the fluorescer will decrease cl quantum yield in comparison to an adequate quantum of free fluorescer. yet, few nanogrammes per ml can still be detected. we labeled human low density lipoprotein (ldl) and anti-ldl-igg (sheep) with rhodamineisothiocyanate (ritc), the limit of detection for proteins appearing from fig. . this offers the possibility of a cl immunoassay with a fluorescent dye instead of luminogen used as label. first in vitro studies as to the interaction between ritc-ldl and isolated human leucocytes admit of the conclusion that this peroxyoxalate system might also be suitable for the detection of cell receptors. brandl [ ] reported on chlorophyll-sensitized peroxyoxalate chemiluminescence producing bright and strongly visible light in ethyl acetate, when aryloxalates, namely bis( , -dinitrophenyl)oxalate (dnpo), were used. on the basis of dnpo we developed a qualitative peroxyoxalate-cl-test for the determination of porphyrins in urine [ ] . its simplicity and comparable sensitivity makes it an useful alternative to the porphyrine fluorescence talc test [ ] , particularly since an analytical quartz lamp is not needed. the system oxalate/dcc/h now also permits a quantitative analysis of porphyrins in urine down to the concentration of about ~tg/ , with some problems of standardization of the procedure remaining to be solved. the use of a suitable photodetector with a maximum sensitivity within a narrow range of the fluorescence (chemiluminescence) maximum of porphyrins (about nm) is a basic requirement for sufficient high sensitivity or further enhancement of sensitivity. determination ofh oa. using dpa as fluorescer in a concentration of rag/ in ethanolic dcc-solution and in the presence of mol/ oxalic acid solution, determination of h : can be achieved down to limiting concentration of - mol/ at ph = , with peak maximum within . s and the reaction being completed to p.c. within s after start. this shows that this procedure can also be used for the determination of enzymes or substrates which are in direct relation to h (e.g. systems catalyzed by oxidase or peroxidase). acridinium esters are highly chemiluminescent molecules with high quantum yield and rapid reaction kinetics [ ] . dna probes can be labeled with acridinium esters using alkylamine linker arms to approximately the same specific activity as the free ester. we have identified conditions in which acridinium ester linked to unhybridized probe is hydrolyzed to a non-chemiluminescent form, while ester linked to hybridized probe is protected [ ] . we have incorporated chemiluminescent labeled probes into a homogeneous dna probe assay referred to as the hybridization protection assay (hpa) and applied the assay to the detection of hepatitis b (hbv) and human immunodeficiency virus (hiv) dna sequences. rapid and sensitive detection methods for screening large numbers of samples in a simple format are needed for clinical diagnoses as well as basic research endeavors, particularly in clinical syndromes in which currently available tests or serological tests cannot be used to follow the course of infection. hiv and hbv are present in levels too low to allow consistent detection by direct methods. detection of these low levels of virus is made possible by specific amplification of viral nucleic acids by enzymatic methods including the polymerase chain reaction or pcr [ ] or transcription-based amplification methods [ ] . current methods for detection of the specific amplification products include visualization after gel electrophoresis and hybridization in solution or to immobilized targets. these methods require many steps and several hours to days to complete, and often involve radioisotopic dna probes. we demonstrate that hpa is a rapid and sensitive method for detection of hiv and hbv dna amplified by pcr. dna probes were labeled as described in arnold et al. [ ] . chemiluminescence was detected following the addition of hydrogen peroxide under basic conditions. the reaction proceeds through a cyclodioxetane-like intermediate with the pro- duction of an excited acridone which emits light upon collapse to ground state. purified cloned dna was amplified with taq polymerase under conditions recommended by the enzyme supplier (cetus) for or cycles in a perkin-elmer cetus thermocycler. ten microliters of the pcr reaction were denatured at °c and hybridized to ae-labeled probe at ° c, followed by a differential hydrolysis step at the same temperature. after differential hydrolysis, remaining chemiluminescence was a direct measure of the amount of hybrid formed. detection of chemiluminescence was performed with a leader i luminometer. the results were given as a numerical reading in relative light units (rlu), allowing quantitation of the amount of target present. the hybridization assay required less than min to complete. the differential hydrolysis of hybridized and unhybridized probe forms the basis of a homogeneous dna probe assay referred to as the hybridization protection assay (hpa). the hpa format was used to detect hiv and hbv dna amplified by pcr. purified cloned hbv dna was amplified by pcr with primers from conserved regions within the hbv genome. a single band was seen on etbr-stained agarose gels, confirming the specificity of the primer sequences. when dilutions of hbv cloned dna were amplified and then analyzed by hpa, reactions containing as few as copies of input hbv dna gave chemiluminescent signals significantly above background, even when only % of the sample was analyzed. the quantitative capabilities of hpa were demonstrated by analyzing serial dilutions of hbv + serum. the assay showed a linear response over three logs of target dilution. one hbsag + serum was positive by hpa even when diluted v-fold prior to amplification. we have also applied hpa to specifically detect hiv- dna amplified by pcr using gag-region primers described in ou et al. [ ] . amplifications containing less than copies of input hiv-i dna gave signals significantly above background. hpa provides a rapid and sensitive technique, which should be useful in studies involving epidemiology, diagnosis, prevention and treatment of viral diseases. the micellar media and the fluorescence techniques have been widely used in the study of the structure and dynamics of biological systems [ ] . analytically, the micellar media present a great interest, specially to improve the sensibility and selectivity of many determinations [ , ] . in the present communication, we report the micellar enhanced spectrofluorimetric determination of a polynuclear aromatic hydrocarbon (pah), benzo(a)pyrene (b(a)p) of great toxicological interest and for its significance in pollution studies [ ] . reagents. the standards pah were ontained from sigma chemical co. and used as received. the surfactants: sodium dodecylsulfate, triton x- , bencyldimethyltetradecylammonium chloride, hexadecyltrimethylammonium bromide and cetylpyridinium bromide were obtained from aldrich chemical co. the stock solutions of pah were prepared in ethanol. apparatus. all fluorescence measurements were made with a perkin-elmer mpf- a recording spectrofluorimeter equipped with a -w osram xbo xenon arc lamp, a dscu- corrected spectra unit ( . % rodamine b in ethylene glycol as the reference), a udr- digital read-out, a selecta frigitherm ultrathermostat and -cm quartz cells. the emission intensity measuring system of the spectrofluorimeter was calibrated daily by using the perkin-elmer set of fluorescent polymer blocks. general procedure for the determination of benzo(a)pyrene. to an aliquot, containing . ng-- . pg of benzo(a)pyrene, in a ml calibrated flask add ml solution of triton x- -z tool/l, and dilute to volume with deionised water. measure the fluorescence at nm using excitation at nm. the calibration curves are obtained from solutions prepared in the same conditions. the behaviour of b(a)p in solvents of different dielectric constant and bipolar moment has been studied as well as in presence of different surfactants. the fluorescence spectra do not present significant changes at the excitation and emission wavelengths maxima, neither in the ratio of emission bands intensitiesz [ ] . however, the fluorescence intensity suffers important changes in cationic and neuter micellar media. figure shows a great increase of the fluorescence intensity of b(a)p in solutions with triton x- , due to an increase in the molar absorptivity and, above all, in the quantum yield of the hydrocarbon. among the reasons which can justify that the non-radiative processes are found less favoured in micellar medium, could be mentioned the lower facility of movement of the fluorophore molecules and the reduction of quenching effects of oxygen or other species [ ] . the fluorescence intensity changes sharply with the concentration of the surfactant when it is close to the critical micellar concentration. in concentrations of triton x- higher than - mol/ remains practically constant. increases in temperature as well as ethanol contents up to % (v-v), produce decreases in the fluorescence intensity. for different intervals of concentrations: . - ppb, - ppb and . - ppb, exist a lineal relationship -with high coefficients of correlation -between the fluorescence intensity and the concentration of b(a)p in solutions . - tool/ of triton x- . in eleven solutions containing . , . , and . ppb of b(a)p, relative errors of . , . , . %, and relative standard deviations of . , . and . % have been obtained, respectively. the method shows a detection limit of . ppb [ ] . other pah, as , -benzoperylene, crysene and perylene, do not interfere the determinations up to ratios of . / , / and / with respect to b(a)p, respectively. the method has been applied to the determination of b(a)p in sea water samples to which known hydrocarbon concentrations have been added. recoveries oscillating from . to . % have been obtained from ten samples containing between and ppb of b(a)p. xith hungarian congress of experimental surgery abteilung urologie der zentralen hochschulpoliklinik der medizinischen akademie ,carl gustav carus lessingstrasse , ddr- jena modern fluorescence spectroscopy acknowledgements. this work was supported by funds provided by the gobierno aut nomo de canarias (research project no. / . . ). key: cord- -qpjvmwmp authors: kinikar, aarti avinash; kulkarni, rajesh k.; valvi, chhaya t.; mave, vidya; gupte, nikhil; khadse, sandhya; bhardwaj, renu; kagal, anju; puranik, shaila; gupta, amita; bollinger, robert; jamkar, arun title: predictors of mortality in hospitalized children with pandemic h n influenza in pune, india date: - - journal: indian j pediatr doi: . /s - - - sha: doc_id: cord_uid: qpjvmwmp objective: to analyse the factors associated with increased mortality among indian children with h n . methods: data were abstracted from available hospital records of children less than y of age, who were admitted to sassoon general hospital in pune, india, with confirmed pandemic h n influenza infection from august through january . logistic regression analysis was used to identify clinical characteristics associated with mortality. results: of pediatric cases admitted with influenza like illness (ili), ( . %) had confirmed h n influenza infection. the median age of hin cases was . y; ( %) had an associated co-morbid condition. median duration of symptoms was d (interquartile range (iqr), – d). all h n cases received oseltamivir and empiric antimicrobials on admission. intensive care unit (icu) admission was required for ( %) children, and ( %) required mechanical ventilation.fifteen children ( %) died; mortality was associated with presence of diffuse alveolar infiltrate on admission chest radiography (odds ratio (or) , %ci : . – ; p < . ), use of corticosteroids in ards in children who required mechanical ventilation (or . , %ci: . – . ; p = . ), spo( ) < % on admission (or . , % ci: . – . ; p < . ) and presence of ards (or . , % ci : . – . ; p < . ). necropsy from all children who died showed ( %) had ards pattern and necrotizing pneumonitis, diffuse hemorrhage and interstitial pneumonia (n = each, %) with gram positive organisms consistent with severe viral and bacterial co-infection. conclusions: hypoxia, ards and use of corticosteroids in children with ards who were mechanically ventilated were the factors associated with increased odds of mortality. necropsy also suggested bacterial co-infection as a risk factor. on may , the first indian case of h n was confirmed. subsequently, one of india's largest documented h n outbreaks occurred in pune, with the first pediatric case reported in july . subsequently, sassoon general hospital (sgh), pune established a separate isolation ward and icu for suspected h n patients. to date, data on the current pandemic suggests that children under y of age represent almost half of all h n influenza cases, with many having at least one underlying medical condition, particularly asthma [ ] [ ] [ ] [ ] . in published reports, the majority of hospitalized children received antivirals; however, they appear to have significant mortality [ ] . a recent publication reported that factors independently associated with in-hospital mortality in adults and children were, requirement for invasive ventilation at intensive care unit (icu) admission, older age and presence of any co-existing conditions [ ] . understanding the factors associated with increase morbidity and mortality among indian children with h n could identify opportunities to prevent deaths due to present and future influenza pandemics in india. therefore, the authors analyzed the factors associated with mortality, among children admitted to the largest public hospital in pune, during the h n pandemic. sassoon general hospitals (sgh)-byramjee jeejeebhoy medical college (bjmc) is a large maharashtra government tertiary care public and teaching hospital, which serves pune city (city with population of approximately million) and surrounding peri-urban and rural areas. available hospital records were retrospectively reviewed for children with pcrconfirmed h n infection, who were less than y of age on admission to sgh and were admitted between august and january to the pediatric swine flu isolation icu and ward. children were admitted to icu if they had severe respiratory distress or hemodynamic instability requiring continuous monitoring and icu care. pathological specimens from children who died were reviewed for histopathological changes and secondary bacterial infections by gram staining. clinical and demographic data were extracted from available hospital records, using a standardized case report form (crf). the crf's were quality assured for completeness and accuracy and were entered via single data entry in a ms access database. the following data were collected: demographic characteristics like age, gender and location of residence; clinical characteristics on admission including duration of symptoms, co-morbid illnesses; clinical findings at presentation; and hospital course including use of antibiotics, corticosteroids and antiviral drugs, requirement of bubble continuous positive airway pressure (cpap)or mechanical ventilation, presence of co-infections, laboratory and radiologic findings. the primary outcome of the study was in-hospital mortality. necropsy data were available and included in the analysis for all children who died. tissue sections of lung and liver were formalin fixed, paraffin embedded and hematoxylin and eosin stained. gram staining of lung tissue blocks was also performed on all lung necropsy specimens. no personal patient identifiers were extracted on the crf's. all children admitted with ili, underwent nasopharyngeal (np) aspirate or swab specimen collection for the presence of h n specific viral nucleic acid on the day of hospitalization. influenza-like illness was defined by the documentation of fever (temperature > °f), and/or cough or sore throat, with any of the following symptoms: myalgia or arthralgia, respiratory distress, or vomiting or diarrhea. patient specimens were analyzed at the national institute of virology (niv), a world health organization (who)certified national reference virology laboratory in pune, india within h of collection. reverse-transcriptase pcr assay was performed according to the protocol recommended by the u.s. centers for disease control and prevention (cdc) [ ] . for the purposes of this analysis, a child was defined as infected with h n influenza based on laboratory confirmation of the presence of h n specific viral nucleic acid in nasopharyngeal specimen collected on hospitalization. the study was reviewed and approved by the ethics committee of sgh and the institutional review board (irb) of the johns hopkins university school of medicine. an epidemic curve of children presenting to the hospital with ili, and among those with pcr confirmed h n was created. demographic and clinical characteristics, on admission and in hospital, were summarized as a whole and also stratified by age categories less than y, - y and more than y. categorical variables were summarized using frequencies, and non-normal continuous variables using medians and iqr. categorical and continuous data across age categories were compared at % level of significance, using a fisher's exact test and nonparametric analysis of variance (kruskal-wallis test) respectively. the primary outcome of the study was mortality defined as in hospital death. logistic regression was used to identify risk factors for mortality. all analysis was done using stata software version . . between august and january , a total of patients with ili were admitted to the h n ward and icu, of which ( %) were children < y old. ninetytwo children ( %) had pcr-confirmed h n influenza infection. epidemic curve shown in fig. , suggests an initial peak in late august and september (wk - ). subsequently, there was a waxing and waning in the number of cases followed by another mild increase in the number of h n cases beginning in november and continuing through january . among the h n -confirmed cases, ( %) were males and the median age was . y (iqr . - ), with ( %) cases less than y of age. thirteen ( %) cases had a confirmed h n positive contact. table shows the demographic and clinical characteristics including signs and symptoms on admission and in-hospital, stratified by age. an underlying co-morbid condition was noted in ( %) of h n cases: congenital heart disease (n= ), asthma (n= ), diaphragmatic hernia (n= ), seizure disorder (n= ) and gastroesphageal reflux disease (n= ). coinfections were noted in ( %) of h n cases: hiv (n= ), dengue (n= ), tuberculosis (n= ), malaria (n= ) and typhoid (n= ). nutritional assessment at admission revealed that % of the h n cases had adequate nutrition and % had moderate acute malnutrition as per who growth standards [ ] . all h n cases received the antiviral drug oseltamivir on admission at the dosage recommended by the cdc [ ] . the median time from illness onset to initiation of oseltamivir was d and ( %) children received oseltamivir within h of symptom onset. two ( %) had received oseltamivir prior to admission. on admission, all children who were subsequently confirmed to have h n were also empirically started on broad spectrum antibiotics ( rd generation cephalosporin), and ( %) received vancomycin, although all children had received antibiotics prior to admission by an outside provider. bacterial co-infections isolated from blood cultures and/ or endotracheal aspirates were identified in ( %) children; gram-negative infections included acinetobacter baumanii (n= ), pseudomonas aeruginosa (n= ), citrobacter freundii (n= ) and escherichia coli (n= ), and gram positive infections included coagulase-negative staphylococci spp. (n= ) and methicillin resistant staphylococcus aureus (n= ). the most common clinical complications observed were acute respiratory distress syndrome (ards) (n= , %), empyema (n= , %), and encephalitis (n= , %). eighty-eight ( %) h n cases required icu care. all received oxygen therapy on admission. thirty six ( %) required ventilatory support on admission; ( %) received non invasive ventilation (nasal bubble cpap) and ( %) received mechanical ventilation. among icu admitted cases, the median time from symptoms onset to initiation of oseltamivir was d (range, - d). a short course of corticosteroids was administered to ( %) children. among icu-admitted cases, ( %) died, of which ( %) died within the first h of hospital admission. all children (n= ) who received non-invasive ventilation (bubble cpap) survived. the median age of children who died was y (iqr, - . y) and the median time from onset of symptoms to death was d (iqr, - d). the median duration of hospital stay among those who died was d (iqr, - d). among those who survived and were on mechanical ventilation, the median duration of hospital stay was significantly higher than those who died ( d vs. d, p . ). the duration of symptoms before admission was significantly lower in those who survived on assisted ventilation compared to those who died (median d vs. d, % ci : . - . ; p . ). mortality was associated with spo < % at admission (or . , %ci: . - . ; p< . ); presence of diffuse alveolar infiltrate (dai) on admission (or , %ci: . - . ; p< . ) and presence of ards on admission (or , %ci: . - ; p< . ) ( table ) . there was a strong trend with late presentation to hospital icu intensive care unit; anemia hb less than mg/dl; thrombocytopenia platelets less than /dl; leucopenia white blood cells less than , /dl; gerd gastro-esophageal reflux disease; ards/ali acute respiratory distress syndrome/acute lung injury defined as diffuse alveolar infiltrate along with pao /fio ratio less than and respectively. a defined as % increase from baseline creatinine. (admission to the hospital ≥ h of symptom onset) being associated with -fold increased odds of mortality; however this was not statistically significant (p= . ).however, late presentation to the hospital combined with need for mechanical ventilation on admission was associated with statistically significant increased risk of mortality (or , %ci: . - . ; p< . ).lastly, there was also a strong trend with the presence of co-morbid condition being associated with an almost -fold increased odds of mortality (or, . , %ci: . - ; p= . ). fourteen ( %) children admitted to icu received oseltamivir within h of symptom onset and survived while one of the children who died, received oseltamivir within h of symptom onset. pneumonia on admission was seen in all the children and was associated with higher mortality if presented with diffuse alveolar infiltrate. secondary bacterial infections particularly, nosocomial infection was associated with higher mortality; however this was not statistically significant (or . , % ci: . - . ; p= . ). necropsy performed on all children who died showed ards pattern (n= ) (fig. a) , necrotizing pneumonitis (n= ), diffuse hemorrhage (n= ) and interstitial pneumonia (n= ) consistent with severe viral and/or bacterial infection (table ) . a polymorphonuclear infiltrate was seen in cases (fig. b) , suggestive of a secondary bacterial infection. further gram staining of lung tissue blocks showed presence of gram positive infection in ( %) patients. liver necropsy revealed varied pathology ranging from fatty changes to sub massive necrosis (data not shown). since the beginning of the present pandemic in pune, india, until st january ; adult and pediatric patients with influenza-like illness were screened at various screening centers (unpublished report from niv, pune, india) and , ( %) underwent nasopharyngeal swab testing. of these, ( %) were confirmed to have h n infection and ( . %) were in the - y age group. the authors evaluated the risk factors associated with mortality in their setting and found that lower admission o saturation, corticosteroid treatment in children with ards requiring mechanical ventilation, diffuse alveolar infiltrate and presence of ards was associated with increased mortality in children with pandemic h n influenza infection. in addition, the authors found a trend towards late presentation to the hospital and bacterial coinfection also being associated with increased risk of mortality (though these were not statistically significant). the present case series of hospitalized children with h n influenza infection during the h n india pandemic depicts the severity of illness seen in hospitalized young children. h n infection caused significant pneumonia and ards, and resulted in icu admissions and deaths in % and % of children, respectively. the reported influenza-like presentations such as fever, cough, sore throat, and myalgia as well as gastrointestinal symptoms in the present setting was comparable to previous reports of h n in children [ ] [ ] [ ] . neurological symptoms and complications such as, altered mentation and seizures along with influenza like symptoms were also noted in the present study and were similar to what has been previously reported [ ] . high-income settings have reported obesity in a significant proportion of adults and children with h n infection [ ] [ ] [ ] . in contrast, the authors did not find an association between nutritional status and risk of h n illness in the present hospitalized cohort; nutritional assessment in the present center revealed that % of those children admitted were neither obese nor undernourished by standard anthropometric measurements. in contrast to reports from the developed world [ ] [ ] [ ] [ ] of the current h n pandemic, underlying medical conditions were lower in the present case series. asthma only accounted for % in the present group, whereas in other studies it has been reported to be % or higher [ ] [ ] [ ] [ ] . hiv has been associated with h n in published reports [ ] and the authors identified % of their children co-infected with hiv, which is higher than the population prevalence of hiv in children in the authors' area (unpublished data). nevertheless, the presence of a co-morbid condition showed a trend towards increased mortality in the present series. all children received oseltamivir and empiric antimicrobials on admission to the present center. although the present data shows that survival and deaths among children who have received oseltamivir within h of symptom onset is not statistically significant, the authors recommend early initiation of oseltamivir under pandemic situation. in spite of receiving antimicrobials prior to admission and upon admission, % had confirmed bacterial co-infection during the course of their hospitalization. this included both gram negative and gram positive organisms and is consistent with previous reports [ ] . the presence of secondary bacterial infection showed a trend towards increased mortality by fold. dengue [ ] and hiv [ ] co-infection with h n has been recently reported, but for the first time, the present case series is reporting coinfections like malaria, tuberculosis and typhoid fever in patients with confirmed h n infection. however, these co-infections were not associated with increased mortality in the present cohort. the mortality rate of % noted in the present study is consistent with prior reports of current pandemic for children [ ] [ ] [ ] . the authors found that lower admission o saturation, diffuse alveolar infiltrate on admission, corticosteroid treatment in children with ards requiring mechanical ventilation and presence of ards was associated with increased mortality in children with pandemic h n influenza infection. the fact that mechanical ventilation was required on admission in patients who died, suggests that these children presented late in the course of their illness. late presentation to the health care system remains a major challenge in influenza pandemics and is frequently associated with poor outcomes, including higher risk of mortality. mass media and community efforts during a pandemic need to emphasize earlier presentation to health care centers equipped to address pandemic influenza with special care taken to transfer critically ill patients in well equipped ambulances. necropsy performed on the children who died demonstrated presence of ards pattern, necrotizing pneumonitis, and diffuse alveolar hemorrhage as the probable cause of mortality. the histological findings are similar to that a recent report [ ] . the gram staining of lung tissue blocks in the present series revealed that more than half had an underlying gram positive bacterial infection suggestive of alveoli filled with dense exudate of polymorphs with scanty mononuclear cell, fibrin deposition, intra alveolar hemorrhage, necrosis of alveolar wall with micro abscess formation and marked congestion of alveolar capillaries streptococcal and staphylococcal infections. cdc has reported bacterial co-infection in almost one third of all fatal h n cases in united states and majority of these infections were streptococcal and staphylococcal infections [ ] . the present study had a potential limitation. since sgh was the only referral center for critically ill patients with suspected h n infection in pune, india during the early pandemic, the patients represented the most critically ill children in the community with h n and are not representative of the typical cases of childhood h n in the community. the authors' experience in india suggests that mortality may be associated with late presentation to tertiary care centers and severe illness at presentation, including severe respiratory distress and ards. in addition, secondary bacterial infection may also be clinically significant contributor to mortality. in resource-constrained settings such as the present one, the authors recommend early referral and admission of critically ill children, prompt initiation of empirical oseltamivir and broad spectrum antibiotics in order to have better outcomes. hospitalized patients with h n influenza in the united states critically ill patients with influenz a (h n ) in mexico critically ill patients with influenza a(h n ) infection in canada the australia and new zealand extracormembrane oxygenation (anz ecmo) influenza investigators. extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome pediatric hospitalizations associated with pandemic influenza a (h n ) in argentina critical care services and h n influenza in australia and new zealand rtpcr) protocol for detection and characterization of swine influenza who child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-forage: methods and development. geneva: world health organization updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the - season clinical characteristics of paediatric h n admissions in birmingham surveillance for pediatric deaths associated with pandemic influenza a (h n ) virus infection: united states neurologic complications associated with novel influenza a (h n ) virus infection in children pandemic influenza a (h n ) in hiv- -infected patients bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n )-united states co-infection with dengue virus and pandemic (h n ) virus clinical profile of h n positive hiv-infected children lung pathology in fatal novel influenza a (h n ) infection contributions all authors participated in data analysis and manuscript preparation.conflict of interest none.role of funding source none. key: cord- -o f vn authors: pitoni, sara; d’arrigo, sonia; grieco, domenico luca; idone, francesco antonio; santantonio, maria teresa; di giannatale, pierluigi; ferrieri, alessandro; natalini, daniele; eleuteri, davide; jonson, bjorn; antonelli, massimo; maggiore, salvatore maurizio title: tidal volume lowering by instrumental dead space reduction in brain-injured ards patients: effects on respiratory mechanics, gas exchange, and cerebral hemodynamics date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: o f vn background: limiting tidal volume (v(t)), plateau pressure, and driving pressure is essential during the acute respiratory distress syndrome (ards), but may be challenging when brain injury coexists due to the risk of hypercapnia. because lowering dead space enhances co( ) clearance, we conducted a study to determine whether and to what extent replacing heat and moisture exchangers (hme) with heated humidifiers (hh) facilitate safe v(t) lowering in brain-injured patients with ards. methods: brain-injured patients (head trauma or spontaneous cerebral hemorrhage with glasgow coma scale at admission < ) with mild and moderate ards received three ventilatory strategies in a sequential order during continuous paralysis: ( ) hme with v(t) to obtain a paco( ) within – mmhg (hme ); ( ) hh with v(t) titrated to obtain the same paco( ) (hh); and ( ) hme settings resumed (hme ). arterial blood gases, static and quasi-static respiratory mechanics, alveolar recruitment by multiple pressure–volume curves, intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and mean flow velocity in the middle cerebral artery by transcranial doppler were recorded. dead space was measured and partitioned by volumetric capnography. results: eighteen brain-injured patients were studied: ( %) had mild and ( %) had moderate ards. at inclusion, median [interquartile range] pao( )/fio( ) was [ – ] and median peep was cmh( )o [ – ]. hh allowed to reduce v(t) by ml [ % ci: – ], v(t)/kg predicted body weight by . ml/kg [ % ci: . – . ], plateau pressure and driving pressure by . cmh( )o [ . – . ], without affecting paco( ), alveolar recruitment, and oxygenation. this was permitted by lower airway (− ml [ % ci: − to − ]) and total dead space (− ml [ % ci: − to − ]). sixteen patients ( %) showed driving pressure equal or lower than cmh( )o while on hh, as compared to ( %) and ( %) during hme and hme (p < . ). no changes in mean arterial pressure, cerebral perfusion pressure, intracranial pressure, and middle cerebral artery mean flow velocity were documented during hh. conclusion: the dead space reduction provided by hh allows to safely reduce v(t) without modifying paco( ) nor cerebral perfusion. this permits to provide a wider proportion of brain-injured ards patients with less injurious ventilation. acute respiratory distress syndrome (ards) affects up to % of critically ill patients with acute brain injury [ ] [ ] [ ] [ ] [ ] , representing an independent predictor of worse clinical outcome [ ] . the use of low tidal volume (v t ) to limit plateau pressure and driving pressure (i.e., plateau pressurepositive end-expiratory pressure, ∆p) reduces ventilator-induced lung injury (vili) and improves survival in ards patients [ ] [ ] [ ] . nonetheless, lower v t yield increased risk of hypercapnia, which is deleterious [ ] , especially in patients with brain injury: in this particular subset of patients, tight control of arterial partial pressure of carbon dioxide (paco ) is needed to prevent any secondary brain injury due to increases in cerebral blood flow and intracranial pressure [ ] . consequently, in brain-injured patients with ards, two competing priorities arise: use of low v t for lung protection and tight paco control to maintain proper cerebral blood flow and prevent undue intracranial pressure increases. the optimal balance between brain and lung protection during mechanical ventilation is not well established, and no recommendation exists on ventilatory management of these patients. in clinical practice, patients with acute brain injury and ards often receive v t exceeding ml/kg of predicted body weight (pbw) [ ] [ ] [ ] [ ] [ ] . heat and moisture exchangers (hme) and heated humidifiers (hh) are used for gas conditioning during invasive mechanical ventilation. although they are simpler to use, hmes carry relevant instrumental dead space and decrease the proportion of v t contributing to alveolar ventilation. previous authors highlighted that replacing hme with hh decreases dead space, promotes co clearance and allows v t and plateau pressure reduction during ards [ ] [ ] [ ] [ ] : however, no data clarify to what extent ∆p is reduced by this approach and whether this is safe in patients with concomitant brain injury, for whom tight control of paco is mandatory and any intervention has to be evaluated also from the perspective of cerebral hemodynamics. we conducted a physiological study to elucidate to what extent v t reduction with hh allows to limit ∆p and whether this is safe in terms of cerebral hemodynamics. the study was conducted in the general intensive care unit (icu) of a university hospital in rome, italy, according to the principles of the declaration of helsinki. the study protocol was reviewed and approved by the local institutional ethics committee. written informed consent was obtained according to committee recommendation. acute brain-injured patients with ards were screened for enrollment. acute brain injury was defined as a traumatic brain injury or a non-traumatic cerebral hemorrhage with a glasgow coma scale at admission < . diagnosis of ards was based on the criteria established by berlin definition [ ] . patients were eligible for inclusion if they had acute brain injury, developed ards, and were monitored with invasive intracranial pressure for clinical purposes, with stable pressure values < mmhg. for safety reasons, because lowering v t may cause alveolar derecruitment and hypoxemia, patients with severe ards (pao /fio < mmhg) were not considered for inclusion in the study. other non-inclusion criteria were: age < , pregnancy, severe hemodynamic instability, contraindication to muscular paralysis, leaking chest tube, and decompressive craniotomy. all patients were lying in the semi-seated position, intubated, sedated, paralyzed (cisatracurium . mg/kg), and mechanically ventilated in volume-controlled mode with an i-to-e ratio set at : . a standard bitube circuit with y-piece and hme filter (hygrobac; dar: dead space ml, resistance . cmh o/l/s) was used in the stabilization phase. ventilatory parameters were set by the attending physician, who was not involved in the study, but was specifically asked to optimize the ventilator settings to obtain a paco between and mmhg and pao > mmhg or a spo ≥ %, as per standard of care in brain-injured patients. two humidification devices were used: hme (hygrobac; dar: dead space ml, resistance . cmh )/l/s) and hh (mr , fisher & paykel, auckland, new zealand). this crossover study was organized into three phases. in phase i (hme ), a hme placed distally to the y-piece of the circuit, as in the stabilization phase. mechanical ventilation, as prescribed by the attending physician, was maintained for min without any changes in the settings: afterward, all relevant data were collected. in phase ii (hh), the hme was removed and a hh was placed in the inspiratory limb of the circuit and v t was titrated ( - ml decrease every min) to obtain paco equal to the one detected at the end of hme ; study data were collected min after reaching the target paco level. in phase iii (hme ), an hme was placed again distally to the y-piece of the circuit and all baseline settings were resumed. all patients received cisatracurium continuous infusion, at a standard dose of mg/h [ ] . patients' sedation, vasopressor dose, set peep, respiratory rate, fio , and i-to-e ratio were kept unchanged over the entire course of the experiment. endotracheal suctioning was performed at study entry and was not repeated over the course of the study period, unless specifically required. the following parameters were continuously monitored (sc monitor, siemens, erlangen, germany) during the study: heart rate, arterial blood pressure, intracranial pressure, cerebral perfusion pressure, and spo . blood flow velocity in the middle cerebral artery was measured at the end of each study step with a mhz pulsed doppler ultrasound device (transcranial doppler [tcd] h -hitachi medical system europe, zug switzerland). the ventilator (servoventilator c, siemens-elema, sweden) and a mainstream capnograph (co analyzer , siemens-elema, sweden) were connected to a personal computer. the ventilator system transducers produced signals representing pressure in the expiratory line, ventilator flow rate, and co at airway opening. these signals were filtered to avoid aliasing and were converted from analog to digital at hz. the flow signal was calibrated under btps (body temperature and pressure, saturated) conditions with a -l syringe. pressure was calibrated using a water manometer and co using a gas mixture with a known composition. tidal volume was measured as digital integration of expiratory flow signal. tidal volume/kg of predicted body weight (pbw) was computed, with pbw calculated as described elsewhere [ ] . total peep (peep tot ) was measured during end-expiratory occlusions, while airway plateau pressure (p plat ) was measured during a -second end-inspiratory occlusion. driving pressure (∆p) was computed as the difference between p plat and peep tot . static respiratory system compliance (c rs ) was calculated as v t /∆p. total, airway, and alveolar dead space was computed using volumetric capnography, according to a method validated elsewhere [ , ] . respiratory system mechanics, gas exchange, physiological dead space, and hemodynamics were measured in each phase of the protocol. elastic pressure-volume curves at set and zero peep were recorded in each phase of the study during low sinusoidal flow inflation, according to a method previously described in detail [ ] [ ] [ ] [ ] [ ] . the linear c rs was calculated as the steeper segment between the lower inflection point and upper inflection point of the curve at zero peep. the derecruited volume from set peep to zero peep was measured (rec) and consisted in the volume difference between the pressure-volume curves recorded at set peep and zero peep that were graphically superimposed and compared at an elastic pressure of cmh o [ , ] . rec was also normalized to the applied level of set peep: rec/peep tot was computed as the ratio between rec and peep tot , and patients were classified as having a highly recruitable profile when rec/ peep tot > . ml/cmh o [ ] . primary endpoint of this physiological study was to assess during isocapnic conditions the gain provided by hh in terms of v t , p plat , and, ∆p reduction, as compared to hme. safety endpoints were the effects of a low v t strategy on cerebral perfusion, as defined by cerebral perfusion pressure and blood flow velocity in the middle cerebral artery, and on respiratory mechanics and lung recruitment, as defined by lower and upper inflection points, linear and static c rs , rec, and rec/peep tot . given the physiological design of the study, we did not perform a formal sample size calculation. based on other investigations on the topic [ , , ] , we planned to enroll - patients that appear an adequate sample to draw conclusions on the specific endpoints addressed in the present investigation. categorical data are showed as number of events (% eighteen patients met inclusion criteria and were enrolled in the study. demographics and clinical characteristics are shown in table . consistently with the design of the protocol, no changes in paco , respiratory rate, set, and total peep were found among the three study steps (all p > . ; table , fig. ). tidal volume, plateau pressure, driving pressure, total dead space, airway dead space, and alveolar tidal volume were significantly lower during hh as compared to hme (all p < . ; heart rate, arterial pressure, intracranial and cerebral perfusion pressure, and flow velocity in the middle cerebral artery were similar in the three study steps ( fig. ) . the application of hh allowed an average v t reduction of [ % ci: - ] ml (p < . ) along with a decrease in v t /kg pbw of . [ % ci: . - . ] ml/ kg (p < . ) (fig. ) . the use of lower tidal volume was associated with an increase in . ml/cmh our results show that, in brain-injured patients with ards, the use of hhs permits to reduce tidal volume and ∆p without affecting cerebral hemodynamics and arterial co tension. consistently with previous investigations [ , , , ] hhs, as compared to hmes, significantly reduced total and airway dead space. the measured dead space reduction provided by hhs was [ % ci: - ] ml and is consistent with the -ml instrumental dead space declared by hme manufacturer. in our study, this several strategies have been proposed to mitigate vili and improve clinical outcome during ards: among these, the most convincing are lower v t , prone positioning and, possibly, mid-to-high peep with/without muscle paralysis in most severe patients [ , , [ ] [ ] [ ] [ ] . prone positioning may yield increases in intracranial pressure [ ] ; the use of high peep may not be safe in all braininjured patients due to its possible detrimental effects on central venous pressure, venous return, cardiac output, and intracranial pressure [ ] ; thus, lowering v t appears as the only available intervention to enhance lung protection in this context [ ] . this appears of crucial importance when brain injury coexists, as these patients are burdened by high risk of respiratory complications, high tracheostomy rates, prolonged mechanical ventilation, and worse clinical outcome [ , , , ] . the ∆p, which is v t normalized to c rs and is a surrogate of the dynamic strain [ ] , represents the final [ ] , the use of hh was not associated with improved clinical outcome in wide unselected cohorts of mechanically ventilated patients [ ] . in previous studies, however, the use of hh was not systematically accompanied by v t reduction as it is in our protocol, so that any possible benefit could have been underestimated. in our study, the use of low v t leads to a significant increase in static c rs without affecting the linear compliance measured between lower and upper inflection point. lung volume, as defined by rec, did not change nor patients' position varied among the study steps, and chest wall elastance was likely constant over the entire course of the study, thus suggesting that any observed change in respiratory mechanics reflects variations in lung mechanics: in particular, the results inhering static and quasi-static compliance indicate some degree of lung overdistention when higher v t were used, as already suggested by other authors [ , , ] . although previous data indicate that lower v t can favor alveolar derecruitment [ , , ] , we do not report significant derecruitment or oxygenation worsening during v t reduction. lung volume change as a response to peep may significantly vary among patients according to different degrees of lung recruitability [ , ] . accordingly, only - % of our patients showed a high recruitability profile (i.e., > . ml/cmh o of peep), as compared to % of patients in previous ards cohorts fig. paco , middle cerebral artery mean blood flow velocity, intracranial pressure, and cerebral perfusion pressure in the three study steps. individual data and medians with interquartile ranges are displayed [ ] , so that the scarce derecruitment effect of lower tidal volume observed in our study may be explained by this particular characteristic of the studied population. in this sense, because of the risk of further impairment in oxygenation that can be fatal in brain-injured subjects, we did not enroll patients with severe ards who, indeed, show the highest lung recruitability profile [ , ] . moreover, higher peep (up to cmh o or further) may be required to achieve optimal lung recruitment [ ] and such values may be difficult to apply in brain-injured patients. finally, and most importantly, our approach is simple, easily bedside available and showed a broad safety spectrum: no hemodynamic instability, abrupt increases in end tidal co (etco ) and intracranial pressure, decreases in spo and cerebral perfusion pressure, or any other adverse events were detected over the course of the entire study. similarly, the use of low v t was not associated with changes in cerebral perfusion pressure or blood flow velocity in the middle cerebral artery. the main limitation of the present study is its sequential crossover design, since the predetermined order of interventions may have affected the outcome. however, we tried to mitigate this aspect introducing a hme step, when all the baseline conditions were resumed. the substantial equivalence between most of the parameters in step hme and hme suggests that the patients were not subject to changes in respiratory, hemodynamic, and cerebral conditions during any of the study period, thus contributing to the strength and reproducibility of our findings. the small differences between hme and hme can be ascribed to the limited sample and the statistical rank-based test used for the analysis. finally, initial tidal volumes and respiratory rates reflect individual fig. tidal volume, plateau pressure, and driving pressure, in the three study steps. individual data are displayed. horizontal line indicating driving pressure = cmh o is showed: note that / ( %) of patients have a driving pressure ≤ cmh o in the hh step, as compared to / ( %) and / ( %) during hme and hme (p < . ). * indicates p < . for comparison hme versus hh; ° indicates p < . for comparison hme versus hh clinician's attitude in the treatment of patients with brain injury, and a strictly low-tidal ventilation strategy was not applied at baseline. this is consistent with previous reports, indicating that patients with brain injury are often exposed non-protective ventilation settings [ ] [ ] [ ] [ ] [ ] . indeed, the aim of this study was limited to the assessment of the physiological effects of changing from an hme device to hh. the use of hh in patients with brain injury and ards reduces instrumental dead space and allows to reduce tidal volume and driving pressure in isocapnic conditions, with no alveolar derecruitment, hypoxemia, changes in cerebral perfusion pressure nor blood flow. this increases the proportion of patients receiving mechanical ventilation within safety limits. given its safeness and strong pathophysiological plausibility, we deem this intervention can be recommended among the first-line ventilatory management in brain-injured ards patients. fig. partitioning of dead space in the three study steps. median and interquartile ranges are displayed. total dead space was lower during hh, as compared to hme and hme (p < . ). the reduction in dead space was due to a lower airway dead space in the hh step. * indicates p < . for comparison hme versus hh; ° indicates p < . for comparison hme versus hh acute lung injury in patients with subarachnoid hemorrhage: incidence, risk factors, and outcome extracranial complications in patients with acute brain injury: a post hoc analysis of the soap study non-neurologic organ dysfunction in severe traumatic brain injury impact of medical complications on outcome after subarachnoid hemorrhage impact of acute lung injury and acute respiratory distress syndrome after traumatic brain injury in the united states the development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a metaanalysis of individual patient data an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome fifty years of research in ards. gas exchange in acute respiratory distress syndrome acute lung injury in patients with severe brain injury: a double hit model management and outcome of mechanically ventilated neurologic patients high tidal volume is associated with the development of acute lung injury after severe brain injury: an international observational study a multi-faceted strategy to reduce ventilation-associated mortality in brain-injured patients. the bi-vili project: a nationwide quality improvement project ventilation practices in subarachnoid hemorrhage: a cohort study exploring the use of lung protective ventilation ability and safety of a heated humidifier to control hypercapnic acidosis in severe ards influence of the humidification device during acute respiratory distress syndrome expiratory washout versus optimization of mechanical ventilation during permissive hypercapnia in patients with severe acute respiratory distress syndrome heat and moisture exchangers and heated humidifiers in acute lung injury/acute respiratory distress syndrome patients. effects on respiratory mechanics and gas exchange acute respiratory distress syndrome: the berlin definition neuromuscular blockers in early acute respiratory distress syndrome validation of bohr dead space measured by volumetric capnography volume capnography in the intensive care unit: physiological principles, measurements, and calculations pressure-volume curves in acute respiratory failure: automated low flow inflation versus occlusion pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower inflection point a single computer-controlled mechanical insufflation allows determination of the pressure-volume relationship of the respiratory system volumepressure curve of the respiratory system predicts effects of peep in ards: "occlusion" versus "constant flow" technique heterogeneity of regional inflection points from pressurevolume curves assessed by electrical impedance tomography what has been learnt from p/v curves in patients with acute lung injury/acute respiratory distress syndrome alveolar derecruitment at decremental positive end-expiratory pressure levels in acute lung injury: comparison with the lower inflection point, oxygenation, and compliance peep-induced changes in lung volume in acute respiratory distress syndrome. two methods to estimate alveolar recruitment the effects of passive humidifier dead space on respiratory variables in paralyzed and spontaneously breathing patients effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome early neuromuscular blockade in the acute respiratory distress syndrome does prone positioning increase intracranial pressure? a retrospective analysis of patients with acute brain injury and acute respiratory failure effects of peep on the intracranial system of patients with head injury and subarachnoid hemorrhage: the role of respiratory system compliance association between ventilatory settings and development of acute respiratory distress syndrome in mechanically ventilated patients due to brain injury tracheostomy procedures in the intensive care unit: an international survey epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in icus across countries lung volumes, respiratory mechanics and dynamic strain during general anaesthesia should we use driving pressure to set tidal volume? driving pressure and survival in the acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the lung safe study heat and moisture exchangers (hmes) and heated humidifiers (hhs) in adult critically ill patients: a systematic review, meta-analysis and metaregression of randomized controlled trials fifty years of research in ards. respiratory mechanics in acute respiratory distress syndrome the effects of low tidal ventilation on lung strain correlate with respiratory system compliance respective effects of end-expiratory and end-inspiratory pressures on alveolar recruitment in acute lung injury influence of tidal volume on alveolar recruitment. respective role of peep and a recruitment maneuver potential for lung recruitment estimated by the recruitment-toinflation ratio in acute respiratory distress syndrome. a clinical trial lung recruitment in patients with the acute respiratory distress syndrome lung recruitment assessed by respiratory mechanics and computed tomography in patients with acute respiratory distress syndrome. what is the relationship? opening pressures and atelectrauma in acute respiratory distress syndrome springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - wxih v authors: you, qinghai; wang, jinmei; jia, dan; jiang, lijuan; chang, yuanmin; li, wenmei title: mir- alleviates lipopolysaccharide-induced acute lung injury by targeting peli date: - - journal: inflamm res doi: . /s - - -z sha: doc_id: cord_uid: wxih v introduction: acute respiratory distress syndrome (ards) is a life-threatening medical condition. it is characterized by serious lung inflammation or injury. characterizing novel mirnas implicated in ards pathogenesis may provide new therapeutic strategy for managing ards. methods: we employed lps-induced lung injury model to profile mirnas associated with ards. we isolated one mirna candidate and characterized its role in lipopolysaccharide (lps)-induced proinflammatory cytokine production in lung macrophages. we further evaluated its functional role in ards model by assessing histological change, neutrophil activation, tissue permeability and tumor necrosis factor alpha (tnfα) production. we also characterized its downstream target using luciferase assay, western blotting, enzyme-linked immunosorbent assay and cell inflammation assay. results: microarray profiling revealed mir- was significantly downregulated in ards mouse model. lps-induced mir- downregulation was confirmed in lung macrophages. overexpression of mir- significantly suppressed lps-induced inflammatory cytokine production in vitro and alleviates lps-induced acute lung injury in vivo. peli was identified as a downstream target of mir- and found upregulated in ards model. overexpressing peli abolished the antagonizing effect of mir- on lps-mediated inflammatory response. conclusion: mir- carried a protective role against lps-induced acute lung injury by downregulating peli . mir- /peli axis may act as intervening targets to manage ards. acute respiratory distress syndrome (ards) is a severe lung inflammatory disorder commonly characterized by infection or injury inducing the development of diffuse alveolar damage that results in severe hypoxemia. it remains a lethal or disabling medical condition. in intensive care unit (icu), the incident rate of patients attributed to ards is high. the mortality rate of patients with severe ards is nearly % as estimated [ ] . even though patients who recover from this disorder are still at high risk for depression, cognitive decline, and persistent skeletal muscle weakness and post-traumatic stress disorder. risk factors for ards include factors that lead to direct or indirect lung injury. for instance, pulmonary contusion, inhalation injury, pneumonia, aspiration of gastric contents and drowning are the common direct lung-injury factors, while pancreatitis, sepsis, major burn injury, drug overdose, transfusion of blood products and cardiopulmonary bypass can indirectly cause lung injury that leads to ards. based on the recent clinical findings, more than % of ards cases are attributed to sepsis, pneumonia and aspiration of gastric contents [ ] . lung injury-induced inflammatory tissue damage is the core pathogenesis event of ards. initial response to injury is characterized by innate cell-mediated inflammation. the prominent innate cell type activated at this early stage is resident alveolar macrophages that subsequently secrete proinflammatory cytokines or chemokines to promote the activation of alveolar epithelial and endothelial cells and recruitments of monocytes and neutrophils. the subsequent activation of alveolar epithelial and endothelial cells contributes to the damage of barrier function and the accumulation of edema fluid flooding in injured lung tissue. the local accumulation of monocytes and neutrophils produces more inflammatory mediators and results in prolonged tissue damages. uncontrolled ards leads to increased mortality [ ] . though clinical validated biomarkers for ards are yet to be defined, common pathological features associated with ards include tissue inflammation, alveolar edema and increased lung permeability. therefore, diffuse alveolar damage is widely recognized as a histological hallmark associated with ards [ ] . animal models of ards, such as sepsis-or ventilator-induced acute lung injury, have been demonstrated to recapitulate these pathological features in human patients. they are very useful to study the ards pathological factors and mechanisms or evaluate the therapeutic factors or agents for managing ards [ , ] . the dysregulated mirna expression can contribute to the pathogenesis of many diseases including pulmonary disorders, chronic inflammation and cancers [ ] . the potential roles of mirnas in the pathogenesis and progression of ards have been reported recently, suggesting a complexity underlying the pathological mechanism of ards [ , ] . elucidating novel mirna players in ards may provide new biomarkers and therapeutic candidates for managing the disorder. in this study, our aim was to characterize a novel mirna associated with ards and provide scientific insight into therapeutic development to treat ards. we used sepsis-induced lung injury as ards animal model to profile mirna expression pattern. the mirna candidate was further functionally characterized in both in vitro and in vivo models. we also identified and validated a downstream target of the mirna in ards. the established signaling axis revealed a novel molecular mechanism underlying ards and provided a new avenue to develop therapeutics for ards. primary alveolar macrophages were isolated from lungs by bronchoalveolar lavage and cultured in dulbecco's modified essential medium (dmem)/ham's f- medium, supplemented with % fetal bovine serum (fbs), u/ ml streptomycin and u/ml penicillin. raw . and a were purchased from atcc and maintained in dmem or roswell park memorial institute (rpmi)- medium supplemented with % fbs, % glutamine and antibiotics at °c and % co . cells were passaged when they reached % confluence. cells were treated with µg/ml lipopolysaccharides (lps, sigma, st. louis, mo) or dmso following the time points as indicated in the study. bms , sb and sp were purchased from santa cruz. total rna from the sample tissue after the treatment was harvested using trizol method (invitrogen, waltham, ma usa). first-strand cdna was labelled with cy or cy and used for hybridization reaction on mouse genechip mirna . array from thermo fisher. fluorescence images were acquired using affymetrix gcs scanner. bioinformatics analysis was performed using the partek genomics suite software. only fold changes more than two between two groups were considered significant. we included three mice for the control and ards group, respectively. the ards mouse model was established by sepsis induction as previously described [ ] . briefly, male balb/c mice were divided randomly into four groups with subjects in each group: ( ) sham control group (receiving saline + scramble control mirna mg/kg); ( ) lps group (receiving lps mg/kg + scramble control mirna mg/ kg); ( ) sham/mirna group (receiving saline + mirna mg/kg); ( ) lps/mirna group (receiving lps mg/ kg + mirna mg/kg). the mirnas were delivered using invivofectamine . as described previously [ ] . h later, the drugs were delivered by intratracheal instillation. mice were killed at day upon lps challenge. the lung tissues were collected for further analysis. the animal study was carried out according to the ethical guidelines approved by animal care and use committee in the first affiliated hospital of anhui medical university. mice lung tissues were harvested at the end of the study. the neutrophil activation levels in the tissues were quantified by mpo activity assay kit (ab ) from abcam following the standard manual. we included eight mice for each group. to measure lung permeability, evan's blue dye ( mg/kg, sigma) was intravenously injected into the mice on the last day of the study. one hour after the injection, the mice were killed and the lungs were harvested and homogenized as previously described [ ] . the supernatants containing the dye were collected from the homogenates by centrifugation and quantified in a plate reader at nm and nm. the corrected value was calculated by abs (corrected) = abs − ( . × abs + . ). we included eight mice for each group. apoptotic cells in the harvested lung tissues were detected by dutp nick end-labelling (tunel) staining kit (roche diagnostics) following the manufacturer's manual. the apoptosis rate was calculated as the ratio of tunel-positive cells over total cells as stained by dapi. mir- mimic and scramble control were synthesized by qiagen. the cells were transfected with the mirnas using hiperfect transfection reagent (qiagen, valencia, ca, usa) following the manufacturer's manual. other gene transfections were done with lipofectamine . to measure tumor necrosis factor alpha (tnfα) secretion in lung tissue, balf from the study groups were collected and processed using mouse tnfα elisa kit from abcam according to the standard protocol. peli protein expression was determined in homogenized lung tissues using a customized elisa kit from cusabio biotech. we included eight mice for each group. the 'utr of peli containing the wild-type or mutated mir target site was cloned into the luciferase reporter plasmid (pmir-report). renilla luciferase vector (prl-sv ) was used as normalization control. both mir- mimic and luciferase reporter plasmids were co-transfected into balf macrophage. the luciferase activity was determined h post-transfection with the dual luciferase assay kit (promega, madison, wi, usa) using a plate reader following the manufacture's instruction. cells were harvested in radioimmunoprecipitation assay (ripa) buffer supplemented with protease inhibitor cocktail (roche, penzberg, upper bavaria, germany). µg protein lysate was first resolved in % sodium dodecyl sulfate-polyacrylamide gel electrophoresis (sds-page) and then transferred onto a nitrocellulose membrane. the membrane was blocked with % non-fat milk for h at room temperature and then incubated with primary antibody ( : ) for overnight at °c. on the nd day, the membrane was washed with pbst before incubating with a nd antibody ( : ) for h at room temperature. the target protein was detected using supersignal west pico plus chemiluminescent kit. peli and nlrp antibodies were from abcam. ubiquitin and gapdh antibodies were purchased from santa cruz. total rna including mirna were harvested using mirvana mirna isolation kit (ambion). one microgram of mrna was converted to cdna using high-capacity cdna reverse transcription kit. and mirna first-stand cdna was synthesised using miscript ii rt kit from qiagen. the gene expression was measured by sybr green kit from sigma-aldrich on quantstudio (applied biosystems, waltham, ma, usa) following the standard protocol. the primer sequences are listed as follows: the statistical analysis was done using spss software. the data were presented as mean ± standard deviation (sd). the unpaired student's t test was employed to compare the differences between the groups. one-way anova analysis followed by a tukey's post hoc test was applied to the comparison of more than two groups. only p value less than . was considered significant. to elucidate the mirna candidates implicated in the pathogenesis of ards, we profiled the expression changes of mirnas in a lps-induced ards mouse model. lps was administrated intratracheally to induce acute lung injury. h later, the lung tissues were harvested and processed for microarray analysis of mirna gene expression. a list of mirnas showing most significant changes is shown in fig. a . among those, mir- was one of the most significantly downregulated targets in ards lung tissue. the role of this candidate in ards or other lung injury has not been reported, which made it a novel mirna in ards field. to explore its function in ards, we subsequently isolated alveolar macrophages from lungs by bronchoalveolar lavage. the primary macrophages were cultured and challenged with lps. we found lps stimulation reduced the expression of mir- to almost fourfold (fig. b) . this was consistent with the in vivo result. we also confirmed the lps-mediated suppression of mir- in raw . , an immortalized monocyte/macrophage line (fig. c) . interestingly, when we challenged a , an alveolar basal epithelial cell line, no mir- reduction was detected (fig. d) . therefore, mir- in lung tissue was suppressed by lps and the reduction was largely attributed to the response in macrophages. next, we proceeded to elucidate the role of mir- in lps-induced lung injury. macrophages are a key cell type in lung in response to lps challenge and proinflammatory cytokine production is a critical step that mediates lpsinduced tissue damage. since mir- was found reduced by lps in alveolar macrophages, we restored the mirna expression in the cells and examines its impact on proinflammatory response induced by lps. as shown (fig. a) , macrophages challenged with lps produced high level of tnfα, while overexpressing mir- before lps stimulation greatly suppressed the tnfα expression. we observed similar suppressing effects of mir- in lps-mediated interleukin- beta (il- β) and il- induction (fig. b, c) . therefore, we concluded mir- expression may antagonize proinflammatory cytokine production during lpsmediated lung inflammatory response and tissue damage. independently prolonged lps challenge could induce cell apoptosis. as shown (fig. d) , lps increased cell death rate in macrophages as measured by tunel assay. however, mir- expression did not change the lps effect on cell apoptosis. therefore, the regulatory function of mir- may be specific to inflammatory pathway. to evaluate the effect of mir- on lps-induced lung acute injury in vivo, the mice were administrated with mir- or scramble control intragastrically before being subjected to sepsis challenge. first, we analyzed the morphological change of lung tissues with h&e staining. as shown (fig. a) , sepsis group showed increasing neutrophil infiltration, alveolar hemorrhage, lung edema, and compromised epithelial/endothelial cell structure compared with the sham group. interestingly pre-treatment of mir- significantly reduced tissue damage and led to a significant improvement on lung morphology. second, we determined the neutrophils activation by measuring myeloperoxidase (mpo) activity in lung tissues. as shown (fig. b) , mpo activity increased greatly in lps-challenged lung tissues and the delivery of mir- reduced the increased mpo activity in damaged lung. lps challenge also increased the permeability of the lung tissues as measured by evan's blue staining (fig. c) . in mir- -treated group, the lps-mediated protein leakage in lung tissues was significantly improved (fig. c) . last but not least, since the suppression effect of mir- in inflammatory cytokine production was found in vitro, we proceeded the measure level in the lung tissues. as expected, lps administration caused a significant induction of tnfα in the damaged tissues and overexpressing mir- markedly antagonized the accumulation of the proinflammatory factor (fig. d) . taken together, the in vivo study suggested a protective role of mir- in lps-induced ards model. next, we sought to identify the downstream target of mir- in lung macrophages. we analyzed the putative targets of mir- in mirbase [ ] . among them peli carried a mir- target site in its 'utr, which was conserved in both mouse and human (fig. a) . peli is an e ligase that mediates the inflammatory response in response to lps [ ] . we hypothesized that mir- may target peli to suppress lps challenge. therefore, we constructed luciferase reporter gene (denoted as wt), in which peli 'utr containing the mirna target site was cloned to the downstream of the coding sequence. as comparison, we constructed the mut vector in which the mirna target site in peli 'utr was mutated (fig. a) . to access the binding, we co-transfected the wt vector with either mir- or scramble control. as shown (fig. b) , mir- but not scramble mirna markedly reduced the luciferase activity. in contrast, co-transfection of mir- with the mut vector did not impact on the luciferase activity (fig. b) . to confirm the direct regulation of mir- on peli , we expressed either the mirna or the scramble control in alveolar macrophages and then measured peli protein level. as shown (fig. c) , overexpression of mir- markedly decreased the protein expression of peli . functionally peli controls the activation nlrp inflammasome by promoting its ubiquitination in response to lps [ ] . thus, we proceeded to measure the effect of mir- in nlrp activation by lps. as shown (fig. d) , lps stimulation promoted the accumulation of k -linked ubiquitinated nlrp , which was an indicator of nlrp next, we sought to confirm the functional relevance of peli in mir- -mediated inflammation suppression in ards model. in ards mouse model, mir- was found downregulated. as the hypothetical target of the mirna, peli level would increase in response to lps challenge in lung tissues. we then compared peli protein expression in lung samples between lps or sham groups. as shown (fig. a) , as expected, peli protein concentration was significantly higher in lps group. in the rescue study, we examined the effect of peli in mir- -mediated inflammation inhibition in primary macrophages with lps challenge. as shown (fig. b) , co-transfection of peli with mir- abolished the antagonizing effect of the mirna on lps-induced tnfα expression. similarly, overexpression of peli was also found to abrogate the inhibition of mir- on il- β and il- production primed by lps (fig. c, d) . overall, these results indicated mir- targeted peli to suppress lps-induced lung inflammation reaction. last but not least, we explored the mechanistic regulation of lps on mir suppression. lps binds to toll-like receptor (tlr ) that leads to tak activation. tak is a pivotal regulator that subsequently activates nuclear factor kappa-light-chain enhancer of activated b cells (nfκb), p and c-jun n-terminal kinase (jnk) sub-pathways [ ] . we treated primary macrophages with specific inhibitors targeting these downstream factors, including bms , a selective inhibitor of iκb kinase to block nfκb activation, sb and sp that directly target p and jnk, respectively. after h, we challenged the cells with lps and measured the effect on mir suppression. as shown in fig. a , only bms but not the other two inhibitors could disrupt the suppression effect on the mirna. to confirm this, we also repeated the same treatment on raw . . consistently only nfƙb could specifically abolish lps-mediated mir reduction (fig. b) . taken together lps-induced mir suppression was nfƙb pathway dependent (fig. c ). with mirna profiling, we identified a list of candidates that may play parts in ards model. at the top of the list, mir- , mir- , mir- , mir- , mir- , and mir- are found significantly downregulated in the disease model. the upregulated candidates are mir- a and mir- b. in this study, we have elucidated the role of mir- in ards. specifically, the mirna downregulation has been confirmed in lps-challenged lung macrophages but not epithelial cells. restoring the mirna expressing level in lps-challenged macrophages can reduce the overproduction of proinflammatory cytokines such as tnfα, il- β and il- . however, the overexpression of mir- cannot inhibit the cell death challenged by lps, suggesting the regulation of mir- in macrophages may be specific to proinflammatory pathway. the benefits of overexpressing mir- in ards can be extended to the in vivo model. we have observed the alleviation in neutrophil activation, tissue permeability and luciferase reporter assay study of the interaction between mir- and 'utr of peli . lung macrophages were first transfected with luciferase reporter genes conjugated with either wild-type (wt) or mutant (mut) 'utr of peli . after h, the cells were transfected with either mir- mimic or scramble control. transfected cells were cultured for another h before the measurement of luciferase activities in a plate reader. c western blotting analysis of peli protein expression in cells trans-fected with mir- or scramble control. gapdh was used as loading control. the normalized peli expression was quantified by densitometry. d western blotting analysis of nlrp ubiquitination in cells transfected with mir- or scramble control. nlrp protein was pulled down with a monoclonal antibody. the immunoprecipitated complex was resolve in sds-page and immunoblotted with ubiquitin antibody. the ubiquitination level on peli was quantified by densitometry. data were expressed as mean ± sd. independent experiments were repeated in triplicate. ***p < . significantly different from control group proinflammatory cytokine secretion in addition to the clinical improvements by histological analysis. in the same study, we have identified peli , a positive regulator in lps/tlr pathway, as downstream target of mir- in macrophages. overexpressing mir- can repress peli expression and nlrp ubiquitination. interestingly, peli expression has been found upregulated in ards model that inversely correlates with the mir- expression. more importantly, coexpression of peli in mir- -transfected macrophages can abolish the antagonizing effect of the mirna in proinflammatory pathway. last but not least, inhibiting nfκb activation but not p or jnk phosphorylation specifically abolishes lps-mediated repression of mir expression. therefore, our study has shown strong evidence to support the involvement of mir- /peli signalling axis in ards (fig. c) . acute respiratory distress syndrome as a severe form of lung injury is commonly found in critically ill patients. lack of effective therapeutic targets for ards leads to the high mortality rate of ards patients. mirnas are emerging as promising drug targets for many diseases. they can regulate the singling proteins post-transcriptionally to control the disease progression. in ards, modified expression of mirnas has been studied to develop the diagnosis and treatment for a the protein expressions of peli in lung tissues between lps-induced ards model and sham group were compared by elisa analysis (n = , for each group). the primary lung macrophages were co-transfected with mirna or peli before lps challenge. h later, the gene expression levels of b tnfα, c il- β and d il- with or without lps stimulation were quantified by real-time pcr. independent experiments were repeated in triplicate. **p < . , ***p < . , compared with dmso control; ## p < . , ### p < . compared with no peli control in the same treatment condition the diseases [ , ] . microarray-based mirna profiling has been employed to study the modified mirna expression in rat ards model [ ] . many mirnas involved in the pathogenesis of ards regulate either tissue repair or inflammatory response in lung tissue. in lps-induced ards model, mir- has been found downregulated with a similar trend as mir- in our study. overexpressing mir- can attenuate lps-mediated inflammation in the disease model. interestingly, mir- has been also found to inhibit nlrp inflammasome by targeting rho-related gtpbinding protein rhob (rhob) [ ] . in another study, mir- has been reported being elevated in bronchoalveolar lavage fluid (balf) samples of ards patients. in this case, the elevation of the mirna is likely an adaptive mechanism to the stress. in the animal experiment, the overexpression of mir- alleviates septic lung injury by targeting transforming growth factor-β-activated binding protein (tab ), a regulatory molecule under tlr signalling [ ] . in another similar study, mir- a has been characterized as a suppressor in lps-induced acute lung injury [ ] . the upregulation of mir- a inhibits the inflammatory responses by suppressing the expression of traf- and irak- . interestingly, irak is acting upstream of peli under tlr activation. the activation of peli by irak enhances its e ligase activity. the activated peli mediates the ubiquitination and activation of nlrp inflammasome [ , ] . there are increasing evidences from ards animal models supporting this signalling axis can be regulated by multiple mirnas including mir- from our study. these studies indicate tlr signalling be critical for the initiation and development of acute lung injury and the signalling components in the pathway carrying the therapeutic potential for managing ards. mir- has been studied intensively in cancer biology. generally, it has been proposed as a tumor suppressor. for instance, in cervical cancer, mir- was downregulated and the restoration of the mirna inhibits serine-/argininerich splicing factor (srsf ) to induce cancer cell apoptosis [ ] . the enforced expression of mir- can antagonize gastric cancer oncogenesis by inhibiting rab expression [ ] . similarly, mir- can also act as a tumor suppressor against tongue squamous cell carcinoma growth and metastasis [ ] . in tongue squamous cells, mir- directly regulates the expression of map k . in addition, mir- has been demonstrated in human prostate cancer to regulate epithelial-mesenchymal transition process by targeting flotillin- [ ] . therefore, the role of mir- is cell type specific and depends on the molecular targets acting downstream. our study reveals that the mirna has a novel role in controlling inflammatory response. in lung tissue particularly lung macrophages, mir- targets peli in tlr pathway. the enforced expression of mir- seems unlikely to induce any unwanted risks such as oncogenesis. therefore, targeting mir- /peli axis holds a promise to develop therapeutics for ards. currently, the first-line treatment for severe ards is extracorporeal membrane oxygenation (ecmo) or extracorporeal co elimination [ ] . early recognition and targeting intervention are crucial to improve the clinical outcomes of ards treatment in the future. newly identified mir- / peli may shed light on precise intervention therapy. to test the validity of mir- /peli in treating ards, it will be important to confirm the mirna expression change in human patients for the next step. furthermore, using sirna or small molecule inhibitor to target peli in animal ards model will also be planned to evaluate whether the fig. lps-mediated mir suppression was through nfκb pathway. a primary macrophages or b raw . cells were incubated with µm each of the following inhibitors for overnight. on the next day, the cells were challenged with µg/ml lps for overnight and harvested to measure mir expression. the representative results from at least three biological repeats were shown. data were expressed as mean ± sd. independent experiments were repeated in triplicate. **p < . , ***p < . , compared with dmso control. c schematic diagram showing the biological role of mir in lpsinduced ards model as supported in our study axis is critical for the pathogenesis of ards. however, our study only focuses on sterile inflammatory ards model induced by lps. it will be important to evaluate the role of mir- in other mouse model of ards, such as an infectious model driven by streptococcus pneumoniae or ventilator-induced acute lung injury [ , ] . in addition, to be more clinically relevant, it is also critical in the future to validate the expression pattern of mir- /peli in human ards patients before developing the intervention targeting strategy on this promising pathway. in conclusion, mir- restoration or peli inhibition may provide a new avenue to treat ards. funding the study was supported by the national natural science foundation of china ( ). ethical approval the animal study was carried out according to the ethical guidelines approved by animal care and use committee in the first affiliated hospital of anhui medical university. acute respiratory distress syndrome: the berlin definition the acute respiratory distress syndrome acute lung injury: a clinical and molecular review the acute respiratory distress syndrome mouse models of acute respiratory distress syndrome: a review of analytical approaches, pathologic features, and common measurements development of animal models for the acute respiratory distress syndrome microrna functions identification of micrornas in acute respiratory distress syndrome based on microrna expression profile in rats microrna and mrna expression profiling in rat acute respiratory distress syndrome downregulation of mir- a protects mice from lps-induced acute lung injury by targeting bcl- evaluation of microrna delivery in vivo acute downregulation of mir- a attenuates sepsis-induced acute lung injury by targeting sirt mirbase: microrna sequences, targets and gene nomenclature kinase-active interleukin- receptor-associated kinases promote polyubiquitination and degradation of the pellino family: direct evidence for pellino proteins being ubiquitin-protein isopeptide ligases the e ubiquitin ligase pellino mediates priming of the nlrp inflammasome tak , more than just innate immunity micrornas as biomarkers of acute lung injury microrna regulation of acute lung injury and acute respiratory distress syndrome microrna attenuates lpsinduced inflammation in an acute lung injury model via the nlrp inflammasome and tlr /nfkappab signaling pathway via rhob mir- alleviates septic lung injury by inducing autophagy via inhibition of transforming growth factor-beta-activated binding protein upregulation of mir- a contributes to the suppression of inflammatory responses in lps-induced acute lung injury pellino proteins contain a cryptic fha domain that mediates interaction with phosphorylated irak microrna- inhibits cell proliferation and induces apoptosis in human cervical cancer by targeting serine/arginine-rich splicing factor upregulation of mir- suppresses gastric cancer oncogenicity via targeting rab expression microrna- plays a tumour suppressive role in tongue squamous cell carcinoma through directly targeting map k microrna- inhibits epithelialmesenchymal transition through targeting flotillin- in human prostate cancer acute respiratory distress syndrome: challenge for diagnosis and therapy key: cord- -e fvj l authors: hamm, h.; fabel, h.; bartsch, w. title: the surfactant system of the adult lung: physiology and clinical perspectives date: journal: clin investig doi: . /bf sha: doc_id: cord_uid: e fvj l pulmonary surfactant is synthesized and secreted by alveolar type ii cells and constitutes an important component of the alveolar lining fluid. it comprises a unique mixture of phospholipids and surfactant-specific proteins. more than years after its first biochemical characterization, knowledge of the composition and functions of the surfactant complex has grown considerably. its classically known role is to decrease surface tension in alveolar air spaces to a degree that facilitates adequate ventilation of the peripheral lung. more recently, other important surfactant functions have come into view. probably most notable among these, surfactant has been demonstrated to enhance local pulmonary defense mechanisms and to modulate immune responses in the alveolar milieu. these findings have prompted interest in the role and the possible alterations of the surfactant system in a variety of lung diseases and in environmental impacts on the lung. however, only a limited number of studies investigating surfactant changes in human lung disease have hitherto been published. preliminary results suggest that surfactant analyses, e.g., from bronchoalveolar lavage fluids, may reveal quantitative and qualitative abnormalities of the surfactant system in human lung disorders. it is hypothesized that in the future, surfactant studies may become one of our clinical tools to evaluate the activity and severity of peripheral lung diseases. in certain disorders they may also gain diagnostic significance. further clinical studies will be necessary to investigate the potential therapeutic benefits of surfactant substitution and the usefulness of pharmacologic manipulation of the secretory activity of alveolar type ii cells in pulmonary medicine. summary. pulmonary surfactant is synthesized and secreted by alveolar type ii cells and constitutes an important component of the alveolar lining fluid. it comprises a unique mixture of phospholipids and surfactant-specific proteins. more than years after its first biochemical characterization, knowledge of the composition and functions of the surfactant complex has grown considerably. its classically known role is to decrease surface tension in alveolar air spaces to a degree that facilitates adequate ventilation of the peripheral lung. more recently, other important surfactant functions have come into view. probably most notable among these, surfactant has been demonstrated to enhance local pulmonary defense mechanisms and to modulate immune responses in the alveolar milieu. these findings have prompted interest in the role and the possible alterations of the surfactant system in a variety of lung diseases and in environmental impacts on the lung. however, only a limited number of studies investigating surfactant changes in human lung disease have hitherto been published. preliminary results suggest that surfactant analyses, e.g., from bronchoalveolar lavage fluids, may reveal quantitative and qualitative abnormalities of the surfactant system in human lung disorders. it is hypothesized that in the future, surfactant studies may become one of our clinical tools to evaluate the activity and severity of peripheral lung diseases. in certain disorders they may also gain diagnostic significance. further clinical studies will be necessary to investigate the potential therapeutic benefits of surfactant substitution and the usefulness of pharmacologic manipulation of surfactant (=surface active agent) is a material capable of lowering surface tension. the existence of a pulmonary surface active substance was first postulated by van neergard in [ ] . he found the calculated surface tension of the alveolar air-liquid interface to be too high to prevent endexpiratory alveolar collapse and atelectasis. therefore, he predicted the presence of an agent able to exert and maintain a low alveolar surface tension as a prerequisite for the adequate ventilation of the peripheral airways and for normal lung function. it was almost another years until pattle [ ] and clements [ ] found a substance in lung edema fluid and in lung extracts that indeed lowered the surface tension dramatically. the material was found to be composed of a phospholipid and a protein fraction. in , avery and mead [ ] drew attention to the role of a surfactant deficit in hyaline membrane disease (irds) of premature infants. thus, clinical relevance and a first therapeutic perspective became apparent in surfactant research. more than another years later, the understanding of the pulmonary surfactant system has grown tremendously. the precise composition of the surfactant is known down to the genetic codes of surfactent-specific proteins, making the industrial production of different surfactants a realistic prospect. much has been learnt about surfactant synthesis in the alveolar type ii cell and its regulation and metabolism. intratracheal surfactant re-placement is on the verge of becoming a routine life-saving therapy in irds. accumulating evidence suggests that in adult respiratory distress syndrome (ards) a similar disturbance of the surfactant system is involved which may possibly be ameliorated by substitution therapy. in recent years, surfactant functions other than the maintenance of normal lung function have come into view. perhaps most important among these findings is that surfactant plays a major role in pulmonary defense mechanisms and local immunomodulation. therefore, the role of surfactant in different lung diseases and in the defense against various environmental impacts on the respiratory tract is attracting growing attention. the purpose of this article is to present a review of the current knowledge on the pulmonary surfactant system with emphasis on possible clinical implications and future perspectives for adult pulmonary medicine. surfactant is a complex mixture of lipids and proteins ( fig. ) . additionally, carbohydrate components are found in both the lipid [ ] and the protein fractions [ ] , but their precise functions remain to be established. most of the present data on surfactant composition is based on analyses of lung lavages [ , ] , which are thought to reflect adequately the situation in the alveolar lining fluid. however, it has to be kept in mind that lavage specimens may to some degree be contaminated with lipids of nonsurfactant origin, e.g., lipids stemming from cell membranes or lipids secreted by airway epithelial cells [ ] . fewer data exist on the intracellular surfactant composition, e.g., in the lamellar bodies of alveolar type ii cells. however, the surfactant composition of the intra-and extracellular compartments seems to be similar [ , ] . the pool size of extracellular surfactant has been investigated in animals and ranges from about - mg/kg body weight in adults. mature newborns have -to -fold higher values [ ] . assuming similar values in man, a kg person would thus have an estimated alveolar surfactant pool of approximately . - . g. however, there are no available data on the normal surfactant pool size in man, and there may possibly be considerable interindividual variations. lipids are the major surfactant component by weight (fig. ) . they make up about %- % of whole isolated surfactant [ ] . approximately % of this lipid fraction consists of a mixture of phospholipids. the remaining % are composed of other lipids, mainly cholesterol, which seems to be blood-derived and is of uncertain functional significance [ ] . phospholipids combine hydrophobic and hydrophilic properties and are therefore involved in the coating of boundary areas and surfaces. they possess the ability to achieve low surface tensions at air-liquid interfaces and support, for example, the formation of micelles and lamellae. however, phospholipids not only have structural functions but may in many ways be involved in different dynamic biological processes [ ] . the phospholipid composition of human lung surfactant is shown in fig. . in other mammals, this distribution is very much the same. none of these phospholipids is unique to surfactant, but in contrast to the phospholipid profile in other organs, the relative concentrations of phospatidylcholine and phosphatidylglycerol are higher. surfactants of amphibians and birds lack phosphatidylglycerol, suggesting that this phospholipid was introduced late in evolution [ ] . in human fetal lung development, phosphatidylglycerol becomes detectable only late in pregnancy and may serve as an indicator of fetal pulmonary maturity [ ] , although it does not seem to contribute to the reduction of alveolar surface tension [ ] . phosphatidylcholine accounts for approximately % of total surfactant phospholipids and for about two-thirds of whole surfactant (fig. ). approximately % of its fatty acids are saturated under normal conditions [ ] , the most common saturated acid being palmitic acid. dipalmitoylphosphatidylcholine (dppc) is the surfactant component which is predominantly responsible for the reduction of alveolar surface tension [ ] . its hydrophilic (choline) residue associates with the alveolar liquid phase while the hydrophobic (palmitic acid) residue reaches into the air phase [ ] . pattle [ ] first noted that a protein component in surfactant material seemed necessary for proper surfactant function. in , king et al. [ ] could, for the first time, demonstrate the existence of specific surfactant proteins. by weight, protein accounts for approximately % of whole isolated surfactant. about % of this protein portion consists of contaminating serum proteins while only % are made up by the surfactant-specific proteins (fig. ) . four surfactant specific proteins (sp) have so far been identified (table ) . a simplified nomenclature of these proteins has recently been proposed [ ] and is increasingly being accepted, despite certain difficulties and disadvantages [ ] . the first three proteins are simply termed surfactant protein a, b, and c in descending rank of their molecular masses. more recently, a fourth protein called sp-d has been described. the primary structures of surfactant proteins a, b, and c have been identified, and their commercial production by modern techniques of molecular biology is possible [ , ] . sp-a is the major surfactant protein in regard to relative abundance as well as size. in vivo, sp-a is found as a group of isoforms with a molecular weight ranging from approximately to kda, depending on the extent of posttranslational modifications [ ] . it has structural homologies with clq, a protein of the classical complement path-way [ , ] , and contains a collagen-like domain [ ] which is the probable association site of sp-a monomeres. after alveolar secretion, sp-a is predominantly :found as a multimeric molecule resembling a flower bouquet [ ] . recent evidence suggests that in man, there are at least two different sp-a subtypes encoded on two separate genes [ , ] . this may have structural implications for the arrangement of the naturally occurring sp-a multimeres [ ] , but the functional significance of these findings awaits further clarification. sp-a seems to play an important role in the formation of a preliminary alveolar surfactant layer called tubular myelin which is found immediately after alveolar secretion [ , , ] . in concert with sp-b and sp-c, sp-a probably enhances the surface activity of the surfactant monolayer [ ] . however, the importance of the presence of sp-a regarding this aspect of surfactant function is still debated [ ] . sp-a seems to be unique among the surfactant specific proteins as it apparently has additional functions in the surfactant complex apart from influencing surface activity. the structural homologies to the complement protein clq stimulated investigations of possible common biological functions of these two proteins. indeed, it was found that the presence of sp-a enhances the phagocytosis of opsonized sheep erythrocytes by macrophages and monocytes in a concentration-dependent manner [ ] . furthermore, sp-a is able to increase the phagocytosis of staphyloccocus aureus [ ] , herpes simplex virus type [ ] , and colloidal gold particles [ ] . thus, sp-a seems to play an important role in the local host defense mechanisms of the lung. another probable function of sp-a is its ability to regulate the alveolar surfactant concentration. in vitro, sp-a inhibits the secretion of phosphatidylcholine from cultured alveolar type ii cells [ ] and enhances the uptake of surfactant lipids [ ] . possibly, these sp-a effects are mediated by an alveolar type ii cell receptor [ ] . sp-b is a small protein of a molecular weight of approximately kda under reducing conditions [ ] . although it is very hydrophobic, it remains soluble in aqueous solutions to some extent. sp-b forms thiol-dependent oligomers of different sizes with the dimer probably being the most common form in vivo [ , ] . it has no known immunomodulatory or regulatory function but seems to be a key protein in the formation of a functionally optimal and stable surfactant monolayer on the alveolar surface [ , , ] . also, sp-b seems to play a role in the formation of tubular myelin in cooperation with sp-a [ ] . its amino acid sequence contains high amounts of cysteine, suggesting that disulfide bridges may be important to the role of this protein in the surfactant complex [ ] . indeed, intramolecular disulfide bridges seem to contribute to the structural properties of the sp-b polypeptide chain, and an intermolecular disulfide link may explain the frequent natural occurrence of sp-b dimers [ ] . furthermore, sp-b has a strong positive net charge (at physiological ph) which seems to be important to the interaction between sp-b and the anionic phospholipids [ , ] . however, the structural interaction between sp-b and other surfactant components still has to be more clearly defined. sp-c is a very small protein with a molecular weight of approximately kda. it is extremely hydrophobic, which is in part due to a high content of the hydrophobic amino acid valine [ ] . it is therefore only soluble in organic solvents. small size, hydrophobicity, and low immunogenicity make the investigation of this protein a difficult task. as far as its functional role in the surfactant complex is presently understood, it contributes to the formation and stabilization of the alveolar surfactant monolayer in cooperation with sp-b [ ] . probably, sp-c has no role in tubular myelin formation [ ] . the molecular structure and most of the properties of sp-c are substantially different from sp-b, suggesting that both proteins have separate roles in the surfactant complex. indeed, in vitro studies indicate that sp-c may be more important to the adsorption of phospholipids, while sp-b supports the reduction of surface tension more effectively [ ] . there seem to be no similarities of sp-c to other proteins of known functions that would suggest an additional role of sp-c [ ] . sp-d is a collagenous glycoprotein synthesized by alveolar type ii cells which has only recently been described [ , ] . the question still remains whether this protein is a true surfactant protein or a protein that is synthesized independently of the surfactent pathway and is only functionally associated with the surfactant complex. in rat bronchoalveolar lavage (bal) fluids, the total sp-d content was found to be approximately % of that of sp-a [ ] . it has a molecular size of approximately kda (reduced) and appears to build polymeric complexes comprised of the -kda subunits. sp-d has certain structural similarities with sp-a and probably is readily soluble in the alveolar milieu. like sp-a, sp-d does not contribute to the surface activity of the surfactant complex [ ] . its function is still hypothetical. structural analogies with proteins like mannosebinding protein, conglutinin, and sp-a suggest that it may have a role in local host defense [ ] , perhaps by functioning like an opsonin. a recent study indicates that sp-d may also have regulatory functions by counteracting the inhibitory effects of sp-a on phospholipid secretion by alveolar type ii cells [ ] . the site of alveolar surfactant synthesis and secretion is the cuboidal alveolar type ii cell which covers less than % of the alveolar surface. there is evidence to suggest that surfactant synthesis and secretion in the lung are not exclusively restricted to the alveolar type ii cell but that they may also take place in higher parts of the airways, for instance in clara cells [ , ] and possibly even in the tracheal epithelium [ ] . this may contribute to normal mucociliary function [ ] . however, the significance of these findings awaits further investigation. the alveolar surfactant components are synthesized and assembled in the endoplasmic reticulum of alveolar type ii cells and then transferred to the golgi apparatus prior to forming socalled lamellar bodies in the cytoplasm (fig. ) . this process has been followed by autoradiography and by immunocytochemistry for phospholipids and sp-a [ ] . as shown by transmission electron microscopy [ ], lamellar bodies undergo a process of maturation while travelling through the cytoplasm and are eventually transported into the alveolar space by merocrine secretion after fusion with the cell membrane. here, the lamellar bodies rapidly transform into tubular myelin, an intermediate surfactant material that is composed of a lattice of highly ordered tubules. sp-a is thought to play a role in the formation of tubular myelin and has recently been located at the corners of the tubular framework by immune electron microscopic techniques [ ] . another recent in vitro study [ ] suggests that in tubular myelin formation the presence of sp-b but not of sp-c is necessary in addition to sp-a. finally, this material is spread to reach its definitive form, the surfactant monolayer (figs. , ) . pulmonary surfactant is not a static accessory of the alveolus but undergoes a constant dynamic process of turnover and metabolism. this review will present only a short summary of the present knowledge on these processes. for more detailed information, the interested reader is referred to a number of recently published reviews which emphasize these aspects [ , , , , - , , , ] . basically, all phospholipid components of surfactant seem to be synthesized and incorporated into the lamellar bodies within the alveolar type ii cell. this is supported by findings that the phospholipid composition of isolated lamellar bodies is virtually identical to that of bal [ ] . dppc is the best studied phospholipid regarding intracellular synthesis pathways. it is de novo synthesized from blood-derived phospholipid precursors and can probably also be remodelled from unsaturated or recycled phosphatidylcholine. less evidence exists on the synthesis and precise pathways of secretion of the surfactant-specific proteins. alveolar sp-a gene expression is restricted to the alveolar type ii cell as shown by in situ hybridization [ ] . it is synthesized as a preprotein of approximately kda and a second variant of approximately kda. different posttranslational modifications of this protein like sialylation, acetylation, and sulfation have been described [ ] . single sp-a monomeres are oligomerized to hexameric bundles resembling flower bouquets [ ] . probably, surfactant proteins and the phospholipids are all assembled and introduced into the lamellar bodies within the type ii cell before secretion [ ] . however, many details of this process remain to be investigated. for instance, it is not yet quite certain whether all of the individual proteins are introduced into the lamellar bodies or if some of them join the surfactant complex after secretion into the alveolar space [ ] . fur-thermore, no evidence exists on the possible association of sp-d with intracellular lamellar bodies and their secretion. surfactant synthesis has been found to be influenced by a number of different stimuli [ ] (table ). glucocorticoids, camp, oestrogens, and thyroid hormones, among others, have been described as enhancing surfactant synthesis. however, the in vivo role and importance of these factors is not clearly determined. some of these stimuli, e.g., glucocorticoids, may vary in their effects depending on dose and time [ ] , and there may be different pathways for the regulation of surfactant phospholipid and protein synthesis [ ] . a recent in vivo study [ ] has investigated the influence of exogenously administered glucocorticoids and of adrenalectomy on the regulation of surfactant proteinsl glucocorticoid administration resulted in the accumulation of mrnas of surfactant proteins sp-a, b, and c, with the highest response being sp-b mrna. however, adrenalectomy did not change the mrna levels but decreased the total pulmonary sp-a levels. this study demonstrates that exogenous glucocorticoids enhance surfactant protein synthesis and suggests that adrenal hormones may have a role in the pulmonary response to stress. on the other hand, endogenous steroids under normal conditions do not seem to be important to baseline surfactant protein synthesis at the mrna level but may to a minor degree contribute to translational or posttranslational processing. the inhibition of surfactant production is possibly controlled by a feedback mechanism involving a surfactant protein [ ] . surfactant secretion into the alveolar space is accomplished by exocytosis of the lamellar bodies. experimental data suggest that various stimuli like high volume lung inflation and increased ventilation rate, adrenergic agents, estrogens, and thyroid hormones may enhance surfactant secretion, while beta-blockade and an sp-a-dependent feedback mechanism have inhibitory effects [ , , ] (table ). sp-d seems to counteract the inhibitory effect of sp-a [ ] . again, the in vivo significance of these experimental data remains under discussion. turnover studies with different labeled surfacrant phospholipids after secretion have demonstrated half-lives of between and h [ , ] . the fate of secreted surfactant material seems to be determined by five mechanisms: -intraalveolar catabolism -phagocytosis and degradation by alveolar macrophages [ , ] -removal by the mucociliary escalator -recycling into the alveolar type ii cell -redistribution into other surrounding tissue clearance studies in rabbits [ ] have shown that approximately % of radiolabeled phosphatidylcholine is removed via the upper airways in h, suggesting that this pathway is only of minor importance. further work by the same group [ ] supports evidence that most surfactant material is probably redistributed into the surrounding tissue or is recycled into alveolar type ii cells. many aspects of the regulation of these processes remain to be clarified. sp-a has been shown to enhance the uptake of liposomes into the alveolar type ii cell [ ] . this process is probably mediated by an sp-a receptor on the epithelial surface of type ii cells, which also controls the reuptake of sp-a [ ] . s u r f a c t a n t a n d l u n g f u n c t i o n this review will only give a short introduction into the role of surfactant in alveolar stability and in the work of breathing. the interested reader is referred to a number of articles [ , , , , ] which discuss these aspects in detail. the lowering of surface tension is the best known function of surfactant material and led to its discovery. however, this classical surfactant function probably was not the initial reason for the development of this material in evolution since animals with less complex lung architectures and thus without a need for surface-tension lowering agents already possess a pulmonary surfactant system [ ] . surfactant material has been shown to reduce the surface tension at the alveolar air-liquid interface down to levels that are required for normal ventilation of the peripheral lung. it reduces the respiratory work load throughout the respiratory cycle and improves lung compliance. the most important surfactant component in this regard is saturated phosphatidylcholine. other surfactant components like sp-a and more importantly, sp-b and sp-c, have been described to enhance the surface activity of this phospholipid. the hydrophobic saturated fatty acids of saturated phosphatidylcholine are aligned in parallel and rise out of the liquid phase into the alveolar air. the hydrophilic choline residues are packed in the aqueous phase of the alveolus. this arrangement remains stable through ventilatory compression and extension of the alveolus and reduces the strong alveolar cohesive forces close to zero. thus, alveolar surfactant material successfully prevents alveolar collapse and atelectasis as observed in surfactant-deficient lungs, e.g., in irds. surfactant material may contribute to pulmonary defense mechanisms and local immunomodulation in four different ways: -support of nonspecific defense mechanisms -direct bactericidal properties of surfactant components -immunomodulatory action on lymphocytes -augmentation of macrophage activities in the alveolar milieu surfactant is part of the alveolar and bronchial epithelial lining fluid which is thought to act as a nonspecific barrier against adhesion and invasion of microorganisms. also, surfactant has antioxidant activities [ ] which may contribute to the protection of the alveolar epithelium by scavenging toxic (reduced) oxygen species. several reports have addressed the possible antibacterial properties of surfactant material. studies of rat alveolar lining material identified long-chain free fatty acids as bactericidal surfactant components and demonstrated their antibiotic action against pneumococci in vitro [ ] . however, studies of human alveolar lining material obtained by bal could not demonstrate antibacterial effects against pneumococci or haemophilus influenzae [ ] . the in vivo significance of these findings is still uncertain, and the antibiotic effect of surfacrant remains controversial. lung surfactant has been shown to influence the activities of lymphocytes and macrophages. these influences are probably of significant in vivo importance for the maintenance of a balance between excessive immune responses and favorable cellular defense mechanisms. surfactant suppresses the activation and the proliferative response of lymphocytes to various stimuli in a dose-dependent manner [ , , ] . this suppressor activity is contained in the lipid fraction of surfactant [ ] . the major surfactant phospholipids phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol were shown to be responsible for this immunoregulatory effect. the mechanism of this effect has not yet been clarified but may be related to changes in cell membrane dynamics [ ] . surfactant exerts its effects only on the resting lymphocyte or on the early stage of lymphocyte activation. activated lymphocytes are not affected. the suppression seems to be largely irreversible, even after the removal of surfactant material from the medium. the inhibitory effects of surfactant have been shown for a variety of lymphocyte activities such as proliferation, differentiation, immunoglobulin production, and natural killer cell activity [ , , , , ] . nearly all studies on the influence of surfactant on alveolar macrophage activity report an enhancement of macrophage functions. in detail, it has been shown that surfactant material supports phagocytosis [ , ] and intracellular killing [ , ] of staphylococcus aureus and the phagocytosis of herpes simplex virus type [ ] . it may also enhance the migration of alveolar macrophages [ ] and their cytotoxicity against tumor cells [ ] . it has to be stressed that these studies report the results of in vitro investigations mostly with animal material. thus, the significance of these findings for normal human lung defense mechanisms is not yet definitely established. in general, alveolar macrophages are thought to be less active than blood monocytes or macrophages residing in other tissues [ , ] . recent studies [ , , ] have shown that sp-a is probably responsible for the enhancement of alveolar macrophage functions as isolated sp-a had the same stimulant effect on macrophages as whole surfactant, while surfactant lipids had no effect [ ] . probably, this macrophage stimulation is mediated by a macrophage receptor which binds sp-a. the specific binding and uptake of sp-a by macrophages has been demonstrated by electron microscopy [ ] . a recent report [ ] suggests that the sp-a receptor may be identical with the leukocyte clq receptor, which is a tempting hypothesis since sp-a has structural homologies with the complement protein clq. surfactant material, as part of the alveolar epithelial lining fluid, is thought to represent a first defense line against inhaled particles and gases reaching the alveolar space. apart from building a "mechanical" barrier, it probably plays an active role in the elimination of foreign particles, e.g., by enhancing macrophage activities and by exerting antioxidant effects [ ] against a variety of oxidant gases. on the other hand, the surfactant system itself may be damaged by inhaled particles and gases. a number of studies have been published addressing the impact of air pollutants and other toxicants on the pulmonary surfactant system. varying study designs such as the use of different animal or in vitro models and different doses and exposure times have led to divergent and sometimes conflicting results. furthermore, some of the studies focussing only on phospholipid alterations leave some doubt as to whether these changes are truly related to surfactant abnormalities or rather reflect other mechanisms like unspecific cell membrane damage. it certainly has to be kept in mind that the surfactant system is only one of the potential targets of pollutants and toxicants reaching the lung periphery, and hazardous effects on the surfactant system may be of a direct or indirect or as yet unknown nature. this review will only give a short overview of the known or proposed effects of some pollutants and toxicants on the surfactant system. for further information, the reader is referred to a number of reviews and articles focussing on this subject [ , , , , ozone is a major component of photochemical smog. it acts as a highly aggressive oxidant and leads to the transudation of blood proteins and to edema in the alveolar space even at comparatively low concentrations. furthermore, chronic low-dose ozone exposure is known to increase the susceptibility to pulmonary infections. it is believed that the pulmonary toxicity of ozone is at least in part due to impairment of the surfactant system [ ] . several reports support this hypothesis. in rats exposed to . ppm of ozone for days, giant lamellar bodies were observed in the alveolar type ii cells after day . this could suggest that ozone may impair surfactant secretion [ ] . short-term exposure ( . h) of isolated rat alveolar type ii cells to variable amounts of ozone resulted in impaired intracellular synthesis of phospholipids [ ] . exposure of bonnet monkeys to variable low-dose concentrations of ozone for - days led to changes of fatty acid compositions and a marked increase in phosphatidylcholine levels in lung lavage fluids [ ] . short-term ( - h), high dose ( ppm) ozone exposure of rats resulted in ultrastructural alterations of intracellular lamellar bodies and inhibited proper unfolding of secreted lamellar body membranes in the alveolar space [ ] . in vitro ozone exposure of sp-a led to impairments of important physiologic sp-a functions like self-association and sp-a-mediated lipid aggregation [ ] . these studies sugest that ozone even at low levels leads to changes in surfactant metabolism and secretion and to alterations of composition and properties of the secreted surfactant material. thus, it seems likely that the pulmonary toxicity of ozone is in part due to impairment of the surfacrant system. one of the many remaining questions is whether ozone-induced surfactant abnormalities are also involved in the increased susceptibility to pulmonary infections of chronically exposed individuals. the majority of atmospheric nitrogen oxides is derived from natural sources. however, in urban areas, nitrogen oxides from energy utilization largely determine air pollution levels with these gases [ ] . the pulmonary toxicity of nitrogen dioxide is similar to that of ozone, inducing free radical reactions and lipid autoxidation [ ] . probably, both these air pollutants have synergistic toxic effects on the lung. short-term exposure ( h) of rats to high levels ( ppm) of nitrogen dioxide resulted in phosphatidylcholine and phosphatidylglycerol accumulation in lung tissue with a peak at h postexposure. incorporation studies suggested that this increase was due to enhanced phospholipid synthesis [ ] . long-term exposure ( months) to low levels ( . ppm), by contrast, led to a significant decrease in the lung lipid content and changes in the phospholipid fatty acid composition [ ] . these studies may indicate that the acute effect of nitrogen dioxide on alveolar type ii cells is enhanced surfactant lipid synthesis, while chronic low-dose exposure leads to a decrease in surfactant synthesis capacity. however, the evidence is still scarce and not all observed phospholipid changes are necessarily related to the surfactant system. further studies are necessary to define more precisely the possible impact of nitrogen dioxide on alveolar type ii cells and surfactant material. also, in view of a more realistic approach to urban air pollution, it seems important to learn more about the co-toxicity of ozone and nitrogen dioxide. the toxicity of hyperbaric oxygen or oxygen at high concentrations is well-known and represents one of the problems of mechanical high oxygen ventilation, e.g., in intensive care units. the toxic effect is due to aggressive oxygen-derived free radicals which attack various cell constituents and probably also the surfactant system. in detail, it has been found that rabbits exposed to % oxygen for h exhibited a marked decrease in phosphatidylcholine synthesis and cell lipid content followed by a recovery to normal patterns and subsequently supranormal levels beginning days postexposure [ ] . the same group [ ] showed that intratracheal surfactant substitution significantly diminished the progression of hyperoxic injury. in rats exposed to % oxygen for h, increased levels of phosphatidylcholine and sp-a were found in lung lavages [ . it was concluded that hyperoxic lung injury is not due to intraalveolar decreases of these two major surfactant components. however, in another animal study dppc was decreased and the pg:pi ratio was markedly lower than baseline values after - days exposure to % oxygen. longer periods of exposure resulted in a further drop of dppc values [ ] . pulmonary oxygen toxicity does not seem to be consistently related to changes of surface tension measured in lung lavage fluids of exposed animals [ ] . in conclusion, hyperoxic lung injury may be associated with alveolar type ii cell changes in surfactant biosynthesis. however, different studies have found partly conflicting results, and the way in which hyperoxic lung injury contributes to quantitative and functional changes of alveolar surfactant is still poorly understood. it should also be remembered that the oxidant attack of oxygen is not limited to type ii cells or surfactant, and thus, some of the described phospholipid changes may not exclusively reflect surfactant abnormalities. cigarette smoke is a complex mixture of particles and gases. a reduced yield of phospholipids from bal fluids of smokers compared with nonsmokers has been described [ ] . this difference was interpreted to be partly due to lower lavage fluid recovery from smokers related to their known tendency to bronchoconstriction. additionally, it was thought to reflect the enhanced phagocytosis activity of alveolar macrophages [ ] . another group found no such quantitative differences between smokers and nonsmokers but described a decreased phospholipid/protein ratio in smokers [ ] . in rats exposed to cigarette smoke, a decrease of surfactant material in lung lavages was found. additionally, a progressive injury of alveolar type ii cells was observed over time as determined by electron microscopy, indicating that type ii cells and therefore possibly the surfactant system may be one of the targets of cigarette smoke in the peripheral lung [ ] . in vitro studies showed that smoke particles but not the gas phase of cigarette smoke interacted with a surface film of surfactant and altered its surface active properties in such a way that the maximum surface area was reduced, but the minimum surface tension was increased [ ] . this may possibly contribute to altered mechanical properties of the lungs of smokers. in conclusion, only a few studies have so far investigated the possible impacts of cigarette smoke on the surfactant system. thus, our knowledge about the effects of this important pulmonary toxicant is still very fragmentary and awaits further investigations. smoke generated from the burning of polyurethane foam has been shown to increase significantly the total phospholipid content of lung lavages from rats after short-term exposure [ ] . diesel exhausts were shown to induce pulmonary phospholipidosis in rats [ ] . in another study, short-term exposure of rats to mg/m diesel exhaust resulted in an increased labeling index in type ii cells and enhancement of whole lung d n a synthesis [ ] . additionally, lavage phospholipid values were increased, and there was evidence of reversible alterations of fatty acid and phospholipid metabolism. hydrogen sulfide is an irritant gas with toxic effects on the respiratory tract. an animal study suggests that higher doses impair the ability of sur-factant to lower surface tension. however, this does not seem to be due to a direct effect of hydrogen sulfide on surfactant material but due to surfactant inhibitors in the pulmonary edema fluid induced by hydrogen sulfide [ ] . dusts, especially those with a high fibrogenic potential, seem to stimulate the production of surfactant [ ] . silica (usually quartz dust) inhalation leads to a striking increase in the alveolar surfactant phospholipid and sp-a content [ , ] . recently, the accumulation of sp-d has also been reported [ ] . morphologically, these observations are accompanied by type ii cell hypertrophy and hyperplasia [ , ] . the lungs of silica-exposed animals share common features with alveolar proteinosis in man so that they may be used as animal models of this disease. asbestos inhalation provokes a very similar accumulation of surfactant material in the alveolar space [ , ] . the heavy metal cadmium is a known pulmonary toxicant. the main sources of human exposure are cigarette smoke, automobile emissions, and metal-processing plants. in rats, the inhalation of cadmium chloride led to an early decrease of phospholipids in lung lavage, accompanied by an increase in tissue phospholipids. after days, levels of lavage phospholipids then markedly increased above normal values [ ] . in vitro studies with alveolar type ii cell cultures exposed to cadmium chloride demonstrated inhibition of surfactant secretion, while cadmium alone had no such effect [ ] . paraquat, a commercially important herbicide, has marked toxic effects on the lung, particularly on the alveolar type ii cell. in vivo and in vitro studies have shown that the synthesis of surfactant phospholipids decreases after exposure. however, it is not yet clear whether this effect on surfactant production is the primary cause for paraquat-associated respiratory failure. a major problem in the clinical treatment of paraquat poisoning is the synergistic toxicity of high oxygen mechanical ventilation [ ] . the number of available studies on surfactant changes in human lung diseases is still limited. however, with further improvement of investigative tools and increasing interest in possible clinical implications, it should be expected that such studies will prosper in the near future. the main material for surfactant studies in man is bal because it is available at a low risk to the patient and gives access to all alveolar surfactant components. nev- ertheless, this method has its limitations. bal does not give direct insight into cellular changes of alveolar type ii cells and methods of quantification of the obtained epithelial lining fluid are limited by the complex nature of fluid dynamics during the procedure [ , ] . also, not all phospholipids in bal fluid must necessarily be surfactant phospholipids. they may in part stem from airway epithelial cell secretions [ ] or from cell membranes (alveolar cells, but also leucocytes, macrophages, etc.), which seems particularly important to consider in inflammatory lung diseases (e.g., [ ] ). nonetheless, the first clinical studies have shown that quantitative changes of surfactant components in different lung diseases can be found in comparison with healthy controls. normal values for sp-a in human bal are found in the range of about . - ~tg/ml lavage fluid ( [ , , ] and own unpublished data). normal total phospholipid levels seem to vary considerably among individuals and also among laboratories [ , , , , , , ] . additionally, chromatographic determination of the distribution of individual bal phospholipids (fig. ) is often used to describe surfactant abnormalities. recently, simpler enzymatic methods were recommended for phospholipid analysis in bal fluids [ ] . however, at present, only phosphatidylcholine and phosphatidylglycerol may be quantified by this method. another frequent approach is to investigate the biophysical properties (ability to lower surface tension) of the obtained surfactant material. various conditions such as severe trauma, major surgical procedures, burns, sepsis, acute pancreatitis, and aspiration pneumonia are capable of inducing this form of acute lung injury. it may rapidly progress to respiratory failure and continues to have a high mortality of around %- % [ , ] with hardly a change over the years in spite of many improvements in modern intensive care medicine. ards may be triggered or aggravated by high oxygen mechanical ventilation which is necessary in many of these patients. surfactant changes are thought to play an important role in the pathogenesis of this condition. however, it should be emphasized that ards is a severe, multifactorial disease in which surfactant is only one piece of the puzzle. serious disturbances of surfactant phospholipid composition and surfactant function as well as a reduced sp-a content in the bal have been described in animal models [ , ] and in man [ , , , ] , while the total phospholipids have not consistently been found to be reduced. the pathogenesis of these changes seems complex and is still only partly understood. again, some of the reported phospholipid changes may not be directly related to surfactant abnormalities but may be caused by other mechanisms like breakdown of cell membranes. one of the major mechanisms leading to surfactant disturbances in ards is probably connected to a massive fluid and protein accumulation in the alveolar compartment. especially in the early stages of ards, the increased permeability of the alveolocapillary barrier leads to noncardiogenic pulmonary edema with high concentrations of plasma-derived proteins. edema fluid and coagulated proteins block the alveolar air spaces and impair normal gas exchange [ , ] . several lines of evidence suggest that many of these plasmaderived proteins also have a strong potential for inactivation of surfactant material [ , , ] . in detail, this has been experimentally demonstrated for fibrinogen [ ] , fibrin monomers [ ] albumin [ ] , and even hemoglobin [ ] . these results suggest that in ards a major problem is probably not only the postulated deficit of alveolar type ii cell function but also a relative deficit of functionally intact surfactant material due to massive protein inactivation. it remains to be investigated whether or not the protein inactivation of alveolar surfactant is, to a minor degree, also relevant to other pulmonary diseases. another possible mechanism of surfactant inactivation in ards is that surfactant phospholipids may be degraded by phospholipase a , an enzyme which is probably involved in ards caused by pancreatitis or sepsis [ , ] . furthermore, it has been shown that e. coli endotoxin reduces surfactant synthesis in vitro [ ] and in vivo [ ] . many authors have called for clinical studies to investigate the benefit of surfactant substitution therapy in ards [ , , , ] , but there are still numerous problems to be solved like dosage, timing, and delivery method [ ] which dampen the enthusiasm for patient trials. much of the optimism is certainly due to the fact that ards shares common features with irds in which surfactant replacement is on the verge of becoming a standard therapy. additionally, animal studies (e.g., [ ] ) and human case reports [ , , , ] support the hope for a beneficial effect of surfactant replacement therapy in ards. the first controlled clinical trials are presently under way. even if beneficial effects on survival can be demon-strated, a significant mortality will probably remain, since the cause of death in ards is not invariably related to respiratory failure [ ] . idiopathic pulmonary fibrosis (ipf) is a progressive fibrosing lung disease of unknown origin which involves alveolar epithelial injury and alveolar type ii cell proliferation [ ] . total phospholipids in bal were found to be reduced, with decreases of pg and dppc and an increase in pi [ ] . another study [ ] reported similar findings in untreated patients. total phospholipids in bal were less than half that of controls, with raised percentages of pi and lowered pg. the severity of these changes correlated with more advanced histopathologic fibrosis. in patients (including the patients of the former study), the sp-a content of bal was reported to be significantly lower than in normal controls [ ] . in patients with untreated ipf, the pg level was lowered, and its increase after the commencement of steroid therapy seemed to indicate clinical improvement [ ] . these studies suggest that surfactant studies may be of clinical value to assess the prognosis and proper management in ipf [ ] . sarcoidosis is a generalized granulomatous disease of unknown origin which frequently involves the lung. in patients, total phospholipids in bal were not significantly decreased, and changes in phospholipid composition were not found [ ] . in partial agreement with these observations, no significant changes in total bal phospholipids were found in untreated patients with sarcoidosis [ ] , but there was an increase in the pg:pi ratio. if confirmed, these findings could be of interest as a clinical tool to separate sarcoidosis from ipf in the differential diagnosis of fibrosing lung diseases. another study of untreated patients described a decrease of dppc in bal [ ] . in untreated patients with active sarcoidosis, our group found raised sp-a levels in bal in comparison with healthy controls [ ] . further studies are necessary to confirm surfactant changes in pulmonary sarcoidosis and to evaluate their role in this disease and their potential in the differential diagnosis of fibrosing lung disorders. the known immunoregulatory role of surfactant makes this pulmonary disease an interesting object of surfactant studies. however, only a few reports have so far addressed the role of surfactant in hypersensitivity pneumonitis (hp). in a recent study, untreated patients with hp are mentioned whose sp-a values in bal were lower than in normal subjects [ ] . by contrast, our own preliminary data from bal fluids of patients with untreated, active hp show higher sp-a values than controls [ ] . also, the sp-a content of alveolar macrophages (obtained by bal) as assessed by immunocytochemistry was elevated in untreated hp patients in comparison with healthy controls [ ] . another recent study demonstrated that acute immune lung injury in guinea pigs is augmented in animals with partial surfactant depletion while surfactant replacement ameliorated the parameters of lung injury [ ] . this prompted a somewhat optimistic comment that surfactant replacement might be useful in the therapy of cell-mediated immune diseases of the lung [ ] . it is an attractive hypothesis that surfactant abnormalities may play a role in the pathogenesis of pneumonia and/or that surfactant changes occur as a consequence of alveolar infection. as an example, viral infection could damage alveolar surfacrant, facilitating the secondary invasion of bacteria. as yet, only a few studies have investigated these questions, so that our knowledge of the role of surfactant in pneumonia is still rather incomplete. in patients with bacterial pneumonia, changes in the fatty acid composition of bal phospholipids have been described [ ] . in an animal model of pneumocystis carinii pneumonia, increased amounts of total phospholipids and decreases in the percentage of pc were observed [ ] . it was hypothesized that these findings contribute to the altered lung mechanics and respiratory distress in this disease. however, it should be stressed once more that phospholipid changes may not necessarily reflect true surfactant abnormalities. in patients with acquired immunodeficiency syndrome (aids)-related pneumonia (mostly p. carinii pneumonia), a marked increase of sp-a in bal was reported in comparison with healthy controls [ ] . phospholipid analysis was not done, and it remained unclear whether the observed changes were primarily related to human immunodeficiency virus (hiv) infection or to pneumonia. further studies of the reactions and the potential role of the surfactant system in bacterial or viral invasion of the alveolar space are certainly necessary and may be awaited with interest. this is a rare disease in which for unknown reasons the alveolar type ii cell synthesizes and secretes excessive amounts of abnormal surfactant material. lungs of silica-exposed animals share common features with human alveolar proteinosis (see above), but there is no evidence that dust exposure has a role in the pathogenesis of this disease in man. a typical finding is the accumulation of tubular myelin-like multilamellated structures in the alveoli [ ] . the bal fluid is characterized by increased content of total phospholipids with a relative decrease in pg and an increase in pi [ ] . diagnosis is usually made histologically but may also be made by the demonstration of excessively high sp-a levels in bal or simply in sputum [ ] . further studies of surfactant material and alveolar type ii cells of these patients may possibly help to identify the cause of this condition, which is presumably related to a disturbance of the normal type ii cell regulation. radiation pneumonitis and subsequent fibrosis are known problems after radiotherapy of thoracic organs. animal studies have shown that the number of lamellar bodies in type ii cells drops dramatically immediately after radiation and that this is accompanied by an increase in lavage surfactant content [ ] . in vitro studies by the same group demonstrated that this is a direct effect of radiation on type ii cells and that these cells exhibit changes which may indicate a switch of phospholipid synthesis to cell membrane repair after radiation damage. these experimental findings indicate that radiation may lead to massive surfactant secretion from type ii cells early after exposure followed by a sharp drop in further surfactant synthesis. in patients with pleural mesothelioma, hemithorax irradiation caused protracted accumulation of proteins in the alveolar epithelial lining fluid which may inhibit the surface activity of surfactant. no significant changes in total phospholipid content were found, but pg, pi, pc, and sp-a levels were decrased, while the sphingomyelin concentrations were markedly increased [ ] . however, the raised sphingomyelin levels in this study probably originate from other sources than alveolar surfactant. the changes were most evident months after the completion of radiotherapy. unfortunately, immediate or early effects of radiation were not investigated. further work will be necessary to determine the role of surfactant abnormalities in the pathogenesis of radiation pneumonitis. drug-induced pulmonary disease (dipd) is often accompanied by histological changes of alveolar type ii cells like dysplasia and proliferation [ , ] . therefore, it is reasonable to expect changes of the type ii cell surfactant production in druginduced lung injury. however, only a few drugs which are potentially able to induce dipd have so far been investigated in this respect. polychemotherapy has in one report been described as inducing decreased phosphatidylcholine levels and increased phosphatidylglycerol levels in bal of patients with bronchial carcinoma [ ] . bleomycin is an antineoplastic drug which has a known capability to induce fibrosing lung disease. in animal studies, bleomycin lung injury is frequently used as a model of pulmonary fibrosis [ ] . bleomycin induces proliferation of type ii cells and giant intracellular lamellar bodies in mice. in rats with bleomycin lung disease, the bal after days and revealed increased amounts of total phospholipids, with increased percentages of pc and pi, while that of pg was decreased. these changes coincided with an altered lung compliance [ ] . another study described an initial decrease of total phospholipids after days and a subsequent . -fold increase over control animals on days and [ ] . the percentage of pg was reduced, and that of pi was increased. sp-a levels did not change throughout the experiment. from these results, a rather general conclusion was drawn that sp-a is insensitive to lung injury and repair. decreased bal phospholipids were also found in the early phase of fibrosis in hamsters. the surface-active properties of surfactant were inhibited and lung pressure-volume curves deteriorated [ ] . in conclusion, bleomycin apparently leads to a decrease of total phospholipid values within the first days of lung injury, followed by an increase above normal values with a decreased pg: p! ratio. it remains to be confirmed that these observations adequately and specifically reflect the injury of alveolar type ii cells. it seems surprising that sp-a, a more specific secretory product of alveolar type ii cells than phospholipids, did not change in the one study cited above. the conclusion that sp-a is insensitive to lung injury is not convincing, since changes in sp-a levels have been reported in idio-pathic pulmonary fibrosis and other lung disorders. it has been hypothesized that an increase of alveolar surfactant material may contribute to the pathogenesis of pulmonary fibrosis by activating alveolar macrophages which in turn stimulate fibroblasts [ ] . however, there is no experimental support to this idea, and from a clinical point of view, this hypothesis appears doubtful since most patients with alveolar proteinosis do not tend to develop pulmonary fibrosis. amphiphilic drugs like amiodarone, propranolol, chloramphenicol, and chlorpromazine may interact with pulmonary phospholipids and thus surfactant phospholipids, causing pulmonary phospholipidosis. a proposed mechanism is that normal phospholipid degradation is impaired by binding to the drugs. inhibition of phospholipases may also be involved [ ] . it seems reasonable to suspect surfactant abnormalities in many other drug-induced lung disorders because dipd is often associated with morphological alterations of type ii cells. as an example, we recently observed morphological changes of alveolar type ii cells in a case of acute mesalazine alveolitis [ ] . subsequent analysis of the bal fluid of this patient revealed an increase of sp-a content approximately -fold above healthy controls. byssinosis is a lung disease observed in cotton workers. clinically, patients present with fever, flulike symptoms, and bronchoconstriction. lipopolysaccharides from gram-negative bacteria found in respirable cotton dusts are thought to be responsible for this disease. a recently published in vitro study suggests that cotton extracts cause biophysical alterations of the lung surfactant [ ] . it is hypothesized that these effects play a part in the pathogenesis of byssinosis. bal from lung transplants of dogs were recently investigated with the principle aim of finding surfactant phospholipid changes specific to infection or rejection [ ] . this differential diagnosis represents one of the major problems in the treatment of lung recipients. however, the data obtained in this study were essentially inconclusive. the optimism that surfactant abnormalities specific to rejection or infection will be found in the future seems somewhat questionable because both are inflammatory processes with presumably similar responses of alveolar type ii cells. another recent study [ ] determined dppc levels in bal of excised dog lungs during hypothermic storage ( ° c for h) and after left lung transplantation ( dogs, -h postoperative observation period). a decrease of dppc levels was found in both situations. however, in a second group of transplanted dogs receiving l-carnitine infusions preand postoperatively, dppc levels and oxygen tension were higher postoperatively than in the group not treated with carnitine. it was concluded that the drop in dppc levels reflected ischemic damage to alveolar type ii cells and that carnitine (a cofactor for fatty acid transport into mitochondria) improved surfactant synthesis and therefore pulmonary gas exchange in the transplants. however, analysis of other bal phospholipids and surfactant-specific proteins is lacking in this study, and it remains to be confirmed that carnitine infusions really have such in vivo effects. a current review of this subject [ ] outlines some of the possible perspectives of surfactant analysis and treatment in lung transplantation in more detail. certainly, much more work has to be done to assess the usefulness of surfactant studies or even surfactant replacement therapies in lung recipients. as outlined before, surfactant therapy may prove to have beneficial effects on the course of ards and is now being investigated in clinical trials. presently, there is no convincing evidence to suggest that such a treatment may also be of use in other adult lung diseases. a number of surfactant preparations are now in use, and some of them are already marketed for the treatment of irds. their composition and therefore their properties vary considerably, and it is not yet clear which preparation will be the best considering efficacy, safety, availability, and price. it seems possible that different surfactants will in the future prove optimal for different indications, thus perhaps leading to a variety of specifically designed preparations. bovine surfactant preparations (e.g., survanta, surfactant-ta, alveofact) are organic solvent extracts of minced cow lungs and contain phospholipids in a natural composition plus sp-b and sp-c but no sp-a. in a randomized controlled trial of a bovine surfactant preparation (single dose) for the prevention of irds [ ] , it could be demon- strated that the survival rate without bronchopulmonary dysplasia was significantly improved. furthermore, there was a tendency to a better overall survival rate and a reduction in total time of mechanical ventilation. a single-dose regimen of survanta reduced the severity of respiratory distress and the frequency of pneumothorax but not the mortality in another randomized controlled study of irds [ ] . survanta has also been reported to improve lung recoil but not arterial blood gases in a rabbit lung model of ards [ ] . surfactant-ta in a randomized controlled trial has been shown to diminish the amount of respiratory support necessary in premature infants with irds [ ] . another similar study demonstrated the reduction of intracranial hemorrhage and bronchopulmonary dysplasia in infants surviving irds [ ] . in an anecdotal report of cases of ards, surfactant-ta was also reported to have beneficial effects, although the dose was unusually low [ ] . porcine surfactants (e.g., curosurf) are organic solvent extracts from minced porcine lungs with a composition comparable to bovine surfactants. beneficial effects of curosurf have been described in patients with ards [ ] and in a series of children with severe irds [ ] . also, natural surfactants from amnion fluid or bal have been used. a serious drawback of all natural surfactants is their limited availability and their high prices. alec is a simple preparation of only two phospholipids, dppc and pg (in a weight proportion of : ). exosurf (or exosurf neonatal) is a mixture of dppc, hexadecanol, and tyloxapol and also does not contain surfactant-specific proteins. in a recently published, large, multicenter trial in infants with irds [ ] , exosurf in a two-dose regimen was shown to reduce mortality and perinatal morbidity. however, in a sheep model of ards, aerosolized exosurf failed to demonstrate a beneficial effect [ ] . presently, great efforts are being made to produce synthetic surfactants which resemble natural surfactants more closely. the genes of sp-a, b, and c have been cloned so that these proteins can be produced by methods of recombinant dna technology [ ] . surfactant phospholipids can easily be produced by chemical synthesis. thus, different surfactant preparations can now be designed and studied in vitro and in vivo. these syn-thetic surfactants will have the advantage of high quality and nearly unlimited availability, which is an important prerequisite for pharmacological trials and subsequent clinical use on a larger scale. however, several remaining issues will have to be solved, e.g., the optimal composition of such "designer surfactants." probably, only the phospholipids dppc and pg will be necessary in conjunction with surfactant proteins to guarantee full surfactant efficacy [ ] . another issue which is presently debated is whether or not sp-a is a necessary component of synthetic surfactant preparations. bovine and porcine surfactant preparations without sp-a have already been shown to be effective, and it is feared that the addition of sp-a may increase the immunogenicity and impair the stability of the preparation. however, the addition of sp-a enhances the biophysical activity and increases the resistance of surfactants against inhibitory proteins in vitro, which seems an important aspect, especially when treating ards [ ] . most data on surfactant dosage in adults are derived from animal studies or clinical trials of irds treatment (e.g., [ , , , , ] ). usually, a single dose or a two-dose regimen is preferred over repeated surfactant instillations. an adequate single dose for the treatment of ards is thought to be in the range of - mg phospholipids/kg body weight [ , , , , ] . alternatively, for example, a cumulative total dose of g has been used [ ] . surfactant preparations containing proteins should be expected to have a potential for sensitization of a patient to foreign proteins. data from children with irds treated with exogenous surfactant indicate that circulating surfactant-anti-surfactant immune complexes frequently occur [ ] . however, many irds patients without substitution therapy also seem to have such circulating immune complexes [ ] , and negative effects have not yet been observed. a recently published study [ ] demonstrated igm antibodies to surfactant specific proteins in patients with severe irds and showed that the antibody occurrence decreased after surfactant treatment. it was concluded that irds can lead to a leak of surfactant-specific proteins into the circulation and that surfactant treat- ment may reduce this leak by reducing the lung damage. another issue is that exogenous surfactant could interfere with endogenous surfactant synthesis and secretion. indeed, in vitro evidence on surfactant regulation (see above) would suggest that surfactant substitution could have such unwanted effects, e.g., by feedback inhibition of type ii cells. however, a recent in vivo study in rabbits [ ] has shown that this was not the case. on the contrary, administration of different surfactant preparations tended to stimulate endogenous surfactant synthesis and secretion. in conclusion, several studies and existing clinical experience suggest that surfactant substitution therapy is not associated with serious risks. however, possible long-term effects are not yet known, and further studies should continue to monitor patients for potential side effects of surfactant treatment. pharmacologic improvement of surfactant abnormalities or deficits in human lung diseases, especially in ards, would be of considerable clinical value. despite some encouraging in vitro and animal studies, no clinical studies have yet convincingly demonstrated the usefulness of theoretically promising pharmacologic agents. one of the problems in ards is probably that successful pharmacological substances would require very strong stimulatory effects on alveolar type ii cells to overcome not only the alveolar surfactant deficit but also the inhibitory effects of exudated proteins in the alveoli. steroids are known to interfere with many of the mechanisms thought to be involved in ards. their actions include beneficial effects on surfactant synthesis. however, a number of large clinical trials have not been able to prove a clinical benefit of steroid therapy in ards (for review see [ ] ). this is not necessarily due to a failure of steroids to enhance surfactant synthesis but may simply reflect the multiple disturbances associated with ards. steroids are frequently and with some success used in mothers at risk of premature delivery to prevent irds (for review see [ ] ). beta-agonists are able to enhance surfactant synthesis and secretion from alveolar type ii cells in vitro. these agents are also used to suppress premature labor in mothers and possibly accelerate fetal lung maturation as a beneficial side effect [ , ] . however, no clear evidence has so far been presented to support such in vivo effects of beta-agonists. ambroxol, a drug which is primarily marketed as a mucolytic agent, seems to enhance surfactant production and secretion [ , ] and has been reported to be useful for the prevention and treatment of irds (for review see [ ]). we were not able to find studies investigating a potential use of ambroxol in ards. this review has attempted to summarize briefly the present knowledge on the pulmonary surfactant system and has tried to outline some of the available information which may in the future become relevant to clinical pulmonary medicine. after more than years of research, the surfactant system of the human lung has not yet become part of routine diagnostic or therapeutic considerations in adult pulmonary medicine. however, with growing knowledge from basic research, surfactant studies are beginning to give us some new insights into the mechanisms involved in various lung diseases and in the degree of involvement of alveolar type ii cells. thus, a variety of possible perspectives have now arisen, ranging from diagnostic to therapeutic implications and preventional aspects. it does not seem likely that surfactant analyses will in the future be used primarily to arrive at a specific diagnosis of a disease since there are probably not many conditions which feature characteristic surfactant abnormalities. however, present evidence fosters speculations that surfactant studies may prove useful in giving some information about the activity, intensity, and perhaps the duration of some pulmonary diseases or pollutant exposure, and they may be found helpful in the differential diagnosis of fibrosing lung disease. furthermore, it can be speculated that surfactant studies may help to monitor the effects of therapies and to assess the prognosis of various lung diseases. however, much more work has to be done to investigate these hypotheses, and possible useful results will have to be weighed against the established clinical tools. therapeutic perspectives are at present mainly focussed on ards. here, the first results of clinical trials will soon be available and are awaited with interest. other indications of surfactant therapy are not yet clearly visible and remain highly speculative. however, the known role of the surfactant system in pulmonary host defense mechanisms and local immunomodulation will continue to stimulate clinical interest in its role in inflammatory and immunologic disorders of the lung. surfactant in pulmonary oxygen toxicity long-term nitrogen dioxide exposure surfactant apoprotein a (sp-a) is synthesized in airway cells surface properties in relation to atelectasis and hyaline membrane disease surfactant protein sp-b induces ordering at the surface of model membrane bilayers ozone stress initiates acute perturbations of secreted surfactant membranes hormonal regulation of pulmonary surfactant chemical structure of phospholipids in the lungs and airways of sheep surface tension induced by dipalmitoyl lecithin in vitro under physiological conditions lung derived surface active material (sam) inhibits natural killer cell tumor cytotoxicity changes in fatty acids in phospholipids of the bronchoalveolar fluid in bacterial pneumonia and in adult respiratory distress syndrome decreased phosphatidylcholine in the lung fluid of patients with sarcoidosis enhancement of macrophage and monocyte cytotoxicity by the surface active material of lung lining fluid sequential changes in phospholipid composition and synthesis in lungs exposed to nitrogen dioxide structure and function of phosphatidylglycerol-deficient lung surfactant toxicity of inhaled cadmium chloride: early responses of the antioxidant and surfactant systems in rat lungs immunomodulation by pulmonary surfactant regulation of lung surfactant secretion surfacrant proteins and anti-surfactant antibodies in sera from infants with respiratory distress syndrome with and without snrfactant treatment surface tension of lung extracts smoking and pulmonary surfactant pulmonary surface tension and alveolar stability pulmonary surfactant protein b (sp-b): structure-function relationships role of surfactant free fatty acids in antimicrobial defenses drug-induced pulmonary disease. part : cytotoxic drugs drug-induced pulmonary disease. part : noncytotoxic drugs decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial lung surfactant associated proteins and type iv collagen share common epitopes surfactant protein d. increased accumulation in silica-induced pulmonary lipoproteinosis biophysical alteration of lung surfactant by extracts of cotton dust effects of silica on the composition of the pulmonary extracellular lining the pharmacology of ambroxol review and new results pulmonary surfactant pulraonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type ii cells acute tung injury induced by phospholipase a surfactant replacement in adult respiratory distress syndrome pulmonary phospholipidosis in rats respiring air containing diesel particulates pathogenesis of pulmonary fibrosis induced by chrysotile asbestos. virchows arch experimental bleomycin lung in mice physiologic and toxicologic responses of alveolar type ii cells low yield of pulmonary surfactant in cigarette smokers in vivo regulation of surfactant proteins by glucocorticoids sixty years of surfactant research isolation and characterization of cdna clones for the -kda pulmonary surfactant-associated protein adult respiratory distress syndrome -prognosis after onset artificial pulmonary surfactant inhibited by proteins surfactant replacement therapy with a single postventilatory dose of a reconstituted bovine surfactant in preterm neonates with respiratory distress syndrome: final analysis of a multicenter, doubleblind, randomized trial and comparison with similar trials lipid content of alveolar lining material collected by bronchoalveolar lavage randomized controlled trial of exogenous surfactant for the treatment of hyaline membrane disease pharmacological treatment of the adult respiratory distress syndrome a multicenter randomized controlled clinical trial of bovine surfactant for prevention of respiratory distress syndrome pulmonary defense mechanisms in boa constrictor effects of hydrogen sulfide exposure on surface properties of lung surfactant increased surfactant protein a (sp-a) content in human alveolar macrophages in hypersensitivity pneumonitis lung surfactant and pulmonary toxicology synthesis and assembly of lung surfactant effects of ozone on phospholipid synthesis by alveolar type ii cells isolated from adult rat lung clinical experience with exogenous natural surfactant absence of phosphatidylglycerol (pg) in respiratory distress syndrome in the newborn analysis of labeling and clearance of lung surfactant phospholipids in rabbit evidence of lung surfactant abnormality in respiratory failure changes in surfactant in bronchoalveolar lavage fluid after hemithorax irradiation in patients with mesothelioma surfactant protein a in bronchoalveolar lavage of sarcoidosis and hypersensitivity pneumonitis phospholipids as dynamic participants in biological processes lung surfactant surfactant cholesterol metabolism of the isolated perfused rat lung pulmonary surfactant apoproteins: a review of protein and genomic structure lung lipids and disease. respiration pulmonary surface film stability and composition the role of lung surfactant role of pulmonary surfactant in the development and treatment of adult respiratory distress syndrome effects of hemoglobin and cell membrane lipids on pulmonary surfactant activity surface property changes from interactions of albumin with natural surfactant and extracted lung lipids type ii pneumocyte changes during hyperoxic lung injury and recovery down-regulation of immune responses in the lower respiratory tract: the role of alveolar macrophages changes in phospholipids in bronchoalveolar lavage fluid of patients with interstitial lung diseases alterations of acidic phospholipids in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis dissolution and reassembly of tubular myelin-like multilamellated structures from the lungs of patients with pulmonary alveolar proteinosis a multicenter, randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome surface and tissue forces, surfactant protein a, and the phospholipid components of pulmonary surfactant in bleomycin-induced pulmonary fibrosis in the rat changes in phosphatidylglycerol in bronchoalveolar lavage fluids from patients with cryptogenic fibrosing alveolitis changes of alveolar stability and phospholipids in pulmonary surfactant in acute pancreatitis surfactant for the treatment of respiratory distress syndrome surfactant protein b : disulfide bridges, structural properties, and kringle similarities human alveolar lining material and antibacterial defenses types of interaction of amphiphilic drugs with phospholipid vesicles enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material analysis of bronchoalveolar lavage and pulmonary alveolar surfactant for diagnosis of rejection and infection in heart-lung transplantation alveolar type ii cells, surfactant protein a (sp-a), and the phospholipid components of surfactant in acute silicosis in the rat structure of alveolar epithelial cells in patients with fibrotic lung disorders fluid dynamics during bronchoalveolar lavage secretions from primary hamster tracheal surface epithelial cells in culture: mucin-like glycoproteins, proteoglycans, and lipids isolation of apoproteins from canine surface active material -and pneumonia-induced lung injury. ii. properties of pulmonary surfactant pulmonary surfactant in bronchoalveolar lavage after canine lung transplantation inactivation of exogenous surfactant by pulmonary edema fluid surfactant protein d (sp-d) counteracts the inhibitory effect of surfactant protein a (sp-a) on phospholipid secretion by alveolar type ii cells characterization of pulmonary surfactant protein d: its copurification with lipids animal models and clinical pilot studies of surfactant replacement in adult respiratory distress syndrome surfactant replacement improves lung recoil in rabbit lungs after acid aspiration injury to type ii pneumocytes in rats exposed to cigarette smoke endotoxin suppresses surfactant synthesis in cultured rat lung cells functional abnormalities of lung surfactant in experimental acute alveolar injury in the dog glucocorticoids both stimulate and inhibit production of pulmonary surfactant protein a in fetal human lung a controlled clinical trial of synthetic surfactant in infants weighing g or more with respiratory distress syndrome bronchoalveolar lavage lipids in idiopathic pulmonary fibrosis biochemical analyses of bronchoalveolar lavage fluids of healthy human volunteer smokers and nonsmokers human leucocyte clq receptor binds other soluble proteins with collagen domains specific interaction of lung surfactant protein a (sp-a) with rat alveolar macrophages limitations of using urea to quantify epithelial lining fluid recovered by bronchalveolar lavage surfactant in adult respiratory distress syndrome surfactant apoprotein.-a concentration in sputum for diagnosis of pulmonary alveolar proteinosis sublethal hyperoxic injury to the alveolar epithelium and the pulmonary surfactant system characterization of antioxidant activities of pulmonary surfactant mixtures idiopathic pulmonary fibrosis. abnormalities in the bronchoalveotar lavage content of surfacrant protein a immunologic consequences of exogenous surfactint administration degradation of pulmonary surfactant disaturated phosphatidylcholines by alveolar macrophages hypertrophy and hyperplasia of alveolar type ii cells in response to silica and other pulmonary toxicants adverse effects of toxins and drugs on the surfactant systems causes of mortality in patients with the adult respiratory distress syndrome toxicological data on nox: an overview pulmonary surfactant: physiology, pharmacology and clinical uses exogenous surfactant treatment for the adult respiratory distress syndrome? a historical perspective effects of pulmonary oxygen injury on airway content of surfactant-associated protein a surfactant for adults with respiratory failure surfactant analysis and replacement therapy: a future tool of the lung transplant surgeon surfactant treatments alter endogenous surfactant metabolism in rabbit lungs bacteremia-induced suppression of alveolar surfactant production rat lung lavage surfactant enhances bacterial phagocytosis and intracellular killing by alveolar macrophages structural and functional changes of surfactant protein a induced by ozone changes of lung surfactant and pressure-volume curve in bleomycin-induced pulmonary fibrosis effects of smoke inhalation on surfactant phospholipids and phospholipase a activity in the mouse lung properties, function and origin of the alveolar lining layer the relation between surface tension and area in the alveolar lining film purification and biochemical characterization of cp (sp-d), a collagenous surfactant-associated protein surfactant protein d is a divalent cation-dependent carbohydrate-binding protein clearance of surfactant phosphatidylcholine from adult rabbit lungs clearance of surfactant phosphatidylcholine via the upper airways in rabbits localization of surfactant protein synthesis in human lung by in situ hybridization increased recovery of surfactant protein a in aids-related pneumonia surfactant abnormalities in patients with respiratory failure after multiple trauma altered pulmonary surfactant in uncomplicated and septicemia-complicated courses of acute respiratory failure a proposed nomenclature for pulmonary surfactant-associated proteins the role of surfactant-associated proteins biochemical modification of pulmonary surfactant after bromhexine derivatc injection rheological and transport properties of airway secretions in cystic fibrosis -relationships with the degree of infection and severity of the disease changes in lipids of lung lavage in monkeys after chronic exposure to ambient levels of ozone immunologic system in the respiratory tract pulmonary surfactant as a physiologic immunosuppressive agent curstedt t ( ) the adult respiratory distress syndrome: first trials with surfactant replacement pulmonary surfactant suppresses the immune lung injury response to inhaled antigen in guinea pigs idiopathic pulmonary fibrosis -abnormalities in bronchoalveolar lavage fluid the surfactant system of the lung changes in pulmonary surfactant composition following macc chemotherapy for lung carcinoma binding and uptake of pulmonary surfactant protein (sp-a) by pulmonary type ii epithelial cells lung surfactant: a biotechnological challenge alveolar macrophage migration -influence of lung lining material alteration of surfactant function due to protein leakage: special interaction with fibrin monomer surfactant abnormalities and adult respiratory failure surfactant phospholipids and lavage phospholipase a in experimental pneumocystis carinii pneumonia giant lamellar bodies in alveolar type ii cells of rats exposed to a low concentration of ozone the effect of pulmonary surface-active material on the generation and expression of murine b-and t-lymphocyte effector functions in vitro isolation and characterization of a sulfated glyceroglucolipid from alveolar lavage of rabbit early versus late surfactant replacement therapy in severe respiratory distress syndrome surfactant replacement: immunological considerations surfactant abnormality after endotoxin-induced lung injury in guinea pigs structure-function relationships of bovine pulmonary surfactant proteins sp-b and sp-c the proximal border of the human respiratory unit, as shown by scanning and transmission electron microscopy and light microscopical cytochemistry human pulmonary surfactant protein (sp-a), a protein structurally homologous to clq, can enhance fcr-and crl-mediated phagocytosis altered lipid synthesis in type ii pneumocytes exposed to lung surfactant correlation of changes in pulmonary surfactant phospholipids with compliance in bleomycin-induced pulmonary fibrosis in the rat synthesis of surfactant lipids in the adult and fetal lung: pathways and regulatory aspects metabolism of phospholipids in the lung aspects of metabolism and storage of pulmonary surfactant: experiments with isolated type ii pneumocytes and lamellar bodies pulmonary surfactant protein a enhances the host-defence mechanism of rat alveolar macrophages surfactant protein a is opsonin in phagocytosis of herpes simplex virus type by rat alveolar macrophages enhancement of biophysical activity of lung surfactant extracts and phospholipid-apoprotein mixtures by surfactant protein a neue auffassungen fiber einen grundbegriff der atemmechanik surfactant protein a is localized at the corners of the pulmonary tubular myelin lattice macromolecular organization of natural and recombinant lung surfactant protein sp - structural comparison of recombinant pulmonary surfactant protein sp-a derived from two human coding sequences: implications for the chain composition of natural human sp-a surfactant proteins and sp-d function and regulation of expression of pulmonary surfactant-associated proteins identification of surfactant proteolipid sp-b in human surfactant and fetal lung mesalazine alveolitis isolation and characterization of the human pulmonary surfactant apoprotein gene glycosylation and secretion of surfactant-associated glycoprotein a endobronchial surface active phospholipids: clinical conclusions changes in lipid structure produced by surfactant proteins sp-a, sp-b, and sp-c immunoregulatory properties of pulmonary surfactant: effect of lung lining fluid on proliferation of human blood lymphocytes immunosuppression by pulmonary surfactant: mechanisms of action relations among recoil pressure, surface area, and surface tension in the lung effects of short-term exposure to diesel exhaust on lung cell proliferation and phospholipid metabolism clearance and recycling of pulmonary surfactant metabolism and turnover of lung surfactant surfactant apoprotein mr= . - . enhances uptake of liposomes by type ii ceils role of bovine pulmonaryassociated proteins in the surface active property of phospholipid mixtures effects of aerosolized artificial surfactant on repeated oleic acid injury in sheep acknowledgements. we would like to thank prof. k. morgenroth, ruhr-universitfit bochum, for the excellent electron mi-croscopic photographs (figs. - ) and prof. schfifer (byk-gulden co., konstanz, germany), prof. akino and prof. kuroki (sapporo medical college, japan) for aiding our laboratory with sp-a antigen and antibodies. key: cord- - c oqn authors: umans, u.; golding, r.; duraku, s.; manoliu, r. title: herpes simplex virus pneumonia: conventional chest radiograph pattern date: - - journal: eur radiol doi: . /s sha: doc_id: cord_uid: c oqn the aim of this study was to describe the findings on plain chest radiographs in patients with herpes simplex virus pneumonia (hsvp). the study was based on patients who at a retrospective search have been found to have a monoinfection with herpes simplex virus. the diagnosis was established by isolation of the virus from material obtained during fiberoptic bronchoscopy (fob) which also included broncho-alveolar lavage and tissue sampling. fourteen patients had a chest radiograph performed within h of the date of the fob. two radiographs showed no abnormalities of the lung parenchyma. the radiographs of the other patients showed lung opacification, predominantly lobar or more extensive and always bilateral. most patients presented with a mixed airspace and interstitial pattern of opacities, but of showed at least an airspace consolidation. lobar, segmental, or subsegmental atelectasis was present in patients, and unilateral or bilateral pleural effusion in patients, but only in patient was it a large amount. in contradiction to the literature which reports a high correlation between hsvp and acute respiratory distress syndrome (ards), of patients did not meet the pathophysiological criteria for ards. the radiologist may suggest the diagnosis of hsvp when bilateral airspace consolidation or mixed opacities appear in a susceptible group of patients who are not thought to have ards or pulmonary edema. the definite diagnosis of hsv pneumonia can be established only on the basis of culture of material obtained by broncho-alveolar lavage. abstract the aim of this study was to describe the findings on plain chest radiographs in patients with herpes simplex virus pneumonia (hsvp). the study was based on patients who at a retrospective search have been found to have a monoinfection with herpes simplex virus. the diagnosis was established by isolation of the virus from material obtained during fiberoptic bronchoscopy (fob) which also included broncho-alveolar lavage and tissue sampling. fourteen patients had a chest radiograph performed within h of the date of the fob. two radiographs showed no abnormalities of the lung parenchyma. the radiographs of the other patients showed lung opacification, predominantly lobar or more extensive and always bilateral. most patients presented with a mixed airspace and interstitial pattern of opacities, but of showed at least an airspace consolidation. lobar, seg-mental, or subsegmental atelectasis was present in patients, and unilateral or bilateral pleural effusion in patients, but only in patient was it a large amount. in contradiction to the literature which reports a high correlation between hsvp and acute respiratory distress syndrome (ards), of patients did not meet the pathophysiological criteria for ards. the radiologist may suggest the diagnosis of hsvp when bilateral airspace consolidation or mixed opacities appear in a susceptible group of patients who are not thought to have ards or pulmonary edema. the definite diagnosis of hsv pneumonia can be established only on the basis of culture of material obtained by broncho-alveolar lavage. key words herpes simplex virusṔ neumonia´chest radiographÁ rds state in patients who had had chemotherapy, organ transplantation, or other major surgery, and also in patients infected with human immunodeficiency virus (hiv) or other diseases which decrease immunity [ , , , , , ] . all these conditions were shown to be associated with an increased risk of herpes simplex virus pneumonia (hsvp). it is also known that intubation causes initial upper airway infection perhaps as a result of local trauma which might lead to hsvp. tuxen et al. reported a relationship between hsvp and the diagnosis of acute respiratory distress syndrome (ards) established clinically and radiologically [ , , ] . this was later confirmed in an autopsy report of patients suffering from burns [ ] . hematogenous spread to the lungs from infected lesions may also occur. this could be initiated by disruption of virally infected tissues by burns or smoke inhalation. in the international literature the chest radiographic findings of hsvp have been rarely reported [ , , , , , ] . the present study was undertaken to (a) document the spectrum of abnormalities on chest radiographs in patients with a proven hsvp, and (b) try to detect if there was any pattern which might lead to a better recognition of this fairly unknown disease. while we were collecting our data aquino et al. published a study on hsv pneumonia [ ] . we compared the results of both studies in an attempt to broaden our knowledge of roentgenographic abnormalities in hsv pneumonia. after a search through all the virological data retrieved in our institution between and the end of we identified all patients in whom hsv was isolated from material obtained during fiberoptic bronchoscopy (fob) which also included broncho-alveolar lavage (bal) and tissue sampling. because we were interested mainly in the sole hsvp without cross-infection, we excluded all patients who also had growth of bacteria, other viruses, fungi, and large amounts of yeast. because of the high predisposition for colonization by candida of critically ill patients, we did not reject patients who only had up to ten colonies per plate besides hsv. from the virological data patients were found to have a hsv type in their lungs detected through fob. only patients had a monoinfection with hsv (or had also a small amount of yeast as well). from the other patients had cross-infection with bacteria only, with bacteria and yeast, with bacteria and fungus, with fungus only, with yeast only, with cytomegalic virus (cmv) and yeast and with cmv, bacteria and yeast. of the patients with sole hsv pneumonia, ranging in age from to years (mean age years) were men. underlying causes that may have predisposed these patients to hsvp were present in patients: had non-hodgkin's lymphoma (all after chemotherapy and had already received bone marrow transplantation), were hiv positive with low cd count, had recent major surgery, had leukemia and patients received immunosuppressive medication for kidney transplantation and idiopathic lung fibrosis, respectively. the remaining patient used prednisolo-ne for bronchial asthma frequently but was not known to be overtly immunosuppressed. indications for fob were fever of unknown origin, unexplained findings on chest radiographs, clinical signs of pneumonia, or respiratory distress of unknown origin. we studied the conventional chest radiograph made within h of the date of the fob. of the patients, were excluded because no chest radiograph was made within h; thus, patients in total were available for study. to determine if there was a relationship with ards we used the pathophysiological criteria proposed by the american±european consensus conference on ards ( ) which states that severe hypoxemia can be defined by an arterial oxygen pressure (pao ) divided by the fraction of inspired oxygen (fio ). a pao :fio ratio of less than indicates ards in the absence of left heart failure. the diagnosis of ards is strengthened by a pulmonary artery occlusion pressure (paop) less than mmhg [ ] . the radiographic studies were reviewed independently by two experienced radiologists who arrived at a consensus with the aid of a third radiologist (figs. , , ) . each chest radiograph was evaluated for the following findings: pattern of lung opacities (airspace consolidation, interstitial opacities, or mixed); location (unilateral, bilateral, focal, diffuse) and extent (segmental, lobar, whole lung) of the abnormalities; atelectasis (not-present, lobar, segmental, subsegmental); pleural effusion (not present, moderate, i.e., less than one-third of the hemithorax, large, i.e., more than one-third of the hemithorax). the pattern was described as airspace consolidation in the presence of lobar, segmental, or patchy opacities. reticular, reticulonodular, and bronchovascular opacities were recorded as interstitial pattern. the use of an endotracheal tube/ cannula or swan-ganz catheter was also noted. the chest radiographic findings are presented in table . in the majority of patients ( of ) lung opacification predominated and was expressed as bilateral, lobar, or diffuse opacities. eight of patients showed a pattern that was partly airspace consolidation and partly interstitial opacities (mixed type), three showed only an airspace consolidation, and one an interstitial pattern. the extent of the opacities ranged from at least lobar to almost the entire lung. diffuse lobar or more extensive opacities were the most commonly recorded abnormalities. we did not notice a predominance for the right or left lung or for a certain lobe. areas of opacification of more than one lobe were seen in almost half of the patients with an airspace pattern. lobar atelectasis was present in and (sub)segmental in patients. pleural effusions were seen in of chest radiographs but only once estimated as a large amount. two chest radiographs showed no abnormalities of the lung parenchyma. one of these patients was admitted with progressive respiratory failure and had a history of immunosuppression because of a kidney transplantation, and the other had fever of unknown origin and a history of cardiac arrest and respiratory failure after chemotherapy for acute myeloid leukemia. twelve patients were intubated and two had in addition a swan-ganz catheter. of intubated patients for whom the pao :fio ratio on the same day of the fob was es-tablished, had a ratio less than . the time from intubation to a positive fob for hsv varied from to days (mean days). reactivated herpes simplex virus type is often isolated from vesicles of the lip region and oropharyngx. far less commonly hsv is found in the lower respiratory tract, although this lower incidence may in part be due to insufficient awareness of hsvp. prellner et al. showed that hsv is a far more common pathogen causing pneumonia than suspected [ ] . in the past decade we have encountered herpes simplex virus pneumonia in patients of our hospital, presenting either as a single infection, or in combination with other pathogenic agents. herpes simplex virus pneumonia was regularly found by bal, although there were not many occurrences. although clinical and pathologic reports of hsvp exist, a search of the international radiology literature revealed a striking paucity. a description of the radiographic changes in neonatal lung infection caused by hsv type contracted during delivery has been provided by dominguez et al. [ ] . they described a chro- fig. a - year-old male operated on for a subarachnoid bleeding. postoperative cardiac complications occurred with myocardial ischemia leading to forward and backward failure and multi-organ failure. chest radiograph taken on day of bal after days of intubation shows a diffuse, bilateral interstitial pattern easily mistaken for pulmonary edema; however, note the small size of the heart and azygos vein fig. a -year-old male with a history of myelodysplastic syndrome developed acute myeloid leukemia. during treatment with chemotherapy patient became even more immunosuppressed. broncho-alveolar lavage was performed because of fever and opacities on the chest radiograph. there is a large opacity in the apex of the right lower lobe, but on closer examination bilateral diffuse opacities are seen (e.g., left perihilar region) nological development consisting of a normal chest radiograph, interstitial changes, airspace consolidation and, lastly, diffuse consolidation of both lungs; however, extrapolation from type to type hsvp and also from infants to adults is a priori not possible. nevertheless, radiological similarities can be expected since both viruses produce identical histopathological changes. other authors have only briefly mention the radiographic findings in studies concerning primarily the pathological and clinical manifestations. schuller et al. examined patients with hsvp and all chest radiographs were abnormal: % showed pulmonary infiltrates, % pleural effusion, and % atelectasis [ ] . ramsey et al. reported patients with hsvp: had focal abnormalities, multifocal, and diffuse abnormalities [ ] . graham and snell describe a healthy -year-old mother with hsvp and bilateral interstitial infiltrates on chest x-ray [ ] . chabot et al. found patients with hsvp after heart transplantation: of them showed diffuse bilateral changes, either mixed airspace±interstitial or interstitial micronodular [ ] . the first major radiological report concerning the conventional chest radiographic patterns of hsvp was written by aquino et al. [ ] . they also describe the abnormalities on ct. the chest radiographs were reviewed within the week prior to the bronchoscopy for each of the patients with hsv pneumonia. twentythree patients ( %) had patchy segmental or subsegmental airspace opacities, and ( %) had in addition a lobar distribution of consolidation and ground-glass opacities. seven patients ( %) had additional reticular opacities. the distribution was diffuse and multifocal in ( %), scattered in ( %), peripheral in ( %), and central in ( %). in patients ( %) pleural effusions were seen. fifteen patients ( %) were intubated; average duration of intubation prior to fob was . days (range ± days). fifty percent had a co-existing clinical diagnosis of ards. this incidence is much higher than in our group ( %), but aquino et al. [ ] do not appear to have used the strict pathophysiological criteria laid down by the american±european consensus conference on ards for the diagnosis of this disorder. since there is overlap in the patient populations susceptible to both ards and hsvp, we think that it is important to point out that the bilateral consolidations caused by hsvp can be ascribed to ards. in our study we selected patients only if they had a proven monoinfection with hsv. our most consistent finding was the presence of bilateral opacities with an airspace or mixed airspace and interstitial pattern. atelectasis and pleural fluid, although frequently found, were not the dominant radiological features. it should be kept in mind that a large majority of patients in the intensive care department have some amount of pleural fluid and also varying degrees of atelectasis. almost all of the radiographic findings in aquino's [ ] study compare very well with our own results with the exception that our series contained two normal chest radiographs. the combination of a normal chest radiograph and a positive bal may be due to contamination of the bal sample by the upper airways. only patient in our group had a ct scan within a week of the diagnosis so that a comparison of ct scan patterns was not possible. in summary, diffuse bilateral opacities with predominantly a mixed or an airspace consolidation was the main finding observed in our series of patients with hsv pneumonia. unilateral consolidation, large atelectasis, and significant amounts of pleural fluid were less frequently observed. our findings do not support definition of a characteristic pattern for hsv pneumonia on chest radiographs. awareness of this disease and with the radiographic abnormalities it can cause may nevertheless increase the diagnostic yield in the appropriate setting. this is important because hsv pneumonia benefits from appropriate therapy; however, the definite diagnosis of hsv pneumonia can only be established on the basis of culture of material obtained by broncho-alveolar lavage. the radiologist may suggest the diagnosis of hsvp particularly when bilateral airspace consolidation or mixed opacities appear in a susceptible group of patients who are not thought to have ards or pulmonary edema. infections with herpes simplex viruses diagnosis of diseases of the chest herpesvirus infection in burned patients herpetic infection in the middle and lower respiratory tract herpes simplex virus pneumonia: clinical, virologic, and pathologic features in patients herpes simplex virus infection of the adult lower respiratory tract. (review) medicine necrotizing toxoplasmic encephalitis and herpetic pneumonia complicating treated hodgkin's disease herpes simplex virus pneumonia: occurrence in an allotransplanted lung opportunistic bronchopulmonnary infections after lung transplantation: clinical and radiographic findings nonbacterial pneumonia after allogenic marrow transplantion: review of years experience herpes simplex virus: the most frequently isolated pathogen in the lungs of patients with severe respiratory distress herpes simplex viral pneumonia in the postthoracotomy patient herpes simplex virus from the lower respiratory tract in adult respiratory distress syndrome prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome herpes simplex infection, an unusual source of adult respiratory distress syndrome pulmonary herpes simplex in burns patients herpes simplex virus pneumonia: patterns on ct scans and conventional chest radiographs neonatal herpes simplex pneumonia: radiographic findings herpes simplex virus from respiratory tract secretions: epidemiology, clinical characteristics, and outcome in immunocompromised and nonimmunocompromised hosts viral pneumonia after heart transplantation: a radioclinical study the american±european consensus conference on ards: definitions, mechanisms, relevant outcome, and clinical trial coordination key: cord- -lfbjvche authors: petran, jan; muelly, thorsten; dembinski, rolf; steuer, niklas; arens, jutta; marx, gernot; kopp, ruedger title: validation of resp and preserve score for ards patients with pumpless extracorporeal lung assist (pecla) date: - - journal: bmc anesthesiol doi: . /s - - - sha: doc_id: cord_uid: lfbjvche background: resp score and preserve score have been validated for veno-venous extracorporeal membrane oxygenation in severe ards to assume individual mortality risk. ards patients with low-flow extracorporeal carbon dioxide removal, especially pumpless extracorporeal lung assist, have also a high mortality rate, but there are no validated specific or general outcome scores. this retrospective study tested whether these established specific risk scores can be validated for pumpless extracorporeal lung assist in ards patients in comparison to a general organ dysfunction score, the sofa score. methods: in a retrospective single center cohort study we calculated and evaluated resp, preserve, and sofa score for ards patients with pumpless extracorporeal lung assist treated between and using the xenios ila membrane ventilator. six patients had a mild, a moderate and a severe ards according to the berlin criteria. demographic data and hospital mortality as well as ventilator settings, hemodynamic parameters, and blood gas measurement before and during extracorporeal therapy were recorded. results: pumpless extracorporeal lung assist of mechanical ventilated ards patients resulted in an optimized lung protective ventilation, significant reduction of p(aco ), and compensation of acidosis. scoring showed a mean score of alive versus deceased patients of ± versus − ± for resp (p < . ), ± versus ± for preserve (p < . ) and ± versus ± for sofa (p < . ). using receiver operating characteristic curves, area under the curve (auc) was . ( % confidence interval (ci) . – . , p < . ) for resp score, . ( % ci . – . , p < . ) for preserve score and . ( % ci . – . , p < . ) for sofa score. conclusions: resp and preserve scores were superior to sofa, as non-specific critical care score. although scores were developed for veno-venous ecmo, we could validate resp and preserve score for pumpless extracorporeal lung assist. in conclusion, resp and preserve score are suitable to estimate mortality risk of ards patients with an arterio-venous pumpless extracorporeal carbon dioxide removal. specific mortality risk scores, especially the respiratory ecmo survival prediction (resp) score [ ] and the predicting death for severe ards on vv-ecmo (pre-serve) score [ ] , were developed and validated for ards patients with veno-venous high-flow extracorporeal membrane oxygenation (ecmo). ards with severe hypercapnia without life-threatening hypoxemia can be treated with extracorporeal carbon dioxide removal (ecco r), especially pumpless extracorporeal lung assist (pecla). despite a high mortality rate validated risk scores are lacking for these devices. during the past decade, ecmo was frequently used for patients suffering severe hypoxemic ards, indicated by a horowitz index pao /fio below - mmhg despite lung protective ventilation, to maintain gas exchange and facilitate lung protection [ ] . in ards patients with severe hypercapnia and respiratory acidosis without life-threatening hypoxemia ecco r was propagated to achieve lung protective ventilation [ ] . arteriovenous pecla represents a specific subgroup of ecco r using a simplified extracorporeal lung assist technique for patients with hypercapnia and respiratory acidosis without cardiac failure. it demonstrated efficient extracorporeal carbon dioxide elimination resulting in lung protective ventilation without respiratory acidosis [ ] and reducing the risk of ventilator induced lung injury (vili) [ ] [ ] [ ] . pecla therapy is limited by a low oxygen transfer with only moderate increase of oxygenation. high mortality rates of ecmo and allocation of limited ecmo resources were leading to the development of mortality prediction scores for veno-venous ecmo in severe ards. especially the resp score [ ] and the preserve score [ ] have been used to identify risk factors for death of ecmo patients (additional files and ). additionally, non-ards-specific scores have been used in critical care. the sequential organ failure assessment (sofa) score, published in , evaluates morbidity by scoring the organ failure of lung, coagulation, liver, cardiovascular system, brain, and kidney (additional file ) [ ] . in the prospective observational lung safe study sofa score was associated with outcome of ards [ ] . resp and/or preserve scores have been compared and evaluated in several studies for ecmo therapy [ ] [ ] [ ] [ ] [ ] [ ] [ ] , but both scores as well as sofa score have not been validated for ards patients treated with a primary extracorporeal co removal, like pecla. in this retrospective study we tested the hypothesis that resp and preserve score are suitable to assume the mortality risk of pecla therapy in case of ards and are superior to the sofa score, which is not specific for extracorporeal lung support and ards. we conducted a retrospective single center cohort study of ards patients undergoing pecla therapy between and at rwth aachen university hospital to validate resp, preserve and sofa score. general ethical approval was received by the rwth aachen university regional research ethics committee for retrospective studies and confirmed for this retrospective study (af / ). inclusion criteria were ards according to the berlin criteria [ ] with pecla therapy and exclusion criteria missing data necessary for calculation of scores. standard therapy included a lung protective ventilation strategy with a pressure controlled ventilation mode, usually biphasic positive airway pressure ventilation: additionally prone position was initiated in moderate to severe ards and inhaled nitric oxide was used as rescue therapy in hypoxemia according to the local standard [ ] . in our institution, indication for pecla and ecmo is confirmed multidisciplinary by physicians of all involved medical faculties. in case of severe hypoxemia due to ards indicated by persistent pao /fio < mmhg despite optimized conservative therapy, patients were treated with veno-venous ecmo as rescue therapy. an indication for pecla was a severe hypercapnia especially in case of concomitant respiratory acidosis (pha > . and/or paco > mmhg) as well as achievement of lung protective ventilation, especially when plateau pressure was more than mbar despite optimization of conservative ards therapy. the pecla consisted of a polymethylpentene oxygenator with heparin coating and a membrane surface area of . m (ila membrane lung®, xenios ag, heilbronn, germany). filling volume was ml. the cannulas were inserted in the femoral artery ( or fr) and in the femoral vein ( or fr) . pecla initiation and therapy was performed according to the manufacturer's instructions of use and local standards. the collected data contained origin of ards at icu admission, demographic parameters such as age, sex, height, weight, diseases, hours of ventilation before pecla initiation, and sofa score before pecla. furthermore, subjects were retrospectively classified in pre-serve and resp scores according to the work of schmidt et al. [ , ] . we recorded ventilator settings with airway pressures (peak/plateau inspiratory pressure, peep, driving pressure) and tidal volume. as all patients were ventilated in a pressure controlled mode peak inspiratory pressure and plateau pressure were equal. registered hemodynamic parameters were mean arterial pressure (map), central venous pressure, heart rate, and norepinephrine dose per minute, and additionally, blood gas measurement with horowitz index (p ao /f io ), p aco , ph, and s ao . all parameters were registered straight before pecla initiation, as well as and h after pecla initiation. calculating the scores required specific additional information, such as laboratory values, organ function, comorbidity, medication, and specific interventions before pecla initiation. hospital mortality rate was recorded according to the development of resp score by schmidt et al. [ ] . for statistical analysis, data are presented as mean and standard deviation (mean ± sd). after confirmation of normal distribution with the kolmogorov-smirnov test, significance was tested within groups with repeatedmeasures anova with post-test and between groups with unpaired t-test (instat version . , graphpad, san diego, ca, usa). a value of p < . was considered statistically significant. a multivariable regression analysis including a variable selection assessed the correlation with mortality. with graphpad prism (graphpad, san diego, ca, usa) receiver operating characteristic (roc) curves of the scores were calculated and an optimum threshold was defined by calculating the maximum youden index (j = sensitivity + specifity - ). between and ards patients were treated with pecla at rwth aachen university hospital. after retrospective screening six patients were excluded due to missing data and subjects were included in the study. table presents demographic data including severity and origin of ards as well as morbidity before pecla in detail. thirteen subjects had an immunocompromised status with a significantly higher mortality rate of %, defined as hematologic malignancies, solid tumor, solid organ transplantation, human immunodeficiency virus, or liver cirrhosis. all subjects fulfilled the ards criteria including a peep of at least cm h o according to the berlin definition [ ] . most patients had a moderate ards (table ) . fifty-two patients had a severe hypercapnia with a p aco ≥ mmhg and a severe acidosis with a ph < . . all subjects were sedated and invasive mechanically ventilated in a pressure controlled mode with a shorter duration before pecla in the survivor group. during pecla all patients received invasive mechanical ventilation. overall hospital mortality rate was %, but demonstrated significant age-related differences. subjects who died in hospital were significantly older and sofa score was higher before initiation of pecla. main causes of death were septic shock with multi organ failure ( %), non-infectious multi organ failure ( %) and persistent respiratory failure ( %). % died due to infaust neurologic prognosis ( severe head injury after trauma and intracranial bleeding under anticoagulation). ventilation, oxygenation, acid-base status, and hemodynamics are presented before initiation of pecla, after and after h in table . after starting pecla therapy a significant reduction of inspiratory pressure and driving pressure was observed in all subjects. after and h p aco was significantly reduced and pre-pecla acidosis was compensated in all subjects. a significant increase of oxygenation index was achieved after h, but remained significantly increased after h only for the surviving cohort. overall pecla therapy achieved a stabilization of cardiovascular parameters such as heart ratio, mean arterial pressure, and central venous pressure ( table ). the results of the multivariable regression analysis are presented in table demonstrating the correlation between parameters before pecla and mortality. for all subjects resp, preserve and sofa scores were calculated at initiation of pecla. calculated scores for alive versus deceased subjects were ± versus − ± for resp score (p < . ), ± versus ± for preserve score (p < . ) and ± versus ± for sofa score (p < . ). roc curves (fig. ) demonstrated an area under the curve (auc) of . for resp score with a % confidence interval (ci) of . - . (p < . ). preserve score achieved an auc of . with % ci . - . (p < . ) as well as sofa score an auc of . with % ci . - . ) (p < . ). the calculation of youden index allowed the definition of a cut-off value for resp score of (sensitivity %, specificity %), for preserve score of (sensitivity %, specificity %) and for sofa score of (sensitivity %, specificity %). with this retrospective study we could demonstrate that resp and preserve score are correlating with the mortality of ards patients with pecla. for the first time two specific risk scores were validated for an ecco r device and were superior to a general organ dysfunction score, the sofa score. in the past resp and preserve score were developed and multiple validated for veno-venous ecmo in hypoxemic ards. in the elso registry, used for the resp score definition, only % of the subjects had a bacterial pneumonia, and major diagnostic groups were other acute respiratory diagnosis with % as well as unspecified with %. this origin of ards also contributes to the calculated resp score [ ] . nevertheless in the recently published eolia ecmo trial % of ards subjects suffered from a bacterial pneumonia and % from viral pneumonia [ ] . in our study, bacterial pneumonia was also the most frequent origin of ards with % and viral pneumonia was observed in %, demonstrating a typical collective of ards patients. resp and preserve score development and validation showed, that age, immunocompromised status, duration of mechanical ventilation, and sofa score are relevant risk factors for outcome of ecmo [ , ] . we observed also a significantly younger age, less immunocompromised status, shorter pre-pecla duration of mechanical ventilation and lower sofa score in the survivor group (table ) . there was no direct impact of ards etiology to survival rate. pre-and post-pecla salvage therapy was not different between survivors and non-survivors. the multivariate analysis of our data revealed also age, sofa score, immunocompromised status and p aco before pecla as relevant factors for mortality ( table ) . as in former pecla studies extracorporeal co removal allowed an enhanced lung protective ventilation. the preserve score used a database of ards subjects with ecmo to identify risk factors and to generate this score [ ] . subjects presented with a median p ao / [ ] . blood gas analysis revealed similar values before ecmo initiation with a median p ao /f io of mmhg (interquartile range - mmhg), median p aco of mmhg ( - mmhg) and a median ph of . ( . - . ). in our study, subjects presented with a better oxygenation, indicated by a horowitz index of ± mmhg, but with a severe respiratory acidosis (p aco . ± . mmhg and ph . ± . ). patients with a severe disturbed oxygenation comparable to the presere and resp validation studies were not suitable for pecla due to the limited oxygen uptake. these patients were primary connected to veno-venous ecmo. nine pecla patients were switched to veno-venous ecmo after further deteriorating oxygenation. nevertheless, oxygenation and acid base status were more compromised than in the prospective randomized controlled xtravent study, which evaluated pecla in combination with an ultraprotective ventilation strategy compared to lung protective ventilation in severe ards [ ] . ecco r therapy as arterio-venous pecla or low-flow veno-venous device seems a promising option to ensure optimized lung protection avoiding further ventilator induced lung injury (vili) [ ] and clinical trials are ongoing [ ] . although there was no leading severe hypoxemia, hospital mortality was % in our study compared to % in the resp score study by schmid et al. [ ] . therefore, in case of extracorporeal carbon dioxide removal a specific risk score seems also useful to identify high-risk patients. in the preserve and resp score validation study most of the included patients suffered from severe hypoxemic ards [ , ] , whereas only % of our subjects had a severe ards before pecla start. in the berlin definition of ards, severity of disturbed oxygenation defines the grade and correlates with mortality [ , ] . on the other hand severe hypercapnia is independently associated with mortality of ards [ ] . therefore, a direct transfer of the resp and preserve score from ecmo to ecco r seems not suitable, because patients have different ards characteristics with leading hypercapnia and concomitant acidosis but without lifethreatening hypoxemia. after positive validation for ards patients with leading hypercapnia and ecco r therapy the established resp and preserve scores could be used for hypoxic as well as hypercapnic ards patients intended for extracorporeal lung support. validation of pecla in our study demonstrated comparable results to other studies analyzing preserve and resp score for veno-venous ecmo (table ) . we additionally tested, if a non-specific sofa score could be an alternative tool to assess the risk profile, but auc as indicator for accuracy was lower. nevertheless a sofa score > represents a risk factor in the pre-serve score but not in the resp score. overall, only the specific scores demonstrated a good diagnostic accuracy for pecla. comparing both scores, the preserve score requires less items and as a result seems easier to handle than the resp score. in conclusion both scores seem suitable for pecla as ecco r device. as mentioned above several studies evaluated resp and preserve scores for other ecmo populations with differing accuracy and without superiority of one score (table ) . survival in the different predefined risk classes demonstrated some inconsistent results but with a generally increasing mortality for a higher risk score (table ) . compared to these studies the performance of preserve and resp was non-inferior for pecla in our study. limitations of our study are the retrospective small validation cohort from one ards center without additional data from other centers to verify our results, the missing long-term survival data and the restriction to one specific low-flow device for ecco r. a prospective registry of ecco r could be able to generate more detailed as well as long-term data. with our retrospective study, preserve and resp score could be sufficiently validated to identify a high-risk profile before starting an extracorporeal carbon dioxide elimination. nevertheless, ards therapy and especially time of initiation and decision for conventional therapy versus ecco r or ecmo require clinical assessment and could not be replaced by a simple scoring. in our study we focused on pumpless ecla as ecco r device, but other veno-venous low-flow ecla systems are also used for hypercapnic ards. for venovenous devices, there is an ongoing transition from leading decarboxylation to decarboxylation plus oxygenation with increasing blood flow. as resp and preserve were primary validated for classical high-flow ecmo and now were additionally validated for pecla as decarboxylation device by our study, we hypothesize that these scoring systems are also suitable for other lowflow ecla systems. further investigations of low-flow veno-venous ecco r could be used to confirm this assumption. performance of resp and preserve score was at least as good for pecla as for veno-venous ecmo, the primary validation cohort and this is the first study expanding the scope from high-flow ecmo to an ecco r therapy. we demonstrated that these risk scores are suitable for ards with leading hypercapnia and pecla additional to severe hypoxemic ards with high-flow ecmo. both scores, resp and preserve, but not sofa score seem suitable to point out the risk profile of ards predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score the preserve mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients role and potentials of low-flow co ( ) removal system in mechanical ventilation a new pumpless extracorporeal interventional lung assist in critical hypoxemia/ hypercapnia pumpless arterio-venous extracorporeal lung assist compared with veno-venous extracorporeal membrane oxygenation during experimental lung injury pumpless extracorporeal lung assist -experience with the first cases the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries external validation of scores proposed for estimation of survival probability of patients with severe adult respiratory distress syndrome undergoing extracorporeal membrane oxygenation therapy: a retrospective study prediction of mortality in adult patients with severe acute lung failure receiving veno-venous extracorporeal membrane oxygenation: a prospective observational study performance of multiple risk assessment tools to predict mortality for adult respiratory distress syndrome with extracorporeal membrane oxygenation therapy: an external validation study based on chinese single-center data venovenous extracorporeal membrane oxygenation in adult respiratory failure: scores for mortality prediction validity of outcome prediction scoring systems in korean patients with severe adult respiratory distress syndrome receiving extracorporeal membrane oxygenation therapy predicting survival after extracorporeal membrane oxygenation for ards: an external validation of resp and preserve scores a comparative analysis of survival prediction using preserve and resp scores acute respiratory distress syndrome: the berlin definition evidence-based medicine in the therapy of the acute respiratory distress syndrome ecmo for severe acute respiratory distress syndrome lower tidal volume strategy ( approximately ml/kg) combined with extracorporeal co removal versus 'conventional' protective ventilation ( ml/kg) in severe ards: the prospective randomized xtravent-study quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ards: the breathe criteria protective ventilation with veno-venous lung assist in respiratory failure: a protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.author's contributions jp designed the study, searched literature, collected as well as analyzed data and prepared the manuscript. tm did literature search, collected as well as analyzed data and prepared the manuscript, rd, ns, ja and gm contributed to the preparation of the manuscript and reviewed the manuscript, rk designed the study, searched literature, designed the study, reviewed the analyzed data, contributed to the preparation of the manuscript and reviewed as well as submitted the manuscript. all author(s) read and approved the final manuscript. the study was funded by the deutsche forschungsgemeinschaft (dfg, german research foundation - / spp ). the datasets used and analyzed during the current study are available from the corresponding author on reasonable request.ethics approval and consent to participate general ethical approval was received by the rwth aachen university regional research ethics committee and confirmed for this retrospective study (af / ). the committee authorized the retrospective acquisition of anonymized patient data without informed consent. not applicable. the authors declare that they have no competing interests. patients with leading hypercapnia and pecla expanding the scope from ecmo to ecco r. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . definition and calculation of resp score.additional file . definition and calculation of the preserve score.additional file . definition and calculation of the sofa score. key: cord- -df ard o authors: müller-redetzky, holger c.; suttorp, norbert; witzenrath, martin title: dynamics of pulmonary endothelial barrier function in acute inflammation: mechanisms and therapeutic perspectives date: - - journal: cell tissue res doi: . /s - - - sha: doc_id: cord_uid: df ard o the lungs provide a large inner surface to guarantee respiration. in lung alveoli, a delicate membrane formed by endo- and epithelial cells with their fused basal lamina ensures rapid and effective gas exchange between alveolar and vascular compartments while concurrently forming a robust barrier against inhaled particles and microbes. however, upon infectious or sterile inflammatory stimulation, tightly regulated endothelial barrier leakiness is required for leukocyte transmigration. further, endothelial barrier disruption may result in uncontrolled extravasation of protein-rich fluids. this brief review summarizes some important mechanisms of pulmonary endothelial barrier regulation and disruption, focusing on the role of specific cell populations, coagulation and complement cascades and mediators including angiopoietins, specific sphingolipids, adrenomedullin and reactive oxygen and nitrogen species for the regulation of pulmonary endothelial barrier function. further, current therapeutic perspectives against development of lung injury are discussed. the inner walls of blood vessels are covered with a continuous endothelial cell monolayer, constituting a semi-permeable barrier between blood and interstitium. neighbouring endothelial cells (ecs) are closely connected to each other by interendothelial junctions. under physiologic conditions, the endothelial monolayer actively controls paracellular and transcellular extravasation of proteins, solutes and fluids, thereby adjusting interstitial fluid homeostasis (komarova and malik ) . in lung alveoli, endo-and epithelial cells and their merged basal laminas build a delicate membrane of less than μm thickness, which ensures rapid and effective gas exchange between alveolar and vascular lumens while at the same time forming a robust barrier against inhaled particles and microbes. moreover, this sophisticated structure importantly contributes to central metabolic and immunologic functions of the lung. however, upon infectious or sterile inflammatory stimulation via either the alveolar (e.g., in pneumonia and mechanical ventilation) or the vascular lumen (e.g., in bacteremia and sepsis), pulmonary endothelial barrier homeostasis may be disturbed, resulting in increased permeability, protein-rich fluid extravasation, lung oedema and finally acute respiratory distress syndrome (ards) with mortality rates ranging from to % depending on severity (ranieri, et al. ) (fig. ) . pneumonia is the most prevalent infectious disease worldwide and the third most frequent cause of death (world health organisation ) . pneumonia is also the most frequent cause of sepsis, a systemic inflammatory response of the organism, which may originate from infections at any other site of the body (abdominal, blood stream, urogenital, etc.) . in both pneumonia and sepsis, the initial innate immune response to invading bacteria, viruses or fungi is insufficient to avert the infection. despite subsequent antibiotic treatment, the interaction of pathogens and host defence culminates in complex inflammatory responses. liberation of inflammatory mediators, recruitment and activation of leukocytes to the lungs and activation of complement and coagulation cascades, are initiated, contributing to pulmonary endothelial hyperpermeability and ards development. for patients with ards, mechanical ventilatory support is an inevitable and life-saving treatment but may also perpetuate the inflammatory response and further enhance pulmonary endothelial barrier dysfunction (verbrugge et al. ) . specific pharmacologic therapies aiming at improvement of endothelial barrier function in patients with pneumonia, sepsis and/or ards are lacking. however, recent experimental studies enhanced our understanding of endothelial pathomechanisms contributing to the development of ards, potentially providing the basis for novel therapeutic strategies. therefore, we try here to give an overview on recent insights into the mechanisms of pulmonary endothelial barrier dysfunction in acute inflammation. inside endothelial cells, filaments of polymerised actin molecules together with polymerised tubulin molecules (microtubules) build the cytoskeleton, which is connected to glycocalyx (yoneda and couchman ) , focal adhesions and junctional proteins. whereas two types of endothelial junctions, adherens junctions (aj) and tight junctions (tj), are known, the current concept is that a sealing belt of tight junctions is present in ec of the blood-brain barrier but play a minor, if any, role in the barrier function of pulmonary endothelium. consisting in vascular endothelial (ve) cadherin and catenin, ajs maintain the tight connection of adjacent ecs and regulate the paracellular passage of fluids and solutes smaller than nm in radius across the endothelial monolayer (komarova and malik ) . in parallel, larger molecules including hormones, drugs, albumin and albumin-bound substances are transported across the endothelial barrier by transcellular trafficking. caveolar vesicles formed at the luminal side of ecs take up the molecules to be transported, cross the ecs and release the molecules at the abluminal surface by exocytosis (predescu et al. ). these two different transport mechanisms actively regulate endothelial permeability and thereby tissue fluid homeostasis. pathogens entering the alveolar compartment by inhalation or via the bloodstream are recognized by pathogen recognition receptors (prrs). the heterogeneous group of prrs comprises toll-like receptors (tlrs), cytosolic nod-like receptors (nlrs), rig-i-like receptors (rlrs) and dna sensors (opitz et al. ) . in alveoli, these receptors are expressed in epithelial cells, macrophages, dendritic cells, ecs and in subsequently recruited immune cells. prrs sense highly conserved microbial molecules called pathogen-associated molecular patterns (pamps) and specific endogenous molecules liberated by cell injury called danger-associated molecular patterns (damps). prr activation evokes cellular production of inflammatory cytokines, interferons and chemokines on transcriptional and post-translational levels (opitz et al ) , resulting in the activation of locally distributed cells and the recruitment of neutrophils and macrophages. thus, upon microbial infection and "sterile" tissue damage by various insults, prrs are central contributors to the inflammatory response. when being controlled, these inflammatory mechanisms are a prerequisite for pathogen clearance and thus for survival. however, control is frequently lost and once the inflammatory cascade is on track even effective antibiotic treatment is unable to stop it, which can (partly) be explained by ongoing pamp and damp release from dying bacteria and injured cells, respectively. inappropriate inflammation induces further unchecked synthesis of cytokines, chemokines and lipid mediators, accumulation and activation of leukocytes, uncontrolled activation of complement and coagulation cascades and last but not least endothelial barrier dysfunction. fig. a airspace-derived activation of the endothelium by mediators, bacterial toxins or physical stress due to mechanical ventilation starts a complex interplay of various inflammatory cascades resulting in vascular permeability. monocytes (m) are recruited to the endothelium (ec) and facilitate its further activation by secretion of tnfα, thereby augmenting the recruitment of neutrophils (pmn). activated platelets stimulate pmn. endothelium-pmn contact leads to permeability ( ). upon stimulation pmn undergo netosis, liberating neutrophil extracellular traps (nets) consisting in dna and histones that cause endothelial toxicity and barrier breakdown ( ). specific soluble mediators also increase permeability ( ). neutrophil-platelet complexes activate blood coagulation. central effector proteases like thrombin directly mediate vascular permeability. further, thrombin activates complement factor c to c a-a permeability increasing anaphylatoxin ( ). tnf tumor necrosis factor; il- β interleukin- β; ros/rns reactive oxygen and nitrogen species. b intracellular signalling regulates endothelial permeability. endothelial contraction results from actin myosin interaction after mlc-phosphorylation, which is regulated by myosin light chain kinase (mlck) and myosin light chain phosphatase (mlcp). mlcp is inhibited by rhoa-rock signalling while mlck is activated by c-src, rhoa and ca + /calmodulin. ca + enters the cytosol from endoplasmatic reticulum (er) or extracellular space. downstream of platelet activating factor (paf) and paf receptor (pafr), phospholipase c (plc) hydrolyses posphatidyl inositol bisphosphate (pip) into inositol , , -triphosphate (ip ) and diacylglycerol (dag). ip mediates ca + liberation from the er while dag opens transient receptor potential canonical (trpc) channels in the cellular membrane. the resulting increase of intracellular ca + leads to the activation of protein kinase c (pkc) α, to further rhoa activation and to ca + /calmodulin complexes, altogether finally leading to mlck activation. actin polymerisation forms stress fibres associated with endothelial contraction. various stimuli like il- β or mechanical force activate mitogen-activated protein kinase (mapk) p (p ), which activates mapk activated protein kinase (mk ), which phosphorylates heat shock protein (hsp ) leading to actin polymerisation. adherence junctions (aj) are mandatory for the sealing of intercellular contacts. ve-cadherin is anchored in peripheral cortical actin to the cytoskeleton. ve-cadherin phosphorylation leads to ve-cadherin internalisation and thereby to increased endothelial permeability. rhoa and c-src phosphorylate vecadherin. rac- and p rhoagap (p ) functionally antagonise rhoa activity. p rhoagap is recruited to the aj by p -catenin (p ), which itself inhibits ve-cadherin internalisation. rock inhibits p rhoagap and pkcα inactivates p -catenin thereby augmenting destabilisation of aj. iqgap recruits and stabilises rac- , protecting against ve-cadherin internalisation not only direct prr ligation by the pathogen but also liberated pathogenic factors may activate prr-dependent inflammatory cascades. for example, cell wall peptidoglycan of streptococcus pneumoniae activates tlr- (schroder et al. ) , while the pneumococcal exotoxin pneumolysin is recognized by tlr- and nlrp- (malley et al. ; witzenrath et al. ) . bacterial toxins rapidly compromise endothelial cell function (rubins et al. ; suttorp et al. suttorp et al. , suttorp et al. , . pneumolysin, for example, may rapidly induce ( ) ca + influx and ( ) liberation of platelet activating factor (paf) followed by thromboxane release (lucas et al. ; witzenrath et al. ). ca + increase and thromboxane receptor ligation both activate myosin light chain kinase (mlck) via pkcα and rho-kinase dependent signaling (hippenstiel et al. ; lucas et al. ; witzenrath et al. ). mlck phosphorylates mlc and subsequent actinmyosin-dependent cytoskeletal contraction evokes disruption of ajs, interendothelial gap formation and paracellular permeability (shen et al. ). in addition, pneumolysin is a cholesterol-dependent cytolysin that kills ecs by pore formation (tilley et al. ) . thus, pathogens may induce endothelial injury via host-dependent inflammatory and via direct mechanisms. upon acute inflammation, neutrophils and distinct monocyte subsets among other recruited leukocytes are involved in the pathophysiology of pulmonary vascular barrier failure. platelets also contribute to vascular injury by activating neutrophils and liberating soluble factors that directly interact with vascular barrier integrity. neutrophils are rapidly recruited to the lung upon different insults (grommes and soehnlein ; yoshida et al. ). in the lungs, the capillary compartment is the place of neutrophil transmigration, in contrast to other vascular beds where neutrophils pass the endothelial barrier in the venules. upon stimulation by various inflammatory agents, the cytoskeleton of the neutrophils changes by forming peripheral actin rims, which leads to neutrophil stiffening and trapping in the capillary bed (yoshida et al. ) . although the initial trapping is independent from expression of integrins and selectins on the cell surface (yoshida et al. ) , further recruitment may indeed depend on selectins and integrins in distinct scenarios (reviewed in grommes and soehnlein ) . however, endothelial leukocyte adhesion and alveolar recruitment of neutrophils does not induce significant vascular permeability per se (martin et al. ; rosengren et al. ) . although not yet shown for the pulmonary endothelium, studies performed in huvecs or cremaster vessel preparations reveal that during the process of neutrophil transmigration, endothelial disruption seems to be controlled by the formation of "endothelial domes / transmigratory cups" (carman and springer ; phillipson et al. ) that encapsulate the neutrophil and further by ring-like structures of neutrophil lfa- and endothelial icam- around the invading leukocyte, thereby potentially sealing the barrier through diapedesis (shaw et al. ) . however, activated neutrophils contribute to vascular permeability by ( ) secretion of soluble factors causing endothelial contraction, ( ) contact mediated mechanisms and ( ) generation of reactive oxygen species. amongst others, soluble factors of neutrophils include tnf-α, which binds to tnf-α receptor and and is known to induce vascular permeability. notably, although tnf-α leads to mlck and rho kinase (rock)-dependent actin stress fibre generation in endothelial cells, this is probably not the main mechanism of tnf-α induced endothelial permeability, as blocking rock or mlck did not ameliorate transcellular electric resistance (petrache et al. ). however, tnf-α also induced p mapk-dependent disarrangement of the microtubule system and thereby loss of intercellular ve-cadherin resulting in barrier disruption. blocking microtubule breakdown strongly protected against barrier failure induced by tnf-α (petrache et al. ) . further soluble factors include: ( ) thromboxane a , which is processed by endothelial cyclooxygenase- (cox ) from neutrophil-derived arachidonic acid, binds to the thromboxane receptor and may induce permeability in endothelial cells (kim et al. ); ( ) leukotriene a , which is processed by endothelial ltc synthetase and binds to the endothelial cysteinyl lt receptor subtype (cyslt r); and ( ) cxcl , - , - , - which bind to cxcr and are involved in endothelial barrier disruption (extensively reviewed in (distasi and ley )). further, neutrophil -endothelial contact via icam- and lfa- /mac- leads to ( ) rapid increase of intracellular ca + , which mediates actin polymerisation and endothelial contraction as well as disassembly of adherence junctions due to phosphorylation of ve-cadherin and ( ) to the secretion of heparin-binding protein, which is also secreted by neutrophils upon binding of ltb to the blt receptor, finally resulting in barrier failure by endothelial contraction (for detailed review of underlying mechanisms, refer to distasi and ley ). activation of neutrophils in the pulmonary microvasculature leads to endothelial hyperpermeability by generation of reactive oxygen species. gao et al. ( ) observed that ros generation upon tnf-α stimulation depends on class a phosphoinositide kinase and cd b/cd , resulting in nadph oxidase activation and finally generation of ros, causing pulmonary hyperpermeability (see below). platelets secrete various mediators upon activation, including thromboxane, thereby decreasing endothelial barrier integrity as observed in human umbilical vein endothelial cells (huvec) and in vivo (kim et al. ) . moreover, platelets mediate vascular permeability in infection and inflammation indirectly via activation of neutrophils (he et al. ; looney et al. ; zarbock et al. ). clark and colleagues have shown that platelets are activated by stimulation of tlr on their surface in murine sepsis (clark et al. ). upon activation, platelets secrete thromboxane, which is mandatory for the formation of permeability-mediating platelet-neutrophil complexes. in contrast, neutrophils solely attached to the endothelium after activation by tnf-α do not increase vascular permeability (he et al. ) . in mouse models of transfusion-related acute lung injury (trali) platelets are crucial for the development of permeability and pulmonary neutrophil sequestration (looney et al. ). further, platelets are involved in the generation of neutrophil extracellular traps (nets). neutrophils can undergo a process termed netosis in which the neutrophil expels its condensed dna, to which histones, antimicrobial peptides and enzymes like myeloperoxidase are bound. nets can bind and kill bacteria and thus contribute to the innate immune response against invading pathogens (brinkmann et al. ). on the other side, nets can be harmful. nets are involved in thrombus generation and cause endothelial permeability and sepsis related organ failure (caudrillier et al. ; clark et al. ; saffarzadeh et al. ) . in trali, platelets are mandatory for net formation in the lung and inhibition of platelet aggregation ameliorated net generation and consecutively pulmonary permeability (caudrillier et al. ). among peripheral blood monocytes a population of gr- high /ccr + /cxccr low monocytes can be defined, which are delivered from the bone marrow to sites of inflammation. this population rapidly homes in the pulmonary microvasculature upon lipopolysaccharide (lps) infusion or the onset of injurious mechanical ventilation and primes the lung for the development of pulmonary oedema formation when a second hit like lps, zymosan or ventilator-induced lung injury (vili) occurs wilson et al. ). the mechanism by which this damage is mediated is not fully clarified but the recruited monocytes secrete tnf-α and activate endothelial cells in a paracrine fashion, thereby directly or indirectly contributing to endothelial barrier dysfunction (o'dea et al. ) . further, they are involved in the process of neutrophil recruitment in ali (dhaliwal et al. ) . although the underlying mechanisms of leukocyte mediated barrier failure are of highest scientific interest, therapeutic interference to ameliorate acute lung injury by depletion or blocking of cell recruitment should raise concerns as neutrophils and monocytes are key players of pulmonary and systemic innate immune responses and therapeutic intervention at this level might leave the patient functionally immunosuppressed. elevated fibrin turnover is a hallmark of acute lung injury regardless of its genesis and may correlate with the severity of the diseases (glas et al. ; prabhakaran et al. ) . intrapulmonary fibrin deposition results from tissue factorfactor vii pathway activation, reduced pulmonary fibrinolytic capacity due to elevation of plasminogen activator inhibitor (pai- ) concentrations, diminished absolute and relative protein c activity due to reduced protein c production and shedding of thrombomodulin, an important activator of protein c on the cell surface, as well as reduced antithrombin iii levels (hofstra et al. ; prabhakaran et al. ; ware et al. ) . pulmonary coagulopathy occurs after alveolar flooding with protein-rich fluid due to high permeability oedema, resulting in alveolar fibrin deposition but coagulopathy also contributes to inflammation and vascular permeability itself, thereby aggravating the disease. thrombin, the central protease of the coagulation pathway activating fibrinogen, mediates proinflammatory effects by binding to protease activated receptors (par), thereby causing secretion of cytokines or leading to liberation of vascular endothelial growth factor (vegf), which contributes to vascular permeability (hippenstiel et al. ). furthermore, thrombin can directly cause endothelial cell contraction and processing of complement factor c a from c , a potent anaphylatoxin causing inflammation and vascular permeability (cirino et al. ; glas et al. ; huber-lang et al. ; khan et al. ; liu et al. ) . the complement system is part of the innate immune system and is also involved in functions of the adaptive immune response (mastellos et al. ) . the complement cascade can be activated by the classical, the lectin and the alternative pathways (markiewski and lambris ) . antigen-antibody complexes activate the classical pathway by binding c q, thereby processing c s, while in the lectin pathway mannose binding lectins (mbl) bind to pathogen associated molecular patterns on bacteria, assembling with mannose binding lectin proteases (mblp) and thereafter. c a and mbl/ mblp + subsequently interact with c and c , processing the c convertase c b a. the alternative pathway is activated after contact with, e.g., bacterial surfaces by spontaneous hydrolysis of c , which forms together with factor bb the alternative c convertase c bbb. both c convertases process c to c aan anaphylatoxinand c b, which is part of the c convertase. the c convertase cleaves c into c aa second anaphylatoxinand c b, the latter one being part of the membrane attack complex that leads to cell lysis, while c a and c a contribute to inflammation and vascular permeability. both c a and c a induce stress fibre generation in endothelial cells and thereby endothelial contraction. notably, the response was only of short duration after c a stimulation, while being prolonged after c a exposition (schraufstatter et al. ) . c a-induced permeability was more severe and phosphaditiyinositol- kinase-, src kinaseand epidermal growth factor (egf) receptor-dependent, while c a mediated its effects via rho kinase-controlled pathways (schraufstatteret al. ) . neutralising c a in rodent models of acute lung injury and systemic inflammatory responses reduced permeability in various organs including the lung (liu et al. ) . however, in c -deficient mice, immune complex-mediated lung injury including vascular permeability was not attenuated, while c a deficiency proved to be protective (huber-lang et al. ). this observation led to the understanding that c a can be alternatively processed by the protease thrombin defining another alternative pathway for complement activation downstream of c a. thus, targeting c a rather than c a to ameliorate vascular permeability seems to be reasonable. a study by kahn and colleagues also even observed aggravated microvascular injury in c -deficient mice suffering from acute rejection after trachea transplantation, while antagonisation of c a was highly protective. again, thrombin-mediated c a activation accounted for this observation (khan et al. ). toll-like receptor (tlr ) dependent signaling tlr is central for recognition of exogenous (e.g., lps) and endogenous (e.g., high mobility group box- , oxidised phospholipids) pro-inflammatory stimuli (imai et al. ; park et al. ) . systemic lps levels have been linked to severity of sepsis and related organ failure (marshall et al. ) . lps induced vascular permeability (mehta and malik ) and mice deficient for tlr were protected against lung injury due to different stimuli including lps, oleic acid, cecal ligation and puncture and gut or lung ischemia/reperfusion injury (ben et al. ; hilberath et al. ; imai et al. ; tauseef et al. ; zanotti et al. ). various signalling cascades have been linked to tlr -mediated pulmonary permeability. oxidised phospholipids induced tlr dependent activation of trif (tir domain-containing adapter-inducing interferon-β) and traf (tnf receptorassociated factor ) leading to nf-κb-dependent il- liberation, which contributed to lung oedema (imai et al. ) . after binding to the tlr /md receptor complex, lps induced nf-κb activation via myd , irak (interleukin- receptorassociated kinase) , irak and irak (kawagoe et al. ; medvedev et al. ) . further, recognition of lps by tlr increased intracellular diacylglycerol (dag) levels, activating transient receptor potential canonical (trpc) channels and leading to calcium influx, thereby activating mlck, which facilitates myosin light chain (mlc) phosphorylation inducing endothelial cell contraction. mlck activation further augmented lps-induced nf-κb-related inflammatory responses that contribute to vascular leakage (mehta and malik ; tauseef et al. ) . further, tlr activation evoked phosphorylation of src-kinase and consecutively of ve-cadherin and p , ultimately resulting in destabilisation of adherence junctions (gong et al. ) . tlr- is involved in the proinflammatory response to hmgb- in monocytes, which again was found to be myd -, irak , , -and nf-κb-dependent (park et al. ). moreover, hmgb- was linked to lung oedema formation in ventilator-induced lung injury (ogawa et al. ). however, hmgb- also induced endothelial permeability via the receptor for advanced glycation end products (rage) (wolfson et al. ) . in summary, tlr is often critically involved in the regulation of vascular barrier function during lung inflammation. thus, enthusiasm was aroused by the development of eritoran, an inhibitor of lps-binding to the tlr- adaptor molecule md- . eritoran reduced pulmonary inflammation in different animal models (mullarkey et al. ) as well as in humans exposed to lps bolus infusion (lynn et al. ) . in a phase ii clinical trial, patients with severe sepsis treated with eritoran tended to have reduced mortality as compared to placebotreated patients (tidswell et al. ). however, a recent multicentre phase iii study found no impact of eritoran on mortality or relevant secondary outcome parameters in sepsis (opal et al. ) , questioning the rationale of tlr inhibition for the treatment of sepsis and related organ failure including ards. although not proven by current data, it is tempting to speculate that targeting a single prr was unsuccessful because of the pleiotropic immune activation by various pamps and damps involving different prrs and downstream signaling pathways in sepsis. angiopoietin- (ang- ) to ang- are ligands of the receptor tyrosine kinase tie . ang- and - are well-known regulators of angiogenesis, inflammation and vascular leakage (reviewed in david et al. ; eklund and saharinen ) , whereas the role of ang- and its murine orthologue ang- has not been extensively investigated. tie is abundantly expressed in endothelium and also in pmns and a subpopulation of monocytes (lemieux et al. ; wong et al. ) . ang- is constitutively expressed in different cell types, including pericytes surrounding the vasculature, vascular smooth muscle cells, fibroblasts, thrombocytes and megakaryocytes (eklund and saharinen ) . steady tie activation by ang- importantly contributes to endothelial quiescence and barrier integrity. in contrast, ang- is expressed in endothelial cells, stored in weibel-palade bodies (fiedler et al. ) and rapidly released upon activation by inflammatory stimuli including tnf-α and thrombin (fiedler et al. (fiedler et al. , . ang- acts as an antagonist of ang- at the tie receptor, thus confirming endothelial quiescence and perpetuating proinflammatory, barrier-disintegrating mechanisms (fiedler et al. ; scharpfenecker et al. ) ang- mrna expression is increased upon stimulation by tnf-α, thrombin, hyperoxia, vegf, pdgf and many other factors (augustin et al. ). in , parikh and colleagues reported that ang- serum levels were generally increased in patients with sepsis, being even more increased when sepsis was accompanied by ards (parikh et al. ). in subjects with acute lung injury, plasma ang- had a prognostic value for mortality in non-infection-related but not in infection-related, acute lung injury (calfee et al. ) . in two experimental models of sepsis, ang- heterozygous mice had reduced ang- levels and were protected against lung injury, indicating that ang- plays a pathogenetic role besides being a marker of disease severity (david et al. ) . the perception of ang- being of central pathophysiologic importance in sepsis is being supported by the recent observation that ang- antibody treatment attenuated acute pericyte loss, permeability, hypotension and mortality in mice subsequent to intravenous lps injection (ziegler et al. ) . in vitro, ang- increased and ang- suppressed, endothelial adhesion molecule expression and pmn adhesion (fiedler et al. ; gamble et al. ) . ang- may also be able to directly recruit inflammatory cells, because the % monocytes expressing tie- have been shown to display chemotaxis towards ang- in vitro (murdoch et al. ). moreover, mice genetically overexpressing ang- or being treated with ang- showed reduced pulmonary cytokine and adhesion molecule expression, pmn infiltration and vascular leakage in endotoxin-or hydrogen peroxide-induced lung injury (mammoto et al. ; mccarter et al. ; witzenbichler et al. ; xu et al. ). ang- reduced pro-inflammatory gene expression and mediator production probably via interaction of the phosphorylated tie- receptor with currently unidentified inhibitors of nf-κb (hughes et al. ) . in addition to regulating inflammation, ang- and - directly alter endothelial integrity. in mice, ang- -induced tie- receptor phosphorylation stimulated the p rhogtpaseactivating protein (p rhogap) via pi -kinase and rac to inactivate rhoa, resulting in reduced f-actin stress fibre formation and diminished endothelial permeability (mammoto et al. ). for rac- activation by ang- , iq domain gtpase-activating protein- (iqgap- ) is required . in line, the ability of ang- to reduce endotoxemia-induced pulmonary vascular leakage was abolished by downregulation of p rhogap in mice (mammoto et al. ). further, ang- ( ) interfered with the inositol triphosphate (ip ) receptor, thereby blocking trpc -dependent ca + influx and reducing endothelial hyperpermeability in vitro (ahmmed et al. ; jho et al. ); ( ) increased the presence of junctional ve-cadherin protein via extracellular signal-regulated kinase (erk) / dependent activation of sphingosine kinase , thereby strengthening the tethering forces between adjacent endothelial cells ; and ( ) decreased basal and vegfinduced phosphorylation and subsequent internalisation of ve-cadherin (gavard et al. ) . adenoviral ang- gene transfer as well as administration of mesenchymal stem cells transfected with ang- almost completely abolished pulmonary hyperpermeability induced by subsequent lipopolysacharide injection witzenbichler et al. ). however, both approaches for ang- delivery were far from translation into effective clinical therapies. in this respect, the development of vasculotide, a pegylated mer peptide that activates tie- (tournaire et al. ) and the demonstration of vasculotide´s therapeutic potential in established abdominal sepsis in mice (kumpers et al. ) may represent important milestones on the long way from understanding the importance of tie- for endothelial barrier function to the clinical application of tie- activation. sphingolipids, a class of lipids containing sphingoid bases as a backbone, form a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. some sphingolipids regulate biological processes, including sphingomyelin, ceramide, sphingosine and sphingosine- phosphate. the current understanding of the role of these four and other sphingoid bases in acute lung injury has been recently reviewed in detail (natarajan et al. ; uhlig and yang ) . ceramide is derived from palmitoyl-coa and serine in a multi-step process or from sphingomyelin by sphingomyelinase. ceramide is deacylated to sphingosine (sph) through the action of ceramidases (canals et al. ) and sph is rapidly phosphorylated by sphingosine kinase (sphk)- and - to sphingosine- -phoshate (s p). s p is either cleaved by s p lyase (s pl) to ethanol-amine phosphate and trans- -hexadecenal, or dephosphorylated to sphingosine by s p phosphatases and (s ppase) or by lipid phosphate phosphatases (lpp). ceramide deteriorates and s p improves, barrier integrity. of note, the gram-negative endotoxin lps and the pneumococcal exotoxin pneumolysin disrupt the pulmonary endothelial barrier in a platelet-activating factor (paf)-dependent manner (uhlig and yang ; witzenrath et al. ) , with paf increasing vascular permeability by an acid sphingomyelinase (asmase)-dependent process (goggel et al. ). in brief, asmase-produced ceramide recruits caveolin- , enos and trpc- channels into caveolae. no usually blocks trpc channels but caveolin- inhibits no production by enos, resulting in trpc activation followed by an increase of [ca + ] i , mlck activation, mlc phosphorylation and finally ec contraction and paracellular permeability (uhlig and yang ) . s p is produced by platelets, erythrocytes, hematopoietic and vascular endothelial cells (hanel et al. ; tani et al. ; venkataraman et al. ; yatomi et al. ) . coordinated biosynthesis and degradation maintain s p concentrations in plasma and tissues in the range required for most favourable physiologic functions, which include regulation of cell proliferation, differentiation, survival, migration, morphogenesis and barrier function (natarajan et al. ) . using mice that selectively lack s p in the plasma, camerer and colleagues noted that basal plasma levels of s p maintain endothelial barrier function. as compared to wild-type littermates, mice with a lack of plasma s p had increased pulmonary vascular leak and demonstrated enhanced susceptibility to paf stimulation, a phenotype reversed by s p transfusion (camerer et al. ) . s p acts as an intracellular messenger (le stunff et al. ) or as an extracellular ligand of five cell surface receptors (s p - ), which are differentially expressed and coupled to various g proteins (uhlig and yang ) . vascular endothelial cells primarily express s p , s p and s p . physiologic s p plasma concentrations ( . - μm) maintain microvascular barrier integrity via ligation of the g i -coupled s p and exogenous addition of s p to lung ecs increased monolayer integrity rapidly and dose-dependently through s p . s p binding to s p induces rac activation, peripheral mlc phosphorylation, adherens junction assembly and cortactin translocation, which protects endothelium from barrier-disruptive effects of thrombin . moreover, teijaro and colleagues recently observed that endothelial s p critically regulates innate immune responses in influenza pneumonia. activation of endothelial s p attenuated cytokine storm, immune cell recruitment and mortality during infection with human pathogenic influenza virus , suggesting that in this case endothelial cells are conducting the innate immunity orchestra (iwasaki and medzhitov ) . in addition to extracellular receptor-dependent effects of s p, intracellular s p enhanced barrier integrity independently from s p receptors requiring rac- and sphk -/mice were more susceptible to lps-induced lung injury compared with wild-type mice (wadgaonkar et al. ). along the same line, lps evoked increased expression and activity of the s p catabolising s pl, thereby reducing s p levels. constitutive reduction of s pl expression in vivo (s pl +/mice) or in ecs (by sirna) reduced lung injury and inflammation upon lps stimulation (zhao et al. ) . most importantly, infusion of s p reduced lung microvascular leakage and also cytokine release, leukocyte infiltration and histologic tissue changes in numerous different in vivo models of lung injury, including ischemia/reperfusion, pancreatitis and endotoxin challenge in mice and dogs mcverry et al. ; okazaki et al. ; peng et al. ). however, s p at supraphysiologic local concentrations (> μm) mediates rhoa-dependent barrier disruption through ligation of s p and s p , which couple to gi, gq and g / (sammani et al. ; siehler and manning ; wang and dudek ). moreover, s p stimulates contraction of human bronchial smooth muscle cells (rosenfeldt et al. ) , enhances murine airway hyperresponsiveness (roviezzo et al. ) and evokes bradycardia through s p (forrest et al. ). the latter findings suggest a rather small therapeutic window for s p, which may limit the therapeutic potential of s p and drugs that increase s p production or reduce s p catabolism. therefore, s p receptor agonists have gained considerable interest. for example, intratracheal as well as intravenous delivery of the s p agonist sew- reduced lung permeability after endotoxin injection (sammani et al. ) and the s p receptor and - ligand aal-r reduced lung permeability and mortality after influenza infection in mice ). closer to clinical application is a derivative of the fungal metabolite myriocin, fingolimod (fty ), which holds structural similarities with s p and has been approved as an immunosuppressive agent for the treatment of multiple sclerosis (brinkmann et al. ). in addition to its immunosuppressive effects, fty enhanced endothelial barrier function in vitro (sanchez et al. ) and in vivo (dudek et al. ) and ameliorated lps-evoked lung injury in mice natarajan et al. ). however, we recently observed that, although lower concentrations of fty enhanced barrier integrity in endothelial cell monolayers ( . - μm fty ) and in mechanically ventilated mice ( . mg/kg fty ), higher concentrations ( - μm fty ) evoked apoptosis and barrier dysfunction in vitro and in mechanically ventilated mice ( mg/kg) but not in spontaneously breathing mice (müller et al. ). if these experimental findings are translatable into the clinical setting, they suggest that, in fingolimod-treated ventilated patients with multiple organ dysfunction syndrome, in whom hepatic metabolism of fty is hampered, increased fty plasma concentrations could harm lungs that are sensitised by mechanical ventilation towards barrier-destabilising effects of the drug. despite recent studies providing valuable insights into possible mechanisms of barrier regulation by fty , the mode(s) of action remain unclear. fty is partly phosphorylated by sphk , thereby increasing its affinity to s p and s p (billich et al. ) . nevertheless, reduction of vegfinduced permeability by fty was independent from s p expression (sanchez et al. ) and endocytosis and degradation of s p by fty has been proposed (cyster ) . several further concepts may possibly explain fty -induced barrier enhancement and have recently been reviewed (natarajan et al. ) . notably, fty , like s p, induces bradycardia and dyspnea along with fev (forced expiratory volume in s) reductions (kappos et al. ). in conclusion, caution is warranted when considering fty for therapeutic lung barrier enhancement in critically ill patients. reactive oxygen species (ros) and reactive nitrogen species (rns) are crucial regulators of cellular function. ros and rns are tightly counterbalanced by antioxidant systems as superoxide dismutase or glutathione. however, excessive ros/rns production or critical reduction of their antioxidative counterparts leads to oxidative stress, which is involved in the pathogenesis of lung injury and particularly vascular permeability. among other molecules displaying oxidative properties, superoxide anions (o -), hydroxyl radical ( oh), hydrogen peroxide (h o ) and hypochloric acid (hocl) are summarised as ros, while metabolites of the nitric oxide ( no) metabolism like nitrite (no -) or peroxynitirite (onoo -) with oxidative power are termed rns. both ros and rns are physiological mediators of functional cell regulation. ros derived from mitochondrial oxidative phosphorylation can modulate the specific cellular pattern by reacting with redox-reactive cysteine residues, thereby altering enzyme activities and controlling cellular signalling (ray et al. ) . under inflammatory conditions, endothelial nadph oxidases, xanthine oxidase, cyclooxygenase and enos are involved in increased ros/rns production. neutrophils deliver even higher amounts of ros due to nadph oxydase activity, which are in part further processed to hocl by myeloperoxidase activity. in addition, neutrophils produce rns by inos . ros and rns contribute to acute lung injury upon different insults. perfusion of isolated rabbit lungs with h o evoked lung oedema (hippenstiel et al. ; seeger et al. ) . h o exposure resulted in a rapid and substantial decrease in endothelial camp content and the effects of h o on endothelial permeability were inhibited by adenylate cyclase activation (suttorp et al. b) . vili increased xanthine oxydoreductase (xor) activity and blocking xorprotected mice from pulmonary hyperpermeability (abdulnour et al. ) . ros signalling leads to mapk activation, which is involved in permeability generation in mice subjected to vili (dolinay et al. ; park et al. ) . underlying mechanisms are proinflammatory functions of this pathway and phosphorylation of heat shock protein (hsp ), which mediates stress fibre generation and endothelial contraction (abdulnour et al. ; damarla et al. ; dolinay et al. ) . further, mice deficient for the transcription factor nrf exhibited increased lung injury and permeability in vili due to significantly reduced antioxidative capacity and could be rescued from exacerbation of lung injury by supplementing the antioxidant n-acetyl-cysteine (papaiahgari et al. ) . no, the most prominent rns, is a highly diffusible and reactive free radical gas, produced from l-arginine in the lung by constitutively expressed endothelial no synthase (enos) in endothelial cells and by inducible nos (inos) in macrophages. expression of enos usually stays constant while enos activity can be rapidly increased, whereas inos expression is inducible but the activity is usually more or less constant. numerous inflammatory incidents induce no production and release, including endothelial stimulation by bacterial pore-forming toxins (suttorp et al. a ). the plethora of no´s biologic effects includes control of vascular tone and permeability, regulation of mitochondrial respiration and adhesion of platelets and leukocytes. no supports protection of cells against oxidant injury and microbial threats but can also have detrimental properties, e.g., activation of inflammatory processes, enzyme inhibition and dna damage. most probably, these cellular responses are differentially regulated by specific no concentrations (thomas et al. ) . the majority of no effects are mediated by ( ) nitrolysation of cysteine residues, ( ) reaction with transition metals like ion, zinc and copper and ( ) formation of onoothrough reaction with o -, which leads to nitration of proteins involved in the regulation of cellular function (korhonen et al. ) . inhaled nitric oxide (ino) is used as rescue therapy in individual cases of hypoxic respiratory failure in adults, children and newborns along with respiratory support and other appropriate treatments. the inhaled vasodilator reduces pulmonary arterial pressure without causing systemic vasodilation and selectively redistributes pulmonary blood flow towards ventilated lung regions, thereby reducing shunt flow and improving oxygenation (raoof et al. ) . nevertheless, although improvement of blood gases has been regularly noted during the first h of treatment, ino does not increase ventilator-free days or survival of ards patients (afshari et al. ) . in addition to its vasodilatory properties, no has endothelial barrier-regulating effects in the lungs but the published experimental studies paint a dichotomous picture. inhaled no was shown to protect against pulmonary barrier dysfunction in isolated perfused and ventilated rabbit lungs upon oxidative stress or ischemia/reperfusion (kavanagh et al. ; poss et al. ; schutte et al. b) . moreover, ino reduced pulmonary transvascular albumin flux in patients with acute lung injury (benzing et al. ). the precise mechanisms accounting for the stabilising effect of no remain to be elucidated but may involve increase of cyclic guanosine monophosphate (cgmp) through activation of guanylate cyclase (gc). no-induced barrier protection in rabbit lung ischemia/reperfusion was associated with increased cgmp production and could be further enhanced by inhibition of the cgmp-specific phosphodiesterase (pde) (schutte et al. ) . also, increase of cgmp by no (donors) and/or inhibition of cgmp-specific pde strengthened the endothelial barrier in pulmonary ecs upon h o treatment (seeger et al. ; suttorp et al. ) , in ecs and perfused mouse lungs stimulated with thrombin (seybold et al. ) and in mice with severe streptococcus pneumoniae pneumonia (witzenrath et al. ). the barrier-stabilising effects of no and cgmp may be partly explained by negative regulation of specific endothelial trp channels (yin et al. ) , some of which are central for [ca + ] i increase, pulmonary endothelial cell contraction and lung hyperpermeability in response to various stimuli (alvarez et al. ; boueiz and hassoun ; hamanaka et al. ; jian et al. ; kuebler et al. ; tiruppathi et al. ; yin et al. ) . on the other hand, endogenous no synthesis contributed to lung injury in hypoxic ischemia/reperfusion of isolated rabbit lungs (schutte et al. a) . moreover, inos expression was upregulated in response to mechanical ventilation in mice and ventilated inos -/mice as well as inos inhibitortreated mice had reduced lung inflammation and permeability compared with control wt mice . in line, pharmacologic inhibition of nos prevented the development of pulmonary hyperpermeability in rats subjected to vili (choi et al. ) . gain and loss of function studies have provided evidence for a contribution of soluble gc activation to ventilator-induced lung injury in mice (schmidt et al. ) . further, ino significantly increased endothelial permeability in rats with pseudomonas aeruginosa pneumonia independently from the inflammatory response (ader et al. ). thus, the individual effects of no on pulmonary vascular barrier function seem to depend on local no concentrations and the precise pathologic conditions. imatinib has been suggested for the treatment of increased vascular permeability. the tyrosine kinase inhibitor imatinib targets c-abl kinase, platelet-derived growth factor-derived receptors, c-kit, arg kinase and discoid domain receptors and and has been implemented into treatment of chronic myelogenous leukaemia. recently, imatinib was found to protect against endothelial barrier dysfunction evoked by thrombin in isolated endothelial cells, by vegf in a murine skin model and in the context of polymicrobial sepsis in mice. as the underlying mechanism, inhibition of arg kinase followed by augmented rac signalling and stabilised intercellular junctions and cell matrix adhesion has been identified (aman et al. ; chislock and pendergast ) . case reports have been published describing reduction of pulmonary oedema in the context of pulmonary venooclusive disease and resolution of bleomycin-induced pneumonitis (carnevale-schianca et al. ; overbeek et al. ) . with respect to clinical development, additional preclinical evidence for imatinib efficacy in ards is required. further, possible relevant undesirable effects have to be considered including cerebral haemorrhage particularly in patients with compromised coagulation, as malfunction of coagulation is also a major issue in sepsis patients (hoeper et al. ) . adrenomedullin (am) is an endogenous peptide with potent barrier protective properties that is expressed in various cells of the vascular system including endothelial and vascular smooth muscle cells and also in cardiomyocytes, epithelial cells and leukocytes. the am gene encodes for a preproadrenomedullin, which is processed to pro-am, from which am and proam n-terminal peptide (pamp) are generated. a m i d a t i o n b y p e p t i d o g l y c i n e a l p h a a m i d a t i n g monooxygenase (pam) is crucial for biologic function of the active am peptide (temmesfeld-wollbruck et al. b) . am binds to the calcitonin receptor like receptor (crlr), which assembles with receptor activity-modulating proteins (ramp) and . in endothelial cells, binding of am to the receptor results in intracellular accumulation of the second messenger camp and in activation of various kinases including protein kinase a (pka), pkc, map kinases and others (hippenstiel et al. ; temmesfeld-wollbruck et al. b) . mice deficient for am, crlr, pam or ramp die prematurely of hydrops fetalis, which highlights the role of am for vascular barrier integrity (bonder et al. ; caron and smithies ; cyster ; czyzyk et al. ; ichikawa-shindo et al. ) . am is up-regulated under inflammatory conditions like sepsis or experimental lung injury (agorreta et al. ; cheung et al. ; matheson et al. ) and mice heterozygous for am exhibit an aggravated inflammatory response and organ damage following lps challenge (dackor and caron ) . treatment with exogenous am protected against pulmonary hyperpermeability induced by various stimuli like staphylococcus aureus alpha toxin, hydrogen peroxide, lipopolysaccaride (lps) or hyperoxia and ventilator-induced lung injury (hippenstiel et al. ; itoh et al. ; müller et al. ; temmesfeld-wollbruck et al. a) . am also protected against barrier breakdown in the gut after challenge with staphylococcus aureus alpha toxin and in ischemia reperfusion injury and stabilised the blood-brain barrier (brell et al. a, b; higuchi et al. ; honda et al. ; kis et al. ; temmesfeld-wollbruck et al a ). at least two major mechanisms may contribute to the impressive function of am. first, am leads to the relaxation of the contractile apparatus of the endothelial cell by avoiding the generation of actin stress fibres and actin myosin interaction (temmesfeld-wollbruck et al. b) . we and others have observed a rise of intracellular camp upon am stimulation of endothelial cells, leading to the inhibition of mlc phosphorylation, thereby blocking actin-myosin interactionmediated cell contraction induced by thrombin or hydrogen peroxide in vitro, or evoked by mechanical ventilation in vivo (brell et al. b; hocke et al. ; müller et al. ). however, equally potent barrier protective effects of am are observed in gut epithelial cells that were not dependent on intracellular camp increase (temmesfeld-wollbruck et al. ). second, besides reducing cell contraction am increases intercellular adherence, thereby mediating barrier stabilisation. in rat intestine, staphylococcus alpha toxin infusion induced vascular hyperpermeability accompanied by loss of ve-cadherin in submucosal blood vessels, which was avoided by am treatment (hocke et al. ) . in endothelial cells, am protected against the loss of ve-cadherin and occludin derangement due to thrombin or staphylococcus alpha toxin stimulation and am enhanced the expression of claudin- in brain microvascular endothelial cells (hocke et al. ; honda et al. ) . immunomodulating effects of am have been described (gonzalez-rey et al. ); however, we observed that the strong barrier protection of am is not coupled to anti-inflammatory properties (müller et al. ) . although the underlying and obviously cellspecific mechanisms of am-mediated barrier protection partly remain elusive, the powerful properties observed in complex models regardless of the stimulus and independent from immunosuppressive effects indicate a high translational potential for am. acute inflammatory diseases including pneumonia and sepsis may result in ards, which is still associated with unacceptably high mortality. research has been successfully uncovering basic disease mechanisms, leading to improvements in therapy including ventilation and resuscitation strategies. nevertheless, although the pulmonary endothelium has long been noted to be central in the pathogenesis of ards and scientists have been elucidating innumerable important mechanisms of permeability increase, most therapeutic strategies to improve ards outcome based on the understanding of lung endothelial barrier dysfunction have so far been frustrating. these drawbacks should be understood as important sources of perception and it might be worth considering some general aspects when moving forward in this field. first, to regain endothelial barrier function once the endothelium is severely injured may be a barely achievable objective. interestingly, the only strategies so far decreasing mortality in ards, reduction of tidal volume and probably early prone positioning, short-term use of neuromuscular blockers and oesophageal pressure-guided positive endexspiratory pressure adjustment (guerin et al. ; network ards ; papazian et al. ; talmor et al. ) , are aimed at alleviation of further inflammatory stress by mechanical ventilation, thus being of a rather preventive nature. it may be promising to focus on strategies that decelerate the progress of "uncomplicated" pneumonia or sepsis to ards instead of trying to reverse severe parenchymal inflammation and injury. therefore, clinical and biological predictors of progress towards ards need to be identified and future therapies should be started before full-blown ards has developed. however, this notion should not encourage the performing of experimental studies in which the treatment of interest is commenced before onset of the initial disease (pneumonia or sepsis in this case), because such a preventive strategy can rarely be translated into clinics. second, the "real life aspect" needs to be respected. icu patients are frequently prone to ards due to multiple simultaneous incidents, unlike, e.g., lps-treated mice, which means that numerous redundant pathways may be differentially involved and should probably be addressed therapeutically at the same time. further, important inter-individual differences need to be considered. third, complexity is an important issue. as our understanding of central contributors to lung injury is growing, we are becoming aware of the differential effects one and the same pathomechanistic system may have. for example, s p seems to differentially affect endothelial integrity, depending on s p concentration, receptor expression and the exact local cellular setting, which implements a further dimension into the picture of barrier destructing mechanisms. probably, systems biology combined with mathematical multi-scale models that integrate knowledge from experimental studies (in vitro, in vivo and in silico), clinical trials and clinical and biological predictors of the individual patient will facilitate development of successful novel therapies and improvement of ards prevention. since the first description of ards in , researchers have made great efforts to unravel the mechanisms contributing to endothelial dysfunction in the lung in order to develop novel therapies. walking all the way to where we are standing today has sometimes been frustrating and possibly not even half of the whole distance has been accomplished. nevertheless, considering the high morbidity and mortality of ards, it is worth trying hard to proceed. mechanical stress activates xanthine oxidoreductase through map kinase-dependent pathways inhaled nitric oxide increases endothelial permeability in pseudomonas aeruginosa pneumonia inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and lps protein kinase calpha phosphorylates the trpc channel and regulates store-operated ca + entry in endothelial cells transient receptor potential vanilloid -mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury effective treatment of edema and endothelial barrier dysfunction with imatinib control of vascular morphogenesis and homeostasis through the angiopoietin-tie system tlr mediates lung injury and inflammation in intestinal ischemiareperfusion inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury phosphorylation of the immunomodulatory drug fty by sphingosine kinases sphingosine kinase regulates the rate of endothelial progenitor cell differentiation regulation of endothelial barrier function by reactive oxygen and nitrogen species adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by staphylococcus aureus alpha-toxin-an intravital microscopic study on an isolated rat ileum adrenomedullin reduces staphylococcus aureus alpha-toxin-induced rat ileum microcirculatory damage neutrophil extracellular traps kill bacteria fingolimod (fty ): discovery and development of an oral drug to treat multiple sclerosis plasma angiopoietin- in clinical acute lung injury: prognostic and pathogenetic significance sphingosine- -phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases a transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with hodgkin's lymphoma: hope for severe chemotherapy-induced toxicity? extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional adrenomedullin gene platelets induce neutrophil extracellular traps in transfusion-related acute lung injury increased adrenomedullin expression in lungs in endotoxaemia abl family kinases regulate endothelial barrier function in vitro and in mice systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury thrombin functions as an inflammatory mediator through activation of its receptor platelet tlr activates neutrophil extracellular traps to ensnare bacteria in septic blood chemokines, sphingosine- -phosphate, and cell migration in secondary lymphoid organs deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock mitogen activated protein kinase activated protein kinase regulates actin polymerization and vascular leak in ventilator associated lung injury angiopoietin- requires iq domain gtpase-activating protein to activate rac and promote endothelial barrier defense angiopoietin- may contribute to multiple organ dysfunction and death in sepsis* mending leaky blood vessels: the angiopoietin-tie pathway in sepsis monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury opening the flood-gates: how neutrophilendothelial interactions regulate permeability mitogenactivated protein kinases regulate susceptibility to ventilatorinduced lung injury pulmonary endothelial cell barrier enhancement by fty does not require the s p receptor angiopoietin signaling in the vasculature the tie- ligand angiopoietin- is stored in and rapidly released upon stimulation from endothelial cell weibel-palade bodies angiopoietin- sensitizes endothelial cells to tnfalpha and has a crucial role in the induction of inflammation immune cell regulation and cardiovascular effects of sphingosine -phosphate receptor agonists in rodents are mediated via distinct receptor subtypes angiopoietin- is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions blockade of class ia phosphoinositide -kinase in neutrophils prevents nadph oxidase activation-and adhesion-dependent inflammation sphingosine -phosphate promotes endothelial cell barrier integrity by edg-dependent cytoskeletal rearrangement angiopoietin- prevents vegfinduced endothelial permeability by sequestering src through mdia bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome paf-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide tlr signaling is coupled to src family kinase activation, tyrosine phosphorylation of zonula adherens proteins, and opening of the paracellular pathway in human lung microvascular endothelia urocortin and adrenomedullin prevent lethal endotoxemia by downregulating the inflammatory response contribution of neutrophils to acute lung injury prone positioning in severe acute respiratory distress syndrome trpv initiates the acute calcium-dependent permeability increase during ventilatorinduced lung injury in isolated mouse lungs erythrocytes store and release sphingosine -phosphate in blood leukocyte-platelet aggregate adhesion and vascular permeability in intact microvessels: role of activated endothelial cells gut hyperpermiability after ischemia and reperfusion: attenuation with adrenomedullin and its binding protein treatment resolution of toll-like receptor -mediated acute lung injury is linked to eicosanoids and suppressor of cytokine signaling glucosylation of small gtp-binding rho proteins disrupts endothelial barrier function vegf induces hyperpermeability by a direct action on endothelial cells adrenomedullin reduces endothelial hyperpermeability perturbation of endothelial junction proteins by staphylococcus aureus alpha-toxin: inhibition of endothelial gap formation by adrenomedullin imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized impres study pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma adrenomedullin improves the blood-brain barrier function through the expression of claudin- generation of c a in the absence of c : a new complement activation pathway the antiinflammatory endothelial tyrosine kinase tie interacts with a novel nuclear factor-kappab inhibitor abin- the gpcr modulator protein ramp is essential for angiogenesis and vascular integrity identification of oxidative stress and tolllike receptor signaling as a key pathway of acute lung injury adrenomedullin ameliorates lipopolysaccharideinduced acute lung injury in rats a new shield for a cytokine storm angiopoietin- opposes vegf-induced increase in endothelial permeability by inhibiting trpc -dependent ca influx high vascular pressure-induced lung injury requires p epoxygenasedependent activation of trpv oral fingolimod (fty ) for relapsing multiple sclerosis effects of inhaled no and inhibition of endogenous no synthesis in oxidantinduced acute lung injury sequential control of tolllike receptor-dependent responses by irak and irak targeting complement component a promotes vascular integrity and limits airway remodeling thromboxane a( ) increases endothelial permeability through upregulation of interleukin- chronic adrenomedullin treatment improves blood-brain barrier function but has no effects on expression of tight junction proteins regulation of endothelial permeability via paracellular and transcellular transport pathways nitric oxide production and signaling in inflammation vascular barrier regulation by paf, ceramide, caveolae, and no -an intricate signaling network with discrepant effects in the pulmonary and systemic vasculature the synthetic tie agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis generation and metabolism of bioactive sphingosine- -phosphate angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses basal and angiopoietin- -mediated endothelial permeability is regulated by sphingosine kinase- sphingosine- -phosphate and its analogue fty diminish acute pulmonary injury in rats with acute necrotizing pancreatitis silencing of c a receptor gene with sirna for protection from gram-negative bacterial lipopolysaccharide-induced vascular permeability platelet depletion and aspirin treatment protect mice in a twoevent model of transfusion-related acute lung injury protein kinase c-alpha and arginase i mediate pneumolysin-induced pulmonary endothelial hyperpermeability blocking of responses to endotoxin by e in healthy volunteers with experimental endotoxemia recognition of pneumolysin by toll-like receptor confers resistance to pneumococcal infection angiopoietin- requires p rhogap to protect against vascular leakage in vivo the role of complement in inflammatory diseases from behind the scenes into the spotlight diagnostic and prognostic implications of endotoxemia in critical illness: results of the medic study effects of leukotriene b in the human lung recruitment of neutrophils into the alveolar spaces without a change in protein permeability complement: structure, functions, evolution, and viral molecular mimicry adrenomedullin is increased in the portal circulation during chronic sepsis in rats the acute respiratory distress syndrome cell-based angiopoietin- gene therapy for acute lung injury sphingosine -phosphate reduces vascular leak in murine and canine models of acute lung injury dysregulation of lps-induced toll-like receptor -myd complex formation and il- receptor-associated kinase activation in endotoxin-tolerant cells signaling mechanisms regulating endothelial permeability prevention of lps-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin inhibition of endotoxin response by e , a novel toll-like receptor -directed endotoxin antagonist adrenomedullin attenuates ventilator-induced lung injury in mice the sphingosine- phosphate receptor agonist fty dose dependently affected endothelial integrity in vitro and aggravated ventilator-induced lung injury in mice expression of tie- by human monocytes and their responses to angiopoietin- sphingosine- -phosphate, fty , and sphingosine- -phosphate receptors in the pathobiology of acute lung injury ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network lung-marginated monocytes modulate pulmonary microvascular injury during early endotoxemia mobilization and margination of bone marrow gr- high monocytes during subclinical endotoxemia predisposes the lungs toward acute injury contribution of high-mobility group box- to the development of ventilator-induced lung injury sphingosine -phosphate inhibits ischemia reperfusion injury following experimental lung transplantation innate immune recognition in infectious and noninfectious diseases of the lung possible role of imatinib in clinical pulmonary veno-occlusive disease genetic and pharmacologic evidence links oxidative stress to ventilatorinduced lung injury in mice neuromuscular blockers in early acute respiratory distress syndrome excess circulating angiopoietin- may contribute to pulmonary vascular leak in sepsis in humans involvement of toll-like receptors and in cellular activation by high mobility group box protein mitogen-activated protein kinase phosphatase- modulates regional effects of injurious mechanical ventilation in rodent lungs protective effects of sphingosine -phosphate in murine endotoxin-induced inflammatory lung injury differential effect of mlc kinase in tnf-alpha-induced endothelial cell apoptosis and barrier dysfunction the role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration inhaled nitric oxide prevents the increase in pulmonary vascular permeability caused by hydrogen peroxide elevated levels of plasminogen activator inhibitor- in pulmonary edema fluid are associated with mortality in acute lung injury molecular determinants of endothelial transcytosis and their role in endothelial permeability acute respiratory distress syndrome: the berlin definition severe hypoxemic respiratory failure: part -nonventilatory strategies reactive oxygen species (ros) homeostasis and redox regulation in cellular signaling sphingosine- -phosphate stimulates contraction of human airway smooth muscle cells leukotriene b -induced neutrophil-mediated endothelial leakage in vitro and in vivo sphingosine- -phosphate/sphingosine kinase pathway is involved in mouse airway hyperresponsiveness toxicity of pneumolysin to pulmonary endothelial cells in vitro neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones differential effects of sphingosine -phosphate receptors on airway and vascular barrier function in the murine lung phosphorylation and action of the immunomodulator fty inhibits vascular endothelial cell growth factor-induced vascular permeability the tie- ligand angiopoietin- destabilizes quiescent endothelium through an internal autocrine loop mechanism soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice complement c a and c a induce different signal transduction cascades in endothelial cells lipoteichoic acid (lta) of streptococcus pneumoniae and staphylococcus aureus activates immune cells via toll-like receptor (tlr)- , lipopolysaccharide-binding protein (lbp), and cd , whereas tlr- and md- are not involved the pde inhibitor zaprinast enhances no-mediated protection against vascular leakage in reperfused lungs endogenous nitric oxide synthesis and vascular leakage in ischemic-reperfused rabbit lungs short-term "preconditioning" with inhaled nitric oxide protects rabbit lungs against ischemia-reperfusion injury hydrogen peroxide-induced increase in lung endothelial and epithelial permeability-effect of adenylate cyclase stimulation and phosphodiesterase inhibition tumor necrosis factor-alpha-dependent expression of phosphodiesterase : role in endothelial hyperpermeability coordinated redistribution of leukocyte lfa- and endothelial cell icam- accompany neutrophil transmigration myosin light chain kinase in microvascular endothelial barrier function pathways of transduction engaged by sphingosine -phosphate through g protein-coupled receptors bacterial exotoxins and endothelial permeability for water and albumin in vitro effects of escherichia coli hemolysin on endothelial cell function adenosine diphosphate-ribosylation of g-actin by botulinum c toxin increases endothelial permeability in vitro pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells role of phosphodiesterases in the regulation of endothelial permeability in vitro role of nitric oxide and phosphodiesterase isoenzyme ii for reduction of endothelial hyperpermeability mechanical ventilation guided by esophageal pressure in acute lung injury mechanisms of sphingosine and sphingosine -phosphate generation in human platelets tlr activation of trpc -dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation endothelial cells are central orchestrators of cytokine amplification during influenza virus infection adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock adrenomedullin and endothelial barrier function adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro the chemical biology of nitric oxide: implications in cellular signaling phase trial of eritoran tetrasodium (e ), a toll-like receptor antagonist, in patients with severe sepsis structural basis of pore formation by the bacterial toxin pneumolysin impairment of store-operated ca + entry in trpc (-/-) mice interferes with increase in lung microvascular permeability a short synthetic peptide inhibits signal transduction, migration and angiogenesis mediated by tie receptor sphingolipids in acute lung injury vascular endothelium as a contributor of plasma sphingosine -phosphate lung protective ventilatory strategies in acute lung injury and acute respiratory distress syndrome: from experimental findings to clinical application differential regulation of sphingosine kinases and in lung injury suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus regulation of vascular permeability by sphingosine -phosphate protein c and thrombomodulin in human acute lung injury role of lung-marginated monocytes in an in vivo mouse model of ventilator-induced lung injury protective role of angiopoietin- in endotoxic shock role of platelet-activating factor in pneumolysin-induced acute lung injury phosphodiesterase inhibition diminished acute lung injury in murine pneumococcal pneumonia the nlrp inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia hmgb induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption the angiopoietins, tie and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non-small cell lung carcinomas the leading causes of death in the world mesenchymal stem cell-based angiopoietin- gene therapy for acute lung injury induced by lipopolysaccharide in mice sphingosine- -phosphate: a platelet-activating sphingolipid released from agoniststimulated human platelets negative-feedback loop attenuates hydrostatic lung edema via a cgmp-dependent regulation of transient receptor potential vanilloid regulation of cytoskeletal organization by syndecan transmembrane proteoglycans neutrophil cytoskeletal rearrangements during capillary sequestration in bacterial pneumonia in rats novel critical role of toll-like receptor in lung ischemiareperfusion injury and edema complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation protection of lps-induced murine acute lung injury by sphingosine- -phosphate lyase suppression angiopoietin mediates microvascular and hemodynamic alterations in sepsis acknowledgement this work was funded by the deutsche forschungsgemeinschaft (sfb-tr b , z to n.s. and c , c to m.w.) key: cord- - xgwjvsv authors: luna, c. m.; valentini, r.; rizzo, o. title: life-threatening respiratory failure from h n influenza: lessons from the southern cone outbreak date: - - journal: yearbook of intensive care and emergency medicine doi: . / - - - - _ sha: doc_id: cord_uid: xgwjvsv a sharp increase in the hospitalization rate for pneumonia, particularly among adults between and years old, and an unusual series of deaths, coincident with an increase in laboratory-confirmed influenza cases, were reported in the spring of in mexico. this outbreak appeared after the end of influenza season, and was associated with mortality in a younger age-group than the pattern observed in temperate areas in the northern hemisphere [ ]. the concurrent finding of a novel, swine-origin influenza a virus (so called pandemic influenza [h n ] ) from infected children in the united states [ ] completed the picture. . sharp increase in the number of cases and rapidly argentina and brazil became the countries with the highest numbers of deaths due to microbiologically confirmed pandemic influenza (h n ) . consistent with this particular situation, the health system in the metropolitan area of buenos aires began to show evidences of collapse, use of ventilators increased critically, achieving an extremely unusual level; about a quarter of the available icu beds were occupied by young and previously healthy patients with ards associated with severe bilateral pneumonia due to 'swine flu' who needed mechanical ventilation. by the time of writing this chapter, during the end of the winter in the southern hemisphere, it is evident that pandemic h n influenza is highly prevalent in south america. in september , the world health organization (who) director general, margaret chan, estimated that up to % of people in densely populated countries risk being infected with h n pandemic influenza, while dr. thomas frieden, head of the us centers for disease control and prevention, predicted that about , people may potentially have been infected in new york city by the spring. these figures are difficult to extrapolate globally and to confirm, as epidemiological studies looking at the population at risk in different world areas are lacking, but the huge number of severely ill patients with ards due to primary influenza pneumonia (an extremely unusual complication) observed in the southern cone, suggest that these estimations could be realistic. calculating the population-corrected mortality rate from estimations made in new zealand [ ] , it can be inferred that by the end of winter in the southern hemisphere, up to about % of the population in argentina could be infected by this novel agent. influenza complications during seasonal influenza occur most frequently in patients older than years old, in those with chronic disorders, including cardiac or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and immunosuppression. pregnant women in the second or third trimester, particularly in the and pandemics, had a higher risk of complications, especially of primary influenza pneumonia, and higher hospitalization rates. pneumonia is the most significant complication of influenza. the presentation of pneumonia includes: 'primary' influenza viral pneumonia secondary bacterial pneumonia and mixed viral and bacterial pneumonia. primary influenza viral pneumonia may be the least common of the pneumonic complications but it is also the most severe. it presents as acute influenza that does not resolve but instead progresses relentlessly, with persistent fever, dyspnea, and eventual cyanosis. sputum production is generally scanty, but the sputum can contain blood. few physical signs may be evident early in the illness. in more advanced cases, diffuse rales may be noted, and chest x-ray findings consistent with diffuse interstitial infiltrates and/or ards may be present (fig. ) . viral cultures of respiratory specimens, especially if a year-old obese male with arterial hypertension secondary to cushing's disease (hypophyseal adenoma) developed bilateral pneumonia and died from respiratory failure secondary to acute respiratory distress syndrome (ards) after days on mechanical ventilation, with multiple organ failure, including renal and hemodynamic compromise requiring high doses of vasopressors. his disease began as an influenza-like illness days before admission; influenza a h n was confirmed with rt-pcr performed on pharyngeal swab. post-mortem microscopic histopathologic findings in the lung included extensive alveolar edema (small arrow) replacing up to % of the effective alveolar space, with hyaline membrane development (big arrow); alveolar cellular infiltrate and bacterial superinfection (arrowhead) were also observed (diffuse alveolar damage pattern) (panel a). there was also mild evidence of a fibroproliferative stage, microthrombi (gray arrow), small areas with well preserved pulmonary parenchyma (blue arrow), and hemorrhagic infarcts (panel b). suprarrenal hyperplasia and acute tubular necrosis were found. samples are taken early in illness, yield high titers of virus. in fatal cases of primary viral pneumonia, histopathologic examination reveals a marked inflammatory reaction in the alveolar septa, with edema and infiltration by lymphocytes, macrophages, occasional plasma cells, and variable numbers of neutrophils (fig. ) . fibrin thrombi in alveolar capillaries, along with necrosis and hemorrhage, have also been noted. hyaline membranes can be found lining alveoli and alveolar ducts. primary influenza viral pneumonia has a predilection for individuals with cardiac disease, particularly those with mitral stenosis, but has also been reported in otherwisehealthy young adults as well as in older individuals with chronic pulmonary disorders. secondary bacterial pneumonia follows acute influenza; in these cases typically improvement in the patient's condition over to days is followed by a reappearance of fever along with clinical signs and symptoms of pneumonia, including cough, purulent sputum, and physical and x-ray signs of consolidation. the most common bacterial pathogens in this setting are streptococcus pneumoniae, staphylococcus aureus, and haemophilus influenzae -usual nasopharynx colonizers. secondary bacterial pneumonia occurs most frequently in high-risk individuals with c.m. luna, r. valentini, and o. rizzo chronic pulmonary and cardiac disease and in elderly individuals. patients with secondary bacterial pneumonia often respond to antibiotic therapy when it is instituted promptly. the risk factors for acquiring severe h n primary influenza pneumonia include age (particularly young children) and comorbidities; some series have observed a particular prevalence of overweight individuals in this group of patients [ , , ] . obesity has not previously been mentioned among the risk factors for complications in patients with influenza. being overweight is associated with a chronic increase in pro-inflammatory cytokines, such as interleukin (il)- and tumor necrosis factor (tnf)-α. in an experimental model of influenza a, smith et al. described higher mortality rates in overweight patients than in lean controls related to minimally expressed interferon (ifn)-α and -β and a delay in expression of the proinflammatory cytokines, il- and tnf-α, which may lead to increased morbidity and mortality from viral infections [ ] . in contrast to what happens with the usual annual seasonal influenza outbreak, in this outbreak of pandemic influenza h n , young adults are dying and between one quarter and one half of the deaths around the world have happened in patients who were previously in good health and without any specific risk factors. in one of the earlier case report publications during the beginning of the pandemic in mexico, the authors observed that % of deaths and % of cases of severe pneumonia involved patients between the ages of and years, compared with average rates of % and %, respectively, in that age group during the reference periods [ ] . features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population [ ] . in the setting of a disease with very high mortality, with no available controlled human clinical data to guide clinicians, in which most patients present with severe disease, a number of combined strategies should be considered for therapy. these include pharmacological strategies (antiviral treatment) and non-pharmacological strategies (standardization of optimal ventilator and fluid management, especially for ards, and management of other complications) necessarily given empirically, as diagnostic confirmation using real time reverse-transcriptase polymerase chain reaction (rt-pcr), can take from several hours to days. p plat eetp c stat pulm drive pr eitp v d /v t most of these patients have ards, and in these patients, ventilatory support should follow the concepts of protective ventilation, with a tidal volume (v t ) of ml/kg of predicted body weight [ ] . ards is usually severe, with pao /fio < than and positive end-expiratory pressure (peep) should be high and optimized according to a mechanical basis. in our experience, we initially select peep according to the methods used in the express trial where peep was adjusted based on airway pressure and was kept as high as possible without increasing the maximal inspiratory plateau pressure above to cmh o [ ] . in more severe respiratory failure, we also set peep according to the transpulmonary pressure, by using esophageal-pressure measurements. in secondary, but also in primary ards the lungs can suffer substantial effects of chest wall elastance and may be effectively compressed by high pleural pressures with their alveoli collapsed at the end of expiration, even though moderate or high peep levels are applied. therefore, peep is set at a level necessary to obtain a positive end-expiratory transpulmonary-pressure to improve the oxygenation, an end-inspiratory transpulmonary-presure less than cmh o to minimize stress-inducing ventilator lung injury, and a pulmonary driving pressure (end-inspiratory transpulmonary pressure less end-expiratory transpulmonary pressure) e cmh o to avoid straininducing ventilator lung injury (fig. ) . using these premises, the mean peep applied in patients with severe influenza h n and ards was cmh o. interestingly, in contrast to other etiologies of ards, in primary influenza pneumonia, high peep levels were necessary for many days. in a group of patients variation in gas exchange and respiratory system mechanics from the onset of mechanical ventilation in a group of mechanically ventilated ards patients with h n pneumonia observed in one of our icus [ ] . all variables improved from day to day of mechanical ventilation; however, in the majority of the patients the pao /fio ratio remained low for many days, inducing us to maintain high levels of peep. cstat: static lung compliance; peep: positive end-expiratory pressure managed by one of us (rv) in cemic medical center, the mean peep after days on mechanical ventilation was cmh o [ ] . at the beginning of this outbreak, we decreased the peep level after a few days of mechanical ventilation, based on improvement in oxygenation levels; however, this produced a dramatic worsening of the pao /fio ratio. because of this observation, it was decided that, in patients with severe ards, high peep levels should be maintained for at least two weeks regardless of the oxygenation levels (fig. ) . most of the patients with severe influenza pneumonia responded to recruitment maneuvers. a recruitment maneuver in pressure controlled ventilation (pcv) with a peep of - cmh o and an inspiratory pressure of cmh o (peak pressure - cmh o) was performed in patients with a pao /fio < mmhg. many of these patients were young, healthy and had good cardiac performance and tolerance of high ventilatory pressures during the recruitment maneuver with adequate intravascular volume repletion. several trials have demonstrated no survival benefit in ards patients managed in the prone position. however, these trials did not select the most severe patients. many of our patients had severe ards with pao /fio < mmhg despite peep optimization and recruitment maneuvers. in this setting, prone ventilation was used and, if pao /fio did not reach > mmhg, a recruitment maneuver was applied in the prone position. prone ventilation was used in % of the patients with ards and in % of patients with severe ards, and was associated with improved oxygenation and reduced distending pressures. we suggest the use of adjunctive therapies when plateau pressure is higher than cmh o, despite a v t of - ml/kg predicted weight, severe hypercapnic acidosis, and refractory hypoxemia (defined as a pao /fio ratio < mmhg after optimization of peep, recruitment maneuvers, prone position, and recruitment maneuvers in the prone ventilatory position). the adjunctive therapies developed to reduce the stress of mechanical ventilation on the already damaged lungs include: nitric oxide (no), extracorporeal membrane oxygenation (ecmo), arterial venous carbon dioxide removal, high-frequency oscillatory ventilation, and liquid ventilation. we prefer to use no because of its availability and easy implementation and we have observed better improvement in oxygenation combining this therapy with prone ventilation, as previously described [ ] . non-invasive positive pressure ventilation (nppv): nppv has been used in respiratory failure due to viral pneumonia, even in cases of high transmission risk like in the epidemic of severe acute respiratory syndrome (sars) in hong kong [ ] . in one study, the efficacy in sars pneumonia with mild acute lung injury (ali) was high and no cases of healthworker infection were observed. however, application of nppv to patients with h n influenza has not been well evaluated and it is not indicated for impending respiratory failure. in mild cases or in patients with chronic obstructive pulmonary disease (copd) or chronic respiratory restriction, nppv could be useful to support the respiratory system, but it should be applied in healthcare facilities where staff have been adequately trained and with strict enforcement of personal protection measures; use of expiratory viral and bacterial filters are necessary to provide safer ventilation. most of the patients with influenza h n will recover without any antiviral therapy. antivirals are indicated to prevent the rapid spread of the disease in a specific population, to prevent the pneumonia syndrome in susceptible patients, or to treat patients with influenza pneumonia. for critically ill influenza patients, antiviral treatment options are limited because no parenteral drug is available and no drug has been proved to be effective once life-threatening disease occurs. currently, four antiviral drugs are available for the treatment of influenza: amantadine, rimantadine (both cannot be used for the treatment of h n influenza due to resistance), oseltamivir, available only for oral administration, and zanamivir, available as an inhalation agent; the two latter drugs are both sialic acid analogs that inhibit viral neuraminidases by competitively binding with the active enzyme site of influenza a and b viruses. the neuraminidase is critical for viral release from infected cells after replication. the earlier the administration of these agents, and the shorter the duration of fever, the greater the benefit of drug intervention [ , ] . oseltamivir has also been shown to reduce lower respiratory tract complications such as bronchitis and pneumonia [ ] . in a prospective case control study, multivariate analysis suggested that treatment with oseltamivir decreased the likelihood of death (odds ratio . [confidence interval . - . , p = . ]) [ ] . immunosuppressed patients (leukemia, organ transplantation, and hematopoietic stem cell transplantation) have a higher rate of viral pneumonia and higher attributable mortality [ ] ; viral shedding is also prolonged in these patients to an average of days [ ] , which is associated with the development of resistance [ ] . a standard dose and duration of antivirals may not be adequate in this population; for these reasons, some authors have advocated a higher dose of oseltamivir ( mg daily) in these patients [ ] . during the pandemic, the therapeutic strategy proposed by the argentinean health authority for mechanically ventilated patients with presumptive primary influenza pneumonia was to use oseltamivir at a dose of mg daily during an extended period of time, typically until the patient was weaned from mechanical ventilation. the most frequent reported adverse effect seen with oseltamivir is nausea and vomiting, but this leads to medication interruption in only a small number of cases. neuropsychiatric disorders (seizure, confusion or hyper-excitation of the nervous system) and severe skin reactions (e.g., toxic epidermal necrolysis) are more severe adverse events that have been observed in some cases during the pandemic. these unusual events have been related to a single nucleotide polymorphism in a gene located near the enzymatic active site of human cytosolic sialidase, a homolog of the virus neuraminidase that is the target of oseltamivir. this polymorphism has been found to occur in . % of the asian population [ ] . because of the high frequency of bacterial co-infection, antibiotic administration is recommended for all patients with pandemic h n influenza infection who require admission to a critical care unit. in immunocompetent patients, without recent antibiotic exposure, combination therapy with a beta-lactam plus a macrolide or a respiratory fluorquinolone, is recommended [ ] . corticosteroids may be used to treat airflow obstruction due to asthma or copd, to maintain immunosuppression in transplant patients, and when adrenal dysfunction is suspected because of refractory vasodilatory shock. corticosteroids are not indicated for ali; prolonged or high-dose corticosteroid therapy can result in serious adverse events, including opportunistic infections. in patients with h n pulmonary infection, corticosteroids were not effective and in one series mortality was % in recipients of corticosteroids, compared with % in patients who did not receive corticosteroids [ ] . one exception to this is cryptogenic organizing pneumonia (cop) described below under 'complications'. in addition to primary viral pneumonia, viral and bacterial co-infection and secondary bacterial pneumonia are frequent. co-infection with s. pneumoniae, s. aureus, and mycoplasma pnemoniae has been detected in some of the reported series from argentina; this co-infection occurs after several days of influenza infection and occurs more frequently in the elderly and in patients with chronic pulmonary diseases [ ] . it has been observed in one series that % of hospitalized patients with communityacquired pneumonia had dual infection with a respiratory virus and a bacterial pathogen, influenza being the most common viral agent [ ] . proposed theories for the high incidence of superimposed bacterial infections in influenza pneumonia emphasize the synergistic effects of viral and bacterial pathogens in producing lung injury. studies suggested that influenza virus can directly damage the respiratory epithelium, allowing free access to invading bacteria. it has also been demonstrated that some life-threatening respiratory failure from h n influenza vi staphylococcus and streptococcus strains may increase viral replication and pathogenicity, contributing to influenza viral pneumonia [ ] . pulmonary embolism has not been recognized as a common complication of severe influenza with ards. however, in a series of patients with pandemic influenza h n infection and ards at a tertiary-care icu in michigan, five had pulmonary emboli [ ] . influenza infections have been associated with procoagulant changes [ ] . pathologic fibrin deposition also occurs in the vasculature in ards and pulmonary artery thrombi are found, implying an anatomic mechanism for the occurrence of increased pulmonary vascular resistance in ards [ ] . it remains unknown whether these cases were secondary to some of the several risk factors that these bed-ridden severely ill patients had, or whether it was a direct consequence of a particular risk in influenza patients. meanwhile, clinicians should periodically search for thrombosis and if necessary use chest multislice spiral computed tomography (ct) to confirm pulmonary embolism. influenza virus does not replicate in the alveoli or tissues beyond the respiratory tract. histopathological analyses revealed that no virus was detected in the liver, spleen, kidney, or brain of animals inoculated with influenza h n virus at or days after inoculation [ ] . however, myocarditis and pericarditis have been described in association with influenza infection and it has been suggested that influenza-associated myocarditis can take two forms: immediate, associated with fulminating disease, and delayed, occurring during late convalescence [ ] . renal failure has been described in a number of influenza patients [ , ] . it is usually the consequence of shock and multiorgan dysfunction. we recommend adequate fluid replacement and, in patients with severe ards, fluid infusion should not be restrictive and diuretic use should be avoided to prevent the progression of renal dysfunction [ ] . using this strategy in our patients, the positive fluid balance at the th day was , ml and hemodialysis was necessary in only % of patients [ ] . occasionally, rhabdomyolysis may facilitate the development of renal failure; in fact, high levels of serum creatine phosphokinase have been described in reports of h n infection [ ] . this condition, occasionally associated with influenza, is characterized by progressive respiratory failure after week of influenza symptoms with chest computerized axial tomography demonstrating multiple, bilateral, patchy alveolar opacities [ ] . if identified, this complication must be treated with high doses of corticosteroids [ ] . ho et al. performed a study to define the prognostic factors for fatal adult influenza pneumonia [ ] . univariate analysis demonstrated that, compared with survivors of septic shock, a respiratory rate & breaths per min, an arterial ph < . , a pao / fio ratio < mmhg, a creatinine value & mg/dl, a pneumonia severity index (psi) of iv or v, and an apache ii score & were all associated with decreased survival. adjustments were made for septic shock, respiratory rate, arterial ph, creatinine and psi in the cox proportional hazard model. the multivariate analysis demonstrate that only the pao /fio ratio < mmhg (p = . ) and an apache ii score & (p = . ) remained associated with death. in another study, the development of ards and a history of immunosuppression were independent risk factors for hospital mortality in critically ill patients with confirmed influenza virus infection [ ] . the emergence of an antigenically novel influenza virus to which little or no antibody was present in a community, resulted in an extensive outbreak; the absence of antibody is worldwide, and for that reason there has been a pandemic. independent of this antigenically new virus, questions regarding the potential effectiveness of vaccination for seasonal influenza arises. in one interim analysis of the pandemic in australia, the authors found that there was no evidence of significant protection from seasonal vaccine against pandemic influenza virus infection in any age group [ ] . a new vaccine has been developed, but there have been concerns based on the experience during the - flu season, during which a swine flu outbreak at fort dix, new jersey led the federal government to expedite vaccine production. some million people had been vaccinated by the time guillain-barré syndrome was identified as a side effect. however, with the pandemic as a reality, it is considered that the benefit of the vaccine far outweighs the risks. pandemics provide the most dramatic evidence of the impact of influenza. the morbidity and mortality caused by this first influenza pandemic in the st century, characterized by an unusual increase in the number of cases of primary viral severe community-acquired pneumonia requiring mechanical ventilation, has been substantial. interestingly this higher incidence of severe cases appeared in a younger age group than that usually involved in the annual seasonal flu outbreak. the percentage of the population that acquired influenza during this pandemic has not yet been estimated but certainly it was much higher than during seasonal influenza; this higher incidence may explain the high number of cases of severe primary pneumonia observed in the southern cone. the apparently less aggressive nature of the infection and the younger population affected may explain an estimated mortality rate of . - . %, lower than that observed in seasonal influenza, as complications and mortality in seasonal flu are more frequent among patients & years old and in those with chronic disorders, including cardiac or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and immunosuppression, also usually associated with older age. improved and standardized optimal icu care for patients with influenza h n , including young and immunocompetent patients, with or without comorbidities, should lead to lower mortality than that previously observed for influenza pneumonia when mechanical support is required. the pandemic h n influenza has resulted in tremendous pressures on the critical care system. the unexpected and rapid influx of such a large number of patients to emergency room and critical care services has highlighted not only a shortage of critical care capacity but also an inadequate supply of critical care resources. the extreme severity of ards in these patients has necessitated a change in the usual approach to the management of these patients to improve success rates. the health system must be prepared to reallocate resources in response to demand. therefore, early recognition of probable viral pneumonia is crucial in order to implement early infection-control strategies and to reduce transmission to health-care workers who are at high risk for exposure to these pathogens. severe respiratory disease concurrent with the circulation of h n influenza swine influenza a (h n ) infection in two children -southern california influenza spread of a novel influenza a (h n ) virus via global airline transportation pandemic influenza a(h n )v in new zealand: the experience from intensive-care patients with severe novel influenza a (h n ) virus infection -michigan influenza a(h n ) epidemic in argentina. experience in a national general hospital (hospital nacional profesor alejandro posadas diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome effectiveness of noninvasive positive pressure ventilation in the treatment of acute respiratory failure in severe acute respiratory syndrome clinical signs and symptoms predicting influenza infection early administration of oral oseltamivir increases the benefits of influenza treatment impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations antiviral therapy and outcomes of influenza requiring hospitalization in ontario viral infections in immunocompromised patients: what's new with respiratory viruses? influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy recovery of drug-resistant influenza virus from immunocompromised patients: a case series a nonsynonymous snp in human cytosolic sialidase in a small asian population results in reduced enzyme activity: potential link with severe adverse reactions to oseltamivir infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults writing committee of the second world health organization consultation on clinical aspects of human infection with avian influenza a (h n ) virus update on avian influenza a (h n ) virus infection in humans mandell, douglas, and bennett's principles and practice of infectious disease viral community-acquired pneumonia in nonimmunocompromised adults influenza pneumonia: a descriptive study influenza infection and risk of acute pulmonary embolism anticoagulants for acute respiratory distress syndrome: can they work? pathogenesis and transmission of swine-origin a(h n ) influenza virus in ferrets the prevalence of myocarditis and skeletal muscle injury during acute viral infection in adults: measurement of cardiac troponins i and t in patients with acute influenza infection pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico case records of the massachusetts general hospital. weekly clinicopathological exercises. case - . acute febrile respiratory illness in a -year-old man with recurrent pulmonary disorders prognostic factors for fatal adult influenza pneumonia outcome of critically ill patients with influenza virus infection interim analysis of pandemic influenza (h n ) in australia: surveillance trends, age of infection and effectiveness of seasonal vaccination severe pneumonia requiring mechanical ventilation, coincident with the influenza h n pandemic key: cord- -u znxf b authors: van bever, h. p.; van doorn, j. w. d.; demey, h. e. title: adult respiratory distress syndrome associated withmycoplasma pneumoniae infection date: journal: eur j pediatr doi: . /bf sha: doc_id: cord_uid: u znxf b a -year-old boy is described who developed severe adult respiratory distress syndrome (ards), biochemical pancreatitis and skin vasculitis after an acute respiratory infection due tomycoplasma pneumoniae. the boy was mechanically ventilated for days, but could be discharged in good clinical condition after days of hospitalization. however, major disturbances of the lung function tests persisted, suggesting interstitial fibrosis. to the best of our knowledge, this is the first case of ards afterm. pneumoniae infection in childhood. infections with mycoplasma pneumoniae can give rise to both respiratory and non-respiratory symptoms [ ] . the former, including pneumonia, are usually benign and self-limiting. however, life-threatening diseases have been described in adults and in children [ , , ] . adult respiratory distress syndrome (ards) is a commonly recognized cause of acute respiratory failure in adults. however this syndrome also occurs in paediatric patients. the hallmark of ards is an increased permeability of the alveolar-capillary membrane resulting in pulmonary oedema [ ] . in adults, ards has been associated with m. pneumoniae infections [ , , ] . to our knowledge, this association has never been described in childhood. the findings in a -year-old boy with ards and increasing complement-fixation titres to m. pneumoniae are presented in this report. sion the patient developed headache, cough, abdominal pain and an influenza-like syndrome with mild fever. two days before admission to our hospital, the patient was prescribed oral erythromycin by his general practitioner. he received a total of • mg/kg. because of persistence of the symptoms, the boy was referred to a general hospital. on arrival, positive meningeal signs and a leucocytosis of /ram were found; lumbar puncture was negative. the boy was prescribed i.v. cefotaxime ( mg/kg per day) and erythromycin stopped. the next day a rapid deterioration was observed, including polypnoea, dyspnoea, abdominal tension and shock. a chest x-ray film showed diffuse bilateral infiltrates (fig. ) . the patient was intubated and transferred to the intensive care unit. on arrival, the boy was unconscious, without having received any sedative treatment, and mechanically ventilated without any spontaneous breathing effort. his arterial tension was / mmhg, body temperature was . ~ and bilateral rnes were heard. treatment with high doses of inotropics, plasma-expanders, and antibiotics (cloxacilline, ceftazidime and erythromycin) were initiated. the boy was ventilated with % oxygen and with a peep of cm h . the po improved towards mmhg and the blood pressure rose towards values around / mmhg. because of symptoms compatible with an acute abdomen, a laparotomy was performed shortly after admission. this revealed the presence of multiple lymph nodes and free abdominal fluid, but without other abnormalities. on histological examination of the lymph nodes non-specific non-diagnostic signs of inflammation were observed. postoperatively the clinical condition was stabilized with artificial ventilation, plasma-expanders ( / h) and ino- a -year-old boy with unremarkable past medical history was referred to the university hospital of antwerp because of increasing respiratory distress, fever and shock. four days before admis-offprint requests to: h.p. van bever abbreviation." ards = adult respiratory distress syndrome fig. . chest x-ray film at day after admission, showing diffuse bilateral infiltrates tropics, including dopamine ( gg/kg per minute), dobutamine ( ~tg/kg per minute) and noradrenaline ( gg/min). the nd day after admission a maculopapular rash developed on the abdomen while on the lower limbs bullous lesions with ecchymotic aspect appeared, suggesting erythema multiforme. there were no oral lesions, nor stomatitis. a skin biopsy showed signs of vasculitis with the presence of iga, igm and c in the vascular wall. pancreatitis became evident on blood analysis with maximum lipase levels of units/ (normal < units/l) and amylase levels of units/ (normal < units/l). after days the expectorations became purulent, but frequent cultures for aerobic and anaerobic bacteria, mycobacteria and fungi were all negative. atelectasis of the left lung developed due to excessive bronchial secretions. because of deterioration shown on the chest x-ray film, persistence of fever and the need of artificial ventilation, antibiotic therapy was changed to vibramycin and high dose cotrimoxazole, together with acyclovir. during the next days, a slow but gradual improvement was noted and on the th day after admission he was successfully extubated. chest x-ray films still showed the presence of infiltrates, although a marked improvement was seen. after days the infiltrates were nearly resolved. on lung function tests, performed on the th admission day, the forced expiratory volume in ls was . ( %), the vital capacity was . ( %) and the total lung capacity was . ( %). the co (carbon monoxyde) diffusion capacity (single breath method) was disturbed, showing a value of . mmol/min, kpa ( %) and . mmol/min-kpa- ( %). on day of hospitalization, the complement-fixation titre to m. pneurnoniae was / , while on the day of admission it was < / . titres towards respiratory viruses, including respiratory syncytial virus, adenovirus, influenza a and b virus, parainfluenza virus type , and , and measles virus remained constant. several determinations of cold agghitinins were all negative. the boy was discharged on day is good general condition. one month later he was seen at the outpatient clinic. he was without complaints and the clinical examination was normal. the chest x-ray film was normal. lung function tests were still disturbed, although a sfight improvement was noted. the forced expiratory volume in is was . ( %), the vital capacity was . ( %) and the total lung capacity was . ( %). the co (carbon monoxyde) diffusion capacity was . mmol/min, kpa ( %) and . mmol/min kpa. ( %). h. the clinical diagnosis of ards was made on the basis of tachypnoea, dyspnoea, hypoxaemia refractory to oxygen therapy, and the presence of diffuse infiltrates on the chest x-ray film. furthermore, the biochemical pancreatitis and the skin manifestations have also been described in association with m. pneumoniae [ , ] . however, in the present case, it might be that the biochemical pancreatitis was induced by the persistent shock. although the overall mortality rate of ards is greater than %, the survivors will likely have a relatively normal life-style with normal pulmonary function [ ] . however, residual abnormalities of pulmonary function with variable clinical significance may persist. our patient was discharged without clinical symptoms, but with major disturbances of the lung function tests, suggesting that there might be some degree of interstitial fibrosis. since the diagnosis of interstitial fibrosis is an entity that can only be made on a biopsy, and since the follow-up is too short to make a statement about permanent lung damage, the diagnosis remains speculative. we suggest that m. pulmoniae infections should be included in the differential diagnosis of pathogens causing ards in childhood. establishing an early diagnosis may have important therapeutic implications, although it remains possible that ards is induced by a reinfection, and is the expression of increasing host immune response to the organism [ ] . however, it can be assumed that in our patient the administration of erythromycin, mg/kg, was sufficient to eradicate any growth of m. pneumoniae, but failed to prevent the development of ards, suggesting that the induced lung damage by m. pneurnoniae may appear early in the course of the disease. m. pneumoniae has been implicated as a common cause of respiratory infections in childhood. the typical course of pneumonia due to m.pneumoniae is benign, with spontaneous resolution of fever and malaise in a few days, although cough, r~les and chest x-ray film resolve over a more prolonged period [ ] . m. pneumoniae infections have been associated with the development of ards in adults [ , , ] . to the best of our knowledge, this association has not been described in children, although lethal cases of m. pneumoniae infections have been reported in childhood [ ] . several causes, including respiratory infections, have been identified in childhood as precipitating events for ards [ ] . among these are respiratory infections with influenza a virus, adenovirus, herpes simplex virus, measles, and parainfluenza virus type infection [ ] . the present case illustrates the severity of the syndrome induced by m. pneumoniae, including the development of ards and septic shock. the pneumonia leading to ards began with influenzalike syndrome with abdominal pain, cough and headache, rapidly progressing to respiratory failure within infections due to mycoplasrna pneurnoniae in childhood respiratory infections due to mycoplasrna pneurnoniae in infants and children adult respiratory distress syndrome caused by mycoplasma pneurnoniae adult respiratory distress syndrome associated with parainfluenza virus type i in children adult respiratory distress syndrome due to mycoplasrna pneurnoniae mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis intravascular coagulation and acute renal failure in a child with mycoplasrna infection rising antibody titers to mycoplasma pneumoniae in acute pancreatitis adult respiratory distress syndrome in pediatric patients. i. clinical aspects, pathophysiology, pathology, and mechanisms of lung injury key: cord- - h ox hu authors: bos, lieuwe d.j.; sinha, pratik; dickson, robert p. title: response to “covid- conundrum: clinical phenotyping based on pathophysiology as a promising approach to guide therapy in a novel illness” and “strengthening the foundation of the house of cards by phenotyping on the fly” and “covid- phenotypes: leading or misleading?” date: - - journal: eur respir j doi: . / . - sha: doc_id: cord_uid: h ox hu we argue that phenotyping of covid- related ards should be done using careful, data-driven approaches. in their letter, drs. cherian et al. take issue with our interpretation of the respiratory physiology of covid- , arguing that it is based merely on "small cohort studies," instead arguing that "a high proportion of mechanically ventilated covid- patients exhibit near-normal lung compliance." [ ] yet the low respiratory compliance of covid- patients has now been extensively demonstrated by studies totaling more than covid- patients [ ] [ ] [ ] [ ] [ ] [ ] [ ] , including a direct comparison with non-covid ards patients that revealed no difference in respiratory compliance. [ ] in contrast, the three case series cited by the correspondents in support of their claim comprise cohorts of, respectively, , and patients [ ] [ ] [ ] . further, even these case series report average respiratory compliance in covid- of - ml/cmh o, which is in fact abnormal and far from "near-normal compliance". [ , ] as an informative comparison, the anzics cohort of ards patients used to derive the berlin definition of ards had an average respiratory compliance of ± ml/cmh o. [ ] we thus find no evidence in the authors' citations (or elsewhere) to support their empirical claim that many or most covid- patients present with "normal" or "near-normal" respiratory compliance. drs. cherian et al. also assume a temporal progression from "early" covid- physiology (characterized by normal respiratory compliance) to "late" physiology (characterized by impaired respiratory compliance). yet three published studies comprising nearly mechanically ventilated covid- patients have reported serial measurements of respiratory compliance [ , , ] , and none has shown any temporal trend towards decreased compliance in the days following initiation of mechanical ventilation. further, a recent report from haudebourg et al. demonstrated no correlation between duration of symptoms and respiratory compliance in covid- patients ( figure a ) [ ] . we have since validated this observation using our own clinical data ( figure b ). figure c , gattinoni et al. recently published their own data countering these findings [ ] . importantly, when data from all three cohorts are combined and analysed together, no temporal trend is present (p= . , r = . ). closer inspection reveals that the purported correlation in one of the cohorts is entirely attributable to two patients with low respiratory compliance and more than three weeks of symptoms, a duration of disease irrelevant to considerations of acute pathogenesis and rarely ) the instability of statistical inferences using small, single variable, data sources; and ) the predictable correction of initial human intuitions when more data emerge. a final, under-appreciated and unmeasurable pitfall of premature phenotyping raised in our editorial, and one that the multitude of publications addressing these purported phenotypes are substantiating, is the opportunity cost to research resources caused by high-profile yet unsupported speculation. this factor is all the more pertinent in the face of an unforgiving pandemic in which clinical icu workload is highly demanding and clinical research is a zero-sum game. further, clinicians have even less time than usual to critically evaluate scientific literature. therefore, it is incumbent as clinician-scientists that whilst our data gathering may be agile and creative, its interpretation should be cautious and deliberate. while we agree with drs. cherian regarding the potential pathophysiologic importance of endothelial injury in covid- , the data at hand are simply insufficient to declare if this aspect of pathogenesis is a central mediator of disease progression and lung injury in covid- . for example, it is worth noting that while endothelial injury has been described in post-mortem histopathological evaluations, it is not ubiquitous. epithelial injury and diffuse alveolar damage, however, are. [ , ] our editorial did not take a position on the pathophysiology of covid- , nor do we dispute the need to identify more homogenous biological pathways. frankly, we do not believe in "typical ards," as the syndrome encompasses diverse etiologic pathways with only partially intersecting clinical and histopathological "bottlenecks." we are merely arguing that the currently postulated phenotypes are unconvincing, and insufficient to justify a widespread change in clinical management (as proposed by the correspondents). in his response to our editorial, dr. rajendram reveals a curious misinterpretation of our editorial: "thus, whilst the net effect of the ardsnet protocol is beneficial at the level of the study population, theoretically, it may harm select patients… contrary to the opinions of the surviving sepsis campaign, and bos and colleagues, the ardsnet protocol is not a panacea." putting aside the wishful thinking of a supportive intervention functioning as a "panacea" for a condition with persistent mortality of - %, the correspondent (along with drs. cherian et al.) seems to think that we dispute the heterogeneity of ards, and advocate for a "one-size-fits-all" approach to its clinical management. quite the opposite: we strongly believe that ards represents a pathophysiologically heterogenous syndrome and have argued the same for covid- related ards. [ ] until well-defined biological subgroups are identified, the ceiling of effective interventions is likely to remain supportive. we also strongly suspect there are likely considerable biological differences between covid- and non-covid- ards. [ ] where we differ with our correspondents, we suspect, is in our lack of confidence that clinicians can identify meaningful subphenotypes using underpowered cohorts and bedside intuitions and then recommend effective interventions without testing them in a scientific study. this was the central point of our editorial and is illustrated with two examples in this response (the "normal compliance" of covid- and its purported temporal worsening). as a contrast, the correspondents may consider recent pre-covid- research identifying hypoinflammatory and hyperinflammatory subphenotypes in ards (to which we have contributed). [ , ] these ards subphenotypes were derived using unsupervised clustering of more than , rigorously adjudicated and extensively characterized patients. [ ] the ards subphenotypes have been consistently validated across multiple cohorts and research groups [ ] [ ] [ ] . in contrast, the high-compliance "l" phenotype, for the reasons detailed above, seems inherently unstable. whereas it was initially described as constituting - % of covid- ards cases [ ] , it now is defined as a rarely encountered extreme of a one-dimensional physiologic continuum. [ ] in comparison, the previously identified ards subphenotypes represent distinct clinical "clusters" of patients, informed by measurements across organ systems and physiologic domains in secondary analyses of well curated cohorts of patients. [ ] yet despite this robustness, we would recommend that any therapeutic interventions for which benefits have been observed in these hyperinflammatory and hypoinflammatory phenotypes require testing in prospective trials before they are implemented into clinical practice, as they were derived using secondary analyses. the objective of our editorial was to challenge the subclassification of patients with covid- that frequently occurred in the early weeks of the pandemic based on "discussions" and "close observations" before they became entrenched dogmas. [ ] an unintended consequence of such a challenge may be that it evokes negative emotions with the reader, especially in these troubling and polarising times. we were, therefore, saddened to learn that our editorial caused irritation among gattinoni et al. [ ] . while we vehemently disagree that "observations of bos and colleagues are expressed with a tone which goes beyond healthy and reasonable scientific debate," we acknowledge that our essay was interpreted as such by the correspondents and that is regrettable. we would like to clarify that the particular quoted sentences from our editorial that prompted the authors' irritation and concern were aimed at premature phenotyping in general. it is an unfortunate misunderstanding that the authors assumed we were speaking directly and exclusively about them. for the reasons outlined above, however, we stand by our editorial. drs. gattinoni et al. state that "the 'l & h' phenotypes were not intended to be tightly descriptive nor mutually exclusive 'bins' into which each patient falls," yet this is what is usually implied by disease "subphenotypes" or "endotypes". [ ] as described in our editorial, for phenotypes to be purposeful, they should be discrete, robust, generalizable, easily-identifiable, and ideally, have an actionable intervention. seemingly, almost none of these conditions are met in the current case. as an illustration, the problem with loosely-defined phenotypes, as described by the correspondents, emerges when we try to precisely identify, at the bedside, who the patients are that the correspondents "hoped to help prevent use of high peep when there is no benefit, and equally important, to avoid maintaining low pressures when higher pressures can be beneficial." it is difficult to conceive how these phenotypes would be identifiable using quantifiable variables and when precisely to intervene, given that the authors themselves concede that these phenotypes are temporally dynamic, neither mutually-exclusive nor discrete, and that "usually, there is overlap". we agree entirely with the correspondents that ventilator management should be individualized to each patient's physiology, and have never argued otherwise. in the theoretical "limit case" of a patient with normal lung compliance and minimal lung recruitability, we would similarly discourage use of high levels of peep, as surely would most practicing intensivists. we merely disagree with the correspondent's conclusions regarding the prevalence of these theoretical patients based on data from patients [ ] , as well as their subsequent recommendations to deviate from safe ventilatory practice for covid- patients based on this limited data. [ ] as catalogued above, the available data show that this purported "phenotype" is rarely encountered in covid- ards. unexpectedly, the correspondents request evidence from us that their efforts at phenotyping have caused harm. basic scientific convention, however, mandates that before they implore the field to deviate from usual practice, the burden is rather on them to demonstrate the benefits and safety of their proposed phenotyping scheme and linked interventions using robust scientific studies. thankfully for our patients, that is how best medical science works -primum non nocere. putting aside the complete absence of efficacy data, the validity of the physiological basis for their proposed interventions for these phenotypes has also been recently questioned. [ , ] we hope our response clarifies for the correspondents and readers that we in no way dispute the underlying heterogeneity of ards, nor the uniqueness of covid- , nor the need for patient-tailored therapy; indeed, much of our research is focused on attaining this. we merely insist that phenotyping be done using careful, data-driven approaches. to paraphrase dr. rajendram, rather than strengthening a house of cards, we should instead aspire to build a foundation out of sturdier, more lasting materials: in this case agile, yet robust, scientific studies using a responsible, data-informed approach. at this stage of the pandemic, sufficient data points exist to equip us to advance from anecdotebased intuitions to evidence-informed science. covid- conundrum: clinical phenotyping based on pathophysiology as a promising approach to guide therapy in a novel illness covid- in critically ill patients in the seattle region -case series subphenotyping ards in covid- patients: consequences for ventilator management respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study icu and ventilator mortality among critically ill adults with coronavirus disease epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study respiratory mechanics and gas exchange in covid- associated respiratory failure respiratory mechanics of covid- vs. non-covid- associated acute respiratory distress syndrome does not lead to a "typical" acute respiratory distress syndrome potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease clinical phenotypes of sars-cov- : implications for clinicians and researchers reference values for dynamic and static pulmonary compliance in men pulmonary mechanics during general anaesthesia. the influence of mechanical irritation on the airway acute respiratory distress syndrome: the berlin definition postmortem examination of patients with covid- pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- covid- related acute respiratory distress syndrome: not so atypical is a "cytokine storm" relevant to covid- ? covid- pneumonia: different respiratory treatments for different phenotypes? subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis stability of ards subphenotypes over time in two randomised controlled trials covid- phenotypes: leading or misleading? toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design management of covid- respiratory distress covid- -associated acute respiratory distress syndrome: is a different approach to management warranted? caution about early intubation and mechanical ventilation in covid- key: cord- - ebo cy authors: nan title: lungenversagen date: journal: chirurgische intensivmedizin doi: . / - - - - _ sha: doc_id: cord_uid: ebo cy das akute lungenversagen ist eine schwere diffuse entzündliche erkrankung der lunge. nach der „american-european consensus conference“ (bernard et al., ) wird zwischen einem ards — acute respiratory distress syndrom und einem ali — acute lung injury unterschieden. das ausmaß der respiratorischen insuffizienz wird nach der höhe des scores definiert. score ist die gesamtsumme der einzelwerte dividiert durch score: kein lungenversagen , - , leichtes lungenverasgen > , schweres lungenversagen multiple pathomechanismen (tabelle ) sind verantwortlich für schwerwiegende morphologische (lorraine et al., ) und funktionelle lungenveränderungen, sodass eine ausreichende oxygenierung der patienten mittels konventioneller beatmung oft nicht mehr möglich ist. in der frühphase des ards findet sich eine massive ansammlung neutrophiler granulozyten in der lunge sowie deren migration durch die gefäßwand. sie setzen eine reihe von endothelschädigenden und den pulmonal-vasku-lären gefäßwiderstand erhöhende substanzen frei (abb. ), die den ausgangspunkt für eine weitere kaskadenartige aktivierung verschiedener mediatorsysteme darstellen. (freisetzung freier radikale, elastase, aktivierung der phospholipase, aktivierung des kallikreinsystems, freisetzung von zytokinen: tnf, interleukin - , , - , - , - , - ; platelet activating factor (paf), komplement-komponente (c a), adhäsionsmoleküle. des weiteren spielt jedoch auch die freisetzung chemotaktischer moleküle, der chemokine ein wichtige rolle (puneet et al., ) . es kommt zunächst einerseits zu einer erhöhung der permeabilität der gefäßwand mit interstitieller Ödembildung und anderseits zu einer permeabilitätsstörung der alveolarwand, hervorgerufen durch membranfragmentationen der endothelzellen und eine degeneration der alveolären epithelzellen (typ-i-pneumozyten) mit ablösung von der basalmembran. sie machen % der alveolären fläche aus und sind vulnerabel als die typ ii zellen, die % der alveolarfläche ausmachen. dadurch wird die entstehung eines proteinreichen interstitiellen und intraalveolären Ödems (patroniti et al., ) ausgelöst, wodurch wiederum der gasaustausch erheblich erschwert wird. das zunehmende gewicht der lunge, bedingt durch das zunehmende Ödem, führt zu einem kollaps von lungenabschnitten entlang eines vertikalen gradienten verursacht durch hydrostatische kräfte, die kompressionsatelektasen erzeugen. diese veränderungen treten bevorzugt in abhängigen lungenabschnitten auf. die in der computertomographie sichtbaren dichteänderungen stellen eine kombination von atelektasen, Ödem, konsolidation oder eine kombination dieser drei formen dar. die schädigung der alveolarepithelien führt weiters zu einer abnahme der surfaktantproduktion und fördert damit die bildung von atelektasen. so kommt es zu einer zunahme des intrapulmonalen shunts und des totraumquotienten. der zusätzliche funktionsverlust des surfactant ist auf die anwesenheit funktioneller inhibitoren, seine abnorme zusammensetzung und die proteolytische störung der einzelkomponenten zurückzuführen. bei längerem bestehen des krankheitsbildes kommt es zur fibrosierung und proliferation der typ-ii-pneumozyten. durch die abnahme der compliance der lunge steigt das risiko für die entstehung eines barotraumas. im gegensatz zu der noch bis vor einiger zeit bestehenden meinung, dass die rückbildung eines alveolaren Ödems alleinig als ergebnis aus der druckdif-ferenz zwischen hydrostatischem und osmotischem druck (starling-kräfte) resultiert, zeigen nun neuere studien, dass die beseitigung eines alveolären Ödems durch einen aktiven natrium-chlorid transport durch das pulmonale epithel, einschließlich der alveolären epithelzellen vom typ i und typ ii als auch der distalen epithelzellen des atemweges reguliert wird , verghese et al., , ware et al., . so erfolgt durch eine na + , k + -at-pase eine aktive förderung von na + von der basolateralen oberfläche in das interstitium (matthay et al., ) . so zeigt es sich, dass bei einer akuten lungenschädigung die alveoläre flüssigkeitsclearance geringer ist als bei einem kardial bedingten hydrostatischem lungenödem. erste medikamentöse therapieansätze zeigen, dass unter einer -adrenergen agonisten (z. b. isoproterenol) bzw. epithelialer wachstumsfaktoren-applikation möglicherweise die alveoläre flüssigkeitsclearance gesteigert werden kann (sartori et al., bei patienten mit ali/ards kann das auftreten apoptotischer vorgänge an pulmonalen epithelialen zellen (song y et al., , li et al., , martin et al., (abraham, ) derselben, sodass es zur aufrechterhaltung eines von leukozyten geführten inflammatorischen prozesses kommt, der typisch für eine akute lungenschädigung ist (wang et al., , yum et al., die verminderte apoptose der neutrophilen ist bedingt durch: . verhinderung einer zytochrom c freisetzung aus den mitochondrien, . hemmung der aktivierung des proapoptotischen protein bad, . gesteigerte transkription des antiapoptotischen protein mci- und bci- , welches die protease caspase- hemmt und unter aktivierung von nf-kb eine gesteigerte transkription antiapoptotischer gene induziert. anschließend an diese zone findet sich meist ein dorsobasal lokalisierter erguss unterschiedlichen ausmaßes. computertomographischen untersuchungen (puybasset et al., , peseti et al., , pelosi et al., der lunge an patienten mit ali zeigen, dass hyperdensitäten entlang eines anteriorposterior gradienten als auch gleichzeitig entlang eines zephalokaudalen gradienten feststellbar sind. diese hyperdensitäten entsprechen nonaerated-nichtbelüfteten lungenarealen, welche sich von aerated lungenarealen unterscheiden lassen. nonaerated lungenareale sind bevorzugt in zwerchfellnahen lungenabschnitten zu finden. bei anwendung eines peep findet sich ein alveoläres rekruitment mehr in den nondependend als in den dependend lungenregionen und mehr in den zephalen als in den kaudalen regionen. wenn jedoch der zur verwendung kommende peep ausreichend hoch ist um in den dorsalen regionen und den unteren lungenabschnitten alveolen zu rekrutieren, dann kommt es zu einer Überdehnung der oberen lungenabschnitte. Überdehnung der lunge (quadri et al., ) auch als atelektrauma (uhlig et al., ) (ranieri et al., , lorraine et al., . konzepte der beatmung von patienten mit ards beinhalten die anwendung von spontanatmungsverfahren (putensen et al., ) (kuhlen et al., , luce , wobei keiner beatmungstechnik ein entscheidender vorteil eingeräumt werden kann, jedoch müssen gleichzeitig respiratoreinstellungen angestrebt werden, welche eine protektive beatmung ermöglichen (malarkkan et al., , eisner et al., . (gattinoni et al., , amato et al., , adams et al., , malarkkan et al., , bhattacharya die anwendung eines peep ist eine unumstrittene maßnahme bei jeder form einer respiratorischen insuffizienz (gattinoni et al., , medoff et al., , durante et al., . diskussionspunkte sind die höhe des verwendenen peep und die klinische umsetzung eines best-peep. ist das lungenvolumen, bei dem es während der exspiration zu einem verschluss der kleinen atemwege kommt. ist die summe aus verschlussvolumen und residualvolumen. Überschreitet die verschlusskapazität die frc, dann tritt endexspiratorisch ein verschluss basaler luftwege auf. der verschluss der kleinen atemwege tritt vor allem in den abhängigen dorsobasalen lungenabschnitten auf, wo der extraluminale gravitations-bedingte gewebsdruck größer ist als der endobronchiale intrapulmonale atemwegsdruck. (neumann et al., ) darauf hin, dass zur vermeidung eines kollapses von alveolen (ohne extrinsischen peep) eine exspirationszeit von weniger als , sec notwendig wäre. bei länger bestehender exspirationszeit kommt es trotz peep-anwendung bis zu einer höhe von cm h₂o zur ausbildung von atelektasen. erst bei einem peep von cm h₂o kann der exspiratorische alveolenkollaps vermieden werden. resultierend aus den experimentellen ergebnissen bedeutet die wertigkeit der zeitkonstante in der klinischen anwendung, dass prinzipiell eine regelmäßige adaptation des respirators an die gegebene lungensituation (compliance, resistance) notwendig ist um z. b. durch adaptation der exspirationszeit des respirators an die exspiratorische zeitkonstante die entwicklung eines inadvertent peep vermeiden zu können. bei Übertragung der experimentellen ergebnisse auf patienten mit schwerer respiratorischer insuffizienz wäre jedoch bezogen auf die respiratortherapie unter anwendung einer sehr kurzen exspirationszeit mit der entwicklung eines erhöhten intrinsischen peep und auch des mittleren atemwegsdruckes zu rechnen. hingegen konnte gezeigt werden, dass bei patienten mit ards eine kinetische therapie in form der bauchlage eine signifikante reduktion der exspiratorischen zeitkonstante (vieillard- baron et al., ) in der akutphase des lungenversagens sind ein beträchtlicher teil von lungenarealen bedingt durch einen kollaps von alveolen nicht belüftet. ziel eines open-lung-konzeptes (lachmann, ; blanch et al., , lim et al., , haitsma, ist es eine eröffnung von kollabierten alveolen bzw. rasche rekrutierung von konsolidierten lungenarealen unter kurzfristiger anwendung hoher inspirationsdrücke ( - mbar) zu erzielen und dann durch entsprechend hohe peep-werte ein offenhalten der alveolen zu garantieren (abb. ). dazu ist es notwendig, dass der inspiratorische plateaudruck den alveolar-Öffnungsdruck übersteigt und dann der peep über dem alveolarverschlussdruck liegt. ausgehend von dem hier beschriebenen grundkonzept gibt es inzwischen unterschiedlichst angewandte modifikationen (methoden) von rekrutierungsverfahren. wird der peep schrittweise auf - cm h₂o erhöht. damit sollen alle während der sich anschließenden inspiratorischen druckerhöhung rekrutierten alveolen offengehalten werden. . nun wird schrittweise der atemwegsspitzendruck auf - - mbar über atemzüge erhöht, womit ein kritischer wert des Öffnungsdrucks erreicht wird. diese hohen inspiratorischen druckwerte werden als notwendig angesehen, um einerseits die adhäsivkräfte kollabierter alveolen (böhm et al., ) , anderseits auch die kapillarkräfte in den flüssigkeitsgefüllten atemwegen überwinden zu können. als parameter der erreichung des Öffnungsdrucks ist das arterielle po₂ anzusehen, welches sich in einer deutlichen erhöhung zeigt. bei optimaler rekrutierung von alveolen führen nun weitere drucksteigerungen zu keiner erhöhung des pao₂. sind alle rekrutierten alveolen offen, dann ist ein derart hoher atemwegsspitzendruck für deren beatmung nicht mehr notwendig. resultierend aus dem zusammenwirken von surfactant und dem "la place gesetz" ist der notwendige innendruck in der alveole nach ihrer eröffnung geringer als vor ihrer eröffnung. es muss nun der verschlussdruck der lunge ermittelt werden, indem der atemwegsspitzendruck schrittweise gesenkt wird. kommt es zu einem pao₂-abfall, dann ist er durch einen kollaps von alveolen bedingt und somit ist der kritische verschlussdruck der alveolen festgestellt. die sich nun entwickelnden atelektatischen lungenareale müssen erneut eröffnet werden. die zuvor bestimmten eröffnungsdrucke sind bekannt. durch eine kurze beatmungsdauer mit diesen bekannten drücken, über einen zeitraum von sekunden, wird die lunge erneut eröffnet. anschließend kann der atemwegsspitzendruck soweit gesenkt werden, dass ein druck verwendet wird, der cm h₂o über dem bekannten verschlussdruck liegt. eine permissive hyperkapnie wird als teil einer lungenprotektiven maßnahme bei einem akuten lungenversagen angesehen (carvalho et al., nachdem no lange zeit als schadstoff angesehen wurde, gelang erst und im rahmen dreier studien der nachweis, dass der endothelium-derived relaxin factor (edrf), entdeckt von furchgott und zawadzki, ident mit no ist (ignarro et al., ; palmer et al., ; furchgott, ) die hochfrequenzbatmung ist eine form der künstlichen beatmung, bei der kleine tidalvolumina mit einer supraphysiologischen frequenz appliziert werden. verschiedenste typen der hochfrequenzbeatmung sind in den letzten jahren entwickelt und angewendet worden worden (froese et al., ) . von den zahlreichen möglichen anwendbaren hochfrequenzbeatmungsformen wie: hfp-high-frequency pulsation, fdv-forcierte diffusionsventilation (baum et al., ) , hfjv-high frequency jet oscillation haben sich im klinisch anwendbaren bereich jedoch techniken wie die hfpp-high-frequency positive-pressure ventilation, hfj-high frequency jet- chang ( ) beschreibt in einer Übersichtsarbeit mehrere mechanismen des gasaustausches, die vor allem bei der hochfrequenzoszillation von bedeutung sind. (shimaoku et al., ) . erste klinische ergebnisse zeigen, dass es möglicherweise unter hochfrequenter beatmung zu einem rascheren rekruitment von dependend lungenarealen kommt, ohne dass es gleichzeitig zu einer massiven Überdehnung von non-dependend lungenarealen kommt. denkbar ist, dass der unter hochfrequenzbeatmung oft zu beobachtende bessere gasaustausch nicht so sehr über mechanismen einer gesteigerten diffusion zu erklären ist, sondern durch pulsatile mechanismen, die zu einer rascheren rekrutierung von lungengewebe führen. . des weiteren kann diese jet-ventilationstechnik mit no-applikationsgeräten kombiniert werden, wobei eine exakte no-dosierung gewährleistet ist . meist kommt sie erst dann zu einsatz, wenn eine konventionelle beatmung versagt. in der literatur handelt es sich daher meist um fallberichte oder nicht randomisierte kleinstudien. jedoch zeigt es sich, dass die angewandten techniken, wenn oft auch aufwendig, sicher in der anwendung sind und oft eine verbesserung der oxygenierung ermöglichen. durch die verwendung eines konventionellen beatmungsteiles (abb. ) mit niedriger beatmungsfrequenz mit konventionellem peep, jedoch mit größerem vtid, ist eine ausreichende co₂-elimination gewährleistet. Überlagert wird dem konventionellen teil eine hochfrequente beatmungsform (tabelle ). die oxygenierung wird bevorzugt durch den hochfrequenten pulsatilen teil der beatmung verbessert. so wurden konventionelle beatmungstechniken mit unterschiedlichen hochfrequenten beatmungstechniken kombiniert. die jet-gasapplikation erfolgt bei einer kombinierten jet-ventilation (chfjv) (abb. ): abb. . darstellung des hochfrequenten jet-gas-impuls-volumens unter variabler jetfrequenz bei konstantem trachealdruck von mbar. bei anwendung einer hohen jet-frequenz (links) ist das tidalvolumen des jet-gasimpulses niedrig. je niedriger die jet-frequenz (rechts), desto höher ist das jet-impuls-gasvolumen ein suffiziente anfeuchtung und erwärmung des atemgases ist für eine maschinelle beatmung von wesentlicher bedeutung. als zielwerte werden eine temperatur von grad und eine relative feuchtigkeit von % angesehen (roth, ) . als optimaler feuchtigkeitsgehalt der inspirationsluft werden werte bis mg/l angesehen (williams et al., , christiansen et al., . (perkins gd et al., ) im entzündungsgeschehen bei einem ards (verminderung der sequestration von neutrophilen, beschleunigung der alveolären flüssigkeitsclearance, erhöhung der sekretion von surfactant) zugeschrieben. dennoch liegt auch eine beschreibung über die entwicklung eines lungenödems (russi et al., ) unter der kontinuierlichen therapie einer tokolyse mit -mimetica vor. bei patienten mit ards konnte abnahme von atemwegsspitzendruck, plateaudruck sowie des atemwegswiderstandes erzielt werden (morina et al., ) . antiphlogistica ist ein inhalatives glukokortikoid, lokaler entzündungshemmender effekt dosierung × atemhub bei der jet-ventilation sollte nach stunden eine kontrolle der trachealschleimhaut durchgeführt werden, um frühzeitig schleimhautveränderungen, die durch eine zu geringe befeuchtung bedingt sind, zu verhindern. danach weitere kontrollen der befeuchtung durch bronchoskopien in größeren zeitabständen. bei der jet-ventilation werden kleine gasvolumina mit hoher frequenz von einer düse über den endotrachealtubus in die trachea appliziert. wird nur --ein einzelimpuls des jet-gas-volumens abgegeben, dann gelangt das gasvolumen höchstens einige trachealdurchmesser in die trachea; aber durch die periodische kontinuierliche abgabe eine jet-impulses mit hoher frequenz wird das gasvolumen kontinuierlich bis in die alveolen transportiert. dieser gastransport ist begleitet von einer interaktion zwischen konvektion und molekularer diffusion innerhalb der atemwege. der konvektive teil des gasbewegung setzt sich aus zwei teilen zusammen: so besteht erstens ein turbulent konvektiver gasaustausch mit der atmosphäre verursacht durch den jet in der trachea und zweitens eine konvektive strömungsbewegung entlang der atemwege gesteuert durch eine interaktion zwischen dem jet und einer expandierenden und kontrahierenden bewegung der atemwege, verursacht durch die compliance der lunge (scherer et al., ) . in den peripheren atemwegen besteht ein pulsierender bidirektionaler koaxialer gasfluss sowie eine verstärkte konvektive dispersion die so genannte "augmented diffusion", die um ein vielfaches größer ist als die normale molekulare diffusion. unter anwendung der superponierten hochfrequenz-jet-ventilation dürfte neben gesteigerten gasaustauschmechanismen jedoch ein rasches rekruitment von minderbelüfteten abhängigen lungeanarealen ursächlich an der oft feststellbaren raschen verbesserung des pulmonalen gasaustausches beteiligt sein, wie es mittels einer computertomographischer studie (kraincuk, ) gezeigt werden konnte. wobei der pulsatilen gasbewegung offensichtlich eine wichtige rolle zuzukommen scheint. die hochfrequenzoszillation unterscheidet sich von der hochfrequenz-jet-ventilation, dass sowohl neben der inspiration auch die exspiration aktiv ist, die tidalvolumina kleiner sind als bei einer combined hfjv (meist unter ml), der möglich anwendbare frequenzbereich erstreckt sich bis hz (meist liegt er bei hz ähnlich der jet-ventilation). kolla et al., ; lewandowski et al., ) größere patientenzahlen mit einer Überlebensrate von über % aufwiesen, des weiteren schwere bakterielle als auch virale pneumonien (vida et al., ) als auch sekundäre lungenschädigungen, die nach einem trauma, einer pankreatitis, nach systemischer erkrankung mit lungenbeteiligung (loscar et al., ) nach einer chemischen pneumonitis sowie einer sepsis auftreten können. zur anwendung kommt sie auch bei transplantations-empfängern unmittelbar postoperativ nach einer lungentransplantation als auch nach herzchirurgischen eingriffen. ebenso ist der frühzeitige beginn mit anschließenden mobilem inter-hospitalen transfer an ein ecmo zentrum beschrieben linden, ) . die anwendung extrakoproraler oxygenierungsverfahren stellt eine notwendige therapieoption (kopp et al., , henzler et al., bei schwerster respiratorischer insuffizienz dar, die mit der laufenden weiterentwicklung (bartlett, , bensberg et al., einschließlich der entwicklung kleinerer und einfacherer systeme den einsatzbereich erweitert. betreffend die gesundheitsbezogene lebensqualität (stoll et al., ) bei einer zunahme des herzzeitvolumens steigt der mikrovaskuläre druck, gleichzeitig kommt es zu einer rekrutierung von bis dahin nicht oder kaum perfundierten gefäßen. damit kommt es zu einer zunahme von kapillaroberfläche über die flüssigkeit filtriert wird. das so genannte permeabilitäts-oberflächenprodukt steigt. bei einem anstieg des hzv kommt es somit durch rekrutierung von gefäßen und der damit einhergehenden vergrößerung des gefäßquerschnittes zu einem abfall des postkapillären gefäßwiderstandes der gesamten lunge, wobei dennoch die transvaskuläre flüssigkeitsfiltration zunehmen kann. akutes nierenversagen durch eine extreme hypovolämie splanchnikusischämie vermeidung einer extremen hypovolämie: akutes nierenversagen splanchnikusischämie hypovolämie bedingt eine freisetzung vasoaktiver mediatoren. im tierexperiment führt volumenmangel zu translokation von bakterien und endotoxinfreisetzung aus dem darmlumen in den intravasalraum und zu gesteigerter freisetzung von tnf-. die kinetische therapie ist eine lagerungstherapie mit dem ziel einer verbesserung der lungenfunktion und damit des pulmonalen gasaustausches. zahlreiche arbeiten beweisen die effektivität dieser maßnahmen (langer et al., , hörman et al., , lamm et al., , stiletto et al., , koutsoukou, (spragg rg et al., ) nur eine kurzfristige besserung des gasaustausches innerhalb der ersten stunden nach seiner verabreichung sowie keine verbesserung des outcome. die problematik liegt in der notwendigen schwierigen zerstäubung einer fetthaltigen lösung, der platzierung in der gesunden lunge, der inaktivierung in geschädigten -----alveolen (baudouin sv ) , der hohen dosierung beim erwachsenen und der damit verbundenen hohen kosten der jeweiligen präparate, die eine routinemäßge applikation derzeit nicht rechtfertigen, obwohl kleine studien auf die positiven effekte hinweisen (seeger et al., , günther et al., , von kaam et al., , calkovska et al., . (seear et al., , kudoh et al., die endotheliale permeabilität und das lungenödem. in klinischen studien (the ards clinical trials network ) konnten jedoch keine entsprechenden ergebnisse erzielt werden, die eine gezielte applikation von pentoxyphyllin rechtfertigen würden. acetylcystein -antioxidans wurde als antioxydans in verschiedenen studien verwendet. die tierexperimentell günstigen ergebnisse (bernard et al., ) konnten jedoch in klinischen studien (bernard et al., ) cepkova, ) dieser substanzgruppe bei ali oder ards. es fand sich keine verbesserung des gasaustausches, keine reduktion der der mortalität. -adrenoceptor agonisten es ist bekannt, dass -agonisten über alveolar type ii zellen die surfactantproduktion stimulieren. ₂-agonisten erhöhen in der lunge jedoch auch den transepithelialen flüssigkeitstransport einer klinischen studie zeigen, dass eine applikation von -ago neutrophils and acute lung injury ventilator-induced lung injury beneficial effects of the "open lung approach" with low distending pressures in acute respiratory distress syndrom; a prospective randomized study on mechanical ventilation effect of a protective-ventilation strategy on mortality in the acute respiratory di stress syndrome incidence, risk factors and outcome of barotrauma in mechanically ventilated patients -the ards clinical trials network. randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome extracorporeal life support: history and new directions forced diffusion ventilation (fdv), bases and clinical application artificial lung and extracorporeal gas exchange the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome recruitment maneuvers in acute lung injury exogenous surfactant replacement in ards -one day, someday, or never? effect of nacetylcystein on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function a trial of antioxidans n-acetylcysteine and procysteine in ards. the antioxidant in ards study group chest das konzept der offenen lunge exogenous surfactant administration by asymmetric high-frequency jet ventilation in experimental respiratory distress syndrome temporal hemodynamic effects of permissive hyperkapnia associated with ideal peep in ards pharmacotherapy of acute lung injury and the acute respiratory distress syndrome mechanisms of gas transport during ventilation by high-frequency oscillation messungen des feuchtigkeitsgehaltes der inspirationsluft bei beatmeten patienten bei verwendung verschiedener befeuchtungssysteme high frequency percussive ventilation in pediatric patients with inhalation injury granton j and the multicenter oscillatory ventilation for acute respiratory distress syndrome trial (moat) study investigators, high frequency oscillatory ventilation for acute respiratory distress syndrome in adults high frequency oscillatory ventilation in the management of a high output bronchopleural fistula: a case report ardsnet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome the acute respiratory distress syndrom network: efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome combined high-frequency ventilation for management of terminal respiratory failure: a new technique combining high-frequency oscillatory ventilation and recruitment maneuvers in adults with early acute respiratory distress syndrome: the treatment with oscillation and an open lung strategy (tools) trial pilot study high frequency ventilation -state of art dramatic beneficial effects of sildenafil in recurrent massive pulmonary embolism the concept of "baby lung regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome inhaled nitric oxide therapy in adults bronchoskopic administration of bovine natural surfactant in ards and septic shock: impact on biophysical and biochemical surfactant properties hemodynamic effects of high-frequency oscillatory ventilation in severe pediatric respiratory failure open lung in ards biphasic positive airway pressure (bipap)-a new mode of ventilatory support extracorporeal life support for adult patients with severe respiratory failure turn the ards patient prone to improve oxygenation and decrease risk of lung injury alveolar recruitment of atelektasis under combined high-frequency jet-ventilation: a computed tomography study hypercapnic acidosis and mortality in acute lung injury inhaled nitric oxide and inhaled prostaglandin e : effect on left ventricular contractility when used for treatment of experimental pulmonary hypertension high-frequency ventilation for acute lung injury and ards the effect of pentoxifylline on acid-induced alveolar epithelial injury die intensivtherapie bei akutem lungenversagen open up the lung and keep the lung open mechanism by wich the prone position improves oxygenation in acute lung injury the prone position in ards patients extracorporeal membrane oxygenation for severe acute respiratory failure high survival rate in ards patients managed according to a clinical algorithm including extracorporeal membrane oxygenation effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of the patient inter-hospital transportation of patients with severe acute respiratory failure on extracorporeal membrane oxygenation -national and international experience ventilator-induced injury: from barotrauma to biotrauma acute lung injury and the acute respiratory distress syndrome hochfrequenzventilation (hfo) bei akuter lungenschädigung und ards application of transtracheal pressure oscillations as a modification of "diffusing respiration new aspects of ventilation in acute lung injury-review article temporal dynamics of lung aeration determined by dynamic ct in a porcine model of ards apoptosis and epithelial injury in the lungs lung epithelial fluid transport and the resolution of pulmonary edema alveolar epithelium, role in lung fluid balance and acute lung injury alveolar fluid clearance in patients with ards -does it make a difference science review: apoptosis in acute lung injury high-frequency oscillation in acute respiratory distress syndrome (ards) use of recruitment maneuvers and high positive end-expiratory pressure in a patient with acute respiratory distress syndrome prospective trial of highfrequency oscillation in adults with acute repiratory distress syndrome effects of nebulized salbutamol on respiratory mechanics in adult respiratory distress syndrome an expanded definition of the adult respiratory distress syndrome hedenstierna g, effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acidinduced lung injury pesenti a, measurement of pulmonary edema in patients with acute respiratory distress sindrome computed tomography in adult respiratory distress syndrome: what has it taught us benchto-bedside review: beta -agonists and the acute respiratory distress syndrome computerised tomography scan imaging in distress sindrome acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension chemokines in acute respiratory distress syndrome long-term effects of spontaneous breathing during ventilatory support in patients with acut lung injury a computed tomography scan assessment of regional lung volume in acute lung injury high tidal volume ventilation induces proinflammatory signaling in rat lung endothelium administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion albumin influences total plasma antioxidant capacity favourably in patients with acute lung injury effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome -a randomized contolled trial a prospective comparison of atrio-femoral and femoro-atrial flow in adult venovenous extracorporeal life support extracorporeal membrane oxygenation for transport of hypoxaemic patients with severe ards intensivmedizinisches seminar band beatmung high permeability pulmonary edema (ards) during tocolytic therapy -a case report beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human und rat lungs effect of pentoxifilylline on hemodynamics, alveolar fluid reabsorbation, and pulmonary edema in a model of acute lung injury alveolar epithelial fluid transport in acute lung injury: new insights convective mixing in high frequency intermittend jet ventilation erste erfahrungen mit der superponierten hochfrequenz-jetventilation in der intensivmedizin superponierte hochfrequenz jetventilation (shfjv) unter verwendung von no, technische grundlagen und erster klinischer einsatz surfactanttherapie des ards, hintergrund und erste klinische erfahrungen high frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung injury conventional ventilation versus high-frequency oscillation: hemodynamic effects in newborn babies ventilation with small tidal volumes effect oof recombinant surfanctant protein c-based surfactant on the acute respiratory distress syndrome national heart, lung, and blood instituete acute respiratory distress syndrome (ards) clinical trials network. efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome kinetische therapie zur therapie und prophylaxe der posttraumatischen lungeninsuffizienz. ergebnisse einer prospektiven studie an polytraumatisierten gesundheitsbezogene lebensqualität; langzeitüberleben der erwachsenen patienten mit ards nach extracorporaler mmbranoxygenation (ecmo) mechanotransduction in the lung ventilation-induced lung injury and mechanotransduction: stretching it too far high-frequency percussive ventilation improves oxygenation in patients with ards alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema prolonged ecmo support for virus-induced cardiorespiratory failure early after cardiac surgery prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome response to exogenous surfactant is different during open lung and conventional ventilation alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome the acute respiratory distress syndrome fas-induced apoptosis epithelial cells requires ang ii generation and receptor interaction pathophysiologie und aktuelle medikamentöse therapiekonzepte relationship between the humidity and temperature of inspired gas and the function of the airway mucosa high-frequency jet ventilation produces auto-peep involvement of phosphoinositide -kinases in neurtophil activation and the development of acute lung injury arteriovenous carbon dioxide removal: development and impact on ventilator management and survival during severe respiratory failure key: cord- - jblod j authors: meduri, gianfranco umberto; chrousos, george p. title: general adaptation in critical illness: glucocorticoid receptor-alpha master regulator of homeostatic corrections date: - - journal: front endocrinol (lausanne) doi: . /fendo. . sha: doc_id: cord_uid: jblod j in critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (grα) and are associated with an enormous bioenergetic and metabolic cost. appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. emerging literature place the activated grα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. by the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. we review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing grα and mitochondria number and function. present understanding of the activated gc-grα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. the activated grα interdependence with functional mitochondria and three vitamin reserves (b , c, and d) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis. in critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (grα) and are associated with an enormous bioenergetic and metabolic cost. appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. emerging literature place the activated grα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. by the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. we review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing grα and mitochondria number and function. present understanding of the activated gc-grα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. the activated grα interdependence with functional mitochondria and three vitamin reserves (b , c, and d) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis. keywords: critical illness, glucocorticoid receptor-alpha, nuclear factor-κb, mitochondria, hypovitaminosis the reasons behind the evolutionary success of mammals and other multicellular organisms is their extraordinary capacity to adapt to changing environmental conditions and survive by maintaining their homeostasis ( ) . homeostasis refers to the relative stability in the activity of the physiological systems of the organism that are essential to support life ( ) . the process of maintaining stability within a harmless range via homeostatic physiologic corrections to both predictable and unpredictable adverse forces or stressors is termed "eustasis" ( ) . in the course of human evolution, homeostatic corrections have emerged to increase the host's ability to cope with adverse or even catastrophic events ( ) . these responses are shaped by trade-offs, sometimes with benefits and disadvantages in different periods of the life cycle ( ) . following the cambrian explosion, about million years ago, when multicellular organisms-originally formed in water environments-colonized the land physiological homeostatic changes emerged to allow survival. these corrective changes were essential to mammalian species evolution and emerged to solve a frequent conflict between environmental changes and preservation of the individual allowing survival and, hence, reproduction. these alterations permitted progression to future generations i.e., survival of the species through the active process of natural selection ( ) . these corrections involved profound neural, metabolic and immune changes mediated by a few major physiological systems (e.g., the central nervous, autonomic, cardiorespiratory, endocrine, and immune systems), and acting through integrated crosstalk pathways, that was associated with appropriate responses throughout the organism ( ) . such changes have been relatively conserved across many vertebrates, including mammalian species ( , ) . they have evolved to allow coping with lack of energy, dehydration, hemorrhage, infections, toxic substances, or relatively short-lived inflammatory responses, such as those of wound healing or exposure to foreign substances ( ) . when the organism is exposed to stressors that exceed the harmless stability range, individual survival is maintained at the expense of this organism's health and longevity. this condition is different from healthy homeostasis or eustasis and is called "allo-stasis" or different (allo)-stasis or even more accurately "caco (bad) -stasis. the cumulative cost of cacostasis for the organism, has been called allostatic or cacostatic burden. excessive or prolonged cacostatic burden results in severe acute and/or chronic cacostatic pathology ( , ) . the intensive care unit (icu) stress state represents a new and very different ecosystem from those within which humans evolved in the past. actually, critical illness epitomizes an acute and/or chronic cacostatic burden that goes beyond an evolutionarily conserved physiological adaptive response, and if left untreated it could rapidly exhaust homeostatic compensation and lead to death of an organism (lethal cacostasis). in critically ill patients, the need for vital organ support (maintenance of arterial blood pressure, mechanical ventilation, and other support measures, which were not available until the middle of the last century), reflects near exhaustion or exhaustion of (i) neuroendocrine homeostatic compensation, also known as "critical illness-related corticosteroid insufficiency" (circi) ( ) ; (ii) cell bio-energetic and other functions; and (iii) reserves of vital micronutrients (vitamins and minerals). even when it allows survival of the patient, homeostatic failure, ranging in acuity and severity, has a major impact on morbidity and mortality during and after hospitalization. circi-associated dysregulated systemic inflammation and mitochondrial dysfunction are central to the increased morbidity and mortality of acute and/or chronic critical illness and the subject of this review. in multicellular organisms, the innate immune system with its recognition and signaling mechanisms is the most ancient form of host defense to infectious and non-infectious threats during evolution ( ) . the nuclear factor-κb (nf-κb) system, a "rapidlyacting" primary transcription factor regulated cellular response, is a central activator of innate immunity. it appears that the nf-κb was incorporated into this ancient signaling pathway more than million years ago, and has been shown to play independent roles in vertebrate and insect lineages ( , ) . in most cell types, the inactive form of nf-κb, a heterodimeric protein composed of the dna-binding proteins p and p , is retained in the cytosol by association with inhibitory factors, such as iκb proteins; when activated, the latter are rapidly phosphorylated and degraded via the proteasomal pathway, liberating nf-κb and allowing it to translocate into the nucleus ( ) . in tumor necrosis factor-α (tnf-α)-stimulated hela cells, a genome-wide study identified , genome binding sites of p ( ) . among the , distinct nf-κb target genes identified, nf-κb controlled the expression of target genes, including inflammatory cytokines, chemokines, inflammatory enzymes, adhesion molecules, and immune system receptors, which are known to orchestrate the integrated inflammatory and immune responses. interestingly, an additional identified nf-κb target genes were involved in metabolic processes ( ) . in critical illness, nf-κb-driven systemic inflammation, also known as a "cytokine storm" ( ) , activates a multi-system response that includes at least three major domains: (i) the stress system composed by the hypothalamic-pituitary-adrenal (hpa) axis and the locus caeruleus-norepinephrine/sympathetic nervous system activated to provide sufficient energy and hemodynamic stability to overcome the initial phase of critical illness ( ) ; (ii) the acute-phase reaction (apr), which has several adaptive functions, including increasing the production of procoagulant factors in preparation for possible tissue damage ( ) ; and (iii) the tissue defense response (tdr) of the target organs [ figure ; ( , ) ]. the main effectors of systemic inflammation are the inflammatory cytokines, the acutephase reactants, and the peripheral effectors of the sensory afferent nervous system. the inflammatory cytokines include tnf-α, interleukin- β (il- β), il- , chemokines, and other mediators of inflammation. the acute-phase reactants are mostly of hepatic origin and include the c-reactive protein (crp), figure | systemic inflammation-associated multi-system responses: stress, acute phase, tissue defense. systemic inflammation-associated multi-system response that includes at least three major domains: (i) the stress system composed by the hypothalamic-pituitary-adrenal (hpa) axis and the locus caeruleus-norepinephrine/sympathetic nervous system; (ii) the acute-phase reaction (apr), and (iii) the tissue defense response of the target organs. fibrinogen, and plasminogen activator inhibitor- . during the acute-phase reaction, myelopoiesis is favored at the expense of both lymphopoiesis and hematopoiesis, explaining in part the persistent lymphopenia and anemia of critical illness ( ) . substance p is an example of an effector of the sensory afferent nervous system, while hypothalamic corticotropin releasing hormone (crh), vasopressin, cortisol, the catecholamines (norepinephrine and epinephrine), and peripheral neuronal crh represent effectors of the stress system [reviewed in ( ) ]. the tissue defense response is an integrated network of three simultaneously nf-κb-activated pathways that account for much of the histological, physiological, and laboratory changes observed in vital organs during critical illness ( ) . these three pathways are those of tissue inflammation, hemostasis, and tissue damage repair: (i) tissue inflammation includes changes in the endothelium, such as loss of the glycocalyx, adhesion/diapedesis of activated neutrophils, endothelial injury, increased porosity with interstitial exudative edema, and loss of vascular tone, and changes in the epithelium, such as loss of integrity and cell apoptosis; (ii) the hemostasis pathway includes platelet activation and aggregation, intravascular clotting with decreased microvascular patency, extra-vascular fibrin deposition, and, lastly, inhibition of fibrinolysis, and (iii) tissue damage repair includes regenerating native parenchymal cells, fibroproliferation and deposition of extracellular matrix, resolution of granulation tissue, and clearance of apoptotic cells and debris ( ) . the roles of macrophages and mitochondria in homeostatic corrections is the subject of intense research. mononuclear phagocytic cells (mpcs), including macrophages and dendritic cells, are widely distributed throughout the tissues of the organism, where they perform essential homeostatic, surveillance, and regenerative tasks. as the neuro-endocrine-immune response progresses, macrophages change phenotype and play an essential role in both innate and adaptive immune responses, in the resolution of inflammation and in the tissue repair and regeneration (discussed further in section glucocorticoid receptor-alpha and homeostatic corrections) ( ) . mitochondria are targets of gr and critical modulators of homeostatic corrections owing to their critical role in energy production, synthesis of stress-associated steroid hormones, and their capacity to generate signals that promote cellular adaptation (see section cellular energetics-mitochondrial function) ( ) . systemic homeostatic corrections are driven by elevated levels of circulating inflammatory cytokines, and based on disease progression, can be broadly divided into either adaptive/resolving (regulated systemic inflammation) vs. maladaptive/unresolving (dysregulated systemic inflammation) ( , ) . evidence from the literature on severe sepsis ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , acute respiratory distress syndrome (ards) ( ) ( ) ( ) ( ) ( ) , and trauma ( , ) provides strong support that the degree of nf-κb-driven elevation in inflammatory biomarkers at icu entry and during icu stay correlates with disease severity and hospital mortality ( , ( ) ( ) ( ) . in addition to elevated inflammatory markers, critically ill patients have profound activation of the coagulation system (elevated d-dimer levels, prolonged prothrombin time and activated partial thromboplastin time, and reduced levels of the anticoagulant proteins, protein c and antithrombin) and evidence of endothelial cell activation with disturbed vascular integrity that correlates with disease severity and outcome (see section endothelium) ( ) ( ) ( ) . evidence that hemostasis and inflammation evolved from a single-triggered mechanism can be traced back more than million years ago, based on studies with the horse-shoe crab (limulus polyphemus) ( ) . in hospital survivors, failure to achieve homeostatic correction has a significant negative long-term impact, with experimental work suggesting that it might potentiate the peripheral and brain pro-inflammatory cytokine response to a subsequent inflammatory challenge ( ) . independently of age and comorbidities, patients with elevated circulating biomarkers of inflammation and hemostasis at hospital discharge have persistent elevation over time with increased risk for cardiovascular events, re-hospitalizations, and -year mortality ( , , ) . "persistent inflammation, immunosuppression, and catabolism syndrome" (pics) has been postulated as the underlying pathophysiology of chronic critical illness (cci) ( , ) . about % of sepsis patients have a debilitating condition characterized by a self-perpetuating cycle of persistent low-grade systemic inflammation mimicking chronic stress (elevated cortisol) ( , , ) , glucocorticoid resistance, altered hemostasis ( , ) , mitochondrial dysfunction ( , ) , and accelerated inflamm-aging ( , ) , with increased risk for chronic inflammatory systemic diseases ( , ) . the evolutionary trade-off between acutely beneficial and chronically harmful homeostatic corrections was the subject of a recent review ( ) . recently, a critical role was identified for the fkbp gene, which encodes the fk binding protein , a co-chaperone of the gr along heat shock proteins (hsp), including hsp . the expression of fk is stimulated by glucocorticoids and has an inhibitory effect on gr signaling, preventing the nuclear translocation of gr. if short-lived, this negative feedback mechanism to reduce gc signaling may be important to restore hpa axis homeostasis. however, aging and certain stress-related phenotypes are associated with epigenetic upregulation of fkbp via decreases in dna methylation at selected enhancer-related fkbp sites, promoting nf-κbrelated peripheral inflammation and chemotaxis, and heightened cardiovascular risk ( ) . importantly, translational research indicates that the type of response (regulated or dysregulated) is established early in critical illness ( , , ) , and the previously espoused hypotheses of the second-hit model ( , ) , or the two-phase model (compensatory anti-inflammatory response syndrome) are now both considered obsolete ( , , ) . based on this pathophysiological construct, we will focus on emerging evidence indicating the central role played by the activated glucocorticoid receptor-alpha (grα), the master regulator of nf-κb and homeostatic corrections, in the development and resolution of critical illness. this role is conditioned by its interdependence with functioning mitochondria and by presence of adequate micronutrient reserves. additionally, we present evidence on how circi, mitochondrial dysfunction/damage, and hypovitaminosis negatively interact to accelerate an anti-homeostatic process of natural selection. the stress system is a complex, sophisticated, and carefully regulated adaptation mechanism that has been shaped by natural selection because it offers a selective advantage ( ) . all vertebrates express the proopiomelanocortin protein (pomc) that gives rise to adrenocorticotropic hormone (acth) which then stimulates the secretion of glucocorticoids. acth has long been closely associated with other signaling molecules, such as crh, vasopressin, biogenic amines (epinephrine and norepinephrine), steroids such as cortisol and aldosterone, cytokines, such as il- β, and nitric oxide. all of these substances are crucial to adaptation to stressors. it is remarkable that the gene dna sequences for these molecules have not only been conserved over hundreds of millions of years but also continue to serve closely related adaptive functions ( ). this is apparently a result of strong selective forces against mutations that change their sequences and functionality of their products. cortisol, the end-product of hpa axis activation, is synthesized from cholesterol in the mitochondria and endoplasmic reticulum of the zona fasciculata of the adrenal cortex. its synthesis depends entirely on scavenger receptor class b type-i (sr-bi)-mediated cholesteryl ester selective uptake from circulating high-density (hdls) and low-density (ldls) lipoproteins ( ) . in critically ill patients, low serum hdl levels correlate negatively with circulating tnf-α and il- levels ( , ) , and positively with mortality ( , ) . the combined effects of reduced hdl and sr-bi during systemic inflammation may lead to significant reductions in glucocorticoid production ( ) . low hdl ( ) and low total cholesterol ( ) correlate with inadequate response to acth stimulation. in septic shock, prolonged glucocorticoid administration is associated with significant increase in total cholesterol levels within days of treatment ( ) . glucocorticoids are the primary adaptive response mediators, whose signaling system interacts with other cell signaling systems, all essential for maintaining the homeostasis of many of the body's complex functions, including neural, cardiorespiratory, endocrine, metabolic, bioenergetic, and immune responses ( ) . within tissues, glucocorticoids are regulated at the pre-receptor level by the isozymes of βhydroxysteroid dehydrogenase ( β-hsd), which are located in the endoplasmic reticulum (er). glucocorticoids (gcs) bind to the ligand-binding domain of grα to produce a biological response. because of their lipophilic nature, gcs can readily diffuse across cellular membranes to bind to their intracellular receptor and produce a biological/pharmacological response [ figure ; ( , , ) ]. the glucocorticoid receptor is a member of the nuclear receptor (nrs) ( ) superfamily that emerged in the vertebrate lineage ∼ - million years figure | genomic, non-genomic, and mitochondrial glucocorticoid signaling pathways. glucocorticoid receptor mechanisms of action. the classic actions of grα are shown in the middle of the panel. the dormant but ligand-friendly receptor, located in the cytoplasm, is bound to co-chaperon molecules, such as heat-shock proteins and the immunophilin fkbp. upon binding to the ligand, the activated receptor translocates into the nucleus, where it interacts with gres and/or other transcription factors, such as nf-κb and ap , to regulate the activity of glucocorticoid-responsive genes, which represent ∼ % of the human genome. in addition, cell membrane-associated grα may be activated by the mapk and pi k kinases, as shown in the left of the panel. in addition, by as yet unknown mechanism, the grα translocates into the mitochondria, where it interacts with the mitochondrial dna gres, regulating the activity of mitochondrial genes. see text for additional details cpla α, cytosolic phospholipase a alpha; enos, endothelial nitric oxide synthetase; fkbp, immunophilins; gr, glucocorticoid receptor; hsp, heat shock proteins; mapk, mitogen-activated protein kinases; no, nitric oxide; pi k, phosphatidylinositol -kinase; tf, transcription factor. ago (similarly to nf-κb) from sequential duplications of two ancestral genes, those of the estrogen and the glucocorticoid receptors; the latter ultimately evolved into the glucocorticoid and the mineralocorticoid receptors ( , ) . underlying its essential role in formation and regulation of multicellular life, the gr is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions ( ) while grs are vital for the structural and functional maturation of fetal organs ( , ) , affecting almost , genes ( ) . in late gestation of mammals, fetal glucocorticoid levels rise dramatically, an essential step for maturation in preparation for life after birth. also, an association was found between greater maternal affection and warmth in early life and increased expression of glucocorticoid receptor genes in the offspring resulting in long-term health benefits ( ) . grs are present in the cytoplasm ( ) and cell membrane (non-genomic effects) ( ) in almost all cells of the body and in high concentrations (in neutrophils ∼ , ; in macrophages ∼ , ) ( ). however, gr levels within the cell are not static, but are tightly controlled by numerous factors and at multiple levels. notably, variants of the human gr (hgr) have been identified to date with the potential of at least combinations of homo-and hetero-dimers ( ) . recent research indicates that the expression of different gr transcriptional and translational isoforms might be a significant factor determining how gcs influence the biological function and activity of specific cells and tissues ( ) . in contrast to grα, the alternatively transcribed grβ, which resides primarily in the cell nucleus, does not bind glucocorticoid, but can form homodimers with itself or heterodimers with a grα subtype, functioning as an antagonist of grα. grβ homodimers can interact with glucocorticoid response elements (gre) in the dna, however their binding does not activate transcription ( ) . generally, grβ is expressed at very low levels compared to grα; however, its expression is increased in inflammatory diseases, including critical illness, and this might be associated with decreased sensitivity to gcs and circi ( ) . activation of grα is not only an essential component of the general adaptation to stress, but also contributes to the maintenance of homeostasis in stress-free conditions ( ) . the biological response to the gc-grα complex is affected by cell type, tissue type, and species-specific variations in the repertoire of partnering proteins, ligand concentrations, and other contextual variables ( , ) . in stimulated hela and neuronal pc cells, genome-wide studies identified , and , gr genomic binding sites upon treatment with gc, respectively ( , ) . of interest, the availability of these binding sites for interacting with the gc-gr complex depends on the chromatin landscape, which is tissue-and cell type-specific, explaining to some extent, why the gr has a certain effect on one tissue and a totally different effect on another ( ) . thus, even though the signaling system is the same, the landscape of the landing site is not. thus, different cells recognize these signals differently, resulting in a highly context-dependent action by glucocorticoids ( ) . after gc binding takes place in the cytoplasm, the activated gc-grα complex can either (i) bind to several pro-inflammatory transcription factors, or (ii) act as a transcription factor, after translocation into the nucleus and mitochondria ( , ) . glucocorticoids regulation of mitochondrial transcription via activation of mtgre was the subject of a recent review ( ) . in pathway (i), the activated gc-grα complex interacts directly with activated transcription factors nf-κb and ap- , leading to the transcriptional repression of major downstream proinflammatory factors. in pathway (ii), gc-grα binds to positive (transactivation) or negative (transrepression) specific dna regions, the glucocorticoid-response elements (gres) on the nuclear and mitochondrial dna ( ) , to directly regulate transcription of target genes. finally, gc activation of membrane-bound gr rapidly induces the activity of several kinases, such as the mitogen-activated protein kinase (mapk) or the phosphatidylinositol -kinase (pi k) pathways [ figure ; ( ) ]. the non-genomic effects of gcs clearly differ from their well-known genomic effects, with the former responding within several minutes independently of protein synthesis. genomic studies have shown that the gc-grα complex regulates more than , genes in unstimulated peripheral blood mononuclear cells (pbmc) from healthy donors ( ) , in human pulmonary type ii cells ( ) , and several organs, including the heart ( ), liver ( , ) , and uterus ( ) of unstimulated mice, underscoring its essential role as a master modulator in sustaining life and restoring health. the discordance between the number of regulated genes and the gr sites ( , ) suggests that multiple sites are involved in the regulation of a single gene and/or that binding of a transcription factor is not sufficient to drive gene expression ( ) . control of mrna turnover is critical in regulating the levels of inflammatory-and immune-mediated gene expression. recent studies indicate that the gr can mediate gc actions beyond transcriptional gene control; it may actually directly participate, via association with mrna, in gc-mediated control of cytoplasmic post-transcriptional mechanisms of gene expression ( ) . in an experimental model (spret/ei mice), increased gr levels and activity were associated with strongly reduced expression levels of cytokines and chemokines in response to lps-induced lethal inflammation ( ) . in , munck et al. reviewed the actions of cortisol and proposed that "stress-induced increases in glucocorticoids levels protect, not against the source of stress itself, but rather against the body's normal reactions to stress, preventing those reactions from overshooting and threatening homeostasis ( ) ." this work and the results of the above genomic studies have led to a reevaluation of glucocorticoids' role in homeostatic corrections. busillo and cidlowski ( ) recently reviewed the master regulatory role played the activated gc-grα complex in the three major phases of homeostatic correction involved in disease development and resolution (figure ). while distinctions are made between the different states, variable degrees of overlap are likely. first, in the pro-inflammatory phase, gc-grα prime the innate immune system to remove or neutralize pathogens by: (i) inducing the expression of tolllike receptor , nod-like receptor pyrin containing (nlrp ) inflammasome, and purinergic receptor p y r; (ii) repressing adaptive immunity (energy conservation); and (iii) cooperating with pro-inflammatory transcription factors nf-κb and activator protein (ap- ) in promoting leukocyte redistribution. the gc induction of nlrp sensitizes the cells to extracellular atp and significantly enhances the atp-mediated release of proinflammatory molecules, including mature il- β, tnf-α, and il- ( ). in addition, inflammatory cytokines, particularly il- , nitric oxide, and gcs trigger and modulate the systemic and hepatic acute phase protein response ( ) . in stimulated hela cells, a genome-wide study identified , gene collectively regulated by the activation of nf-κb and grα, with % of regulated genes responding only when both ligands are added, indicating that grα and nf-κb crosstalk alters signaling pathways that are regulated by each factor separately ( ) . during systemic inflammation, peripherally generated tnfα, il- β, il- , and other inflammatory cytokines activate the hpa axis at multiple levels to produce gc ( ) ( ) ( ) ( ) . in addition, inflammatory cytokines increase the expression and enzymatic activity of β hydroxysteroid dehydrogenase type ( βhsd ), which converts the inactive cortisone to the active cortisol in different cell types, as for example occurs after addition of tnf-α or il- β on endothelial ( ) or lung epithelial cells ( ) . thus, cytokines seem to amplify gc bioavailability ( ) . microarray studies have shown that tnf-α and gc synergistically co-regulate genes involved in inflammation figure | glucocorticoid receptorα as cellular rheostat of homeostatic corrections. the glucocorticoid receptorα (grα) acts as a cellular rheostat to ensure that a proper response is elicited by the neuroendocrine immune system throughout the three phases of homeostatic corrections: the pro-inflammatory (ready-reinforce), the anti-inflammatory (repress), and the resolution (resolve-restore) phase. modified with permission from busillo and cidlowski ( ) . tlr , toll-like receptor ; purinergic receptor p y r; nlrp , nod-like receptor pyrin containing ; apr, acute phase response; tf, transcription factor; nf-κb, nuclear factor-κb; ap- , activator protein ; anxa , annexina ; alxr, anxa receptor; gilz, glucocorticoid-induced leucine zipper; tgfβ, transforming growth factor β. ( ) . in this context, the synergy between gcs and proinflammatory cytokines is a useful mechanism for rapidly reenforcing initial pro-inflammatory responses. importantly, gc-grα is necessary to prevent excessive phagocytic cell activation and improve intracellular bacterial killing ( ) . in the second phase, when regulated systemic inflammation prevails, gc-grα exerts classic anti-inflammatory action by (i) inhibiting nf-κb, ap- and other signaling pathways involved in inflammation, and (ii) increasing transcription of anti-inflammatory genes and the nf-κb inhibitory protein iκb ( , ) . gc-grα anti-inflammatory action has been extensively investigated, and we direct the reader to excellent reviews on the ( , , , ( ) ( ) ( ) . in upcoming sections, we will review selected mechanisms involved in gc-grα failure to downregulate systemic inflammation and achieve disease resolution. the third phase involving disease resolution, i.e., restoration of tissue anatomy/structure and function, is an active and elegantly orchestrated process associated with multiple biochemical pathways, including switching production from pro-inflammatory to pro-resolving mediators ( ) . as downregulation of systemic and tissue inflammation continues, the activated gc-grα engages in a host of pro-resolution mechanisms changing, among others, the phenotype of both granulocytes and macrophages. in these immune cells, via genomic mechanisms, gc-grα increases the expression of annexina (anxa ), anxa receptor (alxr), and glucocorticoid-induced leucine zipper (gilz), while via non-genomic mechanisms it increases the secretion of anxa ( ) ( ) ( ) . the coordinated action of gilz and anxa is essential to regulating resolution ( ) . granulocytes undergo constitutive apoptosis, disabling their potentially injurious secretion responses, i.e., nf-κb activation and transcription of inflammatory cytokines, and decreasing trans-endothelial migration leading to their rapid recognition and internalization by macrophages (efferocytosis) ( ) ( ) ( ) ( ) . apoptotic cells also serve as resolution cues for macrophages, which, after phagocytosis of apoptotic granulocytes, change their phenotype toward a more resolving/restorative one. the changes in phenotype from m (classically) to m (alternatively) leads to an orchestrated series of actions leading to successful resolution of inflammation. interestingly, gcs promote phagocytosis ( , ) and reduce the apoptotic granulocyte ingestion requirements for generation of m ( ) . gc-mediated change to m phenotype is associated with (i) immune silencing, where the release of inflammatory mediators and inducible nitric oxide synthase (inos) are suppressed ( ) ; (ii) an increased release of the anti-inflammatory mediators il- and tgfβ and several pro-resolving lipid mediators ( ); (iii) protection from apoptosis; (iv) non-phlogistic degradation; (v) production of angiogenic growth factors; (vi) increased macrophage chemokinesis (by upregulation of genes involved in cell mobility) and lymphatic clearance; and (vii) induction of acquired immunity ( , , ( ) ( ) ( ) ( ) ( ) . gc-mediated annexin -derived peptide (ac −− ) acting through the alxr receptor has a pivotal role in the clearance of apoptotic cells ( ) . in models of self-resolving inflammation, various phenotypes of macrophages may coexist. in the later phase of resolution, m macrophages switch to the resolution-promoting macrophage (mres) phenotype, which display reduced phagocytosis, while producing antifibrotic and antioxidant proteins that limit tissue damage and fibrosis (resolution of granulation tissue) ( ) . in human monocytes, gcs induce the expression of genes with upregulation of anti-oxidation, migration, phagocytosis, and anti-inflammation with consequent downregulation of adhesion, apoptosis, and oxidation ( ) . in agreement with microarray data, spontaneous, as well as pma-induced production of reactive oxygen species, was significantly reduced in gc-treated cells, and gcs promoted survival of an anti-inflammatory monocytic phenotype in inflammatory reactions ( ) . since grα ultimately controls gc-mediated activity, any condition that affects its concentration, binding affinity, transport to the nucleus, interactions with gres (nuclear and mitochondrial), cofactor activity (see section hypovitaminoses), or interaction of other relevant transcription factors (nf-κb, ap- ) and co-regulators, can eventually affect the response of cells to glucocorticoids ( , ) . the many different ways grα function can be negatively influenced by the pro-inflammatory environment of critical illness was the subject of recent reviews ( , ) . critical illness-related corticosteroid insufficiency is a term used to define the central role played by the hpa-axis and the activated grα complex in the pathogenesis of dysregulated systemic inflammation in critical illness ( ) . three major pathophysiologic events account for the neuroendocrine decompensation observed in circi: (i) multi-level dysregulation of the hpa-axis correlating with circulating inflammatory cytokine levels; (ii) altered cortisol metabolism [reviewed in ( ) ], and (iii) secondary generalized circulating and tissue specific reduction in grα number/function with observed multifactorial tissue resistance to endogenous glucocorticoids ( ) . the role of mitochondrial oxidative stress in reducing grα number/function is reviewed later (see section oxidative stress and circi). experimental and clinical studies have demonstrated that critical illness is associated with a significant reduction in grα density and transcription and an increase in grβ-mediated dominant negative activity on grα-induced transcription. in a human cell line, activation of nf-κb by tnf-α had a direct doseand time-dependent effect on gr levels with a disproportionate increase in grβ over grα ( ) . experimental sepsis is associated with decreased grα transcription in circulating cells ( ) , heart ( ), lymph node-spleen ( ), liver ( ) ( ) ( ) , kidney ( ) , lung tissue ( ) ( ) ( ) ( ) ( ) , and skeletal muscle ( ) . moreover, the endothelial grα is required for protection against sepsis (see section endothelium) ( ) . importantly, the reduction of grα expression is rapid and persists for at least days ( ) while it is associated with increased grβ expression in the heart and lung but not liver ( ) , and increased nf-κb activation ( ) . similarly, in experimental ards, lung tissue shows a significant reduction in grα expression ( , , ) and an increase in grβ expression ( ) , leading to decreased grα nuclear translocation ( ) . in transgenic mice, expression of grα above wild-type levels leads to increased resistance to lps-induced endotoxic shock ( ) . clinical studies, including autopsies, in patients with severe sepsis and septic shock have reported a significant reduction in grα expression in circulating cells ( , ( ) ( ) ( ) ( ) ; heart ( ), liver and skeletal muscle ( , ) , and a significant increase in grβ expression in the heart and liver ( ) . grα mrna in neutrophils correlates negatively with plasma il- levels and shows gradual recovery overtime in survivors ( ) . in another study, neutrophil grα mrna levels decreased fold by day in the icu and remained low for weeks ( ). in ex vivo experiments with pbmcs exposed to longitudinal plasma samples from patients with ards results suggested that insufficient gc-grα-mediated activity at disease onset and over time was a central mechanism for the upregulation of nf-κb activity (figure ) . over time, patients with regulated systemic inflammation have a progressive increase in all measured gc-grα-mediated activities, including grα number, binding to nf-κb and to nuclear gre, as well as increased transcription of iκbα and il- , and a corresponding reduction in nf-κb nuclear binding, and transcription of tnf-α and il- β. in contrast, patients with dysregulated systemic inflammation had only a modest longitudinal increase in gc-grα-mediated activities and a progressive increase in nf-κb nuclear binding that was most striking in non-survivors ( ) . by day of ards, no overlap was observed between groups for nf-κb and gc-grα nuclear binding. in lung tissue obtained by open lung biopsy, histological severity correlated with increased nuclear uptake of nf-κb and a lower ratio of grα: nf-kb uptake ( ) . a decrease in grα expression in critical illness is maladaptive granted that proinflammatory pathways are not properly restrained ( ) . randomized studies ( , , ) demonstrated in both circulating and tissue cells, that quantitatively adequate and prolonged glucocorticoid supplementation increased grα number and function, reversing critical illness-associated cellular glucocorticoid resistance. in experimental ards, low-dose glucocorticoid treatment restored grα number and function leading to resolution of pulmonary inflammation ( , ) . similarly, in an ex vivo ards study, prolonged methylprednisolone treatment was associated with upregulation in all measurements of grα activity leading to reduction in nf-κb dna-binding and transcription of inflammatory cytokines [ figure ; ( ) ]. glucocorticoid treatment changes the longitudinal direction of systemic inflammation from dysregulated (nf-κb-driven, maladaptive response) to regulated (grα-driven, adaptive response) with significant improvement in indices of alveolar-capillary membrane permeability and markers of inflammation, hemostasis, and tissue repair ( ) . the vascular endothelium constitutes the innermost lining of the body's circulatory system and the largest tissue in the body figure | correlation between mean levels of nuclear nf-κb and nuclear gc-grα during the natural progression of ards, and in response to prolonged glucocorticoid treatment. mean intracellular changes of nuclear gc-activated grα and nf-κb observed by exposing pbls of a healthy volunteer to plasma samples collected longitudinally (days , , , and ) and after randomization to methylprednisolone treatment [randomization day (r) and post-randomization days , , , and ]. the mean values of nuclear nf-κb are plotted against the mean nuclear gc-grα levels. improvers had a pre-defined improvement in lung injury score ( ) and/or gas exchange component by day . the left panel shows ards patients with adaptive and maladaptive responses. in improvers, an inverse relation was observed between these two transcription factors, with the longitudinal direction of the interaction shifting to the left (decreased nf-κb) and upward (increased gc-grα). in contrast, in non-improvers nf-κb increased over time while gc-grα had no significant changes. we define the first interaction as gc-grα-driven, and the second interaction as nf-κb-driven ( ) . the right panel shows non-improvers-survivors randomized after day of ards to methylprednisolone (n = ) vs. placebo (n = ). after natural logarithmic transformation and adjustment for repeated measurements, partial correlations among responses to plasma from the methylprednisolone group were − . (p < . ) both for nuclear nf-κb and nuclear grα. for responses to plasma from the placebo group, no significant relation was found between nuclear nf-κb and nuclear grα (r = . ; p = . ) ( ). reproduced with permission from meduri et al. ( ) . (close to , miles long) containing ∼ . × endothelial cells that are typically flat and susceptible to injury, with a thin basement membrane enriched in type iv collagen and laminin ( ) . the endothelial lining is in continuous contact with circulating cells and soluble proteins, and the capillaries, represent the primary barrier between elements in the blood and the parenchymal cells. the space between two contiguous endothelial cells, known as the endothelial cleft (etc), acts as an important site of regulation of endothelial (paracellular) permeability ( ) . importantly, the vascular endothelium (micro-and macro-circulation) is clothed with a protective barrier, the glycocalyx, which is critical to maintain endothelial homeostasis. the endothelial glycocalyx is a negatively charged, organized mesh of membranous glycoproteins and plasma proteins that include superoxide dismutase, antithrombin iii, and cell adhesion molecules, all involved in maintaining the oncotic gradient across the endothelial barrier ( ) . the intact glycocalyx protects endothelial cells from oxidative stress and prevents the interaction between circulating leukocytes and endothelial adhesion molecules ( ) . conformational changes in glycocalyx structure lead to short bursts in the release of endothelial nitric oxide (eno) ( ), inhibiting vascular smooth muscle contraction, platelet aggregation, and leukocyte adhesion, all three processes essential for patency of microcirculation. the blood-brain barrier (bbb), composed of highly specialized endothelial cells with tight junctions that seal paracellular spaces to restrict permeability, serves as a highly restrictive interface between the systemic circulatory system and the brain ( ). damage to the glycocalyx precedes vascular pathology. endothelial activation with ubiquitous shedding of the glycocalyx is a major component of critical illnesses and a key pathogenic mechanism in multiple organ dysfunction. the pathways by which sepsis induces injury to the endothelium were recently reviewed ( ) . the "vasculo-centric view" of critical illness derives from the observation that, despite the remarkable heterogeneity of diseases, the pathobiology of multiple organ dysfunction shares near-stereotypical features that are mostly related to widespread endothelial dysfunction ( ) . endothelial dysfunction manifests with a diffuse increase in paracellular permeability, expression of luminal cell adhesion molecules, recruitment of activate leukocytes, altered vasomotor tone, and microvascular thrombosis with decreased capillary density ( ) . increasing evidence points to endothelial dysfunction with impairment of the bbb as a critical component of the pathobiology of delirium during critical illness ( ) . oxidative stress (see section mitochondrial cacostatic load, oxidative stress, and mitochondrial damage) impairs endothelial function by interfering with eno synthesis ( ) and by participating in the degradation of the glycocalyx ( ) . after shedding of the glycocalyx, adhesion molecules are released in the blood and can be found in the circulation ( ) . microvascular alterations, such as decreased functional capillary density and increased perfusion heterogeneity, are frequently observed in patients with sepsis and contribute to the defect in oxygen extraction by the peripheral organs and tissues of the organism ( ) . endothelial activation may also affect the hpa-axis. the adrenal gland is a highly vascularized organ, with every steroidogenic cell in close vicinity with at least one sinusoid, and a clear positive relation between adrenal blood flow and steroidogenesis has been demonstrated ( ) . in critical illness, disruption of endothelial homeostasis within the adrenal gland can contribute to the hpa-axis dysfunction ( ) . hypovitaminosis may also contribute to endothelial dysfunction (see section hypovitaminoses). in studies of circulating inflammatory cytokines, there is substantial evidence that in critically ill patients, an increase in circulating markers of endothelial integrity (angiopoietin- ; angpt- ) ( ), dysfunction [angiopoietin- (angpt- ), von willebrand factor (vvf) ( ) , soluble intercellular adhesion molecule- (sicam- ), ( ) vascular endothelial growth factor (vegf)] ( , ) , and cell damage associated with circulating endothelial cells ( , ) correlate with disease severity and mortality. fittingly, a large study acquiring sublingual measurements of microcirculation in early sepsis, found that mortality strongly correlated with the severity of alterations in the proportion of perfused small vessels, i.e., the functional capillary density ( ) . the endothelial grα is a critical regulator of vascular homeostatic corrections and essential for decreasing the rolling on and adhesion of activated neutrophils to the endothelium ( ) . in experimental sepsis, elimination of the endothelial grα resulted in prolonged activation of endothelial nf-κb, with increased expression of inos and inflammatory cytokines, both accounting for hemodynamic collapse and mortality ( ) . importantly, the presence of the endothelial gr itself was necessary for gc-mediated suppression of nf-κb and for achieving survival ( ) . grα also regulates the tightness of the bbb, inducing expression of the tight junction proteins occludin and claudin- , and the adherens junction protein vascular endothelium cadherin (ve-cadherin) ( ) . gc-grα is also strongly involved in vascular development ( ) . experimental studies have shown gr-dependent upregulation of multiple mediators involved in endothelial cell homeostasis, such as sphingosine kinase (sphk ) ( ), angiopoietin- (angpt- ) ( ), serum glucocorticoid kinase- (sgk- ) ( , ) , gilz ( ) , and enos ( ) ( ) ( ) . in experimental ards, upregulation of sphk , an important regulator of endothelial barrier integrity, was shown to improve alveolo-capillary membrane (acm) permeability ( ) . in human brain microvascular endothelial cells (hbmecs), gc treatment was associated with transcriptional activation of angpt- and suppression of vegf ( ) . in umbilical vein endothelial cells (huvecs), upregulation of sgk- reduced oxidative stress and improved cell survival and senescence ( ) ; meanwhile, gr-induced gilz expression (see section glucocorticoid receptor-alpha and homeostatic corrections) correlated negatively with vascular inflammation ( ) . in neuro-vascular tissue, physiological doses of hydrocortisone rapidly activated enos via non-genomic mechanisms ( , ) . grα is also a critical regulator of myocardial function. in experimental work, the gr-via kruppel-like factor -was found to play a direct role in the regulation of cardiomyocyte function and protection from hypoxia and dna damage ( ) . gr inhibits cells death triggered by ischemia reperfusion, mechanical stress, or tnfα [reviewed in ( ) ]. the endothelial response to gcs in inflammatory diseases was extensively reviewed covering topics such as inhibition of proinflammatory transcription factors, restoration of endothelial barrier integrity, and induction of protective molecules ( ) . in experimental sepsis, low-dose glucocorticoid (hydrocortisone or dexamethasone) preserved the endothelial glycocalyx, sustained the vascular barrier and reduced interstitial edema ( , ) , and had beneficial effects on mesenteric blood flow and helped with resolution of organ injury ( ) . gcs play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoconstrictive responses to catecholamines and other hormones, such as argininevasopressin, through glucocorticoid receptors ( ) . finally, they inhibit the expression of inducible nitric oxide synthase and other vasodilatory agents in vascular endothelial cells ( ) . additional experimental studies have shown that gr stimulates transcription of the zonula occludens (zo)- tight junction protein, leading to reduced bbb paracellular permeability ( ), while it activates enos increasing cerebral blood flow ( ) . in patients with septic shock ( , ) or ards ( , ) , prolonged glucocorticoid (hydrocortisone or methylprednisolone) treatment resulted in the following: (i) increased plasma activated protein c levels ( ); (ii) reduction in markers of endothelial injury such as sicam- ( ); (iii) rapid and consistent improvement in capillary perfusion, independently of the cortisol response to acth ( ) ; and (iv) improvement in alveolar-capillary ( ) and renal ( ) endothelial permeability. in addition, septic shock is associated with vascular dysfunction through nf-κb-mediated downregulation of the endothelial mineralocorticoid receptor (mr) and α -adrenoceptor, which can be restored with mineralocorticoid (fludrocortisone) treatment ( ) . a transforming event in the history of life was the evolution of photosynthetic bacteria, with biochemical pathways that allowed them to capture energy from sunlight and store it in simple sugars, a process known as photosynthesis that generates oxygen as a waste product. as a result, over the course of about one billion years, the earth's atmospheric oxygen increased from almost zero to nearly modern levels ( ) . the development of an ozone layer in the upper atmosphere to absorb damaging uv radiation from the sun, a derived outcome of increased atmospheric oxygen, permitted organisms to live on land for the first time ( ) . some groups of organisms adapted to increased oxygen levels; the most notable adaptation was the evolution of the biochemical pathways of cellular respiration, which use oxygen to extract the energy stored in organic molecules much more efficiently. about billion years ago, complex life surfaced with two major endosymbiotic (eukaryotic cells ingesting a prokaryote bacterium that resulted in a symbiotic relationship between the engulfing and engulfed cells) events igniting the evolutionary progression to animals and plants ( , ) . first, the ancestral eukaryotic cell engulfed an aerobic prokaryote bacterium (i.e., capable of using oxygen to produce energy) that eventually evolved into mitochondria (specialized for cellular respiration) populating the cell cytoplasm (modern heterotrophic eukaryote) to afford a selective advantage for survival ( ) . in the second endosymbiotic event, the early eukaryotic cell engulfed a photosynthetic prokaryote bacterium that evolved into the chloroplast (modern photosynthetic eukaryote). central to the integrated actions of immune and neuroendocrine responses ( , , ) is cellular energetics, involving the mobilization of energy resources from gc-grαmediated breakdown of glucose (via glycolysis), fatty acids and amino acids for mitochondrial energy production ( ) . in fact, gcs were originally named by hans selye based on their ability to increase blood glucose concentration. activation of the hpa axis mobilizes these energetic substrates into the circulation within minutes, underscoring the widespread role of gc-grα in the regulation of systemic metabolism ( ) . mammalian cells, apart from erythrocytes, contain within their cytoplasm hundreds to thousands of mitochondria, the number determined by the energy demand of each cell type. mitochondria are autonomous and highly dynamic doublemembrane organelles that function as the powerhouses of the cell and utilize ∼ % of total body oxygen consumption. oxidative phosphorylation (oxphos) is the metabolic pathway in the inner membrane of the mitochondria which use enzymes to oxidize ingested calories to produce adenosine triphosphate (atp) required for normal cell functioning. ultimately, this conversion provides energy for most cellular processes within the body intracellular reactions (gene transcription and translation, epigenetic modifications), hormonal changes in the endocrine system, structural changes in tissue, and behavioral and cognitive responses] ( ) , and in theory, determines the limits of an organism adaptive capacity ( ) . by virtue of their origins as aerobic bacteria, mitochondria have their dna, rna, and protein synthesis systems. the mitochondrial dna (mtdna) in our proto-eukaryotic ancestors was significantly larger in genetic complement, but transfer of mtdna encoded genes to the nucleus has occurred over the . - billion years since the origin of the eukaryotic cell, and today the mammalian mtdna (inherited from the mother) encodes polypeptides, two rrnas ( s and s) and trnas that are essential for oxphos and proper cell function ( ) . since the mtdna encodes for only a handful of proteins, mitochondria depend on the cell nucleus and other cellular compartments for most of their proteins and lipids ( ) . in addition to being the major source of intracellular atp, mitochondria are deeply involved in signaling pathways, elicited by perturbations in homeostasis, which promote cell adaptation ( , ) . mitochondria constantly generate reactive oxygen species (ros) as a by-product of substrate oxidation and oxidative phosphorylation, a physiological process that is normally kept in check by a diversified set of antioxidant defenses ( ) . the introduction of oxygen to earth's early biosphere stimulated remarkable evolutionary adaptations, and in this context, ros should be viewed as an essential consequence and driver of evolution and survival over time ( ) . reactive oxygen species are required in numerous physiological cell functions, such as cellular signaling systems linked to the transcriptional machinery, maintenance of vascular tone, oxygen sensing, and host defense against pathogens ( ) . one of the mitochondrial oxidases, the nadph oxidase of polymorphonuclear leukocytes (primarily neutrophils), is pivotal to the body's defense against pathogenic microorganisms ( ) . mitochondria are involved in a multitude of cellular processes, well-beyond their long-established role as the cell's powerhouse. these include processes such as intracellular calcium homeostasis (buffering of cytosolic calcium), regulation of mitochondrial metabolism, cell migration, production of biomolecules such as amino acids, lipids, hemes, purines, and steroid hormones (see section mitochondria and hpa-axis cross-talk), and activation of cell death pathways ( ) . mitochondria trigger cell death pathways by two mechanisms, first via necrosis when atp levels fall below a certain threshold, and second via apoptosis through the release of mitochondrial cytochrome c into the cytoplasm ( ) . mitochondrial integrity is, therefore, essential for the function and survival of cells, and several recent publications have highlighted the critical role played by these organelles in sustaining homeostatic corrections ( , ( ) ( ) ( ) ( ) ( ) ( ) . in critical illness, tissue oxygen consumption and total energy expenditure are increased, with intracellular metabolism boosted by up to % compared to the healthy state ( ) . cells that represent the innate immune system, like neutrophils, and macrophages, are mainly responsible for the oxidative burst that takes place early in critical illness ( ) along with the generation of ros and nitrogen oxygen species (rns) that are important for host defenses. in neutrophils of critically ill patients, oxidative activity correlates positively with the degree of intranuclear nf-κb expression ( ) . according to the "mitohormesis theory, " when present in moderate amounts, ros and rns function as intracellular signaling molecules that may improve systemic defense mechanisms by inducing an adaptive response ( ) . however, when intracellular ros and rns concentrations overwhelm antioxidant defenses, cell homeostasis becomes compromised ( ) . for example, peroxidation of the mitochondrial lipid cardiolipin in the inner mitochondrial membrane leads to dissociation of cytochrome c, reduced production of atp, and increased generation of ros ( ) . increased energy and metabolic demands associated with nf-κb-driven dysregulated systemic inflammation, leads to overproduction of ros and rns, resulting in significant damage of lipids, proteins, and nucleic acids, both within the mitochondria and in other compartments of the cell [ figure ; ( ) ]. oxidative stress is a predictor of mortality in septic shock patients ( ) . glutathione is one of the most important redox buffers of the cells, as it can be found in all cell compartments and acts as a cofactor of several enzymes, helps in dna repair, scavenges ros (e.g., hydroxyl radicals, hydrogen peroxide, and lipid peroxides), and generates other antioxidants, such as ascorbic acid (see section hypovitaminoses) and tocopherols ( ) . vitamins d and c upregulate glutathione synthesis and prevent depletion (see section hypovitaminoses) ( , ) . the multi-level organization of mitochondrial molecular composition, structures, functions, and signaling roles within the cell was recently reviewed ( ) . in laboratory models of sepsis, mitochondrial respiration is often increased in the early phase of illness, but consistently falls with protracted inflammation [reviewed in ( ) ]. many clinical studies implicate mitochondrial dysfunction and bioenergetic failure as an important pathophysiological mechanism underlying dysregulated systemic inflammation-associated multiorgan dysfunction. in a study of skeletal muscle biopsies obtained in septic patients, an association was first reported between nitric oxide overproduction, antioxidant depletion, mitochondrial dysfunction, and decreased atp concentrations, with progression of multiorgan failure and mortality ( ) . human septic cardiomyopathy is accompanied by widespread downregulation of cardiac mitochondrial genes and decrease in the expression of genes that govern cardiac myocyte contractility, analogous to the transcriptional reprogramming that occurs in myocardial hibernation ( ). early sepsis is associated with a reduction in pbmc mitochondrial copy number, and a rise in markers of mitochondrial damage, in a linear relation to proinflammatory cytokine expression ( ) . the pbmcs of patients with severe vs. less severe pneumonia have increased ros density, increased dna damage, and decreased superoxide dismutase (sod) concentrations ( ) . loss of mitochondrial function may lead to compensatory secondary metabolism, glycolysis, to produce atp as well as lactate ( ) . a epithelial cell line study demonstrated that this glycolytic switch is promoted by the activation of the redox sensitive phosphoinositide -kinase (pi k) pathway and subsequent inactivation of glycogen synthase kinase- β (gsk- β) resulting in increased production of inflammatory cytokines and reduced sensitivity to glucocorticoids ( ) . decades of laboratory and clinical studies have revealed that dysregulated systemic inflammation, including sepsis, is associated with significant macromolecular damage to mitochondria, particularly in the cells of highly metabolically active tissues, such as the liver, heart, kidneys, brain, and skeletal muscles ( , ) . in contrast to nuclear dna, which is nonimmunogenic, mitochondrial dna resembles bacterial dna (see section cellular energetics-mitochondrial function) and acts as a damage-associated molecular pathogen (damp) to activate immune responses through toll-like receptor -mediated activation of nf-κb ( ) and the nlrp inflammasome ( ) . also, in comparison to nuclear dna, mtdna is -fold more sensitive to oxidative stress ( ) , as its close proximity to the electron transport chain and the absence of chromatin proteins makes it an easy target for oxidative damage ( ) . as a consequence of increased ros generation, mtdna can undergo several qualitative and/or quantitative alterations. recent studies have found that critically ill patients have decreased cellular mtdna levels and increased circulating cellfree mtdna levels ( , , ) . in septic patients, mtdna depletion in circulating cells (mainly neutrophils) correlates with severity of illness (apache ii scores) ( ), while high tnf-α expression in neutrophil lysates correlates with increased plasma mtdna levels ( ) . the exact mechanism of mtdna delivery into the cytoplasm and then into the systemic circulation is currently unknown ( ) . in icu patients with sepsis and ards, elevated plasma mtdna levels (> , copies/µl) are associated with dysregulation of phospholipid metabolism ( ) , and increased mortality ( ) . the cycle of mtdna damage with loss of function of electron transport enzymes (atp depletion) and increased ros generation, a state in which the antioxidant systems are overwhelmed may eventually lead to cell death, a phenomenon known as the "toxic oxidative stress" ( ) . in critical illness, impaired cell energy metabolism and mitochondrial damage augment systemic inflammation directly via nf-κb activation and indirectly by multi-level impairment of the hpa axis and gr homeostatic functions (see section oxidative stress and circi). effective homeostatic corrections in the adaptive response during the resolution of critical illness are associated with increased mitochondrial biogenesis, restoration of oxidative metabolism, and mitochondrial content ( ) . in many studies, restoration of mitochondrial homeostatic functions was observed in association with improved organ recovery and survival [reviewed in ( ) ]. the association between mitochondrial dysfunction, circulating cell-free mtdna, muscle wasting, sterile inflammation, and inflamm-aging was recently reviewed ( ) . micronutrient deficiencies may also impair mitochondrial function. in septic patients, the marked early reduction in selenium levels may affect selenium-dependent anti-oxidants glutathione peroxidase and thioredoxin ( ) . the role of hypovitaminoses on mitochondrial function is reviewed in section hypovitaminoses. abundant mitochondria are one of the most prominent ultrastructural features of the adrenocortical cells ( ) in which intracellular steroidogenic cholesterol is ultimately converted to cortisol in a tightly controlled manner ( ) . the central role of mitochondria in essential physiological processes has rendered these organelles a receiver and integrator hub of multiple regulatory signals ( ) . mitochondria participate in the stress response, in part, by sensing levels of glucocorticoids ( ) . it is now accepted that mitochondria are under gc control because grs are present in mitochondria, and gres reside in the mitochondrial genome ( , ) . a number of studies in several tissues have observed a cytoplasmic-to-mitochondrion gr translocation or vice versa in response to gc, indicating that mitochondrial gr is dynamically regulated upon exposure to gcs ( ). lee and collaborators have classified five pathways in the functional modulation of the mitochondria by gc-gr ( ) . in addition to direct mitochondrial gr-mtgre interactions, mitochondrial gene expression is regulated indirectly by nuclear gr-nugre interactions that result in increased transcription of the following: (i) genes encoding oxphos and other mitochondrial regulatory functions, (ii) transcription factors for control of nudna-encoded mitochondrial proteins, and (iii) several antioxidant mechanisms including uncoupling protein- (ucp ) ( , , , , , ) . of interest, mitochondrial thioredoxin, an antioxidant and anti-apoptotic factor essential for cell viability and vascular homeostasis ( ) , interacts directly with both the ligand and the dna-binding domains of gr, keeping the receptor in a reduced, transcriptionally active form ( , ) . studies have shown that fine-tuning of the response to cellular demands is coordinately regulated by the nucleus and mitochondria, making mitochondrial-nuclear interaction vital to optimal mitochondrial function ( ), with gc-grmediated increased mtdna gene expression augmenting the total number of mitochondria per cell, and, thus, total cellular energy production capacity ( ). altogether, there is substantial evidence that cross-talk between neuroendocrine control of the stress response and cellular antioxidant systems is essential for mammalian homeostatic regulation ( ) . consistent with the cacostatic load model ( ) , administration of physiological doses of gcs acutely increases mitochondrial membrane potential, calcium buffering capacity, anti-oxidant capacity, and resistance to apoptotic signaling ( ) , whereas chronic exposure to high doses of gcs suppresses anti-oxidant capacity, decreases mitochondrial membrane potential, and sensitizes cells to apoptosis ( , , ) . oxidative stress is accompanied by multi-level impairment of the hpa axis and gr homeostatic functions (figure ) . in non-survivors of septic shock, marked overexpression of inos in hypothalamic parvocellular neurons (pvn) was associated with decreased expression of pituitary acth, suggesting that the pro-apoptotic action of inos in the pvn may partially account for reduced activity of the hpa axis in sustained septic shock ( , ) . in experimental sepsis, adrenal cellular extracts demonstrate a pronounced increase in mrna for inos and inflammatory cytokines that correlate positively with the degree of neutrophil infiltration, adrenal cell apoptosis, and mortality ( ) . changes within the adrenal gland microenvironment may also affect the hpa axis response in critical illness ( ) , with mitochondrial damage leading to a decreased responsiveness to acth ( ) . importantly, inos expression in adrenal cells diverges at h, with a significant increase observed in nonsurvivors vs. a reduction in survivors ( ) . in experimental endotoxemia, nf-κb-mediated inos release is associated with mitochondrial oxidative stress in adrenocortical cells with inhibition of steroidogenesis and response to acth ( ) . oxidative stress has a direct deleterious impact on grs number and function. experimental studies involving tissue cultures ( , ( ) ( ) ( ) and murine models ( , ) have demonstrated that oxidative stress is associated with decreased: (i) gr number ( ) , (ii) gc binding to gr ( , ( ) ( ) ( ) ( ) , (iii) gc-gr nuclear translocation ( , ) , (iv) binding to dna ( ) , and (v) inducible gene transcription ( , ) . nitrosylation, the covalent incorporation of a nitric oxide "nitrosyl" moiety into the critical cysteine(s) residue(s) of the gr is associated with loss of the steroid binding capacity ( ) . in human monocytes, genes involved in oxidative functions were significantly overrepresented among gc down-regulated genes, while genes with antioxidant functions were upregulated ( ) . a few studies have evaluated the impact of gc treatment on oxidative stress. in human monocytes, spontaneous, as well as phorbol myristyl acetate (pma)-induced production of reactive oxygen species, is significantly reduced in gc-treated cells in comparison to controls ( ) . in murine macrophages, glucocorticoid treatment is associated with rapid (non-genomic) inhibition of superoxide anion production ( ) . in murine sepsis, gc treatment attenuated renal dysfunction by reducing mitochondrial injury with preservation of cytochrome c oxidase and suppression of pro-apoptotic protein levels ( ) . in clinical ( , ) and experimental ( , ) randomized trials, participants with severe sepsis receiving gc treatment had, in comparison to controls, a significant reduction in (i) circulating nitric oxide levels ( , , ) , and (ii) spontaneous release of hydrogen peroxide (h o ) by neutrophils ( ) . metabolic homeostasis is substantially disrupted in critical illness, and the degree of a vitamin deficiency can negatively impact health outcomes. three vitamins, namely thiamine (vitamin b ), ascorbic acid (vitamin c), and vitamin d, are important for the proper function of the gr system and mitochondria, and their reserves are rapidly exhausted in critical illness ( ) . vitamins b , c, and d impact mitochondrial function, while vitamins c and d also impact gr function. a comprehensive list of suggested mechanisms for the efficacy of thiamine, ascorbic acid, and glucocorticoids in sepsis was recently reviewed ( ) . thiamine is a water-soluble vitamin, which is passively absorbed in the small intestine. after ingestion, free thiamine is converted to the active form thiamine pyrophosphate (tpp), commonly known as vitamin b , by thiamine pyrophosphokinase. the majority of tpp in the body is found in erythrocytes and accounts for ∼ % of the body's total storage ( ) . thiamine pyrophosphate is a key co-factor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, transketolase, and branchedchain keto-acid dehydrogenase ( ) . pyruvate dehydrogenase is the gatekeeper for entry into the krebs cycle, without which pyruvate would be converted to lactate as opposed to acetylcoenzyme a. alpha-ketoglutarate dehydrogenase is required for completion of the krebs cycle once it has begun. transketolase is a key enzyme for the pentose phosphate pathway and for the production of nadph with glutathione cycling, an important anti-oxidant pathway ( ) . there are also other proposed non-cofactor roles of thiamine within the immune system, gene regulation, oxidative stress response, cholinergic activity, chloride channel function, and neurotransmission ( ) . the human adult can store around mg of thiamine in muscle tissue, liver and kidneys, however, these stores can become depleted in as little as days after the cessation of thiamine intake ( ) . a thiamine deficiency syndrome, beriberi, bears a number of similarities to sepsis, including peripheral vasodilation, cardiac dysfunction, and elevated lactate levels ( ) . in critical illness, the prevalence of thiamine deficiency is - % upon admission ( , ) and can increase up to % during icu stay, suggesting rapid depletion of this vitamin ( ) . based on limited data, no association was detected between thiamine levels, markers of oxidative stress ( ) and mortality ( , ) . in one study, a significant negative correlation was reported between thiamine and lactic acid levels in patients with sepsis without liver dysfunction ( ) . in a pilot randomized controlled trial (rct) of patients with septic shock (n = ), the administration of thiamine ( mg twice a day for days) reduced lactate levels and improved mortality over time in a predefined subgroup of patients with thiamine deficiency ( % of cohort) ( ) . in a retrospective, single-center, matched cohort study, administration of thiamine within h of septic shock (n = ) was associated with improved likelihood of lactate clearance and a reduction in -day mortality ( ) . despite some promising results, there is insufficient evidence to support or reject thiamine supplementation as a monotherapy in critically ill patients ( ) . vitamin d is an ancient molecule that functions as both a nutrient and a hormone with metabolic and immunomodulatory properties; it regulates over , genes of the human genome ( , ) . the vitamin d receptor (vdr) is a member of the nuclear receptor gene family and is expressed in virtually all nucleated cells. decreased serum levels of vitamin d have been associated with several autoimmune inflammatory diseases. genome-and transcriptome-wide studies indicate that vitamin d signaling modulates many inflammatory responses on several levels ( ) , including interference with nf-κb, via upregulation of iκb expression ( ) . in addition, the ability of vitamin d to inhibit metabolic stress and energy expenditure in a cell microenvironment suggests that this pleiotropic hormone has a broad task as a pro-survival agent ( ) . a growing body of scientific and medical literature supports the important anti-inflammatory functions of vitamin d in health and disease, including the enhancement of gc-mediated anti-inflammatory actions ( ) . the anti-inflammatory effect of vitamin d was consistently observed in studies of cell lines and human pbmcs, and was the subject of a comprehensive review ( ) . pbmcs activated with tlr ligands after incubation with , (oh)d showed decreased release of tnf-α and il- β and increased anti-bacterial activity ( ) . in pbmcs, physiologic levels of vitamin d reduce inflammatory activities, by upregulating gc-mediated mitogen activated protein kinase (mapk; see section glucocorticoid receptor-alpha) phosphatase- (mkp- ) ( ) to down-regulate p mapkmediated inflammatory gene expression (including tnf-α, il- β, il- , and il- ) ( ) . in lps-activated pbmcs ( ) and pbmcs from patients with asthma ( ), vitamin d enhanced dexamethasone-induced expression of mkp- ( ) , and this synergism was dependent on vitamin d-induced gm-csf release ( ) . one study suggested that the interaction between vitamin d, glucocorticoids and their cognate receptors is related to the duration of exposure to vitamin d ( ) . beside this indirect modulation of signaling cascades, vitamin d and its receptor complex vdr/rxr can interact directly with the gc receptor and other transcription factors ( ) . of interest, vitamin d has a high affinity binding for the gr ( ) , and was recently shown to increase, in a dosedependent manner, gr concentration in t cells ( ) . based on its pleiotropic functions, vitamin d is considered a "master tuner" in shifting homeostatic balance from a pro-inflammatory to a pro-resolving status ( ) . several studies demonstrated a dose-dependent response of vitamin d with respect to reducing inflammation, with nm and nm concentrations causing the greatest effects ( ) . one study showed that serum (oh)d levels as high as nmol/l may be necessary for optimal immune function ( ) . a small study in healthy patients with hypovitaminosis d reported that significant antiinflammatory benefits of vitamin d supplementation were only seen by achieving serum (oh)d levels greater than nmol/l ( ) . the mitochondria also appear to be a direct target of the vitamin d endocrine system, and the two most important enzymes responsible for activation or inactivation of (oh)d, namely cyp b ( α-hydroxylase) and cyp a ( -hydroxylase), are located in the mitochondria ( ) . in u monocytes, , (oh) vitamin d upregulates glutamate cysteine ligase (gclc) and glutathione reductase (gr), resulting in an increase of cellular glutathione formation, and decreased ros and il- secretion ( ) . two recent studies have evaluated the impact of vitamin d on skeletal muscle mitochondrial function. primary human skeletal muscle cells treated with , (oh)d vs. vehicle demonstrated marked effects on mitochondrial number, morphology, physiology, and expression of key mitochondrial proteins, resulting in increased atp production ( ) . in vitamin d-deficient symptomatic patients, vitamin d supplementation was found, using phosphorus- magnetic resonance spectroscopy, to augment muscle mitochondrial maximal oxidative phosphorylation after exercise and improved symptoms of fatigue ( ) . treatment of skeletal muscle with vitamin d is associated with a change in expression of ∼ nuclear mrnas encoding proteins known to localize in mitochondria ( ) . hypovitaminosis d is common in critical illness, despite parallel elevations of pth ( ) with one small study reporting a progressive drop in vitamin d levels in the first week of illness ( ), while a low (oh)d status was significantly associated with all-cause and sepsis mortality ( ) . in early critical illness, vitamin d status is associated with a differential metabolic profile. glutathione and glutamate metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly upregulated by vitamin d ( ) . however, evidence of a mortality benefit of vitamin d as monotherapy still remains uncertain ( , ) . a recent large rct investigated a single dose of , international units of vitamin d in critically ill patients with , (oh)d levels < ng/ml ( ). by day , the treated group achieved a level of -hydroxyvitamin d of . ± . ng/ml; measurements of systemic inflammation were not reported. treatment was not associated with improvement in mortality or secondary variables ( ). ascorbic acid (vitamin c) is a potent water-soluble antioxidant and an enzymatic cofactor that plays a key role in neuroendocrine and immune homeostatic corrections ( ) . most vertebrates can synthesize ascorbic acid from glucose- -phospate in the liver, with synthesis increasing during stress. in humans and other primates, however, ascorbic acid cannot be synthesized and has to be obtained through the diet. this is the result of a random mutation in the enzyme that catalyzes the final step of ascorbic acid biosynthesis in the common ancestor of the teleost fish some million years ago ( , ) . to date, there is no satisfactory evolutionary explanation for this apparent random loss of ascorbic acid synthetic ability. individuals from species which have lost the ability to make their own ascorbic acid were not selected against, as long as their diet contained sufficient quantities of vitamin c ( ) . ascorbic acid is actively transported into all cells of the body (except erythrocytes) by the sodium vitamin c transporter- (msvct ). ascorbic acid is differentially accumulated by most tissues and body fluids. studies using radiolabeled ascorbic acid predict that body stores in healthy humans are about , mg; scurvy is thought to occur when this level falls below mg, with plasma ascorbic acid concentrations < . µm ( ). importantly, the highest concentrations (µm) of ascorbic acid are found in critical organs involved in homeostatic corrections, such as the pituitary gland ( , - , ), the adrenals ( , - , ), the brain norepinephrine-synthesizing nuclei ( - ), and liver ( - ) ( ) . this vitamin-sequestering may represent an evolutionary protective or "safety" function. ascorbic acid is a key cellular antioxidant. as such, ascorbic acid is an electron donor that directly scavenges for free radicals, and inhibits the generation of new free radicals through its suppressive effects on the nadph oxidase (nox) pathway ( ) . ascorbic acid also prevents the depletion of other circulatory antioxidants, such as lipid-soluble vitamin e and glutathione, although this is not the case in reverse ( ) . the anti-oxidant effects of ascorbic acid result in reduced endothelial permeability, improved microvascular and macrovascular function, attenuated cellular apoptosis in pathological states, and improved gr function ( ) . ascorbic acid is maintained at high levels in mature circulating leukocytes (µm amounts in lymphocytes ∼ , ; monocytes ∼ , , and neutrophils ∼ , ) ( ), suggesting an important role in many aspects of the immune response. in leukocytes, ascorbic acid content responds to variations in plasma ascorbate availability ( ) . following activation, immune cells undergo dramatic metabolic reprogramming with increased aerobic glycolytic activity and fatty acid oxidation (warburg effect) under the regulation of hypoxia-inducible factors (hifs) ( ) . the result of this change is to rapidly provide atp and metabolic intermediates for the biosynthesis of immune and inflammatory mediators. importantly, the hydroxylase enzymes that regulate the actions of the hifs require ascorbate for optimal activity ( ) . the immune-enhancing properties of ascorbic acid regulation of hifs include increased neutrophil and macrophage bacterial killing and phagocytic capacity ( , ) . in addition, ascorbic acid plays an important role in protecting host cells from the excessive oxidative stress caused by infections ( ) . ascorbic acid plays a crucial role in hpa axis function (figure ). in adrenocortical cells ascorbic acid is sequestered in two pools, one of which can be depleted by acth. in response to inflammatory cytokine-mediated acth release from the anterior pituitary gland, the adrenal gland rapidly secretes ascorbic acid in amounts that are sufficient to increase, by several fold, plasma ascorbic acid concentrations in the adrenal vein, without increasing systemic levels ( ) . more than years ago hans selye, the pioneer of stress research, reported that the adrenal glands not only contain some of the highest concentrations of ascorbic acid in the human body, but they also employ this vitamin to synthesize cortisol in the adrenal cells ( ) . today, in vitro and in vivo studies have shown that ascorbic acid is an essential cofactor required in both adrenal mitochondrial steroidogenesis and catecholamine biosynthesis ( ) . the level of ascorbate in the adrenals might affect their capacity to convert cholesterol into pregnenolone, the precursor from which nearly all steroid hormones, including cortisol, are made ( ) . additionally, ascorbic acid, as an antioxidant, has a positive impact on gr functions (see section oxidative stress and circi). oxidative conditions modulate negatively ligand-dependent and independent nuclear import of the gr, affecting gc-grα dna binding, and inducible gene expression ( , ) , while a phosphodiester compound of ascorbic acid reverses oxidation of the gr, thereby, restoring the cellular glucocorticoidresponsiveness in oxidant conditions ( ) . finally, the cellular uptake of ascorbic acid, mediated by msvct , is downregulated during inflammatory conditions. in a time and concentrationdependent manner, gcs increase the expression of msvct , facilitating the uptake of vitamin c into cells ( ) , providing the rationale for combination treatment using gcs and ascorbic acid ( ) . interestingly, there is a strong inverse correlation between the ability of an animal to endogenously produce vitamin c and the induction of a cortisol response when stressed ( ) . in human cell lines and primary endothelial cells (ecv and huvec), ascorbic acid inhibits tnfα and il- βinduced activation of nf-κb, in a dose-dependent manner, by inhibiting phosphorylation and degradation of iκbα ( , ) , independently of its antioxidant properties ( ) . preclinical studies show that high-dose vitamin c can prevent or restore microcirculatory flow impairment, reinstate vascular responsiveness to vasoconstrictors, and preserve the endothelial barrier ( ) . both ascorbic acid ( ) and the gr (see section endothelium) ( ) are essential for endothelial cell homeostasis, and the combination of glucocorticoids with ascorbic acid is superior to either one on its own in protecting vascular endothelium that is critical to allow recovery ( ) . many studies have demonstrated that vitamin c levels are rapidly depleted in critically ill patients, with about % of the septic patients having reduced serum levels, similar to those seen at scurvy diagnosis (< . u/mol/l) ( , ) . as intracellular ascorbate concentrations in mononuclear leukocytes and in granulocytes are, respectively, and times higher than in plasma, a high production and turnover of these cells may also contribute to its depletion ( ) . low plasma concentrations of vitamin c are associated with more severe organ failure and increased risk of mortality ( ) . similar to thiamine, ascorbic acid deficiency syndrome (scurvy) bears a number of similarities to sepsis, including coagulation abnormalities, and breakdown of the endothelial wall ( ) . in a phase i safety trial, intravenous ascorbic acid infusion was safe, well-tolerated, and associated with improvement in multiple organ dysfunction and decreased biomarkers of inflammation and endothelial injury ( ) . additionally, a small rct investigating high dose ascorbic acid administration in patients with septic shock reported a reduction in -day mortality ( ) , while a larger trial in patients with sepsis-associated ards reported a significant reduction in -day all-cause mortality in response to acth release from the corticotrophs of the anterior pituitary gland, the adrenal gland rapidly secretes ascorbic acid, an essential cofactor required for adrenal steroidogenesis in mitochondria, contributing to increased glucocorticoids synthesis. (bottom) cells: glucocorticoids, in a time-and concentration-dependent manner, increase the expression of msvct , facilitating the uptake of ascorbic acid into the cell. ascorbic acid reverses oxidation of the gr, restoring cellular glucocorticoid-responsiveness in oxidant conditions. in addition, ascorbic acid inhibits tnfα-and il- β-induced activation of nf-κb in a dose-dependent manner by inhibiting phosphorylation and degradation of iκbα. these combined actions result in increased glucocorticoid availability and gc-grα activation and improved homeostatic corrections. (secondary outcome) ( ) . the rationale for glucocorticoid treatment in association with high dose ascorbic acid was the subject of recent reviews ( , ) . the promising findings of a recent retrospective study in patients with severe sepsis and septic shock has spurred considerable interest in the subject ( ) . randomized data to confirm or refute the observational evidence for the drug combination are needed, and several clinical trials are ongoing or planned in the near future ( ) . in critical illness, homeostatic corrections, the culmination of millions of years of evolution, are modulated by the activated gc-grα and associated with an enormous bioenergetic and metabolic cost. we have reviewed how circi, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. importantly, the allostatic overload imposed by homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality, while the bioenergetic and metabolic reserves to support homeostatic corrections are time limited. for these reasons it is prudent to implement early interventions designed to achieve the following: (i) reinforce innate immunity, (ii) inhibit further systemic tissue damage, (iii) limit the metabolic and bioenergetic cacostatic overload imposed during vital organ support, (iv) accelerate disease resolution, and (v) prevent persistent-chronic low-grade systemic inflammation ( ) . this approach is supported by experimental ( ) and clinical studies in patients with septic shock or ards ( ) ( ) ( ) ( ) . the actions of the activated grα cannot be categorized as merely anti-inflammatory, as it is now clear that insufficient intracellular grα regulatory action and not relative adrenal insufficiency is the primary driver of circi ( ) . therefore, glucocorticoid treatment should not be viewed exclusively as anti-inflammatory or as a hormone replacement for relative adrenal insufficiency. it also is equally relevant that one should recall that full biological resolution lags weeks behind clinical resolution of an acute illness, making the clinical criteria that we frequently employ to guide duration of treatment, an inadequate reference point ( ) . for these reasons, glucocorticoid treatment, and other co-interventions should be directed at supporting the activated grα regulatory function throughout all phases of homeostatic corrections, and not limited to the acute phase of organ support. randomized studies provide evidence that prolonged glucocorticoid administration is associated with increased grα number and function and decreased oxidative stress (see sections glucocorticoid receptor alpha in critical illness and mitochondria and hpa-axis cross-talk). additionally, the activated grα interdependence with functional mitochondria and three vitamin reserves provides a rationale for cointerventions that include rapid replacement of vitamins b , c, and d. recent evidence generated from a retrospective before-after clinical study in patients with severe sepsis has generated momentum for increased research in this field ( ) , with ongoing confirmatory randomized trials in progress ( ) . additional co-intervention with critical hormones and mediators involved in homeostatic corrections are also necessary, such as fludrocortisone ( , , ) or vasopressin ( ) ( ) ( ) in patients with septic shock. fludrocortisone is a mineralocorticoid and glucocorticoid receptor agonist that binds to cytoplasmic receptors, activates their translocation into the nucleus and subsequently initiates the transcription of mineralocorticoid-and glucocorticoid-responsive genes ( ). the inclusion or exclusion of fludrocortisone, as a cointervention with hydrocortisone, may partly explain the differences reported in outcomes of some rcts (see explanation for figure below) ( , ) . other potential co-interventions directed at increasing glucocorticoid receptor expression, such as statins ( ), melatonin ( ), beta-blockers ( ), calcium channel blockers ( ) , or directed at improving mitochondrial function ( , , ) have not been investigated in association with glucocorticoid treatment in acute illness or alone in chronic critical illness. present understanding of the activated gc-grα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and in monitoring treatment responses. there are many variables to consider, including the type of gc to be used, timing, dosage, mode of delivery, co-interventions, duration, and tapering. over the last years, multiple randomized trials investigating gc treatment in critical illness have clearly shown that the design of a treatment protocol has a profound impact on treatment response and outcome ( , ) . the consort ( ) and grade ( ) systems, while useful in evaluating the quality of a randomized trial, unfortunately lack a position on two fundamental elements of a trial design, namely the disease pathophysiology and the pharmacological principles applicable to the investigated drug. unfortunately, lack of these specific reference points has generated misinterpretation of the literature, fueling a non-sensical controversy that clearly is not serving the patient ( ) . based on this updated pathophysiological understanding, we offer a few observations and make recommendations for future research. early initiation of treatment, before homeostatic corrections reach exhaustion, is critical and should be directed at approaching maximal saturation of the glucocorticoid receptor (∼ mg of methylprednisolone equivalent) ( ) . an adequate initial loading bolus is necessary to achieve prompt elevation in plasma levels and to assure higher grα saturation in the cytoplasm and on the cell membrane for genomic and non-genomic actions, respectively. in human monocytic cells activated with graded concentrations of lps and then exposed to graded concentrations of methylprednisolone (figure ) , reduction in inflammatory cytokine transcription was initially modest, then-after reaching an inflection point-followed by a rapid reduction, likely related to achieving maximal drug receptor saturation and adequate time for a measurable effect ( ) . to achieve optimal results, the initial loading bolus should be followed by an infusion (daily dose over h) to rapidly achieve a steady state. in patients with septic shock, graded concentrations of lps were followed by progressively higher inflammatory cytokine transcription (for tnf-α: , , , and , respectively). these cells were then exposed to graded concentrations of methylprednisolone [(µg/ml): , , , , ] for h followed by repeated measurement of inflammatory cytokine expression (see below). the steady state mrna levels of tnf-α, il- β, or il- in lps-activated cells were reduced by treatment with methylprednisolone in a concentration-dependent manner. the effective dose of methylprednisolone was mg, a value that appeared to be independent of the priming level of lps and type of mrna measured ( ) . modified with permission from meduri et al. ( ) . hydrocortisone administered as an infusion vs. an intermittent bolus was associated with more rapid resolution of shock ( ) , and fewer hyperglycemic episodes ( , ) . in general, synthetic glucocorticoids are more potent immunoregulators than is cortisol, because they are not subject to endogenous clearance and inhibitors of cortisol activity, including βhsd inactivation. moreover, synthetic glucocorticoids bind the glucocorticoid receptors with higher affinity and remain longer in the cell nucleus, while they bind to mineralocorticoid receptors with lower affinity than do endogenous glucocorticoids, thereby minimizing mineralocorticoid-related side effects ( ) . pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids are reviewed in reference ( ) . hydrocortisone and methylprednisolone are the two glucocorticoids most often investigated in critical care rcts ( ) . in the past, different exogenous glucocorticoids were thought to be qualitatively indistinguishable from each other because they act via the same glucocorticoid receptor, however, qualitative differences have been recently discovered, and one glucocorticoid cannot be simply replaced by another ( ) . while hydrocortisone was initially chosen as the drug of choice for adrenal replacement, methylprednisolone may actually offer unique advantages over hydrocortisone as follows: (i) greater affinity for the glucocorticoid receptor ( ); (ii) higher penetration in lung tissue (important for ards or pneumonia), and with longer residence time ( - ), (iii) higher potency of genomic activity especially nf-κb inhibitory activity ( ) ; and (iv) higher potency of non-genomic activity ( ) . grα binding affinity, expressed as relative receptor affinity (rra), correlates with glucocorticoid potency. the log rras for selected glucocorticoids are . , . , and . for hydrocortisone, methylprednisolone, and dexamethasone, respectively ( ) . a comparison study between these three types of glucocorticoids is needed. the suggested mode of administration for septic shock [hydrocortisone < mg/day for > days ( ), or hydrocortisone mg qid for days without tapering] is based in part on an outdated pathophysiological model and a misconception about the risk associated with longer duration of treatment (small) and discontinuation without tapering (high). there is some evidence that a treatment duration of - days directed at reducing acuity of illness (transient reduction in systemic inflammation) might shortchange the full beneficial effects of glucocorticoid therapy ( ) . the impact of a longer duration of treatment on medium-and long-term mortality, as observed in rtcs of patients with pneumocystis jiroveci pneumonia ( ), needs to be investigated. while glucocorticoids have an important role in supporting homeostatic corrections, this is achieved at the expense of reversible suppression of the hpa axis. in addition, the risk of glucocorticoid treatment-associated adrenal suppression in critically ill patients with dysregulated systemic inflammation is underappreciated. it has been shown that neither the total or the highest dose, nor the duration of glucocorticoid treatment is a significant predictor of hpa axis recovery ( ) . in the recent "reduction in the use of corticosteroids in exacerbated copd trial" that evaluated prednisone mg daily for or days, adrenal suppression was detected at hospital discharge and at days in and % of patients, respectively; no differences were detected between or days of glucocorticoid exposure ( ) . similarly to the experimental literature ( , ) , critical care rcts have shown that abrupt glucocorticoid discontinuation after a -to- days treatment was rapidly followed by a reconstituted inflammatory response with a clinical relapse in approximately one-third of the patients ( , , , ) , and increased mortality ( ) . in the lasrs trial ( ) , discontinuation of study drug h postextubation was associated with clinical relapse in one-quarter of methylprednisolone-treated patients. these patients were rapidly returned to mechanical ventilation (mv) without reinstitution of study treatment, fared poorly, required additional days of mv and had a -fold increased risk of -day mortality (p = . ) in comparison to patients that did not return to mv ( ) . gradual tapering is necessary to preserve the disease improvement achieved during glucocorticoid administration, to sustain continuous resolution and restoration of tissue homeostasis, to achieve gradual recovery of the suppressed hpa axis, to forestall disease relapse from reconstituted systemic inflammation, and finally to comply with the food and drug administration package insert warnings (reference id: ) ( ) . with rapidly expanding knowledge, appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand and appreciate the complex pathobiology of critical illness. we have reviewed emerging literature clearly placing the activated grα at the center of the homeostatic corrections in the general adaptation to critical illness. future research directions should include a reassessment of the pharmacological principles that guide glucocorticoid treatment in critical illness and to devise co-interventions to improve cellular responsiveness to glucocorticoids by correcting conditions associated with a reduction in grα and mitochondrial concentration and function. in addition to the previously used sources ( ), we searched the google scholar and pubmed databases, employing the following keywords: "glucocorticoid, " "corticosteroid, " "glucocorticoid receptor, " "stress response, " "acute phase response, " "regulation, " "resolution, " "critical illness related corticosteroid insufficiency, " "treatment, " "systemic inflammation, " "dysregulated" systemic inflammation, " "nuclear factor kappa b, " "evolution, " "endothelium, " "mitochondria, " "reactive oxygen species, " ascorbic acid, thiamine, vitamin d, melatonin, "acute, " "longterm, " chronic, " "homeostasis, " "allostasis, " "cacostasis, " and terms related to critical illness, sepsis, septic shock, acute respiratory distress syndrome, "cardiac events." manual searching of articles, including reference lists of cited publications, was also performed to avoid omissions. gm conceived and initiated the article and wrote the original draft. gc contributed to the conception and worked on successive drafts. this material was the result of work supported with the resources and use of facilities at the memphis va medical center. funding for the respective trials was disclosed in the original publications. linking cellular stress responses to systemic homeostasis the concept of allostasis in biology and biomedicine endocrine changes in critical illness evolutionary origins and functions of the stress response immune-neuro-endocrine reflexes, circuits, and networks: physiologic and evolutionary implications importance of the glucocorticoid stress response in a changing world: theory, hypotheses and perspectives chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs stress and disorders of the stress system activation of innate immunity system during aging: nf-kb signaling is the molecular culprit of inflamm-aging molecular evolution of the nf-kappab signaling system activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy coactivation of gr and nfkb alters the repertoire of their binding sites and target genes a database and functional annotation of nf-kappa b target genes a genomic storm in critically injured humans stress, the stress system and the role of glucocorticoids turning up the heat: immune brinksmanship in the acute-phase response critical illness-related corticosteroid insufficiency (circi): a narrative review from a multispecialty task force of the society of critical care medicine (sccm) and the european society of intensive care medicine (esicm) chronic critical illness and the persistent inflammation, immunosuppression, catabolism syndrome cytokine dysregulation, inflammation and well-being changes in macrophage phenotype as the immune response evolves mitochondrial allostatic load puts the 'gluc' back in glucocorticoids infections and the inflammatory response in acute respiratory distress syndrome molecular inflammatory responses measured in blood of patients with severe community-acquired pneumonia circulating cytokines as markers of systemic inflammatory response in severe community-acquired pneumonia determinants of short and long term functional recovery after hospitalization for community-acquired pneumonia in the elderly: role of inflammatory markers understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (genims) study systemic and bronchoalveolar cytokines as predictors of in-hospital mortality in severe community-acquired pneumonia contrasting inflammatory responses in severe and non-severe community-acquired pneumonia immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study * the host response in patients with sepsis developing intensive care unit-acquired secondary infections persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il- beta and il- levels are consistent and efficient predictors of outcome over time inflammatory cytokines in the bal of patients with ards. persistent elevation over time predicts poor outcome nuclear factor-kappab-and glucocorticoid receptor alpha-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. evidence for inflammation-induced target tissue resistance to glucocorticoids lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury interleukin- and soluble intercellular adhesion molecule- during acute respiratory distress syndrome and in response to prolonged methylprednisolone treatment plasma cytokines il- , il- , and il- are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury role of nf kappa b in the mortality of sepsis increased nuclear factor kb activation in critically ill patients who die predictive value of nuclear factor kappab activity and plasma cytokine levels in patients with sepsis universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism d-dimer levels in assessing severity and clinical outcome in patients with community-acquired pneumonia. a secondary analysis of a randomised clinical trial comparative analysis of the host response to community-acquired and hospital-acquired pneumonia in critically ill patients causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective stress-induced glucocorticoids as a neuroendocrine alarm signal of danger inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis long-term host immune response trajectories among hospitalized patients with sepsis protracted immune disorders at one year after icu discharge in patients with septic shock inflammation versus glucocorticoids as purveyors of pathology during stress: have we reached the tipping point? a functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased nf-kappab signaling effects of aging on inflammation and hemostasis through the continuum of critical illness consumptive coagulopathy is associated with organ dysfunction during pics fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets stress and glucocorticoid receptor regulation of mitochondrial gene expression circulating mitochondrial dna increases with age and is a familiar trait: implications for "inflamm-aging" risk of cardiovascular events in survivors of severe sepsis epigenetic upregulation of fkbp by aging and stress contributes to nf-κbdriven inflammation and cardiovascular risk a dysregulated balance of proinflammatory and anti-inflammatory host cytokine response early during therapy predicts persistence and mortality in staphylococcus aureus bacteremia stentz infections f, sirs, and cars during ards and in response to prolonged glucocorticoid treatment genome-wide transcription profiling of human sepsis: a systematic review scavenger receptor class b, type i (sr-bi) is the major route for the delivery of high density lipoprotein cholesterol to the steroidogenic pathway in cultured mouse adrenocortical cells low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients changes in hdl-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation sr-bi protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance hdl-cholesterol level and cortisol response to synacthen in critically ill patients gluco-and mineralocorticoid biological effects of a -day treatment with low doses of hydrocortisone and fludrocortisone in septic shock hench lecture award: the evolution of glucocorticoids comprehensive overview of the structure and regulation of the glucocorticoid receptor novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes. hormones protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor glucocorticoid receptor uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization glucocorticoid receptor is required for foetal heart maturation minireview: glucocorticoid regulation of lung development: lessons learned from conditional gr knockout mice glucocorticoid receptor isoform-specific regulation of development, circadian rhythm, and inflammation in mice mothers' attachment is linked to their children's anti-inflammatory gene expression via maternal warmth why do we need nongenomic glucocorticoid mechanisms? glucocorticoid receptors, in human alveolar macrophages and peripheral blood cells decreased glucocorticoid receptor expression during critical illness glucocorticoid signaling: an update from a genomic perspective a genome-wide signature of glucocorticoid receptor binding in neuronal pc cells glucocorticoids and their receptors: insights into specific roles in mitochondria stress and corticosteroids regulate rat hippocampal mitochondrial dna gene expression via the glucocorticoid receptor gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells differentiation of human pulmonary type ii cells in vitro by glucocorticoid plus cyclic amp krüppel-like factor is a major mediator of glucocorticoid receptor signaling in cardiomyocytes and protects these cells from dna damage and death glucocorticoid receptor-dependent gene regulatory networks human glucocorticoid receptor β regulates gluconeogenesis and inflammation in mouse liver the human glucocorticoid receptor as an rna-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target rna motif increased glucocorticoid receptor expression and activity mediate the lps resistance of spret/ei mice physiological functions of glucocorticoids in stress and their relation to pharmacological actions the five rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore glucocorticoids sensitize the innate immune system through regulation of the nlrp inflammasome acute phase reaction and acute phase proteins cytokines and the hypothalamicpituitary-adrenal axis synergistic roles of interleukin- , interleukin- , and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo tumor necrosis factor-alpha regulates steroidogenesis, apoptosis, and cell viability in the human adrenocortical cell line nci-h r systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland hermanowski-vosatka a. induction of beta-hydroxysteroid dehydrogenase type but not− in human aortic smooth muscle cells by inflammatory stimuli proinflammatory actions of glucocorticoids: glucocorticoids and tnfα coregulate gene expression in vitro and in vivo dominance of the strongest: inflammatory cytokines versus glucocorticoids effects of methylprednisolone on intracellular bacterial growth prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases glucocorticoid receptor signaling in health and disease glucocorticoid-independent modulation of gr activity: implications for immunotherapy annexin a and glucocorticoids as effectors of the resolution of inflammation annexin a modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis the role and effects of glucocorticoid-induced leucine zipper in the context of inflammation resolution glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes glucocorticoid-mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation glucocorticoids induce protein s-dependent phagocytosis of apoptotic neutrophils by human macrophages glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes saturated-efferocytosis generates pro-resolving cd blow macrophages: modulation by resolvins and glucocorticoids local amplification of glucocorticoids by betahydroxysteroid dehydrogenase type promotes macrophage phagocytosis of apoptotic leukocytes local amplification of glucocorticoids by beta-hydroxysteroid dehydrogenase type and its role in the inflammatory response glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor a modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide ac( - ) new lives given by cell death: macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation glucocorticoid resistance as a major drive in sepsis pathology systemic inflammation-associated glucocorticoid resistance and outcome of ards adrenal function and dysfunction in critically ill patients proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance expression of the glucocorticoid receptor is decreased in experimental staphylococcus aureus sepsis cecal ligation and puncture alters glucocorticoid receptor expression down regulation of hepatic glucocorticoid receptors after endotoxin treatment nitric oxide up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis effects of different doses of hydrocortisone on acute lung injury in rats with early septic shock glucocorticoid receptor expression on acute lung injury induced by endotoxin in rats endothelial glucocorticoid receptor is required for protection against sepsis modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone low-dose dexamethasone alleviates lipopolysaccharide-induced acute lung injury in rats and upregulates pulmonary glucocorticoid receptors mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock decreased cytosolic glucocorticoid receptor levels in critically ill patients glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis reduced glucocorticoid receptor protein expression in children with critical illness corticosteroid resistance in sepsis is influenced by microrna- -induced downregulation of glucocorticoid receptor-alpha tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness an expanded definition of the adult respiratory distress syndrome endothelial response to glucocorticoids in inflammatory diseases dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of zo- tight junction protein endothelial biomarkers in human sepsis: pathogenesis and prognosis for ards dysregulation of the angiopoietin-tie- axis in sepsis ards angiopoietin- and angiopoietin- as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients vitamin c revisited microcirculatory alterations: potential mechanisms and implications for therapy. ann intensive care the role of adrenal gland microenvironment in the hpa axis function and dysfunction during sepsis von willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury plasma vascular endothelial growth factor in severe sepsis circulating endothelial cells in patients with septic shock evaluation of endothelial damage in sepsis-related ards using circulating endothelial cells microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome a mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule and intercellular adhesion molecule glucocorticoids and endothelial cell barrier function glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of sphk dexamethasone coordinately regulates angiopoietin- and vegf: a mechanism of glucocorticoid-induced stabilization of blood-brain barrier serum glucocorticoid inducible kinase (sgk)- protects endothelial cells against oxidative stress and apoptosis induced by hyperglycaemia serum-and glucocorticoid-inducible kinase delay the onset of endothelial senescence by directly interacting with human telomerase reverse transcriptase downregulation of the glucocorticoid-induced leucine zipper (gilz) promotes vascular inflammation comparative effects of recombinant human activated protein c and dexamethasone in experimental septic shock rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx tnf-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin dexamethasone effects on vascular flow and organ injury in septic mice glucocorticoids and vascular reactivity glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells effects of hydrocortisone on microcirculatory alterations in patients with septic shock low-dose hydrocortisone during severe sepsis: effects on microalbuminuria plasma and bal cytokine response to corticosteroid rescue treatment in late ards effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome aldosterone and vascular mineralocorticoid receptors in murine endotoxic and human septic shock the science of life course guidebook on the origin of mitosing cells symbiosis in cell evolution: life and its environment on the early earth beyond retrograde and anterograde signalling: mitochondrial-nuclear interactions as a means for evolutionary adaptation and contemporary disease susceptibility the role of the host defence response in the progression and outcome of ards: pathophysiological correlations and response to glucocorticoid treatment mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress an energetic view of stress: focus on mitochondria mitochondria: in sickness and in health mitochondria as key components of the stress response mitochondria: master regulators of danger signalling reactive oxygen species: radical factors in the evolution of animal life: a molecular timescale from earth's earliest history to the rise of complex life the role of mitochondrial dysfunction in sepsis-induced multiorgan failure glucocorticoids increase protein carbonylation and mitochondrial dysfunction new insights into the role of mitochondrial calcium homeostasis in cell migration circulating mitochondrial dna at the crossroads of mitochondrial dysfunction and inflammation during aging and muscle wasting disorders dynamic regulation of mitochondrial function by glucocorticoids mitochondria in lung biology and pathology: more than just a powerhouse cross-talk between hpa-axis-increased glucocorticoids and mitochondrial stress determines immune responses and clinical manifestations of patients with sepsis multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation role of oxidative stress and mitochondrial dysfunction in sepsis and potential therapies enhanced expression of intranuclear nf-kappa b in primed polymorphonuclear leukocytes in systemic inflammatory response syndrome patients mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ros) oxidative stress mitochondrial dysfunction in sepsis serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock metabolome alterations in severe critical illness and vitamin d status how to give vitamin c a cautious but fair chance in severe sepsis the rise of mitochondria in medicine mitochondrial dysfunction in sepsis widespread down-regulation of cardiac mitochondrial and sarcomeric genes in patients with sepsis peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis vitamin c mitigates oxidative stress and tumor necrosis factor-alpha in severe communityacquired pneumonia and lps-induced macrophages mitochondrial dysfunction increases pro-inflammatory cytokine production and impairs repair and corticosteroid responsiveness in lung epithelium overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia circulating mitochondrial damps cause inflammatory responses to injury circulating mitochondrial dna in patients in the icu as a marker of mortality: derivation and validation plasma mitochondrial dna and metabolomic alterations in severe critical illness fall in circulating mononuclear cell mitochondrial dna content in human sepsis role of mitochondria in toxic oxidative stress glucocorticoids induce mitochondrial gene transcription in hepg cells: role of the mitochondrial glucocorticoid receptor glucocorticoids suppress mitochondrial oxidant production via upregulation of uncoupling protein in hyperglycemic endothelial cells thioredoxin: a key regulator of cardiovascular homeostasis interaction of mitochondrial thioredoxin with glucocorticoid receptor and nf-kappab modulates glucocorticoid receptor and nf-kappab signalling in hek- cells thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. cross talk between endocrine control of stress response and cellular antioxidant defense system changes in crh and acth synthesis during experimental and human septic shock adrenocortical function during prolonged critical illness and beyond: a prospective observational study mortality of septic mice strongly correlates with adrenal gland inflammation redox manipulation of dna binding activity and bugr epitope reactivity of the glucocorticoid receptor restoration of the glucocorticoid receptor function by the phosphodiester compound of vitamins c and e, epc-k (l-ascorbic acid -[ , -dihydro- , , , -tetramethyl- -( , , -trimethyltridecyl)- h- -benzopyran- -yl hydrogen phosphate] potassium salt), via a redox-dependent mechanism importin- mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity inhibition of glucocorticoid receptor binding by nitric oxide in endotoxemic rats neuronal nitric oxide synthase is an endogenous negative regulator of glucocorticoid receptor in the hippocampus redox-dependent regulation of nuclear import of the glucocorticoid receptor inhibition of glucocorticoid receptor binding by nitric oxide rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages glucocorticoids attenuate septic acute kidney injury immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebocontrolled, crossover study stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions risk of death does not alter the efficacy of hydrocortisone therapy in a mouse e. coli pneumonia model : risk and corticosteroids in sepsis vitamin therapy in critically ill patients: focus on thiamine, vitamin c, vitamin d ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation vitamin b in critically ill patients: needs and challenges randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study thiamine deficiency in critically ill patients with sepsis prevalence of vitamin deficiencies on admission: relationship to hospital mortality in critically ill patients effect of thiamine administration on lactate clearance and mortality in patients with septic shock vitamin d and critical illness outcomes the role of vitamin d in the immune system as a pro-survival molecule vitamin d in inflammatory diseases the vitamin d analogue tx blocks nf-kappab activation in peripheral blood mononuclear cells of patients with crohn's disease vitamin d enhances glucocorticoid action in human monocytes: involvement of granulocyte-macrophage colonystimulating factor and mediator complex subunit the impact of vitamin d levels on inflammatory status: a systematic review of immune cell studies altered blood levels of vitamin d, cathelicidin and parathyroid hormone in patients with sepsis-a pilot study glucocorticoids inhibit map kinase via increased expression and decreased degradation of mkp- vitamin d inhibits monocyte/macrophage proinflammatory cytokine production by targeting mapk phosphatase- anti-inflammatory and corticosteroidenhancing actions of vitamin d in monocytes of patients with steroidresistant and those with steroid-sensitive asthma vitamin d affects glucocorticoid action in target cells are statins analogues of vitamin d? vitamin d augments glucocorticosteroid efficacy via inhibition of mtorc vitamin d deficiency impacts on expression of tolllike receptor- and cytokine profile: a pilot study vitamin d upregulates glutamate cysteine ligase and glutathione reductase, gsh formation. and decreases ros and mcp- and il- secretion in high-glucose exposed u monocytes -dihydroxyvitamin d regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells improving the vitamin d status of vitamin d deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle vitamin d kinetics in the acute phase of critical illness: a prospective observational study when not to use meta-analysis: analysing the meta-analyses on vitamin d in critical care effect of high-dose vitamin d on hospital length of stay in critically ill patients with vitamin d deficiency: the vitdal-icu randomized clinical trial is vitamin c beneficial to patients with cap? the genetics of vitamin c loss in vertebrates vitamin c for the treatment of sepsis: the scientific rationale vitamin c: the known and the unknown and goldilocks vitamin c and immune cell function in inflammation and cancer the warburg effect then and now: from cancer to inflammatory diseases ascorbic acid: its role in immune system and chronic inflammation diseases vitamin c is an important cofactor for both adrenal cortex and adrenal medulla effects of ascorbic acid deficiency on adrenal mitochondrial hydroxylations in guinea pigs dexamethasone induces sodium-dependant vitamin c transporter in a mouse osteoblastic cell line mc t -e catravas hydrocortisone j. vitamin c, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study the adrenal-vitamin c axis: from fish to guinea pigs and primates vitamin c inhibits nf-κb activation by tnf via the activation of p mitogen-activated protein kinase vitamin c suppresses tnfα-induced nfκb activation by inhibiting iκbα phosphorylation ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis glucocorticosteroids as adjunctive therapy for acute respiratory distress syndrome and sepsis? yes, but not as monotherapy phase i safety trial of intravenous ascorbic acid in patients with severe sepsis doctor-your septic patients have scurvy! effect of high-dose ascorbic acid on vasopressor's requirement in septic shock effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial the resolution of inflammation: principles and challenges glucocorticoid receptor function is decreased in neutrophils during endotoxic shock : timeliness of corticosteroid use in icu patients with pneumonia and ards efficacy of corticosteroids in acute respiratory distress syn-drome: an observational study early administration of hydrocortisone replacement after the advent of septic shock: impact on survival and immune response * early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study glucocorticoid treatment in community-acquired pneumonia hydrocortisone plus fludrocortisone for adults with septic shock immune effects of corticosteroids in sepsis vasopressin deficiency contributes to the vasodilation of septic shock circulating vasopressin levels in septic shock dieter ayers for the, and i. septic shock trial, interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock the australian-new zealand intensive care society clinical trials, adjunctive glucocorticoid therapy in patients with septic shock successful treatment of acute lung injury with pitavastatin in septic mice: potential role of glucocorticoid receptor expression in alveolar macrophages influence of drug treatment on glucocorticoid receptor levels in patients with coronary heart disease mechanistic insights into the protective impact of zinc on sepsis the protection potential of antioxidant vitamins against acute respiratory distress syndrome: a rat trial an historical review of glucocorticoid treatment in sepsis. disease pathophysiology and the design of treatment investigation prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature grade: an emerging consensus on rating quality of evidence and strength of recommendations why cheap drugs that appear to halt fatal sepsis go unused standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology timing, method and discontinuation of hydrocortisone administration for septic shock patients bolus or continuous hydrocortisone-that is the question effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial immune regulation by glucocorticoids pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids guidelines for the diagnosis and management of critical illnessrelated corticosteroid insufficiency (circi) in critically ill patients (part i): society of critical care medicine (sccm) and european society of intensive care medicine (esicm relative immunosuppressive potency of therapeutic corticosteroids measured by whole blood lymphocyte proliferation prednisone and methylprednisolone disposition in the lung methylprednisolone achieves greater concentrations in the lung than prednisolone. a pharmacokinetic analysis penetration of corticosteroids into the lung -evidence for a difference between methylprednisolone and prednisolone evaluation of ap- and nf-kb inhibitory potency for oral glucocorticoids different glucocorticoids vary in their genomic and non-genomic mechanism of action in a cells corticosteroid treatment in severe community-acquired pneumonia: duration of treatment affects control of systemic inflammation and clinical improvement adjunctive corticosteroids for pneumocystis jiroveci pneumonia in patients with hiv infection why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself prospective analysis of adrenal function in patients with acute exacerbations of copd: the reduction in the use of corticosteroids in exacerbated copd (reduce) trial potentiation of butylatedhydroxytoluene-induced acute lung damage by oxygen. effects of prednisolone and indomethacin enhanced acute lung damage following corticosteroid treatment la voie, corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. a double-blind, placebo-controlled trial efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome an exploratory reanalysis of the randomized trial on efficacy of corticosteroids as rescue therapy for the late phase of acute respiratory distress syndrome available online at: www key: cord- -md om x authors: ketcham, scott w.; sedhai, yub raj; miller, h. catherine; bolig, thomas c.; ludwig, amy; co, ivan; claar, dru; mcsparron, jakob i.; prescott, hallie c.; sjoding, michael w. title: causes and characteristics of death in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: a retrospective cohort study date: - - journal: crit care doi: . /s - - -w sha: doc_id: cord_uid: md om x background: acute hypoxemic respiratory failure (ahrf) and acute respiratory distress syndrome (ards) are associated with high in-hospital mortality. however, in cohorts of ards patients from the s, patients more commonly died from sepsis or multi-organ failure rather than refractory hypoxemia. given increased attention to lung-protective ventilation and sepsis treatment in the past years, we hypothesized that causes of death may be different among contemporary cohorts. these differences may provide clinicians with insight into targets for future therapeutic interventions. methods: we identified adult patients hospitalized at a single tertiary care center ( – ) with ahrf, defined as pao( )/fio( ) ≤ while receiving invasive mechanical ventilation for > h, who died during hospitalization. ards was adjudicated by multiple physicians using the berlin definition. separate abstractors blinded to ards status collected data on organ dysfunction and withdrawal of life support using a standardized tool. the primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. results: we identified decedents with ahrf, of whom ( %) had ards. the most common primary causes of death were sepsis ( %), pulmonary dysfunction ( %), and neurologic dysfunction ( %). multi-organ failure was present in % at time of death, most commonly due to sepsis ( % of all patients), and % were on significant respiratory support at the time of death. only % of patients had insupportable oxygenation or ventilation. eighty-five percent died following withdrawal of life support. patients with ards more often had pulmonary dysfunction as the primary cause of death ( % vs %; p = . ) and were also more likely to die while requiring significant respiratory support ( % vs %; p < . ). conclusions: in this contemporary cohort of patients with ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. the vast majority of deaths occurred after withdrawal of life support. ards patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ards. conclusions: in this contemporary cohort of patients with ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction, but few patients had insupportable oxygenation or ventilation. the vast majority of deaths occurred after withdrawal of life support. ards patients were more likely to have pulmonary dysfunction as the primary cause of death and die while requiring significant respiratory support compared to patients without ards. keywords: acute respiratory distress syndrome, acute hypoxemic respiratory failure, mortality, cause of death background acute hypoxemic respiratory failure (ahrf) is among the most common causes of critical illness, with a hospital mortality of approximately % [ ] . in patients meeting the definition of acute respiratory distress syndrome (ards), mortality is approximately % [ ] . however, while ahrf and ards are each defined by severe hypoxemia and associated with high mortality, death due to refractory hypoxemia is reportedly rare. in cohorts of ards patients treated in the s, only - % of deaths were due to refractory hypoxemia, while deaths due to multi-organ failure from sepsis were the cause of up to % of deaths [ ] . these findings suggested that therapies focused on reducing the complications of sepsis would have a greater impact at improving ards survival than therapies for severe hypoxia. since the s, however, cause of death specifically related to organ system dysfunction has not been described despite substantial evolution in critical care practices. ventilator management now focuses on minimizing ventilatorinduced lung injury, as opposed to normalizing oxygenation and ventilation [ ] , which may have led to further reduction in death due to refractory hypoxemia. in addition, there has been growing attention to minimization of sedation, early mobilization, and sepsis recognition and treatment, the latter of which may mitigate mortality due to sepsis [ ] [ ] [ ] [ ] . finally, there has been an increased focus on palliative care in the intensive care unit (icu), which may lead to earlier treatment limitations [ ] [ ] [ ] . because of these changes in practice and how they may affect causes of death in the icu, we hypothesized that causes of death among ahrf and ards patients may be different from historical cohorts. an updated understanding of the causes of death in these populations would help identify the most important targets for new therapies and help direct future investigation to improve survival. we sought to determine the causes and circumstances of death in a contemporary cohort of ahrf patients, and assess whether causes of death differed among patients with and without ards. we performed a retrospective cohort study of adult patients (aged ≥ years) hospitalized at michigan medicine (january , , to december , ) with ahrf who experienced in-hospital death. patients were identified via an electronic query tool of the electronic health record. as in prior studies [ , ] , patients were defined as having ahrf when the following criteria were met: ( ) receipt of invasive mechanical ventilation for at least h (to exclude routine post-operative ventilation) in the medical, surgical, cardiac, trauma, or neurologic icu, and ( ) a pao /fio ratio ≤ . lowtidal volume ventilation and protocols for daily awakening and spontaneous breathing trials for mechanically ventilated patients were employed [ ] . demographics, comorbidities, highest sequential organ failure assessment (sofa) score within the first h of ahrf onset, the lowest glasgow coma scale during the h prior to death, and icu setting were also collected from the electronic health record through use of the electronic query tool. patients were classified as having ards by multiple physician adjudication as part of a prior study [ ] . specifically, two critical-care trained physicians reviewed each ahrf hospitalization to determine whether patients met berlin criteria [ , ] for ards: ( ) new or worsening respiratory symptoms began within week of a known clinical insult, ( ) pao /fio ≤ while receiving a positive end-expiratory pressure ≥ cm h o, ( ) bilateral opacities on chest x-ray, ( ) unlikely to be cardiogenic pulmonary edema, and ( ) no other explanation for these findings. disagreement between physicians was resolved by a third physician in % of patients [ ] . in addition to ards status, specific ahrf or ards risk factors were collected as part of the prior study (pneumonia, aspiration, non-pulmonary sepsis, non-cardiogenic shock, major trauma, major surgery, transfusion, pancreatitis, major burn, inhalation injury, vasculitis, pulmonary contusion, drowning, or none) [ ] . patients transferred from another hospital were excluded as we were unable to reliably determine ards status, ahrf risk factors, or illness severity on presentation. patient data were reviewed by one of internal medicine-trained physicians who did not participate in the adjudication of ards and were blinded to adjudicated ards status. data regarding causes and circumstances of death were collected using a structured abstraction form (appendix , online supplement). specifically, we abstracted presence and severity of sepsis, presence and severity of organ system dysfunction, withdrawal of life-sustaining treatments, and cause of death, as described further below. all data required for abstractions were available in the electronic medical record. to ensure consistency across reviewers, excellent inter-rater reliability was demonstrated on an initial test set of charts (appendix , online supplement). for each patient, we assessed for sepsis and dysfunction of organ systems during the h prior to death. we classified sepsis and each organ dysfunction as severe or irreversible using definitions from a prior study by stapleton et al. [ ] , with the following changes (table ) . we changed the sepsis definition to align with sepsis- (appendix , online supplement). in addition, we changed the definition of severe pulmonary dysfunction from specific diagnoses (ards, bilobar pneumonia, bronchopleural fistula, or pulmonary embolism) to receipt of significant respiratory support (high-flow oxygen, invasive mechanical ventilation, or non-invasive positive-pressure ventilation) to better capture patients with severe pulmonary dysfunction. if a patient underwent withdrawal of life support before meeting any of the objective organ dysfunction criteria outlined in table , abstractors were instructed to assign irreversible dysfunction to the organ system primarily responsible for the decision to withdraw life support in order to accurately capture cause of death (appendix , online supplement). finally, as in stapleton et al., we defined multi-organ failure as organ dysfunction in at least two organ systems [ ] . for each patient, we assessed ( ) the primary organ system responsible for death, ( ) whether death was related to progression of an initial ahrf risk factor or a complication after ahrf, and ( ) whether withdrawal of life support occurred prior to death. the primary organ system responsible for death was defined as the organ dysfunction ( table ) that most directly resulted in the patient's death or the decision to withdraw life support (appendix , online supplement). for patients with a primary cause of death other than pulmonary dysfunction, cause of death was further classified as being due to progression of an ahrf risk factor (e.g., sepsis, aspiration) or a complication that arose after ahrf onset (appendix , online supplement). withdrawal of life support was determined from clinical documentation of intent to withdraw life support and/or not escalate life support in the event of clinical decompensation and subsequent removal or nonescalation of life-sustaining interventions. we present data as numbers (proportions) or medians (inter-quartile range). we compared characteristics of ards vs non-ards patients using chi-square and kruskal-wallis tests and considered p < . to be significant. data analysis was completed in r. the study was deemed exempt by the institutional review board since all patients were deceased. we identified adult patients with ahrf who died during a hospitalization in - , of whom ( %) had ards. the cohort was a median age of years ( - ), % female, % white, and had a median sofa score of ( ) ( ) ( ) ( ) ( ) at ahrf onset. most patients were admitted to a medical icu ( %). patients had a median of ( - ) risk factors for ahrf, most commonly non-cardiogenic shock ( % of patients), transfusion ( %), sepsis ( %), and pneumonia ( %, table ). patients with ards had a higher median sofa score within the first h of ahrf onset ( vs ; p = . ) and had higher prevalence of pneumonia ( % vs %; p < . ), aspiration ( % vs %; p = . ), and noncardiogenic shock ( % vs %; p < . ) compared to patients who did not meet the berlin definition of ards (table ) . among the patients, there were occurrences of organ system dysfunction in the h prior to death (etable , online supplement). there were ( . %) patients that had multiple organ systems with irreversible dysfunction. the most common organ system dysfunctions were pulmonary ( %), neurologic ( %), and cardiac ( %). sepsis was present in ( %) patients and patients ( %) had multi-organ failure prior to death. however, irreversible pulmonary dysfunction was only present in ( %) patients (table )- ( % of all patients) with insupportable oxygenation or ventilation, and patients with withdrawal of life support because of a poor pulmonary prognosis. patients with ards higher rates of sepsis ( % vs %; p < . ), pulmonary dysfunction ( % vs %; p < . ), irreversible pulmonary dysfunction ( % vs %; p = . ), and hematologic dysfunction ( % vs %; p = . ) compared to patients without ards. overall, the most common primary causes of death were sepsis ( %), pulmonary dysfunction ( %), and neurologic dysfunction ( %, fig. ). among the patients whose primary cause of death was not pulmonary dysfunction, ( % of all patients) died primarily due to progression of an ahrf risk factor and ( %) died primarily due to complications that arose after the onset of ahrf (table ). cause of death by icu setting can be found in etable in the supplementary appendix, with some variation in causes of death noted. ards patients were more likely to have a primary cause of death due to pulmonary dysfunction ( % vs %; p = . ) compared to patients without ards and less likely to have a primary cause of death from cardiac dysfunction ( % vs %; p = . , table ). in addition, ards patients were also more likely to die while receiving substantial respiratory support ( % vs %; p < . ). the majority of patients ( %) died after withdrawal of life support. the proportion of deaths that occurred after withdrawal of life support did not differ between patients with and without ards ( % vs %; p = . , table ). in this contemporary cohort of adult patients with ahrf, the most common primary causes of death were sepsis, pulmonary dysfunction, and neurologic dysfunction. the majority of patients had multi-organ failure prior to death, most commonly due to sepsis. more than half of patients were receiving substantial respiratory support at the time of death and the vast majority of patients died after withdrawal of life support. sepsis and pulmonary dysfunction were the top two primary causes of death among both patients with and without ards. our study is consistent with prior reports indicating that sepsis is the leading cause of death among patients with respiratory failure. stapleton et al. found that sepsis was the most common cause of death in ards patients pulmonary°inability to liberate from mechanical ventilation, non-invasive ventilation, or heated high flow nasal cannula due to inadequate oxygenation or ventilation without aforementioned support insupportable oxygenation or ventilation defined as pao < mmhg on fio - . for > h or respiratory acidosis with ph < . on maximum ventilator settings ∞ . option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to pulmonary organ system dysfunction. either cardiac output < . l/min/m or documented cardiogenic shock or reversible ventricular fibrillation or asystole cardiogenic shock or arrhythmia not responsive to treatment. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to cardiac organ system dysfunction. glasgow coma scale < for ≥ days meets brain death criteria. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to neurologic organ system dysfunction. microvascular bleeding with either fibrinogen < mg/dl, prothrombin time and partial thromboplastin time > . times control, or platelets < , /μl ongoing microvascular bleeding not surgically correctable with map < mmhg not reversible with blood products. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hematologic organ system dysfunction. hemorrhage map < mmhg for > h (or requiring vasopressors) necessitating blood transfusions and excluding other causes of hypotension uncontrollable "surgical" bleeding from a non-microvascular source. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hemorrhage. hepatic bilirubin > . mg/dl and albumin < . g/dl and prothrombin time or partial thromboplastin time > . times control severe criteria plus hepatic encephalopathy and/or hepatorenal syndrome not responsive to treatment. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to hepatic organ system dysfunction. gastrointestinal resectable ruptured or necrotic bowel, or pancreatitis causing shock (map < mmhg for > h or requiring vasopressors) inoperable ruptured or necrotic bowel or pancreatitis causing irreversible shock. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to gastrointestinal organ system dysfunction. either creatinine > . mg/dl or requiring hemodialysis renal failure with acidosis, hyperkalemia, and/or hypercalcemia causing irreversible cardiac arrest. option was given to apply irreversible dysfunction if care was withdrawn due to poor prognosis related to renal organ system dysfunction. *definition of sepsis changed to reflect current practices. please see appendix , online supplement for previous definition of severe and irreversible sepsis syndrome°d efinition of severe pulmonary organ system dysfunction changed to reflect current practices. previously defined by stapleton et al. as "[acute respiratory distress syndrome], bilobar pneumonia, bronchopleural fistula, or pulmonary embolism documented by high-probability ventilation/perfusion scan or pulmonary angiogram" ∞ pao arterial partial pressure of oxygen, fio fraction of inspired oxygen † blood pressure parameters previously described by stapleton et al. as "hypotension" for irreversible hematologic organ system dysfunction or "systolic bp < " for severe hemorrhagic and gi organ system dysfunction changed to "map < mmhg" treated in the s [ ] . despite increased attention to earlier identification and treatment of sepsis in the intervening decades [ , ] , our study found that sepsis remained the most common cause of death in ahrf patients. this is consistent with recent studies showing that sepsis is the leading contributor to death among patients hospitalized for any cause [ ] . sepsis was slightly more common in patients with ards than those without ards, which may reflect the higher rates of pneumonia and sepsis as risk factors for ards. however, it may also suggest that ards patients are at a heightened risk for secondary infections compared to patients without ards. these findings suggest that therapies targeting sepsis-induced multi-organ dysfunction may have the greatest impact on survival among ahrf patients. we found only small differences in the causes and circumstances of death among ahrf patients with and without ards. patients with ards were more likely to have a pulmonary dysfunction as the primary cause of death and more likely to die while receiving substantial pulmonary support than patients without ards. this indicates that the berlin ards definition identifies a subset of patients with ahrf who are more likely to die directly from respiratory failure and would benefit from therapies to enhance resolution of respiratory failure. however, the difference in rates of pulmonary dysfunction as the primary cause of death was relatively small among patients with and without ards. our study confirms the findings in prior studies indicating that insupportable oxygenation and/or ventilation is rare among patients with respiratory failure. one of the major findings of stapleton et al.'s study was the relatively low proportion of deaths due to insupportable ahrf acute hypoxemic respiratory failure, ards acute respiratory distress syndrome *sofa sequential organ failure assessment. represents the highest sofa score within the first h of ahrf onset † other risk factors for ards/ahrf, each present in < % of the cohort, include major trauma ( %), major surgery ( %), pulmonary contusion ( %), pancreatitis ( %), major burn ( %), inhalation injury ( %), vasculitis (< %), or drowning ( %) oxygenation or ventilation, occurring in only - % [ ] . given the increased awareness and effort to treat sepsis in the period after this original study, we hypothesized that pulmonary dysfunction may be a more common primary cause of death in a contemporary ahrf cohort. however, we found that only % of patients had pulmonary dysfunction as the primary cause of death, and only a handful of patients ( %) had insupportable oxygenation and/or ventilation. there are several potential explanations for these findings. first, with more consistent use of lung protective ventilation, contemporary ahrf patients may be less likely to develop ventilator induced lung injury and progressive respiratory failure [ ] . second, patients with severe ards may be more likely to be initiated on extra-corporeal membrane oxygen therapy prior to developing refractory pulmonary dysfunction [ ] . finally, other strategies such as prone positioning may prevent refractory hypoxemia [ ] . however, these hypotheses do not explain why a similar proportion of patients still ultimately die from respiratory failure despite not developing insupportable oxygenation and/or ventilation. while some patients may be supported through the initial phase of their respiratory failure, eventually life support is withdrawn when providers are unable to completely reverse their need for significant respiratory support. our study also highlights the increasing proportion of deaths that occur after a decision to withdraw or not escalate life support. stapleton et al. showed that from to , the proportion of ards deaths that occurred after withdrawal of life support rose from to % [ ] . similar trends have been reported for all-cause critically ill patients during this time period [ ] . our study suggests that this trend has continued, as we report that % of all deaths among ahrf are now occurring after a decision to withdraw or not escalate life support. our finding is also consistent with a recent study showing that % of deaths among critically ill patients treated in europe from to occurred in the setting of treatment limitations [ ] . there are likely several explanations for why a growing proportion of deaths occur after withdraw of life support. stapleton et al. hypothesized that icu clinicians have earlier and more frequent goals-of-care discussions [ ] , as is recommended in various clinical practice guidelines [ ] . indeed, early multidisciplinary meetings with patients and families may lead to an earlier transition to palliative care among patients likely to die [ , ] . more recently, there has been increased emphasis on family involvement in icu decision-making and treatment planning, for example, as recommended in the abcdef treatment bundle [ ] . overall, the greater emphasis on family involvement in early shared decision making may contribute to earlier transitions to palliation among patients who ultimately die in the icu [ ] . our study has several limitations. first, as a singlecenter study, it is possible that it may be lacking generalizability. however, we examined all deaths among patients with ahrf over a -year period who were treated in distinct icus with different practice patterns. as such, we believe these findings are more broadly applicable. second, while we tried to harmonize our study definitions to those of stapleton et al. to facilitate cross-study comparisons, some changes had to be made to account for interval changes in definitions (e.g., sepsis) and treatments (e.g., high-flow oxygen). we limited deviations in study definitions to those deemed absolutely necessary to reflect the current state of icu practice. third, patients were classified as having undergone withdrawal of life support regardless of the time lag between withdrawal and death. for patients in whom only minutes elapsed between withdrawal of support and death, death may be more accurately representative of the cessation of medical interventions due to futility. however, our approach for determining rates of withdrawal and the rates of withdrawal we observed are consistent with prior reports [ ] . fourth, given a high rate of withdrawal of life support, the most proximate cause of death is cessation of support. however, our methodology identifies which organ dysfunction or syndrome most directly led to that decision, thereby reflecting the primary pathophysiologic cause of death. fifth, there may be some subjectivity to assigning cause of death. however, we developed a standardized approach to assess causes of death based on the presence of irreversible and severe organ dysfunctions and confirmed excellent interrater reliability in identifying the primary cause of death among reviewers, which serves to strengthen the validity of our methodology. furthermore, chart review was performed by physicians only, as medical training may limit the subjectivity in identifying cause of death. in this contemporary cohort study of patients who died after ahrf, the most common primary causes of death were sepsis and pulmonary dysfunction. few patients had insupportable oxygenation or ventilation, but most received substantial respiratory support in the h prior to death. the vast majority of deaths occurred after a decision to withdraw or not escalate life support. patients with ards were more likely to have a primary cause of death of pulmonary dysfunction and to receive substantial respiratory support during the h prior to death. supplementary information accompanies this paper at https://doi.org/ . /s - - -w. additional file : appendix . redcap abstraction tool. appendix . inter-rater reliability. appendix . previous definition of severe and irreversible sepsis syndrome. appendix . examples. appendix . determining cause of death by organ system. etable . total organ system dysfunction. etable . cause of death by icu setting. abbreviations ahrf: acute hypoxemic respiratory failure; ards: acute respiratory distress syndrome; icu: intensive care unit; sofa: sequential organ failure assessment the epidemiology of acute respiratory failure in critically iii patients epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries causes and timing of death in patients with ards an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial a binational multicenter pilot feasibility randomized controlled trial of early goal-directed mobilization in the icu early intensive care unit mobility therapy in the treatment of acute respiratory failure increasing incidence of withholding and withdrawal of life support from the critically ill palliative care in intensive care units: why, where, what, who, when, how the changing role of palliative care in the icu interobserver reliability of the berlin ards definition and strategies to improve the reliability of ards diagnosis differences between patients in whom physicians agree and disagree about the diagnosis of acute respiratory distress syndrome evaluating delivery of low tidal volume ventilation in six icus using electronic health record data acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material surviving sepsis campaign: international guidelines for management of sepsis and septic shock the third international consensus definitions for sepsis and septic shock (sepsis- ) hospital deaths in patients with sepsis from independent cohorts comparison of the berlin definition for acute respiratory distress syndrome with autopsy extracorporeal life support organization registry report prone positioning in severe acute respiratory distress syndrome changes in end-of-life practices in european intensive care units from to an intensive communication intervention for the critically ill impact of a proactive approach to improve end-of-life care in a medical icu the abcdef bundle in critical care limitation of life-sustaining care in the critically ill: a systematic review of the literature publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank daniel molling, ms, of va ccmr, for his careful data analysis. authors' contributions sk made substantial contributions to the conception and design of the work, acquisition, analysis, and interpretation of the data, and drafted and substantively revised the work. ys, hm, tb, aw, ic, dc, and jm made substantial contributions to the acquisition of data. hp made substantial contributions to the conception and design of the work, analysis, and interpretation of the data and drafted and substantively revised the work. ms made substantial contributions to the conception and design of the work, acquisition, analysis, and interpretation of the data and drafted and substantively revised the work. all authors have approved the submitted version and have agreed both to be personally accountable for the authors' own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. dr. prescott was supported in part by k gm from the nih/nigms. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. this study was approved by the university of michigan institutional review board. this study does not involve living individuals and therefore consent was waived. competing interests this material is the result of work supported with resources and use of facilities at the ann arbor va medical center. this manuscript does not represent the views of the department of veterans affairs or the us government. the authors declare that they have no competing interests. key: cord- -i s fh authors: bromberg, z.; deutschman, c. s.; weiss, y. g. title: cell regeneration in lung injury date: journal: intensive care medicine doi: . / - - - - _ sha: doc_id: cord_uid: i s fh the acute respiratory distress syndrome (ards) is a lethal inflammatory disorder of the lung. its incidence is estimated at cases per , population and appears to be increasing [ ]. even with optimal treatment, mortality is about % [ – ]. as such, ards represents a major public health problem. the effects of two recent crises created by unusual viral infections of the respiratory tract — the severe acute respiratory syndrome (sars) epidemic caused by the novel sars coronavirus [ ], [ ] and the bird flu [ ] highlight the importance of research into ards. both viruses cause an ards-like picture. because lung repair and regeneration contribute substantially to the pathophysiology of ards, understanding these processes is essential [ ]. this chapter focuses on specific cell populations and markers involved in cell division and regeneration. in addition, a brief review of two pathways intimately associated with cell division is provided because of their potential for pharmacologic manipulation. ards is primarily a disease of disordered inflammation. early ards is characterized by increased inflammation where alveolar epithelial cells are damaged and ultimately may be destroyed [ ] [ ] [ ] . while some mechanisms contributing to the pathophysiology of ards have been identified, most are poorly understood. as a result, treatment is largely supportive. a better understanding of the fundamental biological changes leading to ards would be of scientific and therapeutic value. the magnitude of injury to the alveolar epithelial barrier is one of the most important determinants of the severity of lung injury [ ] . similarly, early repair of epithelial injury may be a major determinant of recovery. most recent therapeutic approaches were developed to attenuate pulmonary inflammation and thus minimize the initial injury [ ] . unfortunately, specific interventions to accelerate alveolar epithelial repair do not exist. this reflects our limited understanding of the cellular mechanisms that modulate alveolar epithelial repair in ards. histological sections from patients dying of ards and from animal models of the disease demonstrate that the first abnormality is interstitial edema. this is followed by severe damage that is characterized primarily by extensive necrosis of alveolar type i (ati) cells [ ] . pathological examination of lung tissue from patients with sars was similar to changes seen in established ards. this included diffuse alveolar damage, desquamated epithelial cells, atii hyperplasia, fibrin and collagen deposition in the alveolar spaces, and a loss of the normal barrier crucial for gas exchange [ , - ] cell regeneration is a fundamental biological response to cell damage. through adult life, multicellular organisms must generate new cells to maintain the structure and function of their tissues [ ] . this is especially important in the lung. the adult lung is a vital and complex organ that normally turns over slowly. nevertheless, it is able to respond to specific injuries that mimic damage caused by environmental or infectious agents [ ] . in most cases, pulmonary injury predominantly affects ati cells. these highly differentiated and flat cells facilitate gas exchange. in contrast, the cuboidal, metabolically-active atii cells that produce surfactant and other products essential to pulmonary function may be relatively spared. following injury, regeneration of alveolar epithelial cells proceeds via an organized paradigm where atii cells and other specific stem cells appear to function as progenitor cells for ati cells [ - ] (fig. ). most research in ards has focused on the finding that atii cells ( ) can be found adjacent to neuroendocrine bodies. within proximal bronchioles, two types of cells can transdifferentiate. ciliated cells may proliferate and transdifferentiate into clara cells after injury ( ) while clara cells may proliferate after injury and give rise to ciliated cells ( ) . at the bronchioalveolar duct junction (badj) between the conducting and respiratory epithelium, columnar clara cells ( ) can serve as progenitors. a sub-population of clara cells termed bronchioalveolar stem cells (bascs) ( ), retains features of stem cells and may also participate in lung repair. in the alveolus, atii cells ( ) give rise to ati cells ( ) after injury. left panel: following lung injury atii cells may reenter the cell cycle, differentiate into ati cells and spread along alveolar septa. this results in coverage of denuded basement membrane and re-establishment of epithelial continuity. in severe inflammation or pulmonary fibrosis, however, proliferation of atii cells may become excessive. this can prevent appropriate replacement of ati cells and lead to fibrosis and scarring. the precise control mechanisms and pathways involved in these processes are unknown. modified from [ ] with permission cell regeneration in lung injury reenter the cell cycle, differentiate into ati cells and spread along alveolar septa. this results in coverage of denuded basement membrane and re-establishment of epithelial continuity [ , , ] . in severe inflammation or pulmonary fibrosis, however, proliferation of atii cells may become excessive (fig ) . this can prevent appropriate replacement of ati cells and lead to fibrosis and scarring [ , ] . in such a situation, the fibrinous alveolar exudate characteristic of acute lung injury (ali) will be covered by the migrating atii cells. this transforms the intra-alveolar debris into interstitial tissue and stimulates fibrosis [ - ] . the significant morbidity and mortality associated with these pathological changes accentuates the importance of deciphering the mechanisms involved in cell division, repair and differentiation. for all living eukaryotic organisms it is essential that the different phases of the cell cycle be precisely coordinated and that one phase be completed before the next phase is entered (fig ) . in the first phase, g , the cell enlarges. when it has reached fig. . the e f-retinoblastoma (rb) cell signaling pathway controlling the g /s restriction point of proliferating cells. passage through the restriction point and transition to s phase is triggered by the activation of the cyclin d /cdk complex. this phosphorylates rb. phosphorylated rb dissociates from e f and is degraded further by the proteasome. e f binds to the chromosome and initiates dna replication. cyclin e/ cdk accumulates during late g phase and triggers passage into s phase. the entire genome is replicated during the s phase. cyclin a/cdk accumulates during s phase and activates transition to the g phase. this results in inhibition of dna replication, cell growth and new protein synthesis a certain size, it enters s phase, in which dna is replicated. this is followed by the g phase, where there is an internal check to assure that dna-replication is completed and that the cell is prepared to divide. finally, in the mitosis or m phase, chromosomes separate and cell division occurs. after m phase, most cells exit the cell cycle and enter a resting stage [g ]. however, some re-enter the cycle and remain in the g phase for a prolonged period, awaiting a signal to proceed on to the s phase. this resting point in the g phase is often referred to as the 'g restriction point'. cell division is initiated when the integration of diverse metabolic, stress and environmental signals stimulate a transition past the g restriction point and facilitate entry into s phase [ ] . several pathways control pulmonary cell replication at the g restriction point. we will briefly describe two major pathways: e f-retinoblastoma (rb) and wnt/ qcatenin. these pathways may prove to be important sites for future pharmacological interventions. the e f-rb pathway is critical in controlling progression beyond the g restriction point (fig. ) [ , ] . passage through the restriction point and transition to s phase is triggered by the activation of the cyclin d /cdk complex that phosphorylates rb. phosphorylated rb dissociates from e f. e f binds to the chromosome and initiates dna replication. cyclin e/cdk accumulates during late g phase and triggers the passage into s phase. the entire genome is replicated during s phase. cyclin a/cdk accumulates during s phase and its activation triggers the transition to g , a phase characterized by the accumulation of cyclin b/cdc , which results in the inhibition of dna replication, cell growth and new protein synthesis [ , ] the wnt/␤catenin cell signaling pathway the wnt/ q catenin cell signaling pathway has been shown to be fundamental for cell division, regeneration, and differentiation processes [ ] . within this pathway, q -catenin is a key effector of the wnt signaling pathway (fig. ) , and persists as an important regulator of homeostasis in adult self-renewing tissues. q -catenin has been shown to participate in signal transduction in epithelial cells. specifically, activation of q -catenin results in a loss of differentiation and trans-differentiation of mammary epithelial cells into epidermis-like structure [ ] . others have shown that the wnt/ q -catenin cell signaling pathway is activated in idiopathic pulmonary fibrosis [ ] . further, q -catenin has been shown to regulate differentiation of respiratory epithelial cells in vivo. an activated form of q -catenin was expressed in respiratory epithelial cells of the developing lung. activation of q -catenin caused ectopic differentiation of atii-like cells in conducting airways, goblet cell hyperplasia, and airspace enlargement, demonstrating a critical role for the wnt/ q -catenin signal transduction pathway in the differentiation of the respiratory epithelium in the postnatal lung [ ] . stem cells are cells capable of limited self-renewal. they can develop into more differentiated cell types [ ] . stem cell turnover is relatively slow, allowing them to act cell regeneration in lung injury fig. . cell replication at the g restriction point-wnt/ q -catenin cell signaling pathway. left panel: wntstimulation leads to reduction of gsk- q kinase activity via phosphorylation. as a result, q -catenin is retained in the cytoplasm. once q -catenin accumulates it can further translocate to the nucleus. in the nucleus, q -catenin binds to tcf/lef and acts as a co-activator to stimulate transcription of target genes such as c-myc and cyclin d . this facilitates cell proliferation. right panel: in the absence of wnt activation, dsh, through its receptor frizzled, causes gsk- q dissociation from axin. axin and adenomatous polyposis coli (apc) gene products serve as a scaffolding for phosphorylation of q -catenin by the enzyme gsk- q . the phosphorylated form of q -catenin is targeted for ubiquitination and proteasomal degradation. this prevents transcription of q -catenin target genes. as a source for differentiated cells throughout the lifespan of the organism [ ] . embryonic stem cells are divided from the inner cell mass of the blastocyte and are considered 'totipotent' in that they can regenerate all three germ layers of an organism. in contrast, adult stem cells are considered multi-or 'unipotent', able to give rise to one or several mature cell types [ , ] . two major categories of tightly regulated adult stem cells have been described: the 'dedicated' stem cells capable of long term self renewal and the transient amplifying (ta) daughter cells characterized by a high rate of proliferation. ta cells can self-renew over a short period [ , ] . in addition, adult stem cells, called 'progenitor cells', are found in a number of adult tissues, including the lungs [ , , , ] , where constant exposure to potential toxic agents and pathogens in the environment may require that cells regenerate rapidly and effectively. these progenitor cells are patterned very early in embryogenesis [ , ] . there is evidence that some differentiated epithelial cell types can act as progenitor cells and proliferate and 'transdifferentiate' in response to specific conditions [ ] . the pulmonary tree contains cells with potential stem cell properties in distinct anatomical regions of the respiratory tree and lung [ , ] . these include the submucosal gland ducts and intercartilagenous region of the tracheobronchial tree, neuroepithelial bodies in the bronchioloes, and the bronchoalveolar duct junctions [ , ] . in the trachea and bronchioles, secretory progenitor cells can be found. immunostaining for the nuclear proliferative marker, ki , expressed in proliferating cells, has been shown in human proximal airways to correlate with the most highly proliferative cells [ ] . within the proximal area, ciliated clara cells are present in small numbers adjacent to neuroendocrine bodies. non-ciliated, columnar clara cells located at the junction between the conducting and respiratory epithelium (bronchioalveolar duct junction [badj]) label with bromodeoxyuridine (brdu, a thymidine analog incorporated into dna during the s phase). such label retaining cells could repair the tracheal airway epithelium after polidocanol detergent or inhaled so injury [ ] . another mouse model of lung injury using naphthalene inhalation resulted in loss of most of clara cells of the badj area. however, these cells can be divided into two distinct populations, based on their susceptibility to naphthalene injury [ ] . one sub-population of clara cells retains features of stem cells. this regional pulmonary stem cell population was termed bronchioalveolar stem cells (bascs) [ ] . these cells, identified by a dual expression of the clara cell secretory protein (ccsp) and surfactant protein-c (sp-c) [ ] , are resistant to bronchiolar and alveolar damage and proliferate during epithelial cell renewal. circulating progenitor cells also may have a role in lung repair. recently, one distinct population of blood-borne, mesanchymal stem cells was found to be associated with engraftment of donor derived atii cells [ ] . thus use of exogenous cells to supplement the regenerative process in the lung may be feasible. type ii pneumocytes also may function as stem cells. atii cells have been shown to self renew and to give rise to ati cells after lung injury [ , ] . this atii progenitor function may depend on the nature of the airway injury and the microenvironment [ , ] . specifically, there appear to be two subpopulations of atii cells. these are distinguished by expression of a specific marker. hyperoxic injury in rats induces expression of e-cadherin in some atii cells [ ] . this e-cadherin positive subpopulation has minimal levels of telomerase activity, indicating a low proliferative index. in contrast, the e-cadherin negative subpopulation expresses high levels of telomerase activity and proliferates well in culture. several well differentiated cell lines in the lung can undergo 'transdifferentiation'; these include the clara cells that differentiate into ciliated cells and the atii cells that differentiate into ati cells. accumulated evidence suggests that epidermal growth factor (egf), transforming growth factor-q (tgf-q ) and the related receptor, epidermal growth factor receptor (egfr), may regulate epithelial repair in vivo and in vitro. tgf-q is elevated in pulmonary edema fluid from patients with ards and has been shown to induce alveolar epithelial repair in vitro [ ] . other studies have reported an increased concentration of cytokines (tumor necrosis factor [tnf]-[ , interleukin [il]- , il- , and il- ) in the broncholaveolar lavage (bal) fluid of patients with acute phase ards [ ] . among the cytokines implicated in lung fibrosis, tnf-q , a multifactorial peptide capable of enhancing mesenchymal cell proliferation and extracellular matrix synthesis [ ] , plays a fundamental role. the presence of receptors for this protein cell regeneration in lung injury after lung injury may contribute to the upregulation of tgf-q expression [ ] . additionally, tgf-q has been associated with the pathogenesis of pulmonary fibrosis [ ] . a variety of pro-inflammatory cytokines have been shown to upregulate keratinocyte growth factor (kgf) and hepatocyte growth factor (hgf). the roles of these proteins have been investigated widely and it appears that they play an important role in both normal lung development and in injured lung repair. indeed, kgf and hgf may have therapeutic potential in lung disease. endogenous kgf plays an important role in epithelial repair. studies in animal models of hyperoxia, demonstrated a -fold increase in kgf mrna [ ] . this increase was followed by increased atii cell proliferation, suggesting that kgf stimulates atii hyperplasia [ ] . endogenous hgf from both bronchial epithelial cells and alveolar macrophage participates in the reparative response to lung injury [ ] . it is of interest that the lung may be a source of hgf after injury to other organs. six hours after partial hepatectomy, hgf levels within the lung were increased [ ] . similar elevations in lung, liver, and kidney were noted in acute pancreatitis [ ] . these findings suggest that the lungs serve as an endocrine organ, contributing to organ repair and regeneration by excreting hgf [ ] . a feedback mechanism may be operative as atii cells express the c-met receptor for hgf [ ] . il- plays a key role in liver regeneration [ ] . for example, this cytokine appears to initiate hgf synthesis [ ] . absence of il- has been associated with failed regeneration in septic liver injury [ ] . il- is elevated in lung injury and also may impact on repair mechanisms in chronic pulmonary inflammatory disorders. previously published studies have examined the role of il- on proliferation and cell-cycle kinetics in primary human lung fibroblasts obtained from patients with idiopathic pulmonary fibrosis. il- was mitogenic for idiopathic pulmonary fibrosis fibroblasts. this effect appears to involve a sustained activation of mitogen-activated protein kinase (mapk) that, in turn, inhibited the production of p kip . this allowed activation of cyclin d and hyperphosphorylation of rb protein [ ] (fig ) . in an ozone/cigarette smoke model of lung injury, brdu labeling within terminal bronchiolar epithelium and proximal alveolar regions was significantly reduced in il- knowck-out mice compared to il- sufficient mice. further, ccsp abundance was markedly reduced in the terminal bronchiolar epithelium of these il- knock-out mice [ ] . pulmonary surfactant forms the surface-active film that is crucial for normal lung function. this substance consist of complexes of phospholipids and four protein components known as surfactant-associated proteins [ , ] . among them, sp-a has important autocrine effects on cells of the lung epithelium. atii cells produce and secrete pulmonary surfactant proteins. sp-a signals through an atii cell surface receptor and regulates anti-apoptotic gene expression. hence, surfactant proteins may represent a local regulatory system for cell regeneration. in ards, cell proliferation may be either beneficial or detrimental (fig. ) . early in the disease process, when loss of pulmonary epithelial cells may contribute to pathology, enhancing cell division may be of value. however, cell division also may increase vulnerability to oxidative stress-induced dna damage. in contrast, in the fibroproliferative phase of the disease, cell overgrowth contributes to pathological scarring and fibrosis. hence, increased knowledge on the mechanisms and pathways of cell division and regeneration may stimulate the development of novel pharmacological interventions. due to the complex nature of the mechanisms and time course involved in the pathophysiology of ards, understanding of the role of ards-associated cellular proliferation is essential. the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome a novel coronavirus associated with severe acute respiratory syndrome epidemiological and genetic analysis of severe acute respiratory syndrome bird flu, influenza and : the case for mutant avian tuberculosis ace receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia mechanisms of alveolar epithelial repair in acute lung injury--a translational approach pulmonary edema fluid from patients with acute lung injury augments in vitro alveolar epithelial repair by an il- beta-dependent mechanism lung pathology of severe acute respiratory syndrome (sars): a study of autopsy cases from singapore pulmonary pathology of severe acute respiratory syndrome in toronto pathological study on severe acute respiratory syndrome tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases epithelial stem cells of the lung: privileged few opportunities for many? mouse strain modulates the role of the ciliated cell in acute tracheobronchial airway injury-distal airways stem cells and pulmonary metamorphosis: new concepts in repair and regeneration identification of bronchioalveolar stem cells in normal lung and lung participation of pulmonary alveolar epithelial cells in lung inflammation alterations in the alveolar epithelium after injury leading to pulmonary fibrosis branching and differentiation defects in pulmonary epithelium with elevated gata expression state of the art: surfactant and the adult respiratory distress syndrome damage to surfactant-specific proteins in acute respiratory distress syndrome serial changes in surfactant-associated proteins in lung and serum before and after onset of ards murine coronavirus replication induces cell cycle arrest in g /g phase the e f transcriptional network: old acquaintances with new faces cyclin c/cdk promotes rb-dependent g exit the pezcoller lecture: cancer cell cycles revisited wnt signaling in the intestinal epithelium: from endoderm to cancer activation of beta -catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias aberrant wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis beta catenin regulates differentiation of respiratory epithelial cells in vivo stem cells and chronic lung disease stem cells: a new lease on life an introduction to stem cells socializing with the neighbors: stem cells and their niche evidence for stemcell niches in the tracheal epithelium progenitor cells of the adult human airway involved in submucosal gland development terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction identification of bronchioalveolar stem cells in normal lung and lung cancer number and proliferation of basal and parabasal cells in normal human airway epithelium mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects stem cells of the alveolar epithelium isolation of a putative progenitor subpopulation of alveolar epithelial type cells interleukin- and development of adult respiratory distress syndrome in at-risk patient groups macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation expression of tnf and the necessity of tnf receptors in bleomycin-induced lung injury in mice hyperoxia increases keratinocyte growth factor mrna expression in neonatal rabbit lung alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice hepatocyte growth factor increases in injured organs and functions as an organotrophic factor in rats with experimental acute pancreatitis keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair liver failure and defective hepatocyte regeneration in interleukin- -deficient mice recombinant human interleukin- induces hepatocyte growth factor production in cancer patients sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin- -/-mice fibroblasts isolated from normal lungs and those with idiopathic pulmonary fibrosis differ in interleukin- /gp -mediated cell signaling and proliferation the role of interleukin- in pulmonary inflammation and injury induced by exposure to environmental air pollutants survival signaling in type ii pneumocytes activated by surfactant protein-a key: cord- -ga dzj v authors: tsolaki, vasiliki; zakynthinos, george e. title: are patients with covid- dying of or with cardiac injury? date: - - journal: am j respir crit care med doi: . /rccm. - le sha: doc_id: cord_uid: ga dzj v nan i thank dr. modesto-alapont and colleagues for their thoughtful comments on my editorial ( ) . they state that mechanical ventilation is ideally instituted on the basis of precise diagnosis and cite one of my chapters. the chapter says the exact opposite. indeed, they quote a sentence in which dr. laghi and i say that physicians do not initiate mechanical ventilation consequent to "slotting a patient into a particular diagnostic pigeonhole." ( ) dr. modesto-alapont and colleagues claim that the berlin definition enhances the ability to make a precise diagnosis of acute respiratory distress syndrome (ards) in patients with coronavirus disease (covid- ). on the contrary, the question of whether patients with covid- have typical ards (or not) is presently much debated. but there is a deeper question. criteria used in formulating all definitions of ards (over the past years) have been chosen arbitrarily with the goal of setting tight boundaries to achieve greater uniformity of patients entered into clinical research studies. none of the definitions of ards constitute, in nosological terminology, a "natural kind" ( ) on a clinical, etiologic, or even a physiological level. if pa o /fi o is on positive end-expiratory pressure , the patient has ards by the berlin definition. if, minutes later, body posture is altered and pa o /fi o increases to , the patient no longer has ards. it is imperative that explicit criteria be followed meticulously when entering patients into clinical trials. a wise clinician, however, would believe it daft to switch between diagnostic categories on the basis of a -unit difference on a single laboratory test. leaving aside the arbitrary nature of ards criteria, the diagnosis does not provide justification for a fixed course of action (other than avoiding a vt of ml/kg). some patients with ards undergo invasive mechanical ventilation, whereas others are sustained with high levels of supplemental oxygen or noninvasive ventilation without ever being intubated ( , ) . dr. modesto-alapont and colleagues discuss the role of hypothesis and refutation in science. although they do not state their hypothesis explicitly, it would appear to be along the lines that instituting mechanical ventilation on the basis of a physician's gestalt versus a precise diagnosis results in inferior clinical outcome. they claim that the results of the randomized control trial by the reva research network have tested (and refuted) that hypothesis. leaving aside that the hypothesis does not possess the characteristics of a good hypothesis ( ) , especially in terms of parsimony, the data of the reva trial cannot be used to refute or accept the hypothesis. the focus of the reva trial was the target for oxygenation during the entire course of mechanical ventilation subsequent to intubation. the results of the reva trial do not relate to the decision of whether (or not) to intubate a patient. drawing a parallel between the two is to conflate fundamentally different situations. n comorbidities (hypertension, diabetes, and coronary heart disease), and patients ( %) died from cardiac problems, namely cardiac arrest, acute coronary syndrome (acs), and malignant arrhythmia ( ). cardiac involvement probably complicates severe acute respiratory syndrome coronavirus (sars-cov- ) in patients, but the true incidence (considering specific echocardiographic findings) and the attributable mortality are aspects not yet well clarified. very few reports have used echocardiographic criteria beyond biomarkers to diagnose cardiac injury, but none have differentiated between myocarditis, cardiomyopathy (stress or septic), acs, and acute heart failure in the era of covid- . acute cardiac injury was reported in . % of the fatalities in the report by du and colleagues, but the specific echocardiographic abnormalities are not presented ( ). did these "cardiac injuries" involve patients with myocarditis? or were there features indicative of stress or even septic cardiomyopathy, mostly reversible entities? considering biomarkers, troponin levels are markedly increased in myocarditis and acs. on the contrary, in takotsubo and septic cardiomyopathy, there is a disparity between biomarker levels and the extent of myocardial dysfunction. in addition, hypoakinesia usually does not correspond to a specific coronary artery territory ( ) . therefore, a reference on the nature of cardiac injury would be worthy. a diagnosis of "cardiac injury" mainly relying on biomarker levels may be misleading. in a recent report involving hospitalized patients from wuhan, . % presented with "acute myocardial injury." the diagnosis relied on increased cardiac biomarker (hypersensitive troponin i) levels, regardless of the electrocardiographic and echocardiographic findings ( ). du and colleagues presented a high percentage of patients with "cardiac injury"; data on lactate dehydrogenase, creatinine kinase, and aspartate aminotransferase are reported but not on cardiac-specific enzymes ( ). on the other hand, cardiac-specific biomarkers alone may not be diagnostic of cardiac damage. tni is elevated in septic shock, pulmonary embolism, and critically ill patients in icu. in patients with "cardiac injury," nt-probnp (n-terminal prohormone of brain natriuretic peptide) levels were found to be elevated ( ). however, we have previously found that bnp is a biomarker that correlates with the severity of sepsis ( ) . bnp may be elevated when patients with sars-cov- present septic shock resulting from a superinfection, even with normal cardiac function. additionally, the troponin and bnp levels were normal in a -year-old female patient from our icu, who acutely established pericarditis on the th day after covid- diagnosis. moreover, in figure c of du and colleagues, they present a computed tomographic image of a -year-old female patient with covid- . the cardiac structure seems greatly enlarged; considering the young age of the patient, this finding could correspond to true myocarditis (therefore, ground glass opacities could depict hydrostatic pulmonary edema) ( ) . it would be informative if the authors provided data on this aspect (increased cardiac dimensions on computed tomographic imaging, a finding beyond the criteria used for "cardiac injury" diagnosis). inciardi and colleagues reported a -yearold woman with covid- who presented acute myopericarditis and cardiogenic shock with severe systolic dysfunction, confirmed with magnetic resonance imaging. noteworthy, the patient never presented signs of respiratory involvement ( ) . finally, data on the attributable to cardiac injury mortality are totally lacking ( ) . the proportion of the patients with "cardiac injury" who actually died because of cardiogenic shock is not mentioned. markers of perfusion, such as low central venous oxygen saturation, would add information on the contribution of cardiac dysfunction to the fatal outcome. furthermore, did the patients, dying of malignant arrythmia and cardiac arrest, suffer from cardiac comorbidities? did the arrhythmia occur on a substrate of "myocardial injury," or was this a complication of the prescribed medications (i.e., chloroquine)? all these issues need to be clarified to thoroughly understand the "myocardial damage" that covid- induces. n author disclosures are available with the text of this letter at www.atsjournals.org. basing respiratory management of covid- on physiological principles principles and practice of mechanical ventilation philosophy of medicine: an introduction use of high-flow nasal cannula oxygen therapy in subjects with ards: a -year observational study a multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome consilience: the unity of knowledge clinical features of fatal cases of covid- from wuhan: a retrospective observational study pathophysiology of takotsubo syndrome association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china clinical characteristics of hospitalized patients with novel coronavirusinfected pneumonia in wuhan, china new insights into the mechanisms involved in b-type natriuretic peptide elevation and its prognostic value in septic patients cardiac involvement in a patient with coronavirus disease (covid- ) we appreciate the great interest in our paper in the journal entitled key: cord- -mgsuwft authors: machado, roberto f.; garcia, joe g. n. title: genomics of acute lung injury and vascular barrier dysfunction date: - - journal: textbook of pulmonary vascular disease doi: . / - - - - _ sha: doc_id: cord_uid: mgsuwft acute lung injury (ali) is a devastating ­syndrome of diffuse alveolar damage that develops via a variety of local and systemic insults such as sepsis, trauma, ­pneumonia, and aspiration. it is interestingly to note that only a subset of individuals exposed to potential ali-inciting insults develop the disorder and the severity of the disease varies from complete resolution to death. in addition, ali susceptibility and severity are also affected by ethnicity as evidenced by the higher mortality rates observed in african-american ali patients compared with other ethnic groups in the usa. moreover, marked differences in strain-specific ali responses to inflammatory and injurious agents are observed in preclinical animal models. together, these observations strongly indicate genetic components to be involved in the pathogenesis of ali. the identification of genes contributing to ali would potentially provide a better understanding of ali pathobiology, yield novel biomarkers, identify individuals or populations at risk, and prove useful for the development of novel and individualized therapies. genome-wide searches in animal models have identified a number of quantitative trait loci that associate with ali susceptibility. in this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population- based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ali susceptibility. acute lung injury (ali) is a devastating syndrome of diffuse alveolar damage that develops via a variety of local and systemic insults such as sepsis, trauma, pneumonia, and aspiration [ ] . deranged alveolar capillary permeability, profound inflammation, and extravasation of edematous fluids into the alveolar spaces are critical elements of ali, reflecting the substantial surface area of the pulmonary vasculature needed for alveolar gas exchange. ali, together with its severest form, acute respiratory distress syndrome (ards), afflicts approximately , patients per year in the usa and has a mortality rate of - % [ , ] . it is interestingly to note, however, that only a subset of individuals exposed to potential ali-inciting insults develop the disorder and the severity of the disease varies from complete resolution to death. in addition, ali susceptibility and severity are also affected by ethnicity as evidenced by the higher mortality rates observed in african-american ali patients compared with other ethnic groups in the usa [ ] . moreover, marked differences in strain-specific ali responses to inflammatory and injurious agents are observed in preclinical animal models [ ] . together, these observations strongly indicate genetic components to be involved in the pathogenesis of ali. the role that genetics plays in determining ali risk or the subsequent severity of the outcome is one of the many unanswered questions regarding ali pathogenesis and epidemiology. the identification of genes contributing to ali would potentially provide a better understanding of the pathogenic mechanisms of ali, yield novel biomarkers, identify individuals or populations at risk, and prove useful for the development of novel and individualized therapies. however, a traditional genetic approach to studies using family linkage mapping is not feasible given the sporadic nature of ali and the necessity of an extreme environmental insult. further, genetic studies of ali are challenging owing to the substantial phenotypic variance in critically ill patients, diversity in the lung injury evoking stimuli, presence of varied comorbid illnesses common in the critically ill patient, complex gene-environment interactions, and potentially incomplete gene penetrance [ , ] . despite these inherent challenges, the unrivaled progress made in the post-human genome era combined with the utilization of sophisticated bioinformatics and high-throughput methods have allowed significant advances to be made. for example, these tools are now linked to escalating knowledge of the molecular mechanisms of lung endothelial permeability, a hallmark of ali and an attractive target for the design of novel therapies, to identify candidate genes whose variants are potentially involved in ali susceptibility. genome-wide searches in animal models have identified a number of quantitative trait loci that associate with ali susceptibility [ ] . in this chapter, we utilize a systems biology approach combining cellular signaling pathway analysis with population-based association studies to review established and suspected candidate genes that contribute to dysfunction of endothelial cell barrier integrity and ali susceptibility. the integration of high-throughput gene expression profiling in preclinical models of ali with bioinformatics has led to the identification of differentially expressed genes in response to ali whose variants are potentially involved in ali susceptibility and severity. this approach confirmed long-suspected ali-associated candidate genes, but more importantly, identified novel genes not previously implicated in ali. increasing knowledge of the molecular mechanisms of endothelial-barrier-regulatory pathways has also enhanced the ability to find novel ali candidate genes. the analysis of the molecular pathways involving the cytoskeletal scaffolding and the dynamic cytoskeletal changes driving cell shape alterations, a key feature of vascular permeability, has identified additional genes contributing to the development and severity of ali, thereby providing novel therapeutic targets in this devastating illness. genes encoding proinflammatory cytokines, growth factors and mediators, receptors for barrier-regulatory agonists, and mechanical-stress-sensitive genes expressed in endothelium which regulate inflammatory responses also serve as attractive ali candidate genes and are representative of the diverse but fertile areas of exploration for candidate snps affecting ali susceptibility and severity. angiotensin-converting enzyme (ace) is a member of the rennin-angiotensin system (ras), balancing the levels of angiotensin i and angiotensin ii, with significant expression in lung vascular endothelium as compared with other vascular beds [ ] . the ras is considered to be an important regulator of inflammation that contributes to ali by altering vascular permeability, vascular tone, fibroblast activation, and endothelial-epithelial cell survival [ ] [ ] [ ] . for example, angiotensin ii activates inflammatory processes by upregulating proinflammatory cytokines and chemokines via type i and type ii angiotensin ii receptors that subsequently activate the nuclear factor kb (nf-kb) pathway [ , ] . the ras is also involved in the fibrotic response to ali via induction of transforming growth factor expression [ ] . the most compelling evidence for ras involvement in ali has come from the effective attenuation of ali pathobiology by ace inhibitors or angiotensin receptor blocking drugs [ , ] and ace knockout mice in preclinical models of ali [ ] . an intronic insertion (i) or deletion (d) of a -bp alu repeat sequence in the human ace gene, located on chromosome q , has been associated with ace levels and activity in serum [ , ] . the d allele possesses a higher enzyme activity which parallels the higher gene expression in individuals with dd genotype [ ] . the initial association of the dd genotype in the ace gene with increased ali mortality provided the impetus for subsequent studies to more firmly establish a genetic basis of ali and to identify ali candidate genes [ ] . caucasian patients with ards show significantly higher frequencies of the dd genotype and the d allele as compared with ventilated intensive care unit (icu) patients without ards, patients after coronary artery bypass surgery, or healthy controls. moreover, ards patients with dd genotype show markedly higher mortality ( %) in comparison with the ii genotype ( %) or strike '' '' id genotype ( %) [ ] . the higher mortality rate in ards patients with dd or id genotype as compared with ii genotype was subsequently confirmed in han chinese patients in taiwan, although the frequency of the d allele is significantly lower in the chinese population as compared with western populations [ ] . compared with caucasians, a higher frequency of d allele has been reported among africans (nigerian and african-american populations) [ , ] , potentially contributing to the observed disparity in ali-associated higher mortality rates in african-americans [ ] . however, to date, no association study of ace polymorphisms and lung injury has been performed in african-americans. in contrast, mexican and amerindian populations have slightly lower allelic frequencies of the d allele [ ] . thus, ace represents a highly viable endothelial candidate gene and attractive target in acute inflammatory lung disease. tumor necrosis factor (tnf) a, an early mediator of ali development, is a potent proinflammatory cytokine which dramatically increases endothelial cell permeability, cytokine production, and a variety of cytotoxic and proinflammatory compounds which lead to subsequent vascular leakage and disturbed lung water balance. both tnfa and tnfb subtypes appear in the circulation, in bronchoalveolar lavage (bal) fluid and in pulmonary edema fluid during the onset of lung injury. as such, the elevated levels of tnf and its soluble receptors are commonly used as markers of inflammation and are associated with morbidity and mortality in ali patients [ ] . both the tnfa and tnfb genes lie in close proximity within the major histocompatibility complex, with several polymorphisms described in this region. the - g/a promoter polymorphism in the tnfa gene and the ncoi restriction fragment length polymorphism in the tnfb gene appear to influence the expression of tnfa. the carriers of the - a allele and homozygotes for the tnfb allele exhibit increased tnfa expression and have increased susceptibility and mortality to sepsis [ , ] . in patients with ards, the - a allele is also associated with increased -day mortality, with the strongest association found among younger individuals [ ] . however, in ards patients with direct or indirect pulmonary injury, these snps are associated with alterations in ali susceptibility (tnfa - g/a snp only in the direct pulmonary injury group, and tnfb ncoi only in the indirect pulmonary injury group). owing to the extent of linkage disequilibrium in the region, it remains unclear as to whether these are regulatory snps or if the tnf protein level is modulated by a third locus or a haplotype [ ] . promoter snps within the tnfa gene (- g/a, - c/t) have been associated with inflammatory bowel disease along with the - g/a snp [ ] . thus, the role of tnf variants in inflammatory disorders is apparent and indicates a need for further study of other tnf variants in association with ali. interleukin- (il- ) is an acute-phase response cytokine that plays a key role in the activation of b and t cells. inflammatory cytokines, including il- , are essential for the immune system homeostasis; however, when il- production is exaggerated as observed in inflammatory lung disorders including ali [ , ] , clearly detrimental outcomes are observed. ali-related increased levels of il- have been established in the bal fluid of critically ill patients with ards, sepsis, and trauma [ , ] in association with ali adverse outcome [ ] and development of multisystem organ failure [ ] . in prior reports, we observed significantly higher expression of il- and the il- receptor genes across multiple-species ali models and in human lung endothelium exposed to ventilator-induced mechanical stress as well as in differential region-specific expression in lungs of the canine ali model [ ] [ ] [ ] . on the basis of these data, the il- gene constitutes an excellent candidate gene to understand the genetic basis underlying ali. a functional polymorphism in the il- gene promoter region at the - position (g- c) has been associated with alterations in both gene expression and il- levels and lower circulating il- concentrations and lower mortality rates in patients with acute respiratory failure admitted to the icu [ ] . the contrasting correlation between g- c alleles and circulating il- levels has also been reported [ ] . the haplotype involving - g/c, c/g, and g/c is associated with higher mortality (and other secondary clinical outcomes) in a cohort of septic patients of european descent [ ] . we further evaluated il- gene tagging snps covering the entire gene for potential association in sepsis and ali patients of european descent [ ] . no single snp was identified as significantly associated with ali; however, a common haplotype (comprising - g/- g/- g/ a/ a/ c) with a frequency of % in cases and % in controls showed a significant association with ali susceptibility. in addition, homozygote carriers of the risk haplotype are twice as frequent in ali cases ( . %) than in controls ( . %), yielding a highly significantly increased odds ratio for developing ali (odds ratio . ; % confidence interval, . - . ; p = . ). this haplotype spans the entire il- gene including the g allele at position - , i.e. the risk allele for susceptibility to ali noted above. these data support the association of the il- gene with ali susceptibility and illustrate the value of haplotype analysis as a robust approach in association studies. vascular endothelial growth factor (vegf) is an endothelialcell-specific mitogen that regulates angiogenesis, migration, and cell permeability [ ] . vegf plays an important role in several organs by directly regulating vascular permeability to water and proteins. lung overexpression of vegf induces increased pulmonary vascular permeability, resulting in marked pulmonary edema [ ] , and plasma vegf levels are significantly elevated in ali patients [ ] . several studies have reported the association of low levels of vegf with the severity of ards and elevated levels with the recovery from ards, indicating a role for vegf in the repair process of lung injury [ ] . several polymorphisms have been described in the vegf gene, primarily in association with cancer susceptibility and severity. the c/t snp at position of the ¢ untranslated region (utr) of the gene has been associated with higher vegf plasma levels in healthy subjects [ ] . recently, the c t snp in the vegf gene has been associated with ards susceptibility and severity (increased mortality) in subjects of european descent [ , ] . the haplotype tct at position c- t, c + g, and c + t was significantly associated with a higher rate of mortality in ards patients and higher plasma levels of vegf [ ] . these studies highlight the vegf gene as an attractive barrier-regulatory ali candidate gene and molecular target in ali therapeutic strategies. chemokine receptor (cxcr ) is an a-chemokine receptor specific for stromal-derived factor (sdf- ; also known as cxcl ) that plays an important role in cell migration, inflammation, b lymphocyte development, angiogenesis, and human immunodeficiency virus (hiv) infection (hiv coreceptor) [ ] [ ] [ ] . chemokine receptors are g-protein-coupled receptors, which trigger diverse signaling cascades including activation of g proteins and the phosphatidylinositol -kinase, janus kinase/signal transducer and activator of transcription, rho-p rho kinase, and mitogen-activated protein kinase signaling pathways [ ] . the activation of these signaling pathways is often accompanied by the internalization of chemokine receptors and their trafficking back to the plasma membrane. this intracellular turnover determines the leukocyte responsiveness to chemokines [ ] . nonmuscle myosin ii a is a molecular motor that binds with the cytoplasmic tail of cxcr and ccr and participates in the sdf- -dependent endocytosis of cxcr via dynamic interaction with a-arrestin, a key component of the cxcr internalization pathway [ ] . the cxcr gene was identified as a novel candidate gene in ali as it survived two filtering strategies dedicated to identifying ali-susceptibility genes associated with elevated levels of mechanical stress as observed in mechanical ventilator-associated lung injury (vali). our orthologous gene approach determined ali-specific gene ontologies -coagulation, inflammation, chemotaxis/cell motility, and immune response [ ] -involving recognized genes likely to participate in ali pathogenesis [il- , aquaporin (aqp- ), plasminogen activator inhibitor type i (pai- )], as well as novel genes not previously known to be mechanistically involved in ali, including cxcr [ ] ( table ) . we subsequently utilized a consomic rodent approach with introgression of rat chromosomes , , , and , which contained the highest density of vali-responsive genes [ ] . introgression of the vali-sensitive brown norway (bn) rat chromosome , containing several genes, including cxcr- , into the vali-resistant dahl salt-sensitive (ss) rat resulted in conversion of the ss consomic rats to a valisensitive phenotype [ ] . surface expression of cxcr is downregulated by interleukin- , interleukin- , and granulocyte-macrophage colony-stimulating factor and upregulated by interleukin- and transforming growth factor-b (tgfb) [ ] , suggesting that cxcr may also play a role in the fibrotic response to ali via tgfb signaling. polymorphisms in the cxcr gene have not yet been reported; however, a snp in the ¢ utr of the sdf- gene (g a), is associated with susceptibility to aids and type diabetes [ , ] . we are currently exploring cxcr as a potential ali-associated candidate gene as suggested by the density of pubmatrix citations relating cxcr to inflammation ( , published papers), endothelium ( published papers), ali ( published papers) and endothelial permeability (eleven published papers). pubmatrix is a web-based tool that allows simple text-based mining of the ncbi literature search service pubmed using any two lists of keywords terms, resulting in a frequency matrix of term co-occurrence. the advent of high-throughput gene sequencing and expression technologies, and complete genome sequencing of model organisms, now provides the tools to perform largescale analyses of the genome in complex disorders such as ali. whole genome scans, in silico approaches, utilization of consomic rats, and a candidate gene approach involving expression profiling and pathway analysis are proving exceptionally useful in identifying novel candidate genes and genetic variations (fig. ). high-throughput whole genome scanning technology has recently emerged as a powerful tool, particularly in detecting disease-susceptibility genes with modest effects. the haplotype mapping project [ ] , which identified blocks of snps associated with each other, has allowed selection of the most informative snps for further disease association studies [ ] . currently, the most commonly used high-throughput snp platforms involve assessment of over one million snps spanning the genome, i.e. genome-wide association studies (gwas). gwas platforms are effective and have been successfully used in diverse disorders such as agerelated macular degeneration [ ] , inflammatory bowel disease [ ] , type diabetes [ ] , and stroke [ ] . although this approach has yet to be employed in either sepsis or ali, the application of gwas to the disease is clearly imminent. another method to identify ali candidate genes is an orthologue gene in silico approach. the basis of this approach is the hypothesis that patients with ali and preclinical animal models of ali would exhibit commonality in expression of evolutionarily conserved genes across species. for example, profiling results from more than affymetrix microarray chips obtained from ventilator-associated ali models (human, rat, mouse, canine) identified , genes whose expression was altered across all four species in response to ventilator-associated high-throughput gene sequencing and expression technologies, and complete genome sequencing of model organisms, now provide the tools to perform large-scale analyses of the genome in complex disorders such as ali. genome-wide association study (gwas) platforms are effective and have been successfully used in diverse disorders, but although this approach has yet to be employed in either sepsis or ali, the application of gwas to the disease is clearly imminent. the differential gene expression between lung apex/base regions as well as between gravitationally dependent/nondependent regions of the lung base in a canine model of ventilator-associated lung injury (vali) identified aliimplicated lung genes in response to local mechanical stress within the lung. this approach identified the already established ali gene macrophage migration inhibitory factor and novel genes such as growth arrest dna damage inducible (gadd ) and pre-b cell colony enhancing factor (pbef). our multispecies orthologous gene approach in human (endothelial cells), rat, mouse, and canine models of vali exhibits expression of common ali-implicated evolutionarily conserved genes (orthologues) across the species. the genes with a unidirectional . -fold change (p > . ) are found to reside in high density on rat chromosomes and , the chromosomal loci used to develop the consomic rodent model. together, these approaches identified novel ali genes such as pbef, chemokine receptor (cxcr- ) gadd . interrogating the prospective pathways involved in endothelial permeability and correlation with these differentially expressed genes in vali models identified the most putative ali genes such as myosin light chain kinase (mylk), sphingosine -phosphate receptor , cmet, and vascular endothelial growth factor (vegf) mechanical stress [ , ] . filtering these results for a unidirectional change in gene expression with greater than . fold change in expression refined the list to genes, reflecting specific ali-associated gene module/ontology categories: coagulation, inflammation, chemotaxis/cell motility, and immune response. this approach identified multiple genes already recognized as ali genes (such as il- , aqp- , and pai- ), but also identified several novel genes that were not previously known to be mechanistically involved in ali [ ] . complementing the in silico approach described above, a consomic rat approach can also be utilized to identify novel ali gene candidates. in an experimental study, two strains of inbred rodents were determined to have differing susceptibility to vali ( ml/kg, h): vali-sensitive bn rats and the valiresistant dahl ss rats. using microarray analysis and a bioinformatic-intense candidate gene approach, we identified differentially expressed potential vali genes with ontologies such as transcription, chemotaxis, and inflammation. because chromosomes , , , and were found to contain the highest number of vali-response genes, consomic ss rats containing substituted bn chromosome were exposed to vali mechanical stress, resulting in conversion of the resistant ss rat to vali sensitivity [ ] . extensive expression profiling across preclinical ali models can extend the identification of ali gene candidates to determination of allelic frequencies of gene polymorphisms (snps) that may confer ali risk or severity. this "candidate gene approach" has identified several candidates with hypothesized significant mechanistic roles in lung injury, inflammation, or repair in the setting of ali and vali [ ] . further, given the availability of sophisticated bioinformatic methods and increasing knowledge of the molecular and cellular mechanisms of lung injury, candidate genes can also be identified via analysis of cellular pathways involved in ali pathogenesis [ , ] . the application of the novel techniques described in the previous section is proving to be exceptionally useful in identifying novel candidate genes and genetic variations in the study of the pathobiology of ali. these novel gene and biomarkers are discussed in this section. myosin light chain kinase (mlck) is an enzyme that phosphorylates regulatory myosin light chains, which allows myosin cross-bridging interactions with f-actin. in endothelial cells, the contraction of the actomyosin complex generates a stronger centripetal force that overcomes the force keeping the adjacent endothelial cell tethered, leading to endothelial retraction, decreased intercellular adhesion, and increased vascular permeability [ , ] . this phenomenon is physiologically relevant as evidenced by nonmuscle mlck (nmmlck) isoform knockout mice [which retain the smooth muscle mlck (smmlck) isoform] that are less susceptible to lipopolysaccharide (lps)-and ventilator-induced ali [ , ] . further, treatment with a mlck inhibitor prior to lps exposure in the wild-type mice attenuates endothelial cell barrier dysfunction and inflammation [ ] . thus, the myosin light chain kinase gene (mylk), which encodes for mlck, is an excellent ali candidate gene. since initial cloning of the highly expressed nmmlck in endothelium in our laboratory [ ] , we have identified substantial roles of nmmlck in cytoskeleton rearrangement of endothelial cells regulating vascular barrier function [ , ] , angiogenesis, and leukocyte diapedesis [ ] , consistent with a potential mechanistic role for mlck in the genesis of ali. the human mylk gene is located on chromosome q and encodes three proteins, including nmmlck, smmlck, and telokin. we sequenced exons, exon-intron boundaries, and kb of the ¢ utr of mylk in healthy individuals, patients with sepsis alone, and patients with sepsis-associated ali, all of european and african-american descent [ ] , and identified snps (ten exonic, intronic, nine in the ¢ utr, and one in the noncoding exon ), of which were chosen for further linkage disequilibrium studies. five of the ten coding mylk snps confer an amino acid change (pro his, pro ser, val ala, ser pro, and arg gln) in mlck. subsequently, association analysis of both single snps and haplotypes demonstrated very strong associations in both ethnic groups [ ] . in european americans, the rs a/ mylk_ c haplotype was associated with more than a fivefold increase in the risk of developing ali and sepsis. in contrast, the haplotype mylk_ g/mylk_ g/ mylk_ t conferred specific risk for ali but not sepsis [ ] . the ¢ haplotype of the mylk gene also conferred alispecific risk in both european-and african-descent subjects; however, the ¢ region haplotype was associated with ali only in african-descent subjects. in african-americans, the haplotype hcv c/mylk_ a/rs g is substantially more prevalent in ali ( %) as compared with sepsis ( %). this cag haplotype is not found in european americans, suggesting a potential genetic contribution to the observed ethnicity-specific differences in ali/ards prevalence and susceptibility [ ] . we noted similar findings in association studies involving a cohort with trauma-induced ali [ ] . we have also evaluated the association of mylk genetic variants with severe asthma in both european american and african-american populations and identified a snp highly associated with severe asthma in african-americans [ ] consistent with data linking this chromosomal locus (mylk, q . ) to asthma and asthmarelated phenotypes [ ] . taken together, these data strongly implicate mylk genetic variants as risk variants in inflammatory lung disorders, such as ali and asthma. macrophage migration inhibitory factor (mif) is an ali candidate gene and recognized biomarker, initially discovered as a soluble product of activated t cells and named for its role in inhibiting random macrophage migration [ ] . mif is a proinflammatory cytokine which binds to cd and cd and is produced by many cell types, including monocytes/macrophages, pituitary cells, vascular endothelium, and respiratory epithelium [ , ] . mif may serve as a delicate regulator of the cytokine balance between immunity and inflammation as mif counterregulates the immunosuppressive effects of glucocorticoids [ ] . the role of mif as an endogenous prosurvival factor has been demonstrated in vitro. lps-mediated induction of flice-like inhibitory protein (flip) by mif confers resistance to lps-mediated endothelial cell death [ ] . suppression of mif by rna interference induces cell death and sensitivity to apoptotic stimuli [ ] . in addition, mif interacts with the multidimensional nmmlck [ ] isoform which regulates tnf-mediated apoptosis in addition to its potent effects on endothelial cell barrier dysfunction as discussed earlier [ , ] . together, these findings implicate the role of mif in regulation of nonmuscle cytoskeletal dynamics and vascular pathophysiology, which is evident from the enhanced mif levels in the serum, bal fluid, and alveolar endothelium of patients with ards as compared with other critically ill patients [ , , ] . we found significant increases in mif transcript and protein levels in murine and canine models of ventilator-induced lung injury (vili) (using high mechanical ventilation and endotoxin exposure, respectively) [ ] and in human lung endothelium cells exposed to h of cyclic stretch [ ] . mif deficiency or immunoneutralization appears to protect mice or rats from fatal endotoxic shock or other inflammatory diseases [ ] although these results are not without controversy [ ] and our own studies in - -week-old mice failed to demonstrate a vili/ali-related phenotype which was different from controls (data not shown). mif also upregulates the expression of aqp- , the water channels expressed in alveolar endothelial and epithelial cells, and a candidate gene we identified in models of vili-associated mechanical stress [ ] . mif may serve to modulate fluid movement into alveolar spaces, a cardinal feature of ali [ ] . to extend the likelihood that mif serves as a putative candidate gene in ali and sepsis, we studied the association of eight mif polymorphisms, including the most studied mif promoter g/c snp at position - , in a sepsis-induced ali cohort (n = ) of african-and european-descent cases [ ] . no individual snp showed a significant association with either ali or sepsis; however, the carriers of the cc genotype (rs ) and the carriers of the tt genotype (rs ) showed more than twofold increased risk of developing sepsis and ali, respectively. this association was lost, however, after age and gender adjustment in a logistic regression model. in contrast, mif haplotypes at the ¢ region of the gene display strong association with ali and sepsis, conferring both protection as well as susceptibility to ali, in european and african populations [ ] . furthermore, the haplotype at the ¢ promoter region of the gene involving a short tandem repeat at position - (catt) and the - g allele show significant association with both ali and trauma [ ] ; however, no association was found between promoter region haplotypes and mif levels. rheumatoid arthritis patients with the - c allele have higher levels of mif in the serum and synovial fluid than the carriers of the g allele and have a higher probability of developing idiopathic arthritis [ ] . thus, given these diverse mif functions, mif remains an attractive target in inflammatory diseases including the lung. the bioactive sphingolipid metabolite sphingosine -phosphate (s p) is an important lipid mediator that enhances endothelilal cell barrier function in vivo and in vitro by ligating s p receptor (s p ), which is encoded by an endothelial differentiation gene (edg or s p ) [ , ] . s p is a pertussis-toxin-sensitive, g i -coupled receptor which induces rac gtpase-dependent substantial increases in cortical actin polymerization critical to endothelial cell barrier enhancement [ , ] . s p activation enhances the organization and redistribution of vascular endothelial cadherin and b-catenin in junctional complexes in endothelium by phosphorylation of cadherin as well as p catenin and inducing the formation of cadherin/catenin/actin complexes [ ] . understanding the role of s p in enhancing endothelial cell barrier function underscores its importance as a therapeutic target in reversing loss of endothelial cell barrier integrity. in vivo administration of selective s p competitive antagonists induces a dose-dependent disruption of barrier integrity in pulmonary endothelium [ , ] , whereas s p agonists, sew and fty , promote vascular endothelial barrier function [ ] [ ] [ ] . a compelling argument for s p as an attractive ali candidate gene is not only its ability to transduce signals which restore barrier integrity but also that s p is the target for transactivation by receptors for other potent barrier-protective agonists. these include epcr (receptor for activated protein c) [ ] , c-met [receptor for hepatocyte growth factor (hgf)] [ ] , cd (receptor for high molecular weight hyaluronan) [ ] , and the atp receptor [ ] . we recently resequenced the s p gene ( african-americans and european americans) to search for common variations in the edg gene and identified snps in the edg gene, with several promoter snps associated with asthma, another inflammatory lung syndrome [ ] . receptor) the role of hgf and its tyrosine kinase receptor c-met has been investigated in lung development, inflammation, and repair [ ] as well as in neoplastic processes such as cellular transformation, neoplastic invasion, and metastasis [ , ] . snps causing underexpression of c-met have been associated with autism and c-met snps/mutations appear to be linked to lung cancer disparities in different ethnic groups. these include an n s mutation in the hgfbinding domain of c-met, an r c snp/mutation in the juxtamembrane domain, and an activating m t mutation in the tyrosine kinase domain (exon ), all linked to development of solid tumors such as lung cancer, renal cancer, gastric cancer, and hepatocellular carcinoma [ ] . hgf influences morphogenesis in epithelial cells from a variety of organs, including lungs, where hgf antisense oligonucleotides block alveolar and branching morphogenesis [ ] . hgf expression and activity increase after - h of lung injury with intratracheally administered hydrochloric acid, suggesting that hgf plays a role in reparative responses to lung injury [ ] . c-met expression on type ii pneumocytes is likely involved in increased type ii pneumocyte proliferation and restoration of an intact alveolar epithelium [ ] . c-met is composed of a -kda extracellular a subunit and a -kda transmembrane b subunit [ ] which contains tyrosine kinase domains, tyrosine phosphorylation sites, and tyrosine docking sites [ ] . we demonstrated that hgf-mediated c-met phosphorylation and c-met recruitment to caveolin-enriched microdomains (cems) protects against the lps-induced pulmonary vascular hyperpermeability that is regulated by high molecular weight hyaluronan (cd ligand) [ ] . our novel findings indicate that hgf/c-met-mediated, cd -regulated cem signaling promotes tiam (a rac exchange factor)/dynamin dependent rac activation, and peripheral recruitment of cortactin (an actin cytoskeletal regulator), processes essential for endothelial cell barrier integrity. understanding the mechanism(s) by which hgf/c-met promotes increased endothelial cell barrier function may lead to novel treatments for diseases involving vascular barrier disruption, including inflammation, tumor angiogenesis, atherosclerosis, and ali. however, on the contrary, the higher mortality rate in ali patients with increased levels of hgf in bal fluids [ ] and in pulmonary edematous fluids [ ] indicates severer injury and inflammation in response to increased hgf levels. it has now become increasingly clear that hgf plays an important role in normal and injured lung and may have a therapeutic potential in lung diseases. pre-b cell colony enhancing factor (pbef), was first identified by samal and colleagues in as a protein secreted by activated lymphocytes in bone marrow stromal cells that stimulate early stage b cell formation in conjugation with stem cell factor and interleukin- . a large body of work has now highlighted the power of a systems biology approach in the search for novel disease-susceptibility genes and potentially novel biomarkers, with pbef serving as an excellent example of this approach (fig. ) . we first identified marked upregulation of pbef via microarray analyses of murine and canine models of vili/ali with increased gene/ protein expression in bal fluid and serum samples from critically ill icu patients with ali and sepsis [ ] . with only a total of eight papers in pubmed at that time, we next directly sequenced the pbef gene in subjects with ali, sepsis, and healthy controls and conducted a pbef snp-based association study in ali subjects of european and african-american descent [ ] . we identified snps in the pbef gene with two promoter snps, t- g and c- t, associated with ali and sepsis. genotyping of pbef c- t and t- g snps revealed significant associations of sepsis and ali, with the strongest association found with the - c/- g haplotype. univariate analysis found carriers of the g allele (t g) to have . -fold higher risk of developing ali as compared with controls (p = . ) [ ] . these results were subsequently confirmed in a comparable but distinct replicate ali population [ ] . interestingly, the - g/- c haplotype was also associated with increased icu parient mortality, whereas the - t/- t haplotype was associated with fewer ventilator days and decreased icu patient mortality [ ] . a key challenge in genomic explorations is the ability to confirm the contribution of a snp to a dysfunctional-geneinvolved disease process. additional reports have highlighted the capacity for the pbef gene to have an influence far beyond any b-cell regulatory function, with a key role in regulating vascular permeability [ ] as well as inhibiting neutrophil apoptosis [ ] . to further explore mechanistic participation of pbef in ali and vili, we focused on the contribution of pbef to endothelial function. our prior immunohistochemical staining of canine-injured lung tissues localized pbef expression to vascular endothelial cells, in addition to infiltrating neutrophils and type alveolar epithelial cells [ ] . our in vitro studies showed that expression of pbef in pulmonary artery endothelial cells increases thrombin-mediated vascular permeability [ ] , suggesting that enhanced pbef expression may mediate the early increase in vascular permeability that is characteristic of ali. neutrophils harvested from the circulation of septic and ali patients show marked inhibition of the apoptotic process in association with evidence of enhanced respiratory burst capacity [ , ] , with both activities largely restored with administration of pbef antisense oligonucleotides. our initial in vitro studies further demonstrated recombinant human pbef (rhpbef) as a direct rat neutrophil chemotactic factor, with in vivo studies demonstrating marked increases in bal fluid leukocytes (polymorphonuclear leukocytes, pmns) following intratracheal injection in c bl/ j mice [ ] . these changes were accompanied by increased bal fluid levels of pmn chemoattractants (kc and mip ) and modest increases in lung vascular and alveolar permeability. we also noted synergism between rhpbef challenge and a model of limited vili and observed dramatic increases in bal fluid pmns, bal protein, and cytokine levels (il- , tnfa, kc) compared with either challenge alone. gene expression profiling identified induction of ali-and vili-associated gene modules (nf-kb, leukocyte extravasation, apoptosis, toll-receptor pathways). heterozygous pbef +/− mice were significantly protected (reduced bal fluid protein levels, bal fluid il- levels, peak inspiratory pressures) when exposed to a model of severe vili ( h, ml/kg tidal volume) and exhibited significantly reduced gene expression of vili-associated modules. finally, strategies to reduce pbef availability (neutralizing antibody) resulted in significant protection from vili [ ] . pbef is now recognized as associated with modestly increased risk of type diabetes and elevated levels of acute-phase proteins [ ] and a c- g snp has been associated with an increased diastolic blood pressure in obese children [ ] . these studies implicate pbef, now associated with a number of inflammatory disorders such as inflammatory bowel disease, multiple sclerosis, cystic fibrosis, and asthma [ ] [ ] [ ] , as a key inflammatory mediator intimately involved in both the development and the severity of ventilator-induced ali. growth arrest dna damage inducible a (gadd a), a member of an evolutionarily conserved gene family, is implicated as a stress sensor that modulates the response of mammalian cells to genotoxic or physiological stress [ , ] . gadd a is a small -kda predominantly nuclear protein that interacts with other proteins implicated in stress responses, including proliferating cell nuclear antigen, p , cdc /cyclin b , mekk , and p kinase [ , ] . gadd induces cell cycle arrest and apoptosis in most of cells as well as promoting dna repair functions and survival [ ] . growth arrest and dna damage gene (gadd ) also maintains genomic stability in a p -responsive manner [ ] . despite the multiple known functions of gadd , its role ali, endothelial/epithelial barrier dysfunction, or repair of injured lung is unknown [ ] . gadd exhibited differential expression in orthologous global gene expression profiling, in multispecies ali models [ ] , in region-specific lung tissue expression profiling [ ] , and was markedly upregulated in response to the vili [ ] . we explored the mechanistic involvement of gadd a in endotoxin (lps)and ventilator-induced inflammatory lung injury (vili) by comparing multiple biochemical and genomic parameters of inflammatory lung injury in wild-type c bl/ and gadd a −/− knockout mice exposed to high tidal volume ventilation (vili) or intratracheally administered lps [ ] . gadd a −/− mice were modestly susceptible to lpsinduced injury but were profoundly susceptible to vili, demonstrating increased inflammation and increased microvascular permeability. vili-exposed gadd a −/− mice manifested striking neutrophilic alveolitis with increased bal fluid levels of protein, igg, and inflammatory cytokines. expression profiling of lung homogenates revealed strong dysregulation in the b cell receptor signaling pathway in gadd a −/− mice, suggesting the involvement of phosphatidylinositol -kinase/akt signaling components. western blots confirmed a threefold reduction in akt protein and phosphorylated akt levels observed in gadd a −/− lungs. electrical resistance measurements across human lung endothelial cell monolayers transfected with small interfering rnas to reduce gadd a or akt expression revealed significant potentiation of lps-induced endothelial barrier dysfunction which was attenuated by overexpression of a constitutively active akt transgene. whereas other lung injury studies failed to demonstrate a role for gadd in hyperoxic lung injury [ , ] , our studies validate gadd a as a novel inflammatory lung injury candidate gene and a significant participant in vascular barrier regulation via effects on akt-mediated endothelial signaling [ ] . thus, both akt and gadd are extremely attractive ali candidate genes. the human gadd a gene contains validated snps (national center for biotechnology information snp database) whose role in ali pathogenesis is completely unknown [ ] . we are currently pursuing further characterization of the role of gadd a and its association of genetic variants with sepsis and ali. the identification of novel pathways involved in the pathobiology of ali also opens doors for the exploration of new therapeutic targets for the disease. as such, the use of agents that attenuate the endothelial barrier dysfunction and the inflammatory response characteristic of ali have shown promise in preclinical studies which will hopefully lead to their use in trials of human ali (fig. ). s p, an important lipid mediator generated by the phosphorylation of sphingosine by sphingosine kinase, decreases endothelial permeability to both water and solute via cytoskeletal reorganization and adherens junction assembly [ , ] . s p-induced barrier protective effects could serve to attenuate the increased pulmonary vascular permeability essential factor in the development of ali. the s p analogue fty ( . mg/kg),when administered to c bl/ mice with endotoxin-induced lung injury, decreases lung edema formation, solute transport across the alveolar capillary endothelium, and inflammatory cell infiltration into lung parenchyma [ ] . similarly, the prophylactic administration of s p attenuates both alveolar and vascular barrier dysfunction while significantly reducing shunt formation associated with lung injury in rodent and canine models of ali induced by combined intrabronchial endotoxin administration and hightidal-volume mechanical ventilation [ ] . in a recent study of a canine model of ali, we demonstrated that when bacterial endotoxin was instilled intratracheally followed in h by intravenous administration of s p ( mg/kg) or vehicle and h of high-tidal-volume mechanical ventilation [ ] , s p treatment attenuated the severity of ali-induced increases in shunt fraction and the presence of both protein and neutrophils in bal fluid compared with vehicle controls. interestingly, bal fluid cytokine production was not altered fig. mechanism-based novel therapies for ali. the identification of novel pathways involved in the pathobiology of ali also facilitates the exploration of new therapeutic targets. sphingosine -phosphate (s p ) attenuates the endothelial barrier dysfunction associated with ali, whereas blocking of pbef attenuates vali significantly by intravenous administration of s p and s p potentiated the endotoxin-induced systemic production of the inflammatory cytokines tnfa, c-x-c chemokine ligand- , and il- , without resulting in end-organ dysfunction. these data suggest that s p may represent a viable therapy for the prevention and treatment of ali. as previously described in this chapter, pbef appears to play a central role in the promotion of several pathogenetic aspects of ali and vali. therefore, interventions aimed at attenuating the effects of pbef could have a potential therapeutic effect in these disorders. to begin to address the potential for pbef to serve as a therapeutic target in ameliorating vili, we assessed the effect of pbef neutralizing antibody on rhpbef-stimulated lung inflammation [ ] . simultaneous instillation of rhpbef and pbef neutralizing antibody produced dramatic reductions in rhpbef-induced neutrophil recruitment. further, the intratracheal delivery of pbef neutralizing antibody ( min before high-tidal-volume mechanical ventilation) abolished vili-induced increases in total bal fluid cell counts and significantly decreased neutrophil influx into the alveolar space as well as vili-mediated increases in the level of lung tissue albumin. ali is a major cause of morbidity and mortality in critically ill patients. given the unacceptably high mortality rate observed in ali and the paucity of novel therapies and biomarkers, it is essential to recognize molecular targets associated with ali to identify individuals at risk and to develop novel therapeutic targets and biomarkers. it is clear that derangements in endothelial cell barrier regulation play a major role in the pathobiology of ali and genetic variants regulate endothelial cell barrier function, thereby determining ali risk or subsequent severity of outcome. high-throughput gene sequencing and expression technologies, and complete genome sequencing of model organisms, have allowed for the performance of large-scale analyses of the genome in ali. in this chapter, we have highlighted how global gene expression profiling in multispecies ali models served to broaden our net knowledge of ali-implicated genes and provide a basis for hope that increased insights and therapies may be forthcoming. as genotyping becomes more rapid and easily accessed, combining advanced bioinformatics techniques with high-throughput methods will be the future practice of personalizing treatment strategies. continued challenges will be the gene-gene and gene-environment interactions, which add complexity to our understanding of the genome. these novel genetic approaches may prove exceptionally useful in ushering in the era of personalized medicine for critically ill individuals. the acute respiratory distress syndrome genomics of acute lung injury clinical predictors of the adult respiratory distress syndrome race and gender differences in acute respiratory distress syndrome deaths in the united states: an analysis of multiple-cause mortality data ( - ) ozone-induced acute pulmonary injury in inbred mouse strains making genomics functional: deciphering the genetics of acute lung injury wading into the genomic pool to unravel acute lung injury genetics susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities fate of angiotensin i in the circulation angiotensin ii induces apoptosis of human endothelial cells. protective effect of nitric oxide haemodynamic and endocrine effects of type angiotensin ii receptor blockade in patients with hypoxaemic cor pulmonale angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome angiotensin ii, via at and at receptors and nf-kb pathway, regulates the inflammatory response in unilateral ureteral obstruction inflammation and angiotensin ii angiotensin ii and the fibroproliferative response to acute lung injury angiotensin ii induces apoptosis in human and rat alveolar epithelial cells abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor angiotensin-converting enzyme protects from severe acute lung failure an insertion/deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels evidence, from combined segregation and linkage analysis, that a variant of the angiotensin i-converting enzyme (ace) gene controls plasma ace levels alhenc-gelas f ( ) angiotensin i-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in t-lymphocytes genetic polymorphisms associated with susceptibility and outcome in ards polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome differences in frequency of the deletion polymorphism of the angiotensinconverting enzyme gene in different ethnic groups angiotensin-converting enzyme gene (ace) insertion/deletion polymorphism in mexican populations elevated plasma levels of soluble tnf receptors are associated with morbidity and mortality in patients with acute lung injury high berylliumstimulated tnf-a is associated with the - tnf-a promoter polymorphism and with clinical severity in chronic beryllium disease tumor necrosis factor gene polymorphism and septic shock in surgical infection ga and tnfb polymorphisms in acute respiratory distress syndrome influence of tnfa gene polymorphisms on tnfa production and disease single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk il gene-wide haplotype is associated with susceptibility to acute lung injury cytokine balance in the lungs of patients with acute respiratory distress syndrome a prospective study of inflammation markers in patients at risk of indirect acute lung injury persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il- beta and il- levels are consistent and efficient predictors of outcome over time pressure-time curve predicts minimally injurious ventilatory strategy in an isolated rat lung model science review: searching for gene candidates in acute lung injury orthologous gene-expression profiling in multispecies models: search for candidate genes use of consomic rats for genomic insights into ventilator-associated lung injury the association of interleukin haplotype clades with mortality in critically ill adults vascular endothelial growth factor and related molecules in acute lung injury lung overexpression of the vascular endothelial growth factor gene induces pulmonary edema vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome decreased vegf concentration in lung tissue and vascular injury during ards a common c/t mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome genotypes and haplotypes of the vegf gene are associated with higher mortality and lower vegf plasma levels in patients with ards chemokine receptors as hiv- coreceptors: roles in viral entry, tropism, and disease involvement of chemokine receptors in breast cancer metastasis myosin iia is involved in the endocytosis of cxcr induced by sdf- a the a-chemokine, stromal cell-derived factor- a, binds to the transmembrane g-protein-coupled cxcr- receptor and activates multiple signal transduction pathways rab -family interacting protein and myosin vb are required for cxcr recycling and receptor-mediated chemotaxis role of tyrosine phosphorylation in ligand-independent sequestration of cxcr in human primary monocytes-macrophages a common stromal cell-derived factor- chemokine gene variant is associated with the early onset of type diabetes genetic restriction of aids pathogenesis by an sdf- chemokine gene variant. alive study, hemophilia growth and development study (hgds) high-resolution haplotype structure in the human genome complement factor h polymorphism in age-related macular degeneration a genome-wide association study identifies il r as an inflammatory bowel disease gene a genome-wide association study identifies novel risk loci for type diabetes genomewide association studies of stroke microarray analysis of regional cellular responses to local mechanical stress in acute lung injury novel interaction of cortactin with endothelial cell myosin light chain kinase cytoskeletal regulation of pulmonary vascular permeability activated protein c mediates novel lung endothelial barrier enhancement: role of sphingosine -phosphate receptor transactivation novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury transactivation of sphingosine -phosphate receptors is essential for vascular barrier regulation. novel role for hyaluronan and cd receptor family regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation regulation of endothelial cell gap formation and paracellular permeability protein kinase involved in lung injury susceptibility: evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment critical role of non-muscle mlck in ventilator-induced lung injury myosin light chain kinase in endothelium: molecular cloning and regulation adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration variation in the mylk gene is associated with development of acute lung injury after major trauma a variant of the myosin light chain kinase gene is associated with severe asthma in african americans macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease macrophage migration inhibitory factor role for macrophage migration inhibitory factor in acute respiratory distress syndrome mif as a glucocorticoid-induced modulator of cytokine production macrophage migration inhibitory factor governs endothelial cell sensitivity to lps-induced apoptosis intracellular interaction of myosin light chain kinase with macrophage migration inhibition factor (mif) in endothelium macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations role of macrophage migration inhibitory factor (mif) in human and animal models of acute lung injury (ali) and sepsis: association of a promoter polymorphism and increased gene expression a novel dna vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis role of macrophage migration inhibitory factor (mif) in allergic and endotoxininduced airway inflammation in mice aquaporin- : a candidate gene in sepsis and lung injury a novel ¢-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis sphingosine -phosphate promotes endothelial cell barrier integrity by edg-dependent cytoskeletal rearrangement regulation of sphingosine -phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by s p receptor, pi kinase, tiam /rac , and alpha-actinin regulation of the micromechanical properties of pulmonary endothelium by s p and thrombin: role of cortactin protective effects of high-molecular weight polyethylene glycol (peg) in human lung endothelial cell barrier regulation: role of actin cytoskeletal rearrangement synthesis and biological evaluation of g-aminophosphonates as potent, subtypeselective sphingosine -phosphate receptor agonists and antagonists enhancement of capillary leakage and restoration of lymphocyte egress by a chiral s p antagonist in vivo protective effects of sphingosine -phosphate in murine endotoxin-induced inflammatory lung injury tipping the gatekeeper: s p regulation of endothelial barrier function effect of s p receptor agonists on murine lung airway function differential regulation of sphingosine- -phosphate-and vegf-induced endothelial cell chemotaxis. involvement of g ia -linked rho kinase activity endothelial cell barrier enhancement by atp is mediated by the small gtpase rac and cortactin sphingosine- -phosphate receptor variant increases promoter activity and decreases susceptibility to human asthma hepatocyte growth factor/scatter factor induces a variety of tissue-specific morphogenic programs in epithelial cells the biological role of hgf-met axis in tumor growth and development of metastasis ) c-met mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions involvement of hepatocyte growth factor in formation of bronchoalveolar structures in embryonic rat lung in primary culture hepatocyte growth factor may act as a pulmotrophic factor on lung regeneration after acute lung injury intratracheal administration of hepatocyte growth factor/scatter factor stimulates rat alveolar type ii cell proliferation in vivo met receptor dynamics and signalling c-met signalling: spatio-temporal decisions cd regulates hepatocyte growth factor-mediated vascular integrity. role of c-met, tiam /rac , dynamin , and cortactin keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients hepatocyte growth factor and keratinocyte growth factor in the pulmonary edema fluid of patients with acute lung injury. biologic and clinical significance pre-b-cell colonyenhancing factor as a potential novel biomarker in acute lung injury pre-b-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome pre-b-cell-colonyenhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregulation pre-b cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase- activity essential role of pre-b-cell colony enhancing factor in ventilator-induced lung injury a visfatin promoter polymorphism is associated with low-grade inflammation and type diabetes effects of genetic variation in the visfatin gene (pbef ) on obesity, glucose metabolism, and blood pressure in children genome-wide search for atopy susceptibility genes in dutch families with asthma two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes , and chromosome q - and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin- gene egad, more forms of gene regulation: the gadd a story gadd in the response of hematopoietic cells to genotoxic stress liebermann da genotoxic-stress-response genes and growth-arrest genes gadd, myd, and other genes induced by treatments eliciting growth arrest myeloid differentiation (myd)/growth arrest dna damage (gadd) genes in tumor suppression, immunity and inflammation genomic instability in gadd a −/− cells is coupled with s-phase checkpoint defects inhaled carbon monoxide confers antiinflammatory effects against ventilatorinduced lung injury gadd a is a novel candidate gene in inflammatory lung injury via influences on akt signaling -independent induction of gadd and gadd in mouse lungs exposed to hyperoxia loss of gadd a does not modify the pulmonary response to oxidative stress modulation of lipopolysaccharide-induced gene transcription and promotion of lung injury by mechanical ventilation sphingosine -phosphate reduces vascular leak in murine and canine models of acute lung injury sphingosine -phosphate rescues canine lps-induced acute lung injury and alters systemic inflammatory cytokine production in vivo key: cord- - cqqj n authors: li, tiao; zou, chunbin title: the role of deubiquitinating enzymes in acute lung injury and acute respiratory distress syndrome date: - - journal: int j mol sci doi: . /ijms sha: doc_id: cord_uid: cqqj n acute lung injury and acute respiratory distress syndrome (ali/ards) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ards occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. the prevalence of ards is approximately % in patients of intensive care. there is no effective remedy with mortality high at – %. most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (dubs). deubiquitination plays an important role in the pathobiology of ali/ards as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. in this review, we provide an overview of how dubs emerge in pathogen-induced pulmonary inflammation and related aspects in ali/ards. better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways. acute lung injury and acute respiratory distress syndrome (ali/ards) are a group of illnesses with features of lung inflammation, air-blood barrier disfunction, and hypoxemia. ali/ards are life-threatening with a severe public health concern, approximately , people per year develop into ali/ards in the united states, and the mortality rates are high at - % [ ] [ ] [ ] [ ] [ ] . it is believed that about~ % of patients in intensive care units eventually develop into ali/ards worldwide. etiologically, microbial pneumonia, sepsis, aspiration of gastric contents, or severe trauma are the major causes of ali/ards. approximately % of the ali/ards patients are linked with viral and bacterial pneumonia. the outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ), which causes coronavirus disease (covid- ) , has become a pandemic disease. by now, millions of people have suffered from this disease with hundreds of thousands of deaths in almost all countries all over the world because of the pandemic, and the numbers of the diagnosed patients and the deaths due to this disease are climbing each day (https://coronavirus.jhu.edu/map). for severe covid- patients, ali/ards represent one of the major pathological changes; phenotypes include inflammatory infiltration and inflammatory storm, alveolar epithelial-capillary damage, lung embolism and hemorrhage, hypoxia, and poor prognosis with high mortality. the pathobiology of the disease is incompletely understood [ , [ ] [ ] [ ] . furthermore, no specific effective therapeutic method has been developed to treat the illness. thus, understanding the molecular mechanisms of ali/ards is of particular important in developing effective remedies against the illness. overwhelmed immune responses are believed to be a major contributing factor in the pathogenesis of ali/ards. in the initial pulmonary infection, invaded microbial pathogens including viruses and bacteria attract and activate residential microphages to release chemokines and cytokines, along with infiltration of leukocytes, particularly neutrophils and lymphocytes, into the alveolar sacs [ , ] . in ideal scenarios, host immune responses clear and exclude the invaded pathogens and repair the diseased tissues. however, host immune responses may be unable to achieve this goal due to the pathogenicity of the microbe or the compromised capacity of the host defense, such as in patients with cancer, organ transplantation, diabetes, or hiv infection. higher inflammatory responses may occur in these cases and an over-reacted inflammatory response eventually leads to an overwhelmed inflammatory response. an overwhelmed inflammatory response is increasingly noticed as one of the key contributors to the poor prognosis of ali/ards. a dysregulated high inflammatory response, also referred to as a "cytokine storm", increases mortality in ali/ards patients [ , ] . along with the process of cytokine storm, dysregulated molecular signaling may cause deleterious damage independent of microbial pathogens that increase mortality. however, a high inflammatory storm turns into low inflammation in the later stage due to immune paralysis that may lead to immunosuppression, which contributes to secondary infection and worsens the prognosis of the patients as well [ ] . in the meantime, the invasion of microbial pathogens causes airway epithelial and pulmonary endothelial cell death, destroys alveolar architecture, and damages the air-blood barrier [ , ] . these pathological changes impair effective air-blood exchange, which results in edema and hypoxemia. clinically, hypoxemia in patients with ards is caused by ventilation-to-perfusion mismatch, as well as right-to-left intrapulmonary shunting [ ] . in addition, impaired excretion of carbon dioxide is a major component of respiratory failure, resulting in elevated minute ventilation that is associated with an increase in pulmonary dead space (that is, the volume of a breath that does not participate in carbon dioxide excretion). elevation of pulmonary dead space and a decrease in respiratory compliance are independent predictors of mortality in ards [ ] . the pathophysiological mechanisms of ali/ards are yet to be fully understood. a large number of signal transduction pathways have been revealed to be involved in this process. signal transductions in control of protein stability and availability, including protein ubiquitination and degradation, are typical among the pathways. several review articles have introduced the role of ubiquitination and proteolysis in lung diseases [ ] [ ] [ ] . in this review, we summarize recent findings regarding the importance of deubiquitination and dubs in regulation of inflammation and related pathologies and highlight the role of dubs in ali/ards. proteins dynamically exert their diversified functions in life processes in response to different pathophysiological settings. in concert with gene transcription, ubiquitin proteasome degradation governs the abundance and availability of the protein in the cell. most of the proteins modified by a post translational modification called ubiquitination are deemed to be degraded [ , ] . ubiquitination involves the covalent attachment of the small conserved protein called ubiquitin (ub, amino acids in length) to a target protein, almost exclusively at a lysine residue. ubiquitination is an enzymatic cascade that requires the orchestrated interplay of three different enzymes ( figure ). e ub-activating enzymes bind to both atp and ubiquitin and expose a cysteine residue, the active site of ubiquitin, with the release of an amp. e ub-conjugating enzymes take over activated ubiquitin from e enzymes and cooperate with e ub-ligases. the e ub-ligases interact with e enzymes and recruit protein substrates to initiate conjugation of single ubiquitin or polymeric ubiquitin chains to the protein substrates. e ub-ligases recognize the protein substrates and determine the specificity of protein substrates [ , ] . in humans, there are two e ub-activating enzymes, e ub-conjugating enzymes, and approximately e ub-ligases [ ] . protein ubiquitin proteasomal degradation and deubiquitination. a protein destined for degradation unleashes a cascade of enzymatic activity involving ubiquitination and proteasomal degradation. e ub-activating enzymes activate ubiquitin and pass the ubiquitin to e -ub-conjugating enzymes. e ub-ligases recognize the protein substrates and couple e -ub-conjugating enzymes to covalently add the ubiquitin or ubiquitin moieties to the protein substrates. the ubiquitinated proteins are then degraded by the proteasome. deubiquitinating enzymes remove the mono-ubiquitin or polyubiquitin chains from the ubiquitinated protein to stabilize the protein from proteasomal degradation and recycle ubiquitin units. ub: ubiquitin; e : e ub-activating enzyme；e : e -ub-conjugating enzyme，e : e ub-ligases; dub: deubiquitinating enzyme. the process of ubiquitination is reversible, a group of enzymes called deubiquitination enzymes conduct the enzymatic process [ ] (figure ). deubiquitination is the reverse process of ubiquitination, that removes the mono-ubiquitin and poly-ubiquitin chains from the modified proteins to generate free ubiquitin, which terminates the function of ubiquitinated protein, and specifically, stabilizes the ubiquitinated protein from degradation. deubiquitination also replenishes the ubiquitin pool, and maintains homeostasis of the cellular ubiquitin [ ] . this process is performed by deubiquitinating enzymes (dubs), which are a large set of proteases. the number of dubs in humans is about , while ~ dubs exist in the yeast saccharomyces cerevisiae [ ] [ ] [ ] . a number of approaches are utilized in studying dubs and the related diseases. these approaches include conventional protein-protein interaction techniques such as immunoprecipitation, enzymatic assays, bioinformatics, proteomic, transcriptomic, and structure analysis techniques. based on the architecture of their catalytic domains, to date, six structurally distinct dub families have been described [ ] . five families of dubs are cysteine proteases, including members of usps(ubiquitin-specific proteases)in humans, four members of uchs(ubiquitin carboxy-terminal hydrolases), members of otus(ovarian tumor proteases), four members of mjds (machado-josephin disease protein domain protease) [ , ] , and four members of mindys (motif interacting with ubiquitin (miu)-containing novel dub family) [ ] . the sixth subfamily is jamms (zn-jab /mpn/mov domain protease), which includes a conserved zinc metallopeptidase [ , ] . all dub family members bear a catalytic domain that removes ubiquitin from the protein substrates [ ] . the catalytic domain of miu family sub-members is a new folding variant within the superfamily of cysteine protease and shows a remarkable selectivity for cleaving long lysine (k )-linked ubiquitin chains. in particular, cleavage selectivity of dubs is determined by catalytic the process of ubiquitination is reversible, a group of enzymes called deubiquitination enzymes conduct the enzymatic process [ ] (figure ). deubiquitination is the reverse process of ubiquitination, that removes the mono-ubiquitin and poly-ubiquitin chains from the modified proteins to generate free ubiquitin, which terminates the function of ubiquitinated protein, and specifically, stabilizes the ubiquitinated protein from degradation. deubiquitination also replenishes the ubiquitin pool, and maintains homeostasis of the cellular ubiquitin [ ] . this process is performed by deubiquitinating enzymes (dubs), which are a large set of proteases. the number of dubs in humans is about , while~ dubs exist in the yeast saccharomyces cerevisiae [ ] [ ] [ ] . a number of approaches are utilized in studying dubs and the related diseases. these approaches include conventional protein-protein interaction techniques such as immunoprecipitation, enzymatic assays, bioinformatics, proteomic, transcriptomic, and structure analysis techniques. based on the architecture of their catalytic domains, to date, six structurally distinct dub families have been described [ ] . five families of dubs are cysteine proteases, including members of usps(ubiquitin-specific proteases)in humans, four members of uchs(ubiquitin carboxy-terminal hydrolases), members of otus(ovarian tumor proteases), four members of mjds (machado-josephin disease protein domain protease) [ , ] , and four members of mindys (motif interacting with ubiquitin (miu)-containing novel dub family) [ ] . the sixth subfamily is jamms (zn-jab /mpn/mov domain protease), which includes a conserved zinc metallopeptidase [ , ] . all dub family members bear a catalytic domain that removes ubiquitin from the protein substrates [ ] . the catalytic domain of miu family sub-members is a new folding variant within the superfamily of cysteine protease and shows a remarkable selectivity for cleaving long lysine (k )-linked ubiquitin chains. in particular, cleavage selectivity of dubs is determined by catalytic domain alone, whereas a dub called mindy requires a motif interacting with ubiquitin (miu) as well as a catalytic domain for maximal dub activity [ ] . the physiological roles of dubs include controlling protein stability and quality, maintaining ubiquitin homeostasis, and regulating ubiquitin signals against the functions of e ub ligase [ ] . therefore, dubs regulate numerous cellular events such as the cell cycle, dna damage response, inflammatory signaling, and proliferation and cell death. mounting studies have focused on inflammation to dissect its underlying molecular mechanisms in the pathogenesis of ali/ards. deubiquitinating enzymes play crucial roles in modulation of inflammation by changing the protein stability of the critical molecules (table ) . several usps have proved to play emerging roles in the regulation of lung inflammation [ , ] . innate immunity provides the first line of host defense against pathogens. in lung inflammation, usp protein is over-expressed, reducing i-κb protein levels and thus increasing cytokine release in lung epithelial cells [ , ] . usp acts as a negative regulator of the nf-κb pathway by mediating the deubiquitination of nemo, traf and ikkγ, which leads to the retention of nf-κb in the cytosol, thus suppressing its activity [ , ] . pro and anti-inflammatory cytokines increase in bronchoalveolar lavage fluid and circulating plasma of patients at different stages of ards. tnf-α and il- β are important proinflammatory cytokines in the pathogenesis of ards [ ] . after their receptor activation, ciap-mediated k -ubiquitination of ripk and the traf proteins leads to the recruitment of linear ubiquitin chain assembly complex (lubac). the stability of lysophosphatidic acid receptor (lpa ) is up-regulated by ubiquitin-specific protease (usp ), which deubiquitinates lpa and enhances lpa -mediated proinflammatory effects [ , [ ] [ ] [ ] [ ] . furthermore, the deubiquitinating enzyme usp stabilizes the anti-inflammatory receptor il- r /sigirr to suppress lung inflammation [ ] [ ] [ ] . [ , ] regulates tlr signaling [ ] inhibits inflammation [ ] akt [ ] regulates tgf-β signaling [ ] pai- [ ] regulates acute lung injury [ ] usp- nlrp [ ] regulates nlrp inflammasome activation [ ] nf-κb [ ] , nemo [ ] regulates nf-κb signaling [ , ] vp [ ] involves in virus replication [ ] tat [ ] involves in virus production [ ] traf /traf [ ] modulates antiviral signaling [ ] traf /ikkγ [ ] regulates tlr signaling [ ] usp- cftr [ , ] epithelial mucosal clearance [ , ] nicd [ ] regulates notch signaling [ ] usp- e f [ ] regulates lung epithelia proliferation and wound healing [ ] lpa [ ] enhances inflammation [ ] usp- il- r /sigirr [ ] suppresses lung inflammation [ ] pten [ ] regulates cell apoptosis [ ] mcl [ ] regulates transformation of fibroblasts [ ] stat [ ] regulates ifn signaling [ ] sting [ ] negatively regulates antiviral responses [ ] usp- i-kb [ ] increases cytokine release [ ] cbp [ ] lung inflammation [ ] usp- iκbα [ ] nf-κb activation [ ] usp- hdac [ ] reverses glucocorticoid resistance [ ] traf /traf [ ] lung inflammation [ ] [ ] inhibits type i ifn signaling and antiviral response [ ] poh pro-il- β [ ] negatively regulates the immune response [ ] brcc nlrp [ ] promotes the inflammasome activation [ ] stambp nalp [ ] reduces pro-inflammatory stress [ ] alveolar residential macrophages are central to the development of the inflammatory response by recruiting neutrophils and circulating macrophages to the site of injury, their functions are modulated by deubiquitinating enzymes [ , ] . these cells secrete cytokines, chemokines, reactive oxygen species, proteases, and other mediators that modulate the inflammatory responses and injure the alveolocapillary barrier. gram-negative bacteria-derived endotoxin lipopolysaccharide (lps) promotes stability of a histone acetyltransferase hbo via the function of usp . hbo is believed to fire dna replication licensing at the s-phase of the cell cycle, however, it also regulates inflammatory gene transcription in settings of pulmonary infection. usp -stabilized hbo promotes inflammatory gene transcription in monocyte thp- cells [ ] . in addition, inhibition of usp and usp blocks the nlrp inflammasome by preventing apeck-like protein containing a card (asc) oligomerization and speck formation in macrophages [ ] . usp mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating traf /traf complex formation [ ] . the activity of deubiquitination regulates inflammasome assembly and function. deubiquitination of nlrp has been suggested to contribute to inflammasome activation. upon treatment with nlrp ligands after the priming step, abro , a subunit of the brisc deubiquitinating complex, is required for optimal nlrp -asc complex formation, asc oligomerization, caspase- activation, and il- β and il- production. this evidence indicates that efficient nlrp activation requires abro [ ] . protein kinase jnk catalyzes nlrp phosphorylation at s within nlrp , which is critical for nlrp deubiquitination and facilitates its self-association and the subsequent inflammasome assembly [ ] . another inflammasome component nalp is regulated by the deubiquitinating enzyme stam-binding protein (stambp), targeting the stambp with a small molecule that inhibits nalp inflammasome activity [ ] . the activities of deubiquitinating enzymes are involved in many aspects of the pathogenesis in ali/ard. lung epithelial cell death is a hallmark in ali/ards. massive lung epithelial cell death has been reported in ards patients. lung epithelial cell death is regulated by deubiquitinating enzymes. loss of dub cyld can activate nf-κb to inhibit apoptosis in lung epithelial cells [ ] . in lung infection, usp are aberrantly expressed, inhibition of usp reduces the abundance of anti-apoptotic protein mcl in the lung [ ] . on the other hand, recent mechanistic studies have reported that lung epithelial cells may defend from bacterial invasion through several mechanisms. usp may regulate the degradation of a deacetylation enzyme hdac to modulate cellular pseudomonas aeruginosa bacterial load, probably via interferon signaling in bronchial lung epithelial cells [ ] . otub interferes with bacterial uptake by modulating the rhoa level [ ] . furthermore, deubiquitination has been proposed to play an important role in alveolar epithelial dysfunction during ali. usp exerts an effect on mucociliary clearance by regulating the endocytic recycling of the cystic fibrosis transmembrane conductance regulator (cftr) in airway epithelial cells [ , ] . in addition, accumulating data suggest that deubiquitination may regulate structural components of the alveolar epithelial monolayer. structural integrity of epithelial cells and intercellular junctions plays an important role in the maintenance of alveolar epithelial barrier integrity. a study suggests that phosphorylated e f is stabilized by nuclear usp to drive peg gene expression and activate proliferation of lung epithelial cells [ ] . finally, airway barrier integrity is primarily maintained by intercellular junctions, which in turn control the paracellular transport of proteins, fluids, and small molecules. cell junction and junctional protein recycling and remodeling is pivotal in barrier integrity. deubiquitination and dubs have been shown to regulate adherence of junctional proteins [ ] . for example, usp regulates e-cadherin mrna levels through stabilizing the traf -jnk pathway in lung epithelial cells [ ] . this study exhibits an indirect effect of dubs on regulation of e-cadherin levels and lung epithelial barrier integrity. until now, the mechanism of covid- infection has not been well illustrated yet. from the biopsy or autopsy of covid- patients, diffuse damage of lung parenchyma has been shown [ , ] . experts hypothesized that sars-cov- invasion severely interrupts the integrity of the airway barrier, thus inducing aberrant inflammatory release ("cytokine storm") and further worsening the lung injury and microcirculation dysfunction, resulting in uncontrolled sepsis in severe cases [ ] . whether dubs participate in the mechanism of sars-cov- infection has not been reported. the coronavirus family contains six members. sars-cov and middle east respiratory syndrome coronavirus (mers-cov) are the two members that have brought an epidemic in recent years. sars-cov and mers-cov, containing the papain-like cysteine proteases (plpro), termed sars-covplpro and mers-covplpro respectively, are antagonists of the host antiviral immune response as they remove ubiquitin and its modifier interferon-stimulated gene (isg ) signals from host cell factors [ , ] . whether such a protease encoded by the sars-cov- genome exists has not been reported, which might expand the field of sars-cov- study. furthermore, human dubs might be potential targets for sars-cov- invasion. we scanned the related dataset of genes and proteins in covid- and the sars-cov- infected cells. data showed that a majority of dubs are decreased in human ipsc-cardiomyocytes infected with sars-cov- via rna-sequencing [ ] . in ace positive type ii pneumocytes, a number of usps including usp and usp are elevated compared to ace negative cells using next generation sequencing [ ] . sars-cov- spike (s) protein invades human tissue through binding angiotensin-converting enzyme (ace ), which reminds us that usps might play an important role in covid- development. however, in the sera of covid- patients, no dubs have been found through proteomics [ ] . in all, the above data revealed that dubs might be involved in the mechanism of sars-cov- infections, but further studies are still urged to explore the function of dubs in covid- . the usp subfamily contains the majority of dubs encoded by the human genome, which are the most diversified members within the dub family [ ] [ ] [ ] . the most studied dub family member in usps is cylindromatosis (cyld). cyld was originally identified as a tumor suppressor, where loss of which causes a benign human syndrome cyld [ ] . with sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (uch), cyld cleaves k -linked polyubiquitin chains off its target proteins [ ] [ ] [ ] . cyld is proven to be induced by gram-negative and gram-positive bacterial pathogens or their products [ , , , ] . the transcription factor nf-κb activated by bacteria is essential for induction of cyld, in turn, induced cyld negatively regulates the bacteria induced nf-κb signaling [ , ] . cyld deubiquitinates traf and traf to negatively regulate peptidoglycan-induced toll-like receptor (tlr ) signaling and inflammation [ ] . cyld is also highly induced by pneumolysin (ply). cyld deficiency protects mice from acute lung injury in lethal streptococcus pneumoniae infections by inhibiting plasminogen activator inhibitor- (pai- ) expression [ , ] . furthermore, evidence shows that cyld negatively regulates the s. pneumoniae-induced nuclear factor of activated t cells (nfat)signaling pathway by deubiquitinating tgf-β-activated kinase (tak ) [ ] . in contrast, cyld(-/-) mice are hypersusceptible to escherichia coli pneumonia with enhanced nf-κb activation [ ] . perhaps different pathogens may use distinct mechanisms to promote lung inflammation. in the late stage of bacterial infection, cyld exhibits negative effects on injury-induced lung fibrotic response by inhibiting tgf-β-signaling [ ] . these discoveries indicated that cyld might possess a potential drug target for the treatment of bacterial infection pneumonia. usp (hausp)is originally identified as a viral binding protein that preferentially cleaves k -, k -and k -linked ubiquitin chains [ , ] . usp is involved in viral infection by targeting virus related protein to modulate virus replication and production [ ] [ ] [ ] . usp is reported to deubiquitinate and stabilize nf-κb to increase its transcriptional activity in tlr-induced inflammatory gene expression [ ] . furthermore, usp fine-tunes notch signaling in angiogenic sprouting by deubiquitinatingnotch intracellular domain (nicd ) to slow down its turnover of the short-lived form of the activated notch receptor [ ] . ups is also reported to regulate antiviral responses, however, its function is controversial. usp is considered to promote ifn signaling and play an antiviral role by stabilizing stat [ ] . nevertheless, usp deficiency enhances antiviral responses through deubiquitinating stimulator of interferon (sting) [ ] . during bacterial infection, usp loses its activity for iκbα deubiquitination by interacting with e ub-ligase hrd to promote tlr -induced inflammation [ ] . usp mediates deubiquitination and stabilization of hdac in cigarette smoke extract-induced inflammation [ ] . usp also preserves a negative effect on tnf-α-and il- β-triggered nf-κb activation by deubiquitinating tak [ ] . usp interacts with tir domain-containing adaptor inducing interferon-β (trif), and thus impairs its recruitment to tlr / [ ] . usp deficient mice produce exacerbated inflammatory cytokines and are more susceptible to septicemia death [ , ] . usp affects ddx /rig-i-mediated type i interferon signaling through ubiquitinating becn and promoting the formation of autophagosomes [ ] . usp plays a protective role in virus or bacterial infection. several studies showed that usp negatively regulates virus-induced type i ifn signaling by stabilizing traf , traf and traf [ , , , , [ ] [ ] [ ] [ ] . furthermore, usp inhibits tlr -activated innate immunity via removing k ubiquitination of traf [ ] . usp deficient mice have been shown to be more susceptible to virus infection and lps-induced septic shock [ , ] .il- -mediated inflammation is also attenuated by usp through traf and traf deubiquitination [ ] . the anti-malarial drug chloroquine is suggested to alleviate lps-induced inflammation by up regulatingusp in macrophages [ ] . the otu family dubs can be divided into four subfamilies, including otulins (otulin and fam a), otubs/otubains (otub and otub ), otuds (otud , otud /yod , otud , otud , otud /duba, otud a, otud b, alg , and hin l), and a s (a , cezanne, cezanne , trabid, and vcpip) [ ] . the majority of otu members are reported to regulate pathogen-induced cell signaling cascades. in innate and adaptive immunity, otulin is an essential negative regulator of lubac, which hydrolyzes lubac induced met- lineal ubiquitination to prevent nf-κb-or tnf-induced inflammation augmentation [ ] [ ] [ ] ] . otulin can also control antiviral signaling by regulating the lineal ubiquitination chain of stat [ ] . for the negative role of otulin in immune responses, otulin deficiency might cause auto-inflammatory syndrome [ ] . otub and otub regulate virus-triggered ifn inflammation by deubiquitinating traf and traf [ ] . otub suppresses the e ubiquitin-ligase by co-opting k ubiquitin recognition to regulate dna damage [ , [ ] [ ] [ ] [ ] . recent studies also show that otub augments nf-κb-dependent immune responses in dendritic cells in infection and inflammation by stabilizing ubc [ ] . otub recruits phosphorylated smad / and inhibits its ubiquitination by binding with e ub-conjugating enzyme to enhance tgf-β signaling [ ] . otub regulates the maturation and activation of nk and cd +t cells via inhibiting akt ubiquitination [ ] . furthermore, virus-induced otub degradation blocks the rig-i-dependent immune signaling cascade and antiviral response [ ] . several studies showed that otud plays an important role in inflammation regulation [ , ] . rna viruses induceotud to promote the degradation of the mavs/traf /traf signalosome to inhibit innate immunity [ ] . furthermore, otud inhibits type ifn induction after virus infection through cleaving noncanonical k -linked ubiquitination of irf [ ] . otud knockout mice show more resistance to virus infection and lps stimulation [ , ] . otud is a k -specific deubiquitinating enzyme that is previously been reported to maintain the stability of the alkylation repair enzyme alkbh for promoting dna damage repair [ ] . however, otud also preserves k -linked deubiquitinating activity, specifically targetingmyd to inhibit nf-κb signaling [ ] . a recent study shows the role of otud in innate antiviral immunity. otud is induced by virus infection and targets mavs ubiquitination, triggeringirf and nf-κb signaling to sustain antiviral responses [ ] .like most of the dubs, the family member a shows the negative effect on the activation of nf-κb signaling [ , , ] .myeloid-a -deficiency shows a higher inflammatory reaction and sustained nf-κb activation [ ] . a terminates tlr signals by targeting traf deubiquitination [ ] . similar to otub , a suppresses nf-κb signaling by conjugating to e ub-ligase [ ] . histone methyltransferase-enhanced a can also suppress the inflammatory response by modulation of nemo and deubiquitination of traf [ ] . due to its role in inflammation inhibition, a induced by tnfα participates in age-related macrophage dysfunction in the lung [ ] . otuds are newly discovered in antiviral immune responses, which reminds us of the potential drug target for the treatment of virus-induced lung injury. the jamms are the third largest subfamily in dubs, and it comprises members: cop signalosome subunit (csn) , s proteasome non-atpase regulatory subunit (poh ), brca /brca -containing complex subunit (brcc , also known as brcc in humans), mpn domain containing (mpnd, myb-like swirm and mpn domains (mysm ), eukaryotic translation initiation factor subunit (eif )h, csn , s proteasome non-atpase regulatory subunit (psmd ), eif f, anti-müllerian hormone (amsh), amsh-lp, and pre-mrna-processing-splicing factor (prpf ) [ , [ ] [ ] [ ] [ ] .stambp (also known as the associated molecule with the sh domain of stam or amsh), a metalloprotease and a member of the jab /mpn metalloenzyme (jamm) family of dubs, impedes the lysosomal degradation of nacht, lrr and pyd domain-containing protein (nalp )to inhibit inflammasome activity [ , ] . poh deubiquitinates pro-il- β and inhibits mature il- β production, thus restricting inflammasome activity and lps-induced inflammation [ ] . dubbrcc forms a multi-protein complex (brisc) with abro , nba , and bre that specifically cleaves k -linked ubiquitin in the cytoplasm [ ] . abro is important in efficient nlrp activation. abro deubiquitinates nlrp to promote nlrp inflammasome activation [ ] . brcc also targets nlrp to regulate inflammasome formation [ ] . the enzymes of the uch protein family includes four members, uchl /pgp . (protein gene product . ), uchl , uchl /uch , and brca associated protein- (bap ), which contain a conserved catalytic uch domain of~ amino acids [ , ] . the activities of these proteins have been associated with the occurrence and development of cancer [ ] . uchl /uch is suggested to play an anti-apoptotic role in lung epithelial cells through altering bax/bcl- , caspase , and caspase signals [ ] . uch /uch deubiquitinates both smad and smad to promote tgfβ- induced lung fibrosis [ ] . studies of uchs in lung injury and pathogen invasion are still lacking. the mjd family onlycontains four members: ataxin (atxn) , atxn l, josephin domain containing (josd), and josd [ ] . studies show that atxn andjosd are involved in antiviral responses. atxn enhances type ifn signaling during viral infection through deubiquitinating and stabilizing hdac [ ] . nevertheless, josd exhibits a negative role in antiviral activity. josd inhibits the ifn signal cascade via deubiquitinating and stabilizing socs [ ] . the mcpip, also known as zc h a (zinc finger ccch-type containing a) family includes mcpip - members [ ] [ ] [ ] . mcpip implicates a negative role in regulation of the cellular inflammatory responses [ ] . mcpip is the most studied in the mcpip family. acting as a deubiquitinating enzyme, mcpip inhibits nf-κb and c-jun n-terminal kinase (jnk) signaling pathways by removing the ubiquitin moieties from tnf receptor-associated factors (trafs), including traf , traf and traf [ ] .as an rnase, mcpip also regulates inflammatory cytokines like il- by regulating rna decay [ ] and innate defense via degrading viral rna [ ] . mcpip deubiquitinates traf to impede nf-κb signaling [ ] . like the recently identified dubs, the mindy family contains four members: mindy - [ ] , which are highly selective at hydrolyzing k -linked poly-ubiquitin. no data about mindys in ali/ards pathogenesis has been reported. the above dubs play essential roles in the initial development of cancer. however, their functions in lung injury are not fully elucidated. pathogen-related dubs are promising potential targets of drug discovery for human pathogen infection and associated inflammatory disorders. bacteria-encoded dubs might promote bacterial pathogenicity through inhibiting the human ubiquitin-proteasome system [ ] . furthermore, viruses with genes for dubs might inhibit the antiviral pathways using a dub strategy to modulate protein-protein interactions. the sars-covplpro and mers-covplpro papain-like cysteine proteases have been reported, showing a conserved similar structure to the usp family of dubs by x-ray structure, which shows the potential targets of dubs for antiviral drug discovery [ , ] . in addition, several rna virus-related proteases containing the out domain can also remove ubiquitin and isg- signals from host cellular proteins, which represents a potential promising domain for antiviral therapy [ ] . the above findings present great interest to explore a dub-associated anti-infective strategy for human pathogen invasions. however, despite the possibility of dubs as drug targets, the drug discovery for ali/ards is still challenging, with few dub inhibitors or activators having been explored. during the past decade, studies began to dissect the role of dubs in ali/ards. increasing evidence proved that immune responses, inflammation, cell death, air-blood barrier integrity, and invasiveness of the pathogens are fine-tuned by dubs in ali/ards (figure ). modulation of critical proteins via ups and dubs plays a central role in the pathogenesis of diseases such as cancer and autoimmune disease. furthermore, dubs are drawing increasing interest as therapeutic targets against these diseases. our understanding of dubs in ali/ards is limited, and the specific role of dubs remains largely unknown. particularly, the global outbreak of covid- has raised the demand for research on the pathological mechanisms of ali/ards. discovery of the role of dubs in ali/ards might bring valuable information on the pathogenesis of the illness and thereafter drug discovery. the diversified microbial pathogens may cause ali/ards via distinct molecular mechanisms, which increase the complexity of the whole picture that we are attempting to figure out. on the other hand, the current studies are mostly focused on the function of dubs on the regulation of protein degradation and stability. the functions of dubs other than protein stability are yet to be studied in the setting of ali/ards.as a post-translational modification, ubiquitinated proteins may exert a range of functions in life processes and in the pathogenesis of ali/ards, such as signaling transduced via ubiquitinated protein. it is hoped that more data on dubs might lead to identification of novel molecular mechanisms in ali/ards, thus allowing the development of specific dub inhibitors/agonists for the treatment of this acute and severe respiratory illness. funding: this work is supported with r grants (hl and hl ) from national institute of health at the united states to c.z. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. funding: this work is supported with r grants (hl and hl ) from national institute of health at the united states to c.z. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. proteasome non-atpase regulatory subunit prpf pre-mrna-processing-splicing factor psmd proteasome non-atpase regulatory subunit rig- retinoic acid-inducible gene i ripk receptor-interacting protein kinase sars-cov- severe acute respiratory syndrome coronavirus stambp stam-binding protein sting stimulator of interferon tak tgf-β-activated kinase tgfβ- transforming growth factor β- trif tir domain-containing adaptor inducing interferon-β tnf-α tumor necrosis factor-α traf tumor necrosis factor receptor-associated factor uba ub-activating enzymes ubc ub-conjugating enzymes uchs ubiquitin carboxy-terminal hydrolases usps ubiquitin-specific proteases the acute respiratory distress syndrome: from mechanism to translation acute respiratory distress syndrome: the berlin definition the acute respiratory distress syndrome in acute respiratory distress syndrome acute respiratory distress syndrome novel concepts of acute lung injury and alveolar-capillary barrier dysfunction mechanisms of pulmonary edema clearance during acute hypoxemic respiratory failure: role of the na,k-atpase healthcare disparities in patients with acute respiratory distress syndrome. toward equity early local immune defences in the respiratory tract the pathogenesis and treatment of the 'cytokine storm' in covid- into the eye of the cytokine storm. microbiol the acute respiratory distress syndrome: pathogenesis and treatment pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome ubiquitin-proteasome signaling in lung injury ubiquitination and proteolysis in acute lung injury role of ubiquitination in na,k-atpase regulation during lung injury the ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction the ubiquitin system regulation of protein stability by gsk mediated phosphorylation diversity of degradation signals in the ubiquitin-proteasome system the emerging role of the ubiquitin proteasome in pulmonary biology and disease ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome deubiquitinating enzymes in cellular signaling and disease regulation regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes deubiquitylases from genes to organism breaking the chains: structure and function of the deubiquitinases mechanisms of deubiquitinase specificity and regulation mindy- is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes toll-like receptor and rig-i-like receptor signaling innate immune recognition of viral infection overexpression of usp protease reduces i-kappab protein levels and increases cytokine release in lung epithelial cells regulation of the ubiquitylation and deubiquitylation of creb-binding protein modulates histone acetylation and lung inflammation hscarg downregulates nf-kappab signaling by interacting with usp and inhibiting nemo ubiquitination hsv icp recruits usp to modulate tlr-mediated innate response inflammatory mechanisms in the lung destabilization of lysophosphatidic acid receptor reduces cytokine release and protects against lung injury the deubiquitinating enzyme usp regulates the endocytic recycling of cftr in airway epithelial cells lopez-castejon, g. usp and usp deubiquitinases regulate nlrp inflammasome activation deubiquitination of nf-kappab by ubiquitin-specific protease- promotes transcription the deubiquitinase usp stabilizes the anti-inflammatory receptor il- r /sigirr to suppress lung inflammation down-regulation of usp mediates phenotype transformation of fibroblasts in idiopathic pulmonary fibrosis deubiquitinase usp dictates mcl stability and sensitivity to bh mimetic inhibitors tumor suppressor cylindromatosis acts as a negative regulator for streptococcus pneumoniae-induced nfat signaling cylindromatosis (cyld) inhibits streptococcus pneumonia-induced plasminogen activator inhibitor- expression via interacting with traf- the tumor suppressor cylindromatosis (cyld) acts as a negative regulator for toll-like receptor signaling via negative cross-talk with traf and traf tumor suppressor cyld acts as a negative regulator for non-typeable haemophilus influenza-induced inflammation in the middle ear and lung of mice cyld negatively regulates transforming growth factor-beta-signalling via deubiquitinating akt tumor suppressor cyld regulates acute lung injury in lethal streptococcus pneumoniae infections regulation of the ebola virus vp protein by sumo usp deubiquitinase controls hiv- production by stabilizing tat protein usp -dependent regulation of traf activation and signaling by a viral interferon regulatory factor homologue a pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic system deubiquitinase usp regulates notch signaling in the endothelium phosphorylated e f is stabilized by nuclear usp to drive peg gene expression and activate lung epithelial cells ubiquitin-specific protease regulates ifn signaling by stabilizing stat usp negatively regulates antiviral responses by deubiquitinating sting er-localized hrd ubiquitinates and inactivates usp to promote tlr -induced inflammation during bacterial infection usp -mediated deubiquitination and stabilization of hdac in cigarette smoke extract-induced inflammation usp mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating traf /traf complex formation usp inhibits tnf-alpha-and il- beta-triggered nf-kappab activation by deubiquitinating tak regulation of trif-mediated innate immune response by k -linked polyubiquitination and deubiquitination the becn -usp axis plays a role in the crosstalk between autophagy and antiviral immune responses ubiquitin-specific protease regulates tlr -dependent innate immune responses through deubiquitination of the adaptor protein traf ubiquitin-specific proteases negatively regulates virus-induced type i interferon signaling induction of usp by viral infection promotes innate antiviral responses by mediating the stabilization of traf and traf negative regulation of il- -mediated signaling and inflammation by the ubiquitin-specific protease usp lps promotes hbo stability via usp to modulate inflammatory gene transcription in thp- cells cigarette smoke extract modulates pseudomonas aeruginosa bacterial load via usp /hdac axis in lung epithelial cells the deubiquitinating enzyme usp stabilizes traf and reduces e-cadherin-mediated adherens junctions ubiquitin carboxyl-terminal hydrolase-l promotes tgfbeta- signaling by de-ubiquitinating and stabilizing smad /smad in pulmonary fibrosis otulin restricts met -linked ubiquitination to control innate immune signaling otulin antagonizes lubac signaling by specifically hydrolyzing met -linked polyubiquitin the deubiquitinase otulin is an essential negative regulator of inflammation and autoimmunity regulation of the linear ubiquitination of stat controls antiviral interferon signaling regulation of virus-triggered signaling by otub -and otub -mediated deubiquitination of traf and traf the deubiquitinase otub augments nf-kappab-dependent immune responses in dendritic cells in infection and inflammation by stabilizing ubc the deubiquitinase otub controls the activation of cd (+) t cells and nk cells by regulating il- -mediated priming post-translational modification of the deubiquitinating enzyme otubain modulates active rhoa levels and susceptibility to yersinia invasion otub is a key regulator of rig-i-dependent immune signaling and is targeted for proteasomal degradation by influenza a ns otub enhances tgfbeta signalling by inhibiting the ubiquitylation and degradation of active smad / induction of otud by rna viruses potently inhibits innate immune responses by promoting degradation of the mavs/traf /traf signalosome mutations of deubiquitinase otud are associated with autoimmune disorders otud negatively regulates type i ifn induction by disrupting noncanonical ubiquitination of irf otud is a phospho-activated k deubiquitinase that regulates myd -dependent signaling induction of otud by viral infection promotes antiviral responses through deubiquitinating and stabilizing mavs noncanonical regulation of alkylation damage resistance by the otud deubiquitinase the ubiquitin-modifying enzyme a is required for termination of toll-like receptor responses inhibition of nf-kappab signaling by a through disruption of ubiquitin enzyme complexes klf alleviates lipopolysaccharide-induced inflammation by inducing expression of mcp- induced protein to deubiquitinate traf atxn positively regulates type i ifn antiviral response by deubiquitinating and stabilizing hdac josd inhibits mitochondrial apoptotic signalling to drive acquired chemoresistance in gynaecological cancer by stabilizing mcl josd negatively regulates type-i interferon antiviral activity by deubiquitinating and stabilizing socs poh deubiquitinates pro-interleukin- beta and restricts inflammasome activity deubiquitination of nlrp by brcc critically regulates inflammasome activity targeting the deubiquitinase stambp inhibits nalp inflammasome activity diverse macrophage populations mediate acute lung inflammation and resolution the contributions of lung macrophage and monocyte heterogeneity to influenza pathogenesis abro promotes nlrp inflammasome activation through regulation of nlrp deubiquitination nlrp phosphorylation is an essential priming event for inflammasome activation loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating nf-kappab the role of ubiquitination and deubiquitination in the regulation of cell junctions pathological findings of covid- associated with acute respiratory distress syndrome pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer sars-cov- and viral sepsis: observations and hypotheses sars hcov papain-like protease is a unique lys linkage-specific di-distributive deubiquitinating enzyme a noncovalent class of papain-like protease/deubiquitinase inhibitors blocks sars virus replication human ipsc-derived cardiomyocytes are susceptible to sars-cov- infection sars-cov- receptor ace is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues proteomic and metabolomic characterization of covid- patient sera structural basis of ubiquitin recognition by the deubiquitinating protease usp . structure amino-terminal dimerization, nrdp -rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease (usp ) structure and mechanisms of the proteasome-associated deubiquitinating enzyme usp identification of the familial cylindromatosis tumour-suppressor gene cyld: a deubiquitination enzyme with multiple roles in cancer the tumour suppressor cyld negatively regulates nf-kappab signalling by deubiquitination cyld is a deubiquitinating enzyme that negatively regulates nf-kappab activation by tnfr family members nf-kappab is essential for induction of cyld, the negative regulator of nf-kappab: evidence for a novel inducible autoregulatory feedback pathway cyld is a crucial negative regulator of innate immune response in escherichia coli pneumonia targeting ubiquitin specific proteases for drug discovery screening of dub activity and specificity by maldi-tof mass spectrometry critical role of traf in the toll-like receptor-dependent and -independent antiviral response specificity in toll-like receptor signalling through distinct effector functions of traf and traf regulation of antiviral responses by a direct and specific interaction between traf and cardif duba: a deubiquitinase that regulates type i interferon production chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of usp . can otu deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis linear ubiquitination signals in adaptive immune responses otulin deficiency causes auto-inflammatory syndrome otub co-opts lys -linked ubiquitin recognition to suppress e enzyme function non-canonical inhibition of dna damage-dependent ubiquitination by otub evidence for bidentate substrate binding as the basis for the k linkage specificity of otubain the mechanism of otub -mediated inhibition of ubiquitination a (tnfaip ) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis histone methyltransferase ash l suppresses interleukin- production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme a elevated a contributes to age-dependent macrophage dysfunction in the lungs k -specific deubiquitination by two jamm/mpn+ complexes: brisc-associated brcc and proteasomal poh structural basis for specific cleavage of lys -linked polyubiquitin chains sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of trim activation of the endosome-associated ubiquitin isopeptidase amsh by stam, a component of the multivesicular body-sorting machinery the lys -specific deubiquitinating enzyme brcc is regulated by two scaffold proteins localizing in different subcellular compartments up-regulation of expression of the ubiquitin carboxyl-terminal hydrolase l gene in human airway epithelium of cigarette smokers ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications effect of ubiquitin carboxy-terminal hydrolase on apoptotic in a cells deubiquitylating enzymes and drug discovery: emerging opportunities monocyte chemotactic protein (mcp)- promotes angiogenesis via a novel transcription factor, mcp- -induced protein (mcpip) regulatory feedback loop between nf-kappab and mcp- -induced protein rnase mcpip negatively regulates toll-like receptor signaling and protects mice from lps-induced septic shock a novel ccch-zinc finger protein family regulates proinflammatory activation of macrophages mcp-induced protein deubiquitinates traf proteins and negatively regulates jnk and nf-kappab signaling zc h a is an rnase essential for controlling immune responses by regulating mrna decay mcpip ribonuclease exhibits broad-spectrum antiviral effects through viral rna binding and degradation the molecular basis for ubiquitin and ubiquitin-like specificities in bacterial effector proteases crystal structure of the middle east respiratory syndrome coronavirus (mers-cov) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression crystal structure of the papain-like protease of mers coronavirus reveals unusual, potentially druggable active-site features ovarian tumor domain-containing viral proteases evade ubiquitin-and isg -dependent innate immune responses this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -jjjr ymt authors: eastin, carly; eastin, travis title: risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china: wu c, chen x, cai y, et al. jama intern med. doi: . /jamainternmed. . . date: - - journal: j emerg med doi: . /j.jemermed. . . sha: doc_id: cord_uid: jjjr ymt nan was days (range - ). nearly all were categorized as asymptomatic ( . %), mild ( . %), or moderate ( . %) severity, leaving only . % as severe or critical. looking at breakdown by age, infants made up the highest proportion of severe or critical disease ( %) with preschool ages ( - years) next with . %. half ( ) of the critical patients were under year old. no significant differences were seen between male or female patients. there was one death in the sample: a -year old boy. limitations included lack of clinical characteristics, as only data from the chinese cdc was used rather than electronic medical records from individual patients. additionally the majority of cases were suspected, not confirmed, and some of the children remained hospitalized at the end of the study therefore severity of disease may not be accurate. the authors concluded that covid- caused infection in all ages without obvious gender differences, however younger children appeared to have higher severity of disease. [carly eastin, md travis eastin, md, ms university of arkansas for medical sciences, little rock, ar] comment: this is the largest cohort of pediatric covid- patients to date. this study is based on the china cdc dataset and is limited to the variables that are reported to the cdc. we cannot assume children in the united states will be affected similarly. overall, this dataset suggests that critical disease is rare in children with covid- . emergency physicians should use caution with infants and young children, however, as they appear to be at highest risk of severe disease and may need closer observation in the emergency department or inpatient admission. presenting symptoms of severe acute respiratory syndrome coronavirus (sars-cov- ) typically include fever, dyspnea, myalgia, and cough. previous data suggest that older adults tend to have more severe illness. this study reports characteristics of and potential risk factors for patients who developed acute respiratory distress syndrome (ards) or who died as a result of sars-cov- , the virus that causes covid- . patients aged to who had confirmed covid- and were admitted to jinyintan hospital in wuhan, china between december , and january , were included in this retrospective study. trained clinicians abstracted data through february , and included epidemiological data, clinical characteristics, laboratory and radiologic findings, treatments, and outcomes. all patients had confirmed sars-cov- by throat swab sampling. older age was defined as over years old and fever was defined as a temperature higher than . degrees celsius. the primary outcomes were development of ards or death among patients with ards. a total of patients met inclusion criteria. the median age was (iqr - ), with . % of patients aged years or older. major comorbidities included hypertension ( . %), diabetes ( . %), and cardiovascular disease ( . %). the most common presenting symptoms were fever ( . %), cough ( . %), productive cough ( . %), dyspnea ( . %), or fatigue/myalgia ( . %). most ( %) had bilateral infiltrates on chest imaging. a separate respiratory viral panel was tested on patients, but only had a coinfection (influenza a). notable abnormal laboratory values included lymphocytopenia in %, elevated ldh (> u/l) in %, elevated high sensitivity c-reactive protein (> mg/l) in . %, elevated erythrocyte sedimentation rate (> mm/h) in . %, and elevated ddimer (> . ug/ml) in . %, among others. once admitted, % of patients required oxygen. the majority ( . %) of patients were on nasal cannula, but many ( . %) required noninvasive ventilation. six patients were intubated and of those was also treated with extracorporeal membrane oxygenation (ecmo). most received antibiotics and antivirals ( . % and . %, respectively), half ( . %) received antioxidant therapy, and systemic steroids were given to . %. at the end of the study, ( . %) patients had been discharged and median length of stay was days (iqr - days). a total of patients ( . %) died, all of whom had developed ards. the remainder of the patients remained hospitalized. in comparing patients with ( , . %) or without ards, those with ards were older (mean difference years, % ci [ - ]), more likely to have comorbidities like hypertension or diabetes (differences . %, % ci [ . %- . %] and . %, % ci [ . %- . %], respectively) and more likely to present with dyspnea (difference . %, % ci [ . %- . %]). other findings more likely to occur in patients with ards included lymphocytopenia, neutrophilia, elevated liver or renal measurements, and elevated inflammatory markers. of those with ards who subsequently died, these patients were older (difference years, % ci [ - ]), had lower temperatures (difference in proportion of high fever - . %, % ci [- . % to - . %]), and received antivirals less often (difference - . %, % ci [- . % to - . %]). additionally, they had even greater abnormalities of liver and renal function, inflammatory markers, or coagulation indices than those with ards who survived. high fever (> o c) was found to be positively associated with developing ards ( the authors concluded that major risk factors for ards and subsequent death were older age, neutrophilia, and evidence of end-organ damage. comorbidities and fever appeared to be associated with ards but not death. limitations included selection bias, as only patients with severe covid- were hospitalized therefore poor outcomes may appear inflated. [carly eastin, md travis eastin, md, ms university of arkansas for medical sciences, little rock, ar] comment: this is a large dataset in the limited nascent sars co-v /covid- literature, and, though it should be the journal of emergency medicine this study is consistent with other data that those of increased age and with comorbid conditions have worse outcomes than younger, healthier patients. interestingly, it appears some of those with ards did not receive mechanical ventilation, which brings the generalizability of these results into question. antivirals and corticosteroids may have a role in treatment of patients with ards related to covid- key: cord- - kizif authors: deng, guangcun; bi, jianmin; kong, fuli; li, xuezhu; xu, qiang; dong, jun; zhang, miaojie; zhao, lihong; luan, zhihua; lv, nana; qiao, jian title: acute respiratory distress syndrome induced by h n virus in mice date: - - journal: arch virol doi: . /s - - - sha: doc_id: cord_uid: kizif h n avian influenza viruses have repeatedly caused infections in swine and humans in some countries. the purpose of the present study was to evaluate the pulmonary pathology caused by h n viral infection in mice. six- to eight-week-old balb/c mice were infected intranasally with × ( ) mid( ) of a/chicken/hebei/ / (h n ) virus. clinical signs, pathological changes and viral replication in lungs, arterial blood gas, and cytokines in bronchoalveolar lavage fluid (balf) were observed at different time points after infection. a control group was infected intranasally with noninfectious allantoic fluid. h n -infected mice exhibited severe respiratory syndrome, with a mortality rate of %. gross observations showed that infected lungs were highly edematous. major histopathological changes in infected lungs included diffuse pneumonia and alveolar damage, with neutrophil-dominant inflammatory cellular infiltration, interstitial and alveolar edema, hemorrhage, and severe bronchiolitis/peribronchiolitis. in addition, h n viral infection resulted in severe progressive hypoxemia, lymphopenia, and a significant increase in neutrophils, tumor necrosis factor-α and interleukin- in balf. the features described above satisfy the criteria for acute respiratory distress syndrome (ards). our data show that h n viral infection resulted in ards in mice, and this may facilitate studies of the pathogenesis of future potential h n disease in humans. h n avian influenza viruses have become highly prevalent in poultry in many eurasian countries since the early s [ , ] . although these viruses generally cause only mild to moderate disease, they have been associated with severe morbidity and mortality in poultry as a result of coinfection with other pathogens [ ] . since , h n viruses have been isolated from pigs and humans with influenza-like illness in hong kong and mainland china [ - , , , , , , ] . these findings indicate that the h n avian influenza virus can also cross species barriers and expand its host range from avians to mammalians. to date, h n virus has usually caused relatively mild clinical signs in humans [ , ] . however, recent studies have shown that infection of swine with h n viruses causes significant morbidity and mortality [ ] . most of the diseased pigs showed typical respiratory signs, including fever, nasal and ocular discharge, coughing and dyspnoea. in some cases, paralysis associated with fatal disease was also observed [ ] . pigs are believed to serve as intermediate hosts for adaptation of avian influenza viruses that infect humans, and it has been shown that some of the h n influenza viruses currently circulating in china have molecular features that allow them to preferentially bind to human a- , -neuacgal receptors [ , ] . the recurring presence of h n infections in pigs and humans has raised concerns about the possibility that h n viruses are capable of evolving into pandemic strains [ , , ] . previous studies revealed that h n viruses were able to infect mice without adaptation, and this resulted in different levels of lethality and kinetics of replication [ , ] . more recently, it was demonstrated that an h n virus showed enhanced replication and efficient transmission by direct contact in a ferret model [ ] . it is well known that influenza viruses mainly cause pulmonary infection in animals and humans, but little information is available regarding h n viral infection in lungs in mammals. therefore, it is urgent to evaluate the pathology of pulmonary infection caused by currently circulating h n viruses in an appropriate animal model. here, an h n avian virus with high lethality for mice, isolated recently from northern china, was used to address this in a mouse model. the results suggest that h n viral infection induces a typical acute respiratory distress syndrome (ards) in mice that resembles the common features of ards [ , ] . our data may facilitate studies of the pathogenesis of future potential avian h n disease in humans. the h n virus used in this study was isolated from chickens in hebei province of northern china in and was identified by means of hemagglutination inhibition and neuraminidase inhibition tests. the isolate was designated as a/chicken/hebei/ / (h n ) (ck/hb/ / ). the complete genome sequences of the virus are available from genbank under accession numbers fj -fj . our previous studies showed that this isolate was a reassortant virus containing a/chicken/beijing/ / -virus-like ha, na, and ns genes, an a/quail/hongkong/g / -like m gene, and a/chicken/shanghai/f/ -like rnp genes. we analyzed its pathogenicity in chickens and mice in detail and found that it replicated efficiently in chicken lungs but did not cause obvious clinical signs in specificpathogen-free (spf) chickens. however, the mice exhibited high mortality rates and severe lung injury when inoculated with ck/hb/ / virus without prior adaptation (data not shown). the virus was propagated in the allantoic cavities of -day-old embryonated spf chicken eggs at °c for h and stored at - °c for use in all of the experiments described herein. the % mouse infectious dose (mid ), % mouse lethal dose (mld ) and % egg infectious dose (eid ) of ck/hb/ / were determined by serial titration of virus in -day-old embryonated spf chicken eggs at °c. titers were calculated by the method of reed and muench as described previously [ ] . all manipulations were performed under bsl- ? laboratory conditions. animal experiments were conducted according to established guidelines and approved by the animal care committee of china agricultural university (beijing, people's republic of china). to assess the pathogenicity of h n virus in mice, six-to eight-week-old female spf balb/c mice, purchased from beijing laboratory animal research center (beijing, people's republic of china), were housed in microisolator cages ventilated under negative pressure with hepa-filtered air. during the experiment, mice had access to food and water ad libitum. a pilot experiment indicated that a dose of mid of ck/hb/ / h n virus was optimal, because the course of the disease was prolonged and the infected mice presented obvious signs of respiratory illness. therefore, in the present study, the mice were lightly anesthetized with diethyl ether and then inoculated intranasally ( ll) with mid of ck/hb/ / h n virus diluted in sterile saline. mock-infected control animals were inoculated intranasally ( ll) with an equivalent dilution of noninfectious allantoic fluid. two types of experiments were carried out in this study. the first experiment was to investigate clinical signs, gross lesions and mortality rates of h n -infected mice over a -day time period. in this experiment, mice were divided randomly into two groups of mice each. the h n -infected group was inoculated with ck/hb/ / virus, and the control group received the noninfectious allantoic fluid, as described above. the animals' general behavior and clinical signs, including food intake, body weight, inactivity, anal temperature (measured with an infrared thermometer) and mortality, were monitored daily in each group for days. in the second experiment, we studied the features of ards induced in mice by h n viral infection. mice were divided randomly into two groups with mice in each group. since some infected mice died between day and day postinfection (p.i.), larger groups ( per group) of mice were used. ten mice of each group were chosen randomly, weighed and euthanized on days , , , , , , and p.i., and the following parameters were observed: lung injury was assessed by testing lung water content and histopathology. arterial blood gas, white blood cell counts, tumor necrosis factor (tnf)-a and interleukin (il)- levels in bronchoalveolar lavage fluid (balf), and viral titers in the lungs were measured at different times. lung histopathology and assessment of lung water content three mice per group were weighed and sacrificed on days , , , , , , and p.i. the whole lungs were removed. the left lobes of the lungs were fixed in buffered % formalin and embedded in paraffin for histopathological evaluation. five-micrometer-thick sections were stained with hematoxylin-eosin for light microscopy. the upper parts of the right lung lobes were used to determine the lung wet weight:body weight ratio and lung wet:dry weight ratio. the remaining lobes of the right lung were stored at - °c until needed for determining the lung virus titer. to assess lung water content, the lung wet weight:body weight ratio and lung wet:dry weight ratio were determined by weighing the right lung before and after oven desiccation at °c, and this was used as an indicator of lung edema [ ] . lung wet:dry weight ratio = weight of the whole wet lung/weight of the whole dry lung; lung wet weight:body weight ratio (%) = weight of the whole wet lung/body weight %. virus titration was performed as described previously [ ] . lungs, kidneys, brains, livers, spleens, and hearts were collected and homogenized in cold phosphate-buffered saline on days , , , , , , and p.i. clarified homogenates were titrated for viral infectivity in embryonated chicken eggs from initial dilutions of : . viral titers were expressed as mean log eid per milliliter ± standard deviation ( mid is about eid ). arterial blood gas analysis and peripheral blood leukocyte counts after blood sample collection, blood gas analysis was conducted as described by fagan et al. [ ] . briefly, arterial blood samples ( . ml) were collected in a heparinized syringe by percutaneous left ventricular sampling of lightly anesthetized mice spontaneously breathing room air. blood gas analysis was immediately conducted with an il ph/blood gas/electrolytes analyzer (instrumentation laboratory, lexington, ma). heparinized blood samples ( ll) were used for leukocyte counts at various time points. cell numbers for three individual mice were determined in triplicate by counting with a hemocytometer. for differential counts, two blood smears from each mouse were stained with wright stain, and the number of lymphocytes was determined. at least cells were counted for each slide at a magnification of , [ ] . neutrophil counts and measurement of tnf-a and il- in balf according to the protocol described by majeski et al. [ ] and nick et al. [ ] , bronchoalveolar lavage was performed immediately following sacrifice of the animal by cervical dislocation on the days indicated. in brief, the lungs were lavaged twice in situ with the chest cavity opened by midline incision with a total volume of . ml of saline ( °c) inserted through an endotracheal tube. the rate of recovery of balf was not less than % for all of the animals tested. after the amount of fluid recovered was recorded, an aliquot of balf was diluted : with . % crystal violet dye and . % acetic acid for leukocyte staining and erythrocyte hemolysis. the number of leukocytes in balf was counted with a hemacytometer under a microscope. the remaining balf was centrifuged ( g, min). neutrophil differential counts were determined by wright staining of a spun sample, on the basis of morphological criteria, under a light microscope with evaluation of at least cells per slide. all slides were counted twice by different observers blinded to the status of the animal. the supernatant for cytokine analysis was immediately frozen and stored at - °c. the concentrations of tnf-a and il- were determined in balf and serum, using elisa kits (sigma, st. louis, mo). all data are expressed as means ± sd. statistical analysis was performed with the spss statistical software package for windows, version . (spss inc., chicago, il). differences between groups were examined for statistical significance by two-tailed student t test. a p-value less than . was considered statistically significant. overall, infected mice presented a relatively acute clinical process. some mice showed inactivity, altered gait, ruffled fur, inappetence, and an average weight loss of . % on day p.i. by day p.i., most mice presented severe signs of respiratory disease, including visual signs of labored respiration and respiratory distress, and exhibited more severe inappetence, emaciation, and . % weight loss. sixty percent of the mice ( of ) died between days and p.i. gross observation showed the infected lungs to be highly edematous, with profuse areas of hemorrhage (fig. a) . retention of gas in the stomach was occasionally found in infected mice. surviving mice began to recover on day p.i. no obvious gross lesions were observed in the hearts, livers, brains or kidneys in infected mice. the infected mice displayed a similar histopathological pattern with severe diffuse pneumonia, characterized by inflammatory cellular infiltration, interstitial and alveolar edema and hemorrhage, as shown in fig. . diffuse pneumonia with severe alveolar damage was found in the whole lung (fig. b) on day . figure b -h showed the kinetic observations of lung lesions of h n -virus-infected mice. on day p.i., lung lesions were characterized by edema around the small blood vessels (fig. c, d, solid arrows) , thickening of the alveolar wall, and dropout of mucous epithelium adhering to the surface of bronchioles (fig. c, d, open arrows) . on days - p.i., as shown in fig. e , f, severe edema and neutrophil-dominant inflammatory cellular infiltration could be seen around small blood vessels (solid arrows) as well as diffuse pneumonia with fig. g, h) . severe peribronchiolitis (solid arrows in fig. g, h) , edema around blood vessels and severe hemorrhage were found (fig. g, h) . in addition, prominent dropout of bronchial epithelium and a great number of neutrophils, fibrin, and suppurative exudates infiltrating the bronchioles were also observed (solid arrows in fig. g, h) . in comparison, lungs from control mice had no apparent histological changes. kinetic observation of h n viral replication in mouse tissues indicated that the viruses in the lung replicated more efficiently than those in other tissues. viral infection resulted in high titers of virus in the lungs on days - p.i. (fig. ) . the peak viral titer was observed on day p.i., reaching . log eid /ml. however, viral titers dropped to a relatively low level on day p.i. viruses were also isolated with lower titers from livers, kidneys, spleens, and hearts on days - p.i., but was not isolated from brains (data not shown). lung water content: edema fig. a shows the dramatic increased lung wet:dry weight ratios on days - p.i. (p \ . ) after h n viral infection. a similar change in lung wet weight:body weight ratios was also observed in infected lung, shown in fig. b , with the peak value nearly fourfold that of the control on day p.i. table shows the time courses of arterial blood gas parameters in mice. the partial pressure of arterial oxygen (pao ), saturation of arterial oxygen (sao ), and ph value were slightly decreased, while partial pressure of arterial carbon dioxide (paco ) was increased in infected mice on day p.i. subsequently, when most of the infected mice presented apparent clinical signs of respiratory distress at day p.i., pao and sao also dramatically decreased as compared with the controls (p \ . ). figure a shows that the number of leukocytes in peripheral blood progressively decreased on days - p.i. in infected mice compared with those in control mice. the lowest value was seen on day p.i. differential blood counts (fig. b) revealed that the lymphocytes of infected mice dropped by about % on day p.i. from day p.i. onwards, both leukocytes and lymphocytes gradually increased in survived mice. white blood cell summary and differential counts in balf figure shows the time course of white blood cell (wbc) summary and neutrophil counts in balf on days , , , , , , and p.i. the number of wbcs in infected mice increased gradually from day p.i. and reached its peak, with about fourfold that of the control group, by day p.i. neutrophils in balf increased dramatically from days - p.i., and the peak was approximately -fold greater than that of the control group on day p.i. concentrations of tnf-a and il- in balf and serum were measured at different time points after h n infection. as shown in fig. a , levels of tnf-a in infected mice significantly increased on days - p.i. in balf (p \ . ) compared with those of the controls. tnf-a levels also rose significantly in serum on days - p.i. (fig. b) , but this alteration was not as significant as that in balf. il- levels increased slightly on days - p.i. in serum but increased dramatically in balf on days - p.i. and reached a peak on day p.i., with about . fold that of control mice. previous studies have revealed that h n viruses demonstrate different levels of lethality and kinetics of replication inflammatory cellular infiltration, interstitial and alveolar edema, hemorrhage, and severe bronchiolitis/peribronchiolitis. additionally, arterial blood gas analysis demonstrated that the pao decreased dramatically and the paco increased significantly when disease was exacerbated. this indicated that most of the infected mice developed progressive and severe hypoxemia consistent with the time course of clinical signs and pulmonary lesions for ards. the features described above satisfy the criteria of ards [ , [ ] [ ] [ ] ] and show that h n viral infection resulted in the prominent ards in mice. in comparison with ards in mice with h n viral infection [ ] , h n viral ards in mice shows a shorter course of disease. most of the h n virus-infected mice presented overt signs and died between days and p.i., while death of mice with h n viral infection occurred between days and p.i. besides this, the infected lungs are more edematous after h n viral infection. observation of viral replication showed that the h n viruses replicated efficiently in the lung. viral infection resulted in high titers of viruses on days - p.i., with the peak viral titer on day p.i. this was consistent with the time course of the severity of h n viral respiratory disease in mice, indicating that high viral replication may be important for h n viral disease pathogenesis. it is believed that tnf-a and il- may play an important role in the development of ards [ , , ] . in most studies, cytokines in patients with ards have been described as an inflammatory 'cascade' or 'network', and thus their actions were not easily manipulated [ ] . h n virus induced high levels of tnf-a and il- in balf and serum in the mouse ards model [ ] . in this regard, our finding that h n viral infection resulted in significantly increased tnf-a and il- in balf is similar to that of the previous study of h n virus infection. the role of these cytokines in lung inflammation during h n viral infection remains to be investigated. a secondary intense neutrophil-predominant host inflammatory response is usually considered an important feature of ards. the inflammatory response triggered by direct or indirect insults to the lung involves the recruitment of blood leukocytes, the activation of tissue macrophages, and the production of a series of different mediators such as cytokines, chemokines and oxygen radicals [ , , , , , , ] . lung injury may be a direct consequence of this inflammatory response. in h n -virus-infected mice, we observed that circulating leukocytes dramatically decreased in the blood and that a great number of inflammatory cells infiltrated the lungs. in addition, the neutrophils in balf increased approximately -fold compared to control mice on day p.i. these results suggested that a great number of leukocytes, especially neutrophils, were recruited from the bloodstream and sequestrated mainly in the lungs, and this might be involved in the host inflammation response and severe pulmonary lesions induced by h n viral infection. some studies have shown that h n viruses could cause upper respiratory tract illnesses in humans [ ] . subsequent studies have revealed that h n viruses can also infect pigs and cause typical respiratory signs with significant morbidity and mortality [ , ] . further investigation demonstrated that currently circulating h n influenza viruses in china continued to evolve and generate multiple genotypes [ , , ] , raising the possibility that the h n virus might increase pathogenicity and transmissibility in humans and would be a potential threat to the human population. our findings highlight the serious potential threat of h n for human health. in summary, our data show that h n viral infection induced typical ards in mice, which might facilitate studies of the pathogenesis of future potential avian h n disease in humans. evaluation of pathogenic potential of avian influenza virus serotype h n in chickens acute respiratory distress syndrome: a historical perspective role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome human infection with an avian h n influenza a virus in hong kong in antigenic and genetic characterization of h n swine influenza viruses in china swine infection with h n influenza viruses in china in the pulmonary circulation of homozygous or heterozygous enos-null mice is hyperresponsive to mild hypoxia molecular characterization of h n influenza viruses: were they the donors of the ''internal'' genes of h n viruses in hong kong? characterization of the pathogenicity of members of the newly established h n influenza virus lineages in asia infections and the inflammatory response in acute respiratory distress syndrome sequence analysis of the hemagglutinin gene of h n korean avian influenza viruses and assessment of the pathogenic potential of isolate ms evolution of h n influenza viruses from domestic poultry in mainland china avian-to-human transmission of h n subtype influenza a viruses: relationship between h n and h n human isolates respiratory reovirus /l induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on t lymphocytes h n influenza a viruses from poultry in asia have human virus-like receptor specificity the comparative pathology of severe acute respiratory syndrome and avian influenza a subtype h n -a review role of p mitogenactivated protein kinase in a murine model of pulmonary inflammation cocirculation of avian h n and contemporary ''human'' h n influenza a viruses in pigs in southeastern china: potential for genetic reassortment? human infection with influenza h n prone position in acute respiratory distress syndrome pulmonary and extrapulmonary acute respiratory distress syndrome are different chemokines in acute respiratory distress syndrome a simple method of estimating fifty percent endpoints characterization of a human h n influenza virus isolated in hong kong bronchoalveolar and systemic cytokine profiles in patients with ards, severe pneumonia and cardiogenic pulmonary oedema genetic analysis of four porcine avian influenza viruses isolated from shandong depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza a (h n ) virus isolated from humans replication and transmission of h n influenza viruses in ferrets: evaluation of pandemic potential acute lung injury and the acute respiratory distress syndrome: a clinical review characterization of a pathogenic h n influenza a virus isolated from central china in isolation and identification of swine influenza recombinant a/swine/shandong/ / (h n ) virus acute respiratory distress syndrome induced by avian influenza a (h n ) virus in mice key: cord- -lcgeingz authors: nan title: th international symposium on intensive care and emergency medicine: brussels, belgium, - march date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: lcgeingz nan introduction: increasing evidence supports a central role for "immunosuppression" in sepsis. it is necessary to develop biomarkers of immune dysfunction that could help to identify patients at risk of poor outcomes [ ] . the decreased expression of human leucocyte antigen (hla)-dra is proposed as a major feature of immunodepression and its persistent decrease is associated with mortality in sepsis [ ] . in a previous study, we evidenced that fcer a (fc fragment of ige receptor ia) is the gene showing the lowest expression levels of the entire transcriptome in sepsis [ ] . here we studied the association between fcer a expression and mortality in infected surgical patients. methods: fcer a and hla-dra expression levels were quantified by droplet digital pcr in blood of infected surgical patients. patients died within days ( . %). spearman test was used to evaluate the association between gene expression and the sequential organ failure assessment (sofa) score. areas under receiver operating curves (auroc) were used to determine the gene expression cut-off values predicting mortality. kaplan-meier survival curves were obtained and differences in survival between groups were evaluated using the log rank test. cox regression was employed to assess mortality risk at days. results: gene expression levels of fcer a and hla-dra correlated inversely with patients' severity (r: - . p< . ; r: - . , p< . respectively). both genes showed significant aurocs to predict survival, but fcer a showed the best accuracy (fig. ) . patients with introduction: severe pulmonary and renal conditions such as acute respiratory distress syndrome (ards), respiratory failure, and deterioration in kidney function often occur in patients with nosocomial pneumonia (np). the emergence and course of infection is genetically determined, hence host genetic landscape may influence an ability to resist infection. methods: variants for genotyping were selected using the phewas catalog which presents genotypic data for caucasian patients, phenotypes and single nucleotide polymorphisms (snps) with p < . [ ] . snps with the lowest p-values for phenotypes with both, respiratory and renal manifestations were selected: intergenic variants rs and rs , rs (edil ) and rs (cyp a ). cyp a gene was associated with pneumonia and ards in our previous investigations, so we included in our analysis three sites of cyp a gene (rs , rs and rs ) studied on a smaller sample. genotyping was performed on sites for a sample results: allele rs -g of the cyp a gene was protective against ards and an increase in creatinine level (fig. ) . the rs -g allele was associated with lung complications and with the development of severe respiratory insufficiency (fig. ) . conclusions: the snps rs and rs can influence the aggravation of pulmonary and renal symptoms through genetically mediated response to infection. introduction: an uncontrolled inflammatory response plays a major role in the sepsis related organ dysfunction. mesenchymal stem cells(mscs) can improve survival of sepsis experimental models by modulating the inflammatory response. macrophages have been considered as important immune effector cells and their polarization imbalance aggravates the disordered inflammation reaction. the project aims to identify the effects of mscs on macrophages polarization against dysregulated inflammatory response. methods: raw . cells were plated in the lower chambers of transwell system in the presence or absence of lipopolysaccharide (lps). then, mscs were seeded in the upper chambers and incubation for different time. finally, transforming growth factor beta (tgfβ) receptor (tgf-βr) inhibitor was added in transwell system. the phenotype of raw . cells were analyzed by flow cytometry, the levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (elisa). results: our data showed that lps increased the level of interleukin (il)- in raw . cells (p< . ) (fig. ). in line with il- expression, lps induced the expression of m macrophage (p< . ). moreover, lps stimulated raw . cells co-culture with mscs in transwell system, mscs inhibited the expression of il- and m macrophages, while increased m macrophages (p< . ). compared with lps group, the concentration of tgf-Β was obviously increased in mscs treatment groups (p< . ), furthermore, there were no significantly difference between mscs directed and indicted groups. more significantly, tgf-βr inhibitor abolished the impact of mscs on lps stimulated raw . cells (p< . ) (fig. ) . conclusions: mscs polarized m macrophages into m macrophages and decreased pro-inflammatory cytokine levels by paracrining tgf-β. introduction: sepsis is dysregulated response to an infection, which can lead to progressive microcirculatory dysfunction, release of reactive oxygen intermediates (roi) and life-threatening organ dysfunction. our aim was to investigate the relationship between organ damage -characterized by the sequential organ failure assessment (sofa) scores, microcirculatory failure and roi production, in a large animal model of experimental sepsis. methods: fecal peritonitis was induced in anesthetized minipigs (n= ; . g/kg autfeces containing - x cfu bacteria i.p.), control animals (n= ) received sterile saline i.p. invasive hemodynamic monitoring and blood gas analyses were performed between - hrs, the signs for failure of circulatory, respiratory and urinary systems were evaluated in accordance with the sofa score. the microcirculatory perfusion rate in the sublingual region was measured by orthogonal polarization spectral imaging technique (cytoscan a/r). the leukocyte-origin roi production was determined by lucigenine (mostly o -. ) and luminol-based (h o ) chemiluminescence methods. results: between - hrs after induction the sofa score indicated moderate organ failure in animals (m: . ; p: . , p: . ) and the change was statistically significantly higher in pigs, suggesting severe organ dysfunction (m: . ; p: . , p: . ). the microcirculation was significantly deteriorated in all cases, independently of sofa score data. the h o production was significantly lower in septic animals as compared to controls, while the lucigenine enhanced roi production correlated with the sofa score-indicated moderate and severe organ dysfunction. conclusions: sublingual microcirculatory parameters are not correlating with the severity of sofa score-indicated organ dysfunction in abdominal sepsis. the measurement of roi production of the whole blood seems to be better biomarker for the detection of the progression of events from moderate to severe organ damages. introduction: the purpose of this study was to characterize differences in sepsis management in patients with and without left ventricular (lv) dysfunction. septic patients with lv dysfunction have higher mortality, and limited guidance exists for sepsis management of patients with lv dysfunction. the possibility exists that the cornerstones of sepsis management may contribute to these poor outcomes. methods: a retrospective chart review was conducted from may -january at two centers. adult patients who had a diagnosis of sepsis, were treated with vasopressors for > hours, and had an echocardiogram within months were included. patients were divided into two groups: reduced ejection fraction (ef) of < % and preserved ef defined as ef ≥ %. information about patient outcomes and sepsis management were collected. the primary outcome was the need for mechanical ventilation (mv). categorical and continuous data were analyzed using the chi-squared and mann-whitney u tests, respectively. the irb has approved this project. results: a total of patients with ef < % and patients with ef ≥ % were included. no significant differences in fluid management, vasoactive agent maximum rate or duration, or steroid use were observed. net fluid balance between low and preserved ef was positive . liters vs. . liters (p = . ), respectively. the number of patients that needed mv was higher in the low ef cohort ( % vs. %, p = . ), and this cohort had fewer mv-free days ( , iqr - vs. (iqr - ), p= . . conclusions: no significant differences were observed with regard to sepsis management, reflecting current guidelines. the significantly increased need for mv is a provocative result. a potential mechanism is the inability of a patient with reduced lv dysfunction to maintain appropriate cardiac and respiratory function in the face of fluid overload. prospective analysis of the role of fluid balance in septic patients with lv dysfunction is warranted. introduction: the relationship between myocardial injury and systemic inflammation in sepsis response is not well understood [ ] . it´s proposed to evaluate the association between myocardial injury biomarkers, high-sensitive troponin t (hs-ctnt) and n-terminal pro-brain natriuretic peptide (nt-probnp), with inflammatory mediators (il- , il- Β , il- , il- , il- / il- p , il a, il- and tnf-α ) and biomarkers, c protein reactive (cpr) and procalcitonin (pct), in septic patients methods: this was a prospective cohort study performed in three intensive care units, from september to september enrolling patients with sepsis (infection associated with organ dysfunction), and septic shock (hypotension refractory by fluids infusion requiring vasopressor). blood samples were collected up to h after the development of first organ dysfunction (d ) and on the th day after inclusion in the study (d ) results: ninety-five patients were enrolled, with median age years (interquatile? - ), apache ii: median ( - ), sofa: median ( - ); . % were admitted in icu with sepsis and . % with septic shock. hospital mortality was . %. in d , nt-probnp correlated with il- (r = . , p < . ) and il- (r = . , p < . ). in d , hs-ctnt and nt-probnp correlated with pct (r = . , p < . and r = . , p < . ; respectively). nt-probnp d was higher in nonsurvivors than in survivors on mortality in seventh day (p = . ) and in-hospital mortality (p = . ). hs-ctnt d (p = . ) and nt-probnp d (p < . ) were significantly higher in non-survivors on in-hospital mortality. nt-probnp d (or . ; ic % . - . , p= , ) and hs-ctnt d (or , ; ic % . - . , p= , ) were independently associated with in-hospital mortality conclusions: nt-probnp plasma levels at d correlated with il- and il- , and both nt-probnp and hs-ctnt at d correlated with pct. in addition, nt-probnp has been shown to be an important predictor of mortality introduction: heparin-binding protein (hbp) acts proinflammatory on immune cells and induces vascular leakage through cytoskeletal rearrangement and cell contraction in the endothelium and is a promising novel prognostic biomarker in sepsis and septic shock. however, studies on repeated measures of hbp are lacking. our objective was to describe the kinetics of plasma hbp during septic shock and correlate it to hemodynamic parameters. methods: we included patients with septic shock (sepsis- ) on admission to helsingborg hospital's intensive care unit (icu) during september to february . patients were sampled from icu admission and every hours for hours or until death or icu discharge. the plasma samples were analyzed for hbp and converted using the natural log (lnhbp) for normality. lnhbp was then evaluated against mean arterial pressure (map) as primary analysis and against systemic vascular resistance index (svri) as a secondary analysis, using mixed-effects linear regression models, treating patient id as a random intercept and adjusting for hemodynamic parameters. results: a total of patients were included with median age years, females ( %), surgical admissions ( %), median sofa-score points on day one and deaths from all causes within days ( %). plasma hbp ranged from to ng/ml with a median of ng/ml (lnhbp range . to . , median: . ). an increase lnhbp was significantly associated with a decrease in map (coef. - . mmhg, % ci: - . to - . , p= . , n= ), when adjusting for heart rate (hr), noradrenaline (na), vasopressin (vp), dobutamine (dbt) and levosimendan (ls). in a secondary subgroup analysis, an increase in lnhbp was also significantly associated with a decrease in svri (coef. - . dyne*s*cm- *m- , % ci: - . to - . , p= . , n= ), when adjusting for map, hr, na, vp, dbt, ls and cardiac index. conclusions: repeated measures of plasma hbp during septic shock were correlated with important hemodynamic parameters in this small pilot study. introduction: mid-regional pro-adrenomedullin (mr-proadm) comes from the synthesis of the hormone adrenomedullin (adm), which is overexpressed during inflammation and progression from sepsis to septic shock. thus, mr-proadm can be a useful biomarker for the clinical management of septic patients [ ] . the aim of our study was to understand the ability of mr-proadm to predict -day ( -d) mortality and to find a correlation between mr-proadm and sequential organ failure assessment (sofa) score in the first hours from intensive care unit (icu) admission. methods: we evaluated consecutive septic shock patients according to sepsis iii definitions. clinical data from the medical records included demographics, comorbidities, laboratories, microbiology and biomarker levels. whole blood samples for biomarker profiling were collected at , and hours from icu admission. mr-proadm measurement was detected in edta plasma using a sandwich immunoassay by trace® (time resolved amplified cryptate emission) technology (kryptor thermo fischer scientific brahms). results: overall -d mortality rate was . %. mr-proadm [odds ratio (or) = . ], sofa score (or = . ) and lactate (lac) levels (or = . ) in the first hours were associated with -d mortality in univariate logistic analysis (p value < . , table ). -d mortality rate was not associated with procalcitonin (pct) levels (or = . ). further linear regression analysis showed significant correlation between mr-proadm and sofa score at hours from icu admission (p value< . , fig. , table ). conclusions: mr-proadm demonstrated superior accuracy to predict -d mortality compared to pct levels and is directly linked to sofa score at hours from admission. mr-proadm may aid early identification of poor prognosis septic patients who could benefit a more intensive management. introduction: study of the expression of cell free dna (cfdna) in the search for new biomarkers for infection, sepsis and septic shock. methods: the population studied was all patients included in the sepsis protocol from march to january , hospitalized patients of a federal public hospital. plasma samples were collected for quantification of cfdna, which after centrifugation were stored at - °c and then thawed and analyzed by fluorescence using a varioskan flash fluorometer). cfdna values were expressed as ng/ml. the patients were divided into groups: infection and sepsis/septic shock. we analyzed mortality, sequential organ failure assessment score (sofa score), qsofa (quick sofa), comorbidities, cfdna and laboratory parameters of patients. results: among the patients, % were classified as infection and % sepsis/septic shock. overall lethality was %, infection . %, and sepsis/septic shock . % (p< . ). the mean of cfdna, sofa and lactate was higher according to the classification of infection and sepsis/septic shock: cfdna ( . ± . and . ± . , p= . ), sofa ( . ± . and . ± . , p< . ), qsofa (positive in % and %, lactate ( . ± . and . ± . , p< . ). we analyzed leukocytes, creatinine, crp (c reactive protein), inr (international normalized ratio), as predictors of severity and only crp showed no association with disease severity (p= . ). levels of cfdna and qsofa showed worse prognostic utility as a predictor of sepsis / septic shock when compared to lactate and sofa: or . ( % ci . - . ), p= . for cfdna, or . ( % ci . - . ), p= . for sofa and or . ( % ci . - . ), p= . for lactate. negelkerke r square was , for cfdna. in addition, area under the curve for cfdna mortality was . ( % ci . - . ) and sofa . ci % . - . ). conclusions: our study suggests that cfdna and qsofa have worse prognostic accuracy when compared to lactate and sofa, variables already used in clinical practice and easily measured. introduction: the aim of this study is to develop a "molecular equivalent" to sequential organ failure assessment (sofa) score, which could identify organ failure in an easier, faster and more objective manner, based on the evaluation of lipocalin- (lcn /ngal) expression levels by using droplet digital pcr (ddpcr). sepsis has been classically defined as the exuberant, harmful, pro-inflammatory response to infection. this concept is changing [ ] and the presence of a life-threatening organ dysfunction caused by a dysregulated host response to infection is now considered a central event in the pathogenesis of sepsis [ ] . methods: lcn expression levels were quantified by ddpcr in blood of a total of surgical patients with a diagnosis of infection. spearman analysis was used to evaluate if lcn correlated in a significant manner with sofa score. area under the receiver operating curve (auroc) analysis and multivariate regression analysis were employed to test the ability of lcn to identify organ failure and mortality risk. results: spearman analysis showed that there was a positive, significant correlation between lcn expression levels and sofa score (fig. ) . aurocs analysis showed that lcn presents a good diagnostic accuracy to detect organ failure and mortality risk (fig ) . in the multivariate regression analysis, patients showing lcn expression levels over the optimal operating points (oops) identified in the aurocs showed a higher risk of developing organ failure (table ) and a higher mortality risk (table ) . conclusions: quantifying lcn expression levels by ddpcr is a promising approach to improve organ failure detection and mortality risk in surgical patients with infection. introduction: sepsis is an inflammatory state due to an exacerbated immune response against infection. in cancer patients, sepsis presents a -fold higher mortality than in general population and leads to longer intensive care unit (icu) and hospital lengths of stay. it has been shown that reduced levels of circulating immunoglobulins (ig) might be a surrogate marker of unfavorable outcome in sepsis [ ] . the aim of this study was to evaluate the association between ig levels in plasma and -day mortality rate in cancer patients with septic shock. methods: from december to november , we conducted a prospective study in the intensive care unit (icu) of cancer institute of state of sao paulo, an -bed icu linked to university of sao paulo. patients ≥ years old with cancer and septic shock were enrolled. descriptive statistics were computed for demographic and outcome variables. laboratory data and ig levels were collected at icu admission and at days , and . a multivariate analysis was performed to evaluate predictors of -day mortality. results: a total of patients were included in the study. the -day and -day mortality were . % and . %, respectively. no significant differences in igm and igg levels were observed between survivors and non-survivors. in both groups, the median igm levels were low and the median igg levels were normal. in the multivariate analysis for -day mortality, a favorable status performance measured by the eastern cooperative oncology group (ecog) was associated with better survival; metastatic disease, higher sequential organ failure assessment (sofa) score at admission and higher levels of initial lactate were associated with increased mortality. conclusions: low levels of serum endogenous immunoglobulins are not predictors of -day mortality in cancer patients with septic shock. introduction: cytovale has developed a rapid biophysical assay of the host immune response which can serve as a rapid and reliable indicator of sepsis. neutrophils and monocytes undergo characteristic structural and morphologic changes in response to infection. one type of response is the generation of neutrophil extracellular traps (nets), these have been proposed as potential mediators for widespread tissue damage. during netosis there is a fundamental reorganization of a cell's chromatin structurea signal that we have shown is sensitively measured by the cytovale cytometer. we hypothesized that quantification of plasticity (deformability) of leukocytes in the peripheral blood provides an early indicator of sepsis. the cytovale assay uses microfluidic cytometry to measure the plasticity of up to , white blood cells from edta-anticoagulated, peripherally-collected whole blood and provides a result in minutes. methods: in two prospective studies conducted in two academic medical centers in baton rouge, la, the cytovale test was performed on peripheral blood samples obtained from patients who presented to the emergency department with signs or symptoms suggestive of infection. the two studies included high acuity patients ( patient study) and low acuity patients ( patient study). an adjudicated reference diagnosis of sepsis or no sepsis was established for each subject, using consensus definitions, by review of the complete medical records. results: the receiver operator curve (roc) performance of the cytovale assay for both studies demonstrated an area under the curve (auc) greater than . (fig. ) . conclusions: measurement of neutrophil and monocyte plasticity by a novel assay provides an accurate and rapid indication of sepsis in patients who present to an emergency room with signs or symptoms of infection. plasma hepatocyte growth factor in sepsis and its association with mortality: a prospective observational study introduction: sepsis and septic shock are commonly associated with endothelial cell injury. hepatocyte growth factor (hgf) is a multifunctional protein involved in endothelial cell injury and plays a pivotal role in sepsis. this study assesses its correlation with relevant endothelial cell injury parameters and prognostic value in patients with sepsis. methods: a prospective, observational cohort study was conducted in patients with sepsis admitted to the department of critical care medicine at the zhongda hospital from november to march . the plasma hgf level was collected on the first h after admission (day ) and day , then was measured by enzyme-linked immunosorbent assay. the primary endpoint was defined as all-cause -day mortality. furthermore, we analyzed the correlation of hgf with relevant endothelial cell injury markers. results: eighty-six patients admitted with sepsis were included. hgf levels of non-survivors were elevated upon day ( . ± . pg/ml vs. . ± . pg/ml; p = . ) and day ( . ± . pg/ml vs. . ± . pg/ml; p = . ) compared with that in survivors, and showed a strong correlation with von willebrand factor (r = . , p < . ), lactate (r = . , p = . ), pulmonary vascular permeability index (r = . , p = . ), first h fluid administration (r = . , p < . ) and sequential organ failure assessment score (r = . , p = . ) (fig. ) . plasma levels were able to discriminate prognostic significantly on day (auc: . , %ci: . - . ) and day (auc: . , %ci: . - . ) (fig. ) . conclusions: hgf levels are associated with sepsis and are correlated with established markers of endothelial cell injury. elevated hgf level in sepsis patients is a predictor of mortality. methods: adult patients with septic shock by the sepsis- classification due to lung infection or primary bacteremia or acute cholangitis are screened using two consecutive measurements of ferritin and of hla-dr/cd co-expression for mals (ferritin above , ng/ml) or immunosuppression (hla-dr/cd less than %) and randomized into immunotherapy with either anakinra (targeting mals) or recombinant ifnγ (targeting immunosuppression) and into placebo treatment. main exclusion criteria are primary and secondary immunodeficiencies and solid and hematologic malignancies. results: patients have been screened so far. most common infections are community-acquired pneumonia ( . %), hospitalacquired pneumonia ( . %) and primary bacteremia ( . %). mean +/-sd sofa score is . +/- . and charlson's comorbidity index . +/- . ; patients have mals ( . %); two immunosuppression ( %); the majority remain unclassified for immune state. conclusions: current screening suggests greater frequency of mals than recognized so far in a setting of septic shock due to lung infection or primary bacteremia or acute cholangitis. development of an algorithm to predict mortality in patients with sepsis and coagulopathy d hoppensteadt , a walborn , m rondina , j fareed study was to develop an equation incorporating biomarker levels at icu admission to predict mortality in patients with sepsis, to test the hypothesis that using a combination of biomarkers of multiple systems would improve predictive value. methods: plasma samples were collected from patients with sepsis at the time of icu admission. biomarker levels were measured using commercially available, elisa methods. clinical data, including the isth dic score, sofa score, and apache ii score were also collected. -day mortality was used as the primary endpoint. stepwise linear regression modeling was performed to generate a predictive equation for mortality. results: differences in biomarker levels between survivors were quantified and using the mann-whitney test and the area under the receiver operating curve (auc) was used to describe predictive ability. significant differences (p< . ) were observed between survivors and non-survivors for pai- (auc= . ), procalcitonin (auc= . ), hmgb- (auc= . ), il- (auc= . ), il- (auc= . ), protein c (auc= . ), angiopoietin- (auc= . ), endocan (auc= . ), and platelet factor (auc= . ). a predictive equation for mortality was generated using stepwise linear regression modeling. this model incorporated procalcitonin, vegf, the il- :il- ratio, endocan, and pf , and demonstrated a better predictive value for patient outcome than any individual biomarker (auc= . ). conclusions: the use of a mathematical modeling approach resulted in the development of a predictive equation for sepsis-associated mortality with performance than any individual biomarker or clinical scoring system. furthermore, this equation incorporated biomarkers representative of multiple physiological systems that are involved in the pathogenesis of sepsis. the effects of biomarker clearances as markers of improvement of severity in abdominal septic shock during blood purification t taniguchi , k sato , m okajima introduction: sepsis associated coagulopathy (sac) is commonly seen in patients which leads to dysfunctional hemostasis. the purpose of this study is to determine the thrombin generation potential of baseline blood samples obtained from sac patients and demonstrate their relevance to thrombin generation markers. methods: baseline citrated blood samples were prospectively collected from patients with sac at the university of utah clinic. citrated normal controls (n= ) were obtained from george king biomedical (overland park, ks). thrombin generation studies were carried out using a flourogenic substrate method. tat and f . were measured using elisa methods (seimens, indianapolis, in). functional antithrombin levels were measured using a chromogenic substrate method. results: the peak thrombin levels were lower ( ± nm) in the dic patients in comparison to higher levels observed in the normal plasma ( ± nm). the auc was lower ( ± ) in the dic group in comparison to the normals ( ± ). the dic group showed much longer lag time ( . ± . ) in comparison to the normal group ( . ± . ). wide variations in the results were observed in these parameters in the dic group. the f . levels in the dic group were much higher ( ± pmol) in comparison to the normal ( ± pmol). the tat levels also increased in the dic group ( . ± . ng/ml) in comparison to the normal ( . ± . ng/ml). the functional antithrombin levels were decreased in the dic group ( ± %). conclusions: these results validate that thrombin generation such as f . and tat are elevated in patients with dic. however thrombin generation parameters are significantly decreased in this group in comparison to normals. this may be due to the consumption of prothrombin due to the activation of the coagulation system. the decreased functional at levels observed in the dic group are due to the formation of the complex between generated thrombin and antithrombin. introduction: sepsis-associated disseminated intravascular coagulation (dic) is a complex clinical scenario involving derangement of many processes, including hemostasis. assessment of markers including inflammation, endothelial function, and endogenous anticoagulants may provide insight into dic pathophysiology and lead to improved methods for assessment of patient condition and response to treatment. methods: citrated plasma samples were collected from patients with sepsis and suspected dic at icu admission and on days and . dic score was determined using the isth scoring algorithm (e.g. platelet count, pt/inr, fibrinogen and d-dimer). cd ligand (cd l), plasminogen inhibitor (pai- ), nucleosomes, procalcitonin (pct), microparticle tissue factor (mp-tf) and prothrombin . (f . ) were measured using commercially available elisa kits. protein c activity was measured using a clot-based assay. interleukin (il- ), interleukin (il- ), interleukin (il- ), tumor necrosis factor alpha (tnfα), and monocyte chemoattractant protein (mcp- ) were measured using biochip technology. results: significant differences in levels of protein c (p= . ), pct (p= . ), il- (p= . ), il- (p= . ), pai- (p= . ), were observed between survivors and non-survivors. significant variation of protein c (p= . ), nucleosomes (p= . ), pct (p< . ), il- (p= . ), il- (p= . ), il- (p= . ), tnfα (p= . ) and mcp- (p= . ) were observed based on severity of dic score. conclusions: markers from multiple systems perturbed in dic were associated with mortality, suggesting that while these systems may not be routinely evaluated in the normal course of patient care, dysfunction of these systems contributes significantly to mortality. in addition, numerous inflammatory cytokines showed an association with dic score. this suggests that the measurement of additional markers in sepsis-associated dic may be of value in the prediction of mortality and may be helpful in guiding treatment for these patients. introduction: the endotoxin activity assay (eaa) is a rapid immunodiagnostic test based on chemiluminescence. it was approved by the fda in as a diagnostic reagent for risk assessment of severe sepsis in the icu. ascertaining endotoxin levels in the bloodstream is important in targeting patients and determining the appropriate timing for initiation of treatment. it has high sensitivity and specificity for endotoxin, and is considered to be useful in predicting clinical symptoms and determining prognosis. the usefulness of the eaa has yet to be fully clarified. methods: a total of patients admitted to the icu between january and june with suspected sepsis or sepsis were enrolled. the eaa was conducted within hr after admission. patient characteristics were determined, together with levels of il- , procalcitonin, presepsin, and pao /fio . thereafter, the patients were classified into groups depending on their eaa value: ) < . ; ) from ≤ . to < . ; ) from ≤ . to < . ; ) from ≤ . to < . ; and ) ≤ . ). the transition of various markers was also examined. the spearman rank correlation, wilcoxon rank sum test, and a nonrepeated anova were used for the statistical analysis. a p-value of < . was considered statistically significant. the eaa values showed a positive correlation with both the apache ii (r= . ) and sofa scores (r= . )(p< . ), although that with the latter was stronger. a significant correlation was also observed with levels of procalcitonin (r= . ) and presepsin (r= . early diagnosis is important to allow early intervention. the current clinical methods are insufficient for early detection. we hypothesized that intraperitoneal microdialysis allows detection of peritonitis prior to changes in standard clinical parameters in a pig model. methods: bacterial peritonitis was induced in pigs by bowel perforation and intraperitoneal fecal instillation, one pig underwent sham surgery. intraperitoneal microdialysis catheters were placed in each abdominal quadrant. the observation time was hours. results: in peritonitis pigs the intraperitoneal lactate increased during the first two hours and remained elevated throughout the observation time (table ) , whereas the arterial lactate remained within reference range (< . mm). intraperitoneal glucose decreased significantly. hemodynamics were hardly influenced during the first two hours, and decreased thereafter. sham surgery did not influence in any of the parameters. conclusions: a rapid and pronounced increase in intraperitoneal lactate and decrease in intraperitoneal glucose was observed after instillation of intraabdominal feces. systemic lactate increase was absent, and the hemodynamic response was delayed. postoperative intraperitoneal microdialysis is applicable in detecting peritonitis earlier than standard clinical monitoring and should be evaluated in a clinical study in order to explore if early intervention based on md data will reduce icu length of stay, morbidity and mortality. introduction: procalcitonin (pct) is a serum biomarker suggested by the surviving sepsis campaign to aid in determination of the appropriate duration of therapy in septic patients. trauma patients have a high prevalence of septic complications, often difficult to distinguish from inflammatory response. pct values typically declined after h from trauma and increased only during secondary systemic bacterial infections. the aims of the study are to evaluate reliability and usefulness of pct serum concentration in trauma. methods: we retrospectively analyzed data from trauma patients admitted to icu at bufalini hospital -cesena, from july to august . we collected data about antimicrobial therapy, injury severity score (iss), first arterial lactate in emergency room, sofa score and sepsis severity. plasma pct concentration was measured using an automate analyzer (modular e-brahms) on st day of antimicrobial therapy and every h hours. antimicrobial therapy was stopped according to a local protocol; however medical judgment was considered the overriding point for therapeutic decision. results: median iss of patients was . , inter quartile range (iqr) . . pct mean concentration at the starting of antimicrobial treatment was . μg/l (d.s . ), median . (iqr . ). no significative correlation (spearman´s rho test) was found between pct at day of antimicrobial therapy and iss (rho - . ), between first arterial lactate in er and pct (rho . ). daily course of pct was not related to distance from trauma (rho - . ). in of patients ( . %) pct measurement led physician to save days of antimicrobial therapy compared with standard clinical practice. we couldn´t find any cut off value. conclusions: our experience suggests that pct could help physician to optimize duration of antimicrobial therapy in trauma patients. no standard approach can be recommended at present. introduction: long duration of antimicrobial treatment may predispose to colonization and subsequent infections by multidrugresistant organisms (mdro) and clostridium difficile. progress (clinicaltrials.gov registration nct ) is an on-going trial aiming to use pct for the restraining of this calamity. methods: adult patients with sepsis by the sepsis- classification and any of five infections (pneumonia community-acquired; hospital-acquired or ventilator-associated; acute pyelonephritis; primary bacteremia) are randomized to pct-guided treatment or standard of care (soc) treatment. in the pct arm antibiotics are discontinued when pct on or after day is decreased by more than % of the baseline or remains below . ng/ml; in the soc arm antibiotics are discontinued at the discretion of the attending physician. patients are followed for six months. primary endpoint is the rate of infections by mdro and/or c.difficile or death. serial stool samples are cultured for mdro and screened for glutamate dehydrogenase antigen and toxins of c.difficile. results: patients have been enrolled so far. mean ± sd sofa score is . ± . . most common diagnoses are community-acquired the progress trial is the first trial assessing the probable benefit from pct guidance to reduce ecological sequelae from long-term antibiotic exposure. analysis of baseline patient characteristics indicates that progress is a real-world trial so that results can have major clinical impact. prospective multi-site validation of -gene host response signature for influenza diagnosis s thair , s schaffert , m shojaei , t sweeney there are no blood-based diagnostics able to identify influenza infection and distinguish it from other infections. we have previously described a blood-based -gene influenza meta-signature (ims) score to differentiate influenza from bacterial and other viral respiratory infections. methods: we prospectively validated the ims in a multi-site validation study by recruiting individuals ( patients with suspected influenza, healthy controls) in community or hospital clinics across australia. we assayed the ims and genes from viral genome of influenza strains to generate the blood flu score (bfs) as a measure of viremia using nanostring from whole blood rna. results: using clinically determined phenotypes, the ims score distinguished patients with influenza from healthy (auc= . ), non-infected (auc= . ), bacterial (auc= . ), other viruses (auc= . ) ( figure a) . interestingly, probes of bfs were found in all phenotypic groups (non-infected, bacterial, and other viral infections) to varying degrees, and positively correlate with the ims score (r= . ). ims aurocs improve when the bfs is used to inform the phenotypic groups: healthy (auc= . ), non-infected (auc= . ), bacterial (auc= . ), other viruses (auc= . ) ( figure b ). patients who were clinically influenza negative but had a high ims and bfs were admitted less often, yet had~ -fold higher mortality than those who were clinically influenza negative with low ims and no bfs (table ) . conclusions: collectively, our prospective multi-center validation of the ims demonstrates its potential in diagnosis of influenza infections. introduction: previous findings of our group suggest that patients with gram-negative hospital-acquired severe sepsis have better prognosis when sepsis is developing after recent multiple trauma through stimulation of favorable interleukin (il)- responses [ ] . under a similar rationale, we investigated if preceding osteomyelitis may affect experimental osteomyelitis. methods: sham or experimental osteomyelitis was induced in male new zealand white rabbits after drilling a hole at the upper metaphysis of the left tibia and implementing diluent or log of staphylococcus aureus using foreign body. after three weeks, the foreign body was removed and experimental pyelonephritis or sham surgery was induced after ligation of the right pelvo-ureteral junction and instillation of log of escherichia coli in the renal pelvis. survival was recorded and circulating mononuclear cells were isolated and stimulated for the production of tumour necrosis factor-alpha (tnfa) and il- . at death or sacrifice, tissue outgrowth and myeloperoxidase (mpo) were measured. results: four sham-operated rabbits (s), rabbits subject to sham surgery and then pyelonephritis (sp) and rabbits subject to osteomyelitis and then pyelonephritis (op) were studied. survival after days of group sp was . % and of group op % (log-rank . ; p: . ). lab findings are shown in figure . il- production was blunted. negative correlation between e. coli outgrowth and tissue mpo was found at the right kidney of the op group (rs: - . , p: . ) but not of the sp group (rs: - . , p: . ). conclusions: preceding staphylococcal osteomyelitis provides survival benefit to subsequent experimental osteomyelitis through downregulation of innate immune responses leading to efficient phagocytosis. introduction: activation of neutrophils is a mandatory step and a sensitive marker of a systemic inflammatory response syndrome (sirs) which is closely related to development of multiple organ failure. the search for drugs that can prevent sirs and reduce mortality in critically ill patients remains significant. the aim of this study was to study the anti-inflammatory effect of the synthetic analogue of leu-enkephalin (dalargin) on human neutrophils. methods: the study was conducted on isolated from the blood of healthy donors neutrophils. their activation was assessed by fluorescent antibodies to markers of degranulation cd b and cd b (sd b-fitc and cd b-alexafluor (bd biosciences, usa). as inductors of inflammation lipopolysaccharide (lps) and the peptide formyl met-leu-pro (fmlp) were used. mkm fmlp and dalargin in concentrations of and μ g / ml were added to neutrophils at a concentration of ppm / ml and incubated for min at °c; then antibodies were added and incubated for min on ice; then fluorescence was assessed by flow cyto flow meter beckman-coulter fc . non-parametric criteria were used; data were presented as a median and %- % interquartile intervals. the statistical significance was estimated using mann-whitney test. the difference was considered statistically significant at p< . results: synthetic analogue of leu-enkephalin in various concentrations has an anti-inflammatory effect on both intact and preactivated with bacterial components neutrophils, reducing their activation and degranulation in a dose-dependent manner (figs. , ) . conclusions: synthetic analogue of leu-enkephalin prevents neutrophil activation by bacterial compounds. this has a potential of translation into clinical practice for sepsis treatment. introduction: the endothelin system plays important roles in circulatory regulation through vasoconstrictor et-a and et-b receptors and vasodilator et-b receptors (etar; etbr, respectively). tissue hypoxia during the progression of sepsis is associated with microcirculatory and mitochondrial disturbances. our aim was to investigate the possible influence of etar antagonist, etbr agonist or combined treatments on oxygen dynamics, microcirculatory and mitochondrial respiration parameters in experimental sepsis. methods: male sprague-dawley rats (n= /group) were subjected to faecal peritonitis ( . g/kg faeces ip) or sham-operation. septic animals were treated with sterile saline solution, or received the etar antagonist etr-p /fl peptide ( nmol/kg iv), etbr agonist irl- ( . nmol/kg iv) or same doses as combination therapy, hr after sepsis induction. invasive hemodynamic monitoring and blood gas analyses were performed during a -min observational window. introduction: sepsis often induces immunosuppression, which is associated with high mortality rates. nivolumab is a human igg- antibody directed against the programmed cell death (pd- ) immunecheckpoint inhibitor, which disrupts pd- -mediated signaling and restores antitumor immunity. nivolumab is an approved anti-cancer drug that may have the potential to improve sepsis-induced immunosuppression. methods: this multicenter, open-label study investigated the safety, pharmacokinetics and pharmacodynamics of a single intravenous infusion of or mg nivolumab in japanese patients with immunosuppressive sepsis (lymphocytes ≤ /μl). the dosing of nivolumab was set using the predicted steady state concentration of nivolumab at mg/kg every weeks (q w), which was the approved dosage for cancer patients at the time of planning. results: five and eight patients were assigned to the and mg groups, respectively. the mean (standard deviation) peak serum drug concentration in the mg group was comparable to the predicted median concentration ( % pi [prediction (figures and ). adverse events (aes) were observed in four patients in each group. drug related-aes were observed in only one patient in the mg group (table ) . no deaths related to nivolumab occurred. conclusions: a single dose of mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentration in patients with sepsis. results suggest both and mg nivolumab therapy could improve relevant immune indices. introduction: the systemic inflammatory response syndrome (sirs) accompanies tissue trauma and infection and, when severe or dysregulated, contributes to multiple organ failure and critical illness. observational studies in man and animal have shown that low-dose acetyl-salicylic acid promotes resolution of inflammation and might attenuate excessive inflammation by increasing the synthesis of specialised pro-resolving lipid mediators (spms). methods: we randomly assigned patients with sirs who were expected to stay in icu for more than hours to receive enteral aspirin ( mg per day) or placebo for days or until death or discharge from the icu, whichever came first. the primary outcome was il- serum concentration at h after randomisation. the secondary outcomes included safety and feasibility outcomes. in one center, additional blood samples were taken during the first three days for exploratory analysis of spms using reversed-phase highperformance liquid chromatography -tandem mass spectrometry (rp-hplc-ms/ms). results: from march through december a total of patients across four general icus in australia underwent randomization (table ) . compared to placebo patients, il- serum concentration after h in aspirin-treated patients was not significantly lower ( [ - ] pg/ml vs [ . - ] pg/ml; p= . ). there were no significant differences for control vs. aspirin-treated patients in the change of pro-resolving/anti-inflammatory lipids between the time points (figure , ). there were no between-group differences with respect to icu or hospital mortality, number of bleeding episodes or requirements for red cell transfusions (table ) . conclusions: in patients admitted to the icu with sirs, low-dose aspirin did not result in a decreased concentration of inflammatory biomarkers compared with placebo. introduction: sepsis is associated with excessive ros production, nf-kb, inos and inflammatory mediators overexpression. vitamin c is a cellular antioxidant, it increases enos and decreases nf-kb; it has several immune-enhancing effects and is crucial for endogenous vasopressors synthesis. vitamin c reserves in sepsis are often as poor as in scurvy [ ] . in recent studies, intravenous high vitamin c dose seems to reduce organ failure and improve outcome in septic shock. methods: we treated all septic shock patients admitted to our icu in months (from / to / ) with intravenous vitamin c . g/ h and thiamine mg/ h (for its synergistic effects) [ ] as adjunctive therapy for consecutive days and we compared data to septic shock patients admitted in the previous months period. we enrolled patients: received vitamins supplementation, standard of care. we analysed -days mortality, sofa at and hours, pct variation from baseline in first days, vasoactive therapy length and daf (days alive and free from vasopressors, mechanical ventilation and rrt in days follow up). patients with end stage kidney disease were ruled out. we analysed data with mann-whitney and wilcoxon tests. results: vit c group showed lower -days mortality ( % vs . %: ns); sofa improvement at (- . ± . vs - . ± . : p= . ) and hours (- . ± vs - . ± : p< . ) was higher in vit c group; vit c patients had faster pct reduction without statistical significance. mean vasoactive therapy length was quite similar. daf was . (± . ) days in vit c group and . (± . ) in controls (p= . ). control patients needed rrt, none in vit c group. conclusions: despite small study size, we found that vit c has positive effects on survival and improves sofa score (fig. ) and daf (fig. ) in septic shock. no vit c patient developed oxalate nephropathy nor worsened renal function. introduction: toxin-producing gram-positive organisms cause some of the most severe forms of septic shock [ , ] . adjunctive therapies such as intravenous immunoglobulins (ivig) have been proposed for these patients [ , ] . however, at patient presentation, the presence of a toxin-producing organism is most often unknown. methods: we reviewed the use of ivig in our patients requiring extracorporeal membrane oxygenation (ecmo) in a -year period between february and march . results: in % ( / ) of the patients that received ivig for presumed toxin-mediated shock, group a streptococcus or panton-valentine leukocidin producing s. aureus was isolated, but the clinical characteristics of these patients were not significantly different from the ones with other final diagnoses, except for a predisposing influenza infection and the presence of an often very high procalcitonin level. these patients were extremely unwell at presentation with a sofa score of ± , high lactate levels ( . ± . mmol/l) and need for vasopressors (equivalent norepinephrine dose of . ± . μ g/kg/min). they had very high inflammatory parameters with a procalcitonin ≥ ng/ml in more than half of patients ( / ). ivig use in these patients was generally safe, with only possible transfusion reaction. the mortality of % ( / ) was lower than predicted based on the sofa scores. conclusions: ivig administration can be considered in a selected group of patients presenting with acute and very severe septic shock, as part of a multimodal approach [ ] . introduction: extra corporeal treatments are used in septic patients to decrease the inflammatory mediators, but definitive conclusions are lacking . more over in many studies the effect of aki isn't evaluated and this may be an important bias. . the aim of this study is to evaluate in septic patients with aki: the effect of the adsorbing membrane oxiris on the immunological response -the different response in survivors and non survivors methods: from our local data base we analyzed retrospectively septic shock patients with aki (kdigo classification) submitted to crrt with the adsorbing membrane oxiris (baxter, usa ) . at basal time ( t ) and at the end of the treatment ( t ) we evaluated the following variables: il il procalcitonin endotoxin (eaa). all data are expressed as mean ±sd or median and iqr. student t test or mann-whitney was used to compare values changes. p < . was considered statistically significant. results: thirty patients with sepsis /septic shock and aki were enrolled in this study. patients had aki , patients aki , patients aki . the duration of treatment was ± hours. patients had citrate as anticoagulation and heparine continous ev. at table are shown the main results of this study in all the patients. survivors vs non survivors had a significant decrease of il , procalcitonin and eaa. conclusions: data of this study confirm on clinical ground previous study "in vitro" [ ] that the adsorbing membrane oxiris has important immunological effect during septic shock with aki. this must be confirmed in a rct. introduction: sepsis is common and often fatal, representing a major public health problem. hemoadsorption (cytosorb) therapy aims to reduce cytokines and stabilise the overall immune response in septic shock patients. methods: a prospective, multi-centre, investigator initiated study to evaluate hemoadsorption (cytosorb) therapy in septic shock patients admitted to a tertiary icu's in india during to . all centres followed a common protocol and received ethics committee approval. results: a total of patients were administered cytosorb in addition to standard of care. a total of patients ( %) survived out of patients. among survival group, patients ( %) were administered cytosorb within hours of icu admission resulting in significant reduction in sepsis scores, apache ii ( . vs . ) and sofa ( . vs . ) post cytosorb therapy. also there was reduction in inflammatory markers like cytokines il in most of the patients. all patients in survivor group showed a significant improvement in map ( . vs . ) and reduction in vasopressors (epinephrine . to . mcg/kg/min, nor-epinephrine . to . mcg/kg/min) after cytosorb therapy. no device related adverse effect was observed in any of the patients. among the non-survivor group, ( patients, %) we observed that cytosorb was administered after hours of icu admission. although a few patients showed improvement in sofa score, majority did not show a significant improvement with map ( . vs . mm of hg) and required increased demand in vasopressors. conclusions: in this multi-centered prospective iis study, we could observe clinical benefits of hemoadsorption (cytosorb) therapy in septic shock patients if the therapy was initiated early. larger randomised study are required to establish the above clinical benefits in larger patient population. a single centre experience with hemoadsorption (cytosorb) in varied causes of sepsis and mods y mehta , c mehta , a kumar , j george , a gupta , s nanda , g kochar , a raizada introduction: sepsis and the multiorgan failure is a leading cause of mortality in the intensive care unit. promising new therapies continue to be investigated for the management of septic shock. we tried to evaluate a novel hemoadsorption therapy (cytosorb) through a retrospective evaluation of patient's data in our centre. we used it as an adjuvant therapy in our patients with sepsis due to varied causes. methods: we retrospectively analysed data of introduction: septic shock is a life-threatening multiple organ dysfunction that has high morbidity and mortality in critically ill patients, due to a dysregulated host response to infection. the aim of this study was to evaluate the efficacy of therapeutic cytokine removal (cytosorb®) in the management of patients with septic shock. methods: we retrospectively analyzed patients admitted to icu with septic shock between june and november . patients included in the study were diagnosed according to the third international consensus definitions for sepsis and septic shock (sepsis- ), received maximal supportive care including continuous veno-venous hemodiafiltration (cvvhdf) for acute kidney injury and cytosorb® haemoadsorption column was added to return limb of the cvvhdf circuit. demographic data, procalcitonin and leukocyte levels before and after therapeutic cytokine removal and duration of cytosorb® haemoadsorption column application and apache ii scores were recorded. results: the mean age of patients included in the study was ± . years ( % male) and the mean body mass index was . ± . . the mean apache ii score was . with an expected and actual mortality rates of % and %, respectively. % of the patients were admitted with sepsis and % of them with septic shock. . % (n= ) of the cases were solid organ transplant recipients. cvvhdf was applied in all patients during therapeutic cytokine removal. treatment was combined with ecmo in patients. while the mean duration of cvvhdf was . hours, the duration of cytosorb® haemoadsorption column application was . ± . hours. procalcitonin ( . ± ng/ml vs ± ng/ml) and leucocyte levels ( ± / mm vs ± mm ) after therapeutic cytokine removal were found significantly lower than the pretreatment values (respectively p= . , p= . ). conclusions: therapeutic cytokine removal applied with cvvhdf in septic shock patients have positive contributions to biochemical parameters and provide survival advantage. introduction: recent studies have focused on demonstrating the potential benefits of immunomodulation in the management of septic patients. the aim of our study was to assess the effects of a hemoadsorption column (cytosorb®) in critical ill septic patients. methods: after ethical approval was obtained, we prospectively included patients admitted to the general icu of fundeni clinical institute. three consecutive sessions of renal replacement therapy (continuous venovenous hemodiafiltration) in combination with cytosorb® were applied after icu admission. clinical (heart rate, arterial pressure, temperature, glasgow coma scale) and paraclinical data (pao , serum bilirubin and creatinine, platelet count, white blood cell count, ph, c-reactive protein and procalcitonine), vasopressor support and need for mechanical ventilation were recorded before and after the three sessions. results: the mean age in the study group was ± years. median number of organ dysfunction at the time of icu admission was [ ] [ ] [ ] [ ] [ ] and the mean sofa score was . ± . . the use of cytosorb® was associated with a non-significant increase in pao /fio ratio from ± to ± (p= , ) and creatinine levels from . ± . to . ± . mg/dl (p= . ). although we observed a non-significant increase in c-reactive protein levels from ± mg/l to ± mg/ l (p= . ), we noted a significant decrease in procalcitonine levels from a median of . [ . , . ] ng/dl to a median of . [ . , . ] ng/dl (p= . ). a significant decrease in platelet count was also noted from ± /mm to ± /mm (p= . ). mean sofa score decreased non-significantly from . ± . to . ± . (p= . ). conclusions: the use of cytosorb was associated with a slight nonsignificant improvement in organ function and a decrease of procalcitonine levels. thrombocytopenia remains one of the most important complications of renal replacement therapy. introduction: circulating cell-free neutrophil extracellular traps (nets) would induce a microcirculatory disturbance of sepsis. the removal of nets remnants from the circulation could reduce nets-dependent tissue injury. to address this issue, we evaluated the effect of hemoperfusion with a polymyxin b cartridge (pmx-dhp; toray, japan), which was originally developed for the treatment in patients with gram-negative bacterial infection, on circulating cell-free nets in patients with septic shock and in phorbol myristate acetate (pma)-stimulated neutrophils obtained from healthy volunteer. methods: ex vivo closed loop hemoperfusion was performed through a circuit formed by connecting the small pmx module to a tube and a peristalsis pump. whole blood from healthy volunteers incubated with or without pma or from septic shock patients were applied to circuit and perfused. blood was collected at , and hr after perfusion. circulating cell-free nets were assessed by myeloperoxidase (mpo)-, neutrophil elastase (ne)-, and cell free (cf)-dna. results: plasma mpo-dna, ne-dna and cf-dna levels were significantly increased at hr after pma stimulation when compared with plasma levels without pma. when either blood from septic shock patients or pma-stimulated neutrophils obtained from volunteers were applied to circuit, circulating mpo-dna, ne-dna and cf-dna were significantly reduced in perfusion with pmx filter than in perfusion without pmx filter at times and hr. conclusions: in the ex vivo experiments, mpo-dna, ne-dna and cf-dna were found to decrease after ex vivo perfusion through pmx filters. selective removal of circulating components of nets may improve the remote organ damage in patients with septic shock. a retrospective study of septic shock patients who were treated with direct hemoperfusion with polymyxin b-immobilized fibers based on the levels of endotoxin activity assay s sekine, h imaizumi, i saiki, a okita, h uchino tokyo medical university, anesthesiology/icu, tokyo, japan critical care , (suppl ):p introduction: the purpose of this study was to evaluate the outcomes for septic shock patients with direct hemoperfusion with polymyxin b-immobilized fibers (pmx-dhp) and endotoxin activity assay (eaa). methods: according to the levels of eaa, patients were classified for three groups (low group (gl); eaa < . , intermediate group (gm); eaa > . or eaa < . , high group (gh); eaa > . ). in order to evaluate the severity of illness, acute physiology and chronic health eva-luationii (apache ii) score, the sequential organ failure assessment (sofa) score, catecholamine index (cai) were recorded. and the presence of pmx-dhp treatments were also recorded. blood samples were obtained to measure eaa levels, inflammatory markers (procalcitonin (pct), c-reactive protein (crp), and white blood cell count (wbc)), serum lactate level as an indicator of tissue hypoxia, and for blood culture. apache ii score, sofa score, cai, inflammatory markers, serum lactate levels (lac) and blood culture results were examined for diagnosis of septic shock and prognosis of -days mortality. each values were also compared to eaa levels. results: septic shock patients were included (gl/ gm/ gh: / / ). in gh, apache ii and sofa score was significantly higher than that in gl (p< . ). eaa levels were significantly increased in gramnegative bacteremia patients compared to the patients with grampositive bacteremia or fungemia. there was no relationship between eaa levels and other inflammation markers, cai, and lac. in gm, days mortality in patient with pmx-dhp treatments was lower than that of without pmx-dhp treatments ( . ( / ) vs . ( / ), p= . ). in gh, -days mortality in patient with pmx-dhp treatments was same as that of without pmx-dhp treatments ( . ( / ) vs . ( / ), p= . ). conclusions: these results of this study suggest pmx-dhp treatment may improve the outcome of septic shock patients with intermediate eaa levels. introduction: numerous inconclusive randomized clinical trials (rcts) in sepsis in the past years suggest a need to re-think trial design to improve resource allocation and facilitate policy adoption decisions. the inclass study (clinicaltrials.gov nct: ) is an ongoing rct evaluating clarithromycin as an immune modulator in high-risk septic patients with clinical and cost-effectiveness outcomes. we aim to compare the original one-shot trial with an alternative sequential design that balances trial costs and value of information. methods: adult patients with sepsis, respiratory failure and total sofa score of at least , are randomized to receive intravenous clarithromycin or placebo adjunctive to standard-of-care therapy. for the cost-effectiveness study, efficacy is measured in quality-adjusted life years (qalys) by eq- d- l questionnaire at days. the endpoint is the incremental net monetary benefit (inmb) of clarithromycin compared to placebo, defined as wtp x (increment in qaly) -(increment in costs), where wtp is willingness to pay per qaly gained. fixed and variable costs of trial execution (including administrative, insurance, supplies, tests) are calculated; hospitalization cost is extracted from patient records; medical care beyond day is recorded; cost of adoption in the general population is estimated. previous data from rcts using clarithromycin are used to form a prior belief about the inmb. known incidence of sepsis with respiratory failure allows estimation of the population to benefit from trial decision. a bayesian model is used to determine the sequential design that maximizes trial value. results: we will compare the performance of the sequential trial design with the one-shot design of inclass trial in terms of sample size, cost, social-welfare, and probability of correctly identifying the best treatment. conclusions: in this protocol we validate a bayesian model for sequential clinical trials and assess the benefits for the patient population and health care system. the effect on the outcome of critically ill patients with catecholamine resistant septic shock and acute renal failure through implementation of adsorption therapy g schittek introduction: cytosorb-adsorption has been described as an effective way for hemodynamic stabilisation in septic shock [ ] . aim of this study was to examine whether the adsorption-therapy could influence patient-outcome with catecholamine resistant septic shock (crss) and acute renal failure(arv). furhtermore we tried to identify clinical constellations that would predict an effective use of adsorbers [ , ] . initial il- in patients with catecholamine-reduction through adsorption was non-significantly different to those with no reduction ( ng/l [ , ] vs. ng/l [ , ]). mortality did not differ significantly between the groups ( % vs %). length of intensive care unit stay (los) did differ significantly ( days [ , ] vs days [ , ] ). conclusions: il- can be reduced with adsorption. patients with catecholamine-reduction did not differ in regard to their initial il- . los was shorter for patients treated with adsorption. according to our experience adsorption can be taken into consideration when crss is beginning. introduction: in our intensive care unit (icu), we have already started expanded application to the contact precautions. applied patients are; ) emergency admission, ) patients who had already had bacteria* that are required to contact precautions, ) scheduled surgical patients with prolonged icu stay, although we have not yet decided the started period of expanded application exactly. *detected bacteria(db);mrsa, cd, mdrp, esbl, pseudomonas a, pisp, prsp, vrsa. the aim of this study was to determine the adequate starting period of expanded application to the contact precautions in the scheduled surgical patients in the mixed icu. methods: we performed retrospective observational study on patients who were admitted to our icu after planed surgery from may to dec. . we detected the patients who acquired bd newly and investigated the relation to the length of icu stay. the relationship between detection rate and categorized date was also analyzed using logistic regression adjusted for age, gender, apache , and sofa score. using youden´s index and roc curve, we also calculated cutoff point of the duration of icu stay related to detection rate. finally, we made the logistic regression model of each cutoff day(day to ) and compared odds ratio(or) and auc of each models using stata. results: category day or more, especially day or more had significantly higher detection rate of db compared to day ( results: pao /fio was lower than mmhg in ( %) patients. compared to patients in group , patients in group were less severely ill at admission but presented a higher sofa and cpis score and a greater incidence of ards and shock at pneumonia onset (fig ) . ( %) patients in group had a microbiological diagnosis of pneumonia, compared to patients ( %) in group (p= . ). pao /fio ≤ mmhg was associated with less probability of having microbiological diagnosis of pneumonia (or . , % ci . to . , p= . ). when adjusted for other variables significantly associated with positive microbiology, pao /fio ≤ mmhg remained significantly associated with less probability of a microbiological diagnosis (adjusted or . , % ci . to . , p= . ). hospital mortality was significantly higher in patients in group compared to group ( % vs %, p= . ). however, no difference was found in non-response to treatment, icu and hospital stay, icu mortality (table ) and -days survival (fig ) . conclusions: a significant higher number of patients with vap didn't have a definitive etiological diagnosis when using the proposed threshold criteria of pao /fio ≤ mmhg. pao /fio ratio does not seem a good predictor of etiology in patients with vap. introduction: immunological dysfunction is common in critically ill patients but the optimal method to measure it and its clinical significance are unknown. levels of tumor necrosis factor alpha (tnf-α) after ex-vivo whole blood stimulation with lipopolysaccharide has been proposed as a possible method to quantitate immunological function. we hypothesized that patients with a lower post-stimulation tnf-α level would have increased rates of nosocomial infections (nis) and worse clinical outcomes. methods: a secondary analysis of a phase randomized, multicentre, double-blinded placebo controlled trial [ ] . there were no differences in allocation groups; all the patients were analyzed as one cohort. on enrolment, whole blood was incubated with lps ex-vivo and tnf-α level was measured. patients were grouped in tertiles according to delta and peak tnf-α level. the primary outcome was the development of nis; secondary outcomes included -day mortality. results: data was available for patients. baseline characteristics and outcomes are reported in tables and . patients in the highest tertile for post lps stimulation delta tnf-α compared to the lowest tertile were younger, had a lower acuity of illness and had lower baseline tnf-α. when grouped according to peak post-stimulation tnf-α levels, patients in the highest tertile had higher serum tnf-α at baseline. both comparisons showed no difference between nis and clinical outcomes between tertiles. in multi-variate analysis peak or delta tnf-α were not associated with the occurrence of nis. conclusions: admission ex-vivo stimulated tnf-a level is not associated with the occurrence of nis or clinical outcomes. further study is required to evaluate the ability of this assay to quantify immune function over the course of critical illness. results: sanitary and epidemiological examination revealed the connection between infection and intravenous infusion of dexamethasone performed concurrently with chemotherapy. in patients fever with chills and hypertension developed within hours after infusion of the infected drug; empirical intravenous antibiotic therapy started immediately after collecting blood culture. in patients fever appeared after - days outpatiently, so they received antibiotics per os. all these patients had permanent vascular access, and bsi was detected either the next chemotherapy course when fever reappeared ( pts) while using vascular access, or as a result of a specific examination ( pts). in all cases empirical antibiotic therapy started on the first day of fever, drug correction was performed in patients according to results of bacteriological research. septic shock developed in patient, pneumonia in patients. permanent vascular access was preserved only in case. all patients were cured and continued to receive antitumor treatment. conclusions: detection of more than case of b. cenocepacia bsi should be the reason for sanitary and epidemiological examination. a favorable outcome of bsi treatment is associated with the early start of antibiotic therapy and its correction after microbiological examination. emerging conclusions: implementation of asp in hospital allows to decrease incidence of eskape-bacteremia and candidemia, which may lead to improved clinical outcomes in icu's patients (fig ) . association of multi-drug resistant (mdr), extended-drug resistant (xdr) and pan-drug resistant (pdr) gram negative bacteria and mortality in an intensive care unit(icu) s chatterjee , s sinha , a bhakta , t bera , t chatterjee , s introduction: colistin-resistant klebsiella pneumoniae (cr-kp) is increasingly reported around the world. it is worrying to note emergence of resistance to last line of defence against mdr gram negative infections in regions endemic to carbapenem resistance. we report the first outbreak of cr-kp co-producing carbapenemases in an adult intensive care unit (icu) from south india. methods: retrospective analysis of all patients with carbapenem resistant klebsiella pneumoniae blood stream infection (bsi) was done between january and december . microbiological and clinical variables along with outcomes were analysed. results: seven patients had cr-kp with no prior exposure to colistin. all seven were modified hodge test (mht) negative making probability of blakpc unlikely. in resource limited setting, analysis beyond mht could only be performed for cr-kp samples. / samples belonging to cr-kp isolates produced the blandm- whilst / cr-kp isolates did not produce either blakpc or blandm carbapenemases prompting hypothesis of blaoxa- or blavim as the causative factor. compared to carbapenem resistance only group, cr-kp group had higher apache ii, icu length of stay and mechanical ventilation duration. day mortality was noted to be . % for carbapenem resistant and % for cr-kp groups. aggressive infection control measures were undertaken with successful containment of cr-kp strains along with reduction in overall bsi. conclusions: infection control measures form the backbone of patient care in centres showing endemicity for carbapenem resistant klebsiella to prevent colistin resistance and also to reduce occurrence of overall blood stream infections. rapid diagnosis of carbapenem resistance: experience of a tertiary care cancer center with multiplex pcr s mukherjee tata medical center, critical care medicine, kolkata, india critical care , (suppl ):p introduction: sepsis due to carbapenem resistant organisms has high mortality; inappropriate empirical antibiotic is one of the main causes of this poor outcome. on the contrary, "too much" broad spectrum empiric antibiotics will increase drug resistance, even in community, because of selection pressure. so, early diagnosis of resistance pattern (carbapenemase genes) is crucial. aim of this study is to compare rapid diagnostic test like polymerase chain reaction (pcr) with conventional culture sensitivity (c/s) to identify carbapenem resistance. methods: this is a prospective observational study done in tata medical center, kolkata, india. real time multiplex pcr technique has been developed "in house" in our microbiology lab and can identify ndm, ndm , kpc, oxa - , oxa - , oxa - & vim carbapenemase genes. blood cultures were sent as per clinical & laboratory diagnosis of sepsis in icu patients. culture positive samples had been used for conventional c/s by vitek system along with pcr study to identify carbapenemase genes. result of pcr technique was been compared with conventional c/s method. results: multiplex pcr results were available within - hours of positive blood culture compared to conventional c/s method that takes - days. among positive blood cultures, samples were positive for carbapenemase genes. most common gene identified was oxa - ( %), followed by ndm ( %). our pcr technique has very high sensitivity, specificity, positive & negative predictive value ( . %, . %, . % & . % respectively) while comparing with final c/s report by vitek system (table ) . there was only one false negative diagnosis for carbapenem resistance. conclusions: real time multiplex pcr for carbapenemase gene can be helpful for early diagnosis of carbapenem resistance and can help us to choose / modify antibiotics or to use 'targeted therapy'. it is more practical to "rule -in" infection rather than "rule -out" by this technique. carbapenemase producing enterobacteriaceae colonization in an icu: risk factors and clinical outcomes m miranda, jp baptista, j janeiro, p martins centro hospitalar e universitário de coimbra, intensive care unit, coimbra, portugal critical care , (suppl ):p introduction: carbapenemase-producing enterobacteriaceae (cpe) colonization has been increasingly reported in intensive care units (icus) since their first identification more than years ago. colonization with cpe seems to constitute a risk factor for mortality. the aim of our study was to identify associated risk factors and clinical outcomes among patients with fecal colonization by cpe admitted to a portuguese tertiary hospital icu. methods: a -year retrospective study was performed in patients with previous unknown cpe status (colonization or infection), admitted to our icu. rectal swabs were performed and analyzed using real-time polymerase chain reaction testing. clinical records were reviewed to obtain demographic and clinical data. results: of patients admitted, ( . %) harbored cpe, ( . %) were colonized at admission and ( . %) acquired cpe colonization during icu stay. the most frequent carbapenemase genes detected were kpc ( . %) and vim ( . %). cpe carriers had high rates of hospitalization (previous or ongoing), invasive procedures (mainly intraabdominal surgery), malignancy (hematopoietic or solid tumor), introduction: gram-negative pathogens-particularly pseudomonas aeruginosa and enterobacteriaceae-predominate in nosocomial pneumonia (np) and ciai both. these infections are becoming difficult to treat with available treatment options due to growing antimicrobial resistance in india. ceftazidimeavibactam has in-vitro activity against gram-negative organisms producing class a, class c and some class d beta-lactamases. we carried out a qualitative analysis to assess the safety and efficacy outcomes of the indian population cohorts involved in the re-prove and reclaim trials. methods: in line with the global reprove protocol, indian patients enrolled in the study with np, were randomly assigned ( : ) to mg ceftazidime and mg avibactam or mg meropenem. in the reclaim study, indian patients with a diagnosis of ciai were enrolled in the study and were randomly assigned ( : ) to receive either ceftazidime-avibactam ( mg of ceftazidime and mg of avibactam) followed by metronidazole ( mg); or meropenem ( mg). the primary efficacy outcome measure in the reprove and reclaim studies was clinical cure rate of caz-avi compared with that of meropenem at toc (test-of-cure) visit in pre-defined analysis sets. in both studies, non-inferiority was concluded if the lower limit of the twosided % ci for the treatment difference was greater than - · % in the primary analysis sets. as the indian subset study was not statistically powered to detect a difference in the subgroup, we descriptively analysed the efficacy results in the indian population and compared them with the overall results in the global trial. in addition, the study also analysed the safety of caz-avi in the indian patients by monitoring the number and severity of adverse events. introduction: early administration of effective intravenous antimicrobials is recommended for the management of the patients with sepsis. although meropenem (mepm) is one of the first-line drugs in patients with sepsis because of its broad spectrum, the optimal dose in the critical care settings especially during continuous renal replacement therapy (crrt) has not been established since therapeutic drug monitoring of mepm has not been popular. methods: eighteen critically ill patients who received crrt were enrolled in this study. one gram of mepm was administered over hour, every hours, and blood samples at , , , and hours after administration were collected on day , and . all samples were stored at - °c until analysis. the measurement of the blood concentration of mepm was performed using high performance liquid chromatography with ultraviolet detection (hplc-uv introduction: meningitis is one of the complications of severe traumatic brain injury, and it is often associated with encephalitis (incidence from . - . % to - %). the aim of the investigation was to study the dynamics of the concentration of meropenem in serum and cerebrospinal fluid (csf) with intravenous and intrathecal administration of meropenem. methods: in eight patients with bacterial meningoencephalitis blood serum and csf were studied prior to the administration of meropenem and - min, , . and hrs after it. antibiotic regimen: mg of vancomycin ( mg bid) and meropenem ( mg tid diluted in ml of saline iv + mg bid diluted in ml of saline bolus slowly intrathecally). meropenem infusion was carried out for minutes, mins after it ml of blood and ml of csf were sampled. prior to antibiotics administration blood and csf were taken for microbiological examination. to determine the concentration of antibiotics iquid chromatography/mass spectrometry was used. the samples were analyzed on an agilent infinity liquid chromatograph coupled to a sciex qtrap mass detector (sciex, us introduction: the prophylactic use of probiotics has emerged as a promising alternative to current strategies viewing to control nosocomial infections in a critically-ill setting. however, their beneficial role in vap prevention remains inconclusive. our aim was to delineate the efficacy of probiotics for both vap prophylaxis and restriction of icu-acquired infections in multi-trauma patients. methods: randomized, placebo-controlled study enrolling multitrauma patients, requiring mechanical ventilation for > days. participants were randomly assigned to receive either probiotic (n= ) or placebo (n= ) treatment. a four-probiotic formula was applied and each patient received two capsules per day from day to day post icu admission. the content of one capsule was given as an aqueous suspension by nasogastric tube, while the other one was spread to the oropharynx after being mixed up with water-based lubricant. the follow-up period was days, while icu stay and mortality were also assessed. ], while no difference in -day mortality rate was identified between groups ( . % probiotics vs . % placebo). conclusions: the prophylactic administration of probiotics exerted a positive effect on the incidence of vap or other icu-acquired infections and icu stay in a critically-ill subpopulation being notorious for its high susceptibility to infections, namely multi-trauma patients. use of a c-reactive protein-based protocol to guide the duration of antibiotic therapy in critically ill patients: a randomized controlled trial i borges introduction: the rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. in this study we aimed to evaluate the effectiveness of a c reactive protein (crp) based protocol in reducing antibiotic treatment time in critically ill patients. methods: an open randomized clinical trial was conducted in two adult intensive care units of a university hospital in brazil (clini-caltrials.gov: nct ). patients were randomly allocated to: i) intervention -duration of antibiotic therapy guided by crp levels, and ii) control -duration of therapy based on best in the intention to treat analysis, the median (q -q ) duration of antibiotic therapy for the index infection episode was . ( . - . ) days in the crp group and . ( . - . ) days in the control group (p= . ). in the cumulative suspension curve of antibiotics, a significant difference in the exposure time between the two groups was identified, with less exposure in the crp group (p= . ). in the pre-specified per protocol analysis, with patients allocated in each group, the median duration of antibiotics was . ( . - . ) days in the crp group and . ( . - . ) days in the control group (p= . ). mortality and relapse rates were similar between groups. conclusions: daily levels of crp may aid in reducing the time of antibiotic therapy in critically ill patients, even in a scenario of judicious use of these drugs. introduction: the macrophage activation syndrome (mas) or hemophagocytic lymphohistiocytosis(hlh) is a life threatening complication characterized by pancytopenia, liver failure, coagulopathy and neurologic symptoms and is thought to be caused by the activation and uncontrolled proliferation of t lymphocytes and well differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction [ , ] .the etiology is unknown, but is considered to have an infectious trigger.the aim of our study is to evaluate the impact of hlh in our beds infectious diseases icu, during months period ( - ). methods: a retrospective study based on electronic databases, including all patients admitted in our icu, that have matched at least out of criteria for hlh diagnosis ( ):fever; hepatosplenomegaly; > cytopenia (hb < g/dl, plt</dl, pmn -n< /mmc); hypertriglyceridemia> mg/dl, fibrinogen< mg/dl; hemophagocytosis-bone marrow, spleen, and/or lymphnodes; nk activity reduced/ absent; ferritin level> ui/l; cd > . we have evaluated the etiology established with cultures, serology, and molecular methods, treatment with corticosteroids, iv immunoglobuline, cyclosporine, etoposide and outcome ( ) . results: patients were admitted to icu, patients( . %) met the criteria for hlh. the average length of stay in icu was days; patients died ( %) without relation with the followed treatment. conclusions: hlh is not a rare condition in infectious diseases icu. the etiology is more frequent established compared with literature data. treatment (corticosteroids, immunoglobuline, cyclosporine, etoposide) is not associated with increased survival forecasting hemorrhagic shock using patterns of physiologic response to routine pre-operative blood draws introduction: irreversible hemorrhagic shock (ihs), a critical condition associated with significant blood loss and poor response to fluid resuscitation, can induce multiple organ failures and rapid death [ ] . determining the patients who are likely to develop ihs in surgeries could greatly help preoperative assessment of patient outcomes and allocation of clinical resources. methods: machine learning model of ihs is developed and validated via porcine induced bleed experiment. healthy sedated yorkshire pigs first had one ml rapid blood draw during a stable period, and then were bled at ml/min to mean arterial pressure (map) of mmhg. subjects had ihs defined as map< mmhg. arterial, central venous and airway pressures collected at hz during the blood draw [ fig ] were used to extract characteristic sequential patterns using graphs of temporal constraints (gtc) methodology [ ] , and a decision forest (df) model was trained on these patterns to determine subjects at high risk of impending ihs. results: in a leave-one-subject-out cross-validation, our method confidently identifies % ( % ci [ . %, . %]) of the subjects who are likely to experience ihs when subject to substantial bleeding, while only giving on average false alarm in , such predictions. this method outperforms logistic regression and random forest models trained on statistically featurized data [tab , fig ] . conclusions: our results suggest that by leveraging sequential patterns in hemodynamic waveform data observed in preoperative blood draws, it is possible to predict who are prone to develop ihs resulting from blood loss in the course of surgery. future work includes validating the proposed method on data collected from human subjects, and developing a clinically useful screening tool with our investigations. work partially funded by nih gm . introduction: the h s and oxytocin(oxy) systems are reported to interact with one another [ ] . h s plays a major role in the hypothalamic control of oxy release during hemorrhage [ ] . there is scarce information about oxy receptor(oxyr) expression in the brain in general and what is there is ambivalent. oxyr has been immunohistochemically(ihc) detected in the human hypothalamus but not in the hippocampus, in contrast to rodents [ ] , which underscores the need for additional characterization in relevant animal models. thus the aim of this study is to map the expression of the oxy and h s systems in the porcine brain in a clinically relevant model of hemorrhagic shock (hs). methods: anesthesized atherosclerotic pigs (n= ) underwent h of hs (map +/- mmhg) [ ] , followed by h resuscitation. ihc detection of oxy, oxyr, the h s producing enzymes cystathionine-γ -lyase (cse) and cystathionine-β -synthase(cbs) was performed on formalin fixed brain paraffin sections. results: oxy, oxyr, cse and cbs were localized in the porcine brain. proteins were differentially expressed in the hypothalamus (fig ) , parietal cortex and cerebellum (fig ) . cell types positively identified were: magnocellular neurons of the hypothalamus, cerebellar purkinje cells and granular neurons, and hippocampal pyramidal and granular neurons of the dentate fascia. arteries and microvasculature were also positive for oxyr and cse. conclusions: our results confirm the presence of oxy and oxyr in the hypothalamus similarly to the human brain. novel findings were: oxyr in the cerebellum and cse expression in the hypothalamus and cerebellum. the coexpression of oxyr and cse may link and help better understand neurochemical systems and physiological coping in hemorrhagic shock. funding: crc introduction: septic shock is one of the main causes of intensive care unit (icu) admission, leading to mortality up to % of patients. acute kidney injury (aki) frequently occurs and is associated to great morbidity and mortality. hemodynamic optimization may reduce the incidence of aki, but the use of vasopressors to increase mean arterial pressure (map) could have deleterious effect on renal perfusion. we aimed at investigating the effect of map and norepinephrine (ne) on the incidence of aki in septic shock patients methods: retrospective study based on prospectively collected data on digital medical records (digistat) at our icu. introduction: in patients with distributive shock, increasing mean arterial pressure (map) to a target of > mmhg can improve tissue perfusion. patients unable to achieve the target map of > mmhg despite adequate fluid resuscitation as well as catecholamines and vasopressin standard care (sc), may benefit from the noncatecholamine vasopressor angiotensin ii to increase map. this posthoc analysis examined whether patients from the athos- study with a baseline (bl) map < mmhg and treated with sc plus either angiotensin ii (ang ii) or placebo achieved a map of > mmhg for consecutive hours, without increasing the dose of sc therapy. methods: patients were assigned in a : ratio to receive ang ii or placebo, plus sc. randomization was stratified according to map (< or > mmhg) at screening. in patients with bl map < mmhg, we evaluated whether patients achieved a map of > mmhg for the first hours after initiation (map measurements taken at hours , , and ), without an increase in the dose of sc. results: among treated patients, had bl map < mmhg (ang ii, ; placebo, ). median bl map (iqr) was ( - ) and ( - ) mmhg for placebo and ang ii groups, respectively. patients with bl map < mmhg who were treated with ang ii were more likely to achieve map ≥ mmhg for consecutive hours after initiation without an increase in sc dose ( %, %ci - ), compared with placebo-treated patients ( %, %ci - , or= . , p< . ). conclusions: in this post-hoc analysis of patients with bl map < mmhg, patients receiving ang ii plus sc were significantly more likely to achieve a map > mmhg for the first consecutive hours after initiation than patients receiving sc only. this suggests that administering ang ii may help patients with catecholamine-resistant distributive shock to achieve the consensus standard target map. norepinephrine synergistically increases the efficacy of volume expansion on venous return in septic shock i adda, c lai, jl teboul, l guerin, f gavelli, c richard, x monnet hôpitaux universitaires paris-sud, hôpital de bicêtre, aphp, service de médecine intensive-réanimation, le kremlin-bicêtre, france critical care , (suppl ):p introduction: through reduction in venous capacitance, norepinephrine (ne) increases the mean systemic pressure (psm) and increases cardiac preload. this effect may be added to the ones of fluids when both are administered in septic shock. nevertheless, it could be imagined that ne potentiates in a synergetic way the efficacy of volume expansion on venous return by reducing venous capacitance, reducing the distribution volume of fluids and enhancing the induced increase in stressed blood volume. the purpose of this study was to test if the increase in psm induced by a preload challenge were enhanced by ne. methods: this prospective study had included septic shock adults. to reversibly reproduce a volume expansion and preload increase at different doses of ne, we mimicked fluid infusion through a passive leg raising (plr). in patients in which the decrease of ne was planned, we estimated psm (using respiratory occlusions) at baseline and during a plr test (plr high ). the dose of ne was then decreased and psm was estimated again before and during a second plr (plr low ). . the increase in cardiac index induced by plr low was significantly greater than that induced by plr high (p< . ). Δ psmhigh -Δ psmlow was moderately correlated with the diastolic arterial pressure at baseline-high (p= . , r= . ) and with the ne-induced change in mean arterial pressure (p= . , r= . ). conclusions: ne enhances the increase in psm induced by a plr, which mimics a fluid infusion. this suggests that it may potentiate the effects of fluid in a synergetic way in septic shock patients. this may decrease the amount of administered fluids and contribute to decrease the cumulative fluid balance. introduction: arginine vasopressin (avp) can be used in addition to norepinephrine (ne) for ne-resistant septic shock. however, a subgroup who will response to avp is unknown. the purpose of this study was to determine factors which could predict the response to avp in patients with ne-resistant hypotension. methods: this was a single-center, retrospective analysis of patients who administered avp for ne-resistant hypotension in our intensive care units (icus). eligible patients were adult patients who administered avp in addition to ne due to hypotension (mean arterial pressure (map) < ) in our icus between august and december . we divided all patients into two groups by response to avp; responders and non-responders. the responders were defined as an increase of map ≥ mmhg at h after avp initiation. we conducted univariate and multivariate logistic regression analysis to evaluate the effect of variables on avp response. results: a total of patients were included; responders ( %), non-responders ( %). there was no significant difference for map at the time of avp initiation ( vs mmhg; p = . ), initiation dose of avp ( . vs . u/min; p = . ), and dose of ne at the time of avp initiation ( . vs . μ g/kg/min; p = . ). map at h after avp initiation was significantly higher in responders than non-responders ( vs mmhg; p < . ). responders were older ( vs ; p = . ) and had lower heart rate (hr) ( vs. ; p = . ) and lactate ( . vs. . mmol/l; p = . ) at the time of avp initiation. the multivariate logistic analysis revealed that hr ≤ (or . , % ci . - . , p < . ), lactate ≤ (or . , % ci . - . , p < . ) and age ≥ (or . , % ci . - . , p = . ) were significantly associated with the response to avp. conclusions: hr, lactate levels and age before avp initiation can predict the response to avp in icu patients with ne-resistant hypotension. the maximum norepinephrine dosage of initial hours predicts early death in septic shock d kasugai , a hirakawa , n jinguji , k uenishi nagoya university gtaduate school of medicine, department of emergency and critical care, nagoya, aichi, japan; fujita health university, department of disaster and traumatology, fujita health university, toyoake, japan; fujita health university hospital, department of emergency and general internal medicine, fujita health university hospital, toyoake, japan critical care , (suppl ):p introduction: the mortality of septic shock refractory to norepinephrine remains high. to improve the management of this subgroup, the knowledge of early indicator is needed. we hypothesize that maximum norepinephrine dosage on the initial day of treatment is useful to predict early death in septic shock. methods: in this retrospective single-center observational study, septic shock patients admitted to the emergency intensive care unit (icu) of an academic medical center between april and march were included. cardiac arrest before icu admission and those with do-not-resuscitate orders before admission were excluded. the maximum dosage of norepinephrine initial hours of icu admission (md ) was used to assess -day mortality. results: one-hundred-fifty-two patients were included in this study. median sofa score was ( - ), and median md was . ( . - . ) mcg/kg/min. vasopressin and steroid were administered in ( %) and ( %) cases. nineteen patients ( %) died within a week. non-survivors had higher md , higher sofa score, and higher rate of vasopressin use. the higher md predicted -day mortality (area under curve . , threshold . mcg/kg/min, sensitivity %, specificity %). after adjustment of inverse probability of treatment weighing method using propensity scoring, md higher than . mcg/kg/min was independently associated with -day mortality (or: . , %ci: . - . , p < . ). conclusions: the maximum dosage of norepinephrine higher than . mcg/kg/min initial hours was significantly associated with day mortality in septic shock, and may be useful in the selection of higher severity subgroup. the impact of norepinephrine on right ventricular function and pulmonary haemodynamics in patients with septic shock -a strain echocardiography study k dalla sahlgrenska university hospital mölndal, göteborg, sweden critical care , (suppl ):p introduction: septic shock is characterized by myocardial depression and severe vasoplegia. right ventricle performance could be impaired in sepsis. the effects of norepinephrine on rv performance and afterload in septic shock are not immediately evident. the aim of the present study was to investigate the effects of norepinephrine on rv systolic function, rv afterload and pulmonary haemodynamics. methods: eleven, volume-resuscitated and mechanically ventilated patients with norepinephrine-dependent septic shock were included. infusion of norepinephrine was randomly and sequentially titrated to target mean arterial pressures (map) of , and mmhg. at each target map, strain-and conventional echocardiographic were performed. the pulmonary haemodynamic variables were measured by using a pulmonary artery thermodilution catheter. the rv afterload was assessed by calculating the effective pulmonary arterial elastance (epa) and pulmonary vascular resistance index (pvri). results: the norepinephrine-induced elevation of map increased central venous pressure ( %, p< . ), stroke volume index ( %, p< ), mean pulmonary artery pressure ( %, p< . ) and rv stroke work ( %, p= . ), while neither pulmonary vascular resistance index nor epa was affected. increasing doses of norepinephrine improved rv free wall strain from - % to - % ( %, p= . ), tricuspid annular plane systolic excursion ( %, p= . ) and tricuspid annular systolic velocity ( %, p= . ). there was a trend for an increase in cardiac index assessed by both thermodilution (p= . ) and echocardiography (p= . ). conclusions: the rv function was improved by increasing doses of norepinephrine, as assessed both by strain-and conventional echocardiography. this is explained by an increase of rv preload. pulmonary vascular resistance is not affected by increased doses of norepinephrine. peripheral perfusion versus lactate-targeted fluid resuscitation in septic shock: the andromeda shock physiology study. preliminary report g hernandez , r castro , l alegría , s bravo , d soto , e valenzuela , m vera , v oviedo , c santis , g ferri , m cid , b astudillo , p riquelme , r pairumani , g ospina- tascón table . conclusions: this preliminary results suggest that using crt as a target for fr in septic shock appears to be feasible, and not associated with impairment of tissue perfusion-related parameters as compared to lactate-targeted fr. grant fondecyt chile introduction: shock patients often become resistant to catecholamines which often require the addition of a non-catecholamine vasopressor. preclinical studies suggest that in the presence of aadrenoceptor antagonism, the renin-angiotensin aldosterone system exerts the major vasopressor influence. we sought to determine the effects of angii or lypressin (lyp [porcine vasopressin]) on blood pressure in a norepinephrine (ne)-resistant hypotension pig model. methods: phentolamine (phn), a reversible α-blocker that antagonizes the vasoconstriction by ne, was continuously infused to induce hypotension. after ne-resistant hypotension was established, lyp or angii was then co-infused with phn. mean arterial pressure (map) and heart rate were continuously recorded (fig. ) . results: as shown in fig. conclusions: in a background of α-adrenoceptor blockade, at clinically comparable doses, the vasopressor effect of ang ii was maintained while those of ne and lyp were attenuated. these data suggest that the blood pressure effect of vasopressin-like peptides may require a functioning α-adrenoceptor. patients with shock who are resistant to increasing doses of catecholamines may also have vasopressin resistance potentially making angiotensin ii a preferred vasopressor for these patients. introduction: resuscitative endovascular balloon occlusion of the aorta (reboa) has been increasingly used for the management of both traumatic and non-traumatic hemorrhagic shock. however, there is limited evidence for its use in gastrointestinal bleeding (gib), especially in the icu setting. we successfully treated a patient with massive gib using reboa in the icu. we will discuss the difficulty performing the procedure and its countermeasure. methods: a case report. results: an -year-old woman was transferred to our hospital with shock. coffee grounds material was found in a nasogastric aspirate after intubation and upper gastrointestinal endoscopy identified a pulsating large duodenum ulcer without active bleeding, for which an elective procedure was planned. she was admitted to our icu, responded to initial resuscitation, and thereafter extubated. her systolic blood pressure (sbp) suddenly dropped to mmhg with massive hematochezia at that night, and did not increase despite resuscitation with blood products, crystalloid and norepinephrine. to buy time until measures for stop bleeding, we planned to place reboa in the icu. following the placement of a sheath in the left femoral artery, we tried to place a fr intra-aortic balloon occlusion catheter, which unintentionally and repeatedly went into the right common iliac artery because her left femoral artery was tortuous. after compressing the right lower abdomen, we managed to introduce reboa in zone . it took approximately minutes to successfully place the catheter. the patient's sbp increased immediately after the balloon inflation and bleeding was endoscopically controlled. introduction: the natural components of the pomegranate fruit may provide additional benefits for endothelial function and microcirculation. we hypothesized that chronic supplementation with pomegranate extract might improve glycocalyx properties and microcirculation during anaerobic condition. methods: eighteen healthy and physically active male volunteers aged - years were recruited randomly to the pomegranate and control groups ( in each group). the pomegranate group was supplemented with pomegranate extract for two weeks. at the beginning and end of the experiment, the participants completed a high intensity sprint interval cycling-exercise (anaerobic exercise) protocol. the systemic hemodynamics, microcirculation flow and density parameters, glycocalyx markers, and lactate and glucose levels were evaluated before and after the two exercise bouts. results: no significant differences in the microcirculation or glycocalyx were found over the course of the study. the lactate levels were significantly higher in both groups after the first and repeated exercise bouts, and were significantly higher in the pomegranate group relative to the control group after the repeated bout: . ( . - . ) vs. . ( . - . ) mmol/l, p = . . conclusions: chronic supplementation with pomegranate extract has no impact on changes to the microcirculation and glycocalyx during anaerobic exercise, although an unexplained increase in blood lactate concentration was observed. introduction: extracorporeal membrane oxygenation in adults in accompanied by high mortality. our ability to predict who will benefit from ecmo based on currently available clinical and laboratory measures is limited. the advent of single cell sequencing approaches has created the opportunity to identify cell populations and pathophysiological pathways that are associated with mortality without bias from a priori cell type classifications. identification of such cell populations would provide both an important prognostic markers and key insight into immune response mechanisms and therefore a possibility for advanced drug matching that may impact clinical response to ecmo in these patients. methods: whole genome transcriptomic profiles were generated from a total of , peripheral blood monocytes obtained from patients at the time of cannulation for ecmo (fig ) . differential gene expression analysis was performed with the monocle package for the r statistical analysis framework. time-to-event data were analyzed in a survival analysis with a log-rank test for differences. results: genes encoding several members of the heat shock family of proteins were up-regulated in cells from non-survivors. notably, these genes were expressed by a small fraction of cells ( . % on average). nevertheless, the proportion of cells expressing these genes was a significant predictor of survival to days (p = . by log rank test), with a particularly pronounced effect in the first days after initiation of ecmo support (fig ) . conclusions: the proportion of cells expressing genes encoding members of the heat shock proteins is predictive of survival on ecmo. majority of pt ( %) had no known predisposing conditions, followed by immobility ( %) and cancer ( %). in ecg analysis tachycardia and v -v t wave inversion were the most common findings whereas hypoxemia± hypocapnia were the most prominent features in abg analysis. pt ( %) had bleeding complications (none intracranial), ( . %) during rtpa, ( . %) in the first h and only pt required transfusion. mortality rate was %: % directly due to pe (all during cpr) and % due to late complications (newly diagnosed cancer and infections). conclusions: in our experience, fibrinolytic therapy is safe and effective but in submassive pe should be applied after thorough assessment of risks and benefits on individual basis aiming to patient tailored precision medicine. [ ] trials evaluated the role of levosimendan in preventing low cardiac output syndrome in patients undergoing cardiac surgery. the studies were similar in their design and recruited patients with preoperatively low lvef undergoing either isolated cabg or valve surgery combined with cabg (table ). in both, a -hour levosimendan infusion was started at induction of anesthesia. neither study met the primary efficacy composite enpoints, but both showed a clear tendency for better outcome in patients undergoing a cabg compared to a valve procedure. we are currently evaluating the solidity of a co-analysis based on shared end-points. we are planning a shared analysed of the data related to the cabg settings and analyze the aggregated mortality data for both studies at and months by cochran-mantel-haenszel odds ratio. data from individual studies would be analysed as fixed effect and breslow-day test was used to evaluate homogeneity of the odds ratios results: in the placebo groups of the two studies, the mortality is similar; . % ( / ) in levo-cts and . % ( / ) in licorn, corroborating the working hypothesis that the two studies can be coanalysed. in a preliminary combined analysis (fig ) , -day mortality was . % ( / ) in the placebo group and . % ( / ) in the levosimendan group. odds ratio was significantly in favor of levosimendan ( . ; % confidence interval . - . ; p= . , fig. ) conclusions: the levo-cts and licorn trials can be co-analysed in their sub-setting of patients requiring isolated cabg surgery for mortality at and months. a preliminary analysis on mortality reinforce the hypothesis that, in isolated cabg surgery, levosimendan lowers post-operative mortality significantly both at and months, when started at the induction of anesthesia introduction: emergency medical system (ems) -based st elevation myocardial infarction (stemi) networks allows not only stemi diagnosis in the pre-hospital phase but also reduces treatment delays; treat your fatal complications and the immediate activation of the catheterization laboratory. the aim of study was to investigate the effect of out-of-hospital by mobile intensive care (micu) versus hospital beginning treatment in hospitalization length and survival of patients with stemi diagnosis introduction: contrast induced nephropathy (cin) is a complex acute renal failure syndrome, which can occur after primary percutaneous coronary intervention (pci) and is an important cause of morbidity and mortality in this subgroup of patients. the aim of our study was to establish the incidence and predictors of cin after primary pci. we performed a retrospective analysis of stemi patients treated with primary pci in the period from january until september of . cin was defined as an absolute increase in baseline serum creatinine of ≥ . mg/dl ( μmol/l) or > % relative rise within hours after primary pci. we analyzed demographic characteristics, risk factors, clinical status at hospital admission, laboratory parameters, left ventricle ejection fraction and data regarding pci procedure. results: the study included patients, with an average age of . ± . years, . % of the patients were males. an average of . ± . ml of contrast medium per patient was utilized. cin developed in ( . %) patients and overall intra-hospital mortality was . %. in multivariate analysis, the independent predictors of cin were age> years ( introduction: left main coronary artery (lmca) disease is a disease of the main coronary branch that gives more than % of blood supply to the left ventricle, it carries high mortality without surgical intervention; [ ] however the influence of lmca surgery on morbidity icu measures needs to be explored. we aim to determine whether lmca is definitive risk factor for prolonged icu stay as a primary outcome and whether lmca is definitive risk factor for early morbidity methods: retrospective descriptive study with purposive sampling analyzing patients underwent isolated coronary artery bypass surgeries (cabg). patients were divided into groups those with lmca disease as group ( patients) and those with coronary arty disease requiring surgery but without lmca disease as group ( patients) then we will correlate with icu outcome parameters including icu stay length, postoperative atrial fibrillation, acute kidney injury, re-exploration, perioperative myocardial infarction, post operative bleeding and early mortality. results: patients with lms had significantly higher diabetes prevalence ( . % vs %, p= . ). however, we did not find a statistical significant difference regarding icu stay, or other morbidity and mortality outcome measures conclusions: diabetes was more prevalent in patients with lms. the latter group showed similar outcome as those without lms in this study these findings may help in guiding decision making for future practice and stratifying the patients care. introduction: multimorbidity in patients admitted for acute myocardial infarction [ami] is associated with higher risk for in-hospital mortality and adverse clinical outcomes. we investigated to what extent an increasing number of comorbidities affects the age-stratified excess risk of death and other clinical outcomes among patients with myocardial infarction. methods: we analyzed nationwide administrative data of ` admissions for an acute myocardial infarction between and . we calculated multivariate regression models to study the association of four comorbidities (chronic kidney disease [ckd], diabetes mellitus, heart failure [hf], and atrial fibrillation) and excess risk of in-hospital mortality, length of hospital stay [los] , and -day readmission and stratified the analysis for different age categories. results: the incidence of admissions for ami increased continuously during the observed decade without an increase in in-hospital mortality, los, and -day readmission. among admitted patients with ami, there was a stepwise increase in risk for adverse outcomes for each comorbidity. compared to patients with no comorbidity, patients with comorbidities had -fold increased risk for mortality (adjusted odds ratio [or] . , % confidence interval [ci] . to . ) and a similar risk for readmission (or . , ci . to . ). the los was . days (ci . to . ) in patients with no comorbidity and increased by . days (ci . to . ) with each additional comorbidity. these associations were stronger in younger compared to older patients. ckd was the strongest predictor of in-hospital mortality and los, while hf was the strongest predictor of -day readmission. conclusions: this study of nationwide admitted patients with ami found a stepwise increase in the risk for adverse outcome with increasing number of comorbidities, particularly in the younger patient population. younger, multimorbid patients may thus have the largest benefits from multidisciplinary treatments. introduction: certified cardiac arrest centers, sophisticated post cardiac arrest care and prehospital ecls teams aim to increase survivor rates with a preferable neurological outcome after cardiac arrest. centers also provide emergency ecls and ecls pick ups for cardiogenic shock patients before arresting. few data answer the question of the long-term quality of life after ecls therapy. methods: in a retrospective single center register we included patients after emergency ecls (ecpr and cardiogenic shock) between / and / discharged alive and performed a follow-up after years on average at / . in our center criteria to initiate ecls therapy in cardiogenic shock or under cardiac arrest are an observed collaps, shockable rhythm, absence of frailty and severe comorbidities. all patients were requested to take part in a telephone interview. thus, we analyzed survival, cpc scores and sf scores. results: patients with hospital survival after ecls were screened. % (n= ) had survived until / ; patients were not accessible; had ceased. survivors (mean±sd; min-max; ± ; - years, women) answered sf questionaires ± ; - months after ecls ( % cardiogenic shock, % ecpr with shockable rhythm in %). the participantsĆ pc scores were in median . the results of the sf were physical functioning ± , physical role functioning ± , bodily pain ± , general health ± , vitality ± , social role functioning ± , emotional role functioning ± and mental health ± . survivors who did not take part at the sf had a cpc score of in median (n= , personally signed refusals, language barriers, vegetative states). conclusions: after emergency ecls therapy and hospital survival % of our patients survived the following years up to over years with a preferable neurological outcome and a general mentally and physically satisfactory quality of life. a vague outcome in % limits the results of our study. introduction: successful weaning from va-ecmo requires the restoration of a sufficient cardiac function to ensure an adequate tissue perfusion. skin blood flow (sbf) is among the first to deteriorate during circulatory shock and the last to be restored after resuscitation. sbf would be a good predictor of successful weaning from va-ecmo. methods: patients with va-ecmo, who required a first weaning attempt, were included. weaning procedure (wp) was performed by a reduction of va-ecmo blood flow to l/min for minutes. the weaning criterion was an aortic velocity-time integral (vti) > cm. successful weaning from va-ecmo was defined as hemodynamic stabilization and without the need to increase the vasopressor dose during the next hours. sbf, assessed by skin laser doppler (peri-flux , perimed, right index finger); perfusion unit: pu), together with global hemodynamic parameters were obtained before and after min of weaning. receiver operating characteristic curves (roc) were generated to assess the ability and reliability of baseline parameters to predict a successful weaning. results: we studied wps in patients with va-ecmo for pulmonary embolism (n = ), post cardiotomy (n = ), acute coronary syndrome (n = ), myocarditis (n = ). these were successful (sw) in and unsuccessful (nsw) in . at baseline, hemodynamic variables, lactate, ecmo blood flow were similar in both groups (table ). sbf was greater in sw than nsw patients (table ). during wp, ci rose from baseline and was similar in sw and nsw (p= . ) ( table ). vtis were higher in sw than nsw ( ( - ) vs ( - ), respectively, p= . ). sbf decreased in sw and remained low in nsw (table ) . from the roc curves analyses, baseline sbf had the highest area under the roc curve with a cut off ≥ pu (sensitivity %, specificity %) (figure ). conclusions: sbf is a good predictor of successful weaning from va-ecmo introduction: postoperative cognitive dysfunction (pocd) is defined as a temporarily decline in cognition associated with surgery. long-term pocd ( months after surgery) occurs in - % of cardiac patients and is associated with a higher morbidity and mortality. endo-cabg is a new minimally invasive endoscopic coronary artery bypass grafting (cabg) technique that requires retrograde arterial perfusion which may be associated with a higher incidence of neurological complications. the aim of this study is to assess the incidence of pocd after endo-cabg. methods: sixty consecutive patients undergoing an endo-cabg were enrolled. pocd was assessed following the recommendations of the " statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery". a comparative group of patients undergoing percutaneous coronary intervention (pci) and a control group of healthy volunteers were also enrolled. additional tests included the digit span test and digit symbol-coding test. patients were tested at baseline and at month follow-up. pocd is defined as a reliable change index (rci) ≤ - . (significance level %), or z-score ≤ - . in at least two different tests. results: after enrolling patients in each group, respectively in the endo-cabg-group, in the pci-group and healthy controls were analysed. patients suffering from a cva within three months after their procedure were automatically classified as having pocd (pci: n= ; endo-cabg: n= ). the total incidence of pocd was not different between groups (pci: n= ; endo-cabg: n= , p= . ). conclusions: our results suggest that the risk of pocd after endo-cabg is low and comparable with the risk of pocd after pci. introduction: rhabdomyolysis ( rml) post aortic surgery probably affects the renal outcome adversely [ , ] . there is no robust data regarding the same in literature. methods: retrospective single center data review; prior approval from institutional review board. patients were divided to two groups group -with rml ( ck above cut off levels u/litre) and group without rml. the determinants of rml and the impact of the same on outcome; predominantly renal function was evaluated. chi-square tests are performed for categorical variables whereas, student t tests (un-paired ) are performed with continuous variables. correlation is performed between creatine kinase and creatinine rise. p value . (two tailed) is considered for statistical significant level. results: out of patients, patients ( . %) developed rhabdomyolysis ( group rml) and did not( group non rml). demographic and intraoperative factors had no significant impact on the incidence of rml. there was a significantly higher incidence of renal complications including new postoperative dialysis in the rml group. other morbidity parameters were also higher in the rml group. conclusions: there is high prevalence of rml after aortic dissection surgery -identification of risk factor and early intervention might help to mitigate the severity of renal failure introduction: we investigate whether central venous pressure (cvp) pressure waveform signal can be informative in detection of slow bleeding in post-surgical patients. we apply a novel machine learning method to analyze cvp datasets to characterize bleeding in a porcine model of fixed rate blood loss. methods: thirty-eight pigs were anesthetized, instrumented with catheters, kept stable for minutes, and bled at a constant rate of ml/min to mean arterial pressure of mmhg. cvp waveforms were extracted from inspiration and expiration phases of respiration and statistically featurized. the proposed machine learning method, canonical least squares (cls) clustering, identifies correlation structures that differ between subsets of observations. we extend it to supervised classification. both clustering and classification methods yield human-interpretable models that reflect distinctive patterns of correlations within cvp waveforms. results: we conducted three experiments to discover structure in the physiological response to bleeding. first, we clustered respiration cycles with full knowledge of blood loss. the color-coded cluster assignments are shown in the figure . they are consistent with escalation of bleeding. second, we deployed clustering on only cvp features without blood loss. temporal structure was complemented with some subject-specific clusters (fig ) . third, we ran cls classification to decide whether an observation came from before or after the onset of bleeding (performance shown in the results: over the last decade, the number of patients with hlhs who underwent norwood has increased. interstage mortality has decreased, and is currently - %. significant morbidity was not seen at a rate higher than in the international literature. discharge planning, and community access to allied health professional services remained a concern. conclusions: the paediatric congenital cardiac surgical service in the united arab emirates is relatively new (compared to some services around the world). interstage mortality in hlhs is improving as a result of programme development, surgical progress and postoperative care. in the interstage period, there is currently no home monitoring programme in place. some patients were found to have had very extended hospital admissions. improved community support may reduce interstage mortality further, as well as improve the social situation of many of these patients. postoperative complications were observed in ( . %) patients. we lined out the prevalence of cardiac complications, such as heart failure and rhythm disturbances, observed in ( . %) and ( . %) patients respectively. hospital mortality rate was . % ( / ). the cause of mortality in all cases was acute heart failure, due to the initial severity of the disease, and in ( . %) cases an acute myocardial infarction was diagnosed. duration of postoperative period was . ± . days. conclusions: off-pump coronary artery bypass grafting can be safely performed with relatively low incidence of mortality and postoperative morbidity. prognostic value of mid-regional pro-adrenomedullin and midregional pro-atrial natriuretic peptide as predictors of multiple organ dysfunction development and icu length of stay after cardiac surgery with cardiopulmonary bypass in adults introduction: one of the most harmful complications after cardiac surgery with cardiopulmonary bypass is a syndrome of multiple organ dysfunction (mods). we consider that mid-regional proadrenomedullin (mr-proadm) and mid-regional pro-atrial natriuretic peptide (mr-proanp) plasma concentrations can be used as predictors of mods development and los in icu. methods: thirty six adult patients (mean age years, male) with cardiovascular diseases undervent cardiac surgery with cardiopulmonary bypass (heart valve(s) replacement - ( . %) patients, aorta and it`s branch surgery - ( . %) patients, valvular surgery and coronary artery grafting - ( . %) patients). nyha heart failure class ii was in ( . %) patients, iiiin ( %) patients, ivin ( . %) patients. in the dynamics levels of mr-proadm and mr-proanp were measured in the venous blood with the kryptor compact plus analyzer (thermo fisher scientific, germany) before day and on the st and th days after surgery. all patients were divided into subgroups according to the lengths of stay in the icu and the development of mod in the postoperative period. the data are shown as median and th and th percentiles. the data were compared by mann-whitney u-test, pvalue of < . was considered statistically significant. results: levels of mr-proanp did not significantly change at the study stages and did not have a significant difference between subgroups. the levels of mr-proadm increased in the first postoperative day and remained elevated for days. this increase was significantly higher in subgroups of increased los in icu and with mods. the data are shown in the table . conclusions: mr-proadm can be used as predictor of mods and los in the icu for adult patients underwent cardiac surgery with cardiopulmonary bypass. introduction: prolonged intensive care unit (icu) stay after cardiac surgery is associated with increased mortality and cost .the aim of this study was to investigate factors influencing prolonged icu stay. methods: consecutive patients who underwent cardiac surgery from june to october in our cardiothoracic department, were retrospectively investigated. group a consisted of pts with prolonged stay defined as more than days and group b the rest of the cohort. the following characteristics and perioperative factors were compared between the groups: smoking, diabetes, copd, redo(re-operation), ejection fraction (ef)< %, emergent procedure, cardiopulmonary bypass time (cpb)> min, low cardiac output syndrome (lcos), acute kidney injury(kdigo) and mortalitychi square test was used for the statistical analysis. introduction: hemorrhagic complications of extracorporeal membrane oxygenation (ecmo) pose a major morbidity and mortality. optimal anticoagulation strategies balancing risks of bleeding and thrombosis in children are poorly understood. we aimed to identify factors associated with non-surgical bleeding in the first ecmo hours. methods: we evaluated all pediatric (< yrs) post-cardiotomy patients requiring ecmo between dec -july stratifying them by presence/absence of surgical bleeding. non-surgical bleeding was defined as chest tube output > cc/kg/hr during the first -hours not requiring reoperation. patient characteristics and coagulation parameters at various time points after ecmo initiation were compared between groups, and receiver operator characteristic (roc) curves were constructed to identify models and thresholds with optimal predictive performance. figure . conclusions: deranged coagulation parameters, particularly kaolin rtime may predict non-operative bleeding in pediatric ecmo patients. these findings may guide therapeutic anticoagulation while avoiding hemorrhagic sequelae in at risk patients. introduction: elevated cardiac troponin (ctn) level in patients (pts) admitted in the intensive care unit (icu) is multifactorial and has been associated with a worse prognosis. the aim of the study was to review the frequency and the main cause of ctn elevation and to calculate a discriminating index. methods: we retrospectively assessed all pts admitted in our eightbed general icu during a -month period with at least one measurement of ctn during their icu stay. we recorded clinical characteristics, the level of ctn on admission, the maximum ctn during icu stay and the possible causes of elevation. variables are expressed as mean ± sd or as median and interquartile ratio (ir), according to the normality of their distribution. student´s Ô test or the mann whitney u tests were used to compare the group of elevated ctn with the group of normal ctn. the prognostic performance of elevated ctn was evaluated by the receiver operating characteristics (roc) curve. statistical analysis was performed using spss version . (spss, inc., chicago, illinois). results: in out of pts that ctn was measured at least once, abnormal levels (> . pg/ml) were found in ( %) of them, and the maximum ctn value was ( . ) pg/ml. the clinical characteristics of the pts are depicted in table . sepsis was the main cause of troponin elevation, which complicated by acute kidney injury (aki) in pts ( %). maximum ctn, aki and the difference of maximum -admission ctn (Äctn) differed significantly between pts who survived and pts who died (p= . and . , respectively). the area under the curve (auc) was . and the optimal prognostic cut-off value of Äctn was pg/ml with a sensitivity of . and a specificity of . conclusions: raised cardiac troponin values is a frequent finding in icu pts and sepsis is the driving cause. aki and the difference between maximum and admission ctn measurements differ significantly between pts who survive and pts who die. an elevation of ctn during icu hospitalization > pg/ml seems to be a threshold indicating poor prognosis regarding both mortality and aki. the prognostic role of nt-pro-bnp in septic patients with elevated troponin t level introduction: sepsis is frequently accompanied with release of cardiac troponin t (tnt) and nt-pro-bnp, but the clinical significance of this myocardial injury and cardiac dysfunction remains unclear [ ] . tnt is known to be an independent predictor of mortality, whereas the prognostic role of nt-pro-bnp is uncertain. methods: here, we report data of va-ecmo-patients, treated with dobutamine, levosimendan, suprarenin or no inotropic agens, in respect of -day survival. all data were collected retrospectively ( / to / ) at a single center, all patients with a survival below hours were excluded. while treatment of va-ecmo patients is strongly guided by standard operation procedures at our institution, no recommendation on positive inotropic therapy could be made. results: a total of va-ecmo patients were evaluated, of which patients were treated with levosimendan within hours after cannulation. day survival in the whole cohort was . %. a total of patients did not receive any positive inotropic therapy at hours after implantation (survival . %). survival was best in the levosimendan plus dobutamine group %, followed by dobutamine mono-therapy . % and levosimendan mono . %. survival with suprarenin mono was . %, suprarenin plus levosimendan . % and suprarenin plus dobutamine , %. pooling data, we found no evidence that levosimendan and/or dobutamine (survival . %, n= , p= . ) improves survival over no inotropic therapy (fig ) . therapy with any combination including suprarenin however resulted in poor survival ( . %, n= , p= . ). adjustment for lactate levels or ecpr did not change the results. conclusions: this retrospective analysis of va-ecmo patients shows no evidence that early inotropic therapy improves outcomes in va-ecmo patients. this conclusion is obviously biased by retrospective design. until randomized data are available, suprarenin however should be avoided. survey of non-resuscitation fluids in septic shock a linden-sonderso introduction: positive fluid balance is associated with poor outcome in septic shock. the objective of the present study was to characterize non-resuscitation fluids in early septic shock. methods: consecutive patients > years of age were screened for inclusion criteria during a -month period in icus in sweden and in canada. inclusion criteria were septic shock per sepsis- definition within hrs of icu admission. a maximum of patients per center were included. type, indication and volume of non-resuscitation fluids were recorded during the first days of admission. fluids other than colloids, blood products and crystalloids given at rate > ml/kg/h were considered to be non-resuscitation fluids. the study was registered on clini-caltrials.gov (nct ). data are presented as median (interquartile range). results: a total of patients were included between march st and june th (see table for demographics). patients received ( - ) milliliters (ml) of non-resuscitation fluids introduction: we aimed to ascertain the extent and make-up of fluid overload in critically ill patients and to identify whether delivery of more concentrated medications could reduce this. positive fluid balance is associated with increased mortality [ ] . a recent study has shown that the predominant component of fluid overload was from iv medications and maintenance fluid [ ] . methods: we reviewed sequential patients admitted to our icu with an apache ii score of greater than and a length of stay (los) greater than hours. the patients' electronic admission summary was interrogated to establish: length of stay (los) fluid balance at hours, total volume administered as iv medications, total volume administered as maintenance fluid and total fluid administered introduction: in children less than kilograms, maintenance fluids are routinely added to the resuscitation requirements calculated using parkland's or other formulae. the contribution of this component for fluid resuscitation in children can add a significant quantity to total estimated fluid requirements. for example, in a child who is kilograms with a % burn, the maintenance fluid requirement is mls per hours and the resuscitation component per parkland's will be x x %= mls. hence, the maintenance requirement can exceed the resuscitation requirement in this child if the burn surface area is less than a % burn. the contribution of maintenance fluids to the total fluid requirements in small children with thermal injuries is under-recognised and not frequently studied. methods: to understand the contribution of maintenance fluids to the total fluid requirements in children less than kilograms who need resuscitation for thermal injuries of different sizes, we numerically simulated . children who had similar weights but different burn sizes and . children with similar burn size but different weights. the results are as shown in fig introduction: accurate quantification of fluid in resuscitation of thermal injuries is important for benchmarking, comparing and improving outcomes. in adults, it is usually expressed as mls/kg/%tbsa. in children, maintenance fluids are added to the resuscitation requirements. this is kept constant and the resuscitation component is titrated to meet pre-defined end points-usually urine output. maintenance fluids are not uniformly stratified across the weight ranges. we propose that quantification of fluids in mls/ kg/%tbsa in children does not accurately capture fluid needs for resuscitation due to the maintenance component of the fluid requirement. methods: we conducted this retrospective study in children admitted to a single-center burns intensive care unit (bicu) between january and december . children ≤ kilograms with tbsa ≥ % admitted within hours of their injury were included. oe (observed to expected ratio) and fluid in mls/kg/% tbsa were calculated as shown in figure . results: there were children in the cohort with half requiring invasive mechanical ventilation in the bitu and nearly a quarter requiring inotropic support. the demographic details are as shown in table . the oe ratio at the end of hours in the cohort was . ( . - . ). the total fluid given was . ( . , ) mls/kg/ % tbsa. the titrated resuscitation component was . ( . , . ) mls/kg/tbsa. total fluid (which included the maintenance fluid) had a poor correlation with oe ratio r = . (fig ) . exclusion of the maintenance fluid had a better correlation with the oe ratio r = . conclusions: to capture differences in the titratable resuscitation component rather than differences in the maintenance requirements, fluid should be quantified in children by excluding the maintenance component when expressed as mls/kg/%tbsa. dynamic arterial elastance for predicting mean arterial pressure responsiveness after fluid challenges in acute respiratory distress syndrome patients p luetrakool , s morakul , v tangsujaritvijit introduction: dynamic arterial elastance (eadyn; pulse pressure variation/stroke volume variation; ppv/svv) is a dynamic parameter of arterial load that can be continuously monitored. previous study proposed that eadyn was able to predict mean arterial pressure (map) responsiveness after fluid challenge [ ] [ ] [ ] [ ] [ ] . the objective of this study was to assess whether the eadyn was able to predict map responsiveness in acute respiratory distress syndrome (ards) patients ventilated with low tidal volume. methods: we performed a prospective study of diagnostic test accuracy in adult ards patients with acute circulatory failure and fluid responsiveness. all patients are continuously monitored blood pressure via arterial line connected with flotrac® transducer and vigileo® monitor. once the attending physicians decided to load intravenous fluid, we recorded ppv/svv and also other hemodynamic parameters before and after fluid bolus. map responsiveness was defined as an increase in map ≥ % from baseline after fluid challenge. results: twenty-three events were included. nine events ( . %) were map-responsive. cardiac output, heart rate and stroke volume were similar in both map-responder and map-nonresponder group. baseline map, diastolic blood pressure (dbp) and pulse pressure (pp) were significantly different after fluid challenge in map-responder group. eadyn of preinfusion phase was failed to predict map conclusions: one of the arterial load parameters such as eadyn derived from non-calibrated pulse contour analysis method was unable to predict map responsiveness in ards patients with low tidal volume ventilation. the our aim is to test the hypothesis that in fr septic shock patients, fluid load will determine a significant increase in pmsf but not in cvp. we prospectively included all mechanically ventilated patients with diagnosis of septic shock with invasive hemodynamic monitoring (transpulmonary thermodilution volumeview-ev ed-wards©). we collected hemodynamic and metabolic data and pmsf with the inspiratory holds technique, before and after a fluid challenge (fc) of ml of ringer lactate in minutes). fr was defined as an increase in cardiac output (co)> %. results: measures were obtained in patients. in case we observed fr. we found a significant increase in pmsf after a fc (mean difference(md) . ± . mmhg, p=. ). cvp increased significantly (md . ± . mmhg, p=. ). pmsf increased significantly in non-fr (md ± mmhg, p=. ) but not in fr while cvp was higher after fc only in fr (md . ± . mmhg, p=. ). venous return gradient (pmsf-cvp) globally increased after fc (md ± mmhg, p=. ), but only in non-fr such increase was significant (md ± mmhg, p=. ). no correlation was found between the variation co and venous return gradient. we did not find any improvement in metabolic parameters after the fluid challenge. conclusions: pmsf and combined cvp variations do not correlate with fr in our cohort of septic shock patients. inspiratory holds may not be adequate to infer pmsf in such context. further studies are warranted to investigate the effect of fc on pmsf in this field. evaluation of pre-load dependence over time in patients with septic shock i douglas , p alapat , k corl , m exline , l forni , a holder , d kaufman , a khan , m levy , g martin , j sahatjian , w self , e seeley , j weingarten , m williams , c winterbottom , d hansell is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. we have previously shown that fluid responsiveness is a dynamic state, changing frequently over a hour monitoring period. methods: fresh is a currently enrolling prospective randomized controlled study, evaluating the incidence of fr and patient centered outcomes in critically ill patients with sepsis or septic shock (nct ). patients randomized to plr guided resuscitation were evaluated every - hours over the first hours of care and classified as fr if the sv increased > % when measured with non-invasive bioreactance (starling sv, cheetah medical). the time of first fr was noted. results: a total of plr assessments were performed in patients over a hour monitoring period. % were female, and the average age was years. plrs were evaluated over time, with time representing initial fluid resuscitation ( figure ). when individual subjects were evaluated over time, % of subjects who became fr only after hours showed evidence of lv/rv dysfunction ( figure ). conclusions: fluid responsiveness or preload dependence frequently changes for septic shock patients over the first hours of care. evidence suggests it is beneficial to periodically perform an assessment of preload responsiveness to guide fluid administration, as preload dependence is a dynamic and changing state. preload dependence provides additional information beyond fluid responsiveness. those patients who remain primarily fluid non-responsive (preload independent) are more likely to demonstrate echo confirmed lv/rv dysfunction, as the delay in return to cardiac function may be related to underlying cardiac deficits. further evaluation may be indicated in preload independent patients. introduction: hydroxyethyl starch (hes), a synthetic colloid, has been used as a volume expander, and is associated with renal impairment in patients with sepsis. however, a small dose of hes ( %, / . ) has sometimes been used in acute ischemic stroke. therefore, we investigated whether a small dose of hes was linked with renal deterioration in patients with acute ischemic stroke. methods: a consecutive patients with acute ischemic stroke within days from onset were included between january and may (fig ) . we collected admission serum creatinine (scr), estimated glomerular filtration rate (egfr), and renal function was assessed using kdigo definition of acute kidney injury on hospital days to as to patient's hospitalization period. is crucial for venous return and volaemic status, and as such it is a useful parameter in physiology and clinical settings alike. we tested whether: near infra-red spectroscopy (nirs) could be effective at measuring msfp both in healthy individuals and in conditions with a rise in interstitial pressures; after an occlusion pressure is relieved, the decrease in venular blood volume could allow calculation of τ (time constant) and thus venous resistances (rv). in order to verify these hypotheses we used a forearm nirs probe on healthy individuals at rest and during different degrees of maximal voluntary contraction (mvc). methods: healthy subjects volunteered in the study that took place at sant'andrea hospital in rome (italy). all subjects had venular pressures and volumes assessed via a nirs probe positioned on the forearm using a pressure-cuff in steps of mmhg from to mmhg, at rest and at % and % mvc. for each patient msfp, unstressed volume (vu) and stressed volume (vs) were measured. a temporary mmhg occlusion was obtained and volume time course was calculated upon release, to derive τ . results: p-v relationship was found to have a -slopes shape reflecting venular network changes. we measured vu, vs, and obtained msfp values of . ± . mmhg, p< . ; during exercise no changes in vu and vs were noted but msfp values rose; value was found to be . ± . sec at rest and . ± . sec after exercise, reflecting a reduction in rv. conclusions: nirs measurements on healthy subject may have implications in the clinical assessment of critical care patients where changes in interstitial pressure are possible. introduction: in the pathogenesis of multiple organ dysfunction syndrome (mods) important role plays the development of hepatic dysfunction. a known method for assessing hepatic blood flow is reohepatography (rhg). however, it requires the analysis of a large number of parameters of the rheogram curve. the aim of this study was to develop a method for assessing arterial hepatic blood flow based on the rhg in patients with mods after abdominal surgery. methods: patients in the department of anesthesiology and intensive care unit were included in a prospective study ( men and women, age . ± . years, weight . ± . kg.). all patients were divided into two groups: group -patients after orthopedic and trauma surgery (n = ), group -patients after abdominal surgery with mods (n = ). patients in the groups did not have statistical differences by sex, age, body weight, height. rhg was carried out using the "reo-spectr" (russian federation). we have compared the rhg indicators between the groups ( table ) . we have developed a method for assessing hepatic arterial blood flow, which consists in determining the area under the arterial part of rhg curve using the simpson's rule. its normal values range from . mΩ *s to . mΩ *s. the method is non-invasive, can be applied at the patient´s bed. its advantage is simplicity, it can be used for rapid diagnosis and monitoring the effectiveness of treatment. area under the rhg curve in the group were . ± . mΩ *s and . ± . mΩ *s in the group (p < . ). conclusions: patients after abdominal surgery with mods have impaired hepatic blood flow, which may be associated with liver pathology caused by main surgical disease (obstructive jaundice) and hemodynamic disorders caused by acute cardiovascular failure. the method we developed allows us to determine disorders of hepatic arterial blood flow in the early stages before signs of liver dysfunction appear. comparison of pulse oximetry hemoglobin with laboratory measurement of arterial and central- results: patients: % male, median years ( - ); p:f ratio ( - ); peep ( - ); apache iii . ( ); median ventilation time days ( - ). fair agreement was seen in subjective assessment vs objective measures with binary assessment of rv size and function. ordinal data analysis showed poor agreement with rvfws ( figure ) and rv dimensions. if onestep disagreement was allowed the agreement was good ( table , ). significant overestimation of severity of abnormalities was seen comparing subjective assessment with rv eda and tapse, s' and fac. there was no difference in agreement values when accounting for clinician echo experience, perceived expertise (at level of cardiologist) or type of qualifications. conclusions: relatively low levels of agreement were seen with subjective assessment vs objective measures of rv size and function assessed by echo. it seems prudent to avoid subjective rv assessment in isolation and a combination of objective and subjective measures should be used. introduction: even short periods of hypotension are associated with increased morbidity and mortality. using high-density numerical physiologic data, we developed a machine learning (ml) model to predict hypotension episodes, and further characterized risk trajectories leading to hypotension. methods: a subset of subjects with / hz physiological data was extracted from mimic , a richly annotated multigranular database. hypotension was defined as > measurements of systolic blood pressure ≤ mmhg and mean arterial pressure ≤ mmhg, within a -minute window. derived features using raw measurements of heart rate, respiratory rate, oxygen saturation, and blood pressure were computed. random forest (rf), k-nearest neighbors (knn), and logistic regression models were trained with -fold cross validation to predict instantaneous risk of hypotension using features extracted from the data leading to the first episode of hypotension (cases) or icu discharge in subjects never experiencing hypotension (controls). for a given subject, risk trajectory was computed from the collation of instantaneous risks. results: from a source population of subjects, subjects met our definition of hypotension, and subjects without hypotension comprised the control group. features were generated from the four vital signs. the area under the curve (auc) for random forest classifier was . , out-performing logistic regression (auc . ) or k-nearest neighbors (auc . ) (fig ) . risk trajectories analysis showed average controls risk scores < . (< % risk of future hypotension), while the hypotension group had a rising risk score ( . to . ) in the hours leading to the first hypotension episode, and significantly higher scores leading into subsequent episodes (fig ) . conclusions: hypotension episodes can be predicted from vital sign time series using supervised ml. subjects developed hypotension have an increased risk compared to controls at least hours prior to the episode. introduction: in critically ill patients or in patients undergoing major surgery, monitoring of co is recommended [ ] [ ] [ ] . less-invasive advanced hemodynamic monitoring with pwa is increasingly used in perioperative and critical care medicine. in this study, we evaluate the measurement performance of an uncalibrated pulse wave analysis (pwa) device (mostcareup, vygon, ecouen, france) compared with cardiac output (co) assessment by pulmonary artery thermodilution (patd) in patients after cardiac surgery. methods: in patients after cardiac surgery, we performed seven sets of patd measurements to assess patd-co. simultaneously, we recorded the pwa-co and compared it to the corresponding patd-co. to describe the agreement between pwa-co and patd-co we used bland-altman analysis showing the mean of the differences and %-limits of agreement and calculated the percentage error. results: we included patients in the analysis. the bias between pwa-co and patd-co was . l*min- . upper and lower % limits of agreement were + . l*min- and - . l*min- . the percentage error was . %. conclusions: pwa-co estimated with using the mostcareup device shows good agreement with pulmonary artery thermodilutionderived co in patients after cardiac surgery. introduction: non-invasive continuous blood pressure monitoring devices have been investigated, however, these devices did not have sufficient accuracy and precision. we developed a continuous monitor using the photoplethysmographic technique and tested the accuracy and precision of this system to ensure it was comparable to conventional continuous monitoring methods used for critically ill patients. methods: the study device was developed to measure blood pressure, pulse rate, respiratory rate, and oxygen saturation, continuously with a single sensor using the photoplethysmographic technique. patients who were monitored with arterial pressure lines in the icu were enrolled. the physiological parameters were measured continuously for minutes at -minute intervals using the study device and the conventional methods. the primary outcome variable was blood pressure. results: pearson fs correlation coefficient between the conventional method and photoplethysmography device were . for systolic blood pressure, . for diastolic blood pressure, . for mean blood pressure, . for pulse rate, . for respiratory rate, and . for oxygen saturation. percent errors for systolic, diastolic and mean blood pressures were . % and . % and . %, respectively. percent errors for pulse rate, respiratory rate and oxygen saturation were . %, . % and . %, respectively. conclusions: the non-invasive, continuous, multi-parameter monitoring device presented high level of agreement with the invasive arterial blood pressure monitoring, along with sufficient accuracy and precision in the measurements of pulse rate, respiratory rate, and oxygen saturation. conclusions: stroke volume measurement using bioreactance technique had strong correlation with odm while pwtt had moderate correlation. both devices had small bias with wide limits of agreement and percentage error compared with odm. therefore, these devices are not interchangeable with odm. however, using trends in stroke volume to guide treatment might still be acceptable. introduction: hemorrhage is the most common cause of trauma deaths and the most frequent complication of major surgery. it is difficult to identify until profound blood loss has already occurred. we aim at detecting hemorrhage early and reliably using waveform vital sign data routinely collected before, during, and after surgery. methods: we use waveform vital sign data collected at hz during a controlled transition from a stable (non-bleeding) to a fixed bleeding state of pigs. these vital signs include airway, arterial, central venous and pulmonary arterial pressures, venous oxygen saturation (svo ), pulse oximetry pleth and ecg heartrate, continuous co, and stroke volume variation (lidco). we used gated recurrent units (gru), long short-term memory (lstm) and dilated, causal, one-dimensional convolutional neural (table ) . however, outside of the very low fpr range (cf. rocs in fig. and ), our models appear inferior to a referenced random forest (rf) classifier. conclusions: our work demonstrates the applicability of deep learning models to diagnose hemorrhage based on raw, waveform vital signs. future work will address why the rf classifier can address the greater homogeneity of subjects when they bleed compared to an apparently wide dispersion of their statuses when being stable. this work is partially supported by nih gm . can myocardial perfusion imaging with echo contrast help recognise type acute myocardial infarction in the critically ill? introduction: many instances of significant bleeding may not occur in highly monitored environment, contribution in the delay in recognition and intervention. we therefore proposed a noninvasive monitoring for early bleeding detection using photoplethysmography (ppg). methods: fifty-two yorkshire pigs were anesthetized, stabilized and bled to hemorrhagic shock, and their invasive arterial blood pressure (abp), and ppg data were collected [ ] . time series of vital signs were divided into data frames of minute updated every seconds and beat to beat features were computed. the final feature matrix contained abp features and ppg features. a supervised machine-learning framework using least absolute shrinkage and selection operator regularized logistic regression model was constructed to score the probabilities for hemorrhage of each data frame. data in stabilization was set as negative and data in bleeding was set as positive. model performance was evaluated by receiver operating characteristic (roc) area under the curve (auc) with leave-one-out cross validation, and its precision was assessed with activity monitoring operative characteristic (amoc). results: two different models were proposed using abp and ppg features separately. figure showed the ppg model could classify the hemorrhage with auc = . , where the auc of abp model was . . figure showed the ppg model could detect the hemorrhage on average . minutes (equals to ml blood loss) if the false alarm rate of / was tolerated, whereas the average detection time of abp model were . minutes at same threshold of false alarm rate. conclusions: we proposed a novel non-invasive bleeding detection approach using ppg signals only. this method potentially can improve the identification of hemorrhage with in patients and environments where invasive monitoring is unavailable. table , catheter and procedure characteristics are shown in table . the median angle of bed position was °. no patients were positioned in neutral or tp. all procedures were successful with a mean of . punctures per patient, and a maximum of . the median procedure time was . minutes. no major complications occurred in any of our patients. conclusions: central venous catheterisation in moderate upright position is feasible and can be done safely when using realtime ultrasound by well-trained physicians. we recommend performing clinical assessment and pre-procedural ultrasound to choose the optimal puncture site and position in order to attain an optimal ultrasound visualisation of the vessel and patient comfort. methods: a retrospective analysis of patients presenting to tertiary-care emergency department who required cvc for vasopressor administration was carried out. all central venous cannulation into the right brachiocephalic vein was performed with ultrasound guidance using the high frequency linear probe. right brachiocephalic vein was visualised in its long axis. the needle was positioned just beside the centre of ultrasound probe degrees below the coronal plane and degrees angle to the ultrasound probe and advanced just behind the clavicle. results: the mean puncture time taken to perform this procedure, calculated from the needle piercing the skin until to the aspiration of blood from the brachiocephalic vein through the needle, was ± . s. no procedure-related complications were detected. conclusions: the oblique needle trajectory of right brachiocephalic vein cvc in adult is feasible and able to visualised well the anatomical structure, hence avoid complications. introduction: central venous cannulation, a routine procedure on intensive care units, is associated with a low complication rate. as a consequence, the routine use of chest x-ray (cxr) or ultrasound (us) to assess these complications is under discussion. our aim was to identify risk factors for central venous catheter (cvc) placement associated complications that can help decide whether or not follow-up using cxr and/or us is indicated. methods: multicenter prospective, observational study. consecutive critically ill adult patients who underwent cvc placement. either the internal jugular vein or subclavian vein was cannulated. complication rates were determined. predicting factors were obtained through a questionnaire filled in by physicians after placing a cvc. if the questionnaire was incomplete or data was missing, analyses were performed using the available data. patient characteristics were duplicated if a patient recieved more than one cvc. outcomes were iatrogenic pneumothorax and malposition. pneumothorax was detected using us, whereas cxr was used to determine cvc malposition. table . usguidance, insertion site, and setting were predictive for complications. the overall cvc placement associated complication rate is low and multiple risk factors associated with the occurrence complications were identified. a complication rate this low, strongly suggests that routine post-procedural diagnostics is superfluous. therefore, we suggest, provided that uneventful execution of the procedure is assured, post-procedural diagnostics are only necessary in selected cases with (multiple) risk factors. introduction: the use of ultrasound for subclavian vein cannulation (scv) has developed poorly due to the difficulty of visualizing this vein via the classical infraclavicular approach. we explored the feasibility of ultrasound-guided subclavian vein catheterization via a supraclavicular approach methods: prospective study conducted over six-month period in intensive care unit. after approval of the ethics committee, we included patients over years of age and requiring central venous access. exclusion criteria were: hemostasis disorders, puncture area infections and cervico-thoracic vascular malformations the procedure consisted of catheterization of the vsc with a supraclavicular approach under ultrasound guidance using an ultrasound in plane approach (fig and ). data collection included clinical and ultrasound data: scv depth, diameter and length, catheterization time, number of needle redirection, cannulation success and complications. results: thirty four patients were included. age: ± (mean ± sd), % of whom were male. the success rate of scv catheterization was % (one failure). the depth of the scv was ± . mm and its diameter was ± . mm. the puncturable length of the scv was ± mm and the puncture angle was ± °. the time required to obtain an adequate ultrasound image was ± seconds. the interval between the beginning of the puncture and the insertion of the guidewire into the vein was ± sec. the total catheterization time was ± seconds. the number of needle redirection . +/- . redirects. the quality of the ultrasound image was excellent or good in . % of cases. an arterial puncture was observed in two patients conclusions: this preliminary study demonstrated the feasibility of the subclavian vein cannulation via the supraclavicular approach. more study are required to confirm its safety and to compare this approach to the infraclavicular acces using ultrasound. introduction: lung ultrasound b-lines, a comet-like reverberation artefacts arising from water-thickened interlobular septa, indicate extravascular lung water which is a key variable in heart failure management and prognosis. aim of this study is to measure the correlation between lung ultrasound b-lines and nyha functional classification. methods: this is a months prospective study on congestive heart failure patients conducted in urban emergency departments in malaysia. following enrolment, patients had their functional capacity categorised based on nyha classification, followed by point of care ultrasound (pocus) lung scan using a mhz linear probe. the scanning was performed by trained emergency physicians. the longitudinal scan done at the recommended zones of both left and right lungs and the total number of b-lines identified were summed up as the comet score. comet score of , , and were categorised based on amount of blines of less than , - , - and more than b-lines respectively. results: hundred and twenty-two patients were analysed ( males( . %) and females( . %)) ranging from to years old. comet score of , and were found to be statistically significant with presence of paroxysmal nocturnal dyspnoea, elevated jugular venous pressure, lung crackles, bilateral pitting oedema and chest radiographic findings. a moderate correlation between nyha classes with comet score , and (rs= . (p< . )) was documented. conclusions: our study demonstrated a moderate correlation between nyha classes and lung ultrasound b-lines. lung ultrasound may be a potential tool to objectively determine the functional capacity in patients with congestive heart failure and monitor its changes in response to treatment and disease progression. the introduction: point of care ultrasound (pocus) is a tool of increasing utility in the management of the critically ill patient. guidelines exist for training and accreditation in pocus [ , ] however the widespread use of pocus has been hampered by a lack of mentors. online communication with end-to-end security, such as whatsapp ™ are increasingly used in medicine as a communication aid [ ] . some individuals are using such communications to share pocus images for review-the overall sentiment around these tools is unknown. methods: an online survey of pocus users was conducted via twitter ™. the question was "in situations where an expert opinion on an ultrasound is not immediately available, is it acceptable to get an expert review via an online medium such as whatsapp, and would you be happy to be that expert?" results: votes were received. voters were a mix of pocus users from the usa, europe, and australia. % said the medium was acceptable, and that they would be happy to provide expertise. % voted "no", with % voting "other" (fig ) . conclusions: in this international survey of pocus users, % were happy to provide and receive mentorship using remote software such as whatsapp. distance mentorship for pocus training should be explored. [ ] . a description of the development and refinement of insight -a feasibility and clinical effectiveness randomized controlled trial. methods: a modified delphi exercise was used to select the most beneficial ultrasound windows and imaging questions to ask for each window in scheduled inter-professional ultrasound. nurses, doctors and physiotherapists from critical care were given the same information regarding potential utility of each window. the windows and associated questions were individually ranked; each window and question tested against three further criteria; and filtered by ease of training to level standard; clinical usefulness; time of practical delivery and applicability across an inter-professional group. results: the modified delphi exercises and prioritization exercise ranked ease of adoption by training; feasibility within the time frame and clinical usefulness to develop a core insight scan of domains, each with set binary questions (tables and ) conclusions: we have developed a research intervention that will allow us to test the effectiveness of inter-professional scheduled whole body assessment of critically ill patients by ultrasound. we now plan to conduct a clinical effectiveness trial with an internal pilot to confirm feasibility. to search for optimal pressing time, the plots from the color sensor during nail bed compression were analyzed. we found two phases in the color sensor plots. in the initial part of compression, the plots changes rapidly (rapid phase) and then the slope of plots reduces (slow phase). the pressure release during the rapid phase could destabilize the measurement. the longest period of the rapid phase was . s among all the study subjects. thus, a pressing time of s seems to be needed to obtain stable crt measurements. conclusions: on our study for the investigation of standard pressing time and strength for crt measurements, pressing the nail bed with - n and s appears to be optimal. detection of pancreas ischemia with microdialysis and co sensors in a porcine model introduction: pancreas transplantation is associated with a high rate of early graft thrombosis. current postoperative monitoring lack tools for early detection of ischemia, which could precipitate a graft-saving intervention. we are currently exploring the possibility of ischemia detection with microdialysis and co -sensors in the organ tissue or on the surface in a porcine model. methods: in anesthetized pigs, co -sensors and microdialysis catheters are inserted into the parenchyma or attached to the surface of the pancreas. pco is measured continuously and lactate is sampled with microdialysis every min. ischemia is induced by sequential arterial and venous occlusions for minutes, with minutes of reperfusion in between. results: pco increased and decreased in response to ischemia and reperfusion within minutes. lactate increased and decreased with the same pattern, but with a considerable delay as compared to pco . an example is depicted in figure . the values are presented in introduction: reliable automated handheld vital microscopy (hvm) image sequence analysis is a prerequisite for use of sublingual microcirculation measurements at the point-of care according to the current consensus statement. we aim to validate a recently developed advanced computer vision algorithm [ ] versus manual analysis in a wide spectrum of populations and contexts. methods: our collaborators were invited to contribute raw data of published or ongoing institutional review board approved work. inclusion criteria were use of the cytocam hvm device, manual analysis with the ava software, and image quality as independently assessed by massey score of < in > % of recordings in a random subset of each study. subjects from studies were included, covering clinical and experimental populations, major shock forms and interventions to recruit the microcirculation (table ) . results: , , red blood cells were tracked by the algorithm across , frames in measurements in real time. a good to excellent correlation was found between algorithm-determined and manual capillary density (p< . , r . - . , figure ). capillary perfusion was classified using space-time diagram derived red blood cell velocity (rbcv), yielding good correlation with manual analysis for functional capillary density und proportion of perfused vessels. microcirculatory alterations during disease and interventions were equally detected by the algorithm and manual analysis. change in flow short of severe abnormality was reflected in absolute rbcv but not microcirculatory flow index. conclusions: we demonstrate the validity of automated software for hvm image sequence analysis across broad populations, disease conditions and interventions. thus, microcirculatory assessment at the bedside may finally complement point-of-care evaluation of disease severity and treatment response in critically ill patients and during surgery. introduction: in , naumann et al introduced the poem score as a real-time, point-of-care score to assess sublingual microcirculation [ ] . our study aimed to determine the reproducibility of the poem score. methods: two expert operators used a sidestream darkfield (sdf) videomicroscope (cytocam, braedius, netherlands) to separately acquire four high-quality video clips and assign a poem score to each image in adult mechanically ventilated patients. each operator was blinded to the other's images and analysis. video clip scores and acquisition times were recorded. results: of the patients enrolled in this study, % (n= ) required vasopressors. we categorized poem scores - as "normal" and poem scores - as "impaired." (fig ) . with only one instance of interrater disagreement (i.e., a single image scored as versus ), cohen's kappa ( . ) confirmed a strong correlation between interpreters. the mean time to complete a study session was minutes. conclusions: the present inability to quickly characterize the quality of sublingual microcirculation as either normal or impaired at the point of care limits real-world clinical application of this resuscitative endpoint. the rapidly obtained poem score appears to be reproducible between bedside interpreters. future studies should assess the effect of poem score-guided resuscitation. . sublingual microcirculatory images were obtained using a cytocam-idf device (braedius medical, huizen, the netherlands) and analyzed using standardized published recommendations. results: the median age of participants was years. we found no significant difference in proportions of hemodynamic responders before and after marathon ( % vs %, p= . ). also we did not find differences between plr induced changes of total vessel density (tvd) and proportion of perfused vessels (ppv) of small vessels before and after marathon. correlations between changes of sroke volume and changes of tvd or ppv of small vessels during plr were not significant. conclusions: marathon running did not change microcirculatory responsiveness. introduction: clinical measurement of mitochondrial oxygen tension (mitopo ) has become available with the comet system [ ] . a question with any novel technique is whether it is feasible to use in clinical practice and provides additional information. in elective cardiac surgery patients we measured cutaneous mitopo and tissue oxygenation (sto ). methods: institutional research board approved observational study in patients undergoing cardiopulmonary bypass (cpb). mitopo measurements were performed on the left upper arm (comet, photonics healthcare b.v.) by oxygen-dependent delayed fluorescence of aminolevulinic acid (ala)-induced protoporphyrin ix [ ] . priming of the skin was done with ala (alacare, photonamic gmbh) applied the evening before surgery. sto measurements (invos, medtronic) were done in close proximity to the comet sensor. results: at the time of writing of patients were enrolled and mitopo measurements were feasible in this clinical setting. mitopo appeared sensitive with a high dynamic range. for example, highdose vasopressor therapy decreased mitopo and blood transfusion increased a low mitopo but not a high mitopo . in the example in figure , mitopo is clearly dependent on cpb flow and the restored cardiac circulation is able to maintain good cutaneous oxygenation after cpb even before returning of cellsaver blood. sto had the tendency to provide relatively stable values within a small bandwidth and little response to even major hemodynamic changes. conclusions: mitopo shows the effect of interventions on mitochondrial oxygenation and provides additional information compared to standard monitoring and sto . introduction: traumatic asphyxia is a rare condition in which breathing and venous return is impaired due to a strong compression to the upper abdomen or chest region, and induces swelling, purplish red appearance, and petechiae around the face and neck. to our knowledge, there are no reports describing details of traumatic asphyxia including the clinical course and the therapeutic reactivity from cardiac arrest. we focused on cardiac arrest among all traumatic asphyxia patients treated at our hospital, and investigated their clinical features and therapeutic reactivity. methods: sixteen cases of traumatic asphyxia involved with our hospital between april and march were reviewed by using the pre-hospital activity record, medical record, and hyogo prefectural inspection record. these patients were divided into three groups. the first group had already cardiac arrest at the time of rescue from the trapped place (group a; cases). the second group became cardiac arrest after the rescue (group b; cases). the third group did not experience cardiac arrest (group c; cases). results: all cases had abnormal findings in skin or conjunctiva (table ) . total mortality rate reached %, but among cases of group a and b who resulted in cardiac arrest, there were cases with injury severity score or more and abbreviated injury scale in the chest or more. they had pneumothorax, flail chest, pericardial hematoma. seven of them restored spontaneous circulation, and two cases achieved neurologically full recovery. conclusions: there are some cases of traumatic asphyxia whose therapeutic reactivity is very good even after cardiac arrest, so it is important not to spare efforts for life support in such cases. rhythm and % witnessed arrest, five hundred ten ( %) patients had a good functional outcome at -months. physiological derangements were each negatively associated with outcome in bivariate analysis at the p < . level. a summary score of physiological derangements was included with potential confounders in the final regression model, and was independently associated with outcome with the chance of a good outcome decreasing by % for each increase of one physiologic derangement ( % ci . - . ). conclusions: uncorrected physiological derangements are independently and cumulatively associated with worse outcome after cardiac arrest. although causality cannot be established, it is reasonable to consider that the correction of physiological parameters may be an important step in the chain of survival after resuscitation. characteristics introduction: glan clwyd hospital (gch) was recently designated one of three cardiac arrest centres for wales. it has offered a / percutaneous coronary angiography (pci) service to a geographically dispersed north wales population of approximately , since june . prior to this, urgent coronary angiography was available on a more limited basis to patients requiring pci. the aim of this study was to investigate factors associated with hospital mortality after critical care admission following cardiac arrest. methods: retrospective review of the ward watcher critical care database at gch to identify patients who had undergone cpr in the hours prior to critical care admission in - . patients likely to have sustained ooha of cardiac aetiology (ooha-c) were identified from primary and secondary diagnoses and free text entry. data were subsequently analysed using excel and spss. the project was registered as a service evaluation with gch audit department. results: there were cardiac arrest admissions over this period, increasing from in - to in - . of these were ooha, of which were considered ooha-c. although ooha-c hospital mortality appeared to decrease over the time period ( %% to %), this was not statistically significant (p= . ). factors associated with survival to hospital discharge are presented in the tables below. on logistic regression, only pci and low ph within the first hours of critical care remained statistically significant (p= . and p< . respectively). conclusions: although we have been unable to make a distinction between patients presenting following stemi and nstemi, and appreciating a potential influence of selection bias, the significant association between pci and survival to hospital discharge supports the introduction of clinical pathways enabling pci access following ooha-c [ ] . chest radiography. [ ] here, we aimed to derive and validate rules to estimate p_max.lv using anteroposterior chest radiography (ches-t_ap), which is performed for critically-ill patients urgently needing determination of personalised p_max.lv. methods: a retrospective, cross-sectional study was performed with non-cardiac arrest adults who underwent chest_ap and computed tomography (ct) within h (derivation:validation= : ). on chest_ap, we defined cd (cardiac diameter), rb (distance from right cardiac border to midline) and ch (cardiac height, from carina to uppermost point of left hemi-diaphragm) (fig , ) . [ ] setting p_zero ( , ) at the midpoint of xiphisternal joint and designating leftward and upward directions as positive on x and y axes, we located p_max.lv (x_max.lv, y_max.lv). the coefficients of the following mathematically-inferred rules were sought: x_max.lv=a *cd-rb; y_max.lv=ß *ch+γ . (a : mean of (x_max.lv+rb)/cd; ß , γ : representative coefficient and constant of linear regression model, respectively ) . conclusions: evaluable echocardiographic records were reached in most of the patients. etco positively correlated with all parameters under consideration, while the strongest correlation was found between cimax and etco . therefore, cimax is a candidate parameter for real-time monitoring of haemodynamic efficacy of chest compressions during cpr. introduction: the uk resuscitation council has set out guidelines for management of patients post cardiac arrest [ ] . this is in line with european resuscitation council guideline. we set out to find if we are following the guideline. methods: we did a retrospective audit over the course of years looking at the data of patients who had in hospital and/or out of hospital cardiac arrest and after the return of spontaneous circulation were admitted to the intensive care unit (icu). we focused on whether the care they received was as per the standards set by the uk resuscitation council. results: we had in the hospital and out of hospital cardiac arrests; patients had less than minutes of cpr, had more than minutes cpr and patients the data was not recorded; patients needed more than minutes to reach from the site of arrest to the icu. the partial pressure of carbon dioxide was > . kpa in patients at two or more occasions. target map was not documented in patients; blood sugar target was not documented in patients and was not maintained within limits in patients. target temperature was not documented in patients. the withdrawal of treatment was not delayed for hours in patient out of . in patients neurological tests were not documented. multimodal assessment tools were not used in patient. electroencephalography and serum neuron specific enolase were not used to diagnose brain deaths as they were not available at our trust. patients were discharged, died in the icu and died in hospital after discharge from icu. conclusions: the audit reflected our local practice and showed that our mortality was in line with the acceptable limits; poor documentation of plan of care which posed problems in analyzing the care that these patients received; some of the parameters were not being maintained as set by uk resuscitation guideline. introduction: high-quality chest compressions (cc) with minimized interruptions are one of the most essential prerequisites for an optimal outcome of resuscitation. therapy of reversible causes of cardiac arrest often requires intra-hospital transportation (iht) during ongoing cpr. the present study investigated cc quality during transportation depending on the position of the provider. methods: paramedics were enrolled into a manikin study with four groups: a reference group with the provider kneeling beside manikin on the floor (group ), and groups performing cc during a simulated iht of meters: walking next to the bed (group ), kneeling beside the patient in bed (group , fig. ) or squatting above the patient in bed (group , figure ). indicators of cc quality were measured as defined in the erc guidelines (pressure point and depth, compression frequency, complete relief, sufficient pressure depth) [ ] . all paramedics performed cc during each scenario (group - ). results: there were no statistical differences in quality of cc between groups , and . notably, group performed significantly worse in respect to the proportion of cc with correct pressure point (p = . vs group ), correct cc depth (p= . vs. group , p= . vs. group , p= . vs. group ). the results are shown in table . conclusions: carrying out guideline-compliant cc [ ] during iht is feasible with multiple provider positions. based on the present results, kneeling or squatting position next to the patient ( figure and ) is recommended, whereas "walking next to the bed" while performing cc should be avoided. methods: a retrospective review of clinical notes was undertaken for patients admitted to icu following return of spontaneous circulation but whom remained comatose. this audit encompassed three-month periods before and after introduction of the care bundle in october . audit standards were assigned from target parameters documented in the bundle and reflected guidance from the cheshire and merseyside critical care network. results: patients were included in our audit; admitted prior to and admitted following implementation of the care bundle. in patients whom targeted temperature management was indicated, improved adherence to thermoregulation between - °c was observed ( vs %). significant improvements were since in the observance to target values for oxygen saturation ( vs . %, p= . ) and mean arterial pressure ( vs . %, p< . ) following the introduction of the care bundle. improved observance of ventilation targets was also seen; maintenance of p a co > . kpa ( vs %, p= . ) and tidal volumes < ml/kg ideal body weight ( to . %, p= . ). conclusions: the introduction of a post-cardiac arrest care bundle in our icu has improved care by providing discrete physiological targets to guide nursing staff and standardising management between clinicians. variations in care are associated with poorer patient outcomes [ ] and introduction of this bundle has reduced disparities in practice. array of cardiac diseases and reported survival rate is low in spite of advances in resuscitation and ems services. methods: single-centre retrospective study analyzed outcomes of ohca patients admitted to cardiac icu between .- . we studied demographic data, initial rhythm, type of cpr, comorbidities and various post admission diagnostic findings in order to identify their impact on survival. results: ohca comprised , % of all admissions. mean los was . days ( - ). mean age was , y ( - ), m: f ratio : and bystander cpr was performed in only % ohca patients. the most common initial rhythm was vf ( . %), followed by vt ( . %), pea was found in , % and asystole in . % of pt more than half of pt received adrenalin ( %) and defibrillation ( %) and only % required a temporary pacemaker. % of pt had an ecg consistent with mi after rosc, % underwent coronary angiography resulting in pci in % of cases. in pt ( %) therapeutic hypothermia protocol was performed. most ohca pt had hypertension ( %) and hyperlipidaemia ( %) as the most common risk factors followed by cardiomyopathy ( %), diabetes ( %) and cad ( %). only % had a preexisting significant valvular disease and the rest were extracardial comorbidities: chronic renal disease ( %), copd ( %) and cerebrovascular disease ( %). patients survived ( %) and gcs on admission was the only significant impact factor on survival along with comorbidities (mean gsc was in survivors vs. in deceased). interestingly, age, initial rhythm, troponin i level, ph and therapeutic hypothermia had no impact on survival. conclusions: our data demonstrate the importance of early onsite resuscitation as the most important factor of neuroprotection and outcome and puts an emphasis on the importance of cpr education for layman population. prediction of acute coronary ischaemia and angiographic findings in patients with out-of-hospital cardiac arrest j higny , a guédès , c hanet , v dangoisse , l gabriel , j jamart introduction: coronary artery disease (cad) is the leading cause of out-of-hospital cardiac arrest (ohca). however, diagnosis of acute coronary ischaemia (aci) remains challenging, particularly in patients without st-segment elevation on the post-resuscitation ecg. in this regard, a consensus statement recommends the implementation of a work-up strategy in the emergency room (er) to exclude noncoronary causes of collapse within hours. methods: retrospective single-centre study performed on consecutive patients with resuscitated ohca who underwent a diagnostic coronary angiography (ca). we present data on coronary angiograms for patients who underwent cardiac catheterization after resuscitation. afterwards, we sought to identify parameters associated with aci. results: st-segment elevation was noted in patients ( %). stsegment depression or t-wave abnormalities were noted in patients ( %). invasive coronary strategy allowed to identify an acute culprit lesion in cases ( %). patients with st-segment elevation underwent an immediate angioplasty for an acute coronary occlusion. patients without st-segment elevation underwent an ad hoc percutaneous coronary intervention for a critical lesion. stable cad was found in cases ( %) and a normal angiogram was found in only cases ( %) (figure ). conclusions: aci was the leading precipitant of collapse. stsegment elevation was highly predictive of coronary occlusion. in addition, a culprit coronary lesion was identified in nearly % of patients undergoing ca despite the lack of stsegment elevation. finally, our findings suggest that the identification of risk criteria may help to improve the recognition of aci after ohca. the prediction of outcome for in-hospital cardiac arrest (pihca) score e piscator , k göransson , s forsberg , m bottai , m ebell , j herlitz , t djärv figure. predictive value for classification into < % likelihood of favorable neurologic survival was . %. false classification into < % likelihood of favorable neurologic survival was . %. the phica score has potential to be used as an aid for objective prearrest assessment of the chance of favorable neurologic survival after ihca, as part of decision making for a dnar order. introduction: prognosis of survival in patients with cardiac arrest remains poor. during and after cardiopulmonary resuscitation, pathophysiological disturbances in relation with a cytokine storm, are described as "post-resuscitation" disease like a combination of cardiogenic and vasodilatory shocks. veno-arterial extracorporeal membrane oxygenation (va ecmo) allows to restore adequate perfusion but little is known about its effect on left ventricular (lv) function and about the role of cytokines. methods: this study was performed in an experimental model of cardiac arrest performed in groups of anesthetized and mechanically ventilated pigs. cardiac arrest was obtained by application of electrical current to epicardium inducing ventricular fibrillation. after a no-flow period of minutes, medical resuscitation with catecholamines and vasopressors was performed in "control" group while va ecmo was started in "ecmo" group and va ecmo in combination with cytosorb (extracorporeal blood purification therapy designed to reduce excessive levels of inflammatory mediators such as cytokines) was started in "ecmo-cyto" group. lv function was assessed with transthoracic echocardiography and arterial pressure with aortic pressure catheter. results: hemodynamic stability was obtained after ± and ± minutes in ecmo and ecmo-cyto groups, respectively. no return of spontaneous circulation was observed in control group. at minutes following cardiac arrest, lv area fractional change on short axis was normalized in ecmo and ecmo-cyto groups ( ± and ± %, respectively). vasopressor requirements were significantly lower in ecmo-cyto group than in ecmo group. conclusions: after cardiac arrest (no-flow) of minutes duration, va ecmo allowed complete lv recovery and hemodynamic stability within minutes of "post-resuscitation" disease. cytosorb added to va ecmo could contribute to reduce post-resuscitation vasodilatation. impact of rapid response car system on ecmo in out-of-hospital cardiac arrest: a retrospective cohort study m nasu , r sato , k takahashi introduction: extracorporeal life support (ecls) has been reported to be more effective than conventional cardio-pulmonary resuscitation (cpr). in ecls, a shorter time from arrival to implantation of extracorporeal membrane oxygenation (ecmo; door-to-ecmo) time has been reported to be associated with better survival rates. this study aimed to examine the impact of the physician-based emergency medical services (p-ems) using a rapid response car (rrc) on door-to-ecmo time in patients with out-of-hospital cardiac arrest (ohca to study the interest and the educational contribution in the short and medium term of medical simulation compared to a classical training. methods: cohort, prospective, observational, single-center, randomized study with control group including residents ( in anesthesia resuscitation and in emergency medicine). all benefited from a theoretical training with a reminder of the latest recommendations on the management of cardiac arrest and anaphylactic shock. they were randomized into groups and received practical training on a high-fidelity simulator for the management of either cardiac arrest (acc group) or anaphylactic shock (ca group). each group was evaluated at weeks (t ) and at months on two scenarios: refractory ventricular fibrillation (fv) scored on points and grade anaphylactic reaction (ra ) scored on points. each group served as the control group for the pathology in which they did not receive specific simulator training. the results are expressed on average with their standard deviations with "p" < . . introduction: simulation is a tool for improving the quality and safety of care, and its recognized as an essential method of evidence-based education. emergency medicine is a discipline in which there is a constant concern for the safety of patients. the emergency physician is often called upon to take charge of critical situations that use knowledge, know-how and knowledge as skills that must be mastered and whose theoretical learning alone is insufficient. methods: it´s a prospective study including residents in emergency medicine performing their specialty courses in emergency services and emergency medical assistance in the region of sousse from january to june . they were randomized into two groups: the one benefiting from a traditional education and the other from an education based on simulation sessions. the chosen scenario was the management of a cardiac arrest. a pre-test and a post-test were performed in both groups. results: we included emergency residents who did not receive specialized training in the management of cardiac arrest, there was a female predominance with an average age of , there was no significant difference regarding the pretest between the two groups with . there was no significant difference with respect to the pre-test score between the two groups . ± . / for the control group versus . ± . / for the simulation group. there was a significant progression after the course with an average posttest score of . ± . in the simulation group while this score was . ± . in the control group with a statistically significant difference (p < . ). conclusions: simulation learning has led to a better acquisition of cognitive knowledge by learners. the simulation is not intended to replace bed-based teaching, nor theoretical or faculty teaching, but it is an essential complement . in tunisia, the simulation must continue its current integration in the initial and continuous training of doctors. introduction: recent studies have shown that obesity and its related metabolic dysfunction exacerbates outcomes of ischemic brain injuries in some brain areas, such as the hippocampus and cerebral cortex when subjected to transient global cerebral ischemia (tgci). however, the impact of obesity in the striatum after tgci has not yet been addressed. the objective of this study was to investigate the effects of obesity on tgci-induced neuronal damage and inflammation in the striatum and to examine the role of mtor which is involved in the pathogenesis of metabolic and neurological diseases. methods: gerbils were fed with a normal diet (nd) or high-fat diet (hfd) for weeks and then subjected to min of tgci. hfd-fed gerbils showed the significant increase in body weight, blood glucose level, serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol without affecting food intake. results: in hfd-fed gerbils, neuronal loss occurred in the dorsolateral striatum days after tgci and increased neuronal loss were observed cholesterol days after tgci; however, no neuronal loss was the in ndfed gerbils after tgci, as assessed by neuronal nuclear antigen immunohistochemistry and fluoro-jade b histofluorescence staining. the hfd-fed gerbils also showed severe activated microglia and further increased immunoreactivities and protein levels of tumor necrosis factor-alpha, interukin- beta, mammalian target of rapamycin (mtor) and phosphorylated-mtor in the striatum during pre-and postischemic conditions compared with the nd-fed gerbils. in addition, we found that treatment with rapamycin, a mtor inhibitor, in the hfd-fed gerbils significantly attenuated hfd-induced striatal neuronal death without changing physiological parameters. conclusions: these findings reveal that chronic hfd-induced obesity results in severe neuroinflammation and significant increase of mtor activation, which could contribute to neuronal death in the stratum following tgci. abnormal mtor activation might play a key role. associations between partial pressure of oxygen and neurological outcome in out-of-hospital cardiac arrest patients introduction: exposure to hyperoxemia and hypoxemia is common in out-of-hospital cardiac arrest (ohca) patients following return of spontaneous circulation (rosc) but its effects on neurological outcome are uncertain and study results are inconsistent. methods: exploratory post-hoc substudy of the target temperature management (ttm) trial [ ] , including patients after ohca with rosc. the association between serial arterial partial pressures of oxygen (pao ) during hours following rosc and neurological outcome at months, evaluated by cerebral performance category (cpc), dichotomized to good (cpc - ) and poor (cpc - ), was investigated. in our analyses, we tested the association of hyperoxemia pao > kpa and hypoxemia pao < kpa, time weighted mean pao , (twm-pao ) (fig ) , maximum pao difference (Δ pao ) and gradually increasing pao levels ( . - . kpa) with poor neurological outcome. a subsequent analysis investigated the association between pao and a biomarker of brain injury, peak serum tau levels. results: patients were eligible for analysis. patients ( %) were exposed to hyperoxemia or hypoxemia after rosc (table ) . our analyses did not reveal a significant association between hyperoxemia, hypoxemia, twm-pao exposure or Δ pao and poor neurological outcome at -month follow-up after correction for co-variates (all analyses p= . - . ) (fig ) . we were not able to define a pao level associated with the onset of poor neurological outcome. peak serum tau levels at either or hours after rosc were not associated with pao . conclusions: hyperoxemia or hypoxemia exposure occurred in one third of the patients during the first hours of hospitalization and was not significantly associated with poor neurological outcome after months or with the peak s-tau levels at either or hours after rosc. introduction: cerebral hypoperfusion may aggravate the developing neurological damage after cardiac arrest. near-infrared spectroscopy (nirs) provides information on cerebral oxygenation but its clinical relevance during post-resuscitation care is undefined. we wanted to assess the possible association between cerebral oxygenation and clinical outcome after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) where both moderate hyperoxia and high-normal arterial carbon dioxide tension (paco ) increased regional cerebral oxygen saturation (rso ) as compared with normoxia and low-normal paco , respectively. rso was measured from ohca patients with nirs during the first h of intensive care and neurological outcome was assessed using the cerebral performance category (cpc) scale at months after cardiac arrest. we calculated the median rso for patients with good (cpc - ) and poor (cpc - ) outcome and compared the results using the mann-whitney u test. we compared the rso over time with outcome using a generalised mixed model. finally, we added median rso to a binary logistic regression model to control for the effects of possible confounding factors. results: the median (interquartile range [iqr]) rso during the first h of intensive care was . % ( . - . %) in patients with good outcome compared to . % ( . - . %) in patients with poor outcome, p = . . we did not find significant association between rso over time and neurological outcome ( figure ). in the binary logistic regression model rso was not a statistically significant predictor of good outcome (or . , % ci . - . , p = . ). conclusions: we did not find any association between cerebral oxygenation during the first h of post-resuscitation intensive care and neurological outcome at months after cardiac arrest. fig. introduction: near-infrared spectroscopy (nirs) provides a noninvasive means to assess cerebral oxygenation during postresuscitation care but its clinical value is unclear. we determined the possible association between cerebral oxygenation and the magnitude of brain injury assessed with neuron-specific enolase (nse) serum concentration at h after out-of-hospital cardiac arrest (ohca). methods: we performed a post hoc analysis of a randomised clinical trial (comacare) comparing two different levels of carbon dioxide, oxygen and arterial pressure after ohca and successful resuscitation. we measured rso continuously with nirs from patients during the first h of intensive care. we determined the nse concentrations at h after cardiac arrest from serum samples using an electrochemiluminescent immunoassay kit. the samples were tested for haemolysis and all samples with a haemolysis index > mg of free haemoglobin per litre (n = ) were excluded from the analyses. we calculated the median rso for all patients and used a scatterplot and spearman's rank-order correlation to assess the possible relationship between median rso and nse at h. in addition, we compared the nse concentrations at h after cardiac arrest in patients with good (cerebral performance category scale [cpc] - ) and poor (cpc - ) neurological outcome at months using the mann-whitney u test. results: we did not find significant correlation between median rso and serum nse concentration at h after cardiac arrest, rs = - . , p = . (figure ). the median (iqr) nse concentration at h was . ( . - . ) μg/l and . ( . - . ) μg/l in patients with good and poor outcome, respectively, p < . . conclusions: we did not find any association between cerebral oxygenation during the first h of post-resuscitation intensive care and nse serum concentrations at h after cardiac arrest. the association between lactate, cerebral oxygenation and brain damage in post-cardiac arrest patients introduction: patients admitted to the intensive care unit (icu) after being successfully resuscitated from a cardiac arrest (ca) have a large cerebral penumbra at risk for secondary ischemic damage in case of suboptimal brain oxygenation. therefore, resuscitation during icu stay should be guided by parameters that adequately predict cerebral hypoxia. the value of lactate as resuscitation parameter may be questioned in post-ca patients since the brain critically depends on aerobic metabolism. we aimed to investigate the relationship between arterial lactate, cerebral cortex tissue oxygenation (scto ) by near infrared spectroscopy (foresight) and unfavorable neurological outcome at days (cpc score - ) methods: subanalysis from the neuroprotect post-ca trial. lactate values and scto were recorded hourly in post-ca patients during hours ttm and subsequent rewarming. results: in total paired lactate/ scto measurements were analysed. we found no correlation between paired lactate and scto² (fig. ) . moreover, temporary trends in lactate did not correlate with corresponding trends in scto during the same one-hour time interval (r²= . ) (fig ) . if lactate values above . mmol/l are considered to be abnormal, lactate could not adequately detect clinical important brain ischemia (scto < %): sensitivity % and specificity % (table , ). nevertheless, time weighted lactate at h (or . ; p . ), h (or . , p . ), h (or . ; p . ) and h (or . ; p . ) were inversely correlated with unfavorable neurological outcome at days (fig , ) . conclusions: although lactate was a marker of prognosis in post-ca patients, it should not be used to guide resuscitation since lactate values were not correlated with scto and changes in lactate do not correspond with changes in scto during the same time interval. simplified introduction: the aim of the study was to investigate whether simplified continuous eeg monitoring (ceeg) [ ] post-cardiac arrest can be reliably interpreted by icu physicians after a short structured training, and whether acceptable interrater agreement compared to an eeg-expert can be achieved. methods: five icu physicians received training in interpretation of simplified ceeg (fig ) consisting of lectures, hands-on ceeginterpretation, and a video tutorial -total training duration day. the icu physicians then interpreted simplified ceeg recordings. basic eeg background patterns and presence of epileptiform discharges or seizure activity were assessed on -grade rank-ordered scales based on a standardized eeg terminology [ ] . an experienced eeg-expert was used as reference. results: there was substantial agreement (κ . ) for eeg background patterns and moderate agreement (κ . ) for epileptiform discharges between icu physicians and the eeg-expert. sensitivity for detecting seizure activity by the icu physicians was limited ( %), but with high specificity ( %). among icu physicians interrater agreement was substantial (κ . ) for eeg background pattern and moderate (κ . ) for epileptiform discharges. conclusions: after a one-day educational effort clinically relevant agreement was achieved for basic eeg background patterns after cardiac arrest. assessment of epileptiform patterns was less reliable, but bedside screening by the icu physician may still be clinically useful for early detection of seizures. interpretation of simplified ceeg requires awareness of its limitations and support from an eeg-expert when clinically indicated. introduction: hypoxic-ischemic injury on head computed tomography (ct), which manifests with varying degrees of cerebral edema and loss of gray-white matter differentiation, is a poor prognostic sign after resuscitated out-of-hospital cardiac arrest that may influence early clinical decision-making. agreement among physicians on the presence of hypoxic-ischemic injury on early head ct is unknown. methods: we recruited faculty physician participants ( emergency medicine, critical care, neurocritical care, and general radiology; average . years of practice) across academic medical centers each with > admissions for resuscitated out-of-hospital cardiac arrest each year. participants, blinded to clinical context, reviewed unique head cts obtained within hours of cardiac arrest that were randomly selected from a local registry. a blinded neuroradiologist also reviewed all scans (gold standard). participants determined if hypoxic-ischemic injury was present on each ct, and agreement was determined using multi-and dual-rater kappa statistics with % confidence intervals. results: overall agreement among physicians regarding the presence of hypoxic-ischemic injury on head ct was fair (kappa . ; % ci, . - . ) with agreement consistent across most specialties (table ) . when compared to the neuroradiologist, individual physician agreement ranged widely, from poor (kappa . ) to substantial (kappa . ), with of physicians having fair or worse agreement compared to the gold standard interpretation. conclusions: the finding of hypoxic-ischemic injury on early head ct after cardiac arrest had high interobserver variability as interpreted by acute care physicians and general radiologists. pending the development of objective diagnostic criteria, clinicians should bear in mind the subjectivity and subtlety of cerebral edema or loss of graywhite matter differentiation soon after return of spontaneous circulation in these patients. figure ). baseline characteristics and differences between the wlst and no-wlst groups are shown in table . utilization of neuro-prognostication tests is shown in table . while ct and eeg were commonly employed, ssep and mri were used less frequently. basic multimodal neuroprognostication (arbitrarily defined as at least one ct or mri, plus eeg, plus ssep) was performed only in . % of all patients undergoing wlst but the rate increased significantly over six years (p< . ) and was higher in the time period after , compared to the one prior to ( figure ). this association remained significant after adjustment for confounders such as age, arrest rhythm, downtime, targeted temperature management, apache ii score and organ failure in a logistic regression model (p= . ). in an institution with access to a wide range of imaging and neurophysiology tests, mri and ssep remained underutilized but the rate of basic multimodal neuro-prognostication increased significantly over the study period, especially in the period after . introduction: although multiple reports using animal models have confirmed that melatonin appears to promote neuroprotective effects following ischemia/reperfusion-induced brain injury, the relationship between its protective effects and the activation of autophagy in cerebellar purkinje cells following the asphyxial cardiac arrest and cardiopulmonary resuscitation (ca/cpr) remains unclear. methods: rats used in this study were randomly assigned to groups as follows; vehicle-treated sham-operated group, vehicletreated asphyxial ca/cpr-operated group, melatonin-treated shamoperated group, melatonin-treated asphyxial ca/cpr-operated group, melatonin plus (+) p-pdot (the mt melatonin receptor antagonist)-treated sham-operated group and melatonin+ p-pdot-treated asphyxial ca/cpr-operated group. results: our results demonstrate that melatonin ( mg/kg, ip, time before ca and times after ca) significantly improved the survival rates and neurological deficits compared with the vehicle-treated asphyxial ca/cpr rats (survival rates ≥ % vs %). we also demonstrate that melatonin exhibited the protective effect against asphyxial ca/cpr-induced purkinje cell death. the protective effect of melatonin in the purkinje cell death following asphyxial ca/cpr paralleled a dramatic reduction in superoxide anion radical (o ·-), intense enhancements of cuzn superoxide dismutase (sod ) and mnsod (sod ) expressions, as well as a remarkable attenuation of autophagic activation (lc and beclin- ), which is mt melatonin receptor-associated. furthermore, the protective effect of melatonin was notably reversed by treatment with p-pdot. conclusions: this study shows that melatonin conferred neuroprotection against asphyxial ca/cpr-induced cerebellar purkinje cell death by inhibiting autophagic activation by reducing expressions of ros, while increasing of antioxidative enzymes, and suggests that mt is involved in the neuroprotective effect of melatonin in cerebellar purkinje cell death induced by asphyxial ca/cpr. introduction: fucoidan is a sulfated polysaccharide derived from brown algae and possesses various beneficial activities, such as antiinflammatory and antioxidant properties. previous studies have shown that fucoidan displays protective effect against ischemiareperfusion injury in some organs. however, few studies have been reported regarding the protective effect of fucoidan against cerebral ischemic injury and its related mechanisms. methods: therefore, in this study, we examined the neuroprotective effect of fucoidan against cerebral ischemic injury, as well as underlying mechanisms using a gerbil model of transient global cerebral ischemia (tgci) which shows loss of pyramidal neurons in the hippocampal cornu ammonis (ca ) area. fucoidan ( and mg/kg) was intraperitoneally administered once daily for days before tgci. results: pretreatment with mg/kg of fucoidan, not mg/kg fucoidan, attenuated tgci-induced hyperactivity and protected ca pyramidal neurons from ischemic injury following tgci. in addition, pretreatment with mg/kg of fucoidan inhibited activations of resident astrocytes and microglia in the ischemic ca area. furthermore, pretreatment with mg/kg of fucoidan significantly reduced the increased -hydroxy- -noneal and superoxide anion radical production in the ischemic ca area after tgci and significantly increased expressions of superoxide dismutase (sod ) and sod in the ca pyramidal neurons compared with the vehicle-treated-group. we found that treatment with diethyldithiocarbamate (an inhibitor of sods) to the fucoidan-treated-group notably abolished the fucoidanmediated neuroprotection in the ischemic ca area following tgci. conclusions: these results indicate that fucoidan can effectively protect neurons from tgci-induced ischemic injury through attenuation of activated resident glial cells and reduction of oxidative stress following increasing sods. thus, we strongly suggest that fucoidan can be used as a useful preventive agent in cerebral ischemia. the effects of cold fluids for induction of therapeutic hypothermia on reaching target temperature and complications-a sub-study of the tth study a holm , m skrifvars , fs taccone ). there was no difference in early bleeding incidences (fig ) . during late observation, ttm patients had fewer minor bleeding ( . % vs. %) and more intracranial bleeding ( . % vs. %; fig ) . adjusted calculated risk ratio for major bleeding (including intracranial) for ttm was . ( %ci . - . ) at baseline and . ( %ci . - . ) over time. conclusions: bleeding complications were common. although the risk ratio for major bleeding increased over time in ttm patients, residual and unmeasured confounding in addition to selection and detection bias may limit the clinical relevance of this finding. methods: patients with neurological deficit > by nhiss were included. the t°of the brain was recorded non-invasively using radiothermometer rtm- -res (russia). we measured t°in symmetric regions of left & right hemispheres, calculated the average t°of brain, fig. (abstract p ) . temperature of patients given and not given pre-icu fluids (table ) . conclusions: observed moderate brain t°heterogenecity in hp, marked increase brain t°heterogenecity in is & sharp decline of t°h eterogenecity in cci. supposedly, correcting the impairment of cerebral tb (increase or decrease t°) through physical (selective cerebral hypothermia, magnetic stimulation etc.) or pharmacological (sedation) can contribute to positive therapeutic results in is & cci. nonivasive radiothermometry of the brain can be an objective method of patients' condition evaluation & their rehabilitation potential. introduction: basilar artery stroke has a multitude of different presentations and may not be captured on plain computed tomography (ct). it can progress to severe disability, locked in syndrome and death [ ] . with the advent of thrombolytic and endovascular therapies, prompt diagnosis can change the outcome. we present a case of basilar artery stroke, which was heralded by tongue spasticity and dysarthria, indicative of pseudobulbar palsy. methods: case reviewed with consent. a literature search was conducted using pubmed and medline. results: a -year-old presented with pulmonary oedema and hypertension. he was transferred to our intensive care unit for treatment of a suspected anaphylaxis. his marked lingual swelling was associated with dysarthria. glyceryl-trinitrate and labetalol infusions were started for hypertension. he developed left sided weakness and deteriorated over several days to the point that he could only move his right foot (table ) . magnetic resonance imaging (mri) showed midbrain ischaemia and angiogram showed no flow in the basilar artery (fig , ) . conclusions: common presenting features of basilar artery occlusion include dysarthria, vertigo, vomiting, headache and motor defects; these may evolve gradually or be intermittent [ , ] . presentation with pseudobulbar palsy is described in early literature [ ] . delayed recognition of the stroke led to aggressive treatment of hypertension, potentially compromising perfusion to the penumbral area [ , ] . this case highlights the need for a wide index of suspicion with posterior strokes. consent: informed consent to publish has been obtained from the patient prognosis is related to gcs < or = on admission (p = . ) and to malignant cerebral edema (p = . ). conclusions: our study has shown some predictive factors closely related to mortality and morbidity in patients with acute ischemic stroke. gcs at admittance < or = and onset of malignant cerebral edema lead to a worst prognosis at discharge from nicu. coherence analysis of cerebral oxygenation using multichannel functional near-infrared spectroscopy evaluates cerebral perfusion in hemodynamic stroke tj kim table ). in addition, severe stroke patients were more likely to have higher phase coherence in interval iii (p = . ). conclusions: our results demonstrated that the higher phase coherence of oxyhb in myogenic signal, which was originated locally from smooth muscle cells in brain was related to impaired cerebral perfusion. this suggests that monitoring cerebral oxygenation using fnirs could be a useful noninvasive measuring tool for evaluating impaired cerebral autoregulation in stroke patients. is esmolol associated with worse outcome at the acute phase of ischemic stroke that receives thrombolysis? introduction: ischemic stroke patients experienced frequent early neurological deterioration (end) events. since ischemic stroke has also been shown as inflammatory disease, the neutrophil-tolymphocyte ratio (nlr) may associated with end events. however, the direct study regarding this association has not been addressed. poor grade sah, use of vasopressors, mechanical ventilation, intracranial pressure monitoring, external ventricular drainage, blood transfusions and renal replacement therapy were all more frequent among nonsurvivors (all p< . ). mortality was also higher with initial lactate above mmol/l, in those admitted to public hospitals and when admission to icu was delayed more than hours after ictus. after adjusting for common predictors (age, gender and wfns) saps non-neuro, sofa non-neuro, early vasopressor use and admission to a public hospital were independently associated with hospital mortality. moreover, the area under the curve for prediction of mortality with saps , sofa and wfns was . ( figure ). hospital, austria. the association of intensity and duration of intracranial hypertension episodes with -month glasgow outcome score (gos) was visualized using the methodology introduced by güiza et al. [ ] . results: in both cohorts, it could be demonstrated that the combination of duration and intensity defined the tolerance to intracranial hypertension, and that a semi-exponential curve separated episodes associated with better outcomes from those associated with worse outcomes. the association with worse outcomes occurred at a lower pressure-time burden than what has been previously observed in patients with tbi. nevertheless, the percentage of monitoring time spent by every patient in the zone associated with poor gos was independently associated with worse -month neurological outcome, even after correcting for age and fisher score ( introduction: apnea test is an essential component in the clinical determination of brain death, but it may incur a significant risk of complications such as hypotension, hypoxia and even cardiac arrest [ ] . we analyzed the risk factors associated with failed apnea test during brain death assessment in order to predict and avoid these adverse events. methods: medical records of apnea tests performed for brain-dead donor between january and january in our institution, were reviewed retrospectively. age, gender, etiology of brain death, use of catecholamine and results of arterial bleed gas analysis (abga), systolic/diastolic blood pressure (sbp/dbp), mean arterial pressure (map) and central venous pressure (cvp) prior to apnea test initiation were collected as variables. a-a gradient and pao /fio were calculated for more precise assessment of the respiratory system. in total, cases were divided into a group which was completed apnea test and the other which was failed the test. introduction: tunisia has already suffered recurrent outbreaks since . outbreak started relatively earlier this year. we were interpellated by the frequency of neuroinvasive presentation of the disease. methods: we report a case series of patients presented to icu with niwnd. results: we report cases of niwnd with different severe presentations overlapping neurological manifestation including encephalitis (n= / ), meningitis (n= / ) and flaccid paralysis (n= / ). almost all patients live in the locality of sousse. six patients presented a long course of isolated fever before developing neurological signs. cerebrospinal fluid was consistent with encephalitis within the patients. cerebromedullar mri identified brain lesions (n= / ), myelitis (n= / ) and polyradiculoneuritis (n= / ).three patients had electromyography for flaccid paralysis showed diffuse axonal polyneuropathy with motoneuron involvement. ten cases had a positive wnv igm antibody and nine had a positive wnv igg antibody in serum. urine polymerase chain reaction was positive for wnv in / patients. ten patients were mechanically ventilated. all patients were managed symptomatically. two received high doses of methylprednisolone for days, one patient received polyclonal immunoglobulin intravenous and one patient had plasmapheresis. two patients died consecutive to brainstem lesions. two patients recovered significantly and discharged with no complications. five other patients evolved to persistent flaccid paralysis with a minimal consciousness state and weaning difficulties requiring tracheostomy. the last remaining patient is still evolving. conclusions: modification of the regional climatic conditions accounted probably for the early outbreak of niwnd. this initial case series displays the severity and the poor outcomes of niwnd with higher incidence compared to past epidemics. noninvasive estimation of intracranial pressure with transcranial doppler: a prospective multicenter validation study c robba , c fig. ], mean bias was - . mmhg (limits of agreement are ± sd . mmhg). . % measures were outside the limit of agreement in the overall population. however, when icp was high, % of measures were out of the limit of agreement. the auc [ fig. introduction: surgical treatment of aortic aneurysm needs extracorporeal circulation (ecc), aorta clamp and hypothermia, and it is often related to poor systemic perfusion and blood flow velocity. one of the main concerns of intensive care team is to prevent secondary neurological injury after long time without blood flow pulsatility, such as brain edema and seizure. the most common parameters for neuromonitoring would be intracranial pressure and eeg, however, for non-neurological patients this information is unusual and prevents optimal management. methods: we aimed to assess brain compliance and neurological condition of icu patients on immediate post-operative recovery of bentall-de bono procedure and/or other aortic aneurysm surgical treatment using a novel non-invasive intracranial pressure (icp) device. this device uses mechanical displacement sensor capturing extracranial continuous volumetric variation of the skull and this information proportionally reflects intracranial dynamic [ ] . results: twenty patients were included in this study. ecc mean time was minutes for patients and only one did not need it. eleven presented altered icp curves with poor brain compliance (p /p ratio > . ) assessed by icp curve morphology analysis. volemic optimization and neuroprotective measures were taken based on this icp information for acute case management. among these patients with altered icp curves, eight were discharged from icu with good clinical condition and glasgow coma scale of . overall mortality rate was six out of twenty ( %) and three of these had altered icp curves. conclusions: brain monitoring of cardiovascular post-operative patients is important to prevent secondary neurological complications and can be a helpful tool for neuroprotective acute management on icu. the technique supplies electrical current to muscle, combined with passive cycling. prior to a clinical trial, we first investigated the effects of one session of fes in healthy volunteers. methods: healthy male volunteers (n= ) were recruited. the participants had their postural sway assessed on a pressure sensitive board, and measurement of maximal inspiratory pressure (mip). ultrasounds were taken assessing thickness of the quadriceps and rectus abdominis. they performed minutes of supine passive cycling, with fes supplying the lower limbs and abdomen. after a minute rest, the tests were repeated. a further participants performed just the initial baseline tests, to help assess muscular factors affecting balance and sway. results: the current needed for palpable contraction was significantly correlated to weight in the abdomen (r= . , p< . ) and quadriceps (r= . , p< . ). current required to stimulate the abdominal muscles was also correlated to depth of the subcutaneous fat layer (r= . , p< . ) and echogenicity of the muscle (r= . , p= . ). pre-cycling, left and right vastus lateralis thickness inversely correlated to postural sway in the antero-posterior (r=- . , p< . ) plane. compared to pre-cycling, postural sway in the antero-posterior and lateral planes increased significantly after cycling. there was a significant decrease in mip after cycling and greater reductions in mip were found in participants who had thinner rectus abdomni. conclusions: sway at baseline is related to quadriceps thickness, which atrophies during critical illness, and could worsen balance. mip is reduced during fes and the severity of reduction is related to the thickness of the abdominal wall muscles at baseline, suggesting that fes can fatigue the diaphragm and abdominal muscles. in awake healthy volunteers, fes is a safe, comfortable technique. introduction: in most cases postoperative cognitive dysfunction (pocd) is transient, but still some patients suffer from persistent cognitive impairment which is associated with increased length of hospital stay, early withdrawal from labor market and higher mortality. available data on the prevalence of pocd after cardiac surgery is very diverse from % to % upon discharge and up % months after surgery. we aimed to investigate the prevalence of short-term and long-term pocd after off-pump coronary artery bypass grafting (cabg) surgery. methods: psychometric testing was performed in (mean age . ± . ) patients before, days and months after the surgery. we used following tests to assess cognitive capacity: auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop's test and trail making test (tmt). a decline in comparison to preoperative test results for % or more in two or more tests was declared as pocd. results: the prevalence of pocd after days was . % ( patients) and . % ( patients) after months. when comparing patients who developed pocd with those who did not we found the former were older ( . ± . vs . ± . years; p< . ), had lower education level ( . ± . vs . ± . years; p< . ) and had longer surgery duration ( . ± . vs . ± . minutes; p< . ). the most affected cognitive domains were long term memory (avlt) and executive function (tmt) and least affectedworking memory (dst) and selective attention (stroop's test). conclusions: in our prospective study the prevalence of long-term pocd after cardiac surgery was slightly less ( . %) in comparison to available data (from % to %). it might be due differences in psychometric testing and interpretation of its results among authors. advanced age, low cognitive reserve and long duration surgeries are linked with higher incidences of pocd. introduction: postoperative cognitive dysfunction (pocd) is a common and widely described phenomenon in surgical patients. advanced age, major surgery, certain general anesthetics, genetic factors, sleep deprivation and other factors were described as contributing factors to pocd. the hospital stay itself is a major 'social' trauma for patients; social isolation, sleep deprivation and changes in daily regimen may effect neurocognitive behavior of patients. in this trial we tried to assess the link between pocd and the length of hospital stay in cardiac surgery patients. methods: patients who underwent 'off-pump' coronary artery bypass grafting (cabg) surgery selected for this trial. neuropsychological testing was performed prior to the operation and upon discharge. we used auditory verbal learning test (avlt), digit span test (dst), digit-letter substitution test (dlst), stroop test and trail making test (tmt). a % or more decline in two or more tests in comparison to preoperative test results was declared as pocd. patients were allocated into two groups according to the length of hospital stay: the short-stay group (group ) included patients (n= ) who were discharged on the th day after surgery or earlier and the long-stay (group ) group consisted of patients (n= ) who were discharged on the th day after surgery or later. patients received similar anesthesia, postoperative care and were operated by the same surgical team. reasons for prolonged duration of hospital stay were mainly surgical. results: patients ( . %) in group and patients ( . %) in group had pocd upon discharge (p< . ). mean length of hospital stay were ± . and ± . days in group and group patients respectively (p< . ). conclusions: prolonged length of hospital stay increased the prevalence of pocd in our trial. studies with various types of surgical procedures and larger patient populations needed to further understand the effect of length of hospital stay to pocd. the influence of multiple trauma with head trauma on posttraumatic meningitis: a nation-wide study with hospital-based trauma registry in japan introduction: posttraumatic meningitis is one of severe complications and results in increased mortality and longer hospital stay among head trauma patients. however, it remains unclear whether there is a difference in the incidence of post-traumatic meningitis due to single traumatic brain injury (tbi) and multiple trauma including head injury. methods: this study was a retrospective observational study during years we included trauma patients registered in japanese trauma data bank whose head ais score was > in this study. multivariable logistic regression analysis was used to assess potential factors associated with posttraumatic meningitis such as csf fistula, skull base fracture, type of injury that divided into single tbi and multiple trauma. introduction: the aim of this study was to determine if regional cerebral oxygenation (rsco ) can be used as an indicator of tissue perfusion in icu patients with tbi [ , ] , and to determine the prognostic value of cerebral oxygenation rsco in survival prediction. methods: patients were enrolled retrospectively from january through july in the icu of derince kocaeli training hospital. patients with trauma patients and traumatic braine injury patients who were admitted to the icu from the emergency room were included in the study. the sedation levels of the patients were followed up with bis. the rsco , bis was taken as well as blood lactate level, mean arterial blood pressure and cardiac output at baseline time, , , , and hours. results: no significant difference was also detected between the value of rsco in all patients . it was average sco (right) . ± . and average rsco (left) . ± . . conclusions: cerebral regional oxygen saturation might be helpful as one of the perfusion parameters in patients with tbi but it could have no prognostic value in mortality prediction. however, further studies with larger sample size are still needed to validate these results. introduction: tbi in elderly is an increasingly cause of admission in icu. data regarding management and prognosis of these patients are lacking. validated prognostic models refer to younger patients and do not adequately consider the influence of pre-injury functional status, which often compromises with aging. frailty has been defined as a state age-related of increased vulnerability and decline in autonomy of daily life activity. aim of the study is to evaluate the impact of frailty on outcome in tbi elderly patients. methods: moderate and severe tbi patients > years, admitted in neuroicu from january to may , were prospectively enrolled. data of age, comorbidity, glasgow coma scale (gcs), pupils' reactivity, ct scan characteristics, neurosurgical intervention and gose (extended glasgow outcome scale) at -months were collected. frailty status was measured by clinical frailty scale (cfs) [ ] and patients were divided as frail (cfs> ) and not frail (cfs< ). bad outcome was defined as gose< . results: ( %) of the studied patients were frail. frailty was not related to age. frail patients had more comorbidities and worse pupils' reactivity at admission (table ) . other variables did not differ between groups. in univariate analysis neurological diseases, gcs, tsah (traumatic subarachnoid haemorrhage), compressed/absent basal cisterns, non-reactive pupils and cfs were significantly associated to bad outcome. in multivariate analysis only gcs and cfs remained associated to bad outcome ( table ) . conclusions: pre-injury frailty is strongly associated to outcome in tbi elderly patients. the age of the patients was . ± . years. patients were operated on for intracranial traumatic ( cases) and non-traumatic hematomas ( ), brain tumors ( ) and the need for plastic of postoperative skull defects ( ). general endotracheal total intravenous anesthesia with fentanyl, propofol, rocuronium, or tracrium was used. after tracheal intubation, - nerves were blocked (e.g., supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, great auricular, greater and lesser occipital nerves), depending on the surgical site. . - . % ropivacaine was used. for blockade of one nerve used . - . ml of local anesthetic. fentanyl was applied on section of a periosteum, dura matter and at inefficiency of blockade of nerves. anesthesiology monitoring included hr, ecg, spo , nib, respiratory parameters, eeg (csi), body temperature, blood glucose and lactate levels. in and - hours post-surgery, the intensity of pain was ranked by alert patients using vas. results: the volume of local anesthetic for blockade in one patient was . ± . ml. in ( . %) from patients, an additional fentanyl injection was required to skin incision due to an increase in blood pressure and heart rate by % of the baseline values, and an increase in csi until un. patients available to productive contact in hours post-surgery ranked the pain by vas at ( ; ) point, and in - hours post-surgery ranked it at ( ; ) p. conclusions: at patients with craniotomies scalpe-block with lowvolumes of a ropivacaine showed high efficiency ( . %). were transferred to hospital ward or ( . %) to the center of intensive nursing care; ( . %) went to the surgical recovery room. acute renal failure, hypernatremia and hyperphosphatemia were independent predictors of mortality as described in table . conclusions: hypernatremia and hyperphosphatemia were independent predictors of mortality in critically ill patients. introduction: the strong ion difference (sid) is essential for the assessment of acid-base equilibrium, thus requiring an accurate measurement of plasma electrolytes. currently there is no gold standard for electrolyte measurements and sid computation. differences in electrolyte values obtained with point-of-care (poc) and central laboratory (lab) analyzers have been reported [ , ] . in previous studies [ , ] we have shown that changes in pco induce electrolyte shifts from red blood cells to plasma (and vice versa), yielding variations in sid. aim of the present in-vitro study was to induce sid changes through acute changes in pco and compare values of electrolytes and sid obtained with poc and lab techniques. methods: blood samples from healthy volunteers were tonometered (equilibrator, rna medical) with gas mixtures at fractions of co (fco ) of , , and %. electrolytes were measured quasisimultaneously with a poc analyzer (abl flex, radiometer) and a routine lab method (cobas ise, roche). for both techniques a simplified sid was computed as sodium + potassiumchloride. results: bland-altman analysis of sid calculated with poc and lab showed a proportional bias (slope = . , r = . , p < . ), indicating a variable agreement between methods according to the average sid value (fig. ) . sid values measured with poc and lab at different fco differed significantly (p< . , fig. ) . a similar discrepancy was observed for chloride (p < . , fig. ), while sodium (p= . ) and potassium (p= . ) were similar. conclusions: sid measured with poc and lab differed significantly, mainly due to a variable discrepancy in chloride. our findings suggest that our poc analyzer is superior to the lab in measuring electrolytes and thus compute sid. introduction: this study evaluated the safety of half dose insulin (hdi) versus standard dose insulin (sdi) for the treatment of hyperkalemia in a medical intensive care unit (micu) population with renal insufficiency. recent emergency medicine data demonstrated a lower incidence of hypoglycemia in patients with renal insufficiency when hdi was used for the treatment of hyperkalemia [ ] . there is limited data describing the safety of hdi in a micu population with renal insufficiency. methods: this was a retrospective, chart review of patients admitted to the micu with a diagnosis of aki and/or ckd stage - with a serum potassium ≥ . meq/l from january to september . sdi is defined as units of regular iv insulin and hdi as units. the primary outcome was the incidence of hypoglycemia within hours of insulin administration. secondary outcomes included severe hypoglycemia and change of serum potassium after insulin administration. results: a total of patients were screened and were included for analysis. the incidence of hypoglycemia occurred in / patients ( . %) and / patients ( . %) who received sdi and hdi, respectively. one patient in the sdi group and two patients in the hdi group developed severe hypoglycemia. the mean decrease in serum potassium after insulin administration was . meq/l in both groups. patients in the hdi group who were re-dosed with units of regular insulin did not have any hypoglycemic events. conclusions: in a micu population with renal insufficiency, sdi and hdi regimens appear safe and effective for the treatment of hyperkalemia. introduction: sepsis and septic shock are common causes of admission in the intensive care unit with a high mortality rate [ , ] . hence, electrolyte disturbances are common in this group of patients. acute hypernatremia is one of the multiple features of homeostasis disturbances and available data in the literature suggest that its incidence can reach % [ , ] . (fig , ) . the main source of sepsis was pneumonia with affected patients ( . %). conclusions: hypernatremia is significantly associated with higher mortality in septic patients. (abstract p ) . the outcome versus the sodium levels higher in the group - % vs . % (p= . ). there were no significant differences between the groups in length of stay in the icu. in group , there was an increase of serum phosphorus level and in the group the tendency to decrease. however, statistically significant differences were obtained only on the nd day after surgery . ± . mmol/l (group ) vs . ± . mmol/l (group ) (p= . ). the roc curve was constructed to assess the predictive significance of serum phosphorus levels (fig. ) . auc was . ; % ci . - . ; p= . ; sensitivity . %, specificity . %. the kaplan-meier survival analysis (fig. ) introduction: the rate of extubation failure might be higher in obese patients than in non-obese patients. effect of obesity on mortality is controversial [ , ] (obesity paradox). several pathophysiological changes contribute to an increase of respiratory complications [ ] . we sought to identify incidence of extubation failure in obese and non-obese patients. methods: the primary endpoint of this post-hoc analysis of a prospective, observational, multicenter study [ ] performed in intensive care units was extubation failure, defined as the need for reintubation within hours following extubation. only patients with body mass index (bmi) recorded were included. results: between december , and may , , among the patients with bmi available undergoing extubation, obese patients ( %) and non-obese patients ( %) were enrolled. extubation-failure rate was . % ( / ) in obese patients, and . % ( / ) in non-obese patients (p= . ). delay of reintubation did not differ between obese and nonobese patients (figure ). length of intubation > days was significantly more frequent in obese patients ( / , %) than in non-obese patients ( / , %, p< . ). precautions to anticipate extubation failure were more often taken in obese patients ( / , %) than in non-obese patients ( / , %, p< . ). spontaneous breathing trial (sbt) characteristics differed between obese and non-obese patients (table ) . physiotherapy was more often used in obese patients ( / , %) than in non-obese patients ( / , %, p= . ). conclusions: incidence of extubation failure did not differ between obese and non-obese patients. in obese patients, clinicians anticipate more a possible extubation failure, delaying the moment of extubation, performing more physiotherapy and providing an optimal sbt. introduction: in the acute phase of critical illness, growth hormone (gh) resistance develops, reflected by increased gh and decreased insulin-like growth factor-i (igf-i), mimicking fasting in health. the epanic rct observed fewer complications such as muscle weakness and faster recovery with accepting a macronutrient deficit in the first icu week, as compared with early full feeding [ , ] . we characterized its impact on the gh axis in relation to the risk of acquiring muscle weakness. methods: in this epanic rct sub-analysis, for matched patients per group, and all patients assessed for muscle weakness (n= ), serum gh, igf-i, igf binding protein (igfbp ) and igfbp were measured upon icu admission and at day or the last icu day for patients with shorter icu stay (d /ld). for matched patients per group, gh was quantified every min between pm and am, and deconvolved to estimate gh secretion. groups were compared with wilcoxon test or repeated-measures anova. associations between changes from baseline to d /ld and muscle weakness were assessed with logistic regression analysis, adjusted for baseline risk factors, baseline hormone concentrations and randomization. results: in the fully fed group gh, igf-i and igfbp increased, whereas igfbp decreased from admission to d /ld (all p< . ). accepting an early macronutrient deficit prevented the rise in gh and igf-i and the decrease in igfbp (all p< . ) but did not affect igfbp , whereas basal, but not pulsatile, gh secretion was lowered (p= . ). a stronger rise in gh and igf-i was independently associated with a lower risk of acquiring muscle weakness (or ( %ci) per ng/ml change . ( . - . ) for gh; . ( . - . ) for igf-i). conclusions: accepting an early macronutrient deficit suppressed basal gh secretion and reduced igf-i bioavailability during critical illness, which may counteract its protection against muscle weakness. introduction: aim of the study was to relate hypokalemia (hypok) and hypoglycemia as diabetic ketoacidosis (dka) treatment complications and precocious insulin interruption also use of sodium bicarbonate with length of stay (los) in intensive care unit (icu). methods: analysis of retrospective cohort study data of patient (pt) treated for dka at icu of hospital kaunas clinics of lithuanian university of health sciences during - has been carried out. serum kalemia, glycaemia; rate of episodes of hypok, hypoglycaemia and precocious insulin interruption; use of sodium bicarbonate, in relation with los in icu were analysed. spss . was used for statistic calculations. traits evaluated as significant at p< . . results: at the beginning of dka treatment hypok ( . ± . mmol/l) was recorded in / ( %) pt. due to disregarding of blood ph ( . - . ( . ± . ) kalemia was falsely misinterpreted as "normo-" or "hyperkalemia" . - . ( . ± . mmol/l) in of ( %) pt, as normo-and hyperkalemia thus not treated and complicated by hypok additionally in / ( %) pt. in hypok los in icu was . ± . vs . ± . h, p< . . insulin use has caused hypoglycaemia ( . - . ( . ± . mmol/l)) in / ( %) pt, los in icu . ± . vs . ± . h, p< . . insulin use was interrupted in case of normo -and hypoglycaemia with still persisting ketoacidosis in / ( %) pt, los in icu was found to be . ± . vs . ± . h, p< . . sodium bicarbonate was given for symptomatic treatment of acidosis during the first h of dka in / ( %) pt with stable hemodynamic: hco buffer has increased ( . ± . - . ± . mmol/l), p< . , but ketoacidosis has still persisted, los in icu was . ± . vs . ± . h, p< . . conclusions: hypok ( %), hypoglycemia ( %), precocious interruption of insulin use ( %) have prolonged los in icu almost twice. symptomatic treatment of ketoacidosis with sodium bicarbonate ( / pt) didn't control it and has prolonged los in icu. introduction: cystathionine-γ -lyase (cse), a regulator of glucocorticoid (gc)-induced gluconeogenesis [ ] , correlates with endogenous glucose production in septic shock [ ] . the hyperglycemic stress response to noradrenaline (noa) is mediated by the kidney [ ] and less pronounced with low cse [ ] . gc receptor (gr)-mediated gene expression is differentially regulated: the gr monomer is considered to repress inflammation, and gc side effects are attributed to the gr dimer; recent reports challenge this view [ ] . gc-induced gluconeogenic gene expression is reduced in gr dimerization deficient (grdim) mice [ ] . the aim of this study is to investigate renal cse expression and systemic metabolism in grdim and grwt mice in a resuscitated model of lps-induced endotoxic shock. methods: anesthetized grdim (n= ) and grwt (n= ) mice were surgically instrumented, monitored, resuscitated and challenged with lps. noa was administered to maintain map and c glucose was continuously infused. h after lps, cse expression was determined via immunohistochemistry of formalin-fixed paraffin sections (n= p.gr.). results: grdim required . -fold more noa than grwt and had . fold higher glucose and . -fold higher lactate h after lps. this was concomitant with elevated endogenous glucose production ( -fold), % lower glucose oxidation and . -fold higher renal cse expression in grdim. conclusions: increased cse expression together with higher glucose production (confirming [ , ] ) and glucose levels in grdim mice suggest an association that may link cse to gc signaling. the higher noa administration in grdim mice could contribute to these effects. introduction: to achieve safe glycemic control in critically ill patients frequent blood glucose (bg) measurements and according titration of insulin infusion rates are required. automated systems can help to reduce increased workload associated with diabetes management. this bi-centric pilot study combined for the first time an intraarterial glucose sensor with a decision support system for insulin dosing (sgcplus system) in critically ill patients with hyperglycemia. methods: twenty-two patients ( females, males, with preexisting diabetes mellitus, age . ± . years, bmi . ± . kg/ m , creatinine level . ± . mg/dl, saps (simplified acute physiology score) . ± . , tiss- (therapeutic intervention scoring system) . ± . who were equipped with an arterial line and required iv insulin therapy were managed by the sgcplus system during their medical treatment at the intensive care unit. results: sgcplus-based bg determinations were performed and . ± . sensor calibrations per day were required. sensor glucose readings correlated well with reference bg (figure ). mean treatment duration was . ± . days. time to target was ± min ( - mg/dl) and ± min ( - mg/dl). mean blood glucose was ± mg/dl with seven blood glucose values < mg/dl. mean daily insulin dose was ± u and mean daily carbohydrate intake ± g /day (enteral nutrition) and ± g/day (parenteral nutrition). acceptance of sgcplus suggestions was high (> %). the novel intraarterial glucose sensor demonstrated to be highly accurate. the sgcplus system can be safely applied in critically ill patients with hyperglycemia and enables good glycemic control. introduction: we aimed to assess the effect of frailty as assessed by clinical frailty scale (cfs) and karnofsky performance score (kps) on critical care (cc) and hospital mortality in this group at a nonspecialist tertiary critical care unit. methods: patients admitted to critical care were identified from our electronic database by screening for liver disease or cirrhosis in the admission diagnoses. those with an aetiology of liver disease other than alcoholic liver disease (ald) were excluded. data was collected on patient demographics, length of stay, status at discharge from critical care and hospital and cfs. kps was also calculated where sufficient in-formation was available in the medical record. data was analysed using logistic regression multivariate analysis with stata software. [ ] . results: tg diagnosis criteria and severity grading criteria for acute cholangitis and acute cholecystitis were judged from numerous validation studies as useful indicators in clinical practice and adopted as tg diagnostic criteria and severity grading without any modification. provide initial treatment, such as sufficient fluid replacement, electrolyte compensation, and intravenous administration of analgesics and full-dose antimicrobial agents, as soon as a diagnosis has been made. in new flowchart for the treatment of acute cholecystitis (ac) in the tg , grade iii ac was indicated for gallbladder drainage, but some grade iii ac can be treated by laparoscopic cholecystectomy (lap-c) at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. we also redefine the management bundles for acute cholangitis and cholecystitis. introduction: c-acetate breath tests provide a non-invasive assessment of gastric emptying [ ] and could, hence, be used to judge tolerance to enteral nutrition. result values like t (time for % absorption) correlate with scintigraphic measurements. the data evaluation is based on model equations like the β -exponential function (bex) [ ] . it considers a mono-phasic breath gas response. this may not be the case during critical illness, which could reduce precision too low for a reliable personalized assessment [ ] . methods: we recently developed an evaluation of irregular gastric emptying patterns, which separates absorption from post-absorptive distribution and retention of tracer and from the terminal respiratory release of the oxidized tracer [ ] . using breath test data of icu patients (mean saps +/- ) the precision of this approach was compared with a bex analysis to explore how often an extended analysis is warranted and whether it improves the reliability of estimates. results: patients had a release profile consisting of series of peaks with a periodicity of - min. a first dominant peak carries about % of the released moiety, as reported [ ] for controls. for these patients the precision in t for the bex approach was +/- % of that observed for the new approach. for the other patients, the secondary peaks had a similar periodicity but were more pronounced, indicating persisting peristaltis, which has been linked to tolerance to enteral nutrition [ ] . the bex approach achieved a precision of +/- % relative to the new one, challenging its applicability for these patients. introduction: clinical scoring systems used to prognosticate the severity of acute pancreatitis (ap), such as apache ii, are cumbersome and usually require hours or more after presentation to become accurate, at which time the window for early therapeutic intervention has likely passed. sirs at presentation is sensitive but poorly specific for severe ap. we postulated that sirs and accompanying hypoxemia would specify at presentation patients with ap who have severe inflammation and are at risk for clinically severe disease. methods: patients with ap who had sirs and hypoxemia at presentation were enrolled in an open-label study evaluating the safety and efficacy of cm -ie, a calcium release-activated calcium (crac) channel inhibitor (nct ). hypoxemia was defined as an estimated pao < mm hg calculated using a log-linear equation and the spo on room air at the time of presentation. a contrastenhanced computed tomography (cect) was performed at presentation and a cbc with differential, d-dimer and crp were analyzed daily. the cect was read by a blinded central reader who assessed the degree of inflammation using the balthazar scoring system (table ) . results: patients, seven men and six women, have been randomized in the study. the mean estimated pao at presentation was mm hg. patients had sirs criteria present and the other patients had sirs criteria present. the median value for age was . (iqr - ), initial neutrophil-lymphocyte ratio (nlr) . ( . introduction: to investigate whether circulating immune profiles were able to serve as early biomarkers in predicting persistent organ failure (pof methods: thirty-nine patients with predicted severe acute pancreatitis (psap) and healthy control subjects were prospectively enrolled in our study. we measured the expression of monocytic human leukocyte antigen-dr (mhla-dr), the proportions of dendritic cells (dc) and its subtypes (including myeloid dendritic cell (mdc) and plasmacytoid dendritic cell (pdc)), the different cytokineproducing cd + t helper (th) cells and regular t (treg) cells. plasma crp and several inflammatory mediators levels were measured by elisa. results: compared with healthy controls, there is a significant decrease in the expression of mhla-dr, the frequencies of total circulating dcs and its subsets, and percentage of th cells in patients with psap. however, we found significantly higher frequencies of th cells, higher proportion of treg cells than healthy subjects. of interest, we observed that there was a significant decrease in the positive percentage and mean fluorescence intensity (mfi) of mhla-dr, the proportions of total dcs and pdc, and th cells in patients with pof compared with transient organ failure (tof). besides, there is a significantly higher frequency of th cells in pof than those in tof. area under the receiver-operating characteristic curve analysis showed that disease severity scores had a moderate discriminative power for predicting pof in patients with psap. more importantly, the expression of mhla-dr and the percentage of dcs and pdc had a significantly higher auroc and thus, better predictive ability than disease severity in patients with psap. conclusions: circulating immune profile show multiple aberrations in patients with psap who have developed pof. both the expression of mhla-dr and the percentage of total dc and pdc may be early good biomarkers for predicting risk of pof in patients with psap. introduction: pancreatic fistula (popf) due to anastomosis insufficiency is a common ( - %) complication after pancreaticoduodenectomy and often discovered with delay, causing severe morbidity, icu stay and deaths. microdialysis (md) catheters have been shown to detect inflammation and ischemia in several postoperative conditions and organs. the aim was to investigate if md catheter monitoring could facilitate earlier detection of popf than current standard of care. methods: in a prospective, observational study patients ( to years) were investigated. a md catheter was fixed to the pancreaticojejunal anastomosis. samples for analysis of glucose, lactate, pyruvate and glycerol were acquired hourly during the first hours, then every - hours to discharge. popf was defined according to the international study group of pancreatic fistula update definition. results: patients who developed popf (n= ) had significantly higher glycerol levels (p< . ) in microdialysate than did patients without popf (n= ) during the first h. thereafter, the difference diminished. a glycerol concentration > μmol/l during the first h detected patients who later developed popf with a sensitivity of % and a specificity of %. lactate and lactate to pyruvate ratio were significantly higher (p< . ) and glucose was significantly lower (p< . ) in patients with popf from about h. fig. shows microdialysis measurements in patients with (red lines) and without (blue lines) popf. conclusions: a high level of glycerol in microdialysate is an early (first hours) indicator of popf. glucose, lactate and lactate to pyruvate ratio are indicators of peritonitis caused by the leakage. thus, md monitoring detects popf several days earlier than current methods and may play an important clinical tool in the future. we are currently conducting a rct to explore if md monitoring will improve prognosis in these patients the phenomenon of total impaired of metabolic activity of gut microbiota in critically ill septic patients introduction: during a critical condition, dramatic disturbances occur not only in the change of species diversity, but in gut microbiota metabolism as well, that might lead to nonreversible breakdowns of host homeostasis and death [ ] . metabolic activity of microbes can be assessed by the measurement of the levels of aromatic microbial metabolite (amm) in blood serum, which are associated with the severity and mortality of icu patients. critically ill patients are characterized by the totally different sfs profile than in healthy people, particularly by the absence of phpa; but dominated by p-hphaa and p-hphla [ ] . the purpose of our study is to assess the gut metabolic activity via amm in sepsis. methods: in this study simultaneously serum and fecal samples (sfs) were taken from icu patients: -with sepsis, -chronic critical ill (cci) patients and control - sfs from healthy people. after liquid-liquid extraction from serum and fecal samples, phenylcarboxylic acids (amm) were measured using gc/ms (thermo scientific). results: the sum of the level of most relevant amm in serum samples were higher in patients with sepsis (median - . μm) than in cci patients ( . μm) and healthy people ( . μm). at the same time the opposite pattern was observed in the fecal samples - . , . and . μm, respectively. the ratios of sums amm gut/serum were higher in healthy people than icu patients (fig. ) introduction: the aim of this study is to describe the characteristic of bioelectric impedance vector analysis (biva) and muscular ultrasound during the first week after admission in the icu, and their correlation with indices of metabolic support. biva is a commonly used approach for body composition measurements [ ] . muscular ultrasound represents a valid tool to provide qualitative and quantitative details about muscle disease [ ] . methods: consecutive patients admitted to icu and expected to require mechanical ventilation for at least hours were enrolled in the study. within the first hours of icu admission (t ), patients were evaluated with muscular ultrasonography comprehensive of diaphragm thickness (dth) and rectus femoris cross-sectional area (csa). at the same time, biva and biochemical analysis. all the same measures were repeated at day (t ) and (t ) (figure (table ) . dividing the patients in two groups based on prealbumine changes (t vs t : increase, anabolic vs decrease, catabolic), those in which prealbumine increased had a higher reduction in muscle mass ( figure ). conclusions: this study showed how the pa tends to be reduced in the first week of icu stay. it is correlated with a concomitant introduction: the modified nutrition risk in critically ill (mnutric) has been developed in order to identify critically ill patients who may receive benefit from nutrition support [ ] . several evidences showed the association between the mnutric score and clinical outcomes [ , ] , however there are no data in thai critically ill patients. the purpose of this study was to find the association between mnu-tric score and -day mortality in medical intensive care unit (icu) patients, ramathibodi hospital. methods: we retrospectively reviewed the medical patient records from june to january . a mnutric score of each patient was calculated to evaluate the risk of malnutrition. statistical analysis of the association between mnutric score and -day mortality, length of stay in icu and hospital were performed. results: a total of critically ill patients were included in the study. the -day mortality was . % in patients with high mnutric score ( - ) and . % in patients with low mnutric score ( - ). modified nutric score was significantly correlated with day mortality (r = . , p< . ), length of stay in icu (r = . , p< . ) and length of stay in hospital(r = . , p< . ). in the receiver operating characteristic (roc) curve analysis, the auc of mnutric score and -day mortality was . ( % confidence interval (ci), . - . ) (fig ) . optimal cut-off value of showed sensitivity of . % and specificity of . % in mortality prediction (youden's index, . ). additionally, patients who received adequate nutrition supplement within days was . % for calorie and . % for protein. there was no association between nutrition support and -day mortality. conclusions: in thai medical intensive care population, the mnutric score was associated with -day mortality in critically ill patients. fig. (abstract p ) . within the first hours of icu admission (t ), patients will be evaluated with muscular ultrasonography comprehensive of diaphragm thickness and rectus femoris (medial vastus) cross-sectional area. at the same time, anthropometric measure will be collected (such as body height, ideal body weight, real body weight declared, right arm circumference) as well as biva measure (xc, r, pa, lean body weight and % of extracellular body weight) and biochemical analysis (inclusive albumin, pre-albumin, blood count, lymphocyte count, magnesium, phosphorus, reticulocytes, renal and hepatic function test). the day after, the fluid balance will be calculated as well as the nitrogen balance. all the same measures will be repeated at day (t ) and days (t ) introduction: ultrasonography is an essential imaging modality in critical care to diagnose and guide for therapeutic management of shock, multiple organ failure, etc. enteral tube feed intolerance occurs frequently in hospitalized patients and more so in critically ill patients. in present study, we consider that nursing staff may be able to use bedside ultrasound as an alternative to standard aspiration protocol or radiographic studies to assess gastric volume and nasogastric (ng) tube in patients with enteral feed intolerance. methods: in present prospective, single-center study, we performed ultrasound residual stomach volume and ng tube placement assessments of adult critically ill patients (figure ) compared to standard protocol of stomach volume assessment (routine daily shift -ml syringe aspirations) and ng (nasogastric) tube placement verified by abdominal x ray. we used an abdominal (linear ultrasound transducer) probe ( - mhz). the residual volume was calculated according to formula: gv (ml) = + . x right-lateral csa- . x age). results: hundred simultaneous double (ten critically ill patients) ultrasound measurements sessions were performed by nursing staff of our intensive care (icu) (fig ) . double simultaneous measurements of the ultrasound assessments were compared to standard nurse icu protocol for assessment of residual volume of stomach. the new ultrasound assessment method demonstrated excellent intra-class reliability (icc- . ( . - . , p< . ) and strong correlation with standard residual volume assessment method (icc- . ( . - . , p< . ). ng tube placement was successfully verified by ultrasound measurements in all ten critically ill patients and, thereafter, confirmed by abdominal x-rays. conclusions: preliminary results of our study demonstrated good correlations between both methods of ng tube placement and residual stomach volume: standard icu nurse protocol and ultrasound assessment. evaluating the documentation of nasogastric tube insertion and adherence to safety checking l roberts introduction: enteral feeding into a misplaced nasogastric (ng) tube is recognised by the national patient safety agency as a never event. ng tubes are commonly indicated in level / patients, thus we set out to evaluate current practice in critical care. the aim was to evaluate: documentation of insertion, adherence to safety guidance pertaining to checking safe use, chest x-ray interpretation. methods: this prospective cohort study was based on inpatients in critical care who had insertion of ng tubes over four weeks; there were insertions. data was analysed from patients' medical notes and the hospital's imaging system. results: % of insertions were documented using proformas. . % of proforma documentations included or more details: type of tube, tube length at the nostril, nex measurement, aspirate adequacy, chest x-ray adequacy, whether it was safe to feed. only . % of hand-written documentations included or more details. % of initial aspirates were obtained on insertion, of these, % had an appropriate ph between and . . this led to % of patients having chest x-rays to confirm initial placement of the ng tube. only % of chest x-rays adequately satisfied the four criteria. written documentation in medical notes stating if it was safe to feed was completed in % of cases. conclusions: we found that proformas ensure a higher level of detail and uniformity in the documentation of ng tube insertions. there was a high incidence of chest x-rays performed to confirm correct placement of tubes due to difficulties in obtaining aspirates and failure to follow guidelines. a need for a uniform, ward-specific proforma on ng tube insertion has been identified, as well as a teaching session on chest x-ray interpretation and on techniques to aid obtaining aspirates. we have established critical care's shortcomings in ng tube insertion documentation and tube safety checking. introduction: pressure ulcers(pu) are considered as important types of public health problems, due to high mortality and cost. we aimed to investigate the efficiency of curcumin and fish oil on prevention and treatment of pu using a feasible mice model. methods: mice were randomly divided into control(group ), curcumin(group ), fish oil(group ), curcumin and fish oil(group ) groups. mm skin bridge between two gauss magnets was formed on the back of mice, followed by ischemia reperfusion cycles as hours of rest after hours of magnet placement [ ] . a single dose of curcumin and fish oil was injected intraperitoneally. tissue samples had taken th day of first compression, rates of pu, inflammation, reepithelisation, neovascularisation and granulation were examined histopathologically. the data analyzed by pearson chi-square test. results: third degree pu were observed in all groups.there was no significant difference between groups in terms of inflammation.the formation of reepithelisation showed a significant difference between groups.partial reepithelisation ratios in group and group was elevated.there was significant difference between groups in terms of neovascularisation, the highest rate as % was observed in group .formation of granulation was observed at maximum rate as . % at group . conclusions: depending on positive results of curcumin, fish oil, cur-cumin+fish oil on wound healing it may be advised to use them in treatment of acute pu.after similar rate of pu with control group we consider that it should be beneficial to evaluate the effect of these therapies with more studies by changing the mode of administration, time of initiation and duration of therapy. introduction: inflammation is a key driver of malnutrition during acute illness and has different metabolic effects including insulin resistance and reduction of appetite. whether inflammation influences the response to nutritional therapy in patients with disease-related malnutrition remains undefined. we examined whether the effect of nutritional support on the risk of mortality differs based on the inflammatory status of patients. methods: this is a secondary analysis of a multicentre trial in eight swiss hospitals, where patients with a nutritional risk score (nrs) of ≥ upon hospital admission were randomly assigned to receive protocol-guided individualized nutritional support according to nutrition guidelines (intervention group) or a control group. the inflammatory status was defined based on admission crp levels as low inflammation (cpr < mg/dl), moderate inflammation (crp - mg/dl) and high inflammation (crp > mg/dl). results: we included a total of , patients of which . %, . % and . % had low, moderate and high inflammation levels on admission. while overall there was a significant reduction in day mortality associated with nutritional support (adjusted or in the overall cohort . , %ci . - . ), the subgroup of patients with high inflammation did not show reduced mortality (adjusted or . , %ci . - . , p for interaction = . ). there was no difference in other secondary endpoints when stratified based on inflammation. nutritional support did not affect crp levels over time (kinetics). conclusions: this secondary analysis of a multicentre randomized trial provides evidence, that the inflammatory status of patients influences their response to nutritional support. these findings may help to better individualize nutritional therapy based on patients initial presentation. introduction: low plasma glutamine levels have been associated with unfavourable outcomes in critically ill patients. this study aimed to measure plasma glutamine levels in critically ill patients and to correlate glutamine levels with biomarkers and severity of illness. methods: we enrolled critically ill patients admitted to three icus in south africa, excluding those receiving glutamine supplementation prior to admission. we collected clinical, biochemical and dietary data. plasma glutamine levels were determined within hours of admission, using liquid chromatography mass spectrometry and categorized as low (< μmol/l), normal ( - μmol/l) and high (> μmol/l). results: of the patients (average age . ± . years, % male), % were mechanically ventilated, with a mean apache ii score of . ± . and a mean sofa score of . ± . . plasma glutamine levels were low in . % (median plasma glutamine of . μmol/l). baseline plasma glutamine correlated inversely with crp (r=- . , p< . ) and serum urea (r=- . , p< . ), and positively with serum bilirubin (r= . , p< . ) and serum alt (r= . , p= . ). significantly more patients with low admission glutamine levels required mechanical ventilation (chi = . , p< . ) and had higher apache scores (p= . ), higher sofa scores (p= . ), higher crp values (p< . ), higher serum urea (p= . ), higher serum creatinine (p= . ), lower serum albumin (p< . ) and lower bilirubin levels (p= . ). using multiple logistic regression analysis, apache score (odds ratio, [or] . , p= . ), sofa score (or . , p= . ) and crp (or . , p< . ) were significant predictors of low plasma glutamine levels. roc curve analysis revealed a crp threshold value of . mg/l to be indicative of low plasma glutamine levels (auc . , p< . ). conclusions: . % of critically ill patients had low plasma glutamine levels on admission to icu. this was associated with increased disease severity and higher crp. introduction: the east of england deanery operational delivery network in the united kingdom came together as a group of intensive care units to comply an evidence-based care bundle. one of the branches of this care bundle is on parenteral nutrition and states: 'parenteral nutrition should not be given to adequately nourished, critically ill patients in the first seven days of an icu stay.' this is based on evidence [ ] [ ] [ ] that showed that 'in patients who are adequately nourished prior to icu admission, parental nutrition initiated within the first seven days has been associated with harm, or at best no benefit, in terms of survival and length of stay in icu.´the objective of this second cycle was to assess whether or not we are adhering to the guidelines, last year we were failing to hit targets and after some action i reassessed how we performed in the year compared to . methods: a retrospective audit of the whole year of for all patients admitted to icu who had parenteral nutrition started at any point during their stay. results: there is a significant improvement in the percentage of patients who are being started incorrectly on tpn before days ( % compared to %) (fig , ) . i also found a total reduction in the number of patients prescribed tpn, a reduction in the number of bags being used and a reduction in length of hospital stays. conclusions: as we have recently switched over to an electronic icu programme for all documentation and prescriptions, as part of our plan and act in the pdsa cycle we are organising for several things to be put in place on the new system on prescription: pharmacy authorisation, links to guidelines and alert/justification boxes. i will do a further cycle in another year. jg and mpc contributed equally. introduction: recent rcts revealed clinical benefit of early macronutrient restriction in critical illness, which may be explained by enhanced autophagy, an evolutionary conserved process for intracellular damage elimination [ ] . however, in the absence of specific and safe autophagy-activating drugs, enhancing autophagy through prolonged starvation may produce harmful side effects. a fasting-mimicking diet (fmd) may activate autophagy while avoiding harm of prolonged starvation, which also improved biomarkers of age-related diseases in an experimental study [ ] . we evaluated if short-term interruption of continuous feeding can induce a metabolic fasting response in prolonged critically ill patients. methods: in a randomized cross-over design, prolonged critically ill patients receiving artificial feeding were randomized to be fasted for hours, followed by hours full enteral and/or parenteral feeding, or vice versa. patients were included at day in icu and blood glucose was maintained in the normal range. at the start and after and hours, we quantified total bilirubin, urea, insulin-like growth factor-i (igf-i) and beta-hydroxybutyrate (boh) in arterial blood. insulin requirements were extracted from patient files. changes over time were analyzed by repeated-measures anova after square root transformation. results: as compared to hours of full feeding, hours of fasting decreased bilirubin (- . ± . mg/dl; p= . ) and igf-i (- . ± . ng/ml; p< . ), and increased boh (+ . ± . mmol/l; p< . ), without affecting urea concentrations (fig ) . fasting reduced insulin requirements (- . ± . iu/hour; p< . ). conclusions: short-term fasting induces a metabolic fasting response in prolonged critically ill patients, which provides perspectives for the design of a fmd, aimed at activating autophagy and ultimately at improving outcome of critically ill patients. introduction: recent evidence has led to changed feeding guidelines for critically ill patients, with a shift towards lower feeding targets during the acute phase [ ] . when micronutrients are not provided separately, prolonged hypocaloric feeding could induce micronutrient deficiencies and increase risk of refeeding syndrome once full feeding is restarted, which are both potentially lethal complications [ ] . since there is limited evidence how to optimize micronutrient provision in order to avoid deficiencies, we hypothesized that there is a great variation in current practice. methods: within the men section of the european society of intensive care medicine (esicm), we designed a questionnaire to gain insight in the current practice of micronutrient administration. in email blasts, invitations were sent to all esicm members, with currently more than respondents. the survey will be closed at december , . results: first, we will describe demographic characteristics of the respondents, including geographical location, icu and hospital type, and function. second, we will describe some aspects of the current practice of micronutrient administration. we will identify the proportion of respondents having a protocol, on which evidence such protocol is based and whether it takes into account the stability and daylight sensitivity of micronutrients. next, bearing refeeding syndrome in mind, we will identify whether there are respondents who never measure and/or separately administer micronutrients and phosphate. finally, we will make a top of the most measured and most supplemented micronutrients. conclusions: this survey will deliver more insight in the current practice of micronutrient provision across different types of icus and may identify areas for future research. furthermore, we will evaluate whether there is need to increase awareness for refeeding syndrome. introduction: large gastric residual volumes (grvs) have been used as surrogate markers of delayed gastric motility to define enteral feeding intolerance (efi). recent studies have challenged the definition of efi. study objectives: ) investigate the potential relationship between grvs and clinically outcomes, ) develop an algorithm for early identification of patients at increased risk of mortality due to efi. methods: a retrospective study of inpatient encounters from electronic health record charts within the dascena clinical database. , patients were included in the study; patients had efi. eight vital signs (diastolic/systolic bp, heart rate, temperature, respiratory rate, grv, glasgow coma scale, and feeding rate) and their trends were input to the classifier. machine learning classifiers were created using the xgboost gradient boosted tree method with -fold cross validation. results: rate of change in grv (Δ grv) was measured over a -day period, beginning at the time of efi onset (figure a) . figure b shows a high likelihood of mortality for patients with none or modest grv reduction. patients with an increase in grv over the five-day period after efi onset had the highest mortality likelihood. a stratification algorithm was developed to identify efi patients who died inhospital despite grv reduction at , , and hours in advance of efi onset. area under the receiver operating characteristic (auroc) curves demonstrated high sensitivity and specificity of algorithm predictions of in-hospital death up to hours in advance of efi onset (table ) . conclusions: the analysis suggests an association between grv and mortality, especially in patients with persistent grv increase over the -day period after efi onset and the potential of algorithmic models to predict efi development. prospective validation of these fig. (abstract p ) . changes in metabolic markers of fasting over time for both randomization groups algorithms may assist in clinical trial design to develop treatments for patients at highest risk of experiencing serious outcomes due to efi. a quality improvement project to improve the daily calorific target delivery via the enteral route in critically ill patients in a mixed surgical and medical intensive care unit (icu) b johnston, d long, r wenstone royal liverpool and broadgreen university hospital trust, critical care, liverpool, united kingdom critical care , (suppl ):p introduction: 'iatrogenic underfeeding' is widespread with the calo-ries study reporting only %- % of prescribed daily kcal was actually delivered to patients [ ] . in the present project, quality improvement methodology was utilised with the aim of delivering greater calories by implementing -hour volume-based feeding and allowing increased feeding rates for, 'catch up' of missed daily feed volume. methods: baseline data assessing the percentage of daily kcal delivered to ventilated patients was collected in september . data was presented and new intervention guidelines agreed based upon the pepup protocol [ ] . nurse champions were identified and were responsible for cascade training of the pepup protocol. educational tools to help determine daily calorific requirement and volume of feed required were provided. repeat data was collected at months (cycle ) after pepup implementation. results: ten patients were included in cycle . during cycle the percentage of kcal achieved via enteral feeding was %. following intervention this increased to % (p< . ) during cycle . this increased further to . % of daily kcal when calories obtained from propofol were included. conclusions: a -hour volume-based feeding regimen is a simple and cost-effective method of improving enteral feeding targets. through the use of quality improvement methodology, we demonstrated that this approach is achievable. the success of this project has led to the adoption of the protocol in other icu units in a regional critical care network. effect of non-nutritional calories on the calory/protein ratio in icu patients s jakob, j takala university hospital bern, dept of intensive care medicine, bern, switzerland critical care , (suppl ):p introduction: nutritional diets are composed to match the needs of critically ill patients. while effective calory needs can be measured or calculated, the needs of proteins are more controversial. we aimed to calculate non-nutritional calories and assess how they influence the ratio of calories to protein delivered to the patients. methods: in this retrospective analysis, nutritional and nonnutritional calories and protein delivery were calculated in consecutive icu patients receiving enteral nutrition in . introduction: marked protein catabolism is common in neurocritical patients. optimal nutritional monitoring and protein nutritional adequacy could be associated with outcome in neurointensive care unit (ncu) patients. we aimed to evaluate the impact of monitoring and optimal support of protein using nitrogen balance on outcome in neurocritical patients. methods: a consecutive patients who were admitted to ncu were included between july and february . nitrogen balance was calculated using excreted urine urea nitrogen during icu admission. follow-up nitrogen balance monitoring was performed in patients. we divided patients into two groups based on the results of nitrogen balance (positive balance and negative balance). moreover, we evaluated improvement of nitrogen balance in patients. we assessed the outcome as length of stay in hospital, length of stay in ncu, and in-hospital mortality. we compared the clinical characteristics and outcome according to nitrogen balance. results: among the included patients (age, . ; and male. . %), ( . %) patients had negative nitrogen balance. the negative balance group was more likely to have lower glasgow coma scale (gcs), longer length of stay in hospital, and longer length of stay in ncu. in patients with follow-up nitrogen balance monitoring, improvement of nitrogen balance group had lower in-hospital mortality ( . % vs. . %, p = . ), and received adequate protein intake ( . g/kg/day vs. . g/kg/day, p = . ) compared to no change group (table ) . there was no significant difference in baseline nitrogen balance, baseline body mass index, and gcs between two groups. conclusions: this study demonstrated that critical illness patients in ncu are underfeeding using nitrogen balance, however, adequate provision of protein was associated improvement of nitrogen balance and outcome. this suggests that adequate nutrition monitoring and support could be an important factor for prognosis in neurocritical patients. increased protein delivery within a hypocaloric protocol may be associated with lower -day mortality in critically ill patients introduction: to test the hypothesis, using real world evidence that increasing protein delivery and decreasing carbohydrates (cho) may improve clinical outcomes. methods: retrospective analysis of existing electronic medical records (emr) of patients admitted to the intensive care units (icu) at the geisinger health system. logistic regression analysis was used to determine correlation between protein delivered (which was proportional to the concentration of protein in the formula utilized) and clinical outcomes. results: medical encounters for a total number of , icu days were collected and analyzed. average age was . years ( . % male) and . % were obese and overweight. primary diagnoses included sepsis or septic shock, acute and/or chronic respiratory failure (or illness), cardiovascular diseases, stroke and cerebrovascular diseases among others. median hospital los was . days, . days in the icu, median days of invasive mechanical ventilation of . -day readmission rate among patients discharged alive was . %. patients in the high protein group received lower amounts of chos (data not shown). unadjusted -day post-discharge mortality was inversely proportional to the amount of protein delivered (table ) . conclusions: a significant improvement in mortality is observed with increased protein delivery while decreasing carbohydrate loads. prospective randomized trials are warranted to establish causality. introduction: acute kidney injury (aki) is associated with high mortality. the risk increases with severity of aki. our aim was to identify risk factors for development and subsequent progression of aki in critically ill patients. methods: we analysed patients without end-stage renal disease who were admitted to the icu in a tertiary care centre between january to december and did not have aki on admission. we identified risk factors for development and non-recovery of aki as defined by the kdigo criteria. results: the incidence of new aki in days was % (aki i %, aki ii %, aki iii %). multivariate analysis revealed bmi, sofa score, chronic kidney disease (ckd) and cumulative fluid balance as independent risk factors for development of aki. among patients who developed aki in icu, % had full renal recovery, % partial recovery and % had no recovery of renal function by day . aki patients without renal recovery in days had significantly higher hospital mortality ( %) compared to the other groups. independent risk factors for non-recovery of renal function were ckd, mechanical ventilation, diuretic use and extreme fluid balance before and after first day of aki. (table ) the association between cumulative fluid balance before aki and hours after aki with risk of aki non-recovery are shown in figure and . conclusions: aki is common and mortality is highest in those who do not recover renal function. cumulative fluid accumulation impacts chances of aki development and progression. (table ). all were in r . / ( %) of those with an admission ck> had aki or . all ( %) patients who required crrt for aki associated with rm were at risk for aki regardless of initial ck: vascular surgery ( / ), multi-organ dysfunction ( / ), and/or pre-existing renal disease ( / ). conclusions: raised ck is common in icu but its cause is multi factorial thus an isolated measure > does not require immediate high output treatment for rm aki. aki is more common in patients who have more than ck> on sequential days or those whose first ck was > as rm may be contributing. a single ck> in patients with a clear reason to develop rm should also start treatment. surgical outcomes of end-stage kidney disease patients who underwent major surgery p petchmak , y wongmahisorn , k trongtrakul introduction: acute kidney injury (aki) occurs in more than % of successfully resuscitated out-of-hospital cardiac arrest patients treated with targeted temperature management (ttm) [ ] . the effect of the duration of cooling on aki has not been well studied. in this post-hoc analysis of the tth randomized controlled trial that compared vs -hours of ttm ( °c) after cardiac arrest [ ] , we studied the impact of ttm length on the development of aki. fig. . duration of ttm had a significant impact on the development of creatinine values during the first days in the icu, p< . . this was primarily driven by an increase in creatinine during rewarming on day for the hour and day for the -hour group (fig ) . conclusions: in a trial of vs hours of ttm after out-of-hospital cardiac arrest, the length of ttm did not affect the incidence of aki. fig. (abstract p ) . creatinine over time patients [ ] , but there are no published data on longer-term renal outcomes in adult patients. the purpose of this study was to assess longer-term trends in serum creatinine in this cohort. methods: a retrospective study was conducted of all patients admitted to an adult regional referral centre for ecmo at a uk university hospital between and . those who survived for > months were included. demographics, baseline serum creatinine, presence of aki during icu admission, and serum creatinine at hospital discharge were determined. serum creatinine and dependence on renal replacement therapy (rrt) were assessed at and months post ecmo. results: patients had a complete (or near-complete) data-set available. the mean age was . years, % of whom were male. / had aki during their critical care admission. none were dependent on rrt at or months post ecmo. most patients had lower serum creatinine results at hospital discharge compared to their pre-hospitalisation baseline, but creatinine concentrations at and months post ecmo tended to be higher than at hospital discharge ( figure ) . conclusions: in this cohort of ecmo patients who were discharged from hospital alive, serum creatinine tended to be lower at hospital discharge compared to baseline and rose again in the following months. decreased creatinine production due to deconditioning and muscle wasting may offer a biological rationale for the lower creatinine results at hospital discharge [ ] . therefore, caution should be exercised in the use of serum creatinine at hospital discharge to assess renal dysfunction -further research is warranted. introduction: aki complicates more than half of icu admissions [ , ] and is associated with development of chronic kidney disease (ckd), need for renal replacement therapy (rrt) and increased mortality [ ] . we prospectively evaluated all icu admissions during a one-year period in order to determine incidence, etiology and timing of aki as well relevant clinical outcomes. methods: prospective observational study of all patients admitted from jan to dec to a multidisciplinary icu in greece. patients with end-stage renal disease and anticipated icu stay less than hrs were excluded. aki diagnosis and classification was based on kdigo criteria [ ] . lowest creatinine level within months before admission or first creatinine after icu admission served as reference. (fig ) . conclusions: although aki alert does not include urine output criterion or aki risk factors, it remains a helpful tool to point out patients with aki. education and diagnostic algorithms are still needed to early diagnose and treat aki patients. influence of severity of illness on urinary neutrophil gelatinaseassociated lipocalin in critically ill patients: a prospective observational study c mitaka, c ishibashi, i kawagoe, d satoh, e inada untendo university, anesthesiology and pain medicine, tokyo, japan critical care , (suppl ):p introduction: neutrophil gelatinase-associated lipocalin (ngal) is a diagnostic marker for acute kidney injury (aki). ngal expression is highly induced not only in kidney injury, but also in epithelial inflammation of intestine, bacterial infection, and cancer. however, the relationship between ungal and severity of critically ill patients has not been well understood. the purpose of this study was to elucidate whether ungal is associated with severity of illness and organ failure in critically ill patients. methods: we prospectively enrolled patients with sepsis (n= ) and patients who underwent esophagectomy with gastric reconstruction for esophageal cancer (n= ). sepsis was defined according to sepsis- . ungal levels were measured on icu day , , , and . ungal levels and aki rate in patients with sepsis were compared with those in patients who underwent esophagectomy. aki was defined according to kdigo. acute physiology and chronic health evaluation (apache) ii score and sequential organ failure assessment (sofa) score were calculated. results: median ungal level ( ng/mg creatinine) was significantly higher in patients with sepsis than that ( ng/mg creatinine) in patients who underwent esophagectomy on day . median apache ii score and median sofa score in patients with sepsis were significantly higher than those in patients who underwent esophagectomy. four patients with sepsis developed aki, and out of them underwent continuous renal replacement therapy, whereas no patients who underwent esophagectomy developed aki. ungal levels were positively correlated with apache ii score and sofa score in patients with sepsis. ungal levels were remarkably elevated (> ng/mg creatinine) in urinary tract infection (n= ), loops enteritis (n= ), and obstructive jaundice due to cholangiocarcinoma (n= ). conclusions: these findings suggest that ungal level is associated with severity of illness and organ failure in patients with sepsis. ungal levels might be influenced by severity of illness and inflammation. to assess the quality of the course us renal images had to be evaluated in "post-renal obstruction" (p-ro) or "no p-ro". the rate of correctness (roc farius ) was determined. in we, once again, contacted the students to attend a web-based online "follow-up". this online survey was created with "google formular". new and unknown us images were presented and rated in "p-ro" or "no p-ro" (roc fup introduction: septic-induced kidney injury worsen the patient's prognosis [ ] . renal resistance index (rri) is correlated with an increased mortality in septic patients [ ] . the aim of this study was to describe the evolution of rri in a rat sepsis model. methods: the local ethics committee approved the study (apa-fis# - ). sepsis was induced in -month-old male rats by caecal ligation and puncture (clp) [ ] . the rri was assessed before and h after clp by pulse doppler on the left renal artery (rri=(peak systolic velocityend diastolic peak)/ peak systolic values expressed as % per column. abbreviations in alphabetical order: aki acute kidney injury; akin acute kidney injury network definition; ckd chronic kidney disease. there were statistical differences between subgroups with and without aki for the subgroups of patients with previous ckd (p = . *), sepsis at admission (p = . **), hypotension (p= . ***) fig. (abstract p b) . target comparing accuracy and precision of aki alert and actual aki diagnoses velocity) (fig ) . rri were compared by a paired wilcoxon test (r software v. . . ). a p value < . was considered significant. results: rats were included. hours after sepsis induction, all rats were in septic shock with cardiac dysfunction. the rri increased after sepsis induction compared to baseline ( . ± . vs . ± . , p< . ) and mean renal artery velocity decreased ( . ± . vs . ± . , p< . ) (fig ) . systolic and diastolic peaks velocity of the renal artery were unchanged. conclusions: sepsis induced changes in rri and mean velocity on the left renal artery whereas no changes in systolic or diastolic velocities were seen. these results are consistent with available clinical datas. the rri could be an additional tool to assess renal failure in septic rats. further studies are needed to confirm the validity of this marker during sepsis. kidney failure is one of the most common organ dysfunction during sepsis. the rri could be an additional tool in small animals to assess the effects of potential therapeutic targets on renal function induced by sepsis. (fig ) . the egfr improved more with the heparin group ( % vs %; p= . ) (fig ) . interruptions of the filter circuit were as expected less with the citrate group ( mins vs mins; p= . ). finally, inotropic requirements increased following therapy interruptions, more so with patients receiving citrate ( . % vs . %; p= . ). conclusions: our analysis suggests that using citrate anticoagulation for rrt results in a monitoring cost saving of approximately £ per hours, alongside the other conferred savings previously reported. furthermore, results demonstrate the efficacies of both systems are similar in the initial hours, although there is a suggestion that heparin systems improves renal parameters more quickly. finally, interruptions and 'filter downtime' caused an increase in the patient's inotropic requirements, however results suggestive that this is greater in the citrate group. mmol/l respectively. demographic characteristics of the study group and the main parameters of the procedure were presented in fig . conclusions: regional citrate is a safe and effective anticoagulation method for crrt in children, when it is applied following a protocol. it significantly prolongs circuit survival time and thereby should increase crrt efficiency. we did not find any serious adverse effects of regional citrate anticoagulation. - ) , deceased at year n= ( %). the mdrd trend is more indicative than creatinine of decline of renal function in the post operative period (fig ) . crrt was used in . % ( pts) and was associated to a greater los and mortality (fig ) . preoperative bilirubin, bun and creatinine are among the greatest risk factors for its use ( table . at year follow up n= pts ( . %) were on hemodialysis. conclusions: aki requiring crrt in after lt is associated with higher mortality and los. identify patients at risk and adopt preventive strategies in the perioperative period is mandatory. introduction: we developed a new co removal system, which has a high efficiency of co removal at a low blood flow. to evaluate this system, we conducted in vivo studies using experimental swine model. methods: six anesthetized and mechanically ventilated healthy swine were connected to the new system which is comprised of acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. in vivo experiments consist of four protocols of one hour; baseline= hemodiafiltration only (no o gas flow of membrane lung); membrane lung = "baseline" plus o gas flow of membrane lung; "acid infusion" = "membrane lung" plus continuous acid infusion; "final protocol" = "acid infusion" plus continuous alkaline infusion. we provided an interval period of one hour between each protocol. we changed the respiratory rate of the mechanical ventilation to maintain pco at - mmhg during the experiment. results: the amount of co eliminated by the membrane lung (vco ml) significantly increased by . times in the acid infusion protocol and our final protocol compared to the conventional membrane lung protocol, while there was statistically no significant difference observed in the levels of ph, hco -, and base excess between each study protocol. minute ventilation in the "final protocol" significantly decreased by . times compared with the hemodiafiltration only protocol (p < . ), the membrane lung (p= . ) and acid infusion protocol (p= . ). we developed a novel ecco r system which efficiently removed co and is easy-to-setup to permit clinical application. this new system significantly reduced minute ventilation, while maintaining acid-base balance within the normal range. further studies are needed for the clinical application of this easy setup system comprising of the materials typically used in a clinical setting. , and psychomotor agitation ( %) while the most common symptoms of hypertensive emergency were chest pain ( . %), dyspnea ( . %) and neurological deficit ( %). clinical manifestations of hypertensive emergency were cerebral infarction ( . %), acute pulmonary edema ( . %), hypertensive encephalopathy ( . %), acute coronary syndromes ( . %), cerebral hemorrhage ( ,. %), congestive heart failure ( %), aortic dissection ( . %), preeclampsia and eclampsia ( . %). conclusions: hypertensive urgencies were significantly more common than emergencies ( . % vs. . %, p< . ). there was no statistically significant difference in the number of patients with hypertensive urgency and emergency in relation to age, gender, duration of hypertension, except for the - age group, where urgency was statistically significantly higher (p= . ). introduction: emergency department (ed) crowding is a major public health concern. it delays treatment and possible icu admission, which can negatively affect patient outcomes. the aim of this study was to investigate whether ed to icu time (ed-icu time) is associated with icu and hospital mortality. methods: we conducted an observational cohort study using data from the dutch nice registry. adult patients admitted to the icu directly from the ed in academic centers, between and , were eligible for inclusion. for these patients nice data were retrospectively extended with ed admission date and time. ed-icu time was divided in quintiles. the data were analyzed using a logistic regression model. we estimated crude and adjusted (for disease severity; apache iv probability) odds ratios of mortality for ed-icu time. in addition, we assessed whether the apache iv probability (divided into quartiles) modified the effect of ed-icu time on mortality. results: a total of , patients were included. baseline characteristics are shown in table . the median ed-icu time was . [iqr . - . ] hours. icu and hospital mortality were . and . %, respectively. the crude data showed that an increased ed-icu time was associated with a decreased icu and hospital mortality (both p< . , figure a ). however, after adjustment for disease severity, an increased ed-icu time was independently associated with increased hospital mortality (p< . , figure b ). figure shows that only in the sickest patients (apache iv probability > . %), the association between increased ed-icu time and hospital mortality was significant (p= . , figure d ). we found similar results with respect to icu mortality. conclusions: this study shows that a prolonged ed-icu time is associated with increased icu and hospital mortality in patients with higher apache iv probabilities. strategies aiming at rapid identification and transfer of the sickest patients to the icu might reduce inhospital mortality. reliability and validity of the salomon algorithm: -year experience of nurse telephone triage for out-of-hours primary care calls e brasseur, a gilbert, a ghuysen, v d´orio chu liege, emergency departement, liège, belgium critical care , (suppl ):p introduction: due to the persistent primary care physicians (pcp) shortage and their substantial increased workload, the organization of pcp calls during out-of-hours periods has been under debate. the salomon (système algorithmique liégeois d'orientation pour la médecine omnipraticienne nocturne) algorithm is an original nursing telephone triage tool allowing to dispatch patients to the best level of care according to their conditions [ ] . we aimed to test its reliability and validity under real life conditions. methods: this was a -year retrospective study. out-of-hours pc calls were triaged into categories according to the level of care needed: emergency medical services (amu), emergency department visit (maph), urgent pcp visit (upcp), delayed pcp visit (dpcp). data recorded included patients' triage category, resources and potential redirections. more precisely, patients included into the upcp + dpcp cohort were classified under-triaged if they had to be redirected to an emergency department. patients from the amu+maph cohort were considered over-triaged if they did not spend at least resources, emergency specific treatment or any hospitalization. results: calls were actually triaged using the salomon tool, of which . % were classified as amu, . % as maph, . % as upcp and . % as dpcp (fig ) . as concerns the amu+maph cohort, the triage was appropriate in . % of the calls, with an over-triage rate of . %. as concerns the upcp + dpcp cohort, . % of the calls were accurately triaged and only . % were under-triaged. sal-omon sensitivity reached . % and its specificity . %. these results indicate that salomon algorithm is a reliable and valid nurse telephone triage tool that has the potential to improve the organization of pcp out-of-hours work. introduction: inappropriate visits to the emergency department (ed), such as patients manageable by a primary care physician (pcp), have been reported to play some role in the ed crowding [ ] . indeed, non-urgent patients directly managed by pcps could reduce ed workload [ ] . triage and diversion to alternative care facilities, eventually co-located within the ed, could offer a solution [ ] provided fig. (abstract p ) . distribution of different calls, their triage using the salomon algorithm and the inappropriate triages (over and undertriages) based on the preselected criteria the availability of a reliable triage tool for their early identification. we created a new triage algorithm, persee (protocoles d'evaluation pour la réorientation vers un service efficient extrahospitalier) and tested its feasibility, performance and safety. methods: after initial evaluation with a -level ed triage scale [ ] , ambulatory self-referred patients classified as level or below benefited from a simulated triage with persee identifying categories of patients: ed ambulatory patients and primary care (pc) treatable patients. we collected patients data and resources. patients requiring less than resources, no specific emergency treatment and no hospitalization were considered as manageable in a pc facility. results: patients were included in the study of whom . % were self-referred (fig ) . among those self-referrals, . % were triaged as level or below. . % patients were triaged as ambulatory patients of whom % were as pc treatable. we noted a redirection rate of % of the global visits or % of the self-referrals, an error rate of %, a sensitivity of . % and specificity of . %. conclusions: using advanced ed triage algorithm in addition to classical ed triage might offer interesting perspectives to safely divert self-referrals to pc facilities and, potentially, reduce ed workload. introduction: generally, prehospital medical provider should minimize staying prehospital scene to reach the patient to definitive care as soon as possible in prehospital medical activity. in addition, some textbook and report saids that medical provider minimize the number of procedure or limit minimum requirement procedure because unnecessary procedure may extend the staying time in prehospital scene. however, there are few studies evaluating this hypothesis and that this "extension is significant or not. therefore, we perform this study. methods: we evaluated the operated air ambulance(doctor-heli) case from st april to st march , in gifu university hospital using our mission record. we evaluated about time from landing to ready for taking off(activity time), operation doctor, mission category (i.e. trauma), number of procedure in the each activity and work load. we only focused on prehospital care and exclude transportation from hospital to hospital . in addition, we exclude the case which are not suitable for analysis. results: cases were operated in these period. cases were suitable for analysis. average activity time in prehospital scene was . ± . . there was weak correlation between the number of procedure and activity time. (r= . ) the length of the activity time did not depend on mission category. if the doctor perform and over procedures, staying time was minutes longer, this was significantly longer than that of under and under procedures. conclusions: we confirmed that we have to minimize the number of procedure or limit minimum requirement procedure in prehospital scene. and our result suggest we may have to limit appropriate number of procedures. introduction: organ failure is a critical condition, but the prevalence is largely unknown among unselected emergency department (ed) patients. knowledge of demographics and risk factors could improve identification, quality of treatment, and thereby improve the prognosis. the aim was to describe prevalence and all-cause mortality of organ failure upon arrival to the ed. methods: this was a cohort-study at the ed at odense university hospital, denmark, from april , to march , . we included all adult patients, except minor trauma. organ failure was defined as a modified sofa-score > within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic, and coagulation. the first recorded vital, and laboratory values were extracted from the electronic patient files. primary outcome was prevalence of organ failure; secondary outcomes were - -day and - -day mortality. results: of , contacts . % were female and median age (iqr - ) years. the prevalence of new organ failure was . %, individual organ failures; respiratory . %, circulatory . %, cerebral . %, renal . %, hepatic . %, and coagulation . %. the - -day and - -day all-cause mortality was . % ( % ci: . - . ) and . % ( % ci: . - . ), respectively, if the patient had new organ failures at first contact in the observation period, compared to . % ( % ci: . - . ) and . % ( % ci: . - . ) for patients without. seven-day mortality ranged from hepatic failure, . % ( % ci: . - . ) to cerebral failure, . % ( % ci: . - . ), and the - -day mortality from cerebral failure, . % ( % ci: . - . to renal failure, . % ( % ci: . - . ). conclusions: new organ failure is frequent and serious, with a prevalence of . % and a one-year mortality of % with wide variation according to type of organ failure. results: we proceeded to a descriptive study that showed that % of patients were male and % of them were female with a sex ratio of . .the average age of patients was years old and ranged between and years old.we found that patients of our population had medical background, dominated by diabetes in cases, high blood pressure in cases and asthma in cases.the results also showed that . % of patients had a history of abdominal surgery while % of them had history of other types of surgery.the patients were oriented according to their severity level as following: % care unit of emergency department, . % close monitoring room .the vaspi score was ranged between and with an average of ± . it was higher than in . % of cases.the results of physical examination found an isolated pain in , % of cases, a reactionnal pain syndrom in % of cases, a peritoneal syndrome in % of cases and an occlusive syndrome in % of cases.the final diagnosis was mostly represented by the following causes: . % of gastroenteritis . % of constipation and % of ulcer disease.the final orientation of patients according to the diagnosis led to hospitalization in % of cases and to outpatient clinic in % of cases while % of them did not need any more care. conclusions: appropriate diagnostic evaluation and decision for or against hospitalization is a challenge in the patient who comes to the emergency department with acute abdominal pain it need an adequate evaluation and management. introduction: we assessed patients' impressions of a selfadministrated automated history-taking device (tablet) to gather information concerning emergency department (ed) patients prior to physicians' contact. the quality of communication was compared with the traditional history-taking. methods: the algorithm content was developed by two emergency physicians and two emergency nurses through an iterative process. item-content validity index (i-cvi) was measured by five experts rating the relevance of each item (from : not relevant to : highly relevant) [ ] . next, quality control was realized by research team. to assess the feasibility, we used a computerized randomization. low acuity, ambulatory adult patients presenting to the ed were assigned either to a control group (cg, n= ) beneficiating form a traditional history-taking process or to the experimental group (eg, n= ) assigned to use the tablet with further history-taking by the ed physician. communication was analyzed by the health communication assessment tool [ ] and satisfaction assessed by questionnaires. results: after two rounds, validity was excellent for each item (i-cvi > . ). the universal agreement method was of . . refusals (n= ) to participate were analyzed: they fear using an electronic device or the experimentation. content satisfaction revealed that % of patients understood the questions. % of patients indicated that the device was easy to hold and use. medical communication was not affected by the device (p= . ). we noticed that, among the subsections, physicians significantly introduced themselves better in the eg (p= . ). conclusions: in this feasibility study, patients were highly satisfied. the use of a self-administrated automated history-taking device does not generate miscommunications and allow physicians better introduce themselves. . a positive point we have established is the possibility for the detorsion of a twisted retention ovarian cyst after its transvaginal aspiration. we used this method only in cases when the onset of torsion did not exceed hours. . % of all emergency conditions associated with retention cysts were recurred by conservative therapy, and . % of patients with the retention cysts rupture were successfully treated in this way. conservative management is possible in the case of a small loss of blood (up to . - . ml), hemodynamic stability and the absence of signs of continuing bleeding. the detorsion and resection of the cyst when torsion is not more than °and even longer than hours, in most cases did not reveal necrosis in the appendages. conclusions: improvement of organs of preservation and reproduction in women. criteria for admission to an intensive care unit of a tertiary hospital: analysis of the decisions of the outreach intensivist and day in-hospital mortality introduction: the aim of this study was the analysis of icu admission criteria and evaluation of in-hospital mortality of patients assessed by our critical care outreach team. criteria for admission to the icu should be defined to identify the patients most likely to benefit from icu admission. this triage process is complex, associated with several factors, including clinical characteristics of the patients, but also subjective factors because it depends on the judgment of the intensivist who decides whether to admit or not the patient and is obviously conditioned to the structure and size of the icu. methods: the outreach intensivist records the patient observation in a form with questions (reversibility of acute illness, objective of admission in icu, comorbidities, functional reserve and intuitive prognosis of the doctor). analysis of months (january through june , ) of admission decisions in icu, mean delay, icu mortality, and day in-hospital mortality ( hm). results: the intervention of the intensivist in "outreach" was requested on occasions. the main places of observation were the emergency room ( . %) and the wards ( . %). the hm increased with the degree of comorbidity decompensation. functional reserve also influenced hm, reaching . % in partially dependent patients and . % in totally dependent patients. there was agreement between the mortality and the physician´s intuitive prognosis in % of the cases. conclusions: a larger sample is needed to draw sustainable conclusions, however, the evaluation algorithm correlated well with hospital mortality. decompensated comorbidities and low functional reserve have a negative impact on prognosis, regardless of acute disease. there was agreement between mortality and the physician´s intuitive prognosis. electrochemical methods for diagnosing the severity of patients with multiple trauma introduction: multiple trauma is one of the leading causes of death worldwide [ ] . timely diagnosis and treatment is crucial in this state. one of the promising areas is the use of new electrochemical methods they are simple, flexible, efficient and of low cost. among these methods, attention is paid to the measurement of open circuit potential (ocp) of the platinum electrode and cyclic voltammetry (cva). the ocp is a reflection of the balance of pro-and antioxidants in the body, and the amount of electricity (q) determined by cva is proportional to the antioxidant activity of the biological environment. methods: a total of patients with severe multiple trauma ( . ± . y.o., men and women) were enrolled; apacheii . ± . ; iss . ± . ; blood loss ± ml. blood plasma was collected from patients. measurement of the ocp was carried out according to [ ] , cva analysis -according to the original method on a platinum working electrode. results: a shift in the ocp towards more positive potential values (fig. ) , while the antioxidant activity of blood plasma decreased (fig. ) . a more significant change of ocp, as compared to the q values, may indicate not only a deficiency in the components of the antioxidant defense system of the body, but also an increase in the concentration of prooxidants (e.g., reactive oxygen species), which are involved in oxidative stress. who underwent surgical fixation). information was collected from tarn, icnarc and surgical team databases. our primary outcome was itu resource utilisation (itu los and mechanical ventilation days). our secondary outcomes were morbidity and mortality (hospital los, infection burden, inotrope use and death before discharge). data was collected and analysed in microsoft excel and r. results: patients were included (group = , group = , group = ). mortality was significantly higher when comparing the post groups undergoing conservative ( %, / ) vs. surgical fixation ( %, / ), p-value = . . regarding potential temporal changes, there was no significant difference in mortality between the non surgical groups; pre- (group : / ) and post (group ), p-value . . group patients did spend more time mechanically ventilated (p-value . ) and used more antimicrobials (p-value . ) ( table ) . conclusions: patients undergoing surgical rib fixation at the rlh had significantly improved mortality with more days spent mechanically ventilated. pilot study on ultrasound evaluation of epiglottis thickness in normal adult a osman introduction: as the prevalence of epiglottitis is decreasing due to immunization, the difficulty in early detection remained. the aim of this study is to determine the thickness of epiglottis in normal adult with the utilization of bedside ultrasound. methods: this was a prospective observational study of convenience selection among healthy staff in emergency department, university malaya medical centre. the identification and measurement of epiglottis were performed using a mhz linear transducer by trained emergency physicians and registrars in em. subjects were scanned in either standing or upright seated position with the neck neutral or mildly extended. the epiglottis, thyroid cartilage and vocal cord were visualized and the epiglottis anteroposterior(ap) diameter was measured. difference in categorical parameters were analyzed by independent-sample t-test. the relationship between height, weight and epiglottic size was analyzed using pearson's correlation. results: fifty-six subjects were analyzed with males and females age ranging from to years old. the epiglottis ap diameter ranged from . cm to . cm, with average of . cm. there was significant difference in epiglottic ap diameter between male (m= . cm, sd= . ) and female (m= . cm, sd= . ; t( )= . , p=< . , twotailed). moderate positive correlation between height and epiglottic ap diameter (r= . ) and weight (r= . ) was documented. conclusions: our study demonstrated the identification and visualization of epiglottis was feasible and easy with the use of bedside upper airway ultrasonography. there was a little variation in the ap diameter of epiglottis in adults. indoor vs. outdoor occurrence in mortality of accidental hypothermia in japan y fujimoto , t matsuyama , k takashina introduction: the impact of location of accidental hypothermia (ah) occurrence has not been sufficiently investigated so far. thus we aimed to evaluate the differences between indoor and outdoor occurrence about baselines, occurrence place, mortality, and length of icu stay and hospital stay. methods: this was a multicenter retrospective study of patients with a body temperature ≤ °c taken to the emergency department of hospitals in japan between april and march . we divided the included patients into the following two group according to the location of occurrence of ah (indoor versus outdoor). the primary outcome of this study was in-hospital death. secondary outcomes were the length of icu stay, and hospital stay. results: a total of patients were enrolled in our hypothermia database. there were and patients with the outdoor and indoor occurrence. the indoor group was older ( versus . years-old, p< . ) and worse in adl than the outdoor group. the proportion of in-hospital death was higher in the indoor group than the outdoor group ( . % [ / ] versus . % [ / ], p< . ). the multivariable logistic regression analysis demonstrated that adjusted odds ratio of the indoor group over the outdoor group was . ( %ci; . to . ) ( table ) . as for secondary outcomes, both of the length of icu stay and hospital stay in survivors were longer in the indoor group than the outdoor group. conclusions: our multicenter study indicated that indoor occurrence hypothermia accounts for about % of the total in this study, and the proportion of in-hospital death was higher in the indoor group. we have to raise an alert over the indoor onset accidental hypothermia and need to take countermeasures for prevention and early recognition of ah in indoor location. conclusions: during acute asthmatic attack, arterial hyperlactatemia is frequently present at ed arrival. nevertheless, the plasma lactate level was no significant difference between ed admission and hr after treatment. the introduction: this is a case series of traumatic aortic injury (tai) which was diagnosed by transesophageal echocardiography (tee) in the emergency department. the number of patients with blunt thoracic aorta injury arriving at emergency department is on the rise and survival rate is time-dependent on early diagnosis. tee offers several advantages over transthorasic echocardiography (tte) including reliability, continuous image acquisition and superior image quality. methods: all trauma patients who presented to emergency department from st january until th november at hospital raja permaisuri bainun, perak, malaysia with suspected tai were evaluated with transesophageal echocardiography. over the years period, tee was performed in patients. patients had positive findings suggestive of tai. results: the first case was an old lady who presented after a deceleration injury in a car accident. tee was performed due to hemodynamic instability and found an intimal flap along the ascending aorta. the second case, a stanford type a (figure ) , was complicated with pericardial tamponade. the intimal flap was visualised from the aortic arch extending to the descending aorta by tee. the third case was a case of intramural haematoma involving distal aortic arch extending to the descending aorta which survived until corrective surgery. in the fourth case, tee revealed a motion artefact which mimicked an intimal flap in the ascending aorta. in the fifth case, tee showed intimal flap at aortic isthmus which was not detected by tte. in the last case, a traumatic aortic dissection was complicated by aortic regurgitation (figure ) . conclusions: tee can be a useful point of care tool use by emergency and critical care physicians for early diagnosis of blunt traumatic aorta injury. introduction: reboa is an endovascular intervention intended to preserve central perfusion in the context of shock due to noncompressible torso haemorrhage. more so, it is less invasive than the traditional approach of resuscitative thoracotomy (rt) and aortic crossclamping. though its use dates back to the korean war, it has not been widely adopted in trauma management, as evidence demonstrating clear benefit compared with conventional rt is lacking [ ] . we aimed to evaluate feasibility, outcomes and complications after reboa for haemorrhagic shock and traumatic cardiac arrest. methods: we performed a systematic literature review, searching scopus and pubmed databases using relevant terms (july ). we included studies enrolling patients with haemorrhagic shock or cardiac arrest after civilian trauma who had undergone reboa and reported hospital mortality (our primary outcome). abstract-only studies and single-patient case reports were excluded. we collated and analysed data using review manager v . . the newcastle-ottawa scale was used to assess risk of bias. results: sixteen in-hospital studies met inclusion criteria (n= ). ten were case series and six were cohort studies comparing reboa outcomes with those of rt. there were wide differences between studies' inclusion criteria, case-mix (including cardiac arrest), injury severity, insertion details, and reported outcomes. overall hospital mortality post-reboa was . %. meta-analysis of cohort studies indicated notably lower mortality in patients undergoing reboa (or . , . - . ) than rt with low statistical heterogeneity between studies (i = %), shown in fig . conclusions: whilst our findings are limited by methodological differences and biases in the included studies, almost % of patients undergoing reboa for haemorrhagic shock and/or cardiac arrest survived to discharge. furthermore, reboa appeared to offer a consistent mortality benefit compared with rt. introduction: trauma related coagulopathy remains a primary contributor to mortality on battlefields and in civilian trauma centres. fibrinogen is considered to be the first to drop below critical level and correspondingly compromised coagulation process. however, it is unclear if fibrinogen concentrate at a very early stage is feasible and effective to prevent from coagulopathy. methods: a total of acutely injured patients in austria, germany and czech republic were screened and enrolled in this controlled, prospective randomized placebo controlled double blinded multicentre and multinational trial. upon the completion of randomization, fibrinogen concentrate ( mg/kg, fgtw©, lfb france) or placebo was reconstituted and given to the patients at the scene or during helicopter transportation from the scene to nearby hospitals. blood samples were taken at baseline (scene of accident before study drug administration), at the emergency room, three hours, nine hours and twentyfour hours after admission to the hospital as well as after three and seven days after admission, for measurements of blood gases and coagulation, together with clinical data and outcome records. results: the demographic and injury characteristics and the estimated blood loss, iss, and gcs at the scene were similar in both groups. in the placebo group, fibrinogen concentration dropped from mg/dl at injury site to mg/dl () at er admission and clot stability reduced from . mm ( , mm) to mm (p= . ) (fig ) . fibrinogen concentrate administration prevented the drop of fibrinogen level (baseline of mg/dl to mg/dl and improved clot stability from mm at baseline to mm at er. conclusions: pre-hospital administration of fibrinogen concentrate in traumatic bleeding patients is feasible and effective in preventing the development of coagulopathy. data from this study support the use of fibrinogen to prevent trauma related coagulopathy. fibrinogen concentrate vs cryoprecipitate in pseudomyxoma peritonei surgery: results from a prospective, randomised, controlled phase study results: the per-protocol set included pts (hfc, n= ; cryo, n= ). the mean total intraoperative dose of hfc was . g vs . pools of cryo (containing approx . g of fibrinogen). median duration of surgery was . h. overall haemostatic efficacy of hfc was non-inferior to cryo and was rated excellent or good for % of pts receiving hfc and cryo, with similar blood loss. intraoperatively, only red blood cells were transfused (median: unit). intraoperative efficacy is shown in table . infusions were initiated . h earlier with hfc than cryo due to faster product availability. preemptive hfc led to a greater mean increase vs cryo in fibtem a ( figure ) and plasma fibrinogen (figure ). there were serious adverse events (saes) in the hfc group and in the cryo group, including thromboembolic events (tees; deep vein thromboses, pulmonary embolisms). no aes or saes were deemed related to the study drug. conclusions: hfc was efficacious for treatment of bleeding in pts undergoing surgery for pmp. no related aes and no tees occurred in pts treated with hfc. fig. (abstract p ) . fib mcf t to t with % ci fig. (abstract p ) . fibtem a prior to and following the preemptive dose of hfc/cryoprecipitate introduction: patients in the intensive care unit often suffer from thrombocytopenia. in dealing with this problem, we need to figure out not only the cause of thrombocytopenia but also the risk of bleeding. however, there is no reliable method for evaluating bleeding risk. methods: in this preliminary study, four thrombocytopenic patients who required platelet transfusion before undergoing invasive procedure were enrolled. written informed consent was obtained from all patients for participation in the study. bleeding was graded using the who bleeding scale. thrombogenic activity was evaluated using total thrombus-formation analysis system (t-tas), rotational thromboelastometry (rotem), and multiplate impedance aggregometry. for t-tas analysis, we prepared a novel microchip, named hd chip, which is suited for analyzing low platelet samples rather than those with normal platelet counts. , key patient groups in which it was wasted and the use of standard laboratory tests (slts) to guide its use. the purpose was to assess the potential benefit a point of care viscoelastic haemostatic assay (vha) could have on ffp transfusion and waste. the national blood transfusion committee and nhs blood and transplant committee have published data showing that up to % of ffp is transfused inappropriately [ ] . methods: blood bank data was obtained evaluating haemorrhaging patients in whom ffp was requested across a nine-month period in . patient bleeds were categorised by speciality. the mean time ffp dispensed and wasted was recorded, as were timings of slt requests. where available, the inr result was recorded. results: patients were identified. transfusions were requested. table shows that the highest transfusion requirements are for acute medical emergencies and major trauma. % of transfusion were surgical specialities, it would be expected that these patients would have anaesthetic or critical care input. units were wasted. acute medical emergencies wasted the highest amount of ffp ( units). table demonstrates that . % of transfusions had an inr available one hour prior to ffp being dispensed. conclusions: we conclude that use of slts to guide ffp transfusion is low. this suggests transfusion decisions are being made clinically. a point of care vha could give treating physicians better access to timely haemostatic data. introduction: we developed the process for the out-of-hospital packed red blood cells (prbc) transfusion in the hems of castilla-la mancha clm according to criteria of medical indications, security, monitoring and tracking. haemorrhage is a preventable cause of death among population suffering accidents or bleeding injuries in regions with low population density where health services should reach people in remote areas. hems of clm is the first out-ofhospital emergency service in spain that provides prbc transfusion there where the accident takes place. this program has been developed jointly between hematologists of the center for transfusions ct and the hems team. methods: observational retrospective study with data collected from june to august . the medical helicopter was provided with two prbc o rh(d) negative (fig ) . shock index was selected as indication for transfusion. to achieve feasibility and preservation of the prbc it was established a prospective monitoring and microbiological culture for both groups: case group for the prbc kept in the hems and control group in the hospital (fig ) . controls and comparison of hematologic analysis were performed immediately and days after collection. statistics used spss . (signification p< . ). results: prbc were evaluated, case - control. analyses were tested days and after collection. hemolysis was not observed. all cultures were negative. results obtained of the prbc after days transported in the hems related to monitoring parameters were not different than those observed on prbc conserved in the ct. prbc were transfused to patients in out-of-hospital assistance. neither post-transfusional reactions or undesirable events have been registered. prbc units are changed every days. conclusions: the process designed (collection, conservation, tracking and tests) to make prbc available in the medical helicopter has demonstrated to keep the standard conditions and properties to be transfused in critically ill patients out-of-hospital. outcomes in patients with a haematological malignancy admitted to a general intensive care unit a corner east sussex healthcare nhs trust, intensive care, eastbourne, united kingdom critical care , (suppl ):p introduction: recent published data have challenged the view that critically ill patients with a haematological malignancy have a poor prognosis [ ] . reports have largely originated from tertiary centres. the aim of this audit was to evaluate the intensive care unit (icu), in hospital and one year mortality for a cohort of patients admitted to a mixed medical and surgical icu in a district general hospital. methods: details were obtained for all patients with a haematological malignancy admitted to eastbourne and hastings icu between march and august . patient characteristics, type of malignancy, reason for admission, degree of organ support and survival rates at icu discharge, hospital discharge and year postadmission were collected. results: patients, % male, were identified. median (interquartile range, iqr) age was ( - ) years. % had neutropenia. the commonest malignancies were acute leukaemia %, lymphoma % and myeloma %. reasons for admission were respiratory %, cardiac % and renal %. organ supports used were noradrenaline %, intubation and mechanical ventilation %, renal replacement therapy (rrt) % and dobutamine %. overall survival rates are shown in figure . patients were discharged from hospital following a period of mechanical ventilation. for these patients, median (range) age was ( - ) years. all were male. median (iqr) time in hospital prior to admission was ( - ) days, / patients required vasoactive support, / required rrt, median icu length of stay was ( - ) days. / were admitted following surgery for an unrelated condition. to date, only / patient has survived years post icu admission. conclusions: although survival rates were disappointing, particularly in those patients requiring mechanical ventilation, selected patients have the potential for a good outcome. these results outcomes have been presented to our haematology department to aid patient counselling. analyses. cox regression was used for the survival analysis. organ failure was defined as the occurrence of renal failure based on acute kidney injury network (akin)-creatinine or need for; vasopressors, invasive ventilation or continuous renal replacement therapy (crrt) the first days after admission. length of stay was only analysed in survivors. results: the study included unique patients. prolonged aptt was associated with mortality with a % confidence interval (ci) of hazard ratio . - . . prolonged aptt correlated also with the occurrence of renal failure and the need for vasopressor and crrt with % ci of odds ratio (or) . - . , . - . and . - . (fig ) . increased pt-inr was associated with the need for vasopressors and invasive ventilation with % ci of or . - . and . - . . both aptt and pt-inr correlated with length of stay with % ci of or . - . and . - . . conclusions: activated partial thromboplastin time on admission to the icu is independently associated with mortality. both aptt and pt-inr are independently associated with length of stay and the need of organ support. all regression models were adjusted for saps score which means that aptt prolongation and pt-inr increase on admission represent morbidity that is not accounted for in saps . introduction: the goal was to assess if daily venous thromboembolism (vte) assessment was being done in our critical care (cc) unit, and if not, what changes could be made. a mortality review showed the need for a dynamic vte assessment in cc patients, who are subject to daily changes influencing vte risk. a daily risk assessment was introduced, and a 'tab' on our clinical information system, metavision(r)(mv) was created. recently published national institute for health and care excellence guidelines on vte risk assessment in cc provided us cause to assess our compliance [ ] . methods: data was collected from mv. review of daily vte assessment was made and a percentage completion of daily vteassessments was calculated per patient.interventions were done using standard improvement methods through pdsa cycles. results: baseline data, of patients, was collected in july, .compliance with daily vte assessment was %. the results were presented at the clinical governance forum(cgf), and posters were displayed in cc. the second cycle, of patients, was collected in october. compliance had increased to %.following discussion from presenting results at the cgf, the vte tool was appropriately modified.the responsibility of vte assessment was also shifted to becoming more shared, including all clinical staff, rather than mainly consultants. the third cycle, of patients, was collected in november. compliance had increased to %.introducing a nursing care bundle with vte is in progress. conclusions: despite the identification of a risk in our clinical practice and the development of an appropriate it tool to facilitate improved practice, the advent of new national guidance revealed poor compliance with agreed standards. this shows the difficulties with achieving practice change in complex multiprofessional clinical environments. a sustained effort is required focusing on dissemination and engagement across the whole team. introduction: we describe the changes in anti factor xa (afxa) activity, thrombin generation and thromboelastography (teg) in critically ill patients with and without acute kidney injury (aki) following routine administration of tinzaparin as part of venous thromboembolism (vte) prophylaxis. methods: pilot prospective observational study. patients divided into those with and without aki were administered tinzaparin by subcutaneous injection as per established local guidelines. patients who did not receive tinzaparin were recruited as a 'control'. plasma afxa activity and thrombin generation were measured at intervals over a hour period. teg parameters were collected at t and t . results: afxa activity: results are shown in figure . / patients failed to achieve a prophylactic afxa level of > . at any point. / patients achieved a level of > . however in all cases this was at the lower end of the prophylactic range and was achieved for only a short time (median . hours). / achieved a level of > . for the whole h period. there was no difference between the aki and no aki groups. endogenous thrombin generation: there is no significant difference in thrombin generation between the aki and no aki groups. there is a significant decrease in thrombin generation between h and h (p< . ) and a significant increase between h and h (p< . ) (figure ). there is no significant difference between h and h (p= . ). teg: all teg parameters for all patients were within normal range conclusions: standard vte prophylactic dose tinzaparin rarely achieves an afxa range that has been suggested for vte prophylaxis. however, as assessed by thrombin generation, a hypo-coagulable state is generated in response to lmwh. there is no difference between critically ill patients with or without aki that would suggest the need for dose reduction in this context. (abstract p ) . thrombin generation at h, h and h. t = time of tinzaparin administration, with the sample taken just prior to administration. patients from aki group shown with dotted line and from no aki shown with solid line % which takes the third place between cpb-associated complications . current data demonstrates the importance of researching of changes in haemostatic system in paediatric patiens after cpb. provided below data is an intermediate result of our research. methods: patients in age up to mohth days (median age - , months, youngest age - days after birth, oldest - months days), who underwent cardiac surgery with cpb to treat congenital heart diseases, were enrolled in this study. all patients were divided into two groups: stwithout tc, ndwith tc. protein c (pc) and fibrin-monomer (fm) plasma levels were assessed in there points: before surgery, -hours and hours after surgery. thrombotic cases were provided by doppler ultrasound or mri. results: thrombotic complications were diagnosed in chidren ( %). between all tc ischemic strokes were diagnosed in % ( cases), arterial thrombosis in % ( cases), intracardiac thrombus in % ( cases). in group with tc fm-mean values in points , and respectively were . ; and mcg/ml, meamwhile in group without thrombosis - . ; . and . mcg/ml .pc-mean value in st groupwere ; and %, in the nd group - ; and % respectively in the points , and . statistically significant differences between groups in rd point (p< . ) and correlation between pc and fm (r=- . ; p< . ) were detected. conclusions: cpb causes hypercoagulation with increasing of pc consumtion and fm level. moreover, cp associated with a high risk of tc on the rd day after cardiac surgery. further studies to investigate prognostic values of fm and pc in thrombosis are required. these studies would help to asses fm and pc as markers of tc and possibility of pc-prescribing for prevention and treatment of these complications. introduction: thrombocytopenia is a common condition in critically ill patients and an independent predictor of mortality. the relevance of a supranormal platelet count remains unclear. septic patients with disseminated intravascular coagulation (dic) are also known to have a high mortality, but the influence of sepsis on mortality rates in coagulopathic patients is less well characterised. our objectives were to: ) evaluate mortality amongst patients with sepsis and nonsepsis associated dic. ) assess incidence of dic during the first days of admission. ) assess the relationship between platelet count and mortality. methods: records of adult critical care patients admitted to the royal liverpool university hospital between - were retrospectively reviewed. the presence of sepsis (using the definition of sirs with infection), coagulopathy, degree of thrombocytopenia and day mortality were noted. modified isth dic score was used to define dic. results: the overall mortality rate was %. patients were identified as having sepsis ( %) and non septic patients ( %). mortality rates of patients with sepsis were significantly higher than without sepsis ( % vs % respectively, p< . ). in patients with dic, their dic scores tended to be 'positive' for the first days of admission. fibrin-related markers were often not available for dic scoring. mortality rates amongst patients with sepsis-associated dic were greater than patients with non-sepsis related dic. thrombocytopenia severity was associated with mortality, and patients with platelets above the upper limit of normal had lower mortality rates ( % when platelets > x ^ /l, % when platelets < x ^ /l). conclusions: sepsis-associated coagulopathy is associated with a higher mortality rate than non-sepsis associated coagulopathy. supranormal platelet counts may be associated with a mortality benefit. introduction: deep vein thrombosis (dvt) is a major problem in icu and affects overall lethality. dvt is widespread complication in icu, especially in elderly patients, when early activisation may not be achieved. aim of this study is comparison of haemostatic potential and analgesia methods of elderly patients who underwent major urological surgery during their stay in icu. methods: a cross-sectional study was employed. participants were ≥ y.o., underwent major urological surgery, have had normal initial hemocoagulation data (thromboelastography was performed to all of them), had received analgesia with epidural catheter or iv by opioids use and were treated in icu > days due to non-coagulopathy states, were included. data were collected from october till october . the patients were examined with thromboelastograph "mednord" for thromboelastogramm (teg) and with esaote usg for thrombi occurrence in lower limb deep veins. the anticoagulants were prescribed under the esa guidelines . results: participants (n= ) were divided in two groups -non-opioid analgesia with epidural catheter (n= ) and opioid analgesia (n= ). we received moderate decrease in anticoagulants dosage to the patients with epidural analgesia with the same teg goals compared to the patients with opioid analgesia. other factors as comorbidities may provoke dvt events, but was not evaluated in this study. the dvt events were monitored by expert with the use of usg to locate thrombi in the vein. conclusions: use of epidural catheter analgesia provides moderate decrease of anticoagulants dosage compared to opioid analgesia patients; however strict control of teg data must be presented. comorbidity need to be monitored for early detection and prevention of dvt events. introduction: patients with morbid obesity (mo) have a high risk of thromboembolic events. in patients with a bmi > , the hypercoagulable state is due to impairment of all parts of the blood coagulation as well as anticoagulation mechanisms by obesity. methods: the hemostasis system was studied in patients with a bmi> kg/m with various pathologies that were admitted to icu. all patients were divided into groups depending on the type of therapy: group (n= ) received monotherapy with enoxaparin sodium . % . ml sc times a day every h; group (n= ) received combination therapy with enoxaparin sodium . % . ml sc times a day every h and pentoxifylline mg times a day every h. to study the hemostasis system, we used lpteg immediately after hospitalization, on , , days. results: in both groups, prior to treatment: contact coagulation intensity (icc) was increased by . %, intensity of coagulation drive (icd) -by more than . %, clot maximum density (ma) -by . %, index of retraction and clot lysis (ircl) - . % above normal. patients of the st group: icc increased by . %, icd was close to normal values, ma increased by . %, ircl was increased by . %. patients of the nd group on the th day: icc decreased by . % compared with the norm; the coagulation and fibrinolysis parameters were close to normal values and the decrease in fibrinolysis activity reaches to normal. conclusions: combined therapy of thromboembolic complications in patients with obesity sodium enoxaparin sodium and pentoxifylline is more effective than enoxaparin sodium monotherapy because it affects all parts of the hemostatic system. introduction: a laryngeal injury secondary to blunt neck trauma can lead to life-threatening upper airway obstruction [ , ] . ultrasound enables us to identify important sonoanatomy of the upper airway [ ] . the purpose of this report is to discuss role of pocus airway in blunt neck trauma and to determine airway management based on standard schaefer subgroups classification. methods: three cases of blunt neck trauma presented to our centre with either subtle or significant clinical signs and symptoms. standard airway management was performed prior to pocus airway using mhz linear transducer and it findings were later compared to flexible fibreoptic laryngoscopy and computed tomography (ct). results: pocus airway had identified one out of cases to have schaefer and the remaining as schaefer . all pocus airway findings were confirmed with flexible fibreoptic laryngoscopy and ct scan (figs , ) . based on schaefer, supportive care and early steroid administration are advisable for group and . for groups to , immediate open surgical repair is deemed necessary due to extension of injuries.all cases were intubated using glidescope.all including those presented with schaefer were managed conservatively and discharge well with proper follow-up. conclusions: upper airway ultrasound is a valuable, non-invasive and portable for evaluation of airway management even in anatomy distorted by pathology or trauma. an organised approach using pocus airway as an adjunct can expedite care and prevent early and long term complications in facilities without flexible laryngoscope and ct. introduction: high-flow nasal oxygen (hfno) and helmet noninvasive ventilation (hniv) are increasingly used for the early management of acute hypoxemic respiratory failure (ahrf). we compared the physiological effects of hfno and hniv during ahrf. methods: in this randomized cross-over study, we enrolled patients with acute-onset (< days), non-cardiogenic respiratory distress (respiratory rate> /min), pulmonary infiltrates at the chest-x-ray and hypoxemia (spo < % while breathing on room air). all patients received hniv (peep cmh o, pressure support adjusted to achieve a peak inspiratory flow of l/min) and hfno (flow l/min) for one hour each, in a randomized cross-over manner. at the end of each period, arterial blood gases, inspiratory effort (esophageal pressure) and respiratory rate were recorded. self-assessment of dyspnea and device-related discomfort ( [ ] [ ] [ ] [ ] [ ] ). conclusions: as compared to hfno among critically ill patients with ahrf, hniv ameliorates oxygenation, limits inspiratory effort and relieves dyspnea, without affecting paco , respiratory rate and comfort. introduction: pre-intubation hypoxemia is a predictor of negative patient outcomes including in-hospital mortality. while successful first intubation attempt is also an important factor of patient outcomes, little is known about whether physicians achieve successful first intubation attempt for the hypoxemic patients in the emergency department (ed). the aim of this study is to investigate the first-pass success for patients with pre-intubation hypoxemia in the ed. methods: this is an analysis of the data from the second japanese emergency airway network study (jean- study)a multicenter, prospective, observational study of eds in japan. we included all patients who underwent intubation in the ed from through . we excluded patients ) aged < years and ) patients who underwent intubation for cardiac arrest. we grouped pre-intubation hypoxemia as follows: non-hypoxemia (oxygen saturation [spo ], ≥ %), moderate-hypoxemia (spo , %- %), and severehypoxemia (spo , < %). primary outcome was the first-pass success rate. to demonstrate the association between pre-intubation hypoxemia and the first-pass success in the real-world setting, we fit two unadjusted logistic regression models ) using grouped preintubation hypoxemia as a categorical variable and ) using the preintubation spo as a continuous variable. results: among , patients who underwent intubation in the ed (capture rate, %), , patients were eligible for the analysis. compared to the non-hypoxemia, the first-pass success rate was low in moderate-hypoxemia ( % vs %; or= . [ %ci, . - . ]) and severe-hypoxemia ( % vs %, or= . [ %ci, . - . ]). additionally, there was a linear association between pre-spo and lower first-pass success rate (or for the success, per one pre-spo decrease, . [ %ci, . - . ]). conclusions: based on the large, multicenter data, the first-pass success rate was low in hypoxemic patients compared to nonhypoxemic patients in the ed. introduction of rapid-sequence induction guideline to reduce drug-associated hypotension in critically unwell patients introduction: the aim of this project was to assess whether the introduction of a rapid sequence induction (rsi) agent guideline changed drug choice and the incidence of peri-intubation vasopressor use at st john's hospital, livingston. it is well documented that emergency airway management in the critically ill can be a source of significant morbidity and mortality [ , ] and the choice of induction agent matters [ ] . methods: an rsi agent guideline was instituted for all critically ill patients being intubated in icu and the ed [ figure ]. following this, we set up an intubation registry to collect data from all intubation events. this data was then compared to a previous audit of intubations completed in . results: the choice of agent used pre-and post-intervention are summarized in figure . forty-five intubation events were included in the initial audit in , of which, ( %) required vasopressor support immediately following intubation. of the intubation events following the guideline's introduction, ( %) required vasopressors. ketamine use changed from % to %, propofol use from % to % and midazolam from % to %. thirty-eight of these intubation events ( %) were compliant with the guideline. conclusions: the introduction of the rsi guideline dramatically affected the choice of induction agent and reduced the incidence of significant hypotension requiring vasopressors ( % versus %). overall compliance with the guideline was excellent ( %). introduction: the purpose is to test the feasibility of using the i-gel® device for airway maintenance during bronchoscopic-guided percutaneous dilatational tracheostomy (pdt). usually pdt is accomplished via the tracheal tube. failure to position the endotracheal tube correctly can result in further complications during the procedure. the alternative implies extubation and reinsertion of an i-gel® airway device. methods: the pdt was performed using the blue dolphin method in patients in intensive care unit. before undertaking bronchoscopicguided percutaneous dilatational tracheostomy (pdt), the patient's tracheal tube (et) was exchanged for i-gel®, as a ventilatory device for airway maintenance. the insertion of the i-gel®, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good ( ), good ( ), barely acceptable ( ), poor ( ), and very poor ( ) [ ] . results: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were or in % of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. conclusions: the i-gel® successfully maintained the airway and allowed adequate ventilation during percutaneous tracheostomy in all patients. the ratings were or in % of cases with regards to ventilation and to blood gas analysis, for identification of relevant structures and tracheal puncture site, and for the view inside the trachea during pdt. no damages to the bronchoscope, reports of gastric aspiration or technical problems were detected. the bronchoscopic view obtained via an i-gel® seems to be better than that obtained through an endotracheal tube (et) or through traditional laryngeal mask [ ] . introduction: the purpose of this study was to investigate the efficiency of nasal airway inserted in the oral airway (on airway) in securing the airway patency during mask ventilation [ ] (fig ) . methods: fifty eight patients undergoing general anesthesia were randomly assigned to either oral airway group (group o) or on airway group (group n). in both group, mg/kg of propofol was infused intravenously and mask ventilation was performed in the sniffing position without head extension or jaw thrust. the patients were ventilated with a volume-controlled ventilator with o flow of l/min, tidal volume of ml/kg (ibw), and respiratory rate of /min. before the start of mask ventilation, airway was placed in the oral cavity. oral airway was used in group o and on airway was used in group n. peak inspiratory pressure (pip), tidal volume and etco were compared between the two groups. the location of airway tip was graded by fiberoptic bronchoscope as; : airway obstructed by tongue, : epiglottis visible, : airway touches epiglottis tip, : airway passes beyond epiglottis tip [ ] . methods: a prospective uncontrolled observational study in - in ukrainian hospitals. sma-pts from - mo were involved. all pts. ready for extubation: afebrile, no infiltrations on chest x-ray, normal wbc. however, each sma-pts. failed sbt (t-tube or psv). we evaluated: extubation success (no reintubation in hours), icu los, one year survival. three pts. were excluded: two pts. by staff decision, family have choosen tracheostomy. sma-pts. included. a cuff leakage test performed -with a negative, dexamethazone mg iv was administered. after extubation niv was started by ventilogik ls in st mode via nasal mask giraffe. the epap and ipap settings were titrated to reach the chest excursion and target levels of spo ( - %) and etco ( - mmhg). a sputum was draining by mechanical insufflation-excuflation (mie) and aspirator results: all pts, were extubated successful. the mean icu los was . days ( - days), one year survival rate was %, respiratory failure fully compensated by niv, there was no icu admission. every sma-pts. are in good condition, gaining weight introduction: aerosol delivery has previously been assessed during simulated adult hfnt, delivered by various stand-alone humidification systems [ ] . the objective of this study was to evaluate aerosol delivery during simulated hfnt delivered by a mechanical ventilator, across three clinically relevant gas flow rates. methods: ml of mg/ml salbutamol was nebulised using an aerogen solo nebuliser (aerogen, ireland). an adult head model was connected to a breathing simulator (asl , ingmar, us), vt ml, bpm and i: e, : (fig ) . hfnt was supplied via the servo-u ventilator (maquet, getinge, sweden), using the integrated nebulisation option. tracheal dose was recorded at two nebuliser positions; a (after the humidification chamber) or b (before of the cannula), at three gas flow rates ( lpm, lpm and lpm) (n= ). the mass of drug captured on a filter placed distal to the trachea (tracheal dose) was quantified using uv spectroscopy at nm. results: presented in table . conclusions: to our knowledge, this is the first study to successfully demonstrate aerosol delivery during simulated hfnt, delivered by a mechanical ventilator. increasing gas flow rate was associated with a reduced tracheal dose (p= < . ). at lpm, a significantly greater tracheal dose was observed when the nebuliser was positioned before the nasal cannula (p= < . ). at lpm, a greater tracheal dose was yielded when the nebuliser was positioned after the humidifier (p= < . ). introduction: tracheotomies are often performed in critically ill patients who are in need of prolonged mechanical ventilation and respiratory care. our aim was to evaluate the possible effect of percutaneous and surgical tracheotomies on thyroid hormone levels. methods: eighty seven adult patients were included in our study from january to september . patients were in need of prolonged mechanical ventilation and tracheotomies were performed after consent was taken. we have excluded patients with preexisting thyroid diseases. forty five patients were undergone percutaneous tracheotomies and forty two patients were undergone for surgical. thirty eight female patients and forty nine male, age range - . we studied tsh, t and ft serum levels using chemiluminescence immunoassay method before either procedure and hours post each procedure.: statistical analysis was performed using spss . significance was estimated at the level of p< . results: tsh levels were increased in surgical group compared to percutaneous group at hours post procedure but the difference was not found statistically significant (p> . ). the rise in post operative levels of t compared to preoperative was found statistically significant for surgical tracheotomy group (p< . ).elevated ft levels for both groups have shown statistically significant difference between preoperative and postoperative period for the surgical tracheotomy group (p< . ) conclusions: we analyzed the effect of surgical versus percutaneous tracheotomy on thyroid hormones and it was found that both introduction: insertion of a tracheostomy for weaning purposes is associated with prolonged critical length of stay (los) and several adverse patient outcomes [ ] . previous work has suggested that protocolised weaning may reduce weaning times [ ] . we aimed to assess the impact of protocolised weaning on los following introduction of a standardised weaning protocol in . conclusions: introduction of a standardised weaning protocol for patients with a tracheostomy in our unit has had a beneficial effect on several patient outcomes, notably duration of weaning and length of critical care admission. introduction: delirium is a relatively frequent neurologic complication in liver transplantation (lt) recipients, which is an important cause of increased morbidity, mortality, extended icu stay, and increased cost of medical care. extubation of the endotracheal tube at an appropriate timing is an essential part of intensive care after lt, suggested to improve graft perfusion and systemic oxygenation, and thus decrease intensive care unit (icu) stay and positively affect prognosis. the aim of this study was to compare the incidence of delirium between early and late extubation groups after lt. methods: medical records from patients who received lt from january to july in a single university hospital were retrospectively reviewed. patients were divided into groups: those who underwent early extubation after lt (group e, n = ) and those who underwent extubation within few hours of icu admission after surgery (group c, n = ). the data of patients´demographics, perioperative management, and postoperative complications were collected. early extubation was defined as performing extubation in the operating room after lt. a propensity score matching analysis was performed to minimize the effects of selection bias. results: postoperative delirium occurred in / ( . %) in group e and / ( . %) in group c, respectively (p = . ). after propensity score matching, there was no difference in icu stay (p = . ), time to discharge after surgery (p = . ), and incidence of delirium between groups (p = . ). conclusions: although this study is retrospective in nature, limited by small sample size, early extubation did not affect the incidence of delirium after lt. further prospective studies on this area are required. weight estimation and its impact on mechanical ventilation settings in queen elizabeth hospital intensive care unit a nasr, a iasniuk, a roshdy queen elizabeth hospital, icu, london, united kingdom critical care , (suppl ):p introduction: documented weight in the intensive care unit (icu) can be the total, ideal, adjusted or predicted body weight (pbw). lung protective ventilation depends on tidal volume (vt) delivery which is based on accurate calculation of patients´weight [ ] . the weight is most probably documented on admission to the icu using estimation or one of many available equations. the aim of this study is to assess the documented versus the pbw and its impact on tidal volume delivery for mechanically ventilated patients in queen elizabeth hospital icu. methods: data was collected prospectively from all ventilated patients over a period of weeks in june . vt delivered in the first hour was calculated for each patient. documented body weight and height of each patient was obtained from the nursing chart. pbw was calculated and compared with the documented weight. the difference in vt attributable to the difference in weight has been subsequently calculated. results: ventilated patients were included ( males). the mean tidal volume delivered according to the documented body weight was . ml/kg versus . ml/kg based on pbw. vt more than ml/ kg was delivered in % of patients based on documented weight versus % when correcting the weight according to the pbw equation. conclusions: inaccuracy in documenting weight on patients´admission to the icu is a potential cause of delivering unsafe tidal volume [ ] . the harm can extend to drug dosage, nutrition provision and renal replacement therapy. introduction: ventilator-associated pneumonia (vap) is the leading cause of death among mechanically ventilated critically ill patients [ ] . chest radiography (cxr) is essential in the diagnosis of vap. in the past decade lung ultrasonography has proven to be a valuable tool in the diagnosis and monitoring of lung diseases. the aim of the study is to assess sensitivity and correlation between cxr, lung ultrasound and clinical pulmonary infection score (cpis). methods: in this retrospective, non-randomized study seven patients with proved vap were enrolled. in all patients cpis and lung ultrasound score (lus) [ ] were assessed. comparison of patients that had lus≥ and cpis≥ points was performed. the correlation between lus and cxr was done using the pearson model. results: we found significant difference between positive cxr patients with lus≥ and cpis≥ ( % vs %, p< . ). there is a very high correlation between cxr and lus. these results render lung ultrasound as a highly sensitive tool in the diagnosis of vap. conclusions: our study shows that lung ultrasonography could be used as a reliable supplementary method in the diagnosis of vap. the benefits of lung ultrasound include the ability to perform it at the patient´s bed without need for transportation, no radiation exposure and repeatability. the high correlation between cxr and lung ultrasound makes echography a valuable adjunct in the diagnosis of vap. color introduction: it is difficult to differentiate between pneumonia and atelectasis as cause of lung consolidation in intensive care unit patients. tools like the clinical pulmonary infection score are of little help (sensitivity % and specificity % for detecting pneumonia) [ ] . the objective of this study was to determine the accuracy of ultrasound assessed vascular flow within the consolidation to distinguish these causes. methods: adult patients with pulmonary symptoms and lung consolidation on lung ultrasound that were scheduled for chest-ct were included. vascular flow was analyzed with color doppler imaging (flow velocity scale was chosen at . m/sec.). the final diagnosis made by the treating physician was regarded as the gold standard. results: patients were included of which nine ( %) were diagnosed with pneumonia. vascular flow in the consolidation was present in seven ( %) out of nine patients with pneumonia, compared to three out of ( %) patients with atelectasis (p = . ). the diagnostic accuracy in differentiating between pneumonia and atelectasis was %. the sensitivity and specificity were % and % respectively. the positive predictive value was % while the negative predictive value was %. conclusions: vascular flow in lung consolidations assessed by lung ultrasound in icu patients aids in differentiating between pneumonia and atelectasis. it outperforms the frequently used clinical pulmonary infection score. methods: three intubated patients for various causes of respiratory distress undergoing mechanical ventilation were subjected to tee. at the level of mid-esophagus, the descending aorta short-axis view ( °) the imaging plane is directed through the transverse axis of the descending aorta. sector depth was increased to image the left pleural space beneath the aorta. for the right lung, the tee is rotated to the right at the level of atria until lung is seen or until the image of the liver is seen and the probe was withdrawn until the right lung is seen. recruitment manoeuvres were performed after identifying pbl atelectasis. atelectatic lungs were visually observed to open up during and after the recruitment manoeuvres. results: the time to acquire the image of pbl atelectasis from the time of insertion by tee is short. the images of posterior lung and the effect of lung recruitments is successfully viewed (fig ) . no immediate complication seen. conclusions: tee provides an excellent view of pbl atelectasis and able to directly monitor the success and failures of recruitment manoeuvres. introduction: high respiratory driving pressure (Δ prs) is strongly associated with increased risk of lung injury and increased mortality during mechanical ventilation. Δ prs consists of the pressure required to distend the lung the transpulmonary driving pressure (Δ pl) and the pressure required to distend the chest wall. Δ pl is the pressure that increases the risk of lung injury. data on Δ pl is limited because its measurement requires an esophageal catheter. we aimed to assess changes in Δ prs and Δ pl during proportional assist ventilation (pav+) at different experimental conditions. methods: we retrospectively analyzed patients ventilated with pav+ who had esophageal pressure measurements before and after dead space or chest load addition. we calculated end-inspiratory plateau pressure (pplateau), Δ prs, respiratory system compliance (crs) and Δ pl during occluded breaths in pav+ (figure ). data were compared with wilcoxon signed rank test and p value< . was considered significant. results: patients were analyzed. dead space increase ( patients) did not affect the studied parameters. chest load ( patients) significantly increased pplateau (p= . ) and Δ prs (p= . ) and decreased crs (p= . ) but Δ pl remained the same (p= . ). median (iqr) changes were . ml/cmh o ( . - . ) for crs, . cmh o ( . - . ) introduction: particle flow in exhaled air from mechanically ventilated patient's mirrors the opening and closing of small airways and can be detect by optical particle counter [ ] . we hypothesized that this particle flow is affected by cardiac function. methods: exhaled air from mechanically ventilated patients was analyzed using a customized optical particle counter pexa, figure . introduction: we assessed the diagnostic accuracy of mechanical power (mp) and driving pressure (dp) alone and combined with stress index (si) to identify ventilator settings likely to produce ventilator induced lung injury caused by tidal hyperinflation [ ] [ ] [ ] . methods: secondary analysis of a previous database of ards patients [ ] . computerized tomography markers of tidal hyperinflation (were used as a "reference standard". analysis of the area under the receiver-operating characteristics curve (auc) was used using a two-fold cross-validation. results: in a cluster of patients, a "training set" of not hyperinflated patients was compared with a "validation set" of hyperinflated patients. (figure - ) . conclusions: si seems to be more accurate than mp and dp in identifying tidal hyperinflation in patients with ards. specificity and sensibility were not improved combining si with mp or dp. the introduction: the pao /fio (p/f) ratio is widely used to assess the severity of lung injury. conceptually, the p/f ratio should be independent of the fio and solely depend on the pulmonary condition. however, effect of fio modulation on the p/f ratio has not been well characterized in ventilated intensive care (icu) patients. the purpose of the present study was to investigate the relationship between fio and the p/f ratio in icu patients on mechanical ventilation. methods: in a prospective, interventional study patients with a swan ganz catheter in situ were included. the p/f ratio was calculated at fio levels ranging from . to . with minute intervals. during the study other ventilator settings were not modulated. to understand the physiological effects of fio modulation on gas exchange and hemodynamics, mixed venous oxygen saturation and cardiac output were assessed. shunt fraction was calculated as described by west [ ] . results: patient characteristics and ventilator settings are reported in table . all patients were admitted to the icu after elective cardiac surgery. modulation of fio did have a significant effect on the p/f ratio, following a u-shaped pattern (p < . ) (figure ). the shunt fraction varied with altering fio levels, also exhibiting a u-shaped pattern (p < . ) (figure ). cardiac output was not affected by fio . conclusions: in contrast to current thinking, the p/f ratio varied substantially with altering fio levels in mechanically ventilated icu patients. this is an important novel physiological observation. in addition, it demonstrates that the assessment of the severity of respiratory failure by using the p/f ratio should be standardized to a fixed fio level. conclusions: in patients undergoing prolonged mechanical ventilation, we must take into account all the factors that may affect our patients. the assessment of diaphragmatic dysfunction is key to preventing weaning failure. an optimal level of consciousness as well as a good management of secretions are key to a successful weaning. prognostic value of the minute ventilation to co production ratio as a marker of ventilatory inefficiency in the icu r lopez , r pérez , Á salazar , i caviedes , j graf introduction: ventilatory inefficiency for co clearance may provide better severity stratification in acute respiratory failure than oxygenation [ ] . ventilatory inefficiency (vi) is best assessed by the bohr-enghoff physiological dead space [ ] . we recently reported that the minute ventilation to co production ratio (ve/vco ), a simplified vi index from exercise testing that obviates the paco measurement, correlates better than other vi indices to physiological dead space in mechanically ventilated patients [ ] . here we report the prognostic performance of this index using a survival analysis. mean±sem ve/vco was higher in patients who died than those who survived ( ± vs ± , p< . , figure ). we found a ve/ vco cutoff value of . mortality was higher in patients with high-ve/vco (≥ ) as compared to those with low-ve/vco ( % vs %, p= . ) with an odds ratio of . [ %-ci . - . ]. cumulative mortality was higher in the high-ve/vco than in the low-ve/vco group (log-rank p= . , figure ). conclusions: in this unselected cohort of mechanically ventilated patients an early high ve/vco ratio was associated to -days mortality. the ve/vco ratio may be a simple and non-invasive vi index with prognostic value in this population. introduction: sodium thiosulfate (sts) is a clinically relevant and safe hydrogen sulfide donor that improved acute lung injury (ali) and brain ischemia/reperfusion injury in previous studies [ , ] . methods: in a prospective, controlled, randomized, and doubleblinded trial, twenty adult, anesthetized, mechanically ventilated and surgically instrumented swine with preexisting coronary artery disease [ ] underwent h of hemorrhagic shock (hs; removal of % of the calculated blood volume and subsequent titration of mean arterial pressure to mmhg). post-shock resuscitation ( h) comprised re-transfusion of shed blood, crystalloids, and norepinephrine. animals were randomly assigned to "placebo" or "sts" ( . g·kg - ·h - for h). before, at the end of and every h after shock, hemodynamics, blood gases, and lung function were recorded. results: survival rates did not differ between groups. sts-infusion attenuated the hs-induced impairment of lung mechanics and pulmonary gas exchange (table , ), resulting in a significantly higher horovitz/peep-ratio ( figure ). conclusions: sts during acute resuscitation from hs may protect comorbid swine against hs-induced ali. introduction: alveolar epithelial cell (aec) death is a main mechanism of severe respiratory failure in acute respiratory distress syndrome (ards). classically, cell death is classified into necrosis or apoptosis. recent studies have reported that not only apoptosis but also certain types of necrosis are molecularly regulated and that these regulated necrosis can be therapeutic targets for various diseases. however, the relative contribution of necrosis and apoptosis to aec death in ards has not been elucidated. our study aimed to elucidate which type of cell death is dominant in aec death and to evaluate whether the regulated necrosis is involved in lps-induced experimental ards. methods: we established ards model by instilling μ g of lps intratracheally to mice. to estimate the relative proportion of apoptosis and necrosis in aec death, we measured cytokeratin m level (total cell death marker) and m level (apoptosis maker) in bronchoalveolar lavage fluid (balf) by elisa, and quantified propidium iodide-positive necrotic cells and tunel-positive apoptotic cells in the lung sections. moreover, we performed pathway enrichment analysis of gene expression data from pcr array to evaluate whether regulated necrosis pathway is associated with the ards model. results: both m and m levels were increased in the ards mice. the m /m ratio (an indicator of the proportion of apoptosis to total cell death) in the ards mice was significantly lower than that of healthy controls. moreover, the number of propidium iodidepositive necrotic cells was significantly higher than that of tunelpositive apoptotic cells in ards mice. in the pathway enrichment analysis, the necroptosis pathway, a regulated necrosis pathway, was associated with lps-induced experimental ards. conclusions: aec necrosis is more dominant than apoptosis in lpsinduced ards model. moreover, necroptosis may contribute to ards pathogenesis. aec necrosis including necroptosis is a potential therapeutic target for ards. clinical ards diagnosis is not associated with a unique circulating neutrophil cell surface phenotype t craven , s duncan , s johnston , c haslett , k dhaliwal , t introduction: acute respiratory distress syndrome (ards) is a form of non-cardiogenic oedema due to alveolar injury secondary to an inflammatory process. the clinical diagnosis is defined by the berlin criteria but this may not reflect the underlying biological process. the activated neutrophil is central to the pathogenesis of ards, characterised by altered cell surface markers. methods: three cohorts of seven participants were recruited. the first cohort suffered from mild, moderate or severe ards as defined by the berlin criteria [ ] . the second cohort was composed of ventilated patients on the intensive care unit with acute inflammatory lung disease (diagnosis of clinical suspicion) but did not meet the berlin criteria for ards. a third cohort was composed of age and sex matched healthy volunteers. procurement of human tissue was approved by a regional ethics committee ( /ss/ or /s / or amrec: -hv- ) and with the informed consent of the participant or their personal legal representative. patients were excluded if aged under or over years of age, were expected to survive for less than hours, if the attending physician refused, due to the absence of suitable indwelling vascular catheter, if the haemoglobin concentration was below . g/dl, or if the patient was enrolled in a trial of novel anti-inflammatory agent. whole blood (lysed erytocytes) underwent flow cytometry to determine cd b, , b, , l and . results: a description of the enrolled cohorts can be found in table . there were no significant differences between the mechanically ventilated, critically ill cohorts for any cell surface molecule in the multiplicity adjusted p values (fig ) . the results support the conjecture that clinical diagnostic criteria should not be used as a surrogate to stratify patients according to biological changes, with implications for the testing of biological therapies. introduction: aim of the present study was to compare the global and regional diagnostic accuracy of lung ultrasound (lus) compared to lung computed tomography (ct) scan in patients with the acute respiratory distress syndrome (ards). ards is characterized by a diffuse, inhomogeneous, inflammatory pulmonary edema. lung ct scan is the reference imaging technique, but requires transportation outside the intensive care and exposes patients to x-rays. lung ultrasound (lus) is a promising, inexpensive, radiation-free, tool for bedside imaging. methods: lung ct scan and lus were performed at peep cmh o. lus was performed using a standardized assessment of regions per hemithorax: superior and inferior; anterior, lateral and posterior. each region was classified for the presence of normally aerated, alveolar-interstitial syndrome, consolidation regions and pleural effusion. agreement between the two techniques was calculated, and diagnostic parameters were assessed for lus using lung ct as a reference. both a global and a regional analysis were performed. results: thirty-two sedated and paralyzed ards patients (age ± years, bmi . ± . kg/m and pao /fio ± ) were enrolled. global agreement between lus and ct was . ± . . the overall sensitivity and specificity of lus are shown in table . similar results were found with regional analysis (anterior/lateral/posterior lung regions is a common practice in our icu. during the interruption eit belt was positioned. when the presence of spontaneous breathing activity was evident by clinical assessment and ventilator traces analysis, nmba were administered to reach full paralysis, in accordance with the treating physician. eit tracing were analyzed offline and the change in eeli after nmba bolus, as compared to before nmba administration, was measured. respiratory mechanics and arterial blood gas (abg) data were collected results: we enrolled ards patients, undergoing controlled mechanical ventilation with muscle paralysis. baseline respiratory mechanics and abg data are shown in table . in out of patient the bolus of nmba led to an increase of eeli. in case, the nmb administration led to no changes in eeli. the mean change in eeli was ± ml conclusions: in our small population of ards patients, the administration of a bolus of nmba after the regain of spontaneous breathing activity led to an increase in eeli in out of patients. further study are needed to ) correlate this increase to global and regional respiratory system compliance and ) correlate this increase to the time needed to wean the patient from nmba introduction: to analyze the use of the orthostatic board as an auxiliary device for the treatment of severe ards by assessing its risks and benefits. methods: we selected patients, females and males, hospitalized in a neurological icu, between june and july , in a physiotherapeutic follow-up with diagnosis of severe ards. the patients were submitted to orthotics assisted for to minutes and monitored hr, pam, fr, sato at °and °of inclination and the pao / fio ratio after the procedure. the mean number of sessions per patient was . . all patients were undergoing anticoagulation in rass - , in the treatment of the cause of ards. the mean time of mechanical ventilation was . days. results: among the patients selected, . % presented tachycardia above bpm, requiring intervention in . % and interruption of the procedure in . %. pam arterial hypotension < mmhg was observed in . %, requiring intervention (increase of vasopressor dose and / or change of plank angulation) in % and interruption of the procedure in . %. hypoxemia sato < % was observed in . %, without interruption, but an improvement in pao / fio was observed in only . % of the patients. conclusions: assisted orthostatism as an auxiliary device for the treatment of severe ards was shown to be an alternative, with improvement of pao / fio in . % of the patients, safe and without significant hemodynamic repercussions that could lead to interruption of the procedure. introduction: the eolia trial found that vvecmo compared to conventional mechanical ventilation (cmv) did not improve mortality in patients with severe ards [ ] . the cmv strategy consisted of airway pressures below cmh o. in patients with severe ards higher airway pressures are required to maintain lung aeration. grasso et al. measured the transpulmonary pressure (p l ) in patients with severe ards and increased peep until p l was cmh o, accepting airway pressures above cmh o. fifty percent of patients responded to an increase in airway pressure and did not require vvecmo [ ] . we hypothesized that a p l guided open lung concept (olc) improves oxygenation and prevents conversion to vvecmo in patients with severe ards. methods: a retrospective study was conducted in a tertiary referral icu. the records of patients referred to our icu for advanced medical care were reviewed. inclusion criteria were severe ards according to the berlin definition and the eolia trial inclusion criteria for vvecmo. results: mechanical ventilation was limited to a p l of < cmh o instead of plateau pressures below cmh o. the p l guided olc resulted in an increase in p/f ratio and none of the patients required vvecmo. during the first hours peak airway pressure was increased, but was reduced within hours while peep was maintained ( fig. ). at hours both peak airway pressures and peep were reduced to baseline values while p/f ratio remained stable. only one patient ( . %) died of disseminated invasive aspergillosis. conclusions: the p l guided olc improved oxygenation and none of the patients required vvecmo. these findings support a ventilation strategy guided by transpulmonary pressures instead of plateau pressures in patients with severe ards. introduction: the mortality benefit conferred by early prone positioning in the treatment of acute respiratory distress syndrome (ards) has been well established. we also know that aprv improves oxygenation, and more recently has been shown to reduce ventilator dependent days and icu length of stay [ , ] . however, controlled ventilation remains the mainstay mode of ventilation used during prone position. literature looking at combined aprv and prone positioning is scarce. we aim to explore and report our institutional experience with respect to feasibility and outcomes in combining aprv and prone positioning, and perform a literature review in this area. methods: we undertook a single-centre retrospective cohort study within a surgical icu of a tertiary hospital in singapore between jan -oct . patients with ards who received combined prone positioning and aprv were reviewed retrospectively. a literature review of patients with ards who received combined intervention was also performed. results: adult patients aged - years old diagnosed with ards received a combination of aprv and prone positioning for a duration of - h ( table ). all the patients tolerated aprv with prone positioning well. our patients saw an improvement of p:f ratio ranging from - upon completion of combination therapy. out of patients were extubated within hours of turning supine, was weaned to tracheostomy mask after days and died while on the ventilator. only case report and randomized clinical trial were found on this topic upon literature review, which corroborated our findings. conclusions: in our experience, aprv is a practical and feasible alternative mode of ventilation that can be employed in the prone position, yielding significant p:f ratio improvements. the synergistic effects on improving oxygenation herald potential, especially in the subset of severe ards patients with refractory hypoxemia, where extracorporeal membrane oxygenation is unsuitable or unavailable. introduction: the recirculation during veno-venous extracorporeal membrane oxygenation (vv ecmo) had been a drawback, which could limit sufficient oxygenation. purpose of this study is to compare the short-term oxygenation in acute respiratory distress syndrome (ards) patients under vv ecmo according to their cannula configurations, especially in the national environment of the absence of newly developed double-lumen, single cannula. introduction: vv-ecmo is most commonly used in severe potentially reversible respiratory failure. this report looks at two patients in whom vv-ecmo was used to facilitate surgical airway stenting. methods: case -a -year-old with recurrent respiratory arrests, on a background of neurofibromatosis type and kyphoscoliosis. he had complex airway pathology, including, airway neurofibromas and granulation tissue, tracheobronchomalacia, severe kyphoscoliosis and a permanent tracheostomy tube. rigid bronchoscopy was performed and following debridement of granulation tissue, a trouser-leg stent was deployed. case -a -year-old with progressive stridor due to recurrence of a malignant melanoma, which was causing mid-lower tracheal compression. three tracheal stents were deployed via a rigid bronchoscope. in both cases, percutaneous bi-femoral vv-ecmo was established prior to general anaesthesia and decannulation took place the following day. results: in these cases, vv-ecmo provided stable extracorporeal gas exchange without conventional tracheal intubation. cardiopulmonary bypass and veno-arterial ecmo have been described in patients at risk of compression of the heart and distal airway [ ] . however, if the major threat is airway collapse, vv-ecmo can provide cardio-respiratory support without the problems associated with arterial cannulation and with lower anticoagulation requirements. introduction: ecco r facilitates the use of low tidal volumes during protective or ultraprotective mechanical ventilation when managing patients with acute respiratory distress syndrome (ards); however, the rate of ecco r required to avoid hypercapnia remains unclear. methods: we determined ecco r requirements to maintain arterial partial pressure of carbon dioxide or co (paco ) at clinically desirable levels in ventilated ards patients using a six-compartment mathematical model of co and oxygen (o ) biochemistry [ ] and whole-body transport [ ] with the addition of an ecco r device for extracorporeal veno-venous removal of co . the model assumes steady state conditions and is comprehensive from both biochemical and physiological perspectives. o consumption and co production rates were assumed proportional to predicted body weight (pbw) and adjusted to achieve pao and paco levels at a tidal volume of . ml/(kg of pbw) as reported in lung safe [ ] . clinically desirable paco levels during mechanical ventilation were targeted at mm hg for a ventilation frequency of . /min as previously reported [ ] . results: model simulated paco levels without and with an ecco r device at various tidal volumes are tabulated in tables and , respectively. table shows a substantial increase in paco at a tidal volume of ml/(kg of pbw) that is more pronounced when further reducing the tidal volume. additional simulations showed that predicted ecco r rates were significantly influenced by ventilation frequency. conclusions: the current mathematical model predicts that ecco r rates that achieve clinically acceptable paco levels at tidal volumes of - ml/(kg of pbw) can likely be achieved with current technologies; achieving such paco levels with ultraprotective tidal volumes of - ml/(kg of pbw) may be challenging. figure a ). pulmonary infections for each subtype of immunosuppression are shown in figure b . conclusions: ards vv-ecmo patients with underlying immunosuppression have higher mortality rates and higher rates of ecmo weaning failure. immunosuppressed patients suffer from a different spectrum of pulmonary infections in comparison to not immunosuppressed patients. introduction: acute asthma attack in children is a life-threatening emergency that requires urgent medical intervention. in the present study, we aim to clarify the effect of non-invasive ventilation (niv) on the heart rate (hr), respiratory rate (rr), and fraction of inspired oxygen (fio ) in children with acute severe asthma (asa) who failed to respond to standard medical treatment; and to evaluate the associated complications and length of stay (los) at the pediatric intensive care unit (picu). methods: this is a retrospective descriptive study of prospectively collected data. it was carried at the picu of a tertiary university hospital, saudi arabia. the study included children ≤ years old with asa admitted to the picu from november to november and required niv. outcome measures include the effect of niv on the hr, rr, fio , and los. the study included children with asa and ( %) of them required niv. of those patients, ( %) were excluded due to incomplete data, and ( %) patients were included in the final analysis. they were ( %) male and ( %) female with a mean age of months and a median pediatric index of mortality (pim ) score of . %. of them, ( %) had moderate asthma scores (≥ - ) and ( %) had severe asthma scores (≥ ). the median duration of niv was hours and the median los in the picu was three days. at hours, only rr showed a significant decrease compared to initiation of niv (p-value < . ) (fig ) ; while hr, rr, and fio were significantly improved at hours from initiation of niv (p-value < . ) (fig ) . conclusions: non-invasive ventilation, in association with standard medical treatment, was associated with clinical improvement in children with asa not responding to standard medical treatment alone. niv was not associated with significant complications or side effects. neurally adjusted ventilatory assist (nava) is a partial support ventilatory mode which triggers and tailors the level of assistance delivered by the ventilator to the electrical activity of the diaphragm. the objective of this study was to compare nava and pressure support ventilation (psv) in patients who were difficult to wean. methods: a total of difficult-to-wean patients who were able to sustained psv in the critical care medicine unit (icu) of the zhongda hospital, southeast university were enrolled in the study (fig ) . patients were classified according to the reason for weaning failure and were randomly assigned to receive nava or psv during weaning ( table ). the primary outcome was the duration of weaning. secondary outcomes included the proportion of successful weaning and patient-ventilator asynchrony. results: there were % ( / ) and % ( / ) patients in the psv and in the nava group never weaned from mechanical ventilation (p = . ). the duration of weaning was significantly shorter in the nava group [ . ( . - . ) days], than in that in the psv group [ . ( . - . ) days] (p = . ). the proportion of patients with successful weaning was % (n= / ) in nava group which was much higher than that in psv group ( %, n= / ) ( table ) . compared with psv, nava improved the rate of successful weaning in patients with single reason ( % vs. %, p = . ) but not in patients with multiple reasons for difficult weaning ( % vs. %, p = . ). nava decreased ineffective efforts and improved the trigger and cycling-off delays when compared with psv. mortality was similar in the two groups (fig ) . in patients who were difficult to wean, nava decreased duration of weaning and increased the probability of successful weaning. nava which improved patient-ventilator asynchrony, is safe, feasible and effective over a prolonged period of time during weaning. conclusions: only mrc score is independently associated with sbt failure and difficult or prolonged weaning. hgs is also associated with these two outcomes related to mv weaning and may serve as a simple tool to identify icuamw. introduction: there is evidence to support that in patients with hypoxemic respiratory failure (ahrf) under non invasive ventilation (niv), high tidal volume (tv) and high respiratory rate (rr) are associated with niv failure and possibly poor prognosis. we postulated that high minute ventilation (mv); or tv x rr; is associated with mortality in ahrf, when niv is initiated. methods: single-center, prospective and observational study. we included consecutives ahrf adults requiring niv. ahrf was defined as acute dyspnea with new pulmonary infiltrates on chest radiography and paco below or equal to mmhg. we registered demographic and clinical parameters (including rr, mv, arterial blood gases, heart rate and blood pressure) at baseline and after hours of first session of niv, apache ii score, diagnosis, need for intubation and icu mortality. we performed a multivariate analysis to assess independent factors associated with mortality and roc . ) and (auc = . ; p = . ), respectively for mortality, future exacerbations and readmissions. the optimal cut-off point for the mwt ratio to predict mortality was . and to predict future exacerbations and readmissions was . . the mwt ratio performed at icu discharge reveals interesting discriminative properties to predict early mortality, future exacerbations and readmissions in ae/copd patients. diffuse alveolar haemorrhage in an intensive care unit -search and you will find m matias , e ribeiro , j baptista , p martins introduction: the incidence of diaphragmatic ruptures after thoracoabdominal traumas is . - % [ ] and up to % diaphragmatic hernias present late [ ] when there is a complication. we report two cases of delayed traumatic diaphragm rupture to highlight the diagnostic difficulties. methods: case (image ) presented left diaphragmatic hernia containing the stomach, spleen, bowel and pancreas. the patient reported a motor vehicle accident dating months. he had thoracoabdominal trauma with several broken ribs on the left side. he then reported occasional pain in his left shoulder and occasional dyspnoea. case (image ) showed right diaphragmatic hernia containing right hemicolon, right hepatic lobe and gallbladder, he reported occasional dyspnoea and recent right chest pain. he had a years car accident in which three ribs broke on the right side. results: almost % of the patients with delayed diaphragmatic rupture presented with complications between and months after trauma, singh [ ] reported a diaphragmatic rupture presenting years after the traumatic event. the physical examination is often not helpful. conclusions: those cases emphasizes on the delayed presentation, patients may be asymptomatic or produce only mild, nonspecific symptoms, such as vague abdominal pain, chest pain or recurrent dyspnoea for months or years. the best tool to guide the clinician toward the appropriate diagnosis is a high index of suspicion whenever there is a history of high velocity trauma, regardless of how remote. factors associated with asynchronies in pressure support ventilation (psv), a bench study introduction: critically ill patients frequently have increased risk of ocular surface disorders (osds) due to poor eyelid closure and reduced tear production due to sedation during mechanical ventilation. we conducted a study to look at the incidence of osds in our icu with the current eye care practices and the impact of a protocolised eye care on the incidence and outcome and to determine the correlation of risk factors with the incidence of osds methods: this study was done in our mixed medical surgical icu. it had a prospective cohort design and was done as before and after study in two phases (phase i and phase ii). in phase i existing eye care practices were continued. in phase ii protocolised eye care was implemented and incidence of osds was noted in both phases. introduction: both fentanyl and morphine are known as opioid analgesics, which blocks the brain from receiving pain signals, the route of administration and the adverse effects affect their use. we compare the efficacy of intranasal fentanyl versus intravenous morphine adults population presenting to an emergency department (ed) with acute post traumatic severe pain. methods: we conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary emergency department between october and june . adults with severe post traumatic was included to receive either active intravenous morphine ( mg immediately and then mg every min if persistence of severe pain maximum mg) and intranasal placebo or active intranasal concentrated fentanyl ( μ g /kg maximum μ g) and intravenous placebo. exclusion criteria: significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring, pain scores were rated by using a digital scale at , , , and minutes. routine clinical observations and adverse events were recorded. conclusions: iscs were related to k over-use in our bicu. burnt patients are at risk of hepatic injury [ ] , but k related hepatic injury likely occurred. its not clearly understood mechanisms may involve a cumulative dose effect. although involvement of concomitant medications is being investigated, k restriction policy seemed to contain hepatic disorders. introduction: in november , our institution switched from using alfentanil to fentanyl for analgesia and sedation in adult patients receiving ecmo. there is no published evidence comparing the clinical use of alfentanil vs fentanyl for sedation in ecmo patients, although some reported increased fentanyl sequestration into the circuit [ ] . for these reasons, we conducted a retrospective observational study to explore whether there were any significant differences in patient outcome or adjunctive sedation before and after the switch. methods: outcome data and total daily doses of alfentanil or fentanyl as well as adjunctive sedation/analgesia for each patient where obtained from our clinical information system (philips icca®). data was included from ecmo patients who were sedated with alfentanil or fentanyl from / / to / / until ecmo decannulation. patients not requiring either opiate or who were switched between the two during ecmo therapy were excluded. all medicines prescribed for the management of sedation or agitation were included. for each patient an average total daily dose of each drug, was calculated. data was analysed using stata®. results: both groups were found to be statistically equivalent for mode of ecmo, age, apache score and charlson score (p= . ) except for bmi (p= . ). no difference in patient outcomes were found between groups (table ) . patients in the alfentanil group were found to have received significantly higher median average total daily dose of quetiapine and midazolam (table ) . conclusions: no differences in patient outcomes were found between patients sedated with alfentanil compared to fentanyl. we introduction: the european society of intensive care medicine consensus statement recommends that for comatose survivors of cardiac arrest hours without sedation is the minimum acceptable before neurological assessment. they highlighted the need to investigate the pharmacokinetics of opioid drugs in post-cardiac arrest patients, especially those treated with controlled temperature [ ] . methods: following approval by research ethics committee, we measured the blood concentration of fentanyl in post-cardiac arrest patients treated with ttm following cessation of continuous infusion. the fentanyl was discontinued when the patients were rewarmed to a temperature of . degrees celsius and a blood sample taken hours later. the blood was analysed using a commercial elisa kit (neogen corporation). using the total dose of fentanyl administered, the half-life of fentanyl was calculated for each patient. patient physiological data, cyp a and abcb polymorphism and drug history were compared with half-life. results: the median fentanyl concentration at hours was . mcg/l with a very wide range ( . - . mcg/l). the results for calculated half lives are shown in figure . there was no correlation between fentanyl level and bmi, illness severity (saps ll), creatinine clearance, transaminase or lactate level. there was no correlation between co-administration of drugs of metabolised by the cyp a and abcb enzyme systems or genotype. conclusions: there is marked variation in the concentration of fentanyl at hours in patients managed with ttm following cessation of fentanyl infusion. the calculated clearance of fentanyl in some patients is greater than hours and a hour cut off is not safe. introduction: objective of this study was to compare the effects of three analgesic regimens, one opioid and two multimodal ones, on cardiovascular stability and pain intensity in patients undergoing elective surgery under general endotracheal anesthesia during the h postoperative period. methods: sixty elderly patients, asa ii, undergoing elective knee sugary were assigned to receive ) morphine or mg iv q h, depending on body weight, and paracetamol g iv q h (mp group), or multimodal nerve block: ) femoral nerve block, single shot (fnb group) or ) fascia iliaca compartment nerve block single shot (ficnb group). measurement of pain intensity was performed with numerical introduction: opioids are frequently used in the intensive care unit (icu) to relieve pain and facilitate tolerance of life-support technologies. when discontinued abruptly, patients may develop a cluster of symptoms known as opioid-associated iatrogenic withdrawal syndrome (oiws). this phenomenon is poorly described in critically ill adults although it is associated with unfavourable outcomes, such as prolonged icu stay. the objective of this study was to describe the signs and symptoms of oiws in adult icu patients. methods: a prospective observational study was conducted in two tertiary care centres in patients requiring mechanical ventilation and regular opioids for more than hours. after an opioid dose reduction of at least %, patients were assessed daily for signs and symptoms of withdrawal using a standardized form. concomitantly, the presence of oiws was assessed daily by a physician using modified dsm- criteria. all physician evaluations were blinded and performed independently. inter-rater reliability for dsm- evaluations was assessed with the kappa coefficient. results: a total of patients were screened and twenty-nine enrolled. the majority were male ( . %) with a median age of . the median apache ii score was . withdrawal occurred in . % of patient within a median of three days (iqr to days) from opioid weaning. according to investigator assessment, restlessness, agitation, anxiety, hallucinations, insomnia/sleep disturbance, mydriasis and elevated blood pressure were more prevalent in oiws-positive patients. dsm- evaluations identified dysphoric mood, muscle aches, lacrimation/rhinorrhea, pupillary dilation/piloerection/sweating, diarrhea and yawning more frequently in oiws-positive patients. the kappa coefficient showed good agreement ( . ). conclusions: oiws in critically ill adults presents with a large spectrum of signs and symptoms that occur within a median of three days from onset of opioid weaning. further studies are needed to confirm these preliminary findings. withdrawal reactions after discontinuation or rate reduction of fentanyl infusion in ventilated critically ill adults s taesotikul introduction: propofol is a well-known sedative, commonly used in intensive care units (icu s), that on rare occasions has been reported to cause green urine and has also been associated with pink or transient white urine discoloration. it can cause several adverse effects, such as low blood pressure, pain on injection, apnea, hypertriglyceridemia and when administered in high doses it may lead to the "propofol infusion syndrome". methods: we present two examples of interesting urine discolorations observed unexpectedly in our icu in patients under propofol sedation requiring mechanical ventilation. results: dark green urine discoloration as presented in fig. is the result of a phenolic metabolite of propofol that is produced in the liver and is subsequently excreted in the urine, thus changing its color. it is considered a reversible phenomenon that resolves after propofol discontinuation.respectively, pink urine discoloration as presented in fig. can also be the result of propofol infusion. the increase in urine excretion of uric acid caused by propofol, in combination with a low urinary ph can lead to the formation of uric acid crystals and turn the urine pink. discontinuation of propofol and urine alkalization can reverse the phenomenon. conclusions: green or pink urine discoloration due to propofol is generally a benign, reversible condition. its presence should not compel the physician in charge to perform unnecessary testing, although other causes of discoloration should be considered. as far as green urine discoloration is concerned, other factors such as drugs, dyes, certain nutritional supplements or even a pseudomonas urinary tract infection may be at fault. on the other hand, pink urine syndrome due to propofol infusion seems to be even rarer. although its presentation is not alarming, it may well increase the risk of uric acid lithiasis, a fact that the physician in charge should always keep in mind. conclusions: hepatic changes related to propofol are frequently observed and should be systematically monitored to ensure patient safety. fig. (abstract p ) . dark green urine discoloration introduction: clevidipine (clev) and propofol (prop) are lipid-based medications used in the intensive care unit (icu) for hypertension and sedation, respectively. no data exists regarding potential adverse effects of concurrent therapy with this combination. this study aims to evaluate the incidence of hypertriglyceridemia (htg) and pancreatitis in icu patients using concurrent clev and prop. methods: this was a single-center, retrospective chart review in patients utilizing clev and prop concurrently from february to november . patients were included if they were years and older, on clev and prop concurrently for at least hours with no more than hours of interruption at a time, had at least one triglyceride (tg) level during concurrent therapy, and admitted to the medical or surgical icu. the incidence of htg (defined as tg equal to or greater than mg/dl) and pancreatitis (provider assessment based on american college of gastroenterology guidelines) was evaluated. patients with and without htg were compared to identify risk factors for the development of htg. results: of patients screened, patients were included which comprised observations. the incidence of htg was . % with no patients developing pancreatitis. patients with htg had a higher median age compared to without htg ( . vs. ), p= . . in patients with htg the median dose of clev and prop were mg/h and . mcg/kg/min, respectively, which was higher but not statistically significant when compared to patients without htg. cumulative lipid load (g/kg/d) was non-significantly higher in patients with htg ( . vs. . ), p= . . conclusions: the incidence of htg was comparable to what is cited in literature for prop alone. patients with htg were older, had higher median clev and prop doses, and a larger cumulative lipid load compared to patients without htg. introduction: the society of critical care medicine guidelines for pain, agitation and delirium suggested use of nonbenzodiazepine sedatives like dexmedetomidine which is associated with a reduced duration of mechanical ventilation, shorter length of hospital stay and a lower incidence of delirium [ ] . enteral clonidine represents a potentially less costly alternative for agitated patients with prolonged dexmedetomidine infusion. limited literature exists examining this transition for management of agitation [ ] . methods: the critical care management initiated an action plan on the transition of patients with prolonged dexmedetomidine infusion to oral clonidine. a protocol was prepared with clinical pharmacist's assistance. risk factors were assessed and inclusion criteria were applied as per protocol. dexmedetomidine infusion rate was reduced gradually with oral clonidine administration in selected patients. other rescue managements were implemented as per protocol. oral clonidine was then tapered down by reducing frequency of administration over few days. results: post intervention data in showed significant decrease of dispensed doses and cost of the injections compared to . the annual cost saving was % equating to , usd (table , figure ). conclusions: transitioning to clonidine may be safe and less costly method of managing agitated critically ill patients on prolonged dexmedetomidine infusion. more studies are needed to evaluate the efficacy and safety of this practice. incidence of dexmedetomidine associated fever at a level trauma center na beaupre, jt jancik hennepin county medical center, pharmacy department, minneapolis, united states critical care , (suppl ):p introduction: we evaluated the incidence of dexmedetomidine associated fever (daf) in a level trauma center's medical intensive care unit (micu). hypotension and bradycardia are the most commonly reported adverse effects associated with dexmedetomidine (dex) infusion. case reports suggest dex can cause fevers and the clinical trials that led to the approval of dex demonstrated fever rate to be - % [ ] . methods: this was a single-center, retrospective chart review of patients admitted to the micu at hennepin county medical center between march and july of that were started on a dex infusion. patients were included if they were years and older, on a dex infusion for at least hours, and had temperature data available. fever was defined as > . c and other causes of fever including infections, medications, withdrawal, recent surgery, thromboembolic disease, thyroid disorders and seizures were excluded from analysis. results: of the patients screened, were included. the mean age was years and . % were males. of all the patients included, the mean change in temperature after initiation of dex infusion was + . c from baseline. the mean initial dose was . mcg/kg/hr. four of patients ( . %) had a daf. of those that had a daf, the median initial dose was . mcg/kg/hr; the median time of infusion was . hours; and the median cumulative dose was . mcg/kg/hr. the median time to fever after initiation of dex was hours, with a range of to hours. the median time to fever cessation after discontinuation of dex was hours. conclusions: in our population, the incidence of dexmedetomidine associated fever was relatively rare at . % and similar to current literature rates. the results obtained showed a statistically significant fact that fewer points on the test, from to points, received older patients who underwent an urgent surgical procedure, over years of age, of which % . also statistically significant data were obtained that patients who used a higher amount of sedatives during emergency surgery, % had a worse test result than under points due to increased preoperative anxiety. the older population is more susceptible to postoperative delirium, especially in emergency surgery situations, which they carry, unpreparedness for surgery, increased use of medication for fig. (abstract p ) . flowchart of enrolled patients calm, unpredictability of the duration of surgery, and therefore anesthesia as well the use of anticholinergics, which is sometimes impossible to avoid in operative procedures such as gall bladder surgery. the results of the study suggest that in cases of emergency surgery, the use of protocols for postoperative delirium should be planned regularly to prevent or at least mitigate the clinical picture of delirium that can lead to complications postoperatively. introduction: delirium is a serious and often underestimated condition with implications for morbidity, mortality and healthcare costs. as it presents in a wide range of settings from admission to discharge, early prediction and risk assessment are essential. e-pre-deliric is a delirium prediction score which has been validated in itu patients but not in other populations, and we conducted a quality improvement project using this score to assess its utility in other settings. methods: data was gathered from three patient categories: those undergoing elective surgery (es), admissions to the emergency observation unit (eou) in the a&e, and patients with fractured neck of femur (nof). clinical notes were reviewed to collect data to calculate e-pre-deliric score at admission, along with a number of other clinical variables including incidence of delirium, and statistical analysis performed. results: a total of patients were included, with in the es group, in the eou group, and in the nof group respectively, with an overall average e-pre-deliric score of . %. es had a . % average e-pre-deliric score, a mean age of and no cases of delirium. the eou group had an average age of , a . % average e-pre-deliric score and no incidence of delirium. the nof group had a mean age of and an average e-pre-deliric score calculated on admission of . %. this was the only group in which patients developed delirium. a % cut off was demonstrated to be the most accurate to predict delirium in this population with a sensitivity of . and a specificity of . . conclusions: despite the limitation of a small sample size, this project has shown that e-pre-deliric score could be a useful tool to predict patients at high risk of delirium in a non-itu setting, with a % cut off in hip fracture patients. further investigation should be conducted into the potential use of e-pre-deliric in non-itu patients. comparison of long-term mortality between patients with and without delirium during admission in medical intensive care units in a university hospital n kongpolprom king chulalongkorn memorial hospital, pulmonary unit, bangkok, thailand critical care , (suppl ):p that delirium is linked with preoperatory comorbidities. the complexity of surgery has a big influence on the development of delirium, especially in the cases of aortic dissection. delirium was associated with intraoperatory blood transfusions. finally, our data point to a bridge between postoperatory electrolytic disturbances, as well as inflammation as factors potentially triggering delirium onset. introduction: we did a retrospective case note study of mortality due to sepsis of our unit over three months as observational study in which we noted the causes of deaths, origin of sepsis, organism, patient characteristics and icnarc physiology scores and icnarc h model predicted risk of acute hospital mortality percentage. methods: icnarc data base was used to gather the data and coding was used to identify the patients with sepsis for three months. patients mortality attributed to sepsis were identified from mortality list.causes of death were noted from patients notes and death certificates.cyber lab was used to access the data and case note were ordered for review.patients characteristics were noted including dnacpr orders and treatment withdrawal orders. scores (apache scores, icnarc physiology scores, icnarc h predicted risk models of acute hospital mortality percentage) were noted. results: mortality percentage was found to be % as per codig which was reduced to % as % deaths were attributed to other causes. % patient had dnacpr in first hrs. average length of stay was . days with median of . days.median age was yrs in surviving age group and years in other. icnarc physiology score with predicted risk of . %. commonest cause was found pneumonia % followed by urine tract infection. % patients were with no source identification. conclusions: conclusion was made that we do need to improve the coding as significant percentage was mentioned as sepsis as cause of death where clinicians differed. pneumonia was found to be the commonest killer in critical care followed by urine tract infection. it was pointed to be useful to carry out further audit targeting pneumonia .review of icnarc case mix program, development of icnarc physiology score, which provides excellent local use with downside of lacking international comparison was done also. introduction: hospitals vary widely in the quality of care they provide for septic patients. since many septic patients present to their nearest hospital, local variations in care quality may lead to geographic disparities in access to optimal sepsis care. we sought to better understand geographic access to high quality sepsis care, taking advantage of publicly reported data on sepsis management and outcomes in a large us state. methods: we performed a cross-sectional analysis of geographic access to high quality sepsis care, taking advantage of a new york state initiative that mandates public reporting of sepsis quality data to the state government. we linked these data to the locations of hospitals in new york state from the us centers for medicare and medicaid services and population data from the us census bureau for . we defined hospital sepsis performance using self-reported risk-adjusted mortality rates (ramr) and defined high-performing hospitals as those with a ramr < %, which represents the lower end of short-term mortality typically observed in sepsis. we used arcgis to generate drive-time estimates and assess population access to high performing acute care hospitals for sepsis care. results: hospitals publicly reported treating , cases of sepsis from a population of , , persons. overall access to an acute care hospital was excellent at the -minute drive threshold ( . %), good at the -minute threshold ( . %), and marginal at the -minute threshold ( . %). we classified hospitals ( . %) as high-performing based on a ramr < %. high-performing hospitals reported , ( . %) of the total sepsis cases. high-performing hospitals were geographically dispersed across the state, although population access diminished substantially with increasing drive times ( . % at -minutes, . % at -minutes, and . % at minutes; figure ). conclusions: one in six people do not have timely access to a high performing hospital for sepsis care using a -minute threshold. [ ] . this poses a significant safety risk. a previous study found that the implementation of a multidisciplinary medication safety group in intensive care increased reporting of errors and near misses [ ] . the purpose of our work was to set up a multidisciplinary group to provide a forum to review and improve medication safety at all stages of the process. here we discuss some of the initiatives and outcomes implemented in the last months. methods: ccmsg was formed in , under the leadership of the critical care pharmacy team, with representation from medical and nursing disciplines. the group meet fortnightly to analyse trends in medication errors, implement changes to local practice and review outcomes to improve patient safety. the cohesive, multidisciplinary nature of the group allows medication safety initiatives to be delivered in the most effective way. results: on average, ccmsg reviewed medication errors per month. the most common high risk drug classes involved are seen in table . medication safety initiatives implemented were based on these trends and included writing guidelines and policies, bedside education, teaching and training, informatics optimisation and operational changes. examples are seen in table . conclusions: initiation of a ccmsg provides a cohesive approach to facilitate the implementation of targeted safety initiatives, which are proven to reduce some of the most common medication errors in critical care. in addition, these often result in optimisation of operational and financial inefficiencies. introduction: cis/hospital electronic medical records downtime can cause major disruptions to workflow, patient care, key communication and information continuity [ ] . here we describe the consequences of deploying a business continuity plan (bcp) designed to support a critical care clinical informatics system (cis) failure, during an -hour unplanned downtime in a large central london icu. the institutional bcp was developed through an iterative process based on cis provider recommendations and internal workflow knowledge. it consisted of a web offline chart (woc) that is accessible at every computer connected to the network (in the event of a cis server fault), and via hard copy from designated back up computers connected to a printer (in the event of whole network loss). operational and clinical consequences were recorded during informal and formal debrief of the informatics team. the decision making around´drop-to-paper´was reviewed. -the bcp permitted´drop-to-paper´, service continuity and controlled uptime -patchy network loss and lack of a general institutional bcp delayed initial system failure diagnosis (network vs primary server); reduced reliability of´read-only´data and delayedd rop-to-paper-day-to-night handover during downtime led to loss ofḿ emory´of key patient data/events, and should have accelerated decision to´drop-to-paper-transfer of prescriptions was time consuming, distracting (occupied cis team) and prone to error conclusions: previous end-to-end testing of the bcp had not identified many of the observations and recommendations that came from the analysis of an actual period of unplanned downtime. we recommend sharing of similar experiences and scheduled high-fidelity simulated downtime in other institutions to replicate real world conditions, particularly in a critical care setting. . ) were predictors of icu transfer. we developed a simple score to predicting icu transfer from previous variables and performed analysis of auc of roc, which was compared to that of apa-che ii. the result showed the auc of roc of a new score was slightly higher than the apache ii, namely . vs. . respectively. conclusions: the immunocompromised patients take two times higher risk than the immunocompetent ones regarding icu transfer. the other risk factors are lower gcs, lower sbp, and higher rr. a newly developed score may be a promising tool for predicting and triaging site of care in patients who require imcu admission. introduction: this research aims to explore the role of situation awareness in the decision-making of patient discharge from the intensive care unit (icu). the discharge of these patients is a complex and, moreover, a challenging transition of care. readmissions are undesirable given the association with a more extended hospital stay and a possible chance of higher mortality. little is known on how the decision-making process takes place and accordingly, the role of situation awareness of patient discharge from the icu. in order to improve the quality of care of patient discharge from the icu, further research is necessary. methods: this research concerns a qualitative study in which various health care providers, working in an icu adults of a large teaching hospital, were interviewed. through purposive sampling, six nurses, two physician assistants, two intensivists and a physiotherapist were included. on the obtained data a thematic analysis was applied, based on the principles of the grounded theory. results: the discharge decision of icu patients seems mainly based on the team´s situation awareness, with the initiating role of the intensivist and the guiding role of the nurse. furthermore, there is an additional role for the physician-assistant and a consultative role for physiotherapy in the process of the decisionmaking. worries of patients and family seem not to affect the decision-making directly. in the decision-making process, the well-being of the patients and the possibility to provide the most suitable and best possible care were central. organizational factors, such as an urgent demand for icu beds do count but seem not to push the decision to transfer patients from the icu to the regular hospital ward. conclusions: the decision to dismiss icu patients is a complex process with different disciplines and a variety of factors involved. obtained knowledge and insights into the role of situation awareness provide starting points for improving the quality of the discharge process of icu patients. conclusions: despite the fact that older people was more severe illnes, and similar frequency of respiratory failure, the use of mechanical ventilation, the use of central venous catheter and arterial catheter was less frequent. the addition of a simulation fellow within the intensive care team and introduction of in situ simulation n bhalla, d hepburn, g phillips royal gwent hospital, intensive care unit, newport, united kingdom critical care , (suppl ):p introduction: traditionally, simulation based medical education has been carried out in off site simulation centres, however, we trialled the addition of a simulation fellow, within our intensive care team, to run an in situ simulation (iss) program on our intensive care unit over a month period. methods: our multi-disciplinary iss program, led by a simulation fellow, incorporated participants, observers and facilitators including doctors (junior trainees up to consultants of varying medical specialties), nursing staff, healthcare support workers, operating department practitioners, physiotherapists and medical students. we ran simulated emergency scenarios and technical skills sessions. with every scenario, we collected data on participant and observer feedback using the world health organisation participant feedback form and conducted a satisfaction survey at the end of our trial period. results: our results, highlighted in table , show participants found iss led by a simulation fellow realistic, well structured and organised. it was useful for testing and understanding our response systems, fig. (abstract p ) . patient journey of group : those patients discharged home days after step down from critical care identifying strengths and gaps and establishing individual roles/functions within emergencies; overall leaving us feeling better prepared for critical care emergencies. from our satisfaction survey, % of participants found the simulation fellow a useful addition to the intensive care team and expressed the need for more in situ simulation. conclusions: the addition of a simulation fellow allowed for numerous disciplines within the critical care team to be involved in challenging emergency scenarios (fig , ) , with the additional realism of being on the intensive care unit playing the role they would in real life; as well as having opportunity for spontaneous discussion and learning. from this they reported great benefit and satisfaction. following our initial success with this program, we plan to have a simulation fellow as an ongoing role within our critical care team. impact of multidisciplinary team in readmission in a brazilian cardiac intensive care unit c bosso , p introduction: the aim of this study is to determine the importance of the multidisciplinary team at readmission rates in a cardiac intensive care unit (cicu). methods: retrospective study with analysis of patients in a cicu of a medium size brazilian hospital. the years of and represent the reduced team (physician, nurse and physiotherapist) and and the complete multidisciplinary team (additional presence of phonoaudiologist, psychologist, pharmacist, dentist and nutritional professional). the risk of mortality was determined by saps score. in order to compare the teams, it was utilized odd ratio of a logistical sample to the discrete data, and t-student test to the continuous data. the data analysis was executed from the software rstudio ( . . ), and the significance level adopted was %. results: the number of patients was of n= ( from the reduced team and from the multidisciplinary team). the age, sex and bmi didn`t present significant difference between groups. the average age of the sample was ± years old (p= . ). the male sex represented % (p= . ), and the bmi was around . ± . (p= . ). the main diagnoses were similar in both groups -coronary angiography with stent ( %), unstable angina and non st elevation myocardial infarction ( %). table shows the average, standard deviation, p-value to t-student test to saps score and lengh of stay (days), according to both reduced and multidisciplinary teams. table exposes the mortality rate and readmission for both teams. the figure shows the odds ratio and its ic % to the comparison of the mortality, readmission, hours readmission and hours readmission rates between the teams. conclusions: the multidisciplinary team performance reduced the number of hospital readmissions in and hours in a cicu. methods: during the initial audit hours' worth of waste from one itu bed was manually divided into the categories above. results: based on these figures it was estimated that a saving of £ per year would be made (£ . per bed space) over the course of a year should domestic waste bins be placed across the bed icu/hdu. a business case was made, and every bay had a domestic waste bin installed with poster signs for explanation.the reaudit in which all domestic waste across the unit was weighed produced an even greater figure of a saving of £ per bed space (£ ) per year. conclusions: introducing a domestic waste bin may save approximately £ per year per bed. in a typical itu such as lewisham ( itu beds/ hdu beds) that may mean a saving of £ per year (with % capacity). there are also environmental benefits, burning of plastics releases harmful dioxins. the authors wish to make intensive care units and indeed all areas of the hospital aware of the cost and environmental impact associated with disposing of waste in incorrect categories. we hope that our quality improvement project demonstrates how easily money may be saved and environmental footprint reduced. association between resilience and level of experience in intensive care doctors in india j gopaldas, a siyal manipal hospital, bangalore, critical care medicine, bangalore, india critical care , (suppl ):p introduction: attrition of doctors in intensive care unit (icu) is one of the highest amongst all medical specialities globally, and is strongly associated with stress and burn out syndrome (bos). factors that contribute to bos are low pre-morbid resilience and low level of icu experience. studies from india have shown high levels of stress in intensive care doctors (> %), but there are no published studies measuring pre-morbid resilience and risk of burnout in relation to years of experience amongst icu doctors. our main aim was to measure cross sectional resilience levels in icu doctors compared between those with less than years of experience to those with years or more. a secondary aim was to assess the impact of other factors that may contribute to low scores. methods: an anonymised survey was conducted involving doctors in icus across different states in india, using the connor-davidson resilience scale (cd-risc ), which is validated in indian population. results: a statistically significant correlation was found between low levels of resilience in icu doctors with under years of experience . ) , and the significance level adopted was %. a logistic regression model was used to test the difference between the mortality and readmission rates in < and ≥ groups, which enabled the calculation of odds ratios. chi-square test was used to evaluate categorical variables and t-student test to some quantitative variables. the roc curve was constructed to verify the sensitivity of prediction of mortality through different saps scores. results: among the < and ≥ groups, respectively % and % was male (p = . ). mean weight of the> years was ± kg and < years was ± (p < . ). odds values indicated a significant difference only for the mortality rate, which was more than double among ≥ . readmissions in any time, h and h as well the mortality is shown in table and odds in figure . there was a significant difference in saps points between groups ( table ). the ≥ group presented an average of points higher on the severity scale when compared with those in the < group. there was no significant difference in lengh of stay. the highest amount provided by saps scores was % and a specificity of % for hospital mortality not group < years. in ≥ group the highest sensitivity was % and the specificity was %. roc curve for saps is shown in figure . conclusions: the extremely elderly patients of a cicu is more severe, with higher mortality and have the same lengh of stay and readmission rates. introduction: the purpose was to assess the prevalence and impact of non-urgent interruptions (nui) within critical care (cc).a root cause analysis of a never event in our cc discussed nui as a contributory factor, paralleled by learning from serious incidents.the negative impact of nui is well evidenced, resulting in delayed task completion, increased stress, and affecting patient safety. methods: any nui during a consultant ward round (cwr) or invasive procedure (ip), not relating directly to the current clinical episode, was included. qualitative data was collected by a survey, assessing the cc multidisciplinary teams(mdt) perception of nui. results: one third of reviews during the cwr, and %of ips, had a nui. adverse effects included prescription omissions, delayed cwr, near-miss with a cvc, and failed picc insertion. overall, % of staff considered nui a problem; % had experienced nui that led to distraction in train of thought. % felt that nui had led to an error: % of doctors, versus % of nurses. % overall felt nui contributed to stress at work. reasons for interruptions included: feeling overloaded, needing to resolve concerns before forgetting/being distracted, unable to prioritise, and to shift responsibility.lack of leadership or clinical supervision providing a point of contact for problems during shifts was mentioned as contributory. senior staff raised that whilst attempts have been made to level hierarchy, allowing a voice for all to express concerns contributes to interruptions. potential solutions included awareness on impact of nui, jobs book,´sterile cockpitd uring ips, and increased clinical supervision during shifts. conclusions: we have demonstrated the prevalence and consequences of nui within cc is significant.the impact on staff is significant, both for contribution to errors and also the negative impact on stress in the workplace. identified potential solution will be implemented. the impact of an education package on the knowledge, skills and self-rated confidence of medical and nursing staff managing airway & tracheostomy/laryngectomy emergencies in critical care l o´connor , k rimmer , c welsh methods: the factors affecting the delivery of intensive care was elucidated by a comprehensive review of the intensive care literature. a further understanding of intensive care delivery in south africa was obtained by "making sense of the mess" with eight workshops and interviews using a systems approach. systemic intervention served as the meta-methodology and methods and techniques from interactive planning, critical systems heuristics, soft systems methodology and the viable system model were employed. results: making sense of the mess emphasised the complexity of intensive care delivery, on both a situational and a cognitive level. it became clear that a single methodology would not suffice, but that a pluralist methodology was required to guide improvement in intensive care delivery. based on this understanding, nine principles were formulated to guide the development of a framework. systemic intervention was again used as the meta-methodology. interactive planning was identified as the key methodology, incorporating methods and techniques used in the making sense of the mess phase to build a systemic framework for the improvement of intensive care delivery. embedded in the proposed framework are matters relating to systemicity, complexity, flexibility, empowerment, and transformation of intensive care delivery. the proposed framework allows for multiple-perspectives, including that of marginalised stakeholders, the mitigation of multivested interests and power relationships (fig ) . it is both flexible and adaptable to promote learning about the complex problems of intensive care delivery and it accommodates the strengths of various relevant approaches to complex problem solving. conclusions: the proposed framework aims to facilitate sustainable improvement of intensive care delivery and to ensure the "just-use" of resources to foster distributive justice. the perioperative management of adult renal transplantation across the united kingdom: a survey of practice c morkane , j fabes , n banga , p berry , c kirwan introduction: there is a limited evidence base to guide perioperative management of patients undergoing renal transplantation and no national consensus in the uk. we developed an electronic survey to provide an overview of uk-wide renal transplant perioperative practice and determine the need for future guidelines on patient management. methods: a -question survey was developed to encompass the entire renal transplant perioperative pathway with input from clinicians with expertise from renal transplant surgery, anaesthesia, nephrology and intensive care. the survey was sent to lead renal anaesthetists at each of the transplant centres across the uk. results: twenty-two centres ( %) returned complete responses. there was limited evidence of guideline-based approaches to preoperative work-up, with marked variety in modality of preoperative cardiorespiratory function testing performed. questions regarding intraoperative fluid management (fig ) , blood pressure targets and vasopressor administration (fig ) identified a broad range of practice. of note, the routine use of goal-directed fluid therapy based on cardiac-output estimation was reported in six ( %) centres whilst nine centres ( %) continue to target a specific central venous pressure (cvp) intra-operatively. a dedicated renal ward was the most common postoperative destination for renal transplant recipients ( % of centres), whilst a renal or transplant-specific hdu provided postoperative care in ( %) centres. the need for care in an icu setting was decided on a case-by-case basis. conclusions: this questionnaire highlighted a high degree of heterogeneity in current uk practice as regards the perioperative management of renal transplant recipients. development of evidence-based national consensus guidelines to standardise the perioperative care of these patients is recommended. fig. (abstract p ) . framework for the improvement of intensive care delivery introduction: postoperative care of high risk patients in the icu used to be considered the gold standard of care in terms of reducing perioperative mortality [ ] . new evidence comes to question this practice [ ] . the primary objective of our study was to detect any benefit of postoperative icu care after elective surgery in terms of patient's outcome, length of hospital stay, complications and cost. methods: a -month retrospective analysis of high perioperative risk patients who were about to be subjected into an elective operation were included into the study. subsequently they were allocated into two groups. group i patients were those admitted into the icu for postoperative care while those admitted into the standard ward consisted group ii. demographic data, length of hospital stay, outcome, need of mechanical ventilation, complications and total cost were recorded. results: a total of patients were recorded, in each group. there was no statistical difference regarding the demographic data between the two study groups. seven patients died before hospital discharge ( in group i and in group ii, p> . ). there was no impact of icu admission on length of hospital stay (p= . ) which is primarily affected by the need of mechanical ventilation (p= . ) and reoperation (p< . ). the total cost and the postoperative cost of hospital care did not statistically differ among study groups. conclusions: according to our study the need of postoperative care of high risk patients in the icu is rather questionable in terms of perioperative mortality, length of hospital stay and cost of care. introduction: tivap is a preferred vascular access device for patients with solid tumors and radiological-guided insertion is a standard of care. however, many hospitals have no access to interventional radiology service. our study aimed to determine whether it is safe to place tivaps in icu for immediate administration of chemotherapy. methods: we analysed prospectively maintained database of our department and collected data for adult pts with tivaps implanted between / and / . the median age was (range - ) years, % were women. all procedures were performed by trained physicians with experience in ultrasound (us). puncture technique was used and tip location was controlled with electrocardiographic (ecg) and us with subsequent chest x-ray confirmation. pts were followed up for at least days after the procedure for complications, functioning of tivap and surgical wound healing. results: all tivaps were successfully implanted in pts. infraclavicular route was used in cases ( . %). difficulties with indwelling guide wire were observed in ( . %) pts but did not precluded implantation. placement complications included pneumothorax (n = ), catheter malposition (n = ) and artery bleeding (n = ). these complications required additional therapy but were managed successfully and resolved without consequences. in the rest cases internal jugular vein (jv) was used. complications were not observed. ecg and us navigation provided optimal tip location control in these situations. surgical wound healed after - days and chemotherapy initiation did not affect healing. all tivaps had adequate functioning days after placement. conclusions: it is feasible to implant tivaps in icu. these devices can be used on the implantation day without jeopardizing patient safety. jv catheterization seems to be optimal approach and us navigation and ecg are sufficient methods for placement control. introduction: there is increasing use of clinical information systems to improve patient safety and quality of care in critical care. with all these systems, a rigorous business continuity access (bca) plan needs to be in place so patient safety is not compromised [ ] and ensure continuity of care. here we evaluate the types of medication errors that occurred during a period of unscheduled downtime; potential contributory factors [ ] and the number of errors involving critical medicines [ ] were analysed. methods: during the unscheduled downtime, all prescribing and administration of medicines were transferred to a paper based system using the patients' web offline chart (woc -philips healthcare). pharmacists at the time double checked the paper charts that were transcribed, to mitigate errors but this was not consistent due to the timing of the event. we retrospectively compared the paper drug charts against the electronic prescriptions and noted all errors for patients. results: in total medication errors were identified & allergy omission ( table ) . pharmacists double checked % of the paper charts. conclusions: our data highlights the risks associated with unscheduled electronic patient management system downtime and the heterogeneity of the types of errors & potential contributory factors. it underscores the need for robust local bca plan implementation, critical review of the woc document and regular staff training around potential unscheduled system downtime. introduction: the transfer of patient care (toc) between the intensive care unit (icu) and hospital ward is associated with a high risk of medical errors [ ] .according to uk national data between - % of patients have an error or unintentional medication change made when moving between care settings [ ] . currently different prescribing systems without interoperability are used between icu areas & ward settings in our institution, resulting in medications needing to be re-prescribed on transfer. we aimed to evaluate the time delay in medication re-prescribing, number of unintentional omissions of drug doses and reasons, as well as percentage of critical medicines [ ] omitted in the first h following discharge. methods: over a month period, discharged patients ( % of all discharges) from two icu units were included. the icu discharge letter which contained the medication list on transfer was compared against the ward based electronic drug chart to identify all unintentional omitted medication doses during the first hours. the starting time point was when the patient physically left icu. results: / ( %) of patients had their medication prescribed more than hours post discharge. there were a total of / , ( %) unintentional omitted doses (table ) . of these / ( %) were considered critical medicines ( table ) . conclusions: this data confirms the risk associated with toc especially around medicines. the need of interoperable electronic prescribing systems is one solution and could improve patient safety by streamlining the process. introduction: staff perceptions of safety may contribute to workforce stress and be organisationally important [ ] . this study explored the feasibility of capturing perceptions of safety with a bedside professional reported (bpr) shift safety score, and explored relationships between bpr and measures of staffing and workload. methods: uk health research authority approval was obtained (id ). data were collected for consecutive days at imperial college healthcare trust ( general critical care beds on sites).the bpr asked all icu staff to rate each shift as "safe, unsafe, or very unsafe". responses were described and correlated with data on organisational staffing (care hours per patient day chppd) and nursing intensity (total number of organs in failure/ total number of nurses). results: a total of bpr scores were recorded (response rate %). we noted heterogenous responses between sites and days, and within shifts, only % of shifts were unanimously rated. whilst % of shifts were rated by staff as "unsafe" or "very unsafe", organisational metrics recorded only % as 'unsafe'. we did not find a correlation between measures of staffing (chppd) and perceptions of safety ( figure ). preliminary analyses suggest that staff perceptions of safety are not well correlated with nursing intensity (figure ), although these numbers commonly inform staffing metrics. conclusions: completing the bpr tool was feasible and acceptable to staff. responses showed variations in perceptions of safety and a gap between organisational metrics and individual perceptions. introduction: delivery of intensive care (icu) is complex because of multiple stakeholders with varied perspectives and conflicting goals that interact and are interdependent. to inform the development of a framework for the improvement of icu delivery in south africa, it was essential to first understand icu delivery or "make sense of the mess". a systemic approach such as systems thinking is required to holistically explore and understand the complexity of icu. no methodology is perfect and methodological pluralism as proposed by systemic intervention, a systems thinking approach, was used for a more flexible and responsive intervention. the methods used was the making sense of the mess phase of interactive planning, stakeholder analysis as describe by critical systems heuristics, rich pictures from soft systems thinking and viable systems model diagnosis. making sense of the mess was done in phases: first the mess was formulated with rich pictures generated in workshops and interviews. the discussions of the rich pictures by the respective stakeholders were transcribed and analysed using braun and clark's thematic analysis. secondly, based on the data generated from phase a diagnosis of the viability of the icu system was made. results: the data from the phases were very rich and complex and themes emerged (figure ). these themes were interdependent and resulted in disorganised icu delivery with limited opportunities for learning to improve icu delivery with dichotomies that existed at various levels of icu. it was a problem to present the complex data in the traditional linear manner due to the interdependence of the themes. the analysis is presented as stories, a known approach in the complexity discipline, where the themes of the analyses are portrayed. the making-sense-of-the-mess phase confirmed the complexity of icu delivery, at both a situational and a cognitive level and with this understanding a framework for the improvement of icu delivery could be developed. introduction: improving prescribing practice involves changing prescriber behaviour. education is assumed to change behaviour but other approaches may be more effective (figure ) [ ] . changes to the presentation of information and the configuration of choices have potential to rectify common prescribing errors through subtle 'nudges' [ ] . the implementation of clinical information systems (cis), including electronic prescribing, provides an opportunity to deploy strategies such as standard orders, dose limits, and product level prescribing. with an infinite number of configuration options available, clinical leaders need to know which interventions are most effective. we evaluated several of these strategies in a before and after observation study methods: interventions, utilising cis nudges, were chosen to improve four areas of prescribing practice in a tertiary critical care unit using methods matched to the top levels of the hierarchy. data were collected for months before and after interventions to map changes in compliance with a pre-defined standard except for the standardisation intervention where months' data were collected due to low prescription numbers. no education on changes was given during the baseline data collection so any change in performance after the go-live date is entirely attributable to the intervention. results: the change in performance for each level ranks the intervention levels in the order (highest first) forced function, automation and standardisation ( table ). the use of point of prescribing reminders was not associated with a significant difference in performance. conclusions: the effectiveness of intervention levels seen in practice is consistent with that of the model. further studies could be undertaken to strengthen these conclusions but in the meantime the approach to changing practice using cis nudges should focus on standardisation or above. introduction: intensive care unit (icu) sound pressure levels (spl) are persistently above world health organisation recommendations for clinical areas [ ] . this may impact patient recovery. standard spl monitoring records single values for each h period (laeq ). we hypothesise this reporting rate is unsuitable for icu. methods: we measured spl october -may , logging frequency (hz), spl (db), and loudness (perception of sound) every second [ ] . the resulting dataset was of a size that conventional statistics programs would require computational resources not easily obtainable on standard university commodity hardware. we processed the full dataset without sampling by using distributed task dispatching, parallelism and scheduling of a cluster computing framework (apache spark). we created a system consisting of a single workstation ( cores; gb ram) running ubuntu . lts, oracle java . , apache spark . , scala . , r core . , r studio . and sparklyr . . . we utilised the sparklyr library in r studio to run arbitrary r code using the dplyr library. we analysed aggregate data in r core & used ggplot (v ) to create visuals. results: we achieved more complex analysis than standard spl reporting with relatively modest computing resources. specifically we identified lower spl peaks in the early hours & loudness levels considerably higher than parallel spl. conclusions: simple laeq do not facilitate reflection on practice thus impetus for change is limited. loudness data highlight the patient experience of spl in the icu is more intrusive than laeq indicates due to high sensitivity to sounds~ - khz, a common frequency range for alarms. higher fidelity increases understanding of spl which can lead to targeted interventions to reduce patient disturbance. introduction: survivors of critical illness face significant long term impairments in mental and physical function. early mobilisation (em) in the intensive care unit has been suggested to improve functional outcomes and reduce delirium in the icu. we hypothesized that implementing a protocol for em in the icu would improve mobilisation rates while remaining safe. methods: design: prospective non-blinded observational cohort study, based on a quality improvement project. data was collected conclusions: only of variables in boyd criteria were significant associated with morbidity or mortality. the physiologic score and operative score were significant higher in the patient on mortality and morbidity after sicu admission. effects of structural hospital characteristics on risk-adjusted hospital mortality in patients with severe sepsisanalysis of german national administrative data d schwarzkopf introduction: the quick sequential organ failure assessment (qsofa) score is a simple tool used to identify severe patients with infection. as this score is calculated from three variables that can be measured at the scene of trauma-systolic blood pressure, respiratory rate and consciousness-the prehospital qsofa score may also be a good predictor of mortality in trauma patients. so we evaluated the discriminative ability of the prehospital qsofa score in patients with trauma for in-hospital mortality. methods: this is a retrospective multicenter study using the data from nationwide trauma registry in japan. we included patients with trauma aged ≥ years old transferred to hospitals from scene. primary outcome is in-hospital mortality. results: the mean age was . ± . years old and patients ( %) were male. in-hospital mortality occurred in patients ( %). in-hospital mortality in each qsofa score was / ( . %), / ( %), / ( %) and / ( %) in qsofa score , , and , respectively (p< . for trend). area under receiver operating characteristics curve (auroc) of the aqsofa score for inhospital mortality was . ( % confidence interval . - . ). if we use the cutoff ≥ , sensitivity and specificity of the qsofa score were . and . . conclusions: in patients with trauma, the prehospital qsofa score was strongly associated with in-hospital mortality. we can identify patients with very low risk of death by using the cutoff ≥ of the prehospital qsofa score. introduction: only one prospective study is available of the validation of the diagnostic and prognostic role of qsofa (quick sofa score) in the emergency department (ed). a prospective study was conducted in greek eds. methods: the prompt study (clinicaltrials.gov nct ) run in the ed of six hospitals in greece among patients with suspected infection and presence of at least one of fever, hypothermia, tachycardia, tachypnea and chills. clinical data were collected and the -day outcome was recorded. sepsis was defined by the sepsis- criteria. results: the sensitivity and the specificity of at least signs of qsofa for the diagnosis of sepsis was . % and . % respectively and for the prognosis of -day mortality . % and . % respectively. the odds ratio for -day mortality when qsofa was equal to or more than was . among patients with charlson's comorbidity index (cci) equal to or less than ; this was . among patients with cci more than (p: . between the two ors by the breslow-day's test; p: . by the tarone's test). conclusions: data validated the sensitivity of qsofa for the diagnosis of sepsis. cci was an independent predictor of severity. qsofa could better predict unfavorable outcome among patients with low cci. comparative accuracy between two sepsis severity scores in predicting hospital mortality among sepsis patients admitted to intensive care unit n sathaporn, b khwannimit prince of songkla university, internal medicine, hat yai, thailand critical care , (suppl ):p introduction: recently, the new york sepsis severity score (nysss) was developed to predict hospital mortality in sepsis patients. the aim of this study was to compare the accuracy of nysss with the sepsis severity score (sss) and other standard severity scores for predicting hospital mortality in sepsis patients. methods: a retrospective analysis was conducted in a medical intensive care unit of a tertiary university hospital. the performance of severity scores was evaluated by discrimination, calibration, and overall performance. the primary outcome was in-hospital mortality. results: overall , sepsis patients were enrolled, patients ( . %) were classified to septic shock by sepsis- definition. hospital mortality rate was . %. the nysss predicted hospital mortality . +/- . %, which underestimated prediction with smr . ( %ci . - . ) . however, the sss predicted hospital mortality +/- . %, which slightly overestimated mortality prediction with smr . ( %ci . - . ). the nysss had the moderate discrimination with an auc of . ( % ci . - . ), in contrast to the sss presented good discrimination with an auc of . ( %ci . - . ). the auc of sss was statistically higher than that of nysss (p< . ). nevertheless the apache iv and saps ii showed the best discrimination with auc of . . the auc of the nysss and sss was significant lower than that of apache ii, iii, iv, saps ii and saps ( figure ). the calibration of all severity scores was poor with the hosmer-lemeshow goodness-of-fit h test < . . the nysss was the lowest overall performance with brier score . . the apache iv present the best overall performance with brier scores . . conclusions: the sss indicated better discrimination and overall performance than the nysss. however the calibration of both sepsis severity scores and another severity score were poor. furthermore, specific severity score for sepsis mortality prediction needs to be modified or customized to improve the performance. introduction: metabolic markers, especially lactate, have been shown to predict mortality in acutely unwell patients. we hypothesised that early changes in metabolic markers over time would better predict mortality and length of stay, with patients who correct their metabolic derangement having lower risk of death and reduced length of stay (los). methods: single centre, retrospective cohort study in a bed icu. we included all patients who had an arterial measurement of lactate, paco , base excess (be) and ph on admission and at hours after admission to icu between / / and / / . the 'clearance' of these markers was calculated using the equation ((value at admissionvalue at hours)/value at admission). clearance calculations only included those patients with deranged results on admission (lactate> mmol/l, be<- mmol/l, ph< . , paco > . kpa). roc analysis was used to predict in-hospital mortality and length of stay, using both the initial admission values, and using the clearance value, as well as icnarc and apache ii scores for comparison. if a patient was admitted twice in the time period, only the first admission was included. results: patients were included (sex ratio . , mean age . ). table ). none of the values tested had a auc greater than . for predicting length of stay. conclusions: the clearances of metabolic markers over the initial hours after icu admission does not provide better prognostic information than the value at admission. initial lactate level was the best predictor of mortality, but compared poorly to icnarc score. metabolic markers do not accurately predict length of stay. . - . ) vs . (iiq . - . ), p= . ]. the other hemogram parameters did not differ between groups (table ) . when adjusted for severity score, in patients submitted to emergent surgery, the mpv value was still independently associated with mortality (or . ci . - . , p= . ), and its roc curve (auc) was . to mortality (figure ). conclusions: mpv is a cheap and easily accessible marker which can add prognostic value in this specific population. in the future, we will validate it in a larger cohort of cancer pts admitted to intensive care. haematological malignancy in critical care: outcomes and risk factors c denny introduction: about % of patients admitted to hospital with a haematological malignancy will become critically ill [ ] . life expectancy in these patients is poor with a month mortality of % or more in specialist units [ ] . in contrast, patients without critical illness can expect a year survival rate exceeding % for many cancers. this disparity results in differences of opinion on the best strategy for such patients among haematologists and critical care physicians. we conducted a local quality improvement project to quantify mortality and risk factors in critically ill patients with a haematological malignancy in our hospital. methods: patients admitted to the critical care unit of broomfield hospital, a district general hospital with tertiary specialist services, from january to december with haematological malignancy were included in the analysis. patients in remission for more than years and patients admitted following elective surgery were excluded from analysis. death in critical care or in hospital after critical care discharge were the primary outcomes. mortality was correlated with demographic data using simple statistical measures and regression analysis. results: patients were included in the analysis. overall mortality was %(n= ). survivors tended to be younger ( vs years) but had similar clinical frailty scores. early critical care admission (within hours) was associated with better survival ( . vs . %). nonsurvivors had a greater incidence of sepsis and respiratory failure, and required more ventilatory and vasopressor support. mortality was higher in patients requiring more than one organ support. conclusions: the overall mortality in our data is lesser than previously published data but supports the conclusion that mortality is determined primarily by the number of organs supported with the effects of malignancy playing a secondary role. (figure ). increasing levels of frailty were associated with increasing risks of death at year (p< . ) (figure ). frailty significantly increased -year mortality hazards in unadjusted analyses (hr . ; %ci; . - . ; p< . ) and covariate-adjusted analyses (hr . ; %ci . - . ; p= . ) ( table ) . conclusions: frailty was common and associated with greater age, more severe illness and female gender. frailty was significantly associated with heightened mortality risks in both unadjusted and covariateadjusted analyses. frailty scoring may encapsulate variables affecting mortality which are omitted in current predictive systems, making it a promising risk stratification and decision-making tool in icu. fig. (abstract p ) . unadjusted survival curves stratified by frailty status. frail patients were statistically significantly less likely to survive to year plateau at day = , delta peak= and hpr= . . were assigned respectively a point value of , , and to these predictors based on their beta coefficient in the predictive model. the score yielded a roc-auc: (auc= . ; %ci, [ . - . ]; p= . ). using the validation data set (n= ), the score had an roc-auc= . and similar estimated probabilities for mortality. conclusions: the paw-mps seems to demonstrate interesting discriminative properties to predict mortality. what is the role of the pulmonary embolism severity index (pesi) and rv/lv ratio as clinical risk assessment tools for patients undergoing ultrasound-assisted catheter-directed thrombolysis (uacdt)? introduction: to evaluate if the pulmonary embolism severity index (pesi) score correlates with rv/lv ratio, biomarkers of cardiac injury, fibrinogen and length of stay(los). also to evaluate the correlation between rv/lv ratio with biomarkers of cardiac injury, fibrinogen and los for patients who underwent uacdt. methods: a retrospective review of patients with sub-massive pulmonary embolism (pe) who underwent ultrasound-assisted catheterdirected thrombolysis (uacdt) was performed. pesi score, rv/lv ratio, length of stay(los), fibrinogen levels, troponin levesl, and brain natriuretic peptide(bnp) levels, were calculated and collected prior to uacdt. spearman's rank correlation coefficient was calculated for all non-parametric variables. results: patients, males and females, were included in the study. the mean (±sd) age was ± years. the mean pesi score was ± . mean rv/lv ratio was . ± . . a significant correlation between the rv/lv ratio and both fibrinogen and troponin level (p= . , p= . ) was noted. no significant correlation existed between pesi score and rv/lv (p= . ). no significant correlation existed between both rv/lv ratio and pesi score with length of stay (p= . ) after uacdt. there were no noted mortality or complications. conclusions: pesi score is used as a prognostic factor for the patients with pe, however, our study shows that pesi score does not correlate with rv/lv ratio or length of stay after the uacdt. there was inverse correlation between rv/lv ratio and fibrinogen. there was also positive correlation between rv/lv ratio and troponin for patients with and without heart failure. according to our data, there may be limited use of pesi score and rv/lv ratio for risk stratification of pe patients undergoing uacdt. introduction: conventional scores for prediction of risk and outcome, such as sapsii and sofa, have not been validated for patients admitted to level ii critical care units (intermediate level or imcus). we compared the performance of sapsii and sofa scores with the intermediate care unit severity score (imcuss) in a general population admitted to imcu. methods: we conducted a prospective observational cohort study in a -bed level ii-iii icu from a university-affiliated hospital, during a three-month period. we applied sapsii, sofa day one and imcuss to all patients admitted during that period. primary outcome was a composite of hospital mortality and need to increase level of care. additionally, we tested the relevance of each variable within each score to predict the outcome. results: we included patients with a mean age of . ± . years. patients were considered "step-down" (transferred from our level iii beds), and the remaining originated from the emergency conclusions: months after completion, the primary care management intervention had no effect on mental health-related quality of life and physical function among survivors of sepsis. increase in ptsd symptoms in the control group may suggest a possible protective effect of the intervention. introduction: critically ill patients and their families are often confronted with an overwhelming amount of clinical information shortly after hospital admission. their reliance on internet resources for additional information is increasing, particularly for unfamiliar medical terminology. yet, little is known about whether these online resources meet the recommended reading level and complexity appropriate for the average reader. methods: an online search of websites containing four common critical care diagnoses in the icu (respiratory failure, renal failure, sepsis and delirium) was performed. a total of readability formulas were used. the flesch-kincaid grade reading level (grl) and flesch reading ease (fre) were used in the final analysis. document complexity was evaluated using the pmose/ikirsch formula. results: websites on respiratory failure were written at the th grl with fre of . . renal failure resources had a th grl with fre of . . sepsis websites had an th grl with fre of . . delirium websites had a th grl with fre of . . when comparing website types (government, non-profit and private), anova showed a difference in fre across all groups and government websites had a conclusions: online resources used by intensive care unit patients and families tend to be written at higher than the recommended th grl, with government sites better meeting this target than nonprofit and private organizations. online resources should be improved to lower this unfortunate barrier to patient education. introduction: the recent enactment of the data protection act , the general data protection regulations, and a series of data breaches in the healthcare sector, have renewed interest in how our patients' information is collected, used and shared. the complex framework of laws and regulations governing the use and disclosure of personal data may lead to professional and financial consequences if information is disclosed inappropriately. disclosures to the police when they concern incapacitous patients are particularly challenging, as the disclosure may have no direct benefit to the patient and may cause the patient considerable harm. methods: we have reviewed the relevant laws and regulations to identify the circumstances in which doctors must release information regarding incapacitous patients to the police. the laws and regulations are examined to identify the extent of the disclosure required, and any requirements for the disclosure to be lawful. we have also identified laws which confer a power to disclose information about incapacitous patients, and the circumstances in which these powers can be used. results: in conjunction with a local police constabulary we have developed an information request form which makes it easier for those requesting and disclosing information to understand the legal basis of the disclosure. we have also developed guidelines to allow practitioners to understand where a disclosure is obligatory or discretionary. conclusions: the next stage of the project is to audit disclosures of information in the intensive care unit, and identify whether information is being released lawfully and following the correct procedure. introduction: family members are affected both physically and psychologically when their relative is admitted to icu. there is limited knowledge describing their experiences and structured interventions that might support them during their relative's critical illness. the aim of this review is to describe published literature on the needs and experiences of relatives of adult critically ill patients and interventions to improve family satisfaction and psychological well-being. methods: design: scoping review. standardised processes of study identification, data extraction on study design, sample size, sample characteristics and outcomes measured (figure ) . results: from references, studies were identified for inclusion four key themes were identified: ) different perspectives on meeting family needs ) family satisfaction with icu care ) factors impacting on family health and well-being and capacity to cope ) psychosocial interventions conclusions: family members of patients in icu experience unmet information and assurance needs which impacts on their physical and mental health. structured written as well as oral information show some effect in improving satisfaction and reducing psychological burden. icu's who are able to support interventions based on meeting family information needs, in addition to reducing psychological burden and increasing satisfaction will enable each family to provide more support to their relative within the icu. introduction: unmet informational needs lead to dissatisfaction with care and psychological distress. identifying interventions to help meet specific needs is a crucial and necessary step in providing family centred care in icu. we aimed to implement and evaluate the impact of delivering a structured communication strategy on levels of anxiety, uncertainty and satisfaction with care and decision making in families of critically ill adults. methods: a quasi experimental study with pre and post test design. a convenience sample of family members were recruited from july to february . the intervention group (n= ) received both oral and printed information to guide them in preparing for a structured family meeting. the control group (n= ) received usual fig. (abstract p ) . article selection process for scoping review routine care and existing family informational support. anxiety, uncertainty and family satisfaction were measured in the two groups on icu admission and icu discharge. results: mean anxiety, uncertainty and satisfaction with care and decision making scores pre and post intervention were compared. there were no significant differences in mean anxiety, uncertainty or satisfaction scores between the two groups before the intervention (p> . ). mean scores on anxiety ( . vs . ), and uncertainty ( . vs . ) were lower post intervention, but not significantly so ( figure & ). total satisfaction, satisfaction with care and satisfaction with decision making mean scores were similar in both groups before and after the intervention (p. . ). conclusions: providing relatives with a combination of targeted written and oral information delivered by nursing and medical staff reduced anxiety and uncertainty with this reduction being evident through to discharge from icu. although not statistically significant, there was what may be seen as a suggestion of a clinically significant drop in anxiety and uncertainty following the intervention introduction: clinical studies in intensive care unit (icu) patients are warranted in order to improve healthcare. the aim of this study was to analyse barriers and challenges in the process of achieving informed consent from icu patients. methods: we analysed patients considered for inclusion in a prospective observational study of venous thromboembolism in the icu, i.e. the norwegian intensive care unit dalteparin effect (norides) study. data were collected from the screening log, consent forms and associated research notes of the norides study. results: we observed that of ( %) eligible patients according to inclusion and exclusion criteria were omitted from the nor-ides study due to barriers and challenges in the process of receiving informed consent. were categorized as psychiatric diseases consisting of known psychosis or recent suicide attempt, likely or actual treatment withdrawals and due to language barriers among non-norwegians. among the patients included in the norides study, ( %) consents were from patients and ( %) obtained from their next of kind. from the patient consents, ( %) consents were oral and ( %) were written. patients were physically unable to sign, and patients did not recognize their own signature. the study further pointed at some specific challenges in the process of consent, herein questionable competence to give consent, failure to remember being asked/included, inability to separate research from treatment etc. there were also difficulties in evaluating who was next of kin and how to reach them. conclusions: barriers and challenges in obtaining informed consent from icu patients led to exclusion of one fifth of the eligible patients in our study. informed consent directly from patients was obtained from less than half of the included patients. obstacles in the process of achieving informed consent were practical, medical, ethical and/or legal. determinants of end-of-life decision-making in the intensive care unit p eiben, c brathwaite-shirley, s canestrini king´s college hospital nhs foundation trust, london, united kingdom critical care , (suppl ):p introduction: although the majority of intensive care unit (icu) deaths follow the decision to forgo life sustaining treatment (lst), variability in patterns is commonly observed [ , ] . we reviewed end of life (eol) practice at our institution in order to explore: (i) patient characteristics affecting eol decision-making, (ii) communication among surrogate decision-makers, and (iii) eol management. methods: we retrospectively analyzed data from consecutive patients who died in our ten-bed icu over months (study period). patient demographics, apache ii, functional status, diagnosis on admission, icu length of stay (los) were collected; family/next-of-kin (nok) involvement and rationale for lst limitation were recorded ( conclusions: our analysis shows that in our institution eol deliberations follow a shared decision-making process. lack of family/nok involvement and incomplete documentation was exceptional. the significant difference in los between w-group and nw-group, in the face of similar apache ii, warrants further investigation. vae calculator rheumatology review . van der jagt m. crit care consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine cardiac output monitoring: how to choose the optimal method for the individual patient perioperative cardiovascular monitoring of highrisk patients: a consensus of guidelines for nutrition support therapy in the adult critically ill patient references . nice guideline for aki: prevention, detection and management serial creatinine results pre-and post ecmo references . polit et al. research in nursing & health reference . sherliker et al national blood transfusion committee, nhs blood and transplant arch otolaryngol head neck surg fig. (abstract p ). rsi agent guideline references . nuckton tj nejm icm baseline characteristics reference elso guidelines for cardiopulmonary extracorporeal life support s -leitlinie invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz .auflage p handgrip strength does not predict spontaneous breathing trial failure or difficult or prolonged weaning of critically ill patients g friedman total burn care introduction: we aimed to evaluate safety and efficacy of light sedation with dexmedetomidine (dex-ls) in acute brain injury (abi) patients. methods: retrospective analysis on icu patients with traumatic/medical abi, out of the neuroprotection window and undergoing dex-ls. data of pre-infusion and infusion periods were compared. results: patients (age ± , males . %) were included. traurespectively. conclusions: dex-ls among icu patients affected by abi turned out to be feasible and safe. it enabled discontinuation from mv and maintenance of spontaneous breathing in the majority of cases %) delirious patients and of ( . %) non-delirious patients could be discharged from the hospital. we evaluated the -year mortality in the hospital survivors. results: totally, patients participated in our study. the majority of them ( . %) were male with the median age of [ , . ] years and the median apache ii score on the first day of icu admission of risk of delirium was associated with preoperatory euroscore ii (p= . ) and history of previous cardiac surgery (p= . ). moreover, in the intraoperatory period the risk of delirium was associated with red blood cell transfusion, intervention for aortic dissection (p= . ), hypothermic circulatory arrest (hca) with anterograde cerebral perfusion (acp) (p= . ) (table ). in the postoperatory period risk of delirium was associated with levels of creatinine clearance (p= . ) and c-reactive protein (crp) (p= . ). conclusions: delirium is relatively frequent in the cardiac surgical icu patient journey of group : those patients discharged directly home from critical care unit poor compliance with co-signing in icca ( %, n= ) compared to paper ( %, n= ) (figure ) and the reported difficulty in co-signing ( %, n= ) reveals significant usability concerns and potential safety issues. % (n= ) found icca intuitive, though % (n= ) found navigating the interface difficult and reported concerns with losing saved work ( %, n= ). conclusions: this study highlights important usability issues that may impact staff satisfaction th national audit project of the royal college of anaesthetists and the difficult airway society. major complications of airway management references . guidelines for provision for intensive care services (gpics), version medicines optimisation: the safe and effective use of medicines reducing harm from omitted and delayed medicines. a tool to support local implementation p understanding the delivery of intensive care in south p mobilising ventilated patients early with interdisciplinary teams (move it) singapore general hospital, department of respiratory and critical care p validation of boyd criteria and possum-score on mortality and morbidity in general surgical intensive care unit k chittawatanarat, y chatsrisuwan faculty of medicine pts with central nervous system neoplasms or submitted to elective surgeries were excluded. descriptive analysis and χ test, pearson´s, wilcoxon rank-sum, uni and multivariate logistic regressions were used when appropriate. results: from a total of pts identified, . % (n= ) were admitted after emergent surgery and . % (n= ) for medical reasons. global icu mortality was . % (n= ). in comparison to survivors, the patients that died had a similar age were recorded data regarding demographics, clinical variables, paw (at admission and at day ), high pressure ratio (hpr = number of days with high pressures: peak ≥ and/or plateau ≥ ; and/or driving pressure ≥ ; and/or auto-peep ≥ ; divided by los), trends of paw (paw at day -paw at admission) and outcomes. the patients were divided into two groups: a construction group (n= ) and a validation group(n= ). the paw-mps was developed and validated by analyzing in a multivariate regression model the different paw ± . ; pco , ± mmhg paw were respectively for peak, plateau, driving, and auto-peep at admission: ± , . ± , . ± and three independent mortality risk factors were identified centro hospitalar do porto p five-year mortality and morbidity impact of prolonged icu stay n van aerde , g hermans laboratory of cellular and molecular medicine we investigated differences in mortality and morbidity after short (< days) and prolonged (≥ days) icu-stay. methods: prospective, -year follow-up study of former epanicpatients (clinicaltrials.gov:nct , n= ). mortality was assessed in all. for morbidity analyses, all long-stay and a random sample ( %) of short-stay survivors were contacted. primary outcomes were total and post- -day -year mortality in multivariable cox regression analysis, icu-risk factors comprised hypoglycaemia, corticosteroids, nmba, benzodiazepines, mechanical ventilation, new dialysis, new infection, liver dysfunction, whereas clonidine may be protective. among long-and short-stay -year survivors hgf, mwd and pf sf- were lower in long-stayers mwd: % ( %ci: %- %) vs % ( %ci: %- %) multivariable regression identified associations with benzodiazepines (hgf and pf-sf ), vasopressors (pf-sf ) and opioids ( mwd) ptsd related symptoms were accessed with the post traumatic stress syndrome questions inventory (ptss- ) at the post icu follow up clinic, six months after the acute stress event. the post icu consultation was carry out by an icu doctor and an icu nurse. exclusion criteria: previous severe psiquiatric disorders, not able to respond the questionnaire medical %, surgical % and trauma %. patients ( %) were on imv and the median ventilation days was . ptsd scores ranged from to . delusional memories were conclusions: in this study the rate of ptsd was lower . % and related with a lower saps ii and the presence of memories of the icu stay. no relation was found with delusional memories, imv or superior icu length of stay. patients with lower illness severity and without imv, should be elective to the follow up-clinics. p long-term effects of a sepsis aftercare intervention k schmidt united states; jena university hospital patras general university hospital, intensive care unit, patras, greece; patras general university hospital, division of infectious diseases results: ( . %) patients were readmitted within hours and ( . %) in to days. the two groups didn't differ in age, gender, charlson comorbidity index and length of stay on both admissions. elective surgery was the most common type of admission ( . %) followed by medical ( . %), emergency surgery ( %) and trauma ( . %). the mean time to readmission in the late group was . (± . ) days. patients in the late group had higher apache ii score on their first and second admission, ( . ± . vs . ± . ; p= . ) and ( . ± . vs . ± . ; p= . ) respectively. respiratory insufficiency was the most common cause of readmission in both groups followed by sepsis and cardiac arrest. finally in the early group p introduction: in intensive care units, perceived inappropriate treatments (pit) have been associated with negative impact on caregivers univariate analysis revealed that burn-out, pit and intention to leave were greater in units where nurses´teams included no activity in the icu, compared to "shared" work in icu and idtcu. in multivariate analysis, perception of non beneficial treatment of patients with life support witholding was associated with: bad collaboration with other units p profile of intensive care unit (icu) patients on whom life-sustaining medical treatment were withdrawn or withheld s chatterjee variables collected-age, sex, apa-che iv score, diagnostic-category and co-morbidities. primary outcomes were icu and hospital mortality. secondary outcomes included icu and hospital length of stay(los) female sex, n (%) ( . %) diagnosis on admission: medical, n (%) rrt at time of wlst, n (%) ( . %) dnr order, n (%) ( . %) organ donation services involved, n (%) ( . %) introduction: high flow nasal cannula(hfnc) is a new modality in respiratory failure management [ ] . this study objectively held to compare the physiological outcomes in the non-invasive ventilation(niv) treatment of cardiogenic acute pulmonary oedema(apo) patient in the emergency department(ed) delivered by helmet cpap(hcpap) and hfnc. methods: single-centre randomized controlled trial on patients presenting with cardiogenic apo. primary endpoint was a heart rate reduction.secondary endpoints included: improvement in subjective dyspnoea scales, respiratory rate, blood oxygenation, intubation rate and days mortality rate. results: patients were enrolled and randomized ( patients to hcpap; to hfnc) ( to . ± . ). intubation rate was lower in hcpap ( . % for hcpap versus . % for hfnc) and days mortality rate is lower in hcpap ( . % for hcpap versus . % for hfnc). conclusions: both hcpap and hfnc significantly improved patient condition in patient presenting to the ed with cardiogenic apo. however, hcpap was better than hfnc in improving physiology outcomes, lower intubation rate and mortality rate in patient introduction: the aim of the study was to compare the confusing assessment method of the intensive care unit (cam-icu) and the nursing delirium scoring scale (nu-desc) for assessment of delirium in the icu. furthermore we wanted to test the interpersonal variation of the nu-desc. delirium is proved to be associated with increased mortality [ ] . nu-desc is an observational five-item scale that does not require patient participation and is adapted to the fluctuating nature of delirium. each item can be scored from to . delirium is defined with a score > . the nu-desc has recently been translated into danish (nu-desc dk) but has not been validated.methods: icu patients, who met the inclusion-criteria for the cam-icu were scored with both cam-icu and nu-desc dk. patients were scored of two independent nurses at approximately the same time every day.results: a total of patients were enrolled, and comparisons between cam-icu and nu-desc dk were registered ( figure ).there was agreement between nu-desc and cam-icu in of registrations (hereof registrations were delirium negative). in interpersonal variation, registrations were made. the conclusion was identical in % of registrations, but only % agreed in all scoring-scale items (all negative).conclusions: a high agreement between nu-desc and cam-icu was found however the comparison was based on predominately patients with negative delirium score. the interpersonal variation of nu-desc scoring was substantial. a future validation of the nu-desc dk as a screening tool in the icu requires thorough training and instructions to minimize interpersonal variation. introduction: an increasing number of patients are being discharged directly home from critical care units and this is currently viewed as a negative quality indicator [ ] . the purpose of this audit was to characterise a cohort of patients who can be safely discharged directly home from adult critical care at st thomas´hospital (sth). methods: retrospective observational study of two groups of patients; ) those discharged directly home from critical care, ) those discharged within two days of step down to a ward from critical care (admissions st june- st october ). the clinical notes of these patients were reviewed via online systems. results: baseline demographics of the patients in group and patients in group were similar (mean age of years, versus years, p= . ); average length of stay in critical care was also similar ( . days versus . days respectively p= . ). in group , of icu days were after considered fit for step down versus of days in group , p= . (fig , ) . in group , drug related presentations were more common ( % versus % p= . ), fewer patients had specialist follow up post discharge ( % versus %, p< . ). in group , patients ( %) were readmitted within days, to critical care. in group , patients ( %) were readmitted, to critical care (p= . and . respectively); none of these readmissions were felt to have been preventable.conclusions: there is a cohort of patients suitable for discharge directly home from critical care who did not spend significantly longer in icu awaiting discharge than those who were stepped down to the ward. identifying these patients early, potentially by their diagnosis, and creating a pathway including access to specialist follow up clinic could allow prompt discharge directly from critical care, thus improving patient satisfaction and reducing hospital-acquired morbidity healthcare costs [ ] . the evaluation of the usability of a critical care information system ( introduction: critical care information systems (ccis) support clinical processes by storing and managing data, but poor usability can lead to staff dissatisfaction and increased workload, promoting workarounds that may compromise patient safety [ ] . the purpose of the study was to evaluate the usability of a philips intellispace critical care and anaesthesia (icca) ccis, recently implemented in beds across three critical care units of a large uk teaching hospital. methods: a prospective, mixed method observational study conducted in may , comprising of ( ) an audit assessing the ease of linking bedside devices to icca, ( ) an audit assessing the usability of co-signing medications in icca compared with a non-icca paper factors that commonly drive workforce metrics may not correlate with staff perceptions of safety. the bpr is a pragmatic, staff driven, tool to augment other measures of safety and is applicable to various icu settings. further research is needed to explore staff perceptions in order to understand the importance of this organisationally, and for staff stress. ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rates of deep vein thrombosis (dvt) and stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, dvt prophylaxis duration, stress ulcer prophylaxis duration, icu and hospital mortality, -day mortality, rate of central venous catheter infection, length of stay in icu and hospital between two groups were analyzed. results: rate and duration of dvt prophylaxis in the intervention group were . % and ( , ) days respectively, in the control group were . % and ( , ) days, the differences between two groups were statistically significant(p< . ) ( table ). there were no differences in ventilator-free duration in icu, central venous catheter duration, urinary catheter duration, rate of stress ulcer prophylaxis, rates of de-escalation antibiotic therapy, stress ulcer prophylaxis duration, icu and hospital mortality, -day mortality, rate of central venous catheter(cvc) infection, length of stay in icu and hospital between two groups ( table ) . conclusions: electronic checklist in ward rounds can increase the rate of dvt prophylaxis and reduce the duration, but it cannot improve the prognosis of critically ill patients. introduction: the goal of the project "i see you" is family-centeredcare based on family meetings that improve the experience of the patient´s family members during hospitalization in the icu. the meetings focus on relaying information, raising knowledge and addressing the social and emotional needs of families. providing support along with information was found to be the strongest predictor of family satisfaction and could lead to improve cooperation between family and staff [ ] .methods: meetings and questionnaire: family meetings consist of a multidisciplinary team, a group facilitator and combined with a multimedia presentation about the unit and equipment. in addition, they focus on social and emotional needs: managing daily routine, sharing problems, fears and anxieties and more. at the end of the session a questionnaire was given to assess the impact of the intervention. sharing data: at the end of the first quarter, the data from meeting was summarized and sent to the staff alongside tools for effective communication.results: the project began in february . to date, family members of patients have attended the sessions. the topics discussed by the participants include: contact with the patient, prevention of infections, procedures, visits, conversations with doctors, medical confidentiality; guardianship; tracheotomy and social issues (fig ) . a sample of questionnaires was transferred to participants report satisfaction at a very high level.conclusions: the meeting received a very positive feedback from the participants. the project has achieved its goals and therefore it has been decided to be continued.introduction: possum score and boyd criteria are used to predict the outcome for high risk surgical patients. the aim of this study was to validation of these two measurement tools on mortality and morbidity in a university-based surgical intensive care unit (sicu) in thailand.methods: nine hundred and fifty two patients were enrolled onto this prospective review. all patients who had been admitted to sicu in a university-based hospital were included. all patients were collected for boyd criteria and possum score and outcomes and morbidity during sicu admission and discharge. introduction: aromatic microbial metabolites (amm), such as phenyllactic (phla), p-hydroxyphenylacetic (p-hphaa), and phydroxyphenyllactic (p-hphla) are involved in the pathogenesis of septic shock and are associated with mortality [ ] . according to previous studies, amm have a high prognostic value in patients with abdominal infection [ , ] . we hypothesize that amm have the prognostic value in patients with pneumonia in icu. methods: data of patients with community-acquired pneumonia was obtained on admission to icu. the levels of amm (phla, p-hphla and p-hphaa) were measured in blood serum using gas chromatography with flame ionization detector and compared in groups of patients: with favorable and with lethal outcome (mann-whitney utest). spearman's correlations between amm and clinical and laboratory data were calculated. using method of logistic regression and roc analysis, we measured the prognostic value of amm. (table ) . it was revealed, that some amm have similar prognostic characteristics in comparison with sofa and curb- scales; high level of amm is associated with high risk of death (roc-analysis - fig. ) .conclusions: serum concentrations of amm can be used as independent and practical criteria for the assessing of prognosis in patients with infection in icu. introduction: frailty in the critically ill is associated with increased morbidity and mortality but the optimal timing of frailty assessment, how to best measure frailty, reasons for adverse outcomes and how critical illness impacts frailty are unknown [ ] . in preparation for a multi-center study designed to address these knowledge gaps, we conducted a pilot study whose aim was to assess feasibility as determined by recruitment rates, ability to assess frailty at icu admission and hospital discharge, ability to measure icu and hospital processes of care and ability to conduct -month assessments. conclusions: a multi-center study is feasible but follow-up losses due to mortality and inability to return for assessment will require sample size adjustment. frailty characterization is method dependent, can be done on hospital discharge but varies with time of assessment. these findings will need to be confirmed in our larger study currently in progress. introduction: given the ageing of the world´s population, the demands of critical care resources for elderly patients has increased during the past decade. however, little is known about quality of life and outcomes of elderly icu survivors. the aim of the study is to assess outcomes of elderly icu survivors at least months after discharge: quality of life and mortality. methods: it is a retrospective study performed in a medical adult icu between january to december . the study included all elderly survivors ( ≥ years) after icu admission. outcomes were assessed by telephone interviews at least months after icu discharge. the primary outcome was assessing the quality of life after icu stay, measured by euro qol d questionnaire. the eq- d descriptive system contains five dimensions (mobility, self-care, usual activities, pain and discomfort, and anxiety and depression). for each dimension, there are five levels (no problems, slight problems, moderate problems, severe problems and unable to/extreme problems figure . conclusions: most elderly survivors patients showed a good health related quality of life using the euroqol d- l after icu discharge. fig. (abstract p ) . quality of life (euroqol d) scores after icu discharge introduction: sepsis survivors face mental and physical sequelae even years after discharge from the intensive care unit (icu). effects of a primary care management intervention in sepsis aftercare were tested. exploratory analyses suggest better functional outcomes within the intervention group compared to the control group at six and months after icu discharge. longer term effects of the intervention have not been reported. methods: a randomized controlled trial was conducted, enrolling patients who survived sepsis (including septic shock), recruited from nine german icus. participants were randomized to usual care (n= ) or to a -months intervention (n= ). the intervention included training of patients and their primary care physicians (pcp) in evidence-based post-sepsis care, case management provided by trained nurses and clinical decision support for pcps by consulting physicians. usual care was provided by pcps in the control group. the primary outcome of the trial was the change in mental healthrelated quality at -months after icu discharge. secondary outcomes included measures of mental and physical health. data were collected by telephone interviews using validated questionnaires at the -months follow-up ( months after the -year intervention).results: [ . %, intervention, control] of patients completed the -months follow-up. unlike the intervention group, the control group showed a significant increase of posttraumatic symptoms (diff. ptss- to baseline, mean (sd) . ( . ) control vs.- . ( . ) intervention; p= . ). there were no significant differences in the mcs and all other secondary outcomes between intervention and control group.introduction: survivors of sepsis often show symptoms of posttraumatic stress disorder (ptsd). only few studies report on courses of more than month after discharge from the icu. the aim of this study was to identify predictors for changes in ptsd symptoms over time up to month. methods: follow-up data of the smooth triala rct to evaluate a primary care management intervention on sepsis survivorswere analyzed. included patients were surveyed by phone for ptsdsymptoms at one, , and months after discharge from icu using the post-traumatic-stress-scale (ptss- ). scores changes between follow-up periods were analyzed using latent-change scores in structural equation models. predictors were clinical and sociodemographic baseline characteristics as well as physical, cognitive and functional sepsis sequelae assessed by validated questionnaires.results: patients were included of which participated in the month follow-up. a decrease of ptsd symptoms between and months was predicted by higher education (b=- . , p= . ), while higher pain intensity at one month predicted an increase (b= . , p= . ). increasing ptsd symptoms between and months were predicted by reporting more than two traumatic memories at one month (b= . , p= . ), more sleep problems (b= . , p= . ) and worse cognitive performance at months (b=- . , p= . ) as well as more neuropathic symptoms at months (b= . , p= . ).conclusions: sepsis patients that suffer from physical, cognitive and functional impairments after icu discharge may be at increased risk for developing late-onset ptsd. these predictors need to be replicated by future studies. early versus late readmission to the intensive care unit: a ten-year retrospective study v karamouzos , n ntoulias , d aretha , a solomou , c sklavou , d logothetis , t vrettos , m papadimitriou-olivgieris , d velissaris , f fligou conclusions: icu patients whose life-sustaining treatment was withdrawn or withheld had higher illness-severity scores, were older, had longer icu los and higher mortality than those in active-treatment group. healthcare introduction: caring for the critically ill patient is a complex task and becomes tougher when a death process takes place. a number of needs and coping strategies emerge from the healthcare providers before these issues but are mostly displayed out of individual skills and intuition. if those approaches are unappropriate and the needs are not met, patients' death process may be burdensome for caregivers. this could affect the quality of care for patients and families during the whole end-of-life care process. the aim of our study was to explore the different needs and coping strategies used by icu healthcare providers when facing patients in the dying process. methods: qualitative and collective case study. ten semi-structured interviews were conducted in icu personnel ( physicians and nursing professionals). a thematic analysis was done using nvivo software. local ethics committee approved the study. results: respondents were % women, had . ± . years-old and . ± . years of icu experience. main needs identified in icu healthcare providers refer to a lack of tools for doing emotional containment when delivering bad news to families, handling personal mourning, the need to perceive consistency regarding end-of-life care management across the icu team, and a wish of having regular training from a psychologist. main identified coping strategies included closing rituals, finding quiet spaces to spend time, and asking for counselling with more expert colleagues. a need for systematic, although basic training on these issues from qualified professionals is demanded. conclusions: usually, basic needs from patients and families in the process of dying are well addressed, but healthcare providers' needs are underrecognized and coping strategies mostly unknown. visibilization of those needs and basic but formal training in emotional containment, self-care and coping strategies are greatly desired. introduction: in the intensive care unit (icu), patients often exhibit cognitive impairments that prevent them from participating in decisions related to therapeutic options at the end of life. consequently, their families are often asked to speak for them when difficult decisions must be made. the main of this study was to determine the frequence in wich family want to share in end of life decisions and factors associated with this desire.methods: a prospective study was conducted in one mixed icu in montevideo. relatives of patients were invited to participate in this study after hours in the icu and completed a survey that included the hospital anxiety and depression scale. results: we analized relatives from patients hospitalized in the intensive care unit. the relationship with the patient was as follows: % spouses, % siblings, % grown children, % parents, and % other family members and friends. of them, . % reported a desire to share in end of life decisions. anxiety and depression symtoms were present in % and % respectively. factors asociated with the desire of involvment in end of life decisions by bivariate analysis were: female sex ( % vs %, p= . ), presence of anxiety ( % vs %, p= . ) and patient ecog - ( % vs %, p= . ). multivariate analysis shows that the presence of anxiety is the only independent factor associated with the desire to participate in end of life decisions (or . , ic % . - . ; p= . ). conclusions: have a loved one in icu is often associated with anxiety and depression after hours of admission. only % of the relatives want to participate in end of life decisions. the presence of anxiety is independently associated with the want to share in decisions making process. introduction: intensive care aims to treat failure of vital organ systems. sometimes, a patient's condition is of such a degree that intensive care is no longer beneficial, and decisions to withdraw or withhold intensive care are made. this means that life-sustaining treatments are terminated or not initiated. we aimed to identify variables that are independent factors for the decision to withdraw or withhold intensive care. methods: registry study using extracted data from a national quality registry the swedish intensive care registry (sir) - . data are delivered to the registry by nurses and doctors daily, during each patients' stay in the intensive care unit (icu). a total of , intensive care cases reported to the sir from - . results: data regarding each patient´s age, sex, diagnoses, condition at admission (expressed as simplified acute physiology score version , saps ), comorbidities and registered decisions to withdraw or withhold intensive care were analyzed. of the , cases reported, . % were women and . % men, and . % were - years old. a total of . % received a decision to withdraw or withhold intensive care, accounting for . % of all women and . % of all men, p< . . independent variables associated with increased odds of receiving a decision to withdraw or withhold intensive care were older age, worse condition at admission, and female sex. female sex was associated with an increased odds of receiving a decision to withdraw or withhold intensive care by % (ci . - . %) after adjustments for condition at admission and age. conclusions: older age, worse condition at admission and female sex was found to be independent variables associated with an increased odds to receive a decision to withdraw or withhold intensive care.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -iyh d mj authors: ding, lin; zhao, yu; li, xuyan; wang, rui; li, ying; tang, xiao; sun, bing; he, hangyong title: early diagnosis and appropriate respiratory support for mycoplasma pneumoniae pneumonia associated acute respiratory distress syndrome in young and adult patients: a case series from two centers date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: iyh d mj background: mycoplasma pneumoniae (m. pneumoniae) is one of the most common causes of community acquired pneumonia (cap). establishing an early diagnosis of m. pneumoniae pneumonia in patients with acute respiratory distress syndrome (ards) may have important therapeutic implications. methods: we describe diagnosis and management of m. pneumoniae pneumonia induced ards in a case series of adults and youth hospitalized with radiographically confirmed cap prospectively enrolled in an observational cohort study in two university teaching hospitals, from november to october . results: in all patients, early and rapid diagnosis for severe m. pneumoniae pneumonia with ards was achieved with polymerase chain reaction (pcr) or metagenomic next-generation sequencing (mngs) testing of samples from the lower respiratory tract or pleural effusion. the average pao( )/fio( ) of all patients was mmhg. of the cases, cases had moderate ards ( mmhg ≤ pao( )/fio( ) < mmhg) and cases had severe ards (pao( )/fio( ) < mmhg). high flow nasal cannula (hfnc) was applied in all patients, though only two patients were sufficiently supported with hfnc. invasive mechanical ventilation (imv) was required in patients. high resistance (median l/cmh( )o/s) and low compliance (median ml/cmh( )o) was observed in cases. in these cases, recruitment maneuvers (rm) were applied, with patient demonstrating no response to rm. prone positioning were applied in cases. two cases needed ecmo support with median support duration of . days. no patient in our case series received corticosteroid therapy. all patients were survived and were discharged from hospital. conclusions: early and rapid diagnosis of severe m. pneumoniae pneumonia with ards can be achieved with pcr/mngs tests in samples from the lower respiratory tract or pleural effusion. in our case series, half of m. pneumoniae pneumonia induced ards cases were adequately supported with hfnc or niv, while half of cases required intubation. rm and prone position were effective in % of intubated cases, and % needed ecmo support. when early anti-mycoplasmal antibiotics were given together with sufficient respiratory support, the survival rate was high with no need for corticosteroid use. mycoplasma pneumoniae (m. pneumoniae) is one of the most common causes of community acquired pneumonia (cap) often seen in children and young adults, and accounts for - % of all cases of adult cap cases [ , ] . m. pneumoniae pneumonia is typically mild and characterized by a persistent dry cough or self-limiting pneumonia that resolves with no medication [ ] . however, respiratory failure and severe acute respiratory distress syndrome (ards) occur in . - % of all m. pneumoniae pneumonia cases and primarily affect young adults [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the rates of intensive care unit (icu) admission of hospitalized m. pneumoniae pneumonia patients are reported as % in the us and . % in europe [ , ] . the rate of icu admission is even higher at . % in patients older than years, compared to % in patients older than years [ ] . in one retrospective study from our hospital, . % of m. pneumoniae pneumonia patients needed icu admission for acute respiratory failure in the setting of an epidemic [ ] . severe ards and fatal outcome as a result of m. pneumoniae pneumonia may be the result of unclear clinical features [ ] , delayed diagnosis, inappropriate respiratory support, and/or insufficient initial treatment. when acute nonbacterial pneumonia progresses, m. pneumoniae must be considered as a possible cause, and appropriate diagnosis, respiratory support and therapeutic measures should be promptly instituted. previous studies suggest that m. pneumoniae infection should be included in the differential diagnosis of ards, and that establishing an early diagnosis may have important therapeutic implications [ ] . in recent years, rapid diagnostic methods have been developed, allowing for early diagnosis of m. pneumoniae pneumonia. detection of m. pneumoniae using fluorescence-quantatitive pcr in respiratory samples [ , [ ] [ ] [ ] [ ] and metagenomic next-generation sequencing (mngs) has increased [ ] ; these methods are especially useful for early detection of rare, atypical, and slow-growing microbes. case reports have also described using new forms of respiratory support for m. pneumoniae pneumonia induced ards, such as highflow nasal cannula (hfnc) [ ] , non-invasive ventilation (niv) [ ] and veno-venous extracorporeal membrane oxygenation (ecmo) [ , , ] . however, there has not yet been a full evaluation of the new available diagnostic and therapeutic measures in m. pneumoniae pneumonia induced ards. the aim of our study was to describe a case series of patients with m. pneumoniae pneumonia induced ards and provide an overview of available modalities for diagnosis and treatment. we describe the epidemiological, clinical, imaging, and laboratory features of our patients, review the available procedures for early diagnosis, and evaluate available respiratory support techniques in clinical practice in order to highlight the importance of rapid recognition and appropriate treatment. we retrospectively identified all cases of young and adult patients (age over years) with ards caused by m. pneumoniae pneumonia who were admitted to the respiratory icu in two teaching hospitals (beijing chao-yang hospital and beijing luhe hospital, beijing, china) with radiographically confirmed cap from november to october . the study was approved by the institutional review boards (irb) at each institution. written informed consent was obtained from all participants, where participants are children (under years old) from their parent or guardian. case definitions for m. pneumoniae pneumonia induced ards criteria for diagnosis of m. pneumoniae pneumonia were based on ) clinical signs and symptoms (cough, fever, productive sputum, dyspnoea, chest pain or abnormal breath sounds); ) radiographic pulmonary abnormalities that were at least segmental and were not explained by pre-existing or other known causes; and ) positive detection of m. pneumoniae nucleic acid by pcr or mngs from lower respiratory tract secretion (sputum and balf), which were considered as microbiological evidence of infection. all cases of pneumonia occurring more than days after hospitalization were considered nosocomial and were excluded. patients with hiv infection, neutropenia, or who were receiving immunosuppressive chemotherapy were excluded. the diagnosis of ards was assigned to patients who met the berlin definition criteria: ) presence of acute hypoxemic respiratory failure; ) onset within days of insult, or new (within days) or worsening respiratory symptoms; ) bilateral opacities on chest x-ray or ct not fully explained by effusions, lobar or lung collapse, or nodules; and ) cardiac failure not the primary cause of acute respiratory failure. we categorized patients into mutually exclusive classes of ards severity using previous definitions based on degree of hypoxemia: ) mild ( mmhg ≤ pao /fio < mmhg); ) moderate ( mmhg ≤ pao /fio < mmhg); and ) severe (pao /fio < mmhg). patient specimens, including sputum, whole blood, and serum samples, were collected upon admission and during hospitalization for bacterial and viral testing. microbiological tests were performed at the department of infectious disease and clinical microbiology laboratories in our centers. throat swabs, sputum, endotracheal aspiration or balf were collected for m. pneumoniae pcr assay. all severe ards patients had m. pneumoniae infection confirmed by pcr assay or mngs from lower respiratory tract secretion (sputum and balf). pcr of pleural effusion fluid were also tested in some patients for the detection of m. pneumoniae. clinical information collected included the following: characteristics (age and sex), comorbidities, clinical symptoms (fever, cough, sputum, dyspnea, chest pain, rash, nausea, vomiting, abdominal pain, diarrhea and headache), clinical signs (body temperature, heart rate, respiratory frequency, blood pressure and crackles in the lungs), laboratory tests (whole-blood cell count and blood chemistry), and microbiological findings and images of the lung, including chest x-ray (cxr) and high resolution computed tomography (hrct). concomitant medications, respiratory support (hfnc, niv, invasive mechanical ventilation, prone position and ecmo), complications, and outcomes were also recorded. pooled epidemiological, clinical, imaging, and laboratory data are shown as median with range for quantitative variables and as absolute and relative frequencies for qualitative variables. the enrolled patients were divided into two groups based on use of invasive mechanical ventilation. continuous variables were compared using the mann-whitney u-test, whereas categorical data were compared using the chi-squared test or the fisher's exact test, where appropriate. all comparisons were performed using the spss statistics package version . . differences were considered statistically significant when p was < . . between november and october , patients met criteria of severe m. pneumoniae pneumonia. of the patients, one patient was excluded due to diagnosis of lymphoma combined with adenovirus pneumonia. therefore, immunocompetent patients were included in the final analysis. the age range of our patients was to (median ) years. there were male and female patients. all cases were admitted in different months of the year except for january, february and september. only one patient (case ) had diabetes mellitus. the other patients had no underlying diseases (table ) . seven ( %) and ( %) patients had positive serum m. pneumoniae igg and igm, respectively. m. pneumoniae pcr of the sputum was performed in ( %) cases, and was positive in all cases. three of the cases had m. pneumoniae pcr from balf at the same time, and all cases ( %) were positive. another patient was diagnosed with m. pneumoniae pneumonia through pcr of pleural effusion fluid. five cases had mngs from balf, and all these cases were positive for m. pneumoniae (table ) . acinetobacter baumannii was detected in patients ( %) who were transferred from another hospital after icu admission, but these were isolated from the lower respiratory tract (lrt) samples collected after more than days of their icu stay, and therefore were not considered as causative agents of ards together with m. pneumoniae (table ) . all patients had cough and fever at the onset of illness. they presented with a high fever, with a median body temperature of . °c (range, . °c to . °c). eight patients ( %) had dry cough and two patients had productive cough. four patients ( %) had diarrhea and one patient ( %) had abdominal pain (table ) . acute respiratory deterioration occurred to (median ) table ). nine patients were tested for cell-mediated immunity, immunoglobulins (serum igg, iga and igm), and components (attached file , e- table ). table ). all patients had cxrs. cxrs revealed bilateral multilobular or segmental consolidation in nine ( %) patients. one patient's cxr showed diffuse peribronchial infiltration. all patients underwent chest hrct. unilateral or bilateral consolidation and infiltration were found on hrct scans of patients ( %). large areas of consolidation within a single lobe or several lobes ( %), followed by pleural effusion ( %), were the most common findings on hrct (fig. ) . only the hrct of case showed peribronchial infiltration without consolidation and pleural effusion. the average pao /fio of all patients was mmhg. four ( %) cases had moderate ards ( mmhg ≤ pao /fio < mmhg), and three cases ( %) had severe ards (pao /fio < mmhg). hfnc was applied in all patients ( %), with a median gas flow of l/min ( - l/min) and fio . ( . - . ), but only two patients were sufficiently supported with hfnc. niv was used in four patients with a median duration of ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) h, and one patient had niv failure and needed intubation ( table ) . invasive mechanical ventilation (imv) was carried out in patients ( %). high airway resistance (median l/cmh o/s) and low respiratory system compliance (median ml/cmh o) was observed in all cases. recruitment maneuver (rm) was applied in cases, with patient not responsive to rm, and cases were put into prone position. the maximum peep was cmh o (range, - cmh o). two cases ( %) needed ecmo support with median support duration of . days ( table ). as shown in table , case had the worst compliance and was unresponsive to rm, and ecmo was established. case , case , and case were responsive to rm and prone position. all patients did not receive fluoroquinolones at the onset of their illness, and switched to fluoroquinolones . ± . days after onset. all patients received β-lactams treatment as first therapy, and patients received treatment combined with macrolides before their admission to icu. after icu admission, moxifloxacin were given to all patients. no patients in our case series received corticosteroid therapy. all patients survived in the icu and were discharged from the hospital. the mortality of our cases was %. the average length of icu stay was days, and the average length of hospital stay was days. as shown in table , compared to non-intubated patients, patients in intubated group were younger, were less likely to be male, had lower pao /fio and higher apache ii scores, and had higher procalcitonin and neutrophil proportion at icu admission. to our knowledge, our study is the first and largest case series to evaluate diagnostic and therapeutic modalities in severe m. pneumoniae pneumonia induced ards. our main findings are as follows: ) early and rapid diagnosis for severe m. pneumoniae pneumonia with ards was achieved with pcr/mngs test of samples from the lower respiratory tract and pleural effusions; ) ct findings mainly showed alveolar patterns with bilateral consolidations rather than interstitial patterns; ) respiratory mechanics showed low respiratory system compliance and high airway resistance; ) % of m. pneumoniae induced ards were adequately supported with hfnc or niv, % required intubation, rm and prone position were effective in % intubated cases, and % needed ecmo support; ) when early anti-mycoplasmal drugs together with sufficient respiratory support are given, the survival rate was high with no need for corticosteroids; and ) younger patients with lower pao / fio and apache ii scores, and higher pct and higher neutrophil cell proportion at icu admission were more likely to require intubation. in our study, the clinical manifestations of severe m. pneumoniae pneumonia induced ards were primarily dry cough, high fever, and acute respiratory failure with bilateral consolidations on radiologic examination. respiratory failure occurred a median of days (range, to days) after onset of symptoms, similar to the previous descriptions [ , ] . however, these clinical features are not specific for early recognition and diagnosis of severe m. pneumoniae pneumonia. therefore, early and precise laboratory detection of m. pneumoniae infection is essential to prevent deterioration. previous methods, such as mycoplasma culture and serological tests, which may require several weeks, are not practical. as presented in our study, early definitive diagnosis is now dependent on pcr or mngs [ ] , which had high specificity and sensitivity. thus, further development of these relatively new diagnostic tools is warranted, and should be applied in cases of severe cap induced ards with suspected m. pneumoniae infection. furthermore, our study found that most of our cases had pleural effusion, and pcr was positive for m. pneumoniae in pleural effusion fluid. similar findings were also reported in a previous case report [ ] . therefore, in patients with dry cough and difficulty obtaining a lower respiratory sample, early pcr/mngs for m. pneumoniae using pleural effusion fluid may be an option. as ards is a clinical syndrome with many different causes and may induced by some less common pathogens, mngs is used in our icu for early detection of possible unknown etiology, and we found that mngs had a good value in diagnosis for m. pneumoniae in our cases. however, in most cases mngs is more appropriate to be used for patients with unknown etiology, and may not be suitable for routine examination of some common pathogens such as adv, rsv, and m. pneumoniae. thus, once commercial pcr kits are available for diagnosis of m. pneumoniae infection, it is not necessary to detect m. pneumoniae using mngs as a primary option. in both our case series and previously reported cases of m. pneumoniae associated ards, deterioration of the clinical state presumably due to a significant period of inadequate antibiotic treatment [ , ] . in a review of severe or fatal m. pneumoniae pneumonia, the average duration from onset of infection to the development of respiratory failure was . days (range, - days) [ ] . chan and miyashita et al. reported durations of - and . days, respectively, from onset to first administration of appropriate anti-mycoplasma agents [ , ] . the duration of an average of days to change the treatment from our study was similar to the previous studies. therefore, our management would still be considered as late intervention, and the delay as a risk factor for development of respiratory failure and ards. earlier recognition of m. pneumoniae in the differential diagnosis and earlier initiation of appropriate antibiotics would potentially prevent m. pneumoniae pneumonia from progressing to ards. furthermore, more awareness is needed on the emergence of macrolide-resistant m. pneumoniae infection in adults [ , ] . a previous report from our center found the rate of resistance to macrolides was . % of the isolated m. pneumoniae, and all resistant strains harbored a g mutations. the isolated macrolide-resistant m. pneumoniae were resistant to erythromycin, and also showed cross-resistance to clarithromycin and azithromycin. all isolates were sensitive to tetracyclines and fluoroquinolones. moxifloxacin was more active than ciprofloxacin and levofloxacin [ ] . however, sequencing of macrolide resistance genes is not a routine test in clinical practice in our centers, and we did not perform sequencing for macrolide resistance genes in our cases. we speculated that we have the similar high rate of resistance and similar type of resistant genes in our case series. thus, early fluoroquinolones were considered as first line treatment for m. pneumonia induced severe ards cases in adults. a previous epidemiological study from one of our centers (beijing chao-yang hospital) that routinely screened for m. pneumoniae in outpatients during - determined that only patients out of patients ( . %) with m. pneumoniae infection needed icu admission [ ] . however, after that study concluded, m. pneumoniae infection was only routinely screened in patients with a diagnosis of community acquired pneumonia who were hospitalized in our general ward or admitted to our icu. during our study period, of severe cap were admitted to our icu and were diagnosed with m. pneumoniae pneumonia ( . %). additionally, as shown in table in our study, the first lrt sample for m. pneumoniae was collected on an average of ± days after the onset of symptoms. the higher rate of m. pneumoniae pneumonia in our case series suggests that early detection for the pathogen may be needed to start an early intervention and proper treatment. the patients with mild ards in our study were successfully supported by hfnc and niv without intubation. one patient with moderate ards was successfully supported with a combination of hfnc and awake prone positioning, which proved safe and effective in moderate ards patients by our team in a prospective study [ ] . hfnc or niv, combined with early prone positioning, may be a new support strategy for acute respiratory failure in m. pneumoniae indunced mild to moderate ards patients. although the radiologic findings showed a diffuse alveolar pattern with consolidations and the respiratory mechanics showed decreased respiratory system compliance, most intubated patients were responsive to rm and prone positioning during invasive ventilation, with a maximum peep of - (median ) cmh o was applied. however, two cases deteriorated to severe hypoxia despite anti-mycoplasmal therapy and invasive ventilation, eventually requiring ecmo support. in a recent case report and literature review for use of ecmo in m. pneumoniae associated ards, the mean ecmo run was h/ . days [ ] , similar to that of our cases. the overall survival rate for cases of m. pneumoniae requiring ecmo with reported outcome was . % ( / ) , demonstrating that ecmo may be safely and effectively used to treat severe ards caused by m. pneumoniae infection [ ] . previous reports support the hypothesis that the severity of the disease and pulmonary infiltrates may be directly correlated with the level of the individual immune response. however, in our study, we did not observe significant increases of cell or humoral immunity as demonstrated by t cell subset cell count or immunoglobulin levels in more severe disease. most interestingly, we found that with appropriate respiratory support and anti-mycoplasmal therapy, all patients had a rapid clinical improvement. therefore, no corticosteroids were given, and all patients finally recovered from ards without corticosteroid use. prolonged or inappropriate use of corticosteroids may cause excess downregulation of cell-medicated immunity and result in immunosuppression, making individuals more susceptible to more severe m. pneumoniae infection or opportunistic infections. a recent case report revealed that m. pneumoniae associated ards had no elevated pulmonary vascular permeability, and was successfully treated using low-dose short-term hydrocortisone, suggesting that pulmonary infiltration in ards caused by m. pneumoniae does not match the criteria of permeability edema observed in typical ards [ ] . therefore, careful consideration is required when deciding whether to use high dose corticosteroid in the future cases similar to ours. there are several limitations for our study. first, performing statistical analysis on a small sample size was prone to bias, potentially yielding spurious findings. increasing the sample size and collecting more cases in a further study may avoid this kind of limitation. second, this study is a retrospective study with the associated limitations on complete data collection. in conclusion, early and rapid diagnosis for severe m. pneumoniae pneumonia with ards can be achieved by pcr/mngs test in samples from lower respiratory tract or pleural effusion. in our case series, half of m. pneumoniae induced ards cases were adequately supported with hfnc or niv and % required intubation. rm and prone position were effective in % of intubated cases, and % needed ecmo support. when early antimycoplasmal therapy was given together with sufficient respiratory support, the survival rate was high with no need for corticosteroid use. viral and mycoplasma pneumoniae community-acquired pneumonia and novel clinical outcome evaluation in ambulatory adult patients in china etiology and antimicrobial resistance of community-acquired pneumonia in adult patients in china clinical features of severe or fatal mycoplasma pneumoniae pneumonia fulminant mycoplasma pneumoniae pneumonia clinical features of severe mycoplasma pneumoniae pneumonia in adults admitted to an intensive care unit adult respiratory distress syndrome caused by mycoplasma pneumoniae adult respiratory distress syndrome due to mycoplasma pneumoniae report of a fatal case, and a review of the literature fulminant mycoplasma pneumoniae infection: report of a fatal case, and a review of the literature mycoplasmal pneumonia and adult respiratory distress syndrome: a complication to be recognized three severe cases of a common infection adult respiratory distress syndrome associated with mycoplasma pneumoniae infection adult respiratory distress syndrome due to mycoplasma pneumonia two cases of fulminant mycoplasma pneumoniae pneumonia within months severe acute lung injury caused by mycoplasma pneumoniae: potential role for steroid pulses in treatment fulminant mycoplasma pneumoniae pneumonia acute respiratory distress syndrome in mycoplasma pneumonia: a case report and review fatal mycoplasma pneumoniae pneumonia in a previously healthy -yearold girl molecular detection and characterization of mycoplasma pneumoniae among patients hospitalized with communityacquired pneumonia in the united states increased rates of intensive care unit admission in patients with mycoplasma pneumoniae: a retrospective study epidemiological characterization of respiratory tract infections caused by mycoplasma pneumoniae during epidemic and post-epidemic periods in north china a fulminant case of acute respiratory distress syndrome associated with mycoplasma pneumoniae infection acute respiratory distress syndrome caused by mycoplasma pneumoniae diagnosed by polymerase chain reaction life-threatening pneumonia caused by macrolide-resistant mycoplasma pneumoniae application of metagenomic next-generation sequencing for bronchoalveolar lavage diagnostics in critically ill patients a fulminant case of acute respiratory distress syndrome associated with mycoplasma pneumonia treated with nasal high-flow oxygen therapy does noninvasive ventilation work in ards? a case report and review of the current literature fulminant mycoplasma infection requiring ecmo in a previously healthy child: case report and review clinical features, risk factors and treatment of fulminant mycoplasma pneumoniae pneumonia: a review of the japanese literature mycoplasma pneumonia: late treatment leading to acute respiratory distress syndrome and renal failure an adult case of severe life-threatening mycoplasma pneumoniae pneumonia due to a macrolide-resistant strain, japan: a case report mycoplasma pneumoniae in pediatric patients: do macrolide-resistance and/or delayed treatment matter? molecular characterization and analysis of mycoplasma pneumoniae among patients of all ages with community-acquired pneumonia during an epidemic in china efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study acute respiratory distress syndrome caused by mycoplasma pneumoniae without elevated pulmonary vascular permeability: a case report publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thanked ann andee wang m.d. (from feinberg school of medicine, northwestern university, chicago, il, usa) for her advices and help for the manuscript revision. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . e- table . the laboratory findings for the patients with severe m. pneumoniae pneumonia on the first day of admission.additional file . e- table . the result of pleural effusion biochemistry and pleural effusion routine of the severe m. pneumoniae pneumonia.additional file . e- table . cell-mediated immunity and humoral immunity on the immunocompetent patients with severe m. pneumoniae pneumonia on the first day of admission. authors' contributions ld, yz, xl, rw, yl, xt, bs and hh carried out the treatment, collected analyzed the data and wrote the manuscript. hh and ld conceived of the study, and participated in its design and coordination and draft the manuscript. all authors read and approved the final manuscript. no. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. this study is approved by the irb of beijing chao-yang hospital and beijing luhe hospital. written informed consent was obtained from all participants (where participants are children under years old, from their parent or guardian). written informed consent was obtained from all participants for their data to be used for research and publication. written informed consent for participation in the study was obtained where participants are children (under years old) from their parent or guardian. we confirm that the patients, and in the case of minors their parents/guardians, provided written informed consent for the publication of potentially identifying images and clinical details. the authors declare that no conflicts of interests. key: cord- -z hh c authors: cotogni, paolo; trombetta, antonella; muzio, giuliana; brizzi, maria felice; canuto, rosa angela title: polyunsaturated fatty acids and cytokines: their relationship in acute lung injury date: journal: diet and nutrition in critical care doi: . / - - - - _ sha: doc_id: cord_uid: z hh c acute lung injury (ali) and acute respiratory distress syndrome (ards) are inflammatory diseases whose clinical severity depends on the grade of inflammatory response. inflammatory cytokines are key elements in the pathogenesis of ali/ards, and the occurrence of an imbalance between pro- and anti-inflammatory cytokines leads to additional non-pulmonary organ dysfunction which contributes to excess mortality rates. treatment of these patients includes nutrition support with lipids, usually soybean oil-based lipid emulsions, which are rich in omega (n)- polyunsaturated fatty acids (pufas) and deficient in n- pufas; however, too much n- pufas are detrimental due to their pro-inflammatory effects. conversely, a large amount of experimental studies and some randomized clinical trials showed the benefits of the n- pufa administration in the context of ali because of their anti-inflammatory properties. based on these data, several scientific societies recommended in their guidelines, with an a or b grade of recommendation, the use of n- pufas in ali/ards patients. however, at present, the issue of lipid therapy in ali/ards is still controversial due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n- pufas. acute lung injury (ali) and acute respiratory distress syndrome (ards) are inflammatory diseases whose clinical severity depends on the grade of inflammatory response. inflammatory cytokines are key elements in the pathogenesis of ali/ards, and the occurrence of an imbalance between pro-and antiinflammatory cytokines leads to additional non-pulmonary organ dysfunction which contributes to excess mortality rates. treatment of these patients includes nutrition support with lipids, usually soybean oil-based lipid emulsions, which are rich in omega (n)- polyunsaturated fatty acids (pufas) and deficient in n- pufas; however, too much n- pufas are detrimental due to their pro-inflammatory effects. conversely, a large amount of experimental studies and some randomized clinical trials showed the benefits of the n- pufa administration in the context of ali because of their anti-inflammatory properties. based on these data, several scientific societies recommended in their guidelines, with an a or b grade of recommendation, the use of n- pufas in ali/ards patients. however, at present, the issue of lipid therapy in ali/ards is still controversial due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n- pufas. acute respiratory distress syndrome (ards) is considered a form of acute diffuse lung injury (ali). according to the berlin definition (ferguson et al. ) , each subcategory of ards (mild, moderate, and severe) is defined by mutually exclusive ranges of the ratio between arterial oxygen partial pressure (pao ) and fractional inspired oxygen (fio ) ( mm hg<pao /fio mm hg, mm hg<pao /fio mm hg, and pao / fio mm hg, respectively). the acute phase of this syndrome is manifested by the early onset of respiratory failure (characterized by hypoxemia refractory to oxygen supply within week of a known clinical insult or new/worsening respiratory symptoms) related to several triggers and clinical disorders generally distinguished in pulmonary [pneumonia (bacteria or virus), microbial products (e.g., endotoxins), pulmonary aspiration of gastric contents] and extrapulmonary (trauma/hemorrhagic shock, extensive burns, ischemia/reperfusion injury, acute pancreatitis, cardiopulmonary bypass, transfusions of blood products) (leaver and evans ) . ards is frequently progressive and it is characterized by distinct phases with different clinical, radiographic, and histopathological findings. radiographic findings are similar to those observed in the case of cardiogenic pulmonary edema, mainly bilateral infiltrates (irregular and asymmetric) and sometimes pleural effusions (fig. ) . histopathological findings of ali include diffuse alveolar epithelium damage (principally, denudation of the basement membrane of the alveolus and necrosis of type i cells) with activated neutrophils, alveolar macrophages, hyaline membranes, and protein-rich edema fluid in the alveolar spaces (fig. ) . the pathophysiology of ali is complex and multifaceted. the lung inflammatory response involves various interactions among many cell types, and it is characterized by the production and release of several chemical mediators. figure is a simplified graphic description of how the anatomy and physiology of alveolar space, the main site of inflammatory reactions occurring in ali, change. the lung is a complex organ with many different cell types, i.e., pneumocytes (alveolar type i and ii), fig. anteroposterior chest radiograph from a patient with the acute respiratory distress syndrome who was receiving mechanical ventilation. irregular and asymmetric infiltrates are present throughout both lung fields pulmonary capillary endothelial cells, alveolar macrophages, and fibroblasts. several studies suggest that the lung itself can be an important cytokine-producing organ. cytokines are a diverse group of inflammatory mediators, produced by a wide variety of cell types, which initiate and orchestrate the host response to different injuries. intercellular communication through cytokine networking plays a key role for homeostasis. cytokines seem to have concentration-dependent effects. at lower concentrations, they modulate tissue response to injuries; at higher concentrations, they induce proportionally more severe local and systemic inflammatory responses. if this cytokine overproduction is not regulated, it may remarkably amplify the release of further pro-inflammatory mediators and, at least, the overall inflammatory response. both ali and ards are characterized by an intense inflammatory response. in ards early phase, the alveolar space is the site of significant inflammatory reactions (pugin et al. ) . ali/ards are characterized by alveolar infiltration with neutrophils and macrophages, both able to release inflammatory cytokines. however, recent theories suggest that it is not the neutrophil and macrophage number but their the normal alveolus and the alveolus in acute lung injury. neutrophil is shown migrating through a gap in the capillary endothelium into the alveolar space (activated neutrophil). in the alveolar space, an alveolar macrophage is secreting cytokines: tumor necrosis factor (tnf)-α, interleukin (il)- β, il- , il- , and il- . the alveolar type i cells are damaged or necrotic, while alveolar type ii cells are intact and release cytokines. the tissue architecture is disrupted with the formation of hyaline membranes on the denuded basement membrane. the alveolar space is filled by protein-rich edema fluid fig. alveolar damage in acute lung injury/acute respiratory distress syndrome. the tissue architecture is disrupted, alveoli are collapsed, alveolar type ii (atii) cells are hyperplastic, and alveolar type i cells are necrotic. alveoli contain protein-rich edema fluid and macrophages. collagen deposition in the interstitium has begun. hematoxylin and eosin staining, Â magnification. the picture was kindly given by luisa delsedime, md, anatomia patologica, aou città della scienza e della salute, turin, italy pro-inflammatory cytokine release that produces lung injury. in this setting, cytokines have a central position as signaling mediators that initiate, increase, and maintain inflammatory responses on a local basis. indeed, in ali/ards, an accumulation of both pro-and anti-inflammatory cytokines within the alveolar spaces is demonstrated. many cytokines were detected at elevated levels in bronchoalveolar lavage (bal) fluid in patients with ards, i.e., tumor necrosis factor (tnf)-α, interleukin (il)- β, il- , il- , and il- . tnf-α is the main pro-inflammatory cytokine and it is important in driving the initial lung inflammatory response, principally indirect by the stimulation of other cytokines (i.e., il- and il- ). il- occupies a crucial place in the ards inflammatory response. chemokine il- is the major neutrophil chemotactic factor into the alveolar space, and it is an early marker for the development of ards. finally, il- , which has anti-inflammatory effects, plays a pivotal role in closing down the inflammatory response once it achieves its primary purpose. the pivotal role of a hyper-inflammatory response, characterized by overproduction of tnf-α, il- , and il- , in the evolution of the disease from ali to ards is documented. indeed, many studies report a higher mortality in patients who have increased pro-inflammatory cytokine concentrations in the bal at the onset of ards or persistent increased concentrations in days - . physiologically, the critical dependency on the presence of the inflammatory ligand (e.g., platelet-activating factor) and free arachidonic acid (aa) may help to confine the outbreak of lipid-mediator production to sites of initial inflammatory process. conversely, compartmentalization of alveolar cytokines can be lost in the case of a damaged alveolar barrier. cytokines generated in the alveoli may go into the systemic circulation leading to the beginning of a systemic inflammatory response syndrome. the reason why a patient with ali develops ards while another recovers is still not completely clear. in ards-developing patients, it is hypothesized that, at some level, regulation of the inflammatory response must be inadequate, but why or when this regulation is insufficient is a matter of debate. the study of the balance between pro-and anti-inflammatory cytokines is of greater importance to understand the pathophysiology of ali than a single cytokine concentration, because the degree of cytokine imbalance is a contributing element to disease severity (park et al. ) . persistently high levels of pro-inflammatory cytokines, as well as a reduced production of anti-inflammatory cytokines, have been demonstrated to be correlated with the severity of lung injury. the degree of this cytokine imbalance has a pivotal role in inducing other non-pulmonary organ dysfunctions and increasing mortality rates in ards patients. in particular, the pro-inflammatory activity depends on the balance between the cytokine and its inhibitor(s). in ards early phase, the finding of low levels of anti-inflammatory cytokines (i.e., il- and il- receptor antagonist) in the bal is associated with an increase in patient mortality. the ratio tnf-α to il- in the bal fluid was significantly higher ( . vs. . ) in patients with ards than in those at risk of developing ards. among ali ventilated patients, malnutrition has been associated with adverse outcomes due to increased infection risk, prolonged mechanical ventilation dependency, prolonged intensive care unit (icu) length of stay (los), and higher mortality. in general, critically ill patients receive nutrition support including lipids. administration of lipid emulsions offers many advantages in patients with acute respiratory failure, because compared with glucose they provide a richer source of calories in a small volume with a lower carbon dioxide load and less hyperglycemia. moreover, lipid supply is mandatory to avoid essential fatty acid (fa) deficiency. accepted guidelines recommend providing - % of nonprotein calories as lipids in patients with ali/ards (mizock ) . lipids were introduced into parenteral nutrition (pn) formulations in the s. however, there is a lack of consensus about the optimal source and composition of lipids (long-vs. medium-chain triglycerides, soybean oil vs. olive oil and fish oil) both in parenteral and enteral formulas for the patient with ali/ards. commonly used parenteral lipid emulsions (i.e., soybean oil-based fat emulsions) contain large amounts of n- polyunsaturated fatty acids (pufas) (i.e., more than % of linoleic acid) that form aa [omega (n)- pufa], while only % α-linolenic acid can be metabolically converted to eicosapentaenoic acid (epa, n- pufa) and docosahexaenoic acid (dha, n- pufa). therefore, intravenous fat emulsions have a very low n- /n- pufa ratio, ranging between : and : . likewise, the n- /n- ratio in enteral products may be as low as : . thus, ali/ards patientseither on standard enteral nutrition (en) or pnare generally exposed to a large quantity of linoleic acid. however, administration of high quantities of linoleic acid is not desirable in ali/ards patients because it causes a production of high amounts of aa, whose main functional role is to be a substrate for the synthesis of bioactive pro-inflammatory mediators known as eicosanoids [above all, prostaglandin (pg)-e , thromboxane (tx)-a , and leukotriene (lt)-b ] and platelet-activating factor, which modulates severity and duration of inflammatory responses. the impact of parenteral lipid supply on the lung function of patients with acute respiratory failure has been contradicting. potential harmful effects have been related to type and/or administration rate of lipid emulsions. in particular, some authors thought that these negative effects might correlate to the infusion of soybean oil-based lipid emulsionsbecause they are rich in linoleic acidand suggested that linoleic acid-derived synthesis of eicosanoids may worsen gas exchange and pulmonary hemodynamics in critically ill patients. eicosanoids are major pathogenetic factors of ards, and their negative effects on pulmonary function (e.g., increased permeability, edema formation, polymorphonuclear activation, thrombocyte aggregation, vasoconstriction, and bronchoconstriction) have been widely investigated. as early as , the immunomodulatory properties of lipids were displayed. over the past years, there has been an improved understanding of pufa pathophysiology, and several mechanisms for the interaction between pufas and inflammation or immune response have been demonstrated. indeed, after pufa supply (diet, as well as en or pn), many cell properties and related functions are modified, mainly the inflammatory and immunity responses (calder ) . briefly, n- pufas are more regarded as anti-inflammatory, whereas n- pufas as proinflammatory. more recent studies suggested that n- pufas may be involved in the resolution of inflammation (calder a) . since a network of factors regulates the relationship between n- and inflammation, the mechanisms underlying the effects of n- pufas on cell event modulation are complex. to summarize the mechanisms of n- pufa modulation of the inflammatory response, it can be said that the main and well-demonstrated anti-inflammatory actions of n- pufas include the following: (a) a decreased production of aa-derived mediators such as -series pg and ltb as a result of a reduction in aa content of cell membranes and of inhibition of aa metabolism. (b) an increased production of eicosanoid mediators from epa (e.g., -series pg and ltb ), since these mediators have weak biological potency compared with those produced from aa; for example, ltb is -to -fold less potent as a neutrophil chemotactic agent than ltb , or pge is a less potent inducer of cyclooxygenase- gene expression in fibroblasts and of il- production by macrophages compared with pge . (c) a decreased t-cell proliferation and production of il- induced by epa and dha providing. (d) a decreased expression of some adhesion molecules on the surface of monocytes, macrophages, lymphocytes, and endothelial cells induced by epa and dha providing. (e) a decreased production of pro-inflammatory cytokines, due to decreased activation of pro-inflammatory transcription factors such as nuclear factor κ-b and increased activation of anti-inflammatory transcription factors such as peroxisome proliferator-activated receptor-γ. (f) an increased production of resolvins (e-series from epa and d-series from dha) and protectins (from dha) having potent antiinflammatory or inflammation-resolving properties. pufas and lung injury: nutrients or drugs? over the last years, the discovered ability of n- pufas to downregulate many different responses of the inflammatory process has suggested to several researchers that these fas might have a key role in determining the grade of severity of some inflammatory diseases. consequently, n- pufas have been widely used not only as nutrients but mainly as pharmacological agents. briefly, the rationale of the therapeutic use of n- pufas was based on several well-established issues: ( ) pufas are key structural and functional elements of the phospholipids in cell membranes; ( ) cells involved in the immunity and inflammation (neutrophils, monocytes, macrophages, dendritic cells, and endothelial cells) are richer in n- pufas than n- , but the contents of aa, epa, and dha can be modified by n- pufa (i.e., epa and dha) administration (oral, enteral, and parenteral); ( ) pufa challenge, as well as the fa composition of cell membrane of human inflammatory cells, influences the functions of those cells; and, last but more important, ( ) n- pufas and n- pufas have opposing influences on inflammation. ali/ards are inflammatory diseases too; therefore, numerous studies have been carried out to evaluate strategies (drugs or interventional procedures) to reduce the severity of lung inflammatory processes by lowering the production of pro-inflammatory mediators (eicosanoids and cytokines). nonetheless, few studies have found a significant improvement on mortality in those patients. since , many editorials have stressed the possibility to manipulate the inflammatory response in ali/ards patients using n- pufas as drugs (the so-called pharmaconutrition) (mayer and seeger ) . the research on the influence of fas on immunity started in the s. subsequently, a great number of works with cell or animal models have been carried out with the aim to demonstrate efficacy in modifying the inflammatory responses of fish oil or their main active components (i.e., epa and dha). likewise, there have been some clinical trials of enteral or parenteral administration of fish oil-enriched nutrition formulas in critically ill patients with ali/ards. the experimental models used were animal isolated lungs or, mainly, cell line models. frequently, a human lung carcinoma cell line (a cells) was used. a are alveolar epithelial cells with type ii pneumocyte properties that retain many of the characteristics of normal human type ii epithelial cells and could synthesize lecithin and phosphatidylcholine with a high percentage of desaturated fas. several authors used alveolar type ii cells because it was shown to have a central position in the pathophysiology of the alveolar space. after in vitro administration, fas were rapidly incorporated in the phospholipid spectrum of alveolar cell membranes; in fact, as pulmonary surfactant (the surface-active phospholipoprotein complex) producers, alveolar type ii cells have a higher lipid metabolism, e.g., a significant increase in dha concentration in the lung phospholipid fraction was observed h after dha infusion. several experimental studies with isolated lungs and culture of different pulmonary cells clearly showed a pivotal role of aa and its metabolites as mediators of injury. in contrast, supplementation of n- pufas demonstrated to reduce alveolar release of pro-inflammatory mediators and to reduce organ failure in animal lung models. rapid changes in cell membrane phospholipid fa composition and lipid-derived inflammatory mediator generation were observed both after short cell exposure to n- pufas and short-term intravenous administration of n- pufas. it was observed that pg was produced within min of a cell exposure to epawith a peak at hand this rapid increase of pg was correlated with the metabolism of epa by cyclooxygenases in the a cells. experimental data suggested that epa and dha are both able to inhibit pge production. a short-term n- pufa supplementation induced a significant increase in the n- pufa composition of perfusate (after min) and lung tissue (after h). after as little as h of lung perfusion with an n- pufa-enriched emulsion, significant alterations in the spectrum of eicosanoid generation were found in the isolated lung model. likewise, after min in a model of septic lung injury, it was found that the vascular leakage provoked by bacterial exotoxin in rabbit lungs was differentially influenced by aa versus epa, related to the generation of -versus -series lts. early studies demonstrated that epa and dha inhibited endotoxin-stimulated production of il- and il- by cultured human endothelial cells and n- pufas inhibited endotoxin-induced tnf-α production by cultured monocytes. the differential impact of manipulation of cell membrane phospholipid composition due to n- pufa versus n- pufa administration on cytokine production provoked by pro-inflammatory mediators was demonstrated in a cells. although dha is not able to give rise to lts, it has a pivotal role since it can be incorporated unchanged into membrane lipids or retroconverted into epa. evidence suggests that the antiinflammatory and immunosuppressive effects of n- pufa supply may be attributed mainly, or even exclusively, to dha supplementation. in the past two decades, many authors have highlighted that the n- /n- pufa ratio in nutrition support may influence inflammation since optimal n- administration was not only dose related but was also independently affected by the n- /n- pufa ratio. different n- /n- pufa ratios from : to : have been proposed, but the question of the most favorable n- /n- pufa ratio in ali/ards patients is still to be defined. the impact of the n- /n- pufa ratio on cytokine release by a cells exposed to an endotoxin (i.e., lipopolysaccharide -lps) challenge was investigated in a recent experimental study (cotogni et al. ) . as in many studies, the inflammatory process was elicited by administration of lpsa component of gram-negative bacteria cell wallbecause lps is an important mediator in the pathogenesis of ards and a cells are able to produce the acute phase protein lps-binding protein. in particular, it was determined the time-and dose-dependent effect of lps on the tnf-α response in a cells (fig. ) . the fa composition in phospholipids of a cell membranes was also analyzed, and the n- /n- pufa ratio was reported to be : , with aa as the most prevalent pufa (table ) . the administration of different ratios of aa and dha on the lps-induced cytokine response from a cells showed that the supply of : and tnf-α concentrations were measured in cell culture media by elisa assay at the time points indicated. the results were expressed as picograms of released cytokines per adherent cells (pg/ cells) and as mean ae sd (n = experiments). lps lipopolysaccharide, tnf-α tumor necrosis factor-α. * p < . lps and versus baseline, at and h; ** p < . lps versus baseline, at h; *** p < . lps versus baseline, at h; # p < . lps h versus lps h : dha/aa ratios reversed the baseline predominance of n- over n- in the n- /n- pufa ratio of cell membranes. particularly, the release of pro-inflammatory cytokines (tnf-α, il- , and il- ) was reduced by : and : dha/aa ratios; on the contrary, it was further increased by : and : dha/aa ratios if compared to lps challenge alone (fig. ) . moreover, the : and : dha/aa ratios were effective in increasing antiinflammatory il- release and in modifying the balance between pro-and anti-inflammatory cytokines (fig. ). this finding confirmed previous studies showing that il- protects against the lethal effects of lps by significantly reducing the production of pro-inflammatory cytokines in table percentage content of fatty acids in phospholipids of a cell membranes fatty acid c : (saturated) . c : (saturated) . c : (monounsaturated) . c : (saturated) . c : (monounsaturated) . c : (linoleic acid, n- ) . c : (arachidonic acid, aa, n- ) . c : (docosahexaenoic acid, dha, n- ) . n- /n- pufa ratio lipopolysaccharide-stimulated tnf-α, il- , il- , and il- release from a cells treated with different dha/aa ratios. interleukin concentrations were measured in cell culture media by elisa assay at h. the results were expressed as picograms (pg) of released cytokines per adherent cells and as mean ae sd (n = experiments). aa arachidonic acid, bl baseline, c control, dha docosahexaenoic acid, il interleukin, tnf-α tumor necrosis factor-α. * p < . versus control; ** p < . versus all; # p < . versus control and : human monocytes and murine peritoneal macrophages. these data suggested that inflammatory cytokine release was dependent on the proportion of n- in the n- /n- pufa ratio of alveolar cell membranes, being reduced with the supply of dha and increased with a high proportion of aa. according to several other data, shifting the pufa supply from n- to n- with a ratio of : may be a good means to dampen pro-inflammatory responses in ali. experimental studies with animal models demonstrated that production of aa-derived eicosanoids and cytokines decreases with a diet containing fish oil in ali and septic murine models. macrophages isolated from mice fed with a diet containing fish oil produced less pge and il- in response to lps stimulation than those isolated from mice fed with other lipid-enriched diets. feeding rats with an n- pufa-enriched diet, as compared with an n- pufa-enriched one, was associated to: ( ) a reduced severity of lung microvascular protein permeability and hypotension in a model of endotoxin-induced ali, ( ) a reduced synthesis of pro-inflammatory eicosanoid (ltb , pge , and txb ) released from stimulated alveolar macrophages, and ( ) a decrease in aa and an increase in epa and dha in cell membrane phospholipids of alveolar macrophages. after intraperitoneal injection of lps, peak plasma tnf-α, il- β, and il- levels were more reduced in mice fed with a fish oil diet than in those fed with a safflower oil diet (i.e., a diet rich in n- pufas). using either a model of ali, in which lps was instilled in the trachea, or a model of intraperitoneal inflammation, in which lps was injected intraperitoneally, it was demonstrated that a -day course of intravenous lipid emulsion infusions was sufficient to modify inflammatory responses. fish oil-based lipid emulsions reduced alveolar leukocyte transmigration, protein leakage, and cytokine production, as well as cytokine concentrations in the intravascular compartment. conversely, soybean oil-based lipids lead to a further increase in the inflammatory response. tnf-α /il- (log pg/ cells) il- /il- (log pg/ cells) il- /il- (log pg/ cells) clinical data showing benefits associated with the administration of nutrition formulas enriched with n- pufas in ali/ards patients came initially from three randomized controlled trials (rcts) using the enteral route. these rcts showed that en with a study formula containing epa, γ-linolenic acid, and antioxidants (vitamins c and e, β-carotene, and taurine), as compared with high-fat formula (control formula), reduced alveolar inflammatory mediators and improved clinical outcomes in patients with ali, ards, or sepsis. the first rct showed the ability of an enteral formula with a high n- /n- pufa ratio ( : ) to reduce pulmonary inflammation and improve clinical outcomes, i.e., better oxygenation, shorter requirement for mechanical ventilation, shorter icu-los, and less incidence of new organ failure; however, no difference in mortality was observed in ards patients (gadek et al. ) . similarly, an rct in ali/ards mechanically ventilated patients showed that an n- pufaenriched enteral diet may be more beneficial for gas exchange, respiratory dynamics, and length of mechanical ventilation if compared with a control formula, but no difference both in icu or hospital los and mortality was found between the two formulas (singer et al. ) . another rct was able to demonstrate that the administration of the same enteral diet contributed to guarantee an improved oxygenation and an independence from mechanical ventilation, less incidence of new organ dysfunction, and more icu-free days and, mainly, was associated with lower mortality rates in ards mechanically ventilated patients with severe sepsis and septic shock (pontes-arruda et al. ) . in , a meta-analysis of the pooled outcomes from these three rcts concluded that the n- pufa-enriched enteral formula could reduce mortality, rate of new organ failure, icu-los, and length of ventilation in ali/ards patients (pontes-arruda et al. ) . nevertheless, in , three further rcts were published that addressed the issue of the potential positive effects of an enteral n- pufa-enriched nutrition in ali/ards patients showing mixing results. the first rct analyzed the effect of an enteral n- pufa-enriched diet in septic patients with ali or ards showing that the administration of the study formula, compared to a control formula with less lipids than in the previous three studies, was associated to a shorter icu-los but not to an improvement in gas exchange or in a lower incidence of novel organ failures (grau-carmona et al. ) . a phase placebocontrolled rct in ali patients investigating an enteral administration of fish oil for up to days did not demonstrate a decrease in cytokine or other inflammatory marker concentrations both in bal fluid from baseline to day or and in plasma, as well as a decrease in ventilator-free days, icu-free days, organ failure score, or -day mortality (stapleton et al. ). the last rct tested the effects of enteral feeding with n- pufas, γ-linolenic acid, and antioxidants on clinical outcomes in ali patients in a phase trial (omega trial) using a twice-daily bolus administration (rice et al. ) . contrary to all other rcts, the authors reported that enteral administration of this formula was associated to significantly fewer ventilator-free days, icu-free days, and non-pulmonary organ failure-free days, as well as more days with diarrhea. the trial was stopped early for futility at the first interim analysis. the interpretation of the omega trial presents some difficulties (lev and singer ) . firstly, it was used a different approach of twicedaily bolus administration of enteral formulas instead of continuous enteral infusion. secondly, the enteral diets administered to the study group (i.e., megadoses of n- pufas and lower protein content) and to the control group (i.e., higher protein and carbohydrate content) are notably different from those used in the first three rcts. enteral administration of n- pufas might require more time before effectively influencing the cellular fa composition and the lipidmediated inflammatory response. moreover, the daily volume of enteral formula prescribed is calculated such as to meet patients' requirement of calories rather than a scheduled "pharmacological" dosage of n- pufas. it is well known that icu patients exhibit different degrees of tolerance to en, as it is well documented that the more patients are critically ill, the less they tolerate en. thus, an unpredictable number of critical patients might not receive the "pharmacological" dosage of n- pufas. an alternative approach to provide n- pufas to icu patients unable to meet their nutrition requirements by oral or enteral route is to administer a parenteral formula prepared from fish oil. differently to oral/enteral feeding, parenteral administration of pufas can induce more rapid changes in lipid-derived responses. indeed, in ali, there is the need of promptly active treatments to early modulate the net inflammatory response in the alveolar spaces. in septic patients, intravenous infusion of n- pufas modified lipid mediator synthesis and reduced endotoxin-stimulated monocyte proinflammatory cytokine production, while cytokine production was markedly amplified by n- pufa administration (mayer et al. ) . conversely, pn administered for days with a : mixture of medium-chain triglycerides and longchain triglycerides, with the n- /n- pufa ratio of : compared with a same mixture supplemented with fish oil with the n- /n- pufa ratio of : , did not affect inflammatory marker production or measures of clinical outcomes in an rct in unselected critically ill medical patients (friesecke et al. ) . in the last years, three rcts have investigated the effects of parenteral administration of n- pufa-enriched lipid emulsions in ali/ards patients. the first rct investigated the effects of an n- pufa-enriched lipid emulsion in ards patients with en intolerance showing no significant changes in hemodynamic and gas exchange parameters (sabater et al. ) . previously, the same authors had showed that parenteral administration of an n- -enriched lipid emulsion was accompanied by the synthesis of a smaller amount of pro-inflammatory lipid mediators compared to long-chain triglyceride % emulsion in ards patients. in a second trial, patients with systemic inflammatory response syndrome or sepsis were randomized into two groups to receive an intravenous lipid emulsion enriched or not in fish oil (barbosa et al. ) . the authors reported that the pao :fio ratio at day was significantly higher and plasma il- concentration significantly decreased in the group treated with fish oil; however, fish oil administration did not improve the length of ventilation or icu-los and mortality. the last rct investigated the effects of an intravenous administration of n- pufas with the n- /n- pufa ratio of : as supplementation of en for days in ards patients finding that fish oil administration alone did not improve ventilation, icu-los, or survival (gupta et al. ). ards is the most severe life-threatening manifestation of ali. both remain a significant health burden for intensivists and critical care physicians because of their considerable morbidity and mortality. in , in the usa, the crude incidence of ali was . per , person-years; each year, there are , cases of ali associated with , deaths and . million hospital days. in , in icus of ten european countries, ali occurred in ( %) out of , admissions, and in the % of the whole mechanically ventilated patients, % cases occurred on icu admission. pathologically, ali and ards are inflammatory diseases; clinically, their severity depends on the grade of inflammatory response. thus, numerous studies have been carried out investigating new strategies to reduce the grade of this inflammatory response, mainly by reducing the release of pro-inflammatory mediators. however, pharmacological therapies such as corticosteroids, ketoconazole, antioxidants, nitric oxide, prostacyclins, exogenous surfactants, and β agonists failed to show positive results in human studies. supplementation with n- pufas was demonstrated to exert beneficial effects in a number of inflammatory diseases. the rationale for their use in ali/ards patients is consistent and based on several issues. firstly, a large amount of experimental studies in lung models supports the antiinflammatory properties of n- pufas. secondly, patients at risk for ards and with established ards have plasma epa concentrations about % and %, respectively, as compared with normal, hypothesizing a potential benefit for n- pufa administration in those patients. finally, in three level i studies involving patients with ali, ards, and sepsis, the use of an enteral diet enriched with n- pufas (in the form of epa), γ-linolenic acid, and antioxidants was shown to significantly reduce icu-los, mechanical ventilation length, organ failure incidence, and mortality if compared to the use of a standard enteral formula. based on these data, the european society for clinical nutrition and metabolism, american society of parenteral and enteral nutrition, society of critical care medicine, and canadian guidelines recommended, with an a or b grade of recommendation, in their guidelines published between and , the use of n- pufas in ali/ards patients. however, nowadays, the clinical application of these recommendations has been lagging behind in critical or intensive care, which is due, at least in part, to inconclusive or contradicting results in several recent clinical trials using n- pufas. over the last years, the data coming out from a great number of studies have left us an improved knowledge of how n- pufas and their derivate mediators modulate inflammation/resolution and immunity. evidence that supports both the antiinflammatory and antitumor effects of n- pufas has been gathered; moreover, the molecular pathways underlying these effects have been clarified both in vitro and in vivo. in particular, there is now a better understanding of various mechanisms generating the production of inflammatory cytokines in several inflammatory, metabolic, and neurodegenerative diseases, as well as in inflammation-related cancers. the capacity of n- pufas to determine a shift from a strongly pro-inflammatory environment to one of reduced inflammation supports the hypothesis that these fas might be useful as a component of the therapy in various inflammatory diseases. thus, epa and/or dha have been evaluated in some inflammatory conditions. for the potential or in-use applications of n- pufas to clinical conditions different from ali, see a recent review (calder b) . briefly, fish oil or its derived epa and dha have demonstrated the efficacy in animal models of rheumatoid arthritis, inflammatory bowel diseases, and asthma. there have been a number of clinical trials evaluating the effects of administration of n- pufas in those diseases with contradicting results. for example, there is some pretty good evidence of the efficacy of n- pufas in rheumatoid arthritis. conversely, despite positive results in some studies, there is only weak evidence that n- pufas have clinical benefits in inflammatory bowel diseases. finally, clinical studies on fish oil in adult patients with asthma do not show benefit. the "european society for clinical nutrition and metabolism guidelines on enteral nutrition: intensive care" (kreymann et al. ) stated that "patients with ards should receive en enriched with n- fatty acids and antioxidants" as a b grade recommendation. however, this recommendation was not evaluated in the "espen guidelines on parenteral nutrition: intensive care" (singer et al. ), although the authors stated that "addition of epa and dha to lipid emulsions has demonstrable effects on cell membranes and inflammatory processes; fish oil-enriched lipid emulsions probably decrease length of stay in critically ill patients" both as b grade recommendations. the american society for parenteral and enteral nutrition "guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient" (mcclave et al. ), also being co-published by the society of critical care medicine, stated that "patients with ards and severe ali should be placed on an enteral formulation characterized by an antiinflammatory lipid profile (i.e., n- fish oil, borage oil) and antioxidants" (a grade recommendation). this recommendation was based on the three positive trials published at that time. the canadian guidelines (updated june ) stated that "based on level studies and level studies, the use of an enteral formula with fish oils, borage oils and antioxidants in patients with ali and ards should be considered. when pn with intravenous lipids is indicated, lipids that reduce the load of n- fa/soybean oil emulsions should be considered. however, there are insufficient data to make a recommendation on the type of lipids to be used that reduce the n- fa/soybean oil load in critically ill patients receiving pn." ali/ards patients are at high risk of malnutrition; therefore, they need nutrition support, including lipids. soybean oil-based lipid emulsions, rich in n- pufas and commonly used for these patients, may aggravate the inflammatory response. in contrast, fish oil-based lipid emulsions, rich in n- pufas, may exert an anti-inflammatory effect. these data suggest that shifting the pufa supply from n- to n- could be an important element affecting the alveolar cytokine and eicosanoid release and consequently ameliorates the clinical outcome in ali/ards patients. in summary, there are good experimental evidence and convincing rationale according to the n- pufas used in ali/ards patients. however, recent rcts using n- pufas in these patients did not confirm these positive effects. further studies are necessary to offer more precise indications, timing, and modalities for n- pufa administration. • acute lung injury (ali) and acute respiratory distress syndrome (ards) are inflammatory diseases whose clinical severity depends on the grade of inflammation. • cytokines are key elements in the pathogenesis of ali/ards. • soybean oil-based lipid emulsions, rich in omega (n)- polyunsaturated fatty acids (pufas), may aggravate the inflammatory response. in contrast, fish oil-based lipid emulsions, rich in n- pufas, may exert an antiinflammatory effect. • experimental and clinical data suggested that shifting the pufa supply from n- to n- decreases the alveolar cytokine and eicosanoid release and consequently ameliorates the clinical outcome in ali/ards patients. • based on these data, several scientific societies recommended in their guidelines the use of n- pufas in ali/ards patients. effects of fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: a randomized, controlled clinical trial n- polyunsaturated fatty acids, inflammation, and inflammatory diseases n- fatty acids, inflammation and immunity: new mechanisms to explain old actions omega- polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? canadian clinical practice guidelines for nutrition support in mechanically ventilated impact of the ω- to ω- polyunsaturated fatty acid ratio on cytokine release in human alveolar cells the berlin definition of ards: an expanded rationale, justification, and supplementary material fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomised controlled trial effect of enteral feeding with eicosapentaenoic acid, gammalinolenic acid, and antioxidants in patients with acute respiratory distress syndrome. enteral nutrition in ards study group effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and antioxidants on the outcome of mechanically ventilated, critically ill, septic patients efficacy and safety of parenteral omega- fatty acids in ventilated patients with acute lung injury espen guidelines on enteral nutrition: intensive care acute respiratory distress syndrome n- fatty acids and γ-linolenic acid supplementation in the nutritional support of ventilated patients with acute lung injury or acute respiratory distress syndrome fish oil in critical illness parenteral nutrition with fish oil modulates cytokine response in patients with sepsis guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition nutritional support in acute lung injury and acute respiratory distress syndrome cytokine balance in the lungs of patients with acute respiratory distress syndrome effects of enteral feeding with eicosapentaenoic acid, gammalinolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock the use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data the alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome enteral omega- fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury effects on hemodynamics and gas exchange of omega- fatty acidenriched lipid emulsion in acute respiratory distress syndrome (ards): a prospective, randomized, double-blind, parallel group study benefit of an enteral diet enriched with eicosapentaenoic acid and gammalinolenic acid in ventilated patients with acute lung injury espen guidelines on parenteral nutrition: intensive care a phase ii randomized placebo-controlled trial of omega- fatty acids for the treatment of acute lung injury key: cord- -ff gm j authors: bromberg, z.; weiss, y. g.; deutschman, c. s. title: heat shock proteins in inflammation date: journal: mechanisms of sepsis-induced organ dysfunction and recovery doi: . / - - - _ sha: doc_id: cord_uid: ff gm j hsps are important mediators of a number of key intracellular reactions. of importance to the care of the critically ill are their involvement in protein repair and tertiary structure. hsp is known to modulate inflammation and apoptosis. in models of acute lung injury and ards, over-expression of hsp improves outcome, ameliorates lung injury and attenuates inflammation. the involvement of hsp in other aspects of lung injury and in other components of mods is under investigation. proteins may induce the formation of protein aggregates [ ] . in contrast to misfolding, aggregation is a highly cooperative inter-molecular process that strongly depends on the concentration of misfolded monomers. aggregates may be composed of different oligomers over a wide distribution of sizes. the presence of these aggregates is common in a number of disease processes, including neurodegenerative disorders such as alzheimer's, parkinson's, and huntington's diseases. the exposure of hydrophobic protein domains to unaffected proteins or membranes may disrupt normal activity. for example, association of the hydrophobic region of a damaged protein with a neuronal cell membrane may change ion flux and alter function. hsp may prevent this and this may be a key mechanism by which hsps limit or prevent intra-cellular pathological processes. this underscores the fundamental importance of the hsps to normal living cells [ ] . while this review will focus on hsp , other subclasses among the hsps play important roles. these are organized by their molecular size: hsp , hsp , hsp , hsp (j-domain proteins) and small hsp families, such as hsp / [ , ] . most hsps are constitutively and ubiquitously expressed molecular chaperones that guide the normal folding, intracellular disposition, and proteolytic turnover of many of the key regulators of cell growth and survival [ ] . thus, the protective process involves the interaction of many different hsps. for example, hsp , which comprises - % of total cellular protein in non-stress conditions [ ] , supports meta-stable protein conformations and expresses a high affinity binding state to hormone receptors. this involves both hsp , which participates in assembly of multiprotein complexes, and hsp , a co-chaperone that stimulates hsp atpase activity [ ] . at the transcription level, hsps, such as hsp and hsp , are regulated by the activities of a family of heat shock transcription factors (hsf). one of these, hsf- , normally is expressed in a negatively regulated state as an inert monomer in either the cytoplasm or nuclear compartments [ ] . upon exposure to a variety of stresses, hsf- trimerizes and accumulates in the nucleus. hsf- trimers bind dna regions called heat shock elements (hses) with high affinity. some small hsps are transcribed constitutively due to multiple binding of low levels of hsf [ ] . the great divergence in hsp expression explains the multiple function of these proteins. elevated levels of hsp following diverse inciting causes have led researchers to conclude that hsp is involved in cellular protection in the normothermic environment [ , , ] . a wide range of noxious stimuli, such as hypoxia, ischemia/reperfusion, hypoglycemia, endotoxemia, inflammation, and exposure to heavy toxic metals or reactive oxygen species (ros), induce hsp expression in a large number of tissues. since hsps respond to environmental changes, expression in organs that are 'outside' the organism (for example, skin, lung, gastrointestinal epithelium) may occur in the absence of any apparent insult [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . it has been demonstrated, both in vivo and in vitro, that exposure to a mild stress, such as heat pretreatment, induces high levels of hsp . increased hsp levels may confer protection from subsequent noxious stimuli and result in 'cyto-protection'. this should be of benefit against cellular injury caused by inflammation and infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] . thus, altering hsp expression might be of importance in modulating highly lethal inflammatory diseases. ards is characterized by an increased inflammatory process in the lungs. in this disorder, alveolar epithelial cells are damaged and ultimately may be destroyed [ , ] . while some contributory pathophysiologic mechanisms have been identified, most remain obscure. therefore, a better understanding of the fundamental biological changes leading to ards would be of scientific and therapeutic value. several papers have explored the role of hsp in a model of lipopolysaccharide (lps)-induced lung injury. these investigators concluded that heat pre-treatment lps stimulates the production and the release of many endogenous mediators of sepsis. these include tumor necrosis factor alpha (tnf-α), interleukin (il)- and il- [ ] . a distinct profile in the expression of genes encoding members of the hsp family was demonstrated in leukocytes obtained from different phases of the disease course in septic patients [ ] . these findings strongly suggest that hsp may play a role in the outcome of septic shock patients [ ] . further, studies proved that in an animal model of ards, heat pretreatment prevented mortality [ ] . previous studies had revealed that sepsis induced by cecal ligation and double puncture (clp) resulted in an ards-like state characterized by neutrophil accumulation and protein-rich interstitial edema formation [ , , - ]. using this model, we found impaired hepatic expression of several essential liverspecific genes, including those encoding proteins that catalyze gluconeogenesis, β-oxidation of fatty acids, ureagenesis, and bile acid transport [ ] [ ] [ ] . further, we have demonstrated inappropriate downregulation of the expression of several key genes within the lung. these include surfactant proteins (sp)-a and (sp)-b and, most importantly, hsp [ , , ] . we found that hsp mrna increased after a sham operation but failed to increase after clp [ ] . hsp protein levels were unchanged after either clp or sham operation. therefore, hsp mrna fails to increase after clp despite significant damage to alveolar cells. this lack of increase in hsp implies profound pulmonary epithelial dysfunction, similar to our findings in the liver, and is supported by several other studies indicating that sepsis and endotoxemia impair hsp expression [ , , , ] . these experiments led us to investigate in depth the role of hsp in ards and inflammation, by using an adenovirus (adhsp) to enhance hsp expression [ ] . we have demonstrated that intratracheal administration of adhsp significantly attenuates lung injury in rats with sepsis-induced respiratory distress [ ] . adhsp, when compared to phosphate buffer saline (pbs) or a virus expressing a marker protein (adgfp), attenuated clp-induced neutrophil accumulation, septal thickening, interstitial fluid accumulation, and alveolar protein exudation [ ]. more importantly, adhsp treatment significantly decreased mortality in rats subjected to clp [ ] . in contrast to studies that provoked the entire heat shock response [ , , ] , our investigations present a unique approach to explore the effects of hsp on a single tissue, the lung [ ]. we previously documented that adhsp preferentially increases hsp expression in pulmonary epithelial cells [ ] . an interesting finding was that hours following clp, virus uptake occurred primarily in pulmonary epithelial cells, especially type ii pneumocytes [ ]. the heat shock response is known to modulate inflammation [ ] . the mechanisms that have been investigated involve the attenuation of both cytokine-induced inflammatory mediator production and apoptosis [ , , , ] . both processes are important in the pathogenesis of ards [ ] [ ] [ ] . this involves cytokines such as tnf-α and il- β [ ] [ ] [ ] ] . hsp inhibits the apoptotic machinery including the apoptosome, the caspase activation complex, and apoptosis inducing factor [ ] [ ] [ ] . hsp also participates in the proteasome-mediated degradation of apoptosis-regulatory proteins [ ] . tnf-α and il- β exert their effects in part via cell signaling pathways involving the nuclear transcription factor, nuclear factor-κb (nf-κb) [ ] [ ] [ ] . this important acute inflammatory pathway is modulated by hsp . nf-κb is a dimeric protein, most often consisting of two subunits, p and p (rel a). normally, this dimer is retained in the cytoplasm by an inhibitory molecule, iκbα [ ] . an essential step in nf-κb activation is iκbα degradation. this permits the migration of nf-κb into the nucleus where it can initiate transcription [ , ] . degradation of iκbα involves three sequential biochemical reactions. the first is phosphorylation of iκbα by iκb kinase (ikk). ikk is a complex molecule that contains two catalytic subunits, ikkα and ikkβ, an essential regulatory subunit ikkγgalso called nf-κb essential modulator (or nemo) [ ] , and a recently identified co-modulator, the kda protein, elks [ ] [ ] [ ] . the dominant catalytic subunit in inflammation is ikkβ [ ] . phosphorylation of iκbα is followed by poly-ubiquitination by scf β-trcp ubiquitin ligase and, finally, proteolysis by the s proteasome [ ] [ ] [ ] [ ] . several in vitro models have proven that heat shock or elevated levels of hsp suppresses nf-κb activity and that this inhibition of nf-κb results in a general reduction in the inflammatory response [ , , , ] . however, the exact molecular mechanism of the hsp -nf-κb interaction is still unknown. ran et al. [ ] demonstrated that hsp promotes rather than inhibits tnf-mediated cell death, by binding to ikkγ. this resulted in inhibition of ikk activity and consequently inhibited nf-κb-dependent antiapoptotic gene induction [ ] . earlier, yoo et al. demonstrated that hsp prevented phosphorylation of iκbα by ikkβ [ ] . both activation and modulation of inflammation require coupling of extracellular signals with intra-cellular events, processes involving a number of specific biochemical pathways. we investigated the hypothesis that adhsp limits sepsisinduced acute inflammation within alveolar epithelial cells in part by suppressing nf-κb activation. in contrast to the observations of others [ , ] , we found that hsp reduced, but did not abolish, ikkβ activity. more importantly, we have uncovered a novel mechanism of iκbα stabilization that results from an association with hsp [ ] . hsp binds to an incomplete protein degradative complex composed of phosphorylated-ubiquitinated iκbαsgf-κb, and partial ikk complexes that contain elks, ikkβs and/or ikkγg(nemo). the association of hsp leads to stabilization of these intermediate complexes in a way that prevents proteasomal degradation of iκbα. consequently, nf-κb is retained in the cytoplasm and is unable to induce inflammatory responses. hsps are important mediators of a number of key intracellular reactions. of importance to the care of the critically ill are their involvement in protein repair and tertiary structure. hsp is known to modulate inflammation and apoptosis. in models of acute lung injury and ards, over-expression of hsp improves outcome, ameliorates lung injury and attenuates inflammation. the involvement of hsp in other aspects of lung injury and in other components of mods is under investigation. effects of heat on animals and man heat shock proteins: facts, thoughts and dreams heat shock proteins and cardiovascular pathophysiology heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology protein translocation: how hsp pulls it off heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance folding of newly translated proteins in vivo: the role of molecular chaperones molecular chaperones in the cytosol: from nascent chain to folded protein quality control of protein folding in extracellular space specificity in intracellular protein aggregation and inclusion body formation molecular chaperones: cellular fold-controlling factors of toxic protein aggregates in neurodegenerative diseases molecular chaperones in cellular protein folding the hsp and hsp chaperone machines hsp and the chaperoning of cancer hsp and hsp -a relay team for protein folding heat shock response modulators as therapeutic tools for diseases of protein conformation overexpression of the rat inducible -kd heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury structure-function analysis of hscc, the escherichia coli member of a novel subfamily of specialized hsp chaperones intrahepatic stat- activation and acute phase gene expression predict outcome after clp sepsis in the rat sepsis-induced alterations in phosphoenolpyruvate carboxykinase expression: the role of insulin and glucagon sepsis-induced depression of rat glucose- -phosphatase gene expression and activity complexity of inflammatory mediators in acute respiratory distress syndrome (ards) alterations of the endogenous surfactant system in septic adult rats endotoxin inhibits heat induced hsp in rats the chaperone function of hsp is required for protection against stress-induced apoptosis major stress protein hsp interacts with nf-κb regulatory complex in human t-lymphoma cells major heat shock protein hsp protects tumor cells from tumor necrosis factor cytotoxicity fas/fasl-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice neutrophils induce apoptosis of lung epithelial cells via release of soluble fas ligand soluble fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ards) differential effect of mlc kinase in tnf-alpha-induced endothelial cell apoptosis and barrier dysfunction signal transduction by tumor necrosis factor and its relatives the role of toll-like receptors and myd in innate immune responses heat shock protein and the acute respiratory distress syndrome heat-shock protein inhibits apoptosis by preventing recruitment of procaspase- to the apaf- apoptosome heat-shock protein antagonizes apoptosisinducing factor negative regulation of the apaf- apoptosome by hsp hsp and hsp : potentially oncogenic apoptosis inhibitors the role of nuclear factor-κb in pulmonary diseases the ikappab-nf-kappab signaling module: temporal control and selective gene activation the two faces of ikk and nf-kappa b inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion nf-κb and rel proteins: evolutionarily conserved mediators of immune responses ikkγ/nemo facilitates the recruitment of the iκb proteins into the iκb kinase complex ikk and ikk : cytokine-activated iκb kinases essential for nf-κb activation activation of the i kappa b kinases by rip via ikkgamma /nemo-mediated oligomerization activation of transcription factor nf-κb requires elks, an iκb kinase regulatory subunit nedd modification of cul- activates scf(beta(trcp)-dependent ubiquitination of i kappab alpha regulatory functions of ubiquitination in the immune system ubiquitin-mediated proteolysis: biological regulation via destruction the proteasome: structure, function, and role in the cell anti-inflammatory effect of heat shock protein induction is related to stabilization of i kappa b alpha through preventing i kappa b kinase activation in respiratory epithelial cells heat shock inhibits radiation-induced activation of nf-kappab via inhibition of i-kappab kinase ablation of the heat shock factor- increases susceptibility to hyperoxia-mediated cellular injury hsp promotes tnf-mediated apoptosis by binding ikk gamma and impairing nf-kappa b survival signaling hsp- expression in the lung attenuates ards by disrupting nf-κb acknowledgement. supported in part by nih grant gm . key: cord- - dpo b authors: tronche, p.-a.; lalande, r.; blondonnet, r.; roszyk, l.; zhai, r.; morand, d.; pereira, b.; sapin, v.; malinovsky, j.-m.; mourvillier, b.; constantin, j.-m.; cousson, j.; jabaudon, m. title: assessment of a novel method for non-invasive sampling of the distal airspace in acute respiratory distress syndrome patients receiving inhaled sedation with sevoflurane: the anaiss study protocol date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: dpo b introduction: recently, fluid collected from the heat-and-moisture-exchange filters, which are commonly used in most mechanically ventilated patients under intravenous sedation, has been reported as a potential surrogate for fluid in the distal airspace. therefore, collection of this fluid represents a promising, non-invasive method for sampling the distal airspace in patients with acute respiratory distress syndrome (ards) and for facilitating a mechanistic understanding of this devastating disease. the current study protocol was constructed to assess whether this fluid could be sampled from a dedicated device (anaesthetic conserving device [anaconda-s], sedana medical, danderyd, sweden) used to deliver inhaled sevoflurane for sedation in patients with ards. methods and analysis: a total of adult patients within hours of meeting the berlin criteria for moderate-severe ards and receiving inhaled sevoflurane as standard sedation in participating centres will be eligible for inclusion into this investigator-initiated, exploratory, prospective, bicentre study. after at least h of inhaled sedation, a sample of directly aspirated, undiluted pulmonary oedema fluid will be collected concurrently with fluid from the anaconda-s device. levels of proinflammatory cytokines (il- {beta}, il- , il- , tnf- and stnfr- ) and markers of lung endothelial (ang- ) and epithelial (srage) injury will be measured in both fluids by multiplex. the primary endpoint is the correlation between protein markers (il- {beta}, il- , il- , tnf-, stnfr- , ang- and srage) measured in the undiluted pulmonary oedema fluid versus the anaconda-s fluid. ethics and dissemination: the study was approved by the appropriate ethics committee (cpp est i). informed consent is required. the fluid collection from the anaconda-s has potential to foster our understanding of the potential effects of inhaled sedation in clinical ards and to open up novel perspectives for prognostic and predictive enrichment in future trials. the results will be published in a peer-reviewed journal. acute respiratory distress syndrome (ards) continues to be a major critical care concern, with high mortality rates and long-term impact in survivors ( , ) . these issues are particularly highlighted by the current coronavirus disease (covid- ) outbreak ( ) . no targeted pharmacologic therapies are yet available to treat this syndrome, and its management is currently based only on the treatment of its cause(s), intensive care unit (icu) supportive care, lung-protective mechanical ventilation, and conservative fluid management whenever possible ( , ) . a major limitation impeding the development of new therapies for ards is the difficulty in obtaining an easily reproducible and comparable sample from the injured distal airspace. each of the currently available methods for studying the airspace of ards patients has significant drawbacks. for example, bronchoalveolar lavage (bal) can be difficult to perform, is impractical for serial collections and can introduce an unknown dilution factor to the measured analytes ( ) . the direct aspiration of undiluted pulmonary oedema fluid (of) is possible ( ) ( ) ( ) ( ) , but this is feasible only early in the disease course and in patients with a significant degree of oedema. exhaled breath condensate may be useful for characterizing the airspace ( ) , but the current collection equipment is costly, the sample volume is limited, and the collection is labour-intensive. identification of a simple, non-invasive way to accurately sample the distal airspace in ards would be a major advance for studying the biology of injured lungs. the heat-and-moisture-exchanger (hme) filter is an in-line, disposable, hygroscopic bacteriostatic sponge that is routinely placed between the patient and the ventilator to minimize the loss of heat and moisture from exhaled breath ( , ) . during mechanical ventilation, moisture from the patient's exhaled breath condenses on this filter until the filter is exchanged after several hours. a wide variety of hme filter devices are commercially available, with varying filter designs and dead space volumes. hme filters are produced for neonatal and pediatric use as well. very recently, fluid collected from hme filters used in most mechanically ventilated patients under intravenous sedation has been reported as a potential surrogate for fluid in the distal airspace, thereby representing a promising, simple and non-invasive method to sample the distal airspace in patients with ards. this sampling is also a powerful tool to facilitate mechanistic understanding of this syndrome ( ) . inhaled sedation with halogenated agents, such as isoflurane or sevoflurane, is now available to critical physicians worldwide using disposable medical devices such as the anaconda-s (sedana medical, danderyd, sweden) ( ) ( ) ( ) . the anaconda-s also acts as a hme filter and contains a bacterial/viral filter. during breathing, the volatile anesthetic agent is re-circulated through the reflector (consisting of an active carbon filter) that is also included in the device. the first pilot randomized controlled trial in patients with moderate-severe ards confirmed that inhaled sevoflurane improved arterial oxygenation compared to intravenous midazolam, while decreasing plasma and alveolar marker levels of inflammation (interleukin [il]- β, il- , il- and tumour necrosis factor [tnf]-α) and lung epithelial injury (soluble receptor for advanced glycation end-products [srage]) ( ) . these results, along with preclinical evidence ( ) ( ) ( ) ( ) , suggest that inhaled sevoflurane may have lung-protective effects in ards, although the mechanism warrants further investigation ( , ) . taken together, the available clinical evidence supports the safe use of inhaled sevoflurane for icu sedation, with no major adverse effect on processes such as renal function or respiratory mechanics ( ) ( ) ( ) ( ) . it is now used as standard practice in some french icus ( ) . because we hypothesised that the condensed fluid from the anaconda-s device could be representative of distal airspace fluid in patients receiving inhaled sevoflurane, the (anaiss) study protocol was designed to assess whether the composition of the anaconda-s fluid could represent that of the distal airspace fluid in patients with ards. the primary objective is to compare the protein composition of simultaneously collected undiluted pulmonary of and anaconda-s fluid from patients with moderate-to-severe ards. a further aim of the study will be to evaluate the correlation between protein marker levels measured in anaconda-s and the radiographic assessment of lung edema (rale) score ( , ) ; to compare protein marker levels measured in anaconda-s fluid between lung . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . imaging phenotypes of focal and nonfocal ards ( ) ( ) ( ) ; to compare protein marker levels in undiluted of and in plasma; and to assemble a biological collection of anaconda-s fluids for future mechanistic studies of inhaled sevoflurane in ards. the anaiss study is an investigator-initiated, prospective, bicentre, observational study with a collection of biological samples that will include invasive alveolar (of) sampling. therefore, it is labelled as a "research involving the human person (rihp) because inhaled sedation with sevoflurane is current standard practice in participating icus, the study protocol includes no other specific intervention apart from the alveolar and anaconda-s sampling. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . all adult patients within h from meeting the berlin criteria for moderate or severe ards ( ) and receiving inhaled sedation with sevoflurane as standard practice will be eligible for inclusion in the study. patients under years old and those declining to provide informed consent will not be included in the study. in this study, no specific interventions will be performed apart from a single sampling of lung of, anaconda-s fluid, and blood. patients within h of moderate-to-severe ards onset and receiving inhaled sedation with sevoflurane as current practice in participating centres will be enrolled. overall intensive care management practice in both participating icus will not be influenced by the study protocol. after at least h of inhaled sedation with sevoflurane through the anaconda-s device, a sample of directly-aspirated, undiluted of will be collected in a ml-edta tube, as previously described ( ) ( ) ( ) ( ) . concurrently, fluid will be collected from the anaconda-s . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint device (removed and changed for the first time simultaneously with pulmonary sampling, and then routinely removed at least every h, as per manufacturer instructions). the anaconda-s device will be closed at each end with specific plugs and further processed under a laboratory hood (according to local safety policies) by suctioning the contents of the device through a bal vial connected between the anaconda-s and a vacuum system, at maximal depression (inducing air intake with the thumb at the other end of the device, if needed) ( figure ) . the collected fluid will be pipetted into a ml-edta tube and centrifuged at , × g for min. the supernatant will be evenly distributed into two cryotubes stored at - °c at each local laboratory for further analysis. undiluted pulmonary of will be centrifuged at , × g for min; the supernatant will be distributed into two cryotubes stored at - °c. a ml blood sample will be simultaneously collected from an indwelling catheter (routinely used in icu patients) into an edta tube, centrifuged at , × g for min, and the supernatant (plasma) aliquoted and stored into a cryotube at - °c. at the end of the recruitment period, samples will be transferred from laboratories at each site to the department of medical biochemistry and molecular genetics at chu clermont-ferrand for further analysis. because of the current health crisis caused by the emergence of the sars-cov virus, specific protective measures must be followed for the collection of samples if the patient is positive or considered at risk. the patient will have to be hospitalised in a dedicated specialized covid unit, in an individual room with negative pressure with air treatment, or failing this, at neutral pressure with closed doors and sufficient ventilation. the protections for the sampler in the room will follow the protections necessary for an air and contact isolation (hat covering hair and ears, goggles, ffp mask, long-sleeved waterproof overshirt, gloves with a strict dressing / undressing procedure) because of the important risk of aerosolisation of the procedure. of will be sampled in a bal vial with a closed-suction system to avoid lung derecruitment and transferred into ml-edta tube, placed immediately in a hermetically-sealed triple packaging. filter fluid extraction will be performed directly in the room using the icu vacuum system, following the same instructions than for of. centrifugation procedures must be carried out in a biosafety level laboratory under class ii biological safety cabinet, following safety guidance for high-risk sample management in patients with covid- ( , ) . levels of il- β, il- , il- , tnf-α, stnfr- , ang- and srage will be measured in duplicate using multiplex (biorad, hercules, ca, usa) in all samples. these markers were selected a priori because they have previously been reported as markers of a . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . hyperinflammatory ards phenotype (il- β, il- , il- , tnf-α, stnfr- ) ( ) ( ) ( ) ( ) , of ventilator-induced lung injury (il- ) ( ) , and of lung endothelial (ang- ) ( , ) and epithelial (srage) ( , ) injury in ards. the primary outcome measure is the correlation between protein marker levels measured in the undiluted pulmonary of and those measured in the anaconda-s fluid. secondary outcome measures are: the correlation between protein marker levels (il- β, il- , il- , tnf-α, stnfr- , ang- and srage) measured in the anaconda-s fluid and the rale score, the difference in protein marker levels measured in the anaconda-s fluid between patients with focal versus nonfocal ards, the correlation between protein marker levels measured in undiluted of versus plasma, and the correlation between protein marker levels measured in the anaconda-s fluid versus the plasma. the participant timeline is described in the table . recruitment patient recruitment is expected to proceed during an -month inclusion period beginning in september . this duration was estimated based on a high incidence of ards in the icu setting ( % of icu admissions, and nearly % of icu patients requiring mechanical ventilation, in a large recent observational study) ( ) and available data from each participating centre that indicate the study is highly feasible (each of the two centres will need to include less than one patient per month, holidays excluded). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . the study data will be prospectively collected and managed by trained research coordinators and/or investigators at each participating centre, using the redcap electronic data capture tools hosted at chu clermont-ferrand ( ) . redcap (research electronic data capture) is a secure, web-based application designed to support data capture for research studies. it provides an intuitive interface for validated data entry, audit trails for tracking data manipulation and export procedures, automated export procedures for seamless data downloads to common statistical packages, and procedures for importing data from external sources. data registration will be monitored by trained research coordinators. patient data prospectively collected from the medical record will include demographics, ards risk factor(s), murray's lung injury score ( ) , acute physiology and chronic health evaluation (apache) ii score ( ) and chest x-ray at study enrolment. the ventilator settings at the time of biological sampling, the hospital and icu length of stays, and the hospital mortality will also be recorded. this study has been primarily designed as an exploratory proof-of-concept pilot study; therefore, performing a formal sample size calculation is difficult. to date, only one study (including nearly patients with ards) has reported that hme filter fluid is representative of distal airspace fluid ( ) . however, in order to highlight a concordance coefficient greater than . with a two-sided type i error at . (due to multiple tests) and a statistical power around %, we have decided to enrol patients in the anaiss study. an exploratory sequential analysis is planned at every inclusions, without correction of type i error, to estimate the statistical power according to effect size (here, the correlation coefficient) and % confidence interval. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint all analyses will be performed with stata software (version , statacorp, college station, usa). a two-sided p value of less than . will be considered for statistical significance. however, when appropriate, a correction of the type i error (sidak's inflate) could be performed for multiple comparisons. categorical data will be presented as exact numbers and percentages, whereas continuous variables will be presented as means and standard-deviations or as medians and interquartile ranges, according to their statistical distributions. the shapiro-wilk test will be used to assess normality. the concordance between marker levels measured in the undiluted of versus anaconda-s fluid will be assessed using lin's concordance coefficient, a correlation coefficient (pearson or spearman, according to statistical distribution), and bland-altman plotting. the % confidence intervals will be reported. passing and bablok regression will be used to evaluate non-systematic and non-proportional differences in the agreement between the two sample types (undiluted of and anaconda-s fluid). protein marker levels measured in the anaconda-s fluid will be compared between patients with focal versus nonfocal ards using the unpaired t-test or the mann-whitney u-test when appropriate. the shapiro-wilk and the fisher-snedecor tests will be used to assess normality and homoscedasticity, respectively. the receiver operating characteristic (roc) curve will then be computed and the area under the curve will be used to evaluate which protein marker levels, as measured in the anaconda-s fluid, distinguish focal versus nonfocal ards. the concordance between marker levels measured in the undiluted of versus the plasma, and between those measured in the anaconda-s fluid versus the plasma, will be explored in a pairwise manner using lin's concordance coefficient, a correlation coefficient (pearson or spearman according to the statistical distribution), and bland-altman plotting. the % confidence intervals will be reported. passing and bablok regression will be used to evaluate non-systematic and non-proportional differences between sampling methods (plasma versus of or anaconda-s fluid) . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint for each protein marker, areas under the roc curves will be reported with % confidence intervals and will be compared with those of other biomarkers ( , ) . following the suggestion of ray et al., the value of a biomarker will be considered relevant when the lower bound of the confidence interval of the area under the roc curve is > . ( ) . the relationship between the protein marker levels measured in the anaconda-s fluid and the rale score will be studied using correlation coefficients. pearson's correlation analysis will be used for variables that follow a normal distribution, and spearman's rank correlation coefficient analysis for variables that do not. no missing data are expected (few data to collect, few patients to enrol within experienced centres). however, a sensitivity analysis will be performed in order to study the nature of missing data (missing at random or not) and to apply the most appropriate approach to the imputation of missing data. in the anaiss study, the sampling method will be unblinded both to patients (if not under deep sedation) and to clinical staff members. however, to reduce the risk of bias, the investigators and personnel in charge of measuring protein markers will be unaware of the fluid type (either anaconda-s fluid or undiluted of). the study statistician will also be blinded during statistical analyses. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the anaiss study will be conducted in accordance with the declaration of helsinki because patients will be receiving inhaled sedation, they will not have full capacity to provide informed consent for enrolment in the study; therefore, the anaiss study protocol provides for a waiver of informed consent from the patient. in addition, in case consent from the patient's next of kin cannot be obtained, local investigators will be able to include the patient in the study using an emergency consent procedure. in this case, no consent from the patient's next of kin will be required, but the investigator will inform the patient's next of kin of the decision as soon as possible. as per french law and good research practice, deferred informed (oral or written) consent from the patient will be sought as soon as technically possible for potential continuation of the research. as per the french public health code (articles l. - and r. - ), research investigators and staff members with direct access to data (who are all bound by professional secrecy, in accordance with articles - and - from the french penal code) shall take all necessary precautions to ensure patient data confidentiality. in particular, all investigators and staff members shall ensure anonymity for all data collected and transferred (through the electronic case report form) to the study sponsor (chu clermont-ferrand) by utilising a study-specific, anonymous identifying number. the sponsor . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint will ensure that each research subject has given consent for study participation and data collection. data will be handled in a confidential and anonymous manner by the sponsor, according to french law. all original records will be archived at trial sites for years, as will the clean anonymised database file. the study is an investigator-initiated study sponsored by chu clermont-ferrand, clermont-ferrand, france. the investigators have no conflict of interest regarding the publication of this study protocol. no specific funding has been received for this study apart from institutional funds. findings will be published in peer-reviewed journals and presented at local, national, and international meetings and conferences to publicise and explain the research to clinicians, commissioners, and service users. all investigators will have access to the final dataset. both study sites will be acknowledged, and all investigators at these sites will appear with their names under 'the anaiss investigators' in an appendix to the final study report. authorship will be granted according to the vancouver definitions. funding sources will have no influence on data handling, analysis or writing of the manuscript. side studies will be allowed if approved by the scientific committee (rb, vs, lbw, jab, jmc, and mj), and anonymised participant-level data sets will be made accessible on a controlled-access basis. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . https://doi.org/ . / . . . doi: medrxiv preprint the primary hypothesis of the anaiss study is that fluid collection from the anaconda-s device could be a novel method for assessing the distal airspace in mechanically ventilated patients with ards who are receiving inhaled sedation with sevoflurane. if successful, this study will have potential to further inform our understanding of the effects of inhaled sevoflurane on lung injury during ards through the use of a non-invasive, inexpensive and simple method. biomarker studies may have important value by providing a better understanding of biological mechanisms, for assessing severity and prognosis, for identifying distinct biological or radiographic phenotypes, and for predicting and/or monitoring response to therapy in ards ( , , ( ) ( ) ( ) . from this perspective, assessing the composition of the anaconda-s fluid, while validating previous findings with hme filters ( ) is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . multiple tests. a further limitation is that the method used to collect the anaconda-s fluid may be associated with some technical issues. in preliminary tests, we found that the suction technique described in this protocol will be the most likely to enable fluid collection from the anaconda-s device in an efficient and reproducible manner. however, this method requires specific equipment and strict adherence to the adequate safety policies on airway sample processing, particularly in the current context of sars-cov epidemic. in addition to these technical considerations, the only risks for the patient related to the anaiss study protocol may be those related to the sampling method for the undiluted of. however, these risks are minor, infrequent, and reversible in most cases (e.g. alveolar de-recruitment, transient and moderate decreases in arterial oxygenation), and both participating centres have safe and strong experience in this technique ( ) ( ) ( ) ) . this study also has several strengths. to our knowledge, it is the first study to focus on a non-invasive method of collecting biomarkers from ards patients receiving inhaled sevoflurane for sedation. in the future, this type of method may allow regular monitoring of pathophysiology and responses to therapeutic interventions in patients with ards. the assembly of a biobank of biological (alveolar, plasma, and anaconda-s fluid) samples will also allow future translational studies that will ultimately further our understanding of the lung-protective effects of sevoflurane ( , ) . finally, although study samples will be collected in an open-label manner, all biological measurements and statistical analyses will be performed in a blinded approach to limit the risk of evaluation bias. in conclusion, the anaiss study is an investigator-initiated, prospective, bicentre study that was primarily designed to assess the concordance in biomarker measurements between undiluted lung oedema fluid and fluid collected from the anaconda-s device, as used to deliver inhaled sedation to ards patients. the ability to collect fluid from the anaconda-s as a surrogate for distal airspace fluid could be important in furthering our understanding of the potential beneficial effects of inhaled sevoflurane in ards and for prognostic and predictive enrichment in future ards trials. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . acute respiratory distress syndrome acute respiratory distress syndrome. nat rev dis primers covid- -associated acute respiratory distress syndrome: is a different approach to management warranted? diagnostic workup for ards patients alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome soluble receptor for advanced glycation end-products predicts impaired alveolar fluid clearance in acute respiratory distress syndrome net alveolar fluid clearance is associated with lung morphology phenotypes in acute respiratory distress syndrome diagnosis of acute respiratory distress syndrome by exhaled breath analysis heat and moisture exchangers and breathing system filters: their use in anaesthesia and intensive care. part -practical use, including problems, and their use with paediatric patients heat and moisture exchangers and breathing system filters: their use in anaesthesia and intensive care. part -history, principles and efficiency novel method for noninvasive sampling of the distal airspace in acute respiratory distress syndrome volatile anesthetics. is a new player emerging in critical care sedation? inhalational volatile-based sedation for covid- pneumonia and ards sevoflurane for sedation in acute respiratory distress syndrome. a randomized controlled pilot study the immunomodulatory effect of sevoflurane in endotoxin-injured alveolar epithelial cells sevoflurane ameliorates gas exchange and attenuates lung damage in experimental lipopolysaccharide-induced lung injury sevoflurane reduces severity of acute lung injury possibly by impairing formation of alveolar oedema sevoflurane, but not propofol, reduces the lung inflammatory response and improves oxygenation in an acute respiratory distress syndrome model: a randomised laboratory study lung protective properties of the volatile anesthetics long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam a pharmacokinetic study of -hour sevoflurane inhalation using a disposable delivery system (anaconda®) in icu patients safety and efficacy of volatile anesthetic agents compared with standard intravenous midazolam/propofol sedation in ventilated critical care patients: a meta-analysis and systematic review of prospective trials sevoflurane for procedural sedation in critically ill patients: a pharmacokinetic comparative study between burn and non-burn patients use of volatile agents for sedation in the intensive care unit a national survey in france severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ards early changes over time in the radiographic assessment of lung edema (rale) score are associated with survival in acute respiratory distress syndrome regional distribution of gas and tissue in acute respiratory distress syndrome. i. consequences for lung morphology elevated plasma levels of srage are associated with nonfocal ct-based lung imaging in patients with ards: a prospective multicenter study recent directions in personalised acute respiratory distress syndrome medicine acute respiratory distress syndrome: the berlin definition recommandations d'experts portant sur la prise en charge en réanimation des patients en période d'épidémie à sars-cov cdc. information for laboratories about coronavirus subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy phenotypes in acute respiratory distress syndrome: moving towards precision medicine development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network plasma angiopoietin- in clinical acute lung injury: prognostic and pathogenetic significance distinct molecular phenotypes of direct vs indirect ards in single-center and multicenter studies receptor for advanced glycation end-products is a marker of type i cell injury in acute lung injury patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support an expanded definition of the adult respiratory distress syndrome apache ii: a severity of disease classification system a method of comparing the areas under receiver operating characteristic curves derived from the same cases comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach statistical evaluation of a biomarker toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design key: cord- - p x ge authors: qadir, nida; chen, jen-ting title: adjunctive therapies in ards: the disconnect between clinical trials and clinical practice date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: p x ge nan nearly years have passed since the advent of low tidal volume ventilation, yet the mortality for patients with ards remains high. revisiting the treatment modalities used to manage this syndrome has become increasingly important in light of the covid- pandemic. although ventilator management comprises a large component of ards care, adjunctive, nonventilator therapies also make up an important part of a clinician's toolkit. over the years, a number of studies on adjunctive therapies for ards have been conducted, but their implementation and impact as a whole on patient outcomes are unclear. in this issue of chest, duggal et al set out to address an important issue: the use of adjunctive therapies in patients with moderate to severe ards, a timely subject in the setting of covid- . their objectives were to evaluate the frequency and patterns of use of adjunctive therapies in this patient population, as well as to understand the factors associated with the use of these therapies. although the large observational study to understand the global impact of severe acute respiratory failure (lung-safe) previously assessed the frequency of adjunctive therapy use all patients with ards, a closer look at patients with a pao /fio ratio < is needed, as it is primarily this subset of patients in whom adjunctive therapies are recommended. in this cohort assembled in , a small proportion of patients with moderate to severe ards ( %) received early adjunctive therapy; the most frequently used modality was neuromuscular blockade ( %). prone positioning, the adjunctive therapy that has most clearly been shown to have a survival benefit in ards, was only used in % of patients. this study sheds some light on the patient-, clinician-, and systems-level factors associated with the use of adjunctive therapy, but many questions remain. although the patient-level characteristics associated with adjunctive therapy use (younger age, more severe hypoxia, and hypercapnia) are unsurprising, other elements associated with adjunctive therapy use are thought-provoking and warrant more in-depth investigation. the finding that differences in geoeconomic region and clinician staffing ratios were associated with different rates of adjunctive therapy use suggests that health systems-level issues play a role. among high-income countries, the fact that decreased adjunctive therapy use was seen in non-european countries compared with european countries was particularly compelling, as this finding suggests that the disparities were not solely related to cost. these relationships must be examined further. regarding clinician-level factors, it is worth highlighting that adjunctive therapy was used more frequently in patients who had ards recognized on day . the underrecognition of ards by clinicians has been previously reported, and this phenomenon likely affects treatment decisions. additional clinician-level factors that might play a role in adjunctive therapy use were not addressed in the current study but may include expertise with specific modalities, or lack of belief in their utility. benefits of adjunctive therapies are less well established than benefits of low tidal volume ventilation. randomized controlled trials, including the reevaluation of systemic early neuromuscular blockade (rose) and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome (eolia), chestjournal.org blockade or extracorporeal membrane oxygenation in patients with ards with specific levels of hypoxia. previous studies have suggested possible harm associated with the use of pulmonary vasodilators. , thus, clinician reservation for the utilization of these therapies may be expected. conversely, a lack of evidence cannot be the sole reason for the underutilization of adjunctive therapy. the rose study was published after the lung-safe cohort was collected. prior to rose, papazian et al reported a potential mortality benefit associated with use of neuromuscular blockade. although neuromuscular blockade was the most commonly used therapy in the cohort of duggal et al, it was still used in less than onequarter of patients with moderate to severe ards. furthermore, there was a particularly low rate of prone positioning, a modality that has shown mortality benefit in patients with moderate to severe ards, yet remains grossly underutilized for reasons that are unclear. a multicenter observational study on prone positioning found that clinician judgment of hypoxemia being insufficiently severe was the most common reason for not using this therapy. although this indicates a clinician-level factor in its underutilization, this study was performed in icus that agreed to participate in a study about proning, which likely resulted in a selection bias toward centers whose staff were trained in this technique. the level of clinician training and comfort with prone positioning outside of centers participating in clinical research has not yet been established and potentially plays a substantial role in its underuse. duggal et al categorize prone positioning as a "widely available" adjunctive therapy due to the lack of requirement for specialized equipment. although specific technology is not required for prone positioning, training and expertise of physicians and allied health professionals are crucial and may be lacking in some centers. prone positioning can also be more laborintensive for nursing staff, making it less feasible in centers with lower nurse-to-patient ratios. all of these factors may prevent prone positioning from indeed being a widely available therapy in a practical sense. ultimately, the study by duggal et al highlights the disconnect between evidence-based society guidelines and actual practice patterns in the real world. whether this disconnect has persisted in the setting of the covid- pandemic has yet to be seen. nevertheless, barriers to the use of adjunctive therapies outside of the context of interventional trials must be identified and addressed, particularly regarding prone positioning. although underrecognition of ards represents one culprit and a potential target for improvement, the contribution of other clinician-, systems-, and patientbased factors must be examined before a comprehensive approach to implementation strategies for improving ards care can be developed. mortality in ards remains high; the failure of advances in ards management to reach this vulnerable patient population may be the reason why. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome patterns of use of adjunctive therapies in patients with early moderate to severe ards: insights from the lung safe study epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries prone positioning in severe acute respiratory distress syndrome refractory hypoxemia and use of rescue strategies. a u.s. national survey of adult intensivists early neuromuscular blockade in the acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome inhaled nitric oxide for acute respiratory distress syndrome (ards) in children and adults aerosolized prostacyclins for acute respiratory distress syndrome (ards) neuromuscular blockers in early acute respiratory distress syndrome a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study an official american thoracic society/european society of intensive care medicine/ society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome key: cord- -mbwm ytg authors: chiumello, davide; marino, antonella; cammaroto, antonio title: the acute respiratory distress syndrome: diagnosis and management date: - - journal: practical trends in anesthesia and intensive care doi: . / - - - - _ sha: doc_id: cord_uid: mbwm ytg acute respiratory distress syndrome (ards) is characterized by a new acute onset of hypoxemia secondary to a pulmonary edema of non-cardiogenic origin, bilateral lung opacities and reduction in respiratory system compliance after an insult direct or indirect to lungs. its first description was in s, and then several shared definitions tried to describe this clinical entity; the last one, known as berlin definition, brought an improvement in predictive ability for mortality. in the present chapter, the diagnostic workup of the syndrome will be presented with particular attention to microbiological investigations which represent a milestone in the diagnostic process and to imaging techniques such as ct scan and lung ultrasound. despite the treatment is mainly based on supportive strategies, attention should be applied to assure adequate respiratory gas exchange while minimizing the risk of ventilator-induced lung injury (vili) onset. therefore will be described several therapeutic approaches to ards, including noninvasive mechanical ventilation (nimv), high-flow nasal cannulas (hfnc) and invasive ventilation with particular emphasis to risks and benefits of mechanical ventilation, peep optimization and lung protective ventilation strategies. rescue techniques, such as permissive hypercapnia, prone positioning, neuromuscular blockade, inhaled vasodilators, corticosteroids, recruitment maneuvers and extracorporeal life support, will also be reviewed. finally, the chapter will deal with the mechanical ventilation weaning process with particular emphasis on extrapulmonary factors such as neurologic, diaphragmatic or cardiovascular alterations which can lead to weaning failure. the first of the acute respiratory distress syndrome (ards) description was in by laennec. since that many and more accurate definitions followed. nowadays almost % of hospitalized and mechanically ventilated patients present ards diagnostic criteria [ ] . ards can be generally defined as a new acute onset of hypoxemia and bilateral opacities after an insult direct or indirect to the lungs [ ] [ ] [ ] . in there was the first shared definition, and then, in , an update known as "berlin definition" was made by an expert panel of the european society of intensive care medicine [ ] . according to this new definition, ards is an acute form of diffuse lung injury that happens in patients with predisposing factors, with: -symptoms onset within week of a known clinical insult or new or worsening respiratory symptoms -bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules -respiratory failure not fully explained by cardiac failure or fluid overload -hypoxia, classified by pao /fio ratio measured with at least peep of cmh o into: mild ( mmhg ≤ pao /fio ≤ mmhg), moderate ( mmhg ≤ pao / fio ≤ mmhg), severe (pao /fio ≤ mmhg) [ ] [ ] [ ] . this new definition brings a small, but very important, improvement in predictive ability for mortality (area under the curve [auc] . ) [ ] . evaluate lung morphology, which in ards is characterized by consolidated regions (homogeneous areas with increased density without identifiable vessels or bronchi), ground glass regions (areas with increased density but with still visible vessels), and normally aerated regions. since lungs are characterized by diffuse edema, with the superimposed pressure causing atelectasis and collapse of dependent lung zones, consolidated areas are typically located in dependent lung regions [ ] . lung ct scan is also helpful in lung potential of recruitment evaluation, i.e., the proportion of consolidated lung that regain aeration after an increase in alveolar pressures. in ards patients, potential of recruitment could range between % and %. moreover, lung ct scan could help clinician in identifying ards etiology; in fact, in pulmonary ards consolidated and ground glass areas are similar, while in extrapulmonary ards ground glass areas are predominant [ ] . next to ct scan, ultrasound of lung parenchyma, pleura, and air may be helpful in diagnostic evaluation, clinical management, and monitoring of ards patients [ ] [ ] [ ] [ ] . in respiratory failure patients, lung ultrasound is characterized mainly by b-line (hyperechogenic vertical artifact line that starts from pleura) [ ] , while the b-pattern composed of three or more b-lines appears to be correlated with an interstitial pathological process [ ] . a bilateral homogeneous b-pattern is not decisive between ards and cardiogenic edema and deserves further analysis [ ] , while bilateral, nothomogeneous b-pattern plus c-pattern composed of consolidated areas and pleura abnormalities are suggestive of ards etiology [ ] . figure . shows possible lung ultrasound patterns. the acute respiratory failure management includes early recognition of the triggering cause and timely targeted treatment. besides that, supportive treatments must be started to assure adequate respiratory gas exchange while minimizing the risk of ventilator-induced lung injury (vili) onset. actual knowledge suggest that in most severe ards patients, spontaneous respiratory triggering could be dangerous; thus the spontaneous breathing approach should be used only in mild and moderate ards patients. different therapeutic targets should be met using different pharmacological and non-pharmacological approaches and different mechanical ventilation modalities. noninvasive mechanical ventilation (nimv) is able to reduce patient's work of breathing and intrapulmonary shunt, improving gas exchange, avoiding patient's deep sedation, and reducing the ventilator-associated pneumonia risk. however, nimv use is widely debated due to the high risk of failure (i.e. an intubation rate between % and % and a mortality rate between % and %) [ ] , and the consequent risk of delaying intubation and mechanical ventilation in patients who fail this kind of support. high-flow nasal cannula (hfnc) represents an additional noninvasive ventilatory support that ensures patient's administration of a heated and humidified high flow of oxygen through the patient's nose and has shown to be able to reduce respiratory work while improving oxygenation and co elimination, providing the patient with a positive end-expiratory pressure (peep) that varies between and cmh o. a recent study carried out on patients diagnosed with ards, as in the case of niv [ ] , showed however a high rate of hfnc failure, equal to % [ ] . invasive mechanical ventilation is a supportive therapy able to guarantee adequate gas exchange (increase pao and clear co adequately) and reduce the respiratory muscle activity [ ] . mechanical ventilation presents a double effect on patient oxygenation: it allows a continuous and precise fio titration and during the inspiratory phase applies a positive airway pressure that reopens collapsed alveolar units. this second effect is likely to be limited in time, unless an adequate positive endexpiratory pressure is applied during the expiratory phase to avoid the alveolar recollapse [ ] . the ventilatory setting in ards patient remains a daily challenge, and the choice should be adapted to each patient considering his/her hemodynamic parameters, respiratory mechanics, and gas exchange. during the last years, literature has already widely demonstrated that high-volume/high-frequency ventilation can damage the lungs [ ] mainly through the cycling collapse-reopening and alveolar overdistention phenomena that contribute to the so-called atelect-trauma [ ] . the application of high peep allows collapsed alveoli reopening and intrapulmonary shunt reduction, moreover it reduces the repetitive alveolar opening and closing which occurs during the respiratory cycle [ ] . however, it's not always useful to set high peep levels, as it could appear at first; indeed, two randomized and controlled trials comparing ards patients treated with low vs. high peep [ , ] have not shown any benefit from the use of the high peep strategy. these contradictory results can be explained by the pulmonary recruitment concept, i.e., the volume of collapsed pulmonary parenchyma in which is possible to re-establish a normal aeration by an increase in the airway pressure [ ] . to recruit collapsed lung regions and keep them open, it is necessary to apply an airway pressure higher enough to counterbalance the superimposed pressure, i.e., the pressure generated by the weight of the lung and the rib cage that acts on the lung below [ ] . several maneuvers can be used to recruit the lung: the sigh (i.e., one high-volume breath intermittently provided by the ventilator), the extended sigh (i.e., a progressive increase in peep or a progressive increase in both peep and plateau pressure), and the sustained inflation (i.e., a static sustained increase in the airway pressure [ ] [ ] [ ] [ ] [ ] [ ] protracted for - seconds) [ ] . the target of these maneuvers is to increase the transpulmonary pressure for a period of time sufficiently long to reinflate the alveolar units previously closed. while these maneuvers are able to improve the oxygenation for a variable period of time, their systematic use did not result in a mortality reduction [ ] . while the lung ct scan is the gold standard for the potential of recruitment evaluation, the lung ultrasound seems to be a promising alternative available at the patient's bedside with several advantages such as safety and repeatability; however further studies are necessary to confirm this data [ ] . as known, the choice of a too low end-expiratory positive pressure could cause the collapse of otherwise recruited parenchymal areas, while the choice of a too high end-expiratory positive pressure could increase dead space and tissue stretch thus raising the risk of lung damage. the peep optimization is therefore crucial in the individual patient to avoid the continuous opening and closing and the overdistention phenomena in some parenchymal areas. different approaches have been proposed to choose the best peep, but the most commonly used is the one based on the peep/fio table, which use the patient's saturation/oxygenation as target [ ] . another method is based on the respiratory mechanics: peep is progressively increased while keeping the tidal volume constant and the airway pressure within a safety range ( - cmh o) [ ] . conversely, our group uses the esophageal pressure variation during the breath, to evaluate the transpulmonary pressure. it is measured as: (plateau pressure − total peep) − (esophageal pressure at plateau − esophageal pressure at zeep the main determinants of the ventilator-induced lung injury are strain (defined as the lung deformation induced by the application of the tidal volume) and stress (i.e., the transpulmonary pressure determined by the strain) [ ] . therefore, to maintain low stress and strain, it is necessary to apply a low tidal volume or have a high residual functional capacity [ , ] . a recent meta-analysis has shown how the use of "protective ventilation," with a tidal volume of ml/kg (calculated on kg of ideal body weight), guarantees a reduction in mortality [ ] . since the actual body weight isn't an accurate index of lung size, it is recommended the use of the ideal weight (calculated based on gender and height) to calculate the best tidal volume; however, the ideal weight is not correlated with the functional residual capacity of the lung, highlighting that the same tidal volume can generate very different stress and strain values [ ] in people with the same gender and height but different functional residual capacity. amato, in a recent study performed over a group of patients with ards ventilated with different combinations of peep and tidal volume, showed that the variable most closely associated with the outcome of patients is represented by the driving pressure of the airways, calculated as (plateau pressure − total peep). furthermore in that study was demonstrated that high levels of peep appeared protective only when associated with reduced driving pressure, with a pressure cutoff of cmh o [ ] . however, the use of driving pressure has several limitations: the main one is the fact that the pressure that extends the lung is the transpulmonary pressure and not the airway pressure. current recommendations encourage the use, in mechanically ventilated patients, of a conservative oxygen strategy with an o arterial saturation target ranging from % to %. the associated use of a "protective ventilation," with the aim of reducing the damage induced by ventilation, can however cause the development of hypercapnia; however a paco around mmhg and a ph of about . have been proved to be safe [ , ] , except in special cases such as patients with intracranial hypertension or severe heart failure. the rationale for this permissive strategy lies in the known effect that hypercapnic acidosis exerts on arterial and tissue oxygenation [ ] . in order to guarantee a better patient adaptation to the ventilator, to reduce the oxygen consumption related to the respiratory muscle activity and to guarantee a protective transpulmonary pressure, the use of neuromuscular blockers is accepted in clinical practice [ ] . moreover, neuromuscular blockers have the ability to reduce stress and strain applied to the parenchyma. neto demonstrated that, in patients with severe ards, a short course of treatment with neuromuscular blockers was associated with a mortality decrease [ ] . the indications for the prone positioning have changed over time: once it was used to improve arterial oxygenation in the most severe forms of respiratory failure [ , ] ; while nowadays it aims to achieve a more homogeneous distribution of stress and strain within the lung parenchyma, acting in synergy with the remaining therapies and protecting against the ventilator induced lung injury [ ] . the prone positioning improves ventilation/perfusion coupling thus improving the co elimination and improves the ventilation distribution across the dorsal regions of the pulmonary parenchyma [ , ] . the association of prone positioning and the use of neuromuscular blockers, in patients with severe ards, seems to have a synergistic effect on oxygenation and overall duration of mechanical ventilation and seems to be associated with a better outcome. however, these data needs further studies to confirm. in any case, the prone positioning presents few absolute contraindications, namely, pregnancy, open abdominal treatment, unstable fractures, and hemodynamic instability [ ] . as shown above, the central role in the pathogenesis of ards is played by the inflammatory response that develops in the lung. several trials have been performed over time to evaluate the use of corticosteroids in the treatment of respiratory distress syndrome, but the results appeared controversial [ , ] . meduri in his study carried out in the early phases of the ards, showed that the use of a decremental infusion scheme of corticosteroids leads to a mortality reduction in intensive care [ ] . however, in other studies, this result has not been confirmed [ , ] . although nitric oxide (no) has a known vasodilatory effect on the pulmonary vessels thus ensuring an improvement of the ventilation/perfusion coupling, its use in patients with ards is not universally accepted [ ] . in fact, it has not been clearly demonstrated its benefit in terms of mortality, while its use is burdened by possible serious complications, such as renal failure [ ] . the use of extracorporeal membrane oxygenation (ecmo) in the treatment of severe respiratory failure was born around the s with the aim of properly oxygenating the patient ensuring a protective ventilation, reducing the chances of lung damage. several observational studies have demonstrated various ecmo's benefits in patients with respiratory failure. however, the cesar study, a recent randomized trial, showed an increase in survival at months ( % vs. %) but no difference in quality of life and spirometric parameters between patients undergoing conventional mechanical ventilation and extracorporeal support in reference ecmo centers [ ] . therefore, considering the non-univocal interpretation of the data coming from this trial, nowadays it is not possible to conclude for a superiority of ecmo support compared with the association of the supportive therapy listed above [ ] . it is of crucial importance the choice of the right moment to start the weaning from mechanical ventilation and to extubate the patient: any delay in extubation increases the risk to develop ventilator-associated pneumonia [ ] ; while a premature extubation can lead to a prolonged stay in icu [ ] and/or to a new need of invasive respiratory support. the weaning from mechanical ventilation is considered difficult in the - % of mechanical-ventilated patients: the failure of the weaning process is defined as the inability to overcome a spontaneous breathing test or as the need for re-intubation within the first hours from the endotracheal tube removal [ ] . the causes of weaning failure are complex and determined by different factors; the main ones are listed below. in the patient with a difficult weaning, an increase in the airways resistance should be considered. moreover, a secondary tracheal obstruction caused by tracheal stenosis, tracheomalacia or the development of granulation tissue, can contribute to a complicated weaning from mechanical ventilation [ ] . in ards patients an increase in airway resistances is typically due to bronchial walls edema of the small airways. the delirium seems to be the more frequent neurological alteration associated with a difficult weaning, with a four-time extubation failure rate than a patient without neurological complications [ ] . delirium diagnosis is simple thanks to the use of validates scales, such as cam-icu. psychiatrists and psychologists could be helpful in other cognitive disturbances diagnosis different from delirium. a well-known risk factor for delirium is represented by sedation, in particular when midazolam is used [ ] . the implementation of a daily sedative wash-out protocol, possibly together with a spontaneous breathing trial, can be associated to a reduction in ventilatory support length [ ] . the depression development, common in patients staying in icu for long periods, seems to be associated to an increased risk of weaning failure [ ] . antidepressant drugs seem to foster weaning from mechanical ventilation, even if only few data are available at the moment [ ] . in the patient affected by an alteration of the myocardial contractility, the shift from mechanical ventilation to spontaneous breathing causes an increase in the cardiovascular work, mainly due to two factors: an intrathoracic pressure variation that causes changes in preload and afterload and an increase of the oxygen consumption by respiratory muscles [ ] . an accurate cardiovascular evaluation in mechanically ventilated patients makes the introduction or the optimization of the appropriate therapy possible: this allows a reduction of the weaning failure risk. the beginning of weaning causes an increase in respiratory muscle workload that frequently appears to be already weakened. in assessing the cause of muscle weakness, it is important to bear in mind that the respiratory muscle dysfunction can result from a damage located anywhere on the axis from the afferent chemoreceptors, to the respiratory center, to the single muscle fiber [ ] . the cause of the failure is frequently represented by a diaphragm alteration that can be secondary to two conditions that often coexist in the same patient: the critical illness polyneuropathy (cip) involving the phrenic nerve and, more often, the critical illness myopathy (cim). several works have demonstrated that in mechanicalventilated patients, there is often an alteration of the respiratory muscle contractility [ ] . before implementing weaning-from-mechanical-ventilation protocols, it is necessary to carefully assess the diaphragmatic function so as to exclude the presence of alterations. to do so, some tests used in clinical practice are here below displayed. • p . : it is the most frequently used test for the respiratory drive evaluation in mechanically ventilated patients. in order to carry out this test, the ventilator's inspiratory valve is closed, and the pressure fall within the first msec after the patient's inspiratory attempt is recorded. usually, the p . value varies between . and . cmh o. it is important to note that this parameter depends both on the inspiratory muscular strength and on the respiratory drive. • maximal inspiratory pressure (mip): represents the maximum pressure that the patient can generate by inhaling against a completely occluded airway, starting from functional residual capacity (frc). the minimum thresholds are - cmh o for men and - cmh o for women [ ] . theoretically, the most negative values exclude the presence of a significant muscular weakness. • rapid shallow breathing index (rsbi): introduced by tobin [ ] , it is one of the most common indexes used to evaluate patients in weaning process. it is defined as the ratio between the respiratory rate and the tidal volume expressed in liter. patients that tend to breathe with a higher respiratory rate and with a smaller tidal volume have a high rsbi and more probably a higher risk of weaning failure. the majority part of centers considers a rsbi < adequate to start weaning the patient from mechanical ventilation [ ] . mechanical ventilation is a life-saving intervention in patients affected by acute respiratory distress, but it is also associated with complications. therefore it is desirable to wean patients from mechanical ventilation as soon as the underlying cause that led to the need for ventilatory support is resolved or the patient has sufficiently improved and is able to sustain spontaneous breathing with adequate respiratory mechanics and gas exchange. recently, there were published some guidelines aimed at giving indications on which weaning/extubation techniques it is recommended to use in patients under mechanical ventilation [ ] : -for acutely hospitalized patients ventilated more than h who are able to make a weaning attempt, it is recommended to carry out an initial spontaneous breathing trial with inspiratory pressure support ( - cmh o). -for acutely hospitalized patients ventilated for more than h, it is suggested to use protocols to minimize sedation or guarantee sedative suspension periods, during which carry out a spontaneous breathing trial. -for acutely hospitalized patients ventilated more than h at high risk for extubation failure and who have passed a spontaneous breathing trial, it is recommended the application of noninvasive ventilation (niv) following extubation. still today, ards represents a syndrome with a globally high incidence and a high mortality rate that varies between % and %. the use of a systematic diagnostic approach can help physicians to rapidly identify the triggering cause of the syndrome, making it possible to quickly start with the right therapy. chest imaging, mainly represented by ct scan, is of primary relevance both in the diagnostic pathway and in the evaluation of lung parenchyma recruitability. the use of lung ultrasound is gaining a pivotal role in the daily bedside evaluation of the patient, thanks to its role in the differential diagnosis and to the possibility to evaluate right and left ventricular function. the supportive treatment guaranteed to patients with respiratory distress needs to be oriented to the maintenance of vital functions, to the improvement of gas exchange and to the reduction of lung injury risk. in order to avoid ventilator-induced lung injury and to set a lung protective ventilation, it is useful to monitor functional residual capacity (frc) and transpulmonary pressure. in the most severe cases, it can be useful to use neuromuscular-blocking drugs and prone position so as to improve ventilation/perfusion ratio. another challenge for physicians seems to be the weaning from mechanical ventilation: the aim is to exclude all the alterations that may delay or make fail the respiratory weaning. the latest guidelines written by the american thoracic society and the american college of chest physicians are useful to treat the patient in this crucial phase. evolution of mechanical ventilation in response to clinical research acute respiratory distress in adults the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition current concepts of ards: a narrative review lung recruitability is better estimated according to the berlin definition of acute respiratory distress syndrome at standard cm h o rather than higher positive end-expiratory pressure: a retrospective cohort study the berlin definition of ards: an expanded rationale, justification, and supplementary material the acute respiratory distress syndrome viral community-acquired pneumonia in non immunocompromised adults incidence and characteristics of viral community-acquired pneumonia in adults virus-induced acute respiratory distress syndrome: epidemiology, management and outcome viral infection in patients with severe pneumonia requiring intensive care unit admission clinical aspects of pandemic influenza a (h n ) virus infection diagnostic workup for ards patients molecular diagnosis of legionella infections--clinical utility of front-line screening as part of a pneumonia diagnostic algorithm acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition vertical gradient of regional lung inflation in adult respiratory distress syndrome adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: ct, clinical, and functional correlations ultrasound in the management of thoracic disease international evidence-based recommendations for point-of-care lung ultrasound ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia the value of lung ultrasound monitoring in h n acute respiratory distress syndrome relevance of lung ultrasound in the diagnosis of acute respiratory failure: the blue protocol early detection of acute lung injury uncoupled to hypoxemia in pigs using ultrasound lung comets chest sonography: a useful tool to differentiate acute cardiogenic pulmonary edema from acute respiratory distress syndrome role of noninvasive ventilation in acute lung injury/acute respiratory distress syndrome: a proportion meta-analysis predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study use of high-flow nasal cannula oxygen therapy in subjects with ards: a -year observational study ultra-protective ventilation and hypoxemia recruitment and derecruitment during acute respiratory failure: an experimental study experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. protection by positive end-expiratory pressure multiple system organ failure. is mechanical ventilation a contributing factor? lung opening and closing during ventilation of acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial lung recruitment assessed by respiratory mechanics and computed tomography in patients with acute respiratory distress syndrome. what is the relationship? compressive forces and computed tomography-derived positive end-expiratory pressure in acute respiratory distress syndrome recruitment maneuvers in acute respiratory distress syndrome and during general anesthesia effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment lung stress and strain during mechanical ventilation: any safe threshold? low-dose chest computed tomography for quantitative and visual anatomical analysis in patients with acute respiratory distress syndrome stress and strain within the lung the assessment of transpulmonary pressure in mechanically ventilated ards patients lung protective ventilation strategy for the acute respiratory distress syndrome lung stress and strain during mechanical ventilation for acute respiratory distress syndrome driving pressure and survival in the acute respiratory distress syndrome balancing neuromuscular blockade versus preserved muscle activity low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study driving pressure and intraoperative protective ventilation neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials the prone position in ards patients use of extreme position changes in acute respiratory failure prone position in acute respiratory distress syndrome. rationale, indications, and limits prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: yes effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome high-dose corticosteroids in patients with the adult respiratory distress syndrome pulmonary vasodilators. respir care inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal life support in critically ill adults respiratory failure in the elderly effect of failed extubation on the outcome of mechanical ventilation weaning from mechanical ventilation significant tracheal obstruction causing failure to wean in patients requiring prolonged mechanical ventilation: a forgotten complication of long-term mechanical ventilation neurologic status, cough, secretions and extubation outcomes a clinical prediction rule for delirium after elective noncardiac surgery efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (a wakening and breathing controlled trial): a randomised controlled trial depressive disorders during weaning from prolonged mechanical ventilation treatment of depression with methylphenidate in patients difficult to wean from mechanical ventilation in the intensive care unit clinical review: the abc of weaning failure--a structured approach is weaning failure caused by low-frequency fatigue of the diaphragm? maximal respiratory pressures: normal values and relationship to age and sex a prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously liberation from mechanical ventilation in critically ill adults: an official american college of chest physicians/ american thoracic society clinical practice guideline: inspiratory pressure augmentation during spontaneous breathing trials, protocols minimizing sedation, and noninvasive ventilation immediately after extubation key: cord- - j cdt b authors: chiang, eddie t.; wang, ting; garcia, joe g. n. title: acute lung injury: the injured lung endothelium, therapeutic strategies for barrier protection, and vascular biomarkers date: - - journal: textbook of pulmonary vascular disease doi: . / - - - - _ sha: doc_id: cord_uid: j cdt b the vascular endothelium can be considered as an organ/tissue which comprises a monolayer of endothelial cells which serve as a semipermeable cellular barrier separating the inner space of blood vessels from its surrounding tissue and to control the exchange of fluids and cells between the two compartments. since the pulmonary circulation receives the entire cardiac output, the large surface area of the lung microvasculature is well suited for sensing mechanical, chemical, and cellular injury by inhaled or circulating substances. this endothelial barrier is dynamically regulated through exposure to these various stimuli of physiological and pathological origin and serves to regulate multiple key biological processes (including lung fluid balance and solute transport between vascular compartments). for example, an increase in vascular permeability is a necessary feature of the body’s defense mechanism to provide injured tissues with access to leucocytes, resulting in tissue edema due to fluid extravasation. however, during conditions of intense lung inflammation such as observed in acute lung injury or its severer form of acute respiratory distress syndrome, the large surface area becomes a liability and provides the opportunity for profound vascular permeability resulting in massive fluid accumulation in the alveolar space and progressively leading to pulmonary failure. alterations in vascular permeability occur not only in acute inflammatory lung disorders primarily caused by sepsis, pneumonia, and trauma which result in high rates of patient morbidity and mortality, but are an attractive target for therapeutic intervention in subacute lung inflammatory disorders such as ischemia–reperfusion injury, radiation lung injury, and asthma. thus, understanding the mechanisms of endothelial barrier dysfunction is vital for the management and treatment of key and enigmatic pulmonary disorders. the vascular endothelium can be considered as an organ/ tissue which comprises a monolayer of endothelial cells (ecs) which serve as a semipermeable cellular barrier separating the inner space of blood vessels from its surrounding tissue and to control the exchange of fluids and cells between the two compartments. since the pulmonary circulation receives the entire cardiac output, the large surface area of the lung microvasculature is well suited for sensing mechanical, chemical, and cellular injury by inhaled or circulating substances. this endothelial barrier is dynamically regulated through exposure to these various stimuli of physiological and pathological origin and serves to regulate multiple key biological processes (including lung fluid balance and solute transport between vascular compartments). for example, an increase in vascular permeability is a necessary feature of the body's defense mechanism to provide injured tissues with access to leucocytes, resulting in tissue edema due to fluid extravasation. however, during conditions of intense lung inflammation such as observed in acute lung injury (ali) or its severer form of acute respiratory distress syndrome (ards), the large surface area becomes a liability and provides the opportunity for profound vascular permeability resulting in massive fluid accumulation in the alveolar space and progressively leading to pulmonary failure. alterations in vascular permeability occur not only in acute inflammatory lung disorders primarily caused by sepsis, pneumonia, and trauma which result in high rates of patient morbidity and mortality [ , ] , but are an attractive target for therapeutic intervention in subacute lung inflammatory disorders such as ischemia-reperfusion injury [ ] , radiation lung injury [ , ] , and asthma [ , ] . thus, understanding the mechanisms of endothelial barrier dysfunction is vital for the management and treatment of key and enigmatic pulmonary disorders. a key concept of the dynamically regulated lung ec barrier is the notion that two general pathways, transcellular and paracellular, that describe the movement and flow of fluid, macromolecules, and leukocytes into the interstitium (and subsequently the alveolar air spaces) produce clinically significant pulmonary edema during inflammatory lung processes (fig. ) . the transcellular pathway utilizes a tyrosine kinase dependent, gp -mediated transcytotic albumin route, an active process of albumin transport in which endocytic vessels fuse with the endothelium in response to surface glycoprotein (gp ) receptor ligation [ ] . however, there is general consensus that the primary mode of fluid and transendothelial leukocyte trafficking occurs by the paracellular pathway as shown by the elegant electron microscopy studies of majno and palade [ , ] , who demonstrated lung ec rounding and paracellular gap formation at sites of active inflammation within the lung vasculature. disruption of the integrity of the ec monolayer is now recognized as a cardinal feature of inflammation, ischemiareperfusion injury, and angiogenesis and occurs in response to a variety of mechanical stress factors, inflammatory mediators, and activated neutrophil products [reactive oxygen species (ros), proteases, cationic peptides]. the dramatic cell shape change which results in paracellular gap formation implicates the direct involvement of endothelial structural components composed of cytoskeletal proteins (microfilaments and microtubules). thus, although once perceived as a passive cellular barrier, ecs are now recognized as a highly dynamic tissue contributing to the multiple dimensions of ec function, including interactions with a number of barrier-regulatory effectors via the endothelial cytoskeleton. the duration and outcome of inflammatory disease processes depends upon the balance between the severity of endothelial injury caused by adhesive biophysical forces, mechanical shear stress (ss), or receptor ligation by specific inflammatory mediators and the efficiency of endogenous repair mechanisms to restore vascular integrity [ , ] . in this chapter, we will ( ) address the role of cytoskeletal rearrangement in mechanistic regulation of pulmonary vascular barrier function and permeability, ( ) define current strategies designed to enhance the integrity of the lung vascular endothelium, and ( ) identify vascular biomarkers and potential prognostic determinants of acute inflammation. it is now well accepted that dynamic cytoskeletal elements, actin, microtubules, and intermediate filaments (ifs) , are key elements of vascular barrier regulation. the vast majority of the studies contributing to this recognition have focused on agonist-mediated signaling to the actomyosin cytoskeleton with subsequent effects on lung vascular barrier-regulatory properties. historically viewed as separate and distinct cytoskeletal systems, microtubules and actin filaments are now known to interact functionally during dynamic cellular processes. the microtubule scaffolding complex [ , ] , with a central role of tubulin dynamics, actively contributes to cytoskeletal rearrangement and in transducing competing barrier-regulatory forces, often in close collaboration with microfilament elements. much less is known about ifs, an enigmatic component of the ec cytoskeleton consisting of dimer structured a-helical proteins which combine to form fibrils. if proteins are expressed in a specific manner, with vimentin the primary if protein found in ecs. the role of ifs in regulating ec barriers represents a fertile area for future investigations as only limited information is available [ , ] . nevertheless, cytoskeletal constituents together provide the capacity for dynamic regulation of cell shape and, as a consequence, of moment-to-moment adaptation to an ever-changing vascular environment. actin, a globular protein with a centrally located atp-binding site, is critical to many cellular processes, including cell motility, cell division, cell signaling, and as we and others have shown, ec permeability [ ] [ ] [ ] . g-actin reversibly assembles to form polymerized actin fibers called filamentous actin (f-actin) or actin microfilaments ( -nm diameter), conferring strength to structural elements regulating cell shape, particularly when accompanied by phosphorylated myosin. dynamic remodeling of actin filaments within peripherally distributed cortical bands is essential for maintenance of endothelial integrity and basal barrier function, with inhibition of actin polymerization (cytochalasin d) directly increasing ec permeability [ ] . edemagenic agents initiate dramatic cytoskeletal rearrangement characterized by the loss of peripheral actin filaments with a concomitant increase in organized actin cables that span the cell, known as "stress fibers." critically involved in regulating the spatial locale and level of actin cycling (polymerization-depolymerization) are numerous actin-binding proteins which serve as cross-linking/ bundling proteins, polymerization/depolymerization proteins, and capping/severing proteins. one key actin-binding protein and central regulator of the ec contractile apparatus is the ca + /calmodulin-dependent nonmuscle isoform of myosin light chain kinase (nmmlck). phosphorylation of the substrate myosin light chain (mlc) by nmmlck is central to paracellular gap formation and increased permeability by many edemagenic agents, including thrombin [ ] and vascular endothelial growth factor (vegf) [ ] , both in vitro and in preclinical models of inflammatory lung injury. studies with nmmlck knockout mice have revealed protection from sepsis-induced ali and our laboratory has shown that nmmlck knockout mice, as well as mice treated with an inhibitory peptide which reduces mlc kinase (mlck) activity, are protected against ventilator-induced lung injury (vili) [ ] . in addition, we have shown that genetic variants (single-nucleotide polymorphisms) in mylk, the gene on chromosome q encoding mlck, confer significant susceptibility to sepsis, and sepsisand trauma-induced ali [ ] , as well as contributing to risk of severe asthma in african americans, another inflammatory lung disorder [ ] . a key regulatory feature of nmmlck is the posttranslational modification (ptm) by increased levels of nmmlck tyrosine phosphorylation catalyzed by either p src kinase or c-abl kinase, or by inhibition of tyrosine phosphatases (vanadate). this ptm serves to increase kinase activity and modulates ec barrier responses [ , [ ] [ ] [ ] . diperoxovanadate, a potent tyrosine phosphatase inhibitor, also increased nmmlck activity, the number of stress fibers, and ec contraction via activation of p src kinase. the nmmlck isoform binds cortactin, another actin-binding protein and ec barrier regulator which localizes to numerous cortical structures within cells [ ] . the sh domain in cortactin binds the proline-rich areas in nmmlck [ , , ] , with this interaction enhancing cortical actin formation and tensile strength. the central region of cortactin binds and cross-links actin filaments, with its c-terminus site for p src kinase-mediated phosphorylation which reduces cross-linking activity. tyrosine phosphorylation of cortactin by p src potentiates and stabilizes actin polymerization, and strengthens cortactin-nmmlck interactions [ ] , and is a key step in a sequence of events that produce cytoskeletal changes, reassembly of adherens junctions (ajs), and barrier restoration during lung inflammation. microtubules are -nm polymers of a-tubulin and b-tubulin that form a lattice network of rigid hollow rods spanning the cell in a polarized fashion from the nucleus to the periphery while undergoing frequent assembly and disassembly [ , ] . important functions of microtubules include intracellular transport of vesicles and organelles, as well as signal transduction and cytoskeletal structure. in addition, microtubules act in concert with the actin cytoskeleton to promote ec barrier integrity. microtubules and actin filaments exhibit complex, but intimate functional interactions during dynamic cellular processes [ ] [ ] [ ] [ ] . microtubule disruption with an agent such as nocodazole or vinblastine induces rapid assembly of actin filaments and focal adhesions, isometric cellular contraction that correlates with the level of mlc phosphorylation, increased permeability across ec monolayers, and increased transendothelial leukocyte migration, events that can be reversed or attenuated by microtubule stabilization with paclitaxel [ , ]. the mechanisms involved in these effects are poorly understood but are likely to be mediated through interaction with actin filaments, suggesting significant microfilament-microtubule cross talk. disruption of microtubules causes actin cytoskeletal remodeling, cell contraction, and decreased transendothelial resistance through a rho kinase induced phosphorylation of mypt , a mlc phosphatase [ , ] . nocadozole causes formation of stress fibers and myofilament assembly accompanied by increases in mlc phosphorylation, remodeling of ajs [ , ] , and barrier disruption [ ] . microtubule stabilization with paclitaxel inhibits the formation of stress fibers and preserves cellular shape and intercellular contacts [ ] . although these effects are poorly understood, microfilament-microtubule cross talk represents an intriguing area of ec barrier regulation [ , ]. ifs, the third major element involved in ec cytoskeletal structure, were defined on the basis of their - -nm filament structure which distinguished them from -nm microfilament and -nm microtubules. despite greater diversity than the highly conserved components of either actin microfilaments or microtubules, if proteins share a common dimer structure containing two parallel a-helices which combine to form polar fibrils that associate with an array of if-binding proteins while connecting to the nuclear envelope, peripheral cell junctions, and other cytoskeletal components. if proteins are expressed in a highly cell specific manner, with vimentin being the primary if protein found in ecs and other cells of mesenchymal origin. although these data suggest potential roles for ifs in ec cytoskeletal structure and barrier function, these effects are likely to be subtle and subject to compensation by biological redundancy and the function of ifs in ec barrier regulation is much less understood [ ] . assembly of ifs is a complex process likely highly regulated by signaling cascades associated with cell motility. vimentin is a dynamic structure undergoing constant assembly/disassembly, as well as anterograde and retrograde movements. microtubulebased movement of ifs is likely critical for assembly and maintenance of the vimentin if network [ , ] . the physical and dynamic properties of the vimentin network in the vascular ec are likely important in regulation of cell shape and resistance to hemodynamic stress that accompanies blood flow and resistance to shear strain, physiological changes regulated by the if cytoskeleton, and if-associated proteins which serve as internal scaffolding for ecs, linked to the plasma membrane, and to junctional contacts. vimentin protein expression is higher in macrovascular ec lining vessels subjected to the highest hemodynamic strain, such as the aorta, compared with microvascular ec lining vessels under less ss. vimentin knockout mice develop normally without gross blood vessel abnormalities, but with reduced mesenteric artery vessel dilation in response to flow [ , ] . downstream responses to flow may be the result of intracellular mechanosignaling events triggered by deformation of the if cytoskeleton. changes in unidirectional laminar flow results in rapid adaptation of the ec vimentin network, with directional displacement within minutes of initial exposure. as noted with microfilaments and microtubules, over a period of hours, cytoskeletal filaments align themselves in the direction of flow, with significantly larger change in the vimentin distribution around the nucleus compared with displacement occurring in the cytosol closer to the substrate. these observed spatial changes may be a means of distribution of local shear force transmission throughout the cell and therefore convey cell signaling messages via a mechanosignaling pathway. thus, vimentin ifs are likely critical for maintaining the structural integrity of ecs under ss, and may also be a conduit for signaling cascades triggered by mechanical force, again an exciting area for future examination. dynamic equilibrium exists between ec contractile forces and the adhesive protein-cytoskeleton linkages with cellcell and cell-matrix interactions necessary for proper barrier function. a major contributor to the intact cellular barrier is the tight apposition of individual ecs with neighboring cells via intercellular junctions which collectively contribute to basal endothelial barrier function. the two primary types of intercellular contacts between ecs are ajs and tight junctions (tjs), both of which link the ec actin cytoskeletons of neighboring cells to each other while providing mechanical stability and mediating signal transduction [ ] (fig. ) . in addition to cell-cell junction stability, cell-matrix interaction also contributes to stability of the barrier function. specific components of the focal adhesion complex, i.e., the integrin-based linkage between the extracellular matrix (ecm) and the endothelial cytoskeleton, provide strong tethering of the endothelium to the vessel wall and thus enhanced barrier integrity. ajs are composed of cadherins bound together in a homotypic-and ca + -dependent fashion to link adjacent ecs [ ] . cadherins interact through their cytoplasmic tail with the catenin family of intracellular proteins (primarily b-catenin), which in turn provide anchorage to the actin cytoskeleton [ ] . the primary adhesive protein present in human endothelial ajs, vascular endothelial cadherin (ve-cadherin) [ ] , is critical to maintenance of ec barrier integrity as demonstrated by increased vascular permeability induced in mice after infusion of ve-cadherin blocking antibody [ ] . similarly, in cultured ecs, ve-cadherin blocking antibody enhanced neutrophil transendothelial migration while producing reorganization of the actin cytoskeleton [ ] . anchorage of ve-cadherin to the actin cytoskeleton is crucial to maintaining barrier integrity since a cytoplasmic-deleted ve-cadherin which cannot anchor to the actin cytoskeleton still forms cadherin-cadherin binding but results in increased vascular permeability [ ] . tjs, or zona occludens, are areas that surround the entire apical perimeter of adjacent cells and are formed by the fusion of the outer layers of the plasma membranes. these associations are sufficiently tight as to form a virtually impermeable barrier to fluid [ , ] and are composed of occludins, claudins, and junctional adhesion molecules coupled to cytoplasmic proteins [ ] (fig. ). similar to ve-cadherin at ajs, ecs express a cell-type-specific transmembrane adhesion protein, claudin- , at tjs. the cytoplasmic components of tjs are linked to the ec actin cytoskeleton by the zona occludens family (zo- ). tjs are particularly abundant and prominent in the brain microvasculature and epithelial cells, where strict control of permeability is needed. in contrast, most microvascular beds of ecs, particularly leaky lung microvasculature, have less defined tj structures and more prominent aj structures. therefore, ajs and not tjs have historically been considered the primary targets involved in junctional protein dissociation resulting in increased paracellular permeability, but there is growing evidence that tjs may play a larger role in the regulation of paracellular permeability in the lung than previously thought [ ] . finally, focal adhesions are intimately involved in lung ec barrier regulation via signaling between the cytoskeleton to the ecm. focal adhesions are attachments of ecs to the underlying ecm and are mediated by ecm proteins (i.e., collagen, fibronectin, laminin, etc.), integrins, and cytoplasmic adhesion plaques (containing vinculin, talin, and paxillin) [ , ] . integrins couple the ecm to the cytoskeleton and transmit signals from the surrounding environment and play a key role in the formation of cell adhesion complexes which attach to the actin cytoskeleton via the cytoskeletal proteins actin, vinculin, talin, and a-actinin. focal adhesions, primarily through integrins, form a bridge for bidirectional signal transduction between the actin cytoskeleton and the cell-matrix interface. disruptions of the integrin-ecm connection can increase ec permeability [ , ] and integrins modulate ec permeability to ss and inflammatory mediators [ ] . integrin-ecm binding stimulates tyrosine phosphorylation of proteins such as paxillin, cortactin, and focal adhesion kinase (fak), as well as calcium influx [ , ] . fak is the principal kinase which catalyzes the downstream reactions of integrin engagement and focal adhesion assembly [ ], with fak activity regulated by tyrosine phosphorylation mediated by the src family. activation of fak through tyrosine phosphorylation produces cell contraction and increased ec barrier permeability. we previously reported that integrin b expression is dramatically upregulated upon challenge with the barrier-protective agent simvastatin [ ] . furthermore, the upregulation of integrin b attenuates endotoxin-and ventilator-induced expression of inflammatory cytokines interleukin (il)- and il- [ ], suggesting a novel mechanism of modulating endothelial barrier function via integrin b and focal adhesion signaling. inflammatory mediators increase vascular permeability by disrupting endothelial junctions and focal adhesion complexes as well as inducing cellular contraction to open paracellular gaps [ , - ]. as tjs and ajs are ideally situated in a locale between cell-cell junctions, they logically are key participants in the control of vascular paracellular permeability and monolayer integrity. recent studies in brain ecs have focused on the importance of claudins in tj formation and maintenance [ , ] . mice with claudin- gene knocked out did not have a morphologically altered vascular network or tj structures, but the claudin- -deficient pups died within h of birth owing to size-selective loosening of the bloodbrain barrier against molecules of less than kda. it appears that moderate redundancy among the claudin isoforms may allow for the formation of the tj, but not for the complete function of the tj. claudin- appears to act in concert with claudin- to form the tightly organized strand network, but in claudin- mutants, claudin- can only maintain the barrier against larger molecules [ ], suggesting claudin- is a structural barrier, whereas claudin- is crucial for the dynamic regulation of tj permeability. gene inactivation of claudin- and occludin also has no effects on vascular morphology or barrier permeability, suggesting a minor role in tj function in endothelium as compared with claudin- and claudin- inactivation of these genes in mice does not cause any defect in the development of the vascular system in the embryo, but in adult mice these molecules play an important role in modulating leukocyte diapedesis through ecs. jam-cs however, is unique in that unlike other junctional proteins, it increases endothelial permeability when expressed at the ec surface, suggesting a role in promoting and/or organizing junction formation [ ] . this activity is mediated by ve-cadherin activity and actin organization, as well as by kinases and phosphatases that modulate tj protein phosphorylation and endothelial permeability. many of the studies on tj have been using brain ecs, where the adhesion molecules are prominent. nevertheless, recent studies on lung ecs have demonstrated that despite the less prominent formation of tjs as compared with ajs, tjs may play a critical role in the endothelial barrier dysfunction associated with exposure to particulate matter from air pollution, which has been shown to induce a gradual and prolonged barrier dysfunction in cultured lung endothelium [ , ] . ajs were found unexpectedly to be unaltered but the tjs, specifically zo- , were degraded through a calpain-dependent proteasome pathway, a novel mechanism of lung endothelial barrier regulation. in contrast to tjs, the regulation of lung vascular integrity involving ajs has been well characterized. although ve-cadherin is present in high concentration in all ecs, different types of vessels appear to modify ve-cadherin expression to complement the vascular barrier function of that particular vessel. four modes of aj protein regulation of permeability have been described, all involving ve-cadherin: phosphorylation, internalization, cleavage, and expression. simultaneous coordination of ve-cadherin phosphorylation and internalization appears to be crucial for a rapid response to an increase in permeability [ ], whereas ve-cadherin cleavage and expression are progressive alterations. edemagenic stimuli induce tyrosine phosphorylation of aj proteins (ve-cadherin, b-catenin, and p catenin), which parallels increases in permeability, with the tyrosine kinase src implicated in the phosphorylation of aj proteins as it directly associates with the ve-cadherin/catenin complex, and src gene inactivation or treatment with inhibitors blocks vegf-induced ve-cadherin phosphorylation [ ] . phosphorylation of ve-cadherin is dependent on kinase activation as well as inhibition of associated phosphatases such as the endothelial-specific phosphatase ve-ptp, which also associates with ve-cadherin, and inactivation of the ve-ptp gene leads to a phenotype comparable to that of ve-cadherin null embryos, suggesting that vessels cannot form correctly if ve-cadherin is constantly phosphorylated [ ] . permeability may also be regulated by ve-cadherin internalization. typically, p catenin binds to ve-cadherin and acts as a plasma membrane retention signal to prevent ve-cadherin internalization; however, upon challenge with barrier-disrupting stimuli, activated src phosphorylates vav , a guanine exchange factor (gef) for rac, which then phosphorylates ve-cadherin at ser , inducing b-arrestin recruitment and promoting clathrin-dependent ve-cadherin internalization [ ]. angiopoietin induces src trapping by mdia, reducing its activity at ajs, and thus reducing vascular permeability [ ] . the third pathway that may induce vascular permeability is ve-cadherin cleavage. ve-cadherin is particularly susceptible to enzymatic proteolysis, specifically elastase and adam- , which are released in high amounts by leukocytes, promoting ve-cadherin cleavage, cell extravasation, and vascular leakage. lastly, permeability control may also be achieved through ve-cadherin gene expression. the ve-cadherin promoter contains several binding sites for transcription factors, tal- , erg, and hypoxia-inducible factors. therefore, the interendothelial junction is a key site of regulating vascular permeability, with various stimuli targeting either the tj or the aj, or both. furthermore, there are various combinatory modes of regulating the aj that promote dissociation of adhesion proteins in the cell-cell junction. however, additional factors often accompany junctional dissociation, such as disbanding of cortical cytoskeleton and increase in cellular contraction, which augment the barrier dysfunction. the monolayer integrity is regulated by the dynamic equilibrium which exists between contractile forces and tethering forces [ , , ] . transcellular stress fiber formation and activation of actomyosin interaction, along with the cortical actin ring disassembly, results in contractile tension that induces cell rounding, which contributes to cell-cell gap formation ( fig. ) , with inhibition of this cytoskeletal reorganization attenuating barrier dysfunction [ , ] . contraction triggered in ecs is regulated by nmmlckcatalyzed mlc phosphorylation on thr and ser which increases actomyosin atpase activity and shifts the equilibrium between the folded and unfolded myosin forms [ ], thus providing the assembling and functioning of the contractile apparatus of the cells. the mylk gene on chromosome in humans encodes three proteins: the nmmlck isoform, the smooth muscle mlck isoform , and telokin [ ] [ ] [ ] [ ] . in smooth muscle, nmmlck is expressed at relatively low level, being present together with a shorter smooth muscle isoform, whereas only nmmlck can be detected in ecs [ ] and exists as a , amino acid high molecular weight ( -kda) protein. the nmmlck shares essentially identical catalytic and cam regulatory motifs with smooth muscle mlck, but contains a unique amino acid n-terminal domain comprising potential novel ptm sites [ ] . inflammatory agonists such as vegf and thrombin produce rapid increases in mlc phosphorylation, reflecting coordinated nmmlck activity and the small gtpase rho and its effector, rho kinase, result in phosphorylation and, thereby, inhibition of the mypt myosin phosphatase, resulting in stabilization and accumulation of phosphorylated mlc. the aggregated result is actomyosin interaction and ec permeability which is significantly attenuated by mlck or rho kinase inhibitors [ , [ ] [ ] [ ] . despite the clear contribution of mlck/rho kinase driven increases in mlc phosphorylation to tension development and increased vascular permeability, mlck-independent pathways are also involved in the regulation of cellular contraction. protein kinase c (pkc)-mediated pathways exert a prominent effect on barrier regulation in a time-and speciesspecific manner without significantly increasing mlc phosphorylation and without inducing formation of actin stress fibers, but with alterations in other components of the endothelial cytoskeleton [ , , ] . pkc-mediated increases in ec permeability involve phosphorylation of caldesmon, an actin-, myosin-, and calmodulin-binding protein present in smooth muscle actomyosin cross-bridges as a -kda protein and in ecs as a -kda protein [ ] . the phosphorylation of caldesmon alters smooth muscle crossbridge activity [ ] . caldesmon-mediated regulation of actomyosin atpase in smooth muscle is also modified by the actin cross-linking protein filamin and gelsolin [ ] . although filamin participates directly in barrier regulation via cam kinase ii activation [ ], its effects on actin cytoskeletal rearrangement are regulated through rho family gtpases [ , ], thereby providing another link with a known modulator of ec barrier function. the cytokine tumor necrosis factor a (tnf-a) induces slow-onset barrier disruption in cultured ecs independent of mlck activity [ ] . finally, p kinase activation also has been linked to contractile regulation in smooth muscle [ ] , ec migration [ , ], and lipopolysaccharide (lps)-induced ec permeability [ ] . the mechanism through which p exerts these effects is unclear but may involve the actin-binding protein hsp [ ], a known p mitogen-activated protein kinase (mapk) target whose actin-polymerization-inhibiting activity dramatically decreases after phosphorylation [ , ] in association with stress fiber development [ , ]. the pulsatile nature of blood pressure and flow exposes blood vessels to constant hemodynamic forces in the form of ss and cyclic stretch (cs). the flow of blood parallel to the vessel surface produces fluid ss from the friction of blood against the vessel wall. in contrast, cs is an important mechanical force generated in the lung circulation either by circulating blood, which results in the rhythmic, pulsatile distension of the arterial wall, or by tidal breathing. the endothelium converts these mechanical stimuli to intracellular signals that effector cellular functions including proliferation, migration, remodeling, apoptosis, and permeability, as well as gene expression. the cytoskeleton is the key structural framework for the ecs to transmit mechanical forces between its luminal, abluminal, and junctional surfaces to its interior, including the cytoplasm, nucleus, and focal adhesion sites. changes in mechanical stress among the organs in the body, the lung exists in a high-oxygen environment and is susceptible to injury by oxidative stress. cigarette smoking and inhalation of airborne pollutants/toxins/ oxidant gases and particulate matter result in direct lung damage as well as the activation of lung inflammatory responses [ - ]. long-term exposure of lungs to higher oxygen tension (hyperoxia), as observed with premature infants and critically ill patients on ventilators, causes oxidative stress and lung injury [ ]. thus, increased ros production has been directly linked to inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease, and ards. ros are essential for normal lung/endothelial function [ ] , but an imbalance of the redox equilibrium may contribute to pulmonary edema [ , ] . the imbalance of oxidants produced to oxidants detoxified, i.e., a change in the redox equilibrium appears important in the development of various inflammatory lung diseases, and increased ros production have been directly linked to oxidation of dna, proteins, lipids and sugars, remodeling of ecm, alteration of mitochondrial respiration, and apoptosis. furthermore, increased levels of ros have been implicated in initiating signaling cascades of activation of transcription factors (nf-kb and ap- ), chromatin remodeling, and gene expression of proinflammatory mediators [ , ] . also, ros generated by phagocytes that have been recruited to sites of inflammation and excess generation of ros by vascular cells are a major cause of edema and lung injury. generation of ros and ros signaling in lung endothelium alter vascular permeability in vivo [ , ] and in endothelial monolayers [ , , ] . despite several potential sources of ros [mitochondrial electron transport chain, cytochrome p- enzymes, xanthine oxidase, nitric oxide synthases, myeloperoxidase (mpo) system], the vascular nadph oxidase family of proteins has been shown to be a major contributor of endothelial ros in response to hyperoxia [ ] since nadph oxidase mediated superoxide production increases endothelial permeability [ , ] . a variety of agonists, cytokines, growth factors, and mechanical forces alter pulmonary vascular barrier properties and serve to increase vascular permeability [ , , , , , , , ] . the serine protease thrombin represents an ideal model for the examination of agonist-mediated lung endothelial activation and barrier dysfunction as thrombin evokes numerous ec responses that regulate hemostasis and thrombosis, and is recognized as an important mediator in the pathogenesis of ali [ ] . thrombin increases ec leakiness to macromolecules by ligating and proteolytically cleaving the extracellular n-terminal domain of the thrombin receptor, a member of the family of pars [ ] [ ] [ ] . the cleaved n-terminus, acting as a tethered ligand, activates the receptor and initiates a number of downstream effects, including cytoskeletal rearrangement (fig. ) . in vivo studies have detailed events which followed thrombin infusion into the pulmonary artery of the chronically instrumented lung lymph sheep model initiating a cascade of events that culminate in intravascular coagulation, inflammation, and vascular leak [ ] [ ] [ ] . naturally occurring agonists, such as the cytokines tnf-a and il- b, have a prominent effect early in ali, causing microthrombosis, and eliciting a cascade of inflammatory signals which result in capillary endothelial production of p-selectin, an adhesion molecule which enhances leukocyte-ec migration [ ] [ ] [ ] and actin reorganization, and paracellular gap formation [ ] . tnf-a also increases tyrosine phosphorylation of ve-cadherin, leading to increased paracellular gaps in human lung endothelium [ ] . much less is known about pre-b-cell colony-enhancing factor (pbef), a relatively unknown cytokine we identified via functional genomic approaches as a novel ali candidate gene [ , ] . pbef is also known as visfatin, following its identification as a visceral fat hormone [ ] , and nicotinamide phosphoribosyltransferase (nampt), as it serves as the rate-limiting component in the nad biosynthesis pathway that catalyzes the conversion of nicotinamide and phosphoribosylpyrophosphate into nicotinamide mononucleotide. we demonstrated pbef as a novel biomarker in sepsis and sepsis-induced ali with genetic variants conferring ali susceptibility [ , ] . furthermore, pbef is highly expressed in polymorphonuclear neutrophils (pmns) of sepsis subjects, with expression upregulated by mechanical force and inflammatory cytokines, and is involved in ec barrier regulation [ , , ] . we explored the mechanistic participation of pbef in ali and vili and demonstrated that recombinant human pbef is a direct neutrophil chemotactic factor and elicits marked increases in the levels of bronchoalveolar lavage (bal) pmns and pmn chemoattractants (kc and mip- ) after intratracheal injection in mice [ ] , changes accompanied by modest increases in lung vascular and alveolar permeability. dramatic increases in bal pmns, bal protein, and cytokine levels (il- , tnf-a, kc) were observed in recombinant human pbef-and vili-challenged mice [ ] , whereas heterozygous pbef +/− mice were significantly protected (reduced bal protein levels, bal il- levels, peak inspiratory pressures) when exposed to a model of severe vili and exhibited significantly reduced expression of vili-associated gene expression modules. the role of the renin-angiotensin system in pulmonary vascular regulation is now well recognized with angiotensin ii, a key component of the renin-angiotensin system, generated primarily by angiotensin-converting enzyme (ace) from angiotensin i and its effects are mediated through angiotensin type i (at- ) and angiotensin type ii (at- ) receptors which are expressed in the normal lung. the pulmonary endothelium represents a major site of ace expression and angiotensin ii production, with ace , a homologue of ace, expressed in the lung inactivating angiotensin ii, leading to the downstream generation of angiotensin - , which acts through at- receptors to induce vasodilatation. although components of the renin-angiotensin system have been implicated in a variety of lung diseases, including pulmonary hypertension and fibrotic lung diseases, the system has been strongly linked to the pathophysiology of pulmonary vascular leak syndromes. for example, ace serves as the receptor for the coronavirus, first identified in , responsible for severe acute respiratory syndrome [ , ] , with a mortality rate of more than % in the elderly. ace and at- serve a protective role in ards, whereas ace , angiotensin ii, and at- mediate lung edema and injury associated with ards. a role for ace via angiotensin ii and/ or bradykinin in ali was proposed [ ] . reductions in ace activity by captopril attenuated the inflammatory response and apoptosis, whereas blocking bradykinin receptors did not attenuate the anti-inflammatory and antiapoptotic effects of captopril [ ] . captopril did not attenuate ace activity or necrosis, indicating that inflammation and apoptosis in vili is due to ace-mediated ang angiotensin ii production [ ] . new blood vessel formation, or angiogenesis, is defined by the generation of new capillaries by ecs either by sprouting or by splitting from pre-existing vessels. sprouting angiogenesis involves ec detachment from the basement membrane, migration, and subsequent proliferation, tube formation, and, finally, functional maturation of the new vessel [ ] . vegf is key in vasculogenesis as mice lacking the vegf receptor flt- fail to develop fully functional blood vessels [ ] . inhibition of vegf as a promising therapeutic strategy in the management of patients with advanced malignancies [ ] . pulmonary hypertension is a devastating disease with many similarities to neoplastic processes and is characterized by aberrant angiogenesis, with vegf serving as a target in pulmonary hypertension [ , ] . vegf increases ec permeability and was originally named "vascular permeability factor" for its profound effects on vascular barrier function [ ] . vegf levels are highest in the lungs and plasma and vegf levels are increased in patients with ards compared with the other groups [ ] . vegf increases cytosolic calcium levels and levels of mlc phosphorylation at high doses and vegf inhibition decreases ec permeability [ , ] . additional angiogenic factors with barrier-regulatory properties include angiopoietin and angiopoietin , which are critical for normal vascular development. the angiopoietin family is compopsed of vascular growth factors which are ligands to the family of tyrosine kinases that are selectively expressed in the vascular endothelium. vegf induces ec differentiation and migration, whereas angiopoietin stabilizes vascular networks [ ] [ ] [ ] . angiopoietin and angiopoietin modulate ec permeability by altering the state of ajs and specifically inhibit vascular leakage in response to vegf or other barrier-disruptive agents, as well as promoting vessel maturation. angiopoietin antagonizes angiopoietin and promotes barrier dysregulation by blocking the ability of angiopoietin to activate its receptor [ ] . understanding the mechanisms of barrier dysfunction offers the advantages to design therapeutic strategies which target barrier-integrity preservation or reverse established barrier dysfunction by restoring vascular integrity. prior to the last decade, permeability-reducing strategies primarily consisted of cyclic amp (camp) augmentation, producing only modest barrier enhancement [ ] [ ] [ ] [ ] . more recently, a number of barrier-promoting agents have been identified which share common signal transduction mechanisms which are distinct from camp signals and target the endothelial actin cytoskeleton to facilitate barrier-restorative processes. the dynamic process of actin polymerization allows for the rapid reorganization of actin structures, with profound functional consequences for barrier regulation that are highly dependent on the exact spatial location of this actin rearrangement occurring as either barrier-disrupting cytosolic stress fibers or as a barrier-enhancing thickened cortical actin ring. we have demonstrated that the quiescent ec phenotype is characterized by a cortical actin ring and few stress fibers, a structure which favors cell-cell adhesion and cell-matrix tethering. we have conceptualized a paradigm whereby barrier recovery after edemagenic agonists involves development of a cortical actin ring to anchor cellular junctions and a carefully choreographed (but poorly understood) gap-closing process via formation of rac gtpase-dependent lamellipodial protrusions into the paracellular space between activated ecs (fig. ) within these lamellipodia, signals are transduced to actin-binding proteins (nmmlck and cortactin) and phosphorylated mlcs in spatial-specific cellular locations. lamellipodia also require formation of focal adhesions (regulated by the cytoskeleton) critical to the establishment of the linkage of the actin cytoskeleton to target effectors that restore cell-cell adhesion and cell-matrix adhesion. this process is essential to the restoration of endothelial barrier in response to exposure to agonists such as sphingosine -phosphate (s p), hepatocyte growth factor (hgf), simvastatin, activated protein c (apc), atp, oxidized phopholipids, and hyaluaron [ , , [ ] [ ] [ ] [ ] [ ] . central to these events is the activation of small gtpases, rac and cdc [ ] , which follows ligation of barrier-protective receptors and drives cortical actin remodeling and lamellipodia formation (fig. ). in addition to lamellipodia, there is increased actin polymerization at the cell periphery (i.e., the cortical actin ring) which occurs with increased force driven by the actin-binding proteins cortactin and nmmlck, which also translocate to this spatially defined region. like lamellipodia formation, rac gtpase-dependent increases in the level of cortical actin follow exposure to multiple barrier-enhancing levels of ss or to potent barrier-enhancing agonists [ , , ] , including s p [ , ] , hgf [ ], atp [ ] , simvastatin [ ] , apc [ ] , prostaglandin e [ ] , and oxidized phospholipid -palmitoyl- -arachidonoyl-sn-glycero- -phosphochlorine (oxpapc) [ ] (table ). these observations serve to highlight the importance of the cellular location of cytoskeletal proteins in maintaining or enhancing ec barrier function, with cortactin directly interacting with nmmlck, an association which is increased by p src tyrosine phosphorylation of either cortactin or nmmlck [ ] . rac activation is in conjunction with akt-mediated phosphorylation events known to be involved in ec proliferation and migration [ ] and ec barrier enhancement. akt-induced phosphorylation of the s p receptor is important in barrier enhancement produced by high molecular weight hyaluronan [ , ] . [ , , ] s p s p receptor s p induces rapid and potent endothelial barrier enhancement through reduction of the numbers of central actin stress fibers and enhancement of cortical actin formation to stabilize cell-cell junctions. s p attenuated endotoxin-induced pulmonary edema in mice and canine models of injury [ , , , , ] simvastatin patients on cholesterol-reducing statin regimens have exhibited improved vascular function. the hmg-coa reductase inhibitor mitigates vegf signaling through rhoa inhibition and rac activation. in vitro, simvastatin pretreatment protects ec from thrombin-induced stress fiber formation and barrier dysfunction [ , , , ] atp g i /g o protein, but not atp receptor atp induces endothelial barrier enhancement through a rac-dependent cytoskeletal rearrangement with reduction of the numbers of central actin stress fibers with increase cortical actin formation. in vivo, nonhyrolyzable atp protected mice from endotoxin-induced lung injury [ , , ] hgf cdc . oxpapc accentuates peripheral f-actin in a unique ziplike configuration with novel interaction between focal adhesion and aj complexes. in vivo, oxpapc protects rats from mechanical-stress-induced lung injury [ , [ ] [ ] [ ] ] mntx mop-r that inhibits s p receptor pretreatment with mop-r antagonist protects ecs from thrombin-and lps-induced barrier dysfunction through an mop-r-independent antagonism involving inhibition of rhoa-dependent s p receptor. the fda recently approved mntx for treatment of postoperative ileus, and it may rapidly translate into a treatment for pulmonary edema [ ] [ ] [ ] anti-pbef neutralizing antibody extracellular pbef pbef is significantly upregulated in the lung during injury. extracellular release of pbef promotes endothelial barrier dysfunction and neutrophil extravasation. anti-pbef neutralizing antibodies, which target extracellular pbef without altering beneficial intracellular pbef, protected lungs from ventilator-induced lung injury in mice [ , ] adherens junction, activated protein c, endothelial cell, endothelial protein c receptor, filamentous actin, hepatocyte growth factor, hydroxy- -methylglutaryl coenzyme a, lipopolysaccharide, mitogen-activated protein kinase, myosin light chain kinase, methylnaltrexone, mu opioid receptor, phosphatidylinositol -kinase, -palmitoyl- -arachidonoyl--glycero- -phosphochlorin, pre-bcell colony-enhancing factor, protein kinase c, sphingosine -phosphate, vascular endothelial growth factor historically, cyclic nucleotides have represented the sole strategy for retarding the edema phase observed in inflammatory lung syndromes, possibly via camp-dependent protein kinases that phosphorylate proteins such as mlck and inhibit f-actin reorganization [ , , , ] . we examined nmmlck as a molecular target involved in increase of lung epithelial and ec barrier permeability utilizing genetically engineered mice and complementary strategies to reduce nmmlck activity or expression. both mlck inhibition (membrane-permeant oligopeptide, pik) and silencing of nmmlck expression in the lung significantly attenuate lps-induced lung permeability and inflammation. we also targeted pulmonary vessels and utilized ace antibody-conjugated liposomes with nmmlck small interfering rna (sirna) as cargo in a murine vili model, again with significant attenuation of vili. furthermore, nmmlck −/− knockout mice were significantly protected when exposed to a model of severe vili. thus, the multidimensional cytoskeletal protein nmmlck represents an attractive target for reducing lung vascular permeability and lung inflammation in the critically ill [ , , ] . s p is a sphingolipid resulting from the phosphorylation of sphingosine, a product of sphingomyelinase catabolism of sphingomyelin, catalyzed by sphingosine kinase [ ] . s p ligates a family of receptors known as s p receptors (also termed endothelial differentiation gene or edg receptors) with prominent effects on the vasculature, promoting ec mitogenesis, chemotaxis, and angiogenesis. our earlier studies were the first to demonstrate that s p is the most potent ec chemoattractant in serum [ ] and to link s p and its receptor ligation to enhanced vascular barrier regulation and demonstrated that physiological doses of s p induce ec activation, marked cytoskeletal rearrangement, and stabilization of lung ec barrier function in vitro [ ] . this novel function for s p was of particular relevance to clinical medicine as thrombocytopenia is well known to be associated with increased vascular leak [ ] and although the mechanism of this effect was unknown, we demonstrated that activated platelets are an important source of s p and directly enhance barrier function via s p receptor ligation [ ] . platelets contain significant levels of sphingosine kinase but reduced levels of sphingosine lyase, thereby serving as enriched sources for the barrier-promoting s p [ ] . ligation by s p of the barrier-enhancing g i -protein-coupled s p receptor (also known as edg ) [ , , , ] increases rac gtpase activity [ ] , cytosolic calcium level [ ] , and aggregation of key barrier-regulatory signaling components into caveolin-rich lipid rafts, including the rac gtpase target p -associated ser/thr kinase (pak) and its downstream target cofilin, an actin-binding protein [ ] , nmmlck, cortactin, and c-abl. pak and cofilin allow polymerization-depolymerization cycling to occur and thus facilitate rearrangement of actin from primarily transcytoplasmic to primarily cortical in a spatially distinct organization as a cortical actin cellular ring, processes which are integral to ec barrier function [ ] . increases in mlc phosphorylation within a peripheral distribution within the cortical actin ring [ ] provide strength to this spatially directed scaffolding force and enhance cell-cell tethering as we described via atomic force microscopy [ ] . immunofluorescence studies demonstrated that overexpressed green fluorescent protein-nmmlck distributes along cytoplasmic actin fibers, but rapidly translocates to the cortical regions of the cell after s p treatment, rapidly catalyzing mlc phosphorylation. in addition, confocal microscopy studies showed ecs challenged with s p demonstrate colocalization of nmmlck with the key actin-binding and ec barrierregulatory protein cortactin [ ] . the interaction of cortactin and nmmlck decreases cortactin-stimulated actin polymerization [ , ] and is essential to s p barrier protection. the p src is not involved in this pathway, but other tyrosine kinases such as c-abl are likely involved [ ] . s p-induced cytoskeletal rearrangement produces increased linkage of actin to aj components, as well as s p-induced phosphorylation of focal-adhesion-related proteins paxillin and fak, with translocation of these proteins to the ec periphery, further implicating s pinduced cell-cell adhesive changes as part of the mechanism of s p-induced barrier enhancement [ , ] . the potential utility of s p in restoring lung water balance in patients with inflammatory injury was underscored in studies involving small-and large-animal models of ali in which s p provided dramatic attenuation of lps-mediated lung inflammation and permeability [ , ] . mice treated with s p had significantly less histological evidence of inflammatory changes/lung injury, with decreased neutrophil alveolitis on bal and decreased lung mpo activity [ ] . interestingly, mice treated with s p after intratracheal administration of lps also showed an attenuated renal inflammatory response compared with controls, measured by tissue mpo activity and evans blue dye extravasation as a measure of capillary leak. s p also protected against intrabronchial lps-induced ali and concomitant vili in a canine model, with decreased shunt fraction, decreased bal protein, decreased extravascular lung water, and improved oxygenation [ ] . use of a large-animal canine model allowed investigation of regional lung changes in ali and the effect of s p on these changes. computed tomography scans of animals subjected to lps/vili found that animals treated with s p had a dramatic improvement in alveolar air content (with decreased edema) in all lung regions [ ] . additional in vivo studies found that s p protects against vili in a murine model as assessed by evans blue dye extravasation [ ] . we have also evaluated a potential role for s p in ameliorating lung ischemia-reperfusion injury, a common sequela of lung transplantation, which is characterized by alveolar damage, edema, and inflammation in donor lungs and is a significant cause of transplant failure. utilizing a rat model of ischemia-reperfusion injury (pulmonary artery ligation and reperfusion), we determined that rats pretreated with s p exhibited reduced lung vascular permeability and inflammation compared with controls [ ] . lung mpo activity, an index of parenchymal leukocyte infiltration, and levels of il- , il- b, and il- were also attenuated in s ptreated animals exposed to ischemia-reperfusion injury [ ] . together, these findings suggest that s p may serve as an effective permeability-reducing agent in diverse conditions which share an element of lung inflammatory burden. despite the profound attractiveness of s p as a therapeutic agent which targets the endothelium in high-permeability states, s p has several attributes which limit its potential utility as a permeability-reducing strategy. with an affinity for ligation of the s p receptor, intratracheal s p has been implicated as a cause of pulmonary edema via endothelial/ epithelial barrier disruption [ ] . s p also causes bradycardia via ligation of cardiac s p receptor [ ] . these findings generated increased interest in fty , a derivative of the natural immunosuppressant myriocin [ ] , and a recently described immunosuppressive agent that causes peripheral lymphopenia by inhibiting cellular egress from lymphoid tissues. fty is structurally similar (but not identical) to s p and is phosphorylated by sphingosine kinase to fty -phosphate, which is an agonist at s p receptors [ ] . this characteristic prompted investigation of the effect of fty on ec barrier function. fty did not have superior efficacy compared with mycophenolate mofetil in preventing renal transplant rejection [ ] , but it is in phase iii clinical trials as an immunosuppressant in multiple sclerosis patients. the clinical availability of fty makes it attractive as a potential mediator of ec barrier function in patients with ali. our in vivo studies demonstrated that intraperitoneally administered fty protected against intratracheally administered lps in a murine model of ali, as measured by evans blue dye extravasation [ ] . the mechanism of fty -induced ec barrier enhancement diverges from the mechanism described for s p in several ways, including the delayed kinetics of the rise in total energy requirement (ter) compared with s p [ ] . decreased expression of the s p receptor prevented an s p-induced increase in ter but only partially altered fty -induced ter increases. unlike s p, fty did not result in threonine phosphorylation of the s p receptor, nor did inhibition of phosphatidylinositol -kinase (pi- -kinase) prevent fty -induced ec barrier enhancement [ ] . furthermore, fty did not cause the increased intracellular calcium level, the mlc phosphorylation, or the cytoskeletal rearrangement seen in response to s p [ ] . downregulation of rac or cortactin using sirnas attenuated the barrier-enhancing effect of s p, but not that of fty [ ] . although fty is an s p receptor agonist, its mechanism of barrier enhancement is distinct from that of s p and does not require the s p receptor. we are currently pursuing novel s p and fty analogues for use in inflammatory lung injury models [ ] [ ] [ ] . another class of prominent barrier-protective agonists under intense scrutiny is the statin family of compounds known as -hydroxy- -methylglutaryl coenzyme a reductase (hmg-coa reductase) inhibitors [ ] . these drugs inhibit cholesterol synthesis in the liver, are commonly used in clinical practice as lipid-lowering agents, and prevent acute coronary events. a plethora of reports have now demonstrated that the benefits of statin therapy cannot be entirely attributed to decreased serum cholesterol level. we have been interested in the effect of statins on endothelial function in ali as an ever-growing body of literature demonstrates improved outcomes in patients with sepsis who are treated with statins, with decreased mortality in bacteremic patients admitted to the hospital while on statin therapy [ ] . a retrospective study in human patients with multiple organ dysfunction syndrome found that those receiving statins had significantly lower -day mortality and hospital mortality compared with matched controls not receiving statin therapy [ ] . animal studies suggest dramatically improved survival in mice treated with simvastatin prior to initiation of sepsis by cecal ligation and puncture compared with mice which were not pretreated with simvastatin [ ] . we have pursued the mechanism of statin action on the endothelium and found that simvastatin attenuated thrombininduced stress fiber formation, paracellular gap formation, and barrier dysfunction [ ] . co-incubation with mevalonate (the product of hmg-coa reductase activity) eliminated the protective effect of simvastatin against thrombin-induced ec permeability, indicating this effect is due to hmg-coa reductase inhibition and did not involve either intracellular increased camp levels or increased levels of endothelial nitric oxide synthase. statins inhibit geranylgeranylation of small gtpases, essential for gtpase interaction with cell membranes [ ] , and translocation of the small gtpases rac and rho to the plasma membrane. ec pretreatment with simvastatin prevented thrombin-induced translocation of rho to the plasma membrane [ ] and simvastatin was found to confer greater protection against thrombin-induced barrier dysfunction than rho inhibition alone. rac inhibition may be protective via decreased activation of nadph oxidase and resultant superoxides that induce barrier dysfunction, and this was also found to be important in simvastatin-induced ec barrier protection [ ] . simvastatin pretreatment resulted in reduced diphosphorylated mlc levels, reduced numbers of stress fibers, increased rac gtpase activation [ ] , cortactin translocation to the ec periphery [ ] , and increased cortical actin and decreased paracellular gap formation after thrombin treatment. unlike s p, simvastatin does not cause an increased baseline ter [ ] . simvastatin elicits changes in ec gene expression with downregulation of caldesmon and the thrombin receptor par- , as well as upregulation of integrin b (known to function in cell-cell adhesion), rac , and gefs, which may regulate rho gtpase activity [ ] . the importance of new protein synthesis to the barrier protective effect of simvastatin was established by the elimination of the protective effect by coincubation of ecs with simvastatin and the protein synthesis inhibitor cycloheximide [ ] . in vivo data from an intratracheal-lps murine model of ali support the in vitro finding that simvastatin is protective of ec barrier function and against markers of inflammatory lung injury compared with controls, with decreased bal neutrophil count and mpo activity, decreased vascular permeability, and a marked reduction of inflammatory histological changes [ ] . investigation of gene expression in lung tissue of mice pretreated with simvastatin in this lps-induced model of ali found that simvastatin caused differential regulation of several families of genes, including inflammatory and immune response genes, as well as nfkb regulation and cell adhesion genes [ ] . simvastatin may prove to be clinically relevant in treating ali, as ali typically has a prolonged course, and treatment with simvastatin along the trajectory of the illness may be beneficial. to this end, a blinded, randomized controlled clinical trial of simvastatin in ali is currently under way. atp is found in abundance in the ec microenvironment and participates in ec barrier regulation, with constitutive release of atp across the ec apical membrane in basal conditions [ , ] . atp reduced ec albumin permeability in a concentration-dependent manner in ecs from a variety of origins, including porcine aorta and pulmonary artery, bovine aorta, and human umbilical vascular endothelial cells [ ] . the mechanism of atp-induced ec barrier enhancement involves g i /g o proteins [ ] but does not involve adenosine receptors [ ] , increased pkc activity, or increases in cyclic gmp levels [ ] . however, atp-induced decreases in ec permeability were found to involve the phospholipase c signaling pathway [ ] , as well as alterations in ec mlc phosphorylation [ , ] . we demonstrated that atp produces ca + -and p / mapk-independent increases in cell-cell interfaces (ve-cadherin staining) and increased thickness and continuity of zona occludens (zo- ) in tjs [ ] , mediated in part via camp-independent activation of protein kinase a (pka). we also noted that atp produced a biphasic effect on mlc phosphorylation, with an initial increase followed by a decrease in levels of phosphorylated mlc. however, the delayed decrease in the levels of phosphorylated mlc was prevented by phosphatase inhibitors, emphasizing the importance of g-protein-mediated phosphatase activity in the atp-induced decrease in mlc phosphorylation and atp-induced barrier enhancement [ ] . similar to s p (as well as hgf, apc, etc.), atp-mediated barrier enhancement required rac-dependent cytoskeletal rearrangement with decreased numbers of central actin stress fibers, increased cortical distribution of actin, peripheral mlc phosphorylation, and cortactin translocation to the cortical actin ring [ ] . in addition, a rapid, transient increase in mlc diphosphorylation was observed after atp stimulation, with phosphorylated mlc localized at the cell periphery, a stark contrast to the central, stress-fiber-associated phosphorylated mlc seen in ecs treated with thrombin [ ] . as an extension of these in vitro studies, the effect of purinergic stimulation was assessed in a murine model of ali with intratracheally administered lps. as atp is rapidly degraded intravascularly, the nonhydrolyzable analogue atpgs was used for in vivo studies. mice given atpgs intravenously concomitant with intratracheal administration of lps were protected from lps-induced ali compared with controls as assessed by neutrophil infiltration and mpo activity [ ] . atpgs also attenuated the lung microvascular permeability elicited by lps, with decreased bal protein and decreased evans blue-albumin extravasation in mice treated with atpgs compared with controls [ ] . atpgstreated animals were also protected from the lps-induced decrease in body weight that was seen in control mice [ ] . in addition, in vitro studies found that atpgs alone produced an increased ter in ecs and also showed delayed protection against the reduction in ter caused by lps [ ] . alterations in vascular permeability are requisite steps in the angiogenic process [ , ] . we were the first to report that hgf, a well-known angiogenic factor, like s p, is a potent ec barrier-protective agonist [ ] and acts via stabilization of the ec actin cytoskeleton. hgf-mediated ec protection from the barrier-disrupting effect of thrombin [ ] evolves via increased rac activation involving the racspecific gef tiam as well as decreased rho activation with increased pak phosphorylation [ ] . hgf signals via a tyrosine kinase receptor, c-met, and serves to recruit cd v , a key transactivated receptor for cd , into caveolin-enriched microdomains (cems) or lipid rafts [ ] . in experiments using sirna, both c-met and cd were found to be important in hgf-induced increases in ec ter [ ] . furthermore, pretreatment of ecs with the ceminterfering compound methyl-b-cyclodextran also prevented hgf-induced increases in ter [ ] . in addition, rac activation by hgf was found to require cem formation, c-met, cd , tiam , and dynamin- [ ] . in a mouse model of lps-induced ali, hgf was protective against markers of lung inflammation, an effect not noted in cd knockout mice [ ] . the signaling mechanism involved in hgfinduced ec barrier enhancement is complex, with important roles for c-met, cd , and cem formation. hgf produced rac-dependent increases in the levels of cortical actin, cortactin translocation, and cortical levels of phosphorylated mlc [ ] . further mechanistic studies found that hgfinduced ec barrier enhancement critically involves pi- -kinase activity, distinguishing the mechanism of hgfinduced barrier enhancement from that of s p [ ], with important roles for mapks (erk and p ) and pkc in hgf-induced ec barrier enhancement [ ] . attention to the role of improved cell-cell or cell-matrix adhesion elicited by hgf found that hgf produced increased b-catenin localization to the ec periphery alongside cortical actin and increased association of b-catenin with ve-cadherin [ ] . the cell signaling effectors of hgf (pi- -kinase, erk, p , pkc) were found to converge at phosphorylation of glycogen synthase kinase- b, which regulates the association of b-catenin and cadherin, thereby controlling cell-cell adhesion [ ]. apc is a serine protease that modulates coagulation and inflammation. in , the food and drug administration approved xigris ® , or recombinant human apc (rhapc), also known as drotrecogin alfa (activated), for treatment of severe sepsis in adults after a randomized trial found a -day survival benefit in treated patients [ ] . because severe sepsis involves ali and systemic increased vascular permeability, the effect of apc on pulmonary ec permeability is intriguing. interest in the effect of the anticoagulant apc on ec permeability is also related to the well-described role of the procoagulant thrombin in ec barrier disruption. furthermore, the mechanism of the survival benefit imparted by treatment with rhapc is unclear, as apc given to human subjects in the setting of endotoxin infusion improved hemodynamics but did not have an anti-inflammatory or antithrombotic effect [ ] , suggesting that a different mechanism may be involved. we demonstrated that apc prevented and was able to reverse thrombin-induced increased permeability [ ] . apc also increased mlc phosphorylation and the level of actin at the ec periphery and decreased the number f central stress fibers. the barrier-enhancing effect of apc was found to be mediated by rac activation, similar to the barrier-enhancing effect of s p, simvastatin, and hgf [ ] . the endothelial protein c receptor (epcr) is critical to apc-induced barrier enhancement and mlc phosphorylation. furthermore, epcrmediated transactivation of the s p receptor via pi- -kinase is essential and involves direct interaction between epcr and s p receptor [ ] . this novel pathway for apc-induced ec barrier enhancement may contribute significantly to the survival benefit offered by rhapc in patients with severe sepsis. more recent work has focused on apc in animal models of ali. using a rat model of intestinal ischemia-reperfusion injuryinduced ali, investigators found that apc treatment just prior to reperfusion attenuated subsequent pulmonary edema, which was accompanied by fewer neutrophils on histological examination and a marked improvement in the histological appearance compared with animals that did not receive apc [ ] . in addition, rats treated with apc prior to intestinal reperfusion had lower serum levels of tnf-a, il- , and d-dimer compared with controls [ ] . investigation of apc in a mouse model of vili found that apc pretreatment was protective against vili caused by high tidal volume ventilation, with mice pretreated with apc exhibiting significant reductions in bal protein and evans blue dye extravasation compared with controls [ ] . oxidized phospholipids are derived from oxidized low-density lipoproteins and have been the focus of much investigation in the areas of vascular injury and inflammation [ ], with increased levels noted in ali [ ] . oxidized phospholipids resulting from the oxidation of oxpapc activate mapks erk, and c-jun n-terminal kinase, but not p or its downstream target, hsp [ ], and increased the activity of both pkc and pka [ ] and src kinases, processes involved in oxpapc-mediated ec barrier enhancement, whereas rho, rho kinase, erk, p , and pi- -kinase were not involved [ ] . furthermore, oxpapc resulted in phosphorylation of the actin-binding protein cofilin as well as phosphorylation of the focal adhesion proteins fak and paxillin, indicating that oxpapc may affect the ec actin cytoskeleton and cellcell adhesions [ ] . oxpapc protects against ec barrier dysfunction in vitro [ , ] after thrombin and lps stimu lation [ ] . oxpapc accentuates peripheral f-actin in a unique, ziplike configuration [ , , ] and results in continuous focal adhesions with accumulation of b-catenin [ ] . the signaling pathways involved in oxpapc-mediated endothelial barrier protection involve rac and cdc [ ] , the rac effector pak [ ] , the upstream rac/cdc specific gefs tiam and bpix [ ] , and the actin-binding proteins cortactin and arp [ ] . oxpapc was found to cause a novel interaction between focal adhesion and aj complexes, a process mediated by association of paxillin and b-catenin and dependent upon rac and cdc [ ] . in vivo studies have shown that intravenous oxpapc delivery results in significant attenuation of lps-induced inflammation in a rat model [ ] and vili [ ] . oxpapc protects ecs from mechanical-stress-induced injury via cytoskeletal rearrangements and changes in rho and rac activation and remains a potential therapy for the profound pulmonary edema associated with inflammatory states. methylnaltrexone (mntx) is a peripherally restricted mu opioid receptor (mop-r) antagonist recently approved by the food and drug administration for the treatment of postoperative ileus and also recently found to work synergistically with -fluorouracil and bevacizumab to inhibit vegf-induced pulmonary ec proliferation and migration [ ] . antagonists of mop-r are of interest as potential ec barrier-enhancing agents because of the barrier-disruptive properties of the mop-r agonist morphine [ ] . pretreatment of human pulmonary microvascular ecs with . mm mntx was found to protect against the decrease in ter caused by the mop-r agonists morphine and damgo and also protected against the barrier-disruptive effects of thrombin and lps, which act independently of mop-r [ ] . mntx augments the barrier-enhancing effect of s p [ ] . ec pretreatment with naloxone, a charged mop-r antagonist, protected against morphine and damgo-induced barrier disruption, but was not protective against barrier disruption caused by thrombin or lps. these data, together with the observation that sirna targeting mop-r had a minimal effect on mntxinduced protection against thrombin and lps, suggest that the protective effect of mntx cannot be attributed to mop-r antagonism alone [ ] . further experiments found that mntx confers its barrier-protective effect by inhibiting the association of the rhoa-activating gef p rhogef with the s p receptor and resultant rhoa activation that is caused by barrier-disrupting agents [ ] . complementary in vivo experiments found that intravenous administration of mntx after ali had been established via intratracheal administration of lps was protective against ali at h, as assessed by histological examination and bal protein and tnf-a levels [ ] . as noted already, pbef is a biomarker in sepsis and sepsisinduced ali and intratracheal injection of recombinant pbef into mice results in increased lung inflammation and vascular permeability [ , ] , indicating that extracellular pbef promotes endothelial barrier dysfunction. intracellular pbef may have a contrasting beneficial response in ali function via effects on cell apoptosis. neutrophils in sepsis patients increase expression of pbef, which promotes cell survival through the enzymatic process of nad biosynthesis via nicotinamide phosphoribosyltransferase (nampt) activity, a feature cancer cells have utilized to prevent cell death. the nampt inhibitor fk- is currently in trials as a cancer drug to promote apoptosis. thus, pbef therapies are complicated, with intracellular pbef appearing to have beneficial effects in cells by promoting cell survival, whereas extracellular pbef appears to induce inflammatory response. to specifically target extracellular pbef that may induce deleterious cellular response, we generated neutralizing antibodies against pbef to act as a molecular sponge for extracellular pbef without altering intracellular pbef function, which may be beneficial for the cell. using a mouse model of lung injury, we demonstrated that the anti-pbef neutralizing antibodies significantly protected lungs from vili by reducing the availability of extracellular pbef from sensitizing the lung endothelium [ ] . the study implicates pbef as a key inflammatory mediator intimately involved in both the development and the severity of ventilator-induced ali and demonstrated that anti-pbef neutralizing antibody has potential clinical utility. various molecules participating in the activation of inflammation in ali serve as indicators for the progression of normal to pathological biological processes, providing important tools to detect disease and support diagnostic and therapeutic decisions. ideally, vascular biomarkers have strong correlation between the presence/absence of a disease state and clinical outcome and provide predictive points of intervention to slow or reverse the disease. furthermore, the indication of a specific biomarker may allow for customized therapies that are more effective in different phases of the disease. new research and novel understanding of the molecular mechanisms of ali have revealed an abundance of exciting new biomarkers with high potential value as prognostic tools ( table ) . cofactor in the thrombin-induced activation of protein c in the anticoagulant pathway reduced plasma thrombomodulin level is predictive of higher mortality and worse system dysfunction [ , ] pai- inhibitor of plasminogen activator in plasma pai- level increase is predictive of death [ , ] sicam- marker of ec activation; adhesion molecules icam- level increase is predictive of death [ , ] il- cytokine; inflammation il- level increase is predictive of death [ , ] cytokine; inflammation secretion of extracellular pbef upon mechanical stress induces pulmonary edema and neutrophil extravasation in mice [ , ] icam- intercellular adhesion molecule- , interleukin, pai- plasminogen activator inhibitor- , sicam- soluble intercellular adhesion molecule- the importance of sphingolipids to maintain physiological vascular integrity has been well established and thrombocytopenia, a clinical condition in which there is a deficient number of circulating platelets, is associated with increased vascular leak [ ] via an unknown mechanism. activated platelets are an important source of s p and contain significant levels of sphingosine kinase but reduced levels of sphingosine lyase, thereby serving as enriched sources for the barrier-promoting s p [ ] which directly enhance barrier function via s p ligation [ ] . although the role of s p at physiological concentration is critical to maintaining normal endothelial barrier function, the differential ligation to s p receptors has differential responses. in contrast to the ligation to s p , the ligation of s p induces endothelial barrier dysfunction via activation of rho-dependent actin stress fiber and cell-cell gap formation. recently, we discovered that culture of ecs challenged with barrier-disrupting agents induces tyrosine nitration of s p receptors, which are released into media in microparticles or exosomes [ , ] . the occurrence of protein tyrosine nitration under disease conditions is now firmly established and represents a shift from the physiological signaling actions of •no to oxidative and potentially pathogenic pathways. protein tyrosine nitration is an irreversible ptm mediated by reactive nitrogen species, a process that suggests the regulatory function of proteins that undergo phosphorylation in signal transduction cascades might be seriously compromised by peroxynitrite-promoted nitration. we explored s p as a potential biomarker and observed from immunoblot analysis of serum from mice exposed to various models of vascular injury that they had significant tyrosine-nitrated s p expression [ , ] . in addition, we examined serum from patients with sepsis and ali and discovered tyrosine-nitrated s p receptor was correlated with disease progression [ , ] . therefore, our data indicate tyrosine-nitrated s p receptor is released from challenged ecs in microparticles and serves as a novel biomarker for vascular injury in various disease models. the family of pmn chemotactic cytokines, known as the cxc chemokines have been described and characterized and include il- , gro-a, gro-b, gro-g, ena- , and granulocyte chemotactic peptide (gcp)- . these chemokines are all produced by human alveolar macrophages and contain a glutamylleucyl-arginine (elr) motif that is critical to their neutrophil binding and chemotactic functions [ ] . il- is present in biologically significant concentrations in bal fluid from patients with ards, tracking pmn concentrations [ ] . although gro-a and ena- concentrations are higher than il- concentrations, il- is the predominant chemoattractant in ards bal fluid via its high-affinity binding to cxc chemokine receptors, cxcr and cxcr , on human pmns. unlike ena- , gro-a, gro-b, and gro-g with a high-affinity binding only to cxcr , il- and gcp- can bind to either receptor with high affinity [ ] . in the presence of a systemic inflammatory process such as severe sepsis, cxcr is tonically downregulated and the function of only cxcr receptor predominates [ ] . thus, of the multiple neutrophil chemotactic factors produced in humans, there appears to be a small group that is particularly relevant to patients with ards, with il- and its cognate receptor cxcr being the dominant receptor-ligand pair. il- also binds to its circulating high-affinity polyclonal igg and igg autoantibodies naturally [ ] , therefore preventing binding to cxc chemokine receptors on pmns [ ] . these autoantibodies are present in lung fluids from patients who are at-risk for ards as well as in patients after the onset of ards. the ratio of il- autoantibody:cytokine complex was significantly higher at the onset of ards than in patients at risk for ards. in addition, patients with ards with an elevated anti-il- -autoantibody:il- complex ratio are more likely to die than patients with lower concentrations of anti-il- -autoantibody:il- complex [ ] . thus, the anti-il- -autoantibody:il- complex ratio in lung fluid samples was more revealing than lung fluid protein concentrations to predict the development of ards in patients who were at-risk, and also for predicting mortality in patients with ards [ ] . the protein c pathway is one of the most important regulators of blood coagulation and serves as a critical link between coagulation and inflammation in sepsis and ali [ ] [ ] [ ] . protein c is a vitamin-k-dependent plasma glycoprotein that is synthesized by the liver and circulates as a two-chain biologically inactive zymogen. it is transformed to its active form, apc, by the thrombomodulin-thrombin complex on the cell surface. apc suppresses further thrombin formation by proteolytically inactivating coagulation factors va and viiia [ ] . the membrane-bound epcr potentiates this activation about -fold [ ] . recent evidence suggests that, in addition to its anticoagulant effects, apc also has anti-inflammatory properties. thus, the protein c pathway is important for the control and modulation of both coagulation and inflammation [ ] . apc inhibits the production of tnf-a via nfkb activation in monocytes and ecs [ ] , and inhibits neutrophil activation and chemotaxis through interaction with a cell-surface receptor similar to the epcr [ ] . decreased protein c activation on the pulmonary vascular endothelium surface may contribute to the widespread microvascular thrombosis that occurs in the acutely injured lung and may also be proinflammatory and proapoptotic. administration of apc attenuates experimental sepsis-induced lung injury. in human studies, an infusion of apc h prior to and h after administration of an intravenous injection of lps prevented lps-induced increase in tissue factor expression and thrombin formation in plasma after lps injection, as well as circulating levels of il- or tnf-a, markers of inflammation [ ] . loss of thrombomodulin and epcr from the cell surface results in a decreased ability to activate protein c, a phenomenon that has been implicated in the pathogenesis of sepsis and lung injury. release of the protein c pathway components throm-bomodulin and epcr into the plasma has been reported in experimental sepsis models [ ] . in clinical studies, plasma protein c levels were reduced in patients with severe sepsis, with % of patients meeting the criteria for acquired protein c deficiency. low levels of protein c were associated with ventilator dependency and a higher prevalence of ards and correlated with higher mortality [ ] . another study demonstrated that patients with severe sepsis varied markedly in their ability to generate apc [ ] . modulation of coagulation and inflammation through the activation of protein c is a critical mechanism in the pathogenesis of sepsis and ali [ ] . protein c levels and thrombomodulin levels are lower early in the course of ali and reduced plasma protein c and thrombomodulin levels are associated with higher mortality and more nonpulmonary organ system dysfunction, with the combination of low levels of protein c and other predictors such as high levels of plasminogen activator inhibitor- (pai- ) conferring an even higher risk of mortality. the prognostic value of protein c and thrombomodulin was not altered by exclusion of patients with coexisting sepsis [ ] . the balance between activation of coagulation and activation of fibrinolysis is likely an important determinant of the amount and duration of fibrin deposition in the injured lung, and the fibrinolytic system is profoundly altered in patients with ali/ards, both systemically and in the alveolar compartment. plasminogen activator (pa) and pai- regulate fibrinolysis, the dissolution of fibrin clots, through modulation of the conversion of plasminogen to plasmin, a major fibrinolytic enzyme [ ] . upregulation of pai- , the major inhibitor of fibrinolysis, appears to play a primary role in the shift from profibrinolytic to antifibrinolytic phenotypes in a variety of cell types, including ecs, indicating a risk factor for ali and sepsis. there are two forms of pa, urokinase-type pa (upa) and tissue-type pa (tpa). upa is a cell-surface protein that is responsible for activating fibrinolysis at the tissue level, whereas tpa is a soluble protein that activates intravascular fibrinolysis [ ] . two major endogenous pa inhibitors have been identified, pai- and pai- , which are produced by platelets, endothelial, mesothelial, and epithelial cells, including those of the lung [ ] . pai- is the major pa inhibitor in plasma and extravascular fluids and has been implicated in the fibrinolytic defect associated with ali [ ] . human lung ecs isolated from patients with ards constitutively express greater levels of pai- than controls with lower fibrinolytic potential as measured by the pa to pai- ratio. in limited ali/ards clinical studies, reduced fibrinolytic capacity and an increase in upa and in pai- activity was noted in ards patents, with levels of pai- higher in both pulmonary edema fluid and plasma of ali/ards patients, and correlated with mortality in patients with ali/ ards [ , ] . a variety of strategies are being explored to develop inhibitors of pai- that might be of therapeutic use in ali/ards or other diseases associated with high levels of pai- such as cardiovascular disease [ ] . intercellular adhesion molecule- (icam- ; cd ) is an adhesion molecule constitutively expressed in the normal lung and is a critical participant in pulmonary innate immunity [ ] . soluble icam- (sicam- ) represents a circulating form of icam- that is constitutively expressed or is inducible on the cell surface of different cell lines [ ] . structurally, icam- belongs to the immunoglobulin superfamily, serving as a counterreceptor for the leukocyte integrin lfa- . interaction between icam- , present on ecs, and lfa- facilitates leukocyte adhesion and migration across the endothelium; however, sicam- binding to lfa inhibits lymphocyte attachment to ecs [ ] . sicam- is found in bal fluid and the release of sicam- is induced by several cytokines and various factors, including il- , il- , tnf-a, interferon-g, and angiotensin ii via proteolytic cleavage of icam- or direct transcription from its messenger rna [ ] . studies correlating sicam- levels to disease have led to the identification of sicam- as a marker for diseases such as viral infections, autoimmune disease, atherosclerosis, coronary heart disease, cancers, and neurological disorders [ ] . increased bal sicam- has been described in adults with granulomatous lung diseases such as sarcoidosis, tuberculosis [ ] , hypersensitivity pneumonitis, and radiation pneumonitis [ ] , and in children exposed to second-hand smoke [ ] . importantly, the level of sicam- is increased in pediatric ards during high-frequency oscillatory ventilation [ ] and in ali patients [ ] . il- , a well-recognized ali candidate gene and ali biomarker [ , ] , and is produced by a wide range of cells, including ecs, in response to stimulation by endotoxin, il- b, and tnf-a [ ] . il- in the acute-phase response stimulates synthesis of c-reactive protein from hepatocytes in vitro and in vivo [ ] . elevated levels have been described in acute conditions such as burns, major surgery, and sepsis and may predict development of multiple organ failure and the severity of ards of different orgins, such as sepsis and acute pancreatitis [ ] . the elevation of the level of and persistence of circulating il- has been associated with increased mortality in critically ill patients with ards, sepsis, and trauma, and il- concentrations have been shown to be elevated in the bal fluid from patients with established severe ali [ ] . functional polymorphisms in the promoter region of the il- gene exist (g c), with the c allele associated with reduced gene promoter activity, lower circulating il- concentrations, and a lower mortality rate in patients with acute respiratory failure admitted to the icu [ ] . in the multispecies ali studies performed, significant il- gene expression across all species as well as differential region-specific expression in the canine ali model has been noted. all of these facts suggest that the role of il- in ali is complex and il- may have a dual role in the temporal response to sepsis and mechanical stress. the pbef gene is one of a handful of genes with extremely high level of expression across the range of ali models used and in human ali samples. whereas we were the first to report that pbef is significantly upregulated in the lung as well as in models of lung injury [ ] , the published literature on pbef is quite sparse [ , ] . this gene encodes for a proinflammatory cytokine, originally described for its role in the maturation of b-cell precursors, with gene expression upregulated in amniotic membranes from patients undergoing premature labor, especially with amniotic infections. pbef protein levels were significantly increased in both bal fluid and serum of human, murine, and canine ali models as well as in cytokine-or cs-activated lung microvascular endothelium [ , ] . triple immunohistochemical staining of canine lungs revealed colocalization of increased pbef expression in lung endothelium, type ii alveolar epithelial cells, and infiltrating neutrophils, as well as upregulation of pbef expression in inflammatory cytokine-stimulated human pulmonary microvascular ecs in vitro [ ] . these results support pbef as a potential biomarker in ali and potentially involved in inflammatory lung processes, a notion supported by recent studies in patients with sepsis which convincingly demonstrate that pbef inhibits neutrophil apoptosis [ , ] . common variants in the human pbef gene are also confirmed to be associated with susceptibility to sepsis-associated ali [ ] . the t allele in the c- t single-nucleotide polymorphism in the pbef promoter region was associated with a nearly twofold decrease in the reporter gene expression. this result is consistent with our observations from animal models of ali, human patients with ali, and in vitro cell culture experiments, and suggests that higher expression of pbef is implicated in the pathogenesis of ali. these results further suggest that genetically determined increased pbef expression contributes to susceptibility to ali. despite decades of frustration in the pursuit of potent barrierregulatory therapies, progress has now been made for alleviation of the human suffering associated with uncontrolled lung vascular leakage and alveolar flooding. novel biologically compatible agents have now been identified which can preserve or restore vascular integrity, leveraging new insights into the mechanisms which govern the integrity of the vascular endothelium, particularly the role of cytoskeletal linkages to junctional proteins. in addition, several endothelial target proteins or protein pathway participants also serve as potentially novel biomarkers in the management of these patients. the newly revised scientific armamentarium offers promise for the future management of pulmonary edema associated with increased vascular leak in the critically ill as well as other lung conditions which exhibit strongly dysregulated barrier function such as radiation pneumonitis, acute chest syndrome in sickle cell patients, and in subacute inflammatory disorders such as asthma. nearly each barrier-regulatory agent discussed herein has been successfully evaluated in preclinical models of ali and one agent, fty , is in phase iii trials, whereas three agents, statins, apc and mntx, are currently approved by the food and drug administration for other medical conditions. thus, the prospects for the rapid translation of these lung vascular barrier-protective strategies to clinical practice are high. additional translational bench-to-bedside genomic and genetic strategy approaches combined with dissection of the basic mechanisms of endothelial structure/function during inflammation will lead to greater specificity in advancing clinical trials of agents for the treatment of inflammatory lung injury in a manner which represents personalized medicine for critically ill individuals. ( ) pathophysiology of acute lung injury and the acute respiratory distress syndrome the acute respiratory distress syndrome attenuation of rodent lung ischemia-reperfusion injury by sphingosine -phosphate protective effects of simvastatin in a murine model of radiation-induced lung injury (rili) simvastatin attenuates radiation-induced lung injury and dysregulated lung gene expression a common cortactin gene variation confers differential susceptibility to severe asthma functional variant of the sphingosine- -phosphate receptor gene associate with asthma susceptibility in vivo versus in vitro oviductal glycoprotein (ogp) association with the zona pellucida (zp) in the hamster and baboon studies on inflammation. . the effect of histamine and serotonin on vascular permeability: an electron microscopic study studies on inflammation. ii. the site of action of histamine and serotonin along the vascular tree: a topographic study differential effect of mlc kinase in tnf-alpha-induced endothelial cell apoptosis and barrier dysfunction role of ca + /calmodulin-dependent phosphatase b in thrombininduced endothelial cell contractile responses the role of protein kinase c in alphathrombin-mediated endothelial cell activation vimentin function in lymphocyte adhesion and transcellular migration cytoskeletal regulation of pulmonary vascular permeability role of endothelial cell cytoskeleton in control of endothelial permeability thrombin-induced increase in albumin permeability across the endothelium regulation of endothelial cell gap formation and paracellular permeability differential regulation of diverse physiological responses to vegf in pulmonary endothelial cells critical role for non-muscle mlck in ventilator-induced lung injury (vili) novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury a variant of the myosin light chain kinase gene is associated with severe asthma in african americans h o and genistein differentially modulate protein tyrosine phosphorylation, endothelial morphology, and monolayer barrier function chronic granulomatous disease: more than the lack of superoxide? redox signaling in the lungs glutathione, stress responses, and redox signaling in lung inflammation lung ischemia: endothelial cell signaling by reactive oxygen species. a progress report inflammatory cells and oxygen radicals reactive oxygen species in pulmonary inflammation by ambient particulates reactive oxygen species in cell signaling role of ca + in diperoxovanadate-induced cytoskeletal remodeling and endothelial cell barrier function hyperoxiainduced nad(p)h oxidase activation and regulation by map kinases in human lung endothelial cells oxidant stress and endothelial cell dysfunction protein kinase c modulates pulmonary endothelial permeability: a paradigm for acute lung injury signal transduction and regulation of lung endothelial cell permeability. interaction between calcium and camp leukocyte-induced microvascular permeability: how contractile tweaks lead to leaks clearance of thrombin from circulation in rabbits by high-affinity binding sites on endothelium. possible role in the inactivation of thrombin by antithrombin iii thrombin receptor activating peptides induce ca + mobilization, barrier dysfunction, prostaglandin synthesis, and plateletderived growth factor mrna expression in cultured endothelium molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation abrogation of thrombininduced increase in pulmonary microvascular permeability in par- knockout mice isoproterenol reduces thrombin-induced pulmonary endothelial permeability in vitro enzymatic activity is necessary for thrombin-mediated increase in endothelial permeability cytokine regulation of endothelial cell function: from molecular level to the bedside the role of p map kinase in tumor necrosis factor-induced redistribution of vascular endothelial cadherin and increased endothelial permeability tnf-a increases tyrosine phosphorylation of vascular endothelial cadherin and opens the paracellular pathway through fyn activation in human lung endothelia pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury pre-b-cell colonyenhancing factor as a potential novel biomarker in acute lung injury pre-b-cell-colonyenhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregulation visfatin: a protein secreted by visceral fat that mimics the effects of insulin activated protein c mediates novel lung endothelial barrier enhancement: role of sphingosine -phosphate receptor transactivation molecular cloning and characterization of canine pre-b-cell colony-enhancing factor essential role of pre-b-cell colony enhancing factor in ventilator-induced lung injury the endothelium in acute lung injury/ acute respiratory distress syndrome the discovery of ace and its role in acute lung injury captopril decreases plasminogen activator inhibitor- in rats with ventilatorinduced lung injury role of the renin-angiotensin system in ventilator-induced lung injury: an in vivo study in a rat model angiotensinconverting enzyme inhibitor captopril attenuates ventilator-induced lung injury in rats implementation of intussusceptive microvascular growth in the chicken chorioallantoic membrane (cam): . pillar formation by folding of the capillary wall role of the flt- receptor tyrosine kinase in regulating the assembly of vascular endothelium vegf-targeted therapy: mechanisms of anti-tumour activity janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension discovery of vascular permeability factor (vpf) diverse effects of vascular endothelial growth factor on human pulmonary endothelial barrier and migration vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome basal and angiopoietin- -mediated endothelial permeability is regulated by sphingosine kinase- circulating angiopoietin correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome vascular endothelial growth factor and related molecules in acute lung injury role of cyclic adenosine monophosphate in the induction of endothelial barrier properties regulation of endothelial barrier function by the camp-dependent protein kinase role of campdependent protein kinase a activity in endothelial cell cytoskeleton rearrangement protein kinase a attenuates endothelial cell barrier dysfunction induced by microtubule disassembly sphingosine -phosphate promotes endothelial cell barrier integrity by edg-dependent cytoskeletal rearrangement cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin endothelial cell barrier enhancement by atp is mediated by the small gtpase rac and cortactin epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via cdc and rac transactivation of sphingosine -phosphate receptors is essential for vascular barrier regulation. novel role for hyaluronan and cd receptor family cdc regulates the restoration of endothelial adherens junctions and permeability prostaglandins pge and pgi promote endothelial barrier enhancement via pkaand epac /rap -dependent rac activation vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase akt phosphoinositide -kinase, src, and akt modulate acute ventilation-induced vascular permeability increases in mouse lungs control of camp in lung endothelial cell phenotypes. implications for control of barrier function myosin light chain kinase in endothelium: molecular cloning and regulation a differentiation-dependent splice variant of myosin light chain kinase, mlck , regulates epithelial tight junction permeability the non muscle light chain kinase isoform is a viable molecular target in acute inflammatory lung injury in vitro and in vivo modulation of vascular barrier integrity by sphingosine -phosphate: mechanistic insights sphingosine -phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis preservation of vascular integrity in organs perfused in vitro with a platelet-rich medium role of sphingosine- phosphate in the enhancement of endothelial barrier integrity by platelet-released products induction of endothelial cell chemotaxis by sphingosine -phosphate and stabilization of endothelial monolayer barrier function by lysophosphatidic acid, potential mediators of hematopoietic angiogenesis endothelial cell barrier regulation by sphingosine -phosphate sphingosine -phosphate-induced mobilization of intracellular ca + mediates rac activation and adherens junction assembly in endothelial cells quantitative proteomics analysis of human endothelial cell membrane rafts: evidence of marcks and mrp regulation in the sphingosine -phosphate-induced barrier enhancement regulation of the micromechanical properties of pulmonary endothelium by s p and thrombin: role of cortactin s p induces fa remodeling in human pulmonary endothelial cells: role of rac, git , fak, and paxillin protective effects of sphingosine -phosphate in murine endotoxin-induced inflammatory lung injury sphingosine -phosphate reduces vascular leak in murine and canine models of acute lung injury s p receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by tnf immune cell regulation and cardiovascular effects of sphingosine -phosphate receptor agonists in rodents are mediated via distinct receptor subtypes fty , a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine -phosphate receptors fty versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study pulmonary endothelial cell barrier enhancement by fty does not require the s p receptor effect of s p receptor agonists on murine lung inflammation synthetic analogues of fty [ -amino- -( -[ -octylphenyl]ethyl)- , -propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro synthetic analogues of fty regulate pulmonary vascular permeability in vivo and in vitro the effect of statins on mortality in patients with bacteremia association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome hmg-coa reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis simvastatin improves disturbed endothelial barrier function endothelial cell barrier protection by simvastatin: gtpase regulation and nadph oxidase inhibition simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury signaling pathways involved in adenosine triphosphate-induced endothelial cell barrier enhancement extracellular atp signaling and p x nucleotide receptors in monolayers of primary human vascular endothelial cells atp reduces macromolecule permeability of endothelial monolayers despite increasing [ca + ] i atp induces dephosphorylation of myosin light chain in endothelial cells atp antagonism of thrombin-induced endothelial barrier permeability protective effect of purinergic agonist atpgs against acute lung injury hgf attenuates thrombin-induced endothelial permeability by tiam -mediated activation of the rac pathway and by tiam /racdependent inhibition of the rho pathway cd regulates hepatocyte growth factor-mediated vascular integrity. role of c-met, tiam /rac , dynamin , and cortactin efficacy and safety of recombinant human activated protein c for severe sepsis effects of drotrecogin alfa (activated) in human endotoxemia activated protein c attenuates intestinal reperfusioninduced acute lung injury: an experimental study in a rat model activated protein c protects against ventilator-induced pulmonary capillary leak signaling pathways involved in oxpapc-induced pulmonary endothelial barrier protection oxidized phospholipids reduce ventilator-induced vascular leak and inflammation in vivo oxidized phospholipids reduce vascular leak and inflammation in rat model of acute lung injury protective effects of oxidized phospholipids on ventilator-induced lung injury tiam and bpix mediate rac-dependent endothelial barrier protective response to oxidized phospholipids paxillin-b-catenin interactions are involved in rac/cdc -mediated endothelial barrier-protective response to oxidized phospholipids protective effects of oxidized phospholipids on endotoxininduced lung injury synergistic effects of methylnaltrexone with -fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis dual effects of morphine on permeability and apoptosis of vascular endothelial cells: morphine potentiates lipopolysaccharide-induced permeability and apoptosis of vascular endothelial cells attenuation of vascular permeability by methylnaltrexone: role of mop-r and s p transactivation critical role of pbef expression in pulmonary cell inflammation and permeability sphingosine- -phosphate receptor (sip ) is a novel biomarker for acute lung injury and idiopathic pulmonary fibrosis sphingosine- -phosphate receptor (s p ) is a novel biomarker for acute lung injury cytokinemediated inflammation in acute lung injury interleukin (il- ) in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome (ards) and patients at risk for ards granulocyte chemotactic protein- and related cxc chemokines: from gene regulation to receptor usage expression and function of the chemokine receptors cxcr and cxcr in sepsis neutrophil attractant protein- and monocyte chemoattractant protein- in human serum. effects of intravenous lipopolysaccharide on free attractants, specific igg autoantibodies and immune complexes anti-il- autoantibodies in alveolar fluid from patients with the adult respiratory distress syndrome anti-interleukin- autoantibody:interleukin- immune complexes in acute lung injury/acute respiratory distress syndrome anti-interleukin- autoantibodies in patients at risk for acute respiratory distress syndrome acute lung injury and the coagulation pathway: potential role of gene polymorphisms in the protein c and fibrinolytic pathways the protein c pathway the role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome the anticoagulant protein c pathway the endothelial cell protein c receptor augments protein c activation by the thrombin-thrombomodulin complex activated protein c induces the release of microparticle-associated endothelial protein c receptor expression and function of the endothelial protein c receptor in human neutrophils has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia thrombomodulin release in baboon sepsis: its dependence on the dose of escherichia coli and the presence of tumor necrosis factor low levels of protein c are associated with poor outcome in severe sepsis patients with severe sepsis vary markedly in their ability to generate activated protein c prognostic determinants of acute respiratory distress syndrome in adults: impact on clinical trial design the fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome elevated levels of plasminogen activator inhibitor- in pulmonary edema fluid are associated with mortality in acute lung injury post-transcriptional regulation of plasminogen activator inhibitor- by intracellular iron in cultured human lung fibroblastsinteraction of an -kda nuclear protein with the '-utr shedding of soluble icam- into the alveolar space in murine models of acute lung injury soluble intercellular adhesion molecule- (sicam- ): an overview differential regulation of transendothelial migration of thp- cells by icam- / lfa- and vcam- /vla- role of oxidative stress in pulmonary fibrosis circulating markers of endothelial function in cardiovascular disease sicam- as a serum marker in the diagnosis and follow-up of treatment of pulmonary tuberculosis soluble intercellular adhesion molecule (sicam- ) in bronchoalveolar lavage (bal) cell cultures and in the circulation of patients with tuberculosis, hypersensitivity pneumonitis and sarcoidosis bronchoalveolar lavage fluid cellularity and soluble intercellular adhesion molecule- in children with colds plasma soluble intercellular adhesion molecule- (sicam in pediatric ards during high frequency oscillatory ventilation: a predictor of mortality elevated pulmonary edema fluid concentrations of soluble intercellular adhesion molecule- in patients with acute lung injury: biological and clinical significance functional genomic insights into acute lung injury: role of ventilators and mechanical stress il gene-wide haplotype is associated with susceptibility to acute lung injury inflammatory mediators in chronic obstructive pulmonary disease c-reactive protein, inflammation, and innate immunity cytokine balance in the lungs of patients with acute respiratory distress syndrome genetic polymorphisms associated with susceptibility and outcome in ards cloning and characterization of the cdna encoding a novel human pre-b-cell colony-enhancing factor genomic organization of the gene coding for human pre-b-cell colony enhancing factor and expression in human fetal membranes making genomics functional: deciphering the genetics of acute lung injury biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury protein c and thrombomodulin in human acute lung injury key: cord- -sjz mbbr authors: mahida, r. y.; matsumoto, s.; matthay, m. a. title: extracellular vesicles in ards: new insights into pathogenesis with novel clinical applications date: - - journal: annual update in intensive care and emergency medicine doi: . / - - - - _ sha: doc_id: cord_uid: sjz mbbr acute respiratory distress syndrome (ards) is a major cause of acute respiratory failure that develops following several clinical disorders, including pneumonia, sepsis, aspiration and major trauma. despite numerous clinical trials, there is still no effective pharmacotherapy available for ards patients. however, recent research on extracellular vesicles provides new insights into pathogenesis, prognosis, and potential therapeutic options for ards. extracellular vesicles are membrane-bound anuclear structures which constitute a recently recognized and important intercellular communication mechanism, allowing targeted transfer of diverse biologic cargo between different cell types. there is new evidence that extracellular vesicles play an important role in the pathogenesis of ards and also potentially a protective role. in this chapter, we highlight recent translational and clinical studies that have advanced our understanding of the critical role extracellular vesicles play in both inducing and attenuating inflammatory lung injury in ards. this review also considers the wide range of potential clinical applications for extracellular vesicles, ranging from use as biomarkers of lung injury to therapeutic agents for ards. extracellular vesicles represent a new frontier for research in ards. acute respiratory distress syndrome (ards) is an inflammatory disorder of the lungs that can develop following various insults, the commonest being pneumonia. patients develop acute hypoxemic respiratory failure following inflammatory injury to the alveolar epithelium and endothelium [ ] . the precipitating injury can be direct (e.g., pneumonia, aspiration) or indirect (e.g., peritonitis, pancreatitis, shock). our understanding of ards pathogenesis has increased in the years since this syndrome was first described; however, there are many aspects which continue to elude us [ ] . following the same insult, why do some patients develop ards and others do not? how can we predict which critically ill patients are at higher risk of developing ards? advances in ventilation strategies [ ] and fluid management have helped to reduce mortality; however, this still remains unacceptably high at - % [ ] . despite numerous clinical trials, there is still no effective pharmacotherapy available for ards patients. however, the rapidly developing field of extracellular vesicles may provide a major new opportunity for an improved understanding of ards pathogenesis, valuable biomarkers of injury, and targets for new therapies. extracellular vesicles are anuclear structures released by cells and bounded by a phospholipid bilayer membrane. cells can release extracellular vesicles during states of health, injury/activation, and apoptosis. extracellular vesicles can contain diverse cargo, including messenger rna (mrna), micro rna (mir), cytokines, and mitochondria. surface markers on extracellular vesicles can indicate the parent cell from which they were derived, and also determine which cells can incorporate specific extracellular vesicles. we are now beginning to appreciate the role extracellular vesicles play in intercellular communication in health and disease states, facilitating transfer of genetic material, proteins, and organelles between cell types. distinctions between the two main subtypes of extracellular vesicles are based on size and origin: exosomes are smaller (< nm diameter) and may have an endosomal origin. microvesicles are larger (up to μm diameter) and derived from the cell membrane. in this chapter, we highlight recent translational and clinical studies that have deepened our understanding of the role extracellular vesicles play in both mediating and attenuating inflammatory lung injury in ards. we discuss what future directions can be taken to utilize extracellular vesicles as diagnostic or prognostic biomarkers, as targets for novel therapeutics, or as therapeutic agents in their own right ( fig. . fig. . clinical relevance and applications of extracellular vesicles in acute respiratory distress syndrome (ards). representative extracellular vesicle (ev) shown with phospholipid bilayer, surface markers, and cargo. surface markers indicate cell of origin (e.g., cd + /cd b + indicates a neutrophil-derived extracellular vesicle, cd + endothelial-derived, cd + platelet-derived, and cd + epithelial-derived). surface markers from different cell types shown for illustrative purposes; extracellular vesicles will not concurrently express all surface markers shown. extracellular vesicle cargo can include micro rna, messenger rna, mitochondria, and protein (e.g., cytokines). epc endothelial progenitor cell, msc mesenchymal stem cell, tnf-α tumor necrosis factor-α preclinical models of ards have shown that extracellular vesicles released following lung injury can mediate inflammation and have an injurious effect. endothelial injury is often the earliest pathological event leading to the development of ards [ ] . circulating endothelial and leukocyte-derived extracellular vesicles are elevated in the intratracheal lipopolysaccharide (lps) rat model of lung injury [ ] . human endothelial cells also release extracellular vesicles following stimulation with plasminogen-activated inhibitor- [ ] . several studies have reported that intravenous administration of endothelial extracellular vesicles in rodents induced lung injury with alveolar neutrophilic infiltration, pulmonary edema, elevated inflammatory cytokines (myeloperoxidase [mpo] , interleukin [il]- β and tumor necrosis factor [tnf]-α), and increased lung endothelial permeability [ ] [ ] [ ] . these changes were similar to those observed following intratracheal lps injury. endothelial extracellular vesicle treatment of murine or human arterioles impaired nitric oxide release and vasodilation, which partly explains the in vivo findings [ ] . endothelial extracellular vesicles administered concurrently with lps (intratracheal or intravenous) caused a greater increase in alveolar endothelial permeability and inflammatory cytokine release than either lps or extracellular vesicles alone [ , ] . however, when endothelial extracellular vesicles were administered h prior to intravenous lps, the resulting circulating and alveolar inflammatory cytokine release was significantly greater than with concurrent administration of extracellular vesicles and lps. an initial endothelial injury triggered release of endothelial extracellular vesicles, which then primed the lung for a greater inflammatory response when exposed to a subsequent infectious insult. following lps treatment, human endothelial cells release extracellular vesicles containing nitrated sphingosine- -phosphate receptor- (s pr ) [ ] . elevated circulating s pr concentrations are associated with mortality in critically ill sepsis patients, with or without ards. endothelial extracellular vesicles could therefore represent a potential biomarker and/or offer a novel therapeutic target for ards. simvastatin treatment given concurrently with intravenous lps in mice reduced endothelial extracellular vesicle release and lung endothelial permeability [ ] . this is a particularly interesting finding, since a secondary analysis of an ards trial showed that simvastatin reduced mortality in patients with a hyperinflammatory endotype, suggesting that statin therapy was working in part by inhibiting extracellular vesicle release and lung injury [ ] . therefore, therapies aimed at reducing or blocking endothelial extracellular vesicles may attenuate lung injury. recently, the results of studies in the ex vivo perfused human lung model have provided compelling new evidence for the potential role of extracellular vesicles in mediating lung injury in ards. in an ex vivo perfused human lung model of gram negative pneumonia, injury with intrabronchial escherichia coli led to release of extracellular vesicles by lung tissue into the perfusate [ ] ; these extracellular vesicles were predominantly endothelial-and platelet-derived. administration of e. coli-induced extracellular vesicles either into the perfusate or into the air spaces in naïve, uninjured human lungs induced injury similar to the degree of lung injury with e. coli pneumonia: pulmonary edema, impaired alveolar fluid clearance, neutrophilic infiltration, and elevated bronchoalveolar lavage fluid (balf) tnf-α. e. coli-induced extracellular vesicles contained high levels of tnf-α and il- mrna, which explained at least part of their pro-inflammatory effects. monocyte uptake of e. coli-induced extracellular vesicles resulted in increased secretion of tnf-α and il- . high molecular weight hyaluronic acid bound cd on the surface of e. coli-induced extracellular vesicles, thus preventing their uptake by monocytes. intravenous administration of high molecular weight hyaluronic acid to ex vivo human lungs injured with e. coli or e. coli-induced extracellular vesicles attenuated lung injury, pulmonary edema, balf tnf-α levels, and histologic evidence of lung injury. this important study showed that following infectious injury, human lung tissue releases pathogenic extracellular vesicles, which can mediate more severe inflammatory lung injury. the results suggest that strategies to sequester extracellular vesicles could prevent their uptake and biologic cargo delivery to target cells, thereby reducing subsequent inflammatory injury; extracellular vesicle sequestration may therefore offer a therapeutic strategy in ards. ards patients have a higher total concentration of alveolar extracellular vesicles, compared to control patients with hydrostatic edema [ ] . a significant proportion of alveolar extracellular vesicles in ards patients are derived from alveolar epithelial cells; these extracellular vesicles contain higher concentrations of tissue factor and exert a pro-coagulant effect. alveolar epithelial cell-derived extracellular vesicles may therefore also contribute to the increased pro-coagulant activity observed in ards and thereby represent a therapeutic target. different alveolar cell types release extracellular vesicles in sequential order following murine intratracheal lps lung injury [ ] . alveolar macrophage-derived extracellular vesicles are rapidly released first, followed by endothelial extracellular vesicles and then neutrophil extracellular vesicles. this temporal difference in balf extracellular vesicles release by different alveolar cell types may give insight into the pathological mechanisms underpinning ards. alveolar macrophage-derived extracellular vesicle release may subsequently trigger pro-inflammatory extracellular vesicle release by epithelial cells and neutrophils. the alveolar macrophage extracellular vesicles can deliver high concentrations of tnf-α cargo to alveolar epithelial cells, resulting in increased production of the neutrophil chemotactic factor keratinocytederived cytokine (kc) and expression of intercellular adhesion molecule- (icam- ). balf extracellular vesicles generated from intratracheal lps treated mice resulted in lung injury when they were administered intratracheally to naïve mice, with increased alveolar neutrophil infiltration, alveolar protein permeability, and elevated balf kc levels. administration of these pathogenic balf extracellular vesicles caused lung injury similar to lps treatment. alveolar macrophage extracellular vesicles containing tnf-α may play a significant role in instigating the inflammatory cascade in early ards; therefore alveolar macrophage extracellular vesicles should be considered as potential novel biomarkers and/or therapeutic targets. different modalities of lung injury can induce release of extracellular vesicles from different cell types. one group found that following sterile lung injury, most balf extracellular vesicles were derived from type alveolar epithelial cells [ ] . however, following infectious lung injury, most balf extracellular vesicles were derived from alveolar macrophages. balf extracellular vesicles generated from both sterile and infectious lung injury models promoted the recruitment of macrophages to the alveolar space. sterile lung injury balf extracellular vesicles (predominantly alveolar epithelial cell-derived) upregulated toll-like receptor (tlr) and downregulated tlr expression in macrophages. infectious lung injury balf extracellular vesicles (predominantly alveolar macrophage-derived) upregulated tlr on macrophages. differential effects on cytokine release were also observed with balf extracellular vesicles: sterile injury extracellular vesicles upregulated alveolar macrophage release of il- and tnf-α, whereas infectious injury extracellular vesicles upregulated il- β and il- release by alveolar macrophages. balf extracellular vesicles generated following different modalities of lung injury promote inflammation via different pathways. remarkably, mouse models have indicated that release of extracellular vesicles following distant injury, e.g., traumatic brain injury [ ] or trauma and hemorrhagic shock [ ] , can mediate lung injury. following trauma and hemorrhagic shock, gutderived extracellular vesicles were released into the mesenteric lymphatic system. intravenous administration of these extracellular vesicles to naïve mice caused lung injury via macrophage tlr activation, including increased alveolar vascular permeability and inflammatory cell infiltration [ ] . these findings indicate that similar mechanisms may be present in patients who develop ards following similar distant (indirect) insults. this pathway might explain in part the development of neurogenic pulmonary edema as well as lung injury following shock and ischemia-reperfusion. following lung injury, pro-inflammatory mirnas can be transported between cells by extracellular vesicles. one group found that mir- - p was upregulated in balf extracellular vesicles from patients with influenza a-induced ards; these extracellular vesicles were likely alveolar epithelial cell-derived. when influenza a infected alveolar epithelial cells were transfected with mir- - p, this downregulated expression of the antiviral factor mx and increased viral replication [ ] . other investigators found that balf extracellular vesicles contained high concentrations of mir- in intratracheal-lps mice [ ] . transfection of macrophages with mir- was found to upregulate the nucleotide-binding oligomerization like receptor (nlrp ) inflammasome, and stimulate increased release of il- β following lps stimulation. by learning how endogenous extracellular vesicles mediate inflammation and increase endothelial and epithelial permeability, it will be possible to gain greater insight into the protein and rna pathways involved in the pathogenesis of ards. these pathogenic extracellular vesicles can be utilized as diagnostic/prognostic biomarkers, or as targets for novel therapeutic strategies. in the prior section, we discussed the evidence for how extracellular vesicles may contribute to ards pathogenesis; these harmful extracellular vesicles are predominantly derived from specific cell types (endothelium, alveolar epithelial cells, and alveolar macrophages). there is also evidence to suggest that extracellular vesicles from other cell types may have a protective, anti-inflammatory role in the context of ards. clinical studies investigating harmful and protective extracellular vesicles in ards patients are summarized in table . . the data suggest that extracellular vesicles within a given biofluid cannot be considered as a homogenous entity; the origin and cargo of extracellular vesicles from different cell types at different stages of ards are likely to have divergent effects. heterogeneity in cellular function and transcriptome has been shown to impact on patient outcomes in sepsis-related ards [ ] . it is therefore likely that heterogeneity in extracellular vesicle profiles will similarly impact on patient outcome. some clinical studies have reported that total leukocyte extracellular vesicle numbers are associated with a better prognosis in ards patients. an observational study characterized balf and circulating extracellular vesicles from ventilated patients with ards; control groups included ventilated patients without ards, and non-ventilated patients undergoing outpatient bronchoscopy [ ] . the majority ( %) of ards patients had direct lung injury; % had pneumonia. the balf from ards patients contained elevated leukocyte-and neutrophil-derived extracellular vesicles compared to controls. in early ards, elevated balf and plasma concentrations of leukocyte extracellular vesicles were associated with increased survival and ventilator-free days, thus suggesting a potential role for balf and serum leukocyte extracellular vesicles as prognostic biomarkers in early ards. in a separate study, total plasma extracellular vesicle concentrations were measured in critically ill patients on intensive care unit (icu) admission; of these patients subsequently developed ards [ ] . elevated plasma extracellular vesicle concentrations were associated with a lower risk of developing ards; this association was seen most strongly in patients admitted to icu with sepsis. another group of investigators [ ] found that a subset of circulating leukocyte extracellular vesicles expressing α -macroglobulin (a mg) were associated with survival in icu patients with sepsis secondary to pneumonia, but not in patients with sepsis secondary to fecal peritonitis. a mg-ev treatment in vitro reduced endothelial cell permeability and increased bacterial phagocytosis by neutrophils. several studies have revealed a protective role for neutrophil extracellular vesicles in lung injury. binding of neutrophil extracellular vesicles to mer tyrosine kinase (mertk) receptors on macrophages increased secretion of the pro-repair factor tgfβ and decreased secretion of pro-inflammatory cytokines tnf-α and il- [ , ] . therefore, neutrophil extracellular vesicles have an anti-inflammatory effect on macrophages. neutrophil extracellular vesicles containing mir- were found to have an anti-inflammatory effect on alveolar epithelial cells, via suppression of poly(adenosine diphosphate-ribose) polymerase- [ ] . in murine staphylococcal or ventilator-induced lung injury (vili), intratracheal delivery of extracellular vesicles containing mir- reduces inflammatory cytokine release, alveolar protein permeability, and lung injury. infiltration of neutrophils into the alveolar space is a hallmark of ards pathogenesis, and their pro-inflammatory role is established [ ] . however, this evidence suggests that neutrophils may also have a concurrent anti-inflammatory role, via release of extracellular vesicles that modulate alveolar macrophage and alveolar epithelial cell functions. innate mechanisms that inhibit release or promote clearance of pro-inflammatory extracellular vesicles may be present in ards patients. alveolar macrophages can phagocytose inflammatory balf extracellular vesicles via mertk binding, to prevent their uptake by alveolar epithelial cells [ ] . the inflammatory balf extracellular vesicles have a more injurious effect on alveolar epithelial cells compared to alveolar macrophages. as discussed in the previous section, lps-stimulated macrophages release extracellular vesicles containing tnf-α, which can initiate an inflammatory cascade. lps-stimulated alveolar epithelial cells can release il- , which acts on macrophages to suppress release of inflammatory extracellular vesicles containing tnf-α [ ] . strategies to enhance il- signaling or alveolar macrophage phagocytosis of extracellular vesicles may have therapeutic benefit in ards. subsets of leukocyte-derived extracellular vesicles appear to have a protective role in ards, which may be related to delivery of anti-inflammatory mirnas. mechanisms also exist to either inhibit inflammatory extracellular vesicle release or prevent their uptake by susceptible cell types. therapeutic strategies to upregulate innate protective extracellular vesicles or enhance existing protective mechanisms may attenuate inflammation in ards. extracellular vesicles derived from non-pulmonary cell types can have a protective effect in some models of ards. mesenchymal stromal cells (mscs) can attenuate inflammation and lung injury in preclinical models of ards, due to their intrinsic anti-inflammatory abilities [ ] . mesenchymal stromal cells mediate their effects via cell-cell contact and via release of paracrine factors; administration of mesenchymal stromal cell conditioned media was previously shown to attenuate lung injury in intratracheal-lps injured mice [ ] . mesenchymal stromal cell-derived extracellular vesicles isolated from conditioned media attenuated inflammation and lung injury in both intratracheal-lps and e. coli pneumonia models of murine lung injury [ , ] . prophylactic treatment with mesenchymal stromal cell extracellular vesicles increased survival in rats undergoing traumatic lung injury; inflammatory cytokines, infiltrating leukocytes, and pulmonary edema were all reduced [ ] . these effects were in part due to mesenchymal stromal cell extracellular vesicle transfer of mir- [ ] . in a pig model of influenza-induced lung injury, administration of mesenchymal stromal cell extracellular vesicles similarly reduced lung injury, alveolar protein permeability, and inflammatory cytokine release. mesenchymal stromal cell extracellular vesicle treatment of alveolar epithelial cells reduced viral replication and virus-induced apoptosis. in addition, an experimental model of infant respiratory distress syndrome and bronchopulmonary dysplasia in newborn mice showed a therapeutic effect of extracellular vesicles isolated from mesenchymal stromal cells in reducing lung injury and restoring lung function, in part through induction of antiinflammatory and pro-resolving macrophages [ ] . mesenchymal stromal cell extracellular vesicles can transfer mitochondria to alveolar macrophages, inducing a modified m (pro-resolving) phenotype [ ] . mesenchymal stromal cells stimulated with il- β release extracellular vesicles containing mir- a, which also induces an m macrophage phenotype [ ] . these mesenchymal stromal cell extracellular vesicle modified alveolar macrophages have pro-resolving characteristics (increased secretion of anti-inflammatory cytokine il- , reduced secretion of inflammatory cytokines tnf-α and il- ), but also increased phagocytic activity against bacteria [ , , , ] . mesenchymal stromal cell extracellular vesicles modulate alveolar macrophages to clear bacteria more effectively, while minimizing surrounding tissue injury. mesenchymal stromal cell extracellular vesicles also contain mrna for keratinocyte growth factor (kgf) and angiopoetin- , which can be transferred to alveolar epithelial cells and endothelial cells [ , ] , thereby increasing the integrity of the alveolar-capillary barrier. these findings explain the ability of mesenchymal stromal cell extracellular vesicles to restore alveolar fluid clearance in ex vivo human lungs [ ] . in an e. coli pneumonia model using ex vivo human lungs, administration of mesenchymal stromal cell extracellular vesicles reduced bacterial load within the alveolar space, reduced protein permeability, and increased alveolar fluid clearance [ ] . mouse studies indicated that mesenchymal stromal cell extracellular vesicle transfer of mir- to macrophages was responsible for the increased bacterial phagocytosis [ ] . endothelial progenitor cells (epcs) also release extracellular vesicles that have a protective role in lung injury. endothelial progenitor cells release extracellular vesicles containing mir- , which are taken up by endothelial cells [ ] , resulting in enhanced endothelial cell proliferation, migration, angiogenesis, and transepithelial electrical resistance. administration of endothelial progenitor cell extracellular vesicles decreased lung injury, hypoxia, alveolar cell count, protein permeability, pulmonary edema, and inflammatory cytokines in the murine intratracheal-lps model [ , ] . work in human small airway epithelial cells found that mir- could increase expression of tight junction proteins [ ] . therefore, endothelial progenitor cell extracellular vesicles containing mir- have a protective effect on both the epithelium and endothelium in models of ards. mesenchymal stromal cells and endothelial progenitor cells mediate their antiinflammatory and pro-repair effects in part by release of extracellular vesicles, which deliver mirna, mrna, and mitochondrial cargo to different alveolar cell types. administration of mesenchymal stromal cell extracellular vesicles or endothelial progenitor cell extracellular vesicles may therefore offer a novel therapeutic strategy for ards patients. as summarized in fig. . , extracellular vesicles have wide-ranging potential clinical applications in ards. extracellular vesicles from specific cell types could be used as diagnostic or prognostic biomarkers. human endothelial extracellular vesicles can induce lung injury in mice [ ] , and a subset of endothelial extracellular vesicles has been associated with mortality in ards patients [ ] . therefore, endothelial extracellular vesicles could be used as diagnostic and prognostic biomarkers in ards. by understanding how extracellular vesicles mediate intercellular transfer of genetic material, organelles, and proteins between different cell types in the alveolar space, it will be possible to learn how the rna and protein pathways of injury are involved in ards pathogenesis. circulating and balf pathogenic extracellular vesicles offer therapeutic targets in ards. studies have thus far identified endothelial-and alveolar macrophagederived extracellular vesicles as having the ability to induce lung injury [ , ] . therapeutic targeting of pathogenic extracellular vesicles could prevent transfer of pro-inflammatory genetic material and proteins to target cells. nonspecific extracellular vesicle sequestering with hyaluronic acid [ ] would target all extracellular vesicles expressing cd (a widely expressed glycoprotein), but has a potential disadvantage of sequestering both pathogenic and beneficial extracellular vesicles. alveolar macrophages can phagocytose pathogenic extracellular vesicles via mertk receptors, thereby preventing extracellular vesicle uptake by alveolar epithelial cells and subsequent inflammatory injury [ ] . therapeutic strategies to upregulate mertk expression on alveolar macrophages may aid uptake of pathogenic extracellular vesicles and attenuate inflammation in ards. strategies to inhibit pathogenic extracellular vesicle release also require consideration: alveolar epithelial cells can release il- to inhibit the release of pathogenic alveolar macrophage extracellular vesicles [ ] . simvastatin can inhibit the release of pathogenic endothelial extracellular vesicles in murine models of lung injury [ ] and this may be relevant in the setting of ards [ ] . surprisingly, neutrophil extracellular vesicles have been shown to have an anti-inflammatory role in sepsis and ards [ , ] . therefore, strategies to stimulate extracellular vesicle release by neutrophils in vivo or administration of neutrophil extracellular vesicles generated ex vivo could be considered. extracellular vesicles derived from exogenous mesenchymal stromal cells and endothelial progenitor cells mediate the anti-inflammatory actions of the parent cell by delivery of mitochondria, genetic material, and proteins to injured alveolar cells. as described above, therapeutic use of mesenchymal stromal cell extracellular vesicles has shown efficacy at reducing lung injury in several preclinical models. in mouse models of lung injury, mesenchymal stromal cell extracellular vesicles have similar efficacy to mesenchymal stromal cells themselves. finally, exogenous extracellular vesicles could be modified to package custom drugs or protective rna cargo, which could be delivered to specific cell types as determined by the extracellular vesicle surface markers [ ] . several studies that have investigated the role of extracellular vesicles in acute lung injury and ards have been done in animal and in vitro models, although one recent study was done in the ex vivo perfused human lung [ ] , and there are a few clinical studies as well [ , , [ ] [ ] [ ] . future studies will need to characterize balf and circulating extracellular vesicles from ards patients with regard to the cell of origin, cargo assessment (rna, protein, organelle content), and their biological effect on human cells and human tissues. standardized methods of biologic fluid collections and rna isolation from extracellular vesicles are now possible, so that the data will be comparable and generalizable [ ] . extracellular vesicle profiles from ards patients will need to be compared with those from animal models and ex vivo human lung models in order to determine how well the extracellular vesicles released in these models correlate with those observed in the clinical setting of ards. clinical studies to test the utility of extracellular vesicles as diagnostic and prognostic biomarkers in ards patients will be needed. clinical trials of mesenchymal stromal cell extracellular vesicles are needed to determine therapeutic utility in patients with ards as well as infant respiratory distress syndrome and bronchopulmonary dysplasia. extracellular vesicles constitute an important intercellular communication mechanism, which allows targeted transfer of biologic cargo including rna, micro rna, proteins, and mitochondria between different cell types. new evidence indicates that extracellular vesicles are likely to be critical to the induction and resolution of injury in ards. consequently, it is likely that there will be a wide range of clinical applications for extracellular vesicles, ranging from use as biomarkers to therapeutic agents for ards. acute respiratory distress syndrome respiratory support in patients with acute respiratory distress syndrome: an expert opinion epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries the acute respiratory distress syndrome: pathogenesis and treatment isolation and phenotypic characteristics of microparticles in acute respiratory distress syndrome endothelium-derived microparticles induce endothelial dysfunction and acute lung injury endothelial microparticles induce inflammation in acute lung injury administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome sphingosine- -phosphate receptor- is a novel biomarker in acute lung injury simvastatin attenuates acute lung injury via regulating cdc -pak and endothelial microparticles acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial therapeutic effects of hyaluronic acid in bacterial pneumonia in the ex vivo perfused human lungs procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome alveolar macrophage-derived microvesicles mediate acute lung injury functional evidence of pulmonary extracellular vesicles in infectious and noninfectious lung inflammation traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via toll-like receptor proviral micrornas detected in extracellular vesicles from bronchoalveolar lavage fluid of patients with influenza virus-induced acute respiratory distress syndrome increased extracellular vesicle mirna- family in the bronchoalveolar lavage fluid as a precipitating factor of ards heterogeneity in sepsis: new biological evidence with clinical applications high levels of circulating leukocyte microparticles are associated with better outcome in acute respiratory distress syndrome circulating microparticle levels are reduced in patients with ards microvesicle subsets in sepsis due to community acquired pneumonia compared to faecal peritonitis ectosomes released by polymorphonuclear neutrophils induce a mertk-dependent anti-inflammatory pathway in macrophages activated polymorphonuclear neutrophils disseminate antiinflammatory microparticles by ectocytosis neutrophil transfer of mir- to lung epithelial cells dampens acute lung injury in mice neutrophil extracellular traps (nets) are increased in the alveolar spaces of patients with ventilator-associated pneumonia phagocytosis of microparticles by alveolar macrophages during acute lung injury requires mertk lung epithelial cell-derived il- negatively regulates lpsinduced exosome release from macrophages fifty years of research in ards. cell-based therapy for acute respiratory distress syndrome. biology and potential therapeutic value stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action human mesenchymal stem cell microvesicles for treatment of escherichia coli endotoxin-induced acute lung injury in mice therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice prophylactic treatment with msc-derived exosomes attenuates traumatic acute lung injury in rats mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer exosomal mir- a contributes to the enhanced therapeutic efficacy of interleukin- beta-primed mesenchymal stem cells against sepsis mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by ang- mrna microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe e. coli pneumonia mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice exosomes derived from endothelial progenitor cells ameliorate acute lung injury by transferring mir- exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury hyaluronan binding by cell surface cd exosomes from ipscs delivering sirna attenuate intracellular adhesion molecule- expression and neutrophils adhesion in pulmonary microvascular endothelial cells small rna sequencing across diverse biofluids identifies optimal methods for exrna isolation key: cord- - dq gdo authors: kaisy, dr. maythem abdulhassan al title: chest drain insertion following pneumothorax due to cpr in a covid – patient. date: - - journal: visual journal of emergency medicine doi: . /j.visj. . sha: doc_id: cord_uid: dq gdo nan chest drain insertion following pneumothorax due to cpr in a covid - patient. dr. maythem abdulhassan al kaisy, mbchb jmcc.a&em, emergency department, al ain hospital, al ain, uae. chest drain, covid- , pneumothorax, cpr. cardiopulmonary resuscitation (cpr) can sometimes be traumatic to the patient. sternal fractures reported to occur in of resuscitation attempts, while costal fractures occur in of , in addition to causing range of lung injuries such as contusions, pneumothorax and haemothorax ( ) . in covid- patients, lung injuries have been described as pneumocytes desquamation, formation of hyaline membrane, together interstitial lymphocyte infiltration, and multinucleated syncytial cells in the lungs ( ) .those will be shown on chest ct scans and chest x-rays as bilateral patchy shadows or ground glass opacity in the lungs. those patients often have atypical pneumonia, acute lung injury, and acute respiratory distress syndrome (ards). when the latter happens, there will be uncontrolled inflammation with accumulation of fluid, and progressive fibrosis that damages the gas exchange capacity of the lungs ( ). thus, in patients with severe acute respiratory syndrome coronavirus (sars-cov ) infection lungs are fragile and especially those with positive pressure ventilations, the dangers of pneumothorax arise, and comprehensive management is warranted. a years old male patient was transferred to our hospital, intubated on mechanical ventilation, he had a week history of fever, cough and shortness of breath, with positive pcr test for covid- , and ct scan showing extensive bilateral multiple, multilobed ground glass appearance with areas of consolidation, there was no given history of previous lung diseases or smoking history ( figure ). patient was admitted to icu, and was hemodynamically stable, he was started on hydroxychloroquine, favipravir and azithromycin. his blood results shows crp of , ferritin level of , normal renal function and d-dimer of , he was anticoagulated with enoxaparin mg bid. after days in icu, he developed cardiac arrest, cpr continued for minutes and the endotracheal tube was dislodged and re -inserted, rosc achieved, and patient became hypotensive / with heart rate of - . a portable chest x-ray was ordered, and the patient was found to have significant amount of left sided -pneumothorax with underlying lung collapse , mild mediastinal shift to the right side, with progressive course regarding the right side opacities (figure ), compared to previous x-ray. a formal chest drain was inserted in the th intercostal space according to guidelines and a chest x-ray was ordered (figure ) , which showed mild regression of pneumothorax, and still significant amount of pneumothorax remained. we were not sure whether the patient had previous infection with fibrosis, bullae, smoker, or any history indicating previous lung disease, hence we were also unsure whether the pneumothorax was spontaneous or traumatic due to chest compression. patient condition did not get better after chest drain insertion, and he continued to have low bp and tachycardic, further needle decompression was done, and chest drain was manipulated, and another chest x-ray was ordered (figure ) , which shows more regression we wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. we confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. we confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. in so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. we understand that the corresponding author is the sole contact for the editorial process (including editorial manager and direct communications with the office). he is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. we confirm that we have provided a current, correct email address which is accessible by the corresponding author and which has been configured to accept email from (dr.maythem @yahoo.com) signed by the author: which of the following is true about primary spontaneous pneumothorax? a) it is generally a less dangerous finding than primary spontaneous pneumodiastinum. b) most patients develop it after vigorous exercise. c) expiratory chest radiographs are critical to make the diagnosis. d) smoking is the most significant risk factor. e) hamman's crunch is pathognomonic. most patients develop primary spontaneous pneumothorax while at rest, traditionally it was thought that expiratory chest x-rays aid in the diagnosis of pneumothorax, clinically however, expiratory films have not demonstrated much utility. pneumomediastinum is less common, and generally benign finding and self-limited. in contrast, a secondary pneumomediastinum is a morbid diagnosis and results from significant underlying disease such as boerhaave's syndrome. hamman's crunch is a sign of pneumomediastinum. the correct answer is e, it was found that male smokers have -fold increased risk for developing a spontaneous pneumothorax, whereas female smokers have -fold increased risk. other risk factors include height and cold weather. there is also increased incidence in falls and winter. regarding acute respiratory distress syndrome (ards), which of the following summarizes the best ventilation strategy? a) due to high compliance, patients with ards do not require peep b) due to low compliance, patients with ards require low tidal volume and high peep to prevent barotrauma. c) due to low compliance, patients with ards need higher tidal volumes and higher peep to ensure adequate ventilation. d) because of airway obstruction, such patients require very low or no peep just like asthmatic patients to avoid air trapping. e) because of high compliance, such patients need low tidal volume and low peep to provide better oxygenation. correct answer: b in ards, the alveoli are filled with protein-rich fluid because of leaking pulmonary capillaries. this will result in poor compliance and poor ventilation. because of low compliant alveoli, both peak and plateau airway pressures are high in ards patients, so ventilating those patients with normal or higher tidal volumes will further increase the airway pressures and leads to barotrauma. the lung protective strategy involves ventilating those patients with much lower tidal volumes than normal people. owing to lower tidal volumes, however, such patients need higher peep levels in order to recruit more alveoli to achieve better oxygenation. skeletal chest injuries secondary to cardiopulmonary resuscitation pathological findings of covid- associated with acute respiratory distress syndrome covid- : what has been learned and to be learned about the novel coronavirus disease short-term outcome of critically ill patients with severe acute respiratory syndrome key: cord- -qjp j x authors: sryma, p.b.; mittal, saurabh; madan, karan; mohan, anant; hadda, vijay; tiwari, pawan; guleria, randeep title: reinventing the wheel in ards: awake proning in covid- date: - - journal: arch bronconeumol doi: . /j.arbr. . . sha: doc_id: cord_uid: qjp j x nan disease and has been reported from more than countries. severe illness is marked by the development of dyspnea, hypoxemia, and progression to acute respiratory distress syndrome (ards) within one week of onset of symptoms. the most documented reason for admission to the intensive care unit has been the need for respiratory support. among these, around two-thirds of patients meet the criteria for ards. care of critically-ill patients of covid- is resource-intensive, which may become the bottleneck of management. apart from the low tidal volume ventilation, and prone positioning (pp) in severe ards, none of the other approaches have been shown to reduce mortality conclusively. pp has been shown to increase the average ratio of arterial oxygen tension to the fraction of inspired oxygen (pao /fio ) by mmhg. non-invasive methods of oxygen delivery, such as high flow nasal cannula (hfnc) and non-invasive ventilation (niv), have been used in mild-moderate ards and may reduce the need for invasive mechanical ventilation (imv). these methods of oxygen delivery are associated with the high aerosol generation, and thus, are less often preferred for managing patients with covid- . although the use of a facemask while using hfnc reduces the possibility of infection transmission, it does not eliminate it. whether combining non-invasive methods of oxygen delivery, along with pp, helps in preventing the need for imv is still an unanswered question. prone positioning results in improved oxygenation by multiple mechanisms. it leads to a reduction in intrapulmonary shunt by increasing aeration in the dorsal lung, which continues to receive higher blood flow even in the prone position. it is also believed to reduce ventilator induced lung injury (vili) by reducing atelectrauma and improve drainage of secretions. experimental studies have demonstrated the beneficial effects of spontaneous breathing in ards, such as improved ventilation-perfusion matching, reduced muscle atrophy, and reducing vili. though suggested by international guidelines for use in moderate-severe ards, observational data globally showed that pp was employed in only . % of mild ards, . % of moderate ards, and . % of severe ards. the pathophysiology of ards in covid- was seen to involve two different phenotypes as noted from a study of patients. it includes the "happy or silent hypoxic" who do not have breathlessness or tachycardia, despite their low oxygen saturation as well as the remarkably dyspneic patient. the dissociation between relatively well-preserved lung mechanics and the extent of hypoxia could be explained by the loss of lung perfusion regulation and hypoxic vasoconstriction. the early lung injury, l phenotype, is characterized by low elastance, low ventilation to perfusion ratio, low lung weight, and low recruitability. conversely, the phenotype h pattern fits in the usually described severe ards physiology with high lung weight and high recruitability. in this conceptualized model, it was hypothesized that treatment of the l phenotype with a high peep strategy might result in more incidence of vili in the compliant lung. however, emerging evidence on the respiratory physiology in intubated covid- patients has not supported this concept. in a study of intubated individuals with % having mild-moderate ards, patients had a median pao /fio of , and compliance of ml per cm h o with very few exhibiting nearnormal compliance, findings consistent with prior large cohorts of patients with ards. prone ventilation was employed in almost half of these patients and resulted in improved gas exchange and lung compliance. case series of admitted patients with covid- from hospitals employing early-intubation strategy have reported vastly better outcomes in the non-intubated patients with less need for renal replacement therapy as compared to intubated patients. though this may be due to confounding by the severity of illness leading to a more complicated course in intubated patients, it is possible that ventilator-induced lung injury and hemodynamic effects of ventilation played a role and may argue for the judicious use of non-invasive respiratory support in covid- . data available till now do not support an objective way of characterizing which group of patients will improve with noninvasive oxygen delivery with or without prone positioning. the silent hypoxic represent a subset of the covid- hypoxemic patients, in whom a trial of non-invasive oxygen therapy may be given with strict monitoring for any deterioration. the hypoxic patient with dyspnea and increased work of breathing is not a candidate for non-invasive oxygen delivery as it may increase the chance of patient self-inflicted lung injury (p-sili). the use of awake pp, along with non-invasive modalities, may result in improved ventilation-perfusion relationships and avert intubation. the rox index ([oxygen saturation/fio ]/respiratory rate) can be useful to predict outcomes of patients with hypoxemic respiratory failure treated with non-invasive oxygen therapy. it is non-invasive and simple to calculate at the bedside. at a value of > . , it has a positive predictive value for the success of hfnc of more than % between -and -h post-initiation and cutoff values of . at h, and . at h demonstrate specificities of %- %. clinicians could use the serial rox index as a way to monitor progress in patients on non-invasive oxygen therapy, and incorporate it when considering decisions to escalate care. in the studies describing the radiology of lung parenchymal involvement in covid- , it is seen that majority of patients have peripheral distribution ( %) with predominant posterior lung involvement ( . %). this table steps of awake proning. assist the patient: explain procedure, its benefits and help in position change check oxygen therapy/niv/hfnc is secure with adequate length on the tubing. continue pulse oximetry monitoring help the patient to change to prone position. pillows may be required to support the chest reverse trendelenburg position may aid comfort monitor oxygen saturation and respiratory rate post-prone monitoring at min: check for desaturation or patient intolerance. serial measurement of rox index (so /fio : respiratory rate) to be done. any fall in rox index should prompt escalation of care. if desaturation-check oxygen tubing for disconnection. if intact, increase delivered oxygen concentration or escalate the type of respiratory support, if the patient is comfortable. if patient intolerance-change to supine position if the patient is tolerating with oxygen saturation %- %, advise to remain in the prone position for - h or as long as possible as per tolerability. monitor for desaturation at min of each position change when to stop pp? in case of any respiratory distress rox index of ≤ . at h, and ≤ . at h may suggest poor response and should prompt escalation of care in case of sustained improvement in saturation to more than % in room air after h of stopping prone positioning pattern may suggest an added advantage of pp in covid- ards patients. prone positioning in non-intubated patients is a newer concept that, if successful, may have far reaching impact in this time of covid- pandemic. the first use was reported in a retrospective study of fifteen non-intubated patients with acute respiratory failure. there were cumulative sessions of pp, and it demonstrated improvement in pao /fio ratio though it did not report the effect on clinical endpoints. the average duration of pp was three hours, and the patients included were on niv/hfnc/conventional oxygen masks. there were no reported adverse hemodynamic consequences. a recent study of twenty patients with moderate-severe ards compared the use of niv and hfnc with and without pp. the use of pp for an average of two hours twice daily was associated with an improvement in pao /fio ratio with maximum improvement in niv with the pp group. eleven out of the twenty patients were able to avoid imv. the duration of pp employed in this study was significantly lower than the usual approach of pp in imv, where the target duration of pp is at least h/day. the use of awake pp has also been reported from china in the setting of the covid- pandemic. use of intensivist guided intervention, hierarchical management strategy along with awake pp in patients with room air saturation less than % were associated with better outcomes with < % requiring imv. the authors did not report the exact duration of the awake pp. other data on pp in hypoxemic respiratory failure in spontaneously breathing, non-intubated adult patients are limited to few case reports. most recently, awake proning in patients of covid- hypoxemic respiratory failure in the emergency department resulted in significant improvement in saturation from % to % at the same concentration of inspired oxygen, and % patients improved avoiding intubation. this study lacked a control group to enable meaningful outcomes to be drawn as to the benefit in reducing the need for mechanical ventilation with awake pp. during current pandemic of covid- , data is emerging regarding the feasibility as well as utility of awake proning in patients with ards. a study of patients from france demonstrated improvement in oxygenation in % patients who sustained prone positioning for more than three hours and back pain was most commonly reported complications. prone positioning during niv use outside icu has also been shown to be safe and is associated with improvement in oxygenation as well as patient comfort. there is no universally approved protocol for awake pp in ards, and a proposed algorithm was published recently in the context of covid- . the basic requirements include a conscious co-operative patient with mild-moderate hypoxemia and the availability of close monitoring. the indication, contraindications, and steps to proning are explained in table and fig. . the choice of the oxygen delivery device depends upon the availability and physician's judgment. the pp should be stopped if there is patient intolerance, worsening of hypoxia, or the patient has recovered from respiratory failure. prone positioning in the spontaneous breathing patient has significant advantages. on the one hand, it potentially reduces the vasoplegia genesis and therefore, probably the need for vasopressors, by avoiding the high doses of sedo-analgesia required by these patients while on spontaneous ventilation. on the other hand, positive pressure in patients on mechanical ventilation clearly affects the preload, generating in many occasions a hemodynamic pattern of hypovolemia. this can be avoided by keeping the patient on spontaneous ventilation, if appropriate. however, non-invasive oxygen therapies, including hfnc, require strict monitoring for the failure of therapy. a reduction in the need for imv and its resultant complications might lead to a reduced hospital stay. as the patients are awake and able to co-operate with position changes, prone positioning allows for more patient involvement in self-care. in very extreme situations of patient overload, this strategy may help in reducing the physical work of health care workers. this hypothesis needs to be validated in real-world settings and could be the game-changer in managing the respiratory failure of this pandemic. none. dear editor, chronic thromboembolic pulmonary hypertension (cteph) results from obstruction of the pulmonary arterial bed by organized thrombus after acute or recurrent pulmonary embolism (pe). its pathogenesis associates small-vessel vasculopathy. the resultant increased pulmonary pressures may lead to right ventricular dysfunction and death. cpeth patients are usually aged and present with comorbidities in contrast with the usual demographics in the pulmonary arterial hypertension (pah) population. as cteph is consequence of thrombus formation, lifelong anticoagulation is mandatory; while treatments to address increased pulmonary pressures include: pulmonary endarterectomy (pea), percutaneous balloon pulmonary angioplasty (bpa), and pahspecific medication. , the clinical picture of the new coronavirus disease of (covid- ) varies greatly, ranging from asymptomatic cases to a severe acute respiratory distress syndrome (ards) responsible for most covid- fatalities. a severe course occurs more likely in patients with previous cardiac or respiratory conditions. noteworthy, coagulopathy appears to play a substantial role in covid- pathogenesis. by may the rd, three cteph patients had been diagnosed with covid- pneumonia. baseline characteristics and covid- course are presented in table . patient was a -year-old female diagnosed with cteph at the age of . other previous conditions included chronic kidney disease (ckd) on haemodialysis, bronchiectasis and a previous severe pneumonia. she underwent pea in , later enrolled in our bpa programme. she was on phosphodiesterase- inhibitors (pdei), endothelin receptor antagonists (era) and domiciliary oxygen. in march , she was admitted to hospital with poor general clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan prone position for acute respiratory distress syndrome. a systematic review and meta-analysis prone ventilation in acute respiratory distress syndrome a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study covid- does not lead to a "typical" acute respiratory distress syndrome respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study clinical characteristics of covid- in new york city predicting outcomes of high-flow nasal cannula for acute respiratory distress syndrome. an index that rox coronavirus disease (covid- ): a systematic review of imaging findings in patients prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: a retrospective study efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study lower mortality of covid- by early recognition and intervention: experience from jiangsu province early self-proning in awake non-intubated patients in the emergency department: a single ed's experience during the covid- pandemic is the prone position helpful during spontaneous breathing in patients with covid- ? use of prone positioning in nonintubated patients with covid- and hypoxemic acute respiratory failure respiratory parameters in patients with covid- after using noninvasive ventilation in the prone position outside the intensive care unit ics guidance for prone positioning of the conscious covid patient none of the authors have any conflict of interest. key: cord- - rvfsx p authors: nan title: ps - date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: rvfsx p nan as a base line, we retrospectively reviewed patient characteristics (time ventilated and icu mortality) of all patients ventilated > days over months. over the following months, we determined the impact of the long term care plans on patients ventilated > days. those who failed > weaning attempts from mechanical ventilation were assessed by the mdt for suitability for long term weaning plans. not all were accepted by the mdt team due to resource limitations. both groups were similar with regard to age, gender and apache ii. in the second group, patients adhered mdt weaning plans; all survived to icu discharge. the introduction of the mdt plan was associated with a significant reduction in mortality for all patients ventilated > days (p< . ), with the most significant difference seen in those patients ventilated > days (p< . ). the duration of mechanical ventilation was greater following the introduction of the long term plans. conclusion. we demonstrated the feasibility of applying a long term mdt weaning approach to patients receiving prolonged mechanical ventilation across different consultant weeks. our preliminary data suggests that this approach did not lead to harm and was in fact associated with a significant reduction in icu mortality. the increase in median time to wean requires further investigation. multidisciplinary team involvement with this difficult patient group was essential to enable a change in practice to occur and led to a culture shift within the unit. conclusion. the inclusion of plasmatic levels of transthyretin as an a additional variable improves the predictive ability of the severity scales and indicators of organ failure. . early administration of aas in the acute coronary syndrome, during the months of the study we diagnosed a total of patients with acs, all of them received aas in the first hours which results in a % compliance for this indicator. . semi-upright positioning of patients with invasive mechanical ventilation (imv), during the period of monitoring we attended patients with imv > hours, which made a total of days of imv, we complied to the indicator of semi-upright position % . prevention of tromboembolic events, in the days of monitoring we attended to a total of patients with a stay over hours and we achieved profylaxis of deep venous thrombosis in , which leads to a compliance of %. . pneumonia associated with mechanical ventilation, during the months of monitoring we recorded a total of days of imv in a total of patients and pneumonias associated with imv, which comes down to a total of per episodes. . profylaxis of gastrointestinal hemorrhage in patients with invasive mechanical ventilation, during the days of the study we attended a total of patients with imv > hours with a compliance to the indicator of %. conclusion. discussion. in our unit the indicators have a high percentage of compliance, the only divergence being the pneumonia associated with mechanical ventilation which is due to the small number of patients with imv. due to the characteristics of our unit, with the private setting and the high number of admissions of post surgical patients ( %), imv > hours constitudes a low percentage of our patients. we also have to stress the fact that there where non-labour days during the time of the study. conclusions. in our unit the indicators of quality of the critical patient have a high compliance rate. the use of imv > hours in our unit has a low occurance rate. grant acknowledgement. work group of quality indicators of the semicyuc. drug-drug interactions can cause adverse drug events (ades) and affect icu patient care. a pharmacist on rounds decreases the number of preventable order-writing ades and positively impacts patient safety, outcome and drug costs. the aim of this study is to describe the frequency of drug-drug interactions and its implications on patient outcome. from august to february our clinical pharmacist, present on daily rounds, conducted an active screening of all icu physician orders searching for drug-drug interactions (epocrates rx ® drug reference). these interactions were classified in seven different groups according to potential adverse effects: neurological, cardiovascular, gastrointestinal, renal / metabolic, pharmacokinetic, hematological and others. once an interaction was identified the icu team was warned to detect and report any possible ade and the pharmacist could make interventions judged necessary like a recommendation of an alternative therapy or dose adjustments. physicians , acceptance rate of these interventions and incidence of ades were recorded. we analyzed orders with prescribed items. there were drug-drug interactions identified ( interaction per prescribed items) and these interactions were present in orders ( %). neurological was the leading group with . % (n= ) followed by cardiovascular . % (n= ), gastrointestinal . % (n= ), renal/metabolic . % (n= ), pharmacokinetic . % (n= ), hematological . % (n= ) and others . % (n= ). a great variety of therapies was involved in these interactions. the clinical pharmacist made interventions in order to change the prescribed drug therapy and acceptance rate was %. the incidence of order-writing ades was . per patient days. there was not ades-associated mortality rate during the study period. conclusion. drug-drug interactions are frequent and involve the majority of routinely prescribed items in icu environment. neurological and cardiovascular are the most common affected systems. these interactions can adversely affect patient outcome and a clinical pharmacist integrating the multiprofessional icu team can help to identify and minimize its effects. patients with severe and persistent bleeding have high mortality rates despite standard therapy. recombinant activated factor vii (rfviia) must be considered as a pharmacological complementary treatment for critical ill patients suffering from acute bleeding (acbl). the aim of this report is to evaluate the role of rfviia in the management of severe bleeding refractory to other treatments following a regular protocol for its administration in our icu. during a one year period (february -february ) a protocol of rfviia was applied to patients who were admitted with acbl diagnosis in our icu. the protocol was developed by a commission of experts according to the recommendations of use of rfviia indicated by martinowitz et al ( ). indication: any salvageable patient suffering from massive uncontrolled bleeding that fails to respond to appropiate surgical measures and blood component therapy. preconditions: fibrinogen > mg/dl, platelets > xmm , ph > , , no hypothermia. results. patients with acbl fulfilled the criteria of the protocol. etiology of the bleeding: surgical and obstetric. the average of age was . mean apacheii was . in all cases only one dose of rfviia of mcgr/kg was given. transfusion requirements: red blood concentrates (rbc), fresh frozen plasma (ffp), cryoprecipitate (cry) and platelets (plt) decreased significantly. in addition, prothrombin time (pt) and activated partial thromboplastin time (aptt) improved. patients survived and were discharged from hospital, one patient died due to nosocomial pneumonia. there were no adverse events. before an after rfviia administration before-after pt (s) case . - . - . - . following an agreed protocol model, the use of rfviia may have an important role in achievement of an adequate hemostasis, reduces blood requirements and the adverse events in patients with acbl. intensive care units (icus) provide intensive observation and treatment for critically ill patients, but the total hospital mortality is high at . %. this is according to statistics from the intensive care national audit and research centre (icnarc) case mix programme database. most of the deaths occur in icu itself ( . %), rather than after discharge from icu ( . %). the purpose of this study was to see if the deaths in the lister hospital icu were related to the initial clinical insult or caused by a complication that developed during the icu stay. methods. this retrospective study included all patients admitted to the lister hospital icu over a -year period from april to march . for all patients who died in icu, an icu consultant classified the cause of death into the following three categories: ( ) initial reason for admission; ( ) co-morbidity -e.g. myocardial infarction that occurred after icu admission on a background of ischaemic heart disease in a patient who was admitted after having had major surgery; or ( ) complication that developed because the patient was in icu -e.g. line sepsis or ventilator-associated pneumonia. results. there were admissions to lister icu over the -year period. some were repeat admissions, leaving individual patients to study. the total hospital mortality was . %. patients ( . %) died in icu, patients ( . %) died after discharge from icu but prior to hospital discharge and patients ( . %) survived to hospital discharge.we were able to obtain medical notes for of the patients who died in icu. of these patients, patients ( . %) died due to initial reason for admission, patients ( . %) died due to co-morbidity, and patients ( . %) died due to a complication that developed because the patient was in icu. of the patients for whom we could not obtain medical notes, patients stayed in icu for day, patients stayed for days and patient stayed for days before dying in icu. the short lengths of stay for these patients suggest that they died due to initial reason for admission. our study reveals that most of the deaths in icu were related to the initial clinical insult for which they were admitted. less than a third of the deaths were related to a complication that developed during their icu stay, whether the complication was related to co-morbidity or being in the icu environment. this is surprising, as icu admissions are for patients who suffer an acute deterioration that is potentially recoverable. therefore, deaths that occur in icu should be related to complications that subsequently develop rather than the initial clinical insult. our finding that the converse is true could imply that we may be too unrealistic in our assessment of whether the acute clinical problem is potentially recoverable or not. the practise of withdrawal of treatment varies from unit to unit. if it is carried out properly it could decrease the amount of suffering the patients and the relatives undergo and it would also save valuable resources, which could be utilised more constructively. there was a relative's complaint on unnecessary prolongation of treatment and this lead to this prospective study. we proposed to study the frequency, reasons, documentation, delays and the process of withdrawal of treatment. the study was carried out at the new cross hospital, wolverhampton uk over a period of months may and june . the critical care unit has itu and hdu beds. a proforma was prepared after obtaining the suggestions from the consultants and the nursing staff working in this critical care unit. i was contacted when a decision to withdraw treatment was made. i went through the notes and the monitoring charts to fill in the details in my proforma. the patients were followed up from this point. . treatment was withdrawn on patients and there were admissions during the audit period. the commonest reason was 'unfavourable response in spite of aggressive treatment' followed by 'poor neurological condition'. out of patients suffered from multi organ failure while patients suffered irreversible neurological damage. the decision to withdraw was made by a single itu consultant in majority of the cases. withdrawal decision to death time ranged from minutes to hours. the commonest mode of withdrawal was by extubation. dnar forms were filled for patients only. quality of documentation varied from short and concise to long notes lacking relevant information. there was no documentation in one case. the documentation by the trainees was found to be sub standard. conclusion. partial withdrawal was associated with delay in death. complete withdrawal was associated with quicker death. documentation was sub optimal. inadequate information was provided when trainees did the documentation. majority of the patients suffered from multi organ failure. identification of variables correlated with predisposition p is an initial step. subsequent studies would then be needed to test the clinical efficacy of piro scoring system in the diagnosis and management of sepsis. grant acknowledgement. we acknowledge elililly for the access to the databases. we declare no financial support. to identify genetic markers of proc and proc c loci that may be associated with the susceptibility to develop sepsis, which may adversely affect the prognosis of patients. in the group of patients with severe sepsis and/or septic shock, there were statistically significant differences (p = . ) for the mean apache ii score in genotype cc of snps of proc c, without significant differences for the remaining variables (sofa h, prothrombin time, partial thromboplastin time). snp type groups or subgroups or % ci-p rs cases vs controls . . - . * . rs presence of shock . . - . . rs presence of mof . . - . . † or: odds ratio, ci: confidence interval, mof: multiple organ failure, *sasieni test, †homozygous test conclusion. genotype aa + ga vs gg of the proc gene (snps ) was found to be involved in a higher susceptibility to develop sepsis, genotype cc (snps ) to present multiple organ failure, and genotype gc to develop shock. genotype cc of proc c was related to a higher apache ii score. none of the snps studied seemed to affect the prognosis of patients. patients with sepsis, particularly those in septic shock often develop atrial fibrillation (af) ( , ). interestingly, incidence and prognostic impact of af in septic shock have scarcly been examined so far. the aim of the present study was to answer the following questions: . what is the incidence of newly diagnosed af on a surgical intensive care unit (icu)? . which percentage of patients suffering a septic shock eventually does develop af? . what is the impact of newly diagnosed af on mortality and length of icu stay in patients with septic shock? we prospectively recorded data of all patients who were newly diagnosed with af and all those with a septic shock on a surgical icu (no cardiac surgery) during a one year period according to the requirements of the local ethical committee. during the observation period patients were admitted to the icu. patients ( , %) newly developed af during their stay on the icu. patients ( , %) had a septic shock. of the patients with septic shock had chronic af. of the remaining septic patients, ( %) were newly diagnosed with af. those patients with septic shock who developed af, had a higher mortality as compared to septic patients without af ( % versus %). moreover the median length of stay in the icu of surviving patients was significantly longer in patients with newly diagnosed af as compared to those without af ( versus days). conclusion. according to our data, more than % of patients with septic shock develop af. those patients who do develop af during septic shock seem to have a considerably poorer prognosis compared to those without af. af is a clinically important complication in septic patients and might be a useful criterion in assessing the prognosis of patients with septic shock. to our knowledge this is the first study to describe the incidence and prognostic relevance of newly diagnosed af in septic shock. a. socias* , a. rodríguez salgado , l. gutiérrez , r. morales , a. villoslada , b. comas , m. borges intensive care unit, surgery department, internal medicine, emergency department, h. son llàtzer, palma de mallorca, spain our objective was to evaluate the utility of seriated lactate measurement as a part of a cpims to predict outcome in patients with sepsis. prospective study, conducted in a teaching hospital in patients with sepsis included in a cpims. it automatically produces an annotation on the medical chart and a serie of analytics forms when activated. plasmatic lactate levels were determined at the moment of activation and after and h. clinical and analitical variables, as well as severity scores were also collected. patients have been included fron january to january . statistical tests: chi-square, mann-whitney, anova, kruskal-wallis, spearman, logistic regression. roc curves were traced for all seriated lactate determinations and for lactate clearance at h [ ] . results. patients were included, ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock. eighty-five ( , %) patients deceased, of whom ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock at the moment of activation. mean lactate levels were , ( , ) mmol/l, , ( , ) mmol/l and , ( , ) mmol/l at the activation moment, at and a hour respectively. patients with septic shock had significantly higher lactate levels at every moment (p< , ). moreover those levels correlated with the number of organ failure (nof) for the first d (table ) and the sofa score for the first days (p< , ). using roc curves we established a cutoff of mmol/l for lactate levels and of % for lactate clearance. pacients with initial lactate > (p< , ), at h (p , ) or at h (p < , ) and those with a lactate clearance at h < % (p , ) had higher mortality. recently it was suggested that critically ill patients can tolerate hemoglobin levels as low as g/dl and a more "liberal" red blood cell (rbc) transfusion strategy may in fact lead to worse clinical outcomes. objective: to study the rbc transfusion practice in critically ill patients and to examine the relationship of rbc transfusion to clinical outcomes. prospective observational study of patients admitted in the icu between / / and / / . we excluded patients with active haemorrhage. data on demographics, comorbidities, length of icu stay and icu mortality were collected. . patients were enrolled. ( . %) were transfused. pre-transfusion hemoglobin was . ± . g/dl. related factors to transfusion in multivariate analysis (od (ic)): uci los . ( . - . ). mv . ( . - . ). rr ( . [ ] [ ] [ ] [ ] [ ] [ ] [ ] . chronic anemia ( - ). transfused patients had higher icu mortality ( % vs %, p < . ). however, in a multivariate analysis including saps , mv, rr and transfusion, only saps was significantly related to outcome. conclusion. our transfusional trigger was approximately gr/dl. rbc transfusion was related to chronic anemia (prior to icu admittance), the use of invasive supports and the icu los. in our group of patients, rbc transfusion was not related to icu mortality. w. huber* , m. neudeck , a. umgelter , w. reindl , m. franzen , c. lampart , m. hennig , r. schmid nd medical department, institute for medical statistics and epidemiology, klinikum rechts der isar,technical university of munich, munich, germany introduction. np still has a high mortality and the outcome is hard to predict in the individual patient. while in the last years non-surgical therapy of sterile necroses has become the standard of care, infected necroses are currently treated surgically in most centres. we here present the data of consecutive patients with np treated non-surgically regardless of the infection of the necroses. it was the aim of our study to find prognostic factors relevant for the outcome of patients with conservative therapy of np focussing on the relevance of the infection of pancreatic necrosis. methods. data analysis of consecutive patients with np proven by contrast-enhanced ct-scan admitted to a medical icu. patients were treated with with imipenem as first line antibiosis and ct-guided puncture or drainage if appropriate. surgery was restricted to complications of the puncture or fluid collections not accessible to radiological drainage (n= ). hemodynamic monitoring using picco or pac and monitoring of intra-abdominal pressure if appropriate. statistics: multiple regression analysis (backward selection); chi-square-test (comparison of survival); sas software. patients characteristics: n= ; female; male; age . +/- . years, maximum crp . +/- . mg/dl, max. apache-ii-score . +/- . , max. lipase +/- u/l; max. ldh +/- u/l. / ( %) of the patients required mechanical ventilation and / ( %) dialysis/hemofiltration. .) prognosis: the only independent risk factors at admission to the icu for an unfavourable outcome were the level of serum creatinine (p= . ) and old age (p= . ). the following parameters were not predictive: etiology of pancreatitis, blood/serum levels of lipase, calcium, glucose, leukocytes and hematocrit as well as the presence of a cullen-and/or a grey-turnersign. .) mortality: the overall mortality was / ( %). in patients puncture and drainage of the necroses was performed. the mortality of these patients ( / ; %) was not different compared to the patients without puncture/drainage ( / ; %). in / ( %) of the patients with puncture bacteria and/or fungi were cultured in the aspirates. the mortality of these patients ( / ; %) was not different compared to the patients with sterile necrosis ( / ; %). conclusion. .) the overall mortality of % was low with regard to the severity of np. .) infection of the necroses had no impact on the outcome. therefore, the presence of infected necrosis is no contraindication to conservative management of np. .) the most important predictors for the outcome were serum creatinine levels and old age. x. schmit*, j. vincent intensive care, erasme university hospital, brussels, belgium sepsis remains an increasingly common killer. although there are a lot of studies about sepsis, it is a clinical syndrome and uncertainties will remain in its clinical course. the patient populations are very heterogeneous. some patients will respond well to initial empirical antibiotic therapy while others do not improve and need an adaptation or even a procedure in order to contol the infection. our study addresses for the first time the value of a dynamic evaluation of blood crp concentrations in an icu heterogeneous population of septic patients. clinical an other biological variables were also studied. in critically ill patients with sepsis, enrolled in a prospective observational multicenter study, crp levels and standard clinical and biological variables were measured daily from the day of identification of sepsis until death, transfer to the regular floor, or the th day, whatever came first. patients were divided into three groups according to their clinical course: group -patients with a favourable response to the initial antibiotic therapy; group patients who required a change in antibiotic therapy (shift to or addition of another antibiotic class); group -patients who needed surgery or drainage to control the infection. the studied population, from two large institutions was similar to those found in most of the icu's, with a median age of years, a majority of male patients and the lungs as the most common infectious site, and about % of positive cultures. we found that an increase in crp of at least . mg/dl in the first hours was associated with an inadequate response to therapy with a sensitivity of % and a specificity of %. crp concentrations decreased more rapidly and more significantly in group than in group (p= . ). there is quite a significant variability in baseline crp levels but we show that the time course during therapy is meaningful. in contrast, no correlation was found between crp levels and any of the clinical or other biological studied variables. these variables may also vary in numerous other situations than sepsis. conclusion. changes in crp over the first hours of therapy can help to evaluate the response to therapy in septic patients. the daily dosage of crp is easily accessible, inexpensive to perform, and offers much information, aiding in the clinical course of sepsis and early adequate therapeutic attitudes. is it not our rescuer? in septic patients scoring systems such as acute physiology and chronic health evaluation ii (apache ii) as well as sequential organ failure assessment (sofa) on admission and during treatment quantify the disease severity and therefore stratify the risk of adverse outcome. predictive roles of certain in-hospital parameters such as hypoalbuminemia, increased serum creatinine, c-reactive protein (crp), lactate and serum blood glucose were studied in some prospective clinical studies, however, their independent predictive roles of outcome in septic patients remain uncertain. our aim was to evaluate the predictive role of admission apache ii, admission and total maximum sofa score, hypoalbuminemia, increased serum creatinine, c-reactive protein, lactate, and serum blood glucose for the -day mortality of septic patients admitted to medical icu. included were all consecutive patients admitted to our medical icu in with criteria for sepsis according to sccm/esicm/accp/ats/sis international sepsis definitions conference. the data were collected retrospectively and the predictive roles of variables were tested by univariate and multivariate regressional statistical method. in patients (mean age . +/- . years, . % men) mean admission apache ii was . +/- . , mean admission sofa score . +/- . and total maximum sofa score . +/- . . -day mortality was present in %. we observed significant differences between nonsurvivors and survivors in mean apache ii ( . +/- . versus . +/- . , p = . ), peak blood glucose ( +/- . mmol/l vs . +/- . mmol/l, p = . ) peak serum lactate ( . +/- . mmol/l vs . +/- . mmol/l, p < . ), minimum serum albumin ( . +/- . g/l vs . +/- . g/l, p < . ), peak serum creatinine ( . +/- . micromol/l vs . +/- . micromol/l, p < . ), admission sofa score ( . +/- . vs . +/- . , p < . ) and total maximum sofa score ( . +/- vs . +/- . , p < . ). according to regressional statistical analysis, minimal serum albumin level was the most significant independent predictor of the -day mortality of septic patients in medical icu (or . , hi-square . , p = . , % ci . to . ). serum hypoalbuminemia was the most significant independent predictor of the -day mortality in septic patients. conclusion. the early decrease in mhla-dr expression is related with mortality, but after the severity adjustment, it does not predict outcome globally or in septic subgroups. a flat trend curve of mhla-dr expression is associated with a high risk of ni, which increases the icu length of stay. reference(s). ( )v caille, shock ;( )monneret g icm grant acknowledgement. university paris (ea ), all investigators introduction. intravenous fluid therapy is a cornerstone in the management of severe sepsis and septic shock but the effects of rapid boluses of either crystalloids or colloids on septic-induced microcirculatory alterations are not well defined. we hypothesized that fluid administration may improve the microcirculation in the early phase of severe sepsis and septic shock. we used a sidestream dark-field (sdf) imaging device (microvision medical, amsterdam, the netherlands) to evaluate the sublingual microcirculation in patients with severe sepsis or septic shock during the first hours of resuscitation, in whom fluid challenge was indicated to improve tissue perfusion. hemodynamic and microcirculatory measurements were obtained before and after a fluid challenge with either ml of a % albumin solution or ml of crystalloid over min. at each assessment, sequences of seconds each were recorded and stored under a random number. an investigator blinded to the patient's clinical course and sequence order, analyzed the images semi-quantitatively. the vessels were separated into large and small using a cut-off value of µm in diameter and two microcirculatory variables were evaluated: percentage of perfused vessels and percentage of perfused small vessels. a student t-test was used and data are presented as mean ± sd. a p< . was considered as significant. while arterial pressure and vasopressor use remained unchanged, microcirculatory perfusion increased and lactate levels decreased during fluid challenge (table ) . before after p mean art p, mmhg , ± , , ± , , card outp, l/min (n) , ± , ( ) , ± , ( ) , scvo , % , ± , , ± , , lactate, mmol/l , ± , , ± , , % total perfus vessel , ± , , ± , < , % small perfus vessel , ± , , ± , < , these results suggest that fluid resuscitation can improve the sublingual microcirculation in the early phase of severe sepsis. sdf monitoring may become a new tool to guide fluid therapy in critically ill patients. the study was held in a bed multidisciplinary icu of a tertiary hospital. twenty four norepinephrine dependent (> . γ/kg/min) patients, fulfilling the criteria of septic shock, were enrolled in the study. patients were divided in groups according to the continuous administration of mg hydrocortisone for > days (group a: pts) or conventional treatment (group b: pts). end points of the study were, the within days vasopressors weaning, evolution of mods and -day as well as -day survival. mods was described by sofa score. statistics : statistical analysis was computed by using paired t-test and linear regression analysis. groups were similar regarding demographics ( + vs + y), initial sofa score ( + vs , + ), initial norepinephrine dose ( . + . vs . + . γ/kg/min) and mean elapsed time from the onset of shock ( . + . vs . + . days). an early and significant decrease in norepinephrine dose (p< . ), was observed in all group a pts, while no difference was detected in group b pts. this decrease was associated with hemodynamic stability. on days and mean abp was significantly higher in group a pts (p< . , p< . ). weaning from vasopressors within days was achieved in pts in group a ( . %) and pts in group b ( . %). seven day mortality was . % in group a vs % in group b while -day mortality was % and % respectively. in the treatment group a positive correlation between the within days shock reversal and survival (cor coeff = . , r = . , p= . ) was found. there was no relation between the time elapsed from the onset of shock to the steroid administration and survival (p= . ). oxygenation parameters (fio /po ), sofa score and creatinine did not differ between groups. wbc in group a pts were significantly higher (p< . ) only on day . no significant adverse effects were detected. in late septic shock patients with mods the administration of low doses of hydrocortisone is associated with decreased vasopressors requirements, hemodynamic improvement and beneficial effect on survival. the within days shock reversal was a good predictor of survival. prolonged sepsis is associated with the development of immunoparesis, a down-regulation of the immune system, the degree of which is associated with a poor outcome. little is known about its evolution during the septic process (including the recovery phase), particularly in terms of functionality of the different leukocyte populations. below are preliminary data from an ongoing study. after appropriate consent was obtained, ml blood samples were drawn from previously healthy patients with septic shock (n= ). associated demographic and clinical data (eg sofa score, steroid use etc) were also collected plus icu and hospital outcomes. samples from healthy volunteers acted as controls (n= ). total and differential counts were performed by coulter counter. flow cytometry was used to assess viability (dual staining annexin v/ propidium iodide to determine apoptosis and necrosis), and characterization of populations (surface molecule expression of characterising lymphocytes, monocytes, and neutrophils). functional assays were performed on the phagocyte cell population using phagotest (phagocytic activity assessed as % ingestion of opsonized fitc-labeled bacteria) and phagoburst (measure of oxidative burst activity in response to opsonized e coli, pma and the chemotactic peptide fmlp expressed as % positive cells vs non-stimulated controls, and the increase in median fluorescence intensity [mfi]) (kits from orpegen pharma). compared to controls, septic shock samples taken on icu day showed a wide range of functional responses with some having a reduced number of functionally phagocytic phagocytes while others retained their phagocytic capacity. changes in phagocytic capacity were not related to the respiratory burst. respiratory burst was generally suppressed in septic patients. the viability of the phagocytic population ranged between - % in all septic patients. the proportion of neutrophils of total leukocytes remained constant ( - %) whereas the monocyte population was more variable ( - %) . conclusion. phagocytic populations of septic patients differ from healthy controls. variable effects were seen in phagocytic activity and/or respiratory burst in different septic shock patients on day of admission. this may possibly relate to previous priming or to as yet unexplained immunoparetic mechanisms. further work will assess the evolution of leukocyte number and functionality, and any relationship to outcome. it has been established that raised procalcitonin (pct) levels > ng/ml in critical care patients are associated with an elevation of infection-related mortality risk . we have performed a study to assess the effect of drotrecogin alfa (activated)(daa) on outcome in patients with severe sepsis and very high procalcitonin levels > ng/ml. we examined the outcome data for consecutive patients with severe sepsis and two or more organ failures who had procalcitonin levels greater than ng/ml at the time of critical care admission. pct was measured using the brahms pct-q immunochromatographic test. patients were divided into groups depending on whether or not they received drotrecogin alfa (activated). for all patients we recorded age, sex, apache ii score, and outcome at days. risk of death and standardised mortality ratio (smr) were then calculated. between july and november a total of patients with severe sepsis and multiple organ failure had pct > ng/ml. fourty-seven were not given daa because of or more contraindication or because their prognosis was so poor. the results are shown in the table. the smr was lower in the group not given daa. in patients with very high pct > ng/ml there was no reduction in mortality associated with the administration of daa. it is known that mortality increases with elevated pct > ng/ml and there may be a point at which the physiological derangement is so severe that daa is less effective. given that this drug is expensive and has significant side effects it would be prudent to avoid its use under such circumstances. pct may be useful in selecting patients for this treatment if our results are repeated in a larger study. since adrenergic stress and catecholamine-induced myocardial stunning may contribute to the pathogenesis of septic cardiomyopathy we evaluated the effects of beta blockers in patients with septic cardiomyopathy and shock. twenty patients with septic shock requiring milrinone therapy who were treated with enteral metoprolol after stabilization of cardiovascular function and within hours after onset of shock were included into the retrospective study protocol. hemodynamic, laboratory and clnical data documentation was performed immediately before, , , , , , and hours after the first metoprolol dosage. the incidence of the following adverse events was evaluated during metoprolol therapy: symptomatic or asymptomatic bradycardia, decrease in mean arterial blood pressure, cardiac or stroke volume index, central venous oxygen saturation, and hypoglycemia. descriptive methods and a linear mixed effects model was used for statistical analysis. metoprolol therapy was started after cardiovascular function had been stabilized ( . ± . hrs after onset of shock) and was targeted to reduce heart rate to - bpm. hemodynamic data and laboratory parameters were documented immediately before, , , , , , and hours after the first metoprolol dosage. a linear mixed effects model was used for statistical analysis. heart rate (p< . ), central venous pressure (p= . ), norepinephrine (p< . ) and milrinone dosages (p= . ) significantly decreased during beta blocker therapy. cardiac, stroke volume and cardiac power index remained unchanged. metoprolol was discontinued in two patients because of asymptomatic bradycardia. norepinephrine and milrinone dosages had to be increased in seven and four patients, respectively. in none of the four patients with a decrease in cardiac index a decrease in central venous oxygen saturation occurred. arterial lactate levels (p< . ) and c-reactive protein serum concentrations (p= . ) decreased during the observation period. enteral metoprolol therapy in combination with phosphodiesterase inhibitors seems to be safe and may be beneficial in patients with septic cardiomyopathy and shock. further studies on the use of beta blockers for septic cardiomyopathy are warranted. septic shock represents the leading cause of mortality in critically ill patients worldwide. the cornerstone of therapy continues to be early recognition and prompt initiation of antibiotic plus hemodynamic support measures. continuous renal replacement therapies (crrt) seem to play an important role in the early management of septic patients with acute renal failure, based on classical depuration properties and mediator clearance capacity. different crrt include: -convection techniques as high-volume hemofiltration (hvhf). -adsorption techniques as coupled plasma filtration adsorption (cpfa); introduced in recent years,it's a technique that separates plasma from the blood by means of a plasma filter. the plasma is then passed through a synthetic resin cartridge and returned to the blood. a second blood filter is used to remove excess fluid and small molecular weight toxins. the aim of this prospective and not randomized study was to analyze and compare the hemodynamic effects of both techniques(hvhf and cpfa). we studied twelve patients (n= ) with septic shock and acute renal failure. we initiated either of the two crrt when patients fullfilled renal depuration criteria. we analyzed the clinical effects by measuring main hemodynamic parameters and vasoactive drugs requirements during the first twelve hours. we started cpfa in four patients (mean age was years, % were male, and mean apache ii was ), and hvhf in eight patients (mean age was years, % were male, and mean apache ii was ). in table we represent the variation percentages in main hemodynamic parameters and norepinephrine requirements after the first twelve hours of crrt. no adverse effects due to crrt were registered. (up to %) . the aim of this study was to analyze the clinical presentation and to evaluate mortality associated factors (timing and accurancy of diagnosis, timing of surgery, severity score and organ failure, surgical and medical treatments). this study retrospectively investigated the medical records of patients (pts) diagnosed and treated for nf who were admitted to a -bed general icu from to . the pt characteristics are shown in table . the mean delay from onset of symptoms and hospital admission was . ± days. the provisional clinical diagnosis was incorrect in % pts. eighty % of pts was admitted with clinical signs of septic shock (ss). the mean time from diagnosis until surgery was ± , hrs. all pts underwent a mean of ± , surgical procedures related to necrotic tissue debridement. the wounds were sealed with a vacuum-assisted closure device which was exchanged every days until second intention healing. only pt required above-knee amputation. after surgery % of pts were submitted to hyperbaric oxygen therapy (n= - /pt). all pts received broad-spectrum antibiotics therapy which was changed according to the results of culture and sensitivity. mechanical ventilation was performed in all pts for respiratory failure (mean time= , ± days). two pts required surgical tracheostomy at admission for airways obstruction due to nf. all pts were in ss requiring vasopressor therapy for , ± days. thirty % of pts showed renal dysfunction (rifle class injury) and % were treated with high volume hemofiltration for anuric renal failure. disseminated intravascular coagulation was diagnosed in % of pts. low dose steroids were prescribed in % of pts and pts were treated with apc. the average lenght of icu and hospital stay were respectively of , ± and , ± days. overall mortality in our series was %. two pts died of severe ss and mof. in one case hyperkaliemia of unknown origin (after ss resolution) was fatal. sepsis is a common source of morbidity and mortality among critically ill patients. targeting measures to reduce the incidence and promote early recognition and treatment of sepsis is at the forefront of many critical care initiatives. advances in the management of severe sepsis have evolved over recent years in an attempt to combat the spiraling mortality trends. the "surviving sepsis campaign" (ssc) is a worldwide initiative promoting the evidence-based treatment of sepsis, with the explicit goal of reducing both the morbidity and mortality associated with sepsis. protocol watch (pw) was developed as a tool to assist clinicians at the bedside with the implementation and compliance of the ssc guidelines. participants were critically ill patients in -bed intensive care unit in a large university-affiliated teaching hospital in the northwestern united states. prior to the installation of pw, implementation of the ssc was done using a paper-based system of standing orders. base line data on compliance with the ssc guidelines were collected. protocol watch, which offers an electronic version of the guidelines and is resident on the bedside patient monitor, was then installed in all critical care beds. the post pw installation data collection is currently being completed. preliminary results show a significant improvement in both the early identification of sepsis as well as compliance with the ssc guidelines. in addition, the feedback from the clinical users has been extremely positive. if the final data analysis supports the preliminary findings, pw could emerge as an important method for assisting in the implementation of the ssc guidelines, thus making a valuable contribution in the care of critically ill patients with sepsis. hyperglycemia during acute brain injury such as ischemic stroke, cerebral hemorrhage, or head trauma is frequent and is associated with increased morbidity and mortality [ ] . there is also a profound increase in glucose utilization (hyperglycolysis) that can persist for up to one week after traumatic brain injury (tbi). however, little is known about the optimal glycolytic rate and about the influence of intensive insulin therapy on the tbi-induced changes in glucose metabolism [ ] . this study was designed to estimate the safety of routine versus intensive insulin therapy on the basis of hypoglycemic episodes defined as blood glucose concentration < . mmol/l (< mg/dl), in patients admitted to intensive care unit (icu) after severe tbi. in this prospective, single-blind, randomized clinical trial patients admitted after severe tbi, were enrolled and randomly assigned to one of two groups on the basis of the targeted levels of glycemia. insulin infusion was administered either at conventional rates, to maintain glycemia at . - . mmol/l ( - mg/dl), or intensive rates, to maintain glycemia at . - . mmol/l ( - mg/dl). hypoglycemic episodes, duration of icu stay, infections rate, mortality and neurologic outcome measured using the glasgow outcome scale (gos) at months follow-up, were recorded. in patients receiving intensive insulin therapy, hypoglycemic episodes were significantly higher ( . % vs . %, p< . ), duration of icu stay shorter ( . vs . days; p< . ), and infections rate lower ( . % vs. . %, p< . ) than in patients treated with conventional insulin therapy. mean gos and overall mortality at months were similar in the two groups ( . % vs. . %). intensive insulin therapy significantly increased the risk of hypoglycemic episodes. despite the shorter icu stay and lower infection rates, no differences were observed at months follow-up mortality and neurologic outcome. therefore, in tbi patients receiving intensive insulin infusion, whether to avoid episodes of hypoglycemia either with a stricter blood glucose monitoring or with a wider target blood glucose level needs further investigation. severe head injuries are a frequently encountered problem in intensive care medicine, and a cause of significant mortality and long term morbidity. various clinical features related to the initial trauma and secondary brain injuries are associated with adverse outcomes. [ ] we developed a head injury database, and investigated the management and outcome of head injured patients in our department, with particular emphasis on ventilation and haemodynamics in the pre-hospital and resuscitation phases. in this observational cohort study we collected data on head injured patients admitted to the icu at the royal london hospital (rlh) between march and november . demographic, clinical and outcome data was extracted from the patient notes and the icnarc database and then entered in a data collection proforma and subsequently in a ms excel spreadsheet for analysis. outcome measures were primarily mortality, and for survivors, the length of stay both in intensive care and in hospital were recorded. data was collected on head injured patients. the group of patients that died tended to be older, to have a lower gcs at the scene, a higher systolic blood pressure both at the scene and in the emergency department, and a lower pao in the emergency department although these results were still in the physiological range for the majority of patients. of the patients that had abg results recorded, only % had an initial paco < . in the emergency department. the lowest mortality ( . %) was associated with an initial a&e paco in the range . - . kpa. the mortality rate for patients brought directly to rlh was . % compared with . % for patients transported from other hospitals. ( , ) . we evaluated the association between bnp and the presence of sah, intracranial hypertension, hyponatremia, csws as well as water and salts balance in patients with severe traumatic brain injury (tbi). we examined patients with severe tbi coming from emergency ward. serum bnp was measured five times: t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day), t ( ˚- ˚day). daily and cumulative balance of water, sodium and potassium were calculated for all the patients. the presence of hyponatremic events, csws, intracranial hypertension episodes, sah (tc evidence) and the use of cathecolamines were notified, as well. seventeen male patients were included in the study (with a total of days of monitoring in icu and samplings of bnp). no association between bnp and the other observed variables (hyponatremia, csws, sah, the use of cathecolamines and intracranial hypertension) was observed. on the other hand, positive correlations between bnp levels and cumulative sodium balance (r= , ; p< , ) as well as between bnp and water balance (r= , ; p< , ) were observed. bnp level was higher in patients with positive cumulative sodium balance than in patients with negative balance: mean (sd) , ( ) pg/ml vs ( ) pg/ml (p= , ), respectively. bnp levels were also higher in patients with positive cumulative water balance: mean (sd) , ( , ) vs , ( , ) pg/ml (p= , ), respectively. our study does not confirm the role of bnp in the genesis of hyponatremia and csws. moreover, observing higher bnp levels in patients with positive sodium and water balance, we conclude that bnp in patients with severe tbi has a physiological role in the regulation of water and salts balance in order to avoid the excessive expansion of extracellular compartment. brain tissue oxygen monitoring plays important role in prevention of secondary brain injury. values of partial brain oxygen pressure (pbto ) in first hours after severe brain trauma should predict final patient's outcome. aim of this study is to analyze relationship between early values of brain oxygen in severe head trauma and the patient's outcome one year after this traumatic accident. study follows up our previous observation. we analyzed data of consecutive adult patients treated in our icu during time period of month for severe head trauma with glasgow coma scale (gcs) and less and with monitoring of intracranial pressure (icp) and partial brain oxygen pressure (pbto ). we placed sensor for pbto monitoring at the same time as icp sensor. all patients were treated according standard therapeutical protocol used in our department. target of our treatment was to avoid icp hypertension, to maintain cerebral perfussion pressure above mmhg and to reach optimal pbto levels. we compared data of first hours of the treatment in icu with neurological status using glasgow outcome scale (gos) in time intervals , and months after trauma in all patients. all this studied patients were already not at these times treated in our hospital. group with gos at the time of leaving icu had patients and initial values of pbto in first hours of treatment , mmhg (mean). group with gos had patients and initial valus of pbto , mmhg (mean). from this group patients died a one improved to gos . group with gos had patients, initial values of pbto , mmhg. from this group patients improved to gos and patients to gos , both in months. there were no changes in neurological status between and month after injury. group with gos had no patients. group with gos had patients and initial values of pbto , mmhg at a time of leaving icu. conclusion. there were found in our study no clear relationship between initial values of brain tissue oxygen and long term outcome. patients in vegetative state at a time of leaving of icu had in our group bad prognosis. all patient with severe dissability improved. values of brain tissue oxygen were in this group below mmhg. group with gos had values also relative low. we have no database of patients treated without brain tissue oxygen monitoring to make direct comparation and to evaluate real benefit of brain tissue oxygen monitoring. can protein s predict neurological deterioration after moderate or minor traumatic brain injury? p. bouzat* , p. jaffres , p. declety , j. brun , g. francony , j. c. renversez , a. kaddour , c. jacquot , j. f. payen department of anaesthesiology and critical care medicine, department of biochemistry, department of emergency medicine, albert michallon hospital, grenoble, france serum protein s "eta (ps ) is believed to reflect brain damage following traumatic brain injury (tbi). since patients with moderate tbi (glasgow coma scale, gcs, score - ) or minor tbi (gcs - ) may be at risk for subsequent neurological deterioration, we wondered whether the determination of serum ps on admission could be associated with the neurological outcome. methods. patients with moderate or minor tbi were prospectively studied. they had normal or moderate ct scan (trauma coma data bank, tcdb, classification i or ii, respectively) on admission. serum ps dosages were performed on admission within hours post-injury using a commercially available kit (elecsys s roche, detection limit . mathrmµg/l). neurological outcome was assessed up to days after trauma. secondary neurological deterioration was defined as a decrease in gcs score of points or more from the initial gsc score, or any treatment for neurological deterioration. two groups of patients were defined : group (absence of secondary neurological deterioration) and group (presence of neurological deterioration). data are expressed as median and range. univariate analysis (non parametric mann-whitney test, chi test) was used to identify factors related to the neurological outcome. . patients had a secondary neurological deterioration days after trauma (group ). they had significant higher gcs score and more injuries on ct than group . however, serum ps were not different between the groups (table) . ( - ) serum ps (µ µ µg/l) . ( . - . ) . ( . - . ) tcdb classification i/ii (n) / / ** gcs score on admission ( - ) ( - )** **p< . conclusion. serum ps cannot be viewed as a biological marker for detecting patients at risk for neurological deterioration after minor or moderate tbi. the contribution of this blood sampling is not as informative as a ct scan or the gcs. methods. seventy patients with traumatic brain injury (tbi) and stroke with glasgow coma scale (gsc) < were evaluated. thirty-degree head-up position was used during the study. icp was monitored during the following procedures: chest compression, vibration associated to chest compression, unilateral continuous chest compression, tracheal suction with open circuit and closed circuit, passive mobilization of arms and legs, hip rotation, scapular mobilization in lateral decubitus and lateral flexion of the lower trunk. wilcoxon test was used to evaluate changes on icp during the procedures. algorithm of intracranial hypertension (ich) therapy in patients with tbi should be modified on the base of the level of cerebral autoregulation (ca) impairment. the aim of the study was the application of the pressure reactivity index (prx) monitoring in the treatment of tbi patients. tbi patients with gcs< underwent the monitoring of the arterial blood pressure (abp), icp, prx. analog outputs from the monitors abp and icp were connected to the analog-to-digital converter (dt , data translation) installed into a laptop computer. data were sampled, digitized, and stored on the hard disk with the software for the waveform recording. digital signals were processed with software (icm plus, england). the therapeutic strategy modified on the base of results clinical evaluation and prx, abp and icp. all the patients were divided into two groups. patients had preserved ca with prx [- ; , ], gcs , +/- , ; icp , +/- ;cpp , +/- mmhg. in patients gos was favorable ( -with good recovery; -moderate disability) and unfavorable in patients ( -severe disability; -vegetative state). in this group we used iv infusion of colloids and vasopressors for cpp-protocol. in patients were determined "optimal" levels of cpp: in it was - mmhg, in - - mmhg, and in - - mmhg. in patients developed ca failure on the day after brain trauma and uncontrolled intracranial hypertension demanded decompressive craniotomy. second group included patients with impaired ca -prx [ , ;+ ], gcs , icp , +/- , , cpp , +/- mmhg. gos: both patient had unfavorable outcome (one-severe disability, other-vegetative state). conclusion. the monitoring of prx added to routine measuring of the abp and icp in tbi patients is helpful in choice of the best therapeutic strategy. grant acknowledgement. we thank dr. marek czosnyka and peter smielevski for their scientific support. a. raigal*, g. hernandez, l. marina intensive care unit, hospital virgen de la salud, toledo, spain severe traumatic brain injury (tbi) defined with a glasgow coma score (gcs) ≤ with normal or near normal craneal ct at hospital admission (type i-ii traumatic coma data bank classification) represents a common clinical dilemma about the real severity of cerebral lesions and neurological prognosis. the aim of the study was to relate some clinical factors with a higher probability of developing neurological complications (intracraneal hypertension) and bad neurological function on icu discharge defined as the presence of a motor component of gcs≤ . retrospective series of patients consecutively admitted for severe tbi in the general -bed icu of a tertiary trauma center during one year. we study patients with craneal ct admission classified as tcdb i-ii, after excluding those with another non traumatic cause of the coma and encephalic death on admission. after the admission ct the radiologic study was repeated in the first hours posterior to the trauma. icp was monitorised in all patients with tcdb> in the second ct or type i and confirmed gcs ≤ after transitory withdrawal of any sedative agent. the radiologic study was repeated after hours, on the th day and if the clinical evolution or icp required it. epidemiological, clinical and radiologic associated variables were also analysed and the gcs at icu discharge. a multivariant study was done adjusted by age, genre, initial gcs, radiologic lesion, associated trauma lesions and vital signs during the early phase of the traumatic injury (arterial oxygenation, blood pressure, etc). five patients ( %) had a poor gsc on discharge (m≤ ). those five patients showed an early damage of tcdb type at second ct and hypericp during icu admission. a sixth patient showed unfavorable outcome of the second ct with normal icp and gcs= on discharge. of the left over patients with a favorable neurologic evolution, showed hemodynamic and/or respiratory deterioration. the multivariant study displayed a relation between the early progression of lesions in the second craneal ct (or . , % ci: . - . ) with increase of icp or a poor gcs on icu discharge. also, the presence of systemic factors associated to admission was related to a good gcs on discharge (or . , % ci: . - . ). conclusion. . the early progression of type tcdb is related to hypericp and bad neurologic prognosis on icu discharge. . systemic factors in the initial phase of trauma (hypotension, hypoxia, etc) are related in these patients with a good final neurologic outcome, absence of both radiologic deterioration and intracraneal hypertension. the glasgow coma score on hospital admission has been shown to be correlated with outcome in patients with traumatic brain injury( ). however many patients who arrive at a neurosurgical referral centre have been sedated and intubated some time prior to transfer and so their glasgow coma score cannot be accurately recorded. an option in these cases is to use the last recorded score prior to sedation and intubation. this may be the glasgow coma score recorded in the accident and emergency department of the referring hospital, or in some cases that recorded on the ward after deterioration. in some cases the only available score is that recorded at the scene of the injury. in our study we examined the degree of correlation between these various glasgow coma scores and outcome at one year in order to assess the validity of using a surrogate for the admission glasgow coma score when this is not available. data were collected prospectively on all patients admitted to the queens medical centre from to with a recorded glasgow coma score of or less within hours of a traumatic brain injury. three glasgow coma score groups were identified. patients in group (certainty factor ) had a glasgow coma score recorded on admission to the queens medical centre. group (certainty factor ) was made up of patients in whom the last pre sedation and intubation glasgow coma scores was recorded at the referring hospital. in group (certainty factor ) the glasgow coma scores were recorded at the injury scene. for each group we looked at the strength of the association between the glasgow coma score and glasgow outcome score using linear regression analysis. results. data were available on patients. mean age years (range - ), % male and % victims of road traffic accidents. linear regression between the glasgow coma score and glasgow outcome score was highly significant in all three groups (p = < . for all three groups). the strength of the association was similar for groups and and superior to group (r = . for group , r = . for group , r = . for group ). we found a good correlation between the glasgow coma scores and outcome for all three groups. the best predictor of outcome is the glasgow coma score actually recorded on admission to the referral centre, but the pre-intubation glasgow coma score at the referring hospital provides an acceptable alternative. head injury remains a common cause of hospital admission, morbidity and mortality. uk recommendations are that all head injuries are managed either in the emergency department or the regional neurosciences centre. many patients are managed in local hospitals despite evidence that outcomes are improved by specialist care. we reviewed outcome data for all head-injured patients admitted to a regional centre over a -month period (sept -aug ). consecutive adult patients (> years) were studied prospectively. gcs following resuscitation, demographic data and surgical intervention were recorded. glasgow outcome scores were determined at discharge from the regional centre, and at and months following injury. whilst at the regional centre, patients were managed according to locally established protocols. . patients were admitted ( m, f). gcs following resuscitation was - in patients, - in , and < in . patients were aged - years, were - years and > years. patients had evacuation of an extradural haemorrhage, had evacuation of a subdural haemorrhage, had contusionectomies and patients required decompressive craniectomy. gos data were available for all patients at discharge, at months and at months (table ) . for patients with initial gcs < , gos was available for at discharge, at months and at months ( table ). mortality from head injury was % with only / patients with severe head injury dying. patients were discharged in a vegetative state with only remaining so at months. a bolus infusion of . % saline in % hydroxyethyl starch / . (hs) attenuates mean intracranial pressure (icp) in patients suffering from spontaneous subarachnoid hemorrhage (sah) ( ). it has been suggested that intracranial pulse pressure is more useful for prediction of intracranial compliance than mean icp alone ( ) . in this study, the effect of an infusion of hs on the parameter mean icp wave amplitude (i.e. intracranial pulse pressure) is compared with the effect on mean icp. prospectively collected data was retrospectively analyzed. all patients included were sedated and mechanically ventilated patients suffering from spontaneous sah. nine patients received infusions of hs, mean . (range . to . ) ml/kg. mean values of a minute period just prior to the infusion were compared with a -minute period after maximum effect was reached. results. the mean icp wave amplitude decreased . mmhg ( % confidence interval - . to - . ) from a baseline of . (sd . ) mmhg, p = . . mean icp decreased . mmhg ( % confidence interval - . to - . ) from . (sd . ) mmhg, p <. . comparing mean icp and mean icp wave amplitude, there was no statistically significant correlation for baseline values or change (table ). there was a stronger correlation between baseline values and change for mean icp wave amplitude than for mean icp (table ) . this study documents an effect of osmotherapy on intracranial pulsatility; mean icp wave amplitude was attenuated after infusion of hs. this reduction was strongly correlated to baseline mean icp wave amplitude. however, regarding the association between mean icp wave amplitude and mean icp, we found neither any correlation for baseline values nor for change after hs infusion. hence, monitoring of one parameter can not substitute the other. the value of mean icp wave amplitude in clinical practice should be further evaluated. hyponatraemia is an important electrolyte dysbalance in acute brain diseases. there are two known syndromes: the more frequent cerebral salt wasting (csw) syndrome due to natriuresis, and the less common syndrome of inappropriate secretion of antidiuretic hormone (siadh) caused by free water retention. differentiation between them can be made using renal function parameters, and is essential because each syndrome requires different therapy. we retrospectively analysed all patients (pts) with acute brain diseases admitted to our neurologic-neurosurgical care unit (nnicu) over a period of five years who developed hyponatraemia (serum sodium < ). first we divided them according to measured serum osmolality (normal values - mmol/kg) and then we evaluated the group with hypoosmolality (s osm < mmol/kg). the type of hyponatraemia was diagnosed using renal function parameters established in clinical practice in our nnicu. there were pts (mean age +/- yrs, m ) with days of hyponatraemia. the majority of pts had normal serum osmolality ( pts, days), some had hyperosmolality ( pts, days) and only pts ( days) had low plasma osmolality. osmolality was not measured for the remainder. pts in the hypoosmolal group (mean age +/- yrs, m ) were with the following diagnoses: subarachnoid haemorrhage , intracerebral haemorrhage , ischemic stroke , tumour , trauma , infection and others . the mean gcs at the start of hyponatraemia was . (range - ), the mean discharge gos was . (range - ). hyponatraemia lasted from to days (mean . days) and in patients was already present on the day of admisson. the mean value of hyponatraemie was . mmol/l (range - mmol/l, p< . ) and the mean value of serum osmolality was . mmol/kg (range - mmol/kg, p< . ). the mean increase of natraemia over hours was . mmol/l (range - mmol). no patients had central pontine myelinolysis. renal function parameters were examined in patients ( %), of whom patients were diagnosed csw syndrome (diuresis +/- ml/day; fu na+ . +/- . mmol/day, p< . ; c osm . +/- . ml/s, p< . ; c el . +/- . ml/s, p< . ; c na+ . +/- . ml/s, p< . ; ewc - . +/- . ml/s, p< . ; fe na+ . +/- . , p< . ), patients had other causes of hyponatraemia and no one siadh. renal function parameters are very useful to diagnose the type of hyponatraemia and available to put into clinical practice. hyponatraemia with hypoosmolality is not so frequent, and csw syndrome is more prevelant then siadh. microbial colonization of the respiratory and gastrointestinal tract (rt and gt) of a critically ill patient is an early event in the chain leading to invasive infection. systematic colonization surveillance permits monitoring of transmission dynamics, early detection of epidemics in the icu and possibly guidance for adequate empiric antimicrobial treatment in infectious episodes. we retrospectively analyzed the ability of colonization surveillance to predict microbial etiology of subsequent infections and permit adequate empiric therpay in septic episodes. the study was performed in a -bed general icu from november to december . infection control policy included weekly surveillance cultures of bronchial secretion and stool samples. all cases of ventilator-associated pneumonias (vap) and bloodstream infections (bsi) during the study period were recorded and the relationship between infectious etiology and most recent colonization was analyzed, based on species, antimicrobial susceptibility patterns and molecular typing by rep-pcr of selected isolates. in cases of new septic episodes, empiric treatment was determined, among other risk factors, by the antimicrobial susceptibility of most recent colonizers in either the rt or gt. during the three years of the study, we recorded vap and bsi cases ( catheter-related). pathogens isolated from vap cases correlated with bronchial or stool colonizers in %, with prior rt colonization being most important. in bsi cases, gram-negative pathogens were recent colonizers in % associated with both the gt and rt. no relationship was observed between gram-positive colonization and subsequent infection. rep-pcr techniques confirmed pathogen and colonizer concordance in all cases tested. systematic colonization surveillance use to determine empiric antimicrobial treatment in new vap episodes permitted % adequacy, compared to only % if the hellenic society of intensive care vap guidelines were used. empiric treatment for bsi cases was adequate % of the time. conclusion. rt and gt colonization is strongly related to microbial etiology of subsequent infection. systematic weekly colonization surveillance of rt and gt specimens could be helpful in implementing adequate antimicrobial therapy, especially for multidrug resistant gram (-) pathogens, in the icu. s. barbadillo* , m. olsina , a. leon intensive care unit, microbiology, capio hospital general de cataluña, sant cugat del vallés, spain production of extended-spectrum beta-lactamases (esbl) by enterobacteria is an important resistance mechanism against antimicrobial beta-lactamics. klebsiella pneumoniae and escherichia coli (esbls) strains had mostly been described but infection due to enterobacter producing extended-spectrum beta-lactamases (esbls) is a relatively uncommon clinical entity. this study was performed to investigate the risk factors associated with the acquisition of enterobacter-esbls strais infections in an intensive care unit (icu). this case-control study took place at a tertiary spanish hospital with a polyvalent icu beds from january to december . demographic data, underlying diseases, risk factors, length of icu stay and hospitalization and antimicrobial treatment were investigated by comparing infections due to enterobacter esbl-positive to cases due to esbl-negative strains. enterobacter were tested for esbl production by double disc diffusion synergy test (ddst) as well as by the mic reduction test. thirty-six enterobacter infections over a period of years were collected. ventilator associated pneumonia was the most frequent infection ( %). nine cases ( %) of esbl-producing eneterobacter isolates were compared to those infections with enterobacter non-esbl. days of mechanical ventilation, length of icu stay, tracheotomy, peripherical venous catheter and administration of cephalospin were all associated with esbl-enterobacter infections in the univariate analysis. there was not differences for sex, age, prognostic scores and mortaliy between groups. the multivariate analysis revealed the administration of broadspectrum cephalosporin as the unique risk factor for the presence of esbl-producing strains [odds ratio (or) . ; % confidence intervals (ci) . - . ; p= . ]. use of cephalosporines was associated with enterobacter esbl-positive isolates. thus, rational antimicrobial administration and antibiotic protocol regimens appears to be critical for control emergence of esbl production. to evaluate and characterize the ni in two intensive care units (icu) of a central portuguese hospital. a retrospective study of patients with ni, hospitalized in two icu (one medical and other surgical)between / / and / / identified by a computer-based program vigi@ct (biomerieux) and confirmed after. in the surgical icu we found episodes of ni. of this ( . %) were respiratory infections; ( . %) were surgical site infections and ( . %) bacteriemias. in the respiratory infections the most frequent agents were acinetobacter baumannii ( - . %) and pseudomonas aeruginosa ( - . %). enterococcus faecalis ( - . %) was the most frequent in surgical site. staphylococcus epidermidis ( - %) and acinetobacter baumannii ( - . %) the most frequent agents in bacteriemias. among all microrganisms . % of acinetobacter baumannii; . % of pseudomonas aeruginosa and . % of klebsiella pneumoniae were multiresistent bacteria (mrb). in the medical icu we found episodes of ni. half of these were due to respiratory infections ( - %), ( . %) were bacteriemia and ( . %) were urinary infections. pseudomonas aeruginosa was the most frequent microrganism ( - . %) among respiratory infections. in the bacteriemias coagulase negative staphylococcus (cns) (staphylococcus epidermidis and staphylococcus hominis) were the agents most frequently found ( - . %). escherichia coli was the bacteria most isolated in urinary infections ( - %). in medical icu we found mrb, among these were pseudomonas aeruginosa ( . %); were staphylococcus epidermidis ( . %) and ( . %) were acinetobacter baumannii. conclusion. ni is a significant problem in our icu's. we found more ni episodes in the surgical icu than in the medical. respiratory infection were the most common ni in both icu. as expected surgical site infection is also a serious occurence in the surgical icu as well bacteriemia. in the medical icu bacteriemia was also a considerable issue. gram negative bacteria and cns were predominat in this ni. acinetobacter baumannii was the most frequent mrb. we study retrospectively icu pts, men ( %), women ( %) who developed bacteremia. all had been operated at least once under general anaestesia. mean age: . ± . years, length of stay (los): . ± . days. all were mechanically ventilated and were divided in groups according to their age: group a ( . %) < and group b ( . %) ≥ years. in groups a and b we had respectively: mean age: . ± . and . ± . years. los: . ± . and . ± . days. underlying diseases: multiple trauma ( . %) and ( . %), complicated surgery ( . %) and ( . %), other ( . %) and ( . %). in groups a and b respectively: site of infection: pneumonia ( . %) and ( . %), intra-abdominal infection ( %) and ( . %), central venous catheter-related infections (cvc-ri) ( . %) and ( . %), other ( . %) and ( . %). invading microorganisms in single strain bacteremia: ps. aeruginosa ( . %) and ( . %), ac. baumannii ( . %) and ( . %), st. aureus ( . %) and ( . %), kl. pneumoniae ( . %) and ( . %), st. epidermidis ( . %) and ( . %), other and ( . %). mods occurred in ( . %) and ( . %). mortality rates (mr): / ( . %) and / ( . %). global mr: / ( . %). conclusion. ) cvc-ri appeared more frequently in elderly (p< . ), while all other sites of infection did not differ. ) invading organisms were similar in both groups except ac. baumannii which was isolated much more frequently in younger pts and very rarely in the elderly (p< . ). the resistance was similar in both groups. ) los was smaller in elderly (p< . ). ) elderly developed more frequently mods (p< . ) and had higher mr (p< . ), while the outcome of the infection was independent of the type of invading organism and its resistance. j. pavleas , a. skiada* , g. thomopoulos , i. stefanou , n. kouna , b. kaitanidi , a. salvari , p. tassiopoulou , a. papadopoulou , e. christofilou intensive care medicine, laikon general hospital, research laboratory for infectious diseases "g.l. daikos", athens university, microbiology laboratory, laikon general hospital, athens, greece nosocomial catheter-related bloodstream infections (cr-bsi) have been associated with increased morbidity and possibly increased mortality in critically ill patients. the aim of this study was to analyze the epidemiology of cr-bsis in our intensive care unit. prospective epidemiological study, in a mixed icu of a tertiary care hospital, of the incidence of cr-bsis, the responsible bacteria and the outcome of the episodes of bacteremia. the demographic and clinical characteristics of all patients admitted in the icu were recorded. each bacteremia recorded was classified as primary, catheter-related or secondary. the study took place in a tertiary care hospital, mixed icu, during a thirty-two months period. three hundred and thirty patients were admitted. their mean age was years and % of them were male. mean apache score was and the mean duration of stay in the icu was days. the total number of bloodstream infections (recorded in patients) was . of these, % were catheter-related. specifically, sixty-five cr-bsis occurred in catheter days ( . per catheter days). sixteen cr-bsis were due to gram-positive ( methicillin-resistant staphylococcus aureus, coagulase-negative staphylococci and enterococcus spp.) and to gram-negative bacteria ( acinetobacter baumanii, pseudomonas aeruginosa, klebsiella pneumoniae and one each of morganella morganii, enterobacter cloacae and serratia marcescens). of the gram-negative bacteria, % were multi-drug resistant, while % of the enterococci were vancomycin resistant. a positive outcome was noted in % of the catheter-related and in % of the other bacteremias. although cr-bsis have a better prognosis than the other bacteremias, they are still a serious cause of morbidity and mortality in the icu. since these infections are preventable, appropriate measures should be meticulously applied. opportunistic invasive aspergillosis in an immune compromised patient is being increasingly reported. however, this condition is thought to be rather rare in an immune competent host and therefore often unrecognized. we report two cases of invasive aspergillosis in patients without previous medical history of conditions leading to immune compromised status admitted to our intensive care unit. first case concerns a -year old woman who underwent an exploratory laparotomy because of acute abdomen without any significant findings. in the postoperative period, the patient developed sepsis with multiorgan failure necessitating ventilation, vasopressive and inotropic support and hemofiltration. early microbiologic analysis of the sputum showed an aspergillus fumigatus and patient was treated with voriconazol. the further evolution was unfavorable with hemodynamic instability and the patient died after two months of treatment. the autopsy revealed a severe tracheobronchitis and aspergillus endocarditis. the second patient, a -year old man admitted to our intensive care unit due to recurring arterial embolism and fever was diagnosed culture-negative endocarditis of the native mitralis valve on the transoesophageal echocardiography. subsequently, patient underwent a successful valve replacement. the culture of explanted valve revealed an aspergillus fumigatus infection and appropriate antimycotic treatment was started. in the postoperative period, the course was complicated by a sudden neurological condition with altered consciousness and patient eventually died of cerebral aspergillosis. in both patients, an exogenous infection possibly took place. the first patient was admitted to our hospital during the reconstruction work next to the intensive care unit. this may have led to her exposure to increased pathogen load during the early postoperative period. the second patient probably contracted the infection during the reconstruction work he was executing himself at his house before the admission to the hospital. invasive aspergillosis is a severe condition which is not only limited to patients with immune compromised status. alertness of the physicians ensuing in early diagnosis may be crucial for determining the individual patient prognosis. k. clabault* , f. soulis , m. tavolacci , g. beduneau , f. tamion , g. bonmarchand , j. richard medical intensive care unit, epidemiology and public health, rouen university hospital, rouen, france introduction. surgical hand rubbing (sr) has been proved to be an efficient alternative to traditional hand scrubbing. we tested an educational program based on continuous direct observing practice in order to implement this technique in a medical icu. residents and medical students benefit from an educational program included a ten minutes video demonstration of the sr presented by the infection control practionner. results of each observation was immediatly feed back to residents. medical students were encouraged to complete a form for each sr occuring h activity. data collection were due to sr (in emergency or not), duration of sr procedure, quantity of alcohol hand based (ahr) rub used. two successive groups of residents and groups of students participated to the study. two hundred and twenty-five observations were performed during a month period. the mean of the procedure time was s (sd . ). time expected according to the institutionnal protocol was s. . % of sr was inferior to mn , . % between mn and mn , . % superior to mn . time of sr did not differ between emergency or planned procedure ( s vs s, p= . ). cumulative volume of ahr was significantly correlated with duration of the procedure (r= . ,p< - ). our study suggest that implement of a new procedure of surgical hand disinfection in a icu is feasible on result on good adhesion of educated residents. the original method based on a audit performed by medical students may allow both hand hygiene education and adherence to an infection control program of future practionnners. infection surveillance: it is based in the unit not in the patient, using the envin-helics tool. this information from the patients was gathered: age, diagnosis on admission, apache ii, exposure and use to invasive devices (mechanical ventilation, central venous and urinary catheter). a multidisciplinary team from microbiology, preventive and intensive care units composed the team. the criteria for infection diagnosis were those from the cdc. incidence rates were calculated. handwashing surveillance: it was recorded in two periods: january-march (p ) and october-december (p ); each observation period lasted minutes. we observed the opportunity, defined as every time in which an indication for handwashing exists. . patients were enrolled, , % male, mean age ± ; more frequence of patients with medical pathology ( , %) with a media ± standard deviation of , ± , . apache ii . ± , . overall mortality rate was , %. a greater incidence of infections were found in the traumatic group. there is a large number of central venous catheter (use rate , %, , %:coronary patients). infections were detected as acquired in our unit ( , % and , %o patient-day). the respiratory tract infections and bactraemias were the most frequent localizations, with ventilator-associated pneumonia (vap) as the predominant nosocomial infection ( . % over total infections; , % in intubated patients, an incidence rate of , %o). there were two outbreaks of methicillin resistant staphylococcus aureus (mrsa). thus, the most frequent were pseudomona aeruginosa ( , %), escherichia coli ( , %) and staphylococcus aureus ( , %); acinetobacter baumanii and methicillin resistant staphylococcus aureus were quite very infrequent ( , % and , % repectively). opportunities of handwashing were detected (p : , p : ). the compliance increased from , % in p to , % in p . conclusion. )nosocomial infections affected to one out of five of the admitted patients. the vap was the most frequent infection. )we had a large rate of vap but similar to spanish standard ( , / days of use of mechanical ventilation). )the microbiology was similar to other critical care units, with a predominance of pseudomona aeruginosa. there were two outbreaks by mrsa. ) despite an increase in handwashing compliance, the rate of vap did not was lowered. m. karvouniaris* , s. xitsas , p. kasviki , d. lagonidis , m. stougianni , a. tefas icu, microbiology lab, general hospital of giannitsa, giannitsa, greece introduction. icu physicians are nowadays faced with the formidable task of dealing with bacteria that can hardly treat. multidrug resistant gram(-) bacteria are usually isolated from brocheal aspirates and associated with the development of vap , while their presence increases the risk of death. sometimes the only option for treating them is colistin , which was until recently an obsolete antibiotic of questionable efficacy. methods. patients with at least a -day stay in our icu had the following characteristics : men ( . %) , median age years ( interquartile range years) , median icu stay days (interquartile range days) , a mean apache ii score of . ( % confidence interval . - . ) these patients where retrospectively divided in two groups. the first one included patients with at least one brocheal culture positive for panresistant gram ( -) bacteria and the second one consisted of patients carrying bacteria sensitive to colistin only. a comparison was made according to days of stay in the icu , survival in months , age and apache ii score. statistical analysis was made using mann-witney analysis and a kaplan-maier analysis for survival. the patients in the group with the panresistant bacteria spend more days in the icu (p< . ) , while tended to live longer ( mantel-cox pairwise , p< . ). multidrug resistant bacteria are poorly responsive to colistin which failed to make an impact in survival. introduction. aids is a increasing chronic disease , with a great impact in medical costs. objective: to analyze incidence and epidemiological factors and outcome in aids patients (with previous or actual diagnosis) admitted to a general adult icu, comparing them with non-aids patients. retrospective cohort comparative study made in a general adult -bed icu of a university hospital, in a -month period. it were analyzed all patients admitted during this period. it was made descriptive statistics, analysis of variance and t-test. during studied period, there were patients admitted with a previous or actual diagnosis of aids. most common admission cause in these patients was sepsis by community pneumonia ( patients) and neurological diseases ( cases). there were patients with association with pulmonary tuberculosis, and patient with coexistent pulmonary paracoccidioidomycosis. among most frequent complications, ( . %) had acute renal failure (arf), ( . %) plaquetopenia (of these, had associated leucopenia), and ( . %) ards (all secondary to pneumonia). conclusion. in this study, aids patients admitted to icu were younger, mainly male, more severe and with a higher icu and hospital mortality. systemic complications were frequent, and commonest admission cause was community pneumonia with sepsis. it is emphasized the association with tuberculosis and paracoccidioidomycosis. grant acknowledgement. this study was not supported by any companies. th esicm annual congress -berlin, germany - - october a. sencan* , t. adanir , h. er , m. aksun , g. aran , n. karahan anesthesiology and icu, infection deseases, anesthesiology, izmir ataturk training and research hospital, izmir, turkey acinetobacter baumanii is a gram-negative coccobacillus that is normally a commensal pathogen but can be a nosocomial pathogen which is responsible for severe icuacquired infection, mainly pneumonia and bacteraemia. the aim of this study was to determine the risk factors and mortality rate of acinetobacter baumanii infections in icu patients. in this retrospective study, we analyzed acinetobacter baumanii infections developing in all patients who were admitted into our icu between january , and december , . a comparison of data was collected from the patients' record cards. age, gender, mortality ratio, apache ii and sofa values, length of mechanic ventilation (lomv) and length of icu stay (loicus) up to determination of infection, total length of mechanical ventilation (tlomv) and icu stay (tloicus), region of culture from which the infectious agent was obtained, existence of another microorganism together with acinetobacter baumanii (eamo), tracheotomy, intubation tube, central catheter, urinary catheter and nasogastric tube days up to the determination of infection and the feeding route were evaluated. these characteristics were compared between living and dead patients. during that time period, cases of acinetobacter infection were found in our clinic. the mortality ratio was %. the comparison of living and deceased cases is shown in the following table. we observed that this nosocomial infection was seen in the - year-old age group and in the first week of mechanical ventilation. mortality was greater in patients with high sofa scores and the infection prolonged the length of total icu stay. if the infection was located in the lungs, the mortality rate could be higher. there were cases of a baumanii nosocomial pneumonia and of them died. in addition, the rate of female patients dying was greater ( of female patients died). r. e. farah* , a. kondratov , r. michelis , n. makhoul internal medicine, intensive care unit, eliachar research laboratory, nahariya hospital, nahariya, israel community-acquired pneumonia, that requires hospitalization, is a severe illness with high mortality rates, especially, in the cases of delay of appropriate treatment. at times, the correct diagnosis of the disease is difficult due to equivocal clinical picture or chest film, accompanying diseases that could mask or simulate the pneumonia. the aims of our study were: .follow-up levels of scd and oxidized fibrinogen (of) throughout hospitalization in the group of patients admitted to the hospital due to pneumonia and pulmonary edema of non-infectious origin; .an estimation opportunity using them as possible new markers for diagnosis of pneumonia and for following response to treatment. three groups of patients were studied: a group of patients admitted due to pneumonia, a group of patients admitted due to pulmonary edema, and a control group - healthy subjects. the blood samples for white blood cells count, erythrocyte sedimentation rates, levels of fibrinogen, c-reactive protein, albumin, scd , oxidized fibrinogen were taken for each patient on admission, and hours following admission and on discharge day. the received dates were compared using student t-test. the levels of scd were higher, but still in the normal ranges, on admission in the patients with pneumonia and pulmonary edema in comparison with control group (p< . for both groups), with gradual declining throughout hospitalization period (p> . for both groups in discharge day). the comparison of scd levels between groups of patients with pneumonia and pulmonary edema did not reveal statistically significant results (p> . ). the rates of oxidized fibrinogen were in the normal ranges (< . nmol/mg) throughout hospitalization period in both groups of patients, but surprisingly higher in the control group (p< . ). oxidized fibrinogen and scd can't be used as reliable markers neither for primary diagnosing of pneumonia or differential diagnosis from pulmonary edema, nor for patient follow-up throughout hospitalization period. the finding of elevated levels of of in the group of healthy persons demands additional studies for discovering other factors that cause changes in fibrinogen oxidation rates. appearance of myocardial infarction and stroke during the same hospitalization is rare and has great mortality ratio. it was expected these events to take place more often during winter and in connection with infection. we have retrospectively analyzed data of patients with diagnose of acute myocardial infarction and stroke during the same hospitalization, treated in our internal intensive care unit from january to december . none of these patients were subjugated to thrombolytic therapy, percutaneus coronary intervention or coronary artery bypass graft. all included were caucasians (who were maked . % of total number of hospitalised patients during that period), ( %) males,and ( %) females. age of patiens was between and years, mean ± . (ci - ). six patients have survived ( %), and died ( %) ( males and females). the average age of deceased males was ± . years (ci - ), and females was ± . (ci - ). mean apache ii score was ± (ci - ), and mean gcs was ± (ci - ). most of the patients ( patients or %) were admitted during the winter, six in autumn ( %), five in spring ( %) and in summer only one patient ( %). in patients ( %) ( males and females) we found connection between current state with recent infection (within last month) or signs of infection on admission in icu. respiratory infection was found in patients, urinary infection in , and in cases we have found some other source of infection. also we found significant connection between current state (myocardial infarction and stroke during same hospitalization) and infection during winter (p= . ) and positive correlation between infection and mortality of these patients (r= . , p< . ). although exact mechanisms are still unknown. we can expect these events more often during winter period when are respiratory infection are more frequent. introduction. vap is the most frequently occurring nosocomial infection among patients requiring mechanical ventilation in the icu and is associated with increased morbidity and mortality. the major route of acquiring vap is oropharyngeal colonization by the endogenous flora or by pathogens acquired from the icu environment. oral decontamination with hexetidine , % reduces the risk for vap according the results of many reported studies and is the most common oral antiseptic in greek icus. our aim was to determinate the effect of oral decontamination with hexexidine , % on development of oropharyngeal colonization and vap. methods. patients admitted to the icu and received mechanical ventilation for more than days. were males ( , %) and ( , %) females. mean apache ii score on admission was , ± , . we excluded patients with multiple icu admissions. only the first admission was considered for analysis. we excluded also all patients with a diagnosis of pneumonia on or before the first day of mechanical ventilation, so that the sample would include only patients who had hospital-acquired pneumonia develop while receiving mechanical ventilation. all patients were randomized to hexetidine . % applied every hrs into the mouth, beginning hrs after admission. oropharyngeal sample cultures were obtained on admission on the nd and on the th day of hospitalisation and analyzed for gram positive, gram negative microorganisms and fungi. all patients were examined daily for the presence of vap with clinical criteria and chest x-rays. the most common isolates were: pseudomonas aeruginosa , %,klebsiella pneumoniae , %,s.aureus %,enterococcus faecium % ,acinetobacter %,e.coli , %,proteas mirabilis , % and candida species , %. coupled plasma filtration adsorption (cpfa), using a sorbent once the separation between plasma and blood has been obtained with a plasma filter, has been designed to non-selectively remove inflammatory mediators released in sepsis and septic shock. the aim of this study was to test whether cpfa is beneficial in septic shock. fourteen h-fasted, anesthetized, invasively monitored, mechanically ventilated female sheep ( . ± . kg) received . g/kg body weight of feces s lactate (rl)+ hydroxyethyl into the abdominal cavity to induce sepsis. ringer starch (voluven) (volume ratio= : ) was titrated to maintain cardiac filling pressures at baseline levels throughout the experimental period. four hours after feces injection, animals were randomized to two groups: cpfa treatment (n= ) or control (n= ). a four-pump hemofiltration machine (lynda, bellco, mirandola, italy) was used for the study. although mean arterial pressure and cardiac index were significantly lower in the cpfa group compared to the control group (p= . and p= . , respectively) and blood lactate concentrations tended to be higher in the cpfa treated group (p= . ), survival time tended to be longer in the cpfa than in the control group ( . ± . vs . ± . hours, log rank p= . ). in this clinically relevant septic shock model, cpfa treatment tended to prolong survival time. acute severe liver failure (alf) is a clinical syndrome that results from rapid loss of the major liver functions. despite improvements in the treatment of these patients, including liver transplantation, mortality rates remains high. a liver support system capable of removing endogenous toxins may be useful in alf patient's management. the aim of this study was to assess the efficacy of the extracorporeal liver assist device mars ® (molecular adsorbent recirculating system) in patients with alf unresponsive to intensive medical therapy. the study was performed in a medical-surgical intensive care unit of a tertiary referral hospital with multi-organ transplant program. a prospective clinical case-control study was designed. patients with severe alf of any etiology admitted to icu were included if mods was present and an indication for liver transplantation was done. standard treatment measures were applied in all cases according to patient's clinical condition. patients received mars ® treatment after this therapy was introduced in our icu. patients without mars treatment were the control group. outcome parameters were the main variables for comparison between groups. complications related with mars treatment were also analyzed. methods. in a previously-described test set-up, a l jar serving as a dummy lung was ventilated through a heated water-filled reservoir placed on a weighing scales so that gain or loss of water from it could be detected. the ventilator was a viasys sensormedics b using a fisher/paykel mr humidifier the ventilator was set to maximum power at a frequency of hz. three investigations were performed with humidifier temperatures of . ˚c, . ˚c and . ˚c. weight gain or loss over - hours was recorded and calculated in g/h. four measurements were made at . ˚c, four at . ˚c and two at . ˚c. previous spirometry studies suggested - % tracheal stenosis following percutaneous tracheostomy(pt) based on techniques that involved either the original ciaglia serial dilatation or griggs modified forceps blunt dilatation of the trachea. subjective voice changes and hoarseness has been reported at an incidence of % following pt by the blue rhino single dilator technique. aim of this study was to assess upper airway narrowing effects based on spirometry and symptoms following pt by blue rhino technique. invitations were sent to patients(identified from the liver database) who underwent pt during their intensive care stay and were attending liver clinic beyond months after the procedure. all participants underwent formal pulmonary function tests and filled in a standardized questionnaire on symptoms (pain, dysphonia, dyspnoea, cough, throat tightness, dysphagia) and scar appearance. flow volume loops were recorded using a jaegar master-lab . pneumotachograph, and best values for forced vital capacity(fvc),forced expiratory volumes at . and second(fev . ,fev ),peak expiratory flow rate(pefr),forced inspiratory flow at %vital capacity(fif ),forced expiratory flow at %vital capacity(fef )and peak inspiratory flow(pif) recorded. values for fev /pefr,fef /fif and fev /fev . ratios were then calculated. during august to january , patients underwent pt, of whom survived. of the outpatient attendants participated in the study. median age was . years ( - y) and m:f ratio was : . of the current or past smokers had obstructive airway disease based on fev /fvc ratio. median interval between pt and review was months ( - mth,n= ; - mth,n= ; - mth,n= , beyond y,n= ). median apache ii score on day of pt procedure day was . nine patients had failed extubation, and one patient underwent pt procedures during the same hospital stay. median duration of translaryngeal intubation prior to pt and from pt placement to decannulation were days ( - d) and days ( - d) respectively. moderate/severe dyspnoea was reported by patients (mild,n= ) and cough by patients (mild,n= ). patients reported voice changes and patient with hoarseness. assessment of scars at the time of review showed patient with keloid scar and patient with an ugly indurated scar (at and months respectively); all others were good to barely visible. satisfactory flow-volume loops were obtained for patients. patients had evidence of extrathoracic tracheomalacia based on the fef /fif ratio > ( with symptoms), however fev /pefr ratio did not suggest obstruction in any of them. dyspnoea and cough were the most common symptoms, notably in smokers. late complications were uncommon, other than one patient with indurated scar, hoarseness and possible tracheomalacia. leonard rc. chest fikkers bg. anaesthesia j. dellamonica*, a. lyazidi, f. vargas, l. brochard medical icu, henri mondor hospital, creteil, france high frequency percussive ventilation (hfpv) is a technique that delivers small bursts of gas with frequency higher than hz (usually - hz). intrapulmonary percussive ventilation using hfpv has been used during spontaneous breathing, but is also proposed superimposed to conventional ventilation (cv). airway humidification during hfpv has not been studied, however, and is generally provided with an aerosol. a poor airway humidification could lead to secretion thickening and atelectasis. we therefore performed a bench study to assess hygrometry provided by different devices when hfpv is added to cv. methods. circuits have been tested: . a heater humidifier (hh) (fisher & paykel mr ) placed on the inspiratory line of the cv. .& . heat and moisture exchanger (hme) and active hme (ahme) were tested placed at the y piece. for these circuits, hfpv was connected to a branches y piece with inspiratory and expiratory lines of the cv. . hh was connected between hfpv and y piece. all circuits were tested with the aerosol provided by the manufacturer. hygrometry (relative and absolute humidity rh and ah) was measured using psychometric method at y piece. hygrometry provided was compared with non parametric test. p< , was considered significant. conclusion. the minimal level of humidity recommended during prolonged mechanical ventilation is mgh o /l, and the fourth circuit was the only one to provide sufficient ah. temperature drop due to gas acceleration and large admission of gas during hfpv may explain the lack of efficacy of the other devices. coagulation abnormalities are very frequent in critical illness. these, often secondary to sepsis and dic, significantly contribute to mortality in the intensive care unit (icu). thrombelastography (teg ® ), a cell-based whole blood analysis, enables global evaluation of the haemostatic system and the purpose of the present study was to evaluate whether the haemostatic competence on admission to the icu, evaluated by teg ® was associated with mortality in critical ill patients. blood samples were prospectively obtained upon arrival from consecutive patients admitted to a multidisciplinary tertiary icu. teg ® analysis was performed (teg ® haemostasis analyzer, haemoscope corporation, niles il, usa), measuring clot formation,stability and degradation in whole blood. the teg ® parameters r time, angle, and the maximal amplitude ma were evaluated. the r time represents the initiation of the coagulation process (normal reference - min), the ma represents maximal clot strength mainly dependent on the platelet function (normal reference - mm), and angle represents the clot build up, involving fibrinogen function (normal reference - ˚). the primary endpoint of the study was defined as death within days. data are presented as mean (sd). mann-whitney's u-test and fischer's exact test were applied with a p value < . considered statistically significant. the age was . ( ) years in a cohort of . % medical (n= ) and surgical (n= ) patients of whom were male ( . %). length of stay in the icu was . ( . ) days and the apache ii score was . ( . ). thirty-one patients died ( . %). r time ( . ( . ) min vs. . ( . ), respectively; p= . ), ma ( . ( . ) mm vs. . ( . ), respectively; p= . ) and angle was significantly lower in non-survivors than in survivors ( . ( . )v s. . ( . ), respectively; p= . ). patients with a normal teg did receive less cvvhdf ( . % vs. . % (p< . )and had a lower mortality rate ( . % vs. . (p< . ) than patients with not-normal teg. a compromised haemostatic competence on admission to the icu as evaluated by the teg ® r time, angle, and ma are associated with increased -day mortality in un-selected critically ill patients. this finding is consistent with the hypothesis that a dysfunctional haemostatic system could be a central part of developing organ failure and, hence, mortality. this prognostic tool may be useful as a rapid, point-of-care assessment. the possibility of goal-directed haemostatic intervention should be investigated in a randomized controlled trial. n. komitopoulos* , a. kanavou , a. giakoumaki , i. ioannidis , a. komitopoulou , e. varsamis nd internal medicine dpt, biochemistry lab, konstantopoulion general hospital, athens, greece introduction. brain natriuretic peptide (bnp) is a -amino-acid polypeptide mainly secreted by the ventricles of the heart in response to excessive stretching of myocytes. cardiac dysfunction, characterized by reduced ejection fraction, biventricular dilatation and decreased response to resuscitation with fluids, is often present in patients with sepsis. the myocardial depression is probably due to tumour necrosis factor-α and interleukin- β acting in synergy. the aim of the study was to determine whether bnp levels in elderly septic patients are related to the severity of the disease. in patients ( males) with sepsis of various origin, aged ± years, hospitalized in the internal medicine department, bnp serum levels (direct immunochemiluminescence, centaur, bayer) and apache ii score were measured within hours after hospital admission. sepsis was determined according to the criteria of the consensus of the american college of chest physicians and the society of critical care medicine ( ) . patients with acute myocardial infarction were excluded from the study. the mean bnp value (pg/ml) in our subjects was ( - ). the bnp levels in the subgroup of individuals with chronic heart failure (n: ) were higher than those of the rest of the patients [ ( - ) vs ( - ), p= . , mann-whitney test]. a statistical significant difference was also found in bnp levels of the patients with apache ii score ≥ as compared to those of lower score [ ( - ) vs ( - ), p= . , mann-whitney test]. patients who succumbed (n: , %) had extremely high bnp levels [mean: ( - ) ]. a positive correlation was observed between bnp values and apache ii score (linear regression analysis , r= . , p< . ). in conclusion, brain natriuretic peptide was found to be correlated with the severity of sepsis in elderly patients and thus it might be used as a useful prognostic marker in septic process. prometheus ® is a newly developed extracorporeal liver support that combines fractionated plasma separation and adsorption (fpsa) with high-flux hemodialysis. clearance of albumin-bind and water-soluble toxins are achieved in several steps. here we present our results in applications. thirteen patients ( patients with viral hepatitis acute on chronic liver failure, three mushroom intoxication, one liver failure after metastatectomy and one cittrullinemi) have undergone ( . ± . [ - ] ) times fpsa with high flux hemodialysis between june till march in our icu. inclusion criteria were hyperbilirubinemia (total bilirubin > mg/dl), or hepatic encephalopathy (grade ), or inr > . during a six-hours period of application, a variety of clinical and biochemical parameters were assessed; and data before and after the procedure were recorded. seven of the patients survived. one patient has undergone liver transplantation; six survived without liver transplantation. there was a decrease of ± % in total bilirubin per application (from . ± , mg/dl to . ± . mg/dl; p< . ), blood urea nitrogen (bun) was decreased from ± gr /dl, to , ± , gr/dl (p< . ), white blood cell (wbc) increased from , ± , mm to ± , mm (p< . ), albumin decreased from , ± , gr/dl to , ± , gr/dl (p< . ). consequent applications have led to additional decreases in bilirubin. regarding the hemodynamic parameters, there were no significant changes during the procedure. conclusion. fpsa obtained decreases in bilirubin and bun (but also in albumin levels). there can be an increase in white blood cell count. this procedure can be considered a bridge therapy for liver transplantation: it can increase the tolerance time until the liver transplantation or can improve the clinical status achieving a treatment without an organ donation. at present orthotopic liver transplantation is the only treatment modality that provides significant improvement in outcome of hepatic liver failure; but the availability of transplantation is hindered by organ shortage resulting in extended wainting list. extracorporeal liver support devices are effective therapies to overcome periods of descompensation or to bridge until transplantation. although its main therapeutic indication is hepatic failure, the possibility of removing metabolits opens new therapeutics options for other entities. we reports clinical cases where patients were treated with prometheus as a bridge to transplant or to treat refractory pruritus. several analytics results like bilirubin, platelets, creatinine, urea were measured before and after each treatment. extracorporeal liver support devices have recently attracted increasing interest. although its role in liver failure and other conditions with toxin accumulation is yet to be better characterized, we believe that its use may be advantageous and life saving in selected patients. thrombocytopenia is a common problem in the icu and cardiovascular patients. it has been considered to play a role in worsening the prognosis of icu patients. especially patients submitted to cardiac surgery may be exposed to high dose of unfractionated heparin (ufh) infusions, mainly during extra-corporeal circulation. after open-heart surgery, as opposed to other surgical procedures, the platelet count falls, primarily due to platelet damage and destruction in the bypass circuit and hemodilution. heparin is the most common drug to be implicated in thrombocytopenia in icu patients. determining the etiology for the low platelet count is important for the implementation of appropriate management. the use of a direct thrombin inhibitor in treatment should be considered early (< hours) if a diagnosis of heparin-induced thrombocytopenia is possible( ). the aim of the study is to present one case of heparin-induced thrombocytopenia after a mitral valve replacement surgery and to compare the rotational thromboelastometry (rotem) and coagulation tests before and after argatroban administration. an -year-old female patient was hospitalized because of acute mitral regurgitation secondary to chordal rupture and submitted to a mitral valve replacement. past medical history included hypertension, diabetes, chronic atrial fibrillation and mild renal failure. before the surgery, a coronary angiography was performed and revealed normal coronary arteries and a normal left function. after four days using ufh, the platelet count dropped % and the anticoagulation was changed from ufh to low molecular weight heparin. postoperatively, the patient presented in shock, acute renal failure and signs of peripheral hypo perfusion and increased abdominal pressure. seven days after the surgery, the suspicion of hit was confirmed by elisa test for pf -heparin antibodies. heparin was stopped and argatroban was initiated. the patient died from multiple organ failure week later. we evaluate the rotem and coagulation tests (platelets; ptt; tat; pai; ptn-c; fibrinogen; d-dimer and antithrombin-iii) before and after the argatroban use. conclusion. comments: in this case the roteg was as good as a wide coagulation profile test to evaluate the effects of anticoagulation using argatroban in a hit patient. the objective of this study is to evaluate the efficacy and safety of this technique in a multidisciplinary icu environment following a procedures' protocol. it was created a fiberoptic bronchoscopy protocol to implement in a routine basis, and we are testing it in this study. we applied it, in a prospective manner, in every patient undergoing fiberoptic bronchoscopy from january to march , to evaluate the indications, risk factors, the use of drugs (sedatives, analgesics and muscle relaxants) and monitoring (ecg, bp, spo , etco , plateau pressure and blood gas analysis), complications and results of this technique. our sample included patients (medical, surgical and trauma patients), with a median saps ii of ( - ). ten patients had criteria of severe respiratory failure (pao /fio < ). twenty four fbo were done in the study period; for diagnostic reasons ( pulmonary infiltrates, hemoptysis and stridor), for therapeutic reasons (bronchial toilet) and to assist percutaneus tracheostomy. seventeen of our patients had risk factors for this procedure (bronchodilator therapy in patients, pao /fio < in patients, peep > cmh o in patient, platelet count < /mm in patient and altered coagulation screen in another). all exams were successfully concluded. the median procedure time was minutes ( - minutes). beyond sedation, exams were done with topical anaesthesia and with muscle relaxants. concerning safety, the exam was interrupted due to hypoxemia in one patient and due to episodic tachycardia in another patient, both concluded without major problems. two patients showed new pulmonary infiltrates in x-ray evaluation hours after the technique. no significant variation of the pao and paco were noticed during the first hour after the procedure. concerning efficacy, from broncho-alveolar lavage samples, were microbiology positive. one small-cell lung carcinoma was diagnosed by a bronchial biopsy. all these findings have therapeutic relevance. full pulmonary reexpansion was achieved after fbo in cases of lobar atelectasis. conclusion. implementation of a protocol and an individual risk assessment policy may improve safety of bfo in ventilated patients in icu. fbo contributes to valuable diagnostic information and is useful for therapeutic purposes. n. markou* , p. malamos , p. myrianthefs , i. alamanos icu-b, athens university school of nursing icu, kat hospital, athens, greece there is a scarcity of data on the effects on oxygenation of the position of the mixing tube relative to the t-piece and the venturi mask. some data show that while a mixing chamber positioned between the venturi mask and the t-piece is associated with improved oxygenation, positioning of the t-piece between the mixing chamber and the venturi mask has no effect on patients' pao ( ). yet there are no data on an alternative arrangement, with two mixing chambers, one at each end of the t-piece. we relate our experience with this arrangement. we studied critically ill patients who were either intubated or on tracheostomy and who although clinically stable and spontaneously breathing on a t-piece for at least hours could not be extubated. the patients initially (t- ) had one mixing chamber that was positioned between the t-piece and the venturi mask. after sampling of arterial blood gases, a second mixing chamber was inserted at the other limb of the t-piece and arterial blood gases measured again after a further minutes (t- ). patients in whom interruption of these arrangements (for administration of nebulized drugs or for endotracheal suction) was needed at the time period starting at minutes before t- and up to t- , were excluded from the study. during this time period fio for all patients was , . in all patients ( intubated and on tracheostomy) were studied. results are expressed as median and interquartile range. statistical analysis was performed with wilcoxon signed-rank test. there was a significant increase in pao from t- (median mmhg, %- % range - mmhg) to t- (median mmhg, %- % range - mmhg) (p = , ), with no significant change in paco , breathing frequency, arterial blood pressure or heart rate. a second mixing chamber adjusted to the limb of the t-piece opposite to the venturi mask is associated with significant improvements in oxygenation. presumably the second mixing chamber acts as a reservoir with high-content oxygen mixture, and this might be beneficial, especially in patients with higher peak inspiratory flows. percutaneous dilatational tracheotomy (pdt) is one of the procedures more frequently performed at the patient bedside in icu. airway control is usually maintained through an endotracheal tube (ett) but a laryngeal mask airway (lma) can be successfully used as well ( , ). lma ensures a high quality fiberoptic view of laryngotracheal structures; furthermore mechanical ventilation is easier and more uniform with lma than with an ett withheld at vocal folds level. potential disadvantages of lma are the risk of inhalation and a failed ventilation in case of oedematous airway. methods. icu patients were scheduled for pdt in the last three years. all pts were admitted to pdt after a - hours fast time from enteral nutrition. predictive anatomic and anthropometric parameters or history of difficult airway were considered. in case of suspected difficulties in airway management, an evaluation laryngoscopy was made. if tube removal was considered possible, a lma, proportional to body weight, was positioned. the following parameters were registered: • classification of fiberoptic laryngeal view through lma • uniformity of inspired/expired tidal volumes during mechanical ventilation • trends of pco and po during whole procedure by seriated blood gas analysis • need of lma repositioning or its substitution with an ett during the procedure • suspect or clinical evidence of airway inhalation • chest x-ray after pdt results. in patients lma positioning was unsuccessful; in patients lma did not allow an adequate ventilation due to a increasing laryngeal oedema evident at fob endoscopy. in these cases the ett was soon repositioned. in other patients ventilation was maintained thorough lma but an increase in pco higher than % was registered during procedure. in all the other patients we had no problem neither in lma positioning nor in mechanical ventilation. in all our population we did not have any difficulty in airway management. no cases of airway inhalation were registered. conclusion. in our experience lma is an effective and successful ventilatory device during pdt. it improves the quality of endoscopic view, makes easier tracheal puncture and allows a more uniform ventilation. it is important to remember that, before removing ett, we must always evaluate the risks related to full stomach and to the presence of a difficult airway. single dilator technique is increasingly used for percutaneous tracheostomy ( ). although complications have shown a decreasing trend, there remains a concern that the posterior tracheal wall damage can occur during tracheostomy tube placement over a loading dilator. the lip between the loading dilator and the tracheostomy tube tip often causes an obstruction requiring greater force which may be responsible for posterior tracheal wall damage. the percutan tracheostomy set ( tracoe medical, gmbh, frankfurt) claims to overcome this problem by having a tracheostomy tube-loading dilator assembly with a collapsible silicone sleeve covering the tip of the tracheostomy tube. we were interested to evaluate this in practice. a total of patients scheduled for elective pdt were enrolled in this open prospective observational clinical trial. assent was obtained from the immediate relatives. patients were excluded if they had unidentifiable anatomy, severe coagulopathy, a history of difficult tracheal intubation or required significant levels of ventilatory support ( fio > . or peep > cmh o). experienced operators conversant with pdt techniques performed the procedures whilst the airway and bronchoscopy were maintained by an anaesthertist. the trachea was punctured in all cases between the nd and rd tracheal rings and dilated using the percutan single rhino dilator. the tracheostomy tube-loading dilator assembly was then inserted. the ease of tracheostomy tube insertion was graded by the operator on a scale of - , being extremely difficult and extremely easy. all complications were recorded during the procedure. a total male and female patients aged ± years (mean±sd) were enrolled. patients were ventilated for . ± . days (range - days) before tracheostomy. the operating time was . ± . minutes (range - minutes). stoma dilatation and placement of a size tracheostomy tube was successful patients. other two cases required a second dilatation before tracheostomy tube placement. average grade of tracheostomy tube placement was median (range - ). the operators stated that the force required to place the tracheostomy tube was less than that required with other single dilator manufacturers kit. there were no serious perioperative complications and blood loss was estimated for all cases between - ml except in one patient surgical ligation of a venous bleed was required. no significant difference was seen in pre and post tracheostomy arterial blood gases. this study suggests that the percutan tracheostomy set allows a single step dilation of tracheal stoma and relatively easier placement of tracheostomy tube. further randomised controlled trials are warranted to assess its advantages over the other singe dilator techniques. nebulizers designed for use with oxygen or air require high flows of heliox to create aerosol in the respirable range. this aerosol is not well characterized for standard nebulizers and the high flow of heliox is costly. the objective of this study was to characterize the performance of a new breath enhanced nebulizer designed for use with heliox ( / ) gas and compare it to an industry standard breath enhanced nebulizer. using a malvern spraytec laser difractor we measured the aerosol particle size (vmd), total output rate (tor), respiratory fraction (rf) and calculated the respiratory drug delivery rate (rddr = tor x rf). heliox flows of and lpm were used and normal saline was nebulized. we performed trials with each flow. a pari lc plus reusuable breath enhanced nebulizer was used for comparison at lpm source gas flow. table . a novel active humidification system has been developed which can heat and humidify dry therapeutic gases during mechanical ventilation. this study measures the ability of this in-line humidification device (pari hydrate , pari respiratory equipment, midlothian, va, usa) to heat and humidify gas during mechanical ventilation. the new technology (c-force ; pari respiratory equipment) produces water vapor from an in-line, small device placed proximal to the circuit 'wye' in the inspiratory line. a controller allows precise water vaporization and heating directed into the gas flow. this study was performed to determine the performance of this humidification device for mechanical ventilation. we used a puritan bennett mechanical ventilator under various settings to produce minute ventilation volumes of , , , . , and . litres. our test lung (quick lung, ingmar medical, pittsburg, pa, usa) was set to normal lung settings to simulate cp= . l/cm h o and ra= cm h o/l/s. the disposable c-force was inserted into the ventilator circuit inches proximal to the patient wye. gas temp and relative humidity (rh) were recorded at the patient wye using an electronic thermometer and hygrometer. the source gas was dry medical air; measured at % rh and oc. ambient temperature was . oc and relative humidity was . %. although the amount of water and the temperature are adjustable with this device we used a constant temperature setting of oc and the calculated water setting that would saturate the volume of gas using minute ventilation. no attempt was made to optimize the temperature and humidification of the gas beyond these settings. patients were similar in terms of demographics,type of admission and reason for intubation. the overall incidence of severe life-threatening complications was significantly lower in the after group than in the before group ( % vs. , p< . ) (fig ). the implementation of eti management protocol permitted to decrease the incidence of severe life-threatening complications in icu patients. ( , ) . the aim of this study was to review the tracheostomy practice and to determine if either technique was associated with better outcomes in the setting of an inner city general hospital. we identified patients who had had tracheostomies over a / year period (may -dec ) by using our institution's icnarc (intensive care national audit and research centre) database. the case notes of these patients were examined in detail. we divided the patients into two groups (st and pt) depending on method of tracheostomy insertion. patient age, sex, weight and apache score were recorded. we collected figures on icu length of stay (los) and icu & hospital mortality. we also compared the following data: duration from intubation to tracheostomy, time from clinical decision to actual procedure, size of tracheostomy tube inserted and number of tracheostomy days. high flow gas therapy is a new therapy which has been shown to reduce intubations, ventilator days and non-invasive ventilation. the purpose of this study is to determine the efficacy of a novel humidification device (pari hydrate tm g) for high flow gas therapy and compare it to current high flow oxygen humidification devices. we compared aquinox (smiths medical ), mr (fisher & paykel), i (vapotherm) and pari hydrate (pari respiratory equipment). each device was setup as per manufacturer's instructions to heat and humidify medical air at flow of lpm. temperature settings were adjusted to c. we recorded warm-up time from "on" to highest stable temperature when set at c, exiting gas temperature, maximum device surface temperature, and water condensate. water condensate was obtained from a condensation tube connected to outlet side of the devices and measured after minutes. temperature of the condensate tube water was set at c. ( ) suggest that, in patients liberated from mechanical ventilation (mv), the persistence of the tracheostomy tube at discharge from icu to the ward may increase the post-icu mortality rate. our objective was the confirmation of this hypothesis with close attention to selection biases as confounding by indication, patients characteristics and the prognosis at icu-discharge ( ). prospective observational study in the general -bed icu of a tertiary hospital without a step-down unit. inclusion criteria: patients tracheostomized in our icu during a -month period without neurological damage. exclusion criteria: patients tracheostomized before icu-admission, tracheostomies for difficult to control airway, and patients with "do-not-resucitate" orders. data collection: age, gender, comorbidities, severity of illness at icu admission, admission category, indication for tracheostomy, length of icu and hospital stays, length of mv, need for aspiration and characteristics of respiratory secretions, and glasgow coma scale (gcs) at icu-discharge. patients with tracheostomy tube were discharged only to wards with specific "tracheostomy care protocols" with a nurse-to-patient ratio of : - . statistical analysis: multivariate logistic regression analysis adjusted for age, gender, body-mass index (bmi), severity of illness and diagnosis at icu-admission, indication for tracheostomy, duration of mv, glasgow coma scale, need for aspiration and characteristics of respiratory secretions at icu-discharge. lung recruitment (rm) can be considered as an adyuvant for lung protection in the ventilatory support of ards patients. the recruitment pressures needed to achieve full lung recruitment in these patients are generally above cmh o. however little is known about the hemodynamic effects of the brief application of pressures beyond this level in ards patients when using a sequential cycling recruitment maneuver. we , ) that were± mmhg; lis , ±present six ards patients (pao /fio managed with a global lung protective ventilation (lpv) strategy. we used trans-esophageal echocardiography (tee) to assess the effects of a rm using increasing levels of pressure. after confirming hemodynamic stability with predefined criteria, patients were submitted to a cycling sequential rm in pressure controlled ventilation that included three consecutive pip/peep levels of / , / and / cmh o each one of them maintained for min and followed by a min period of pressure reduction to / cmh o before the next pressure level was explored ( ). data were collected during the second minute of each recrutiment step. after rm, lpv was reinstituted: vt - ml/kg and a peep level adjusted to a level immediately above maximum dynamic compliance obtained during a decremental peep trial after recruitment ( ). all patients could be mmhg). no significant decreases in mean±fully recruited (pao + paco systemic arterial pressure (less than % during maximal intrathoracic pressure) and in heart rate were observed. tee measured left (lv) and right (rv) cardiac output (co) and systolic volume (sv) decreased significantly only at rm pressures of and cmh o (around and % respectively). recovery to baseline levels occurred within minutes after reducing the airway pressures (table) . central venous pressure increased progressively to a maximum of % of the baseline value at maximal rm pressures. we hypothesized that patients in acute (arf) on chronic respiratory failure (crf) have complex acid-base disorders and that stewart's quantitative approach may be useful to make the situation clearer. in this approach, plasma ph is dependent on independent variables: strong ion dissociation (sid), total weak acid negative charge (atot) and paco . in a prospective observational study, arterial plasma from consecutive patients with crf, obstructive and restrictive, admitted to our medical icu in arf between november , and april , were studied. they were compared with those from patients with ards admitted to our icu in the same period. in addition, values in patients were compared with those in normal subjects from the literature( ). the plasma values were taken from the samples obtained at icu admission (d ), d and d . arterial blood gas, electrolytes, lactate and albumin were measured and the following variables computed: sid = hco − + albuminate (alb-) + phosphate (pi-)) from reference ( ), strong ion gap (sig) computed from reference ( ), atot= (alb-)+(pi-). the values (mean±sd) were compared using anova (table ) . there was no effect of time on the variables and, therefore, the values in table correspond to icu admission. for statistical similar ph between crf and ards, paco was higher in obstructive crf than ards. sid was not different between crf and normal subjects but greater in crf than in ards, as was sig. atot was lower in ards than in obstructive crf. in crf patients, low ph mostly resulted from hypercapnia without metabolic alkalosis on average. in ards patients, acidemia is mostly metabolic. the positive sig expresses accumulation of unmeasured anions. ( ) open lung approach has been based on a lower inflection point (lip) and an upper inflection point (uip) of the pressure-volume (p-v) curve. but we cannot always find out them, so we examined the method to get maximal compliance point in stead of uip and lip from static compliance curve. in ten patients with ards(ards group) and twelve non-ards patients (control group), we found a maximal compliance point by the static compliance curve induced by differentiation of the pressure volume curve led by polynomial approximation of scattergram of plateau pressure and tidal volume. in the ards group the compliance at the range from to cmh o were smaller than that of the control group (p< . ). but there was no difference between the maximal compliance point of the ards group and that of the control group ( . ml/cmh o at . cmh o vs. . ml/cmh o at . cmh o). we conclude that maximal compliance points were detected in all patients by this method and there was difference of the compliance between the ards group and the control group in low pressure range. p. kopterides* , i. i. siempos , a. armaganidis critical care department, attikon university hospital, department of experimental surgery, "evangelismos" hospital, critical care department, "attikon" university hospital, athens, greece prone positioning is increasingly used to improve oxygenation in patients with hypoxemic respiratory failure, especially those with acute respiratory distress syndromeacute lung injury. however, its benefits in regard to clinical outcomes are uncertain. we performed a systematic review and meta-analysis of the pertinent randomized controlled clinical trials to assess at what extent prone positioning has an effect on mortality and various clinical outcomes in patients with hrf. we conducted a systematic literature search of medline, current contents, and cochrane central register of controlled trials (from inception to january ). we included only rcts(in which prone positioning was the applied intervention and supine positioning the control treatment) that reported clinical outcomes in patients with hrf. there were no language restrictions. four trials met our inclusion criteria, including patients randomized to prone and patients to supine ventilation. data were extracted independently to assess intention to treat intensive care unit (icu) and hospital mortality, days of mechanical ventilation, length of stay, incidence of ventilator-associated pneumonia and pneumothorax, and associated complications of the implemented intervention. data were also collected to assess the quality of the included studies. the pooled odds ratio (or) for the icu mortality in the intention-to-treat analysis was . (confidence interval . - . ), for the comparison between prone and supine ventilated patients. interestingly, the pooled or for the icu mortality in the selected group of the more severely ill patients favored prone positioning (or . ; ci . - . ). the duration of mechanical ventilation and the incidence of pneumothorax were not different between the two groups. the incidence of ventilator-associated pneumonia was lower, but not statistically significant, in patients treated prone compared with patients treated supine (or . ; ci, . - . ). however, prone positioning was associated with a higher risk for development of pressure sores (or . ; ci, . - . ) and a trend for more complications related to the endotracheal tube (or . ; ci, . - . ). despite the limitations of the meta-analysis (ie the included studies were heterogeneous in terms of design, case mix, report of outcomes etc), the available evidence suggests that prone positioning has no discernible effect on mortality in the general population of patients with hypoxemic respiratory failure. it may decrease the incidence of ventilatorassociated pneumonia at the expense of more pressure sores and complications related to the endotracheal tube. however, some data imply that the more severely ill patients may benefit most from the intervention and await confirmation from adequately powered and designed clinical trials. in severe acute respiratory distress syndrome (ards), short-term high frequency oscillation (hfo) and tracheal gas insufflation (tgi) improves oxygenation relative to both standard hfo and ards network conventional mechanical ventilation (cmv)( ). we hypothesized that hfo-tgi may improve pulmonary function indices relative to cmv, if repeatedly employed on a daily basis. thirty adult patients with severe ards {pao /inspired o fraction (fio ) < mm hg at peep > cm h o}were randomized to receive either low tidal volume cmv ( - ml/kg predicted body weight) alone or in combination with daily, - -h-lasting hfo-tgi until resolution of severe ards or death. primary end-points were the time courses of gas exchange, respiratory mechanics, and hemodynamics. survival to days following randomization was also evaluated. data from all patients were analyzed. patient clinical profiles were similar. median hfo-tgi use was h/day for days. within the first eight days following randomization, study (hfo-tgi) group patients vs. controls had higher pao /fio ( . - . ± . - . mm hg vs. . - . ± . - . mm hg; p < . - . ) and quasistatic respiratory system compliance, and lower oxygenation index ( . - . ± . - . vs. . - . ± . - . ; p < . - . ), shunt fraction, and plateau and mean airway pressures. hemodynamics were not significantly affected by hfo-tgi. there was a trend toward improved -day survival in the study group vs. control ( / vs. / , p = . by fisher's exact test). in severe ards, the systematic daily use of hfo-tgi substantially improves gas exchange and respiratory mechanics. pressure-volume (pv) curve could help knowing which patient can benefit from a recruitment manoeuvre (rm). this study has been design to compare the hys of the quasi-static pv curve and the volume recruited by a rm. after ethical approval and relatives informed consent, early onset (< h) ards patients were investigated (igs ii = [ - ], lis = , [ , [ ] [ ] [ ] ] ). patients were sedated and paralyzed throughout the study. a to cmh o pv curve (pv tool, hamilton medical) was realized to measure hys i.e. the surface between the inflation and deflation curve measured between and cmh o. after min of ventilation, a rm consisting of a seconds pause at cmh o was realized using the pv tool. the volume recruited during the seconds/ cmh o rm was obtained by integration of the flow signal necessary to maintain the pressure of cmh o. no correlation was found between the lower/upper inflection points and the point of de-recruitment on the deflation limb of the pv curve. the volume recruited during a pause at the end of the inflation curve was well correlated with hys (r = , ; p = , ) (figure). in the early course of ards, the hys of the pv curve may be an indicator of how much the lung can be recruited by a seconds/ cmh o rm. treating acute respiratory failure (ali/ards) in the icu often requires mechanical ventilation, which carries a risk of vili. it is now commonly accepted that these patients should be ventilated "gently", i.e. reducing transpulmonary pressure fluctuations during ventilation. it is however still much debated as to how peep should be applied. methods to identify "best peep" are based upon descriptions of respiratory mechanics. however, only little is known as to how changes in peep modify pulmonary gas exchange. pulmonary gas exchange is usually described by arterial blood gas analysis or over-simplifying models such as the pao /fio ratio, the alveolar-arterial oxygen difference or the effective shunt. we describe the use of a more complex two-parameter model ( ) describing the effects of a peep-change using routine icu equipment. this method has potential for non-invasive use and may be incorporated in standard respiratory monitoring. eleven adult patients with acute respiratory failure on mechanical ventilation were included in the study. the patients were studied at two different levels of peep, i.e. either increasing or decreasing peep with cmh o. on each occasion the fio was varied in - steps to achieve values of sao ranging from - %. at each fio level measurements were taken of ventilation and arterial acid base and oxygenation status. these data were then used to estimate pulmonary shunt (shunt) and a measure of ventilation/perfusion mismatch, i.e. deltapo . upon increasing peep shunt decreased significantly by % (median) in patients, whereas deltapo improved in patients by kpa (median). as assessed by the p/f ratio oxygenation improved in patients by kpa (median). the increase in p/f ratio was, however, in cases explained by decreased deltapo not shunt. in patients where p/f-ratio was unchanged the value of shunt decreased significantly. the results suggest that by describing gas exchange by shunt and deltapo additional information can be obtained. these information may enable improved assessment of potential for recruitment and/or peep optimization. further studies are warranted. optimal peep avoids ventilator induced lung injury. this study determined the value of the elimination time-constant for co (tau-co ) to assess optimal peep. methods. pigs received lung lavage and hrs of injurious mechanical ventilation. a recruitment maneuver (rm) was performed for ' at / cmh o of peep/plateau pressure. the open lung peep (ol-peep) was defined as the level of peep after rm that kept the lung free from collapse. ol-peep was determined by respiratory dynamic compliance (cdyn), during a peep titration trial using the open lung tool ® (maquet, sweden), which was performed in vcv at a vt of ml/kg while decreasing peep from to cmh o in steps of cmh o every ' ( ). thereafter, we randomly assigned six ' periods at diff. peeps: ol-peep and peep either cmh o above or below it both, in recruited and non-recruited conditions. baseline ventilation was applied between study periods. we recorded dynamic lung mechanics and volumetric capnography data on a breath-by-breath basis (nico, respironics, usa). abg data were collected at the end of each period. paco was added to volumetric capnography to perform a complete dead space analysis using the standard bohr-enghoff formula. tau-co was calculated multiplying the respiratory time constant (cdyn x raw) by the amount of co eliminated per breath (vtco ,br). lung mechanics and gas exchange were best at ol-peep after rm. tau-co was longest at this moment due to an increase in both, cdyn and vtco ,br. the increase in cdyn and the decrement in raw slowed down peak expiratory flow during ol-peep ventilation. a reduction in vdalv/vtalv after rm and ol-peep indicated an increased ventilatory efficiency ( ) . vdalv/vtalv was more sensitive for determining ventilatory efficiency than the classical vd/vt. positive pressure ventilation in patients suffering from acute lung injury (ali) affects both, the distribution of ventilation (v) and perfusion (q) within the lungs. the aim of this work was to study the effect of lung recruitment and peep on v/q as assessed by multiple inert gas elimination technique (miget). a recruitment maneuver (rm) was performed for ' at / cmh o of peep/plateau pressure. the open lung peep (ol-peep) was defined as the level of peep after rm that kept the lung free from collapse. ol-peep was determined by respiratory dynamic compliance (cdyn), during a peep titration trial using the open lung tool ® (maquet, sweden), which was performed in volume control at a vt of ml/kg while decreasing peep from to cmh o in steps of cmh o every ' ( ). thereafter, we randomly assigned six 'periods at diff. peep levels: ol-peep and peep either cmh o above or below it both, in recruited and non-recruited conditions. baseline ventilation was applied between study periods to standardize lung volume history. we recorded dynamic lung mechanics on a breath-by-breath basis. hemodynamic data were recorded continuously and discont. by the picco monitor (pulsion, munich, germany). miget and abg data were collected at the end of each study period. ventilation at ol-peep after a rm resulted in better oxygenation and lung mechanics, lower shunt and lower amounts of areas with a high v/q as compared to the other periods studied (table) . recruited lungs ventilated at ol-peep showed better gas exchange and ventilatory condition than any other condition studied. these findings show that rm in conjunction with ol-peep make ventilation and perfusion more homogeneously distributed within the lungs and lead to an adequate matching of both. the onset mechanism of ali/ards and subsequent tissue injury are considered to be associated with neutrophil elastase, and the main two causes( direct lung injury: group d. and indirect lung injury: group i) of ali/ards are considered to be pneumonia ( bacterial, fungal, viral et al), aspiration pneumonia and sepsis. in japan, sivelestat sodium hydrate, a selective elastase inhibitor, was approved in for ali/ards accompanied by sirs, and this medicine has been evaluated in clinical situation. in this study, we performed a retrospective comparison of the sivelestat sodium hydrate administration between two groups of patients: group d, consisting of patients ( males and females, aged ± years old) , and group i, consisting of patients ( males and females, aged ± years old) with ali/ards accompanied by sirs who were treated with sivelestat sodium hydrate at a dose of . mg/kg/hour for hours or more in the icu. il- , il- , elam- (endothelial leukocyte adhesion melucule- ), pai- (plasminogen activator inhibitor- ) and pct (procalcitonin) were measured every hours. elisa and eia methods were used for the measurement of il- , pai- and elam- , respectively, and icl method was used for pct. the apache ?scores of group d and group i were ± and ± , and the lung injury score(lis) were . ± . and . ± . , respectively, with no significant differences between the groups. sofa scores of group d and group i were ± and ± , which was significantly higher than that of group d (p< . ). the pao /fio ratios under mechanical ventilation management , and hours after the beginning of drug administration were ± , ± , and ± mmhg in group d, and ± , ± , and ± mmhg in group i. furthermore, the survival rate after days was significantly higher in group d than in group i (group d: . %, group i: . %, p< . ). these results suggest that sivelestat sodium hydrate is a good option as a treatment strategy for neutrophil elastase-associated direct lung injuries accompanied by sirs. grant acknowledgement. no disclosure pulmonary edema significantly contributes to ventilation-perfusion mismatching and hypoxemia in ards. while inhaled nitric oxide (ino) has been shown to lower pulmonary pressures and edema accumulation in experimental acute lung injury (ali)( ), its clinical use has been questioned because of a lack of improvement in outcome, rebound phenomena and potential toxicity. we investigated the effects of aerosolized iloprost, a stable prostacyclin analogue, compared to ino on pulmonary pressures and lung edema in oleic acid lung injury. the most effective dose of iloprost in this setting was determined in healthy animals prior to the experiment. the anesthetized and ventilated sheep received a central venous oleic acid infusion ( . ml/kg) and were continuously infused with ringer's lactate to achieve a positive fluid balance ( ml/kg/h). in the ino group (n= ), inhaled nitric oxide ( ppm) was then administered continuously for hours, while animals in the iloprost group (n= ) received aerosolized iloprost ( µg every hours). animals in the control group (n= ) had no further intervention. pulmonary edema was measured by transpulmonary thermodilution (extravascular lung water). oleic acid infusion was associated with impaired oxygenation, pulmonary hypertension, and lung edema in all groups. while ino significantly decreased pulmonary vascular resistance index (pvri), effective pulmonary capillary pressure (pceff), and extravascular lung water index (evlwi), both parameters were unaffected by iloprost. oxygenation index (pao /fio ) increased significantly both during no and iloprost inhalation but also tended to improve in the control group over time. conclusion. this is the first study directly comparing the effects of inhaled nitric oxide and aerosolized iloprost on pulmonary hemodynamics and lung edema in experimental lung injury. in contrast to ino, µg iloprost inhaled every hours was ineffective to reduce pulmonary pressures and extravascular lung water. these findings partly contradict previous investigations, and may be best explained by dissolution of the highly water soluble iloprost in alveolar edema, which is a common finding in oleic acid lung injury. much higher doses of iloprost may thus be required to achieve a reduction of pulmonary pressures and fluid filtration when alveolar edema is present. while inhaled nitric oxide (ino) may be used in the management of ards, data would suggest that its benefits pertain to a short-term improvement in oxygenation with no significant beneficial effect on mortality . we performed a retrospective audit on the use of ino in our mixed medical and surgical intensive care unit. the following data were collected; age, apache ii score, length of icu stay, duration and cost of ino therapy, percentage change in pao /fio ratio, icu mortality. patients were sub-divided into responders/non-responders and survivors/non-survivors. a response to ino was defined as > % increase in pao /fio ratio . results are displayed in the table below. five responders survived to icu discharge ( . %), while non-responders survived ( . %). this difference did not reach statistical significance (p = . , chi-square). the total group costs of ino for responders, non-responders, survivors and non-survivors were £ , , £ , , £ , and £ , respectively. responders only accounted for % of the total ino expenditure in our icu. conclusion. ino is an expensive therapy. in this small retrospective audit we were unable to show any significant benefit of ino on outcome. the use of ino within our icu needs to be reappraised, especially in those ards patients classified as non-responders. the pvm tool of the respirator was easy to use. we observed no clinically evident haemodynamic complication. as a consequence of the pvm peep was increased in patients from ± to ± cm h o and decreased in patients from ± to ± cm h o. peep was not changed in two patients. there was a significant increase in pao /fi o ratio from ± to ± (p= . ) ( figure) while the change in paco was not significant ( ± versus ± ; p= . ). changes in peep did not correlate with changes in paco (r = . ; p= . ). after the implementation of the pvm into commercially available respirators, this manoeuvre can be performed safely and quickly. the setting of peep according to the results of the pvm lead to an improved oxygenation of the patients. we conclude that patients with ali/ards may profit from a routinely performed pvm. introduction. ards is a common syndrome with a high mortality rate in intensive care units. several pharmacological therapies have been proposed but none of them improved survival up to now. pulmonary hypertension occurs already in early stages of the disease and its magnitude has been shown to be associated with poor outcome. the phosphodiesterase type inhibitor sildenafil selectively dilates pulmonary vessels and has been approved for treatment of pulmonary arterial hypertension.. we investigated the effects of oral sildenafil in combination with inhaled prostacyclins in five patients with ards and septic shock. five patients with severe ards were investigated. underlying diseases were: copd (n= ), small airway disease (n= ), idiopathic fibrosing alveolitis (n= ), as well as cardiac insufficiency (n= ). four patients showed severe obesity, mean bmi was , ( ± , ). all patients fulfilled criteria of septic shock, three of them developed acute renal failure requiring continuous venovenous hemofiltration. all patients were monitored by a pulmonary artery catheter. mechanical ventilation was carried out according to recommendations of the ards-network. prone positioning (at intervals of hours) was instituted if possible. inhaled prostacylins (iloprost) were given times daily (max. concentration µg/d). if no persistent improvement of oxygenation could be achieved, sildenafil was added per os ( x mg/d). the combination of oral sildenafil ( x mg/d) and inhaled prostacylins resulted in a significant decrease of the mean pulmonary arterial pressure (pap-m). on the third day of therapy pulmonary arterial pressure was reduced by about % of the initial value (table ) . within a week a % improvement of the horowitz indices could be achieved. administration of sildenafil was continued in four patients until they could successfully be weaned from mechanical ventilation. these four patients left hospital alive. one patient died because of cardiogenic shock. , ± , * * significant difference from day (p < , ) conclusion. sildenafil in combination with inhaled prostacyclins causes significant reduction of pulmonary arterial hypertension as well as significant improvement of oxygenation in patients with ards and septic shock. increasingly the mouse has become the experimental animal of choice in immunological research because of the large set of immunological tools that is available. this is of particular interest in the area of inflammatory and immunological response to mechanical ventilation. most available rodent ventilators only ventilate one mouse at a time. in order to expedite the results of interventions, larger series of mice must be ventilated in a short period of time. therefore, we developed a method to ventilate mice simultaneously using a conventional ventilator. twelve mice were anesthetised, tracheotomised and subsequently connected to a servo ventilator c with a distribution system allowing simultaneous ventilation of six mice. a canula was inserted into the carotid artery for bloodsampling. for consecutive hours the mice were ventilated in a pressure-controlled, time-cycled mode, pip cm h o, peep cm h o, i/e ratio of : , fio . and a frequency of /min. during the hours of ventilation, arterial bloodgasses were collected after various periods of ventilation, with a maximum of bloodsamples per individual mouse. (n= ) not only demonstrated normocapnia (paco . ± . ) but also a normal ph (ph . ± . ) and adequate oxygenation (pao . ± . ). six mice can be ventilated simultaneously using a servo ventilator c with a distribution system, thereby decreasing the number of days spent to the experimental procedure and expediting experimental time. pulmonary vascular permeability increases in response to lung overstretching. phosphoinositide -kinase gamma (pi k gamma) is activated by mechanical stretch. akt, a major downstream signal molecule of pi k gamma, induces nitric oxide (no) production. we investigated the contribution of pi k gamma to acute alveolar edema formation by mechanical stretch. in wild type (wt) and knock-out (ko) pi k gamma mice, lungs were ventilated and perfused with two settings: eip - cmh o and eep cmh o (stress) or eip - cmh o and eep - cmh o (no stress). at the end of each experiment histological alveolar edema, lung elastance, pulmonary expression of erk, akt, enos, nitrate/nitrite (nox) on pulmonary perfusate were measured. see table . data are mean ± sd. during high stress ventilation vascular permeability changes were pi kgamma, akt, enos mediated. the lack of pi k gamma activity protected from alveolar edema increases. recent experimental data suggest that intrapulmonary cxc chemokine release, neutrophil infiltration and myeloperoxidase activity is considerably increased in aged individuals [ ] . years represented the best age threshold value that discriminated survival in mechanically ventilated patients [ ] and, we speculated that inflammatory responses may differ considering this age threshold. in patients bronchoalveolar lavage (bal) was performed with aliquots of ml . % saline on initial hospital presentation within hours after multiple trauma. cytokines were quantified using a sandwich immunoassay and neutrophil secretion products were determined with immunoluminometric assays. bal-phospholipids were determined with electrospray ionization mass spectrometric analysis. we compared older (> years, n= ) with younger patients (< pg/ml) (n= ) using the mann-whitnes-u-test or fisher's exact test and used the spearman rank correlation to assess relations between inflammatory parameters and age. older patients (mean±sd, . ± . years) had similar injury severity scores, thoraxtrauma severity and pao /fio -values as compared to younger patients ( . ± . years) (p> . ). of the older and of the younger patients developed ards (p> . ). only one patient died days after trauma. he was years old and developed ards due to sepsis weeks after trauma. intraalveolar il- release and both pulmonary and systemic neutrophil activation as reflected by myeloperoxidase and lactoferrin concentrations were reduced in older compared to younger patients (p< . ). pulmonary inflammatory parameters decreased significantly with increasing age: bal-neutrophils (rho=- . , p= . ), the inflammatory cell membrane phospholipid phosphatitylinositol : / : (rho=- , , p= . ), bal-lactoferrin (rho=- . , p= . ) and bal-il- (rho=- . , p< . ). in contrast to experimental data proinflammatory responses were reduced in aged individuals. it is tending to speculate that reduced immune competence instead of exacerbated inflammation may contribute to worse prognosis seen in the aged given an inflammatory insult. design: prospective, randomized controlled study. setting: medical and surgical intensive care units in a university tertiary care centerpatients: a total of patients with localized ards ready for recruitment maneuver (rm) were included. intervention: patients were randomized to receive mechanical ventilation (mv) in supine (smv, control group) or in prone position (ppmv, study group). both groups were ventilated with protective lung strategy (tidal volume to ml/kg). an rm was applied using a pressure control mode (pcv) with a cm h o and a cm h o peep for s. peep was subsequently reduced by cm h o increments until a decrease in compliance was observed. a second rm was then performed and peep was set one step above the level at which compliance declined. pcv level was kept at cm h o during the determination of optimal peep. results: bronchoalveolar lavages (bal) and blood samples were collected before randomization and at hours to determine the concentrations of interleukine (il- ), interleukine (il- ), interleukine (il- ) and tumor necrotic factor (tnf-±), pao / fio . pao /fio was improved and paco was lower in ppmv when compared with smv with statistic significance. at hours after rm, il- ( p = . ), il- ( p = . ) and il- ( p = . ) in bal was lower in the ppmv group than smv group. the serum level of il- ( p = . ) and tnf-± ( p = . ) were reduced with statistic significance and il- was reduced also (p = . ) for the ppmv group. conclusion. ppmv may improve oxygenation and reduce pco than in the smv position in patients with the localized ards during rm. the pro-inflammatory cytokines can be reduced during ppmv, which indicates attenuation of vili during pcv with peep recruitment maneuver for these patients. grant acknowledgement. this research is sponsored by the grants of vghnsu - . inflammatory cytokines have been found to be elevated in bronchoalveolar lavage fluids (balf) of ards patients. mediators formed from n- fatty acids (fa) and those developed from n- fa have opposite influences upon inflammatory processes. the aim of this study was to investigate whether n- fa may modulate inflammatory cytokines release in a cell culture of human pneumocytes exposed to balf of ards patients. thirty-one patients ( males, ± yr, sapsii ± ) with ards (as defined by the american-european consensus conference) requiring mechanical ventilation were included in the study. the p. were divided into those with pulmonary ards [ardsp, pneumonia (pn) n= ], and those with extrapulmonary ards (ardsexp, sepsis n= ; other n= ) without pn. all p. were examined by bal for clinical purposes within h after intubation. tnf-alpha, il- beta, il- and il- levels were measured in balf. we exposed a cells, a human pulmonary cell line with type ii pneumocyte properties, to the collected balf. after h, fa were added as docosahexaenoic acid (n- ) and arachidonic acid (n- ) in two different n- /n- ratios ( : and : ). h later, culture supernatants were collected to evaluate cytokine and prostaglandin (pg)e release. the fa percentage content was determined in phospholipids of a cells. level of peroxisome proliferator-activated receptor (ppar)gamma and nf-kb binding activity were determined. cytokine levels in balf were found higher in ardsp than ardsexp (p<. ). the baseline n- /n- fa ratio of : in a cell phospholipids approximately dropped to : and raised to : after : n- /n- ratio and : ratio incubation, respectively. we found that pge levels were significantly lower in a cells treated with the : ratio than those with : (p<. ). the release of cytokines from a cells was reduced by the : ratio (p<. ), but increased by the : (p<. ). nf-kb activity was induced in a cells by balf. addition of : ratio to the cells resulted in an increased expression of ppargamma, whereas nf-kb activity was more inhibited compared to : (p<. ). our results showed that increasing the n- share in n- /n- fa ratio induces a significant reduction of pro-inflammatory mediator (cytokines,pge ) release in stimulated a cells, whereas the administration of an n- fa predominance increases their release. although different cytokine levels in ardsp vs. ardsexp, the cause of ards did not influence the effect of n- addition. fa are ligands for ppargamma. our results suggested that n- fa might exert their anti-inflammatory effects through direct actions on the intracellular signaling pathways which lead to activation of ppargamma and inhibition of nf-kb activity. inflammatory response in a cells exposed to balf can be modulated by n- fa, due to their incorporation into membrane phospholipid pools that modifies lipid-related intracellular signaling events. th esicm annual congress -berlin, germany - - october s type plasminogen activator inhibitor (pai- ) is one of the primary regulators of fibrinolysis in vivo. a - g- g sequence polymorphism in the promoter of the pai- gene has been described as response polymorphism, since its release is regulated by various inflammatory factors. elevation of pai- levels after stressful events is much more pronounced in patients with the g allele. thus, the formation of microthrombi is no longer counteracted by the fibrinolytic system, resulting in impaired microcirculation, multiple organ dysfunction and poor outcome. our aim was to study the impact of the g allele on the survival rate of ali-ards patients. methods. ali-ards ( ali) due to sepsis ( ), pneumonia( ), aspiration ( ), severe trauma ( ), cardiac surgery ( ), pancreatitis ( ) and pulmonary embolism ( ) were studied. the mean apache ii score was ± . identification of the g- g polymorphism was based on polymerase chain reaction and reverse-hybridization. the comparison of the death rates between the two polymorphism groups ( g g versus non- g g group) was done by means of a logistic regression model, with survival as the dependent variable and the polymorphism, as well as the apache score, as the independent variables. . patients died (mortality . %). patients had a genotype g- g, patients were g- g heterozygous, while were g- g homozygous. apache scores were not significantly different between subgroups. the death rate among the g- g patients was %, while in the non- g- g patients was %. the univariate analysis showed that the g- g patients had % higher odds of dying compared to the non- g- g patients (odds ratio = . , % ci: . to . , p-value= . ). in the multivariate analysis the g- g patients had approximately . times higher odds of dying compared to the non- g- g patients (odds ratio = . , % ci: . to . , p-value= . ). however results were not statistically significant. our findings suggest a negative effect of this polymorphism on the survival odds of ali-ards patients. however, the small number of patients limited our power to detect a statistically significant difference regarding its influence on the prognosis of ali-ards patients with disorders triggering the coagulation cascade. our data might support further research on the relation between g- g polymorphism and outcome of ali-ards patients. excessive production of nitric oxide by neuronal nitric oxide synthase (nnos, nos- ) is one major factor in the pathogenesis of acute lung injury and systemic inflammation after burn and smoke inhalation injury. we hypothesized that the use of the selective nnos inhibitor -nitroindazole ( -ni) will block molecular mechanisms in ovine acute lung injury. adult ewes (n= ) were chronically instrumented to determine cardiopulmonary hemodynamics and pulmonary transvascular fluid flux. after seven days of recovery, sheep were randomly allocated to either an injured untreated control group (n= ), or an injury group treated with -ni (n= ). the injury consisted of a % total body surface area flame burn and breaths of cotton smoke. -ni ( mg/kg/h) was continuously infused from h post injury to the end of the -h study period. this double hit injury was associated with oxidative stress, severe pulmonary derangements and systemic inflammation, as evidenced by a . -fold increase in plasma nitrite/nitrate (nox) levels, as well as -fold, -fold, -fold and -fold increases in interleukin- (il- ), myeloperoxidase (mpo), malondialdehyde (mda) and poly-adp-ribose-polymerase (parp) lung tissue concentrations, respectively. compared to untreated controls, -ni significantly reduced nox plasma levels ( . ± vs. ± µmol/l) and decreased il- , mpo ( . ± . vs. . ± . u/g tissue), mda ( . ± . vs. . ± . nmol/mg protein) and parp lung tissue content ( . ± . vs. . ± . ), thereby decreasing pulmonary obstruction ( . ± . vs. . ± . obstruction score) and increasing pao /fio ratio ( ± vs. ± , each p< . ). these data show that nnos-derived no plays a pivotal role in the pathophysiology of combined burn and smoke inhalation injury and suggest selective nnos inhibition as a useful approach to attenuate pulmonary injury. h. qiu*, p. li, y. yang department of critical care medicine, nanjing zhong-da hospital, nanjing, china hpmecs were cultured, and used lps with a gradient concentration ( ng/ml, ng/ml, ng/ml, and ng/ml) to stimulate the cells for h, h, h, and h. subsequently, the experiments below were carried out. total ribonucleic acid was extracted from the cells for reverse transcription polymerase chain reaction (rt-pcr) to identify the expression level of angii receptor mrna. the total protein was extracted from the adhere cells for western blot to identify the protein expression of the at receptor. radioreceptor assay (rra) was used to obverse the affinity (kd) and maximum receptor binding (bmax) of angii with its receptor after lps stimulation. rt-pcr demonstrated that angiotensinii type (at ) receptor mrna level escalated after varying concentrations lps stimulating in h, h, h and h. there was obvious time-dependent increase in ng/ml group. the level of the at receptor mrna in ng/ml and ng/ml groups have not time-dependent increase. irrespective of lps stimulating or not, hpmecs didn't express mrna of angiotensinii type receptor (at ). western bolt presented that the protein level of at receptor had a predominant increase followed the lps treat compared with control group ( ng/ml). after stimulated for h, the level of at receptor protein reached to the peak value in ng/ml group, and no notable difference was defined at every time after that. the significant dose-dependence was showed in every stimulating time, but the time-dependence was defined just in ng/ml and ng/ml groups. rra was confirmed that there was no striking statistics difference between each group for kd. as far as bmax is concerned, bmax of the three groups ( ng/ml, ng/ml, and ng/ml) had a significant increase compared with the control group. the groups of ng/ml and ng/ml had peak value at h and h respectively, and had a significant decrease after respective peak value time. the bmax of the ng/ml group escalated to the peak value and demonstrated a notable time-dependence. lung ischemia and reperfusion in the pulmonary vascular compartment is an unavoidable consequence of transplantation. it is associated with release of inflammatory mediators promoting chemotaxis and adherence of neutrophils, which finally disrupt endothelial cell layer and increase permeability, possibly leading to acute lung injury ( ). rare data exist about similar mechanisms in the upper and lower respiratory compartment with tracheobronchial (tbec) and alveolar epithelial cells (aec). purpose of this study was to evaluate the effect of hypoxia/re-oxygenation (h/r) regarding the inflammatory response in the respiratory compartment. aec and tbec were placed in a hypoxic incubator with % oxygen for hours and re-oxygenated at % oxygen during , , and hours. for each time point, control cells were left at % oxygen. supernatants were analyzed performing a sandwich enzymelinked immunosorbent assay (elisa) for mcp- and cinc- (pharmingen, san diego, ca). caspase- and ldh measurements were performed. statistical significance was assessed by student's t-test. (values: mean ±sem). protein expression of mcp- and cinc- in aec was decreased upon h/r: at h hypoxia with h re-oxygenation mcp- decreased fromm ± pg/ml to ± pg/ml (p< . ), cinc- from ± pg/ml to ± pg/ml (p< . ). at h/ h h/r no difference in mcp- and cinc- expression could be observed in comparison to control cells. interestingly, inflammatory mediators released from tbec did not show any differences upon stimulation compared to control cells. caspase- activity in stimulated and unstimulated aec was similar. in tbec, however, caspase- activity was decreased by % at h/ h h/r, at h/ h by %, and at h/ h by % (p< . ). ldh values did not differ in stimulated and unstimulated aec and tbec, indicating that no process of necrosis is involved. upon h/r the lower respiratory compartment with aec reacts with decreased production of inflammatory mediators, while the upper compartment with tbec shows diminished apoptosis rate. biological significance of this attenuation of epithelial injury upon h/r has to be further investigated. , . : - grant acknowledgement. société suisse d'anesthésiologie et de réanimation schweizerische gesellschaft für anästhesiologie und reanimation: ssar/sgar methods. ards was induced in healthy pigs ( ± kg) by repeated saline lung lavage until pao decreased to less than mmhg. after a stabilisation period, the animals were randomly assigned to two groups: cmv: fio = . , vt = ml/kg, and hfov/av-ecla: fio = . , frequency = - hz. after lung recruitment, the peep in the cmv group and the mean airway pressure (mpaw) in the hfov/av-ecla group was set cmh o above the lower inflection point (lip) of the p/v-curve. gas exchange and hemodynamic data were determined hourly. after h, mrna expression of tnf-alpha, il- -beta, il- , il- and il- in lung tissue was quantified by real time pcr. histopathologic analysis from the lungs was performed using a four point semi-quantitative severity based scoring system. ( ). h s also exerts a variety of cytoprotective effects in vitro and in vivo ( ) . therefore, we tested the potential cytoprotective effect of infusing the h s-donor nahs during porcine thoracic aortic occlusion-induced ischemia/reperfusion(i/r)-injury. methods. after random assignment to either nahs (n= ); mg/kgxh started h before and continued until h after aortic occlusion) or vehicle (n= ) anesthetized, ventilated and instrumented pigs underwent min of aortic occlusion using inflatable balloons placed immediately downstream the a.subclavia and upstream the aortic bifurcation. during aortic occlusion, mean arterial pressure (map) was maintained between - % of the baseline levels using continuous i.v. esmolol, nitroglycerine and atp. during the reperfusion continuous i.v. noradrenaline (na) was titrated to maintain map> % of the baseline level. dna damage in blood samples was evaluated with single cell gel electrophoresis (tail moment in the comet assay). data are median (range), within group effects over time were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. results. infusing nahs resulted in significantly lower heart rate and cardiac output, while map and stroke volume remained unchanged. nahs significantly reduced the na requirements needed to achieve the hemodynamic targets, significantly decreased glucose turnover, and completely blunted the i/r-induced dna damage (see septic shock is associated with increased oxidative stress, which in turn depresses mitochondrial activity. the key antioxidant enzyme superoxide dismutase (sod) was reported to restore mitochondrial function ( ). since glucose oxidation represents the most effective energy generating process, we investigated the effect of genetic cuzn-superoxide dismutase overexpression on glucose oxidation in a clinically relevant model of murine septic shock ( ) . h after sepsis induction by cecal ligation and puncture (clp) or sham-operation heterozygous (he), homozygous (ho) sod overexpressing and wildtype (wt) mice were anesthetized, mechanically ventilated and instrumented. in the clp groups normotensive, hyperdynamic hemodynamics were achieved with colloid fluid resuscitation and intravenous noradrenaline (na) titrated to maintain mean arterial pressure (map) > mmhg. glucose oxidation rate was calculated from simultaneous determination of co enrichment and co concentration (gas chromatography/mass spectrometry) in the expired gas during continuous i.v. stable-isotope , , , , , - c -glucose infusion. measurements were recorded , and h after clp. within group effects over time were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. all parameters of gut and liver macro-and microcirculatory perfusion and oxygenation were well maintained. na infusion rates did not differ between clp groups. glucose oxidation (percentage of the infused c -glucose) did not differ between groups nor over time. liver sod-activity prior to anesthesia and surgery was . -fold and -fold higher in he and ho mice, respectively. while it decreased by about % in the septic he and ho mice, sod activity was not significantly affected in the wt animals. given the comparable parameters of macro-and microcirculatory perfusion and oxygenation, the lacking na-induced increase in glucose oxidation rate confirms the sepsis-related defect in energy metabolism. the higher tissue sod-activity did not restore the impaired carbohydrate utilisation, possibly due to a sepsis-related loss of tissue sod and/or catalase activity. anemia is frequent in icu and involved both functional and true iron deficiency due to inflammation and blood loss. hepcidin (hepc) is a negative regulator of iron recycling by macrophages. its synthesis is highly inducible by inflammation and repressed by iron deficiency and stimulation of erythropoiesis. we explored iron metabolism and hepc gene expression in this complex situation of icu anemia. we developed a model of inflammation in c bl/ mice, by ip injections of zymosan (z), combined or not with repeated blood withdrawals (w). we followed blood numeration and tissue iron concentrations. using qrt-pcr, we quantified hepc and il- mrna in the liver as well as erythropoietin (epo) mrna in the kidney (normalised to s mrna and expressed as a ratio to controls (c)). hepatic ferroportin protein concentrations were assessed by western-blot. kruskal-wallis or anova were used for comparisons of mean±sd. p< . significant. anemia was found already days after zymosan injection, and was more severe blood withdrawals, either alone (w) or following z (z+w). at day , epo mrna expression was stimulated in both w ( . ± ) and z+w ( ± . ), as compared to c( ± . ) or z ( . ± . )(p< . ). as expected, z injection induced il- mrna expression ( . ± . for z; . ± . for z+w). interestingly, hepc mrna was induced following z injection ( ± . ) but the combination of inflammation and w repressed hepc mrna expression ( . ± . ). to confirm that it was due to erythropoiesis stimulation, we injected epo on consecutive days following z and found that it prevented activation of hepc mrna( . ± . ). in mice undergoing w or epo injections, spleen iron was reduced, as opposed to c and z ( ± , ± , ± , ± vs ± and ± µg/g for z+w, w, z+epo, epo, c and z). ferroportin was reduced in z and increased by w and epo (western-blot). conclusion. in this mouse model of inflammation, induction of hepc gene expression is prevented by repeated w or epo ip. it seems that the signalling pathway which represses hepc expression in response to activation of erythropoiesis dominates over the pro-inflammatory signal. furthermore iron exporter ferroportin is also induced. these results raise the possibility that iron supplementation might be proposed for critical care patients' anemia. studies examining the effect of glutamine supplementation in critical illness have demonstrated significant beneficial effects in animals and man although the mechanisms by which this protection occurs are not understood. we aimed to examine the effect of various glutamine concentrations on the ability of c c myoblasts to differentiate and its effect on heat shock protein expression (hsp). methods. c c myoblasts were raised under standard conditions. differentiation to multinuclear myotubes was induced by replacing fcs with % horse serum. cells were supplemented with glutamine at concentrations between and mm throughout and this was replaced every other day. photographs were taken at day of differentiation. hsp content of cells was determined using western blotting as described previously (maglara et al, ) . at low levels of glutamine ( - mm), cell survival was greatly impaired and differentiation was reduced. however hsp content of cells grown in media of . m and m glutamine showed an increased hsp response compared with cells grown and differentiated in physiological glutamine concentrations. no effect of higher glutamine concentrations (between . - mm) on cell viability or hsc and hsp content was evident. conclusion. glutamine supplementation affects heat shock protein (hsp) expression in various cell types. several authors have suggested that exposure of cells to relatively high concentrations of glutamine results in increased hsp expression and an enhanced cell survival (wischmeyer et al. ) skeletal muscle degeneration occurs following a number of insults and muscle repair is reliant upon activation and differentiation of stem cells or myoblasts to form mature multinucleated muscle. transgenic studies in our laboratory have demonstrated that the ability of skeletal muscle cells to produce hsps during stress and development is crucial to the correct maturation and functioning of these cells (mcardle et al, ) . our data suggests that the glutamine concentration for optimal myoblast proliferation and differentiation is ∼ mm. reduction below this value resulted in reduced cell viability and modified hsp although levels higher than physiological had little effect on cell growth and differentiation. this might suggest that reduced glutamine concentrations in it self acts as a stressful stimulus. further reduction however renders the cell unable to respond at all. in addition g regulation might be linked to other stress hormones, such as cortisol (c) and prolactin, in rats and humans in physiological conditions. our aim is to study the circadian variations of cortisol and ghrelin plasma levels in patients with acute coronary syndrome (acs) admitted to the intensive care unit. eight male ( ± years old) patients with acs were studied. seven showing non-st-elevation and one with st-elevation. within the first hours of admission, blood samples were taken every hours (nine samples) in all acs patients. patients were kept nothing per os during the sample drawing period. eight patients admitted in the department of internal medicine in a stable clinical situation were studied on the day before being discharge, as control group. g and c levels were measured in all samples using specific ria (phoenix pharm. usa). control subjects showed a cortisol circadian rhythm with peak values at : a.m. ( , ± , mcg/dl) and nadir values around : p.m. ( , ± , mcg/dl). in this patients g levels also present circadian variations, with peak values at : a.m. ( , ± , pg/ml) and nadir values at : p.m. ( ± , pg/ml). in contrast, patients with acs showed a very demised c circadian rhythm, and the amplitude of the circadian variations of g levels is markedly reduced, showing a shift of the peak values to : p.m.( , ± , pg/ml ) and nadir values around : a.m. ( , ± , pg/ml). there is a circadian rhythm of ghrelin with a peak ranging from : a.m. to : a.m. in hospitalized subjects. those variations are o shifted in phase respect to cortisol rhythm. opposite, in patients with acs the circadian variations of ghrelin levels are lost. the results of lft of patients admitted to the general intensive care unit of a large teaching hospital in south london, between st december and th february were obtained from the chemical pathology department. mortality statistics were obtained from the hospital electronic patient record. lft of patients who were readmitted were excluded. a total of patients had a first admission to the general icu during the three months studied. the average age was . yrs (sd . ), % were male and the mean length of stay was . days (range - ). mortality rate at days was % ( / ). at the time of admission only ( %) patients had entirely normal lft. patients with cholestatic lft above the normal range on admission were more likely to be female (akp odds ratio: . ( . - . ), gammagt or: . ( . - . )). abnormalities in alt, akp and gammagt on admission, were associated with a higher likelihood of death at days (table). average length of stay was greater in those with abnormal lft but only reached statistical significance with akp above the normal range (table) . conclusion. abnormality of liver function tests is common in the critically ill patient admitted to the general intensive care unit. even relatively minor elevations of lft are associated with an increased risk of death within days. the cause of these abnormalities is likely to be multifactorial and further studies are needed to elucidate the cause. myxedema coma with extreme hypothermia: a case report e. brands* intensive care, academisch ziekenhuis maastricht, maastricht, netherlands a patient is presented with an undiagnosed hypothyroidism which progressed to myxedema coma with extreme hypothermia, bradycardia, anaemia and somnolence. a year old male patient, with a history of hypertension and a cerebral vascular accident, was admitted to the emergency room after a collapse. during several months he showed progressive disability due to fatigue, unstable gait and chilliness. the last weeks his condition worsened leading to muscle weakness, dysarthria, dysphagia, cognitive dysfunction and somnolence. upon physical examination we saw a somnolent patient with a gcs (glasgow coma scale) of - - , with hyporeflexia and pareses of the lower extremities. respiratory rate of per minute. blood pressure was / with a heart rate of beats per minute. the patients temperature was . oc. the patients gcs decreased to - - upon which an endotracheal tube was placed and mechanical ventilation instituted. laboratory tests showed a haemoglobin . normal adrenal function test. one day after thyroid hormone substitution ( µgr t intravenously on day one, followed by µgr t once a day, µgr t orally every hours on day one only), the patients regained consciousness. his heart rate increased to beats per minute after normalisation of body temperature. gastroscopical evaluation showed an ulcus duodeni. despite of a ventilator associated pneumonia the patient recovered well. hypothyroidism may lead to a variety of symptoms ranging from malaise and fatigue to specific organ related complaints. especially in the elderly the symptoms may be mistakenly attributed to the physiological aging process, psychiatric, neurological illnesses or even dementia. numerous precipitating factors can evolve untreated hypothyroidism to myxedema coma. in our patient infection, cold exposure, gastro intestinal bleeding or iron deficiency could have played a role. the elderly patient is already prone to hypothermia due to physiological changes, in myxedema this may lead to an extreme low temperature. myxedema in its classical, full clinical presentation is a rare occurence in present times. especially in the elderly patient it can cause pronounced hypothermia. according with surviving sepsis guidelines we must control blood glucose levels to a less than mg/dl after h of admission to an icu. objectives: to evaluate the results obtain with the use of an intensive insulin treatment (iit) in a polyvalent intensive care unit. we conducted a prospective cohort study in a -bed polyvalent icu in a portuguese university hospital. adult patients who were assumed to require at least days of intensive care were eligible for inclusion. the study was carried out during months. capillary blood glucose (cbg) levels were measured on admission and subsequently every two or four hours in all patients during days. with the iit, insulin infusion was started when the blood glucose level exceeded mg per decilitre. we enrolled patients, age: , ± , ( , ), sapsii: , ± , ( , ), sofa: , ± , ( , ), length of stay in icu: , ± , ( , ), mortality rate: . %. , % of the patients were diabetes. incidence of hypoglycemia - , %. to examine the effect of central venous catheter (cvc)location on the incidence of catheter related blood stream infection (crbsi) in a total parenteral nutrition (tpn) population over a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . . bed university hospital. tpn population includes all medical and surgical patients hospital-wide referred for tpn. service based in intensive care. tpn committee meets quarterly to examine prospectively collected data. . cvcs were included. we compared incidence in different anatomical locations(figure). femoral cvcs were rarely used for tpn and so were excluded. subclavian cvc insertion was associated with a peak incidence of crbsi of per cvc days in which dropped to in . peak incidence of crbsi in internal jugular cvcs was per cvc days in , per cvc days in . this study prospectively examines the effect of anatomical location on crbsi. crbsi in subclavian cvcs remains almost consistently lower than internal jugular throughout study. this correlates with published data in the literature and cdc recommendations for use of subclavian site in preference for cvc insertion . patients after urgent abdominal surgery require adequate nutritional support. we aimed to assess the effectiveness of parenteral nutrition (pn) by "all-in-one" system with adding of glutamine to eliminate metabolic disturbances in patients after small bowel obstruction surgery. methods. patients after small bowel obstruction surgery (mean age . ± . years) was divided into groups. control group (n= ) received standard basic intensive therapy including pn by "all-in-one" system "oliclinomel" in first hours after an operation. glutamine group patients (n= ) received additional glutamine (dipeptiven - ml/kg/day). plasma whole protein and its fractions, amino acids spectrum, transferrin concentration, glucose and insulin levels, as well as standard laboratory and instrumental data were assessed before, at rd and th day of pn. in all patients metabolic disturbances with protein status shifts was revealed. dynamic analysis of data showed faster compensation of these disturbances in glutamine group. in both groups whole protein and albumin/protein ratio decreased gradually while amino acid sum, essential and nonessential amino acid concentration, glucose and insulin levels remained normal. by th day glutamine group showed faster increasing of transferrin concentration ( . ± . g/l vs. . ± . g/l) and fisher index ( restoration of metabolic activities confirms adequate nutritional support in both groups but glutamine adding provides faster improvement of protein disturbances and helps to avoid glutamine deficiency. y. kang* , h. jiang , x. qiang , x. jin , q. yi icu, general surgery, respiratory, west china hospital of sichuan university, chengdu, china to investigate the effect of supplementation with alanyl-glutamine dipeptide on insulin resistance and outcome in critically ill copd and respiratory failure patients. prospective, randomized and controlled study. patients who were admitted to west china hospital icu between jan and feb were selected and randomized into two groups which were given the similitude nutrition support protocol. two groups' nonprotein calorie were kcal/kgd, % were provided by fat emulsion. the nitrogen supply were . g/kg in each group. in treatment group %- % of nitrogen was given from the parenteral nutrition by the alanyl-glutamine dipeptide, the rest was the equilibrium amino acids. in the rd and th day, blood glucose clamp were performed in both groups, and blood glucose was rigidly controlled between . to . mmol/l. daily blood gas, glucose and insulin dosage and th day mortality , length of stay (los) in hospital and in icu, duration of mechanical ventilation (dmv) and the costs of icu and hospital were measured respectively. . patients completed the research. there was no difference in blood gas between two groups, but pao rose gradually. compared with control group, the five day's blood glucose level have a decreasing trend in treatment group. during the five days, the average insulin dosage have an obviously decreasing in treatment group. there were no difference between two groups in th day mortality, los in hospital and the costs of hospital. but the los in icu and dmv have a decreasing trend in treatment group. alanyl-glutamine dipeptide have not improved pulmonary function in critically ill patients with copd and respiratory failure. however, alanyl-glutamine dipeptide have contained certain function at attenuated insulin resistance and stabilized the level of blood glucose. alanyl-glutamine dipeptide did not reveal the effect of improving outcome in critically ill patients with copd and respiratory failure, the th day mortality, los in hospital and the costs of hospital. but the the los in icu and dmv have a decreasing trend in treatment group. adrenocortical dysfunction is a common finding in severe illness. however, it remains currently unclear whether adrenocortical responses predict outcome in acute critically ill patients. to investigate this, ( men) acute critically ill patients, with a median age of years were studied. admission diagnoses included multiple trauma (n= ), medical (n= ) or surgical (n= ) critical conditions. within hours of icu admission, a morning blood sample was obtained to measure baseline cortisol, corticotropin (acth), and dehydropiandrosterone sulphate (dheas). subsequently, a low-dose ( mcg) acth test was performed to determine stimulated cortisol. the incremental rise in cortisol was defined as stimulated -baseline cortisol. overall, patients survived and patients died. non-survivors were older and in a more severe critical state, as reflected by the higher sofa and apache ii scores. furthermore, non-survivors had a lower incremental rise in cortisol ( . vs. . mcg/dl, p< . ) along with lower dheas than survivors ( vs. ng/ml, p= . ). the two groups had similar baseline and stimulated cortisol. multivariate logistic regression analysis revealed that age (odds ratio= . , % c.i. . - . , p= . ), sofa score (odds ratio= . , % c.i. . - . , p< . ), and the incremental rise in cortisol (odds ratio= . , % c.i. . - . , p= . ) were independent outcome predictors. in mixed critically ill patients a blunted cortisol response to acth within hours of icu admission is an independent predictor for poor outcome. in contrast, baseline cortisol or adrenal androgens are not of prognostic significance. teicoplanin is a gycopeptitide antibiotic for treatment of highly resistant gram-positive bacteria such as methicillin resistant staphylococci and enterococcus faecalis. it is eliminated unchanged by the kidneys. in renal impairment the maintenance dose has to be reduced. data on pharmacokinetics of teicoplanin in patients requiring continuous veno-venous haemofiltration (cvvh) are sparse. therefore teicoplanin pharmacokinetics was assessed in critically ill patients during on cvvh. teicoplanin serum levels were measured in adult critically ill patients requiring cvvh for acute renal failure after the first dose and at approximate steady state conditions (day - of therapy). cvvh was performed using . m polyetersulfone membranes; blood flow was ml/min and the ultrafiltration rate amounted ml/kg body weight. a loading dose of , mg of teicoplanin was administered (infusion time h). subsequently the dosage was guided by serum levels and reduced to an average daily dose of ± mg per day. samples were drawn , , , , and h after start of infusion. teicoplanin was measured by a fluorescence polarisation immunoassay in serum and ultrafiltrate. pharmacokinetics was calculated using a non-compartmental model by kinetica . concentration time profiles of patients were determined after the first dose and of patients during steady state. the teicoplanin peak concentration was . ± . µg/ml (mean sd) after the first dose and . ± . µg/ml at steady state. trough levels amounted . ± . µg/ml and . ± . µg/ml, respectively. the half-life increased from . ± . h after the first dose to . ± . h at steady state, whereas the clearance declined from . ± . l/h to . ± . l/h. the apparent volume of distribution decreased from ± to ± l. the sieving coefficient of teicoplanin amounted . after the first dose and . after repeated administration. a loading dose of , mg of teicoplanin followed by a maintenance dose of about , mg per day appears to result in adequate serum levels in a majority adult critically ill patients on cvvh. however, because of a considerable variability of teicoplanin pharmacokinetics in this group of patients, therapeutic drug monitoring is recommended to warrant safety and efficacy of treatment. although heparin is the most frequently used anticoagulant in cvvh, alternatives to heparin are needed in case of heparin induced thrombocytopenia (hit). argatroban, a direct thrombin inhibitor approved for hit is primarily metabolized by the liver, thus, should not accumulate in renal failure. however, there is only limited data regarding its use in continuous venovenous hemofiltration (cvvh). we report a patient with acute renal failure where anticoagulation by argatroban appears to be influenced by cvvh. a years old woman was admitted to the icu department with septic shock and acute renal failure. bilateral infected crural ulcers could be identified as focus and therefore both calves had to be amputated. after days of cvvh with heparin as anticoagulant a rapid drop in platelet count of more than % occurred, a suspected hit was confirmed by heparin-pf antibodies (elisa). although there was no hepatic failure argatroban was started at mg/h ( , µg/kg/min) because of cholestatic cholecystitis and severe sepsis. results. aptt increased from to seconds after hours of argatroban infusion and further to sec after hours (figure ). at the same time pt fell from % to %. therefore argatroban dose was reduced by % to , mg/h. after h cvvh had to be stopped for h. after discontinuation of argatroban a decrease in aptt from to sec, as well as an increase in pt from to % was observed. h after argatroban was restarted at , mg/h, cvvh was stopped again for , hours without discontinuing argatroban. shortly after cvvh was halted aptt increased from to sec and pt decreased from to % within hours. this trend continued even after stepwise reduction of the dose of argatroban to , mg/h. the trend could not be reversed until the dose was further reduced to , mg/h and argatroban was stopped. after restarting cvvh without argatroban infusion a further decline in aptt as well as an increase in pt was observed. conclusion. this case demonstrates that argatroban may be influenced by cvvh and that dose may have to be substantially reduced in these patients. regional citrate anticoagulation (rca) is the recommended strategy when risk of bleeding is increased in continuous venovenous hemofiltration. we evaluated the feasibility and the safety of this method in high volume hemofiltration (hvhf) in critically ill patients with severe coagulopathy. methods. patients ( ± years, saps ii ± , sofa . ± . , septic shocks and sirs) have been retrospectively studied between january, and december, . continuous renal replacement therapy, daily limited to hours, was performed with a frésénius hdftm generator. blood flow was ml/min. the generated replacement fluid, calcium free, was used in pre-dilution. a citrate solution (acdar-fréséniustm) was infused to target a prefilter ionised calcium level below . mmol/l whereas systemic calcium perfusion maintained normal plasmatic calcium level. hemofiltration characteristics, filters lifetime and metabolic complications were the main collected data. . hfhv days ( filters needed) were analysed. mean hemofiltration volume was ml/kg per hour (about l per hour or l per day). percent of the prescribed hfhv dose could be carried out. mean filters lifetime was . hours. percent of them prematurely clotted. citrate and calcium perfusion flow respectively needed to be modified an average of and , time per day. metabolic alkalosis (ph> . ), hypocalcemia (ca++< . mmol/l), hypercalcemia (ca++> . mmol/l), hypernatremia (na+> mmol/l) and one citrate intoxication (total to ionised calcium ratio> , ) occurred. none of these events lead us to modify the anticoagulation strategy. prefilter ionised calcium level in non clotting filters was , ± , mmol/l versus , ± , mmol/l in clotting filters (p= , ). % of the patients died in hospital whereas predicted mortality was %. conclusion. rca is a reliable and simple method for hvhf with high hemorrhagic risk patients. frequent minor metabolic complications require a narrow biological monitoring. to improve our practices, prefilter ionized calcium levels should be decreased. continuous venovenous hemofiltration(cvvh) or hemodiafiltration (cvvhd) are the commonest renal replacement therapies(rrt) prescribed to the patients with the septic shock having renal failure. each cvvh session for hours costs around e in india as against intermittent hemodialysis(ihd),which costs around e per to hour session. hence ihd is still the commonest form of rrt in indian icus. major concern of ihd in septic shock patients is hemodynamic instability. whether stringent hemodynamic monitoring and maintaining preset goals would reduce these instabilities & deliver optimal rrt is not clear. we undertook a prospective study to evaluate this concept. we attempted to achieve preset goals of keeping mean arterial pressure (map) > mm, cardiac output (co) > lit./min & cardiac index (ci) > . lit./min/m throughout the session by following the protocol in the given sequence-: ) fluid boluses ) increase in vasopressor or inotrope dose ) adjustment in ultra filtration rate between - ml/hr and )adjustment in blood flow rate between - ml/min on hemodialysis machine. dopamine, norepinephrine, vasopressin and dobutamine were used alone or in combination to achieve these goals. hemodynamic monitoring & data collection was done with flotrac-vigileo monitoring systemtm (edwards lifesciences,irvine,ca,usa) and intellivue mp (philips,germany). . ihd sessions of patients with septic shock needing vasopressor were monitored and managed in icu. base line apache ii score was . ± . and all patients had at least organ failure. average duration of ihd was . ± . hrs and net negative fluid balance achieved per ihd session was . ± . ml. table showing hemodynamic parameters before ihd and during ihd preset goals were maintained without any intervention in sessions, with fluids alone in sessions, fluids and escalation of vasopressor in sessions and fluid bolus plus vasopressor escalation plus reduction in ultra filtration & blood flow in sessions. only / sessions were terminated at & min. due to development of new myocardial infarction in one and persistent hypotension in the other. additional cost of c. o. and c.i. monitoring was aboute per session. continuous veno-venous haemofiltration (cvvh) clears solutes and improves acidosis in critically ill patients with renal failure and sepsis. we studied solute clearance and filtration quantity prospectively in the first hours of patients requiring cvvh on two teaching hospital intensive care units. data collected included demographic data, reason for starting cvvh, blood biochemistry prior and after starting cvvh as well as duration of cvvh, including reasons for any interruptions. blood tests were collected once in a -hour period. data was collected for the entire period that patients required cvvh. solute clearance on cvvh within the first hours was expressed as a percentage change of urea and creatinine levels compared with levels prior to cvvh. quantity of haemofiltration was calculated over the interval between the first two blood tests and expressed in relation to bodyweight. data from patients is presented ( patients died before blood samples on cvvh was taken). the main indication for commencing cvvh was sepsis/acidosis in patients and renal failure in patients. the values for urea and creatinine on admission differed considerably between both groups. patients with sepsis/acidosis received a median cvvh-dose of . mls/kg/hr, whereas patients with renal failure were treated with a median cvvh-dose of . mls/kg/hr. table shows the respective median values for urea and creatinine prior to cvvh and from the first sample on cvvh, as well as the median (interquartile range;iqr) cvvh dose delivered in the period between the two samples. ( ) . we therefore studied the effect of anticoagulation on cvvh delivery. over a four month period data from patients across adult intensive care units was recorded. the number and reasons of interruptions and subsequent time lost as well as the type of anticoagulation was documented. infusion of heparin into the circuit was the primary form of anti-coagulation. heparin was started at units/kg/hr and adjusted according to local protocol to achieve a target heparin ratio (aptr) of . - . . aptrs taken from the circuit within the previous hours were defined to represent the degree of heparinisation at the time of a filter clotting off. a total of . patient hours of cvvh was delivered. filter clotting was implicated in of interruptions ( %). table shows the various forms of anticoagulants used, the number of interruptions and total time lost due to filter clotting. in the heparin group, aptrs were recorded. only % of these were therapeutic and % were sub-therapeutic. aptrs were recorded within the hours prior to filter clotting, representing % of all clotting events occurring on heparin. clotting events occurred with a therapeutic aptr, with recorded subtherapeutic ratios (relative risk . ), and event with an aptr > . filter clotting is by far the most common cause for interruptions in cvvh delivery ( %). adequate anticoagulation of cvvh circuits with heparin is problematic and failure to achieve the terget aptr carries a considerable risk of filter clotting. % of ap-trs were subtherapeutic despite use of a written protocol, suggesting that many patients are exposed to an increased risk of filter clotting regardless of other causative factors. whilst we recognise that the aetiology behind filter clotting is multifactorial, reducing these interruptions with adequate anticoagulation is important and may have positive effects on patient outcome. during continuous renal replacement therapy (crrt) anticoagulation of the extracorporeal circuit is generally required to prevent clotting of the circuit, preserve filter performance, optimize circuit survival, and prevent blood loss due to circuit clotting. unfractionated heparin (ufh) and low molecular weight heparin (lmwh) are generally used to perform this strategy. however, this anticoagulation may cause dangerous bleeding especially in acute renal critical patients. in these patients, it's very difficult to predict bleeding or thrombosis correctly during crrt. to asses the safety and efficacy of the use of an enoxiparin dose protocol based on anti-xa activity in crrt. methods. consecutive patients with acs was admitted to a coronary care unit of terciary hospital between [ ] [ ] patients presented heart failure during their hospitalization. clinical, ecg, echocardiographic, features were prospectively investigated. we also took blood samples in the first hours of their admittance to the ccu for a complete hemogram, levels of total cholesterol, hdl cholesterol, ldl cholesterol, triglycerides, creatinine, clearance of creatinine (mdrd equation), glucose, hbac , high sensibility-c reactive protein (hs-crp) and a follow up of levels of troponine, ck and ck-mb. we determined the presence of microalbuminuria (ma) (> mg/dl in a -hour urine sample). all patients were submitted to a coronary angiography in the first hours. we defined rd if the clearance of creatinine < ml/min/ . m . non-st segment elevation myocardial infarct (nstemi) was the most frequent cause of heart failure ( . %). the rd was present % of hf. the patients of this group was oldest, more diabetes mellitus, more previous myocardial infarct more anterior descendent occlusion. moreover, the patients with hf and rd had a lowest hematocrit ( % vs %), troponin i peak concentration ( . ng/ml vs ng/ml) and had higher of creatinine ( . mg/ml vs . mg/ml), ma, admission glycemia ( mg/dl vs mg/dl), nt probnp ( pg/ml vs pg/ml) and cystatin c ( . vs . ). both group present similar reduced ejection fraction ( % vs %). this group presented higher incidence of post infarct angina ( %; p= . ). in-hospital mortality was in patients with hf and rd % vs % in hf without rd (p= . ). in the follow-up (median days) the mortality of patients with hf and rd was % (p= . ). the mortality of the group with rd and treatment with ace-inhibitors was % vs % without ace-inhibitors (p= . ). the multivariate analysis identified the rd was a independent predictor of mortality in the patients with heart failure ( . ; p= . ) and the impact negative of rd was reduced by ace-inhibitors (or= . , ci % . - . ; p= . ). conclusion. the rd is common and a strong predictor of mortality in patients with hf complicating acute coronary syndrome. it is associated with a worse risk profile. ace-inhibitors improve the prognosis this group of patients. acute renal failure is a very frequent problem in the critically ill patients and contributes to their high mortality. the most frequent cause is sepsis,usually in the context of multiple organ dysfunction. the more prevalent admission cause in our arf patient were medical illness and pos-operative urgent surgery. the arf patients presented higher saps ii and initial sofa scores. the most common risk factor was shock;other factors frequently seen were sepsis,mod and rhabdomyolysis. the mortality rate measured was lower than that referred in the literature. following a needs-assesment, realistic acute-care simulations were designed using a modified delphi approach. didactic instruction was given regarding crm strategies including "the three c's of communication": clear instructions, citing names, closing the loop (eliciting feedback following instructions). teams of four: two physicians (a leader and an assistant);a pre-briefed critical-care nurse (rn) and critical-care respiratory therapist(rt), then responded to standardized simulation scenarios, delivered using a laerdal high-fidelity mannequin in a working critical care unit. we found insufficient crm skills on the first simulation (suggesting poor retention from didactic instruction alone) with gradual improvement following the three simulations (suggesting simulation offers a supplementary technique but may still be insufficient). we therefore made the team perform a fourth resuscitation, but with the physician-leader blindfolded. we found immediate/marked improvement in crm skills: physicians elicited help sooner and ensured instructions were completed. other members were quicker to volunteer changes in vital signs. debriefing confirmed that this novel approach was well received and participants reported enhanced understanding of the importance of teamwork. in the early stages of undifferentiated shock we are essentially "blind" to the diagnosis, and hence must rely on others. this strategy is also useful for trainees whose first language is not english: blindfolding forces them to focus on communication, with the result of increasing their confidence and reassuring supervisors. this technique allowed us to emphasize crm principles. we now expectat senior trainees to perform at least one blindfolded simulated-resuscitation. it is no longer an exaggeration to say our teams are "good enough to resuscitate blindfolded"! in current spanish population around % of people are over years of age. in our country, life expectancy is years. it is obvius that this population aging has modified some approachs in organs donation and transplantation process, forcing to include older people in waiting lists. the increase in the organs demand for transplantation has conditionated changes in the donor profile, therefore the evaluation, acceptance and rejection criteria of donors have been changing. the acceptance for older donors with associated comorbidity provide transplantations with acceptable results getting to reduce tranplant waiting lists and mortality. the consequence that arise from it is the concept of expanded criteria donor (ecd). we studied retrospectively donors from a hospital with no neurosurgery service from january to december , comparing donation potential between over and under years of age donors. . four of the donors younger than years (n: ) were not appropriate ( , %) whereas older than years (n: ) were ( , %) (p-ns). donors older than years provided kidneys and livers available for transplantation ( , % and , % of total organs, respectively) whereas younger than years group obtained kidneys and livers available ( , % and , % of total organs, respectively). number of useful organs per donors was , and , for younger and older than years donors, respectively (p: , ). conclusion. in our serie, age was not a predictor variable for hepatic usefulness whereas it was for renal usefulness. nowadays dce are indispensable and age can not be an exclusive factor in this donors evaluation. pct has many indications in icu patients, mainly prolonged mechanical ventilation / weaning difficulties and airway protection in comatose patients. the consensus conference on artificial airways in patients receiving mechanical ventilation recommended translaryngeal intubation for an anticipated need of up to days and a tracheostomy if an artificial airway for more than days is anticipated. however this decision should be individualized. the aim of this study is to analyse the indications and timing pct in our icu patients, and icu and hospital survival. we conducted a retrospective study, analysing patients submitted to pct, in months: since the technique was implemented in our icu in december , until march . we reviewed their age, gender, apache ii score, length of icu stay, ventilation time before and after pct, icu and hospital survival. patients were stratified in groups, based on the indication for the pct: prolonged mechanical ventilation (n= ) and airway protection in comatose patients (n= ). data was treated in spss programme, using the mann whitney test. the results presented are in mean values. conclusion. )the indications for pct in our icu were prolonged mechanical ventilation (n= ) and airway protection in comatose patients (n= ), a reduced sample size to analyse. )there was no significant difference in age ( years), gender, apache ii ( , ) and saps ii ( , ) scores. )comatose patients submitted to pct for airway protection had less ventilation days prior ( , vs , p= , ) and after ( , vs , p= , ) tracheostomy. their length in icu was shorter ( , vs , p= , ) . they had a lower hospital survival rate ( % vs , % p= , ), although there was no significant difference in icu survival. ) , % of patients submitted to pct due to prolonged mechanical ventilation were discharged alive from our icu, but only , % were discharged alive from hospital. recent literature suggests that early pct (in - days) could have had an influence on this high mortality hospital rate. )overall icu survival rate is %, but hospital survival is only % -a high mortality rate is seen after discharge from icu, in hospital wards. t. van galen*, o. p. groenendijk recovery room -high care, vu university medical center, amsterdam, netherlands introduction. the vu university medical centre (vumc) has chosen to integrate competence management (cm) within the human resource structure. functioning as an health care professional is not only about performing medical or nursing interventions. cm explicates not only knowledge and skills, but also attitude. cm contributes in developing abilities to cope with complex medical and nursing situations. cm is about managing professional behavior for reaching personal and organizational objectives. cm also contributes to an organization wide understanding of achieving the mission statement objectives. after introducing cm to the high care (hc) nursing staff, the set of (chosen) competences was integrated within the unit's mission statement (september ) . during team sessions competences were described to fit into the daily organizational and professional practice (october ) . personalizing cm is performed during an (competence based) assessment (december ) . strengths and weaknesses are determined. personal objectives are integrated within a defined educational and development structure guided by the clinical supervisor educator. although cm is relatively new in our organization and the return on investment is hard to determine, some results are clear. with cm observable behaviors were defined and thereby manageable, next to the set of nursing skills definitions (already defined as part of the primary training course and daily practice). increased employee responsibilities led to % more (non mandatory) training course attendance. during the hc nurse attended full training course hours. in the training course attendance increased to full hours for each hc nurse. with cm the relation between organizational and individual performance objectives is more clear. a prismant survey proclaimed decreasing sickness absence when cm is implemented. this result was confirmed on our ward. sickness absence decreased from > % to < %. because most of the personal development targets were easy to combine, the educational/training course budget was not exceeded. cm provides more different development levels, thereby individual talents are easier to discriminate. the employee satisfaction with cm is growing. conclusion. cm was successfully implemented on our hc unit within a month period. starting with a manageable package of competences the rollout strategy was easy to cope with for the hc supervisor and nursing staff. there are a few conditions the organization has to facilitate. cm must be integrated in the organization mission statement and adopted by hospital management. nursing supervising staff, including the clinical supervisor educator, must be capable to apply and practice cm. span of control and educational/training budgets must be fitted for applying cm. cm is a well manageable and applicable tool to increase and improve nursing outcomes. [ ] have shown immune modulatory effects. the alpha agonist dexmedetomidine produces sedation more analogous to nrem sleep compared to traditional agents [ ] . obstructive sleep apnoea and depression are known to alter both sleep architecture and immune function. we postulated that immune modulation could be produced by pharmacologically altered sleep pathways. methods. pvg hooded lister rats (harlan)were randomly allocated to midazolam, dexmedetomidine or sham infusions. all animals were instrumented with implanted telemetry week, and jugular lines day prior to the infusions. infusion rates were targeted to maintain deep sedation, mg/kg/hr for midazolam and . - mcg/kg/min for dexmedetomidine. infusions were commenced at am, and continued for hrs during the sleep phase, and recommenced hours later for a further hrs. animals were then given mg/kg ultrapure e.coli lps at am the following day. blood was taken every mins for facs and cytokine analysis. at mins post lps animals were sacrificed and their brains and lungs harvested. lungs were macerated and the samples were stained for ox and cd b and analysed by facs. there was no statistical significance difference between the groups at any time points for serum tnf,il- ,il- , crp, total blood pmn and monocytes, platelet-leukocyte aggregates. there was a non-significant trend to lower monocyte/neutrophil margination into the lung bed in the dexmedetomidine group. conclusion. in this underpowered study pharmacological manipulation of sleep does not produce immunoparesis in a rat model of icu sedation and sub-lethal endotoxaemia. from these data animals in each group would be required to detect a true difference. gut microbiota is a stable community with high biodiversity index and plays a key role in maintenance of health status. several factors of gut ecology alteration occur during the critical patients(pts) care:luminal hypoxia/hypercarbia, gastric-secretions inhibitors, vasoactive, sedation, nutrient/fiber scarcity, antibiotics, sepsis/injury, digestive surgery. ecological balance disruption of gut microbial community often results in reduced protection against pathogens,including opportunistic ones. we studied faecal microbiota changes in critical pts during icu stay. consecutive pts expected to need mechanical ventilation (mv) for> days were enrolled. exclusion criteria: hospital stay and/or antibiotic treatment before icu admission, opportunistic/autoimmune diseases, cancer/steroid therapy. faeces were collected at icu admission(t ) then weekly(t ,t ,t ). pts were excluded if t or t samples could not be harvested. total bacterial dna pattern analysis was performed by denaturing gradient gel electrophoresis (dgge). the % of similarity between the t -dgge profile and the following ones in each pt was used as index of microbiota modification. a similarity value > median at t versus t was defined as index of microbiota biodiversity preservation. new dominant dna bands were analyzed to identify bacteria species. . pts ( peritonitis, lung infections, cellulitis, meningitis, trauma) were enrolled. pts ( alive) were discharged before t , pts ( alive) before t , and pts ( alive methods. rfviia was used in adult patients aged between - (mean ± ) years average bmi . ± . underwent massive perioperative haemorrhage. all patients were admitted to icu with the diagnosis of sepsis or severe sepsis. all septic patients has been received da therapy within - hrs of icu admission. the following diseases were diagnosed: post abdominal surgery bleeding (severe sepsis after surgery: laparoscopic cholecystecomy, laparotomy due to peritonitis) - pts, gastrointestinal bleeding (severe sepsis in acute pancreatitis ) - pts, postpartum bleeding (septic shock in the course pyelonephritis and right hydronephrosis) - pts, intracranial bleeding (septic shock in pregnancy) - pts. we used the questioners of novo nordisk to asses the indications and effectiveness of treatment. we compared haemoglobin level, haematocrit, number of platelets and laboratory coagulation profile parameters before treatment, hours and hours after treatment. the dosage of rfviia was . ± . µg/kg. continuous iv mg infusion is effective for spasticity due to tetanus. compared to previous reports, our case series contributes meaningful additional data, as mg therapy was applied effectively for up to days without major toxicity, and all pts had good outcome. iv mg therapy has been proposed as first-line treatment for tetanus ( ), but the optimal dose and maximum duration of therapy are unknown. we believe that iv mg is a promising treatment option but, until more data are available, it should be reserved for carefully selected tetanus cases. observational, prospective, multicenter study in which patients admitted to the icu during the periods of the envin study for the years and were included. the following rates as markers of quality were defined: ) rate of amc use, ) rate of directed treatments, ) overall rate of changes in the amc used for therapy, ) rate of amc change due to inappropriate treatment, ) rate of amc change due to adjustment of treatment or deescalating therapy, ) rates of use of selective digestive decontamination (sdd), and ) duration of prophylaxis of cefazolin, amoxicillin-clavulanate, and cefuroxime. data of all variables in and are compared. high rate of use of antimicrobials in the icu. twenty-five percent of antimicrobial agents were used as directed therapies and in % of cases, antimicrobials were changed. changes for inappropriate treatment decreased, whereas changes for adjustment of treatment increased. there was an increase in the use of sdd. duration of prophylaxis with antimicrobials was is longer than the length of days prescribed. [ , ] . our goal was to evaluate this marker in critically ill patients with severe sepsis and sirs. methods. patients with severe sepsis and patients after coronary artery bypass grafting (cabg) have been included in this pilot study. plasma samples have been collected daily in the sepsis group or on day after surgery in the cabg-group. bg was measured with the turbidometric assay (wako pure chemical ind.) with a cut-off of pg/ml. results. bg levels were elevated after uncomplicated cabg and differed to the sepsis group. median concentrations were in the normal range in sepsis patients but fraction of elevated beta-glucan levels tend to increase with length of stay and were higher in nonsurvivors. this first observational study demonstrated consistent results of higher bg levels in different populations of critically ill patients. while bacterial translocation has been suspected as reason for sirs after cabg, this has never been associated with fungemia. this finding and higher bg levels in nonsurvivors with sepsis warrants further research. reference(s a prospective, observational and multicenter study in which an analysis was made of antimicrobials used in patients admitted to the spanish icu during the time periods of the envin study. the present report includes data for the years to . reasons for the use of antimicrobials included community-acquired infection, extra-icu nosocomial infection, and as a prophylactic measure. empirical or directed treatments were also differentiated. the antimicrobial drugs most frequently used for each indication as well as the mode of therapy are described. rate of antimicrobial use is expressed as percentage of patients in which one or more drugs were administered. descriptive statistics are presented. of a total of , patients admitted to the icu during the study period, , ( %) received , antimicrobials. changes in the number of antimicrobials and rates of antibiotic use are shown in table . table shows the distribution of antimicrobials according to reasons of prescription and modes of use antimicrobial agents most frequently used in the -year study period were amoxicillin-clavulanic acid, piperacillin-tazobactam, cefazolin, and vancomycin. data of the drugs most frequently used in each category are available. candidemia is a major cause of morbidity and mortality in modern icus. candidemia rates and patterns in icu appear to be changing over time. non-albicans spp, especially c. tropicalis and c. glabrata may be associated with higher mortality ( ). we describe the epidemiology and outcome of candidemia caused by candida albicans and non-albicans spp. from to , consecutive cases of candidemia in a general medical-surgical icu were identified from the computerized microbiology database. apache ii scores, demographic and clinical data were abstracted from clinical records. antibiotic usage was retrieved from the pharmacy database. . cases of candedemia were identified, giving an incidence of ( %ci - ) per patient-days. candidemia rates (per patient days) increased, with non-albicans making up a greater proportion over time ( fig. ). antibiotic use did not change significantly over time. non-albicans species made up % of isolates -c. tropicalis ( . %), c. glabrata ( . %), c. parapsilosis ( %), c. krusei ( . %), c. guillermondi ( . %). risk factors more commonly present in non-albicans species were: haematological neoplasm (p= . ) and neutropenia (p= . ). c. albicans was associated with diabetes (p= . ) and male sex (p= . ). baseline apache ii scores for non-albicans vs c. albicans (median, iqr , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) were similar, however patients with non-albicans had a higher icu mortality ( % vs %, p= . ), and a trend towards higher hospital mortality ( % vs %, p= . ). despite stable antibiotic usage, candidemia rates are progressively increasing over time, with non-albicans making up a higher proportion of cases. mortality rates were higher than generally reported, but may be partly related to the high baseline illness severity. the comparatively higher mortality of non-albicans candidemia may be related to the high incidence of c. tropicalis and c. glabrata, which made up > % of non-albicans spp. risk factors associated non-albicans were identified and could help guide early empiric therapy in this group. previous studies have investigated the role of diabetes mellitus(dm) as risk factor for infections. tight glycemic control has recently been proved to reduce morbidity in icu patients. the aim of our study was to assess the association of prior dm history with bsi in icu patients. we prospectively studied medical patients admitted to a -bed general icu, during a -month period. history of dm, age and apache ii at admission were recorded. all patients were under tight glycemic control and were followed up for the development of bsi during icu stay. cox proportional hazards regression models were fitted for each consecutive bsi episode. statistical significance was set at p< . . although myocardial systolic dysfunction is common in sepsis/sirs, its time course over longer periods in severely ill patients is not well investigated. the aim of this project is to investigate the time course of left ventricular (lv) systolic function over a period of days in patients with severe sepsis/sirs using transthoracic echocardiography (tte), and to evaluate the adequacy of different tte methods. methods. patients with severe sepsis/sirs with circulatory failure despite adequate fluid resuscitation were included. tte examinations were performed daily for a total of days. lv systolic function was assessed by eyeballing ejection fraction (eb), simpson's biplane method in the chamber view, atrioventricular plane displacement (avpd) with m-mode in the septal, lateral, anterior and inferior view, tissue velocity imaging (tvi) in the mitral annulus and stroke volume in the left ventricular outflow tract (sv-lvot). data were analysed for differences over time using anova. systolic function was impaired and there were statistically significant changes with time in the measured parameters except tvi. table . avpd, eb, tvi, sv-lvot and simpson's were obtained in %, %, %, % and % respectively of all possible measurements. conclusion. lv systolic function was impaired in this heterogeneous group of patients as expected . all parameters improved significantly throughout the observation period reaching normal values by day . simpson's biplane method was difficult to perform due to poor imaging quality. the eb method was inconclusive in several patients due to hyperdynamic status. the fact that tvi was not significantly improved was unexpected and may be due to small sample size, wall filter settings and variations in sampling volume. the avpd method was easy to obtain and seemed the most consistent marker of systolic function in this group of patients. the small sample size of this study precludes subgroup analysis however it would be relevant to study differences, eg. between survivors and non-survivors. in view of the adverse consequence of af "chronic or paroxysmal" comprising hemodynamic deterioration, risk of thromboembolic complications, and the intolerable fast palpitation, etc., cardioverting af to sinus rhythm seems an ideal goal. there had been some controversy concerning the effects of af on atrial and ventricular dimensions as well as functions. the present work addresses the latter issue through trial of cardioverting patients( females and males) with a mean age of . years (range from to years). underlying cardiac examination revealed rheumatic heart disease in pts, hypertension in , ischemic heart disease in , and lone af in pts. only one pt had cardiomyopathy and one pt had thyrotoxicosis. prior to cardioversion, all pts were subjected to clinical evaluation, and transthoracic echocardiography (tte). transesophageal echocardiography (tee) was done only in cases with heparin or warfarin anticoagulation for at least days. standard m-mode, cross sectional and pulsed doppler echocardiography were obtained using hewlett-packard sonos echocardiograph. echo parameters measured before cardioversion comprised left ventricular end diastolic diameter (lvedd), left ventricular end systolic diameter (lvesd), fractional shortening (fs), and left atrial dimensions (length, diameter and volume by planimetry). left atrial function after cardioversion was expressed as atrial ejection force (aef) and doppler a-wave, with aef defined as the force that the atrium exerts to propel blood into the lv and expressed as aef= . *mitral orifice area*(peak a velocity) . effective mechanical atrial function (emaf) was defined as a-wave more . m/s. the presences of la thrombus or spontaneous echo contrast (sec) were studied by tte or tee. measures were recorded weeks after cardioversion to avoid la stunning. a questionnaire was sent to the lead clinicians of itus in germany inviting them to describe their current practice for the management of new-onset af. the questionnaire sought to establish the type of hospital and unit in which the intensivist practiced, whether there was a protocol in place for the management of af, satisfaction with current management strategies, and opinions about the immediate goals of treatment. in addition, colleagues were asked to identify and rank their choice of medical treatment. there were responses, with describing their units as mixed medical-surgical, as medical, surgical and cardiothoracic. thirty were teaching hospitals, district hospitals, and the remainder specialist or unstated. sixty-seven had no protocol for treatment of af in itu patients, but only expressed dissatisfaction with their current approach. those who did use a guideline cited the european society of cardiology guideline most commonly. for reversion to sinus rhythm was the goal of treatment, whilst for ventricular rate control was satisfactory. for hemodynamically unstable af in the itu, considered electrical cardioversion to sinus rhythm to be optimal treatment, would use medication with the aim of reversion to sinus rhythm, and for ventricular rate control with medication was sufficient. when medication was thought appropriate, the ranked choice of drugs is given in the table (findings for uk practice are given in parentheses, and percentages are used for easier comparison). conclusion. the lack of a uniform approach to the management of new-onset atrial fibrillation in the itu is common to both uk and germany. however, both consider amiodarone to be the first choice drug, while β-blockers and calcium channel blockers feature more prominently in germany. the use of magnesium appears to be far more emphasised in the uk. we suggest a pan-european consensus to manage this prevalent problem. atrial fibrillation is a common problem in the intensive care population, with a reported incidence between % and %. it is associated with an increased mortality, but there is some question whether this represents a true mortality increase, or whether it occurs in a group with a higher risk of dying. few studies have defined the extent of the problem in the mixed medical-surgical intensive care population. all patients admitted to our intensive care unit for more than hours were enrolled into the study over a six month period, with the exclusion of children and those who had an existent or treated tachyarrhythmia. they were then followed up prospectively for days, with various parameters recorded, including the development of atrial fibrillation, the presence of sepsis, apache ii score, treatments and interventions, and outcome at days. the population studied were divided into those who developed new-onset atrial fibrillation (new-onset af) and those that did not (no af). data from the two groups were then compared to determine any significant associations. two hundred and twenty-eight patients were admitted over a six month period, with one hundred and twenty-two meeting the inclusion criteria (excluded were for duration of stay less than hours; who already had af or a pacemaker; and who were children). twenty-eight patients developed new-onset af ( %). of the patients who had sepsis, ( %) developed af, as opposed to out of ( %) in the non-septic group. the af group tended to be older (mean age vs ) and more ill (mean apache vs ), with a higher mortality rate ( % vs %). when the mortality rate was standardised (observed/predicted mortality), the af group still appeared to have a worse outcome (smr . vs . ). this result is in contrast with a recent finding that showed smr to be similar in the two groups . our study found no association with low serum potassium or magnesium levels. findings are summarised in the table. conclusion. the rate of new-onset af in our mixed medical-surgical intensive care unit is %. there is a strong association with sepsis, with over one third of septic patients developing af ( %). our findings of older age and greater degree of illness being independent risk factors for af concur with other studies, but we have also shown an increased standardised mortality rate associated with af, suggesting that the arrhythmia confers a higher risk of death. after myocardial infarction, venous lactate levels as determined in the central laboratory are known to be increased. the relationship between systemic lactate levels and hemodynamic parameters at presentation is largely unknown. we hypothesized that arterial lactate immediately measured in the catheterization laboratory provides optimal information to study this relation. we determined arterial lactate with a point-of-care analyzer (poc) in patients with st-elevation myocardial infarction (stemi) prior to primary percutaneous intervention (pci), and investigated if lactate was related with blood flow in the involved coronary vessel. we prospectively measured arterial lactate levels (reference values , - , mmol/l) in patients with stemi directly before treatment with primary pci. patients on mechanical ventilation were excluded. all blood samples were analyzed within minutes from sampling. thrombolysis in myocardial infarction (timi-)flow in the infarct-related vessel at first angiogram was recorded for all cases and dichotomized as timi - (inadequate) and - (adequate). additional data was taken from the medical chart. lactate levels were analyzed after lognormal transformation. . with multivariate analysis, shock, body mass index, tachycardia, smoking and especially timi-flow were independently related with lactate levels. the relation of timi-flow with lactate was more pronounced than the relation of timi-flow with heart rate and blood pressure. in patients with myocardial infarction, systemic arterial lactate measured before revascularisation with a poc-device allowed detection of a strong relation between poor timi-flow and elevated arterial lactate levels. there are few echocardiographic investigations of myocardial dysfunction in sirs and sepsis. the aim of this project was to investigate left ventricular diastolic function over a period of days in patients with sirs/sepsis and circulatory shock using transthoracic echocardiography (tte). methods. patients with severe sepsis/sirs were included. tte examinations were performed daily for days. diastolic function was assessed by transmitral pulsed doppler with e/a ratio, deceleration time(dt), and tissue velocity imaging (tvi) in the mitral annulus. patients were subdivided into < and > years of age. changes in these parameters over time were analyzed using anova. median values for dt, e/a, e/É andÉ for all patients were calculated. there were no differences with time for all parameters exceptÉ (table ). in patients < y.o., subnormal values for e/É andÉ were seen ( table ) . reliable continuous hemodynamic monitoring of critically ill patients is essential for effective volume management and adequate administration of vasoactive drugs. the picco-system (pulsion, germany) allows continuous measurement of cardiac index (ci) using arterial pulse contour analysis. calibration of this system by transpulmonary thermodilution is recommended every hours. in this study we examined the reliability of the continuous measurement of the cardiac index using the arterial pulse contour analysis (cipc) compared to the cardiac index acquired by the transpulmonary thermodilution (citd) when calibrating the system. our study includes measurements in critically ill patients ( male, female, age - years, mean . ± . ) requiring hemodynamic monitoring with the picco-system. patients had an infection, hepatorenal syndrome, gastrointestinal bleeding, acute pancreatitis and were admitted to the icu for other reasons. first the cipc was recorded immediately before the next calibration and afterwards the citd was measured times what resulted in a simultaneous calibration of the pulse contour algorithm of the picco-system. we performed a mean of . ± . measurements per patient ( - ). the time-lag between the measurements was h min ± h min ( min- h min). the comparison of cipc immediately before calibration and the calibration-derived citd resulted in a correlation coefficient of . with a p-value of < . . in mean the aberration between cipc and citd was . ± . l/min*m . in the bland-altman-analysis the cipc was in mean . l/min/m lower than the mean of citd and cipc. the standard deviation was . l/min/m . there was no correlation of the time-lag between the calibrations and the difference of cipc and citd (r= . ; p= . ). there was an increase of the aberration of cipc and citd in low and high cipc values. reliable cipc values with an aberration from citd less than . l/min*m can be obtained with a cipc in-between and l/min*m . ) the picco-system allows a reliable continuous measurement of the ci using the pulse contour analysis. ) in our study we could not find an increased difference of cipc and citd even with longer time periods in-between the calibrations using transpulmonary thermodilution. ) reliable ci values using the pulse contour analysis can be obtained in-between and l/min*m . ) because calibration is easy to achieve and additional data for the intrathoracic blood volume and the extravascular lung water are obtained a - hours period in-between the calibrations is reasonable. n. zoremba* , g. schälte , j. bickenbach , b. krauss , r. rossaint , r. kuhlen intensive care medicine, anaesthesiology, university hospital rwth aachen, aachen, intensive care medicine, helios klinikum, berlin-buch, germany cardiac function monitoring in patients at risk for cardiac failure is a very useful tool to recognize and treat cardiac dysfunctions. the objective of this study was to compare a new method of non-invasive determination of cardiac output (ev-co) based on electrical velocimetry with invasive cardiac output measurements performed with a pulmonary artery catheter (pa-co). methods. twenty-five patients ( male, female) were included into the study during a three month period. the non-invasive measurements of cardiac output (co) were obtained with a new cardiovascular monitor (aesculon eletrical velocimetry, osypka medical gmbh, berlin, germany). simultaneous invasive measurements of co were made by injection of iced . % saline and the recording of thermodilution curves with a pulmonary artery catheter (baxter swan-ganz catheter, . french, edwards life sciences, irvine, usa). the analysis of the data was performed based on statistical methods recommended by bland and altman for evaluation studies( ). in all patients invasive and non-invasive co values could be obtained. the analysis of co showed a strong linear correlation (r= . ) between ev-co and pa-co (fig. a) . the mean difference between ev-co and pa-co was - . ± . litre*min − (mean±sd). the lower and upper limits of agreement for the comparison of ev-co with pa-co were - . litre*min- and . litre*min − and are defined as the mean difference± sd (fig. b) . the percentage error between ev-co and pa-co was . %. in this present study we found a good correlation between the haemodynamic values measured by electrical velocimetry and those obtained from pulmonary artery catheter measurements. therefore, electrical velocimetry, a new icg algorithm, is a suitable method to evaluate haemodynamic parameters with clinically acceptable accuracy. reference(s). ) bland jm, altman dg: statistical methods for assessing agreement between two methods of clinical measurement. the pulmonary artery catheter (pac) is still used to assess the hemodynamic status in cardiac patients, because it allows the measurement of pulmonary artery occluded pressure (paop), an indirect marker of left ventricular function. we studied the relationship between the cardiac function variables derived from pac and those provided by the transpulmonary thermodilution technique (picco) in patients with acute heart failure (hf) and severe sepsis or septic shock. twenty-one patients with circulatory failure requiring invasive hemodynamic monitoring were included. icu diagnosis was hf in and severe sepsis or septic shock in patients. all patients were monitored with a pac (edwards lifesciences, usa) and a picco catheter (pulsion medical system, germany). the following parameters were simultaneously assessed during the first day in each patient: cardiac index by either method (ci-pac, ci-picco), paop, cardiac function index (cfi), global ejection fraction (gef), and global end-diastolic volume index (gedvi). pearson correlation, bland-altman analysis and nonparametric mann-whitney u test were performed, as appropriate. results are given as median (interquartile range, iqr). a total of simultaneous measurements were performed during the first hours after icu admission ( measurements in each patient). the overall correlation showed a pearson correlation coefficient between ci-picco and ci-pac of . (p< . ). bland-altman analysis showed a mean bias of . l/min/m and limits of agreement (± two standard deviations) - . to + . l/min/m . using the pac the median (iqr) ci in hf and septic patients was . ( . - . ) and . ( . - . ) l/min/m (p< . ), respectively. the paop was ( - ) in hf and ( - ) mmhg in septic patients (p= . ). the gedvi in hf and septic patients was ( - ) and ( - ) ml/m (p= . ), respectively. in hf patients the cfi was . ( . - . ) and in those with sepsis . ( . - . ) min- (p< . ), and the gef was ( - ) versus ( - ) % (p< . ), respectively. in critically ill medical patients, assessment of cardiac function using transpulmonary thermodilution technique is a valuable alternative to the more invasive pulmonary artery catheter. cardiac output and cardiac function index better discriminate between patients with and without impaired cardiac function than pulmonary artery occluded pressure. endotoxin (lipopolysaccharide, lps) tolerance is characterized by a reduced sensitivity to subsequent challenge of lps. in animal models lps tolerance is closely associated with marked, unbalanced production of pro-and anti-inflammatory cytokines as several animal studies have shown a decrease in proinflammatory cytokines and an increase in il- (anti-inflammatory cytokine). the presence and mechanism of lps tolerance in humans is unclear. the aim of this study was to test whether -day administration of endotoxin leads to lps tolerance by an enhanced anti-inflammatory response and a suppressed proinflammatory response. methods. healthy volunteers received iv bolus injections of ng/kg escherichia coli lps on consecutive days. blood samples (tnfα, il- , il- β, ifnγ and il- ) were drawn before (t= ) and after (t= , , min, , , and hrs) administration of lps on day and and on t= hrs on day till . symptom scores were obtained including nausea, vomiting, headache, muscleache, backache and shivering. the volunteers were asked to score above mentioned complaints ranging from 'nihil' (score ) up to 'severe'(score ) every half hour after administration of lps on five consecutive days. both tnfα (proinflammatory cytokine) and il- (anti-inflammatory cytokine) showed a peak level the first day which was almost completely abolished on the fifth day (anova repeated measures between day and : p< . , figure ). all volunteers experienced the expected and transient influenza-like symptoms on the first day, at t= . hrs after the administration of±maximum clinical symptom score . . (p±lps. the symptom score on day was . < . )(figure ). conclusion. endotoxin tolerance developed after consecutive days of lps administration as demonstrated by the attenuated release of proinflammatory cytokines on the fifth day. in contrast to animal studies, the attenuated cytokine response was not limited to the proinflammatory response, but also the anti-inflammatory response was diminished. this human endotoxin tolerance model appears to be useful in exploring the possible beneficial effects of endotoxin tolerance, for example, in ischemia-reperfusion damage. t. eduardo* , f. alvarez , j. gomez-hererras , s. florez , s. soria , c. lajo anaesthesiology and reanimation, university hospital, pharmacology and therapeutics, faculty of medicine, university of valladolid, valladolid, spain systemic inflammatory response occurs frequently after coronary artery bypass surgery, and it is strongly correlated with the risk of postoperative morbidity and mortality. we have analysed the effects of gelatin priming versus ringer's lactate priming on cytokine release and during the inflammatory state following coronary artery bypass surgery with cardiopulmonary bypass. a prospective, randomized study was designed. forty four patients undergoing elective coronary artery bypass grafting were allocated randomly to one of two groups: patients with ringer's lactate prime and patients with gelatine containing prime during coronary artery bypass surgery. the study protocol was approved by the ethics committee of the 'clinico' hospital of valladolid. written informed consent was obtained from each patient. plasma levels of interleukin il- , il- , tnf-alpha, c-reactive protein (crp), complement (c ), and sris score were measured along the surgery and within the first postoperative hours at various time points. cytokine levels were measured by enzyme-linked immunosorbent assay from plasma sample obtained. the spss program (version ) was used for the statistical analysis of the data. differences from baseline and between the groups were evaluated by two-way analysis of variance for repeated measurements (anova, followed by scheffe's test). correlation analysis between variables was calculated using pearson's correlation coefficient. a probability value of p < . was considered significant. there were no significant differences between the groups regarding pre-operative data. patients were similar with regard to type of procedure, bypass time, aortic cross-clamp time and number of grafts. in both groups the serum levels of the proinflamatory cytokines (il- , il- , tnf-alpha), sris score, c , crp, and leukocytes increased significantly over baseline, with no difference between either the colloid or crystalloid group. the operation time, blood loss, need for inotropic support, extubation time, and length of intensive care unit stay did not differ significantly between the two groups. priming with gelatin versus ringer's lactate produces no significant differences in the inflammatory response in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. a prerequisite to evaluate resuscitation from hemorrhagic shock is a reproducible experimental model, which leads to a predictable outcome. in order to evaluate the best predictor of death, blood lactate was compared to mean arterial pressure in hypotensive animals submitted to severe controlled hemorrhage. forty immature pigs were anesthetized with ketamine, atropine and halothane, intubated and maintained breathing spontaneously with atmospheric air and halothane. pulmonary, femoral and jugular vein catheters, were inserted in order to measure cardiac output, mean arterial pressure (map), blood gases and blood lactate. group i (n= ) was hemorrhaged to a map of mmhg breathing room air with halothane . %. group ii (n= ) remained as control of group i, breathing room air with halothane . % and no bleeding. group iii (n= ) was hemorrhaged to a map of mmhg breathing room air with . % halothane. finally, group iv (n= ) remained as control of group iii breathing room air with halothane . % and no bleeding. variables were recorded every ten minutes with no further intervention for minutes, when anesthesia was discontinued in the surviving animals. death of the animals was registered up to twenty four hours after the experiment. all animals in group i died. all animals in group iii survived, despite the fact that both groups had equal degree of hypotension (map = mmhg). however, only group i exhibited high levels of blood lactate. receiver operating characteristic (roc) curve analysis with death of the animals as the variable of interest, demonstrated that only blood lactate exhibited % sensitivity, % specificity and a roc curve area of . . mean arterial pressure was less accurate in predicting the death of the animals. tissue oxygen tension (tpo ) represents the balance between local supply and demand and may be a useful monitoring modality. we previously reported that lipopolysaccharide infusion produced different responses in four organ beds studied ( ). in the present study we sought to compare peripheral tpo measurements (bladder, muscle) against those measured in more vital organs (liver, renal cortex) during acute hypoxaemia. under isoflurane anaesthesia, male wistar rats (approx g weight) underwent left common carotid and right jugular venous cannulation for blood sampling/bp monitoring and fluid administration, respectively. flow in the descending aorta (abf) and left renal artery (rbf) were monitored by ultrasonic flow probes (transonic systems, usa). arterial po was measured using a blood gas analyser (radiometer, copenhagen, denmark). tissue po was determined using oxylite probes (oxford optronix, uk) placed in thigh muscle, between the right and left lobes of the liver, in the left renal cortex and within the bladder lumen. after a -min stabilisation period, fluid-resuscitated rats ( ml/kg/h, n-saline) were subjected to progressive increases in hypoxaemia ( , . and % inspired oxygen). comparisons were made to time-matched controls breathing room air. statistics were performed using two-way rm-anova and post-hoc tukey's test. results. data shown as mean (± se), *p< . between control (c; n= ) & hypoxaemia (h; n= ); $ p< . between timepoint & baseline. ( ) ( ) conclusion. patients with erd have higher severity and more frequently immunodepression and medical pathology. they needed more invasive procedures and antibiotic therapy so infection rates and resistance patterns are superior to the rest of icu patients. conclusion. an improvement of the methods of regulation and of the monitoring of treatments are essential if we take into account the increasing bacterial resistance. if glycopeptides are still the initial standard treatment of serious infections, new therapeutic strategies should be emerging, depending on the confirmation of presented innovations. prospective observational cohort study, performed in a -bed icu. all copd patients with ae who required intubation and mechanical ventilation were eligible. at icu admission, information on endotracheal aspirate purulence, and hyperthermia was collected. in all patients, gram stain and quantitative endotracheal aspirate culture (positive at cfu/ml) were performed. in addition, leucocytes count, c-reactive protein (crp), and procalcitonin (pct) levels were measured. univariate and multivariate analyses were used to determine variables associated with bacterial severe aecopd. positive predictive value and negative predictive value were calculated for variables independently associated with bacterial severe aecopd. . severe aecopd were diagnosed in patients. bacteria were isolated at significant threshold in exacerbations. s. pneumoniae ( %), methicillin-sensitive s. aureus ( %), and h. influenzae ( %) were the most frequently isolated bacteria. age ( ± vs ± ), male gender ( % vs %), saps ii ( ± vs ± ), duration of mechanical ventilation ( ± vs ± d), and mortality ( % vs %) were similar in patients with bacterial severe aecopd and those with nonbacterial severe aecopd. rate of patients who received prior antibiotic treatment was significantly lower in patients with bacterial severe aecopd than in patients with nonbacterial severe aecopd ( % vs %, p = . ). no significant difference was found in rates of patients with hyperthermia ( % vs %), purulent endotracheal aspirate ( % vs %), and leucocytosis ( % vs %) between the two groups. although leucocytes, crp and pct levels were similar in the two groups, rates of patients with pct > . ng/ml ( % vs %, p = . ), and patients with positive gram stain of endotracheal aspirate ( % vs %, p< . ) were higher in patients with bacterial severe aecopd than in patients with nonbactrerial severe aecopd. pct > . ng/ml (or [ % ci] = . [ . - ], p = . ), and positive gram stain of endotracheal aspirate ( [ - ], p < . ) were independently associated with bacterial severe aecopd. conclusion. positive gram stain of endotracheal aspirate, and pct > . ng/ml are independently associated with bacterial severe aecopd. these results could be helpful for future interventional studies aiming at reducing antibiotic use in these patients. systemic inflammatory response (sir) in patients with infection clearly influences outcome. the aims were to study the sir in icu-acquired infection (i-icu) according to the source and etiology and evaluate outcome impact. multicentre prospective study from april to july in ucis of hospitals. the number of patients admitted to icu> h until icu discharge or a -day period. i-icu diagnosed according to the cdc's criteria, source, etiology and sir were analyzed. conclusion. % of the i-icu worsen in sepsis severe/septic shock. vap and bacteriemias had more severe sirs and uti less frequent. septic shock presented a high mortality (> %) without significant differences in infection sites. c albicans, a baumannii and p aeruginosa developed the worst sir. conclusion. this analysis confirms that a small percentage of long stay patients occupy a large proportion of icu patient-days. the mortality is higher in this group than the overall unit, but the survival rate of . % could justify the extra resources required to treat these patients. age does not appear to influence length of stay in this study. the patients who are most likely to have a prolonged length of stay are re-admissions, patients who are peri-transplant or have ventricular assist devices. editorial: safe use of cricoid pressure cricoid pressure: knowledge and performance amongst anaesthetic assistants assessment of the ml syringe as a simple training aid in the application of cricoid pressure reference(s). possum and portsmouth-possum for predicting mortality possum scoring for patients with fractured neck of femur this study would not have been possible without the contribution of all icu team and the following people: wagner fontes, marilia calipo ferreira and ivy dantas gangiredddy ch admission of older patients to intensive care units is a controversial issue. the outcome of elderly patients with critical illness in india has not been previously studied. retrospective chart review of males > years & female > years from may till november . data collected included age, gender, disease category, comorbidities, mechanical ventilation days, length of stay in icu and hospital, apache ii, sofa, premorbid functional state and mortality. in admissions to micu, were critically ill elderly [ ( . %) males, ( . %) females]. premorbid functional state assessment showed: independent ( . %), partially dependent ( . %) and wholly dependent ( . %). at admission, organ involvement was respiratory [ ( . %) ], renal [ ( . %)], neurology ( . %), metabolic ( . %) and cardiac ( . %). mean apache ii and sofa scores were . + . (median ). and . + . (median . ) respectively. mean length of stay (los) in icu was . days + . and . days + . in hospital. mean icu stay was . + . & in hospital was . + . in - year age group, vs . + . and . + . in the over group [ . ] . total mechanical ventilation days were (range - ). died ( %) of which [ / ( %) ] were in - yrs and / ( . %) in > yrs [ns] . decisions to limit life support were taken in / cases ( . %), dnr in ( %) and withholding in ( %). apache score > correlated with mortality ( deaths in score> ; death in score < (chi square test . ). there was no correlation between premorbid functional status and mortality. respiratory involvement was the predominant cause of admission. the hospital mortality for the elderly was only %. apache ii score correlated with mortality. the sample size was too small to detect any significant differences between age groups in terms of los and mv days. % of the deaths were preceded by eol decisions. introduction. the phenomenon of increased intra-abdominal pressure and the resultant physiologic compromise were first described in the late s. acs has been defined as the cardiovascular, pulmonary, renal, splanchic, abdominal wall and intracranial disturbances resulting from elevated iap. korn and associates first used the term acs in . malbrain et al found during one day point prevalence study in icus had . % of patients has acs. intra abdominal pressure (iap) was measured in consecutive patients (age range - ; males: females) who were admitted to the micu with diverse clinical problems. iap was routinely measured using the transurethral measurement of urinary bladder pressure using a foley's catheter. abdominal compartment syndrome (defined as > cm h o) was found in patients (age range - , males; females). of these patients had primary acs, had secondary and had recurrent acs. the mean apache ii score was and sofa score was . in the acs group; the apache ii score was . the sofa score was . the group without acs. ( p value not significant) out of , patient with acs had a surgical intervention to reduce iap (pd catheter in , decompressive celiotomy in ). the indications for intervention were unexplained respiratory deterioration seen as in increase in plateau pressure or fio , fall in urine output despite adequate map and fluid resuscitation and iap> cm of water. / in the intervention group died ( . %). patients in the raised iap group managed conservatively with fluid restriction and diuretics. the mortality in the patients without acs was . %. in addition, increased iap alone gave a clue to the need for surgical intervention in / patients; these would have otherwise been managed conservatively. our study suggests that routine iap measurement of patients in the icu is beneficial because of the presence of unsuspected acs in a significant proportion of patients ( %) irrespective of the primary disease. acs may cause renal, hemodynamic and respiratory compromise that can be improved by judicious and timely intervention. further, raised iap alone may sometimes give a clue to the need for a surgical intervention, which may beneficially affect the clinical course. a. lorx* , b. szabó , m. hercsuth , z. hantos anesthesiology and intensive therapy, semmelweis university, budapest, medical informatics and engineering, university of szeged, szeged, hungary introduction. the low-frequency respiratory impedance (zrs) has been shown to reflect the respective contributions of the airway and tissue mechanical properties accurately in healthy subjects. little information is available, however, on the values of airway and tissue parameters derived from low-frequency zrs data in ali patients before and after bronchodilator therapy. zrs was measured with small-amplitude forced oscillations between . and hz at three peep levels ( , and hpa) before and after nebulised berodual in mechanically ventilated patients including with severe pneumonia and with postoperative respiratory failure, without any previous pulmonary disease. airway resistance (raw) and inertance (iaw), and constant-phase tissue damping (g) and elastance (h) were estimated from zrs spectra by model fitting. raw decreased with peep, and on the administration of berodual in both groups. in the postoperative patients, g decreased with peep, and g and h decreased following berodual inhalation; this indicates that bronchodilation was accompanied by recruitment of previously closed regions of the lungs. there was no change in iaw and hysteresivity (g/h), suggesting that the peripheral airway inhomogeneity was not markedly affected by the intervention. the decreases in raw reflect the presence of reversibly elevated airway resistance in all patients. the decreasing g/h in the pneumonia patients after berodual indicates improved homogeneity in the mechanical properties of the peripheral lung with consequent improvement in ventilation, although the changes did not reach the level of statistical significance. berodual inhalation results in improved tissue properties of the respiratory system, i.e. decreases in elastance and tissue damping, which is associated with the bronchodilator effect. overall, the low-frequency oscillation technique proves to be an informative and accurate method for bedside monitoring of critically ill patients. dialysis disequilibrium syndrome -report of cases n. shaikh* , m. kettern , y. hanssens anesthesia and intensive care, pharmacy, hamad medical corporation, doha, qatar introduction. dialysis disequilibrium syndrome (dds) is a central nervous system disorder occurring in pts (pt), either during or within hours of dialysis. dds is unknown in pt who are on dialysis for some time and no case had been reported in ventilated pts. report of cases of fatal dds in ventilated pts with acute renal failure (arf) on haemodialysis (hd) for more than a week. case : a year old male pt victim of motor vehicle accident, spleenic and bowel injury. ct head normal, gcs / . he underwent spleenectomy, hartman's procedure and abdominal packing. post-op, he was in dic and haemorrhagic shock. he remained hypotensive, adrenaline and noradrenaline were started. pt was oliguric and developed arf on day , daily hd was started over hours, normal bath and heparin free. on day , pt was trying to obey commands. on day , pt developed sepsis and meropenem was started. on day , pt underwent hd, became unresponsive after hour and pupils fixed-dilated. ct brain showed severe oedema and herniation. eeg was flat and brain stem reflexes absent. diagnosed as brain dead on day and expired same evening. case : a year old male pt fell from height, on arrival gcs was / . he had severe chest trauma and liver laceration,underwent laprotomy, haemostasis and packing of abdominal cavity. on day , pt developed arf, started on slow hd ( - hours) , low sodium, potassium and heparin free. ct brain on day was normal. on day pt developed septic shock, started vancomycin and ciprofloxacin. pt required noradrenaline. on day , during hd (increased potassium, heparin free), pt developed hypotension, pupils became dilated and fixed. hd was stopped, mannitol was given and pt was hyperventilated. ct brain showed severe oedema and herniation of brain. brain stem functions were absent. eeg was flat and heart stopped after hours. tioxidant capacity, as well as the detection of oxidized biological markers. the direct, in vivo quantitative measurement of the production of superoxide radical, an important parameter of the oxidative load, is difficult due to its low concentration and a short half life ( ) . in this study, the effect of h/s and resuscitation on the oxidative state in vital organs (gut, liver, lungs, kidneys) was estimated for the first time by measurement of the production of superoxide radical in vivo, using a new superoxide assay.methods. male wistar rats were divided in two groups (n= ): sham and h/s group. h/s was induced by withdrawal of blood targeting to a mean arterial blood pressure of - mmhg, which was maintained for minutes. at the end of the shock period, rats were resuscitated with re-injection of the removed shed blood volume. tissue samples were collected hours after resuscitation and the oxidative load was assessed by a new superoxide assay which directly measures the production of superoxide radical and an established lipid peroxidation assay which measures the production of organic hydroperoxides. statistical analysis was performed using anova. animals that underwent h/s exhibited a statistically significant increase in the production of organic hydroperoxides in the gut (p< . ), liver (p< . ) and lung (p< . ) tissues, whereas no change was observed in the kidneys. the rate of production of superoxide radical increased more in the gut and the liver (p< . respectively) and to a lesser extent in the lungs (p < . ), while kidneys were not affected as well.conclusion. this study demonstrates an increase in oxidative load in the gut, the liver and the lungs after h/s-resuscitation, which was estimated by two different methods. moreover, and for the first time in a model of h/s, the new superoxide assay directly and more precisely estimates oxidative stress in vivo, since the formation of superoxide radical seems to play a pivotal role in the cataract of reactions that lead to the oxidation of biological structures. these results suggest that predominantly the gut and the liver, and to a lesser extent the lungs, but not the kidneys are the organs primarily affected by h/s in this model. reference(s). . biasi f, et al.: free radic. biol. med. ; : - . . georgiou cd, et al.: anal. biochem. ; : - . g. luckner* , s. jochberger , v. d. mayr , v. wenzel , h. ulmer, in this retrospective analysis, we examined if a low-dose avp infusion ( iu/h) can reverse isolated postoperative vasodilatory hypotension and prolonged vasopressor requirements (> hrs) in fifteen patients under chronic ace inhibitor treatment. hemodynamic and laboratory parameters were recorded , , hrs, and immediately before start of avp therapy, , , , and hrs after start of avp, as well as , , and hrs after cessation of avp infusion. the primary endpoint was to evaluate hemodynamic effects and changes in phenylephrine dosages during avp infusion. the secondary endpoint was to evaluate changes in laboratory parameters during avp. . avp infusion did not show any significant effects on hemodynamic variables. only mild, non-significant effects on map (+ . %, p= . ) and phenylephrine (- . %, p= . ) dosages were observed during the first hrs after avp infusion. there were no changes in laboratory parameters during avp infusion. a supplementary, low-dose avp infusion proved to be ineffective to improve hemodynamic function and reverse vasopressor dependency in patients with chronic ace inhibitor therapy and prolonged postoperative hypotension. results. drotaa was administered in patients [ ± years old, simplified acute physiology score (sapsii): ± ]. a community acquired infection was the causal infection in % of cases. patients had > organ failures before the drotaa onset (hemodynamic failure in patients,respiratory in ). all patients received hydrocortisone (started ± hours before the onset of drotaa) and patients received hemofiltration (started ± hours before the onset of drotaa). serious bleeding events occurred in patients. interestingly, the icu mortality was % while mortality predicted from saps ii was %. we observed a significant improvement in the pao /fio ratio and in the blood lactate level after the onset of drotaa (h ) ( table ). in patients treated with norepinephrine (n= ), we also observed a rapid decrease in the vasopressor dose after drotaa onset while the mean arterial pressure was maintained stable in the same period ( figure) . in this observational study, we evidenced significant improvement in the hemodynamic and respiratory failures and a decrease in blood lactate after the onset of drotaa administration. in the past few years new insights in the role of microcirculatory alterations during sepsis have been elucidated by means of orthogonal polarization spectral (ops) imaging. persistent alterations appeared to have prognostic value. several other techniques, such as near infra red spectroscopy, laser doppler and peripheral temperature have been used to asses peripheral circulation. however there is unclarity about relation between peripheral and microcirculation during sepsis. aim of this study was to evaluate the relation between peripheral and microcirculatory alterations during sepsis. we performed a single centre observational study in patients with < h severe sepsis/septic shock. ops imaging of the sublingual region and semi-quantitative analysis were performed as described in detail elsewhere . skin perfusion was measured as central-to-toe temperature difference (deltat). non-parametric rank correlation is expressed as spearman's rho(rs). , ( , - , ) , ( , - , ) , serratia marcescens (n= ) , ( , - , ) , ( , - , ) , acinetobacter baum (n= ) , ( , - , ) , ( , - , ) , klebsiella pneumoniae (n= ) , ( , - , ) , ( , - , ) , all pathogens (n= ) , ( , - , ) , ( , - , ) , msc -meropenem serum concentration, mic -minimum inhibitory concentration conclusion. we conclude that continuous infusion of meropenem in dose g per hours in critically ill patients provides reliable serum meropenem concentrations in relation to mics of meropenem sensitive pathogens. grant acknowledgement. this study is supported by the czech ministry of education (project msm ) s. boyes* , g. l. thomas speech and language therapy, salford primary care trust, intensive care unit, hope hospital, salford, united kingdom although several key documents recommend that slt should be integral to the multidisciplinary care of critically ill patients , , , these services are often not funded. without this input there is increased risk of nosocomial pneumonia, malnutrition and dehydration. antibiotic prescription and length of stay may increase with higher dependency and a slower transition through levels of care. communication difficulties may also impact on the patient experience. as per royal college of speech & language therapists guidelines our project explored unmet need and defined the potential role of slt at hope hospital, a regional neuroscience centre. slt provided daily input to critical care patients for a month period. prospective data were collected detailing referrals and slt management, and were compared with retrospective data from months prior to the project. stakeholder evaluation was carried out using pre and post project staff questionnaires, and by collecting anecdotal evidence from patients and staff.results. referrals to slt increased by % ( pre-project versus during the project). pre project, % referrals( ) were inappropriate and % ( ) transferred before asessment. % referrals ( ) during the project were appropriate and assessed. % of pre-project referrals were seen on the day of referral compared to % during the project. pre-project slt intervention focused on assessment and advice alone. the project promoted earlier identification of needs, early management of clinical risk and contributed to multidisciplinary care. major training and education needs were identified. stakeholder evaluation was overwhelmingly positive, demonstrating slt contribution to multidisciplinary care and the patient experience.conclusion. dedicated slt input in critical care increased referrals to slt. the number of inappropriate referrals and the time to slt assessment decreased. input promoted the identification of clinical risk, facilitating early intervention and rehabilitation. training needs and additional roles for slt (weaning, decannulation and risk management) were identified. stakeholder evaluation demonstrated improved patient experience. these findings form the basis of a business case to expand slt resources in critical care. whereas several studies established cefotaxime, or other rd generation cephalosporins, amoxicillin/clavulanic acid and oral quinolones as effective first-line antibiotic regimens in community-acquired cases, little is known about the spectrum of antimicrobial resistance, impact of an effective initial antibiotic regimen on survival and the spectrum of causative micro-organisms in hospital acquired cases. all cases of sbp diagnosed in a university hospital between january and august were retrospectively analysed. . cases ( m, f) were retrieved. mean (± sd) age was (± ) years. meld-score was . (± . ) at the time of the diagnostic tap. in patients the infection was community acquired, in patients hospital acquired. patients ( . %) died in the hospital. the initial antibiotic regimen was a third generation cephalosporin in , an ampicillin/sulbactam in and a quinolone in cases. cases (all hospital-acquired infections) were initially treated with a carbapenem and vancomycin had been added in cases. in patients the antibiotic regimen had to be changed during the course of treatment. survival was not worse in hospital-acquired cases than in community-acquired cases, but hospital-acquired cases were more often treated with broader antibiotic regimens at the onset of therapy. patients in whom the initial antibiotic treatment had to be modified had a higher mortality than patients in whom the initial treatment was continued ( % vs. %; p= . ). in patients with positive culture results, an effective first-line antibiotic regimen was associated with lower mortality ( % vs. %; p= . ). binary logistic regression analysis found meld-score at diagnosis (p= . , % confidence interval (ci) . - . ), ascitic fluid cell count (tsd) (p= . , % ci . - . ) and an escalation of antibiotic therapy (p= . , % ci . - . ) to be independently associated with mortality. the most commonly cultured micro-organism was e. coli (n= ), followed by enterococcus faecium (n= ). among culture positive cases the causative micro-organism was resistant to ceftriaxone in ( %), to ampicillin/sulbactam in ( %) and to ciprofloxacin in ( %).conclusion. the incidence of resistance to one of the recommended standard regimens is high in hospital-acquired and community-acquired cases of sbp. failure of the initial antibiotic regimen is associated with higher mortality. broader antibiotic regimens should be considered as initial approach. the multidrug-resistance (mdr) of gram (-) strains in the icu is a severely growing problem, so colistin has been recently reintroduced in clinical practice. colistin had fallen out of favour after due to nephrotoxicity, neurotoxicity and poor pharmacokinetics in lung tissue. the aim of this clinical trial is to study the efficacy and safety of colistin in mdr gram (-) nosocomial infections (ni) in the icu during the last months. we enrolled retrospectively icu patients (pts), men ( %) and women ( %), who developed a mdr gram (-) ni. mean age: . ± . years, mean stay: . ± . days. underlying diseases: multiple trauma , complicated surgery , other . the pts were treated ( courses) with intravenous (iv) colistin . . iu x daily (adjusted for creatinine clearance) in combination with carbapenems or b-lactamase inhibitors. in pts aerosolized colistin ( . iu x daily) was added to iv colistin. the ni treated were: pneumonia ( . %), central venous catheter-related infection ( %), peritonitis ( %), central nervous system infection (cnsi) ( . %). pts with cnsi additionally received colistin intrathecally. the responsible bacteria were: ac. baumannii ( . %), ps. aeruginosa ( . %) and kl. pneumoniae ( . %), with double pathogen in episodes of ni. clinical success (important lessening of the signs and symptoms of ni) occurred in ni ( . %); microbiological success (eradication of the pathogen in cultures of blood, peritoneal fluid, bronchial secretions or celebrospinal fluid) was obtained in ( . %). nephrotoxicity was observed in pts ( . %); it was reversible. mortality rates: / = . %.conclusion. ) colistin in combination with other antibiotics is an effective treatment of severe mdr gram (-) ni in the icu. ) the incidence of adverse events is low; a close surveillance of renal function is needed. ) when aerosolized colistin was included in treatment, microbiological success was accelerated (p< . ). ) pneumonia was the ni best corresponded to colistin than other sites of ni, but not statistically significantly (p< . ). ) prognosis was independent of type of invading gram (-) microorganism. introduction. the biggest concern in infection epidemiology in intensive care is the emergence of multidrug-resistant gram-negative (pseudomonas aeruginosa, klebsiella pneumoniae and acinetobacter baumannii) and gram-positive (staphylococcus aureus) organisms. two periods of six months were analyzed for each icu: in the first six months (from mar/ to aug/ ) no infectious disease advice was given in any; in the following six months (sep/ the fev/ ) infectious disease consultation was given in icu when requested, as opposed to icu , where it was continuously provided by an infectious disease consultant with degree in intensive care. the number of multi-resistant organisms grown was then compared. a t-test for two independent samples was used in statistics. the species distribution of the pathogens evaluated in icu is summarized in table . there was reduction in the occurrence of p.aeruginosa % ( - , %), a.baumannii % ( , - %) and s.aureus % ( , - , %), with significant p value for p.aeruginosa, the most common microorganism.* k.pneumoniae percentage of increase = , %. table summarizes the results in icu , where the decrease in growth of the multi-resistant stains was higher: % for p.aeruginosa ( , - , %), , %for k.pneumoniae ( , %- , %) and % for s.aureus ( , - %) also with significant p value for p.aeruginosa. introduction. intravascular catheter related infections are very critical in icu environment, with elevated morbi-mortality and impact on costs. in our unit, according to a quality political, it had established standards on prevention, diagnosis and treatment of nosocomial infections, with a periodic review of the ours rates. we will describe the managerial model chosen when we noticed an increase of the catheter related infections incidence: outcome management. in december it was created a multi-professional work group ( doctors, nurses and respiratory therapists) who performed a weekly meeting with the brainstorm technique. all the infections data were reviewed. the group identified main risk factors related to the problem using a diagram cause-effect. then, it had established corrective measures, deadlines and ways for execution. measures chosen: team for catheter insertion; using full-barrier precautions for insertion of central venous catheters; using of semipermeable and transparent dressings; avoiding the jugular and the femoral sites; routine replacement of the catheters after ten days insertion; removal of the unnecessary catheters. target was return of catheter related infection rate to level of the previous year. in the first three months after the intervention, we noticed a reduction of the median rate of catheter-related bloodstream infection per catheter-days: , infections to , . catheter-related bloodstream infection is the nosocomial infection par excellence: costly, common, and frequently fatal. efforts to improve patient safety must focus on simple and inexpensive interventions and prevention measures. the managerial tool showed us main causes of the problem and caused the adhesion of all staff around the catheter related infections and the correct measures to solve it. limited data suggest that vancomycin when given by intermittent injection may not be as affective as linezolid for the treatment of ventilator acquired pneumonia and this inferiority may be negated by administering vancomycin by continuous infusion ( ). administration in this fashion may improve the drug's tissue penetration and is easier to control but a double blind randomised controlled trial has not been carried out. the way in which vancomycin was administered in our icus was changed in may so that any patient with central venous access was given vancomycin by continuous infusion according to a strict protocol ( ) . data from our electronic prescribing system was correlated with icnarc data for mortality. we conducted a retrospective audit from december to october comparing icu outcome in patients who were treated with one agent only. patients who received both linezolid and vancomycin or were on a bd and infusion regiment were excluded. . patients were treated with vancomycin infusion, of whom . % died. this was not significantly different from the mortality for vancomycin when given by intermittent injection of . %. interestingly the mortality for those treated with linezolid in an unmatched group of patients was . % (p< . ). conclusion. contrary to previous audits, our data suggest that vancomycin is not inferior to linezolid for icu mortality. the mode by which vancomycin is administered does not affect mortality. the increased mortality found in patients treated with linezolid has yet to be explained. further analysis is required. there are recommendations for control and prevention of methicillin-resistant staphylococcus aureus (mrsa) ( ); surveillance reduction in antibiotics use, screening, nasal and skin decolonization, handwashing, isolation, decontamination of clinical areas, adequate staffing. these recommendations however, are frequently based on large series and case reports rather than randomised trials ( ) . of those recommendations, only two (handwashing and adequate staffing) are reliably carried out in our icu. even conventional 'deep cleaning' has been shown to be unreliable ( ). all patients admitted to itu at university hospital birmingham between june and may were retrospectively studied so that any microbiological sample that was positive for mrsa was correlated with the date of icu admission. conclusion. there has been a steady decline in the number of primary mrsa infection occurring in our icu whilst the number of cases admitted has remained constant. colonisation pressure from patients admitted to icu is independent of mrsa acquisition. the reasons for our decline in mrsa infection remain unclear as full recommendations to inhibit mrsa spread can not be implemented. in our tertiary surgical icu, antibiotic policy restricts prescription of meropenem to ) the empirical treatment of suspected bacterial severe sepsis in patients with risk factors for antimicrobial resistance or with documented colonisation with multiresistant gram negative (mrgn) organisms, or ) the directed treatment of infections caused by mrgn organisms. to evaluate compliance with these restrictions, the indications for meropenem use were reviewed, and the feasibility of a de-escalation strategy in case of empirical meropenem prescription was evaluated. we performed a retrospective study of all meropenem prescriptions in the surgical icu from / / to / / . patients who received more than one dose of meropenem were included in the analysis. age, apache ii, prior length of stay, duration of meropenem administration, antibiotic prescription other than meropenem, microbial etiology and site of infection were recorded. the presence of risk factors for antimicrobial resistance, i.e. either previous exposure to broad spectrum antibiotics or a hospital stay for longer than days prior to infection were documented. data are presented as mean (standard deviation). data from hundred and thirteen meropenem prescriptions were available for analysis. mean age of the patients was ( . ), and the mean apache ii score was ( . ). pulmonary ( %) and intraabdominal ( %) infections were the most frequent sites of infection. meropenem was prescribed according to the restricted indications in / patients ( %). in patients it was initiated empirically with both risk factors for antimicrobial resistance present, and in patients it was used because of documented colonisation with mrgn organisms prior to the current infection; in cases it was used after identification of a mrgn organism as the causative organism of the infection. in the other patients (n= ), meropenem was started empirically with no or only risk factor for resistance and without documented colonisation with mrgn organisms. empirical prescription of meropenem was de-escalated in patients ( %). reasons for not de-escalating were the identification of mrgn organisms or uncontrolled polymicrobial infections. compliance with the restricted indications for meropenem in our icu was high. empirical prescription of meropenem was de-escalated upon culture results in half of the cases. d. r. goldhill , a. badasconyi* , a. a. goldhill , c. waldmann anaesthetic department, the royal national orthopaedic hospital, stanmore, anaesthetic department, the whittington hospital, medical school, kings college london, london, anaesthetic department, the royal berkshire hospital, reading, united kingdom patient position in icu is important for preventing complications such as pneumonia [ ] . two hourly turning is a common standard of care [ ] . evidence suggests that patients may not be turned this frequently [ ] . we therefore conducted a prospective observational study of patient position and turning in icu and the factors that may affect the frequency of turns. forty eight of uk icus contacted agreed to participate in this study. the position of each icu patient was recorded every hour over two hour periods, one midweek and one weekend. the patient age, gender, estimated height and weight, diagnosis, whether intubated and ventilated, hourly sedation score, nurse:patient ratio and number of patients on the unit were also recorded. patients could be on their back, front, left or right side. a turn was defined as a change from one of these positions to another. the degree of rotation and whether patients were flat, head down or head up was also noted. analysis of the relationship between the average time between turns and factors that may be associated with this was performed using multiple regression on the log transformed dependent variables. . sets of observations were analysed. patients were prone at some time. other positions are in the table. the average time between turns was . hours, median . (range . - ; interquartile range - . ). there was no significant association between the average time between turns and age, gender, respiratory tract-related diagnosis, intubated and ventilated, sedation score, day of week or nurse:patient ratio. there were significant differences between hospitals in the frequency with which they turned patients on their unit. patients are rarely nursed flat. some patients go for prolonged periods without a change in their position. there was no association between the average frequency of turns and the patient and organisational factors we examined. however there are differences between hospitals in the practice of turning patients. introduction. this study compares the incidence of vap in traumatic patients receiving mechanical ventilation for > hours with a endotrachealtube with a dorsal lumen for intermitent drainage of subglotic secretions with others that received mechanical ventilation with a conventional endotracheal tube. traumatic patients admitted to the reanimation unit of the complexo hospitalario de ourense from march to august that received mechanical ventilation for at least hours were eligible for study. the follow-up period consisted of the patients remaining stay in the reanimation unit. demographic and clinical characteristics of patients were collected on admission. vap was suspectted in patients with a clinical pulmonary infection score or more. the diagnosis was done by tracheal aspiration and protected specimen brush. the bacteriologic examination was done by cuantitative and cualitative methods. patients were included inthe study ( that received intermitent drainage of subglotic secretions and in group control). there were not early-onset pneumonia on patients with intermitent drainage of subglotic secretions. there were not significative stadistycal differencies in incidence, duration of ventilation, reanimation length of stay or mortality.conclusion. this study didn't find statystical differences between the two groups because of the short number of patients; but it is important that inthe group wich received intermitent drainage of subglotic secretions there weren't eppisodies of early-onset pneumonia. f. lambiotte* , t. levent , x. lemaire , m. castro , l. gaybor , w. joos , t. ngheim intensive care, chsa, maubeuge, infectious disease, tourcoing, france to analyze the indications and the quality of the prescription of glycopeptides (gp) in an intensive care unit of beds. a -months retrospective study. the treatment was indicated if it answered the recommendations were selected. it was correct if:correct initial dose,corrects glycopeptides concentrations,serum dose obtained with fixed levels, antibiogram justifying the prescription of a gp in the event of bacteriological documentation. . saps ii , (± , ), age years (± , ),gender (m/f) , . , % of the patients presented a renal insufficiency. treated pathology: pneumoniae( %), septic shock( %), intra-abdominal infections ( %), blood stream infections, hyperthermia of unknown origin ( %), infections of the skin ( %), pyelonephritis ( %). frequency of organism recovery was: coag-neg staphylococci (including oxa-r), staphylococci aureus (including mrsa), entérococcus (including ampi-r),others : . the indications of regulation were largely respected but the methods of use of the gp were failing. even when the regulation was correct (n= ), the fixed serum rate was reached only in % of the cases. there is no difference between this patients in septic shock and other patients. taking into account the profile of the patients of intensive care unit, it seems difficult to predict that a treatment will be effective and that sub-inhibiting serum concentrations will be avoided even if the recommendations were respected. the situation becomes more and more delicate because of the increasing bacterial resistance. nosocomial pneumonia (np) continues to be an important cause of morbidity and mortality in the icu. the type of icu (medical, md or surgical, sg) has been described as an important factor to influence their etiology. prospective, observational study conducted between / and / in specialized icus of a tertiary hospital. all patienst who fulfilled clinical criteria ( of ) of np were included. epidemiological and microbiological features were registered. the patients were grouped according their origin from a md or sg icu. we included patients (md, n= and sg n= ). age ± yrs. icu admisión apache ii . ± . the distribution of infections between icus was for md and sg respectively: ventilator-associated pneumonia (vap) % vs %, ventilator-associated tracheobronchitis (vat) % vs %, and np % vs %. we could not find significant differences in epidemiological characteristics (except age ± vs ± , p= . ), risk factors for nn and blood test between the groups. patients ( %) had microbiological diagnosis (md= vs sg= ). the most frequent microorganism producing pneumonia in these patients were mrsa and mssa (same distribution: , % vs , %, p= . ), followed by p. aeruginosa ( , % vs %, p= . ). the inadequate initial ab therapy was slightly higher in sg patients ( % vs %, p= . ) and the mortality rate was not influenced by this variable. the icu and hospital los were alike and hospital mortality rate was significant higher in md than sg icu patients ( , % vs , %, p= . ). for a predicted mortality of % and %. we find some differences in this small cohort of md and sg icu patients with np. the microbiology profile showed important differences between the groups. the main limitation of this study is the small sample size. renal insufficiency is a frequent complication of septic shock. aminoglycosides are highly potent bactericidal antibiotics that together with beta-lactam antibiotics will result in a broad antibacterial coverage. yet, the use of these antibiotics in the treatment of early gram-negative septic shock has been hampered by the assumption that aminoglycosides may be nephrotoxic even in short term therapy. as this is very difficult to investigate in the clinical setting, an experimental study was set up, the aim of which was to evaluate whether the addition of tobramycin further deteriorates kidney function in pigs with endotoxin-induced renal damage. the animals were anaesthetised, catheterized, mechanically ventilated and randomised to groups. groups i (n= ) and ii (n= ) received endotoxin infusion in a dose of mcg x kg- x h- for h, whereas groups iii (n= ) and iv (n= ) received corresponding amounts of saline. groups i and iii received a -min infusion of tobramycin sulphate in a dose of mg x kg- starting minutes after the initiation of the endotoxin infusion, whereas groups ii and iv received corresponding amounts of saline. in parallel with the tobramycin/saline infusions, a cefuroxime infusion in a dose of mg x kg- was given to all pigs. renal function was evaluated by cefuroxime clearance, creatinine clearance, plasma cystatin c, plasma urea, urine output and urine nag (n-acetyl-beta-d-glucoaminidase) excretion. there was no significant difference in physiological baseline variables between the groups of pigs. the elimination rate of cefuroxime - h decreased in both endotoxemic groups whereas it was constant in the non-endotoxemic groups. at h cefuroxime concentration and cystatin c were higher in endotoxemic vs. non-endotoxemic pigs (p< . and p< . , respectively), whereas urine output and creatinine clearance were lower (p< . for both). however, there were no differences between groups i and ii or iii and iv in cefuroxime elimination, urine production, cystatin c or creatinine clearance. plasma urea and urine nag did not differ between any of the groups. endotoxin in the dose administered caused a significant renal dysfunction in this porcine model. the results indicate that the addition of a high single dose of tobramycin seems not to further aggravate the endotoxin-induced renal injury.grant acknowledgement. this work was financed by grants from the nielsen-olinder foundation. the overall nosocomial infection rate was decreased in the chx-treated patients by % ( / vs / ; p< . ). we also noted a % reduction in the incidence of total respiratory tract infections in the chx-treated group ( / vs / ; p< . ). gram-negative organisms were involved in significantly less (p< . ) of the nosocomial infections and total respiratory tract infections by % and %, respectively. no change in bacterial antibiotic resistance patterns in either group was observed. a reduction in mortality in the chx-treated group was also noted ( / : . % vs / : . %). inexpensive and easily applied oropharyngeal decontamination with chx oral rinse reduces the total nosocomial respiratory infection rate in patients undergoing off pump cabg surgery. this results in significant cost savings for those patients. staphylococcus aureus (mrsa) has sparked development of alternative anti-microbial strategies. one such approach involves the use of light-activated antimicrobial agents (photosensitisers), termed photodynamic therapy (pdt). following excitation of the photosensitiser by light of an appropriate wavelength, singlet oxygen and free radicals are generated locally which directly attack the plasma membrane and lead to bacteriolysis. although pdt is well established as an oncological treatment, its use in the treatment of wound infections, in particular those involving resistant strains of bacteria, has yet to be established. after anaesthesia and depilation, week old female c black mice received either a single excisional wound or a superficial scarified wound that were immediately inoculated with an emrsa- bacterial suspension ( cfu/wound) and treated after hour with pdt using methylene blue (mb) as the photosensitiser and laser light with a wavelength of nm to a dose of j.cm − per wound. at the end of treatment, the wounds were excised and processed to assess the total number of viable bacteria per wound. two further experiments investigated the heating effect of pdt and possible collateral damage caused by pdt. three control groups were used to sequentially test the effect of mb alone, light alone and an untreated group which received neither mb nor light illumination. pdt treatment resulted in at least a log reduction (p< . mann whitney-u test) in the number of viable bacteria isolated from the wounds (figure) . there were no obvious histological differences between pdt-treated and untreated wounds. the temperature of the treated wounds rose by an average of . ˚c (± . ˚c) at the end of the treatment.conclusion. pdt is effective in reducing the total number of viable mrsa in an inoculated wound and this effect is not due to local heat generation. there were no gross histological changes apparent between pdt-treated and untreated inoculated wounds. candida species have become the third most common nosocomial bloodstream isolates worldwide. an early adequate treatment is undoubtedly a major prognostic factor. on the basis of efficacy and cost considerations, the empirical treatment often consists in fluconazole administration. yet, given the ever increasing incidence of potentially azoleresistant species such as candida glabrata (which currently accounts for one fourth of cases), this therapeutic option may be ineffective and result in subsequent poor prognosis. moreover, definite identification of candida glabrata may take up to five days, thus delaying modification of initial antifungal therapy and further impairing prognosis. the purpose of this study was to identify early risk factors for candida glabrata candidemia, likely to guide and improve the efficacy of the empirical treatment. all non neutropenic patients with blood culture-confirmed candidemia were included in this prospective study, performed in five french icus. for each patient, baseline characteristics and potential risk factors for candida glabrata candidemia available at candidemia diagnosis were collected. comparisons between patients with and those without candida glabrata candidemia were based on student's t-tests or chi-square tests, as appropriate.variables with a p value < . were entered into a multiple logistic regression model to determine independent risk factors for candida glabrata candidemia. of the patients included over a -year period, had a candida glabrata candidemia. independent risk factors for candida glabrata candidemia were: age > yrs (odds ratio -or- . , p < . ), recent abdominal surgery (or . , p < . ), recent use of cephalosporins (or . , p < . ), solid tumor (or . , p = . ), and diabetes mellitus (or . , p = . ). the model showed satisfying goodness of fit (hosmer-lemeshow statistic = . ) and discrimination (auc = . ). we found early available and easy-to-identify risk factors for candida glabrata candidemia. when these factors are present, alternatives to fluconazole for the empirical treatment should be considered. ventilator-associated pneumonia (vap) is an airways infection that must have developed more than hours after the patient was intubated. vap is the leading cause of death amongst hospital-acquired infections, exceeding the rate of death due to central line infections, severe sepsis, and respiratory tract infections in the non-intubated patient. hospital mortality of ventilated patients who develop vap is percent compared to percent for ventilated patients who do not develop vap.[ ] reducing mortality due to ventilator-associated pneumonia requires an organized process that guarantees early recognition of pneumonia and consistent application of the best evidence-based practices. the ventilator bundle is a series of interventions related to ventilator care that, when implemented together, will achieve significantly better outcomes than when implemented individually. to evaluate the implementation effect of a vap bundle in a general intensive care unit (icu), with the utilization of a software house made designed for this goal.(http://www.bundles.com.br) in a bed general icu, implementation of the bundle was done over months beginning on january . the key components of vap bundle are: elevation of the head of the bed; daily "sedation vacations"; ventilation tube with subglotic aspiration system; peptic ulcer disease prophylaxis; deep venous thrombosis prophylaxis; oral feeding tube instead of nasal feeding tube and oral hygiene with chlorexidine twice a day. we compared the incidence density rate from april to december to the same period in (software stata . ). the vap incidence rate reduced from , / to , / mechanical ventilation days (p< , ) -incidence rate ratio , (ci: % , - , ). after months, the rate of vap was zero. this period was the lowest incidence of vap ever registered in the icu. the incidence of multi-resistant gram-negative bacteria infections was also the lower than before bundle implementation. after five months of a vap bundle implementation with the aid of software house-made to help clinicians follow the results in daily basis, has demonstrated an important reduction in the incidence of vap in our icu. the impact of this system implementation for longer period should be followed. amphotericin b desoxycholate (ampho b) has been nebulized in transplant patients to prevent aspergillus infections, but also as part of selective digestive decontamination (sdd) to decrease fungal colonization and infection in critically ill patients. severe adverse effects of ampho b after systemic administration, particularly nephrotoxicity, led to its substitution by less toxic antimycotics. however, it is still unknown whether even small amounts of ampho b found systemically after inhalation therapy ( ) may be associated with organ dysfunction and increased mortality in critically ill patients subjected to sdd prophylaxis. topical (polymyxin, tobramycin, ampho b) and systemic (cefotaxime for days) antimicrobial chemotherapeutics were routinely administered to ventilated surgical patients who were expected to remain in the icu for more than hrs. a prospective observational study was conducted to accompany the change in sdd regimen ( months of data collection with nebulization of ampho b ( mg every hrs) and months without). conclusion. the use of nebulised amphotericin b as part of a sdd prophylaxis was associated with an increased incidence of renal failure and increased mortality in this study. in the view of the nephrotoxic properties of ampho b, this finding may be potentially explained by systemic effects after prolonged drug inhalation in predisposed critically ill patients. however, in the ampho b group, there were a slightly higher percentage of patients suffering from pre-existing diabetes and renal insufficiency, and potentially nephrotoxic antibiotic regimens were administered more frequently in the study period. drainage for septic focus is the most important process in the management for severe sepsis and septic shock. however, there is no reliable evidence concerning the drainage technique, because the condition is usually so complexed and various that there can not be managed with the uniform standard technique. we have preferred double luminal drain with continuous high pressure aspiration method (dld-chpa) in patients with these conditions. the aim of this study is to clarify the effectiveness and safetiness of dld-chpa by clinical experience.methods. dld-chpa was performed for septic foci. the effectiveness of drainage was examined before and after dld-chpa. the structure of dld is same as that of aspiration device used during surgery which consists of outer tube with multiple pore and inner tube directly connected with high pressure aspirating central vacuum system. the aim of dld-chpa is rapid and continuous removing of discharge and pus, to maintaining dry condition of the abscess and fistula, and stimulating granulation; which leads (a) to quickening the closure of the abscess and fistula and (b) prevention of worsening of local condition of localized abscess and leaking point of injured intestine until definitive surgery. mean grade of discharge soaking in gauze, a wash recovered in intermittent lavage, local inflammation of skin surrounding drain (dld) improved after dld-chpa. mean volume of discharge from wound and drain other than dld was depressed after dld-chpa. the sum of volume of discharge and aspirated material after dld-chpa is smaller than before dld-chpa. the frequency of dressing change was decreased. in all cases, we could perform definitive surgery without worsening of local inflammation, especially inflammation of skin around drain. there was no complication with dld-chpa.conclusion. dld-chpa is useful and safe procedure for managing septic foci by draining mucinous purulent fluid effectively, which can prevent worsening of local condition of localized abscess, and keeping the local condition good until definitive surgery, if definitive surgery is necessary. to evaluate pre-dialysis full-dose aminoglycoside administration in septic anuric critically ill patients. in a prospective observational study, all septic patients with anuria received fulldose gentamycin (g), tobramycin (t) or amikacin (a) consisting in a mg/kg (g/t) or mg/kg (a) dose, infused hours before daily dialysis. the pharmacokinetic study of serum dosages was compared to that of septic patients with normal renal function. dosages were compared to that of patients with normal renal function who received infusions and served as controls. anuric patients' demographic data were as follow: mean age [iqr - ], mean saps ii [iqr - ], former renal failure %, respiratory tract infection %, nosocomial infection %, icu mortality %. pre-determinated aminoglycoside peak concentration targets for g/t ( - mg/l) and a ( - mg/l) were achieved in respectively % and . % of anuric patients versus and % of controls. compared to target (theoretically non-toxic) trough mg/l for a), trough concentrations in≤ mg/l for g/t and ≤concentrations ( anuric patients were higher (g/t : median . mg/l; a: median . mg/l) than in normorenal patients (g/t : median . mg/l; a: median . mg/l). with aminoglycoside clearance due to intensive dialysis (median kt/v . / session), delay in aminoglycoside infusion was reduced to hours with an observed half-life of . hours.conclusion. this pilot study supports the feasibility of a new aminoglycoside dosing schedule consistent with full-dose administration three hours before dialysis in anuric septic critically ill patients. the prerequisite is that hemodialysis should be performed daily, using high efficacy membranes. further randomised controlled trials are needed to confirm these results. conclusion. mortality in gram negative nosocomial infection remains high but the impact is greatest for nf-gnb due to their intrinsic resistance to many antibioitics, making selection and optimal therapy difficult. in our population, bsi due to nf-gnb was not associated with significantly increased mortality. this could be explained by older age in f-gnb cf nf-gnb. our study highlights the importance of risk stratification to identify patients at risk. empirical combination antimicrobial therapy (ecat) has been recommended for bacteraemia due to gram positive microorganisms during many years, especially for streptococcus pneumoniae, although its use still remains controversial. the aims of this study were to determine the prevalence of ecat in icu patients with gram positive bacteremia (gpb), to describe the main clinical, epidemiological and microbiological features of such patients comparing with monotherapy treatment and to know the impact of this strategy on related mortality to gpb in critically ill patients. during a ten years and a half period, from to , icu-patients with gpb were prospectively evaluated. empirically antibiotic combination or monotherapy regimen was administrated until the agent of infection was identified following the patient's physician criteria. the administration of two or more antibiotic with activity against gram positive microorganism was defined as ecat. clinical and microbiological variables were recorded. logistic regression analysis was performed to deterrmine the impact of this strategy on related mortality to gpb. there is evidence that current practice could be improved. to achieve this, teaching and assessment techniques that are acceptable to both consultants and trainees must be developed. in other specialities video is used to teach communication skills, although its application to intensive care training has not been widely studied. after obtaining ethics approval, specialists in intensive care at general hospitals in the north-east of england were invited to take part in the study. participants were given a written scenario describing the admission to the icu of an elderly woman with pneumonia. data was included which suggested deterioration despite treatment and progression toward multi-organ failure. the consultants were then videoed conducting an initial meeting with the patient's closest relative (played by an actress). questionnaires were used to record previous experience of communication skills training and reaction to the video exercise. . consultants gave written, informed consent to take part. only half of the participants had previous, limited experience of audio or video recording to teach communication skills. none felt 'significantly experienced' in this area or had used the technique with trainees. most had developed their communication skills by sitting-in as an observer when colleagues were talking to relatives. participants stated they had never had any formal teaching in communication skills either through lectures, workshops or role-play. the plausibility of the scenario and actress were rated highly by all the participants. despite individuals choosing to agree with the statement 'i was anxious and uncomfortable throughout the video exercise', none of the respondents disagreed with the statement 'i managed to settle into the normal style i use when speaking to relatives'. only participants did not support the statement 'overall i feel happy with the way the consultation went'. of the participants disagreed or strongly disagreed with the statement 'i feel the video does not represent my normal practice of speaking to relatives.'conclusion. this study shows that video techniques can be used to reproduce realistic intensive care scenarios. the format was well received by a majority of specialists and despite no previous experience of being filmed, participants felt that the simulation closely replicated their normal practice. teaching-training would be required to introduce these techniques as current specialists have received little formal training in communication skills. during a two-month period, consecutive adult icu patients (sapsii score: ± ; ventilated patients) requiring a transthoracic echocardiography were prospectively studied. after a curriculum including a -hour training course and hours of hands-on, one of noncardiologist residents and an intensivist experienced in ultrasound subsequently performed hand-held echocardiography (hhe), independently and in random order. assessable "rule in, rule out" clinical questions were purposely limited to easily identifiable conditions by the sole use of two-dimensional imaging. cricoid pressure should be applied lightly ( n) before induction of anaesthesia and while the patient is still awake. once the patient is unconscious the force should be increased to n (vanner & asai, ) . a simple training aid using an air filled, capped ml syringe has been described (ruth et al., ) , but a lack of knowledge and poor technique amongst anaesthetic assistants has already been highlighted (meek et al., ) . the aim of this study was to investigate knowledge and skills of a group of intensive care unit nurses in performing cricoid pressure, using a structured interview questionnaire and simple practical test. we asked intensive care nurses from queen elizabeth hospital, birmingham uk to participate in a structured interview. volunteers were asked about their own experience, training and knowledge of cricoid pressure in a questionnaire conducted by one of the authors. each subject was then asked to apply the force that they would normally use in clinical practice to the plunger of a plastipak (b-d) ml syringe filled with air. the destination of the plunger was recorded (ml). the subjects were then informed of the recommendations stated above and allowed to practice the application of n on the syringe ( . ml standard destination). they were than asked if they thought a simulator would be useful for training. . % respondents (n= ) were staff nurse with to years experience, and % performed cricoid pressure less than monthly. only % nurses had formal training and % described their training as 'totally inadequate'. . - % nurses applied and released cricoid pressure only on instruction by anaesthetist and . % respondents did not know the optimum force to use. on simulation, the mean force applied was nearer n than n (mean plunger destination . ml, less than . ml standard. s.d = +/- . , variance = . ). of ( . %) respondents thought simulation training would be useful. intensive care nurses perform this procedure infrequently and become deskilled. this study also highlights the inadequacy of training they receive. using a readily available training aid such as a ml syringe is reliable and may improve staff confidence, performance and patient safety. j. m. boles* , g. prat , a. berthouloux , b. seys , a. renault réanimation médicale, hôpital de la cavale blanche -chu, psychothérapie, société civile alternatives, brest, france the policy of our -bed medical icu includes helping members of the staff to cope with the burden of job stress. our university hospital agreed to finance a focus group to help staff relieve their stress. we performed an evaluation months after. a first non-anonymous survey was conducted in / amongst the staff to know who was willing to attend a focus group. an independant family therapy psychologist was selected out of candidates. a focus group was set up in / open to any volunteer; -hour monthly reunions were conducted by the psychologist. an anonymous questionnaire was sent to all staff members in / . initial survey: mds/ , daytime nurses/ ( night nurses/ ), / auxiliary nurses,the secretary and the chief nurses agreed to attend = , % of the daytime staff. the group held reunions, attended respectively by , , and members of the staff. the group was then suspended. anonymous evaluation: / staff members answered = , %. conclusion. ) in a two hour icu oriëntation in the undergraduate curriculum the icu nursing staff was as successful as the medical staff in improving understanding of the icu organization as well as in improving the ability to recognize vital organ functions and principles of the monitoring of critically ill patiënts. this study suggests that icu nursing staff can enhance learning the basic practical monitoring of undergraduates and can be successfully integrated into undergraduate medical education. in meeting the needs of increasing numbers of medical students there is a potential for this role to be to developed. ) interest to qualify as an intensivist increased significantly when the intensivist was the teacher. guidelines for cpr teach us to do chest compression per minute and to ventilate for a minimum time. however, paramedics tended to do chest compression more quickly and to do ventilation more slowly. in japan, prehospital cpr has been performed by emergency life support techniciens (elst), who belongs to the fire department. in this study, we tried to clarify the actual condition concerning prehospital cpr. japanese elsts are licensed after hours of lecture and , hours of experience, and they are trained repeatedly. in yokohama, one supporting medical doctors is working in the central operation center of the fire department. they can detect the frequency of chest compression and ventilation during cpr in the ambulance. we recorded these frequency for and evaluate the quality of cpr by elst.results. in our system, elst performed chest compression times per . sec, that meant times per minute. they perfom ventilations for . sec. we should train elsts more frequently and repeatedly and should use metronome, voice guide or aed with voice guide during cpr in the ambulance. tracheostomy is often required in icu patients to prevent the consequences of long term translaryngeal intubation, indicated in prolonged mechanical ventilation and long term airway maintenance. it has lots of benefits like increasing patient comfort, less need for sedation, improving oral and bronchial hygiene, allowing oral nutrition, and ease the process of weaning from mechanical ventilation. percutaneous tracheostomy (pct) as opposed to surgical tracheostomy (st) has many advantages: it can be made at bedside (and be performed immediately once the decision is made), being safe and easy, with less operative time, and less intra and early postoperative complications (reduced stomal bleeding and infection, due to the tamponade effect of the tightly fitting tracheostomy tube). it is also associated with lower costs and has better cosmetic results than st. the aim of this study is to compare the timing and outcomes of tracheostomies in our icu, and hospital mortality of these patients. we conducted a retrospective comparative study in distinct periods: and , when all patients in our icu were submitted to st (n= ); and and when patients were preferentially submitted to pct (n= ). we reviewed their indications for tracheostomy, age, gender, apache ii and saps ii score, days to tracheostomy, length of icu stay, ventilation time before and after tracheostomy, icu and hospital mortality. the results presented are in mean values. conclusion. )there was no significant difference in indications for tracheostomy (prolonged mechanical ventilation and airway protection in comatose patients), age( ), gender, mean ventilation days prior to( , ) and after ( , ) tracheostomy. )pct was performed sooner ( , vs , day), and these patients had a sooner icu discharge ( , vs days). )patients submitted to st had higher apache ii( , vs , ) and sapsii( , vs , )scores; higher icu( % vs , %) and hospital mortality ( % vs , %). reported here. the study was carried out in finland. the expert panel was formed of intensive and critical care nurses and physicians of five university hospitals and four central hospitals. altogether (=n) experts participated in first round. the experts completed a questionnaire which consisted of demographics and one essee question. text were analysed according to research questions by content analysis. competence requirements in intensive and critical care nursing can be described as five main domains: specific ) knowledge base, ) skill base, ) attitude and value base and ) experience base of intensive and critical care nursing. additionally competence can be described as several ) personal attributes of competent intensive care nurse. competence requirements can be divided into clinical and professional competence requirements. the sub domains of clinical competence requirements are implementation of principles of nursing care, implementation of clinical guidelines and implementation of nursing interventions. the sub domains of professional competence requirements are then ethical activity, decision making, development work and collaboration.conclusion. competent nurse in intensive and critical care nursing has to have specific knowledge base, skill base, attitude and value base and experience base that differs from overall competence in nursing. additionally competent intensive and critical care nurse has to have spesific personal attributes.grant acknowledgement. we would like to thank the experts of university and central hospitals who participated in this study. to define examine catheter related bloodstream infections (crbsi) over a -year period ( - ) , and compare three expressions of incidence.methods. -bed tertiary referral centre. hospital-wide, total parenteral nutrition(tpn) service based at department of intensive care. quarterly meetings of tpn committee analyse prospectively collected data to examine crbsi incidence. effect of introduction of education protocols and appointment of dedicated tpn nurse were assessed. . patients, cvcs were included. a consistent decline in incidence was observed, % of patients in to % in (figure) . incidence may also be expressed as percentage of cvcs infected, decreasing from % of cvcs to % . finally, incidence is expressed per cvc days which peaked at / cvc days dropping to / cvc days .conclusion. crbsi occurs commonly in tpn populations, but published data remains limited. irrespective of means of expression, our data demonstrates a falling incidence in crbsi, which we attribute to the appointment of a tpn nurse, ongoing education protocols regarding cvc insertion and maintenance. this data supports the pronovost paper that an intervention may result in a sustained decline in the incidence of crbsi. dimension and course of cognitive ability change after elective coronary bypass (cabg) or valvular replacement (vr) interventions are discussed controversely. the aim of our study was ( ) to measure the difference of cognitive abilities concerning attention, memory and fluid intelligence before and after cardiosurgery, ( ) to investigate the outcome difference between cabg-and vr-patients and ( ) to investigate the relevance of duration of bypass-and aortic-clamping as well as duration of anesthesia as predictors of cognitive outcome. subjects: consecutive patients; cabg, vr; timepoints of measurement: t : - days before intervention, t : days and t : - days after intervention: cognitive assessment instruments: d -test (selective attention), rbmt (memory), cft- (fluid intelligence). a significant decline of all measured cognitive functions at t compared to t could be demonstrated for the cabg-(d : p< . ; cft : p< . ; rbmt: p< . ) as well as for the vr-sample (d : p< . ; cft and rbmt: p< . ). both groups showed a remission at t concerning memory and intelligence scores, only vr-patients had persistent deficits in selective attention (p< . ). there were no significant differences between cabgand vr-samples at any time of measurement. no parameter of surgery reached significance as predictor for cognitive outcome in regression analysis. in the early postacute phase ( days) after cabg-and vr-surgery we could show deficits in various areas (attention, memory, fluid intelligence) of cognitive performance as well as rapid remission within one week. despite expectations there were no significant differences between cabg-and vr-samples. abdominal complications in postoperative cardiac population are not frequent but may be catastrophic. non-occlusive mesenteric ischemia appears when there is a mismatch between perfusion and metabolic demands. the symptoms and signs are not incontrovertible and the suspicion of this complication may improve prognosis. indocyanine green plasma disappearance rate (icg-pdr) has been proposed as a tool for the assessment of liver perfusion and function ( , ) so that it may help in diagnosis and to optimize treatment. a prospective study was conducted in cardiac surgery patients. icg-pdr values were measured hours and hours after icu admission transcutaneously by a commercially available system (limon; pulsion medical systems, munich, germany). icg-pdr values and other postoperative data were compared between patients suffering and not suffering from abdominal complications. mann-whitney and wilcoxon tests were applied for statistics. significance was considered when p < . . . patients were analysed but we did not find major abdominal complications. minor abdominal complications were suspected in because they suffer abdominal pain, ileus and higher serum amylase values. this group of patients were older ( ± vs ± , p= . ) and suffer from more hypertension (p= , ). their preoperative risk (numeric eu-roscore) was higher(es num ± vs ± , p= . ) and so was the apache ii score ( ± vs ± , p= , ). twelve hours after icu admission icg-pdr values were lower ( . ± vs ± ,p= . ) and normalized at hours. length of stay (los) was longer (icu-los was ± vs ± , p= . and hosp-los was ± vs ± , p= . ). they had associated more complications : cardiovascular (p= . ), renal (p= . ), neurolgical disorders (p= . ) and infectious (p= . ). procalcitonine (pct) values were also higher(p= . ). they suffer from higher preoperative pulmonary hypertension (pap de ± vs ± , p= . ). cardiac index values were lower hours after admission (ic- . ± . vs ± . , p= . ). serum amylase values were higher in first postoperative day (amy- was ± vs ± , p= . and amy- was ± vs ± , p= . ). and so were aspartate amino-transpherasa (ast) values hours after admission (p= . ). the incidence of gastrointestinal hemorrhage was also higher (p= . ).conclusion. . patients suffering from minor abdominal complications had worse icg-pdr values hours after admission. . they were were older and their preoperative risk and apache ii score were higher. . they suffer more complications and their los was longer. . serum amylase, ast, pct, pap and cardiac index values were worse in these patients. deployment of an intraaortic balloon pump is a technique that is used and recommended in high-risk surgical patients. this group includes patients with haemodynamically significant stenosis of the left coronary artery trunk and ejection fraction minor %, preoperative unstable angina, and intraoperative and postoperative cardiogenic shock. we examined the pre-and post-operative use of an intraaortic balloon pump in our surgical series and its association with morbidity and survival. we undertook a prospective, observational, cohort study of patients who underwent cardiac surgery with extracorporeal circulation between january -june who were admitted to the polyvalent intensive care unit of our third-level hospital. the data collected were analysed statistically with spss . . the study included patients, with a mean age of . ± . years and % were men. the incidence of iabp were: preoperative . %, intraoperative . %, postoperative . %, technically imposible . % and no need of iabp . %. % had some degree of surgical morbidity (including atrial fibrillation). the overall mortality was % and the mean stay was . ± . days (range, - days). the indication were: ejection fraction %, unstable angina %, vessel disease %. after an univariate analysis iabp and postoperative complications there was relation with low output or shock (the indication of iabp, p< . ). the others postoperative complications (mechanical ventilation > h, kidney failure, important haemorrhage and perioperative infarction) were no relationed and has the same incidence as the moderate-low risk interventions.conclusion. the intraaortic balloon pump is a commonly used technique in high-risk patients, reducing the incidence of postoperative complications to the limits of those in moderateor low-risk patients. mecc is a new approach to cardio-pulmonary bypass (cpb). the system differs from conventional bypass (cpb) as follows: minimal priming volume (< ml); no venous reservoir (closed system); active venous drainage; no cardiotomy suction; heparin coating (tip-tip). practical advantages of mecc include: minimal haemodilution; no blood-air interface; reduced foreign-body contact; less haemolysis; reduced heparin given. potential improvements in clinical outcome in icu as a result include: reduced requirement for inotropes; fewer blood transfusions; less systemic inflammation; reduced coagulopathy; improved endorgan function. these factors combine [ ] to significantly reduce prbc transfusion (u/patient) requirements with mecc ( . ± . ) compared with cpb ( . ± . ), or opcab surgery ( . ± . ). mecc has recently been introduced in the swcc for routine cabg surgery. intraoperative data were collected for quality control purposes (n= ), compared with historical controls (same surgeon and anaesthetist) but with cpb (n= ). conclusion. an improved haematological profile (seen here with hb, but theoretically reflected in other blood components) with mecc may reduce postoperative coagulopathy, costs and risks associated with blood and other blood product transfusion, and improved oxygen delivery and therefore end-organ function. g. satkurunath*, p. wilton intensive care and anaesthesia, harefield hospital, harefield, united kingdom cardiothoracic units have high usage of intensive care unit (icu) beds and patient flow-through affects their continued productivity and cost-effectiveness. prolonged icu stay patients are a small percentage but consume a disproportionate amount of resources and have a higher mortality. our aim was to determine the type and the outcome of icu patients requiring prolonged stays at our institution to determine if resources were used appropriately on patients with a reasonable chance of survival. our institution is a cardiothoracic hospital specializing in adult cardiothoracic surgery and transplantation. a retrospective analysis of the institution icu database was performed and all admissions with a duration ≥ days from april to march were identified. the medical records of these patients were reviewed to determine individual risk factors for prolonged icu stay. this data was compared to the overall icu outcome audit data for that year. there were a total of icu admissions of which ( . %, patients) were ≥ days. the median icu length of stay in the study group was . days (range - ). the patients had a cumulative total of bed days which was . % of the total icu bed days ( ). icu mortality was . times greater than the overall unit mortality ( . % versus . %). mean and median age was similar to that of the overall unit. the percentage of readmissions in the study group was . times greater than the overall percentage ( . % versus . %). in the prolonged stay group patients ( . %) survived the hospital admission: were discharged home and were transferred to another hospital for further rehabilitation. cardiac surgery necessitating cardiopulmonary bypass involves periods of ischaemia followed by reperfusion. reperfusion of previously ischaemic tissue may itself result in tissue damage through the activation of neutrophils, production of oxygen free radicals and endothelial damage. this phenomenon has been termed ischaemia reperfusion injury (iri). the consequences of iri may be observed locally in the form of reversible cellular dysfunction or more remotely with effects observed in the lung, liver and cardiovascular system. ultimately, a systemic inflammatory response syndrome (sirs) may develop with the potential to progress to multiple organ failure in the most extreme cases. remote ischaemic preconditioning (ripc) is a technique which provides protection against experimental iri in humans. we performed a randomised controlled trial to investigate the effect of ripc on patients with triple vessel coronary artery disease undergoing cabg surgery (n = ). ripc was induced by cycles of minutes of inflation ( mmhg) and deflation of a blood pressure cuff around the upper arm hours prior to surgery. patients were assessed post operatively for the development of sirs. blood samples were collected up to hours post operatively. myeloperoxidase (mpo), interleukin- (il- ), c-reactive protein (crp), and von willebrand factor (vwf) were measured as biochemical markers of neutrophil activation and endothelial damage.results. sirs developed in % of patients who had undergone ripc compared to % in the control group (p = . ). mpo, il- , (table ) crp, and vwf (table ) were elevated post operatively but no protection was observed in patients pre-treated with ripc. of note, the study was not powered to measure these variables as the primary outcome and thus it is possible that a protective effect may be observed in a larger study population. gender differences in the coronary bypass surgery have been the focus of numerous publications in recent years. compared to men, women undergoing coronary artery bypass grafting appear to have a higher morbidity and mortality, particular in the perioperative period. the aim of this study was to analyze which clinical parameter and laboratories data effect on gender differences in postoperative course. . to the end of december .,all patients on whom were performed elective coronary bypass surgery were included in this retrospective study. age,ef,euroscore,numbers of days in jil,total numbers of day in hospital stay, troponin t (t - hours after addmision,t - hours after addmision in jil),lactate (l ,l ),cardiac output,cardiac index were observed. for all variables was made descriptive statistics. we used student-t test and mann-whitney u test. . patients ( m and f)were observed. analyzing age, ef,euroscore,cardiac output and cardiac index we did not find statistical important differences man versus female. analyzing troponin t, level of lactate (particulary l )we found statisticaly important higher levels in women group. women needed longer support with inotropes and are more likely to spend longer time in the hospital. fortunately, the last decade has produced a surge of public interest and scientific research in womens health, including gender issues related to cabg. it is now well accepted that there are major differences in the risk profile of man compared to the profile of woman undergoing cabg procedures. even when both genders share a common risk factors, the relative impact of risk factor is often quite different in man as compared to woman. w. baulig* , v. hinselmann , m. lachat , k. rentsch , e. schmid devision of cardiac anaesthesia, department of cardiac surgery, institute of clinical chemics, university hospital zurich, zurich, switzerland reports regarding the benefit of continuous local analgesia after various surgical procedures are conflicting ( ). the aim of this prospective, randomized, double-blind study was to investigate the efficacy of continuous local anaesthesia using the pain relief system (i-flow corp, usa) in patients after abdominal aortic surgery. after closing the peritoneum, two multi-hole catheters (length cm) were placed in the opposite direction of the skin incision. following skin closure, both catheters were connected to the elastomeric pump filled with ml of an unknown solution (either sodium chloride [nacl] . % or ropivacaine . %) and a continuous infusion of ml.h- was started through each catheter. every hours until h after surgery combined visual analog pain scale (vas) and numeric rating scale (nrs), partial oxygen (pao ) and partial carbon dioxide pressure (paco ), arterial oxygen saturation (sao ), pulse rate, and mean arterial pressure were recorded. the serum concentration of ropivacaine, free ropivacaine and alpha- -acid glucoprotein were measured daily. the total amount of intravenous morphine sulphate and nonsteroidal analgetics, ventilation time, length of stay in the icu, and the condition of the removed catheters were documented. sixteen patients were enrolled, but one patient had to be excluded because of accidental catheter removal at icu arrival. demographic and surgical data were not different between groups. ropivacaine was applied in , nacl . % in patients. vas/nrs was lower in the ropivacaine group during the first postoperative hours ( . ± . ) than in the control group ( . ± . ), but this difference did not reach statistical significance. no significant intergroup differences were found with regard to morphine sulphate, metamizole and paracetamole consumption, pao , paco , sao , ventilation time and length of stay in the icu. serum concentrations of free ropivacaine ( . ± . µmol/l) were well below toxic levels ( . ± . µmol/l). in two thirds of the removed catheters > % of the holes were closed. . ± . . ± . metamizole (g) . ± . . ± . continuous infusion of ropivacaine . % ml.h- using two multi-hole catheters at the surgical site in patients after abdominal aortic surgery did not reduce the consumption of intravenous morphine and nonsteroidal analgetic drugs. introduction. prognostic scores have been developed for assessing patients's risk of complications or death and are useful to identify high risk patients allowing specific interventions. surgical scores have been developed but it is still not clear if they offer any benefit compared to general icu scores. the aim of this study was to compare the accuracy of the scores apache ii, apache iii and p-possum in a brazilian surgical intensive care unit. consecutive surgical patients admitted in the surgical unit were included prospectively from august to march . cardiac and neurosurgery, age < and length of stay in the icu < h were excluded. after exclusion, the scores were applied in patients. we compared actual in-hospital mortality with those predicted by the apache ii, apache iii and p-possum scoring systems applying receiver operating characteristic (roc) curve analysis by integrated methods using r-system . . . the physiological parameters of p-possum score were obtained in the postoperative period. the operative parameters in orthopedic surgery were adapted. the most common surgeries were: abdominal surgery ( . %), orthopedic ( . %), urologic ( . %), vascular ( . %), bariatric ( %) and thoracic ( . %). procedures done before h of hospital admission were and before h of admission were . the average number of days in icu was . (+- . ) and the mean number of postoperative days before discharge was . (+- . ). the rate of icu readmission in days was . %. the median age was years. overall hospital mortality was . %. the mean absolute values of apache ii, apache iii and p-possum were . (+- . ), . (+- . ), . (+- . ) and mean predicted in-hospital mortality were . %, . % and . %. respectively. the area under the curve from receiver operator characteristic curve analysis for apache ii was . , for apache iii was . and for p-possum was . . these data suggest that p-possum may provide a better estimate of the risk of mortality than apache ii and is at least as accurate as apache iii. p-possum requires fewer individual patient parameters to be calculated and is thus easier than apache iii to be generated. preeclampsia is a multisistemic disease that may occur in pregnancy or in the immediate post-partum period. the incidence of pregnancy induced hypertensive disease is observed in . % in spain. we analise the mortality and the clinical profile of this entity in our icu. the study comprise prospectively women admitted in icu with the diagnose of severe gestosis, from january to october . we define preeclampsia, eclampsia and hellp syndrome as used by the american college of obstetric and gynecology. we consider hellp as a different disease as its mortality rises up to a %. cualitative variables are shown as percentage and cuantitative variables as mean ± standard deviation or median and range in asymmetric variables. we used chi square test, t-test and multivariant testing for statistical analysis of the data. we report data from women admitted in icu in the period january . we didn't find significant difference on systolic pressure between preeclampsia, eclampsia or hellp nor in uric acid levels. there were significant differences in aminotransferase enzymes and platelet count between preeclampsia-eclampsia and hellp. gestational age was significantly lower in preeclampsia than in eclampsia or hellp (p< , ) and, additionally, the weight of newborn were significantly lower in preeclampsia versus eclampsia and hellp. fetal death is associated with a birth weight below gr (p< . ), or . , ci % ( . - . )). maternal death is associated with renal failure, heart failure or coagulopathy (p< . ) or . (ci % . - . ). multivariant analysis show that primiparity appears as a protection versus mortality, p< . or . (ci % . - . ) and pulmonary oedema as a risk factor p< . or . (ci % . - . ). fetal mortality is associated in multivariant analysis with gestational age and consequently with low weight (p< . ) and (p< . ) respectively, or . , ci % . - . and or . ci % ci . - . respectively. women admitted to the icu are mostly years old, in the week gestational age of their first pregnancy. in our environment, delivery mostly occurs in the following to days of admission. maternal mortality is low but not so fetal mortality that rises up to , %. maternal mortality is associated with multiparity and complications such as pulmonary oedema, and fetal mortality mostly with gestational age and low birth weight. in order to reduce postoperative morbidity and mortality following liver resection due to hepatic failure it is important to carefully monitor liver function. as lactate is mainly cleared by the liver, it has the potential to be a good indicator of liver performance. many factors may determine liver function, such as the extent of the liver resection, pre-existent liver conditions, the amount of blood loss, and other patient and operation characteristics. we assessed the value of fast and inexpensive point-of-care lactate measurements as an indicator for liver function next to prothrombin time which is the current standard. in a retrospective observational study we included all patients admitted to the surgical icu after liver resection between april and march . lactate levels were frequently measured in arterial blood with a point-of-care device (abl radiometer). maximal lactate during the first hours after icu admission were determined. extent of liver resection, preoperative liver condition and red blood cell transfusions were recorded. . patients were studied ( males, females) with a median age of years (range - ). abnormal liver parenchyma was present in ( %) patients. in patients, more than % of the liver was resected (major resection). red blood cells were administered in patients with a mean of . (± . ) packed cells. lactate measurements were performed during the first postoperative day. multivariate analysis with the parameters volume percentage resected, peri-operative blood loss, age, gender, preexistent liver condition, showed that the extent of liver resection was significantly associated with lactate levels (p= . ). mean lactate levels were respectively . for major resections and . for minor resections. blood lactate levels were significantly correlated to pt (pearson's r= . ; p< . ).conclusion. the extent of liver resection was an independent predictor of lactate levels. age, gender, amount of blood loss and preexistent liver disease were not associated with lactate levels. lactate levels were clearly correlated with prothrombin time. phaeochromocytoma is a rare chromaffin cell tumour predominantly arising in the adrenal medulla. following pharmacological control, elective surgical excision is performed ( ). postoperative admission to itu is standard as cardio-respiratory, renal and metabolic complications (hypertension, hypotension, pulmonary oedema and hypoglycaemia) may occur ( ) . the aim of this study was to identify postoperative complications following adrenalectomy, requiring critical care support. the data collected would allow us to evaluate the statement that, 'not every patient following adrenalectomy for phaeochromocytoma requires itu admission'. over years, adrenalectomy patients with a clinical, laboratory and histological diagnosis of phaeochromocytoma, were studied retrospectively. twenty three patients were identified from clinical databases and data collection followed a review of the perioperative records.results. % of the adrenalectomies were open, the remainder were laparoscopic ( were converted to open). multiple anaesthetic techniques were used by four anaesthetists. % arrived on itu intubated, but extubation followed within to hours. with a map between and mmhg, % received postoperative inotropic support (noradrenaline . to . mg/h) for to hours. one patient ( %) required inotropic support for hours and remained intubated for hours. six developed postoperative respiratory infections ( % were open adrenalectomies); one of which required reintubation, ventilation and inotropic support. all of those that developed respiratory infections had morphine infusions or pca for analgesia. although the difference between the preinduction and peak intraoperative blood pressures (systolic and mean) were smaller in those receiving remifentanil, it was not statistically significant.conclusion. ) following adrenalectomy for phaeochromocytoma, few patients experienced significant perioperative morbidity and the traditional practice of electively admitting all patients to the itu, should be reviewed. ) an experienced team approach ( ) is more likely to limit perioperative complications than using surgical duration, tumour size and urinary catecholamine concentration to predict postoperative complications ( ). ) standardising the anaesthetic technique could increase the 'in theatre' extubation rate. ) the routine use of epidural analgesia may reduce the incidence of postoperative respiratory infections and may influence the incidence of reintubation. ) the role of remifentanil requires further investigation but prior to venous ligation of the tumour, it appears to improve intraoperative haemodynamic stability. thoracoabdominal aortic aneurysm (t(a)aa) repair is associated with major blood loss exceeding the intravascular volume and complex perioperative coagulopathies requiring transfusion of blood products. there have been three reports evaluating bloodproducts needs in t(a)aa repair. the combination of surgery induced tissue damage and massive blood products transfusion may enhance post operative organ dysfunction and infections. mortality in cabg surgery is associated with number of bloodproduct transfusions. in t(a)aa surgery this relation has not been studied. this question might be of clinical importance as elective t(a)aa repair is associated with considerable mortality ( - %) and morbidity (e.g. respiratory failure - %). in this retrospective single centre study we identified all consecutive patients with taa(a) surgery during the period - . patients records in an icu database and transfusion database were combined and evaluated. baseline characteristics, apache ii score, respiratory failure (ventilator support > hours), transfusion and mortality data were collected. association between variables was determined with multivariate regression analysis. in all patients cellsaver was used. results. patients underwent t(a)aa surgery in the study period. patients ( ( . %) male and ( . %) female) were identified in both databases. the mean age was . ± . years. in hospital mortality was . %. mean apache ii score in the first hours was ± . rbc transfusion results in an significantly increased mortality risk (or . ( %ci . - . )). rbc transfusion was significantly associated with respiratory failure (or . ( %ci . - . )). increased post operative apache ii score results in significantly more rbc infusion (p< . ). these findings could not be demonstrated for ffp and platelets infusion. we did not find a significant difference in blood transfusions and extent of aneurysm, as found by others. our quantity of blood transfusion is much less than reported previously (with and without cellsaver use). conclusion. large volume of blood transfusion may be necessary during and after t(a)aa surgery. rbc transfusion is associated with increased mortality rates. as apache ii score is related to rbc transfusions, peri operative optimalisation might contribute to less blood transfusions. blood transfusion in our population is less than reported previously. cardiac surgery is occasionally complicated by refractory postcardiotomy bleeding, leading to increased mortality and morbidity. recombinant activated factor vii is being increasingly used as rescue therapy in such cases. we report our experience with the use of rfviia in our -bed csicu. all patients who received rfviia as rescue therapy for intractable bleeding during or after cardiac surgery over a -year period was analyzed. we assessed and compared the use of blood products (rbc, ffp, plt), coagulation indicators (international normalized patio [inr] , activated partial thromboplastin [aptt], and fibrinogen), and platelet levels before and after rfviia administration. results. patients (mean age, , +/- , years) received a single dose of rfviia ( , +/- , microg/kg). surgical procedures were aortic surgery (n= ), double valve operation (n= ) and left ventricular assist device (n= ). the men time between icu admission and rfviia administration was hours while patient received it intraoperatively. the mean blood product usage prior and after the administration of rfviia was the following: packed rbc, , versus , u; ffp, , versus u; platelets versus , u; bleeding stopped in all cases and no patient needed reoperation. the mean coagulation results were ptt, , +/- . versus , +/- , seconds; p= , ; inr, , +/- , versus , +/- , ; p< , . in all cases, blood loss decreased considerably after rfviia administration almost eliminating the need for additional blood products, and the prolonged prothrombin time normalized. no side effects of rfviia treatment were noted. there were no thrombotic complications, cardiac ischemic events or deaths. our results support the use of rfviia as rescue therapy in severe, uncontrollable, nonsurgical, postoperative hemorrhage after cardiac surgery as efficacious and safe. however the data are still limited, and further studies are necessary to determine the safety and efficacy of this new hemostatic agent. coumarin oral anticoagulants are widely used to prevent thromboembolic complications in patients at risk for such events. rapid reversal of anticoagulant effects may be required in cases of severe bleeding or emergency surgery and the use of prothrombin complex concentrate (pcc) is recommended. as a surrogate marker international normalised ratio (inr) is used to evaluate the effective use of treatment with pcc. however, a clear correlation between correction of inr and improved haemostasis has not yet been established. this study intended to validate the correlation between the correction of inr, shortening of time to haemostasis, and reduction of blood loss in anticoagulated rats. four groups of female wistar rats were used in the study. rats in groups to were anticoagulated with . mg/kg body mass of phenprocoumon on occasions ( and hours), group , the control group, received isotonic saline. approximately hours after the second treatment, ml/kg body mass isotonic saline was administered intravenously (iv) in groups and . groups and received and iu octaplex ® /kg body mass. fifteen minutes after treatment blood samples were taken. the tail tip was cut off and the tail immersed in isotonic saline at + ˚c. bleeding time and haemoglobin concentration in the saline were measured subsequently. mean bleeding time in group was ± s. in groups and , the maximum observation time of minutes was recorded (except of one which died after minutes). in group mean bleeding time was ± s, complete cessation of bleeding was observed in out of animals. one animal died before minutes and in the remaining clotting was noted with markedly reduced bleeding. haemoglobin concentrations in groups and ( , µg/ml and , µg/ml) were significantly higher (p < . ) than in group ( µg/ml). no statistically significant difference was found between group ( µg/ml) and group . pulmonary thromboembolism (pe) is a critical complication after general surgery with an incidence ranging between , % and % and a mortality rate up to %. systemic thombolytic therapy is the core treatment of submassive and massive pe but may be associated with severe bleeding complications after major surgery. we report a case series of four postoperative patients with suspected (n= ) or proven (n= ) massive, life threatening pulmonary thromboembolism. diagnostic and therapeutic measures as well as decision-finding pro and contra thrombolytic therapy are discussed. one female and three male patients (age to years) presented with acute hypoxemia and severe cardiogenic shock (n= ) or cardiac arrest (n= ) on postoperative day to day following major surgery. pe was suspected in all cases and confirmed by a computer tomography pulmonary angiography (ctpa) in two patients. thrombolytic therapy with mg alteplase (actilyse ® ) was indicated in one patient under cardiopulmonary resuscitation and in two patients by severely impaired right ventricular ejection fraction, and was waived in one patient with moderately impaired right ventricular function. immediate thrombolysis lead to successful resuscitation and to a marked improvement in right heart function and gas exchange within min after administration. bleeding complications following alteplase injection occurred in all patients within the following hours requiring transfusion of - units packed red cells as well as minor surgical revision in two patients. three patients survived in good conditions and one patient died from progressive therapy-refractory right heart failure. we carried out a single-centre, prospective, randomized, double-blind trial with the aim of assessing the efficacy of postoperative prophylactic treatment. this prospective study examines the relationship of haemoviscoelastography (hvg) mednord (ukraine co analyser), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation, system and serum anti-xa concentration in patients treated with enoxaparin. patients scheduled for open prostatectomy using epidural anesthesia were enrolled. epidural catheters were removed the morning after surgery before the commencement of subcutaneous enoxaparin mg once daily. venous blood samples were obtained at: ) the induction of anesthesia (baseline), ) immediately before the third dose of enoxaparin operatively; ) h after the third dose postoperatively, and ) immediately before the fifth dose postoperatively. whole blood samples were obtained for haemoviscoelasthgraphy (hvg), activated clotting time, and anti-xa level analyses at each of the four time intervals. at the four sample intervals, the r time (mean ± sem) ( , ± , ; , ± , ; , ± , min) and the κ time ( , ± , ; , ± , ; ± , ± , min) of the hvg were significantly correlated with the expected peak and trough levels of lmwh and serum anti-xa levels (p < . ). after fifth dose immediately, hvg r times exceeded the normal range in of patients ( %). prolongation of r time and κ time on postoperative day may indicate an exaggerated response to lmwh. lowfrequency haemoviscoelastography is a test that could potentially correlate with the degree of anticoagulation produced by low molecular weight heparin enoxaparin. lowfrequency haemoviscoelastography mednord (ukraine co analyser), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation system is a test that could potentially correlate with the degree of anticoagulation produced by lmwh. the r time from the haemoviscogram correlates with serum anti-xa concentration. hvg is a convenient test to measure the degree of anticoagulation from lmwh. despite the evidence of perioperative hypercoagulability in cancer patients, there are no consistent data evaluating the extent, duration, and specific contribution of platelets and procoagulatory proteins by in vitro testing. this study compared efficacy of haemoviscoelastography versus thromboelasthgraphy for monitoring of coagulation imbalance. patients undergoing open surgery for abdominal cancer received mednord (ukraine co analyser) analysis (hvg), a viscoelastic test, measures clot formation and includes information on the cellular, as well as the plasmatic coagulation system. we examined the efficacy of a variety of coagulation tests. a complete coagulation screen, activated clotting time (act), thromboelasthgraphy (teg) and haemoviscoelastography (hvg) were performed before surgery, at the end of surgery, and enoxaparin anticoagulation monitoring on postoperative days , , , and . there were analyzed for the reaction time and the maximal amplitude (ma). we calculated the elastic shear modulus of standard ma (gt) and hvg ma (gh), which reflect total clot strength and procoagulatory protein component, respectively. the difference was an estimate of the platelet component (gp). there was a % perioperative increase of standard ma, corresponding to a % increase of gt (p < . ) and an %- % contribution of the calculated gp to gt. we conclude that serial standard thromboelas-tography and hvg viscoelastic test may reveal the independent contribution of platelets and procoagulatory proteins to clot strength. using multiple linear regression, all coagulation, teg and hvg variabities were used to model postoperative hypercoagulation. results showed that some components of the teg failed to identify hypercoagulation (r < . , p > . ). however, three components of the routine coagulation assay, including bleeding time, prothrombin time, and platelet count could be modeled to show prolonged postoperative hypercoagulability (p < . ). we conclude that all components of the hvg test reflect postoperative coagulopaties, these results suggests that it may be usefull in determining the coagulation status of cancer patients perioperatively. postoperative hypercoagulability, occurring for at least week after major cancer abdominal surgery, may be demonstrated hvg viscoelastotest. hypercoagulability is not reflected completely by standard coagulation monitoring and teg and seems to be predominantly caused by increased platelet reactivity. hvg provides a fast and easy to perform bedside test to quantify in vitro coagulation, may be usefull in determining the coagulation status of cancer patients perioperatively. in the epidural anaesthesia group (n = ), haemoviscoelasthography (hvg) was performed after crystalloid preloading and during the immediate postanaesthesia course. in the general anaesthesia group (n = ) hvg was performed before induction and during the immediate postanaesthesia course. hvg were repeated postoperativly at , and h. [kk] in the preanaesthesia period were similar in both groups. intraoperative blood loss was not significantly different between between the epidural and general anesthesia groups. there was no significant difference in measured coagulation variables between both groups, but there were significant differences in postoperative r, t and f variables (p < , ). in the postanaesthesia period r and t significantly decreased (p < , ), and ar and f increased (p < , ) in general anaesthesia group. the total blood loss after open prostatectomy was correlated (r = , ; p < , ) with the prostatic tissue weight. when the tissue weight resected exceeded g, blood loss was in excess of the linea correlation shown with the weight of resected prostatic tissue. ( , %) patients has significantly increased f (fibrinilytic activity) and h postoperatively. thromboelastography (teg) provides information on patients' coagulation status within minutes. the value of the teg has not been established in general icu patients. we present cases of critically ill patients with bleeding tendency in whom clinical decisions based on conventional laboratory results were modified by teg. we started implementing routine use of teg (haemoscope,usa). we describe patients in whom teg results changed clinical decisions that were taken before information from teg was available. case - y. o parturient admitted with massive pulmonary hemorrhage of unknown etiology. because of concern of a bronchial tear and bronchial arterial source bleeding, angiography with embolization was performed. despite this, bleeding recurred. there were no coagulation abnormalities and the patient was not thrombocytopenic. teg showed significant early thrombolysis and therefore treatment with tranexamic acid begun. within few hours bleeding stopped and did not recur. case - y. o man with autoimmune vasculitis presented with acute on chronic renal failure and epistaxis. after dialysis which was performed without heparin,the patient became hemodynamic unstable,was intubated and ventilated due to massive pulmonary hemorrhage. blood samples showed inr . ,prolonged ptt,normal fibrinogen level,thrombocytopenia and hemoglobin . g/dl. teg showed no primary fibrinolysis. repeated teg with heparinase showed normalization of the teg tracing. it thus evident that the patient did receive heparin during dialysis and the diagnosis of dic was negated. the patient was treated with packed red cells only,and further bleeding was not demonstrated. case - y.o man with status epilepticus due to an a-v malformation and brain edema,developed left arm compartment syndrome secondary to thrombophlebitis. the patient's platelet count was , . he was operated uneventfully without correcting the thrombocytopenia. a few hours later there was bleeding from the operative site. a teg test showed normal parameters. therefore,despite an initial assessment by the surgical team that the reason for bleeding is a coagulopathy,the patient was taken for a re-exploration of the wound. an arterial bleeder was found which was coagulated.conclusion. laboratory abnormalities are critical for making decisions in critically ill patients. occasionally, the clinical setting of bleeding with mild coagulation and platelet count abnormalities, preclude the patient from receiving invasive procedures prior to correction of the abnormality. thromboelastography can identify alteration in platelet number and function and abnormalities in the coagulation system. in our cases teg tracings were performed in addition to other coagulation tests. we found that in some patients as demonstrated here, the information provided by teg is different from that derived from conventional coagulation tests and leads to a change in clinical decisions. candida airway colonization is common in mechanically ventilated icu patients but the implications of this finding are not well appreciated. fluconazole prophylaxis is a reasonable approach to decrease fungal infections in critically ill surgical patients and is routinely administered in all of our cardiac surgery patients that stay in sicu for more than days. the present study was undertaken to evaluate the incidence and clinical significance of positive bronchial secretion cultures (bsc) for candida in mechanically ventilated cardiac surgery patients, who were febrile (t> c) after the first h in sicu. positive bsc for candida developed in . % of our general sicu population ( . % after cabg, . % after vr, . % after cabg+vr and % in others). the average time for candida airway colonization of sputum was . ± d. the vast majority ( %) of patients developed positive bsc prior to initiation of fluconazole prophylaxis ( pts within - d, pts within - d and pts after d of sicu stay). the icu stay ( ± d), hospital stay ( ± d) and mortality ( %) were significantly higher in patients with positive bsc for candida, compared to the general sicu population (icu stay . ± . d, hospital stay . ± d, mortality . %). candida airway colonization of febrile cardiac surgery patients after the first h in sicu is associated with a grave prognosis and could be a marker of compromised immune response. this colonization appears early in the course of icu stay and therefore the initiation of earlier fluconazole prophylaxis may be necessary. the current incidence of ie is estimated as cases per . population per year and continues to increase. the prognosis is significantly influenced by proper diagnosis and adequate therapy. cardiac surgery for active ie is established as a cornerstone therapy as it is required in % of patients but remains a challenging and high-risk procedure. the purpose of this study was to analyze the clinical characteristics of the patients underwent cardiac surgery for active ie in our center for a -month period. to evaluate principal indications for cardiac surgery and assess the major causes of surgical morbidity and mortality in ie patients. retrospective review of ie cases who underwent cardiac surgery from december to november in our -bed csicu. we collected age, gender, site of endocarditis, native or prosthetic, microbiological agent, indication of surgery, postoperative complications, icu stay and mortality. . patients with ie underwent surgical intervention in acute phase of infection. their ages ranged from to years (mean , ) and % were males. the causative agents were: streptococci-enterococci ( %), staphylococci ( %), candida spp ( %), pseudomonas aeruginosa ( %). the principal indications for cardiac surgery were development of heart failure due to severe heart valve defects or prosthetic valve dysfunction and intracardiac abscess. all patients had positive blood culture endocarditis but only two were still positive before operation. cases of aortic valve involvement were the most frequent, followed by cases of mitral valve endocarditis. native valve endocarditis prevailed over the prosthetic ones versus . surgery was performed using a mechanical prosthesis of the infected valve. in patients the procedure was complemented with tricuspid valve annuloplasty. patients underwent bentall procedure. the mean icu stay was , days (range to ). thirty-days mortality of patients undergone surgery for ie was %, patients died in the icu. operation for active ie carries a relatively higher mortality in comparison with elective surgery. an indication of surgery depends on several clinical variables but the main indication remains heart failure due to severe heart valve defect or prosthetic valve dysfunction. a high degree of clinical suspicion, at an early diagnosis, and indication of surgical treatment prior to deterioration of ventricular function and installation of generalized sepsis may improve prognosis. severe sepsis is a major cause of morbidity and mortality following major surgery. factors that are associated with an increased risk of sepsis following surgery include emergency surgery, patient comorbidities and degree of surgical insult. the risk of developing severe sepsis following major surgery for cancer has been shown to relate to the charlson comorbidity score , with a higher score predicting a greater risk of developing severe sepsis .we conducted a prospective observational study in order to investigate whether the charlson score could be correlated to the risk of developing sepsis following elective major general surgery in patients without cancer. we collected data on patients undergoing elective major surgery in a large teaching hospital. the charlson comorbidity index was calculated preoperatively for each patient. the patients were followed up for days postoperatively, and signs of the systemic inflammatory response syndrome (sirs), sepsis and septic shock were documented each day. the source of sepsis was recorded, if present. admission to critical care bed was also documented. . data was complete on patients, ( . %) were male, and ( . %) had cancer. the median age of the patients was years. mean operation time was hours, and mean transfusion requirement intraoperatively was . units. the median charlson score was . ( . %) patients were admitted to a critical care bed for reasons other than routine postoperative care. ( . %) patients developed sirs postoperatively. ( . %) patients developed sepsis postoperatively, and ( . %) of these went on to develop septic shock. there was a progressive, but non-significant difference in charlson score in those patients who developed septic shock or sepsis and those who did not. those patients who developed septic shock had a mean charlson score of . , while those with sepsis had a mean charlson score of . . those patients who did not develop sepsis had a mean charlson score of . . sepsis and septic shock are common after elective major surgery, but the charlson comorbidity index was not a useful predictor of the likelihood of developing sepsis in our population of cancer and non-cancer patients. rate of neurological complications after central nerve blockade is < . % ( ) and spinal epidural abscess vary from : to : ( ) . we audited the complications following epidural analgesia in postoperative patients admitted to our critical care unit with sepsis. we performed a retrospective case note review of all septic patients who had epidural analgesia for postoperative pain relief or for weaning from mechanical ventilation. all patients who had a major laparotomy and sepsis were included. we looked into the complications of epidural during insertion, usage and after removal of epidural catheter. patients were followed up by the critical care outreach and acute pain teams on discharge from the critical care unit. data are presented as mean and standard deviation. in a year period there were septic patients who had epidural analgesia. of these were commenced immediately prior to the laparotomy and were inserted in itu to enable weaning from mechanical ventilation. the male: female ratio was : with an average age of . ( . ). there were patients with or more organ failure. only ( . %) patients had positive blood cultures during the period of epidural analgesia. multiple attempts at epidural insertion were found in patients. mean duration of epidural catheter was . ( . ) there were survivors and non-survivors in this group. of the nonsurvivors died during the period epidural analgesia. the other nonsurvivors were followed up for an average period of . days and a median duration of days after the epidural catheter was removed. none of the patients developed any complications attributable to the epidural. the serious complications of epidural analgesia like epidural abscess and nerve injuries, although rare, are reported in case series( ). we did not note any adverse complications of epidural analgesia in this high risk group of septic patients admitted to the critical care unit. key: cord- -jby btv authors: rilinger, jonathan; zotzmann, viviane; bemtgen, xavier; schumacher, carin; biever, paul m.; duerschmied, daniel; kaier, klaus; stachon, peter; von zur mühlen, constantin; zehender, manfred; bode, christoph; staudacher, dawid l.; wengenmayer, tobias title: prone positioning in severe ards requiring extracorporeal membrane oxygenation date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: jby btv background: prone positioning (pp) has shown to improve survival in patients with severe acute respiratory distress syndrome (ards). to this point, it is unclear if pp is also beneficial for ards patients treated with veno-venous extracorporeal membrane oxygenation (vv ecmo) support. methods: we report retrospective data of a single-centre registry of patients with severe ards requiring vv ecmo support between october and may . patients were allocated to the pp group if pp was performed during vv ecmo treatment or the supine positioning group. vv ecmo weaning success and hospital survival were analysed before and after propensity score matching. results: a total of patients could be analysed, and patients ( . %) received pp. there were no significant differences in vv ecmo weaning rate ( . % vs. . %, p = . ) and hospital survival ( . % vs. . %, p = . ) between the prone and supine groups, respectively. the analysis of propensity score matched pairs also showed no difference in hospital survival ( . % vs. . %, p = . ) or vv ecmo weaning rate ( . % vs. . %, p = . ). hospital survival was superior in the subgroup of patients treated with early pp (cutoff < h via youden’s index) as compared to late or no pp ( . % vs. . %, p = . ). conclusion: in this propensity score matched cohort of severe ards patients requiring vv ecmo support, prone positioning at any time was not associated with improved weaning or survival. however, early initiation of prone positioning was linked to a significant reduction of hospital mortality. in case of severe acute respiratory distress syndrome (ards), veno-venous extracorporeal membrane oxygenation (vv ecmo) support may be considered when lung-protective mechanical ventilation is not able to prevent hypoxia or hypercapnia [ ] [ ] [ ] . nevertheless, mortality of severe ards remains high-even with ecmo support. the eolia trial for instance showed a mortality rate of % in patients treated with ecmo compared to % in patients without ecmo support in very severe ards [ ] . moreover, several studies showed that prone positioning (pp) is able to improve survival in these critically ill patients [ , ] . pp provides various positive effects on oxygenation and lung compliance [ , ] . furthermore, pp can reduce ventilator-induced lung injury [ ] and is associated with less days on mechanical ventilation (mv) and shorter length of intensive care unit (icu) stay [ ] . hence, pp might be beneficial for patients receiving ecmo support. it has been demonstrated that pp can be performed safely [ ] [ ] [ ] [ ] [ ] during ecmo support and improves oxygenation and lung compliance [ ] . so far, there is little evidence about the outcome of these patients. we performed a retrospective analysis of ards patients treated with pp during ecmo support at our centre. we report retrospective data of a single-centre registry of patients with severe ards treated with vv ecmo. all patients treated at the interdisciplinary medical intensive care unit at the medical centre, university of freiburg, germany, between october and may were registered. patient identity data derived from the registry were blinded, and the study plan was approved by the local ethics committee (ek-freiburg / ). all patients suffered from severe ards. vv ecmo support was initiated in cases of severe hypoxic respiratory failure or co retention despite of mechanical ventilation as suggested by the elso guidelines. patients receiving pp during ecmo support were allocated to the prone group, whereas the remaining patients formed the supine group. pp before initiation of ecmo support did not influence the allocation of patients in one or the other group. primary endpoints were successful ecmo weaning, and icu and hospital survival. successful ecmo weaning was defined as being free from ecmo and alive for at least h after decannulation. unsuccessful weaning was defined as the inability to explant the ecmo device because of persistent respiratory failure or death during ecmo support and the need for recannulation within h. moreover, ventilator settings of the first days after ecmo initiation were analysed. to compare the patients' disease severity, the resp [ ] , sofa [ ] , and apache ii scores [ ] as well as the horowitz index (pao /fio ) were analysed. our institution features a / ecmo centre localised within a tertiary hospital with a -bed medical intensive care unit. cannulations in our ecmo centre are performed by two experienced intensivists and a perfusionist in seldinger's technique without primary surgical cut down. all member of the ecmo team can be gathered within min. typical numbers for veno-arterial and veno-venous cannulations are and per year, respectively. there is a h/ days outreach team. for this research, only in-house cases were considered. as ecmo system, either scpc (sorin centrifugal pump console, livanova, london, uk) or cardiohelp (maquet getlinge group, rastatt, germany) was used. cannulation was predominantly performed with dual-lumen cannula (avalon, maquet, rastatt, germany). for patients without life-threatening bleeding, anticoagulation was provided by intravenous unfractionated heparin aiming at a partial thromboplastin time . times upper normal limit. the management of vasopressors and fluid therapy was driven by clinical judgement of the ecmo experienced intensivist in charge and has been reported earlier [ ] . treatment algorithms and standard operating procedures were subject to optimizations during the observational period, reflecting current state-of-the-art recommendations and scientific knowledge. controlled mv mode used at our institution mostly was biphasic positive airway pressure (bipap). in few patients, airway pressure release ventilation (aprv) was used, when considered beneficial. vv ecmo support was implemented in case of severe but potentially reversible respiratory failure, when lung-protective mv resulted in hypoxemia or hypercapnia. lung-protective mv was defined as positive end expiratory pressure (peep) ≤ cmh o, plateau pressure ≤ cmh o, driving pressure ≤ cmh o, and fio ≤ %. cannulation was performed predominately jugulary using a duallumen cannula. after initiation of the vv ecmo support, invasivity of mv was reduced and ecmo flow was adjusted aiming for a peripheral oxygen saturation of - % and partial pressure arterial oxygen of approximately mmhg, respectively. typical ventilator settings were as follows: peep cmh o, plateau pressure cmh o, fio %, and respiratory rate /min. indications and performance of prone positioning during ecmo support ards treatment was carried out according to the currently valid guidelines [ ] . the decision on whether to perform pp in the individual case lays with the treating medical team's judgement. prone positioning was done face down. sedation for pp patients at our institution was titrated to preserve spontaneous breathing if possible. neuromuscular blockade was not given on a routine basis for executing pp. however, in individual cases, especially in cases of strong respiratory drive and concerns about a self-inflicted lung injury [ ] , neuromuscular blocking agents were used. summary results for categorical variables are presented as frequency and percentage. results for numeric variables are presented as median with interquartile range (iqr). fisher's exact test and pearson's chisquared test were used for analysing nominal variables. in dependence of normal distribution, student's t test or mann-whitney u test was performed for continuous variables. multivariate regression analysis was performed for univariate (dependent) predictors of hospital survival. results are given as odds ratio [(or), % confidence interval (ci)], and a p value of ≤ . was considered statistically significant. roc analysis and youden's index (youden's index = sensitivity + specificity − ) were used for reaching the optimal cutoff of survival-associated factors with highest discrimination of sensitivity and specificity. propensity score matching was performed using spss with a nearest neighbour matching algorithm using a calliper of . . matching was performed for age, sex, sofa score, the duration of mv before ecmo, and performance of prior pp before ecmo. cumulative incidences of -day mortality were calculated using competing risk regression (fine and gray method) with discharge alive considered a competing event [ ] . statistical calculations were performed using ibm spss statistics . (armonk, ny: ibm corp, ). a total of patients with complete medical data could be analysed (age . ( . - . ) years, % male). the collective showed a relatively high rate of comorbidities, and this was especially true for immunosuppression ( %, table ) . thirty-eight patients ( . %) received pp during ecmo therapy. no relevant complications (e.g. decannulation) occurred during the positioning procedures. patients with pp during ecmo support had a higher rate of pre-existing chronic renal failure and pneumoniainduced ards. patients in the prone group displayed a different pulmonary pathogen spectrum (more viral and fungal infections, especially pneumocystis jirovecii, table ). survival prediction scores (sofa, apache ii, and resp) did not differ between both groups. pp before ecmo initiation was performed in . % of the patients in both groups. on average, the first pp during ecmo support was performed after . ( . - . ) days on ecmo support, with . ( . - . ) pp manoeuvres performed per patient. average pp duration was . ( . - . ) h (additional file , table e ). patients with pp during ecmo support showed higher peep levels from day and higher plateau pressures from day to (additional file , figure e ). there was no difference in driving pressures as well as in tidal volumes. however, patients with pp during ecmo support showed less spontaneous breathing on day and day to . there were no differences in ecmo weaning rate ( . % vs. . %, p = . ), and icu or hospital survival ( . % vs. . %, respectively, p = . ) between the prone and the supine groups (table ) . cumulative incidences of -day in-hospital death were % and % for the prone and supine groups, respectively (p = . , fig. ). thirty-eight propensity score matched pairs ( patients) with similar baseline characteristics could be analysed (fig. , see also additional file , table e ). successful ecmo weaning rate was . % vs. . % (p = . ) in patients with and without pp during ecmo support, respectively. furthermore, there was no difference in survival between both groups ( . % vs. . %, p = . ). cumulative incidences of -day in-hospital death were % and % for the prone and supine groups, respectively (p = . , additional file , figure e ). underlying lung fibrosis, status of immunosuppression, and aspiration were associated with death, whereas proof of bacterial infections was associated with survival (table ) . moreover, a high proportion of spontaneous breathing in the first days was strongly associated with survival. in multivariate analysis, only underlying lung fibrosis (odds ratio . [ % ci . - . ]) and a high proportion of spontaneous breathing in the first days (odds ratio . [ % ci . - . ]) were independent predictors for death and survival, respectively. in patients with pp, higher age, acute renal failure, and underlying pulmonary disease were associated with death. proof of pulmonary bacterial infection and timing of the first pp after ecmo initiation were associated with survival in a univariate analysis (additional file , table e ). in a multivariate analysis, only early initiation of pp (< h) was associated with survival (odds ratio . [ % ci . - . ], fig. ). optimal cutoff value for duration from ecmo initiation to first pp was calculated using roc analysis (auc = . ) and youden's index. highest sensitivity and specificity for beneficial survival were achieved for initiation of pp in < h. next to this optimal cutoff, a clinical cutoff of day ( h) also was associated with improved survival (p = . ). patients treated with early pp during ecmo (n = ) showed a superior survival to patients treated with late pp or without pp during ecmo support ( . % vs. . %). cumulative incidences of -day in-hospital death were % for the early pp group and % for the late and no pp group, respectively (p = . , fig. ) . also, in a separate comparison of patients with late pp as well as patients without pp, early pp showed superior survival rates ( . % vs. . % and . %, p < . and p = . , respectively). patients in the early pp group were younger than patients with late or without pp during ecmo support ( . vs. . years, p = . ). the groups did not differ concerning vasoactive support or in sofa and apac he ii scores at the time of ecmo implantation. moreover, there was no difference in the sofa score between both groups in the first days (additional file , table e ). the resp score of the patients with early pp was higher ( . ( . - . ) vs. (− . - . ), p = . , additional file , table e ). the resp score without including age was ( . - . ) vs. ( - . ), p = . ). prone positioning has shown to improve survival in non-ecmo ards patients [ ] . there is sparse data on pp in ards patients with vv ecmo support. we therefore retrospectively analysed a large cohort of ecmo patients suffering from severe ards treated with or without pp at our centre. our results do not indicate an overall survival benefit for pp during ecmo support per se. however, timing of pp may be crucial when designing future studies. in comparison to previous pp studies, technical execution of pp in this analysis showed favourable characteristics. beginning of pp after ecmo initiation was earlier than in other studies ( . vs. or days, respectively) [ , ] . moreover, the average duration of each performed pp was longer ( . h) and more pp manoeuvres were performed per patient ( . ) than described before [ , , ] . this is especially important, as the survival benefit for pp in ards without ecmo support shown by guerin et al. was achieved with long pp periods ( h) [ ] . patients treated with pp in our patient collective showed increased peep and plateau pressure levels but still remained in the recommended limits of the elso guideline [ ] . as intended by the treating medical team, driving pressure was kept below cmh o, as high driving pressures are strongly associated with increased mortality [ ] . furthermore, no differences in driving pressure were found between both groups. patients with pp during ecmo showed a reduced rate of spontaneous breathing compared to patients without pp, despite the fact that neuromuscular blocking agents were not used on a routine basis during pp periods. however, it seems reasonable that pp patients might have been on deeper sedation levels than patients in the supine group. in contrast to this, the elso guidelines recommend an early reduction of sedation levels and a switch to spontaneous breathing after to h after ecmo initiation [ ] . furthermore, low proportions of spontaneous breathing episodes were associated with a higher mortality. however, this only allows hypothesis generating, since causality between a reduced rate of spontaneous breathing and increased mortality cannot be proven in this analysis and could also be an expression of higher disease severity. nevertheless, the reduced rate of spontaneous breathing in patients with pp should be considered in the discussion of benefits and disadvantages of this additional treatment. our results are in contrast to the study of guervilly et al. their retrospective study of additional pp showed an encouraging survival benefit [ ] . survival rate in the pp group was markedly higher than in the supine group ( -day survival % vs. %). in terms of age, sex, and pp manoeuvres performed per patient, the cohort of guervilly et al. and our patients did not differ. however, our patients were sicker than those of guervilly and coworkers (predicted mortality by sofa score approx. % vs. % [ ] ) and showed a much lower rate of fig. in-hospital death of ecmo patients with vs. without prone positioning during ecmo. the fine-gray model for in-hospital death (shr . , p = . , cumulative incidence of -day death % vs. %). ecmo, extracorporeal membrane oxygenation fig. propensity score matched pair patient assignment. *matching was performed for age, sex, sofa score, the duration of mv before ecmo, and performance of prior pp before ecmo. ecmo, extracorporeal membrane oxygenation; mv, mechanical ventilation; pp, prone positioning; sofa, sequential organ failure assessment prior pp before ecmo ( % vs. %). furthermore, guervilly et al. reported deep sedation and routine use of neuromuscular blocking agents during pp which is in contrast to our approach. to compare our findings with those from guervilly et al., we used the same matching parameters for propensity score matching, which did not alter our findings. timing of pp was an independent predictor of survival in our cohort. early initiation of pp after ecmo cannulation was strongly associated with improved survival. a beginning of pp in less than day (cutoff < h via youden's index) in comparison to late or no pp showed a strong survival benefit ( % vs. %). this finding is in line with the study protocol of the proseva trial [ ] , where the survival benefit for pp in non-ecmo ards patients was achieved with an early beginning of pp (initiated in average h after beginning of mechanical ventilation). this association suggests that an early beginning of pp after initiation of ecmo support could be an important factor for survival, which requires further investigation. because of the retrospective design of this study, the reasons why patients were treated with pp or not, or received early or late pp, cannot be pinned down. patients receiving early pp were younger, but they did not differ in terms of haemodynamic stability and showed no difference regarding the sofa and apache ii scores. patients of the early pp group showed a higher resp score ( . vs. ), indicating a certain difference in predicted mortality rate ( % vs. %). nevertheless, the factor age could have influenced the team's decisionmaking for or against early pp. interestingly, in the early pp group, in contrast to the whole pp group, a higher rate of spontaneous breathing within the first days was observed (not significant), which could be one factor that may improve survival rate for early pp. from a theoretical standpoint, there are many positive effects of additional pp in patients receiving ecmo support, like improving oxygenation and lung compliance as well as reducing ventilator-induced lung injury [ ] [ ] [ ] . in clinical practice, patient-safety concerns often prevent prone positioning during ecmo therapy, even though feasibility and safety have been demonstrated in several studies. in this retrospective analysis, pp at any time was not associated with improved survival per se. however, our results indicate that a very early initiation of pp therapy (within day after cannulation) could be beneficial. no complications related to pp were detected. in consideration of the retrospective design of this study, we think that a randomised controlled trial is imperatively needed for further evaluation of pp in ecmo patients. considering the pros and cons of a pp therapy, pp should not be withheld from ards patients requiring ecmo support. our data suggest that pp should be initiated very early in the clinical course. this is a retrospective observational study and therefore contains the risk of selection and reporting bias. another limitation is the small sample size of only patients with pp and patients in the matched pair analysis, respectively. moreover, this is a single-centre report and specific processes may influence the presented results. the same internal standard operating procedures applied to the entire treating physician team. however, the indication for performing pp during ecmo support was on basis of the treating ecmo physician and therefore was not standardised. despite using propensity score matching for outcome analysis, this among other factors might be remaining confounders that we did not control for. together, due to these limitations, our findings should be considered as hypothesis generating and should not prompt clinical decision-making. this retrospective analysis did not reveal an overall survival benefit associated with pp in patients with ards requiring ecmo support. however, a subgroup analysis suggested that early initiation of pp may improve survival and should be considered in the design of a randomised controlled trial for further evaluation. supplementary information accompanies this paper at https://doi.org/ . /s - - - . efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for severe acute respiratory distress syndrome guidelines for adult respiratory failure effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome prolonged prone positioning under vv-ecmo is safe and improves oxygenation and respiratory compliance the effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta-analysis. areas of uncertainty and recommendations for research prone position augments recruitment and prevents alveolar overinflation in acute lung injury complications of prone positioning during extracorporeal membrane oxygenation for respiratory failure: a systematic review prone positioning during veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults application of prone position in hypoxaemic patients supported by veno-venous ecmo prone positioning use to hasten veno-venous ecmo weaning in ards prone position during ecmo is safe and improves oxygenation combination of positioning therapy and venovenous extracorporeal membrane oxygenation in ards patients predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score prognostic accuracy of the sofa score, sirs criteria, and qsofa score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit apache ii: a severity of disease classification system early fluid resuscitation and volume therapy in venoarterial extracorporeal membrane oxygenation deutsche gesellschaft für anästhesiologie und intensivmedizin (dgai). s -leitlinie -invasive beatmung und einsatz extrakorporaler verfahren bei akuter respiratorischer insuffizienz. . auflage mechanical ventilation to minimize progression of lung injury in acute respiratory failure a proportional hazards model for the subdistribution of a competing risk effect of prone positioning on cannula function and impaired oxygenation during extracorporeal circulation driving pressure and survival in the acute respiratory distress syndrome prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions jr and tw contributed to the conception of the study; jr, cs, and tw contributed to the data collection; jr, vz, xb, pmb, dd, kk, ps, cm, mz, cb, dls, and tw contributed to the data analysis and interpretation; jr and tw drafted the manuscript; vz, xb, pmb, dd, kk, ps, cm, mz, cb, and dls revised the manuscript for important intellectual content. all authors approved the final version of the manuscript. none. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. not applicable. the authors declare that they have no competing interests.author details key: cord- - d yyzu authors: fiedler, m. o.; reuß, c. j.; bernhard, m.; beynon, c.; hecker, a.; jungk, c.; nusshag, c.; michalski, d.; brenner, t.; weigand, m. a.; dietrich, m. title: fokus beatmung, sauerstofftherapie und weaning: intensivmedizinische studien aus / date: - - journal: anaesthesist doi: . /s - - - sha: doc_id: cord_uid: d yyzu nan wie wichtig die erkenntnisse zur beatmungs-und sauerstofftherapie sind, wurde ende des jahres durch eine akute respiratorische erkrankung durch ein neuartiges coronavirus (sars-cov- ) gezeigt, das sich von china aus verbreitet hat. die erkrankung wird als "coronavirus disease (covid- )" bezeichnet. am . . wurde die epidemie durch die weltgesundheitsorganisation (who) offiziell als pandemie bezeichnet, da sich covid- weltweit ausbreitet. die Übertragung zwischen den menschen scheint überwiegend durch tröpfcheninfektion zu erfolgen. die klinischen symptome der patienten, die auf sars-cov- positiv getestet worden sind, zeigen primär das bild einer respiratorischen erkrankung mit fieber, husten, dyspnoe und müdigkeit, aber auch gastrointestinale beschwerden (z. b. diarrhö) und neurologische symptome wie geruchsverlust [ ] . remdesivir ist die einzige gezielte antivirale therapie, die für die behandlung von sars-cov- -infizierten patienten zugelassen ist (stand: . . ) [ ] . die behandlung orientiert sich an der symptomatik der patienten. im vordergrund der schweregradeinteilung steht die hypoxämie mit dem respiratorischen versagen und der notwendigkeit für die applikation von sauerstoff. kritisch kranke patienten, die auch trotz high-flow-sauerstofftherapie nicht adäquat oxygenieren, müssen zur gewährleistung der sauerstoffversorgung schlussendlich intubiert und invasiv beatmet werden [ ] . die fundamentale pathophysiologie der schweren viruspneumonie entspricht in etwa einem schweren "adult respiratory distress syndrome" (ards). allerdings spielen beim lungenversagen durch covid- z. t. perfusionsheterogenitäten, pulmonalvaskuläre endothelentzündungen und mikrothrombosen eine bedeutende rolle [ ] . unabhängig von der noch nicht im detail geklärten pathophysiologie sollten patienten mit covid- , die eine schwere pneumonie mit hypoxie entwickeln und auf eine invasive beatmung angewiesen sind, eine lungenprotektive beatmungstherapie zur verbesserung der oxygenierung erhalten. dieses verfahren der protektiven beatmung beruht auf ergebnissen der jahrzehntelangen ards-forschung [ ] und aus untersuchungen zu viralen pneumonien [ ] . tab. die standardtherapie bei der beatmung von patienten mit einem akuten lungenversagen (ards) wird als lungenprotektive beatmung bezeichnet und beinhaltet die anwendung von niedrigem tidalvolumen und eine begrenzung des oberen plateaudrucks [ ] . bereits vor jahren zeigte die studie ards et curarisation systématique (acurasys), dass patienten mit moderatem bis schwerem ards von einer -stündigen tiefen sedierung und muskulären relaxierung durch die i.v.-gabe von cisatracurium profitierten [ ] . es war eine der ersten multizentrischen placebokontrollierten studien, die lungenprotektive beatmung zeigte sich in beiden studien durch ein geringes tidalvolumen und einen niedrigen "driving pressure" (pplat-peep). diese konsequenten einstellungen waren daher auch lungenprotektiv für die kontrollgruppen der jeweiligen studien. ein erhöhter respiratorischer antrieb ("respiratory drive") bei patienten im schweren ards ohne tiefe sedierung und ohne muskelrelaxierung kann das risiko einer "ventilatorinduzierten lungenschädigung" ("ventilator induced lung injury", vili) erhöhen. der einsatz von tiefer sedierung und zusätzlicher muskelrelaxierung könnte dies reduzieren, indem z. b. die atemfrequenz gesenkt und der patient mit dem beatmungsgerät synchronisiert wird [ , ] . auf der anderen seite führt die spontanatmung unter leichter sedierung zu einer verkürzung der beatmungszeit und des krankenhausaufenthalts [ ] . aber auch die spontanatmung mit hohem respiratory drive kann zu einem lungenschaden führen ("self-inflicted lung injury", sili) [ ] . ein weiteres phänomen, das zu einer lungenschädigung führen kann, ist das "breath stacking". dabei versucht der patient einzuatmen, und das zwerchfell kontrahiert sich nach einem bereits verabreichten atemhub. somit erhöht sich das eingeatmete tidalvolumen, und es zeigt sich eine dyssynchrone atmung. durch tiefe sedierung und die applikation von muskelrelaxanzien können patient und beatmungsmaschine wieder synchronisiert werden [ , ] . zusammenfassend ergeben beide studien, dassdereinsatzvonmuskelrelaxanzien weiterhin im moderaten bis schweren ards eine individuelle therapieoption darstellt. basierend auf den ergebnissen der acurasys-und rose-studie sind muskelrelaxanzien erst einzusetzen, wenn eine reihe von lungenprotektiven maßnahmen zur beatmung eingehalten wird und diese nicht ausreichend ist, um den patienten vor einem vili zu bewahren oder die oxygenierung darunter nicht besser wird. dazu zählen die lungenprotektive einstellung der beatmungsparameter (niedriges tidalvolumen, peep), die optimierung der sedierung und die bauchlagerung. sind die patienten unter leichter sedierung synchron mit dem beatmungsgerät, so ist der einsatz von muskelrelaxanzien nicht indiziert. bellani g, grassi a, sosio s et al ( ) driving pressure is associated with outcome during assisted ventilation in acute respiratory distress syndrome. anesthesiology : - [ ] durch diese arbeitsgruppe wurde eine retrospektive kohortenanalyse unter einschluss von patienten mit ards während mechanischer beatmung durchgeführt. dabei wurde zur ermittlung des driving pressure während assistierter beatmungshübe der plateaudruck gemessen. unter dem driving pressure versteht man die differenz zwischen plateaudruck und positivem endexspiratorischem druck (peep) (pplat-peep = driving pressure). ein hoher driving pressure (≥ mm hg) ist bei patienten mit ards mit einer erhöhten mortalität assoziiert [ , ] . obwohl dieser zusammenhang während kontrollierter mechanischer beatmung gezeigt worden ist, wird während unterstützter spontanatmung der plateaudruck oftmals nicht gemessen, weil unsicherheit bezüglich der validität des errechneten driving pressure besteht. die autoren bellani et al. wollten deswegen in ihrer studie zeigen, dass während unterstützter beatmungsformen (z. b. "pressure support ventilation") sowohl ein erhöhter driving pressure als auch eine erniedrigte compliance mit einer erhöhten mortalität einhergehen. im vergleich zwischen verstorbenen vs. überlebenden patienten waren der driving pressure während der assistierten beatmung der ards-patienten etwas höher ( [ ] [ ] [ ] [ ] [ ] [ ] vs. [ ] [ ] [ ] [ ] beitler jr, sarge t, banner-goodspeed vm et al ( ) effect of titrating positive endexpiratory pressure (peep) with an esophageal pressure-guided strategy vs an empirical high peep-fio strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial. jama [ ] ; - [ ] trotz jahrzehntelanger forschung sind der klinische vorteil von einem höheren peep und die beste methode zur peep-titration immer noch unklar [ ] . [ ] . diese wurde aufgrund signifikant höherer pao /fio -werte in der interventions-tab. ards-network-tabelle "lower peep/higher fio " [ ] ; peep "positive endexpiratory pressure" (cmh o) tab. ards-network-tabelle "higher peep/higher fio " [ ] ; peep"positive endexpiratory pressure" (cmh o) fio , , , , , , , , , , , , , , [ ] . die verwendung der low-peep-tabelle in der epvent-studie mag im vergleich mit der interventionsgruppe zu einem besseren ergebnis der peep-titration durch Ösophagusdruckmessung geführt haben [ ] . auf der anderen seite ist die verwendung der high-peep-tabelle (. tab mackle et al. haben in ihrem intensive care unit randomized trial comparing two approaches to oxygen therapy (icu-rox), in australien und neuseeland an beatmeten erwachsenen patienten auf intensivstation, eine prospektive randomisierte studie durchgeführt. die patienten wurden entweder der konservativen oder der üblichen sauerstofftherapie zugeteilt ("conservative or usual oxygen therapy") [ ] . es gab große unterschiede in bezug auf die verabreichung des sauerstoffs in den beiden gruppen. zum beispiel verblieben patienten in der "konservativen" sauerstoffgruppe eine längere zeit auf dem fio -level von , (gleichzusetzen mit der raumluft) als die in der "üblichen" sauerstoffgruppe (mediane dauer h vs. h; absoluter unterschied h; %-konfidenzintervall [ %-ki], zu ). es gab jedoch keinen signifikanten unterschied im primären endpunkt bezüglich der beatmungsfreien tage ( , vs. , tagen; differenz, - , tage; %-ki, - , bis , ; p = , ) oder der mortalität zwischen den grup-pen. die autoren hatten keine sicherheitsbedenken mit der "konservativen" sauerstofftherapie. das schwierige an dieser art studie ist, dass die messung des arteriellen partialdrucks nicht kontinuierlich durchführbar ist und deswegen veränderungen der sauerstoffgabe nicht zeitgleich zu veränderungen des arteriellen partialdruckes führen. es kommt immer zu zeitlichen verzögerungen, da dem patienten bei veränderung der fio zunächst blut abgenommen wird und dieses dann einem analysegerät zugeführt werden muss. es ist nur möglich, sich einen zielbereich anzuschauen (z. b. ausreichende pao -werte im bereich von - mm hg), da eine kontinuierliche messung noch nicht möglich ist. stattdessen wird die kontinuierliche messung der sauerstoffsättigung (spo ) betrachtet. diese korreliert ganz gut mit den pao -werten, aber sie ist in kritischen situationen sehr störanfällig (z. b. im schock, minderperfusion bedeutet hypoxämiegefahr). die schwierigkeit besteht also in der genauigkeit der messungen, auf der einen seite im zielbereich zu messen und auf der anderen seite veränderungen schnellstmöglich und genauestens zu erfassen. ein weiteres problem besteht darin, dass patienten unterschiedlichste organschäden mit einer heterogenen perfusion aufweisen können. ein zielbereich für eine ausreichende oxygenierung kann für das gewebebett des einen organs gut sein, während es für andere organe schädigend sein kann. die patientenpopulation kann noch so homogen und das studienprotokoll exakt gleich sein, schlussendlich ist es bisher noch ungewiss, welcher sauerstoffbedarf in den zielorganen jeweils ausreichend ist. barrot l, asfar p, mauny f et al ( ) liberal or conservative oxygen therapy for acute respiratory distress syndrome. n engl j med : - [ ] in dieser französischen multizentrischen studie wurden ursprünglich patienten mit ards in randomisierter form einer "konservativen" oder einer "liberalen" sauerstofftherapie zugeführt. die "konservative" therapie hatte als ziel einen pao von - mm hg und eine sauerstoffsättigung (spo ) von - %, während die "liberale" therapie einen pao von - mm hg und eine spo ≥ % für tage vorsah. beide patientengruppen wurden nach denselben strategien beatmet. der primäre endpunkt war die -tage-mortalität. die studie musste vorzeitig beendet werden, da es sicherheitsbedenken bezüglich der "konservativen" strategie gab und die sinnhaftigkeit infrage gestellt wurde. es konnten patienten in die untersuchung eingeschlossen werden. der primäre endpunkt -tage-mortalität wurde bei , % in der "konservativen" und bei , % in der "liberalen" sauerstoffgruppe (differenz , prozentpunkte; %-ki, - , bis , ) erreicht. die -tage-mortalität lag bei , % und , % (differenz , prozentpunkte; %-ki , bis , ). in der "konservativen" sauerstoffgruppe gab es außerdem episoden von mesenterialischämie. obwohl in früheren studien ein vorteil der "konservativen" sauerstofftherapie bei beatmeten patienten gezeigt werden konnte [ ] , so zeigt die icu-rox-untersuchung keinen benefit, und die loco -studie zeigt die tendenz zu einer potenziellen schädigung der patienten. aufgrund der ergebnisse der letzten beiden studien stellt sich nun die frage, wie es zu solch einer diskrepanz kommt. betrachtet man die studien, so fällt auf, dass die konfidenzintervalle sehr weit auseinanderliegen, besonders in der loco -studie. die kernaussagen beider studien ähneln sich, aber es gibt zwischen icu-rox und loco einige unterschiede zu beachten. die patientengruppe der ersten studie ist sehr groß und heterogen, währen die gruppe der zweiten studie im vergleich deutlich kleiner ist und nur patienten mit ards betrachtet. die patienten aus der loco -studie hatten bereits einen höheren sauerstoffbedarf und wiesen einen schlechteren gasaustausch zu studienbeginn auf (fio ist bereits zu beginn der studie hoch eingestellt). zudem war bei den patienten der loco -studie eine längerdauernde invasive beatmung notwendig. darüber hinaus bedurften insbesondere die patienten in der "konservativen" sauerstoffgruppe häufiger einer bauchlagerung. die kontrollgruppe der loco -studie hatte als zielkorridor eine sauerstoffsättigung (spo ) in höhe ≥ %, während es in der kontrollgruppe der icu-rox-studie kein oberes spo -ziel gab und dies vom jeweiligen arzt abhängig war (je nach untersucher wurde womöglich auch eine spo von % als oberste grenze toleriert). als letztes betrachtet sind die ziele der oxygenierung in der "konservativen" gruppe in beiden studien unterschiedlich. bei icu-rox lagen die spo -zielwerte in der interventionsgruppe bei - %. bei loco lagen die zielwerte bei - % (und korrespondierend niedrigeren pao -bereichen). womöglich waren die patienten mit niedrigeren sauerstoffsättigungen als % in der loco -studie eher hypoxämisch, sodass diese häufiger in die bauchlage verbracht werden mussten. in der icu-rox-analyse waren die oxygenierungsziele beider gruppen vielleicht zu nah beieinander liegend, sodass kein großer unterschied gefunden werden konnte. aus den beiden studien lernen wir, dass es schwierig ist, die optimale oxygenierung für den individuellen intensivpatienten während der beatmung zu generieren und es noch weitere große studien benötigt. wir sollten jedoch eine hyperoxygenierung vermeiden und womöglich das untere ziel der sauerstoffsättigung bei % (pao ca. mm hg) ansiedeln. combes a, fanelli v, pham t et al ( ) feasibility and safety of extracorporeal co removal to enhance protective ventilation in acute respiratory distress syndrome: the supernova study. intensive care med ( ): - [ ] wie wir bereits aus zahlreichen ards-studien wissen, führt die lungenprotektive beatmung mit niedrigen tidalvolumina ( ml/kg idealem körpergewicht) und niedrigen drücken (plateaudruck < cmh o) zu einer geringeren sterblichkeit [ ] . es ist bisher noch nicht geklärt, ob eine ultraprotektive beat-mung mit tidalvolumina von - ml/kg (bezogen auf das ideale körpergewicht) noch schonender ist [ , ] . jedenfalls ist das problem der ultraprotektiven beatmung, dass diese in der regel zu einer schweren hyperkapnie und acidose führt. durch die direkte minimierung des co -gehalts im blut wird eine acidose während einer ultraprotektiven beatmung verhindert. dazu wird die notfallmäßige extrakorporale co -elimination (ecco r) eingesetzt [ , ] . in diesem zusammenhang haben combes et al. eine prospektive, multinationale studie durchgeführt, um die durchführbarkeit und sicherheit der ecco r zur ermöglichung einer ultraprotektiven beatmung bei erwachsenen mit moderatem ards (pao /fio - mm hg) zu bewerten [ ] . der primäre endpunkt war die ermittlung der patienten, die unter einer ecco r eine beatmung mit einem tidalvolumen (vt) von ml/kg erhalten konnten, wobei das paco nicht über % vom ausgangswert ansteigen sollte und der ph-wert bei , gehalten werden konnte. nach einschluss der patienten wurde zu beginn der beatmung das tidalvolumen bei ml/kg eingestellt und der peep passend zu einem plateaudruck von - cmh o titriert. alle patienten erhielten eine tiefe sedierung sowie muskelrelaxierung. die perkutane initiierung der ecco r (unter nutzung eines von den möglichen systemen zur co -eliminierung) erfolgte über die katheterisierung eines venösen gefäßes. anschließend wurde das vt auf ml/kg reduziert und der peep so eingestellt, dass der plateaudruck bei - cmh o gehalten werden konnte. von patienten aus zentren erhielten % eine ultraprotektive beatmung für h (mittelwert vt = , ± , ml/kg; mittelwert plateaudruck pplat = , ± , cmh o) während paco und ph-wert im zielbereich gehalten wurden (mittelwert paco = , ± , mm hg; mittelwert ph = , ± , ). verglichen mit den ausgangswerten war der driving pressure (plateaudruck-peep) signifikant reduziert innerhalb der h ( , ± , cmh o vs. , ± , cmh o; p = , ). bei ( %) patienten wurden ecco r-bedingte komplikationen beobachtet: blutkoagel im bereich der membran ( %), hämolyse ( %), thrombozytopenie ( %) und blutungen ( %). es wurden schwere komplikationen berichtet, wovon durch die extrakorporale co -elimination bedingt waren (massive intrakraniale blutung und katheterassoziierter pneumothorax). diese multizentrische pilotstudie zeigt trotz der geringen patientenanzahl, dass eine ultraprotektive beatmung bei patienten mit moderatem ards mit zusätzlicher etablierung eines ecco r-systems möglich ist. aufgrund der nichtunerheblichen komplikationen im zusammenhang mit ecco r sind randomisierte, kontrollierte studien notwendig, um zu eruieren, ob diese methode der ultraprotektiven beatmung in kombination mit einem ecco r-system als klinisch sinnvoll anzusehen ist. effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial. jama ( ): - [ ] mehr als mio. menschen weltweit erhalten jährlich aufgrund respiratorischer insuffizienz eine invasive beatmungstherapie. die herausforderung dabei besteht nicht nur in der lungenprotektiven therapie, um einen vili zu verhindern, sondern auch in der entwöhnung der beatmungstherapie und schlussendlich der erfolgreichen extubation (weaning). entscheidet sich der intensivmediziner dabei für eine zu frühe extubation, so besteht die gefahr der respiratorischen erschöpfung mit reintubation des patienten. eine verlängerung der mechanischen beatmung birgt wiederum das risiko der ventilatorinduzierten pneumonie, erhöhung der mortalität und weiterer nebenwirkungen. wird die extubation des patienten verzögert, so bedingt dies meist eine vertiefung der sedierung sowie ein erhöhtes risiko für die entwicklung eines delirs [ , ] die beatmungstherapie der patienten auf intensivstation bleibt weiterhin eine herausforderung und sollte individuell betrachtet und durchgeführt werden. der einsatz von muskelrelaxanzien stellt im moderaten bis schweren ards weiterhin eine individuelle therapieoption dar. basierend auf den ergebnissen der acu-rasys-und rose-studien sind muskelrelaxanzien erst einzusetzen, wenn trotz einhaltung aller lungenprotektiver beatmungsmaßnahmen die entwicklung eines vili droht oder die oxygenierung nicht ausreichend ist. sind die patienten unter leichter sedierung synchron mit dem beatmungsgerät, so ist der einsatz von muskelrelaxanzien nicht indiziert. während der beatmungstherapie bei patienten mit ards ist die drivingpressure-messung auch bei beginnender spontanatmung mit assistierten atemhüben von bedeutung. die einstellungen und evaluierung der beatmungspara-meter sollten regelmäßig erfolgen und individuell angepasst werden. die titration des optimalen peep-levels beim patienten mit ards ist weiterhin schwierig und kann durch die messung des Ösophagusdrucks nicht erleichtert werden. die ards-peep-tabellen zur optimierung der oxygenierung bleiben eine günstigere variante der orientierungshilfe zur einstellung des peep-werts. jedoch auch diese bergen die gefahr der Überdehnung oder der atelektraumen bei unsachgemäßer anwendung. obwohl in früheren studien ein vorteil der "konservativen" sauerstofftherapie bei beatmeten patienten gezeigt werden konnte, so zeigt die icu-rox-untersuchung keinen benefit, und die loco -studie zeigt die tendenz zu einer potenziellen schädigung der patienten mit ards. beide studien zeigen, dass es schwierig ist, die optimale oxygenierung für den individuellen intensivpatienten während der beatmung zu generieren und es noch weitere große studien benötigt. eine hyperoxygenierung sollte jedoch vermieden und womöglich das untere ziel der sauerstoffsättigung bei beatmeten patienten bei % angesiedelt werden. die supernova-studie zeigt trotz der geringen patientenanzahl, dass eine ultraprotektive beatmung bei patienten mit moderatem ards mit zusätzlicher etablierung eines ecco r-systems möglich ist. aber der aufwand ist groß, und es muss ein zusätzliches invasives verfahren eingesetzt werden, das den patienten zusätzlich schaden zufügen kann. schließlich clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study empfehlungen zur intensivmedizinischen therapie von patienten mit covid- -s -leitlinie the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak-an update on the status pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- acute respiratory distress syndrome: advances in diagnosis and treatment critical care management of adults with community-acquired severe respiratory viral infection acute respiratory distress syndrome: the berlin definition early neuromuscular blockade in the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network neuromuscular blockers in early acute respiratory distress syndrome mechanical ventilation to minimize progression of lung injury in acute respiratory failure extremelyhightranspulmonary pressureinaspontaneouslybreathingpatientwith early severe ards on ecmo early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: yes quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ards: the breathe criteria mechanical ventilationinduced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling driving pressure is associated with outcome during assisted ventilation in acute respiratory distress syndrome drivingpressureandsurvival in the acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries effectoftitratingpositiveendexpiratory pressure (peep) with an esophageal pressure-guided strategy vs an empirical high peep-fio strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial fifty years of research in ards. setting positive end-expiratory pressure in acute respiratory distress syndrome mechanical ventilation guided by esophageal pressure in acute lung injury higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome conservative oxygen therapy during mechanical ventilation in the icu liberal or conservative oxygen therapy for acute respiratory distress syndrome effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomizedclinicaltrial feasibility and safety of extracorporeal co removal to enhance protective ventilation in acute respiratory distress syndrome: the supernova study low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress syndrome. a systematic review and meta-analysis tidal volume reduction in patients with acute lung injury when plateau pressures are not high lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study tidal volume lower than ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal lower tidal volume strategy (approximately ml/kg) combined with extracorporeal co removal versus 'conventional' protective ventilation ( ml/kg) in severe ards: the prospective randomized xtravent-study effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomizedclinicaltrial outcomes of extubation failure in medical intensive care unit patients incidence of and risk factors for ventilator-associated pneumonia in critically ill patients a comparison of four methods of weaning patients from mechanical ventilation. spanish lung failure collaborative group effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously effectofpostextubationhighflow nasal oxygen with noninvasive ventilation vs high-flow nasal oxygen alone on reintubation among patients at high risk of extubation failure: a randomizedclinicaltrial effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial key: cord- -dii zszf authors: khan, sheharyar; choudry, erum; mahmood, syed uzair; mulla, aisha y; mehwish, syeda title: awake proning: a necessary evil during the covid- pandemic date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: dii zszf the spread of covid- has been exponential throughout the globe. though only a small percentage of infected individuals reach the critical stage of the disease, i.e., acute respiratory distress syndrome (ards), this percentage represents a significant number of patients that can overwhelm the healthcare system. patients presenting with ards need mechanical ventilation, as their lungs are unable to oxygenate blood on their own due to fluid accumulation. one way to manage this excess pressure of fluid build-up around the lung tissues is to relieve the dorsal alveoli by prompting the patient to lie face down on the stomach; this is called awake proning. it is a procedure that is directed towards the recruitment of lung parenchyma when infected with pneumonia or when the condition has worsened into ards. this helps in relieving the pressure from the dorsal lung surface that has markedly higher perfusion than the ventral surface. awake proning delays the use of mechanical ventilation and facilitates the patients with severe ards or severe pneumonia in maintaining the supply of oxygen to the body tissues. since medical institutes are overburdened and limited ventilators are available, awake proning can reduce not only the burden on hospitals but also decrease the need for ventilators. covid- is a respiratory viral illness that is responsible for taking the lives of more than , , people all around the world as of june , . becoming a rampant worldwide phenomenon, the number of patients with covid- rises exponentially on a daily basis [ ] . it is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus- (sars-cov- ) [ ] . the illness that it causes starts with mild symptoms like fever, dry cough, and sore throat and, in several people, with a recent loss in the senses of smell (anosmia) and taste (ageusia) [ ] [ ] . as it progresses, the disease presents with more severe symptoms like viral pneumonia, which causes acute respiratory distress syndrome (ards). ards is a condition of distress in respiration that results in poor ventilation, as well as poor perfusion of oxygen into the alveoli and, therefore, into the bloodstream. this poor perfusion causes hypoxic conditions, and congestive chest pain occurs along with a sense of drowning. the lungs are filled with exudate due to pneumonia and the alveoli start collapsing, which makes the condition even worse. once a patient presents with ards and needs mechanical ventilation via intubation, the survival rate drops from % to % [ ] . to prevent hypoxia and continue the process of gaseous exchange, it is vital that the effect of the exudate filling the lung parenchyma is decreased, and awake proning plays a major role in rescuing the lungs. awake proning limits the lung collapse by making the dorsal alveoli available for gaseous exchange. the patient is made to lie on their stomach, which has been proven to be of value in decreasing the rate of intubation according to several studies [ ] . acute respiratory distress syndrome is a condition that results in pulmonary deficiency and in the case of severe symptoms, a need for mechanical ventilation arises. it is an acute and progressive onset of hypoxemia that is detected by the presence of bilateral infiltrates on the chest x-ray or a computed tomography (ct) scan. ards presents with a marked increase in the vascular permeability of the capillaries in the alveoli. this increased permeability is due to the damage caused to the endothelial layers of the capillaries, which result in an increased fluid passage into the alveolar lumen. apart from vascular tissue damage, the excessive release of factors like sphingosine- phosphate (s p) that binds to its receptor, s p , which regulates vascular permeability. regarding the basic physiology of vascular stability, angiopoietin- (ang- ) attaches to its receptor, tie- , and stabilizes the vascular structure as the blood flows through the capillary bed by the activation of syx and rho a. angiopoietin- (ang- ) competes with ang- to bind with the receptor sites at tie- and promotes the destabilization of the vascular structure. hence, factors like s p and ang- are indicators of ards [ ] . the body's natural inflammatory response and the cells responsible for innate immunity like neutrophils are also responsible for the condition to escalate into ards. upon activation, neutrophils release the molecules that are cytotoxic in nature, like enzymes, bioactive lipids, cytokines, and reactive oxygen species. these molecules, when released in excess, are responsible for cell necrosis and tissue damage. these damaged tissues induce autophagy as well as apoptosis, which are classical markers of ards [ ] . table lists the biomarkers of ards that can be identified in serum [ ] . all the instances mentioned above result in the rapid increase of fluid accumulation inside the thoracic space surrounding the lung tissue, and the fluid presses against the alveoli. the shape of the lungs inside the human body favors heavy perfusion towards the back or dorsal side of the body. there is a comparatively lower rate of perfusion towards the front or ventral side of the body. when a patient is diagnosed with pneumonia or ards, the fluid collected in the thoracic space puts additional pressure on the delicate alveoli, which may lead to alveolar collapse [ ] . in addition to an increase in pressure over alveoli, fluid also hinders efficient gaseous exchange to meet the requirement of the body. together, these factors cause a decreased availability of oxygen for the tissues and results in hypoxemia. hence, the patients diagnosed with pneumonia or ards often present with atelectasis (lung collapse) in the dorsal region. this condition arises because the patient, lying supine, accumulates fluid in the dorsal alveoli, i.e., the region with higher perfusion [ ] . in ards, there is an excessive accumulation of secretion in the peripheral lung parenchyma, which exerts pressure against the fragile alveolar walls and impedes gaseous exchange. a method to redirect this excessive fluid away from the dorsal lung parenchyma is to manage it via awakeproning,whichis majorly directed towards conserving the alveolar structure of the lungs [ ] . the procedure is focused on limiting the collapse of the alveoli and reducing the fluid accumulation on the areas with a higher perfusion rate, i.e., the dorsal region. the prone position is achieved when the patient lies on their stomach or front, this helps in the recruitment of the alveoli previously collapsed into the dorsal surface of the chest cavity [ ] . in prone positioning, the intra-abdominalorgansmoveundergravitationalpull in a downward (gravitational) and forward (toward the thorax) direction,which aimsthe excesspleuralpressure at the ventral region of the alveoli as opposed to the dorsal regionin the case of lying in a supine position. redistribution of the pressure towards the ventral region also helps in preventing the compression of dorsal alveoli and aids in better breathing [ ] . figure illustrates the steps of awake proning. note: reassess the respiratory rate and saturation after minutes of repositioning the patient and later after every to minutes. awake proning is associated with an improved mortality rate after an incident of ards or severe pneumonia. this procedure is noninvasive and provides instant results. in emergency situations where the patient's vitals keep worsening, applying prone positioning helps in improving the oxygen saturation instantly. several studies show that awake proning improves oxygen saturation in merely five minutes [ ] . . it maintains an optimal respiratory rate and enhances the gaseous exchange in a favorable range [ ] . . ventilation stays homogenous throughout the lung parenchyma, and redistribution of the blood flow is improved with higher efficacy, which, in turn, improves the ventilation/perfusion ratio (v/q ratio). . an intrapulmonary shunt prevents the proper oxygenation of blood in the lungs. the areas shunted are prone to hypoxia and may result in tissue damage. by prone positioning, this shunt is reduced and lung compression is decreased. therefore, oxygen levels improve [ ] . . awake proning also helps decrease the accumulation of excess interstitial fluid in the dorsal part of the lungs. lying on the stomach directs the fluid to collect in the ventral region where there is comparatively less perfusion [ ] . . no specialized instruments are needed for the procedure, and it can be done easily in emergency situations [ ] . a recent study conducted in new york regarding the effectiveness of self-proning came out with promising results. the study was based on quick proning of patients that presented with moderate to severe ards after an incident of covid- . the patients were put into the prone positions for about hours a day while the breathing cycles started showing improvements after five minutes of assuming the position of awake proning. fifty patients with confirmed hypoxia were under focus for this study and their median saturation of oxygen in blood was %, which was raised to % after the provision of supplemental oxygen. after five minutes of lying in the prone position, the levels of oxygen saturation were raised to %, and the patients were also put on supplemental oxygen. in this study, intubation was not needed in nearly two-thirds of the admitted patients. these patients were shifted towards the non-invasive procedures of oxygen provision like bi-level positive airway pressure (bipap) and awake proning [ ] . another study focused on patients who were not intubated. these patients were subjected to prone positioning times over the course of treatment. the patients presented with ards and breathing difficulties. the respiratory rate and blood oxygenation were substantially improved, during and after the cycle of pronation and there were patients who had improved breathing after pronation. the blood oxygen levels also improved after the cycles of prone positioning, and endotracheal intubation was avoided in patients with ards, which would have been the only option to opt from if awake proning was not administered [ ] . furthermore, a study had subjects with covid- and severe ards. the median blood oxygen levels were found to be % and after the aid of supplemental oxygen, these levels improved to %. prone position was maintained, and the blood oxygen before and after proning was noted. at five minutes of proning, the levels went up to %. in this study, however, patients failed to respond to the treatment by proning and had to undergo endotracheal intubation. for emergency support, the numbers suggest that proning provided improved levels of oxygen saturation in the patients who would have been treated with endotracheal intubation and mechanical ventilation [ ] . one of the indications of awake proning is the need for quick relief from the dyspneic condition. covid- patients in a critical condition escalate into moderate, severe, or critically severe ards. this calls for the need for a quick fix until their condition stabilizes [ ] . the two types of awake proning are indicated for different situations: a. short-term awake proning: it may have limited use but there are instances when short-term awake proning is the best option to handle the patient's condition. the time period of short proning spans from three hours to eight hours [ , ] . . it is indicated to treat mild to moderate hypoxemia. . it helps in airway drainage and improves refractory maneuvers in relation to atelectasis. . lower lobe atelectasis is most effectively treated with short-term prone positioning. . improved breathing rate and decreased crackles during each breathing cycle can be observed. b. long-term awake proning: it is the most widely used maneuver to administer awake proning and has shown the most significant results. the time period of long-term awake proning spans for more than eight hours. . it is indicated to treat severe hypoxemia. . severe ards is most effectively treated with long-term awake proning. the condition is characterized by a steep decline in blood oxygenation and severe dyspnea indicating loss of efficient breathing. it is the last stage in the development of covid- infection [ ] . awake proning is contraindicated in the following situations [ however, the presence of these contraindications should be balanced with the need for the treatment. the risks associated with awake proning should be considered in relation to the necessity of the procedure at the time of treatment, making it a necessary evil. physicians may encounter a few complications associated with awake proning, as illustrated in a setback of lying prone for an extended period is that it causes pain in the back, neck, and lower limbs. this pain is caused by the body's weight being projected on to the spine. sleeping in a prone position hinders the spine to position itself accurately and leads to a multitude of problems. if the spine remains unstable, the nerves exiting the spinal segment might impinge and cause pain in the area it supplies. this could feel like tingling or numbness and, in extreme cases, may cause severe pain. in rare cases, the airway can be obstructed and it may present as obstructive sleep apnea. it is recommended that patients suffering from ards be advised to acquire a prone position while they are conscious but while falling asleep, a neutral position should be advised [ ] . a covid- patient presenting with severe pneumonia or ards can be managed with awake proning as a supportive treatment to relieve symptoms. awake proning helps in improving oxygenation by the optimization of the lung parenchyma and the recruitment of the alveoli along the dorsal surface with higher perfusion, hence, better ventilation is provided to the body. prone positioning helps in protection against ventilator-induced lung injury (vili), as the need for mechanical ventilation is avoided for some time by the distribution of stress and strain in a homogenous manner throughout the parenchyma of the lungs. the long-term use of awake proning is, however, not indicated for mild and moderate cases of ards. awake proning does not require any special instrumentation and can be done in an emergency situation. it presents itself as a tool that can improve the oxygen saturation of a patient suffering from hypoxemia due to conditions such as ards. with the shortage of ventilators and their high demand during the covid- pandemic, we recommend that each medical institute should invest in or should seek help to acquire prone position comfort cushions or bolsters as they help maintain awake proning rather than opt for expensive ventilators. disclosures covid- ): current status and future perspectives coronavirus disease (covid- ): a perspective from china. radiology. olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid- ): a multicenter european study higher mortality rate in ventilated covid- patients in large sample lower mortality of covid- by early recognition and intervention: experience from jiangsu province angiopoietin signaling in the vasculature interactions between mechanical and biological processes in acute lung injury biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise the gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes? prone positioning in severe acute respiratory distress syndrome self-proning in covid- prone position in acute respiratory distress syndrome. rationale, indications, and limits fifty years of research in ards. gas exchange in acute respiratory distress syndrome prone positioning combined with high-flow nasal cannula in severe noninfectious ards prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: a retrospective study early self-proning in awake, non-intubated patients in the emergency department: a single ed's experience during the covid- pandemic prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis role of the heart in the loss of aeration characterizing lower lobes in acute respiratory distress syndrome prone positioning improves survival in severe ards: a pathophysiologic review and individual patient meta-analysis prone position and mechanical ventilation is it bad to sleep on your stomach in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. key: cord- - jiycem authors: tarazan, nehal; alshehri, moayad; sharif, sameer; al duhailib, zainab; møller, morten hylander; belley-cote, emilie; alshahrani, mohammed; centofanti, john; mcintyre, lauralyn; baw, bandar; meade, maureen; alhazzani, waleed title: neuromuscular blocking agents in acute respiratory distress syndrome: updated systematic review and meta-analysis of randomized trials date: - - journal: intensive care med exp doi: . /s - - - sha: doc_id: cord_uid: jiycem purpose: existing clinical practice guidelines support the use of neuromuscular blocking agents (nmba) in acute respiratory distress syndrome (ards); however, a recent large randomized clinical trial (rct) has questioned this practice. therefore, we updated a previous systematic review to determine the efficacy and safety of nmbas in ards. methods: we searched medline, embase (october to july ), the cochrane (central) database, and clinical trial registries (clinicaltrials.gov, isrctn register, and who ictrp) for rcts comparing the effects of nmba as a continuous infusion versus placebo or no nmba infusion (but allowing intermittent nmba boluses) on patient-important outcomes for adults with ards. two independent reviewers assessed the methodologic quality of the primary studies and abstracted data. results: seven rcts, including four new rcts, met eligibility criteria for this review. these trials enrolled patients with moderate to severe ards at centers in the usa, france, and china. all trials assessed short-term continuous infusions of cisatracurium or vecuronium. the pooled estimate for mortality outcomes showed significant statistical heterogeneity, which was only explained by a subgroup analysis by depth of sedation in the control arm. a continuous nmba infusion did not improve mortality when compared to a light sedation strategy with no nmba infusion (relative risk [rr] . ; % ci . – . ; moderate certainty; p = . ). on the other hand, continuous nmba infusion reduced mortality when compared to deep sedation with as needed nmba boluses (rr . ; % ci . – . ; low certainty; p = . ). continuous nmba infusion reduced the rate of barotrauma (rr . ; % ci . – . , moderate certainty; p = . ) across eligible trials, but the effect on ventilator-free days, duration of mechanical ventilation, and icu-acquired weakness was uncertain. conclusions: inconsistency in study methods and findings precluded the pooling of all trials for mortality. in a pre-planned sensitivity analysis, the impact of nmba infusion on mortality depends on the strategy used in the control arm, showing reduced mortality when compared to deep sedation, but no effect on mortality when compared to lighter sedation. in both situations, a continuous nmba infusion may reduce the risk of barotrauma, but the effects on other patient-important outcomes remain unclear. future research, including an individual patient data meta-analysis, could help clarify some of the observed findings in this updated systematic review. acute respiratory distress syndrome (ards) is a life-threatening condition that complicates a variety of critical illnesses, including sepsis, pneumonia, and trauma [ ] . in a recent international observational study involving , patients, % of all patients admitted to the intensive care unit (icu) and % of mechanically ventilated patients had ards [ ] . importantly, the mortality among patients with severe ards was . % [ ] . patients who survive ards are at high risk for cognitive decline, depression, posttraumatic stress disorder, and persistent muscular weakness [ , ] . the priorities in the care of patients with ards are identifying and treating the underlying cause, along with supportive therapies to prevent further lung injury. most recent advances in the treatment of ards focus on the latter, i.e., minimizing ventilator-associated lung injury through the application of low tidal volumes, high levels of positive end-expiratory pressure (peep), prone ventilation, and neuromuscular blockade [ ] [ ] [ ] . of the pharmacologic treatment options for adults with ards, only neuromuscular blocking agents (nmbas) have demonstrated a mortality benefit in patients with severe ards [ ] . previous trials showed that a continuous nmba infusion for h improves survival in patients with moderate to severe ards [ ] . the mechanism of this benefit may be multifaceted, but likely involves a reduction in patient-ventilator desynchrony and, in turn, ventilator-associated lung injury [ ] . nmbas also reduce the work of breathing, and may reduce the accumulation of alveolar fluid [ ] , decrease pulmonary and systemic inflammation, and decrease oxygen consumption [ ] . a multicenter observational study from centers in canada and saudi arabia suggested that % of critically ill adults with moderate to severe ards receive nmba therapy [ ] . results of a recent multicenter clinical trial have challenged current practice recommendations. the reevaluation of systemic early neuromuscular blockade (rose) trial randomized patients with moderate or severe ards to receive either deep sedation with a continuous cisatracurium infusion (an nmba), or lighter sedation with short intermittent nmba infusions only when deemed necessary by the attending physicians [ ] . the trial stopped early for perceived futility [ ] . given these results and the possible publication of other rcts, we undertook an updated systematic review and meta-analysis to clarify the effects of nmbas on patient-important outcomes for adults with ards. the results of this systematic review will help inform practice guidelines [ ] . this review followed an internal protocol and adhered to the preferred reporting items for systematic reviews and meta-analyses (prisma) reporting guidelines [ ] . eligible studies met all of the following criteria: ( ) the design was a parallel-group rct; ( ) the population was adults with ards of any severity; ( ) the intervention included any continuous nmba infusion, at any dose or duration, compared to placebo or no continuous nmba infusion but allowing the use of as needed nmba boluses; ( ) outcomes included any of: mortality at days, icu discharge, or hospital discharge (truncated at days); long-term outcomes (physical function at months; quality of life at months; cognitive function at months); icu-acquired weakness; duration of mechanical ventilation; ventilator-free days (vfds); icu or hospital length of stay; barotrauma (including pneumothorax, pneumomediastinum, pneumatocele, or subcutaneous emphysema); or changes in oxygenation measured by using the ratio of arterial oxygen partial pressure to fractional inspired oxygen (po /fio ratio). we updated our prior search strategy and electronically searched medline, embase (october to july ), the cochrane (central) database, and clinical trial registries (clinicaltrials.gov, isrctn register, and who ictrp). the search strategy can be found in the electronic supplementary material (esm). two reviewers independently screened titles and abstracts in duplicate. the same reviewers assessed the full-text of potentially eligible articles and abstracted relevant data from eligible studies. a third reviewer resolved disagreements between reviewers. for each study, reviewers used the cochrane handbook risk of bias tool to judge the adequacy of randomization, concealment, blinding, and outcome-data completeness, and to check for selective outcome assessment and other possible sources of bias [ ] . they judged the risk of bias in each of these domains as high, low, or unclear. the overall risk of bias for an individual study was categorized as low when the risk of bias was low in all domains; unclear when the risk of bias was unclear in at least one domain, with no high-risk domains; or high when the risk of bias was high in at least one domain. we used revman . software to perform the analyses. if appropriate, we pooled the effect estimates across studies using a random-effects model with mantel-haenszel weighting and the methods of dersimonian and laird [ ] . if less than rcts contributed to the analysis, we used a fixed effect model instead. we generated summary estimates of relative risk (rr) for dichotomous outcomes and mean differences (mds) for continuous outcomes, each with associated % confidence intervals (cis). we assessed for heterogeneity between studies using the chi statistic (p < . indicating substantial heterogeneity) and the i statistic (> % indicating substantial heterogeneity), and by inspecting forest plots. we identified less than studies; therefore, we did not use funnel plots or conventional statistical methods to assess for publication bias [ ] . we stipulated a number of pre-planned, a priori exploratory analyses to assess potential reasons for differing results (if any) across studies. we hypothesized that the following factors might generate estimates of greater benefit: high or unclear risk of bias (versus low), more severe hypoxemia at baseline (po /fio < , versus to ), targeting deep sedation in the control group (versus light sedation) as defined by individual studies, high peep strategy as defined by individual studies (versus low peep), early (within h of intubation) initiation of nmba infusion (versus late), the use of prone ventilation (versus not), duration of nmba infusion (< h versus > h), and the cause of ards (sepsis versus non-sepsis related ards). when significant statistical heterogeneity was present in the pooled analysis and was explained by a subgroup analysis, we reported the subgroup estimates separately as the primary results. we used the grading of recommendations assessment, development and evaluation (grade) approach to assess the certainty of evidence for each outcome [ ] . reviewers assessed the impact of risk of bias, inconsistency, indirectness, imprecision, and publication bias on the certainty of the evidence. the certainty of evidence can be classified as very low, low, moderate, or high. after screening titles and abstracts, reviewers assessed full-texts for eligibility. four new trials were eligible for this review (fig. ) , resulting in a total of trials ( patients) [ , , [ ] [ ] [ ] [ ] [ ] . of the new trials, the largest was conducted in the usa (n = ), with one in france (n = ), and the other two in china (n = and n = ). the former two trials studied cisatracurium, and the latter two studied vecuronium. all seven studies were specifically designed to investigate the effects of a continuous nmba infusion on gas exchange, inflammatory markers, and/or clinical outcomes in patients with ards. four studies used a -h infusion of cisatracurium [ , , , ] , whereas the other three studies did not pre-specify a duration for nmba infusions. weight-based dosing of cisatracurium was used in two of the studies [ , ] , and a fixed high dose was used in another three studies ( mg bolus, followed by a continuous infusion of . mg per hour) [ , , ] . the two studies of vecuronium used the following maintenance doses, without boluses being reported: . mg/kg/h and μg/ kg/min [ , ] . all studies reported -day mortality; other reported outcomes varied by study. the interventions used in the control arm varied between studies; three studies used a -h infusion of placebo (normal saline) with deep sedation, an additional three studies did describe the control they used, and one study used light sedation in the control group. five studies allowed the use of nmba boluses as needed in the control group [ , , , , ] . the proportion of patients receiving nmba boluses in the control group ranged between . % and % across studies. deep sedation was defined as a ramsay score of , and light sedation was defined as a ramsay score of - [ ] , richmond agitation-sedation scale (rass) score of to − , and/or a riker score of to . in total, patients included in this review received concomitant corticosteroid therapy during the study period of nmba infusion. the characteristics of the included studies are presented in table . all studies were judged to be at low risk of bias except that were at high risk of attrition and reporting bias [ , ] . seven studies ( patients) reported on mortality and five reported the depth of sedation. of note, one trial reported -day mortality; we included this trial in the analysis of -day mortality as both time-points reflect a short-term mortality outcome that is fairly similar [ ] . the use of nmba infusion was associated with lower -day mortality (rr . ; % ci . - . ; i = %; low certainty; p = . ). however, the effect on -day mortality was not statistically significant (rr . , % ci . - . , i = %; low certainty; esm; p = . ). due to significant clinical and statistical heterogeneity, we have more certainty in the effect estimates from the subgroup analysis of light versus deep sedation; therefore, the analysis separating studies by depth of sedation are the more trustworthy estimates for mortality outcomes (fig. ) . nmba infusion reduced the risk of barotrauma (rr . ; % ci . - . , i = %; moderate certainty; p = . ; fig. ), but did not affect vfd at days (md . ; % ci- . , . , i = %, p = . ; low certainty) or the duration of mechanical ventilation (md − . ; % ci − . , . ; i = %; low certainty; p = . ; esm). only one rct reported icu length of stay, and this did not differ between the two groups (md − . days; % ci − . - . ; p = . ; low certainty). the use of nmba infusion may increase the risk of icu-acquired weakness; however, the % ci included no difference (rr . ; % ci . , . , i = %; moderate certainty; p = . ; fig. ). the pooled analysis suggested better pao /fio in the nmba group at , , and h, but only the result at h was statistically significant (esm). the rose trial reported on long-term outcomes; the use of nmba did not improve long-term outcomes ( table ) . we performed four pre-planned subgroup analyses to investigate the source of heterogeneity for the primary outcomes (esm). the subgroup analysis by depth of sedation in the control arm indicated the presence of subgroup difference (p-interaction = . , i = %), showing that the effect estimate for hospital mortality was larger in the subgroup that used deep sedation in the control arm (rr . ; % ci . , . ; p = . ), compared to light sedation (rr . ; % ci . , . ; p = . ) (fig. ) . due to this subgroup difference indicating a different intervention being studied (paralysis and deep sedation versus light sedation), we performed a post hoc sensitivity analysis without the rose trial. the results of other subgroup analyses can be found in the (esm). we were not able to conduct subgroup analyses by proning intervention, peep level, or cause of ards because of lack of subgroup data, hopefully these important subgroup analyses can be assessed in a future individual patients' data meta-analysis. in the post hoc analysis excluding the rose trial, trials ( patients) reported on mortality. the use of nmba infusion was associated with lower -day mortality (rr . ; % ci . - . ; i = %; low certainty; p < . ) and hospital/ -day mortality (rr . ; % ci . - . ; i = %; low certainty; p = . ). in addition, nmba infusion reduced the risk of barotrauma (rr . ; % ci . - . , i = %; low certainty; p = . ) and increased vfd at days (md . ; % ci . , . , i = %; low certainty; p = . ). table summarizes the certainty of evidence for each outcome. overall, we judged the certainty of evidence as moderate or low for -day mortality. the certainty of evidence was moderate for barotrauma, and for icu-acquired weakness, but low for other outcomes. this updated systematic review and meta-analysis included trials (n = ). for mortality, we found significant clinical and statistical heterogeneity that precluded we downgraded the certainty of evidence by two levels for very serious inconsistency, although the i was %, there is inconsistency between the results of the most recent and large rct (rose trial) and the rest of the studies, which was not explained by any of the subgroup analyses, difficulty in reconciling and explaining the differences in results have lead us to lower our certainty in the estimates by levels f the rcts reported deaths which is enough for us to consider the pooled estimates precise g we downgraded the certainty of evidence by two levels for very serious inconsistency, although the we downgraded the certainty of evidence by one level for serious imprecision; the ci included both harm and benefit, and the number of patients who were included the analysis at months is small (< % of the original sample size) n we downgraded the certainty of evidence by two levels for serious imprecision; the ci included both substantial harm and small/no benefit. in addition, the number of events was small (n = events) o we downgraded the certainty of evidence by one level for serious imprecision; the ci included both substantial harm and trivial benefit p we downgraded the certainty of evidence by one level for serious indirectness, the rose trial which contributed to % of the weight in the analysis for this subgroup, included patients with ards and p/f > not q we downgraded the certainty of evidence by one level for serious imprecision; the ci included both substantial benefit and small harm r we downgraded the certainty of evidence by one level for serious inconsistency; although the i = % the forest plot showed that the results of the rose trial are inconsistent with the results of other trials s we downgraded the certainty of evidence by one level for serious indirectness, the rose trial which contributed to % of the weight in the analysis for this subgroup, included patients with ards and p/f < not only < t we downgraded the certainty of evidence by two levels for very serious inconsistency; the we downgraded the certainty of evidence by one level for serious imprecision; the number of events was small and the confidence interval although did not include , it included substantial variation in benefit v although i = %, we did not downgrade for inconsistency w we downgraded the certainty in the evidence by two levels for very serious imprecision; the ci included extreme benefit and harm x we downgraded the certainty of evidence by one level for serious indirectness, the intervention, and control in the rose trial differed from other trials (early nmba and targeting light sedation) y we downgraded the certainty of the evidence by one level for serious imprecision; the ci included both benefit and harm z we downgraded the certainty in the evidence by one level for serious imprecision; the ci included both trivial and moderate benefit meta-analysis of all trials. it appears that a -h infusion of nmba in moderate-tosevere ards probably improves -day mortality when compared to using a deep sedation strategy, but has no important effect on -day mortality when compared to a lighter sedation strategy. a -h infusion of nmba reduces the risk of barotrauma compared to no infusion; however, it did not affect the duration of mechanical ventilation, vfd, icu length of stay, icu-acquired weakness, adverse events, and long-term outcomes. the included studies need to be interpreted in the appropriate methodological context as sedation type and depth, peep strategy, and time to enrolment differed. first, all studies, with the exception of the rose trial, used deep sedation in both arms which was frequently used in that era; the control arm in the rose trial received lighter sedation. this raises the question of unequal comparators across the included studies as evidence suggests that deep sedation may be associated with increased mortality [ ] . second, all the included studies used a low peep strategy except for the rose trial, which used a higher peep strategy ( . [ , ] . given these differences, the rose trial may be too dissimilar to pool with the other studies. in the subgroup analysis by depth of sedation, the effect estimate for hospital mortality was larger in the subgroup that used deep sedation in the control arm (rr . ; % ci . , . ), compared to light sedation (i.e., only the rose trial). nmba infusion with deep sedation may be superior to deep sedation without paralysis, but not better than light sedation alone. the results of the rose trial diverged from the results of published studies. one possible explanation is the difference in control arms (light sedation vs deep sedation) or the timing of use of nmba (early vs late). other factors may have led to inconsistency in the results and future individual patient data meta-analysis could help shed some light on these issues. lastly, it is possible that the benefit observed in older trials with nmba arm may not be due to the use nmba, but instead a detrimental effect of deep sedation in the control arm. a recent meta-analysis on this topic drew a different conclusion [ ] . hua et al. reported that an nmba infusion in ards reduces -and -day mortality, barotrauma, and improves oxygenation at h. however, authors only included of the trials, thus less comprehensive. furthermore, authors did not address the statistical heterogeneity of their results; therefore, relaying a message that nmba infusion is beneficial in any context, which we consider an inappropriate interpretation of the literature. similar to the findings of our previously published review [ ] , we found a significant, and more precise, reduction in barotrauma with the use of nmba infusion. there are several physiologic hypotheses for this finding. one possible mechanism is by minimizing swings in transpulmonary pressures with spontaneous breathing, known as the pendelluft phenomenon [ , ] . an additional mechanism is by improving patient-ventilator synchrony. studies that assessed ventilator dyssynchrony using an esophageal balloon showed that the use of nmba improves patientventilator interaction [ , ] . in this meta-analysis, the pooled data demonstrate improvement in oxygenation as shown by the increasing pao /fio ratio at h post-randomization. the change is modest and may not be clinically important. however, a careful review of previous studies suggests that the maximum increase in pao /fio happens in day - which might explain the incremental increase in pao /fio at h [ , ] . the notion that nmbas improve hypoxemia among those with moderate to severe ards has been supported by clinical studies but the mechanism remains unclear [ , ] . some of the proposed mechanisms include improved ventilator synchrony, decreased work of breathing, facilitation of lung protective strategy, better lung recruitment, and improved lung compliance. with regards to the safety of nmba infusion use, this review did not detect an increase in the rate of icu-acquired weakness with nmba infusion (rr . ; % ci . , . ). the incidence of icu-acquired weakness in ards patients, in general, approximates % [ ] . previous studies failed to show a clear association between nmba use and the development of icu-acquired weakness [ ] . moreover, the use of corticosteroids, a clear confounder for icu-acquired weakness, was similar in both groups among the included studies. this re-assuring result could also be explained by the fact that nmbas were used for a short duration in all of these studies. recently, several reviews were published on this topic [ , , ] . however, all have ignored the statistical and clinical heterogeneity between trials and performed metaanalysis of all trials combined. therefore, yielding potentially misleading conclusions. in addition, most published reviews missed relevant trials. this review has noteworthy strengths including adherence to a review protocol, a comprehensive literature search, duplicate independent judgements about study eligibility and risk of bias, inclusion of non-english published studies, and the use of subgroup analyses to test the robustness of the data. there are several important limitations of the results. first, we were unable to assess for publication bias because of the limited number of included studies. second, the open-label design in three studies may have also influenced the measurement of secondary outcomes. third, two of the included studies, contributing . % of the weight in this meta-analysis, used vecuronium instead of cisatracurium; an observational study found cisatracurium to be associated with better outcomes [ ] . lastly, as with any subgroup analysis, the results should interpreted with great caution, we can only speculate about why the results of the rose trial differed from prior trials, as many factors, measured or unmeasured, may have influenced the results. in summary, this review suggests that the impact of nmba infusion on mortality depends on the strategy used in the control arm, showing reduced mortality when compared to deep sedation, but no effect on mortality when compared to lighter sedation. although, nmbas reduce barotrauma, their effect on other outcomes remains unclear. future research, including an individual patient data meta-analysis, could help clarify some of the observed findings in this updated systematic review. acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries recovery and outcomes after the acute respiratory distress syndrome (ards) in patients and their family caregivers functional disability years after acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials neuromuscular blockers in early acute respiratory distress syndrome neuromuscular blocking agents in ards management of acute respiratory distress syndrome and refractory hypoxemia. a multicenter observational study early neuromuscular blockade in the acute respiratory distress syndrome intensive care medicine rapid practice guidelines (icm-rpg): paving the road of the future relationship-based predictors of sexual risk for hiv among msm couples: a systematic review of the literature cochrane bias methods g, cochrane statistical methods g ( ) the cochrane collaboration's tool for assessing risk of bias in randomised trials meta-analysis in clinical trials bias in meta-analysis detected by a simple, graphical test grade: an emerging consensus on rating quality of evidence and strength of recommendations effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome clinical study of early use of neuromuscular blocking agents in patients with severe sepsis and acute respiratory distress syndrome effects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome to retain spontaneous breathing or eliminate spontaneous breathing with neuromuscular blockers in acute respiratory distress syndrome patients? practice patterns and outcomes associated with early sedation depth in mechanically ventilated patients: a systematic review and metaanalysis neuromuscular blockers in the acute respiratory distress syndrome: a meta-analysis fifty years of research in ards. spontaneous breathing during mechanical ventilation. risks, mechanisms, and management spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury quantifying unintended exposure to high tidal volumes from breath stacking dyssynchrony in ards: the breathe criteria a comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients clinical testing of new drugs in psychiatry critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis risk factors for the development of polyneuropathy and myopathy in critically ill patients systematic evaluation of neuromuscular blocking agents on prognosis of patients with moderate to severe acute respiratory distress syndrome validation of neuromuscular blocking agent use in acute respiratory distress syndrome: a meta-analysis of randomized trials an observational study of the efficacy of cisatracurium compared with vecuronium in patients with or at risk for acute respiratory distress syndrome supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file : table s : search strategy. table s : risk of bias assessment. table s : subgroup analyses for hospital mortality outcome. figure s : pooled mortality outcome. figure s : duration of mechanical ventilation. figure s : oxygenation at , , and hours. figure s : hospital mortality subgroup analysis by severity of ards. figure not applicable.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -oujgcciq authors: gupta, ena; awsare, bharat; hiroshi, hitoshi; cavarocchi, nicholas; baram, michael title: don’t drive blind: driving pressure to optimize ventilator management in ecmo date: - - journal: lung doi: . /s - - -y sha: doc_id: cord_uid: oujgcciq introduction: driving pressure (dp) while on ecmo has been studied in acute respiratory distress syndrome (ards) but no studies exist in those on ecmo without ards. we aimed to study association of mortality with dp in all patients on ecmo and compare change in dp before and after initiation of ecmo. methods: consecutive patients placed on ecmo either veno-arterial ecmo or veno-venous ecmo between august and february were reviewed. the outcomes were compared based on dp before and after ecmo initiation. results: a total of patients were included: ( %) had ards while ( %) did not. there were individuals for whom dp was available, ( %) had a decrease in dp, whereas ( %) had an increase in dp and ( %) had no change in dp after ecmo initiation. those with an increase in dp had a higher initial peep ( vs cm h( )o, p < . ) and a higher peep decrease after ecmo ( . cm h( )o vs by . cm h( )o, p < . ). those with an increase in dp had a significantly longer stay on ecmo than those without (p = . ). on multivariable analysis, higher dp h after ecmo initiation was associated with an increase in -day mortality (or . , % ci . – . , p ≤ . ). conclusion: a significant proportion of patients experienced an increase in driving pressure and decrease in compliance after initiation of ecmo. higher driving pressure after initiation of ecmo is associated with increased adjusted -day mortality. individualized ventilator strategies are needed to reduce mechanical stress while on ecmo. the past decade has seen an increased utilization of extracorporeal membrane oxygenation (ecmo) as a life sustaining strategy for respiratory and/or cardiac failure [ ] . veno-venous (vv)-ecmo is used to provide temporary gas exchange support in patients with primary respiratory failure and preserved cardiac function. however, veno-arterial (va)-ecmo is used for temporary circulatory assistance in patients with cardiogenic shock or refractory cardiac arrest. despite the increasing use, optimal management of mechanical ventilation on ecmo is not well established [ ] . research has focused on indications, timing, and outcomes in patients requiring ecmo; however, there are no large randomized control trials focusing on a preferred mechanical ventilatory strategy during ecmo. ecmo support theoretically allows for a reduction in intensity of mechanical ventilation. the resultant decrease in lung stress and strain permits lung rest with potentially improvement in outcomes. ultra-low tidal volume ventilation for lung protection is well accepted as best practice during ecmo [ ] . however, how best to achieve this remains unclear. an international survey of all elso-registered ecmo centers showed a huge variability in the approach to mechanical ventilation during ecmo for acute respiratory distress syndrome (ards) [ ] . the majority of these centers ( %) reported "lung rest" to be the primary goal of mechanical ventilation, whereas % reported "lung recruitment" to be their ventilation strategy. various trials of ecmo have also used variable settings in both the treatment and control arms. this variability may impact outcomes in ecmo-supported patients. there has been mounting evidence of the direct relationship of mechanical power applied to the lung and worsening injury [ ] . however, a safety limit or the ideal titration method is unclear. in ards, driving pressure (dp) has emerged as a target to adjust tidal volume and peep to limit cyclic and dynamic strain during mechanical ventilation. several retrospective studies following the initial analysis by amato et al. have found dp as the variable that is most associated with mortality in ards [ ] . even though there are no prospective studies for dp as a target for ventilator management, it has consistently been replicated, is physiologically sound and easily measured at the bedside, making dp an increasingly accepted target for monitoring during mechanical ventilation in ards. however, dp while on ecmo has not been well studied. one retrospective study of ards patients by cheu et al. has shown that dp during first days of ecmo initiation was an independent predictor of mortality [ ] . also, even though dp is a term defined for ards, individuals requiring va-ecmo support for cardiac failure are also at risk for atelectrauma and barotrauma, and dp may play a role in the ventilation in the setting of pulmonary edema due to acute cardiac failure. prolonged mechanical ventilation while on ecmo support makes this group highly susceptible to ventilator-induced lung injury. there are no studies evaluating role of driving pressure in this subset of ecmo patients. we aimed to study driving pressures before and after initiation of ecmo to compare groups with increase and decrease in driving pressure and their outcomes. we also aimed to study association of dp with mortality in patients on both va-and vv-ecmo. we hypothesized that a shift to ecmo would lead to a decrease in driving pressure as it allows for ultra-lung protective ventilation. in conjunction, higher driving pressure while on ecmo would be associated with higher mortality. a retrospective study was performed including all the patients placed on either va-or vv-ecmo between august and february at our tertiary care referral center. patients who were cannulated at an outside facility and transferred to our hospital were also included. those who had ecmo duration shorter than h from cannulation were excluded in this study. the local institutional review board for human research approved this study (irb # d ) and the need for informed consent was waived due to the retrospective nature of the study. before consideration of ecmo initiation, all patients were sedated and ventilated with lung protective ventilation based on the mechanism of their disease process, arterial blood gas, and ventilator mechanics. the decision to initiate ecmo was made by the treating intensive care specialist [ ] . majority of patients received the rotaflow pump (n = , %), whereas ( . %) received biomedicus and ( . %) received the cardiohelp pump for ecmo cannulation. initial mechanical ventilator setting protocol after ecmo support was as follows: tidal volume - ml/ kg pbw; peep - cm h o; peak inspiratory pressure - cm h o; respiratory rate - breaths per minute; and fio adjusted to maintain arterial oxygen saturation above %. plateau pressure was measured by performing an end inspiratory hold maneuver on the ventilator. dp was calculated as the plateau pressure minus peep. static respiratory system compliance was measured by tidal volume divided by dp. murray score was calculated before and after ecmo initiation to stratify severity of acute lung injury [ ] . data were collected retrospectively on baseline characteristics, comorbidities, ards status, severity of illness score like apache ii score among all included ecmo patients. information regarding the ecmo circuit and ventilation parameters before and after initiation of ecmo was also recorded. data collected included duration on ecmo, death on ecmo, status at hospital discharge, and status at days after termination of ecmo. all individuals who had dp measured both before and after initiation of ecmo were identified. among those individuals, change in driving pressure was calculated as dp after ecmo minus dp before ecmo. group a was defined as those who had an increase in dp and group b was defined those who had a decrease in dp h after initiation of ecmo. those with no change in driving pressure were not included in this analysis. we described baseline characteristics of all patients on ecmo by ards status. categorical variables were reported as numbers (percentages) and continuous variables as means ± standard deviation. single-variable comparison was performed by student t test for continuous variables and chisquare or fisher exact tests for categorical variables. we then compared ventilatory parameters before and after initiation of ecmo by ards status. we performed single-variable and multivariable logistic regression analyses to evaluate association of driving pressure on ecmo with -day mortality in all patients. known risk factors for mortality were included in the regression model for adjustment. we adjusted for age, sex, va/vv-ecmo, days in the hospital before ecmo initiation, steroid use before ecmo, and cardiac arrest. odd's ratio (or) was expressed with % confidence interval (ci) and p value less than . was considered to be significant. we also performed comparative analyses of characteristics and outcomes between groups a and b. analyses were conducted in stata . (stat corp, college station, texas). a total of patients including ( . %) with ards and ( . %) with no ards were reviewed. a majority of ards patients (n = , . %) were on vv-ecmo and a majority of non-ards patients (n = , . %) were on va-ecmo. a schematic distribution of the study population is shown in fig. . the indication for ecmo initiation is listed in table for both va-and vv-ecmo. the patient's characteristics are shown in table based on the presence or absence of ards. patients with ards were younger and had a higher bmi. no difference seen in apache ii score between those with ards and without ards. before staring ecmo, individuals were ventilated with an average peep of . cm h o and average plateau pressure of . cm h o. both plateau pressure and peep were higher in those with ards than those without ards before initiation of ecmo as shown in table . plateau pressure and peep decreased significantly after initiation of ecmo in both ards (p < . ) and non-ards individuals (p = . ). however, dp showed no change in both ards and non-ards after initiation of ecmo. murray score among those without ards was . ± . before ecmo and . ± . after ecmo indicating a mild/moderate lung injury. further comparisons of ventilatory parameters before initiation of ecmo and h after ecmo among ards and non-ards patients are shown in table . overall outcomes in the entire cohort of ecmo patients comparing those with ards and those without ards are shown in table . the overall -day mortality of the entire study cohort was %. the -day mortality was higher in those without ards as compared to those with ards ( % vs %, p = . ). in single-variable analysis, higher dp on ecmo was associated with an increase in odds of -day mortality (or . , % ci . - . , p = . ) among all ecmo patients. this association was significant among those with ards (or . , % ci . - . , p = . ) and those without ards (or . , % ci . - . , p = . ). on multivariable analysis, higher dp on ecmo was significantly associated with an increase in mortality after adjusting for age, sex, va/vv-ecmo, days in the hospital before ecmo initiation, steroid use before ecmo, cardiac arrest (or . , % ci . - . , p ≤ . ). among the individuals for whom dp was available both before and after ecmo, group a (those with increase in dp) consisted of patients ( %), group b (those with decrease in dp) consisted of patients ( %), and the rest ( %) had no change in dp after ecmo initiation. table shows comparisons of the groups of the patients. group a had ( %) patients with ards and ( %) without ards as compared to ( %) with ards and ( %) without ards in group b. group a had a significantly longer stay on ecmo than group b ( ± days in group a vs ± . days in group b, p = . ). this trend was similar among those with ards ( ± days in group a vs ± . days in group b, p = . ) and those without ards ( ± days in group a vs ± . days in group b, p = . ). death on ecmo and -day mortality was not significantly different between the two groups (table ). in this study, % of patients had an increase in driving pressure (group a) after initiation of ecmo. these patients were more likely to be on vv-ecmo as compared to va-ecmo. they also had a significantly higher drop in peep as compared to those in group b (p < . ). all patients on ecmo in our institution were ventilated at a tidal volume of cc/kg ibw. the increase in driving pressure after ecmo is likely related to a protocolized application of ventilator settings including lower peep after initiation of ecmo. this implies that those maintained on high peep setting before ecmo were also ventilated with peep between and cm h o leading to decrease in compliance and increase in driving pressure. both groups had a similar initial static compliance, but group a had a lower compliance after ecmo. this decrease in compliance is likely due to an increase in atelectasis and decrease in lung recruitment. even though ultra-lung protective ventilation while on ecmo is protective against barotrauma, there may be an increased risk of atelectrauma due to under-recruitment. alveolar o tension decreases rapidly in an atelectatic lungs [ ] leading to alveolar hypoxia, a potent inducer of lung inflammation [ ] . atelectasis can therefore lead to worsening of ventilator-associated lung injury. these factors apply to patients on vv-or va-ecmo. in our study, those without ards were also noted to have a decreased compliance and an elevated murray score. patients on va-ecmo have risk factors including cardiogenic pulmonary edema, postoperative lung damage, and thoracic compliance reduction after cardiac surgery making them susceptible to worsening lung injury and ards. hence, atelectrauma can have deleterious consequences in both ards and non-ards patients. in this study, those with an increase in driving pressure after ecmo had a significantly longer length of ecmo stay as compared to those with a decrease in driving pressure. along with the mechanisms of lung injury and atelectrauma described above, it is also possible that those with underrecruitment have slower weaning due to worse oxygenation on weaning trials and also worse appearance of radiological abnormalities due to atelectasis impacting decision to wean by physicians. although this group had higher initial peep which could represent higher severity of illness, initial compliance was similar in both groups and decreased after ecmo in this group with an increase in driving pressure. this highlights the importance of individualizing peep for adequate recruitment especially for those with severe disease requiring high initial levels of peep. some patients especially those on va-ecmo and right heart failure can be adversely affected by high peep [ , ] . caution must be experienced in these patients and merits of high peep must be balanced with deleterious effects of positive pressure on right heart. on the other hand, patients with left heart failure on va-ecmo who have a propensity for pulmonary edema may benefit from higher peep [ ] . this further supports the fact that if ultra-lung protective ventilation is applied it should be applied with higher peep [ ] . a recent study showed that near apneic ventilation in a pig model of acute lung injury supported by ecmo when compared to conventional protective ventilation decreased driving pressure by % and reduced mechanical power times [ ] . this resulted in less histologic lung injury and metalloproteinases activity as compared to conventional protective ventilation or non-protective ventilation. therefore, reducing intensity of mechanical ventilation by reducing mechanical power and driving pressure is essential for prevention of ventilator-induced lung injury [ , ] . in our study, a higher driving pressure on ecmo was an independent predictor of -day mortality in both unadjusted and adjusted analysis among all patients on ecmo. driving pressure has previously been shown to be an independent predictor of mortality in ards patients [ ] , however, has not been evaluated in non-ards patients. pham and colleagues also showed, in a cohort of patients with influenza a(h n )-induced ards, that a higher plateau pressure on the first day of vv-ecmo for acute respiratory failure was significantly associated with icu death (odds ratio = . , % confidence interval = . to . , p < . ) [ ] . our study further demonstrates that ventilation during ecmo may have an impact on mortality in both ards and non-ards patients. overall mortality among all patients with ecmo was %, higher among non-ards ( %) than those with ards ( %). this is because the non-ards patients include patients on va-ecmo due to post-cardiotomy failure, acute myocardial infarction, and post-cardiac arrest including those who received cardiopulmonary resuscitation ( %) before ecmo. we acknowledge the limitations of this study. the retrospective nature of analysis lends itself to misclassification and bias. also, we only collected mortality information at days after ecmo termination and no long-term outcomes were assessed, although we consider this short-term mortality as relevant and more directly related to the variable of interest, i.e., mechanical ventilation on ecmo. secondly, we acknowledge that this is a very heterogenous group of patients as this includes all patients on ecmo including ards and non-ards patients. these groups have differences in their lung mechanics and different pathophysiological risks for lung injury. we note ventilatory parameters and murray scores before and after initiation of ecmo but lack serial measurements of volume status or wedge pressures among those without ards. however, we showed that driving pressure was associated with mortality in both the subgroups of ards and non-ards patients. third, we did not have direct information on the tidal volumes used in these patients. our institution protocol mandated tidal volume of - ml/kg ibw for patients on ecmo; however, we are unable to evaluate protocol deviations in this cohort. also, initial driving pressure before ecmo initiation is not available for all patients. this is due to the high volume of patients transferred from outside hospitals for ecmo or cannulated at an outside facility for ecmo. these patients did not have full ventilator mechanics recorded before ecmo. in spite of these shortcomings, this study is unique in evaluating driving pressures in both va-and vv-ecmo population and one of the first studies to compare at driving pressure before and after initiation of ecmo. current elso guidelines published in now recommend using peep as high as tolerated in the first h of ecmo [ ] . this is a change from the guidelines when no peep recommendations were provided. however, protocol and practices continue to vary. also, there are no set guidelines on driving pressures on ecmo. this study points towards targeting low driving pressure on ecmo in both ards and non-ards patients. more controlled studies are needed to establish exact targets while on ecmo. at our institution, we have now moved away from a uniform application of peep in patients on ecmo and focus on titrating peep based on lung compliance, adequate recruitment, and driving pressure. a significant proportion of the patients had an increase in driving pressure and decrease in compliance after initiation of ecmo despite ultraprotective ventilation. this may be due to inadequate recruitment while on ecmo. those with increase in driving pressure had a longer length of stay on ecmo. elevated driving pressure after ecmo initiation was associated with increased adjusted -day mortality among both va-and vv-ecmo. adequate recruitment with individualized application of peep along with ultraprotective ventilation may improve outcome while on ecmo. author contributions all authors listed have contributed sufficiently to the project to be included as authors, and all those who are qualified to be authors are listed in the author by-line. data availability raw data can be made available on request. trends in u.s. extracorporeal membrane oxygenation use and outcomes mechanical ventilation during extracorporeal membrane oxygenation in patients with acute severe respiratory failure a extracorporeal life support organization: elso guidelines for cardiopulmonary extracorporeal life support and patient specific supplements to the elso general guidelines mechanical ventilation during extracorporeal membrane oxygenation. an international survey near-apneic ventilation decreases lung injury and fibroproliferation in an acute respiratory distress syndrome model with extracorporeal membrane oxygenation association of driving pressure with mortality among ventilated patients with acute respiratory distress syndrome: a systematic review and meta-analysis dynamic driving pressure associated mortality in acute respiratory distress syndrome with extracorporeal membrane oxygenation an expanded definition of the adult respiratory distress syndrome magnitude and time course of acute hypoxic pulmonary vasoconstriction in man hypoxia-induced inflammation in the lung: a potential therapeutic target in acute lung injury? acute leftward septal shift by lung recruitment maneuver monitoring of right-sided heart function high inflation pressure pulmonary edema. respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure mechanical ventilation during extracorporeal membrane oxygenation driving pressure and survival in the acute respiratory distress syndrome ventilator-related causes of lung injury: the mechanical power extracorporeal membrane oxygenation for pandemic influenza a(h n )-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis the authors declare that they have no conflict of interest. key: cord- -v yetn f authors: martin-loeches, ignacio; dickson, robert; torres, antoni; hanberger, håkan; lipman, jeffrey; antonelli, massimo; de pascale, gennaro; bozza, fernando; vincent, jean louis; murthy, srinivas; bauer, michael; marshall, john; cilloniz, catia; bos, lieuwe d. title: the importance of airway and lung microbiome in the critically ill date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: v yetn f during critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. this so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill icu population. it is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances. bronchoscopic studies have revealed that the carina represents the densest site of bacterial dna along healthy airways, with a tapering density with further bifurcations. this likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. though bacterial dna density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. the dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology. the body’s resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity. in this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia. the normal microbiota is the ecological communities of commensal, symbiotic and pathogenic microorganisms whilst the microbiome comprises all of the genetic material within a microbiota (the entire collection of microorganisms in a specific niche, such as the human gut). this can also be referred to as the metagenome of the microbiota [ , ] . approximately billion microorganisms are found in the body due to recent discoveries in molecular analysis such as next-generation sequencing (ngs) and whole metagenome shotgun sequencing (wmgs); there is an increasing body of evidence pointing towards the dysbiosis that is often defined as an 'imbalance' in the microbial community that is associated with disease [ ] [ ] [ ] . a microbiome is shaped by multiple factors including the resident flora of the animate or inanimate vicinity and the external forces that modulate this flora [ ] . it becomes a changeable reflection of diversity, and so its study can provide valuable insights into the factors that drive that diversity [ ] . just as the study of global climate or the roots of language requires input from around the world, so the interpretation of the microbiome of an individual or a group of patients needs comprehensive comparative data to generate insight [ , ] . the variability of the host microbiome-either in an individual patient over time in response to the pressures of illness [ ] or in a geographically localized population in response to environmental-can yield important insight into factors that can be manipulated to improve clinical outcomes. such factors include risk of infection, emergence of resistance, spread from the environment, host susceptibility and even the resilience of the health care system [ ] . in this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome (ards) and ventilator-associated pneumonia (vap). though for years textbooks taught that 'the normal lung is free from bacteria', this dogma was generally repeated without citation or argument [ ] . in retrospect, this claim of lung sterility was remarkable: virtually no environment on earth exists that is so extreme in temperature, ph, salinity or nutrient scarcity that microbial communities cannot be detected [ ] . yet for more than a century, it was taken as fact that the warm, wet mucosa of the lower respiratory tract-mere inches below the microbial reservoir of the pharynx-is an exception to this rule [ ] [ ] [ ] [ ] [ ] . each individual has a unique microbiota profile that plays many specific functions in host nutrient metabolism, maintenance of structural integrity and protection against pathogens. there is not a unique optimal microbiota composition as it can be different for each individual [ , ] . thus, the 'revolution' in culture-independent microbiology has merely confirmed with certainty what has long been inferred indirectly: human lungs are constantly exposed to environmental bacteria. to date, more than studies have used sensitive, culture-independent techniques to study lung bacteria in healthy volunteers, and none has failed to detect a distinct bacterial signal [ ] . the viability of bacteria in healthy lungs has been confirmed via advanced cultivation [ ] and indirectly validated via correlation with healthy alveolar immune tone in humans and mice [ , ] . some of the confusion regarding the existence of lung microbiota reflects flawed parallels with the lower gut microbiome, which represents a wholly different ecosystem with radically different ecologic forces. whereas the gut lumen is densely populated by dense communities' bacteria, lung microbiota is scarce and associated with mucosal surfaces. whereas gut communities are relatively stable dayto-day, reflecting stable selective pressure on resident bacteria, lung communities are in constant turnover, with their identities and burdened determined by the relative balance of immigration (via microaspiration and mucosal dispersion) and elimination (via cough and mucociliary clearance). whereas the gut microbiome is nutrient-rich and characterized by intense metabolic competition amongst dense communities, the lung microenvironment is nutrient-poor, and the primary competition is between immigrating pharyngeal microbes and locally calibrated alveolar and airway host defences attempting to minimize their outgrowth [ , ] . these ecologic differences between the lower gut and the lungs erode somewhat in conditions of acute and chronic disease: the influx of mucus and proteinrich oedema provide nutrient sources for bacteria, and once-transient bacteria become resident, shaped by selective pressure. further confusion arose via misinterpretation of clinical culture protocols, which have been optimized for detection of respiratory pathogens, not the 'background' microbiota of uninfected patients. sequencing-based studies have revealed that the normal microbiota of healthy lungs closely resembles that of the oropharynx [ ] [ ] [ ] and, whilst commonly cultured, are routinely dismissed by clinical microbiology laboratories as 'normal oral flora'. bronchoscopic studies have revealed that the carina represents the densest site of bacterial dna along healthy airways, with a tapering density with further bifurcations [ ] . this likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. though bacterial dna density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. bacterial communities within the lungs of healthy volunteers are relatively homogenous; the bacteria of a given individual's right middle lobe far more closely those of the same individual's left upper lobe than do other individuals' right middle lobe (i.e. intraindividual similarity is greater than interindividual similarity) [ ] . how to study the lung microbiome? high densities of bacteria are always present on the skin, in the mouth, and in the upper respiratory tract. for this reason, it is important to avoid contamination with commensal bacteria from other sites when taking samples for investigation of the lower respiratory tract microbiome [ , ] . since samples from the lower respiratory tract may have a low biomass, it increases the risk for contamination that can occur at any time from sampling to sequencing [ , ] . the first molecular techniques used for studying the bacterial microbiome in humans were based on s rrna gene sequencing many years ago which is an appropriate method to assess diversity on taxonomic levels above species level. a limitation of s rrna gene sequencing is that whilst bacteria can normally be identified on genus and family level, species identification usually requires simultaneous evaluation of several genes [ ] [ ] [ ] . newer technology of whole genome sequencing and metagenomics has shown better definition of the gut microbiome and what has currently been shown of the lung microbiome will also be significantly updated by these newer sequencing technologies [ ] [ ] [ ] . an important matter is that when studying the lung microbiome, the pathogens and host response needs to be simultaneously studied by molecular methods, for instance, microbial metagenomics and transcriptomics. langelier et al. [ ] performed in almost patients with acute respiratory failure (arf) metagenomic nextgeneration sequencing (mngs) on endotracheal aspirates (eta) and simultaneously assessed pathogens, the airway microbiome and the host transcriptome. this study found that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome and host transcriptome represents a new tool for diagnosis in lower respiratory tract infections (lrti). the progress in molecular microbiology has developed very fast in the last years and several rapid technologies will provide biological signals taking into account the interaction of the host (e.g. via digital enzyme-linked immunosorbent assay (elisa) [ ] ) and the microbes (e.g. via nanorod-pcr [ ] ). another technology is microgas chromatography for the analysis of bacterial function and virulence and metabolic indices of the host response on exhaled breath [ , ] . the field of lung microbiome is no longer limited by the speed of sequencing, processing, or measurement, but rather our ability to make sense of the highdimensional data we generate. ards is a complication of critical illness characterized by protein-rich pulmonary oedema, hypoxaemia and alveolar inflammation. alveolar inflammation, damage and subsequent oedema may be initiated by a change in pulmonary microbiome, or a change in lung microbiome may be initiated by an alveolar nutrient available after the onset of oedema [ ] . even though ards is traditionally not considered to be related to microbial changes in the lung, these physiological considerations resulted in the hypothesis that pathogenic bacteria may be present in the lung of patients with ards. kyo et al. [ ] analysed the lung microbiome from the bronchoalveolar lavage fluid (balf) of patients with ards found that lung bacterial burden ( s rrna gene copy numbers tended to be increased) tended to be increased, and the alpha diversity (copy numbers and relative abundance of betaproteobacteria) was significantly decreased in ards patients. in an experimental mouse model of lung injury following abdominal sepsis induced by cecal ligation and puncture, the lung microbiome was enriched with gut bacteria [ ] . how did these bacteria get there? it is hypothesized that bacteria can translocate from the gut into the lymphatic system and portal circulation during critical illness [ ] . if so, these changes should also be observed in patients on the icu. indeed, enrichment of gut bacteria was also observed in balf from ards patients [ ] . gut bacteria and more specifically enterobacterieae enrichment in patients with ards were confirmed in a second observational cohort study [ ] . both studies were performed in a selective cohort of patients with potential biases of prolonged antibiotic exposure before measurement. in a more recent study conducted in europe, patients who were treated with selective decontamination of the digestive tract (sdd) during admission at the icu, but were not treated with antibiotics prior to icu admission, validated the specific enrichment of enterobacterieae in the lungs of ards patients [ ] . taken together, the current body of evidence suggests that amplification of enterobacterieae in the lung is strongly associated with ards. this association is not sufficiently explained by potential confounders such as geographical location of sampling, exposure to antibiotic therapy, amplification protocols or exact definitions of ards. the evidence for consistent dysbiosis in lung microbiome is actually stronger for ards than for most other respiratory diseases, where other microbes are enriched in different studies. however, no causal link between dysbiosis of the lung microbiome and development of lung injury has been established. this link needs to be further explored before we can conclude that lung microbiome dysbiosis is a potential target for treatment (fig. ) . in ecological terms, pneumonia can be described as the collapse of local microbiome diversity and the emergence of a dominant pathogen [ ] . several studies have therefore hypothesized that the lung changes considerably during nosocomial lower respiratory tract infections. some critically ill patients can develop pneumonia due to their clinical condition such as patients with ischaemic stroke and/or with loss of neurological control of the respiratory system. these clinical conditions can be associated to reduced airway clearance and increased bacterial translocation and therefore can develop more often respiratory infections [ ] . so, the more appropriate question is 'do patients that develop pneumonia have more dysbiosis of the lung microbiome than mechanically ventilated icu patients who do not develop pneumonia'? two studies addressed this problem. the first included consecutive patients at risk for pneumonia with a duration of mechanical ventilation of more than days [ ] . endotracheal aspirates were performed every third day and the microbial composition was evaluated with s sequencing. there was a small, but significant increase in the change in beta-diversity (change in diversity of species from one environment to another) in patients who went on to develop pneumonia as compared to patients who did not develop any signs of infection and were not colonized by any bacteria according to traditional bacterial cultures. the composition of the microbiome in these patients also showed a slight enrichment of pseudomonadales. a second study conducted had a similar design and showed no difference in the change of microbiome during mechanical ventilation between patients who did and did not develop pneumonia [ ] . as discussed in the accompanying editorial, the results from these studies have elegantly shown that it is time to let go of any simplistic view of vap pathogenesis [ ] . one conclusion might be that lrti cannot simply be defined as a collapse of bacterial ecology as this is present also in part of the patients without pneumonia who do not show any signs of pneumonia. one could also argue that the studies did not sample the alveolar space and additional studies with balf are needed to confirm or discard these findings. furthermore, evaluation of microbial composition may be more useful in establishing the presence of a pathogen in patients who already have a clinical suspicion of pneumonia. indeed, with pre-test probability, metagenomics may provide valuable information on the pathogen causing pneumonia [ ] . future studies have to consider these possibilities before we disregard the lung microbiome in nosocomial pneumonia. in the critically ill, changes in the microbiome in all habitats, including the lungs, are particularly striking. due to the devastating consequences of untreated severe infections, broad eradication is accepted as lesser evil and collateral damage on beneficial or commensal microbes is generally accepted. however, the potential long-term consequences of unwarranted side effects on the microbiome warrant a reassessment of the microbiome as a diagnostic or even therapeutic target. for example, dysbiosis of the gut microbiome itself has been described as a predictive factor for late-onset neonatal sepsis [ ] suggesting that the microbiome can serve at least as a biomarker to predict ensuing nosocomial infection. moreover, albeit solid data are still missing to support interventions to restore a healthy microbiome, the strategy holds promise to impact on incidence and outcome of nosocomial infection and ensuing organ injury, including ards [ , ] . in the light of a better understanding of off-target effects of broad-spectrum antibiotics on the microbiome, the liberal administration of antibiotics must be discussed against more sophisticated interventions to treat the bacterial infection (non-antibiotic therapies such as bacteriophages) or manipulation of the microbiome to make the residing communities more resilient (for example probiotics). in particular, the need to combine multiple anti-infective compounds in the light of diagnostic uncertainty might outweigh the benefit of early source control and explain controversial results for aggressive antibiotic strategies. for instance, in a before-andafter study hranjec et al. reported that the subgroup with least benefit from 'calculated' broad-spectrum antibiotics were patients presenting with septic shock, i.e. those in which the current paradigm would expect the highest need to initiate early anti-infective therapy [ ] . thus, a holistic approach taking the microbiome into consideration carries the potential to initiate a paradigm shift in the treatment of infections in the icu. as discussed in the previous paragraphs, the lung dysbiosis seems to be common in the icu and enrichment of gut bacteria might be an important contributor to the development of lung injury and infection (fig. ) . the relationship between gut and lung microbiome is described as the gut-lung axis [ ] . because the gut microbiome can be targeted directly or indirectly with therapeutic interventions, this is an area of active study. investigations have thus far fallen into two specific pathways-first, using probiotics to help restore a premorbid microbiome, or second, to use antibiotics through an sdd approach to target specific families of organisms so as to alter the microbiome in possibly beneficial ways. further novel pharmacologic options that have direct gut microbiome modifying effects are also under development, including faecal transplantation as a possible novel treatment for microbiota dysregulation (considering the immune system during faecal microbiota transplantation for clostridioides difficile infection [ ] and for the decolonization of antibioticresistant bacteria in the gut [ ] ). one of the major challenges of studying the effect of these interventions is the huge variability in the gut microbiome of critically ill patients, even during the first days of icu admission [ ] . furthermore, any beneficial effect of these interventions on the microbiome has yet to be assessed formally in a prospective, large-scale, randomized manner. attempting to attribute a causal impact of microbiome modifications upon clinical outcomes has been difficult to tease out as to whether changes in the microbiome are merely surrogates of some other mechanistic pathway that leads to improved clinical outcomes [ ] . fundamentally, probiotics in critical illness aim to provide bacteria that may have been eradicated during the pre-and early phases of critical illness [ ] . this eradication may be through administering antibiotics early in critical illness, which have been shown to greatly modify the gut microbiome [ ] . alternatively, the mere onset of critical illness-be it sepsis, ards or any number of conditions, is associated with alterations of the gut fig. island model for the development of lung injury based on sites of dysbiosis microbiome, which may be independent of antibiotic administration [ ] . regardless, the stated goal of probiotic administration is to restore a pre-morbid microbiomeprimarily to the gut, but partially to other microbiome communities through generalized cross-talk [ ] . through yet-unknown mechanisms, administering lactobacillus or bifidobacterium species through a probiotic may increase the diversity of microbial species in the gut, although more studies with rigorous outcome determinations are required [ ] . in the critically ill, randomized studies and meta-analyses of randomized trials demonstrate a possible benefit of probiotic administration on the outcome of ventilator-associated pneumonia, without a difference in mortality [ , ] , with a major challenge being a lack of standardization in dosing and composition of probiotic products [ ] . larger scale studies are nearing completion and further data on the impact of microbiome modifications are forthcoming in the years ahead [ ] . selective digestive decontamination, a regimen of prophylactic antibiotic administration, has been shown in small series to result in important alterations in gut microbiota, when compared with controls [ ] . these changes are typically related to increasing selection for resistant organisms and decreased microbiome diversity, per a number of different metrics. given a possible benefit on patient mortality in some randomized trials [ , ] , exploring the specific impact of this strategy on the microbiome, and related clinical outcomes, is a vital area for further study. additionally, given burgeoning evidence of crosstalk between the lung and gut microbial communities, the impact of either of these strategies on the non-gut microbiome communities in the critically ill patient remains under-investigated. given the apparent conflicting goals of sdd and probiotic administration in the critically ill as it relates to the microbiome, the role of co-administration may be difficult to conceive. however, most currently used sdd regimens are unlikely to affect the administered probiotic agent, and this may be a strategy for further investigation in targeted patients [ ] . both sdd and probiotics appear to mediate their effect on patientrelated outcomes through reducing the incidence of ventilator-associated pneumonia, speaking to a crucially under-investigated relationship between the two microbiome communities and host immunology, a tantalizing area for future research. novel pharmacologic agents have also been suggested as modifiers for the gut microbiome but have yet to be formally tested in the critically ill. butyrate, a large bowel microbial fermentation product, is being investigated in pre-clinical trials as a specific modifier of gut-derived regulatory t cells [ ] . administering a sialic acid analogue is being investigated as to whether it may reduce the burden of antibiotic-associated pathogens such as c. difficile by altering metabolic pathways [ ] . older drugs such as metformin may have a role, with their demonstrated effects on altering the gut microbiome in patients with diabetes [ ] . the lung microbiome is clearly more difficult to target than the gut microbiome due to the lack of routine administration of bacteria and bacterial products into the airways. the low biomass environment may also cause the lung microbiome to be more prone to infection induced by the introduction of, for example, probiotics. therefore, direct intervention in the lung microbiome may be sought via the alteration of regional growth conditions via the availability of nutrients or through immunomodulation. an example is the administration of macrolides in chronic obstructive pulmonary disease (copd): there is a selection for anti-inflammatory microbial metabolites and an alteration of the lung microbiome [ ] . all of these possible interventions speak to the importance of achieving a better understanding of the gut-lung axis in critical illness. as this understanding evolves, the possibility of personalizing interventions for individual microbiome communities, or widespread initiation of interventions such as sdd or probiotics, would be possible. whilst patient-to-patient or staff-to-patient transmission of infection occurs within the intensive care unit, most nosocomial infections in critically ill patients arise through the invasion of normal host defences by bacteria and fungi that have become a part of an altered microbiome-either by changes in numbers or by the incorporation of species from the environment [ ] . the hospital environment itself acquires a microbiome that reflects the patients that have been in it, and environmental reservoirs such as sinks, plumbing, work surfaces, and equipment can become reservoirs of resistant organisms that can infect the critically ill [ ] . the inherent variability of the microbiome, therefore, provides an opportunity to study not only the individual patient, but also the forces in the environment that shape patient's outcome, and to identify specific opportunities where the persistence and transmission of pathogens can be prevented or minimized. because of the high prevalence of nosocomial infection, the environmental concentration of causative pathogens and the multiple risk factors for exposure, the icu provides a unique opportunity for intensive study of the microbiome and its role in the establishment and transmission of resistant organisms. with the emergence of new models of global acute care research collaboration through the international forum for acute care trialists (infact; www.infactglobal.org), and the launch of an infact initiative to leverage icu data to understand variability in patterns of resistance through the antimicrobial resistance in intensive care (amric) initiative. in previous years, we believed that the normal lung was free from bacteria. certainly, some features in the respiratory tract such as temperature, ph and nutrients were not beneficial for microbial growth. during critical illness, antibiotic use, mechanical ventilation, diet changes and inflammatory responses can bring the microbiome to dysbiosis. with the use of molecular techniques, we have had the opportunity to study the lung microbiome and not only in the microbial aspect but also in the responses from the host. one of the most important aspects to better determine the physiopathology of host-pathogen interaction in pulmonary complications such as ards and va-lrti is the gut-lung axis. further study of patients with disease in the respiratory tract will help us to better determine microbial diversity and constitution when comparing healthy and diseased subjects. dysbiosis and analysis of extra-pulmonary microbiome have helped to understand the complex interaction of bacterial clearance in the lung tissue and the off-target effects of broad-spectrum antibiotics on the microbiome. through therapies targeting host-pathogen interaction and the development of advance molecular testing, we will be able to have a deeper understanding in the analysis of the lung microbiome. how can we define "optimal microbiota?": a comparative review of structure and functions of microbiota of animals, fish, and plants in agriculture host-microbiota interactions in immunemediated diseases genomic approaches to studying the human microbiota defining dysbiosis and its influence on host immunity and disease the vocabulary of microbiome research: a proposal the human microbiome: our second genome factors that drive variation among gut microbial communities tools for the microbiome: nano and beyond extensive unexplored human microbiome diversity revealed by over , genomes from metagenomes spanning age, geography, and lifestyle extreme dysbiosis of the microbiome in critical illness the influence of ethnicity and geography on human gut microbiome composition robbins pathologic basis of disease, vol. xv. philadelphia: saunders microbial life in extreme environments expériences relatives aux générations dites spontanées. comptes rendus hebdomadaires des séances de l'académie des sciences d: sciences naturelles l; studien über die aetiologie und histologie der pneumonie im kindesalter und der pneumonie im allgemeinen the relationship of sinusitis and bronchiectasis the internal surface area of the adult human lung surface area of the digestive tract -revisited what is the healthy gut microbiota composition? a changing ecosystem across age, environment, diet, and diseases a human gut microbial gene catalogue established by metagenomic sequencing the microbiome and the respiratory tract application of a neutral community model to assess structuring of the human lung microbiome enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a th phenotype the lung microbiota of healthy mice are highly variable, cluster by environment, and reflect variation in baseline lung innate immunity the role of the microbiome in exacerbations of chronic lung diseases analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography bacterial topography of the healthy human lower respiratory tract specific ribosomal dna sequences from diverse environmental settings correlate with experimental contaminants reagent and laboratory contamination can critically impact sequence-based microbiome analyses the lung microbiome and ards. it is time to broaden the model dysbiosis in the intensive care unit: microbiome science coming to the bedside advancing our understanding of the human microbiome using qiime ribofr-seq: a novel approach to linking s rrna amplicon profiles to metagenomes the murine lung microbiome in relation to the intestinal and vaginal bacterial communities whole genome sequencing revealed microbiome in lung adenocarcinomas presented as ground-glass nodules classification of methanogenic bacteria by s ribosomal rna characterization methanogens: reevaluation of a unique biological group integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations attomolar dna detection with chiral nanorod assemblies fully automated portable comprehensive -dimensional gas chromatography device breathdx -molecular analysis of exhaled breath as a diagnostic test for ventilatorassociated pneumonia: protocol for a european multicentre observational study unique patterns of lower respiratory tract microbiota are associated with inflammation and hospital mortality in acute respiratory distress syndrome lung microbiota predict clinical outcomes in critically ill patients the influence of the microbiome on respiratory health aspiration pneumonia the dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia identification of respiratory microbiota markers in ventilator-associated pneumonia gut microbial colonisation in premature neonates predicts neonatal sepsis critical illness and the role of the microbiome the essential role of the intestinal microbiota in facilitating acute inflammatory responses aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study more of the gut in the lung: how two microbiomes meet in ards considering the immune system during fecal microbiota transplantation for clostridioides difficile infection faecal microbiota transplantation for the decolonization of antibiotic-resistant bacteria in the gut: a systematic review and metaanalysis critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for prospect pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection impact of antibiotics on the gut microbiota of critically ill patients enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials manipulation of the microbiome in critical illness-probiotics as a preventive measure against ventilator-associated pneumonia probiotics for preventing ventilator-associated pneumonia in mechanically ventilated patients: a meta-analysis with trial sequential analysis blurred lines: dysbiosis and probiotics in the icu effects of selective digestive decontamination (sdd) on the gut resistome decontamination strategies and bloodstream infections with antibiotic-resistant microorganisms in ventilated patients: a randomized clinical trial decontamination of the digestive tract and oropharynx in icu patients lactobacillus species: taxonomic complexity and controversial susceptibilities commensal microbe-derived butyrate induces the differentiation of colonic regulatory t cells microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens metformin alters the gut microbiome of individuals with treatment-naive type diabetes, contributing to the therapeutic effects of the drug randomised, double-blind, placebo-controlled trial with azithromycin selects for antiinflammatory microbial metabolites in the emphysematous lung hospital-associated microbiota and implications for nosocomial infections investigation of a multiyear multiple critical care unit outbreak due to relatively drugsensitive acinetobacter baumannii: risk factors and attributable mortality publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. key: cord- -cyhcbk j authors: nan title: ps - date: - - journal: intensive care med doi: . /s - - -y sha: doc_id: cord_uid: cyhcbk j nan in our -bed icu-cum-hdu of a -bed tertiary referral cancer centre, medical oncology admissions increased from < % of total admissions to over % in the last years. we audited outcomes in these patients to determine prognostic factors that may aid patient selection and management. methods. consecutive admissions ( males, females, age > years) from february , to february , were prospectively studied. the total sofa score on day (sofa ), the highest sofa score of the first three days (max ) and the change in sofa score between day and day (delta ) and between day and day (delta ) were calculated. predictors of outcome were identified using univariate and multivariate binary logistic regression. results. patients had solid tumours , had leukemia, lymphoma, myeloma, and had other diagnoses. mean age was . ± years and apache ii score was . ± . . icu mortality was % and hospital mortality . %. / patients ( . %) with icu stay < day died. overall length of icu stay was . ± . days. in survivors vs. nonsurvivors, sofa , delta and delta (median, interquartile range) were . ( . to . ) vs. . ( . to . ; p< . ), - . (- . to ) vs. . (- . to . ; p< . ) and (- . to . ) vs. . (- . to . ; p< . ), respectively. several factors were associated with mortality on univariate analysis (table ) . on multivariate analysis, only need for vasopressors (or . , p= . ) and max (or . , ci . - . , p= . ) were independently associated with hospital mortality, while type of cancer and leucopenia were not. for patients staying > days, no factor predicted hospital mortality, but sofa (or . , ci . - . , p= . ), delta (or . , ci . - . , p= . ) and delta (or . , ci . - . , p= . ) predicted icu mortality. usually, the cgr transfused in our icu are old (about % of rbc are stocked more than days). icu outcome is independently associated with the number of rbc transfused, but not with their age. this result in contradiction with previous report could possibly be explained by the systematic leucodepletion performed before storage in france, contrary to precedent studies where rbc were not leukodepleted. we compared them with ≥ years old and an icu stay < days patients, the differences in icu mortality, apache ii, age, gender and the necessity for renal replacement therapy (rrt) were not significant (see table) . the survivors patients (≥ years old and an icu stay ≥ days) were more older and ( ' %) were still alive one year later. when we analyzed the overall patients, according their stay < or ≥ days, did not find statistically significant differences between both groups in the mortality (p= ' conclusion. icu mortality rates in elderly patients with a stay < or ≥ days at icu were comparable. the year-survival of elderly patients with a long-term intensive care unit stay was high. results. seventy patients were admitted to our icu with the diagnosis of acute pancreatitis during study period and of them were later confirmed as having sap. the average icu length of stay in patients with sap was days compared to days in patients with mild form of the disease. pancreatic infection was present in patients. the mortality rate in the group with sap was % compared to , % in the group with mild acute pancreatitis, p< , . the most common etiology of patients with sap was biliary and this was similar both in survivors and non-survivors. the most common cause of death in the group with sap was multiple organ dysfunction/failure syndrom(mods/mof) in % followed by bleeding complications in %. twelve patients with sap ( %) underwent the surgical intervention. mortality in the group of patients who underwent a surgical intervention was % ( patients). , +/- , , +- , apache ii score( mean+/-sd) , +/- , , +- , * necrotising form (%) infected necrosis (%) ct guided fnab (%) * p > . conclusion. the patients with mild form of acute pancreatitis had low mortality rate (similar to general ward population) despite positive icu admission criteria in our case series with fifty per cent development of severe form with organ dysfunction/failure later on. apache ii score was better predictor of mortality in patients with sap than presence, extent or infection of pancreatic necrosis. patients with higher risk for development of severe form of acute pancreatitis should be admitted to multidisciplinary icu prior to definitive diagnostic evaluation of pancreas. further studies are warranted. conclusion. absi is an aprropiate score for estimating the probability of death in critical brun injury patients. preexisting cardiac and liver diseases have a little influence on mortality and its addition to the absi variables don't predict mortality more accurately. poisoned patients constituted up to , % of all icu admissions in our hospital. demographic data and specific poisons have been presented at the table. the total poisoned mortality rate was , %. methyl alcohol poisoning has a higher mortality than others poisoning. conclusion. childhood poisoning is usually accidental and is usually associated with a low morbidity and mortality. in adults, self-poisoning is usually deliberate suicide or parasuicide) and has a higher morbidity and mortality rate. ( ) the most important part of the poisoned patient's care are the general supportive management and specific antidotes therapy. it has abundantly been demonstrated that duration of mechanical ventilation can be reduced by the use of protocols for weaning and sedation [ , ] . utilization of the required sedation scales and adherence to protocols, however, is poor in daily practice, as has been shown in recent studies [ , ] . it has been proposed to use daily checklists to improve the quality of care [ ] . to improve adherence to the established guidelines for weaning and sedation in our icu, we included two questions in a checklist printed on patients' charts which had to be answered daily by the physician on duty: conclusion. the checklist as a daily reminder to observe established weaning and sedation protocols may have significantly accelerated weaning from mechanical ventilation. we carried out a prospective and descriptive study in patients admitted to our icu from to . we defined tolerance as the need to use more than mg/h, at least for four hours, or the need either to use or to change to other sedatives to obtain a to level on the ramsay scale ( ). the appearance of tolerance in the first hours was considered as tachyphylaxis or early therapeutic failure to this sedative. in our sedation protocol we use propofol preferably in patients who need frequent neurological consciousness evaluations, or in patients whose sedation is expected to have short to medium duration, and who have haemodynamic stability. also, we use propofol as a sequential strategy when early weaning from ventilation is expected. all patients received analgesic drugs. during this time, we admitted patients, of them needed mechanical ventilation and in patients we administered continuous analgesic and sedative infusions. continuous propofol infusions were administered in patients at some point of their sedative strategy, and ( % of the sedated patients) received propofol for more than hours. tolerance development was observed in patients, % of the patients sedated with propofol. in thirty-seven of them, this situation was present in the first hours (early therapeutic failure). conclusion. in our sedative protocol for propofol use, the incidence of tolerance in patients sedated with this drug was %, which is substantially less than the usual described midazolam tolerance. most of these cases ( %) happened in the first hours. diabetes mellitus (dm) with its chronic and acute complications puts patients suffering from the disease at increased risk. none of the scoring systems used for risk prediction in intensive care units accounts for diabetes as a risk factor, although, in everyday practice, patients with dm admitted to icus may be recognized as those with higher risk. not much data is available on how much risk can be attributed to diabetes. we have compared course and outcome of patients with dm with non-diabetics to try to answer this question. we have analyzed data from the "croicu.net", national pilot-project which collects data on patients from icus in croatia. data collected during the first months (nov -dec have been analyzed. adult patients from icus in university hospitals were included; three most frequent admission diagnoses were selected for comparison of diabetic and non-diabetic patients. the diagnosis of dm had to be established prior to admission according to the usual criteria. icu mortality and icu length of stay (los) were primary outcome measures. incidence of organ failure was a measure of disease course. in the analysed period there were admissions to the analysed icus, ( . %) with documented dm prior to admission. patients with md did not differ significantly from non-diabetics in age or sex distribution. overall mortality was higher for dm patients ( . % vs. . %), as was los ( . vs. . days). three most frequent diagnoses were: sepsis (n= ; . %), pulmonary oedema ( ; . %) and myocardial infarction (n= ; . %). patients with diabetes had significantly higher mortality and higher los in all three subgroups. in the sepsis subgroup, patients with diabetes had higher incidence of organ failure and higher number of failing organs. in the other two subgroups, the differences were not significant. in multivariate analyses which was performed separately for all three diagnoses and included dm, age, apache ii score and sofa score, diabetes mellitus was shown to be an independent predictor of mortality and los in all three cases. although some chronic effects of diabetes mellitus can be included in multiparameter scoring systems such as apache ii score, the disease itself is not scored. we have shown on three most common diagnoses in icus of university hospitals that diabetes mellitus is an independent predictor of mortality and los and that it has significantly higher incidence of organ failure in sepsis. patients with dm should be given appropriate attention as high risk patients in the icu. introduction. neuromuscular abnormalities are common in critically ill patients with systemic inflammation and organ failures. we assessed the incidence of a clinically diagnosed critical illness polyneuro-myopathy (cipm), and its potential impact on mortality and long-term neurological outcome. methods. consecutive critically ill patients on mechanical ventilation for hours and with the presence of or more sirs criteria were prospectively studied. based on daily clinical neurological examinations, cipm was defined as symmetric limb muscle weakness [ or more muscle groups, m or less (mrc)] without other explanation than cipm in patients with normal neurology at icu admission. a barthel index (score for activities in daily living) was performed at day and months after icu discharge. after months a neurological examination was also performed. . cipm was diagnosed in patients ( %). patients with suspected cipm had a prolonged icu stay and a high mortality. the barthel index was significantly lower in this group at day but improved over the next six months. of patient who survived could be reached months after discharge and of them were clinically examined. at this time the most compromised activity in daily living is climbing stairs. patients with a clinical diagnosis of cipm have a high mortality. if they survive, they are severely limited in simple daily activities one month after icu discharge, but improve later. host infection by pathogens triggers innate immune response leading to a systemic inflammatory response, often followed by a paradoxical compensatory antiinflammatory response. this immune dysfunction can impair the eradication of primary infections and favor the emergence of nosocomial sepsis. dendritic cells (dcs) have a central role in initiation and control of innate and adaptative immune responses to infectious challenges. dcs might contribute to sepsis-induced immunodepression. indeed, depletion of dcs has been reported in secondary lymphoid organs of patients who died from sepsis and in animal models of lethal sepsis. in order to investigate the mechanisms of sepsis-induced immunodepression, we studied quantitative and functional features of dcs in a murine model of sublethal sepsis. we developed a sublethal murine model of polymicrobial sepsis through cecal ligature and puncture followed by short course of antibiotics and volume resuscitation. we isolated splenic dcs by immunomagnetic procedure and generated bone marrow-derived dcs (bmdcs) by -day culture of medullar progenitors in the presence of gm-csf before stimulation with lps to induce maturation. we counted spleen dcs and studied the following functional features of spleen dcs and bmdcs in the early (day ) and late (day ) phases of sepsis : maturation (expression of mhcii, cd and cd through facs analysis), production of cytokines (tnf-alpha, il- , il- ) and priming of cd -positive t-cell lymphocytes ( h-thymidine proliferation assay in allogeneic mixed lymphocyte reaction). upon anesthesia induction with isoflurane sepsis was initiated by cecal ligation and double puncture in groups of c bl/ j-mice per group [ g, g, g] (clp). control mice underwent laparatomy and manipulation of the cecum only (sham). , and hrs post-surgery in and g mice and hrs post surgery in g mice single cell suspensions of thymus and spleen were analyzed by means of cell surface staining and flow cytometry. fluorescence-labeled antibodies included cd , cd , cd , b , igm, igd, cd , cd . data are presented as mean+sem. results. similar to previous results, thymi primarily demonstrated a time-dependent reduction of cd +cd + double-positive cells which was more pronounced during severe sepsis ( + g). at hrs post-clp cd + cells and cd + t-cells recovered to values of sham mice in g animals, which previously recovered fastest with highest survival rates of about %. in contrast cd + cells and cd + cells, respectively, raised to maximum levels at hrs in g animals. concerning spleocytes cd + and cd + cells were similarly reduced to about % and % after hrs and to % and % in g and g mice compared to sham mice. splenocytes of g-treated mice, which could only be investigated at hrs postclp showed no difference to sham mice. as far as b cells are concerned no significant differences between the groups or different time points could be detected. relative numbers of peripheral t cells expressing the early activation marker cd or cd were clearly more pronounced at hrs compared to hrs in and g mice. in g treated mice cd and cd positive t cells were significantly higher at hrs compared to sham mice. a mild clp model is more appropriate to study during murine sepsis. the rapid occurrence of peripheral activated t cells suggest a very early function of the adaptive immune system during sepsis. considering a milder disease course of g mice they seem to more efficiently use their t cells to fight the infection. thymocyte data suggest a block in lymphopoiesis from cd -cd -to cd +cd +. b cells are not likely to play a major role in polymicrobial murine sepsis. further studies have to be performed to elucidate the turnover and the homing of lymphocytes during sepsis. endotoxaemia is associated with intestinal perfusion deficits and gut barrier failure. regional sympathetic blockade by means of thoracic epidural anaesthesia (tea) has been shown to positively affect intestinal microcirculation during endotoxaemia. this study tests the hypothesis that the microvascular changes observed with tea go along with an increase in overall gastrointestinal blood flow. in addition we investigated whether the use of tea influences gut barrier function. after approval of the animal care committee rats were anaesthetised (urethane/ketamine), hemodynamically monitored and mechanically ventilated with room air. lidocaine % or normal saline were administered as a bolus ( µl) and subsequent continuous infusion ( µl x h − ) via an epidural catheter (tip at t / , spread t -t ). organ blood flow (n = rats) was measured by the fluorescent microspheres technique at baseline, min after epidural infusion, and min and min after the infusion of endotoxin (e. coli lipopolysaccharide, . mg x kg- x h − ) or normal saline. for assessment of gut barrier failure rats (n = ) received a bolus infusion of endotoxin ( mg x kg- ) or normal saline and epithelial permeability to low molecular fluorescein isothiocyanate-dextran ( kd) was quantified using a ligated loop of terminal ileum after hours of normotensive endotoxaemia. in hypodynamic shock models pure o breathing was shown to redistribute blood flow in favour of hepato-splanchnic organs and to improve survival. in contrast, this therapeutic approach has not yet been evaluated in hyperdynamic septic shock, since an increased production of o radicals, which is directly related to the increased o partial pressure, is considered as harmful. therefore, we investigated the effects of pure o breathing on hepato-splanchnic macro-and microcirculation, energy balance and tissue cell death during porcine fecal peritonitis. after induction of fecal peritonitis, pigs were randomly ventilated for h with % o (n= ) or an fio adjusted to yield a sao > % (n= ). before as well as at and h of peritonitis we measured cardiac output as well as hepatic artery and portal vein (pv) flows (ultrasound flow probes), microcirculation in the intestinal wall (laser doppler flow), intestinal wall oxygenation, portal and hepatic-venous acid-base status, and lactate/pyruvate (l/p) ratios. apoptosis was analysed post-mortem in liver biopsies with the tunel assay. within group effects were analyzed using a friedman anova on ranks, intergroup differences with an unpaired rank sum test. at the end of experiment the contribution of both pv and total liver blood flow to cardiac output was significantly higher in the hyperoxic animals than in the control group (qliver/co ( ; )% vs. ( ; )%, p= . ; qpv/co ( ; )% vs. ( ; )%, p= . , respectively), which was concomitant with attenuated regional venous metabolic acidosis and lower hepatic-venous l/p-ratios. intestinal wall microcirculation and oxygenation did not significantly differ between the two groups. the hyperoxic animals presented with a markedly reduced number of apoptotic cells in the liver. our results show that early % o ventilation redistribute blood flow in favour of the hepato-splanchnic system even in peritonitis-induced hyperdynamic septic shock. furthermore, the hepatic energy balance is improved and the morphologic integrity of the liver better maintained under these conditions. grant acknowledgement. supported by the eli lilly-esicm sepsis elite award, the alexander-von-humboldt-stiftung, and the deutscher akademischer austauschdienst glucocorticoids are known as strong modulators of immune response that play an important role in patophysiology of sepsis and inflammation. they have strong influence on the development of immune system, its effector functions, and trafficking of immune cells.the biological activity of glucocorticoids depends not only on their plasma concentration, the number of receptors and the responsiveness of the target cells but also on the local metabolism of glucocorticoids that is predominated by b-hydroxysteroid dehydrogenase ( hsd). two isoforms of hsd are known. the isoform hsd operates in vivo predominantly as a nadph-dependent reductase that locally increases glucocorticoid concentration (cortisol, corticosterone) by reduction their -oxo derivatives (cortisone, dehydrocorticosterone) . the isoform hsd is a sole nad+-dependent dehydrogenase that inactivates biologically active glucocorticoids to their inactive -oxo derivatives. the aim of this study was to investigate peripheral metabolism of glucocorticoids in immune cells and tissues in experimental model of sepsis and inflammation. sepsis was induced in balb/c mice and wistar rats by intraperitoneal administration of lipopolysaccharide or pooled fecal inoculum. in these animals and in healthy controls we measured expression and activity of hsd in lymphatic nodes, peripheral blood leukocytes and alveolar macrophages. activity was measured by incubation with corticosterone and -dehydrocorticosterone, following hplc determination. the abundance of hsd mrna was measured by semi-quantitative real-time rt-pcr. for years etomidate has been known to cause adrenal insufficiency in the critically ill and is a confounder when studying corticosteroids in septic shock. subgroup analysis of a prospective, randomized, placebo-controlled study of corticosteroids in septic shock. patients underwent a short high dose acth test before study drug administration. patients received d treatment with hydrocortisone (hc) or placebo (p). the affects of etomidate administration on acth responsiveness and d mortality were studied. results. patients were enrolled. overall . % patients died in the hc group and % in the p group (p= . ). in total % of patients received etomidate. received etomidate before baseline [ % hc group + % p group] and in after baseline [ % hc group + % p group]. overall, more of the patients receiving etomidate were acth nonresponders [ % vs %] . no mortality differences was seen between patients receiving etomidate at any time during study and those who did not receive etomidate [ . % vs. . %](p= . ). there was a possible trend towards a difference in mortality between patients who received etomidate in the hrs before randomisation [ % hc vs. % p] or not receiving etomidate during this time period [ % hc vs. % p](p= . ). etomidate was commonly used in patients in the corticus study. etomidate was associated with an increased likelihood of adrenal hyporesponsiveness in all patients. there was no increase in mortality associated with etomidate administration at any time, there was a trend towards increased mortality in those who received it in the hours before trial baseline. this result comes from an underpowered subgroup and should be considered exploratory. d. pestaña* , e. martinez-casanova , a. buño , r. madero , a. criado anestesia-reanimación, análisis clínicos, bioestadística, hospital universitario la paz, madrid, spain introduction. steroids are indicated in septic shock patients when relative adrenal insufficiency is suspected. our aim was to study if the measurement of total proteins ( ) and eosinophil count ( ) improves the accuracy of cortisolemia to predict the hemodynamic response to steroid treatment in this setting ( ). we analysed data from consecutive surgical patients with criteria of septic shock receiving steroid treatment. four criteria were chosen to define hemodynamic improvement based on the combination of noradrenaline (na) withdrawal (at and h) and an increase of the hemodynamic index (hi = mean arterial pressure/na dose) of % at h and of % at h. the accuracy of the baseline cortisolemia to predict the hemodynamic response to steroid treatment following the four criteria was determined by roc curve analysis. the largest area under curve (auc) was found for the noradrenaline withdrawal or an increase of the hi > % at h after starting the steroid treatment (table ) . this criteria was met by patients ( %) and was associated with a lower mortality ( . % vs . %, p= . , % sensibility and . % specificity). however, no clear cortisolemia cut-off value for the diagnosis of adrenal insufficiency based on the hemodynamic response could be found. neither the basal proteins nor the eosinophils improved the accuracy of cortisolemia to predict a hemodynamic improvement. mortality was also related to age (p= . ), apache ii (p= . ) and sofa score (p= . ). neither basal cortisolemia nor lactate were related with icu mortality. twelve septic shock patients admitted to the icu < hours after family consent were enrolled. we excluded all patients in use of steroids in the preceeding months, etomidate, espironolactone, oestrogens, oral contraceptives, ketoconazole or any other drug known to suppress adrenal function; aids, pregnancy, history of disease of the hypothalamic-pituitaryadrenal axis, shock of other etiologies. after a baseline serum cortisol was obtained, a ld ( ug) corticotropin stimulation testing was performed. subsequently, serum cortisol at and min was measured. four hours later, another bc was obtained. then, a hd ( ug) corticotropin stimulation testing test was performed and serum cortisol was again measured after and min. results. both baseline serum cortisols were similar. delta hd cortisol was higher than delta ld cortisol ( . ± . vs. . ± . ug/dl, p= . ). five patiens had a bc < ug/dl, but only one showed rai in both tests. concordance between ld and hd tests was % ( / ). it was strong for responders ( %, / ) but weak for non-responders to ld test ( %, / ). the preliminary results of our study suggest that a ld test is a more sensitive test than a hd test. a further study comparing treatment of rai defined by a ld or a hd test is still needed. the potassium channels (kc), atp-sensitive k+ (katp) channels and calcium-activated potassium (bk) channels, may be implicated in shock induced vasoplegia. the aim of our study was to demonstrate that the potassium channels are overexpressed in experimental shock independently of the etiology. three rats models of shock were used : peritonitis by caecal ligation and perforation (clp, n= ) observed at h, ischemia-reperfusion model (hemorrhagic shock + resuscitation + laparotomy, n= ) observed at h, and pressure fixed hemorrhagic shock (n= ) observed at h. these three models were compared to a control group. we performed quantitative real-time pcr (lightcycler technology -roche -and sybr green -sigma) and western blot on aorta and mesenteric arteries. we studied the expression of the vascular smooth muscle katp channels -kir . and sur b subunits -and bk channels -bk alpha subunit. we assessed the inflammatory syndrome in studying inos expression. we were able to detect kir . , sur b, bk alpha and inos arnm in both vessels. quantitative real-time pcr results (reference gene : beta-actine) clp clp ir ir hs hs aorta mesenteric aorta mesenteric aorta mesenteric inos . ± . * . ± . * . ± . * . ± . * . ± . * . ± . * expression kir . . ± . . ± . * . ± . * . ± . * . ± . * . ± . * expression sur b . ± . . ± . * . ± . * . ± . * . ± . * . ± . expression bk alpha . ± . * . ± . * . ± . * . ± . * . ± . . ± . expression * : p< . vs control group conclusion. various potassium channels are activated and up-regulated during shock independently of the etiology. thus, potassium channels likely play a major role in sepsis but also in prolonged and severe hemorrhagic shock and in ischemia reperfusion. (cars) . a predominantly anti-inflammatory reaction induces immunosuppression with impaired host defense. application of gm-csf to patients with major surgery or sepsis has been proposed to improve host-defense. in this study we investigated the differential effects of gm-csf production in an ex-vivo model. and lps on the tnf-a. whole blood of healthy donors (age - years, mean years) was used to determine optimal concentrations and incubation time for lps. the immunomodulating properties of gm-csf (leukine ® (sargramostim), berlex)) were investigated in whole blood of healthy donors ( - years, mean years) and icu patients suffering from sepsis. six of the patients had immunoparalysis as defined according to local standards by a monocytic hla-dr expression of < mfi and an ex-vivo stimulation test of < pg/ml after lps incubation (dpc biermann, bad nauheim , germany), whereas the other displayed a hla-dr expression of > mfi and a ex-vivo stimulation test of > pg/ml. samples were primed either with gm-csf, gm-csf simultaneously or lps prior to incubation. tnf-a and il- concentrations were determined with the immulite chemoluminescence immunoassay system (dpc-biermann, bad nauheim, germany). leukocyte phenotyping was performed by dual-colour flow cytometry using whole blood lysis technique and monoclonal antibodies. in healthy donors, ex-vivo stimulation with lps leads to a massive increase of tnf-a production. however, if whole blood is incubated with gm-csf hours prior to the lps challenge, the tnf-a production is significantly increased. the simultaneous incubation with lps and gm-csf leads to a significant decrease in tnf-a levels in the same patient population. gm-csf stimulation of whole blood hours after the production. in patients lps challenge causes no significant change in tnf-a levels of with sepsis and endogenous tnf-a < pg/ml, gm-csf pre-incubation production, whereas patients leads to a significant increase in ex-vivo tnf-a had a blunted ex-vivo reaction to lps with higher endogenous levels of tnf-a stimulation. both the sequence of stimulation with either gm-csf or lps and the presence or absence of systemic tnf-a determine the ex-vivo cytokine response of whole blood. hence, it may be speculated that . the administration of gm-csf prior to the inflammatory stimulus would be most efficient, and that . the lack of stimulation effect in patients with high endogenous tnf-a may mirror endotoxin tolerance. the most common acquired causes of weakness and muscle wasting in the critically ill patient in the intensive care units (icu) are critical illness polyneuropathy and critical illness myopathy. there is significant clinical and neurophysiologic overlap between the two conditions, such that the term critical illness polyneuropathy and myopathy (cipnm) is often used. over a -mo period, critically ill patients who needed prolonged intensive care were studied. clinical manifestations include delayed weaning from the respirator not explained by pulmonary complications, muscle weakness and prolonging of the mobilization phase. included patients were classified as having mof, sirs and sepsis according to established consensus definitions. the occurrence of a positive emg for cipnm, as defined by an electrophysiologist who was blinded for treatment allocation, was analyzed during icu stay. variables recorded at baseline and during follow-up included patient demographics, principal diagnosis, routine blood tests and microbiological culture results. levels of tnf-alpha, il- , il- , il- , procalcitonin (pct) and c-reactive protein concentrations were repeatedly measured by elisa. all patients were divided in: patients without cipnm at any time (group a, n= ), with a positive emg during icu stay (group b, n= ), and with a diagnosis of cipnm since the admission (group c, n= ). emg testing demonstrated severe acute denervation with striking involvement of proximal muscles in patients. patients died of complications of sepsis. critically ill patients without cipnm showed serum il- levels lower (p < , ) than those with a diagnosis of cipnm while no differences were found as concerned serum il- levels. il- and tnf-alpha did not show any difference between the two groups. il- levels resulted higher in groups a and b (p < , ) while il- levels were higher in group a (p < , ). in the group b, we observed a characteristic pattern of il- and il- serum concentrations that may be important for clinical outcome. il- levels were higher than il-l in patients with worse clinical outcome. the opposite pattern was observed in those with a good prognosis. no differences in clinical and laboratory variables were observed between patients with and without cipnm. pct appeared to be most helpful in differentiating patients with sepsis from those with sirs (p < , ), exhibiting a greatest sensitivity ( %) and specificity ( %). conclusion. the analysis of the serum cytokines il- , il- , tnf-alpha and il- to standard indicator did not improved the predictive power of detecting cipnm but may contribuite to explain its pathogenesis. high dose glucocorticoids are known to induce muscle weakness. we investigated in a pilot study the occurrence of cip/cim in septic shock patients treated with low dose hydrocortisone (hc). patients were enrolled in the randomized controlled study of hc in septic shock (corticus) and received hc ( mg q h for days, tapered until day ) or placebo (pl). electrophysiological testing (ep) consisted of the assessment of compound muscle (cmap) and sensory nerve action potentials (snap), spontaneous activity (spa), and muscle membrane excitability investigated by direct muscle stimulation (dms). clinical muscle weakness was defined by a medical research council scale (mrc) below . cmap and snap were categorized based upon normal age related values. ep results were categorized as unspecific (cim or cip or both) when cmaps and spas were pathological in >/= muscles. presence of cip was defined by pathological snaps in >/= nerve, and cim by dms values < mv. data are shown as mean and %ci, chi square test and mann-whitney-u-test were performed for statistical analysis. from jun -feb , patients were enrolled in sites: hc and pl. median time for ep assessment was days ( - ) after study enrolment. pl and hc patients had unspecific electrophysiological signs; pl patients, but only hc patient had reduced snaps indicating cip. in patients dms could be performed, / pl and / hc patients showed reduced muscle membrane excitability indicating cim. in patients (pl , hc ) evaluation of mrc score was possible. muscle strength did not differ between placebo [ . ( / . )] and hc group [ ( . / . )]. none of the parameters reached statistical significance. conclusion. the frequency of cip/cim diagnosed by electrophysiological examination was higher in patients who received placebo. the clinical diagnosis of muscle weakness assessed by mrc scale was not different in both groups. with limitations of the small sample size, this first prospective evaluation showed no impact of hc on the development of cip/cim in this cohort of patients with septic shock. surviving sepsis campaign guidelines recommend treatment with hydrocortisone in septic shock patients requiring vasopressor support. however, the association of fludrocortisone remains controversial. the objective of the study was to determine if the association of fludrocortisone in patients with septic shock and adrenal insufficiency treated with hydrocortisone is related to an improved outcome. from a database including patients with septic shock requiring vasopressor support, we retrospectively studied patients who fulfilled criteria for adrenal insufficiency (baseline cortisol less than µg/dl and/or an increase after injecting µg synacthen less than µg/dl). all patients included received treatment with hydrocortisone (h) or hydrocortisone plus fludrocortisone (h+f) for at least h. data are presented as mean ± standard deviation. groups were compared by using student's t test for continuous variables and chi-square test for categorical variables. long rank test and kaplan-meier curves were used to analyze time to shock reversal and mortality. forty-eight patients received hydrocortisone (h group) and hydrocortisone plus fludrocortisone (h+f group). overall mortality was % ( patients). both groups were comparable in baseline clinical and demographic characteristics. no differences were found in age (mean age ± ), gender, weight ( ± vs ± , p , ) (kg), infection site and severity scores: saps ii ( ± vs ± , p , ), apache ii ( ± vs ± , p , ) and sofa max ( ± vs ± , p , ). both groups presented no differences regarding baseline ( ± vs ± ,p , ), stimulated ( ± vs ± , p , ) and delta cortisol values ( , ± , vs , ± , , p , )(µg/dl). we did not find differences between both groups in norepinephrine(ne)maximal dose received(µg/kg/min), time to shock reversal (days of ne use), time of mechanical ventilation, icu and in-hospital length of stay (days) and mortality ( prospective, randomized, double-blind, placebo-controlled study of -day mortality in patients with septic shock for less than hr who underwent a short high dose acth test in centres in european countries. patients received -day treatment with hc ( mg q h for days, q h for days, q hr for days) or placebo (p). serum electrolytes levels were obtained at baseline, day (d ), day (d ), day (d ) and day (d ) from randomisation. from mar -nov , patients were enrolled. baseline serum sodium were ( ) mmol/l and ( ) mmol/l in the hc and p group respectively. serum sodium peaked at d ( mmol/l) and remained elevated up to d ( mmol/l) in the hc group. in the placebo group, serum sodiumpeaked at d ( mmol/l). the mean change in serum sodium were, in hc treated and p treated patients respectively, at d : . ( . sd) vs . ( . ) mmol/l; d : . ( . ) vs . ( . ) mmol/l; d : . ( . ) vs . ( . ) mmol/l; and at d : . ( . ) vs . ( . ) mmol/l. the difference between groups reached statistical significance at day (p= . ). there were no significant changes in mean potassium levels over time between the two treatment arms. according to the guidelines for the management of severe sepsis and septic shock, low doses of steroids are recommended in septic shock patients requiring vasopressors, despite adequate fluid replacement. the aim of this retrospective case control study was to assess the effectiveness of low doses of hydrocortisone in patients with late septic shock and mods. the study was held in a bed multidisciplinary icu of a tertiary hospital. twenty four norepinephrine dependent (> . γ /kg/min) patients, fulfilling the criteria of septic shock, were enrolled in the study. patients were divided in groups according to the continuous administration of mg hydrocortisone for days (group a: pts) or conventional treatment (group b: pts). end points of the study were, the within days vasopressors weaning, evolution of mods and -day as well as -day survival. mods was described by sofa score. statistics : statistical analysis was computed by using paired t-test and linear regression analysis. groups were similar regarding demographics ( ± vs ± y), initial sofa score ( ± vs , ± ), initial norepinephrine dose ( . ± . vs . ± . γ /kg/min) and mean elapsed time from the onset of shock ( . ± . vs . ± . days). an early and significant decrease in norepinephrine dose (p< . ), was observed in all group a pts, while no difference was detected in group b pts. this decrease was associated with hemodynamic stability. on days and mean abp was significantly higher in group a pts (p< . , p< . ). weaning from vasopressors within days was achieved in pts in group a ( . %) and pts in group b ( . %). seven day mortality was . % in group a vs % in group b while -day mortality was % and % respectively. in the treatment group a positive correlation between the within days shock reversal and survival (cor coeff = . , r = . , p= . ) was found. there was no relation between the time elapsed from the onset of shock to the steroid administration and survival (p= . ). oxygenation parameters (fio /po ), sofa score and creatinine did not differ between groups. wbc in group a pts were significantly higher (p< . ) only on day . no significant adverse effects were detected. in late septic shock patients with mods the administration of low doses of hydrocortisone is associated with decreased vasopressors requirements, hemodynamic improvement and beneficial effect on survival. the within days shock reversal was a good predictor of survival. introduction. early microcirculatory impairment followed by mitochondrial dysfunction may combine to produce multi-organ failure in sepsis. we recently reported that tissue oxygen tension (tpo ), the balance of local o supply/demand, is variably affected in four different organs (kidney cortex, liver, muscle, bladder) at h' post-endotoxin challenge ( ). we seek to measure temporal changes in tpo in these organs in a resuscitated rat model for up to h following the onset of faecal peritonitis. here we present our -hr timepoint results with assessment of the impact of fluid loading. methods. male wistar rats (approx g weight) with tunnelled right jugular venous cannulae in situ received i.p. injection of faecal slurry. fluid ( : mixture of % glucose/ % hetastarch; ml/kg/h) was started h later. at h, rats were anaesthetised with isoflurane, and then instrumented with a left common carotid arterial line and tissue po probes (oxford optronix, uk) sited in thigh muscle, between right and left liver lobes, in the left renal cortex and within the bladder lumen. after -min stabilisation, recordings were made of bp, tpo , and end-diastolic volume (edv) and cardiac output (co) by echocardiography (vivid , ge healthcare, bedford, uk). this was performed before (bi, baseline instrumented) and after fluid challenge (f) of ml/kg bolus of % hetastarch given to optimise lv filling. comparisons were made against sham-operated animals that underwent instrumentation but received no i.p. injection. notwithstanding considerable volume resuscitation beforehand, left ventricular filling and output were significantly reduced at h in this faecal peritonitis model. despite the % reduction in output, baseline tpo values were similar in bladder and renal cortex compared to sham animals but showed a decreased trend in muscle and a significant reduction in liver. fluid loading restored cardiac output to control values, however only muscle and liver tpo increased, albeit not significantly. these data suggest a combination of microcirculatory and mitochondrial dysfunction with each predominating in different organ beds at this timepoint. confirmation is required using complementary techniques. microcirculatory dysfunction leads to inadequate tissue oxygenation and multi organ failure during sepsis or septic shock. aim of this study was to compare non-invasive assessment of tissue oxygen saturation (sto ) with systemic oxygenation using mixed venous oxygen saturation (svo ) as an indicator in an established model of porcine septic shock. in a prospective animal study anaesthetised, ventilated pigs ( . ± . kg) were investigated. animals received g/kg/body weight faeces into abdominal cavity to induce sepsis and were observed over hours. volume therapy was administered to maintain a central venous pressure of mmhg. svo measured by co-oxymetry (radiometer, copenhagen) was obtained hourly after induction of sepsis. at the same time quadriceps muscle sto was measured by near-infrared spectroscopy (nirs) (inspectra tm , hutchinson, usa). correlation was analyzed by linear regression analysis. a total of measurements were performed in animals. sto was significantly correlated with the svo . r = . (r = . ) (p< . ) and y = , x + , . comparing the change in sto and svo of two successive measurements reveals a correlation of r = . (r = . ) (p< . ). changes in sto and svo were parallel in % of two successive measurements (both measurements changed at the same time in the same direction). although there is a significant correlation between sto and svo in our experimental septic shock model, paired sto and svo changed in the same direction only in %. thus, svo may not be estimated on the basis of sto in treatment of experimental septic shock and tissue oxygenation may not be estimated on the basis of svo either. whether a combination of sto and systemic oxygenation measurements is a useful monitoring approach in sepsis needs to be revealed. grant acknowledgement. inspectra device was provided by hutchinson. systemic immune response syndrome (sirs) frequently develops in critically ill patients and may lead to multiple organ dysfunction or failure even in the presence of normal or normalized global hemodynamic parameters, mainly due to tissue dysoxia and microvascular dysfunction. near infrared spectroscopy (nirs) is a validated method for the assessment of tissue oxygenation but its accordance with routine parameters has not yet been sufficiently studied. aim: to compare nirs parameters to routine monitoring parameters of the critically ill. thirty two consecutive critically ill patients (age= ± years, male/female= / , length of icu stay= ± days) were enrolled. all patients were evaluated with nirs and the occlusion technique within hours of icu admission. all patients were mechanically ventilated and were sedated. routine hemodynamic parameters (mean arterial pressure= ± mmhg, central venous pressure= ± mmhg, heart rate= ± ), full blood analysis (hemoglobin= . ± . g/dl, white blood cells= , ± , /dl) and arterial blood gases analysis were recorded. sofa, apache ii and saps iii ( ± ) scores were assigned on icu entry day. tissue oxygen saturation (sto %) was continuously monitored before, during and after -min occlusion of the brachial artery via pneumatic cuff inflated up to mmhg above measured systolic arterial blood pressure. (elwi) has been demonstrated to predict mortality and to correlate to pao /fio -ratio and to the compliance of the lungs in patients with sepsis and ards. however, with an increasing number of obese patients, there is the question which body weight should be used for indexation of elwi. therefore it was the aim of our study, to investigate the correlation of elwi to pao /fio -ratio and oxygenation index (mean airway pressure* / pao ) using different weight parameters for indexation. in patients of a medical icu with a body mass index > kg/m , measurements of extravascular lung water were performed using the picco system (pulsion, munich; . . software). extravascular lung water was indexed using the actual body weight (abw), predicted (pbw), ideal (ibw) and adjusted body weight(adbw) , respectively. these data were correlated to pao /fio -ratio and oxygenation index. spearman correlation, spss-software. the highest correlation to pao /fio -ratio was found using adbw, the highest correlation to oxygenation index for elwi adjusted to pbw. .) although the extent of correlation varied within smaller limits (- , to - . and . to . , respectively), the distribution of the patients within "normal", "modestly elevated" and "significantly elevated" elwi would have changed markedly using different indices. .) with regard to impaired respiratory function in the patients of our study, pbw, ibw and adbw seem to more accurately reflect "functional" extravascular lung water than abw with % of the patients in the normal range. our objective is to analyse the hemodynamic profile and the extravascular lung water in the first stages of severe acute pancreatitis (sap) that are admitted at the intensive care unit (icu), through the collected data by transpulmonary thermodilution. observational and prospective study, in which -sap-diagnosed patients consecutively admitted at the icu were analyzed. all of them were monitorised at their admission with continuous cardiac output system picco ® (pulsion medical systems). demographic variables, general (apache ii and sofa) and specific (balthazar) severity scores as well as the development or not of respiratory failure, were collected. the ordinary hemodynamic parameters [heart rate (hr), mean arterial pressure (map), cardiac index (ci), vascular resistances (svri)] were determined on days , , and as well as preload parameters [intrathoracic blood volume index (itbi), global end-diastolic volume index (gedi)], extravascular lung water index (elwi) and pulmonary vascular permeability index (pvpi) according to picco ® methodology. the results are expressed as means±sd and percentages. the non-parametric mann-whitney test for quantitative variables was performed and statistical significant level was established at p< . . age was ± years with a majority of males ( %). the biliar was the most frequent cause ( %). apache ii= ± and sofa= ± . all patients showed an alteration determined by ct scan (balthazar grading system) degree c or higher. seven patients ( %) needed mechanical ventilation in the first hours. hospitalary mortality was of %. on day , the ci ( . ± . l/min/m ) and the rvsi ( ± din.seg.cm - .m ) were at normal parameters and only patients needed vasopressor support. however, on days and , the preload parameters were low (itbi= ± ml/m and gedi = ± ml/m ) and improved on the th day (itbi= ± ml/m and gedi = ± ml/m ). patients with respiratory failure and mechanical ventilation showed neither higher elwi nor higher pvpi than the rest (day , elwi: . ± . vs . ± . ml/kg; pvpi: . ± . vs . ± . ; p=ns). in our population, certain hypovolemia degree in the first stages of the disease was found, corresponding to the development of the third space. the respiratory failure associated is not mainly due to an extravascular lung water increase or to a permeability increase. . ( . - . ) . ( . - . ) . cpo after dobutamine (w) . ( . - - ) . ( . - . ) . poap: pulmonary occlusion arterial pressure, swi: stroke work index. conclusion. cpodelta after dobutamine challenge is a good predictor for mortality in ss. septic shock is a common disorder with a high mortality. recent guidelines for the haemodynamic management of severe sepsis have emphasized the importance of aggressive volume resuscitation in the initial phase. central venous pressure (cvp) and pulmonary capillary pressure (pcp) are common end-points for volume resuscitation, however these cardiac filling pressures are poor predictors of fluid responsiveness in septic patients. right ventricular end diastolic volume index (rvedvi) is a better predictor of preload, and it allows the identification of patients with right ventricular (rv) dysfunction and dilation (> - ml/m ), as well as predicting mortality. we correlated rvedvi with pcp, cvp and hypoperfusion variables during septic shock initial management. longitudinal, prospective and observational study. demographic, haemodynamic (rvedvi, pcp, cvp) and hypoperfusion (lactate, base deficit) variables were obtained. descriptive statistics with mean ± sd (numerical variables) and frequencies and percentages (categorical ones). comparisons between groups with u mann-whitney test and x and fisher exact test as needed (statistically significant value if p< . ). results. patients (mean age ± )were divided in: survivors n= (rvedvi ± ml/mt ) and non-survivors n= (rvedvi ± ml/mt ). early dilation of rv predicts survival with a sensibility of % sensibility and specificity of %. methods. ten patients with severe sepsis ± yr, patients with septic shock ± yr and polytrauma patients with hemorrhagic shock ± yr, who remained in icu more than hours were included in the study. serial bnp measurements were performed for at least days. consecutive hemodynamic measurements were done using a right ventricular ejection fraction (rvef) thermodilution catheter (edwards). transthoracic echocardiography was performed in the first two days. . bnp values ( st day) was dramatically elevated in septic shock ( ± pgml- ), significantly elevated in severe sepsis ( ± pgml- ), but within normal limits in hemorrhagic shock ( ± pgml- ) (p< . ). inotropes (noradrenaline) were similar in patients with septic or hemorrhagic shock on day . bnp levels did not correlate with pulmonary arterial wedge pressure, right atrial pressure, rvef or left ventricular ef (lvef) measured by echocardiography. eleven patients with septic shock, with sepsis and with hemorrhagic shock died during days. bnp decreased gradually in survivors from septic shock after day . septic shock survivors had lower apache ii, and increased rvef and lvef compared to non-survivors ( ± , ± and ± vs ± , ± and ± respectively, all p< . ), but not bnp ( ± vs ± pgml- ). in conclusion, bnp is significantly elevated in sepsis, mainly in patients with septic schock, probably indicating the level of inflammation severity. inotropes, shock and myocardial stretch, as it is expressed from hemodynamic parameters, do not seem to be implicated to bnp release. sepsis and septic shock are major causes of mortality and morbidity in the icu. if inflammatory mediators responsible of sepsis remain elevated or if there is a poor cardiac function, septic myocardial dysfunction may occur, increasing morbidity and mortality. brain natriuretic peptide (bnp) is an adequate biomarker for cardiac failure so our objective was to determine its utility in predicting myocardial dysfunction in septic patients. the role of hemofiltration, its dose and biological effects in sepsis remain a contentious issue. although some beneficial effects on systemic hemodynamics and reduced vasopressor requirement were reported, the potential of hemofiltration to prevent sepsis-related disturbances of microcirculation and energy balance has not been evaluated. therefore, we investigated the effects of standard hemofiltration (hf, ultrafiltration rate ml/kg/h) and high volume hemofiltration (hvhf, ml/kg/h) during h hyperdynamic porcine septic shock. in mechanically ventilated and instrumented pigs fecal peritonitis was induced by inoculating autologue feces. h after induction of sepsis pigs were randomly assigned to three groups: ) controls (n= ), ) hf (n= ), ) hvhf (n= ). before, , and h after the induction of peritonitis we measured, in addition to systemic and regional hemodynamics, ileal mucosal and renal cortex microvascular perfusion (ops and laser doppler flowmetry). energy balance was determined by measuring arterial lactate pyruvate (l/p) and hepatic venous ketone body (kbr) ratios. in the control group hyperdynamic septic shock resulted in a progressive deterioration of intestinal mucosal and renal cortex microvascular perfusion despite well-maintained regional blood flows. altered microcirculation was paralleled by gradually increased l/p and kbr indicating disturbed energy balance. compared to six animals in the control group, only three and two pigs required noradenaline support in hf and hvhf group, respectively. however, neither hf nor hvhf blunted the sepsis-induced alterations in microvascular perfusion and cellular energetics. in this clinically relevant model of septic shock, the protective systemic hemodynamic effects of early hemofiltration did not translate into the improved microvascular perfusion and energy metabolism. hvhf did not confer any additional benefit. the value of hemodynamic improvement as a surrogate marker for efficacy of hf is therefore ambiguous. patients in prolonged septic shock show enhanced pressor sensitivity to vasopressin(vp) yet decreased response to norepinephrine(ne). as both act via g protein-coupled receptors and activate the inositol phosphate cascade to increase vascular smooth muscle(vsm) ca + levels, the reason for this disparity is uncertain. we postulate that these drugs may have diverse effects on different ca + mobilisation pathways during sepsis. we investigated this using specific modulators of ca + release and influx on contractile responses to vp and ne in mesenteric arteries from septic and sham-operated rats. sepsis was induced in awake, fluid-resuscitated wistar rats by ip injection of fecal slurry. paired sham controls received no injection. rats were sacrificed after h, and mesenteric arteries mounted on a wire myograph to measure isometric tension responses to vp and ne. the contributions of sarcoplasmic reticulum(sr) ca + release and ca + entry through the store-operated channel(socc) were assessed by removing and returning extracellular ca + respectively. the contribution of the voltage-gated ca + channel(vgcc) was assessed by applying vp/ne in the presence of nifedipine. contractions were significantly enhanced to vp but depressed to ne in septic vessels . in all arteries, constriction to both agonists relied predominantly on extracellular ca + influx rather than sr ca + release. ne responses were more sensitive to extracellular ca + removal in septic vessels. the ca + influx in response to ne was almost entirely vgcc-mediated, with a negligible contribution from soccs in both sham and septic arteries. soccs contributed significantly to vp contraction however, and socc-rather than vgcc-mediated influx of ca + predominated in septic arteries. patients in prolonged septic shock show enhanced pressor sensitivity to vasopressin (vp) yet decreased responsiveness to norepinephrine (ne). we have reproduced this pattern in ex-vivo contractile responses of resistance arteries taken from rats subjected to a clinically realistic septic insult ( ). we hypothesise that an underlying mechanism is vp-mediated sensitisation of the vascular smooth muscle contractile apparatus to calcium. to investigate this, we performed simultaneous wire myography and fluorescence microscopy to examine the relationship between contractile response and intracellular calcium concentration ([ca + ]i). sepsis was induced in conscious, tethered, male wistar rats by intra-peritoneal injection of faecal slurry. paired sham controls received no such injection. both groups received ml/kg/hr of intravenous fluid. after hours, animals were sacrificed, and rd order mesenteric arteries dissected and mounted on a wire myograph (danish myo technology). arteries were loaded with a fluorescent calcium indicator (fura- , mum) for hour and imaged by fluorescence microscopy. [ca + ]i and isometric tension kinetics were measured simultaneously in response to vp ( nm) and ne ( mum). ]i was higher in arteries taken from septic rats. tension responses to vp were significantly enhanced in septic arteries, however the associated increases in [ca + ]i were comparable in septic and sham groups. tension responses to ne were significantly decreased in septic arteries, with a similar degree of depression in delta [ca + ]i. data were analysed for statistical significance using un-paired t tests. conclusion. the higher baseline [ca + ]i in the vascular smooth muscle of septic arteries suggests an abnormality of intracellular calcium storage. the ability of vp to produce a greater contractile response in septic compared to sham arteries, despite an equivalent degree of [ca + ]i elevation, implies sensitisation of the contractile apparatus to the effect of vp. there was contractile hyporesponsiveness to ne in the septic vessels and no evidence of calcium sensitisation to this agonist. these findings provide one potential explanation for the hypersensitivity to vp observed in patients with septic shock. mitochondrial dysfunction and compromised cellular energetic status are associated with poor outcome in septic patients [ ] . maintenance of mitochondrial function is mediated in part by activity of transcription factors nrf- and nrf- , the transcriptional co-activator pgc -alpha and mitochondrial transcription factor alpha (tfam). these markers of mitochondrial biogenesis were elevated in a rodent model of endotoxaemia [ ] . in an ongoing study in critically ill patients, we have investigated the relationship between cellular energetics and mitochondrial biogenesis. with ethics approval and appropriate consents, critically ill patients were recruited within h of icu admission. age-matched control patients were undergoing elective hip surgery. muscle biopsies were taken from vastus lateralis. atp and creatine compounds were determined by hplc of perchloric acid extracts and standardised to total creatine [total cr = phosphocreatine (pcr) + creatine (cr)]. mrna levels for pgc -alpha, nrf- and tfam were determined by rt-pcr and standardised to s mrna. data were analysed for significance using one-way anova. the ratio of pcr/cr was significantly decreased in both survivors and non-survivors. mrna levels of the mitochondrial biogenesis markers pgc- alpha and nrf increased in survivors but not in non-survivors. a similar pattern was observed with the mitochondrial transcription factor tfam, although statistical significance was not reached. ( ) the decreased pcr in both survivors and non-survivors indicates increased demand for atp in the acute phase of critical illness. ( ) increased levels of markers of mitochondrial biogenesis in survivors indicate that maintenance of mitochondrial function, specifically atp synthesis, may be crucial to recovery. failure to maintain adequate mitochondrial function through biogenesis may contribute to atp depletion and mortality. local metabolic changes are not well investigated in sepsis and sirs. our aim was to describe subcutaneous metabolic changes using microdialysis (md) concurrently with systemic hemodynamics over days in patients with sepsis/sirs and circulatory failure. methods. patients with severe sepsis/sirs were recruited. at inclusion, all patients had circulatory failure despite resuscitation according to the rivers concept. cardiac index (ci), intrathoracic blood volume index (itbvi), extravascular lung water index (evlwi), blood lactate (p-lac), md lactate (md-lac) and md lactate-pyruvate ratios (md-lac/pyr) were analysed - hourly. data were tested for differences over time using anova. patients were subdivided into sepsis and sirs groups, and intergroup differences were tested using the rank sum test. mean apache scores were & for sepsis & sirs respectively. sofa decreased from . to . with no difference between sepsis & sirs. ci increased over time and itbvi, evlwi, p-lac & md-lac decreased. md-lac & p-lac were maximal at day . lactate concentrations were generally higher in md than in blood, and in the sepsis group. severe sepsis and septic shock have been recognized as a serious clinical problem that shows an increasing incidence and that is responsible for substantial morbidity and mortality in intensive care units. sepsis has been defined as the systemic host response to infection with an overwhelming systemic production of both pro-and anti-inflammatory mediators. continuous hemofiltration has been suggested as possible therapeutic option that may remove the inflammatory mediators. on the other hand, hemodialysis and hemofiltration were reported to influence cardiac electrophysiological parameters and to increase the arrhythmogenic risk. therefore, in this study we have investigated the effects of hemofiltration on electrophysiological properties of the septic pig heart. methods. pigs of both sexes were divided into groups: ) control group without hemofiltration; ) control group with conventional hemofiltration ( ml/kg/hour); ) septic group without hemofiltration; ) septic group with conventional hemofiltration ( ml/kg/hour); ) septic group with high-volume hemofiltration ( ml/kg/hour). in septic groups, the sepsis was induced by fecal peritonitis and maintained for hours. hemofiltration was applied for the second hours of this period. ecg was measured just before and after -hours period of sepsis in septic groups and at the same time points in non-septic groups. action potentials were recorded in isolated ventricular preparations obtained from the hearts at the end of experiments. . rr and qt intervals were significantly shortened by sepsis in all septic groups, in non-septic groups they were not influenced by the experiment. action potential duration (apd) was also significantly shortened by sepsis (septic group without hemofiltration vs. control group without hemofiltration) at all cycle lengths tested ( , , ms). both conventional and high-volume hemofiltration in septic groups shortened apd further at slow pacing rates. hemofiltrate obtained in septic groups by both conventional and high-volume hemofiltration prolonged significantly and reversibly apd at all pacing rates. substitution solution alone had no effect on apd. neither hemofiltration nor hemofiltrate in control, non-septic groups influenced apd. we conclude that the hemofiltration in septic groups and the septic hemofiltrate influence significantly the electrophysiological properties of the heart, probably due to removal/content of various inflammatory mediators in the septic hemofiltrate. introduction. the precise mechanism by which multiorgan failure develops in severe sepsis and septic shock remains unclear. potential mechanisms include alterations of microvascular flow distribution, mitochondrial dysfunction and treatment effects. we investigated the effects of lps and different catecholamines on oxidative respiration of rat skeletal muscle fibers and hepatocytes. muscle fibers (m. gastrocnemius) were isolated from anesthetized male wistar rats ( - g). human hepatocytes (hepg cells) and human monocytes (monomac -mm ) were also used. to avoid systemic effects of endotoxin and catecholamines, experiments were performed in vitro using the skinned-fiber technique. the mechanically dissected muscle fibers were incubated with lps ( µg/ml) for h. after h of lps incubation, norepinephrine, dopamine, and dobutamine ( µm each) were added. monocytes and hepatocytes were treated with different concentrations of lps only. mitochondrial respiration was determined after permeabilization with saponin, using a clark type electrode (oxygraph k, orobros instruments, innsbruck, austria). septic shock is associated with severe cardiac dysfunction, whose mechanisms remain only partly defined. recent data suggested that it might be triggered by the direct action of microorganisms and their products on the heart itself. we previously shown that flagellin (flag), the protein monomer from bacterial flagella, is a potent activator of nf-κb-dependent pro-inflammatory signaling in cultured cardiomyocytes. therefore, the aim of the present study was to evaluate whether flag might induce such an inflammation in the heart in vivo and contribute to cardiac dysfunction. h c cardiomyocytes were stimulated with recombinant salmonella muenchen flag ( - ng/ml, min to h). in vivo, balb/c mice were injected (tail vein) with - µg flag ( min to h). the effects of flag were evaluated by its ability to activate nf-κb, and to induce transcription of tnfα and mip- cytokines. in vivo, cardiac neutrophils recruitment was evaluated by myeloperoxidase (mpo) activity. the expression of the flag receptor tlr was also determined. in vivo physiological measurements: left ventricular pression-volume curves. a microtip pressure-volume (pv) catheter (spr- ; millar instruments) was inserted into the left ventricle (lv) via the right carotid artery. the pressure and volume signals were continuously recorded and heart rate, cardiac output, end-systolic and end-diastolic volumes, stroke volume, ejection fraction and end-systolic and end-diastolic pressures were measured. load-independent indices of lv systolic and diastolic functions were determined by the slope of the end-systolic, respectively end-diastolic pv relationships in conditions of rapidly reduced preload (transient compression of the vena cava). . flag activated nf-κb in cardiomyocytes in vitro and in vivo, and also upregulated the transcription of tnfα and mip- . flag also increased cardiac neutrophils recruitment. flag induced significant increases in end-systolic and end-diastolic lv volumes, indicating cardiac dilation, and a significant reduction of the load-independent indices of lv systolic function (end-systolic pv relationship, espvr, and maximal elastance, emax), indicating significant lv systolic dysfunction. in contrast, no change in the slope of the end-diastolic pv relationship (edpvr) was noted. bacterial flagellin induces a prototypical inflammatory response in cardiomyocytes in vitro and in the myocardium in vivo. these effects are associated with a profound alteration of the lv systolic function in vivo, suggesting that flagellin may represent a critical mediator of cardiac dysfunction in septic shock. current guidelines recommend either dopamine (da) or norepinephrine (ne) as the initial vasopressor in septic shock (ss), but the management of moderate to severe ss is still controversial. to explore this issue is important, because pharmacodynamic differences between vasopressors might be irrelevant in mild cases, but could potentially affect outcome in more severe patients. beside clinical implications, there are also economical considerations since these drugs are not cost-equivalent. this subject may be specially important for developing countries. the aim of our study was to compare ne vs da as the exclusive vasopressor for established moderate to severe septic shock (requirements of > . mcg/k/min of ne or > mcg /k/min of da to maintain map to mmhg) multicentric rct involving nine polivalent icus from argentina, brazil and chile, randomizing moderate to severe ss patients to ne or da titrated to target map or maximal dose of mcg/k/min ne or mcg/k/min da. after inclusion patients were switched blindly to the assigned drug. the study could be stopped if severe hypotension or arrhythmias developed. epinephrine was used as a rescue drug. main outcome criteria were day mortality, organ dysfunctions and adverse effects (ae). the study was stopped early after randomizing patients because of low enrollment rate. only patients were evaluable. main results are shown on the table. adverse effects with da were cases of atrial fibrillation (af) and supraventricular paroxysmal tachycardia (spt), which were considered serious in cases. aes with ne were two af and one spt, which resolved with no drug suspension. aes occurred more frequently with higher doses of da. conclusion. the use of dopamine as exclusive vasopressor for established moderate to severe septic shock appears to be associated with a worst outcome and more adverse effects. this should be explored in a future better powered rct. although arterial blood pressure (abp) is a widely used guide for hemodynamic therapy in sepsis, few data exist on its association with mortality and on critical abp limits that should be maintained. in this retrospective cohort study, clinical, hemodynamic, and laboratory parameters were extracted from a prospectively collected database in sepsis patients. the severity and duration of hypotension was calculated by the area under the curve (auc) of systolic arterial blood pressure (sap), mean arterial blood pressure (map), and mean perfusion pressure (mpp = map -central venous pressure). laboratory parameters included the most aberrant variables during the icu stay. urine output per hour during the first hours and need for renal replacement therapy were recorded. the sepsis-related organ failure assessment (sofa) score was calculated from given clinical and laboratory parameters. binary and linear regression models were corrected for the severity of disease by inclusion of the saps ii (excluding sap count) as a covariate and were used to examine the association between abp and day-mortality or organ function. similarly, a binary logistic regression model including saps ii as a covariate was used to determine the best discriminating cut-off limit of abp in regards of day-mortality. the goodness of fit of each limit was assessed by the r -value according to the nagelkerke method. . sap and map were recorded for . ± . hours, mpp for . ± . hours. there was a significant association between day-mortality and the auc of sap (p< . , r = . ), map (p< . , r = . ), mpp (p< . , r = . ). the area under map mmhg and mpp mmhg was associated best with day-mortality. one or more episodes of map < or mpp < mmhg increased day-mortality by . (ci % . - . , p= . ) and . (ci % . - . , p= . ), respectively. there was a linear association between time under the critical map and mpp limit and day-mortality. while abp was significantly associated with the sofa score, arterial lactate levels, and renal function, no association with liver function or troponin i was observed. the critical map and mpp limits for the need for renal replacement therapy were mmhg (r = . , p< . ) and mmhg (r = . , p< . ), respectively. during early sepsis, abp is associated with day-mortality and organ function. mpp shows the best association with mortality and may be a new resuscitation target. animal models of traumatic brain injury (tbi) are used to elucidate sequelae underlying human head injury in an effort to identify potential neuroprotective therapies. although human tbi is a highly complex multifactorial disorder, animal trauma models tend to replicate only single factors involved in the pathobiology of clinical head injury and may thus partly underlie the discrepancy between preclinical and clinical trials of neuroprotective therapeutics. we here present our experience with a large animal model of tbi which was designed to closely resemble the forces impacting the brain in e.g. traffic accidents. anesthetized, mechanically ventilated instrumented sheep (n= ) were placed in prone position with the head resting on a support to allow free lateral movements of the head. a left-temporal head impact was then delivered by mechanical stunning device (mk , schermer, germany), which is approved for euthanasia of domestic lifestock. a captive bolt with a mushroom-shaped head is propelled from the muzzle of the stunner against the skull by the discharge of blank cartridge inserted in a chamber behind the proximal end of the bolt. depending on the charge and the positioning of the stunner, this device delivers an intracranial atmospheric pressure of approximately bar in sheep at a bolt velocity of approximately ms- . to prevent skull fractures, a steel plate was attached to the left temporal fossa. a fiberoptic intracranial pressure (icp) catheter and a brain tissue oxygen (pbro ) probe were introduced in the parietal white matter. unilateral ultrasound flowprobes were attached to the internal carotid artery to measure cerebral blood flow. after measurements, sheep were killed and the brains removed for neuropathological examination. brain injury was characterized by a marked increase in icp from ± to ± mmhg (mean values ± standard deviations) hours after head impact. intracranial hypertension was accompanied by a significant decrease of cerebral blood flow. pbro significantly decreased from ± to ± mmhg. the decrease in sinus venous oxygen saturation did not reach statistical significance. in instrumented control animals (n= ), parameters remained unchanged. neuropathological examinations revealed the presence of multifocal traumatic subarachnoid hemorrhage in , and diffuse axonal injury in out of animals. while interstitial brain edema was found in all sheep brains, contusion zones were present only in a minority of the animals. the pathobiological characteristics of the head impact model presented here closely resemble the alterations frequently found in human tbi. the relatively high variability of neuropathological changes after head impact may be seen as a disadvantage of this model. non-neurologic organ dysfunction triggered by infection represents a frequent and independent predictor of poor outcome in traumatic brain injury (tbi) patients admitted to intensive care units ( ). because tbi itself significantly increases susceptibility to infection ( ) and infection is a potentially modifiable risk factor, we developed a combined experimental model of tbi and sepsis in the rat. controlled cortical impact (cci) was produced in left parietal cortex by using a mm diameter tip (velocity m/sec; depth mm). sepsis was induced contemporarily by cecal ligation and puncture (clp). the outcome was evaluated in terms of mortality, neurological function (via the morris water maze (mwm) and beam balance (bb) tests)and histologically. rats were subdivided into groups: sham, cci, clp, and cci + clp. -day mortality was % in sham, % in cci and % in clp group respectively. adding clp to cci increased mortality up to % (p< . vs cci and p< . clp alone). at h and week post-injury mwm and bb test performance was significantly worse in cci and cci + clp than in sham and clp groups (p< . ). lesion volume was similar in injured groups. ca cell loss in left hippocampus was unaffected in the sham and clp groups, while it was % in cci and % in cci + clp groups (p< . cci vs cci + clp). our results show that the occurrence of systemic sepsis exacerbates mortality and cerebral damage in rats subjected to traumatic brain injury. t. j. p. lieutaud* , j. rhodes , p. j. d. andrews anesthesiology and intensive care medicine, hospices civils de lyon, lyon, france, anesthesiology and intensive care medicine, university of edinburgh, edinburgh, united kingdom introduction. human recombinant erythropoietin (epo) appears promising in different brain injury models but its cellular mechanisms remain poorly understood. following brain trauma injury (tbi), inflammation (il- b) and chemokine expression (mip- , neuropath appl neurobiol ) are important. the aim of this study was to measure the effects of acutely administered rhepo on il- b and mip- after tbi. methods. with home office approval, under isoflurane anesthesia rats sd were subject to lateral fluid percussion tbi ( . - . atm) (dixon j neurosurg ) of the left parietal cortex. epo ( , or iu/kg) or placebo were injected in a random and double blinded manner by the intra-peritoneal (ip)route. the ipsi-and contra-lateral cerebral cortices were removed h later and homogenized. il- b and mip- were measured in the surnageant using elisa kits. results are expressed as pg/mg of protein (mean ± sem). there was a significant increase in il- b and mip- in the ipsilateral cortex in comparison with the contralateral side for both proteins analyzed. neither nor and iu/kg rhepo did not exhibited any significant effect (figure ). conclusion. this study confirms that inflammation is important and occurs early after lfp-tbi. epo did not display significant effects on two of the main inflammation mediators. the purpose of this study was to evaluate the effects of agmatine on histopathological damage following traumatic injury using a clinically relevant model of diffuse axonal injury (dai) on the rat. a total of male sprague-dawley rats weighing - g were anaesthetized and subjected to head trauma using marmarou's impact-acceleration model. the rats were then separated into two groups; one group was treated with agmatine and the other group was treated with saline for up to four days immediately after the head trauma. rats from both groups were killed one, three or eight days post-injury. the brains were examined histopathologically and scored according to the neuronal, vascular and axonal damage. there were no significant histopathological differences between the control and agmatine-treated group after one or three days (p> . ), but evaluation after eight days revealed a significant improvement in the group treated with agmatine (p< . ). our data indicate that agmatine has a beneficial effect in diffuse axonal injury and should be tried for therapeutic use in the management of this condition. d. morii*, y. miyagatani critical care department, national hospital organization kure medical center, kure, japan the disadvantageous effect of haemorrhagic shock on head trauma related mortality are well known. thus, efficacious shock treatment is a surely significant measure against the development of secondary brain damage. the small volume resuscitation by hypertonic saline has been shown to promote systemic and cerebral haemodynamic benefits. similarly, many clinical studies have demonstrated the effects of long-term mild hypothermia on outcome of traumatic brain injury. in this study, we evaluated the new strategy consisting of therapeutic mild hypothermia and hypertonic saline therapy to the multiple trauma patient with severe traumatic brain injury. severe multiple trauma patients (iss>= , head ais>= ) were studied to evaluated the efficacy of therapeutic hypothermia ( . ˚c for h) and hypertonic saline therapy (na+: meq/l for the first h , meq/l for to h, meq/l for to h) which were applied to them in parallel with massive blood transfusion . we evaluated glasgow coma scale (gcs), injury severity score (iss), the probability of survival (ps), the volume of blood transfusion, infusion and urine volume during the first days, and glasgow outcome scale (gos). we monitored the extent of brain swelling by head ct. four male patients (age: ± y.o., mean±sd) were examined. the characteristics of injury mechanism were explosion , mva , fall . on admission, gcs, head ais, iss and ps were . ± . , . ± , ± and . ± . , respectively. the sum of blood transfusion, infusion, and urine volume during the first h were ± ml, ± ml, ± ml. no patient was died and their gos on posttrauma day was . ± . . the combined therapy of therapeutic hypothermia and hypertonic saline to multiple trauma patients with brain injury may lead to good outcome in spite of the necessity of a large quantity of blood transfusion and infusion. recent data suggest that commonly used anaesthetic agents, e.g. propofol, cause neurodegeneration in the developing brain. the intention of our study was to investigate the effects of propofol on primary neuronal cultures referring to the cell survival rate. primary cortical neuronal cultures were prepared from wistar rat embryos at days gestation. to test the effect of propofol on neuronal survival, cultures were exposed to µl gibco neurobasal-a medium per well with propofol at a concentration of mg/ml for , , , , , and hrs. cell viability was assessed using the methyltetrazolium method (mtt) and was related to untreated cells as controls. all cells were kept in normoxia. after three and six hours of exposition to propofol cell viability values of the propofol treated cells were significantly higher ( . ± . %, p= . and . ± . %, p= . , respectively) compared to untreated control cells ( %). after hours, values were decreasing to levels of the control cells ( . ± . %). after , and hours of exposition to propofol, in contrast, cell viability was significantly reduced ( . ± . %, p= . , . ± . %, p< . and . ± . %, p< . ) compared to controls. at high concentrations, propofol has a time-dependent effect on the viability of primary cortical neurons. during the first hrs propofol has a potential neuroprotective effect, whereas it seems to cause neurodegeneration in the period of to hrs of exposition. e. paramythiotou* , j. papanikolaou , p. ntagiopoulos , a. armaganidis , a. karabinis icu, attikon university hospital, icu, george gennimatas hospital, athens, greece multiple trauma patients constitute a significant majority of admissions in a general icu. brain injury is often present in those patients. the aim of our study was to investigate demographic, clinical and management characteristics in trauma patients suffering a brain injury in a five year period. in a retrospective study all trauma patients hospitalized in the -bed multivalent icu of a bed -tertiary hospital between st jan and th dec suffering a traumatic brain injury were enrolled. recorded data included age, gender, cause of the injury, icu length of stay, initial glasgow coma score (cgs), submission or not to an emergent neurosurgical intervention, all cause mortality and neurological outcome. a total of trauma patients were hospitalized during the study period. tbi was present in patients ( . %). among them, were women ( %) and ( %) were men. their mean age was . years (range - ). icu length of stay (los) ranged between two and days (mean . days). traffic road accidents were the cause in cases ( . %) while tbis ( %) were due to fall from a height on the ground which happened either accidentally or as a result of a suicide attempt. the rest cases ( . %) were due to accidents during work. mean glasgow coma score was seven (range - ). an extradural hematoma was present in p and a subdural one in p. intracerebral hemorrhage was noticed in p, hemorrhagic contusions in p (with or without diffuse axonal injury) and a traumatic subarachnoid hemorrhage in p. twenty nine patients were submitted to craniotomy and p were submitted to unilateral or bilateral decompressive craniectomy. mean los was . d for p submitted to a surgical intervention versus d for the other group. barbiturates were used in p ( %). a total of patients survived ( . %). death was due to neurological cause (herniation of brain stem and subsequent cerebral death) in p. other causes of death included sepsis, multi organ failure, severe injury in other organs, and hemorrhage from upper gastrointestinal tract. a poor neurologic outcome (mean glasgow outcome score < ) was noticed in % of patients. almost two thirds of trauma victims suffer from a cerebral injury. most of them are young males, victims of traffic road accidents. the injury is often severe and one third of patients are submitted to a neurosurgical operation. though overall mortality is rather low, long duration of treatment is often required and severe disability is present in a not negligible number of patients. in the majority of the intensive care units (icu), several of the admissions involves patients with primary nervous system illnesses. a great progress of the technologies used in the icu in the last few decades had reduced neurological illnesses mortality and morbidity. since september of we had beginning an longitudinal e prospective coort study verifying the characteristics of the patients years older that had been admitted in the icu for primary neurological cause (clinical or surgical). the study occurred in a private hospital icu with beds. we recorded patients until the moment. the number of neurological patients corresponds % of the admissions in the unit. the average age of this group of patients is significantly lesser of the remain icu patients ( vs. years), however does not have difference estatistically significant between apache ii ( vs. ) and the mortality ( vs. %) of the neurological patients and others. the stay of length in the unit is bigger ( , vs. , ) . we also recorded mechanical ventilation time length ( % ventilated patients with for average time days). in ventilated patients, % was tracheostomyzed (on average in days). % developed sepsis ( % with septic shock). the patients were divided and analised in several goups (for example: trauma, surgery, central nervous sistem infection, vascular disease,...). neurology was one of the most benefited specialties with the intensive care units progress and evolution. however, high mortality and morbidity caused by the neurological illness, and the social and economic impact that its sequels cause, still deserve the attention of the involved professionals cares of these patients in the acute illness. n. baffoun* , w. gdoura , h. ouragini , k. baccar , m. lamourou , t. chaoua , r. souissi , c. kaddour , n. ben romdhane , s. mahjoub anesthesia and intensive care, national institute of neurology, departement of haematology, chu la rabta, tunis, tunisia trauma victims develop frequently various degrees of haemostatic disorders. the severity of such post traumatic coagulopathie is considered to be major detrimental factor of outcome. the aims of our study were: to identify the origin of such disorders, time course and their correlation with mortality. our aim was identification of coagulopathy disorders and relation to outcome in severely head injured. prospective study,june -march . included:critically ill isolated closed severe head trauma. collected data:demographics,management prior and during icu hospitalization (sedation, catecolamin drug use, blood product transfusion, intra-cranial pressure monitoring, neurosurgical emergency surgery etc.),ct-scan results, daily worst glasgow coma scale, admission simplified acute physiology score ii. we inserted an arterial catheter for invasive pressure monitoring, a central venous catheter and a unilateral jugular bulb in front of the most damaged brain hemisphere(cf. ct-scan). jugular bulb thrombosis was prevented by continuous infusion of ml per hour isotonic serum without heparin. blood samples were obtained simultaneously from the central venous line(k) and jugular bulb(b) at admission, th, th hour, and then in case of neurological aggravationt or daily till th day. we measured platelet count,prothrombin time (pt),activated partial thromboplastin time (act),fibrinogen concentration (fib), prothrombin fraction + (f) and thrombin anti-thrombin complex (tat). during the study only central venous blood samples (pt, act, fib and platelet count) could be available if necessary. otherwise blood samples were centrifuged and preserved refrigerated for post hoc analysis. statistical analysis by student's t test, paired t test for paired results and analysis of variance. significance set as p< , . results. n= ; survivors(s) and deaths (ns). no differences between s and ns in demographics,management modalities, admission gcs( ± ), ct-scan,saps ii ( ± vs ± , p= , ). b vs simultaneous k platelet count was significantly lower in all drawn blood samples,with a trend to decrease overtime. s vs ns at day and day : ± vs ± (p= , ). admission b thrombin fractions was higher in ns( ± vs ± , p= , ). b day tat was higher in ns: ± vs , ± p= , . no difference for other tests between b vs k and s vs ns for different paired tests. pro-coagulant factors (f and tat) are valuable prognostic factors at day in closed isolated severe head trauma. severe traumatic injury is a multisystemic disease where normal homeostatic mechanisms are lost. this situation involves an increase in physiological needs. usually these patients present anormalities in the hypothalamic-hypophyseal axis, which become neuroendocrine dysfunctions with deteriorated physical or neuropsychological secuelae. the aim of this study is to improve our knowledge about this part of the axis in acute phase of politraumatism. methods. an observational prospective study was carried out, with patients who were admitted to our icu with a critical traumatic injury, for six months. demographic and epidemiological data were registered. apache-ii (acute physiology and chronic health evaluation system) and apache-iii scores during the first three days were measured. tiss (therapeutic intervention scoring system) score during the hospital stay was recorded. also gh (grown hormone), igf- (insulinlike-grown-factor- ) levels and nitrogen urinary losses in the first three days after traumatic event were measured. statistical data were analysed with the spss . program. in our study , % ( cases) were men and , % ( cases) were women. the average age was , years old. the hypothalamic-hypophyseal-somatotrophic axis role in the first three days was characterized by a progressive increase in gh levels and a progressive decrease in igf- levels. connections between average hormonal levels in the first three days and apache-ii, apache-iii and tiss scores during this time were studied. a good inverse connection between igf- and prognosis was shown si (spearman index) - , , - , p value , and , respectively with apache-ii and apache-iii. this appropriate connection could not be shown with tiss score sp - , p value , ; but the connection between gh and tiss was better, sp , p value , . conclusion. gh levels increase and igf- levels decrease in the first three days after acute trauma. lower igf- levels can mean a worse prognosis. there are no connections between igf- and sanitary resources used (tiss score) but these connections seem to get better when gh levels are higher. trimodal distribution of deaths and the golden hour concepts are in part responsible for the genesis of all modern trauma systems but these concepts have been challenged recently. our aim was to describe distribution of death in trauma using data from a trauma system and discuss what can be done from the organizational point of view to improve outcome. all traumatic deaths occurring between and in a trauma system were. data on age, gender, time and place of injury, time of first and second hospital arrival, cause of trauma and type of accident, hospital characteristics, dominant injury and time of death were collected for this study. for mortality distribution the variable time was transformed applying a natural logarithm. results. deaths occurred over a period of months. % at the scene, % in the level i trauma centre, % in level iii trauma centre and the remaining in level iv/v trauma centre. death distribution using a logarithmic scale in minutes showed four peaks: deaths at the scene, deaths in the first hours, deaths in the first two days and finally deaths in the second week that we referred as minutes, hours, days and weeks peak (image ). we found statistically significant differences in age and dominant injury concerning timing of death. a tetramodal pattern of death distribution could be described. our data support the need to focus on the treatment of severe head injuries namely in the intensive care environment. anaemia is usually detected in critically ill patients. red bloos cell transfusion is not free of risk. we want to start an alternatives to transfusion protocol but fist we tryed to dercrive our critically ill patients anaemia. our objectives were to: study the red blood cell and iron metabolism in the icu patients at admission. observe changes in these parameters across the first seven days after admission. observe rbc transfusion and his relation whit morbidity and mortality. find transfusion predictors at the admission moment. during tree mounths of , we include all the admissions in a trauma and neurocritical icu of our hospital that stay in unit more than hours. at the moment of admission we determinated haematocrit, (hto), haemoglobin (hb), and reticulocytes (%retic) levels, iron metabolism, folic acid, b , epo and creatinin (kr) we repeated determinations seven days after admission if patient was still in icu. adverse events occurred during icu stay were also registered (mainly infections) together the number of rbc transfusions (with hb levels before and after administration). we included in the study patients. severe traumas ( %), neurocritical patients ( %), tumoral neurosurgery ( , %) and other patients ( %) . average age was . years and apacheii . ± . points. % were males . results of admission blood determinations and seven days after are exposed in table i . there is a tendency to decrease in hto and hb parameters, but not significant. the only parameter we observe difference statistically significative was the reticulocites rate (%retic), significative lower days after admission. (p< . ) in graphic we describe anaemia groups in admission and the evolution of anaemia groups seven days after admission. we appreciated that no anaemia group suffers a severe decrease. % of patients were transfused during their fist week stay. average levels of pre-transfusional hb were . g/dl . we analysed transfusion predictors. hto and hb levels at admission predict transfusion. there is no other analytical parameter at admission that predicts transfusion. we also detected tracheal intubated patients at admission and patients with inotropic drugs perfusions at admission were significative more transfused (p< . and p< . ). conclusion. the high mortality rate in our patients is related to the initial gcs and cranial cat at the moment of admission. it is necessary to continue the study to determine the influence of the rest of the variables in the mortality rate of these patients. introduction. traumatic brain injury, subarachnoid hemorrhage (sah) and spontaneous intracerebral hemorrhage (ich) are associated with systemic inflammatory response syndrome (sirs). early diagnosis of sepsis versus sirs is frequently difficult in neurointensive critical care units. procalcitonin (pct) has been used as a predictor marker of bacterial infection in different groups of patients. there is variable and scarce information about pct in neurocritical patients. the aim of this study was to evaluate the utility of serum pct in the early diagnosis of fever from bacterial infectious origin in patients with acute brain hemorrhage. we made a prospective diagnostic study between july and january . we analyzed serum level of pct and c-reactive protein (crp) on consecutive patients with diagnosis of sah, ich or tbi who have fever during the intensive care unit admission. we excluded patients with antibiotic therapy previous to admission. pct and crp were blindely measured from samples of serum extracted within hs of fever onset and within hs of antibiotic administration. blinded to pct and crp results and according to previously defined criteria patients were classified in two groups: proved bacterial infection (pbi) and non proved bacterial infection (npbi). serum pct was measured by immunochromatographic semiquantitative method brahams pct-q (brahams diagnostica, berlin, germany). its sensitivity is . ng/ml. we analyzed sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) of serum pct and crp for diagnosis pbi. we defined negative serum pct as < . ng/ml and negative crp as < mg/l. we studied patient, with sah ( %) and with ich ( %). ten patients had pbi ( %, %ci - %). pbi were pneumonia ( ), urinary tract infection ( ), meningitis ( ) and central line associated blood infection ( ). two patients had simultaneous infection sources. there were bacteremic infections. pct was positive in patients in pbi group ( pneumonia and bacteremic central line associated blood infection) and in of npbi. sensitivity was % ( %ci - %), specificity % ( %ci - %), ppv % ( %ci - %) and npv % ( %ci - %). crp was positive in pts, pbi and in npbi. sensitivity was % ( %ci - %), specificity % ( %ci - %), ppv % ( %ci - %) and npv ( %ci - %). in this study serum pct had an adequate ppv to diagnose pbi, without false positives results. however, it has a low negative predictive value to diagnose pbi. due to the results obtained, we consider that the quantitative pct assay with a sensitivity limit of . ng/ml should be used for the future study to evaluate the role of pct as a predictor marker of acute bacterial infection in patients with acute brain hemorrhage. in different published series cerebral infarction occurs in - % of patients with symptomatic vasospasm after subarachnoid hemorrhage (sah) despite maximal therapy. standard triple-h treatment is associated with life-threatening side-effects (such as myocardial ischemia and pulmonary edema) and has not been properly validated. milrinone, a phosphodiesterase iv inhibitor, has few side effects and exhibits inotropic, vasodilatory and immunomdulatory properties besides inhibiting platelet aggregation and thromboxane a synthesis. we present our experience using our m&h protocol (milrinone and homeostasis) in patients with vasospasm. it consists of cvp-guided normovolemia (maintain cvp=or> ), aggressive temperature control, maintenance of normal serum sodium and step-wise interventions based on symptoms (milrinone . - . mg/kg bolus plus infusion, levophed and angiogram plus intra-arterial milrinone). we retrospectively reviewed the charts and imaging studies of patients diagnosed with symptomatic vasospasm based on the development of focal symptoms and the results of angiographic and doppler studies. cerebral infarction was defined as a new hypodensity on ct scan appearing at least days after aneurysm clipping or coiling. conclusion. among the different physiological scores, the sah-pds was most strongly associated with the major outcomes and the h&h score was better than the other aneurysmal bleed scores. the strong association of physiological scores with outcomes suggest that interventions targeting physiological derangements may improve outcomes in sah patients. contrast induced nephropathy (cin) is the acute deterioration of renal function due to parenteral administration of radio-contrast media. cin is defined as an increase in serum creatinine concentration of > µmol/l ( . mg/dl) or % above baseline within hours after contrast administration. [ ]epidemiologic data in neurosurgical patients undergoing endovascular coiling are sparse and only one study in stroke patients reported figures of % prevalence. [ ] cin is associated with increased morbidity, length of hospital stay and costs. pre-existing renal failure and the dose of contrast media are known risk factors for the development of cin in cardiac patients where the condition is well-described. [ ]although the pathogenesis of cin is not entirely clear, several mechanisms for contrast-induced renal injury have been proposed, including alterations in renal medullary perfusion, direct cytotoxicity and oxygen-free radical generation. [ ] we conducted a twelve month retrospective electronic patient record based review of data from patients presenting to the hospital for endovascular coiling. renal dysfunction was based on increase in serum creatinine of µmol/l ( . mg/dl) or % above baseline within hours after contrast administration; the incidence of contrast induced nephropathy was investigated. peri-operative care and post-operative management were analysed. a multi-variate analysis of risk factors was conducted and statistical tests done using microsoft excel. . patients visited our hospital neurosciences unit and underwent endovascular coiling over a one year period (sept -sept ). the incidence of contrast induced nephropathy was %. . % had pre-existing renal disease and . % needed haemofiltration on intensive care for renal failure post-operatively. the odds ratio for developing cin in patients with diabetes mellitus was . ( . - . ) p= . . the odds ratio for developing cin with pre-existing kidney disease was . ( . - . ) p= . . the development of cin did not show any correlation with patient age, emergency or electively performed procedure or the number of coils used. no anti-oxidants were given for prophylaxis and no protocol for peri-operative hydration was used though fluids were administered intra-operatively. conclusion. cin is a common cause of acute renal functional impairment and accounts for significant morbidity in patients undergoing endovascular coiling. patients with pre-existing renal failure are at high risk; other predisposing factors should be identified. there is some evidence regarding use of peri-procedural hydration and anti-oxidants and, therefore, management protocols should be developed. open prospective observational study. were studied patients treated by embolization after spontaneous intracranial aneurysm rupture. included: embolization complicated by rupture of aneurysm during the obliteration procedure. rupture was ascertained by extravasation of contrast. current results of period ranging from july till october . thirty two patients embolized for aneurysms. one patient pesented a rupture during the embolization: she was a y.o female; she came to our institution's emergency suffering from acute headache, nausea vomiting and a mild meningism. she got no neurological defect (wfns grade i). ctscan showed a mild sah (fisher class ). an angiography followed, confirming presence of a mm ruptured pericallosum aneurysm. during embolization procedure, a sudden hemodynamic instability (bradycardia, unstable blood pressure) was noticed and rerupture of aneurysm confirmed by extravasation of contrast medium. this complication occurred during placement of the first coil. the procedure continued successfully and aneurysm was completely obliterated by three coils. ctscan performed immediately after end of the procedure showed no massive cerebral haemorrhage (class fisher). the patient was thereafter transferred to our icu where she was extubated. she developed a transient neurological defect (right hemiparesis). she was discharged alive without any disability. aneurysmal perforation during embolization seems to be a rare event. in our case it doesn't cause much damage, but clinical severity is variable and far from being predictable. re-bleeding can result in severe intracranial hypertension and ultimately brain death. aneurysm thrombosis complicated procedures, and was fatal for both (respectively and days after embolization) due to massive ischemia (aneurysm of the internal carotid artery) and refractory intracranial hypertension (aneurysm of anterior communicating artery). those two patients got respectively wfns grade / fisher classification: iii/ and ii/ . the patient with wfns grade iv got a successful uncomplicated procedure days after the initial insult and partial clinical recovery. he continued to improve and was discharged alive from hospital without major neurological disability (gos: good, modified rankin scale = ). conclusion. endovascular coiling could be an efficient therapeutic tool. incidence and outcome of procedures complications is still to be determined. strategy in patients with high wfns grade is certainly try embolization because of too risky surgery. right management timing is still to be determined. the quantitative estimation of blood loss helps in the choice of the best treatment tactics. the purpose of the study is to evaluate the ability of central blood volume index (cbvi, volume in heart and lungs and large vessels divided on body weight) and total end diastolic volume index (tedvi, sum of the end-diastolic volumes of the atria and ventricles divided on body weight) to reflect the magnitude of a hemorrhage. normo-volumic values of cbvi and tedvi were measured in cardiac icu cardiac patients, pigs and rats with weight range of . kg to kg. blood loss in the order of - ml/kg ( - steps) was applied in rats and pigs. ultrasound dilution technology utilizes the decrease in blood ultrasound velocity caused by injecting isotonic saline, and can be used in species of any size. cardiac index (ci), cbvi and tedvi were measured by hcp (transonic systems inc., usa) before and after blood loss. a disposable extracorporeal av loop filled with heparinized saline was connected between an existing artery catheter and central venous catheter. reusable ultrasound sensors were clamped on to the arterial and venous limbs of the loop. a peristaltic pump (nipro, japan) was used to circulate the blood from the artery to the vein at - ml/min for - min. measurements were obtained by injecting . - ml/kg (max ml) of isotonic saline. at the conclusion, the av loop was flushed with heparinized saline. in normo-volemic situations indexes are in the range of cbvi = - ml/kg and tedvi = - ml/kg, despite times differences in weight. a dramatic blood loss of - ml/kg in experimental animals produces the same magnitude - % decrease in cbvi and tedvi. severe dysphagia associated with silent aspiration and the danger of asphyxia requires translaryngeal intubation or tracheostomy. the aim of the study was to apply the clinical screening test (cst) and fibrooptic evaluation of swallowing test (fest) to determine the best method of upper airway protection. it was a prospective cohort study during the period of - . it included patients operated for fpt. all patients were delivered to icu intubated and mechanically ventilated after operation. after full recovery from anesthesia, returning to consciousness and passing spontaneous breathing test (sbt) (if not -mechanical ventilation continued) they underwent cst of points. the patients who passed cst without deficit were considered to have none or low level of dysphagia. the patients who passed cst with some deficit were considered to have dysphagia. all the patients were extubated and underwent fest. in patients with poor cst, icu crew was ready to perform translaringeal intubation immediately if necessary. patients with severe cases of dysphagia underwent tracheostomy and received cuffed tracheostomy tubes to prevent aspiration and ensure free air passage. on the next day after performing tracheostomy, swallowing rehabilitation therapy began. tracheostomiesd patients underwent fest every week. after passing fest with blue dye, decanulation was possible. results. patients of total group who did not recover consciousness or did not pass sbt in hours after operation were determined for prolonged artificial ventilation and were excluded from further study. the patients who passed cst without any deficit were successfully extubated and showed absent or mild dysphagia in fest. patients passed cst with deficit and after fest were divided into three groups by the level of dysphagia -mild, -intermediate and -severe. the regress of swallowing disorders was evaluated by fest every week. in the first group the earliest recovery was in three days, in the two other groups none recovered earlier than after three weeks. the latest recovery was determined after a year of swallowing rehabilitation therapy. two patients were not decanulated at all. postoperative recovery made possible to reduce rs. but insufficient rs exhaust the patient and may result in secondary impairment of the brain. the aim of the study was the analysis of different respiratory strategies in these patients to choose the best. it was a prospective cohort study of patients after removal of pft with complicated postoperative period during and no significant difference in± - . the age of the patients was severity of complications and neurological status. all patients included into study demanded rs after operation because of low rd. all patients had bulbar palsy syndrome (bps). patients with bps were tracheostomiesed. after full recovery from anesthesia and returning to consciousness ventilation modes were simv+ps or cpap+ps (ventilator pb ). rr (respirator and patient), tv, ps, fio , peep, pao and paco and neurological status were evaluated and registered daily. the criteria of readiness to wean were determined as: pao /fio > , peep< , ps< - , spo > %, rr< , fio < %, gcs> . weaning was successful if patient could breathe spontaneously for more than hours without neurological deficit arise. patients were divided into groups: . simv+ps ventilation (respirator rr - % of total rr) - cases; . cpap+ps ventilation - cases; . failed extubation in first hours - cases. all patients of the group were ventilated in simv+ps after reintubation. the patients of the group were extremely unstable and the modes of ventilation were corrected - times per day. duration of ventilation was minimal in the group with maximum replacement of spontaneous breathing with artificial ventilation -simv+ps (table ). in this group was minimal number of breathing disorders (minimal number of ventilator mode corrections) and patients were most stable. in first group was tendency to regress of bps ( %) and there wasn't cases of arising neurologic deficit. but in the group there was increase of bulbar palsy syndrome in % cases and no regression. c. a. eynon* , p. collins neurosciences icu, wessex neurological centre, southampton, wessex regional transplant, queen alexandra hospital, portsmouth, united kingdom the management of severe brain injury in the uk is undergoing significant change. national recommendations are that all severely brain-injured patients are referred to specialist centres. protocolised guidelines for the management of brain injury have resulted in improvements in mortality and morbidity. with this has come a reduction in the numbers of brainstem dead patients suitable for solid organ donation. however, there still exists a group of patients for which continued treatment is felt to be futile and who may be suitable as solid organ donors following death by cardiorespiratory criteria. all deaths during a -month period were audited prospectively. when patients did not fulfill the requirements for brainstem testing, futility in continuing medical treatment was determined by the supervising consultant neurosurgeon, neurointensivist and senior nurse. in such patients, treatment other than comfort care was withdrawn. patients (< yrs) where medical treatment was to be withdrawn were considered for nhb organ donation. . patients died during a -year period. patients had death confirmed by brainstem tests of which became solid organ donors. patients were potential nhb donors. nhb donation was considered in cases and offered to the family in . in one case the next of kin were untraceable, in one case the coroner refused permission. consent for donation was obtained from the family in / cases. nhb organ donation occurred in cases. in the remaining cases, patients died outside the time window for organ retrieval, in one the next of kin withdrew permission and in one the coroner did not grant permission. of the patients who died outside the time window for nhb organ donation, subsequently donated tissue. a total of kidney transplants, liver transplants and one double lung transplant were performed from nhb donors. conclusion. the number of brainstem dead patients is declining in the uk. patients in whom continuation of medical care is felt to be futile can provide a source of solid organs suitable for tranplantation. successful transplantation of solid organs from potential nhb donors occurs in a significant proportion of cases. feedback from family members has been supportive regarding the decision to donate. the studies on treatment of patients with head injury and brain damage, with sudden cardiac arrest due to various reasons revealed, that it is very useful to introduce neuroprotective therapy in those patients. it allows to decrease the consequences of local and global brain ischemia. the aim of the study was to present the efficacy and tolerance of treatment with amantadine sulphate (amantix, merz, germany), as a neuroprotective therapy. in the intensive care unit, between and we monitored a group of patients with consciousness disorders, in the age of . +/- . , with average bmi of . +/- . . the level of coma's deepness and its reasons were different. the examination plan, methods used, choice and classification of patients were carried out based on previously prepared protocols. the minimal period of treatment with intravenous infusion of amantadine sulphate was days, however, if possible, the therapy was continued for days. after this period the patients received amantix in tablets. many additional therapeutic measures from different groups were used in those patients. an endotracheal intubation and ventilation were necessary in all of the patients. amantix was used as treatment's supplementation in the dose of x mg/day. at the admission the patients were classified with the use of gcs (glasgow coma scale). in order to evaluate the effects of use of the preparation, some specific function of the patients were examined before the use of amantix and after finishing of the therapy. the examination was carried out by the intensive care unit doctors, neurologist and nurses taking direct care of the patients. the results were compared with the control group of patients, age , +/- , . those patients were treated with the use of standard methods. all of the collected data were worked up statistically. the authors revealed statistically important difference in gcs grading between the groups. the average gcs score in amantix group at the admission was: . +/- . , and at the discharge: . +/- . . analogically, in the control group the admission score was: . +/- . , and at the discharge: . +/- . . in patients using amantix we have noted the presence of side effects, usually it was hiperactivity. patients were transferred to different wards. patients died. the average hospitalization period in the amantix group was: . +/- . , and in the control group: . +/- . days. . this has been fuelled by increasing evidence demonstrating either sub-optimal care or poor end of life decision making as antecedants to cardiac arrest calls on acute wards. outreach and medical emergency teams have developed as a result, but their effectiveness remains unproven [ ] . at southend, development of a critical care outreach service began in . the aim of this study was to establish the trends in cardiac arrest call rates from the acute wards in the years prior to, during and after the introduction of the outreach team, to assess any potential impact this may have had. hospital switchboard records were analysed retrospectively to provide data relating to the date, time and location of ward cardiac arrest calls occurring between january and december . arrest calls to all acute wards except the critical care unit were included. the data collected was then related to hospital inpatient activity (in terms of completed in-patient consultant episodes, supplied by the hospital's information department) to enable meaningful interpretation of the observed trends. table summarises the results from the medical and surgical wards separately and then together to present data for the hospital's acute wards as a whole. the data shows an upwards trend for the years prior to and during the establishment of the outreach service, and a falling trend subsequently. conclusion. the establishment of a comprehensive outreach service that promotes all aspects of outreach critical care (expediting appropriate and preventing inappropriate critical care admissions, following up patients post critical care discharge and promoting critical care skills throughout the hospital) is likely to lead to a reduced frequency of cardiac arrest calls. however, this effect may take years and not months following introduction to be manifest. we suggest all outreach services should collect and present this simple data locally to demonstrate the potential impact of their activities. intracerebral haemorrhage (ich) represents - % of all strokes. the acute and subsequent blood pressure management presents a therapeutic dilemma. it is necessary decrease high systolic blood pressure, but there is the risk of decrease cereb. objective: can the regional cerebral oximetry helps us to determine individual adequate blood pressure? ral perfusion pressure and risk of ischemia developing. methods. regional oxymetry is the method of measurement the cerebral oxygen content based on near-infrared spectroscopy, which is carried out by means of the invos device (in vivo optical spectroscopy). this method is non-invasive, delivers continuous information and it allows the possibility of emergency therapeutic response. rso is transcutaneous monitoring of regional cerebral saturation with hemoglobin oxygen (rso ) in mixed blood in the frontoparietal regions, which represents interface beetween the basin of the anterior and middle cerebral arteries. the normal value of rso is beetwen - % in a majority of the population, and every change from the baseline in both directions by more than - % signifies the risk of ischemia for the observed tissue. during a twelve-month period all pacients admitting with ich in our neurointensive care unit (nicu) were managed by regional cerebral oximetry (n = ). arterial blood pressure was monitored and was corrected farmacologically. the functional outcome of patients when discharged from the nicu and after six month were evaluated by the glasgow outcome scale, barthel index and modified rankin scale. data was collected retrospectively for comparison with pacient which didn't monitor by rso . we found correlation between discovery of patological rso values and age, initial gsc and volume of ich. there are less septic and hemodynamic complications in the group with monitoring rso . using this method, the probability of successful improving outcome all patients with intracerebral haemorrhage will be estimated. there is the need for guidelines regarding the blood pressure managemet of these patients. elaborated data are available on iccollege.be. of ( , %) icu directors, representing icu beds completed the extended query. main findings were: visits limited < h/day ( h + h ) ; hcp dedicated to family ( %) children admitted from y of age ( %) ; family accompanied by hcp during resuscitation ( %) ; no witnessed resuscitation procedures ( %) ; scare possibilities for family to stay during night ( %) ; insufficient bad news delivery ( , %) ; poor team psychological support ( - %). icu physicians completed the follow-up simplified query. main findings were: psychological support for family ( , %) and team ( , %) ; post-resuscitation debriefing ( , %) ; identification of dedicated hcp ( , %) ; use of ( , %) and written ( , %) dnr-orders ; comprehension of ( , %) and family witness ( , %) of patients' will ; structured bad news delivery ( , %) ; witnessed resuscitation ( , %) and invasive procedures ( , %) ; children accepted < y ( , %). in belgium, although there's obvious concern from the majority of icu's to communicate with relatives, recommendations for psychological team support, teaching bad news delivery, schedule of visits and witnessed procedures are made. sudden death constitutes an important sanitary problem. early diagnosis and advanced cardiorrespiratory live support are considered the most important factors related with short term prognosis. the objective of this study was to analyze the prognosis, clinical characteristics and evolution of patients who initially recovered after an episode of out-of/hospital or in-hospital cardiac arrest and who were admitted to a medical-surgical intensive care unit (icu). sixty three consecutive patients were included and retrostectively studied when they were admitted to a medical-surgical icu. for two years, from april of until april of , sixty three consecutive patients were included. eighteen of the patients were women ( . %) and were men ( %). cpr was given out of hospital to patients, and patients suffered sudden death on a conventional hospital ward and patients in special units (surgery, coronary, emergency room, etc.). the etiology of the arrest was considered to be of probable primary cardiac origin in % of the episodes and the rest of the origin of arrest was considered secondary to other pathologies (respiratory, sepsis. . . ). mortality in icu was . % and , % were discharge alive but of that percentage of patients only % were released without important neurological damage. patients recovering following cardio-pulmonary arrest out of hospital and hospital ward had greater mortality than those who suffered an event in a monitored area ( %).(p< , ) the lengthy resuscitation times (greater than minutes), elevated apache ii scores and advanced age is associated with greater mortality. recovered cardiac arrest is a pathology with high mortality and morbidity in intensive care. in our series only % were released alive without severe neurological damage. the existing condition of the patient and the excessively long resuscitation times were decisive factors in these results. we conducted a retrospective case-note study in a six-month period at an innercity district hospital (distant from any international airport), and report three patients who deteriorated about the time of overseas travel by air. results. case . a retired gentleman of -years with progressive idiopathic pulmonary fibrosis requiring home oxygen therapy travelled by air without a medical escort. he deteriorated shortly after his arrival at the family home in the uk. he presented to the emergency department in respiratory failure requiring non-invasive ventilatory support. he died during prolonged hospitalization. case . a -year old woman with obstructive sleep apnoea reduced her diuretic prescription without her physician's knowledge prior to a long-haul flight. she deteriorated with acute shortness of breath shortly after her arrival at the family home in the uk. she was brought by her family to the emergency department where she was found to be in cardiogenic pulmonary oedema, requiring non-invasive ventilation. she survived hospitalization and was discharged with home oxygen therapy. case . a -year old man collapsed in the street explaining to passers-by that he had swallowed some packages. he had a travel ticket from the airport in his possession but was able to give no other history. he was taken to the emergency department and required intubation due to extreme agitation. he was found radiographically to have ingested multiple wrapped packets. he required laparotomy to remove differently coloured packs some of which had ruptured releasing their contents. urinalysis revealed cocaine metabolites. he subsequently made an uneventful recovery after extubation and transfer to a surgical ward. patients may present to hospitals distant from international airports with clinical deterioration consequent upon risks associated with long-distance air travel. ( ) prospective observational study of a cohort including every septic patient admitted in a medical icu of an university hospital from may to december . demographic, clinical, laboratory and therapeutic variables were registered. a clinical examination assessing motor deficit and tendon reflexes was daily performed in order to check cipnm criteria. univariate and multivariate logistic regression tests were used. . septic patients were included with age ± , apache ii score ± , maximum sofa score . ± , icu mortality %, in-hospital mortality %. patients survived at least days. patients did not require mv and none of them developed cipnm. finally the analysis was performed with the patients who survived at least days and required mv, with a cipnm incidence of %. variables were included in the univariate analysis. after multivariate analysis, it was found that several variables were significantly related with risk for the development of cipnm (odds ratio, or; % confidence interval, ic; signification level of change in log likelihood, p): . mv length (days): or . patients in the icu often develop an acute neuromuscular disorder characterised by difficulty of weaning from mechanical ventilation and associated with variable degrees of muscular weakness including quadriplegia [ ] . often associated with steroid treatment, neuromuscular blocking agents (nmba) and septic patients, the pathogenesis of cim is poorly understood [ ] . originally thought to be neuropathic in nature, however, today myopathy is more often diagnosed [ ] . to further clarify this point we present a series of patients. between and a retrospective study was carried out on patients diagnosed with cim and whose muscle samples were analysed in the dept. of neuropathology of chuvi, spain. in the clinical studies special attention was paid to the neuromuscular status apache ii, and treatments with steroids, nmba,total parenteral nutrition (tpn)and insulin. all patients underwent electromyographic studies and biopsy and in those with sensitive neurography an abnormal nerve biopsy. of the patients, were women and were men, all aged between and , (mean ± ). in three of the patients admission to the icu was not necessary. all save two received prolonged high doses of steroids and two were on chronic treatment of steroids. only one was treated with nmba for more than days. two patients were diabetic with no electromyographic signs of neuropathy. seven needed insulin to control glucemia during the critical period. received tpn, and had sings of sepsis. muscle biopsy showed signs suggestive of cim (atrophy of both types, alteration of the intermiofibrilar pattern) and in some cases miofagia and thick filament loss. in two cases there was discrepancy between neurophysiologic and biopsy findings (muscle and nerve). the seven patients that survived the acute illness showed neuromuscular symptoms on release from hospital. follow up was possible on three patients for , and years respectively. all recovered muscle strength, the electromyography normalized and currently have normal independent daily life activities. the aim of this clinical trial is to study cip in icu patients (pts) after surgical procedures. we enrolled retrospectively icu pts ( men ( . %), women ( . %) who underwent at least one surgical procedure under general anaesthesia and developed cip. all of them were mechanically ventilated and stayed > days. underlying diseases: multiple trauma , complicated surgery , pancreatitis . mean age: . ± . years. operation sites: abdomen , cns , orthopaedics , thorax , other . mean anaesthesia time: ± min. in all pts an electromyogram was performed twice, as well as daily neurological examination. we analyzed several parameters predisposing to cip. conclusion. ) sepsis predisposes to cip, but cip can be appeared without sepsis ( . %). ) age and serum albumin values do not predispose to cip (p< . ); however the early implementation of a nutritional protocol is useful. ) although not well correlated, we try, if possible, to avoid neuromuscular agents. ) high pgl predispose to cip (p< . ); it is important to maintain pgl < mg%. ) cip prolongs lmv (p< . ), los in icu (p< . ) and los in hospital (p< . ), but does not increase mr significantly (p< . ). s. kjaergaard* , s. e. rees intensive care, anaesthesia and intensive care, region north jutland, aalborg, center for model-based medical decision support, aalborg university, denmark ( ) is accepted as the gold standard method of describing pulmonary gas exchange. in the clinical setting, if any, only very simple one-parameter models are used. the parameters of these varying upon changing the fio . in a previous paper we have compared the miget with a simpler model, and shown that this simpler model is a good fit to the inert gas data obtained from the miget experiment ( ) . this study explores whether the simpler model can reproduce oxygenation data in an oleic acid lung damage model upon changing the fio and compared these results with those obtained using the miget. seven pigs were used for the study. lung damage was induced by an intravenous infusion of oleic acid. six inert gases were infused to estimate the distribution of v/q-ratios of the miget model and dead space, shunt and a parameter describing v/q mismatch, i.e. fa , of the simpler model ( , ). measurements were taken at five different ventilator settings. the two models were then used to simulate arterial oxygenation data when the model-parameters along with measurements of mixed venous blood gases at different values of fio were given as input to the models. both models can be used to simulate sao at varying fio . this is shown in the figure where the models have been used to simulate sao at varying values of fio (miget "+", simple "squares") ranging from . - . . it shows that the models simulate identical values of sao with a mean difference = - . +/- . . since the miget and the simpler models provide both equally good fit to the inert gas data ( ) and precise predictions of arterial oxygenation, they might be interchangeable in a clinical setting where only a limited amount of data are accessible. in addition, the parameters of the simpler model can be obtained quickly and non-invasively ( ). the model could therefore have applications a clinical situation. ethanol may be used in the management of toxic alcohol poisonings , or as sedation in alcohol withdrawal. ethanol may be a component within drug formulations, for example nimodipine infusion or chemotherapeutic agents . ethanol flush has also been used to restore the patency of occluded catheter lumens . in clinical practice, ethanol should only be infused via a pcvc and not a peripheral venous cannula, as the high osmolality of ethanol can cause thrombophlebitis. given anecdotal reports of pcvc deterioration during ethanol infusion , , this study applied a bench testing method and statistical modelling to develop clinical practice guidelines at our institution. the test solutions used were: dextrose (d) %; ethanol (e) %, %, %, %, % and %. each test solution was perfused through pcvcs. a total of pcvcs were perfused. (b) hour perfusion. the test solutions used were: d %, e %, e % or e %. each test solution was perfused through pcvcs. after perfusion, the strength of all pcvcs was assessed. the pcvc was attached to a force gauge. a known force was applied to the pcvc and the pcvc length was measured. this was repeated for increasing forces until the pcvc broke. length-force relationships were plotted and were described statistically using linear mixed effects models. . this bench test model produced reproducible data. the pcvcs were not directly traumatised by the testing apparatus. (a) minute perfusion. pcvcs perfused with e % , e % or e % perished with obvious structural deterioration. two distinct length-force relationships were described on linear mixed effects models: e %, e % or e % weakened the pcvcs , whilst d %, e %, e % and e % had no effect upon pcvc structure (p< . ) (b) hour perfusion. the pcvcs did not perish. on linear mixed effects models, e % and e % weakened the pcvcs, whilst d % and e % had no effect (p< . ). conclusion. this model quantifies the effect of ethanol infusion upon pcvcs. this has not been demonstrated previously. the infusion of e % e % or e % via pcvcs should be avoided. infusion of e % and e % for hours weakens pcvcs. nimodipine and other drugs using ethanol as a carrier vehicle should be infused via pcvcs with caution. these potential hazards should be outlined in individual pcvc package inserts and drug product information leaflets. ( ) in septic shock patients tissue microcirculation is altered despite an increased tissue oxygen tension ( ). microcirculatory distress could be one of the earliest stages in the progress of sepsis to multiple organ failure, and microcirculatory shunting could be an important contributing factor to this development ( ) . sofa score has been suggested to clinically assess the level of organ dysfunction( ). we've done a prospective observational study to determine if changes in the rate of thenar muscles tissue deoxygenation during stagnant ischemia in patients with severe sepsis and septic shock are related to changes in organ dysfunction using the sofa score. fourteen septic shock patients were included in a preliminary study during the first days of sepsis evolution. , hutchinson?thenar muscle sto was measured noninvasively by nirs (inspectra technology, usa) before and during upper limb ischemia. sto decrease (downslope) after limb ischemia were analyzed during first and fifth day after icu admission. changes in sto downslope, sofa score, cardiac output, lactate and the use of vasoactive drugs between first and fifth days were recorded. we found good correlation between ∆sto downslope and ∆sofa between the first and the fifth day. (spearman's rho = - , ; p< , ). our results are in accordance with those reported by pareznik( ) wich correlated isolated values of sto with sofa in septic shock patients but moreover we show that changes in both variables during evolution are also correlated. in septic shock patients, thenar muscle ∆sto downslope is well correlated with changes in ∆sofa, a clinically accepted tool to measure organ dysfunction evolution during sepsis. ∆sto downslope monitoring could be not only a good marker of microcirculatory state but also a good indicator of organ dysfunction evolution during sepsis and consequently a potentially therapeutic objective. one of the important tasks that the anesthesiologist should perform is to monitor the functions of body organs; lung airway pressure is among the most important ones. a real-time continuous monitoring device which would be designed in a small volume and is portable could be used by anesthesiologists for this purpose. so, this device could improve the quality of anesthesia care while being efficient and cost containing. the device consists of four consisting parts as follows: sensors (pressure transmitter and gas velocity transmitter), processors (two avr microprocessors), monitor and software. software simulation: the performance of the monitor was controlled through a simulation process with matlab-simulink software (the mathworks inc. ma, usa),( ). the monitoring device demonstrated acceptable results, both clinically and at the lab assessments. the study demonstrated this device as an effective, reliable and cost containing device. a. rodríguez salgado* , a. socias , b. comas , a. llompart , i. losada , p. ibáñez , m. borges intensive care unit, emergency department, internal medicine, h. son llàtzer, palma de mallorca, spain since we have a global computerized system on our hospital we used it to develope an integral and multidisciplinary working protocol for the early recognition of sepsis and its appropiatte therapy. prospective study conducted in a four-hundred bed teaching hospital with medical and surgical areas and the support of a global computerized system and on line internet conexion among areas. a computerized protocol to improve management of sepsis was developed. it automatically produces an annotation on the medical chart and a serie of analytics forms when activated. additionally clinical guidelines on sepsis management can be consulted. it was started on january , and here we present all patients included until january . during the study period patient were included in the protocol, with a mean age of , ( , ) y, , % were male. we have observed an ascending tendence in the number of patients included in the protocol, having arised from patients on january to on january . the protocol was activated at the icu in ( , %) cases, at the emergency department in ( , %) and at hospitalization units in ( , %). two-hundred and two ( , %) patients were admited at the icu. though initially the protocol was exclusivelly directed to patient with severe sepsis or septic shock, lately some patients with sepsis have been included. so, ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock. only ( . %) had fever and ( . %) had arterial hypotension at the protocol entry. sepsis was community-adquired in ( , %) cases, nosocomial-non icu adquired ( , %) cases and icu adquired in ( , %). the the most frequent site of infection was the lung in ( , %) patients, followed by the abdomen in ( , %) patients. isolation of the causal microorganism was achieved in ( %) patients. blood cultures were positive in ( . %) cases. forty seven ( %) had organ disfuntion (od), ( . %) od, ( . %) od and ( . %) or more od. mean lactate levels were , ( , ) mmol/l, , ( , ) mmol/l and , ( , ) mmol/l at the activation moment, at and a hour respectively. mean c-reactive protein levels were , ( , ) mg/l. eighty-five ( , %) patients deceased, of whom ( %) had sepsis, ( , %) severe sepsis and ( , %) septic shock at the moment of activation. conclusion. it is possible to implement a global multidisciplinary computerized protocol for identification and management of the sepsis, although this is a laborious and continual process. t. kyprianou* , g. panayi , d. zeinalipur-yazti , m. dikaiakos intensive care unit, nicosia general hospital, ngo, intensive care forum, dept of computer science, universiy of cyprus, nicosia, cyprus introduction. the physiological condition of icu patients is marked by rapidly evolving and frequently life-threatening derangements as well as 'silent' yet important alterations in homeostasis. reliable monitoring i.e. the capability to collect, store, process, and share inpatient monitoring data along with physicians' remarks can bring tremendous benefits to all aspects of intensive care medicine (practice, research, education). currently, grid infrastructures assemble an extensive collection of resources and expertise (egee grid: + sites around the world with more than , cpu's - pb of storage, adequate for storing and managing icu-related data. we present the design and implementation of the intensive care window (ic-window), a software tool that enables the retrieval and integration of data from patient-attached medical sensors. ic-window follows a modular design to retrieve data from different patient monitoring devices. the tool includes a full-edged interaction protocol and graphical user-interface to interact with the phillips intellivue mp monitor. ic-window is implemented in the context of icgrid (intensive care grid), a novel data-grid framework that utilizes the egee infrastructure to enable the seamless integration, correlation and retrieval of 'clinically interesting episodes' across intensive care units clusters. we present preliminary data from software's use in icu patients. conclusion. ic window belongs to a new generation of tools that could improve dramatically intensivist's capabilities as offers virtually unlimited storage capacity for every possible type of patient's data. in the future we plan to extend the ic-window application to communicate with other medical devices found within the icu. this will provide an open platform for the aforementioned applications. introduction. strict glycemic control by lowering blood glucose levels to - mg/dl reduces the intensive care unit (icu) mortality, morbidity, duration of the hospital stay, and overall medical care costs. to provide an intelligent system for tight glycemic control, the eu-project "closed loop insulin infusion for critically ill patients (clinicip)" was started in january . three different sensor technologies -two based on an enzymatic reaction with immobilised glucose oxidase using either amperometry or fluorimetry as transducer and another based on reagent-free infrared spectroscopy -have been developed to continuously monitor the glucose levels in the subcutaneous interstitial body fluid. monitoring of the subcutaneous interstitial fluid is realized using a microdialysis catheter cma from cma microdialysis ab as a body interface to all glucose sensors. experiments were carried out at the center for medical research (graz, austria), lasting up to h with the probands starting under fasting condition, but receiving later their normal diet. after microdialysis probe implantation, the perfusate (either % mannitol solution or elo-mel) flow rates were around µl/min. for reference measurements, dialysate samples were collected. in parallel, blood glucose concentrations in venous blood samples, collected under arterialised conditions with the arm resting in a hot box, were determined using a glucose analyzer from beckman instruments. a clarke error grid analysis of the results from all three sensors has shown all values in clinically acceptable zones. the blood reference and sensor measurements were further compared using bland-altman plots. owing to the tubing connecting the catheter outflow and sensor, the lag times for the sensor readouts were between and min. for the electrochemical and infrared sensors a simultaneous micro-dialysis recovery rate determination has already been implemented for improving the correlation of the sensor readout to the whole blood levels. some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality. we performed a randomized trial to study outcome benefit of using pulmonary artery catheter (pac) in ards patients when compared to standard care using central venous catheter (cvc). the subjects were ards patients on mechanical ventilator who were assigned either to pac (pac group), or cvc (cvc group). the base-line characteristics of the two treatment groups were similar. the primary outcome was icu and in-hospital mortality from any cause. the pac group had a significantly lower icu mortality than the cvc group ( vs , p value= . ) but there was no difference between the groups in in-hospital mortality (one case mortality in cvc group). there were no significant differences between pac and cvc groups in urine output ( . ± . vs. . ± . ), use of vasopressors ( . ± . vs. . ± . ), and length of hospital stay ( . ± . vs. . ± . ) respectively. our findings suggest that pac can be used in ards patients for better hemodynamic assessment that may result in reduced icu stay and mortality rate. ethanol may be used in the management of toxic alcohol poisonings , or as sedation in alcohol withdrawal. ethanol may be a component within drug formulations, for example nimodipine infusion or chemotherapeutic agents . ethanol flush has also been used to restore the patency of occluded catheter lumens . in clinical practice, ethanol must be infused via a pcvc, as its high osmolality can cause peripheral thrombophlebitis. given anecdotal reports of pcvc deterioration during ethanol infusion , , this study applied a bench test and a statistical model to develop clinical practice guidelines at our institution. each cm triple lumen pcvc was perfused with a single test solution only. (a) minute perfusion. the test solutions used were: dextrose (d) %; ethanol (e) %, %, %, %, % and %. each test solution was perfused through pcvcs. a total of pcvcs were perfused. (b) hour perfusion. additional pcvcs were perfused with d %, e %, e % or e %. after perfusion, the strength of all pcvcs was assessed. the pcvc was attached to a force gauge. a known force was applied to the pcvc and the pcvc length was measured. this was repeated for increasing forces until the pcvc broke. length-force relationships were plotted and were described statistically using linear mixed effects models. . this bench test model produced reproducible data. the pcvcs were not directly traumatised by the testing apparatus. (a) minute perfusion. pcvcs perfused with e % , e % or e % perished with obvious structural deterioration. two distinct length-force relationships were described on linear mixed effects models: e %, e % or e % weakened the pcvcs , whilst d %, e %, e % and e % had no effect upon pcvc structure (p< . ). (b) hour perfusion. the pcvcs did not perish. e % and e % weakened the pcvcs (p< . ). not been demonstrated previously. the infusion of e % e % or e % via pcvcs should be avoided. infusion of e % and e % for hours weakens pcvcs. nimodipine and other drugs using ethanol as a carrier vehicle should be infused via pcvcs with caution. these potential hazards should be outlined in individual pcvc package inserts and drug product information leaflets. ( ) introduction. inadvertent esophageal intubation may lead to serious complications such as hypoxia, cardiac arrythmias and death. auscultation of breath sounds may be an inaccurate method to determine correct endotracheal tube placement of endotracheal tube placement. vibration response imaging (vri) is a novel non-invasive technology that measures vibration energy of lung sounds during respiration. as air moves in and out of the lungs, vibrations propagate through lung tissues and are recorded by sensors spacially distributed on the patient's back over the lungs and a dynamic image is created. a year old female patient presented with lung cancer. plain chest radiograph and ct scan revealed a large left lung mass comparable for a neoplasm. she was admitted for left lung lobectomy. after informed consent was obtained, she underwent vri before and after intubation. the esophagus was inadventently intubated and recognized immediately after the vri recording was obtained. the patient went on to have a successful operation. analysis of the vri data obtained during esophageal and tracheal ventilation are compared along with a normal vri image. during esophageal ventilation most of the vibrations ( %) were detected by the upper sensors and the least by the lower sensors ( %) (fig. ) . following the endotracheal intubation as well as in a normal image, the vibrations were more evenly distributed with the sensors from the middle region receiving more vibrations. quick detection of inadvertent esophageal intubation is crucial to prevent serious complications but commonly used methods of confirmation such as auscultation and plain chest radiograph are inaccurate or do not provide timely results. vri is a novel technology that offers the potential to quickly identify inadvertent esophageal intubation in the or and perhaps other settings. the acapella ® is a small hand-held vibratory device that combines the resistive features of the positive expiratory pressure (pep) and the vibratory features of a flutter valve to mobilize secretions in the airway. vri is a novel dynamic imaging technique that measures vibration energy of lung sounds generated during respiration. in this study, our aim is to determine, using the vri, what regions of the lungs receive the most vibrations when the acapella is being used. a second vri recording was performed on a healthy volunteer during normal breathing (first three breaths) and while using the acapella device (last four breaths). the vri recordings were obtained in second periods of respiration. dynamic digital images and numerical raw values for vibration energy are analyzed and compared any regions of interest. . vri images at maximal expiration while using acapella show increased total vibration intensity. when the distribution of expiratory vibration is examined, it appears that vibration from the acapella goes more to the lower lung regions (figure and ) . asymptomatic catheter-related central vein thrombosis (cvt) which is diagnosed by venographic studies is mentioned to be as high as %. moreover, when thrombosis occurred, the risk of catheter related sepsis was declared to be . % higher. in this prospective study we aimed to diagnose cvt early as possible, its incidence and risk factors. icu patients (pts) that needed a central venous access for at least hours without chemotherapeutic agents administration were included in this prospective study. the catheters were inserted via internal jugular or subclavian vein at bedside under aseptic conditions using the seldinger technique. diagnosis of vein thrombosis was detected by color doppler ultrasound examination performed in less than h after catheter removal (picture). the protocol was approved by the ethic committee. three hundred and thirty eight pts ( f, m), mean . years old ( - years), were included in the study. catheters mean duration time was . days and duration of insertion mean time was . min ( - min). in pts catheter insertion was performed with a single puncture, in pts with double and in pts with three and more punctures. catheter localization was : in pts right subclavian vein, in pts left subclavian vein, in pts right internal jugular vein and in pts left internal jugular vein. catheter related thrombosis was diagnosed in pts ( . %) while catheter infection was seen in patient ( . %) (table). generally the chemotherapeutic agents administered via the central vein catheter have thrombogenic effect. when we study our cvt diagnosed pts we found out that all of them were over years old, the mean catheter duration time was . days (table) . but these results were not statistically significant when compared with the other pts under years old and more than . days of mean catheter duration time. out of pts who were not under anticoagulant therapy had cvt while out of pts under anticoagulant therapy had cvt diagnose which was found statistically insignificant (p> . ). our results show that patients under anticoagulant therapy have a three fold more cvt risk ratio than the others who are not using this anticoagulant therapy. patients under anticoagulant therapy have to be followed more closely regarding to cvt. the provision of good glycaemic control is thought to have some beneficial aspects in critical care patients. we have previously described the introduction of a web-based insulin dose calculator program to support the control of blood glucose in critical care. the aim of this study is to describe a modified version of a calculator program based on van de berghe's studies. this allows nursing staff to enter blood glucose values together with the insulin infusion rate into a calculator. the calculator then provides a recommended insulin infusion rate to control blood glucose with the added ability to recommend small bolus doses of insulin when appropriate, store blood glucose concentrations, insulin rates, bed number and the date and time of calculation. we also modified our feeding protocol to restrict the target enteral feed from kcal to kcal per day and removed the night time rest period. we studied the data stored by the program which was used for all patients admitted to a -bedded intensive care unit (approximately % of whom have neurological injuries) between june and may . overall there were patients admitted (mean apache ii score [sd +/- ], with a mean age of years [sd +/- ]. patients died prior to icu discharge. there was a total of patient days with recorded calculation data points. the mean blood glucose concentration was . mmol ( ci . - . ). there were episodes of treated hypoglycaemia of which were on an insulin infusion. there were two troughs in the time of data entry that corresponded with staff handover. there was no diurnal variation in blood glucose concentration or in insulin infusion rates, although this did peak slightly in the early morning. the mean value of the insulin infusion rate was . units / hr (sd +/- . ). in normal subjects there is a decreased level of endogenous insulin in the early morning, that is only partly lost with constant nutrition. from this study we concluded that the web based insulin calculator facilitates the dosing of insulin in critical care in an economic manner. the lack of diurnal blood glucose concentration variation, suggests that once daily estimation of blood glucose may be an acceptable method of monitoring blood glucose concentrations in critical care. systemic inflammatory response syndrome (sirs) is a common entity in the intensive care units. early institution of an appropriate antimicrobial regimen in infected patients is associated with a better outcome. both c-reactive protein (crp) and procalcitonin (pct) are accepted sepsis markers. however, there is still controversy concerning the correlation between serum concentrations, infection and sepsis severity. objective:to determine the clinical aplication of procalcitonin (pct) and c-reactive protein (crp) plasma concentrations in the detection of sirs related to infection and sepsis and the assesment of severity of sepsis. desing: prospective observational study. setting: medicosurgical intensive care unit. patients: over a period of months (january-february ), forty seven consecutive adult patients admitted in a intensive care unit for an expected stay > hrs.and sris symtoms and signs. informed consent was obtained from all patients. measurements: pct and crp plasma concentrations and white blood cell counts , apache ii y sofa within the first h . each patient was examined at the time of enrollment and was classified in one of the following four categories according to the accp criteria: siris and sepsis group (sepsis, severe sepsis and septic shock). statistical analysis: were performed with spss . . differences in continuous variables between infected and non infected patients were compared with the nonparametric mann-whitney test. and lineal.regressión. pct levels were significantly higher in the severe sepsis(p= , ) and shock septic group (p< , ). pct and cpr levels no weren found differences between sepsis of less gravity group and noninfectious sirs. pct and crp levels are significantly correlated to the severity of organ dysfunction (sofa y apache ii). pct and crp levels were significantly higher withing short space of time in patient with infection than in patients with non-infectious sirs, but for sepsis of less gravity, pct and crp plasma values not differentiate between sepsis and non-infectious sirs. investigators have reported microcirculatory alterations in critically ill patients using various techniques. persistent microvascular alterations might be associated with the development of organ failure and death. in this study, microcirculatory blood transit time was measured in intensive care patients using micro-channel flow analyzers and related to the severity score and mortality. thirty-one patients were included in this study. mean apache-ii score was . . patients were divided into two groups, group l (apache-ii< , n= ) and group h (apache-ii>= , n= ). in both groups, blood transit time was measured using microchannel flow analyzers (mc fans). the micro-machined silicon chip is utilized in these instruments to simulate human capillary blood flow. microcirculatory alteration was presented as a blood transit time (second) of heparinized blood through micro-channel array under the pressure difference of cmh o. hematocrit, white blood cell (wbc) count, platelet count, and labolatory data were obtained at the same time. blood transit time was significantly longer in group h comparing that in group l ( . +/- . sec, . +/- . sec, p< . ). wbc count was larger in group h comparing that in group l ( +/- /ul, +/- /ul, p< . ). triglyceride (tg) and immunogloblin (igg/m/a) levels were significantly higher in group h comparing these in group l. none of the group l patients died, however, hospital mortality rate was . ? in group h. blood transit time through micro-channel array was prolonged in patients with high apache score )wbc, tg, and immunogloblin levels might be associated with patients blood fluidity. ) micro-channel flow analysis may become a valuable tool to monitor microcirculation in critically ill patients. a. roman* , t. el mahi , c. hanicq , d. gnat , f. vertongen , e. stevens intensive care, clinical chemistry, chu saint-pierre, brussels, belgium bedside glucose monitoring is mandatory for icu patients under tight glycemic control. point-of-care (poc) glucometers are based on glucose-dehydrogenase coupled with pyrroloquinoline-quinone/ferricyanide (gd/pqq)or phenanthroline-quinone/nad (gd/pqnad), or glucose-oxydase/ferricyanide (go) enzymatic methods for whole blood measurements. the laboratory reference method is hexokinase for measuring the plasma glucose levels. some drugs and metabolites can interfere with poc methods. the aim of this study was to evaluate the effect of the uric acid levels on the accuracy of these bedside methods. in this prospective observational study, arterial blood glucose was measured simultaneously on the accu-chek inform roche (gd/pqq), on the precision pcx abbott (gd/pqnad), on the rapidlab bayer (go) and each value was compared with the reference laboratory result. measures were done in adult icu patients. uric acid was obtained only once a day. a bland-altman analysis was done. biases were expressed as the poc minus the laboratory result. data were also analysed using linear regression. spearmann's rho squares were calculated to evaluate the uric acid level effect on the difference between poc and laboratory methods. the uric acid level range was . to . mg/dl. the biases, the % limits of agreement between each poc method and the reference method, the r of spearmann for the correlation between uric acid level and the difference of result glucose level for each poc method are shown in table . the accu-chek inform overestimates moderately the glucose level while the precision pcx and the rapidlab underestimate it slightly. the wilcoxon ranked test with bonferroni correction gave a p < . for comparing the bias from the accu-chek to the bias from the precision pcx, p < . when compared to the bias obtained for the rapidlab. no statistical difference between the precision pcx bias and rapilab was found. the r of spearmann correlating the effect of the uric acid level and the difference between the accu-chek and the reference method was . . the weak effect of the uric acid level of the patient on the overestimation of the glucose measured by the accu-chek can be summarized as : glucose difference(accu-chek-laboratory) = . x uric acid (mg/dl) - . . for the other poc glucometers, such correlations were absent. a patient presented with severe acidosis, point-of-care (poc) lactate of mmol/l, suspicion of mesenteric ischemia and potential need for laparotomy. however, plasmalactates was < mmol/l, and ethylene glycol (eg) ingestion was subsequently diagnosed. we, therefore, wished to determine why discrepant lactates occur and if this "lactate-gap" could be clinically useful. we phlebotomized blood, added various concentrations of eg metabolites, and tested with the five most common lactate analyzers. the pressure-volume(p-v)curve of the respiratory system defines the mechanical properties of the lung and the chest wall by relating airway pressure(paw)in no-flow conditions with lung volume at the same pressure level. objective:to evaluate a new technique for p-v curve tracing. two p-v curves were obtained in ali/ards patients using the continuous positive airway pressure (cpap) method and an automated system built into a commercial ventilator (p-v tool , galileo, hamilton). for the cpap method, ventilators were switched to cpap and pressure was raised from to cmh o in cmh o steps and then decreased while respiratory inductive plethysmography measured lung volume. for the automated method, we selected the automatic pv mode(galileo, hamilton)with flow l/m and maximum pressure of cmh o. lung-volume and airway-pressure data were recorded. p-v pairs were fitted to a mathematical model. lower (lip) and upper (uip) inflection points on the inspiratory limb and maximum curvature point on the deflation limb were obtained. correlation between methods was calculated using bias and % agreement limits for lips and uips and the intraclass correlation coefficient (icc) for absolute agreement for each pressure level. no adverse events were observed. p-v curves were equivalent for each method, with icc > . for each pressure level. bias and precision for lip and uip were:lip . ± . cmh o and uip . ± . cmh o. the automated method for tracing p-v curves is equivalent to the cpap method. easily applicable at the bedside, it avoids ventilator disconnection and can obtain both inspiratory and deflation limbs of p-v curves. introduction. hypoxic hepatitis (hh) is a common cause of acute hepatic impairment. however, few is known about the degree and duration of the reversal of the liver impairment. therefore we assessed the liver function by indocyanine green (icg) clearance via limon (pulsion medical systems, munich, germany) in patients with hh. icg clearance was assessed in critically ill patients fulfilling the criteria of hypoxic hepatitis. mean apache iii score was ± . nine patients were male. icu survival was %. icg -plasma disappearance rate (pdr) (normal range: - %/min) and the retention rate of icg extrapolated to minutes (r ) were obtained on the day of development of hh and till day five. nine patients with decompensated liver cirrhosis child c requiring intensive care therapy served as control group. results. icg-pdr and r expressed as mean ± standard deviation were . ± . %/min and . ± . %, respectively ( patients), on the day of development of hh. icg-pdr and r were . ± . %/min and . ± . %, respectively, in the control group and was comparable to the hh group (p=ns). icg-pdr and r improved continuously from time of development of hh to day five ( patients alive and at icu) and were comparable to the course of laboratory data during observation period (table ) . exhaled breath condensate (ebc) is a non-invasive means of collecting samples of airway lining fluid from the lower respiratory tract and monitoring respiratory diseases. we have used ebc acidification to study the effects of mechanical ventilation. ebc was collected ( - minutes at - o c: ecoscreen, jaeger). immediately after collection and as soon as the sample returned to room temperature, we measured conductivity and ph before and after deareation with helium ( minutes). results are expressed as median (interquartil range). we have applied spsswin with spearman correlation and mann-whitney test. our earlier evaluations of a decision support system for tight glucose control (tgc) in the critically ill utilising model predictive control (mpc) documented clinically acceptable performance with hourly bg sampling. the mpc advises on insulin infusion based on blood glucose (bg) measurements and carbohydrate content of parenteral and enteral nutrition. in the present study, we evaluated an improved version of the mpc (v . . to . . ), which extends the advice by suggesting the time of the next bg measurement in the range from half-to four-hourly to reduce nurse workload. patients were admitted at one medical (mug; n= ) and two surgical (kul: n= ; cup: n= ) icus. patients were followed for a minimum of hours and up to hours. we evaluated safety of tgc (hypoglycaemia frequency), efficacy (mean bg; hyperglycaemic index, hgi; and time spent in the target range . - . mm), and efficiency (time between bg measurements). nonparametric statistical tests evaluated differences among icus. one hypoglycaemia (bg < . mm) occurred in one subject at mug and in another at cup. there was no hypoglycaemia at kul. bg was within the target range but differed among icus with values of . ( . - . ), . ( . - . ), and . ( . - . ) mm [median ( strict glycemic control of plasma glucose has become general practice in most icus. frequent glucose control is required to titrate the amount of insulin infused and detect episodes of hypoglycemia. for practical reasons bedside glucometry is often used. aim of our study was to determine the accuracy of several glucose point-of-care (poct) devices in critically ill icu patients. arterial blood samples from unselected icu patients were collected and glucose measurements were performed on a bloodgas analyzer (glucose-oxidase; rapidlab bloodgas analyzer, bayer diagnostics) and three different poct devices (gdh-pqq, accu-chek sensor, roche diagnostics), gdh-nad+ (precision, abbott diagnostics) and modified gdh (hemocue). results of paired measurements were compared in three ways. paired values were plotted on a bland-altman plot. the pearson correlation coefficient (r) between the different methods was determined by linear regression. each pair was also analysed using the international organization for standardization (iso) criteria: -glucose > , mmol/l value within % of reference -glucose ≤ , mmol/l value within . mmol/l of reference. comparison between accu-chek and rapidlab of samples from unselected icu patients (n= ) showed a good correlation (r = . ). bland-altman analysis and analysis by iso criteria revealed clinical significant differences in . % of pairs. in all cases the poct values were higher than the values from the bloodgas analyzer. comparable results were found using the precision and hemocue: although correlation was high, analysis by iso criteria showed differences in / ( . %) and / ( . %) of pairs. a clinically important inaccuracy was found between poct devices and bloodgas glucose measurements in critically ill icu patients. in the most cases values from poct devices were false high, increasing the risk of hypoglycemia. in the context of an insulin infusion protocol for aggressive glucose control in sedated icu patients poct devices are potentially dangerous and should be avoided. acute hyperglycaemia associated with insulin resistance is common in critically ill patients. acute tight control of blood glucose is considered important, although difficult to perform in routine care. we developed a software to implement tight glycaemic control (cgao): after each glucose level measure, the cgao advises a new insulin pump rate and the schedule for the next glucose control, gives indication for correcting any hypoglycaemia episode, and presents numerous parameters describing the quality of glycaemic control. in a retrospective case control study, we compared the software cgao (lk , igny, france) used routinely in our unit since may with our previous method for glycaemic control based on daily medical prescriptions. patients without cgao (group pres) were randomly selected from our prospective intensive care database (admission after january , ) and matched : for sex, age, simplified acute physiologic score (saps ii), medical or surgical category, history of type diabetes, and length of stay (los) with patients for whom we used cgao. type diabetic patients or patients with los < days were excluded. endpoints were average glucose level, hyperglycaemic index calculated above . mmoles/l, fractions of time (ft) resp. with normoglycaemia [ . - . mmoles/l] and hyperglycaemia [> . mmoles/l], cumulative duration of hypoglycaemia [< , mmoles/l], average insuline requirements per day, and mean sampling interval for glucose control. we included patients (mean age: ± years, saps ii: ± , surgical: %, type diabetic: %), permitting to compare cgao patients with pres patients. a. sigalas*, d. w. patch, a. k. burroughs, j. p. o'beirne liver transplantation and hepatobiliary medicine, royal free hospital, london, united kingdom recently a number of studies have reported that relative adrenal insufficiency (rai) is common in critically ill cirrhotics. depending on the definition used the prevalence of rai in critically ill cirrhotics has been reported to be - %, whilst in patients immediately post liver transplantation the incidence of rai has been reported to be %. given the high prevalence of rai in critically ill cirrhotics and patients undergoing liver transplantation, we hypothesised that adrenal function impairment may be a feature of chronic liver disease per se. the aim of this study was to define the prevalence of impaired adrenal function in patients with stable cirrhosis. we also examined whether the use of the µg or µg acth tests was associated with different responses. methods. patients with biopsy proven cirrhosis (or compatible imaging and biochemistry) underwent adrenal function testing with the µg (n= ) or µg(n= ) short synacthen tests (sst). patients were those with stable cirrhosis undergoing evaluation for transplantation or assessment for tips insertion for refractory ascites. patients with a recent history of infection or bleeding were excluded. . patients underwent adrenal function testing. the median age of the group was (iqr - ). the commonest cause of cirrhosis was alcohol in %. disease severity was measured by meld and childs-pugh scores. the median meld was (iqr . - . ) and the median childs-pugh score was (iqr - ). patients ( %) showed a baseline cortisol < nmol/l and an increment < nmol/l following sst. patients ( %) had an increment in cortisol < nmol/l following sst. patients ( %) had a baseline cortisol < nmol/l. overall abnormalities in the sst (low baseline, peak or increment) were seen in patients ( %). there were no significant differences in the frequency of abnormalities in the sst between the µg or µg sst groups. in multivariate analysis only meld score significantly predicted abnormalities in the sst. the above data suggest that adrenal dysfunction is a frequent finding in patients with stable cirrhosis and is correlated with liver disease severity. the underlying mechanism of this finding is unknown but may account for the very high frequency of rai in critically ill cirrhotics. the direct relation between glucose and lactate levels in critically ill patients has hardly been studied. we studied the relation between glucose and lactate in general and during hypoglycemia. intensive insulin therapy was performed with the nurse-centered grip computer system that aimed at a glucose level of . mmol/l or less. glucose and lactate were routinely measured together. all hypoglycemias detected over a -month period at the surgical icu were analyzed. hypoglycemia was divided in mild ( . thru . ), moderate ( . thru . ) and severe (<= . mmol/l) hypoglycemia. . , glucose/lactate measurements were analyzed in patients. glucose and lactate both were not normally distributed. after taking these distributions into account no evident relationship between simultaneous measurements of glucose and lactate was seen. hypoglycemias were identified ( mild; moderate; severe). lactate showed a with a nadir value two hours after the hypoglycemia. the magnitude of hypoglycemia was not related with lactate response. evidence accumulates that improved glucose control in intensive care patients results in better outcome. improved glucose control requires rapid point of care glucose measurement. however, the reliability of point of care glucose measurements has been questioned. this study was done to evaluate the accuracy of accucheck point of care glucose measurement in intensive patients as compared to glucose measurement by the central hospital laboratory. the unit is a bed mixed closed format icu. glucose regulation is performed by nurses for all patients using a computerised protocol( ). for this study, paired glucose measurements were randomly done in patients in the icu, only when glucose measurement was clinically indicated and only if workload permitted the extra task. the accucheck inform device (roche diagnostics) measures whole blood glucose in a single drop of blood. the central laboratory uses glycoseoxidase vitros to measure glucose in serum. from patients paired measurements were obtained (table ) . central laboratory glucose measurement was generally higher than accucheck glucose measurement. the mean difference was , mmol/l. correlation coefficient r was , . the difference was more than , mmol in % of cases. blood samples were mostly ( %) derived from arterial lines. the correlation and bland altman plots are presented in figure . related literature was examined for benchmarking purposes. data collection was carried out over a one month period, two days a week, in the icu. each blood sugar level (bsl) was recorded and ensuing action chosen on adjusting the insulin infusion rate, and resultant information analysed. a survey was carried out on nursing staff regarding their views on the protocol. statistical analysis was carried out using microsoft excel ® . the bsls were in the target range of . - . mmol/l . % of the time (n= ). the proportion of bsls that complied with the surviving sepsis guidelines target of less than . mmol/l was good at . %. the incidence of severe hypoglycaemia, defined as less than . mmol/l, was low at . %. compliance with the action chosen on adjusting the insulin infusion rate was high at . %. total compliance (action and timing) with the protocol was %, and a relationship between compliance and achieving target bsls was shown. in general, a positive view of the protocol was obtained from the nursing staff regarding the protocol. the amnch icu insulin infusion protocol is effective at achieving tight glycaemic control in a safe manner. the low incidence of severe hypoglycaemia and high proportion of bsls complying with the surviving sepsis guidelines illustrates this. compliance with the protocol is achievable, demonstrated by the high level of compliance on action taken on the insulin infusion rate and the survey responses. however the timing of bsl checking needs to be addressed in future drafts of the protocol, as this is an area that needs improvement in terms of feasibility and compliance. further changes and auditing of the protocol are necessary to ensure consistency and improvement of the tight glycaemic control. introduction. intensive insulin therapy might be able to reduce mortality and/or morbidity in critical patients. besides adherence to strict protocols this strategy implies multiple, accurate measurements of glycemia. gold-standard laboratory assessment isn't able to provide immediate readings and capillary or arterial blood samples may differ too much when bedside reflectance meters are used, particularly in shock patients. our aim was to assess the accuracy of two methods of blood glucose analysis (bedside "glucometer" using capillary and arterial blood) in two groups of critical ill patients (shock and non-shock). prospective non-randomized, cohort study, in a university hospital general icu. a group of consecutive icu patients with shock syndrome and vasoactive amines and another contemporary patients without shock, were included (shock-sg and non-shock-nsg groups). for each patient to "triplets" of blood samples were collected in a h period, and included concomitant samples of blood drawn from fingerstick (cap) and non-heparinized arterial line(art). drops of capillary and arterial blood were analyzed with a bedside glucometer (glucotouch ® , lifescan), and a sample of arterial plasma was sent to laboratory for glycemia determination (lab). . total group had a median age of years, mean saps ii of , . sg was older (median age - vs ys) and more ill (mean saps ii , vs , ) than the nsg. total mortality was , % (sg- , %; nsg- , %). in the sg , % had septic and , % cardiogenic shock. in the nsg , % had politrauma and , % pneumonia. a total of "triplets" were studied. non parametric wilcoxon test was applied to test agreement between cap-lab and art-lab paired samples. although we've found a highly significant correlation (spearman r> , ) between cap-lab and art-lab values, agreement were rejected by -tailed wilcoxon signed ranks test, both in total, sg and nsg (p= . ). an error grid-analysis using iso for blood glucose determination showed that , % of cap and , % of art determinations had a deviation more than % the reference lab value in the sg. in the nsg % of cap and % of art samples had more than % deviation. this study show that the glucometer we used had an unacceptable accuracy, both in shock and non-shock patients, far from the iso criteria that imposes only % of values can be more than % apart the reference value. glucose control is a major issue in the icu and standard procedures for its determination are still lacking. introduction. arginine (arg) is a precursor of the vasodilator nitric oxide (no), while asymmetric dimethylarginine (adma), derived from proteolysis of methylated arg residues, is a no synthase inhibitor. accumulation of adma is related to oxidative stress, impairing its degradation, and to renal-and liver failure. accumulation is associated with increased mortality ( ). aim of this study was to evaluate the relation between plasma arg, adma, arg/adma ratio, organ failure and survival in patients with shock. we measured plasma concentrations of arg, adma and lactate, sofa scores and hospital mortality in septic (ss) or cardiogenic shock (cs) patients on d , d and d of icu admission. patients were enterally fed with impact (arg-enriched). values are presented in mean ± sd or median (iqr). for regression analysis, arg, adma and arg/adma were log transformed. of the patients, had ss, cs. mean age was ± yrs, sofa ± , apache ii ± . . hospital mortality was %, predicted mortality was ± %. at d , median (iqr) of arg was ( - ) mumol/l (normal range - mumol/l), adma . ( . - . ) mumol/l, arg/adma ( - ) and lactate . ± . mmol/l. arg and arg/adma at d were inversely related to lactate (r = . , p < . , for arg; r = . , p < . for arg /adma), and to sofa scores. the table presents the relation between arg and arg/adma to sofa score during sampling, and of arg and arg/adma on day to maximum sofa score. apneic oxygenation (ao) is apllied during several operations in thoracic surgery and some procedures in th icu. retention of co often leads to hypoxemia, limiting the tolerable time in ao. this experimental study was designed to evaluate the effects of recruitment maneuver on oxygenation, co retention and survival times ao. following the ethic committee approval, male sprague-dawley rats were anesthetized, tracheostomized, cannulated via the a. carotis and ventilated with pressure controlled ventilation (peak pressure: cmh o, frequency: /min, cm h o peep) for minutes. following the basal (t ) arterial blood gas sample, they were randomized into groups and disconnected from the ventilator: in group (n= ), rats underwent ao with a cannula inserted to carina (o -flow: . l/min), in group (n= ), recruitment maneuver ( cm h o (peep) ventilation pressure during seconds) was performed before ao. in control group (group , n= ), data were recorded after apnea (this group was stopped after the first subjects have died during the study period). further arterial blood gas samples were drawn in st, rd and th minutes, and ph, po , pco , hco and be values were recorded. survival times after the initiation of ao were also investigated. kruskal-wallis test was used to compare the values in different times, and mann-whitney-u the values in different groups. there were no significant difference in t values. compared to t values, there was a significant decrease in po and a significant increase in pco during rd and th minutes in all subjects, with a less change in g . there was a significant difference between g and g in po after and minutes p< . ; table ), the difference in pco was not significant. survival time in g was significantly longer (g : , ± , min; g : , ± , min; p< . ). to investigate potential prognostic factors and to predict extent of risks for postoperative pulmonary complications by logistic regressive analysis, and to evaluate the role of non-invasive ventilation in reducing the incidence of complications in elderly patients. stair-climbing test was carried out with asa score, fev , changes of spo and hr et al were noted at the same time. logistical regressive analysis based on the parameters above were used to assess the relation between potential prognostic factors and postoperative complications. patients with limited pulmonary reserves were selected using the equation, and protective effect of non-invasive ventilation on these patients was assessed. incidence of postoperative pulmonary complications for high-risk patients with non-invasive ventilation was . %, and incidence of pulmonary complications for high-risk patients without non-invasive ventilation was . %. there was not a significant difference between these two groups with low-risk (p> . ). conclusion. the mathematical model of logistic regressive analysis using stair-climbing testing combined with other parameters is a simple, reliable method to predict the cardiopulmonary reserved function in elderly patients. non-invasive ventilation can effectively reduce the incidence of postoperative pulmonary complications for high-risk patients, but it has no effect on patients with low-risk. continuous epidural analgesia (ea) and intravenous analgesia (ia) are widely used for postoperative thoracic pain control. the aim of this study is to compare the advantages and the disadvantages of both analgesic techniques. ropivacaine . % to mg/h using thoracic epidural catheters (ea) vs intravenous analgesia with remifentanyl . µgr/kg/min (ia). one hundred patients, undergoing pulmonary surgery, were recruited and divided, after randomization into groups. patients included in ea group had an epidural thoracic catheter placed at th -th space, received ropivacaine . % by continuous infusion (rate ml/h). patients included in ia group received an ev continuous infusion of remifentanyl (rate . µgr/kg/min for hours). rescue medication consisted of morphine mg ev at patients demand. analgesia at rest and while coughing as evaluated by visual analogue scale (vas). haemodynamics, motor blockade (bromage scale) and side effects such as nausea, vomiting and pruritus were observed. the follow-up took place after weaning and every hour to hours at rest and coughing. data are reported to media ± standard deviation (sd). analgesic effects were compared by using chi square statistics (p< . ). both groups showed good analgesic effects. remifentanyl seems to decrease the incidence of side effects and the need of rescue analgesia. conclusion. )our data show that both analgesic techniques are able to guarantee a good pain relief after thoracotomy. )epidural analgesia was more difficult to perform and it showed less acceptance by patients. non-invasive ventilation (niv) has become an effective treatment to reduce morbidity and mortality in patients with acute respiratory failure. its application has been restricted to critical care o intermediate care areas, and little data is available on its usefulness in the post-anaesthesia care units (pacu). the aim of this study is to document our experience after eight patients treated in the pacu. we undertook a retrospective audit of patients treated with niv between october and december . data of past medical history, age, asa physical status, surgical procedure, anaesthesia modality, type of respiratory failure, ventilatory mode, and time of niv were recorded. we also recorded side effects related to niv application. descriptive statistical analysis was used. eight patients were included. the mean age was . ± . (sd) years. five patients were classified as asa ( . %), two as asa ( . %), and one as asa ( . %). three patients had morbid obesity, two chronic heart failure, and two chronic obstructive pulmonary disease. general and regional anaesthesia were employed in and cases respectively. type of surgery was thoracic ( %), urologic ( %), and plastic ( %). there was one case of abdominal surgery and another one of oral surgery. hypoxemic failure was detected in three patients ( . %), and cpap was applied in these cases. bipap was applied in cases of hypercapnic ( . %) or global ( %) respiratory failure. the mean time of niv was . ± . (sd) minutes. no complications related to niv occurred. no patient required either intubation or transfer to the icu. all of them were transferred to the surgical wards the same day. conclusion. niv can be safely applied to selected patients in the pacu, to treat respiratory failure after either general or regional anaesthesia. it is an effective method to avoid intubation and icu stays, with minimal side effects. further studies should be conducted to analyze the clinical and economic impact of niv in the pacu. the routine use of volatile anesthetics in intensive care medicine has been limited so far due to technical difficulties and the need for an anaesthetic machine. the new anesthetic conserving device (anaconda)can provide a safe application of isoflurane or sevoflurane under intensive care conditions. this system is a modified heat and moisture exchanger which includes activated carbon fibres and works as a miniaturized vapor with recirculation. we studied the effectiveness of sevoflurane sedation in operative intensive care patients undergoing mechanical ventilation. we included ventilated patients (neurosurgery, septic patients) in our retrospective analysis. the anaesthetic conserving device (anaconda-system) replaces the common heat and moisture exchanger in the ventilator circuit. the volatile anaesthetic is continuously applied in liquid status via a syringe pump to the minivapor where the anesthetic is vaporized. the expired anaesthetic gas is stored in the carbon filter and about % are resupplied into the breathing circle. first experiences with sevoflurane at our institution with a mean application time of . ± . hours per patient, showed a mean dose of . ± . ml sevofluran to achieve the individually targeted sedation level. . ± . minutes after the end of sevoflurane application, the patients could be neurologically evaluated or transferred to spontaneous breathing or extubated. no relevant side effects like nausea, vomiting or elevated enzymes were observed. we could demonstrate a safe application route, no development of tolerance as well as short wake-up times after long-term sedation with sevoflurane. the current literature suggest that volatile anaesthetics present an alternative for long-term sedation on intensive care units, providing optimized pathways from a medical as well as from an economical viewpoint. safety and effectiveness of sedation and analgesia in permanent pacemaker implant (ppm) is of special concern, due to age and comorbidity of the implanted patients. remifentanil pharmacological properties appear to be of interest in this setting. to date, there are no reports describing the use of remifentanil in this procedure, without the use of mechanical ventilation. consecutive patients in whom a ppm or other procedures, such as pacemaker battery change, was scheduled were included. a sedation and analgesia protocol for ppm implantation was performed: metoclopramide premedication, remifentanil infusion ( mg/ml), local anaesthesia with mepivacain %, magnesic metimazol administration at the end of procedure, and remifentanil infusion withdrawal minutes later. remifentanil infusion was initiated at a rate of mcg/min, increasing the rate to attain a sedation ramsay scale grade or , to a maximum of mcg/min. remifentanil failure was defined as the need to administer a different sedation after the maximum dosage was attained. adverse effects, lenght of infusion and dosage were recorded. .two hundred and thirty-six consecutive patients were included. the men age was , ± , . procedures: bicameral pacemaker , %, unicameral , %, battery change , %, other , %. infusion description and adverse effects are showed in tables and . serious adverse effects were resolved with remifentanil infusion withdrawal. all the procedures were completed. remifentanil is safe and effective as sedation and analgesia for ppm implantation, even for old patients, with the dosages used in our protocol. nausea is the most frequent adverse effect. serious adverse effects are uncommon and can be resolved with infusion withdrawal. glass psa, gan tj, howell s. a review of the pharmacokinetics and pharmacodynamics of remifentanilo. anesth analg ; : s -s . peripheral arterial occlusive disease (paod) can cause intense neuropathic/ischemic limb pain in patients (pts) with end stage renal disease (esrd). although fentanyl may be an excellent choice in esrd due to the absence of active metabolites, the use of fentanyl as pca in esrd has never been reported. we used iv fentanyl pca for ischemic lower extremity pain in esrd patients ( m, f), of whom were scheduled for amputation. pts received iv fentanyl pca via a gemstar (abbott) pump. initial settings were mcg bolus, min lockout, no basal, and dose was adjusted as needed to achieve visual analogue scale (vas) score < . pca started hours preamputation and continued postoperatively for h in pts ( pts had epidural postoperative analgesia and one terminal cancer pt did not have surgery). pain was assessed twice daily with vas. the mcgill pain questionnaire (mpq) -total ranked rating index (pri(r)), was administered immediately before and h after pca started. sedation was assessed twice daily on a four-point scale: ) agitated, ) awake, ) roused by voice and ) unarousable. pain scores were compared with paired t-test. group data are presented as mean ± sd. mean sedation score was in men and in women. we did not observe respiratory depression in any patient. the aim of this study was to determine risk factors for relapse, and for icu-mortality in patients with ventilator-associated pneumonia (vap) related to nonfermenting gram negative bacilli (nf-gnb). retrospective case-control study based on prospectively collected data. vap diagnosis was based on clinical, radiographic and microbiologic (endotracheal aspirate ≥ cfu/ml) criteria. patients with monobacterial vap related to nf-gnb were eligible. patients with subsequent superinfection or persistent pulmonary infection were excluded. patients with relapse of nf-gnb vap were matched ( : ) with patients without relapse according to duration of mechanical ventilation before vap occurrence. univariate and multivariate analyses were used to determine risk factors for relapse, and for icu-mortality in cases and controls. . patients were eligible. patients were excluded for superinfection. no persistant infection was diagnosed. ( %) patients developed a relapse of nf-gnb vap, and were all successfully matched with controls. pseudomonas aeruginosa was the most frequently isolated bacteria ( %), followed by acinteobacter baumannii ( %) and stenotrophomonas maltophilia ( %). no significant difference was found between cases and controls with regard to age ( ± vs ± ), male gender ( % vs %, p = . ), and surgery ( % vs %). however, saps ii at icu admission ( ± vs ± , p = . ) was significantly lower in cases than in controls. duration of adequate antibiotic treatment for first vap episode was significantly shorter in cases than in controls ( ± vs ± d, p = . ). inadequate initial antibiotic treatment was the only variable independently associated with relapse of vap related to nf-gnb (or [ % ci] = . inadequate initial antibiotic treatment is independently associated with relapse of vap related to nf-gnb and with icu-mortality. ∆ radiologic score and saps ii at day after vap diagnosis are independent risk factors for icu-mortality in these patients. s. blot* , j. solé-violán , j. blanquer , j. almirall , a. rodriguez , j. rello icu, ghent univ hosp, ghent, belgium, icu, dr negrin hosp, gran canaria, respiratory care, clinic hosp, valencia, icu, mataró hosp, barcelona, icu, joan xxiii univ hosp, tarragona, spain practice guidelines suggest processes of care such as timely pulse oximetry monitoring and antibiotic therapy, as quality indicators for the management of communityacquired pneumonia (cap). the objective of this study was to determine whether postponed initial processes of care such as pulse oximetry monitoring delays initiation of antibiotic therapy and adversely affects intensive care unit (icu) survival in patients with severe cap. a prospective observational multicenter study was conducted including patients with cap admitted to the icu in hospitals. a secondary analysis was conducted to evaluate processes of care and icu survival. postponed blood culture sampling, arterial blood gas sampling and pulse oximetry monitoring was predictive for delayed antibiotic administration (p< . ). linear regression analysis demonstrated that a delay of > h in blood culture sampling was associated with a delay of . h ( % confidence interval [ci], . - . ) in antibiotic therapy, a delay of > h in blood gas sampling with a delay of . h ( % ci, . - . ), and a delay in pulse oximetry monitoring of > h with a delay of . h ( % ci, . - . ). a delay in antibiotic administration of > h was associated with increased mortality in univariate analysis (relative risk [rr], . ; % ci, . - . ), but not after adjustment for disease severity. a delay in pulse oximetry monitoring of > h was associated with increased mortality in univariate analysis (rr, . ; % ci, . - . ) and after adjustment for disease severity (hazard ratio, . ; % ci, . - . ). in patients with severe cap timely executed processes of care are associated with a short time to antibiotic administration and reduced risk of death. appropriateness of antibiotic therapy is associated with reduction of bacterial load. c-reactive protein (crp) is a valid biochemical surrogate. our objective was to determine the correlation of bacterial load, measured by quantitative tracheal aspirate (qta), with crp as an indicator of inflammatory response in episodes of lower respiratory tract infection. to evaluate whether appropriateness of antibiotic treatment influences microbiologic (qta), biochemical (crp) and clinical resolution criteria (temperature, wbc, sofa and po /fio fraction). prospective cohort study. sixty-five intubated patients with monomicrobial lower respiratory tract infection were included. crp and bacterial load variation were evaluated through the ratio between d and d measures. a qta was performed on lower respiratory tract onset (d ) and h afterwards (d ). its logarithm value (logqta) was recorded. logqta correlated positively with crp, temperature and wbc. logqta has decreased significantly more from d to d in patients receiving appropriate empirical antibiotic therapy compared to those with inappropriate treatment (logqta ratio . vs . , p< . ). mean crp levels showed a similar pattern, decreasing from d to d in patients receiving appropriate empirical antibiotic treatment, but not in episodes with inappropriate treatment (crp ratio d /d . vs . , p< . ). ancova showed that crp level on d was significant lower in patients with appropriate antibiotic treatment compared to inappropriate empiric treatment ( ± mg/l vs ± mg/l, p< . ). the best cut-off to predict appropriateness of antibiotic therapy is a crp levels reduction of % on d (auc= . ). conclusion. c-reactive protein correlates with bacterial load and is a valid biochemical surrogate of bacterial burden in lower respiratory tract infection. follow-up measurements of crp anticipate the appropriateness of antibiotic therapy. a. günther* , p. schenk , m. maggiorini , a. betbesé , p. f. laterre , n. fedorovskiy , f. j. h. taut , r. g. spragg university of giessen, lung center, giessen, germany, , medical university vienna, vienna, austria, , universitätsspital zürich, zurich, switzerland, , hospital sta cruz y san pablo, barcelona, spain, , hôpital saint luc, brussels, belgium, , city clinical hospital n , moscow, russian federation, altana pharma ag, a member of the nycomed group, konstanz, germany, , uc san diego, san diego, united states the formal diagnosis of ards requires the acute onset of a severe impairment in oxygenatio(pao /fio <= mm hg), exclusion of a hydrostatic cause, and the presence of diffuse bilateral opacities. pneumonia is one of the most common underlying reasons for development of ards, but when only unilateral opacities are present, these patients fail to fulfil ards criteria. it is currently not known whether fulfilment of the formal ards criteria has any impact on -day mortality in patients with pneumonia suffering from severe gas exchange abnormalities. the valid study, a randomised, double-blind study in intubated and mechanically ventilated patients with severe respiratory failure (pao /fio <= mm hg) due to pneumonia or aspiration of gastric contents investigates the effect of rsp-c surfactant (venticute ® ) on mortality. the study does not require a formal diagnosis of ards for patient enrolment. however, the presence or absence of ards is documented. we conducted univariate and multivariate logistic regression analyses using preliminary blinded data from the first patients randomised with a diagnosis of pneumonia. the prognostic value of the formal diagnosis of ards was determined. univariate logistic regression analysis failed to identify a significant correlation (p= . ) between the formal diagnosis of ards and mortality at day . pao /fio was more likely to be associated with mortality (p= . ) as was the number of quadrants on chest radiograph that showed opacities (p= . ). age and apache ii score were highly associated with mortality (p< . ). multivariate logistic regression identified age (p< . ), the number of involved quadrants (p= . ), and apache ii (p= . ) as independent factors affecting -day mortality. conclusion. the prognosis of ventilated patients with pneumonia is not dependent on the formal diagnosis of ards. instead, age, apache ii score, and the number of lung quadrants with radiographic opacities are more predictive of outcome. bernard gr et al. intensive care med. ; : - . to determinate the clinical-epidemiological characteristics and risk factors for postsurgical pneumonia (psp) after lung cancer resection in a university hospital. a retrospective case-control paired study ( : ) was performed in cases of lung cancer collected from to . definition of psp case was a new or changing radiographic infiltrates with two or more of the following criteria: fever > o c, wbc> mm or/and purulent secretions. control group was formed by patients matched by age and lung cancer stage. . patients were evaluated ( psp and controls). overall, data of both groups were: age ± yr, males ( %), smoking habit (active or past smokers) patients ( %), copd patients ( %) and weight loss over kg in patients ( %). incidence of psp was %, crude mortality rate and attributable mortality estimated for psp was % and %, respectively. in the psp group, we found the following isolates ( %): p. aeruginosa ( %), s. viridans ( %), h. influenzae ( %) s. pneumoniae ( %) and undeterminated ( %). psp was associated with low bmi (p= . ), low fev (p= . ), stage iiia (p= . ), anaesthetic time (p= . ), pneumonectomy (p= . ), thoracic pain (p= . ), reintubation (p= . ) and haemorrhage (p= . ). conclusion. the incidence of psp in our series is low but with a high mortality. identification of risk factors (some of them suitable for medical intervention) may improve the management of lung cancer patients treated with surgery. j. karhu* , h. syrjälä , p. ylipalosaari , j. laurila , p. ohtonen , t. i. ala-kokko anesthesiology, division of intensive care, infection control, surgery, oulu university hospital, oulu, finland introduction. scap (severe community acquired pneumonia) and hap (hospital acquired pneumonia) requiring icu treatment have been shown to be associated with significantly higher mortality compared to those not requiring icu treatment ( , ). we compared pneumonias acquired outside the icu to that acquired in the icu, during mechanical ventilation (ventilator-associated pneumonia, vap). patients admitted into a mixed university level icu during a month period whose icu stay was longer than hours were included. the occurrence of scap, hap and vap were prospectively assessed. the following information was collected: age, severity of underlying disease on admission, underlying malignancy and recent use of immunosuppressive therapy. the length of icu and hospital stay as well icu, hospital and day mortalities were recorded. a total of patients fulfilled the inclusion criteria during the study period. there were a total of pneumonias. majority of the pneumonias were scap ( / ), while there were hap and vap cases. patients with hap tended to be older ( . , p= . ) and a larger proportion of them had malignancy ( %, p< . ), compared to vap ( years, %) or scap ( years, %). there were no significant differences between the mean admission apache ii scores (scap . vs. hap . vs. vap . ) . the icu length of stay was longest in vap; while the hospital stay was longest in patients with hap (table ). the survival rates were highest in hap, although this did not reach statistical significance. in apache ii and age adjusted multivariate logistic regression analysis vap (or . , % ci . - . , p= . ) and scap (or . , % ci . - . , p< . ) remained significant risk factors for hospital mortality together with immunosuppression (or . , % ci . - . , p= . ). heart surgery in infants is often associated with pulmonary inflammatory process. at the same time, the blood level of pro-inflammatory factors: interleukin- (il- ) and interleukin- (il- ) is increased. the number of polymorphonuclear leukocytes (pmn-elastase) and neutrophils is raised as well. a qualitative evaluation of the factors, cellular composition analysis of nonbronchoscopic trachebronchial lavage (ntl) combined with clinical findings can help early diagnose pneumonia. the objective of the study was to reveal the peripheral blood level of pro-inflammatory cytokines (il- , il- ), the activity of pmn-elastase and α antiprotease inhibitor (α -pi), as well as examine the ntl cellular composition and cytokine level in infants before and after heart surgery. we studied infants aged from days to months, weighting between . and kg. patients underwent cardiopulmonary bypass surgery, patients were operated on without cardiopulmonary bypass. in cases a clinical diagnosis of pneumonia was made between and days postoperatively. early postoperative survival was %. the peripheral blood cytokine concentration in operated infants pre-and postoperatively is presented in the study (table ) . a significant increase in pro-inflammatory factors after surgery can be observed. we examined the ntl of infants who underwent heart surgery and who did not develop pneumonia. we noticed that the number of neutrophils increased significantly in all patients after cardiopulmonary bypass surgery, sometimes reaching %. we consider it as a sign of pulmonary inflammatory process. the number of nonviable alveolar macrophages before and after surgery exceeded %. it indicates a decrease in cellular pulmonary protection. the pmn-elastase peripheral blood activity was . ± . iu/ml preoperatively and ± . iu/ml postoperatively; the α -pi level was . ± . iu/ml and . ± . iu/ml, respectively. conclusion. thus, an increase in the peripheral blood level of pro-inflammatory cytokines was observed in infants who underwent heart surgery. at the same time, the ntl relative number of neutrophils was increased. an early detection of the mentioned factors appears to be a diagnostic marker of the pulmonary inflammation reaction onset. all colistin resistant gram-negative isolates from patients hospitalized in a -bed icu during one-year period were retrospectively recorded. demographic data, the underlying disease, prior antimicrobial therapy, microbiological data and the clinical and bacteriological response to treatment were recorded. the antimicrobial susceptibility of the isolates was determined using the disk-diffusion (kirby-bauer) method, the vitek ii system and the etest method (ab biodisk, solna-sweden). interpretation of the susceptibility results was in accordance to the clinical and laboratory standards institute (clsi). nine patients with infections caused by colistin resistant gram-negative isolates were recorded. all patients had prolonged icu stay, were under mechanical ventilation and had a significant exposure to antibiotics including colistin for mdr gram-negative bacteria. three k.pneumonia isolates producing metallo-beta-lactamases (mbl), two k. pneumonia isolates producing extended spectrum b-lactamases (esbl) and mbl, two acinetobacter baumannii isolates susceptible to tetracyclines, one pandrug resistant (pdr) acinetobacter baumannii and one pdr pseudomonas aeruginosa were recorded. the bacteria were isolated from bronchial secretions in four cases and from the blood stream in five patients. in five patients antibiotic treatment was based on susceptibility tests, with clinical and bacteriological success. antibiotic combinations including colistin plus meropenem or colistin plus cefepime were provided in patients harbouring pdr isolates. these patients failed to respond to treatment and had a fatal outcome. the overall clinical success and survival rate was . % at days. conclusion. the development of colistin resistant strains with increasing mortality rates urges for the continuous surveillance on these highly resistant organisms and the strict implementation of infection control practices. ventilator-associated pneumonia (vap) is one of the most severe infections in the icu, continuing to complicate a high percentage of the patients receiving mechanical ventilation and leading to increased morbidity and mortality, especially when it is due to highrisk pathogens. our aim was to study the incidence and outcome of vap due to mdr bacteria in our icu. prospective, epidemiological study, in a mixed icu of a tertiary care hospital. all patients admitted from august to march were included. lower respiratory tract samples of all patients with suspicion of vap were cultured. standard diagnostic criteria were followed. statistical analysis was performed with spss v. . during the months period of the study patients were admitted. their mean age was years and % of them were male. their mean apache score was and the average duration of stay in the icu was days. forty-two episodes of vap due to mdr bacteria were recorded in patients. the bacteria isolated from lower respiratory tract samples were acinetobacter baumanii, pseudomonas aeruginosa, klebsiella pneumoniae and enterobacter cloacae, while in cases concomitant bacteremia was recorded. the mean time from admission to the icu to diagnosis of vap was days. positive outcome was noted in % of cases and was found to be reversely related to the apache ii score (p= . ), to days of stay in the icu (p= . ) and to multi-organ failure (p= . ). of the patients with vap, had normal renal function before the lung infection. of these, developed renal failure due to the lung infection and had to be started on renal replacement therapy. the mortality of these patients was significantly higher than for the patients who did not develop renal failure (p= . ). regarding the crude mortality of patients with and without vap, this was found to be . % and . % respectively (p= . ). (pa) is not a frequent pathogen in this setting but could be associated with poor prognosis. in our population of patients undergoing cs, we compared risk factors and prognosis of pa-eop with eop due to others micro-organisms. this retrospective study performed on years ( - ) involved patients (pts) who underwent cs with cardiopulmonary by-pass. diagnostic of pneumonia was based on clinical and laboratory criteria: t˚> . , purulent tracheal secretions, wbc> , /mm , chest x-ray changes and microbiological criteria (broncho-alveolar lavage> cfu/ml). pre, per and postoperative risk factors, empiric antibiotic, and prognosis of pa-eop were compared with those obtained for eop due to others germs. the groups were compared using chi-square. p< . was considered significant. over the studied period, eop occurred in pts (incidence %), including pts ( conclusion. in our experience, pa-eop following cs seems to be more frequent than what was previously reported. criteria for prediction of pa-eop remain to be assessed. in case of pa eop, empiric antibiotic is often inappropriate with a possible increased risk of mortality. these results lead us to modify our empiric broad-spectrum antibiotic treatment and to take into account pa, especially in severe forms of eop and in copd pts. antibiotic exposure and timing of pneumonia onset influence ventilatorassociated pneumonia (vap) isolates. the first goal of this investigation was to evaluate whether trauma also influences prevalence of microorganisms. a retrospective, single-center, observational cohort study. . vap isolates in a multidisciplinary icu documented by quantitative respiratory cultures and recorded in a -month database were compared, based on the presence (t) or absence of trauma (at). causative microorganisms were classified in four groups, based on mechanical ventilation duration (> days), and previous antibiotic exposure. one hundred eighty-three patients developed episodes of vap ( trauma). methicillin-sensitive staphylococcus aureus (mssa) was more frequent ( . % vs . %, p< . ) in trauma, whereas mrsa was more frequent ( % vs . %, p< . ) in nontrauma. no significant differences were found between trauma and nontrauma patients regarding prevalence of other microorganisms. in trauma patients, mssa episodes were equally distributed between early and late-onset vap( % vs %) but no mrsa episode ocurred in the early-onset group. conclusion. trauma influences the microbiology of pneumonia and it should be considered in the initial antibiotic regimen choice. our data demonstrate that patients with trauma had a higher prevalence of mssa, but the overall prevalence was sufficiently high to warrant an s. aureus coverage for both groups. on the other hand, since no mrsa was isolated during the first days of mechanical ventilation on trauma patients, mrsa coverage in these patients is only necessary after ten days of admission. a retrospective study of a hiv patient's cohort that stays in icu with acquired community pneumonia in the period between january and december . data analyzed included age, clinic stage, years of disease evolution, antiretroviral therapy, cd levels and viral charge at the hospitalization, positive hcv and/or hbv, severity scores and microorganism isolated. chi-square analysis was used to compare categorical data. continuous data was compared using student's t-test. prognostic factors of mortality were studied by multivariate logistic regression analysis. . fifty-three patients were studied. % were males. the average age was ± years. the most frequently risk practice was intravenous drug addiction ( % we prospectively collected data regarding demographics and microbiology of bacteremias. blood cultures were obtained on clinical suspicion of bacteremia and followed up on days , , and th. severity of illness scores, apache and sofa were recorded at baseline and days , , and th. improving hand hygiene is a cost-effective way of decreasing hospital-acquired infection rates. in this study we recorded opportunities for and compliance to hand hygiene in our icu. four trained nurses and a doctor monitored opportunities for hand hygiene performance (hand antisepsis and glove use) as well as compliance to the cdc guidelines in our icu for days. the procedure was anonymous, involved all icu personnel and was performed in -min sessions, throughout all shifts. we collected opportunities for hand hygiene, mostly related to nurses ( %). compliance to hand antisepsis was %, higher in nursing and assistant staff ( % and %, respectively) compared to doctors ( %). compliance was lowest before contact of healthcare staff with a patient or his inanimate environment ( % and %, respectively). the activity index (=the need for hand antisepsis performance) for the nursing staff was high ( opportunities per hour per nurse in the morning shift, ie opportunities per shift). however, no significant correlation was found between compliance rate and activity index of the staff (r=- . , p= . ). alcohol-based hand-rub was used in % of the cases. technique of antisepsis performance was uniformly poor and mean duration of the procedure was low ( . seconds). compliance with glove use guidelines was % and was high in all staff categories and all types of opportunities. is an aerobic non-fermenting gram negative bacillus. it is generally considered an opportunistic pathogen. s. maltophilia is increasingly recognised as a cause of nosocomial infection among ventilated and immunocompromised patients, and in those receiving broad spectrum antibiotics. s. maltophilia infections are commonly resistant to multiple antibiotics including beta lactams, quinolones, aminoglycosides and carbapenems. reported mortality rates for patients with bacteraemia due to s. maltophilia vary from - %. the mid western regional hospital, limerick, ireland, is a bed hospital located on three sites. the intensive care unit(icu) is a seven bed medical and surgical unit with approximately admissions per year. the s. maltophilia clusters prompted epidemiological investigation, restriction fragment-length polymorphism typing (rflp) of genomic dna of outbreak strains, and finally, instituting revised infection control measures to limit spread. we conducted a retrospective chart review of affected patients noting admission apache ii scores, medical co-morbidity, immunocompetence, antibiotic history, and patient outcome. we collected cultures of icu cubicle/ room surfaces, sinks, ventilatory equipment, and water sources. patients and environmental isolates were examined by rflp typing. this preliminary analysis suggests that pct can be use to accurately early identify sepsis only at levels above ng/ml and then use them to decide to rapidly beginning the use of antibiotic. in patients with pct below ng/ml we cannot use them to exclude the diagnosis of sepsis. with the cutoff , ng/ml we found the same analysis. other studies with more samples are necessary to confirm this conclusion. during these three years patients were hospitalized in total. one hundred and thirty one ( . %) were hospitalized less than h and were excluded. a total of bacteremias were observed. forty -four bacteremias were catheter related bloodstream infections. fifty five were due to gram negative microorganisms (pseudomonas aeruginosa %, acinetobacter baumanni %, klebsiella pneumonia %). in the following table, resistance to broad spectrum antimicrobials is presented during these three years. infection in patients with severe stroke is an important problem and the sensitivity and specificity of its diagnosis with clinical criteria are deficient. fever is a common event and, as leucocytes or c-reactive protein, its specificity is very low in this kind of patient. our objective was to evaluate the utility of a biological marker such as procalcitonin (pct) in the diagnosis of infection in patients with severe stroke. we followed patients with severe stroke receiving mechanical ventilation because of coma. during the first days of evolution nih and apache ii scales were registered, we measured pct and c-reactive protein on days and and if infection was suspected microbiological samples were collected. infection was diagnosed if the patient fulfilled the cdc criteria. mann-whithney u and x-square tests were used. twenty-six cases corresponded to haemorrhagic stroke. baseline characteristics were: mean age years, % males, glasgow scale ( - ), nih scale ( - ), apache ii ( - ), temperature . o c ( - . ), leucocytes /mm ( - ), pct . ng/ml ( . - . ) and c-reactive protein . mg/dl ( . - ). on the third day of evolution cases of ventilator-associated pneumonia were diagnosed. when compared with the noninfection group there were no differences in baseline characteristics and on the infection day we only found differences in pct, . ng/ml in front of . ng/ml; p < . . seventeen ( %) of the patients without infection presented a temperature o c sometime during the follow-up and in all cases pct did not show any change. these results indicate that pct is a useful tool in the diagnosis of infection in patients with severe stroke. the ongoing challenge of accurately diagnosing infection in the icu motivates a search for novel molecular diagnostics. we reported recently that microarray analysis of circulating leukocytes can be used to derive a "riboleukogram", which captures the dynamics of the host response to and recovery from ventilator-associated pneumonia (vap). in the current study, we tested the hypothesis that the informational content of circulating leukocytes differs, thereby allowing one to rank leukocyte populations on their potential to contribute to rna diagnostics for pneumonia. sixteen patients ( male, female) at risk for vap were entered into our irbapproved study that collects blood and clinical data every hours for up to days. four of the sixteen patients developed vap as diagnosed and treated by the attending icu physician. previously reported blood protocols were used to isolate buffy coat, enriched neutrophil, and enriched monocyte populations by using negative selection. cellular purity was assessed by facs for one of the vap patients. genome-wide expression analysis was performed on rmanormalized signal from affymetrix u . plus genechips. edge software (fdr= . ) was used to determine changes in mrna abundance over time for each cell population. during the -day window in which each of the four patients (all males) developed vap, significant changes in gene expression were observed (table) , but the information content (number of genes altered) varied across leukocyte populations. these differences were not due to signal variance (coefficient of variation, cv) or differences in the number of samples available for analysis. moreover, only . % of the monocyte gene list overlaps with the neutrophil list, arguing that neutrophil contamination of monocyte populations is insufficient to explain the -fold difference in gene number. the aim of the present study was to evaluate the relationship between the cytokine expression in bronchoalveolar lavage fluid and bacterial burden in mechanically ventilated patients with suspected pneumonia. mechanically ventilated patients with suspected pneumonia admitted in icu from november to january were prospectively enrolled. fiberoptic bronchoalveolar lavage (bal) was performed with ml of sterile isotonic saline in aliquots of ml, local anesthetic were not used. bal samples for microbiologic quantitative cultures and bal cytokines: interleukin (il) , il , tumor necrosis factor-alpha (tnf-alpha), granulocyte colony stimulating factor (g-csf) and granulocyte-monocyte colony stimulating factor (gm-csf) were measured. . patients were included, most of the patients ( . %) were with prior antibiotic therapy. patients ( . %) had a positive bacterial culture defined than a diagnostic threshold of > colony-forming unit/ ml. the concentration of tnf-alpha was significantly higher in the group of patients with positive bal (table ) . it has been demonstrated in a swine model that therapeutic hypothermia ( ˚c) facilitated transthoracic defibrillation. however, the mechanisms leading to reduced defibrillation threshold (dft) remain unclear. we hypothesized that therapeutic hypothermia promotes the wavefront organization of ventricular fibrillation (vf), therefore facilitating defibrillation. methods. by using a two-camera optical mapping system, epicardial activation patterns of vf were studied in isolated rabbit hearts at baseline ( ˚c), -min therapeutic hypothermia ( ˚c), and -min rewarming ( ˚c). in additional hearts, dft (voltage required to achieve % probability of successful defibrillation, n= hearts) and apd (action potential duration)/conduction velocity (cv) restitutions (n= hearts) were determined at these stages. results. comparing with at baseline ( ± %) and rewarming ( ± %), there was a higher percentage of vf duration containing organized repetitive activities during hypothermia ( ± %, p< . ). however, there was no significant difference of dft among these stages ( ± , ± , and ± v, p= . ). the electrophysiologic characteristics of ventricles at these stages were summarized in table . in brief, hypothermia prolonged apd, decreased cv, and subsequently shortened wavelength. hypothermia also failed to flatten the slope of apd restitution. furthermore, apd dispersion at the epicardial surfaces of both ventricles and cv heterogeneity among epicardial lines were all enhanced by hypothermia. (pt) with acute coroanry syndrome (acs) at admission is a associated with a high mortality. the mechansims are poorly understood. we sought to determine an interrelation between no coronary reflow after percutaneous coronary intervention (pci), the likelihood of developing cardiogenic shock, death in hospital and plasma glucose level at admission. we performed a prospective analysis of consecutive pt presenting with an acs in our emergency room. we recorded basis data (gender, age, bmi), cardiovascular risk factors, burden of coronary artery disease (cad), coronary blood flow after pci, killip-classification, left vetricular ejection fraction, probabilty of developing cardiogenic shock and the likelihood of dying in-hospital. our findings suggest that elevated bs at admission is a useful risk marker to identify pt with a high risk to develop coronary no reflow-phenomenon after pci. this may be due to increased inflammatory activity and hypercoagulability. if one dies in cardiogenic shock, these pt present always with elevated bs at admission. prull mw, trappe hj. activation of blood coagulation in nstemi: does diabetes mellitus matter? intensivmed . we measured serum cortisol levels before and minutes after a , mg corticotropin stimulation test in pts with cs following acute myocardial infarction (mi) and in a control group of pts with uncomplicated mi at day , , , , , and after onset of shock/mi. rai was defined by an increase in serum cortisol levels in response to corticotropin of less than µg/dl. data were correlated to vasopressor-need and interleukin (il) levels (il ,il ,il ,il ). baseline cortisol levels in pts with cs were significantly higher than in control pts especially on day ( ± vs ± , p= . ). in cs-pts the test-series were stopped at day to because the physician in charge started a therapy-trial with hydrocortisone due to increasing vasopressor need. three other pts died within the seven day period. rai was observed only at day in of the cs-pts but in none of the control pts (p= . ). these cs pts with rai had higher il- and il- levels at baseline ( during tidal mechanical ventilation, an end-expiratory pause abolishes the cyclic increase in intra-thoracic pressure. this may produce a transient increase in cardiac preload and then in cardiac output in volume responsive patients. our objective was to test whether the effects of an end-expiratory pause on cardiac index and pulse pressure may help in detecting fluid responsiveness in patients with acute circulatory failure. in mechanically ventilated patients with an acute circulatory failure and no spontaneous ventilator triggering who were deemed at volume expansion, we performed a -sec end-expiratory pause. we continuously measured the systemic arterial pressure and the pulse contour-derived cardiac index (picco device) at baseline, during the last seconds of the end-expiratory pause and after a ml saline administration. volume expansion induced an increase in cardiac index ≥ % in patients (classified as responders). in these patients, volume expansion increased the cardiac index by ± % from . ± . l/min/m . before volume expansion, the end-expiratory pause had induced an increase in cardiac index by ± % and in pulse pressure by ± % as compared to the baseline values. by contrast in the non-responders, before volume expansion the cardiac index and the pulse pressure did not change during the pause as compared to baseline ( ± % and ± % increases, respectively). importantly, an increase in cardiac index ≥ % during the end-expiratory pause predicted fluid responsiveness with a sensitivity of % and a specificity of %. a pause-induced increase in pulse pressure ≥ % detected fluid responsiveness with similar sensitivity and specificity ( % and %). in responders, a second end-expiratory pause was performed again immediately after volume expansion. in patients, the increases in cardiac index induced by this second pause induced had dropped below %. in the remaining responders, the second pause induced an increase in cardiac index still higher than % ( ± %). in these patients, the pause-induced increase in cardiac index was abolished by a second ml saline administration. conclusion. an increase in cardiac index and in pulse pressure during an end-expiratory pause enables to detect fluid responsiveness in critically ill patients with mechanical ventilation and acute circulatory failure. , and tissue doppler imaging measurements of the mitral annulus velocities like early (ea) peak diastolic velocity. the aim of the study was to examine which echocardiographic index is the best marker of preload by making the hypothesis that a good measure of preload should increase with fluid-induced increase in stroke volume (sv) but not with dobutamine-induced increase in sv. comparison of the capacity of the intra thoracic blood volume index (itbvi) and the central venous pressure (cvp) to predict fluid responsiveness in critically ill patients with acute circulatory failure (systolic blood pressure < mmhg or vasopressor requirement). methods. this prospective interventional study performed in a surgical intensive care unit of a tertiary university hospital included ( males) mechanically ventilated and sedated patients with acute cardiovascular failure requiring cardiac output measurement (transpulmonary thermodilution technique)and a fluid challenge. intervention: fluid responsiveness was defined as an increase in stroke index (si = cardiac output/heart rate/body surface area) ≥ %. receiver operating characteristic (roc) curves were generated for itbvi and cvp. in eligible patients, could not be included because of cardiac arrhythmia (n = ) or moribund status (n = ) or protocol violation (n = ). the cause of acute circulatory failure was septic shock in ( %) patients, haemorrhagic shock in ( %) patients, and systemic inflammatory response syndrome in ( %) patients. fluid challenge induced an si increase ≥ % in ( %) patients (responders(r). no statistical difference was shown between responders and non responders for cvp and itbvi. the areas under the roc curves of itbvi and cvp were . [ % ci: . - . ], and . [ % ci: . - . ], respectively, without any statistical difference (p = . ). the best cut of value for cvp and itbvi were mmhg (sensitivity = %; specificity = %) and ml.m- (sensitivity = %; specificity = %), respectively. the relative changes in si and ci were correlated with relative changes in itbvi (r = . , p = . ; r = . , p = . respectively) but no correlation was found between relative changes in si and ci and relative changes in cvp (r = - . , p = . ; r = . ; p = . ). conclusion. itbvi is similar to cvp to predict fluid responsiveness in critically ill patients with acute circulatory failure. the pulse pressure variation (ppv) is used to predict fluid responsiveness in mechanically ventilated patients. nevertheless false positive of this parameter have been reported especially in patient with right ventricular dysfunction. the peak systolic velocity of tricuspid annular motion (sta) assessed by doppler echocardiography (dec) is a parameter of right ventricular systolic function. the aim of the study was to find out whether sta can discriminate between false and true positive of vpp. methods. mechanically ventilated patients were prospectively included. all patients had a measurement of ppv> %. a dec was realised before and after infusion of ml of colloid solution. patients were separated into groups as they were responders (r) (at least % increase in stroke volume (sv)) or non-responders (nr) to fluid infusion. all data are expressed as mean [standard deviation]. the comparison of demographic, hemodynamic and echocardiographic parameters in r and nr patients was performed using a t-test. a p value < . was considered statistically significant. roc curves were plotted. a threshold value of sta was calculated with roc curve. in the resting patient, pulse pressure (pp = systolic -diastolic pressure) is mainly related to arterial stiffness and stroke volume index (svi). the dynamic effects of fluid loading on pp are poorly documented and were studied in the critically ill using arterial tonometry. we tested the hypotheses that i) arterial stiffness was unchanged after fluid loading, ii) pp changes paralleled svi changes such that pp increased in fluid-responders only, and iii) aortic pp was more indicative of svi changes than radial pp. twenty-two critically ill patients ( f), mean age(sd), ( ) years, were prospectively included. radial pressures were calibrated from brachial cuff pressures. radial applanation tonometry (sphygmocor ® ) allowed us to estimate aortic pp, left ventricular ejection time, and the augmentation index which quantifies wave reflection. the svi was calculated by transpulmonary thermodilution. the arterial stiffness was estimated from the aortic pressure curve using standard formula. fluid challenge ( ml saline . %) was required by the patient's hemodynamic status. data were obtained before and immediately after fluid loading. responders had increases in svi > %. baseline mean values were as follows: svi = ( ) ml.m- , heart rate= ( ) bpm, mean arterial pressure (map) = ( ) mmhg, radial pp = ( ) mmhg, aortic pp = ( ) mmhg. after fluid loading, svi increased from ( ) to ( ) ml.m- and map increased from to ( ) mmhg (each p < . ). arterial stiffness was unchanged ( . ( . ) vs . ( . ) mmhg.ml- . m ) as well as heart rate, left ventricular ejection time, radial and aortic pps and augmentation index. there was a positive linear relationship between the svi changes and the changes in radial pp (r = . ) and aortic pp (r = . ) (each p < . ), not map (r = . ). when responders (n= ) and non responders (n= ) were compared, the increases in map were similar while the changes in pp were higher in responders (radial: mmhg, %; aortic: mmhg; % ) than in non responders. (radial: - mmhg, - . %, aortic: - mmhg; - . %) (each p< . ). given the unchanged arterial stiffness throughout the fluid infusion, the changes in aortic pp (and slightly to a lesser extent radial pp) paralleled the changes in svi. both radial and aortic pps increased in responders but not in non responders, while map similarly increased in the two groups. the capability of arterial pp changes to track svi changes during fluid loading appears promising but deserves a further large scale study. new device may be used in intensive care unit to measure cardiac output (co) by arterial pulse pressure waveform analysis , but comparative studies with co thermodilution in cardiac surgery have shown large bias between the methods . aim of this study is to evaluate in critical ill patients not submitted to cardiac operation -cardiac output (co wave) obtained using flo track tm vigileo . -the correlation with co obtained by thermodilution (co therm). methods. critical care patients admitted to a general intensive care were enrolled in the study . all patients were mechanically ventilated ( tv - ml /kg pl press < cmh ) and connected to an integrated monitoring system ( flow trac tm / vigileo tm , ewdards lifescience ,irvine ,ca, usa ) that attaches to an arterial cannula . a central venous catheter and a pac ( thermodilution catheter ; arrow international , inc ., reading ,pa,usa ) was inserted via the jugular internal vein . after haemodynamic stabilization co wave was calculated from an arterial pressure based algorithm that utilises the relationship between pulse pressure and stroke volume , primarily based on the standard deviation of the pulse pressure waveform. at the same time a co therm. determination was performed by triple injection of ml of iced isotone na cl into the central line of the pac. every patients had two co determination at two time point. for each measurement of co therm corresponding simulataneous co wave was documenteted . a regression analysis and bland altman analysis was used to compare the two methods of co determination. a total of co determination was performed in patients . co vigileo correlated co thermodilution with r = . , p< , . at table are reported the bland altman's results. the left ventricular ejection fraction (lvef) as measured by echocardiography is considered as the reference estimate of the lv global contractility at the icu bedside. the transpulmonary thermodilution technique (picco system) continuously provides a measure of the cardiac function index (cfi), which is the ratio of cardiac output over global end-diastolic volume. thus it could be considered as a marker of cardiac global contractility and could enable a continuous monitoring of this key parameter. we tested whether cfi could actually behave as an indicator of lv systolic function by testing if it fulfilled the following criteria: (i) increase with inotropic stimulation, (ii) no alteration by fluid loading, (iii) correlation with the echographic lvef and (iv) ability to track the changes in lvef during inotropic stimulation. in patients ( cases) with an acute circulatory failure, we simultaneously measured the echographic lvef (transthoracic -chambers apical view) and the cfi at baseline, after a ml saline administration in a group of cases and after -min of dobutamine administration in a group of cases. volume expansion did not alter lvef significantly ( ± % vs. ± % at baseline) nor cfi ( . ± . vs. . ± . min- at baseline). by contrast, dobutamine infusion induced a significant increase in lvef from ± % at baseline to ± %(+ ± %) and in cfi from . ± . at baseline to . ± . min - (+ ± %). considering the whole set of cfi:lvef pairs of measurements (n= ), a significant correlation was observed between cfi and lvef (r= . , p< . ). importantly, a cfi value < . min - predicted a lvef value higher than % with a sensitivity of % and a specificity of %. in patients receiving dobutamine, there was a significant correlation between the changes in cfi and the changes in lvef induced by dobutamine infusion (r= . , p< . ). our study demonstrates that cfi fulfilled the criteria that are required from a bedside indicator of lv contractile function: it was increased by inotropic stimulation while it was not altered by volume expansion, it was fairly correlated with the echographic lvef and it was able to track the changes in echographic lvef with reliability. this suggests that the continuous monitoring of cfi provided by transpulmonary thermodilution could help in assessing the effects of inotropic therapy and could alert the physician in case of abrupt lv contractile deterioration. passive leg raising (plr) is a predictive test of preload responsiveness in patients with acute circulatory failure. it could predict fluid response to fluid loading in mechanically ventilated patients. critically ill patients have an increased risk of lower extremity deep venous thrombosis. elastic compression stocking (ecs) is frequently used in association with unfraction or low molecular weight heparin. the aim of this study was to evaluate the effect of the elastic compression stocking on the plr test variations. methods. patients undergoing cardiac surgery were included. all of them were anaesthetised and mechanically ventilated (tidal volume ≥ ml/kg). pre-operative left ventricular ejection fraction was > % for all patients. they were monitored with central venous pressure (cvp), invasive blood pressure and esophageal doppler. hemodynamics parameters were obtained before and after plr, without and with elastic compression stocking respectively (ssv = systolic stroke volume, co = cardiac output, ppv = pulse pressure variation and sbp = systolic blood pressure). results are presented as median [inter quartile range](iqr) and compared with mann whitney test. . table represents hemodynamics variations after plr without and then with elastic compression stocking. second table represents hemodynamics effects of the elastic compression stocking in supine position (sp). conclusion. this study shows a clear improvement in gut permeability after surgery. the effects of early feeding shall be assessed in a future study. methods. descriptive-prospective study. pre and post-class question -survey (administered one week before and after). the transplant co-ordination team gave informative classes in secondary schools, - / - . . surveys collected; pre/ post-class: % of eso ( years old), % bachiller ( years old) and % ciclo formativo ( years old) / post-class: % eso, % bachiller and cf % . % had some prior awareness and % broad knowledge. massmedia is usually sole information channel ( %), ticked in all cases. other sources were: family, school and peers. regarding attitude to donation: we found no differences in refusals between own donation or relatives'( %); or in doubts % - %. related to transparency and parity of the health system: % believed equality did not exist and % had doubts. % felt this inequality was worse abroad. % are convinced that organ trafficking exists and % assume it is possible. pre-course standpoint by course is showed in figure . % had prior knowledge about spanish transplant law. following classes the students claim higher awareness ( %). in general they maintain their standpoint on donation, % have reconsidered their previous attitude. regarding transparency and equality, % maintain doubts and % are convinced of its absence. on trafficking: % assume it is possible, % occurs exclusively abroad, uniform group distribution. post-course attitudes by course are in figure . despite an in-depth discussion about the law and its consequences (presumed consent), they generally disagree and some consider this too extreme , refusing to accept that donation is an obligation (only % agree) and believing that it should be an optional act of solidarity ( %). conclusion. knowledge about donation and transplant in urban areas is slanted, due to information sources ( usually mass media ) and a warped (tv-dominated) perception of the health system's transparency and equality. a considerable number of students still refuse donation or maintain their scepticism, despite a decrease following classes. however, our desire is not to convince them to become donors, we simply wish to provide decision-making tools. generally college students ,without gender differences, are the most resistant to the process, having the greatest incidence of refusals and doubts about transparency, equality and organ trafficking. ( - ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c (pao /fio ) / peep day . ( . - . ) . ( . - . ) . c conclusion. the pao /fio ratio on day one is useful to predict mortality, but not in the subsequent days. the (pao /fio )/peep index is a better predictor in later days, specially on the third and seventh day of mv. a. roch* , l. fouché , j. forel , d. blayac , c. aglioni , d. lambert , j. carpentier , l. papazian réanimation médicale, dar, hôpitaux sud, réanimation, hôpital laveran, marseille, france introduction. general anesthesia promotes atelectasis of the dependent parts of the lung. we evaluated the differential effects of neuromuscular blocking agents (nmba) on consolidation formation in healthy or injured lungs. methods. pigs ( ± kg) were anaesthetized with pentobarbital, fentanyl and ketamine in order to prevent spontaneous ventilation and ventilated using volume controlled ventilation (vt ml/kg, fio . ) for hours after randomization into groups: healthy lungs ventilated without (hzeepno) or with nmba (cisatracurium, hzeepnmba), healthy lungs ventilated with nmba and peep (hpeepnmba) and injured lungs ventilated without (tweenpeepno) or with nmba (tweenpeepnmba). lung injury was induced using instillation of . ml/kg of . % tween . injured lungs were ventilated with peep , fio . and vt ml/kg. after lung removal, six sections of equal thickness were obtained from the right lower lobe and from the upper. sections were photographed and analyzed using a software (sigmascan pro , spss inc). the areas of consolidated, edematous and normal parenchyma were measured on each section and then added to obtain the percentage of consolidated lung. . nmba use induced a two-fold increase of the consolidation (from ± to ± %)that was totally prevented by peep . the deleterious effect of nmba on derecruitment did not occur in injured lungs. consolidation was located to the dependent parts in healthy lungs and nmba extended consolidation towards more cephalad parts. in injured lungs, consolidated parenchyma was diffuse and its cephalo-caudal distribution was not affected by nmba. pao to fio ratio was affected neither by nmba nor by peep. * p< . vs hzeepno and hpeepnmba; **p< . vs hzeepno and hzeepnmba. conclusion. nmba increase dependent lung consolidation during volume-controlled ventilation of healthy lungs. this effect is prevented by a moderate peep level. in contrast, nmba do not increase the extent of pathologic lung areas in injured lungs ventilated during a -h period. th esicm annual congress -berlin, germany - - october s m. amigoni* , m. scanziani , g. bellani , g. balconi , e. zanotto , s. masson , n. patroniti , r. latini , a. pesenti dept of experimental medicine, milano-bicocca university, monza, cardiovascular research, istituto di ricerche farmacologiche mario negri, milano, italy introduction. surfactant dysfunction seems to play a pivotal role in the deterioration of gas exchange and lung mechanics that occurs in ali/ards following aspiration pneumonitis. we investigated the effects of exogenous surfactant administration in a murine model of unilateral acid-induced lung injury. we instilled . ml/kg bw of . m hydrochloric acid in the right bronchus of anesthetized and mechanically ventilated mice (vt - ml kg- bw, rr min- , fio and peep of . cmh o). mechanical ventilation was stopped minutes after injury; animals were then placed in an oxygenated chamber (fio . ). after ', hr or hrs from acid instillation, the mice were reintubated and received a single bolus of surfactant in the injured lung at a low or high dose. each animal was again mechanically ventilated for minutes, placed in oxygenated chamber until full awakening. acid-injured mice instilled at the same time and with the same volume ( ml/kg bw) of sterile saline ( . % nacl) were used as controls. lung mechanics, blood gas analysis, and lung myeloperoxidase activity (mpo) were assessed hrs after acid aspiration. no effect of surfactant administration was present upon oxygenation hrs after the injury. at the opposite the high dose group showed a significantly better compliance at hrs, when compared to both the low dose and control groups. this effect was present only in the late ( hrs) administration group. mpo activity did not change after surfactant treatment in the right (injured) lung while in the controlateral, it tended to be lower in both low and high dose when treatment administration occurred at hrs (n= /group: n right lung ± left lung . ± . ; s(low dose) right lung . ± . left lung . ± . ; s(high dose) right lung . ± . left lung . ± . ). pulmonary aspiration is associated with significant morbidity and mortality . several risk factors for aspiration have been highlighted in the literature . the aims of this study were to: (i) identify specifically which patient factors predispose to aspiration and (ii) determine the outcome of patients admitted to our inner city hospital intensive care unit (icu) with a diagnosis of aspiration. we identified patients with a diagnosis of pulmonary aspiration on our icu over a year period (august - ), by using our institution's icnarc (intensive care national audit and research centre) database. of these patients' case notes were able to be retrieved and reviewed in detail. patient demographics, risk factors for aspiration, number of ventilated days, icu & hospital length of stay and mortality were analysed. we also looked at any documented signs that supported the diagnosis of aspiration. median age of the patients was years (range - ). / patients ( %) were male. the main risk factor was a reduced glasgow coma score ( / patients, %): the median score was (range - ). the following risk factors were also identified: obesity ( / patients, %), excessive alcohol intake ( / , %), acute cerebrovascular event ( / , %) and cardiorespiratory arrest ( / , %). the following signs were most frequently observed: perioral vomitus ( / patients, %), acute hypoxaemia ( / , %) and a new radiographic infiltrate ( / , %). one patient exhibited all three markers. all patients required mechanical ventilation. the median duration of ventilation was days (range - ). the median length of icu stay was days ( - ) and the median length of hospital stay was days ( - ). icu mortality was % ( / patients) while hospital mortality was % ( / ). patients who presented to our inner city icu with aspiration had risk factors that included impaired conscious level, obesity, a recent cerebrovascular event or cardiorespiratory arrest. signs that supported the diagnosis of aspiration were the presence of perioral vomitus, acute hypoxaemia and a new radiographic infiltrate. icu and hospital length of stay were both prolonged, but icu and hospital mortality were no higher than our institution's overall rate. a high index of suspicion should be applied to these patients at risk of aspiration, to facilitate the early initiation of appropriate care. reference(s). . hickling k. a retrospective survey of treatment and mortality in aspiration pneumonia. int care med ; : - . . kozlow j. epidemiology and impact of aspiration pneumonia in patients undergoing surgery in maryland, - . crit care med : - . t. tagami* , s. kushimoto , t. atsumi , r. oyama , k. matsuda , m. kawai , h. yokota , y. yamamoto surgery, tokyo metropolitan saiseikai central hospital, critical care medicine, nippon medical school, tokyo, critical care medicine, yamanashi prefectural central hospital, yamanashi, japan introduction. restoration of intravascular volume by massive fluid administration without pulmonary edema formation is one of the biggest challenges in the early treatment of burn shock. although it is not easy to predict the development of the respiratory failure before the treatment, the hallmark of the edema is increased capillary permeability which may be possible to measure by the pulmonary vascular permeability index (pvpi). the aim of the present study was to clarify whether the pvpi is predictable indicator of pulmonary edema formation in patients with burn. we studied mechanically ventilated patients with burn involving more than % of the body surface area that were treated at intensive care burn unit between july and january . all patients had a central venous catheter and a thermistor-tipped arterial thermodilution catheter (picco system) for hemodynamic management. we measured the extravascular lung water index (evlwi) and the pulmonary vascular permeability index(pvpi) as soon as the picco catheter was inserted. infusion volume was calculated according to the parkland formula. only crystalloid fluid (lactated ringer's) was infused during the first hours after the thermal injury. we investigated the medical records and defined the respiratory failure during the period of burn shock as a clinical syndrome of acute respiratory distress associate with pulmonary rales and radiographic evidence. inclusion criteria were: )acute onset and rapid progress, )oxygenation index (pao /fio ratio< and ) bilateral infiltrates on chest x-ray. those are the part of the standard criteria of acute respiratory distressed syndrome. the pvpi was significantly higher in the patient with respiratory failure (n= pvpi: . ± . ) than in patient without respiratory failure(n= pvpi: . ± . ) before the fluid treatment. there was no significant difference between the groups in terms of evlwi at the beginning ( ml/kg vs . ml/kg). although the evlwi increased after hours in the patient with respiratory failure, it did not change in patient without respiratory failure( . ml/kg vs . ml/kg). the pvpi increased before the evlwi increased in patient with respiratory failure. the pvpi is considered to be the predictable value to identify the risk of respiratory failure during the period of burn shock. ultrasonography allows observation of diaphragm. in healthy subjects, a correlation was found between its excursion and the tidal volume. in addition, diaphragm thickness variation measured in the zone of apposition has been used to evaluate paralyzed diaphragm. we assessed the accuracy of these indexes to assess diaphragmatic function and respiratory workload. five patients were studied in spontaneous ventilation (sv) and during noninvasive ventilation at different levels of pressure support (ps). diaphragmatic excursion (e) was carried out subcostally. diaphragm thickness was measured in the zone of apposition and the thickening fraction (tf) was calculated as tf = (thickness at inspiration -thickness at expiration)/thickness at expiration. diaphragmatic pressure time product per breath (ptpdi) was measured by assessment of esophageal and gastric pressure. ptpdi and tf both decreased as the level of pressure support increased (fig and ) . a positive correlation was found between ptpdi and tf(r= . ; p= . ; fig ) . in addition, there was also a significant correlation between tidal volume and e (r= . ; p< . ; fig ) . ultrasonography of the diaphragm could be applied in intensive care to assess diaphragmatic function. tf and ptpdi decrease as the level of pressure support increases. these results suggest that tf could help to assess diaphragmatic contribution to respiratory workload. reference(s). ( ) fantus g. metformin's contraindications: needed for now frequency of inappropriate metformin prescriptions systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing arteficial ventilation catheter infection is a common concern in the intensive care unit (icu). recent works have pointed that the site of catheters is related to this problem. we analysed data obtained from our data base to confirm the results of previous works. methods. catheters were inserted in a surgical-medical icu, along five years. semiquantitative cultures were obtained if the catheter was kept in place more than hours and it was no longer necessary, the catheter was withdrawn because of fever of unknown origin or an infection was suspected at the point of insertion. every catheter site, culture and germ was registered in our patient data base. we studied the following variables: type of catheter, site and results of cultures. statistical analysis: variables were compared by chi-square. a p< , was considered statiscally significant. results. a total of . catheters were registered (venous catheters , arterial ). rate of germs was as follow: gram-positive , %, gram-negative , %, fungi %, contaminated flora , %. site and germs were not statistically associated. table shows type, site and rate of infection of cultured catheters. femoral arteries were more frequently cultured than radial arteries (p< , ); no differences were found for cultured venous catheters. femoral arteries were infected more frequently than radial (p< o, ); yugular and femoral venous catheters were more frequently associated to infection. (sc) in non neutropenic patients is increasing with a high cost and mortality. we define the clinical and epidemiological profile of patients admitted to our icu and the microbiological aspects of the pathogen. mortality analysis was done, including sevilla score system (sss). we include patients admitted in icu from to with candidas ssp (cd) positive blood cultures (bacter system). we analysed demographic factors, reason for admission to the unit, associated risk factors, need of multi-instrumentation or parenteral nutrition, value of apache ii, and length of stay in the icu. the kind of cd diagnosed, its sensitivity profile, and the existence or not of previous wide spectrum antibiotic or antifungic therapy were determined. the sevilla score system was applied and correlated with mortality. chi square, t-test and multivariant analysis were made. there were . % male patients, with years old median age and with a length of stay longer than days. the reason for admission was sepsis ( %), surgery ( . %), acute respiratory failure ( . %) and trauma patiens ( %). apache ii median was . points.risk factors related with fungal infections were diabetes ( . %), neoplasia ( %), steroid therapy ( , %), a length of stay longer than days ( %) and antibioticoterapy. none had neutropenia. % of patiens received antibioticoterapy previous to diagnosis, . % parenteral nutrition and % of them underwent multi-instrumentation. patient isolation was achieved in % of them ( % in period - ). candida albicans was isolated in . % of cases against . % of candida nonalbicans, specially c. parapsilosis , %. first antifungal therapy was fluconazole ( %), caspofungin ( . %) and lipid amphotericins ( . %). we found a significant increase of sc cases along the years, ( % in - vs . % in - , p< . ), being unresponsive to azoles . %. mortality was specially high ( . %), unrelated with cd type; those with high/moderate sss risk had a significative higher mortality (p< . ). candida albicans was more frequently found in septic patients while candida nonalbicans was gaining place in patients under parenteral nutrition (c.parapsilosis).conclusion. ) systemic candidiasis affects men admitted with sepsis or surgery, with a high apache ii index, multiple organ failure, multi-instrumentation and more than two weeks intensive care unit stay. ) we observe a progressive incidence of non albicans candidiasis (c. parapsilosis). ) type of candida ssp did not affect mortality. ) c. albicans was more frequently isolated in septic patients, while candida nonalbicans was predominant in cases with parenteral nutrition. ) mortality was greater in moderate/higher sss risk group. f. alvarez-lerma* , m. palomar , p. objetive: to present changes of multiresistance markers in icu-acquired infections. a prospective, cohort, multicenter study. all patients admittted to the participating spanish icus between the years and were included. patients were followed until discharge from the icu or up to a maximum of days. the following infections were studied: mechanical ventilation-related pneumonia (mv-p), catheter-related urinary tract infection (cr-uti), and primary bacteremia (pb). markers of multiresistance were those defined by the cdc ( ) of a total of , pacientes included in the study, , ( . %) developed , infections ( . %) during their stay inthe icu, in which a total of , pathogens were identified.multiresistance markers are shown in table . pulse pressure variation greater than % predicts fluid responsiveness in patients ventilated with large tidal volumes. the aim of this study is to evaluate the influence of a low tidal volume on the capacity of pulse pressure variation (deltapp) to predict fluid responsiveness.methods. this is a prospective interventional study that took place in a -bed university hospital medico-surgical icu. the study included eighteen mechanically ventilated critically ill patients with a low tidal volume ( - ml/kg) requiring fluid challenge. fluid challenge was performed with , ml crystalloids or ml colloids. complete hemodynamic measurements including deltapp were obtained before and after fluid challenge. overall, the cardiac index increased from . ± . to . ± . l/min/m (p < . ). it increased by more than % in patients (responders). pulmonary artery occluded pressure was similar ( . ± . vs. . ± . mmhg, p= . ) but deltapp higher in responders than in non-responders ( ± % vs. ± %, p= . ). fluid responsiveness was equally predicted by deltapp (roc curve area . ± . ), pulmonary artery occluded pressure ( . ± . ) and right atrial pressure ( . ± . ) (p=ns). the best cutoff value for deltapp was % with a sensitivity of % and a specificity of %. the preliminary results suggest that deltapp is not a better predictor of fluid responsiveness then paop or rap in mechanically ventilated patients when tidal volume is - ml/kg. if used, a lower critical value may help to predict fluid responsiveness. svv and ppv are proven influenced by the different airway pressures due to depth of tidal volume and peep. the effect of respiratory rate or respiration frequency on svv and ppv is however unclear. aim of this study was to evaluate the effect of respiration frequency on svv and ppv in mechanically ventilated patients. after obtaining informed consent, (coronary bypass grafting) patients were studied immediately after surgery. cardiac output (co), svv and ppv were assessed by arterial pulse contour analysis (lidco, lidco ltd). all patients were ventilated in pressure controlled mode (settings: fio . , tidal volume ml/kg, peep cmh o, frequency min- ) and sedated with propofol. in this study svv and ppv were evaluated with fixed ventilator frequencies of , and min- . this protocol was repeated to times (before and after volume loading of ml) in each patient. during the study the mean airway pressure was maintained constant by adjusting inspiration time. collected data points are described in means (sd) and evaluated using anova. in six patients (female/male ratio / ) after coronary bypass grafting, mean age (± . ) years [range - years], data points by fixed respiratory frequencies could be analysed ( / , / and / ). all measurements were performed in hemodynamically stable conditions, hr mean (± . ) min- , map . (± . )mmhg, cvp . (± . )mmhg and co . (± . ) l/min (p for all ns). mean airway pressure . (± . )mbar (levene statistics, p = . ), for resp-f . (± , )mbar, resp-f , (± , )mbar and resp-f . (± . )mbar. on fixed respiratory rates svv and ppv were unchanged: for svv (resp-f ) . (± . )%, (resp-f ) . (± . )%, (resp-f ) . (± . )%, p = . , for ppv (resp-f ) . ( . )%, (resp-f ) . (± . )%, (resp-f ) . (± . )%, p = . . in ventilated cardiothoracic surgical patients, svv and ppv were not influenced by forced changes in respiratory frequencies between and min- . (svv) has been studied as a dynamic preload marker to predict fluid responsiveness in critically ill patients. patients undergoing major abdominal surgical procedures with the aid of pneumoperitoneum may have a difficult preload management, due to either a preoperative hypovolemic status or an excessive intraoperative fluid loading to maintain an adequate volume and tissue perfusion. the aim of this study was to use the svv to optimize the fluid management in patients undergoing major abdominal robot-assisted laparoscopic surgery. methods. patients (asa score - ; mean age . +/- . ) were prospectively enrolled. cardiac index (ci), stroke volume variation (svv), and central venous saturation (scvo ) were calculated with the vigileo system. gastric carbon dioxide pressure (pgco ) was measured with a gastric tonometer. before the induction of anesthesia, ml/kg normal saline solution was administered. later, colloids were infused whenever a svv > % resulted. hemodynamic variables and pgco were measured before, during, and after the end of surgery. the total amount of intraoperatively administered fluids (iaf) was calculated. subsequently, the iaf was compared with theoretical iaf using the formula proposed by miller. analysis of variance and student's t-test were applied. mean surgery time was . +/- . hours. ci ranged from . to . liters/min/m . scvo ranged from % to %. the pgco ranged from . to . mmhg. anova did not show significant variations of ci, scvo and pgco . mean baseline and postoperative svv% were +/- . and . +/- . , respectively. with respect to preoperative values, anova showed a significant reduction for svv%. moreover, at the end of surgery the svv% resulted less than % for each patient. the total amount of fluid was . +/- vs . +/- . ml/kg per hour (calculated vs theoretical, respectively. p< . ). no patient showed signs of hypoperfusion. no complication or death occurred.onclusion. the vigileo system seems to be a reliable tool to provide indications for fluid administration and volume responsiveness. it could be useful especially in major surgical procedures at risk of fluid overfilling. svv continuously monitored may help physicians to avoid fluid overloading in patients undergoing major abdominal robot-assisted laparoscopic surgery. recently, the preload parameters global enddiastolic volume gedv and intrathoracic blood volume itbv measured with transpulmonary thermodilution were convincingly shown to be superior to the historically used central venous pressure . the extravascular lung water evlw was shown to be a prognostic marker in critically ill patients . however, in our clinical experience, we failed to achieve the proposed normal ranges for gedv/itbv indexed to body surface area in a substantial number of patients. as hypothesis, we investigated the dependence of transpulmonary thermodilution parameters on the patient's age. we retrospectively analyzed the transpulmonary thermodilution data in a series of patients treated on our neurosurgical intensive care unit. diagnosis was predominantly severe subarachnoid hemorrhage, but included traumatic brain injury and polytrauma, too. itbvi and gedvi were measured with the picco ® system (pulsion medical systems ag, munich, germany). measurements were performed with cc iced saline injected repeatedly in a central venous line. all data was stored online and pooled for analysis. mean patient age was . (sd . ) years. pooled thermodilution measurement sequences consisting of single injections were analyzed. mean gedvi was (sd ) ml/m , mean itbvi was (sd ) ml/m and mean evlwi was . (sd . ) ml/kg. younger patients had lower mean values calculated by linear regression, with an increase of . ml/m for gedvi and . ml/m for itbvi per patient year. evlwi was independent of age.conclusion. the thermodilution data from our patient collective contrasts the use of fixed age-independent normal values for gedvi and itbvi but not for evlwi. this data set, however, comprises a neurosurgical patient collective and may not be validly extrapolated to other clinical surroundings. . michard f., et al.: chest ; : - . sakka, s., et al.: chest : - thirty mechanically ventilated patients with severe sepsis or septic shock (age ± ; apache-ii score ± ; male) requiring invasive hemodynamic monitoring due to cardiovascular instability were included in a prospective observational trial. the study was performed in a university hospital setting with a -bed medical intensive care unit (icu) and a -bed anaesthesiological icu. volume-based hemodynamic parameters were assessed using the single-pass thermal-dye transpulmonary dilution technique. simultaneously, ivc diameter was measured throughout the respiratory cycle by transabdominal ultrasonography. we found a statistically significant correlation of both inspiratory and expiratory ivc diameter with central venous pressure (p= . and p= . ), extravascular lung water index (p= . , p< . ), intrathoracic blood volume index (p= . , p= . ), the intrathoracic thermal volume (both p< . ), and the pao /fio oxygenation index (p= . and p= . , respectively).conclusion. sonographic determination of ivc diameter is useful in the assessment of volume status in mechanically ventilated septic patients. this approach is rapidly available, non-invasive, inexpensive, easy to learn and applicable in almost any clinical situation without doing harm. ivc sonography may contribute to a faster, more goal directed optimisation of fluid status and may help to identify patients in whom deleterious volume expansion should be avoided. it remains to be elucidated whether this approach influences the outcome of septic patients. a severe burn injury is associated with hypermetabolism and catabolism that has been shown to persist for over months post injury. propranolol has been shown to reduce hypermetabolism during the acute hospital course. the effect of propranolol, a nonselective beta blocker, on respiratory variables in children with severe burns has not been established. beta-blockade is associated with a known risk of bronchoconstriction in children with hyper-reactive airway disease, but it is not known whether the effects are also seen in severely burned children. the purpose of this study was to determine the effect of propranolol, given during acute hospitalization, on respiratory variables. forty-six patients with burns > % total body surface area (tbsa) were enrolled into the study and randomized to receive propranolol at . mg/kg/day (n= ) or placebo (n= ). administration of propranolol was started the day following the first operation and continued for three weeks. respiratory variables were measured by a flow transducer attached to a bicore cp respiratory monitor. all patients were breathing spontaneously and non-intubated. study variables included respiratory rate (rr), minute ventilation (mv), tidal volumes (vt), and peak inspiratory/expiratory flow rates (pifr/pefr). baseline measurements were taken at rest before the drug or placebo was initiated. follow-up measurements were performed at the end of the study period. data were analyzed using paired t-test within groups and un-paired t-test between groups. data are reported as mean ± sd. significance was accepted at p< . . the mean age in both groups was ± years. as expected, heart rate was reduced by approximately % in the propranolol group compared to placebo (p< . ). there was a significant increase in pefr from . ± . to . ± . l/s in the propranolol treated group (p= . ). in contrast, neither placebo nor propranolol significantly affected rr, vt, ve or pifr. results indicate that short term administration of propranolol showed significant effects on pefr suggesting increased pulmonary conductance. further studies on the effects of propranolol on gas exchange and lung compliance are needed. grant acknowledgement. funded by nih grants p -gm and ko -hl a. storesund* , e. wallestad , l. rygh postoperative section, surgical department, surgical department, haukeland university hospital, bergen, norway international studies point out that to work with agitated children, described as restless and disorientated are particularly stressful for the child, parents and caregiver. this project is based on the assumption by nurses in the post anaesthetic unit (pau) that there was a noticeable post anaesthetic agitation difference between the children who received long-term opioids initially and in the end of the operation (refill, a) compared to those who only got long-term opioids in the beginning of the operation (no refill, b). the main purpose of this project was to examine whether there were any difference in postsurgical agitation between the refill and no refill group. further, this project seeks to uncover if there are any factors that can be improved per-and postoperative for these patients. we observed post anaesthetic children, lip-(n= ), cleft-(n= ), and palateclosure (n= ), adeno-(n= ), & adeno-tonsillectomy (n= ). these children were recruited using a convenience sampling strategy at the pau at haukeland university hospital, norway, over a week period in - . a pilot-tested fixed cross sectional designed questionnaire was utilised by the nurse responsible for each patient. several statistical tests by the use of spss made it possible to analyse and answer the research question: are children who only get long-term opioids in the initial anaesthetic phase (b) of the operation more agitated than those who where also given a refill of long-term opioids (a)? we found that / got refills of long-term opioids (a), / did not get refills (b), % were recorded as missing values. t-test result = , is greater than , , hence there is no statistically significant difference between the two groups. levene's test tells us that the two variances are not significantly different (levene's test sig= , ). there were no significant relationships between the parameters recorded. however, there was a tendency that more preoperative anxious children got refills ( / ) compared to non-anxious children ( / ) (fisher's exact test p= , ). the latter results may conceal the agitation-scores in the two groups; refill and non-refill-group. this possible bias may have been eliminated if the patients had been randomized to either refill or non-refill. the present study confirms previous observations by others indicating no singular factors can explain why some children experience agitations and others do not. analysis of the parameters studied did not discover any statistical significant relationships. thus, how to minimise the cohort of children who experience post anaesthetic agitation still remains a recurrent challenge. pulmonary hypoplasia with severe cardiorespiratory dysfunction is often the leading cause of death in neonates with congenital renal disease and oligo-anhydramnios. aim of the study was to determine whether ino is effective to improve respiratory function in these critically ill neonates. we retrospectively reviewed the charts of all newborns who were admitted between february and september with the diagnosis of oligo-anhydramnios of renal origin. during this period all patients were treated according to a standardised algorithm. they were intubated either if post cpr or if fio had to be increased above . . mg/kg of bovine surfactant were applied for improvement of ventilation. pre-and postductal oxygen saturation were measured simultaneously with target values of - %. if fio remained above . a transthoracic echocardiography was performed. the presence of a ductal or atrial right to left shunt or a difference in oxygen saturation between the pre-and postductal measurements of > % led to the diagnosis of pulmonary hypertension and to the initiation of ino therapy. further, ino was applied as a rescue therapy if oxygen saturation remained below % despite a fio of . and optimization of ventilator settings and therapy with catecholamines. all patients had informed parental consent. the patient population (n= ) included children receiving ino of whom suffered from obstructive uropathy and two had polycystic kidneys, whereas patients did not receive ino treatment. in this group there were children with obstructive uropathy and born with polycystic kidneys. all data are presented as median (range). we concentrated on the group receiving ino. in this group mortality was . %. therapy was started at an age of . ( - ) hrs. initial dose of ino was . ( - ) ppm with peak dose of . ( - ) ppm. ino led to a decrease of oxygenation index (oi) from . ( . - . ) to . ( . - . ). five children suffered from obstructive uropathy. three of them had a favourable long-term outcome, one child died immediately, whereas one child was initially stabilized but finally succumbed to its underlying disease. two children demonstrated genetically determined pulmonary hypoplasia due to the presence of polycystic kidneys. both children died within the first three days despite ino treatment. children with obstructive uropathy and severely impaired oxygenation seem to benefit from ino therapy. patients suffering from a hereditary renal and pulmonary hypoplasia did not respond favourably to ino therapy and had a fatal outcome. a. khaldi*, k. menif, a. bouziri, a. hamdi, s. belhadj, n. ben jaballah pediatric intensive crae unit, children's hospital, tunis, tunisia the use of high-frequency oscillatory ventilation (hfov) and ino resulted in a decline in the need for extracorporeal membrane oxygenation (ecmo) in near-term and term neonates with persistent pulmonary hypertension (pphn). association of hfov and ino is actually an accepted treatment modality even in non-ecmo centers. however, because not all neonates respond to hfov + ino, identification of factors related to a poor response is very important for prognosis and for early transfer to ecmo canters if possible. the objective of this study was to identify the risk factors predicting poor shortly outcome in near-term and term neonates with pphn treated with hfov and ino in a tertiary care pediatric intensive care unit in a university hospital. we conducted a prospective clinical study including all neonates with gestational age ≥ weeks with echocardiographic signs of pphn. patients with pulmonary hypoplasia or congenital diaphragmatic hernia were excluded . patients were ventilated with conventional mechanical ventilation (cmv) with ino ( - ppm). hfov were instituted if patient required, on conventional ventilation (cmv)+ino, a fraction of inspired oxygen (fio ) . , and a mean airway pressure > cm h o to maintain adequate oxygenation or a peak inspiratory pressure > cm h o to maintain tidal volume between and ml/kg of body weight. hfov were used in association with ino in seventy infants (gestational age, ± , weeks), after a mean duration of cmv of ± hours. arterial blood gases, oxygenation index (oi), and alveolararterial difference in partial pressure of oxygen (p[a -a]o ) were recorded prospectively before and during hfov. there were a rapid and sustained decreases in mean airway pressure (map), oi, and p[a -a]o during hfov (p ≤ . ). this improvement, along with decreased need for oxygen, was sustained through the subsequent course of hfov. sixty-six infants ( %) were weaned successfully from hfov. five infants ( %) were classified as meeting treatment failure and died from their underlying disease. treatment failure was associated with lack of improvement in p[a -a]o and oi at hour of hfov (p < . ) and the presence of intractable shock requiring epinephrine or norepinephrine (p= , ). in near-term and term neonates with pphn, the association of hfov and ino lead to a rapid and sustained improvement in gas exchange in the most cases. the magnitude of improvement of oi and p[a -a]o at hrs can predict outcome early. early burn sepsis is notable for the complexity of diagnostics, malignant course and high lethality. the problem remains actual for the children who got a severe burn trauma (more than % body surface area). purpose to define procalcitonin test (pct) effectiveness for early sepsis diagnostics for children with thermal trauma. during the period of time from january up to april there were children in our clinic with extensive burns from %up to % body surface area (bsa) at the age from months to years old. patients at the age from months to years old with the burns from % to % bsa were included in our research. all the children got surgery in shortest time after trauma (tangential excision with authodermoplastics), antibacterial, and infusion therapy. from the moment of registration in icu all the patients, who were suspected to have sepsis, simultaneously with traditional examinations (blood analysis, bacteriological investigation) were taken pct analysis with the help of "pct-express test" (brahms, germany). . patients ( , %) were diagnosed sepsis, children died. these patients pct level was from to ng/ml; together with this all the patients had increasing quantity of leucocytes, acceleration the level of c-reactive protein, fever. ( %) patients had no sepsis, so pct figures fluctuated in the bounds of , ng/ml. among these patients traditional markers of inflammation were increased. no trustworthy difference is found as for the level of leucocytes and c-reactive protein figures between the patients without infectious complications and with sepsis. only with the help of pct the beginning of sepsis and sirs manifestation can be differentiated.conclusion. . burn trauma itself is not the reason for pct increase. pct level increases in cases of burn injuries as the sign of infectious complications joining. . with the help of traditional sepsis markers it is difficult to differentiate sirs manifestation and first stages of infectional complications in case of thermal trauma. . in cases of severe burns pct test is a highly sensitive method of sepsis early stages diagnostics. . surgery treatment at early stages after trauma allows to avoid development of severe sepsis. h. knoester* , m. b. bronner , a. p. bos , m. a. grootenhuis pediatric intensive care unit, psychosocial department, emma children's hospital, amc, amsterdam, netherlands introduction. improved survival in children with critical illnesses has led to new disease patterns due to long-term complications and effects of the original illness and its treatment. as a consequence, health related quality of life (hrqol) has become an important outcome measure in pediatric intensive care unit (picu) survivors. little is known about hrqol in picu survivors,. hrqol evaluation could contribute to improvement of support after discharge. the purpose of this study was to assess hrqol in picu survivors. october all parents of children, acutely admitted to our picu were invited to complete hrqol questionnaires, and months after discharge. hrqol in children from - years of age was evaluated with a dutch validated questionnaire, the tno-azl preschool children quality of life questionnaire (tapqol). the tapqol covers domains of hrqol; norm data from the general dutch population are available. data analyses was done by non-parametric testing (patients versus norm group) and by calculating effect sizes (difference in mean scores between the patients and the norm group divided by the standard deviation of the scores in the norm group). effect sizes give an indication of changes in hrqol in comparison with the norm group. . of ( . %) eligible patients were evaluated. statistically significant differences with the norm group were found on domains, and months after discharge (more lung problems and worse liveliness) and on domain months after discharge (better appetite). moderate ( . ) and large ( . ) effect sizes were found on five respectively four domains and months after discharge: indicating worse hrqol on lung problems, sleeping problems, motor functioning, anxiety, positve mood and liveliness; and indicating better hrqol on problem behaviour. no statistically significant changes over time were found for all domains and months after discharge. our results indicate that hrqol in young picu survivors is decreased in some domains of physical and emotional functioning. these problems do not diminish over time. positive evaluation by parents regarding appetite and problem behavior could be influenced by response shift (changing of internal standards and values due to confrontation with a life-threatening disease). more research is necessary because of the small study group and to determine the influence of risk factors such as length of stay, age of the child at admission, severity of illness and physical sequelae of the disease and its treatment on hrqol. hrqol evaluation can be a useful tool as part of screening after picu survival to determine the necessity for follow-up care. coarctation of the aorta is not an uncommon congenital heart defect. one of the possible postoperative complications is the so-called postcoarctectomy syndrome (mesenteric arteritis). the purpose of the present study is to assess the changes in gut flow through the dual sugar permeability test. five patients have been included in the study until now. median age month ( . - ) and median weight . kg ( - ). premedication and anaesthesia was the same for all the patients. the test solution contains -o-methyl-d-glucose, d-xylose, l-rhamnose and lactulose. patients received ml/kg of the test solution after induction of anaesthesia, at and hours after the initial dose. urine production is measured during a three-hour period after each instillation. the sugar content is analysed by capillary gas chromatography (normal values l/r = . , omdg and xylose - %). a. monsel , p. durand , v. haas , c. beaujard , p. rouleau , s. el aouadi , d. benhamou , k. asehnoune* anesthesie reanimation, reanimation pediatrique, anesthesie réanimation, hopital de bicetre, bicetre, anesthesie réanimation, chu hotel-dieu, nantes, france pediatric epidural anesthesia (ea) is considered to be without hemodynamic impairment in children. however, when compared with information relating to adults, little is known about the hemodynamic effects of epidural anesthesia on the cardiac output (co) in infants. using transesophageal doppler (ted) monitoring of co, we prospectively studied infants < kg who were scheduled for abdominal surgery. during sevoflurane general anesthesia, ted monitoring of co was performed before and after lumbar ea with . ml/kg of . % bupivacaine and : , adrenaline. co, arterial blood pressure, and heart rate were measured before and , , and minutes after performance of ea. in patients anesthetized with sevoflurane and sufentanil, ea resulted in an increase in stroke volume by % (p< . ) and a decrease in heart rate by % (p< . ). ea also induced a significant decrease in systolic, diastolic, mean arterial blood pressure and systemic vascular resistances by %, %, %, and % respectively. conversely, co remained unchanged. the increase in sv observed is probably explained by optimization of afterload due to the sympathetic blockade induced by ea. these results confirm that ea provides hemodynamic stability in infants weighing < kg and support the use of ea in this pediatric population. bleeding is the most frequent complication during extracorporeal life support (ecls) after pediatric cardiac surgery. we would like to present our experience with ecls and recirculation blood saving, volume auto-regulation system using the law of connected vessels based on converted cpb set in infants after cardiac surgery with significant bleeding. since to ecls in the postoperative period was performed ( , % of all cardiac operations in this period). the significant bleeding (> ml/kg/h) was noted in pts. in most recent pts the volume recirculation system was implemented, whereas in previous patients blood was sucked out the circuit. the retrospective analysis of data was carried out. there were infants with single ventricle anatomy and with two-ventricle anatomy. there were no significant differences with respect to age, weight and prevalence of single ventricle anatomy between groups. the indication for ecls was cardiac arrest in , low cardiac output in , hypoxemia in and sepsis in patients. the overall mortality rate was %. the mortality did not differ significantly between groups ( , % versus % in non-recirculation group; p= , ). there was significantly lower number of blood products transfusions(p< , ), lower number of surgical explorations(p< , ) lower mean lactate level hours after ecls institution p(< , ) and shorter ecls duration (p< , ) in the recirculation group. the system of blood recirculation in children with bleeding on ecls is simple, highly effective in stabilization of the haemodynamics and no-cost consuming. it can reduce necessity of chest exploration, blood product transfusions and duration of support. t. tunc* , t. topal , m. kul ,Ö.Öngürü , a. korkmaz , s.Öter neonataloji bilim dali, fizyoloji anabilim dali, patoloji anabilim dali, gülhane askeri tip akademisi, ankara, turkey necrotizing enterocolitis (nec) is the most common gastrointestinal emergency in the premature infant. the major risk factors in nec include prematurity, hypoxia, enteral feeding, and bacterial colonization. these factors predispose at-risk infants to an exaggerated intestinal inflammatory response leading to ischemic bowel necrosis. experimentally induced ischemia and reperfusion (i/r) of the intestine is a model which can be appropriately used to imitate nec. n-acetylcysteine (nac), erdosteine (erd) and alpha-lipoic acid (ala) are well-known antioxidants with similar structural properties. in the present study, the effectiveness of these three sulfur-based antioxidants against intestinal i/r-injury was evaluated.methods. one month old male spraque-dawley rats were randomly divided into five groups (n = for each): i/r (control), i/r+nac, i/r+erd, i/r+ala and sham-operated group without i/r. animals were operated at a temperature of o c under ketamine anesthesia. ischemia was provided by occluding the superior mesenteric artery via a microvascular clamp. collateral vessels of the small intestine were ligated to prevent collateral circulation. min of ischemia was followed by min of reperfusion. nac ( mg/kg/day, i.p.) was administered first min before operation and followed once daily for days. erd ( mg/kg/day, oral gavage) administration was begun days before operation and continued daily doses. ala ( mg/kg/day, i.p.) was injected only one time h before operation. at day after operation the ileum was resected and the rats were sacrificed. protein oxidation (carbonyl content, pco), lipid peroxidation (malondialdehyde, mda), superoxide dismutase (sod) and glutathione peroxidase (gsh-px) were measured in the ileal tissue. oxidative and antioxidant parameters of resected ileal segment (mean ± sd) groups as a clinically relevant model to nec, our experimental i/r protocol resulted with marked rise in oxidative stress levels and fall of antioxidant enzymes activities. these changes were ameliorated with the antioxidants used. among all, ala presented the strongest and nac the weakest effect. this outcome promises beneficial usage of these sulfurbased antioxidants against oxidative stress which plays an important role in nec pathogenesis. a. khaldi* , k. menif , a. bouziri , a. hamdi , s. belhadj , n. ben jaballah pediatric intensive crae unit, children's hospital, pediatric intensive crae unit, children's hospital, tunis, tunisia high-frequency oscillatory ventilation (hfov) may significantly improve oxygenation and outcome in newborns with respiratory dysfunction and beyond the neonatal period in patients with a variety of diffuse alveolar diseases. in small airway disease like respiratory syncytial virus (vrs) bronchiolitis, hfov is considered potentially hazardous because of the risk of air trapping. however, a few studies had reported utility of hfov in children with acute hypoxemic or hypercapnic respiratory failure caused by vrs and failing optimal conventional mechanical ventilation (cmv). the objective of the study is to evaluate the effectiveness and safety of hfov in pediatric patients with acute respiratory failure due to rsv and failing cmv. we conducted, over -year period (october to october ), a prospective clinical study in a tertiary care pediatric intensive care unit. fourteen ( ) patients (ages to days) with acute respiratory failure due to rsv bronchiolitis and failing optimal cmv were included. passage to hfov was indicated for severe hypoxemia in patients (median alveolar-arterial oxygen difference [p(a-a)o ]: [ - ] mmhg, median oxygenation index [io]: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ) and for severe hypercarbia in patients (median ph: , [ , - , ] , median paco : [ - ] mmhg). hfov was instituted after a median length of cmv of ( - ) hours. ventilator settings, arterial blood gases, oi and p(a-a)o was recorded before hfov (h ) and at a predetermined intervals during hfov and compared using the one-friedman rank-sum procedure and a two-tailed wilcoxon matched-pairs test. after starting hfov, a distinct decrease in fio at hrs that continued to hrs (p< , ). in all patients, there were significant decreases in oi and p(a-a)o at hrs, that were sustained up to hrs (p< , ). target ventilation was achieved in all cases and paco significantly decreases after hr of hfov (p= , ) and remained within the target range thereafter ( - mmhg). the median maximum pressure amplitude used on hfov was ( - ) cm h o and the median maximal paw was ( - ) cm h o. no significant complications associated with hfov were observed. twelve patients ( %) survived to hospital discharge without supplementary oxygen. tow patients ( %) died from septic shock. in pediatric patients with either hypoxemic or hypercapnic acute respiratory failure due to rsv bronchiolitis, hfov can be used successfully and safely if conventional ventilation fails to improve gas exchange. however, randomized controlled trials are needed to identify its benefits over conventional modes of mechanical ventilation. and are influenced by numerous factors like patient's disease severity, policies of the treating unit, religious and cultural traits, education and awareness of the patient's family, financial status of the family and legal provisions. majority of published studies on eol reflect either european or american ethos; that is either physician's paternalistic approach about the patient or patient's autonomy and self determination,( , ) about this sensitive process. studies on eol which reflect the influence and pivotal role of closely knit indian family on eol decision making are scant. we retrospectively analysed the eol decisions taken by the family in our icu as majority of the patients which merit eol care were not in a condition of decision making. setting- bedded multidisciplinary icu of a bedded tertiary care teaching hospital in pune in india. case papers of all icu admissions during one year i.e. st january to st december where eol decision was documented, were reviewed. data collected included demographics, underlying disease process, duration of aggressive treatment till eol consent, duration between eol decision and death, consenting person's relation with the patient, organ failure & level of life sustaining supports at decision and mode of payment of the treatment. during the study period patients died in our icu of which eol decision and consent was explicitly documented in cases which constitute study population. average age of the patient was years (range to ), average duration of active treatment till eol consent was . hours(range to ),average duration between consent and death was . hours(range to ). . % consents were signed by close relatives( son/daughter, brother/sister, spouse, father/mother) and . % were by other relatives( cousins, son in law/daughter in law). at the time of eol decision . % patients were having glassgow coma scale and below, . % patients were on mechanical ventilation, . % were on vasopressors and . % were needing renal replacement. metastatic disease ( . %) and traumatic or vascular brain injury( . %) were the commonest causes of death. only . % patients had medical insurance or employer assistance as a mode of payment for the treatment and in . % cases family members were the payers. withholding of non beneficial life sustaining therapies as eol process was practised in . % of the total icu deaths. all ( %) eol decisions as well as directive requests and consents were signed by patients' relatives, reflecting the importance of close family ties in indian eol practices. our objective was to study frequencies of withholding and withdrawing treatment and time until death in a dutch university hospital icu. between october and february we collected data of all patients that died. data were collected from patient files and during interviews with the doctors and nurses who were responsible for the patient at the time of death. we analyzed which treatments were withheld or withdrawn and calculated the time until death following withholding or withdrawal. preliminary results show that of admissions, patients died ( %). nonsurvivor's (median age years [range - ]) median length of stay was days (range minutes - months). in patients ( %) treatment was withdrawn and in patients ( %) treatment was withheld but not withdrawn. of all patients ( %) were mechanically ventilated of which ( %) were weaned and extubated before death. in of these patients it was decided not to intubate again and other patients not to intubate at all (median time until death: hours). in ( %) ventilator-dependent patients mechanical ventilation was withdrawn; ( %) were extubated. the median time until death after ventilator withdrawal was minutes. when patients were also extubated, it was minutes (p= , [mann-whitney test]). in patients mechanical ventilation was not withdrawn, but fio was decreased to . (median time until death minutes). in patients ( %) inotropic medication was withdrawn (median time until death minutes). in cases, the withdrawal of inotropic medication was combined with the withdrawal of mechanical ventilation. in patients ( %) it was decided not to increase inotropic support (median time until death : hours). in patients ( %) the decision was made not to resuscitate in case of cardiac arrest. median time of this decision before death was hours. in the patients that died treatment was withdrawn in the vast majority of patients. withdrawal of mechanical ventilation and/or withdrawal of inotropic support were most often used. a considerable number of patients died within minutes following withdrawal of therapy. r. veiga* , g. silva , g. campello , c. dias , c. granja intensive care department, hospital pedro hispano, matosinhos, biostatistics and medical informatics, faculty of medicine, porto, portugal the high mortality of critically ill patients underscores the need for icu teams to recognize end-of-life care as an integral component of critical care. besides survival, the success of intensive care should also include the quality of lives preserved and the quality of dying. the aim of this study was to evaluate the incidence and type of end-of-life decisions in critical patients that died in an icu. retrospective analysis of all patients that died in the icu in the period of january to december and evaluated the following variables: demographic characteristics (age, gender); co-morbidities: (heart failure, chronic obstructive pulmonary disease (copd), diabetes mellitus, neoplasia, chronic renal disease, hiv/aids, alcoholism); reason for admission; saps ii; length of icu stay (icu los) and type of end-of-life decisions. three concepts were defined in order to classify the end-of-life decisions: comfort care: a change from curative therapy to comfort care therapy; limited therapy: maintenance of curative therapy but without escalating it (e.g. not raising rate of vasopressor agents, no renal substitution); without previous end-of-life decisions: when no attitudes toward end-of-life care were considered. given the diminished number of patients in the without previous end-of-life decisions group we decided to evaluate them apart from the other two groups.results. two-hundred and twenty seven patients were admitted in the icu and of them died ( %). reason for admission in those who died was septic shock/ severe sepsis ( %), post-cardiac arrest ( %); cardiogenic shock ( %); acute respiratory distress syndrome ( %). the most common co-morbidity was alcoholism ( %), followed by diabetes mellitus ( %), neoplasia ( %), heart failure ( %) and copd ( %). forty seven patients ( %) died after comfort care decision, eleven patients ( %) after limited therapy decision and four ( %) patients died without previous end-of-life decisions. comparing the groups comfort care and limited therapy we found significant differences in the following variables: hemorrhagic shock at admission ( % vs. %) (p= . ); saps ii ( vs. ) (p= . ); icu los ( . days vs. . days) (p< . ). patients in the limited therapy group had more admissions with hemorrhagic shock, a higher severity score and stayed less time in the icu. this analysis suggests that end-of-life decisions in this group express their higher severity. patients of the comfort care group presented less severity and stayed longer in the icu. their shift of curative therapy to one designated to provide comfort care reflects an absence of a clinically favorable response. the low percentage of patients without previous end-of-life decisions is consistent with previous reports and should be seen as a positive issue. non invasive positive pressure ventilation (nippv) is widely accepted as an initial approach to providing ventilatory support to many patients with acute respiratory failure (arf). palliative approaches focused on the quality of life and comfort; represent a challenge for family's physicians and the patients. nippv is an attractive option to treat acute respiratory failure in end stage patients when the failure is irreversible and it is a final outcome of the primary disease. the approach to providing ventilatory support to patients with arf, to relieve them from the sensation of dying suffocate without intubating them because they don't wish it either, is very challenging. after institutional approval and patients consent, we conducted a prospective observational study of patients that fulfilled the criteria. cases received nippv ( with end stage cancer and with pulmonary fibrosis). when nippv was ordered we recorded: respiratory rate, heart rate, arterial blood pressure, neurological status and arterial blood gases, before nippv initiation (baseline data) and then st, th and th hour. at the time of initiation of nippv, all patients were alert and cooperative with nippv. analgesia and/or sedation were used when it was necessary. pao , pco and ph measures were analyzed using statistical methods. percentage changes from baseline (pre-nippv) of these measures were used as dependent variables. (mean value of measurements at different time points was used). dependent variables (percentage of pao , pco and ph) were regressed on time, for each patient. in all cases the results were statistically significant, with p-values ranging from a low of . to a high of . . for all patients, the regression coefficient for the percentage change was positive; indicating that the percentage change was increasing with time. we can remark that pao increases over time, pco and ph p values > . . we believe that nippv via helmet cpap is a means of potentially ensuring the highest quality of end-of-life care. nippv can be applied for palliative care, and it might be used to keep patients whom developed acute respiratory failure comfortable before the inevitable. decisions regarding the resuscitation status of patients are among the most difficult facing healthcare professionals, patients and families. these groups often need to discuss decisions regarding resuscitation yet their understanding and expectations can differ greatly. this study sought to determine the knowledge and beliefs of doctors, nurses and the general public regarding resuscitation decisions.methods. an observational study was designed. three study groups (doctors, nurses and general public) were interviewed using a face-to-face interview by a single interviewer and questionnaires completed. questions examined opinion, factual knowledge and knowledge of the ethics surrounding hospital resuscitation attempts. . doctors, nurses and general public were randomly selected. % doctors, % nurses and % of public correctly estimated survival to discharge following in-hospital resuscitation attempt. the remainder overestimated survival. . % of doctors and % of nurses consider resuscitation decisions to be made too infrequently. deficiencies were identified in doctor and nurse knowledge of the ethics governing resuscitation decisions and public opinion was found to conflict with ethical guidelines. public understanding of the nature of cardiopulmonary arrests and resuscitation attempts, and of the implications of a dnar order is poor. . % of public report television medical dramas as their primary source of information on such matters. knowledge regarding resuscitation principles, outcomes and ethics is poor among both healthcare staff and the general public. these knowledge differences may not be appreciated or addressed in discussions regarding resuscitation and this reduces the likelihood of meaningful discussion and acceptable decisions. there is a need for educational initiatives to address these deficiencies. public apprehension surrounding this subject needs to be identified and corrected during discussions and this could be facilitated with a patient information leaflet. [ ] poor communication during this process may lead to unnecessary anger and a delay in the grieving process that could linger for many years to come. giving the family the option to be present during resuscitation offers a more compassionate and family-centred approach to this crisis. this option of family presence however is frequently met with resistance and uncertainty by health care workers who may view the family's presence as increasing their risk of making a mistake or worse, being sued. a study in the uk estimated that out of one-hundred-and-sixtytwo uk emergency departments family witnessed resuscitation was allowed by % for an adult patient and % for a child. [ ] another us study also found that amongst patients in emergency departments, % preferred to have their family present during resuscitation. [ ] a survey was conducted amongst the doctors, nurses and paramedics who work in two uk eds to assess their attitudes and beliefs. experience, life support training, years in practice, consent issues, ethical factors and concerns regarding medico legal implications were sought for. a -point likert scale was used and mean scores analysed using microsoft excel. . staff were surveyed. % of doctors, % of nurses and % of paramedics believed in the concept in trauma fwr. in cardiac arrest patients, % were in favour of it, % opposed to it and % undecided. % of staff believed that litigation was possible with family witnessed resuscitation. % of respondents thought that critical incident de-briefing would be of benefit to assist staff dealing with stress. fewer doctors believed in cardiac fwr compared to nurses (p= . ) and paramedics (p= . ). in trauma, difference was non-significant. as health care professionals caring for families in the emergency departments, we need to recognize the need for compassionate family-centered care. with a well trained and motivated team equipped with effective, well thought out guidelines, there is considerable benefit for family members and staff in this difficult situation. thorough information about the events that are going to take place in the icu after an elective procedure might facilitate the awakening process and weaning from the ventilator, mitigating patient's anxiety and increasing their comfort. the aim of this study was to analyze the impact of preoperative information on the patient's perceptions and reactions to the usual inconveniences, such as orotracheal tube (ott), associated with the first postoperative hours in the icu. prospective, cohort study with a group of cases (a) and a control group (b). duration: two months. inclusion criteria: all patients undergoing elective cardiac surgery. there were no exclusion criteria. setting: cardiac surgical icu of a tertiary hospital. the survey was made in the first hours. the study was blinded for the doctors in charge of the patients. the characteristics of both groups are presented as a/b with the p value into brackets. the quantitative variables are shown with the mean value and the qualitative variables as a percentage. the number of patients included was : cases (a) and controls (b). age: , / , years ( , ); men: / %( , ); time receiving sedative drugs: , / , hours ( , ); total hours with ott: , / , ( , ); hours with ott after stopping sedation: , / , ( , ). the first patient's perceptions were: discomfort related to ott in , / , % ( , ); surgical pain in , / , % ( , ); thirst in , / , % ( , ); welfare or calm in , / , % ( , ), and nothing in , / , % ( , ). additional sedatives were required in , / , % ( , ). information was considered very useful in , %. patients valued very positively the provided information. in addition, this information had a significant impact on the tolerance to the ott, requirement of additional sedatives, and in the sense of welfare. there were not differences in the time under sedative drugs or in the perception of thirst or pain. a multiparameter questionnaire was sent to icu. each questionnaire comprised informational topics groupe into categories (table). one relative per patient was asked to quote (yes/no) within days after admission, each item, i.e. if he would like to find information on that item in an ib. if "no" was quoted, he was asked to say why (closed answers). demographic data on patient and relatives were correlated to the scores (nbre of "yes"), in each item category (factor analysis with varimax rotation followed by stepwise multiple linear regression). . questionnaires were analyzed (patients: age ± year, saps : ± , sofa: ± ). table: % of positive response for each item ("would you like information on this topic in an icu booklet?") grouped into categories. "no" answers were mostly explained by "i trust the team to manage information about this" (median: %, range: - ). mulitvariate analysis showed that demographics data describing patient condition (age, saps , chronic disease) correlated (p< . ) with "yes" score of the items comprized in "icu rules" (table) but not with other items grouped in other information categories. conclusion. interestingly, as a whole, most items were highly wished in a booklet, suggesting that - % of relatives express a plea for transparency in face of "difficult icu issues", without taboo. only the "yes score" to "icu rules" items correlated with patient status whereas items from other topics did not. this sounds, as relatives visiting the most severe patients may consider visiting rules as crucial. other items did not correlate to profiles, and may thereby be considered as societal standard requirements in terms of information. in / , our -bed medical icu signed a convention with the asp iroise association defining hv's role and presence. the association, a member of a national network of hv associations, works with our university hospital. four hvs took alternate turns in the icu one afternoon per week. hv were free to meet any conscious patient or any family member who wished so; icu staff also asked them to meet patients or families who seemed particularly distressed. hv wrote a brief commentary in a special transmission logbook which could be consulted by the staff and gave feedback about their visits whenever needed. patients (pts)and families (fam)who met an hv were sent a questionnaire either in / or in / . pts were admitted during the period of study: the hv met pts ( , %) and families ( , %). people answered the questionnaire ( , %): pts and fam: spouse, parents, sister, children( no answer). ethics consultation has been introduced into the practice of medicine during the last decades as a way to help physicians and nurses come to a decision about a medical treatment where value-laden conflicts are involved. the primary goal is helping to identify, analyze, and resolve ethical problems. the aim of this study was to evaluate ethics consultation in a dutch university hospital intensive care. intensivists, residents, fellows and nurses can consult a clinical ethicist specialized in intensive care for advice in value-laden situations. we evaluate ethics consultation on our icu between january and april . the clinical ethicist was consulted times. in / cases ( %) advice was asked before withdrawal of life-sustaining therapy. in this category / ( %) cases concerned palliative care. in / cases ( %) the independent advice was in confirmation with the physician's view. in / cases ( %) advice was sought in cases were there was doubts to proceed with intensive care therapy. in four cases relatives wanted to withdraw therapy, where the intensivist did not consider this as futile. in / cases ( %) the advice was in accordance with the treatment plan. in cases ( %) questions about information asked by non-relatives. all advises were followed. cases concerned triage, cases withholding therapy, brain death declaration, a deadly iatrogenic complication and in patients a question concerning emergency research. in ( %) cases a lawyer specialized in health care was consulted. in the cases about 'withdrawal of therapy', the advise could be given within minutes in % of the cases. ethical advise by a clinical ethicist specialized in intensive care can be additional, affirmative and reassuring, and improves quality of care. in most cases advice could be given immediately. . deferred consent has been proposed as a surrogate for a priori subject or proxy consent. the aim of this report is to evaluate the practicality and efficacy of a deferred consent procedure in an ongoing dutch multi-centre clinical trial. screening logs were collected from two participating centres of a clinical trial that is currently conducted to evaluate the efficacy of early lactate-directed therapy and that uses deferred consent. screened patients were analyzed for eligibility and reasons for exclusion. ( %) were not reported to the study investigators, patients ( %) were not included for medical-ethical reasons (e.g. treating clinician deemed risk/benefit ratio of the study intervention unacceptable), in patients ( %) study participation was practically impossible (e.g. unavailable study materials) and the reason was unknown in patients ( %). only patients (or their relatives)( %) refused informed consent. in an ongoing dutch multi-centre emergency clinical trial using deferred consent, only % of patients or their relatives refused informed consent. deferred consent in emergency research is practical and facilitates a high inclusion rate. adult respiratory distress syndrome (ards) and peep have been linked to right ventricular dysfunction (rvd). this has been attributed to elevated pulmonary artery pressure (pap) and pulmonary vascular resistance (pvr) due to ards as well as increased intrathoracic pressure due to peep therapy. we wondered if rvd was a late phenomenon in ards or could also be detected during early peep treatment of hypoxia in patients with multiple ards risk factors. pulmonary embolism is a highly prevalent disease associated with severe morbidity and mortality. although the hemodynamic changes induced by pulmonary embolism are known, the alterations in respiratory mechanics after an embolic event are not completely understood. the aim of this study was to evaluate acute changes in hemodynamics, static and dynamic respiratory mechanics and lung histology induced by an experimental model of pulmonary microembolism. ten large white pigs (weight - kg) were instrumented with arterial and pulmonary catheters and pulmonary embolism was induced in pigs by injection of polystyrene microspheres (diameter ∼ µm), in order to obtain a pulmonary mean arterial pressure (pmap) of twice the baseline value. five other animals were injected with saline and served as controls. hemodynamic and respiratory data were collected and pressure x volume (pxv) loops of the respiratory system were performed by a quasi-static low flow method. animals were followed for hours and after death lung fragments were dissected and sent to pathology. the average amount of microspheres necessary to generate microembolism was . ± . mg/kg. pulmonary embolism induced a significant reduction in stroke volume ( ± ml/min/bpm pre vs ± post, p< . ), an increase in pmap ( ± mmhg pre vs ± post, p< . ) and pulmonary vascular resistance ( ± mmhg/l/min pre vs ± post, p< . ). respiratory dysfunction was evidenced by significant reductions in pao /fio ratio ( ± pre vs ± post, p< . ), dynamic lung compliance ( ± ml/cmh o pre vs ± post, p< . ) and increase in dead space ventilation ( ± pre vs ± post, p< . ). pxv curves of the respiratory system were affected by embolism, with shift of the loops to the right and consequent reduction in static compliance and pulmonary hysteresis. pathology depicted inflammatory neutrophil infiltrates, alveolar edema, collapse and hemorrhagic infarctions. pulmonary microembolism induced by polystyrene microspheres is associated with cardiovascular dysfunction, as well as respiratory injury characterized by decrease in oxygenation, dynamic and static lung compliances and pulmonary hysteresis. pathology findings were similar to those verified in inflammatory-induced acute lung injury. the similarities between respiratory and histologic features of this model and those from conditions associated with lung inflammation suggest that pharmacologic and ventilatory interventions already used to treat acute lung injury may also be tested in pulmonary embolism. the presence of patent foramen ovale (pfo) is frequently underdiagnosed in icu patients suffering from refractory hypoxemia. however, it is relatively common in the general population. we examined the prevalence of pfo in mechanically ventilated icu patients with refractory hypoxemia and abnormal chest x-ray findings. over a period of five years, mechanically ventilated patients with refractory hypoxemia and abnormal chest x-ray findings were examined with transesophageal echocardiography (tee) for the presence of pfo as a contributing factor to their hypoxemia (right to left intracardiac shunt). all patients were ventilated with tidal volume - ml.kg - and peep between - cmh o. their mean pao /fio ratio was ± mmhg. the coexisting pathology consisted of: ards ( cases), massive pulmonary embolism ( cases), copd ( cases), cabg surgery with rv infarction ( cases), cerebrovascular accident ( case) and pulmonary oedema due to fluid overload ( case during a two-month period we investigated the possibility of opening of the foramen ovale during a recruitment maneuver in either patients with ards or in patients with atelectasis and a pao /fio ratio< . we enrolled consecutive patients (ards: cases, patients with atelectasis and hypoxemia: cases), likely to benefit from a recruitment maneuver. mean pao /fio ratio was and mean compliance was ml.cmh o - prior to the maneuver. all data regarding the mechanical properties of the lung were recorded from the ventilators monitor screen. after deficits of intravascular volume had been addressed and hemodynamics had been optimized, a baseline transesophageal echocardiographic study using contrast material was performed to rule out the possibility of a foramen ovale already patent prior to the maneuver. the recruitment inflation pressure was chosen as the lesser of cm h o or the peak pressure at ml.kg - tidal volume. the ventilator was then adjusted to deliver this high inflation pressure for secs. five seconds after the onset of inflation, ml of a contrast material were injected through a central venous line with the transesophageal probe already in place to detect the passage of the material to the left atrium. passage of the contrast material to the left side of the circulation was detected using two dimensional echocardiography. we found that the sustained high inflation pressure resulted in foramen ovale opening in patients, whereas it did not produce such a result in patients. in of the studied patients, the baseline transesophageal study revealed a patent foramen ovale before recruitment was attempted. no adverse effects following the recruitment maneuver were noted. mean pao /fio ratio was and mean compliance was ml.cmh o - twenty minutes after the recruitment maneuver, with only one of the recruited patients showing a significant improvement in oxygenation.conclusion. patent foramen ovale may be a contributing factor of refractory hypoxemia in icu patients. opening of the foramen ovale is not an unlikely event during a recruitment maneuver. acute respiratory distress syndrome (ards) remains a major problem in critically ill patients, with mortality rates of - %. to date, no specific treatment has been shown to decrease mortality, but this may largely be due to the heterogeneity of the populations meeting the ards criteria.objectives: to evaluate patients who died with a clinical diagnosis of ards and who had a postmortem examination in order to: -define the pathological alterations associated with the syndrome, with particular reference to the typical pattern of diffuse alveolar damage (dad); -evaluate whether etiologies or precipitating factors were missed; and -speculate whether a lung biopsy could have guided the clinical management. three year ( ) ( ) ( ) review of all patients with ards (using the aecc criteria) who had a postmortem examination. comparisons between ante-and post-mortem diagnoses were classified as major and minor discrepancies using the goldman classification. results: of a total of admissions, patients had a clinical diagnosis of ards. of these, died; had a postmortem examination and of these had complete data for analysis. the main causes of death were multiple organ failure in ( %) and refractory hypoxemia in ( %). postmortem lung examination revealed dad in ( %) patients ( associated with a lung infection), (broncho)pneumonia without dad in ( %), invasive pulmonary aspergillosis without dad in ( %), and other diagnoses in ( %). major unexpected findings were found in ( %) patients, classified as goldman class i errors and class ii errors. the class i errors included cases of invasive pulmonary aspergillosis.conclusion. ards as a syndrome, can be due to various pathological patterns; at autopsy, only half of patients with ards have typical dad. special attention should be paid to the possibility of aspergillosis; in this setting, lung biopsy may have a role. g. s. georgieva*, s. kurata, c. zhu, a. bilali, t. imai critical care medicine, tokyo medical and dental university, tokyo, japan development of efficient lung preservation method has been anticipated and we elucidated that positive pulmonary venous pressure (pvp) ( mmhg) prevented ischemia-reperfusion (i/r) injury in isolated mechanically ventilated rat lungs. the aim of this study is to determine whether cpap accompanied with mmhg of pvp would be effective for prevention of i/r injury. after tracheostomy rats were ventilated at strokes /min with air ( % c ) and with peep of . cmh , cannulated to the left atrium and pulmonary arteries (pas), and perfused with krebs -henseleit solution supplemented with albumin ( %) ( . ml/g/min). the lungs and heart "en block" were isolated and placed in a chamber; right and left bronchus as well as pas were dissected which permit each lung to be ventilated and/or perfused selectively by selective occlusion of each bronchus and/or pa. after min control condition, the left lung (ll) was maintained under cpap (selective occlusion of left broncus); the control right lung (rl) was ventilated with peak airway pressure of cmh above peep;perfusion to the both lungs was stopped (ischemia). pulmonary venous outflow was elevated so as to be applied mmhg to the left atrium during ischemia. after -min ischemia, reperfusion with mmhg pvp and both lung normal ventilation were resumed for min. perfusion pressures of rl and ll was measured at the beginning and at the end of the experiment by occlusion either the left or right pulmonary artery, as appropriate. albumin content in bronchoalveolar lavage fluid (balf) separately for each ll and rl, and lung weight were measured. protein content in balf was calculated as (mg of protein)/(ml of balf)/(g of lung dry weight). all the data were compared by wilcoxon's rank-sum or mann-whitney u-test and expressed as mean +/-sd. in i/r lung maintained at cpap, wet/dry and balf as well as perfusion pressure increased compared to the control rl. conclusion. cpap( . cmh ) and mmhg pvp cannot prevent ischemic lung injury despite constant distention of pulmonary vasculature and alveolar space. this suggests that gas exchange during ischemia would be necessary for escaping from i/r injury. potential peripheral airway obstruction is of importance for the choice of ventilatory strategy in acute lung injury (ali). use of a limited expiratory time counteracts early regional expiratory collapse but might cause hyperinflation in case of significant peripheral obstruction. the aim of this study was to assess regional expiratory time constants and gas trapping in early ali. ten anesthetized pigs were ventilated in volume-controlled mode with i:e ratios of either : or : at a rate of breaths per minute. starting from the end-inspiratory level, sequential computed tomography (ct) exposures were performed during passive, uninterrupted expiration to the atmosphere. the procedure was performed before and after oleic acid-induced lung injury (oai) had been induced in the lower lobe on one side. the gas volume of bilateral dependent and non-dependent regions of interest (rois) was calculated from radiographical attenuation values. the expiratory time constant was calculated from a mono-exponential decay of roi gas volumes during expiration. gas trapping in injured and non-injured regions were compared. during ventilation with i:e ratio : , oai caused overall compliance to decrease from +/- . to +/- . ml/cmh o (p< . ). dependent, injured regions showed a shorter time constant and a lower volume of gas than dependent non-injured regions regardless of whether the preceding end-inspiratory volume had been increased or not by application of a limited expiratory time. in non-dependent, non-injured regions, the gas volume was similar on both sides after both patterns of ventilation. one of the additional approaches in the therapy of the acute respiratory distress syndrome (ards) is the use of a pumpless arteriovenous extracorporeal membrane oxygenator (interventional lung assist (ila)). the aim of our study was to test the effects of an ila system on hemodynamics and gas exchange during resuscitation and to establish whether ila should be kept open or clamped under these circumstances. the study was designed as a prospective experimental study. the experiments were performed on pigs ( to kg body weight). the pigs were anesthetized and mechanically ventilated. one femoral artery and one femoral vein were cannulated and connected with ila. acute lung injury was induced by repeated bronchoalveolar lavage until arterial partial pressure of oxygen (pao ) was lower than torr for at least min during ventilation with % o . ventricular fibrillation was then induced by an indwelling pacemaker. manual compressions of the thorax were started at once and continued for minutes. in animals, ila was kept open, in the other it was clamped immediately. statistical analysis was performed using graphpad prism. two-way analysis of variance was applied and significance was accepted at p values < . . the data is given as mean ± sd. with a mean systolic arterial pressure in the group with ila open of ± mm hg and ± mm hg with ila clamped and mean blood pressures of ± mm hg with ila open and ± mm hg with ila clamped the blood pressure did not differ between the two groups. endtidal carbon dioxide decreased from ± torr with ila open and ± torr before intervention to ± torr and ± torr, respectively. the arterial partial pressure of carbon dioxide (paco ) was significantly lower in the group with the ila system open ( ± mm hg versus ± mm hg at minutes) and the pao was higher (although significant only at minutes, mm hg ± mm hg versus mm hg ± mm hg). the blood pressure generated with thorax compressions did not differ significantly between the two groups and endtidal co was also in the same range. therefore we assume that circulation was not significantly affected by ila and that the shunt caused by the ila system did not deteriorate circulation. paco was significantly lower in the group with the ila system open and pao was higher. our results indicate that the ila system was not harmful during resuscitation, it even might have a beneficial effect.grant acknowledgement. the study was partially supported by novalung, hechingen, germany. respiratory failure -miscellaneous - increased thorax rigidity and high intraabdominal pressure reduce the stretch ability of the thoracic cage and modify the regional lung function. this phenomenon is often seen in intensive care patients, e.g. with abdominal compartment syndrome. objective of this study was to determine the effect of decreased thoracic cage compliance on regional distribution of spontaneous ventilation in different postures by the non-invasive method of electrical impedance tomography (eit). for this survey we examined ten healthy male spontaneously breathing volunteers (mean age ± sd: ± years; body weight: ± kg, height: ± cm). the compliance of the thoracic cage was restricted by external abdominal and thoracic corsets respectively. the eit examinations were performed with the goe-mf ii eit device (viasys healthcare, höchberg, germany). sixteen self-adhesive electrodes ( m red dot , m health care, borken, germany) were applied on the chest circumference in one transverse plane and used for rotating electrical current injection and voltage measurement. the eit data were acquired at a rate of scans/s. impedance data and spirometry were obtained during spontaneous ventilation in three body positions (sitting, left and right side). statistical analysis was performed using repeated anova with bonferroni's multiple comparison test and student's t test. p values < . were considered significant.results. the regional distribution of ventilation in subjects without restrictions revealed a close match with physiologically expected values. thoracic and abdominal restrictions led to reduction of ventilation in the dependent lung areas. the non-dependent lung areas were not affected. the fractional ventilation in the dependent lung areas was reduced in the right side position from . ± . % to . ± . % (thoracic restrictions) and . ± . % (abdominal restrictions), in the left side position from . ± . % to . ± . %, and . ± . %. thoracic and abdominal restrictions of the thoracic cage reduce ventilation only in the dependent lung regions in spontaneously breathing healthy volunteers. eit is a suitable method for non-invasive determination of regional lung ventilation. k. raymondos* , k. vieweger , j. ahrens , m. przemeck , m. homann , s. piepenbrock anaesthesiology, medical school hannover, anaesthesiology, annastift, johanniter-unfall-hilfe e.v., ortsverband wasserturm, hannover, germany germany are still performed with ambulances in that only limited monitoring and usually only volume-cycled emergency ventilators can be used. we established an intensive care ambulance system and evaluated the transfers of critically ill patients performed with this system. we prospectively recorded interhospital-transfers. the ventilatory modes before and during the patients' transfer and further characteristics of the interhospital-transfers were evaluated. transport ventilation was performed with the raphael ® silver ventilator (hamilton medical ag, rhäzüns, switzerland) with that also pressure-support ventilation (psv), airway pressure release ventilation (duopap ® /aprv) and the combination of both could be used. indications for the interhospital-transfers included ischemic ( . %) and other ( . %) cardiac diseases, cerebral diseases ( . %) of which % required neurosurgy, pulmonary disease ( . %) and others ( . %). ( . %)% of the transferred patients received ventilatory support, patients ( . %) breathed spontaneously with and patients ( . %) without oxygen insufflation. the majority of the mechanically ventilated patients received ventilatory modes supporting spontaneous breathing before ( . %) and during the transfer ( . %). the patients were transferred in minutes ( minutes - hours) over a distance of km ( - km) (median (range)). at least motor syringe pumps were needed during the transfer of patients ( . %). monitoring during the transfer was similar or more extended compared to the monitoring in the hospital prior to transfer (ecg % vs. %, pulse oximetry % vs. %, non-invasive blood pressure % vs %, intraarterial pressure % vs % and capnography % vs. %). most ventilated patients received weaning techniques and most of these ventilatory modes were continued during the transfer. these ventilatory modes and a more extended monitoring including intraarterial pressure monitoring and capnography cannot be applied in emergency ambulances. the less invasive ventilatory modes and the extended monitoring enable a less invasive and safer interhospital-transfer as the intensive care treatment and monitoring prior to transfer is maintained or even extended during the transport. a. sánchez*, m. palomar, r. alcaraz, a. socias, d. moreira intensive care unit, hg vall d'hebron, barcelona, spain introduction. some series have shown the bad prognosis of patients with pulmonary fibrosis (pf) who require admittance at icu for respiratory failure. there are doubts of the benefit of the ventilatory support if the precipitating cause is not well defined. lung transplant (lt) could be a therapeutical option. the aim of this study was to analyze the prognosis of the patients with pf who are admitted to an icu of a hospital with lt program.methods. case-series, observational study of patients with pf and acute respiratory failure admitted to the icu of a third level hospital with lt programm between january until june . information about the cause of pf, clinical course, current status, ventilatory support, length of stay, pulmonary functional tests, possibility of trasplantation, complications and mortality was collected. . patients ( men, women) with pf ( idiopathic pf, connectivopaty and due to radiotherapy) were admitted for acute respiratory failure (arf) to our icu. mean age was , ( - ) years. the median duration of illness from diagnosis until admittance was , ( - ) years. apache-ii score was ( - ). the precipitating cause of arf was identified in patients: bacterial pneumonia was documented in patients; had a pulmonary embolism; fungic infection and cases were due to the progression of the disease. in cases the precipitating cause could not be identified. mechanical ventilation (mv) was required by patients ( , %) during an average of , ( - ) days with a mortality rate of , %. pa o /fi o at admittance ( - ) mm hg; and paco at admittance ( - ) mm hg. respiratory functional studies were available in eleven patients with a fev of . ( . ) l and fvc of . ( . ) l. patients ( %) died during their stay at icu. the cause of death was multi-organic failure in ( . %); refractary hypoxemia in ( . %) patients and of them died while the transplantation was being performed. mean length of stay was ( - ) days. patients were included in the urgent lt list and were transplanted. no donor was found in cases and died on the waiting list. there were performed single-lung and double-lt. mean age was ( - ) years. the time from the admittance until transplantation was ( - ) days. of them ( %) required mv with a mortality rate of , %. from this group ( , %) patients died during their stay at the icu. of the patients died while the transplantation was being performed.conclusion. literature shows a bad prognosis of patients with pf who need admittance to an icu for arf. in our experience the survival was % so the existance of a lt programm could offer a chance to these patients. m. e. lugarinho*, p. p. souza intensive care unit, hospital de clinicas mario lioni, rio de janeiro, brazil introduction. acute kidney insufficiency (aki) worsens the outcome in critical ill patients. we investigate whether the presence of aki had any effect on lenght of mechanical ventilation and mortality rate. observational, prospective study in a -bed general intensive care unit (icu) from january to december . the inclusion criterion was invasive mechanical ventilation for more than hours. aki was defined as the presence of dialysis during the icu stay. patients were then separated into aki and non-aki patients (control group). the primary end point was duration of total length of mechanical ventilation and the secondary end point was the icu mortality. a total of patients were studied: with aki and non-aki. the groups were similar in regard to age, sex, and apache ii score. the median (interquartile range) duration of mechanical ventilation [ - ] versus [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days, (p< , ). the icu mortality rate were significantly greater in the aki patients: % versus , % (p< , ).conclusion. this study shows that renal insufficiency has serious impact on the duration of mechanical ventilation and morbi-mortality in critically ill patient. these data elicits the poor outcomes of mechanical ventilated patients who demands for dialytic methods. it will be useful in end of life discussions and decisions in our icu. introduction. -ht a-r-agonist -oh-dpat has been shown to counteract morphine induced ventilatory depression, while opiate antinociception remained unaffected. repinotan-hcl, another -ht a-r-agonist, is unlike -oh-dpat suitable for the use in humans. it was hypothesized that repinotan-hcl is capable to antagonize ventilatory depression without impairing anti-nociception in rat. with approval from local animal care committee, rats were anesthetized with sevoflurane and tracheotomized to record respiratory rate (rr), tidal volume (vt) minute ventilation (mv). inguinal vessels were catheterized to monitor arterial blood pressure and apply drugs iv. nociception was assessed by tail-flick reflex. morphine was administered at increments of mg/kg until a target % reduction of rr was achieved. subsequently, repinotan-hcl was added cumulatively at increasing doses ( . , . , , , µg/kg, n= ). another group received nacl . % to serve as control (n= ). morphine ( . ± . mg/kg) depressed rr to - ± %, and tfr was abolished with first dose of morphine in any experiment. repinotan-hcl antagonized ventilatory depression dose-dependently, mcg/kg repinotan-hcl re-established ventilation almost at pretreatment level (rr + . ± %, p< . , -anova, compared to control). tfr remained absent throughout repinotan administration. repinotan functionally antagonized morphine-induced ventilatory depression, while suppression of nociceptive reflex sustained. -ht a-r-agonists such as repinotan-hcl appear to be promising candidates to stabilize spontaneous breathing. a. makowski* , b. misztal , c. plowright , k. safranow anaesthetics, medway maritime hospital, gillingham, united kingdom, biochemistry, pomeranian medical university, szczecin, poland vapotherm's (vap) patent pending membrane technology makes higher flows from to lpm possible by saturating breathing gases with water vapor at body temperature. fio is ranging from . - . . heat and humidity allow nasal flow to be well tolerated by the patients. high flow in animal study caused small amount of peep. can we achieve desired therapeutic goal in treatment of respiratory failure (rf) with this very simple, non-invasive method? we investigated effectiveness and hospital outcome of patients with rf treated on vap at surgical hdu between december and march . data were taken during retrospective investigations. we analysed type and reason of rf as well as respiratory rate (rr), fio , flow, arterial blood gases (abg). data were collected before (bef) vap was commenced, hour after, and every day of treatment. we also recorded length and outcome of vap therapy and patient satisfaction. data were analysed with wilcoxone and also spearman's rank correlation tests. the patients ( % female, % male) at age - ( . ± . ) were treated - ( . ± . ) days. we applied vap therapy for . % patients with type i rf and . % with type ii rf. the reasons of rf were pneumonia in . %, sepsis in . % pulmonary oedema in . %, copd in . %, others in . %. for . % patients there was a sufficient and definite treatment whereas . % required mechanical ventilation and icu admission. the . % of patients were satisfied with therapy. the . % survived and were discharged from the hospital. high flow and small amount of peep reduce work of breathing and significantly decrease rr. after effective vapotherm therapy we observed in abg significant increase of oxygen saturation and pao . vast majority of patients were satisfied during the treatment. in critically ill patients who need long-term mechanical ventilation, early tracheostomy may facilitate weaning and shorten the length of stay in intensive care ( ). however, there are no clinical tests that identify patients as being at an increased risk for prolonged ventilatory support; clinicians must predict the duration of arteficial ventilation by their clinical experience. in our surgical intensive care unit we conducted a prospective clinical study to determine if there was an association between different clinical parameters (age, body mass index, gcs, saps score, vasopressor use, pao /fio ratio) and long-term mechanical ventilation. furthermore, we examined the positive predictive value of clinicians' prediction; to do that, clinicians had to indicate whether they considered prolonged mechanical ventilation as the most likely (but not always certain) outcome or not. we enrolled patients and collected date on days - th and th of treatment. prolonged meshanical ventilation was defined as at least more days on respirator. none of the examined parameters could be used alone to predict long-term mechanical ventilation. overall sensitivity of clinicians' prediction was . %, and positive predictive value was . %. . % of patients died, . % was weaned from respirator ( . % extubated) within days despite predicted by clinicians as having prolonged ventilatory need. suprisingly, the best positive predictive value ( . %) was found on the day of admission, the worst ( . %) on day ; the difference was not significant (p= . with chi-square test). this result could be explained by the fact that most patients in the study group were ventilated on day , but only a few on day .conclusion. prediction of prolonged mechanical ventilation was found to be very inaccurate, and did not improve in the course of first week of treatment. however, in our department where many neurosurgical patients are treated, only a minority could be extubated within days when long-term ventilatory support was predicted. as selection of patients who need tracheostomy seems not to be better after one week of treatment than at an early stage, there can be a reason for early tracheostomy if we anticipate prolonged arteficial ventilation. n. abidi , h. thabet* , o. béji , h. elghord , n. brahmi , m. ben othmen , n. kouraichi , m. amamou intensive care medicine, emergency medicine, centre d'assistance médicale urgente, tunis, tunisia introduction. acute exacerbation of copd is a frequent cause of admission in icu and usually have a poor outcome. such a patient consume a large amount of resources particulary if they need endotracheal intubation. the aim of this study is to report epidemiological, clinical features,treatment and outcome of patients admitted in icu for acute exacerbation of copd. a retrospective study was carried out of consecutive admisions in icu over a years (from january to december ). american thoracic society criteria are usued to define copd. exacerbation is defined as a worsening of copd symptoms. a total of patients were included in this study with episodes of acute exacerbation. mean age was ± , years. the sex ratio was , (m/f: / ). eighty percent were current tobacco users. seventy two percent had one or more associated comorbities mainly cardiovascular disease. according to copd severity , % of patients were in stage iii. , % were receiving home oxygen and ( %) were previously mechanical ventilated. on icu admission severity score are apache ii ± ; igsii ± . patients ( %) have a shock and ( , %) have a coma (gcs< ). treatment consist of starting non invasive ventilation (niv) for patients ( %); patients ( %) need immediate intubation and mechanical ventilation. failure of niv was noted for patients. in the course of hospitalisation in icu main complications were: nosocomial infection for patients ( , %), barotrauma patients ( , %) and thromboembolic complications for patients ( , %). the median icu stay was , ± , days and mortality was , % ( patients). the main cause of mortality were septic shock ( cases, , %) and ards ( cases, %). in this retrospective study patients admitted for exacerbation of copd need a mechanical ventilation in , %. failure of niv were %. main complications were nosocomial infection ( , % of cases). mortality is high , % but not different for patients admitted in icu for other disease. it is described, that gelatin leads to red blood cell (rbc)-coating, which is protective against shear stress in extracorporeal circuits. ( ) an increase of mean corpuscular volume (mcv) without an increase in mean corpuscular hemoglobin content as well as a reduction of red blood cell (rbc) counts can be assumed to reduce pulmonary oxygen transfer. increased rbc aggregability (accelerated blood sedimentation rate, bsr), as could occur due to coating, impairs microcirculation. since adequate oxygen delivery is important in ventilated patients to counteract metabolic acidosis, we compared rbc features in acidotic pigs undergoing hemofiltration. healthy pigs (male, dlxde, - kg) were anesthetized, received acid infusion ( . m) and low tidal ventilation with fio > . resulting in normoxic acidosis (ph . - . ; paco - mmhg). tris-hydroxymethylaminomethane (tham) was infused to titrate a ph of . - . . either hes or gel (n= - /colloid-group) was infused additionally to crystalloids (colloid to crystalloid ratio was : ). samples were collected before acid and colloid infusion (bs), after induction of acidosis (baseline acidosis, bsa), and after h of continuous acidosis ( ha). thereafter, acid infusion was stopped and tham was infused with . mol/kg/h for h in order to normalize ph-values. final values (fv) were taken. parameters investigated were: paco , rbc counts, mcv, and bsr. the fio /pao ratio was also determined. compared to hes application, gel infusion was associated with a reduction in rbc count, an increase in mcv and an accelerated bsr from bsa until fv. values did not recover from initial deterioration (bsa) even not after normalization of ph (fv). based on the healthy lungs in this porcine model, these changes did not impair pao /fio ratio. whether increases in mcv were due to gel coating or due to unhampered swelling of rbcs during acidosis could not determined. however, in acidotic pigs gel induced unfavorable effects concerning rbc features with respect to rheology while hes did not. in individuals with impaired pulmonary function and hypodynamic state the described difference between the two types of colloids could become crucial with respect to total oxygen delivery. perctaneous dilational tracheostomy (pdt) has become more common procedure used in intensive care. however, several complications, such as hemorrhage, posterior tracheal wall injury, tracheal stenosis have been recently reported. the aim of this study was to confirm whether the ultrasound can easily and clearly delineate the pretracheal anatomy and identify the potential problems for pdt. we also examined the accuracy in identifying the correct puncture level between and tracheal cartilages blindly (by hand). we studied patients and volunteers. before ultrasound scanning, the circumference of the neck was measured and the puncture level between and tracheal cartilages was marked blindly in each subject. in ultrasound scanning, we examined the relationship of the thyroid to the trachea, aberrant vascular anatomy in the pretracheal region, counted the number of extrathoracic tracheal rings. the distances from the skin to cricothyroid ligament and anterior tracheal wall at the level between and tracheal cartilages were estimated and the relationship between depth of trachea and circumference of the neck was analyzed by simple regression. we also checked the level of trachea pointed by operator blindly was correct or not by comparing the level identified by ultrasound images. the mean age and circumference of the neck were ± years (range: - ) and ± cm. ultrasound examination of the trachea and thyroid was easily carried out in each subject except subjects. approximately extrathoracic tracheal rings could be imaged with ultrasound. anterior jugular veins were seen in subjects ( %) and six were near the midline. the depth of trachea between and tracheal cartilages were varied in each subject ( . - . cm) and there were stastistically relatioship between circumference of the neck and depth of trachea (r = . , p= . ). the accurate decision of trachea level was made in % of the subjects.conclusion. this study showed that: ) ultrasound can delineate the neck structure and detect variations related to the complication of pdt; ) blind identification of the puncture level for tracheostomy without ultrasound was not necessarily correct. our results demonstrated that the routine use of ultrasound could be recommended before pdt. introduction. fluid therapy system of critically ill patients is very variable, and it is based in the interpreting of differents physiologic parameters with a double aim, by one hand keep an adequate perfusion of vital organs, and the other hand avoid overload volumen. our objective was analyze changes in critically ill patients fluid therapy when we including evlw in treatment protocol and evaluate response in short time. observational and prospective study in a neurotraumatological icu. we included consecutives patients that were admited with acute lung injury/adult respiratory distress syndrome and/or septic patients who needed monitoring with central venous and arterial catheterization with picco system. we made a therapeutic reassessment of the fluid therapy and/or vasoactives after we knew evlw when one of the following events in the patient evolution hapenned: hypoxemia, hypotension, olyguria/anuria, or its addition. response in short time was also evaluated. our sample included patients and determinations( patients with determinations, patient with determination and patient with determination). after we knew evlw we changed initial therapeutic plan in . %; this change affected fluids in . % and vasoactives in . %. evlw in patients who therapeutic plan was modified was . ± . and if therapeutic plan was not modified, evlw was . ± . (p< . ). association is observed between evlw value and decision about fluids, so when we decided increase fluids was . ± . ; if the decision was decrease fluid, evlw was . ± . and in the cases that diuretics were added . ± . , in all cases statistics significant was found. no differences was observed in evlw values about vasoactives decision. we found improvement of initial event in short time after intervention in . %.conclusion. evlw determination affects in important way to fluids therapy plan in critically ill patients. we think that inclusion of evlw contributes to a more racional management of these patients. patients who had received ino were identified from icnarc records. hospital notes and icu charts were reviewed. data collected included diagnosis, apache ii and unit and hospital outcome. the pao /fio ratio (in mmhg) was recorded prior to starting ino (day ) and subsequently on days - using the data from the time at which oxygenation was best in each hour period. . patients received ino. patients received it for treatment of hypoxaemic respiratory failure, and for treatment of pulmonary hypertension. mean apache score was . on admission (survivors . ; non-survivors ) . the mean pao /fio ratio was . on day and improved to . on day . in unit survivors, the mean pao /fio increased from . to . on day , compared with unit non-survivors in whom it increased from . to . . ( %) of patients were responders to ino (defined as a > % increase in pao /fio ratio). unit and hospital survival figures for responders and non-responders are presented below. hospital surviviors (n= ) hospital non-survivors (n= ) responder (n= ) ( %) ( %) non-responder (n= ) ( %) ( %) fisher's exact test ( tailed) p= . conclusion. ino was used in patients with more severe hypoxia than those included in randomised trials. ( ) in this review, responders were found to have a significantly reduced unit mortality and a reduced hospital mortality compared with non-responders. we believe ino may be a valuable therapy in ards patients with severe refractory hypoxaemia, and that studies in this subgroup of patients are warranted. outcome predictors of hfov in severe ards are not well studied. we prospectively evaluated the outcome predictors of hfov in adult ards. methods. ards patients receiving mechanical ventilation as per the ardsnet protocol with po /fio ≤ inspite of peep≥ cm and fio ≥ . ,were considered for hfov. continuous distending pressure(cdp),frequency ,amplitude, inspiratory time and bias flow of hfov were optimised with the help of frequent blood gas analysis. weaning from hfov to pressure support ventilation was attempted once po /fio ratio remained ≥ with cdp≤ cm &fio ≤ . . responders(r) were defined as patients who were successfully weaned to a state which required no ventilatory support for > hrs. non responders(nr)were defined as patients who could not be weaned off ventilatory assistance. results. out of total patients were r & were nr. both the groups were similar prior to hfov as shown in table. improvement in po /fio ratio and oxygenation index (oi) at hrs & hrs in r group was statistically significant as compared to that in nr group. we could show that chaotic variation of pressure support improves pressure support ventilation (psv), and named this new mode noisy psv. in this work, we compared noisy psv to conventional biphasic positive airway pressure ventilation (bipap), which has been claimed to be a "gold standard", in experimental acute lung injury. after approval by the local animal care committee, juvenile pigs ( . - . kg) were anesthetized and mechanically ventilated (dräger evita xl lab; volume controlled ventilation, vt = ml/kg; fio = . ; peep = cmh o). after induction of acute lung injury by saline lung lavage ( ml/kg), lungs were recruited and a decremental peep trial was performed to determine the optimal peep according to the elastance of the respiratory system (ers). thereafter, spontaneous breathing was resumed and animals were randomly assigned to noisy psv or bipap groups (n= each group). the ventilator settings were as follows -bipap: fio = . ; plow = according to peep of minimal ers; phigh = titrated to generate vt of ml/kg; thigh = s; tlow = s -noisy psv: fio = . ; peep = according to peep of minimal ers; mean pasb = titrated to generate vt of ml/kg. noisy psv was accomplished by means of remote control of the evita xl lab by a laptop, which generated a sequence of respiratory cycles with different pressure support levels (mean = pasb; sd = % of mean). gas exchange, respiratory parameters and hemodynamics were measured at baseline, injury, after resuming of spontaneous breathing (baseline ) and during an observational period of h. statistical analysis was performed with general linear model statistics adjusted for repeated measures using baseline as covariate. significance was accepted at p< . . bodyweight, peep and number of lavages as well as hemodynamics did not differ significantly between groups. oxygenation and co elimination were significantly improved with noisy psv (p< . both). analysis of respiratory parameters revealed significant lower mean airway pressures with noisy psv as compared to bipap (p< . ), as well as increased mean peak airway pressure, spontaneous respiratory rate, and mean tidal volume (p< . all).conclusion. this study represents the first evaluation of the recently developed noisy psv combined with peep levels titrated according to lowest ers. noisy psv was found superior to conventional bipap with regard to gas exchange and respiratory parameters. further experimental studies are necessary to determine the potential role of noisy psv in intensive care therapy. we investigated if chaotic variation of pressure support (noise) can improve the performance of pressure support ventilation (psv) in experimental acute lung injury (ali). with approval of the local animal care committee, pigs weighing to kg were anesthetized, intubated and mechanically ventilated (volume-controlled mode, fio = . , peep= cmh o, tidal volume= ml/kg). following that, ali was induced by surfactant depletion, and biphasic intermittent positive airway pressure (bipap) was initiated with: lower cpap (cpaplow) = cmh o, higher cpap (cpaphigh) titrated to obtain tidal volumes of - ml/kg, respiratory rate set to obtain paco between - mmhg. then, depth of anesthesia was decreased to allow spontaneous breathing, and animals were ventilated with two different modes ( hour each, random sequence): ) traditional psv, with pressure support level set at cpaphigh -cpaplow; ) noisy psv, with random variation of pressure support and mean value set at cpaphigh -cpaplow, and standard deviation set at % of the mean value (normal distribution). gas exchange, inspiratory drive (p . ) and inspiratory pressure time product of esophageal pressure (ptp) were assessed. helical computed tomography (ct) of chest was performed at end-expiration and the hyperaerated, normally aerated, hypoaerated and non-aerated lung compartments were calculated in animals. patients with respiratory failure treated with vm with fio . were included. after minutes of oxygen therapy, arterial blood gases were collected and patients were asked to quantify (from to ) three items: dyspnea, dry mouth and general confort. then, vm was changed for hfnc (optiflowtm, fisher & paykel, new zeland) . the same variables were collected after minutes using hfnc. results are expressed as median (interquartil range). we have applied spsswin v . with wilcoxon test. patients n= ( m), age ( - ). in the moment of inclusion, one patient ( %) presented mods and sofa score was ( . - . ). during their evolution, five patients ( %) finally need endotracheal intubation. main results are presented in the following tables: a computer-driven system (cds) has been recently used to optimise psv to patient's needs during weaning. in some pts, the cds fail to find a "comfort window" despite stepwise increase in pressure support (ps) levels. for these pts, cds could further increase respiratory muscle workload. we speculate that failure to adapt respiratory rates (rr) and vt following changes in ps levels might identify a subset of pts unlikely to benefit from the cds.to test this hypothesis, we used a bedside test before switching ventilated pts to a closed-loop algorithm of psv. we studied pts at initiation of weaning with psv using the smallest ps level resulting in rr≤ , vt> ml/kg. we collected baseline values and assessed changes in vt (dvt), rr (drr) during min after cmh o-increase and decrease in ps levels. then, a cds session was started at the baseline ps level. we searched for correlations between dvt, drr, and outcome (failure/success) of the cds sessions. a cds session was deemed successful when the system detected criteria for separation of the ventilator or when psv was efficiently adjusted by the cds within h after starting the session. in pressure support ventilation auto-peep is considered a major contributor to the inspiratory work of breathing. measurement of auto-peep requires esophageal pressure tracings, which are not routinely available. the presence of auto-peep is likely, when flow is interrupted at end-expiration, a pattern well-established in controlled ventilation. we studied expiratory flow-volume relationships as substitute for detection of auto-peep in patients on pressure support ventilation. in patients successively admitted to our icu respiratory mechanics were obtained from consecutive breaths on pressure support ventilation. auto-peep was considered present when in flow-versus-time recordings flow was interrupted at end-expiration. from flow-volume relationships expiratory time-constants were calculated and related to actual expiration times. all measurements were obtained with a nico-computer; for analysis a computer program analysis plus was used (both respironics/novametrix, inc.). in of the patients flow at end-expiration was interrupted suggesting the presence of auto-peep (interrupted flow group). in the remaining patients flow was zero at end-expiration (zero flow group). in the flow-volume curves of patients in the interrupted flow group versus the zero flow group end-expiratory flows varied between . - . l/s and . - . l/s respectively. the expiratory time-constants ranged from . - . s in the interrupted flow group and . - . s in the zero flow group. the ratios between expiration times and expiratory time-constants varied between . - . and . - . for the interrupted and zero flow groups respectively . the means and standard deviations for both groups were:means +/-sd in patients on pressure support ventilation with interrupted flows at endexpiration higher expiratory time-constants and lower ratios between expiration times and time-constants were found, suggesting the presence of auto-peep. these variables can be used as substitute for detection of auto-peep. non invasive ventilation (niv) is the delivery of assisted mechanical ventilation to the lungs, without the use of an invasive endotracheal airway. niv has decreased the need for invasive mechanical ventilation and its attendant complications. acute cardiogenic pulmonary edema (acpe) is defined as an episode of acute heart failure accompanied by severe respiratory distress and oxygen saturation < % on room air before all treatment. our study aimed to asses the respiratory effects of a device that delivers a continous positive airway pressure via face mask in patients with severe acpe, the feasibility of using this technique in an emergency department (ed) and estimed the need of endotracheal intubation (ei). we evaluated a series of patients consecutively treated in our ed for acpe, from june to december . a peep level of cm h o delivered by cpap-boussignac device (vygon, ecouen, france) was used in all patients. fio was estimed to range from to %. clinical and blood gas parameters were recorded at entry and also after minute and hour of treatment. all patients were treated with standard medical therapy. the average of age was years ( - ), were male and were female. the inclusion criteria for niv were: ph < , but > , , paco > mmhg or an acute augment of - mmhg, respiratory rate > /min, pao /fio < mmhg on room air and score kelly max . resolution of respiratory distress occurred from to minute ( media minute). all patients showed an improve of clinical and emogasanalytic impairment. only patients needed ei and were transferred in icu. patients were treated in ed and after normalization and stabilization of their vital signs they were discharged in other medical departments ( cardiology department and pneumology department). the rate of ei was %.conclusion. cpap delivered using boussignac device is feasible in an emergency care setting. it can quickly improve respiratory distress in acpe patients and reduce the need of ei. in clinical practice niv is being used as a sole respiratory support modality or in the weaning period in at least % of arf patients admitted to emergency department. the remaining patiens need imv as primary and secondary forms of respiratory support. failure of niv seems to predict higher mortality rates. as a conclusion we need both support modalities and the physician has to use them carefully according to patients condition and their expertise. methods. medline, pubmed, cochrane, & cinahl databases ( to were searched using the terms: aprv, bipap, bilevel & lung protective strategy, individually and in combination. reference lists of identified papers were also examined. two independent reviewers determined eligibility of papers based on predefined criteria. database searching yielded citations, of which were selected on review of title and abstract. data were abstracted onto pre-designed forms from experimental studies and discussion articles on further review. of the experimental studies, used a randomised design, were cohort studies and case series. aprv was the named mode in ( %) studies, bipap in ( %), and inverse mandatory pressure release ventilation in one study. extreme inverse inspiratory:expiratory (i:e) ratio was used in ( %) aprv compared to bipap studies (p = . ); ( %) aprv and ( %) bipap studies used mild inverse ratio (up to : ). a : ratio was used more often with bipap ( , % vs , %, p = . ) as was a normal i:e ratio ( , % vs , %, p = . ). in adult studies, mean inspiratory pressure was cmh o (aprv) and cmh o (bipap) (p= . ). mean expiratory pressure was . cmh o for both modes (p= . ). seven aprv studies described synchronisation, ( %) stated the mode did not synchronise to patient effort. all bipap studies that described synchronisation stated it was available.conclusion. aprv assumes inverse ratio ventilation (irv). some studies advocate extreme irv with short release times to improve gas exchange, haemodynamic stability, renal and splanchnic blood flow( ). extreme irv was used in only % of aprv studies, % described an i:e ratio of : . further, ventilator settings used for studies of aprv may be indistinguishable from bipap studies ( , ) . given the variation in ventilatory settings described, uncertainty of optimal settings may exist. commercial ventilator branding may further add to confusion. generic naming of ventilatory modes, as with drug prescribing, combined with consistent definitions of the parameters that define the modes, may avoid confusion, improve consistency of patient response and assist the implementation of these modes into clinical practice. pav is intended to normalize neuro-ventilatry coupling by assisting each breath in proportion to patient effort, but requires reliable measurements of elastance (e) and resistance (r). pav+ allows to (a) automatically and non invasively measure e and r, and (b) continuously adjust ventilatory support accordingly. aim of our study was to test the physiological effects of pav+ versus cmv (ardsnet lung protective strategy) in a model of ards. in pigs ards was induced through chloridric acid inhalation ( ml/kg). at t (after damage) each pig was randomly assigned to pav+ or cmv. gas exchange and lung ct scan at (t ) hours were compared with those obtained at t (delta = t -t ). data are mean +/-standard deviation; *) p < . pav+ versus cmv cmv pav+ ∆ hyperinflated areas (cm ) +/- +/- ∆ normally aerated areas (cm ) - +/- +/- * ∆ poorly aerated areas (cm ) +/- +/- * ∆ nonaerated areas (cm ) +/- - +/- * ∆ pao /fio - +/- +/- * ∆ paco (mmhg) +/- - +/- * our data suggest the ability of pav+ to improve gas exchange, principally through an increase in normally aerated areas. the impact of pav+ on ventilator induced lung injury deserves further investigation.grant acknowledgement. university of bari. introduction. the major advantage of high-frequency oscillatory ventilation (hfov) to conventional mechanical ventilation (cmv) is delivery of smaller tidal volumes to an optimally recruited lung. assuming there is a save window in the pressure volume curve of the lung between a lower zone with atelectasis and a upper zone with overdistension, surpassing this zone would result in either cyclic recruitment and decrecruitment, overdistension, or both. in diseased lungs this safe window may be too small to harbor the relatively large tidal volumes of cmv. co removal (v'co ) and therefore paco is a function of frequency (f) and alveolar delivered tidal volume (vt): v'co = f x vt . it is an inherent technical feature of all oscillators that vt at maximal power decreases as frequency increases. in addition, pressure swings fall down the endotracheal tube and the airways. this fall in pressure swings is a function of frequency and mechanical properties of the respiratory system. as a result of both phenomena vt delivered to the alveoli decreases substantially at higher frequencies. up till now oscillation is set at a fixed frequency, in adults at hz, in children and neonates at hz. paco is regulated by adjusting the power, and thus the pressure swings (delta p) and the delivered volume. if the maximum power has been reached, decreasing the frequency can lower the paco further. we calculated vt required to keep v'co constant at different oscillation frequencies and measured the delivered vt at maximal power as function of frequency with the sensormedics a. . vt needed to keep v'co constant and maximal delivered vt can be plotted against oscillatory frequency. by increasing frequency, vt needed to keep v'co constant and maximal delivered vt both decrease. however, a point is reached at which the required vt to maintain v'co equals the maximal delivered vt. at this point vt has its lowest possible value to maintain paco . at higher frequencies the delivered volume of the oscillator is lower than required and paco would rise above the pre-arranged level. we advocate a ventilatory strategy with the oscillator set at its maximal power and the frequency to be adjusted according to the paco . with this strategy the lowest vt is delivered to the alveoli with the largest safety margins between atelectasis and overdistension. automatic tube compensation (atc) compensates the resistance caused by the endotracheal tube. tube resistance is defined by the equation hagen-poiseuille: r = ( x x l) / π x r . (r= resistance, = viscosity, l= length of the tube, r= radius of the tube). atc is designed to lower the work of breathing in intubated spontaneous breathing patients by creating a higher initial flow and therefore a higher peak pressure. the aim of this study was evaluate the consequences of atc during controlled mechanical ventilation without spontaneous breathing activity on peak pressure distal of the tracheal tube, in comparison to the set pressure. moreover, the time needed to reach the set inspiratory pressure distal of the tube with and without atc was assessed. in an experimental laboratory setting using an artificial lung the maximum pressure in the ventilator (draeger evita ), proximal and distal of the tube with and without % inspiratory atc in a tube id , and a tube id , were measured. the time needed to reach the set inspiratory pressure distal of the tube with and without % inspiratory atc were compared. baseline ventilator settings were bipap, asb , peep mbar, i:e-ratio : , fio %, rise time seconds. a set of measurements where performed for each of the following settings: pressure constant group (pcg): frequency of respectively: , and a minute at a fixed pinsp of mbar. frequency constant group (fcg): pinsp of respectively: , and mbar at a fixed frequency of a minute. no peak pressure were measured at any time distal of the tube regardless of frequency or set pressure. the pressure distal of the tube never exceeded the set pressure level in the ventilator. the time needed to reach the set inspiratory pressure distal of the tube was significant shorter during atc. (see table) conclusion. there is no danger of creating a higher pressure distal of the tube than the set inspiratory pressure at any time during the use of atc % with the draeger evita . with the use of atc the set inspiratory pressure at the distal end of the tube is reached more quickly. atc creates a faster rise time on the tracheal level, resulting in a higher mean airway pressure. key: cord- - yfs ve authors: flores, carlos; del mar pino-yanes, maria; villar, jesús title: a quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: yfs ve introduction: clinical observations and animal models provide evidence that the development of acute lung injury (ali), a phenomenon of acute diffuse lung inflammation in critically ill patients, is influenced by genetic factors. association studies are the main tool for exploring common genetic variations underlying ali susceptibility and/or outcome. we aimed to assess the quality of positive genetic association studies with ali susceptibility and/or outcome in adults in order to highlight their consistency and major limitations. methods: we conducted a broad pubmed literature search from to june for original articles in english supporting a positive association (p ≤ . ) of genetic variants contributing to all-cause ali susceptibility and/or outcome. studies were evaluated based on current recommendations using a -point quality scoring system derived from criteria, and the gene was considered as the unit of replication. genes were also categorized according to biological processes using the gene ontology. results: our search identified a total of studies reporting positive findings for genes involved mainly in the response to external stimulus and cell signal transduction. the genes encoding for interleukin- , mannose-binding lectin, surfactant protein b, and angiotensin-converting enzyme were the most replicated across the studies. on average, the studies had an intermediate quality score (median of . and interquartile range of . to . ). conclusions: although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of european descent, are needed for identifying firm genetic modifiers of ali. critical illness in adults often is followed by acute lung injury (ali). ali and its most severe form, the acute respiratory distress syndrome (ards), are currently defined as a phenomenon of acute diffuse lung inflammation pathologically characterized by an acute onset of non-cardiogenic pulmonary edema resulting from increased capillary-alveolar permeability. both are clinically manifested by hypoxemia under mechanical ventilation (arterial partial pressure of oxygen/fraction of inspired oxygen [pao /fio ] of less than or equal to mm hg for ali and pao /fio of less than or equal to mm hg for ards), diffuse bilateral pulmonary infiltrates on chest radi-ographs, and reduced lung compliance [ ] . pneumonia and sepsis are the main and most common risk conditions associated with the development of both disorders [ ] . ali and ards remain a major health problem worldwide: it has been estimated that each year in the us there are , cases of ali, which are associated with , deaths and . million hospital days [ ] . our understanding of the pathogenesis of ali and ards has improved in recent years with the appreciation that inflammation is a fundamental component of the pathophysiology of these two clinical manifestations of the same syndrome. ali: acute lung injury; ards: acute respiratory distress syndrome; ci: confidence interval; fio : fraction of inspired oxygen; il- : interleukin- ; iqr: interquartile range; ld: linkage disequilibrium; ncbi: national center for biotechnology information; pao : arterial partial pressure of oxygen. clinicians have long recognized that all critically ill patients with ali are not alike. it is becoming apparent that the diversity of clinical manifestations and the response to treatment and outcome among patients with the same disease process are influenced by genetic factors [ ] [ ] [ ] . the first piece of evidence supporting a role for genetic differences in infection risk and outcome came from an epidemiological study reporting a strong association between death from infection in adoptees and their biological, but not adoptive, parents [ ] . for ali, this is further strengthened by the mortality rate disparities across the different ethnic groups in the us [ ] . in addition, ali models in inbred rodents have demonstrated differences for susceptibility and severity traits, allowing the identification of several loci and pinpointing the multigenic nature of the condition [ ] [ ] [ ] . in our attempt to better define patients at risk, recent trends have turned our attention to the search for common genetic variation underlying ali susceptibility and/or outcome. based on the extensive evidence that common genetic variation with modest effects underlies susceptibility to common complex diseases [ ] and on the impossibility of linkage analysis to detect such signals [ ] , association studies have constituted the main tool for improving our understanding of the genetic factors affecting ali susceptibility and outcome. association studies compare two groups of samples (cases and controls) for statistical differences in the frequency of variants at one or more sites of the genome. although the international hapmap project and the development of genotyping technologies have made possible the testing of more than one million of these variants in a single experiment [ ] , they have been available for a short period of time [ ] . thus, currently, association studies in ali have exclusively used a candidate gene approach, in which one or several genes -known to be etiologically involved in the disease -are studied for relevant variant sites. in general, the inconsistency of findings across association studies [ ] -partially attributed to inappropriate designs, implementations, and/or interpretations of studieshas motivated the formulation of standards to improve their quality and to help perform meta-analysis [ ] under the premise that the replication of previous findings most likely reflects interesting biological processes rather than methodological quirks. here, we aimed to examine studies reporting positive findings with all-cause ali susceptibility and/or outcome in adults in order to evaluate their relative merits and caveats based on actual recommendations. we conducted a broad pubmed literature search from to june for original articles by querying for 'polymorphism and acute lung injury' and 'polymorphism and ards'. the retrieved references were then manually curated, and those reporting genetic association studies and published in english were sought. studies were considered if a positive association (p ≤ . ) was reported with either susceptibility or outcomes of all-cause ali or ards. since the current tendency to perform association analysis at the individual variant level may be problematic (for example, there may be important differences in allele frequency or linkage disequilibrium [ld] structure across different populations), we instead considered the gene as the unit of replication [ ] . the gene ontology was used to categorize associated genes according to biological processes [ ] . among reports with positive associations, study qualityrather than significance value -was reviewed based on current recommendations. since performing a checklist of all issues to consider in association studies would require more than a single article, we have focused on the most relevant criteria from a checklist suggested recently [ ] . all together, criteria were considered and each of them was scored as if present or if absent. scoring was performed independently by two authors. studies were divided into case-control or cohort studies based on the design in which the authors reported the positive association. if a case-control study reported a positive association with an outcome in the case series, the positive finding of the study was also considered as found in a cohort design. a final quality score was obtained by adding up scores from all criteria (see below). a reported association could have a maximum score of points for casecontrol studies if more than one polymorphism was analyzed, a maximum of points if reporting a case-control study for a single polymorphism (multiple testing adjustment not needed) or for a cohort with more than one polymorphism analyzed (definition of the control group not needed), or a maximum of points for cohorts analyzing a single locus (definition of the control group and the multiple testing adjustment are not needed). to facilitate comparison across study designs, scores were then transformed to a -to -point scale. criteria that were evaluated in relation to the study design included power calculation, characterization of cases and controls or the cohort, and whether the study considered common gene-wide variation. power calculation was scored as present only if it was explored prospectively or retrospectively as part of the original study. controls were considered to be adequate if obtained from the same population as cases and described in such a way that could be replicated. this criterion was not scored in the cohort studies. adequacy of case groups was considered if demographical and clinical data were reported in sufficient detail in the text and/or a table. mentioning accepted international guidelines for phenotype definition [ ] as the sole description of cases was not considered to be acceptable. to cover the adequacy of exploring gene-wide variation in the association, ld must have been explored for polymorphism selection and/or for the interpretation of results. to evaluate study reproducibility, unambiguous identification of polymorphisms by means of national center for biotechnology information (ncbi) reference numbers or flanking sequences was scored as present. the sole description of amplification primer pairs and/or a reference to a previous publication that reported the assay was not considered to be acceptable. the three other criteria evaluated as part of study reproducibility relate to genotyping quality control measures. duplicate genotyping of a portion of individuals by means of the same or alternative genotyping techniques to calculate an error rate was considered to be adequate and scored as present. testing of hardy-weinberg equilibrium was scored as present even when significant p values were reported for any of the groups as long as a duplicate genotyping was performed. finally, adequate studies performed an interpretation of results blind to the clinical status of samples. to evaluate the statistical analyses, we considered the presence of multiple testing adjustments to be adequate. however, note that this category was not scored if a single polymorphism was assessed since we did not consider an adjustment for the multiple explored phenotypes or outcomes for the adequacy of the study to be necessary. three other categories scored as adequate included an evaluation of other recorded risk factors by means of regression models, reporting major findings in terms of risks (as hazard or odds ratios) and their % confidence intervals (cis), and an empirical assessment or adjustment for population stratification by means of an independent set of polymorphic markers. finally, we scored as adequate additional support from studies performing a validation in at least a second independent sample as part of the original study. studies designed to confirm previously associated polymorphisms were not considered to be acceptable for this category. studies that also included experiments providing evidence of functionality for associated variant(s) were scored as adequate. the sole reference to previous publication(s) providing the functional evidence of the associated polymorphism was scored as absent. searching for 'polymorphism and acute lung injury' or 'polymorphism and ards', we retrieved and original articles, respectively. this allowed us to identify a total of articles [ - ] on genes that showed a positive association with susceptibility and/or outcomes of all-cause ali or ards in at least one study (table ) . although we used broad terms for this search, the possibility for missing additional studies with positive findings might still exist. nevertheless, a complementary search querying for the disease name in the hugenet navigator [ ] gave completely overlapping results, showing studies for additional genes, albeit reporting negative findings. most studies ( . %) were carried out exclusively in populations of european descent (defined as 'whites' or caucasians). a minority of studies were performed in east asians ( %) and the remaining . % of studies included populations of both european and african descent. among the genes that showed a positive association in at least one study, four genes were replicated in at least a second article, three genes were replicated in at least three studies, and one gene was replicated in four studies (figure ). since with only two exceptions [ , ] none of these studies attempted to validate the association results in an independent sample, all studies were counted as a single contribution for the purpose of this assessment. ontology analysis of these genes showed that the majority of them were involved in the response to external stimulus ( . %) and cellular signal transduction ( %). there was also a prominent representation of genes implicated in cell proliferation ( . %), inflammatory response ( . %), immune response ( %), and chemotaxis ( %). seventeen studies ( . %) reported positive findings using a case-control design and ( . %) using a cohort. median sample sizes among studies were of cases (interquartile range [iqr]: to ) and controls (iqr: to ), whereas the median sample size for cohort studies was patients (iqr: to ). overall median quality score was . (iqr: . to . ) and maximum and minimum scores were . and . , respectively. when studies were classified by design, the median quality score in case-controlled studies ( . ; iqr: . to . ) was significantly higher than in cohort studies ( . ; iqr: . to ) (p = . , mann-whitney u test). when studies were explored by the year of publication, there was an improvement trend of association studies over time (spearman rho = . , p = . ), but this was due mostly to case-controlled studies (spearman rho = . , p = . ) since no significant trend was observed for cohort studies (spearman rho = . , p = . ). genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome. ace, angiotensin-converting enzyme; cxcl , chemokine cxc motif ligand ; f , coagulation factor v; il- , interleukin- ; il- , interleukin- ; mbl , mannose-binding lectin- ; mif, macrophage migration inhibitory factor; mylk, myosin light-chain kinase; nfkb , nuclear factor kappa light polypeptide gene enhancer in b cells; nfk-bia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf , nuclear factor erythroid-derived factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sftpb, surfactant pulmonary-associated protein b; tnf, tumor necrosis factor; vegf, vascular endothelial growth factor. almost two thirds of the studies ( . %) did not explore their power to detect positive findings. nearly all studies ( %) fulfilled the internationally accepted definition criteria for ali and ards [ ] , and most studies ( . %) appropriately described demographical and clinical data from cases ( figure ). more heterogeneity was found for the criteria to select a control group: although most studies used healthy subjects or population-based controls ( %), a great proportion of studies preferred icu patients as controls ( %). in any case, . % of studies fulfilled the required criteria to have an adequate control group. most studies ( . %) analyzed a few variants per gene ( . % analyzed a single variant with anticipated functionality) without providing appropriate coverage or discussion to other untyped common variation by means of ld-based methods. in almost half of the studies ( . %), we were not able to identify the associated polymorphism(s) in ncbi databases straightforwardly and unambiguously since flanking sequences or genetic reference numbers were lacking. less than half of the studies reported genotyping error checks ( . %) or a blinding strategy ( . %) to avoid biased results ( figure ). however, hardy-weinberg equilibrium was assessed separately in cases and controls or in the cohort in . % of studies. remarkably, three of these studies reported a positive finding for polymorphisms that nominally deviated from hardy-weinberg expectations in control samples. adjustments for multiple testing were lacking in most studies since only . % of them made adjustments during statistical interpretation. conversely, regression analyses to adjust for covariates were used in a high proportion of studies ( . %). likewise, the magnitude of effects has been appropriately reported in terms of hazard or odds ratios and their % cis in most studies ( . %). by contrast, adjustments for the underlying population stratification were nearly absent as part of the statistical toolbox of the studies ( . %). as few as studies ( . %) supported the association in an independent validation sample [ , ] . only of studies ( . %) explored functional significance of variants associated with disease, either by evaluating the functionality of the associated polymorphism using gene reporter assays [ , ] or by its correlation with serum protein levels [ , , , ] . this quality assessment of genetic association studies with positive findings in susceptibility or outcome of ali and ards identified a total of articles and genes. due to our limited knowledge of the pathogenesis of these conditions and given that it is likely that many common genes and pathways contribute to the onset, course, or severity of these two forms of the same disease process, for the purpose of genetic susceptibility and outcome in this systematic review, we considered ali and ards as a single entity. the top gene ontologies represented in current association studies fit within the major biological processes underlying ali development on the basis of different microarray experiments among several studies using diverse animal models of the disease and cellular models of stretch-induced injury [ ] . overall, the paucity and quality of association data in ali/ ards call for more and better designed studies with larger sample sizes with unambiguous identification of the studied variants and procedures that allow monitoring of genotyping quality for a consistent replication and with better statistical a names are those originally reported in the corresponding reference. ins/del, insertion-deletion polymorphism. ace, angiotensin-converting enzyme; ali, acute lung injury; ards, acute respiratory distress syndrome; cap, community-acquired pneumonia; cxcl , chemokine cxc motif ligand ; f , coagulation factor v; il- , interleukin- ; il- , interleukin- ; mbl , mannose-binding lectin- ; mif, macrophage migration inhibitory factor; mv, mechanical ventilation; mylk, myosin light-chain kinase; nfkb , nuclear factor kappa light polypeptide gene enhancer in b cells; nfkbia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf , nuclear factor erythroid-derived factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sars, severe acute respiratory syndrome; sftpb, surfactant pulmonaryassociated protein b; sirs, systemic inflammatory response syndrome; snp, single-nucleotide polymorphism; tnf, tumor necrosis factor; tr, tandem repeat (polymorphism); vegf, vascular endothelial growth factor. positive genetic association studies with acute lung injury/acute respiratory distress syndrome susceptibility and/or outcome (by year of publication) percentage of studies scored as adequate for criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury percentage of studies scored as adequate for criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury. ld, linkage disequilibrium; pop. stratification adjust., population stratification adjustment. analyses. some of the reported associations, mostly in populations of european descent, have already set the bar high in the field with 'high-quality' studies, either with well-powered studies [ , ] or with a functional correlation of the associated polymorphism [ ] . however, most of those association studies examining the functional effects of polymorphisms have reported the plasma levels of the gene product (protein) at one time point during the development or evolution of the disease process, so the role of those protein levels in the natural history of ali or ards remains to be defined. additionally, positive association studies on ali/ards have focused essentially on exploring genetic risk effects of candidate gene variants in european populations. thus, future studies must try to fill this gap by extending the association analysis to other populations that might give us an overall picture of cosmopolitan and population-specific genetic risks. this also requires authors to give a more appropriate interpretation of results in light of power estimates since genetic effects are expected to be weak and sample sizes will rarely increase to the extent considered necessary [ ] . the current evidence also encourages more replication studies, especially of those genes that have been positively associated in at least two studies [ ] . a strong candidate would be the gene encoding the pro-inflammatory cytokine interleukin- (il- ). extensive cross-species gene expression pattern comparisons in experimental models of ali have shown that il- is highly upregulated [ ] and at increased circulating concentrations in ali patients [ ] . however, undisputed evidence supporting the association of il- gene variants with ali/ards susceptibility or outcome is still lacking, even though positive results have been found in four studies. one of the major reasons is that the predicated association has been explored in a single polymorphism of the il- gene (g/c at position - from the transcription start site). association studies using a gene-wide coverage of common variation may reveal more robust patterns of variation associated with the disease [ , ] . in this sense, a (nearly) full coverage of common variation of the candidate gene in association studies of ali is especially important since no association is yet definitive and our understanding of the functional elements of our genome is incomplete [ ] . classification and characterization of ali/ards across reviewed studies were highly concordant. however, another face of the problem is that ali/ards is still ill defined and the problem is further confounded by the diversity of etiological mechanisms such as sepsis, pneumonia, trauma, and massive transfusion that predispose patients to the condition. furthermore, it has been recently shown that patients meeting current american-european consensus conference ards criteria may have highly variable levels of lung injury and outcomes [ ] . we believe that the development of novel diagnostic tools to precisely characterize the ali and ards phenotypes or the risk factors underlying disease development might result in associations that are more reproducible. as a result of the progress of our understanding of this disease and the use of high-throughput methodologies [ ] , it is expected that robust well-replicated associations between genetic polymorphisms and ali/ards susceptibility and outcome will become a reality in the near future. to reach this point, guidelines to report genotype data fulfilling minimum quality standards need to be implemented to improve our understanding of the genetic architecture of this disease. in addition, statistical methodologies such as multiple testing and population stratification adjustments, which to date have been almost completely absent in these studies, need to be routinely employed as well. since all studied candidate genes await validation in independent studies using larger samples, the search for genetic variants determining susceptibility and outcome in ali or ards still needs to grow and continue improving for the identification of true associations between genotype and clinical outcomes important in the care of ali/ards patients. integration of data across studies (for example, gene expression profiling, association studies, and proteomics) may reveal novel insights into ali development which may allow us to identify cellular pathways specific to the disease. this knowledge will speed up the development of better and increasingly efficient tailored therapies for ali/ards patients admitted to the intensive care unit. tions, mechanisms, relevant outcomes and clinical trial coordination the help network: an early peep/fio trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome incidence and outcomes of acute lung injury understanding genetic predisposition to sepsis injury research in the genomic era. lancet genetic determinants of phenotypic diversity in humans genetic and environmental influences on premature death in adult adoptees race and gender differences in acute respiratory distress syndrome deaths in the united states: an analysis of multiple-cause mortality data ( - ) genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice use of consomic rats for genomic insights into ventilator-associated lung injury reciprocal congenic lines of mice capture the aliq effect on acute lung injury survival time genetic association studies the future of genetic studies of complex human diseases the international hapmap consortium: a second generation human haplotype map of over . million snps what can genome-wide association studies tell us about the genetics of common disease? what makes a good genetic association study? meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease the future of association studies: genebased analysis and replication gene ontology: tool for the unification of biology. the gene ontology consortium working group on replication in association studies: replicating genotype-phenotype associations polymorphisms of human sp-a, sp-b, and sp-d genes: association of sp-b thr ile with ards genetic polymorphisms associated with susceptibility and outcome in ards angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome association between surfactant protein b + polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia polymorphism in the surfactant protein-b gene, and the risk of direct pulmonary injury and ards pre-b-cell colony-enhancing factor as a potential novel biomarker in acute lung injury mannose-binding lectin in severe acute respiratory syndrome coronavirus infection the association of interleukin haplotype clades with mortality in critically ill adults functional genomic insights into acute lung injury: role of ventilators and mechanical stress and tnfb polymorphisms in acute respiratory distress syndrome vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury interleukin- polymorphism in position - and acute respiratory distress syndrome polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations pre-bcell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome functional polymorphisms in the transcription factor nrf in humans increase the risk of acute lung injury a cxcl polymorphism is associated with better outcomes in patients with severe sepsis polymorphisms in the mannose binding lectin- gene and acute respiratory distress syndrome ace i/d but not agt (- )a/g polymorphism is a risk factor for mortality in ards inhibitor kappab-alpha haplotype gtc is associated with susceptibility to acute respiratory distress syndrome in caucasians insertion/deletion polymorphism in the promoter of nfkb influences severity but not mortality of acute respiratory distress syndrome genotypes and haplotypes of the vegf gene are associated with higher mortality and lower vegf plasma levels in patients with ards association between urokinase haplotypes and outcome from infection-associated acute lung injury variation in the mylk gene is associated with development of acute lung injury after major trauma mannose-binding lectin and mannose-binding lectinassociated serine protease in susceptibility, severity, and outcome of pneumonia in adults an il gene-wide haplotype is associated with susceptibility to acute lung injury the - interleukin- polymorphism is associated with acute respiratory failure after major trauma: a prospective cohort study factor v leiden mutation is associated with improved -day survival in patients with acute respiratory distress syndrome a navigator for human genome epidemiology microarray-based analysis of ventilator-induced lung injury the complex interplay among factors that influence allelic association angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome orthologous gene-expression profiling in multi-species models: search for candidate genes persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il- beta and il- levels are consistent and efficient predictors of outcome over time encode project consortium: identification and analysis of functional elements in % of the human genome by the encode pilot project highly parallel genomic assays this work was supported in part by ministerio de ciencia (spain) (saf / ) and funcis ( / ). cf was supported by a specific agreement between instituto de salud carlos iii and funcis (emer / ) under the encyt framework. the authors declare that they have no competing interests. all authors contributed equally in the assessment design and the literature search and read and approved the final manuscript. • current evidence suggests that acute lung injury (ali) and its most severe form, the acute respiratory distress syndrome, are influenced by genetic factors.• association studies, the main tool for the exploration of common genetic variation underlying ali, have thus far reported a total of genes associated with ali susceptibility and/or outcome.• these genes are involved mainly in the response to external stimulus and cell signal transduction.• more studies with improved designs, as well as replication of previous findings with larger sample sizes, are needed to definitely identify genetic factors predisposing patients to ali. key: cord- -ea wn f authors: fowler, alexander j.; wan, yize i.; carenzo, luca; haines, ryan w. title: covid- phenotypes and potential harm of conventional treatments: how to prove the hypothesis date: - - journal: am j respir crit care med doi: . /rccm. - le sha: doc_id: cord_uid: ea wn f nan ( ). in this letter, the authors describe patients with coronavirus disease (covid- ) who have a mean respiratory system compliance of . . ml/cm h o and marked shunt physiology. the authors suggest that these patients are representative of the primary pattern of physiologic derangements among their patients and those of colleagues with whom they've conferred. they discourage the use of prone positioning when compliance is "relatively high," similar to their recommendations in a recent article in which they additionally support ventilation with vt up to ml/kg in select patients with covid- and relatively preserved compliance ( ) . we appreciate the authors' clinical observations and their expertise; however, we have several concerns with these two recommendations, which diverge from the best established evidence for acute respiratory distress syndrome (ards). first, the authors' reported cohort is small and heterogeneous, in keeping with the well-established heterogeneity of ards. many of their patients have similar compliance to those enrolled in clinical trials for ards therapies ( ) . for reference, patients enrolled in the proseva (prone positioning in severe ards) trial had a mean respiratory system compliance of ml/cm h o (sd, ) at the time of enrollment ( ). interestingly, a recent report of patients with covid- from seattle, washington, described median respiratory system compliance of ml/cm h o (interquartile range, - ) ( ) . that is to say, % of the patients in the seattle cohort had lung compliance of ml/cm h o or less. the discrepancy between the compliance measurements in the cohorts from gattinoni and colleagues and seattle highlights the difficulty in interpreting observations of small cohorts in a disease with well-established marked heterogeneity such as ards ( ) . second, respiratory system compliance was not used to determine eligibility for prone positioning in past trials. the proseva trial enrolled severely hypoxemic patients, meeting the berlin criteria for ards, who failed to stabilize early in the course of management ( ) . though the authors may not support prone ventilation in patients with "relatively high compliance," exclusion of patients by these criteria would be inconsistent with existing evidence. also, the effects of prone position on gas exchange are not limited to the shunt in fully atelectatic regions but instead include changes in edematous regions. discouraging prone position based on a perception of limited recruitability risks foregoing a therapy with mortality benefit ( ) . finally, progression to a classic ards with dense posterior consolidation and elevated critical opening pressures (recruitability) is well described after mechanical ventilation, even in patients with initially preserved mechanics and without established lung injury ( ) . patients with covid- -associated respiratory failure have multifocal pneumonia even in milder stages, and these regions are expected to have different elastic properties than unaffected tissue, causing regional stress and strain concentrations with potential to progress to severe ards ( , ) . lung-protective strategies, including low vt and prone positioning, exist to prevent this progression of lung injury. we fully agree with the authors' final sentiment that patience and gentle ventilation are the best therapies for covid- with associated ards. furthermore, the rapid search for new insights into covid- is appropriate and commendable. however, adopting the paradigm that covid- is inconsistent with ards, with resulting specific treatment recommendations, risks discouraging compliance with our best evidence-based standards of care. evidence from randomized controlled trials suggests that prone positioning and low vt ventilation are the precise strategies for gentle ventilation that patients with ards, "typical" or not, should receive. n author disclosures are available with the text of this letter at www.atsjournals.org. to the editor: on the basis of recent correspondence ( ) and an expert editorial ( ), two phenotypes of severe coronavirus disease (covid- ) pneumonia have been proposed: "type l, characterized by low elastance (i.e., high compliance), low ventilation to perfusion ratio, low lung weight and low recruitability and type h, characterized by high elastance, high right-to-left shunt, high lung weight and high recruitability" ( ). features of the l phenotype are not typical of acute respiratory distress syndrome (ards) as defined by the berlin criteria. importantly, the authors suggest that recommended treatment strategies for severe covid- pneumonia based on ards management ( ) may lead to disease progression and excess harm ( , ) . the authors provide anecdotal evidence for their observations based on their combined experience of treating several hundred severe covid- cases. as outlined by singer and colleagues ( ), we need a rational approach. considering the potential importance for modifying the management of these patients and the growing volume of data available from china and italy, quantitative data are needed to test this hypothesis. balancing the trade-off between "learning" and "doing" in this pandemic is crucial ( ) . large randomized controlled trials are not yet available, and observational data remain at high risk of bias. a number of predictive models have been described with severe methodological flaws ( ). the appropriate use of emerging observational data requires collaborative input to improve understanding of treatment effects and complement the results of ongoing randomized controlled studies. the wealth of data generated by critically ill patients and the complexity of covariate interactions make it challenging to use traditional statistical modeling to establish causal relationships. we aim to determine the causal pathway between the use of an ards management strategy for l-phenotype patients and subsequent harm using a directed acyclic graph (dag) (figure ). the dag achieves two things. first, we can construct a complex system of interacting baseline, clinical, and disease features, allowing explicit statement of prior knowledge before any data analysis. second, we can use the dag to determine a minimal adjustment set of variables to reliably estimate the direct effect of our exposure (ards ventilation strategy in covid- l-phenotype patients) and outcome (icu mortality). the dag was developed on the basis of the information in the expert editorial outlining the two phenotypes. in doing so, we have transformed the initial hypothetical construct into a testable mechanistic structure. arrows represent proposed causal pathways, such as the link between a high positive end-expiratory pressure strategy of standard ards management and worsening edema and cardiovascular instability. combined, these paths can be used to elucidate the appropriate adjustment set of variables. in this case, one adjustment set included cardiovascular instability, hypoxia, and acute kidney injury, all of which are readily measurable among intensive-care patients receiving treatment for covid- . this approach has a number of limitations, including the fact that the evidence underpinning the structure is currently anecdotal. without high-quality, unbiased evidence, it will be challenging to determine the true direct effect because of unmeasured confounders. highlighting different phenotypes and different responses to treatment is a welcome approach that echoes the thoughts of some intensivists treating patients with covid- and, if supported through the appropriate use of data, has the potential to reduce harm to future patients. the dag allows easy inclusion of increasing knowledge as new findings emerge and provides an objective analytical framework to facilitate ongoing discussion. we welcome comments and encourage readers to examine the structure themselves by running the code (code freely available on request). we would also be interested to know the calculated effects if anyone wishes to test the hypothesis with appropriately collected data. n author disclosures are available with the text of this letter at www.atsjournals.org. to the editor: luciano gattinoni is widely acknowledged and respected for his work on acute respiratory distress syndrome, and this time he has suggested a very interesting concept describing the pathophysiology of the atypical presentation of severe acute respiratory syndrome coronavirus (sars-cov- )-induced respiratory failure ( ). based on detailed observation of several cases, the hypothesis of dividing the time-related disease spectrum within two primary "phenotypes," type l and type h, looks logical and might be helpful in the management of patients with coronavirus disease (covid- ) . the suggested cause of hypoxemia in type l is the loss of regulation of perfusion and loss of hypoxic vasoconstriction. hypoxemia, leading to increased minute ventilation, primarily by increasing the vt (up to - ml/kg), is associated with a more negative intrathoracic inspiratory pressure, and the magnitude of this pressure swing is projected as a factor that may determine the transition from the type l to the type h phenotype. however, the authors did not give an explanation for loss of regulation of perfusion and loss of hypoxic pulmonary vasoconstriction. we believe that diffuse pulmonary microvascular thrombosis is the cause of hypoxemia in early pneumonia by sars-cov- . the histologic and immunohistochemistry studies suggest that in severe covid- infection, a catastrophic, complement-mediated thrombotic microvascular injury occurs, with sustained activation of the actin pathway and lectin pathway cascades ( ), leading to the recommendation of the use of early anticoagulation with low-molecular-weight heparin ( ) . we agree with the authors that to reverse hypoxemia, oxygenation by high-flow nasal cannula may be tried in patients with type l. however, we have reservations on the "early intubation and the use of peep [positive end-expiratory pressure] to prevent the transition to type h," as the authors themselves have suggested that "the lung conditions are too good." effective oxygenation using high-flow nasal cannula/extracorporeal membrane oxygenation in type l should prevent pleural pressure swings and self-inflicted lung injury, leading to transition to type h. covid- does not lead to a "typical covid- pneumonia: different respiratory treatments for different phenotypes? proseva study group. prone positioning in severe acute respiratory distress syndrome covid- in critically ill patients in the seattle region -case series comparison of the berlin definition for acute respiratory distress syndrome with autopsy ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation covid- does not lead to a "typical covid- pneumonia: different respiratory treatments for different phenotypes? surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) a call for rational intensive care in the era of covid- optimizing the trade-off between learning and doing in a pandemic prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal key: cord- -v lck l authors: kim, kyeong tae; morton, sophie; howe, sarah; chiew, yeong shiong; knopp, jennifer l.; docherty, paul; pretty, christopher; desaive, thomas; benyo, balazs; szlavecz, akos; moeller, knut; shaw, geoffrey m.; chase, j. geoffrey title: model-based peep titration versus standard practice in mechanical ventilation: a randomised controlled trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: v lck l background: positive end-expiratory pressure (peep) at minimum respiratory elastance during mechanical ventilation (mv) in patients with acute respiratory distress syndrome (ards) may improve patient care and outcome. the clinical utilisation of respiratory elastance (cure) trial is a two-arm, randomised controlled trial (rct) investigating the performance of peep selected at an objective, model-based minimal respiratory system elastance in patients with ards. methods and design: the cure rct compares two groups of patients requiring invasive mv with a partial pressure of arterial oxygen/fraction of inspired oxygen (pao /fio ) ratio ≤ ; one criterion of the berlin consensus definition of moderate (≤ ) or severe (≤ ) ards. all patients are ventilated using pressure controlled (bi-level) ventilation with tidal volume = – ml/kg. patients randomised to the control group will have peep selected per standard practice (spv). patients randomised to the intervention will have peep selected based on a minimal elastance using a model-based computerised method. the cure rct is a single-centre trial in the intensive care unit (icu) of christchurch hospital, new zealand, with a target sample size of patients over a maximum of years. the primary outcome is the area under the curve (auc) ratio of arterial blood oxygenation to the fraction of inspired oxygen over time. secondary outcomes include length of time of mv, ventilator-free days (vfd) up to days, icu and hospital length of stay, auc of oxygen saturation (spo( ))/fio( ) during mv, number of desaturation events (spo( ) < %), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation) and hospital and -day mortality. discussion: the cure rct is the first trial comparing significant clinical outcomes in patients with ards in whom peep is selected at minimum elastance using an objective model-based method able to quantify and consider both inter-patient and intra-patient variability. cure aims to demonstrate the hypothesized benefit of patient-specific peep and attest to the significance of real-time monitoring and decision-support for mv in the critical care environment. trial registration: australian new zealand clinical trial registry, actrn . registered on september . (https://www.anzctr.org.au/trial/registration/trialreview.aspx?id= &isreview=true) the cure rct clinical protocol and data usage has been granted by the new zealand south regional ethics committee (reference number: /sth/ ). mechanical ventilation (mv) support is crucial for patients with acute respiratory distress syndrome (ards). while there is agreement on the preference for lower tidal volumes [ , ] , there is relatively little consensus on the selection of positive end-expiratory pressure (peep) [ ] [ ] [ ] [ ] [ ] [ ] [ ] . traditionally, lower peep has been used [ , ] , but low peep can lead to increases in oxygen desaturation and hypoxaemia [ , ] and worsening of lung injury, indicated by greater use of rescue therapies and deaths after rescue therapy [ ] . high peep can increase alveolar recruitment, but can decrease cardiac output and lead to further lung injury due to barotrauma and/or volutrauma [ ] or overdistension [ , ] . peep can be optimised to reduce hypoxaemia [ ] and intrapulmonary shunting [ ] and improve gas exchange [ ] and oxygenation [ , , ] , by maintaining recruitment of injured or collapsed alveoli [ ] . in patients with ards, peep reduces ventilator-induced lung injury (vili) [ , ] , increases recruitment [ ] [ ] [ ] , and reduces inflammatory mediators in plasma and bronchoalveolar lavage fluid [ ] . mv strategies combining low tidal volumes with recruitment manoeuvres (rms) and higher peep to prevent vili have been hypothesized as ideal for lung protection [ , ] . however, currently, there is still no standardized approach to the selection of this optimal peep, or to deciding how often peep should be adjusted or recalculated. reports from experimental animal trials performed by carvalho et al., suarez-sipmann et al. and lambermont et al. [ ] [ ] [ ] indicate that pigs induced with ards experience minimal respiratory elastance at a specific peep associated with higher oxygenation, maximum recruitment, and higher functional residual capacity, all without signs of lung overdistension. equally, it has been proposed that peep should be set whereby the lung has minimal respiratory elastance (or maximum compliance), which could be clinically beneficial by balancing the risks of peep that is set too low or too high [ ] [ ] [ ] . aside from the work by suter et al. [ ] , pintado et al. also showed that peep selection at minimal elastance is beneficial to patients [ ] . despite some consistent findings, the application of minimal elastance peep selection remains limited and hindered by the lack of an objective, reliable, and easy-to-use method to determine elastance at the bedside in real time. chiew et al. showed the potential benefit of minimalelastance peep selection in a pilot study [ , ] . following the study, a phase- randomised controlled trial (rct) was designed to assess mechanical ventilation at minimal elastance peep in patients with ards versus standard practice of care in a single-centre hospital. in particular, patientspecific respiratory system elastance and corresponding minimal elastance peep is determined using a validated model-based method and computer software [ ] . this trial uses real-time-identified patient-specific respiratory system elastance, and thus the trial is named the clinical utilisation of respiratory elastance (cure) rct. this manuscript presents the detailed clinical protocol for the phase- cure rct. this trial is registered with the australian new zealand clinical trial registry (anzctr): actrn . the cure rct is a two-arm rct comparing modelbased mechanical ventilation (mbv) with current standard practice mechanical ventilation (spv) in patients with a ratio of partial pressure of arterial blood oxygen (pao )/fraction of inspired oxygen (fio ) (p/f ratio) ≤ . it is to be conducted in a single-centre hospital intensive care unit (icu) at christchurch hospital in christchurch, new zealand. the primary objective is to assess the impact of model-based ventilation in peep selection (mbv) therapy on clinically significant patient outcomes and patient-centred quality of care metrics. the other objectives of this study include ( ) to provide the knowledge and methods to make care more patient-specific and timely to optimise treatment and improve outcomes in a large cohort of critically ill patients and ( ) to improve the understanding of the pathophysiological basis of critical illness through what we learn about the hourly and daily evolution of lung injury in terms of patient-specific elastance and response to care through this study. the primary outcome of this study is the area under the curve (auc) of pao /fio over the period of mechanical ventilation. secondary outcomes include length of time of mv (lomv), ventilator-free days (vfd) up to days, icu and hospital length of stay (los), auc of spo (oxygen saturation)/fio during mv, number of desaturation events (frequency and fraction of time spo < %), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation (ecmo)) and hospital and -day mortality. these outcomes and their corresponding four levels of specification based on zarin et al., is shown in table . the secondary analysis includes comparison of the means of lomv, vfd, hospital and icu los, -day mortality, chest x-ray index scores and rescue therapies used. a difference in primary and secondary outcomes will show the impact of mbv compared to spv. no difference would show that enhanced, model-based metrics of patient-specific condition have no effect on patientcentred or clinical outcomes. either outcome will yield clinical guidance. eligible patients are randomised to either the modelbased intervention group (mbv) or the control group (spv). both groups will have designated computer software to monitor their breathing [ ] . the software uses real-time measurements of pressure and flow from the ventilator to objectively calculate the patient-specific and breath-specific respiratory system elastance for every breath [ ] . participants on mbv will undergo recruitment manoeuvres (rm), an initial maximum recruitment manoeuvre (rm max ) or subsequent peep adjustment and monitoring procedure (pump) mini recruitment manoeuvres. the respiratory elastance at each peep step during these protocolised rms is calculated and recorded. the software will recommend a patient-specific minimal-elastance peep to the clinicians in setting ventilator peep. patients on spv will have peep selected using current clinical practice without the aid of the software, but all breaths will be analysed and elastance recorded; clinical staff will be blinded to these data. patients recruited into this study will be under constant supervision in the icu. however, their outcomes will be measured based on the intention-to-treat principle, taking into account protocol variations, which naturally occur. these variations will be reported to the primary investigator at the earliest opportunity and followed up. there will be detailed training on the use of cure equipment and on the protocol, to allow adherence to trial. this trial is based on the intention-to-treat principle. thus, protocol amendments may be required to ensure patient safety and outcomes, and the primary investigators will instigate protocol amendments if necessary. the amendments will be reviewed by the data monitoring committee (dmc) to warrant patient safety and outcomes. the dmc may also refer protocol amendments based on outcomes of the interim analysis reports. finally, if participant enrolment is slow, the protocol may be amended to allow faster recruitment. the trial involves critically ill participants who are mechanically ventilated. thus, it is likely and acceptable for participants to be receiving medication related to any other concomitant comorbid conditions while participating in the cure rct. participants in this study will not be concomitant to another study that would affect the results of this study. participants will not be co-enrolled in another study that uses different oxygenation settings, recruitment manoeuvre procedures or anything that may affect the outcomes of this study. the following are the cure rct inclusion, exclusion and p/f ratio criteria. the inclusion criteria are: i. on any level of peep or fio , or ii. p/f ratio ≤ on fio = % and peep = (see "p/f ratio criteria") the exclusion criteria are: the p/f ratio criteria are: . if the p/f ratio is ≤ , the patient is eligible for enrolment . if < p/f ratio ≤ , set fio = % and peep = cmh o and repeat the analysis of arterial blood gases (abg) within min of the change to measure the new p/f ratio a. if the new p/f ratio is ≤ , the patient is eligible for enrolment b. if the new p/f ratio is > , the patient is not eligible for enrolment and, if appropriate, will be re-screened at a later time this trial will recruit patients who have a p/f ratio ≤ , a criterion in the definition of severe to moderate ards as defined by the ards definition task force in the berlin definition [ ] . they will be eligible if their p/ f ratio is ≤ on any level of peep and fio . those patients with a < p/f ratio ≤ will be placed on peep = cmh o, and fio = %. if a subsequent p/f ratio is ≤ they will also become eligible (see additional file ). the p/f ratio measured at fio of % and peep of cmh o is based on villar et al. [ ] . first, it is important to note that standard ventilation practice may include recruitment manoeuvres to increase lung recruitment and oxygenation. however, these clinical practices are widely variable and often not standardised. the recruitment techniques used to improve oxygenation and mechanics of ventilation in the intervention and control arms of this study are within the scope of standard icu clinical practice. the protocols used will standardise these existing interventions to recruit lung volume and titrate peep. study participants will be unable to consent to participation in this study prior to enrolment as they will be sedated and mechanically ventilated. it is also equally important to randomise participants to either arm of the rct at the commencement of mv to ensure a fair comparison. patients who have been ventilated ≤ h are eligible for the cure rct. given this time frame, the cure rct will recruit patients once family consent is obtained. however, if the treating clinician firmly believes a recruitment manoeuvre is in the best interests of the patient, and no family is available for consent, the participant will be enrolled and randomised and the appropriate protocolised recruitment manoeuvre will follow. in this case, delayed consent is obtained as early as possible. once the participant recovers from their condition and is discharged from the icu, we will seek their informed consent. in cases where the family cannot attend the hospital to sign a statement of assent, their opinion will be obtained by telephone in the first instance. information about the study will either be made available by emailing them the information sheet and contacting them later by telephone, or the information sheet will be read to them over the telephone. the telephone conversation(s) and their opinions will be documented in the patient's medical record. as soon as the family is able to attend the hospital, they will be asked to sign the statement. if the family are not able to sign a statement during the patient's time in the icu, they have the option of printing out the statement, signing it, and mailing, emailing or faxing it back. the sample study information and consent forms can be seen in additional file . if the participant's family, relative or friend does not agree to their continued participation, they will be withdrawn from the study and we will seek agreement from them to use information related to mechanical ventilation that was collected up until that point. if a participant chooses to withdraw from the trial, we also will seek agreement to use information related to mechanical ventilation that was collected up until that point. if they do not agree, then all study information obtained will be destroyed. participants will be block-randomised, with block sizes generated using a randomisation programme. the programme will randomly assign patients into either a control group or intervention group through a random block size (the block size is , , or patients). eligible and consented patients will be block-randomised in a ratio of : . no effort will be made to stratify the subgroups considered in the secondary analyses. by the nature of the intervention, cure cannot be double-blinded. un-blinding is not applicable due to the nature and setting of the intervention. all patient data collected are de-identified using a single patient numbering system. patients are assigned to a study number to ensure no bias in the results. this system will be a simple incrementing scheme, such that patients randomised into the cure trial are identified as study- , study- , etc. the v t is adjusted to - ml/kg per ideal body weight (ibw), and the maximum minute ventilation (v emax ) to ≤ . l/kg/min. the ibw is measured using the patient's height and look-up table at the bedside or is calculated using the formulae: women the dp is the plateau pressure (p plat ) minus the peep. in patients with very severe ards the adjustment of v t to - ml/kg ibw may be injurious if the dp is higher than cmh o. a dp ≤ cmh o was associated with better patient survival when assessed using a multilevel mediation analysis of patients in nine rcts of ards [ ] . therefore, the dp will be limited to ≤ cmh o at all times. in addition, during spontaneous ventilation, pressure support will be limited to ≤ the ventilation rate is set between and breaths per minute. the aim is to keep the plateau pressure p plat ≤ cmh o. if necessary, v t may be reduced to as low as ml/kg and the respiratory rate (rr) kept at ≤ breaths per minute. co will frequently rise in severe lung injury (permissive hypercapnia) when patients are mechanically ventilated within these guidelines. however, if co is ≥ mmhg or increased by ≥ % in the previous h, the intensive care specialist on duty will be notified, and they may choose to deviate from these guidelines. all patients enrolled are to be ventilated using a pressurecontrolled mode, for example, the bi-level ventilation mode on the puritan bennett pb ventilator (covidien, boulder, co, usa) or pc-simv+ on the dräger evita® in-finity® v . patients will be ventilated using bi-level/pc-simv+ mode, which allows unrestricted spontaneous breathing efforts to lessen ventilator dyssynchrony. however, during any recruitment manoeuvre procedures, synchronized intermittent mandatory ventilation (simv) with pressure-controlled (pc) ventilation is used and returned to original mode afterwards. should patients already be ventilated using a ventilator incompatible with the cure computer system, they will have their ventilator changed to a compatible ventilator for the trial. patients will be transitioned to assisted spontaneous breathing (asb) if they meet the weaning criteria (see "weaning"). in severe ventilator dyssynchrony, a very high respiratory drive may result in sub-atmospheric circuit pressures and risk of aspiration of gastric contents around the endotracheal cuff. if a participant has a high respiratory drive on bi-level/pc-simv+ ventilation, producing a fall in airway pressure during inspiration, muscle relaxants will be considered to facilitate controlled breathing. however, if the clinician feels the participant may benefit from breathing spontaneously, transition to asb may be made if they substantially meet the weaning criteria (see "weaning"). however, spontaneous breathing efforts may mask high trans-pleural pressures and produce high levels of regional lung strain. oesophageal pressure will not be measured during this trial. if the treating clinician is concerned about patient self-inflicted lung injury (p-sili) [ , ] , they will consider using muscle relaxants to control ventilation. patients will not undergo any procedures using a cough-assist machine prior to weaning and transitioning to spontaneous breathing. however, the treating clinician may use a cough-assist machine to aid secretion removal (during spontaneous breathing) if they believe it is in the patient's best interests. finally, in any circumstances where the patient is planned to be temporarily disconnected from the ventilator, their endotracheal tube will be clamped to prevent de-recruitment. to ensure a fair comparison, all cure study participants will have inspired oxygen levels titrated to achieve the following pulse oximetry saturations: i. spo = - % if fio is less than % ii. spo = - % if fio is greater than or equal to % the aim is to spend greater than or equal to % of time in the target range. the fio should only be increased above % if these targets are not met, using % increments starting with a fio = %. there is natural variability in spo . to avoid toggling between two fio levels, min of settling time will be allowed before changing the fio . the best fio is chosen to keep the saturation within the specified targets ranges over % of the time. patients are kept at °head up whenever possible. this position maximises recruitment of the lung and may reduce the risk of aspiration. wherever possible, patients should be rolled from supine to right-side down, back to supine, then to left-side down. this turning of patients is ideally performed every h. transient hypoxaemia frequently occurs after a patient has been turned and may be worse if there is inadequate peep. hypoxaemia may also become more severe if participants are rolled from left-side down to right-side down due to cyclical de-recruitment of the non-dependent lung and re-recruitment of the dependent lung. this cyclical de-recruitment of the lung has the potential to contribute to vili. thus, patients with severe lung injury may be very intolerant of being turned. in some instances, the lungs may need to be re-recruited. if desaturation does occur, this will be recorded as a serious adverse event (sae). prone positioning of patients may be considered if the p/f ratio is ≤ and fio ≥ %. patients randomised to the intervention arm (mbv) may still undergo a protocolised recruitment manoeuvre. for patients in the standard practice ventilation arm (spv) a staircase recruitment manoeuvre is left to clinical judgement. the primary outcome of this trial is the auc of the p/f ratio. for this reason, mandatory daily abg recordings are performed for up to days after enrolment. abgs are taken around hours and hours. the abgs are also acquired within min of any recruitment manoeuvre procedure and - min after the recruitment manoeuvre procedure. the added abgs from rm procedures will be used in secondary analysis, but will be omitted during primary analysis to ensure the same number of data points per day for all patients. patients randomised to the model-based ventilation (mbv) cohort will remain in the protocol up to days. thereafter, they will receive the same care as participants assigned to standard practice ventilation (spv). however, if participants have been extubated, but then require intubation and re-ventilation at any time within days of enrolment, they will return to the original assigned protocol (mbv or spv). all patients will receive standard care beyond days of enrolment, and their data, including abg recordings, will continue to be collected for up to days. this intervention schedule is shown in fig. . procedures for the control group (spv) the procedures are as follows: . peep is selected as per standard practice. . the decision to carry out a staircase recruitment manoeuvre will be based on clinical judgement. the protocol for performing the staircase recruitment manoeuvre is explained in "recruitment manoeuvres (rm)". . abgs will be taken twice daily. . ventilator data are collected continuously until the ventilator is disconnected. the procedures are as follows: . for patients included in the mbv (intervention) group, the peep and mv will be guided by clinicians using bedside computers, while maintaining v t and fio . iii. when they have a new neurological condition. iv. they are awake and breathing normally without evidence of respiratory distress, and where sedation (with or without paralysis) is not considered to be in their best interests. . abgs will be recorded twice daily and before and after any recruitment procedure. . data will be collected continuously until the patient is disconnected from the ventilator. patients enrolled in this study will undergo rms. the rms are only carried out by senior medical staff or senior trainees familiar with this technique. rm max and pumps are for participants randomised to the mbv protocol arm only. patients assigned to the spv arm may undergo a staircase rm (srm) at the discretion of the treating clinician according to standard practice. (see "standard practice staircase recruitment manoeuvre"). all rms will be performed in simv pressure controlled (pc) ventilation mode. the peak inspiratory pressure (pi) is set to achieve a v t of - ml/kg ibw. preferably, v t should result in dp ≤ cmh o above peep. before and after each rm, abgs (ph, paco , pao , hco ), spo , end-tidal co partial pressure (etco ), fio , peep, rr), and v t will be recorded. in addition, during the rm max (model-based ventilation arm) or (standard practice ventilation (srm) arm, at each peep increment, heart rate, rhythm, mean arterial pressure (map), spo , fio , v t , rr, etco and rates of use of vasoactive drugs will be recorded. this data will be valuable in assessing the safety of the rm max , pump and srm. in many cases, where the lung stiffness, or respiratory elastance (e) is high, it will not be possible to deliver a v t of ml/kg ibw. furthermore, during the rm, the delivered v t may fall further as the elastance increases. as a result, it may be necessary to increase the respiratory rate to accommodate the reduction in minute ventilation. for example, if e is > cmh o/l (or compliance < ml/cmh o) in a patient weighing kg (ibw), (normal range - cmh o/l), the v t will be < ml/kg (< ml) when the driving pressure is cmh o. it is important that oxygenation targets in both arms are carefully followed to ensure a fair comparison between them. the spo will be kept in the target range prior to any rm. this approach allows small decreases in oxygenation to be detected during the decremental peep phase of the recruitment manoeuvre, while also providing a sufficient buffer in the event of significant de-saturation due to ventilation perfusion (v/q) mismatch. v/q mismatch increases with higher airway pressures when pulmonary arterial blood is shunted away from the pulmonary capillaries by-passing aerated regions of the lung. before performing any rm, the following criteria are considered. any rm must be delayed until these conditions are corrected in the consideration of the following at-risk patient conditions: . haemodynamic instability (e.g. ongoing haemorrhage). . not optimally resuscitated with fluids (e.g. stable blood pressure, but pulse pressure variation ≥ % because of inadequate left ventricular preload)? this is only applicable in the absence of spontaneous breathing. . evidence of barotrauma since enrolment? a. if there is new barotrauma, rms must not be attempted and the participant will be withdrawn from trial. they will continue to be observed and followed up. a sae will be reported. once the rm checklist conditions are met, the patient can be prepared for a rm by ensuring: rms should be terminated if at any time during the rm any of the following changes persist for more than min: . desaturation, with spo < %. . new bradycardia (heart rate < beats per minute) or, . new tachycardia (heart > beats per minute) or, . new arrhythmia leading to new bradycardia ( ) or new tachycardia ( ) or, . new hypotension (reduction in map by % or map < mmhg). this rm termination criteria applies to all rm procedures in both arms. the rm max is a computer-guided staircase rm procedure in the mbv intervention arm. this method is designed to safely increase the inspiratory pressure to a maximum airway pressure of - cmh o, with dp limited to cmh o, and maximum peep limited to - cmh o. the rm max is guided by the cure software using a validated model-based method, which estimates elastance to determine the optimal peep [ , ] . the rm max is carried out by intensive care specialists or senior trainees familiar with this technique. this procedure is only carried out during working hours ( - hours), but preferably within - h of enrolment. however, for patients enrolled overnight, unless there are compelling reasons to carry out an rm max , this procedure may be delayed till the following morning ( hours). contra-indicated preconditions to an rm max are excluded using the rm checklist. if it is safe to proceed, the patient is prepared for the rm max . the following instructions are given to the clinician: the rm max may be repeated only when the following conditions are met: . if there is a significant change in the participant's condition, e.g. new severe hypoxaemia (spo < % and fio ≥ %; p/f~ ) and . patient conditions for which lung recruitment is contraindicated are excluded (e.g. endobronchial intubation, mucous plugging, pneumothorax etc) and . analgesia and sedation and patient position have been optimised (consider small changes to respiratory rate, v t and pressure support, or a rocuronium infusion) and . the pump fails to improve oxygenation pump: peep adjustment and monitoring procedure pump is a regular mini-recruitment manoeuvre procedure designed to adjust peep based on patient-specific changes in condition. this mini-rm is also guided by cure software and moves between ± cmh o from the current peep. pump should be performed twice daily during normal working hours ( - hours) or at any other time if lung de-recruitment is considered to be the likely cause of new desaturation. the pi will be left the same as in the current ventilator settings. to ensure a pump can be safely carried out, the rm checklist and preparation steps are to be followed. if the checklist preconditions are met, the pump may be carried out. the following instructions are given to the clinician: . titrate sedation so the patient is not verbally responsive and has loss of their eyelash reflex. use fentanyl or morphine increments with propofol to provide a "balanced" deeper sedation level. give rocuronium . if the oxygenation does not improve with the aforementioned interventions, then peep may be increased in increments of cmh o. if the peep is ≥ cmh o and fio is ≥ %, (p/f~ ) in spite of addressing the aforementioned points, a staircase recruitment manoeuvre (srm) may be considered if the clinician feels this is in the best interests of the patient. the srm procedure does not utilise the cure software to perform recruitment and therefore the software will not guide the user, nor make any peep suggestions. the software will still record airway pressure and flow through this procedure. to ensure a srm, can be safely carried out, the rm checklist and preparation steps are to be followed. if the checklist preconditions are met, the srm may be carried out (note, the srm procedure does not utilise cure software to perform recruitment). the following instructions are given to the clinician: . titrate sedation so the patient is not verbally responsive and has loss of their eyelash reflex. use fentanyl or morphine increments with propofol to provide a "balanced" deeper sedation level. ventilator dyssynchrony occurs when a patient's spontaneous respiratory efforts are not synchronised with the ventilator. this commonly causes agitation and respiratory distress; often described as "fighting the ventilator". dyssynchrony should be considered in patients with increased respiratory efforts, unexplained agitation, tachycardia, or sweating. ventilator wave forms can be used to identify dyssynchrony. in participants assigned to mbv, dyssynchrony will often cause large spikes in the elastance recordings. the cure soft algorithm does not account for patient breathing efforts and "sees" inspiratory effort as a rapid reduction in lung elastance [ , ] . in contrast, coughing, breath-holding, and other dyssynchronous efforts may cause an apparent increase in elastance [ ] . figure shows an example of ventilator dyssynchrony in a pressure-controlled mode. dyssynchrony may be seen as negative deflections ("m" waves) in the flow-time waveform, as shown in fig. . in contrast the airway pressure may only be changed minimally by patient effort. it is important to exclude reversible mechanical causes that might lead to patient distress and ventilator dyssynchrony. endobronchial intubation, obstruction of a major bronchus or pneumothorax should be excluded. usually ventilator dyssynchrony can be managed by increasing sedation. however, in many cases it may be preferable to use intermittent muscle relaxants to fully control ventilation. it also may be helpful to trial the patient on assisted spontaneous breathing (asb) to improve ventilation synchrony, if peep is ≤ cmh o and the fio is ≤ %. however, caution should be exercised, lest the patient become exhausted (see "weaning"). these guidelines are a pragmatic and consistent way to transition patients to asb. weaning is challenging and difficult to protocolise because there are many different factors to consider. for this reason, the weaning process is typically determined by clinical judgement. however, the guidelines presented here are set to ensure consistency of care. asb is considered when the participant's condition is improving. they should preferably be afebrile, have resolution of the underlying processes that led to their icu admission and improving gas exchange. they should have improving muscle strength, decreasing sedation requirements with an improving glasgow coma score (gcs) and richmond agitation sedation score (rass) between − and + . generally, the fio should be ≤ % and peep ≤ cmh o. if the following are substantially present, then participants may be transitioned to asb: . improving condition . minute ventilation acceptable (ve) ≤ . l/kg . fio ≤ % . spo - % . ph ≥ . . heart rate ≤ beats/min . low vasoactive drug requirements (noradrenaline + adrenaline ≤ mcg/min) the following instructions or recommendations are used to guide transition to asb: the following observations should be made: oxygenation, re-sedate and revert back to the previous controlled ventilation mode (bi-level or pc-simv+ or equivalent); e. if the oxygenation has not improved after h on controlled ventilation, or there is an unanticipated new problem causing deterioration, the participant should return to their previously assigned ventilation arm (mbv or spv), e.g.: iv. new lung injury/de-recruitment/aspiration/ sepsis. v. haemodynamic instability. vi. need to return to the operating room or to undergo invasive procedure. . if there is continual improvement, proceed towards separation from mechanical ventilation (extubation or continuous positive airway pressure (cpap) via a tracheostomy). a simplified flow chart of the patient enrolment process can be found in additional file . all study data, including ventilation data, patient and family/friend consent, sae reports and other documentation will be stored in a repository. consolidated standards of reporting trials (consort) figure shows the consort diagram for the cure rct. patients recruited into the cure rct will have the following data collected. patient demographic and history the following data will be collected: . patient gender, height, weight and ethnicity . primary patient diagnosis contributing to ards or impaired lung function . secondary patient diagnosis contributing to ards or impaired lung function . relevant past medical history, e.g. smoking, medication, cardiovascular disease . chest x-ray score derived by the murray index [ ] patient mechanical ventilation data data on patient airway pressure and flow generated from the mechanical ventilator will be recorded using the cure software (cure soft.) provided with the rct. the patient data are backed up regularly to external storage with encryption applied using veracrypt encryption software [ ] . the following information will be collected: or ventilation-free days . amount of sedation -to account for possible data variation resulting from use of different sedatives . duration of icu stay . frequency and duration of renal support therapies . all causes of icu, hospital and -day mortality no person or authority will have access to the participant's blood. the blood samples are not stored. they are discarded and incinerated as soon as practicable, in accordance with nzs : "healthcare waste management". all cure rct data will be stored at the university of canterbury (uc). all paper forms (patient sheets, consent forms, etc.) will be scanned and stored at the uc. all electronic data will be stored in double-encrypted repository and only the participating researchers have access to it. currently there are no plans for sharing the data, but if requested, data may be shared. participants in the study can request their copy of data. the data will be backed up weekly and again, once the participant has finished the trial and left the hospital. this task will only be performed by the participating researchers. any protocol variations will be followed up and noted. the cure rct will store data for years. the trial will utilise a primary composite end point incorporating the auc of the p/f ratio over the period of mv. every participant in the intervention (mbv) group is compared with every participant in the control (spv) group. test statistics will be calculated using the onesided wilcoxon rank sum test at alpha of . . if results show no statistically significant difference between the intervention and control, it will result in the rejection of the intervention treatment as a standard of care and thus, the secondary clinical outcome assessments will include the number of desaturation events measured as peripheral capillary oxygen saturation < %, lomv, vfd for days, the quality of mechanical ventilation care measured as the auc of spo /fio and chest x-ray index scores over time. the test statistic will be calculated using the one-sided wilcoxon rank sum test at alpha of . . a difference in the primary outcome will show the impact of mbv compared to spv. no difference would show that enhanced, model-based metrics of the patient-specific condition have no effect on patient-centred or clinical outcomes. either outcome will yield clinical guidance. a monte-carlo simulation was performed to determine the sample size and determined that a minimum effective sample size of approximately patients per arm is required to identify a % reduction in median lomv, with . power, at a double-sided significance level of % [ ] . a linear alpha spending approach will be used for early termination of the trial for safety. linear alpha spending falls between a pocok and o'brien-fleming boundary [ ] . with analysis points of , , , and patients per arm, and assumed control group mortality of . , the mortality difference required to stop the trial (mortality intervention -mortality control ) at each analysis point respectively is . , . , . , . and . . this approach has cumulative α = . . ethics approval has been filed with the new zealand national health and disability ethics committee. the cure rct clinical protocol and data usage has been filed with the new zealand south regional ethics committee (reference number /sth/ ). the cure trial is also registered in the australian new zealand clinical trial registry (actrn ). all results and any subsequent analysis will be published and only the participating investigators will be authors. currently there is no plan to share data with other organisations. the data collected in this study will also be used for future research. adverse event (ae) and sae reporting (aes are defined as any unexpected change in physiology in a study participant associated with either the rm max or pump. this does not necessarily have to have a causal relationship with the aforementioned procedures. typically, this would be an unexpected, non-life-threatening event, which rapidly resolves following simple corrective measures. for example, hypotension will occur in most participants undergoing an rmmax or pump. however, if the procedure had to be shortened or abandoned, but the participant recovered with simple corrective measures (e.g. temporarily increasing noradrenaline by ≥ mcg/min) or giving > ml fluid bolus) this would be recorded as an ae. it is very important these events are accurately recorded as risk factors for aes that need to be defined when carrying out rms (as seen in additional file ). saes are defined as any untoward medical occurrence that ( ) results in death; ( ) is life-threatening; ( ) prolongs hospitalisation or ( ) results in disability or incapability. however, baseline mortality in the patients in intensive care who are enrolled in the trial will likely be high due to the critical illness necessitating admission to the icu. despite attempts at prevention, trial participants will frequently develop lifethreatening organ failure(s) unrelated to study interventions. events that are a part of the natural history of the primary disease process or expected complications of critical illness will not be reported as saes in this trial. additionally, events already defined and reported as study outcomes, such as mortality or readmission to the icu, will not be labelled and reported separately as saes unless they are considered to be causally related to the study intervention or are otherwise of concern in the investigator's judgement. saes will be reported to the principal investigator within h of any investigator becoming aware of the event. the minimum information to report includes: the nature of the event the time the event commenced and ceased an investigator's opinion of the relationship between study involvement and the event (not related, unlikely, possibly, probably or definitely related) whether treatment was required for the event and what treatment was administered saes could include pneumothorax, hypotension leading to cardiac arrest, transient desaturation leading to severe or prolonged desaturation, tachycardia, bradycardia, arrhythmia, anaphylaxis and unintended protocol deviations. in the unlikely event of a physical injury to the participant as a result of their participation in this study, they will be eligible to apply for compensation from the accident compensation corporation (acc) nz within its limitations. if the participant's family/friend have any questions about the acc, they will be able to ask the researchers for more information before they agree to take part in this trial. acc cover is not automatic and their case will need to be assessed by the acc according to the provisions of the injury prevention rehabilitation and compensation act. if the claim is accepted by the acc, the patient still might not receive compensation. this depends on a number of factors such as whether they are earners or non-earners. the acc usually provides only partial reimbursement of costs and expenses and there may be no lump sum compensation payable. there is no cover for mental injury unless it is a result of physical injury. if your relative or friend has acc cover, generally this will affect their right to sue the investigators. an independent dmc comprising experts in clinical trials, biostatistics and intensive care medicine is established before patient enrolment, to review all trial protocols and oversee and advise on this trial. the dmc will be forwarded a copy of all sae reports as soon as they become available to the trial investigators. the dmc will review all sae reports that they receive and report back to investigators if any further action is required. the steering committee of the cure rct comprises the primary investigators geoff shaw, geoff chase, chris pretty and yeong shiong chiew. the clinical data are collected by research nurses in the icu and mechanical ventilation data and oxygenation (bedside monitor) data will be collected by researchers from the uc. all study data will be stored in the double-encrypted repository at uc. data will be interpreted by participating researchers. the open and closed case interim reports will be compiled by paul docherty every months and when and patients have been included. the dmc will have authority to continue or stop of the trial based on the interim reports. mechanical ventilation using peep set at minimum elastance has long been investigated in both experimental and clinical trials. these studies ranged from healthy patients under general anaesthesia to those with ards. however, only a few studies have investigated the clinical potential of peep set at minimum elastance. recent studies by pintado et al. [ ] and chiew et al. [ ] have shown the potential and feasibility of ventilating patients using minimum elastance peep. however, setting peep based on elastance is problematic due to the increased need of muscle relaxants, protocol burden and potential contradictory findings [ , ] . the pilot trial was also underpowered and thus, a larger clinical trial such as the cure rct is required to provide further insight and validate the potential benefit of optimising mechanical ventilation peep with model-based methods. the cure rct implements a protocolised staircase peep recruitment manoeuvre together with novel computer software to calculate respiratory system elastance in real time. the computer software, cure soft [ ] , uses a single compartment lung model [ ] together with other model-based approach [ , ] to aid clinicians during peep selection. this process potentially reduces selected peep variability and provides more consistent clinical guidance. there are several limitations of the cure rct design that should be noted. in particular, the rm is a doublestaircase manoeuvre and is design specific. studies have shown that not all patients benefit from rms [ , ] , and the benefit of an rm is dependent on the patientspecific disease state, as well as the design of the rm. the double-staircase rm in this trial was designed to assess lung recruitment and provide consistent peep titration. it is noted that not all patients included in this study will necessarily demonstrate alveolar lung recruitment. another limitation worth noting is the control group clinical protocol. clinically, there is relatively little consensus an optimal mechanical ventilation mode. thus, the standard practice ventilation in the participating hospital relies on general approaches [ ] and is highly variable between clinicians. there may be no equal comparator for a mechanical ventilation study resulting from this variability. patients recruited to the cure rct will have the mv mode set to bi-level ventilation in both the intervention and the control group; it is debatable that bi-level ventilation may lack certain ventilation advantages. however, this procedure will reduce variability and provides the opportunity for fair comparison between groups. in the participating icu, there are > patients per year requiring invasive mv; however, only an average of < patients were diagnosed with ards as the primary diagnosis per year. ards is nearly always regarded as a complication of an acute process. one concern is that the desired sample size cannot be achieved. however, this number is also too small compared to reports [ , ] . the small number may be due to changes in the ards definition [ , ] and misdiagnosis [ ] . estenssoro et al. [ ] report that misdiagnosis could occur due to delayed screening. thus, in the cure rct, any patient requiring invasive mechanical ventilation is screened immediately, as per villar et al. [ ] , whereby the p/f ratio is measured at peep = cmh o, and fio = %. equally, retrospective screening was also performed and identified > patients eligible for the trial per year. hence, a -year study is planned to achieve the target sample size at an estimated recruitment rate of %. optimising patient-specific mechanical ventilator settings remains a huge clinical challenge due to patient disease variability, as well as clinical practice variability. thus, there is a need for a method to provide consistent patient-specific treatment. the cure rct is the first single-centre large clinical rct using model-based minimum elastance peep selection in mechanical ventilation. it provides a means to select patient-specific peep in a consistent fashion and patient outcomes are compared to current practice. the cure rct investigation group hope that the results from this trial will support the use of model-based methods to estimate optimal peep, and will serve as a platform to assess other patient-centred outcomes in future mechanical ventilation studies in ards/ali. analysis. td, bb, as and km provided advice on the study protocol. all authors read and approved the final manuscript. this research is funded by the new zealand health research council (hrc) (hrc reference / ) under project pulmods: pulmonary model-based decision support to optimise ards/ali care. hrc does not have any role in this study and future analysis. they were not part of study design and will not be part of any management or analysis of the trial. currently there are no plans to share any of the data. the cure rct clinical protocol and data usage has been granted by the new zealand south regional ethics committee (reference number /sth/ ). the cure rct is registered in the australian new zealand clinical trial registry (actrn ). the trial was registered on september (https://www.anzctr.org.au/trial/registration/trialreview.aspx?id= &isreview=true). the cure rct will recruit patients once family consent is obtained. however, if the treating clinician firmly believes a recruitment manoeuvre is in the best interests of the patient, and no family is available for consent, the participant will be enrolled and randomised and the appropriate protocolised recruitment manoeuvre will follow. in this case, delayed consent is obtained as early as possible. once the participant recovers from their condition and is discharged from the icu, we will seek their informed consent. not applicable. mechanical ventilation in ards: a state-of-the-art review ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial positive end-expiratory pressure setting in adults with acute lung injury high levels of peep may improve survival in acute respiratory distress syndrome: a meta-analysis higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome positive end-expiratory pressure the preventive role of higher peep in treating severely hypoxemic ards combined effects of ventilation mode and positive end-expiratory pressure on mechanics, gas exchange and the epithelium in mice with acute lung injury reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome how large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography computed tomography assessment of positive end-expiratory pressure-induced alveolar recruitment in patients with acute respiratory distress syndrome ventilation and weaning practices in australia and new zealand positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study comparison of functional residual capacity and static compliance of the respiratory system during a positive end-expiratory pressure (peep) ramp procedure in an experimental model of acute respiratory distress syndrome optimum end-expiratory airway pressure in patients with acute pulmonary failure individualized peep setting in subjects with ards: a randomized controlled pilot study feasibility of titrating peep to minimum elastance for mechanically ventilated patients model-based peep optimisation in mechanical ventilation the clinical utilisation of respiratory elastance software (cure soft): a bedside software for real-time respiratory mechanics monitoring and mechanical ventilation management the ards definition task force, definition tb a universal definition of ards: the pao /fio ratio under a standard ventilatory setting-a prospective, multicenter validation study driving pressure and survival in the acute respiratory distress syndrome mechanical ventilation to minimize progression of lung injury in acute respiratory failure ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: yes a minimal algorithm for a minimal recruitment model-model estimation of alveoli opening pressure of an acute respiratory distress syndrome (ards) lung patient-ventilator asynchrony during assisted mechanical ventilation patient-ventilator asynchronies: may the respiratory mechanics play a role? observational study of patientventilator asynchrony and relationship to sedation level ☆ an expanded definition of the adult respiratory distress syndrome effective sample size estimation for a mechanical ventilation trial through monte-carlo simulation: length of mechanical ventilation and ventilator free days designs for group sequential tests lung mechanics at the bedside: make it simple time-varying respiratory system elastance: a physiological model for patients who are spontaneously breathing recruitment maneuvers for acute lung injury new and conventional strategies for lung recruitment in acute respiratory distress syndrome the australian and new zealand intensive care society clinical trials group. incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three australian states incidence and outcomes of acute lung injury report of the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes and clinical trial coordination impact of positive end-expiratory pressure on the definition of acute respiratory distress syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors wish to thank the christchurch hospital intensive care medical, nursing and technical staff for the support of this clinical trial. the authors declare that they have no competing interests. the trial has not started recruiting yet. the trial is estimated to start in december in christchurch hospital intensive care unit. the trial is estimated to be completed by may . this is protocol version number . , dated august . supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . screening process diagram. key: cord- - t pd authors: grimaldi, d.; aissaoui, n.; blonz, g.; carbutti, g.; courcelle, r.; gaudry, s.; d'hondt, a.; higny, j.; horlait, g.; hraiech, s.; lefebvre, l.; lejeune, f.; ly, a.; piagnerelli, m.; sauneuf, b.; serck, n.; soumagne, t.; szychowiak, p.; textoris, j.; vandenbunder, b.; vinsonneau, c.; lascarrou, j. b. title: characteristics and outcomes of acute respiratory distress syndrome related to covid- in belgian and french intensive care units according to antiviral strategies. the covadis multicenter observational study. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: t pd background limited data are available for antiviral therapy efficacy especially for the most severe patients under mechanical ventilation suffering from covid- related acute respiratory distress syndrome (ards). methods observational multicenter cohort of patients with moderate to severe covid- ards, comparing antiviral strategies (none, hydroxychloroquine (hcq), lopinavir/ritonavir (l/r), others (combination or remdesivir). the primary end-point was the day- ventilator free days (vfd), patients which died before d were considered as having vfd. the variable was dichotomized in patients still ventilated or dead at day vs patients being extubated and alive at day (vfd = or > ). results we analyzed patients ( with standard of care (soc), treated with l/r, with hcq, and others). the median number of d -vfd was (iqr - ) and was different across the different groups (p= . ), the soc patients having the highest d -vfd. a multivariate logistic regression including antiviral strategies, showed that age (or . ci %: . - . ), male gender (or . ci %: . - . ), charlson score (or . ci %: . - . ) and plateau pressure (or . ci %: . - . ) were associated with having d -vfd whereas p/f ratio (or . ci %: . - . ) was associated with having > or = d -vfd (ie. being extubated and alive). acute kidney injury (aki) was frequent ( %), its incidence was different across the patients groups (p= . ). in a post-hoc logistic multivariate regression apart from demographics characteristics and comorbidities, the use of l/r (administered to of patients) was associated with occurrence of aki (or . ci %: . - . ) and need for renal replacement therapy (rrt). conclusion in this observational study of moderate to severe covid- ards patients, we did not observed a benefit of treating patients with any specific antiviral treatment. we observed an association between l/r treatment and occurrence of aki and need for rrt. jbl and dg should be considered as co-corresponding authors for france and belgium respectively. limited data are available for antiviral therapy efficacy especially for the most severe patients under mechanical ventilation suffering from covid- related acute respiratory distress syndrome (ards). observational multicenter cohort of patients with moderate to severe covid- ards, comparing antiviral strategies (none, hydroxychloroquine (hcq), lopinavir/ritonavir (l/r), others (combination or remdesivir). the primary end-point was the day- ventilator free days (vfd), patients which died before d were considered as having vfd. the variable was dichotomized in patients still ventilated or dead at day vs patients being extubated and alive at day (vfd = or > ). we analyzed patients ( with standard of care (soc), treated with l/r, with hcq, and others). the median number of d -vfd was (iqr - ) and was different across the different groups (p= . ), the in this observational study of moderate to severe covid- ards patients, we did not observed a benefit of treating patients with any specific antiviral treatment. we observed an association between l/r treatment and occurrence of aki and need for rrt. any specific covid- antiviral treatment is associated with higher ventilator free days at day as compared to no antiviral treatment for patient in icu under invasive mechanical ventilation. lopinavir/ritonavir is associated with an increased risk of acute kidney injury. [ ] . the respiratory disease appears to be a very homogenous entity [ ] . it mainly affects people older than years, predominantly men with cardiovascular comorbidities [ ] . it is characterized by severe hypoxemia, radiological ground glass opacities and especially crazy paving. its evolution is prolonged with an aggravation phase - days after symptoms onset [ ] leading to death between % for patients in the ward [ ] to % of patients in the icu [ ] . although many unknowns persist, such a great homogeneity of presentation was previously unseen in acute pathologies leading to intensive care unit (icu). despite expert recommendations that were implemented quickly [ ] , management was not based on high levels of evidence during the west-european first wave (march-april ). the treatments applied vary from one country to another, from one center to another and even from one patient to another. a desperate search for efficient antiviral treatment has been ongoing since the epidemic started. first candidates were already-developed molecules that demonstrated in vitro effect, mainly remdesivir [ ] , lopinavir/ritonavir [ ] and hydroxychloroquine [ ] . the last two are already on the market with an acceptable safety profile; however, they have not been used widely in critically ill patients so that potential previously unknown side effects may exist. even some randomized clinical trials are now available such as for remdesivir [ ] , or for lopinavir/ritonavir alone [ ] or in association [ ] , only a small proportion of patients included were under mechanical ventilation not allowing efficacy and safety analysis for patients sicker than in conventional ward. the main objective of this study was to set up an observational study of patients suffering from moderate to severe covid- related ards, by collecting the strategies used in belgian and french icus, in order to be able to detect a possible signal of efficacy or deleterious effects of used therapies. we reported here the data regarding the antiviral strategies. this study was compliant with strobe guidelines [ ] . the covadis project is observational and regroups icus in france (n= ) and belgium (n= ). inclusion criteria were: -age older than years, -moderate to severe ards according to berlin definition [ ] (pao /fio ratio < mmhg with a peep of at least mmhg receiving invasive ventilation), -positive sars-cov- reverse transcriptase polymerase chain reaction (pcr) regardless of site sampled (patient with negative pcr but chest ct scan with abnormalities such as crazy paving were not included). non-inclusion criteria were: -cardiac arrest before intensive care unit admission, -extra corporeal mobile oxygenation (ecmo) requirement within first hrs of icu length, -chronic obstructive pulmonary disease with gold class or [ ] , or home oxygen. for this observational multicenter study, all consecutive covid- patients were screened in the participating centers. patients fulfilling inclusion and non-inclusion criteria were included in participating icus between march , and april , . each local investigator filled an ecrf to collect data (castor edc, amsterdam, the netherlands). we recorded demographics data, known medical history and co-morbidities using the charlson score [ ] , with the addition of history of chronic hypertension. we collected data on management interventions delivered during hospitalization including settings of mv after intubation, duration of mv, administration of advanced therapies for acute respiratory failure (neuromuscular blocking agents, inhaled pulmonary vasodilators, prone-positioning, and extracorporeal membrane oxygenation), anti-viral treatment and immunomodulatory agents (interleukin- -receptor antagonists and corticosteroids) with time from onset of symptoms to initiation and occurrence of acute kidney injury (aki), acute cardiac injury (defined as a rise in troponin level over times the normal threshold or the needs for inotrope), pulmonary embolism and deep venous thrombosis. considering the absence of efficacy or safety data on antiviral treatments in the area of critically ill patients requiring invasive mechanical ventilation, we decided to choose a composite outcome which included death and length of mechanical ventilation: number of ventilator free days (vfd) at day [ ] . vfd at day was determined as follow: -vfds = if subject dies within days of mechanical ventilation, -vfds = − x if successfully liberated from ventilation x days after initiation, -vfds = if the subject is mechanically ventilated for > days. the variable was dichotomized in patients still ventilated or dead at day vs patients being extubated and alive at day (vfd = or > ). -aki defined by a rise in serum creatinine of at least % as defined in kdigo stage [ ] , and classified as none, present without need for renal replacement therapy (rrt), present with need for rrt, -deep venous thrombosis, and pulmonary embolism. as many candidate for specific antiviral treatment are currently under evaluation, our variable of interest was use of anti-viral treatment according to one of the pre-specified following category: none (standard of care), lopinavir/ritonavir (abbvie, rungis, france), hydroxychloroquine (sanofi, gentilly, france), and others (more than one anti-viral treatment or remsedivir (gilead, foster city, usa) as it was not commercially available). discrete data were described by their frequency expressed as a percentage together with the % confidence interval. numerical data were described by the mean (with the % confidence interval) and standard deviation. discrete data were compared using a chi-square test or fisher's exact test, as appropriate. continuous normally distributed data were compared by anova and continuous non normal data by kruskal-wallis as appropriate. a pre-planned multivariate analysis was performed to identify factors associated with day vfd. we included in the model variables associated with day vfd in univariate analysis with a p value < . and we forced in the model the type of antiviral strategy. given / the non-normal distribution of day vfd and / the median value at , accordingly to pre-specified rules in the protocol we discriminated the day vfd variables in having at least one day of vfd or not, ie. being extubated and alive at day or not. we performed then a backward conditional logistic regression. homesher-lemeshow test and visual inspection were used to ensure the quality of the regression. a post-hoc multivariate logistic regression on the factors associated with aki was performed following the same rules given results of univariate analysis. we re-run multivariate logistic regression on the factor associated with the need for renal replacement therapy (rrt). to account for centre effect, a factor related to patient's icu was added in all logistic regression and forced in all models. no imputation strategy was used for missing data. p value < . was considered significant. no adjustment was made for multiple comparisons especially for safety outcome [ ] . all analyses were performed using stata (version , statacorp, college station, tx, usa). this study was approved by appropriate regulatory committee in france and in belgium in accordance with national regulation. each patient was informed about the study. in case of incompetency, next of kin was informed. the requirement for written informed consent was waived due to the study design (france) and after ethical committee statement (belgium). according to paucity of data on antiviral treatments efficacy, we planned to include at least patients to allow comparison of each antiviral treatment candidate. this study was not funded by any sources. baseline characteristics (table ) as secondary outcomes (table ) day , and day survival was similar across treatment groups. at day , the distribution of ventilatory modes was similar across treatment groups most of the patients being under controlled mode (table ) . aki, pulmonary embolism, cardiac injury involved respectively %, % and % of the patients. we observed a difference in aki repartition in the different groups (p= . ), whereas the highest creatinine level until day did not differ significantly (p= . ). we compared patients' characteristics according to the occurrence of aki (table ) . age, bmi, cardiovascular comorbidities, complicated diabetes mellitus and previous chronic kidney diseases were more frequent in patients with aki. although, ( %) of the patients that received l/r (either in mono or combination therapy) presented aki, use of l/r was not significantly more frequent in patients who developed aki ( % vs %; p= . ). in a post-hoc logistic multivariate regression we identified age, male as gender, history of chronic hypertension, moderate to severe ckd, peripheral arterial disease and use of lopinavir/ritonavir (or . ci % . - . ) as independent factors associated with aki ( figure ). in addition we observed that lopinavir/ritonavir treatment was more frequent in patients that required rrt during their icu stay ( / , %) as compared with patients without rrt ( / , %; p= . ). post-hoc sensitivity logistic regression on the need for rrt provided similar results (efigure ). center effect was not significantly associated with occurrence of aki nor with need for rrt (p> . ). in this observational study of moderate to severe ards complicating covid- in france and belgium, we did not observe a benefit of treating patients with any of the antiviral molecule under evaluation. however, there was an association between l/r treatment and aki, including the need for rrt. our study is in line with previous findings regarding covid- related ards in other countries [ , ] . patients were mostly overweighed males between and years of age, with mostly mild cardiovascular comorbidities. duration of ventilation was high in our cohort exceeding by far the usual duration in ards patients ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days in the lung-safe cohort [ ] , with day vfd = [ - ]), although day mortality was % in our cohort as compared to the % in moderate to severe ards in the lung-safe cohort. each center managed the ventilator support settings on his own. we observed that in line with ards guidelines [ ] , physicians set tidal volume near ml/kg of ibw, peep at moderate-high level, used largely prone positioning and paralysis. we observed significant differences in peep level, tidal volume and plateau pressure across patients' groups (possibly favored by the limited dispersion of the value), but the clinical significance of these differences are uncertain. hence, although patients were not randomized, we think that the absence of association between any antiviral treatment and positive outcome (neither at day nor at day ) deserves consideration. conversely we observed a higher day vfd in the patients without antiviral treatment that questions treatment safety. this finding was not confirmed in the multivariate analysis, which did not show a significant association between any antiviral strategies and day vfd. duration between antiviral initiation and onset of symptoms was in accordance with previous studies: [ ] [ ] [ ] [ ] [ ] [ ] days in study by cao et al [ ] . while the present study was ongoing, several scientific data emerged on the absence of efficacy of antiviral candidates: for hcq with possible higher rate of cardiac events especially if combined with azithromycin [ , ] , for l/r in a small randomized controlled trial (rct) none dedicated to critically ill patients [ ] . in parallel, results of us trial dedicated to rem did show a potential benefit on time to recovery but only for patients outside icu with a mild disease severity [ ] . as clinical benefit seems improbable for hcq, we believe that only the results of ongoing rcts will determine if rem or l/r have a true effect on outcome, yet we are of the opinion that our data plead to avoid compassionate use of these drugs, following the "first do not harm" rule [ , ] . indeed, regarding potential side effects as secondary outcomes, we observed that patients treated by l/r had a higher frequency of renal failure and need for renal replacement therapy. this effect was confirmed after adjustment for potential cofounders associated with a greater risk of renal failure. several reports in hiv patients indicate that l/r use was associated with an increased risk of chronic kidney disease [ ] and acute tubular injury has been described with ritonavir [ ] . renal disease characterized by a proximal tubulopathy have been reported in covid- [ ] and have been described as a prognostic factor [ ] . we report a high frequency of aki in our cohort, in line with us data, with % of rrt [ ] . we observed in our cohort a strong association between day -mortality and aki although we cannot determine if aki is a marker of a more severe, systemic viral sepsis or a causal determinant of survival but consistent with previous report [ ] . to our best knowledge no study dedicated to patient in the icu analyzed the factors associated with covid- aki. in our cohort, we observed that besides treatment by l/r, age, gender, bmi, renal and cardiovascular comorbidities were independently associated with aki. higher incidence of aki may then be due either to a previous nephron loss and/or to a specific susceptibility of these patients to sars-cov through a greater expression of ace- in podocytes and proximal straight tubule cells [ ] . another possible hypothesis is occurrence of hypovolemia related to l/r associated diarrhea and "dry lung" strategy promoted for patients with severe ards although usual hemodynamic monitoring in participating icus did not support this hypothesis. last, recent report highlights extremely high dosage for patient with covid- receiving l/r as compare to cohort of hivinfected patients. [ ] our study was not designed to favor one of these speculative hypotheses. finally, neither peep nor plateau pressure were associated with aki in opposition with some hypotheses [ ] . finally, we highlight the limitations of our observational study: the patients were not randomized so that we cannot exclude indication bias although collected variables suggest high similarity across treatment strategies. non-measured confusion biases may exist as well. we did not collect severity score but these scores have been done to compare patients with different diseases in the icu, and charlson score, associated with gender and age, have been shown to predict mortality with good accuracy [ ] . we have also some missing data which can impact our results. for reasons of lack of time during covid- crisis, we limited strongly the numbers of collected variables so that we are not able to report important data such as the use of ace inhibitors, or daily ventilator settings. but clinical significance of those factors is also a matter of debate [ ] . lastly, some of these patients have been included in other studies. in moderate to severe ards covid- patients, we did not observe an association between treatment with hydroxychloroquine or lopinavir/ritonavir and ventilatory free days as compared to no antiviral treatment. we observed an association between lopinavir/ritonavir and aki. our data does not support use of these drugs until rcts results dedicated to patients hospitalized in intensive care will be available. this study was approved by appropriate regulatory committee in france (cnil ) and in belgium (ec n°p / ) in accordance with national regulation. each patient was informed about the study. in case of incompetency, next of kin was informed. the requirement for written informed consent was waived. not applicable. the database of the study will be freely accessible online within months after publication upon reasonable request to corresponding author. jt is a part-time employee of biomérieux, an ivd company, and hospices civils de lyon, a university hospital. other authors have no disclosures. authors contributions dg and jbl were responsible for the study concept and design; all authors: acquisition of the data; dg, jbl, na, sg, cv, jt: analysis and interpretation of the data; dg and jbl: drafting of the manuscript; all authors: critical revision of the manuscript for important intellectual content. all authors read and approved the final manuscript. the corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( a novel coronavirus from patients with pneumonia in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan clinical characteristics of coronavirus disease in china risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease risk factors of fatal outcome in hospitalized subjects with coronavirus disease from a nationwide analysis in china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study a trial of lopinavir-ritonavir in adults hospitalized with severe covid- compassionate use of remdesivir for patients with severe covid- hydroxychloroquine in the management of critically ill patients with covid- : the need for an evidence base. the lancet respiratory medicine remdesivir for the treatment of covid- -preliminary report triple combination of interferon beta- b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with covid- : an open-label, randomised, phase trial. the lancet the strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. the lancet acute respiratory distress syndrome: the berlin definition global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gold executive summary a new method of classifying prognostic comorbidity in longitudinal studies: development and validation statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome definition and classification of kidney diseases an introduction to multiplicity issues in clinical trials: the what, why, when and how respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries formal guidelines: management of acute respiratory distress syndrome. ann intensive care association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with covid- in hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid- : a multinational registry analysis. the lancet the harm of "first, do no harm use of tocilizumab for covid- -induced cytokine release syndrome: a cautionary case report cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in hiv-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. the lancet hiv ritonavir-induced acute kidney injury: kidney biopsy findings and review of literature renal histopathological analysis of postmortem findings of patients with covid- in china kidney disease is associated with in-hospital death of patients with covid- impact of early acute kidney injury on management and outcome in patients with acute respiratory distress syndrome: a secondary analysis of a multicenter observational study identification of a potential mechanism of acute kidney injury during the covid- outbreak: a study based on single-cell transcriptome analysis lopinavir pharmacokinetics in covid- patients comparison of charlson comorbidity index with saps and apache scores for prediction of mortality following intensive care cardiovascular disease, drug therapy, and mortality in covid- we thank mariana ismael for castor edc (amsterdam, the netherlands) for technical support to design ecrf.we thank covadis study group investigators: t a b l e : a s s o c i a t e d f a c t o r s w i t h a k i w i t h i n d a y s a f t e r i n t u b a t i o key: cord- -fxo z s authors: ghelichkhani, parisa; esmaeili, maryam title: prone position in management of covid- patients; a commentary date: - - journal: arch acad emerg med doi: nan sha: doc_id: cord_uid: fxo z s sars-cov- virus causes a pneumonia that was identified through fever, dyspnea, and acute respiratory symptoms and named covid- . this disease exacerbates in a number of patients and causes pulmonary edema, multi-organ failure, and acute respiratory distress syndrome (ards). prevalence of ards among covid- patients has been reported to be up to %. among the introduced treatment methods for management of ards patients, prone position can be used as an adjuvant therapy for improving ventilation in these patients. here we reviewed the literature regarding the role of prone position in management of covid- patients. dear editor: in late , a new virus was introduced to the world, which caused covid- . the virus rapidly spread all over the world and led to a high rate of mortality and became a great challenge for the healthcare staff. sars-cov- virus causes a pneumonia that was identified through fever, dyspnea, and acute respiratory symptoms and named covid- . ( ) . this disease exacerbates in a number of patients and causes pulmonary edema, multi-organ failure, and acute respiratory distress syndrome (ards). prevalence of ards among covid- patients has been reported to be up to % ( ) . ards was first introduced in with clinical presentations such as acute hypoxemia, non-cardiac pulmonary edema, decrease in pulmonary compliance, and increase in work of breathing. it was especially seen in patients who had an underlying sepsis, pneumonia, and aspiration or severe trauma and all of these patients were in need of positive pressure ventilation ( ). % of patients who are admitted to the intensive care unit (icu) develop ards ( ) and despite all the treatment advances made, the rate of mortality is still high among these patients and has been reported to be between * corresponding author: maryam esmaeili; school of nursing and midwifery, tehran university of medical sciences, nosrat st., tohid sq.,tehran, iran. email: esmaeiliem@yahoo.com; tel: + , fax: + % and % ( ). among the introduced treatment methods for management of ards patients, prone position can be used as an adjuvant therapy for improving ventilation in these patients. it should be prescribed along with low tidal volume ( cc per kg body weight) and infusion of neuromuscular blockers (cisatracurium for hours). these treatment strategies together, lead to improvement in oxygenation and survival of ards patients ( ). the main mechanisms of prone position in improvement of ards patients' condition are affecting recruitment in dorsal lung regions, increasing end-expiratory lung volume, increasing chest wall elastane, decreasing alveolar shunt, and improving tidal volume ( ) . patients remaining in lengthy prone position sessions leads to decrease in mortality of patients ( ) . however, correct selection of patients and applying the proper treatment protocol for prone positioning are key to its effectiveness. for instance, in a meta-analysis, munshi et al. expressed that prone position can lead to a drop in the rate of mortality among patients with severe ards when applied to patients for least hours a day ( ) . additionally, in another meta-analysis it was revealed that prone position can only reduce mortality due to ards when patients are ventilated with low tidal volume, the treatment is started within the initial hours of initiation of the disease, and patients have severe hypoxia. in other words, prone position can reduce mortality only when prescribed for patients with severe impaired oxygenation, in the initial hours, and for long durations ( ) . recently, in a multi-centered observational study, guÃl'rin et al. showed that only . % of patients with ards have been placed in prone position. even in patients with severe ards, the rate of using this technique was . %. in the mentioned study, main reasons were given for the physicians' reluctance to use this treatment method: -based on the judgment of the physicians in most cases, the hypoxia in severe ards patients is not severe enough to justify using prone position. -most ards patients have hemodynamic instability, which prevents the physicians from deciding to use prone position ( ) . in addition to the effectiveness of this treatment method, caretaking aspects and the side effects of this position on ards patients should also be considered. patients that undergo ventilation with ventilator in prone position face risks such as accidental removal of the tracheal tube, limited access to the venous route, bending or pulling of the catheters and chest tube, pressure wound, bruising around the mouth due to presence of the tracheal tube, edema around the eyes and facial edema, gastroesophageal reflux, hyper-salivation and skin injuries ( ) . in prone position, the patient should face the ventilator and in patients with tracheostomy, a roll of fabric or pillow should be placed under the shoulders to prevent airway obstruction, these patients should receive muscle and nerve relaxant medications and high-dose sedation as infusion, eye pads should be used for closing the patients' eyes to prevent corneal ulcers. considering the condition of these patients and presence of pressure on their stomach, the probability of reflux after gavage is very high, so they must be closely monitored regarding aspiration of gastric contents ( ) . the position of patients placed in prone position should be changed every hours and sides should be switched. at least to individuals should participate to correctly put intubated patients in prone position, which is a serious limitation for keeping the patient in this position for a long time. to solve this problem a tool called vollman has been introduced for facilitation of moving patients placed in this position to prevent pressure wounds and deformity of joints ( ) . overall, it seems that studies on the effectiveness of prone position in ards patients clearly point out that correct patient selection, timely initiation and duration of patient's placement in this position can all affect the effectiveness of this treatment method. available meta-analyses show that prone position can decrease mortality in ards patients when performed in the initial hours of disease manifestation, in patients with severe impaired oxygenation and for a long time ( ) . the minimum suggested duration of prone position is hours a day. all authors met the criteria for gaining authorship based on the recommendations of the international committee of medical journal editors. parisa ghelichkhani: - - - maryam esmaeili: - - - no fund has been received. none. diagnosing syncope in clinical practice. implementation of a simplified diagnostic algorithm in a multicentre prospective trial-the oesil study (osservatorio epidemiologico della sincope nel lazio) epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study acute respiratory distress syndrome use of extreme position changes in acute respiratory failure a comprehensive review of prone position in ards prone positioning in severe acute respiratory distress syndrome prone position for acute respiratory distress syndrome. a systematic review and meta-analysis. annals of the the effects of prone position ventilation in patients with acute respiratory distress syndrome. a systematic review and metaanalysis a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study nursing the ards patient in the prone position: the experience of qualified icu nurses. intensive and critical care nursing prone positioning in patients with acute respiratory distress syndrome: the vollman prone positioner key: cord- -t w pw authors: imai, yumiko; kuba, keiji; penninger, josef m. title: the renin–angiotensin system in acute respiratory distress syndrome date: - - journal: drug discov today dis mech doi: . /j.ddmec. . . sha: doc_id: cord_uid: t w pw angiotensin-converting enzyme (ace ) counterbalances with ace and functions as a negative regulator of the renin–angiotensin system (ras). the importance of ras in acute respiratory distress syndrome (ards) has recently re-emerged owing to the identification of ace as a receptor for the sars-coronavirus. recent studies have demonstrated that ace protects mice from acute lung injury as well as sars-mediated lung injury. we review the role of the ras, in particular ace , in the pathogenesis of ards. angiotensin-converting enzyme (ace) and ace share homology in their catalytic domain and provide different key functions in the renin-angiotensin system (ras). ace cleaves angiotensin i (ang i) to generate angiotensin ii (ang ii) [ , ] , whereas ace reduces angiotensin ii levels [ , ] and is a negative regulator of the system. the importance of the ras in acute respiratory distress syndrome (ards) has recently re-emerged owing to the identification of ace as a receptor for the severe acute respiratory syndrome-coronavirus (sars-cov) [ ] . in , sars spread throughout the world causing more than deaths due to ards [ ] . our studies demonstrated that ace protects mice from acute lung injury [ ] as well as sars-mediated lung injury [ ] . in this article, we review the role of the ras, in particular ace , in the pathogenesis of ards. the possible applications of modulating the ras for the treatment of ards are also discussed. ards is the most severe form of acute lung injury. multiple predisposing factors for ards have been reported and include sepsis, acid aspiration, trauma or infections with viral pathogens such as sars-cov. moreover, very recently h n avian influenza virus has caused high lethality due to ards [ ] . despite recent progress, the mortality associated with ards remains very high, and there is no pharmacological therapy that has been shown in large-scale trials to impact mortality in ards [ ] . factors predicting the onset or severity of ards are poorly understood, but the low incidence of ards in the relatively large group of patients at risk has been shown. also, there are large differences in plasma ace concentrations between individuals but such concentrations tend to be similar within families [ ] . these suggest the involvement of genetic components in the pathogenesis of ards. the human ace gene (dcp ) is located on chromosome q and contains a restriction fragment length polymorphism defined by the presence (insertion, i) or absence (deletion, d) of a -bp alu repeat sequence in intron . nearly % of the variance in plasma ace activity can be accounted for by this ace insertion/deletion (i/d) polymorphism, the d allele being associated with higher ace activity [ ] . importantly, recent cohort studies of ards showed a significant association between an ace i/d polymorphism and the susceptibility and mortality of ards [ ] . the d/d genotype frequency was increased in patients with ards compared with the control cohort. ninety-six patients fulfilling the criteria for ards were genotyped for the ace polymorphism together with individuals from three comparison groups: patients with non-ards respiratory failure ventilated in the intensive care unit (icu), icu patients undergoing coronary artery bypass grafting and individuals from a general population group. dd genotype frequency was increased in the patients with ards compared with the icu (p = . ), coronary artery bypass grafting (p = . ) and the general population group (p = . ). in addition, the ace d/d allele significantly correlated with mortality in the ards group. another study showed that patients carrying the ace i/i genotype have a significantly increased survival rate [ ] . in that study, the -day mortality rates were significantly different in the three ace genotypes ( %, % and % for i/i, i/d and d/d, respectively; p = . ) in the ards group. taken together, these data suggest a potential role for ras in the pathogenesis of ards and implicate genetic factors in susceptibility and progression of this syndrome. in addition to genetic correlation studies, substantial clinical studies suggest the possible activation of ras in patients with ards. for instance, in patients with ards, an elevation of ace levels in bronchoalveolar lavage fluid has been observed despite a reduction in circulating ace [ ] . reduced circulating ace levels may reflect loss of enzyme release from a damaged pulmonary vascular endothelium and may not be representative of activity in the lung compartment. also, it has been reported that the pulmonary capillary endotheliumbound (pceb) ace activity correlates with the severity of lung injury in the patients with acute lung injury [ ] . these data suggest the possible activation of ras in patients with ards. interestingly, recent retrospective epidemiological studies demonstrated that the prior outpatient use of an ace inhibitor was associated with decreased mortality in patients hospitalized with community-acquired pneumonia, although further studies are needed to examine whether ace inhibitors are protective when used in an inpatient settings for patients lacking traditional indications for the use of these medications [ ] . in , a novel homologue of ace was cloned, termed ace [ , ] . ace and ace share homology in their catalytic domain and provide different key functions in the ras. ace cleaves angiotensin i to generate angiotensin ii [ , ] , whereas ace reduces angiotensin ii levels [ , ] . the biological effects of ang ii are mediated through two specific receptors, ang ii receptor type (at r) and ang ii receptor type (at r) [ , ] . the targeted disruption of murine ace resulted in increased ang ii levels, impaired cardiac contractility in aged mice, upregulation of hypoxia-induced genes in the heart [ ] and worsened heart failure following aortic banding [ ] . loss of ace on an ace background or pharmacological inhibition of the ras can at least partially reverse the cardiac phenotypes [ ] . these genetic data demonstrate that ace counterbalances the function of ace and negatively regulates ang ii levels within the ras (fig. ) . our group has investigated the role of ace in ards using ace knockout mice [ ] . in acid aspiration-induced ards, endotoxin-induced ards, as well as peritoneal sepsisinduced ards, ace knockout mice exhibited very severe disease compared with control mice that express ace . loss of ace expression in mutant mice also resulted in enhanced vascular permeability, increased lung edema, neutrophil accumulation and worsened lung function. of note, these pathologic manifestations occurred without apparent changes in heart contractility or pulmonary vascular tone among the experimental groups. mechanistically, the negative regulation of ang ii levels by ace accounts, in part, for the protective function of ace in ards. for example, at inhibitor treatment or additional ace gene deficiency on an ace knockout background rescues the severe phenotype of ace single mutant mice in acute lung injury. in addition, ace knockout mice and at r knockout mice, but not at r knockout mice, showed improved symptoms of acute lung injury. therefore, in acute lung injury, ace, ang ii and at r promote acute lung injury, whereas ace and the at r figure . current view of the renin-angiotensin system. angiotensin i serves as a substrate for both ace and ace . angiotensin ii is known to act as vasoconstrictor as well as mitogen for smooth muscle cells or fibroblasts, mainly through the angiotensin ii type receptor. the function of angiotensin - is not well understood. both ace and ace are involved in the production of the vasodilator peptide angiotensin - . protect from lung injury [ ] . importantly, the treatment with catalytically active, but not enzymatically inactive, recombinant ace protein improved the symptoms of acute lung injury in wild type mice as well as in ace knockout mice, suggesting ace protein as a possible novel therapeutic target for ards (fig. ) . within a few months following the publication of the sars-cov genome, ace was identified as a potential receptor in cell line studies in vitro [ ] . ace binds sars-cov spike and supports 'syncytia formation', the fusion of spike-protein expressing cells into large multinucleated cells that can be also seen in 'real' sars infections. using a mouse sars infection model with ace knockout mice, our group then provided evidence that ace is indeed essential for sars infections in vivo [ ] . when ace knockout mice are infected with the sars coronavirus, they were resistant to virus infection. virus titers from the lung tissues of infected ace knockout mice were -fold lower than that isolated from the lungs of sars-cov-infected wild type mice. thus, without excluding a second functional sars-cov receptor, ace is an essential receptor for sars infections in vivo. despite many studies on sars-cov, one mystery of sars-cov is why, in contrast to the other coronaviruses, infections with the sars-cov trigger severe lung disease with such high mortality. accumulating evidence further indicates that severe sars infections are dependent on the burden of viral replication as well as on the immunopathologic consequences of the host response. our studies have implicated the involvement of the ras in sars pathogenesis. intriguingly, wild type mice infected with sars-cov showed markedly downregulated ace expression in lungs. similarly, treatment with recombinant sars-spike protein, in the absence of any other virus components, downregulates ace expression in vitro and in vivo. thus, sars-cov-infected or spike protein-treated wild type mice resemble ace knockout mice, and, similar to ace mutant mice, spike-treated wild type mice show markedly more severe pathology in acute lung injury. in addition, in spike-treated mice, ang ii peptide levels were increased and the worsened ards symptoms could be partially reversed by at r blocker treatment. thus, the downregulation of ace expression in sars-cov infections might play a causal role in sars pathogenesis, especially in disease progression to ards. pulmonary circulation is a potentially important target for the ras activation in the lung. for instance, ang ii via its type receptor (at r) induces pulmonary vasoconstriction in response to hypoxia, suggesting important roles of at r in elevating pulmonary vascular tone that can result in pulmonary edema [ ] . also, infusion of ang i [ ] or ang ii [ ] can produce pulmonary edema independent of catecholamine release. these data suggest an important role for the ras in regulating pulmonary vascular tone, which might also contribute to the pathogenesis of ards. in addition to increased vascular tone and a subsequent hydostatic edema formation, accumulating data suggest that ang ii also increases vascular permeability via at r, whereas stimulation of at receptors exerts an opposite effect [ ] . several mediators have been implicated in ang ii regulated vascular permeability changes, including eicosanoids (i.e. leukotriene c , prostaglandin e and i ), and vascular permeability factor. however, relatively few studies have addressed whether the ras is involved in the increased vascular permeability observed in ards. our study demonstrated that loss of ace results in increased vascular permeability using evans vol. , no. drug discovery today: disease mechanisms | immuno-disorders and autoimmunity figure . schematic diagram of the proposed role of the reninangiotensin system in development of ards. in ards induced by sars-cov infections, acid aspiration, pneumonias, sepsis or other pathogenic conditions, the generation of ang ii from ang i is mediated by ace. ang ii contributes to acute lung failure through stimulation of the angiotensin ii type receptor (at r), whereas ace and angiotensin ii type receptor (at r) negatively regulate this pathway and protect from acute lung failure. however, additional ace regulated, but ang ii-independent pathways seem to also contribute to ards. www.drugdiscoverytoday.com blue dye injections as an in vivo indicator of albumin leakage in mice. this vascular permeability was significantly attenuated in the lungs of at r mutant mice. these data indicate that loss of ace expression and increased ang ii levels can trigger leaky pulmonary blood vessels through at r stimulation in ards [ ] . both ace and ace are unspecific proteases and can cleave additional substrates that might also play important roles in ace/ace -regulated ards independent of ang ii. one of the ace and ace targets is bradykinin and its peptide metabolites. bradykinin is the key effecter in the kallikrein-kinin system and also functions as a major proinflammatory mediator. bradykinin is degraded by two main kinases, which are ace (also known as kinase ii in this system) and neutral endopeptidase. the biological effects of bradykinin are mediated by b receptor (b r) and b receptor (b r). b r mediate most the known effects of bradykinin, including antiproliferative, antioxidant and antithrombotic effects [ ] . the in vivo effects mediated via b r or b r are still poorly characterized. a recent study suggests that expression of b r is induced by cytokines during inflammation in rats [ ] , albeit the role of bradykinin in ang ii-induced inflammation remains unclear. ace can remove in in vitro assays the c-terminal residue from apelin and other vasoactive peptides such as neurotensin and neurotensin-related peptide kinetensin. moreover, the opioid peptides dynorphin a ( - ) and b-casamorphin are also substrates of ace . in contrast to ace, ace does not metabolize bradykinin, but catalytically inactivates both [des-arg ]-bradykinin and lys[des-arg ]-bradykinin [ , ] . thus, although many ace functions have been attributed to the regulation of ang ii levels, ang ii itself is probably only part of the ace story and other ace substrates might play a major role in understanding ace functions. importantly, our own preliminary results suggest that inhibition of the bradykinin receptor can also alleviate ards (y.i. and j.m.p., unpublished). recently, the critical importance of ras in the pathogenesis of ards has been established in genetic animal models. ace protects murine lungs from acute lung injury induced by acid aspiration, endotoxin shock and peritoneal sepsis [ ] . in addition, ace knockout mice and at r knockout mice, but not at r knockout mice, showed improved symptoms of acute lung injury [ ] , consistent with other experimental studies [ , , ] . also, ace has been identified as a key sars-cov receptor [ , ] and importantly, ace plays a protective role in sars-cov-mediated lung injury [ ] . therefore, in acute lung injury, ace, ang ii and at r promote acute lung injury, whereas ace and the at r protect from lung injury. these findings might provide the opportunity to develop recombinant ace as a novel drug in ards along with at r inhibitor or ace inhibitor to possibly treat emerging infectious lung diseases such as avian influenza a (h n ) and other diseases that affect lung function ( table ). in addition, as ace is an unspecific protease, it would be also interesting to investigate the role of ace and its metabolites including angiotensin-( - ), des-arg( )-bradykinin, apelin or dynorphin in ards. we look forward to the use of angiotensin system-modulating agents/molecules, in particular ace , as novel therapeutic agents to treat severe acute lung failure, a syndrome that affects millions of people without any yet effective drug treatments. reported studies and references in vivo mouse [ , ] angiotensin ii receptor type (at r) inhibitor human [ ] in vivo mouse [ , ] in vivo rat [ ] angiotensin converting enzyme (ace) inhibitor in vivo mouse [ ] in vivo rat [ ] the biochemistry of the renin-angiotensin system peptidyl dipeptidase a: angiotensin i-converting enzyme a novel angiotensin-converting enzymerelated carboxypeptidase (ace ) converts angiotensin i to angiotensin - a human homolog of angiotensin-converting enzyme. cloning and functional expression as a captopril-insensitive carboxypeptidase angiotensin-converting enzyme is a functional receptor for the sars coronavirus severe acute respiratory syndrome angiotensin-converting enzyme protects from severe acute lung failure a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury avian influenza virus infection of children in vietnam and thailand the acute respiratory distress syndrome familial resemblance of plasma angiotensinconverting enzyme level: the nancy study an insertion/deletion polymorphism in the angiotensin i-converting enzyme gene accounting for half the variance of serum enzyme levels angiotensin converting enzyme insertion/ deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome angiotensin converting enzyme in bronchoalveolar lavage in ards pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury the impact of prior outpatient ace inhibitor use on -day mortality for patients hospitalized with communityacquired pneumonia angiotensin-converting enzyme is an essential regulator of heart function deletion of angiotensin-converting enzyme accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin ii haemodynamic and endocrine effects of type angiotensin ii receptor blockade in patients with hypoxaemic cor pulmonale pulmonary edema induced by angiotensin i in rats angiotensin ii-induced pulmonary edema in a rabbit model effect of angiotensin ii on microvascular permeability bradykinin receptor ligands: therapeutic perspectives bradykinin b( ) receptor-mediated changes in renal hemodynamics during endotoxin-induced inflammation hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase losartan, a selective inhibitor of subtype at receptors for angiotensin ii, inhibits neutrophil recruitment in the lung triggered by fmlp angiotensin ii receptor blockade inhibits pneumocyte apoptosis in experimental meconium aspiration we thank chengyu jiang, shuan rao and many others for their contributions. supported by grants from the national bank of austria, the austrian ministry of science and education, institute of molecular biotechnology in austrian academy of sciences (imba) and eugeneheart to j.m.p. k.k. is supported by a marie curie fellowship from the eu. key: cord- -bz ui a authors: hans-peter, kapfhammer title: posttraumatic stress disorder in survivors of acute respiratory distress syndrome (ards) and septic shock date: - - journal: psychosom konsiliarpsychiatr doi: . /s - - -x sha: doc_id: cord_uid: bz ui a acute lung injury (ali) and acute respiratory distress syndrome (ards) define medical conditions of acute respiratory insufficiency deriving from direct and indirect damage of the alveolar parenchyma and often associated with multiorgan dysfunction (mods). as a rule, intensive care is based on mechanical ventilation often requiring high doses of sedatives and narcotics. despite major progress in intensive care medicine the rate of mortality is still very high. whereas in the past the level of medical progress has been rated based on the mortality rate alone, the many negative somatic and psychological sequelae in long-term-survivors of ards are only now being appreciated. from a perspective of c/l psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (ptsd) in their negative impact on health-related quality of life are intensively investigated. in the etiopathogenesis of ptsd associated with ali/ards, many influences have to be discussed, e.g., increases in co( ) triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. consolidation and retrieval of traumatic memories of the icu stay are influenced by complex factors. from a clinical point of view prophylactic stress doses of hydrocortisone may reduce the major risk of ptsd associated with ali / ards. abstract acute lung injury (ali) and acute respiratory distress syndrome (ards) define medical conditions of acute respiratory insufficiency deriving from direct and indirect damage of the alveolar parenchyma and often associated with multiorgan dysfunction (mods). as a rule, intensive care is based on mechanical ventilation often requiring high doses of sedatives and narcotics. despite major progress in intensive care medicine the rate of mortality is still very high. whereas in the past the level of medical progress has been rated based on the mortality rate alone, the many negative somatic and psychological sequelae in long-term-survivors of ards are only now being appreciated. from a perspective of c/l psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (ptsd) in their negative impact on health- in the etiopathogenesis of ptsd associated with ali/ ards, many influences have to be discussed, e.g., increases in co triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. consolidation and retrieval of traumatic memories of the icu stay are influenced by complex factors. from a clinical point of view prophylactic stress doses of hydrocortisone may reduce the major risk of ptsd associated with ali / ards. [ ] . in den letzen bis jahren gab es geradezu einen explosionsartigen wissenszuwachs zur pathophysiologie und differenzialtherapie von mods bis hin zur aufdeckung molekularer mechanismen. neben untersuchungen zu akuten krankheitsstadien von ali und ards zeichnen sich die mittel-und langfristigen probleme eines Überlebens aber ebenfalls immer deutlicher ab. auf einer somatischen ebene sind vor allem ein reduziertes körpergewicht, eine eingeschränkte körperliche belastungsfähigkeit, persistierende schmerzsyndrome, neuropathien, heterotrophe ossifikationen, kosmetisch störende narben von tracheostomien, fixierte deformationen an fingern und schulter hervorzuheben [ ] . hiermit assoziierte bedeutsame einbußen in der gesundheitsbezogenen lebensqualität sind im langzeitverlauf zu beachten [ ] . in einer konsiliarpsychiatrischen perspektive sind die vielfältigen psychopathologischen komplikationen, die eine schwerwiegende somatische erkrankung wie ards oder septischer schock sowie deren intensivmedizinische therapiemodalitäten während des aufenthalts auf einer intensivstation begleiten können, seit langem bekannt [ ] . die langfristigen psychosozialen und psychologischen probleme als konsequenzen aus dieser erkrankung und dem notwendigen intensivmedizinischen behandlungskontext werden in studien erst in den letzten jahren zunehmend stärker beachtet. diskutiert wird vor allem eine erhöhte psychiatrische komorbidität hinsichtlich neurokognitiver dysfunktionen, angst-und stimmungsstörungen und speziell posttraumatischer belastungsstörungen. negative interferenzen sowohl mit der gesundheitsbezogenen lebensqualität als auch mit der somatischen morbidität werden erkennbar. einflussfaktoren auf diese komplexen somatopsychischen und psychosomatischen zusammenhänge zeichnen sich erst allmählich ab. dies gilt auch für die erprobung therapeutischer und präventiver interventionsstrategien. Überlebende einer akuten respiratorischen insuffizienz im rahmen eines ali oder ards weisen ein signifikant erhöhtes risiko für anhaltende neurokognitive dysfunktionen im langzeitverlauf auf. hierauf machte bereits eine frühere neuropsychologische studie aufmerksam [ ] . mittlerweile existieren mehrere untersuchungen von unterschiedlichen arbeitsgruppen zu diesem thema. sie bestätigen, dass eine subgruppe von früheren ards-patienten in der tat persistierende kognitive leistungseinbußen zeigt [ ] . die prävalenzzahlen schwanken zwischen einem drittel und ca. drei viertel der Überlebenden eines ards. zahlreiche methodologische probleme erschweren aber die interpretation dieser stark divergierenden häufigkeitsangaben. nicht selten ist die unterscheidung von daten zur prävalenz und zur inzidenz unmöglich, da in den studien nur ausnahmsweise informationen zur prämorbiden kognitiven performanz enthalten sind. dies ist von bedeutung, da in einigen bedingungskonstellationen wie z. b. einer vorbestehenden alkoholabhängigkeit nicht nur ein erhöhtes risiko zu einem ards selbst besteht, sondern auch eigenständig kognitive dysfunktionen assoziiert sein können. ebenso bleibt unklar, ob eher spezifische kognitive leistungsdomänen wie aufmerksamkeit, merkfähigkeit oder exekutivfunktionen oder überwiegend das globale kognitive leistungsvermögen diffus durch den somatischen krankheitsprozess und/oder interferierende therapiemaßnahmen negativ beeinflusst werden. auch wenn zahlreiche variable wie hypoxie, delir, glukosedysregulation, metabolische entgleisung, inflammation, medikamenteneffekte von sedativa und narkotika mögliche und auch wahrscheinliche mechanismen einer vermittlung dieser kognitiven beeinträchtigungen andeuten, ist eine differenzielle ätiopathogenetische bewertung noch nicht möglich. der sich in einigen studien andeutende spezielle zusammenhang von deliranten zuständen während der intensivmedizinischen behandlung und kognitiven defiziten in der langzeitperspektive stellt sich wiederum in anderen untersuchungen nicht so klar dar [ ] . von großer klinischer relevanz allerdings erscheint, dass diese dauerhaften neurokognitiven defizite mit signifikanten einschränkungen der gesundheitsbezogenen lebensqualität, der beruflichen rehabilitation sowie mit beachtlichen ökonomischen kosten einhergehen [ , , ] . nach intensivmedizinischen behandlungen wegen eines ards liegt die inzidenz einer neu auftretenden major depression bei ca. % [ ] , nach sars (severe acute respiratory syndrome im kontext einer infektion mit dem sars-coronavirus) in einem ähnlich hohen umfang [ , ] . die rate an angststörungen, vor allem an panikstörungen ist ebenfalls deutlich erhöht und bewegt sich zwischen bis % [ , ] . in einer konsiliarpsychiatrischen perspektive überwiegen angststörungen eher schon während der unmittelbaren intensivmedizinischen behandlung, während depressive störungen sich erst allmählich gegen ende des aufenthalts auf intensivstation und in der weiteren folge darstellen. nicht selten kann bei letzteren auch bereits prämorbid eine depressive vulnerabilität nachgewiesen werden [ ] . in einer allgemeinen ätiopathogenetischen betrachtung darf nicht allein auf die bedingungen von ali/ ards und intensivmedizinische interventionen fokussiert werden, sondern ist eine multifaktorielle betrachtungsweise zu fordern. somatische folgezustände nach überlebtem ali/ards bedeuten für viele patienten erhebliche funktionsbehinderungen (s. oben). sie können pessimismus, resignation und demoralisierung fördern. sowohl angst als auch depression bewirken im verlauf sehr häufig eine subjektive befundverschlimmerung, ohne dass hiermit auch objektivierbare verschlechterungen der lungenfunktionsparameter einhergehen müssen. sie führen zu einer erhöhten inanspruchnahme von medizinischen einrichtungen und zu einer unnötig intensivierten medikamentösen therapie. die gesundheitsbezogene lebensqualität ist oft gerade infolge persistierender angst und depressivität dramatisch reduziert [ ] . im kontext einer betrachtung von affektiven und vor allem von angst-und panikstörungen nach ali und ards ist in den letzten jahren eine klinische und wissenschaftliche diskussion auch um ein erhöhtes risiko einer posttraumatischen belastungsstörung als möglicher langzeitfolge entstanden. in einer ersten retrospektiven untersuchung wiesen schelling et al. [ ] bei insgesamt patienten ( patienten nach ards und nach septischem schock) ca. jahre nach der erkrankung auf eine prävalenz von ca. % an schweren posttraumatischen stresssyndromen hin. prävalenz und schweregrad der in einem selbstfragebogen (ptss- ) erfassten posttraumatischen stresssymptome korrelierten in dieser studie nicht mit dem schweregrad von ards/septischem schock oder dem ausmaß der assoziierten organdysfunktionen sondern mit der von den patienten nach intensivbehandlung jeweils erinnerten anzahl traumatischer erlebnisse (definiert als angst / panikreaktionen, atemnot, schmerz und alpträume / halluzinationen). patienten mit multiplen (> ) traumatischen erfahrungen während der intensivmedizinischen behandlung zeigten eine signifikant schlechtere gesundheitsbezogene lebensqualität, wobei insbesondere die psychosoziale, weniger die körperliche funktionsfähigkeit der patienten eingeschränkt war. kapfhammer et al. [ ] bestätigten an derselben patientenpopulation in einer nachfolgenden konsiliarpsychiatrischen studie, die sich methodisch auf ein standardisiertes klinisches interview mittels scid sowie auf verschiedene psychometrische tests stützte, im wesentlichen diese zusammenhänge. zum zeitpunkt der entlassung von der intensivstation hatten , % dieser patienten das vollbild einer ptsd, , % wiesen eine sub-ptsd auf. zum follow-up termin acht jahre später zeigte sich bei noch , % das vollbild eines ptsd und bei , % ein sub-ptsd. kein patient ohne posttraumatische symptome bei der entlassung hatte eine ptsd mit verzögerter manifestation entwickelt. bei patienten mit ptsd-vollbild zum zeitpunkt der entlassung persistierte diese störung über die gesamte follow-up zeit und schwächte sich im günstigeren fall in richtung eines sub-ptsd ab. in der psychometrischen testung erzielten die patienten mit dem vollbild einer ptsd durchwegs ungünstigere resultate. die deutlichsten einbussen zeigten sich in der gesundheitsbezogenen lebensqualität (sf- ), der situationsangst (stai-x ) sowie der somatisierung (soms). das ausmaß an koexistenter depressivität (madrs) erschien in dieser gruppe vergleichsweise nur moderat auffällig. kognitive dysfunktionen (skt) waren zwar in einer subgruppe nachweisbar, diskriminierten aber nicht hinsichtlich des ptsd-status. als risikofaktoren für die entwicklung eines ptsd konnten nicht die schwere der somatischen erkrankung (apa-che ii score, lung injury score), aber die anzahl der tage der intensivmedizinischen therapie sowie multiple subjektive traumatische erinnerungen (> alpträume, angst/panik, respiratorischer distress, erstickungsgefühle oder unzureichend behandelte schmerzen) auf intensivstation identifiziert werden. mittlerweile existiert eine reihe weiterer studien aus unterschiedlichen arbeitsgruppen, deren ergebnisse in mehreren systematischen reviews detailliert dargestellt sind [ , , ] . in einer zusammenfassenden beurteilung scheint wenig zweifel daran zu bestehen, dass persistierende symptome eines ptsd mögliche langzeitfolgen nach ali/ards sein können und hiermit erhebliche einschränkungen in der gesundheitsbezogenen lebens-qualität einhergehen. ebenso klar muss aber festgehalten werden, dass große unterschiede in den designs der einzelnen studien, ihr überwiegend retrospektiver charakter, meist nur sehr kleine sample-größen, heterogene messzeitpunkte im hinblick auf den zeitabstand zur intensivmedizinischen behandlung, ein erheblicher verlust von patienten in der perspektive des follow up und damit fragliche generalisierbarkeit der gefundenen ergebnisse hinsichtlich der definierten ausgangsstichprobe, eine häufig unzureichende psychiatrische diagnostik, eine nichtbeachtung von zwischenzeitlichen einflussfaktoren eine realistische einschätzung des ausmaßes eines ptsd nach ali/ ards etwa im vergleich nach exposition gegenüber anderen traumatischen ereignissen noch nicht erlauben. diese zurückhaltung ist auch im hinblick auf diskutierte risikovariablen wie länge des aufenthalts auf intensivstation und krankenhaus, beatmungsdauer, sedierungsgrad, weibliches geschlecht, lebensalter, prämorbide psychopathologie, anzahl traumatischer erinnerungen, verfügbare psychosoziale unterstützung angezeigt [ , ] . Über neurobiologische mechanismen der traumatisierung und der entwicklung eines ptsd jenseits der oft beeindruckenden subjektiven berichte von patienten, an welche traumatische erfahrungen sie sich während einer intensivmedizinischen behandlung erinnern und sowohl in intrusiven tagesbildern als auch in wiederkehrenden alpträumen oft über viele jahre wiedererleben, kann vorläufig nur in ersten ansätzen diskutiert werden. einige aspekte sollen aufgenommen werden. nach der prominenten hypothese von klein [ ] ist das auftreten von panik pathophysiologisch auf einen falschen erstickungsalarm zu beziehen. panikattacken resultieren demnach aus einer abnorm sensitiven reagibilität des medullären chemorezeptorensystems, dem entscheidenden atmungskontrollsystem im hirnstamm auf ein ansteigendes arterielles carbondioxid (co health-related quality of life stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single center study indications and practical use of replacement dose of corticoids in critical illness epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study a randomized trial of intermittent lorazepam versus propfol with daily interruption mechanically ventilated patients lung disease. in: levenson jl (ed) textbook of psychosomatic medicine psychiatric morbidity in survivors of the acute respiratory distress syndrome: a systematic review glucocorticoidinduced reduction of traumatic memories: implications for the treatment of ptsd social support during intensive care unit stay might improve mental impairment and consequently health-related quality of life in survivors of severe acute respiratory distress syndrome the pharmacology of oversedation in mechanically ventilated adults connors af ( ) outcomes up to years after severe, acute respiratory failure risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study the prevalence of post traumatic stress disorder in survivors of idu treatment: a systematic review delirium, cognitive dysfunction and posttraumatic stress disorder one-year outcomes in survivors of the acute respiratory distress syndrome quality of life, emotional abnormalities, and cognitive dysfunction in survivors of acute lung injury/acute respiratory distress syndrome longterm neurocognitive function after critical illness neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome post-traumatic stress disorder and posttraumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care anpassungsstörung, akute und posttraumatische belastungsstörung posttraumatic stress disorder in long-term survivors of ards: results of a psychiatric follow-up study and psychological tests false suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis the long-term psychological effects of daily sedative interruption on critically ill patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation quality of life and psychological status in survivors of severe acute respiratory syndrome at months postdischarge acute respiratory distress syndrome ahl ström g ( ) severely ill icu patients recall events and unreal experiences of hospital admission and icu stay -- and months after discharge intensive care unit drug use and subsequent quality of life in acute lung injury patients controlled sedation with alphaxolonealphadolone factual memories of icu: recall at two years postdischarge and comparison with delirium status during icu admission --a multicentre cohort study the relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study psychiatric and psychosocial outcome of cardiac surgery with cardiopulmonary bypass: a prospective -month follow-up study epidemiology and outcomes of acute lung injury short-and long-term followup of intensive care unit patients after sedation with isoflurane and midazolam -a pilot study stressful memories and psychological distress in adult mechanically ventilated intensive care patients -a -month follow-up study post-traumatic stress disorder in somatic disease: lessons from critically ill patients the effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder in survivors stress doses of hydrocortisone, traumatic stress, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized trial health-related quality of life and posttrauamtic stress disorder in survivors of the acute respiratory distress syndrome the effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder and health-related quality of in life in survivors (eds) handbook of liaison psychiatry epidemiology and treatment of psychiatric conditions that develop after critical illness epidemiology of depression and antidepressant therapy after acute respiratory failure medical post-traumatic stress disorder. catching up with the cutting edge in stress research post-icu consequences of patient wakefulness and sedative exposure during mechanical ventilation stress doses of hydrocortisone reduce chronic stress symptoms and improve healthrelated quality of life in high-risk patients after cardiac surgery: a randomized study posttraumatic stress, anxiety, and depression in survivors of severe acute respiratory syndrome (sars) post-traumatic stress disorder key: cord- -g wcfrfi authors: badraoui, riadh; alrashedi, mousa m.; el-may, michèle véronique; bardakci, fevzi title: acute respiratory distress syndrome: a life threatening associated complication of sars-cov- infection inducing covid- date: - - journal: journal of biomolecular structure & dynamics doi: . / . . sha: doc_id: cord_uid: g wcfrfi acute respiratory distress syndrome (ards) is a form of respiratory failure in human. the number of deaths caused by sars-cov- infection inducing this severe pneumonia (ards) is relatively high. in fact, covid- might get worsen in ards and provoke respiratory failure. a better understood of ards key features and the pathophysiological injuries of the pulmonary parenchyma are linked to lessons learned from previous severe diseases associated previous coronaviruses outbreaks (especially sars-cov and mers-cov) and more the ongoing sars-cov- . the ards mechanism includes a diffuse alveolar damage associated disruption of alveolar capillary membrane, pulmonary edema, damaged endothelium and increased permeability. a diffuse inflammation, with acute onset, on the lung tissue accompanied by release of biochemical signal and inflammatory mediators (tnfα, il- and il- ) leading to hypoxemia, low pao( )/fio( ) ratio and the chest radiological expression of bilateral infiltrates in ards. the ongoing outbreak could lead to a better understood of ards pathophysiology and prognostic. an overview is also highlighted about the seven coronaviruses proved to infect human especially those having ability to cause severe disease sars-cov, mers-cov and sars-cov- . in this review, we focused on the major pathological mechanisms leading to the ards development as a result of viral infection, severe covid- worsening. communicated by ramaswamy h. sarma a cluster of novel pneumonia cases has emerged in wuhan-china on december and by the end of the st week in january, the chinese authorities reported its association with a novel coronavirus. the novel coronavirus, finally named as severe acute respiratory syndrome coronavirus (sars-cov- ) by the international committee on taxonomy of viruses, and it's inducing coronavirus disease (covid- ) (gorbalenya et al., ; khailany et al., ) . the world health organization (who) confirmed the transmissibility of the novel coronavirus from human to human. similarly, to sars-cov and mers-cov, the ongoing coronavirus (sars-cov- ) could cause disease with severe symptoms. sars-cov- has been, already, considered to be as a sister virus to sars-cov based on similarities to their hole genome sequences (su et al., ; khailany et al., ) . the major common symptoms include fever, cough, difficult (short and rapid) breathing and myalgia or muscular fatigue. while sars-cov- induces mild symptoms in several infected patients (low pathogenic), it can also be associated with a fast onset of widespread infection in the lungs worsened in an acute respiratory distress syndrome (ards) . this family of viruses has a simple-strand rna genome of to kb . coronaviruses were identified in different animal including birds and mammals such as cat, dogs, bats, camels. they were first identified in humans in mid s and get the name of coronaviruses due to the crown-like spikes on their surfaces. covid- is a disease caused by the seventh confirmed coronavirus to infect the human being. it has been preceded by six known human coronaviruses hcov- e, hcov-oc , sars-cov, hcov-nl , hcov-hku- and mers-cov (shown in figure ) (tao et al., ; zhou et al., ) . overall, these viruses are mainly targeting the respiratory system and causing health problems ranging from symptoms of mild upper respiratory tract to severe respiratory syndrome and even death. coronaviruses can provoke diseases in different and multiple organ systems in animals and target mainly the respiratory system in humans. while hcov- e, hcov-oc , hcov-nl and hcov-hku- induce upper respiratory disease associated with mild symptoms, sars-cov, mers-cov and sars-cov- are categorized as highly pathogenic that could cause critical and serious diseases in humans (cui et al., ; corman et al., ; lu et al., ; yin & wunderink, ) . the covid- infected people commonly exhibit fever ( - . %), nonproductive/dry cough ( . - %), fatigue/muscle pain ( - %) and breathing difficulties . as shown in table , sars-cov was detected in guangdong in china in and was responsible for deaths among confirmed infections. its mortality rate was estimated %. the infection reached countries. both sars-cov and mers shared the same potential natural reservoir which is bats and the possible intermediate hosts are civets and dromedary camels respectively. mers-cov was first detected in saudi arabia in then spread in in countries. mers-cov resulted in reported infections and death and a mortality rate of % (cui et al., ; tao et al., ; zhou et al., ) . sars-cov- was first detected in december in wuhan-china and is still an ongoing pandemic that infected countries and resulted in more deaths and infected cases. the potential natural reservoir for sars-cov- is still not known and further investigations are needed to determine the exact zoonotic source. however, it has been proposed that the potential natural reservoir are probably bats and the possible intermediate hosts seems to be pangolin (zheng, ) . sars-cov- started in huanan seafood wholesale market in wuhan-china, and it has subsequently spread worldwide. the outbreak of infection with sars-cov- causing covid- , which was confirmed as new by sequencing all its genome, has rapidly met the criteria for public health emergency of international concern (pheic, at th january ) and had been declared pandemic by the who on march , . as of july , , more than , million cases of infection with covid- have been confirmed in countries and , death cases. the case fatality rate of sars-cov- is estimated to be . based on notified cases. unlike sars-cov transmission of covid- could occur before symptoms development. common symptoms in covid- include fever, cough and feeling tired/muscle pain … it has been outlined, by several authors from different centers, that covid- is more likely to be fatal in elderly people with comorbidities (mainly cardiovascular and cerebrovascular diseases and diabetes), as a consequence of less rigorous immune system, in a similar way to mers-cov (badawi & ryoo, ; channappanavar et al., ; chen et al., ) . additionally, it and can be associated with fatal respiratory disease such as ards. . angiotensin-converting enzyme ii (ace ) receptor and susceptibility to sars-cov- membrane receptor of host cells play a key role in the entry of coronaviruses into the host cells as well as their pathogenesis. coronavirus recognizes and bind to its host receptor via its envelope-anchored spike (s) protein, then enters into the cell by fusing of host and viral membranes (bosch et al., ; gallagher & buchmeier, ) . comparisons of genome sequences of sars-cov- with other coronaviruses showed . % sequence identity with sars-cov zhou et al., ) . coronavirus genome annotations revealed four major structural proteins so called ( ) the spike (s) protein, ( ) nucleocapsid (n) protein, ( ) membrane (m) protein and ( ) the envelope (e) protein (schoeman & fielding, ) . two functional subunits of spike protein s and s have been proved to be responsible for receptor binding and fusion of viral and cellular membranes, respectively (he et al., ) . the angiotensin-converting enzyme (ace ) has previously been reported as a receptor for both the sars-coronavirus (sars-cov) and the human respiratory coronavirus nl (li et al., ) . while sequence comparisons of s proteins of sars-cov- with sars-cov showed only % sequence identity, most amino acid residues essential for receptor binding in the receptor binding domain (rbd) in the s protein were conserved between sars-cov and sars-cov- zhou et al., ) . recent studies have uncovered that sars-cov- mediates ace as a host cell receptor for cellular entry and a serine protease tmprss for s protein priming (hoffmann et al., ; lu et al., ; xu et al., ; zhou et al., ) . a strong interaction has been found between rbd domain of the sars-cov- s-protein with human ace molecules . ace , an enzyme playing a key role in the renin-angiotensin system (ras), is an integral membrane protein and a zinc metalloprotease of the ace family, mainly expressed in vascular endothelial cells, the renal tubular epithelium, leydig, lung, kidney, and gastrointestinal tract (harmer et al., ; ksiazek et al., ; leung et al., ) . ace -expressing cells may become susceptible and accordingly become targets to sars-cov- . previous studies have demonstrated a positive correlation of sars-cov- with high ace expressing cells in various organs (chai et al., ; zhao et al., ; zou et al., ) . therefore, both expression level and pattern of ace in different human tissues might be involved in the susceptibility, symptoms and consequently the outcome of covid- . ace expression in lung tissues from asian and caucasian populations, based on the single-cell rna seq analysis, suggested higher ace expression in the asian donors than white and african-american donors . on the other hand, no significant difference has been found between asian and caucasians in ace expression from lung tissues of controls using the rna-seq and microarray datasets. a recent study investigated the mechanism of sars-cov- infection by studying ace expression in various human tissues . they have proposed that sars-cov- may also infect more tissues relatively with the higher level of ace expression other than lungs. since there were no significant differences in ace expression levels between different sexes, ages and races. it was concluded they all are equally prone to be infected by sars-cov- , but have different immune responses due to differences in their ace expression level and immune signature in the lungs. these findings may partially elucidate differences in covid- severity between male and female and young and old persons. another important issue in infection and progression of coronavirus disease is an interaction between viral spike figure . the seven confirmed coronavirus to infect the human being. note that sars-cov- has been preceded by six known human coronaviruses hcov- e, hcov-oc , sars-cov, hcov-nl , hcov-hku- and mers-cov. note also that these viruses are mainly targeting the respiratory system and causing health problems ranging from symptoms of mild upper respiratory tract (such as hcov- e, hcov-oc , hcov-nl and hcov-hku- ) to severe respiratory syndrome that can even lead to death (such as sars-cov, mers-cov and sars-cov- ). (c) this number is by july , and it does not include the holland america's ms zaandam and diamond princess cruise ships, two international conveyances, hosted in usa and japan respectively. the number of countries is still increasing and might reach the entire world's countries and territories in the next few days. protein and ace receptors of host cells. this host-pathogen interaction of coronaviruses is critically important since it is likely that more could evolve in the future because of their high mutation rate. therefore, a substantial effort has been spent on viral genetic variants known to be related with covid- progression. on the other hand, only few studies have published on the genetics basis of risk factors that might have an effect on the susceptibility in human. earlier studies on the ace poymorphism in human populations have been carried out in order to determine their associations with several diseases such as hypertention, cardiovascular diseases, diabetes, kidney diseases and more recently covid- luo et al., ; ramachandran et al., ; reich et al., ; yang et al., ; zhou & yang, ). in fact, this gene is a peptidase that regulates the renin-angiotensin-aldosterone system. previous studies on a group coronavirus, a mouse hepatitis virus, showed an association between allelic variants of viral receptor and binding activity of virus (ohtsuka & taguchi, ) . hence, it was proposed that genetic variants of ace may ease the symptoms of sars-cov- infection. although a previous study (chiu et al., ) has proposed that ace gene polymorphisms do not support an association between its common genetic variants and sars susceptibility or outcome, there is no evidence if this is true for sars-cov- infection. cao et al. ( ) have investigated the candidate functional coding variants in ace and the allele frequency (af) differences between populations. they have found the differences in distribution and afs of qtls in different populations indicating diversity of ace expression in populations. their findings showed differences in distribution and afs of eqtls for ace in different populations (much higher in the east asian populations) indicating different susceptibility or response to -ncov/sars-cov- from different populations under the similar conditions. a recent study investigated the interaction between proteins encoded by different ace variants and sars-cov- spike protein (hussain et al., ) . data analyses showed that most ace variants displayed a similar binding affinity for sars-cov- spike protein alike wild-type ace . however, intermolecular interaction between ace alleles, rs (s p) and rs (e g) and viral spike protein showed a considerable variations indicating a potential individual resistance against sars-cov- infection. stawiski et al. ( ) have recently investigated ace polymorphisms in a large cohort of human population to predict sars-cov- susceptibility. they have proposed that while human ace variants s p, i v, e k, k r, t a, n k, t i, q p and h r are those increasing susceptibility to sars-cov- , k r, n i, h r, e k, e k, d v, y f, n s, m v, k e, f v, y h, g e, g v, d n, q l and d y are putative protective variants decreasing sars-cov- s protein and ace binding. however, there was no significant difference between ace variant allele frequencies of the studied populations. in addition to the ace gene, the relationship between ace d/i polymorphism associated with alterations in circulating and tissue concentrations of ace and covid- infections has also been investigated in different european countries with the prevalence and mortality of covid- . results of this study have showed that prevalence of covid- infections are inversely correlated with ace d allele frequency. alike, there was a significant correlation between covid- mortality and the prevalence of ace d allele. furthermore, a meta-analysis study on , healthy subjects from different countries showed that a significant correlation between ace d/i allele frequency ratio and the prevalence of covid- but no significant difference in the case of death rate (hatami et al., ) . since human ace gene is x-linked, males will express each allelic variants of ace coding variants separately due to their homozygosity that increase chance to observe phenotypic expression of rare coding variants in males. however, females will express those variants in a mosaic manner because of early x-inactivation. gibson et al. ( ) have used the gnomad database (the genome aggregation database: a resource cataloging genetic coding variants) for , adults and detected missense variants of which rs ace (thought to encode p.lys arg) predicted to be located at or close to the ace binding site for ssars-cov- spike protein. this allele in among ashkenazi jewish males and in among non-finnish european males (higher frequency in females) but absent in korean and japanese participants. to date no studies have been carried out on the people infected by sars-cov- with no symptoms, mild symptoms and severe symptoms for determining association between different variants of ace gene and susceptibility to sars-cov- . ace receptor could play a key role in developing vaccines and therapeutics for covid- . since ace is a gate for entry of sars-cov- , angiotensin-converting enzyme inhibitors (acei) and angiotensin ii receptor blockers (arb) that has been proved to upregulate ace expression in some animal models are being hope in treating covid- (ishiyama et al., : ferrario et al., . therefore, regulation of ace may improve outcomes of sars-cov- infection (gurwitz, ; kuba et al., ) . however, it has been proposed that use of arbs and acei in certain high-risk covid- patients may be harmful (reynolds et al., ) . in a recent cohort study of patients showed that there is no correlation between acei/arbs use and testing positive for covid- (mehta et al., ) . despite the lack of sufficient clinical evidence, several professional societies have recommended to continued use of these medications for covid- treatment. another approach to prevent sars-cov- infection is to use antibodies to stop the viruses from attaching to ace receptor. an antibody so called 'decoy' ace receptor has been developed to block the virus before it reaches to the ace on the cell surfaces and cause infection. a number of antibodies carrying ace have been developed but particularly one, called mdr , have been more tightly bound to sars-cov- and effectively neutralize the virus and blocked it from entering the cells (iwanaga et al., ) . ards is a form of respiratory failure, for which the first case has been described in by ashbaugh and his collaborators (ashbaugh et al., ; irwin & rippe, ) . wang et al. reported, in , that the average time observed to develop ards, if any, is days after the first appeared symptom following covid- infection. ards is considered as a significant life threatening. in fact, the death is estimated to range between and % even with the best medical care. it could reach % in same cases (ferguson et al., ) . these averages are mainly related to the severity of the disease, for which types have been categorized according to the severity of hypoxemia: mild, moderate and severe cases (ferguson et al., ) . hypoxemia is assessed by the following ratio pao /fio . pao stands for the pressure of the arterial oxygen and fio stands for the fraction of the inspired oxygen. so far, ards is categorized as a mild whenever pao /fio is ranging between mmhg and mmhg (or kpa), moderate if pao / fio ranges between mmhg and mmhg (or kpa), and severe if pao /fio is less than mmhg (or . kpa) (brown et al., ; fan et al., ; ferguson et al., ) . moreover, ards pathogenesis excludes heart related pulmonary edema and should exhibits an acute onset (matthay et al., ) . lung injury in ards is described as a fast onset (worsening within a week) of widespread inflammation. x-ray radiographs of the chest exhibit several radiological opacities as a result of bilateral infiltrates (matthay et al., ) . the total average of worldwide death, related to ards, is estimated to be million per year (bellani et al., ) . in patients, ards is resulting into symptomatic features such as difficulty (short and rapid) in breathing and bluish skin coloration due to low oxygen level in the blood. ards has been largely described and several research activities have been done for a better prognostic. however, until nowadays no efficient pharmacological treatment has been described to date. thus, the mechanical ventilation is still the principal used way and one of the best practices together with the treatment of the underlying cause of the edema. furthermore, the patients who survive the ards would most often have long hospital stay. physical and neurological morbidity is very common among the surviving patients, even several years after their hospital discharge. however, because treatment of covid- induced-ards is an ongoing challenge, it may be a good opportunity for a better understanding of the disease prognostics. lessons learned from previous severe diseases caused by coronaviruses outbreaks (sars-cov and mers-cov) and more recently sars-cov- lead to a better understood of ards key features associated covid- . ards is categorized as a diffuse alveolar damage inducing pulmonary edema together with damaged lungs endothelia (kao et al., ; vasudevan et al., ) . the damaged endothelia show much more permeability to both water and proteins (exudate) and disrupt the alveolar capillary barrier (kao et al., ; vasudevan et al., ) . in ards, the viral infection caused with sars-cov- and others, leads to injury of the entire lung not only a particular area as what is happening in pneumonia (wujtewicz et al., ; yang et al., ) . once an organism has been infected by sars-cov- , similarly to sars-cov, the novel coronavirus uses one of the spikes, particularly the s-protein type, as a key to enter the cells of the body (li et al., ) . in fact, the s-protein bind with specific cytoplasmic receptor called ace which is a crucial component of ras , khailany et al., . while, mers-cov bind to cd , it is believed that sars-cov and sars-cov- bind to ace (khailany et al., ) . ace counteracts the ras activation, protects the tissue injuries and is much more expressed in females than in males. likewise, it's also much more expressed in young than in elderly people (soro-paavonen et al., ) . regardless its activity in most tissues, it is widely active in the lungs but also in several other organs such as the hearts, testis and kidneys ohtsuki et al., ) . once the virus enters the body, it is believed that sars-cov- targets, mainly, the pneumocytes ii, and these tensionprotective cells will be destroyed. being infected by covid- , the pneumocytes ii seem to be largely involved the replication and amplification sars-cov- before being damaged. moreover, the infected cells secret a high amount of specific inflammatory mediators that enhance macrophages to release cytokines including tumor necrosis factor alpha (tnfa) and interleukins (il- and il- ). these cytokines lead to the disruption of the alveolar-capillary membrane integrity, which is associated with vasodilation and increased vascular permeability. the latter is mainly related to the cytokines (tnfa, il- and il- ) induced endothelial contraction. the disrupted integrity of the alveolar-capillary allow the plasma leakage into the alveoli and the lungs interstitial spaces. a loss of osmotic pressure gradient leads to a leaky barrier and an increased sensitivity to hydrostatic forces are believed to play key role in the diffuse edema formation. the formation of protein rich edema, known as exudate, in the interstitium and alveolar spaces leads to alveolar flooding making it very difficult to breathe and then lead to hypoxemia, which is one of the common symptoms of covid- infection (matthay et al., ) . the flooded interstitium itself exert additional pressure on the alveoli that might lead to their contraction; alveolar collapsing enhanced by reduced surfactant level due to the damaged pneumocytes ii. typical lung histopathological micrographs, at this stage, exhibit already diffuse alveolar damage (dad) and hyaline membrane formation in the alveolar wall. furthermore, pulmonary macrophages release much more interleukins (il- and il- ) and tnfa, which exhibit a chemotaxis towards polymorpho-nuclear neutrophils (pmns) (zemans & matthay, ) . the invading pmns release especially reactive oxygen species (ros), neutrophil extracellular traps (nets) and proteases to the pathogens; sars-cov- in the case of covid- . however, the pmns of the inflamed tissue amplify the phenomena by damaging the different cells existing in the lung inflammatory microenvironment including endothelial cells and pneumocytes and (shown in figure ). hence, significant decrease in both gaseous exchanges and surfactant production would be outlined together with a consolidation process related to the cellular debris, pmns, macrophages and edema, which become more and more a protein-rich fluid … the consolidation is also enhancing and worsening the alveolar collapsing. in normal physiological conditions, during inhalation the oxygen that reach the alveoli oxygenate the blood which turns back to the heart and then to the different cells of the body. so the exchange of the gases, is facilitated by the alveolar capillary membrane which should be very thin. however, in ards, the inflammatory process it widespread not only within the alveoli but also in the intersititium. so instead of having functional little small alveoli able to inflate and deflate during the inhalation and exhalation respectively, the lungs stiff and it becomes very difficult to inflate due to fluid and the inflammation. finally, a significant increase in the load to breathe occurs in vain leading to the pulmonary failure. ards is a life threatening associated with fast onset of widespread inflammatory damage. it concerns mainly the alveolar epithelial cells (type and type ) and the vascular endothelial cells. this damage is associating release of several biochemical signals and inflammatory mediators by local endothelial and pulmonary epithelial cells. in this context, during ards worsening, lung epithelial cells might secrete srage, sp, kl- , cc and kgf (for soluble receptor of advanced glycation end-products, surfactant proteins, krebs von den lungen protein , clara cell protein and keratinocyte growth factor respectively) (determann et al., ; koh et al., ; sato et al., ) . in ards, endothelial cells might secrete ang- , ang- , vwf and vegf (for angiopoietin- , angiopoietin- , von willebrand factor and vascular endothelial growth factor respectively). these secreted products may be used as biomarkers of ards. pro-inflammatory (il- b, il- , il- , il- and tnfa, for interleukin , , and and tumor necrosis factor alpha respectively) and anti-inflammatory biomarkers (il- ra, il- , stnf-ri and stnf-rii for interleukin receptor antagonist, interleukin and soluble tumor necrosis factor receptors i and ii respectively) are often used to have an idea about neutrophils and their toxic mediators. plasminogen activator inhibitor- (pai- ) is a useful biomarker indicating the degree of coagulation and fibrinolysis which is a common feature on ards (spadaro et al., ) . microrna (mirna) are also good biomarker candidates as their expression varies in early stages of gene expression associated ards (cardinal-fern andez et al., ; ferruelo et al., ) . specifically, mirna- a and mirna- have been reported to increase significantly in patients with severe sepsis and sepsis induced acute lung injury (han et al., ) . similarly, these non-coding rna molecules may play important role in ards associated covid- . hence, several biomarkers are used for patient in severe trauma associated ards but some biomarkers combinations were reported to be efficient in ards prognostic and even to predict the mortality associated to this syndrome (ware et al., , ware & calfee, . recently, the development of methods for gene expression and sensitive immunoassay is offering a great potential for personalized treatment (spadaro et al., ; sweeney & khatri, ) .taken together, these biomarkers could certainly have potential relevance for mortality prediction, diagnosis and therapy of ards due to sars-cov- infection. the ards treatment requires a clear defining of the underlying anatomo-physiological properties of lung tissues being managed. otherwise, the ards treatment would be based mainly on the response likelihood and its adjustment (dries, ; gattinoni et al., ) . even the ventilation management is independently associated with improved survival . nevertheless, some new clinical trials sound promising such as the use of higher positive end-expiratory pressure (dries, ) . it has also been shown that lung recruitment maneuvers may improve the oxygenation process and shorten the hospital stay period in ards (cui et al., ) and avoid the pro-inflammatory processes triggered by mechanical ventilation (spadaro et al., ) . because in ards, the lung injury is accompanied with an acute onset, the recognition and the determination of the respiratory damage threshold would certainly be a key point for a better and efficient ards therapy (dries, ) . to date, no specific treatment has been proven for sars-cov- infection and who management still focus on preventing the infection, figure . pathophysiology of ards in sars-cov- inducing covid- patients with severe symptoms. once sars-cov- gets into the body, it uses its s-spike type, as a key to enter the cells by binding to angiotensin-converting enzyme (ace ). the virus use the mainly pneumocytes components for its own proliferation. the infected cells secret a high amount of specific inflammatory mediators that enhance macrophages to release cytokines tumor necrosis factor alpha (tnfa) and interleukins (il- and il- ). these cytokines lead to the disruption of the alveolar-capillary membrane integrity and increased the vascular permeability. the disrupted integrity of the alveolar-capillary allow the plasma leakage into the alveoli and the lungs interstitial spaces. the formation of protein rich edema, known as exudate, in the interstitium and alveolar spaces leads to alveolar flooding making it very difficult to breathe and lead to hypoxemia. driven by il- , il- and tnfa, pmns invade the alveoli and release reactive oxygen species (ros), neutrophil extracellular traps (nets) and proteases that damage the vascular and the alveoli components that exacerbates the hypoxemia, the alveoli collapsing and lead to a worse situation: alveolar consolidation. detection and monitoring of cases together with supportive care. however, extracorporeal membrane oxygenation (ecmo) has been reported to be effective in treating ards. similarly, ecmo might be effective in treatment of covid- severe cases (hong et al., ) . development and availability of simple and rapid diagnostic tests for covid- is as important as the development of treatment of its serious ards complication. moreover, there is an important need for early identification of patients with higher ards risk following critical sars-cov- infection. more investigations, about what is highly needed to know about the etiology of covid- associated ards, needed to be done by taking into account several linked factors mainly the age of the infected patients and their comorbidities. in this context, mathematical modeling might help both to understand the ards outcomes and to predict its severity in the populations at risk. it could also help in the therapeutic processes. elsewhere, a better understanding of ace receptor (which is playing a key role in cellular entry of coronaviruses including sars-cov- ) polymorphisms and susceptibility to sars-cov- inducing covid- could help in understanding ards phenotypes and outcomes. regarding the key protective role played by ace on several diseases including ards, investigation on spike protein-based vaccination and drugs might be promising to enhance ace activity for the treatment of covid- including ards. because the ards associated with covid- is an ongoing challenge, the sars-cov- pandemic period would certainly be helpful for a better understood of the ards life threatening, which is associated with several pathogens. acute respiratory distress in adults prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov): a systematic review and meta-analysis epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries the coronavirus spike protein is a class i virus fusion protein: structural and functional characterization of the fusion core complex nonlinear imputation of pao /fio from spo /fio among patients with acute respiratory distress syndrome comparative genetic analysis of the novel coronavirus ( -ncov/sars-cov- ) receptor ace in different populations characteristics of micrornas and their potential relevance for the diagnosis and therapy of the acute respiratory distress syndrome: from bench to bedside specific ace expression in cholangiocytes may cause liver damage after -ncov infection sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study organ-protective effect of angiotensin-converting enzyme and its effect on the prognosis of covid- ace gene polymorphisms do not affect outcome of severe acute respiratory syndrome hosts and sources of endemic human coronaviruses origin and evolution of pathogenic coronaviruses lung recruitment maneuvers for ards patients: a systematic review and meta-analysis covid- infections are also affected by human ace d/i polymorphism the host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in covid- infections plasma levels of surfactant protein d and kl- for evaluation of lung injury in critically ill mechanically ventilated patients ards from syndrome to disease-treatment strategies acute respiratory distress syndrome: advances in diagnosis and treatment the berlin definition of ards: an expanded rationale, justification, and supplementary material effect of angiotensinconverting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme micrornas as biomarkers of acute lung injury coronavirus spike proteins in viral entry and pathogenesis time to rethink the approach to treating acute respiratory distress syndrome ace coding variants: a potential x-linked risk factor for covid- disease severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- the prognostic value of plasma microrna- and microrna- a level in severe sepsis and sepsisinduced acute lung injury patients quantitative mrna expression profiling of ace , a novel homologue of angiotensin converting enzyme worldwide ace (i/d) polymorphism may affect covid- recovery rate: an ecological meta-regression receptor-binding domain of sars-cov spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor extracorporeal membrane oxygenation (ecmo): does it have a role in the treatment of severe covid- ? structural variations in human ace may influence its binding with sars-cov- spike protein irwin and rippe's intensive care medicine upregulation of angiotensin-converting enzyme after myocardial infarction by blockade of angiotensin ii receptors novel ace -igg fusions with improved activity against sars-cov diffuse alveolar damage associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy genomic characterisation of a novel sars-cov- vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome a novel coronavirus associated with severe acute respiratory syndrome a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury enteric involvement of severe acute respiratory syndrome-associated coronavirus infection expression of the sars-cov- cell receptor gene ace in a wide variety of human tissues angiotensin-converting enzyme is a functional receptor for the sars coronavirus genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding association of ace genetic polymorphisms with hypertension-related target organ damages in south xinjiang treatment for severe acute respiratory distress syndrome from covid- acute respiratory distress syndrome association of use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with testing positive for coronavirus disease (covid- ) mouse susceptibility to mouse hepatitis virus infection is linked to viral receptor genotype angiotensin converting enzyme gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure association of insertion/deletion polymorphism of angiotensin-converting enzyme gene with essential hypertension and type diabetes mellitus in malaysian subjects decreased glomerular and tubular expression of ace in patients with type diabetes and kidney disease renin-angiotensin-aldosterone system inhibitors and risk of covid- kl- levels are elevated in plasma from patients with acute respiratory distress syndrome coronavirus envelope protein: current knowledge circulating ace activity is increased in patients with type diabetes and vascular complications biomarkers for acute respiratory distress syndrome and prospects for personalised medicine human ace receptor polymorphisms predict sars-cov- susceptibility epidemiology, genetic recombination, and pathogenesis of coronaviruses generalizable biomarkers in critical care: toward precision medicine surveillance of bat coronaviruses in kenya identifies relatives of human coronaviruses nl and e and their recombination history acute lung injury and acute respiratory distress syndrome a novel coronavirus outbreak of global health concern clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan biomarkers of ards: what's new? intensive care medicine biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome sars-cov- is an appropriate name for the new coronavirus covid- -what should anaethesiologists and intensivists know about it evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission the association between angiotensin-converting enzyme polymorphisms and essential hypertension risk: a meta-analysis involving , patients clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study mers, sars and other coronaviruses as causes of pneumonia what drives neutrophils to the alveoli in ards? single-cell rna expression profiling of ace , the putative receptor of wuhan -ncov sars-cov- : an emerging coronavirus that causes a global threat meta-analysis of association of ace g a polymorphism with chinese han essential hypertension fatal swine acute diarrhoea syndrome caused by an hku -related coronavirus of bat origin a pneumonia outbreak associated with a new coronavirus of probable bat origin single-cell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to -ncov infection the authors have no acknowledgments to declare. the authors declare no competing financial interest. rb drafted of the manuscript. additional content has been provided by key: cord- -ck lh rg authors: perez-nieto, orlando ruben; guerrero-gutiérrez, manuel alberto; zamarron-lopez, eder ivan; deloya-tomas, ernesto; gasca aldama, jose carlos; Ñamendys-silva, silvio antonio title: impact of asynchronies in acute respiratory distress syndrome due to coronavirus disease date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: ck lh rg nan to the editor: t he severe acute respiratory syndrome coronavirus (sars-cov- ) infection in mexico, in the month of may, has reached an alarming case fatality rate (cfr) of %, with a high prevalence of acute respiratory distress syndrome (ards) by coronavirus disease (covid- ). these patients have shown a high asynchrony index and a correlation with the cfr. asynchronies are common in patients with ards, and invasive mechanical ventilation (imv) is common and can occur in all ventilatory modes. blanch reported that an asynchrony index greater than % (number of asynchronies among the total respiratory cycles multiplied by ) is associated with an increase in mortality and more days of imv ( ). patients with ards due to covid- that needed intubation and imv present a challenge for the physician and have been associated with a mortality rate of . % ( ) , despite this, to this date, it has not been described the prevalence of asynchronies in patients with ards because of covid- infection and its relationship with the prognosis of their disease. we present a series of nine patients diagnosed with ards for covid- and mechanical ventilation. six patients were men; the average age was years ( - yr), in % of patients it was ventilated by assisted-volume-controlled mode, with tidal volume (tv) of ml/kg of predicted weight. four patients died, in whom the asynchronies observed were double and triple triggering. the average -minute asynchrony rate was % ( - %) for patients who died versus . % ( - %) for survivors. the asynchronies observed in survivors were delayed triggering and delayed cycling (fig. ) . obesity was present in % ( ) of the deceased patients ( table ) . a possible explanation for the multiple, double, and triple triggering could be that, according to the pathology reports of patients with ards by covid- , diffuse alveolar damage, scaling of pneumocytes, and hyaline membrane formation have been observed, which generates alterations of the gas exchange and subsequent hypoxemia ( ); therefore, the patient's respiratory drive could be increased, as well as their inspiratory effort, same that added to a low tv of ml/kg of predicted weight, could not satisfy their "air hunger, " generating an excessive inspiratory effort that will culminate in multiple triggerings that can cause volutrauma and barotrauma ( ). neuromuscular blockade (nmb) for to hours could be an alternative to avoid triggering asynchronies in this type of patient; nmb has been shown to improve oxygenation, reduce the prevalence of barotrauma and is associated with a reduction in mortality in patients with ards ( ) . a problem raised during the pandemic is fatigue and burnout of physicians, this type of critical care patients with covid- under imv needs a constant monitoring ( ) . the limitation of this study is the small sample size; however, it corresponds to the characteristics of the patients reported worldwide, which reports a predominance of covid- in male patients with cardiovascular comorbidities and obesity, as well as the percentage of mortality associated with patients who required imv ( ) . in summary, close monitoring of patients with covid- and mechanical ventilation is required, staying at the patient's bedside is necessary to identify life-threatening asynchronies and must be resolved promptly, as well as finding strategies for their prevention of asynchronies. studies are needed to determine the prevalence of asynchronies in patients with imv and sars-cov- infection and its association with poor results. the authors have disclosed that they do not have any potential conflicts of interest. dr. perez-nieto was responsible for the conceptualization of the study and the revision and approval of this article. dr. guerrero-gutiérrez was responsible for the accuracy, collect the data, and drafted the article. dr. Ñamendys-silva critically reviewed the article. all the authors read and approved the final version of the article. collected data and ct images are found in the clinical records of patients at their respective medical centers, data are available on request. the present study did not require approval by the ethics committee or consent to participate because no intervention was performed and is limited to nine cases. we respect the confidentiality of patients. asynchronies during mechanical ventilation are associated with mortality presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area pathological findings of covid- associated with acute respiratory distress syndrome patient-ventilator asynchronies during mechanical ventilation: current knowledge and research priorities neuromuscular blockers in the acute respiratory distress syndrome: a meta-analysis rising to the challenge of covid- : advice for pulmonary and critical care and an agenda for research key: cord- -zw s authors: elsayed, hany hasan title: dexamethasone for treatment of severe covid- , a surprise? date: - - journal: cardiothorac surg doi: . /s - - - sha: doc_id: cord_uid: zw s nan the inclination that we lack all the knowledge needed to treat covid- related ards may be dangerous in depriving covid- patients from evidence-based medication. the berlin criteria defined ards as an acute syndrome of hypoxia (p/f ratio less than ) with bilateral lung opacities on imaging not fully explained by a cardiogenic cause or fluid overload [ ] . currently, the majority of patients with covid- respiratory failure exhibit a similar gas exchange, respiratory system mechanics, and response to prone ventilation as prior large cohorts of patients with ards. although most severe covid- patients will fulfil the classic definition of ards, gattinoni et al. [ ] suggested that a subset of covid- pneumonia patients have preserved lung compliance and present with "silent hypoxaemia". they suggested the presence of an lphenotype in an interesting article that stimulates thought and suggests a framework for how to manage covid- patients. the problems were the small number of patients and that "compliance" does not fit in the berlin criteria, so we still need to categorise these patients as having ards. in fact, the surviving sepsis campaign panel recently recommended that "mechanically ventilated patients with covid- related ards should be managed similarly to other patients with acute respiratory failure in the icu" [ ] . ards has always been a construct in the minds of clinicians and researchers. it exists not because it is perfect, but because it has utility. it has utility for clinicians as it gives us a frame of reference for categorising patients, providing appropriate therapies, and prognosticating. it has utility for research as it allows otherwise heterogeneous patient groups to be studied in adequately powered clinical trials and provides a touchstone for new concepts and discoveries. the role of steroids in reducing mortality and ventilation days in patients with ards is well established [ , ] . in fact, villar and his colleagues have published the largest meta-analysis of using dexamethasone treatment for the acute respiratory distress syndrome few months back and this has shown a mortality benefit [ ] . the recovery trial (www.recoverytrial.net) is the largest existing randomised controlled trial to find the best treatment for covid- patients. it is uk based and expected to recruit , patients to six different treatment arms in addition to standard treatment in each hospital: no additional treatment vs lopinavirritonavir vs low-dose corticosteroids vs hydroxychloroquine vs azithromycin. in a factorial design, eligible patients are allocated simultaneously to no additional treatment vs convalescent plasma. a report announced from the main trial investigator on june stated that a total of patients were randomised to receive dexamethasone mg once per day (either by mouth or by intravenous injection) for days and were compared with patients randomised to usual care alone. among the patients who received usual care alone, -day mortality was highest in those who required ventilation ( %), intermediate in those patients who required oxygen only ( %), and lowest among those who did not require any respiratory intervention ( %). dexamethasone reduced deaths by one third in ventilated patients (rate ratio . [ % confidence interval . to . ]; p = . ) and by one fifth in other patients receiving oxygen only ( . [ . to . ]; p = . ). there was no benefit among those patients who did not require respiratory support ( . [ . to . ]; p = . ). based on these results, death would be prevented by treatment of around ventilated patients. this is concomitant with all the previous evidence of the role of steroids in ards patients. in fact, patients with severe covid- ards requiring mechanical ventilation in the recovery trial did not receive steroids. if we have solid evidence that dexamethasone is beneficial for patients with established ards due to a variety of causes and we believe that patients with severe covid- disease develop ards, how can we deprive five out of six arms of treatment in the recovery trial who will develop covid- related ards from steroids (or namely dexamethasone)? i believe that most intensivists around the world were using dexamethasone for their patients with severe covid- developing ards before the recovery trial results were released based on the evidence they had on how to manage this unique entity from a variety of causes. the question will remain: are we in a breakthrough of a new medication giving hope to millions around the world awaiting an efficient medication for covid- or are we solidifying the evidence we already know about what is effective for an ards patient regardless of its cause? abbreviations ards: adult respiratory distress syndrome; icu: intensive care unit acute respiratory distress syndrome: the berlin definition covid- pneumonia: different respiratory treatments for different phenotypes? surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ards guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (circi) in critically ill patients (part i): society of critical care medicine (sccm) and european society of dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations author's contributions hhe conceived the study and wrote the article. the author read and approved the final manuscript. availability of data and materials all data and material are available on request.ethics approval and consent to participate not applicable the author consents for publication. received: august accepted: september key: cord- -s lqdpvn authors: jose, ricardo j.; manuel, ari title: does coronavirus disease disprove the obesity paradox in acute respiratory distress syndrome? date: - - journal: obesity (silver spring) doi: . /oby. sha: doc_id: cord_uid: s lqdpvn obesity is associated with a decrease in mortality in patients with adult respiratory distress syndrome (ards) and is referred to as the obesity paradox. ards is a type of respiratory failure characterised by rapid onset of widespread inflammation in the lungs and is usually the result of infectious or chemical injury. the obesity paradox in ards patients has been investigated by ni et al, who conclude that obesity and morbid obesity were associated with a lower mortality rate in patients with ards. we are writing in reference to the editorial "covid and the patient with obesity -the editors speak out" ( ) . obesity is associated with a decrease in mortality in patients with acute respiratory distress syndrome (ards) and this is referred to as the obesity paradox ( ) . ards is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs and is usually the result of infectious or chemical injury. the obesity paradox in patients with ards has been investigated by ni et al. ( ) , who conclude that obesity and morbid obesity were associated with a lower mortality rate in patients with ards. one pathophysiological mechanism postulated to explain the decreased mortality in critically ill patients with obesity is preconditioning, a chronic pro-inflammatory status in obesity that creates a protective environment, limiting the detrimental effects of a more aggressive second hit, such as ventilatorinduced lung injury or sepsis ( ) . patients were further divided into a nonsurvivor group (n = ) and a survivor group (n = ). among the nonsurvivors, . % ( of ) of patients had bmi > kg/m , which was significantly higher than that of survivors ( . % ( of ), p < . ). wu et al. ( ) found that a group with severe covid- had significantly higher mean bmi values than a group of patients with mild disease ( . ± . vs. . ± . kg/m , p = . ). what could be causing the apparent difference in the severity of covid- in patients with obesity compared with previous studies of ards in patients with obesity? clinicians tend to consider patients with obesity at higher risk of worse outcomes; thus, this might result in earlier admission to the intensive care unit for monitoring purposes in normal circumstances ( ) . in this current pandemic, clinicians are not afforded this luxury. patients with obesity have reduced chest-wall elastance and lower total respiratory system compliance, with a decreased expiratory reserve volume. difficult airway management, as well as this altered lung and chest-wall physiology, in combination with positional gas trapping is routinely encountered in patients with obesity ( ). proning appears to be critical to success in ards, which is likely to be difficult in patients with obesity because of staff and equipment shortages in this pandemic situation. furthermore, right ventricular ( ) dysfunction seems to be an issue in patients with covid- , and patients with obesity may be at increased risk because of impaired right ventricular contraction due to higher circulating plasma volume, increased sympathetic nervous system activation, and metabolic dysregulation driving higher filling pressures. we do not know whether the obesity paradox has been broken by covid- . patients with obesity may be less affected by aspects of covid- , harder to treat because of obesity-related factors, and at greater risk because of obesity-relayed vulnerabilities. taken together, these elements may contribute to difficulties for patients with obesity in accessing care during a pandemic if they are wrongly perceived by clinicians and policy makers to be at a higher risk for worse outcomes.o covid and the patient with obesity -the editors speak out can body mass index predict clinical outcomes for patients with acute lung injury/ acute respiratory distress syndrome? a meta-analysis adipose-lung cell crosstalk in the obesity-ards paradox clinical characteristics and outcomes of cardiovascular disease patients infected by -ncov early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (covid- ) perioperative management of obese patients how to ventilate covid- patients. european society of intensive care medicine webinar key: cord- - alqfkd authors: revzin, margarita v.; raza, sarah; warshawsky, robin; d’agostino, catherine; srivastava, neil c.; bader, anna s.; malhotra, ajay; patel, ritesh d.; chen, kan; kyriakakos, christopher; pellerito, john s. title: multisystem imaging manifestations of covid- , part : viral pathogenesis and pulmonary and vascular system complications date: - - journal: radiographics doi: . /rg. sha: doc_id: cord_uid: alqfkd infection with severe acute respiratory syndrome coronavirus (sars-cov- ) results in coronavirus disease (covid- ), which was declared an official pandemic by the world health organization on march , . the infection has been reported in most countries around the world. as of august , there have been over million cases of covid- reported worldwide, with over covid- –associated deaths. it has become apparent that although covid- predominantly affects the respiratory system, many other organ systems can also be involved. imaging plays an essential role in the diagnosis of all manifestations of the disease, as well as its related complications, and proper utilization and interpretation of imaging examinations is crucial. with the growing global covid- outbreak, a comprehensive understanding of the diagnostic imaging hallmarks, imaging features, multisystemic involvement, and evolution of imaging findings is essential for effective patient management and treatment. to date, only a few articles have been published that comprehensively describe the multisystemic imaging manifestations of covid- . the authors provide an inclusive system-by-system image-based review of this life-threatening and rapidly spreading infection. in part of this article, the authors discuss general aspects of the disease, with an emphasis on virology, the pathophysiology of the virus, and clinical presentation of the disease. the key imaging features of the varied pathologic manifestations of this infection that involve the pulmonary and peripheral and central vascular systems are also described. part will focus on key imaging features of covid- that involve the cardiac, neurologic, abdominal, dermatologic and ocular, and musculoskeletal systems, as well as pediatric and pregnancy-related manifestations of the virus. vascular complications pertinent to each system will be also be discussed in part . online supplemental material is available for this article. (©)rsna, describe in detail the key imaging features of the varied pathologic manifestations of this infection that involve the pulmonary and peripheral and central vascular systems. all medical professionals, including radiologists, have been given the daunting task of recognizing the varied presentations and complications of covid- to ensure prompt diagnosis and thereby limit viral spread, as well as provide appropriate care to patients with the goal of improving recovery. coronaviruses are nonsegmented enveloped rna viruses with a single-strand linear positive-sense rna ( , ) . six types of coronavirus have been identified that cause human disease. four of these cause mild respiratory symptoms whereas the other two, middle east respiratory syndrome (mers-cov) coronavirus and severe acute respiratory syndrome coronavirus (sars-cov- ), have previously resulted in epidemics with high mortality rates ( ) . although the genome of sars-cov- is % identical to that of sars-cov- , it is more similar to the genome of bat coronaviruses ( % identical) ( ) . both sars-cov- and sars-cov- have similar receptor-binding gene regions, thus for cell entry both viruses use the same angiotensin-converting enzyme (ace ) receptor ( ) . currently, two different types of sars-cov- have been identified. however, the implications of this finding are uncertain ( ) . covid- is generally diagnosed with the results of a real-time reverse transcription-polymerase chain reaction (rt-pcr) test of a nasopharyngeal specimen obtained with a swab. however, this test may obtain false-negative results owing to a variety of factors, including insufficient viral load, improper collection of viral samples, and technical errors during the swabbing procedure ( , ) . more than million confirmed cases of co-vid- have been reported to date around the world, within all continents except for antarctica, and the incidence has been steadily rising ( ) . in the united states, covid- has been reported in all states, the district of columbia, and at least four territories ( ) . the cumulative incidence varies by state and is likely dependent on a number of factors, including population density and demographics, the extent of testing and reporting, and the initiation of mitigation strategies. in the united states, outbreaks in long-term care facilities and homeless shelters have underscored respiratory illness is the most commonly associated manifestation of sars-cov- . this is due to abundant ace receptor expression in the lung parenchyma, specifically on the acinar side of lung epithelial cells (pneumocytes) within the alveolar spaces, allowing virus entry. this correlates with the observation that the earliest lung injury is often seen in the distal airways. chest radiography and chest ct may be performed as adjuncts in cases of an initial negative rt-pcr test with persistent high clinical suspicion for disease. similar to those at chest radiography, the most suspicious ct features for covid- infection in the lungs include multifocal bilateral peripheral ggos, with or without focal consolidations, in lung regions close to pleural surfaces, including the fissures. patients admitted to the icu with barotrauma as a result of intubation or as a complication of ards may develop pneumothoraces or pneumomediastinum, further complicating the pulmonary manifestations of covid- infection. in december , a novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), was identified as the cause of a cluster of pneumonia cases in wuhan, a city in the hubei province of china. in the first few months of , infection with this novel coronavirus led to a global pandemic that has now affected almost every country in the world, and, by august , over million cases had been documented ( , ) . although sars-cov- disease (or coronavirus disease ) primarily manifests as a lung infection, with symptoms ranging from those of a mild upper respiratory infection to severe pneumonia and acute respiratory distress syndrome (ards), other multisystemic manifestations of this disease and related complications are becoming more commonly recognized ( ) . in this article, we provide an inclusive review of this potentially life-threatening and highly contagious infection, with emphasis on clinical presentation, the pathophysiology of the virus, and the role of imaging in diagnosing and monitoring the viral infection and its related complications. we provide a system-by-system review of the key imaging features of the various pathologic manifestations known to date, as well as offer relevant prognostic information that can be inferred from imaging findings. in part of this article, we discuss general aspects of the disease, with an emphasis on virology, the pathophysiology of the virus, and clinical presentation of the disease. in addition, we receptor of the host, with subsequent fusion of the viral and cell membranes (endocytosis), resulting in viral cell entry and depletion of ace receptors on the cell surface ( ) . once within a cell, the virus activates the intracellular immune system, which causes immune and nonimmune cells to release large amounts of proinflammatory cytokines that activate a cytokine storm and result in damage to the host ( ) (fig ) . antibodies to the virus are induced in those patients with sars-cov- infection. however, it is unknown whether all patients with sars-cov- infection mount a protective immune response and how long any protective effect will last. preliminary data on protective immunity are beginning to emerge ( , ) . the incubation period for covid- is believed to be less than days following exposure, with most cases manifesting - days after exposure ( , ( ) ( ) ( ) . the clinical presentation spectrum varies and includes mild to moderate symptoms ( %), severe symptoms ( %- %), and critical illness ( %). there is increasing evidence that many patients with covid- are asymptomatic yet are able to transmit the virus to others. on the basis of data from several most recent metaanalyses, it has been estimated that approximately %- % of patients with confirmed covid- are asymptomatic. however, it is important to recognize that a large percentage of patients with no symptoms at the time of detection will become symptomatic later. for a more accurate estimation of patients with confirmed covid- who remain asymptomatic throughout the disease course, longitudinal data must be collected over a sufficient period of time to allow distinction between asymptomatic and presymptomatic cases ( , ) . in addition, various studies have reported that children are likely to have a higher proportion of asymptomatic infection than adults. however, the largest meta-analysis and systematic review studies to date report that only approximately %- . % of confirmed pediatric cases are asymptomatic ( , ) . as with the adult population, the accuracy of this reported data remains unclear, as there are significant concerns regarding potential selection bias and testing error. the most common symptoms at presentation are fever, cough, and shortness of breath. mild to moderate disease is generally characterized by constitutional symptoms and the possible development of mild pneumonia, while symptoms of severe disease include dyspnea and hypoxia, as well as more than % lung involvement at the risk of exposure and infection in group settings ( ) . the main mode of transmission is person to person. however, other sources of transmission have also been implicated ( ) ( ) ( ) . person-toperson transmission is thought to occur mainly through respiratory droplets that are released in a cough or sneeze or during conversation. droplets typically do not travel more than ft (about m) and are not thought to linger in the air, although this notion has been challenged ( ) ( ) ( ) . environmental contamination also plays a role in viral transmission and occurs through droplet accumulation on frequently touched surfaces, with subsequent spread to susceptible mucous membranes within the mouth, nose, and eyes ( ) ( ) ( ) . men are disproportionately more commonly affected by an infection with sars-cov- , and the in-hospital mortality rate among male patients is significantly higher compared with that of female patients ( ) . there is uncertainty regarding the time interval during which an individual with covid- is infectious. it appears that the virus can be transmitted before the development of symptoms and throughout the course of illness. however, definitive data are not yet available, as most information on this subject comes from studies that evaluated the presence of viral rna in respiratory and other specimens, which may not correlate with infectivity. transmission of sars-cov- from asymptomatic individuals (or individuals within the incubation period) has been well documented ( ) ( ) ( ) ( ) ( ) . however, the extent to which asymptomatic and presymptomatic transmission occurs and their relative contribution to the spread of the pandemic remain unknown. the length of time an individual remains infectious is also uncertain. the duration of viral shedding is variable, and there appears to be a wide range, which may be dependent on the severity of illness ( ) ( ) ( ) . the life cycle of the virus within the host consists of the following five steps: (a) attachment, (b) penetration (viral entry to the cell), (c) biosynthesis (viral replication), (d) maturation (assembly and accumulation), and (e) release (through cell destruction). ace has been identified as a functional receptor for sars-cov- ( ) . in the human body, ace expression is high in the lung (expressed on lung epithelial cells), heart, gastrointestinal system, kidney, pancreas, spleen, bladder, cornea, and blood vessels ( , ) . sars-cov- enters a human cell by binding its spike or s protein to the ace imaging within - hours of symptom onset. critically ill patients are diagnosed with respiratory failure, shock, or multiorgan dysfunction ( ) ( ) ( ) ( ) ( ) ( ) . although most symptoms are respiratory in nature, clinical features of the disease may vary, with both typical and atypical presentations (table ) . recovery time appears to be around weeks for mild infections and - weeks for severe disease ( ) . the sars-cov- virus has the potential to cause complications in every body system. ards is a major complication of severe covid- , seen in %- % of patients with severe symptoms, and typically develops within - days after the onset of dyspnea. up to % of patients with ards will require mechanical ventilation ( , ) . ards is usually seen in patients greater than years of age and/or those with risk factors (discussed in the following section) ( ) . cardiac complications include arrhythmias (including atrial fibrillation), acute myocarditis, cardiomyopathy, and shock ( , ) . abdominal and/or pelvic solid organ injury is also commonly seen. thromboembolic complications, including pulmonary embolism (pe), peripheral venous and arterial thrombosis, and acute stroke (seen also in patients older than years without risk factors) have all been reported ( - ). individuals of any age can acquire sars-cov- infection, although adults middle-aged and older are most commonly affected, and older adults are more likely to experience severe disease ( , , ) . older age is also associated with increased mortality ( , , ) . eighty-seven percent of patients diagnosed with covid- are - years of age ( ) , and % percent of reported deaths have occurred in those aged greater than or equal to years. children are significantly less affected and exhibit a milder spectrum of disease. an increased risk of developing severe illness and increased mortality have been reported in patients with underlying cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, cancer (particularly hematologic malignancies, lung cancer, and metastatic disease), obesity, and chronic kidney disease ( , ( ) ( ) ( ) . the centers for disease control and prevention also includes immunocompromised status and liver disease as potential risk factors for severe illness, although specific data regarding risks associated with these conditions are limited. common laboratory test findings in those patients admitted to the hospital with covid- include lymphopenia and elevated aminotransaminase, lactate dehydrogenase, and inflammatory marker figure . illustration shows the proposed mechanism of sars-cov- cell entry and activation of the immune system. sars-cov- enters human cells by attaching to a cell surface receptor (ace ) and by utilizing a human enzyme called transmembrane serine protease (tmprss ). once bound to the receptor, sars-cov- undergoes endocytosis and enters into the cell, along with the ace receptor. this process reduces the number of ace receptors on cells, leading to an increase of angiotensin ii (angii) levels in the blood. angiotensin ii triggers an inflammatory pathway involving nf-κb and interleukin -signal transducer and activator of transcription protein (il- -stat ), particularly in nonimmune cells including endothelial and epithelial cells. this pathway forms a positive feedback cycle, named il- amplifier (il- amp), resulting in its excessive activation and therefore the cytokine storm and ards. part of this pathway involving nf-κb, il- -stat , or both is enhanced with age, which could be the reason why older patients are more at risk for death following covid- diagnosis compared with other age groups. s = viral spike protein subunit , s = viral spike protein subunit ,tnf-a = tumor necrosis factor-α. levels (eg, ferritin, c-reactive protein, and erythrocyte sedimentation rate) ( , , ) . lymphopenia is particularly common and is characterized by a lymphocyte count less than /microl. up to % of patients have leukocytosis (> / microl) and % of patients have leukopenia (< /microl) ( ) . in those patients who require treatment in the intensive care unit (icu) for pneumonia and/or other multisystem manifestations, serum procalcitonin levels are more likely to be elevated ( , ) . several laboratory test features, including elevated d-dimer levels (> . mg/ ml) and severe lymphopenia, have been associated with higher mortality rates (table ) ( , ) . respiratory illness is the most commonly associated manifestation of sars-cov- . this is due to abundant ace receptor expression in the lung paren-chyma, specifically on the acinar side of lung epithelial cells (pneumocytes) within the alveolar spaces, allowing virus entry (fig ) ( ). this correlates with the observation that the earliest lung injury is often seen in the distal airways ( ) . as discussed previously, alveolar damage is also attributable to the release of cytokines and chemokines that allow fluids to fill the pulmonary interstitium and acini, and the hypercoagulable state associated with covid- that results in micro-and macrothrombosis of the pulmonary vasculature ( ) . chest radiography is typically the first-line imaging modality performed in patients with suspected covid- infection. at patient admission, initial posteroranterior or anteroposterior (ap) chest radiographs are obtained, usually with the use of an intervening glass door to minimize exposure to the technologist (this technique provides adequate quality for chest radiograph acquisition when compared with that of conventional methods) ( ) . pulmonary consolidations and other pneumonia-related changes may be diagnosed when interpreting images obtained using this technique, as well as changes related to ards in patients who are critically ill. at early stages of disease and in mild cases, findings at chest radiography may be normal. wong et al ( ) found that initial chest radiography findings were abnormal in % of patients who required hospital admission, and in % of patients who had already been hospitalized ( ) . chest radiography and ct.-the most commonly reported findings of covid- at chest radiography include lung consolidation and ground-glass opacities (ggos) ( ) . reticular opacities may accompany areas of ggos and can be well depicted on standard chest radiographs. viral pneumonias, including covid- , typi-cally produce lung opacities in more than one lobe. additionally, evidence of multifocal airspace disease on chest radiographs can be indicative of covid- pneumonia, most frequently in a lower lung distribution and bilateral (fig ) . peripheral lung involvement is one of the most specific features of this infection, although it may resemble other inflammatory processes with multifocal, patchy, or confluent distribution of findings, such as organizing pneumonia (fig ) . a pattern of diffuse lung opacities may also be seen with covid- infection, as well as a number of other infectious and/or inflammatory processes, such as ards. during the disease course, lung opacities may rapidly evolve into a diffuse coalescent or consolidative pattern within - weeks after symptom onset, often peaking around - days after initial clinical presentation ( fig ) ( , ) . pleural effusions, lung cavitation, and pneumothorax are rare findings in covid- and, when depicted on chest radiographs, should raise suspicion for other potential causes ( ) ( ) ( ) . in young and middle-aged patients, the extent of ggos at chest radiography have been shown to correlate with the need for hospitalization and performing intubation. toussie et al ( ) reported that patients with ggos depicted in at least two lung zones are more likely to require hospitalization and those with ggos in three zones were more likely undergo intubation ( ) . on the basis of the pattern and distribution of the opacities and the presence or absence of certain clinical signs (such as obesity), the authors developed a chest radiography severity scoring system that could be used as a prognostic factor of outcomes in young adult patients with covid- (fig ) . advancements in new technologies such as artificial intelligence have allowed the utilization of automated assessment and tracking of covid- pulmonary disease severity on chest radiographs. the results of this artificial intelligence-based longitudinal assessment could potentially be used for the prediction of patient prognosis (with respect to the likelihood of requiring intubation or death) ( ) . chest radiography and chest ct may be performed as adjuncts in cases of an initial negative rt-pcr test with persistent high clinical suspicion for disease. the american college of radiology advises against using ct as a first-line tool in the diagnosis of covid- , recommending that it be used sparingly and reserved for symptomatic hospitalized patients with specific clinical indications, such as assessment of complications ( , ) . chest radiography is a less sensitive modality for the detection of covid- lung disease when compared with that ct, with a reported baseline chest radiography sensitivity of % ( ). the longitudinal assessment of covid- pneumonia progression in a -year-old man who presented to the emergency department with dyspnea and dry cough. (a) ap chest radiograph obtained at hospital admission at the time of symptom onset shows bilateral pulmonary opacities (arrows) at the periphery of the right mid lung and at the left lung base. (b) ap chest radiograph obtained on day of hospitalization shows progression of multifocal opacities bilaterally, which now involve more than two lobes, and interval development of bibasilar consolidations. these findings correspond to a higher severity score and carry a worse prognosis. in addition, there is mild pulmonary edema, suggestive of fluid overload. note that the patient had undergone intubation. (c) ap chest radiograph obtained on day of hospitalization shows progression of the multifocal bilateral peripheral opacities. true sensitivity and specificity of ct for detection of covid- remains relatively unknown. one study showed that radiologists identified cases of covid- versus other viral pneumonias correctly %- % of the time on the basis of typical ct features ( ) . however, the results of this study should be treated with caution, as the control and covid- -positive groups evaluated in this study came from two different institutions (the cases of covid- came from china and control cases from the united states) ( ). pulmonary us.-pulmonary us is another imaging modality that has been shown to be useful in the evaluation of critically ill patients with covid- , as it can be performed at the bedside and allows detection of pneumonia ( ) . the most commonly depicted features of lung involvement at us include the presence of b-line artifacts, an irregular thickened pleura, and subpleural consolidations (fig , movies , ) ( ). b-line artifact distribution corresponds to subpleural thickened interlobular septa, as demonstrated at ct. b-line artifacts are vertically oriented, highly dynamic, and hyperechoic artifacts that originate from the pleura or from areas of consolidation that usually manifest in pa-tients with alveolar-interstitial syndrome ( ) ( ) ( ) . these lines indicate accumulation of fluid in the pulmonary interstitial space (lung rockets) or alveoli (ground glass). when multiple, they are associated with pulmonary edema of cardiogenic, noncardiogenic, or mixed origin and are indicative of lung interstitial syndrome. b-line artifacts usually move with lung sliding. absence of lung sliding should raise concern that the lung is not inflated or that there may be a pneumothorax. hanced ct pulmonary angiography is performed to assess for possible pe in patients who develop acute dyspnea or acute deterioration of respiratory symptoms, or those in whom d-dimer markers are significantly elevated. the utilization of pulmonary scintigraphy (ventilation-perfusion scanning) in patients with suspected covid- pneumonia should be limited, unless deemed essential for medical management. if ventilation-perfusion scanning is deemed necessary, the ventilatory phase of the examination should be eliminated and only the perfusion phase should be performed ( ) . dual-energy ct has also been shown to be helpful for the evaluation of lung perfusion abnormalities ( ) . chest ct and reporting.-the role of chest ct in covid- is constantly evolving, with respect to clinical evaluation and treatment decisions. whereas the th chinese novel coronavirus pneumonia diagnosis and treatment plan incorporates ct into the criteria that clinically define covid- , the american college of radiology and the society of thoracic radiology, among others, advocate its use only in cases that require problem solving ( , , ) . the suitability of chest ct has also been assessed in various scenarios by the fleischner society, which deemed ct a major tool for diagnosis in patients with worsening symptoms or those in an environment that is resource constrained, with respect to rt-pcr testing availability ( ) . the recent radiological society of north american expert consensus statement on reporting proposed standardized nomenclature and an imaging classification for covid- pneumonia that involves four categories: typical appearance, indeterminate appearance, atypical appearance, and negative for pneumonia (table ) ( ) . in an attempt to pursue standardized reporting, a covid- reporting and data system (co-rad) based on a five-point scale of suspicion for . although subpleural involvement has been frequently documented, subpleural sparing may also be present (fig ) ( ) . there are two types of ggos that have been described: pure type and a mixed pattern, which is characterized by the presence of both ggos and areas of consolidation (fig ) . at ct, ggos with or without consolidation are typically depicted in a peripheral, posterior, and diffuse or lower-lung zone distribution ( , ) . pure-type ggos, the most commonly observed pattern, usually develop between days and after symptom onset, peaking at - days ( , ( ) ( ) ( ) . therefore, a negative chest ct examination should not be used to exclude the possibility of covid- , particularly early in the disease process ( ) . later in the disease course, the frequency of consolidation increases (fig ) . in fact, wang et al ( ) noted that after symptom onset, the predominant imaging abnormality becomes a mixed pattern of ggos, which typically peaks during days - of the illness and has been shown to be the second most prevalent pattern thereafter. as discussed previously, similar temporal changes have been observed on plain radiographs (fig ) ( ) . pulmonary vascular abnormalities such as vessel enlargement and regional mosaic perfusion patterns are also commonly found in covid- pneumonia ( ) . other more atypical or infrequent signs described in patients with covid- , such as the halo and reverse halo (or atoll) sign, usually manifest later in the disease course and are often absent at the time of symptom onset (figs , ) ( ) . the halo sign describes a nodule or mass surrounded by ground glass opacification, while the reverse halo (or atoll) sign is defined as a crescent or complete ring of consolidation that surrounds a focal area of ggo (figs , ) ( ) . both appearances may be embedded within an area of consolidation. however, it is important to note that these findings are not specific, as they have been previously described in early stages of opportunistic invasive fungal infections in immunocompromised patients (eg, aspergillosis, mucormycosis), as well as in immunocompetent patients diagnosed with nonfungal endemic infections, cryptogenic organizing pneumonia, vasculitis, neoplasm, and inflammatory diseases ( ) . unifocal unilateral lesions are uncommon and found only in % of patients with covid- (fig ) ( ) . the development of gelatinous mucus secretions may be responsible for lung collapse that can coexist with adjacent areas of consolidation. contrast-enhanced ct aids in the differentiation of collapsed atelectatic lung from pneumonia by demonstrating parenchymal lung enhancement within atelectatic lung and absent or markedly diminished lung enhancement in the setting of pneumonia (fig ) . bronchial wall thickening was described in %- % of patients with co-vid- (fig ) ( ) . pleural effusion, cavitation, pulmonary nodules, tree-in-bud opacities, and lymphadenopathy have not been reported in patients with covid- and can be useful in differentiating covid- pneumonia from other conditions ( ) . in normal lung, subsegmental vessels are usually inconspicuous within the subpleural regions. however, it has been shown that many patients with covid- exhibit tortuous and dilated distal vessels in the subpleural lung ( ) . these findings should not be confused with pulmonary vascular thickening (or thick vessel sign) within pulmonary opacities in covid- pneumonia, which has been reported to range from % to % in patients with covid- ( , , ) . pulmonary vascular thickening is a nonspecific sign and can be seen in other conditions, including pulmonary hypertension, pulmonary venoocclusive disease, hepatopulmonary syndrome, and portopulmonary hypertension ( ). one of the most common respiratory complications of covid- infection is ards (fig ) . while ards is a clinical diagnosis that has a grading system based on the degree of hypoxia, imaging plays a supportive role in its diagnosis and management. it has been suggested that abnormal pulmonary vasoregulation may play a large role in patients with covid- infection before the onset of radiologic or clinical manifestations that would suggest ards, and may be even more pronounced when ards does occur ( , ) . the presence of disordered vasoregulation is supported by the frequency of pronounced dilatation of vasculature within regions of diseased lung, leading to significant ventilation and perfusion mismatches early in the disease. perfusion abnormalities in the setting of covid- pneumonia, most optimally assessed at dual-energy ct, may suggest an underlying vascular process. chest radiography and ct can aid in the identification of additional underlying causes of ards symptoms, such as superimposed bacterial pneumonia or congestive heart failure, although findings are frequently nonspecific. in the acute phase of ards, chest radiography may demonstrate bilateral airspace opacities with air bronchograms (fig ) . unless pulmonary edema is also present, septal lines and pleural effusions are not expected findings. in the acute exudative phase of ards, within the first week, ct demonstrates diffuse ggos in a posterior and basal predominance, and a crazy-paving pattern may also be depicted ( fig ) . the crazy-paving appearance is thought to be attributable to superimposition of thick interlobular septa on ggos and was detected in % of patients with covid- ( ) . in the subsequent subacute phase of ards, consolidations may develop posteriorly or anteriorly if the patient is prone, with reversible bronchiectasis (figs , ) . in the late phase of ards, more patients admitted to the icu with barotrauma as a result of intubation or as a complication of ards may develop pneumothoraces or pneumomediastinum, further complicating the pulmonary manifestations of covid- infection (figs - ) . in fact, patients with covid- who require mechanical ventilation were found to be at increased risk of barotrauma when compared with patients with ards alone and patients without covid- . barotrauma was associated with a longer length of hospital stay and was an independent risk factor for death in patients with covid- ( ). pe is another complication of covid- infection, described in further detail in the "peripheral and central vascular manifestations of co-vid- " section. in recently published studies, the incidence of pe in patients with covid- who underwent pulmonary ct angiography was reported to be between % and % ( , , ) . currently, there are conflicting results as to whether there is increased probability of pe in patients with covid- who are receiving intensive care or require mechanical ventilation when compared with those who are not admitted to the icu ( , ) . a notable risk factor for the development of pe is obesity, with recent data showing that patients with a body mass index greater than kg/m are . times more likely to develop pe. additionally, african american patients are at higher risk of developing pe when compared with other ethnic groups ( ) . with respect to the location and distribution of thrombi, pe is more commonly found in the segmental and lobar branches and less commonly in the central pulmonary arteries (fig ) ( ) . long-term effects of the disease and followup long-term imaging sequelae have not been well established at this point and are still under investigation. organ-specific vascular manifestations and complications will be discussed in the corresponding part article in a future issue of radiographics. manifestations of covid- there is growing evidence of coagulopathy related to covid- , which may predispose patients to both venous and arterial thromboembolism and result in deep venous thrombosis (dvt), pe, limb ischemia, stroke, and myocardial infarction ( ) ( ) ( ) . although the pathogenesis and incidence of thrombotic complications are not clearly understood, coagulopathy has been noted to be a poor prognostic indicator and is associated with higher mortality ( , , , ) . the most common pattern of coagulopathy observed in patients hospitalized with covid- is characterized by elevated d-dimer and fibrinogen levels ( ) and correlates with a parallel rise in inflammatory marker levels, including but not limited to levels of c-reactive protein, tumor necrosis factor-α, and various interleukins ( fig ) ( , ( ) ( ) ( ) . initial data have demonstrated that co-vid- -associated coagulopathy manifests with features of both sepsis-induced coagulopathy and thrombotic microangiopathy ( , ( ) ( ) ( ) . multiple factors, including inflammatory cytokine release, critical illness, platelet activation, and endothelial dysfunction, play a role. this is further evidenced by recent histologic data that have demonstrated diffuse alveolar damage, microthrombi formation, and occlusion of small pulmonary vessels ( ) . however, it is still uncertain whether covid- has other unique characteristics that result in direct activation of coagulation. as seen in other infections that result in sepsis-induced coagulopathy, the primary infection of covid- initiates cellular injury and results in an inflammatory response, which includes production of inflammatory cytokines, endothelial activation, and recruitment of neutrophils and mononuclear cells. the activation of coagulation is a host immune response that contributes to the compartmentalization of pathogens in an attempt to prevent dissemination. however, endothelial cell dysfunction results in excess thrombin production and disrupted fibrinolysis, which results in a hypercoagulable state. following cellular injury, tissue factor, which is a critical initiator of the extrinsic coagulation pathway, is expressed on macrophages, monocytes, and endothelial cells and plays a central role in the development of coagulopathy and disseminated intravascular coagulation. additionally, fibrinolysis is suppressed in sepsis ( , ) . compared with the typical pattern of sepsisinduced coagulopathy, patients with covid- figure . covid- complicated by pneumothorax and pneumomediastinum in a -year-old man who underwent intubation with increased oxygen requirements. posteroranterior chest radiograph obtained in the prone position shows moderate-size right pneumothorax and small left apical pneumothorax (black arrows). pneumomediastinum is evident by the presence of air around the aortic arch and beneath the heart (red arrows). the endotracheal tube and feeding tube are in place. a large amount of subcutaneous emphysema is depicted bilaterally (white arrows). the patchy bilateral hazy opacities are compatible with covid- pneumonia. are diagnosed with less prominent thrombocytopenia ( ) . additionally, prothrombin time and partial thromboplastin time remain near normal and fibrinogen levels are elevated until later in the disease process when they decrease and patients subsequently develop disseminated intravascular coagulation ( , ( ) ( ) ( ) . additionally, authors of a recent study have suggested that a small subset of severe co-vid- cases demonstrate complement-mediated microvascular injury and thrombosis, consistent with activation of the alternative pathway and lectin pathway cascades ( ) . it is also important to note that hypoxia itself can stimulate thrombosis through an increase in blood viscosity and a hypoxia-inducible transcription factor-dependent signaling pathway. additionally, ards may be a potential cause for hypoxic pulmonary vasoconstriction, pulmonary hypertension, and right ventricular failure ( ) . aside from hemostatic derangements, underlying comorbidities (cancer, obesity, etc) and immobility and the use of mechanical ventilation, central venous catheters, and extracorporeal circuits contribute to thrombotic risk. in addition, current investigational medications for treating covid- may have adverse drug-drug interactions with antiplatelet agents and anticoagulation therapy ( ) . to summarize, the pathophysiology of the hypercoagulable state found in association with covid- disease is extremely complex and multifactorial in nature, with many varied factors playing a role in its occurrence (fig ) . it is important to note that the existing evidence is primarily derived from a few small retrospective analyses, and further evaluation with large prospective cohort studies must be conducted to better understand this illness. duplex us, mr angiography, and ct angiography, as well as mr and indirect or combined ct venography are the primary noninvasive modalities for the diagnosis of arterial and venous thrombosis and thromboembolism in patients with covid- ( , ) . however, it is important to note that these disease processes may also be detected at routine contrast-enhanced ct performed in the portal venous phase, particularly when the main or large branch vessels are affected. taking into consideration that many multiorgan and multisystem complications of covid- are caused by or directly associated with vascular thrombotic events, careful assessment of the vasculature is essential in the evaluation of all imaging examinations performed in patients with covid- . the risk of venous thromboembolism (vte), which is already greater in all critically ill patients, is higher in those with critical illness due to sars-cov- infection ( ) . an ever-increasing number of published studies have assessed the risk of vte in patients with covid- , with reported incidences of dvt ranging from % to % ( , ( ) ( ) ( ) . the incidence was found to be much higher if both symptomatic and asymptomatic patients were assessed and in patients with prolonged hospital stays in the icu (cumulative incidence rates were as high as % at days of hospitalization) ( ) . the wide range of reported incidences can be explained by the fact that vte remains largely underdiagnosed in patients with severe covid- , as only symptomatic patients generally undergo imaging. this is in part due to the contagious nature of covid- , as its high transmissibility rate complicates the workup of patients with infection. in an attempt to minimize exposure to radiologic technologists and transport personnel, only symptomatic patients are typically eligible to undergo imaging, often using abbreviated protocols and portable machines that may result in a limited evaluation. additionally, the concern over shortages of personal protective equipment (ppe) influenced the number and types of examinations that were offered to this group of patients. underdiagnosis of complications of vte in patients with co-vid- is a significant issue, as many of these patients who are severely ill already have ards and its complications (including hypoxic pulmonary vasoconstriction, pulmonary hypertension, and right ventricular failure), and further insult from a pe may be fatal. it is important to note that veins of any caliber may be affected, and therefore all vessels should be scrutinized for potential thrombus. elevated d-dimer levels, commonly found in patients with covid- , do not currently warrant routine investigation for acute vte in the absence of clinical manifestations or other supporting information ( ) . however, in patients with high clinical suspicion for vte, there should be a low threshold for ordering diagnostic tests to evaluate for dvt and/or pe. the imaging examinations performed to diagnose dvt or pe in patients with covid- may not be requested or performed, potentially owing to patient instability. moreover, performing imaging examinations may be challenging in patients with severe ards who require prone positioning. investigating for pe as well as lower and upper extremity dvt may not always be feasible owing to these clinical and positioning issues. although deterioration of right ventricular function in this setting may be a critical finding that justifies the need for establishing a diagnosis of pe, it could also be argued that the prognosis of patients with ards who require prone positioning is so grave that investigation for an underlying vte may not alter the clinical course. preventive and therapeutic use of antithrombotic agents is helpful toward mitigating the occurrence thrombotic and hemorrhagic events in these high-risk patients ( ) . lower and upper extremity doppler us is the first-line imaging modality for diagnosis of peripheral venous thrombosis and can be performed at the bedside. occlusive and partially occlusive thrombi and their potential associations with central lines can be readily diagnosed . noncompressible veins, echogenic clot, and minimal or absent flow within a distended vein are the us hallmarks of acute or subacute dvt (figs - ) . superinfection may result in thrombophlebitis and can be diagnosed by the demonstration of hyperemia in the wall of an otherwise thrombotic vessel at color doppler us. in cases of incomplete and/or inadequate thrombus evaluation or extension of thrombus into a more central vessel, ct and mr venography can be employed (fig ) . the presence of a filling defect within a vessel, with or without occlusion, is the characteristic finding of venous thrombosis. us, absence of flow within an arterial segment is diagnostic of an occlusive thrombus. abnormal waveforms (stump waveforms), character- the authors of only a few studies to date have evaluated the frequency of peripheral arterial thrombosis in patients with covid, with a reported incidence of . % ( ) . the authors of a few reported cases of lower extremity arterial thrombosis have suggested a link between preexisting peripheral arterial disease and the development of arterial thromboembolism. it has been hypothesized that acute and progressive thrombosis may be attributable to a combination of the hyperinflammatory state induced by covid- superimposed on a preexisting condition ( , ) . doppler us and ct angiography of the extremity vessels are both instrumental in the evaluation of peripheral arterial thrombosis. at ized by a low amplitude and high-resistance pattern with absence of diastolic flow, can aid in identification of a more distal occlusion. alternatively, tardus parvus waveforms within more distally recanalized vessels are findings suggestive of a more proximal significant stenosis or occlusion (fig ) . reconstituted flow, sometimes with collateralization, may be depicted distal to an occlusion. peripheral and central arterial thromboembolism may also be the result of atrial fibrillation. ct angiography aids in the assessment of the extent of thrombosis and its potential complications such as ischemia to a related structure or organ. an abrupt cutoff of the affected vessel may be readily detected at ct angiography (figs - , movie ). the few reported cases ( ) of peripheral arterial thromboembolism associated with covid- have involved both upper and lower extremity arteries, and carotid and vertebral artery involvement have been described as well. the larger central arterial system may also be involved (eg, floating thrombi may be visualized in the aorta and aortic arch) ( fig ) ( ) . it is important to keep in mind that covid- can affect more than one organ or structure, and every organ and vessel should be scrutinized when assessing for complications . it is also essential to recognize that patients with covid- may develop thrombosis of various vascular systems, and there could be concomitant involvement of one or more venous or arterial vascular beds. therefore, if evidence of thrombosis is detected, careful assessment of the entire imaged vascular system, as well as correlated organ or structure, is essential. sars-cov- is a novel coronavirus that has rapidly resulted in a worldwide pandemic and has been the cause of extreme morbidity and mortality. it primarily affects the respiratory system but may also impact a multitude of other systems in the human body, resulting in multiorgan injury and, in some cases, failure. imaging plays a significant role in the detection, diagnosis, and assessment of virus-induced injury, as well as its associated complications. a recognition and understanding of the pathophysiology of the virus and its effects on the immune system and coagulation is paramount toward improving radiologists' ability to accurately identify key imaging findings and promptly recognize possible complications, specifically those affecting the pulmonary and vascular systems, thereby minimizing the number of diagnostic misses and misinterpretations. appropriate application of the described chest radiography and ct scoring systems in the evaluation of lung involvement, including automated assessment, may increase the consistency of reported findings and aid in risk stratification, as well as offer prognostic information. owing to the complexity of the viral pathophysiology and its targeting of multiple organ systems, the recognition of one complication should prompt intense scrutiny for others, particularly if the patient is critically ill. a thorough knowledge of diagnostic imaging hallmarks, atypical imaging features, multisystem manifestations, and evolution of imaging findings is essential to optimize patient care. in a and b) . (c-f) sagittal (c), coronal (d), and axial (e, f) ct angiographic images show a large thrombus extending from the abdominal aorta into the superior mesenteric artery origin (arrow in c), which resulted in bowel ischemia, evidenced by thickening of the watershed splenic flexure of the large bowel (arrow in d). note the multifocal bilateral wedge-shaped renal cortical infarcts (arrows in e). note also a nonocclusive thrombus in the left profunda femoris artery (white arrow in f), indicative of a concurrent presence of a peripheral thrombosis. there is normal opacification of the patent right profunda femoris artery (black arrow in f). this case demonstrates multifocal multisystem manifestations of covid- complicated by coagulopathy that resulted in injury to various organs and systems. it is an example of the need for increased awareness among radiologists to thoroughly evaluate all covered anatomy for covid-related complications. covid- coronavirus pandemic saving mothers' lives: reviewing maternal deaths to make motherhood safer: - -the eighth report of the confidential enquiries into maternal deaths in the united kingdom comorbidities and multiorgan injuries in the treatment of covid- novel coronavirus: what neuroradiologists as citizens of the world need to know tissue distribution of ace protein, the functional receptor for sars coronavirus: a first step in understanding sars pathogenesis covid- ) outbreak: what the department of radiology should know a pneumonia outbreak associated with a new coronavirus of probable bat origin the genetic sequence, origin, and diagnosis of sars-cov- detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction sars-cov- viral load in upper respiratory specimens of infected patients tubal ectopic pregnancy geographic differences in covid- cases, deaths, and incidence: united states prevalence of sars-cov- infection in residents of a large homeless shelter in boston surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient aerosol and surface stability of sars-cov- as compared with sars-cov- stability and inactivation of sars coronavirus comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with covid- : a systematic review and meta-analysis transmission of -ncov infection from an asymptomatic contact in germany a familial cluster of infection associated with the novel coronavirus indicating possible person-to-person transmission during the incubation period presumed asymptomatic carrier transmission of covid- clinical characteristics of asymptomatic infections with covid- screened among close contacts in nanjing covid- transmission within a family cluster by presymptomatic carriers in china viral dynamics in mild and severe cases of covid- viral load dynamics and disease severity in patients infected with sars-cov- in zhejiang province, china factors associated with prolonged viral rna shedding in patients with coronavirus disease (covid- ) functional assessment of cell entry and receptor usage for sars-cov- and other lineage b betacoronaviruses single-cell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to -ncov infection expression of sars-cov- receptor ace and tmprss in human primary conjunctival and pterygium cell lines and in mouse cornea structural basis of receptor recognition by sars-cov- covid- : a new virus, but a familiar receptor and cytokine release syndrome virological assessment of hospitalized patients with covid- treatment of critically ill patients with covid- with convalescent plasma early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical characteristics of coronavirus disease in china a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster prevalence of asymptomatic sars-cov- infection: a narrative review proportion of asymptomatic coronavirus disease : a systematic review and metaanalysis clinical characteristics of children with covid- : a meta-analysis persons evaluated for novel coronavirus: united states clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical characteristics of covid- in new york city epidemiological and clinical aspects of covid- ; a narrative review profile of rt-pcr for sars-cov- : a preliminary study from covid- patients illinois department of public health. covid- statistics cardiovascular disease, drug therapy, and mortality in radiographics.rsna.org acute pe associated with covid- pneumonia detected with pulmonary ct angiography acute pe and covid- pneumonia: a random association? coagulopathy and antiphospholipid antibodies in patients with covid- neurologic manifestations of hospitalized patients with coronavirus disease incidence of thrombotic complications in critically ill icu patients with covid- large-vessel stroke as a presenting feature of covid- in the young covid- : consider cytokine storm syndromes and immunosuppression radiographics update: venous thrombosis and hypercoagulability in the abdomen and pelvis-findings in covid- characteristics of hospitalized adults with covid- in an integrated health care system in california cancer patients in sars-cov- infection: a nationwide analysis in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study obesity in patients younger than years is a risk factor for covid- hospital admission clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china d-dimer levels on admission to predict in-hospital mortality in patients with covid- frequency and distribution of chest radiographic findings in patients positive for covid- gross examination report of a covid- death autopsy policies and guidelines for covid- preparedness: experiences from the university of washington ct imaging features of novel coronavirus ( -ncov) ct features of coronavirus disease (covid- ) pneumonia in patients in wuhan, china chest ct findings in coronavirus disease- (covid- ): relationship to duration of infection essentials for radiologists on covid- : an update-radiology scientific expert panel portable chest x-ray in coronavirus disease- (covid- ): a pictorial review coronavirus disease (covid- ): a systematic review of imaging findings in patients clinical and chest radiography features determine patient outcomes in young and middle age adults with covid- automated assessment of covid- pulmonary disease severity on chest radiographs using convolutional siamese neural networks. medrxiv advocacy-and-economics/acr-position-statements/ recommendations-for-chest-radiography-and-ct-for-suspected-covid -infection ct should not be used as first-line tool against coronavirus, acr warns following pandemic declaration performance of radiologists in differentiating covid- from non-covid- viral pneumonia at chest ct radiological society of north america expert consensus statement on reporting chest ct findings related to covid- : endorsed by the society of thoracic radiology, the american college of radiology, and rsna-secondary publication is there a role for lung ultrasound during the covid- pandemic? sonographic signs and patterns of covid- pneumonia bedside lung ultrasound in the assessment of alveolar-interstitial syndrome lung ultrasonography and cardiac surgery: a narrative review re: ventilation-perfusion scans during the coronavirus disease (covid- ) outbreak pulmonary vascular pathology in covid- co-rads: a categorical ct assessment scheme for patients suspected of having covid- -definition and evaluation henry ts; six signatories. a role for ct in covid- ? what data really tell us so far the role of chest imaging in patient management during the co-vid- pandemic: a multinational consensus statement from the fleischner society time course of lung changes at chest ct during recovery from coronavirus disease (covid- ) temporal changes of ct findings in patients with covid- pneumonia: a longitudinal study novel coronavirus ( -ncov) pneumonia the diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts chest ct manifestations of new coronavirus disease (covid- ): a pictorial review chest ct features and their role in covid- radiology perspective of coronavirus disease (covid- ): lessons from severe acute respiratory syndrome and middle east respiratory syndrome coronavirus disease (covid- ): role of chest ct in diagnosis and management relation between chest ct findings and clinical conditions of coronavirus disease (covid- ) pneumonia: a multicenter study ct findings in diseases associated with pulmonary hypertension: a current review covid- does not lead to a "typical" acute respiratory distress syndrome imaging of diffuse lung disease in the intensive care unit patient high incidence of barotrauma in patients with covid- infection on invasive mechanical ventilation acute pe in patients with covid- at ct angiography and relationship to d-dimer levels acute pe and covid- diagnosis, prevention, and treatment of thromboembolic complications in covid- : report of the national institute for public health of the netherlands covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: jacc state-of-the-art review venous thrombosis and hypercoagulability in the abdomen and pelvis: causes and imaging findings abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia the procoagulant pattern of patients with covid- acute respiratory distress syndrome hypercoagulability of covid- patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis thromboinflammation and the hypercoagulability of covid- advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation difference of coagulation features between severe pneumonia induced by sars-cov and non-sars-cov complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases cardiovascular considerations for patients, health care workers, and health systems during the covid- pandemic indirect ct venography at kvp with sinogram-affirmed iterative reconstruction compared to kvp with filtered back projection: assessment of image quality and radiation dose combined direct and indirect ct venography (combined ctv) in detecting lower extremity deep vein thrombosis confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of venous thromboembolism in hospitalized patients with covid- d-dimer is associated with severity of coronavirus disease : a pooled analysis rhabdomyolysis as a presentation of novel coronavirus disease venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with novel coronavirus disease: a case report severe arterial thrombosis associated with covid- infection this journal-based sa-cme activity has been approved for ama pra category credit tm . see rsna.org/learning-center-rg. key: cord- -ew eef authors: dos santos rocha, andre; fodor, gergely h.; kassai, miklos; degrugilliers, loic; bayat, sam; petak, ferenc; habre, walid title: physiologically variable ventilation reduces regional lung inflammation in a pediatric model of acute respiratory distress syndrome date: - - journal: respir res doi: . /s - - -x sha: doc_id: cord_uid: ew eef background: benefits of variable mechanical ventilation based on the physiological breathing pattern have been observed both in healthy and injured lungs. these benefits have not been characterized in pediatric models and the effect of this ventilation mode on regional distribution of lung inflammation also remains controversial. here, we compare structural, molecular and functional outcomes reflecting regional inflammation between pvv and conventional pressure-controlled ventilation (pcv) in a pediatric model of healthy lungs and acute respiratory distress syndrome (ards). methods: new-zealand white rabbit pups (n = , ± g [half-width % confidence interval]), with healthy lungs or after induction of ards, were randomized to five hours of mechanical ventilation with pcv or pvv. regional lung aeration, inflammation and perfusion were assessed using x-ray computed tomography, positron-emission tomography and single-photon emission computed tomography, respectively. ventilation parameters, blood gases and respiratory tissue elastance were recorded hourly. results: mechanical ventilation worsened respiratory elastance in healthy and ards animals ventilated with pcv ( ± %, ± %, p < . ), however, this trend was improved by pvv ( ± %, − ± %). animals receiving pvv presented reduced inflammation as assessed by lung normalized [( )f]fluorodeoxyglucose uptake in healthy ( . ± . standardized uptake value, suv) and ards animals ( . ± . suv) compared to pcv ( . ± . and . ± . suv, respectively, p < . ), particularly in the well and poorly aerated lung zones. no benefit of pvv could be detected on regional blood perfusion or blood gas parameters. conclusions: variable ventilation based on a physiological respiratory pattern, compared to conventional pressure-controlled ventilation, reduced global and regional inflammation in both healthy and injured lungs of juvenile rabbits. acute respiratory distress syndrome (ards), characterized by the acute onset of severe hypoxic respiratory failure, remains a prevalent and often lethal condition in intensive care [ ] . although mechanical ventilation is a crucial life-saving treatment for ards, there is a considerable body of evidence indicating that prolonged positive-pressure ventilation can initiate, perpetuate or aggravate injury to lung tissue [ , ] . the resulting exaggerated mechanical stress, along with the monotonous alveolar opening and closing, exerts shear stress and increased strain in the lung tissue [ ] , conditions that contribute to ventilator-induced lung injury (vili). while various modalities of mechanical ventilation have been proposed to reduce vili [ ] [ ] [ ] [ ] , protective ventilation with monotonous tidal volume (vt) may not be the only rational strategy. in recent years, it has been advocated that mechanical ventilation reproducing the natural variability of breathing is better than conventional modes [ , ] . variable ventilation has been shown to be beneficial for gas exchange and respiratory mechanics in various animal models with healthy [ ] [ ] [ ] or injured lungs, including ards [ ] [ ] [ ] [ ] . we have previously established a variable ventilation modality using pre-recorded breathing patterns of healthy animals [ ] . this physiologically variable ventilation (pvv) is characterized by breath-to-breath variability of vt and respiratory rate, in contrast to the monotonous conventional ventilation modes. recent interest in variable ventilation stems from the need to reduce cyclic alveolar reopening during mechanical ventilation, especially in injured lungs, to avoid development or propagation of lung inflammation, atelectasis and subsequent hypoxemia [ ] . whereas some studies demonstrated the beneficial effect of introducing variability into lung recruitment [ , ] , and others reported improvement in global respiratory mechanical and functional parameters [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , there is still a lack of detailed knowledge about the pathophysiological background related to the functional and regional behavior of the lung during variable ventilation. moreover, the potential of pvv in the context of pediatric ards has not been characterized. to investigate the effect of pvv, lung functional and structural changes were compared to those obtained with conventional monotonous ventilation in normal lungs and ards, in a pediatric model. global respiratory parameters were measured to characterize the overall lung condition. regional lung aeration, pulmonary perfusion and inflammation were assessed by functional imaging using positron-emission tomography (pet) and single-photon emission computed tomography (spect) combined with x-ray computed tomography (ct). a more detailed description of the methods can be found in additional file . new zealand white rabbit pups of both sexes, aged to weeks, were included in the present study (mean weight: g, - g). this age can be approximated to an equivalent human age of to months [ ] . rabbits underwent tracheostomy and continuous intravenous (iv) anesthesia using propofol ( mg/kg/h), fentanyl ( µg/ kg/h), midazolam ( . mg/kg/h) and atracurium ( . mg/ kg/h). the protocol of the study is depicted in fig. . under baseline (bl) conditions, pressure-controlled ventilation was applied, using a positive end-expiratory pressure (peep) of cmh o, a fraction of inspired oxygen (fio ) of . , a vt of ml/kg and a respiratory rate to achieve normocapnia (end-tidal co of . - %). arterial and central venous blood gas analyses and respiratory mechanical measurements were performed at bl. subsequently, animals were randomized for the absence (ctrl) or presence (ards) of lung injury. mild ards, according to the berlin definition [ ] , was induced by combination of intravenous lipopolysaccharide ( µg/ kg) and injurious ventilation (vt = ml/kg, cmh o peep, fio = . ) with a target range of partial pressure of arterial oxygen (pao )/fio ratio of - mmhg. when the target range of pao /fio was reached, animals were further randomized for the ventilation mode: five-hour mechanical ventilation (vt = ml/ kg, peep = cmh o) was applied using either pressure-controlled ventilation (pcv) or pvv. fio was adjusted according to pao /fio : using fio = . above mmhg; fio = . between - mmhg; fio = . between - mmhg, and fio = . in the case that pao decreased below mmhg. arterial blood gas and respiratory mechanics were measured hourly (t -t ). after h (t ), in vivo lung imaging was performed under continuous application of the ventilation mode. subsequently, animals were euthanized with iv sodium thiopental ( mg/kg). bronchoalveolar lavage was performed ex vivo in the right lung, and the left lung was extracted for histological analysis. respiratory mechanical parameters were assessed by the wave-tube method of the forced oscillation technique, as detailed previously [ ] . the constant-phase model [ ] was fitted to the spectra to separate airway and tissue compartments of the respiratory system. airway resistance (raw), tissue damping (g) and tissue elastance (h) were estimated from the fits. a commercially available pediatric ventilator (servo-i, maquet critical care, solna, sweden) was used with special firmware. the applied variable pattern was the reproduction of physiological breathing in rabbit pups, obtained using unconstrained whole-body plethysmography. structural imaging of the respiratory system was acquired using ct. regional lung perfusion was assessed though spect imaging using m tc-labeled iv albumin macroaggregates. regional distribution of inflammatory activity was assessed using pet imaging of fluorodeoxyglucose ( f-fdg) [ ] . lung radiodensity was expressed in mean pixel value (mpv), while pet and spect activity were expressed as standardized uptake value (suv) normalized for voxelwise fraction of lung tissue [ ] . ct images were segmented to well aerated, poorly aerated and non-aerated zones, based on radiodensity, as well as to ventral and dorsal halves. these segmented zones were considered when analyzing pet and spect images. cell and cytokine content of the bronchoalveolar lavage fluid (balf) was analyzed as detailed previously [ ] . a histological lung injury score was determined according to the american thoracic society guidelines [ ] . tracheal pressure, airflow, arterial pressure, central venous pressure (cvp) and electrocardiogram were digitized and continuously recorded. mean arterial pressure (map) and heart rate (hr) were assessed from these curves. the primary outcomes of the present study were defined as respiratory mechanical parameters (raw, tissue damping and elastance), arterial blood gas parameters (lactate, ph, pao /fio and paco ) and imaging parameters. secondary outcomes were hemodynamic and ventilation parameters, cytokine levels and lung injury histological indices. data are presented as mean ± half-width of % confidence interval. normality of the data was assessed for each variable with the shapiro-wilk test. in case of a failed normality test, the variable was log-transformed. repeated measures analyses of variance (anova) using linear mixed-effect model fits by a restricted maximum likelihood (reml) method were applied to calculate statistical significances followed by dunnett or holm-sidak post-hoc tests, using a significance level of p < . , and all p values two-sided. forty-four rabbits were randomized into one of four experimental groups. eight rabbits were excluded from the analysis due to vital issues precluding the h of ventilation (pneumothorax, n = ; hemorrhage, n = ). therefore, rabbits were included in the final analyses, with zrs: impedance of respiratory system; bg: blood gas; peep: positive end-expiratory pressure; lps iv: lipopolysaccharide intravenous; pcv: pressure-controlled ventilation; pvv: physiological variable ventilation; ctrl: control; ards: acute respiratory distress syndrome the following distribution: rabbits were included in the pcv-ards group, rabbits in pvv-ards, rabbits in pcv-ctrl and rabbits in pvv-ctrl. parameters characterizing respiratory mechanics obtained prior to initiating the -h ventilation are displayed in additional file : table s . changes in respiratory mechanical parameters relative to those obtained immediately after the induction of lung injury are displayed in fig. . applying pcv for h led to significant increases in tissue elastance (t -t , p < . ) in the control animals and in raw in the ards model (t -t , p < . ). conversely, ventilating the lungs with pvv resulted in a significant decrease in tissue damping in control animals (t -t , p < . ), whereas no change in respiratory mechanics was detected in the ards model. comparison of the two ventilation modes revealed significantly lower relative changes with pvv in tissue damping for the control animals (t -t , p < . ) and tissue elastance for the ards model (t -t , p < . ). figure depicts the blood gas parameters during the -h ventilation. inducing lung injury led to significant impairment of the blood oxygenation index (pao /fio ), confirming the presence of mild to moderate ards, according to the berlin definition [ ] . further drift in pao /fio was observed in the pvv-ards group that resulted in statistically significant decreases after the monotonous ventilation with pcv had no effect on the blood gas parameters in the control animals, whereas a systematic decrease in ph and plasma lactate concentration was observed in the ards groups (t -t , p < . ). applying variable ventilation for h in the control group had no systematic effect on gas exchange, whereas higher paco levels (t -t , p < . ) were associated with significantly diminished ph and elevated lactate in animals with ards (t -t , p < . ). representative ct, pet and spect images with the corresponding regional aeration maps in control and ards conditions are shown in fig. . more heterogeneous lung structure, as indicated by heterogeneous regional distribution of f-fdg uptake and m tc-labeled albumin macroaggregates, was observed in the presence of ards. the pet uptake values calculated for the total lung and at regional levels are summarized for the study groups in the left panels of fig. . when averaging the entire lung, significantly lower mean f-fdg uptake was evidenced for the lungs in the animals ventilated with pvv, regardless of the presence of lung injury. this difference was also detected at the regional level in rabbits with healthy lungs ventilated with pvv (p < . ). characterizing the differences in f-fdg uptake among the various aeration zones, defined by ct density, revealed the highest activity in the well aerated zones, with to threefold differences compared to the non-aerated zones (p < . , well aerated vs. poorly aerated or non-aerated). likewise, ventral (non-dependent) regions presented significantly higher f-fdg uptake compared to dorsal (dependent) regions in both ventilation modes. furthermore, significantly decreased mean f-fdg uptake was observed in the control animals ventilated with pvv compared to those with pcv (p < . ). no evidence for a difference in spect activity was detected between the protocol groups (fig. , right panels). however, regional perfusion was significantly and consistently higher in the well aerated zones and the dorsal zones of the lung, without differences between the experimental groups. the detailed results on secondary outcomes (hemodynamic and ventilation parameters, cytokine levels and lung injury histological indices) can be found in additional file . in the presence of ards, significantly higher driving pressure was required to maintain the same minute ventilation than in healthy animals (p < . , ards vs. ctrl, additional file : figure s ). in the ctrl group, a progressive reduction in driving pressure was observed with pvv (p < . vs. t , additional file : figure s ) , which was not observed in animals ventilated with pcv. no differences were detected between the two ventilation modes in regards of the hemodynamic parameters (additional file : figure s ), lung injury score (additional file : table s ), cytokine and cell content of balf (additional file : table s ). in the present study, a combined approach consisting of lung functional and structural assessment was used to investigate differences in the global and regional effects of pvv and the conventional monotonous pressure-controlled mode in a pediatric model of normal lungs and ards. the use of pvv decreased pulmonary inflammation, as assessed by f-fdg uptake, independent of lung condition. the decreased lung inflammation observed with pvv was also detected as an improvement in respiratory tissue elastance. neither the use of pcv nor pvv affected blood gas and lung morphology indices. respiratory system mechanical parameters obtained in bl conditions or following induction of lung injury exhibited excellent agreement with previous data from the same species with similar weight range [ ] [ ] [ ] ] . furthermore, the time course of the respiratory mechanical parameters over h of ventilation in the control groups is in accordance with that observed previously in an experimental model using adult rabbits [ ] . since increases in tissue damping and elastance reflect lung volume loss and stiffening of the lung tissue [ , ] , the lack of an increase of elastance in the pvv-ctrl group suggests that lung derecruitment did not occur, and this conclusion is also supported by the lower inspiratory driving pressure achieved in this group. moreover, the significant differences in elastance between the pcv-ards and pvv-ards groups observed after the -h ventilation suggest a protective effect of the variability on the conservation of lung volume in the presence of ards. studies using models of mild-to-moderate lung injury have found similar beneficial effects on respiratory mechanics for variable ventilation [ , ] , and this protective effect was not observed in the presence of more severe ards [ ] . global and regional lung metabolic activity were measured by f-fdg uptake, a reliable biomarker of inflammation in the lung [ ] . this marker is indicative of neutrophil activation in acute lung injury and ards [ ] [ ] [ ] . previous studies have shown that voxelwise ratio of lung parenchyma and air content influences f-fdg fig. left panels depict pulmonary inflammation characterized by pet imaging normalized to the tissue fraction. right panels show pulmonary circulation characterized by spect imaging, normalized to tissue fraction. upper panels represent mean pet and spect intensities averaged for the entire lung. middle panels demonstrate the regional distribution based on aeration zones. bottom panels represent the regional distribution based on the dependent (dorsal) and non-dependent (ventral) zones. suv: standardized uptake value; pcv: pressure-controlled ventilation; pvv: physiological variable ventilation; ards: presence of lung injury; ctrl: absence of lung injury. *p < . vs. well-aerated or vs. dorsal, † p < . vs. pcv uptake quantification, requiring normalization for the tissue fraction [ , ] , which was performed in the current study. after h of ventilation, we observed significantly lower indices of global and regional lung inflammation in the animals ventilated with pvv. specifically, a significantly higher inflammatory activity characterized the well aerated and non-dependent lung zones, both in control and injured groups. this finding is consistent with results from previous experiments studying injured lungs, in which lung inflammation assessed by f-fdg uptake was correlated with regional strain [ , ] . the significantly lower inflammation associated with pvv may be explained by the fact that the variability of the delivered vt contributes to tidal recruitment [ , ] , therefore reducing strain in the open, aerated zones. it is worth noting that pvv exerts the most beneficial effect in the well and poorly aerated zones under both control and ards conditions (fig. ) . conversely, the collapsed non-aerated zones were obviously unaffected by ventilation modes since these units were not subjected to strain. these findings further confirm the importance of focusing on regional ventilation when assessing the benefit of ventilation strategies. spect imaging confirms differences in regional distribution of lung perfusion when it is related to aeration zones. however, the lower blood perfusion in the ventral lung regions as compared to the dorsal zones can be attributed to the gravity effect and/or to the blood shift to the dorsal zones as a consequence of positive pressure and lung overdistension. the beneficial effects of pvv on respiratory mechanics and lung inflammation were not reflected in changes in blood gas parameters. the lack of improvement in oxygenation may be related in part to the more severe hypoxemia in this group, which required a higher fio ( % vs % in groups pvv-ards and pcv-ards, respectively). moreover, the increase in lactate levels suggest the development of metabolic acidosis in both groups of ards animals, which may be the consequence of inadequate tissue oxygen delivery. moreover, the timespan of the experiment ( h) may be too short to detect effects on gas exchange. we may hypothesize that the more prominent inflammation observed in the pcv groups would build up and potentially cause gas exchange problems over the course of days. the presence of ards was evident in the elevated lung injury score compared to control groups. in agreement with previous studies, lung injury score did not differ between the ventilation modes [ , ] . the discrepancy between the functional and structural findings may be explained by the faster onset of functional changes, compared to the relatively longer time needed for morphological changes to become apparent. lung inflammation quantified using balf cell counts and pro-inflammatory cytokines, unlike in vivo imaging, did not reveal differences between the ventilation modes. in vivo imaging gives a more comprehensive measure of pulmonary inflammation at the early phase of ards, as it demonstrates the alveolar as well as the interstitial compartments of the lung. additionally, f-fdg uptake reflects the acute metabolic activation of neutrophils and captures lung inflammation without barrier disruption, opposite to balf neutrophils and cytokines, providing a more rapid assessment of inflammatory processes. in this context, it is worth noting that the control groups also showed increased inflammation and lung injury indices (balf cytokines and histological injury score). these findings suggest that, despite the use of protective ventilation in the control groups, prolonged mechanical ventilation triggered the development of lung inflammation. this could potentially explain the lack of significant difference in normalized f-fdg uptake between control and ards lungs. the similarity in the values of systemic hemodynamic parameters observed for the experimental groups is expected from the similarity in the overall lung perfusion as assessed by spect imaging. however, the significantly higher regional perfusion measured in the dependent zones can be attributed to the physiological distribution of lung perfusion that occurs in supine position [ ] and is enhanced under positive pressure ventilation [ ] . considering the regional aeration of lung tissue, the significantly lower perfusion observed in the poorly and non-aerated zones can be explained by the hypoxic pulmonary vasoconstriction mechanism [ ] . there are some methodological aspects of the present study that warrant consideration. in this study we used a cone beam ct [ ] . this device uses less radiation and creates higher resolution images than the regular fan beam ct; however, it produces more scatter artefacts, which can alter the measured values [ , ] . due to technical limitations, breath gating was not performed in any of the acquisitions; therefore, basal lung areas had artefacts due to motion of the abdominal organs during breathing. the lung volume containing these artefacts was similar however, among rabbits. the animal model to induce ards calls for some considerations as well. the components of the model were chosen to mimic the various pathophysiological aspects of ards observed in humans. namely, intravenous lps contributes to the inflammatory component of the disease and it has also been described to induce surfactant dysfunction [ ] . injurious ventilation using high vt combined with no peep contributes to development of volume-and barotrauma due to the supraphysiologic tidal volumes and respiratory pressures, whereas the absence of peep promotes tidal closures and exerts shear stress on the lung tissues [ ] . the use of an fio of . during this injurious ventilation period facilitates lung volume loss and development of ventilation heterogeneities [ ] . while the surfactant dysfunction can restore to some extent during the -h timeframe of the experimental protocol, the functional and morphological damage is still present in the lungs, supported by the marked and highly significant changes observed between the control and ards groups regardless of the ventilation mode applied. measurements of respiratory mechanical parameters also warrant some considerations. while raw is mainly specific to the flow resistance of the conducting airways [ ] , the tissue parameters damping and elastance include not only pulmonary components but are also influenced by other structures of the total respiratory system, mainly the chest wall [ ] . previous literature attributed a chest wall contribution of approximately - % to these parameters [ ] and since the chest wall contribution is not expected to change after lung injury and mechanical ventilation [ ] , the observed changes are interpreted as being mainly of pulmonary origin. therefore, the corresponding changes registered in tissue damping and elastance are predictably underestimating the real pulmonary changes. our data demonstrate the beneficial effect of variable ventilation based on a physiological breathing pattern in healthy lungs and in mild to moderate ards, in an experimental pediatric model. this positive effect was detected in the absence of deterioration in respiratory tissue elastance and in decreased regional lung inflammation measured by pet imaging. ventilation for five hours with physiologically variable ventilation provided better protection on aerated lung zones than with monotonous pressure-controlled ventilation. while further studies in humans might be needed, our results suggest that the application of a physiological breathing pattern as the driving signal of mechanical ventilation may have a better lung protective ability than conventional modes in scenarios where prolonged mechanical ventilation is required. supplementary information accompanies this paper at https ://doi. org/ . /s - - -x. additional file . supplementary information on methods and ancillary results ( figures s -s and tables s -s ). epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries ventilator-induced lung injury: from the bench to the bedside ventilator-induced lung injury ventilator-induced lung injury: in vivo and in vitro mechanisms effect of positive end-expiratory pressure on regional ventilation distribution during mechanical ventilation after surfactant depletion recurrent recruitment manoeuvres improve lung mechanics and minimize lung injury during mechanical ventilation of healthy mice acute respiratory distress syndrome: advances in diagnosis and treatment fifty years of research in ards. vt selection in acute respiratory distress syndrome life-support system benefits from noise when mechanical ventilation mimics nature variable ventilation induces endogenous surfactant release in normal guinea pigs biologically variable ventilation prevents deterioration of gas exchange during prolonged anaesthesia variable ventilation associated with recruitment maneuver minimizes tissue damage and pulmonary inflammation in anesthetized lung-healthy rats variable ventilation is equally effective as conventional pressure control ventilation for optimizing lung function in a rabbit model of ards variable tidal volume ventilation improves lung mechanics and gas exchange in a rodent model of acute lung injury comparison of variable and conventional ventilation in a sheep saline lavage lung injury model variable ventilation improves pulmonary function and reduces lung damage without increasing bacterial translocation in a rat model of experimental pneumonia comparison between neurally-assisted, controlled, and physiologically variable ventilation in healthy rabbits mechanisms of ventilator-induced lung injury in healthy lungs quantitative computed tomography in porcine lung injury with variable versus conventional ventilation: recruitment and surfactant replacement resolution of pulmonary edema with variable mechanical ventilation in a porcine model of acute lung injury rabbits and men: relating their ages acute respiratory distress syndrome: the berlin definition input impedance and peripheral inhomogeneity of dog lungs pet/ct in nononcological lung diseases: current applications and future perspectives improved correction for the tissue fraction effect in lung pet/ct imaging an official american thoracic society workshop report: features and measurements of experimental acute lung injury in animals the protective effects of volatile anesthestics against the bronchoconstriction induced by an allergic reaction in sensitized rabbit pups airway inhomogeneities contribute to apparent lung tissue mechanics during constriction comparison of static end-expiratory and effective lung volumes for gas exchange in healthy and surfactant-depleted lungs variable tidal volumes improve lung protective ventilation strategies in experimental lung injury in vivo assessment of lung inflammatory cell activity in patients with copd and asthma effects of positive end-expiratory pressure and spontaneous breathing activity on regional lung inflammation in experimental acute respiratory distress syndrome micro-autoradiographic assessment of cell types contributing to -deoxy- -[( )f]fluoro-d-glucose uptake during ventilator-induced and endotoxemic lung injury positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung the importance of correction for tissue fraction effects in lung pet: preliminary findings does regional lung strain correlate with regional inflammation in acute respiratory distress syndrome during nonprotective ventilation? an experimental porcine study effect of prone position on regional shunt, aeration, and perfusion in experimental acute lung injury periodic fluctuation of tidal volumes further improves variable ventilation in experimental acute respiratory distress syndrome the influence of gravity on regional lung blood flow in humans: spect in the upright and head-down posture v/q distribution and correlation to atelectasis in anesthetized paralyzed humans hypoxic pulmonary vasoconstriction development and validation of two phantoms for quality control in cone-beam ct image quality improvement in cone-beam ct using the super-resolution technique dental cone beam ct: a review • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research: over m website views per year submit your research ? choose bmc dynamic mechanical interactions between neighboring airspaces determine cyclic opening and closure in injured lung high inspired oxygen fraction impairs lung volume and ventilation heterogeneity in healthy children: a double-blind randomised controlled trial repeated measurements of airway and parenchymal mechanics in rats by using low-frequency oscillations different contributions from lungs and chest wall to respiratory mechanics in mice, rats, and rabbits lung and chest wall impedances in the dog in normal range of breathing: effects of pulmonary edema publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank aurélie baudat, xavier belin and sylvie roulet for their technical assistance in animal handling, surgical preparation and sample processing. the authors thank didier colin, stéphane germain and frédéric bois for their technical support in imaging acquisition. the authors also thank matts wallin and magnus hallback for their excellent technical support in the application of the variable pattern. authors' contributions adsr: study design, experimental work, data collection, data analyses and article drafting. ghf: study design, experimental work, data collection, data analyses and article drafting. mk: data collection and data analyses. ld: data collection and data analyses. sb: study design, interpretation of results and article drafting. fp: study design, data analyses, interpretation of results and article drafting. wh: study design, data analyses, interpretation of the results and article drafting. all authors read and approved the final manuscript. this work was supported by the swiss national science foundation [ b_ ]. ghf received a research grant of the european society of anaesthesiology and sb received a grant from alliance campus rhodanien. key: cord- -wrouqdcj authors: haywood, nathan; byler, matthew r.; zhang, aimee; roeser, mark e.; kron, irving l.; laubach, victor e. title: isolated lung perfusion in the management of acute respiratory distress syndrome date: - - journal: int j mol sci doi: . /ijms sha: doc_id: cord_uid: wrouqdcj acute respiratory distress syndrome (ards) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. while our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. there is a dramatic need for the development and breakthrough of new methods for the treatment of ards. isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ards. this review presents current tenants of ards management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (evlp) has paved the way for current investigations utilizing in vivo lung perfusion (ivlp) in the treatment of severe ards. acute respiratory distress syndrome (ards) is a severe, life-threatening form of acute lung injury characterized by inflammation, lung permeability, and edema [ ] [ ] [ ] . clinical sequelae include significant hypoxia and bilateral infiltrates on chest imaging ( figure ) [ ] . since the original description by ashbaugh in , significant advances have been made in the understanding of this disease process [ , ] . however, this syndrome remains common, and is associated with significant morbidity and mortality [ ] . diagnostic criteria of ards rely on imaging and other clinical findings. the most recent definition, the berlin definition (table ) , deviates from the previous division of acute lung injury (ali) and ards [ ] . instead, mild, moderate, and severe ards severity categories are described based on the pao /fio ratio. additional tenants include respiratory failure not explained by fluid overload or cardiac failure, characteristic imaging findings (figure ), and origin of onset within days of symptoms or known clinical insult [ ] . most common etiologies of ards include sepsis, pneumonia, and aspiration, but a number of other less common risk factors exist (table ) [ , ] . in addition, new pathogens may emerge that manifest in ards, such as the novel coronavirus disease (covid- ) [ ] . table . diagnosis of acute respiratory distress syndrome: berlin criteria [ ] . imaging bilateral opacities noted on either cxr or ct scan that are not otherwise explained by fluid overload or cardiac failure ventilator-induced lung injury pancreatitis trauma and burn injury blood product administration cardiopulmonary bypass ischemia-reperfusion injury following lung transplantation covid- infection while our understanding of this syndrome has improved over the past half century, it remains a significant burden with a large impact on both the individual and health system. a large recent international evaluation of ards in the critical care population demonstrated that . % of intensive care unit (icu) patients and . % of intubated icu patients had ards [ , ] . in-hospital mortality for the severe subgroup reached as high as . % [ , ] . a recent analysis of the national inpatient sample from - by eworuke et al. demonstrated increasing incidence of ards and a most recent rate of . cases per , population [ ] . while a downward trend in in-hospital mortality has been reported, it remained quite high over this time period, with rates for sepsis, shock, and pneumonia approximating % [ ] . in those who physically recover, high risks of cognitive dysfunction, muscular weakness, depression, and post-traumatic stress disorder have been reported [ ] . additionally, the management of patients with ards is often resource-intensive (prolonged ventilation and icu stay) resulting in significant economic impact [ ] . identification and appropriate treatment of the underlying cause of ards is essential (e.g., antibiotics, resuscitation, and source control for sepsis) [ ] . beyond this, the current management of identification and appropriate treatment of the underlying cause of ards is essential (e.g., antibiotics, resuscitation, and source control for sepsis) [ ] . beyond this, the current management of ards is largely supportive in nature, with basic tenants including lung protective ventilation, conservative fluid management, neuromuscular blockade, and prone positioning for severe disease [ , ] . the use of pharmacologic agents, such as inhaled vasodilators and corticosteroids, can be considered, but their use is controversial and not widely accepted [ , ] . in severe, refractory ards, the addition of extracorporeal assistance may provide some benefit [ , , ] . lung-protective ventilation with low tidal volumes may cause hypercapnia and associated respiratory acidosis. this is, to some degree, an accepted consequence, leading to a concept known as permissive hypercapnia. beneficial effects of hypercapnia have been demonstrated, including reduction in pulmonary inflammation and oxidative stress [ , ] . however, recent evidence has emerged suggesting negative impacts of hypercapnia on lung tissue repair and alveolar fluid clearance [ , ] . as such, extracorporeal co removal with venovenous extracorporeal membrane oxygenation (ecmo) has been utilized as an alternative means of improving hypercapnia and gas exchange in severe ards [ , ] . however, it carries the typical risks associated with extracorporeal circulation [ ] . while early evidence has suggested improved outcomes in patients with severe ards managed with ecmo [ ] , a recent international, randomized clinical trial evaluating the use of routine ecmo in severe ards showed no difference in mortality compared to conventional ventilatory management with ecmo as a rescue therapy [ ] . for this reason, the routine use of ecmo in severe ards remains controversial. recent guidelines suggest consideration of venovenous ecmo in severe ards when pao /fio < mmhg despite optimal ards treatment, including neuromuscular blockade, high positive end expiratory pressure (peep), and prone positioning [ ] . the last half decade has produced numerous advances regarding the previously described management paradigm of ards, and outcomes have improved over this period. however, mortality remains high, with reports in severe subgroups greater than % [ , ] . given this, and the continued emergence of pathogens causing severe ards, such as covid- , development and breakthrough of new treatment modalities is crucial [ ] . because current treatment strategies in ards largely rely on supportive measures to stabilize and allow for innate lung recovery over time, there is opportunity for targeted therapeutic approaches to limit disease severity and improve outcomes. isolated lung perfusion is an active area of investigation that may ultimately serve in this role. first studied in , isolated lung perfusion was initially implemented in an ex vivo fashion for donor lungs prior to transplant [ ] . coined ex vivo lung perfusion (evlp), it has since undergone numerous advances, leading to its current clinical use in donor lung evaluation and in the reconditioning of marginal donor lungs prior to transplant [ ] . the ability of evlp to rehabilitate lungs injured in a porcine sepsis model [ ] has provided the basis for a similar application-the use of isolated lung perfusion in vivo in the management of ards. here, early animal studies have demonstrated the ability of in vivo lung perfusion (ivlp) to rehabilitate sepsis-induced ards [ ] . below, we review the history and current evidence for isolated lung perfusion techniques, with a focus on how evlp has provided the basis for and led to investigations into the use of ivlp for the treatment of ards. relevant works included in our review were identified from pubmed, using the following search terms: ali, ards, isolated lung perfusion, evlp, and ivlp. primary graft dysfunction (pgd) is the result of severe ischemia-reperfusion injury following lung transplant that can result in detrimental early and late outcomes [ ] . surgeons are often conservative in donor lung selection, as lesser quality lungs increase the likelihood of pgd development [ ] . it has been reported that only - % of lungs from multiorgan donors are deemed usable for transplantation [ ] [ ] [ ] . the unfortunate consequence of this is revealed in lung waitlist mortality-reported as high as . deaths per waitlist years [ ] . one strategy to extend donor lung availability is through the use of evlp. clinical application of evlp was first described by hardesty et al. in [ , ] . since this time, numerous advances have been made, many of which are due to the work of steen and colleagues, who developed a lung-specific perfusion solution (steen solution) and first utilized evlp in donation after cardiac death (dcd) lungs in [ , ] . following this achievement, there was a body of work in the early s, with additional contributions by steen et al. and wierup et al., demonstrating the ability of evlp as a clinical platform for continued assessment and rehabilitation in lungs considered unusable at the time of initial evaluation [ , ] . the toronto lung transplant group then demonstrated the efficacy of extended-duration evlp in a landmark study published in the new england journal of medicine in [ ] . here, they described cases in which lungs were initially "not considered suitable for transplantation" that underwent reevaluation during a h period of evlp and were ultimately successfully transplanted. the incidence of pgd within h was % in the evlp group compared to % in the control group (p = . ), and there were no significant differences for any secondary endpoints, including ecmo, post-transplantation icu days, day mortality, p/f ratio, or any severe adverse events directly attributable to evlp [ ] . in the last decade, the clinical use of evlp has become more widespread, and is now used in many large lung transplant centers in north america, europe, and australia [ ] . a recent multicenter prospective clinical trial (novel) examining the use of evlp has demonstrated similar early outcomes and one-year survival compared to patients that underwent transplantation with standard criteria donor lungs [ , ] . evlp utilizes physiologic, normothermic perfusion of donor lungs [ ] . this allows for a period of lung assessment during which direct examination, imaging, bronchoscopy, and blood gas analysis can be performed [ ] . a general circuit for evlp is shown in figure . the device is made up of two main components. the first is a ventilator to provide oxygen to the donor lungs, and the second is a circuit that drives perfusion, deoxygenates, and filters the perfusate [ ] . the perfusate is deoxygenated using a gas exchange membrane with a sweep gas consisting of nitrogen, co , and o [ ] , which is then filtered using a leukocyte filter prior to advancing into the pulmonary artery [ , ] . the perfusate is drained from the left atrium into a reservoir prior to repeating the sequence [ ] . clinical application of evlp was first described by hardesty et al. in [ , ] . since this time, numerous advances have been made, many of which are due to the work of steen and colleagues, who developed a lung-specific perfusion solution (steen solution) and first utilized evlp in donation after cardiac death (dcd) lungs in [ , ] . following this achievement, there was a body of work in the early s, with additional contributions by steen et al. and wierup et al., demonstrating the ability of evlp as a clinical platform for continued assessment and rehabilitation in lungs considered unusable at the time of initial evaluation [ , ] . the toronto lung transplant group then demonstrated the efficacy of extended-duration evlp in a landmark study published in the new england journal of medicine in [ ] . here, they described cases in which lungs were initially "not considered suitable for transplantation" that underwent reevaluation during a h period of evlp and were ultimately successfully transplanted. the incidence of pgd within h was % in the evlp group compared to % in the control group (p = . ), and there were no significant differences for any secondary endpoints, including ecmo, post-transplantation icu days, day mortality, p/f ratio, or any severe adverse events directly attributable to evlp [ ] . in the last decade, the clinical use of evlp has become more widespread, and is now used in many large lung transplant centers in north america, europe, and australia [ ] . a recent multicenter prospective clinical trial (novel) examining the use of evlp has demonstrated similar early outcomes and one-year survival compared to patients that underwent transplantation with standard criteria donor lungs [ , ] . evlp utilizes physiologic, normothermic perfusion of donor lungs [ ] . this allows for a period of lung assessment during which direct examination, imaging, bronchoscopy, and blood gas analysis can be performed [ ] . a general circuit for evlp is shown in figure . the device is made up of two main components. the first is a ventilator to provide oxygen to the donor lungs, and the second is a circuit that drives perfusion, deoxygenates, and filters the perfusate [ ] . the perfusate is deoxygenated using a gas exchange membrane with a sweep gas consisting of nitrogen, co , and o [ ] , which is then filtered using a leukocyte filter prior to advancing into the pulmonary artery [ , ] . the perfusate is drained from the left atrium into a reservoir prior to repeating the sequence [ ] . while there are a number of ex vivo perfusion systems under investigation, the two most common systems used in clinical practice are the xvivo perfusion system (xps) (xps perfusion, goteborg, sweden) and the organ care system (ocs) (transmedics, andover, ma, usa) [ ] . a comparison of these two systems is shown in table . while both systems utilize the normothermic perfusion of donor lungs, the specific perfusate utilized is different. xps utilizes an acellular perfusate (steen solution), which contains albumin, dextran, and electrolytes, and often includes additives such as steroids and antibiotics [ , ] . the perfusate used for ocs includes a cellular component (packed red blood cells) as well as ocs solution, which is composed of a low-potassium dextran solution and additives, such as steroids, glucose, bicarbonate, and antibiotics [ ] . another distinction between these systems is that ocs is portable while xps is static [ , ] . the ocs system integrates all components into a compact unit small enough to fit in a passenger seat in a car or plane [ ] . given the portability, lungs can be instrumented onto the ocs system at the donor hospital following cold antegrade and retrograde flush. this has the theoretic benefit of minimizing cold ischemic time during transport to the recipient hospital [ , ] . alternatively, xps is typically maintained at the recipient hospital, and lungs are instrumented onto the system upon arrival-following a period of cryopreservation [ ] . arterial blood gasses are performed hourly using xps and are monitored continuously with ocs. if deemed acceptable, lungs are flushed with cold perfusate and kept cool prior to the implantation procedure [ ] . evlp has undergone a transformation from an assessment and diagnostic tool to a therapeutic platform that also allows for active lung rehabilitation. this platform provides an ideal environment to deliver targeted drug therapy for lung rehabilitation, as it allows the opportunity to re-evaluate function to confirm positive treatment effect, and allows for targeted treatment of the lung, minimizing the risk of treatment side effects that may preclude systemic administration of therapeutic agents. one target of pharmacological agents in evlp has been minimizing inflammation and the reduction of pulmonary edema. numerous investigational agents have shown promise. for example, the administration of aerosolized exogenous catecholamines into the distal airspaces during evlp has been demonstrated to enhance the clearance of pulmonary edema, resulting in better graft oxygenation, pulmonary compliance, and reduced pulmonary vascular resistance [ ] [ ] [ ] . this effect is not isolated to aerosolized delivery, as perfusion with a short-acting selective beta- adrenergic receptor agonist has also been associated with lower pulmonary artery pressures and better lung mechanics [ ] . our laboratory and others have recently studied evlp as a platform to recondition lungs via pharmacologic treatment during ex vivo perfusion. using both murine and porcine models, we have demonstrated that the addition of a selective adenosine a receptor (a ar) agonist to the evlp perfusate is associated with less pulmonary edema, lower levels of pro-inflammatory cytokines, and improved lung function [ , ] . similarly, utilizing a porcine dcd model, our lab has demonstrated that delivery of a ar agonist during evlp increased the likelihood of successful transplantation following prolonged periods of cold preservation [ ] . the addition of a selective adenosine b receptor antagonist to the evlp perfusate has also been associated with improved lung function in both murine and porcine models [ , ] . numerous other pharmacologic agents administered using the evlp platform have shown promise in mitigating the pulmonary inflammatory response, including, but not limited to, sphingosine- -phosphate [ ] , neutrophil elastase inhibitor [ ] , and alpha- -antitrypsin [ ] . alpha- -antitrypsin treatment was found to significantly reduce pulmonary edema, pulmonary cell apoptosis, and pro-inflammatory cytokine levels (il- α and il- ) in the perfusate [ ] . similar to drug therapy, several studies have demonstrated that gene therapy coupled with evlp can repair injured lungs before transplantation. cypel et al. showed that delivery of an adenoviral vector encoding human il- (adhil- ), an anti-inflammatory cytokine, to human lungs improved arterial oxygen pressure and vascular resistance during evlp, concluding that delivery of adhil- can improve lung function [ ] . yeung et al. later showed that ex vivo delivery of adhil- to lungs is superior to in vivo delivery, in that it leads to less vector-associated inflammation and provides superior post-transplant lung function [ ] . a variety of recent studies have begun to evaluate molecular and cellular changes that occur during evlp. using a porcine model, tavasoli et al. showed that evlp resulted in reduced concentrations of nitric oxide metabolites and l-citrulline in lung tissue [ ] . in addition, the ratio of l-ornithine over l-citrulline, a marker of the balance between l-arginine metabolizing enzymes, was increased in the evlp group, and expression of both arginase isoforms was increased during evlp. these data suggest that evlp induces a shift of the l-arginine balance towards arginase, leading to nitric oxide deficiency in the lung. using a rat model of evlp, lonati and colleagues described a remarkable anti-inflammatory response during evlp, including the activation of protective and anti-apoptotic pathways [ ] . they also detected resolution factors in perfused, uninjured lungs, including transcripts that encode for feedback inhibitors of toll-like receptors and cytokine signaling, such as inhibitors of nuclear factor-κb (nf-κb) signaling iκb (inhibitor of κb), il- receptor antagonist , ll- decoy receptor, and nonfunctional interleukin receptor-associated kinase-m. importantly, their data obtained in uninjured lungs was confirmed in perfused injured (dcd) lungs. these results led lonati and colleagues to conclude that the evlp molecular signature is very similar to the pattern induced by ischemic preconditioning [ ] . to identify potential biomarkers during evlp, hsin et al. used a metabolomics approach in a clinical study to identify a small panel of metabolites in evlp perfusate that were highly correlated with the development of pgd after transplant [ ] . in another clinical evlp biomarker study, hashimoto et al. demonstrated that levels of m (indicative of epithelial apoptosis) and high mobility group box (hmgb- , related to cell death and inflammation) protein in the evlp perfusate correlated with pgd after lung transplantation, and might therefore be useful biomarkers to improve donor lung assessment during evlp [ ] . a recent study by elgharably et al. showed that two micrornas (mir- and mir- b) were significantly upregulated in the alveolar epithelial cells of human lungs that underwent cold ischemia and evlp [ ] . both mir- and mir- b have expected target genes related to lung injury and share a number of mutual targets, suggesting that mir- and mir- b may interact at some level in the signaling pathway and potentially provide novel therapeutic targets [ ] . yeung and colleagues examined gene expression changes in human lungs during h of evlp, and found that, despite increases in endothelial markers of inflammation, circulating, leukocyte, cell-specific gene expression fell during evlp [ ] . these results suggest that perhaps the mechanisms underlying the benefit of evlp are nonspecific and related to innate recovery capabilities of the lung. finally, a recent study by wong et al. performed a retrospective transcriptomics analysis of dcd lungs with or without evlp, and showed that pathways associated with leukocyte function, such as phosphatidylinositol biosynthesis, phospholipase c signaling, cholesterol biosynthesis, protein targeting to vacuoles, and golgi vesicle trafficking were all downregulated in lungs after evlp [ ] . these results support those of yeung et al. above [ ] , which inferred that passenger leukocytes are depleted during evlp. the ability of evlp to rehabilitate injured, marginal lungs prior to transplantation has led to investigation into other forms of lung injury-namely, ards. our laboratory has demonstrated the ability of evlp to rehabilitate ards in a porcine sepsis model [ ] . in this study, intravenous lipopolysaccharide (lps) was used to generate a systemic inflammatory response with associated ards [ ] . lungs that were subjected to evlp with steen solution demonstrated improved oxygenation and compliance compared to the control (no evlp) [ ] . this finding provided the basis for investigation of a similar in vivo technique, ivlp, in the management and rehabilitation of ards. in vivo lung perfusion (ivlp) was first investigated in the s as a method for delivering high-dose chemotherapy [ , ] . ivlp involves isolation and placement of cannulas into the pulmonary artery and veins of a single lung in vivo, so that its perfusion is removed from systemic circulation. this allows for the delivery of high dose medication to the lung parenchyma while limiting adverse systemic effects. in this way, much higher doses of chemotherapy could be used to treat lung cancer than would have otherwise been tolerated systemically. multiple clinical trials investigating the utility of ivlp in the treatment of lung cancer have shown increased survival benefit [ , ] . these studies, coupled with studies showing that evlp can rehabilitate sepsis-induced lung injury [ ] , have provided the basis and rational for investigating the use of ivlp to rehabilitate end-stage lung injury from ards. currently, investigations into the use of ivlp for the rehabilitation of ards have been limited to swine animal models, as described below. unlike evlp, which perfuses previously resected donor lungs, ivlp provides isolated lung perfusion to lungs that remain inside of a host. ivlp investigations have achieved this via a sternotomy or thoracotomy approach [ , ] . prior to beginning the procedure, an injurious model is used to establish lung injury, which can be achieved by various protocols, including intravenous lps, surfactant washout model, intravenous oleic acid, or gastric aspiration [ , ] . our laboratory has established a systemic lung injury model in swine using an lps infusion administered at µg/kg over h to establish ards, defined as a p/f ratio less than mmhg. this model creates a reproducible injury and simulates the increased capillary permeability observed in a septic response. due to the systemic, hemodynamic instability associated with this injury model, we performed ivlp via a sternotomy, in order to provide necessary cardiopulmonary support via central, venoarterial ecmo [ ] . our ivlp investigations utilized perfusion of the left porcine lung, due to its optimal venous anatomy for an open approach. the left pulmonary artery and superior and inferior veins were circumferentially dissected, and cannulas were placed into the vessels, as outlined in figure . these cannulas are circumferentially secured so as to isolate the left lung from systemic circulation. the cannulas are connected to an ivlp circuit that is designed similarly to that used for cardiopulmonary bypass. the circuit uses a special gas mixture and a membrane deoxygenator, which provides physiologic levels of carbon dioxide and removes oxygen from the steen perfusate. after the perfusate circulates through the lung, the lung's oxygenation and ventilation capacity are evaluated by blood gas analysis at predetermined intervals. the back pressure on the pulmonary venous drainage was maintained at between to + mmhg by adjusting the height of the hard-shelled cardiotomy reservoir. after completion of a predetermined ivlp perfusion period ( or h), the cannulas were removed, and the lung was allowed to reperfuse back into systemic circulation. circuit includes reservoir, pump, deoxygenator, and leukocyte filter. ecmo: extracorporeal membrane oxygenation; hcu: heating-cooling unit. used with permission [ ] . arrows indicate direction of perfusate flow in ivlp circuit and venous outflow/arterial inflow in ecmo circuit. multiple studies have investigated the use of ivlp for the delivery of isolated, high-dose chemotherapy to the lung. the duration of this treatment has been for min [ ] . however, the use of ivlp to treat ards has utilized longer treatment (perfusion) times. in , dos santos and colleagues evaluated the use of prolonged ivlp in a large animal study, where they delivered ivlp for h via a thoracotomy to six swine, followed by a h reperfusion period [ ] . here, they demonstrated that using ivlp for this duration is feasible and safe, and there was no change in lung function parameters (oxygenation and compliance) or histologic evidence of acute lung injury [ ] . in , our laboratory was the first to investigate the use of ivlp to rehabilitate sepsis-induced ards [ ] . after undergoing an lps infusion and confirmation of ards, h of left-lung ivlp with steen solution was performed in eight swine. the right lung served as an internal control, and was compared the ivlp-treated left lung. after the ivlp treatment period, the animal was decannulated from ivlp and allowed to reperfuse for h. over the course of the experiment, the treated left lungs demonstrated improved oxygenation performance from baseline when compared to the right lung controls. additionally, total lung compliance was increased. the mechanism behind these improvements may be due in part to the observed decrease in levels of tumor necrosis factor alpha (tnf-α) and interferon gamma (ifn-γ) in the treated left lungs. additionally, there was evidence of decreased pulmonary edema, demonstrated by lower wet-to-dry weight ratios in the treated left lungs. finally, there was decreased expression of the cellular adhesion molecules vascular cell adhesion molecule (vcam- ) and intercellular adhesion molecule (icam- ). these data suggest that there was decreased transmigration of leukocytes, which resulted in decreased histologic evidence of inflammation in the ivlp-treated lungs [ ] . most recently, we performed a study comparing the previously used ivlp perfusion time of h to h of ivlp perfusion [ ] . similar to our previous study, eight adult swine underwent lps infusion to induce ards, and then were randomized to either h ivlp (n = ) or h ivlp (n = ) treatment groups. the results demonstrated that h of ivlp outperformed h of ivlp when evaluating each circuit includes reservoir, pump, deoxygenator, and leukocyte filter. ecmo: extracorporeal membrane oxygenation; hcu: heating-cooling unit. used with permission [ ] . arrows indicate direction of perfusate flow in ivlp circuit and venous outflow/arterial inflow in ecmo circuit. multiple studies have investigated the use of ivlp for the delivery of isolated, high-dose chemotherapy to the lung. the duration of this treatment has been for min [ ] . however, the use of ivlp to treat ards has utilized longer treatment (perfusion) times. in , dos santos and colleagues evaluated the use of prolonged ivlp in a large animal study, where they delivered ivlp for h via a thoracotomy to six swine, followed by a h reperfusion period [ ] . here, they demonstrated that using ivlp for this duration is feasible and safe, and there was no change in lung function parameters (oxygenation and compliance) or histologic evidence of acute lung injury [ ] . in , our laboratory was the first to investigate the use of ivlp to rehabilitate sepsis-induced ards [ ] . after undergoing an lps infusion and confirmation of ards, h of left-lung ivlp with steen solution was performed in eight swine. the right lung served as an internal control, and was compared the ivlp-treated left lung. after the ivlp treatment period, the animal was decannulated from ivlp and allowed to reperfuse for h. over the course of the experiment, the treated left lungs demonstrated improved oxygenation performance from baseline when compared to the right lung controls. additionally, total lung compliance was increased. the mechanism behind these improvements may be due in part to the observed decrease in levels of tumor necrosis factor alpha (tnf-α) and interferon gamma (ifn-γ) in the treated left lungs. additionally, there was evidence of decreased pulmonary edema, demonstrated by lower wet-to-dry weight ratios in the treated left lungs. finally, there was decreased expression of the cellular adhesion molecules vascular cell adhesion molecule (vcam- ) and intercellular adhesion molecule (icam- ). these data suggest that there was decreased transmigration of leukocytes, which resulted in decreased histologic evidence of inflammation in the ivlp-treated lungs [ ] . most recently, we performed a study comparing the previously used ivlp perfusion time of h to h of ivlp perfusion [ ] . similar to our previous study, eight adult swine underwent lps infusion to induce ards, and then were randomized to either h ivlp (n = ) or h ivlp (n = ) treatment groups. the results demonstrated that h of ivlp outperformed h of ivlp when evaluating each lung's oxygenation capacity and total lung compliance. similar to the study by mehaffey et al. [ ] , this was likely due to a reduction in pulmonary edema, as indicated by improved wet-to-dry weight ratios. we also observed decreased expression of the pleiotropic cytokine il- [ ] . this cytokine is characteristically elevated in the hyperinflammatory subphenotype of ards, and has been targeted by monoclonal antibodies in the treatment of ards associated with covid- [ , ] . together, these physiologic and biochemical improvements in the treated lungs allowed more animals to successfully wean from venoarterial ecmo support in the h group (three of four) than in the h group (two of four). these two studies shared some limitations, such as they were performed in farm-raised animals that may have physiologic variability and were comprised of low group sizes. because we have not yet determined if the results with the lps model of ards are translatable to other etiologies of ards (e.g., pulmonary contusions, massive transfusion reaction, aspiration, etc.), the results may not be generalizable. the invasive sternotomy and thoracotomy approaches used in ivlp investigations are currently much too invasive to use in a critically ill, unstable patient. the future of ivlp in the treatment of ards will be contingent upon the advancement of catheter-based technologies that can be translated into a percutaneous platform. this will provide a minimally invasive application of ivlp in lung rehabilitation via catheters placed into peripheral vessels and threaded over a wire into the pulmonary artery and veins, instead of large surgical incisions (figure ). lung's oxygenation capacity and total lung compliance. similar to the study by mehaffey et al. [ ] , this was likely due to a reduction in pulmonary edema, as indicated by improved wet-to-dry weight ratios. we also observed decreased expression of the pleiotropic cytokine il- [ ] . this cytokine is characteristically elevated in the hyperinflammatory subphenotype of ards, and has been targeted by monoclonal antibodies in the treatment of ards associated with covid- [ , ] . together, these physiologic and biochemical improvements in the treated lungs allowed more animals to successfully wean from venoarterial ecmo support in the h group (three of four) than in the h group (two of four). these two studies shared some limitations, such as they were performed in farm-raised animals that may have physiologic variability and were comprised of low group sizes. because we have not yet determined if the results with the lps model of ards are translatable to other etiologies of ards (e.g., pulmonary contusions, massive transfusion reaction, aspiration, etc.), the results may not be generalizable. the invasive sternotomy and thoracotomy approaches used in ivlp investigations are currently much too invasive to use in a critically ill, unstable patient. the future of ivlp in the treatment of ards will be contingent upon the advancement of catheter-based technologies that can be translated into a percutaneous platform. this will provide a minimally invasive application of ivlp in lung rehabilitation via catheters placed into peripheral vessels and threaded over a wire into the pulmonary artery and veins, instead of large surgical incisions (figure ). there remains a myriad of questions to be answered, in order to establish the optimal protocol for ivlp in the treatment of ards. we have demonstrated improved pulmonary function following ivlp and a h reperfusion period [ , ] . however, the optimal timing of ivlp, as well as the longterm effect of ivlp on lung function beyond h of reperfusion, is yet to be determined. the early exudative phase of ards is characterized by innate inflammatory cell activation, resulting in damage to the alveolar epithelium and capillary endothelium [ , , ] . while further studies are needed to determine the optimal timing of ivlp, it is likely within this early phase of ards that ivlp will there remains a myriad of questions to be answered, in order to establish the optimal protocol for ivlp in the treatment of ards. we have demonstrated improved pulmonary function following ivlp and a h reperfusion period [ , ] . however, the optimal timing of ivlp, as well as the long-term effect of ivlp on lung function beyond h of reperfusion, is yet to be determined. the early exudative phase of ards is characterized by innate inflammatory cell activation, resulting in damage to the alveolar epithelium and capillary endothelium [ , , ] . while further studies are needed to determine the optimal timing of ivlp, it is likely within this early phase of ards that ivlp will provide the most benefit. less damage in this phase would decrease the negative impact of innate recovery pathways that can result in lung fibrosis. limiting the progression to fibrosis is critical for recovery, as this final fibrotic phase is associated with prolonged ventilation and increased mortality [ , ] . additionally, the rehabilitative effect of ivlp on pulmonary function in different ards models remains to be evaluated. these are important questions that warrant further investigation prior to translation into human applications. causes of ards can be grouped into two broad categories: those that cause direct lung injury and those that cause an indirect lung injury. the latter often results from the deleterious impact of a systemic inflammatory response, such as sepsis. the pathophysiology of these two categories differs, and while we have demonstrated the beneficial impact of ivlp in a sepsis model, we have yet to determine the impact in a direct lung injury model, such as aspiration or ventilator-induced lung injury. the benefit of ivlp in a sepsis model is multifactorial, but a large part is due to the protective effect of isolated lung perfusion in the setting of systemic inflammation. future use of ivlp will extend beyond simply the perfusion of steen solution to ameliorate lung injury and decrease pulmonary edema. similar to evlp, the technique of ivlp can be advanced and used as a platform for the delivery of a myriad of lung-specific drug therapies. this avenue may provide additional benefit in more direct causes of lung injury, such as gastric aspiration, pneumonia, and ventilator-induced lung injury. with administration to lung circulation that is isolated from systemic circulation, the delivery of higher-dose drug therapies than would otherwise be tolerated from systemic side effects would be possible. these therapies may include powerful antimicrobials, antivirals, immunomodulators, stem cells, genetic therapies, and any combination thereof to target the exact etiology of a patient's ards and limit the local injurious inflammatory response [ ] . ards remains associated with high rates of morbidity and mortality, and advances in management will be critical to improve outcomes and decrease the drastic impact on healthcare resource utilization [ , , ] . in vivo isolated lung perfusion is a promising investigational method for lung rehabilitation in severe ards. author contributions: all authors contributed to manuscript design, writing, and editing. all authors have read and agreed to the published version of the manuscript. funding: this work was supported by several research grants from national heart, lung, and blood institute (nhlbi)/national institutes of health (nih) (t hl , r hl , and r hl ). the content is solely the responsibility of the authors and does not represent the official views of the national institutes of health. the authors declare no conflict of interest. acute respiratory distress syndrome the acute respiratory distress syndrome corticosteroids in acute lung injury: the dilemma continues current concepts of ards: a narrative review acute respiratory distress in adults acute respiratory distress syndrome clinical characteristics of coronavirus disease in china patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries national incidence rates for acute respiratory distress syndrome (ards) and ards cause-specific factors in the united states ( - ) recovery and outcomes after the acute respiratory distress syndrome (ards) in patients and their family caregivers acute respiratory distress syndrome: cost (early and long-term) extracorporeal membrane oxygenation for ards in adults the role of hypercapnia in acute respiratory failure protective effects of hypercapnic acidosis on ventilator-induced lung injury hypercapnic acidosis attenuates pulmonary epithelial wound repair by an nf-kappab dependent mechanism efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for severe acute respiratory distress syndrome formal guidelines: management of acute respiratory distress syndrome autoperfusion of the heart and lungs for preservation during distant procurement normothermic ex vivo lung perfusion in clinical lung transplantation ex vivo lung perfusion rehabilitates sepsis-induced lung injury in vivo lung perfusion rehabilitates sepsis-induced lung injury evlp: ready for prime time? isolated lung perfusion organ donation and utilization in the united states application of ex vivo lung perfusion (evlp) in lung transplantation transplantation of lungs from a non-heart-beating donor transplantation of lungs from non-heart-beating donors after functional assessment ex vivo first human transplantation of a nonacceptable donor lung after reconditioning ex vivo ex vivo evaluation of nonacceptable donor lungs ex-vivo lung perfusion and ventilation normothermic ex vivo lung perfusion as an assessment of marginal donor lungs-the novel lung trial the novel lung trial one-year outcomes extracorporeal lung perfusion (ex-vivo lung perfusion) ex vivo lung perfusion early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study machine perfusion of thoracic organs adrenoreceptor agonist inhalation during ex vivo lung perfusion attenuates lung injury bronchodilator inhalation during ex vivo lung perfusion improves posttransplant graft function after warm ischemia stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine adrenergic agonist infusion during extracorporeal lung perfusion: effects on glucose concentration in the perfusion fluid and on lung function adenosine a a agonist improves lung function during ex vivo lung perfusion ex vivo perfusion with adenosine a a receptor agonist enhances rehabilitation of murine donor lungs after circulatory death ex vivo lung perfusion with adenosine a a receptor agonist allows prolonged cold preservation of lungs donated after cardiac death lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine a b receptor antagonism attenuation of pulmonary ischemia-reperfusion injury by adenosine a b receptor antagonism increasing circulating sphingosine- -phosphate attenuates lung injury during ex vivo lung perfusion a neutrophil elastase inhibitor improves lung function during ex vivo lung perfusion α -anti-trypsin improves function of porcine donor lungs during ex-vivo lung perfusion functional repair of human donor lungs by il- gene therapy ex vivo adenoviral vector gene delivery results in decreased vector-associated inflammation pre-and post-lung transplantation in the pig increased arginase expression and decreased nitric oxide in pig donor lungs after normothermic ex vivo lung perfusion influence of ex vivo perfusion on the biomolecular profile of rat lungs metabolic profile of ex vivo lung perfusate yields biomarkers for lung transplant outcomes higher m and high mobility group box protein levels in ex vivo lung perfusate are associated with primary graft dysfunction after human lung transplantation human lungs airway epithelium upregulate microrna- and microrna- b in response to cold ischemia and ex vivo reperfusion towards donor lung recovery-gene expression changes during ex vivo lung perfusion of human lungs potential therapeutic targets for lung repair during human ex vivo lung perfusion isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals isolated lung perfusion with adriamycin. a preclinical study multicenter phase ii clinical trial of isolated lung perfusion in patients with lung metastases phase ii multicenter clinical trial of pulmonary metastasectomy and isolated lung perfusion with melphalan in patients with resectable lung metastases modified in vivo lung perfusion allows for prolonged perfusion without acute lung injury overview of the pathology of three widely used animal models of acute lung injury regeneration of severely damaged lungs using an interventional cross-circulation platform two hours of protocol-driven in vivo lung perfusion improves lung function in sepsis model of acute respiratory distress syndrome thoracic breakout session subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials tocilizumab treatment in covid- : a single center experience in vivo lung perfusion as a platform for organ repair in acute respiratory distress syndrome this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -xhx pzhj authors: nan title: nd world congress on pediatric intensive care rotterdam, the netherlands, – june abstracts of oral presentations, posters and nursing programme date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: xhx pzhj nan we present the results of a prospective population-based audit of paediatric intensive care activity in two comparable communities with markedly different delivery systems. in the trent region of the uk ( . million people), children receive intensive care largely without the supervision of a paediatric intensivist in a variety of hospitals, few of which have designated paediatric intensive care units (picus). critically ill children otherwise receive intensive care in children's wards, special care baby units (scbus) or adult intensive care units. in the australian state of victoria ( . million people), children receive intensive care almost exclusively in one centre -a picu staffed by full time paediatric intensivists. the two regions are otherwise demographically comparable. in both groups, data were collected on all children admitted to an intensive care unit between / / and / / and children who received intensive care (defined by levels of intervention and nurse dependency) in other sites during the same period. values of each variable at first contact with the icu, and the highest and lowest values over the first hours were recorded. the principal outcome was survival to discharge from the intensive care unit. severity of illness was assessed using pim (paediatric index of mortality) and prism. risk-adjusted mortality was compared using flora's z test and logistic regression. the rate of utilisation of intensive care (> admissions in each region) were similar. there was some variation in case mix between the two groups, but crude mortality rates were similar ( . % in trent and . % in victoria). however severity corrected data and other measures of picu performance were dramatically better in' the centralised delivery system. the substantial excess mortality in the trent region provides strong evidence for the benefits of centralisation of paediatric intensive care services. there are considerable difficulties in evaluating the efficiency and effectiveness oflcare in children presenting with respiratory failure during acute medical illness. optimal outcomes for such episodes include survival and the shortest length of stay (los) in intensive care with negligible risk of readmission. we have tried to determine whether or not the time course of acute severe medical illness with respiratory failure is predictable. study i (n= ): a retrospective study of intubated and mechanically ventilated children (> days, < years) with acute severe medical illness. measures: diagnosis, intensive care los in calender days, and survival. results: the underlying diagnosis fell within one of three broad categories: respiratory disease (n= , mortality . %), central nervous system (cns) disease (n= , mortality . %), and systemic inflammation or multisystem (sims) disease (n= , mortality . %. the los in survivors was: respiratory -median (interquartile range) ( - ) days, cns ( - ) days, £p, £ ( -g) days. :i'~'-+cen diag~,~is-rc!ated-grnnp~ (drgs) were identified ( respiratory, cns, sims disease) and each have been characterised by mortality and los. study ii (n= ): a prospective study of patients supported by the hypothesis that los for the above drgs was predictable (compared with study i data). in certain instances attributable causes for variances in los were identified: e.g. disease severity, timing ofdrug therapy, and associated disease. with daily paediatric risk of morality scoring within each drg, four profiles of instability were identified. discussion: the time course of acute severe medical illness with respiratory failure is predictable and variance may be attributable to specific care or diagnostic factors. we are now developing a means of linking drg-specific clinical care pathways with an integrated computerised decision support and education facility at the bedside. the objective of this open, prospective study was to assess the relation between basic patient characteristics as well as effectiveness of treatment on the one hand and resource utilization in pediatric intensive care on the other. as universal, non-monetary indicators of resource utilization we used the therapeutic intervention score system (tiss) and length-ofstay (los), from which indicators for total resource utilization per admission (tisstot) and average daily resource utilization (tiss-mean = tisstot/los) were obtained. overall admissions, totalling days, were included. mortality was . %; non-survivors accounted for . % of overall resource utilization. in non-survivors, both total resource utilization per admission and average daily resource utilization were higher, whereas los was not different from survivors'. severity of illness, surgical status, the presence of substantial chronic comorbidity, emergency admission and transfer from another hospital constituted the major predictive determinants of tisstot (r:= . ) and tissmean (ra= . ) in multiple regression analysis (p< . ). hence these indicators are appropriate non-monetary measures of resource utilization, a considerable proportion of which are determined by a concise set of basic clinical characteristics. subsequently we analysed the relation between effectiveness of care and resource utilization by assessing severity of illness corrected mortality in low, medium and high resource users, respectively. these categories were delineated by percer/tiles of resource utilization (< p , p -ps , > ps ). despite on average long los and high resource utilization in the high risk group, a relatively low standardized mortality was found, probably warranting prolonged intensive treatment in this patient category. summary: objective:the primary purposes of intensive care are to provide treatments to patients with life-threatening physiological dysfunction or to monitor and observe patients perceived to be at significant risk of dying. this collaborative study was performed to describe our patients and their outcome. in order to improve our results we tried to identit~ high risk groups, patients and methods: picus entered the study, the data included all the admissions with > hs. during a days period between the l°june and the th september . the records included: age, sex, weight, mechanical ventilation (mv), post-operative condition (p.op), malnutrition, diagnosis, length of stay, prism score and outcome. student test, mann-whitney or wileoxon were performed for univariate analysis. fisher exact test or chi square for dicotomic variables. risk group analysis was performed by logistic regression, odds ratio and % confidence interval. results: patients entered the study. mean age was . months (ds hh¢# ) and median months. we found significant statistical differences in calculated ,is observed mortality rate comparing malnourished with euthrofic patients; mechanical ventilated (mv) with non mv patients. no differences in ter ~,h of stay or di~ noses were found. effect of the un sanctions on the morbidity rate araong the iraqi small children ( below years old of age ) in bagdad. abdulsamad a.abood / institute of medical technology, bagdad. meningitis is essentially a childhood disease (i). the risk of infection are increased by powerty and overcrowding ( ). the impah'ed immunity may be an important pathogenic factor underlying the susceptibility to infections in undernourished subjects ( ). in general, malnutrition is a man made disease and it begins quite in the womb and ends in the grave (i). small children, below years of age were admitted to the pediatric hospital in washash with meningitis over cold months in i , in contrast to only child admitted with meningitis over the same period in . all of the children who admitted in were frankly undernourished, % of them were infected with enterobacteriae, because they were exposed to faulty hygiene and lack of asepsis. these facts showed precisely that our small children had suffered at most from the un_ sanctions against iraq, because of food, milk and drug shortage, since years which had resulted a severe undernutrition among them, which impaired their immune status. m wells, of riera-fanego, j lipman. baragwanath intensive care unit, university of the witwatersrand, south africa. background the use of prism or other scoring systems in the icu is of great importance for evaluating the efficacy and efficiency of a particular icu, the prism score was developed and validated in the usa and europe but has recently been shown to be inaccurate in a south american population, a south african population as well as several european studies. part of the poor performance of the prism score is as a result of differences in the case mix between the reference population and other paediatric icus. since scoring systems should generally be used only in populations similar to the reference population from which the prediction model was developed, a modification of the prism score is necessary to improve its discriminatory ability in a wide range of patient groups, aim to improve the predictive power of the prism score in a south african paediatdc icu population. patients & methods we analysed prism, demographic and clinical data collected prospectively from consecutive paediatrie icu admissions. the prediction of actual mortality by prism was evaluated by standard statistical methodology (goodness-of-fit test and receiver operating characteristic (roc) analysis), the components of the prism logistic regression equation (prism score, operative status and age) and the physiological variables making up the prism score in addition new variables analysed (nutritional index, the need for inotropes and institution of mechanical ventilation) were subjected to discriminant analysis to determine their association with outcome. results the goodness-of-fit test showed a significant failure of prism to accurately predict mortality over a wide range of expected mortality (chi [ ] = , p = ). prism underpredicted mortality at lower prism scores, but overpredicted mortality in patients with high prisms. similarly roc annysis indicated apoor predic~jve power (az = . ± . ), with an area under the curve significantly less than that for the prism reference population (p = ), prism showed equally poor discriminatory function at all age groups and diagnosfic categories. '~mth the addition of an index of nutrifional status (proportional weight-far-age), and indicators of early respiratory and cardiovascular failure to the logistic regression formula, and a recalibration of the acute physiological score component, the roc can be improved to . ± . , with a good fit described by the goodness-of-fit test (cn ] = , p = . ). discussion the prism score is not accurate in our patient population has been recalibrated in view of the poor discriminatory function that we have shown. part of the inaccuracy derives from the different demographic characteristics of our icu population and a different pattern of diseases. in addition to assessments of acute physiological aberrations, an assessment of nutritional status and early respiratory and cardiovascular failure significantly improve the discriminatory ability of the prism score, these parameters have been devised with a view to improving the accuracy of prism in our population, while not decreasing its accuracy in icus similar to the reference population. in interviewing parents regarding how physicians have communicated bad news, the response i have received is that it has not infrequently been done without appropriate care, understanding and compassion. personal experience and the lessons learned from parents, chaplains and others who deal extensively with these situations have provided me with an approach that has been supportive, compassionate, and caring. an especially difficult communication situation for the intensivist occurs when the parents have to be informed of the death of their child. for the parent, death is the hardest loss of all -the ultimate unalterable loss. circumstances surrounding the death are an important consideration (e.g., a fatal crash caused by a drunken driver, a prolonged illness, a suicide, aids). each produces a different grief reaction. the physician needs to inform parents of their child's death sympathetically coming right out with the news and leaving details until later. allow pauses and time for the paren~ to express sorrow and grief, the best communication may be thoughtful silence and a tender touch. there is disbelief that this happened. it is necessary to repeat oneself. acknowledgment of the parent's "feeling terrible" and the physician's acknowledgment of how terrible he/she feels that the life of the child could not be saved is an important first step in the parent's dealing with this tragic loss. with prolonged resuscitation, it is helpful to have a member of the icu team talk to the parents while the resuscitative efforts are ongoing so that the parents are not left unsupported at this time. a progress report should be delivered in a caring, lucid, and sensitive.manner, indicating that every effort is being made to save the life of their desperately injured child. after a child has died, it is helpful to the family if the physician maintains some contact with them. this should take the form of follow-up telephone calls at approximately , , and months. this can help to screen for depression in the parents. in giving bad news to the family and making every effort to support them through this tragic time, it is necessary to remind oneself that the intensivist has personal needs for dealing with grief and will also require support to pass through this stage. direct evidence that child mortality is lower in specialist pediatric icus comes from studies. a study in oregon (ccm ; : - ) found that mortality adjusted for severity of illness was % of expected in pediatric units and % of expected in general units (p< . ). a study in holland (ccm ; : - ) found that mortality in high risk patients was % of expected in tertiary pediatric units, and % of expected in nontertiary units (p< . ). a third unpublished study, has found that children in victoria (who almost all receive intensive care in a pediatric icu) have a much lower standardised mortality rate than children in the trent region of the uk (where many children receive intensive care in adult icus). there is indirect evidence that icus looking after many children are likely, on average, to perform better than icus looking after few children: numerous studies in many specialities have found that units looking after many cases of a particular disease have better results than units with few cases. see luft hs, "hospital volume, physician volume, and patient outcomes", happ, ; and farley d, medical care ; : - . compared to general icus, medical and nursing staff in pediatric icus are likely to be better at looking ~fter children, and plcu rmos have greater skills in pediatric intubation, ventilation, iv drip insertion and drug doses. picus are more likely to have appropriate equipment to manage children -especially for uncommon but life-threatening situations. icus in pediatric hospitals are more likely to have physicians and surgeons with pediatric expertise available for consultation at all times. the american academy of pediatrics, the society of critical care medicine, the british paediatric association and the australian nh&mrc have all said that children should receive intensive care in'specialist pediatric units. the weight of authoritative opinion, and direct and indirect evidence is strongly in favour of looking after children in dedicated pediatric icus. neurological deficit showed higher cbf values ( . / . ml/ g/ rain.) than the patients with good outcome (mean cbf . sd + . ; cbf . sd _+ . ml/ g/rain}. discussion: in asphyxia decrease of ph is due to reduced tissue oxygenation and indicates the severity of metabolic derangements. co reactivity in newborns with perinatal asphyxia correlates with the lowest ph and therefore may reflect severity of asphyxia. continuous monitoring of cerebral activity is carried out in our unit on all admissions at risk of cerebral dysfunction, a number of monitors are commercially available and we report our experience with the cfam which provides in addition to amplitude integrated eeg analysis, continuous raw eeg display and frequency distribution. bilateral recordings are commenced as soon as possible and continued while clinically indicated. forty one children ranging in ages from weeks to years were monitored for periods from hours to i days, diagnoses included traumatic brain injury ( ), sepsis/meningitis/encephalitis ( t), status epilepticus ( ) and miscellanous others ( ). results are tabulated below. patients status epilepticus * beta activity * background voltage * < i o/zv or more of above * (*z p < , ) asymmetry developed in children, all of whom died. positive predictors of good outcome included a mean background activity of > zzv, the presence of faster frequencies (usually ) in response to sedative drugs and the absence of seizures. all monitoring is performed by the picu staff and increasing expertise in interpretation has resulted in earlier therapeutic and diagnostic interventions. regional it was previously found that histamine, a vasoactive mediator, accumulated in brain compartments (kov~ics et al neurosci lett : ) , and antihistamines prevented brain edema formation (dux et al. neuroscience : ) in asphyxiated newborn pigs. in the present study we investigated the effect of intracarotid histamine injection on the blood-brain barrier (bbb) permeability, left internal carotid artery of newborn pigs ( - h; , - , g; ketamine anesthesia, mg x kg ) was catheterized through the external branch and different doses of histamine ( , - , xi - , - , x , m, respectively, in groups of animals; n= in each) diluted in . ml isotonic saline was injected into the vessel through rain. bbb permeability was determined for a small (sodium fluorescein, sf, da) and a large (evans blue/albumin, eba, kda) tracer ( %, mlxkg , rain circulation time for both dyes) concomitantly in frontal, parietal and occipital cortex, hippocampus, and periventrieular white matter both on left and right sides h after the challenge. then, intravascular dyes were removed by perfusion and bbb permeability for both tracers was quantified by fluorescence spectrophotometry (wavelengths for excitation and emission were nm and nm for sf; and nm and nm for eba, respectively). histamine injection, in doses higher than . m, significantly (p< . ; kruskal-wallis one way anova on ranks followed by dunn's test) increased bbb permeability for both tracers in each brain region. changes in left hemisphere were more intense (p< . ) than those in right one after the doses of xi - and - m in each region, i m histamine administration induced similar edema in both sides. increased intracarotid histamine levels resulted in a dose-dependent vasogenic brain edema formation. histamine might have a pathogenetic role in neonatal hypoxicischemic cerebral injuries. supported by otka f- and h-u.s,-jfno. , $ in coma caused by traumatic brain jnjury, an indication of the likely outcome is provided by the best motor response to pain in the first .$ hours after the insult. in a study in our picu, the proportion of children who died or had a severe disability was % in who had no response to pain, % in with an extensor response, % in with a flexor response, and % in who localized in response to pain. the long term outcome of traumatic brain injury appears to be worse in children < years old. other risk factors in traumatic brain injury are absent basal cisterns, midline shift or subdural haemorrhage on ct scan (or loss of grey-white differentiation in nontraumatic injury); or an intracranial pressure > mmhg despite hyperventilation, mannitol and barbiturate infusion. apart from brain death, there are two findings implying such a poor prognosis that consideration should be given to stopping treatment: first, after traumatic injury, the absence of any motor response to painful stimulus in the cranial nerve distribution (providing drug effects and a post-ictal state have been excluded); and second, in acute brain injury from trauma, infection, hypoxia, or ischaemia, the b{lateral absence of short-latency somatosensory evoked potentials (providing brain stem haemorrhage, subdural and extradural effusions, and decompressive craniectomy have been excluded). in children over months of age, recovery from prolonged coma or a vegetative state is exceedingly rare when more than months have elapsed after traumatic brain injury, and when more than months have elapsed after nontraumatic injury. overproduction of nitric oxide (no) via an inducible isoform of" no synthasc (inos) produces profound vasodilatation in adult septic shock. high nitrate levels have been reported in hypotensive children with sepsis syndrome ]. cardiovascular collapse is a prominent feature of severe meningocoecai disease (mcd). however, systemic vascular resistance (svr) was slightly higher in a group of non-survivors ~ and the rote of no in ivicd remains unclear. children with a presumptive diagnosis of mcd were enrolled. parental consent was obtained. blood was drawn on admission and hrly thereafter. plasma was separated immediately and stored at - °c. the final concentrations reported represent the product of nitrite and nitrate (nox). nox was measured spectrophotometrically using the greiss reaction. children were studied (median age (range); m ( - )). the diagnosis of mcd was confirmed in children, of whom had a glasgow meningococcal score (gms) of" ~ . in this group with severe mcd there were deaths. peak nox was significantly higher (,. ( - ) vs ( - )nmol/ml, median) and systolic btood pressure was significantly lower in children with severe mcd than mild mcd (p< . . wilcoxon rank test). there was a significant correlation between peak nox and gms (spearman's rank correlation r= . (p= . )) and prism (r= . (p: . )). nox production from adm.ission onwards was also higher in the severe mcd group (p: . , kmskal ~wallis). we have demonstrated that plasma nox levels are elevated in children with mcd, correlate directly with the severit ' of disease and are inversly related to systolic blood presssure. similar to hypotensive septic syndrome, mcd appears to be associated with an up-regulation of the l-arginine-no pathway.. non-survivors with mcd have higher svrs and may be relatively hypovolaemic. in our group of severe mcd there was a significantly lower systolic pressure and increased no formation. excess inos expression at different stages in mcd may contribute to the pathology of the disease. the identification of agents which can boost and/or inhibit no reiease may therefore represent different treatment strategies for mcd. u. merz, th. peschgens, g. kusenbach, m. b hle, h. h rnchen in this controlled, prospective study ventilated premature infants with a birth weight < g were randomized to receive treatment with dexamethasone (dex) either on day of life or on day of life. dex was given over days tapering from . mg/kg/day to . mg/kg/day. the infants treated with dex on day of life could be weaned earlier from the ventilator -in median after days (range - ) versus days (range - ) in the [ate treatment group (p = . ). the need for supplemental oxygen was shorter in the early treatment group -in median days (range - ) versus days (range - ) (p = . , ns). the incidence of chronic lung disease was lower in the early treatment group - of infants ( . %) versus of patients ( . %) (ns). to evaluate the long-term efficacy of early dex treatment we performed a respiratory function test in the age of - months using an infant whole body-plethysmograph. the intrathoracic gas volume (itgv), the airway resistance (r.w) and the airway conductance (gaw) were measured and no significant differences could be detected between the groups. the frequency of adverse effects due to dex therapy was found to be without significant differences between the early and the late treatment group. we conclude that early dex treatment had short-term improvements in pulmonary outcome in our study population, long-term efficacy however, remained unproven. several factors contribute to the development of chronic lung disease (cld) in premature infants including structural immaturity of the lung, mechanical ventilation, and oxidative stress. reactive oxygen species are formed during normal cellular metabolism but they are generated in higher concentrations during inflammation or inhalation of high oxygen concentrations. to study the relationship between increased oxidative stress, antioxidants and the development of cld we examined ventilated premature infants with birth weights below t g. infants developed severe chronic lung disease of prematurity (cld), defined by radiological signs of cld and an increased oxygen requirement at a postconceptional age of weeks, and infants had moderate cld with an increased oxygen requirement on day but not at an age of weeks. ventilator settings (fio , peak inspiratory and mean airway pressure) and the incidence of early-onset-sepsis were significantly higher in the severe cld group than in infants with moderate cld or without cld (n= ) during the first week of life. plasma concentrations of the two antioxidative substances bilirubin and uric acid (ua) were comparable in all groups during the first days of life. however, on day seven bilirubin and ua were significantly decreased in the plasma of infants with severe and moderate cld compared to the non cld group (p<o. ). there was no difference between both cld groups. in serially obtained tracheal aspirate fluids (taf) malondialdehyde (mda) was measured by hplc as an indicator of lipid peroxidation reflecting oxygen injury of the lung. ua was found in higher concentrations in taf than bilirubin. ua has been proven to be a potent antioxidant, capable to react especially with hydroxyl radicals and hydrochlerous acid, which play an important role in the induction of lipid peroxidation. infants with severe cld had significantly higher mdnua ratios in taf from day to compared to the non-cld group (p<o. ). mdnua ratios in taf of infants with moderate cld were significantly higher from day on but still lower than in the severe cld group. in addition, the ratio oxidized / reduced glutathione was significantly increased in taf of infants with cld compared to infants without cld between day and . the data support the hypothesis that an imbalance of oxidative stress and antioxidant defense contributs to the onset of cld at the end of the first week of life. introduction. rocuronium bromide (roe), a neuromuscular blocking agent with an onset time dose to that of succinyleholine l'z, has been studied in american society of anesthesiologists' physical status (asa) i or ii pedlatrie patients under non-critical elective conditions. there is a paucity of studies looking at the pharmacodynamics of roc under emergent conditions, involving pediatric patients who are asa iii or iv, without the use of adjuvant inhaled anesthetics ~. methods. with approval of our committee on clinical investigations (irb), roe . mg/kg was administered to asa iii/iv pediatric intensive care patients (age days to months; m:f= : ) on intravenous sedation. the time to reach % a~d % of b~elinc tetanie stimulus response was recorded using a r.elaxogra'ph/qmt- nerve stimulator/recorder (datex, helsiaki). depth of clinical relaxation at the % level was recorded. results. the time from rapid bolus to % was . + . see with a range of - see; and to % was . + . see, with a range of - see. at the % level, excellent clinical relaxation was seen. conduslon. in critically ill children, use of roe at . mg/kg produces rapid onset of neuromuscular blockade and excellent clinical relaxation, such that roe should be considered for rapid sequence intubation. int anesth clin. ; ( ): - . anesthesiology. ; ( ) computed tomography of the chest (ct) in mechanically ventilated adults can detect intrathoracic pathology not appreciated on chest radiographs (cxr) and influence intensive care management. no such data exists for ventilated children. aims: ) to assess if ct provides additional information over cxr regarding extent and nature of intrathoracic disease in ventilated children. ) to determine whether such information alters clinical management, inclusion criteria : ventilated children with cxr changes inconsistent with their respiratory status underwent ct if either a) pao :fio ratio < and/or mean paw> cm h or b) there was an unexplained increase in ventilatory requirement. methods : high resolution ct was performed in patients and spiral ct in patierits, to ensure minimal transport related morbidity, patients were transferred to the ct scanner by a specialised mobile intensive care team. results: in / patients ct demonstrated greater extent of disease than appreciated on cxr but did not significantly alter clinical management. in / patients ct provided additional information regarding the nature of disease present, in / children this involved a further diagnosis and in / children the exclusion of a suspected pathology. new information led to a positive therapeutic intervention in children, prevented inappropriate manoeuvres in , and had no significant effect on acute management in children. conclusions: initial data suggests that in a selected group of mechanically ventilated children chest ct can add to the sensitivity and specificity of intrathoracic diagnosis provided by the chest radiograph and directly influence acute management. case selection criteria and choice of the most appropriate protocol requires further study. pressure control ventilation (pcv) utilizes a decelerating flow pattern which may improve gas distribution and lead to alveolar recruitment. in contrast, volume control ventilation (vcv) employs a constant flow. in children, the effects of pcv as compared to vcv are unclear. the purpose of this study was to determine how these two modes compare in terms of dynamic compliance (cdyn). peak iaspiratory pressure (pip), and mean airway pressure (paw) at equivalent minute ventilation. methods: sixteen infants and pediatric patients ranging in age from day to years were studied. diagnoses included ards ( ), postoperative cardiac surgery ( ), head trauma ( ), and resfrictive lung disease ( ). patients were randomized to pcv ( ) or vcv ( ). initial measurements of gas exchange (abg's) and respiratory mechanics (ventrak, novametrix medical systems) were obtained after a minute stabilizadon period. respiratory mechanics included pip, peep, paw, delivered tidal volume, and cdyn (avolume/apressure). the patients were then crossed over to the alternate mode of ventilation holding delivered tidal volume, peep, inspiratory time, minute ventilation, and fio constant. data were collected after minutes, in each mode the absence of intrinsic peep was confirmed. to assure that the measurements were not affected by changes in clinical status, the patients were returned to the initial mode of ventilation and measurements repeated (final) . patients were ventilated with a siemens c or sv . reselts: data were analyzed using -way analysis of variance with repeated measures. ~ < . vs. vcv) vcv pcv ~ initial ] final ! cdljn . _+ . . _+ . * . _+ . . _+ . i , pip + . l-_t. * _+ , +- , paw . _+ . . i-_ . * . + . . -!-_ . pao _+ +- _+ _+ discussion: at the same minute ventilation, the decelerating flow pattern of pcv resulted in a % increase in cdyn and an % increase in paw while decreasing pip by %. the lack of a significant change in oxygenation may be a result of the limited time in each ventilator mode as well as the inclusion of patients with both normal and abnormal lungs. there was no significant difference in initial and final measurements indicating patient stability. the beneficial effects of iecre~l~iug cdyn and paw while decreasing pip indicate that pcv may be a preferable mode of ventilation in patients with lung injury. further randomized studies examining the effect of pcv on respiratory outcome measures in pediatrics are indicated. prolonged positive pressure ventilation following repair of cdh is associated with a high prevalence of iatrogenic lung injury, in our unit dudng - late deaths after repair of cdh were due to chronic lung disease. since babies requiring assisted ventilation for more than days following surgery were transferred to a cnep chamber to limit lung injury. cnep of - cm of h was combined with positive pressure ventilation via an endotracheal tube dudng the transition phase. immediate reduction of peak inspiratory and positive end pressures were possible and following extubation respiratory support was maintained by cnep v~th appropriate inspired oxygen. overall outcome: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] n= deaths before surgery (%) ( ecmo during - / who were ventilated for more than days received cnep and there were no deaths and no chronic lung disease in that group. cnep assisted ventilation may be an important management option for babies who require prolonged respiratory support to avoid the adverse effects of chronic positive pressure ventilation, introduction so far modes of liquid ventilation (lv) have been used in experimental animals and, exceptionally, in humans: . total liquid ventilation (tlv)-functional residual capacity (frc) is filled by perfluorocarbons (pfc), and slow tidal volume (tv) breathing is performed by pfc. . partial liquid ve, ti,la~ion (page) -only frc is filled by pfc. gas tv is delivered by conventional mechanical ventilation (cmv), high frequency jet ventilation (hfjv) or high frequency oscillation (hfo). the aim of our study is to present our limited experience with page in newborns and infants. page was used in two groups of infants: , in infants with brain death before disconnection from cmv, because recipients for organ transplantation were not available. these infants have relatively normal lungs (fio~ less than . ). infants stayed on page for hour, during that period no ventdator manipulations were made. after page, infant were switched to cmv for next hours. . very critically diseased infants with ards (rds) - on ecmo more than days, before cannulation for ecmo, on hfo because of intractable respiratory failure, preoxygenated rm (miteni, italy) was used in the doses up to ml/kg intratrachealy. blood gases and parameters of pulmonary mechanics were followed (dynamic compliance -c dyn, airway resistance -raw, bicore monitor). page was combined with no inhalation ( - p.p.m, in infants). in both groups ad hoc an approvement from e local ethical commission and informed parental consent were obtained. in the first qroud with relatively normal lung parameters of oxygenation drops after pfc instilation intratracheally and stayed depressed for - hours. slight pco retention occured in both cases during page. c dyn increased almost double during page period, raw drops transitorily after pfc instilation but in minutes they were identical like in prepage period, parameters of oxygenation (peo /fio ) after - hours after page improved and were better than in prepage period. after that time infants were disconnected and died. in the second group no improvement of oxygenation was seen in one ecmo baby, in spite ()f transient improvement of c dyn. in the second ecmo baby, oxygenation improved and flow of pump could be decreased by more than %. none of these babies, however, survived, improvement was only transient in spite of repeated dosis of pfc. in these babies serious problems were to maintain the adequate frc by liquid, because of severe air leak, in babies on hfo/hfjv with severe ards/rds the improvement of oxygenation were seen in all the cases immediately after pfc instiletion for the period of - hours. after that period, pfc dose had to be repeated. two babies of this group survived. conclusion. page is going steadily from tabs to clinical practice. it is simple, could be performed anywhere, cheaper than tlv. however, because liquivent -perflubren (aliance pharmaceutical) is not available in europe, rm of (mitenti, italy) is the only solution, which could be currently used here. before the widespread use of page in clinics, liquid network among most nicus and picus must be built up, the criteria for page must be defined and ethinal-legal problems resolved as well. after resolution of these particular problems page can be life saving procedure for very special part of critically ill newborns end infants. catherine caronia, peter silver, laura nimkoff, cad quinn, jack gorvoy, and mayer san. division of pediartic critical care, medici,, schneider children's hospital, new hyde park, ny , imroduetiun: cystic fibrosis (cf) patients awaiting lung transplantation present a therapeutic dilenuna when severe respir, aory decompemalion occurs, endotracheal intubation and mechanical ventilation is known to have no long term benefits and is associated with high morbidity and mortality. noninvasive respiratory support appears to be a beneficial alternative. methods: we instituted bipap (respironics, inc,, murrayville, pa) in end-stage cf patients who were admitted to the pediatric icu with severe respiratory decompeusation. all patients were awaiting tung transplantation. after a control period, bipap was applied via a tight fitting nasal or facial mask, using the spo~aneous breathing mode, expiratory pressures were set at - cm hhzo. inspiratory pressures were started at cm ~i o and increased in cm i-i increments until the patient's respiratory comfort was achieved and substantiated by non-invasive monitoring. patients were instructed to use bipap during night sleep and whenever subjectively required, data are reported as mean _+ s.d. results: all patiems utilized nocturnal bipap for - hours/day during a follow-up period of - months. compared to their pre-bipap status, the patiems' oxygen requirement and respiratory rate both oz~ cundusion: bipap tl~rapy improves the respiratory status of decompeusatir!g end-stage cf paacnts. it is well tolerated for long term use at home, and provides an extended period of respiratory comfort and stability for cf patients awaiting lung transplantation. l. bindl*, g. kiihl**, p. lasch***, appel**, j.m er**** and the "arbeitsgemeinschaft ards im kindesalter" background acute respiratory distress syndrome (ards) is a therapeutic challenge in pediatric intensive care in view of the high mortality, in about german paediatlic hospitals founded a working group aiming on collaborative clinical research in this field. aims and methods the aim of both a prospective and retrospective survey conducted in german pediatric intensive care units in was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ards patients who were treated in the tt~ee year period from to .all patients had acute bilateral alveolar infiltration of noncardiogenic origin and a po ~io ratio < mmhg. the influence of sex, underlying disease and single organ failure was analyzed using the fischer's exact test, the influence of additional organ failure on mortality was tested with the cochran-mantel-haenszet statistics. results patients were reported giving an incidence of cases per admissions to pediatric icus. median age was month. in % of the cases, ards was associated with a pulmonary, in % with a systemic underlying disease. in % immunocompetence was impaired. mortality was % and not dependent on age, sex and triggering event. the number of associated organ failures, however, strongly influenced mortalib,. mortafity in immuno-compromised patients was t %. the analysis of treatment modalifies employed in the patients revealed a lack of uniform therapeutic strategies. on the other hand, the patients were exposed to interventions not yet supported by controlled trials. conclusions the observation of the lack of uniform treatment strategies led to the elaboration of recommendations on ventilator therapy and patient monitoring within the working group. the data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modafities in pediatric ards. recurrent apnea and respiratory failnre due to severe lower respiratory tract disorders such as bronchiolitis or pneumonia are the most common reasons for mechanical ventilation during respiratory syncytial virus (rsv) infection. acute respiratory distress syndrome (ards) has been described as a complication of severe rsv infectionj in contrast to the low mortality rates associated with rsv infection (< %), mortality rates in the range of - % have been reported in pediatric patients with ards. however, studies on ards are usually lumped in respect to causation and the disease course of rsv induced ards has not been previously studied. we examined the lung function abnormalities of infants with rsv induced respiratory failure requiring assisted ventilation, measurements included respiratory mechanics, maximal expiratory flow-volume curves and lung volumes, ards was defined clinically using the criteria which were recently proposed by the american-european consensus conference on ards~: acute disease onset, pao /fio~ ratio _< mrn hg, bilateral infiltrates on chest radiograph and absence of clinical evidence of left atrial hypertension. we calculated the murray lung injury scores modified for use in pediatric patients from total respiratory system compliance, radiographic findings, ventilator settings and blood gas results. we identified infants with severe restrictive lung disease that fialfilled the clinical criteria fbr classification as ards. all had lung injury scores above . which is the recommended cut-off for a diagnosis of ards, twenty-seven infants had obstructive disease consistent with a clinical diagnosis of bronchiolitis. the ards patients were significantly younger, had a longer time of assisted ventilation (p < . ) and a greater proportion of infants with preexisting illnesses (p= . , odds ratio = . ) when compared to the patients with obstructive disease. with the exception of one immunodeficient patient, none of these infants died. given the low mortality despite a clinical picture of severe lung injury, there is evidence that rsv induced respiratory failure may represent a relatively benign cause of ards in pediatric patients, bachmann an audit of patients with severe acute bypoxic respiratory failure (ahrf) receiving highfrequency oscillatory ventilation (hfov) in our unit ( n= , mortality %) revealed that sub-groups with severe underlying disease (n= , mortality %)and those with mu~pie organ failure ( > systems failing, n= mortality %) accounted for all the deaths beyond the neonatal period. v~ therefore hypothesized that in a modem paedistric intensive care unit (picu): a) children greater than one month of age with ahrf do not die in the absence of severe, pre-existing disease or multi-organ dysfunction syndrome, b) respiratory parameters alone will predict outcome poorly in ahrf. method prospect~/e sty/of all adm~ns to our tertiary picu. data it, citing the respiratory parameters (oxygena~n index [ol] , aiveolar-artedal oxygen tension gradient , pao /fio ratio) were collected hourly from the bedside charts throughout admission. patients were included in the study if ahrf was present at admission either none or in combination with other organ dysfun~on. ahrf was defined as the acute (< hour) onset of respiratory dysfunctk:~l with a pao /fio ratio.< for six consecutive hours dunng the first hours of admission (with no evidence of left anal hypertension), x-ray review defined a sub-group of patients with acute respiratory distress syndrome (ards) by the presence of bilateral interstitial infiltrates. results to date children (ages - months, weight . - kg) have been admitted in ahrf. of these also had ards. the overall mortality was . % ( / ), and greater in the ards group than the non-ards group ( t , . % vs, , . %, p< o. ) . it was not possible to predict survivors from non-survivors on the basis of the seventy of the respiratory failure alone, the a-ado on the day of admission (best in hours) was not significantly different between survivors and non-survivors: (mean, + sd)( mmhg +_ , vs mmhg _+_ ). kdl non-survivors were immunodeficient (n= ), previously extmrnsly premature infants (< ),(n= ) or suffedng fcom chronic metabolic or gastrointestinal disease (n= ). no previously normal child died. conclusion the severity of respiratory failure does not allow predioljon of outcome in our patients. we believe that this reflects that modem picu is so effective at providing respiratory support that pre-existing pathology alone de~ prognosis. this suggests that an abnormally regulated host response or abnormal persistence of a pathogen may be required to induce lung injury of sufficient severity that the resulting respiratory failure cannot be supported in a modem picu. introduction: postural changes (supine to prone) is a therapeutic intervention that could be useful in children with adult respiratory distress syndrome. objective: to determine the effects of postural changes in the oxygenation of young children with ards. method,s: a prospective stud ," was performed in eleven subjects aged to months (mean= ) with the diagnosis of ardsreceiving vendlatory support. (mean peep and fio of and . respectively). postural changes was performed every - hours, during a period of time ranging from to days. arterial blood gases were determined before and - n~n after the postural change, no modification in the mechattical ventilation other that changes in the fio were performed. the oxygenation was determined by the index pao /fi (p/f). to study the differences between the oxygenation mean, before and after the postural changes the wilcoxon test for paired samples was used, results: changes were performed ( from supine to prone and from prone to supine). a % increased p/f ratio was obtained after the change from supine to prune. although, not all the patients receiving postural changes improved their p/f. six of them (group i) showed an improve in the p/f when changed from supine to prone, returning to their base line when positioned from prone to supine. no improvement on the p/f was observed in the remaining subjects (group ii)after postural changes (table ) . during the maneuver no complications were observed. two patients had a pneumothorax, not related with the postural change. conclusions: postural changes (supine to prone) is an easy way to improve oxygenation in some children with ards. change to prone change to supine introduction: the common noninvasive diagnostic efforts to identify possible obstruction of the intrathorucic airway, are of limited value. invasive procedures such as bronchoscopy and bronchography may also be noncontributory and entail risks. we evaluated the usefulness of d-ct in the diagnosis and management of pediatric patients with suspected intrathoracic airway obstruction (itao). methods: we used a diagnostic algorithm (see diagram) in patients with suspected itao resulting in respiratory distress. three-dimensioual imaging of the tracheobronchial tree was reconstructed, following high speed spiral ct scan, by specific computer software (advantage window computer work station, general electric, milwaukee, wisconsin). non-ionic contrast medium was injected, in some patients, to delineate the intrathoracie large vessels.. results: eight patients were studied. in patients the d-ct revealed intrathoracic airway abnormalities. these patients underwent further invesive studies which confirmed the following diagnoses: patients had bronchomalacia, had bronchial stennsis due to a dilated pulmonary artery mad patients had subglottie stenosis extending to the thoracic cavity. three patients had no significant disruption in the configuration of the tracheobronchial tree and thus did not require invasive diagnostic procedures. conclusion: computer reconstruction of three dimensional images of the tracheobronehial tree is a safe and reliable diagnostic tool for itao. ards and ecmo; preliminary data from a randomized clinical trial. j fackler, c steinhart, d nichols, d bohn, m heulitt, t green, l martin, k newth, m klein, j ware. many suggest ecmo be considered experimental for ards and undertaken only with careful data collection and reporting. a mtflticenter pediatric rct is in progress to determine whether ) ecmo and/or ) permissive hypercapnia, offer significant advantage for the treatment of ards. methods: all patients aged wk to yr (without congenital heart disease) are eligible for study. data collection begins when a patient receives at least % oxygen and a peep of cm h for hours (stage t). if the predicted mortality reaches % within days (stage ), eligible patients are asked for written consent for randomization. patients are excluded from randomization with significant chronic lung disease, immune compromise, cardiac disease; or profound acute central nervous system damage. the prime outcome variable is survival. at the studies onset, pts were estimated to be required so that pts were randomized per arm. results: patients are enrolled from centers. data are complete on . patients never reached stage (i.e. % mortality). patients improved and died. of the latter, had randomization exclusion criteria even if stage was reached. patients reached stage . had exclusions from randomization and all died. eight patients ( survivors were eligible for randomization; consent was obtained in no case. two patients received ecmo. overall survival is % ( / ). in patients without randomization exclusions, survival is % ( / ). morbidity m survivors (discharge -admission popc or pcpc score >_ ) was seen in none of the stage surviviors and % ( / ) of those who reached only stage !. conclusion: the rct requires completion. the records of hospital in-patients at king faisal specialist hospital and research center who received external cardiac massage as part of their cardiopulmonary resuscitation were reviewed. success of resuscitation was analyzed as ( ) short term (restoration of spontaneous circulation), and ( ) long term (discharge from hospital). of such patients, ( . %) survived the initial resuscitation, and ( . %) were discharged. success of outcome was not related to age, location of patient, time of day, or rhythm at arrest, including asystole. longer resuscitation time was associated with less chance of restoration of spontaneous circulation (p< . ), but not associated with hospital discharge rate. results for patients with congenital heart disease were similar to those with other medical or surgical conditions. in this series, . % of ward in-patients survived to discharge, compared to two "*;'~r ~r;~' ,.,.'her,, the r-e~ult~ were c/ "'~d ~, ~,°(. overall, % of patients who survived the initial resuscitation were discharged from hospital. where resuscitation continued for more than minutes, . % of patients had tong term survival. outcome from asystole was no worse than for other cardiac rhythms, we believe that previous reports of poor outcome from asystole in pediatric cardiac arrest should noi influence decisions to stop resuscitation for pediatric in-patients prematurely. successful restoration of spontaneous circulation with long term survival can be achieved after prolonged resuscitation. abdelmoniem~ lindsey jahusou~,mariano fiallos, university of florida, prudential drive, suite jacksonville, florida usa central acidosis is well recognized as a marker of inadequate tissue perfusiou, and ventilation. however, obtaining central venous blcod is difficult and fraught with complications in the child undergoing cardiopuimonary resuscitation. intraosseous blood may be used instead of central venous blood to judge ph and pcoz during short durations of cardiopulmonary resuscitation and during hemorrhagic shock. the purpose of this study is to compare the ph and pcoz status of intraosseous and central venous during prolonged cardiopulmonary resuscitation after fluid and drug infusion. we hypotbesized that there would be no difference in ph and pco values of simultanecusly obtained intraosseous and central venous blood samples. eighteen ( ) introduction: cardiopulmonary arrest (cpa) in children is usually preceded by a deterioration of cardiac or respiratory function due to sepsis, dehydration and hypovolemia. early recognition of clinical and laboratory signs followed by immediate intervention are essential for prevention of cpa. the purpose of the present study was to identify factors which contributed to high rates of mortality from cpa in patients admitted to a paediatric intensive care unit (p cu). methods: a prospective study was done of all non-surgical patients with cpa who were admitted to the picu, hospital baca ortiz, quito ecuador from january to october . clinical and laboratory variables before and after admission to the picu, time from hospital admission to picu admission and the pediatric risk of mortality score (prism) were recorded on a questionnaire designed specifically for this study. results: of the non-surgical patients admitted to the picu, ( %) were admitted after developing cpa on the general pediatric wards. mean age was + . months, with of patients under months of age. initial diagnoses upon picu admission included meningitis (n= ), respiratory failure (n= ), congenital heart disease (n= ), severe neurological impairment (n= ), end stage neoplastic disease (n= ), hypovolaemic shock (n=l), peritonitis (n=l) and sepsis (n=l). mean time from hospital admission to p cu admission was _+ . hours. the mean prism score upon hospital admission was + . (score > = > % mortality). % ( / ) of the patients died. one of the three survivors had severe neurologie injury. prior to picu admission, patients experienced tac~,cardia (n= ), hypotension (n= ), neurological deterioration (n= ), respiratory, distress (n= ), oliguria (n= ), bradycardia (n= ), metabolic acidosis (n= ), hyponatremia (n= ), hypokalemia (n= ), hypocalcemia (n= ) and severe hypoglycemia (n= ). there were serious delays from the time of development of clinical and laboratory abnormalities to the time of admission to picu. conclusion: in the critically ill pediatric patient, rapid recognition of clinical and laboratory signs of deterioration, followed by immediate intervention, are required to prevent end stage shock and cpa. we found serious delays in intervention following development of important premonitory clinical and laboratory abnormalities in patients less than months of age on the general pediatric wards, which iikely contributed to the dismal % mortality rate. hospitals throughout ecuador should institute immediate improvements in ctinical supervision, and provide training in paediatric advanced life support (pals) to decrease excessively high rates of and mortality from cpa. intraosscous access is recommended by the american heart association and american academy of pediatries as a means of rapid access to the vascular system for childhood emergencies. bone marrow and fat embolism is a concern and has been reported post intraosseous infusion in stable animals but has never been studied in animals subjected to cardiopuimonary resuscitation. we undertook this study to investigate the incidence and magnitude of lat and bone marrow embolism with the use of intraosseous infusion during prolonged cardiopuhaonary resuscitation and after fluid and drug infusion. we hypothesized that there will be no difference in the magnitude of fat embolism between cardiopulmonary resuscitation only and other cxperirnental conditions. thirty-one ( ) piglets were anesthetized, mechanically ventilated, and instrumented (carotid artery, pulmonary artery and intraosseous earmulas ). the animals then underwent bypoxic cardiac arrest followed by chest compressions with the mechanical thumper (michigan insmunents) and mechanical ventilation for a minimum of minutes. the animals were divided in groups: a (n= ) which had no intraosseous, ~'oup b (n= ) had intraosscous with no infi~ion, and groups c (n= ), d (n= ), e (n= ) had intraosseous with infusion of adrenaline, normal saline and sodium bicarbonate, at cessation ofcardiopulmonary resuscitation, representative lung samples were collected fi'om upper and lower lobes of each lung, embedded in ocp and firozen immediately. ltmg specimens were stained using oil red-o dye and observed for fat globules and bone marrow elements. the amount of emboli present was rated as a percentage in relationship to iung tissue, by a pathologist blinded to the experimental groups. buffy coat specimens were collected before and at cessation of cardiopuimonary resuscitation, stained with oil red-o dye and observed for fat globules. percentage of fat present were compared using analysis of variance. fat globules were seen in the prebronchial blood vessels and in intravascular areas throughout all lung fields. there was no difference in appearance or distribution of fat globules between groups. quantity varied in the different groups[(a) %, (b) %, (c) % (d) %, (e) %], but were not statistically significant (p = . ). fat globules in the buffy coat were few and inconsistent with lung findings. fat and bone marrow emboli were present in all experimental conditions, the use of the intraosseous cannula does not increase the magnitude of embolization during cardiopuimonary resuscitation. the decision to use the intraosscous route should not be influenced by the risk of embolization. tzareva iv/,, md*, nedialkova r, md**, *dept. of pathophysiol, *~dept. of child surg. and icu, emergency medical institute pirogov, sofia, among children with blunt abdominal trauma, treated in emi pirogov during the last five years, children had serious disturbances of the basic vital functions, connected with the trauma, and most often with massive haemorrhage, for this reason being an object of reanimation and intensive care. in the group of children who survived - , predominated the trauma of only one abdominal organ (mainly the spleen, rarely the kidneys, the intestine) and only children had injuries of more than one abdominal organ. in the same group, in children the abdominal trauma was combined with chest or head trauma or bone fractures. in the group of children who died - , a profound combined trauma was present. the haemodynamic parameters in all children showed a characteristically significant tachycardia along with normal or even high blood pressure, while hypotonia was present in only % of the children on the first trauma day. despite the fact that only . % of the children had direct chest injury as well, the gas exchange was considerably disturbed - ' of the children were hypoxemic during the first, and % during the third trauma day -in % significant -below . kpa ( mmhg). together with the markable decrease in haemoglobin levels, this determines the pronounced disturbance in oxygen transport. during the first trauma day all the children were acldo~c, and a metabolic alkalosis was present during the following days. twelve of the children with severe combined trauma died within several hours, with the symptoms of irreversible haemorrhagic shock, or in the next - days, developing multiple organ failure. in conclusion, the intensive therapy of children with severe abdominal and combined trauma, should take in consideration the special haemodynamical trauma answer in children, and requires dynamic monitoring of the most influenced homeostatic parameters -blood gases, acid-base metabolism, haemostasis. introduction: endocrine emergencies, other than diabetic ketoacidosis, are uncommon causes of pediatric intensive care unit (picu) admissions. we report our experience of children diagnosed of adrenal insuficiency (ai) admitted in the picu, during the last four years. subjects: five eases of ai requiring intensive care unit admissions are presented. four females anna male, with ages ranging from days to years, none of them had a previous systemic or endocrine diseases that could suggest al the initial clinical manifestations were: dehydration ( ), vomits ( ), abdominal pain ( ), seizures ( ), lethargy ( ) and hyperpigmentation in the muco-genitat area in a newborn male and ambigna genitalia in a newborn female. the reason for their admission in the p cu were: shock in two subjects; three because of hyperkalemia and hyponatremia (k/na: . / ; / ; , / meq/l); and two with severe hyponatremia (na: ; meq/l). laboratory findings: severe hyponatremia ( ), increased concentration of urinary sodium and chloride ( ); metabolic acidosis ( ); hyperkalemia ( ); increased levels of urea ( ) and hypoglycemia ( ). in all of them, the electrolytes abnormalities did not normalize with replacement and only normalized after the administration of hydrocortisone. tile ai was due to: autoimmtme disease in two subjects, congenital adrenal hypoplasia, congenital adrenal hyperplasia secondary to alia hydroxylase deficiency and in one no etiology was found, at the present time, comments: aiis an uncommon disease in the pediatric age. anearly diagnosis is crucial, as if the treatment is delayed could lead to patients death. in subjects with arterial hypotension and electrolytes abnormalities refractory to the usual treatment, they should be treated with corticosteroids, if no etiology is found. although, previously samples must be obtained to make the diagnosis, : denotes the number of cases. gerbaka b; hakme c; akatcherian c. toxics are frequently involved in domestic accidents during childhood; among non medical products ingestion, carbohydrate poisoning is a serious injury often made possible by inadequate stocking. over years, children aged years and less were examined in the emergency department of hotel-dieu de france hospital for carbohydrate ingestion. , % are boys; age goes from months to years (moan = , years). kerosene is found in , % of cases; all were admitted (mean = , days). , % were symptomatic on first examination but % of all children presented signs of gastric ( %) or respiratory ( , %) irritation sometime during their history; , % had neurological signs and , % presented some fever. leucocytosis is found in % of cases; , % of the children received antibiotics. chest x ray was abnormal in , % of cases: mainly parahilar infiltrates were found, all children survived; , % with a normal course ( , days of hospital stay) whereas those who presented complications (severe pneumonia, coma) stayed in the hospital for days (mean) with short course of assisted ventilation for two of them; long term follow up was not possible. we fonnd nick's criteria for hospital admission to be of value: -symptomatic children with normal x ray } to hours monitoring -asymptomatie children with x ray abnormality } -symptomatic children with x ray abnormality: hospital admission -asymptomatic children with normal x ray : no admission. these criteria would have helped to avoid admission in children and would have allowed a short t hours stay for more. we found chest x ray to be mandatory in carbohydrate ingestion; other tests were not helpful, aside arterial blood gases measurement in case of respiratory involvement; we now also advocate more restriction in antibiotic use. prevention remains efficient and should be stressed on. severe liver failure [slf] is a rare but severe condition in infants. we report our experience. patients: slf was defined as liver insufficiency with hepatic encephalopathy and a decrease in the level of factor v to below %. between and , infants (mean : mo) were admitted for slf (neonates excluded). main causes were metabolic disorders ( . %) (tyrosinemian= , hemochromatosis n= , reye's syndrome n= , other n= ), virus-induced flf ( . %) and hematologic diseases ( . %). in cases, the causes remained undetermined. results: olt was contraindicated in cases because of multiple organ failure (n= ), or underlying disease. all of them died within days after admission. patients had no indications for olt, all but one are alive. ( of them was transplanted later for tyrosinemia and died lately (virus induced-slf). among the t infants who underwent emergency olt, are alive and died because of primary non function of the graft. conclusion: slf in infants admitted before their first birthday is a severe condition with an overall mortality rate reaching %. inherited metabolic disorders are the first cause of slf at this age. contraindications for olt are frequent because of underlying disease or multiple organ failure. a number of children undergo primary graft failure after liver transplantation. it is unknown if there is any increased morbidity or mortality following retransplantation. this study seeks to explore these issues. methods: a pediatric intensive care/iiver transplant database is in formation. records of all liver transplant patients are reviewed and abstracted. this data is then computerized to allow analysis. this data provides the source for this study. statistical analysis was performed via student's t-test where appropriate. results: of the patients who have thus far received at our center orthotopic liver ransplants, the records of who underwent transplants form the basis for this review. twenty-three patients underwent multiple transplants, required one additional, three required organs, and one patient survived after a fourth organ transplant, there was no significant difference in age at first transplant between those who received multiple organs and those who did not ( vs, months, p=ns). the anesthesia time for the procedure did not significantly increase tbr subsequent transplants ( . vs, , hours), nor did time in the intensive care unit (t . vs. . days), nor did time on the ventilator ( . vs. . days) subsequent transplants did not predispose to having more bleeding in the intensive care unit for usage of packed red blood cells or platalets was not significantly altered ( vs ml and vs ml respectively). patients who required retransplantatior~ did receive mere fresh frozen plasma (ffp)daring their first transplant than in the subsequent ones ( vs ec, p < . ). however ffp use was not significantly different than patients who did not require retransplant. patients who underwent retransplant had a markedly increased mortality ( %) than the overall mortality for liver transplants at our center ( %), conclusion: children who require another liver transplant have a markedly increased mortality. bleeding and prolonged icu stay is not significantly different between the first and subsequent transplants, fulminant hepatic failure and ortothopic liver transplantation.dr.sasb n,j;centeno,m;entin,e;acarenza,m;ciocca, m:gofii,j;bianco,g;weller, g;imventarza,o. unidad de cuidados intensivos.hospital de pediatria "dr.j.p. garrahan" .buenos aires.argentina. introduction:fulminant hepatic failure (fhf) is a clinical syndrome, defined by the development of hepatic encefalopathy within weeks from onset of illness in a previously healthy person.by far,the most comun cause of pediatric fhf in all series, is acute viral hepatitis.we report our experiences with the pediatric fhf and ortothopic liver transplantation (olt) as attemative of treatment. patients: childrens with fhf diagnosis were admitted at the picu from / / to / / .symptomatic treatment was given to all children and all were put on list for olt,) following the king's college criterion (protrombina time,age,atiologies,bilirrubin,and encefalopathy state). results:etiologic causes corresponded to the childrens were: , hav ( %); , noa nob ( %); ,autoinmune ( %).the age was mean: years (range: month- years).seventeen patients were transplanted, chidmn were discarded because:no donors: ;withdrow of the list: ,because sepsis in and bleeding of cns ;and no admission at list: because genetic syndrome ,massive intestinal necrosis, ,mitral valvulopathy and sepsis, . patients ( %) had at least one complication dudng the post operative period.the most frequent was the acute renal insufficiency(ari) and patients requiered continuos hemofiltration.the gtobal mortality rate was %.the mortality of patients without olt was % and the mortality of patients with olt was %, patients dayed because sepsis, ( candidiasis) and the others because mof.the actuarial survival at year is % and the follow up of months. conclusions:the fhf is a very severe and frequent disease at picu. supportive treatment only is associated with a very poor prognosis and high mortality rate.the most frequent etiology in our country is the hav. the olt is applicable in this cases and is a valid alternative of treatment (mortality in our series %).the ari is the most frequent complication during the post opeative period.in argentina,due the high prevalence of hav,prevention must be considered the main and only way to avoid this catastrophic illness.- to assess the efficacy of gastric intramucosal ph (phi) for evaluation of tissular perfusion and prediction of hemodynamic complications m critically ill children. patients and methods: thirty critically ill children ( boys and girls) whose age ranged from month and years old were studied. a tonometry catheter was placed in the stomach of all patients at their °admission in pediatric icu. intramucosal ph measures were made at the admission and each - hours during the study: a total of determinations were made. the catheter was removed after extubation and/or checking of hemodyrmmic stability of the patient. the intramucosal ph was derived from application of the henderson-hasselbaeh formula using the pco value from the tonometer and the arterial bicarbonate. values of phi between . and . were considered normal. the relationship between phi and severity of patient measured through prism, presence of major (cardiorespiratory arrest, shock) and minor (hypotension, hypovolemia or arrhytlmtias) hemodynamic complications, mortality and stay in the picu, was analysed. results: the admission value of phi was . -t- . (range . - . ). five patients ( %) had an admission phi < . . no relationship was found between an admission phi < . and a higher incidence of hemodynamic complications. sixteen patients ( %) showed some values of phi < during their evolution. patients with phi < . had a higher number of hemodynanuc complications than the rest (p< . ). every cardiorespiratory arrest (cra) and shock cases were related to a phi < . . patients with major complications (cra and shock) had a phi lower (p= . ), as well as a higher number of measurements of low phi (p= . ) than patients with minor hemodynamie complications. the value of phi lower than presented a % of sensibility and % of specificity with regard to hemodymanic complications. there was no relationship between phi < . and prims score and stay in picu. patients with phi < . presented a prims higher than the rest of patients (p< . ). conclusions: the phi value may be an early sign of presence of hem dyaaimc complications in the critically ill child. we tested the hypothesis that gastric intramural ph (phi) can be used as an early sign of failure m weaning pediatric patients because the blood flow from nonvital areas is diverted to meet the increased demands of respiratory muscles. methods: children (mean age ( . _+ . ) years + sd) who were thought by their physicians to be weanable from mechanical ventilation (mv.). these patients were ventilated on serve c ventilators, receiving ranitidine, and had intestinal tonometer (tonometrics, inc.) minutes before obtaining a sample.. all children were placed on pressure support (ps) at levels judged to overcome the resistance of the endotracheal tube and ventilatory circuit ( em h.,o). a sample of arterial blood and a sample oftonometer were obtained during vm and weaning (ps). phi, hemodynamic and respiratory data were recorded during vm and weaning we did not interfere with the primary caretaker's decisions regarding extubation. patients were considered to be successfully weaned if they were able to sustain spontaneous ventilation for more than hours after extubation. paired t-test were used to compare the values obtained during mechanical ventilation with those obtained during weaning trials. unpaired ttest were used to compare values from the group that was successfully weaned (a=i ) with those from the group that were not (b= ). results: we did not find statistical differences in any of those variables mesured during mv for patients who were successfully weaned(group a) and those who were not (group b). gastric phi was in group a: . + . (vm) and + . (weaning); in group b: . _+ . (vm) and . t _+ . (weaning). discussion: although we did not find differences in gastric phi during vm, the group a had a lower value than group b because of the number of cardiac patients ( %) and transfusion therapy, in fins group. in group b % of patients showed a problem in upper airway (subglottic edema, and enlarged tonsils). we found it after extubation. conclusion: ) gastric phi is a good predictor of risk in critically ill patients but maybe because of the small size of the sample, in our study is not of practical value as a predictor of failure in weaning pediatric patients from vm. ) this test is not a predictor of problems in upper airway~ important etiology of failure weaning in children. objectives: i-to determine the prognostic value of the gastric intramueesal phi in mortality and multiple organ dysfunction (sdmo) in critically ill children. -to compare this value, with the pediatrics risk index mortality score (prims). methods: aprospective study was performed with critically illcbildren, aged from mouth to years. the athnittiug diagnosis was: post-surgery ( neurosurgery, spinal fusion and thoracic or abdominal surgery), sepsis, polytraumatism, adult respiratory distress syndrome and with miscellaneous. all the subjects were monitorized on picu admission and treated for their underlying condition. gastric intramucnsal pt{ was measured following the tonometric method, ou admission and every - hours depending on the patients state. the severity of the clinical condition was evaluated using the the prims, on admission (prims-i) and during the first hours, when the clinical condition deteriorate, the worse score was utilized for the statistical analysis (prims- ). to perform the statistical analysis the subjects were divided in two groups, one with the phi< . and the other with phi> . .aunivariate analysis (student's tand wilcoxon two tailed test, chi-square) and multivariate analysis were used. results: out of the subjects dyed. of children developing multiorgan failure (mof) expired. % of the patients admitted to the picu with sepsis, ards and miscellaneous had a phi < . . in contrast, with % of post-surgical and none of the postqraan~atism. the mortaliry rate, in children with a phi< . was % (ci %: . ; , ) and . % (ci %: , ; . ) in children with phi> . (p= . ). mofwas observed in , % of children withphi< . v.s, . % with phi > . .no relatiouship was observed between the phi and the score of prims-i and . perforating an unconditional logistic regression analysis, two independent variables have mortality predictive value: the phi and the prism- . (table i) following induction of anaesthesia, a laser doppler probe (moorsoft instruments ltd) was inserted cm into the patient's rectum, the probe's special design ensuring that the optical prism lay against the mucosa. continuous monitoring of rectal mucosal perfusion ("flux") was continued throughout the operation. after rain cpb at °c, "steady state" readings of nasopharyngeal temperature, mean femoral arterial pressure (map) and flux were recorded over a further min before cpbinduced core cooling to - °c. steady state was defined as a rain period with no change in core temperatures or map. other rain steady state recordings were taken immediately prior to low flow, immediately prior to rewarming and after rewarming to °c, before initiation of any vasoactive drugs. the cpb flow rate was kept at m l k g - min q, the pcv at _+ %, the p~co at . + . kpa and the pro at + kpa. results: initial warm and rewarm map (both mmhg) were significantly lower ( = . ) than during the cold cpb periods ( & mmhg). the mean cold flux before ( ) and after ( ) low flow were both significantly lower (p= . ) than the mean initial warm cpb flux ( ). the mean rewarm cpb flux ( ) was significantly lower than all other flux values (p= . ). there were no siglaificant correlations between map and flux except at the first warm cpb period (r= , , p= . ). conclusions: although hypothermia significantly reduces rectal mucosal perfusion, rewarming produces an even greater reduction in gut perfusion which, considering that mucosal oxygen constmaption is highest during this time, may prove crucial in the postoperative development of mof. therapy aimed at improving gut perfusion during cpb should be directed at the rewanning period in particular. abstract this work is aimed at establishing a clinical procedure for the diagnosis of enteritis necroticans (en), even at the communal level, and to define criteria for diagnosis able to distinguish between acute forms. subjects and method : cases admitted at the institute for protection of children's health dpch), having characteristic symptoms, were examined clinically, by roentgenography of the abdominal cavity, with the analysis of the blood (total protein, electrolytes, hematocrite) and cultures of intestinal fluid and faeces. through surgical operations, the pathological lesions were observed and recorded. results: common epidemiological features: the average age is - years old ( - ) ; male/female : . ; in % of the cases, the disease occurred after a meal rich in protides. the acute toxic form accounted for % : severe shock appearing early, with very severe dehydration associated with profoundly decreased blood protein concentration and lowered natriemia as well. the lesions of the small intestine were expanded, all of them were necrotic. in the surgical form ( %), the predominant feature was an obstruction -peritonitis syndrome, the peritoneal fluid showed a characteristic inflammatory reaction. for the rest of cases % were the internal form, the shock syndrome was less severe, the abdominal distention was light and disappears gradually, the inflammatory reaction of the peritoneal fluid was not so characteristic. conclusion (ino) is a selective pulmonary vesodilator that is rapidly inactivated compared to intravenous vasodilators. these qualities make ino an attractive agent for the treatment of pulmonary hypertension (pittn). the efficacy of ino has been studied in persistent fetal circulation, acute respiratory distress syndrome (ards), and congenital heart disease (chd). potential adverse effects oflno include: nitrogen dioxide (no toxicity, methemoglobinemia, and platelet dysfimction. our objective was to evaluate the safety of ino in pediatric patients (pts). methods: pediatric pts. with phtn from ards or chd were studied under an established, approved protocol conforming to fda guidelines tbr an investigational new drug. informed consent was obtained for each child prior to treatment. no was sequentially titratad from parts per million (ppm) to , , , and ppm at ten minute intervals. parameters monitored before and during therapy included nitric oxide (no) and no~ concentrations (cone.), mean arterial blood pressure (map), and percent methemoglobin (mhg). no and noz levels were continuously monitored using an inline dr~ger electrochemical detection device. ~,litp was continuously measured with an indwelling arterial catheter. mhg was measured by co-oximetry. a mhg level e % or no cone. ~ ppm were considered adverse effects by study criteria. pretreatment map was compared to map at and ppm ino using paired t-tests. ap value < . was considered statistically significant. results: thirty-two mechanically ventilated children with phtn ( with ards, with chd) were studied. five pts. were treated following cardiopulmonary bypass. methemoglobin (met-hb) levels were routinely measured in two prospective clinical studies on no inhalation in pediatric patients with pulmonary hypertension following heart surgery with extracorporeal circulation and in pediatric and neonatal ards patients, the observed differences between the groups prompted in an in vitro study, red blood cells (rbc) of patients sampled before and after surgery with and without extracorporeal circulation (ecc), respectively, were incubated with ppm no for rain, met-hb, atp, and nadht nadph concentrations were compared, during therapeutic exposure no increased met-hb from . - -_ . to . _+ . % in cardiac surgery patients and from . ± , to . ± . % in ards patients (p < . ). rbc's having undergone ecc were more susceptible to met-hb formation (p< , ) whereas intracellular coenzymes did not differ neither between the groups (table) nor before and after no exposure. ecc predisposes to increased methemoglobinemia upon exposure to no both in vivo and in vitro. our data suggest a reduced activity of met-hb reducing enzymes rather than diminished availability of energetic substrates, variation of the inhaled nitric oxide concentration with the use of a continuous flow ventilator. anne pmc de jaegere ~, frans im jacobs , nico gc laheij , john n van den anker t . dept. of paediatrics ~, central instrumentation , sophia children's hospital, erasmus university rotterdam, rotterdam, the netherlands. objective: to investigate the homogeneity of nitric oxide (no) concentration in a delivery system with a continuous flow ventilator. design: bench study, setting: biomedical laboratory. interventions: a nitrogen/nitric oxide (njno) gas mixture was injected at three different sites in the patient circuit: just before and just behind the humidifier, and centimetres before the y-connector. ventilator flow ( , , l/rain), ventilator rate ( to , increments of ) and compliance of the testlung ( . ; . ; . ml/cm h ) were changed. carbon dioxide (co ) instead of n /no was injected at the same points in the circuit. measurements and main results: a) though the flow ratio of the njno and the ventilator gas were kept constant, the no concentration ([no]) raised with increasing ventilator rates. the increase in [no] was up to % when the n /no injection site was close to the y-connector of the ventilator circuit. minimal changes in [no] were noticed when the n~/no was mixed to the ventilator gas before the humidifier. b) analysis of the ventilator flow pattern showed variations at different places in the ventilator circuit. the magnitude cf the p, ow change depended on the meas~:rement site. the closer to the expiratory valve the highest the flow change was. the duration of the flow change was inversely proportional to the adjusted ventilator flow. c) real time measurements of the co concentration ([coz]) showed variations during tile respiratory cycle. these [co ] variations were higher when the co gas was blended closer to the yconnector. conclusions: the ventilator flow variations in relation to the fixed side flow of the n /no gasmixture result in changes of the inhaled [no] during the respiratory cycle. the no concentration during inspiration is always higher then during expiration. this could not be detected with the available monitoring system. to ensure a constant [no] by blending a njno gas balance in a continuous flow ventilator, the site of injection should be as close as possible to the inspiratory outlet. nitric oxide, a potent and selective pulmonary vasodilator, has recently been successfully used to treat pulmonary hypertension of variable etiology in infants and children. side-effects and complications in infants are so far not well known. we describe here two cases in which prolonged ( and- days respectively) high-dose ( - ppm) nitric oxide was used to treat refractor~¢ pulmonary hypertension. one patient was a newborn infant with pulmonary hypertension secondary to a large leftsided diaphragmatic hernia. nitric oxide was begun under conventional ventilation (babylog ) at hours of life with a slight initial improvement in oxygenation. he was then placed on oscillation with the same nitric oxide concentration due to worsening respiratory failure. he died on th day of life. monitored nitric dioxide concentration never exceeded ppm. the other patient was a months old infant with severe pulmonary hypertension due to a complete atrioventricular septal defect. he required high-dose nitric oxide to come off cardiopulmonary bypass after surgical repair of his heart defect. he slowly improved over the week following surgery but developped suddenly respiratory failure due to massive pulmonary hemorrhage and died. surprisingly, a particular autopsy finding in both infants was a massive acute necrotizing tracheobronchitis. we conclude that nitric oxide is an excellent and sometimes lifesaving treatment of pulmonary hypertension in infants. tracheobronchitis has not yet been reported as a possible complication of nitric oxide administration. we suggest that caution needs to be taken with prolonged high-dose administration and this possible complication to be looked for at autopsy. introduction: permissive hypereapnia (ph) is a beneficial strategy for patients with acute respiratory distress syndrome (ards) to minimize barotrauma by decreasing the peak inspiratory pressure (pip). hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (pa) hypertension, and, thus, an increased afterload to the right ventricle. this increased afterload may result in increased right ventricular (rv) work load and subsequent rv dysfunction. one therapeutic approach is the use of inhaled nitric oxide (inn), a selective pa vasodilator. the objectives of this study were to test the hypothesis that in a swine model of ards with ph, inn would improve rv work load and not change intrinsic rv contractility. methods: in swine ( - kg), ards was induced by surfactant depletion. hypercapnia was achieved by decreasing the pip while increasing the peep to maintain a constant mean airway pressure, inn was administered in concentrations of , , and ppm in a random order. pulmonary blood flow (qpa) was determined by an ultrasonic flow probe. rv total power (tp) and stroke work (sw) were calculated by fourier transformation of the pa pressure (ppa) and qpa data. preload recruitable stroke work (prsw), a preload and afterload independent measure of ventriculur contractility, was determined by a shen-subtraction method and vena caval occlusion. respiratory failure with pulmonary hypertension in piglets gerfried zobel*, bernd urlesberger*, drago dacar**, siegfried rtdl*, fritz reiterer* and ingeborg friehs** depamnents of pediatrics* and cardiac surgery**, university of graz,austria objective: to evaluate gas exchange, pulmonary mechanics and bemodynamic data during partial liquid ventilation (plv) combined with inhaled nitric oxide (no) in acute respiratory failure with pulmonary hypertension. design: prospecfive~ randomized, controlled study. setting: university research laboratory. subjects: twelve piglets weighing to kg. interventions: acute respiratory failure with pulmonary hypertension was induced by repented lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. thereafter the animals were randomly assigned either for plv or conventional mechanical ventilation. initially perfhiorocarbon liquid ( ml/kg) was instilled into the endotracheal tube over min followed by - ml/kg~. all animals were treated with different concentrations of no ( - - ppm) inhaled in random order. measurements and results: continuous monitoring included ecg, cvp, mpap, map, san and svo measurements. during plv pao /fio increased significantly from _+ . mmhg to ± mmhg (p< . ) within rain, while pao ]fio remained constant at -+ . mmhg. qs/qt decreased significantly from -+ % to -+ % (p< . ) during plv and did not change during conventional mechanical ventilation. static pulmonary compliance (cstat) increased significantly ff~m . r± . to . _+ . ml/cmh /kg (p< . ) during plv and decreased slightly from . _+ . to . e . ml/cmh /kg during conventional mechanical ventilation. the infusion of the endoperoxane analogue resulted in a sudden decrease of pao /fio from _+ to _+ . mmhg in the plv group and from ± to +_ . mmhg in the control group. inhaled no significandy improved oxygenation in both groups (pao /fio : _+ mmhg during plv and +_. mmhg during conventional mechanical ventilation). during inhalation of no mpap decreased significantly from -+ m ± mmhg (p< . ) in both groups. there was no significant change in oxygenation and mpap during inhalation of and ppm no. conclusions : plv significantly improves oxygenation and pulmonary compliance in acute respiratory failure. the additional application of inhaled no further improves oxygenation and pulmonary hemodynamics when acute respiratory failure is associated with severe pulmonary hypertension. inhaled no is very effective in improving oxygenation and pulmonary blood flow even at low doses. the work was supported in part by grants of the austrian nationalbank nr . as in neonates, severe respiratory failure in infants and children can be aggravated by pulmonary hypertension, resulting in further deterioration of oxygenation due to increasing intrapulmonary shunting. we analysed the influence of inhalational nitric oxide (ino) in treatment, course and outcome of severe ards in a pediatric population. since infants and children (age: - months) with ards and oi > (mean value: . ± ) underwent a trial with ino (concentration: , , , and ppm) to prevent further respiratory failure. patients had a significant improvement of their oxygenation (rise of pa > mm hg) for at least hours (responders); mean best ~fficient no dose: . ppm. the non-responders had only a short-term improvement or ino had no effect. in responders and nonresponders there was no significant difference with regard to age, underlying disease, ards severity, time on mechanical ventilation, blood gases and ventilator settings before notrial, nor was there a different grade of pulmonary hypertension (estimated by echocardiography). the only difference was an higher ol in the group of the non-responders: . ± .i vs. . ~ . , p < . . in the group of the respenders there was a secondary deterioration of lung function after i - days on ino in children (transient responders): in these patients, as well as in the group of the non-responders, alternative modalities of treatment (hfov and/or ecmo) became necessary. children ( %) died: transient respenders and non-responders. in infants and children with ards due to different underlying diseases ino can acutely lead to a significant improvement of oxygenation in about % of the cases. the right selection of patients for no therapy and the influence of ino on the survival rate of ards in childhood has to be evaluated in further studies. and pediatric cardiology, university of graz, a- graz purpose: after fontan procedure cardiac output is critically dependent on the pulmonary vascular resistance. even minor elevations of the pulmonary vascular resistance may significantly decrease cardiac output. inhaled no is an effective, selective pulmonary vasodilator in experimental and clinical situations of pulmonary hypertension. the aim of this study is to evaluate the effects of inhaled no on oxygenation and pulmonm , circulation in children after a bidirectional glenn-anastomosis (n-~) or a fontan-like operation (n= ). material and methods: from june t to january children with a mean age of . +~ . (sem) yrs and a mean body weight of . -+ . (sem) kg were treated with inhaled no after glenn-or fontan-like operations. all but one had complex cardiac malformations with single ventricle. all children were mechanically ventilated with an fin > . . inhaled (no) was applied using a rrdcrdproeessor based system which additionally allowed measurement of no/nox using the chemihimniscence method. methemogtobin concentrations were determined times a day. the major indication for postoperative inhalation of no was a high (> mmhg) transpulmonary pressure gradient (tpg--cvp-lap). severe myocardial dysfunction of the single ventricle was excluded by echocardiography. results: the mean duration of mechanical ventilation was . _+ . (sem) days the. mean dose of inhaled no was . -+ . (sem) ppm, the mean duration of no-inhalation was _+ (sem) hours. the mean methemoglobin concentration was . -+ . (sem)%. hemodynamic data and arterial oxygen saturation before inhaling no and minutes later are given in table acute hypoxaemic respiratory failure (ahrf) in children occurs in a heterogenous group of diseases with pulmonary pathophysiological processes ranging from reversible physiological intrapulmonary shunting to fixed structural lung damage. we hypothesized that inhaled nitric oxide (ino), a selective pulmonary vasodilator, might identify those patients with potentially reversible disease, i,e, large response may indicate a greater likelihood ef reversibility and thus survival. a retrospective review of the early response to ino in infants and children (aged month to years, median months) with severe ahrf( with ards). the mean p(a-a)o , pao / fio , oxygenation index (oi) and acute lung injury (all) score prior to the commencement of ino were +_ . , +_ . , _+ , and . +_ . respectively, the magnitude of response to ino was quantified as the % change in oi occurring within minutes of ppm ino therapy. this response was compared to patient outcome data. results. there was a significant correlation between response to ino and patient outcome, kendall tau b r= , , p< . (table) conclusion. in ahrf response to ino appears te define a subgroup of patients with improved outcome compared to nonresponders. we speculate that response to ino may be useful in selecting patients with potentially reversible lung disease for special support therapies such as ecmo. randomised controlled trials are needed to define the role of ino in paediatric ahrf. between may and december , patients (pts) were treated for mas. treatment groups were: group i only : pts; group i conventional mechanioal ventilation (cmv): pts; group ii hfo: pt; group iv hfo+no: pts. therapy was stepwise intensified until oxygenation improved ( i -) ii -) iii --) iv). "high volume strategy" was used with hfo (mawp - cm h ). the initial no-concentration was - ppm, with rapid reduction down to - ppm once oxygenation improved. results: one pt (group it) died of hypoxic-ischemic encephaiopathy (termination of therapy); all other newborn babies survived. in group iv pt and showed barotrauma prior to hfo. pt , and were treated with additional mgci (max. mg serum concentration . - . mmol/i). following the identification of inhaled nitric oxide "no) as a selective pulmonary vasodilator (frostell et al ) [ .+ , + . data are compared to baseline values within each group. *=p< . , **=p< . , ***=p< . l among patients who fulfilled ecmo criteria, improved with no and did not required extracorporeal life support. tltree out of ecmo patients eventually survived. conclusions: m our study low-dose of irthaled no showed a variable effect on oxygenation in newborns with acute respiratory failure. an acute response to no appeared to be correlated with a better short-term outcome and the avoidance of extracorporeal support in ecmo candidates. differently, lack of acute and/or sustained response was associated with death or need for ecmo. although the nature and severity of the underlying disease or the degree of prematurity may play an important role in these patients, we believe lack of acute response to no may be an early predictor of bad outcome, prompting toward alternative treatments such as ecmo or liquid ventilation. *picea s., °bartuli a.,°dionisi-vici c., *dello strologo l., §villani a., §bianchi r., ^salvatori g.,*rizzoni g, °sabetta g. *div. of nephrology, °div. of metabolism, §intensive care unit, ^div. of neonatology. "bambino gesfl" children research hospital. rome, italy. successful prevention of handicaps or death in newborns with ~ depends on rapidity and efficiency of treatment. poor response to nutritional and/or pharmacological treatment requires extracorporeal removal of nh . efficiency and cardiovascular tolerance are often difficult to obtain with peritoneal or hemodialysis in neonates. we report the results of cavhd in newborns with hc. methods: vascular access: femoral vessels. blood flow: - ml/min, dialysate flow: - ml/h. filter: amicon minifilter plusrm(polysulfone membrane; . sq.m.). no ultrafiltrate(uf) production, patients: case with carbamoytphosphate synthetase deficiency (body weight -bw-: . kg) showed hc at day , a relapse of hc occurred at day due to an infectious event. case and (bw: . and . kg), both affected by propionic aeidemia, showed hc at day and day , respectively. plasma nh (~tg/dl) decrease is shown in the complications: transitory ischemia of arterial cannulation limb and transitory thrombocytopenia occurred in case ; surgical repairing of artery after cavt-id was necessary in case ; no cardiovascular instability was observed during cavhd . outcome,'all patients recovered from hc in less than day: case : alive, mild b)iootonia at mos; case : dead after days from cavhd withdrawal for pulmonary hemorrhage; case : alive, normal development at mos. conclusions: ) in newborns with hc, ca~q-id provides good cardiovascular tolerance,high efficiency and quick removal of nh , even without uf production (i.e. only by diffusion). this allows easier management (no need of fluid and electrolyte balance). ) arterial complications seem frequent in neonates treated by cavhd. venovenous circulation could overcome this problem. vb nguyen, m jokie, c leeaeheux paediatric intensive case service, hospital university centre, avenue c te de nacre, caen cedex, france background, the implication of polymorphonuclear neutrophils (pmns) in the physiopathology of children's haemolytic.uraemie syndrome (hus) becomes more and more evident. the purpose of the present study is to role out their impact among other pronostie elements during the course of the disease. patients and methods. diarrheal prodrome and its duration, patient's age, maximal blood nitrogen level, anuria and dialysis time, extra.renal involvements, white enll and pmn counts and thrombopenia duration have been retrospectively analysed in infants with good outcome and in another children with unfavorable outcome. results. neither diarrhoea or its duration, nor children's age, nor blood nitrogen level, nor anuria or dialysis time had any predictive value for the disease evolution in the acute phase of our patients. adversely, extra-nenal involvements was accompanied by severe and complicated courses of the disease (p< , ). the elevation of white cells and pmns (heyon x /i) and pmns (more than x / ) as well as its persistence beyon a week were most frequently observed in complicated forms (p< , , p< , and p< , , respectively). a transient thrombopenia (less than day@ in patients with elevated counts of white cells may be a filrther obvious sign of an unfavorable course of the disease ( < , ). conclusion. the elevated count of white cells and pmns, either alone or associated to one rapid regeneration of platelets, seems enabled to predict an unfavorable evolution of the hus in children. msud results from an inherited impairement of catabolic pathway of branch chain amino-acids. high leucine blood levels may induce acute brain dysfunction. this dramatic complication led us to propose leucine removal procedures as continuous hemofiltration. patients and methods three newborns in acute msud onset were treated by hf, hdf and hd. extracorporeal circulation was performed through a . fr catheter, a circuit with a blood pump (priming volume = ml). patients and procedures characteristics are summarized below in the sucralfate (an aluminium salt of sucrose octa sulfate) is used to prevent and treat upper gastrointestinal bleeding in critically ill patients. with minimal absorption, the potential for side effects is thought to be limited, though aluminium toxicity has been reported in patients with chronic renal failure. these patients may already have had high body stores of aluminium. we report critically ill children with high serum concentrations of aluminium following sucralfate therapy. all had renal impairment. the normal aluminium level is < . gmol/l and in patients with chronic renal failure < . ].tmol/l. none of these patients had known preexisting chronic renal disease. cpb was conducted under deep hypothermia (t,° °c) and cardiocirculatory arrest (cca) or under hypothermia (t,° °c) and low-flow perfusion. continuous holter-electrocardiograms (h-ecg) were recorded from the ilranediate postoperative (po) period on for hours. h-ecg were also recorded prior to the operation and before discharge. following dr were observed: snpraventricutar (sv) and ventricular (v) extrasystoles (es) (> / h), sv and v tachycardia (svt and vt), accelerated junctional rhythm (ajr) and junctional ectopic tachycardja (jet), and nd and rd degree atrioventricular block (avb and avb ). the incidence of po dr was % in the pre-op h-ecg, % on the st, % on the rid, % on the rd po day and % befbre discharge. compared to the pre-op findings, an increased incidence of sves, ves, svt and avb on the st po day was observed, whereas vt and a jr or jet were exclusively observed po. all types of dr were observed up to the rd po day. ty e of dr before discharge was similar to pre-op findings and there was no definitive avb . considering patient groups according to the most frequent isolated op-procedure, the incidence of dr on the first po day was % after asd ii-closure (n= ), % after stthaortal vsd-closure (n=lg), % after correction of a complete avsd (n= ), % after correction of a tetralogy of fallot (n= ) and % after fontan-operation (n= ). incidence and type of dr were not significantly different between groups. longer cpb-dttration and use of cca were risk factors for po ves and vt (p< , and p< , , respectively) whereas use of cca and degree of hypothermia were risk factors for the development of a jr and jet (p< , and p< , , respectively). -our results indicate that po dr after cpb in children m'e frequent but mainly transient. in our series, specific cpb-related parameters are of greater influence than surgical procedure itseif for the development of dr and are discriminant risk factors for particular types of dr. the course of anp, cgmp/anp (as indicator for atrial natriurefic peptide biological activity), and no and no (as indicator for endogenous nitric oxide (no) synthesis) was investigated in i infants (median age months) undergoing cardiopulmonary bypass (cpb). patients were divided into groups according to whether they had (group , n= ) or not (group , n= ) preoperative heart failure (hf) and pulmonary hypertension (pht). group patients had preoperatively significantly higher levels of anp (p< . ), cgmp (p< . ) and no and no (,p< . ) but had significantly lower cgmp/anp (i < . ) than group patients. during cpb, anp was significantly higher in group patients ~< . ). as compared with prebypass values, cgmp/anp was reduced in both groups during cpb (p< . ). cgmp/anp inversely correlated with duration of cpb and aortic clamping time (p< . , respectively). no and no were significantly higher in group than in group patients (p< . ) without any intraindividual change during cpb. from the early postoperative period on anp, cgmp/anp and no and no were similar in both groups. after cpb, anp correlated in both groups with blood pressure (p< , ) and diuresis (p< . ). no and no inversely correlated with pulmonary arterial pressure immediately after cpb ( < . patients after a fontan-type of procedure have elevated central venous pressures (cvp) leading to congestion in the gastrointestinal system and often ascites. purpose of this study was to evaluate whether this causes a different postoperative gastric mucosal ph (phi). methods: we evaluated a series of patients, who underwent cardiac surgery with cardiopulmonary bypass (age: days to years (mean , yrs), weight: . to kg (mean . kg). a commercially available tonometer (tonometics®) for sigmoidal use in adults was inserted into the stomach after induction of anesthesia. the phi measurements were done according to manufacturer recommendations we compared three groups of patients: ) aeyanotic (n= ), among them p with vsd and p with avsd; ) cyanotic (n= ): tof: p, tga: p; ) cyanotic after a fontan-type procedure (n= ). phi were measured at picu arrival and after h. fudhermore we compared lactat levels at these time points. differences between the groups were evaluated with one way anova on ranks with pairwaise multiple comparisons (dunn's method). the relationship between cvp and phi was investigated by regression analysis. results: the median phi for groups i, and were . , . and . at ardval and . , . and . after h respectively. at picu arrival group was significantly (p< . ) different from groups and . there was no significant difference between the latter two groups, after h group was different from group , there were no other significant differences. the median lactate levels for groups t, and were . , , and . at ardval and . , . and . after h respectively. at ptcu arrival group was significantly (p< . ) different from group , after h there were no significant differences. there was a weak negative correlation between cvp and phi: r= - . ; p< . . conclusion: patients after a fontan-type of procedure have lower phi than patients after other cardiac surgical procedures, however, this is only in part due to the elevated cvp and venous congestion. eleven children were investigated months (median) after postoperative mof. iviof was defined as the failure of at least two vital organ systems (kidney, liver, lung, central nervous system) in addition to cardiac insufficiency and high fever. underlying surgical procedure was repair of tetralogy of fallot (n= ), fontan-(n= ) or seuning procedure (n=l). all patients fulfilled criteria for mof in the first postoperative (po) days. six patients needed peritoneal or hemodialysis for days (median) during the po period. one patient showed cerebral infarction due to thromboembolism in the territory of the right internal carotid artery immediately after the operation. the follow-up protocol consisted of extensive investigations of heart-, renalliver-, and lung functions as well as complete neurological and psychological examinations. all patients had adequate cardiac examination. lung function was normal in all but patients who had an obstructive syndrome. only patient showed an isolated decreased creatinine clearance. abnormalities of the liver ftmction tests were only noticed in patients after fontan procedure. severe neurological sequels such as paraplegia (n = ) and diplegia (n-i) were observed in of the patients. the remaining children presented with a delayed graphomotorical and speech development associated with normal intelligence. -in our series the most frequent and severe sequels after postoperative mof were neurological. -abnormal liver fimction tests are more likely to be a consequence of the fontan hemodynamics than a sequel of mof. the optimal dosing schedule of surfactant therapy for the treatment of neonatal respiratory distress syndrome (rds) remains unclear. goal: surfaetant function and the concentration of phospholipids (pl) in tracheal aspirates are compared in a prospective randomized trial involving neonates with rds who received either two or more ( or ) doses of survanta. methods; ventilated neonates < w with rds were treated with survanta oo mg/kg if fio >_ % or mean airway pressure _> , cm hzo, after h a nd dose was given (same criteria), if the support still exceeded the criteria h after the nd dose, the patient was randomized to no extra dose (two}, or to an extra dose of survanta (morel (and a th dose h later; same criteria), pl was measured in tracheal aspirates and corrected for dilution with the urea method. "active" large aggregates and "non-active" small aggregates of surfactant were separated by centrifugation and quantified. surface tension of the large aggregate fraction was measured by pulsating bubble surfactometer, results: neonates were randomized, x two and x more ( x and x doses), gestational age was , ± , w and birth weight ± g. most patients had severe rds with initial ventilation: rate . _+ , , peak inspiratory pressure (pip) , -+ . cm hzo, fio . ± . %. at randomization: rate . ± . , pip . -+ . cm hzo, fio . ± . %, and h after randomization: rate . ± . , pip . _+ . cm hzo, fio . ± . %, without signif, differences between the groups. there was relapse (again fio _> % within h) in group two and t bpd in group more. in total, tracheal aspirates were analyzed. pl was not signif, different before randomization (two . ± . vs more . ± . /jmol/ml), but neither after randomization (two . -+ . vs more . ± ,o /~mol/ml). there was no difference in the % small aggregates (two . ± . vs more . ± . %), the surface tensions (ran/m) were not signif, different (each time two vs more): before randomization . ± , vs . -+ . , in the h after randomization . ± . vs . -+ , , or - h after randomization . -+ . vs . ± . , or - h after randomization . _+ . vs . -+ . . conclusion: neonates who received more than two doses of survanta did not have higher pl, nor a better surfactant function than neonates who received only two doses of survanta. continuation of the trial is necessary to evaluate clinical outcome. may not indicate need for treatment p.c. clemens s.j. neumann university of hamburg, department of pediatrics, klinikum schwerin, wismarsche str.. , d- schwerin. aim of the study: the finding of elevated tsh and decreased t in the newborn usually is classified as "transient hypothyroidism", thus the elevation of tsh is classified as consequence of the lowered t . but on the other hand several data sets show that tsh elevation as well as low t , one independently of the other one, are associated with different kinds of perinatal stress. each of these laboratory deviations, if not associated with the other value being abnormal too, is generally accepted not to be an indication for treatment. from this we conclude, that more pefinatal stress, as in intensive care neonates, may produce tsh elevation as well as low t , but only coincidentially, not the tsh elevation being the consequence of low t , thus not to be classified as "hypothyroidism", thus not indicating treatment. if this hypothesis is right, we should find an association of increasing pefinatal stress with an increasing number of neonates from tsh and t normal via tsh or t abnormal to high tsh and low t . method: in the newborn screening program in germa w we determine primarily tsh, and only in the neonates with elevated tsh, in addition we determine t . thus in our study we asked whether we find an association of increasing perinatal stress with an increasing number of neonates from tsh normal via tsh abnormal while t normal to high tsh and low t . definitions for this study were: tsh elevation = > mu/ (as usual in the german screening programs), t lowered = < p_g/dl perinatal stress score was or or or in dependency of the neonate having stress in none to all of the following three categories: (a) forceps or vacuum extraction or sectio co) birth weight below g (c) at the th day existence of a relevant neonatal disorder (rds, ictems gravis, infection/sepsis, vitium cordis with hemodynamic relevance, severe malformation). results: our data of neonates show a high significant association (chi = , p < . ) of, on one hand, perinatal stress score with normal tsh, versus, on the other hand, perinatal stress score or with high tsh and low t . discussion: facing the background given above, in the intensive care newborn, the constellation of high tsh and low t may be only a coincidential addition of two independent abnormalities. in tbese cases -the high tsh not being the consequence of low t -the classification as "hypothyroidism" is not justified, thus a therapy not indicated. on the other hand of course there exist rare cases with high tsh as consequence of low t thus with hypothyroidism tlms with indication for therapy. unfortunately we have no criteria, that enable a certain discrimination of these two categories thus in respect to the question of therapy or not. conclusion: further research has to be done to learn how to discriminate the coincidential high tsh and low t from the causal constellation of high tsh and low t . until we have certain discrimination criteria we have to treat both groups of neonates. few studies have focused on fa composition of surfactant pc in preterm infants before and after surfactant therapy. methods: tracheal aspirates were collected in venttlated mfants from birth until extubatlon ( / _ /twk ga, .+ g bw). after lipid extraction, t.l.c,, and methylation, fas of pc were quantified by gaschromatography. intralipid a ( . % linoleic acid, : • ) was started h after birth. results: six infants developed respiratory distress syndrome (rds) and received survanta r i mg/kg (sr), all doses within h after birth (ix s r n=l, x s r~ n= , x s r n= ). one child did not develop rds. in alt patients, the patmitate % in pc was ~ % (before sr<=natural composition), increased to ~ % after s r, and remained > % for i h after lx s a, . .+i . h after x, and . .+ . h after doses. in patients, intubated long enough, the palmitate % decreased with a half-life of . _+ . h to a new plateau which was still higher than baseline after week. linoleic acid % was . _+ . (with rds), decreased after s r~ and returned to baseline due to the decrease in patmitate %. thereafter the linoleic acid % increased linearly with . % per h, in patient even up to . %. other fas did not increase after return to baseline. in neonatal medicine the current parameters, arterial oxygen saturation and arterial oxygen pressure, are poor indicators for oxygen delivery and oxygen demand. the purpose of this study was to obtain venous blood samples from the inferior vena cava in stable neonates with respiratory failure and to determine a parameter that reflects more adequately the balance between oxygen delivery and oxygen demand. "l~e study included neonates requiring mechanical ventilation tbr severe respiratory insufficiency. an umbilical venous and arterial catheter were inserted in the inferior vena cava and in the aorta respectively. paired blood samples were obtained at the time that the patients were hemodynamically stable. fifty paired arterial and mixed venous blood samples were analyzed. jnear regression analysis showed the following correlations: in a neonatal intensive care unit adjacent to a delivery room caring for mothers per year, (with a referral of mostly for preterm delivery), virtually every neonate <ls g was seen by the same ophtalmologist, j.o. the incidence of retinopathy of prematurity (rop) was in - of ii cases ( preterms <ls g with % surviving to discharge, and % rop in survivors; % if less than weeks). in - , cases of rop were diagnosed by the same ophtalmologist. were born at less than weeks, of which ( %) survived to discharge, and among those survivors, rop was present in ( %), with rates varying from % at weeks to % at . objective: to compare a method of teicoplanine (teico) infusion using an electrical syringe-pump with a manual injection. methods: infusion of teico was simulated through a standart neonatal i.v. system. the infusion system consisted of an life care infusion pump (abbo'it lab.) with its i.v. set for maintenance intravenous fluid (flow < mi/h) connected to a -way stopcock. an meter extension tubing (vygon lab.) was placed between the stopcock and a neonatal catheter, an another meter tubing (injection tubing) was connected to the stopcock. the volume of the injection circuit was . ml. simulations were realised for weights ( or kg), with a doses of mg/kg and a injected volume of , ml to ml. our goal was to perform a complete infusion in minutes. we compare one method of infusion with an electrical syringe-pump with manual methods: a: teico was infused with a syringe-pump pilot c (becton & dickinson lab.) according to a protocol using ) a priming before connecting the syringe to the tubing (for immediate starting of infusion), ) a programmed volume injected in minutes (the drug volume was greater than the dose prescribed to avoid loss of teico into the syringe), ) a ml wash out was performed over minutes with the syringe pump. b: teico was manually injected in a few seconds in the tubing followed by a ml wash out over minutes. c: idem as b but a nu site valve (medex) was connected to the proximal end of injection tubing to avoid leakage between removal of the teico syringe and connection of the wash out syringe. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes was calculated and expressed as a perventage of the total amount of teico prescribed. results are a mean of to rons. a b c kg . + , % , + . % , -+ . % kg -+ , % -+ , % . -+ % conclusion: with a drug volume injected < circuit volume and a valve, a direct i.v. administration of the drug in the circuit followed by a wash out seems an accurate alternative to drug infusion conbroled by a syringe pump and is easier to perform. doxapram hydrochloride is a central and respiratory stimulant which is used in neonatal intensive care units to treat caffeine-resistant apnoes of the newborn. routinely, doxapram is administered intravenously. oral administration would be much easier but data on bioavailability after oral administration are limited (two studies) and show a large variation. we therefore studied the oral bioavailability of doxapram in preterm infants. doxapram treatment was started with an intravenous loading dose of , mg/kg during minutes, followed by a continuous infusion of mg/kg/h. after h the intravenous administration was changed to continuous oral administration with the same dosage, blood samples were collected h after both the intravenous and oral administration and analyzed by hplc-assay. apnoea rates per hours were listed before and after starting doxapram treatment. the median apnoea rate per hours declined from to after both the intravenous and oral administration. the oral bioavailability of doxapram is between and %, indicating that the oral route can be used effectively in these infants . there were no differences in the decline of the apnoea rate after intravenous versus oral administration of doxapram, infasurf r has been comnared with exosurf r in two studies: one as drodhvlaxis and the other a rescue trial. similar. althouah non-sianificant benefits were found for the natural surfactant. in trials there was a sianificant reduction in dulmonarv air leaks for . : % ci . - . for babies treated with natural comnared to svnthetic surfactants. for trials ( babies~ comdarina natural and synthetic surfactants for rds { comdarina survanta r and exosurf r. and one infasurf r and exesurfr% neonatal mortalitv was sianificantlv reduced (or . : % ci . - . with natural compared to synthetic surfactant treatment. in two further trials different natural surfactant drenarations were compared. reduced oxvaen needs for hours after treatment were found for r r infasurf and curosurf respectively when each was compared to survanta r. andarent lonaer-term benefits from these surfactants were not statisticallv sianificant. further trials will be needed to ascertain differences between various surfactant preparations. introduction bacterial meningitis is a common cause of admission in the paediatric age group, and one which still carries a high morbidity and mortality. these complications are strongly associated with a delay in antibacterial therapy. a significant proportion of these patients require mechanical ventilation; it is in this particular group of patients that survival is greatly diminished. the identification of risk factors for mechanical ventilation associated with bacterial meninges may help improving survival by shortening the delay to icu referral. the paediatdc risk of mortality score (prism) is the most widely used scoring system in the paediatric icu literature; the accuracy of prism on predicting outcome in meningitis has been shown to be poor. aim we aimed to describe our population of patients with bacterial meningitis requiring ventilation, and then to identify predictors of survival. methods this study was conducted at the baragwanath hospital in south africa which is an universityaffiliated institution with end average annual paediathc admission of patients. baragwanath icu admits non-neonatal paediatdc patients per year. a retrospective chart review from january to december of consecutive paedistdc icu admissions with bacterial meningitis was performed. results approximately cases of bacterial meningitis are admitted to the general paediatric wards every year; this constitutes ± % of all admissions. the mortality of these patients is + %. during this time ( m, f) patients ( %) were accepted for icu admission, with a mortality of . %. the median age was months (range days to years). the median delay to hospital admission was hours, and the median delay to icu admission was a further hours. the median duration of tcu stay was hours ( for non-survivors, for survivors). the main presenting features were convulsions ( %), altered mental state ( %), fever ( %), respiratory symptoms ( %), headache ( %), and diarrhoea and vomiting ( %). the most common indications for icu admission were seizures ( %), coma ( %), shock ( %), respiratory failure ( %) and acidosis ( %). in % of patients there was a cardiorespirstory arrest prior to admission. the most common organisms in the csf was pneumococcus ( %), haemophilus influenza ( %) and e coli ( %). the presence of leucopenia (wcc < ), a low platelat count (< ), acidaemia (ph< . ), and the need for inotropic support were strongly associated with nonsurvival. tachycardia and hypotension were not significantly essorjsted with poor outcome, as has been previously reported. discussion early diagnosis of meningitis and prompt institution of antibiotic therapy requires a high level of clinical suspicion. paediatric patients with bacterial meningitis that require mechanical ventilation have a poor prognosis. there is little evidence to suggest that nomsurviva[ can be predicted prior to icu admission, but a rapid deterioration requiring ventilation and inotrepic support with evidence of severe sepsis (low platelet count, leucopenia) is nmost invariably associated with a fatal outcome. the long term functional outcome of these patients make this disease even more devastating; the rote of icu in the management of these patients has yet to be fully estanished. objective and study design: a retrospective study was pertbrmed for all patients diagnosed with hemorrhagic shock and encephalopathy syndrome (hse) during to . soroka medical center is the only medical facility in the southern negev region of israel serving a population of - , residents, consisting primarily of jews and bedouins. results: patients ( bedouins and jews) were diagnosed with hse. main features on arrival included profound shock and coma with con~alsions. active bleeding and/or disturbing coagulation tests with falling heuroglobin levels and thrombocytopenia was noted in every case. all infants developed diarrhea shortly after arrival. elevated urea, creatinine and liver enzymes was noted in all cases. annual incidence tbr inlhnts < year of age was : , for bedouins and . : , for jews. patients ranged in age from - wks and arrived at the hospital late night/early morning ( : am-ll: am), during winter/early spring (november-april). all were healthy prior to admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in cases. most infants had markedly elevated body temperature on arrival. a history of overwrapping and/or excessive hearing was obtained in of infants. bacteriological and virological cultures were negative in all infants. one infant died and neurological sequelae were observed in all survivors. the high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive hearing, and the high incidence of rise among a closed, culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that hse results from hyqperpyrexia, originating in most cases from a "physiologic" heat induced trigger which starts and peaks during the night in previously healthy infants with susceptible, predisposing genetic underlie. approximately % of hospitalised infants with respiratory syaacytial virus (rsv) infection require mechanical ventilation. our general practice is not to use specific antiviral therapy. we have undertaken studies of rsv-infected mechanically ventilated patients without underlying congenital heart disease or immunodeficiency. study i (n= ): a retrospective review of infants (mean post-conceptual age weeks; median duration of intubation was days (interquartile range - ). blinded review of chest x-rays during the first three days of mechanical ventilation revealed a spectrmn of lower respiratory tract findings from marked diffiase consolidation in all zones without hyper-inflation (n= ) to gross hyperinfiation without consolidation (n= ), with the remaining patients have an intermediate picture (n= ). death occurred only in patients who were at the poles of this continuum ( / consolidation and / hyperinflation). patients at these poles could be differentiated by gender predominance, birth gestation, alveolar-artarial (a-a) oxygen gradient (p< . l), oxygenation index (p< . l), peak inspiratory pressure (p< . ), and intubation days (p< . ). study ii (n= ): prospective audit of infants with the aim of verifying the above differentiation. separating patients based on their early x-rays and a-a gradient we confirmed the above predictable difference in duration of supportive therapy (consolidation v intermediate: ( - ) v ( - ) p< . ). severe lower respiratory tract rsv-infecrion in young infants results in different distinctive partems of disease with characteristic radiological and clinical features, and each has a predictable timecot~se. conflicting reports on special therapy should be interpreted with respect to these observations before making conclusions about the efficacy of any specific treatment. the clinical data of children wich suffered from a severe mycosis between jan. -dac. and wich were treated with amphotericin b in spanish hospitals were collected. mean age was + . years; were mate ( %) and female ( %). the most common underlying diseases were leukemimymphoma ( %) and congenital heart defects ( %). the major pathogens isolated were candida albieans ( %), other candida ( %) and aspergillus ( %). and liposomal amphotericin (la) in ( %). in the ca group, the starting dose was , ~ , mg/kg, reaching a maximal dose of . + , mg/kg after . + days. maintenance time was + days and the cumulative dose: ~ rag. in the la group, the starting dose was . ± mg/kg, reaching a maximal dose of . _+ . mg/kg (p< . ) after + days. maintenance time was ~ days (p< . ) and the cumulative dose _+ mg (p< . ). the reasons for la use were: elective in % of cases, previous renal failure in %, and ca inefficacy in %. hepatic or renal function impairment was two times more frequent in la group than in ca group, the antifungal efficacy was % for ca and % for la. therapeutic failure or toxicity induced withdraw of ca in % of cases, vs, , % for la (p< , ). mortality was not different in both groups ( vs. %), adverse effects were related to ca in events vs, only one in la group (p< , ). the commonest side effects in ca patients were fever ( %), chilis ( %) and nausea ( %). in ca group, cases ( %) developped analitical anormalities related with amphotericin, vs. cases ( %) in la patients (p< . ). in the first group, the commonest serum alterations were hypokaliemia ( %), raised creatinine ( %) and bilirrubin ( %). in the second one, hypokaliemia presented in % of cases (p< . ), raised bilirrubin in % and creatinine in % (p< , ), the antifungal efficacy of la is at least the same of ca. from the clinical and analitical points of view, la is much less toxic than ca. la can be used at a greater dose than ca and is safe in children with renal failure. laurence desplanques -serge gottot -christian dageville d~artement de sant~ publique -facult~ xavier bichat - rue henri huchard paris -france -the french << reaped ~> network was created to implement a nosecomial infections (ni) quality care program in nicu and picu, the first objective was to describe the annual ni incidence rate in each icu population : all patients stayed more than hours in icu. methods : n] criteria were defined by the reaped group according to cdc criteria. all data were collected by a medical and nursing team. all infection data were validated by an external investigator. results : patients were admitted over a months period. % were newborns. ni were identified among patients. the overall ni incidence rate (ir) was . % and . °/ person day (from . to . °/ according to age, lowest rate for newborns). septicemia ( % of ni) and pneumonia ( % of ni) were the two main ni. according to age, the septicemia ir varied from . to . °/oo catheter day (lowest rate for newborns) and the pneumonia ir from . to . °/ ventilator day (lowest rate for newborns). there were very few other infections (uti : %, ir : . °/ catheter day). gram positive cocci were isolated in % of septicemia ( % of them were coagulase negative staphylococcal). gram negative bacilli were isolated in % of pneumonia ( % of them were pseudomonas). % of ni were caused by candida, mostly septicemia. the septicemia and pneumonia ir varied according to unit even after adjustment for age. discussion the aminoglycoside antibiotics are frequently used in newborns for the treatment of severe infection and sepsis due to gram-negative microorganisms. the currently recommended dosage schedule for tobra ( . mg/kg q h) does not take into account differences in gestational or postnatal age during the first weeks of life. we questioned the validity of these recommendations and studied the population kinetics of tobramycin to establish predictive equations that enables the clinician to select the appropriate initial dosing schedule. methods tobra trough (t= ) and peak values (t= ) were taken on day - after birth in newborns. tobra was administered as a -minute intravenous infusion already in an adapted dosage schedule: . mg/kg q h in infants with gas < weeks; . mg/kg q h in infants with gas between - weeks and . mg/kg q h in infants with gas > wks, tobra concentrations were analyzed by tdx-assay, a one-compartment model was assumed and non-linear mixed effect modelling (using nonmem) was applied to the data, a trough level < mg/l and a peak level between and mg/l was required, with the present dosage scheme % of the trough levels were too high and almost % of the peak levels too low. calculations showed that the following dosage schedule should result in optimal levels of tobra. preterm infants gas < wks: mg q h preterm infants gas - wks: . mg q h preterm infants gas > wks: the currently recommended dosage schedules for toeira result in high trough and low peak levels. prolongation of the dosing interval and increasing the amount of drug per dose according to the above scheme will improve tobra level control. since january british clinicians have been conducting a randomized controlled trial of neonatal ecmo. mature infants (>- weeks gestation and birthweight kg) with severe cardiopulmonary failure have been randomized to receive continued care in their referring institution or referral to a designated ecmo centre for further management. we now present the preliminary results which have prompted closure of recruitment to this trial. the final outcome will be assessed as intact survival against death or severe disability at one year of age for all the recruited patients. patients were categorised by diagnosis such as isolated persistent fetal circulation, secondary persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia and by severity of illness at the point of first contact with the clinical coordinators of the trial -judged primarily by the oxygenation index ( before randomization). patients were randomized ( in each arm). hospital outcome data are reported for all patients and year outcomes on t ( survivors). at this stage of the babies allocated to ecmo are known to have died compared to of those allocated to conventional management (rr . ; % ci . - . ; p= . ). fewer deaths have been obsea-ved amongst ecmo allocated babies in all the diagnostic categories used. a % incidence of disability and impah~nent has been observed amongst survivors. this rate is similar in both groups and the survival advantage is not offset by an increased rate of disability or impairment following allocation to ecmo. we consider that these data combined with those available from other studies provide conclusive evidence that the survival to discharge from hospital is substantially higher in patients allocated to ecmo than in comparable infants not so allocated. therefore recruitment to this trial has been closed whist awaiting complete one year outcome data. sigston pe, goldman ap. #keating j. crook r. ~e dj~. great ormond street hospital for children nhs trust, and ~biochemistry department, kings college hospital, london, united kingdom. isoflurane is a safe and effective means of long term sedation in both children and adults in the intensive care setting. the use of isoflurane, by adding it to the sweep gas allows the use of this volatile anaesthetic agent in patients on ecmo, enabling rapid control and weaning of sedation. a potential problem with the long term use of isoflurane is fluoride ion accumulation with the possibility of renal toxicity, the purpose of this study was to assess plasma fluoride levels in patients receiving prolonged isoflurane on ecmo. method: fifteen infants and children (aged day - years, median weeks) receiving ecmo support for either cardiac or respiratory failure were recruited to this study. the patients were sedated with isoflurane as well as intravenous agents (morphine and midazolam). isoflurane was administered ( % - %) via a calibrated vaporiser to the sweep gas, adjusting the level to maintain adequate sedation. blood samples were obtained on a daily basis for plasma inorganic fluoride assay. the relationship between plasma fluoride and amount of isoflurane administered, as %-hours (vaporiser setting in % x hours) was calculated by linear regression. results: the duration of ecmo ranged from to (mean ) hours, during which the amount of isoflurane administered varied from to (mean ) %-hours. blood samples were anaiysed, demonstrating individual peak plasma fluoride levels of . to . #mol/ , mean , p.molli (toxic threshold = gruel/f). the plasma fluoride positively co;related with the %-hours of isoflurane (r = . , p = < . ). conclusion: this study shows that although there is a dose related accumulation of inorganic fluoride ions in patients sedated with isoflurane on ecmq, the peak fluoride levels are well below the suggested toxic threshold. merzel y, lev a, bar yosef g, halbertal m, lorber a ecmo center, picu, emek medical center, israel. the mortality rate of pediatric patients with acute myocarditis is - % according to the severity of myocardial damage. a month old gzrl presented with high fever, respiratory and cardiac failure. diagnosis of acute myocarditis was made and the patient was ventilated with high pressures and fio of . . she required high doses of inotropes. echocardiography revealed a dilated la and lv with severe mr. lvedd was mm and lvsf %. calculated oxygenation index was . she was resuscitated after a cardiac arrest. she was commenced on ecmo (using biomedicus centrifugal pump and avecor oxygenator) at a flow of ml/kg/mm with immediate improvement of hemodynamlcs, oxygenation and pc . resptratory assistance and vasoactive drugs were reduced. the patient was transported by air, on ecmo, to the ecmo cevter. she developed arf and cvvh-d was performed. cardiac fimction started to improve after days. ecmo was discontinued on day . echo revealed lvedd mm and lvsf %. ippv was discontinued on day . on discharge, a month later, her lvedd was mm and lvsf %. she behaves normally for age without neurologic or other medical sequellae. literature search revealed no case of acute myocarditis, as severe, that was treated successfully. survavors of disease this severe usually suffer dilated cardiomyopathy and permanent disability. the use of ecmo allows myocardial rest which prevents long term myocardial damage. introduction ecmo is increasingly used in the care of critically ill newborns. despite the frequent use of betalactam antibiotics in the treatment of these infants there are no data available on the dispbsition of cefotaxime (ctx) and amoxicilfin (am) d ring ecmo. the purposes of this study were to determine the pharmacokinetics of these two drugs in infants on ecmo and consequently formulate appropriate dosing regimens. we therefore studied the pharmacokinetics of ctx ( mg/kg ql h) and am ( mg/kg q h) in term infants on day after birth, blood samples were taken before (t-o) and . , , , , (am) and t h (ctx) after the intravenous bolus injection and analyzed by hplc-assays. . ctx mg/kg q h results in adequate serum levels of ctx in fullterm infants on ecmo, am mg/kg q h results in very high serum trough levels. recalculation based on the known volume of distribution and elimination serum half-life of these infants resulted in the following dosage recommendation: mg/kg q h. persistent pulmonary hypertension of the new-born (pphn) is characterised by rapid fluctuations in pulmonary artery pressure (pap) and a clinical impression of stifflungs. lung mechanics were measured in term infants, mean age . +_ . days who were paralysed and ventilated within the first three days of life. fourteen infants had pphn with systemic or suprasystemic pap measured by echocardiography. in these patients, the respiratory system resistance was . % higher (p < . ) and compliance . % lower (p = . ) during systemic or suprasystemic pap compared to when the pulmonary hypertension had resolved. in contrast, there were no changes in resistance in the infants with respiratory distress syndrome (rds) and no pulmonary hypertension or in the seven infants with normal lungs, where two readings were taken hours apart. the changes in lung mechanics interfered with mechanical ventilation, resulting in a . mmhg rise in paco (p= . ) during pulmonary hypertension. inhalation of nitric oxide ppm resulted in a % decrease in respiratory system resistance and an improvement in oxygenation. the bronchial and vascular smooth muscle was increased by % in postmortem lung samples from eight infants with pphn compared to six age matched post-mortem controls with normal lungs (p< . ). these findings suggest a co-constriction and co-hypertrophy of bronchial and vascular smooth muscle during pphn. anatomically the pulmonary vasculature and bronchi lie in close proximity to each other. thus mediators such as endothelin- released locally may act on both vascular and bronchial smooth muscle to produce the observed vasoconstriction, bronchoconstriction and smooth muscle hypertrophy. prince of wales children's hospital university of new south wales, randwick, n.s.w. australia. introduction an increasing mortality in asthmatic children has been reported. the increased severity of asthmatic illness leads to an increased demand for icu admission, and a corresponding increased need for mechanical ventilation. geographic end environmental factors are thought to be partly responsible for differences in disease sevedty throughout the wodd. for this reason, epidemiological studies from diverse areas are important, risk factors for icu admission, and for the institution of mechanical ventilation should be identified, to optimise icu admission criteria and to avoid unnecessary delays in admitting at-risk patients. aim to document the clinical characteristics of ventilated and non-ventilated asthmatic patients admitted to icu. methods this is a retrospective study of all paediatric asthma icu admissions from january to december . results there were patients admitted to the icu for acute severe asthma in the study period. the male:female ratio was : , the mean age . • . months, the mean prism . - . %, and the mean duration of admission . hours. there was no seasonal variation in admissions. only % ( / ) patients required mechanical ventilation. in % of all patients this was the first presentation with asthma. there were some significant differences between ventilated and non-ventilated patients (see table) . there was a significantly higher incidence of concomitant and nosocomial pneumonias in the ventilated patients ( . % vs . %) as well as segmental lung collapse ( . % vs . %). there were no deaths. discussion the need of mechanical ventilation significantly increases the morbidity of and duration of icu stay of asthmatic patients. younger asthmatic paediatdc patients have a significantly higher risk of ventilation. the need for ventilation is predicted principally from a worsening pco and respiratory acidaemia, which is often independently interpreted by the clinician as respira ory exhaustion. this study has shown that icu admission is important in the management of young paediatdc patients with acute severe asthma and respiratgry fa!!ure. intravenous salbutamoi in the emergency, department management of severe asthma in children. g.j.browne,a. perma,x. phung,m.soo westmead hospital, sydney, australia. it is postulate that if an initial intravenous loading dose of salbutamol is given in severe asthma, a more rapid clinical response will occur, reducing requirements for continued high doses of nebulised salbutamoi with fewer side effects. this double blinded study was conducted in the emergency department of westmead hospital a university hospital in sydney, australia. all children with severe asthma had initial nebuliser therapy ( rag of salbutamol with ml of saline). if asthma remained severe minutes later, they were given a dose of intravenous hydrocortisone ( mg/kg) and either normal saline or salbutamol microgm/kg intravenously. frequent nebulised salbutamoi therapy continued during the initial first hour if clinically indicated. continuous respiratory and haemodynamic monitoring occurred in the first hours. serum potassium and glucose determinations were made at study commencement and hour after intravenous therapy. salbutamol determination was made at study commencement. children remained clinically monitored for the next hours, with their ongoing treatment determined by clinical response. children with severe asthma months to years of age were studied, with given intravenous salbutamol and given intravenous saline. the intravenous satbutamol group (ivsg) showed rapid reduction in asthma severity scale in the first hours, with reduced need for high frequency nebuliser therapy ( _< hourly), occurring . hours.earlier. no clinically significant side-effects were found in either group, although, tremor more frequent in the [vsg. biochemistry and salbutamol concentrations were similar in both groups. the use of intravenous salbutamol (i microgm/kg) in the management of severe childhood asthma is a safe and effective therapy with no significant side-effects and the potential to abort severe asthma attacks in the emergency department. intravenous terbutaline in picu piva j., amantra s, rosso a., zambonato s, giugno k, maia t. introduction: the admission to a picu of children with respiratory failure secondary to an acute obstructive lower airway disease is a common event, especially during winter seasons. these diseases have several causes, but most of them (especially asthma and chronic airway disease) have a good response to the administration of b -adrenergic drugs. objective: to find the dosis of intravenous terbutaline that is safe, efficient and with minimal adverse effects when used in children admitted to a picu with acute obstructive lower airway disease and respiratory failure. material and methods: we study the records of all children that were admitted to our picu during the winter of . only the patients that had respiratory failure and acute lower airway disease and who needed the use of iv terbutaline were selected. the records were divided in two groups: less than months and more than a year old these two groups were compared in the following aspects: the minimal and maximal dosis, and the length of time of use of iv terbutaline, frequency of tachycardia, hypokalemia, and mechanical ventilation. to establish any difference in the two groups we use the t exact test of fisher and x , with p< . , results: during the period of study were admitted patients to the picu, and ( , %) of them used of iv terbutaline. the mean age was . + . month, used iv terbutaline during . + . days ( . to days), the initial rate was . + . p~g/kg/min, and the means of therapeutic dosis was . +l. ~g/kg/min (ranged from . to . ). twelve ( . %) patients had tachycardia art obstacle to the increases in the rate of use of iv terbutaline during any time. mechanical ventilation was necessary in patients ( . %) and ( . %) patients died. the children under year of age used initial dosis of iv terbutaline lower than the children up of year old ( . p.g/ kghnin x . ~tg &g/rain, p< . ), but without difference in the length of use, the maximal dosis, the rate of mechanical ventilation and tachycardia. the frequency of hypokalemia was most common in the group of children under year of age. acute respiratory failure during status asthmaticus may require mechanical ventilation. current therapy includes paralysis, pressure control ventilation (pcv) and permissive hypercapnia to limit pulmonary barotranma and its hemodynamic consequences. asthmatic children exert a significant amount of respiratory effort during exhalation. with paralysis, this expiratory effort is lost. unloading the inspiratory work of breathing while maintaining the patient's expiratory eftbrt using pressure support ventilation (psv), may be beneficial. methods: children receiving pcv (peak inspiratory pressure (pip) = kpa. rate breaths/min) and pco > kpa were switched to psv. children were initially ventilated with psv . kpa and peep = . kpa (servo c). all children received beta agonist therapy, ipratropium and anesthesia with ketamine or inhalational anesthesia, and were breathing spontaneously. respiratory parameters and blood gases are shown be~bre psv, within minutes (start) and when the ph had normalized (during). data are presented as median and range, * p < . compared to before psv. results: children with hypercarbia during pcv responded to psv, normalizing pcos and ph within hours. the mean respiratory rate decreased from a median of ( - ) to ( - ) while the pip was decreased to . ( . - . ) kpa within hours. the i:e ratio also significantly decreased. conclusion: psv permitted patients to active/y exhale while unloading the inspiratory work of breathing. perhaps this strategy shifts the patient's respiratory effort from inspiration to exhalation, thus permitting the child to meet the excess work of breathing caused by bronchoconstriction. maged z. youssef, peter silver, laura nimkoff, and mayer sagv. division of pediatric critical care medicine, schneider children's hospital, new hyde park, ny . introduction: mechanical vemiladon of patients with severe bronchospasm can be difficult, due to poor chest compliance and increased airway resistance. ketarmne is a cormnonly used anesthetic agent that has been shown to have bronchodilator properties. the purpose of this study was to determine ifa continuous infusion of ketamine had an effect on the oxygenation and chest compliance of children with severe lironchospasm who were mechanically ventilated. methods: a retrospective chart review was conducted of pediatric patients in severe bronchospasm who were mechanically ventilated in our picu and treated with a continuous ketamine infusion. all patients were receiving aggressive bronchodilator therapy and adequate sedation prior to keramine. patients were excluded if any new bronchodilator or sedative agents were started within hours of initiation of ketamine treatment. all patients were simultaneously treated with benzodiazepines. for each patient, the pao /fio ~ ratio and dynamic compliance [tidal volume/(peak imp. pressure -peep)] was determined immediately prior to ketamine, and at , , and hours post-ketsmine initiation. data are presented as mean ± s.d., and were a~yzed using one way anova and the multiple comparison method of bonferroni. patients (age . ± . yrs.) received * p< . ketamine for severe bronchospastu during mechanical ventilation in our picu. both . .xto-* * the pao /fio ratio and dynamic . . -.... . compliance increased significantly following initiation of the ketamine infusion (see figure) . the mean ketamine dose was ± mcg/kg/min, and the -, mean infusion duration was ± too-[/ hours. one patient required glycopyrrotate ~' to control excessive airway secretions, and " one patient required an additional dose of o--j i ~-~ ~/me diazepam to control hallucinations after i cessation of ketamine. all patients were t~n~,mr~ *~am~ successfully weaned off mechanical ~l~s ~,~s~on ventilation and discharged from the picu. conclusion: continuous ketamine infusion to mechanically ventilated pediatric patients with refractory broncliospasm results in a significant improvement in oxygenation and dynamic compliance of the chest. reports of adults with status nsthraaticus document significant morbidity and mortality, whereas studies in children have had more varied results. different centers report mechanical ventilation (mv) in to % of admissions, occurrence of pneumothoraces or paeutuomediastinums in to %, and mortality in up to % of patients ~'t . we retrospectively reviewed status asthmaticus admissions to the pediatric intensive care unit (picu) between january and december . seventy-five of these patients were admitted fr~an the emergency department of chla (er admit). the mean length of stay in the picu was . days and the mean length of stay in the hospital was . days. based on patients who had arterial blood analyses, patients had hyperoapnia (pco > ). all patients received oxygen, inhaled albuterol (alb), and cortieosteroid therapy. ninety-five percent of patients also received methylxanthine (mx) therapy. of the admissions, patients ( %) required mv. only of these patients were admitted through our emergency department, whereas the remaining patients were intuhated at outside facilities. twenty-three cases required intr:wenous beta-agonist therapy, either isoproterenol osop) or terbutaline (terb). h~ff of the ea.~es re~%wed were complicated with hypokalemia (k+< . ). c,', ,~lications ofpoeumothoraces or pneumomediastinums were seen in % of ,'r:u~ported patients, but in only % of er admit patients. only % of these were in mechanic.all, )atients. there were no deaths in the review. respiratory mechanics measurements 'are useful in mechanically ventilated children to optimize ventilator settings. nevertheless, the transducers used to measure flow (f) and pressure (p) remain expensive. objective. to evaluate the performances of piezoelectric p transducers ( us dollar) in measuring f and p. methods. we used a previously described monitoring system measuring respiratory parameters [ ] . in this study f was obtained by a differential piezoelectric p transducer (_+ . cmi-i , honeywell) whose sensitivity has been reduced to +_ cmh by an electronic amplification equipment and p by a piezoelectric p transducer (_+ (). cmhzo, honeywell) connected to a grid pneumotachymeter &nt) ffleisch or ). volume (v) ( to ml) obtained by numeric integration off ( . to l/rnin ) and p ( to cmh ) were respectively delivered through a calibrated seringe and an electronical manometer (pic premier) and calculated by the computer. bland and altman analysis was used for assessment of results bias. coefficient of repeatability (cr) was estimated by the standard deviation of repeated measurements of the parameters as calculated in a oneway analysis of variance. results. mean difference (mdi between injected v ( to ml) and measured v using pnt was . ml, sd = . ml. difference and mean v were not correlated. sd of repeated v measurements were not correlated to v. cr was . ml. mdif between injected v ( to ml) and measured v using pnt was lrd, sd = ml sd of repeated v measurements were not correlated to mean v. cr was ml. mdif between injected p and measured p was . cmi-i , sd . cm h sd of repeated p measurements were not correlated to mean p. cr was . cmh . conclusion. inexpensive piezoelectrical transducers can be used to measure f and p and evaluate respiratory mechanics in ventilated children. previous studies have already shown the problem of the reproducibility of pft in preterm ventilated babies. were studied preterm ventilated babies {mean weight gr) in the first week of life in clinically stable condition, measuring flow, airway pressure and esophageal pressure simultaneously. each baby was studied twice with an interval of one hour and each study was done increasing the rate till to inhibit spontaneous breaths. none sedative has been used. only mechanical breaths were analyzed. compliance and resistence were calculated with a computer system using the linear regression method. we expressed quantitatively the intrapatient variability as the percentage of variation of tidal volume, compliance and resistence between the two studies in each baby. then intraclass correlation coefficient test (icc) was applied to confirm qualitatively our results (total agreement = , good reproducibjtity > . ). we h~£ed, an a eept~ble ~efiabirl¢, ~-~r;= '~ . during mechanical ventilation, an air leak (al) and plateau phase duration (pl) may influence dynamic and static compliance (cdy and cst, respectively). this study evaluated the effect of al and pl on two methods of measuring c.dy and est. methods. intubated, ventilated patients in a pediatric intensive care unit were evaluated after obtaining informed consent. patients were intuhated with a cuffed endotracheal tube and ventilated with a serve ( ventilator. cdy and cst were determined using the serve ands~rmedics . objective: evaluate the repercussion in respiratory mechanics and arterial blood gases and the impact of the ventilator adjustments on the auto-peep magnitude. material and methods: the measurement of the auto-peep was performed using an eletronic-pneumatic controlled device with a oclasion valve installed between endotracheal canutla and the ventilator circuit. the d~'ice was connected to a solenoid to detecte the end of inspiratuo phase and thus, the activation of the oclusion valve. the signs of pressure and flow were monitorized using a diferential transducer and it was processed using a pc computer and tmeumoview® software. the stud were divided in phases: phase a. where the ventilator adjustments was performed using the routine of the unit and phase b, where the targets of mechanical ventilation were to minimize the auto-peep. static compliance (crs) was ineasured by the single-breath occlusion technique, using a mean of ten occlusions for analysis. passive respiratory resistance measurements and the tidal breathing flow-volume loops were also obtained., while the ventilatory settings were siguificantly reduced soon atier ecmo was started. before ecmo crs measured in all patienls was . _+t). ml/cmh /kg (mean_+sem). for each patient the ecmo course was divided into four periods, proportional to the duration of the treatment, and the best ~alue of crs in each period was chosen for analysis. as shown on the figure. crs significantly improved (*p< , ) from the second half of the ecmo course in the group of patient that finally were successfidly weaned from ecmo. no change ill compliance was measured in the group of patients who failed to respond to the extracorporeal hmg support our data suggest that compliance measurements during ecmo can be useful togelher with overall clinical evaluation to predict both outcome and duration of cxtracorporeai support in the neonatal and pediatric population. objectives: brain temperature determines the amount of neuronal damage caused by hypoxic insults. thus measuring brain temperature at standardised conditions is in request. we investigated whether brain temperature of neonates varies with head insulation environmental temperature, body activity and time course. patients and methods: we investigated non-invasive brain temperature analogues in healthy prematures tess than two weeks of age in an incubator (gestational age . + . wks; x + sd, weight + g). we measured nasopharyngeal temperature (tnasoph) by a thermistor placed in the nasopharynx via a feeding tube, zero-heatflux temperature (zht) at the temple by a thermistor and healflux transducer, insulated by two pads, as well as rectal and incubator temperatures. patient activity was documented by video taping. measurements were performed during periods of increased insulation ) by turning the head with its measuring site on to the mattress ( ( ) ( ) - ( ) ( ) ( ) ( ) . ( ) ( ) { ) ( ) ( ) - ( ) ( ) ( )i ( ) ( ) ( ) ( ) . ( ) ( ) t ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) web (lmg/kg) at rain ( ) - ( ) ( ) ( ) ( ) - ( ) the vehicle had no effect. paf caused dose dependent rise in ao and pa pressure and reduction in flow to lpa (up to % like the vascular endothelium, the endocardial endothelium (ee) has a significant impact on adjacent myocytes, and may critically alter myocardial function.~ we have previously shown that ee cells are capable of sensing and responding to hypoxia by the release of prostacyclin (pgl). potassium channels in other cell types have been reported to be oxygen sensitive. to determine whether potassium channels modulate the ee hypoxic response, we investigated the effects of three potassium channel inhibitors on hypoxia-induced pg] release from ee cells. methods: ovine endothelial cells were harvested and passaged onto ,~ microcarriers. cells were constantly perfused with normoxic and hypoxic kreb's solution, and with three potassium channel blockers: glibenclamide (gb, #g/ml), tetraethyl-antmonium (tea, ram) and aminopyridine ( ap, i mm), perfusate was assayed for prostacyclin (ria). data were compared by analysis of variance. * p<. compared to normoxic control; # p< . compared to hypoxic control. adrenaline is extensively used for resuscitation in neonates with rds. however, effects of adrenaline on systemic, pulmonary and cerebral hemodynamics have not been defined in newborns with rds. thirteen anesthetized, and ventilated newborn piglets were subjected to repeated saline lung-lavage series while mean systemic arterial pressure (abp), mean pulmonary arteriat pressure (pap), mean left atrial pressure (lap) and mean central venous pressure (cvp), cardiac output and blood flow in the internal carotid artery (ica) were measured. systemic vascular resistance (s~), pulmonary vascular resistance (pvr) and cardiac index (ci) were calculated. sixty minutes after luug-lavage, the adrenaline group (a) (n= ) received adrenaline as a continuous infusion of . lag/kg/mi, while the control group (c) (n= ) received saline. none of the varlables were changed by saline. however, significant increases in abp (p< . ), pap (p< . ), ci (p< . ) and svr (p< . ) were observed after administration of adrenaline, whiie pvr and ica were not modified. mean±sd for abp/pap (p/a), fvr/svr (p/s) and ci (ml/mirdkg) were: ratios of pap/abp and pvpjsvr significantly increased following infusion of adrenaline. these data suggest: ) the cerebral perfusion is preserved during the infusion of adrenaline; ) effect of the adrenaline infusion on the systemic circulation is more pronounced than its effect on the pulmonary circulation in newborn piglets with surfactant deficiency. s demirak~a, ch knothe, kj hagel, j bauer department of pediatrics, justus-liebig-university giessen, frg inhaled no is a short acting selective pulmonary vasodilator. we studied the effects of ppm no and % oxygen during heart catheterization in children (age - years, median years) with heart defects and elevated pulmonary vascular resistance index (pvri) in order to asses the value of no as a tool of decision making for corrective cardiac surgery. patients were eligible for testing when they were more than one year old and had a pathologically elevated pvri in a previous heart catheterization. intubation, 'anesthesia and muscle paralysis were performed in all patients during testing of pulmonary reagibility. calculations of pulmonary vascular resistance and flow were based on the fick method. response to no was assumed when pvri declined more than %, of the patients were responders to no. effects of no and oxygen on pvri, mean pulmonary arterial pressure (mpap) and pulmonary vascular flow (qp) in all responders are described in the table below. cardiac surgery was offered to all responders, and of them were successfully operated. surgery is planned in another patients and parental consent for surgery was not given in one patient. in ebstein disease, during the first days of life, the ability of right ventricle to propel blood to the pulmonary artery is impaired due to high pulmonary vascular resistances. the flow is mainly directed to left atrium through tricuspid insufficiency, right atrium and foramen ovale. to decrease pulmonary resistances and increase pulmonary blood flow, high frequency oscillations, mechanical ventilation, nitric oxide and prostaglandin are required. after few days, a forward circulation is normally established. we cared two newborns with ebstein disease where this approach was hindered by a large pulmonary valve insufficiency. both of them were diagnosed in utero, showing a large tricuspid insufficiency with a non opened pulmonary valve and a ductal left to right shunt. one fetus was hydropic. at birth, blood stream from the ductus arteriosus was directed to the right ventricle through the pulmonary valve insufficiency then to right atrium, left atrium and ventricle, aorta and ductus arteriosus. a low pulmonary blood flow was demonstrated by low mean velocities ( cm/sec). a high reverse flow was seen in descending aorta with a negative flow in the renal artery. both of these newborns were oliguric because of ductus arteriosus steal. pulmonary blood flow doppler evaluation allowed different strategies of ventilation, switching between hfo and conventional ventilation, modulation of pge doses, inhaled pulmonary vasodilators (nitric oxide) and surfactant. the hydropic baby died, the other survived after weeks of intensive care complicated by supraventricular arythmia (wpw). in conclusion, during neonatal period, in ebstein disease, a large pulmonary insufficiency leads to a vicious circle where lungs are excluded, inducing severe asphyxia and high pulmonary resistances. the blood is backward propeled from the aorta through the ductus arteriosus to the right ventricle and atria, then left cavities to aorta. arec must be considered when pulmonary blood flow does not increase despite optimal therapy. guti~rrez-larraya f*, mandoza a*, velasco jm*, zavaneua ( **, gatindo a ~, s&nchez-andrede r, s&nchez jl***, mellon a***, mar f***. pediatric cardiology*, pediatric cardiac surgery**, pediatric intensive care unit***. hospital de octubre. madrid. background: transesophageal pacing (tp) is effective and sate both for diagnosis and treatment of pediatric arrhythmias. material and methods. eleven consecutive patients are included. a tri or quaddpolar or f temporal transvenous catheter with an interpolar distance of to mm was advanced through the nares and positioned to the point with the largest amplitude of atrial deflection, surface ecg and a bi or monopolar electregram were recorded simultaneously, selecting filters when needed ( to mhz). pacing was performed with a programmable stimulator (medtronic ) beginning with ms and increasing ma to and then increasing up to . ms. narula method was selected to diagnose sinusal node disfunction (snd) and overdrive pacing to treat tachyarrhythmias. results. tp was useful in all the patients and no complications were observed: in patients a snd was diagnosed (one needing a definitive pacemaker), in two patients with atrial ratter (ripe ) sinus rhythm was recovered, in one patient with a postoperative junctional ectopic tachycadia we were able to get atrial synchrony with marked bemodinamic improvement, and patients with paroxysmal supraventricular tachycardia sinus rhythm was easily and quickly restored ( of them recquirad repited episodes of tp until pharmacelogycal levels of antiarrhythmic drugs were raised). mean age and weight were months and . kg (one patient had . kg). there was a close relation between height and depht insertion (r= . ). mean stimulation parameters were , ms and . ma. discussion. in experiencied hands tp is an effective and safe way to treat and diagnose cardiac arrhythmias even in newborns. it should be tried before endovenous pacing is stablished and it is faster than pharmacologycal treatment. bailing g., eicken a., sebening w., vogt m., schumacher g., bl~hlmeyer k.; kinderkardiologie, deutsches herzzentrum m nchen, germany to assess the outcome of balloon valvuloplasty in infants with cardiac failure caused by critical aortic stenosis a retrospective study was performed. between and neonates, aged - days (median d), weight .t - , kg (median , kg) with critical valvar aortic stenosis were dilated by balloon (aovp) as the first line treatment. patients received prostaglandin el, needed inotropic drugs and mechanical ventilation. associated cardiac lesions : persistent ductus arteriosus (pda) in patients (restrictive pda in cases), a mitral regurgitation (mivr) in cases ( severe and moderate or mild mivr), angiographic findings of endocardial fibroelastosis (efe) in patients, mitral stenosis (mivs) in , coarctation of the aorta (coa) in , and finally a small musculary ventricular septum defect (vsd) in i patient. vascular approach for ballooning : a. axitfaris in cases ( %) a. femoralis in t ( %) and v. femoralis in cases ( %). the median ratio between inflated balloon and aortic valve diameter was , . dilatation was achieved in all cases. the peak systolic gradient across the aortic valve (pre aovp) ranged from to mmhg (median mmhg) and was reduced to to mmhg (median ; gradient reduction is significant (p < , )). aortic regurgitation (aovr) was absent or mild in , moderate in and severe in patient after aovp. children survived (actual suwival rate: %; early mortalffy: n = ; late mortality: n = ). mid term follow up ( - , years; mean , years) showed an increase of the systolic peak doppler gradient across the aortic valve (median mmhg) but no increase of aovr. re-interventions (re-aovp: n = , commissurotomy: n = , mitral valve replacement n = , resection of subaortic stenosis: n = , resection of coarctation: n = ,vsd-closura: n = ) were performed in patients. rv contractility and pulmonary vascular mechanics(pvm) in immature animal models are poorly underslood. we developed an acute rv injury model to measure rv contractility and pvm in response to commonly used cateehalamines. ten anesthetized piglets ( - kg) were instrumented with micromanometers in the lv, rv, pa, and la. a pulmonary artery flow probe was placed to measure cardiac output(qpa). ultrasonic dimension crystals were sutured to the myocardium and dynamic chamber volumes estimated using shell subtraction methodology. rv injury was induced with - cryoprobe injuries at - to - °c for - minmes each. da at mg/kg/min, db at mg/kg/min, and ep at . mg/kg/min were infused in random order. rv contractility was evaluated by calculating a load independent measure of contractility, the preload recmitable stroke work(prsw), during vena caval occlusions. to describe pvm, input resistances), characteristic impedance(z ), total pewer(tp), and efficieacy f=qimo"p) were measured. measurements were made pre-and post-injury, during infusions, and between infusions. clyoablation decreased prsw ( . _+ . to . + . , p< . ). at the end of the experiment, prsw remained depressed to this level indicating stability of the model. one factor contributing to organ dysfunction for infants undergoing repair of congenital heart defects (chd) is their "inflammatory response" to cardiopulmonary bypass (cpb). this response is characterized by an increase in cytokine release, complement activation and endothelial injury. modified ultrafiltration (muf) is a method for removing tissue water and inflammatory mediators by rapid ultrafiltration followin~ cpb, muf may acutely improve post-operative end organ function. in this study, we evaluated the effects of muf on the pulmonary and cerebral function of infants undergoing cpb for repair of chd. we prosnecrivety randomized infants (.~ mos) to either muf (n= ) or no muf (n= )(control) following correction for chd. the study intervals were ) before cpb, ) immediately after cpb, and ) minutes after cpb. pulmonary function was evaluated by measuring dynamic compliance (cdyn) and airway resistance (raw). for pts (mue= pts; control= pts) exposed to a period of deep hypothermie circulatory arrest (dhca), cerebral metabolism (cmro ) was calculated at each interval using the xe clearance technique for cerebral blood flow measurements and arterial and jugular bulb saturation measurements to calculate cmro . a reduction in cmro has been consistently demonstrated after dhca. the effects of muf on cdyn and on cmro are shown below: p< . vs pre-cpb; # p< . vs post-cpb • p--o. vs. post-cpb this study demonstrates that immediately following exposure to cpb, muf will improve pulmonary compliance. raw was not different between groups. there was no significant difference in hours of post-op ventilation for either group. in those pts exposed to dhca a trend towards better cerebral metabolic recovery compared to control was demonstrated. this is the first technique applied to infants undergoing dhca where cmro after cpb was greater than precpb measm~s. although this may be beneficial to postoperative hemodynamics, ventilatory management and long-term neurologic recovery, more patients and longer follow up will be necessary to verify such an effect. the effects of conventional mechanical ventilation (cmv) on left ventricular (lv). diastolic filling in neonates are not well established. one approach to improve lv filling is the use of cmv to provide a phasic increase in airway pressure {thoracic augmentation). this phasic increase in airway pressure may result in an increase in lv filling similar to that which occurs with cpr. thoracic augmentation has not been evaluated in neonates with ventricular dysfunction who frequently demonstrate increased heart rates. attempts to maintain low peak airway pressures during cmv may result in a prolonged inspiratory time that occurs over multiple cardiac cycles. this may alter lv filling in the later cardiac cycles. to determine the effects of inspiratory time on lv diastolic filling, infants were examined with doppler echocardiography less than hrs after surgery for the arterial switch procedtme. pulsed doppler recordings of the millal valve (mv) were obtained with the inspiratory time adjusted to occur over cardiac cycles ( sec.). a pressure transducer was placed in line with the ventilator, and the respiratory cycle was recorded superimposed on the doppler tracing to provide accurate determination of inspiration and expiration. doppler recordings were obtained from the apical -chamber view and the following measurements were made: peak e and peak a velocities, eia ratio, and deceleration time. compared to the expiratory phase of cmv, the initial beat during the iuspiratory phase of cmv resulted in an increase in mv peak e (. +-. vs . -+ . m/s, p< . ) and peak a (. + . vs . -+ . m/s, p< . ) velocities with no change in mv deceleration times (p<. ). compared to the initial beat during tile inspiratory phase, the third beat during the inspiratory phase resulted in decreased peak e (. + . vs . + . m/s, p< . ) and peak a (. + . vs . + . m/s, p< . ) velocities with no difference in deceleration times. thus, cmv augments lv filling during the initial phase of inspiration. however, as the increase in airway pressure is distributed over multiple cardiac cycles, lv filling falls below baseline levels. these observations indicate that while thoracic augmentation may be beneficial, to optimize lv filling the inspiratory time of cmv must be < cardiac cycles. energy expenditure in pediatric orthotopic liver tranaplantat~on, to determine the actual calorie requirements of critically ill children and evniuate the correlations between measured, stress-p~lictod and repleted energy exponditttm and the severity of illness. des/gn: a prospective, dinlcal study. se~ng: tertiary care pediatric icu in a university hospital. patients: ten patients aged to months with disorders prompting picu admission, including sepsis, respiratory failure, solid organ transplantation, and cardiovascular surgery. inta~entions: all patients were studied within hrs of major surgery or transplantation, or following acute illness. all patienls were severely stressed clinically and all but two were intubated by cuffed tubes, in three of them, still in a stress state, the study repeated on the third day of the disease, energy expenditure mensurements (mee), as well as illness seventy scoring systems, mtfltisystern organ failure scores and various anthropemetric and clinical indices of nutritional status, the stress-predicted energy expenditure (s-pee), the basal metabufie rote (pbmr), the repleted energy (re) and the recommended dietary allowances (rda) were measured or calculated in each patient. multiple regression analysis was used to analyze the data. measurements and main results: although the mean mee was significantly lower than the mean s-pee ( . + kcal/kg/day vs. . : kcal/kg/day, p<. ), it did not differ significantly from the pbmr (mean difference - . kcal/kg/day, range - . to + . kcal/kg/day). the s-pee/mee ratio ranged from . to . , while the re/rda ratio ( . : kcal/kg/day)/( . : kcal/kg/dny) ranged from only . to . . the prism/tiss ratio was not correlated better with mee than the diagnostic category (r~=. vs.. , respectively). the re was positively correlated withthe mee (rz=. , i)=. ) while negative oarrelatian has been found between mee and age, mid-arm circumference, triceps skinfotd and the use of vaseactive agents (r~. , - , -. , p<. and -. resp~lively). concl.m~: if s-pee is used for caloric repletion in the stressed oritic~ly fll el~d, these patients will be substantially overfed by as much as %. although pbmr appears to approximate the mee by ± %, other clinical and nutritional indices should also be ennsidered. objective: to deter .mine..t.he metabpli.c and.nutritional state of mechanically ventilated intants and children m relatmn wlm severity or msease. patients and methods: mechanically ventilated infants and children, median age months (range days to years), were studied. severity of illness was assessed using prism, prism-ii~ and fiss-scores. oxygen consumption (vo ), energy expenditure (mee) and respiratory quotient (rq) were determmed by mdirect calorimetry. total urinary nitroger(tun) and creatinine excretion, levels of albumin and crp were aetermmed in patients. in these patients daily caloric intake and substrate utilization were assessed. they were categorized in subgroups: a partial feeding (recent admission to p cu); b complete feeding. results: mee of the total group (n= ) a) i=intake g/kg/day (% total intake); u=utilization g/kg/day (% total production). nitrogenba]ance was negative in all patients in group a (mean - . -- : mffkg/day) and positive in all but one patient in group b (.mean . ± .d n~g/..kg/day;p= . ). no significant correlations were round between creatinine height index, crp, albumine, jun vs v u /kg conclusions: the mean measured energy expenditure does not exceed predicted resting energy expenditure, but ~ere is a wide range. in a majority ot patients with complete feeding h.igh carbohydrate intake resulted, in high kq and lipogenesis. in patients witla partial teeding the highly negatwe nitrogen'balance suggests that in the early phase of diseasean higher protein intake should be provided. severity of illness scores ann oiocnemicm markers of physiologic stress correlatedpoorly with oxygen consumption. leite,hp; iglesias, s; faria, c; ikeda, a; albuquerque, mp; carvalho, wb pediatric icu -s~o paulo federal university -s~o paulo, brazil objectives: ) to evaluate patterns of use and monitoring of nutritional support in critically ill children; ) to evaluate an education program in nutrition support given throughout the resident physician training in the pediatric icu. patients and methods: records of patients receiving nutritional support during were reviewed. aider this first phase, knowledge and understanding of the role of nutrition support was conveyed to the residents through didactic lectures. in a second phase thedata were reevaluated in children who were given nutrition support in . results: from a total of days ofthempy, the single parenteral route was utilized in , %, the digestive route (tube feeding or oral route) in , %. of this time. a previous nutr~ional assessment was performed in children; no patient had the nutr~on goals set. the nitrogen to nonprotein calories ratio ranged among : and : . only , % of the patients had their estimated caloric needs supplied and this goal was achieved only in those patients who were on enteral tube feeding. patients did not achieved their goals for vitamins. the supply ofoligonleme~s was adequate except the zinc. nutritional monitoring parameters including weight, serum albumin and serum triglycerides were performed in almost all the patients but without uniformity. the reevaluation ofthase parameters showed adequacy of protein and micronutrients supply; however deficiency in nutritional monitoring and infrequent enteral feeding were still detected. conclusion: there were lacks in the implementation of nutritional support, which were partially corrected in the rid phase of the study, although the training of residents may have contributed to give them cognitive skills, it didn't changed policies and procedures as desired. we recommend reinforcement of the education program concerning basic nutritional aspects, and the organization ofa multidisciplinary team in charge of coordinating the providing of nutritional support. plasme free fatty acids (ffa) are the meier energy source for mast tissues. during fasting ffa are released from the breakdown af triglycefides in edipose lissue (at). lipalysis, le. the rote of release o/ ffa, has been megsured in humans by means of stable isotope techniques using labeled pa or glyeerd as traces. no information is avoilob!e io dale on the ro of la. we infused albumin hound u c-pa and u c-la in critically ill infants, receiving kcel/kg/doy of iv glucose end na oral feeding (weight . ,i., kg;, range . - . ; ego : days, range ) and measured simultaneously the ra of pa and la from (he isotopic enrichment of plasma fea by gas chromatography-mass speclrome|ry ai : , : and : hours from tile shod of the infusion. a subcutaneous gluted at biopsy was obtained far fatty acid (fa) composition. we intended to ( ) in fie infants sbjdied atipa ~'os hi her than attla (~p<o.o )' and ihe ra of pa was higher then thai of la (~p= . §). however the ratio el the re's to the respeclive fa in at was higher for la than far pa (*p= . ). in conclusion the ra af la was higher then expected from ~he fa composition of at. we speculate [hat la is preferentially released during tipolysis and its contributuion to the energy metnbolism of the sick infonl could io !orger than what: is normai!y assumed from ihe fa composilion of at and of plasma fea. preoperative starvation can be prevented in infants undergoing non gi surgery by continuing feeds till as long as it is safe to do so. some gi disorders require withholding of feeds for a long period. for these and for infants already suffering from pem~ parenteral feeds are given preoperatively. peroperatively nutrition is maintained by ensuring adequate glucose supply in the infusion fluid and its smooth metabolism. proper placement of feeding tubes are also carried out peroperatively. postoperative early resumption of oral feeds is ensured by new techniques of anaesthesia and pain relief and methods to ensure early return of peristalsis. enteral feeds of pre digested substances and feeds through transanastomotic tubes and through gastrostomies and jejunostomies can prevent starvation in many situations. parenteral feeding is carried out only when enteral feeding is not possible, for example in necrotising enterocolitis~ gastroschisis, short gut syndrome, high enteric fistula and acute pancreatltls. the artedal ketone body ratio (akbr) is established as a valuable tool in the management of adult patients undergoing surgery for severe liver disease.the redox theory emphasises the central role of the liver in preserving homeostasis and the importance of the hepatic mitochonddal redox potential (nad+/nadh) in monitoring liver function and integrity.the akbr (plasma acetoacetate/ hydroxybutyrate) is a measure of hepatic mitochonddal redox status, reduced ratios associated with poorer outcome. the venous ketone body ratio (vkbr) is influenced by peripheral ketone utilisation and therefore thought unreliable in assessing hepatic redox its use has been dismissed as no correlation with the ratio in hepatic venous blood was found. inspite of this. vkbr is used in the diagnosis of lactic acidoses and respiratory chain defects. the objective of this study was to determine the relationship between the akbr and vkbr in a paediatnc intensive care population. children admitted to the paediatdc intensive care unit, with indwelling arterial and central venous lines as part of their routine care, were recruited for the study. the median (range) age was . years ( - . years) with prism score ( - ), simultaneous akbr and vkbr were measured. suppression of ketogenesis was confirmed using a rapid -hydroxybutyrate strip test (ketofilm, genzyme diagnostics) pdor to sampling. the median vkbr . (range . - . ) was lower than median akbr . (range . - , ), there was good agreement between artedal and venous ratios, bland-altman analysis giving a % confidence interval for relative bias of - . to - . . there was a significant correlation between vkbr and akbr r , , p, . (intercept . , slope , ) conclusions; values for akbr tend to be higher than vkbr, however there is a consistent relationship in critically ill children. in paediatdc patients in whom ketogenesis is suppressed, vkbr may be considered equivalent to akbr. this simple test may prove to be a useful adjunct in predicting mortality in cdt{cally ill children. to understand the present status of pediatric intensive care in china, we conducted a survey between october and december, , involving hospitals in provinces and municipalities. the results showed that there were totally icus for pediatric patients, including pediatric icus (picu), neonatal icus (nicu) and pediatric surgical icus (sicu), with total of beds. the physicians to bed and nurses to bed ratios were : . and : . respectively. the average number of equipment per bed was . ventilator, . multi-fnnction monitor and . infusion pump. very few of the icus had portable x-ray machine, biochemical and blood gas analyzers, and hemodialysis machines. the most frequently treated diseases/conditions were pneumonia, intracraniat infections, post-operation and sepsis in picus, and neonatal pneumonia, hypoxic ischemic encephalopathy and sclerema in nicus. pneumonia and respiratory failure accounted for . % and . % of all the diseases/conditions treated in the icus and the mean case fatality rate of respiratory failure was . %. the results of the survey suggest that there is shortage of tcu beds and modern equipment, and treatment is often delayed due to excessively strict criteria for mechanical ventilation. a set of simple, and nationally acceptable criteria for evaluation of severity and cure of the diseases/conditions is urgently required. the medical reports of children were reviewed and each admission was analysed in terms of age, sex, diagnosis, management within the hosp~al, length of hospital stay and type of poisoning. the youngest age was days and the oldest was years. hundred and twelve ( . %) of the children were girls and ( . %) were boys. the most common ( . %) reason of admission was intoxication among all of the cases and the greatest group ( . %) of the poisoned children had ingested medication which was followed by another group of patients ( . %) who had eaten mushrooms. the peak incidence of drug ingestion was salicylate intoxication ( %). forty drug poisoninigs were accidental while was intentional. the majority ( . %) of the cases that committed suicide was between and t years old, and the main cause of suicide was being unsuccessful at school. we conclude that poisoning -especially salicylate intoxication -is still a major problem in turkey and we believe that emphasis on the need to stere all kinds of drugs in a secure place and re-examination of a chin resistant packaging should help to reduce childhood poisoning significantly which is a preventable condition. included were all patients who died in the hospital, except those treated in the neonatal icu (predominantly premature and sga newborns) and those who died in the emergency room. among a total of hospital admissions (excluding the neonatal icu and emergency room), patients died ( . %). of these patients ( %) died in the pediatric icu, ( %) in the ward and ( %) in the operating room. a chronic underlying disease was present in ( %). withholding or withdrawal of therapy was implemented in ( %) children, ( %) died due to failed cpr, ( %) were brain dead and ( %) died following a dnr order. justification for therapeutic restrictions in the patients of the dnr and w/w groups was imminent death in ( %), lack of future relational potential in ( %) and excessive health burden in ( %). withdrawal or withholding of therapy was carried out by extubation in %, vasoactive drugs were stopped in %, and mechanical ventilation was withdrawn in %, analgetics and sedatives were frequently used (in % and %, respectively). hence decisions concerning restrictions of treatment are common in pediatric practice, mostly due to imminent death. patients in which treatment was restricted were characterised by a longer hospital stay, a worse prognosis, a higher frequency of chronic underlying diseases and a lower acute mortality risk. despite restrictions of intensive therapy, most patients were allowed to die in the pediatric icu. background microalbuminuria (mca), a subclinical increase in urinary albumin, reflects glomerular and overall vascular permeability " . an increase in urinary excretion of albumin occurs after burns and trauma. transcanillary albumin escape rate is also increased in response to elective surgery and in critically ill adult patients . we investigated a possible relationship between urinary albumin levels and clinical instability, as measured by pediatric risk of mortality (prism) scores. method we studied consecutive patients (median age of months, range - ). patients whith nephropathies or any abnormality of urine analysis were excluded from the analysis. prism scores, mca (mg. - ) (immunonepbelometric) and urinary creatinine (cu) (mmol.l -!) (jaffb) ( hour collection sample) were determined within hours from admission to the picu. the mca/cu ratio (mg.mmol. "l) was used to correct for urine output variability. diagnoses included respiratory failure ( ), postoperative ( ), neurologic ( ), sepsis ( ), trauma ( ) and miscellaneous cases ( ). pearson's correlation was performed to correlate data. results and conclusions. mean prism score and mca/cu were . ± . sd and - sd, respectively. a significant correlation was found between mca/cu and prism scores (r= . , p< . ). our observations show that, independently of the initial insult, the paediatric unstable patient may have increased capillary permeability, which is correlated with the degree of physiological derangement, as measured by prism scores. microalbuminuria can be rapidly determined since it is routinely used in the management of diabetic patients, it is inexpensive, simple to measure and blood-spearing. therefore, it might have a role in the clinical assessment of capillary permeability and transcapillary albumin escape worldwide the demand for paediatric intensive care services exceeds the supply. in developing countries sporadic access to such services alters expectation of care and can lead to children being either mechanically or handventilated in general paediatric wards. the outcome of children requiring ventilation in a major teaching hospital in india was reviewed.children were ventilated on an adult intensive care unit (aicu) if a bed was available, otherwise in the general paediatric wards. over a year period children were ventilated on aicu with deaths. yearly mortality rates varied between - %. over a month period patients were ventilated on the paediatric wards. of the p~tients over weeks of age died (chi squared .t >p> . ) reasons for the higher mortality rate on the paediatric ward likely include the higher patient:nurse ratio, and more limited resources. a predictor of mortality based on simple physiological observations without the need for expensive blood tests and including chronic health status would be a useful tool. the establishment of a paediatric intensive care unit is proposed to redress the balance of care. to assess the performance of the pediatric intensive care unit of hospital dona estef~nia by an international standard score, the authors did a prospective study of consecutive admissions to the unit during a period of months. mean age was . _+ . months; mean lengh of stay was . + . days. the effectiveness and efficiency were determined by the admission prism. admission efficiency was defined by two criteria: a) mortality risk > % or b) the administration of at least one intensive care unit-dependent therapy. the cumulative observed mortality was . % and the expected mortality was . %, with a standardized mortality ratio (smr) = . . the overall performance of the prism score-based predictive model was found to be good (goodness-of-fit test x [ ] = . ;p= . ). of patients admitted, combining the two criteria (icudependent therapy and mortality risk) an admission efficiency of ( . %) was found, equating to ( . %) of cu days. conclusion: in our study the assessment of the admission efficiency and of the effectiveness of the unit was possible by using the prism score of admission. there was no significant difference between mean values for otiss and ntiss)in level l patients (p= . paired t-test).for level and patients mean value of ntiss was greater than otiss (p< . ). there was a significant correlation between levels using either ntiss or otiss (mean difference level and , level and , ( p < o.oool). conclusions: a new tiss has been developed and used in a picu. nurses were able to accurately score the interventions on their shift. the assignment of patients to intensive care levels correlates with tiss values allowing a quantitative measure of severity. objective : to compare the rate of cerebral palsy (cp) between monochorionic-twins, dichorionic-twins and singletons born at to weeks' gestation. design : two-year prospective cohort study. setting : geographically defined study (region of franche-comt~., france). main outcome measures : type of plasentation was obtained by anatomopathological, or macroscopic examination of placenta and comparison of twins' blood-groups. neurological assessment was performed at two years of age (uncorrected for gestational age) by family doctor (pediatrician or physician), or neonatologist of the icu at tertiary center. sample : of i survivors aged of two years ( % follow-up rate), born between / / and / . triplets and chromosomic malformation were non included. results : thirteen ( %) of the singletons had cp.vs / ( %) of dichorionic twins and / ( %) of monochorionic twins (p= . ). four of the monochorionic twins ( %), / dichorionic twins ( %) and / ( %) nngletons suffer from quadriplegia (p< . ).in a multivariate approach, monochorionic twin placentation was the strongest risk-factor of cerebral palsy (or= . , ic % = a- , p< . ). others risk-factors of cp were : lack of father's profession (or , p< . ), maternal antecedent of abortion (or . , - , p< . ), vaginal delivery (or . , - , p< . ), hyaline membrane disease (or . , . -t , ~ . ). discussion : this is the first population-based study to uplight the role of monochorial twin-placentation as a strong risk factor of cp for premature infants. cp is more severe in monochodonic twins than in other infants. mecanism of cerebrat deficiency is not clear since none of our infants with cp was survivor of an in utero cotwin's death, and none of these infants was exposed to twin to twin transfusion syndrome. were these monochorionic-twins affected by an undiagnosed neurological structural defect that could lead both to prematurity and handicap remains an open question, a vital role of the intensivist is to ensure that knowledge and practice are imparted to trainees in the icu so that patients receive optimal care. teaching effectiveness varies widely leaving gaps in knowledge and practice in the trainee. being an effective teacher should not be a "gift" of a privileged few. the icu provides a fertile ground for using a variety of methods for teaching, e.g. didactic, at the bedside, emergencies, and in the performance ofproeeaures. in this environment, much can be learned. we have embarked upon a program to facilitate this learning process. i) teaching needs to be recognized as the foundation of good clinical care, i.e., patient related, and in its ability to generate discussion and research investigation. ) teaching structurally has many components including the speaker, audience, varying situations, and the message delivered. ) establishment of a program using these components to enhance teaching abilities at all levels, a) evaluate base-line teaching skills initially, b) individualize interventions to improve teaching skills, e) demonstration of learned skills with re-evaluation. this process is analogous to the analysis of a clinical disorder in a patient which, once recognized, interventions are then instituted and then re-evaluated. ) instill the desire to use these attained skills to teach and interest others to teach. teaching excellence should be recognized through awards, honors, and academic advancement. a major emphasis of this program is to provide participants with skills necessary to teach thought processes, decision-making skills (what to do, what to avoid) and implementing appropriate management during stressful emergency situations common to the picu. introduction: many" e-mail based discussion groups exist on the internet to provide medical professionals with a rapidly responsive medium for the international exchange of ideas relating to patient care. several such lists each serve more than a thousand professionals in more than countries, each distributing a dozen or more messages each day to every subscriber. there is very little known about the time being spent by professionals interacting with these lists, and very little known about the impact of the discussions on patient care. we wished to test the hypothesis that these discussion groups provide infortuation which is being used to change the care of individual patients and the general approach to patient problems. methods: in early january a pilot electronic survey was sent to a small fraction (n= ) of the memberships of e-mail discussion groups, picu@its.mew.edu, and nicu-net@u.washington.edu (the full memberships of both. groups (n=t for nicu-net, n= for picu) will be surveyed in early february of ). participants were asked for demographic information, experience and skill level relating to e-mail, time spent with the discussion groups, perceived usefulness of different types of discussions, and the ways in which the discussions were used clinically. the pilot study was analyzed for construct validity by correlating an overall assessment question with a summary of the specific questions. scale reliability was measured by cronbach's alpha statistic. results: the pilot survey response rate was ( %). the majority of respondents were male physicians, with an average age of +_ years, who had completed subspecialty training in intensive care, and were working at a university-affiliated hospital. most had been using e-malt for more than months, and considered themselves moderately adept in that use. % felt that the list helped weekly to keep them informed about current issues and practices in their field(s), and % felt that, at least monthly, they used information from the list(s) that was not readily available in medical journals. overall, % agreed that the list improved their professional competency. when asked to compare the value of months of membership on an e-mail discussion group with more traditional educational media, % compared it with attending a national conference, and % compared it to a journal subscription. cronbach's alpha was . , construct validity testing yielded coeff=. , p <. . conclusior~: internet-based e-mail discussion groups for health care professionals can be an important part of a strategy for maintaining professional competency. despite the very low cost of this medium for most, the value is felt to be comparable to that of t~r more expensive forums for education. further study will include distribution of the full survey in early february of . fronk shann, tony slater, gale pearson and the pim study group we have developed a new score for predicting the risk of mortality in children admitted to intensive care. the score is calculated from only seven variables collected at the time of admission to icu: mechanical ventilation (yes/no), booked admission after elective surgery (yes/no), the presence of any one of specified underlying conditions, both pupils fixed to light (yes/no), the base excess, the pao divided by the fio , and the systolic blood pressure. most scores used to predict outcome in intensive care require the collection of a large number of variables (so many icus do not calculate them routinely), and they use the worst value of each variable in the first hours in intensive care. this means they appear to be more accurate than they really are (about % of child deaths in icu occur in the first hours -so they are diagnosing these deaths rather than predicting them), and they blurr the differences between traits (a child admitted to a good unit who recovers will have a low score; but the same child who is mismanaged in a bad unit will have a high score -the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients). pim was developed in the picu at the royal children's hospital in melbourne, and has been tested in six other picus in australia and one in the uk. objectives: to study the characteristics of the muhiorgan dysfunction syndrome (mds) in children. methods: a retrospective study with all the children with mds diagnosed from january to june is presented. children fulfilled the wilkinson criteria (i). in all of them the number of organs affected and the prims score were determined during the first hours. several groups were performed according to the clinical diagnosis, the hospital of origin and the order of organs affected. results: the subjects studied were an % of the pediatric intensive care unit admissions. of them expired ( %). no differences in age, sex and weight were observed between the children dying and the survivals. the most common causes of mds were sepsis, both nosocomial ( %) and medingococcal (i %) and acute respiratory failure. sixty-fivepercent of the patients were from the hospital wards and the remaining were directly admitted to the pigu from the emergency room. the systems affected were: respiratory ( %), cardiovascular ( %), hematologic ( %), central nervous system ( %), renal ( %) and (hepatic) liver ( %). the organs initially failing were: heart ( %), tung ( %) and central nervous system ( %). the children dying had a larger number of organs with failure than the survivors ( . v,s. . , p< . ).the prmis score was higher in the children expiring than in the survivors ( . v.s. , p < . ). s.mmary: the mds is a common pathology in picu, with a high mortality, the mortality is higher in children with a larger number of organs affected and a higher prism score. sepsis is the most common etiulogy. methods : from june ist to july th , all patients admitted to the pediatric icu were included. the score was measured at day (d ) and day (d ) and we used variables. for each organ system, we defined categories : dysfunction or failure, which we respectively confered or points. results : patients were admitted : newborns, children. were medical and were surgical patients. ( %) patients had two or more organ failure at the admission, ( , %) patients died, which ( %) in the first hours. the mortality rate was the same for children with two or more organ faiiure at d and d : / ( , %) at d , / ( , %) at d . the mean score is different for children who survived or who died : , versus , at d ; , versus , at . when the score is > , the mortality rate is significant. conclusion : in this study, there is a good correlation between the score of severity and the mortality rate but we have few included patients. we need a prospective multicentric study to assess these results and we must compare this score to other scores of severity used in picu. back.qround: injury to the central nervous system is the cause of death in the majority of pediatric trauma victims, studies have identified a wide range of factors associated with poor outcome from brain injury. however, when single features are analyzed, they are not sufficiently accurate predictors. few studies have used a multivariate analysis of these factors and pediatric outcome, methods: clinical and radiographic features of comatose children after traumatic brain injury were analyzed, clinical parameters, the initial cranial ct scan, and demographic characteristics were analyzed for an association with death or vegetative survival at months. a tree diagram in which risk factors may differ within the study subpopulations was constructed using recursive partitioning. results: chitdren with a motor score _< had an -fold increased risk of poor outcome compared to those with motor scores > . among patients with scores of _< , those with abnormal pupillary reflexes experienced a -fold increased risk of death compared to those with normal pupillary reflexes. among patients with a motor score > , an intracranial diagnosis code (no pathology, mild shift _< mm, swelling, shift > mm, surgical mass lesions, or non-operative mass lesions) was highly predicative of poor outcome at months. children with ct findings other than normal or mild swelling had a -fold increased risk of poor outcome. of children with swelling, shift or mass lesions, the pupillary light reflex was associated with outcome. children with abnormal pupils had a -fold increased risk of poor outcome. discussion: a few clinical and radiographic features stratified comatose children into fairly distinct risk groups. information available early after traumatic brain injury in comatose children provides useful prognostic information on the likelihood of death or devastating injury. a retrospective study of children with the diagnosis of epidural hematoma was made during - period. ages ranged between days and years ( % less than year, % between and years, and % older than years), % of them were admitted at the picu. % of the cases were due to falls, % to road traffic accident and % to other causes. on admission gcs was less than in % of the cases and more than in %. diagnosis was made during first hours in % of patients and delayed more than hours in % of them. neurologic impairment was present at admission in % of patients, and delayed in %. even so, % remained without impairment. radiological findings at first ct were skull fracture ( %); epidural hematoma localization was: in the right side ( %), frontal area ( %), temporoparietal ( %) and occipital (t %). associated lesions were: several ( %) or unilateral ( %) cerebral contusions, diffuse brain oedema ( %), unilateral hemispheric oedema ( %) and % showed shifted middle line. four patients died, half of them during the first hours. fully recovered ( . %) and have sequelae of different nature : were left with severe motor disability ( %); at the follow-up t have some degree of neurodisability. next datas keep correlation with death or neurosurgical impairment: only were significative multiple cerebral contusion (p= . ) and brain oedema (p= . ), gcs less than at the admission (p-- . ), shock (p= . ) and remaining cerebral contusion in control ct correlated with death or diasability at discharge. on the other hand, neither surgical drainage volume nor first or highest levels of icp ( cases),nor pupillary abnormalities ( cases) correlated with worse prognosis. conclusion: gcs equal or less than an shock are main factors related to worse prognosis, also multiple cerebral contusions in ct and diffuse brain oedema. the results of a modified gcs were compared to outcome and intensive therapy in children (mean age , t , years) with head and associated injuries ( , % of all cases) of different causes (traffic accidents, falls). the gcs was regularly used inn the course of intensive therapy. according to our own and other experiences the gcs was divided in stages: stage ( - points), stage ( - points) und stage ( - points) palhuiugy wile sp, tdhlg c~'lcb al blood ~ w. sabgcqucntl}. rhc slat,: rerltncd to t tl, iiltlils. the p st,~pem~v~ b}i~g wij!!,:q ! ,:_a!~p!ica!j n~:. ri~;¢ ill the level of sensibflizatjou lo tile cerebn~ anhgrns up to t. -o was flofcd iu i,alicnts. there wa.~ al~ iuclt~a~e ill cerebral vdociij,. ~m d~;'ati a il~ p¢fiphc~ai re~ista/isc of the large ce~'bral ve~ds. neur h;~c ~:yn'.pt,m~at !a~, (s::mno!en~', _r_uscu!~r l~:pot ni& !ryper*'flema) was nbserwed tu lt~ese pal~enls o. cbruc~l ~ nnds. rile ple~c.ut abse~vafion~ suggesl ihal die ~tttdy at" ihe stale ~f hematocr~chcplm/itic bm~ic~ in ckil&en with on emergensy is of abviou.~ !?ece~sib; in co~.te ctin g severe pa~ lo ~-i~mnediately f u wing ne ,:~per,'~fion. background: reconstruction of the heart by three-dimensional ( d) echocardiography provided new information on anatomy of complex congenital heart defects, we assessed the utility of d ultrasound in detecting morphological changes in cerebral anatomy in newborns before and after cardiac surgery. methods: transfontanel cross-sectional ultrasound, scans were obtained in standardized coronal and median sagittal planes. subsequently, rotational scanning was used to acquire the multiple sequential crosssections of the brain. for rotational scanning, a conventional mhz transducer was rotated degrees.scanning took less than one minute and required no sedation, data was stored in the image processing computer which allowed for off-line three dimensional reconstruction of different brain regions.twelve infants aged - (median ) days were assessed before and after cardiac surgery, results: cavity of lateral ventricle, choroid plexus and the periventricular brain parenchyma could be reconstructed in all. accurate estimation of size and volume of lateral ventricle, aqueduct, and other ultrasonographic visible pathological brain lesions could be performed. reconstruction of various brain areas was accomplished in - minutes. the localisation and extension of severe periventricular hemorrhage which was detected preoperatively in one infants was better visualized than in conventional ultrasonography. epicortical and subarachnoidal space could be reconstructed in all and allowed detection of hemorrhage in one case which was not detected by conventional ultrasound. conclusion: d reconstruction of different areas of the brain may provide additional quantitative information on size and volume of the internal ventricle and choroid plexus, and better understanding of the topographical aspects and the extension of intra-and periventricular hemorrhage than conventional cross-sectional ultrasound. introduction: intracranial cerebral blood has been estimated to be % venous, the invasive measurment of venous blood saturation in the jugular bulb provides quantitative information on cerebral oxygen supply and consumption. however, routine oxymetric measurement of blood saturation in the jugular bulb by insertion of a catheter line into the internal jugtdar vein is an invasive procedure which has limited use especially in infants and young children. thus the aim of this study was to investigate the correlation between the non-invasive spectroscopic measurement of rso and the oxymetric determination of the blood saturation in the jugular bulb in infants and children undergoing routine cardiac catheterization.. methods: during routine cardiac catheterization infants and children (age day- year, median , year) the rso was measured continuously using a two chanel cerebral oxymeter (invos a). the sensor was placed in standardized location at the left temporal head side. after the routine oxymetric blood sampling in the superior vena cava the oxymetric catheter was manupilated into the left jugular bulb. after control of the catheter position simultenuous values of the rso were documented. results: over a range of ( - %) sjo , a significant linear correlation was found between the spectroscopic measurement of rso and the oxymetric determination of venous blood saturation in the jugular bulb (r= , , p< , ) and the superior vena cava (r= , , p< , ). no significant correlation was found between rso and the arterial blood saturation in the descending aorta and as well as to the standared hemodynamic parameters. conclusion: meusurement of rso by mrs may provide continuous non-invasive information on cerebral venous blood saturation and thereby possibly on cerebral oxygen supply and consumption in infants and children. these may be of clinical value particulary during and immediately after heart surgery by means of non-pulsatile cardiopulmonary bypass. information on refractory status epilepticus (rse) from developing countries is scarce. we analysed cases of rse admitted over last yrs. the objective was to study etiology end evaluate efficacy of diezepam infusion. median age of the patients was . years irange . months to t . yrs); % were boys. onset of seizures was -t hours (median hours) prior to hespitalisation. the glasgow coma scale score ranged from . (mean+sd + ). the commonest underlying causes were acute cns infections ( / , %; bacterial meningitis, , encephalitis, ) and epilepsy ( / , %). oiazepam infusion in incremental dose (range . - . mg/kg/min) was used in patients over . _+ . days. seizures were controlled n ( %), mechanical ventilation was required in ( %)only, while none had hypotension; % patients survived. thiopental infusion (holus mg/kg followed by . mglkg/min, and increments of . mg/kg/min till seizure control) was used in patients over . _+ . days; seizure were controlled in all, but five patients needed mechanical ventilation, six developed hypotension needing infusion of vasopressoi drugs, out of ( %) died, overall mortality was %, mainly due to acute cns infections (n- ) and prolonged se. the patient was a -year-old gift di~aosed of dov,~'s s~drom¢, tetralogy of fallot. (t.f.) before admission a vasovagal crisis after coughing and vomiting was seen, and she was taken to the emergency room. mother said she had eyanosis in the mucous membranes of the mouth with exercise.on physical examination, she ~as afebrile, normal fundi and neurologic examination was normal. a harsh systolic murmur was hear~ with decrased intensity during bradycardia. chest rx disclosed a decreased pulmonary vascular markings. ecg: synus rhythm, with bradycardia and nodal escape rhyflmas. she was transferred to our picu because of severe h ,pertomc seizure, lost conciousness, and deeembrate poslamng~ ~t cyancx~is. the episode lasted for ~weral seconds, and ceased v~th diazepam. on admission she was lethargy, and neurologlc exammation showed weakness of left leg without babinski, and normal funduscopic. the patient had two episodes of bradycardia and isoproterenol was begun. during those episodes the patient was cyanotic, and the murmur was heard with the same intensity. act scan disclosed a tight parieto-temporai abscess with midline shift, lnmediately after the diagnostic ct, we administered antibiotics, antiedema treatment and it was drained. the abscess culture was negative. a ct control disclosed air and midlme shift. ~ the next two days she had three episodes of h oxia and c'yauosis ceased with o@gen, morphine and propanolol the patient died during a fourth episode. discussion: arrhytmias are uncommon in patients with tetralogy of fallot before surgery. in our case the first diagnosis was sick sinus syndrome vs bradycardia secondary to cyanotic episodes. the incidence of cerebral abscess in children with congenital heart disease (chd) is approximately %. tetralogy of fallot is the most common associated lesion, and is unusual in children under years of age. conclusion: ) brain abscess is a rare complication of patients with cyanotic chd, but should be suggested in patients with °'apparent" sick sinus syndrome. in patients with down's syndrome, t.f.,with cyanotic episodes, and difficult neurologic exploration, a brain ct scan is recommended. guillain-ba~re syndrome (gbs) is an acute autoimmune reaction, directed primarily toward the myelin encasing the peripheral motor nerves= this reaction causes a delay or block in nerve conduction. the presentation often can be very subtle but is followed by rapid loss of neuromuscular power, leading to acute respiratory distress, resulting from weakness of muscles and aspiration pneumonia. there were boys - , , and i i years old with gbs, treated in our icu. two of them due to the respiratory distress were intubated nasotracheally and ventilated mechanically with servo- ooc (siemens-elema, sweden) ventilator. duration of ventilation was i i and days, respectively. plasma exchange was performed in all cases. the numbers of plasma exchange sessions were - in each case. mean amount of plasma exchanged per session was , ml/kg. plasma was substituted with albumin, plasma or saline. the most important aspect of the management of patients with gbs in the icu involves the airway care, prevention and treatment of aspiration pneumonia and the mechanical ventilation if respiratory distress presents. endotracheal intubation should be performed whenever there is evidence of retention of pulmonary secretions, refractory to chest physical therapy, weakness of protective reflexes of the airway, leading to aspiration pneumonia and (or) atelecr~sis. cardiac arrhithmias too, is a main threat to the circulatory stability in gbs. therapeutic plasmapharesis has been shown to be beneficial, reducing the time for weaning from the ventilator and for achieving independent ambulation. however, plasma exchange is expensive and not without significant risks for the patient. some authors find that plasmapheresis is not effective for patients with fulminant course of gbs and blocking of nerve conduction. recent studies have demonstrated that intravenous high-dose immunoglobulin can be equally effective. there were no significant complications associated with plasma exchange. all presented patients survived without residual disability. tetraparesis associated with long-term paneuronium use in an infant. paneuronium is a muscle relaxant used in ventilatory management of patients with respiratory distress in intensive care unit. after the end of sedation some patients were found to have severe tetraparesis. paresis was accompanied by complete areflexia and diffuse atrophy of alt extremity muscles. this neuromuscular complication is caused by prolonged high-dosage pancuronium treatment. in the last years, numerous reports have linked the use of pancuronium bromide with prolonged paralysis, disuse atrophy and areflexia. this side-effect is well known in adults patients but rare in a pediatric intensive care unit. we describe one pediatric observation of tetraparesis after prolonged pancuronium treatment in a -month-old girl, this female infant developed respiratory distress syndrome and was intubated and mechanically ventilated. to decrease chest wall rigidity pancuronium bromide was administered during days. (she received approximately mg of pancuronium bromide). on day the drug was discontinued and the patient had severe tetraplegia and areflexia with normal head movements. electromyograpliy showed absence of any disorder of neuromuscular transmission. this infant showed a recovely of muscles after months. the other causes of peripheral neuropathies were eliminated. electroencephalograms and head scans were normal. the recovery pattern observed in our patient correspond to the process of regeneration after axonal degeneration. it is suggested that these neuromuscular complications were caused by prolonged high-dosage pancuronium treatment (associated with cortieoid and aminoglucosides). polyneuropathy syndrome in adult lc.u. appeared in literature in and is extremely common in long stay cases. the etiology of these disorders remains elusive. it is tempting to ascribe them to administration of drugs (muscle relaxants, steroids, aminoglycosidea), plolonged immobility, malutrition, sepsis and ischemia associated with reperfusion injury. to our knowledge there is only one case report of similar condition in a children i.c.u. (pascucci ) we present a serie of previously healthy children, aged months to years, who admitted in i.c.u with respiratory failure and who following weaning from m.v, remained in profound diffuse hypotonia with proximal and distal muscle weakness for various length of time, recovery of muscle strength occured in a week or months {the longest i months), all children, except one, - days before admission developed symptoms of either respiratory or upper airway infection with fever. on admission viral and bacterial cultures were positive in cases (haemophilus influenze, herpes virus). during treatment patients became septic. muscle histological and neurophusiological investigations have not been done. considering the multifactorial nature of the aquired nmd in adult critically ill pts, is impossible to attribute the muscle weakness of our pts to any specific cause, in conclusion, our findings suggest the need for further investigation of nmd in critically ill children treated in i.c.u. a van esch, ha van steen~l-m , ir ramtal, g derksen-lubsen, idf habbema. febrile status epilepticus (fse) is a prolonged and serious febrile seizure. little is known about the outcome of fse in neurologically normal children. this survey involved patients between months and years of age who had visited due to their first fse, the sophia children's hospital during the period of january till december . patients with a history of neurologic disorders were excluded. patients were identified, % were male. the cause of the fever remained unknown in % of the cases. in all case the fse was generalized and it most frequently occurred at night ( %). the mean age at fse was t. years ( . - . ), the mean temperature . °c ( . - °c). the mean follow up time was . year. twelve children ( %) had neurologic sequelea. the neurologic sequelae varied from speech deficit ( case mild, v - year delayed; case moderate > year delayed) to severe retardation and epilepsy ( cases). speech deficit was detected after a mean period of months (range - ), age, gender, temperature, family history and time of onset were no significant risk factors for neurologic sequelae. duration of seizure [rr . ( . - . )] and more than two drugs to treat fse (rr . (t. - . ) were related to neurologic sequelae. we recommend that fse children should be followed for at least a year to detect possible speech disorders properly and start early intervention. unusual presentation of myasthenlg gra%qs ibtza e. modesto ,v~ abe~gochea a, sanch]s l all, go l varas k folgado s, garcia e. p. .c.u. la fe, valencia. spain case report: the patient was a -year-o!d gift transferred to our pic because of severe respiratory failure. the patient, convaleseem of ehiekenpox, came into contact with horse manure previous afternoon. in the morning, she was lethargy, and irritability, with poor finding, and ~ an episode of coughing, cyanosis and acute respiratory failure after mucous vomiting when she was drinking milk. on admission she had severe respiratory distress, respiratory acidosis, and the sat was %. she was mtubated without difficulty, and was transferred to our p.i.c.u. physical examination reveals stable hemodynamies, pupils equal, round, reactive to light, normal fandi, and muscle relaxation. crusted vesicles diseminats~d. rhonehi over both lungs. hepatomegaly (+) and splenomegaly (+). ~lhe urine, hematologic, and c.s.f. laboratory findings were normal. c.t. scan of the brain, e.e.g., and ekg. revealed no'abnormalities. rx chest disclosed a retrocardiac atelectasis. speci~ts of stool and blood were obtained for cultures and study of c. botul#num toxins. pending receipt of these results, a broad-speotmm antibiotic and acyctovir was begun. the initial differennal diagnosis consisted of laryngospasm associated with aspiraqlon, botulism, and postmfecfious varicella encephalitis. after hours, weatm~ was begun. the neurologic examination showed a low modified glasgow coma ~ale (mgcs), generalized hypotouia and muscle weakness. these data suggested three diagnoses, posfnfecfious encephalitis, residual neuroumsoaar blockade, and excessive doses of sedative and analgesic drugs. after hours she regained skeletal muscle poxver and ufltlcient respiratory effort, the mcgs was acceptable, and blood gases were normal. she was given n~-tigmine and atropine, and her tr~ma was extubated. an acute respiratory failure ocurrs ram. after. chest radioga'aph disclosed a left inferior lobe atelectasis. after hours weaning begun~and the same episode w~as seen. at this point her mother stated that the girl showed weakness of the eyelids or extraneular muscles. it suggested myasthenic syndrome vs ~-barr syndrome. c. botul#num toxins were negative, chotinesterase level ~as normal. edrofoinum test ~as positive. anti-acetyleholine receptor antibodies were negatives. e.m.g. confirmed myasthenia gravis (congenital vs juvenile serenegative). pyridostigmine was begun and the trachea was extubated without complications. conclusion: din the differential diagnosis of weamng failure we must consider ~c gravis~ )myasthenia gravis could resemble encephalitis, because of low ocs, overall if is triggered by viral infection. )in some diseases (this case) gcs could not he an aemuate index of mental state. a burguet*, a menget*, e monnet**, a gasca-avanzi*, c fromentin*, h allemand**, jy pauchard*, ml dalphin*. * r animation infantile potyvaiente chu st jacques besancon cedex. ** d~padement de sant publique besancon cedex, france, objective : to point out that strabism is) of one-year-old premature is a good predictor of a poor neurological outcome at two years of age. design and setting : two-year prospective cohort study and geographically defined study (region of franche-comte, france). main outcome measures : neurological assessment was performed at one and two years of age (uncorrected for gestationnal age). a mailing questionnaire was sent to the famity and fuu-filled by thefamily doctor (pediatrician or physician), or neonatologist of the icu at tertiary center, s was diagnosed at one year of age by the examinator but s was not used to diagnose cerebral palsy (cp). sample : of survivors ( %) evaluated at one and two years of age. results : correlation of one and two years neurological evaluation is weak (kappa= . ). correlation of s at one year and cp at two year is fair (kappa= , ). the goal of this paper is to review evidence related to hypothesis that the "waiting" axons and cells of the transient subplate zone may participate in the structural plasticity of the human cerebral cortex after perinatai brain damage (kostovic et al, metabot brain res : , t ) and to correlate this phenomenon with different forms and mechanisms of structural plasticity. it is our basic assumption that all lesions occuring during cortical histogenesis will lead to more or less pronounced structural reorganization. here we show that various components of the subplate zone participate in several forms of the structural "plastic" responses in the human cortex: modification of convolutional pattern, changes in size of cytoarchitecturat areas~ columnar reorganization, dendritic and synaptic plasticity. the etiological factors which induce lesions and subsequent plastic changes act via the following pathogenetic mechanisms: * disturbances of radial unit formation (rakic); * changes in ingrowth of afferent fibres; * changes in the rate of normally occuring reorganisational events, depending on the critical period for a given histogenetic event. in the present study developmental lesions (localized perlventricular leukomalacia and haemorrhages) were demonstrated by ultrasound in live-born infants ranging between to weeks of gestation. in younger infants ( - w) who died shortly after birth, examination revealed lesions of the white matter with the preservation of the subplate zone. in infants who died one week of more after the lesion, we have observed localized micropolygyria, cavities, condensed layer vi -subplate zone, and columnations of the cortical plate. these changes are less prominent if the lesion occurs after diminishment of the subplate zone (after w). since in the fetal cortex the subplate zone serves as predominant source of growing fibers, transient neurons, trophic factors and contains cellular substrata for migration, this zone is the most likely candidate for major types of structural plasticity. in conclusion, cerebral cortex of the low -birthweight infants is more susceptible to the various lesions but shows vigorous structural plasticity and conspicuous functional recovery due to the growing, transiently located neuron at elements. the mortality due to meningoccocal sepsis is high in spite of important progress in emergency and intensive care medicine. during the last decade multiple scoring-systems have been developed in order to establish a therapeutic approach and to evaluate the final outcome of a meningococcal infection. different clinical and biological data (shock, ecchymosis, peripheral wbc and platelet count, coagulopathy, acidosis, meningism, etc) are taken into consideration and the importance given to these data depends on the scoring-system used. a review of the different scoring-systems is given and a clinical case is presented. we report the case of a year old male, who was transfered to our icu hours after onset of temperature and skin rash. the parents described a fast deterioration of his condition. the boy presented wide spread ecchymosis, high temperature, no signs of meningism, circulatory insufficiency and shock, coagulopathy and low peripheral wbc and platetet count. disseminated intravascular coagulopathy developed promptly. the glasgow meningococcal septicemia prognostic score (gmss) was used and the obtained score reached the highest level ( / ). this corresponds to a % mortality. the patient required mechanical ventilation for days. at admission he received human albumine, fresh frozen plasma, dexamethason, dopamine, dobutamine and a continuous infusion of adrenaline. antibiotical treatment consisted of ceftdaxone. the evolution was favorable and the infant fully recovered. retrospectively the gmss was compared to other meningococcal scoring scales which gave the same mortality ( %). we conclude that the scoring-systems are important to evaluate the seriousness and to assess the therapeutic approach, but they should be used cautiously even when % mortality is predicted by several risk evaluations scoring-systems. the aim of this study was to assess the haemodynamic status on admission and the critical care management of children presenting with meningococcat infection. this was a retrospective study of the charts of consecutive admissions. mean age was . years (+/- . ). the average duration of symptoms prior to admission was . hours (+/- . ). on admission . % were hypotensive, . % had clinical signs of haemodynamic instability and . % of cases that had a blood gas analysis on admission had a metabolic acidosis (bases excess < - .q): the mortality rate was . %. % of patients that died were hypotensive on admission and all had a metabolic acidosis. of the survivors . % were hypotensive on admission, % had clinical signs of haemodynamic instability, % required invasive pressure monitoring and . % were ventilated and received inotropic support. this study demonstrates that at the time of presentation with meningococcal infection children had a high incidence of established haemodynamic instability. successful management of this infection is dependent on early presentation and initiation of therapy and on aggressive support of the cardiovascular and vital organ systems. dept. of intensive care medicine and dept of infectious diseases, our lady's hospital for sick children, crumlin, dublinl , ireland. jude. pediatric intensive care unit, ch&u, lille-france. more than % of children surviving sip (defined as purpura with shock) have snli. objective. to search for a specific hemostatic profile in children with snli. patients and methods. between may and march , children with sip were admitted to our picu : ( . %) died and ( . %) ranged in age from to months (mean : ) survived, of them ( . %) with snli (defined as the need of a surgical procedure). in survivors, two hemostasis studies (between h and h , and h later) included the determination of coagulation factors (routine tests), protein c (pc : amidolytic activity, biogenic), total protein s (ps : elisa, stago), c b binding protein (c bbp : laurell's technique, stago), antithrombin (at : chomogenic test, stago), and plasminogen activator inhibitorl (pail : chromogenic test, biopool). three severity scores were determined at admission : french group of pediatric intensive care, gedde-dahl, and crp. statistical analysis used the wilcoxon's test. results. at admission (lst sample) severity scores and at , pc, ps, c bbp levels were not different between the group with snli and the group without snli ; quick time ( - % vs ± % ; p = . ), vti+x ( . % vs - % ; p = . i) and pall ( - ui/m! vs . ui/ml ; p = . ) were lower in the group with snli. on the nd sample there was no difference between the two groups. kinetics of hemostatic abnormalities was not different between the two groups. conclusion. in the literature, intravascular coagulation (dic), low fibronectin and at were identified as predictors of snli, and a negative correlation was found between the mean size of the skin lesions and pc activity, at , and total ps. in this series, apart from dic, there were no specific hemostatic abnormalities that support the use of treatments such as pc, at , and pail antibodies administration to prevent snli. further studies including more children are needed. the aim of study was to investigate the efficacy of intravenous immunglobulin with enriched igm content pentaglob/n /biotest/. in our pediatric intensive care unit ten septic children /group i/-their average age , years /sd:o, /, of them with gramm negative and one with gramm positive blood cultures, and two with unindentified bacteria-were treated with basis sepsis therapy and pentaglobin. the application of pentaglobin was as follows: , ml/kg loading dose for one hour, followed by a continuous intravenous infusion , - , ml/kg/hour depending on body temperatura /lanser scheme/ for - hours. another ten septic patients /control-group ii/the mean age , years/sd:o, /, their blood cultures were gramm negative bacteria , positive , and the bacteria was not indentified in two cases -were treated with only the basis therapy. results: the duration of intensive treatment decreased from an average , days /sd: , min -max days/ to , days /sd: , min -max days/ in the group treated wit pentaglobin. the difference was significant /x p< , /. in the group i nobody died, but three in the group ii. conclusion: the pentaglobin therapy can improve the efficacy of the basis therapy of sepsis. sinus bradycardia after an episode of sepsis is a rare symptom complex decribed in children with hematologic malignancies. we present a case of postsepsis bradycardia following severe typhlitis and septic shock in a year old boy with relapse common all. blood and ascitic fluid specimen grew clostridium species and pseudomonas aeruginosa. at surgery there was a necrotic gangrenous terminal ileum and cecum, requiring ileocecal bowel resection with ileostoma. while clinically recovering from sepsis he developed bradycardia for hours. extensive diagnositic procedures was given and the heart rate slowly increased to normal range of age. postsepsis bradycardia in children with hematologic malignancies after an episode of sepsis is self-limiting and after careful differential diagnostics warrants an expectative attitude. nitrate level is known to be enhanced during sepsis. serum nitrate is the stable metabolic end-product of endogenous nitric oxide generation. nitric oxide has demonstrated to be a powerful anti microbial final mediator and also a key molecule driving to the lethality of one of the most common complication of sepsis; the endotoxic shock. such facts prompted us to investigate the possible diagnostic and/or prognostic value of monitoring serum level in high risk, presumptive and confirmed sepsis patients. additionally we have explored the usefulness of this mediator as index of therapeutic response. in our study it is demonstrated that there is an important relationship between nitrate level and the occurrence of neonatal sepsis. septic newborn group showed fold higher nitrate level than that of healthy control group. in addition, the group of patients with high risk of sepsis which finally became septics, exhibited fold higher nitrate level at - hours before the first symptoms appeared, when compare with those who did not develop sepsis. however in the presumptive sepsis group, there was no difference between the patients which finaliy ,&'ere considered septics and those which not. in all septic cases, after days of a successful therapy with antibiotics, the level of nitrate diminish fold. our results suggest the utility of monitoring nitrate as index for the diagnosis of neonatal sepsis. the potential benefits of exchange transfusion, plasma exchange, and haemofiltration have all been described in children with overwhelming sepsis. however, little hard evidence exists to prove the benefits of any of these techniques. i have treated five patients with plasma exchange (pe), having been asked to see all these patients at a point when it was felt death was inevitable. two of the patients had staphylococcal, two meningococcal and one enterococcal septicaemia. all patients showed a dramatic haemodynamic improvement following pe with improvement in blood pressure, reduction in inotrope requirement and improvement in tissue perfusion. three patients survived. one of the patients with staphylococcal sepsis and both of the patients with meningococeal sepsis had developing gangrene of the limbs which showed remarkable reperfusion with pe. in two of the patients measurements of cardiac output (co) and systemic vascular resistance (svr) showed ~a reduction in co and a rise in svr over the course of a pe despite the reduction or cessation of vasoconstricting inotropes. many believe haemofiltration is of value in septic shock. a trial with a no treatment limb is difficult to achieve. i believe we now have enough evidence to justify a controlled trial of haemofiltration versus plasma exchange in patients with septic shock and unstable haemodynamic status whilst on inotropic support. during the next several days, cough and chest pain suggested pulmonary embolism confirmed by radiologic evaluation. echocardiographic examination showed multiple thrombosis of the superior vena cava, right atrium and ventricle and pulmonary artery. estimated protein c level was . % (normal range - %); identical deficiency was found in patient's mother and elder sister. cvc was removed, and alter -month heparin therapy and supstitution of protein c with fresh frozen plasma, there was almost complete thrombolysis of the great vessels and cardiac chambers. we conclude that invasive diagnostic and therapeutic procedures in such patients may result in higher risk for severe thrombosis at unusual sites, and numeuos further complications bronchopulmonary dysptasia (bdp) is a chronic pulmonary disease of preterm and term babies treated with mechanical ventilation for respiratory problems of different origin and requiring oxygen therapy days after birth. bpd is a disease affecting the growth and development of pulmonary tissue. such pulmonary }esions heal by squamous metaplasia leading to scar formation and fibrous tkssue r~growth, the pediatric intensive care unit makes the survival of babies w~h very low birth weight ( - g) possible. with the increase in their aulyival, the number of complications in low birth weight babies increases as well. bdp is a very serious complication. therefore the importance of early diagnosis and treatment of bdp must be stressed in order to reduce the consequences. babies with bdp must be under medical suveillance for at least years as the disease needs at least that long for complete resolution. tn the icu of pediatric department at madbor teaching hospital: during the past two years ( - ) newborns were treated with mechanical ventilation. the neonatal and postnatal death rate of all newborns admitted to our icu was , %o.ln the two years from to , newborns were admitted to our icu ( %~ of all newborn babies at maribor teaching hospital), with birth weight - g. in the icu, the survival of these babies and parallel to it the number of complications is increasing. during the mentioned -year period, babies with very low birth weight ( - g) survived: in and in t . in - %, first or second stage bdp was treated,there was no case of third of fourth stage bdp. the treatment consisted of eary removal from mechanical ventilation, oxygen therapy~ intensive treatment of infection, volume and caloric intake contro}, corticosteroid treatment throught weeks with decreasing doses, diuretic end antioxydant therapy. the children are to be reevaluated at the age of and months and again at i and years. oeure j van der, markhorst do, haasnoot k department of pediatrics, pediatric intensive care unit, free university hospital, amsterdam, the netherlands. case summary a %-month . kg girl of african origin was admitted to the pedfatric irtensive care unit with pneumonia and progressive respiratory irlsuffjderey. she was intubated and ventilated by pressure regulated volume controijed ventilation (servo c, siemens, soma, sweden). maximum conditions were inspiratory minute volume . l, peep cm h~o ahd % ~. chest x-ray showed bilateral interstitial consolidation. material obtained by broncho-alveolar lavage showed preumocystis car}nil htv-serology (elisa and westerll blott) and p -antigerl were positive, confirming the diagnosis of pediatric aids. she was then treated with high dose co-tllmoxazoie, penthamldine, z{(~ovudire and steroids iv. because of thee x-ray features, high need for o ( %, pad mm hg), not responding to elevatiofi of peep (max cm h=o) and pao /fio = < (s ). m acute respiratory distress syhdrome (ards) was diagnosed. because conventional ventilation (cv) failure, hfo-v ( ooa, serisor medics,yorba linda, ca) was initiated. starting mean airway pressure (map) of cm h~o was based or map of the cv, oscillatory pressure amplitude (dp) of was, at ii~itial frequency of . hz, adjusted ur~til chest wall vibrations were visible, it was required to raise map to cm h and dp to before optimal lung volume and ventilation were achieved and need for o reduced within hours, this was monitored by frequent blood-gas analysis and chest x-rays. map and dp could slowly be reduced, after a good response the first day, gradually demand reduced and the patient could be weaned from the ventilation. map, dp, fi and oxygenation index (map x pa ~jfio ) are shown in table i. chest x-ray follow-up showed gradually improving lung features, with marked improvement of aereation. after days hf -v she could be succesfully detubated when a map of cm h was acmeved. results : sianificant increase in ventilato~ rate and mean airway pressure was noticed after the change to savi. no differences in oxygenation, co partial pressure and systolic, diastolic or mean blood pressure between imv and savi periods were noted. in infants however an improvement in pao /p .ol/ and decrease in paco was observed after the switch to savi. these babies had a lower initial a/a oxygen tension ratio and required higher initial ventilator rate /p<o. / in comparison to the rest of the studied patients. conclusion:infants with low a/a po ratio who need high initial ventilator rate are likely to obtain benefit from savi.. fumimare hatori, haruo uchida, masao katayama, and rika muto department of anesthesia and critical care medicine chiba children's hospital, chiba city, japan. purpose: this study was made to find out whether the heat and moisture exchangers (hme) was effective enough to humidify in the respiratory management for children. patients: the study population consisted of patients who were provided with artificial airway. they were divided into the two groups: ii with heated humidifier (a) and i with hme (b). methods: hme could be used for those without pulmonary complication and with less leakage around the endotracheal tube. in both a and b groups, (i) we have measured relative humidity, temperature, and absolute humidity at the endotracheal tube connector. for these measurements, humidity sensor system was utilized. ( ) any troubles and complications caused by the artificial airway were investigated. results: (i) in group a, we confirmed the mean values as the relative humidity of . %, the temperature of . ~c, and the absolute humidity of . mg/l. in group b, they were . %, . °c, and . mg/l respectively. no difference was noted between the two groups as to the relative humidity, but the temperature and absolute humidity were lower in group b with a significant difference (p< . ). ( ) in neither of the groups, any respiratory complications such as obstruction or stenosis of the artificial airway were noted. in pediatric icu, hme can be used without any problems under given conditions. titei: objective: evaluate the precision, reproductibility and aplicability of a new device to measure auto-peep in pediatric patients during mechanical ventilation. material and methods: it's an electromc-pneumatic eontolled device with an oclusion valve and a pressure monitor installed between endotracheal canulla and the ventilator circuit. the measurements were performed with a sollenoid conected with to the ventilator to detect the end of inspiration phase and the actwation of the oclusion valve. the signs of pressure and flow were moniturized using a difere~rtial transducer and it was processed using a pc computer and a pneumoviaw® software. the auto-peep also displayed in the ventilator pressure monitor. results: we submitted children with neuromuscular disease or respiratory distress in this study. the incidence of auto-peep was %, with variability between , to cmh . all the measurements were performed times to verify the precision and the reproduetibility and evaluation of the pressure and flow curves. conclusion: the device is low cost, easy to use and can be used without the pneumotacograph. the auto-peep measurement can be done during mechanical ventilation with time cycled, pressure limited and continuous flow, the most commom ventilator used in pediatric patient. resistance was modeled by endotracheal tube (ett) sizes ( . , , , ), and compliance by test lungs ( and ml/crnh ), for each resistance -compliance arrangement, we measured tidal volume (vt) at various frequencies, peak to peak (p-p) and mean airway pressures. results vt increased when ett size increased with all ventilators in accordance with fredberg results (jap, ; : - ) . the maximum vt delivered was smaller with the hfv-babyiog than with the ohf or the sm a at a given frequency (figure on the left). increasing p-p resulted in a linear increase in vt delivery in the - % range of maximum p-p (figure on the right). hfv-babylog didn't provide significant vt increase when p-p was set above % and vt deliven/decreased when mean airway pressure decreased. --i ~ sm a a number of ventilatory parameters had been analyzed with russia-produced monitor humitemp htm (servisinstrument j,-s. co) in newborn infants with rdsn of t-iv stages on cmv, cppv, imv, and cpap steps using respirators of various kinds (stephan-staxel, bear- , newport rezee, sechrist). parameters investigated were: temperature of inspired mixture (t), relative and absolute humidity (rh and ah, respectively), static compliance (c), expired tidital volume (vte), expired minute volume of ventilation (mve). the monitor read these parameters in following ranges; rh-from to %; ah-up to mg/i; mve-up to . i/mini vte-from to ml; t-accurate to %; c-from . to t ml/cm h . continuous monitoring time ranged from to hours, it was noted, that during this time the monitor and transducers had no malfunctions, and it's using didn't require additional calibration, it was found, that humidifiers mr and mr (fisher, paykel) couldn't maintain parameters t and ah continuously (these values varied from , to . c and from , to . mg/i, respectively, when heating regulator position was unchanged). changes of parameters c depended clearly on cppv conditions and rdsn severity (with rdsn of stages i-ii c value ranged from . to . ml/cm h ; and with stages iit-tv-from . to . ). tn newborn suffering from rdsn of stages ii-ltl and ill-lv with pip> mbar, fi > , , peep= - mber, c-from . to . ml/cm h , effectivity of exosurf therapy was studied. in newborns in - hours of therapy pip decreased to . - . , and c increased to , - . ml/cm h . in newborn infants with aad > mmhg and c from , to . mltcm h positive effects of exosurf on lung compliance were not observed. in newborns the monitor had revealed decreased of c (from . - . to , - . ml/cm h ), manifested clinically by pneumothorax. in general, monitor htm made possible; ), to estimate the adequacy of cmv-parameters and regimes in newborn infants; ). to select optimal t and ah values in the respiratory outline in dependence on lung damage severity and infused volume; ). to reveal rdsn severity; ), to optimize indications and adequacy of surfactaot therapy; ). to diagnostieate the air leakage syndrome; ). to effects to some agents (broncholytics, spasmolytics); ). to obtain objective indications for imv/simv and cpap regimes. albano communication is an important aspect of human development and existence, and an inability to vocalise can be a problem in ventilatordependent patients. we present our experience with speaking aids as a means of enhancing verbal communication in four ventilatordependent children in our paediatric intensive care unit. the age of the children ranged from months to years, and the period of ventilation ranged from months to months via a tracheostnmy. they require continuous flow generated pressure limited or control ventilation at rates of - bpm. the reasons for ventilation include tetraptegia following a shrapnel injury; tetraplegia following congenital cervical spine damage; tetraplegia following atlanto-axial subluxation; and critical illness polyneuropathy following adult respiratory distress syndrome from prolonged ventilation for a severe head injury. the first three patients have passy-mnir one-way speaking valves and the final patient has a bivona foam cuffed tmcheostomy tube with a talk attachment in view of recurrent aspiration. an improvement in quaiity of speech has been shown by independent assessment. we will review the present literature on this subject and discuss the advantages and disadvantages of these two types of speaking aids in the light of our experience. the prognosis of antenatally diagnosed cdh is closely related to the degree of ph. there have been attempts to correlate antenatal or postnatal criteria to mortality: none have been demonstrated to be predictive of lethal ph. the aim of this retrospective study was to determine whether antenatal or early postnatal data could correlate with the findings of post-mortem examinations. patients and methods: between july and july , cdh patients have been antenatally and postnatally managed at our institution. twentythree infants underwent a post-mortem examination. ph was assessed by using the lung weight to body weight ratio (lw/bw) and the radial alveolar count (rac). antenatal results: cdh diagnosis was made at weeks of gestation (wg) ( - ). twenty-eight patients had a left sided cdh, had a right sided cdh, and one had a bilateral cdh. herniated organs were stomach none (n= ), or liver alone (n= ), or both stomach and liver (n= the patient was a -yenr-old girl with chronic renal insufficiency see~ to renal dysptasm, two months before admission a kidney trar~ptant was performed. one morah later she showed acute graft rejection with serum ereafinine (cr) level of . mg%. the rejection was unreslxmsive to an increased steroid dosage, and okt was begun with resolution of the rejection. one week arer, new rejection episode was seen marestxmsive to an increased steroid dosage, and transp~ ~s performed five days before admission to our ptc. hemedialysis and peritoneal dialysis (p.d.) each other day, was indicated (g.r.f.< ml/rnin). four days before admission t ~ rose to °c. "lhe diagnosis of opporttmistic pneumoma was made on the basis of tach ,pr',e~ hypoxi~ and diffuse interstitial infiltrates. senma ~ was positive for cytomegaloviras (cmv), and stool culture for c albicans. pentamidine, ganciclovir (dhpg), arai-cmv gamma globulin, eritromicine and amphotericin b was administered. on admission in our picu, trachea was mmbated, (a-a) o gradient was , paofffio~: , lung injury score > with peep level of cm hzo. she had normal fiver function. during te next days she had fever and developed ards. bal was negative. p.d. was of little efficiency. we adjusted pentanfdine, and dhpg doses for severe renal failure, with supplements after hero, sis, and at~rp.d.. during ~ next days she was afebrile, and the chest became radiologlcally normal. after ten days on menhani~al ventilation (mv.), the patient was extubated. cr. level was . rag%, (a-a) oz gradient was , and paoyfioz was , the patiem was discharged with chronic ambulatory p.d. discussion: opportunistic pneumonia is a major complicalaou in imm~romised children, specially after kidney tvansplaraafion. c m.v. infection can result at~r okt administration. in the treatment dhik} dose must be adapted to the degree of renal insu~cieney, with supplements after hemedialysis, and after pd. pneu~y~tis cann# tmeumov~ is ehemeterized by ventilafion-perfusion mistmaeh, decreased pulmonary compliance, hypoxia arld elevated (a-a) oz gradient, with diffuse interstitial infiltrates. in our ease bal was negative. although we did not find the etiology the prevoclons eombh~ation of arairmcrobiat therapy, along with m.v., and supportive measures were the most effective trealme~. conclusion: ) in patients with severe renal failure and life-threatening infections, we must co~ider drug adjuslments. ) in our patient we gave dhpg supplements at~r pd. with excett~at results, although p.d. was of little effiele~. introduction: endotracheal intubation and mechanical ventilation have become an important treatmem for many diseases accompanied by respiratory failure. with the frequent use of this treatment modality, an increasing number of complications associated with endotracheal intubation have gained clinical significance. material and methods: a transversal study was realized to find the prevalence of pulmonary aspiration with endotracheat tubes in infants and children. aspiration was assessed by applying two dyes (evans blue, er)¢rosine sodic) on the tongue and searching for the dye during suctioning in the endotracheal aspirate. the factors, that potentially have influenced the aspiration, including weight, age, sex, cause of respiratory failure, main pressure airway (map), level of consciousness, presence of swallowing and body position were evaluated. all the variables studied had their association with aspiration tested by chi-square method with relative risk considering a confidence interval of %. the results were adjusted by multivariate analysis. results: the overall prevalence of aspiration was . %. among all children who aspirated, compared to those who did not, there was a statistically significant difference in the presence of swallowing (p= . ). the odds ratio to aspiration in the presence of swallowing was . (t. - c.i. %) and the relative risk . . aspiration was not significantly affected by sex, weight, age, cause of respiratory failure, map, level of consciousness and position of the body during the ventilation. conclusion: the endotracheal intubated children frequently aspirate as intubated adults and that preventive measures are ineffective. the presence of swallowing movements is the main risk factor to aspiration of oropharingeal content in intubated patients. clinical features and shortterm outcome skling, rp gie pneumonia is the second most important cause of death in young south african children. the clinical features, intensive care course and outcome of children being ventilated for pneumonia in the developing world is unreported. aim: to describe the clinical findings, aetiology and shortterm outcome of children younger than months with pneumonia requiring ventilation. the data of all babies under the age of six months with a lower respiratory tract infection admitted to the paediatric icu for ventilation were prospectively collected over a period of months. tracheal aspirates and blood specimens were submitted for viral and bacterial cultures. results: forty-seven babies aged to days were ventilated for pneumonia. twenty-six infants had been born prematurely; t had been ventilated during the neonatal period and had bpd. the median duration of symptoms was day, the most common being cough, tachypnoea, apnoea and cyanosis. five babies ( %) died. the mean duration of ventilation was days (range - days) and of ward stay after icu discharge days (range - days), blood euttures were positive in children ( %). viruses were cultured in children ( %). conclusion: ) fifty-five percent of children below months requiring ventilation for pneumonia were premature infants, of whom % had been ventilated during the neonatal period. ) the median duration of symptoms prior to admission was day. ) ninety percent of the children survived and were discharged from hospital. ) viral pneumonia was responsible for % of the admissions. mechanical ventilation and atrial natriuretic factor release ulloa santamarfa, e, p rez navero jl, ibarra de la rosa i, espino hernladez m, velasco jabalquinto mj, frfas p rez m. picu. reina sofia children's llospital. c rdoba. spain. mechanical ventilation effects on renal function decreased diuresis and natriuresis due several factors including anf. several studies have demostrated anf released due increaasing pressure in right atrium. on the other hand, mechanical ventilation, overall peep modality, inhibits peptide release althougt cvp increased is found. this study was designed to demostrate anf stimulation is due rigth atrium stretch which be higher during mechanical ventilation instead of atrium pressure. we desing a prospective study including patients, age range months- years with congenital heart disease. all of them were admitted at pediatric intensive care unit after extracorporeal surgery and were assisted by mechanical ventilation. hemodinamic state was stabilized in all patients and nor renal neither neurological diseases were found. after hours with mechanical ventilation, plasmatic levels of anf were measurement, pvc, pericardical pressure were assessment; all patient were sedated with midazolan and paralized with neuromuscular blocking agent; mechanical ventilation technique was as follow: imv between and , tidal volume and fi o enough to mantain respiratory parameters in normal range. afterwards, at least twentyfour hours in spontaneous breathing, the study was made again in each patient. atrial stretch was assesssment according to following equation: transmural pressure= cvp -pericardial pressure. cvp were significantly higher with mechanical ventilation than when the patient was breathing by himself. ( . +__ . vs . + . mm hg; p< . ). however, transmural pressure during mechanical ventilation were lower than during spontaneous breathing ( . +__ . vs . +__ . mm hg; p < . ) equal, plasmatic anf levels were lower during mechanical ventilation ( . + . vs . + . pg/rnl; p< . ). in conclusion, anf secretion decreases during mechanical ventilation, even with cvp higher. anf release would depend on atrial stretch meassured by transmural pressure, lower in patients with mechanical ventilation and it would not depend on atrial pressure. the paediatric intensive care unit shaikh zayed hospital, lahore is an acute care area devoted to the care of critically sick children upto the age of years. in a bedded unit with limited equipment, constant care is ensured by the presence of at least one nurse aed one doctor round the clock. in this setup we have the facility to ventilate - children at one time, between sep. and dec. , out of patients admitted to icu, ( . %) were below yr of age, while ( %) were below month of age. life support was discontinued in ( . %). total mortality was ( . %), major mortality was in - month age group ( . %), and month to month ( . %). majority of the patients were of sepsis ( . %), cns disorder ( , %) followed by respiratory problems ( . %). it seems therefore that the major indicatiou for ventilation was overwhelming septicemia leading to multiple organ failure, rather than purely respiratory problems. high frequency oscillation (hfo) in the therapy for ards in pediatric patients requiring aggressive conventional mechanical ventilation (cmv) -routine or experimental mode ef pre ecmo therapy. fedora m., nekvasi~ r, vobruba v., srnsky p,, zapadlo m. dpt. critical care medicine, nicu and ecmo center, university children's hospita! brne, nicu of university hospital prague, czech republic. introduction: pediatric patients ( males, female, average age . months, average body weight , kg) with severe ards ventilated with aggressive regimen of pcv or prvc were connected to hfo (sensormedics ) as the last "rescue" therapy due to uncontrollable respiratory failure before intended ecmo. in the course of hfo of them were given no in the concentrations of - p.p.m., were subjected repeatedly to surfactant replacement therapy (alveofact). results: ecmo was needed in no patient, patients survived, patient was disconnected from the ventilator because of brain death in spite of conspicuous improvement of oxygenation and other parameters, some relevant parameters hours before and hours after starting hfo are given in table ~ in all the cases, the disconnection from hfo was carried out through the simv regimen, never directly to cpap. table : the levels of blood gases, oxygenation index (oi), aado ,map,fio and pao /fio ratio hours before and hours after starting hfo. conclusion: although none of the patient had to be subjected to pediatric ecmo, hfo should be carried out only in workplaces having the immediate possibility of using this method in the case of hfo failure. speculation: should not hfo be used ir pediatric patients with ards earlier than aggressive cmv? can hfo ce considered standard, not experimental method of therapy? refractory hypoxemia in premature patients is characterized in a persistent elevation of pulmonary vascular resistance, with right to left shunt through the ductus arteriosus and or foramen oval. we report the case of a vlbw patient (ga w, bw g) who present a severe hypoxemia related to hyaline membrane disease and a pulmonary and systemic infection to group b streptococcus, refractory to conventional ventilatory support and surfactant therapy, associated to hemodynamic failure falling in ecmo criteria used for term infants. a rescue therapy with hfov (sensor medics a) is decided at h of live, the table resume the patient's evolution before and after hfov. at w of postgestational age the patient present a fio of . with a chest x ray compatible with a cld type l at discharge no oxygen requirements was needed and actually he's doing well. conclusion: hfov, using an adequate alveolar recruitment strategy, was effective in the rescue of a severe hypoxemic respiratory failure with a rapid off of ecmo criteria entry in our vlbw premature patient, during the united nmioffs embargo ~nst yugoslavia the prevalence of the ast}nnafic ~acks in c~dldren aratsed. the mo~t common causes have beem dramm~e worsening of life standard, ecom~c disaster in global community, gr~ number of refugees from the other parts of former yugodavia. it wm obviom that mcio-ecoumnical conditions took a part in the exacerbations of previously known cldldhood asthra~, ~av~ of micro-and m~mclimaflc changes, psychosocis] and emotional cryses, lack of medics-m~nts for p~ve~on and tl~rspy of acute asflanatic attacks. about % of d-dldv~ tmslod in our picu for these year~ exp~dvncod ~vcr~ attack for the flint time iu ~jzeir lifts. it has been cu~ ~%~ children in mspir~ry picu of our hos~mt. the scut~ revere attack (more ~asn ~/o of hight clinical score) was detected in % of all children admitted with respirak~ problems. from tl~ mmlysss we exclu&d: bmncldolifis, ~i anomalies, ~eve~ i~ccqions. concerning our drug supplies (which wc~e reduced), we started our therapy by administration of oxygen, ~ta -ago~dst inhalations (but sometimes we had the solution for jet nebulizcm only for o~e inhalation per p~cnt), mwinophyllin and mefl~ylpr~ini~done in/ravenously. % of ih~ asthmatics needed repea~ doses of muinophyl~n pinch.ally, tnch.,ding the fluids. the bronchodilak)r msponm was poor ~r~cl slow, hospital stay in picu was for days and for days in other units sl~rwsvds. tim ~ of their stable condifio~ was hard at borne (or refugees camps), without p~ventkm, so they came bsvk to hospital for morn than times in % of cases, dtrdng ~e je last motlfl~s file dtustion improved, concerning tim drugs supply for prevention, and we hope that these lifc~restening conditions wouldd~ introduction: the incidence of ards is increasing as survival of critically ill patients is higher. the application of new therapeutic modalities have increased the survival rates in (ards) adult patients. objective: to study the therapeutic efficacy of new tleamlents in children with ards material and methods: a retros~ctive study was conducted from to . children with severe ards, (lung severity score > , ) (r), aged days to years, were included. the diagnosis were as follows: interstitial pneumonitis, non interstitial lung infection, with lung aspiration and with clinical sepsis. patients had different tipes of cancer and to suffer inmunodeficiency disease, the first subjects (group t) were treated with conventional measures. from october of new therapeutic modalities were introduced, including: less agressive ventilatory support, postural changes (prone to supine) in subjects, administration of corticosteroids in patients, rfitric oxide in , pe~ssive hypercapnia and administration of exogeans sarfactant in one, pao /fio , d(a-a)o , oxigenation index (oi) and the score of respirator), severity disease were similar in both groups. the two groups evolntiou was compared. results: -ten patients died, from group i and from group ii ( % v.s. : %,ns). -the evolution time, either to exitus or weaning from ventilatory support was higher in group ii ( . v.s. . days in group i, ns), -the incidence of barotrauma was observed in subjects ( . %), from group i and from ii. of these patients % expired. -during the course of the disease, ( %) patients had more than one damaged organ. only in one subjet mof was considered to be the main cause of death. the majority of the patients expired because of their respiratory disease, although, % of them met criteria of mof. -fifty percent of the subjects were infected at the time of death. stmmry: a trend toward a higher survival rate is observed in the subjects receiving the new modalifies therapeutic intervention (corticosteroides, postural changes and permissive hypercapnia). our results are not significative,probably because of the small number of subjects studied. a new doubleaurae~t two-stage et-tube (dl-ett) was desig~aed and tested in the rabbits with acute king injury under conventional mechanical ~entilation_ ventilation efficiency of dl-ett was emrrpared with that of canveniionally t~sed single lumen et-tube (sl-ett). meth~s: dl-ett was specially made out of two sl-ett. vertical crosssections at the distal end of two et-tube (td _ rmn portax) were adhered with each other to form a tracheal stage lumen wifu id . mm the two remained uncut parts of the tubes corlntithted the oval s~ge with two separate imnens. dl-ett and sl-ett were randomly applied to five adult paralyzed rabbits with acute lung injury (by . nffkg oleic acid. iv). a bird inter vetffttator (bird products corporation) was used for time-cycled pressure-limited ventilation at /min of respiratory rate, ern h of peak i_~piratory pressure, l: of ire ratio, ljmin. of flow rate and . of fich. peak inspirntory pressure, mean mrway pressure, posi ve end-expiratory pressure at tip of et-mbe and bemodynamics were measured and recorded continuously. arterial blood and expired gas were measured ~by avl blood gas analyzer) after each stabilization t.~iod of minntes. _analysis w~as by prated t test. result: dl-ett acaltety improve cos removal at all amman. pa(?oz was decreased by t . +_t. (p< . l) and physiologic dead space fraction (v~zvt) reduced by % +- . % (p< . t), compared with dl-ett. there were no significant change in arterial oxygenation. conelus|on: the double-lumen two-stage et-tabe significantly increases ventilation effmiency with simple operation in rabbits v, ith acute hmg injury, lts availability may influence future clinical management of ~ennated patient~. this ~muly was fimded by the science and technology. commiuee of beijing municipality. analis of hemostasis alterations on different coagulation cascades in children with septic shock has shown that coagulation disorder character is dependent on lung affection rate. the initial manifestation of the respiratory distress-syndrome (rds) are characterized by the obvious activation of blood thrombin potential, moderate coagulopathy and not sharply marked endoteliosis, the witlebrand's factor (wf) increase tot - %. progress in the clinical picture of "shock lung" leads to chronometric and structural hypocoagulation with potential hypercoagulation in "mix-test", high level of firbin derivative, thrombocytopenia with thrombocytopaty and the wf increase to ~ %, terminal stages of the rds, as a rule, are characterized by potential hypercoaguletion absense, depletion of at-lit and plasminogen, prevalence of antithrombin and antiaggregating activity, obvious endoteliosis (the wf to increase - %). the arteriowenous difference according to index of the thromboelastography (teg) in the rds ill-iv rates was , % less than in the - rates, disorder of lung filtering ability in severe rds is confimed also by minimal arterio-venous difference of activated euglobulin lyses (ael) in children with the rds ill-iv rates is only , %, while the patients whit rds i-i rates have the ael-activity in arterial blood , times as much than in venous blood. the use of then allows to determine the potential hypercoagulation rate, the at-ill level and fibrinogen quantity during the anticoagulant therapy and also the character of the x-factor activation and thrombocytic hemostasis. the effective therapy component of septic genesis rds in children is the controled coagulation method with the use of the individual selected heparin doses in according to desagregants, kryoplasma, proteolisis inhibitors and trombolytics. it is necessary to avoid the heparintherapy for children with the rds complicated with producting coagulopaties and termal phases of blood disseminated intravascular coagulation (dic). bronchoseopy has been used for evaluation of the potential problems of the airways and for investigation the bronchial specimens for diagnostic purposes. regent technical advances result in performing this procedure at the bedside manner and in critically ill patients. we have performed hronehoaeopy during last three years on pediatric patients with respiratory problems, in % of cases the opentube hroneh seopy was performed (for diagnostic as well as for therapeutic reasons) and collected secretions or bioptic material were examined. the indieatiuns were: acute upper respiratory problems, chronic wheezing, inspiratory strider, tracheal or bronchial bleeding, chronic eongh, retractable atelectssis, severe pulmonary infections, lymph node perforation in lung tuberculosis and soquells like bronehiectssis and fibrosis. our results were: anatomical malformations in %, mueosal oedema with chronic inflammation and thick secretions in %, easuos masses in %, granulation tissue and purulent secretions in foreign bodies and bronehieetasis in %, and only % of eases were normal finding. our exlxdenees pointed that this invasive procedure in carefully selected patients has important role in establishing the diagnosis and in the- introduction: tbg has been a useful investigation in the management of ventilator-dependent infants in our experience. one ml of contrast was hand ventilated into the respiratory tree via their nasotracheal tubes and their anatomy and dynamics demonstrated on radiological screening. case descriptions: three infants who were difficult to ventilate requiring high airway pressures, high peep and a significant oxygen requirement had tbgs. the ages ranged from to months. two cases were complicated by complex cardiac lesions. in all cases there were frequent episodes of desaturation, where hand ventilation proved difficult and various intermittent lobar collapses occurred. microlaryngobronchoscopies (mlb) performed on the infants by experienced paediatric ent surgeons failed to identify the airway problems. more than one mlb was frequently done. concern about introducing contrast into the airways of infants with limited cardiorespiratory reserve combined with an uncertainty about how much extra intbrmafion would be gained often led to a delay in investigation. when performed these fears proved groundless, the anatomy and pathology of the airways were demonstrated in full and the correct therapeutic plan started. in two cases tracheostomy and peep producing patency of bronchomalacic segments allowed weaning to low levels of ventitatory support. in one case tracheal reconstruction was undertaken and in the cardiac cases the respiratory component of the ventilatory dependence was fully assessed. at the age of months, a baby boy with a history of minor respiratory problems, was admitted to hospital with an upper airway infection and severe dyspnoea. shortly after arrival at the icu he had a total airway obstruction. after intubation there were still difficulties to establish a normal gas exchange, and he was tranferred to the regional picu. ct scan and bronchoscopy verified a congenital tracheal stenosis affecting the whole trachea except the upper mm below the vocal cords. the diameter was estimated to less than ram. an unsuccessful attempt was made to dilate the extremely rigid stenosis with a balloon. after the procedure he had a respiratory and circulatory arrest, and he was put on ecmo as a bridge to surgical correction. after stable days on ecmo, surgery was performed during ecmo with a tracheal homograft transplantation. immediately after surgery, ecmo was discontinued. a silastic dumont type stcnt was inserted inside the homogra~, and a nasotracheal tube was placed inside the stent for assisted intermittent mechanical ventilation. repeated bronchoscopies were performed to remove granulation tissue and secretions. at months of age, the stem was removed with an endoscopic procedure. however, the trachea was still soft and collapsable, and another silicon stent was placed inside the trachea for another months period, after removal he had some respiratory problems and he was treated with nebulized salbutamol, mcemic epinephrine and steroids. he was discharged from the hospital at months of age and his condition is now stable. this is the first procedure of its kind in sweden. it was accomplished by international and multidisciplinary collaboration. ecmo may be a bridge to corrective surgery and long time stenting may be necessary in the postoperative period. post mtubation laryngitis ( pil ) is still a frequent complication, occurmg in l - % of intubated patients. inhaled racemic epinephrine has for long been used as an accepted therapy, but this drug is not always available. the authors undertook a randomized, double-blind, placebo-controlled trial to determine the efficacy of inhaled l-epinephrine(le) in the treatment of plu in the period between july/ and may/ , patients were submitted to endotracheal intubation for ventilatory support. atter the extubation procedure patients were considered for enrollement if they met the following criteria: clinical signs of laryngeal estridor and a downes and rafaelly score for upper respiratory obstruction equal to or higher than patients with primary upper respiratory disease were excluded all patients enrolled reeieved either inhaled l-epinephrine % or normal saline. dexametasene ( , mg/kg/day) was given to all patients in both groups. after inhalations, au patients were monitored for a period of - minutes and monitoring included cardiac and respiratory rate, mean arterial blood pressure, arterial blood gases and the dowries and rafaelly score. statistical analysis included, qui-square with the fisher correction test and the z-test for paired variables. thirty eight patients ( , % ) met the criteria for enrollment, to the le group and to the placebo group.there were no significant differences in both groups in regard to age, sex, initial score ( , x , ) and endotracheal tube diameter. the period of ventilatory support and tracheal intubation was significantly higher in the le group ( , x , , p = , ). the follow-up score showed a significant drop only at minutes after the inhalations (p = , ). re-intubation due to laryngitis, occured in patient of the le group and in of the placebo group with no statistical sxgnificance (p = , ). no difference was observed on the monitored hemodynamic variables during the minutes, except for the mean arterial pressure at minutes, being heighar on the placebo group (p = , ). we concluded that, although the l-epinephrine group showed a trend in better scores post-inhalation and fewer re-intubations due to laryngitis, the results were not statistically significant. we especulate that the period of intubation may have affected our results. similarlly there were no differences in the incidence of adverse effects between both groups. objectives:to evaluate the complications of endotracheal intubation in children with upper airway obstruction due to epiglottitis or croup. methodes: during a year period ( - ) all patients with epiglottifis or croup were reviewed to determine the complications of endotracheal intubation, especially upper airway obstruction due to granulomas. results: patients were reviewed. in children (mean age . years) with epiglottitis the mean duration of intubation was . days ( - ). no complications were seen. in patients (mean age . years) with croup the mean duration of intubation until the first extubation was . days ( - days). elective extubation was performed if an airleak was present or after days without airleak but in the absence of fever and obvious secretion. reintubation was not necessary in children ( . %). in this group the mean duration of intubation was . days ( - ). in patients ( . %) reintubation was necessary because of severe upper airway obstruction due to granulomas. mean duration of intubation until the first extubation was . days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . there seems to be a difference in duration of intubation between these two groups with croup, however it is not significant (p > . ). all the patients with granulomas could be successfully extubated after microlaryngeal surgery, with a mean intubation period of . days ( - ). revealed no complications, where as endotracheal intubation in children suffering from croup showed a high incidence ( . %) of granulomas. however laryngeal steepsis and other serious complications were not sesn~ patients ( days averagely] was obviously seen in ~he peak =one of fl, f resonance and in the zone of high freq,-~ncy :r, ~;~e composition while cases( day~ average;y] :~bowed no abnormality both clinically and isryngoscopica!~y. / patients with catheter placement for more than week~ end p~tie,~ts for less than weeks had t;~ryngeal abnormal change in their larynges,abnormal changes of sound spectrogram were all seen in patients with placement for mope than weeks. our data suggest= ca] the complication of endotracheal intubation was increases with increasing length of time of catheter placsm. entjbut aeriuoa complication is rare i (b] the time limit of pernasal endotraoheal catheter placement is weeks within which the procedure is • comparatively safe and effective means for maintaining e tong term artificial airway. in a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) we diagnosed tbm as an apparent dilatation of the trachea and main bronchi ih four premature infants on continued mv for respiratory distress syndrome (rds). the infants were three boys and one girl with gestational age (ga) - weeks and body weight (bw) - g. mv was provided by bourns cub time-cycled and pressure-limited ventilator to attain normal gas tensions. no jet ventilation was used. chest radiographs were reviewed for a complete evaluation, and for the evaluation of the airway. after the intial subjective diagnosis of tbm, the width of the tracheal and main bronchial air column was measured at the lower level of the first and the third thoracic vertebal body it , t ) and near the carina; the width of the main bronchi below the carina was also measured. in all infants, tbm became apparent close to the lh day, that is, after - weeks of mv. therefore, for the time period from birth to the th day the following ventilatory parameters were reviewed and analyzed: ( ) the percentage of total ventilation time when more than % o concentration was required, ( ) the peak inspiratory pressure, ( ) the positive end-expiratory pressure, and ( ) the duration of high frequency ventilation ( - breaths per minute). also noted were the apgar scores ( and min after birth), the duration of hypotension (systolic bp below mmhg) and circulatory instability, the presence of systemic or tracheal conatal or later infection, the duration of mv, and the final clinical outcome. the records were also reviewed for other possible pertinent data. rigid respiratory endoscopy in children fraga j, amant a s, piva j, nogueira a, palombini b. introduction: the respiratory endoscopy is an important procedure to diagnose and treat many airway's diseases in children. although have had advances in radiologic investigation exams and pulmonary function tests, the direct anatomic visualization of airway is important to the management of many respiratory problems. objective: evaluation the respiratory endoscopies performed with a rigid bronchoscope in a pediatric reference hospital. material and methods: we study the records of all children that were submitted to respiratory endoscopy under general anesthesia from march to march . age, sex, clinical to indicate the procedure, diagnosis and complications of endoscopy were registered. results: three hundred and fifty six respiratory endoscopies were performed. the most common indications for endoscopy were strider ( %), suspected foreign body ( %), atelectasis ( %) and difficult tracheal extubation ( %). the most frequent diagnosis were laryngomalacia ( %) and subglottic stenosis ( %) in the glottic and subglottic areas, and foreign body ( %) and tracheomalacia ( %) in the tracheobronchial area. normal endoscopy was performed in ( %) of the children. only three slight complications of the endoscopy were observed. two patients presented bradycardia during the exam, and the third need tracheal intubation due to post-endoscopic subglottic edema. conclusion: the rigid endoscopy in children is efficient and has no serious complications. near drowning; indicators of acute and long term prognosis bernardien t.mj. thunnissen t, reinoud j.b.j. gemke , loes veenhuizer?, krijn haasnoot , a.johannes van vugh department of pediatrics, ~wilhelmina children's hospital, utrecht, sophia hospital, zwolle, and ~free university hospital, amsterdam, the netherlands. in this retrospective study factors that affect short and long term prognosis after submersion were analysed. all patients that were admitted to a tertiary pediatric icu between january i, and january i, were included. of patients, aged - years, died in the icu, one after hospital discharge. survivors and non-survivors showed significant differences with respect to central temperature, pupillary reactions, arterial ph, pediatric risk of mortality (prism) score and therapeutic intervention scoring system (tiss) upon admission (p < . ). non-survivors more frequently required mechanical ventilation, bicarbonate administration and active reheating. ards was seen in patients ( %), invariably within hours after admission. no patients with cardiac arrest on" admission snrvived without sequelae. hypothermia appeared to have no protective effect on hypoxic damage. survivors with persistent sequelae _> months after discharge had significantly higher prism and t ss scores (mean and , respectively) than those with complete recovery (mean and , respectively). long term cognitive problems were present in / survivors ( %) and emotional disturbances in / ( %). in conclusion, a concise number of clinical and laboratory parameters, representing acute severity of illness, are important prognostic indicators for survival and health status of children after submersion. there were ( %) bronchoscopies, and ( %) were oesophagoscopies.the average age was , years for bronchoscopies, and years for oesophagoscopies. the outcome of the patients was good. no complications were observed. extraction is recomended in every symptomatic patient. orphenadrine is an anticholinergic drug mainly used to decrease symptoms of parkinson disease. orphenadrine has a peripheral and central effect and overdose can result in athetoid movements, convulsions, cyanosis, coma, arrhythmias, shock and cardiac arrest. physostigmine is a specific antagonist of the peripheral and central effects and can be a useful antidote. we report the case of a two and a half year old female who was transfered to our icu for general convulsions. the little girl had, three hours before admission, accidently ingested rag of orphenadrinehydrochlodde (disipal®), which was her grandmothers anti-parkinson medication. three hours after ingestion she presented neurological signs: confusion, unstable walking, and periods of aggression. generalized tonic-clonic seizures appeared who were rebel to administration of multiple anti epileptica but ceased after iv administration of diazepam and endotracheal intubation and ventilation. an episode of ventdcular tachycardia responded well to the iv administration of tidocaine. the levels of orphenaddne in the serum were high at admission ( pg/l) and were present in the blood up to hours after ingestion. high serum levels are, in the literature, associated to a high mortality rate. physostigmine was administered three times at a . mg/kg dose in the first hours. we decribe the noted effects of physostigmine on the different symptoms. the patient survived and could leave the icu after one week. in conclusion: orphenadrine poisoning is a very complicated medical problem associated with high mortality. in severe intoxication, the benefit of physostigmine more than counterbalances its side effects. objective: to define the optimal volume of dilution for endotracheal (et) administration of epinephrine (epi) design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine ( . , , and ml of saline) setting large animal research facility ofa universi~ medical center subjects and interventions: epinephrine ( . mg/kg) diluted with four different volumes ( , . . and i rot) of normal saline was injected into the et tube of five anesthehzed dogs. each dog served as its own control and received all four volumes in different sequences at ieast one week apart. arterial blood samples for plasma epinephrine concentration and blood gases.were collected before and . , . . . _ . . , . . , . , . , and minutes after drug administration. heart rate and arterial blood pressure were continuously monitored. measurements and main results: higher volumes of diluent ( and i ml) caused a significant decrease of pao , from :!: tort to ±i torr, compared to the tower volumes of diluent ( and ml), from ± torr tu +_ torr (p< . ). these effects persisted for over minutes. mean plasma epinephrine concentrations significantly increased within seconds following administration for all the volumes of diluent. mean plasma epinephrine concentrations, maximal epinephrine concentration (cmax), and the coefficient of absorption (ka) were higher in the ml and ml groups. the time interval to reach maximal concentration (tmax) was shorter in the ml and ml groups. yet these results were not significantly different. heart rate. systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. conclusions: dilution of endotracheal epinephrine into a ml volume with saline optimizes drug uptake and delivery, without adversely affecting oxygenation and ventilation. the aetiology and outcome of paediatric out-of-hospital cardiac arrest was studied during a -year period in southern finland served by physician staffed emergency care units. the files of prehospital patients less than years old without palpable pulse and spontaneous respiration were analysed retrospectively. fifty patients were declared dead on the scene (dos) and resuscitation (cpr) was initiated in patients. the sudden infant death syndrome was the most common cause of arrest ( %) in the dos patients as well as in patients receiving cpr ( %). asystole was the initial cardiac rhythm in % of the patients in whom cpr was attempted. eight of the hospitalised patients were discharged, of them with mild or no disability, with moderate disability and one in vegetative state. in multivariate analysis the short duration of cpr (< minutes) was the only factor significantly associated with better survival. due to various aetiologies the survival rate from prehospital paediatric cardiac arrest is quite low. on the other hand, hypothermic near-drowning victims seem to have a relatively good prognosis. duration of cpr less than minutes was the best predictor of intact survival, our study supports the previous findings of the importance of early and effective resuscitation efforts for establishing ventilation and perfusion on the scene. in our system well trained physician staffed emergency care units are able to provide immediate and effective als on the scene. on the other hand, these units also appear to be able to refrain from resuscitation when the prognosis is pessimistic. objective: to assess the normal ,gastric intramucosal ph ~hi) by tonometry in healthy children patients and methods: twelve healthy children ( males and females) with age rmaged from months to years scheduled for minor plastic or urologic surgery. children were previously medicated with midazolam ( . mg/kg) and atropine ( . mg~) both i.m.. anaesthetic induction was standardized with -n ( %) administered via facial mask and increased halotane concentrations (up to %). all patients got an endotraeheal tube after iv. administration of femanile ( mcg:jkg) and vecuronium ( . mg/kg) or suxametonio ( mg/kg), pmaesthesia was maintained with o -n ( - %) and isofluorane ( . - %). during surgery, children needed mechanical ventilation and the others maintained spontaneous breathing. ekg, heart rate, blood pressure, and pulse oximetry were moniterized. after anaesthesia, a sigmoid tenometry catheter (tonometrics, inc.) was inserted in the stomach of the patients by direct visualization with laryngoscope and magyll clamps. children were all maintained normoventilated and with normal cardiorespiratery variables. cadet's balloon was £~led with . ml of saline. thirty minutes after the insertion rrd was extracted and rejected, just afterwards the remanent . ml was extracted and immediately analyzed. simultaneously an arterial gasometry by puncture was performed. gastric phi was calculated by the henderson-hasselbalch's equation using the pco obtained from the tenometry catheter and the bicarbonate value obtained from the arterial gasometry. results: average gastric phi was . -i- . , range ( . - . ). objective: demons~ating intramucesai ph (phi) alterations during transport of patients from operative room to pediatric intensive care unit (picu), material and methods: phi measurements were performed with gastric tonometer catheter in t patients undergoing cardiac surgery with cardiopulmona d" bypass (cpb), there was mate and female, the average age = yl ra, average weight = , kg, average time of cpb = rain. the measurements were made at the end of the surged' and when the patients had arrived in the picu statistical aualysis: average and ~andart deviation and test "t" student. objetive: to asses the efficacy of gastric iatramucosad ptt (phi) and arterial lactate levels to evaluate splacalc tissular perfusion in an experimental model of intestinal ischemia. suneets ~nd methods: twelve piglets weights t - kgs. undergoing orthot~ie liver trasplantation. the intestinal ischemia was induced by aortic damping. tonometry catheter (tonometrics inc.) w~s placed in the stomach after artaesthesia and ot intubation. phi ~s determined times and lactate levels was determined fi times in stages: i) pre-ae~hepatic stage (twice: before surgery and before aortic clamping ); ii) end anhepatic stage (only phi): iii) reperfusion stage (a , , and minutes). the phi was derived from application of the henderson-hassdbach formula using the pco value from the tonometer and the arterial bic~rbonate. all pipets received raaitidiila before sttrgery. values of phi above , and lactate levels between and mg/dl were considered nortrm. the results were statistically anaj.izated with anova and bonferroni tests. results: the phi was normal on pre anhepatic stage (> , ) and lactate levels were slightly increased ( , +_ , and , ± , mg/dl ns) . in relalion to we-anhepatics values, phi decreased signncatly at the mid of anhevatic stage ( , _+ , vs , _+ , p< , ), phi remain low in stage iii, at rain ( , + , p< , ) and min(g -+o, p< , ). arterial lactate levels increased significatly in relation to levels in stage i, at rain ( , _+ , p< ,o ) arid rain ( , ± , p< , ) of reperfusion stage. there is a slight improvement on phi and lactate ievels at and t rain althought the differences did not reach significance. cnmments: phi and arterial lactate levels propperly reflect hypoperfusion on the experimental model of acute intestinal isdlemia. b~kground : the paediatrie gallbladder diseases generally described are calculous ¢hol~tstitis, cystic duct obstruction, congenital anomaly of the biliary tract, and inflammation. in the neonatal period, noulithogenie gallbladder disease could be also due to erythroblastosis or hyperalimentation. obieetive : we describe an other type of disease affecting the gallbladder in neonates thought to be related to their vascular vulnerability. methods : four patients with abnormal gallbladder ultrasound not related to classical observations were included. we have studied and reviewed the biological and clinical data, the ultrasound findings and their evolutions. results : four patients, to ~.k-old neonates ~ffth a birthweight be~,een , and , kg, were intubated and under total parenteral nutrition for to days. none of them were symptomatic on repeated clinical evaluations. one newborn developped hypotensien on umbilical bleeding at hours of life. in two cases, signs of cholestasis were discovered : the total bilirubin level has risen to mg/dl; the direct bilirubin level was , mg/dl while the urina were dark and the ~o~,ls :mcolour~. the c~mplct~ ~crology as a!! the culvare~ remained negative. the ultrasound explorations were atypical : in the four eases, an initial increasing broad and thickness of the wall of the gallbladder with an hyperecbogenie inside content, which was not sludge, was discovered. in three eases the images resolved in ten to fifteen days. in one ease, an asymptomatie thrombosis of the vena portu which remained patent was discovered. in this case, at one month, the ultrasound showed images encountered in chronic ebolecystitis and, at one year, the gallbladder appeared atrophic. none of them underwent surgery. conelusiou : the gallbladder diseases are multifactorial. besides the prematurity, the infections, the total parenteral nutrition, the premature neonate is exposed to vascular vulnerability affecting also the gallbladder and this may explain our findings. progress in prognosis of pts with b-nhl had followed the use of multimodality chemotherapy (ct). with the prolonged survival, there are comlications due to myetosupression & desease process. the syndrome of neutropenic enterocolitis (ne) is one of the ominous problems because ofpts increased susceptibility to infection & overwhelming sepsis. this material included neutropenic pts ( - years) with the stages iil& iv of b-nhl who were treated with the modifired bfm- (mtx g/m in -h inf.); males, females. seventeen episodes of ne were observed & only after the first courses of ct ( of after tst, %; of after nd, %). the symptoms existed to days. wbc ranged from to in l~tl (median, ). the first signs of ne were directly correlated to the beginning of the neutropenia & the recovery of neutrophils led to the disappearance of abdominal recovery of neutrophils led to the disappearance of abdominal pain. the conservative treatment included gastrointestinal tract decompression, broad spectrum antibiotics initially, volume & electrolyte substitution, nutritional support, correction of acid-base balance, symptomatic treatment. sixteen pts were treated nonoperatively, died. on autopsy the transmural bowel necrosis due to thrombosis of branches of a.mes.sup, was found. the bowel perforation occurred in one patient, he was undergone laparotomy & hemicolonectomy & survived. we conclude that ne is a frequent complication in neutropenic pts with the st. lii& iv of b-nhl. it occurs after the induction courses of ct. close observation by surgeons, oncologists & pediatric intensivists is mandatory. conservative treatment is effective & more preferable until leucopenia resolves. operation is necessary only for those.with perforation. near infrared spectroscopy as a tool for evaluation of intestinal perfusionpresentation of an animal model. c. scheibenpflug, p. buxbaum and a.m. rokitansky the recent development of and investigations in the so called near infrared spectroscopy ( nirs --transcutanous emission and simultaneous registration of intensity of spectralcolours depending upon modulations of tissue perfusion ) enable physicians to measure and qualify organ perfusion and nowadays is mainly used to control cerebral as well as skeleton muscular blood flow in trauma patients at intensive care units ( icu ). today intestinal perfusion, hypoperfusion , cell damage caused by reperfusion injury, bacterial and toxin translocation are serious problems in critically ill patients at an icu. paediatric intensive care physicians put major concern on intestinal perfusion, which for. instance gains more and more importance, especially in the neonatal period for example as an etiologic factor for necrotizing enterocolitis. we established an animal model, in which we measured intestinal perfusion by nirs under various invasive and noninvasive conditions. methods and results will be referred. for preliminary conclusion we propose near infrared spectroscopy ( nirs ) also as a potent diagnostic tool to determine early intestinal malperfusion in order to prevent lethal outcome. fm'ther investigations in animals as well in paediatric iritensive care patients should be done to estimate our efforts. introduction: following the acute phase of necrotising enterocolitis (nec) starvation of the gut for a period up to weeks is a generally accepted treatment modality in many centres. objective criteria to refeed these patients are hardly available. recently the double sugar test has become available as a parameter for (ab)normal gut permeability ~' . aim of the study: to evaluate the changes in permeability of the small bowel in patients with nec and controls before introduction of enteral feeding. methods: a lactulose! rbarrmose (i/r) test was performed in two groups. group was studied - times within a -week period of starvation (n= , mean gest. age , range - weeks). in group seven different control patients were studied (mean gest.age , range - weeks). the test was performed by giving a patient after at least a hour fast ml/kg bodyweight l/r solution and determination of the /r ratio in a -hour urine sample by chromatography. results: objective: to evaluate the prognostic factors in the response to nitric oxide (no) in children with acute respirator/ distress syndrome (ards) and/or pulmonary hypertension (pht). patients and methods: critically ill children received no inhaled for ands and/or pht treatment. patient before and after cardiac surgery ( cardiac transplants), with bronchopneu~onia, multiple trauma, sepsis and cardiorespiratory arrest. patients showed /j~ds and pht, in with associated ards. we analyzed age, sex, diagnosis, pao , pa /fi , oxygenation index, pht, shock, and sepsis as prognostic factors and response factors to n . results : after no administration oxygenation did not improve in patients ( . %) and pht did not diminishe in one children ( %). patients survived ( %), / ( . % with /d%ds) and / ( %) with pht. the four patients with isolated pht survived , and the patients with pht and ards dead. patients after cardiac surgery presented less mortality ( . %) than the rest of patients ( . %). patients with shock presented higher mortality ( . %) than the rest of patients ( . %). there are no differences in response to no in respect of sex, age, diagnosis, shock, and sepsis. survivors showed higher increase of pao /fi . ± . to no than non-survivors . ± . (n.s). patients with pht showed higher increase in pa /fi to no administration ( ± . ) than patients with ards ( . ± . ), (n.s), but patients with ards showed a higher increase in !, ± . , than patients with pht . ± (p < . ). patients with pa /fi < i showed less increase in pa /fi , . ± . , than the rest of patients . ± . (n.s) conclusions: i. mortality of isolated pht treated with no is less than patients with ap~s. patients with shock and those with pht and ards showed higher mortality. . we have not found any clinical or analytical factor to predict clinical response to no administration. patients showed ards, and severe pht after cardiovascular surgery, in with associated ards. we registered respiratory assistance, blood gases, pao /fi , the oxygenation index (oil, and mean pulmonary pressure/ mean systemic pressure (pap/sap) before and after no inhalation. we measured continuous concentration of no and no by electrochemical method (noxbox, bedfont, airliquide). results: no administration improved oxygenation mean pao from ± tm~g to i ± ~g (p < . ), mean pa /fi fr<xa ~ to £± (p < . )and i from ± to ± (p < . ). patients did not improved with no administration. the oxygenation improved in the first five minutes and the best oxygenation was achieved with - ppm. there is no significant change in pac . pap/sap diminished from ± % to ± % ( p< . ), in one patient there is no response. the no administration was maintained between ~ minutes to days. the effect of no on pulmonary pressure and oxygenation was maintained without change during all the time it was administrated. n concentration were always less than ppm y metahemoglobinaemia less than . %. there are no side effects secondary to no administration. patients survived ( %). concluaions:l.administration of no improves oxygenation in children with ~/eds and diminishes pht after cardiac surgery. .no effect is fast and maintained during the evolution. high frequency oscillatory ventilation in combination with inhaled nitric oxide g~thberg sylvia, md, edberg k e md, phi), dept of paediatric intensive care, children's hospital, s- g teborg, sweden background: for man), years severely sick infants with congenital heart malformations or acute lung disorders have died due to pulmonary hypertension, hypoxia and multiple organ failure. today there are several therapeutic facilities coming up for these infants. ecmo progranunes have been introduced in severul centres as well as improved venlllatory techniques, as high frequency oscillatory ventilatior~ (hfov), which provides adequate ventilation with less risk for hmg injury.. in , the endothelium derived relaxing factor was identified as nitric oxide (no), and extensive studies have sho~-a that inhaled no reduces pnimonm o vascular resistance and improves oxygenation in hypoxic infants with pulmona~ hypertension. material.. from july to january , we have treated severely hypoxic children with combined ttfov-no. seven were newborn, with cdh, one with mas, one with irds, one with paediatric ards due to rsv infection and one with poor oxygenation atler open heart surgery. were between month and years and all had ards of differentorigin but one who was hypoxic after open heart surgery. method: hfov was given by means of sensormedics a oscillatory ventilator to patients, and dr~ger babylog was used in one case. mean airway pwssures varied from - cm h . oscillatory pressures varied from - cm h and ventilatory rates from - hz. fi o varied from , - , . no was administered by nomius classic. no and no was measured in the inspiratory limb with an electrcchemieal device. noconcentration varied from to ppm and the no -concentration between - , ppm. methemoglobin was never more than , % (average , ). duration of treatment varied from to days. combined trealment with hfov and inhaled no improved oxygenation and carbon dioxide elimination in out of treated childretl patients died, due to their underlying congenital heart disease, one of asphyxia due to rsv-infection and one of cdh with progressive hypoxia and multiple organ failure. combined treatment with hfov and inhaled no improves oxygenation in severely hypoxic children. treatment should be slarted early to reduce the risk for chronic lung injury following barotranma and high oxygen concentrations. we speculate that the combined hfov-no may reduce the use of ecmo, and that it may improve outcome in ceotres where ecmo programmes are not introduced. apart from its vasodilative properties nitric oxide appears to act also in physiologic immune defense. intracetlular concentrations of no synthesized by macrophages are in the range of above those produced by vascular endothelium. we investigated the bacteriostatic effect of nitric oxide at concentrations used during inhaled therapy for pulmonary vasodilation in neonates. ten different strains of five species were used (staph. anrens, staph. epidermidis, strop. group b [gbs], e. coil and pseudomenas aeruginosa), which are ~e most often tracheally isolated bacteria in mechanically ventilated premature infants and neonates. we compared bacterial growth of cultures applying three different concentrations of nitric oxide ( ppm. ppm, ppm) m the growth of the same strains in room air for a duration of hours. no bacteriostatic effect was demonstrable at no concentratioes of ppm. e. coil showed decreased bacterial growth at ppm and ppm, however without reaching statistical significance (p= . ). at nitric oxide concentrations of i ppm staph. epidermidis and gbs grew significantly less as compared to colonies of the same strains in room air. no effects were found regarding the growth of staph. aureus and pseudomonas aneruginosa. we conclude that nitric oxide has a selective bacteriostatic effect on some of the most often trachealb, isolated bacteria in premature infants and neonates. this effect appears to be dose-dependant and occurs in the upper range of dosages used with inhaled no therapy. further research is required in order to examine the mechanisms of action as well as specific interactions between different strains of bacteria and nitric oxide. the no,box monitor (bedfont, kent, uk) is used to monitor nitric oxide (no) and nitdc dioxide (no ) during no administration in ventilated neonates. according to the manufacturers specifications the monitor can be applied in cases where airway pressures range from to mbar. we investigated in-vitro the accuracy of the no monitor in a range of ventilatory conditions. using a dr~ger babylog we ventilated an artificial lung. no was administered { ppm no in % nitrogen) with a mass flow controller to the inspiratory tube, at a distance of cm from the y-piece. the no target value was set to ppm. the ventilator was operated in both cpap and ippv modes at different settings. the no sampling tube was placed on two different locations; in the inspiratory tube dose to the y-piece; in the expiratory tube haft way between the y-piece and the ventilator. the no-monitor was ca)ibrated with ppm no at mbar. fig. and show the sensitivity of the no-monitor for respectively static pressure (cpap) and pulsatile pressure (ippv) with the sampling tube located in the inspiratory tube. fig. shows the resur for pulsatile pressure with sampling in the expiratory tube. we conclude that the accuracy of the bedfont no-monitor is dependent upon airway pressure and sampling site, the latter possibly caused by incomplete mixing, pressure and no are linearly related when sampling occured further away from the administration site. based on this study we suggest to place the sampling tube in the expiratory tube. during neonatal care the clinician should be aware of varying inaccuracies depending on the respiratory pressures. hypothesis: availability of therapy with inhaled nitric oxide (ino) decreases ecmo use in patients referred .to a tertiary care hospital for treatment of respiratory, failure unresponsive to conventional therapies. background: at children's hospital of wisconsin (chw) treatment for patients who have failed conventional treatment for respiratory failure, sometimes called "rescue" therapy, has included ecmo since and high frequency oscillatory ventilation since . ino has been in experimental use at chw since may of i and has resulted in the perception of a decreased need for ecmo therapy in those patients referred for rescue therapy. this study was designed to tbst the validity of that perception. study type: retrospective cohort. methods: the medical records of all patients referred to chw from /lj to / / for rescue therapy for severe respiratory failure were included in the chart review. data were collected regarding diagnoses, illness severity, hospital course including interventions and complications, and outcomes. exclusion criteria w~ere the finding of structural heart disease or congenital diaphragmatic hernia as the basis for hypoxemia. qualification for ino treatment included an a-ado - or oi ~- for two hours or -> for twelve hours and echocardiographic demonstration of persistent pulmonary hypertension of the newborn. patients were classified into two groups based on the availability of ino at the time of their hospitalization. results: in the time period of the study, patients were referred for possible ecmo therapy. twelve patients greater than weeks old, with congenital diaphragmatic hernia and with congenital heart disease were excluded from this analysis, leaving patients for study, ino availability reduced ecmo use from of ( %) patients in the ~ino unavailable" group to out of ( . %) patients in the "ino available" group, p=& by fisher's exact test. the fact that the two groups were composed of patients of similar severity of illness is reflected by comparable rates of ecmo and ino rescue therapy ( % vs. %). conclusion: by providing an alternative rescue therapy, ino has reduced the need for ecmo in this group of neonates referred for respiratory failure. introduction: true hepatnrenal syndrome (his) is defined an acute renal failure {arf) in the presence of severe liver disease without other known causes of renal failure. hrs is frequently seen in the course of hepatic cirrhosis• in children, cirrhosis is rare; however, arf can be seen in combination with aseites and liver dysfunction• we describe patients with hepatic dysfunction and aseites in combination with ar~ and abnormal sodium-water handling, leading to the diagnosis of hrs. pathophysiology: three factors are considered in the pathogenesis of hr~: i) hepatic dysfunction, ) deranged hemodynamics, including abnormal blood pressure, reduced effective arterial blood volume and abnormal blood flew distribution, and ) neuro-humoral dysrsgulatiom, including elevated levels of aldosteron, renin, angiotensin-ll, ade, vasodilatim nitric oxide and vasoconstrictor peptide endothelin-l. the main pathogenetic feature is decreased cortical renal blood flow, decrease of glomerulur filtration rate (gfr), vastly increased sodium retention, uliguria, and azotemia. treatment: therapy is based on counteracting sodium and fluid retention by highdose aldosteron antagonists and loop diuretics, improving renal perfusion by lowdose dopamin, and strict restriction of fluid and sodium. interventions as paracenteals of aacites or n peritoneo-systemic shunt are associated with high morbidity and poor outcome in children. reversal of hem by conservative measures can only be attained at early stages of hrl liver transplantation is the only definitive treatment that can reverse ere at advanced stages. patients: the described patients developed severe ascites with insidious renal dysfunction and abnormal sodium-water handling during admission at picu and fullfilled clinical criteria fur hrs. treated according to the cited principles, all patients showed improvement of gfr, with increased natriuresis and gradual decrease of ascites. eventually, renal function normalised completly. conclusion: ere deserves greater recogmitimn in the picu population; diagnosis can be suspected on clinical criteria. with this increased awareness, therapy tun be instituted at an early phase, with better prospects for recovery. positive outcome of hem depends on early recognition of the clinical picture, understanding of the pathophysiology, and early institution of consistent treatment. mtx is an antimetatxflite widely used as chemotherapeutic agents. high dose ivitx (i to ~m ) administered as a prolonged intravenous infusion (over - hours), is often used to treat malignant paediatric diseases. major complications of this treatment are myelosuppression, orointestinal mucositis, dermatitis and impairment of anal function. we report two cases of mtx overd~age occurred in two children ( -year-old. month-old) t~ted for acute lymphoblastic leukaemia. they were treated by cavh and the mtx bhk~d levels rapidly decreasedavoiding multisystemic involvement. establishment of alkaline diuresis and monitoring of plasma mtx levels during treatment is essential to prevent nephrotoxicity. however. leuco',cnn rescue may not prevent the development of potentially lethal toxicities in patients with mtx concentrations persistantl} exceeding t mm. in theses cases, em'ly treatment of mtx intoxication may pm~cnt myelosuppression and reducerenal damage. the goal is to lower the concentration to below mmoll, at which time rescue agents aleme would be expected to be cllcctive. respective indications of these remo',at mctny.:is are still discussed : hacmt~ialysis t~ eharc(~l haemoperfusion should be prolx',sed for massive and acute intoxication. however, rebound has been reported after combined hcmodialysis and hemoperfusion. exchange transfusion may be proposed as a treatment for prolonged and moderate intoxication. peritoneal dialysis is an incflbedve method for remo~ al of mtx. cavh was used in our icu. cavh is a simple method for blood purification and n':dy iluid control. use of cavh was never be reported in this indication to our knowledge. simplicity, rap~d application and gco.l clinical tolerance are the main advantages of this technique. the technique presents ~peclal advantages in terms of low priming volume of extracorporeal circuit, low blood flow, low rate heparinisation. our results show a decreaseof plasma mtx concentration and a rapid reduction of halfqite of elimination (t hours over the period of cavh). moreover, we didn't delec~d rebound after stopping prc,xedure. small size of the i:ratients may present sometime special problems, but these technical problems can be overcome, no severe complication (needing, inlection) were observed during filtration, in summary, aggressive intravenous fluid hydration and alkaliniaation of the urine coupled with careful monitoring of renal function and plasma mtx concentrations during and al'tcr infusion along with lem~overin rescue has reduced the inndcace of life-threatening toxicity after highdose mtx. however, some mtx inu>xication still occurred, leading to se~em toxicity, particularly nephrotoxicity. in these cases, we think that cavh (or cavhd) is a reliable, rapid method without rcix~und increase in plasma mtx concentration or important adverses effects compared to other procedure removal. gouyon jb, germain jf, semama d, pr vot a, desgres j preliminary limited data suggested that hemofiltration and hemodiafiltration may be valuable in some neonates with decompensation of maple syrup urine disease (msud). venovenous hemofiltration (vvhf) and hemodiafiltration (vvhdf) were performed with a new neonatal hemo(dia)filter (miniflow , hospal) on anesthetized rabbits infused with branched-chain amino acids (leucine, isoleucine and valine) and c~-keto-isocaproate. the bcaa and aketo-isocaproate blood levels were close to those previously observed in neonates with msud when extracorporeal blood purification was required. vvhf and vvhdf performances were assessed with two different blood flows (qb = . and . ml/min). vvhdf was performed with dialysate flow rates (qd = , , . , . and . l/h). thus, each animal was submitted to successive procedures. within each studied period, clearances of the bcaa were strictly similar. bcaa clearances obtained by vvhf were similar to ultrafiltrate rates (respectively, . - . and . - . ml/min at high and low qb ; p < . ). the ~x-keto-isocaproate clearances obtained by vvhf were . - . and . - . ml/min at low and high qb (not significantly different). whatever qd value, the vvhdf procedures always allowed higher bcaa and c~-keto-isocaproate clearances as compared with the corresponding v'~hf period with similar qb. bcaa clearances obtained by vvhdf with a . l/h dialysate flow, were . - . mljmin and . - . ml/min at iow and high qb, respectively. the concurrent a-keto-isocaproate clearances were . -,. , ml/min and . _+ , ml/min. at both qb regimens, bcaa clearances provided by vvhdf were markedly higher than values previously obtained with peritoneal dialysis in human neonates with msud. the management of renal failure in the newborn is difficult. when dialysis is instituted peritoneal dialysis (pd) is usually the technique of choice. this is can be problematic and impossible in some patients with pre-existing intra-abdominal pathology. continuous arterio-venous haemofiltration (cavh) has been described in infants but sick preterm infants are not able to support the circuit. i have devised a means of having pumped haemofiltration in small/preterm infants (phis/pi) and describe its use in nine patients ranging in size from to gms for periods of to days. vascular access was achieved through or guage cannulae in either a peripheral artery and a central vein or through two central veins. blood was pumped out using an ivac infusion pump and through a gambro fh haemofilter. a second ivac pump was used to remove haemofiltrate from the filter and a third to infuse replacement solution. removal rate was set to give a clearance of mls/min/ . sq.m and blood flow rate set to between and times the removal rate. heparin was infused into the circuit to prevent clotting of the filter. biochemical and fluid balance control was achieved in all infants. guaranteed fluid removal allowed the administration of full nutritional support. four patients died when treatment was withdrawn because of an untreatable underlying problem. one recovered renal function but died some weeks later from unrelated problems, three survived and recovered renal function and one patient is still on treatment. this system allows a secure means of achieving fluid and electrolyte control in the preterm infant. the use of this technique may allow haemofiltration to become as applicable to preterm infants as it is to older children and adults. unibrtunately, children often receive no treatment, or inadequate treatment for pain and painful procedures. this prospective, multicentric study focuses on the efficacy, safety and side effects of novalgin (metamizol sodium) for this indication. patients and method: novalgin was administered to children, aged between - years, with acute, postoperative or procedural pain. novalgin ( - mg/kg) was given - hourly iv or im respectively, in some cases ( ) in combination with opioids (tramadol , piritramid , butorphanol ). the pain relief was assessed by six-step verbal rating scale (vrs) from to , vital signs were monitored, the side effects, that occured were recorded. results: pain relief was good (vrs less ) in children - . % of study patients. novalgin was very well tolerated, only one patient had adverse reaction -hyperpyrexia following intravenous application of the drug. discussion: novalgin (metamizol sodium) is safe and effective drug in the management of acute pain in children with low incidence of side effects. obie~qve: a prostx~tive study comparing simultaneous, indepeadent ratings conducted by intensi~ sts using an american (comfort) and an european chartwig) sedation scale for mechanically ventilated pediatric patients. measurements and results: the study comprised observations in mechanically ventilated pediatric patients (aged days to years) in a pediatric intensive care unit (from march to january . each patient was sedated by his/her managing physician with opiates, benzodiazepines, barbiturates, used isolated or in combination. each observation consisted of a -mid period of oly~ervatien of the patient in his or her pediatric icu bed, after each observation, the comfort (analyses dimensional physiologic and behavioral subscores -range to paints) and hartwig (analyses dimensional behavioral subsenres -range to points) were performed by the intensivist. we established the comfort scores ~ correspanding to adequate (range to ), excessive (range to ), and inadequate (range to ) sedation; and, hartwlg scores z correslxmding to adequate (range to t ), excessive (range to , and inadequate (range to ). statistical mmlysisj: agreement rate (kappa) and p <. was considere d s!l~nificant. comfort ( . %) ( , %/ ( . %) hap, twig , ( . %) ( . %) ( . %) to the comfort score, the average for adequately sedated, inadequately sedated, and too sedated was . +- . , z _+ . , and a.+_l , respectively. and to the ha~twig scorn, the average for adequately sedated, inadequately sedated, and too sedated was . :k-' . , . -&l , and . l- . , respectively. conclnsion: in our study there were no significantly statistical difference when you apply a more complex scale (conff'ort) or a less complex scale (hartwig) to assess the sedation of mechanically vemilated pediatric patients. the application of local and intravenous morphine infusion after surgery of urinary tract eva nemeth , m.d. semmelweis medical university , first oepartment of paediatrics , budapest , hungary in±roduction:continuous analgesia with morphine may be ~egaroed as a safe and effective method of pain relief during postoperative period. subjects and methods: children /mean age . years/ underwent elective ureteroneoimplanta±ion were randomly selected to receive either morphin intravenously of lo ug/kg/h /group one/ or bladder morphineinfusion ug/kg/h /group two/ after surgery. all patients were prospectively evaluated during their s±ay in the postanaesthetic care unit. cardiac and respirafory rates,blood pressure,sa ~,degree of alertness,pain perception and complaints of the paticnto ~cr~ recorded hourly. pruritus,nausea and vomiting,voiding difficul-±ies,sedation,dysphoria were systematically sough and quoted. statistical analysis was performed by chi square test. results:postoperative analgesia was the same in the two groups,but side effects were less in the bladder morphine group,because of the lower se morphine concentration.the differentes weren't significant in two groups. conclusions:the administration of bladder morphine infusion is a safe and effective method in children. objetive: compare the evaluations of sedation level made by physicians and nurses with the visual analog scale (vas) and the comfort scale (cs) in pediatrics patients receiving difforents modes of intravenous sedation. material ~ method." file evaluations were made by an attending physician and nurse with the vas and by another physician (always the same) using the cs. the observations were divided following the sedation mode: one drug (fentanyl or midazolan), two continuous drugs, one continuous and one intermi~ent drug and two intermittent drug (fentanyl and midazolan). the groups were compared using the t-student test. the groups also were compared between the percentual of agreement of the evaluations of sedation level made by physicians and nurses with the cs and vas using the x . results: we didnk find any statistical difference between the observations made by physicians and nurses with the vas in the differmts modes of intravenous sedation, the average of the observations using the cs betwom one drug and two drugs modes didnk exhibit also statistical difference. the observations made by physicians mad nurses using the the vas when compared with the cs didn't show statistical difference between the sedation level. we found statistical difference only in percentual of concordance of sedation level between physicians and nurses when compared the one and two drugs modes of sedation. conclusion: we didn't find differences in the observations made by physicians and nurses in the sedation level, only in concordance pereentua/ of observations when compared two modes of sedation. the observations using the cs (more complex) didnk show differences when compared with the vas. effects of age, concurrent administration of other pharmacologic agents, and disease [cardiac(n= ) & pulmonary(n= )] on the pk & pd of b were evaluated in volume overloaded infants aged days- mo (n= ). single doses of . , . , . , . , . , , , . , . & . mg/kg iv were given over - min after baseline evaluation. age was used as a continuous vadable to determine its effects on the variability in the pk & pd of b. values for pk parameters were compared between patients in cardiac and pulmonary disease groups. hierarchical multiple regression analyses were used to determine the effects of age, disease and other pharmacologic agents on the variability of bumetanide excretion rate (ber) and pd responses, e.g. urine flow rate (ufr) & electrolyte excretion. cit, cir & cinr increased with age (p< . ) while t, decreased markedly in the first monthe of life (p< . ). ber normalized for dose increased with increasing age. patients with pulmonary disease exhibited significantly greater clearance and shorter t~= (p< . ) than those with cardiac disease whereas vd~ was similar in both groups. the administered dose of b was the primary determinant of ber but increasing age also contributed. penicillin antibiotics decreased ber. dose response curves for ufr and electrolyte excretion were similar between disease groups. more of the variability in ber and pd responses could be accounted for in the pulmonary group than the cardiac group but this was not statistically significant. conclusion: the pk of bumetanide were influenced significantly by age and disease. differences in pk between patients with pulmonary and cardiac disease were primarily due to differences in total clearance. age and the administered dose of b were positive determinants of ber and pd responses while penicillin antibiotics had a negative impact on both, once b reached its site of action, no differences in pd responses were detected between disease groups. the pharmacodynamic effects of bumetanide were evaluated in volume overloaded infants (n= ) aged days- months. single doses of . , . , . , . , , , . , . , . & . mg/kg iv were given over - rain. bumetanide concentration in blood (n=l ) & urine (n= ) samples were quantified by hplc. baseline urine samples were collected over - hours prior to drug administration. determinations of urine volume, electrolytes (na ", k +, ci, ca ++ and mg++), creatinine and osmolality were performed before and at - , - , - , - , - and - hours after bumetanide dosing. changes in urine flow rate and electrolyte excretion were plotted as a function of bumetanide excretion rate which was considered the effective dose of the drug. peak bumetanide excretion rate increased linearly with increasing doses of drug and showed no evidence of approaching a maximum. time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. urine flow rate and electrolyte excretion increased lineady up to a bumetanide excretion rate of approximately #g/kg/hr and either plateaued (urine flow rate) or declined at bumetanide excretion rates > #g/kg/hr. bumetanide had no detectable effect on serum electrolyte concentrations, conclusion: maximal diuretic responses occurred at a bumetanide excretion rate of about ;~g/kg/hr. higher bumetanide excretion rates produced no increased diuretic effect. peak bumetanide excretion rate of about #g/kg/hr corresponded to bumetanide doses of . - . mg/kg. neonates using an electrical syringe-pump. authors: tr~luyer j.m., sertin a., bastard v., settegrana, c., bourget p., hubert p. background and objective: many problems can be observed with drug administration by i.v. route, especially in neonates. so we evaluate different protocols of teico delivery using an electrical syringe-pump. methods: we simulate infusion of teico with a syrlnge-pump (pilot c, becton & dickinson lab.) trough d standart neonatal i.v. system. for weights ( or kg) we used doses of teico ( mg and mg/kg) and a dose volume _< . ml. our goal was to perform a complete infusion in minutes. the infusion system consisted of an life care infusion pump (abbott lab.) with its lv. set for maintenance intravenous fluid (flow _< ml/h) connected to a -way stopcock. an meter extension tubing was placed between the stopcock and a neonatal catheter. an another meter tubing (injection tubing) connected the teicoplanine syringe to the stopc, ock. the volume of the injection circuit (from the syringe to the distal part of the catheter was . ml methods of injections were assessed: a: injection of the predetermined volume of teico in minutes with no wash out. b: idem as a but the teico was injected in minutes, followed by a wash out ( ml / minutes). c: twice the required volume was introduced in the syringe and the volume to infuse was programed in minutes, followed by a wash out ( ml/ minutes). d: ]dem as c but a priming was performed before connecting theteico syringe to the tubing. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at minutes were calculated. the results are a mean of to runs and expressed as the percentage of the total amount of teico prescribed. a , % , % b % , % c a % , % d , % % conclusiom for accurate and reliable intermittent drug infusion with a syringe pump it is mandatory to use a precise protocol of administration and to take in account ) a priming (for immediate starting of infusion), ) a drug volume greater than the dose prescribed and a programmed volume injected, ) a wash out of the tubing (with a volume ~ , x volume of tubing injection) caz is an antibiotic with activity against the major pathogens responsible for neonatal bacterial infections. we previously reported the pharmacokinetics of caz in preterm infants on day of life which showed that the clearance of caz increased with increasing gestationat age (ga). mean serum half-life of infants with gas < wks was . h. we wanted to investigate the effect of postnatal age on caz pharmacokinetics, we therefore studied caz pharmacokinetics on day - of life in preterm infants with gas < wks. caz ( mg/kg) was administered as an intravenous bolus injection. blood samples were coilected before (t = ), and . , , , , and h after the caz dose and analyzed by hplcassay, the pharmacokinetics of caz followed a one-compartment open model. during newborns with complex congenital heart defects requiering either htx or palliative staged single ventricle repair were admitted to our hospital: hlh n= , unbalanced cavsd, tga with hypopl. rv and hypoplastic aoa. tga with hypopl. rv, sas and dextrocardia. /i children had been admitted with cardiogenic shuck and mukiorgan failure due to intermittend closure ofductus arteriosus; in / stabilization failed. parents were informed about the known and unknown risks of the always palliative surgery; in cases parents denied further therapy. one pafiem with hlh underwent orthotopic htx at the age of month after the ducms art. had been stunted in the newborn period. month later he is still in favourable condition and without any sign of acute organ rejection. / underwent first stage of palliative single ventricle repair: norwood -op. ( ) ( n= ), damus-kaye-stansel -procedure ( ). the clue to adequate postoperative management was to archieve a balanced distribution of flow to systemic and pulm circulation, that is to protect the single ventricle from volume overload and to guarantee sufficient oxygenation and pulmonary development as well. with the centralvenous sato at about % provided maintaining the arterial sato at about _+ % is corresponding with a qp/qs of : . using modified bt-shunts of . mm resp. a central anrtopulm, shunt of mm in one case l severe puim. hypertension, surgery at weeks of age ) there was no excessive pulm. blood flow and no need to increase pvr with inspired co . one child ( norwood at weeks, preexisting pnim_ edema ) developed severe pulur hypertension and parenchymal pulm. dysfunction after prolonged bypass and multiple transfusions due to intraoperative bleeding: hypoxemia could be managed successfully by implanting a second shunt of mm hh later and temporarily using prostacyclin and no; at sternum closure dd later the second shtmt was banded to ram. follow-up ranges - month: all children are at home being assigned for second stage operation at about month of age. establishing clinical practice guidelines has become increasingly important in the current health care environment. significant effort has been focused upon development of post-operetive critical care pathways. however, benchmark data upon which such pathways should be based has not been well reported. length of mechanical ventilation (lmv) and length of stay (los) for children following cardiac surgery, for example, is poorly described. we prospectively recorded the lmv and los in patients who underwent cardiothoracic surgery between / / to / / . only patients who belonged in any one of five categories of congenital heart disease (ventricular septal defect _+ other septal defects (vsd), atrioventricular (av) canal, tetralogy of fallot (tof), transposition of great arteries (tga), and single ventricle physiology (fontan)) were included. eight non-survivors were excluded from the analysis. all patients were admitted to an intensive care unit cu) post-operatively where mechanical ventilation was managed by pediatric intensivists. lmv was defined as the period from post-operative admission to planned extubation. length of stay (los) was defined to be from le from the icu. cytokine patterns during and after cardiac surgery in young children. especially in children, cardiac surgery with cardiopulmonary bypass (cpb) can cause a systemic inflammatory response. this process is thought to be mainly a result of inflammation induced by surgery and exposure of blood to an artificial surface, and of reperfusion injury during weaning of bypass. complement activation, degranulation of granulocytes, induction of free oxygen radicals, endotoxemia and release of cytokines, are important contributing factors. we studied cytokine patterns before, during and after cpb in young children admitted for complex surgery or for septal defect correction. in the first group, significant amounts of il- and il-lra could be detected preoperatively. these findings could reflect the already existing hemodynamic dysregutation. in both groups, cpb procedure upregulated the circulating pro-inflammatory cytokines il- / , but not il- b. at the same time, il-lra became detectable. therefore, we suggest that in these patients the production of the anti-inflammatory cytokine il-ira was not induced by the preceding acnvity ot pro-inflammatory cytoidnes. during cpb, we noticed a sharp decline in the capacity of the leucocytes to secrete il- / . the ex-vivo production of il-lra however, was only slightly attenuated. we conclude that there is a differential regulatory pathway for the induction of il- / and il-lra. in addition, we studied the influence of dexamethasone administration on the cytokine pattern. administration delayed the appearance of il- / and il-ira in the plasma, interestingly, it did only interfere with the ex-vivo production of pro-inflammatory cytokines. the latter supports our hypothesis that production of il- / and of il-lra is regulated by two independent pathways, ( %) of pts. % ofpts < months of age developed metabolic alkalosis as compared with % ofpts > months of age.the infants with metabolic alkalosis received more citrated blood products and furosemide. following cardiac pulmonary bypass the highest ph-values and be-values were observed - hours and - hours, respectively. ii. prospective study: metabolic alkalosis was registerd in t children ( %), of those < month ( %) developed metabolic alkalosis and % of those elder than monms.durmg the postoperative course patients younger than months developed the highest ph-and base excess values after and t hours, in the subset of the older patients maximum ph and base excess was found after and hours, respectively. in one case the top level ofph-value exceeded . , the base excess + mvalb. conclusion: children undergoing cardiac surgery with cardiopulmonary bypass often develop metabolic alkalosis.in contrast to previous reports, we did not observe an association between metabolic alkalosis and mortality, nor greater frequency of cardiac arrythmias or prolonged mechanical ventilation. in context with decreasing serum lactate levels, our data show positive correlation of metabolic alkalosis with postoperative improvement of liver function. respirator, mechanics and weaning outcome in children undergoing cardipvascular surgery. vassallo j., cernadas c., saporiti a., landry l., rivello g., buamsha d., rufach d., magliola r. mechanical ventilation (mv) and acute respiratory failure are common events in children unergolg cardiovascular surgery (cvs), the development of new techniques helped to measure some of the main respiratory mechanics (rm) in a non invasive fashion. our goal was to evaluate the predictive value of these measurements in weaning (w) outcome in these patients, patients and methods: we prospectively evaluated children considered clinically to be ready for w with < kg and > hs mv. patients with diaphragm paralysis and those who failed w because of upper airway obstruction were excluded. before patient extubation the following measurements were recorded during spontaneous ventilation (cpap/t piece) using the cp neonatal pulmonary monitor bicore (lrvine, ca): total respiratory system static compliance (cssr) and resistance (rts), rapid shallow breathing index (rsbi). maximal inspiratory negative pressure (pi max) was measured using an unidirectional expiratory valve. threshold values predicting w success (ws) were: cssr > . ml/cm h , rts < cm h /l/sec, rsbi and pi max > - cm t . w failures (wf) -patient reintubation within the following hs, these values were compared between w success and failures using fisher exact test. an apriori level of statistical significance was chosen at p < . . considered, an increase in tnf-a levels is observed after cardiac surgery (p< . ) with a return to previous values after hours (p< . ). hours after cpb, similar values are observed in groups ii and ill, but there is a further increase in serum tnf-a levels in group i when compared with both other groups (p< . ). we found no statistically differences in any other moment. there was a significant correlation between serum tnf-o levels determined hours after surgery and cpb duration (p< , ). conclusions: cpb in childhood provokes a significant increase in serum tnfa levels, in newborns the inflammatory response is maintained hours after surgery. this enhancement of serum tnf-e levels indicates the existence of a relevant inflammatory response in these patients. introduction: cardiac surgery appears to induce a systemic inflammatory response. we have investigated the behaviour of il- i~ and il- before and after cardiac surgery. patients and methods: we studied serum il- and il- levels from children with congenital heart disease ( boys and girls), aged from days to years, undergoing open heart surgery, before cpb (d we found no statistically differences in the il-i levels in the different groups and moments. there is a significant increase in il- immediately after surgery (p< , ) with similar levels hours after cpb and a significant decrease (p< . ) hours after cpb. preoperatory il- levels were higher in the groups i and tl than in group i (p< . ). hours after cpb serum il- levels in group were significantly higher when compared with group (p< . ). conclusions: cpb in childhood induces a significant transient increase in serum il- levels, strongly relevant in newborns. cpb was not associated to a significant modification in serum il- levels. thus, cpb in childhood induces a dissociated behaviour in the proinflammatory il- and il- & pathways. obiective, to evaluate the effects of amg receipt on the clinical condition during the first hours after birth (t ), the morbidity and mortality in immature outborn neonates. methods. we studied outborn neonates with ga to wks, admitted during the years to . eighteen neonates exposed to amg (ga: , +lwks, bw: _+ g) and neonates did not (ga: , _+ wks, bw: _+ g). results. amg-exposed neonates compared to those not exposed had lower incidence of apgar score at min _< ( % vs %, p<. ), lower incidence of ph t < . ( % vs %, p<. ), decrease need of bicarbonate ( % vs %, p<. ), lower fio (fio min> : % vs %, p<. and fio max > : % vs %, p<. ), lower incidence of intubation ( % vs %, p<. ), lower requirements of surfactant ( % vs %, p<. ) and lower mortality ( % vs % p<. ). there were no differences between the two groups for the following parameters: type of delivery, hypothermia hypoglycemia and anemia during admission, hypernatremia, hypotension (map< mmhg), need of dopamine and or plasma , incidences of ptx pda sepsis nec severe rop major ivh (plus pvl) and bpd and duration of intubation. conclusions. the main beneficial effects of amg receipt on the immature outborn neonates were the decrease of mortality and the decrease of surfactant need. there was no effect of amg receipt upon other severe morbidity in this high risk group of neonates. premature babies are very sensitive on homeostatic disturbances, and often develope intracranial haemorrhage (ich). ultrasound scan of the bram shows four grades of ich: -grade i -only periventricular hyperechogenic areas -grade ii -haemorrhage ham the lateral ventricles -grade ili-dilated lateral ventricles -gtrade iv -intracerebral haemorrhage. the purposes of this study were: to show the incidence of ich in premature babies and its correlation with the gestational age, . to determine the severity of ich . to present the outcome &those babies. in the study were included premature babies successively-born at the department of gynecology and obstetrics before gestational week (g.w.) and grouped in three groups: less than g.w., - g.w., - g.w. to all of them was performed ultrasound scan of the brain. results : . the incidence of ich hi premature babies is % and there is ingh level of correlation with the gestational age: -babies born before t~ g.w. have % incidence of ich and graduated : i grade - %, ii grade - %, iii grade - %, iv grade - % -babies old between - g.w. have incidence of % : i grade - %, i[ grade - %, iii grade - %. -babies older than g.w. have incidence of %: i grade - %, ii grade %, iii grade - % . sixty of premature babies have died and it is . % lethality. in all died ilffant was confirmed the grade of ich diagnosed by ultrasotmd scan of the brain. d. maksimo~ c. z.braiko~ic, n.vunjak. p. ivanovski ( ~iversi~, children's hospital. belgrade, yugosla~, ia infantile intracranial hemorrhage is the most frequent and serious manifestation of late hemorrhagic disease of the newborn caused by ,,~tamm k deficiency in earl?,, ti~fancy. in the last two years, we recorded five cases of infantile intracranial hemorrhage due to "dtamin k deficiency, despite routine prophylax~s (intramuscular vitamin k, mg) , with bpieal clinical presentation: age was - days (average days): vomiting, poor feeding, lethar~'irritabiljty, palor, bulging t ntanelle and convatsiones were present in most cases.two patients developed signs of hemorrhagic shock, with hemoglobin level less than g. . in ~ f \qi level was less than % of predicted value. there was no evidence of head trauma or liver disease in none of patients. four inlants were breast fed, while one, who had diarrheal disea.se, was on adapted milk formula. routine therapy wa.s given (including vitamin k and fresh frozen plasma). two patients were discharged with no sequellae, one developed posthemon'hagic hydrocephalus as a complication and two patients died. late hemorrhagic diseo.se of the newborn is sill/ a significant cause of morbidib' and mortality in earl ' infancy, despite different approaches to prophylaxis developed in recent years. background: neonatal hearing screening in at risk newborns can detect % of the children with a congenital hearing loss. automated abr hearing screening (algo- ) has been introduced for healthy newborns. the aim of this study is to test the validity of this algo- screener in at risk newborns in a neonatal intensive care unit. subjects: at risk newborns (median gest.age: . wks, median birthweight g) selected according to the criteria of the american joint committee on infant hearing. interventions: algo-i automated abr-hearing screening at a level of db was performed in the neonatal intensive care unit. when bilaterally referred, further audiologic screening and/or therapeutic intervention took place. when passed uni-or bilaterally, children enrolled in a) a nation wide screening programme (ewlng) at the age of months and b) in a half yearly follow-up programme in which hearing and speech-and language development were observed according to egan an illingworth. results: screening without disturbance from ambient noise or from routine technical equipment was possible in the incubator, even during nasal cpap therapy. ( %) newborns passed algo- screening. ( %) did not pass bilaterally. of with a congenital rubella died shortly after screening.in of bilateral congenital hearing loss of -> db was confirmed. of the newborns passed were still alive at the age of year. ewing screening was performed in of ( , %). / passed, of had passagere conductive hearing loss, in / no further investigation was performed. all children enrolled in the i/ yearly follow-up programme had normal speech-and language development. in this study all at risk newborns with bilateral congeni "tai hearing loss were detected with algo- screening. screening results showed no false negatives at follow-up. the algo- infant hearing screener can be used as an valid automated abr-screener to detect hearing loss in at risk newborns in a neonatal intensive care unit. gancia gp, bruschi l pnlito e, ferrari g, rondini g -divisione di patologia nc~matate e turapia intensiva -irccs policlinico s. mattco -pavia, italy latrogenic esophageal perforations (iep) in preterm and term infants are seldom reported in litteraturc, in association with difficult endotracheal (et) intubation (with or without stylets), insertion of gastric tube, and pharyngeal suctioning with stiff catheters. crieopharyngeal muscle spasm caused by instrumentation may also lead m a narrowing of lumen, with increased risk of local injury. we report iep observed in intubatcd, mechanically ventilated newborn infants ( male, female, all outborn). a common feature of iep was inability to pass a nasogastric (ng) tube into the stomach, mimicking e~)phageal atresia.~se : birth weight (bw) (i g, gestational age (ga) wk, sepsis. before admission to n cu, the baby underwent multiple et inmbations, because of inappropriate securing of et robe. bloody secretions in pharynx were observed. the endoscopy showed a large lesion at the end of proximal third of the esophagus, case : bw g, ga wk, rds. chest x-ray (cxr) showed a retrostcrnal air leak: the ng tube was stopped }~etwcen d and d and soluble contrast was seen in upper mediastinum.case : bw (/g, ga wk, rds. the endo~opy showed an esophageal lesion. cxr showed a paravertebral route of ng tube and a right pneumothorax.case : bw (i g, cz ,.v!:. rd c. ~!,'.::;;: ::':'_'rvt!~' s l" ~k':.rvrx. cwr, d,,,,vs ~,,mr~e, ~n rhe upper mediastinum and abnormal route of ng tube through a false passage. surgical intervention is needed in case of mediastinitis or mediastinal abscess: conservative management included broad spectrum antibiotics, total parenteral nutrition, antireflux therapy and, if necessary, drainage of air leaks. enteral feeding has been stopped lor days and cautiously resumed after radiographic study. [x~cal sequelae and death are uncommon, but iep occur in newborns with high risk of death due to prematurity and other diseases. in our patients, et intubation has been performed by experienced personnel: therefore the lack of skills in resu~itative procedures is not always the main factor of iep. prevention of iep requires appropriate materials (et tubes, laryngoscope blades, suction catheters), and procedures (positioning of the infant with correct neck estension, firm et placement). sedation and pain control may help to prevent the muscle spasm. aggressive treatment has improved the tong-term outcome of extremely low birth weight neonates (elbw) but it has also increased the chances of iatrogenic lesions. reviewing the charts of our neonates we observed a high number of vascular injuries. from to , neonates were admitted to the neonatal intensive care unit (nicu); of them were elbw ( . %). studying the charts of these elbw we observed cases ( m - f) with vascular lesions ( . %). mean gestational age of these patients was . weeks (rain -max ). mean weight at birth was g . mean weight at diagnosis was g ( - ). in the same period patients with vascular injuries were reported in the neonates over g ( . %). the injuries observed in elbw group were: arteriovenous fistula ( bilateral) at femoral,level, carotid lesion and limb ischemic lesions. aetiology was in cases by venipuncture, in one case umbilical catheter and in the case of carotid lesion a wrong surgical maneuver. no general simptoms were observed. the vessels were repaired with microsurgical technique in six cases: the carotid lesion and five arteriovenous fistula; one case was solved with thrombolitic drugs; an amputation at knee level was required in one case after a long period of medical treatment. the last neonate with an arteriovenous fistula was only observed for parent's will. at follow-up (clinical and by ecodoppler) out of neonates presented normal vascular function without sequelae. from our experience elbw neonates have more chances than older neonates to develop iatrogenic vascular lesions. we advocate an aggressive microsurgery and/or medical treatment to obtain good results and prevent late sequelae. a retrospective comparison between natural surfactants l.j.i.zimmermang m.c.m,van oosten. dept. pediatrics, div. neonatofogy, sophia children's hospital/erasmus university, rotterdam, the netherlands. aim: retrospective comparison of alvofact (in ) versus survanta (in ) as rescue treatment for neonatal respiratory distress syndrome (rds). methods: both surfactants were given at an initial dose of mg/kg (except for alvofact mg/kg for mild rds grade mi). repeat doses were attowed (survanta mg/kg, alvofact mg/kg) up to a maximum of mg/kg, all parameters and outcome criteria were strictly defined beforehand. the initial response (good,mild,no response,relapse) to surfactam therapy was defined on the basis of the decrease in fio . results: there were no signif. differences in patient population and initial parameters: ga ( . +_ . vs a _+ , wks), birth weight (t _+ vs -+ g), severity of rds (grade ill-iv: . % vs . %), apgar scores, cord blood gases, initial ventilatory settings. in ' however, the initial surfactant dose was administered earlier than in ' ( . -+ . vs . _+ . hrs postpartum, p= . ). although the average total cumulative dose was equal in ' and ' ( . -+ , vs . _+ . mg/kg), more doses of alvofact were given compared to survanta { . _+ . vs . _+ . , p=o.o ) and more patients in ' received more than two doses than in ' ( % vs % of patients). there was no difference in the incidence of non-putmonarycomplications. aivofact ( there was a better initial response to survanta and a better respiratory outcome in : in the group < g the duration of ventilation was half in , and in the group >~ og the duration of extra o need was half in as compared to . we speculate that the main reason for this difference is the earlier and initially higher dosing used with survanta compared to that used with alvofact which was given in the same total cumulative dose but over a larger time span. background: e×ogerlous sur&ct~t raplacem~t treatmem has become rou~ne k~ the t~eatme~t of respira~"¢ dim'~ syndrome (i~ds) of pr~e~tur~, wh~eas its effica w th odi~ respiratory diseoses is sdi being wader mvesugatio~. objective: "eac~ mt ereat isto report ottr results of prospect/re, non-randomized "re~-o.e" study oe suffact~t replacement in outhom premamae infa~t~ with rds reruirmg me~aical ventilatioa (nfv). p~tien~ and metho .s: from j-aly to june , / ; ( %) out~ ~¢ infaats, at a mesa age of z , horn's ( boys, ~rls; ~ gestafioan age -+ . weeks, mera~ birth weight _+ g, ~ . i" at minutes) with rds, requiring mv, received bov~e-suff~amt (survanta, ros~/aboti, laboratotie~ columbus, ohio) eadotracheally, as was recomm~aded by maaufacturer. as the c,~:ttrol group o~bom premature infants (ot~ of ; %, admitted with rds from euiy to eune ) were saelected ~d who did not receive surfaaam, compared with ~hctant ~'oup they were admitted for treatmeat e~'li~" aft~" daliv~:y (at the age . :: . hours vs. . +- hours), but they did not diff~ in othe~ baseline dam'a~eri~cs at ~ti~ion. entry crkeda for ~¢fa~aut ~hcadou were fractional i~firat o~ oxtgem r~emeats -fio > . - . , ratio au-lerlal to alveolar oxygea pre~are~ao ~ao < , ~ad oxyge~at,~ i~.dex -ol > . primary o~comes were deter~caned by ~hanges m exs'ge~ab, c~ ~r~d vmtilatic~ ~ the following variable~; ( ) fi'aaic~ of i~spired oxtge~ (fio ); ( ) mesa nnvay presmzre (map) ( ) pag ~ao ratio, ( ) oxyge~ion index (oi). commo~ comphcadces of prem,musty ~d con~ol mechamcal v~ati]al~on (pater dumas merios.s, intracr~nlal haemcrn:hage, air leak, br onchop ulmrmm'y dy~pl~a ~d death) were reg~ded as sec~d,~y outcomes. r~suas: in warfactaat group we observed slg~ .c~t improve~aeat (p< . ) in oxygea~thia md veaatilation at hours all~ e~try k~to the m~dy in compari~ion to nons~fa~m" group. compa~on of secondao' outcomes in ~ts with p,.ds showes table l we did not observe ~y major acute hfe fl:u-eattming complicatlola,s m sxlrlhct~mt grou~ tr/lmediately after stu'~actsmt rcplacemev_t therapy. the duramm of mechmucal ven~ation ~ad oxygen lreau~ent m survivals of both groups did not dafter gmficautl y a-ore ead~ other. condusion: l!a premature mthats with rds treated with surfaaaat replacemeaat therapy we observed decrease m mc~de~ce of tme'~m~o~oraces add de~th (p< . and p< . ), whe~e~s m othe~ observed variables thee was uo ,igmfi~t d~=ecce infectious complications during the therapy of respiratory insufficiency in neonates with birth weight less than g in the course of yearsretrospective study. zitek infants on cmv, cppv, and imv were administered exosurf in dose of - mg/kg twice endotracheally (see table) . in newborns ( . %) hours after surfactant admin fi value decreased by . %, and after hours -by . % compared with initial value; pip and peep values decreased by - cm h and - cm h after hours, and by - cm h and - cm h after day, respectively accompanied by mean decrease of aado from , to . mmhg, qs/qt decrease from . to . % (see table) . mean time of cmv, cppv was . days, imv- - hours, cpap - - hours. respiratory therapy in newborns ( . %) was complicated by pneumothorax (bilateral -in infants chorioangioma is a rela~ively rare placentai malformation associated with considerable mortality and morbidity. a chorioangioma can be regarded as an arterio-venous shunt in the circulatory system of the fetus. this causes volume loading eventually resulting in cardiomegaly and high output cardiac failure. a female neonate (gest age wk, birth weight g, - . sd) was born with an apgar score of and after and rain respectively. the placenta showed multiple chorioangioma. ultrasound of the heart showed a hypertrophic cardiomyopathy. she developed severe hypertension ( / mm hg), treated with nitroglycerine and nitropruside. finally blood pressure decreased when enalaprillic acid was given ( . mg.kg ). we measuered the activity of the renin-angiotensinsystem. an elevation in renin-angiotensin system is shown probably to compensate for the low resistance circulation before birth, hypothesis: the instantaneous cut off of a large arteriovenous shunt did not result in a fast downregulation of the renin-angiotensin system resulting in hypertension. hypertension should be added to the list of complications of chorioangioma of the placenta. the authors studied cases of children's septicemia with blood culture yielding staphylocucetts aurens. the age of patients varied from months to years ( , % from years downward), % of the children caught their disease in the hot season (may to october). the deaths also occured in this season: , % ( / ). following were the anatomo-dinical lesions. -skin %, muscle , %, bone , %, joint . %. -viscera : lung %, heart . %, cerebrum . %, kidney . %, fiver , %. -simple lesion skin-muscle-bone joint: %, no death in this group. the concomitant lesions of the soft tissue,bone-joint and viscera : % with one viscera, % with two viscera, % with three viscera and % with four viscera. -bone lesion : mainly on the long bones ( % on the tibia, % on the femur, the remainder being the mandible ( ) and the humerus), inflammation of' the hip joint was the main one. -i,ung lesion had forms pneumatocele ( cases), bronchopneumonia ( cases), pleural effusion ( cases), multimicroabcess bursting into the pleura ( cases), most multimicroabcesses were lethal : / ( , %), -heart: all thethreelay~rs got le@~r~, % had or layers alrected and death ensued. -cerebrum : the meninges had three forms of lesions purulent meningitis ( cases), obturafing embolns of brain vessels ( cases) and cerebral abcess (one case). the characteristic clinical sign was paralysis and meningismus, phlebothrombosis of eavcrnous finus ( cases)was mually ther~sultofalxil vdfi:h burst there were cases of death with lesion of the meninges and cases of obturating embolns of brain vessels. -the main sign of lesion of the kidney was a change in the components of urine: % got proteinuria, % had leucocytes in their urine, % had erythrocytes in their urine, the urea in their blood increased (over rag%) in . % of cases.the lesion of the kidney seemingly had little relation to death. seven cases of ictertts due to an increase of direct bilirubinemia and a decrease of blood-albumin. -the biological characteristics of the pathogen staphylococci showed that all the isolated specimens had positive coagulaza ; the specimens from the dead patients were less semiti~e to, mad ~t to mali~ overag death rate was . % ( / ). the fungal infection to fusariun species in immunocompromissed child have been reported in the literature with a rare, severe and high, mortality rate in spite.of the use of antifungal drugs. we report a case of successful treatment of a severe disseminated fusariun infection in a ll-year-old boy with acute lymphocytic leukemia (lla-l ), after use a chemotherapy followed by absolute granuloeytopenia. the patient developed fever, skin lesions, pneumonia and fungaemia. fusariun species was cultured from the blood, necrotic skin lesions and lung secretion. the child developed multiple organ system disfunctiou in spite of use broad spectrum antibiotcs and antimycotic therapy needing. uci during days. the patient receive suport treatment (mechanical ventilation, inotropie d~.ugs, diuretics, imunestimulants, blood components, a broad spectrum antibiotes and antifungal agents). we absorved a gradual recovery in the white blood cell count and regression on the sites of infection. the association of preeoce diagnostic and the terapentic with increase in the white blood cell count was the most important in a successful treatment. a year old african-american child suffered a severe pulmonary injury in a house fire. initial survey revealed % total body surface burns, soot on the face, and bloody endotracheal secretions. initial chest radiograph revealed diffuse, bilateral infiltrates. severe respiratory failure with an oxygenation ratio of rapidly developed. he developed a pneumomediastinum and subcutaneous emphysema. although transient improvement occurred with inverse i:e ventilation and surfactant, he became more hypoxic (sac as low as %) and acidotic. on day post injury, he was placed on venc~venous extracorporeal life support (ecls). on ecls day he was decannulated. chest radiograph on ecls day showed an opacity in the left chest. ultrasound of the left chest was consistent with atelectasis rather than pleural fluid. flexible bronchoseopy failed to reveal any obstruction in the left lung. a computed tomography (ct) seen of the chest, which was performed after decannulation, revealed a large loculated collection of fluid in the left, anterior chest. under ct guidance, a f cope loop catheter was inserted and cc of thick blood was removed, follow-up ct performed immediately after this procedure revealed minimal change in the size of the fluid cavity. over the next hr, we instilled urokinase , units over minutes every two hours. a minute dwell time was allowed before draining the fluid. repeat ct scan done at the end of the urokinase infusion showed a marked decrease in the size of the fluid cavity. act scan was not performed prior to decarmulation because the ecls circuit tubing was too short to allow appropriate positioning of the child in the ct scanner. after a ct scan revealed loculated pleural fluid, a simple drainage procedure was diagnostic but inadequate treatment. we were able to successfully dissolve the thrombus after hr of urokinase therapy even though the thrombus was > days old. we suggest that large loculated plenral thrombi which develop as a complication of ecls therapy may be successfully managed with urokinase infusion. introduction: haemorrhages, particularly intracranial, are major complications experienced in - % of neonates treated with extracorporeal circulation. an induced thrombocytopenia and impaired platelet function play a key role in the increased bleeding tendency observed in these patients. the aim of the present study was to establish a dose-respons curve for the effect of a synthetic protease inhibiting agent, nafamostat mesilate (fut- ), on platelet membrane glycoprotein density and platelet activation during experimental perfusion. methods: two identical extracorporeal life support (ecls) circuits were primed with fresh, heparinized human blood and circulated for h. four different concentrations of fut- ( . mg/l blood/h; . mg/l/h; . mg/l/h+ % bolus at the start of the perfusion and & mg/l/h+ % bolus) were used in different perfusion experiments. a total of eight paired experiments were performed. platelet count, plasma betathromboglobulin levels and platelet membrane density of glycoprotein ib and lib/ilia were followed as well as plasma concentration of haemoglobin. results: a protective effect of the agent on platelet count, plasma concentration of btg and platelet membrane gpib could be observed during the first hours of the perfusion when a bolus dose was added. no positive effect could be recorded with the two lower doses used. plasma concentration of haemoglobin was higher in all the fut-circuits compared to the control circuits. conclusion: the addition of a bolus dose of fut- at the start of the perfusion seem to induce a protective effect on platelets during the first hours of perfusion. extracorporeal membrane oxygenation (emco) is a form of invasive cardiopulmonary support that can provide imporary physiologic stabilisation in reversible circulatory failure and or respiratory failure. we reviewed our expierence with extra corporeal membrane oxygenetion in children aged day to year between and . two neonates was succesfully decanulated, but died - well after decanulation due to septic complictions. one child years old, one neonates died on day and day" respectively while still on emco. complication which were and encountered were heavy bleeding in case (child), (neonate) and raceway rupture in case (neonate). problems which are specific developing countries like indonisia are: high cost ( . us for days) difficulty in transportation (transporting intubated baby) from the orgin hospital, lack of knowledge and understanding of the primary physician and nm-ses and difficulty organizing in hours emco team. resnratory mon tor/ng in picu z,zjvkovic, s. mihailovic, o, tosev respiratory monitoring in pediatric intensive care unit picu) provide the importartt informations for understanding of the pathophysiology of the clinical signs, aid with the diagnosis, and assist in therapeutic management and predicting prognosis. pien in children's hospital for ~flmonary diseases and tuberentosis remained for the t~s't two end a half years relatively limited for diagnomic tools and therapeutic regimens, mostly because of the poor fmnaeial suptx~rt. the number of children admitted for aurae asthmatic at.lzek~ severe pneumonias, bronehiolitis, complicated pulmonary tuberculosis, foreign bodies and exacerbations of ehronit'. pulatonary diseases was t . for all patients the respirator' monitoring system means: physie~d examination, ehe~ x rays, capillary bltxxl gas mmlyses (vevv few ehiktren experienced itwasive arterial blt~.~'i gases), noninvasive oxyntctry, measuring of the vital capacity in coopo-able patients, as~d capnography. later on, after the imtial critical illness, a complete hmg fimction tests was performed, as well ,~s bronehoscopy in selected eases, (~lr experience revealed that abotrt % of ehil&en heos suecessthl outcome, without s~lllens , instead they had been tremted in limited conditions. ']'he rest of our patients were previously diagnosed ~s ettronie pulmonary patients, with high risk score system ibr having seqnells 'llae mortality rate were , %. the continuous blood gas monitor, pasatrend (biomedical sensors, ltd., high wycombe, bucks, england) has the capability of measuring ph, pco , and po via an indwelling optical absorption optodelclark electrode sensor that is placed through an intra-arterial catheter. we evaluated the accuracy of the sensor in radial and femoral locations in critically ill pediatric patients. methods: the simultaneous values of ph, pcoz, and po recorded from the paratrend monitor were compared to values measured by standard arterial blood gas analyzer (coming , ciba-corning diagnostics, medfield, ma). criteria for the elimination of data points included a core vs. sensor temp. gradient, and sensor pulled back beyond accepted insertion distance. mean time of monitoring per sensor was hours (range . - . hrs). mean time of radial monitoring was hrs (range . - . hrs) and of femoral monitoring was . hrs (range . - . hrs.). linear regression and bland-altman analysis for bias and precision for each parameter were calculated. results: a total of patients (age range weeks to years) had paired samples of ph, pens, and poz made by the sensor and blood g&s analyzer. the range of measurements were ph . - . , pco, . -i . t(n r, and po - torr. the paratrend monitor demonstrated accuracy that is comparable to the accepted standard of blood gas analysis in a group of critically ill pediatric patients manifesting wide variation in ph, pen , and poz..this technique appears m be very useful especially in the extreme values of the parameters measured. funding provided by biomedical sensors. understanding of pulse oximetry d.semple, l.e.wilson. royal hospital for sick children, edinburgh, eh lf, scotland, uk. pulse oximetry is a useful, non-invasive monitor, routinely used on the itu and increasingly often on the general wards. we used a questionnaire incorporating questions on the theory and clinical uses of the pulse oximeter to assess understanding of pulse oximetry in medical and paramedical staff doctors indicated grade, speciality, pulse oximetry tuition and neonatology experience. doctors, itu nurses, t medical students and physiotherapists completed the questionnaire. some confusion existed between the principles of pulse oximetry and transcutaneous oxygen measurement. wide variations in the lowest acceptable saturation in fit children were seen ( - %), with around % of respondents in all groups accepting values of % or less. some potentially serious mistakes were made in the evaluation of oxygen saturations in the clinical scenarios. there were widespread variations in correct responses at all grades of medical staffing. nurses scored well on more clinically-orientated questions but relatively poorly on theory. only % of doctors (mostly senior grades) had received tuition in putse oximetry. neonatology rotations appeared to confer little additional knowledge on pulse oximetry. few doctors and nurses receive tuition in the use of pulse oximetry a significant proportion of nurses and doctors, of all grades, exhibited a lack o{" understanding of the principles of pulse oximetry. this may result in unsafe use of the equipment and put patients at risk. one can see from the table that blood composition in uv and ua differens in some characteristics, and similar in sgp magnitude. venous-asterlal gradients "gas functiomals" between uv and ua represent the measure of difference in this characteristics. the gradient cari be positive, zero -order or negative and change both in value and in sign but not reach apo (positive) and apco (negative) in absolute significance.minimization of "gas functionals" deviations atom the zero is achieved due to"mutual replacement acts" between po and pco in uv and ua blood. we suggest that presented tests can be useful in full evaluation of gas exchange in newborns. (pap) in the context of pulmonary hypertension is oft desired but rarely achieved. inhaled nitric oxide (no) has been shown to produce this desirable effect, but is relatively difficult to administer or monitor. we wondered whether np, chemicaily related to no but more stable in solution, would produce similar physiologic effects when administered in the convenient modality of nebulization. methods: piglets were anesthetized, mechanically ventilated, and surgically instrumented. systemic blood pressure (bp), pap, and cardiac output (co) were monitored continuously. after postoperative stabilization, . % nac} nebulization was begun, and pulmonary hypertensiorr was induced by reducing fio from . to . . the piglets were monitored for minutes during this hypoxic phase, next, without altering fio or ventilator settings, np ( mg/ml, dissolved in . % nacl, flow ipm) was substitued for . % nacl in the nebulizer circuit. np was nebulized for mins. results: during hypoxia, pao fell from to mm hg. pap rose during hypoxia from to torr (p< . ). ,^fhile bp and co did not change significantly. pap fell during nebulized np in each piglet, (mean apap = to torr; p< . ; mean reduction of hypoxia-induced rise in pap = %; range: to %; p < . ). pvr/svr fell by % during np nebulization (p< . ), while bp and co did not fall significantly ( to tort; to mllkg-min), the reduction in pap began within minutes of the onset of nebulized np, and appeared to reach a plateau by minutes. no tachyphylaxis to nebulized np was noted. nebulized np did not significantly affect pap, bp, or co under normoxic conditions. conclusions: ) like no, np selectively reduced hypoxia-induced pulmonary hypertension without altering systemic bp, ) unlike no, np can be administered by nebulizer, a technique familiar to virtually all health-care providers, and potentially adaptable to both intubated and non-intubated patients. } nebulized np may be beneficial in clinical contexts where inhaled no is impractical. dang phuong kiet and nguyen xuan thu examining cases of purulent pericarditis with various clinical forms treated by surgery, the authors drew the following experiences for their diagnosis. t. clinical factors. purulent pericarditis appeared like a cardiac tamponade in a septicemia due to staphylococci with dassieal symptoms: severe dyspnea, tachycardia, faint heartsound, big liver, prominent cervical vein ; rentgenography of the chest showing enlargement of the cardiac silhouette, a diminution of ventricular pulsations, ~i clear lung field. by an emergency operation, ml of diluted blood were drained. purulent pericarditis and pleural effusion appeared at the same time but at first tile symptoms of purulent pericarditis were masked by the predominant symptoms of plearal efihsion. after the pleura was drained, its pus was no more, the general state was relatively stabilized but there still were big liver, dyspnea, enlargement of the cardiac silhouette while central venous pressure increased. purulent pericarditis appeared late. in the first stage (about weeks) there was no suspected sign. later on gradually appeared such symptoms as dyspnea (during serum transfusion for instance). central veinous pressure also raised. the heart chest diametre increased at first (up to - %) then decreased (down to below % ) but the liver kept on swelling together with the particular changes of electroeaediegramme. now the pericardium had no more pus but get fibrous (up to ram) thus constricting the heart and its main arteries ike pick syndrome). . diagnostic values of electrocardiograms : common signs of ecg related of these purulent pericarditis were: a diminution of voltage, a widespread elevation of the st segment, the tf wave flattened and inverted. however, what should be stressed was : the diagnostic values of an electrocardiogram for purulent pericarditis was mainly in the dynamics of their signs: in the first week, the voltage diminished corresponding to a pericardium containing pus, while the st segment went up then seemed parallel to the fibrosis of the epicardium, the liver swelled, the central velnous pressure increased, the heart/chest dimension ratio decreased, the st segment went down, the t wave became more flat and inverted. between and neonates, aged - days (median ), weight , - kg (median , ) with critical valvar pulmonary stenosis were scheduled for balloon dilation (psvp), children ( %) were on pge and ( %) needed mechanical ventilation. after stepwise dilation a final balloon : pulmonary valve (pav) ratio of % ( - ) was achieved, there was a significant correlation (p< , ) between an adequately sized balloon and freedom of reintervention. two valves could not be passed, four neonates underwent surgical procedures (brock n = , commissurotomy n = ), two children ( %) died of sepsis. / patients ( %) were successfully palliated by psvp in the first month of life. the rv : systemic pressure value fell from % ( - ) to % ( - ), complications included transient dysrhythmias, transient hypoxia, vessel occlusions;- right ventricular outflow tract perforation. in / patients follow up data is available. the residual systolic peak doppler gradient over the pav on the last out patient visit ( - months after psvp) was - mmhg (median ). four children needed repea.ted psvp to months after the initial intervention. conclusion: psvp of critically ill newborns is possible. the risk of mortality is relatively low. psvp in neonates with an adequately sized balloon is a challenging alternative to surgical treatment. post hypoxic-ischemic (hi) reperfusion induces the formation of non protein bound iron (npbi), leading to production of the reactive hydroxyl radical. it was investigated if the ironchelator deferoxamine (dfo) could reduce free radical production and improve neonatal myocardial performance after hi. severe hi was produced in newborn lambs and changes from pre-hl values were measured at , and min post-hi for (mean) aortic pressure (mean pao), cardiac output (co) and stroke work (sw). left ventricular (lv) contractility and co were assessed by measuring lv pressure (tip-manometer) and volume (conductance catheter), using inferior caval vein occlusion to obtain slope (ees) and intercept of the end systolic pv relationship (v ). npbi, reduced and oxidized vitamine c ratio (vcred/ox) and lipid peroxidation (mda) were measured from sinus coronarius blood. lambs received dfo ( mg/kg i.v.) immediately post-hi, control lambs (cont) received a placebo. results: mean pao was stable, co and sw decreased up to and % respectively in cont as compared to pre-hi. in both dfo-groups co and sw remained within the normal range. ees and v decreased in all groups post hi, but did not differ between groups. npbi and mda were higher at min post hi (p<o. ), vcred/ox was lower at min post-hi (p<o.o ) in cont as compared to dfo-group, indicating more oxidative stress in cont. conclusions: dfo reduced the oxidative stress of the heart and prevented co and sw to drop, suggesting a positive effect of iron chelation on the myocardium after h{. from we published reports with analysis of performance of the heart as a whole organ.while analysing the heart performance as a whole, we recognize three block in it located intrapericardially: l."atrial"block -left (la) and rigth (ra) atriums; ."aorta-pulmonary" block-aorta 'bulb (a) and pulmonary artery(pa); .ventricular "three-chambered" block (vb) consisting of: -left (lv) and right (rv) myocardial chambers, both frith blood outflow into "aorta-pulmonary" block vessels, and -spongy (venous) myocardial chamber with the blood outflow through coronary sinus (cs) and thebesiau vein (tv) into "atrial" block. the following conceps are introduced for vb functions assessment "common" systole and "common" diastole of "three-chambered" vb. the process of normal "common" vb systole: -begins with blood ejection from vb spongy chamber into the "atrial" block; -continues with blood outflow from rv and lv into "aorta-pulmonary" block wi~ venous minimums -x-coiiapses -~btmation iu "a~riai" block; -completes with "three-chambered" vb general emptying. at this period the following blood volumes are transferring: -two-from rv and lv(their stroke volumes)into"aor~o-pulmonary"block; -two-from "spongy" chamber .into "atrial" block; -two-from systemic and pulmonary veins into "atrial" block during the process of so called "systolic" membrane suction (at pulling atrio-ventricular valves into rv and lv chambers as blood ejects out of them). it appears to be the regulation of blood inflow to "atrial" block by blond outflow from "three-chambered" vb into "aorto-pulmonary" block. objective: to evaluate the efficacy and complications of transpyloric enteral nutrition(ten) in critically ill children patients and methods~ from june to january children (i boys and girls), aged from days to years (mean l. ± . years) were treated with ten. patients were included after cardiac surgery, with acute respiratory failure, and after cerebral surgery. the indication of ten was mechanical ventilation in patients and failure of nasogastric nutrition in patient. children ( %) had previously received parenteral nutrition. and i fg enteral tubes was inserted into duodenus through nasogastric intubation en patients and by endoscopy in patients. rx and ph determination were used as methods to control tube situation. children received adapted formula, caseine hidrolisate, and enteral formulas. (in patients the nutrition formula was changed during ten). patients were supported with mechanical ventilation during ten, received midazolamperfussion(range to mcg/kg/min), fentanyl (i - . mcg/kg/h), and vecuronium ( . - . mg/kg/h). resulte: ten was used during to days (mean . ± . days). mean maximmnvolume ad~iniateredwas ± ml/kg/day (range ) .patients with midazolam, fentanyl and vecuronitml tolerated ten similar than children without sedatives. complications were diarrhoea patient, abdominal distension and/or important gastric fed residuals patients. pulmonary aspiration or respiratory complications were no registered. ten was ended in one patient due to diarrhoea, in due to change to oral or nasogastric nutrition, children continue yet with ten and was discharged of picuwith ten. conolusion: ten is an useful method of nutritional support in critically ill children with mechanical ventilation and/or nasogastric intolerance. introduction: the enteral nutritional support of the critically ill child may reduce the morbidity and mortality by attenuating, the hypermetabolic and catabolic response, decreasing the gut translocation and the septic complications, improving the bowel mucosa integrity and the wound healing. the aim of this study was to show the safety and tolerance of en. methods: we enrolled consecutive patients admitted to our unit from may to december , mean age . years (range imonth to i years). the prism, mechanical ventilation, inotropic use, opiates and other drugs were recorded. the en was delivered by continuous infusion across a polyuretane tube.we kept the patients head elevated °, and we used cisapride routinely. the gap betweeen admission and the en beginning, average time to meet the nutritional objective, en duration, selected formula, patients outcome and complications were recorded. results: prism groups were - = patients; - = ; - = ; - = ; - = . two patients with mof (multiorgan failure) died. % needed mechanical ventilation.the average time elapsed from picu admission to initiation of en was . days (range to ) and the average duration of the en was . days (range to t ). the average time to meet the nutritional objective was days (range to ). the selected formula were: lactose free infant formula in patients, elemental diet in , pediasure in and jevity in . we recorded vomiting in patients, diarrhea in and constipation in . none of them forced the en suspension. we didn't recorded any case of ~spiration or pneumonia. we found no relation between drugs, selected formula and complications. we think that en may be a safe and well tolerated procedure at the picu setting. generation of free radicals in iipid emulsions used in parenterai nutrition (pn) has been described recently. this seems to be due to high polyunsaturated fatty acid content. we studied lipoperoxidation status and antioxidant parameters presurgically and through the postoperative period ( days) in a group of twelve children (ranging from months to years of age), who underwent heart surgery and received nutritional support with pn. malondiaidehyde (mda), an end product of lipid peroxidation was used as a marker of oxidative stress. it was determined by the yagi spectrofluorometric method. antioxidant activity was measured with an assay based on the inhibition of spontaneous autooxidation of a brain homogenate, and vitamin e in serum by the technique of hansen and warick. erythrocyte mda release fonowing incubation in hzo in vitro was used as a functional measure of tissue vitamin e levels. data were compared using one-way variance analysis. there was not significant differences in the plasma mda production among the values obtained before surgery ( :t: . nmol/ml), postoperative pre-pn ( . +_ . nmol/ml) and through the course of pn ( . : . nmol/ml). levels of vitamin e previous to surgery were , : . #g/ml and decreased to . _+ . #g/ml at hours post-surgery before starting pn. while receiving pn, concentrations of vitamin e increased progressively up to + . l #g/ml (p = . ). pre-surgicai plasma antioxidaut activity values ( :i: %) dimiuished in the first postoperative day ( _+ . %) and then showed a clear increasing tendency, directly correlated with that observed in vitamin e levels. the measurements of the maximal percentage of mda release of erythrocytes in vitro, showed an inverse relationship with plasma vitamin e levels and with the plasma antioxidant capacity: preoperative . + . % and postoperative descending from . + % to _+ . %. our results indicate that during surgery and within hours postsurgery, a decline in antioxidant defenses occurs, in the postoperative period, while patients are on pn and taldng into account our obtained data: the unaltered mda values, the rise of plasma vitamin e levels, the recovery of both functional erythrocyte membrane antioxidant protection and the plasma antioxidant activity, they do reflect that during the intravenous administration of lipid infusions, oxidative damage does not occur, probably due to the addition of vitamin e to pn solutions in order to avoid autooxidation of lipid emulsions. garnitine is one of the essential nutrient in the diet of newborn infants. mother's milk represents the natural eamitine source for the newborn infants. we studied enteral earnitine intake in premature infants eutrophic (eu) and hypotrophic (hy), fed with mothers milk trough consecutive days-from fifth to tenth day of life. mean gestational age was (range - ) weeks for eu and (range - ) weeks for hy. birth weight was ranged - g for eu and - g for hy (p < , ). breast milk carnitine concentration was , i.tmol/i in mothers milk delivered eutrophic babies, and singnificant higher mean coenetration , l.tmol/i, of hypotrophic premature infants (p< , ). breast milk earnitine concentration was ranged between , - , ~moi,'l, and daily carnitine excretion was between , - , p.mol/i, mean , +- , i p.molll. the daily mean carnitine intake was from - , mgkg/d, in eutrophic and , - , mg/kg/d, in hypotrophic premature infants, in milk volumene intake from - mllkgld., the results of this study suggest that premature infants should be fed with own mothers mitk in eady neonatal pedod in attempt to prevent camitine deficiency. keto-acids and parenteral lipid admlnistration. castorina m., antuzzi d., ricci r., rendeli c., polidori g. pediatric intensive care unit -catholic university -roma (italy). some metabolic studies have suggested that the administration of mediumchain tltgticerides (mct) might induce a marked increase in ketone body concentrations; the aim of this study is to evaluate the effective ketogenetic risk of infusing mct emulsions in total parenteral nutrition (tpn). two groups of seriously infected children were examined: a- septic infants were given to tpn with a % of long-chain tryglicerides ( lct). b- septic infants, in wich the lipid source in tpn consisted in a - mixture of lct and mct. the children in the different groups showed similar severity and therapeutic scores (prism, tiss, ~, f~ , f~ ); the lipid intake was the same, corresponding to - . g, ckg bodyweight/day. in all patients a sample of urine was taken six times a day for the whole time of tpn the urine samples were screened by the diphenylhydrazone test, and the ketoacids excretion was confirmed by a chromatography. the urinary excretion of -keto-acids equivalent to p-ohphenyl-pymvate (mcg/ml urine) is summarized in the no significant increases in frequence and/or in severity of acid-base disturbances were found in all studied patients in consequence of the lipid infusion. the patients of b-group showed a lower excretion of -ketoacids. the c~-keto-acids excretion was ever unsignificant and seemed to be correlated with the illness severity more than with the lenght of the tryglicerides chain. this observations let us suppose that the mct, at employed doses, can be safely administred also in childen with metabolic acidosis and/or serious illness. reye syndrome cayetano heredia hospital, lima, peru five patients with reye syndrome were studied; included were those diagnosed from january to march and treated at cayetano heredia hospital. the age of presentation varied from z. to months. the syndrome occurred more frequently in males ( / ); the time of illness at the presentation varied from to lo days, and the following features were found: fever ( / ), akeration in mental status ( / ), seizures ( / ), gastrointestinal illnesses (diarrhea) ( / ), and respiratory insufficiency ( / ) --in this case ventilator)-support was needed, in all cases hepatomegaly, intracranial hypertension, hypokalemia hyponatremia, metabolic acidosis, hyperammonemia and elevation of hepatic enzymes were found. coagulation blood tests were abnormal in three patients. cerebrospinal fluid (csf) showed hypocellularity in all cases (less than cells/ram ). the cultives were negative, and the final diagnosis was confirmed by hepatic biopsy. no deaths were due to reye syndrome. a contribuhon to the study of reye's syndrome the aulhors analysed records of patients meeting all the clinical, biochemical and anatomic criteria put forward by hutrealoch~ and samaha ( ) who were ireated at the emergency and resusdlation depammlt tithe ipch in years. the average age of the children was years (the ~umgest monks and the driest year~ most of lhon ( / ) came from lhe countryside to lhe lmfia~ willfin hours of file oulbreak. a few days previously the patients w¢~ld have fever (some of ahem wilh diarrhea or cough) ,,rod vomit then rapidly fidl into coma and c~nvuksien. they ~me to the imtia~ with the signs of typical increased inlracranial pressure ( stages - according to lovejiy for most cases) but the liver was unllkely big. the main biocheafical dmnge of the blood was acute hepatic thilure -the bllod glucose decreased : (ha the aver~ , n~% ( ) ~ not measured in five cases (glucose a"aces). -the blood ammonia ino~ased riven to microg/dl fin lhe average , n = ) -the percentage of p~in was low, in the average , % (n-- ), % at the lowest (a case ofmekaa lasling five days was ctwed with vitamin k). -got and gpt enzymes increased - times (n= ) besides, tht~re was decompcmated addt~is with lhe average valnes ph = . ; pcoz = ~ mmhg and eli = - ~ ~, (n~). the charadaislic dumge in the ¢~'ebrospinal fluid was a low glucose tx~acenwalien h the average of k mg/dl ( cases of glucose it'aces) ; meanwhile protein decreased in the average of mg/dl ( cases below mg/dl). besides ~here was no inflammatory lesion ~tion) : very serious brain oedona and fatty degeneration of live~ scatteredly or parllally.microso~ically (biopsy and necropsy) in file brain appeared bright space around blood arteries and glioma extended v'lrdmw -robin space, with no inflammatory reaction. liver.-the sa~dure was intact there was no " "mtlammal~s ' cell, the kupffer cells did not show hyperplasia but show a heterogenous deg~nerafion~eart: also showed a fatty degencralion in some areas of the myocard eellkidney: the ihtty degenerati~l scattetedly in the tubular cell. pano~as:fatty degeneration scattetedly in file pancreatic cell. two cases of liver biopsy for lhe rid lime (check before leaving file inslitute) found that fatty degeneration was r~tta~ nearty ff~pletely. the exact muse remained unknown. objectives: to analyse whether there exists serum and urine electrolyte disorder in children with respiratory failure, methods: we have made prospective study of children in our icu during a month period, electrolyte concentrations were measured in serum and urine collected during hours (sodium-na, potassium k, chloride-ci, calcium-ca, magnesium-mg and phosphorus-p). results: average values in serum were: na . +/- , (rv: - ) mmol/i, k . +/- . ( . - . )mmol/i), cl . +/- . ( - ) mmol/l, ca .t +/- . ( . . )mm /i), mg . +/- . ( . - . )mmol/i. average electrolyte levels in hours urine were: na . ~/~ . ( - )mmol/day. k . +/- . ( - )mmol/day, ci . +/- . ( - )mmol/day, ca . +/- . ( . - . )mmol/day and p . +/- . ( . - )mmol/day. conclusions: average serum ci and ca levels were decreased in children with respiratory failure. in urine, average k, ci, ca and mg levels were decreased and urine p concentration was increased. we concluded that serum and urine electrolite disbalance may be expected in children with respiratory failure. the nurse is going to kill me! (icu syndrome) anita duvndam ~, sonia v.d,sluis ~dpt. of pediatrics, div. pediatric intensive care, sophia children's hospital, rotterdam dpt. of pediatrics, div. pediatric tntensive care, juliana children's hospital, the hague. content description: this presentation will provide the critical nurse with background information concerning the identification, the prevention and management of the critical ill child who has developed the icu syndrome. the results of a questionnaire concerning the occurrence of icu syndrome on a picu will be presented. behavioral objectives: at the end of this session the participant will be able to: . describe four clinical symptoms of the tcu syndrome, . identify major sources of picu environmental stress, . discuss nursing's unique role in helping the child to cope with the icu syndrome, . discuss nursing's unique role in preventing icu syndrome. content outline: the icu syndrome is a situation in which the individual is not able to deal with changes in observation and interpretation of both quantity and of patterns of sensory perceptions. in other words the borders between the inner and outer world becomes unclear for the person. the exact incidence of the icu syndrome in the critical care setting is unknown, we have limited knowledge of the occurrence of the icu syndrome in critical ill children. yet critical ill children in our hospitals sometimes show the symptoms of icu syndromes. to be able to identify the occurrence of icu syndrome we developed a questionnaire. the thesis of the questionnaire was: does the icu syndrome occur in critical ill children in the age between three and ten, who have been intubated and/or ventilated in a picu? eighteen questionnaires have been send out to parents of critical ill children in two hospitals. the response was percent. conclusions: . most of the children were anxious (n= ), showed regression (n= ) or had sleeping problems (n-lo) during the stay on the picu. . children showed the same problems after discharge. . there is no relationship between environmental factors and symptoms of the tcu syndrome during the stay. . there is no relationship between preexistential behavior and symptoms of the icu syndrome during the stay. because the lack of a scientific definition for the icu syndrome in children and good criteria for diagnosis, we were not able to get an answer to our thesis. more research is needed. continuous veno venous haemofiltration (cvvh) was adopted as a first line renal replacement therapy in our paediatric intensive care unit (picu) some three years ago. ~/he process of introduction and development of cvvh proved to be an exciting challenge for nurses as indeed it was for the whole multidisciplinary team involved. we have successfully used cvvh in the treatment of over infants and children, weighing between - kg. the range of conditions treated is ever increasing. to date we have not only used cvvh for patients in renal failure and fluid overload, but also to gain biochemical control in tumour lysis syndrome-and metabolic disorders. other distinct patient benefits in comparison with more conventional means of renal replacement therapies are that, it is a continuous controlled treatment being extremely effective in creating 'space' for nutrition, which is especially important in the fluid restricted, catabolic patient. of paramount importance in providing this level of service is the education and training necessary to impart the skills and knowledge for nurses to become expert practitioners in this field. we now have a teem of highly advanced practitioners who have developed their nursing skills to provide even more holistic care for their patients. this group are embracing new challenges and responding positively to the developing service whilst expanding their knowledge base. this paper will discuss the advantages and disadvantages of cvvh as we have experienced, relating i t to the wide variety of patients we have treated. we wish to share how cvvh has become an accepted role of the picu nurse and how the service has been successfully implemented. integrated care pathways (icp's) define the optimum course of events in the care of a patient with a specific condition, within a set timescale. aims and methods: icp's and case management (cm) were introduced to evaluate and improve clinical practice. icp's were developed for patients undergoing surgery for atrial septal defect (asd) ventricular septal defect (vsd) and fallots tetralogy. they were based on the median experiences of the last patients. patients have been managed using icp's. results: analysis of variation from the icp's shows a reduction in the following potentially avoidable causes of variation: delay in extubation has been reduced from % to %, and patients ( %) were extubated earlier than the median. prolonged stay on the intensive care unit (icu) has decreased from % to %, and patients ( %) were discharged to the ward a day earlier than the median. the number of patients receiving inadequate post operative analgesia has decreased from % to %. delayed feeding after operation has been reduced from % to %. unavoidable delays in extubation and discharge from icu occurred in patients ( %) because of haemodynamic instability" or lung problems. cm utilising individualised pathways for these patients has reduced variation in care which can improve patient outcomes. pathways have been developed for other conditions and it is anticipated that approximately, % of patients will be treated using an icp revision of icp's results in continuous evaluation and improvement of the care provided, conclusions: the use of icp's and cm has improved patient care and decreased avoidable delays and variations. the future development of other icp's, combined with a case managed model for selected patients, is seen as a viable method of continuously improving patient care. this paper is a retrospective audit of children who received continuous veno venous haemofiltration (cwh) whilst on the paediatrie intensive care unit (picu), data was collected over a month period from may to january . the girls and boys were aged from day to ½ years (median ½ years) and weighed between , and kg (median . kg). length of admission to picu was to days (median days). sepsis syndrome was diagnosed in cases: of these had bowel necrosis and meningoceccal disease. eight patients had an underlying haematological, oncolngical or immune disorder. the remaining children had inborn errors of metabolism ( ), nephrotic syndrome ( ), or cardiac failure ( ). cvvh was instituted for a variety of reasons. muttiorgan dysfunction was present in % of patients, % had acute renal failure, . % tumour lysis syndrome, . % uncontrollable metabolic acidosis with hyperammoneemia and % required fluid management. treatment was continued for between hours and days (median ½ days). haemofiltration was successful in achieving its desired effect in all except one patient. . % of children with haematological, ontological or immune disorders died despite successful haemofiltration. survival was higher in cases of septicaemia ( . %), nephrotic syndrome ( %) and errors of metabolism ( %). overall mortality was . %. this was attributed to the severity of the underlying disease process rather than the effectiveness of cvvh as a renal replacement therapy. asynchronous defibrillation and synchronized cardioversion deliver direct currents of high amplitude through the chest, to stop ventricular fibrillation or to convert life-threatening arrhythmias. since the human body is partially conductant, it should be possible that after a brief delay of time, a derivation of this monophasic defibrillation pulse is measurable in regions of the defibrillated body, other than the traject between anodal ("sternum") and cathodai ("ape~;") paddles. one could also estimate that health care personnel in the immediate environment of defibrillatoty shocks, are always at risk to possible electric injury. accidents might occur when health care personnel do not stand clear from the patient during firing and create an additional electric path from this patient through their own body. most likely, the nonisolated parts creating a transversal eiectric path, will be the hands of the caretaker. since defibrillation generates touch voltages up to v and - a in ved, short delay's ( to millisec), the total body resistance during skin to skin or skin to paddle contact, is calculated to be as [ow as ohm (percentile tank for the entire population). an experimental protocol was developed to evaluate the conducted currents during defibrillation. mature pigs with a weight of up to kg. were used as animal models. the:,, had barbiturate anaesthesia, inotropic support with dobutamine at l micmgrams/kg bodyweight and all had a sinasat rhythm at the begining of the test-rounds. synchronized defibrillation at j (approx. . j/kg) and asynchronized -at j (whenever ventricular fibrillation or ventricular tachycardia occurred), were attempted, through latero-lateral placed and firmly pressed defibrillation paddles and/or adhesive multi-function electrodes. gel pads were choosen as contactmedium to cross the skinpaddle barrier. subdermal electro-myography needle electrodes were put at different parts and regions of the pig's body, but not between the paddles. these electrodes were coupled to a resistance device of ohm and a measuring computer. we measured monophasic and low current pulses up to , a during the defibrillation burst. thus conducted currents are high enough to produce accidental electric shocks when additional electric paths are created by the caretaker. "llaese are usually harmless, but in some "worst case" (wet or transpiring hands, rings,...) or in association with defectuous equipment, peak currents might be harmfull, and can produce pain, bums, apnae or cardiac (transient or persistant) arrhythmias. maria skogbv. karin mellgren, lars-g ran friberg, g sta mellgren, hans wadenvik. g teborg, sweden. bleeding complications in extracorporeal circulation is partly due to perfusion-induced platelet dysfunction. the aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeat system. study: two complete extracorporeal life support systems were perfused with fresh heparinized human blood for hours. piatetet membrane glycoprotein changes, platelet granule release and platelet count were followed. eight paired experiments were performed. one of the circuits was perfused by a roller pump (polystan) and the other by a centrifugal pump (biomecicus), other components were identical. results: a continuous increase in glycoprotein (gp) ib-negative platelets was seen in both circuits. a marked increase of plasma beta-thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. the plasma concentration of glycocalioin increased in parallel with a reduced platelet surface expression of gpib, suggesting that the loss of gpib is caused by proteolysis rather than by a downregulation of this receptor protein. conclusion: hours of ecls perfusion induces pronounced platelet degranutation and causes changes of important membrane receptors. this is in accordance with clinical studies, suggesting that our in vitro model does mirror the platelet exhaustion observed in a clinical reality. no significant difference was observed between the two pumps. the purpose of this study was to examine signs of distress exhibited by several patients following the discontinuation of opioids and benzodiazepines (o & b) in a -bed pediatric intensive care unit. the authors compiled a list of all cases of possible withdrawal reactions reported by nurses in the study setting over a one-year period. five cases were selected for study in terms of their wide diversity of relevant circumstances. the cases were examined through a retrospective chart review. data pertaining to analgesic and sedative administration, along with nurses' reports of behavioral distress, were transcribed and coded. a remarkable pattern of behavioral distress was clearly associated with discontinuation of o & b. cessation of benzodiazepines was associated with severe distress. these reactions were characterized by various combinations of crying, irritability, tremors, grimacing, gagging, vomiting, or feeding problems. some of these persisted in spite of large amounts of bolus drug administration. these signs were manifested for to days following cessation of o & b. these findings demonstrate that the rapid weaning of o & b infusions, sometimes following short-term therapy, can cause severe withdrawal reactions. the particular course that a specific patient will follow will likely be modulated by underlying manifestations of "icu psychosis" and unresolved pain and emotional distress. hermana tezano mt, pilaf orive j, latorre garcia j, lizarraga azparren ma, lopez bayon j ucip hospital de cruces. bilbao. spain a female child, one year old, was referred to our unit from another hospital because she had ischemic syntomsjn her right forearm wich started three days before. she had ~i downs syndrome and fallot's tetralogy with a systemic-pulmonary by-pass. nine days before the admission in our hospital she was undergone to a cardiac catheterization by arterial and venous femoral punctures with no incidences. on the admission to the picu her forearm was cold and pale with absence of cubital and radial pulses and slow capilary filling. treatment with heparine was started unsucessfully in the firsts hours, so uroquinase was added that later was changed to rtpa plus brachial plexus blockade. by the time me arterial tlux became more and more evident (doppi~) il bccuute aiat) evident a regional aedema witch made necessary a fasciectomy &the wrist. she also developped necrotic delimitted areas that included her first and fifth fingers. she was discharged from the picu after days and a week later she went to the operating room where an amputation of the distal phalange of the fifth finger was made. the etiolgy of this ischemic picture can't be attributed to the catheterization itself, but probably it should be due to some attempts in arterial puncture in its course, attempts that could be guess by the little marks noticed at the elbow flexure when she was admitted. long maintenance of cardiovascular funtion by assisted ventricular device with membrane oxigenator hermana tezanos mt, pilar orive j. latorre garcia j, lizarraga azparren ma lopez bay n j. ucip. hospital de cruces. bilbao. spain a little girl of three and a half years came to the intensive care unit from the operating room. affected of great vessels transposition with a pulmona~' banding corrected vith rastelli technique, it became impossible to discharge her from the by-pass circulation. it was assumed that this factt was due to a transient myocardial disfunction dfter the surgeon x~ent through the technique and found no wrong step in it. at the picu admission she had an ejection fraction belox~ % (echncardiografy), and was manteined on veutricular assistance with a circuit consisting ofa plate's membrane oxigenator, a bio-medicus pump and pvc rubber tubes, with monitoring of pulmonary', right and left atrial pressures. initially she needed a ventncular support of . l/min with dopamine. dobutamine and adrenaline; gradually the ejection fraction rose to % aliowing a decrease in the mechanical and inotropic support. the organic function ,.'.-as preserved but x-ray of the thorax showed images of pulmonary aedema with an increase in the needs until a fi of . . even though she was placed in a transplant program, she was remouved when the ejection fraction rose to % on the lth da of the evolution. there were no signs of infection (profilactic coverage). on the fifhteen postsurgery day. with a good cardiac sound and an ejection fraction of at least %. it was considered the withdrawal of the ventficular support, but unsucessfully despite the increase ofinotropic drugs, so she died. we think that our patient is a good example of the posibiti~ to mantain x~ith ecmo during a prolonged period of time a potential transplant receiver without major complicatios. joan wierema; ma )an mourik. sophia children's hospital, department of pediatric surger,j, rotterdam, the netherlands. the success of an ecmo program is heavily determined by the organizational structure and the daily availability of both well trained nurses and physicians. until now there is no general guideline to determine the optimal training schedule to set up an ecmo program. objective: to evaluate the set-up of an ecmo program in an area without direct availability of perfusionists of cardiothoracic surgeons. description of the progress: during the preparation of the ecmo program which started november , different phases are identified. first phase, acquisition of experience by training abroad of one physician, staff member of the icu, physician acting as a fellow and one icu nurse with theprimary task to serve as an ecmo coordinator and train the nursing start. in the second phase animal experiments were performed by paediatric surgeons, staff physicians, fellows and nurses. third phase, start of the actual ecmo program, priming by one trained nurse and ecmo fellow, daily care of the patient by nurses, icu nurse taking care of the patient related activities, ecmo trained nurse taking care of the circuit. fourth phase, transition of the tasks for priming the system from the ecmo fellow to the ecmo nurse and changing daily care for the ecmo patient now including the circuit by trained icu nurse with special legislation for ecmo. ongoing training of to nurses working for at least half a year in the icu. during an ecmo run direct contact between the ecmo nurse and one of the staff members; patient data: in a year period neonatal ecmo cases were performed with an overall mortality of %, ranging from over % in meconium aspiration to % in congenital diaphragmatic hernia. in other patients pediatric ecmo (age range month - months) mortality was %. conclusions: ecmo can be established without perfusionists or cardio surgical back up once a predetermined training schedule is available, resulting in comparable results with the international ecmo registry both for neonatal as well as for pediatric cases. mechanical ventilation at home makes normal development of the child with chronic respiratory failure possible. the parents must be encouraged to accept the treatment at home; therefore, they should be enabled to take care of their children all by themselves and the continuous professional support has to be offered to them. it must be stressed that the nurse is the link between the diseased child and his family introducing them into the process of the medical care at home. all the equipment needed for the mechanical ventilation of the child at home (ventilator, suction device, pulse oxymeter, oxygen tanks) has to be provided before the child is discharged. it is paid by the national insurance company. the maintainance service workers will make the necessary installations available and they will renew oxygen and compressed air weekly. the ventilation assembly must not interfere with the childs activities. the related dispensary and nursing service should be notified of the child's condition and the list of the required material (suction tubes, cannulas, desinfectants etc.) has to be made. our experience is so far -from the nursing and medical point of view -satisfactory, however the social status of the parents needs further regulations, omphalocele. mourik m, sophia children's hospital, department of pediatric surgery, rotterdam, the netherlands. in patients with (giant) omphalocde operative closure is impossible due to the lack of intra-abdominal space and a variable degree of pulmonary hypoplasia. consequently conservative treatment allowing epithelialization is the treatment of choice with a high risk of infection and/or sepsis due to a sometimes very long stay in the icu. this conservative treatment consists of daily application of an antibiotic containing powder on the cele which is covered by sterile gauzes. furthermore the enteral intake is started as soon possible. objective: to evaluate whether this treatment renders a high risk for serious infections. patient characteristics: in a year period patients with a giant omphalocele were admitted; mean birth weight g ( - g) mean gestational age . ( - weeks). overall mortality ( %). patients had to be ventilated for a median duration of t days ( , - ). results: patients were discharged at the mean of days following birth ( - ) following complete epithelialization of the omphalocele. following the initial stabilisation period parents were involved in daily care of all patients even during artificial ventialation. enteral intake was started at a median of days ( - ). colonization of the omphalocele was observed within - days in all patients. although infectious periods were observed at regular intervals, sepsis was the primarily cause of death in only of the patients who died, in conclusion: nursing care to prevent sepsis in patients with (giant) omphalocele is feasible for a long period of time and can be performed with simple measures, since june , we have been using nasal cpap in the treatment of respiratory disorders in newborn infants (severe apnea syndrom, tachypnea, hyaline membrane disease). in newborns presenting hyaline membrane disease, we have used cpap and administered surfactant therapy to premature babies out of . clinical data were : mean ga : . + weeks. mean bw : + g. mean administration time was hours. before administration, mean fio was . + . , mean pao . + . kpa and mean a/ao ratio . . all babies were intubated for administration of surfactant (curosurf) and were extubated after half an hour to hours after administration. this treatment failed for seven babies and they were ventilated by oscillation ventilation ; all babies survived. complications : we have observed pneumothorax in cases and cerebral hemorrage. mean duration time of nasal cpap was hours for the babies without assisted ventilation. nurses in charge of babies with nasal cpap should be aware of neonatal care, of the possibility of surfactant administration and of complications during this type of treatment. therefore nurses should know very well the use of nasal cpap, the monitoring during this treatment, the fixation of the system on the baby, nursing of the babies during this treatment and finally should take care of the baby physical and psychological well being. as a conclusion, nurses in intensive care neonatal units should know the possibility of treatment of rds by nasal cpap and should be aware of baby-nursing. emco in the postcardiotomy infan_t : a simplified circuit and reduced management grillet lsabelle, bosson christa, goelz andrea, helmer pascale, icu nurses, tschaut rudy perfusianist aldo castaneda institute, clinique de genolier, suisse to improve postoperative survival of infants with repaired cardiac tessions but severe residual cardiopnlmonary dysfunction, emco was used in infants, ranging in age from l days to months and in weight from , kg to , kg. diagnosis included tga / intact ventricular septum ( ) (both subiected to rapid arterial switch operation because of unsuitable lv function) and tga +vsd ( ). "['he emco circuit included a sarns roller ump, a medtronic minimax plus hollow fiber oxygenator and tubing ( / - / inch) with bioactive surfaces, an arterial canula fr., venous canulas : right atrial fr, left atrial fr., an air oxygen mixer and a sarns heater. the act was kept between - sec. after the infant was connected to emco by the surgical team and the perfusion technologist, the patients were being cared for and controlled exclusively by the cu nurse assigned to the patient and the physician on call for the icu, pump flows of - ml / kg / mln were targeted to insure an adequate urine output, a brisk capillary fill and physiologic left and right atrial pressures. sodium nitroprusside was used to control systemic hypertension while all other inotropic drugs were discontinued. inspired oxygen fraction on the ventilator was reduced to , at a respiratory rate of - breaths per minute. body temperature was maintened close to normal. when the heart started to eject again, inspired oxygen was increased to about , . the preparation for weaning from emco was done by the icu nurse: including oxygen fraction and ventilator rate. weaning from emcowas coordinated by the medical / surgical team and the perfusion technologist. the duration of emco in the patients ranged from to days. three patients ( %) were saccessflly weaned from emco. one of the three died within hours from neurologic complications, unrelated to the emco. the other patients ( both with tga + vsd ) are long term survivors and are doing well. neither the survivors nor the patients who died bad hemorrhagic complications, despite the fact that of the were placed on emco because of failure to wean from cardiopulmonary bypass. the simplified emco circuit worked reliably throughout this experience and no complications occurred nor could any shortcoming be ascribed to the use of this reduced, cost effective management team. years of praciical experience wiih exiracorporeal membrane oxygenation (echo) -the viewpoint of the nursing siaef monika schindler in a training program was started for the introduction of echo in the kinderklinik of mannheim/germsny. years later ( ) the first european echo patient, a days old newborn baby, ~as treated successfully in our institution. with echo, more treatment modalities ~ere available after failure of conventional therapy in eases of severe lung diseases like meeonium aspiration syndrome, congenital diaphragmatic hernia, sepsis/pneumonia, primary persistent pulmonary hypertension of the newborn and -in infants and children -ards (acquired respiratory distress syndrome) due to multiple underlying illnesses. in the first ards patient, a years old girl, was treated successfully ~ith ecmo in mannheim. until now patients (age: i day - years) were treated with echo in our institution; additional patients were transferred to us from other institutions for therapy with echo, but could be treated ~ieh alternative moda]ities of therapy like improved conventional ventilatory support, high frequency oscillatory ventilation (hfov) and inhaled nieric oxide (no), unexpectedly the more ~ide-spread use of hfov and no -also in other ~ntensive care units -did not lead to a reduction of the echo frequency in our hospital. due to this long ecmo practice, which is helpful in many critical situations, a certain routine came up in the nursing staff of our intensive care units; but ecmo continues to be a maximum strain for all co-workers and implies an high personnel and material/financial-expense. but in our opinion the improved survival rates in severe respiratory failure-( % in neonates and % in infants and children, estimated survival rates under continued conventional management: < %) by the use of echo justifies this expense, even in times of less financial support for public health. • analyse the differences between each urdt. method : ni criteria were defined by the rt~a ped group according to cdc criteria. all data were collected by a nursing and medical team. data vere dealed with epi info software. all u-dections data were validated by an external mvestigatol : patients who stay more than hours in an icu were included over a months period. % were newborns, % infants and , % children. ni were idenlified among sll patients, the overall ni incidence rates was , % and , person day, septicemia was the first cause of ni ( %). staphylococcus epidermidis were isolated in % of septicemia cases. pneumonia was the other main ni ( %) with gram negatwe bacille isolated m % ( % of them beei,ng fseudomonas) accordmg to age, the septicemia mcidence rate varied from , ~., to . %,, catheter/day and pneumonia incidence rate from , %, to , % ventilation/daywith the lowest rate for newborns. : this survey was possible thanks to the collaboration between laboratories, bacteriologist, physicians and nurses, and allowed each concerned unit to work together in~tead of every one in his own field. 'lhe results of this survey bring changes in attlhades and empower the different team work the next step is to analyse the ditferent nurses procedures of indwelling central venous catheter in each unit ar)d implement a ni quatity care. program in all nicu anti picu. v~,~jl~j~'v~y : new born in~ra-v~ nous drugs ~md lheir pr~taration mcounter a lot of risk ~)f utters, due to inadapted conditionn~ng to podia)eric and minimal amount injec~.~d, th~ study t~ed to evaluate degrees of do.~age er~o~ dye tt) dru~ preparaek, n i~ nc,:,~atol~gy and to come out w~th ~ method of dihttion able to reduce risk to minima (errors _< %) at the ~eme t~me, ¢o~,~x-tueaces on cost were studioj methnd~ : amikacine was choosen because this antibiotic is regularly ~,~l in neonatology unit and its dosage is easily used by standardiaud method, amikacine doses ( , mg doses and , mg doses) were prepared" by nurse~ form mg for m) vial. each dose w'a~ diluted to obtain mi volume, tallowing usual ward method, for each dilution, amikacine con<entrati('m and it,s volume was measured and used equipment for preparation wa~ regi~tred. "first s utj(m" were prepared diluting ~t'~ mg amikacine pouder inn ) ml glucnse solution bag (viaflex baxter bag with transfer cap), from tho~e "first solution" doses at mg and doses of ~ rng were prepared, amik~cine coc, cenir,)tmn for each preparabon and their volume were measured, ai,~n ntttl~,ber of seringe were tounted. first soiuhon staeiiity was conrroieo aher one week conservation at + '>c. amjkacine concentration were measured by fluorescence process (tdx abbott) after sample dilurion. on a mg/l sample, tovhnical reliahility show~ > ~ % of result mpmductlon and < % of variation due to dilutions. results : when amikacine injection werv pro.pared from araikacme /) mg for mt vial > % do~ge, ermr~ were found in / cases ; ~ % in ,t ,to cases. if preparation is done from amikacine "~it'st soltltion", les.--concenvr~tcd, it i~ more preci,,,e and only one dosage error ~ % ( , %} is found in eli studied doses. in add)inn to )hal if doses were wep,m-'d from one "first soiatiol~' bag, the cost economy sl~ouid b~" of fr~, and ii dos~$ were prepared tram the same bag the saving mtmey should be o{ i its .cencluslon : .ur survey shows th~t h' ntu)nato|ogy the u~ of a "first sohation which can be kept fi~r one week is enable to reduce dosage erroes and i~ co,~tsavmg, regarding [,v. admimst'rahon method the survey is still on, introduction: so-called vein of galen m~iformations ale rare in~racranial embryologycal anomalies, repl~senti~g tess than of symptomatic intracranied artefiovenoas l~alform~tions. the spontlneous prognosis is ~s~u~lly fatal, because of cardiac frilure due to left-to-right shunt thrq~ugh the fistula. recent developments of new techniques of treatment of the malformation and its cardiac consequence have led to a revolution in the practical approach of children w~th galen malformation. our fukfose is to contribute, with our persoaal series of s newborns and infal~ts admitted in our unit after endov~,scular embolization, to a better management of these children. such a management requ!res a rnultidisciplinary approach. intensive care are required prior to embollzation for patients with cardiac failure or cardiogenic shock and after cmbolization in order to insure cardiac and cerebral hemodyna.mic stabilities. this overlooking suppose for the nursing team to understand: prior to embolization : heart failure and cardiogenic shock. after cmbolization : evaluation of neurological and hemodynamic consequences of this proccdure, without forgetting the nursing and psychologic aspects, in concl'iision, this last ten yerrs, these new approaches give to the patients and their famitiy a good reason to hope a total recovew, in our exl)erience, the global mortality is % aad % of children #j-e neurologically normal after embolizafion, ii ii~ i ~ii i ii i i l i iiii~ i ~i iii i background: venous oxygen saturation (svo z) reflects the residuai oxygen after tissue oxygen extraction and represents the relation between tissue oxygen supply and demand. we studied svo and arterial lactate during progressive isovolemic anemia to assess the relation between svo and tissue hypoxia. subjects: ten - day old anesthetized ventilated piglets sao and svq were measured continuously by a fiberoptic catheter (oximetrix, abbott lab.) in the carotid and pulmonary a~epy tissue hypoxia was confirmed by a reduced vo, and an increase in lactate. conclusion: svo reflects better a reduced dp obtained by progressive anemia surfactant replacement improves gas exchange in early-stage adult respiratory syndrome (ards) [ , ], but not in late-stage ards [ ] . we report the first case of successfull treatment of ards after repeated instillation of surfactant.a ten year old boy, weighing kg, presented with hemorragic shock. biphasic-positive-airways-pressure ventilation was performed (evita ii, dr~ger, germany). he had recieved nine units of packed red blood cells and underwent surgical exeresis of two bleeding gastric ulcus. post-operatively, a cardiac arrest required cardiopulmonary resuscitation for three minutes. hemodynamic status was subsequently stabilised. the chest-radiograph showed infiltrates of both lungs without signs of cardiac failure. on the third day, the patient became severely hypoxic with a pao /fio ratio of . gas exchange was not improved by high ventilator settings. peak inspiratory pressure (pip) and ventilatory rates were cmh~o and breaths/min respectively. inspiratory:expiratory time was : and the positive end expiratory pressure (peep) cmh . after increasing the peep level to cmh , we instilled over minutes, mg/kg of porcine surfactant (curosurf, serene france), in two equal volumes in both main bronchus,the spo~ rose to % within rain, the fie could be reduced to . . twenty four hours later, gas exchange worsened again (pao /fio ratio ). we increased the peep from to cmh , and instilled a second dose of surfactant ( mg/kg). again, fie could be reduced within minutes (spo ; fie . .). the patient was weaned from the ventilator and extubated on the tenth day. follow-up at four month showed normal lung function.we demonstrate improvement in oxygenation after repeated exogenous surfactant administrations. we assume that in early-stage ards, surfactant may potentiate shunt-reducing effect of peep as it has been demonstrated in experimental model of ards [ ] , and allow decrease in fie . in case of secondary deterioration, we think that a second dose of surfactant should be administered. . weg jg, balk ra, tharratt rs, et al. ,lama : : - . . spragg rg, gillard n, pdchman p, et al. chest t : : - . . haslam pl, hughes da, mcnaughton pd. et al. lancet : - . . huang yc, caimulti sp, fawcett ta, et al. jappl physiol : - % (ref) . the aim of this study was to verify these data: patients/~lethods: all pts admitted to our multidisciplinary nicu/picu in were included if they were in respiratory failure recruiting conventional mechanical ventilation (cmv) with peep >_ and 'fig -: % or high-frequency oscillation ventilation (hfo) with mean airway pressure _> t cm h for or more houm. diagnosis, maximal ventilatory parameters, barotrauma, organ/ system failures, mechanism of death and glasgow oulcome scale (gos) and months after study entry were prospectively collected. results: patients were admitted to the unit, o whom required mechanical ventilation for a mean duration of . days. overall mortality was %, patients fulfilled study criteria. survivors had gos , pts with preexisting neurological impairment survived with gos . neonatal diseases included hyaline membrane disease ( ), meconium aspiration syndrome ( ) and cardiovascular surgery ( ), pediatric diseases included bacterial ( ) and viral ( ) pneumonia, aspiration ( ) and cardiovascular surgery beyond the neonatal period ( ). - ) . patients and methods: cefotaxim was used as a prophylactic agent in patients in life threatening situations (e.g. multitrauma, neurosurgery atc.). more than % children required cefotaxim for the treatment of severe infections (epiglotitis, meningitis, sepsis, pneumonia mainly in immunodeficient and neutropenic patients) in monotherapy or in the combination with the other antimicrobial agents. results: cefotaxim as a prophylactic drug was successful in all cases ( %). the effectivity of treatment of infections was . % ( patients). the change of antibiotic therapy required patients ( . %). patients ( . %) died, but only in of them ( . %) the obduction confirmed infection. conclusion: we conclude that cefotaxim is very effective and safe antibiotic and represents "golden standard" in the treatment of severe infections in childhood. in order to improve nursing quality, we recently adapted nursing care to the "five nursing functions" (activities of daily living, accompagnment in crisis, treatment, prevention and research) as described by the swiss red cross in accordance to the new educational guidelines of the european community, the aim of this study was to document complications of "treatment nursing function".methods: all treatment complications were prospectively collected by the nursing and medical staff. the nursing staff included patient (pt) name, time of occurence and exact description of complication, proposal for prevention and information of parents. the medical staff reported type of complication together with pt information, diagnosis, medication, treatment and interventions, outcome and referral, all complications were discussed in monthly meetings including nursing and medical staff.results: from january until december , pts were admitted to the picu/nicu for nursing days ( % of total bed occupancy). pts needed endotracheal intubation for an average of . days and pts required nasal cpap. complications in pts were noted ( per pi): inadequate check-up of equipment ; accidental extubation ( in intubated pts); bedsores ; false drug dosing ; wrong drug ; umbilical bleeding ; wrong transfusion setup ; nasal septal necrosis ). there was no mortality due to these complications. exact documention of treatment complications and their meticulous discussion within the medical and nursing staff may improve "treatment nursing function". however, documentation and evaluation of nursing within all "five nursing functions" will be nessecary in order to achieve optimal nursing care. cardiac output determination by thermodilution, using iced injectate has been shown to be valid and reliable in pediatric patients. it has been demonstrated in adult patients that there is no difference in cardiac output values when using room temperature injectate as compared to iced temperature injectate. the purpose of this study is to examine the effect of injectate temperature on cardiac output values in pediatric patients. our study consisted of sixteen pediatric patients who had oximetric thermodilution catheters in place after cardiac surgery and who had cardiac output determined using both iced and room temperature injectate. with each patient, cardiac output was measured once on the day of surgery and again the following day. in each case cardiac output was measured using both iced and room temperature injectate. statistical analysis included a two-way, repeated measures analysis of variance for each individual injectate administered and no significant differences were found in cardiac output. no statistically significant differences were found between groups with regard to the order of injectate administration or volume of injectate used (i,e., or cc's). the correlation coefficients between groups for cardiac output measurements at each injectate administration time, and for the average measurements across times, ranged between . to . (p < . ). preliminary data analysis suggests that cardiac output measurements for children are not effected by the temperature of injectate. a lenghty stay at a paediatric intensive care unit will always have sideeffects on a child's well-being and will put a high strain on the parents. in order to minimize the side-effects longterm intensive care unit opened in at the childrens' hospital. admitted children are all ~ongterm-ill and technically-dependent and the ventilatory support can alter from a tracheostoma to cpap or portable volume ventilator. nutritional support is applied by gastrostomies. a homelike atmosphere surrounds the children, they share a dormitory, a living-room and a dining-room the main purpose is to send the child home with or without technical equipment. this can only be implemented by giving structured education (theory and practice) to all categories involved. the multi-disciplinary team consists of one anaesthesiologist, head nurse, clinical specialist, rn nurses, nurses, one habilitation doctor, one social worker and therapists. twenty-four patients have been admitted to licu during these six years. length of stay was from one day to four years. four are presently staying at the trait. the assessment of pain in children ( - yrs) is still difficult, because children of this age have limited language and cognitive skills. to standardize the assessment of postoperative pain and distress in the intensive care unit an observational mstrument was needed that met several criteria. it should be easy to use in daily routine care. be suitable for the i.c. situation, and in children of - hrs of age. the comfort scale, an observational instrument designed to assess distress in infants in i.c. units, met these criteria. to accommodate the use of the comfort scale in the i.c. units and in research, nurses should be trained to use the scale. an additional requirement was that the inter-rater reliability should be sufficiently high, (cohen's kappa > . ). objectives: ) to introduce the comfort scale in the i.c.u.; ) to examine whether this instrument can easily, be incorporated into routine care; ) to investigate the inter-rater retiabtlity. methods: the comfort scale is an -item instrument specifically designed for use in pediatric i,c, units and contains both physiological items (heart rate, blood pressure) and behavioral items (e.g., alertness behavior, calmness/agitation, body movement, facial expression respiratory response, muscle tension). the observation period is minutes. the scale is supplemented with an item on crying tbr children who are not mechanically ventilated. groups of t.c. nurses were trained by means of video's and observations at the wards. after the training, each nurse completed scores with other nurses, after which the cohen's kappa was computed. when the kappa's for the items met or exceeded our . criterium, a new group of nurses was trained. results: to date, nurses have been trained. nurses find the comfort scale easy" to administer and a valuable addition to routine care in the i.c. unit. the cohen's kappa's were higher than . for all items that the inter-rater reliability was high. the comfort scale is feasible in postoperative care in the i.v. and is considered a valuable instrument to improve and maintain high postoperative quality of care in the i.c. unit. introduction:children with neuro-muscular disease are believed to have a higher resting energy expenditure (ree), because of their increasedwork of breathing.the influence of nocturnal nasal mask ventilation on energy metabolism and nutritional state of these children has not been studied so far.objective:l,ls the ree inereased? . s there an influence of nasal mask ventilation on the ree? .what is the nutritional state? .what is the estimated total energy expenditure(ete) in relation to the caloric intake? methods:a pilot study of patients( - years) .the following measurements were performed:l.anthropometry. .bioelectric impedance- .ree was measured by indirect calorimetry during the day (in bed) with and without nasal mask ventuation,ree was compared with predicted ree according to schofield(pee), .caloric-intake and activities were recorded during hour before measurement. .total energy expenditure was calculated as follows:measured ree x estimated activity factor. results:tin all children weight for height was too low, <p . .aii children had a low % of fat. .according to the healthy group, ree is not increased. ,nasal mask ventilation lowered ree in patients, in patient we measured a clear decrease.conclueion:l.anthropometry and indirect calorimetry were helpful in evaluating the nutritional state. .there is no increased ree,in t patient there is clearly effect of nasal mask ventilation. .when caloric intake was related to ree and level of activity patients had too low caloric intake. .the influence of nocturnal nasal mask ventilation and nutritional assessment should be evaluated longitudinally. increasing awareness that the neonate can percept pain and suffer following surgical procedures, has major impact on pain management. in our unit continuous morphine infusion (t /~g/kg/hr) was introduced from january as a standard medicatton following surgical procedures. before morphine was given as a bolus (i.m., i.v., rectal) of /~g/kg up till four times a day. repeated gifts of morphine were only gwen following observation by the nurse that the child experienced pain. aim of the study: to evaluate pain management before and tbllowing introduction of a continuous morphine infusion for postoperative pain in our icu. patients and methods: term born babies with isolated oesophageal atresia and tracheo-oesophageal fistula were included in the study. the total amount of morphine (/~£/kg/ hours); number of days morphine was given; duration of artificial ventilation was evaluated in a case control study. res ults: - - central venous catheters (cvc) have been increasingly used also at our picu, university medical centre ljubljana. besides advantages, the cvc has brought numerous risks of complications; the catheter sepsis occurs most often and can be fatal for the patient. for example, in we dealt with children aged - years or in other words . cvp per a child treated at our picu. a specialized unit for preparing parenteral natrition started to function in the university medical centre pharmacy in . after that we equipped a special room for preparing other necessary infusion mixtures and organized a team of nurses -"catheter nurses".their tasks comprise: managing cvcs, replacing and installing infusion systems and mixtures made at pharmacy, preparing drugs and some necessary infusion mixtures in special room, permanent training and co-operation with related disciplines, pharmacy, epidemiology, microbiology, etc. all registered nurses at picu have been trained for this work. the routine is as follows: in the morningafter the doctor's visit, we first check the cvc and change the dressings; according to the nurse's observations, the doctor decides whether there is a need to remove or replace the cvc. if the catheter site is inflamed, swollen, or purulent, a swab is taken for microbiological culture and the area cleaned. in case of systemic infection signs, cvc has to be replaced, blood culture taken and the infection treated with antibiotics. the dressings are always changed by two tmcatheter nurses together. afterwards the infusion mixtures for the next hours are prepared for each child. the infusion mixtures which will not be used immediately are kept on + °c; before application they are, of course, warmed to at least room temperature. finally the "catheter nurse" supplies the cvc with new infusion mixtures made at our pharmacy. our observations show that such work requires responsibility and is demanding; but our pemanent care lessens the number of complications. thus the described scheme fulfilled our expectations. perl- perative management of neonates with hypoplastic left heart syndrome muir warren, blondel maryse, foltz rhonda, farine martine, icu nurses, the aldo castaneda institute, clinique de genolier, switzerland both the pre-operative and post-operative physiology of patient with hypoplastic left heart syndrome is critically determined by the puhnonary-tosystemic resistance ratio. a high ratio results in minimum volume work for the right ventricle but is at the expense of important hypoxemia. a low ratio is reflected in minimum hypoxemia but an unfavorable increase in excess ventricular volume work. a resistance ratio of approximately results in an arterial oxygen saturation of % - %, a qp/qs of , and ventricular volume work only twice normal. this latter physiology appears best for oxygen delivery and systemic perfusion with tolerable volume work. carbon dioxide (co ) in the inspired gas is known to increase pulmonary vascular resistance without significantly influencing systemic resistance in the range of to tort partial pressure. hyperventilation with no co in inspired gas decreases pulmonary vascular resistance. thus, managing co may be useful to modulate the pulmonary-to-systemic resistance ratio, in the tast months, patients with hypoplastic left heart syndrome were managed by a norwood procedur e. patients with endotracheal entubation pre-operatively had co added to inspired gas to modulate the pulmonary-to-systemic flow ratio. patients had co added to inspired gas post-operatively. all but patient had characteristically large pulmonaary-to-systemic flow ratio with oxygen saturation mean % preoperatively, even in those patients receiving co , co was accompanied by elimination of metabolic acidosis pre-operatively. the most comlnon partial pressure of co added post-operatively was torr. po ranged from mmhg to mmhg. all surviving patients developed a metabolic alkalosis ( mean) when treated with co . there were deaths, one from drug toxicity, one from excessive post-operative hemorrhage, two from sepsis or mocardial insufficiency. only one patient benefited from catecholamine support which can increase systemic resistance unfaborably. in this experience co was felt to be an important adjunct in some patients pre-operatively and most patients postoperatively to faborably modulate the critically important systemic-topulmonary flow ratio, to maximize oxygen delivery and systemic perfusion, while minimizing excessive right vantricular volume work. key: cord- -cnrs zpg authors: rizvi, saniya; danic, michael; silver, mark; labond, virginia title: cytosorb filter: an adjunct for survival in the covid- patient in cytokine storm? a case report. date: - - journal: heart lung doi: . /j.hrtlng. . . sha: doc_id: cord_uid: cnrs zpg covid- is a pandemic that has affected not only the united states, but the entire world. the impact it has had has overwhelmed the entire healthcare system, from the unknown carrier status, poor testing capabilities to hospitals running out of ventilators for severely ill patients. there has been a variety of potential treatment modalities for the various forms of illness ranging from asymptomatic carriers to the ventilated icu patients. these include anti-inflammatory medications, antibiotics, immune-modulators, convalescent plasma, and others. the cytokine storm that inflicts some patients can be devastating to the vital organs of the human body in the form of acute respiratory distress syndrome (ards), renal failure, coagulopathy, and death. cytosorbentsⓇ cytokine filter is a potential treatment methodology aimed at reducing the cytokine storm, thus serving as a bridge for therapy in the acutely ill patients infected with covid- . the following case report demonstrates the utility in a critically ill patient who survived the cytokine storm after receiving the cytokine filter via continuous renal replacement therapy bridging him to further definitive therapy. the most common presentation is respiratory in nature. fever, cough and myalgias are the most common symptoms and about half the patients have dyspnea. leukopenia and lymphopenia seem to be a mainstay for laboratory findings. ct findings, if obtained, can be consistent with bilateral ground glass opacities in non-icu patients, however multilobar consolidation is evident in critically ill patients. severe cases of covid- have a variety of systemic signs however, the most critical cases demonstrate the development of ards (acute respiratory distress syndrome), followed by an acute kidney injury and then liver dysfunction. ards is an inflammatory response mediated by innumerable factors including ace , interleukin (il- ), tumor necrosis factor (tnf), and vascular endothelial growth factor (vegf) this type of lung injury is characterized by bilateral pulmonary infiltrates, hypoxemia, however without cardiogenic pulmonary edema being the etiology. the exact etiology is not yet well understood; however, the pathophysiology involves alveolar capillary damage, endothelial cellular damage leading to inflammation, necrosis, and apoptosis. this leads to alveolar edema. the diagnosis is made by a clinical presentation of respiratory failure, chest x-ray revealing bilateral infiltrates, hypoxemia as defined by pao /fio ratio of < mmhg. nih sponsored a multicenter randomized control trial in the treatment of patients with ards. the patients randomized to the low tidal volume arm had a survival benefit. the mortality rate was reduced from % in the conventional arm to the % in the low tidal volume arm. it is speculated that an associated decrease in il- concentrations may be a protective factor in the multisystem organ failure that is incurred in patients with ards. this protocol became known as ards net protocol with decreased tidal volumes ( - ml/kg of predicted body weight), maintaining plateau pressure between - cmh and lower levels of peep. additional therapies in severe ards include prone positioning to improve ventilation perfusion matching and alveolar recruitment, high frequency oscillatory ventilation at high respiratory frequencies, and extracorporeal lung support. with regards to ards in the covi- patient, the demographic for severe illness is unclear. it has affected immunocompromised patients, the elderly population, those with comorbidities, as well as young, and healthy patients. theories include the initial viral load, rate of replication, amount of ace deregulation, etc. the initial onset of rapid viral replication may cause massive epithelial and endothelial cell death and vascular leakage, triggering the production of exuberant pro-inflammatory cytokines and chemokines. the extensive inflammatory response of cytokines may lead to cytokine release syndrome or the "cytokine storm," which occurs when white blood cells are activated and release inflammatory signals (cytokines) that further activate more white blood cells. il- , il- , ferritin, tnf-alpha are some of the pro-inflammatory markers released in this cascade. this cytokine storm has been seen in a variety of medical conditions such as post-operative state after a major surgery, sepsis, shock, among others. the disproportionate release beyond that of a controlled immune response appears to play a crucial role in the significant morbidity and mortality of covid- disease process. the imbalance and pro-inflammatory state causes endovascular or capillary leakage, hemodynamic collapse, and severe end organ dysfunction. cytosorbents Ⓡ is a filter device approved in europe in different countries and being used as a trial basis in the united states to treat patients in a cytokine storm. the hemadsorption filter is inserted in the device medium used for patients receiving continuous renal replacement therapy (crrt) or extracorporeal membrane oxygenation (ecmo) therapy. inflammatory labs such as ferritin, crp, procalcitonin, and il- have been measured throughout the course of the filter therapy to monitor responsiveness. it has been successfully used in cytokine storm patients previously with septic shock, severe pro-inflammatory state in post-operative conditions. not only has it been shown to reduce the measured inflammatory markers, but also improves hemodynamics including map and overall short-term survival as measured. given the limited time since the covid- outbreak, there is not a significant amount of published research data available on covid- patients and their responsiveness to this therapy. currently, medications have been considered that target specific inflammatory markers such as tocilizumab, which targets il- . this cytokine filter essentially targets multiple different cytokines at a larger scale. however, applying the concept of the cytokine storm and the previous indication for cytokine filter, it became a promising consideration for refractory cases. it has been used in europe for treating these refractory cases of covid- who are being treated with mechanical ventilation with severe ards, failing the standard treatment of azithromycin and hydroxychloroquine. currently there are open trials in germany and italy enrolling patients and we hope to soon have more information on a global scale that may be applied to more patients. it has been used in over critically ill patients infected with covid- italy, china, germany, and france for covid- patients and with preliminary data that is very positive in reduction of cytokine levels. in fact, the italy brescia renal covid task force has made a formal recommendation to specifically use cytosorb in severe covid - patients with stage aki and receiving crrt. the following is a case report on a patient encounter and management course through the course of illness in which the cytosorbents Ⓡ filter was used for his presentation of covid- with severe ards, worsening renal dysfunction and evidence of evolving cytokine storm. patient is a -year-old male who presented to ed on march , for complaint of dyspnea, lethargy, myalgias and fever. he presumably came in contact with a covid- positive patient at a birthday party two weeks prior. his past medical history was significant for diabetes, and the patient denied cough, chest pain, vomiting, or diarrhea. initial vital signs revealed heart rate , respiratory rate , blood pressure / , pulse oximeter of % on room air, and fever with a temperature of . f. the patient's oxygen saturation improved to % on liters of nasal cannula oxygen but progressively needed l via a nonrebreather mask to maintain that saturation during his four-hour ed stay. physical examination revealed no signs of acute distress. his breath sounds were coarse, but no focal wheezing or rhonchi. his heart tones were regular and he had no lower extremity edema. overall, there were no remarkable findings on his physical exam. laboratory work-up was obtained in the emergency department shown below. there was no leukocytosis or anemia. hyponatremia, hyperglycemia were also notable. given his glucose of , hgb a c was evaluated and found to be . (reference range . - . ) indicating poorly controlled diabetes mellitus. this sodium level was then corrected to (within normal range) to account for the hyperglycemia. his ldh was significantly elevated to . he also had evidence of acute kidney injury with creatinine of . . initial laboratory results are demonstrated in table . table . laboratory results at initial presentation. his chest x-ray revealed bilateral infiltrates (figure ). per hospital protocol, influenza and respiratory syncytial virus swabs were ordered first and were negative. those negative results allowed for the respiratory viral panel and sars-cov- test to be sent out to the state lab. given his hypoxia, he was admitted to the pulmonary (non-critical care) floor to a primary care team with a pulmonary consultation. the pulmonary team empirically treated him for community acquired pneumonia with ceftriaxone and azithromycin as well as hydroxychloroquine on his first day of admission for presumed covid- infection. his respiratory viral panel came back negative. on hospital day , virology report resulted positive for covid- via nasopharyngeal swab. his first few days in the hospital were relatively benign. at this time, the rest of his laboratory work was grossly unremarkable with the exception of elevated lactate dehydrogenase (ldh) of . he also had one positive blood culture of gram-positive rods, diphtheroids likely due to contamination. he had no leukocytosis (however, had leukopenia), anemia, electrolyte abnormalities, or renal/liver dysfunction. the patient's hypoxemia initially responded to high flow nasal cannula and nrb, but on hospital day he required intubation for respiratory distress and arterial blood gas pao of mmhg and oxygen saturation of %. he was intubated on hospital day for worsening hypoxic respiratory failure. he developed ards as noted by his pao /fio ratio < . he was placed on ards net protocol, as described above of, high peep, low tidal volume ( - ml/kg ibw), and goal plateau pressure less than mmhg. on hospital day # , the patient's clinical status worsened and was persistently hypoxic and became hypotensive. he also developed a fever of . f. repeat sepsis work-up was initiated including urine cultures, blood culture. he was previously on ceftriaxone and azithromycin per pulmonary team from initial admission. once his covid- swab resulted positive, the ceftriaxone was discontinued, and he was only on azithromycin. efforts were made to improve ventilation with paralysis, ards net ventilator settings and prone positioning for alveolar recruitment. these maneuvers with ventilator settings of tv , rr , peep , fio % temporarily improved oxygenation and blood cultures from peripheral sites showed cleared diphtheroids contaminant. sputum revealed minimal candida. however, the team noticed that his creatinine was starting to elevate slightly from . to . . the patient continued to exhibit worsening oxygenation with significant bilateral pulmonary infiltrates (figure ), worse in the right lung. antibiotic therapy was broadened to cover hospital acquired pneumonia with zosyn . g every hours, vancomycin to be dosed by pharmacy for fluctuating renal function, and methylprednisolone mg every hours was added for pulmonary inflammation. as renal function worsened nephrology was consulted, and a right femoral quinton catheter was placed for impending continuous renal replacement therapy (crrt). figure . chest x-ray on hospital day with persistent hypoxia and fever. the patient continued to demonstrate bilateral lung infiltrates, but there is a new appearing consolidation predominantly in the right lung base. the progression of the patient's covid disease began to mimic other patterns the team had seen that often resulted in cytokine storm and eventual mortality, so the team considered applying a cytokine filter before the cytokine storm became insurmountable. in combination with nephrology we sought to obtain emergency irb approval for compassionate use to protect the lungs and kidneys from further damage secondary to cytokine storm. approval from the irb and family occurred on hospital day and the cytokine filter was shipped to our location. initiation of the cytosorbents Ⓡ filter included a live educational webinar to the icu team and live video assistance from the manufacturer of installation of the device to the standard crrt machine. figure . chest x-ray on hospital day which coincided with the first day of cytokine filter therapy showing persistence of infiltrates, improved aeration and improved right lower lobe consolidation. we obtained the filters from cytosorbents Ⓡ (seven deerpark drive, suite k., monmouth junction, nj ). the initial protocol required filter change every hours for the first hours followed by every hours. the flow rate of the filter was consistent at cc/minute blood flow throughout the therapy. a total of devices were used and thus the expected protocol of changing the filter every hours was extended to hours. he received the cytokine filter therapy and crrt spanning twelve days lest one due to hemodynamic instability requiring temporary halt four days into the treatment. that day the patient went into shock and required pressor support for seven more days. the length of treatment was based on recommendations by cytosorbents Ⓡ with the number of devices sent for this patient's treatment. upon initiating cytokine filter therapy, his respiratory status, hemodynamics, inflammatory markers, and labs were monitored. table describes the lung parameters measured during the filter therapy with trends including ventilator settings and abg results on a daily basis. between day - in which the oxygen requirements began to decrease, the patient did develop hemodynamic instability which is discussed below. his peep was decreased from initially on the first day on the filter to upon completion of the therapy. his abg did show persistent hypoxia on hospital day which resulted in the patient being paralyzed with vecuronium for two days after which his oxygenation was above at minimal peep ( ) and fio of %. figure . chest x-ray hospital day , days after the initiation of cytokine filter when the patient developed worsening hypoxia and increased oxygen requirements as indicated in table below. compared with prior x-ray there is worsening of bilateral pneumonia with interstitial and alveolar opacities. after twenty-four hours on crrt with cytokine filter (hospital day # ), the patient was noted to be hypothermic requiring warm blankets and fluids. the subsequent day the patient went into shock with persistent tachycardia, hypotension, and hemodynamic instability. previously, maps were between - mmhg however now dropped persistently with sbp s. bedside echocardiogram was done to assess for potential causes of shock. he did have a poor appearing ejection fraction without focal area of hypokinesis. there was no evidence of right ventricular strain and he was already adequately anticoagulated with iv heparin therapy. furthermore, there was no evidence of active bleeding (i.e. blood in foley catheter, stool, pulmonary secretions, or expanding hematoma in femoral central access site) to suggest hemorrhagic etiology. he was responsive to fluid boluses and pressor support suggesting hypovolemia. he was started on norepinephrine drip and subsequently epinephrine drip which improved his hemodynamic instability, and this improved his ejection fraction on bedside echocardiography. discussion was made with nephrology to halt crrt at this time and fluid resuscitate the patient. it was apparent that there was some difficulty in compatibility of the cytosorbents Ⓡ filter with the conventional crrt hollow fiber filter. subsequently, the filter was placed pre-crrt filter and it appeared to have resolved this issue. the following day, crrt with cytokine filter was reinstated. laboratory results were monitored daily as well. standard testing including acute phase reactants were also periodically evaluated to determine if they were trending in the right direction. these included standard blood counts and chemistry, ferritin, c-reactive protein, d-dimer, and il- level. the il- level was obtained twice and remained stable at on day and of filter therapy with a reference range of - . pg/ml. while unable to monitor il- as frequently as desired, the patient's clinical picture resembled that of cytokine storm and because the filter was in place, we were able to maintain hemodynamic stability with pressors and volume support. in other cases when we have witnessed cytokine storm, the patients were non responsive to pressors and volume and developed severe acidosis. once he was weaned off of pressors (approximately seven days of pressor support total), he began tolerating higher volume removal via crrt. his hemoglobins initially remained stable but decreased on day without any active signs of bleeding. although at this point he had received iv heparin therapy for a total of days. his d dimer remained persistently elevated to beyond the highest range coinciding with hypercoagulable state with this illness. his renal function on the day of initiation was poor with creatinine of . which improved daily with therapy. on hospital day , along with the significant hemoglobin drop as mentioned above, his renal function also worsened from . to . . his crp which was initially downtrending also went up significantly higher than the value on the day of initiation. however, after the setback on this day his status began to stabilize and by the last day of therapy, his crp was within normal range, renal function had improved, and hemoglobin remained low but stable. table discusses the daily hemodynamics, pressor requirements (with dose, if applicable) and relevant laboratory results. figure is a graphic representation of the patient's laboratory trends while on the cytokine filter. on hospital day , he developed dvt in his right upper and lower extremity, consistent with the laterality that included his femoral quinton and picc line for intravenous access. despite adequate anticoagulation initially with heparin drip when the two blood clots developed, he was switched to argatroban drip due to persistent clotting and still developed dvt in all four extremities by day twentytwo, or the last day of the filter therapy. when the crrt and cytokine filter therapy was discontinued, the patient was switched over to hemodialysis for renal replacement. having survived the cytokine storm and sepsis associated with covid the patient was able to tolerate further novel treatment modalities. the patient received tocilizumab mg on hospital day and . he also received one unit of convalescent plasma on hospital day . after days on the ventilator the patient was extubated, however, had to be reintubated within hours. a tracheotomy was performed for respiratory management and the patient tolerated that procedure well and began to communicate with hand motions and facial gestures. the next several days of his admission were uneventful and he was receiving supportive care and peg tube for nutritional support. on hospital day # the patient suffered a pea arrest that resulted in return of spontaneous circulation after three rounds of compressions, mg of epinephrine. this was almost three weeks after the cytokine filter therapy was discontinued. it was suspected due to hypoxia as he disconnected himself from the ventilator just prior to the code blue. he had complete neurological recovery from this code blue once oxygenation had improved. behavioral health was consulted and recommended sertraline mg daily and quetiapine mg daily for treatment of severe depression and anxiety secondary to extensive hospital stay. on hospital day # blood was noted from his nasogastric tube and he had worsening anemia requiring blood transfusion (hemoglobin of . ). gastroenterology team was consulted and an urgent esophagogastroduodenoscopy (egd) revealed that he developed gastric ulcers. this made anticoagulation complicated since he has a thrombogenic disease process resistant to heparin requiring him to be on argatroban for several weeks. the patient is still alive today and was discharge to a subacute rehab facility after days in the hospital. he is motivated to continue with therapy and improve over a long period of time given the active lifestyle he held prior to hospitalization. fda requirements for emergency use criteria include ( ) the patient has a life threatening or serious disease or condition that needs immediate treatment; ( ) no generally acceptable alternative treatment for the condition exists; and ( ) because of the immediate need to use the device, there is no time to use existing procedures to obtain fda approval for the use. cytosorbents Ⓡ required that a patient's lung disease progressed to a severe state and evidence of multiorgan dysfunction was present. it can be speculated that the substantial lung damage may have already occurred prior to the initiation of the therapy and may not resolve quickly or even completely. we believe that earlier application of blood filtering could potentially mitigate cytokine storm before the possibly irreversible damage occurs. this may allow for better recovery. the application of a cytokine filter therapy has shown great potential benefit and it would be worth-while to obtain more studies in regard to this therapy for future use. this patient was a young -year-old male with a past medical history of diabetes that had covid- exposure, respiratory symptoms, and hypoxia. throughout his hospitalization, he developed ventilator dependent respiratory failure, received hydroxychloroquine, azithromycin as well as other supportive measures including vitamin c and zinc. despite this he continued toward cytokine storm, acute kidney injury and was selected for cytokine filter via continuous renal replacement therapy. he has had a very long hospital course and was discharged to a subacute rehab facility on hospital day . upon discharge, he was tracheostomy dependent with pressure support only at night. he required enteral feedings due to persistent dysphagia and aspiration risk. he will still require hemodialysis three times per week. overall, the cytokine filter was by no means a curative therapy. we believe it was a bridge for the patient to prevent imminent death due to severe inflammatory response and extend his life. the patient was most critically ill in terms of ventilator requirements and pressor support just prior to each of the two courses of the cytokine filter therapy and seemed to stabilize correlating to the initiation of blood filtration with oxygen requirements, pressor support and inflammatory markers. he received tocilizumab iv and convalescent plasma. his clinical course was complicated further by a hypoxic cardiopulmonary arrest, upper gi bleed and severe depression and anxiety. given the severity of his illness to begin with, the rapid progression toward cytokine storm and the subsequent medical complications he endured, i believe that the cytokine filter successfully completed the goal of prolonging his life to bridge definitive therapy in cytokine storm. with regards to the submission of cytosorb filter: an adjunct for survival in a covid- patient in cytokine storm? a case report.-for your review and consideration to be included in the the journal of cardiopulmonary and acute care. this manuscript is a case report of which all co-authors were involved. we have no conflicts to acknowledge. in addition, this case report, either in part or total, is not being considered for publication elsewhere. it has not been previously published. brita filter for blood' aims to remove harmful cytokines for covid- first successful combination of ecmo with cytokine removal therapy in cardiogenic septic shock: a case report acute respiratory distress syndrome: new definition, current and future therapeutic options virology, epidemiology, pathogenesis, and control of covid- coronavirus resource center paradigm shift for covid- response: identifying high-risk individuals and treating inflammation preliminary results of initial testing for coronavirus (covid- ) in the emergency department the single-cell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to wuhan -ncov infection key: cord- - a pviol authors: kamilia, chtara; regaieg, kais; baccouch, najeh; chelly, hedi; bahloul, mabrouk; bouaziz, mounir; jendoubi, ali; abbes, ahmed; belhaouane, houda; nasri, oussama; jenzri, layla; ghedira, salma; houissa, mohamed; belkadi, kamal; harti, youness; nsiri, afak; khaleq, khalid; hamoudi, driss; harrar, rachid; thieffry, camille; wallet, frédéric; parmentier-decrucq, erika; favory, raphaël; mathieu, daniel; poissy, julien; lafon, thomas; vignon, philippe; begot, emmanuelle; appert, alexandra; hadj, mathilde; claverie, paul; matt, morgan; barraud, olivier; françois, bruno; jamoussi, amira; jazia, amira ben; marhbène, takoua; lakhdhar, dhouha; khelil, jalila ben; besbes, mohamed; goutay, julien; blazejewski, caroline; joly-durand, isabelle; pirlet, isabelle; weillaert, marie pierre; beague, sebastien; aziz, soufi; hafiane, reda; hattabi, khalid; bouhouri, mohamed aziz; hammoudi, driss; fadil, abdelaziz; harrar, rachid al; zerouali, khalid; medhioub, fatma kaaniche; allela, rania; algia, najla ben; cherif, samar; slaoui, mohamed taoufik; boubia, souhail; hafiani, y.; khaoudi, a.; cherkab, r.; elallam, w.; elkettani, c.; barrou, l.; ridaii, m.; mehdi, rihi el; schimpf, caroline; mizrahi, assaf; pilmis, benoît; le monnier, alban; tiercelet, kelly; cherin, mélanie; bruel, cédric; philippart, francois; bailly, sébastien; lucet, jc; lepape, alain; l’hériteau, françois; aupée, martine; bervas, caroline; boussat, sandrine; berger-carbonne, anne; machut, anaïs; savey, anne; timsit, jean-françois; razazi, keyvan; rosman, jérémy; de prost, nicolas; carteaux, guillaume; jansen, chloe; decousser, jean winoc; brun-buisson, christian; dessap, armand mekontso; m’rad, aymen; ouali, zouhour; barghouth, manel; kouatchet, achille; mahieu, rafael; weiss, emmanuel; schnell, david; zahar, jean-ralph; artiguenave, margaux; sophie, paktoris-papine; espinasse, florence; sayed, faten el; dinh, aurélien; charron, cyril; geri, guillaume; vieillard-baron, antoine; repessé, xavier; kallel, hatem; mayence, claire; houcke, stéphanie; guegueniat, pascal; hommel, didier; dhifaoui, kaouther; hajjej, zied; fatnassi, amira; sellami, walid; labbene, iheb; ferjani, mustapha; dachraoui, fahmi; nakkaa, sabrine; m’ghirbi, abdelwaheb; adhieb, ali; braiek, dhouha ben; hraiech, kmar; ousji, ali; ouanes, islem; zaineb, hammouda; abdallah, saousen ben; ouanes-besbes, lamia; abroug, fekri; klein, simon; miquet, mattéo; thouret, jean-marc; peigne, vincent; daban, jean-louis; boutonnet, mathieu; lenoir, bernard; merhbene, takoua; derreumaux, celine; seguin, thierry; conil, jean-marie; kelway, charlotte; blasco, valery; nafati, cyril; harti, karim; reydellet, laurent; albanese, jacques; aicha, narjess ben; meddeb, khaoula; khedher, ahmed; ayachi, jihene; fraj, nesrine; sma, nesrine; chouchene, imed; boussarsar, mohamed; yedder, soumaya ben; samoud, walid; radhouene, bousselmi; mariem, bousselmi; ammar, asma; cheikh, asma ben; lakhal, hend ben; khelfa, messaouda; hamdaoui, yamina; bouafia, nabiha; trampont, timothée; daix, thomas; legarçon, vincent; karam, henri hani; pichon, nicolas; essafi, fatma; foudhaili, nasreddine; thabet, hafedh; blel, youssef; brahmi, nozha; ezzouine, hanane; kerrous, mahmoud; haoui, saad el; ahdil, soufiane; benslama, abdellatif; abidi, khalid; dendane, tarek; oussama, ssouni; belayachi, jihane; madani, naoufal; abouqal, redouane; zeggwagh, amine ali; ghadhoune, hatem; chaari, anis; jihene, guissouma; allouche, hend; trabelsi, insaf; brahmi, habib; samet, mohamed; ghord, hatem el; habiba, ben sik ali; hajer, nouira; tilouch, najla; yaakoubi, sondes; jaoued, oussama; gharbi, rim; hassen, mohamed fekih; elatrous, souheil; arcizet, julien; leroy, bertrand; abdulmalack, caroline; renzullo, catherine; hamet, maël; doise, jean-marc; coutet, jérôme; cheikh, chaigar mohammed; quechar, zakaria; joris, magalie; beauport, dimitri titeca; kontar, loay; lebon, delphine; gruson, bérengère; slama, michel; marolleau, jean-pierre; maizel, julien; gorham, julie; ameye, lieveke; berghmans, thierry; paesmans, marianne; sculier, jean-paul; meert, anne-pascale; guillot, max; ledoux, marie-pierre; braun, thierry; maestraggi, quentin; michard, baptiste; castelain, vincent; herbrecht, raoul; schneider, francis; couffin, severine; lobo, david; mongardon, nicolas; dhonneur, gilles; mounier, roman; le borgne, pierrick; couraud, sophie; herbrecht, jean-etienne; boivin, alexandra; lefebvre, françois; bilbault, pascal; zelmat, setti-aouicha; batouche, djamila-djahida; mazour, fatima; chaffi, belkacem; benatta, nadia; sik, ali habiba; talik, i.; perrier, maxime; gouteix, eliane; koubi, claude; escavy, annabelle; guilbaut, victoria; fosse, jean-philippe; jazia, rahma ben; abdelghani, ahmed; cungi, pierre-julien; bordes, julien; nguyen, cédric; pierrou, candice; cruc, maximilien; benois, alain; duprez, frédéric; bonus, thierry; cuvelier, grégory; ollieuz, sandra; machayekhi, sharam; paciorkowski, frédéric; reychler, gregory; coudroy, remi; thille, arnaud w.; drouot, xavier; diaz, véronique; meurice, jean-claude; robert, rené; turki, olfa; ben, hmida chokri; assefi, mona; deransy, romain; brisson, hélène; monsel, antoine; conti, filomena; scatton, olivier; langeron, olivier; ghezala, hassen ben; snouda, salah; ben, chiekh imen; kaddour, moez; armel, anwar; youness, lafrikh; abdelhak, bensaid; youssef, miloudi; najib, al harrar; mustapha, amouzoun; noufel, mtioui; mohamed, zamd; salma, el khayat; ghizlane, medkouri; mohamed, benghanam; benyounes, ramdani; montini, florent; moschietto, sébastien; gregoire, emilien; claisse, guillaume; guiot, julien; morimont, philippe; krzesinski, jean-marie; mariat, christophe; lambermont, bernard; cavalier, etienne; delanaye, pierre; benbernou, soumia; ilies, sofiane; azza, abdelkader; bouyacoub, khalida; louail, meriem; mokhtari-djebli, houria; arrestier, romain; daviaud, fabrice; francois, xavier laborne; brocas, elsa; choukroun, gérald; peñuelas, oscar; lorente, josé-angel; cardinal-fernandez, pablo; rodriguez, josé-maria; aramburu, josé-antonio; esteban, andres; frutos-vivar, fernando; bitker, laurent; costes, nicolas; le bars, didier; lavenne, franck; devouassoux, mojgan; richard, jean-christophe; mechati, malika; gainnier, marc; papazian, laurent; guervilly, christophe; garnero, aude; arnal, jean michel; roze, hadrien; richard, jean christophe; repusseau, benjamin; dewitte, antoine; joannes-boyau, olivier; ouattara, alexandre; harbouze, nadia; amine, a. m.; olandzobo, a. g.; herbland, alexandre; richard, marie; girard, nicolas; lambron, lucile; lesieur, olivier; wainschtein, sarah; hubert, sidonie; hugues, albane; tran, marc; bouillard, philippe; loteanu, vlad; leloup, maxime; laurent, alexandra; lheureux, florent; prestifilippo, alessia; cruz, martin delgado maria; romain, rigal; antonelli, massimo; blanch, torra lluis; bonnetain, franck; grazzia-bocci, maria; mancebo, jordi; samain, emmanuel; paul, hebert; capellier, gilles; zavgorodniaia, taissa; soichot, marion; malissin, isabelle; voicu, sebastian; garçon, pierre; goury, antoine; kerdjana, lamia; deye, nicolas; bourgogne, emmanuel; megarbane, bruno; mejri, olfa; hmida, marwa ben; tannous, salma; chevillard, lucie; labat, laurence; risede, patricia; fredj, hana; léger, maxime; brunet, marion; le roux, gaël; boels, david; lerolle, nicolas; farah, souaad; amiel-niemann, hélène; kubis, nathalie; declèves, xavier; peyraux, nicoals; baud, frederic; serafini, micaela; alvarez, jean-claude; heinzelman, annette; jozwiak, mathieu; millasseau, sandrine; teboul, jean-louis; alphonsine, jean-emmanuel; depret, françois; richard, nathalie; attal, pierre; richard, christian; monnet, xavier; chemla, denis; jerbi, salma; khedhiri, wafa; necib, hatem; scarfo, paolo; chevalier, charles; piagnerelli, michael; lafont, alexandre; galy, antoine; mancia, claire; zerhouni, amel; tabeliouna, kheira; gaja, ali; hamrouni, bassem; malouch, abir; fourati, sami; messaoud, rihab; zarrouki, youssef; ziadi, amra; rhezali, manal; zouizra, zahira; boumzebra, drissi; samkaoui, mohamed abdennasser; brunet, jennifer; canoville, bertrand; verrier, pierre; ivascau, calin; seguin, amélie; valette, xavier; du cheyron, damien; daubin, cedric; bougouin, wulfran; aissaoui, nadia; lamhaut, lionel; jost, daniel; maupain, carole; beganton, frankie; bouglé, adrien; dumas, florence; marijon, eloi; jouven, xavier; cariou, alain; poirson, florent; chaput, ulriikka; beeken, thomas; maxime, leclerc; haikel, oueslati; vodovar, dominique; chelly, jonathan; marteau, philippe; chocron, richard; juvin, philippe; loeb, thomas; adnet, frederic; lecarpentier, eric; riviere, antoine; de cagny, bertand; soupison, thierry; privat, elodie; escutnaire, joséphine; dumont, cyrielle; baert, valentine; vilhelm, christian; hubert, hervé; leteurtre, stéphane; fresco, marion; bubenheim, michael; beduneau, gaetan; carpentier, dorothée; grange, steven; artaud-macari, elise; misset, benoit; tamion, fabienne; girault, christophe; dumas, guillaume; chevret, sylvie; lemiale, virginie; mokart, djamel; mayaux, julien; pène, frédéric; nyunga, martine; perez, pierre; moreau, anne-sophie; bruneel, fabrice; vincent, françois; klouche, kada; reignier, jean; rabbat, antoine; azoulay, elie; frat, jean-pierre; ragot, stéphanie; constantin, jean-michel; prat, gwenael; mercat, alain; boulain, thierry; demoule, alexandre; devaquet, jérôme; nseir, saad; charpentier, julien; argaud, laurent; beuret, pascal; ricard, jean-damien; teiten, christelle; marjanovic, nicolas; palamin, nicola; l’her, erwan; bailly, arthur; boisramé-helms, julie; champigneulle, benoit; kamel, toufik; mercier, emmanuelle; le thuaut, aurélie; lascarrou, jean-baptiste; rolle, amélie; de jong, audrey; chanques, gérald; jaber, samir; hariri, geoffroy; baudel, jean-luc; dubée, vincent; preda, gabriel; bourcier, simon; joffre, jeremie; bigé, naïke; ait-oufella, hafid; maury, eric; mater, houda; merdji, hamid; grimaldi, david; rousseau, christophe; mira, jean-paul; chiche, jean-daniel; sedghiani, ines; benabderrahim, a.; hamdi, dhekra; jendoubi, asma; cherif, mohamed ali; hechmi, youssef zied el; zouheir, jerbi; bagate, françois; bousselmi, radhwen; schortgen, frédérique; asfar, pierre; guérot, emmanuel; fabien, grelon; anguel, nadia; sigismond, lasocki; matthieu, henry-lagarrigue; gonzalez, frédéric; françois, legay; guitton, christophe; schenck, maleka; jean-marc, doise; dreyfuss, didier; radermacher, peter; frère, antoine; martin-lefèvre, laurent; colin, gwenhaël; fiancette, maud; henry-laguarrigue, matthieu; lacherade, jean-claude; lebert, christine; vinatier, isabelle; yehia, aihem; joret, aurélie; menunier-beillard, nicolas; benzekri-lefevre, dalila; desachy, arnaud; bellec, fréderic; plantefève, gaëtan; quenot, jean-pierre; meziani, ferhat; tavernier, elsa; ehrmann, stephan; chudeau, nicolas; raveau, tommy; moal, valérie; houillier, pascal; rouve, emmanuelle; lakhal, karim; gandonnière, charlotte salmon; jouan, youenn; bodet-contentin, laetitia; balmier, adrien; messika, jonathan; de montmollin, etienne; pouyet, victorine; sztrymf, benjamin; thiagarajah, abirami; roux, damien; de chambrun, marc pineton; luyt, charles-edouard; beloncle, françois; zapella, nathalie; ledochowsky, stanislas; terzi, nicolas; mazou, jean-marc; sonneville, romain; paulus, sylvie; fedun, yannick; landais, mickael; raphalen, jean-herlé; combes, alain; amoura, zahir; jacquemin, aemilia; guerrero, felipe; marcheix, bertrand; hernandez, nicolas; fourcade, olivier; georges, bernard; delmas, clément; makoudi, sarah; genton, audrey; bernard, rémy; lebreton, guillaume; amour, julien; mazet, charlotte; bounes, fanny; murat, gurbuz; cronier, laure; robin, guillaume; biendel, caroline; silva, stein; boubeche, samia; abriou, caroline; wurtz, véronique; scherrer, vincent; rey, nathalie; gastaldi, gioia; veber, benoit; doguet, fabien; gay, arnaud; dureuil, bertrand; besnier, emmanuel; rouget, antoine; gantois, guillaume; magalhaes, eric; wanono, ruben; smonig, roland; lermuzeaux, mathilde; lebut, jordane; olivier, andremont; dupuis, claire; radjou, aguila; mourvillier, bruno; neuville, mathilde; d’ortho, marie pia; bouadma, lila; rouvel-tallec, anny; rudler, marika; weiss, nicolas; perlbarg, vincent; galanaud, damien; thabut, dominique; rachdi, emna; mhamdi, ghada; trifi, ahlem; abdelmalek, rim; abdellatif, sami; daly, foued; nasri, rochdi; tiouiri, hanene; lakhal, salah ben; rousseau, geoffroy; asmolov, romain; grammatico-guillon, leslie; auvet, adrien; laribi, said; garot, denis; dequin, pierre françois; guillon, antoine; fergé, jean-louis; abgrall, gwénolé; hinault, ronan; vally, shazima; roze, benoit; chaplain, agathe; chabartier, cyrille; savidan, anne-charlotte; marie, sabia; cabie, andre; resiere, dabor; valentino, ruddy; mehdaoui, hossein; benarous, lucas; soda-diop, marième; bouzana, fouad; perrin, gilles; bourenne, jeremy; eon, béatrice; lambert, dominique; trebuchon, agnes; poncelet, géraldine; le bourgeois, fleur; michael, levy; camille, guillot; naudin, jérôme; deho, anna; dauger, stéphane; sauthier, michaël; bergeron-gallant, krystale; emeriaud, guillaume; jouvet, philippe; tiebergien, nicolas; jacquet-lagrèze, matthias; fellahi, jean-luc; baudin, florent; essouri, sandrine; javouhey, etienne; guérin, claude; lampin, marie; mamouri, ouardia; devos, patrick; karaca-altintas, yasemin; vinchon, matthieu; brossier, david; eltaani, redha; teyssedre, sonia; sabine, meyet; bouchut, jean-christophe; peguet, olivier; petitdemange, lucie; guilbert, anne sophie; aoul, nabil tabet; addou, zakaria; aouffen, nabil; anas, benqqa; kalouch, samira; yaqini, khalid; chlilek, aziz; abdou, rchi; gravellier, perrine; chantreuil, julie; travers, nadine; listrat, antoine; le reun, claire; favrais, geraldine; coppere, zoe; blanot, stéphane; montmayeur, juliette; bronchard, régis; rolando, stephane; orliaguet, gilles; leger, pierre-louis; rambaud, jérôme; thueux, emilie; de larrard, alexandra; berthelot, véronique; denot, julien; reymond, marie; amblard, alain; morin-zorman, sarah; lengliné, etienne; pichereau, claire; mariotte, eric; emmanuel, canet; poujade, julien; trumpff, guillaume; janssen-langenstein, ralf; harlay, marie-line; zaid, noorah; ait-ammar, nawel; bonnal, christine; merle, jean-claude; botterel, francoise; levesque, eric; riad, zakaria; mezidi, mehdi; yonis, hodane; aublanc, mylène; perinel-ragey, sophie; lissonde, floriane; louf-durier, aurore; tapponnier, romain; louis, bruno; forel, jean-marie; bisbal, magali; lehingue, samuel; rambaud, romain; adda, mélanie; hraiech, sami; marchi, elisa; roch, antoine; guerin, vincent; rozencwajg, sacha; schmidt, matthieu; hekimian, guillaume; bréchot, nicolas; trouillet, jean louis; besset, sébastien; franchineau, guillaume; nieszkowska, ania; pascal, leprince; loiselle, maud; sarah, chemam; laurence, dangers; guillemette, thomas; jacquens, alice; kerever, sebastien; guidet, bertrand; aegerter, philippe; das, vincent; fartoukh, muriel; hayon, jan; desmard, mathieu; fulgencio, jean-pierre; zuber, benjamin; soufi, a.; khaleq, k.; hamoudi, d.; garret, charlotte; peron, matthieu; coron, emmanuel; bretonnière, cédric; audureau, etienne; audrey, winters; christophe, duvoux; christian, jacquelinet; daniel, azoulay; cyrille, feray; aissaoui, wissal; rghioui, kawtar; haddad, wafae; barrou, houcine; carteaux-taeib, anna; lupinacci, renato; manceau, gilles; jeune, florence; tresallet, christophe; habacha, sahar; fathallah, ines; zoubli, aymen; aloui, rafaa; kouraichi, nadia; jouet, emilie; badin, julie; fermier, brice; feller, marc; serie, mathieu; pillot, jérôme; marie, william; gisbert-mora, chloé; vinclair, camille; lesbordes, pierre; mathieu, pascal; de brabant, fabienne; muller, emmanuel; robaux, marie-aline; giabicani, mikhael; marchalot, antoine; gelinotte, stéphanie; declercq, pierre louis; eraldi, jean-pierre; bougerol, françois; meunier-beillard, nicolas; devilliers, hervé; rigaud, jean-philippe; verrière, camille; ardisson, fanny; kentish-barnes, nancy; jacq, gwenaëlle; chermak, akli; lautrette, alexandre; legrand, matthieu; soummer, alexis; thiery, guillaume; cottereau, alice; canet, emmanuel; caujolle, marie; allyn, jérôme; valance, dorothée; brulliard, caroline; martinet, olivier; jabot, julien; gallas, thomas; vandroux, david; allou, nicolas; durand, arthur; nevière, rémi; delguste, florian; boulanger, eric; preau, sebastien; martin, ruste; cochet, hélène; ponthus, jean pierre; amilien, virginie; tchir, martial; barsam, elise; ayoub, mohsen; georger, jean francois; guillame, izaute; assaraf, julie; tripon, simona; mallet, maxime; barbara, guilaume; louis, guillaume; gaudry, stéphane; barbarot, nicolas; jamet, angéline; outin, hervé; gibot, sébastien; bollaert, pierre-edouard; holleville, mathilde; legriel, stéphane; chateauneuf, anne laure; cavelot, sébastien; moyer, jean-denis; bedos, jean pierre; merle, philippe; laine, aurelie; natalie, de sa; cornuault, mathieu; libot, jérome; asehnoune, karim; rozec, bertrand; dantal, jacques; videcoq, michel; degroote, thècle; jaillette, emmanuelle; zerimech, farid; malika, balduyck; llitjos, jean-françois; amara, marlène; lacave, guillaume; pangon, béatrice; mavinga, josé; makunza, joseph nsiala; mafuta, m. e.; yanga, yves; eric, amisi; ilunga, jp; kilembe, ma; alby-laurent, fanny; toubiana, julie; mokline, amel; laajili, achraf; amri, helmi; rahmani, imene; mensi, nidhal; gharsallah, lazheri; tlaili, sofiene; gasri, bahija; hammouda, rym; messadi, amen allah; allain, pierre-antoine; gault, nathallie; paugam-burtz, catherine; foucrier, arnaud; chatbri, bassem; bourbiaa, yousra; thabet, lamia; neuschwander, arthur; vincent, looten; beck, jennifer; vibol, chhor; amelie, yavchitz; resche-rigon, matthieu; pirracchio, jean mantzromain; bureau, côme; decavèle, maxens; campion, sébastien; ainsouya, roukia; niérat, marie-cécile; prodanovic, hélène; raux, mathieu; similowski, thomas; dubé, bruno-pierre; demiri, suela; dres, martin; may, faten; quintard, hervé; kounis, ilias; saliba, faouzi; andré, stephane; boudon, marc; ichai, philippe; younes, aline; nakad, lionel; coilly, audrey; antonini, teresa; sobesky, rodolphe; de martin, eleonora; samuel, didier; hubert, noemie; nay, mai-anh; auchabie, johann; giraudeau, bruno; jean, reignier; darmon, michaël; ruckly, stephane; garrouste-orgeas, maïté; gratia, elisabeth; goldgran-toledano, dany; jamali, samir; dumenil, anne sylvie; schwebel, carole; brisard, laurent; bizouarn, philippe; lepoivre, thierry; nicolet, johanna; rigal, jean christophe; roussel, jean christian; cheurfa, cherifa; abily, julien; lescot, thomas; page, isaline; warnier, stéphanie; nys, monique; rousseau, anne-françoise; damas, pierre; uhel, fabrice; lesouhaitier, mathieu; grégoire, murielle; gaudriot, baptiste; gacouin, arnaud; le tulzo, yves; flecher, erwan; tarte, karin; tadié, jean-marc; georges, quentin; soares, m.; jeon, kyeongman; oeyen, sandra; rhee, chin kook; gruber, pascale; ostermann, marlies; hill, quentin; depuydt, peter; ferra, christelle; muller, alice; aurelie, bourmaud; niles, christopher; herbert, fabien; pied, sylviane; loridant, séverine; françois, nadine; bignon, anne; sendid, boualem; lemaitre, caroline; dupre, celine; zayene, aymen; portier, lucie; de freitas caires, nathalie; lassalle, philippe; le neindre, aymeric; selot, pascal; ferreiro, daniel; bonarek, maria; henriot, stépahen; rodriguez, julie; taddei, mara; di bari, mauro; hickmann, cheryl; castanares-zapatero, diego; deldicque, louise; van den bergh, peter; caty, gilles; roeseler, jean; francaux, marc; laterre, pierre-françois; dupuis, bastien; machayeckhi, sharam; sarfati, celine; moore, alex; mendialdua, paula; rodet, emilie; pilorge, catherine; stephan, francois; rezaiguia-delclaux, saida; dugernier, jonathan; hesse, michel; jumetz, thibaud; bialais, emilie; depoortere, virginie; michotte, jean bernard; wittebole, xavier; jamar, françois title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: a pviol nan introduction the study of the bacterial cartography in thoracic surgery is extremely important for the treatment of post-operative infections due to the severity of the underlying pathology, the fragility of patients after surgery in addition to the choice of the empiric antibiotic therapy. we led a prospective study following all the patients who underwent a pulmonary resection surgery for a period of months from january to july , jointly with the microbiology department, chu ibn rochd, casablanca. the bronchial secretions were collected by a protected distal bronchial sample using a (combicath) after the intubation. results during the period of the study, patients underwent a pulmonary resection, % for a neoplastic pathology. the medium age was years ± and % of our sample were male. % of our patients had smoking habits and of them had pulmonary tuberculosis, had repeated respiratory infections. the antibiotics used in pre-operative: % of beta-lactams; % of fluoroquinolones; % of macrolides. moreover, % of our patients were classified asa . of the obtained samples, were positive ( . %). the most frequently observed germs were the acinetobacter baumannii ( . %), pseudomonas aeruginosa ( . %), klebsiella pneumoniae ( . %), staphylococcus aureus ( . %). the acinetobacter baumannii was the most resistant germ ( % sensibility to carbapenem). these patients were followed until their d after surgery, of them developed a post-operative pneumonitis with cases of multi-resistant acinetobacter baumanii, of which deceased. conclusion pneumonitis after pulmonary resection are common and severe that's why it is necessary to establish a global prevention strategy mainly based on general patricians and pneumologists' awareness concerning the choice of the prescribed antibiotics, in order to avoid the spread of multi-resistant germs. introduction carbapenemase-producing enterobacteriaceae (cpec) are increasingly reported worldwide and constitutes a real challenge antibiotic for clinicians to preserve the bacterial ecology. its incidence has remarkably increased in our intensive care unit during the last years. the esbl spread has a major consequence in term of antibiotic choices. carbapenem antibiotic are regarded as the most effective treatment. however numbers of authors suggest that alternatives antibiotics (i.e. noncarbapenems) could be used in esbl-pe infections. there are some conflicting data regarding the use of alternatives in case of esbl-pe infections. moreover as far as we know, there are no data in icu. objectives the aim of this study was to describe esbl-pe infections in icu and therapeutic options chosen in these specific situations. patients and methods prospective multicentric observational cohort study conducted in volunteers icu. all consecutive patients hospitalized in icu with esbl-pe infection according to cdc definitions were included. severity of illness was defines according to bone criteria, saps ii and sofa. demographic datas, empirical and definitive antibiotic therapy (et and dt), clinical evolution, and outcome were recorded. in vitro antimicrobial susceptibility testing was performed by the disk diffusion method or the vitek system according to the guidelines of the antibiogram committee of the french microbiologic society. results during the study period patients with esbl-pe infection met eligibility criteria with respectively a median age and saps ii score of ( - ) and ( - ). the median sofa score at first day of antibiotic therapy and icu admission were ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) respectively. the most frequent site of infection were respiratory tract ( %), urinary tract ( %) and abdominal ( %). the most frequent isolated species were: escherichia coli ( %), klebsiella sp ( %) and enterobacter sp ( %). respectively , and % patients had septic shock, severe sepsis and sepsis according to bone criteria. among esbl-pe, . % were carbapenem and . were blbi sensitive. among the whole population, ( %) patients received a carbapenems as et. ( %) received a dt with carbapenems and ( %) patients received an alternative dt. the most frequent reasons for maintaining carbapenems as dt were: antibiotic susceptibility tests ( % of cases), severity level ( % of cases) immunosuppression ( % of cases). the median length of icu stay after infection was respectively ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) days for carbapenems and alternatives dt (p = . ). the d mortality was % for patients with carbapenems dt and % for patients with alternatives dt (p = . ). surprisingly, there were no differences between the groups (carbapenems vs alternatives) in term of severity. conclusion alternatives are frequently used for esbl-pe infections in icu. in our cohort ( %) patients received antibiotics other than carbapenems regardless of the severity. introduction bacterial resistance to antibiotics is a common problem worldwide. in south america, this prevalence is reported to be the highest in the world. however, in french guyana, there is no data on the epidemiology of colonization and infection caused by extended spectrum b-lactamase producing enterobacteriaceae (esbl-pe). we conducted this study to investigate the prevalence of colonization with esbl-pe and subsequent icu acquired infection in french guiana. introduction the implementation of hemofiltration (hf) as a renal replacement therapy in septic shock patients requires the supply of large quantities of replacement solutions. these solutions are either industrially prepared in autoclaved expensive plastic bags (conventional hemofiltration, chf) or continuously provided in unlimited amounts at the dialysis machine directly from the water treatment plant to form the replacing solutions (on-line hemofiltration, olhf).the aim of our study was to evaluate the safety and effectiveness of on-line hemofiltration compared to conventional hemofiltration in septic shock patients. the investigative protocol was approved by the institutional ethics authorities and all patients or their legally authorized representatives provided written informed consent. it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure. patients were randomized to receive either on-line hemofiltration (n = ) or conventional hemofiltration (n = ) for renal replacement therapy during days. hemodynamic monitoring was conducted by conventional devises, including: electrocardiogram and a radial arterial catheter for invasive arterial pressure every h during period study. we collected serum samples also every h (urea, potassium and sodium levels, troponin, hemoglobin, platelets, c-reactive protein and lactates). results the evolution of heart rate (hr), mean arterial pressure (map), biological markers were comparable between the two groups over time except a significant decrease in map in the olhf group compared to chf group only at h (p = . ) and h (p = . ) and a significant decrease in c-reactive protein level in the olhf group at h (p = . ). conclusion on-line hemofiltration seems to be a safe and reliable method of renal replacement therapy in septic shock patients. it may be associated with attenuated pro-inflammatory cytokine profile (c-reactive protein). none. introduction therapeutic plasma exchange (tpe) is crucial for the management of auto-immune diseases like thrombotic thrombocytopenic purpura or myasthenia gravis. tpe is performed either by centrifugation, with specific machines which are not routinely available in icus, or by using specific plasma separation membranes with widely spread in icus hemofiltration machines. regional citrate anticoagulation for tpe is well established with centrifugation but has been seldom described for membrane tpe. we are reporting the experience of our icu in this field. patients and methods retrospective study including all patients who received tpe with citrate regional anticoagulation between and in an -bed icu. tpe is performed solely in the icu in our institution. results patients were included. tpe was required for thrombotic microangiopathy ( patients), vasculitis ( patients), hyperviscosity syndrome ( patients), guillain-barré syndrome ( cases) and others ( patients) . mean saps score was [standard deviation (sd) . ] . tpe were performed, with a mean number of . (sd . ; range - ) tpe per patients. coagulation of the circuit of tpe occurred in ( %) patients. coagulation of the circuit occurred in . % ( / ) of the tpe. minor adverse events have been reported in two patients: one had a rash during the first tpe (no recurrence during the next tpes) and the other had paresthesia during the first two tpes (the calcium infusion was increased and there had been no recurrence during the next tpes). no serious adverse events related to citrate were observed. conclusion regional anticoagulation with citrate allowed us to perform tpe in patients, without significant adverse events. the rate of circuit coagulation was . % per tpe. none. introduction a reduced incidence of membrane thrombosis after injection of anti-thrombin (at) has been reported in septic patients with acquired deficit in at undergoing continuous hemofiltration. as this strategy was routinely performed in our unit until , we investigated its cost-effectiveness. patients and methods data about the use of hemofiltration, the consumption of at and hemofiltration devices during (period with routine use of at) and (period with use of at only if a membrane thrombosis occurred) were extracted from the administrative database of the institution. a decisional tree was built to modelize the impact of at on the consumption of hemofiltration devices and blood products. the decisional tree took into account the probability of membrane thrombosis with and without at and the probability of transfusion after membrane thrombosis. costs were obtained from the pharmacy of the institution (at, hemofiltration devices) and from the literature (blood products). results during , days of hemofiltration were performed, with the use of doses of at ( , €) and hemofiltration devices ( , €) . during , (− %) days of hemofiltration were performed, with the use of (− %) doses of at ( €) and (+ %) hemofiltration devices ( , €) . the mean cost of day of hemofiltration decreased from € to € with the diminution of the use of at. according to the decisional tree, at was almost never cost-effective. the only circumstances associated with a benefit for the use of at was the association of a probability of thrombosis with at inferior to . , of a probability of thrombosis without at equal , of a probability of transfusion after thrombosis equal and a cost of transfusion of €. in these extremely favorable circumstances, at could decrease the daily cost of hemofiltration of . - . €. discussion the model has several limits: the losses of utility related to transfusion and to interruption of hemofiltration due to thrombosis were not taken into account; the cost of at measurement was not estimated; the work load of changing a membrane and of transfusion after membrane thrombosis was not analyzed. conclusion our results suggest that anti-thrombin is not costeffective to reduce the costs of hemofiltration related to membrane thrombosis. none. introduction in intensive care unit (icu), some patients suffering from acute kidney injury need renal replacement therapy (rrt). it requires the circuit anticoagulation, this could be done by a regional citrate method. today, this is a recommended approach for the everyday care, even if the technique isn't widespread yet [ ] . the ionized calcemia dosing through the filter ("post-filter" ionized-calcemia) is used to monitor the technique efficacy, with a target of . - . mmol/l showing a good filter anticoagulation. the objective of our study was the assessment of efficacy and safety of our regional citrate anticoagulation protocol, with a less restrictive post-filter ionized calcemia target ( . - . mmol/l). the main goal was the analysis of the circuit lifespan, considering a lifespan above h, as well as the search of some clinical and biological factors affecting the technique efficacy. moreover, we analyzed the side effects incidence of the protocol (hypernatremia, metabolic alcalosis), and their consequences. the study received the scientific ethical agreement of university hospital of toulouse, and is registered with number - . patients and methods patients, admitted to one of the two university hospital icus of toulouse, needing a continuous rrt method, without any need for systemic heparin anticoagulation, and without severe hepatocellular failure, were included in the study. filters included over a -year period were analyzed. results results show a mean filter lifespan of h, with a lifespan above h for . % of all filters. coagulation was the cessation reason for . % of filters, most of them before h of the filter use. a value of post-filter ionized calcemia at day below . mmol/l was the main factor influencing a filter lifespan above h. an age older than and a saps ii severity score below were other factors conditioning a filter lifespan of more than h. side effects of citrate were rare and didn't have any clinical impact among our patients. discussion these results suggest that citrate used for anticoagulation in rrt could have an additional anti inflammatory effect through the induced hypocalcemia, as well as an energetic gain which could lead to a renal protection against ischemia-reperfusion mechanism [ ] . moreover, these results call into question the need of post-filter ionized calcemia dosing for the monitoring of citrate anticoagulation efficacy, since the method safety is monitored by the total-to-ionized calcium ratio. conclusion during continuous rrt in icu, a regional citrate anticoagulation protocol with a non-restrictive post-filter ionized calcemia target seems to be efficient and could reduce side effects. these results need to be confirmed with a randomised control study. introduction continuous veno-venous haemofiltration (cvvh) is used to treat acute kidney injury in critically ill patients. to optimize its efficiency, cvvh requires effective anticoagulation. systemic anticoagulation with standard heparin, the most used, can lead to major bleeding complications. hemofilters that are able to adsorb heparin molecules on their surface such as an st and oxiris membranes represent an alternative. the objective of this study was to compare these two types of filters in terms of duration, efficiency, dysfunctions and cost. materials and methods from october to may , we conducted a retrospective, observational, and non-interventional study. all patients admitted in the intensive care unit needing cvvh were included. the primary endpoint was the filter lifespan: an st versus oxiris. the secondary endpoint was the filter efficiency (urea reduction ratio: urr). the main analysis did not consider the anticoagulation type. we conducted a subgroup analysis taking into account the use or not of an anticoagulation. results sessions in patients were carried out using filters representing , h of treatment. the mean an st filter lifespan was ± h and ± h for oxiris filters (p > . ). there is no significant difference in terms of duration between the two filters. the subgroup analysis taking into consideration the use or not of anticoagulation did not show any difference either. the mean urr was ± % in the an st group and ± % in the oxiris group (p > . ). concerning the dysfunctions, there were no significant difference between the two filters. one hundred and seventy-six an st filters were used for a total cost of , euros. two hundred and ten oxiris filters were used for a total cost of , euros. conclusion the an st and oxiris lifespans are not significantly different. they were as efficient in terms of blood epuration and had as many dysfunctions. the use of an oxiris filter rather than an an st to extend the circuit's lifespan in the same clinical conditions is not justified considering the extra cost generated. introduction because oliguria is a poor prognostic sign in patients with acute renal failure (arf), diuretics are often used to increase urine output in patients with or at risk of arf. from a pathophysiological point of view there are several reasons to expect that loop diuretics could have a beneficial effect on renal function. however, a review of literature shows that the use of loop diuretics in patients with arf has been associated with inconclusive results despite the theoretical benefits [ ] . to assess the adjunctive effect of diuretics, to alter the progression to kidney injury or failure, in patients at risk for acute renal failure. patients and methods this is a retrospective chart review of consecutive patients who developed arf with oliguria in the intensive care unit. chart abstractors were well trained residents. two chart reviewers (senior intensivists) studied all the charts. an explicit protocol was used to precise all needed definitions. uniform handling of data was ensured especially for conflicting, missing or unknown data. oliguria was defined as urine output lower than . ml/kg/h for at least h. rifle score was assessed before and after urinary output normalisation. therapeutic intervention to optimize pre-renal perfusion was described. mean arterial blood pressure (mbp) before and after therapeutic initiation, oliguria duration, delay from oliguria onset to diuretic administration, delay from diuretic administration to urinary output normalisation were measured. results patients were studied over a years period. ] h. the delay from diuretic administration to urinary output normalization was [ . , ] h. after resumption of diuresis, rifle score was assessed as (patients without risk, %; r, %; i, %; f, % l, zero; e, zero) (fig. ) . increased serum creatinine level, above . fold normal range, was observed only in ( %) patients. conclusion rapid optimization of pre-renal hemodynamic disturbances associated with short delay administration of diuretics could significantly alter the progression to kidney injury or failure in at risk acute renal failure icu patients. the ventilator associated pneumonia (vap) is a common and severe complication of assisted ventilation. it's the leading cause of nosocomial infections in intensive care unit and remain responsible for a high morbidity and mortality because of the emergence of multidrug resistant (mdr) bacterial agent such us acinetobacter baumannii (ab). the aim of this study was to determine the incidence, risk factors and prognosis of ab vap. patients and methods retrospective study extending over a year period (january -january ) that included all patients over patients were divided into two groups: one consisting of patients who developed vap to ab and the second developed vap to another bacterial pathogen. results one hundred and forty patients developed vap. the incidence rate of ab vap was . % with a density of incidence of . per ventilator days. age, male gender, the time between hospitalization and mechanical ventilation and the medical pathology were risk factors for developing ab vap. ab was resistant to ceftazidime in %, to imipenem in %, tobramycin in % and netilmycin in . %, rifampin in % with a sensitivity to colistin in % of cases. the resistance of this germ to imipenem increased from % in to . % in . the evolution of patients with ab vap developed frequently septic shock compared to other patients ( vs . %; p = . ). the ab vap mortality was higher ( vs %; p = . ). conclusion the increasing incidence of multi-drug resistant ab vap is responsible for a high morbidity and mortality. so we need to identify risk factors and to strengthen the means of prevention of hand contamination and cross transmission during invasive procedures. introduction central line associated bloodstream infections (clabsi) are among the serious hospital-acquired infections. the aim of this study is to determine the incidence of clabsi, the pathogens and the risk factors that play a role in the development of bsi among patients followed in a tunisian medical intensive care unit. patients and methods all patients admitted for more than h were included in the study over a -year period in an -bed medical icu. the enrollment was based on clinical and laboratory diagnosis of bsi. blood samples were collected from catheter hub of all patients for culture, followed by identification and antibiotic sensitivity testing of the isolates. was higher compared with the mean rate of clabsi in icu reported by the nnis system surveillance for , which is . / catheter.days [ ] . duration of catheterization, frequent manipulation of catheter, catheter location, catheter type, underlying diseases, suppression of immune system, and types of fluids administered through the catheter are significant risk factors in development of bsis [ ] . in our study both duration of catheterization and number of attempts are independent factors for clabsi. conclusion in a monocenter cohort, clabsi had a moderate density rate but are associated with poor outcome. identifying the risk factors is necessary to find solutions for this major health problem. introduction according to some studies, field-intubated patients have . - times greater risk of ventilator associated pneumonia (vap). endobronchial intubation (ei) can be unrecognized by the physicians and may result in complications such as atelectasis which in turn could increase the risk of vap. the aim of our study was to confirm this hypothesis. patients and methods this monocentric retrospective study included all consecutive patients > years who underwent an out-of-hospital tracheal intubation before their admission to the intensive care unit (icu) between january and december . exclusion criteria were suspected aspiration or pneumonia on admission, patients who died within the first days of icu stay, extubation in less than h and underlying disease making radiological interpretation difficult for vap diagnosis. vap were divided into early onset (< days) and late onset (≥ days) events and were independently diagnosed by two experienced intensivists who had no access to the initial chest x-ray performed to check the position of the tracheal tube, based on the clinical pulmonary infection score. onset of ventilator associated tracheobronchitis (vat) was also noted. inadvertent endobronchial intubation was determined by another independent physician based on the interpretation of admission chest x-ray. results patients were intubated out-of-hospital. of the patients excluded, had an extubation in less than h, were died within the first days, had a suspicion of pneumonia, a suspicion of aspiration and an underlying disease making radiological interpretation difficult. of the patients included, ( . %) had an ei upon admission. no significant difference was observed between the ei and non-ei group for gender, age, saps , comorbidities and diagnostic category (cardiorespiratory arrest, trauma, coma and cardiorespiratory failure). early-onset vap were diagnosed in % in the ei group and in % of non-ei patients (p = . ). adding early onset vat, the respiratory infection rate was % in the ei group and % in the non-ei group (p = . ) (fig. ). late-onset vap were observed in . % in the non-ei group and . % in the ei group, without difference between groups (p = . ). there was no inter-group difference in the duration of ventilation, duration of icu stay and icu mortality. staphyloccocus aureus was the most prevalent pathogen in patients with early-onset vap ( . %, only one strain was methicillin-resistant). conclusion this study found a high rate of inadvertent prehospital endobronchial intubation with a higher incidence of early-onset vap. these results support the implementation of specific procedures to decrease the incidence of ei. introduction ventilator-associated pneumonia (vap) is associated with increased hospital stay and high morbidity and mortality in critically ill patients. the classic dichotomy between early and late onset vap is no longer helpful available. the aims of this study were to determine the incidence of multidrug-resistant pathogens in the first episodes of vap and to assess potential differences in bacterial profiles of subjects with early-onset versus late-onset vap. patients and methods retrospective cohort study over a period of months including all patients who had a first episode of vap confirmed by positive culture. subjects were distributed into groups according to the number of intubation days: early-onset vap (< days) or late-onset vap (≥ days).the primary endpoint was the nature of causative pathogens and their resistance profiles. results sixty patients were included, men and women. the average age was ± years. the igs at admission was . [ ; ] apache [ ; ] . monomicrobial infections were diagnosed in of patients ( %).two different bacteria were isolated in cases ( %). a. baumannii was the most frequently isolated in % (n = ) of patients; followed by p. aeruginosa in % (n = ), enterobacteriaceae in % (n = ) and s. aureus in % (n = ). the isolated bacteria were multidrug-resistant in most cases ( / ). the vap group comprised episodes ( %) of early-onset vap and episodes ( %) of late-onset vap. a. baumannii was isolated in % of early vap (n = ) versus % of late vap (n = ) (p = ns), p. aeruginosa in % of early vap (n = ) versus % of late vap (n = ) (p = ns) and enterobacteriaceae in % of early vap (n = ) versus % of late vap (n = ) (p = ns). for the resistance profile of the different pathogens isolated, there was no difference between early and late onset vap. conclusion according to new data from the literature, there were no microbiological differences in the prevalence of potential multidrugresistant pathogens or in their resistance profiles associated with early-onset versus late-onset vap. the bacterial nosocomial infection is a major cause of morbidity and mortality in burned. the bacterial ecology in an icu has a major impact in terms of morbidity and mortality, particularly in the center of burned or length of stay of patients is increased compared to a general intensive care. we conducted an observational study spread over months in icu for severe burned burnt including any who have spent more than h with nosocomial infection (modified cdc criteria), and in which all biological and bacteriological samples were taken. the different types of infections studied were: skin, urinary, lung and bloodstream infections. they excluded all patients belatedly supported or having stayed in other healthcare facilities. results one hundred twenty ( ) patients showed nosocomial infection during this period. the sex ratio (m/f) was . and the mean age was ± years. bacteremia was present in . % of cases, followed by the urinary tract infection that was present in . % of cases, followed by the cutaneous infection in . % of cases, and last pulmonary infection in % of cases. infection was polymicrobial in . % of cases. the main bacteria identified were: acinetobacter baumanii ( . %) of which % is resistant to imipenem, enterobacteriaceae ( . %), pseudomonas aeruginosa ( %) of which . % is resistant to ceftazidime and . % is resistant to imipenem, enterococcus ( %) and staphylococcus aureus ( . %). conclusion the incidence of nosocomial infection is very high compared to literature. the rate of resistance to common antibiotics is very high. a drastic management of antibiotics in our context, the selection of patients and the frequent use in the operating room for skincare allow a better management of these patients. introduction acinetobacter baumannii (ab) ventilator-associated pneumonia (vap) is common in critically ill patients. the aims of this study were to describing the epidemiological characteristics of ab-vap, to identify risk factors for acquisition and factors predictive of a poor outcome. materials and methods a retrospective-prospective study was conducted at the medical intensive care unit of the university hospital ibn sina, rabat-morocco from january to december . they were included in the study that all patients developed vap with identified germ. for identification of risk factors of acquisition of ab vap, two groups of patients were compared: patients with ab vap versus patients with vap caused by other germs. to identify factors associated with mortality, two other groups were compared: survivors versus died. results patients presented vap among which were caused by acinetobacter baumannii. among isolates of ab, . % were drug susceptible, and . % were multidrug-resistant while % were extensively drug-resistant. they were independent risk factors for acquisition of ab vap in multivariate analysis: the presence of a central venous catheter before the occurrence of vap, duration of prior hospitalization ≥ days and icu duration of stay ≥ days. the mortality rate of ab vap was %. the independent risk factors for poor outcome in multivariate analysis were: duration of antibiotic treatment > days, the reintubation and the presence of a previous hospitalization. discussion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). conclusion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). introduction ventilator-associated pneumonia (vap) is common in critically-ill patients. in fact, - % of patients requiring invasive mechanical ventilation develop this complication. the onset of vap has been reported to be associated with increased mortality. however, data related to critically-ill elderly patients are scarce. the aim of this study is to assess the prognostic impact of vap in critically-ill elderly patients. patients and methods mono-center, retrospective study conducted from / to / / . all old patients (age ≥ years) requiring mechanical ventilation were included. two groups were compared: patients who developed vap (vap (+) group) and those who did not develop vap (vap (−) group). results during the study period, patients were included. the causes of admission in the intensive care unit (icu) were shock (n = ), acute respiratory failure (n = ) and disturbed level of consciousness (n = ). diabetes mellitus, hypertension and chronic obstructive pulmonary disease were the most common comorbidities ( . , . and . % respectively). mean age was . ± . years. sex-ratio (m/f) was . . mean apache(ii) score was ± . the mean duration of mechanical ventilation was ± days. thirty patients ( . %) developed vap. icu-mortality was significantly higher in the vap (+) group ( vs . %; p = . ). multivariate analysis identified two independent factors predicting icu mortality: shock on admission (or = . , ci % [ . - . ], p < . ) and vap (or = . , ci % [ . - . ], p = . ). conclusion vap is common in critically-ill elderly patients and is associated with worse outcome. therefore, preventing its onset is of paramount importance. increased health-care costs. among pathogens responsible of vap, acinetobacter baumannii which is characterized by its ability to spread in the hospital environment and to acquire resistance leading sometimes to therapeutic impasses is associated with a particularly high mortality reaching - %. objective to describe the epidemiological characteristics of a. baumannii vap, to determine their prognosis and identify factors associated with mortality. patients and methods it is a monocentric observational study conducted over a period of years in a tunisian intensive care unit (icu) including mechanical ventilated patients for more than h with confirmed a. baumannii vap. results one hundred and twenty-three patients were included in the study. a. baumannii was responsible for % of vap in our icu. the vap were late in % of cases. more than % of isolates pathogens were resistant to ticarcillin, piperacillin, piperacillintazobactam, ceftazidime and ciprofloxacin. sixty percent of germs were sensitive to imipenem. resistance to imipenem has increased consistently from % at the beginning of the study to % in . all pathogens were susceptible to colistin. a. baumannii vap was complicated by septic shock in % of cases. the median duration of mechanical ventilation and of icu stay were (iqr: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and days (iqr: - ) respectively. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem (odds ratio . , % ci [ . - . ], p = . ). icu mortality was %. it was higher in patients with a. baumannii vap resistant to imipenem ( vs %, p > . ). in the multivariate analysis, the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as factors associated with mortality. conclusion a. baumannii resistance to imipenem became threatening. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem. the choice of empiric antimicrobial for vap caused by this pathogen must take in consideration the epidemiologic data of each country and each icu. a. baumannii vap was associated with high mortality. the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as predictive of poor outcome. none. admission in intensive care unit for severe adverse drug event: what finding? julien arcizet , bertrand leroy , caroline abdulmalack , catherine renzullo , maël hamet , jean-marc doise , jérôme coutet introduction adverse drug events (ade) remain a serious public health problem. they represent between . and . % of hospital admissions and between . and . % of intensive care unit (icu) admissions. they are defined as any injury related to a drug, and include both adverse drug reactions, expected or not, but also underuse, overuse and misuse, unintended or undesired, preventable or not. indeed, mortality from iatrogenic event would rise between . and . %, whereas these ade that resulted in icu hospitalization could be prevented in . - . % of cases. these unplanned admissions overload icu, limit access to health care for other patients and have serious economic consequences for the health system. it is therefore necessary to study these ade to know their main causes and attempt to find a solution to avoid them. the main objectives of our study were to clinically and pharmaceutically analyze and stratify the different ade leading to hospitalization in our icu. this is a monocentric prospective study, between june to january , in medico-surgery icu. from all admissions, we had included patients admitted in our hospital for involuntary ade (plausible, likely and very likely causal). we had collected clinical aspects (failure mode, igsii score, mortality in icu) and pharmaceutical aspect (number of drug, offending drugs) at daily medical staff meeting. conclusion hospitalizations in icu for ade are still too common despite their preventability for most cases. many patients with known cognitive disorder manage their treatment themselves and this is probably one of the reasons of iatrogenic events. anticoagulants and antiplatelet agents, by side effects, misuse, underuse or overuse are very often involved. the onset of kidney failure from dehydration and the continuation of nephrotoxic and antidiabetic treatment also remain one of the most common causes. consequently, it is necessary to continue and develop primary, secondary and tertiary prevention strategies to prevent their appearance, to limit their consequences and to reduce recidivism. introduction intensive care unit (icu) is usually identified as a place of acute care, concentrated over a short period. for many reasons, a prolonged stay in the icu has a pejorative connotation for the intensivist physician. the aim of our study is to describe the epidemiological, clinical, paraclinical profile of patients hospitalized for a long time in icu (over days) and to identify the main prognostic factors and those that can predict the duration of stay in icu. we conducted a retrospective study, over a period of years and months (january to june ), enrolling patients whose length of stay was greater than or equal to introduction despite an improvement in prognosis of patients with hematologic malignancies for the last decade, mortality of such patients admitted to the intensive care unit (icu) remains high. yet, it seems that a first icu stay does not modify prognosis of the malignancy. until now, there is no data on readmission in the icu of such patients and its effect on short and long term prognosis impact. patients and methods this retrospective, single-center study conducted on a years period in the medical icu from our university hospital included patients with hematological malignancies admitted for a first stay. objectives were to evaluate the icu, day and months mortality, to identify prognostic factors associated with mortality within uni-and multivariate analysis, to evaluate readmission rate within the days after discharge, to indentify the admission risk factors associated with icu readmission and the prognosis factors associated with mortality during the second icu stay. multivariate analysis poor performance status, igs ii, hlh, mv and anti-fungal administration were associated with increased icu mortality, infections with pseudomonas were associated with higher day mortality. catheter related infections were associated with better icu survival and cr was associated with lower day mortality. of ( . %) candidate patients for icu readmission after a first stay were readmitted within the days following discharge. median overall survival was lower in readmitted versus non readmitted patients. months mortality was . % for readmitted versus . % for no readmitted patients (p < . ). the second icu stay mortality was . % and month mortality was . %. by multivariate analysis, only mv was associated with prognosis. the months mortality rate of patients who survived to the second icu stay was significantly higher than the patients who survived to the first admission but were not readmitted ( . vs . %, p = . ). conclusion main features, short and long term mortality and prognostic factors associated with icu admission are in lines with previous studies. early readmission rate was high with a negative impact on survival. despite admission in the icu of patients with hematologic malignancies seems not to affect long term prognosis, early readmission seems to have a pejorative impact on the course of the malignancy. introduction lung cancer is among all types of cancer, the most common solid tumour admitted in intensive care [ ] . recent studies showed that the prognosis of patients with lung cancer during intensive care unit (icu) stay has improved [ ] . the aim of our study was to determine the causes of icu admission of lung cancer patients, their prognosis and to identify factors predicting hospital mortality and survival after hospital discharge. in fact, temporary full-code icu management in patients with relapsed aml seems to be appropriate. none of the life-sustaining interventions at admission and on day were able to predict survival. an icu trial of days might not be enough to appraise precisely the outcome. bone marrow transplant was associated with a high mortality in our study. in case of relapsed aml with bmt, icu management is still challenging. the growing population of chronically critically-ill patients has a poor prognosis despite all the resources mobilised [ ] . our primary objective was to analyse the prognostic value of different definitions used to describe them. our secondary objective was to look for early clinical and biological factors that could be associated with the in-hospital mortality. we conducted an epidemiological prospective study in intensive care units (neurosurgical, cardiosurgical and medical) of a large french teaching hospital (henri mondor, créteil). we included all the patients hospitalized for at least days. we tested definitions: the prolonged mechanical ventilation, the definition taken up by kahn et al. [ ] , the prolonged length of stay, the persistent critical illness and the persistent inflammation-immunosuppression and catabolism syndrome. two biological examinations were performed: upon entering the study and week later. the study endpoint was the in-hospital mortality. results thirty patients were included between april and july . among them, only % matched the definition of prolonged mechanical ventilation, which is still the most used in the literature. further, it was not associated with the mortality, but the prolonged length of stay was, with % of these patients, that did not survive to their hospital stay. other parameters that were significantly different between the patients who died and those who survived were an advanced age, an elevated igs ii score at hospital admission, an elevated sofa score at study entry, a late healthcare-associated infection and several biological variables: a high c reactive protein, low albumin and prealbumin and a poor percent of monocytes expressing hla-dr, all measured at day . conclusion the in-hospital mortality of chronically critically-ill is still high. a prolonged length of stay is the only definition who may be helpful to identify the patients with the poorest outcome. among the early factors associated with mortality, we found a late healthcareassociated infection and a low percent of monocytes expressing hla-dr, pointing to the value of studying the immune system of these patients. introduction as a result of demographic transition, the proportion of «very elderly» (≥ years) patients is increasing worldwide and more of these patients are nowadays admitted to intensive care units (icu). among physicians the discussion about appropriateness of these icu admissions still remains controversial mostly due to questionable outcome, limited resources and costs. the aim of the study was to determine and evaluate the clinical characteristics and outcome in a very old population admitted to a medical icu in an urban teaching hospital. we present here a monocentric, retrospective and observational study. we reviewed the charts of all patients (≥ years) admitted to a medical icu between and ( years). we collected epidemiological, clinical and biological parameters and all therapeutic measures during the icu stay. a longterm survival follow-up was also performed. two hundred eighty-four patients were included for statistical analysis. multivariate cox regression was also performed to identify risk factors for -day outcome. results a total of patients were included, which represented . % of admissions to the icu during the period of the study. the mean age was . ± . years, the sex ratio was . . most of patients ( %) were admitted from the emergency department. % of these admitted patients suffered of previous dementia. the mean charlson comorbidity score was . ± . and the mean mccabe score was . ± . . the admission diagnosis in the icu was mainly respiratory distress ( %), septic shock ( %), cardiac arrest ( %) and coma ( %). the mean saps-ii score within h of icu admission was . ± . . half of these patients required support by mechanical ventilation (mean duration . days) and vasoactive drugs and % of patients received renal replacement. icu and in-hospital mortality rates were and % respectively. overall survival at months after hospital discharge was %. multivariate regression revealed necessity of catecholamines and mechanical ventilation as independent risk factors and urinary sepsis as protective factor for -day outcome. in fine, for % of these patients, a limitation of active treatment was decided (on average after days of stay). for all others there was no justification for limiting care because of a well-established treatment plan (with family, gp, icu team). conclusion the proportion of elderly patients remains low, but they are increasingly being treated in intensive care units. nevertheless, the in-hospital mortality is high compared to the average mortality in our icu over the same period ( %). the prognosis is often not as poor as initially perceived by physicians. the indication for icu treatment in our study was mostly justified; in the setting of consistent patient care and good clinical practice. it remains therefore appropriate to discuss every single icu admission of elderly patients without any restriction related to age. thus, the ongoing cluster-randomized trial of icu admissions for the elderly patients (ice-cub study) is deeply awaited to confirm or not these results [ ] . keywords intensive care; prognosis; outcome; elderly patients; over -years old. introduction regardless of the route of delivery, the postpartum hemorrhage (pph) is defined as blood loss ≥ ml after childbirth, and severe pph as blood loss ≥ ml. pph is the leading cause of maternal mortality in africa. the aim of this prospective study was to assess the quality of the initial management of pph in algeria in oran ehu and to determine the factors of care with the severity of this complication. we conducted a prospective cohort study between april and september at the ehu oran. all women who delivered vaginally and showed hpp including the suspected cause was uterine atony were included. the severe pph was defined as bleeding that required invasive surgical treatment (hysterectomy, arterial ligation), a transfusion, a transfer to an intensive care unit or death of the patient. the quality of care was evaluated using objective criteria defined by a delay of diagnosis and care and mortality. results among the women who delivered vaginally during the study period, had a pph, link with uterine atony alleged at diagnosis, of which presented signs of severity. in % of cases, the delay in diagnosis of pph was less than min; % of women received oxytocin within min after diagnosis. the tranexanique acid was used in case. the examination of the cervix, uterine exploration and uterine massage was performed in , and %, respectively. the failure of first line treatment involved % of patients. among them, the time between the diagnosis of pph and administration of blood derivatives was greater than h in a third of cases. the administration of oxytocin delay exceeds min multiplied by . the risk of severe pph. however we had deaths in our series. discussion in our study the optimal period of care was not adequate, obtaining blood derivatives in our institution remains among the factors aggravating among the main risk factors for pph, uterine atony was the main source of complication. bleeding postpartum aggravated in our two patients has led to the deaths from late diagnosis and care that was not optimal. these hemorrhages pp is the leading cause of mortality: % of obstetric deaths ( % in the confidential survey - ) [ ] . a hysterectomy was indicated after failure to conservative treatment. the death rate is estimated at % following a disorder complicated hemostasis of disseminated intravascular coagulation (dic). in some series, the mortality rate is estimated between and % [ ] . conclusion the management of pph in obstetrics gynecology service the ehu oran was not optimal. the issue of timing of diagnosis and initial treatment is crucial. solutions must be sought locally to ensure the administration of essential medicines in time, especially the injection of oxytocin within min after diagnosis. introduction chronic obstructive pulmonary disease (copd) is a common pathology that would represent the third cause of death worldwide by . its evolution is interspersed with episodes of acute exacerbations (aecopd) that may indicate an admission in intensive care unit in the most. objective to study the evolution of management modalities of patients admitted in our intensive care unit for aecopd, to determine their prognosis and to identify factors associated with mortality. patients and methods it is a retrospective, monocentric study, performed in a tunisian intensive care unit (icu) over a period of years. we including all patients admitted in icu for aecopd. parameters collected were demographic features, comorbidities, regular treatment, dyspnea assessed by the mrc scale, initial clinical severity reflected by saps ii and apache ii scores, modalities and icu admission deadlines, initial arterial blood gas analysis, management of patients in the icu (ventilation modalities, prescription of antibiotics, use of vasoactive drugs) and their outcomes (incidence of nosocomial infections and their sites, length of stay and icu mortality). results a total of patients, which represents . % of all hospitalizations, with mean age of years (iqr: - ) were admitted for aecopd during the study period. the mean saps ii and apache ii were respectively (iqr: - ) and (iqr: - ). of these, % were ventilated with niv whose overall failure rate was % with a significant decrease between the beginning and the end of the study ( vs % p = . ). sixty-four percent of patients received antibiotics at admission. the prescription rate of antibiotics has decreased significantly over the years from to %. the incidence of nosocomial infections was %. it remained steady between and %. their sites were pulmonary in % of cases. icu mortality was %. in multivariate analysis, icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. conclusion our study showed the importance of aecopd in the activity of our icu. the management of these patients has evolved over the years, which was reflected by the significant decrease in the prescription of antibiotics and the enhancement of niv success rate. this result could be attributed to the combination of several factors: precocious management of patients, experience of the healthcare team and the use of efficient ventilators. icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. introduction aim. investigate the effect of music therapy on the tolerance of non-invasive ventilation (niv) during its introduction. currently, % of the trauma are intubated. thirty-three percent of the patient admitted in intensive care suffers from acute respiratory distress syndrome (ards). the fmhs chose oxygen concentrator as oxygen source in addition to oxygen pressurized bottles. their supply can be uncertain in conflict areas. insufficient data are available concerning the use of oxygen concentrator in intensive care unit. the primary endpoint was to determine over the total duration of oxygen therapy, the number of days on which the use of pressurized oxygen was needed for patients oxygenated by oxygen concentrator. the secondary endpoints were to identify when pressurized oxygen was needed, describe the characteristics of the population with oxygen therapy and estimate the oxygen quantity economised thanks to the use of oxygen concentrator. the study took place in the forward surgical unit of bouffard. it's a french role located in djibouti republic in africa. all patients over admitted in the intensive care and needing oxygen therapy were included. all the patients were oxygenated with an oxygen concentrator. the oxygen concentrators used were sequaltm integra om, that could deliver up to l/min of normobaric oxygen. the ventilator used were pulmonetictm ltv and . results thirty-six patients were included over the months' study period. sixty percent of the patients were men with an average age of two hundred and fifty-one days represents the total number of days of oxygen therapy divided into days of invasive ventilation, days of noninvasive ventilation and days of oxygen mask. the use of pressurized oxygen was necessary times over the days of oxygen therapy which represents . % of the total time. the causes of its use were in ten cases ( . %) criteria of severe ards, in six cases an emergency intubation and in three cases a transfer. one dysfunction of an oxygen concentrator happened during our study. the oxygen concentrator produced m of oxygen over the study period, which represents oxygen pressurized bottles of litres. this enabled an economy of , euros. conclusion it is safe to use oxygen concentrator to take care of critically ill patients in limited resources environment. the use of pressurized oxygen is still compulsory in two situations: in case of electricity failure and in case of high fio (above %). oxygen concentrators are sufficient in . % of the time. they enable to deliver oxygen any time which is essential when supply is uncertain in conflict areas. none. table ). for the same mv and level of ofr, fdo was in our experiment, with an ofr of l/min, when ifr = l/min (mv = l/min and ti/ttot = . ), the fdo is equal to % (± %) (see table ). to this value of ifr, the fdo is in accordance with the formula of ats, but when ifr increase beyond l/min, the fdo decrease and the formula is not in accordance with ats. this can be explain because during inspiratory phase, air room (fractional oxygen = . ) entry in airway mixes with ofr (fo = ), which modifies the fdo . in this case, when ifr increase then fdo decrease and vice versa. medical and paramedical staff must be aware that with patients who receive ofr by nasal cannula, any change of ofr and/or inspiratory flow changes the fdo . in this case, for maintain the same fdo , it is necessary that modify the value of ofr. the actual fio delivered under oxygen mask in patients with acute respiratory failure and the factors that may influence the fio are poorly known. in clinical practice, different methods including formula or conversion tables based on oxygen flow can be used to estimate delivered fio . we aimed to assess first the factors influencing measured values of fio , and second the best method to estimate fio in patients breathing under oxygen mask. we included icu patients admitted for acute hypoxemic respiratory failure from a previous prospective trial [ ] in whom fio was measured under oxygen mask using a portable oxygen analyzer. we collected demographic variables and respiratory parameters that may influence measured fio . low fio was defined according to the median measured fio . for each patient, measured fio was compared to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ) to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ), and to a conversion table [ ] . a ± % limit of agreement for each estimation method was arbitrarily considered acceptable. results among the patients included, median measured fio was % [ - ]. after adjustment on oxygen flow, the three variables independently associated with low measured fio using multivariate analysis were patient's height, a low paco , and a respiratory rate greater than breaths/min. using paired analysis, each estimation methods differed significantly from measured fio (p < . for each). values outside the limits introduction acute hyperglycemia is common in intensive care. it was associated with poor prognosis and increased mortality. the purpose of our study is to investigate the frequency of hyperglycemia in our icu, to determine the main causes of high blood sugar and to analyze the impact of this hyperglycemia. our study is prospective during months. it was conducted in the intensive care unit of the university hospital habib bourguiba sfax-tunisia. were included in our study all patients admitted to the service during the period of the study. for each patient included were collected from the icu admission, clinical and biological data. results during the study period, patients were hospitalized in our icu and the diagnosis of hyperglycemia (> mmol/l) was admitted in patients ( %). the comparison between patients who developed hyperglycemia and those free hyperglycemia group showed that, the patients of the first group were significantly older (p < . ). additionally, hyperglycemic patients had more medical history including history of diabetes (p < . ), a higher saps ii (p < . ), a more significant frequency of active infections (p < . ). moreover, the presence of hyperglycemia was associated with shock (p < . ) and respiratory distress (p < . ). their evolution was marked by the significantly higher frequency of infectious complications (p < . ), thromboembolic complications (p < . ) and acute renal failure (p < . ). the average duration of mechanical ventilation and the length of stay were also significantly prolonged in hyperglycemia group patients (p < . for both). finally, the presence of hyperglycemia was significantly associated with a higher mortality rate. conclusion we concluded that hyperglycemia is correlated with poor prognosis of morbidity and mortality. but strict glycemic control remain controversial. thus, further studies on this subject will be recommended to define the exact place of glycemic control in intensive care. none. the rrt was prophylactic in four cases started when phophatemia was more than mmol/l, and therapeutic for renal failure and established tls in three cases. the median duration stay in icu was [ ] [ ] [ ] [ ] j. thirteen patients left the icu without major metabolic dysfunction. two patients deceased due to infectious complications. discussion monitoring of electrolytes was done on average, three times a day which is hard to do in onco-hematology unit. the early use of rasburicase and the aggressive iv hydration helped to prevent tls for seven patients. the aggressive iv hydration was made according to echocardiography data and close monitoring of vital signs and urine output which has allowed to avoid volume overload and acute pulmonary edema. the early prophylactic rrt prevented renal failure and metabolic complications. conclusion early management of tls in icu can prevent tls and most of its serious complications and should be considered in tls prophylaxis recommendations. none. the both urinary (expressed as the ratio of ngal on urinary creatinine) and plasma ngal were predictive of aki stage . predictive value of plasmatic measurements was higher than the urinary one (auc of . and . , respectively, p = . between auc), but not higher than either baseline serum creatinine (auc = . ) or h diuresis (auc = . ). backward multivariate regression showed that plasma ngal concentration was associated with serum creatinine, crp and albumin, whereas urinary ngal was associated with leucocyturia and baseline creatinine. discussion previous positive studies with ngal did not compare the performance of this costly biomarker with simple usual clinical parameters to predict aki. moreover, several parameters were associated with ngal concentrations with a high risk of collinearity (crp) and/or false positive results (leucocyturia). our data do not support any added value of ngal concentration over baseline serum creatinine or urine output to predict aki. introduction acute renal failure (arf) is a common entity in intensive care, concern that the heavy morbidity and mortality it is associated [ ] . early diagnosis of this entity remains difficult, neither diuresis and creatinine are early parameters in the diagnosis of arf. the kidney is an organ that suffers long to become faulty, the priority is to recognize renal aggression and to achieve a therapeutic allowing reversibility of the infringement. a number of markers have been developed for the diagnosis of the ira but costs remain high not allowing their routine use. the measurement of resistance index with the renal doppler could be a solution for the diagnosis of aggression and also of the etiology. the elevation of creatinine was seen later within h after the ir > . discussion in our series the resistance index has a value of early diagnosis of renal prognosis aggression in the occurrence and development of renal failure. renal doppler associated with a strictly applied standardized protocol achieves the two goals of monitoring who aid in the diagnosis and guide treatment. although the recommendations of experts to this tool provides that it should probably not use the resistance index measured by renal doppler to diagnose or treat an ira (grade ) [ ] . identifying the cause of kidney aggression is a prerequisite before any therapeutic action. hypovolemia and soda hydro overload are the causes principales. excess filling hyper intra thoracic pressure and hypoxia are the main causes of kidney congestion. conclusion doppler is an early renal medium in the diagnosis of renal aggression. a larger series could assert this observation. none. ), had significantly more pre-eclampsia, / ( %) versus / ( %) p = . . pe were started at an average of . days after foetal extraction, and with an average of sessions. patients of the pe group had significantly lower nadir of hemoglobin but also lower hemoglobin level at day and day . nadir of platelets count was also lower and level remain lower at days , , and . acute kidney injury (using kdigo classification) was more frequent with a higher rate of dialysis in icu, in the pe group ( / ( %) vs / ( %) p = . ) with a more frequent need for dialysis at the exit of icu. proteinuria was significantly higher in the pe group ( . mg/mmol vs . mg/mmol, p = . ). adamts dosage was done only in patients with pe. we find a diminution of adamts activity (before pe) with an average of % [ - ] in this group. there was no death, and adverse effects were not significantly different. discussion this study shows that pe was used when diagnosis was uncertain in the most severe form of pp-tma. low hemoglobin, low platelets, acute kidney injury and high level of proteinuria are the main factors associated with the decision to begin pe. this technique was safe and not associated with major adverse events. several studies show that there are physiopathological crossovers between diseases associated with pp-tma, for example low adamts activity in hellp or mutation in alternative complement pathway which induced hellp. moreover, studies and case reports show a benefit of pe in hellp syndrome. our study did not find significant difference in adverse events (maybe due to a lack of power), but this is another argument to discuss pe in the management of pp-tma in severe patients. the main limits of our study are that none of the patients who had a plasmatic exchange had a diagnosis of ptt and that diagnosis tests were not performed in all patients with pp-tma (complements level, adamts …). conclusion pp-tma treated with pe has lower hemoglobin, lower platelets, higher rate of kidney injury and proteinuria than those treated without pe. no difference were found for adverse events. begining of pe should be discussed for management of a pp-tma without amelioration after foetal extraction. none. introduction diffuse alveolar damage (dad) is the typical histological feature of acute respiratory distress syndrome (ards). however, in a previous study including patients with criteria for ards, we found that only % of them had dad at autopsy exanimation [ ] . it has been shown that patients with ards and dad on open lung biopsy had higher mortality than those without dad [ ] . thus, we aimed to identify markers associated with dad in patients with ards. we included the patients who met criteria for ards at time of death in our large database of clinical autopsies [ ] . we assessed the proportion of dad according to the severity of ards including the degree of hypoxemia and the ancillary variables from the berlin definition: use of high levels of positive endexpiratory pressure (peep at least cmh o), radiographic severity ( or quadrants on chest radiograph), altered respiratory system compliance (≤ ml/cmh o), and large dead space defined as a corrected expired volume per minute (≥ l/min). results dad was associated with all the severity markers abovementioned using univariate analysis. after multivariable logistic regression, the three markers independently associated with presence of dad were the gender with an odds ratio ( conclusion dad was significantly more frequent in females. in addition to the severity of hypoxemia, diffuse infiltrates involving the quadrants was a significant marker of dad. introduction ventilation induced lung injury (vili) is responsible for an increased mortality in ards [ ] . mechanical ventilation may trigger an inflammatory response, comprising alveolar macrophage activation and recruitment, which may be specifically, repeatedly and spatially assessed by functional imaging techniques such as positron emission tomography combined with computerized tomography (pet/ct) [ ] . c-pk is a pet radiotracer with potential to quantify macrophage inflammation. we aim to assess its performance to detect lung macrophage recruitment in an experimental highvolume vili model. materials and methods vili was performed in anesthetized pigs under neuromuscular blockade by rapidly increasing the tidal volume (vt) to obtain a transpulmonary pressure (tpp) between and cmh o under zero end-expiratory pressure. pet/ct acquisitions were performed before (t ) and after h of high-volume ventilation (t ), and image-derived measurements were realized on the whole lungs, and regionally on distinct lung regions (divided along the anteroposterior and the cephalocaudal axes). c-pk lung uptake was estimated using the standardized uptake value (suv), normalized to the ct-derived tissue fraction in the region of interest (roi). mechanical lung aggression was estimated by ct-derived dynamic and static strains, and tidal alveolar hyperinflation (expressed as a fraction of the tidal variation in the roi volume). after euthanasia, alveolar damage and macrophage recruitment were assessed in the lung regions, using semi-quantitative scores. results between t and t , vt and tpp significantly increased from . ± . to . ± . ml/kg and . ± . to . ± . cmh o, respectively. suv on the whole lung significantly increased from . ± . to . ± . between t and t and dynamic strain from . ± to . ± . , whereas static strain did not significantly vary. tidal alveolar hyperinflation significantly increased from ± to ± % on the whole lung between t and t . regionally, dynamic strain, and tidal alveolar hyperinflation significantly differed between regions, as well as between t and t . regional suv differed between t and t but not between regions. regional static strain did not differ between regions, nor between t and t . in multivariate analysis, regional suv was independently and significantly associated with dynamic strain and tidal alveolar hyperinflation. histologic analysis showed significant regional differences in alveolar damage but not in macrophage recruitment. suv was positively associated with macrophage recruitment but not with alveolar damage. discussion in this experimental vili model, c-pk suv was significantly increased after h of injurious ventilation, and was significantly and positively associated with high-volume ct-derived mechanical parameters, such as dynamic strain and tidal alveolar hyperinflation. the radiotracer's specificity for macrophages is confirmed by the suv significant association with macrophage recruitment and the lack of association with alveolar inflammatory edema. conclusion c-pk is a macrophage-specific pet radiotracer, with potential to dynamically and specifically assess alveolar macrophage inflammation induced by high-volume ventilation. research founded by the french society of intensive care medicine (srlf) and la fondation pour la recherche médicale (dea ). the reverse triggering (rt) is the term used to name the contractions reflexes of the muscle diaphragmatic provoked ("triggered") by the periodic insufflations, delivered by the ventilator, at sedated patients under mechanical ventilation [ ] . the rt constitutes a new form of patient-ventilator interaction clinically difficult to detect and little known. the rt could have potential implications during the management of acute respiratory distress syndrome (ards). at present, the management of severe ards consists among others, on the use of an early and systematic perfusion of neuromuscular blockade agents (nmba) during a h' period, continuation to the acurasys essay which showed a reduction of the mortality in the group of the severe ards patient receiving nmba. the reason of the beneficial effect of curare is not perfectly known. it is possible that the phenomenon of rt is a mechanism implied in the deleterious role of the mechanical ventilation during ards. the abolition of this phenomenon by nmba could explain the beneficial effect of nmba in ards [ ] . the objective was to look for the phenomenon of rt in two groups of ards patients: a group receiving nmba and a group not receiving nmba. patients and methods physiological observational and comparative study in intensive care units. we record continuous signals of airflow, airway pressure, and esophageal pressure during h of consecutives patients with ards criteria and pao /fio ratio ≤ at a positive end-expiratory pressure (peep) of cmh o evolving for less than h under mechanical ventilation. recording of esophageal pressure of consecutives moderate to severe ards patients were blinded analyzed (group nmba n = ; group unless nmba n = ). any phenomenon of rt was observed in the group of mild ards patients receiving nmba (fig. a) . we confirmed the existence of rt on patients of in the group of mild ards who not receiving nmba (p = . ) (fig b) . discussion one of the main limits was the quality of the collection of the signal of esophageal pressure. the monitoring of esophageal pressure is technically difficult, and can d influence the quality of the signal and the reliability of the results. conclusion this study confirms the existence of the phenomenon of reverse triggering among deeply sedated patients not receiving nmba with a % incidence. more research is needed to determine if the reverse triggering is a risk factor independent from vili, associated with the bad prognosis of severe sdra patients and, if a strategy of early treatment based on nmba, could improve the prognosis of reached patients. after ecmo removal had a significant median reduction of days in the bipap-aprv group, p = . (fig. ). we reported the feasibility of a protocol based on bipap-aprv aiming at resuming sv as soon as possible in ards patients under ecmo. the occurrence of spontaneous inspiratory efforts in ards patients can major variability of transpulmonary pressure and as result jeopardise vt and driving pressure control. this might be an issue if protective ventilation is not guaranteed anymore. vt with bipap-aprv remains within safe range when the ratio fig. circles are pac group, rhombus are aprv group. mv mechanical ventilation, psv pressure support ventilation. data are presented as median (iqr), comparison between the groups at each time mann-whithney test, *p < . of spontaneous minute ventilation to total minute ventilation is between and % [ ] . bipap-aprv is more efficient than psv to increase lung aeration in patients with ards [ ] . recruitment of dependent region is more likely to achieve if sv is not supported by synchronized positive airway pressure as during bipap-aprv [ ] . our strategy targeting a percentage of sv between and % with high peep could be viewed as a compromise in order to promote sv and protective ventilation at the same time. conclusion protective ventilation combined with sv under ecmo by using a specific protocol based on bipap-aprv is feasible and safe. it may facilitate weaning and thus reduce the time under mv after ecmo. to what extend this beneficial effect is directly due to the presence of sv deserve further investigations. introduction since the first transplant from a patient in a state of brain death conducted in at the university teaching hospital ibn rushd of casablanca, the number of transplants has increased. however, it is still inadequate meet the growing needs of organs. the refusal of families remains the main obstacle to the developpement of organ transplantation in morocco. the aim of our study is to monitor and analyse the evolution of family refusal to organ donation in a brain dead patient. patients and methods this is a retrospective and comparative study from august until december .the data were collected from records of brain dead patients candidates for organ donation at the intensive care units on ibn rushed hospital. the coordination registers were also studied. a questionnaire was distributed to families who refused organ donation to investigate the causes of the refusal. results during this period, patients with brain death have been identified and families had been approached. families ( %) refused organ donation. the main causes of refusal were: fear of body mutilation ( %), lack of will ( %) and religious causes in % of cases. the refusal rate for families decreased from % in to % in . only patients experienced cardiac arrest before transplantation. during this period, cornea transplants from braindead patient were conducted with kidney transplants and two liver transplants. discussion the evolution of the refusal of families saw a decline through awareness and communication campaigns for organ donation. conclusion improvements to our health care system must be proposed including strengthening detection of potential donors and relationships with the donor's family and effective communication policy. in the icu, three major actors are involved in the caring relationship: patient, relatives and caregivers. acting as spontaneous testimonials of the lived experience, thank-you letters from relatives may be considered by icu teams as a source of original information which could help in improving care for critically ill patients and families. this study aimed to investigate the qualitative content of thank-you letters from relatives of patients who stayed in the icu. specifically, our research questions were, with regards to the letters' content, ( ) how is the caring relationship tackled and characterized by relatives? ( ) to what extent does this relationship impact their experience of icu? materials and methods the study took place in a -beds icu during a -month period. the research team consisted in a care assistant, a nurse (also clinical research associate), a psychologist (not working in the icu) and an intensivist. the corpus consisted in twenty thankyou letters received in the icu. we conducted a qualitative study according to the thematic inductive approach. the process of coding was intended to create established meaningful patterns. results two main themes emerged as specific determinants of the caring relationship: ( ) the temporality, comprising the time dedicated to the patients and their family, the time spent with the icu team, the striking time corresponding to significant events for relatives needed to be shared with the staff, the extension of the link with caregivers by evocating a new life after icu stay, the writing time as a countergift to the caregivers; ( ) the caregivers behaviour, including human skills detailed in many core values (kindness, availability, devotion, attention, goodwill, sensitivity) psychological support, emotional sharing, capabilities to give informations. relatives feel to be "at the center of all attention" in the same way as their loved ones. through the narration of icu experience, the caring relationship is characterized as follows: ( ) the caregiver becomes a close person with an equal relationship (feelings of friendship, emotional closeness); ( ) the icu team becomes a new family (contrasting with the poor living environment of icus); ( ) the relative becomes a caregiver (with appropriation of medical terms or speaking of his loved one as a patient); ( ) the caregiver is seen as a "super-hero" through an asymmetrical relationship with an overstatement of personal dedication and investment of the staff members (abnegation, vocation, involvement). the caring relationship impacts relatives' experience of intensive care in several ways: ( ) relatives are deeply touched by caregivers' human behavior, emotional support being a source of solace and resilience in particular for bereaved families; ( ) relatives express the idea that taking care of humans is not a valued and rewarded task and the emerging awareness of hospital realities and difficulties of work in the icu; ( ) the most striking transformational change in relatives is the perception of their own vulnerability and humanity, leading them to exhibit an outward-looking attitude (for example filling out their organ-donation card), and encouraging the icu caregivers to continue their missions for the others. conclusion thank-you letters provide both encouraging and informative messages for icu teams about relational care for patients and families notably the indivisibility of the families and their critically ill loved ones. the relatives' experience of the icu appears strongly influenced by the caring relationship in the way they express an authentic revelation of their own humanity and altruistic thoughts. the thematic content of thank-you letters questions determinants and fundamental values at stake in the patient-relatives-caregivers relationship. introduction far from medical paternalism, the doctor-patient relationship has now evolved to respect "the autonomy and patients' rights". changing behavior has been gradual, while the law offered the patient the freedom to consent to care and then of expressing their wishes regarding the therapeutic intensity they would benefit, in critical situations where consent would not be possible, through advance directives (ad) [ ] . their use is of paramount interest for intensivist in many critical situations. unfortunately, the use of ad remains marginal because of the unfamiliarity of patients with their use and an appropriation default by clinicians [ ] . the aim of our study was to investigate the perspective of the coming family physician generation on advances directives. patients and methods population of interest was general practitioner fellow (gpf) from class of to . we built an online questionnaire survey about knowledge and the place they want to give to ad in their forthcoming daily clinical activity. this questionnaire was sent to gpf emails obtained by universities, unions and via the official mailing lists of different regionals classes provided by the first contacted. descriptive analysis of quantitative data was expressed as mean and standard deviation, qualitative data in number and percentage. the comparison of continuous variables was performed by the student t-test and the comparison of categorical variables by a chi test. analyzes were conducted on biostatgv website and microsoft excel ® . results gpf answered the survey, mainly from ile de france (n = ), toulouse (n = ) and lille (n = ). for gpf the majority of patients do not know the ad ( . %) and % think that those who know do not know how to use it. . % of gpf think writing ad by patients requires better information. according to them, the information should concern the support offered in the icu ( . %), the use of mechanical ventilation ( . %), dialysis ( . %) and the evolution of patients after hospitalization in icu ( . %). nevertheless information on the prognosis of chronic diseases or organ failure seems interesting for only and . % of them respectively. . % of gpf wish to propose the drafting of ad to their patients. however, only . % of them are willing to suggest ad to patients with cancer or hematologic malignancies, . % to patients with neurological and/or degenerative disorders, . % to elderly patients. discussion despite the low proportion of the population we think these observations to be of interest because we probably selected the gpf the most interested in ad as the participation was not mandatory. conclusion a large majority of young of future general practitioner is willing to be involved in the implementation of ad with their patients, however the target population remains very limited, considering that half of them do not want to discuss ad with patients suffering from diseases potentially associated with icu admission or therapeutic intensity discussion. this study was conducted in adult intensive care units in public or private hospitals in four countries: canada, france, italy, spain. in each country, health care professionals were solicited for an exploratory interview about the sources of stress in the work environment: senior physicians, residents, experienced nurses (with more than years of experience in the service) and inexperienced nurses (with less than years of experience in the service). all the interview transcripts were analysed using an inductive coding approach. results one hundred and sixty professionals ( physicians and nurses) were included in the study. eight themes emerged from the analysis, and they concerned the stress linked to ( ) patient ( ) care, ( ) team, ( ) family, ( ) institutional context, ( ) environment, ( ) organizational context, ( ) individual dimensions. in each theme, sub-themes have been identified and determine more precisely the difficulties at work. discussion our findings emphasize the complexity of work in icus and show the specifics factors not taken into account in the generic stress scales such as stress in relation with family relationships, the end of life decisions and inequity of health care. conclusion the specific stress scale should allow to better identified stress in icu and to develop measures of prevention and support and training programs. introduction intensive care units (icu) is a place where caregivers face many constraints that can affect their physical and mental health due to the use of specific care and strong emotional charge related to patient death and pain of the families. the aim of the present study is to detect anxiety disorders and/or depression among staff working in icus. on september , a questionnaire was distributed to staff (medical and paramedical) operating in icus in the university hospital fattouma bourguiba monastir, tunisia ( medical icu, surgical icu, cardiologic ccus and nephrologic intermediate care unit). this questionnaire included demographic data of participants (age, sex, marital status, length of service, psychiatric history, consumption of anxiolytic and/or antidepressant) and the hospital anxiety and depression scale (had: scale composed by items to screen the anxiety (a) and/or depression (d) among hospital staff ). results during the study period, participants completed the questionnaire ( %), % of them were women, the median age was years ± . . forty-nine participants were doctors (the majority of them residents: / ). . % of participants (all paramedics) worked on night shift, seniority of more than a year in the icu was found in % of participants. . % of staff interviewed were married and only . % of them reported consumption of anxiolytics and/or antidepressants. . and . % of the participants had respectively symptoms suggesting anxiety and depression. the median had score was (iqr = ); the medical function seems to be significantly associated with the occurrence of symptoms of anxiety and depression compared to paramedics, however the type of icu (medical/surgical icus vs cordiologic/nephrologic icus) does not appear to be related to the occurrence of symptoms of anxiety or depression (table ) . conclusion anxiety and depression are common symptoms among caregivers in icus. improved conditions of work in these units should be a target to avoid burn out syndrome. none. anxiety, n (%) depression, n (%) introduction carbon monoxide (co) poisoning is one of the common causes of poisoning specially in the cold season, which leads to a significant morbidity and mortality. we retrospectively reviewed the medical data of patients who presented to the toxicology emergency department with co poisoning during january to march . we analyzed patients' characteristics, management, and outcomes. results a total of six hundred and sixty-six patients ( female and male), aged of ± years, were included; poisoning occurred between december and february in % of cases, secondary to an indoor heating system exposure in the majority of cases ( %). the estimated duration of exposure was . ± h [ . - h], with a mean carboxyhaemoglobin (cohb) level on arrival at . ± %. neurological changes were the most presenting symptoms including headache (n = , %), dizziness (n = , %), seizure (n = , . %) and loss of consciousness (n = , . %). digestive disorders involving vomiting and nausea were observed in . % (n = ). one woman without cardiovascular risk factors developed non stsegment elevation myocardial infarction complicated by lung edema. the majority of patients (n = , %) received normobaric oxygen during h (n = ) and h (n = ). hyperbaric oxygen therapy was administered at . ata during h to patients for neurological changes (n = ), pregnancy (n = ) and elevated cohb ≥ % (n = ). mechanical ventilation was required for patients, and admission into intensive care unit in patients ( %). death occurred in cases ( . %). conclusion the carbon monoxide poisoning is a common reason for emergency department visits in winter. the physician should be aware of the serious neurological and cardiovascular complications, if symptomatic treatment and oxygen therapy regimens were not respected. none. neuro-respiratory toxicity of baclofen in the rat: study of the concentrations/effects relationships and role of gabaergic introduction baclofen, a gaba-b receptor agonist is used as muscle relaxant agent and recently for the treatment of alcohol dependence. the number of poisonings has significantly increased since this new indication. clinical presentation of poisoning mainly includes sedation, hypotonia, respiratory depression and seizures. to characterize the neurorespiratory toxicity of this molecule at high doses, we aimed at investigating alterations in sprague-dawley rat ventilation and brain electrical activity after baclofen administration and studied their reversal by gaba-receptor antagonists. materials and methods rat ventilation was investigated using plethysmography and arterial blood gas analysis while brain electrical activity was studied using eeg with one implanted frontal electrode. three baclofen doses were used including . mg/kg ( % lethal dose- %), . mg/kg ( %) and mg/kg ( %). baclofen concentrations were obtained using hplc-msms assay. we modeled baclofen pharmacokinetics and analyzed the doses/effects and effects/concentrations relationships. results baclofen induced early-onset and prolonged dosedependent sedation (p = . ), hypothermia (p = . ), eeg and respiratory depression ( . ) characterized by significant increase in the inspiratory (p = . ) and expiratory times (p = . ). significant increase in paco and decrease in arterial ph and pao were observed at mg/kg (p = . ), peaking at min. eeg showed signal slowing, burst-suppression aspects and spikes peaking at - h post-injection without normalization at the end of the experiment at h. we did reverse baclofen-induced decrease in tidal volume with saclofen (a gaba-b receptor antagonist) and interestingly no alteration of baclofen-induced respiratory depression was observed with flumazenil (a gaba-a receptor antagonist). pharmacokinetic parameters of baclofen were obtained at the three doses and were dose-dependent. significant but non-linear relationships were observed between baclofen-induced effects and concentrations. conclusion baclofen causes dose-dependent neurorespiratory toxicity in rats. however, due to increased poisonings, its safety profile at high doses remains to be established in humans. none. poisoning was deliberate in % of cases. mean ingested dose was . ± mg. the majority of patients presented to the emergency room at . ± h after ingestion. digestive decontamination was performed in . % (n = ) of patients. clinical presentation was dominated by neurological symptoms; including coma (n = ), hypotonia (n = ), hyporeflexia (n = ), agitation (n = ), seizures (n = ) and delirium in case. hemodynamic manifestations included bradycardia in patients, three of them required atropine infusion. one patient presented with hypotension responding to vascular resuscitation. sixteen cases required mechanical ventilation. aspiration pneumonia was noted in cases. mean duration of ventilation was . h ± . mean hospital length of stay was h ± . complications included ventilation associated pneumonia in one case and moderate rhabdomyolysis in cases. all patients evolved favorably. there is no correlation between coma and assumed ingested dose. conclusion baclofen overdose causes mainly neurological effects and except for bradycardia cardiovascular effects were uncommon. prognosis is good if full supportive care is administered properly. none. introduction the lack of an effective treatment for the maintenance of abstinence from alcohol has led physicians to take an interest in baclofen. beyond efficacy, safety of baclofen, prescribed in high doses, is a concern, especially in case of drug overdose. indeed, patients with chronic alcohol abuse frequently develop psychiatric disorders, and are at risk of voluntary drug intoxications. thus, we set up a retrospective study to describe morbidity and mortality associated with baclofen overdose. conclusion baclofen, prescribed in high doses, may lead to severe intoxications: self-poisonings frequently require endotracheal intubation and are associated with an increased risk of death. dialysis decreases baclofen elimination half-time but clinical relevance of this difference could not be determined. none. introduction baclofen, a gaba-b receptor-agonist with muscle relaxant properties established since , has been recently used at elevated doses to treat dependence to ethanol. the number of prescriptions has exponentially increased without an exact evaluation of its toxicity. we aimed to describe acute baclofen poisoning requiring intensive care unit (icu) admission and study the relationships between the toxic encephalopathy and the plasma baclofen concentration. we conducted a single-centre retrospective study including all baclofen-poisoned patients admitted to the icu in - . when requested by the clinical situation, repeated electroencephalograms and measurements of the plasma baclofen concentrations were performed. toxic eeg encephalopathy on a scale of zero to five was graded according to the international rating system (markand, ). plasma baclofen concentration was determined using liquid chromatography coupled to mass spectrometry in tandem developed with a quantum ultra apparatus (thermo fisher scientific) and electrospray source ionization in positive mode (limit of quantification: ng/ml). linear regression and chi- or mann-whitney tests were used as requested for subgroup comparisons. baclofen pharmacokinetics and the relationships between the toxic encephalopathy and the plasma baclofen concentration were modeled using winnonlin software v. ) were closed to the observed values reported at therapeutic doses. the relationship between baclofeninduced encephalopathy as a function of the baclofen concentrations was described using a sigmoidal emax model. conclusion baclofen poisoning may be life-threatening. toxic encephalopathy is well-described with eeg and its grade correlated to the baclofen concentration. prescribers should be aware of the dangers of baclofen which benefits to treat dependence to alcohol are still lacking. none. results initial examination suggested that an illness other than bacterial meningitis was the cause of patients' complaints. first hypothesis was meningitis receiving uncomplete dosage regimen of antibiotics. thereafter owing to apparent loss of consciousness with abnormal eyes movements, non-tonico-clonic seizures were considered meanwhile. the ratio of individuals less y-o to those equal to and greater was / %. the male to female ratio was / %. the mean duration of hospitalisation was . ± . days (extremes - days). extrapyramidal syndrome predominant on the upper part of the body was noted by paediatrician neurologists who suggested considering a genetic disease. however, signs and symptoms were present in people from different families in different areas at the same time. the definitive diagnosis made on pictures and videos of children and adults and was facio-troncular dystonia resulting from drug-induced adverse effect. four urine samples were collected in children and sent to a toxicological laboratory in france. all urine samples were positive for haloperidol meanwhile the other causes of facio-troncular dystonia were excluded, including other neuroleptics, metoclopramide, antidepressants, amodiaquine, anti-histaminic drugs, anti-epileptics, and cocaine. from january to august , hospitalisations were recorded in patients. looking for the source of haloperidol showed that tablets sold as 'diazepam' and consumed by symptomatic patients contained haloperidol as the sole active pharmaceutical ingredient, suggesting that this large outbreak was due to haloperidol toxicity from falsified diazepam. initial treatment was diazepam to relieve severe facio-troncular dystonia which was efficient but resulted in long-lasting sedation more especially in children. a dosage regimen using bipéridène administered by intravenous and oral route was refined to prevent adverse effects related to this anticholinergic agent used in children. the complete reversal of the facio-troncular dystonia was the antidotal evidence supporting the toxicological diagnostic. the mortality rate was less than % meanwhile the direct causal relationship with adr is questionable. an epidemiological study, including toxicological analysis in controls in ongoing. indeed, facio-troncular dystonia induced by haloperidol does not result from a drug overdose but is an adr occurring in about % of patients treated with haloperidol. who is involved in the inquiry related to this counterfeature involving different countries. the cause of the error is presently under investigation. discussion this outbreak emphasizes the need to consider toxicity resulting from counterfeatured medicines when facing collective atypical signs and symptoms in countries with unrestricted access to medication with limited control of qualities of the medicinal drugs. conclusion counterfeatured medicinal drug may result not only in poor efficacy but also in onset of unexpected outbreak of unknown diseases that should suggest a toxic origin. in late -early , médecins sans frontières (msf) had to face an outbreak of severe facio-troncular dystonic syndrome (ftds) in north-east congo. this outbreak resulted from counterfeature of pills sold as diazepam. toxicological analysis revealed one pill contained about mg of haloperidol. ftds induced by haloperidol does not result from a drug overdose but is an adverse drug reaction (adr) occurring in about % of patients treated with haloperidol. nine-hundred and twenty-five individuals were admitted in msf structures for ftds. the ratio of individuals less than y-o and equal to or greater of age was / %, including ( . %) of children less than y-o. initial treatment was based on diazepam which relieved ftds but resulted in long-lasting sedation, preventing given any drug by the oral route. owing to the definitive diagnosis, a shift to the use of a more specific antidote was chosen. biperiden was selected as existing in the intravenous and oral form in the swiss pharmacopea. the study was approved by the ethical committee of the ministery of health of the republic democratic du congo. patients and methods as a whole, biperiden was used in cases ( % of the total). treated children presented with severe dystonia as evidenced by inability to cooperate and to swallow. verbal informed consent was obtained from relatives. the dosage regimen to treat drug-induced dystonic syndrome in the swiss pharmacopea is as follows: for parenteral use in children, intravenously or intramuscularly: . mg/kg or . mg/m bsa every , according to response and tolerance; a maximum of four doses per day should be used. the internal msf recommendations for biperiden use in children were . - . mg/kg of body weight that might be repeated four times a day. initially, biperiden administration was administered under medical supervision by the msf referent at the scene. results there was no pediatric preparation of biperiden. accordingly, the adult preparation was used in children. the preparation contained mg of biperiden in one milliter of solvent. the initial planned dose for children of y-o and less and those up to y-o were and mg, respectively. the mg ( ml) of biperiden was diluted in ml of saline resulting in a final dilution of mg/ml. six children were treated according this dosage regimen. however, the one mg dose was either of limited efficacy while being associated in others of signs suggestive of adr, including agitation, heart rate greater than b/ min, the upper limit for children aged of y-o and less. two children greater than y-o presented severe abnormal behavior resulting in an attempt at escape. owing to question about safety, the dosage regimen was changed, as follows: mg ( ml) of biperiden was diluted with ml of saline resulting in a final dilution of . mg/ml. an initial dose of . mg was administered intravenously as a bolus dose. the effects were looked for over min. in the absence of improvement in facial dystonia, a second bolus dose of . mg was administered, a third dose could be considered min later if the ftds did not resume. the cumulative initial dose should not be greater than mg. in addition to the reversal of facial dystonia, the therapeutic effect of biperiden included the return of swallowing to normal allowing to give further doses of biperiden by the oral route for three days. the first oral dose was administered no less than h after the last initial dose at a dose equal to the efficient initial cumulative dose. the following doses were halved every h. no adr related to biperiden were reported using this dosage regimen. the mean duration of hospitalisation was . ± . days. discussion the bioavailability of biperiden by the oral route is equal to %. accordingly, the corresponding intravenous dose should be divided by a factor three. dosage regimen of anticholinergic drugs in children are poorly documented. the dosage regimen recommended by the pharmacopea resulted in frequent and severe adr. titration of biperiden resulted in efficient and safe dosage. conclusion when biperiden administration is required by intravenous route in children of y-o and less, biperiden should be administered intravenously and titred using bolus dose of . mg till the therapeutic effect is obtained. introduction severe poisoning by rodenticides is frequent. it represents nearly % of patients admitted to the new intensive care unit (icu) of the region. that is why we decided to perform this study. the aim of this work was to describe the epidemiology, clinical features and management of all patients admitted to our unit for acute poisoning with rodenticides. patients and methods it was a retrospective study performed in the year from january to december. the study included all patients admitted in the icu for rodenticide poisoning. results patients were enrolled in the study. our patients were young with a mean age of ± years. poisoning was more common in females (n = ; %). the mean delay between rodenticide poisoning and first medical contact was about ± h in the cases where this information. most of our patients ( %) attended the emergency department of zaghouan with a non-medical transportation. it was a suicide attempt in most cases ( %) and an accidental poisoning in % of patients. the most frequent cause of poisoning in our study was organophosphorus pesticide (n = ; %). the second cause was alpha-chloralose poisoning with seven cases ( %). one patient ingested accidentally an anticoagulant rodenticide. most of patients had ingested (oral route) the rat poison (n = ; %). clinical examination found normal vital signs in ten cases ( %). nine patients ( %) had a shock, eight patients ( %) had an acute metabolic disorder and five patients ( %) had acute respiratory failure or were comatose. all patients enrolled in the study were admitted in the icu for a period of clinical observation of h. stomach pumping (gastric lavage) was performed in patients ( %). an antidote which was atropine was needed in twelve patients. three patients ( %) who ingested alpha-chloralose needed intubation and mechanical ventilation. all patients had a good outcome and were discharged from icu and from hospital. the mean icu length of stay was ± days. conclusion this is the first study of acute poisoning with rodenticides admitted in the new icu. the results of our study were similar to those published in recent literature. cases of acute poisoning with rodenticides reported in this work were not severe. none. introduction the systemic arterial load imposed to the left ventricle (lv) is a major determinant of normal/abnormal cardiovascular function. the lv mean ejection pressure (lvmep) is the best estimate of load faced by the lv throughout ejection. the contribution of the steady and pulsatile blood pressure (bp) component of arterial load to lvmep is debated. we studied the hemodynamic correlates of lvmep using carotid tonometry. intensive care unit patients equipped with an indwelling catheter were studied, thus allowing precise calibration of the tonometer. patients and methods carotid tonometry (complior analyse ® alam medical, france) was prospectively performed on hemodynamically stable, spontaneously breathing patients ( f, mean age ± sd = ± years). carotid waveforms were calibrated from diastolic bp and time-averaged mean bp invasively obtained at the radial (n = ) and femoral (n = ) artery. all patients were free of aortic stenosis. lvmep was the area under the systolic part of the carotid pressure waveform divided by ejection time. results lvmep ( ± mmhg) was strongly related to central systolic bp ( ± mmhg; r = . ) and was also related to mean bp (r = . ), peripheral systolic bp (r = . ), peripheral (r = . ) and central (r = . ) pulse pressure (each p < . ). the lvemp was not related to age, heart rate and stroke volume. systolic pulse wave amplification ratio from carotid to periphery was . ± . . conclusion lvmep was most strongly related to central systolic bp, which combines the influences of the steady and pulsatile components of central arterial load (r = . ). lvmep was less strongly related to peripheral systolic bp, which may be less informative given variable systolic pulse wave amplification across patients. introduction myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to %. many pathological findings were found in the sepsis induced cardiomyopathy including myocardial ischemia, alterations in microcirculation and proinflammatory cytokines. the aim of this study was to assess the prognostic value of a recently developed highly sensitive cardiac troponin i (hstni) assay in patients with septic shock. we performed a prospective observational study in septic shock icu patients within h of admission. exclusion criteria were age > years; pregnancy; post-cardiac arrest and braindead. hstni was measured soon after admission and , , and h after. patients were subjected to transthoracic echocardiography (tte) at study inclusion and regular biochemical and hemodynamic assessments were performed. pearson's chi square and fisher's exact tests were used. p < . was considered significant. conclusion circulating hs-ctni is present in patients with septic shock. a rise of hstni may be an indicator of poor outcome. also, right heart functional abnormalities exist in patients with septic shock. none. evolution of the right distribution width as a pronostic marker during the differents state of shock introduction right distribution width (rdw) has been recently proposed as a pronostic factor in different pathologic situations and especially to the septic patients who stay in icu. some works substantiate the relationship between an alteration of the red blood cell rheology during the septic shock and a severe state of the disease. no one has studied the rdw between the differents shocks yet. we are going to determinate the relationship between rdw and apache ii score, mortality rate in the intensive care unit (icu), at the hospital, at the day and . we investigated those parameters near patients who were admitted at the icu and needed norepinephrine between the first of march and the st of december. they were stratified in différent groups: septic shock n = , cardiogenic shock n = , hemorragic shock n = and obstructive shock n = . results we did not observe any correlation between the rdw and the icu mortality, hospital mortality and at the day and . only a poor significant correlation has been found between the cardiogenic shock and the mortality rate: at the hospital (p = . ), at day (p = . ) and at the day (p = . ) but not in the icu (p = . ). the receiver operating characteristics (roc) curves do not show significant differences between rdw, apache ii score and icu mortality rate or intra hospital. the sample of the hemorrhagic shock and obstructive shock was not usable for this calculation. compared to other studies which were focused on the septic shock where the mortality was approximately %, we determinated a mortality rate near %. conclusion the delta of the rdw d /d did not present any correlation with the mortality rate. in our study, the rdw in the different kind of shocks do not look like to be a good predictive marker of the mortality, except for the patients included in the cardiogenic shock where a poor significant correlation could be highlighted. conclusion cardiogenic shock was the most frequent complication of ami who led to icu admission, whereas mechanical complications are rare at the era of early coronary reperfusion strategies. in addition to severity score, serum creatinine and cardiogenic shock appeared as independent factors of hospital death. none. introduction pulmonary embolism (pe) in high-risk is a partial or total obliteration of the pulmonary arterial network by a fibrin-clot cruoric more than %, the management requires a rapid reduction of pulmonary arterial resistance and right ventricular post load through rapid revascularization by thrombolysis. our aim is to determine the value of thrombolysis in pulmonary embolism and describe the clinical, paraclinical and outcome pulmonary embolism at high risk. patients and methods this is a descriptive study of cases of pulmonary embolism at high risk admitted to the cardiology department to chu oran between and . signs of gravity of (pe) comprising: syncope, circulatory collapse, cardiogenic shock or acute pulmonary sonographic sign of heart. it was confirmed in chest ct. all patients received thrombolysis using the protocol accelerated by two types of molecules: streptokinase or actilyse. the sex ratio was . ; mean age years, ranging from to years; risk factors were dominated by contraception was % and the postoperative % the clinical picture was dominated by cardiogenic shock in % of cases. % cardiovascular collapse and syncope in %; doppler echo all patients had signs of dysfunction of the right ventricle represented by the dilatation of the right cavities and pulmonary hypertension. the cta found a (pe) bilateral in % right in %. thrombolysis using actilyse in patients and streptokinase in cases. the outcome was favorable in patients; with two cases that are complicated by chronic pulmonary heart and the death of patients with cancer. discussion the female predominance is explained by the increase of risk factors hormonal contraception, whose first generation combination hormonal. our patient had a high probability with clinical signs of severity based on the score wells [ ] . this diagnosis was confirmed by chest ct; which shows the vascular bed obstruction degree with a very good sensitivity and specificity. the suspect patients with severe pe and that presented signs of acute pulmonary heart ultrasound have effectively (pe). the indication of thrombolysis was chosen on hemodynamic criteria; success is found in % of patients with improved hemodynamics dice the early hours. this success is explained by the role of thrombolytic in lysis clot to obtain pulmonary arterial revascularization; and reduce pulmonary arterial resistance and the right ventricular afterload which accelerates the healing of right heart failure and improvement of pulmonary capillary volume. the cases who developed a chronic pulmonary heart; it was done immediately a right ventricular dysfunction with pulmonary arterial outset of very high pressures suggestive that the embolism occurred on an already pathological right heart. no cases of massive bleeding were noted in our series. conclusion severe pulmonary embolism is burdened with high mortality; diagnosis is based on the stratification of risk score, was facilitated by the non-invasive strategies that articlent around the doppler echocardiography and ct angiography; thrombolysis can reduce the high mortality related to severe pulmonary embolism. introduction hypertension is a frequent motif for admission to emergencies. the diabetic is increasingly exposed to this risk [ ] . the objective of this study is to evaluate the proportion of diabetic patients presenting to the emergency department with high blood pressure (bp) and to identify their epidemiological and clinical characteristics. introduction sepsis associated liver dysfunction (sld) is usually attributed to systemic and/or microcirculatory disturbance. hypoxic hepatitis, also known as shock liver or ischemic hepatitis, is a life threatening event associated with high morbidity and mortality. doppler ultrasonography is a non invasive method to measure doppler hepatic hemodynamic parameters. the primary objective of this study was to assess the accuracy of the hepatic hemodynamic parameters (portal venous blood flow pvbf and resistance index of the hepatic artery hari) in predicting sld in septic shock patients. the secondary aims were to identify factors associated with sld, investigate the effects of volume expansion (ve) on systemic and intrahepatic hemodynamics and to assess the intra-and interoperator reproducibility. we also analyzed -day mortality. in a prospective design, we included consecutive patients with septic shock ( males; median age: . years) admitted to the icu with septic shock in charles nicolle hospital of tunis from february to july . all patients were resuscitated following the surviving sepsis campaign guidelines. we measured systemic hemodynamic variables (mean arterial pressure (map), and cardiac index (ci)) and performed hepatic doppler before and after volume expansion. we measured pvbf and computed the hari. we recorded the liver function tests (alt, ast and bilirubin) for h. sld was defined as an increase in serum bilirubin ≥ µmol/l (hepatic sofa ≥ ). accuracy of the hepatic hemodynamic parameters to predict sld was measured by the area under the roc curve. p < . was taken to indicate statistical significance. the median sofa score at t was points and the median igs score was points. the sources of infection were as follows: the lungs (n = ), the abdomen (n = ) and the urinary tract (n = ). the incidence of sld in our cohort was . % (n = ). there was no significant difference between "sld group" and "no-sld group" in all hepatic hemodynamic parameters especially the pvbf and the hari. lactate levels were significantly higher in patients with sld (median . vs. . mmol/l). similarly, the platelet count was significantly lower in the "sld group" [mean (± sd) . ± . ( /l) vs. . ± . ( /l); p = . ]. there was no difference in duration of mechanical ventilation, icu length of stay and -day mortality between the groups. the pvbf was significantly lower in patients who died before d (median: vs. l/min in the survivors; p = . ). volume expansion caused a significant increase in ci, mean hepatic artery velocity and the pvbf. the intra-and interoperator reproducibility was good to excellent for the systolic and mean velocities of the hepatic artery, portal vein diameter and the pvbf. conclusion our results don't support the hypothesis that the hepatic sonography is predictive of sld in septic shock. our pilot study showed higher lactate levels and hematologic sofa in sld group. the pvbf was significantly lower in patients who died before d . more experience will be necessary to define the ultimate role of doppler ultrasonography in the evaluation of hepatic perfusion in patients with septic shock. introduction early surgery is the current trend for management of patients with valvular disease. that said many of them, particularly from developing countries, are still operated at a very advanced stage of disease. despite improvements in myocardial protection and surgical techniques, postoperative care after multiple valve surgery (mvs) for advanced rheumatic heart disease (rhd) remains to be a clinical challenge. we conducted a study to determine postoperative complications and morbidity-mortality risk factors in this subgroup of patients. results sixty-two patients were included: with out-of-hospital refractory cardiac arrest and with in-hospital refractory arrest. the initial rhythms was shockable rhythm in ( %) cases. at ecls initiation, the mean no flow was . ± . min and mean low flow (time between the time of refractory cardiac arrest and time at which an ecls flow was provided) was ± min. the mean ecls flow rate was . ± . l/min. initial blood test results were: arterial ph = . ± . and plasma lactate = . ± . mmol/l. eleven ( %) patients survived ( / ( %) acute coronary syndrome, / ( %) severe poisoning due to drug intoxication, / ( %) dilated cardiomyopathy, and / ( %) others). survival was lower for patients with out-of-hospital refractory cardiac arrest, of ( %), than for patients with in-hospital refractory cardiac arrest, of ( %), respectively, p = . . as expected, out-of-hospital refractory cardiac arrest was associated with a more prolonged low flow ( ± min vs ± min, p < . ) and a more profound acidosis (ph . ± . vs . ± . , p = . and arterial lactate . ± . vs ± , p = . ). in univariate analysis, survival was lower for patient with refractory cardiac arrest unrelated to drug intoxication, vs %, respectively, p = . . in addition, mortality was associated with arterial ph ( . ± . vs . ± . , p = . ) and low flow ( ± vs ± min, p = . conclusion in a highly selected group of critically ill patients with refractory cardiac arrest, the potential beneficial effect of ecls could be due only to its clinical impact on reversible causes of circulatory failure (i.e. severe drug intoxication in our cohort). further studies are needed to clarify whether the use of ecls could be considered as a disproportionate tool, specifically in patients with out-of-hospital refractory cardiac arrest due to acute coronary syndrome or associated with prolonged low flow or a profound acidosis. none. post-cardiac arrest shock treated with veno-arterial extracorporeal membrane oxygenation: an observational study and propensity-score analysis wulfran bougouin , nadia aissaoui , alain combes average time between introduction and removed of the ecd was h ( - ). among the esogastroduodenoscopy performed, ( %) were strictly normal. endoscopy showed minor gastric injuries in patients ( %). within these patients, ( %) also presented minor esophageal injuries. esogastric injuries characteristics were mostly similar to usual orogastric probe injuries. one patient ( %) experienced a serious ulcerous esophagitis mimicking a peptic esophagitis, not firmly related to the ecd. no patients necessitated hemostatic local procedure and no significant gastrointestinal bleeding was observed. eight patients ( %) were alive at d , including patients ( %) with a cerebral performance category score of . this compares favorably to outcomes from previous studies. conclusion ecd seems an interesting and safe semi-invasive method of cooling in ohca patients treated with °c-ttm. although it seems slower than more invasive devices to reach °c, ecd was able to strictly maintained the tt within the maintenance phase of ttm. further studies will be necessary to define the exact place of this new device within the cooling strategy in patients necessitating a precise ttm-strategy. none. fig. see text for description introduction since post-cardiac arrest care might influence the outcome, characteristics of receiving hospitals should be integrated in survival evaluation of patients transported in hospital. we aimed at assessing the influence of care level center on survival at discharge in a regional registry of out-of-hospital cardiac arrest (ohca). we prospectively collected utstein and in-hospital data for all non-traumatic ohca patients, in whom a successful return of spontaneous circulation (rosc) had been obtained, from a large metropolitan area (great paris). receiving hospitals were categorized in groups (a, b, c) depending on their respective characteristics (annual volumes, / catheterization availability and temperature management use). we compared patients' characteristics in the groups and performed a multivariable logistic regression using discharge survival at endpoint. results during the study period (may -dec ), patients were admitted in hospitals ( in group a, in group b and in group c). overall survival rate at discharge was / ( %). patients' baseline characteristics significantly differed, as hospitals from group a treated younger patients and more frequent shockable rhythms (p < . ). unadjusted survival rate differed significantly among the groups of hospitals (respectively , and . % for a, b, c, p < . ). however in multivariable analysis, the category of hospital was no longer associated with survival. conclusion in this population-based study, characteristics of receiving hospitals are not associated with survival rate at discharge. this could result from the strategy used for triage, which aims in matching patients' characteristics and resources. introduction acute kidney injury (aki) commonly occurs after cardiac arrest and is associated with an increased mortality and a delayed awaking. early recognition of aki remains challenging, given that serum creatinine increases belatedly after aggression. introduction out-of-hospital cardiac arrests (ohca) are an absolute urgency and have a very poor prognosis. pediatric guidelines differ from adult guidelines for cardiac arrest management. since , adult guidelines apply from the onset of puberty. the main objective was to describe the epidemiological characteristics and outcome of ohca victims while taking puberty into account. the secondary objective was to determine the prognostic factors for survival at d . materials and methods all patients less than years of age, victims of ohca between july , and september , care by a mobile emergency and resuscitation service (smur) participating in french national cardiac arrest registry (réac) were included. patients were split into groups: prepubescent patients (named "children": girls - years, boys - years), pubescent patients (named "adolescents": girls from to years and boys from to years) and "adults" (men and women - years). the "adolescents" group was consecutively compared to the "children" group and to the "adults" group. results children, adolescents and , adults under the age of have been included. ohca in adolescents occurred more often on public roads ( %) or in public places ( %) and were more often traumatic ( %) than those in children and adults. respiratory causes were more frequent in children ( %) than in adolescents ( %) and adults patients ( %). the proportion of shockable rhythm increased with age ( , and % for children, adolescents and adults respectively). survival at d was greater in adolescents ( %) than in children ( %) and adults ( %) (p = . and p = . respectively). in the studied groups, initial shockable rhythm was a survival factor at d (respectively or [ . - . ] for children, adolescents and adults). other risk factors are described in table . conclusion adolescents had better survival at d than the others groups. adolescents and adults had shockable rhythm more often than children. moreover, respiratory failure was less frequent in adolescent and adults patients compared to children. puberty seems to be a good limit to differentiate pediatric patients with ohca. none. introduction non-invasive ventilation (niv) is an effective alternative to endotracheal mechanical ventilation (mv) in the management of acute respiratory failure (arf) patients. nevertheless, it can be still difficult to assess its real feasibility, application and outcome in daily clinical practice. therefore, we report our clinical experience with routine use of niv since the last national recommendations ( ). our aims were to evaluate the clinical efficacy and outcome of niv, and to identify predictive factors for niv failure based on a daily use. patients and methods we conducted an observational retrospective single-center cohort study by reviewing all medical records from january to december in our -bed medical intensive care unit (icu). eligible patients were those having received niv during their icu stay. two groups were defined according to the indication of niv: niv for hypoxemic or hypercapnic arf (arf-niv), and niv used in the post-extubation period for weaning, prevention or treatment of post-extubation arf (post-extubation niv).the main evaluation criteria were the incidence of niv use, success/failure rate of niv and risk factors for niv failure in each group. niv failure was defined as the need for stopping niv whatever the reason (intubation, intolerance, death) within days after its initiation. ( ; ), and was longer in the post-extubation niv group ( days ( ; ) ) than in the arf-niv ( days ( ; ) for hypoxemic arf, ( ; ) for hypercapnic) (p < . ). the overall icu mortality was . % ( . % in hypoxemic group, . % in hypercapnic group, and . % in post-extubation niv group) (p = . ). in multivariate analysis, the main risk factors for arf-niv failure were: saps ii on admission (p < . ), absence of cardiologic history (p = . ) and the cause of arf (p = . ) with a higher failure rate for pulmonary infections than acute cardiogenic pulmonary edema (or . , p = . ). for post-extubation niv, the only independent risk factor for failure was normocapnia before niv initiation (p = . ). conclusion our large longitudinal study demonstrates the feasibility and efficacy of niv applied in daily clinical practice. provided it is performed in a suitable environment by an experienced team, niv should be considered as a first-line ventilatory treatment in various etiologies of arf and a very useful ventilatory support in the postextubation period. nevertheless, risk factors for niv failure should be known by icu clinicians, hypoxemic arf remaining the more difficult indication to manage with niv. réanimation médicale, hôpital saint-louis, paris, france; service de biostatistique et information médicale, hôpital saint-louis, paris, france; réanimation, institut paoli-calmettes, marseille, france; réanimation introduction acute respiratory failure (arf) is the leading cause for icu admission in immunocompromised patients. in these patients, oxygenation strategy is of major interest to avoid the need for mechanical ventilation (mv), which is associated with high mortality rates. in that setting, use of non-invasive ventilation (niv) and oxygen therapy with high flow nasal cannula (hfnc) could be interesting alone or in association, but data about initial ventilation strategy in immunocompromised patients are controversial. to assess how initial oxygenation strategy actually influences the risk of mv on the coming day within the three first days of icu stay. the study end-point was the need for mv on the coming day. we restricted analyses to these first three icu days given, based on our own experience, most of mv was expected to occur by then. we performed a post hoc analysis combining three prospective studies of critically ill immunocompromised patients (two randomized control trials, the ivnictus and the minimax studies and one prospective cohort, the trial-oh study). we only considered patients with arf and a delay between icu admission and study inclusion less than h. we excluded patients who required invasive mv within the first day, those with an icu stay less than day and those with acute pulmonary edema diagnosis at icu admission. in order to estimate and compare the causal effect of daily respiratory management strategy on the probability of intubation in the coming day, we computed inverse probability of treatment weights (iptw) using propensity-score, defined as the probability of actual treatment selection conditionally on observed covariates. to handle confounding in such dynamic regimens, we considered marginal structural models (msm), which have been proposed to estimate the causal effect of a time-dependent exposure when time-dependent covariates that can be affected by the previous treatment are present. two treatment exposure models were considered: niv versus oxygen therapy regardless the device (model ) and hfnc alone, niv alone versus niv + hfnc versus standard oxygen therapy alone (model ). results patients were included in the study. in model , there was no difference between niv and oxygen groups on mv whatever the landmark time. in model , while the unweighted or for intubation at day was significantly higher in the niv group (or . , %ci . - . ) and hfnc group (or . , %ci . - . ) than those in the standard oxygen alone group, these differences disappeared in the weighted samples. using msm, no effect of the oxygenation strategy on mv was found, regardless of the oxygenation devices but the landmark time was associated with a reduced occurrence of mv. conclusion we found no evidence of any significant difference from several oxygenation strategies on mechanical ventilation probability during the first days of icu in a large cohort of immunocompromised patients with arf. none. introduction the role of noninvasive ventilation (niv) is debated in the management of patients with acute hypoxemic respiratory failure. a recent study showed that patients treated with high-flow nasal cannulae oxygen therapy (hfnc) had lower intubation and mortality rates than those treated by the association of hfnc with niv ( ). high tidal volumes (vt) delivewred with niv may be associated with an increased risk of intubation ( ) . we aimed to identify risk factors associated to intubation, in hypoxemic patients with acute respiratory failure and especially the role of vt under niv. patients and methods this is an ancillary study from a multicenter, randomized, controlled trial including patients with acute hypoxemic respiratory failure (florali-study). we focused on only patients with moderate or severe hypoxemia (pao :fio ratio ≤ mmhg) and we excluded those with mild hypoxemia. the criteria for intubation were predetermined including worsened or persisted respiratory failure, impairment of neurologic status and hemodynamic instability. results after adjustment on the oxygenation strategy, the two factors independently associated with intubation were the presence of bilateral pulmonary infiltrates at admission (or . simulation conditions enables to reproduce its occurence, using different types of tools, from physiological parameters to heart rate variability and psychocognitive tests. future research is required to evaluate the impact of these parameters on teaching. none. with stratification by centre and operator experience. an only inclusion criterion was: "patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if: contraindication to orotracheal intubation (e.g., unstable spinal lesion); insufficient time to include and randomize the patient (e.g., because of cardiac arrest); age < years; pregnant or breastfeeding woman; correctional facility inmate; patient under guardianship; patient without health insurance; refusal of the patient or next of kin to participate in the study; previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess occurrence of spo < % during intubation procedure between groups of preoxygenation: bvm (at a minimum flow of l/min, niv ( % fio ), hfnc (at a minimum flow of l/min, with % fio ), and nrm (at a minimum flow of l/min). between-groups difference in desaturation occurrence was adjusted for baseline covariates significantly associated with the group membership (p < . ). multivariate analysis of the occurrence of a desaturation (< %) was performed using logistic regression. bag-valve mask was considered reference. results baseline characteristics were showed in table . groups were similar at baseline except for pao /fio ratio. in univariate analysis, age (p = . ), saps (p = . ), pao /fio ratio (p = . ),spo (p = . ) and method of preoxygenation (p = . ) were associated with occurrence of desaturation below %. in multivariate analysis, spo at randomization and method of preoxygenation were only predictors of desaturation below %. bvm and hrm were associated with similar risk of desaturation occurrence whereas niv (or . introduction intubation procedure is a challenging issue in intensive care unit (icu) [ ] . cardiac arrest related to intubation in critically ill adult patients has been poorly studied. the studies were not powered to conclude on this rare outcome [ ] . the main objective of our study was to establish the incidence of cardiac arrest and to assess the risk factors of cardiac arrest in a large prospective database of intubation procedures performed in icu. five prospective studies were included, with similar data collected before, during and after intubation procedures using the same methodology. the primary outcome was the incidence of cardiac arrest related to intubation. the secondary outcomes were the death (cardiac arrest without return of spontaneous circulation (rosc)), the cardiac arrests with rosc, the complications related to intubation, the length of icu stay and the -day mortality. the factors associated with cardiac arrest related to intubation procedures were assessed by univariate and multivariate analysis based on patient, provider and practice characteristics. results among the intubation procedures included, cardiac arrests ( . %) occurred, including with rosc ( . %) and without rosc ( . %). main patient, provider, procedure characteristics and outcomes according to cardiac arrest related to intubation are presented in table . in multivariate analysis, the independent predictors of cardiac arrest related to intubation were low systolic blood pressure prior to intubation, hypoxemia prior to intubation, no preoxygenation, overweight or obesity and age > years. mortality rate at day was significantly lower in patients intubated without cardiac arrest ( . %, of ) than with cardiac arrests overall ( . %, patients of , p < . ) and cardiac arrest with rosc ( %, patients of , p < . ). conclusion cardiac arrest related to intubation in adult icu is not a rare event occurring in . % of cases with high immediate mortality of . % and at day of . %. we identified five independent risk factors to cardiac arrest which of them could be modifiable. optimal preparation to intubation procedure could help to prevent those cardiac arrests. introduction naasotracheal intubation (nti) has been progressively given up in favour of the orotracheal intubation (oti) in intensive care unit (icu). this could be explained by more frequent infectious (sinusitis and ventilator associated pneumonia) and non-infectious (epistaxis, turbinates bones injury) complications the former being thought to be more frequent with nti. however, whereas infectious sinusitis is a risk factor for vap, no study has yet demonstrated that oti decreases the infectious sinusitis rate compared with nti. furthermore, nasal route could improve patient comfort and decrease auto-extubation. finally nti can be performed without laryngoscopy with less risk of lips and dental injury. in this prospective study, we aimed to compare the complication of nti and oti and to assess the comfort of the patient. we performed a prospective observational study in a -bed medical icu including patients requiring endotracheal intubation. the intubation route was let at the discretion of the physician in care of the patient, however oti was compulsory in case of cardiac arrest, severe hypoxemia (p/f < when available) and clotting perturbation. for each patient, age, sex, sapsii, mechanical ventilation duration. intubation route were recorded as well as complications during the placement of endotracheal tube. infectious and non infectious complications during invasive ventilation period were also recorded. in patients who were successfully extubated, pain, burning feeling, dryness and the wish of tube removal were assessed using visual analogic scales (vas conclusion despite its small size, and the absence of randomization, the present study suggests that nasotracheal intubation improves the comfort and the tolerance of tracheal intubation and is not associated to higher rates of vap. none. effect of mode of hydrocortisone administration in patients with septic shock: a prospective randomized trial oussama jaoued , rim gharbi , najla the baseline characteristics of patients were similar between the two groups. sepsis was secondary to community-acquired infection in % of cases. there was no difference in mortality between groups ( % in continuous groups and % in discontinuous group). sofa score was significantly higher at days , and in discontinuous group. length of stay, duration of mechanical ventilation, number of day without vasopressors, and the occurrence of adverse events were similar in the two groups. conclusion the mode of hydrocortisone administration in patients with septic shock has no influence on morbidity or mortality. the occurrence of adverse events was similar. introduction widespread activation of coagulation with platelet consumption is a pathophysiological feature of severe sepsis and septic shock. thrombocytopenia, either defined by platelet count below g/l or by a significant relative - -percent decrease in platelet count is a potent poor prognostic factor in sepsis. besides their role in hemostasis, platelets also carry various immune and inflammatory functions that are likely to impact on host defense against infections. we aimed to assess whether changes in the platelet count induced by sepsis is associated with the development of subsequent nosocomial infections. patients and methods patients were obtained from two prospective studies about immuno monitoring of dendritic cells and innate-like lymphocytes in critically ill septic patients ( , ) . adult patients with severe sepsis and septic shock were included. exclusion criteria were any immunosuppressive condition (hematological malignancy, hiv infection at any stage, bone marrow or solid organ transplantation, daily corticosteroid therapy > . mg/kg prednisone-equivalent, chemotherapy or any other immunosuppressive treatments), pregnancy, do-not-resuscitate orders on admission. in addition patients who died or who received platelet transfusion during the first week after icu admission were also excluded. platelet counts were collected on the day of sepsis diagnosis (d ) and then on d , d and d . the relative variation in platelet count at day n compared to day was calculated as follows: (count at day n − count at day ) × / (count at day between between d and d , between d and d and between d and d were also similar between patients with and without icuacquired infections (fig. ). discussion in this preliminary study from selected cohorts of nonimmunocompromised patients, sepsis resulted in mild alterations in platelet counts, making it unlikely to become associated with the development of nosocomial infections. it would be relevant to address this question in larger cohorts of non-selected patients, as well as the impact of platelet transfusions in this setting. conclusion changes in platelet counts were not associated with an increased susceptibility towards icu-acquired infections in non-immunocompromised patients with severe sepsis and septic shock. introduction sepsis is the leading cause of mortality in the intensive care unit (icu) patients despite the progress regarding their care. the immunodeficiency due to sepsis with the consequent profound lymphocyte alterations is now well proven. the objective of this work was to determine the prognostic impact of lymphocytopenia in septic patients in icu. retrospective study including all patients hospitalized for sepsis or septic shock between / / and / / . the sepsis and septic shock definitions were adjusted with the third international consensus definitions for sepsis and septic shock. were excluded from the study patients of onco-hematology. lymphocytopenia was defined as an absolute lymphocyte count less than level of /mm during the first h of hospitalization. the prognostic factors analyzed for the lymphopenic and non lymphopenic patients were in hospital mortality, the occurrence of nosocomial infections and hospital length of stay. results among the patients, aged ± years, patients were with septic shock and patients with sepsis. igsii score and sofa score were respectively ± and ± . four patients were immunocompromised due to hiv infection in one case and an immunosuppressive therapy in cases. lymphocytopenia was observed in patients ( %). twenty-eight patients ( %) died within an average of ± days. it was noted the occurrence of nosocomial infections. the median length of stay was days with extremes of one and days. the lymphopenic patients were comparable to non lymphopenic patients in terms of medical history and severity scores. mortality was comparable between the groups with a rate of % (n = ) in lymphopenic patients and % (n = ) in non-lymphopenic patients (p = . ). the earliness of death was correlated with the duration of lymphopenia (r = . , p = . ). the occurrence of nosocomial infections was not different between the two groups: % (n = ) for lymphopenic and % (n = ) for non lymphopenic patients. the hospital length of stay was not different between the two groups but was correlated with the duration of lymphocytopenia (r = . , p = . ). conclusion lymphocytopenia is frequently found in sepsis. lymphocytopenia was not associated with excess of mortality nor with the subsequent occurrence of infectious complications during the icu stay. his persistence was associated with an earlier death and a more prolonged hospitalization. none. introduction relative adrenal insufficiency (rai) is common in icu patients, particularly during septic shock ( ). it has been shown that the rai also occurs during cardiogenic shock ( ) . septic cardiomyopathy occurs in a significant proportion of septic shock patients. the aim of this study was to evaluate the role of rai on septic cardiomyopathy. patients and methods prospective observational study conducted in the intensive care in one university hospital in france. patients meeting the criteria for septic shock without prior corticosteroid therapy and without chronic heart disease were included. total blood cortisol levels were assessed immediately before (t ) a short corticotropin stimulation test ( . mg iv of tetracosactrin) and and min afterward. Δmax was defined as the difference between the maximal value after the test and t . rai was defined as an inappropriate adrenal response with Δmax < µg/dl and septic cardiomyopathy as the appearance of cardiac systolic dysfunction (left ventricle ejection fraction < %) within the first days of septic shock. we performed a multivariable analysis using backward stepwise logistic regression to identify independent predictors of septic cardiomyopathy. discussion although the definition of rai is not consensual, a threshold of Δmax at µg/dl has been widely used in septic shock, with or without the use of t ( ). the usefulness of substitutive doses of steroids in septic shock is controversial, but many authors assume this treatment has a potential in reversing overt vasoplegia. our data suggest an implication of rai in septic cardiomyopathy. conclusion we found rai to be an independent predictor of septic cardiomyopathy. these findings may suggest a new role for substitutive doses of steroids in the hemodynamic management of septic shock. introduction regional perfusion parameters, like lactate, pyruvate and glycerol, may predict outcome in septic shock patients. continuous venovenous haemofiltration (cvvh) has been considered beneficial in septic shock patients. the aim of our study was to investigate whether cvvh, in comparison to intermittent haemodialysis (ihd), is able to improve regional perfusion in septic shock patients studied by muscle microdialysis. patients and methods it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure, aged over years. patients were randomized to receive either cvvh (n = ) or ihd (n = ) for renal replacement therapy. intermittent haemodialysis was carried out during the first h of the h study period. systemic haemodynamics and interstitial tissue concentrations of lactate, pyruvate, glucose and glycerol were obtained at baseline, , , and h after initiation of renal replacement by using muscle microdialysis. results regarding systemic haemodynamics parameters, cvvh caused a decrease in heart rate in contrast to ihd after h (− ± vs + ± /mn). there were no changes in vasopressor support throughout the -h study period and so systolic blood pressure remained stable in both groups. during the h of all renal replacement therapies there was no significant change in muscle pyruvate and glucose levels. during cvvh muscle lactate decreased constantly, as did muscle glycerol levels. this decrease reaches a significant levels at h for muscle lactate and at h for muscle glycerol (fig. ) . conclusion our results suggest that among septic shok patients, cvvh may improves regional perfusion in comparison with ihd. none. introduction acquired hypernatremia (h-na) is an independent risk of death among icu patients ( ). in the rct "hyper s" study, we compared normal to % hypertonic saline during the first h in patients with septic shock with normal serum na concentration (sna) at baseline. the study was prematurely stopped for potential harmful effect associated with more frequent h-na. we assessed the role of h-na on mortality. patients and methods data are a post hoc analysis of the "hyper s" study database including patients. sna was measured at h , every h for days and then daily until d . study fluids were stopped if sna > or > mmol/l increase over h. mild, moderate, and severe h-na were defined as sna > mmol/l, > mmol/l and > mmol/l, respectively. sna profiles were compared between d survivors and non-survivors. acute kidney injury (aki) was defined by doubling serum creatinine and/or need for dialysis. results patients with available data were analysed. ( %) developed h-na (mild: %, moderate: %, severe: %). no matter the absence or presence and its severity, h-na did not affect mortality ( , , , and %, respectively without, with mild, moderate, and severe h-na, p = . ). sna profiles were similar between survivors and non-survivors (table ) . a sensitivity analysis performed among survivors at d did not change the results. compared to patients without h-na, aki occurred in % of patients with h-n vs % (p = . ), atelectasis in versus % (p = . ) and icu acquired weakness in versus % (p = . ). conclusion hypernatremia occurrence is not associated with an increased risk of morbidity and mortality during hypertonic fluid resuscitation in septic shock. none. introduction guidelines about the moderate hypokalemia treatment (between . mmol/l and . mmol/l) are based on experts estimations, and non-specific ones for patients in the intensive care units (icu). the aim of this study was to evaluate the correction of the hypokalemia in an icu and the compliance of recommendations. materials and methods an observational epidemiological, retrospective and monocentric trial has been realized during a period of months (from january to february ). the study population included hospitalized patients in the icu who have shown a first moderate hypokalemia episode, all cause considered. patients who have presented an acute renal failure with a kdigo (kidney disease: improving global outcomes) score of three the day of their inclusion were excluded. the main primary study endpoint was percent correction of the serum potassium after h. the secondary study endpoints were the incidence rate of moderate hypokalemia and the efficacy about the hypokalemia correction in accordance with the achieved treatment consistent or not with recommendations. results patients had at least one episode of hypokalemia. the incidence rate of the hypokalemia first episode was . %. the study population included patients. igs score was . (± ). patients required mechanical ventilation at the inclusion. the serum potassium was greater than or equal to . mmol/l after h about patients ( . %) (corrected group). at h one patient had a serum potassium higher than mmol/l. the average total potassium was respectively . infusion of potassium and ( . %) patients have been a management compatible with the most common recommendations (input potassium chloride of mmol, use of the enteral administration and lack of continuous intravenous infusion). the percent correction of the hypokalemia after h was respectively of / ( . %) in the group in which recommendations had been respected and of / ( . %) in the other one (p = . ). discussion in our knowledge there are no previous studies that have specifically focused on the correction of the moderate hypokalemia in critically ill patients. in our study the incidence rate of the moderate hypokalemia was lower than data from the literature because we have only considered the first episode of the hypokalemia [ ] . among patients without contraindication to the enteral administration, this one was used in less than half of the cases. % of these patients received potassium with a continuous intravenous infusion and only patients received medical care conform to the guidelines. the medium potassium quantity provided was very lower to the guidelines. only % of the patients have been corrected after h without any difference in the medium potassium quantity which has been provided in relation to the uncorrected group. conclusion only . % of moderate hypokalemia in icu are corrected after h. the intravenous way is considerably used (in % of cases) with a poor return. a wide-ranging study is necessary to determine the best correction modes. none. results patients were included. mean ± sd age was ± years, % were male, mean ± sd saps ii was ± . icu length of stay was ± days and icu mortality rate was %. during the first days in the icu, % of patients received at least one nephrotoxic drug. % of patients received one, % received two, % received three and % received more than three nephrotoxic medications. diuretics, antibiotics and iodinated contrast media were the nephrotoxic drugs most frequently administered to, respectively, , and % of patients. aki (kdigo stage or higher) occurred in % of patients during the first days in icu. the proportion of patients with aki increased with the number of nephrotoxic drugs received: / ( %) of the patients not exposed to nephrotoxic drugs developed aki whereas, respectively, / ( %), / ( %), / ( %) and / ( %) of the patients receiving one, two, three, and more than three nephrotoxic drugs developed aki. the univariate association between the number of nephrotoxic medication and aki persisted in the multivariate analysis adjusted on baseline saps ii score (p < . ). conclusion the significant proportion of patients exposed to nephrotoxic drugs and the observed association with aki warrants further investigation. statistical adjustments for multiple potential confounders is needed in order to assess a potential causal relationship which would lay foundations for interventional studies. none. ( ) the minimal kidney aggression by current monomeric nonionic low-osmolar contrast media, late serum creatinine increase being explained by the occurrence of later (between the th and the nd hour) kidney injury due to critical illness or its therapy or ( ) insufficient sensitivity of early ( h) measurements of this biomarker to detect contrast-associated aki. competing interests partial financial support, no implication in data analysis and interpretation. introduction diabetic ketoacidosis, generally resulting from an absolute deficiency of insulin, is a frequent cause of hospitalization in intensive care unit. recommendations for diagnosis of diabetic ketoacidosis, care and site of admission have been published by the english society of diabetology. icu admission are recommended if one of the following criteria is present: gcs < , systolic arterial pressure (sap) < mmhg, spo < %, ketosis > mmol/l, hco < mmol/l, ph < . , potassium level < . mmol/l or anion gap > mmol/l. however, it is suspected that adhesion to recommendations remains low. in this study, we aimed at describing patients admitted for diabetic ketoacidosis in icu. we looked at adhesion to published recommendations regarding admission and care. we also described metabolic complications and looked for an association between complications and dose of initial insulin therapy. complications hypoglycemia (< . mmol/l) was observed in % of patients within the first h in which % were < . mmol/l. this was and % of patients between and h of icu stay. hypokalemia below . mmol/l happened in % of patients within the first h and in % between and h. neither hypoglycemia nor hypokalemia were correlated with initial insulin bolus or initial dosage of continuous intravenous insulin. hypophosphatemia < . mmol/l was observed in % of patients. discussion in this study, admission to icu was consistent with british recommendations since most patients presented at least one clinical or biological criterion indicating icu admission. arterial blood gas were sampled in the large majority of patients despite consistent data showing that venous blood gas might be sufficient in non-hypoxemic patients. also, initial insulin bolus and sodium bicarbonate perfusion were performed in a significant subset of patients despite absence of convincing data or recommendations supporting their use. finally, significant hypokalemia and hypoglycemia were frequent in these patients. these complications are in theory favored by insulin therapy but we did not observe a correlation between administration of an insulin bolus or the dose of continuous intravenous insulin perfusion. conclusion in this retrospective multicentre study, patients admitted in icu for diabetic ketoacidosis were correctly oriented regarding the british recommendations. metabolic complications (hypoglycemia and hypokalemia) were frequent but not correlated with initial dose of insulin. the appropriate rate for hypernatremia (h-na) correction is unknown. under-correction could be associated with worse outcome. experts recommend a rapid correction of acute (< days) and sever (> mmol/l) h-na with a rate of − mmol/l/h until na < mmol/l ( ). correction should be, therefore, obtained within h. in patients with septic shock resuscitated with iso-or hypertonic saline and who acquired acute severe h-na, we assessed if the correction rate was associated with mortality. patients and methods data are a post hoc analysis of the rct "hyper s" database comparing normal to % saline for h in septic shock. serum na (sna) was measured at h , every h for days and ) . h-na correction rate was more rapid in non-survivors, p = . (table ). over-correction occurred similarly in survivors ( %) and non-survivors ( %). the time to reach sna normalization was shorter in nonsurvivors (p = . ). after adjustment for sapsii and maccabe scores, more rapid correction rate remained significantly associated with mortality: or . ; % ci ( . - . ), p = . . conclusion in the context of acute severe h-na induced by fluid resuscitation, a rapid correction rate might be associated with even aggravated rather than improved mortality. introduction systemic capillary leak syndrome (slcs) is a rare disease characterized by recurrent life-threatening attacks of capillary hyper permeability in the presence of a monoclonal gammopathy (mg). during acute episodes, the leak of fluid and proteins from the intravascular compartment to the interstitium results in clinical signs of both acute hypovolemia and interstitial edema. biological profile is pathognomonic with marked hemoconcentration and paradoxal hypoproteinemia. hypovolemic shock is the classical feature of severe scls attacks. however, beside this typical hemodynamic profile, several case report described myocardial dysfunction during scls attacks. the objectives of this study were to assess frequency, characteristics and outcome of myocardial involvement during severe scls attacks. ( %) mechanical ventilation, ( %) renal replacement therapy, ( %) veno-arterial extracorporeal membrane oxygenation, ( %) intra-aortic balloon pump and ( %) an impella. compartment syndrome occurred in ( %) patients and ( %) died in icu. we then compared the patients with myocardial involvement to the without clinical and biological manifestations were similar in between groups. however, chest pain ( vs %, p = . ), dyspnea ( vs %, p = . ) and respiratory failure ( vs %, p = . ) were more frequent in patients with myocardial involvement than in others. there was no difference between groups regarding treatment received in icu, complication and outcome except for the use of va-ecmo ( . vs %, p = . ). conclusion myocardial involvement seems frequent in patients with severe scls attack, occurring in % of the cases. such patients exhibited classical features of scls attacks. myocardial involvement was responsible for altered lvef or transient ventricular hypertrophy. myocardial dysfunction could be severe, even requiring mechanical circulatory support. scls attacks should be known as a cause of severe reversible myocardial dysfunction and hypertrophy. none. introduction in refractory cardiorespiratory emergencies, ecmo appears a good alternative to conventional treatment. its extracorporeal circuit justifies curative anticoagulation explaining haemorrhagic and thrombotic complications. activated clotting time (act) is empirically and commonly used to assess anticoagulation but with large inter and intraindividual variabilities. in practice, antixa activity dosage is available to approach anticoagulant effect of heparin and is less expensive, but data during ecmo are missing. we sought to demonstrate the lack of correlation between antixa and act in patients under ecmo support. we prospectively include patients supported by ecmo in chu toulouse, france, between / and / for circulatory/respiratory support. anticoagulation was achieved by unfractionated heparin: initial bolus then continuous intravenous infusion ( - iu/h), for antixa target of . - . . concomitant dosing of antixa (laboratory) and act (hemocron ® ) was conducted two times a day on the same sample throughout the ecmo period. relationship between act and antixa was analyzed by spearman correlation (rho). after transformation into categorical variables (obtained target = ; outside the target = ), analyzes were completed by a concordance study (kappa). as recognized on literature act's targets were between and . results patients were included: men ( %), median age yo ( - ). indications were veno-arterial (n = ) and veno-venous ecmo (n = ). ecmo median duration was days (hours to days). spearman correlation test found low and inconsistent correlation between antixa and act (rho spearman < . ). this correlation lack present from the day one, worsens over time. analyzed kappa showed no discrepancy between the areas "targets" of act and antixa confirming the results (table ) . conclusion use of act for ecmo anticoagulation monitoring doesn't seem appropriate and high price probably justifies preferential use of antixa in clinical practice. analyzes of relationships between antixa and bleeding/thrombotic events are needed to confirm the antixa place and its target in these indications. introduction postcardiotomy cardiogenic shock (cs) has an incidence of % to % after routine adult cardiac surgery. in . - . % of cases, an venoarterial extracorporeal life support (va-ecls) is requested. the -month survival rate is . % ( ). survivors may suffer of physical and psychological impairments as well as an alteration of quality of life. this study was designed to assess the outcomes, long-term health- since icu discharge, % of patients reported physical sequelae., ecls-related limb pain occurs in % of patients while paresthesia occurs in % and chronic-tiredness in %. mean karnofsky score was % (table ) . conclusion after va-ecls for postcardiotomy cardiogenic shock longterm physical and psychological sequelae are frequent in survivor discussion interest for fluid management is growing in critical patients. nevertheless, no study has yet investigated its impact in selected patients with cardiogenic shock treated with va ecmo. our study suggested a possible association between fluid overload and mortality but lack the power to confirm these results with multivariate analysis. conclusion fluid management is a key therapy during va ecmo but fluid overload could be associated with worsen outcomes. further studies with larger population are warranted before considering fluid restriction trials. introduction extracorporeal life support (ecls) has taken an important place in the treatment of cardiogenic shock (cs) or refractory cardiac arrest (ca). however, ecls deplore a high mortality rate in the first days raising important ethic and economic consequences. in this context, continuation of support should be reassessed precociously. the aim of this study was the research of prognostic factors of -days mortality, h after ecls implantation for cs or ca. materials and methods all patients undergoing ecls in our tertiary center during a -year period were prospectively included. the ecls were managed with a multidisciplinary protocol based on consensus. clinico-biological data were collected just before and h after ecls implantation. these data were compared between survivors and deceased at month. , cpc score was respectively for patients, for , for . at months, cpc score changed only for the patients with a cpc score at (one died after another suicide attempt, one changed his cpc score to ). in the group without ca (n = ), had normal neurological status at months and at months (one patient died because of a cancer). among these patients, % returned at home and % returned to work. ( %) patients re-attempted suicide in the year. the major risk factor of mortality is the presence of a cardiac arrest on hanging site. all the other factors found to be related to mortality are well known risk factors in cardiac arrest of other origin. in univariate analysis, risk factors of neurological sequelae at months were a cardiac arrest on hanging site (p = . ) an elevated diastolic blood pressure ( vs mmhg; p = . ), a lower initial glasgow score ( vs ; p = . ), and an elevated blood glucose ( . vs . g/l p < . ) at admission in icu. discussion our cohort of self-hanging patients can be divided in two parts: a) patients with ca in the pre-hospital period with a high mortality and a good neurological recovery in / surviving patient, but with a small group; b) patients without ca with a very low mortality and a very good neurological recovery. these results seem to be better than in the most important cohort [ ] published until now in self-hanging patients without ca and not treated by hbot (mortality at . % and . % of poor neurological recovery). conclusion patients surviving a self-attempted hanging who have not presented ca and treated by hbot have mainly a good neurological outcome. randomized control study should be undertaken to confirm hbot effectiveness in that indication. introduction venoarterial extracorporeal membrane oxygenation (va-ecmo) is increasingly used to treat refractory cardiogenic shock or cardiac arrest. acute brain injury (i.e. ischemic stroke, haemorrhage and/or failure to awaken because of diffuse brain injury) may occur in up to % of patients on va-ecmo and is associated with increased mortality and poor functional outcome in survivors. however, early indicators of neurological outcome are lacking in this population. we aimed to assess the prognostic value of early electroencephalography (eeg) alterations during va-ecmo. we conducted a prospective single-center study in the medical icu of a university hospital on consecutive patients cannulated to va-ecmo. a standardized clinical neurological evaluation including the rass score, the gcs score, the full outline of unresponsiveness (four) score and brainstem reflexes was coupled to an intermittent eeg. eeg was recorded as soon as possible within the first h after va-ecmo cannulation. eeg characteristics were analyzed by a neurophysiologist who was blinded to the patient's condition. a severely altered eeg pattern was defined as a predominant delta frequency, discontinuous, unreactive and/or an isoelectric background. the primary endpoint was poor neurological outcome, defined as the composite of death or acute brain injury on neuroimaging within days. data are presented as median (interquartile range) or number (percentage). false-positive rates (fprs, corresponding to -specificity) of poor neurological outcome were calculated for each significant predictor, using an exact binomial % confidence interval (ci). results sixty-nine (age ( - ) years) patients with a sofa score of ( - ) were included. main indications for ecmo were: post cardiac surgery (n = , %), terminal dilated cardiomyopathy (n = , %), and acute myocardial infarction (n = , %). cardiac arrest before ecmo cannulation was noted in ( %) patients. eeg was recorded ( - ) days after va-ecmo cannulation and ( %) patients were sedated at time of eeg. at day , ( %) had a poor outcome (n = deaths and n = patients alive with acute brain injury). in univariate analysis, a lower rass score (p = . ), a lower four score (p = . ), a lower score on the motor component of the glasgow coma scale (p = . ), and a lack of cough reflex (p = . ) at the time of eeg were significantly associated with a poor outcome. a severely impaired eeg pattern or presence of a discontinuous background activity were also associated with a poor outcome (p = . and p = . , respectively). indicators of poor neurologic outcome are presented in the table . among all parameters, a discontinuous background activity was the only variable that constantly predicted poor outcome (false-positive poor outcome prediction rate of %, % ci - %). conclusion early intermittent eeg has a strong prognostic value for sedated patients on va-ecmo. presence of a discontinuous eeg background activity seems to be more accurate than clinical alterations to predict a bad neurologic outcome at days. none. table ). it was not found a significant association of ctp to mortality ( % in the case group and % in control group, p = . ). other factors that increased mortality were coma, seizures, shock, oedema, cellularity in csf > units/mm . otherwise, the ventilation length was prolonged with ctp group ( . vs . days, p = . ) and neurological sequels namely the epilepsy was more frequent with the group ctp: ( vs %, p = . ). conclusion the occurrence of ctp on bacterial meningitis was significantly associated with ct scan lesions which seems to be an association be in both directions. also, the positive culture predisposed more to the ctp. mortality was higher with the presence of ctp but without real significance. the ctp was a factor that extends the ventilation time and exposed to the post infectious epilepsy. introduction acute bacterial meningitis requires rapid triage and therapeutic decision-making. the aim of this study was to assess the overall ability of a point-of-care glucometer to determine bacterial infection in cerebrospinal fluid (csf). we performed a prospective, observational study. we included patients for whom an analysis of csf was indicated by the physician in charge with blood sampling performed for glucose concentration measurement within h. we simultaneously measured the glucose concentrations in csf and blood using a central laboratory and point-of-care glucometer. the diagnosis of bacterial meningitis was determined by two physicians after reviewing the complete medical chart. we compared csf and blood glucose concentrations and csf/blood glucose ratios obtained at the bed-side with a glucometer versus those obtained by the central laboratory. we determined the performance characteristics of the csf/blood glucose ratio provided by a glucometer to detect bacterial infection in the csf immediately after csf sampling. conclusion we demonstrated that the csf/blood glucose ratio measured by a glucometer can serve as a clinical decision support tool for the early detection of csf with a high probability of bacterial infection. this costless point-of-care method has the potential to expedite medical decision-making for the triage of adult patients with suspected meningitis in the emergency department immediately after lumbar puncture. none. introduction cardiac arrest remains a frequent cause of admission in intensive care unit. a majority of patients will die during their hospital stay mainly from consequences of hypoxic-ischemic brain injury after a decision of withdrawal of life sustaining therapy support by a prediction of poor outcome. the reliability of prognostication is crucial, but is still a difficult and uncertain exercise. eeg is the most widely used prognostic tool to support a clinical examination and is accessible in most hospitals. it is recommended for both prognostication and ruling out subclinical seizures. there is no high-level evidence for predicting poor prognosis using eeg because of the wide variety of classification systems used and the interrater variability. our objective is to assess the prognostic value of simple eeg features based on the recent american clinical neurophysiology society (acns) standardized classification and to study the interrater variability. we conducted a retrospective monocentric observational study in a bed medical intensive care unit of the university hospital la timone, marseille, france. all patients aged of more than year-old admitted for a resuscitated cardiac arrest between november and july who underwent therapeutic hypothermia and a full multimodal prognostic evaluation including a eeg were included in the study. outcome was classified according to the cerebral performance category score measured at day . unfavorable outcome was defined as death (cpc ), persistent vegetative state (cpc ), or severe neurological disability (cpc ). favorable outcome was defined as moderate neurological disability (cpc ), or no disability (cpc ). eeg was performed in all patients still comatose after rewarming between and h after admission and after discontinuation of sedation. eeg interpretation was made by independent senior neurophysiologists, blind to the outcome. eeg features are based on the latest acns classification. for each eeg feature, sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) for predicting an unfavorable outcome were calculated. results during the study period, cardiac arrest were admitted of which patients went through a full neurologic evaluation and were finally included in the study. according to neurological outcome, % had a favorable evolution, and % had an unfavorable outcome. the presence of burst suppression, and epileptiform activity was constantly associated with an unfavorable prognostic with a % specificity and % false positive. a non-reactive eeg is strongly associated with an unfavorable evolution with a % specificity and % false positive. other features including periodic or rhythmic patterns and low voltage were inconstantly associated with unfavorable outcome. kappa score for all eeg feature was slight or fair and always under . . discussion this study allowed us to identify a homogenous cohort of comatose patient after cardiac arrest who underwent therapeutic hypothermia. we identified simple eeg features based on the new classification of the acns constantly associated with unfavorable outcome. these features must be known by intensivists to better integrate eeg in the multimodal evaluation of neurological prognostic. there is important interrater variability that must lead to caution and to always use multimodal approach to prognostic an unfavorable outcome. conclusion bedside eeg is an excellent tool for predicting outcome of post-anoxic coma through simple eeg features. burst suppression, epileptiform activity and non-reactive eeg are strongly associated to neurological outcome after cardiac arrest. however, the interrater variability emphasize the need of being well trained for the standardized methods of evaluating eeg parameters. introduction emergent reintubation is a well-known risk of laryngotracheal trauma and of ventilatory acquired pneumonia. to precisely define its risk before extubation for each patient is a part of quality of care in intensive care units. none of these consecutive children representative of picu activity has been reintubated. the coming prospective muticentric study which aims to validate alt in childhood must precisely define this criteria of evaluation. conclusion the different methods of alt are feasible in real clinical conditions in picu. because of the increasing use of cuffed etts in a wide variation of patients with different body weight, the best alt to use at the bedside must be definitively validated in this population. introduction prolonged mechanical ventilation (pmv) and chronic mechanical ventilation (cmv) in neonates is associated with a high morbidity and mortality. the objective of the study is to identify, among the patients with pmv, those that evolved to cmv, as well as the adverse respiratory, neurological and feeding sequelae. we conducted a retrospective study of the last years at the chu sainte-justine (montreal, canada). chart review included patients with pmv (≥ days) using the paediatric definition adapted from the namdrc consensus conference ( ) . demographic and clinical data, including follow-up at and months corrected age, was collected for each included patient. the evolution of pmv neonates with cmv (≥ days) and without ( - days) was compared. we identified neonates that met criteria for pmv. patients born between and (n = , % of the cohort) were analyzed. around half of the patients ( - patients a year) are transferred from the neonatal unit to the paediatric intensive care unit. in our center, they represent around % of total admissions, but their length of stay is among the longest. among these newborns, % were preterm (n = ) with % (n = ) born before weeks gestation. of all patients with a malformation ( %, n = ), had a thoracoabdominal anomaly and had congenital heart disease. thirty-six patients had cmv with mean ventilation time of days (range - days). survival at months corrected age was % ( / ) in the pmv group and % ( / ) in the cmv group. at months corrected age, % of patients were dependent on artificial enteral feeding (nasogastric tube or gastrostomy), with % in the pmv group and % in the cmv group. nine percent of patients had oxygen supplementation ( patients in the pmv group and in the cmv group), and % were mechanically ventilated. ten percent of patients had a tracheostomy ( patients in the pmv group and in the cmv group). discussion neonates with cmv have more sequelae. their rapid identification (at days of ventilation) is essential to implement multidisciplinary development care in order to minimize neurodevelopment impairment. conclusion most newborns in our pmv cohort have a congenital malformation. survival at months corrected age appears equivalent in both pmv and cmv group. artificial enteral feeding is more frequent in the cmv group and most patients have no respiratory support at months corrected age. none. the value of pressures and volumes in assessing the fluid responsiveness depend on the systolic cardiac function in adult ( ). we have studied the relative value of static filling volume and pressure to predict the fluid responsiveness, according to systolic cardiac function in children during acute circulatory failure. patients and methods patients under years old with an acute circulatory failure of two intensive care units during a year period of inclusion were analyzed. an exhaustive cardiac echography was performed initially (indexed end-diastolic volume (edvi) and e/e' from transmitral and tissue doppler were recorded), and the stroke volume index (svi) was measured before and after a fluid challenge (a ml/ kg of crystalloid over min results twenty-five children with acute circulatory failure were included. fluid responsiveness occurred in of the fluid loading events with low lvef, and in of the fluid loading events with normal lvef. pressure approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci . - )/ . ( . - ) for a e/e' .the best thresholds of e/e' in low lvef was . with a sensitivity of (ci - ) % and a specificity of (ci - ) %. for low and normal lvef auc roc was respectively . (ci . - . )/ . (ci . - . ) for the pvc. volume approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci - ) and . ( . - ). the best thresholds in normal lvef was an edvi below ml/m wit a specificity of (ci - ) and a sensitivity of (ci - ) %. discussion our study shows a variation of the diagnostic value of e/e' and edvi according to the left ventricular systolic function. therefore, the systolic function should be taken into account to analysed the e/e' and edvi value. few preload dependency markers are validated in children and none for children in spontaneous ventilation ( ) . our study suffers from a lack of power that calls into question the validity of our results. another limitation is that both approaches with volume and pressure are not very discriminant as it is known for static value in adults. our study illustrates that, on a pressure-volume curve, when the cardiac inotropism is reduced, the filling of the left ventricle is moved to the up and right of the curvilinear diastolic function curve. therefore, pressure variations are larger than volume variations. these values should be monitored on a larger scale to define their exact diagnostic value. conclusion static pvc value is a low preload-dependency surrogate. when lvef is low a pressure evaluation based approach seems more accurate. when lvef is normal a volume evaluation based approach seems informative as predicted by the slope of the end diastolic pressure volume curve. those both static approaches remain of poor diagnosis accuracy. introduction acute viral bronchiolitis is a primary cause of respiratory distress in paediatric intensive care unit (icu). prone position (pp) is commonly used in neonates to improve respiratory mechanics and has been found beneficial to adult patients with acute respiratory distress syndrome. we aimed to evaluate the effect of pp on work of breathing as compared to supine position (sp) in children with severe bronchiolitis requiring non-invasive ventilation. the protocol was approved by our irb ( -a - ). fourteen infants ( boys) with median age days [firstthird quartiles - ] with severe bronchiolitis requiring cpap were included after written informed consent. children were investigated in pp and sp each applied for h in a random order with a washout period of min between them. level of cpap was set at cmh o in both conditions. oesophageal pressure probe was inserted orally (cto- pressure transducer, gaeltec, scotland) to measure oesophageal pressure. flow and airway pressure (pmo in fig. ) were simultanuously recorded using a neurovent data acquisition system (neurovent inc, toronto, canada). one hundred breaths were analyzed in each condition, in which work of breathing was estimated from oesophageal pressure-time product (ptpes) and oesophageal swings (fig. ). data were expressed as median (first-third quartiles) and compared by using the wilcoxon two-sample paired sign test. a p-value below . was considered significant. . the edtb contains data from ventilated patients (invasively and non-invasively) and details concerning ionotropic and sedative treatment during picu courses. discussion as far as we know, this edtb is currently the only one as exhaustive available in picu worldwide. after almost years of multidisciplinary collaboration, we are able to collect many useful physiological, therapeutic and medical data in an ongoing edtb. although many concerns remain concerning data validation, organisation and exploitation, this edtb already contribute to the development of clinical decision support systems and virtual patient validation and we create international collaborations to further develop these tools. three research protocols using the database are ongoing including: validation of a neuromonitoring clinical decision support system, validation of a cardio-respiratory simulator, developement and validation of the automatic diagnosis of pediatric acute respiratory distress syndrome and development of spo forecast using artificial neuronal network. conclusion thanks to informatics and electronic devices improvement, data gathering in intensive care units has empowered. we hope that our work in picu will encourage other teams on the way of data gathering, in order to build an international picu edtb in a close future. none. introduction severe trauma is rare in the pediatric setting ( % of all trauma in france). however, its morbidity and mortality remain high, in relation to brain injury. pediatric traumatic brain injury (tbi) prehospital care is challenging for non-pediatric retrieval teams. though, we disseminated pediatric tbi pre-hospital care regional guidelines and thereafter intended to assess severe pediatric trauma pre-hospital care and secondary cerebral insults control. we conducted a retrospective study in a single pediatric trauma center. children admitted in emergency room with severe trauma and moderate to severe tbi (glasgow coma scale ≤ ) from june to march were included. pre-hospital and hospital data regarding primary care, equipment, medications and secondary cerebral insults control (i.e. blood pressure, oxygenation, co level, temperature, glycemia) were collected from medical files. two pediatric transport team experts assessed the quality of pre-hospital care, based on two major endpoints. results twenty-nine files were analyzed. median iss was . all the children had been referred directly from the trauma scene to the pediatric trauma center. they were all intubated in the prehospital setting, ( . %) presented with spo < % before or at emergency room admission, and ( . %) presented with a pco > mmhg at admission. at least one peripheral catheter was inserted in all the children. mean total fluid bolus was . ml/kg (± ). nor-epinephrine was administered in ( %) children. mean blood pressure was below age threshold in ( %) children during transport or at admission. an intracranial hypertension treatment (apart from sedation) was delivered in ( %) children before admission. body temperature was monitored in patients and were hypothermic at emergency room admission. experts concluded on sub-optimal care in children: major endpoint was "respiratory care", "hemodynamic care" and "neurologic care" in , and patients respectively. discussion on this small series, we showed pre-hospital sub-optimal care regarding secondary cerebral insults control, especially regarding co level, blood pressure and body temperature. our results will help to design new care improvement strategies (e.g. sedation, fluid bolus and ventilation optimization, early use of vasoactive drugs, systematic body temperature monitoring…). conclusion data on pre-hospital secondary cerebral insults care are rare in the pediatric setting. based on our results, we aim to improve quality of care of children presenting with traumatic brain injury, and to reduce its morbidity and mortality. introduction unsuccessful extubation from mechanical ventilation increases mortality and morbidity. to reduce the extubation failures in our intensive care unit we used a mechanical ventilator weaning protocol, based on published data. during the first part of the study, risk factors and incidence of extubation failure were first described. afterwards in the second part, our mechanical ventilator weaning protocol was tested to determined its efficiency regarding the extubation failure. patients and methods a monocentric and observational study, was first conducted. we included children aged from birth to old, during a period of months and collected for each patient their medical history, intubation and extubation parameters, and existing events of extubation failure or extubation complication. the second part of the study was prospective, we include patients extubated by applying our mechanical ventilator weaning protocol. results average duration of mechanical ventilation was . h in the first part of the study. using a univariate analysis, duration of mechanical ventilation was a risk factor of extubation failure with an average duration of . discussion our study confirms published data about extubation failure risk factor like duration of intubation, chronic respiratory affection, history of previous intubation, and the administration of benzodiazepine. it is the first pediatric study that shows a reduction of extubation failure by using a specific mechanical ventilator weaning protocol. the mean bias of our its retrospective and prospective character. conclusion our study shows the interest of a mechanical ventilator weaning protocol to reduce the incidence of extubation failure. we currently continue the apply our protocol to include more patients in order to confirm our results. stroke of the child is formidable though it is ten times rarer than in adults, but this scarcity can have adverse consequences on the speed and quality of the management and the consequences on later psychomotor development. our goal is to describe the clinical and therapeutic aspects of these pediatric stroke while bringing our experience. patients and methods retrospective study of cases of children hospitalized in general intensive care unit to the pediatric hospital canastel oran for stroke during the period from january to january . the clinical, etiological, para clinical, and scalable were studied and transcribed on a standard electronic form.all patients had a brain ct. magnetic resonance imaging(mri) was possible in patients for lack of availability of the technical facilities during the study. results ten cases were selected. the mean age was months ( month to years), % are male, patients had a history of chd like tetralogy of fallot and complicated bronchiolitis myocarditis, one patient had a history of petechial purpura, other was a factor deficiency, headache history was noted in patients, and patients with no particular antecedent was found. all patients arrived comatose / score on the scale of glasgow, isochores reactive pupils with a motor deficit of hémicorps, patients have degraded their neurological score with onset of clinical signs of hypertension intra cranial namely anisocoria and hypertension requiring osmotherapy, sedation and mechanical ventilation with an average duration of - day. o child arrived brain dead, patients had generalized tonic-clonic seizures which yielded after taking a benzodiazepine (diazepam) and phenobarbital (like gardenal). cerebral ct was performed in all cases and could we revealed the nature of the stroke hemorrhagic in cases and ischemic stroke in cases. two patients have benefited from an mri that found a thrombosis of the artery internal carotid right sylvian. besides symptomatic treatment, treatment was initiated based on the type of stroke, patients received low molecular weight heparin (lmwh) at . ml/kg in addition to symptomatic treatment, patients received vitamin k. four patients died in an array of autonomic disorders and evolved favorably and six patients were transferred to a pediatric unit. the average length of stay in icu was . days ( - days). discussion the mortality rate is important since no specialized center for children, and difficulty especially in the diagnostic imaging field while suspected stroke should be confirmed by imaging and the diagnostic delay. which is due to a poor assessment of the initial situation in half of the cases by the parents, the other half by the swiss magazine consulté.une doctor showed that in a study in % of children with stroke, this diagnosis was not primarily discussed and that in % of cases the cause of the stroke was poorly evaluated [ ] . heart disease certainly represent the second most important risk factor. a collaboration of a team must be multidisciplinary, death has affected mostly older children whose age is between and years, who have a hemorrhagic stroke against by infants who have an ischemic stroke have evolved and oriented they exceed the acute phase to pediatric services for further investigation and monitoring. conclusion the child may also be having a stroke, which usually reaches the elderly. this justifies a good knowledge of this disease, and multiply the initial management efforts to reduce mortality and improve prognosis. anwar armel , benqqa anas , samira kalouch , khalid yaqini , aziz chlilek introduction nosocomial infections are a main problem for public health for their cost as well as for the morbidity and mortality they generate. they are particularly common in intensive care units due to patient's lower defenses and of invasive procedures proliferation. work's purpose: • determine the epidemiology of bacterial noso-comiales infections (ibn) in the medico-surgical pediatric intensive care department of children's university hospital of casablanca. • to identify factors associated with these infections. we led a retrospective study of hospitalized patients, spending more than h in medical-surgical pediatric intensive care department, at the university hospital ibn rochd of casablanca, over a period of months from january to december . results during the studied period, patients were admitted at intensive care with a stay of more than h. thirty episodes of inb were recorded. the incidence rate was . % and the incidence density was . % per hospitalization's days. the admission average age was . ± -month starting from month to years with a male predominance ( %). most of admissions ( %) was related to medical background, . % received from other hospital department. furthermore, % of the patients received prior antibiotics, usually prescribed before icu admission. invasive procedures (intubation, central catheterization) were used in . % of patients, vvp only in . %, tracheotomy in . and . % had received surgery. gram-negative bacilli (bgn) were isolated for a lot of patients, dominated by acinetobacter baumannii. these bacteria were isolated throughout the study year. risk factors analysis underlined that the presence of invasive procedures enhances in risk, that is central venous catheter and the need for mechanical ventilation. conclusion nosocomial bacterial infections are dominated by pneumonia and central catheter infections, and are mainly due to bgn. the factors associated with these infections were identified. the guillain-barré syndrome (gbs) is the most common cause of acute flaccid paralysis in children since the acute anterior poliomyelitis eradication. few studies have been held on the topic and knowledge of gbs in children, although it is recognized that the etiologic mechanisms, and clinicobiological background, are the same as in adults, prognosis remains different. our work's aim is to study this disease's mortality factors of children hospitalized in pediatric intensive care. patients and methods it is a retrospective, descriptive, mono centric study to review patients with gbs between january and december and hospitalized at pediatric intensive care department of abderrahimharouchi hospital of casablanca. the used software is spss . to compare the bivariate variables, we used the khi test, and to compare quantitative variables, the anova to factor test was used. the level of significance was fixed at % with % confidence interval. the disease was predominant in male with a sex ratio of . men/women. after a prodromal event, usually infectious ( . %) and a free interval of days on average to start motor disorders. these are of two types: either a hypo or areflectic flaccid paralysis of the lower limbs ( . %) of ascending evolution in . % of the cases. either flaccid tetraplegia or hypo areflectic, ( . %). ventilation was required in . % of the cases, and specific treatments based on immunoglobulins were administered in . % of the cases. death's rate is still high ( . %) and mainly due to hospitalization complications. in our study respiratory disease was noted in . % of the cases, also other signs of serious illness such as swallowing disorders ( . %) and autonomic disorders ( . %) also noted what led to management in intensive care for all our patients. these patients study allowed to identify some mortality prognosis factors of the disease in intensive care units (such as male gender, ig administration duration, the occurrence of autonomic disorders like blood pressure instability), the most discriminating remains the occurrence of nosocomial infections. conclusion it must be underlined, that in view of our strict inclusion criteria, focusing only on patients admitted at intensive care and of the relatively small sample size ( cases), our results must be qualified and must be enhanced by additional and more varied studies to better understand this disease in children. introduction early surgical treatment is recommended for refractory intracranial hypertension (htic) in children to improve vital and functional prognoses, whether traumatic or vascular cause. the main objective of this study was to compare the mortality and morbidity of children with severe intracranial hypertension after severe head trauma (tc) or due to vascular cause after decompressive craniectomy (dc) or medical therapy alone. the secondary objective was to identify the initial severity factors associated with higher mortality. patients and methods a retrospective study was performed with data collected from patients aged under years-old admitted to our pediatric intensive care unit for severe intracranial hypertension of traumatic or vascular cause, between january and january . they were divided into groups: patients who received medical therapy alone and those treated with decompressive craniectomy after optimal medical management. results a total of children were included. among them, were treated with dc ( htic of vascular cause and htic of traumatic cause), and were supported by medical means only ( htic of vascular cause and htic of traumatic cause). in the population "traumatic intracranial hypertension", we note that children in the "dc" subgroup are more often in mydriasis upon arrival (p = . ) than in the subgroup treated medically. in this same population, children in the "dc" subgroup received higher doses of mida-zolam (p = . ), of mannitol (p = . ) and hypertonic saline (p = . ) than in the other subgroup. in the population "vascular intracranial hypertension" the two subgroups were comparable. in the case of traumatic intracranial hypertension, mortality rate in the "dc" subgroup was . % against . % for children treated medically (p = . ); "dc" children had more metabolic complications such as hypernatremia than "not dc" children, p = . . mortality rate in the «vascular intracranial hypertension» group was % for children treated with decompressive craniectomy, and . % for children treated medically alone (p = . ). patients treated surgically in the «vascular intracranial hypertension» group had longer overall stays (p = . ) and longer icu stays (p = . ). popc score (pediatric overall performance category) upon discharge for children with intracranial hypertension of traumatic cause treated with decompressive craniectomy was . ± . against . ± . among children treated medically, p = . . in "dc" children with intracranial hypertension of vascular cause, popc upon hospital discharge was . ± . against . ± . among non-operated children, p = . . the schooling rate was higher among children treated medically for intracranial hypertension of traumatic cause, p = . . the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. in the case of traumatic intracranial hypertension, icp monitoring in survivors was . % against . % in children died, with no significant difference. in the population "vascular intracranial hypertension", all the patients who died had not been monitoring pic. discussion the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. other studies have related other severity factors as initial glasgow scale, tardive decompressive craniectomy. conclusion decompressive craniectomy doesn't seem to improve the mortality rate or the outcome in patients with hypertension of traumatic cause in our study but the dc traumatic subgroup was more serious than the subgroup treated medically. in children with refractory intracranial hypertension of vascular cause dc significantly improves survival and outcome. further studies are needed to clarify the role of decompressive craniectomy and its timing in the therapeutic management of refractory intracranial hypertension. introduction shortage of heart grafts is a major problem, leading to a significant mortality rate in the national waiting list, essentially for young children with low weight. the potential paediatric brain-dead donors often have myocardial dysfunction (md), which seems to be reversible. the aim of this study is to assess prevalence, causes and consequences of md when the potential paediatric donors are taken over, up to multi-organ retrieval, and the evolution after cardiac transplantation. materials and methods this observational, monocentric, retrospective study included all brain-dead children aged - years old, who had their myocardial function assessed through a cardiac ultrasound performed by a cardiologist and identified from to . all adult patients and those who didn't undergo a cardiac ultrasound were excluded. md was defined as an lvef ≤ % with or without abnormal segmented cinetic parameters. the main evaluation criteria was the prevalence of md in potential identified donors. the secondary evaluation criteria were the causes and consequences of md on heart retrieval and the origin of this md. results out of included patients, had md. prevalence of md was of %. there was no significant difference between groups regarding aetiology of brain death nor administration of catecholamines. having a cardiopulmonary arrest during intensive care unit stay was associated with a significant risk of presenting a md (p = . ). having a md had no consequences on organ retrieval in general (p = . ), but was significantly associated with a decrease in heart retrieval opportunities (p = . ). the cause of heart grafts refusal was a poor ventricular function in % of cases ( cases out of ). the cause for non-retrieval was parental refusal in one-third of cases. evolution of the cardiac grafts was favorable in cases on , one transplanted patient died (from a non-cardiac cause) and patient was lost to follow up. conclusion md in paediatric brain-dead patients has direct consequences on heart retrieval and transplantation, and otherwise, organ shortage is a major ongoing problem. a better transplant management regarding hemodynamics (with the use of a protocol) could increase the number of heart transplants, especially in small children, and reduce mortality rate in national waiting list. the prone positioning (pp) is a strategy widely used in the treatment of severe forms of acute respiratory distress syndrome (ards) in adults. its early use significantly reduces mortality ( ). however, the studies do not strongly demonstrate its prognostic impact in pediatric ards. the aim of this study was to describe the prone positioning practices in the french-speaking pediatric intensive care units (picu). patients and methods this survey was conducted by email questionnaire to pediatric intensivists belonging to the french society of intensive care medicine and the french-speaking group of pediatric intensive care and emergency medicine. it was conducted from february to may . the survey was addressed to doctors, nurses, physiotherapists practicing in picu. it included questions about indications, contraindications, techniques and medical devices used, and complications. results one hundred and three persons answered ( doctors and nurses) which work in french hospitals and canadian hospital. sixty-eight percent of interviewed persons have more than years experience and % of them treat each year more than children ards. only % of the picu have a pp medical protocol. fifty percent of interviewed persons frequently use pp for the medical care of ards and % systematically use it. thirty-six percent begin pp at the early phase of ards during conventional ventilation, while % before the introduction of unconventional ventilatory strategies (ohf); only % use it after the respiratory failure unless unconventional ventilatory strategies. seventy-three percent report that pp is used with prolonged periods (> h/day), % with short periods (< h/day) and % with very long periods (> h/day). regarding the weaning criteria, most of interviewed persons seem to use multiple and combinated criteria: % use hypoxemia severity parameters (pao /fio , pao , sao ), % use the oxygen level (fio ) and % use the mechanical ventilation parameters (peep, p max, p plate). finally, despite a low level of scientific evidence in children, % of the persons gave a strong recommendation for pp as standard care in severe pediatric ards. see fig. . the survey confirmed the widely use of pp in pediatric ards. however, no specific protocol is avalaible in most of the picu. the timing of the pp beginning can be different according to children, early and prior to use of the conventional ventilation strategy in most cases. the duration of pp seems more consensual. most of the centers use extended periods longer than h/day. these results are close to guérin et al. advocating a duration > h/day. finally, the weaning is a great issue and depends on multiple criteria. in guerin et al. ( ) pp was interrupted if one of the following criteria were present: pao / fio ≥ mmhg, with peep of ≤ cm of water and a fio of ≤ . ; decreased pao /fio than %, compared to compared to the supine position, or the occurrence of complications. no study has validated pp weaning criteria during pediatric ards. conclusion the prone positioning is a strategy commonly used in pediatric intensive care units for the severe pediatric ards. the criterias of implementation and timing are variable, as well as the weaning criterias. more pediatric multicenter randomized studies will be necessary to confirm the benefits of pp in pediatric ards and to define clear weaning criteria. introduction allogeneic hematopoietic stem cell transplantation (hsct) recipients have profound defects in every immunity compartments that can lead to severe opportunistic infections (oi). % of hsct patients require admission to the icu because of diverse infectious or non-infectious complications with dismal outcomes. oi specific course in this population has not been described previously and the management of these infections may be a concern. the aim of this study was to investigate risk factors, management and outcomes of io in hsct recipients admitted to the icu. patients and methods this was a retrospective ( - ) single center study of patients admitted to icu after an allogeneic hsct. patients provided written informed consent according to helsinki declaration. data regarding the transplant, infections and life sustaining therapy use were analyzed. oi were considered if present at the time or during icu admission. results hundred and ninety-four patients (pt) were included. median age was [ ; ] years, . % were males. reason for transplantation was acute leukemia in ( %) pt and the hematological condition was still in complete remission at icu admission in % of patients. ( %) and ( %) had received a myeloablative conditioning regimen and anti-thymoglobulin serum respectively. % had acute graft versus host disease over grade at icu admission. oi was documented in patients ( %). an invasive fungal infection (ifi) was found in pt owing to mucormucosis, trichosporon septicemia and invasive aspergillosis ( possible, probable and proven according to eortc criteria). serum galactomannane antigen was positive in ( %). median time from transplantation and icu admission to ifi diagnosis was respectively [ ; ] and − [− ; ] days. lung was involved in % and patients with aspergillosis were admitted to the icu for acute respiratory failure in % (vs. % for others p = . ). they did not required invasive ventilation more frequently ( vs. % p = . ). and % required vasopressors and renal replacement therapy with no difference as compared to others. median icu length was [ ; ] days. demographic, stem cell source, and donor type were not associated with ifi occurrence in this population. however / had received a total body irradiation ( vs. % p = . ). ifi occurrence was not associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). a viral infection was found in pt owing to cmv, adenovirus, hsv and vrs infections. analyses were focused on cmv reactivation. median time from transplantation and icu admission to cmv reactivation was respectively [ ; ] and − [− ; − ] days. reactivation was mainly positive blood pcr but pt had cmv colitis. a preemptive treatment was started on the same day in median and lasts [ ; ] days. patients with cmv reactivation had more frequently multiple organ failure ( vs. % p = . ) and higher icu admission sofa score ( [ ; ] vs. [ ] [ ] [ ] [ ] [ ] [ ] p = . ). they trend to have higher admission creatinine serum level ( [ ; ] vs. [ ; ] umol/l, p = . ) and more frequently required emergency renal replacement therapy ( vs. % p = . ) mechanical ventilation ( vs. % p = . ) and vasopressors ( vs. % p = . ). median icu length was [ ; ] days and comparable to others. demographic, stem cell source, conditioning regimen and donor type were not associated with cmv occurrence. cmv reactivation was not significantly associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). conclusion oi was found in % of allogeneic hsct recipients admitted to the icu. ifi were mainly responsible for respiratory distress and cmv associated to multiple organ failure. non-invasive diagnostic tests were positives in a majority of these patients. in this cohort, io treatment was started quickly after the diagnostic and we did not find an association with mortality. intensivists should always consider oi in their diagnostic panel in this specific population. introduction over the last two decades, targeted therapies in patients with solid tumors have both increased their length of survival and significantly altered their immune functions. however, data on opportunistic infections in this setting remain scarce. in this systematic review, we sought to identify published cases of opportunistic infections in patients with solid tumors, with a special interest on clinical findings, trends over time and outcomes. materials and methods we performed a search of medical subject headings (mesh) on pubmed using the words pneumonia pneumocystis (pcp), invasive aspergillosis (ia), histoplasma, mucor, geotrichum, cryptococcus, coccidioidomycosis combined with the mesh term neoplasms (breast, lung, ovarian, urologic gastrointestinal, digestive system, abdominal, brain, carcinoid tumor, sarcoma, testicular, seminoma). we identify published cases of opportunistic infections in non hiv patients with solid tumors between / / and / / included. results regarding pneumocystis jirovecii pneumonia, cases could be identified. there were men and women, aged of . ( - ) years. underlying tumors were chiefly brain neoplasms (n = , %), lung neoplasms (n = , %) and breast neoplasms (n = , %). at the time of pneumocystis pneumonia onset, patients ( %) had a history of chemotherapy, ( %) had received long term or high dose steroids, and ( %) had an history of biotherapy targeting the malignancy. of note, patients ( %) had received only chemotherapy, ( %) had received steroids alone, ( %) everolimus therapy alone and ( %) received none of these treatments. regarding invasive aspergillosis cases could be identified. mean age was . ( - ) and ( %) were men. solid tumors associated with invasive aspergillosis were primarily lung neoplasms (n = , %) and brain neoplasms (n = , %). at aspergillosis onset, ( %) patients had a history of chemotherapy, ( %) were receiving long term or high dose steroids and ( %) had received targeted therapy. fourteen ( %) patients had received only chemotherapy, ( %) only steroids, and ( . %) had received targeted therapy alone. for both infection, there was a trend for a higher number of reported cases throughout the studied period. conclusion this systematic review provides objective data showing that an increased proportion of patients with solid tumors present with opportunistic infections. we are convinced that it is a clinically relevant but still neglected problem. selected oncologic population may be becoming eligible for antimicrobial prophylaxis against pneumocystis or aspergillus. care unit of strasbourg in france. patients were included only if they are non-immunocompromised according to the european organisation for research and treatment of cancer (eortc). invasive aspergillosis was defined as an association of microbiological evidence, a radiological imaging and a clinical context. results eighteen patients ( males) were identified during the study period. the median of igs ii was . (interquartile range (irq), . - . ). ninety-four percent was under mechanical ventilation. fourteen ( %) patients were suffering from liver failure. among liver failure, twelve ( %) were beforehand suffering from cirrhosis. the median meld score was (interquartile range (irq), - ). sixty-four percent of aspergillosis were due to aspergillosis fumigatus. hundred percent were pulmonary aspergillosis. fifty-six percent of aspergillosis were associated with bacterial pneumonia. the mortality rate at the date of the latest news (an average of years) was seventytwo percent. discussion invasive aspergillosis is not exceptional in the non-immunocompromised patient especially in patient developing liver failure. an active research of colonization/infection with aspergillus in these patients remain to be discussed. conclusion invasive aspergillosis in icu has a poor prognosis. the liver failure seems to be the most important risk factor in non-immunocompromised patients according eorct criteria. introduction chest wall elastance (ecw) has been found to increase in prone (pp) as compared to supine position (sp) in ards patients [ ] . this makes respiratory system elastance (ers) not reflecting lung elastance (el). little is known about the changes of ecw, el and lung resistance (rl) when moving the patient from the sp to the pp via the lateral position (lp). the goal of present study was to measure ecw, el and rl in ards patients in sp, lp and pp during the proning procedure. patients and methods it was a prospective, single-center, controlled study. ards patients intubated, sedated and paralyzed with pao /fio ratio < mmhg, peep ≥ cmh and an indication of pp were included. mechanical ventilation was delivered in volume controlled mode with constant flow inflation and end-inspiratory pause . s included into the inspiratory time. ventilator settings were unaltered during the procedure. an esophageal balloon catheter (nutrivent device) was used for esophageal pressure (pes) measurement. pressure at the airway opening (pao) and airflow were measured by fleish pneumotachograph proximal to endotracheal tube and upstream heat and moisture exchanger. pao, pes and airflow were continuously measured during min in sp, then during min in lp and min in pp. the side for the lateralization was that selected by routine practice (in the opposite side from central venous line). ers and resistance of the respiratory system (rrs) were obtained by fitting flow and pao signals breath by breath to the first order equation. ecw and resistance of the chest wall (rcw) were similarly obtained by fitting flow and pes signals breath by breath to the first order equation pertaining to the chest wall. el and lung resistance (rl) were obtained by subtracting ers and rrs from ecw and rcw, respectively. our ethical committee approved the protocol. data are shown as median (first and third quartiles). comparisons between positions were made by using paired-t-test. results twenty-nine patients, males, of ( - ) years, saps ( - ) and sofa score ( - ) were included ( - ) days after ards criteria were met. the ards severity was moderate in cases ( %) and severe in ( %). tidal volume averaged . ( . - ) ml/kg predicted body weight, peep ( - ) cmh o, fio ( - ) %, pao /fio ( - ) mmhg. the cause of ards was pulmonary in cases ( %), extra pulmonary in ( %) and undetermined in ( %). lateral positioning was on the right side in ( . %) and on the left side in patients ( . %). the results are shown in the table . conclusion during prone positioning in ards patients, as compared to sp we observed a higher rl in lp and an increased ecw in pp. introduction neuromuscular blocking agents (nmba) could exert beneficial effects in acute respiratory distress syndrome (ards) through properties on respiratory mechanics and particularly in modifying transpulmonary pressures (pl). patients and methods prospective randomized control study in moderate to severe ards patients within the first h of the onset of ards. all patients were monitored by an esophageal catheter and followed during h. moderate ards patients were randomized in two groups according to the systematic administration of a h continuous infusion of cisatracurium besylate or not (control group). the severe ards patients group received a h continuous infusion of cisatracurium besylate. the evolution during the h of the study of the oxygenation and the respiratory mechanics including inspiratory and expiratory transpulmonary pressures and driving pressure were assessed and compared. delta transpulmonary pressure (∆pl) was defined as inspiratory pl minus expiratory pl. results thirty patients were included, in the moderate ards group and in the severe ards group. nmba infusion was associated with an improvement in oxygenation both the moderate and the severe ards patients group accompanied by a decrease in both the plateau pressure and the total positive end expiratory pressure. the mean inspiratory and expiratory pl were higher in the moderate ards patients group receiving nmba as compared with the control group (fig. ) . in contrast, there was no modification of both the driving pressure and the ∆pl related to nmba administration. conclusion nmba could exert beneficial effects in moderate ards patients through higher observed inspiratory and expiratory transpulmonary pressures. none. introduction prone position (pp) is a major treatment in management of acute respiratory distress syndrome (ards). the use of pp in patients with severe ards associated with brain injury is at high risk of intracranial hypertension. the aim of this study is to analyze the effect of pp on intracranial pressure (icp) and cerebral perfusion pressure (cpp) in patients with ards and acute neurological condition requiring monitoring of icp. patients and methods it is a retrospective descriptive study including sixteen patients with acute brain injury (subarachnoid hemorrhage, severe head trauma, and hemorrhagic stroke) and continuous monitoring of icp who developed a severe ards during icu stay from january to december and for which pp was performed. pp sessions were analyzed. hemodynamic and respiratory parameters, blood oxygenation, pic and ppc were studied in supine, before pp and after pp. the study was approved by fics ethic comity. results a significant increase in pao /fio ratio was observed in pp, from ± to ± (p < . ). in pp, the icp was increased ± . - ± . mmhg (p < . ) while the cpp was stable ± versus ± mmhg (ns). median duration of pp session was h ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . increasing of icp during pp required medical treatment in sessions ( %). pp session was interrupted in sessions ( %). in subgroup of patients who respond to pp in terms of oxygenation, the increase of icp was lower than in non-responders ( vs %) (p < . ). cpp was not modified whatever the nature of the response to pp ( ± - ± in non-responders and from ± to ± in responders (ns)) (fig. ). discussion our study shows an improvement of oxygenation during pp in severe ards patient with acute brain injury. we observe a constant increment of pic during pp sessions. the increment of icp is less in responders to pp. significant increased icp requiring an enhancement in the medical treatment was observed in % of the cases, and lead in most cases to a discontinuation of the session. our data underlined the absolute necessity to monitor icp during pp session in patients with acute brain injury and ards, even if icp is controlled previously in supine. only prospective ( , ) and one retrospective studies evaluate the effects of pp on icp in patients with acute brain injury and acute respiratory failure (arf). they results are similar to ours. in all these studies, the severity of arf was often not well specified. roth and al. ( ) had included only % of ards in a population of patient with icp not controlled. in others studies, monitoring of icp during pp was not systematic. despite the retrospective nature of the study and the small number of patients, it is the only work studying the effects of pp on intracranial pressure in patients with acute brain injury at risk for intracranial hypertension and severe ards according to the berlin's definition. conclusion our work suggest that pp is a quite secure technique for use for the treatment of severe ards even patients at risk of intracranial hypertension with a benefit in terms of oxygenation without major increase of icp particularly in pp responders. introduction influenza-associated acute respiratory distress syndrome (ards) requiring extracorporeal membrane oxygenation (ecmo) support is known to have a good prognosis ( ). however, the incidence and impact of co-infection in this setting remain unknown. we conducted a retrospective, observational analysis of data prospectively collected from all patients admitted to our medical icu who received ecmo support for influenza-associated ards between and . co-infection was defined as isolation of a pathogen in the lower respiratory tract at a significant level or in the blood during the h following hospital admission. when no pathogen was identified in a patient receiving antibiotics prior to bacteriological sampling, an independent adjudication committee reviewed all charts to assess if the patient had a "high probability" or "low probability" for bacterial co-infection, based on clinical, radiological and biological results available. results are presented as median [iqr] . results among the patients hospitalized for an influenzaassociated infection in our icu, had an ards requiring support by either veno-venous-(vv, n = ), venoarterial (va, n = ) or venoarterio-venous-(vav; n = ) ecmo. - . ), pre-ecmo sofa score > (or . ; % ci . - . ) as independent predictors of hospital mortality, but not co-infection (or . , % ci . - . ). in a second analysis, patients with proven co-infection and high probability of co-infection were grouped and compared to patients with no co-infection and low probability of co-infection; and results were similar. as compared to others co-infected patients, those co-infected with a pvl-positive s. aureus had same characteristics and similar mortality rate, but all received a treatment active against pvl production. conclusion co-infection is frequent in patients with influenzaassociated ards supported by ecmo, occurring in roughly % of the cases. mortality of patients with co-infection is higher than those without, but seems mainly due to the severity of the disease. s. aureus was the most frequently identified pathogen, with a high prevalence of pvl-positive s. aureus, infection with a pvl-positive strain was not associated with a poorer outcome as compared to other co-infections. whether a treatment active against pvl production should be given in those patients remains to be determined. none. the pancreaticoduodenectomy (pd) is major surgery in visceral surgery. this technique performed for the first time in by whipple has seen much progress and development over the years that have enabled a significant reduction in mortality, while the morbidity remains high. the aim of this study was to analyze postoperative morbidity pancreaticoduodenectomies. we retrospectively studied cases of cephalic duodenopancreatectomy at the department of surgical emergencies resuscitation (wing ) spanning years, between january and december . the average age of patients was . years with % of females and % of males, the frequence of pancreatic resections was years. the indications of cephalic duodenopancreatectomy were: tumors of pancreatic head ( %), ampulla vater ( %), duodenum tumors ( %). the restoration of continuity after cephalic duodenopancreatectomy was realized with a rate of % for pancreaticogastrostomy and % for pancreaticojejunostomy. the average hospital stay was , days, with extreme lengths of - days. the postoperative course was marked by the occurrence of deaths ( %), the morbidity rate was , % after pj and % after pg; the most frequent complications were the pancreatic fistula ( %), the postoperative peritonitis ( %), the digestive bleeding ( %), the gastroparesis ( %). conclusion advances in the overall care of patients by surgical teams, anesthesiologists and intensivists, the dpc mortality is currently low in experienced centers. the multidisciplinary, involving surgeons, radiologists and especially intensive care, to manage more effectively the complications of this surgery remains burdened with high morbidity. introduction severe acute pancreatitis (sap) is a common but potentially lethal pathology due to the multiplicity and severity of complications that can occur at all stages of evolution. in the last decade, mini-invasive interventional treatments of infected pancreatic necrosis (ipn) have been developed. the aim of the present study was to assess the management and outcomes of sap patients, as well as to identify the role of ipn. this was a retrospective study of prospectively collected data from all consecutive patients admitted in intensive care unit (icu) in a single french center (hospital of nantes) from to . using logistic regression, we evaluated the association between ipn and patients characteristics at baseline and the outcomes. (fig. ) , highlighting the prognostic importance of respiratory failure and acute renal failure at the time of lt, as well as complex interactions between donor and recipient features. conclusion ventilator support and/or acute renal failure at the time of lt are major predictors of mortality but complex recipients/donors relationships may moderate these associations, as demonstrated by our cart analysis. none. subtotal gastrectomy ( / ). enlarged gastrectomy was performed in patients ( %). the mean operative time was . ± min. per-operative transfusion was required in patients ( . %). the average length of stay in icu was . ± days. postoperative mortality was . %. in our series, patients ( . %) had at least one postoperative complication: an anastomotic fistula diagnosed in patients ( . %), patients ( . %) had postoperative peritonitis and patients had ventilator associated pneumonia. reoperation was necessary for patients ( . %), it was performed after . days ( - days). in univariate analysis, risk factors for postoperative morbidity after gastrectomy was hypoalbuminemia (p = . ), anemia (p = . ), bmi (p = . ) and malnutrition (p = . ). age, sex, neoadjuvant chemotherapy, extended lymphadenectomy, splenectomy or pancreatosplenectomy, total gastrectomy and operative time were not significantly associated with higher postoperative morbidity. in multivariate analysis, malnutrition (p = . ) and bmi (p = . ) were significantly associated with the occurrence of postoperative complications. conclusion the results of our study are similar to those reported in medical literature. preoperative evaluation and nutritional rehabilitation are crucial to improve patient's outcome and reduce morbidity and mortality after gastrectomy for cancer. the mesenteric ischemia is a condition relatively rarely. it is marked by high mortality. mortality is primarily related to the land on which ischemia occurs and especially the time taken to diagnose. this delay is due to the low specificity of clinical signs and the absence of diagnostic laboratory test. the mesenteric ischemia remains a diagnostic and therapeutic challenge. patients and methods twenty cases of acute mesenteric ischemia have been collected at the surgical resuscitation (resuscitation ) at the hospital center ibn rochd of casablanca from january to december . results the mean age of our patients is year old. it is about a disease that the incidence increases these last years, particularly because of the waxing number of old patients and/or suffers from advanced cardiovascular diseases. the cardiovascular risk factor has been present in % of our patients. the abdominal pain has been present in all the patients. it is a sudden, intensive pain localized the most often at the level of the epigastria, becomes diffuse in few hours or even few days. other clinical signs have been described as the bilious vomiting that becomes fecaloid after few days. the digestive hemorrhages as the moelena and the hematemeses. a stop of the matter and the gazes was noticed in % of our patients. the absence of specificity of the clinical signs forced the realization of complementary examinations. the scanner becomes the reference imaging. it permits a differential diagnosis, the search of direct signs of vascular obstruction and the emphasis of intestinal pain. four etiologies are noticed: the arterial occlusion by emboli ( %), the arterial thrombosis ( %), the venous thrombosis ( %) and the "non occlusive" form ( %). the strategy of management of the acute mesenteric ischemia is multidisciplinary, based on the equips of radiology, vascular surgery and/ or visceral surgery and resuscitation. the treatment consists in measures of general resuscitation, the techniques of endoluminal vascular disobstruction and techniques of surgical revascularization. in spite of the improvements in the diagnosis and the therapeutic procedure of the ima, the disease still know a rate of mortality between and % according the studies. in our study, we noticed cases of death ( %), cases of good recovery ( %), cases are unknown evolution ( %). conclusion it is a vital emergency that the evolution still knows great mortality. it is very important to remind the acute mesenteric ischemia in the case of any acute abdominal symptom in order to anticipate about the natural evolution and to act in a reversible stage of the ischemia. none. introduction emergency departments staff are frequently exposed to many complex stressful situations and consequently burnout syndrome. our study aimed to describe epidemiological particularities and determine the risk factors of burnout syndrome in different categories of emergency. patients and methods we studied five academics and four regional hospitals. the level of burnout was assessed using the "maslach burn out inventory" score and the degree of depression with major depression inventory (mdi) test. results one hundred and forty-three correctly completed questionnaires were collected. the mean age of study population was ± years. sex-ratio was at . . fifty-one per cent of the care staff were married. physicians represented % and paramedical %. the general frequency of burnout syndrome was % (n = ). low level burnout was present in %, moderate level in % and high level in %. the depression frequency was %. a statistically significant correlation was found between burnout and depression firstly (p = . ) and between burnout and lack of equipment (p = . ). their relative risk was . [ . , ] and . [ . , . ] respectively). main risk factors associated with high level burnout are detailed in table . conclusion burnout syndrome frequency in our emergency departments is alarming. helping to resolve social and psychological problems and improving work conditions may help to decrease it. the healthcare activity is recognized as a major polluting activity. in france, it generates , tons of waste cremated each year, and represents % of the tertiary energy consumptions. in the united states, it generates tons of waste per day and % of total co emissions in were attributed to him. ultimately, such waste production is associated with adverse environmental and health effects. nevertheless, near half of the hospital waste would be recyclable, particularly in our intensive care units (icu) [ ] . furthermore, sustainable development solutions generate profits. the aim of this study is to make an overview of waste produced in a icu and offer solutions to conserve natural resources and reduce the carbon footprint bound to the healthcare activity. materials and methods experimental study, single-center, concerning a period of months in an icu-high surveillance unit compound of beds. we have identified all waste generated. our packaging were given to the recycling company in connection with the hospital. then we have studied the impact of the implementation of sustainable development solutions. results firstly, we have studied the non-recycled waste and the quantity produced over a period of month. approximately kg of waste is produced per patient per day with % of infectious waste and % of general waste. these results were linked with a bad distribution of garbage bags in the rooms ( l of infectious waste versus l of general waste). secondly, we have improved our way to sort and consume and we have created recycling dies without compromising patient safety. all these measures have not increased workload. changing bags in the rooms ( l of infectious waste and bags of l of general waste) allowed to reach the normal goals of sectors with a net benefit estimated at euros per year. the medical broken glass containing drugs was thrown into plastic containers of l for infectious waste to prevent the risk of cuts. by creating a specific die intended to the general waste, we could quantify the production of this glass to kg per week and to spare the use and the incineration of containers of l per year (global economy of euros). plastic packaging represented an important proportion of the cremated waste. we have created sectors of recycling including the polypropylene ( - kg per month), the polyethylene colorless and colored polyethylene. this plastic is sold to be recycled without additional cost for the hospital. the linerboards was cremated. we have created a recycling die ( kg per month). this sector was subsequently extended to the entire hospital structure, particularly the pharmacy that produces containers of l per month. they are now sold without additional cost. many unnecessary plastic waste is generated daily. we have removed using mild soap plastic bottles of ml by using the same mild soap in pump of ml (economy of euros). the use of l plastic bags for the transitional deposit of linen has been deleted (economy of euros). concerning the paper: % of the impressions were made in simplex. printers were parametrized on both sides by default allowing the economy of reams per year ( , sheets), several thousand liters of water and the reduction of co emissions. discussion recycling is only one component of the sustainable development in health. other avenues that could be considered to improve icu sustainability would include examining water use (for linen), electricity use (reducing non-essential use at night…). beyond these actions, we need to encourage our suppliers to turn to sustainable and recyclable packages to reduce the use of polluting and depletable fossil fuels such as oil. but also to develop with them circular economies where waste is returned to them to be reused. conclusion we must ask the question also resuscitate our tons of waste. our icu produce large quantities of waste (over tons per year per bed). however, a significant proportion, especially plastic, is recyclable with a significant environmental and financial benefit. waste management also requires an optimal and rational use of supplies because "the best waste is that which is not produced" and that excess is not a guarantee of quality. as already said st exupéry in : "we do not inherit the earth from our parents, we borrow it from our children. " so do not expect tomorrow to reduce major adverse ecological impact paradoxically generated by a great profession whose ultimate goal is to cure people. moreover, an external consultant is rarely applied and palliative cares are insufficiently developed after «non-readmission» decisions. for providing corrective measures, this study lead to propose a «nonreadmission» process by integrating the discussion for a real «patient's care project» at the end of the icu hospitalization. this process would lead to collect patient's opinion through advance directives, to ensure a collegial discussion including an external consultant and to allow reevaluation of global patient's clinical status and one or more organ failure(s). then, «non-readmission» decisions would be integrated in a therapeutic project which would promote the initiation of a palliative care program if necessary. the purpose of this process is well to respect patient's autonomy and dignity as required by french law and medical ethics. the proportion of elderly patients is steadily increasing. due to the growth of this part of the population who suffer from multiple pathologies, the need for hospitalization in intensive care increases. according to the simulations, the proportion of octogenarian patients in icu will increase reaching the third of icu patients. while chronological age is not a significant factor of poor prognosis in the icu ( ), many factors should be taken into account to evaluate the relevance of icu admission in the senior population and withholding such intensification should be consensually discussed between clinicians and obviously as often as possible with the patient himself ( ) . the aim of the study was to assess the role of stakeholders (ward physicians, intensivists, family doctor and patient himself ) in the decision of withholding icu admission for elderly patients in our internal medicine department. we made a prospective observational monocentric study, including all the elderly patients (defined as older than ) admitted in the internal medicine department from january to june . the only non-inclusion criterion was patient's refusal to participate to the survey. collected data involve physiological (cognitive, autonomy, nutritional status), morbidities (acute and chronic diseases) and social parameters (marital status, relatives). and evaluation of quality of life by the patient himself using an analog visual scale was also obtained. internal medicine physicians were asked to report any icu withholds decision for their patients. in absence of notification, every physician was questioned again the day of the concerned patient's discharge. results one hundred ninety-one patients were included between january and june . factors associated with a significant reduction of in hospital mortality were higher age (p = . ), higher lactate level (p = . ), chronic obstructive pulmonary disease (p = . ), diabetes mellitus (p = . ), immunodepression (p = . ) and respiratory failure (p = . ). conclusion in patients hospitalized for vs high body mass index, low left ventricular systolic function, high white blood cell count, low creatinine clearance, high lactate level and st-segment depression are the variables correlating significantly with high-sensitivity troponin-t concentrations. peak of hstnt was not significantly associated with in-hospital mortality in this setting. introduction mitochondria are evolutionary endosymbionts that are derived from ancestral aerobic bacteria and so might bear and release bacterial molecular motifs supporting the role of mitochondria in danger signal regulations. free circulating mitochondrial dna (mtdna) is elevated in a wild range of critical illness observed in intensive care units, and is associated with bad outcomes and mortality. the mtdna is a molecular pattern that belongs to mitochondrial damage associated molecular patterns (mtdamps), and can interact with pattern recognition receptors (prr) to induce self defense reaction. free mtdna activates inflammatory signaling pathways through toll-like endosomal receptor (tlr ) interactions. nevertheless, new evidence advocates a role of the receptor for advanced glycation end-products (rage) in mtdna signaling. experimental data suggest a role of mtdna-prr interaction in systemic inflammation and organ dysfunctions as septic acute kidney injury or pulmonary inflammation. impact of free circulating mtdna on endothelial cell is not known. the main purpose of this study was to test whether mtdamps and mtdna can induce endothelial dysfunction. we also evaluated the role of mtdna-rage axis in mtdamps induced endothelial dysfunction. mitochondria were isolated from livers of wild type c b mice. isolated mitochondria were sonicated on ice to obtain mtdamp preparations. semi quantitative evaluation of mtdamp content was tested by qpcr, with specific markers of mtdna (cytochrome b (cytb), nadph oxidase (nd )). intraperitoneal injection of mg of mtdamps was used as experimental model in wild type and rage ko mice, as previously described [ ] . the mtdamps were also administrated after ex vivo dnase preparation. endothelial function was assessed with a mulvany-halpern style myograph, h after mtdamp administrations on aorta (conductive vessel) and on d division of mesenteric artery (resistive vessel). endothelial-dependent relaxation was studied by cumulative expositions of the vessels to acetylcholine ( . - - . - m). endothelial-independent relaxation was studied by sodium nitroprussiate exposition. results the mtdamps preparation contains a high quantity of mtdna with a /cycle threshold (ct) ratio of . for cytb expression. intraperitoneal administrations of mtdamps induced a decrease of endothelial-dependent relaxation mainly on conductive vessel (p = . , n = per group) and to a lesser extent on resistive vessel (p = . , n = per group). rage-ko mice were protected from mtdamps-induced aorta dysfunction (p = . , n = per group). the ex vivo exposition of mtdamps to a dnase preparation decreased mtdna content in mtdamps solution with a /ct ratio of . for cytb expression. eventually, the pretreatment of mtdamps with a dnase preparation prevented the mtdamps-induced aorta dysfunction (p = . , n = ). discussion more than prognostic markers, mtdamps particularly mtdna seems implicated in endothelial dysfunction in critically ill patient. new evidence suggest rage interaction in endosomal tlr pro-inflammatory and pro-oxidant response to mtdna [ ] . also in sepsis, physiological clearance of circulating dna might be impaired, this results comfort the possibility of therapeutic regulation of free circulating mtdna to prevent septic organ dysfunction related to mtdamps accumulations. conclusion exogenous mtdamps can induce endothelial dysfunction in mice. the mtdna-rage axis is a key component of the signaling pathway involved in this dysfunction. the use of dynamic parameters to assess fluid responsiveness was supported by cyclic changes in stroke volume induced by mechanical ventilation. however, these parameters have several limits. venous to arterial carbon dioxide difference inversely related to cardiac index. consequently, fluid administration would be beneficial if carbon dioxide gap increases. objective to investigate whether carbon dioxide gap predicts fluid responsiveness in patients with acute circulatory failure. patients and methods we conducted a prospective study in the medical intensive care unit of hospital taher sfar at mahdia, between march and april . patients with circulatory failure and who required mechanical ventilation were included. we measured the variation of cardiac index between baseline and after volume expansion of ml of saline fluid. the picco was used to measure cardiac index. response to fluid challenge was defined as a % increase in cardiac index. before and after fluid administration, we recorded carbon dioxide difference and hemodynamic parameters. results among included patients, ( %) were responders. the causes of acute circulatory failure were septic shock (n = ), cardiogenic shock (n = ), and hypovolemia (n = ). carbone dioxide gap was significantly higher in responders group ( ± vs ± mmhg, p = . ). the area under the roc curve for carbon dioxide gap was . ( % ci . - . ). the best cutoff value was mmhg (sensibility = %, specificity = %, positive predictive value = % and negative predictive value = %). the area under the roc curve for delta carbon dioxide was . ( % ci . - . ). conclusion in this study, baseline carbon dioxide gap was not universal indicator to predict the fluid responsiveness in patient with circulatory failure. introduction supraventricular arrhythmia (sva) is commun in intensive care unit (icu). its incidence seems to be higher in patients with sepstic shock. sepsis-associated myocardial dysfunction promote the occurrence of sva by constituting an arrythmogenic substrate or under the effect of inotropic drugs. the aim of this study is to assess the incidence and prognostic impact of sva in patients with septic shock. patients and methods we retrospectively studied all patients with new onset sva suffering from septic shock in non cardiac surgical icu. myocardial dysfunction was evaluated by transthoracic echography (tte) after an adequate cardiac resuscitation using intravenous fluids expansion and adjunctive vasoactive agents. sva was detected by the electrocardiogram scope. during the study period clinical and biologic characteristics, hemodynamic tolerance (vasopressors doses, arterial pressure changes), current treatment (such as corticoid), duration of mechanical ventilation, duration of vasopressor requirement and hospital mortality were collected. results sixty patients were included in the study. the sva occurred in patients, with an incidence of %. the median time to onset was days. cardioversion was performed for patients with an effectiveness of %. clinical and biological characteristics were similar between the groups with and without sva: saps and sofa score at the beginning of septic shock, the existence of ards and cardiac biomarkers (nt-probnp, troponin). however, renal failure and the use of corticoid in septic shock were more frequent in the group with sva. the maximum doses of vasopressor agent were not significantly different between the groups with or without sva. myocardial dysfunction in sepsis defined by the left ventricle ejection fraction (lvef) less than % (or the need for inotropic drug for lvef > %) was not associated with the occurrence of sva (+sva group: n = ; −sva group: n = ; p: . ). sva was poorly-tolerated, observed by a significant decrease in mean arterial pressure and a significant increase in norepinephrine doses within h of the start of sva. the occurrence of sva was associated with longer duration of use of vasopressor agent and a longer duration stay in icu (+sva group: days, −sva group: days; p = . ). there was no difference in duration of mechanical ventilation and hospital mortality between the two groups. conclusion the occurrence of sva is common in septic shock, poorly tolerated hemodynamically and associated with longer duration stay in the icu and vasopressor need. sepsis myocardial dysfunction isn't necessarily associated to the occurrence of sva. introduction a short term beneficial effect of prone position on cardiac index has been shown in % of ards patients, and was related to an increase in cardiac preload in preload responsive patients ( ) . the aim of this study was to evaluate the long term hemodynamic response to prone position in a larger series of ards patients. patients and methods single center retrospective observational study performed on ards patients hospitalized in a medical icu between july and march . patients included were adults fulfilling the berlin definition for ards, undergoing at least one prone position session, under hemodynamic monitoring by the picco ® device, with availability of hemodynamic measurements performed before (t ), at the end (t ), and after the prone position session (t ). prone position sessions were excluded if they were performed > days after ards onset. the following variables were recorded: demographic, sapsii, ards severity and risk factor, sofa score and cumulative fluid balance at pp onset, delay between ards session and pp session, hemodynamic, arterial blood gas, ventilatory settings, plateau pressure, catecholamine dose and additional treatments. statistical analyses were performed using prone position session as statistical unit and mixed models taking into account both multiple prone position sessions by patient and multiple measurements during a prone position session. p < . was chosen for statistical significance. data are expressed as mean ± standard deviation. results patients fulfilled the inclusion criteria over the study period, totalizing prone position sessions ( ± sessions per patient). patients' age was ± y, % were male, % fulfilled the criteria for severe ards, and sapsii at icu admission was ± . ards risk factors were pneumonia in ( %), aspiration pneumonia in ( %), and sepsis in ( %) patients. duration of prone position sessions was ± h. hemodynamic measurements were performed in pp ± h after pp session onset. at session onset, sofa score was ± , and cumulated fluid balance was . ± . l. vasopressor were used in %, inhaled nitric oxide in %, and neuromuscular blocking agents in % of the sessions. hemodynamic and respiratory parameters before, during and after the prone position sessions are reported in table . cardiac index increased by at least %, decreased by at least % or remained stable in ( %), ( %), and ( %) of the sessions, respectively. as compared to both other groups, pp sessions with significant increase in cardiac index had the following significant differences at t by univariate analysis: lower cardiac index, lower global end-diastolic volume, lower cardiac function index, and lower vasopressor dose. multivariate analysis is under investigation. conclusion prone position is associated with an increase in global end-diastolic volume, reversible after return in supine position that may explain the positive effect of pp on cardiac index observed in ¼ of the pp sessions. introduction make sure that our patient have a good circulatory condition is a daily challenge for the intensivist. one of the therapeutics is fluid and one of his purpose is to increase venous return and then cardiac output. in order to examine that, there are several tools as the transthoracic echocardiogram wich allows the visualisation and the study of the respiratory variability from the inferior vena cava (ivc). unfortunately there are some situations where the ivc visualisation is difficult (obesity, gut surgery, emphysema). the ivc is easily seen by a transhepatic ultrasound in her retrohepatic section. we make the hypothesis that the shape of the ivc could be predictive of fluid responsiveness. we have performed fluid challenge in patients under mechanical ventilation. the need for fluid therapy is the intensivist in charge decision. we performed a echocardiogram and we take two measures of the icv: major axis and minor axis, the icv is measured avec the sus hepatic vena. a elastometry index (ei) is determined which is the ratio of minor axis to minor axis. the fluid challenge is ml of isotonic saline then we perform a new echocardiogram. a tag is written on the patient to take the same ultrasound slice. we retain one increase of % of the cardiac index (ic) as a success of the filling. we exclude the presenting patients a right cardiac insufficiency, an arrhythmia and/or a htap. the statistical analysis is realized with the software r. results between august, and january, we included patients. the average age is of years ( - ), igs of ( - ), ejectionnal fraction of % - ) and the s wave tricuspid is ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the causes of the filling were an oliguria ( %), a low blood pressure ( %), a low cardiac output ( %), a hyperlactatémia ( %) and an other cause in % of the cases. we find a positive correlation between the ei and the increase of the ic, also for the area of the vci and the respiratory variations of the vci (p . ) the other variables are not predictive (bp, e/e' , e/a). the data are summarized in the picture . roc curves has been established ( only % of the journals studied required authors to use stard. a high impact factor and the year of the study were the items associated with a better sqs the presence of a conflict of interest was associated with a lower sqs in univariate analysis. a higher impact factor (> ), was the only independent factors statistically significantly (p = . ) associated with higher sqs in a multivariate regression model. discussion our study showed that the sqs were very low. assessment of a study depends on quality of reporting. blindness and participant sampling are the cornerstone to evaluate such bias as spectrum, verification, review and selection bias of a study, and were unfortunately scarcely reported compared to existing data in diagnosis accuracy reporting. one of the limitation is the years sample of the study. we have planned to continue the analysis for a -year review starting just after the stard publication. conclusion our study showed that several items remain poorly reported. we recommend systematic use of stard criteria in the elaboration and reporting of future studies that evaluates the preload dependence. introduction neurological impairment, i.e. encephalopathy, is commonly observed in patients with decompensated cirrhosis and/or portosystemic shunts admitted in icu. often ascribed to high plasmatic levels of ammonia, encephalopathy could also be induced by drugs or infection, due to altered blood-brain barrier (bbb) permeability. this latter setting is often underdiagnosed and encephalopathy related to hyperammonemia (so called hepatic encephalopathy-he) being pointed out as the culpit of all neurological symptoms in cirrhotic patients. quinolones and betalactamins were recently found in the cerebrospinal fluid of he patients and it has been shown that the expression of efflux pumps, responsible for drugs passing through the bbb, was altered in animal models of he. the purpose of this study was to assess the incidence of neurological impairment, i.e. encephalopathy, in cirrhotic patients hospitalized in discussion overall, we reported a higher rate of lumbar puncture than those reporting in others studies concerning status epilepticus. furthermore the rate of % of pleocytosis directly linked to status epilepticus is slightly higher than in most studies. unfortunately we didn't realize a second lumbar puncture to assess the pleocytosis normalization during the days following the first lumbar puncture. the pathophysiological hypothesis of this phenomenon may be that prolonged/repeated seizures during status epilepticus would induce a blood-brain barrier dysfunction thereby favoring a cerebrospinal pleocytosis. conclusion in our study, % of status epilepticus without infectious or neoplastic origin had a cerebrospinal pleocytosis directly linked to status epilepticus. this pleocytosis was significantly associated with myoclonic seizures and blood leukocytosis. these data may help to interpretation of cerebrospinal fluid pleocytosis during status epilepticus. introduction neurological prognostication from cardiac arrest survivor is a current concern. eeg patterns and nse dosage are two important prognostic factors. nse threshold for prediction of poor outcome appear controversial, in part, because of variability in dosage timing and measurement techniques. synek score is routinely used in our center to classify comatose patients in post cardiac arrest. the aim of this study was to assess the prognostic value of nse and synek classification to predict poor neurological outcome. introduction traumatic brain injury (tbi) is a major public health problem. it is the leading cause of death and disability in young subjects. one of the principles of the tbi management is prevention of secondary cerebral insults including maintaining perfusion and cerebral oxygenation, control of intracranial pressure (icp). an increase in icp above mmhg is associated with poor outcome. cerebral hypoxia can occur with normal level of icp and cerebral perfusion pressure (cpp).monitoring of regional partial pressure of brain tissue oxygen (pbto ) is a safe and reliable method for measuring cerebral oxygenation. a retrospective single-center observational study was conducted between january and december , aimed to study the influence of pbto with severe tbi patients outcome at months through glasgow outcome scale (gos). the hourly values of icp, pbto and cpp were recovered on daily monitoring sheets. we compared two groups according to their gos. during the study period, patients underwent a monitoring icp and pbto . results the mean age was . ± . years. . % were men. the initial glasgow score was . ± . . the mean simplified acute physiology score (saps ii) was . ± . and injury severity score (iss) . ± . . at months, patients had died (gos ). forty patients had a good outcome: gos - (group ). sixteen patients had poor outcome: gos - (group ). in group , there are significantly more pbto hourly values below mmhg at day ( . ± . vs . ± , in group , p = . ); and more pbto hourly values greater than mmhg at day ( . ± . vs . ± . , p = . ). conclusion pbto less than mmhg or greater than mmhg at day is associated with poor outcome at months in the severe tbi. the pbto allows a more individual approach of monitored tbi. none. introduction organ donation in patients after a decision to withdraw life-supportive therapies (wlst) (maastricht condition: m ) have been performed in our hospital since may . we report here main characteristics of donors, data on m procedure and results on renal transplant recipients. patients and methods all potential donors were included in a survey from may to june , according to the french national m protocol defined by the french organ procurement agency (agence de la biomédecine:abm) [ ] .the demographical, clinical and biological characteristics of the donors, the different deadlines and times of the protocol and data of renal transplantation were collected and analyzed. results patients had inclusion criteria. patients were admitted in intensive care unit for cardiac arrest ( %), strokes ( %), traumatic brain injury ( %), ards ( %). of them, procedures ( %) were stopped ( refusals of organ donation, medical contra-indications discovered with additional exams, failure of vessel cannulation, deaths more than h after extubation). kidneys were harvested and transplantations performed ( renal cancer discovered during procurement surgery).the characteristics of the donors, deadlines of the protocol and transplant recipients are reported in the table . conclusion the french programm maastricht offered a new possibility of organ donation in our hospital. thanks to these donors, the number of renal grafts increases and the preliminary results on transplant recipients are encouraging in line with the preliminary report of the abm. nevertheless, it is necessary to follow the transplant recipients and extend the procedure to new centres. in this study, we found some relevant risk factors for microaspiration (age, low score at gcs) consistent with literature on the subject. patients with paralytic agents had less gam which may be due to higher peep, higher cuff pressure and less enteral nutrition because of the severity of the underlying diseases. conclusion this study did not show any increased risk of microaspiration in intubated copd patients, whatever stage of copd. introduction protected specimen brush (psb) is considered to be one of the standard methods for the diagnosis of ventilator-associated pneumonia (vap). to our knowledge, there is no study assessing effect of prior antibiotherapy on direct examination, bacteriological culture and concordance of direct microscopy and culture. patients and methods all consecutive episodes of suspected vap were retrospectively evaluated between january and december in a -bed intensive care unit. patient's characteristics and preexisting conditions were abstracted from the medical charts. after assessment of vap probability using the clinical pulmonary infection score (cpis), psb were performed in patients with a cpis of or more. based on antibiotic treatment in patients when bacteriological specimens were obtained, two groups were defined: no antibiotic group and antibiotic treatment started before psb group. two independent bacteriologists retrospectively reviewed direct examination and culture of psb to assess bacteriological concordance, defined as non-concordant when direct examination and culture were different, concordant when direct examination and culture were similar and partially concordant when either direct examination or culture were comparable but with other microorganisms lacking in one or the other method. results during this -months period, among mechanically ventilated patients, episodes of suspected vap with psb were evaluated. we found % of psb (n = ) performed without antibiotic treatment and % of psb (n = ) performed under antibiotherapy. we found no significant differences in patient's demographics, characteristics, and severity between both groups. patients received antibiotics for the following reasons: aspiration pneumonia (n = ), peritonitis (n = ), vap (n = ), community-acquired pneumonia (n = ), septic shock of unknown origin (n = ), pyelonephritis (n = ), meningitis (n = ), acute pancreatitis (n = ) and others (n = ). the median duration of mechanical ventilation in the antibiotic receiving group and in the group without antibiotics was . days (iqr; - days) and days (iqr: - ), respectively. when psb was performed under antibiotic treatment, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. on the other hand, when psb was performed without antibiotics, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. in univariate analysis, we found a significantly higher proportion of negative direct examination and negative culture in the antibiotic group (p > . ). moreover, these methods were significantly more frequently concordant (p = . ), with a higher rate of both negative microscopic exam and culture when compared to the no antibiotic group ( %, n = vs %, n = ). surprisingly, among the patients previously treated with antibiotics with positive culture, % (n = ) of the microorganisms showed antibiotics sensitivity. discussion whether prior antibiotic treatment may induce false negative of false positive treatment is a well-recognized phenomenon, the precise effect of antibiotics on direct examination and quantitative culture is not well assessed in vap. moreover, despite recent development of clinico-radiological score, diagnosis of vap remains difficult, with no gold-standard. therefore, bacteriological guided therapy is of particular importance. we found psb realization under antibiotic treatment is associated with a lower rate of positive direct examination and culture and suggest performing these bacteriological samples without antibiotherapy. some authors have suggested lowering the diagnostic threshold point of this bacteriological technique in order to preserve its accuracy. however, we can postulate that microorganisms responsible of superinfection in mechanically ventilated patients treated with antibiotics may be resistant and therefore the psb could be positive. conclusion in patients with a high pre-test probability of ventilatoracquired pneumonia, recent introduction of antibiotics significantly reduced the diagnostic accuracy of protected brush specimen by reducing rates of positive direct examination and culture. further studies should evaluate if antibiotic discontinuation may revert this effect. ann. intensive care , (suppl ): we have had non conflict of interest in this study. results we included patients in the phase and patients in the phase . baseline characteristics of patients were similar in both groups. compliance with all the measures has been improved between the two period from to . %. the incidence density decreased from . to . vap per ventilator days between observational and interventional period, but the all-cause mortality was almost equal in the groups ( . vs. %). discussion with the implementation of our bundle, observance of the team were improved in the second group, compared to the first and the incidence density decreased from . to . vap per ventilator days between both period. this result is consistent with the littérature. sure enough, many studies show the same effect of vap prevention with a decrease of nearly % of the incidence density of vap, after implementation of a «ventilator -bundle [ ] . conclusion the implementation of a "ventilator bundle, " has significantly reduced the incidence of vap in our service. in the contrary, our study failed to demonstrate a reduction in mortality. introduction with an increasing incidence and high mortality rates, sepsis is a public health issue. there is growing evidence that sepsis induces long lasting alterations of transcriptional programs through epigenetic mechanisms that may lead to protracted inflammation, organ failure, sepsis-induced immune suppression (siis), secondary infections and death. we hypothesized that epigenetic changes contribute to the pathophysiology of siis. to test this hypothesis, we studied the effects of histone deacetylases (hdac) inhibition with trichostatin a (tsa) in a double-hit murine model of siis and secondary pneumonia. materials and methods c bl/ mice were treated with tsa ( mg/ kg ip) or saline serum (ctl) min before induction of sepsis by cecal ligation and puncture (clp). surviving mice underwent intratracheal instillation of . × cfu of pseudomonas aeruginosa days after clp. we evaluated the effect of tsa on survival and cellular responses to the primary and secondary infections. cellular responses in the blood, spleen and bal were assessed by flow cytometry after clp (days , & ) and after pneumonia ( & h). we also studied lymphocyte apoptosis and dendritic cells (dc) expression of cd , cd , and mhcii. bacterial clearance was assessed in the bal and in the blood and h after pneumonia. continuous variables represented as mean ± sd were compared using student t test. kaplan-meier curves were compared by the log rank test. p < . indicated statistically significant differences. results whereas treatment with tsa did not change survival after clp, tsa improved survival after tracheal instillation of p. aeruginosa (p = . , fig. ). tsa-treated mice had significantly higher absolute dc, t and b-lymphocytes counts with reduced lymphocyte apoptosis after clp. four hours after secondary pneumonia, tsa-treated mice had significantly higher dc counts and improved bacterial clearance in the bal, with reduced systemic dissemination of p. aeruginosa. conclusion hdac inhibition with tsa improves survival in our murine model of secondary pneumonia, improves bacterial clearance and attenuate cellular features of siis. these results suggest that sepsisinduced epigenetic changes contribute to the advent of siis. comprehensive characterization of epigenetic changes associated with siis might allow us to identify new therapeutic targets to reprogram immune cells in sepsis and avoid siis. length of icu stay was ± days. patients acquired nis ( . % bsi, . % pneumonia, . % cri and . % uti. there was no bacteriological documentation of ni in . % of cases. nis occured days post burns. the most three isolated pathogens were: acinetobacter spp. ( %), p. aeruginosa ( . %) and extended spectrum betalactamase-producing enterobacteriaceae ( %). the most frequently administered antibiotics were polymyxin/carbapenem/teicoplanin combination ( %), polymyxin/carbapenem combination ( %) and carbapenem/tigecycline combination ( %). in our study, mortality rate was %. conclusion nosocomial infection occured in . % of cases in burn patients, caused by acinetobacter spp, p. aeruginosa and enterobacteriaceae blse. so, eradication of infection in burn patients require effective surveillance and infection control in order to reduce mortality rates, length of hospitalization and associated costs. introduction infection of the lower respiratory tract is the most common cause of infection in intensive care unit (icu) ( ) . although the attributable mortality of ventilator associated pneumonia remains debated, the recurrence of these infections is always associated with a significant morbidity ( ) . staphylococcus aureus methicillin-sensitive (sams) is one of the most frequently germs involved in icu pneumonia especially in trauma patients. the aim of the study was to establish the risk factors associated with microbiological treatment failure of pneumonia, caused by sams. materials and methods we retrospectively identified patients who developed a first episode of ventilator associated pneumonia caused by sams during a years-period ( - ). the primary end point was the microbiological treatment failure defined as a second episode of pneumonia caused by sams corresponding to either a persistent or a recurrence of the pneumonia (fig. ) . the primary aim of the study was to identify factors associated with a treatment failure, the secondary objective was to identify factors associated with the occurrence of second episode (i.e. persistent, recurrence, superinfection and/or relapse of pneumonia caused by any bacteria) during or after treatment of the first episode caused by sams. definition of outcomes was based after analysis of current concepts available in the literature. factors associated with primary and secondary objectives in univariate analysis (p-value < . ), or clinically relevant ones, were entered in a multivariate logistic regression. the final selection was performed using the stepwise selection based on the akaike criterion. results fifty-nine patients ( . %) developed a second episode of pneumonia and among them, ( . %) were considered as a microbiological failure. in a multivariate analysis, the association of oropharyngeal flora (fop) with the sams (or, . ; % ci, . - . ; p = . ) and the need of emergency surgery (or, . ; % ci, . - . ; p = . ) were predictive of a microbiological failure. empirical antibiotic therapy with amoxicillin-clavulanic acid (or, . ; % ci, . - . ; p = . ) and performing emergency surgery (or, . ; % ci, . - . ; p = . ) were predictors of a second episode of pneumonia caused by any bacteria. conclusion in this retrospective, monocentric study, the co presence of orophryngeal flora and the need of emergency surgery were associated with microbiological failure of pneumonia caused by sams in icu. introduction ventilator-associated pneumonia is a major iatrogenic problem since it is a cause of hospital morbidity, mortality and increase of health care costs. it has been studied many times, but data's revision is always necessary. our study aimed to describe epidemiology of ventilator-associated pneumonia and identify local causative pathogens. we carried out a prospective study in an intensive care unit. were included patients intubated for more than h, from april to may , and presenting signs of ventilator-associated pneumonia (fever, abundant and purulent secretion, increase of fio greater than . , signs on chest-x ray) with positive culture of endotracheal aspirate. were excluded patients with germ colonization. results a total of patients were ventilated for more than h. among them thirty-four patients aged of ± . years presented episodes of ventilator-associated pneumonia (that is . ± . episodes per patient). the mean sofa score was . ± . . the main reasons of mechanical ventilation were loss of consciousness secondary to poisoning ( %), respiratory distress ( %) and status epilepticus ( %). the mean duration of stay was . days with extremes at and days. the average time between hospitalization and suspicion of ventilator-associated pneumonia was . ± . days. the average value of the clinical pulmonary infection score at suspicion was ± . . the average time between recurrences was . days with extremes at and days. the culture of endotracheal aspirate identified two pathogens in %. it reveled acinetobacter baumanii in % in which % were imipenem resistant, pseudomonas aeroginosa in %, klebsielle pneumoniae in %, staphylococcus fig. see text for description aureus methicillin resistant in %. extended spectrum β-lactamases bacteria were found in % and carbapenemases producers in %. empirical antibiotherapy was always association of imipenem and colistin. it was necessary to adapt it to antibiograms in / . ventilator-associated pneumonia was complicated by septic shock in % and acute respiratory distress syndrome in %. patients evolved to healing in % of episodes (n = ), to superinfection in % (n = ) and to death in % (n = ). pseudomonas aeruginosa was the most frequent germ in superinfection ( / ) , acinétobacter baumanii was the most pathogen associated to death ( / ). conclusion ventilator-associated pneumonia is an iatrogenic disease that threatens lives. it's in part avoidable. preventive measures have to be implemented to reduce its frequency, consequences and costs. introduction during mechanical ventilation, mismatch between respiratory muscles activity and the assistance delivered by the ventilator results in dyspnea and asynchrony and is commonly observed in intensive care unit (icu) patients. proportional assisted ventilation (pav) is a ventilatory mode that adjusts the level of ventilator assistance to the activity of respiratory muscles estimated by an algorithm. to date, pav has been mostly studied in patients without severe dyspnea or asynchrony. we hypothesized that, compared to pressure support ventilation (psv), pav will prevent severe dyspnea or asynchrony. patients and methods were included icu mechanically ventilated patient exhibiting severe dyspnea or asynchrony with psv. three conditions were successively studied: ) psv on inclusion (baseline), ) psv after optimisation of ventilator settings in order to minimize dyspnoea and asynchrony (optimisation), and ) pav. ten-minutes recording were performed with each condition. the intensity of dyspnea was assessed by the visual analogic state (vas, only in patients able to communicate) and by the intensive care respiratory distress operating scale (ic-rdos) for all the patients. the electrical activity (emg) of extradiaphragmatic inspiratory muscles was measured. the fig. bayesian nma with random effect prevalence of asynchrony was quantified by the visual inspection of the airway flow and pressure traces. results patients were included, % male, aged [ - ] years, saps [ - ], mechanically ventilated for [ ] [ ] [ ] [ ] [ ] [ ] days. the tidal volume (tv) was higher in the optimisation and pav than in the basal condition (table ). the respiratory rate(rr) was lower with pav than in the other conditions. the dyspnea-vas was lower with optimisation and pav than with the basal conditions. the ic-rdos was lower with pav than with the two other conditions. the asynchrony index was lower with pav than with the two other conditions. parasternal emg activity was lower with pav and optimisation (fig. ) . conclusion in icu patients receiving mechanical ventilation with psv and exhibiting severe dyspnea or asynchrony, the optimisation of ventilator settings with psv and the pav mode decrease in the simiar way the severity of dyspnea and the prevalence of patient-ventilator asynchrony. introduction in spite of recent research and progress in weaning protocols, extubation failure still occurs in - % of patients and is associated with poor outcomes, with a mortality rate of - %. many risk factors for planned extubation failure have been suggested, including hypercapnia at end of spontaneous breathing trial (sbt). however, performing arterial blood gases at the end of sbt is not routinely recommended whereas etco may be routinely monitored during a low pressure support sbt. the aim of this prospective observational study was to determine the clinical usefulness of etco to predict extubation failure. patients and methods we recorded clinical data and etco during a successful h low level pressure support sbt (at the beginning, after min and at the end of the trial). patients ventilated through tracheostomy and unplanned extubations were excluded. extubation failure was defined as death or the need for reintubation within h ( ) after extubation; this delay was prolonged to days ( ) in case of noninvasive ventilation after extubation, which was systematic in older patients or those with cardiorespiratory disease, as per our weaning protocol. multivariable logistic regression analysis was performed to identify independent variables associated with extubation failure. results one hundred and fifteen ventilated patients were enrolled in our study from july to june . the median age of these patients was [ - ] years, their median simplified acute physiology score (saps) ii was [ - ] points and . % (n = ) were female. seventeen ( %) patients had chronic obstructive pulmonary disease. reintubation rate was % (n = ). etco at other time points as well as its changes during the sbt were also similar between groups. the three variables predicting extubation failure in the multivariable logistic regression model were a past medical history of cirrhosis, acute respiratory distress syndrome before weaning and lower minute ventilation at the end of sbt. conclusion etco during a successful sbt seems useless to predict outcome of extubation. introduction airway management in intensive care unit (icu) patients is challenging [ ] . "airway failure", defined as the inability to breathe without endotracheal tube, differs from "weaning failure", defined as the inability to breathe without an invasive mechanical ventilation. however, most of the studies assessing predictive factors of extubation failure did not separate airway from weaning failure. we aimed to describe incidence of extubation failure in critically ill patients, separating for the first time airway from weaning failure, in a prospective multicenter observational study. patients and methods a prospective, observational, multicenter study was conducted in french icus. all adult patients consecutively extubated in icu were included. an ethics committee approved the study design (code uf: , register: -a - ). the study was registered on clinicaltrials.gov (identifier no.nct ). clinical parameters were prospectively assessed before, during and after extubation procedure. extubation failure was defined as the need to reintubate less than h after extubation. extubation failure could be due to airway failure, weaning failure or mixed airway and weaning failure. results from december to may , intubation-procedures were studied in patients from centers. patients ( . %) were intubated twice. the median number of intubation-procedures included by center was . the flow chart of the study is shown in fig. . incidence of extubation failure was . % ( of intubation-procedures). incidence of airway failure, weaning failure and mixed failure were respectively . % ( of ), . % ( of ) and . % ( of ). conclusion extubation failure at h occurred in . % of the extubation procedures recorded, % due to airway failure, % to weaning failure and % to mixed airway and weaning failure. specific risk factors will be determined using this multicenter database. introduction acute on chronic liver failure (aclf) have been recently defined by an acute decompensation of a chronic liver disease associated to organ failure and a high mortality rate. few authors reported on the use of total plasma exchange (tpe) in patients with the current definition of aclf. the aim of this pilot study was to evaluate the efficiency and safety of tpe in critically ill cirrhotic patients admitted with aclf in the icu. patients and methods a prospective cohort of cirrhotic patients admitted to the icu between february and february . tpe was performed using a plasma filter (tpe , hospal ® ) on a cvvhdf machine (prismaflex ® , baxter ® ) connected to the patient with a femoral double lumen f catheter. the plasma volume exchanged per session was . - . of the total plasma volume. ratio and type of fluid replacement were % with % albumin solution followed by % with fresh frozen plasma. clinical and biological parameters, and the following scores meld, sofa, clif-sofa, clif-of and child pugh were evaluated prior, after tpe session and days distant of treatment. results seven male patients with a mean age of . ± . years comprised the study and had a total of tpe sessions. the etiology of cirrhosis was alcoholic (n = ) or post-hcv (n = ). the reasons of aclf were acute alcoholic hepatitis (n = ), variceal bleeding (n = ) and sepsis (n = ). prior to tpe, the mean scores of sofa, clif-sofa, clif-of, meld and child-pugh were respectively . , , . , . and c . . mean total bilirubin prior and after tpe sessions was reduced from . ± . µmol/l to . ± . µmol/l (reduction of . %; p = . e− ); at day , mean total bilirubin was still lower at ± µmol/l (p = . ). mean inr prior and after tpe improved from . ± . to . ± . (reduction of inr of . %, p = . e− ) and at day of treatment at ± . (reduction of %, p = . ). mean ggt levels reduced by . % (p = . ). mean platelet counts ( . ± . g/l) reduced by . % (p = ns). the probability of survival at , and days was . , . and . %. one patient was transplanted and still alive. tolerance during sessions was good similar to cvvhdf. two side effects related to the femoral catheter were observed (bacteremia and hemorrhagic shock post catheter ablation). conclusion this preliminary study of tpe in aclf showed a marked reduction of liver enzymes and improvement in coagulation parameters with a relative good safety. a specific caution should be undertaken regarding catheter related complications. tpe worth to be fig. flow chart of the free-rea study introduction extubation is a key moment for the patient on his way to recovery. extubation failure concerns - % of icu patients and is closely linked to nosocomial pneumonia. the practice concerning enteral feeding interruption at time of extubation has not been investigated. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. however, fasting, as recommended before elective general anesthesia is likely to be ineffective in the setting of extubation in the icu, due to patients' gastroparesis and prolonged gastric stasis. beyond the potentially unnecessary burden in terms of paramedical workload, fasting may have some side effects such as caloric deficit, hypoglycemia, or delayed extubation. given the current lack of objective data concerning the clinical practice of feeding/fasting and gastric tube suctioning before extubation in the icu, we undertook this descriptive study to assess current practice. materials and methods we conducted a retrospective, multicenter study in eleven intensive care units in the west of france over a month timespan. all patients extubated were included and data about enteral feeding during the peri-extubation period as well as extubation failure and nosocomial that pneumonia occured within days were recorded. data observed in the eleven participating centers were completed with a short email survey concerning declarative practice performed among intensive care units. results during the study period, patients were included. overall, patients ( %) failed extubation and needed reintubation within the days following planned extubation. pneumonia was significantly more frequent reintubated patients than the other ( vs. %, p < . ). hundred patients ( %) received enteral feeding at the time of extubation. compared to patients who did not receive enteral feeding, those patients had a higher disease severity (sapsii score , [ ; ] vs. [ ; ], p < . ; longer duration of mechanical ventilation [ ; ] vs. . [ ; ] days, p < . ). accordingly, those patients had a higher rate of extubation failure ( vs. %, p = . ) and pneumonia ( vs. %, p = . ). among the patients receiving enteral feeding, fasting was implemented before extubation for patients ( %). similarly, the incidence of pneumonia was not different between groups (n = ( %) vs. n = ( %), p = . ). after extubation, the fasting patients experienced a longer delay until feeding resumption as compared to non-fasting patients ( h [ ; ] vs. [ ; ] ), but this difference did not reach statistical significance. overall gastric content suctioning before extubation was not commonly performed; before extubation: % of the fasting patients and % of the non fasting patients. among the participating centers, while some centers imposed a fasting period before extubation to all their patients, some did it infrequently. however, no center never imposed fasting, illustrating between and within center heterogeneity. this heterogeneity was confirmed on the larger scale declarative email survey ( % response rate amont units) which showed that only % of the units had a written standardized operational procedure for extubation. survey respondents reported to practice fasting before extubation "always", "frequently" and "never or rarely" in respectively , and % of cases. conclusion both practices, fasting as well as pursued nutrition until extubation are commonly performed in icus, with little standardization of practice. safety seems equivalent, as no clinically significant difference in terms of reintubation rate and pneumonia were observed. thus, the equipoise condition appears met to undertake a trial evaluating feeding strategies in the peri-extubation period. introduction noninvasive ventilation (niv) has become a cornerstone for the supportive therapy of acute respiratory failure (arf). survival benefits in chronic obstructive pulmonary disease (copd) and cardiac patients have been demonstrated. although arf and copd patients are at risk of malnutrition that adversely affects patient outcomes, few data are available regarding the management of nutritional support in non-invasively ventilated patients. we sought to describe nutritional management in patients receiving niv as the first line therapy for arf. secondary objectives were to assess the impact of early nutrition use on the need for invasive mechanical ventilation, occurrence of icuacquired pneumonia, length of stay, and death. patients and methods we conducted an observational study from the multicenter french database fed by french icus. our institutional review board approved this study. adult medical patients admitted to the icu and receiving niv for more than days were included. exclusion criteria were patients admitted after surgery, readmitted in icu, patients with neuromuscular disease and treatment-limitation decisions on admission. four groups of patients were defined according to nutrition received during the first days of niv: ( ) no nutrition; ( ) enteral nutrition: patients who received enteral nutrition with or without parenteral nutrition; ( ) parenteral nutrition only ( ) oral nutrition only. the impact of nutrition on day- mortality was assessed through the use of a cox model adjusted on clinically relevant covariates. the impact of nutrition on other secondary end-point i.e. icu-acquired pneumonia occurrence, need for invasive mechanical ventilation were assessed using a fine & gray models. patients were censored after days of follow-up. choice among collinear variables was performed considering clinical relevance, rate of missing variables and reproducibility of definitions. results were given as hazard ratio (hr) for cox models and subdistribution hazard ratios (shr) and % confidence intervals (ci). the impact on duration of stay was estimated by a multivariate poisson regression. p values less than . were considered as significant. statistical analysis was performed using sas . (cary, nc). results during the study period, , patients were included in the database and met inclusion criteria. among them, received no nutrition; received enteral nutrition, received parenteral nutrition only, and received oral nutrition only. overall, patients developed icu-acquired pneumonia ( %), required invasive mechanical ventilation ( . %) and died before day- ( %). median length of stay was days [ ; ]. after adjustment for confounders, type of nutrition support was associated with an increase day- mortality (p = . ). compared to oral nutrition, enteral nutrition was associated with an increase day- mortality [shr . , % ci . - . ; p = . ] whereas parenteral nutrition and no nutrition did not influence this outcome. the type of nutrition was not associated with the occurrence of icu-acquired pneumonia (p = . ). however, patients who received enteral nutrition experienced more frequently icu-acquired pneumonia [shr = . , % ci . - . ; p = . ] as compared to oral nutrition patients. ventilator free days within the days were negatively associated with the type of nutrition (p < . ). compared to oral nutrition, parenteral and enteral nutrition were negatively associated with ventilator free days within the days [rr per day = . , % ci . - . ; p < . and rr per day = . , % ci . - . ; p < . ]. delta paco measured between the first days was not associated with any type of nutrition. conclusion more than half the patients receiving niv were fasting within the first two niv days. oral nutrition was prescribed for onethird of them and was well tolerated. lack of feeding or underfeeding had no impact on mortality and ventilator free days within the days. however, enteral nutrition was associated with an increased occurrence of icu-aquired pneumonia and a higher mortality rate. was high, caloric debt during temporary ecls was low in comparison with previous results [ ] . overnutrition was frequent in the nec group and would justify implementation of nutrition protocol. incidence of gi intolerance remains frequent and could justify systematic used of motility agents with introduction of en. conclusion enteral nutrition in patients treated with temporary extracorporeal life support is feasible and may be improve with systematic motility agents and implementation of nutritional protocol. introduction cardiac surgery with cardiopulmonary bypass (cpb) is associated with a generalized inflammatory response with concomitant immune paresis which predisposes to the development of postoperative infections and sepsis ( ) . lymphocytes are essential agents of innate and adaptive immune responses during infections or inflammation processes. lymphopenia has been associated with immune dysfunction during septic shock, and it has been shown that low absolute lymphocyte count was predictive of postoperative sepsis ( ) . furthermore, impaired lymphocyte function probably occurs after cpb. thus, we investigated mechanisms involved in postoperative lymphopenia and impaired lymphocyte function after cpb. the aims of this study were: ) to describe a potential relationship between lymphopenia and occurrence of postoperative infections. ) to demonstrate that cpb induces lymphocytes apoptosis. ) to demonstrate that cpb impaired lymphocyte function (ability to proliferate). ) to demonstrate that il- , pd-l (programmed cell death ligand ) and indoleamine , -dioxygenase (ido) could be interesting targets to restore lymphocyte ability to proliferate after cpb. patients and methods blood cell counts with differentials obtained within the first postoperative week were analyzed in patients undergoing cardiac surgery in . postoperative lymphopenia was defined as a lymphocyte count < . × cells l − . postoperative infections were defined following cdc criteria. study procedures: the following analysis were performed before (t ) and h after (t ) cardiac surgery with cpb: lymphocyte apoptosis; t-cell proliferation ability following polyclonal stimulation; hla-dr and pd-l expression on monocytes; plasma ido activity and il- levels; and the ability of lymphocytes to undergo a clonal proliferation when stimulated using specific inhibitors of il- and ido. the study was approved by our local ethics committee. patients were informed of the observational nature of the study and gave their consent. . early lymphopenia after cpb was associated with the occurrence of postoperative infection: postoperative infections occured with a median delay of days. patients who developed postoperative infections had a significantly lower lymphocyte count at day , day and day than patients without postoperative infections. . cpb induced lymphocyte apoptosis and decreased t-cell proliferation ability. . cpb during cardiac surgery decreased mhla-dr expression. . cpb increased ido activity, pd-l expression and il- plasma levels. . il- or pd-l inhibition of inhibition could restore ability of lymphocytes to proliferate, although ido inhibitors did not show any effect. we provided new evidences that cpb induces immunosuppression. we also demonstrated that il- and pd-l could be interesting targets to restore ability of lymphocytes to proliferate. as maintaining mv during cpb decreased plasmatic levels of il- , our study brings new evidences that ventilator strategies could be of interest to decrease postoperative infections. respectively . % (n = ), . % (n = ) and . % (n = ) of the included patients. mortality was of . % in the overall population (n = ) and was higher in neutropenic patients ( . vs. . % in non-neutropenic patients; p < . ). neutropenia was independently associated with poor outcome when adjusted for underlying malignancy, allogeneic stem cell transplantation and severity as assessed by organ support (or . ; % ci . - . ). mortality decreased progressively over time in both non-neutropenic (from to %; p < . ) and in neutropenic patients (from to %; p < . ). when adjusted for confounders, admission during a more recent period was independently associated with favourable outcome and did not change the final model. conclusion this preliminary analysis suggests a meaningful survival in neutropenic critically ill cancer patients despite an independent association between neutropenia and mortality. additional analyses are on-going in order to adjust for study weight, heterogeneity across studies, assess the influence of neutropenia duration or g-csf use, and confirm the influence of neutropenia in a predefined subgroup of patients. introduction candida bloodstream infections (cbi) are frequent and increasing in hospitalized patients, especially in intensive care units. considering the results of some experimental in vitro and animal studies, it seems that yeasts belonging to candida genus are able, so as to survive, to modulate the immune response of the host by guiding t cells polarization to th profile. th and th cytokines are known to be involved in host defense against cbi. however, these data are mainly experimental or collected after candidemia. the aim of this study is to precise kinetic of cytokines network during human cbi. this was an ancillary study of an institutional project dedicated to pathophysiology of candidiasis. we have included patients with candidemia and controls ( matched hospitalized controls and healthy subjects). the sera of cases were gathered before (almost days before), during and after the isolation of yeasts from blood culture, defined as day (d ). quantitative analysis of cytokines by luminex ® technology and of ( , )-β-d-glucans by fungitell ® test were performed on samples. the amplitude of th profile response was expressed by summing the amount of the most relevant cytokines for th , th and th profiles, in pg/ ml. for each patient, the highest level of response was considered as %. results are expressed for the population by means of the results. we then performed univariate analysis (fischer exact test for qualitative variables, mann-whitney and wilcoxon test for quantitative variables, spearman for correlation; graphpad prism v software) and a multidimensional analysis by principal component analysis (pca; igorpro software). results patients with candidemia exhibited an increase in proinflammatory cytokines (ifnγ, tnfα and il- ), in comparison with the anti-inflammatory cytokines (il- and il- ) before d (p = . ) in univariate analysis. the ratio between mean values reverses at d and d (p = . ) and the increase of th response level from d to d is correlated to the decrease of th response (r = − . ; p = . ) in univariate analysis and pca. a pro-inflammatory response (th ) is associated with a reduced mortality (rr = . [ . ; . ]) and with a lower β-d-glucans levels (p < . ). discussion we describe here a dynamic cytokine profiles in response to candidemia. pro-inflammatory response predominates before d and reverses after. this is contradictory to the postulate that an antiinflammatory background could predispose to invasive candidiasis in icu patients and exhibiting a "post-infectious immune suppression conditions". but the relative deficiency in th response compared to simultaneous anti-inflammatory cytokines secretion observed after cbi is in accordance with experimental data, suggesting the modulation of the immune response by candida. the link between cytokinic profile and mortality can also raise the hypothesis of an influence by genetic factors on the regulation and direction of the immune response and so, the existence of a high-risk population. conclusion these data suggest a relation between candida and the orientation of the immune response towards a pattern deleterious for the infected host. this could allow to determine the most relevant cytokines varying during cbi. they could be used as biomarkers to identify the patients who could benefit from an early treatment in a preemptive targeted therapeutic strategy. these data will be paralleled to genetic background and to circulating candida derived molecules to precise the relative part of the host and the pathogen in this complex interaction. introduction lung ultrasound is widely used in intensive care, ermergency and pneumology medicine, for assessing acute respiratory pathologies. it is noninvasive, radiation free and rapidly available at the patient's bedside and provides an excellent accuracy. so, lung ultrasound may be an interesting tool for the physiotherapist as it allows to assess with more accuracy the patient improving the chest physiotherapy indication and monitoring ( ) . as far as we are aware, no study has evaluated the impact of lung ultrasound on clinical-decision making by physiotherapists in the use of chest physiotherapy. this case report highlights the lung ultrasound interest in chest physiotherapy in patient with lung consolidation. patients and methods this was a case report written following the recommendations of the care guideline ( ). the case was a -years-old female patient, non intubated, hospitalized in a respiratory icu. she was hypoxemic (pao = mmhg and sao = %), with dyspnoea at rest and an increasing radiological opacity at the right lung base. hypoxemia was the indication for physiotherapist referral. at the clinical examination, the physiotherapist's findings were: decreased mobility, dullness and abolished vesicular sound at the base of right hemithorax. this clinical examination and chest x-rays analysis allowed the physiotherapist to propose several clinical hypotheses: pleural effusion, obstructive atelectasis or pneumonia. the chest physiotherapy treatment differs according to the type of lung deficiencies. for example, the physiotherapist must to refer the patient to the medical staff in case of pleural effusion or may implement hyperinflation technique in case of obstructive atelectasis. determining the nature of lung deficiencies is essential to provide the more suitable therapeutic strategy. so, the physiotherapist decided to perform a lung ultrasound examination to retain the more likely hypothesis. results ultrasound examination performed by the physiotherapist highlighted the presence of a lung consolidation at the infero-lateral and posterior parts of the right lung with a pneumonia pattern: presence of tissue-like sign, shred sign, dynamic air bronchogram and fluid bronchogram. the medical staff implemented antibiotic treatment. the ultrasound findings guided the physiotherapist to choose chest physiotherapy technique improving the alveolar recruitment: nearly prone position (left side down) and continuous positive airway pressure during min. the patient response to the treatment was monitored by ultrasound and showed a decrease of the lung consolidation size and apparition of b lines, meaning a gain of lung aeration. these findings were associated with spo improvement but without decrease of dyspnoea. discussion lung ultrasound allowed the physiotherapist to precise the nature of the radiological lung opacity. as it is more accurate than clinical examination or chest x-ray, this suggests a more suitable choice of chest physiotherapy techniques than conventional clinical decision-making process. ultrasound findings suggested a positive response to the chest physiotherapy treatment. the apparition of re-aeration signs (b lines, decreased consolidation size) showed a short-term efficacy of the chest physiotherapy treatment. this allowed the physiotherapist to continue the treatment during week and obtain a substantial clinical improvement. conclusion the use of lung ultrasound in the clinical decision-making process may help the physiotherapist to choose with more accuracy the therapeutic strategy. moreover, it allows to monitor the treatment in real-time and assess the patient's response. the use of this tool may allow the physiotherapist to determine the optimal indications for chest physiotherapy and thus avoid unnecessary or inappropriate treatments. introduction critical illness together with immobilization have deleterious effects on patients outcome, especially in the presence of sepsis. increased muscle catabolism and membrane inexcitability reduce muscular mass and impair function within the first days after sepsis onset ( ). early mobilization could potentially limit muscle wasting and functional impairment in this population. the purpose of this study was to test whether exercise during the early phase of sepsis is safe and beneficial and to which extent it can limit skeletal muscle protein catabolism and preserve function. patients and methods adult patients admitted with the diagnosis of severe sepsis were included and randomly allocated to two groups; ) control group (ctrl-g): manual passive/active manual mobilization twice a day or ) experimental group (exp-g): additional two times min of passive/active cycling exercise. both groups benefited from a reduced sedation, adjusted nutritional intake and bed to chair transfer as soon as possible. skeletal muscle biopsy and electrophysiological testing were realized at day- and day- . muscle histology, biochemical and molecular analyses of anabolic/catabolic and inflammatory signalling pathways were performed. a group of four healthy subjects was used to obtain non pathological values. hemodynamic parameters and patients perception were collected during each session. results twenty-one patients were included, however died before the second muscle biopsy. ten patients in ctrl-g and nine in exp-g were finally analysed. muscle fibre cross sectional area (µm ) was significantly preserved by exercise (relative changes were ctrl-g: − ± % vs exp-g: ± %, p = . ). markers of catabolic systems were highly increased during sepsis compared to healthy subjects and reduced in both groups days after admission. however the reduction in mrna (relative change) tended to be more important in exp-g: murf- (ctrl-g: − ± % vs exp-g: − ± %, p = . ), mafbx (ctrl-g: − ± % vs exp-g: − ± %, p = . ), lc b (ctrl-g: ± % vs exp-g: − ± %, p = . ) and bnip (ctrl-g: ± % vs exp-g: − ± %, p = . ). anabolic and inflammatory markers were not affected by exercise. electrophysiological testing, including direct muscular stimulation, was abnormal on day- in of evaluated patients. since only a limited number of patients could be reassessed a second time, comparison between groups was not possible. in general, all activities were well tolerated by patients with no adverse events. the pulmonary auscultation is used by respiratory therapist (rt) to evaluate the efficiency of a treatment. listen to the noises coming from the primary bronchi (pb) is important because it is the place where secretions can be accumulated. therefore, it is crucial to know exactly where to place the stethoscope's chestpiece on the chest. few studies have analyzed the chest area where the pb were located. our hypothesis is that pb are localized on a line that joins axillary fossa (bi-axillary line: bal). the aim of our study is to evaluate the probability to find the primary bronchi by analysis of chest radiography. patients and methods a retrospective study was performed by analysis of chest x-ray using the software: tm reception ® , which allows precise measures to the tenth of millimeter. all the x-rays were made on confined to bed patients hospitalized within intensive care unit, internal medicine and abdominal surgery rooms. the following measures (in mm) were made between: the exclusion criteria were: bmi < . kg/m and bmi > kg/m , scoliosis, minor patient, lack of visibility of one of the axillary fossa, lack of visibility of pb, clavicular asymmetry, kyphosis, lack of symmetry in the shot, atelectasis and pneumothorax. statistics: normality test: ks. mean values are expressed with their sd and % ci. discussion in this study, we performed analysis of chest x-rays of bedridden patients and we demonstrated that it is possible to localize easily, on either side of the bs, the right and left pb at ± mm distance (lp) above a line joining axillary fossa. this study constitutes a new tool for the rt who, by using stethoscope with a chestpiece of cm surface area, will be able to listen to noise coming from pb. conclusion the data presented herein (fig. ) show that right and left pb are located at a mean distance of (± ) mm and (± ) mm above the bal, on both sides of the bs. the bal represents thus an easy and precise mode to detect right and left pb by bedridden. finally, the distance between the hyoid bone and the sc is about cm. as the pb are located after the bifurcation, this information constitutes another useful way for the localization the right and left pb by bedridden patient. introduction critically ill patients frequently develop muscle weakness, which is associated with prolonged intensive care unit and hospital stay ( ). this randomized controlled trial (clinical trials nct ) was designed to investigate whether a daily training session using a tilt table, started early in stable critically ill patients with an expected prolonged icu stay, could improve strength at icu and hospital discharge compared to a standard physiotherapy program. the study protocol was approved by an ethics committee and informed consent was obtained from all patients. patients admitted in adult icu of marie lannelongue hospital, france, who were mechanically ventilated for at least days were included. exclusion criteria were cerebral or spinal injury, pelvic or lower limb fracture. patients were assessed each day for temporary contraindications for mobilization out of bed (rass score <− or > ; hemodynamic instability; a continuous intravenous dose of epinephrine/ . no significant difference was observed in terms of mrc score or in terms of pts with or without weakness (mrc > ) at icu or hospital discharge. however, the number of pts with weakness was significantly higher in the group before tilt mobilization, suggesting a more rapid improvement in the tilt group. the icu and hospital lengths of stay were not different between groups. discussion the prevalence of muscle weakness in our population is high before mobilization ( . %, % ci . - . ), is still . % at icu discharge but represents only ~ % at hospital discharge. this low hospital discharge prevalence is probably related to the early and intense physiotherapy in both groups, which may explain our inability to demonstrate superiority of the addition of tilt table positioning, although a faster recovery is suggested. conclusion training sessions using a tilt table, in addition to early and intense physiotherapy did not improve muscle strength evaluated using mrc score in surgical icu patients with muscle weakness. proposed modifications to the duke criteria for the diagnosis of infective endocarditis quantifying the relationship between staphylococcus aureus bacteremia and s. aureus bacteriuria: a retrospective analysis in a tertiary care hospital recommandations formalisées d'experts «prise en charge des infections intra-abdominales strategies to reduce curative antibiotic therapy in intensive care units (adult and paediatric) risk factors for developing esbl e. coli: can clinicians predict infection in patients with prior colonization? kdigo clinical practice guideline for acute kidney injury citrate anticoagulation for continuous venovenous hemofiltration benefits and risks of furosemide in acute kidney injury national nosocomial infections surveillance (nnis) system report, data summary from prospective evaluation of the risk factors, etiology and the antimicrobial susceptibilities of the isolates in nosocomial bacteriemic patients unrecognized endobronchial intubation of emergency patients endobronchial intubation detected by insertion depth of endotracheal tube, bilateral auscultation, or observation of chest movements: randomised trial nosocomial infections in a burn intensive care unit outcomes of critically ill cancer patients in a university hospital setting outcome and prognostic factors of lung cancer patients admitted to the medical intensive care unit intensive care of the cancer patient: recent achievements and remaining challenges chronic critical illness the epidemiology of chronic critical illness in the united states designing and conducting a cluster-randomized trial of icu admission for the elderly patients: the ice-cub study estimation de la mortalité maternelle en france: une nouvelle méthode emergency postpartum hys-terectomy for uncontrolled postpartum bleeding music interventions for mechanically ventilated patients effets de la musicothérapie en réanimation hors sédation chez des patients en cours de sevrage ventilatoire versus des patients non ventilés. annales françaises d' anesthésie et de réanimation evaluation of a low-flow oxygen-conserving nasal cannula performance of six types of oxygen delivery devices at varying respiratory rates high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure international study of the prevalence and outcomes of infection in intensive care units medical intensive care urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature diagnostic strategies for renal impairment in the intensive care unit recommendations formalized expert acute renal failure in the perioperative and intensive care (excluding extrarenal purification techniques) frutos-vivar f. comparison of the berlin definition for acute respiratory distress syndrome with autopsy the presence of diffuse alveolar damage on open lung biopsy is associated with mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury references . akoumianaki e. mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling neuromuscular blockers in early acute respiratory distress syndrome driving pressure and survival in the acute respiratory distress syndrome mortality and pulmonary mechanics in relation to respiratory system and transpulmonary driving pressures in ards organ donation, reasons for family refusal: a retrospective study in a french organ harvesting center - du avril relative aux droits des malades et à la fin de vie comité consultatif national d'ethique c. fin de vie, autonomie de la personne, volonté de mourir reliability, validity, and health issues arising from questionnaires used to measure psychosocial and organizational work factors (powfs) among hospital nurses: a critical review aging and death signalling in mature red cells: from basic science to transfusion practice most reliable indices in differentiation between thalassemia trait and iron deficiency anemia stratification du risque dans l'embolie pulmonaire aiguë.realites cardiologiques • n° -cahier • septembre european resuscitation council guidelines for resuscitation : section . executive summary breakthrough in cardiac arrest: reports from the th paris international conference changing use of noninvasive ventilation in critically ill patients: trends over years in francophone countries noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume réanimation médicale polyvalente, hôpital de la source early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: a prospective, multiple-center study profound and persistent decrease of circulating dendritic cells is associated with icu-acquired infection in patients with septic shock intensive care med specific mait cell behaviour among innate-like t lymphocytes in critically ill patients with severe infections a -level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin prognostic value of relative adrenal insufficiency during cardiogenic shock: a prospective cohort study with long-term follow-up. shock calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase signaling hypocalcemia in critically ill patients diabetic ketoacidosis traps joint british diabetes societies guideline for the management of diabetic ketoacidosis peter radermacher , for the hyper s investigators and reva research network réanimation médicale, hôpital henri mondor réanimation medico-chirurgicale, hopital avicenne institut für anästhesiologische pathophysiologie und verfahrensentwicklung département de réanimation médicale et de médecine hyperbare, c.h.u. d' angers, angers, france; service de réanimation médico-chirurgicale réanimation médico-chirurgicale, assistance publique -hôpitaux de paris, hôpital ambroise paré, boulogne-billancourt, france; service de réanimation adulte quantitative measurement of heparin in comparison with conventional anticoagulation monitoring and the risk of thrombotic events in adults on extracorporeal membrane oxygenation elso guidelines for cardiopulmonary extracorporeal life support, version . . ann arbor: extracorporeal life support organization early and late outcomes of consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock the french sf- health survey: translation, cultural adaptation and preliminary psychometric evaluation weaning of extracorporeal membrane oxygenation using continuous hemodynamic transesophageal echocardiography predictors of successful extracorporeal membrane oxygenation weaning after assistance for refractory cardiogenic shock extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion back from irreversibility: extracorporeal life support for prolonged cardiac arrest microcirculatory perfusion is preserved during off-pump but not on-pump cardiac surgery extracorporeal membrane oxygenation causes loss of intestinal epithelial barrier in the newborn piglet the pulsatile perfusion debate in cardiac surgery: answers from the microcirculation? a meta-analysis of complications and mortality of extracorporeal membrane oxygenation impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation cumulative fluid balance and mortality in septic patients with or without acute kidney injury and chronic kidney disease comparison of two fluid-management strategies in acute lung injury renal function and survival in patients undergoing ecmo therapy extracorporeal membrane oxygenation and the kidney plasma concentrations of inflammatory cytokines rise rapidly during ecmo-related sirs due to the release of preformed stores in the intestine in-hospital mortality and successful weaning from venoarterial extracorporeal membrane oxygenation: analysis of patients using a national inpatient database in japan is the . % rate of in-hospital mortality in patients receiving venoarterial extracorporeal membrane oxygenation really that high? predicting survival after ecmo for refractory cardiogenic shock: the survival after veno-arterial-ecmo (save)-score outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock usefulness of cardiac biomarkers to predict cardiac recovery in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock etiology of troponin elevation in critically ill patients esc guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (esc) accf/aha guideline for the management of heart failure: a report of the american college of cardiology foundation/american heart association task force on practice guidelines nearhanging injuries: a -year experience unité de réanimation neurologique s rapid diagnosis of bacterial meningitis using a point-of-care glucometer geoffroy rousseau service d'information médicale, epidémiologie et economie de la santé guillain-barré syndrome outbreak associated with zika virus infection in french polynesia: a case-control study early predictors of mechanical ventilation in guillain-barré syndrome paediatric prolonged mechanical ventilation: considerations for definitional criteria cardiac filling volumes versus pressures for predicting fluid responsiveness after cardiovascular surgery: the role of systolic cardiac function respiratory variation in aortic blood flow peak velocity to predict fluid responsiveness in mechanically ventilated children: a systematic review and meta-analysis. pediatr anesth effect of prone and supine positions on functional residual capacity, oxygenation, and respiratory mechanics in ventilated infants and children positioning effects on lung function and breathing pattern in premature newborns l'accident vasculaire ischémique en pédiatrie. quand y penser -quoi faire outcomes of early decompressive craniectomy versus conventional medical management after severe traumatic brain injury: a systematic review and meta-analysis myocardial dysfunction evaluation in pediatric brain death donor service de régulation et d'appui, agence biomedecine prone position for acute respiratory failure in adults prone positioning in severe acute respiratory distress syndrome effects of the prone position on respiratory mechanics and gas exchange during acute lung injury does prone positioning increase intracranial pressure? a retrospective analysis of patients with acute brain injury and acute respiratory failure prone position in mechanically ventilated patients with reduced intracranial compliance maud loiselle -maud.loiselle@outlook.fr annals of intensive care boulogne-billancourt, france; réanimation polyvalente adulte, centre hospitalier intercommunal andré grégoire, montreuil, france; réanimation médicale an audit of intensive care unit recyclable waste s point of care ultrasonography: is there a place for pocket size ultrasonography devices? gabriel preda , vincent dubée , naïke bigé eric maury -ejhmaury@gmail.com annals of intensive care outcome, functional autonomy, and quality of life of elderly patients with a long-term intensive care unit stay berlin: springler; . s icu nurses' perception of end-of-life decision making: a french multicenter survey akli chermak , alexandre lautrette ap-hp) anesthésie réanimation et traitement chirurgical des grands brûlés réanimation médicale hôpital d'instruction des armées percy correspondence: fanny.ardisson@gmail.com (fanny ardisson) annals of intensive care circulating mitochondrial damps cause inflammatory responses to injury rage is a nucleic acid receptor that promotes inflammatory responses to dna beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome stard : an updated list of essential items for reporting diagnostic accuracy studies towards complete and accurate reporting of studies of diagnostic accuracy: the stard initiative s neurological impairment in cirrhotic patients admitted to icu: hepatic versus drug-induced encephalopathy unité de soins intensifs d'hépatogastroentérologie réanimation polyvalente, hôpital de mercy, ars laquenexy, france; réanimation médicale, centre hospitalier universitaire d' angers, angers, france; réanimation médicale cerebrospinal fluid findings after epileptic seizures effect of epileptic seizures on the cerebrospinal fluid-a systematic retrospective analysis s synek score and nse to predict poor neurological outcome after cerebral anoxia and therapeutic hypothermia réanimation médicale correspondence: dimitri titeca beauport -titeca.dimitri@chu-amiens.fr annals of intensive care guidelines for the management of severe traumatic brain injury. vi. indications for intracranial pressure monitoring reduced mortality rate in patients with severe traumatic brain injury treated with brain tissue oxygen monitoring s organ procurement and kidney transplantation under maastricht condition (m ): update on year of activity coordination prélèvements organes s reference . conditions à respecter pour réaliser des prélèvements d'organes sur les donneurs décédés après arrêt circulatoire de la catégorie iii de maastricht dans un établissement de santé. agence de la biomédecine. version n° mai crcl by cockroft-gault, mean (ml/mn delayed graft function, n (%) ( . %) réanimation médico-chirurgicale infectious diseases society of america. guidelines for the management of adults with hospital acquired, ventilator-associated, and healthcare-associated pneumonia reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle chiche@aphp.fr annals of intensive care national nosocomial infections surveillance system. national nosocomial infections surveillance (nnis) system report, data summary from critères d'infection chez les brulés unité d'épidémiologie et recherche clinique international study of the prevalence and outcomes of infection in intensive care units risk and prognostic factors of ventilator-associated pneumonia in trauma patients ventilator-associated pneumonia: never enough, never give up! sahar habacha , bassem chatbri , aymen m'rad , youssef blel , nozha brahmi sahar habacha -sahar.habacha@gmail.com annals of intensive care weaning patients from the ventilator automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis unité de réanimation et de surveillance continue, service de pneumologie et réanimation médicale noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial risk factors for extubation failure in patients following a successful spontaneous breathing trial s a multicenter prospective observational study of extubation procedures in intensive care units: the free-rea study audrey de jong -audreydejong@hotmail.fr annals of intensive care early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study faouzi saliba -faouzi.saliba@pbr.aphp.fr annals of intensive care réanimation médicale polyvalente, hôpital de la source mickael landais -mickaelandais@gmail.com annals of intensive care perioperative fasting in adults and children: guidelines from the european society of anaesthesiology the decision to extubate in the intensive care unit service de réanimation médicale s refeeding hypophosphoremia in a medical critical care unit: -month observational study gioia gastaldi -gioia.gastaldi@chu-rouen.fr annals of intensive care refeeding hypophosphatemia in critically ill patients in an intensive care unit. a prospective study refeeding syndrome: problems with definition and management biosit and inserm u , faculte de medecine, université rennes immune dysfunction after cardiac surgery with cardiopulmonary bypass: beneficial effects of maintaining mechanical ventilation s influence of neutropenia on mortality of critically ill cancer patients: results of a systematic review on individual data quentin georges brazil; department of critical care medicine and division of pulmonary and critical care medicine united kingdom; department of intensive care centre d'infection et d'immunité de lille equipe -basic and clinical immunity of parasitic di delta nlr") were calculated. statistical analysis used appropriate non parametric tests and cox regression for survival analysis. the ability of the variables to discriminate survivors from non-survivors was determined using roc curves results during the study period, cirrhotic patients were admitted in icu. the etiologies of liver cirrhosis were alcoholic in % of cases with severe score: median child-pugh score = %) deaths after icu discharge during the same hospitalization. nlr decreased for survivors between d and d univariate analysis, for predicting survival, higher values of nlrd , delta nlr, meld score at admission, sofa score at admission and at day and delta sofad -d were significant factors. predictors of death in multivariate analysis are shown in fig. . area under delta nlr roc conclusion the blood nlr is a novel inflammation index that has been shown to independently predict poor clinical outcomes. we have demonstrated that delta nlr is an independent predictor of mortality in critically ill cirrhotic patients the association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study gene-and exon-expression profiling reveals an extensive lps-induced response in immune cells in patients with cirrhosis celine dupre -duprecece@gmail.com annals of intensive care diagnostic accuracy of procalcitonin in critically ill immunocompromised patients the role of pattern-recognition receptors in innate immunity: update on toll-like receptors esm- is a novel human endothelial cell specific molecule expressed in lung and regulated by cytokines thoracic ultrasound: potential new tool for physiotherapists in respiratory management. a narrative review the care guidelines: consensus-based clinical case reporting guideline development department of physical medicine and rehabilitation icu-acquired weakness and recovery from critical illness o where should we place the stethoscope's chestpiece to hear the noise of the primary bronchi? frédéric duprez , bastien dupuis , grégory cuvelier , thierry bonus frédéric duprez -dtamedical@hotmail.com annals of intensive care o aerosol delivery using two nebulizers through high flow nasal cannula: a randomized cross-over spect-ct study correspondence: jonathan dugernier -jonathan.dugernier@uclouvain.be annals of intensive care introduction in , an international consensus conference took stock of the various measures to be implemented for the prevention of ventilator acquired pneumonia (vap) [ ]. these measures are often gathered in groups of or under the term of "ventilator-bundle. " the effectiveness of these "bundles" was poorly evaluated in african environment. objective to establish a vap prevention program and assess its impact on morbidity and mortality of patients under mechanical ventilation in our service. patients and methods prospective, mono centric, quasi-experimental before-after study. it took place in the intensive care unit of the university clinics of kinshasa in the democratic republic of congo (drc). this service is equipped with beds and a respirator for two beds. the observational period (phase ) was carried out from february st to december st, and the intervention period (phase ) from february st, to february st, . all consecutive patients intubated and mechanically ventilated for more than h were included. five preventive measures were held: hand hygiene, the elevation of the head of the bed at °- °, the daily lifting of sedation, oral decontamination with chlorhexidine and control cuff pressure of the endotracheal tube. compliance with this bundle was assessed by direct observation without the knowledge of caregivers. the diagnosis of "vap" was held before a clinically modified sore (m cpis) > . the main outcomes were the incidence of vap and mortality. the protocol for this study was approved by the ethics committee of the school of public health of the university of kinshasa, under the approval number: esp/ec/ / .introduction nosocomial infections (ni) are common in burn patients due to the loss of the first line of defense against microbial invasion, immunocompromising effects of burn injury, and invasive diagnostic and therapeutic procedures. the objective of this study was to identify the incidence of nosocomial infection (ni), the pathogens and their antibacterial patterns, and prognosis of these burn patients. patients and methods a retrospective study was conducted in a bed intensive burn care unit during months. patients were eligible for the study, if they met the following criteria: total burn surface area (tbsa) > %, length of icu stay ≥ h, and infected in accordance with the criteria of the national nosocomial infections surveillance (nnis) and the criteria of the sfetb [ ][ ]. in this study, nis were classified into four main groups: pneumonias, bloodstream infections (bsi), catheter related infections (cri), and urinary tract infections (uti). for included patients, skin levy, blood cultures, urine and sputum cultures were drawn during fever or clinical features of sepsis. results during the -month study period, patients were admitted to the icu, patients were included ( . %). were male and female. the mean age was ± yr. the mean tbsa was ± %. % were admitted from another hospital. burn injuries were due to domestic accidents in % and self immolation in %. the mean none. none. none. none. none. none. none. none. none. none. ann. intensive care , (suppl ): none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. consulting activities with fisher & paykel. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. failure extubation in intensive care unit: risk factors, incidence and evaluation of a mechanical ventilator weaning protocol lucie petitdemange , anne sophie guilbert none. none. none. none. none. none. opportunistic infections in patients with solid tumors: a systematic review julien poujade , elie azoulay none. invasive aspergillosis in non-immunocompromised patients hospitalized intensive care unit guillaume trumpff , max guillot , thierry braun , ralf janssen-langenstein , marie-line harlay , jean-etienne herbrecht introduction characteristics and outcomes of adult patients with invasive aspergillosis in intensive care unit have rarely been described. we performed a retrospective study on consecutive adult patients with invasive aspergillosis who were admitted form january through january to the intensive none. noorah zaid , nawel ait-ammar , christine bonnal , jean-claude merle , francoise botterel , eric levesque anesthesia and intensive care medicine, chu henri mondor, créteil, france; unité de parasitologie-mycologie, département de virologie, bactériologie-hygiène, parasitologie, hopital henri mondor, créteil, france correspondence: eric levesque -eric.levesque@aphp.fr annals of intensive care , (suppl ):s introduction liver transplant recipients have high rate of invasive fungal disease (ifd) with high morbidity and mortality, in part due to its delayed diagnosis. the fungal cell wall component ( , )-betad-glucan (bg) is a biomarker for fungal infection but its utility remains uncertain. this prospective study was designed to review our experience in ifd and to evaluate the impact of bg in the diagnosis of ifd. patients and methods from january to may , liver transplantation were performed in our institution. serum samples were tested for bg (fungitell; cape cod inc., usa) least weekly between liver transplantation and their discharge from hospital. ifd was defined as proposed by the european organization for research and treatment of cancer/mycoses study group. results nineteen patients ( %) were diagnosed with ifd including cases of candidiasis infection (ci) in eleven out of patients, invasive pulmonary aspergillosis (including one who had previously ci) and one case of septic arthritis of the hip caused by scedosporium spp. ifd was associated with significantly high mortality (log-rank p = . ). the area under the roc curves, for bg to predict ifd, was . ( % ci . - . ). using a cutoff of pg/ml, the most discriminative cut-off point from the roc curve, the sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) values of bg for overall ifd was % ( % ci, - ), % ( % ci, - ), % ( % ci, - ) and % ( % ci, - ). conclusion based on its high npv, bg value appears to be a good biomarker to rule out the diagnosis of ifd when the value is below pg/ml. a single point bg may guide the investigation and the decision to start antifungal therapy in patients at risk for ifd. none. monitoring of changes in lung and chest wall mechanics in the supine, lateral and prone positions during the prone positioning maneuver in ards patients zakaria riad , mehdi mezidi , hodane yonis , mylène aublanc, , sophie perinel-ragey, , floriane lissonde , aurore louf-durier, , romain tapponnier , jean-christophe richard , bruno louis, , claude guérin , plug working group réanimation médicale, hôpital de la croix-rousse, lyon, france; inserm, u , equipe , équipe biomécanique cellulaire et respiratoire, université paris-est créteil -faculté de médecine, créteil, france correspondence: zakaria riad -zakaria.riad@icloud.com annals of intensive care , (suppl ):s none. introduction systemic rheumatic diseases (srd) are autoimmune diseases that are rare but cause substantial morbidity and mortality. srds chiefly affect the lungs, however, data on critically ill patients with srd admitted for arf are scarce. patients and methods retrospective cohort conducted in french icus ( . the major comorbidities were cardiovascular ( %), tobacco exposure ( %), chronic kidney disease ( %) and neoplasia ( %). two-thirds of patients were on systemic corticosteroids at admission, the median dose of (iqr) mg per day. srd diagnosis was made in the icu in . % of patients. clinically or microbiologically documented bacterial pneumonia was the leading arf etiology ( . %). in % of cases, arf was related to an opportunistic infection (mainly aspergillus (n = ) and pneumocystis (n = )). others arf etiologies included specific lung involvement ( . %) and cardiac pulmonary edema ( . %). sofa on day one was [ ] [ ] [ ] [ ] [ ] [ ] [ ] . associated organ dysfunctions were mainly hemodynamic ( %) and renal ( %). mechanical ventilation was needed in % of patients (non invasive only in . % or invasive in . %), % needed vasopressors, and % renal replacement therapy. systemic corticosteroids were started in % of patients and % of patients received pulse steroids. cyclophosphamide and plasma exchange were required in and % of patients, respectively. length of icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. icu-acquired infection occurs in % of cases. in total, patients ( . %) died throughout the icu stay. arf etiology was not associated with mortality. by multivariate analysis, shock on admission (or . [ . - . ], p < . ) and the use of invasive mechanical ventilation (or . [ . - . ], p = . ) were independently associated with mortality, whereas non-invasive ventilation was associated with decreased mortality (or . [ . - . ], p = . ). by considering among the connective tissue diseases, the groups of myositis and scleroderma (n = ), these diseases were associated with a trend for a higher mortality (or . [ . - . ], p = . ). conclusion in patients with srd, arf is associated with a high case fatality, primarily when mechanical ventilation is needed. particular attention must be given to specific srd-sub groups for which pulmonary flare may require intensive immunosuppression. none. none. none. severe acute pancreatitis in icu: management and outcomes of infected pancreatic necrosis charlotte garret , matthieu peron , emmanuel coron , cédric bretonnière , jean reignier , christophe guitton réanimation médicale, chu hôtel-dieu nantes, nantes, france; the acute pancreatitis appears as a pathology that we can define with difficulty because of its clinical presentation or prognosis. patients and methods in our study, we analysed cases of acute necrotic and hemorrhagic acute pancreatitis, hospitalized at the department of resuscitation of the surgical emergencies (p ) of the uhc ibn rochd casablanca during the period ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the purpose of this study is to do a descriptive analysis of the epidemiologic, clinic, radiological, therapeutic and evolutive data of the acute necrotic pancreatitits, we included in our study patients with epidemiologic, clinic, radiologic, biologic criteria of acute necrotic pancreatitits diagnosis whatever is the biliary or alcoholic etiology. the valuation gravity of the pancreatitis has been based on:• ranson bioclinical score > /apache ii > ; • visceral failure.• spreading of the necrosis. the analysis of the results shows that: about the epidemiologic aspect: mean age ( year old), the biliary etiology predominates ( %). about the clinical aspect: pain ( %) vomiting ( %), stop of the transit ( %), the visceral distresses are: the shock ( %), respiratory distress ( %), and neurological distress ( %). about the radiological aspect: pleural effusion ( %), abdominal echography: vesicular lithiasis ( %), dilated principal biliary duct ( %), abdominal computerized tomography: stage e ( %). about the biological aspect: hyperglycemia ( %), hyper-amylasemia ( %). the indexes of gravity that have been appreciated in this study are: ranson score > ( %), imrie score > ( %), igs score ≥ ( %), osf score ≥ ( %). the treatment of the anhp has been symptomatic in particular and the evolution has been characterized by mortality about %, the cause was particularly infectious. the prognostic factors predetermined in this study are:• female type (p = . ).• hemodynamic distress (p = . ).• respiratory distress (p = . ).• scores of gravity:• ranson > (p = . ).• imrie > (p = . ).• osf ≥ (p = ).• infection (p = . ).• duration of the hospitalization (p = . ).• rate of c-reagent protein (p = . ). in conclusion, the mortality is still high in the anhp, considerable effort of search is necessary to prevent the infectious complications of mortality. none. predicting -day mortality following liver transplantation in patients with acute-on-chronic liver failure: a decision-tree model from the french national liver transplantation system, the optimatch study, - none. none. none. none. none. none. the french law and recent expert opinions have emphasized the need for a multidisciplinary approach in decisions to forgo life sustaining therapies for the critically ill. we sought to assess how icu nurses actually rank their involvement and perceive this process. materials and methods we conducted a cross sectional survey using a web-based questionnaire between june and september . results of the icus invited to participate, ( %) agreed. a total of icu participants completed the survey of whom % were nurses and % assistant nurses. median age was (inter quartile range - ) years and % were female. median work experience was ( - ) years and time in the icu was ( - ) years. eighty-five percent of the participants have been involved at least once in a multidisciplinary end-of-life discussion. less than half of the participants reported a good ( %) or partial ( %) knowledge of the current end-of-life legal framework. the decision to start a discussion about withdraw life-sustaining therapy (wlst) was initiated by a senior intensivist in % of the cases, by a nurse in % and an assistant nurse in . %. this decision was approved by % of the participants. the decision-making process was considered to be initiated at the right time for % of the participants, too late for %, and too early for %. the discussion occurred mostly in the afternoon ( %) or during the medical staff ( %), in a dedicated place in % of the cases. a median of ( - ) health-care professionals attended the wlst discussion. half the respondents reported being reluctant to talk during the discussions and % never expressed their own opinion. indeed, although the length of the discussion was ( - ) minutes, participants estimated to talk during only ( - ) minutes. the following reasons were mentioned by the participants to explain these facts: having cared for the patient for too short time ( %), lack of medical knowledge ( %), decision of wlst already taken by the medical staff ( %), their opinion not really taken into account ( %), reluctant to talk during meetings in general ( %), consider that the discussion is limited to a medical expertise ( %), limited professional experience ( %), and fear to express a different opinion ( %). nevertheless, % of the participants were partially ( %) or totally ( %) satisfied by the way the decision making process was conducted, % considered that collegiality was applied, and % agreed with the final decisions.conclusion icu nurses rank favorably multidisciplinary wlst discussions. nevertheless their involvement in the discussion remains limited. beyond factors related to work organization and professional experience, efforts should be made to recognize their role and value, and to encourage them to share their own opinions with the other members of the icu team. none. determinants and prognosis of elevation of high-sensitivity cardiac troponin t in patients hospitalized with vasodilatatory shock marie caujolle , jérôme allyn , dorothée valance , caroline brulliard , none. free plasmatic mitochondrial dna-receptor for advanced glycation end-products: a new signaling pathway of critical illness-induced endothelial dysfunction arthur durand , rémi nevière , florian delguste , eric boulanger, none. quality of reporting of fluid responsiveness evaluation studies: a five year systematic review izaute guillame , matthias jacquet-lagrèze , jean-luc fellahi none. none. none. none. none. introduction microaspiration of gastric and oropharyngeal contaminated secretions occurs frequently in intubated critically-ill patients, and plays a major role in the pathogenesis of ventilator-associated pneumonia (vap). at basic state, patients with chronic obstructive pulmonary disease (copd) have an increased risk of microaspiration (due to gastro-esophageal reflux disease, pharyngo-laryngeal dys-function…), this risk may even be more important under mechanical ventilation. the main purpose of this study is to determine if copd is a risk factor for global abundant microaspiration (gam) in intubated critically-ill patients. we gathered data about two prospective multicentric randomized trials focused on microaspiration in intubated patients. data about copd were retrospectively collected in order to complete previous data. microaspiration of gastric and oropharyngeal secretions was respectively determined by quantitative measurements of pepsin and salivary amylase in all tracheal aspirates during the first h after intubation. gam was defined as the presence at significant level of pepsin (> ng/ml) and/or salivary amylase (> ui/l) in at least % of the tracheal aspirates. in order to find gam independent risk factors, we realized an univariate and multivariate analysis of the variables collected. results out of patients included in the studies, were analyzed among which patients with copd. patients ( %) had gam. neither copd diagnosis, nor spirometric severity nor specific therapeutics were associated with gam. risk factors for gam in univariate analysis were the age, diabetes, low score in glasgow coma scale (gcs), and no recourse to paralytic agents or vasopressors. after none. none. implementation and impact assessment of a "ventilator-bundle" at the university clinics of kinshasa: before and after study josé mavinga , joseph nsiala makunza , m e mafuta , yves yanga , amisi eric , jp ilunga , ma kilembe none. none. amel mokline , achraf laajili , helmi amri , imene rahmani , nidhal mensi , lazheri gharsallah , sofiene tlaili , bahija gasri , rym hammouda , amen allah messadi burn care department, trauma and burn center, tunis, tunisia correspondence: amel mokline -dr.amelmokline@gmail.com annals of intensive care , (suppl ):s none. none. none. introduction mechanical ventilation (mv) weaning is a crucial step in critically ill patients. mv duration is associated with an increased risk of ventilator associated events, even though its specific impact on mortality has never been clearly demonstrated ( ). automated closed loop systems might help the weaning process. a recently published meta-analysis has reported a reduction in mv duration when using an automated weaning mode as compared to non-automated mode ( ) . however, the different automated modes have not been compared to each other. the objective of this network meta-analysis was to compare the performance of the three major automated weaning modes, i.e. the automode°, the smartcare° and the adaptative support ventilation (asv°) for mv weaning in critically ill and postoperative adult patients. we included all randomised control trials that compared automated closed loop weaning applications either to another automated application or standard care, including weaning according to a written weaning protocol or nurse driven protocols. the three modes of automated modes included in the study were asv°, smartcare° and automode°. the primary outcome was the duration of mv weaning, defined as the time between randomization and a successful extubation. we also planned subgroup analyses in the icu and the post-operative populations. the quality of the studies was assessed independently by two blinded investigators, using the evaluation recommended by the cochrane collaboration. a network bayesian meta-analysis using random effect models and based on aggregate data from the included studies was performed using the gemtc package (r project, vienna). this trial was declared in pros-pero in august (crd ). results search of databased identified articles; were screened for eligibility after removal of duplicates. abstract analysis led to the exclusion of articles with a final full text analysis of randomised control trials. ultimately, trials were included in the analysis, representing ventilated patients. nine studies included patients in the post-operative period while six were conducted in icu. the automated mode was asv° (a) in studies, smartcare° (c) in studies and auto-mode° (b) in studies. all studies reported the duration of mv weaning as defined in our protocol. in all studies, the control group was standard care with a weaning process driven either by nurses or physicians. in studies ( %) a written weaning protocol was used in the control group. all icu studies used sedation protocols based on sedation scores, none of them including systematic daily sedation interruption. each one of the automated application was associated with a significant reduction in the duration of mv as compared to the control. when comparing all different modes using the network meta-analysis framework, asv° appeared to be the best automated mode when it pertains to reducing the duration of mechanical ventilation weaning (fig. ) . subgroup analysis showed similar results in the post-operative and the icu populations. conclusion compared to standard weaning practice, the major automated weaning modes significantly reduced the duration of mv weaning in critically ill and post-operative adult patients. asv° was associated with the most significant effect when compared to the two other automated modes (smartcare°, automode°). further physiological respiratory studies would help to understand the underlying mechanisms accounting for the superiority of asv. none. none. introduction in intensive care unit (icu) patients, diaphragm dysfunction is associated with adverse clinical outcomes. ultrasound measurements of diaphragm thickness (tdi), excursion (exdi) and thickening fraction (tfdi) have been proposed as estimators of diaphragm function, but have never been compared to phrenic nerve stimulation. our aim was to describe the relationship between tdi, exdi, tfdi and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (ptr,stim), and to compare their prognostic value. patients and methods ptr,stim and ultrasound variables were measured in mechanically ventilated (mv) patients < h after intubation ("initiation of mv", under assist-control ventilation, acv) and at the time of switch to pressure-support ventilation ("switch to psv"). diaphragm dysfunction was defined as ptr,stim < cmh o. results patients were included. at initiation of mv, ptr,stim was not correlated to tdi (rho = − · , p = · ), exdi (rho = · , p = · ) or tfdi (rho = − · , p = · ). at switch to psv, tfdi and exdi were correlated to ptr,stim, (rho = · , p < . and · , p = · , respectively), but tdi was not (rho = − · , p = · ). at switch to psv, a tfdi < % could reliably identify diaphragm dysfunction (sensitivity and specificity of and %, respectively), but tdi and exdi could not. this value was associated with increased duration of icu stay and mv, and mortality. conclusion under acv, neither tdi, exdi nor tfdi were related to ptr,stim. under psv, tfdi was strongly correlated to diaphragm strength and, when decreased, was associated with poorer outcome. alexandre demoule has signed research contracts with covidien, maquet and philips; he has also received personal fees from covidien and msd. none. none. none. management of enteral feeding during extubation in the intensive care unit: a multi-center retrospective study in french intensive care units mickael landais , noemie hubert , mai-anh nay , johann auchabie , bruno giraudeau , reignier jean , arnaud w thille , stephan ehrmann none. none. nutritional support in patients receiving temporary extracorporeal life support: a retrospective cohort study arthur bailly , laurent brisard , philippe bizouarn , thierry lepoivre , johanna nicolet , jean christophe rigal , jean christian roussel , bertrand rozec réanimation ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france; chirurgie ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france correspondence: laurent brisard -laurent.brisard@chu-nantes.fr annals of intensive care , (suppl ):s introduction the optimal nutritional intake in patients receiving temporary extracorporeal life support (ecls), including extracorporeal membrane oxygenation (ecmo) venovenous (vv) or venoarterial (va), remains controversial. enteral nutrition (en) is suspect to increase risk of gastrointestinal (gi) intolerance and intestinal ischemia. so, total parenteral nutrition (tpn) is often preferred. the purpose of this study is to describe the nutrition practices for critically ill patients receiving ecls and identify opportunities for improving nutrition therapy in this population. patients and methods retrospective analysis of patients requiring ecmo-va or ecmo-vv between and in the cardiac surgery intensive care unit of the university hospital of nantes. nutritional support was daily monitored with parenteral intake (glucose, lipid and propofol, protein and albumin, parenteral nutrition) and enteral nutrition until ecls weaning. two groups were compared during ecls period: no enteral nutrition delivered (none or tpn) (anec, n = ) and at least once enteral nutrition delivered (nec, n = ) including en alone and supplemental parenteral nutrition (spn). primary outcome was incidence of gi intolerance and risk factors. secondary outcomes were nutritional adequacy (calculated as overall of calories and protein delivered divided by the theoretical amount requirements: kcal/kg/d and . g/kg/d) and clinical outcome. data are reported as median ( th and th percentiles) or number (%), and analyzed with student's t test for continuous variables and χ test for categorical variables. p < . was considered as significant. none.introduction refeeding syndrome (rs) is a potentially lethal condition that remains underdiagnosed. it is characterized by severe electrolyte and fluid shifts associated with metabolic abnormalities in malnourished patients undergoing refeeding orally, enterally, or parenterally. clinical criteria have been proposed for determination of its risk and reported in the national institute for clinical excellence (nice) clinical guidelines. hypophosphoremia (hp) is a prominent feature of the rs and seems to be the earliest abnormality. phosphorus is a vital component of nucleic acids, enzyme systems, and various metabolic pathways. objective to determine the incidence of refeeding hypophosphoremia (rh) < . mmol/l, and severe rh < . mmol/l in a medical critical care unit. patients and methods monocentric, retrospective and observational study with patients from french-speaking icu nutritional survey study frans. critically ill adults (more than yo) were enrolled if they were hospitalized for more than days during a -month period and had an artificial nutritional support. refeeding hypophosphoremia is defined by the occurrence of hypophosphoremia after refeeding. we studied the incidence of hr, risk factors, and prognosis. results patients were enrolled between / / and / / . rh appears in . % and severe rh < . mmol/l in . % (fig. ) . there is no correlation between rs risk factors and rh in our study. logistic regression did not permit to identify neither risk factor nor prognostic modification. there is a lack in phosphoremia measuring ( . %), and overfeeding during the first days occurs in . %. discussion we define that an hypophosphoremia appearing after refeeding is a refeeding hypophosphoremia, and we do not consider others etiologies, such as mechanical ventilation, alkalosis, sepsis, alcoholism, malabsorptive states, poor intake, some medication. our cohort is too small to find some possible correlations with risk factors or prognosis. conclusion refeeding hypophosphoremia is common in our population. hypophosphoremia is not an independent predictor of icu or in-hospital mortality in critically ill patients. the knowledge of the sri requires the follow-up of the phosphoremia during nutrition after critical illness in particular in the undernourished patients. none. introduction to determine the possible relationship between days cumulated proteins ( days cpd) and energy deficits ( days ced) observed in ventilated patients and icu length of stay, duration of ventilator support, incidence of infections and days mortality. patients and methods mixed medical or surgical ventilated for at least days adult patients from icus from chu liège belgium were enrolled into the study. they were fed by enteral route with a target of kcal and . g of proteins by corrected kg of bodyweight and by day. if % of the target was not reached on day seven, parenteral nutrition was added with the same target. ced and cpd were calculated for days, taking into account all the sources of nutrition, and was defined as the difference between the amount of energy or protein intake and the target. results from / / till / / , patients were followed. data from patients could be cumulated on the first days. there were males, mean bmi was . ± . ; saps ii score on day was . ± . , sofa score at day was . ± . . they were ventilated for a median of days (iqr - ), median icu length of stay was days (iqr - ). mean sofa max calculated for the first days was . ± . and the day mortality was . %. on day , only % reached the target of kcal/kg and % the target of . g of protein/kg. mean days ced was − . ± . kcal and mean days cpd was − . ± . g. there was a significant negative relationship between both deficits and the sofa max (p = . for ced and p = . for cpd). however, there were no correlations between any of the deficits and icu length of stay, duration of mechanical ventilation, occurrence of infections and days mortality. discussion saps ii level, sofa max level, icu length of stay, all these parameters emphasize the high severity of this cohort of patients. it could indeed been thought that it is in this group of critically ill patients that the impact of nutrition could be easily demonstrated. clear relationships between sofamax on day and the days ced and cpd could be seen. however, both the deficit and the level of organ dysfunctions could be cause or consequence. unlike previous studies, usually performed in less severely ill patients, we did not find any relationship between ced or cpd and patient's outcome. conclusion contrary to some recent studies, we found no relationship between ced and cpe and outcome of patients. future studies are needed. none. cardiopulmonary bypass induces lymphopenia and decreases lymphocyte proliferation ability: il- and pd-l as potential therapeutic targets to reduce postoperative infection fabrice uhel , mathieu lesouhaitier , murielle grégoire , baptiste gaudriot , arnaud gacouin , yves le tulzo , erwan flecher , karin tarte , jean-marc tadié fig. incidence of hypophosphoremia at admission, the first day, and refeeding hypophosphoremia none. the prognostic impact of neutropenia in criticallyill cancer patients remains controversial. hence, several studies in critically ill cancer patients failed to demonstrate the impact of neutropenia on outcome [ ] . this lack of statistical association might however, reflect a lack of statistical power. a previous meta-analysis of aggregated data suggested % ( % ci - %) raw increase in mortality in neutropenic patients. the available data were, however insufficient to allow adjustment with confounders [ ] . the aim of this study was to assess the influence of neutropenia on mortality of critically ill cancer patients using individual data obtained from studies identified by our systematic review. secondary objectives were to assess the influence of neutropenia on mortality of critically ill patients while taking into account underlying malignancy, use of g-csf or changes related to period of admission. patients and methods this systematic review and meta-analysis was performed according to the prisma statements. public-domain databases including pubmed and the cochrane database were searched by using predefined keywords. the research was restricted to articles published in english and studies focusing on critically ill adult patients from may to may . the methods and objectives of this systematic review were reported in the prospero database (crd ). selected manuscripts' authors were then contacted to obtained part of their dataset. mortality was defined as either hospital or day- mortality. this preliminary analysis reports results from the whole dataset before and after adjustment using logistic regression. period of admission and use of g-csf were then assessed and were a pre-planned analysis. results our initial search yielded citations and studies were retained for further analysis. overall, studies were excluded for redundancy with other included studies, as containing only neutropenic patients, and two as containing only palliative patients. finally datasets ( %) containing sufficient data to allow comparison were obtained from authors. overall, patients were included in this study, including patients with neutropenia at icu admission. median age was of years (iqr - ). median sapsii score at icu admission was (iqr - ). respectively and patients had underlying haematological malignancy and solid tumours, and patients underwent allogeneic stem cell transplantation. mechanical ventilation, vasopressors, and renal replacement therapy were required in none. none. ( ) . in icus, cirrhotic patients are widely admitted and revalued after receiving optimal treatments for days. however, little is known about how manage these patients after day according to their prognosis. the blood neutrophil-to-lymphocyte ratio (nlr) as a novel inflammation index biomarker has been reported to be a predictor of clinical outcomes in various malignancies and in unselected critically ill patients ( ) . nlr has also been identified as a predictor of mortality in patients with stable liver cirrhosis. to our knowledge, the ability of nlr to predict outcome in critically ill cirrhotic patients has never been studied. the aim of this study was to evaluate the usefulness of inflammatory marker such as nlr for diagnosis of infection and predicting the outcome in hospitalized critically ill cirrhotic patients. we performed a retrospective monocentric study including consecutively cirrhotic patients hospitalized in a medical icu from to . for each patient, clinical and biological data at admission and day were collected. nlr at admission ("nlrd "), at day ("nlrd ") and the variation of nlr between admission and d none.introduction diagnosis of infection in immunocompromised patients can be difficult. however, diagnosing infection is very important, particularly in critically ill. this study aims to evaluate the benefit of procalcitonin (pct) blood level as a diagnostic marker for bacterial infection in patients with hematological malignancies admitted to the intensive care unit (icu). this retrospective single-center study included all consecutive patients with acute myeloid leukemia or high grade lymphoid malignancy admitted to the icu. patients were sorted into three subgroups, according to clinical and microbiological data: «infectious disease», «no infectious disease» and «unknown». initial serum pct and when available at day and day were recorded. receiver operating characteristic (roc) curve, sensitivity and specificity were calculated. serum pct was considered as decreasing when the decrease was ≥ % at day and/or ≥ % at day . mortality rates in the icu and at day- were also studied. results fifty-four patients were included in the study. at diagnosis, pct levels were significantly different between the "infection disease" group and the "no infection disease" group (p = . ). there was no difference between the "infection disease" group and the "unknown" group (p = . ). for the diagnosis of bacterial infection, best initial serum pct threshold was . ng per milliliter. for that threshold, sensitivity was . % and specificity was . %. pct area under the roc curve was . [ci % = . - ]. youden's j statistic was . . pct levels weren't different between groups according to the presence of neutropenia or in case of inaugural disease. there was a significant difference in pct values between groups according to the sofa score (p = . ), but not the saps score. mortality rate in the icu and at day- were significantly lower for the patients with decreasing pct (p < . and p < . , respectively). when comparing serum pct and crp predictive values, pct was significantly a better marker of bacterial infection (fig. ). discussion we found that serum pct, with a threshold of . ng/ ml, is a reliable marker of bacterial infection disease in patients with aggressive hematological malignancy admitted to the icu. our study confirms the results of a previous study in unselected immunocompromised patients admitted to the icu, showing a % sensitivity, a % specificity and an area under roc curve of . [ . - . ] for a threshold of . ng/ml ( ). the main limitations of our study are its retrospective design and the small number of included patients. conclusion pct is a reliable marker of bacterial infection in patients with hematological malignancies admitted to the icu. pct kinetic seems to be an interesting prognostic marker in this population. none. in this study, we have found that kinetics of secretion and expression of endocan is faster with huvecs stimlated by tlr agonist than tlr agonist. this results could suggest that endocan may be not only a marker of septic shock but could be also a specific marker to recognize the nature of pathogenic microorganisms in septic shock. furthermore, other studies with more tlr agonists could be useful to confirm these results. conclusion studying the effects of diverse tlrs agonists could make the plasmatic dosage of endocan more specific and helpful to recognize the nature of pathogenic microorganisms in septic shock. none. lung ultrasound: help to the diagnostic and the monitoring of response to physiotherapy. a case report of pneumonia aymeric le neindre introduction chronic critical illness (cci) syndrome is a new condition affecting an increasing number of patients, who survived an acute critical illness but have persistent severe organ dysfunction, requiring prolonged specialized care. cci is a iatrogenic process, reflecting the efficacy of modern life support technologies( ), and encompasses multiple organ failure, need for prolonged mechanical ventilation (mv), organ support, and palsy due to polineuromyopathy. the transition from acute to cci is gradual: definitions are based on duration of mv, with cut-offs of , or consecutive days of mv for ≥ h/day. cci patients may come from either medical or surgical icu; their health status fluctuates between improvements and deteriorations implying recurrent transitions between different levels of care ( ) .the risk of death is reported to be as high as %. despite a relatively young age ( years on average), functional status of cci patients discharged is seriously impaired, thus cci patients require long-term rehabilitation. aim: to estimate the frequency of cci syndrome in careggi, a large academic, tertiary care hospital; to describe the clinical course of cci patients through discharge, and their functional status at discharge. patients and methods administrative data on admission, transfer, death and discharge of all cci patients, consecutively admitted in one of the icu beds at careggi hospital from january to december , , were collected. cci was defined with the cut off of ≥ days of icu stay, representing the index event (ie) without contribution of previous or subsequent hospitalization in other hospitals. reasons for admission were grouped into the broad categories of medical causes, surgery, major trauma and cardio-respiratory arrest. patients discharged were evaluated in daily living, cognitive status, and mobility using barthel index. results we identified subjects who developed cci ( males; age . ± . years, mean ± sem); of them came from an external icu, began their cci course within careggi hospital ( from the emergency room, from a regular ward). average duration of the ie was . ± . days. these sample developed accumulative length of icu stay of days, corresponding to a % icu bed occupation over the theoretical total of , . when days of subintensive care and regular ward were separately added, days of highly specialized care and days of total acute hospital stay were reached. surgical patients had longer hospitalizations (p = . ).cci patients confirmed to be highly erratic: a total of transitions across different services were recorded in the patients, with a maximum of in of them. mean age was comparable between the patients who died ( %) and the remaining who were discharged alive ( . ± . vs. . ± . years; p = . ).fourteen subjects continued their icu stay out of hospital. only , whose age was lower ( . ± . years), were discharged home; half of the participants (n = , . %) were admitted to a residential rehabilitation facility. younger subjects scored better in the domains of self care (p = . ) and cognitive status (p = . ) but not in the domain of mobility, including walking ability: patients required maximal assistance in performing activities of daily living and transfers, other required medium/maximal assistance, with no statistical difference between dg group. conclusion cci is a relevant clinical condition that need to be assessed and possibly prevented, as it causes severe morbidity, long-term functional impairment and exceeding healthcare costs. none.conclusion early mobilization during the first week of the sepsis onset was safe and preserved muscle fibre cross sectional area. none. none. study of efficacy on icu acquired weakness of early standing with the assistance of a tilt table in critically ill patients none.introduction patients with high flow nasal cannula may benefit from combined aerosol therapy. clinical efficacy depends on pulmonary deposition which is related to the type of nebulizer. all new nebulizers or delivery methods require rigorous evaluation. the aim of this study was to compare lung deposition between two nebulizers (jet nebulizer vs vibrating-mesh nebulizer) through high flow nasal cannula in healthy subjects. patients and methods aerosol delivery of diethylenetriaminepentaacetic acid labelled with technetium- m ( mtc-dtpa, mci/ ml) to the lungs using a vibrating-mesh nebulizer (aerogen solo ® , aerogen ltd., galway, ireland) and a constant-output jet nebulizer (opti-mist plus nebulizer ® , convatec, bridgewater, nj) through high flow nasal cannula (optiflow ® , fisher & paykel, new zealand) was compared in healthy subjects. flow rate was set at l/min through the heated humidified circuit. pulmonary and extrapulmonary deposition were measured by single photon emission computed tomography combined with a low dose ct-scan (spect-ct) and by planar scintigraphy. results lung deposition was only . ± . and . ± . % of the nominal dose with the vibrating-mesh nebulizer and the jet nebulizer, respectively (p < . ). dose lost in the high flow circuit, humidification chamber and nasal cannula was higher with the vibrating-mesh nebulizer as compared to the jet nebulizer ( . ± . vs . ± . % of the nominal dose, p = . ). expressed as percentage of emitted dose, lung deposition was similar with both nebulizers. conclusion this study demonstrated that aerosol delivery through hfnc is poor in the specific conditions of the study despite the higher efficiency of the vibrating-mesh nebulizer as compared to the jet nebulizer. placing the nebulizer on the hfnc circuit at l/min induces high aerosol loss on the circuit and the oropharynx. key: cord- -jp sqqwc authors: bollag, wendy b.; gonzales, joyce n. title: phosphatidylglycerol and surfactant: a potential treatment for covid- ? date: - - journal: med hypotheses doi: . /j.mehy. . sha: doc_id: cord_uid: jp sqqwc a hypothesis concerning the potential utility of surfactant supplementation for the treatment of critically ill patients with covid- is proposed, along with a brief summary of the data in the literature supporting this idea. it is thought that surfactant, which is already approved by the food and drug administration for intratracheal administration to treat neonatal respiratory distress syndrome in infants, could benefit covid- -infected individuals by: ( ) restoring surfactant damaged by lung infection and/or decreased due to the virus-induced death of the type ii pneumocytes that produce it and ( ) reducing surface tension to decrease the work of breathing and limit pulmonary edema. in addition, a constituent of surfactant, phosphatidylglycerol, could mitigate covid- -induced lung pathology by: ( ) decreasing excessive innate immune system activation via its inhibition of toll-like receptor- and - activation by microbial components and cellular proteins released by damaged cells, thereby limiting inflammation and the resultant pulmonary edema, and ( ) possibly blocking spread of the viral infection to non-infected cells in the lung. therefore, it is suggested that surfactant preparations containing phosphatidylglycerol be tested for their ability to improve lung function in critically ill patients with covid- . introduction covid- , caused by the novel coronavirus sars-cov- , has resulted in massive morbidity and mortality, as well as profound economic difficulties due to the necessity for quarantining to contain and mitigate the pandemic. although many people who become infected exhibit only mild or moderate symptoms, others develop severe symptoms, and covid- appears to be more deadly than influenza, especially in older individuals and those with preexisting conditions. treatment to date is mainly symptomatic supportive care including invasive or non-invasive ventilation. in a recent retrospective study of chinese patients with covid- requiring intensive care, more than % of the patients died [ ] . of the non-survivors about % of the patients developed acute respiratory distress syndrome (ards) [ ] , and respiratory failure associated with ards is the leading cause of covid- mortality [ ] . ards is characterized by lung inflammation and pulmonary edema, which reduces gas exchange and leads to hypoxemia and dyspnea, often requiring mechanical ventilation to provide sufficient oxygenation. ards is also accompanied by enhanced secretory phospholipase a (spla ) activity in the lungs [ , ] ; spla degrades the phospholipids that are components of surfactant, including phosphatidylglycerol (pg) (reviewed in [ ] ). indeed, a recent study has demonstrated an increase in the activity of an spla that preferentially hydrolyzes pg, as well as a significant decrease in pg in the bronchoalveolar lavage fluid of ards patients versus normal control subjects [ ] . the impairment of surfactant function not only can increase surface tension and reduce lung compliance but may also further exacerbate pulmonary edema, since surfactant helps to reduce fluid infiltration into the alveoli through its reduction of surface tension [ , ] . knowledge about this sequence of events has led to studies in humans testing the efficacy of exogenous surfactant in the treatment of ards, and some results have been promising [ ] [ ] [ ] [ ] ; although meta-analyses have largely failed to show an effect of exogenous surfactant administration on the survival of adult ards patients (e.g., [ ] and [ ] ). on the other hand, another meta-analysis determined a benefit of surfactant administration on oxygenation levels and mortality in those patients with severe ards caused by pneumonia or aspiration of gastric contents [ ] , suggesting that co-morbidities other than ards may potentially determine the effect of surfactant administration on survival. in contrast, the pulmonary failure induced by covid- seems to differ in many respects from other types of ards [ , ] . for example, many covid- patients initially present with hypoxemia with maintained lung compliance and low elastance, termed the l type presentation [ ] . these l-type patients can often be treated with oxygen supplementation and prone positioning, or if they are intubated due to worsening hypoxia, mechanical ventilation at low positive end expiratory pressures (peep). however, l-type patients often transition into the second or h-type clinical presentation [ ] , in which they exhibit high elastance and low compliance and usually require mechanical ventilation at higher peep [ ] ; low pulmonary compliance portends worsening lung disease manifested by atelectasis and increasing hypoxia. therefore, only the h-type mimics the lung parameters observed in pre-term infants that produce minimal surfactant, suggesting that at least in the early stages, covid- patients exhibiting l-type disease may retain some pulmonary surfactant activity. a key role of pulmonary surfactant is to reduce surface tension and prevent alveolar atelectasis at end expiration. in the absence of active surfactant, high surface tension at the airliquid interface in the alveoli creates collapsing forces [ ] . in addition, since surface tension draws fluid from the capillaries into the alveolar spaces, surfactant decreases pulmonary fluid accumulation by reducing surface tension to maintain airway dryness [ ] . increased surface tension related to surfactant dysfunction also alters alveolar capillary shape and pulmonary blood flow to exacerbate hypoxemia [ ] . on the other hand, during severe respiratory distress with mechanical ventilation, the role of higher peep is to keep the alveoli "recruited" or, in other words, to prevent end-expiratory alveolar collapse. however, mechanical ventilation and high peep represent a double-edged sword: maintaining or improving oxygenation while causing alveolar lung injury. mechanical ventilation with high peep may also reduce the ability of surfactant to lower surface tension, since compression of surfactant to an area of less than % of its original surface area by higher pressures can result in rupturing of the film on reexpansion, resulting in compromised surface tension-reducing capacity [ , ] . in addition, the stresses of mechanical ventilation also stimulate the inflammatory response [ ] . thus, it seems likely that another function of surfactant may be important: its ability to dampen the inflammatory response to microbial components. thus, at least one of the surfactant phospholipids, pg, has been shown to inhibit activation of toll-like receptors (tlr) of the lung innate immune system by microbial components (reviewed in [ ] ). voelker and colleagues have shown that pg inhibits tlr and tlr activation by microbial components, also known as pathogen-associated molecular patterns (pamps), such as acylated lipopeptides and lipopolysaccharide [ ] . this inhibition then results in reduced production of inflammatory mediators and decreased lung inflammation and damage [ ] [ ] [ ] . these results are also consistent with the results of wu at al. [ ] , who demonstrated that pg inhibits endotoxinstimulated activation of nuclear factor-kappab (nfb), a transcription factor associated with inflammation, to reduce type iia secretory phospholipase a levels/activity in macrophages. the mechanism of action of pg seems to be related to the ability of the tlr and tlr coreceptor cd to bind this phospholipid and somehow prevent tlr activation [ , ] . indeed, martin et al. [ ] have recently suggested blocking cd , but with inhibitory antibodies, to control inflammation in covid- . of note, pamps are not the only molecules that can activate tlrs. tlr activation can also be induced by endogenous proteins that are released by damaged or stressed cells, the so-called danger-or damage-associated molecular patterns (damps) (reviewed in [ ] ). many such tlr-stimulating damps have been identified (reviewed in [ ] ), including several heat shock proteins, high mobility group b (hmgb ) and fibrinogen [ ] , and these can be released extracellularly upon cell damage. we recently showed that pg can inhibit damp-induced inflammatory mediator production [ ] and skin inflammation [ , ] . specifically, pg inhibits tlr and tlr activation by the damps s a and beta-defensin- [ ] . pg can also inhibit tlr and tlr activation in response to pamps in several cell types and in tlr and tlr reporter cell lines [ ] , with minimal effects on the activation of, or stimulation of inflammatory mediator expression by, other pattern recognition receptors, such as the tlr / that recognizes single-stranded rna. in addition, supplementation of surfactant with additional pg (to a molar percentage of %) preserves lung function and prevents alveolar epithelial injury and the expression of pro-fibrotic mediators in a neonatal pig triple injury model of ards [ ] . the ability of pg to protect against cell injury would be expected to be beneficial in covid- ards, furthermore, covid- patients have been reported to exhibit elevated levels of tumor necrosis factor-alpha (tnf) [ ] , and drugs targeting pro-inflammatory mediators, such as interleukin (il)- and il- have been proposed or are in use for the treatment of covid- [ , ] . pg has been shown to inhibit the expression of il- , il- , il- , and/or tnf, as well as il- , interferon-gamma and/or macrophage inflammatory protein- , in response to tlr activation by pamps and damps [ - , , , , , ] . in turn, several of these inflammatory mediators (e.g., il- and tnf) are also known to increase the levels of certain spla s, in particular that encoded by the gene pla g a [ ] , which would decrease pg levels even further. finally, excessive inflammation (e.g., markedly increased c-reactive protein and d-dimer levels) is associated with the hypercoagulopathy sometimes seen in covid- patients [ ] . therefore, the ability of pg to inhibit pamp-and damp-induced might also decrease these covid- sequelae as well. collectively, these results have led to the current hypothesis that pg, in the form of exogenous surfactant, might be efficacious in treating the symptoms of covid- . by analogy with sars-cov [ , ] , sars-cov- is thought to target alveolar type-ii cells [ , ] , the lung cells that produce surfactant; the resulting release of endogenous molecules by these damaged cells would presumably activate tlrs and stimulate inflammatory mediator production and inflammation. these effects likely would, together with the gradual reduction in surfactant resulting from the death of these type ii pneumocytes (and possibly the increased activity of spla ) [ ] [ ] [ ] , promote the pulmonary edema that is a hallmark of covid- . the pulmonary edema, in turn, further impairs gas exchange and leads to ards with further hypoxemia and dyspnea. however, the initial presentation might be expected to show differences from the respiratory distress seen in pre-term infants: phosphatidylcholine represents approximately twothirds to three-quarters of pulmonary surfactant lipid content [ , ] and thus provides the majority of its surfactant activity. therefore, gradual loss of phosphatidylcholine would allow maintenance of compliance despite enhanced inflammation resulting from decreased levels of pg, which comprises only - % of surfactant phospholipid [ , ] , and the resultant pulmonary edema. presumably, loss of the anti-surface tension effects of surfactant would only occur once large numbers of type ii alveolar cells were destroyed and phosphatidylcholine was severely depleted. at this point, then, patients would transition to the h-type clinical presentation, with the low compliance more typical of neonatal respiratory distress syndrome. pulmonary administration of exogenous surfactant would be expected to counter this sequence of events in multiple ways: ( ) it would restore the levels of surfactant to protect against increased surface tension in the lung; ( ) it would inhibit activation of the innate immune system by released damps to reduce inflammation and inflammatory damage; and ( ) it would decrease pulmonary edema through the combination of the first two effects. in addition, it is thought that in some individuals, covid- -related morbidity and mortality may be related to an over-reaction of the immune system and a "cytokine storm" [ , , , ] . by inhibiting innate immune system activation and release of pro-inflammatory mediators that recruit and activate additional immune cells, including those of the adaptive immune system, pg would likely interrupt this process of immune system hyper-responsiveness, acting as a dampening mechanism, or rheostat, to regulate lung inflammation [ ] . finally, it is known that pulmonary surfactant can facilitate recruitment of collapsed airways and offer protection from mechanical ventilation-induced lung injury. thus, exogenous surfactant therapy may restore or replenish insufficient or dysfunctional endogenous surfactant activity and improve outcomes in covid- . thus, we are proposing that pg-containing surfactant medications that are already approved by the food and drug administration for the treatment of neonatal respiratory distress syndrome (table ) be administered intratracheally via bronchoscopy to covid- patients with severe acute respiratory distress syndrome. it should be noted that natural and second-generation synthetic surfactant preparations have been found to exhibit increased efficacy for improving neonatal respiratory distress syndrome relative to first-generation protein-free surfactant medications like exosurf®. these results are consistent with data indicating the importance of certain surfactant proteins to improve the effect of surfactant on surface tension [ ] and others to reduce microbial infection ( [ , ] and reviewed in [ ] ). the histologic description of covid pathology at autopsy shows diffuse alveolar damage with cellular fibromyxoid exudates, acute fibrinous, hyaline membrane formation, organizing pneumonia and desquamation of pneumocytes, all consistent with ards [ , ] . hyaline membrane formation has been observed in histological samples at both the early and later stages of the disease, suggesting early type ii pneumocyte injury with surfactant dysfunction [ ] . although not all covid- patients progress to a low-compliance phenotype, evidence in histological specimens highly suggests that there is surfactant dysfunction and hyaline membrane formation comparable to that observed in the non-covid- ards-mediated alveolar damage described by matthay and zemans [ ] . one approach to improve the dysfunctional surfactant in this disease is to treat with exogenous surfactant, thereby allowing maintenance of its function in the alveoli. indeed, it seems likely that covid- -affected lungs will require functioning surfactant to fully recover. exogenous bronchial surfactant instillation has been a feasible and safe approach in infants, although a higher dose and repeated administration may be required to restore dysfunctional alveoli impacted by covid- . it should also be noted that despite its ability to inhibit tlr activation and inflammation, pg in surfactant does not seem to be globally immunosuppressive. in fact, in animal models in vivo it protects against infection resulting from several viruses, including respiratory syncytial virus, influenza a (h n ) and h n [ , , ] , by inhibiting the interaction of these viruses with their receptors on host cells. although it is not known whether pg has a similar inhibitory effect on the infectious capacity of sars-cov- , a positive-sense single-strand rna virus, the minimal effect of pg on the activation of tlr / [ , ] would suggest that this phospholipid would likely not suppress innate immune system responses to the virus. therefore, surfactant might be useful in preventing the spread of sars-cov- viral infection between infected and naïve cells within the lung without affecting the response to this infection, in addition to protecting against the damage caused by excessive inflammation and edema and the increased surface tension that eventually results from loss of surfactant. on the other hand, the surfactant lipids phosphatidylcholine, in particular disaturated phosphatidylcholine (dipalmitoylphosphatidylcholine), and phosphatidylserine are reported to potentially promote infection by viral pathogens [ ] . however, the mechanisms are thought to involve facilitation of viral entry via the ability of the virus to bind lipid and co-opt reuptake/recycling pathways in the case of pc and promotion of viral fusion by mimicking of an apoptotic signal in the case of ps [ ] . since sars-cov- purportedly gains entry into cells through angiotensin-converting enzyme (ace ) [ ] , these mechanisms used by other viruses seem unlikely to be relevant to sars-cov- and covid- pneumonia. it should also be noted that certain conditions that increase the risk of a severe response to sars-cov- infection are also known to reduce surfactant and/or surfactant phospholipid levels or to impair surfactant function. thus, phospholipid levels inversely correlate with age, at least in horses [ ] . smoking also reduces phospholipid levels in pulmonary surfactant [ ] and is thought to increase the risk of adverse outcomes from covid- [ ] . diabetes causes increased serum levels of high mobility group-b (hmgb ) [ ] , a known damp [ ] that activates tlr [ ] , which would be expected to enhance inflammation. similarly, in some cases hypertension has also been proposed to result from enhanced serum damp levels (reviewed in [ ] ), which again could possibly lead to a chronic low-level inflammation. obesity is also thought to be accompanied by inflammation (reviewed in [ ] ). indeed, serum levels of c-reactive peptide, a marker of inflammation, have been observed to correlate well with sars-cov- viral load and the murray score, which assesses the severity of lung injury in individuals with ards [ ] . diabetes, hypertension and obesity have been suggested to predispose individuals to worse outcomes from covid- [ ] . in addition, serum levels of angiotensin ii, which is also reported to increase inflammation through tlr [ , ] , are reported to be elevated in patients with covid- [ ] . finally, a recent report has suggested that the corticosteroid dexamethasone may improve survival in patients with severe covid- [ ] . if confirmed, this result would be consistent with the hypothesis described here, since glucocorticoids are known not only to suppress inflammation but also to increase lung surfactant synthesis [ , ] . by stimulating any remaining type ii alveolar cells to produce more surfactant phospholipids including pg, dexamethasone could both directly and indirectly decrease lung inflammation. surfactant has already been used in studies to treat ards [ ] [ ] [ ] [ ] in adult patients, although with less than impressive results. it should be noted that walmrath et al. [ ] discussed the likelihood that higher doses and/or more frequent administration of surfactant might be necessary in the case of ards (versus neonatal respiratory distress syndrome) to overcome the ongoing surfactant-inactivating conditions (increased spla levels, inflammation and oxidative stress) often present in ards lungs. we would also like to point out that not all surfactant medications contain pg (for example, exosurf® does not), which could potentially be another explanation, in addition to potentially inadequate dosing and inactivation of surfactant function by shearing [ ] , for why not all studies of surfactant administration in ards have found a benefit [ ] . despite the mixed results concerning exogenous surfactant medication in adult ards [ , ] , it is approved by the food and drug administration for intratracheal administration to pre-term infants to treat neonatal respiratory distress syndrome. in infants there are few side effects, and infants who receive surfactant have shorter hospital stays and better survival [ ] . similarly, eleven clinical trials in adults have indicated that surfactant therapy is both feasible and safe, with no significant adverse effects reported [ ] . therefore, it is postulated that because sars-cov- is thought to target and damage/destroy surfactantproducing type ii pneumocytes, covid- may be more like neonatal ards than are other types of ards. indeed, like pre-term infants, patients with covid- have been found to exhibit hyaline membrane formation [ ] . therefore, it is proposed that investigative studies to administer pg-containing surfactant, either synthetic (e.g., surfaxin®) or isolated from bovine (alveofact®, survanta®, beraksurf® and infasurf®) or porcine lungs (curosurf®), to critically ill covid- patients be initiated, particularly in view of the fact that few therapies for severe covid- have been shown to be effective to date [ ] , and such treatments are actively being sought. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- : consider cytokine storm syndromes and immunosuppression secretory phospholipase a -mediated depletion of phosphatidylglycerol in early acute respiratory distress syndrome clinical and biological role of secretory phospholipase a in acute respiratory distress syndrome infants phospholipase a subclasses in acute respiratory distress syndrome increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs lung morphology and surfactant function in cardiogenic pulmonary edema: a narrative review bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis bronchoscopic administration of bovine natural surfactant in ards and septic shock: impact on gas exchange and haemodynamics bronchoscopic administration of bovine natural surfactant in ards and septic shock: impact on biophysical and biochemical surfactant properties exogenous surfactant in acute respiratory distress syndrome: more is better exogenous pulmonary surfactant for acute respiratory distress syndrome in adults: a systematic review and meta-analysis recombinant surfactant protein c-based surfactant for patients with severe direct lung injury a search for subgroups of patients with ards who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-c surfactant (venticute) covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med covid- does not lead to a "typical" acute respiratory distress syndrome ventilation of covid- patients in intensive care units intensive care management of coronavirus disease (covid- ): challenges and recommendations pulmonary surfactant surface tension influences alveolar capillary shape and oxygenation respiratory physiology: a clinical approach the role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome altered surface tension of lung extracts and lung mechanics phospholipid regulation of innate immunity and respiratory viral infection pulmonary surfactant phosphatidylglycerol inhibits mycoplasma pneumoniae-stimulated eicosanoid production from human and mouse macrophages anionic pulmonary surfactant phospholipids inhibit inflammatory responses from alveolar macrophages and u cells by binding the lipopolysaccharide-interacting proteins cd and md- surfactant protein-a and phosphatidylglycerol suppress type iia phospholipase a synthesis via nuclear factor-kappab structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor and signaling targeting innate immunity by blocking cd : novel approach to control inflammation and organ dysfunction in covid- illness danger signals in the icu endogenous ligands of tlr and tlr : agonists or assistants? journal of leukocyte biology phosphatidylglycerol inhibits toll-like receptor-mediated inflammation by danger-associated molecular patterns soy phosphatidylglycerol reduces inflammation in a contact irritant ear edema mouse model in vivo pathogen-associated molecular patterninduced tlr and tlr activation increases keratinocyte production of inflammatory mediators and is inhibited by phosphatidylglycerol : / : -dioleoyl-phosphatidylglycerol prevents alveolar epithelial apoptosis and profibrotic stimulus in a neonatal piglet model of acute respiratory distress syndrome phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection covid- : towards understanding of pathogenesis sars-cov replicates in primary human alveolar type ii cell cultures but not in type i-like cells innate immune response of human alveolar type ii cells infected with severe acute respiratory syndrome-coronavirus pathogenesis of covid- from a cell biology perspective role of lung surfactant in respiratory disease: current knowledge in large animal medicine understanding the principle biophysics concepts of pulmonary surfactant in health and disease. arch dis child fetal neonatal ed contentti ec, correa j. immunosuppression during the covid- pandemic in neuromyelitis optica spectrum disorders patients: a new challenge surfactant preparations for preterm infants with respiratory distress syndrome: past, present, and future pulmonary surfactant proteins and lipids as modulators of inflammation and innate immunity infection of human alveolar macrophages by human coronavirus strain e the role of collectins and galectins in lung innate immune defense pathological findings of covid- associated with acute respiratory distress syndrome pulmonary and cardiac pathology in african american patients with covid- : an autopsy series from new orleans the acute respiratory distress syndrome: pathogenesis and treatment pulmonary surfactant lipids inhibit infections with the pandemic h n influenza virus in several animal models surfactant and its role in the pathobiology of pulmonary infection. microbes infect influence of age on surfactant isolated from healthy horses maintained on pasture smoking reduces surfactant protein d and phospholipids in patients with and without chronic obstructive pulmonary disease the role of hmgb in the pathogenesis of type diabetes the toll of the gridiron: damage-associated molecular patterns and hypertension in american football inflammatory mechanisms in obesity clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury angiotensin ii induces inflammatory response partly via tolllike receptor -dependent signaling pathway in vascular smooth muscle cells environmental health perspectives chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol role of exogenous surfactant in acute lung injury tensiometric and phase domain behavior of lung surfactant on mucus-like viscoelastic hydrogels surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations toll-like receptors in antiviral innate immunity the authors would like to acknowledge and thank dr. william davis (augusta university) for helpful feedback on this work. this work received no specific funding. wbb was supported in part by veterans affairs merit award #cx and in part by national institutes of health/national eye institute award #r ey . these sponsors had no role in the research, the writing of the manuscript or the decision to publish. the contents of this article do not represent the official views of the department of veterans affairs or the united states government. the authors declare no conflicts of interest. key: cord- -o q hvn authors: shafiee, abbas; moradi, lida; lim, mayasari; brown, jason title: coronavirus disease : a tissue engineering and regenerative medicine perspective date: - - journal: stem cells transl med doi: . /sctm. - sha: doc_id: cord_uid: o q hvn current therapies for novel coronavirus disease (covid‐ ) are generally used to manage rather than cure this highly infective disease. therefore, there is a significant unmet medical need for a safe and effective treatment for covid‐ . inflammation is the driving force behind coronavirus infections, and the majority of deaths caused by covid‐ are the result of acute respiratory distress syndrome (ards). it is crucial to control the inflammation as early as possible. to date, numerous studies have been conducted to evaluate the safety and efficacy of tissue engineering and regenerative medicine (term) products, including mesenchymal stem cells (mscs), and their derivatives (eg, exosomes) for coronavirus infections, which could be applied for the covid‐ . in this review, first, the impacts of covid‐ pandemic in the present and future of term research and products are briefly presented. then, the recent clinical trials and the therapeutic benefits of mscs in coronavirus‐induced ards are critically reviewed. last, the recent advances in the field of tissue engineering relevant to the coronavirus infections, including three‐dimensional platforms to study the disease progression and test the effects of antiviral agents are described. moreover, the application of biomaterials for vaccine technology, and drug delivery are highlighted. despite promising results in the preclinical and clinical applications of msc therapy for coronavirus infections, the controversy still exists, and thus further investigation is required to understand the efficacy of these therapies. term is an emerging field that developed over time and secure longterm investment from both public and private sources is needed to help unlock the potential of term strategies and to boost research translation and commercialization in this area. by having too many patients in the hospitals over the covid- outbreak period, the administration and process of cell and tissue donation programs have consequently slowed down. moreover, concerns over the virus spread have led to a much smaller number of uninfected potential donors to be interested in donating their cells for research and therapies, the protective effects of mscs in the treatment of influenza respiratory infections have been reported previously in preclinical mouse studies. - intravenous administration of × human bone marrow the tissue engineering and regenerative medicine communities and industries have been largely impacted by the covid- pandemic. in this paper, the impact of the recent pandemic on the present and future of tissue engineering and regenerative medicine research and therapies is highlighted. then, the potential use of three-dimensional tissue models and benefits and risks of mesenchymal stem cell therapy for the covid- are discussed. (bm)-mscs in aged h n -infected immunocompetent mice reduced the viral-associated acute lung injury and increased the survival rate. li et al evaluated the effect of systemically administrated mouse bm-mscs ( × cells) in the treatment of h n aiv-induced infection. the administration of mscs reduced the cytokine storm and contributed to reduced h n aiv-induced acute lung injury and improved survival rate. showed that a single infusion of up to million cells/kg pbw was well tolerated and no infusion-associated events or mscs treatmentrelated adverse events were reported. in the weeks after infusion, serious adverse events were noticed in three patients. one patient died on day , one patient died on day , and one patient was discovered to have multiple embolic infarcts of the brain, kidneys, and spleen, but thought to have occurred before the msc administration based on mri results. the authors concluded these severe adverse events were not related to mscs treatment. in a double-blind, multicenter, randomized phase a safety trial, patients with moderate to severe ards were treated with bm-mscs ( × /kg pbw) and compared with the placebo group (n = ) (nct ). the patients were treated within days of ards diagnosis. the -day mortality rate was not significantly different between the msctreated group ( %) and the placebo group ( %). the bm-mscs treated group had numerically higher mean scores for acute physiology and chronic health evaluation iii than the placebo group. still, the sample size in this trial was too small to reliably assess the efficacy of mscs therapy in ards and larger trials are needed. a recent study was conducted to investigate the impact of "angiotensin i converting enzyme " receptor-negative (ace − ) mscs for the treatment of covid- patients ( figure ). ace has a central role in the pathogenesis of covid- and is expressed in the surface of human cells, especially the alveolar type ii cells and capillary endothelium. the intravenous infusion of mscs ( × cells/kg in covid- infection, the host immune system produces an enormous inflammatory response in an attempt to kill the virus, leading to a severe cytokine storm, this process is the main contributor to organ damage in covid- . therefore, avoiding the cytokine storm could be an effective strategy in the treatment of covid- . mscs, due to their powerful immunomodulatory ability not only suppress the cytokine storm but also promote the endogenous repair/regenerative mechanisms in the lungs after the covid- infection. , ards is one of the most severe complications caused by coronaviruses. , indeed, respiratory failure from ards is the leading cause of mortality in covid- patients. , therefore, the management and treatment of ards are essential to reduce the mortality rate. it is believed that mscs regulate the immune system by inhibiting the production of inflammatory cytokines by lymphocytes and induces the production of anti-inflammatory cytokines. therefore, during covid- pandemic, development of robust and reliable tissue-engineered d models as platforms for the screening of antiviral therapeutics, precise understanding of the mechanism of covid- disease, and the host and sars-cov- interactions would be of value ( figure ). the potential of d engineered constructs as robust tools for the assessments of viral pathogenicity and identifying host responses to antiviral therapy has been tested in previous studies. , a recent study aimed to assess sars-cov- infectivity. spike (s) protein of sars-cov- is composed of two subunits s and s . s binds to ace protein, the key entry gate for sars-cov- that facilitates its penetration into target cells, and s fuses on the surface of the cell membrane. transmembrane serine protease (tmprss ) is another host protein that promotes cellular entry of sars-cov- . therefore, both ace- and tmprss are necessary for viral infectivity. organoids. the potential use of human and animal organoids as an experimental virology platform has been discussed somewhere else. , human organ-on-chip technology has been developed and extensively used to recapitulate in vivo cellular responses to drugs or toxic agents. , , the tissue engineering and organ-on-chip technologies apply engineering principles to biological processes and enable rapid translation of technologies from the benchtop to the bedside. previous studies reported lung-on-chip models to offer alternative preclinical tools to mimic human alveolar epithelial cells' responses to viral infection due to their capacity to recapitulate organ-level physiology and pathophysiology. , si et al fabricated a microfluidic device with two microchannels separated by a porous membrane. infection. of significance, no significant inhibitory effects for chloroquine was observed in cmax. this could be explained by the fact that chloroquine may exert its therapeutic effects via mechanism(s) other than contributing to blocking the virus entry. remdesivir (also known as gs- ) is an adenosine analog prodrug with excellent potency against severe acute respiratory syndrome and the middle east respiratory syndrome in human airway epithelial (hae) cell models. , previous studies showed remdesivir might be a promising candidate for the treatment of patients with covid- due to its ability to inhibit viral rna replication. in another study, human octamer-binding transcription factor + (oct- +) progenitor cells and mscs were grown on a collagen type ibased matrix in a serum-free media. the authors reported progenitor cells were able to differentiate into alveolar pneumocytes type i and ii expressing ace . the results displayed that the oct- + progenitor cells, but not the surrounding mesenchymal cells, were susceptible targets for sars-cov- and allowed virus replication. this suggests an important potential role for oct- + progenitor cells, which normally develop into the cilia in the bronchi and are mainly responsible for expressing ace , in the continued destruction of alveoli and loss of the lung capacity for regeneration after sars-cov infection. despite significant advances, a major drawback of current d lung models is the lack of human stromal, hematopoietic, and immune systems, as the critical components in the viral infection and pathogenesis. therefore, future d models should investigate the safety and efficacy of antiviral agents in the presence of human immune and hematopoietic systems. apart from the development of in vitro models, tissue engineering technologies enable the evolution of the next generation of drug delivery systems and facilitate vaccine development and delivery. , tissue-engineered systems allow the controlled extended release of drugs, which are advantageous over multiple injections for clinical practice. besides, the new generation of biomaterials allows us to target the areas of high viral load specifically and extendedly. biomaterials able to act as the drug delivery vehicle for the vaccine as well as the adjuvant, and can boost the immune response to the vaccine. , for h n influenza immunization, wu et al modified chitosan and developed a thermal-sensitive hydrogel as an intranasal vaccine delivery system. the new adjuvant-free vaccine delivery system prolonged the h n split antigen residence time in the nasal cavity and enhanced the transepithelial transport in the nasal epithelial tissue. the adjuvant-free vaccine delivery system could induce larger antigen-specific systemic immune responses and mucosal iga immunity in a mouse model. in addition, the tissue engineering concepts have been utilized to develop immunologically active biomaterial constructs. ali et al fabricated -dimensional, macroporous poly(lactideco-glycolide) matrices that slowly released cytokines such as granulocyte-colony stimulating factor and recruited antigenpresenting cells to the matrices. the biomaterial-based vaccines enhanced effective, prolonged, and specific cytotoxic, t-cell mediated immunity, and eradicated the large established melanoma tumors in mice. the in vivo modulation of host immune cells can be achieved with the spatiotemporal control of biochemical and mechanical cues in biomaterials. mesoporous silica rods of high aspect ratio were fabricated and subcutaneously implanted into mice to form a pocket and formed d interparticle spaces and recruited host cells. the sustained release of inflammatory signals and adjuvants from the scaffold modulated the immune cell function and provoked adaptive immune responses. this system has been applied to tumor vaccines in animal models with promising results, particularly when looking at concentrating many liters of cell solution, this must be done promptly (< hours) to not compromise cell viability and the functionality of the final product. volume reduction and filtration steps using appropriate systems at the scale that is required will need to be evaluated accordingly. most standard laboratory centrifugation systems will not be able to handle large volumes > to l. in the separation step, the choice of the enzyme, the time of exposure, and efficiency of each step are critical in ensuring optimal cell survival. for gmp manufacturing, the use of animal-component free materials, in a ready-to-use solution, is preferred and helps to reduce regulatory burden. . | what can we expect to learn from this pandemic (with new clinical trials approved)? acceleration of trials for covid- will present opportunities to collect more data on both the safety and efficacy of mscs and other cell therapies to treat lung injuries and related complications. however, rational design and a controlled approach to clinical trial design are essential to obtain valuable insights in assessing both the safety and efficacy of treatments. patient safety is paramount and should never be compromised in any circumstance. therapeutic developers and cell therapy manufacturers must uphold their moral integrity to deliver products that meet equally stringent requirements to ensure patient safety. from the manufacturing perspective, this also presents an opportunity for product developers to focus on advancing scalable technologies that can meet critical demands like these in the future. as other cell therapy products are developed and mature, manufacturing will remain a challenge if progress is not made on this front. finally, the cost to manufacture cell therapies will need to go down to make them accessible to everyone. in olsen's peak msc paper, the relationship between technology s-curve and economics for mscs describes how the adoption of each technology platform at the production scale will drive the cost down due to efficiencies of scale. the covid- pandemic is forcing us to think big and look ahead into the future. with every crisis, there is a silver lining, and here we are being presented the opportunity to advance cell manufacturing technologies forward to make cell therapies of the future scalable, safe, and affordable. the term technologies have the potential to revolutionize the whole healthcare system by restoring damaged tissues and organs, in contrast to other pharmaceuticals and surgical strategies that generally manage rather than cure diseases. over the covid- outbreak, the funding for many term projects is being cut, which has a significant impact on the present and future of current clinical trials highlight the potential benefits of stem cell therapies for covid- patients. however, current studies are made up of small case series that lack appropriate control arms and historical controls were not provided, making the interpretation of any reported benefits difficult to quantify. therefore, further investigations are required to understand the safety and efficacy of these therapies and their long-term outcomes. effective multi-institutional collaboration and adequate funding from government and nongovernment sources are also needed to collect and analyze the data from ongoing and new human trials, to better understand the potential benefits of stem cell therapies for covid- patients. mayasari lim is a regional account manager at roosterbio, united states. m.l. declared employment with roosterbio. all the other authors declared no potential conflicts of interest. a.s.: concept and design, manuscript preparation, collection and assembly of data, review and editing, and final approval of the manuscript; l.m., m.l., j.b.: manuscript preparation, discussion, and review and editing. data sharing is not applicable to this article as no new data were created or analyzed in this study. https://orcid.org/ - - - regenerative medicine: current therapies and future directions an investigation of topics and trends of tracheal replacement studies using co-occurrence analysis an engineered cellimprinted substrate directs osteogenic differentiation in stem cells impact of covid- and future emerging viruses on hematopoietic cell transplantation and other cellular therapies the impact of covid- on the provision of donor hematopoietic stem cell products worldwide: collateral damage on behalf of the international foundation of patient blood management (ifpbm) and society for the advancement of blood management (sabm) work group essential role of patient blood management in a pandemic: a call for action current status of cell-based therapies for respiratory virus infections: applicability to covid- human mesenchymal stromal cells reduce influenza a h n -associated acute lung injury in vitro and in vivo mesenchymal stromal cell treatment prevents h n avian influenza virus-induced acute lung injury in mice clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic influenza a (h n ) infection, a hint for covid- treatment. engineering intratracheal administration of umbilical cord blood-derived mesenchymal stem cells in a patient with acute respiratory distress syndrome clinical remission of a critically ill covid- patient treated by human umbilical cord mesenchymal stem cells in vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome exosomes derived from bone marrow mesenchymal stem cells as treatment for severe covid- treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study mesenchymal stem (stromal) cells for treatment of ards: a phase clinical trial transplantation of ace -mesenchymal stem cells improves the outcome of patients with covid- pneumonia human umbilical cord-derived mesenchymal stem cells for acute respiratory distress syndrome primary analysis of a phase / study to assess multistem® cell therapy, a regenerative advanced therapy medicinal product (atmp), in acute respiratory distress syndrome (must-ards) design and implementation of the start (stem cells for ards treatment) trial, a phase / trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (start study): a randomised phase a safety trial sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor mesenchymal stem cell infusion shows promise for combating coronavirus (covid- )-induced pneumonia ukcovid- : consider cytokine storm syndromes and immunosuppression clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china targeting damages in the brain: exosomes derived from msc present migration and homing abilities to different neurodegenerative and neuropsychiatric locations mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation clinical trials in acute respiratory distress syndrome: challenges and opportunities fetal endothelial and mesenchymal progenitors from the human term placenta: potency and clinical potential human organs-on-chips as tools for repurposing approved drugs as potential influenza and covid therapeutics in viral pandemics human organoid cultures: transformative new tools for human virus studies learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by -ncov use of human tissue explants to study human infectious agents three-dimensional human bronchial-tracheal epithelial tissue-like assemblies (tlas) as hosts for severe acute respiratory syndrome (sars)-cov infection novel coronavirus outbreak research teamepidemiologic features and clinical course of patients infected with sars-cov- in singapore inhibition of sars-cov- infections in engineered human tissues using clinical-grade soluble human ace infection of bat and human intestinal organoids by sars-cov- covid- : organoids go viral sars-cov- productively infects human gut enterocytes personalised organs-on-chips: functional testing for precision medicine design and fabrication of three-dimensional printed scaffolds for cancer precision medicine role of tissue engineering in covid- and future viral outbreaks primary human lung alveolus-on-a-chip model of intravascular thrombosis for assessment of therapeutics reproducing human and crossspecies drug toxicities using a liver-chip coronavirus susceptibility to the antiviral remdesivir (gs- ) is mediated by the viral polymerase and the proofreading exoribonuclease remdesivir as a possible therapeutic option for the covid- identification of pulmonary oct- + stem/progenitor cells and demonstration of their susceptibility to sars coronavirus (sars-cov) infection in vitro engineering immunomodulatory biomaterials to tune the inflammatory response thermal-sensitive hydrogel as adjuvantfree vaccine delivery system for h n intranasal immunization relationship of vaccine efficacy to the kinetics of dc and t-cell responses induced by plgbased cancer vaccines in situ regulation of dc subsets and t cells mediates tumor regression in mice injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy biomaterial-based vaccine induces regression of established intracranial glioma in rats meeting lotsize challenges of manufacturing adherent cells for therapy the impact of confluence on bone marrow mesenchymal stem (bmmsc) proliferation and osteogenic differentiation large-scale clinical expansion of mesenchymal stem cells in the gmp-compliant, closed automated quantum® cell expansion system: comparison with expansion in traditional t-flasks efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the quantum cell expansion system expansion and cellular characterization of primary human adherent cells in the quan-tum® cell expansion system, a hollow-fiber bioreactor system scale-up of human mesenchymal stem cells on microcarriers in suspension in a single-use bioreactor culture of human mesenchymal stem cells on microcarriers in a l stirredtank bioreactor scaling a xeno-free fed-batch microcarrier suspension bioreactor system from development to production scale for manufacturing xf hmscs peak msc-are we there yet cell-based therapies for covid- : proper clinical investigations are essential. cytotherapy. . how to cite this article key: cord- - vu b u authors: iba, toshiaki; levy, jerrold h.; levi, marcel; connors, jean marie; thachil, jecko title: coagulopathy of coronavirus disease date: - - journal: crit care med doi: . /ccm. sha: doc_id: cord_uid: vu b u recent studies have reported a high prevalence of thrombotic events in coronavirus disease . however, the significance of thromboembolic complications has not been widely appreciated. the purpose of this review is to provide current knowledge of this serious problem. design: narrative review. data sources: online search of published medical literature through pubmed using the term “covid- ,” “sars,” “acute respiratory distress syndrome,” “coronavirus,” “coagulopathy,” “thrombus,” and “anticoagulants.” study selection and data extraction: articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease , and anticoagulant therapy. reference lists were reviewed to identify additional relevant articles. data synthesis: coronavirus disease is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration. monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions. in the initial phase of the infection, d-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal. increased d-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism. in all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended. the etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system. although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities. conclusions: severe acute respiratory syndrome coronavirus /coronavirus disease frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. d-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations. objectives: recent studies have reported a high prevalence of thrombotic events in coronavirus disease . however, the significance of thromboembolic complications has not been widely appreciated. the purpose of this review is to provide current knowledge of this serious problem. design: narrative review. data sources: online search of published medical literature through pubmed using the term "covid- , " "sars, " "acute respiratory distress syndrome, " "coronavirus, " "coagulopathy, " "thrombus, " and "anticoagulants. " study selection and data extraction: articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease , and anticoagulant therapy. reference lists were reviewed to identify additional relevant articles. data synthesis: coronavirus disease is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration. monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions. in the initial phase of the infection, d-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal. increased d-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism. in all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended. the etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system. although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities. conclusions: severe acute respiratory syndrome coronavirus / coronavirus disease frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. d-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations. (crit care med ; xx: - ) key words: coagulopathy; coronavirus; coronavirus disease ; disseminated intravascular coagulation; hypercoagulability; thromboembolism i ncreasing communications worldwide have reported that hospitalized, critically ill coronavirus disease (covid- ) patients are frequently developing laboratory abnormalities compatible with hypercoagulability and clinically a high prevalence of thromboembolic events ( ). in addition to deep vein thrombosis (dvt) and pulmonary embolism (pe), thrombosis in extracorporeal circuits and arterial thrombosis have been reported ( ) . patients with covid- often present with dyspnea, hypoxemia, and hemodynamic instability with acute respiratory distress syndrome (ards), and in such clinical condition, venous thromboembolism (vte) may be overlooked ( , ) . standard imaging in critically ill patients utilizing contrast-enhanced ct may not always be feasible, and additionally, concerns exist with disease transmission to health-care staff. ranucci et al ( ) recently reported comprehensive coagulation analyses including d-dimers, fibrinogen levels, and viscoelastic testing in the covid- patients with ards, and reported the procoagulant profile on icu admission with median d-dimer levels of . mg/l ( times the upper limit of normal), fibrinogen levels of . g/l, and increased clot strength by thromboelastometry. panigada et al ( ) performed a similar analysis and also noted increased fibrinogen levels, enhanced platelet activation, and increased viscoelastic variables. beyond vte, the relevance of microthrombus formation to organ dysfunction and acro-ischemic change has also been suggested ( ) ( ) ( ) . although the number of postmortem pathologic reports are limited, luo et al ( ) described vascular wall thickening, stenosis of the vascular lumen, and microthrombus formation accompanying the findings of ards. similar pathologic findings are found in small vessels of other organs ( ) ( ) ( ) ( ) . magro et al ( ) reported the deposition of c b- (membrane attack complex), c d, and mannose-binding lectin-associated serine protease- in the lung capillaries and the skin microvasculature. notably, the deposition was co-localized with the severe acute respiratory syndrome coronavirus (sars-cov- ) spike glycoprotein. a recent report also noted mononuclear and polymorphonuclear leukocyte infiltration and pulmonary microcirculation along with apoptosis as induced by caspase staining ( ) . in critically ill covid- patients, there appear to be at least two separate pathologic coagulation pathologic processes that are important in producing clinical manifestations. in the microcirculation of the lung and potentially other organs, there is local direct vascular and endothelial injury producing microvascular clot formation and angiopathy ( , ) . post mortem biopsy of the lung revealed mononuclear and polymorphonuclear infiltration along with apoptosis of endothelial and mononuclear cells ( ) . in the systemic circulation, due to hypercoagulability with hyperfibrinogenemia, there is also the potential for large vessel thrombosis and major thromboembolic sequelae including pe that is reported in - % of icu patients ( ) ( ) ( ) (fig. ) . because of the important role of coagulation activation in critically ill covid- patients, this review summarizes the current knowledge about the coagulopathy and role of anticoagulation in these patients. coagulopathy is a common feature of sars-cov- infection, and an increase in d-dimer is the most common finding. one of the larger initial studies found abnormally elevated d-dimer levels in of cases ( . %) with a prevalence of % in nonsevere patients compared with % in critically ill icu patients ( ) . in another series, elevated d-dimers were associated with a poor prognosis ( ) . more recently, zhang et al ( ) examined cases and showed that d-dimer levels of over . mg/l could predict mortality with a sensitivity of . % and a specificity of . %. tang et al ( ) reported increased d-dimers and fibrin degradation products along with mildly to moderately increased prothrombin times (pts) and activated partial thromboplastin times (aptt) in covid- . of note is they reported that . % of nonsurvivors fulfilled the criteria of sepsis-induced coagulopathy, while . % of the survivors met the criteria. platelet counts in covid- patients are variable depending on the reported studies. a meta-analysis reported significantly lower platelet counts in critically ill covid- patients with weighted mean difference of - × /l ( % ci, - to - × /l), and thrombocytopenia defined as below the lower limit of the reference range was associated with more than fivefold higher risk of severe disease, which may reflect secondary infections ( ) . however, as noted above, thrombocytopenia is not a significant finding initially in covid- ( ). huang et al ( ) reported platelet counts of less than × /l in only % of icu and % in non-icu patients initially at admission. yin et al ( ) compared the platelet count between covid- -associated ards patients and non-covid- ards patients and reported minor clinical differences in platelet counts ( ± vs ± × /l). the lack of thrombocytopenia reflects that this is not a consumptive coagulopathy typical of disseminated intravascular coagulation (dic). the potential for increases in platelet counts in covid- patients is suspected to be caused by increased proinflammatory cytokines such as interleukin (il)- β and il- produced by the macrophages and monocytes in the lung ( ) , and activated platelets may contribute to the lung injury ( ) . interestingly, only . % of covid- patients who died met dic criteria of the international society on thrombosis and haemostasis (isth) ( ) . more recent data suggests the covid- coagulopathy is different from common bacterial infectioninduced dic with relatively minimal changes in platelet counts, antithrombin levels, pt, and aptt ( , ) . the association with increased microvascular thrombosis, increased levels of lactate dehydrogenase (ldh) and ferritin, and mild increases in pt and aptt are reminiscent of thrombotic microangiopathy ( ) . although thrombocytopenia and hemolytic anemia are uncommon in covid- , clinical presentations of increased d-dimers, vascular endothelial injury, and multiple organ damage are also common features of atypical hemolytic uremic syndrome ( ) . the coagulation cascade is activated in viral infections as a host defense to limit the spread of the pathogens ( ) . initially, an adaptive hemostasis response occurs that is associated with a systemic inflammatory response. as a result of increased inflammatory activity, fibrinogen is significantly increased, and thrombin generation occurs ( ) . the enhanced cytokine production during virus infection also stimulates additional procoagulant reactions, with increased tissue factor expression, a major initiator of the activation in coagulation. however, other factors such as phosphatidylserine on the cellular membrane, neutrophil extracellular traps, and damage-associated molecular patterns (damps) may also be involved in the procoagulant profile in covid- ( ) . in some cases, the presence of antiphospholipid antibodies that can induce arterial thrombosis is reported ( ) , and the relevance to stroke and acute coronary disease should be examined in future studies. there is an association between bronchoalveolar coagulation/fibrinolysis and the pathogenesis of ards that enhances intrapulmonary deposition of fibrin ( ) . in cases of bacterial infection, measurement of coagulation and fibrinolysis factors in bronchoalveolar lavage fluid (balf) have demonstrated enhanced intrapulmonary thrombin generation, insufficiently balanced physiologic anticoagulation, and suppressed fibrinolysis mediating the pathogenesis of ards ( ) . in covid- , procoagulant activity is increased through tissue factor pathway, and plasmin activity suppressed by the reduced urokinase-type plasminogen activator and increased plasminogen activator inhibitor- ( , ) . by contrast, ji et al ( ) reported activated plasmin and increased fibrinolytic activity resulting in d-dimer elevation in covid- and reported that the preexisting increased plasmin activity recognized in hypertension, diabetes, and cardiovascular disease enhances the virulence and infectivity of the sars-cov- virus by cleaving its spike proteins. the pathologic findings of ards in covid- suggest the inflammation and diffuse alveolar damage with exudates that mimic sepsis-induced ards are lymphocyte predominant ( ) . gattinoni et al ( ) hypothesized that there are two distinct types of lung damage in ards. type-l is characterized by the low elastance and high compliance, which is rarely seen in ards, while type-h shows high elastance and low compliance that is the typical style of ards. they explain the primary cause of hypoxemia in type-l is perfusion defects presumably caused by vasoconstriction and high shunt fraction. in contrast, the high elastance in type-h is thought to be induced by lung edema. we hypothesize that the intravascular coagulation and clot formation, in addition to the vasoconstriction, contribute to the disturbance of perfusion. the findings as mentioned above suggest that the procoagulant changes are present in both intra-alveolar and intravascular spaces (fig. ) . indeed, dolhnikoff et al ( ) reported the fibrinous thrombi in pulmonary arteriole in areas of both damaged and preserved lung parenchyma. the endothelial damage in the pulmonary capillary is also accelerated by the vascular endothelial damage. sars-cov- infects endothelial cells through an angiotensinconverting enzyme receptor ( ); the rapid viral replication causes massive endothelial cell apoptosis and triggers the loss of anticoagulant function of the vascular lumen. in addition to the derangement of coagulation/fibrinolysis and platelet function, endothelial dysfunction contributes to the procoagulant change in covid- (fig. ) . various proinflammatory cytokines are known to be elevated in covid- , and a "cytokine storm" is estimated to be relevant in the progression and modification of the disease. tumor necrosis factor-α, il- β, il- , interferon-γ, and granulocytecolony stimulating factor are the representative cytokines that mediate inflammation and coagulation. elevation in the circulating blood cytokine levels is also increased in the lung. xiong et al ( ) revealed increased levels of chemokines such as monocyte chemotactic protein (mcp- ), interferoninducible protein- , macrophage inflammatory protein- α in the balf obtained from covid- patients. this cytokine storm leads to the systemic intravascular coagulation, multiple organ dysfunction syndrome (mods), and fatal outcome ( ). indeed, cao et al ( ) integrated data obtained from more than , covid- cases, and reported that the prevalence of ards was . %, that of mods was . %, and the fatality rate was . %. therefore, the regulation of the overproduced cytokines is a focus of treatments targeting suppression of il- family and il- currently in trials ( ) . the multiple inflammatory mediators also can produce microcirculatory injury and thrombus formation. in the postmortem evaluation of covid- pulmonary tissues, the arterial vessels demonstrated neutrophilic and mononuclear cellular infiltration, and apoptosis of endothelial cells and mononuclear cells based on caspase immunostaining ( ). mehta et al ( ) reported that severe covid- resembles hemophagocytic lymphohistiocytosis (hlh) most frequently triggered by viral infection, a clinical scenario with uncontrolled cytokine production and typically presentation of fever, splenomegaly, cytopenia of two or more lineages, increased ferritin, low fibrinogen level, and mods, including ards ( , ) . chest radiographic findings in hlh include bilateral www.ccmjournal.org xxx • volume xx • number xxx ground-glass opacities and consolidation that are similar to covid- . in laboratory testing, hyperferritinemia and high ldh levels are common, but low fibrinogen levels and cytopenias of more than two cell lineages by hemophagocytosis are not reported in covid- . taken together, it may be reasonable to think that the pathophysiology of covid- overlaps with low-grade hlh, and the differences and similarities of hlh and covid- should be examined in future studies. immobilization, inflammation, activated coagulation, and suppressed fibrinolysis increase the risk of vte and pe. increasing reports have indicated an increased risk of vte and pe in covid- ( , ) . cui et al ( ) examined thrombosis in nonsymptomatic lower limbs by ultrasonography in covid- pneumonia patients treated in icu and reported that the prevalence was % ( / ). in another study in sars-cov- infected patients, it was reported that . % of patients had dvt, and . % had pe ( ). klok et al ( ) studied icu patients and confirmed vte in % and arterial thrombotic events in . % patients. it should be kept in mind that the prevalence of vte and pe is underestimated since the access to contrast-enhanced ct may be limited in critically ill patients for practical reasons. d-dimer levels can also not accurately differentiate between the presence of thrombosis and high levels due to the critical illness state. therefore, all critically ill patients should receive vte prophylaxis, preferably using low-molecular-weight (lmw) heparin regardless of their d-dimer level. in case of sudden deterioration, increased oxygenation requirements, right heart failure, and/or shock, a very high suspicion for pe should be maintained ( ) . the effect of sars-cov- infection on pregnancy is not clear and, liu et al ( ) reported pregnancy and childbirth did not aggravate the course of covid- pneumonia in the small case study ( cases). however, dashraath et al ( ) suggested that % of pregnant women will require mechanical ventilation, % will have fetal growth restriction, and % will deliver preterm. in addition, since there are changes in coagulation/fibrinolysis that occur naturally during pregnancy, with hyperfibrinogenemia, there are considerable concerns for the risk of pregnant patients for thrombotic complications and coagulopathy. isth released an interim guideline for the management of covid- -associated coagulopathy and dic in pregnant women ( ) , and this guidance recommends: admission of any patients with markedly raised d-dimer, prolonged pt, platelet county less than × /l, or fibrinogen less than g/l, even in absence of other concerns, with the consideration for the use of prophylactic lmw heparin in all patients who require hospital admission in the absence of contraindications. patients with cancer are more susceptible to sars-cov- infection due to immunosuppression, poor nutrition, . covid- infection causes acute lung injury induced by activation of residential macrophages, lymphocyte apoptosis, and neutrophils. the macrophages produce cytokines and chemokines including monocyte chemotactic protein (mcp- ), interferon-inducible protein (ip)- , macrophage inflammatory protein (mip)- , and releases these mediators into the alveolar space. increased tumor necrosis factor (tnf)-related apoptosis-inducing ligand (trail) stimulates the lymphocyte apoptosis. covid- also induces vascular endothelial damage through activating the complement system that leads to increased permeability and inflammatory thrombus formation. the fibrinolytic system is activated releasing fibrin degradation fragments (d-dimers) in the circulation. when the changes in the blood vessel are dominant and the damage in the alveolar space is relatively mild, that situation is considered as type-l, and when the damage advances to the alveolar space, it turns to type-h. mac = membrane attack complex, nets = neutrophil extracellular traps, sars-cov- = severe acute respiratory syndrome coronavirus . comorbidities, and immobilization ( ) . covid- affected cancer patients require specific attention as they are prone to thromboembolic complications, and thromboprophylaxis is mandatory. however, evidence on the clinical course of covid- in cancer patients is scarce so far, and more studies are warranted. heparin for vte prevention isth interim guidance recommends the use of prophylactic lmw heparin in severe covid- patients ( ) . the effect of heparin, mainly lmw heparin, is reported by tang et al ( ) showing a reduced mortality in cases with coagulopathy and treated with heparin compared with the patients who did have coagulopathy and were not treated with heparin ( . % vs . %, respectively; p = . ). in the same study, increasing levels of d-dimer were related to increasing mortality in nonheparin treated patients. heparin exhibits anti-inflammatory effects by neutralizing damps to protect the endothelial cells by reducing the toxicity of histones on endothelial tight junctions, and decrease lung edema and vascular leakage ( , ) . regarding the type and dose of heparins, we summarize the current recommendation in table . caution is required for the application of the treatment dose of heparins. the overall effectiveness is still under debate ( ) . in addition to vte prevention, anticoagulant therapy may also have anti-inflammatory effects. glas et al ( ) proposed the administration of anticoagulants such as antithrombin and activated protein c for the treatment of classical ards. others have suggested therapies to reverse pulmonary microthrombi in ards with tissue plasminogen activator; however, supporting evidence in humans is currently unavailable ( , ) . although platelets may be involved in the local and systemic thrombotic response in covid- coagulopathy, adding a platelet inhibitor to unfractionated heparin or lmw heparin at therapeutic doses would increase the potential for risk for bleeding. this is a known phenomenon in acute coronary syndromes where anticoagulant therapy along with antiplatelet therapy may decrease arterial thrombosis, but it is associated with increased bleeding risk that also increases adverse events and most p y inhibitors have long half-lives without the availability of any reversal agent ( ) . further, platelet function testing is cumbersome, and research studies on platelet activation biomarkers are still premature. the microvascular thrombosis, dvt, and pulmonary artery thrombosis appear to be due to abnormally elevated coagulation factor levels and the absence of the usual protective effects of the vascular endothelium. the role of platelet activation in this process is less well defined and not clearly implicated. sars-cov- /covid- frequently induces hypercoagulability with inflammation driving increased levels of procoagulant clotting factors and disruption of the normal ). there are four major factors that accelerate thrombosis formation. first, severe acute respiratory syndrome coronavirus infection-induced cytokine storm activates coagulation. proinflammatory cytokines such as interleukin (il)- β and il- stimulate the expression of tissue factor on immune cells and initiates extrinsic coagulation cascade activation. second, the fibrinolytic system is suppressed by the decreased activity of urokinase-type plasminogen activator and increased release of plasminogen activator inhibitor- . third, platelets are activated by various proinflammatory cytokines and the damaged endothelium readily bind platelets. fourth, endothelial damage induced by inflammation further accelerates the thrombotic reaction. www.ccmjournal.org xxx • volume xx • number xxx homeostasis of vascular endothelial cells resulting in microangiopathy, local thrombus formation, and a systemic coagulation defect leading to large vessel thrombosis and major thromboembolic complications including pe in critically ill hospitalized patients. in patients with infection-induced coagulopathies, a critical component of management is treating the underlying disease. in covid- , because we currently do not have a standard antiviral therapy, we believe some of the unique microvascular and macrovascular hypercoagulability clinician are observing represent thromboinflammatory responses to the continuing infection. as a result, sequential monitoring of coagulation tests every - days is recommended. surveillance for development of vte is important with heightened suspicion in patients with sudden decompensation not attributable to other factors. all hospitalized patients should receive vte prophylaxis; higher than conventional doses of lmw heparin are currently being investigated in clinical trials, although many centers have adopted escalated or intermediate doses for vte prophylaxis. whether anticoagulation alone is sufficient to prevent these thrombotic events, especially those driven by endothelial dysfunction, is unknown. additional strategies and studies to address all factors that result in microvascular and macrovascular thrombosis are needed. dr. levy received funding from research, data safety, or advisory committees for csl behring, instrumentation labs, janssen, merck, and octapharma. dr. connors' institution received funding from csl behring; received funding from abbott (consulting), bristol-myers squibb (consulting), and portola (scientific advisory board). the remaining authors have disclosed that they do not have any potential conflicts of interest. for information regarding this article, e-mail: toshiiba@juntendo.ac.jp acute pulmonary embolism and covid- pneumonia: a random association? coagulopathy and antiphospholipid antibodies in patients with covid- risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis the procoagulant pattern of patients with covid- acute respiratory distress syndrome hypercoagulability of covid- patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis clinical and coagulation characteristics of patients with critical covid- pneumonia and acroischemia clinical observation and management of covid- patients hypothesis for potential pathogenesis of sars-cov- infection-a review of immune changes in patients with viral pneumonia clinical pathology of critical patient with novel coronavirus pneumonia (covid- ) covid- ): a clinical update complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases endothelial cell infection and endotheliitis in covid- how i treat disseminated intravascular coagulation incidence of thrombotic complications in critically ill icu patients with covid- lille icu haemostasis covid- group: pulmonary embolism in covid- patients: awareness of an increased prevalence acute pulmonary embolism in covid- patients on ct angiography and relationship to d-dimer levels china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study d-dimer levels on admission to predict in-hospital mortality in patients with covid- abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study clinical features of patients infected with novel coronavirus in wuhan, china difference of coagulation features between severe pneumonia induced by sars-cov and non-sarscov induction of pro-inflammatory cytokines (il- and il- ) and lung inflammation by coronavirus- (covi- or sars-cov- ): anti-inflammatory strategies exploring possible mechanisms for covid- induced thrombocytopenia: unanswered questions clinical characteristics of fatal and recovered cases of coronavirus disease (covid- ) in wuhan, china: a retrospective study prominent changes in blood coagulation of patients with sars-cov- infection will complement inhibition be the new target in treating covid- related systemic thrombosis? circulation multiple roles of the coagulation protease cascade during virus infection immunohaemostasis: a new view on haemostasis during sepsis targeting potential drivers of covid- : neutrophil extracellular traps bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. comparison with the acute respiratory distress syndrome coagulation, fibrinolysis, and fibrin deposition in acute lung injury mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury elevated plasmin(ogen) as a common risk factor for covid- susceptibility autopsy in suspected covid- cases covid- pneumonia: different respiratory treatments for different phenotypes? pathological evidence of pulmonary thrombotic phenomena in severe covid- angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in covid- patients imaging and clinical features of patients with novel coronavirus sars-cov- : a systematic review and meta-analysis uk: covid- : consider cytokine storm syndromes and immunosuppression coagulation disorders in hemophagocytic lymphohistiocytosis/macrophage activation syndrome pulmonary involvement in patients with hemophagocytic lymphohistiocytosis covid- complicated by acute pulmonary embolism prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars diagnosis isth interim guidance on recognition and management of coagulopathy in covid- pregnancy and perinatal outcomes of women with coronavirus disease (covid- ) pneumonia: a preliminary analysis coronavirus disease (covid- ) pandemic and pregnancy isth interim guidance in recognition and management of coagulopathy or dic in covid- -specific issues for consideration in pregnant women cancer patients in sars-cov- infection: a nationwide analysis in china anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy the versatile heparin in covid- unfractionated heparin alleviates sepsisinduced acute lung injury by protecting tight junctions covid- and its implications for thrombosis and anticoagulation treatment of severe acute respiratory distress syndrome: a final report on a phase i study is there a role for tissue plasminogen activator (tpa) as a novel treatment for refractory covid- associated acute respiratory distress syndrome (ards) reversal strategy in antagonizing the p y -inhibitor ticagrelor key: cord- - qfecv h authors: velasquez, t.; mackey, g.; lusk, j.; kyle, u. g.; fontenot, t.; marshall, p.; shekerdemian, l. s.; coss-bu, j. a.; nishigaki, a.; yatabe, t.; tamura, t.; yamashita, k.; yokoyama, m.; ruiz-rodriguez, j. c.; encina, b.; belmonte, r.; troncoso, i.; tormos, p.; riveiro, m.; baena, j.; sanchez, a.; bañeras, j.; cordón, j.; duran, n.; ruiz, a.; caballero, j.; nuvials, x.; riera, j.; serra, j.; rutten, a. m. f.; van ieperen, s. n. m.; der kinderen, e. p. h. m.; van logten, t.; kovacikova, l.; skrak, p.; zahorec, m.; kyle, u. g.; akcan-arikan, a.; silva, j. c.; mackey, g.; lusk, j.; goldsworthy, m.; shekerdemian, l. s.; coss-bu, j. a.; wood, d.; harrison, d.; parslow, r.; davis, p.; pappachan, j.; goodwin, s.; ramnarayan, p.; chernyshuk, s.; yemets, h.; zhovnir, v.; pulitano’, s. m.; de rosa, s.; mancino, a.; villa, g.; tosi, f.; franchi, p.; conti, g.; patel, b.; khine, h.; shah, a.; sung, d.; singer, l.; haghbin, s.; inaloo, s.; serati, z.; idei, m.; nomura, t.; yamamoto, n.; sakai, y.; yoshida, t.; matsuda, y.; yamaguchi, y.; takaki, s.; yamaguchi, o.; goto, t.; longani, n.; medar, s.; abdel-aal, i. r.; el adawy, a. s.; mohammed, h. m. e. h.; mohamed, a. n.; parry, s. m.; knight, l. d.; denehy, l.; de morton, n.; baldwin, c. e.; sani, d.; kayambu, g.; da silva, v. z. m.; phongpagdi, p.; puthucheary, z. a.; granger, c. l.; rydingsward, j. e.; horkan, c. m.; christopher, k. b.; mcwilliams, d.; jones, c.; reeves, e.; atkins, g.; snelson, c.; aitken, l. m.; rattray, j.; kenardy, j.; hull, a. m.; ullman, a.; le brocque, r.; mitchell, m.; davis, c.; macfarlane, b.; azevedo, j. c.; rocha, l. l.; de freitas, f. f. m.; cavalheiro, a. m.; lucinio, n. m.; lobato, m. s.; ebeling, g.; kraegpoeth, a.; laerkner, e.; de brito-ashurst, i.; white, c.; gregory, s.; forni, l. g.; flowers, e.; curtis, a.; wood, c. a.; siu, k.; venkatesan, k.; muhammad, j. b. h.; ng, l.; seet, e.; baptista, n.; escoval, a.; tomas, e.; agrawal, r.; mathew, r.; varma, a.; dima, e.; charitidou, e.; perivolioti, e.; pratikaki, m.; vrettou, c.; giannopoulos, a.; zakynthinos, s.; routsi, c.; atchade, e.; houzé, s.; jean-baptiste, s.; thabut, g.; genève, c.; tanaka, s.; lortat-jacob, b.; augustin, p.; desmard, m.; montravers, p.; de molina, f. j. gonzález; barbadillo, s.; alejandro, r.; Álvarez-lerma, f.; vallés, j.; catalán, r. m.; palencia, e.; jareño, a.; granada, r. m.; ignacio, m. l.; cui, n.; liu, d.; wang, h.; su, l.; qiu, h.; li, r.; jaffal, k.; rouzé, a.; poissy, j.; sendid, b.; nseir, s.; paramythiotou, e.; rizos, m.; frantzeskaki, f.; antoniadou, a.; vourli, s.; zerva, l.; armaganidis, a.; riera, j.; gottlieb, j.; greer, m.; wiesner, o.; martínez, m.; acuña, m.; rello, j.; welte, t.; atchade, e.; mignot, t.; houzé, s.; jean-baptiste, s.; thabut, g.; lortat-jacob, b.; tanaka, s.; augustin, p.; desmard, m.; montravers, p.; soussi, s.; dudoignon, e.; ferry, a.; chaussard, m.; benyamina, m.; alanio, a.; touratier, s.; chaouat, m.; lafaurie, m.; mimoun, m.; mebazaa, a.; legrand, m.; sheils, m. a.; patel, c.; mohankumar, l.; akhtar, n.; noriega, s. k. pacheco; aldana, n. navarrete; león, j. l. Ávila; baquero, j. durand; bernal, f. fernández; ahmadnia, e.; hadley, j. s.; millar, m.; hall, d.; hewitt, h.; yasuda, h.; sanui, m.; komuro, t.; kawano, s.; andoh, k.; yamamoto, h.; noda, e.; hatakeyama, j.; saitou, n.; okamoto, h.; kobayashi, a.; takei, t.; matsukubo, s.; rotzel, h. b.; lázaro, a. serrano; prada, d. aguillón; gimillo, m. rodriguez; barinas, o. diaz; cortes, m. l. blasco; franco, j. ferreres; roca, j. m. segura; carratalá, a.; gonçalves, b.; turon, r.; mendes, a.; miranda, f.; mata, p. j.; cavalcanti, d.; melo, n.; lacerda, p.; kurtz, p.; righy, c.; rosario, l. e. de la cruz; lesmes, s. p. gómez; romero, j. c. garcía; herrera, a. n. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; hualde, j. barado; hernández, a. ansotegui; irazabal, j. m. guergué; spatenkova, v.; bradac, o.; suchomel, p.; urli, t.; lazzeri, e. heusch; aspide, r.; zanello, m.; perez-borrero, l.; garcia-alvarez, j. m.; arias-verdu, m. d.; aguilar-alonso, e.; rivera-fernandez, r.; mora-ordoñez, j.; de la fuente-martos, c.; castillo-lorente, e.; guerrero-lopez, f.; lesmes, s. p. gómez; rosario, l. e. de la cruz; pertuz, e. d. díaz; hernández, a. ansotegui; romero, j. c. garcía; sánchez, m. j. gómez; herrera, a. n. garcía; ramírez, j. roldán; sanz, e. regidor; hualde, j. barado; león, j. p. tirapu; navarro-guillamón, l.; cordovilla-guardia, s.; iglesias-santiago, a.; guerrero-lópez, f.; fernández-mondéjar, e.; vidal, a.; perez, m.; juez, a.; arias, n.; colino, l.; perez, j. l.; pérez, h.; calpe, p.; alcala, m. a.; robaglia, d.; perez, c.; lan, s. k.; cunha, m. m.; moreira, t.; santos, f.; lafuente, e.; fernandes, m. j.; silva, j. g.; rosario, l. e. de la cruz; lesmes, s. p. gómez; herrera, a. n. garcía; romero, j. c. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; echeverría, j. g. armando; hernández, a. ansotegui; hualde, j. barado; podlepich, v.; sokolova, e.; alexandrova, e.; lapteva, k.; kurtz, p.; shuinotsuka, c.; rabello, l.; vianna, g.; reis, a.; cairus, c.; salluh, j.; bozza, f.; torres, j. c. barrios; araujo, n. j. fernández; garcía-olivares, p.; keough, e.; dalorzo, m.; tang, l. k.; de sousa, i.; díaz, m.; marcos-zambrano, l. j.; guerrero, j. e.; gomez, s. e. zamora; lopez, g. d. hernandez; cuellar, a. i. vazquez; nieto, o. r. perez; gonzalez, j. a. castanon; bhasin, d.; rai, s.; singh, h.; gupta, o.; bhattal, m. k.; sampley, s.; sekhri, k.; nandha, r.; aliaga, f. a.; olivares, f.; appiani, f.; farias, p.; alberto, f.; hernández, a.; pons, s.; sonneville, r.; bouadma, l.; neuville, m.; mariotte, e.; radjou, a.; lebut, j.; chemam, s.; voiriot, g.; dilly, m. p.; mourvillier, b.; dorent, r.; nataf, p.; wolff, m.; timsit, j. f.; ediboglu, o.; ataman, s.; ozkarakas, h.; kirakli, c.; vakalos, a.; avramidis, v.; obukhova, o.; kurmukov, i. a.; kashiya, s.; golovnya, e.; baikova, v. n.; ageeva, t.; haritydi, t.; kulaga, e. v.; rios-toro, j. j.; perez-borrero, l.; aguilar-alonso, e.; arias-verdu, m. d.; garcia-alvarez, j. m.; lopez-caler, c.; de la fuente-martos, c.; rodriguez-fernandez, s.; sanchez-orézzoli, m. gomez; martin-gallardo, f.; nikhilesh, j.; joshi, v.; villarreal, e.; ruiz, j.; gordon, m.; quinza, a.; gimenez, j.; piñol, m.; castellanos, a.; ramirez, p.; jeon, y. d.; jeong, w. y.; kim, m. h.; jeong, i. y.; ahn, m. y.; ahn, j. y.; han, s. h.; choi, j. y.; song, y. g.; kim, j. m.; ku, n. s.; shah, h.; kellner, f.; rezai, f.; mistry, n.; yodice, p.; ovnanian, v.; fless, k.; handler, e.; alejos, r. martínez; romeu, j. d. martí; antón, d. gonzález; quinart, a.; martí, a. torres; llaurado-serra, m.; lobo-civico, a.; ventura-rosado, a.; piñol-tena, a.; pi-guerrero, m.; paños-espinosa, c.; peralvo-bernat, m.; marine-vidal, j.; gonzalez-engroba, r.; montesinos-cerro, n.; treso-geira, m.; valeiras-valero, a.; martinez-reyes, l.; sandiumenge, a.; jimenez-herrera, m. f.; helyar, s.; riozzi, p.; noon, a.; hallows, g.; cotton, h.; keep, j.; hopkins, p. a.; taggu, a.; renuka, s.; sampath, s.; rood, p. j. t.; frenzel, t.; verhage, r.; bonn, m.; pickkers, p.; van der hoeven, j. g.; van den boogaard, m.; corradi, f.; melnyk, l.; moggia, f.; pienovi, r.; adriano, g.; brusasco, c.; mariotti, l.; lattuada, m.; bloomer, m. j.; coombs, m.; ranse, k.; endacott, r.; maertens, b.; blot, k.; blot, s.; amerongen, m. p. van nieuw; van der heiden, e. s.; twisk, j. w. r.; girbes, a. r. j.; spijkstra, j. j.; riozzi, p.; helyar, s.; cotton, h.; hallows, g.; noon, a.; bell, c.; peters, k.; feehan, a.; keep, j.; hopkins, p. a.; churchill, k.; hawkins, k.; brook, r.; paver, n.; endacott, r.; maistry, n.; van wijk, a.; rouw, n.; van galen, t.; evelein-brugman, s.; taggu, a.; krishna, b.; sampath, s.; putzu, a.; fang, m.; berto, m. boscolo; belletti, a.; cassina, t.; cabrini, l.; mistry, m.; alhamdi, y.; welters, i.; abrams, s. t.; toh, c. h.; han, h. s.; gil, e. m.; lee, d. s.; park, c. m.; winder-rhodes, s.; lotay, r.; doyle, j.; ke, m. w.; huang, w. c.; chiang, c. h.; hung, w. t.; cheng, c. c.; lin, k. c.; lin, s. c.; chiou, k. r.; wann, s. r.; shu, c. w.; kang, p. l.; mar, g. y.; liu, c. p.; dubó, s.; aquevedo, a.; jibaja, m.; berrutti, d.; labra, c.; lagos, r.; garcía, m. f.; ramirez, v.; tobar, m.; picoita, f.; peláez, c.; carpio, d.; alegría, l.; hidalgo, c.; godoy, k.; bakker, j.; hernández, g.; sadamoto, y.; katabami, k.; wada, t.; ono, y.; maekawa, k.; hayakawa, m.; sawamura, a.; gando, s.; marin-mateos, h.; perez-vela, j. l.; garcia-gigorro, r.; peiretti, m. a. corres; lopez-gude, m. j.; chacon-alves, s.; renes-carreño, e.; montejo-gonzález, j. c.; parlevliet, k. l.; touw, h. r. w.; beerepoot, m.; boer, c.; elbers, p. w. g.; tuinman, p. r.; abdelmonem, s. a.; helmy, t. a.; el sayed, i.; ghazal, s.; akhlagh, s. h.; masjedi, m.; hozhabri, k.; kamali, e.; zýková, i.; paldusová, b.; sedlák, p.; morman, d.; youn, a. m.; ohta, y.; sakuma, m.; bates, d.; morimoto, t.; su, p. l.; chang, w. y.; lin, w. c.; chen, c. w.; facchin, f.; zarantonello, f.; panciera, g.; de cassai, a.; venrdramin, a.; ballin, a.; tonetti, t.; persona, p.; ori, c.; del sorbo, l.; rossi, s.; vergani, g.; cressoni, m.; chiumello, d.; chiurazzi, c.; brioni, m.; algieri, i.; tonetti, t.; guanziroli, m.; colombo, a.; tomic, i.; colombo, a.; crimella, f.; carlesso, e.; gasparovic, v.; gattinoni, l.; neto, a. serpa; schmidt, m.; pham, t.; combes, a.; de abreu, m. gama; pelosi, p.; schultz, m. j.; katira, b. h.; engelberts, d.; giesinger, r. e.; ackerley, c.; yoshida, t.; zabini, d.; otulakowski, g.; post, m.; kuebler, w. m.; mcnamara, p. j.; kavanagh, b. p.; pirracchio, r.; rigon, m. resche; carone, m.; chevret, s.; annane, d.; eladawy, s.; el-hamamsy, m.; bazan, n.; elgendy, m.; de pascale, g.; vallecoccia, m. s.; cutuli, s. l.; di gravio, v.; pennisi, m. a.; conti, g.; antonelli, m.; andreis, d. t.; khaliq, w.; singer, m.; hartmann, j.; harm, s.; carmona, s. alcantara; almudevar, p. matia; abellán, a. naharro; ramos, j. veganzones; pérez, l. pérez; valbuena, b. lobo; sanz, n. martínez; simón, i. fernández; arrigo, m.; feliot, e.; deye, n.; cariou, a.; guidet, b.; jaber, s.; leone, m.; resche-rigon, m.; baron, a. vieillard; legrand, m.; gayat, e.; mebazaa, a.; balik, m.; kolnikova, i.; maly, m.; waldauf, p.; tavazzi, g.; kristof, j.; herpain, a.; su, f.; post, e.; taccone, f.; vincent, j. l.; creteur, j.; lee, c.; hatib, f.; jian, z.; buddi, s.; cannesson, m.; fileković, s.; turel, m.; knafelj, r.; gorjup, v.; stanić, r.; gradišek, p.; cerović, o.; mirković, t.; noč, m.; tirkkonen, j.; hellevuo, h.; olkkola, k. t.; hoppu, s.; lin, k. c.; hung, w. t.; chiang, c. c.; huang, w. c.; juan, w. c.; lin, s. c.; cheng, c. c.; lin, p. h.; fong, k. y.; hou, d. s.; kang, p. l.; wann, s. r.; chen, y. s.; mar, g. y.; liu, c. p.; paul, m.; bougouin, w.; geri, g.; dumas, f.; champigneulle, b.; legriel, s.; charpentier, j.; mira, j. p.; sandroni, c.; cariou, a.; zimmerman, j.; sullivan, e.; noursadeghi, m.; fox, b.; sampson, d.; mchugh, l.; yager, t.; cermelli, s.; seldon, t.; bhide, s.; brandon, r. a.; brandon, r. b.; zwaag, j.; beunders, r.; pickkers, p.; kox, m.; gul, f.; arslantas, m. k.; genc, d.; zibandah, n.; topcu, l.; akkoc, t.; cinel, i.; greco, e.; lauretta, m. p.; andreis, d. t.; singer, m.; garcia, i. palacios; cordero, m.; martin, a. diaz; pallás, t. aldabó; montero, j. garnacho; rey, j. revuelto; malo, l. roman; montoya, a. a. tanaka; martinez, a. d. c. amador; ayala, l. y. delgado; zepeda, e. monares; granillo, j. franco; sanchez, j. aguirre; alejo, g. camarena; cabrera, a. rugerio; montenegro, a. pedraza; pham, t.; beduneau, g.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; soilemezi, e.; koco, e.; savvidou, s.; nouris, c.; matamis, d.; di mussi, r.; spadaro, s.; volta, c. a.; mariani, m.; colaprico, a.; antonio, c.; bruno, f.; grasso, s.; rodriguez, a.; martín-loeches, i.; díaz, e.; masclans, j. r.; gordo, f.; solé-violán, j.; bodí, m.; avilés-jurado, f. x.; trefler, s.; magret, m.; reyes, l. f.; marín-corral, j.; yebenes, j. c.; esteban, a.; anzueto, a.; aliberti, s.; restrepo, m. i.; larsson, j. skytte; redfors, b.; ricksten, s. e.; haines, r.; powell-tuck, j.; leonard, h.; ostermann, m.; berthelsen, r. e.; itenov, t. s.; perner, a.; jensen, j. u.; ibsen, m.; jensen, a. e. k.; bestle, m. h.; bucknall, t.; dixon, j.; boa, f.; macphee, i.; philips, b. j.; doyle, j.; saadat, f.; samuels, t.; huddart, s.; mccormick, b.; debrunnar, r.; preece, j.; swart, m.; peden, c.; richardson, s.; forni, l.; kalfon, p.; baumstarck, k.; estagnasie, p.; geantot, m. a.; berric, a.; simon, g.; floccard, b.; signouret, t.; boucekine, m.; fromentin, m.; nyunga, m.; sossou, a.; venot, m.; robert, r.; follin, a.; renault, a.; garrouste, m.; collange, o.; levrat, q.; villard, i.; thévenin, d.; pottecher, j.; patrigeon, r. g.; revel, n.; vigne, c.; mimoz, o.; auquier, p.; pawar, s.; jacques, t.; deshpande, k.; pusapati, r.; wood, b.; pulham, r. a.; wray, j.; brown, k.; pierce, c.; nadel, s.; ramnarayan, p.; azevedo, j. r.; montenegro, w. s.; rodrigues, d. p.; sousa, s. c.; araujo, v. f.; leitao, a. l.; prazeres, p. h.; mendonca, a. v.; paula, m. p.; das neves, a.; loudet, c. i.; busico, m.; vazquez, d.; villalba, d.; lischinsky, a.; veronesi, m.; emmerich, m.; descotte, e.; juliarena, a.; bisso, m. carboni; grando, m.; tapia, a.; camargo, m.; ulla, d. villani; corzo, l.; dos santos, h. placido; ramos, a.; doglia, j. a.; estenssoro, e.; carbonara, m.; magnoni, s.; donald, c. l. mac; shimony, j. s.; conte, v.; triulzi, f.; stretti, f.; macrì, m.; snyder, a. z.; stocchetti, n.; brody, d. l.; podlepich, v.; shimanskiy, v.; savin, i.; lapteva, k.; chumaev, a.; tjepkema-cloostermans, m. c.; hofmeijer, j.; beishuizen, a.; hom, h.; blans, m. j.; van putten, m. j. a. m.; longhi, l.; frigeni, b.; curinga, m.; mingone, d.; beretta, s.; patruno, a.; gandini, l.; vargiolu, a.; ferri, f.; ceriani, r.; rottoli, m. r.; lorini, l.; citerio, g.; pifferi, s.; battistini, m.; cordolcini, v.; agarossi, a.; di rosso, r.; ortolano, f.; stocchetti, n.; lourido, c. mora; cabrera, j. l. santana; santana, j. d. martín; alzola, l. melián; del rosario, c. garcía; pérez, h. rodríguez; torrent, r. lorenzo; eslami, s.; dalhuisen, a.; fiks, t.; schultz, m. j.; hanna, a. abu; spronk, p. e.; wood, m.; maslove, d.; muscedere, j.; scott, s. h.; saha, t.; hamilton, a.; petsikas, d.; payne, d.; boyd, j. g.; puthucheary, z. a.; mcnelly, a. s.; rawal, j.; connolly, b.; mcphail, m. j.; sidhu, p.; rowlerson, a.; moxham, j.; harridge, s. d.; hart, n.; montgomery, h. e.; jovaisa, t.; thomas, b.; gupta, d.; wijayatilake, d. s.; shum, h. p.; king, h. s.; chan, k. c.; tang, k. b.; yan, w. w.; arias, c. castro; latorre, j.; de la rica, a. suárez; garrido, e. maseda; feijoo, a. montero; gancedo, c. hernández; tofiño, a. lópez; rodríguez, f. gilsanz; gemmell, l. k.; campbell, r.; doherty, p.; mackay, a.; singh, n.; vitaller, s.; nagib, h.; prieto, j.; del arco, a.; zayas, b.; gomez, c.; tirumala, s.; pasha, s. a.; kumari, b. k.; martinez-lopez, p.; puerto-morlán, a.; nuevo-ortega, p.; pujol, l. martinez; dolset, r. algarte; gonzález, b. sánchez; riera, s. quintana; Álvarez, j. trenado; quintana, s.; martínez, l.; algarte, r.; sánchez, b.; trenado, j.; tomas, e.; brock, n.; viegas, e.; filipe, e.; cottle, d.; traynor, t.; martínez, m. v. trasmonte; márquez, m. pérez; gómez, l. colino; martínez, n. arias; muñoz, j. m. milicua; bellver, b. quesada; varea, m. muñoz; llorente, m. Á. alcalá; calvo, c. pérez; hillier, s. d.; faulds, m. c.; hendra, h.; lawrence, n.; maekawa, k.; hayakawa, m.; ono, y.; kodate, a.; sadamoto, y.; tominaga, n.; mizugaki, a.; murakami, h.; yoshida, t.; katabami, k.; wada, t.; sawamura, a.; gando, s.; silva, s.; kerhuel, l.; malagurski, b.; citerio, g.; chabanne, r.; laureys, s.; puybasset, l.; nobile, l.; pognuz, e. r.; rossetti, a. o.; verginella, f.; gaspard, n.; creteur, j.; ben-hamouda, n.; oddo, m.; taccone, f. s.; ono, y.; hayakawa, m.; iijima, h.; maekawa, k.; kodate, a.; sadamoto, y.; mizugaki, a.; murakami, h.; katabami, k.; wada, t.; sawamura, a.; gando, s.; kodate, a.; katabami, k.; wada, t.; ono, y.; maekawa, k.; hayakawa, m.; sawamura, a.; gando, s.; andersen, l. w.; raymond, t.; berg, r.; nadkarni, v.; grossestreuer, a.; kurth, t.; donnino, m.; krüger, a.; ostadal, p.; janotka, m.; vondrakova, d.; kongpolprom, n.; cholkraisuwat, j.; pekkarinen, p. t.; ristagno, g.; masson, s.; latini, r.; bendel, s.; ala-kokko, t.; varpula, t.; vaahersalo, j.; hoppu, s.; tiainen, m.; mion, m. m.; plebani, m.; pettilä, v.; skrifvars, m.b.; son, y.; kim, k. s.; suh, g. j.; kwon, w. y.; ko, j. i.; park, m. j.; cavicchi, f. zama; iesu, e.; nobile, l.; vincent, j. l.; creteur, j.; taccone, f. s.; tanaka, h.; otani, n.; ode, s.; ishimatsu, s.; martínez, l.; algarte, r.; sánchez, b.; romero, i.; martínez, f.; quintana, s.; trenado, j.; vondrakova, d.; ostadal, p.; kruger, a.; janotka, m.; malek, f.; neuzil, p.; yeh, y. c.; chen, y. s.; wang, c. h.; huang, c. h.; chao, a.; lee, c. t.; lai, c. h.; chan, w. s.; cheng, y. j.; sun, w. z.; kaese, s.; horstmann, c.; lebiedz, p.; mourad, m.; gaudard, p.; eliet, j.; zeroual, n.; colson, p.; ostadal, p.; mlcek, m.; hrachovina, m.; kruger, a.; vondrakova, d.; janotka, m.; mates, m.; hala, p.; kittnar, o.; neuzil, p.; jacky, a.; rudiger, a.; spahn, d. r.; bettex, d. a.; kara, a.; akin, s.; dos reis miranda, d.; struijs, a.; caliskan, k.; van thiel, r. j.; dubois, e. a.; de wilde, w.; zijlstra, f.; gommers, d.; ince, c.; marca, l.; xini, a.; mongkolpun, w.; cordeiro, c. p. r.; leite, r. t.; lheureux, o.; bader, a.; rincon, l.; santacruz, c.; preiser, j. c.; chao, a.; chao, a. s.; chen, y. s.; kim, w.; ahn, c.; cho, y.; lim, t. h.; oh, j.; choi, k. s.; jang, b. h.; ha, j. k.; mecklenburg, a.; stamm, j.; soeffker, g.; kubik, m.; sydow, k.; reichenspurner, h.; kluge, s.; braune, s.; bergantino, b.; ruberto, f.; magnanimi, e.; privato, e.; zullino, v.; bruno, k.; pugliese, f.; sales, g.; girotto, v.; vittone, f.; brazzi, l.; fritz, c.; kimmoun, a.; vanhuyse, f.; trifan, b.; orlowski, s.; albuisson, e.; tran, n.; levy, b.; chhor, v.; joachim, j.; follin, a.; champigneulle, b.; chatelon, j.; fave, g.; mantz, j.; pirracchio, r.; diaz, d. díaz; villanova, m.; aguirregabyria, m.; andrade, g.; lópez, l.; palencia, e.; john, g.; cowan, r.; hart, r.; lake, k.; litchfield, k.; song, j. w.; lee, y. j.; cho, y. j.; choi, s.; vermeir, p.; vandijck, d.; blot, s.; mariman, a.; verhaeghe, r.; deveugele, m.; vogelaers, d.; chok, l.; bachli, e. b.; bettex, d.; cottini, s. r.; keller, e.; maggiorini, m.; schuepbach, r.; fiks, t.; stiphout, c.; grevelink, m.; vaneker, i.; ruijter, a.; buise, m.; spronk, p. e.; tena, s. altaba; barrachina, l. galarza; portillo, j. h. rodriguez; aznar, g. pagés; campos, l. mateu; sellés, m. d. ferrándiz; tomás, m. arlandis; muncharaz, a. belenguer; skinner, l.; monsalvo, s.; olavarria, e.; stümpfle, r.; na, s. j.; park, j.; chung, c. r.; park, c. m.; suh, g. y.; yang, j. h.; witter, t.; brousseau, c.; butler, m. b.; erdogan, m.; dougall, p. c. mac; green, r. s.; abbott, t. e. f.; torrance, h. d. t.; cron, n.; vaid, n.; emmanuel, j.; siddiqui, s. s.; prabu, n.; chaudhari, h. k.; patil, v. p.; divatia, j. v.; solanki, s.; kulkarni, a. p.; gutierrez, l. a. rincon; bader, a.; brasseur, a.; lheureux, o.; vincent, j. l.; creteur, j.; taccone, f. s.; hempel, d.; stauffert, n.; recker, f.; schröder, t.; reusch, s.; schleifer, j.; breitkreutz, r.; sjövall, f.; perner, a.; møller, m. hylander; moraes, r. b.; borges, f. k.; guillen, j. a. v.; zabaletta, w. j. c.; ruiz-ramos, j.; ramirez, p.; marqués-miñana, m. r.; villarreal, e.; gordon, m.; sosa, m.; concha, p.; castellanos, a.; menendez, r.; ramírez, c. sánchez; santana, m. cabrera; balcázar, l. caipe; escalada, s. hípola; viera, m. a. hernández; vázquez, c. f. lübbe; díaz, j. j. díaz; campelo, f. artiles; monroy, n. sangil; santana, p. saavedra; santana, s. ruiz; gutiérrez-pizarraya, a.; garnacho-montero, j.; martin, c.; baumstarck, k.; leone, m.; martín-loeches, i.; pirracchio, r.; legrand, m.; mainardi, j. l.; mantz, j.; cholley, b.; hubbard, a.; frontera, p. ruiz; vega, l. m. claraco; miguelena, p. ruiz de gopegui; usón, m. c. villuendas; lópez, a. rezusta; clemente, e. aurensanz; ibañes, p. gutiérrez; aguilar, a. l. ruiz; palomar, m.; olaechea, p.; uriona, s.; vallverdu, m.; catalan, m.; nuvials, x.; aragon, c.; lerma, f. alvarez; jeon, y. d.; jeong, w. y.; kim, m. h.; jeong, i. y.; ahn, m. y.; ahn, j. y.; han, s. h.; choi, j. y.; song, y. g.; kim, j. m.; ku, n. s.; bassi, g. li; xiol, e. aguilera; senussi, t.; idone, f. a.; motos, a.; chiurazzi, c.; travierso, c.; fernández-barat, l.; amaro, r.; hua, y.; ranzani, o. t.; bobi, q.; rigol, m.; torres, a.; fernández, i. fuentes; soler, e. andreu; de vera, a. pareja rodríguez; pastor, e. escudero; hernandis, v.; ros martínez, j.; rubio, r. jara; torner, m. miralbés; brugger, s. carvalho; eroles, a. aragones; moles, s. iglesias; cabello, j. trujillano; schoenenberger, j. a.; casals, x. nuvials; vidal, m. vallverdu; garrido, b. balsera; martinez, m. palomar; mirabella, l.; cotoia, a.; tullo, l.; stella, a.; di bello, f.; di gregorio, a.; dambrosio, m.; cinnella, g.; rosario, l. e. de la cruz; lesmes, s. p. gómez; romero, j. c. garcía; herrera, a. n. garcía; pertuz, e. d. díaz; sánchez, m. j. gómez; sanz, e. regidor; hualde, j. barado; hernández, a. ansotegui; ramirez, j. roldán; takahashi, h.; kazutoshi, f.; okada, y.; oobayashi, w.; naito, t.; baidya, d. k.; maitra, s.; anand, r. k.; ray, b. r.; arora, m. k.; ruffini, c.; rota, l.; corona, a.; sesana, g.; ravasi, s.; catena, e.; naumann, d. n.; mellis, c.; husheer, s. l.; bishop, j.; midwinter, m. j.; hutchings, s.; corradi, f.; brusasco, c.; manca, t.; ramelli, a.; lattuada, m.; nicolini, f.; gherli, t.; vezzani, a.; young, a.; carmona, a. fernández; santiago, a. iglesias; guillamon, l. navarro; delgado, m. j. garcía; delgado-amaya, m.; curiel-balsera, e.; rivera-romero, l.; castillo-lorente, e.; carrero-gómez, f.; aguayo-dehoyos, e.; healey, a. j.; cameron, c.; jiao, l.r.; stümpfle, r.; pérez, a.; martin, s.; del moral, o. lopez; toval, s.; rico, j.; aldecoa, c.; oguzhan, k.; demirkiran, o.; kirman, m.; bozbay, s.; kosuk, m. e.; asyralyyeva, g.; dilek, m.; duzgun, m.; telli, s.; aydin, m.; yilmazer, f.; hodgson, l. e.; dimitrov, b. d.; stubbs, c.; forni, l. g.; venn, r.; vedage, d.; shawaf, s.; naran, p.; sirisena, n.; kinnear, j.; dimitrov, b. d.; hodgson, l. e.; stubbs, c.; forni, l. g.; venn, r.; londoño, j. gonzalez; cardenas, c. lorencio; ginés, a. sánchez; gubianas, c. murcia; sánchez, e. clapes; sirvent, j. m.; panafidina, v.; shlyk, i.; ilyina, v.; judickas, s.; kezyte, g.; urbanaviciute, i.; serpytis, m.; gaizauskas, e.; sipylaite, j.; sprung, c. l.; munteanu, g.; morales, r. c.; kasdan, h.; volker, t.; reiter, a.; cohen, y.; himmel, y.; meissonnier, j.; banderas-bravo, m. e.; gómez-jiménez, c.; garcía-martínez, m. v.; martínez-carmona, j. f.; fernández-ortega, j. f.; o‘dwyer, m. j.; starczewska, m.; wilks, m.; vincent, j. l.; torsvik, m.; gustad, l. t.; bangstad, i. l.; vinje, l. j.; damås, j. k.; solligård, e.; mehl, a.; tsunoda, m.; kang, m.; saito, m.; saito, n.; akizuki, n.; namiki, m.; takeda, m.; yuzawa, j.; yaguchi, a.; frantzeskaki, f.; tsirigotis, p.; chondropoulos, s.; paramythiotou, e.; theodorakopoulou, m.; stamouli, m.; gkirkas, k.; dimopoulou, i. k.; makiko, s.; tsunoda, m.; kang, m.; yuzawa, j.; akiduki, n.; namiki, m.; takeda, m.; yaguchi, a.; preau, s.; ambler, m.; sigurta, a.; saeed, s.; singer, m.; jochmans, s.; chelly, j.; vong, l. v. p.; sy, o.; serbource-goguel, j.; rolin, n.; weyer, c. m.; abdallah, r. i.; adrie, c.; vinsonneau, c.; monchi, m.; mayr, u.; huber, w.; karsten, e.; lahmer, t.; thies, p.; henschel, b.; fischer, g.; schmid, r. m.; ediboglu, o.; ataman, s.; naz, i.; yaman, g.; kirakli, c.; su, p. l.; kou, p. s.; lin, w. c.; chen, c. w.; lozano, j. a. benítez; sánchez, p. carmona; francioni, j. e. barrueco; ferrón, f. ruiz; simón, j. m. serrano; riad, z.; mezidi, m.; aublanc, m.; perinel, s.; lissonde, f.; louf-durier, a.; yonis, h.; tapponnier, r.; richard, j. c.; louis, b.; guérin, c.; mezidi, m.; yonis, h.; aublanc, m.; lissonde, f.; louf-durier, a.; perinel, s.; tapponnier, r.; richard, j. c.; guérin, c.; marmanidou, k.; oikonomou, m.; nouris, c.; loizou, c.; soilemezi, e.; matamis, d.; somhorst, p.; gommers, d.; hayashi, k.; hirayama, t.; yumoto, t.; tsukahara, k.; iida, a.; nosaka, n.; sato, k.; ugawa, t.; nakao, a.; ujike, y.; hirohata, s.; mojoli, f.; torriglia, f.; giannantonio, m.; orlando, a.; bianzina, s.; tavazzi, g.; mongodi, s.; pozzi, m.; iotti, g. a.; braschi, a.; jansen, d.; gadgil, s.; doorduin, j.; roesthuis, l.; van der hoeven, j. g.; heunks, l. m. a.; chen, g. q.; sun, x. m.; he, x.; yang, y. l.; shi, z. h.; xu, m.; zhou, j. x.; pereira, s. m.; tucci, m. r.; tonelotto, b. f. f.; simoes, c. m.; morais, c. c. a.; pompeo, m. s.; kay, f. u.; amato, m. b. p.; vieira, j. e.; suzuki, s.; mihara, y.; hikasa, y.; okahara, s.; morimatsu, h.; kwon, h. m.; moon, y. j.; lee, s. h.; jung, k. w.; shin, w. j.; jun, i. g.; song, j. g.; hwang, g. s.; lee, s.; moon, y. j.; kwon, h. m.; jung, k.; shin, w. j.; jun, i. g.; song, j. g.; hwang, g. s.; ramelli, a.; manca, t.; corradi, f.; brusasco, c.; nicolini, f.; gherli, t.; brianti, r.; fanzaghi, p.; vezzani, a.; tudor, b. a.; klaus, d. a.; lebherz-eichinger, d.; lechner, c.; schwarz, c.; bodingbauer, m.; seemann, r.; kaczirek, k.; fleischmann, e.; roth, g. a.; krenn, c. g.; malyshev, a.; sergey, s.; yamaguchi, y.; nomura, t.; yoshitake, e.; idei, m.; yoshida, t.; takaki, s.; yamaguchi, o.; kaneko, m.; goto, t.; tencé, n.; zaien, i.; wolf, m.; trouiller, p.; jacobs, f. m.; kelly, j. m.; veigas, p.; hollands, s.; min, a.; rizoli, s.; robles, c. m. coronado; de oca sandoval, m. a. montes; tarabrin, o.; gavrychenko, d.; mazurenko, g.; tarabrin, p.; garcia, i. palacios; martin, a. diaz; mendez, m. casado; orden, v. arellano; noval, r. leal; mccue, c.; gemmell, l.; mackay, a.; luján, j.; villa, p.; llorente, b.; molina, r.; alcázar, l.; juanas, c. arenillas; rogero, s.; pascual, t.; cambronero, j. a.; almudévar, p. matía; domínguez, j. palamidessi; carmona, s. alcántara; castañeda, d. palacios; abellán, a. naharro; lucendo, a. pérez; pérez, l. pérez; rivas, r. fernández; sanz, n. martínez; ramos, j. veganzones; villamizar, p. rodríguez; javadpour, s.; kalani, n.; amininejad, t.; jamali, s.; sobhanian, s.; laurent, a.; bonnet, m.; rigal, r.; aslanian, p.; hebert, p.; capellier, g.; contreras, m. r. diaz; mejías, c. rodriguez; ruiz, f. c. santiago; lombardo, m. duro; perez, j. castaño; de hoyos, e. aguayo; estella, a.; viciana, r.; fontaiña, l. perez; rico, t.; madueño, v. perez; recuerda, m.; fernández, l.; sandiumenge, a.; bonet, s.; mazo, c.; rubiera, m.; ruiz-rodríguez, j. c.; gracia, r. m.; espinel, e.; pont, t.; kotsopoulos, a.; jansen, n.; abdo, w. f.; gopcevic, a.; gavranovic, z.; vucic, m.; glogoski, m. zlatic; penavic, l. videc; horvat, a.; martin-villen, l.; egea-guerero, j. j.; revuelto-rey, j.; aldabo-pallas, t.; correa-chamorro, e.; gallego-corpa, a. i.; granados, p. ruiz del portal-ruiz; faivre, v.; wildenberg, l.; huot, b.; lukaszewicz, a. c.; simsir, m.; mengelle, c.; payen, d.; sanz, n. martinez; valbuena, b. lobo; de la fuente, m. valdivia; almudena, p. matía; pérez, l. pérez; carmona, s. alcántara; abellán, a. navarro; simón, i. fernández; muñoz, j. j. rubio; ramos, j. veganzones; carmona, s. alcantara; almudevar, p. matia; abellan, a. naharro; lucendo, m. a. perez; perez, l. perez; dominguez, j. palamidessi; rivas, r. fernandez; villamizar, p. rodriguez; wee, s.; ong, c.; lau, y. h.; wong, y.; banderas-bravo, m. e.; olea-jiménez, v.; mora-ordóñez, j. m.; gómez-jiménez, c.; muñoz-muñoz, j. l.; vallejo-báez, j.; daga-ruiz, d.; lebrón-gallardo, m.; rialp, g.; raurich, j. m.; morán, i.; martín, m. c.; heras, g.; mas, a.; vallverdú, i.; hraiech, s.; bourenne, j.; guervilly, c.; forel, j. m.; adda, m.; sylla, p.; mouaci, a.; gainnier, m.; papazian, l.; bauer, p. r.; kumbamu, a.; wilson, m. e.; pannu, j. k.; egginton, j. s.; kashyap, r.; gajic, o.; yoshihiro, s.; sakuraya, m.; hayakawa, m.; hirata, a.; kawamura, n.; tsutui, t.; yoshida, k.; hashimoto, y.; chang, c. h.; hu, h. c.; chiu, l. c.; hung, c. y.; li, s. h.; kao, k. c.; sibley, s.; drover, j.; d’arsigny, c.; parker, c.; howes, d.; moffatt, s.; erb, j.; ilan, r.; messenger, d.; ball, i.; boyd, j. g.; harrison, m.; ridi, s.; muscedere, j.; andrade, a. h.; costa, r. c.; souza, v. a.; gonzalez, v.; amorim, v.; rolla, f.; filho, c. a. c. abreu; miranda, r.; atchasiri, s.; buranavanich, p.; wathanawatthu, t.; suwanpasu, s.; bureau, c.; rolland-debord, c.; poitou, t.; clavel, m.; perbet, s.; terzi, n.; kouatchet, a.; similowski, t.; demoule, a.; diaz, p.; nunes, j.; escórcio, s.; silva, g.; chaves, s.; jardim, m.; câmara, m.; fernandes, n.; duarte, r.; jardim, j. j.; pereira, c. a.; nóbrega, j. j.; chen, c. m.; lai, c. c.; cheng, k. c.; chou, w.; lee, s. j.; cha, y. s.; lee, w. y.; onodera, m.; nakataki, e.; oto, j.; imanaka, h.; nishimura, m.; khadjibaev, a.; sabirov, d.; rosstalnaya, a.; akalaev, r.; parpibaev, f.; antonucci, e.; rossini, p.; gandolfi, s.; montini, e.; orlando, s.; van nes, m.; karachi, f.; hanekom, s.; andrade, a. h.; pereira, u. v.; filho, c. a. c. abreu; costa, r. c.; parkin, m. s. w.; moore, m.; andrade, a. h.; costa, r. c.; carvalho, k. v. silva; filho, c. a. c. abreu; min, h. j.; kim, h. j.; lee, d. s.; choi, y. y.; lee, e. y.; song, i.; kim, d. j.; e, y. y.; kim, j. w.; park, j. s.; cho, y. j.; lee, j. h.; suh, j. w.; jo, y. h.; kim, k. s.; lee, y. j.; ferrero-calleja, j.; merino-vega, d.; gonzález-jiménez, a. i.; sigcha, m. sigcha; hernández-tejedor, a.; martin-vivas, a.; gabán-díez, Á.; luna, r. ruiz-de; de la calle-pedrosa, n.; temprano-gómez, i.; afonso-rivero, d.; pellin-ariño, j. i.; algora-weber, a.; fumis, r. r. l.; ferraz, a. b.; junior, j. m. vieira; kirca, h.; cakin, o.; unal, m.; mutlu, h.; ramazanoglu, a.; cengiz, m.; nicolini, e. a.; pelisson, f. g. f.; nunes, r. s.; da silva, s. l.; carreira, m. m.; bellissimo-rodrigues, f.; ferez, m. a.; basile-filho, a.; chao, h. c.; chen, c. m.; chen, l.; hravnak, m.; clermont, g.; pinsky, m.; dubrawski, a.; varas, j. luján; montero, r. molina; sánchez-elvira, l. alcázar; díaz, p. villa; delgado, c. pintado; ruiz, b. llorente; guerrero, a. pardo; galache, j. a. cambronero; sherif, h.; hassanin, h.; el hossainy, r.; samy, w.; ly, h.; david, h.; burtin, p.; charpentier, c.; barral, m.; courant, p.; fournel, e.; gaide-chevronnay, l.; durand, m.; albaladejo, p.; payen, j. f.; chavanon, o.; ortiz, a. blandino; pozzebon, s.; lheureux, o.; brasseur, a.; vincent, j. l.; creteur, j.; taccone, f. s.; fumagalli, f.; scala, s.; affatato, r.; de maglie, m.; zani, d.; novelli, d.; marra, c.; luciani, a.; de zani, d.; luini, m.; letizia, t.; pravettoni, d.; staszewsky, l.; masson, s.; belloli, a.; di giancamillo, m.; scanziani, e.; latini, r.; ristagno, g.; kye, y. c.; suh, g. j.; kwon, w. y.; kim, k. s.; yu, k. m.; babini, g.; ristagno, g.; grassi, l.; fumagalli, f.; bendel, s.; de maglie, m.; affatato, r.; masson, s.; latini, r.; scanziani, e.; reinikainen, m.; skrifvars, m.; kappler, f.; blobner, m.; schaller, s. j.; roasio, a.; costanzo, e.; cardellino, s.; iesu, e.; cavicchi, f. zama; fontana, v.; nobile, l.; vincent, j. l.; creteur, j.; taccone, f. s.; park, m.; you, k. m.; suh, g. j.; kwon, w. y.; ko, s. b.; kim, k. s.; xini, a.; marca, l.; lheureux, o.; brasseur, a.; vincent, j. l.; creteur, j.; taccone, f. s.; beane, a.; thilakasiri, m. c. k. t.; de silva, a. p.; stephens, t.; sigera, c. s.; athapattu, p.; jayasinghe, s.; padeniya, a.; haniffa, r.; santiago, a. iglesias; sáez, v. chica; ruiz-ruano, r. de la chica; gonzález, a. sánchez; kunze-szikszay, n.; wand, s.; klapsing, p.; wetz, a.; heyne, t.; schwerdtfeger, k.; troeltzsch, m.; bauer, m.; quintel, m.; moerer, o.; cook, d. j.; rutherford, w. b.; scales, d. c.; adhikari, n. k.; cuthbertson, b. h.; suzuki, t.; takei, t.; fushimi, k.; iwamoto, m.; nakagawa, s.; mendsaikhan, n.; begzjav, t.; lundeg, g.; dünser, m. w.; romero, d. gonzález; cabrera, j. l. santana; santana, j. d. martín; padilla, y. santana; pérez, h. rodríguez; torrent, r. lorenzo; kleinpell, r.; chouris, i.; radu, v.; stougianni, m.; lavrentieva, a.; lagonidis, d.; price, r. d. t.; day, a.; arora, n.; henderson, m. a.; hickey, s.; costa, m. i. almeida; carvalho, j. p.; gomes, a. a.; mergulhão, p. j.; chan, k. k. c.; shum, h. p.; yan, w. w.; maghsoudi, b.; tabei, s. h.; masjedi, m.; sabetian, g.; tabatabaei, h. r.; akbarzadeh, a.; saigal, s.; pakhare, a.; joshi, r.; pattnaik, s. k.; ray, b.; rousseau, a. f.; michel, l.; bawin, m.; cavalier, e.; reginster, j. y.; damas, p.; bruyere, o.; zhou, j. c.; cauwenberghs, h.; de backer, a.; neels, h.; deblier, i.; berghmans, j.; himpe, d.; barea-mendoza, j. a.; portillo, i. prieto; fernández, m. valiente; gigorro, r. garcia; vela, j. l. perez; mateos, h. marín; alves, s. chacón; varas, g. morales; rodriguez-biendicho, a.; carreño, e. renes; gonzález, j. c. montejo; yang, j. s.; chiang, c. h.; hung, w. t.; huang, w. c.; cheng, c. c.; lin, k. c.; lin, s. c.; chiou, k. r.; wann, s. r.; lin, k. l.; kang, p. l.; mar, g. y.; liu, c. p.; zhou, j. c.; choi, y. j.; yoon, s. z.; gordillo-brenes, a.; fernandez-zamora, m. d.; perez-borrero, l.; arias-verdu, m. d.; aguilar-alonso, e.; herruzo-aviles, a.; garcia-delgado, m.; hinojosa-perez, r.; curiel-balsera, e.; rivera-fernandez, r.; lesmes, s. p. gómez; rosario, l. e. de la cruz; hernández, a. ansotegui; herrera, a. n. garcía; sanz, e. regidor; sánchez, m. j. gómez; hualde, j. barado; pascual, o. agudo; león, j. p. tirapu; irazabal, j. m. guergue; pérez, a. gonzález; fernández, p. alvarez; amor, l. lopéz; albaiceta, g. muñiz; lesmes, s. p. gómez; rosario, l. e. de la cruz; hernández, a. ansotegui; sanz, e. regidor; sánchez, m. j. gómez; calvo, s. aldunate; herrera, a. n. garcía; hualde, j. barado; pascual, o. agudo; león, j. p. tirapu; corona, a.; ruffini, c.; spazzadeschi, a.; marrazzo, f.; gandola, a.; sciurti, r.; savi, c.; catena, e.; ke, m. w.; cheng, c. c.; huang, w. c.; chiang, c. h.; hung, w. t.; lin, k. c.; lin, s. c.; wann, s. r.; chiou, k. r.; tseng, c. j.; kang, p. l.; mar, g. y.; liu, c. p.; bertini, p.; de sanctis, f.; guarracino, f.; bertini, p.; baldassarri, r.; guarracino, f.; buitinck, s. h.; van der voort, p. h. j.; oto, j.; nakataki, e.; tsunano, y.; izawa, m.; tane, n.; onodera, m.; nishimura, m.; ghosh, s.; gupta, a.; de gasperi, a.; mazza, e.; limuti, r.; prosperi, m.; bissenova, n.; yergaliyeva, a.; talan, l.; yılmaz, g.; güven, g.; yoruk, f.; altıntas, n. d.; mukherjee, d. n.; agarwal, l. k.; mandal, k.; palomar, m.; balsera, b.; vallverdu, m.; martinez, m.; garcia, m.; castellana, d.; lopez, r.; barcenilla, f.; kaminsky, g. e.; carreño, r.; escribá, a.; fuentes, m.; gálvez, v.; del olmo, r.; nieto, b.; vaquerizo, c.; alvarez, j.; de la torre, m. a.; torres, e.; bogossian, e.; nouer, s. aranha; salgado, d. ribeiro; brugger, s. carvalho; jiménez, g. jiménez; torner, m. miralbés; vidal, m. vallverdú; garrido, b. balsera; casals, x. nuvials; gaite, f. barcenilla; cabello, j. trujillano; martínez, m. palomar; doganci, m.; izdes, s.; besevli, s. guzeldag; alkan, a.; kayaaslan, b.; ramírez, c. sánchez; balcázar, l. caipe; santana, m. cabrera; viera, m. a. hernández; escalada, s. hípola; vázquez, c. f. lübbe; penichet, s. m. marrero; campelo, f. artiles; lópez, m. a. de la cal; santana, p. saavedra; santana, s. ruíz; repessé, x.; artiguenave, m.; paktoris-papine, s.; espinasse, f.; dinh, a.; el sayed, f.; charron, c.; géri, g.; vieillard-baron, a.; marmanidou, k.; oikonomou, m.; nouris, c.; dimitroulakis, k.; soilemezi, e.; matamis, d.; ferré, a.; guillot, m.; teboul, j. l.; lichtenstein, d.; mézière, g.; richard, c.; monnet, x.; pham, t.; beduneau, g.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; prīdāne, s.; sabeļņikovs, o.; mojoli, f.; orlando, a.; bianchi, i.; torriglia, f.; bianzina, s.; pozzi, m.; iotti, g. a.; braschi, a.; beduneau, g.; pham, t.; schortgen, f.; piquilloud, l.; zogheib, e.; jonas, m.; grelon, f.; runge, i.; terzi, n.; grangé, s.; barberet, g.; guitard, p. g.; frat, j. p.; constan, a.; chrétien, j. m.; mancebo, j.; mercat, a.; richard, j. c. m.; brochard, l.; kondili, e.; psarologakis, c.; kokkini, s.; amargianitakis, v.; babalis, d.; chytas, a.; chouvarda, i.; vaporidi, k.; georgopoulos, d.; trapp, o.; kalenka, a.; mojoli, f.; orlando, a.; bianchi, i.; torriglia, f.; bianzina, s.; pozzi, m.; iotti, g. a.; braschi, a.; lozano, j. a. benítez; sánchez, p. carmona; francioni, j. e. barrueco; ferrón, f. ruiz; simón, j. m. serrano; spadaro, s.; karbing, d. s.; gioia, a.; moro, f.; corte, f. dalla; mauri, t.; volta, c. a.; rees, s. e.; petrova, m. v.; mohan, r.; butrov, a. v.; beeharry, s. d.; vatsik, m. v.; sakieva, f. i.; gobert, f.; yonis, h.; tapponnier, r.; fernandez, r.; labaune, m. a.; burle, j. f.; barbier, j.; vincent, b.; cleyet, m.; richard, j. c.; guérin, c.; shinotsuka, c. righy; creteur, j.; taccone, f. s.; törnblom, s.; nisula, s.; vaara, s.; poukkanen, m.; andersson, s.; pettilä, v.; pesonen, e.; xie, z.; liao, x.; kang, y.; zhang, j.; kubota, k.; egi, m.; mizobuchi, s.; hegazy, s.; el-keraie, a.; el sayed, e.; el hamid, m. abd; rodrigues, n. j.; pereira, m.; godinho, i.; gameiro, j.; neves, m.; gouveia, j.; e silva, z. costa; lopes, j. a.; mckinlay, j.; kostalas, m.; kooner, g.; dudas, g.; horton, a.; kerr, c.; karanjia, n.; creagh-brown, b.; forni, l.; yamazaki, a.; ganuza, m. sanz; molina, j. a. martinez; martinez, f. hidalgo; freile, m. t. chiquito; fernandez, n. garcia; travieso, p. medrano; bandert, a.; frithiof, r.; lipcsey, m.; smekal, d.; schlaepfer, p.; durovray, j. d.; plouhinec, v.; chiappa, c.; bellomo, r.; schneider, a. g.; mitchell, s.; durrant, j.; street, h.; dunthorne, e.; shears, j.; caballero, c. hernandez; hutchison, r.; schwarze, s.; ghabina, s.; thompson, e.; prowle, j. r.; kirwan, c. j.; gonzalez, c. a.; pinto, j. l.; orozco, v.; patiño, j. a.; garcia, p. k.; contreras, k. m.; rodriguez, p.; echeverri, j. e. title: esicm lives : part three: milan, italy. – october date: - - journal: intensive care med exp doi: . /s - - - sha: doc_id: cord_uid: qfecv h nan months is better than cole's formula. therefore, we conducted a retrospective analysis to investigate our hypothesis. methods: the ethics committee of our hospital approved this retrospective study. we included consecutive patients aged < years who underwent tracheal intubation under general anesthesia in our hospital from august to october . we collected the following data from the anesthesia records: age in months, height, weight, type of a tracheal tube, and id and od of tracheal tube. patients who were intubated using a cuffed tracheal tube or had incomplete data were excluded. we developed a regression formula for calculating id and od based on age in months and calculated the coefficient of determination r by using a regression analyses. a difference of . mm in the actual and predicted tube size was considered clinically permissible. then, we compared the rate of a clinical permissible estimation of the cole's formula and our new formulas used by multiple comparison analysis and a p value less than . was considered statistically significant. results: a total of pediatric patients received general anesthesia during the study period. of these, patients were excluded because they did not meet the inclusion criteria. finally, we included patients for this analysis. the regression formula for predicting id by based on age in months was id = . × age in months + . , and the coefficient of determination r was . . the regression formula for predicting od based on age in months was od = . × age in months + . , and coefficient of determination r was . . the rate of a clinical permissible estimation of our id and od formulas were significantly higher than that of the cole's formula ( %, % and %, respectively; p < . ). conclusions: our results showed that the prediction of id based on age in months is more useful than that using cole's formula. in addition, estimation of od based on age in months might be more rational because od varies according to the type of the tracheal tube used. these results should be confirmed in a future prospective study. introduction: survival among out-of-hospital cardiac arrest (ca) relies primarily on bystanders and their knowledge of basic life support (bls) manouvers [ ] . many medical societies and organizations recommend teaching bls at schools as part of the educative program [ ] ; being this a reality in north european countries, but not yet an education standard issue in others including spain. moreover, less is written about the perception of ca and cardiopulmonary resuscitation (cpr) among the general population, and even less in school age. objectives: describe the perception and knowledge about ca and cpr among a teenager school population in barcelona, spain. methods: prospective, descriptive study carried out between - and - among teenagers school population, based on surveys before and after bls -cpr classes. during this period , th classes were held, in different schools in barcelona. before attending the class , each pupil was asked to answer a survey with questions related to previous knowledge of sudden death, ca, and cpr, and their attitude towards them. the class consisted on a threehour theorical and practical instruction based on the european resuscitation council guidelines, adapted for laypersons. practices were held with an instructor (ratio instructor:pupil : [ ] [ ] [ ] , with the little anne mannequins (laerdal®). after the class, a new survey (post intervention) was distributed, with questions related to the new concepts and skills learnt, the attitude toward ca and cpr. results: we have instructed pupils ( . (± . ) years, . % female). the . % had heard about sudden death and ca before the class. regarding starting cpr: % said they were not capable of doing it, and . % suggested they would be able to do cpr but in a wrong manner. in a ca scene . % would contact the emergency service and start cpr, . % would call and wait, and . % would only do cpr. after attending the classes . % declared had understood the theorical concepts and practical skilles taught; . % would changed positively their attitude towards cpr; and . % would be prone to start maneuvers. conclusions: cpr and ca remain a well known issue among teenager population in barcelona, as long as being an interesting topic. nevertheless they do not feel capable of starting maneuvers. the concepts taught during the class were easy to learn , and after the intervention the majority were prone to start cpr. this population is adequate to teach cpr. introduction: to meet the need of patients family members and staff we started to guide visiting children at our adult icu in the st elisabeth hospital (ez) in tilburg years ago. to do so we developed a guidance leaflet for parents with practical instructions and information. additionally, practical advice is given, such as what to say to the child and what to expect when visiting. the leaflet is subdivided in developmental stages. furthermore we developed a book "mees op bezoek", in which a child visits his father at the icu. pictures show what children can expect, which helps prepare the child for visiting at home. an instruction box is present at the icu with icu materials such as an iv catheter, a pulse oximetry or a tracheal tube. these materials give children a tactile experience of the icu. the box is divided in two parts; the second part contains guidance materials for when a patient may die. pedagogical staff are available to support parents, children and staff. if there are more profound problems a referral to our children's psychologist is possible. we made some improvements to our waiting area to make it more appealing to children. we instructed and educated our nurses and doctors on how to use these materials and how to guide children. we recently merged with the twee steden hospital in tilburg (tsz), in this hospital there was no program to guide children. with the merger we also wanted to introduce our "child as a visitor program" at the icu on location tsz. we wanted to know if there were differences of opinion between the nursing staff on guidance of children. introduction: critically ill children are underfed early in their pediatric intensive care unit (picu) stay and this may contribute to worse outcomes. acute kidney injury (aki) occurs in % of all picu admissions and the risk of acute and chronic malnutrition is high in these patients with aki, and the presence of malnutrition in the context of aki has been associated with more severe clinical deterioration and organ dysfunction. critically ill children with aki are at high risk of underfeeding. objectives: to evaluate the effects of protein feeding on the resolution of aki. methods: this is a retrospective study of critically ill children admitted from / - / to the picu. patients with a diagnosis of end stage renal disease requiring renal replacement therapy or had received a kidney transplant were excluded. nutritional status assessed by weight and height who z-scores after admission and caloric and protein intakes calculated from i.v. fluids and parenteral and enteral nutrition for the first days of admission. energy and protein needs estimated by schofield and a.s.p.e.n., respectively. aki was defined by prifle (creatinine only) and persistent aki was defined as patients who did not resolve their aki during the first eight days of picu stay. introduction: sedation and analgesia are important components of postoperative management of neonates who underwent cardiac surgery. excessive or inadequate sedation may have a significant adverse effect on patient outcome. objectives. we aimed to determine which drug regimen would be most effective with less side-effect and better outcome. methods: from march till march we conducted a randomized controlled prospective study in neonates with congenital heart disease who underwent arterial switch operation in our clinic. inclusion criteria: ) gestational age more than weeks, ) birth weight over g, ) age -up to days, ) absence of concomitant diseases and surgical complications. patients were randomized into cohorts: patients ( %) were given infusion of dexmedetomidine with morphine boluses (study group) and patients ( %) were randomized to the standard regimen -infusion of morphine with diazepam boluses (control group). results: in both groups there were no differences in pre-and intraoperative indexes, duration of mechanical ventilation, sympathomimetic support, and time of infusion of dexmedetomidine/ morphine. in study group time of icu stay - . h -was significantly shorter than in control group - h (p- . ). onset of peristalsis and start of feeding in study group was earlier than in control group - st vs -d day (p- . ) and -d vs . -day (p- . ), respectively. in the control group there were more patients who had complicated feeding (start after -d day, bloating or vomiting) - ( %) vs ( %) in the study group. we did not observe any decrease of mean blood pressure and heart rate in the study group as it could be expected. conclusion: use of dexmedetomidine with morphine hydrochloride boluses for postoperative sedation and analgesia is effective and facilitates feeding process in neonates, leads to earlier onset of peristalsis and start of feeding, decreasing icu stay. impact of positive end expiratory pressure on cerebral hemodynamic in paediatric patients with post-traumatic brain swelling treated by surgical decompression s.m. pulitano' , s. de rosa , , a. mancino , g. villa , , f. tosi , p. franchi , g. conti introduction: asthma exacerbation is one of the most common diagnoses seen in the pediatric ed. several adult randomized controlled trials have shown that administration of high concentration oxygen leads to rise in carbon dioxide and increases admission rates. however, there are no studies in the pediatric population comparing the effects of high concentration oxygen versus titrated oxygen therapy in asthma exacerbation. objectives: we evaluated the effects of transcutaneous carbon dioxide (tpaco ) in high concentration oxygen therapy versus titrated oxygen therapy to maintain saturation between to % in pediatric patients with acute asthma exacerbation in the ed. methods: children to years with previously diagnosed asthma with moderate to severe asthma exacerbation (asthma score > ) were randomized to high concentration oxygen therapy ( % oxygen via face mask at > l/min.) or titrated oxygen therapy (titrated up from % via a blender continuously) to maintain saturations between to % while receiving their nebulized treatments. exclusion criteria included disorders with hypercapnic respiratory failure, unconscious patient, history of congenital heart disease, pregnancy, history of smoking or using sedatives and depressants. asthma therapy was provided per the ed physician. asthma score, tpaco , pefr (age > years) were measured at the start of the study and every minutes for the first hour then every minutes until disposition decision. the primary outcome was increase in tpaco with high concentration oxygen therapy. secondary outcome included rate of admission to the hospital. results: patients were enrolled with mean age of . years. % were males and % had poorly controlled asthma with mean asthma score of . . there were patients enrolled in the high concentration oxygen group (hcot) and patients in the titrated oxygen group (tot). the minute tpaco were not statistically different( . ± . hcot v. . ± . tot,p = . ); whereas, the minutes tpaco was statistically different( ± . hcot v. . ± . tot, p = . ). the minutes tpaco was . ± . hcot v. . ± . tot, p = . . at minutes, % of the patients had a rise in tpaco in hcot v. % in the tot(p = < . ), and at minutes % had a rise in tpaco in hcot v. % in the tot(p = < . ). the asthma score was similar in the two groups at minute ( . ± . hcot v. . ± . tot, p = . ); whereas, the minutes asthma score was lower in the tot( . ± . hcot v. . ± . tot, p = . ). the rate of admission to the hospital was . % in hcot v. . % in the tot. conclusions: high concentration oxygen therapy in pediatric asthma exacerbation leads to significantly higher carbon dioxide levels. it also causes rise in carbon dioxide from the baseline which increases the asthma scores and rate of admission. introduction: in critically ill patients, temperature measurement is a routine important care task and can lead to important decisions. rectal temperature and bladder temperature are now used as a continuous body temperature measuring method in the pediatric intensive care, but these practices have several disadvantages including the patient´s discomfort, the risk of organ injury and the inaccurate measuring caused by the sensor position. a new temperature monitoring system m tm spot-on tm (spoton) is a non-invasive zero-heat-flux thermometer designed to estimate core body temperature from the skin surface. although the usefulness and accuracy of spoton system in adult patients have been demonstrated, there are no reports on pediatric intensive care patients. objectives: the aim of this study was to evaluate the effectiveness of a new temperature measurement system attached to the forehead, and compare it to rectal temperature sensors in terms of correlation and accuracy. methods: pediatric patients weighing less than kg, who were managed in our icu during the period from february to march , were enrolled in this study. core temperature was measured and recorded at every minute from the both thermistor of a rectal thermal probe and with spoton in these patients. the data when the forehead sensor or rectal probe was taken out for nursing care was excluded from statistical analysis. results: sets of data of children (mean bw g) were examined retrospectively. in all patients, spoton showed higher than the rectal temperatures. the spoton temperature was analyzed to be . degrees ( % limits of agreement of ± . ) higher temperature than the rectal one with a moderate correlation(r = . ). discussion and conclusion: rectal temperature measurement is the gold standard method for pediatric patients in icu despite several complications of rectal injury. our children´s study demonstrated the slightly higher temperature in the spoton than rectal temperature with a substantial correlation. one possible explanation could be that the abundance of brain blood flow of children affected the results. our study concluded that spoton system could be used as a highly reliable noninvasive core body temperature measurement for small pediatric patients. introduction: viral bronchiolitis (vb) remains one of the leading causes of hospitalization in early childhood. despite the heavy burden of vb on the healthcare system, little is known about the incidence of acute respiratory distress syndrome (ards) in this cohort of patients. in , the pediatric acute lung injury consensus conference (palicc) published guidelines for the definition, management and research in pediatric ards (pards) ( ) . objectives: to study the incidence and prevalence of pards in vb and to study the association between pards and specific picu outcomes such as incidence of mechanical ventilation, noninvasive ventilator settings length of picu stay in this group of patients. methods: this is a retrospective single center observational cohort study that examined children - years of age admitted to the picu with vb and respiratory failure (rf) from - . palicc criteria were applied to define pards. clinical and demographic data was collected. patients with a diagnosis of congenital heart disease or pre-existing chronic lung disease were excluded. data was expressed as median with iqr ranges. test of bivariate association were performed using mann whitney u test and chi square test. a two tailed p value of ≤ . was used to denote statistical significance. results: out of patients with rf, with vb met study criteria. eighty of these ( %) patients admitted for vb met the criteria for pards or at risk for pards. out of these patients, ( %) met criteria for pards and ( %) met criteria for "at risk of pards". median age was ( , ) months and the median weight was . ( . , . ) kgs. most common etiology for vb was respiratory syncytial virus (rsv) % followed by rhinovirus ( %). there was no statistically significant difference in age, weight, and etiology of vb in patients with pards and those "at risk of pards." patients with pards had longer hospital and picu length of stay (los) and more likely to receive diuretics compared to those "at risk for pards" ( ( , ) vs ( , . ) , p = . ; ( , ) vs ( , . ), p < . ; and % vs %, p = . respectively). nineteen ( / , %) patients with pards received invasive mechanical ventilation with a median duration of ventilation of ( , ) days. conclusions: almost a quarter of children with vb developed pards or were at risk of pards. the presence of pards in children with vb was significantly associated with longer picu and hospital los compared to those "at risk of pards". children with vb are a high risk group for the development of pards. introduction: mean platelet volume(mpv) seems to be a marker of platelet activation and may be related to severity of illness. changes in mpv and platelet count(plc)could be used for disease prognosis and mortality in icu patients. we hypothesized that mpv changes and plc could be used as prognostic tools in pediatric surgical intensive care units(psicu). objectives: to study the association between mpv changes and mortality and morbidity in psicu. also to study the relation between plc and psicu mortality and morbidity. methods: this descriptive observational study was conducted on consecutive pediatric surgical patients who admitted to psicus at cairo university hospitals starting from / - / / .after approval by research ethics committee,informed consents were obtained from parents and pediatric cases aged from month- years and stayed for > h were enrolled.mpv and plc were obtained and recorded at baseline(preoperative values),on the day of icu admission(day ), st , nd , rd , th and th days.to measure daily mpv changes; (Δmpv) was constructed and computed where Δmpv = ([mpvday(x) − mpvday ( )]/mpvday( ) × %. pediatric index of mortality(pim)score was calculated on day and the pediatric logistic organ dysfunction(pelod)score was recorded daily. results: patients who developed icu complications (fever, sepsis, pneumonia, required mechanical ventilation, needed vasopressors or blood transfusion); showed higher Δmpv compared to non complicated cases (fig. ) . this association was statistically significant on days (p value = . ), (p value < . ), (p value < . ) and (p value = . ) of icu stay but it´s insignificant on day (p value = . ).according to receiver operating characteristics(roc) curve analysis, the sensitivity of Δmpv to detect complications on day was . % but its specificity on day was . %.patients who developed icu complications showed lower plc compared to non complicated cases (fig. ) .this association was statistically significant on days (p value < . ), (p value < . ) and (p value < . ) but it was insignificant on day (p value = . ), (p value = . ) and (p value = . ). on other hand, the sensitivity of plc to detect complications day was . % but the specificity was . %, while the sensitivity of plc to detect complications day was . % but the specificity day was %. conclusions: mpv dynamics and plc have prognostic roles and could be used in determining several complications in critically ill pediatric surgical patients. plc is a more specific and sensitive tool to detect complications than mean mpv dynamics. introduction: limited information exists regarding the association between functional status at icu admission at and outcomes. objectives: we hypothesized that initial functional status assessment as well the amount of physical therapy delivered would be associated with outcomes in icu survivors. methods: we performed a retrospective cohort study in one boston teaching hospital on , adults who received critical care from to and survived hospitalization. all patients had a formal evaluation by a physical therapist in the week prior to icu admission and at hospital discharge. the exposure of interest was functional status determined by a licensed physical therapist based on the functional mobility sub scales of the functional independence measure. all patients received physical therapy to improve functional performance. the primary outcome was -day all-cause mortality. we used logistic regression to describe how -day mortality differed with functional status at icu admission. negative binomial regression was utilized to describe how functional status at hospital discharge differed with functional status at icu admission, the extent of physical therapy received and hospital length of stay. results: the cohort was % male, % non-white and had a mean age of . years. % of the cohort had sepsis, % had acute kidney injury, % had respiratory failure and % were surgical cases. the median [iqr] hospital length of stay was [ , ] days. the -day mortality rate was . %. functional status at icu admission was robustly associated with -day mortality. in a logistic regression model adjusted for age, gender, race, surgical patient type, deyo-charlson index, acute organ failure, sepsis, length of stay and the extent of physical therapy received, the second lowest and lowest quartiles of functional status at icu admission was associated with a . in critically ill patients, decreased functional status at icu admission is associated with increased -day mortality. increased intensity of physical therapy is associated with improved mortality outcomes. both functional status at icu admission and the intensity of physical therapy contribute to functional status determined at hospital discharge. introduction: patients admitted to critical care are shown to lose significant muscle mass, with the degree of muscle loss as high as % in the first week for those in multi organ failure (puthucheary, ) . early rehabilitation has been demonstrated as a safe and effective method of improving functional status at the point of critical care discharge and reducing both icu and hospital length of stay (mcwilliams et al., ) , although the specific impact of this on muscle mass has not been reported. objectives: this study aimed to analyse the impact of enhanced physiotherapy incorporating early mobilisation on the rate of muscle decline for patients admitted to critical care. methods: patients admitted to a large uk teaching hospital during the trial period and ventilated for ≥ days were included in the study. patients were randomised to either enhanced physiotherapy or standard care groups as part of a larger rct. baseline measurements were taken on the day of recruitment and then repeated at critical care discharge. muscle mass was measured using ultrasound to calculate cross sectional area of quadriceps and biceps. to ensure validity , measures were taken and the average of these taken as the final value. all scans were reviewed for agreement by therapists trained in muscle ultrasound. results: patients were included in the analysis. patients in the enhanced physiotherapy group mobilised earlier and achieved a higher level of mobility at the point of critical care discharge (see table .) all subjects demonstrated a reduction in muscle mass of both quadriceps and biceps over the course of their critical care stay. the extent of muscle loss was however lower in those receiving the enhanced physiotherapy, although this did not reach statistical significance (quads % vs %. p = . ; biceps % vs %, p = . ). conclusions: a programme of enhanced physiotherapy appeared to be associated with a lower rate of muscle loss in both biceps and quadriceps in comparison to standard care. an appropriately powered rct is required to assess these findings. introduction: survivors of critical illness experience a range of impairments after intensive care, including physical, cognitive and psychological compromise. the provision of information using a diary to describe the intensive care unit (icu) experience is one strategy that has been proposed to improve psychological health. objectives: the purpose of this study was to explore similarities and differences in patients' and relatives' perceptions of information containing strategies, including icu diaries, to assist recovery after critical illness. methods: an exploratory mixed-methods study was undertaken in an australian tertiary hospital with general icu patients admitted for ≥ days and their relatives. semi-structured interviews were conducted - months after icu discharge. transcripts were analysed using content analysis. results: twenty-two patients and relatives consented to participation and completed interviews prior to reaching data saturation. patients were usually male ( %) and aged ± years. patients raised similar themes to relatives, although with diverse opinions. themes of wanting to have a diary kept and considering they would find a diary helpful were consistent across a majority of participants, although with a minority expressing a desire to 'move on' and would not have liked a diary kept. differences between patients and relatives arose in the areas of the purpose, content, ownership and timing of delivery of a diary. patients viewed the diary as a therapeutic tool while relatives considered it as an information sharing mechanism, including as a mechanism to demonstrate to the patient 'how sick he really was' and 'what he put us through'. possibly as a result of these differences, patients considered that ownership of the diary rested with them while some relatives envisaged shared ownership. patients were more likely to note that the diary should not be provided to them until some weeks after icu while relatives considered an early time point soon after icu discharge to be appropriate. patients were more likely to raise concerns about the potential negative impact of information sharing strategies including diaries and return visits to the icu. conclusions: patients and relatives expressed common themes related to information sharing strategies after icu, but with some important differences. differences in purpose, content, ownership and timing of delivery of a diary suggest there is a need to consider whether the same intervention meets the needs of both groups of stakeholders. introduction: in the intensive care unit (icu) several patients are disturbed in their cerebral function due to their critical illness and medication, leading to discomfort, agitation, restlessness, pain and delirium. rocking chair mobilization therapy (rcmt) is a chair with good seating comfort which gives rhythmic movements. rocking chair studies have shown concrete results to improve patient satisfaction, balance and well-being in patients who suffered from dementia ( ) . however, no studies have evaluated the value and the effect of rcmt for critically ill patients in the icu. objectives: the purpose of the study was to evaluate whether rcmt could be used in the rehabilitation of critically ill patients in the intensive care. the focus was to explore the impact of rcmt on critically ill patients comfort, pain, agitation and delirium. methods: the evaluation took place in a medical/surgical icu in denmark in the period from may to july . patients ≥ years, who were physically stable and had the ability to be mobilized to chair could participate in the evaluation. the rcmt session lasted minutes.each session with rcmt was evaluated by registration of patient consciousness (richmond agitation and sedation scale (rass)), pain (numeric rating scale (nrs) - or by critical-care pain observation tool (cpot)), delirium (cam-icu) before and after the session. patient comfort was assessed by the patients as well as by the nurses during the session. results: sessions with rcmt were evaluated. males and females, age between and years, participated in the evaluation. the results showed a decrease in patient agitation level and an increase in patient consiousness. patients´with rass > decreased from before the session to after the session. patients with rass ≤ − decreased from before the session to after the session. a decrease in delirium where patients were assessed cam-icu positive before the session and patients after the session. a decrease in pain where six patients scored nrs > before the session compared to one patient after the session and patients had cpot scores > before the session compared to patients after the session. assessment and evaluation of comfort by patients themselves and by the nurses, who cared for the particular patient, showed that rcmt was associated with a high degree of patient relaxation and comfort. conclusions: promising results gives reason to recommend rcmt for critically ill patients in the icu, as an alternative holistic nonpharmacological intervention to stimulate patients´bodily awareness and enhance patient comfort and rehabilitation. introduction: critical illness and immobility in the intensive care unit (icu) lead to a loss of muscle mass and reduced exercise capacity for many years following hospital discharge. [ ] nutritional management of the critically ill is challenging and most nutritional studies are focused in this period. nutritional recommendations are for a high protein diet to minimise muscle breakdown and support protein synthesis during rehabilitation. nevertheless, during the rehabilitation period little is known of patients' protein intake and physical functioning. objective: to investigate physical functioning, frailty and dietary protein intake after months of icu discharge. method: our icu is recognised as a therapy rehabilitation centre and the only icu member of the uk rehabilitation outcomes (uk-roc). patients cognitive and physical functioning is assessed as part of their rehabilitation therapy with the functional independence measure (fim) score [ ] . the fim contains items on motor ( ) and cognitive ( ) functions that are scored on a -point ordinal scale based on the amount of assistance a person requires to perform specific activities. the fim scores on icu discharge and also on return to the rehabilitation clinic after months were assessed. in addition, frailty was assessed based on a scale ranging from very fit to very severely frail, terminally ill [ ] and patients were asked to complete a protein food frequency questionnaire. results: twenty patients were assessed. data are reported as mean and (standard deviation). patients were male % and . years ( . ). paired t tests of the changes in fim scores from discharge showed significant increments; . ± . (p = . ) and . ± . (p < . ) for motor and cognitive scales respectively. nevertheless, patients reported that they were "vulnerable to moderately frail" in the frailty scale. dietary intake was also inadequate with a protein intake of . g/kg ( . ). objectives: physiotherapy rehabilitation is a recognised component of icu care. the intensive care society -core standards recommends that rehabilitation is 'at a level that enables the patient to meet their rehabilitation goals for as long as they…are able to tolerate it'. in order to investigate and measure the terms 'tolerate' and 'level', physiological measurements and their relationship with self-perceived exertion and tolerance were analysed. methods: the project was registered with guy's & st.thomas' nhs foundation trust, clinical audit group, (project no. ). a convenience sample, of icu patients undergoing active physiotherapy led rehabilitation, were observed between july and september . a modified exertion scale was used to measure patients' perceived effort. patients also rated tolerance of the session using a tolerability scale, created based on the exertion scale. sessions were timed, heart rate, blood pressure and oxygen saturation were monitored and the cardiovascular impact of the session measured using heart rate reserve (hrr). results: nine rehabilitation sessions were observed; mean length of minutes (range - ). minimum target hrr (> %) was achieved, but not sustained, by patients, while peaked within a normal target hrr ( - %). of the patients, were able to use the tolerability scale and the exertion scale. there did not appear to be a relationship between hrr and either perceived scale measurements. there did appear to be a link between perceived exertion and perceived tolerability with of the patients scoring within points. conclusions: reported perception of exertion and physiological markers could both indicate the 'level' patients are working at. we were able to measure effects of rehabilitation on heart rate. the majority of patients were able to use exertion and tolerance scales. however, the change in heart rate was not great enough to suggest a training effect, despite their exertion scores implying high effort levels. to fulfil the icu society recommendations, a good understanding is needed of how hard patients are working during rehabilitation. further research is needed to determine why there may be disparity between heart rate and patient-reported measures of exertion; and if either is a useful guide for exercise prescription with icu patients. introduction: critically ill patients are at risk of developing deconditioning, muscle atrophy and functional impairments long after hospital discharge. there is evidence demonstrating benefits of mobilization in critically ill patients -improved functional outcome and reduced icu and hospital length of stay. however, there is limited information about how these advances are translated to clinical practice. objectives: to obtain a baseline data on patients who are eligible for mobilisation in icu and how many of these patients are optimally mobilised in icu. this would enable us to undertake a clinical practice improvement project (cpip) using the plan-do-study-act (pdsa) implementation strategy to optimise mobilisation in at least % of all eligible icu patients. methods: setting. -bedded intensivist led closed surgical icu. the mobilisation team composed of physiotherapists, bedside nurses and respiratory therapists who worked along with an intensivist. prospective audit conducted to collect data on the patients who met the eligibility criteria of mobilisation over a -month period. cpip team results: our audit revealed that at baseline, only % of all eligible patients were optimally mobilised. rca revealed a total of barriers and through multi-voting and pareto-charting, we identified the top barriers to change. key barriers identified were: . mobility not being a part of the daily review routine . staff were unsure of the eligibility criteria . lack of knowledge the benefits of optimal mobilisation in the critically ill. the team proposed following strategies to overcome the barriers: . combined icu multi-disciplinary handover rounds with the lead consultant asking the question "can this patient be mobilised?" for every patient reviewed. . providing a bedside decision-making algorithm on eligibility criteria, displayed within visibility of staff's work area. . undertake sharing session with ground staff on the importance and benefits of optimising mobility of the critically ill. conclusions: our audit revealed that less than half of eligible patients received early mobilisation. our cpip -a quality improvement initiative identified barriers in translating knowledge into clinical practice. through various tools of cpip, we identified the key barriers and strategies to overcome these barriers and thereby achieving the goal of optimising mobilisation in icu patients. introduction: bed rest and immobility during critical illness may result in profound physical deconditioning. the multidisciplinary team in intensive care includes physiotherapists, who are responsible for performing diagnoses and procedures for critically ill patients, such as ventilation, respiratory monitoring and assessments of musculoskeletal, neurological, metabolic and cardiovascular diseases, and for the prevention and treatment of the effects of prolonged immobility. objectives: to evaluate the influence of physiotherapy on quality indicators in the intensive care unit of the sagrada esperança clinic in luanda, angola. methods: a retrospective before-after study was designed to assess some quality indicators within the intensive care unit between july and september , where there were no physiotherapists specially trained for respiratory care, and from january to march , where the physiotherapists integrated a multidisciplinary team. the quality indicators analyzed were: the average duration of mechanical ventilation, prevalence of ventilator associated pneumonia and the rate of ventilated patients with non-invasive ventilation. the study population comprised patients for and for . in this study the patientsć ategorization was made by age, sex, pathology and also according with the patient classification systems saps and sofa. the statistical analysis used the systems spss version for a % significance level. results: the results obtained after analyzing the two homogeneous groups according to age, gender, type of admission and severity influencing the physiotherapy care in icu quality indicators, in the sagrada esperança clinic, highlights the decrease of the average number of days with mechanical ventilation but it is not observed a significant relation between physical therapy and this indicator (p = : ). furthermore, it is also observed a decrease ventilator associated pneumonia, and a significant relation between this indicator and the respiratory physiotherapy. last, there is a strong relation between the increase on the number of patients without invasive ventilation and physiotherapy (p = . ). conclusions: in this study it is demonstrated the respiratory therapy influences in some quality indicators, namely regarding the reduction of ventilation associated pneumonia and the promotion of non-invasive ventilation in the icu of the cse. introduction: the incidence of candidemia has increased in icu patients ( ) . in addition, there are differences in epidemiology among different countries. we have previously shown an increased proportion of nonalbicans candida species in our icu ( ) . objectives: to identify the variables associated with candidemia due to non-albicans candida species, as well as with fluconazole-resistant strains in a multidisciplinary icu. methods: all icu patients with candidemia were prospectively studied over two time periods ( - and - ) . demographics, illness severity, clinical and laboratory variables were recorded. sofa score value on icu admission subtracted from the value on the day of candidemia occurrence was defined as delta sofa. patients with c. albicans candidemia were compared to those with non-albicans candidemia. also, patients with fluconazole-resistant candidemia were compared to those without fluconazole resistance. results: among patients with icu-acquired candidemia, in patients candidemia was due to c. albicans and in patients to non-albicans species. c. parapsilosis was the most common ( %) followed by c. albicans ( %). the median time from icu admission to candidemia onset was and days for c. albicans and nonalbicans respectively, p = . . similarly, the median time for candidemia due to fluconazole sensitive isolate was days and days for fluconazole resistant, p < . . resistance to fluconazole was % and % in c. albicans and in non-albicans species respectively, p < . ).presence of shock on candidemia day (or . ; ci: . - , p = . ) and the delta sofa score (or . ; ci: . - . , p = . ) were independently associated with candidemia due to c. albicans. independent risk factors for fluconazole resistant isolates were the length of icu stay before the development of candidemia (or . ; ci: . - . , p = . ) and the presence of shock on candidemia day (or . ; ci: . - . , p = . ). previous fluconazole exposure ( patients) was not associated with fluconazole resistance. conclusions: this study confirms the predominance of non-albicans candida species, in our icu patients with candidemia, with high prevalence of fluconazole resistance. early onset of candidemia and the presence of shock were most likely due to c. albicans whereas late onset was associated with fluconazole-resistant non-albicans species. these findings may be of value for empiric antifungal treatment selection. introduction: invasive aspergillus infections are well-known complications of immunocompromised states, chronic obstructive pulmonary disease and haematopoietic stem cell transplant. bacterial coinfection is well described in influenza literature but there is scarce data on invasive aspergillosis complicated severe influenza infection. objectives: the aim of this study is to describe the clinical and demographic characteristics of patients with aspergillus isolation in severe influenza a(h n ) pneumonia. methods: prospective, observational, multicenter study conducted in spanish icus from to . all individuals with severe primary influenza a(h n ) pneumonia requiring invasive mechanical ventilation were included in the study. influenza a(h n ) patients without coinfection were compared with those with aspergillus isolation in respiratory samples. all serotypes were confirmed using rt-pcr at icu admission. patients´demographic, clinical, radiologic features, laboratory values, icu and hospital length of stay (los) and outcomes were recorded. discrete variables are expressed as counts (percentage) and continuous variables as medians with th to th interquartile range (iqr conclusions: the mortality rate was significantly higher in h n patients with aspergillus isolation in respiratory samples. diagnosis of invasive aspergillosis in critically ill patients in the post-influenza era must be re-evaluated. clinical studies should be conducted in order to know the clinical significance of aspergillus isolation in respiratory samples in intubated patients with primary influenza a(h n ) pneumonia. methods: this prospective, monocentric, study performed over months assessed the value of a twice weekly dosage of fungal biomakers (candida serology iga, igm, igg, ß-d-glucan (bdg) and mannan antigens) in icu patients after lt. proven/probable/possible infection was defined according to the eortc/msg criteria. colonisation was defined by presence of candida sp in respiratory samples without any sign of invasive infection. the study was approved by the ethical committee. results are presented as means. results: we analysed icu patients after lt. % had a candida sp colonisation while an invasive infection was proven in ( %) patients. candida albicans was cultured from % of the pulmonary samples. % of the invasive infections were related to c. glabrata. results of biomarkers dosages are presented in the table. positive candida igg serology was observed in % of the cases. mortality rate at -months after lt was % in the immunised patients versus % in nonimmunised patients. an invasive candidiasis (ic) was present in % of the immunised patients versus % in non-immunised patients. at least one bdg dosage was positive in % of the cases. bdg dosage value decreased after surgery, reaching a non-significant value after the th day. in proven ic, bdg measurements reached concentrations > pg/ml, days before initiation of antifungal treatment. no patient had positive mannan antigen measurement. conclusions: a twice weekly dosage of bdg seems to be useful in the decision making process for early initiation of antifungal therapy in lt patients. the cutoff for a significant value of bdg needs to be defined. pre-transplantation assessment of candida igg serology could help to identify patients at risk of post-operative fungal infection. introduction: the antifungal (af) therapy strategy (pre-emptive vs culture based treatment) in intensive care unit is a matter of debate [ ] . the necessity to not delay the initiation of the af in invasive candidiasis (ic) must be balanced with the cost and risk of selecting resistant pathogens when af are prescribed too widely. burn patients are at risk of ic because of the frequent use of antibiotics and immunodeficiency. objectives: to evaluate our antifungal (af) therapy strategy in suspected or proven ic in terms of prognosis and risk factors of ic. methods: observational, descriptive, retrospective study conducted from june to september in the saint louis hospital burn unit. inclusion criteria: patients treated with pre-emptive (severe sepsis or septic shock with candida sp colonization) or curative (proven, pic) af. the outcome was the pic (candidemia and/or positive peritoneal sample). clinical characteristics, organ supports, af treatments and outcome were collected and compared between pic and suspected ic (sic). the results are presented in median (iqr) or n (%). results: patients were admitted during the study period including with a total body surface area (tbsa) > %. treated with af including pic ( %). in those patients: age ( - ), tbsa ( - ), sapsii ( - ), absi ( - ) and sofa ( - ). renal replacement therapy ( %), mechanical ventilation ( %), parenteral nutrition ( %). inhospital mortality = % ( % sic vs % pic, p = . ). patients with pic ( %) were treated before the ic diagnosis ( because of filamentous infection before the pic). the delay between admission and af treatment initiation was days. patients characteristics, organs supports were not significantly different between pic and sic at the treatment initiation except for the sapsii (pic ( - ) vs sic ( - ), p = . ). patients ( %) received an echinocandin as a first-line treatment. ( . - . ) sites were monitored for candida colonization the week before treatment initiation. patients with pic had higher colonization index than those with sic ( % vs %, p = . ) and a candida score significantly higher ( vs ( . - . ) respectively, p = . ). a semiquantitative estimation of the fungal inoculum had no predictive value. conclusions: in this study, the majority of pic were treated after diagnosis confirmation. only / ( %) patient treated preemptively did declare a pic. the outcome was not different when the treatment was initiated after confirmation. the results of this study highlight the difficulty to identify patients at highest risk of ic, and question the strategy of preemptive treatment in this population. objectives: we wanted to determine whether pct guided antibiotic rationalisation could reduce fungal colonisation and antifungal usage. methods: we undertook a retrospective observational study at a nine bedded icu department in the united kingdom. we collected data on all patients admitted to the unit in the year prior and post the introduction of pct guided rationalisation of antibiotics. we used the pharmacy database to assess the use of antibiotics, correcting for changes in costs over this time. we used the microbiology database to assess the rate of patients colonising fungal species and those requiring treatment. results: since the introduction of pct, the average expenditure on antibiotics per icu admission fell . % (p . ). the rate of icu patients colonised with a fungal species fell from . % to . % (p < . ). the incidence of patient's prescribed systemic antifungal therapy fell from . % to . % (p < . ). conclusions: we demonstrated a significant reduction in patients colonised with fungal species and those requiring anti-fungal therapy since introducing pct guided rationalisation of antibiotics. a prospective randomised controlled trial is required to assess whether this equates to improved patient outcome. ), median days. c. albicans was the most commonly isolated species (sp) ( , %), candidemia was the most common diagnosed infection. the sp isolated in blood cultures (bc) were: , % c. albicans, , % c. haemulonii, . % c. parasilopsis. we had + bc for trichosporon asahii. catheter -related infection by c. albicans, c. parasilopsis, and candida haemulonii was diagnosed in patients. positive urine samples were found mostly for c. albicans . %. the most frequently factors associated with fungal infection were: > than days in the icu . %, urinary catheter . %, broad-spectrum antibiotic exposure . %, indwelling central venous catheter (cvc) . %, feeding tube . %, total parenteral nutrition . %, invasive mechanical ventilation . %. to highlight an association with acinetobacter baumannii in . % of our patients. doctors chose fluconazole in . % as a first line of therapy. an antibiogram was performed and the susceptibility was confirmed. icu mortality rate, . %. conclusions: in our environment, c. albicans continues to be the species that causes the largest number of invasive candidiasis. prolonged stay in the icu is an important risk factor to develop fungal infections. even with the particular features of a burn patient, their complexity, and the negative impact of each infection; fluconazole keeps having an important role in the treatment as a first line. the effect of introduction of daily chlorhexidine bathing on healthcare-associated infections and acquisition of multi-drug resistant organisms e. ahmadnia introduction: it has been suggested that daily bathing with chlorhexidine impregnated cloths may significantly reduce the acquisition of multi-drug resistant organisms (mdros), incidence of central line associated bloodstream infections (clabsis), and the development of intensive care unit (icu) acquired bloodstream infections [ ] . however, more recent data have failed to support daily bathing of critically ill patients with chlorhexidine for these purposes [ ] . objectives: to determine if the implementation of a daily chlorhexidine bathing regimen affects acquisition rates of mdros, the incidence of clabsis, and icu bacteraemias. methods: a quality improvement project was conducted at a bedded adult critical care unit within a uk university hospital (incorporating major trauma, medical, and surgical patients). during the year control period (december to november ), all patients were bathed using soap and water. during the subsequent intervention period (december to november ), all patients were bathed using % chlorhexidine impregnated cloths (clinell, gama healthcare). the acquisition of mdros, incidence of clabsis and icu bacteraemias were recorded during these periods ( months pre-and months post-chlorhexidine for clabsis, one year for the other outcomes). results: the study covered patient bed days ( pre-and post-introduction of chlorhexidine bathing). there were an identical number of mdro acquisitions in each group ( ), giving rise to an mdro acquisition rate per bed days of . in the control group compared to . in the chlorhexidine group (p = . ). clabsi incidence per bed days was higher in the control group compared to the chlorhexidine group ( . vs . ; p = . ). the incidence of significant bacteraemias per bed days was similar in the the two groups ( . before and . during chlorhexidine bathing; p = . ), but the incidence of bacteraemias due to skin commensals per bed days was lower in the chlorhexidine group ( . vs . ; p = . ). conclusions: at our large university hospital icu with a heterogeneous patient population, the introduction of routine daily chlorhexidine-impregnated cloth bathing appears to significantly reduce the incidence of bacteraemias due to skin commensals and demonstrates a non-significant reduction in clabsis. given the uncertainties surrounding diagnosis in the icu, the effect seen may be of benefit in reducing the use of antibiotics to cover for these skin commensals -both in terms of antibiotic stewardship and health economics. introduction: the current cdc guideline published in for the prevention of intravascular catheter-related infections recommends skin preparation with a greater than . % chlorhexidine with alcohol solution before cvcs or acs placement and with dressing changes, which was changed from % chlorhexidine recommended in the guideline. however, few studies investigated the superiority of % chg over either . % chg or % pvi for the prevention of catheter colonization as cdc guideline recommends. objectives: efficacy comparison of three antiseptic solutions [ % aqueous povidone-iodine (pvi), and . % and . % alcoholic chlorhexidine gluconate (chg)] for preventing intravascular catheter colonization. this was a open-label, multicenter, prospective, randomized controlled trial conducted at icus in japan. the intravascular catheters included central venous catheters (cvcs) and arterial catheters (acs). patients aged > years of age undergoing cvc and ac insertion in icu were randomized to receive one of three antiseptic preparations pre-insertion. catheters were removed when no longer necessary or if catheter-related infection was suspected. after catheter removal, distal tips were cultured using semi-quantitative/ quantitative techniques. catheter colonization and catheter-related bloodstream infection (crbsi) incidences were compared. results: while a total of catheters were randomized, several catheters were excluded due to withdraw of their informed consent and lack of cultured catheters after randomization, and ( %) catheters were included in the full analysis ( . % chg n = , . % chg n = , and % pvi n = ). the median catheterization duration was . days ( % ci: . - . days); no significant intergroup differences were observed (p = . ). catheter-tip colonization incidence (per catheter days) was . , . , and . events in % pvi, % chg, and . % chg groups, respectively (p = . ). catheter colonization risk was significantly higher in the % pvi group. no significant intergroup differences crbsi probability were observed introduction: spontaneous intracerebral hemorrhage (ich) is the most fatal stroke subtype worldwide caused by spontaneous vascular rupture due to hypertension or amyloid angiopathy. an accurate prediction of ich outcome would assist both families and physicians to decide therapies and monitorization at an early stage. objectives: to evaluate the relationship between the hematoma volume and location with mortality and functional outcome in patients with spontaneous ich. methods: we performed a prospective observational study, included patients admitted in icu with spontaneous ich. we determined hematoma volume at admission with kothari modified formula (axbxc/ ) and divided them in two groups according the location as infratentorial or supratentorial. we collected gcs, sofa, apache ii and graeb at admission, medical history and complications during the first week in the icu. we established modified rankin scale (mrs: poor outcome > ) and glasgow outcome scale (gos, poor outcome < ) at icu discharge. we used %, mean (sd) and median (minimal/maximum). t-student and χ (p < . ) were used for the univariable analysis. we conducted a multivariable analysis for mortality with binary logistic regression ( % ci, or) p < , . roc curve was determined for the volume of hematoma associated with mortality (ic % p < . ). results: we enrolled patients. % were men, mean age (± . ) years. global mortality was . %. . % were supratentorial and . % infratentorial. mean apache ii (± , ) and gcs . (± , ) and median sofa ( - ) and hematoma volume , cc . there were no significant differences between the two groups (infra and supratentorial) except ich volume (p . ) and length of stay (los)-icu (p . ). in the univariable analysis worse outcome with mrs was related with the volume of the hematoma (p , ) but not with gos (p , ). variables associated with mortality: gcs (p . ), apache ii (p . ), graeb (p . ), sofa (p . ), los-icu (p . ) and ich volume (p . ). after the multivariable analysis we determined hematoma volume was an independent risk factor for mortality (or , ; % ci , - , ; p . ). according the location we obtained a significantly association with mortality in the supratentorial group (p , ). we performed a roc curve of this group and obtained an auc , ( % ci , - , ; p . ) with cutoff point of , cc . conclusions: hematoma volume and los-icu are greater in supratentorial ich. the hematoma volume is associated with a worse outcome at icu discharge and a supratentorial ich volume above . cc is related to higher risk of mortality. introduction: aneurysmal subarachnoid hemorrhage (sah) is an acute cerebrovascular event, which leads to devastating consequences, high mortality and is an important cause of neurologic disability among survivors. incidence is reported between to / and mortality rates vary widely, ranging from to % among different authors. many complications associated with sah, such as delayed cerebral ischemia or hydrocephalus, also play a role in the poor functional outcome in survivors. paulo niemeyer state brain institute is a reference and high-volume center for sah, located in rio de janeiro, brazil, receiving patients from all over the state. objectives: the aim of the study was to describe the characteristics of patients with sah admitted to the icu, as part of a large prospective ongoing study, and to evaluate the factors associated with outcome. methods: from july to march , every patient admitted to the icu with aneurysmal sah, years and older was enrolled in the study. data were collected prospectively during hospital stay. the primary endpoint was mortality and dichotomized functional outcome, (poor outcome defined as modified rankin scale - ) at hospital discharge. results: a total of patients were included. the median age was ( - ), patients ( %) were female. demographic characteristics are presented in tables and . twenty-nine patients ( %) were treated by clipping, and patients ( %) were hydrocephalic and needed an evd. an intracranial pressure monitor was inserted in patients ( %). nine patients ( %) developed sepsis or septic shock during icu stay and pneumonia was present in ( %) patients. rebleeding was diagnosed in patients ( %), vasospasm was present in ( %) patients, post-surgical deterioration was diagnosed in ( %) patients and ( %) patients developed dci. twenty-two ( %) patients were mechanically ventilated. hospital mortality was % ( patients); and patients had unfavorable ( %). in univariate analysis, factors most frequently seen in patients with unfavorable outcome were rebleeding ( % vs %, p = . ), vasospasm ( % vs %, p = . ), post-surgical neurological deterioration ( % vs %, p = . ), dci ( % vs %, p = . ) and pneumonia ( % vs %, p = . ). although not statistically significant, there was a trend towards the association between sepsis/septic shock ( % vs %, p = . ) and unfavorable outcome. conclusions: sah is associated with high morbidity. neurological complications such as rebleeding, vasospasm, post-surgical neurological deterioration and dci, as well as clinical complications (eg. pneumonia) were associated with unfavorable outcomes. therapeutic interventions to prevent neurological and systemic complications may have an impact on clinical outcomes. introduction: the management of patient into the icu after been submitted to a cns resection is an important challenge. surgery is indicated for diagnosis, to reduce tumor bulk and to manage raised intracranial pressure. primary brain tumors are classified based on their cellular origin and histologic appearance. the most common malignant brain tumor is glioblastoma multiforme, this group have a poor prognosis. objectives: the goal was to make a descriptive analysis about the evolution of patient submitted in the icu for postoperative control following a surgical resection of intracranial tumors. methods: a retrospective and observational study was conducted on all elective consecutive surgical procedures for tumor resection admitted into the icu. we analyzed variables related with the tumor, predisposing pathology, surgical data and evolution in the icu. we considered as an unfavorable evolution the death into the first month after the intervention or the decrease in two points or more of the canadian´s scale score (css). is a comparative study analyzed by student´s t-test, anova of one factor and pearson´s chi-square test. comparative study expressed by: mean difference, relative risk and confidence intervals at %. results: we analyzed patients over of years ( - ) . of the total, . % are high-grade gliomas, . % low grade gliomas, , % meningiomas , . % metastasis and . % other type of tumors. average age is . years (sd . ), it is significantly lower in the low-grade gliomas, and in the group of other tumor types compared to other groups. . % are men , the most common in men ( . %) and meningiomas and other tumors in women ( . % and . % respectively) gliomas. . % are supratentorial location. average size is . ml (sd . ) . the average score in the preoperative karnofsky scale is . (sd . ) . the average income apache is . points (sd . ). an unfavorable evolution is observed in . % of patients ( . % per patient died and . % decline in the css) after one month , with no differences between different types of tumors. the percentage of deaths in the first month is higher in those undergoing surgery for metastasis ( . %, rr . , ci . to . ) . mortality at two years of intervention is . %, being higher in sifnificativamente undergoing metastasis ( %; relative risk . , ci . to . ) and high-grade gliomas ( . %; relative risk . , ci . to . ). conclusions: patients undergoing brain tumors have a significant risk of poor outcome , which is significantly higher in metastatic patients from the first month of intervention and in patients undergoing high-grade gliomas at two years. introduction: nosocomial infection (ni) is still an issue in neuroritical care. objectives: we analysed ni in a preventive multimodal protocol in patients with acute brain disease. method: we performed a -year prospective observational cohort study in patients (pts) with acute brain disease admitted to an eight-bed adult neuro-intensive care unit (nicu). we defined our preventive multimodal protocol as: ) keeping a hygienic and epidemiological regime including isolation of pts with multi-drug resistant bacteria ) correct antibiotic policy, and ) regular microbiological screening. there were ( . %; wound . %, respiratory . %, urinary . %, bloodstream . % and other . %) pts with ni. we compared ni group pts with the control group of pts and searching predictors of ni in univariete analysis. we did not find differences in age (p = . ), male (p = . ), weight (p = . ) or body mass index (p = . ), but there were more stroke pts and fewer tumour pts (p < . ). ni pts stayed in nicu longer (mean . vs . , p < . ), on admission had lower glasgow coma scale (mean . vs . , p < . ), higher therapeutic intervention scoring system (tiss, p < . ), acute physiology and chronic health evaluation ii (p < . ), and crp (p < . ); in the nicu they had higher crp (p < . ) and nicu mortality (p < . ); on discharge they had worse glasgow outcome scale (p < . ) and higher tiss sums (p < . ). ni pts had more accesses, which were strong predictors of ni: artery (odds ratio [ conclusions: our study confirmed that nosocomial infection is associated with worse outcome and higher cost, and that accesses are still risk factors in a preventive multimodal protocol. the predictive value of emergency triage codes on the outcome of aneurysmal subarachnoid hemorrhage introduction: outcome of patients with aneurysmal subarachnoid hemorrhage (sah) was associated in different studies with different variables (baseline illness severity, physical status, treatments, complications), but the relationship between outcome and triage assessment in the emergency setting has never been evaluated. emergency triage in italy is carried out with color codes: red (immediate life-saving intervention needed), yellow (urgent intervention needed), green (delayed intervention is sufficient), white (not urgent). objectives: to study the relationship between triage severity codes assigned to patients with sah in an italian emergency setting and the outcome expressed as modified rankin score (mrs) at hospital discharge (good outcome for mrs ≤ , poor outcome for mrs > ). methods: a retrospective clinical study included patients with aneurysmatic sah admitted to emergency departments of bologna catchment area, and then to intensive care unit (icu), from january to january . aneurysm coiling or clipping was performed after neuroradiological diagnosis and clinical stabilization, excluding patients too ill to benefit. intensive care treatment was carried out according to current practical guidelines. demographic, clinical and interventional data, complications, severity scores and outcome scores were recorded. the following parameters were considered in univariate analysis: age, sex, clinical condition on arrival in the emergency department (triage code, gcs, wfsn scale, vomiting and seizures) aneurysm clipping or coiling and other neurosurgical interventions, hydrocephalus, vasospasm, cerebral infarction (ct scan), fever, sepsis, acute respiratory failure with p/f ≤ , cardiovascular complications (hypotension requiring vasopressor therapy, acute cardiomyopathy, arrhythmias requiring treatment); the outcome variable was modified rankin score > at hospital discharge. results: poor outcome (mrs > ) was observed in % of triage green codes, % of yellow codes, % of red codes. the univariate analysis showed the statistically significant (p < . ) association with mrs > for the following variables: triage red code, wfsn scale > , acute respiratory failure, cardiovascular complications, sepsis. on logistic regression analysis, the red code assigned in the emergency department, cardiovascular complications and sepsis were associated with poor outcome. conclusions: the severity of general clinical conditions after subarachnoid hemorrhage needing immediate life-saving intervention, feature labelled "red code" in the emergency triage, was associated with poor outcome (mrs > ), while the other triage codes did not show any significant correlation with outcome. cardiovascular complications and sepsis during hospital stay were other variables associated with mrs > . evaluation of intracerebral hemorrhage (ich) score in patients admitted in intensive care by supratentorial brain hemorrhage l. perez-borrero introduction: intracerebral hemorrhage is a stroke subtype with high mortality and significant disability among survivors. objective: to evaluate in our area the intracerebral hemorrage (ich) score in patients with spontaneous supratentorial brain hemorrhage. methods: multicenter prospective observational study in three hospitals in andalusia (spain). we studied all patients with supratentorial brain hemorrhage admitted to the regional hospital of malaga (between to introduction: within the clinical importance of the sah, there are factors described in the scientific literature that speak of an unfavorable evolution of the disease. our hypothesis is based on trying to demonstrate if only one therapeutic intervention could alter the significance of these factors. objectives: analyze the sociodemographic, laboratory findings, clinical and radiological factors that influence prognosis at months in discharged aneurysmal sah patients treated with endovascular intervention. methods: we performed a retrospective longitudinal observational study of all patients who were diagnosed with an aneurysmal sah in icu services of hospitals between march st and november th . they were treated by endovascular intervention. after being discharged from icu and after months of neurologic follow-up. patients were divided into two groups, one formed by those who presented a favorable outcome (ef) and the other by those who didn´t (ed). the variables studied were age, sex, hbp, dm, smoking and dyslipidemia. at the time of admission po , pco , leukocytosis, hyperglycemia and hypertension was determined as well as sodium, magnesium and chlorine plasma levels. the clinical status of patients on admission was assessed using the hunt-hess and wfns scales. the severity of sah was determined by ct using the fischer scale. the aneurysm was located by four vessel angiography. the time between the sah clinic presentation and the procedure was recorded, as well as if aneurysmal occlusion was complete or not. as for the complications, we took into account the presence of fever, hydrocephalus, vasospasm and infarction. results: for the study, patients who underwent acute endovascular sah treatment using coils, were selected. female sex was the predominant sex % vs . % between ed and ef, respectively. the age group most frequently found was between and years ( % for ed and % for ef). logistic regression analysis determined as associated with a worse outcome factor: hyperglycemia on admission(or . , % ci . - . , p = . ), clinical status on admission determinated by hunt-hess (or . ci . - %, p = . ) and wfns scales (or . , % ci . - . , p = . ). the presence of fever on admission also has proven to be a poor prognostic factor (or . % ci . - , p = . ). conclusions: clinical factors for aneurysmal sah patients treated with endovascular procedure that have shown relation with the clinical outcome at six months are: poor clinical grade on admission, hyperglycemia and fever. these data are similar to those found in the literature and support the idea that the therapeutic decision (surgical or endovascular) is not the determining factor for the evolution of these patients, however, the ones mentioned above could be. background: conflicting results have been obtained by studies attempting to assess the risks of ischemic stroke in patients with venous thromboembolism, while the long-term risk of stroke in survivors of venous thromboembolism remains unexplored. objective: we evaluated whether the risk of ischemic stroke in patients hospitalized with venous thromboembolism is higher when compared to the general population. methods: one million patients from national health insurance beneficiaries in taiwan were sampled. there were , patients who had been hospitalized with diagnosis of venous thromboembolism and , unexposed subjects. all adult patients were followed from january to december to evaluate if ischemic stroke was diagnosed. cox regression models were applied to compare the hazards adjusted for potential confounders. results: after controlling for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, coronary artery disease, hyperlipidemia, history of alcohol intoxication, malignancies, congestive heart failure, atrial fibrillation, smoking, peripheral artery disease and charlson comorbidity index, the adjusted hazard ratio of ischemic stroke was significantly increased in patients with venous thromboembolism ( . ; % ci, . - . ). a subgroup analysis based on patients who survived longer than months in the cohort also revealed higher hazard ratio in the patients with venous thromboembolism. ( . ; % ci, . - . ). conclusion: the possible risk of ischemic stroke is significantly higher in patients hospitalized with venous thromboembolism than in the general population. introduction: status epilepticus (se) is a common neurological emergency with considerable associated health-care costs, morbidity and mortality. , se is defined as a prolonged seizure or multiple seizures with incomplete return to baseline. , the overall mortality of se is around % with convulsive status epilepticus representing about - % of all cases. status epilepticus severity score (stess) is a prognostic score that relies on four outcome measures (age, history of seizures, seizure type and extent of consciousness impairment) determined before treatment institution that ranges between and . objective: evaluation of stess as a prognostic measure of functional impairment, neurologic motor deficits and -day mortality. methods: retrospective observational study of patients with se admitted at a general intensive care unit (icu) from to . age, gender, saps ii/iii, type of se, length of stay, number of anti-epileptic drugs, duration of se, functional impairment, neurologic motor deficits and -day mortality were collected through the icu informatics database -picis®. data is presented as mean ± sd and we used logistic regression to correlate stess with study variables. statistical analysis was performed using xstat ®. results: sample included patients, , % male, age , ± , years, saps ii , ± , , saps iii , ± , , icu length of stay , ± , days and hospital length of stay , ± , days. convulsive se represented , % of cases. stess score`s mean was , ± , . se lasted more than day in , %. electroencephalogram was performed in , % of the patients. , % of the patients needed two or more anti-epileptic drug for se. at hospital discharge , % had functional impairment and , % had neurologic motor deficits. mortality was , % at days. there was a correlation between stess and mortality (or = , ; roc = , ), functional impairment (or = , ; roc = , ) and neurologic motor deficits (or = , ; roc = , ). the number of antiepileptic drugs and se duration had no correlation significance. conclusions: we found an excellent correlation between stess and mortality in our study. besides this, we also found this score to be a good prognostic tool for functional impairment and neurologic motor deficits. we consider our main limitations the sample size and lower mortality. despite we recommend using stess as an outcome predictor. introduction: in order to determine optimal airway protection measures in early postoperative period after fossa posterior surgery (pfs), it is important to carry out a prognosis of neurological dynamics based on the preoperative neurological exam. we have designed neurological evaluation scale (nes). objectives: our study was aimed at determining the potential of nes to predict brain stem deterioration in early postoperative period after pfs based on the assessment of the preoperative neurological status. methods: the prospective study was carried out during the period from december to june and included patients operated for fossa posterior tumors (fpt). to be included in the study, patients had to be over years old and operated for fossa posterior non infiltrative paraxial tumors. we examined all patients before and after the operation, immediately after the extubation in icu. nes provided complex neurological assessment with an emphasis on the brain stem function. postoperative nes points were subtracted from the preoperative points -ab-criterion (abc). positive abc corresponds to intensification of neurological deterioration. negative or zero abc corresponds to neurological improvement. all neurological symptoms were grouped in nes blocks according to their relation to cns. results: we divided all patients in two groups depending on their abc, which revealed that the patients with positive abc had reliability less nes points before operation compared to the patients with negative or zero abc. we found out the frequency of occurrence of each nes block for inclusion in the full neurologic status. we discovered that caudal stem affection occurred more frequently in the patients with more nes points. we evaluated the probability of neurological impairment or regression of neurological symptoms depending on abc with sensitivity , % and specificity %. we created a prognostic model, which could predict the discharge from clinic outcome on the basis of the nes blocks points assigned during the early postoperative period. conclusions: we revealed neurological features of postoperative period in patient after fps. our data could predict neurological outcomes, and be useful in optimization tactic of airway protection. and those who died ( . ± ; . ± and ± . ± vs ; . ± and . ± respectively) but difference was not significant. an inverse correlation between inflammatory biomarkers (pct, crp and il- ) and igm endocab was detected. il showed a higher correlation, but without statistically significant differences. icu mortality rate was %. conclusion: igm endocab were detected in septic shock caused by gpb, it could be explain by a bacterial translocation. patients with major endotoxaemia have higher consumption of antibodies and therefore lower levels of igm endocab that is associated with a worse prognosis. the relationship between the neutrophil/lymphocyte ratio and mortality in the severe sepsis patients y. conclusions: sp compliance is below recommended but the mean hobe reaches the lower limit of the recommendation. the factors affecting sp compliance differ according to the method used for data collection and include other factors than patient's clinical condition. politics targeting to increase its compliance should address various areas of care such as team and professionals, resources and equipment and re-consider clinical indications for sp. the project was funded by the °national award of nursing research from marques de valdecilla hospital (spain). gained to collect staff opinions and anonymised patient data. ed, or and icu professionals were surveyed following a pilot to determine options, ranking and scoring criteria a priori where needed. anonymous patient data from intubated patients who were cared for in the ed, or and icu within their first hours were collected. this included physiological observations and supportive care standards around a, b and c. results: the most striking differences in staff opinion involved the preferential use of artificial colloid-based fluid resuscitation in sepsis ( % ed staff; % or staff; % critical care staff); the value and significance of recording end tidal co ( % ed staff; % or staff; % critical care staff); and the potential preferential use of flowdirected fluid boluses rather than pressure-directed fluid boluses in critically ill patients ( % ed staff; % anaesthetic staff; % critical care staff). when observing supportive care standards the largest differences were in the use of stress ulcer prophylaxis (only prescribed in critical care); patient positioning (head-up: % patients in cc; % in ed); the recording of sedation level ( % ed; % anaesthetic; % critical care) and the recording of ventilator parameterstidal volume, peak pressure and et-co -( % ed; % anaesthetic; % critical care) . finally, in respect to patient pathophysiology, all groups were under ventilated and over oxygenated. mean arterial pressure was most divergent from baseline in the ed. however, changes in pathophysiology were related to interventions (fluid boluses, analgesia, surgical interventions, inotropes, pressors) rather than location. despite the divergent views regarding the relative value of flow monitoring, observed fluid boluses were predominantly triggered by pressure changes in all three locations. conclusions: differences in staff attitudes; application of standards and patient pathophysiology were identified between care locations. the influence of variation in resources and professional composition of teams (nurses:doctors) on these results requires further work. it remains uncertain whether more uniform approaches would improve patient outcomes. lung comet score (lcs) for evaluation of extravascular lung water (evlw) in intensive care unit (icu) patients undergoing renal replacement therapies (rrt) a. taggu methods: a prospective observational study was conducted on patients in icu needing rrt. exclusion criteria were age < years, pregnant, amputees, cardiac pacemakers, pre-existing lung diseases and ascites. lung comet score as per validated technique , bia measurements and baseline data were collected pre and post dialysis. lung comet score and other covariates were fitted into a regression model using bia as the standard test. based on bia delta hydration relative (hs rel), patients were divided into normohydration and hyperhydration using a cut-off of %. results: a linear regression model in predialysis state showed that only lcs could significantly predict lung water (const . , coef. . , p value . ). in the postdialysis state lcs perfectly predicted lung water (const . , coef., . ; p value . ).bland altman plots showed good agreement between lcs and hydration status (bia) pre and post dialysis. the lcs > nearly perfectly predicted hydration status in both pre and post dialysis states. conclusions: lung comet score is a good surrogate of evlw and reliably predicts reflects hydration status pre and post dialysis in icu patients. introduction: treatment withdrawal in intensive care is common ( ) . whilst significant research attention has focused on how treatment is withdrawn and what information is communicated to families ( ) introduction: micro-aspiration of subglottic secretions is considered a major pathogenic mechanism of endotracheal tube-associated pneumonia (etap), either postoperative pneumonia or ventilatorassociated pneumonia. endotracheal tubes (ets) with taper-shaped cuffs have been proposed to provide a better seal of the extraluminal airway, thereby preventing micro-aspiration and possibly etap. objectives: to perform a systematic review and meta-analysis to assess the efficacy of ets with taper-shaped cuffs in the prevention of etap. methods: a systematic search of medline, embase and central/ cctr was conducted in march . eligible trials were randomized controlled clinical trials (rcts) comparing taper-shaped cuffs with standard, cylindrical-shaped cuffs in intubated patients. all studies reporting the incidence of etap were included. inclusion of trials was irrespective of publication status, date of publication or language. random-effects meta-analysis calculated the risk ratio (rr) and % confidence interval (ci) for the incidence of etap between both groups using the mantel-haenszel method. results: three rcts, given a total of patients, met the inclusion criteria. one trial was published as a conference abstract only ( ), while the others were published in full ( , ) . none of the trials was blinded for the intervention. patients were allocated to the intervention arm and to the control arm. etap episodes occurred in the intervention group and in the control group. the pooled rr for the incidence of etap was . ( % ci, . - . ; z = . p = . ). conclusions: the use of endotracheal tubes with taper-shaped cuffs did not show to reduce the incidence of etap. however, the number of available studies is small, and there is an inherent risk of bias due to the unblinded designs. background: understaffing of icu's can have serious adverse consequences both for patients and for nurses, and therefore it is important to have an adequate number of nurses on the ward. nurses however are in short demand and resources are scarce. being able to predict the nursing workload for a certain group of patients may help to allocate nursing capacity as efficiently as possible and thus to reduce costs, without endangering the patients safety and nurses' health. nas is a validated tool for the measurement of nursing workload in an intensive care unit. goal: this study was conducted to investigate whether it is possible to predict the nursing workload for a homogeneous group of patients, admitted after an in or out of hospital cardiac arrest and to assess the effects of baseline characteristics, vital parameters and admittance time on this workload. method: we performed a retrospective analysis of nas scores of all ihca and ohca patients admitted to our icu from october until september during the first hours of stay. the nas was recorded per patient per nursing shift. we furthermore recorded patient characteristics and vital parameters. results: during this period patients, males and females, were admitted to the icu after cardiac arrest. the mean age at admission was . years (sd = . ). the mean nas at admission was . (sd = . ). patients admitted in the evening shift had a significantly higher nas compared to patients admitted in the night shift ( . ; sd = . vs . ; sd = . (p = . )), but no significant difference was found with the day shift (mean nas day shift: . ; sd = . ). after admission the workload decreased in all patients by a mean of . points (sd = . ; p < . ). a higher sofa score, a higher peep and a lower ph at admittance resulted in a higher nas score on average over time (p < . ). conclusions: the nursing workload at admission of patients after cardiac arrest is fairly predictable, with no clinically significant difference between shifts , necessitating a nurse-to-patient ratio of at least : . after the first shift it is almost always possible to decrease the nurseto-patient ratio to : . the nas was influenced by severity of illness. these results can be used to assess the needed nursing staff for the treatment of these patients for the first days after admittance. introduction: major trauma and severe sepsis are both leading causes of admission to the resuscitation rooms in emergency departments across the world. despite obvious differences in precipitating mechanism, there are surprising similarities between subsequent pathophysiology: both disorders lead to disorders of the macrocirculation, microcirculation and host inflammatory response ( , ) . objectives: here we compare the baseline epidemiology, pathophysiology, operational and clinical management of intubated resuscitation room patients with these two critical illness syndromes (major trauma/septic shock). the results will be used to facilitate the design and planning of a study to test the feasibility/effectiveness of advanced monitoring systems (thromboelastography, oesophageal doppler flow monitoring, echocardiography, and microcirculatory monitoring) in the resuscitation room management of critically ill patients with these conditions. methods: institutional approval was gained to collect anonymised patient data over a -month period from a mixture of written and electronic records. where appropriate, significance was tested by mann whitney u (sigmaplot . ). results: patients, intubated pre-hospital or in ed resus, were identified with trauma or sepsis diagnoses. trauma patients were commoner (n = ; %) and more likely to be intubated prehospital ( / ; . % vs / ; %). lactate profiles were similar in the two groups at start and end of resus episode ( figure ). patients with major trauma were more hypertensive but equally tachycardic when compared with patients with severe sepsis/septic shock. patients with septic shock/severe sepsis (median minutes vs minutes) spent longer in resuscitation room, but received less documented consultant-level review ( . % vs . %). imaging of major trauma patients was with ct ( / ; %) and ultrasound ( / ; . %) in contrast to septic patients ( / ct; . %; / , % us). icu and hospital mortality was higher in patients with sepsis ( . % vs . %), but death in resus only occurred in the trauma population. only two patients, both with facial trauma, would have had a relative contraindication to the proposed advanced monitoring. conclusions: this novel preliminary work has highlighted some important differences between the epidemiology, outcomes, pathophysiology and clinical/operational management of intubated patients with severe sepsis versus major trauma. these will influence the conduct and outcome measures of any trial of advanced monitoring in this setting. however, contraindications to any of the advanced monitoring technologies being considered were rare and no obvious barriers to the planned study of advanced monitoring were identified. introduction: in our -bedded gicu, demand for beds has increased while recruitment of icu trained nurses has decreased. there is enduring evidence of links between workload and stress [ , ] , with high levels of burnout reported in icu nurses [ ] . there has been a shift towards measuring what makes people positive and engaged [ ] , rather than why people reach the extreme state of burn out. it is important to understand factors that affect work engagement to develop strategies that enhance nurse retention and improve the quality of icu patient care. objectives: to examine the impact of an education initiative for novice icu nurses on work engagement for the icu nursing staff and organisational resource use. methods: a pre -post design was used to collect data from all icu nurses at the start of the education programme and at months following he intervention. work engagement was measured using the self-report item utrecht work engagement scale (uwes) [ ] with an open question to capture staff experiences. organisational impact was measured using levels of sick leave, % staff turnover, use of agency nurses and staff recruitment. results: fifty three icu nurses completed the pre-intervention survey ( % response) and completed the post-intervention survey ( % response). respondents had reasonable years of icu experience (mean . , sd . ) and time in current post (mean . , sd . ). internal consistency for the uwes was high (alpha . ). levels of work engagement (mean [sd]) increased ( . , [ . ] vs . [ . ]) but did not reach significance and remained in the 'average' band as judged by the scale authors [ ] . when examined by senior and junior nurses, the increase was similar. organisational measures showed decrease in sick leave, turnover, agency use and increase in recruitment of experienced icu nurses. qualitative feedback was positive, with perceptions of improvement in unit morale due to time being invested in the individual and reduced stress and workload for shift leaders. conclusions: providing education for the newest icu recruits can have benefits for the whole icu team. however, it is important to examine how work engagement might be further improved. the incidence of silent aspiration on intensive care n. maistry royal brompton and harefield nhs foundation trust, rehabilitation and therapies, london, united kingdom intensive care medicine experimental , (suppl ):a introduction: the incidence of dysphagia on intensive care is an area of growing research. dysphagia is associated with aspiration pneumonia and increased icu bed days. in general, speech and language therapy (slt), makes recommendations based on the results of a clinical bedside swallowing evaluation, despite the unreliability of this method . this is largely due to the difficulty accessing gold standard assessment methods such as videofluoroscopy (vf) and fibreoptic endoscopic evaluation of swallowing (fees) . referral for these assessment methods are based on a local defined criteria. this study evaluates the incidence of silent aspiration identified by vf and fees in a bedded tertiary cardio-respiratory intensive care unit. objectives: to determine the incidence of silent aspiration, defined as "aspiration before, during, or after swallowing in the absence of cough or visible signs of choking and distress ," in icu patients assessed by vf or fees between july and june . method: data was retrospectively reviewed for month period from all icu referrals made to slt for swallowing evaluation. all patients received a clinical bedside swallowing evaluation. the results are presented as percentages and counts for patients receiving vf and fees that silently aspirated. results: a total of patients were referred for swallowing assessment and % ( / ) had a vf or fees. there were males and ages were . ± . years. in this group, patients had videofluoroscopic assessments and patients had fees. in the vf group % silently aspirated whilst in the fees group the values were %. patients ( %) silently aspirated during objective assessment, impacting on how and when oral feeding was commenced. conclusion: this study suggests that silent aspiration is highly prevalent in this population group. consequently, vf and fees should be part of standard routine assessment in the management of critically ill patients. delerium related incidents at the icu and nursing aspects a. van introduction: at the icu of vu university medical center (vumc) nurses are frequently confronted with delirium , . delirium is known to be present in - % of mechanical ventilated patients and - % in non-ventilated patients. immediate consequences are falling incidents or for patients to remove tubes and iv lines that are necessary for treatment. in literature, this is stated as a result of treatment, but often data is missing. consequences of removal are increased risk of complications , prolonged mechanical ventilation, los and increased morbidity/mortality . objectives: to measure the frequency of removing tubes, lines and falling incidents related to delirium. methods: a multidisciplinary focus group was formed ( ) in order to properly diagnose, prevent and/or treat delirium due to the high prevalence. the first steps were increasing awareness and implementing the cam-icu score. to clarify delirium-related incidents a one year period was set in which the dedicated senior nurse informed and trained the nursing staff regarding delirium and potential risks. to register delirium-related incidents a modified report button was built in the epr (metavision, imd soft) and used beside the regular incident reporting system . results: after one year, individual patient incidents were reported concerning falling or tube or iv line removal. this included gastric tubes, airway tubes, iv/cvc/arterial lines, other lines and fall incidents. in % of the cases the patient was diagnosed with delirium. out of patients received medication or were fixated before the incident despite a % cam-icu registration rate. because the focus group doubted about underreporting nurses were interviewed if the results corresponded with their experience. they were unanimous that there was hardly any underreporting. discussion: despite therapy or fixation delirium-related incidents occur on a weekly basis at our icu, causes harm and increases nursing workload. although the incidence rate is presumed to be low, there is no feeling of satisfaction. further improvement is necessary due to the high risks for the patient. therefore, we need to be able to diagnose incidents faster so we can start treatment sooner. although the cam-icu score was implemented, compliance is insufficient. increasing compliance is the first step to further improvement. the follow-up question is whether delirium-related injury can be reduced when cam-icu compliance improves. second step is to investigate the effectiveness of our fixation protocol. prospective study to determine the predictors of extubation success a. taggu introduction: timely extubation is crucial in critically ill patients. traditional indices like rapid shallow breathing index are considered as accurate during the spontaneous breathing trial. multiple other proposed parameters like diaphragm thickness, fluid balance and cardiac indices have been shown to predict succesful extubation in the recent years. objectives: to assess the reliability of the parameters in predicting successful extubation. methods: a prospective observational study done on adult patients eligible for extubation as decided by the attending intensivists. exclusion criteria: pregnant and tracheostomised patients. along with baseline parameters, following measurements were taken pre and post extubation. . cardiac parameters including simpsons method for ejection fraction, e/a, e/e' (lateral) for diastolic function, tapse and tad for right ventricular function. all recordings were taken just before extubation and within six hours post extubation. . just before extubation,high frequency linear ultrasound probe was used to measure the right sided dt at the zone of apposition (zoa) between th to th intercostal spaces in mid-axillary line.the change in dt fraction(Δdtfrac_pre%) was calculated as dt(end-inspiration)-dt(end-expiration)/dt (end-expiration)x .rsbi was simultaneously recorded. . fluid balance hours were recorded. figure ) . we found no significant difference on mortality when limiting the results just to trial employing cvvh at hemofiltration rate lower or higher then ml kg − h − . conclusions: blood purification with cvvh might be associated with a significant reduction in mortality when performed in patients with sepsis or ards. this is the first meta-analysis suggesting beneficial effects of cvvh on mortality and we could suppose that the beneficial effects of cvvh in these inflammatory conditions could arise from the immunomodulatory properties of hemofiltration. further high-quality randomized controlled trials adequate powered for mortality are needed to clarify the impact of cvvh on these inflammatory conditions. the authors declare no support or funding and no potential conflict of interest. we defined extreme hyperbilirubinemia as a state of total bilirubin above mg/dl and selected all patients whose serum total bilirubin increased above mg/dl at least once during their stay in the intensive care unit. we investigated the overall clinical course of the patients and compared the differences between one group with normalization of total bilirubin (recovery group) and the other group without normalization (non-recovery group). furthermore, we evaluated the association between prognosis and various clinical factors, including the peak total bilirubin levels, increasing rate of total bilirubin (vi), results of laboratory analyses related to hepatic function, and clinical features at the time of extreme hyperbilirubinemia. these data were analyzed using chi-square test and cox and logistic regression analyses. introduction: propofol is widely used in critical care sedation due to its pharmacological properties which allow serial neurological examination ( ) .hypo tension is a common side effect of propofol infusion, which affect patient outcome. introduction: propofol is a common intravenous drug used during anesthetic induction and sedation because of its rapid onset and short duration. its downfall, however, is that patients experience injection pain so severe that they recall induction as the most painful part of the sedation process. among numerous reports in efforts to decrease propofol injection pain, the most effective combination of drug and non-drug intervention evaluated through a quantitative systematic review revealed to be pretreatment with . mg/kg lidocaine in combination with a tourniquet for venous occlusion. the majority of these reports conclude that a single method is insufficient in eliminating propofol injection pain. objectives: we evaluated the effect of heated carrier fluids ( °c) in decreasing propofol injection pain. methods: a randomized controlled clinical trial was conducted in patients (asa or ), ages to . patients were allocated into groups (n = ) each. group w received ml of heated carrier fluids for minutes prior to mg/kg propofol injection; group l received ml of heated carrier fluids for minutes prior to lidocaine pretreatment and mg/kg propofol injection: and group c (control group) received ml of room temperature fluids prior to mg/kg propofol injection. propofol injection pain was evaluated using the verbal pain score (vps). results: group w and l showed significant reduction in the incidence and severity of injection pain compared to group c (p < . ). vps was significantly lower in group w (p = . ) and l (p = . ) compared to group c. there was no statistical difference between group w and group l (p = . ). there was statistically significant difference in mean blood pressures measured after mg/kg propofol injection among groups. conclusions: both heated carrier fluids and combination of lidocaine pretreatment effectively reduced propofol injection pain. objectives: we conducted a prospective cohort study to clarify the epidemiology and the nature of aes in surgical inpatients in japan. methods: the japan adverse event (jet) study was a prospective cohort study which had evaluated aes and medical errors (mes) at tertiary care hospitals. the medical and surgical wards were stratified according to hospital and whether they were medical or surgical wards, and study wards were randomly selected. intensive care units (icus) were all included. we included all adult patients aged > = years old who were admitted to any of the selected study wards ( medical, surgical, and icus) over a -month period. the primary outcome of this study was the epidemiology and the nature of aes and mes in the patients who had operation during the study period. trained nurses placed at each participating hospital reviewed all charts daily on weekends, along with laboratories, incident reports, and prescription queries to collect any potential event. they also collected the characteristics of the patients in the cohort. independent physician reviewers evaluated all potential events and classified to whether they were aes or mes, as well as to their classification, severity and preventability. introduction: whereas the importance of low tidal volume to avoid ventilator-induced lung injury (vili) in patients with ards is well known, several uncertainties still exist regarding how to set positive end-expiratory pressure (peep). many approaches have been considered, but no one showed a clear effectiveness in terms of outcome. recently a ventilator strategy using esophageal pressure to estimate the transpulmonary pressure has been proposed by talmor and colleagues . although they found an improvement in arterial oxygenation, it was not explored whether the increase in oxygenation was due to lung recruitment. objectives: the aim of this study was to assess whether the peep set to maintain a positive end-expiratory transpulmonary pressure (p l ) is associated with an increase in lung recruitment estimated by lung ultrasound score (lus) . methods: patients with moderate and severe ards were enrolled. for the first hours, peep was set according to the acute respiratory distress syndrome network standard-of-care recommendations (phase a). it was then adjusted according to measurements of esophageal pressure for the following hours (phase b) to maintain a positive p l at the end of expiration. the primary end point was the improvement in lung recruitment assessed with lung ultrasound. [ ] no data are available on the relationship between opening pressures and disease severity. objectives: to describe lung recruitment as a function of the transpulmonary pressure in mild, moderate and severe ards. methods: ards patients underwent a low-dose end-expiratory ct scan at peep cmh o and three end-inspiratory ct scans at the plateau pressures reached starting from peep cmh o, cmh o and cmh o. in each of the ct slices, lung profiles were manually delineated, excluding hilar structures. thereafter, quantitative analysis of ct scan images was performed and the gas and tissue fractions were computed. we defined the recruitability as the difference of not inflated tissue between and cmh o, that we arbitrarily assumed to be the "full recruitment". [ ] the grams of recruited tissue were computed across the pressure intervals at which the ct scan were performed, as the differences of not aerated tissue. airway and esophageal pressures were continuously measured and transpulmonary pressure was computed as: driving airway pressure (cmh o) -(esophageal plateau pressure (cmh o) -esophageal end-expiratory pressure at peep (cmh o) [ ] . results: thirty-three patients were studied, with mild, with moderate and with severe ards, according to the berlin definition. [ ] as reported in the table and fig. , the amount of tissue which can be opened between and cmh o was %, % and % respectively in mild, moderate and severe ards). mild ards patients nearly completed recruitment at approximately cmh o transpulmonary pressure while in moderate and severe ards recruitment continues up to cmh o transpulmonary pressure. conclusions: at the clinically recommended plateau pressure of cmh o, in severe ards, up to / of the lung tissue recruitable at cmh o, stays always closed. beyond contributing to the gas exchange impairment (depending on the perfusion), these "always" collapsed regions may also act as stress risers at their interface with aerated regions, though they are theoretically protected from the mechanical ventilation. introduction: extracorporeal membrane oxygenation (ecmo) is a rescue therapy for patients with acute respiratory distress syndrome (ards) by providing additional oxygenation, and removing carbon dioxide thus permitting less injurious mechanical ventilation settings that have been shown to protect the lungs from additional injury. objectives: to evaluate associations between distinct ventilator settings during ecmo, and outcome of ards patients. methods: individual patient data analysis of observational studies in adult ards patients receiving ecmo for refractory hypoxemia. multilevel multivariable logistic regression models and cox-proportional hazards models were used to determine which settings and parameters had an independent association with the primary endpoint all-cause mortality. results: nine studies with patients were selected ( figure ). initiation of ecmo was accompanied by significant decreases in tidal volume, positive end-expiratory pressure (peep), plateau pressure (pplat), and driving pressure (Δp = pplat -peep), respiratory rate and minute volume (figure ), and resulted in higher pao to fio ratios, higher arterial ph and lower paco ( figure ). higher age, lower body mass index, and higher lactate were associated with all-cause mortality after multivariable adjustment. Δp, both before and during the first three days of ecmo, demonstrated an independent association with all-cause mortality ( conclusions: in this series of ards patients receiving ecmo for refractory hypoxia, Δp and fio were the only ventilatory variables that had an independent association with outcome. these findings indicate the potential for improvement in the management of patients with ards undergoing ecmo. lungs were analysed for wet-to-dry ratio, bal protein, static compliance, spo and histology. to detect the timing of injury, rats received evans blue dye (ebd- mg/kg iv) at the initiation and were euthanized immediately before lung deflation or at , , or min afterwards ( /group). terminal bal analysed for ebd absorbance. ultrastructural impact was studied by electron microscopy on lungs sampled from rats euthanized before deflation, and at and min after deflation. hemodynamic data was obtained by echo performed at baseline (peep cmh o), immediately before and after deflation, and at mins after deflation. rv pressure was measured with a millar catheter. results: wet-to-dry ratio ( . ± . vs . ± . ; p = . ) and bal protein ( . ± . vs . ± . ; p = . ) was higher; and static compliance ( . ± . vs . ± . ; p = . ) and spo ( ± . vs ± . ; p = . ) were lower in intervention vs control. histology revealed collapse, hemorrhage and neutrophil accumulation in the intervention group. bal evans blue demonstrated that microvascular leak was absent before deflation and was maximal by min of deflation. ultrastructural analysis showed that sustained inflation caused minimal swelling of epithelium and endothelium before deflation; deflation resulted in major cellular and interstitial edema, and endothelial injury. hemodynamic data showed that rv and lv were under-filled during inflation. upon deflation, rv output, pulmonary vascular resistance, rv systolic transmural and diastolic pressures increased precipitously. rv/lv ratio increased progressively. conclusion: sudden deflation after sustained inflation with peep causes protein leak, inflammation, hypoxemia, reduced compliance, endothelial injury and rv failure. the mechanism appears to be endothelial injury resulting in microvascular leakage, pulmonary hypertension and rv failure. significance: deflation injury may be an important entity to prevent when using sustained inflation manoeuvres and may explain -in partwhy several important rcts in ards have been negative. low dose steroids reduce short term mortality in septic shock patients: results of an individual patient data meta-analysis r. introduction: previous research has suggested that the use of low dose steroids may be beneficial during septic shock. however subsequent inconsistent results explain the lack of consensus amongst doctors around the world about whether treatment with low dose steroids does improve the overall recovery and survival in patients with septic shock. we hypothetize that the lack of consistent evidence on the effect of low-dose steroids on short term mortality may be related to underpower. treated for septic shock. objectives: the primary objective of the present study was to estimate the effect of three different therapeutic regimens (hydrocortisone alone, hydrocortisone plus fludrocortisone, neither hydrocortisone nor fludrocortisone) on -day mortality in patients treated for septic shock using an individual patient data meta-analysis. methods: individual patient data meta-analysis including the major recent randomized controlled trials comparing early lowdose short course hydrocortisone and fludrocortisone to placebo (ger-inf ( )), hydrocortisone alone to placebo (corticus ( )) or hydrocortisone to hydrocortisone and fludrocortisone (coiitss ( )) in septic shock patients. the primary outcome measure was all cause -day mortality. secondary outcomes measures were day mortality, resolution of organ dysfunction (as measured by the time to reach a sequential organ failure assessement score < ), time to vasopressor and mechanical ventilation discontinuation, intensive care unit and hospital lengths of stay as well as the rate of superinfection. treatment effect on the primary outcome was quantified using relative risk and estimated using targeted maximum likelihood estimation. results: a total of , patients were enrolled in the trials. when compared to the placebo, hydrocortisone + fludrocortisone significantly reduced -day mortality (rr = . , %ci = . - . , p < . ). hydrocortisone + fludrocortisone was also superior when compared to the placebo and hydrocortisone pooled together (rr = . , %ci = . - . , p = . ). hydrocortisone + fludrocortisone significantly decreased -day mortality (rr = . , %ci = . - . , p < . ) in the nonresponders, while it was associated with an increase in -day mortality in the responders (rr = . , %ci = . - . , p = . ) ( figure ). hydrocortisone + fludrocortisone was also superior when considering secondary outcomes such as vasopressor discontinuation or lengths of stay. conclusions: in this individual patient data meta-analysis including the major randomized controlled trials on the subject, we found that an early short course of low-dose hydrocortisone and fludrocortisone decreases -day mortality and improves recovery from organ failure in septic shock patients non responding to a corticotropin stimulation test. introduction: statin therapy during intensive care unit (icu) stay has been associated with a reduction in all-cause hospital mortality in some studies. this association was especially noted in septic patients. however, potential benefit needs to be validated in randomized, controlled trials. objectives: the purpose of this study was to compare the effect of simvastatin plus standard therapy on mortality and total icu length of stay (los) to that of standard therapy alone in critically ill septic patients. methods: a prospective randomized, open label, controlled pilot clinical trial was conducted on patients diagnosed with sepsis/severe sepsis as defined by the american college of chest physicians (accp). hundred patients met the study criteria and were randomized into two groups; a standard group who received standard treatment and simvastatin group who received the standard treatment plus mg simvastatin. primary outcomes were days icu mortality and total icu los. plasma c-reactive protein (crp), total creatine kinase (ck) and liver enzymes [alanine aminotransferase (alt) and aspartate aminotransferase (ast)] were measured as secondary outcome measures. results: a total of patients completed the study. simvastatin was well tolerated, with no increase in adverse events between the two groups. total icu los was significantly lower in the simvastatin group. however, the number of patients with days icu mortality in the simvastatin group was lower compared to standard group; but survival failed to reach statistical significance. similarly, plasma creactive protein failed to reach statistical significance between the two groups conclusions: treatment with simvastatin mg in patients with sepsis/severe sepsis is safe and associated with an improvement in number of deaths and icu los but without subsequent improvement in survival. the use of anapnoguard system in intubated critically ill patients a randomized controlled study introduction: the anapnoguard system (ag) (hospitech respiration ltd., petach-tikva, israel) is an innovative respiratory guard system that continuously monitors and controls the cuff pressure by measurements of co levels above the cuff, and allowing simultaneous rinsing and aspiration of subglottic secretions. objectives: to determine the safety and clinical efficacy of ag system compared with usual care in critically ill patients. methods: prospective, single centre, open-label, randomized, controlled feasibility and safety trial. sixty patients, without pneumonia, were randomized to be intubated with the ag tube and connected to the system (n = ) or with a conventional tube (n = ) combined with subglottic secretion drainage and manually control of tracheal cuff pressure (p cuff ). primary outcome was the rate of adverse events. other outcomes included the rate of mechanical complications, the level of icu staff satisfaction, the incidence of ventilator-associated pneumonia (vap), the quality of p cuff control, and the amount of ss drained. results: out of patients enrolled in the study, were included in the analysis ( per each group). both groups were similar at randomization in demographic characteristics, icu admission diagnosis, main comorbidities and severity of illness. no device-related adverse events occurred in any of the two groups. no differences were detected using ag system vs conventional tubes in terms of post- introduction: during sepsis, intrinsic stress responses may become maladaptive and contribute to poor outcomes. targeted intervention with β-blockade to 'de-stress' such patients may be beneficial. we developed a -h rodent model of fluid-resuscitated faecal peritonitis in which mortality (occurring between and h) can be predicted at h by a low stroke volume (auroc . ), and where survivors are clinically improving by study end. [ ] objectives: to investigate the impact of β-blockade on outcomes in predicted survivors and nonsurvivors of faecal peritonitis. methods: instrumented, fluid resuscitated, male wistar rats ( - g) had sepsis induced by intraperitoneal injection of faecal slurry ( . ml/kg). at h, under brief isoflurane sedation, echocardiography was performed to differentiate predicted survivors from nonsurvivors based on a stroke volume cut-off of . ml. rats in each prognostic group were then randomised to receive either esmolol ( μg/kg over min followed by μg/kg/min infusion) or matching placebo ( . % nacl) until h. animals were observed for up to h, and time of death was recorded. the study was powered to detect a mortality reduction in predicted nonsurvivors from % to % with esmolol, with a power of . and type- error of . . results: rats were randomised after prognostication to receive either esmolol or placebo. at h, predicted survivors and nonsurvivors were clinically indistinguishable (both groups appeared only mildly unwell), though predicted nonsurvivors (stroke volume < . ml) had lower cardiac output ( ± vs. ± ml/min), higher heart rate ( ± vs. ± bpm) and blood pressure ( ± vs. ± mmhg) and more haemoconcentration (haemoglobin . ± . vs. . ± . g/dl) (all p < . ). survival was significantly improved by esmolol in predicted nonsurvivors (p = . ), but worsened in predicted survivors (p = . ). conclusions: mortality was approximately halved in predicted nonsurvivors by esmolol, but doubled in predicted survivors. early prognostication appears key in identifying the subset(s) of animals (and, potentially, patients) who might benefit from additional treatment, while avoiding iatrogenic harm in those that would naturally survive. mechanisms by which esmolol impact upon mortality are under investigation. introduction: endotoxins (lipopolysaccharides, lps) have become interesting targets in extracorporeal therapies. lps is a major constituent of the outer cell wall of gram-negative bacteria and strongly triggers inflammatory responses in humans at concentrations as low as ng/kg body weight. although the elimination of lps is promising for the supportive therapy of sepsis and liver failure, endotoxin neutralization using endotoxin adsorbents is controversial. objectives: we could recently show that endotoxin inactivation by low-dose polymyxin b (pmb; ng/ml) could be applied for endotoxin inactivation in blood [ ] . aim of this study was to establish an adsorbent-based system which combines constant pmb release for endotoxin inactivation and effective cytokine adsorption during extracorporeal treatment. methods: we established an adsorbent-based pmb release system which ensures a constant pmb level in plasma during extracorporeal therapies. a polystyrene-divinylbenzene based cytokine adsorbent (cg c) with nanostructured pores was coated with a defined amount of pmb by hydrophobic interactions. the endotoxin inactivation and cytokine adsorption was tested in an in vitro model using fresh donated blood which was stimulated with ng/ml lipopolysaccaride from e. coli. results: in plasma or blood an equilibration between the free and bound form of pmb will lead to a constant pmb level in plasma. the pmb release experiments in plasma clearly show that the adsorption and desorption is a function of the ratio pmb concentration: adsorbent surface. furthermore the pmb release depends on the protein concentration of the plasma. it makes a big difference whether the pmb coated adsorbent is used in plasma or in fractionated plasma where the hydrophobicity is much lower. the experiments suggest that the pmb coating of the cg c adsorbent doesn´t influence the cytokine removal which can take place in parallel. the ability of lps inactivation by the pmb coated cg c adsorbents was similar to pmb which was infused directly into the plasma. conclusions: our in vitro model shows that the combination of cytokine removal and controlled pmb release by the same adsorbent results in a strong suppression of inflammatory effects in blood. objective: management of hemodynamically stable pulmonary embolism (pe) with right ventricular (rv) dysfunction is still controversial. the objective of our study is to evaluate the effectiveness of local intraarterial thrombolysis (lit) in this group of patients and analyze its complications. patients and methods: prospective study (january -december ). patients included had been diagnosed of pe by computed tomography (ct), were hemodynamically stable [systolic arterial pressure (sap) > mmhg] and had a clinical suspicion of rv dysfunction (biventricular quotient in ct > or elevated levels of troponin i), that was confirmed afterwards by the presence of at least one of the following findings in the echocardiogram: subjective alteration of rv contractility, rv basal diameter (four chamber view) > mm, tricuspid annular plane systolic excursion (tapse) < mm or estimated systolic pulmonary artery pressure (spap) > mmhg. lit was done with a urokinase infusion (bolus dose of . ui followed by a perfusion of . ui/h) administered thru a pulmonary artery catheter, placed with radiological guidance, using an antecubital puncture. patients received simultaneous systemic anticoagulation with unfractionated heparin. after - h of treatment, and before ending the urokinase infusion, a radiological control was done using angiography or ct. within the seven days after lit, patients underwent a follow-up echocardiogram. statistical analysis was performed with student´s t test for parametric paired data, wilcoxon´s test for non parametric and stuart-maxwell for qualitative values. results: eighty-seven patients were included and their general data are detailed in fig. . mean treatment time was , ± , h. ninety percent of patients experienced a radiological improvement ( . % a complete/almost complete resolution and, . % a significant improvement). only , % didn´t improve radiologically. the evolutions of the different rv parameters studied are shown in fig. . minimum fibrinogen and platelet values where , ± , mg/dl and x ± . x cells/mm . eighteen patients ( , %) suffered form hemorrhagic complications that, in cases, where puncture site hematomas and, in six occasions ( , %) required an early interruption of the treatment. three patients ( , %) received a blood cell transfusion of ≤ blood units. mean icu and hospital stays where ± , and ± , days. all patients survived. conclusion: in our group of patients, lit rapidly improved the function and decreased the hemodynamic strain of the rv, while being associated with a low incidence of major complications. introduction: atrial fibrillation (afib) is associated with higher shortterm mortality in critical illness, but it is still uncertain whether afib independently contributes to unfavorable outcome. objectives: the aim of this study was to test the hypothesis that afib during critical illness is independently associated with increased in-hospital and long-term risk of death. methods: the frog-icu study was a prospective, observational, multicenter cohort study designed to investigate outcome of critically ill patients. heart rhythm was assessed at inclusion and during icu stay with digital ecg recordings. among patients who had any afib during icu stay, newonset and recurrent afib were diagnosed in patients without and with previous history of afib, respectively. primary endpoints were in-hospital and -year mortality. covariate adjusted logistic regression models and cox proportional hazards models were used to evaluate the association between afib and in-hospital mortality or -year mortality, respectively. in-hospital mortality was adjusted for independent covariates (age, gender, simplified acute physiology score (saps ii), treatment with inotropes or vasopressors, serum lactate level, high-sensitive troponin i, b-type natriuretic peptide), -year mortality was adjusted for covariates (age, gender, saps ii, history of congestive heart failure, treatment with inotropes or vasopressors, serum lactate level, c-reactive protein and serum creatinine). results: the study included critically ill patients. the study population consisted of patients for whom data about heart rhythm during icu stay was available. afib occurred in patients ( %). newonset afib (n = ) had higher in-hospital mortality ( %) compared to no afib ( %, p < . ) or recurrent afib ( %, p = . ). newonset afib showed increased in-hospital risk of death after multivariable adjustment compared to no afib ( introduction: the incidence of the supraventricular arrhythmias is increased in septic shock patient, and it is associated with worse short and long term prognosis. objective: to test that propafenon could be a feasible antiarrhythmic in the absence of contraindications. methods: patients with septic shock who received antiarrhythmic drugs for supraventricular arrhythmias were included over months. the patients were divided into the three groups according to antiarrhythmic agent: amiodarone (group ), propafenon (group ) and metoprolol (group ). in the first h the type of arrhythmia, dosages, cardioversion rates, demographic, haemodynamic, laboratory parameters were recorded. mortality was compared between the groups and between the cardioverted vs those remaining in acute and chronic arrhythmias. clinical studies; presumably due to an impairment of myocardial oxygenation and ventricular filling. a randomised control trial of heart rate (hr) control in septic shock showed an increase of survival for the patients receiving esmolol . an animal study observed a similar improvement of survival and an increase in left ventricular (lv) contractility when esmolol was associated with norepinephrine (ne) . however beta-blockers therapy in sepsis is still debated considering its negative inotropic side effect. ivabradine, a pure bradycardic agent, blocking selectively the if channels in the sinus node, could represent a safer option for hr control. objectives: compare the hemodynamic tolerance of hr control either with intravenous (iv) ivabradine or esmolol perfusion, in a large animal model of septic shock. methods: we used a closed chest swine model of fecal peritonitis. analgesia and sedation were provided by sufentanil and sevoflurane. hemodynamic monitoring included arterial blood pressure (abp); continuous cardiac output (cco); lv maximum rate of pressure (dp/dtmax) and lv elastance (e-lv); mixed venous oxygen saturation (svo ) and arterial lactate (lac). after the development of septic shock, fluid resuscitation was started and animals were randomised in groups of pigs: ivabradine (ivb), esmolol (esm) or control. ivabradine was administered with an iv bolus of , mg/kg that could be repeated at , mg/kg, aiming an hr between and beats per minute (bpm). continuous iv perfusion of esmolol was started at mg/kg/h and adapted to reach the same hr range. after hours of hr control, a fixed dose of , mcg/kg/ min ne was introduced in all groups. results: all animals developed an hyperdynamic distributive shock, including tachycardia above bpm. hr control between and bpm was successful in both ivb and esm groups. ivb administration didn't affect abp, cco, dp/dtmax, e-lv, svo or lac. esm perfusion tended to decrease abp, cco and svo ; e-lv and lac were unaffected but dp/ dtmax decreased markedly. under ne perfusion, e-lv was similar in all groups but dp/dtmax was lower in esm group. conclusions: in septic shock, hr control with an iv administration of ivabradine doesn´t alter global organs perfusion and cardiac function. esmolol perfusion, in order to achieve the same goal, reduces lv dp/dtmax and didn´t enhance lv contractility in association with ne. introduction: patients in critical care settings are often at risk of developing hypotension, which can lead to poor outcomes such as increased morbidity and mortality. current hemodynamic parameters for monitoring such hypotension often exhibit pronounced changes only when the hypotensive event is already occurring or when it is too late. we have developed a hypotension probability indicator (hpi™) to predict hypotensive episodes based on machine learning techniques. the hpi™ model was trained on~ icu and or patients. the objective of this study is two-fold: ) to test the accuracy of hpi™ to predict events on a completely independent test data set of icu patients, not used in the development of the algorithm; and ) to compare timing of interventions in response to an event to the timing of detection of an event by hpi™. methods: data used in this study came from the mimic ii mit research database. arterial pressure waveforms of patients were analyzed for hpi™ and then tested for event detection and prediction accuracy. all features of the hpi™ as well as other hemodynamic parameters for comparison were calculated using flotrac (edwards lifesciences, irvine, ca). a hypotensive event was defined as any time period where map < mmhg for at least minute. an roc analysis was performed to assess auc, sensitivity, and specificity of the hpi™ to identify an event during the event, and , , and minutes prior to the start of event. next, clinical records of the patients were reviewed for any drug or fluid interventions during start of event to minutes after an event and the elapsed time from start of event to intervention time was calculated. a drug or fluid intervention was defined as any bolus or iv infusion start. in addition, the time at which hpi™ probability of event > . prior to the start of an event was also calculated for comparison. data are presented in median [ - th percentiles]. conclusion: in conclusion, hpi™ can accurately detect an event up to minutes prior. hpi™ may serve as a useful addition in the care of critically ill patients by potentially facilitating earlier intervention either in response to an event or serve as a decision support and direct a physician's attention to potential oncoming events when hpi™ is high. this statement is valid for both in-hospital as well as out-of-hospital cardiac arrest. regardless of the location of the cardiac arrest, there are at least four factors that appear to be of major importance for survival. the first is the time from collapse to delivery of treatment; the second is the quality of cardiopulmonary resuscitation (cpr); the third is the patient's co-morbidity and the fourth is the aetiology of the ca and the presenting rhythm. the present study will focus on the first three parts of the chain of survival, time from collapse to call/cpr/defibrillation. objectives: to describe the number of survivors following inhospital cardiac arrest (ihca) in sweden during one year and, based on estimations and assumptions, calculate the potential number of additional lives saved following improvements in the chain of survival. there was a strong inverse relation between delay to call for the rescue team and delay to treatment and survival. if delay from collapse to a/call and, b/start of cpr were reduced to < minute in patients with a longer delay than that and if c/time from collapse to defibrillation was reduced to < minutes among those with a longer delay than that: a/ ; b/ ; and c/ further lives could potentially be saved. we speculate that about additional lives (one per hospital beds each year) could theoretically be saved by improved adherence to guidelines regarding the first three components in the chain of survival in swedish hospitals yearly. conclusions: in , approximately patients (four per hospital beds) were successfully resuscitated following ihca in sweden. there was a strong negative relation between collapse and call for rescue team/cpr/defibrillation and -day survival. with reduced delay times a further lives (one per hospital beds) could theoretically be saved each year in sweden. the study was supported by grants from the laerdal foundation of acute medicine in norway (jh) and the scientific council of halland (fh). prophylactic versus clinically-driven antibiotics in comatose survivors of out-of-hospital cardiac arrest -a pilot study s. results: proportion of patients on antibiotics was significantly greater from day to in prophylactic group while there was no difference on days to . peak c-reactive protein in prophylactic group was significantly smaller ( ± vs. ± mg/l; p = . ). there was no difference in peak white blood cell count ( . ± . vs. . ± . ; p = . ), procalcitonin ( . ± . vs. . ± . microg/l; p = . ) and cd . except for positive mini bal on day ( % vs. %; p < . ), there was no significant impact on other microbiological samples and x-ray signs of pneumonia ( % in each group). use vasopressors/inotropes ( % in each groups), duration of mechanical ventilation ( . ± . vs. . ± . days), tracheal intubation ( . ± . vs. . ± . days), icu stay ( . ± . vs. . ± . days), survival ( % vs. %) and survival with good neurological outcome ( % vs. %) were also comparable. conclusions: tracheobronchial aspiration was documented in more than a quarter of comatose survivors of ohca using bronchoscopy on admission. in the absence of aspiration, prophylactic antibiotics reduced peak crp and the incidence of positive mini-bal on day and had no significant impact on other introduction: survival to discharge after in-hospital cardiac arrest (ihca) is poor ( − %) and has not improved despite developments in modern medicine. data on the aetiology of in-hospital cardiac arrests is very limited, and conducted studies include ihca patients resuscitated in emergency departments, intensive care units and high dependency units. objectives: to determine the underlying causes of ihcas occurring on general wards and investigate, whether the aetiology is independently associated with six months survival. methods: a prospective observational study between - in a finnish university hospital. we included all adult ihca patients on general wards who were attended by icu´s medical emergency team. definite aetiology was determined from the autopsy records and medical records. no autopsies were conducted solely for study purposes. the local ethics committee approved the study protocol (approval no: r ). results: the cohort consisted of patients, of which ( %) were male. median age of the patients was ( , ) years. altogether ( %) ihcas were monitored/witnessed, first rhythm was shockable in ( %) cases and ( %) patients survived six months. autopsy was conducted in ( %) cases. aetiology was determined as cardiac in events, of which were due to acute myocardial infarction and due to acute myocardial ischaemia without infarction. congestive heart failure was the third most prevalent reason in cardiac sub cohort ( ). altogether ihcas were considered non-cardiac; most common causes were pneumonia ( ), exsanguination ( ), pulmonary embolism ( ) and peritonitis ( ). cardiac ihcas were more commonly preceded by subjective symptoms (e.g. chest pain, respiratory distress) than non-cardiac ihcas ( % vs. %, p = . ), while objective vital dysfunctions preceded ihcas as often in both sub cohorts ( % vs. %, p = . ). in a multivariate logistic regression model monitored/witnessed event, shockable primary rhythm and low age-adjusted charlson comorbidity index score were factors independently associated with -day survival, but the aetiology (cardiac vs. non-cardiac) was not. conclusions: aetiology of ihcas on general wards is cardiac in % of the events. ischaemic reasons for ihcas were twice as common as shockable primary rhythms in this study. subjective symptoms and objective vital dysfunctions often precede general ward ihcas. however, neither the aetiology nor the presence of antecedents, but low comorbidity, observed arrest and shockable primary rhythm are factors associated with a favorable outcome. reducing in-hospital cardiac arrest by implementation of innovative early warning information system in a tertiary medical center introduction: in-hospital cardiac arrest (ihca) is a common and high-risk issue with less than % surviving to hospital discharge. most patients show signs of clinical deterioration in the hours before ihca. as a result, the development of vital signbased early warning system was designed to detect early signs of clinical deterioration before ihca attack in order to trigger early intensive care. objectives: in this study, we investigate the impact of the implementation of an innovative early warning information system on the rate of ihca and survival rate in ihca patients. methods: a multidisciplinary team among intensivists, cardiologists, emergency physicians, and nursing staffs in a tertiary medical center was organized since may . the key interventions include automatic national early warning score (news) calculating information system, nurses and physicians computer-based reminding alarm if news ≥ or more than highest scores among previous measurements, real time early warning screen saver and electric board, in service education and early warning monitor team. all patients admitted between january and january were enrolled. total , patients were divided into three groups: pre-interventional group from jan to april (n = , ), interventional group from may to june (n = , ) and post-interventional group from july to jan (n = , ). the definition of in-hospital cardiac arrest is the number of in-hospital cardiac arrest per thousand admitted patients. we compared the rates of ihca, hours survival rate and discharge survival rate in ihca patients among these groups. results: the rate of in-hospital cardiac arrest improved from . ‰ in pre-interventional group, to . ‰ in interventional group and to . ‰ in post-interventional group (p < . ). the hours survival rate in ihca patients increased from . % in pre-interventional group, to . % in interventional group and to . % in postinterventional group (p < . ). the discharge survival rate in ihca patients also increased from . % in pre-interventional group, to . % in interventional group and to . % in post-interventional group (p < . ). conclusions: the study demonstrated that implementation of early warning information system and innovative strategies could attenuate the rate of ihca, hours survival rate and discharge survival rate in ihca patients. introduction: although prolonged unconsciousness after cardiac arrest (ca) is a sign of poor neurological outcome, limited evidence shows that a late recovery may occur in a minority of patients. objectives: we investigated the prevalence and the predictive factors of delayed awakening in comatose ca survivors treated with targeted temperature management (ttm). methods: retrospective analysis of the parisian region out-of-hospital ca registry ( - ). in adult comatose ca survivors treated with ttm, sedated with midazolam and fentanyl, time to awakening was measured starting from discontinuation of sedation at the end of rewarming. awakening was defined as delayed when it occurred after more than h. results: a total of patients ( % male, mean age ± years) were included, among whom awoke. delayed awakening occurred in / ( %) patients, at a median time of h (iqr - ) from discontinuation of sedation. in / ( %) late awakeners, pupillary reflex and motor response were both absent h after sedation discontinuation. in multivariate analysis, age over years (or . , % ci . - . ), postresuscitation shock (or . [ . - . ]), and renal insufficiency at admission (or . [ . - . ]) were associated with significantly higher rates of delayed awakening. conclusions: delayed awakening is common among patients recovering from coma after ca. renal insufficiency, older age, and postresuscitation shock were independent predictors of delayed awakening. presence of unfavorable neurological signs at h after rewarming from ttm and discontinuation of sedation did not rule out recovery of consciousness in late awakeners. grant acknowledgment none note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. introduction: viral infections play a key role in preventable deaths of children globally, and can be antecedents to bacterial pneumonia and sepsis. diagnosis of viral infection is often problematic due to non-specific clinical presentation. we developed a host immune response gene expression signature to distinguish systemic inflammation due to viral infection vs. bacterial or noninfectious causes. objectives: to define and validate the host immune response gene expression signature against multiple independent datasets. methods: four public geo datasets describing transcriptomic responses to viral infection were used to identify biomarkers, ranked by auc, which could separate affected from unaffected subjects. biomarkers that also responded (auc > . ) to non-viral causes of systemic inflammation were removed. remaining biomarkers were then ranked for performance in other geo transcriptomic datasets for viral infection; those with mean auc > . were retained. next, a greedy search was applied to the merged ( + ) viral geo datasets to identify the best combinations of biomarkers for discrimination of viral infection. the signature was then validated using independent datasets. results: a -gene signature (comprised of isg , il , oasl, adgre ) had auc . across the merged ( + ) viral geo datasets. this signature was validated in additional geo datasets covering a wide variety of viral pathogens including a time-course study of respiratory syncytial virus (rsv) in children (fig ) , and in two independent datasets of our own: adults from the emergency department (fig introduction: using a tourniquet to temporary cut off blood supply to the arm (remote ischemic preconditioning -ripc) has been shown to result in myocardial protection and reduced incidence of aki in patients undergoing cardiac surgery. however, a recently performed large multi-center trial in cabg patients showed no beneficial effects on clinically relevant endpoints [ ] . animal studies have shown an`early window of protection' in the - hours after ripc as well as a`late window of protection` - hours after ripc. several mechanisms have been suggested to mediate the protective effects of ripc, of which attenuation of the immune response is an important candidate, although this has hitherto also only been shown in animal studies [ ] . objectives: to determine the effect of single and repeated ripc, thereby investigating both the early and late windows of protection, on the inflammatory response during endotoxemia, a standardized, controlled model of systemic inflammation in humans in vivo. methods: we performed a randomized controlled study in healthy non-smoking male volunteers. subjects were assigned to either the single-dose ripc group, multiple-dose ripc group, or the control group (n = per group). the single-dose ripc group received dose of ripc, consisting of cycles of -minute ischemia of the arm followed by minutes of reperfusion just before administration of ng/kg lipopolysaccharide (lps). the multiple-dose ripc group received one dose of ripc per day on the days before the endotoxemia experiment day, and dose just before lps administration. results: lps administration resulted in a typical increase in body temperature, flu-like symptoms, and hemodynamic changes, with no differences between groups. administration of lps resulted in a sharp increase in plasma levels of the proinflammatory cytokines tnf-α, il- , and il- as well as the antiinflammatory cytokine il- . no differences in plasma levels of these cytokines were observed between the different groups ( figure ). conclusions: in the present study, we demonstrate that ripc does not affect the in vivo inflammatory response induced by administration of endotoxin in humans. these results implicate that ripc does not exert direct anti-inflammatory effects and that the previously observed protective effects are mediated through other mechanisms. furthermore, the absence of immunomodulatory effects of ripc in the present study tempers expectations of using ripc as an immunomodulatory treatment strategy in patients. introduction: sepsis-induced immune alterations are associated with secondary infections and increased risk of death ( ). mesenchymal stem cells (mscs) have been described as a novel therapeutic strategy for the treatment of diseases related to inflammation and tissue injury with their potent modulatory effects on immune system ( ) . objectives: in this study, we evaluated the immune-modulatory effects of human dental follicle mesenchymal stem cells (hd-mscs) on lymphocytes which are isolated from peripheral blood samples of sepsis and septic shock patients. methods: according to the international sepsis definitions conference ( ), patients divided into two groups as sepsis (group i, n = ) and septic shock (group ii, n = ). peripheral blood mononuclear cells (pbmcs) were isolated from venous blood samples of group i, group ii and healthy subjects named as group iii, n = . anti-cd /cd pbmcs were co-cultured with df-mscs, ifn-g stimulated df-mscs and with no mscs about hour. cd + cd + foxp + t cells levels (treg), lymphocyte proliferation and apoptosis were evaluated with the flow cytometry. results: df-mscs and ifn-g induced df-mscs cultures significantly supressed proliferation in sepsis group when compare to septic shock group(p < , ). conclusions: mscs demonstrate their effects on immune system by increasing the number and activity of regulatory t cells (treg) ( ) .in our study, mscs suppressed lymphocyte proliferation and apoptosis but increased the rate of treg cells in sepsis cocultures. this effect was more obvious with ifn -g stimulation. these responses were not seen in septic shock patients´blood samples and might be explained with anergy. our findings revealed that df-mscs application has immunoregulatory effects in sepsis. this approach opened a new area to work how will mscs be used to reduce organ dysfunctions and mortality in the clinical practice. introduction: inhibition of mitochondrial complex i is described in human and animal sepsis. , this may be responsible, at least in part, for the decrease in mitochondrial functionality seen in sepsis. we have recently demonstrated that the mitochondrial uncoupling agent, dinitrophenol (dnp) failed to increase body temperature and oxygen consumption (vo ) in septic rats, as was seen in healthy controls. this suggests that uncoupling is active in sepsis and can contribute to fever. we further postulated that the blunted effects of dnp in sepsis may be related in part to upstream mitochondrial inhibition. objectives: to determine if complex i inhibition by metformin in healthy rats can prevent the increment in temperature and oxygen consumption (vo ) by dnp, and thus mimic the pattern seen in sepsis. methods: vo was measured in awake, cannulated male wistar rats (approx g body weight) in metabolic cages (oxymax, columbus instruments). sepsis was induced with an intraperitoneal injection of faecal slurry at time . sham control animals received no slurry. fluid resuscitation ( ml/kg/h crystalloid) was started at hours and continued throughout the whole experiment. half the septic and sham animals were treated with an iv infusion of metformin ( mg/kg) between hours - . at and hours, all animals received iv dnp ( mg/kg). arterial blood gases, echocardiography and core temperature were measured at times , and , and and hours (i.e. before and after the two doses of dnp). mean arterial pressure was recorded continuously. wilcoxon rank sum test was used to compare groups and two-way anova to compare changes in continuous variables from baseline between groups. p values < . were considered statistically significant. results: pretreatment with metformin completely prevented the increase in temperature and vo induced by dnp in sham animals at hours and reflected that seen in non-metformin treated septic rats ( figure ). the reduction in myocardial contractility (stroke volume and vmax) seen in the septic animals treated with dnp was prevented by complex i inhibition at h. metformin was metabolically well tolerated, with no increase in blood lactate. conclusions: inhibiting complex i with metformin prevents the uncoupling effect of dnp in sham animals. this mimics the pattern seen in septic animals and confirms that both complex i inhibition and pre-existing mitochondrial uncoupling could be active in septic rats. objectives: the inflammasome is a multiprotein complex that stimulates cytokines release such as interleukin- β (il- β) and il- , involved in the inflammatory response. our aim is to quantify the state of activation of the inflammasome complex in septic patients, as well as to study possible differences in the cytokines levels in sepsis and septic shock, its temporary evolution, and its prognostic value. methods: prospective study including patients admitted to the icu with sepsis or septic shock during months. on days , and , il -β serum levels and real-time expression of nlrp inflammasome (nucleotide-binding oligomerization domain, leucine rich repeat domain containing protein and pyrin) were determined by elisa and real time-pcr respectively. demographic variables, severity scores on icu admission (apache ii and sofa), sepsis focus and mortality were collected. statistical analysis: t-student, kruskal-wallis and u-mann-whitney test as appropriate. results: there were included patients (severe sepsis and septic shock ). overall mortality was % ( patients). the levels of il- β on day ( . ± . vs . ± . pg/ml; p < . ) and nlrp inflammasome ( . ± . vs . ± mrna arbitrary units; p < . ) were significantly higher in septic shock patients than in sepsis, with no differences in the following days set ( and ). the il- β and nlrp inflammasome levels decreased significantly on days and compared to first day (p < . ), without differences between survivors and deceased patients. conclusions: in septic patients, inflammasome activation complex occurs, with higher levels detected in septic shock. decreased levels of il- β and nlrp inflammasome in septic process have been observed during evolution, actually without relation with mortality. introduction: according the consensus conference on weaning from mechanical ventilation, intubated patients should pass a spontaneous breathing trial (sbt) to assess their readiness to be extubated. objectives: to characterize patients who are extubated without any sbt and to compare them to patients who had at least sbt during their weaning period. methods: the prospective multicentre observational wind (weaning according new definition) study was performed from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. variables are presented as mean ± standard deviation, median [interquartile range] or number (percentage). comparisons were made using chi test, exact fisher tests, student t-test or wilcoxon rank sum test as appropriate. all statistical tests were two-sided and p value ≤ . were considered significant. results: among the patients included, patients had at least wa comprising patients whose first wa was a sbt and who had another type of first wa. these patients with no sbt had a total of wa: ( . %) planned extubation without sbt, self-extubations ( . %), wa while tracheostomized ( . %) and sbt after their first wa ( . %). the majority of patients with self-extubation had a successful weaning not requiring reintubation ( . %). almost a quarter (n = ) of the patients who were extubated without any sbt had a decision of withholding or withdrawing invasive mechanical ventilation, representing . % (n = ) of the deceased patients. we then excluded patients with a decision of limitation and patients with a self extubation to compare patients who had a planned extubation with or without sbt as first wa (table ) . patients with no sbt were younger, less severe and were more often admitted for unplanned surgery: they had an easier weaning with a lower (but non significative) rate of reintubation, a shorter duration of invasive mechanical ventilation and a shorter length of stay in the icu. conclusion: patients who are extubated without sbt seem to belong to three different groups: self-extubation, terminal extubation and patients in whom physicians anticipate an uneventful weaning and extubation. among the patients with a planned extubation and without any limitation decision, clinical judgment regarding weanability appears to be effective as this group of patients had a good outcome with a low reintubation rate. this study benefited of a grant of the non-profit association départementale des insuffisants respiratoires (adir) of the haute normandie, france introduction: decrease in diaphragmatic maximal relaxation rate (mrr) occurs early in the process of diaphragmatic fatigue and well before the diaphragm fails as a force generator; its measurement would, therefore, be especially valuable in icu patients during a weaning trial. however, the use of oesophageal pressure catheters for that purpose impedes wide clinical use. on the contrary, m-mode sonography, allows non-invasive, real-time measurement of the speed of the diaphragmatic motion. objective: purpose of our study was to investigate a possible correlation between diaphragmatic mrr traditionally acquired with transdiaphragmatic pressure (pdi) catheters (mrr-pdi) and an echo equivalent mrr (mrr-echo) acquired during different breathing conditions. methods: the slope of mrr was measured from the initial steepest part of the descending pdi curve simultaneously with the slope of the initial steepest descending part of diaphragmatic excursion with m-mode sonography. the protocol entrained four consecutive stages: i) breathing spontaneously during t-piece trial, ii) breathing spontaneously with performance of sniff-like maneuvers, iii) breathing with resistances of cmh o/l, and iv) breathing with resistances of cmh o/l with performance of sniff-like maneuvers. statistical comparisons between slope recordings from the two methods were performed with pearson correlation, while bland and altman plots were obtained in order to demonstrate reliable agreement between methods at each different breathing condition. results: a total of separate breaths during the four previously reported breathing conditions from six icu patients were recorded. table summarizes the slopes measured from mrr-pdi and mrr-echo as means ± standard deviations (sd), and their linear correlations with p values. statistical significant correlations were observed in all four stages; i) pearson correlation coefficient r = . , p < . , r = . , ii) r = . , p < . , r = . , iii) r = . , p < . , r = . , and iv) r = . , p < . , r = . . bland and altman plots demonstrating differences of measurements against means, as well as confidence intervals (means of differences ± sd) were obtained for each breathing condition. graph represents the bland and altman plot for spontaneous breathing with sniff-like maneuvers without resistances. high r indexes, indicating high agreement between the two methods were noted: i) . , ii) . , iii) . , and iv) . . the results of our study suggest a statistical significant correlation and reliability between diaphragmatic mrr measured from pdi tracings and the assumed diaphragmatic relaxation rate calculated from simultaneous m-mode sonographic recordings. clinical studies are required to confirm the potential of this non-invasive index of diaphragmatic mrr to be used as a predictor for weaning success. grant acknolwedgement none declared. introduction: high flow nasal cannula oxygen therapy (hf oxy) has been recently shown to decrease re-intubation rate, as compared with low flow oxygen therapy (lf oxy). [ ] , [ ] objectives: to assess the effects of hf oxy as compared with lf oxy on diaphragmatic electrical activity (eadi), respiratory rate (rr), tidal volume (vt) and gas exchange in the post extubation period. our hypothesis was that hf oxy, as compared with lf oxy, would improve gas exchange and decrease eadi. methods: patients underwent a crossover study immediately after extubation. each patient was submitted to three consecutive steps of hour each, according to an on-off design: ) hf oxy; ) lf oxy; ) hf oxy. oxygen fraction was maintained stable throughout the study. the eadi was continuously monitored through eadi cathether (maquet, solna sweden). the heated and humidified hf oxy was delivered through nasal cannula at flow rates of - l/min, (f&p, auckland new zealand). results: rr remained similar throughout the study, vt was significantly higher during the lf oxy step as compared with the hf oxy steps. oxygenation significantly improved during the hf period, whereas paco remained unchanged throughout the study (table ). eadi was significantly higher during lf oxy ( figure ) conclusions: since the eadi is correlated to work of breathing, our physiological data suggest that hf oxy significantly reduces wob while improving oxygenation in the post extubation period. further studies are required to define if diaphragm unloading may explain the favourable results of hf oxy in clinical trials. introduction: i non-invasive mechanical ventilation (niv) has been seen to play a major role in decreasing intubation rates in patients with severe exacerbation of chronic obstructive pulmonary disease and congestive heart failure. unsuccessful niv has been found to be independently associated with increased mortality in patients with arf. the niv failure and their impact on mortality in patients with inlfuenza infection is unknown. objectives: ) to describe non-invasive ventilation failure (nivf) rate, ) to identify risk factor for nivf using chaid (chi-square automatic interaction detection) and ) to determine if nivf is associated with icu-mortality. methods: secondary analysis in , patients with influenza requiring mechanical ventilation(mv). three groups were considered: ) patients with niv who failed (group a); ) patients with niv who succeeded (group b); and ) patients with invasive mv (group c). cox analysis was used to assess survival. risk factors for nivf were obtained using chaid. conclusions: niv failure is frequent and independently associated with icu-mortality in patients with influenza. chaid analysis might be a promising tool to assist in clinical decision-making. introduction: acute kidney injury (aki) after liver transplantation is a common complication with an incidence of approximately % [ ] , resulting in high morbidity and mortality. to increase the possibilities to prevent or treat aki after liver transplantation, it is essential to increase the knowledge on changes in renal physiology after liver transplantation. objectives: the aim of this study was to gain insights into renal perfusion, filtration and oxygenation in the immediate postoperative period in patients undergoing liver transplantation and to compare these data to those obtained from a group of patients undergoing major surgery with no postoperative renal impairment. methods: informed consent was obtained preoperatively from twelve patients with normal renal function accepted for liver transplantation. glomerular filtration rate (gfr) was measured preoperatively by plasma clearance of cr-edta. the patients were studied after liver transplantation in the icu in the immediate postoperative period, sedated and mechanically ventilated. systemic haemodynamics and renal variables where obtained during two -min periods. renal blood flow (rbf) and gfr were measured by the renal vein retrograde thermodilution technique and by renal extraction of cr-edta (=filtration fraction, ff), respectively. arterial (a) and renal vein (rv) blood samples were taken for measurements of arterial (cao ) and renal vein (crvo ) oxygen contents. renal oxygen consumption [rvo = rbf x (cao -crvo )], renal oxygen delivery (rdo = rbf x cao ) and renal oxygen extraction [ro ex = (cao -crvo )/cao )] were calculated. sixty-three patients undergoing uneventful cardiac surgery with no postoperative renal impairment served as controls. results: cardiac index ( %) and systemic oxygen delivery index ( %) were higher and systemic vascular resistance index was lower (− %) in the liver transplant group compared to controls (p < . ). rbf was % higher and renal vascular resistance was % lower compared to controls (p < . ). in the liver transplanted group, gfr was % lower compared to the preoperative value (p = . ), accompanied by a % increase in serum creatinine (p < . ). after surgery, when compared to controls, gfr and ff was % and % lower, respectively (p < . , p < . ), and rvo and ro ex were % and % higher, respectively, in the liver transplanted patients (p < . , p < . ). conclusions: despite the hyperdynamic systemic circulation, gfr is considerably reduced immediately after liver transplantation, most likely caused by a post-glomerular renal vasodilation decreasing upstream glomerular filtration pressure. renal oxygenation is impaired after liver transplantation due to the high rvo , which was not met by a proportional increase in rdo . introduction: acute kidney injury is common in critically ill patients and associated with increased short and long-term mortality. most published studies have focussed on patients with severe aki. little is known about the long-term outcome of patients with less severe aki. our objective was to determine the outcome of patients with different stages of aki at and years after admission to the intensive care unit (icu). we retrospectively analysed the data of all adult patients admitted to a multi-disciplinary icu in a teaching hospital in the uk between march -may . patients with chronic dialysis dependent renal failure were excluded. patients were categorised according to their maximum stage of aki during stay in icu as defined by the serum creatinine criteria of the kdigo classification. apache ii and sofa scores were used to describe severity of illness on admission to icu. in patients with > admission to icu, we only included the first admission in the analysis. results: data of adult patients were analysed of whom % had aki during their stay in icu. patients with any degree of aki had a higher mortality at and years but they were also sicker on admission to icu. conclusions: any stage of aki during critical illness is associated with an increased risk of mortality at and years. mortality is highest in patients with aki ii and iii. more work is necessary to explore the relationship between aki and long-term outcome and to identify independent risk factors for mortality. introduction and objective: observational studies of intensive care unit (icu) patients with acute kidney injury have shown a negative correlation between accumulation of fluids and survival [ ] . it is unknown whether rapid removal of accumulated fluids is feasible and beneficial. therefore we wish to perform a pilot trial of forced fluid removal vs. standard care in critically ill patients with high-risk acute kidney injury and severe fluid overload. methods: the ffaki-trial is a pilot, multicenter, randomized clinical trial recruiting adult intensive care patients with high-risk acute kidney injury and fluid overload defined as > % of ideal bodyweight. to reduce the signal-to-noise ratio we only wish to include patients with a high baseline risk of persistent renal failure. baseline risk will be calculated using a newly developed model, the renal recovery score (rrs), to predict the chance of recovering renal function within days. in-and exclusion criteria are shown in tables and . patients are randomized to either forced fluid removal or standard care for the entire icu stay. forced fluid removal is done by infusion of furosemide and/or fluid removal with continuous renal replacement therapy. the fluid removal rate is adjusted times daily to achieve a therapeutic goal of net negative fluid balance ≥ ml/kg/h. physiologic tolerance to fluid removal is continually evaluated according to predefined criteria of hypoperfusion: lactate ≥ mmol/l, mean arterial pressure < mmhg or mottling beyond the edge of the kneecaps. in case of hypoperfusion, fluid removal is suspended until all criteria have been resolved for a minimum of hour. the flow chart for the experimental ffaki-treatment is seen in figure , , . the primary outcome is cumulative fluid balance days after randomization. by inclusion of patients we are able to detect a difference of . l between groups (α = . and β = . renal recovery score ≤ %. fluid overload defined as a positive fluid balance ≥ % of ideal body weight. able to undergo randomization within hours of fulfilling the other inclusion criteria introduction: enhanced recovery pathways have been a focus for patient optimisation of morbidiy and mortality in the post-operative patient. significant mortality improvement was seen following the implementation of the emergency laparotomy pathway quality improvement care (elpquic) bundle with an adjusted risk of death from . % to . % ( ). the first national emergency laparotomy audit (nela) has since been published demonstrating a -day mortality of % and recommending access to pathways that identify need to escalate care ( ) . however acute kidney injury (aki) in critically unwell patients remains a major source of mortality, of up to %, and morbidity ( ). it is not yet clear whether enhanced recovery pathways, specifically those that utilise early goal directed therapy, affect the incidence of aki. objectives: to determine if there was a difference in incidence of combined aki pre and post implementation of an enhanced recovery protocol, one that had already demonstrated a significant mortality benefit. methods: a subgroup analysis of the data gathered via the elpquic bundle was performed ( ). we obtained buy-in from the participating centres and requested an extrapolation of values from their raw data. if required further data was obtained via the hospital's electronic path system. all data was reviewed by a second investigator. we defined the baseline creatinine as the best available preoperative creatinine from the past year. the data recorded included creatinine at baseline, post-op, worse recorded creatinine between day and day , make , p-possum and -day mortality data. ckd stage was identified via mdrd equation with age, gender and baseline creatinine. patients with aki were stratified according to kidgo stages of akin. primary outcome was the incidence of aki in each of combined pre and post elquic patient population. secondary outcome included the stage specific incidence of aki. results: there was no significant difference between the cumulative incidence of akin pre and post elquic implementation on day post-op ( . % vs . %, p = . ) or day post-op ( . % vs . %, p = . ). conclusion: this multi-centre cohort subgroup analysis demonstrates that the implementation of a quality improvement care bundle does not affect the incidence of aki. this is in contrast to the clear mortality benefit that such a care bundle has provided and provides stimulus to discover what factors may yet improve aki, and so further improve these patients outcome. introduction: it is now well documented that critically ill patients are exposed to stressful conditions and experience discomforts from multiple sources. improved identification of the discomforts of patients in intensive care units (icus) may have implications for managing their care, including consideration of ethical issues, and may assist clinicians in choosing the most appropriate interventions. objectives: the primary objective of this study was to assess the effectiveness of a multicomponent program (mcp) of discomfort reduction in critically ill patients. the secondary objectives were to assess the sustainability of the impact of the program and the potential seasonality effect. methods: we conducted a multicenter, cluster-randomized, controlled, single (patient)-blind study involving french adult icus. the experimental intervention was the implementation of the mcp including the following steps: identification of discomforts, immediate feedback to the healthcare team, and implementation of targeted interventions under control of local champions who received monthly feedback and organized monthly meetings with their healthcare team. all icus started with a -month period with no intervention, and then they were randomized to one of two groups: icus with mcp implemented during a -month period (experimental group) and icus without any programm during the same period (control group). to assess the sustainabilty of the impact of the mcp, the study was completed with a second -month period during which the mcp was no longer applied in the experimental group. the primary endpoint was the monthly overall score of self-reported discomfort from the french -item questionnaire on discomforts in icu patients (iprea) (range from to , the lowest possible level of discomfort to the highest). the secondary endpoints were the scores of each item of iprea. results: at the end of the -month period, taking into account the clustering design, the monthly overall discomfort score was lower in the experimental group ( parents were asked to consent to being contacted months after discharge, at which point they were asked to complete the pedsql, a generic measure of quality of life. the pedsql enables a total score, physical health summary score and psychosocial health summary score to be calculated, with possible scores ranging from - and higher scores equating to better quality of life. results: parents of children aged - . years (median age: . years; ( %) males), the majority of whom had had an emergency picu admission due to sepsis (n = , %) or respiratory problems (n = ; %), completed the pedsql months after discharge from picu. for the group overall the total score was . (sd . ), physical health summary score was . (sd . ) and psychosocial health summary score . (sd . ). babies aged - months (n = ) had total scores (m = . , sd = . ) comparable to those of healthy norms (m = . , sd = . ). however older children in all age groups had lower total scores than healthy norms. whilst % ( / ) of babies had scores of more than one standard deviation below the score of healthy norms, which is recognised as being of clinical significance, this rose to % ( / ) of children aged - years and % ( / ) of children aged - years. of note is that children ( %) aged - years had been admitted to picu for reasons related to trauma or neurological concerns whereas no child aged - months had been admitted for those reasons. conclusions: children who have had an emergency admission to picu are at risk for impaired quality of life months after discharge. the risk appears to be greater for children of years and older which is likely to be at least partly attributable to the underlying reason for their admission. evaluating quality of life outcomes in the longer term after picu discharge is warranted and identification of potential risk factors will enable interventions to be targeted to optimise outcomes after an emergency admission to picu. introduction: cognitive dysfunction is an important long-term complication of critical illness associated with reduced quality of life, increase in healthcare costs and institutionalization. delirium, an acute form of brain dysfunction that is common during critical illness has been shown to be associated with long-term cognitive dysfunction( ). objectives: the aim of this prospective cohort study was to estimate the prevalence and severity of cognitive dysfunction in survivors of critical illness and to evaluate if delirium duration is an independent determinant of the severity of cognitive dysfunction. methods: included were all adult patients admitted to a -bed medical surgical icu over a -month period(from march to february ).we excluded patients with preexisting cognitive dysfunction; those that in the evaluation by the psychologist on admission to the icu had evidence of impaired cognition through the mini mental state examination and patients who could not be reliably assessed for delirium owing to blindness, deafness or language deficit and patients for whom informed consent could not be obtained. after at least months of hospital discharge patients were assessed for cognition using a validated battery of tests including: )the digit span, forward and backward; ) the rey auditory verbal learning test (ravlt); ) the clock drawing test (cdt); ) the verbal fluency test; and the mini mental state examination. we classified patients as having mild or moderate impairment if they had either two cognitive test scores . standard deviation (sd) below the mean or one cognitive test score sd below the mean; we classified patients as having severe cognitive impairment if they had or more cognitive test scores . sd below the mean or two or more cognitive test scores sd below the mean. results: enrolled in the clinical trial were patients and patients were eligible for the cohort (fig. ) . four hundred and thirteen patients were tested ( - ) months after discharge. table shows demographic and clinical data of these patients. cognitive impairment was identified in ( . %) patients; ( . %) had mild or moderate and ( %) severe cognitive dysfunction (table ) . eleven( . %) patients with delirium for days or more presented severe cognitive dysfunction. in logistic regression analysis the duration of delirium for days or more was not an independent predictor of cognitive dysfunction(p = . ). conclusions: this investigation in an unselected population of critically ill medical and surgical patients demonstrates that cognitive dysfunction is a frequent and severe long-term complication in survivors of critical illness. on the other hand, unlike other studies we couldn't demonstrate that the duration of delirium is an independent determinant of cognitive impairment. table positive determinants of the evolution of the eq-index were time and admission glasgow score (p . and . respectively) while age, duration of mv and weakness were negatively associated (p . , . and . ) ]. eq-eva paralleled eq-index changes. conclusions: after icu discharge, patients suffered frequent longterm consequences that negatively affect their hrqol. alterations in mobility, daily activities and personal care exhibited the greatest deterioration. prevalence of pain, anxiety and depression was high even before icu admission, aggravated after -year post-discharge ( % of patients) duration of vm was the only intra-icu variable that affected hrqol. pre-icu conditions as age and the extent of neurological injury and, after icu, time and weakness, were also independent determinants. the present study was supported by the argentinian society of critical care (sati) introduction: diffuse axonal injury (dai) is a common event following traumatic brain injury (tbi), which is likely related to worst long term outcome. diffusion tensor imaging (dti), a magnetic resonance imaging (mri) technique that investigates white matter integrity, is recognized as a useful tool to quantify dai extent in tbi and possibly predict outcome. few studies explored whole brain longitudinal changes of dti-derived parameters in single subjects following tbi. methods: patients with severe tbi underwent brain mri including dti ( directions, b = , voxel size x x ) - weeks and year after trauma. age-matched healthy controls underwent the same dti protocol. we used region of interest (roi) automated analysis (www.mristudio.org) covering the entire brain to quantify white matter integrity. the roi fractional anisotropy (fa), mean diffusivity (md), axial diffusivity (ad) and radial diffusivity (rd) were extracted. abnormalities were defined as dti values more than standard deviations below or above the mean values of controls for each roi. results: tbi patients with a median age of (iqr - ) and a median gcs score of (iqr - ) were included. had diffuse injury according to marshall classification. regions with increased md and reduced fa were more than expected in both early and late scan (p < . binomial test), while ad and rd abnormalities were less common. more than % of the patients had increased md in the early scan in the frontobasal girae, corona radiata and thalami; in late scans md abnormalities were larger and more diffuse, affecting also all frontal and temporal girae and corpus callosum. fa was frequently reduced in the corpus callosum, internal capsule and fronto-basal girae in early scan, while in late phase reductions were similar but more widespread, also including the central girae, cerebellum and inferior longitudinal fascicles. the number of regions with abnormal md increased over time (p < . mann-whitney), whereas for fa it was not statistically different. an inverse correlation between the number of roi with altered md at early scan and outcome evaluated with gose was found (p < . , spearman r). the present results indicate that early alterations of mean diffusivity and fractional anisotropy persist or worsen (for md) at year after tbi, suggesting an ongoing loss of white matter integrity and gliosis. the more frequently affected regions were the frontal girae, corpus callosum, corona radiata, inferior longitudinal fascicles and cerebellum. the number of roi with early abnormal mean diffusivity is inversely correlated with outcome. all patients underwent ssep, aep and tms the day before operation. after operation, all patients were delivered to icu intubated and mechanically ventilated. patients demonstrated full recovery from anesthesia with regaining consciousness, passed spontaneous breathing test (sbt) and gained points on cst without deficiency. these patients had none or low level of dysphagia and were successfully extubated after operation. these patients formed st group. patients had a neurogenic dysphagia and formed nd group. we performed ssep, aep and tms on all patients immediately after admission to icu. results: we revealed no clinical or electrophysiological points that could have predicted neurogenic dysphagia before operation. in our research, we found the ep values which were different for the first group and for the second group. the aep and tms data were not informative. we found instrumental the ssep values that reflected perioperative cct dynamics, lat p , amp n , auc n -n , auc n -n . these ssep values were used to create a prognostic rule through logistic regression and roc-curves. as a result, we were able to predict neurogenic dysphagia in early introduction: eeg monitoring during the first hours robustly contributes to the prediction of either poor or good outcome in comatose patients after cardiac arrest [ ] . quantitative eeg (qeeg) measures can be useful to visualize evolution of the eeg over hours. we recently proposed the cerebral recovery index (cri), an index based on a combination of five qeeg measures grading the severity of hypoxic brain damage on a scale from zero to one to facilitate prognostication [ ] . objectives: to evaluate the prognostic accuracy of a revised cri, after optimalization by the use of a random forest classifier instead of a manually chosen feature combination and the addition of four qeeg measures, resuscitation parameters and patient characteristics. methods: in this prospective cohort study, consecutive comatose patients after cardiac arrest were included in two intensive care units. continuous eeg was recorded during the first three days. outcome at months was dichotomized as good (cpc - ) or poor (cpc - ). nine qeeg measures were extracted: alpha to delta ratio, signal power, shannon entropy, delta coherence, regularity, the number of burst/min, mean and max burst correlation, and fraction of burst correlation > . . these measures were combined with patient characteristics and resuscitation data, including sex, age, initial heart rhythm, in-versus out-of-hospital-cardiac-arrest, and presumed cause of cardiac arrest. patients were randomly divided over a training and a validation set of respectively and patients. within the training set, a random forest classifier was fitted for each hour after cardiac arrest. based on results in the test set, two thresholds were chosen: one for predicting poor neurological outcome and one for predicting good neurological outcome. subsequently, the revised cri was evaluated in the validation set. results: poor outcome could reliable be predicted with the revised cri (with % specificity) in the validation set with a sensitivity of and % at respectively and hours after cardiac arrest. good neurological outcome could be predicted with a sensitivity of and % at a specificity of and %. conclusions: here we show that a combination of qeeg and clinical measures, extracted and combined by a random forest classifier, provides reliable, objective prognostic information. this revised cri can be used for the prediction of both poor and good neurological outcome, thereby poor outcome can be reliable predicted (without false positives) with relatively high sensitivity. the revised cri is expressed as a single index between and , which can be used in real time at the bedside, even by professionals who are not trained in eeg interpretation. introduction: continuous electroencephalography (ceeg) allows real-time monitoring critically-ill patients neurophysiology and to detect non-clinical seizures in comatose patients, delayed cerebral ischemia after subarachnoid haemorrhage, and guide therapies for status epilepticus. the application of ceeg is still limited because it requires awkward analysis by experienced neurophysiologists of huge amount of eeg tracings. quantitative eeg (qeeg) techniques, i.e.amplitude integrated eeg (aeeg) and density spectra array (dsa), have been developed to simplify the complexity of eeg interpretation, to allow rapid evaluation of cerebral background electrical activity and the power spectrum of the eeg frequencies derived from raw data eeg. these developments offer the potentiality to transform an instrument interpreted by neurophysiologist afterwards in a monitoring tool useful to icu staff. objectives: to test the hypothesis that eeg-nonexpert neurointensivists can obtain real-time reliable information from qeeg after training under the supervision of an in-house neurophysiologist. to describe the implementation of qeeg monitoring in neurointensive care units. methods: the implementation occurred in sequential phases. ceeg was recorded using surface electrodes according to the international - system, on a bipolar longitudinal montage in patients with brain injury. qeeg-naïve neurointensivists, after a short training from a neurophysiologist followed by daily supervision for the study period, were subjected to a baseline test evaluating aeeg and dsa traces. each panel consisted of raw eeg data and qeeg tools: the color density spectral array (dsa), amplitude integrated eeg (aeeg) and the burst suppression rate (bsr). after this evaluation, daily qeeg evaluation was performed by the neurointensivists and reviewed by the neurophysiologist. results: from july to april we monitored patients ( ± years, male) admitted for brain trauma ( %), stroke introduction: it has been noted the importance of job satisfaction in healthcare services and the consequences resulting therefrom, such as increasing the quality of care services provided and satisfaction of their users. objectives: to develop a model of influence of human resource management directed to the quality management and organizational excellence in the organizational results, from the perspective of healthcare staff. methods: we carried out a research study, of a transversal nature, whose study population were a total of ( , % physicians, , % nurses and , % nurse assistants) icu staff. a personal questionnaire was used to measure, through likert scales of points, the application of human resource practices of high commitment (hr), the quality of service provided to the patient (quality), the satisfaction with the capacity of the service (capacity), the personal satisfaction with the work done (satisfaction) and the affective commitment with the organization (commitment). results: the measure models of these five constructs were validated by confirmatory factorial analysis, whose results were satisfactory. the measurement model of hr is a second order construct which is introduction: in the period between - , a successful implementation project was finished aimed at strict blood glucose level (bgl) regulation in the intensive care unit (icu) [ ] . we hypothesized that glucose control would afterwards slack and that implementing other measures to modify behavior would be required to regain adequate glucose control. methods: a prospective study was performed in a -bed mixed medical-surgical icu of a university affiliated teaching hospital. all bgl values were extracted from the icu database in years following the implementation project until december . following the project, bgl targets were set at a range of - mg/dl, nurses' instructions for keeping bgl values in target were not changed. after . years, an automated warning system was implemented in the patient data management system that triggered a centrally placed monitor with feedback about the need for obtaining a bgl value, based on the actual value compared to the previous one. the primary outcome measure was mean bgl. secondary endpoints were sampling frequency, bgl within predefined targets, incidences of severe hypoglycemia, and hyperglycemia. the analysis was restricted to patients with at least two blood glucose measurements. these indicators were analyzed over the course of time using the xmr control chart, a tool belonging to statistical process control. results: data of patient admissions were evaluated, which corresponded to , bgl measurements. the bgl sampling interval (figure ), mean bgl and percentage of severe hypoglycemia all increased after introducing nurses' instruction and decreased significantly after monitoring feedback (p < . ). percentage of severe hypoglycemia events, which is associated tosafety, decreased with some delay after nurses' instruction and remained unchanged ( . % on average) and stable after introducing monitoring feedback. percentage of "in range" measurements of both normoglycemia ( - ) and protocol recommended ( - ) decreased after nurses' instructions and then increased after feedback monitoring. mean of per patient's standard deviation as a measurement of variability remained unchanged and stable after nurses' instruction and even decreased after monitoring feedback. conclusion: even after successful implementation of a bgl control system, behavior changed within months with inherent worsening of bgl control. an automated warning monitor in a central location was able to restore bgl control in the icu. using objective: the overall objective of this research program is to use the kinarm to define the neurocognitive phenotype of icu survivors (i.e. required invasive mechanical ventilation and/or vasoactive agents for hemodynamic support). this group is compared to healthy age-and gender-matched controls, as well as active control groups. these active control groups were patients ) pre-and ) post-cardiac surgery, and ) patients postcardiac arrest. methods: participants performed tasks on the kinarm that ranged from simple sensorimotor tasks to more complex executive tasks. for each task, - performance metrics were recorded. these metrics were compared to a normative database of age-and gendermatched controls and z-scores were generated. a composite score for each task was generated using a score derived from maholanobis distance, with increasing scores representing worse performance. cluster analysis was applied to these performance metrics using euclidian distance. (fig. ) . conclusions: serial mlt measurements significantly underestimate muscle wasting in critical illness and are not related to development of muscle weakness. in comparison, changes in rf csa reflect changes in 'gold standard' methods of assessing muscle mass, and are related to loss of muscle mass and function in critically ill patients. there is significant evidence that electronic prescribing can significantly reduce the errors, however implementation of it is a long term project and is not feasible in attempt to improve medicines safety over short period of time. therefore we aimed to improve safety of a current paper based system. multidisciplinary intervention was chosen as this approach has been previously demonstrated to reduce medication errors on icu . objectives: evaluate effect of multidisciplinary intervention to improve medicines safety. methods: over the course of months following interventions were introduced: development and implementation of new icu specific iv infusion chart, prescription checks during nursing handover, introduction of daily pharmacy handover and on-site feedback, additional medicines training for current staff and new medicines safety induction module for new-starters. outcome data was based on monthly spot audits carried out by pharmacy staff. comparison is made between quarter and quarter after the start of intervention. chi-square test was used to compare the two datasets. results: there were prescriptions analysed in q and in q . we observed a five-fold reduction in prescription validity errors from . % to . % (p < . ). and nearly ten-fold reduction in administration of medicines against non-valid prescriptions from . % to . % (p < . ). pre-printed icu specific iv infusion chart eliminated errors related to variable dilutions, choice of diluent, incorrect or inconsistent infusion rates. month-by-month trends are presented in figure . conclusion: multidisciplinary intervention has resulted in significant improvement in medicines safety. introduction: the concept of frailty has been defined as a multidimensional syndrome characterised by the loss of physical and cognitive reserve that predisposes to adverse events. the prevalence of frailty amongst the critically ill is unknown, however it is probably increasing. this audit aimed to look retrospectively at our admissions to intensive care, to categorise them into frail or non frail, and evaluate how frailty correlated with icu length of stay and mortality methods: a retrospective case note review of all patients admitted to intensive care over a six month period in the victoria infirmary and then queen elizabeth university hospital in glasgow. classification of frail or non-frail was done using a combination of the clinical frailty score (cfs) and edmonton frailty scale. [ , ] . once classified into frail and non-frail we looked at icu outcome, length of stay, apache, weight on admission, lowest albumin and admission haemoglobin and compared the frail population to the non-frail population. results: two hundred and eighty four patients were admitted to intensive care in this time period. of those, were over the age of years. of the patients, patients were deemed to be frail, and were deemed to be non-frail using the cfs. approximately % of the patients admitted to intensive care are over the age of . there was no significant difference found in mortality, icu length of stay or hospital stay, apache or weight between the two groups. [see table ] conclusions: we know that the utilisation of intensive care resources by older people is rising. our data shows that almost % of those admitted to icu are over the age of . interestingly, there is no significant difference between the non frail and frail groups of patients admitted to intensive care. this may be because of small sample size. the length of stay of the frail patient is shorter and this may be because as intensivists we are better at treatment limitation in this group of patients. no difference in overall mortality suggests that the patients we deem suitable for intensive care who are frail do as well as the non-frail cohort as the selection process for admission has been adequate. patients deemed to be frail are more likely to be dependant on care if they survive, with % requiring some sort of support on discharge. most studies show that frailty is associated with increased mortality so it is indeed interesting that this audit has shown no difference between the two groups. figure shows a significant increase in admissions among the elder groups along the five-year periods. the severity scores increased significantly as shown in figure (p < . ). icu lenght stay also decreased significantly (table ) introduction: in our intensive care medicine (icu) department we used a database (gespac) with uniform and quality data for all admissions from to , which allows us to study the evolution of severity scales and the clinical activity by age and type of patient. objectives: to describe the effectiveness of severity scales used in our icu over years by age and type of patient. methods: a retrospective, single-center and descriptive study was conducted from to . all patients admitted consecutively were included. patients with lenght of stay less than hours were excluded.the severity scales we analyzed were mpm , mpm , saps , apacheiii. patients were divided in groups of age by quartiles (< years, - years, - years, > years). the type of patient was classified in medical and urgent or scheduled surgery. we used descriptive statistics. qualitative variables are expressed as percentages and quantitative variables are expressed as means and standard deviations (± sd) and roc curves for the analysis of discrimination. we used spss v . results: we included patients, were men ( %), mean age was . years (sd . ). icu mortality was . %. in figure we show curve roc corresponding to the severity scales for all patients, mpm has a significantly worse discrimination respect to the other scales. mpm , saps and apache iii have a similar behavior. in table we show the severity scales effectiveness by age groups. in table we show the severity scales effectiveness by type of patients. we observed a decrease of effectiveness of severity scales over time, however this effectiveness remains optimal in all the severity scales except for mpm . introduction: we implemented a critical care epr using the quadramed system on the th sept . our objective was to evaluate whether the epr had improved the quality of our documention and the responsiveness of our notes. methods: we evaluated the patient record from hospital days prior to the implentation of the epr and hospital days months after using and refining the system. results: the proportion of completed nursing risk assessments did not change after implementation of the epr. they depend on the user to shedule their completion. safety checks for arterial and cvc lines were well established and changed little. there was an improvement in the percentage of shift checks completed when they were automatically sheduled. the system provides a date, time and audit trail for each entry. the user traceability in the medical notes increased. the presence of the author´s name improved from % to %, the date from % to %, the time from % to %, and signature from % to %. legibility improved from % to %. the proportion of entries with a contact number dropped from % to %. the nursing care plans in the paper notes were better completed than the medical notes, but still improved. the presence of the nurse´s name increased from % to %, the date from % to %, the time from % to % and the signature from to %. legibility was % in both groups. the quadramed system provides automatic calculations of early warning scores and fluid balances.the more complicated the calculation, the greater the improvement. integration of data: · the increase in data points that cross populate is: + · the allergy advice populates all the sheets compared to an average of on paper (excluding the drug chart). · the average number of scheduled events (that instruct staff to perform functions) has gone from to . conclusions: . the largest improvement came in the accessibility of the notes. they can now be accessed within one minute from any pc in the trust. previously a standard time to deliver notes was two days, reducing to one day in an emergency. . correct filing of the epr notes and the search facility reduced the average time to complete the audit by minutes per patient. . the user audit trail and traceability improved in both medical and nursing paperwork, more so in the former. this is explained by a baseline of lower documentation standards in the medical group. . the typed out notes are now legible. . there was a large improvement in the quality of data calculations that are now up to %. . there was a large increase in the number of scheduled events, but this these only lead to an improvement in documentation when they were automatically scheduled by the computer. there was no improvement when user scheduling was required. we noticed very high levels of satisfaction regarding the professional care (frequency of communication, physician skill and competence, understanding information, honesty and facilities of getting information) and overall with care. satisfaction was even higher when we considered the usefulness of the ecp. every respondents supported it as a complement to daily information but it was only supposed to replace verbal information in , %. % did not access the website because of sufficient verbal information or cultural or age-related difficulties. the access was mostly via computer ( , %) followed by smarthphone ( , %). particularly desired were daily updates, an established timetable and more detailed information. there were no statistically significant differences in the need of web access among families living near the hospital and not or prior experience with icu familiar admission. conclusions: ecp appears to decrease the level of anxiety of families, improves perceived quality and can help to combine patient care with their work and personal responsibilities without replacing the daily evolution provided by physicians. introduction: neuroimaging shows promise for determining early prognosis after cardiac arrest (ca). nevertheless, conventional mri sequences, as t -weightened sequences, are currently considered not precise enough to detect brain structural anomalies in this context, and therefore are supposed to be unable to accurately predict outcome . objectives: we hypothesize that the combined use of cortical thickness measurement and subcortical grey matter volumetry could provide an early and accurate in vivo assessment of the structural impact of cardiac arrest (ca), and therefore could be used for longterm neuroprognostication in this setting. methods: prospective study undertaken in five intensive critical care units affiliated to the university in toulouse (france), paris (france), clermont-ferrand (france), liège (belgium) and monza (italy). high-resolution anatomical t -weighted images were acquired in anoxic coma patients ( +/− days after ca) and matched controls. patients were followed up one year after ca. cortical thickness was computed on the whole cortical ribbon and deep grey matter volumetry was performed after automatic segmentation . brain morphometric data was employed to create multivariate predictive models using learning machine techniques ( figure ) . results: patients displayed significantly extensive cortical and subcortical brain volumes atrophy compared to controls. a dissociated vulnerability to anoxic insult was observed: subcortical volumes were related to ca duration and cortical thickness values were linked to the time to mri acquisition ( figure ) the accuracy of a predictive classifier, encompassing cortical and subcortical components has a significant discriminative power (auc = . ). the anatomical regions which volume changes were significantly related to patient's outcome were: frontal cortex, posterior cingulate cortex, thalamus, putamen, pallidum, caudate, hippocampus and brainstem ( figure ) conclusions: these findings are consistent with the hypothesis of pathological disconnection within a striatopallidal-thalamo-cortical mesocircuit induced by ca and pave the way for the use of combined brain quantitative morphometry in this setting. clinical and electrophysiological correlates of absent somatosensory evoked potentials after post-anoxic brain damage: a multicentre cohort study conclusions: our data confirm that bilateral absence of n reflects severe post-anoxic cerebral damage and therefore frequently correlates with concordant clinical and eeg signs of poor outcome. however, our study also identified a subset of patients with discordant signs, in whom clinical examination and/or eeg were reactive despite bilaterally absent n . our findings raise further questions on outcome prognostication after ca and underline the importance of multimodal assessment in this setting. the response time threshold for predicting favorable neurological outcomes in patients with bystander-witnessed out-of-hospital cardiac arrest introduction: it is well established that the period of time between when a call in made to emergency medical service (ems) to the point when ems arrive at the scene (i.e., the response time) affects the survival outcomes in out-of-hospital cardiac arrest (ohca) patients. however, the relationship between response time and favorable neurological outcomes remains unclear. we therefore aimed to determine a response time threshold in bystander-witnessed ohca patients that is associated with positive neurological outcomes and to assess the relationship between the neurological outcomes and response time in ohca patient. methods: this study was a retrospective, observational analysis of data from , episodes of bystander-witnessed ohca between and in japan. we used classification and regression trees (carts) and receiver operating characteristic (roc) curve analysis to determine the threshold of response time associated with favorable neurological outcomes (cerebral performance category or ) one month after cardiac arrest. results: both carts and roc analyses indicated that a threshold of . min was associated with improved neurological outcomes in all bystander-witnessed ohca events from cardiac origin. furthermore, bystander cardiopulmonary resuscitation (cpr) prolonged the threshold of response time by min (to . min). the adjusted odds ratios for favorable neurological outcomes in ohca patients who received care within ≤ . min was . ( % confidential interval: . - . , p < . ). conclusions: a response time ≤ . min was closely associated with favorable neurological outcomes in all bystander-witnessed ohca patients. bystander cpr prolonged the response time threshold by min. methods: patients with established out-of-hospital cardiac arrest (ohca) who underwent cardiopulmonary resuscitation with subsequent return of spontaneous circulation were retrospectively enrolled. two hundred and eight dic patients diagnosed by the japanese association for acute medicine (jaam) dic criteria were divided into two subgroups with hyperfibrinolysis ( ) and without hyperfibrinolysis ( ). the definition of hyperfibrinolysis was made by a fdp level > μg/ml. platelet count, global markers of coagulation and fibrinolysis were measured times after admission to emergency department (t , - ; t , - ; t , - ; t , - hr). the outcome measure was the hospital all-cause mortality. results: patients with hyperfibrinolysis had higher dic, sirs, and sequential organ failure assessment (sofa) scores associated with higher prevalence of mods, leading to a higher mortality rate of . % in comparison to patients without hyperfibrinolysis ( . %). stepwise logistic regression analyses confirmed that dic, sofa scores, and lactate levels are independent predictors of patient death. hyperfibrinolysis also predicted patient death. tissue hypoperfusion (as indicated by lactate level) is a main determinant of hyperfibrinolysis. receiver operating characteristic curves showed a significant discriminative performance of dic scores for patient death. kaplan-meier curves showed that dic, especially dic with hyperfibrinolysis, significantly affected patient death. conclusions: dic with the fibrinolytic phenotype during the early phase of post-cpr more frequently results in sirs and mods, and affects the outcome of ohca patients. hypoxia/ischemia during cardiac arrest and cpr are considered to be the cause of increased fibrin(ogen)olysis. the association between tracheal intubation during pediatric inhospital cardiac arrest and survival l.w. andersen , , t. introduction: tracheal intubation is common during pediatric inhospital cardiac arrest, although the relationship between intubation during cardiac arrest and outcomes is unknown. objective: to determine if intubation during pediatric in-hospital cardiac arrest is associated with improved outcomes. methods: this was an observational study of prospectively collected data from united states hospitals participating in the get with the guidelines -resuscitation registry. we included pediatric patients (age < years) with index in-hospital cardiac arrest. we excluded patients who were receiving invasive mechanical ventilation and/or had an invasive airway in place at the time chest compressions were initiated. the exposure was tracheal intubation during the cardiac arrest. the primary outcome was survival to hospital discharge. secondary outcomes included return of spontaneous circulation and neurological outcome. a favorable neurological outcome was defined as a score of - on the pediatric cerebral performance category score. patients being intubated at any given minute (from to minutes) were matched with patients at risk of being intubated within the same minute (i.e. still receiving resuscitation) based on a timedependent propensity score calculated from multiple patient, event, and hospital characteristics. modified poisson regression with adjustment for matching and clustering were then performed to obtain risk ratios. results: patients were included. of these, ( %) were intubated during the cardiac arrest. in the time-dependent propensity score-matched cohort (n = ), survival was lower in those intubated compared to those not intubated during cardiac . ], p = . ) between those intubated and not intubated during cardiac arrest. the association between intubation and decreased survival remained in the majority of our sensitivity and subgroup analyses conclusions: tracheal intubation during in-hospital pediatric cardiac arrest was associated with decreased survival to hospital discharge. these findings challenge the present resuscitation paradigm for pediatric in-hospital cardiac arrest. introduction: substantial proportion of patients who suffered cardiac arrest do not respond to conventional cardiopulmonary resuscitation. recently, extracorporeal cardiopulmonary resuscitation (ecpr) has been introduced as a potentially life-saving procedure in refractory cardiac arrest. objectives. the aim of our study was to evaluate the relation between ecpr survival, lactate levels and blood ph. methods: eligible patients for this analysis had to undergo ecpr after at least ten minutes of unsuccessful cardiopulmonary resuscitation with a minimum of three defibrillation attempts. for extracorporeal life support (ecls) we used cardiohelp system (maquet, germany) or levitronix centrimag blood pump (levitronix, usa). lucas ii system (physiocontrol, sweden) was used for chest compressions during ecls insertion and cannulas were placed with percutaneous puncture under fluoroscopy or ultrasound control. blood lactate and ph levels measured before ecls insertion and after hours were used for this study. results: we analyzed data from patients treated with ecpr for refractory cardiac arrest. the mean age of our patients was years ( - ). out-of-hospital cardiac arrest occurred in patients, patients suffered from in-hospital arrest. thirty-day mortality in our group was % and % of patients recovered with good neurological outcome. percutaneous coronary intervention was performed in ( %) patients. baseline value of lactate was . ± . mmol/l, initial ph . ± . . in comparison with survivors, patients who died had significantly higher initial lactate levels ( . ± . vs. . ± . ; p < . ) and lower baseline ph ( . ± . vs . ± . ; p < . ). moreover, survivors had significantly lower lactate levels after hours. conclusions: ecpr represents virtually the last chance to survive refractory cardiac arrest. the levels of blood lactate and ph are significantly associated with clinical outcomes of ecpr. introduction: post-cardiac arrest survivors treated with therapeutic hypothermia (th) remain comatose after rewarming. in contrast to survivors without th, neurological prognostication is imprecise due to a persistent sedative effect [ ] . objectives: we aimed to evaluate clinical signs and findings that could predict neurological recovery and determined the optimal time for prognosis. methods: we retrospectively reviewed database of post-arrest patients treated with th in our hospital from to . cerebral performance category (cpc), neurological signs and findings in eeg and brain ct were evaluated. neurological recovery was scored as favorable neurological outcome, namely normal cerebral function(cpc ) and moderate disability(cpc ) or unfavorable neurological outcome, namely severe disability(cpc ), vegetative state(cpc ) and death(cpc ). neurological signs and findings in eeg and brain ct, which possibly predicted neurological recovery, and the optimal time to evaluate neurological status were analyzed. results: th was performed in post-arrest patients. approximately % ( / ) of th-patients survived and % of the survivors had favorable neurological outcome. findings predicting unfavorable outcome at discharge were lack of pupillary response and/or gag reflex after rewarming, and the absence of at least one of the brainstem reflexes, no eye opening or motor response worse than pain withdrawal (m ≤ ) on the seventh day. (table ) myoclonus and seizure could not be used to indicate poor prognosis. one of survivors with myoclonus had full recovery and % of the survivors with seizures regained consciousness upon discharge. findings of eeg and brain ct showed that the patients with burst-suppression eeg pattern or brain swelling became vegetative or died, but the prognostic values of these findings were inconclusive. conclusions: our study showed that the simple neurological signs helped predict short-term neurological prognosis of comatose survivors undergoing th. the most reliable signs which determined unfavorable outcome were the lack of the pupillary light response and gag reflex. the optimal time to assess prognosis was either at to hours or days after return of spontaneous circulation. physicians can use these neurological signs to evaluate the prognosis of postcardic arrest survivors treated with th. objectives: procalcitonin (pct) and presepsin are biomarkers associated with severe infections. we asked, if they could be used to reflect the severity of the post-cardiac arrest syndrome and to predict poor outcome. a significantly greater increase in procalcitonin from admission to h was observed in patients with eventual poor outcome compared to those with a favorable one (p < . ). presepsin levels were on average constantly higher in patients with poor outcome but did not show any statistically significant changes in repeated measures analysis of variance. conclusions: plasma procalcitonin may be a useful tool for the evaluation of long-term outcome of out-of hospital cardiac arrest patients at the icu. on the contrary, presepsin did not provide clinically relevant additional predictive value in the study setting. introduction: prognosis of cardiac arrest survivor is mainly determined by ischemic brain injury. post-cardiac arrest state is characterized by elevated circulating cytokines and hemodynamic instability, called as a sepsis-like syndrome. in many critical ill diseases such as acute pancreatitis and sepsis, a low serum level of high-density lipoprotein (hdl) and apolipoprotein a- (apoa ) were associated with poor outcomes. objectives: in this study, we examined whether a serum level of hdl and apoa at intensive care unit (icu) admission is associated with a neurologic outcomes in cardiac arrest survivors. methods: this study was a retrospective observational study conducted in a single tertiary urban hospital icu. all admitted patients following cardiac arrest were screened during from march to december . patients younger than years and without admission lipid panel were excluded. neurologic outcome was determined by hospital discharge cerebral performance categories (cpc). good neurologic outcome was defined as cpc and . note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. we analyzed all patients admitted on hospital ward that were assisted by the ihca team. patients admitted less than hours on ward and patients not eligible for resuscitation were excluded. demographic data (age and gender) were collected. we analyzed the type of patient (medical or surgical), the schedule in which the ihca happens (weekdays from hours am to hours pm and the rest, every day from hours pm to hours am, weekend and holidays), ihca witnessed, the ihca team time reaction, ihca established or not at ihca team´s arrival, return of spontaneous circulation (rosc) and hospital mortality. statistics:qualitative variables are expressed as percentages and compared using the x -test; quantitative ones are expressed as means and standard deviations (± s.d), and analyzed using student´s t-test. multivariate logistic regression was performed, with hospital mortality as the dependent variable. the level of significance was placed at p < . . the statistical analysis was performed using specific software ( ibm spss statistics for windows, version . . armonk, ny: ibm corp). results: patients were assisted by the ihca team and patients were included. in figure we described the characteristics of the study population. the beginning of cardiopulmonary resuscitation (cpr) maneuvers were immediate on ward, according to ihca protocol. the arrival of ihca team was less than minutes in all cases. table shows an assosciation between hospital mortality and the capability of anticipation of ihca situations (schedule, witness, pre-cardiac arrest …). table shows the persistence in the multivariate analysis of the relationship of these factors with the hospital mortality. conclusions: the number of activations of ihca team is remarkable, mortality of these patients is very high despite being patients on ward without a bad expected outcome. the improvement in the factors associated with the capability of anticipation of ihca situations (schedule, witness, pre-cardiac arrest …) could lead to an improvement in the prognosis of ihca. , and vessels with diameter smaller than μm were defined as small vessel. serum level of endothelial cell specific molecule- (endocan) was measured at specific time points. the hemodynamic parameters, the inotropic equivalent score, and prognosis of the patients were recorded. results: patients were iinvestigated in this preliminary report. they were equally divided into two groups (survival and nonsurvival) according to -day mortality. the baseline patient characteristics were not significantly between the two groups. the perfused small vessel density and proportion of perfused vessels at h were higher in the survival group than in the non-survival group. the endocan level were higher in the non-survival group than in the survival group, but the difference was not significant. conclusions: our results revealed that the perfused small vessel density were higher in the survival group than in the non-survival group. it encourages further studies to investigate whether aiming to improve microcirculation can improve outcomes in patient with venoarterial ecmo life support system. demographic data, sedation and vasopressor dose were recorded. enteral feeding was started as soon as possible. the cumulative grv was recorded up to a maximum of days, with a cut-off value of ml used to define intolerance to enteral feeding (ief). all data is presented as median(p -p .) statistical analysis was performed by stats . with mann-whitney u test and chi-square test. results: data from patients were recorded. baseline demographic data were similar in the groups. the average grv and the doses of midazolam were the highest in patients with vv ecmo, while the number of days with ief and the doses of na were the highest in the va ecmo group (table ) . overall, grv and number of days with ief tended to be higher in survivors (n = , grv ( - ), days with ief ( - )) than in non-survivors (n = , grv ( - , days with ief ( - )). conclusion: early enteral feeding is feasible during ecmo, in spite of impairments of gastrointestinal function potentially related to sedation and/or vasopressor treatment. extracorporeal membrane oxygenation for refractory cardiogenic shock in patients with peripartum cardiomyopathy a. chao results: six patients with confirmed ppcm were found. two ( %) patients died of neurological consequences (cerebral infarct and hypoxic encephalopathy) and their left ventricular (lv) ejection fraction remained about %. one patient underwent heart transplantation. the other three patients weaned off ecmo and their lv function began to improve on day . they were discharged uneventfully. conclusions: ecmo can provide an effective and simple treatment for critical ppcm with a satisfactory result. patients supported by ecmo whose heart function did not begin to recover on day and had neurological complications had a poor prognosis. introduction: the use of venoarterial extracorporeal membrane oxygenation (va-ecmo) for prolonged cardiopulmonary resuscitation (cpr) and severe cardiogenic shock after cpr has widely increased ( ). bleeding complications, due to necessary therapeutic anticoagulation and cpr/sirs induced coagulopathy are common ( ) . targeted temperature management (ttm) has shown positive effects on neurological outcome after cpr. although optimal target temperature is not exactly known, ttm remains a recommended approach in patients after cpr ( ). objectives: to determine the incidence of bleeding complications in patients after cpr, who are on va-ecmo and treated with ttm (target temperature °c) simultaneously. methods: we conducted a retrospective observational study from jan to dec and extracted relevant clinical data from electronically medical records. outcomes of interest were d-mortality and incidence of bleeding complications within hrs of cpr. demographic data, (anti-)coagulation status and need for transfusion were also analyzed. results: a total of patients received va-ecmo during the study period of which patients ( , %) underwent cpr before ecmo. of these, patients ( %) were treated with ttm. the median age was yrs (range - yrs) and patients were male ( %). sofa score on admission was ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . patients received cpr mainly because of either acute myocardial ischemia (mi) ( ; %) or malignant dysrhythmias not attributable to acute mi ( ; %). ecmo implantation was performed within hrs ( . - hrs) of cpr and ecmo duration was . hrs ( - hrs). ttm was implemented within hrs ( - hrs) of cpr and the duration of simultaneous treatment with va-ecmo and ttm was . hrs ( - hrs). introduction: during initial resuscitation of patients with shock, last consensus recommend to target a mean arterial pressure of at least mmhg. however, there is no recommendation for the mean arterial pressure target in in the particular setting of extra corporeal cardio pulmonary resuscitation patients in the first hours following a refractory cardiac arrest. objectives: therefore, we conducted an experimental study to assess the effects of two different levels of mean arterial pressure for macrocirculatory, microcirculatory and metabolic functions. methods: randomized animal study in university research laboratory. in fourteen male pigs, a myocardial infarction was induced by a surgical ligature of the inter-ventricular coronary artery, triggering a refractory ventricular fibrillation. after twenty minutes of standardised cardiopulmonary resuscitation, extra corporeal life support was initiated to restore the circulatory flow. then, animals were randomly allocated to a high mean arterial pressure group (high map, - mmhg) or to a standard mean arterial pressure group (standard-map, - mmhg). evaluations at baseline, just before and six hours after ecls initiation were focused on ) lactate, ) amount of fluid infused and ) microcirculatory parameters (sidestream darkfield imaging, renal and liver functions). results: the two groups were similar at baseline and also at time of ecsl initiation including for the lactate levels ( objectives: the goal of our study was to assess the factors associated with percutaneous cannulation success or failure during ca. methods: this was a prospective observational monocentric study conducted between may and february including all consecutive patients with ca (no return to spontaneous circulation after minutes of cardio-pulmonary resuscitation) and an indication of ecls (low-flow below minutes). femoro-femoral cannulation ( fr for arterial cannula and fr for venous cannula, maquet®) was performed using the seldinger technique under ultrasound (us) guidance. patient characteristics, physician's a priori about cannulation conditions (ranging from (expected very easy) to (expected very difficult)) and us measures of femoral vessels diameter were recorded. the primary endpoint was the time to ecls initiation (icu admission -ecls running) and was analyzed using a stepwise multivariable linear regression. as a secondary analysis, we also explored the differences between the patients with a time to ecls initiation < min and all others (> minutes or cannulation failure conclusions: our data suggests that the level of care patients receive does not affect baby being with its mother. however, level patients are admitted to a general critical care unit and not captured in this review. the results also suggest that maternal well-being is affected by and/or affects whether baby is with her, however the % confidence intervals overlap. the above data does not take into account babies being in special care baby units and therefore not able to join their mothers at their bedside (this data will be recorded in the future). when this data is recorded it is expected that a high proportion of babies who are able to be at their mother's bedside during amc will be there. the introduction: high levels of job satisfaction are associated with decreased turnover intention, burnout incidence and absenteeism among health care professionals. moreover, turnover and burnout negatively impact on quality of care and healthcare costs. as the intensive care unit (icu) represents a highly complex and stressful environment, prevention of conflicts among team members as well as improvement of communication and job satisfaction can as such reduce burnout risk. objectives: this study explores the relationship between communication -and job satisfaction and the impact on burnout and turnover intention among icu nurses. %, / ). an average job satisfaction of . / was found. . % ( / ) had a score ≤ on job satisfaction, indicating significant dissatisfaction. icu nurses were most satisfied with the trust received from their supervisor ( . %) and least with the information about accomplishments and/or failures of the organization ( . %). . %, ( / ) had a low, . % ( / ) an average and only . % ( / ) a high turnover intention. % of the icu nurses had an indication for burnout. . % of the nurses had a low experience of their personal accomplishment. conclusions: in this survey icu nurses had a reasonable job satisfaction. they are most satisfied with the trust received from supervisors. despite a low indication for burnout risk, a quarter of icu nurses report low personal accomplishment. this may represent a particular focus for both preventive and interventional actions, which should preferably be developed through and in conjunction with the supervising staff. introduction: in the swiss diagnosis related groups ((swiss)-drg)) was implemented in intensive care units (icu). its impact on hospitalizations has not yet been thoroughly examined. we compared the number of icu admissions according to clinical severity and referring institution, screened whether implementation of swissdrg affected admission policy, icu length-of-stay (los) or icu mortality. methods: retrospective single center cohort study conducted at the university hospital zurich, switzerland between january and end of . demographic and clinical data were retrieved from a quality assurance data base. conclusions: drg introduction had not affected icu admissions policy, except for an increase of in-house patients with a low clinical severity of disease. drg had neither affect icu mortality nor icu los. interactive gaming as part of mobilisation programs is feasible in the icu, but specific explanation about the usefulness of these games to patients is crucial for improving motivation and engagement t. introduction: in recent years, light sedation has gained attention as part of standard daily care in the intensive care unit (icu). consequently, patients are increasingly engaged in their rehabilitation process. particularly early mobilization is associated with shorter time on the ventilator, shorter icu length of stay and better survival [ ] . interactive gaming may be a challenging way of engaging the patient in his own rehabilitation program. few data are available for the use of these interactive games in the icu envirnoment as part of daily routine physiotherapy, although one study showed that it was safe [ ] . we developed a trolley with a wii (tm) device that can be easily used when the patient is mobilized in a chair. we hypothesized that this would be associated with increased motivation to participate in interactive gaming by our patients. methods: the wii device was used with different games. participating patients were offered to play games of their own choice as part of the mobilisation program to improve their strength and coordination. no extensive explanation about the potential usefulness of these interactive games was given to the patients. after finishing the games, a specific survey was administered addressing motivation and affects on mental health. scores were obtained using a likert scale (range - ). results are shown as median and interquartile range {p -p ] results: at the time of abstract submission, participating patients had finished a cycle of games. some of the patients liked to use the wii device, particularly because a choice in games made it more interesting to use. other patients, however, felt they were required to participate. tennis, bowling and boxing were most frequently used. the use of the wii was programmed in the daily mobilization schedule together with a physiotherapist, or just with the attending icu nurse. in general, patients were not that enthusiastic about the wii-games (median score [ - ]), were not convinced that playing these games improved their well-being (median score [ ] [ ] [ ] [ ] ), and most felt that they did not have a choice but to participate (median score [ ] [ ] [ ] ). conclusion: interactive gaming with the wii-device is feasible in icu patients. however, thorough explanation of the potential usefulness of these games is required to engage and motivate patients to participate. methods: descriptive and retrospective study. we include all patients admitted in icu during (previous to rrt establishment) and (year of rrt establishment), and who were discharged to the ward. we analysed the icu and hospital mortality in both groups. results: in we admitted patients ( , % from the ward and , % from the other places like emergency, other icu or other hospitals), with a icu mortality of , % and hospital mortality of , %, with a hospital mortality after icu discharge of , %. in we admitted patients ( , % from the ward and , % from the other places), with a icu mortality of , % and hospital mortality of , %, and a hospital mortality after icu discharge of , % (p = . ). conclusions: after the first year of rrt establishment in our hospital, we appreciate that the continuation of patients after icu discharge, decrease the hospital mortality ( , % versus , %, p = . ). the number of patients admitted in icu from the ward decrease in ( , % versus , %), maybe because we did a previous assessment of this patients, with a stabilization in the ward and avoiding the icu admission. objectives: to identify outcomes and prognostic factors in hm patients admitted over -years to a general intensive care unit in a specialist haematology centre. (figure ). patients with - organ failures had significantly worse outcomes than those with - organ failures (p < . ) or . [ . - . , ci %]. median apa-che ii, sofa and saps ii scores were , and , respectively. median apache ii (p < . ), sofa (p < . ) and saps ii (p < . ) scores were greater in those ventilated for - days vs. ≥ days. conclusions: apache ii scores and mortality were greater than described in similar hm populations. given the severity of critical illness in our cohort, we suggest that admission to icu earlier in the acute illness may improve outcomes. poorer outcomes were observed in those with > organ failures and in ventilated patients. the survival of / rd of patients on icu for ≥ days to hospital discharge suggests that -day trials of icu in hm patients are unlikely to reliably distinguish between survivors and non-survivors. background: dedicated intensive care unit (icu) physician staffing was associated with a reduction of icu mortality in the general medical and surgical icu. however, limited data were available on the role of a cardiac intensivist in the cardiac intensive care unit (ccu). we compared the clinical outcomes in adult patients admitted to ccu before and after implementing the cardiac intensivist-directed care. methods: we enrolled , consecutive patients admitted to a ccu at samsung medical center, from january to december . in january , ccu was changed from a low-intensity staffing model to highintensity staffing model which managed by a dedicated cardiac intensivist. we divided eligible patients into low-intensity group (n = ) and highintensity group (n = , ). the primary outcome was ccu mortality. results: high-intensity group had significantly lower ccu ( . % vs . %; p < . ) and hospital ( . % vs . %; p < . ) mortality compared to the low-intensity group. the decrease in ccu ( . % vs . %; p = . ) and hospital ( . % vs . %; p = . ) mortality in high-intensity group were consistent in (low-intensity group , high-intensity group ) patient with profound cardiogenic shock treated with extracorporeal membrane oxygenation. kaplan-meier survival curve showed significant higher cumulative survival rates in highintensity group at year follow-up (log rank test, p < . ). ccu ( . % vs . %; p = . ) and hospital re-admission rate ( . % vs . %; p = . ) were decreased as well after conversion to highintensity although these results were not statistically significant. conclusions: dedicated cardiac intensivist was associated with reductions of ccu mortality in patient with cardiovascular disease requiring critical care. introduction: opioids are commonly given to alleviate pain and distress in patients admitted to the intensive care unit (icu) patients or undergoing major surgery. previous studies have shown that patients who are already taking opioids prior to surgery or icu admission are more likely to experience an extended duration of opioid use postoperatively or post-discharge ( ). however, it is unknown whether patterns of opioid usage differ between patients who are admitted to the icu and those undergoing a surgical procedure. objectives: the objective of this study was to describe opioid use in critically ill patients before and after icu admission and to compare it with preoperative and postoperative opioid use in a surgical population. methods: retrospective review and comparison of adult patients admitted to the icu or undergoing surgery at a tertiary care center between january , and december , . we divided the populations based on their degree of opioid use into "non-user", "intermittent", and "chronic" opioid users as previously described ( ). we assessed opioid use at months prior to icu admission or surgery, at discharge, and monthly for months thereafter. patients admitted to icu who had surgery were categorized under the icu population. to assess for risk of monthly chronic opioid use, a cox-proportional hazards model was postulated that allowed for recurrent events to account for patients irregularly requiring opioids over the course of the study period. the model showed that the risk of chronic opioid use was . times greater for those with prior chronic opioid use compared to patients who were non-users. there was no difference in risk of chronic opioid use between the icu and surgery group. conclusions: our findings suggest that icu and surgical patients have similar risk of prolonged chronic opioid use post-discharge. chronic opioid use prior to icu admission or surgery is the strongest predictor of chronic opioid usage at and after discharge. a single-centre cohort study of national early warning score (news) and blood gas derived biomarkers in patients with acute medical illness introduction: empirical combination antibiotic therapy for treatment of severe sepsis is a matter of debate. the proposed rationale for using a combination of two or more different antimicrobials is several fold. first, it allows for a broader empirical coverage with a higher likelihood of targeting the causative organism. second, it may decrease the development of resistance to the antibiotics used. third, a combination of active drugs potentially cause a synergistic effect increasing the efficacy of bacterial eradication. the surviving sepsis campaign recommends combination therapy in some patient populations and certain type of infections but the quality of the evidence supporting empirical combination antibiotic therapy is weak and does not include high quality randomised clinical trials (rcts). objectives: to assess benefits and harms of empirical mono-vs. combination antibiotic therapy in adult patients with severe sepsis in the intensive care unit (icu). methods: we performed a systematic review according to the cochrane collaboration methodology, including meta-analysis, risk of bias assessment and trial sequential analysis (tsa). we included rcts assessing empirical mono-antibiotic therapy versus a combination of two or more antibiotics in adult icu patients with severe sepsis. we exclusively assessed patient-important outcomes, including mortality. two reviewers independently evaluated studies for inclusion, extracted data, and assessed risk of bias. risk ratios (rrs) with % confidence intervals (cis) were estimated and the risk of random errors was assessed by tsa. results: thirteen rcts (n = , ) were included; all were judged as having high risk of bias. there was no difference in mortality (rr . , % ci . - . ; p = . ) or in any other patient-important outcomes between mono-vs. combination therapy. in tsa of mortality, the z-curve reached the futility area, indicating that a % relative risk difference in mortality may be excluded between the two groups. for the other outcomes, tsa indicated lack of data and high risk of random errors. conclusions: this systematic review of rcts with meta-analysis and tsa demonstrated no differences in mortality or other patientimportant outcomes between empirical mono-vs. combination antibiotic therapy in adult icu patients with severe sepsis. the quantity and quality of data was low without firm evidence for benefit or harm of combination therapy. introduction: de-escalation antibiotic in sepsis is associated with reduced costs and bacterial resistance. however, often it is not done. objectives: we designed this study with the primary objective to evaluate the prevalence of de-escalation in patients with severe sepsis or septic shock in an academic public hospital in south brazil. secondarily we evaluated antibiotic adequacy and cultures positivity. methods: we analyzed prevalence of de-escalation, antibiotic adequacy and culture positivity in severe sepsis and septic shock patients in an intensive care unit. results: of the patients included, de-escalation could have been performed in % of cases ( patients), but was implemented in only % of cases ( patients). among patients who received deescalation, half was for antimicrobial spectrum narrowing. the mortality was not different between patients with or without de-escalation ( . % versus . %, p = . ). empirical antimicrobial therapy was adequate in % of cases. pathogens were isolate in % of all cultures and . % of blood cultures. conclusion: the rate of empiric antibiotic adequacy was high, reflecting active institutional policy of monitoring the epidemiological profile and institutional protocols of antimicrobial use. however, the antimicrobial de-escalation could have been higher than reported. de-escalation did not impact mortality. there are few data in the literature regarding the care of severe sepsis patients in developing countries. this data can contribute to adequate treatment in this scenario. introduction: despite recent advances, appropriate initial amikacin dose in critically ill patients is still challenging. relationship between pharmacokinetic/pharmacodynamic (pk/pd) parameter peak concentration (cmax)/minimum inhibitory concentration (mic) in critically ill patients is not clear. objectives: we assessed the impact of amikacin pharmacokinetic and pharmacodynamic parameters on clinical and microbiological outcome in these patients. methods: observational prospective study. adult patients (> years) admitted to an intensive care unit (icu) with a gram negative documented infection and treatment with amikacin were included (study period: september -april ). amikacin blood samples were taken to hours after treatment started. amikacin concentration were determined using indiko® (thermo fisher scientific), and drug adjustment were based on the recommendations given by the pharmacokinetics unit (pharmacy service). clinical response, defined as sign and symptoms presented at the moment of infection diagnosis (fever, chest radiography alteration, infection biomarkers elevation and hemodynamic instability), was evaluated. ji-square and u-mann whitney test were used to compare results between treatment responders and notresponders. . mean initial dose was mg (sd: , )/day, equivalent to . ( . ) mg/kg/day. with that dose, patients ( , %) reached a cmax/mic value higher than . final treatment response was higher for those patients with amikacin cmax/mic value > ( , % vs , %; p = . ). no significant differences were reached in early treatment response (initial h) ( , % vs , %;p = , ) or days mortality ( , % vs , %;p = , ). cmax/mic values was not associated with toxicity-related treatment discontinuation ( , vs , ; p = , ). conclusions: initial cmax/mic value is associated with clinical response in those patients treated with amikacin. high initial amikacin dose may be necessary to optimize pk/pd parameters. method: in a bed mixed icu from october , to september , nosocomial infections (pneumonia, urinary tract infections, catheter-related bacteremia (crb) and secondary nosocomial bacteremia) were prospectively collected. envin-helics diagnostic criteria were applied. etiology, inflammatory response to infection, antibiotic treatment (atb t) and treatment modifications according to culture results, were analyzed. sdd was applied to all admitted patients requiring endotracheal intubation over hours. for each groups categorical variables were summarized as frequencies and percentages and number in means and standard deviations (sd) or median with interquartile ranges (iqr).percentages were compared, as appropriate, with the fisher´s exact test or x test and medians with the wilcoxon test for independent samples. for those variables that were associated with de in the univariate analysis were entered into a logistic multidimensional analysis. the model obtained was expressed by p-values and odd-ratios, which were estimated by confidence intervals at %. a hypothesis test was considered statistically significant when p-value was less than . . results: ninety patients ( , %) had atb de and did not. there were no significant differences in demographics or type of admission in both groups (fig. ) . mortality was lower in patients receiving de antibiotic (atb) ( , %, p: . ). in the multivariate analysis, icu mortality and urinary tract infection were the only variables found significant (fig. ) de was performed in out of ( , %) with crb and in out of ( , %) who had nosocomial pneumonia. the atb t was inadequate in out of infections ( , %). targeted therapy was performed in out of patients ( , %) and in out of infections, at least once occasion ( , %). finally, atb were targeted prescribed. in all studied patients with de, this was performed in patients once, in patients twice and in patients three times. the number of antibiotics used was and atb de was performed in occasions. frequency of atb used and of theirs de is shown in fig. of note, meropenem was de in , %. conclusions: patients who received atb de compared to those that did not had a significant lower icu mortality. the factors independently associated to de were icu mortality and urinary tract infection. inadequate atb t in our icu occurred in . % of nosocomial infections. atb de was performed in patients. targeted therapy was applied to , % of infections. the most commonly used antibiotics were meropenem ( , %), levofloxacin ( . %) and piperacillin-tazobactam ( , %). meropenem, was de in , %. introduction: antimicrobial prescription represents a major challenge for clinicians in the daily practice especially in certain difficult clinical scenarios. thus, in critically ill septic patients, prompt and adequate antimicrobial therapy reduces morbidity and mortality objectives: we set out to assess the impact on in-hospital of antibiotic de-escalation in patients admitted to the icu with severe sepsis or septic shock. methods: collaborative study enrolling patients admitted to the icu with severe sepsis or septic shock from two different cohorts. the first one, a spanish prospective and observational cohort and the second one, a multicenter non-blinded, randomized and non inferiority trial conducted in france. severity was estimated by the use of the predicted mortality rate at icu admissionfor every included patientby implementing the likelihood of death logit formule defined according to the apache ii and saps ii scores criteria and taking this cuantititative variable into account as a confounder factor in the regression model. de-escalation was defined as discontinuation of an antimicrobial agent or change of antibiotic to one with a narrower spectrum once culture results were available. to control for confounding variables we performed a multivariatebinomial logistic regression analysis adjusted by wald test. results: nine hundred and one patients with severe sepsis or septic shock at icu admission were treated empirically with broadspectrum antibiotics. eight hundred and seventeen patients were evaluated ( died before cultures were available). de-escalation was applied in patients ( . %). we found no differences in hospital long of stay between de-escalation group comparedto those who did not received it. we also found a significant lower hospital mortality in de-escalation group in front of the others ( . vs. . %; p < . ). by multivariate analysis (adjusted by severity scores-apache and saps), factors independently associated with in-hospital mortality were age (odds-ratio [or] . ; % confidence interval [ci] . - . ), and sofa score at icu admission (or . ; % ci . - . ), whereas de-escalation therapy was a protective factor (or . ; % ci . - . ) as well as urinary focus (or . ; % ci . - . ). analysis of the patients with etiological diagnosis revealed that the factors associated with mortality were age and sofa and conversely de-escalation therapy was a protective factor (or . ; % ci . - . ) conclusions: de-escalation therapy for septic critically ill patients is a safe strategy associated with a lower mortality. efforts to increase the frequency of this strategy are indeed justified. introduction: at the population level, both vancomycin and aminoglycosides are known to be nephrotoxic. the risk of nephrotoxicity might even be higher when combining the agents together ( ). nonetheless, in septic patients, the benefit in terms of sepsis control may outweight the risk of nephrotoxicity. thus, being able to appraise the risk/benefit ratio at the patient level would be of great interest to better tailor individual treatment. objectives: capitalizing on recent statistical innovations in personnalized medicine, our goal was to develop a patient-centered estimation of the impact of the association vancomycin/aminoglycosides on the kidney function. methods: our data come from a cohort study performed between and in the departments of anesthesia, critical care and cardiovascular surgery at a french teaching hospital. this study included all consecutive patients operated for an acute endocarditis ( ). the primary endpoint was postoperative evolution of the kidney function as evaluated by the akin score (stade : elevation in serum creatinine (srcr) ⩾ . μmol/l or ⩾ , xbaseline; stade : elevation in srcr ⩾ xbaseline; stade : elevation in srcr ⩾ xbaseline or creatinine ⩾ μmol/l with increase > μmol/l or need for rrt). the impact of vancomycin/aminoglycosides on kidney function was estimated using targeted maximum likelihood estimation on a risk difference (rd) scale. the association between patient characteristics and the individual effect of the drugs on the kidney function was estimated using conditional recursive partitioning (ctree). results: patients were included in the study. their baseline characteristics are described in table . at a population level, we confirmed the strong association between vancomycin + aminoglycosides and the risk of kidney dysfunction (rd = . , %ci: . - . , p < . ). however, at the patient level, this effect was very variable and could be predicted based on patients characteristics (r = . ) (figure ). conclusions: the individual impact of vancomycin + aminoglycosides on kidney function may be very different than the overall effect at the population level. innovant statistical approaches may be used to identify patients in whom this drug combination is safe, and others in whom it may seriously threaten kidney function. introduction: catheter-related bloodstream infection (crbsi) is one of the most frequent nosocomial infections in critically ill patients, resulting in a significant increase of morbidity and mortality. that is why it is essential to detect crbsi precociously so that optimal treatment can be initiated as soon as possible. objective: our objective is to evaluate the effectiveness of rapid non-invasive tests that may allow clinicians to detect colonisation of the central venous catheter (cvc) as a source of bloodstream infection in critically ill patients, permitting catheter withdrawal and the initiation of early goal-directed antibiotic therapy. methods: over the course of eight months, we selected for evaluation those critically ill patients admitted to our icu who developed fever (> °c) without source, to whom the clinician in charge decided to withdraw the cvc. before extraction, we obtained a skin smear at the insertion site, in addition to a catheter-hubs smear. we sent both smears, along with the catheter tip and blood cultures, to the microbiology laboratory. these results indicate that our test has a negative predictive value of %. to evaluate the degree of association between our test and the gold standard, we calculated the contingency coefficient, which resulted in , out of a maximum , (p < , ). this shows the strong validity of the combination of skin and catheter-hub cultures as a diagnostic method for cvc colonisation. conclusions: the combination of skin and catheter-hub cultures is a rapid and very effective method for detecting the colonisation of cvc as a possible source of bloodstream infection in critically ill patients. while a negative result, which can be obtained within h, would prevent the need for cvc withdrawal, a positive result would not only enable the removal of the likely source of infection, but it would also allow for, if the intensivist deemed it necessary, the initiation of early goal-directed antibiotic therapy. this would mean, in more than % of cases, starting optimal treatment at least hours prior to the diagnosis of crbsi from blood cultures. results: introduction: piperacillin/tazobactam (ptz) is a β-lactam-β-lactamase inhibitor combination with a broad spectrum of antibacterial activity. βlactams are time-dependent antibiotics and their effectiveness is in association with the duration of free drug concentrations over the minimum inhibitory concentration (t > mic) of organisms. prolonged infusion has a pharmacokinetic (pk) advantage compared to intermittent bolus dosing, a continuous infusion lower dose of g ptz may be as effective as a higher dose of intermittent bolus ptz. objectives: in this study we intend to evaluate the continuous infusion of / grams of ptz along with a loading dose of / , grams in patients admitted in a tertiary icu. methods: between october and december eight patients had piperacillin plasma concentration monitored during treatment with continuous ptz infusion in a monocentric prospective observational study. patients received a loading dose of / , grams of ptz followed by infusion of / grams, reconstituted in ml sodium chloride , % and transferred to braun space infusion system®. the pump had a flow rate of ± ml/h. blood was always extracted from the contralateral arm to the infusion, over hours at predetermined times. serum piperacillin/tazobactam concentrations were determined using an hplc method ( ). after extraction, samples ( μl) were injected into a xbridge c column (waters, spain) and were scanned by an uv detector at nm with gradient elution. mobile phase was composed by acetonitrile and a solution of tetrabutylammonium bisulfate ( g/ l). penicillin g was used as internal standard (sigma aldrich, spain). results: patients have been examined ( men and women). the average age was ± , the weight was ± kg, the creatinine clearance ± ml/min and the apache ii score , ± , . the mean concentrations of ptz in serum are represented in the next figures. conclusions: in this icu patient group, our results suggest that continuous infusion of ptz at / g per day is sufficient to obtain therapeutic plasma-concentrations in critical care patients with infections caused by ptz sensitive bacteria with a mic lower than mg/dl. however, in our group there were three patients with levels of mg/dl, which are not sufficient for bacteria with mic lower than mg/dl; these three patients are neurocritical. in conclusion, further studies in this are needed, especially studies regarding the association between piperacillin therapeutic drug monitoring and clinical outcome. introduction: ultrasound guided internal jugular vein cannulation is recommended technique in current anaesthesia and intensive care practice. however, classic short axis view has inherent problem of needle visualization during venous access. in contrast, medial oblique view may enhance needle visibility during venipuncture and decrease overlap between ijv and carotid artery and thereby increase the safety of us guided ijv cannulation ( ) ( ) . objectives: to compare the safety and efficacy of medial oblique view and in-plane technique as compared to short axis view and out-of-plane technique during us guided ijv cannulation. methods: two hundred patients aged between - yrs of either sex and american society of anesthesiologists' physical status i-ii who were undergoing any surgery under general anaesthesia requiring an internal jugular vein cannulation, enrolled for this prospective randomized controlled trial. three patients were excluded due to us machine malfunction. in patients of group m, ijv cannulation was performed with medial oblique probe position and in plane approach. in patients belonging to group s, ijv cannulation was done in out of plane approach with the us probe in short axis position. primary outcome was needle and guide-wire visibility during procedure. results: needle visibility (entire needle tract and needle tip) was significantly higher during ijv puncture in medial oblique probe position ( of patients in group m versus of patients in group s; p = . ). guide wire visibility during insertion was also higher when medial oblique probe position was used ( of in group m versus out of ; p = . ). first insertion success rate for ijv puncture, incidence of posterior wall of ijv puncture and time to cannulation were similar both the groups. no serious complications such as carotid artery puncture, haematoma formation and pneumothorax were reported. conclusions: medial oblique view may increase safety of us guided ijv cannulation in comparison to short axis view by increasing needle visibility during puncture. resuscitation "philosophy" shifted from being heart oriented towards brain oriented since its delay may increase neurological deficits . recent studies are highlighting the role of the bystander-cpr as a critical variable affecting ocha neurological outcome. , objectives: two step prospective interventional observational study to assess the role of the bystander-cpr in affecting neurological outcome in our ohca population. introduction: there is a clear rationale for monitoring microcirculatory behaviour during shock since it is the anatomical location of oxygen and substrate exchange, and may not correspond to global haemodynamics. and yet despite over a decade of research and technological advances such monitoring has not reached clinical bedside utility. analysis of the data is performed offline and too time consuming for clinical use. there is an urgent need for a system to assess the microcirculation at the bedside. we present a novel -point grading system (the point-of-care microcirculation (poem) scoring system) that can be used at the bedside (using sublingual microcirculatory monitoring). objectives: to assess the inter-user variability of the novel poem scoring system amongst doctors and nurses who may use such technology for clinical practice, and to benchmark poem scores against traditional offline computer analysis. methods: the poem score is an ordinal scale from (worst) to (best), and calculated based on assessment of individual video clips. online calculator found at: www.poemscore.com. thirtytwo naïve study participants from two uk teaching hospitals (birmingham and london) participated in a standardised -hour interactive training session in how to assign poem scores based on microcirculatory video clips from sublingual incident dark field (idf) videomicroscopy imaging. they were then asked to assign scores for different video sequences (each of varying clinical status, played in a random order). they were blinded to clinical status. inter-user consistency and agreement were assessed using intra-class correlation coefficient (icc) analysis. blinded expert poem scores were also validated against offline computer analysis of the same clips using traditional microcirculatory parameters, and the time taken to assign each was recorded. results: raters showed good inter-rater consistency (icc . , % ci . , . ) and agreement (icc . , % ci . , . ) for assigned poem scores. expert poem scores correlated well with offline analysis but took far less time to assign (mean times of minutes versus minutes; p < . ). conclusions: a new -point ordinal scale of microcirculatory function has been tested amongst 'front line' emergency physicians and nurses at two large uk teaching hospitals, and has minimal inter-user variability, even after just hour of training. poem scores take a matter of minutes to assign, and correspond well to computer-analysis variables. we present for the first time a bedside microcirculatory grading system that is quick, reliable, and gives potentially meaningful clinical parameters that might guide resuscitation. prospective randomised trials utilising goal directed therapy using the poem score are required to test its reallife clinical utility. introduction: vocal cord palsy is a known postoperative complication following cardiothoracic surgery. , . although the incidence is relatively low its existence cannot be ignored and thus its identification necessary in order to avoid any further complications and maintain patient wellbeing. this study aims to look at the incidence of vocal cord palsy following cardiothoracic surgery in a tertiary referral centre and highlight the importance of the speech and language therapist's role in working with this cohort. objectives: to measure the incidence of vocal cord palsy post cardiac and thoracic surgery and to identify the consequent effects. methodology. a retrospective analysis, within a tertiary cardiothoracic centre. data for all patients who underwent either a cardiac or thoracic surgical procedure between december and april and were referred to speech and language therapy (slt) was collected. vocal cord palsy was identified by fibreoptic endoscopic evaluation of swallowing (fees) or bronchoscopy. results: a total of patients were seen by the slt. patients with vocal cord palsy were identified by fees and bronchoscopy; % and % respectively. six patients assessed presented with vocal cord palsy; patients were post cardiac surgery ( / ) and post thoracic surgery ( / ). the consequence of vocal cord palsy was dysphonia in all the patients and dysphagia in two thirds of patients. the median duration that patients experienced dysphagia was days (range - days) and dysphonia was days (range - ). conclusion: this review highlights the high prevalence of vocal cord palsy post cardiothoracic surgery. vocal cord palsy led to high levels of dysphagia and dysphonia. early identification of these is imperative to ensure patient safety and optimise recovery and quality of life. ) . . % were over years old at the moment of the surgery. figure shows previous cardiac clinical history figure shows other relevant comorbidities. it was first surgery in . % of the patients. , % of the cases were valvular surgery (with or without cabg); , % were isolated cabg; , % thoracic aortic surgery; , % were other surgeries (congenital disease surgery, post ami complications, pericardiectomy). tables and summarizes the results of the application of sf- questionnaire in the patients interviewed in the follow up in the comparative analysis we found worse qol in women than men (p = , ), and a negative correlation between age and qol (p = , ). women in our study were significantly older than men (p = , ). we found no differences between the type of surgery and the postoperative qol, or between surgery or extracorporeal circulation duration and qol. there was a relationship between nyha degree during the follow up and the sf health score prognostic scores showed an inverse relationship with qol, but with a low correlation; pearson coefficient − , (euroscore), − , (saps ). conclusions: in our study, involving hospitals in andalusia (south spain), , % of cardiac surgery patients didn´t show any activity limitation or only a slight limitation before years of follow up. perceived quality of life decreases as age increases or worsens the functional status of the patients. conclusion: concsultation for the severely ill cases in the wards take very much time of the intensivits. it was seen that consultation request was mostly emergent and due to respiratory problems and sepsis. maybe we need another system like rapid response team for decrease the insivists work and decrease the mortality amd morbidity. the limitation of the beds in icu is one of the most important problem, and there must be more empty beds for inhospital emergencies. an external validation study of the qsofa score to predict inhospital mortality in medical patients with infection and derivation of a new enhanced score using automatically available variables: news-hazard l. introduction: sepsis has recently been redefined as´life-threatening organ dysfunction caused by a dysregulated host response to infec-tion´. it is one of the leading causes of mortality internationally. earlier identification of sepsis means more timely management, reduced length of hospital admission, and prevention of septic shock; ultimately reducing sepsis associated mortality. ( ) there is currently no standard diagnostic test for sepsis. distinguishing sepsis from alternative, uncomplicated infections is pertinent to ensuring an appropriate clinical approach. systemic inflammatory response syndrome (sirs) criteria have been used since to define sepsis (sepsis . ). however they have been found to lack sensitivity or specificity. the quick sequential organ failure assessment score (qsofa) is an emerging initial assessment method that uses three simple bedside criteria to measure organ dysfunction; altered mental status, respiratory rate ≥ and systolic blood pressure ≤ mmhg. the aim is to facilitate earlier recognition of sepsis outside of itu by prompting the clinician to think, and adequately screen for sepsis. in cases, the diagnosis of pneumococcal meningitis by culture or pneumococcal crp in csf was confirmed. in all cases, pneumococcus antigen was positive. therefore, there were no false negatives. in cases pneumococcal meningitis was not diagnosed, being the final diagnosis a non-pneumococcal bacterial meningitis or another pathology. in all cases, pneumococcus antigen was negative. therefore, there were no false positives. in conclusion, in our sample of patients, the sensitivity and specificity of the test for s. pneumoniae antigen in csf was %. the ppv and npv were also %. conclusions: in our series, the sensitivity and specificity of the test for s. pneumoniae antigen in csf by immunochromatography ( binaxnow® test ) was %. the vpp and vpn were also %. these results are similar to those reported previously in the literature. knowing the reliability of this fast, simple and inexpensive test, will allow to remove unnecessary isolation and to establish a more specific treatment and a better prognoses of the disease. evaluation of sensitivity and specificity of different criteria using for diagnosis of burn sepsis and without these (group № , n = ). logistic regression was performed to identify the independent factors for the prediction of early death ( days and less). we examined sensitivity and specificity with area under the receiver operating characteristic curve (roc auc). results: there were no significant differences between two groups for demographics, burn size, inhalation injuries. fatal outcome came early in the group № (mean icu length of stay , days vs days, p < , ). organ dysfunction at day was significantly higher in the group № (mean sofa , vs , ; p < , ). there were no significant differences in aba, fsbi and cdbs between two groups, and the highest auc were for cdbs by the day (auc , % ci , - , vs , % ci , - , and , % ci , - , for cdbs, aba and fsbi, respectively). sirs criteria were significantly higher in the group № , auc was , ( % ci , - , ) but specificity and sensitivity was too low (for sirs criteria is , % and %, respectively). independent factors for early death include: more than % immature neutrophils at the day , sofa more than by the day , thrombocytopenia less than by the day . conclusion: patients without specific pathomorphological signs of sepsis have more severe organ dysfunction, greater number signs of systemic inflammation and earlier fatal outcome. diagnostic model of sepsis by chinese experts has more sensitivity and specificity for diagnosis of burn sepsis confirmed by autopsy. immature neutrophils count, thrombocytopenia and sofa score are stronger risk factors for early death. the value of neutrophil to lymphocyte count ratio in diagnosing blood-stream infection s. involved microorganisms: s. pneumoniae and n. meningitidis in communitary abm, s. epidermidis and gram-negative bacilli in nosocomial abm. when comparing both groups, only we observed difference in the c-reactive protein at admission ( ± , in nosocomial abm vs , ± , in communitary, p , ). there were differences with other variables but were not statiscally significant. so, we observed a higher mortality in nosocomial abm group but the difference was not statistically significant (p , ). global icu mortality was % ( ) and hospital mortality was , % ( ). conclusions: the demographic and bacteriological profiles of patients with acute bacterial meningitis have changed in the last years mainly due to the expansion of neurosurgical procedures. still has a high morbidity and mortality. the detection of microbial dna but not cultured bacteria is associated with increased mortality in patients with suspected severe sepsis -a european multi-centre observational study m. introduction: sepsis is a leading cause of worldwide mortality. blood culture results poorly discriminate the mortality risk in critically ill patients with sepsis. here we aimed to determine whether the detection of microbial dna in the blood stream of patients with suspected sepsis was associated with mortality. we performed an analysis of data collected during the rapid diagnosis of infections in the critically ill (radical) study ( ) . patients were considered eligible for this study if they developed suspected sepsis and were either in or were referred for treatment to one of nine intensive care units (icus) in six european countries. when initial blood cultures were taken for clinical indications an additional blood sample was obtained for a culture-independent polymerase chain reaction/electrospray ionization-mass spectrometry (pcr/esi-ms) assay. the results of the pcr/esi-ms test were not communicated to the treating clinicians. results: of the patients analysed in the original study outcome data, blood culture results and pcr/esi-ms results were available for patients (table ) objectives: to evaluate if a "bundle" consisting of a sirs and organ failure (sof)-triage, flow chart response and alert system, and a sirs/ sepsis training course for all wards nurses improved clinical observations, lead to fewer patients developing severe sepsis, decreased length of stay in the high-level care (los) and increased survival. methods: a before and after intervention study in one emergency and community hospital within the mid-norway sepsis study catchment area. all patients with confirmed blood stream infection (bsi) and evidence of sepsis have been prospectively registered continuously since . the severity of sepsis, observation frequency of vital signs, treatment data, los and mortality were retrospectively registered from the patients' medical journals until end . results: the pre-intervention group was patients with confirmed bsi from jan to dec (n = ) whilst the postinterventions group was recruited between nov to dec (n = ). the nurses' observation frequency of vital signs increased in bsi patients with and without severe organ failure comparing these periods. the post-intervention group had, in average, . days shorter los. patients admitted without severe organ failure in the post-intervention group had a lower probability of developing severe organ failure ( . , % ci . - . ) than the pre-intervention group. adjusted for differences in disease severity the post-intervention group also had higher odds of surviving days (or . , % ci . - . ). conclusion: a sepsis specific triage-, flow chart alert and treatment system was an effective tool to increase ward nurses recognition and early treatment of patients with confirmed bsi. in addition to increased survival, the shorter los is important from a hospital perspective in term of resource utilization. this study was supported by the liaison committee between nord-trøndelag hospital trust and nord university introduction: the endotoxin activity assay (eaa™; spectral diagnostics inc., toronto, canada) is a rapid in vitro diagnostic test of the neutrophil's reaction to endotoxin and reflects the endotoxemia ) . recently, eaa is used to confirm endotoxemia such as in the euphrates (evaluating the use of polymyxin b hemoperfusion in a randomized controlled trial of adults treated for endotoxemia and septic shock) trial study in north america ) . however, eaa has not been routinely used to diagnose sepsis, yet. objectives: our hypothesis is eaa is useful to diagnosis for new definition's sepsis due to gram-negative infection. methods: the present study is a single-center retrospective observational analysis. of all adult patients in whom eaa was measured at our medico-surgical icu from july to july , patients with new definition's sepsis in were included in this study. new definition's sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection which is identified with total sofa score of or greater ) . patients were divided into two groups, ) with gram-negative organisms in some cultures and ) with no gram-negative organisms in any cultures. age, sex, body temperature (bt), wbc, crp, procalcitonin (pct), sofa score, and eaa values were compared between two groups. values are expressed as mean ± sd. data was analysed by chi-square test and unpaired students t-test. p values less than . were considered significant. results: five hundred and twenty seven patients ( men and women; mean age . ± . years) were studied. there were ) patients with gram-negative infection and ) patients with no gram-negative infection. eaa values and sofa score were statistically significant differences between gram-negative infection and no gram-negative infection ( . ± . vs. . ± . , p = . , . ± . vs. . ± . , p < . , respectively). pct was different but did not reach to statistically differences between two groups ( . ± . vs. . ± . , p = . ) and age, sex, bt, wbc were no significant differences between two groups. patients and methods: mechanically ventilated patients with severe sepsis/septic shock, treated in icu, were included in this prospective observational study. exclusion criteria were mechanical ventilation for more than hours prior icu admission and brain death. clinical and laboratory data were recorded, on a daily basis. thrombocytopenia was defined as a plt below x /μl. thrombocytopenia was considered as mild ( x /μl ≤ plt < x /μl), moderate ( x /μl ≤ plt < x /μl), or severe (plt < x /μl) depending on plt counts. serum levels of ifnγ, il- , icam, vcam, and soluble urokinase plasminogen activation receptor (supar) were estimated by using luminex xmap technology. results: fifty-six out of ( %) patients enrolled in the study were thrombocytopenic at the time of admission in icu. the overall incidence of thrombocytopenia during icu hospitalization was %, while mild, moderate, and severe thrombocytopenia developed in ( %), ( %), and in ( %) respectively. patients with severe thrombocytopenia had higher apache score, higher serum icam, il- and supar levels, higher incidence of bacteremia and higher probability to present with septic shock as compared with patients with normal platelet counts. moreover, severe thrombocytopenia was associated with statistically significantly higher hospital mortality. patients with severe thrombocytopenia showed significant higher serum icam (p < . ), il- (p = . ), and supar (p < . ) levels respectively, as compared to patients with normal platelets count, or patients with mild or moderate thrombocytopenia. in multivariate analysis, higher apa-che score, thrombocytopenia, and higher serum supar levels were statistically significantly associated with a higher risk of icu mortality. enrolled patients were stratified in different groups according to their apache ii score (apache ii > ), plt counts (plt ≤ . ) and serum supar levels (supar > . ). in multivariate analysis, this new scoring system remained the only and most significant factor associated with statistically significantly increased icu mortality [or = . , ( % ci, . to . ), p < . ]. conclusion: severity of thrombocytopenia in severe sepsis and septic shock parallels the severity of inflammation and subsequent endothelial dysfunction and is associated with higher mortality. the and il- α, were measured and compared between immediately before the first pmx-dhp therapy, before the second pmx-dhp therapy and after pmx-dhp therapy. human cytokine elisa plate array i (chemiluminescence) are used the plate which of cytokine capture antibodies are coated on wells respectively. each cytokine value is shown as relative light units of luminescence. values were expressed as mean ± sd. data were analyzed by wilcoxon signed-ranks test. a p < . was considered as statistically significant. results: all results were provided in about hours after starting this assay. one measurement of all cytokines costed $ . . tnf-α and mcp- values were significantly decreased between immediately before and after the second pmx-dhp therapy ( . ± . vs. . ± . , . ± . vs. . ± . , p < . , respectively). il- , il- and mcp- were also significantly decreased between before the second and after pmx-dhp therapy ( . ± . vs. . ± . , . ± . vs. . ± . , . ± . vs. . ± . , p < . , respectively). there were no statistically significant differences between before and after pmx-dhp therapies in other cytokines. the present study has some limitations because of a retrospective analysis and numbers of patients. however, human cytokine elisa plate array i is a fast and low-cost assay compared with the previous elisa method. and several cytokines are evaluated with one sample at the same time. this assay could be useful especially for the clinical research because small volumes of sample allow to several cytokines' information at the bedside. introduction: critical illness-acquired myopathy in rats is characterized by homogeneous muscle atrophy ( ). conversely, histological abnormalities are heterogeneous: oxidative muscles show patchy alterations (myofascitis, necrosis), while glycolytic types demonstrate normal patterns. akt and mtor are key proteins of the anabolic pathway, leading to myocyte growth when activated. conversely, ampk and foxo are key proteins of the catabolic pathway, leading to myocyte atrophy when activated. whether anabolic or catabolic pathway activation is dependent on skeletal muscle type (i.e. oxidative and glycolytic) during critical illness is unknown. objectives: to characterize activation of the anabolic and catabolic signalling pathways in a long-term rat peritonitis model by skeletal muscle type. methods: male wistar rats were followed for up to weeks after intraperitoneal injection of the yeast cell wall constituent, zymosan or n-saline. soleus (oxidative, slow twitch muscle), and gastrocnemius (mixed glycolytic-oxidative, fast twitch muscle) were harvested from both zymosan and control groups at , and days after the insult. expression of phospho-(p-) and total proteins were assessed by western blots. expression of akt, p-akt (p-threonine , active form), mtor, p-mtor (p-serine , active form), ampk, p-ampk (pthreonine , active form), foxo , and p-foxo (p-threonine , inactive form) were assessed at all time points. results: weight loss was not statistically different in soleus versus gastrocnemius in the zymosan group (− ± % versus − ± %, p = . ) at day . gastrocnemius displayed a decrease in p-akt at day , and an increase of p-akt and p-foxo at day . soleus displayed an increase of p-akt, p-ampk, and p-foxo at day , and an increase of p-ampk, and p-foxo at day . results are detailed in the table . conclusions: in a rodent model of long-term peritonitis, both oxidative and glycolytic muscles display little change in the anabolic signalling pathway. ampk (an autophagy activator) is activated while foxo , (an autophagy and ubiquitin-proteasome system activator) is inhibited up until day in oxidative but not glycolytic muscle. introduction: esophageal pressure (p es ) guided setting of peep has been described in ards patients either to avoid expiratory alveolar collapse or to promote maximum inspiratory recruitment . the proportion of ards patients that may benefit from maximum recruitment strategy and its effects regarding dead space (v d /v t ), shunt, driving pressure (dp), transpulmonary driving pressure (tpdp) and expiratory transpulmonary pressure (tpp exp ) remain unclear. methods: we included moderate and severe ards patients under mechanical ventilation and paralyzed, in the first hours after reaching ards criteria. patients were monitored with esophageal balloon catheter and ventilated with express study settings for hour after recruitment maneuver. then peep was modified to obtain an inspiratory transpulmonary pressure (tpp insp-p ) based on p es between and cmh higher peep in group b led to higher plateau pressure and tpp insp-p , positivation of tpp exp without increase in v d /v t (p = . ), shunt (p = . ), dp (p = . ), tpdp (p = . ) or oxygen stretch index (p = ). however agreement between tpp insp-p and tpp insp calculated from respiratory motion equation and chest wall elastance (tpp insp-e ) was weak with band-altman bias (tpp insp-e -tpp insp-p ) = . ± . [ %ci − ; ]. conclusions: p es measurement in moderate to severe ards patients distinguishes groups of patients in whom peep appears to be taylorized without side-effects. however physiologic studies should assess reliability of transpulmonary measurement based on either p es or chest wall elastance. introduction: to optimize mechanical ventilation different targets are used including tidal volume (tv), peak and mean airway pressure and peep. however, prevention of alveolar collapse not only depends on intra-pulmonary, but also on the extra-pulmonary pressure (epp). epp can be estimated by measuring esophageal pressure (ep). ventilator strategies aiming at optimized trans-pulmonary pressure tpp (difference between intra-and extrapulmonary pressure: tpp = tip-tep) have been shown to improve outcome. tpp-guided ventilator setting might be useful in patients with liver cirrhosis and ascites. however, the impact of paracentesis on tpp is poorly investigated. objectives: to investigate the impact of high volume paracentesis (hvp; ≥ ml) on tpp and on other parameters of pulmonary and circulatory function. methods: analysis of hvp-procedures in patients ventilated with the avea viasys ventilator (carefusion, usa) capable to measure ep via an esophageal tube. haemodynamic monitoring with the picco- -device (pulsion medical systems se, feldkirchen, germany) was available during measurements. intra-abdominal pressure iap was determined by intra-peritoneal (iap_p) and intra-vesical (iap_v) pressure measurement. high grade esophageal varices had been excluded endoscopically before measurement of ep. statistics: spss . results: male, female patients, aetiology of cirrhosis alcoholic (n = ), viral ( ) and cryptogenic ( ) . age ± years, apache-ii ± , sofa ± , meld ± . paracentesis of ± ml resulted in marked increases in inspiratory ( . ± . vs. . ± . ; p < . ) and expiratory (− . ± . vs. - . ± . cmh o; p < . ) tpp. in parallel inspiratory ( . ± . vs. . ± . cmh o; p < . ) and expiratory ( . ± . vs. . x ± . cmh o; p < . ) ep significantly decreased. paracentesis resulted in decreases in iap_p ( . ± . vs. . ± . mmhg; p < . ), iap_v conclusions: paracentesis markedly increases inspiratory and expiratory tpp in parallel with a decrease in iap. increased iap before paracentesis resulted in markedly decreased inspiratory and endexpiratory tpp despite ventilation according to the ardsnet guidelines. to avoid decreased end-expiratory tpp and alveolar collapse in patients with increased iap, paracenteses and/or higher peep-setting should be used. iap and its changes markedly confound cvp, but neither gedvi nor ci. introduction: if the proportional assist ventilation(pav) level is known, then muscular effort can be estimated from the difference between peak airway pressure and peep (△p) during pav. namely, p mus, peak, aw = (p aw, peak -peep) x ( -gain)/gain. pressure time product estimated from airway (ptp aw ) = p mus, peak, aw x inspiratory time/ x respiratory rate [ ] . objectives: validation of this hypothesis by using the esophageal pressure time product calculation. methods: eleven mechanically ventilated patients who received esophageal pressure monitoring under pav were enrolled. patients were randomly assigned to seven pav assist levels ( - %, pav means % pav gain) for minutes. maximal muscular pressure (p mus, peak, es and p mus, peak, aw ) and pressure time product (ptp es and ptp aw ) estimated from △p and esophageal pressure were determined from the last minute of each pav level. results: pav significantly reduced the breathing efforts of patients with increasing pav gain (ptp es . ± . at pav vs. . ± . cmh o•sec/min at pav , ptp es, peepi . ± . at pav vs. . ± . cmh o•sec/min at pav , p < . ). p mus, peak, aw overestimate p mus, peak, es in pav of low gain (pav ) and underestimate in pav of moderate to high gain (from pav to pav ). linear regression analysis revealed that the slope ptp es, br (ptp es per breath)/p mus, peak,es for ptp es, peepi is . (r = . ), for ptp es is . (r = . ), and ptp aw, br (ptp aw per breath)/p mus, peak, aw for ptp aw is . (r = . ). conclusions: adjustments should be made when extrapolating ptp aw into ptp es . an additional % should be added when extrapolating ptp es from p mus, peak, aw and an additional % should be added when extrapolating ptp es, peepi from p mus, peak, aw , assuming p mus, peak, es and p mus, peak, aw are equal. introduction: airway occlusion pressure is a noninvasive measure of motor neural output. if the airway is occluded, the change in pressure in the pleural space and at the airway open, both are equivalent objectives: we studied the similarity of effort and work of breathing measure with pesophageal (peso) at regular cycles, versus inadvertent airway pressure (paw) occluded during end-expiration (paw_occl). methods: esophageal, airway pressure and airway flow, sampling hz, were registered in patients during weaning time, with levels of sedation ramsay , at pressure support ventilation (psv) with differents levels of assistance (high: - cmh o, medium: - cmh o, low: - cmh o). respiratory effort was quantified using pressure-time product (ptp/min) with esophageal and occluded cycle (figure ), and wob_occlusion, using the occlusion pressure with the flow of preceding, not occluded, cycles ( figure ). the work of breathing esophageal referent (wob_peso, j/l)) is obtained from integral of peso versus differential of volume. also we are calculated Δ peso and Δ paw_occl as additional parameter. for all data, the bland-altman analysis and linear regression was applied. the results are expressed as mean ± sd, the comparison was made by t-test. results: a total of paired measures were obtained. the mean comparison of the respiratory effort and work did not show showed statistical differences for all data, except for low assistance (table ) . a good correlation between both measures methods was observed for ptp and wob (r = , and , ; respectively). the mean bias was for ptp and wob: , (± , ) cmh o*sec/min and , (± , ) j/l, respectively; and the % limits of agreement were − , to , cmh o*sec/min and − , to , j/l, respectively; this indicates wide dispersion. conclusions: airway occlusion pressure is a noninvasive procedure that could be useful to assess the effort and work of breathing patients during mechanical ventilation. introduction: chest wall elastance (ecw) is thought to increase in prone (p) as compared to supine (s) position in ards patients ( ) ( ) ( ) . this makes respiratory system elastance (ers) not reflecting lung elastance (e l) . little is known about the changes of ecw, e l and lung resistance (r l ) when moving the patient from the supine to the prone position via the lateral (l) position ( ) ( ) . objectives: the goal of present study was to measure ecw, e l and r l in ards patients in s, l and p position during the proning procedure. methods: ards patients intubated, sedated and paralyzed with an indication of p positioning were included. mechanical ventilation was delivered in volume controlled mode with constant flow inflation. end-inspiratory pause of . sec was set during the breathing cycles. ventilator settings were unaltered during the procedure. airway and esophageal pressures and airflow were continuously measured during minutes in s, then during minute in l and minutes in p. the side for the lateralization was that selected by routine practice (in the opposite side from central venous line). prone positioning was performed manually by caregivers. ecw, e l and r l were obtained by fitting the first order equation model to flow and pressures signals. values are expressed as mean ± sd. results: fifteen patients ( males) of ± years, saps ± and sofa ± were included ± days after ards criteria ( moderate and severe) were met. tidal volume averaged ± . ml/kg predicted body weight, peep ± cmh o, fio ± %, pao /fio ratio ± mmhg. the cause of ards was pneumonia in cases, undetermined in cases. side positioning was the right in and the left in patients. the results are shown in the table . conclusions: during prone positioning in ards patients, as compared to s we observed an increased r l and e l in l and increased ecw in p. introduction: driving pressure of respiratory system (Δp) is defined as the difference between plateau pressure (pplat) and total positive end-expiratory pressure (peeptot) measured after endinspiratory and end-expiratory occlusion, respectively, on airway pressure signal. Δp has recently been shown as a strong predictor of mortality in patients with acute respiratory distress syndrome (ards) ( ) . most of the studies involved in this demonstration measured pplat . sec after onset of endinspiratory pause according to the arma trial ( ) and used peep set on the ventilator (peepvent) instead of the peeptot. this does not take into account slow decay of airway pressure after endinspiratory occlusion and instrinsic peep, respectively. objectives: the aim of the study was to compare Δp when pplat was measured at different times after end-inspiratory pause and whether peeptot or peepvent were used. our hypothesis was that Δp was *p < . versus supine **p < . versus supine higher with pplat measured at . and peepvent than with any other combinations of pplat and peeptot. methods: a retrospective analysis of patients with ards in whom respiratory mechanics was measured. most of the patients had recordings at two levels of peepvent. data were analyzed with acqknowledge software. pplat was measured at . , and seconds after end-inspiratory pause. peeptot was measured after a -sec end-expiratory pause. the low-peep and high-peep measures pertained to peepvent ≤ cmh and peepvent > cmh , respectively. the primary outcome was the comparison of Δp calculated as pplat . sec -peepvent : Δp reference versus Δp computed as pplat sec -peeptot: Δp physiologic . the values are expressed as mean ± sd and are compared by using signed rank test for paired values, anova for repeated measures and bland-altman. results: twenty-three patients were analyzed. Δp reference was significatively higher than Δp physiologic in low and high peep groups: . (± . ) vs . (± . ) cmh o (p < − ) and . (± . introduction: end expiratory lung volume (eelv) is reduced in ventilated patients especially in patients with acute respiratory failure (arf). recruitment maneuvers and different levels of peep are used to restore eelv and to improve oxygenation. however; no matter how useful is the value of eelv in clinical practice his bedside measurement at baseline, at different levels of peep and after recruitment maneuvers is cumbersome. we measured the eelv with two techniques and we noted the technical problems and pitfalls. methods: we measure the eelv in patients with arf at two levels of peep ( and cm h o) with two techniques. with a dilutional nitrogen wash in and wash out method using the carescape r ventilator (ge) and by measuring the expired lung volume after a sudden release of peep to zero peep (zeep). specifically after min of stabilization at each level of peep we performed an expiratory hold and we decrease the ventilator frequency to zero to obtain sufficient time for a complete expiration. therefore, by releasing the expiratory hold we permit the return of the lung to his passive lung volume at zeep(passive frc).the expired volume was calculated by the integration of the expiratory flow. we call this volume Δeelv. correlation and agreement fig. (abstract a ) . variation of driving presure at low peep between the two methods with the bland and altmann analysis were performed. results: mechanically ventilated patients were studied. at zeep eelv was low ( ml) % of the predicted. good correlation was found between the two methods ( ± and ± ml respectively) when eelv was measured at cmh o of peep(r = o. , p < . ). on the contrary at cmh o of peep a wider variability and less agreement was noticed between the eelv values( ± vs. ± , r = . , p < . ). technical problems with carescape were spontaneous breathing attempts or asynchrony in the patient-ventilator interactions leading to instable vo -vco measurements. on the contrary with the release of peep method high expired volumes from peep to zeep induced high expired flow exceeding the lit/sec, thus affecting the linear sensitivity of the ventilator's pneumotachograph. conclusions: the measurement of the eelv remains a precious parameter for the ventilatory management of the icu patients but his measurement is still far away to be accurate by both techniques at bedside. low end-expiratory trans-pulmonary pressure is associated with lung collapse p. somhorst, d. introduction: the open lung concept aims to reduce lung injury due to cyclic opening and closing of alveoli. finding the 'optimal' peep to maintain an open lung proofs difficult and patient-specific. we hypothesize that targeting positive trans-pulmonary pressure (ptp) at end of expiration (ptpee) may prevent collapse. we used electrical impedance tomography (eit) clinically to optimize peep, visualizing over-distention and collapse. objectives: to show the association between collapse and low ptpee, as visualized by eit. methods: we retrospectively analyzed data of ten patients with acute respiratory distress syndrome (ards) who underwent measurement of the ptp and eit due to clinical considerations. a peep trial was performed to identify optimal ventilator settings. esophageal pressure (pes) was measured using endo-esophageal pressure balloons (cooper surgical, germany, or sidam, italy). the ptp was calculated as the continuous difference between the airway pressure and pes. eit was measured at the th/ th intercostal space (dräger, germany) and analyzed using specialized software (dräger, germany). collapse is defined as a local decrease in ventilation after a reduction in peep; over-distention is a local decrease in ventilation after an increase in peep. results: collapse was associated with a lower ptpee at lower peep levels. for most patients ( / ), collapse occurred when ptpee was ≤ cmh o. collapse was also present at a peep level of cmh o. inversely, we showed that collapse and over-distention can occur simultaneously (fig. ) . the ptpee was strongly correlated to the peep level (r = . , p < . ; corrected for each individual patient). the overall regression is shown as a dashed line. conclusions: for most ards patients, collapse did not occur when ptpee was above + cmh o. in addition, peep increase in order to prevent collapse may induce over-distention due to heterogeneity in the ventilation distribution in each patient. introduction: medical experts recommend keeping plateau pressure below cm h o to avoid ventilator-induced lung injury in patients with acute respiratory distress syndrome (ards). transpulmonary pressure (ptp), the difference between alveolar and pleural pressure, has been measured as a surrogate for plateau pressure for lung protective strategies. however, placement of an esophageal balloon catheter is required to measure esophageal pressure. objectives: we investigated the relationship between ptp and ventilator waveform parameters according to the strength of spontaneous breathing effort. methods: eight patients (four patients with ards and four with non-ards) mechanically ventilated with avea® were included in this study. an esophageal balloon catheter (avea® smartcath® esophageal balloon) was placed to measure esophageal pressure. we evaluated the relationship between Δptp (difference between inspiratory and end expiratory ptp) and peak inspiratory flow, or ti ratio (percentage of time until peak negative esophageal pressure to total inspiratory time). spontaneous breathing effort was categorized as strong or weak and was analyzed with inspiratory waveform using voxr data management software. results: although there was no significant relationship between Δptp and peak inspiratory flow (r = . , p = . ), a significant correlation was found between Δptp and ti ratio (r = . , p = . ). median Δptp and ti ratio were significantly higher in patients with strong spontaneous breathing effort compared with those with weak breathing effort ( . vs. . cmh o, p = . , and . vs. . , p = . , respectively). in patients with strong spontaneous breathing effort, median Δptp was higher in the ards group compared with the non-ards group ( . vs. . cmh o, p = . ). conclusions: measuring ti ratio and ventilator waveform parameters may be helpful to estimate ptp. appropriate sedatives, analgesics, or muscle relaxants may be required to limit ptp in cases of higher ti ratio in patients with ards. in vivo calibration of the esophageal balloon catheter: a simplified procedure f. introduction: a calibration procedure has been recently proposed to obtain reliable esophageal pressure (pes) measurements in mechanically ventilated patients [ ] . this procedure helps optimizing esophageal balloon filling and removing esophageal artifacts, but is timeconsuming. objectives: to test accuracy of a simplified procedure, designed according to average values of esophageal elastance (ees) and minimum appropriate filling volume (vmin) previously observed [ ] . methods: in patients under pressure controlled ventilation, pairs of end-expiratory and end-inspiratory calibrated pes values (pes,cal) were obtained with the standard procedure, consisting in measure of ees and detection of vmin and vbest (filling volume associated with the largest tidal swings of pes): pes,cal = pes -ees * (vbest -vmin). "simplified" calibrated pes values (s-pes,cal) were also obtained with a simplified procedure based on detection of vbest and on the assumptions that ees = cmh o/ml and vmin = ml: s-pes,cal = pes -(vbest - ). we used the nutrivent catheter (sidam, italy), equipped with an esophageal balloon that is cm long and has a ml nominal volume. results: in the conditions tested, vmin was . ± . ml, vbest . ± . ml and ees . ± . cmh o/ml. at optimal filling volume (vbest), difference between pes and pes,cal was . ± . cmh o (range . - . ). s-pes,cal strictly correlated with pes,cal (r = . ; p < . ); difference between s-pes,cal and pes,cal was − . ± . cmh o (figure ) . conclusions: when optimal filling of the esophageal balloon is adopted in mechanically ventilated patients, absolute values of pes are affected by significant esophageal artifact. a simplified calibration procedure seems to be adequately accurate in removing this artifact and suitable for clinical use. introduction: mechanical ventilation unloads the inspiratory muscles in case of high work of breathing to prevent development of muscle injury and patient discomfort. on the other hand, over-assist is associated with disuse atrophy and patient-ventilator asynchrony. two indices for assessing respiratory muscle effort have recently been published. patient-ventilator breath contribution (pvbc) index provides an estimation for the percentage of the total work of breathing performed by the patient related to the total work of breathing (patient + ventilator). neuromuscular efficiency (nme) or pressureelectrical activity index (pei) expresses how much pressure the inspiratory muscles generate (pmus) for each microvolt of diaphragm electrical activity (eadi). objectives: the aim of the current study was to assess the repeatability of both pvbc and nme and investigate how these indices changes in time in ventilated icu patients. methods: we included mechanically ventilated adult icu patients with a dedicated naso-gastric feeding tube for assessing diaphragmatic emg activity (eadi catheter). pvbc and nme were calculated at inclusion, after , and hrs and repeated times each with a -minute interval. pvbc was calculated by (tidal volume no assist/ eadi no assist)/(tidal volume assist/edi assist). nme was calculated by measuring change in airway pressure divided by amplitude of the electrical activity during end expiratory occlusion (delta paw/edi). results: the repeatability coefficient (rc) of pvbc and nme was % and . cm h o/uv respectively. median pvbc at t = was % and decreased until % at t = . in the same period, the mean nava level decreased ( . until . ) and mean eadi peak increased ( . until . uv). five patients had a pvbc index > %; four of them had a calculated pressure support (mean eadi peak x nava level) < cmh o. the median nme was . conclusions: we showed a repeatability of % for pvbc and . cmh o/uv for nme. this means that the absolute difference between two repeated measurements lies between this value with a probability of %. for example, with a calculated pvbc of % it is expected that % of the subsequent measurements will be between - %. nme was much more heterogeneous which indicates that neuromechanical coupling changes during icu stay in an unpredictable manner. pressure developed by the diaphragm in our patients appears within physiological limits. use of sigmoid regression for determining the optimal balloon volume in esophageal pressure monitoring: a bench and clinical feasibility study introduction: esophageal pressure (p es ), which has been used as a substitute for pleural pressure, is commonly measured by catheter with air-filled balloon. the accuracy of measurement depends on the proper balloon volume (v b ). assessment of optimal v b is difficult in clinical settings because the surrounding pressure of the balloon cannot be directly measured. in the present study, we introduced a sigmoid fitting method for determining the optimal v b . objectives: to assess the accuracy of optimal v b measured by sigmoid fitting and to evaluate the feasibility of this method in clinical practice. methods: six randomly selected esophageal balloon catheters (cooper catheter, cooper surgical, usa) were tested in a bench model with the lung and the pleural cavity during simulated mechanical ventilation. the balloon was progressively inflated in . ml increments from to . ml, and pressure in the balloon pressure (p b ) and in the pleural cavity (p c ) were measured. balloon transmural pressure (p tm ) was calculated as p b -p c . balloon pressure-volume was fitted by a sigmoid regression: v b = a/[ + e -(p-b)/c ], where a = the vertical distance of the upper asymptote, b = the pressure at the midpoint between zero and a, and c = the pressure range with the greatest volume change ( figure a shows a sample curve). the optimal v b was predicted by zero p tm and zero (p b -b). bland-altman´s analysis was used to assess the accuracy of the optimal v b predicted by p tm and p b . the balloon catheter was introduced into lower third of esophagus in patients with mechanical ventilation, and the balloon was inflated as the same sequence as that in the bench study. p es and v b were also fitted by the sigmoid regression ( figure b shows a sample curve) and the optimal v b was predicted by zero (p es -b). at each v b , dynamic occlusion test was performed, and ratio of changes in p es and airway pressure (Δp es /Δp aw ) was calculated. results: in the bench study, the best-fit coefficient r of sigmoid regression ranged from . to > . with a median (interquartile range, iqr) of . ( . , . ). the natural logarithmically transformed bias (and lower to upper limit of agreement) in optimal v b predicted by p tm and p b was − . (− . to . ). in the clinical study, v b tests were performed. r of sigmoid regression ranged from . to > . with a median (iqr) of . ( . , . ). the optimal v b was . ( . , . ) ml. the b value (r = . , p < . ) and predicted optimal v b (r = . , p = . ) significantly correlated with respective p es measured at the v b with the best Δp es /Δp aw ratio. conclusions: in the determination of balloon pressure-volume response, the performance of nonlinear sigmoid fitting was excellent in introduction: the use of more physiological tidal volumes ( - ml/ kg of ideal body weight) during general anesthesia can minimize the risk of lung injury but may be associated with increased atelectasis. a recent meta-analysis has suggested that high driving pressure and peep level changes that result in an increase of driving pressure are associated with more postoperative pulmonary complications ( ). there is no consensus, however, on how to tailor the level of peep to best suit each patient. objectives: our primary objective is to evaluate the variability of peep titrated by eit in healthy patients submitted to elective abdominal surgery. our secondary objective is to compare the consequences on lung mechanics and on the formation of atelectasis during abdominal surgery in two groups: titrated peep or peep of cmh o. methods: forty patients will be allocated into two groups: laparoscopic (n = ) or open surgery (n = ). after induction of anesthesia and neuromuscular blockade, and before insufflation of abdominal cavity, all patients will be submitted to a recruitment maneuver (rm) in pressure-controlled ventilation mode for two minutes followed by a decremental peep titration starting at peep of and diminished in steps of cmh o. optimal peep is defined as that with the best compromise of atelectasis and overdistention as measured by eit. patients in each subgroup will be randomized to one of two ventilatory strategies during intraoperative period: ( ) peep chosen by the peep titration procedure (titrated peep); ( ) peep set at cm of h o (peep ). a chest ct will be performed one hour after extubation. a density range of − to + hounsfield units (hu) was used to define atelectasis. results: thirty nine patients have been recruited. the median of titrated peep was (iq - ) (table ) . a weak correlation between bmi and titrated peep (r = . ) is shown in figure . lung compliance was significantly lower and driving pressure was significantly higher at baseline, with peep = and before rm, when compared to same measures using titrated peep during peep titration (table ) . during surgery, compliance (p < , ) and driving pressure (p < , ) were also significantly different between peep and titrated-peep group ( figure ). lung collapse evaluated through lung ct after extubation presented less non-aerated lung tissue in patients submitted to mechanical ventilation under eit-titrated peep. conclusions: in this sample of patients, the individualized value of peep titrated by eit had a great variability. peep titrated by eit was able to reduce both lung collapse and driving pressure. introduction: lung protective ventilation strategies could improve clinical outcomes in patients undergoing surgery. these strategies did not include specific goals for oxygenation. there is increasing recognition of potential harmful effect of hyperoxia in critically ill patients. however, little is known about current oxygen management during surgery. objectives: to describe current oxygen administration during general anesthesia in japanese hospitals. methods: a multicenter cross-sectional study was conducted. we screened all consecutive adult patients (≥ years) who received general anesthesia from to september or from to november at the participating hospitals (each participating hospital could choose whichever was more convenient). ventilator settings and the corresponding vital signs were collected hour after the induction of general anesthesia. we investigated the prevalence and risk factors for excess oxygen exposure ( . ± . . ± . . ± . ± . driving pressure with titrated peep (cmh o) . ± . . ± . ± . . ± . fig. (abstract a ) . driving pressure background:. acute kidney injury (aki) is common and is associated with significant morbidity and mortality after liver transplantation (lt). although the creatinine value is highly specific to estimate renal dysfunction, an inadequate sensitivity of creatinine level is demonstrated, particularly in early stage aki. cystatin c is founded to be a stronger predictor of the risk of cardiovascular events and death than creatinine. we aimed to determine whether pretransplant serum levels of cystatin c predict -day major cardiovascular events (mace) and all-cause mortality in lt recipients with normal serum creatinine values. methods: between may and october , consecutive lt recipients (mean age: years; % male; % living-donor lt) who have pretransplant creatinine level < . mg/dl were retrospectively evaluated. the -day mace was a composite of troponin i > . pg/ml, arrhythmias, congestive heart failure, death, cerebrovascular accidents. results: there was a . % -day mace event and . % of lt recipients were dead during a median of . years follow-up. mean values of cystatin c and creatinine were . ± . mg/dl and . ± . mg/dl, respectively. the risk for a -day mace event increased significantly with increasing quartiles of cystatin c; hazard ratios ranged from . to . for the highest versus the lowest quartile (p < . for trend). the kaplan-meier curves showed that the highest quartile (cystatin c > . mg/dl) had a significantly worse survival rate than the lowest quartile (cystatin c < . mg/dl) (logrank p = . ). however, pretransplant creatinine level showed neither increasing mace event rate nor worse survival rate with increasing quartiles of creatinine values (p = . for trends, log-rank p = . , respectively). conclusions: our results demonstrate that pretransplant cystatin c levels were significantly and progressively associated with -day mace and all-cause mortality in lt recipients with normal serum creatinine values, in contrast, the creatinine levels were not significant and gradual predictor of adverse clinical outcomes. were decreased (p < . ), and prevalence of postoperative aki was increased (q : %, q : %, q : %, q : %, respectively, p < . ). odds ratios for aki ranged from . to . for the highest versus the lowest quartile (p < . for trend). on the multivariate logistic analysis, low map was an independent risk factor of the postoperative aki (p < . ), after adjusting factors of age, sex, body mass index, diabetes, hypertension, creatinine, qtc interval, meld score, b-type natriuretic peptide, beta blocker uses, intraoperative red blood cell uses, postreperfusion syndrome, and cyclosporine uses. conclusions: our results demonstrate that pretransplant low map was significantly and progressively associated with the postoperative aki in lt recipients with normal serum creatinine values, therefore, our findings may assist in determining the optimal perioperative management of patients to prevent postoperative aki. introduction: patients undergoing cardiac surgery often develop, in the post operative period, pulmonary impairment and abnormalities gas exchanges ( ) . lung ultrasound (lus) examination may detect main pulmonary abnormalities at the bedside of the patient ( ). to increase bronchial drainage and help lung reaeration, physiotherapy treatment is daily applied starting from the first day after cardiac surgery. objectives: our study was to evaluate if physiotherapy treatment was able to induce changing in lung ultrasound pattern in the postoperative patients. compared total loss of aeration, before and after treatment, we identified a significant increase of rearation after physiotherapy (p = , ) evaluated with wilcoxon test. conclusions: our results confirm an elevate rate of loss of aereation in patients after cardiac surgery. physiotherapy may induce increase of reareation when evaluated with lus even thought it is not able to reduce consolidation. introduction: the therapy of malignant liver diseases has changed over the last years. during this period the frequency of liver resection has increased with great improvement in morbidity, mortality and long-term survival. [ ] thereby, the duration of liver transection and the amount of perioperative blood loss are of great importance for postoperative recovery time and therefore they are measures for choosing the optimal resection method. [ ] furthermore, the release of cytokines, chemokines, and stress hormones correlates with postoperative infection and organ dysfunction [ ] . to minimize cell damage and limit apoptotic cell death the so called heat shock response is initialized by various body cells as countermeasure to increased stress levels [ ] . moreover, pittet et al. showed a positive correlation between the small heat shock protein (hsp ) serum levels and survival after severe trauma. [ ] objectives: measurement of hsp could give an insight about pathological mechanism and their counter regulations of the liver. furthermore the hsp serum level should be correlated with the transection speed of the two resection methods cusa and stabler. . immediately after collection, samples were aliquoted, snap frozen and stored at − °c until further analyzation. to quantify hsp in serum commercially available elisa kits from r&d (duoset ic) have been used according to the manufacturer's protocol. furthermore the duration of transection and the resection surface expressed as cm /s were recorded. results: during surgery a significant increase in hsp levels was detected in patients undergoing stabler hepatectomy or cusa resection (n = , p < . ). during postoperative icu stay, hsp concentrations decline to levels comparable before surgery. the transection speed was significant faster in patients undergoing stapler resection compared to the cusa method (p < . ). the mean length of icu stay after liver resection was in both groups days. conclusions: our data show increased levels in serum of hsp , which might reflect the body's countermeasure to increased systemic stress levels during hepatectomy. moreover the hsp levels are in both groups equal high during surgery even though the resection conducted with the stabler is significant faster than cusa. introduction: performing laparoscopic surgery using carboxipneumoperitoneum usually accompanied with a moderate increase of the concentration of carbon dioxide at the end of expiration, as well as higher peak airway pressure that easily manages to compensate by the correction of ventilation parameters. in the postoperative period marked a fairly long recovery of baseline respiratory function associated not only with the post-operative pain, but with the restriction of the lung as a result of intraabdominal hypertension. objectives: assess the impact of prolonged pneumoperitoneum during laparoscopic surgery on respiratory function and to follow the dynamic of its rehabilitation. the study included patients ( men and women) in the age of . years (min , max ), operated in moscow municipal hospital № . the volume of surgical procedures: gastric resection (n = ), gastrectomy (n = ), pancreatoduodenal resection (n = ), hemicolectomy (n = ), resection of the sigmoid colon (n = ), anterior resection of rectum (n = ). depending on the surgical access patients were divided into two study groups: st -basic -(n = ) group -laparoscopic procedures, nd -control -(n = ) group of traditional laparotomy. all patients were under equal anesthesia during surgery: combined general anesthesia (sevoflurane + fentanil) and epidural infusion of . % ropivacaine solution, as well as myoplegia; postoperative multimodal analgesia: nonsteroidal anti-inflammatory drugs, antispasmodics, epidural analgesia. a study of respiratory function was carried out in four stages: -before surgery, - nd, - th, - th day after surgery. results: in patients of both groups to the second stage of study determined a significant reduction of volume parameters of respiratory function (vc, fvc, fev, fev , mef, mvv etc.). for example vc decreased in patients of group by % against the initial values, and % of patients in group (dynamics presented in the diagram). similarly changes in vc there is a decrease of all volume parameters: fev for the second phase decreased by . % in group and % in group ; mef decreased by . % and . % in the first and second groups, respectively. however, in addition to a statistically smaller decrease in the absolute values of volumetric parameters of respiratory function in the st group, we found them more intense recovery. conclusions: reducing the volume indicators of respiratory function after extensive laparoscopic surgery is less than after similar in volume laparotomy. recovery of acquired restrictive respiratory disorders is more intense and after laparoscopic surgery. at the same time in either group studies we have not observed a complete rehabilitation the initial levels of respiratory parameters, even after days after surgery. introduction: critically ill patients sometimes need laparoscopic surgery. it has been reported that steeped head-down position could increase intracranial pressure during robotic surgery. but we don´t know whether mild trendelenburg position and carbon dioxide pneumoperitoneum cause intracranial hypertension. we conducted a prospective observational study. objectives: the aim of our study was to investigate the change of optic nerve sheath diameter (onsd) in head-down position during carbon dioxide pneumoperitoneum. methods: we included patients scheduled to undergo laparoscopic gynecological surgery. exclusion criteria were ocular disease and central nervous system diseases. onsd were measured mm sagittal behind the globe we assessed onsd after tracheal intubation (t baseline), after pneumoperitoneum and trendelenburg position (t ) and every minutes (t , t , t , t ). anesthetic management were standardized. results: twenty seven patients were enrolled in this study. four patients were excluded from analysis because it was difficult for us to measure onsd. the degree of head-down angle was . ± . . onsd is significantly higher than baseline after pneumoperitoneum and trendelenburg position ( figure ). conclusions: carbon dioxide pneumoperitoneum and trendelenburg position increased intracranial pressure even if the head-down angle was mild. introduction: monitoring the anticoagulant effect of unfractionated heparin (ufh) is mandatory. this monitoring can be done by the mean of the activated partial thromboplastin time (aptt) or by anti-xa levels measurements. compared with anti-xa levels testing, aptt is more frequently impacted by preanalytic variables and biologic factors (increased levels of acute phase reactants, consumption coagulopathy) often encountered among critically ill patients. we studied the agreement of both tests results in unselected critically ill patients. objectives: to study the agreement of both tests results in unselected critically ill patients. methods: aptt and anti-xa levels were simultaneously monitored in patients treated by continuous intravenous infusion of ufh. blood samples were drawn into sodium citrate tubes (greiner bio-one sas, france). aptt was measured with triniclot automated aptt reagent (tcoag, ireland) and anti-xa levels with bio-phen heparin (lrt) (hyphen biomed, france) . an aptt of - times the control and anti-xa levels between . - . iu/ml were defined as therapeutic. results: forty-four patients (mean age . ± . years; mean sap-sii . ± . ) were included. reasons for admission were medical in , surgical in . the indications for ufh therapy were atrial fibrillation ( ), venous thromboembolism/pulmonary embolism ( ), thrombophilia ( ), acute coronary syndrome ( ), arterial thrombosis ( ). paired measurements of aptt and anti-xa were performed on page of samples. linear regression analysis was used to evaluate the relationship between aptt and anti-xa. the correlation between aptt and anti-xa levels was low (r = . ) concordant aptt and anti-xa values were observed in ( . %) data pairs. aptt was discordantly high in ( . %) data pairs and discordantly low in ( . %) ones. considering anti-xa as gold standard, monitoring anticoagulation treatment by aptt leads to a high risk of misdosing. aptt is frequently impacted by biologic factors. although less commonly, anti-xa levels can also be influenced by biological cofounders. poor correlation between aptt and anti-xa could result from lterations in fii and fviii activity. conclusions: use of aptt and anti-xa levels to guide heparin therapy may lead to different estimates of ufh concentration in the same patient. both aptt and anti-xa have limitations when used for ufh monitoring and may not accurately assess anticoagulant status. further investigation (using thromboelastometry or thrombin generation assays) could be useful to determine the optimal anticoagulation testing protocol in critically ill patients. note: this abstract has been previously published and is available at [ ] . it is included here as a complete record of the abstracts from the conference. introduction: the severe capillary leak-induced respiratory and renal failure limit large-volume resuscitation with crystalloids and blood components. the combined use of low volumes of crystalloids and "damage control resuscitation" (dcr), a blood product resuscitation goal of a : : ratio of packed red blood cells (prbc), fresh frozen plasma (ffp) has recently been applied to obstetric patients in hemorrhagic shock. another important consideration is the association of ffp with the risk of transfusion-related acute lung injury (trali), a major cause of death after transfusion. this risk is not present with the use of prothrombin complex concentrate (pcc) as the antibodies responsible for trali are removed during the manufacturing processes. methods: our research involved patients with massive bleeding after cesarean section. patients were divided into groups: st group contained patients as a treatment of massive bleeding with coagulopathy was scheduled pcc in a dose of ml/kg ( iu/kg), packed red blood cells (prbc). nd group ( patients) received fresh frozen plasma (ffp) in a dose of ml/kg and prbc. basic infusiontransfusion therapy was administered according to the protocols of hemorrhagic shock treatment in obstetrics. evaluation of the functional state of the hemostasis system was carried out using lowfrequency pyezoelectric thromboelastography (lpteg) on admission to hospital and every hours after the patient´s admission until normalization of hemostasis state. results: according to lpteg indicators obstetric patients with massive bleeding has a statistically significant abnormality in all parts of hemostatic system: platelet aggregation -intensity of contact coagulation (icc), the coagulation -intensity of coagulation drive (icd), clot maximum density (ma) and fibrinolytic activity -index of retraction and clot lysis (ircl introduction: both anaemia and transfusion of red cells (as defined by who criteria) ( ) have been associated with adverse outcomes, and the potential for anaemia to be a marker of a greater disease burden is frequently raised in discussion. cohort studies of patients aged > years demonstrate that anaemia is associated with increased mortality ( ) . anaemia is also associated with a variety of morbidities in older people, being linked with an increase in hospitalisation, poorer physiological, physical and cognitive function, development of alzheimer´s and parkinson´s diseases, depression, falls and hip fracture rates. we aimed to investigate whether anaemia was associated with adverse outcomes, increased lengths of stay and increased overall mortality in our icu cohort. we also thought it would be interesting to know if there was a difference in haemoglobin level depending on the specialty in which the patients were admitted -hereby defining the physiology of their anaemic process. methods: we conducted a retrospective review of all patients over the age of years that were admitted to the victoria infirmary, glasgow between / / and / / using the wardwatcher national database. we looked at admitting specialty (medicine or surgical), haemoglobin at admission, length of stay and hospital mortality. results: patients were included in the analysis, however full data set was available for patients. the patients were more predominantly male with similar numbers in the medical and surgical groups. medical patients were slightly younger, but with higher physiology scores and mortality. there was no statistical difference between length of stay in intensive care between the two groups. medical patients had a higher admission haemoglobin but this did not trend with outcome or length of stay. (see table ) conclusions: interestingly, and not as expected, it seems that admission haemoglobin to intensive care is not associated with outcome in the elderly population. it is noteworthy that discussion continues in the literature regarding the definition of anaemia in this age group as the population used to generate the who criteria did not include any over ´s. admission haemoglobin levels did not seem to correlate with apache, length of stay or outcome. however, the medical patients with more likely chronic anaemic state had higher apache-ii scores, were younger with higher mortality than the surgical admission who were older, had better outcomes but were more significantly anaemic on admission to intensive care. introduction: because of the substancial morbidity and mortality provoked by massive bleeding, a protocol to guide treatment of this event in each hospital is required. objectives: the aim of this study was to determine whether implementation of the massive transfusion protocol (mtp) was associated with a change in clinical practice or mortality. conclusions: the number of patients is greater in post-mtp group and apache score is lower in the same group since we are warned of these patients at an early stage. there were no differences in clinical practice regarding the administration of blood and hemostatic products.no change in mortality could be documented using the protocol. we have not found any statistically differences probably in part due to the sample size. introduction: discontinuation of life sustaining treatments (lst) is an accepted approach for certain icu patients. there are different ways of limiting lst, and while terminal extubation (te) is one of them, it may lead to dyspnoea and respiratory distress, which can be regarded as morally troublesome. table shows the characteristics of the patients included. conclusions: denial of admission to an intensive care unit due to lst decisions was associated with a high morbidity and mortality. mortality, apache ii and charlson index were significantly lower in the group of patients refused admission to an icu with a non invasive treatment recommendation. introduction: donation after circulatory death (dcd), refers to the procurement of organs from patients whose death is diagnosed and confirmed after circulatory arrest. in the netherlands the timeframe for dcd to proceed is set at two hours. a considerable number of potential donors after circulatory death are lost because they do not die within the specified timeframe after withdrawal of life-supporting treatment (wlst). identification of those dying within hours after wslt results in efficient utilization of the organ procurement teams, hospital resources and above all fulfillment of family expectations. objectives: the aim of this study is to determine factors predicting time to cardiac circulatory death after wslt within hours. methods: in this single-center study we retrospectively evaluated potential and actual dcd iii donors. patients younger than years of age, and clinically brain dead patients in whom relatives requested a dcd procedure, were excluded. univariate logistic regression analyses were performed to establish the effect of different predictors. results: only ( %) converted into actual donor partly due to the fact that cardiac death did not occur within hours. univariate analysis showed an association between the following predicitors and death within introduction: family refusal of organ donation from dbd (donors after brain death) is a limiting factor of the whole donation process and plays an important role in shortage of organs available for transplantation. although croatia is a state with presumed consent when it comes to dbd (donors after brain death) organ donation, family is always informed about the possibility of organ donation after it is verified that the deceased is not registered in the non-donor registry. if the family objects organ donation, their decision is always respected. objectives conclusions: main reason for refusal of organ donation in our hospital is unknown wish or opposition of the deceased person. no family refused donation due to fear of organ trafficking which is an encouraging fact. although refusal rate in our hospital is %, which is higher than croatian average of %, we could not clearly identify contributing factors. we also could not confirm the hypothesis that additional education of transplant coordinators lowers refusal rate. a more detailed prospective evaluation is needed in order to further reduce refusal rate in our hospital. impact of brain injury (bi) and bi with brain death ( the course was aimed to spanish health professionals (nurses and doctors), with a total duration of . hours. it consisted of a small theoretical introduction followed by several workshops, which included: donor after circulatory death management protocol through high fidelity simulator, family interview, preservation and perfusion procedures with extracorporeal membrane oxygenation in animal models. the students sat a pre-course self-assessment -question test to evaluate their knowledge about cdcd. at the end of the course they filled out a survey, offering their opinion on different sections: content, usefulness, documentation and educational support, organization, duration and overall assessment. the score ranged between one, the most negative value, to . average score was analyzed. a survey was sent to students working in different hospitals to evaluate the impact of the course in the cdcd programs at their hospitals. results: students completed the course, their characteristics are in table . students did the pre-course test, with an average score of . points. filled out the survey, results plotted in table . feedback trough the after-course survey was received from students. % of the students worked at hospitals without a cdcd program, established after completing the course. % of these students considered that the course contributed to the development and implementation of cdcd program. all professionals who worked at centers where there was already a cdcd program felt that the course contributed to its improvement. conclusions: despite the fact that there was a high knowledge on the subject among the students, they showed interest and enjoyed the course. the course had a high impact because it helped improving and developing cdcd programs in several hospitals. we believe that this course, based on high-fidelity simulaton training, has been one of the factors that has promoted controlled donation after circulatory death in spain in the last years introduction: the demand for donor lungs thoroughly exceeds the supply.this situation and the application of a strict group of selection criteria, has made donor lung shortage a major problem. to overcome this scarcity, some studies have examined the possibility of using lungs from older donors with mixed results [ ] [ ] [ ] [ ] objective: using as a starting point the favourable clinical evolution of a recipient of a year old lung, we reviewed all of our donors from the last years that were dismissed strictly because advance age (> years) methods: retrospective (feb -jan ) and descriptive study. all donors of a spanish tertiary hospital were analysed. we selected all patients excluded for donation and reviewed their contraindication to serve as lung donors. demographic data and comorbidities, reason for icu admission, icu length of stay, respiratory parameters, days of mechanical ventilation, respiratory cultures and antimicrobial therapy were collected. results: during the period studied we identified potential donors that translated into real donors and only of them ( , %) served as lung donors. after analysing the ( , %) patients that were not considered as lung donors, we identified ( , %) that had been dismissed strictly because advance age. all patients studied were brain death donors. demographic data and comorbidities, reason for icu admission and icu length of stay are detailed on figure .last mean po /fio recorded was , ± (peep , ± , ) and last mean pco recorded was , ± , mmhg. median days of mechanical ventilation were ( - we recorded the main characteristics of the donors, the most important periods in the process and the evolution of liver receptors admitted to the icu. results: patients were admitted. the mean age was , ± , . most were male ( / ). reason for icu admission more frequent: haemorrhagic stroke ( ) . the icu stay until list decision was , ± , days. the cares at the end of life (list) were performed in the first four patients in the uci, and another patients in the operating room, intervening in all of them intensivists who had participated in the previous treatment. the time from extubation to significant hypoperfusion of organs (sbp < mmhg) was minutes, the time to cardiac arrest was , minutes, and to the beginning of the cold perfusión was , minutes. liver transplants were performed without complications in the icu, and the icu stay was days ( , ). the higher alt level was ± , . of the liver transplants are well and with functioning organ today (one died in hospital ward unexpected cardiac arrest). kidneys were obtained from these donors. the maastricht iii donors provide valid organs for transplantation and the intensivists play an important role both in the detection as in the development of care at the end of life. the first transplants had long functional prolonged warm ischemia, which has been reflected in graft function, but the performing of list in operating room, the ultrafast extractions and the presence of the receptor in the hospital are improving the viability of organs, so the results of the last donors are better. thus, maastricht iii donors must be considered today as an additional source of organs for transplantation. ( ), cisatracurium was administered at a constant and high posology without monitoring the depth of neuromuscular blockade. objectives: to assess if the monitoring of the train-of four (tof) and the management of cisatracurium posology by nurses according to an algorithm can ensure an effective neuromuscular paralysis and allow to decrease cisatracurium consumption during ards methods: we conducted a prospective study in medical icus. all the patients with a pao /fio < for more than hours and requiring a continuous perfusion of cisatracurium were included. neuromuscular blockade was monitored by a tof at the adductor pollicis. nurses followed an algorithm of adaptation of cisatracurium posology depending on the tof with an aim of / . the initial posology was based on the maximal doses recommended in anesthesiology and on the patient ideal body weight. this posology was increased and a bolus done each time that the tof was > . the interruption of nmbas was decided by physicians. the initial and final posology and the daily consumption of cisatracurium, the need of performing boli, the results of tof and the occurrence of adverse events such as patient/ventilator asynchrony were noted. effective cisatracurium consumption was compared to the theoretical posology that would have been administered if the patient had been treated according to the acurasys study protocol (i.e. , mg/h). we also evaluated the economic impact of the reduction of cisatracurium consumption. introduction: sepsis-associated acute respiratory failure is frequent, occurs early and is associated with significant mortality. with the increasing use of noninvasive techniques, timing of intubation can vary and may lead to a difference in outcome. objectives: the objectives of this study were ) to draw on practitioners' current practice and perspectives to understand and identify practice variation in intubation and ) to develop an explanatory theoretical model that demonstrates the relationship of various factors contributing to practice variance. methods: between march and july , using a grounded theory approach, we conducted semi-structured interviews with providers involved in intubation and audio recorded them. the interview guide focused on clinicians' perspectives on and practices of intubation in patients with sepsis and impending respiratory failure. results: eighteen interviews were conducted with intensivists, fellows, nurse-practitioners, respiratory therapists and registered nurses. intubation perspective and practice varied dependent on three domains: patient's characteristics, clinician's characteristics, and organizational structure. patient factors included nature of acute illness, underlying comorbidities, clinical presentation, and patient's values. clinician factors included background, training, experience and practice style. system factors included of standardized policies and protocols, hierarchy and team dynamics. although most clinicians agreed that intubation is needed in case of persistent respiratory distress, altered mental status, or shock, they disagreed on when to initiate it. in different contexts, intubation could be considered as preemptive (prophylactic), therapeutic ('just in time'), and as a rescue. assessment, reassessment, and time-limited trial off noninvasive techniques matter. based on these results, we propose a model regarding intubation in sepsis consisting of the steps in the decisional process, a classification of the categories of timing of intubation, and decisional context factors that impact the timing of intubation. conclusions: in patients with sepsis-associated acute respiratory failure, variability of intubation was a natural phenomenon and appeared case-driven. intubation timing should be adjusted based on explicit consideration of each patient situation, their fitness, the cadence and trajectory of their respiratory failure, the team's proficiency in providing noninvasive and invasive ventilator support, and emphasis on clear, frequent closed-loop communication of the treatment plan and rationale within the entire critical care team. ( ) . objectives: to determine the efficacy of rhtm in septic patients with severe respiratory failure. methods: we performed sub-analysis of a retrospective observational study (japan septic disseminated intravascular coagulation study, j-septic dic study), which was conducted in intensive care units in japan. among septic patients enrolled in this original trial, we selected septic patients with severe respiratory failure and compared patients based on rhtm treatment (rhtm group and control group). propensity score analysis was performed between two groups. outcome was the number of ventilator free days. results: patients (rhtm, n = , control, n = ) were analyzed in this trial. after adjusting for baseline imbalances by propensity score analysis, vfds increased significantly in rhtm group (rhtm group: . ± . days vs. control group: . ± . days, p = . ). conclusions: in this analysis, rhtm improved outcomes in septic patients with severe respiratory failure. we need further evaluation. results: during the study period, totally ards patients with pathologic diagnosis of dad were eligible for analysis. these patients were divided as mild (n = , . %), moderate (n = , . %) and severe ards (n = , . %) by berlin definition and the hospital mortality rate were not significantly different between these three groups ( . %, . % and . %, p = . ). according to the etiology, these dad patients were divided into known etiology group (n = , . %) and unknown etiology group (n = , . %), and the hospital mortality rate had no significant difference ( . % vs . %, p = . ). the known etiology group had higher percentage of male and lower pao /fio ratio than unknown etiology group ( . % vs . %, p = . ; . ± . vs . ± . , p = . ). the multivariable logistic regression revealed sequential organ failure assessment (sofa) score at the time of open lung biopsy was the only predictor of hospital mortality (odds ratio . , % confidence interval . - . ; p = . ). in terms of glucocorticoid treatment, there was no significant difference in glucocorticoid use, timing from ards to glucocorticoid use, dose and duration between survival and nonsurvival patients. conclusions: for the ards patients with dad, sofa score was the predictor of hospital mortality but glucocorticoid treatment did not improve the survival rate. introduction: ventilator associated pneumonia (vap) is a known complication of mechanical ventilation. aspiration of oropharyngeal secretions results in infection that leads to significant morbidity, mortality and cost . use of sub-glottic secretion drainage (ssd) devices have been shown to decrease both the incidence of vap and intensive care unit (icu) days , . there have been safety concerns associated with use of ssd devices and herniation of tracheal tissue into the suction port . a study in sheep showed significant tracheal injury associated with continuous suction . human studies have shown conflicting results regarding the risk of tracheal injury , . objectives: to determine the risk of tracheal injury using an ssd device versus a standard endotracheal tube. methods: patients undergoing tracheostomy in the icu were enrolled in the study. patients were intubated in the icu, operating or emergency room, pre-hospital, or referring hospitals. intubation conditions and duration of intubation were documented. at the time of tracheostomy, a bronchoscopy was performed and the presence and degree of tracheal injury were noted. patients were followed to hospital discharge and decannulation, otolaryngology consults, and discharge or death were recorded. results: patients were intubated with a malinckrodt evac ssd device and were intubated with a standard endotracheal tube. patients were found to have a tracheal injury ranging from mild erythema to severe ulceration; / ( %) in the evac group and / ( %) in the standard group (rr - . ; % ci . to . ). / ( %) patients were reported to have injury at the site of the suction port; were reported to have mild edema and erythema and had mild to moderate ulceration. of the patients with tracheal ulceration at the suction catheter port, were decannulated successfully without further complication and patient died prior to termination of mechanical ventilation. conclusions: there was no significant difference in the risk of tracheal injury with ssd devices compared to standard endotracheal tubes. the degree of injury was similar in both groups. a small introduction: vap rates in brazil are higher than those listed in europe and eua.no municipal hospital moyses deutsch since implemented the protocol, applied the five strategies to reduce vap, however we maintained vap density with little reduction and we never zero target . objectives.objective of the study was to examine the effect of healthcare improvement ventilation bundle institute in addition to focusing on three strategies : oral decontamination with chlorhexidine (odc), the head elevation and awakening daily in the incidence of vap in a unit intensive care. methods: the study was conducted in a -bed, medical-surgical icu. criteria for nosocomial pneumonia are those from the cdc. strategy was to implement the ihi's ventilator bundle , focused and optimized in the first three the goals were the icu team adhesion of % achieved in six month after bundle implementation and % after one year of follow up. these measures included five strategies to prevent ventilator-associated pneumonia: - °elevation of the head of the bed, -adequate sedation level (rass − a − ), -oral decontamination with chlorhexidine . %, -dvt/pe prevention and -peptic ulcer prophylaxis . from january on, the icu nursing staff and ict performed a daily checklist in order to observe the five issues accomplishment. if any item was found to be inadequate it was promptly corrected. results: in january and december , adhesion to the whole bundle was % and % respectively. vap density was proportionally lower to bundle adhesion in the same period, per ventilation/day and respectively. in we achieved zero vap in both semesters. conclusions: initial vap rates were extremely high even for brazilian benchmarks. although we could not implement expensive technologies like continuous aspiration of subglottic secretions, icu team and ict efforts were crucial for satisfactory results, as well the administrative board support, which turned this issue an institutional priority. our goals are to reduce even more, implementing ''ventilator bundle-getting to zero'' program, maintaining a continuum effort to sustain these results. introduction: ventilators-associated pneumonia (vap) and its prevention is a significant concern for ventilated patients in the acute care. objectives: to determine if the knowledge and awareness of "ventilator bundle" helped in the prevention of ventilator associated pneumonia in the patients admitted to hospital. methods: a prospective observational study that evaluated vap rates from august through october were evaluated. all the adult medical patients who were intubated and ventilated in medical wards from august through october in the year were included in the study. during the period of june to july the staff nurses were educated and made aware about the problem of vap and the use of ventilator bundle in helping to prevent this vap. patients who expired within hrs of admission, who were transferred to intensive care unit within hrs, and those who were diagnosed with pulmonary embolism or metastasis were excluded from this study. intervention. the concept of "ventilator bundle' was introduced after educating the nursing staff and the medical personnel through group discussions."chula ventilator bundle" is a package of evidence -based interventions that include: ( ) clean equipment and environment; ( ) hand hygiene and elevation of patient's head of bed to - degrees; ( ) use . % chlorhexidine as a part of oral care every hour; ( ) labor over weaning and extubation each day; ( ) aspiration precaution protocol. measurement. demographic data was collected from the patient data files. vap was diagnosed when it met the (clinical non-invasive) diagnostic criteria. incidence of vap and protocol compliant were calculated. results: a total of were on mechanical ventilator for a vary period of - days. average age was . ± . with . % of male. introducing the concept of "chula ventilator bundle to prevent ventilators-associated pneumonia" significantly reduced the vap rate per ventilator days from % to % in the medical group ( medical wards). it significantly reduced the incidence of oral cavity problem ( . ± . vs. . ± . , p = < . ). ventilator bundle compliance was . %. conclusions: however, ventilator bundle compliance was less than %, introducing the concept of "chula ventilator bundle" helped us to reduce the incidence of vap and the incidence of oral cavity problem. grant acknowledgment quality improvement center, king chulalongkorn memorial hospital introduction: patient-ventilator asynchrony is a mismatch between patient and ventilator inspiratory and expiratory time. it is associated with prolonged duration of mechanical ventilation (mv), increased need for tracheostomy and increased mortality. five main patterns of asynchrony are described, without universal agreement on definition. studies on patient ventilator asynchrony have quantified asynchrony at heterogeneous time points and during periods of various durations. in addition, most of these studies were of single centre type. objectives: the aim of the present study was to evaluate the factors associated with and the prognosis impact of asynchrony, according to two methods of quantification: visual inspection of airway flow and pressure signal and a computerized method integrating electromyographic activity of the diaphragm (eadi) as a maker of patient inspiratory time at the early phase of weaning. methods: ancillary study of a multicentre, randomized controlled trial comparing neurally adjusted ventilator assist to pressure support ventilation at early phase of weaning. airway flow, pressure and eadi were recorded during minutes , , and hours following inclusion. asynchrony were quantified according to two methods: ) "flow-and-pressure" based on the visual inspection of the flow and pressure signals ) "eadi-based" with analysis of the eadi signal in addition to the flow and pressure signals. asynchrony index (ai) was calculated as the number of asynchronous breaths divided by the total number breaths multiplied by . results: patients mechanically ventilated for days ( - ) were included, men ( %), aged ( - ) years, saps ii ( - ), % were mechanically ventilated for de novo hypoxemic respiratory failure. prevalence of ineffective efforts was higher with flow-and-pressure method than with eadi-based method. auto-triggering, doubletriggering, premature and late cycling were more frequently observed with eadi-based method than with flow-and-pressure method. ai and the total prevalence of asynchrony were significantly lower with the flow-and-pressure method than with the eadi-based method (table ) . no significant difference in term of gender, age, saps , charlson score or length of mv prior to inclusion was observed with severe asynchrony (ai > %) severe asynchrony was not associated with difference in term of hospital length of stay, duration of mv and day- mortality. icu length of stay determined by the flow-and-pressure method was shorter in patients with ai ≥ % ( ( - ) vs ( - ), p = . ). conclusions: the prevalence of patient ventilator asynchrony varies according the methods and definitions used to quantify asynchrony, which suggests the need for a consensus statement in asynchrony's definition. patient ventilator asynchrony was not associated with a poorer outcome. introduction: tracheostomy is a frequent procedure in intensive care units, in the us over the past decades utilization rose substantially, driven by surgical patients [ ] . the optimal timing for tracheostomy in critically ill patients remains a topic of debate. objectives: to analyse tracheostomy utilization and trends in an intensive care unit (icu) and to determine the impact of tracheostomy timing (early vs late) in critically ill patients on duration of mechanical ventilation, icu stay, overall hospital stay and mortality. methods: retrospective study including all critically ill patients who underwent tracheostomy in an icu from to . the sample was stratified in two groups, according to time of invasive mechanical ventilation until tracheostomy: early tracheostomy (≤ days) and late (> days). results: over the study period a total of tracheostomies were performed, representing , % of the admissions in the icu. tracheostomy was more common in medical patients ( . %). mean time until tracheostomy was days. there was no tendency in tracheostomy rates and timing over the years. early and late tracheostomy groups did not differ significantly by gender, age, sofa score and type of admission. in the early tracheostomy group there was a statistically significant reduction in the length of invasive mechanical ventilation ( days vs days, p < . ) and icu stay ( days vs days, p < . ), with impact in icu and hospital mortality. conclusions: early tracheostomy was associated with reduction in invasive mechanical ventilation days and icu stay, with possible implications in long term morbidity and health care costs. reinforcing that tracheostomy timing should be considered in the decision process, when evaluating risks and benefits. introduction: development of critical care medicine has been decreasing mortality of critical illness. however, - % of survivors suffer functional impairment or icu-acquired weakness (icu-aw). in order to address interventions in icu-aw, it is essential to know when icu-aw developed in addition to its incidence and risk factors. objectives: to assess the onset of icu-aw and its incidence and risk factors in the icu of tokushima university hospital. methods: prospective observational study. critically ill adults were enrolled when they were mechanically ventilated at least days. patients younger than years old, with neuromuscular diseases, central nervous system disorders, and pregnancy were excluded. after we determined feasibility of communication, medical research council (mrc) sum score was measured as soon as possible. when mrc score was less than , we diagnosed patient as icu-aw. basic profiles, underlying diseases, apache ii score, administration of neuromuscular blocking agents (nmba) and corticosteroids, and laboratory data were recorded. introduction: severe traumatic brain injury (stbi) remains as the most significant medical and social problem due to high prevalence and mortality, primarily among young and employable population. the leading problem of intensive care of stbi is the prevention and elimination of intracranial hypertension (ich). one of the methods of ich elimination is mechanical ventilation as a component of complex therapy. among the various methods and modes of mechanical ventilation high-frequency jet ventilation (hfjv) is particularly distinguished, which is enduring "the second birth". in hfv transpulmonary pressure and the pressure in airways is much lower than one during traditional methods, the negative pressure in pleural cavity is maintained during inspiration phase and spontaneous breathing. objectives: comparative assessment of efficacy of different modes of mechanical ventilation in patients with stbi. methods: we studied the cerebral perfusion during various modes of mechanical ventilation in patients with stbi. mean age was ± . the general status in admission was severe, glasgow coma score was ± . all patients had traditional intensive care with different modes of respiratory support: controlled mechanical ventilation -cmv (n = ); synchronized intermittent mandatory ventilation -simv (n = ); hfjv (n = ). the efficacy of all modes were assessed by arterial blood gases analysis (sao - - %, pco - . - . mmhg). intracranial pressure were measured invasively and was ± mmhg. all patients regularly had clinical and neurological examination, control of laboratory tests (common blood count, arterial blood gases, arteriovenous gradient of o (avdo ) and oxygen saturation in jugular vein (sjo ). cerebral hemodynamics was studied by transcranial dopplerography. the registered parameters were mean linear velocity of cerebral blood flow (vm), pulsatile index (pi) and overshoot coefficient (oc). results: there were significant differences in parameters of cerebral hemodynamics in various modes of respiratory support: cmv: vm - . most patients found mobilisation to be a positive experience and the beginning of their recovery. however, mobilization was described as a difficult component of the care, mainly due to pain, tiredness and dizziness. almost all patients commented on the benefits of participation in physiotherapy, which was verified by physical improvements and progression in their abilities. although most improvements discussed were physical, two patients also described the psychological benefits that occurred in the sessions. they reported that the physiotherapists 'built them up' and encouraged them. one patient described a mind shift that occurred once she had mobilised out of the bed. she described it as being able to see what she was capable of. it was described as a precious and muchneeded service, without which some patients felt they may not have survived or recovered as quickly. methods: this retrospective study was performed in a -bed medical icu in spain from to . all patients admitted to the icu during this period were included in the study. cci patients were defined as those with more than days of icu stay. data were collected in ways: review of a prospectively elaborated database, review of electronic records, and telephone survey evaluating the functional status of survivors, one year after their discharge from the icu. results: during the study period, patients ( females − %) were considered cci. the characteristics of these patients are shown in table . all the studied patients needed prolonged mechanical ventilation (median days), defined as > hours/day of ventilator support for > consecutive days. the follow-up period is drawn in figure . the in-icu mortality was %. in the first year, patients ( %) were alive. most patients improved their quality of life over a year, with approximately % of them displaying some help for dressing or to performing the transfer of themselves. symptoms of anxiety and depression improved during the first year, being present in up to % (of the patients), but in % if we refer to the presence of nightmares or hallucinations. % these patients were transferred (discharge) to a rehabilitation center and % needed hospital readmission within the follow-up period. conclusions: for cci patients in-hospital mortality rate is still high after discharge from the icu. however, more than one third of them are alive one year after their hospital stay and in an almost independent condition. efforts focused on early specific therapeutic strategies after icu admission to prevent the progress of the acute disease towards chronic critical illness and to improve the outcome must be explored. [ ] [ ] [ ] [ ] . at icu, . % had delirium, . % needed blood transfusion and . % renal replacement therapy. patients worsened in all parameters of the five dimensions of the eq- d after -days: the extreme problems level increased in the mobility dimension from . % at icu to . %, self-care from . % to . %; usual activities from . % to . %; pain/discomfort from . to . and anxiety/depression from . % to . %. the dependence observed in the katz index worsened in days when . % of patients were dependents before icu admission increasing to . % after days. about family members, . % were spouses and . offspring, their mean of age was . ± . years and . % had previous experience of icu. we observed that they presented more symptoms of anxiety ( %) and depression ( . %) at icu when compared days after ( . %) and ( . %), symptoms of anxiety and depression respectively. conclusions: the most common eligibility conditions of cci were sepsis followed by mechanical ventilation. we observed a great mortality on days and among survivors a worsen quality of life with more dependence in their activities of daily living. we also observed that family members suffered more while in icu stay. introduction: tracheostomy is a favored alternative option for providing prolonged mechanical ventilation and safety airway used for more than years. despite its numerous advantages, tracheostomy may have severe complications as being an invasive method for presenting respiratory tract patency. besides, the tracheostomized patients usually have prolonged icu stay, high mortality and morbidity arise from concomitant comorbidities. objectives: the aim of the study was to evaluate the frequency, patient characteristics, complications and the prognosis related with our percutaneous tracheostomy practice. methods: hospital electronic records and icu files of the patients with percutaneous tracheostomies performed in our bed anesthesiology icu were evaluated between january and december . ethic consent was obtained from local ethic committee. the patients who were discharged with home type mechanical ventilator or their relatives were contacted by phone for getting information about their health status or related complications. (tables and ) . conclusions: the blood serum sodium levels at admission, especially hypernatremia, may also be used as an independent predictor of outcome in the surgical critically ill patients. introduction: who estimates that the worldwide dengue fever incidence is about tens of thousands of cases every year. as taiwan is situated in the high risk subtropical region, dengue fever has virtually become a seasonal infectious disease. climate warming, demographic movement and the higher probability of increase in intermittent rainfall in recent years have added many factors unfavorable to dengue fever prevention. years of prevalence and the emergence of different types have also caused the risk of mortality for dengue fever to become relatively high.of the total , confirmed dengue fever cases in , there were deaths (with a mortality rate of . per thousand), marking the largest outbreak over nearly one decade in taiwan. objectives: analysis was conducted on the confirmed severe cases of dengue fever or dengue hemorrhagic fever reported to this hospital over the period between july and september , in terms of gender, age, history of chronic diseases, warning signs and diagnostic criteria for severe conditions. methods: retrospective case study was also conducted to identify risk factors in dengue fever and dengue hemorrhagic fever as well as predictors of death among dengue fever cases for statistical analysis. results: according to the results, those susceptible to infection concentrated on older people aged over (with an average age of ); in total cases had chronic diseases (with an average rate of . %), among which hypertension and diabetes constituted the majorities; and based on symptoms, fever accounted for . % while gastrointestinal bleeding was the most common at . %. of the cases, there were deaths, with an average apache ii score of . and an average mortality rate of . %. conclusions: this study shows that patients with chronic diseases aged over will have times higher risk of death if infected with dengue hemorrhagic fever. it is therefore suggested that older people aged over and patients with chronic diseases who are infected with dengue hemorrhagic fever must be closely monitored in clinical practice to pinpoint the best time for treatment and effectively reduce mortality rates. to sum up, effective use of knowledge about risk factors and prognostic factors in dengue hemorrhagic fever can help epidemic prevention organizations to focus their limited resources on high risk groups and increase the effectiveness of prevention. cardiorespiratory instability risk escalation patterns: an association study with risk factors and length of stay l. chen (fig. ) . % of them belong to "late onset" types whose risk escalated ≤ minutes before cri onset, but with different initial rr levels (low, medium and high). % of patients belonged to "early onset" type with gradual escalating risk starting about hours before overt cri, and % falling into a "persistently high" type. the mean rr during the first hours of sdu stay are . , . and . for "late onset" types; . for "early onset" type, and . for "persistently high" type, comparing with baseline rr of . for cri negative patients. the mean rr derived in the first -hours after admission is strongly associated with risk escalation patterns observed (p-value < . ), specifically, patients of "persistently high" type were more likely to have higher mean risk levels at sdu admission . risk escalation patterns were not significantly associated with age, cci or sdu los. however, they are significantly associated with hospital los (p = . ). conclusions: there is potential "risk stratification value" of vs collected during initial hours of sdu stay in predicting the cri risk escalation patterns later on, which may in turn predict hospital los. these insights may guide monitoring resource allocation for cri management. - . ] mmol/l and most of patients were on vasopressors therapy. coronary angiography was performed in / ( %) patients with a cardiac cause; continuous renal replacement therapy was initiated in out of the patients ( %) developing acute kidney injury during the icu stay. patients showed a full neurological recovery during the icu stay ( %) but only were still alive with intact neurological function at months ( %); / after ohca ( %) and / ( %) after ihca. eight patients ( %) with irreversible brain damage had organ function suitable for donation and were eventually explanted. conclusions: ecpr provided acceptable survival rate with good neurologic recovery in refractory cardiac arrest. these patients underwent several additional therapeutic interventions, which, in case of irreversible brain damage, could stabilize extra-cerebral organ function and potentially provide some available organs for donation. post-resuscitation treatment with inhaled argon improves outcome even after a prolonged untreated cardiac arrest in a porcine model introduction: after the initial success of cardiopulmonary resuscitation (cpr), the majority of patients die, mainly due to postresuscitation (pr) cardiac failure and ischemic brain damage. inhaled argon has shown neuroprotective effects in a porcine model of cardiac arrest (ca) of short duration. objectives: to investigate the effect of post-resuscitation treatment with inhaled argon on outcome in a preclinical porcine model of prolonged untreated ca and cpr. we hypothesized that argon would ameliorate post-resuscitation neurologic dysfunction. methods: the left anterior descending coronary artery was occluded in pigs ( ± kg), and ventricular fibrillation (vf) was induced. after min of untreated vf, cpr, including mechanical chest compression, ventilation and adrenaline administration, was performed for min prior to defibrillation. following successful resuscitation, animals were subjected to hr ventilation with (a) % argon - % o (n = ) or (b) % n - % o (n = ). hemodynamics were continuously monitored and systolic myocardial function (i.e. ejection fraction (ef), shortening fraction (sf)) was assessed by echocardiography. serial blood samples were obtained for blood gas, serum neuron specific enolase (nse) and plasma high sensitive cardiac troponin t (hs-ctnt) assays. animals were observed up to hr for assessment of survival and neurological recovery (cerebral performance categories (cpc) scale). results: twenty animals were successfully resuscitated and enrolled in the study (table ) . ventilation with argon did not have any detrimental effects on respiratory gas exchange during the hr ventilation (table ) . animals receiving argon showed a significantly lower heart rate and higher mean arterial pressure and stroke volume compared to controls during the hr of observation (table ) . animals treated with argon presented also a significantly better recovery of systolic myocardial function, as represented by the higher sf at hr compared to controls (table ) . nine of the resuscitated animals in the argon group survived for h in comparison to out of in the control group. animals treated with argon presented a significantly better neurological recovery (cpc . ± . ) in contrast to animals in the control group ( . ± . , figure ). lower circulating levels of hs-ctnt (median: ng/ml vs. ng/ml, p < . ) and nse (median . ng/ml vs. . , p not significant) were observed in the animals ventilated with argon compared to controls. conclusions: in this severe model of ca, post-resuscitation treatment with argon allowed for improved hemodynamics, myocardial function and neurologic recovery, without detrimental effects on respiratory gas exchanges. munich, germany, which is staffed with physicians working at a university hospital in the specialities anaesthesia or surgery. ( ) test if there is a difference between specialists and residents in pain treatment of trauma patients. methods: after ethics committee approval, retrospective analysis of the protocols of our prehospital emergency service location in munich, germany of - . statistical calculation was done using logistic regressions with stata (college station, tx, usa). results: documented trauma cases. trauma cases could be assessed for frequency of oligoanalgesia, which was present in of these cases (see figure , dashed frames), leading to an relative frequency of % of cases. there was no difference in frequency between residents and specialists (table ) . relatively more trauma cases where handed by specialists, while documentation of pain was better in residents (table ) . documentation of pain, however, was insufficient, since pain assessment at hospital admission was documented in % of possible cases of oligoanalgesia only. conclusions: frequency of oligoanalgesia in trauma patients seems to vary in different systems, since it was much lower in munich compared to switzerland ( % vs. %, respectively). there are several possible explanations: data from swizerland was from an air resuce service while our data is from a ground based system. second, in our system possibility of treatment by a specialist was much higher ( % residents in switzerland). third, documentation in our system was inadequate. theoretically, frequency of oligoanalgesia could increase up to % if all cases without adequate pain documentation were counted as oligoanalgetic. to assess appropriate numbers improvement in documentation is essential. of the attempted resuscitations were immediately unsuccessful, resulted in rosc ( sent to icu for post-resuscitation care, whilst remained on the ward). at hours (both in icu) were still alive. defibrillation was attempted in cases. intubation was attempted on occasions. in ( %) of the resuscitation attempts cpr was the only intervention reported while ( %) received more than vial of adrenaline, or defibrillation, and or intubation. interviewees reported that in ( %) of these patients they were 'not at all' or only a 'little bit surprised' by the patient having a cardiac arrest (fig ) . they further described the chances of a successful outcome as 'unlikely or very unlikely % of the time and likely or very likely only . % of the time (fig ) . conclusions: perspectives of junior doctors interviewed suggest many cardiac arrests were not a surprise and that the probability of rosc following attempted resuscitation was unlikely. there is high incidence of patients receiving cpr attempts before death in hospitals across sri lanka with dnar practices remaining uncommon. outcomes remain poor, with rosc after cardiac arrest being . % and survival at hrs . %. of the unsuccessful resuscitation attempts, defibrillation and or repeated adrenaline was reported in . % of cases. introduction: pro-coagulatoric effects after cardiac arrest and consecutively appearing microthromboses have been considered major contributors to morbidity and mortality after cpr [ ] . in contrast, recently published data suggest that - % of patients after out-ofhospital cardiac arrest (ohca) present with hyperfibrinolysis during and after cpr [ ; ] . the interpretation of these inconsistent observations remains unclear and complicated, because of methodological differences and lacking analytical approach in the underlying studies. fibrinolytic activation might be the physiological reaction to restore perfusion after hypoperfusion due to microthromboses. this leads to the question, if the duration of no-flow (time without chest compressions) after cardiac arrest influences the level of coagulation activation and subsequent fibrinolysis during cpr. objective: to investigate the influence of a delayed onset of cpr on the extent of fibrinolysis and the function of the coagulation system measured by rotational thrombelastometry (rotem). methods: after approval of the local authorities (nds. laves, approval g - ) cardiac arrest was induced in anaesthetized female göttingen minipigs via rapid ventricular overpacing resulting in ventricular fibrillation (vf). in order to simulate a bls-cpr in animals (cpr-group), chest compressions (cc) and ventilation were started after min of vf ( : -ratio, fio = . ). in order to simulate consecutive als-cpr, continuous cc ( min − ) and ventilations ( min − , fio = . ) were started minutes later. no cpr was started in the remaining pigs (non-cpr-group). blood samples for a complete rotem analysis (rotem delta® analyzer, tem int. gmbh, munich, germany) and laboratory analyses were taken before induction of vf (baseline) and , and min after vf. all parameters were investigated for normal distribution (shapiro-wilks-test). statistical significance of differences (p < . ) was investigated using the unpaired t-test (normal distributed parameters) and the mann-whitney-u-test (notnormal distributed parameters). results: figure summarizes laboratory and rotem results. in no group maximum lysis increased significantly after cardiac arrest ( figure ). maximum clot firmness (mcf) in fibtem analyses decreased significantly in both groups (figure ), but plasma fibrinogen levels (measured using the clauss method) remained stable. introduction: perception and knowledge of hospital staff involved in an emergency evacuation of hospitalized patients is usually low. this is especially remarked in an icu due to the complexity of moving patients who depend on invasive monitoring and organ support due to acute illness. objectives: to analyze the differences between different members of icu staff about their perception and knowledge of self-protection and evacuation plans. methods: a quantitative, descriptive and cross-sectional study was carried out by a fully structured and self-administered survey in public and private icu staff through a total sample of participants. they were asked to complete a questionnaire about their perception and knowledge of self-protection and evacuation plans in the icu. this study pretended to analyze the differences between participants, taking into account their demographic and occupational characteristics and their level of satisfaction and commitment to their jobs. results: on a rating scale from to , icus workers perceive that their preparation and knowledge were too low to meet a possible emergency that could require an evacuation, although they were aware of the need to make an update. however, they state that the different icus where they work do not have these plans, and, consequently, they do not feel prepared to act in an emergency situation, even though they think this type of situation may occur. the significant differences (p < , ) were observed when levels of satisfaction and commitment to their jobs were high. the results of this study showed that there is a need for more knowledge in the area of emergency training. this should be the basis for the development of educational programs and also promoting awareness of icu staff on self-protection and evacuations plans. integrating nurse practitioners and physician assistants in the icu: results of a national survey r. kleinpell rush university medical center, chicago, united states intensive care medicine experimental , (suppl ):a introduction: an increasing number of intensive care units (icus) are integrating advanced practice providers (app) including nurse practitioners (nps) and physician assistants (pas) to meet workforce demands to care for acute and critically ill patients. although these roles are established ones, limited information is known about the specific care models used in icu settings. this information is crucial in objectively evaluating the effectiveness of app roles. objectives: to address this gap, a national survey was conducted targeting nps and pas, including those working in icu settings. methods: a web-based survey was used to assess domains including role components (i.e. direct care management; care coordination; performing procedures; education; quality assurance; research); role responsibilities (i.e. practice autonomy, prescriptive authority, credentialing and privileging delineations) unit-level organization (i.e. physician staffing models, components of the multidisciplinary care team); and hospital organization (i.e. academic status, bed size, location, payer-mix). results: a total of apps responded to the national survey including nps and pas. the respondents reported working in a variety of settings including hospitals, clinics, urgent care centers and specialty practice sites. a total of reported working in an icu setting. of these, reported / coverage of acnps and pas in the icu. main role components included patient care management as part of the multiprofessional icu team; teaching to patients, families and healthcare staff; involvement in quality improvement and research initiatives and administrative components such as committee work. specific aspects include conducting history & physical exams, ordering and interpreting diagnostic test/labs; providing care coordination, performing specialty procedures such as wound care or other specialty care. major areas of impact that were identified included continuity of care, improving evidence based practice care, reducing hospital length of stay, preventing hospital readmissions and promoting patient, family and staff satisfaction. the results of the study provide information from a large national sample of nps and pas that identifies the comprehensive care components of the role as well as areas of impact, highlighting the value of app care. globally, this information can be useful to other countries who are considering use of nps and pas in the icu. national health care resources. with icu beds, the reserves of the system are often overwhelmed. the responsibility for a rational management and distribution of these costly resources burdens the admitting intensivist. intensivists not using protocols expressed a strong desire ( %) to introduce protocol based criteria for admission. conclusions: the most important factors influencing decisions about admission (or refusal of admission) in the icu are bed availability and prognosis of the underlying disease. socioeconomic and religious criteria are clearly of marginal significance. drug abuse and severe psychiatric disease do not emerge as compelling causes of biased decisions. it appears that the intensivist's decisions are largely individualized, as application of admission protocols is limited among the icus. however, the responses documented in this survey strongly indicate that introduction of such protocols would be welcome by a majority of our colleagues. conclusions: it is essential that non-cardiac surgery should be delivered in the most appropriate clinical setting. in scotland, adults with moderate to complex congenital cardiac disease are managed by the scottish adult congenital cardiac service (saccs), based at the golden jubilee national hospital (gjnh), near glasgow. [ ] existing guidelines have established when patients should have elective non-cardiac surgery performed at gjnh. however, many surgical specialties are not routinely available at gjnh, the bed occupancy rate is high and with an increasing saccs population there is a need for appropriate patients to receive optimal care at their base hospital. additionally, urgent and emergency non-cardiac surgery ought to be performed at the base hospital. while nitric oxide is a core cardiac therapy we have shown that it is scarce in scotland and unfamiliar to many icus. there is a need for a national discourse and consensus to ensure that nitric oxide is more widely available as part of a bundle of optimal cardiac critical care. this should include education, material resources, clinical guidelines and perhaps cardiac critical care outreach services to support general icus. introduction: scarcity of intensive care unit (icu) beds has long been a problem. among other things, it increases the work load of emergency department (ed), contributing to its crowding and probably to worst care, jeopardizing outcomes. despite the plausibility of this premise, studies aren't consensual about the impact on outcome of delayed icu admission from ed. hospital de são joão is a portuguese tertiary care center. ed receives around adult admissions per year, and is spatially organized according to manchester triage priorities. emergency room (er) receives patients from the street and all patients from other areas of the ed that need critical care. it is staffed by trained personnel and is equipped with level iii icu material. intensive care department is composed by level iii and level ii icu beds objectives: assess if there's a link between time spent in ed and outcome of patients admitted to level ii and/or iii icu beds. methods: this is a retrospective study analysing older than years old patients admitted to icu from ed from st january to st december . we excluded patients transferred from other hospitals. demographic and clinical data was collected from records. we selected hospital outcome (dead, alive, transferred), hospital length of stay, icu length of stay, vital status at and days after admission and ed and er duration as outcomes. simplified acute physiologic score (saps) ii and sequential organ failure assessment (sofa) were calculated by considering the worst values in the first hours of hospital admission. we performed a descriptive analysis, with median and interquartile ranges presented for continuous variables and proportions for categorical variables. for analysis of subgroups we did a chisquare or mann-whitney test. statistical analyses were done on ibm-spss (version ). a p-value of < , was considered significant. results: adults were assisted in ed in this period, with a median length of stay of minutes. were admitted to icu beds, which accounts for , % of all adults cared for in ed. around % of patients admitted in icu were treated in the er at some point of their ed care. patients admitted to icu stayed around minutes in ed. the more severe the disease, the least time spent (p = , ). patients treated in er were significantly more likely to be admitted quickly in icu (p < , ). taking in consideration the time spent in the ed, we found an opposite relation with global outcome, meaning that patients staying longer periods in ed had lower icu mortality and lower length of stay in icu. there was no association with hospital mortality. conclusions: time spent in ed had no negative impact on outcome. however, given the fact that the majority of patients admitted to icu beds were cared in a devoted area with trained staff and full level iii equipment, we hypothesize that what might impact the most on outcome is provision of early critical care. determination of icu bed requirement using resampling k.k. introduction: planning for icu-bed provision, with a statistical confidence level, required the average number of critically-ill patients, their average icu length of stay (los), and the fluctuation/variance of these two parameters. the actual icu bed occupancy would under-estimates the variance, as icu could never exceed its full capacity. with an under-estimate, the predicted icu bed requirement would be inaccurate, with a tendency of under estimation. objectives: estimate the bed requirement to cover . % of time, by resampling of admission/discharge entries in , for the two busiest icus in hong kong (~ admissions/year each) methods: we assumed that the chance of an icu admission was identical in a period of four weeks before and after a certain date. based on this assumption, a computer simulation of icu admissions was performed as if the year happened again. in brief, we pooled patients admitted on a particular date in , and those admitted on the same day of week in the previous four and subsequent four weeks. then patients were randomly selected from the pool to simulate icu admission on that particular date. a mechanism (not described here) was in place to handle the public holidays. the hourly icu occupancy was calculated using the actual icu los of the selected patient. re-sampling for the whole year was repeated times to provide the estimates required. results: the actual hourly medians of icu occupancy were % and %. they were close to that obtained using resampling ( % and %). as predicted, the distributions of the actual occupancy were skewed to left, indicating a negative bias on the variance estimates. the observed standard deviations of the two icus' occupancy were . % and . % respectively. after resampling, the distributions became more symmetrical, and had higher standard deviations of . % and . % (both p = . ). the . percentile occupancy in reality were % and %, while that from resampling were significantly higher at % and % (both p = . ). this corresponded to three or four additional icu beds in each icu. conclusions: in conclusion, using a simple and conservative assumption, resampling could provide valuable insight for icu bed planning. introduction: the number of available intensive care unit (icu) beds are limited while the request for the beds are high. thus rationing the admission to icu is necessary especially in developing countries where the resources are limited. also models are needed to estimate and re-estimate regularly, shortage in the number of icu beds in any hospital. in the current study we tried to design a model for estimating shortage in the number of intensive care beds in a developing country tertiary university hospital after an initial delphi consensus study. objectives: designing a model for estimating shortage in the number of icu beds in a hospital. methods: initially the standard indications for icu triage were extracted from the literature. four intensivists were served as steering committee and the initial questionnaire were further prioritized by experts with three rounded delphi method and formed a standardized checklist for icu triage. indications were considered as critical, important, and all indications. then a cross-sectional study being performed during a -month period from august to september for all admissions to nemazee hospital, a tertiary healthcare center affiliated to shiraz university of medical sciences. cardiac, transplantation and pediatrics patients were excluded from the study, as to be studied separately. the checklist were filled every day by an observing physician and any indications for icu admission were marked in the questionnaire. decision making for requesting icu admission were performed by the specialized physicians of each ward regardless of the results of completed checklists.the results were further assessed according to the mentioned criteria and the reliability and viability was calculated. finally assuming that there was no available icu bed-days, the required icu bed-days were compared with the total icu bed-days of the hospitals, to estimate the shortage of icu beds. results: totally patients were admitted and studied.the required bed-day regarding critical indications, important indications, and all indications for icu admission was , , and . by comparing the required bed-days with available bed-days of the hospital, beds were calculated as shortage of icu beds. the results of the current study indicate that our center has deficiency in the number of icu beds. it seems that a checklist is not only useful for prioritizing patients but also it is useful for estimating the required number of the icu beds.the actual number of shortage is greater as three group of patients were not included. transfer delay from intensive care unit: retrospective analytical study in an indian tertiary care hospital s. k introduction: there lies scarcity of intensive care unit (icu) beds in every tertiary care hospitals, and on top of it delayed transfer of patients from icu to wards is further increasing the burdensome. numerous factors affect in making delayed transfer, which in itself is a risk factor for patient related morbidity and mortality, especially the after hour transfers. objectives: the aim of the study was to analyze the hours of transfer delay and their effect on readmission rates in the icu. methods: we conducted a retrospective study of patients transfer from our icu to the wards over last one year (jan-dec' ).data collected from the icu database by the secretarial staff during the study period and divided into following categories of transfer delays: results: there were patients admitted to our icu during the study period of which patients were shifted to the wards. the average delay in shifting was around . hours ( - . hrs).delayed transfer of more than hrs was found in % patients and the percentage of after-hours transfer was % of the total transfers. there were readmissions into the icu within hrs of shift out among patients transferred in after hours as against in patients transferred during routine hours. conclusions: prevalence of delayed discharge from icu was significant, especially the after hour discharges, which has got an impact on readmission rate as well. discharge delay should be considered as an important quality indicator for critically ill patients to decrease the morbidity and mortality in icu patients. further studies are warranted to identify factors associated with delayed discharge. introduction: critical illness (ci) and stay in an intensive care unit (icu) are known to induce physical and functional changes. bone is often forgotten in survivors. limited published data reported an altered bone metabolism in case of prolonged icu stay [ ] and a decreased in bone mineral density (bmd) in the year following icu admission [ ] . clinical impact of these changes is still not well described. objectives: our retrospective study aimed to assess incidence of any new bone fractures (bf) two years after a severe ci. methods: patients admitted in our icu during were screened. adults > years (y) old with an icu length of stay (los) > days (d) were included. lost to follow-up were considered exclusion criteria. patients who died in icu or who died during the follow-up period (fup) with an icu los ≤ d were also excluded. demographic data, medical objectives: pulmonary arterial hypertension (pah) is associated with reductions in health-related quality of life (hrql). the patient care still played an important role in improvement of hrql, even though more drug therapy was identified in recent decade.. in this study, we investigated to provide quality care for patients with pulmonary arterial hypertension via multidisciplinary care model. methods: a multidisciplinary team was organized.in a tertiary medical center, including intensivists, cardiologists, pulmonologists, cardiac surgeons, rheumatologists, chest surgeons, rehabilitation physicians, psychologist, pharmacologists, hospice care physicians, nutritionist, social workers and nursing staffs. the key interventions include home based rehabilitation therapy, hours hot line care, pah care nurse training program, hospice care information and consultation, phychological care and autogenic training, prompt pah referral system, social care connections, on-line self pah risk assessment system, on-line and innovative mobile apps patient instructions, facebook patient care group and ourdoor pah patient education program. the pah patients were divided into three groups: pre-interventional group from may to dec , interventional group from jan to june and post-interventional group from july to feb . hrql was measured using the short form health survey (sf- ) in all enrolled subjects. results: the average physical compartment scale of sf- , including physical functioning; role limitations due to physical health, pain and general health improved from ± in pre-interventional group, to ± in interventional group and to ± in post-interventional group (p < . ). the average mental compartment scale of sf- , including role limitations due to emotional problems, energy/fatigue, emotional well-being and social functioning, improved from ± in pre-interventional group, to ± in interventional group and to ± in post-interventional group (p < . ). conclusions: the study demonstrated multidisciplinary care model could improve hrql of patients with pulmonary arterial hypertension. blood pressure management with urapidil for patients with aortic dissection is associated with less esmolol usage than nicardipine j.-c. zhou sir run run shaw hospital, intensive care medicine, hanghzou, china intensive care medicine experimental , (suppl ):a introduction: acute aortic disease is a common but challenging entity in clinical practice. titration the blood pressure and heart rate to a target level is of paramount importance in the acute phase regardless of whether the patient will undergo a surgery or not eventually. in addition to the initially intravenous β-blockers, parenteral infusion of nicardipine and urapidil are the most common used antihypertensive therapy currently in mainland china. however, few empirical data was available with respect to the different effect on patients' outcome of the two antihypertensive strategies, especially given the deleterious reflex tachycardia of vasodilators which may increase force of ventricular contraction and potentially worsen aortic disease. objectives: to evaluate the difference of the abovementioned two antihypertensive strategies on the outcome of patients with aortic disease. methods: all patients with new diagnosed aortic diseases presented to our hospitals from january , to june , were retrospectively reviewed. the antihypertensive strategies and their association with patients' outcomes were evaluated with logistics regression. results: a total of patients with new diagnosed aortic disease were included in the study. of them, patients received urapidil while patients received nicardipine antihypertensive therapy. patients with nicardipine were more quickly to reach the target blood pressure level than those treated with urapidil (median vs mins, p = . ). after adjustment for patient demographics, comorbidity, involved extend of aorta, interventional strategies, antihypertensive therapy with nicardipine (with urapidil as reference) for patients with aortic disease was significantly associated with high esmolol cost (or: . , %ci: . - . , p = . ) and longer icu length of stay (or: . , %ci: . - . , p = . ). however, there was no significant correlation between nicardipine use and icu mortality (or: . ; %ci, . - . , p = . ). conclusions: although nicardipine achieved the target blood pressure level more quickly than urapidil for patients with aortic disease, it was associated with more esmolol use and longer icu length of stay. introduction: postoperative bleeding is one of the most common complications of cardiac surgery. excessive perioperative bleeding continues to complicate cardiac surgery with cardio-pulmonary bypass (cpb) in spite of improvements in extracorporeal oxygenation and surgical techniques. even bleeding after cardiac surgery has variable causes, we thought the applying isth scoring system may be able to predict the postoperative excessive blood loss in patients after cardiac surgery with cpb. objectives: the aim of present study was to examine the effectiveness of international society on thrombosis and hemostasis (isth) scoring system in patients with cardiac surgery. methods: the medical records of patients undergoing elective cardiac surgery using cpb between mar. and feb. were retrospectively reviewed. these demographic and clinical characteristics, perioperative laboratory findings, and postoperative complications were assessed using computerized databases from our institution. isth score was calculated in icu and patients were divided with overt dic group and non-overt dic group. results: among patients with cardiac surgery, patients with overt dic group (n = ) or non-overt dic group (n = ) were enrolled. mean dic scores at icu admission was . ± . (overt dic group) and . ± . (non-overt dic group) and overt dic was induced in % ( / ). overt dic group had much more ebl for hrs (p = . ) and maintained longer time of intubation time (p = . ) conclusions: in spite of limitation of retrospective design, management using isth score in patients after cardiac surgery seems to be helpful for prediction of the post-cpb excessive blood loss and prolonged tracheal intubation duration. renal failure, . % vs %, p ≤ , ; respiratory failure, . % vs . %, p ≤ , ; mechanical > h . % vs . %, p ≤ . ventilation. the variables that reached statistical significance in the multivariate analysis as predictors of mortality were apache ii or . ( % ci . - . ), p = . , euroscore or . ( % ci , - . ), p < . ; acute respiratory failure or . ( % ci . to . ), p = . ; acute renal failure or . ( % ci . - . ), postoperative bleeding or . ( % ci . to . ), p < . conclusions: mortality in this group is similar to other series, being patients with more comorbidities, with the highest score in the euro-score and apache ii and more often subjected to mixed surgery. the euroscore, apache ii, respiratory failure, renal failure and postoperative bleeding, predict higher mortality. methods: we measured rea as ratio of pulmonary pressure at the dicrotic notch (dypap) and stroke volume (sv) [ ] and rees as ratio of the difference between mean pulmonary artery pressure (mpap) and wedge pressure (pcwp) and end systolic volume (resv) (mpap-pcwp/resv) [ ] after the induction of anaesthesia (t ) via pulmonary artery catheter (swanganz f and vigilance ii monitor by edwards lifesciences), after weaning from cpb (t ) and h after in icu(t ) in patients. results: measure of rvac has been demonstrated feasible in all four patients undergoing cardiac surgery. as expected all the patients were found uncoupled (rvac > ) before surgery, immediately after weaning from cpb rvac worsen and in icu it was restored to the basal. conclusions: in this preliminary analysis we demonstrated the feasibility of measuring rvac in critical patients undergoing cardiac surgery, to our knowledge this is the first report in this field. as expected rvac is very much influenced by cpb although further investigation is needed to confirm the utility of this technique to monitor the right heart in such patients. introduction: detection of tissue hypoperfusion is paramount in the management of va ecmo. arterial to pulmonary artery co difference has been demonstrated to be an early marker of hypoperfusion in the shock patient [ ] and during hypothermic cardiopulmonary bypass [ ] , objectives: in this report we investigated the accuracy and feasibility of mixed venous to arterial co difference as an early marker of perfusion mismatch during va ecmo. methods: in a patient treated with va ecmo for refractory cardiac arrest due to acute myocarditis we performed serial measurements of pulmonary artery to arterial co difference as well as svo , map, urine output and lactate level. results: during reduced perfusion periods, assessed by elevated lactacidemia (> mmol/l) we observed high > co difference which is concordant to literature [ ] . during episodes of reduced systemic perfusion, demonstrated by increase of serum lactic acid we were able to early detect hemodynamic derangement (avg minutes) by identifying elevated (> mmhg) co difference. conclusions: this case report underlines the importance of pulmonary artery to arterial co difference as an early marker of hypoperfusion if compared to lactate level in the intensive care unit. to our knowledge this is the first report on venous to arterial carbon dioxide difference in va ecmo. further investigation is needed to confirm those preliminary results. introduction: many studies have shown clinical benefits from sdd for critically ill patients. however, there is still doubt concerning the emergence of antimicrobial resistance in the long term. previously no evidence to support this view was found but long-term effects of sdd on antimicrobial resistance on the unit level is understudied. , objectives: to determine the incidence of antimicrobial resistance in aerobic gram-negative potentially pathogenic micro-organisms (agnbs) to the components of sdd and frequently used i.v. antibiotics on icu-level over a year period with unchanged antibiotic policy. methods: this is a single-center observational cohort study in a dutch -bed adult intensive care unit in a teaching hospital. all consecutive patients admitted to the icu between january and december were included when at least one culture was taken during icu-admission. data on all cultures taken during icu stay were collected from the hospital database. susceptibility testing was performed following the guidelines of the 'clinical and laboratory standards institute' (csli) until and 'the european committee on antimicrobial susceptibility testing' (eucast) from until . incidence rates of antimicrobial resistance to tobramycin, ciprofloxacin, polymyxin b or cefotaxime were calculated per year. only icuacquired resistant pathogens were selected by excluding resistant pathogens in cultures taken on day -day . patients at risk were defined as all admissions with a length of stay longer than days. differences between the incidence in the first and last year of the study were tested using chi-square test. results: data of . cultures was analyzed containing . agnbs. the number of admissions with a length of stay more than days was . in admissions newly acquired resistance to cefotaxime was found, in to polymxin b, to tobramycin and to ciprofloxacin. figure presents incidence rates per year. in - date of discharge to the ward was unknown and therefore incidence rates could not be calculated for these years but absolute numbers were comparably low. there was no significant difference in incidence of icu acquired resistance in cefotaxime (χ = . , p = . ), polymyxin b (χ = . , p = . ), tobramycin (χ = . , p = . ) and ciprofloxacin (χ = . , p = . ) between and . conclusions: the incidence of newly acquired agnb resistant to cefotaxime, polymyxin b, tobramycin and ciprofloxacin continues to be low during a year unchanged antimicrobial policy of sdd. the increase in resistance in the society may impact these numbers and should be studied. results: overall, icu and h mortality rates were and %. . % of the pts ( / ) became infected in the early postoperative period. (icu and h mortality rate and % respectively). crpk infections were present in pts ( . % of the entire series, . % of the infected pts). sarcopenia ( % vs %, p = . ) and meld ( + vs + , p = . ) were significant preoperative risk factors. icu and h mortality rates were % and % in crpk pts, % and % in non -crkp infected pts respectively : while icu mortality was not different (p = . ), h mortality was significantly higher in crkp pts (p = . icu vs h, ci . - . ). if compared to non -crkp pts , crkp pts were more often in septic shock ( % vs %, p = . ) and more frequently underwent crrt ( % vs % p = . ). intraabdominal infections were largely represented ( %) among crkp pts. blood loss and transfusion needs, early gratt dysfunction and reolt were more represented in infected vs non infected pts. however, no differences were found when crkp and non-crkp transplanted pts were compared. conclusions: crkp infections are on the rise also in italy. post olt mortality is high and strategies able to control crkp are urgently needed to be implemented. introduction: the prevalence of antibiotic-resistant pathogens in icu conditions makes it difficult to treat these infections, and treatment becomes impossible in some cases. acinetobacter baumannii is important infectious agent icu patients, which effective antibiotic therapy is currently limited. objectives: we aimed to determine the range of a.baumannii associated infections among icu patients, to summarize the level of resistance to antimicrobial drugs, and provide an overview of strategies to prevent the spread of resistance. methods: a prospective microbiological study of the prevalence and antibiotic resistance of a.baumannii strains isolated from adult icu patients hospitalized to the tertiary hospital after cardiac surgery from to . results: a total of isolates from icu patients were included to the study. . % of the isolated strains ( ) were gram-negative, among which . % ( ) of a.baumannii isolates. strains of a. baumannii showed a high level of resistance to the iii generation cephalosporins ( . % to ceftazidime, . % to cefotaxime, . % to ceftriaxone). resistance to carbapenems was at %. investigation of antimicrobial activity of ciprofloxacin showed the resistance in . % of strains, to levofloxacin - . %. the lowest level of resistance recorded to doxycycline - . % and polymyxin - . %. conclusions: rapid microbiological diagnostics (including the results of antibiotic resistance), strict adherence to infection control, the appointment of an effective regime of antibiotic therapy, optimization schemes appointment of antibiotics, all of which are the most important priorities for the effective fight against a. baumannii associated infections in icu patients. in order to reduce the emergence and spread of drug-resistant strains in the icu, it is strongly recommended to carry out microbiological monitoring and optimization of the use of antibiotics in each hospital. therefore local resistance surveillance programs have the greatest value in the development of appropriate therapeutic recommendations for specific types of patients and infections. introduction: acinetobacter spp. are opportunistic, nosocomial pathogens that may colonize the surfaces in intensive care units. their tendency to harbor multi-drug resistance and to develop resistance mechanisms to commonly available drugs make their treatment a challenge. carbapenem resistance, and newly reported colistin resistance has led to a search for new treatment options. there are in vitro studies which report synergistic effect with rifampicin in combination therapies. objectives: we aimed to present and discuss the results of our patients who were infected with either panresistant ( patients) or only tigecycline susceptible ( patients) acinetobacter spp. and were treated with rifampicin combination regimens. methods: patients reported to be infected with colistin resistant acinetobacter spp. and treated with rifampicin combination regimens upon decision of the responsible teams were traced from the intensive care unit (icu) records between the years and retrospectively. their demographic data, liver function tests, icu and hospital outcomes were recorded. results: there were a total of patients, were women. mean age was . . in patients pulmonary site was the source. nine patients had positive blood cultures. mean sofa score at the start of therapy was . ; all were intubated, and ( %) were on vasopressor therapy. combination regimens comprised of at least antibiotics and all regimens included rifampicin and tigecycline. at the end of first week, mean sofa score was . . of these ( %) survived to hospital discharge. patients who were lost had higher initial and follow-up sofa scores. initial and follow-up liver enzymes and renal function tests were similar to their basal values in patients who survived; unlike the patients who were lost. when lost patients were re-evaluated: the first patient had irreversible lung fibrosis due to bleomycine; in the second patient; combination treatment was delayed until days after the cultures were performed; the third patient had been admitted to icu with acute renal failure and acute respiratory distress syndrome, after autologous stem cell transplantation for multiple myeloma. conclusions: when the importance of accurate antibiotic choice is taken into account for treatment success; rifampicin combinations may be considered as an appropriate treatment option for infections caused by colistin resistant acinetobacter strains. introduction: carbapenem resistant enterobacteriacae (cre) emerged in recent years as one of the most challenging group of antibiotic resistant pathogens. polymyxins are considered as the last resort for the treatment of infections with carbapenem resistant gram negative bacilli (gnb). inadequateor extensive use of colistin leads to emergence of colistin resistance, increasing mortality and morbidity and necessitating prudent use of alternative antibiotics. fosfomycin, a phosponic acid derivative which acts by disrupting bacterial cell wall synthesis, is a broad spectrum antibiotic. it is available as sodium/disodium formulation for intravenous use and is showing promising result against multi drug resistant(mdr)/pan drug resistant (pdr) pathogens. methods: a total of eight colistin resistant (mic ≥ ) gnb were isolated from icu patients with nosocomial mdr infections during a period of one year. all eight isolates were klebsiella pneumonia. among these isolates five were from blood and three from endotracheal aspirate. all the isolates were sensitive to fosfomycin in vitro. all of these patients had multiple co-morbidities with recent history of colistin exposure. intravenous fosfomycin was given as a combination therapy. results: among the five bacterimic patients, three recovered completely from sepsis. one patient took discharge against medical advice and the only one bacterimic patient who died during the course of therapy was later on diagnosed to have azole resistant fungemia as super infection. the patient with ventilator associated pneumonia also responded well after initiation of fosfomycin therapy. average duration of antibiotic therapy in all these cases was ten days. conclusions: based on the evidence of clinical experience and available studies, intravenous fosfomycin therapy may be considered as the last option for the treatment of mdr gnb infection where there is documented colistin resistance and where there is literally no other choice of antibiotic therapy. the success of the therapy is encouraging in selected group of patients. further research on intravenous fosfomycin use specially against mdr pathogens and on the effectiveness and safety of the drug in the treatment of patients with such infections may be warranted. introduction: patients at the intensive care units have an increased risk of infection due to their underlying diseases or conditions, impaired immunity, and exposure to multiple invasive procedures (surgery, mechanical ventilation, central venous catheters, artherial catheters, urinary tract catheters). multidrug-resistant organisms infection has become a public health problem and has been associated with increased morbidity, mortality, and costs. objectives: to analyze the principal features of postsurgical patients with colonization or infection by multidrug-resistant organisms, acquired before the admission at the intensive care unit. methods: retrospective observational study, descriptive, case series, collected from / / to / / in a -bed hospital, with a -bed polyvalent intensive care unit in fuenlabrada, madrid, spain. the hospital is attached to resistance zero project, with screening at admission and every week in all patients (pharyngeal, rectal, nasal, wounds and bronchial suction). postsurgical patients have been identified with multidrugresistant organisms isolation in screening in the first hours of admission to the intensive care unit. studied variables: age, sex, adjusted charlson comorbidity index, barthel index, apache ii, saps , days of hospitalization prior to icu, days of antibiotic treatment administered before icu, previous days of parenteral nutrition, prealbumin, surgical wound infection, multigrug-resistant organisms identified sample. statistical analysis: spss . categorical in frequencies and percentages, mean and standard deviation or median and interquartile range. analysis kolmogorov smirnov, shapiro wlik and qqplot to normality. confidence intervals (ci) % by t student for normal variables, boot stramp to not normal. results: in months we identified postsurgical patients with multidrug-resistant organisms in screening at the admission or before the admission to the intensive care unit. multidrug-resistant organisms identified: pseudomonas aeruginosa ( . %), esbl enterobacteriaceae ( . %), mrsa ( . %), stenotrophomonas maltophilia ( . %). isolated on: surgical wound ( . %), bronchial suction ( . %), peritoneal fluid ( . %), exudates monitoring ( . %), blood ( . %). antibiotic therapy: carbapenem ( . %), piperacilina-tazobactam ( . %). conclusions: in our study the risk of prior acquisition of multidrugresistant organisms at the admission to the intensive care unit in postsurgical patients was characterized by long hospital stay, high comorbidity and dependence, malnutrition, prolonged use of broadspectrum antibiotic, parenteral nutrition and surgical wound infection. introduction: the emergence and dissemination of klebsiella pneumoniae carbapenemase (kpc) is of great concern. outbreaks have been reported in different types of intensive care units (icu). in brazil, there have been reports of kpc since . we recently experienced a large outbreak at our hospital. risk factors for kpc colonization and outcome of icu patients are still to be determined. objectives: to study the differences between patients who acquired from those who did not acquired kpc during their stay in the icu, focusing on risk factors and outcomes. introduction: patients with a prolonged weaning represent a small part of the total icu population but this prolonged state has many implications on their later recovery and can highly impact health expenditures. objectives: to better characterize patients with prolonged weaning and assess factors associated with their survival. methods: the prospective multicentre observational wind (weaning according new definition) study was performed from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. we considered patients as having a prolonged weaning if weaning was not terminated at days following their first wa. conclusions: in this multicentre international prospective cohort, . % of the patients entering the weaning process had a prolonged weaning with a high mortality rate of . %. the only baseline factor associated with death were previous immunodeficiency and chronic cardiac failure. these patients highly impact the icu workload as they receive mechanical ventilation for a median duration of days and their median length of stay in the icu is days. patients with a prolonged weaning spend a long icu time after the end of weaning without mechanical ventilation raising the issue of the need for specialized units. introduction: ineffective efforts (ie), defined as the inability of patient's inspiratory effort to trigger a ventilator-delivered breath, is a commonly encountered asynchrony, and has been reported to adversely affect patient outcome , , . the incidence of ie depends on several factors, including patient population, ventilator settings, and the observation period, which in most studies so far was limited , . objectives: aim of this study was to investigate the incidence of ineffective efforts, using continuous recordings, in critically ill patients mechanically ventilated only on assisted mode and their potential effects on patient outcome. methods: adult critically ill patients hospitalized in the icu of the university hospital of heraklion on mechanical ventilation for > h were enrolled. patients were studied when they were on assisted ventilation for > hour and expected to remain on assisted ventilation for the next hours. patients were studied again on the rd and th day if they remained on assisted ventilation. continuous h measurements were obtained using a monitor validated to identify ineffective efforts (pvi monitor) . the output of pvi monitor data was processed before analysis to optimize data quality and re-sampled to a time-series with the number of ies calculated in uniform intervals of secs while preserving the total number and duration of ies . the ie index was calculated as previously described. because ie occurred in clusters, the concept of ie event was introduced, to describe variable periods of time containing ie > % of breaths. ie events were characterized by their duration and power (number of ie) . introduction: the neural timing during mechanical ventilation can be obtained from conventional airway flow tracing, or invasive esophageal and gastric signal; however, it is difficult clinical practice and could be imprecise. the first derivative of airway flow signal show line segments with distinctly different slopes and with welldefined the inflections points, therefore this closely indicate the respiratory times, it can be calculated easily. objectives: to evaluate the accuracy of the derivative of the flow signal (df) as method for measurement of the respiratory times compared with esophageal-gastric signals. introduction: providing appropriate levels of pressure support (ps) at the bedside is challenging. physicians should avoid both over-support, which increases the risk of lung trauma, muscle atrophy and prolonged weaning; and under-support, which increases the risk of patient discomfort and respiratory muscle fatigue. the latter can be determined by the using the tension time index of the inspiratory muscles (tti es ) derived from measurement of esophageal pressure. tti es values higher than . indicate fatiguing patient effort. the beacon caresystem (mermaid care, denmark) advises on level of ps using physiological models of lung mechanics, pulmonary gas exchange, respiratory drive, acid-base status and muscle function; along with clinical preference functions quantifying the risk of muscle atrophy, patient stress, and lung trauma. mathematical models are tuned to measurements allowing advice to be patient specific. objectives: this study investigates the variation of tti es and other indices of respiratory muscle function induced by an increase/decrease of the level of ps, and whether the consequent advice proposed by the beacon system results in appropriate patient effort. methods: ten patients with acute respiratory failure residing in an icu in ferrara, italy, have currently been included for this analysis. an esophageal balloon was inserted and its correct position determined by the occlusion test. the advice of the beacon system was followed for an hour from states of over-and under-support defined as % and % of baseline ps. the level of peep was kept constant throughout the study. data were analysed in terms of tti es and esophageal pressure developed in the first ms of an occluded inspiration (p . ) results: the baseline tti es values of . ± . were consistent with absence of fatiguing effort in all patients but one. as expected, reducing/increasing the level of ps resulted in tti es and p . increase or decrease, respectively. in patients the reduction of ps was associated with impending muscle fatigue. the levels of ps proposed by the beacon system resulted in tti es of . ± . , slightly higher than obtained by the treating physician, but always below the values indicating muscle fatigue, a part from the patient in which the tti es indicated fatigue at baseline. of note, this new value of tties was not associated with a significant variation p . , which implies that the proposed level of ps was not associated with an increased respiratory drive or higher transpulmonary pressure conclusion: these initial results indicate that beacon caresystem responds appropriately to over-and under-support avoiding muscle fatigue and excessive p . . the use of vo level changes as a predictor for weaning success in the mechanically ventilated patients introduction: experimentally, hyperchloraemia may induce vasoconstriction of the renal afferent arterioles and tubular dysfunction, potentially resulting in acute kidney injury (aki). the clinical implications of these findings are not well established, especially in septic patients. objectives: to investigate whether chloride serum and urinary concentrations as well as chloride load, output, balance and urinary anion gap are associated with the development of aki in septic patients. methods: retrospective analysis of an institutional database including all patients admitted to the intensive care unit (icu) for severe sepsis and septic shock from january to june . inclusion criteria were length of stay in the icu ≥ hours and complete data available on serum and urinary samples for at least days. patients were excluded if they had anuria on icu admission, continuous bladder irrigation, if they were on hemodialysis (of recent onset and chronic) and if they were kidney-transplanted. demographics and data on outcome were also analysed from the database. we collected chloride levels on daily blood (bcl) and urinary (ucl) analyses; chloride load (cl) was calculated by considering the amount of chloride present in the iv fluids administered daily to the patient, while chloride balance (cb) was calculated as: cl -co, where co is chloride output (ucl * daily urine output). creatinine clearance (crcl) was calculated on -hr urinary collection. aki was defined according to standard criteria. conclusions: most of septic patients developed aki and this complication was associated with a significant reduction in renal chloride elimination. the impact of such findings on the management of fluid therapy in this setting remains to be further evaluated. introduction: plasma interleukin (il- ) is associated with acute kidney injury (aki) in sepsis. il- receptor (il- r) is not expressed in the kidney. circulating il- in a complex with soluble il- r (sil- r) activates ubiquitously expressed transmembrane signal transducing glycoprotein on renal epithelial cells. this il- trans-signaling is associated with mortality in experimental sepsis. objectives: to study il- trans-signaling in patients with sepsis in a clinical intensive care setting. methods: in septic patients showing first organ failure at intensive care unit (icu) admission ± hours, we measured plasma il- and sil- r at admission and hours later. our primary endpoint was aki during the first five icu days by kdigo criteria. mann-whitney's, spearman's correlation and chi square tests were used. results: plasma il- was significantly higher in patients with aki at h (p = . ) and h (p < . ). plasma il- correlated with kdigo stage at h (r = . , p = . ) and h (r = . , p < . ). plasma sil- r did not differ between aki and non-aki groups. using cut-off values of pg/ml of il- and pg/ml of sil- r at h (detected by youden method), the combination of low il- and low sil r was associated with non-aki (p < . ). conclusions: combination of low il- and low sil- r in plasma is associated with decreased incidence of aki, suggesting that il- transsignaling contributes to septic aki. . % for the non-aki group (or = . ; % ci, . - . , p < . ). multivariate analysis indicated that the bpv was well associated with aki (adjusted or = . ; % ci, . - . , p < . ) while the mean blood pressure was not (adjusted or = . ; % ci, . - . , p = . ). conclusions: elevated blood pressure variability is associated with increased risk of aki in septic patients. this understanding may be helpful to develop requirement for stabilising blood pressure in the bp management of septic patients. introduction: acute kidney injury (aki) is a frequent and serious complication of sepsis in intensive care units (icu). according to acute kidney injury criteria (akin), the most current diagnostic criteria for aki is an abrupt (within hrs.) reduction in kidney function currently defined as an absolute increase in serum creatinine of more than or equal to . mg/dl, or . fold from baseline or a reduction in urine output (documented oliguria of < . ml/kg per hr. for > hr.). by time of occurrence of these criteria actual kidney insult has occurred & probably this leads to late intervention for kidney protection &/or renal replacement therapy (rrt). so early prediction of aki by using biomarkers like urinary angiotensinogen could help patients to benefit from a quicker and more appropriate therapy. urinary angiotensinogen appears quite promising due to its reported correlation with the intrarenal angiotensinogen and angiotensin ii levels which play a major role in molecular mechanisms of aki. objectives: the aim of this work was to evaluate the role of urinary angiotensinogen as a possible predictor of aki in patients with severe sepsis. methods: the study was carried on adult patients who were admitted to the department of critical care medicine, at the alexandria main university hospital and who suffered from severe sepsis. patients were categorized into two groups according to aki development; non aki group which consisted of patients (group i), and aki group which consisted of patients (group ii). patients were excluded if they have chronic kidney disease, already started rrt, received angiotensin convertase enzyme inhibitors (acei) or angiotensin receptor blockers (arbs), or septically shocked. urinary angiotensinogen and creatnine were withdrawn once from each patient on the day of admission to calculate urinary angiotensinogen/creatinine ratio (uancr, ng/mg). akin staging was assessted daily for seven days. results: there was a significant difference between the two studied groups regarding uancr ratio on admission (p < . ), whereas this introduction: acute pancreatitis with organ dysfunction is termed severe acute pancreatitis (sap) and complex sap if local complications develop (such as infected pseudocyst). we receive tertiary referrals of complex sap patients to our unit, who often have multiple ct scans. muscle wasting is known to occur in critically ill patients ( ) and can be quantified by measurement of the cross-sectional area (csa) of para-spinal muscles at the third lumbar vertebral level on ct imaging. aki is one of the most common causes of death in sap patients ( ) and is a risk factor for developing ckd ( ). kdigo guidelines suggest using creatinine changes to detect aki ( ) but creatinine changes may be inaccurate in the presence of musclewasting (myopenia) ( ). objectives: to utilise measurements of l para-spinal muscle csa (l mcsa) from complex pancreatitis patients between april -december and compare these to changes in plasma creatinine during their icu stay. methods: patients were identified from our icu patient database (wardwatcher software) and additional clinical details including creatinine/egfr level on ct-scan days, were acquired from electronic databases. images were exported from our pacs system as dicom files and analysed using imagej software (ref) in duplicate by two independent users, average values were used. for patients who had no renal-replacement therapy (rrt), between-scan l mcsa and creatinine change were paired and analysis was with excel (ms) and graphpad (prism). results: patients met inclusion criteria. patients had ≥ ct scans in icu, enabling serial estimation of l mcsa. / ( . %) patients did not have rrt in icu. there was no statistically significant difference in overall (start to end of icu) % change of l mcsa between patients who did/did not have rrt. there was also no correlation between overall (start-to-end of icu) % creatinine change and % change/day l mcsa: r = − . , p = . . for between-scan data (n = ): the median (iqr) % creatinine change/scan was − . % (− . to − ) and the % l mcsa change/ scan was − . % (− . to − . ). however, there was no correlation between % l mcsa change and % creatinine change between scans ( r = − . , p = . ). conclusions: l mcsa (relating to lean muscle mass) was shown to decrease in complex severe acute pancreatitis (sap) patients. however, there was no correlation with change in l mcsa and change in creatinine. this suggests that normal/stable creatinine values may be falsely reassuring in the context of muscle mass loss (myopenia) and ongoing aki could be under-diagnosed. acknowledging myopenia and interpreting creatinine value in context is therefore vital. introduction: continuous renal replacement therapy (crrt) is the most common therapy in critical ill patients with acute renal failure, having circuit coagulation as the most frequent complication. the crrt circuit requires careful anticoagulation to avoid coagulation and bleeding complications. critically ill patients with acquired antithrombin (at) deficiency, may have a shorter filter lifespan. objectives: evaluate the relation between the modification of at levels from baseline and circuit survival during ccrt. we would like to determine the existence of an at critical level, related to the risk of the clotting filter. methods: we started an observational study with prospective data collection in a university hospital. from october to april , patients were included, with filters in total. we measured the level of at activity at the beginning (basal at), daily, and at the moment of circuit coagulation. we divided the patients in two groups depending in their at´s basal level (< % or > %). then, we observed the percentage of change in at from baseline, and we divided the patients in tertiles to obtain three comparable groups. the main outcome measure was filter lifespan of first circuit and the correlation with at´s levels. results: low at´s basal level (< %) has significant association with longer filter life span (p = . ). we obtained three groups according to a percentage changes of ± % in at from baseline. one group declined the at´s basal level ( % decrease), other had little changes (between % decrease and % increase) and the last one had an increase ( % increase). the group which presented the highest percentual increase showed the largest median survival time to circuit coagulation ( hours; % ci: - ). we observed a significant association (p = . ) between the greater percentage change in at from baseline, and a larger time intervals to circuit coagulation. conclusions: the circuit lifespan shows a narrow correlation with evolution of at´s levels since the start of crrt until filter clotting. at measurement should be considered an essential factor during crrt. calcium supplementation was required with filters ( %) in patients ( %). in these patients, the median supplementary calcium dose (in addition to replacement fluid ca) was . mmol/hr ( . - . ). of those were initiated with calcium with only requiring further calcium in the next filter and did not ( patient who started on calcium only used filter). one patient in the citrate group was discontinued for alkalosis. no patients were discontinued for hypocalcaemia. conclusions: post dilution rca, using replacement fluid which contains calcium, in patients with a relative contraindication to heparin, reduces need for post filter calcium supplementation and provides acceptable filter life. mortality risk factors in continuous renal replacement therapy in a university hospital from colombia c. introduction: acute kidney injury (aki) occurs in more than % of critically ill patients, % need renal replacement therapy, preferring continuous therapies. however mortality seems not to change with this technology. the research available focus on the right time to start therapy, but only evaluating renal dysfunction characteristics. objectives: to identify mortality risk factors at the start of continuous renal replacement therapy (crrt) for acute kidney injury and early mortality risk factors in this patients. methods: a cohort study was performed in patients over years old with aki who required crrt in the intensive care unit of a university hospital in bogota colombia between and . the crrt was provided with aquarius® edwards® technology, polyethersulfone membrane of . and . m (aquamax®) and replacement fluids with lactate (premixed®). modality selection were guided by the hospital guideline. sample size calculation was estimated selecting cases (death) for each variable associated with mortality. a description of demographic and clinical variables was performed, bivariate analysis with mortality and early death defined as death within hours of onset of crrt, and finally we proceed to perform a multivariate prediction analysis. we considered statistically significant p value < . . results: a total of patients required crrt during the period, ( . %) patients were excluded, (age under years old, incomplete data and chronic kidney disease on dialysis). the mean age was . years (± . ), . % men. the most frequent cause of aki was sepsis in . % of cases. a total of crrt days were conducted with a median of days per patient (range - ). mean charlson comorbidity index was . (± . ), apache ii score . (± . ), total non-renal sofa had a median of (range - ) at the time of starting therapy. the hospital mortality was . % and early mortality was . %. in multivariate analysis: age (p = . ), sofa (p = . ), days door-support (p = . ) and the presence of hypotension (p = . ) were independent risk factors for hospital mortality with an area under the curve of . . for early death lactic acid levels (p = . ), glucosa (p = . ) and age (p = . ) were independent risk factors with an area under the curve of . . conclusions: patients with aki on crrt have high mortality. age, multiple organ dysfunction, hypotension and time door-support were independent mortality risk factors. low levels of glucose and high lactate at onset of crrt are independent risk factors of early death. pediatric formulas for the anesthesiologist the role of bystanders, first responders, and emergency medical service providers in timely defibrillation and related outcomes after out-of-hospital cardiac arrest: results from a statewide registry kids save lives-training school children in cardiopulmonary resuscitation worldwide is now endorsed by the world health organization (who) acute skeletal muscle wasting in critical illness enhancing rehabilitation of mechanically ventilated patients in the intensive care unit: a quality improvement project pdf . nice quality standard (qs ) stroke in adults the sentinel stroke national audit programme (ssnap) interventions to improve the physical function of icu survivors core standards for intensive care units icu early mobilization: from recommendation to implementation at three medical centres revista brasileira de terapia intensiva invasive pulmonary aspergillosis is a frequent complication of critically ill h n patients: a retrospective study isolation of aspergillus in three h n influenza patients. influenza other respir viruses grant acknowledgement supported by fucap and ciberes effect of daily chlorhexidine bathing on hospitalacquired infection chlorhexidine bathing and health care-associated infections: a randomized clinical trial outcome of elderly patients undergoing intracranial meningioma resection -a systematic review and meta-analysis references . an expanded definition of the adult respiratory distress syndrome acute respiratory distress syndrome: the berlin definition jama h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment epidemiology, co-infections, and outcomes of viral pneumonia in adults: an observational cohort study. medicine (baltimore) survival from severe pandemic h n in urban and rural turkey: a case series prognostic importance of neutrophillymphocyte ratio in critically ill patients: short-and long-term outcomes. the american journal of emergency medicine reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock the association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study the mortality risk of over hydration in haemodialysis patients ultrasound assessment for extravascular lung water in patients undergoing hemodialysis. time course for resolution sufficient sleep quality easily measured: a multicenter centre study in dutch icus rd international symposium on intensive care and emergency medicine using nursing activities score to assess nursing workload on a medium care unit nurse staffing levels and the incidence of mortality and morbidity in the adult intensive care unit: a literature review nursing activities score in the intensive care unit: analysis of related factors. intensive and critical care nursing organisation and management of intensive care : a prospective study in european countries impact of performance obstacles on intensive care nurses' workload, perceived quality and safety of care and quality of working life burnout syndrome in critical care nursing staff work engagement: an emerging concept in occupational health psychology diagnostic accuracy of clinical swallow assessment for oropharyngeal aspiration: a systematic review the cruelest lies are often told in silence critical review: is the endoscopic swallowing assessment (abstract a ). lactate (sepsis vs trauma) jaundice in the intensive care unit cooling techniques for targeted temperature management post-cardiac arrest thermoregulatory catheter-associated inferior vena cava thrombus ivtm intravascular temperature management catheter specifications prediction of postoperative pulmonary complications in a population-based surgical cohort lung ultrasound: routine practice for the next generation of internists relevance of lung ultrasound in the diagnosis of acute respiratory failure* assessment of hemostasis after plasma exchange using rotational thrombelastometry (rotem) prevention of pain on injection of propofol: systematic review and meta-analysis prevention of pain on injection with propofol: a quantitative systematic review mechanical ventilation guided by esophageal pressure in acute lung injury ultrasound assessment of antibiotic-induced pulmonary reaeration in ventilator-associated pneumonia ards definition task force endotracheal tubes cuff pressure control: does the co matter? minerva anestesiol incidence and outcome of in-hospital cardiac arrest in the united kingdom national cardiac arrest audit delayed awakening after cardiac arrest: prevalence and risk factors in the parisian registry diaphragm ultrasound as a new index of discontinuation from mechanical ventilation critical ultrasound journal ventilator-induced diaphragm dysfunction: time for (contr)action! the course of diaphragm atrophy in ventilated patients assessed with ultrasound: a longitudinal cohort study critical care effect of postextubation high-flow nasal cannula vs conventional oxygen therapyon early non-invasive ventilation treatment for severe influenza pneumonia use of a pathway quality improvement care bundle to reduce mortality after emergency laparotomy the first patient report of the national emergency laparotomy audit acute kidney injury enhances outcome prediction ability of sequential organ failure assessment score in critically ill patients médecine intensive et réanimation development and validation of a questionnaire for quantitative assessment of perceived discomforts in critically ill patients the emotional and cognitive impact of unexpected simulated patient death the efficiency of instructional conditions: an approach to combine mental effort and performance measures long-term cognitive impairment after critical illness satisfacción laboral de los profesionales sanitarios de un hospital universitario: análisis general y categorías laborales the nurse satisfaction, service quality and nurse retention chain: implications for management of recruitment and retention grant acknowledgement am: moulton foundation hospital/kcl the very elderly admitted to icu: a quality finish? crit care med a global clinical measure of fitness and frailty in elderly people cognitive, functional, and quality-of-life outcomes of patients aged and older who survived at least year after planned or unplanned surgery or medical intensive care treatment outcome of elderly patients with circulatory failure. int care med understanding and reducing disability in older adults following critical illness mechanical ventilation in a cohort of elderly patients admitted to an intensive care unit preferences of current and potential patients and family members regarding implementation of electronic comunication portalls in intensive care units caring for the family of the critically ill patient the carina as a radiological landmark for central venous catheter tip position duration of resuscitation efforts and survival after in-hospital cardiac arrest: an observational study duration of cardiopulmonary resuscitation and illness category impact survival and neurologic outcomes for in-hospital pediatric cardiac arrests duration of prehospital resuscitation efforts after out-of-hospital cardiac arrest neurologic prognosis after cardiac arrest magnetic resonance imaging markers of parkinson´s disease nigrostriatal signature disruption of posteromedial large-scale neural communication predicts recovery from coma james mcdonnell foundation, the belgian american education foundation, university milano bicocca. fig. (abstract a ). study flowchart intensive care medicine experimental neurological prognostication after cardiac arrest strategies for improving survival after in-hospital cardiac arrest in the united states: consensus recommendations: a consensus statement from the cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved -day clinical outcomes in patients with st-segment elevation myocardial infarction complicated with profound cardiogenic shock the current use of impella . in acute myocardial infarction complicated by cardiogenic shock: results from the uspella registry mechanical circulatory support in cardiogenic shock cardiac transplantation research database group, long-term outcomes of cardiac transplantation for peripartum cardiomyopathy: a multiinstitutional analysis cardiopulmonary resuscitation with assisted extracorporeal life support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in countries in europe and the united states nurses' widespread job dissatisfaction, burnout, and frustration with health benefits signal problems for patient care early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial feasibility and observed safety of interactive video games for physical rehabilitation in the intensive care unit: a case series is admission to the intensive care unit associated with chronic opioid use? a -year follow-up of intensive care unit survivors survival to icu discharge in ventilated patients intensive care medicine experimental modified early warning score with rapid lactate level in critically ill medical patients: the views-l score impact of matrix-assisted laser desorption ionization time-of-flight mass spectrometry on the clinical management of patients with gram-negative bacteremia: a prospective observational study. clinical infectious diseases : an official publication of the infectious diseases society of america impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. clinical infectious diseases : an official publication of the infectious diseases society of america impact of rapid identification of acinetobacter baumannii via matrix-assisted laser desorption ionization time-of-flight mass spectrometry combined with antimicrobial stewardship in patients with pneumonia and/or bacteremia. diagnostic microbiology and infectious disease an international cross-sectional survey of antimicrobial stewardship programmes in hospitals continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial hplc determination of plasma free and total tazobactam and piperacillin effectiveness of polymyxin bimmobilized fiber column in sepsis: a systematic review crit care predicting functional impairment in brain tumor surgery: the big five and the milan complexity scale *p. ferroli the "medial-oblique" approach to ultrasoundguided central venous cannulation-maximize the view, minimize the risk medial-oblique" probe position for ultrasound-guided internal jugular vein cannulation: a crossover study improving survival from sudden cardiac arrest: the "chain of survival" concept practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the quality standards subcommittee of the american academy of neurology association of bystander interventions with neurologically intact survival among patients with bystander-witnessed out of hospital cardiac arrest in japan performance of the revised atlanta and determinantbased classifications for severity in acute pancreatitis rational fluid therapy for sepsis and septic shock what do recent studies tell us? review article surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. int care med the third international consensus definitions for sepsis and septic shock fernández-ortega regional university hospital in málaga rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections grant acknowledgement supported, in part cytokines and signaling molecules predict clinical outcomes in sepsis the application of esophageal pressure measurement in patients with respiratory failure mechanical ventilation guided by esophageal pressure in acute lung injury ecmo criteria for influenza a (h n )-associated ards: role of transpulmonary pressure mechanical ventilation guided by esophageal pressure in acute lung injury fig. (abstract a ) grant acknowledgment national cheng-kung university hospital grant a assessment effort and work of breathing by airway occlusion pressure versus esophageal pressure hospital universitario reina sofia, intensive care unit airway occlusion pressure effects of the prone position on respiratory mechanics and gas exchange during acute lung injury effects of prone position on alveolar recruitment and oxygenation in acute lung injury prone position reduces lung stress and strain in severe acute respiratory distress syndrome lateral positioning of ventilated intensive care patients: a study of oxygenation, respiratory mechanics, hemodynamics, and adverse events the effect of lateral position on oxygenation in ards patients : a pilot study the open lung concept of mechanical ventilation: the role of recruitment and stabilization selecting the 'right' positive endexpiratory pressure level esophageal and transpulmonary pressures in acute respiratory failure spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis hepatorenal acute kidney injury and the importance of raising mean arterial pressure a fig. (abstract a ) rotational thrombolelastometry produces potentially clinical useful results within min in bleeding emergency department patients: the deuce study thrombelastography and rotational thromboelastometry early amplitudes in trauma patients with clinical suspicion of severe injury a prospective study of anaemia status, haemoglobin concentration and mortality in an elderly cohort a experience with a hospital-wide implementation of a massive transfusion protocol: before and after a references . experience with a massive transfusion protocol in the management of massive haemorrhage rodríguez villamizar hospital universitario puerta de hierro majadahonda recommendations for end-of-life care in the intensive care unit: a consensus statement by the american college of critical care medicine end-of-life care practices in patients dead as a result of a devastating brain injury and organ donation in spain prediction of potential for organ donation after cardiac death in patients in neurocritical state: a prospective observational study causes of family refusal for organ donation development of the croatian model of organ donation and transplantation evaluation of organ procurement in an area under the influence of a training program grant acknowledgment none. a non-heart beating donor program: seville's experience l. martin-villen , the variables analyzed were: total number of queries activation, of pd, of eligible donors (ed) and of real donors (rd). rd attendance times were registered and we defined out-of-hospital time (from cardiac arrest to hospital arrival), inof-hospital time (from hospital arrival to cannulation onset), cannulation time (beginning of cannulation to perfusion onset) and perfusion (from perfusion onset to the first organ removal). we registered number and type of valid organs and tissues, number of family members or judicial negative, number of non-real-donors (nrd) and its causes regarding attendance times, the median time was (icr - ) minutes for out-of-hospital, (icr - ) minutes for in-of-hospital, ( - ) minutes for cannulation and ( - )minutes for perfusion controlled donation after circulatory determination of death in spain rodriguez villamizar puerta de hierro hospital, intensive care unit, majadahonda, spain correspondence: j. veganzones ramos -puerta de hierro hospital the use of lung donors older than years: a review of the united network of organ sharing database marginal donor lungs: a reassessment liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation the human organ transplant act. legislative acts and guidelines, ministry of health amendment of the human organ transplant act lebrón-gallardo regional university hospital in málaga grant acknowledgment this work was funded by the innovation awards from the department of medicine recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis a successeful strategy to reduce ventilator getting started kit: prevent ventilator associated pneumonia. cambridge ma: institute for healthcare improvement umr_s and hôpital pitié-salpêtrière, respiratory division and medical icu trends in tracheostomy for mechanically ventilated patients in the united states outcome of patients with cirrhosis requiring mechanical ventilation in icu the impact of organ dysfunction in cirrhosis: survival at a cost? does intermediate care improve patient outcomes or reduce costs abbreviations: tbs, tracheobronchial secretions aki, acute kidney injury hd, hemodialysis a patient perceptions of physiotherapy in icu: a qualitative study m dimensionamento da equipe de enfermagem da uti-adulto de um hospital ensino -rev. eletr. enf critérios para admissão de pacientes na unidade de terapia intensiva e mortalidade patient acuity rating: quantifying clinical judgment regarding inpatient stability identification of deteriorating patients on general wards; measurement of vital parameters and potential effectiveness of the modified early warning score the epidemiology of chronic critical illness in the united states impact of chronic critical illness on the psychological outcomes of family members tracheostomy procedures in the intensive care unit: an international survey percutaneous tracheostomy: a yr prospective evaluation of the single tapered dilator technique can outcomes of intensive care unit patients undergoing tracheostomy be predicted? respir care safety and complications of percutaneous tracheostomy in a cohort of mixed icu patients prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change. crit care are the dysnatremias a permanent threat to the critically ill patient? a explore the dengue-related risk factors and death factors in dengue hemorrhagic fever epidemic in taiwan diabeted with hypertension as riak factor for adult dengue hemorrhagic fever in a predominantly dengue serotype epidemic: a case study characteristics of dengue epidemics in taiwan modelling risk of cardio-respiratory instability as a heterogeneous process grant acknolwedgment nih ninr r nr during two years, we included all patients with more than days of stay in a medicalsurgical icu. previous informed consent , we collected demographics data, baseline functional status (barthel scale), mortality intrauci, at hospital and one-year of hospital discharge chronic critical illness a comparison between -dimentional speckle tracking & color-tissue doppler imaging for the assessment of left ventricular global longitudinal systolic strain and strain rate in outcome prediction of sepsis grant acknolwedgment italian ministry of health, italy (convenzione n. /gr- - ); and fondazione sestini exclusion criteria: do not resuscitate order. protocol: data were collected anonymously according to the utstein style. follow-up: months long using registry office and telephonic interview. data: age, sex, cerebral performance category (cpc good moderate disability, severe disability, unconscious), site of cardiac arrest, presumed etiology, initial rhythm (shockable or unshockable), witnessed event, monitored, cpr started within minute. primary end points: return of spontaneous circulation (rosc), survival to hospital discharge and cpc - . secondary end points: months survival and cpc - . statistics: numerical data are expressed as mean ± standard deviation or median (interquartile range), as percentage if ordinal data. chi-square test for ordinal data and t student's test for numerical data were performed. p significant if < . . results: cardiac arrests, cpr was carried out in cases ( %) secondary end points: . % alive at months; . % of them with cpc - . conclusions our experience reflects some aspects common with other european countries: less monitored events as well as more frequent cardiac arrests in unmonitored wards . rrt allowed a reduction of cardiac arrests thus reducing their incidence without modifying mortality incidence and outcome of in-hospital cardiac arrest in the united kindom national cardiac arrest audit epidemiology and outcomes of in-hospital cardiopulmonary resuscitation in the united states effectiveness of rapid response teams on rates of inhospital cardiopulmonary arrest and mortality: a systematic review and meta-analysis national intensive care surveillance, quality secretariat building, castle street hospital for women correspondence: a. beane -network for improving critical care systems and training (nicst), colombo, sri lanka intensive care medicine experimental fig. (abstract a ) fig. (abstract a ) authors thank tem international for providing a rotem analyzer for the study. references . the consort extension for cluster trials mcf fibtem & plasma fibrinogen references . extracorporeal membrane oxygenation for ards in adults cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with inhospital cardiac arrest: an observational study and propensity analysis critical care in resource-restricted settings on behalf of the task force for mass critical care. evacuation of the icu. care of the critically ill and injured during pandemics and disasters: chest consensus statement icu fire evacuation preparedness in london: a cross-sectional study fire on an intensive care unit caused by an oxygen cylinder national questionaire survey on what influences doctors; decisions about admission to intensive care the faculty of intensive care medicine/the intensive care society acute care toolkit . high-quality acute care. royal college of physicians united kingdom; golden jubilee national hospital, department of anaesthesia there is a need for general (non-cardiac) intensive care units (icus) to facilitate more elective and emergency surgery for these patients. inhaled nitric oxide, a selective pulmonary vasodilator, may be required for this purpose. objectives: we wished to determine the availability of inhaled nitric oxide in general scottish icus we excluded tertiary paediatric, cardiothoracic and neuro-critical care units. an online survey was distributed followed, if necessary, by a telephone survey. caldicott guardianship approval was not required. results: four ( %) general icus had nitric oxide immediately available adult congenital heart disease (grown-up congenital heart disease) audit of critical care in scotland scottish adult congenital cardiac service a references . triage of patients consulted for icu admission during times of icu-bed shortage a then performed a cross-sectional survey by visiting each facility, and determining characteristics for each facility critical care in low-income countries functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery sarcopenia is a predictor of outcomes in very elderly patients undergoing emergency surgery oudemans-van straaten hm, beishuizen a. low skeletal muscle area is a risk factor for mortality in mechanically ventilated critically ill patients acetate-versus lactate-based balanced colloids used as priming solutions for cardiopulmonary bypass: an experimental pilot study h. cauwenberghs , a. de backer , h. neels , i. deblier correspondence: h. cauwenberghs -zna middelheim general hospital methods: following irb approval, male non-diabetics gave consent and were randomly assigned to receive either succinylatedgelatin g (geloplasma®) in meq na+, meq k+, meq cl-, meq mg++, meq lactate (sid ) or succinylated gelatin g (isogelo®) meq na+, meq k+, meq ca, meq cl-, meq mg++, meq acetate and bonferroni corrected. results: demographics were comparable. acid-base variables changed similarly throughout without significant differences between groups (sig shown in figure ). by contrast, glucose levels rose very significantly in the lactate group and persisted post cpb (figure ). oncotic pressure, diuresis, osmolarity and oxygen uptake did not differ between groups. discussion. concerning acid-base variables and secondary endpoints the perioperative period stewart's textbook of acidbase pl effects of intravenous solutions on acid-base equilibrium: from crystalloids to colloids and blood components seric pro-adrenomedullin levels in low cardiac output syndrome (lcos) after cardiac surgery we measured am at time-points (t -t ): before surgery; at admission; h and h after surgery. continuous data were showed as average (sd) and categorical ones in percents. comparisons were performed with kruskall-wallis and anova tests. the roc approach was used to assess the predictor capacity of am. all analyses were performed with stata . the ethical committee approved the study. results: patients were included. the average of age was ± . years, and were women . %. the median (iqr) for euroscore was ( - ). comorbidities were hypertension ( %), diabetes mellitus ( %) and atrial fibrillation ( . %). on-pump surgery was performed in the % and the coronary bypass was the most frequent ( %). the incidence of low cardiac output syndrome was %. am levels (mmols/l) were: . ± . (before surgery) postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients consensus on circulatory shock and hemodynamic monitoring. task force of the european society of intensive care medicine canadian cardiovascular society position statement on the management of thoracic aortic disease guidelines for the diagnosis and management of patients with thoracic aortic disease early and midterm outcomes following surgery for acute type a aortic dissection importance of blood pressure control after repair of acute type a aortic dissection (abstract a ). pro-adm levels t -t bleeding complications associated with cardiopulmonary bypass prospective validation of the international society of thrombosis and haemostasis scoring system for disseminated intravascular coagulation towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation hospital regional, intensive care, malaga, spain; hospital serrania, ronda, spain; hospital regional, intensive care, málaga, spain; hospital infanta margarita, intensive care, cabra, spain; hospital virgen del rocio, intensive care we analyze differences in the postoperative incidence of af in both groups. results: cohort of patients, mean age . ± . years. . % was elective surgery. euroscore . ± . points. icu mortality was . %.prior to surgery, . % and . % taking statins present a history of af. . % postoperative af episode presented. the patients treated before surgery with statins had af . % vs . % (p = . ) the sample was divided among the patients who died and those who do not. demographic variables, prognostic scales,type of surgery,early complications, icu stay and mortality were compared.the variables that reached statistical significance in the univariate analysis were analyzed in multivariate logistic regression. data expressed as mean and standard deviation, percentage, mean difference, odds ratio and corresponding confidence intervals. statistical significance level of p < . . results: a total of patients were analyzed, ≥ years ( . %) of which died( . %) predictors of postoperative complications in octogenarians undergoing cardiac surgery a ventricular assist devices, transfusion and health-related quality of life %,median rbc transfused ventricular assist devices and increased blood product utilization for cardiac transplantation. stone ml et all bleeding complications and blood product utilization with left ventricular assist device implantation. schaffer jm et all after completion of cardiac surgery. the patients were divided into two groups: aged < and age ≥ years. association analysis of demographic, clinical, therapeutic factors and complications during icu stay. univariate analysis using chi square (fisher if applicable) and t student. data expressed as percentages, means, estándar desviation (sd), mean differences (dm), odds ratio (or), and confidence intervals % (ci %) results: a total of significant differences in cardiac arrest cardiac surgery in octogenarians: a case series outcomes and cost of cardiac surgery in octogenarians is related to type of operation: a multiinstitutional analysis aortic valve replacement with and without coronary artery bypass graft surgery in octogenarians: is it safe and feasible? short-and long-term outcomes in octogenarians after coronary artery bypass surgery diagnosing and treating the failing right heart matching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. the american journal of physiology university hospital of pisa, department of anaesthesia and critical care medicine, cardiothoracic and vascular anaesthesia venous-to-arterial co differences and the quest for bedside point-of-care monitoring to assess the microcirculation during shock model of pco gap during hypothermic cardiopulmonary bypass central venous o( ) saturation and venous-to-arterial co( ) difference as complementary tools for goal-directed therapy during highrisk surgery patients: closed-vs. opensystem the closed-system pivc was composed of catheter with inteof pivcs, the incidence of bacterial colonization and pivcs-related complications (phlebitis, extravasation, catheter occlusion and hematoma) were recorded. the protocol of the study was approved by the irb of tokushima university hospital. results: ninety-one closed-system pivcs and open-system pivcs were evaluated. the median indwell time did not differ between the closed-and open-system pivcs (median were identified from the database of the microbiological laboratory of the hospital and were included in this study as cases. demographic data, severity of illness, risk factors for colistin-resistance (described in previous studies), clinical management and hospital outcome of all cases were recorded. mdr -resistant to at least one agent from different classes. pdr -resistant to all classes. results: of kp ( . %) and of ec ( . %) isolates were colistin resistant. of ( . %) of kp and of ec ( . %) isolates were colistin resistant colistin-resistant isolates of klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster risk factors associated with the isolation of colistin-resistant gram-negative bacteria: a matched case-control study combination antibiotic treatment versus monotherapy for multidrug-resistant, extensively drug-resistant,and pandrug-resistant acinetobacter infections:a systematic review in vitro synergistic activity of tigecycline and colistin against xdr-acinetobacter baumannii woodlands multispeciality hospital references . combatting resistance in intensive care: the multimodal approach of the spanish icu "zero resistance" program. garnacho montero et als during a kpc outbreak in the -bed icu of a tertiary university hospital in rio de janeiro, brazil. all patients admitted to the icu were included in the study and classified as case (kpc yielded from any biological material, either considered as colonization or infection) or control (all other patients who did not have kpc isolation). both groups were compared according to demographic data, comorbidities, sepsis diagnosis, type and time of life support, sofa and saps iii scores at icu admission, length of stay (los) at icu and hospital, and hospital costs, icu and hospital mortality. results: patients were admitted during the studied period. patients had kpc samples isolated from different biological material conclusions: during a kpc outbreak in the icu of an academic tertiary hospital in rio de janeiro, the isolation of kpc associated with colonization or infection was associated with greater icu and hospital los, more requirements of life-organ support, higher icu and hospital mortality rates impact of carbapenem resistance on the outcome of patients' hospital-acquired bacteraemia caused by klebsiella pneumoniae first report of kpc- -producing klebsiella pneumoniae strains in brazil attributable mortality rate for carbapenem-resistant klebsiella pneumoniae bacteremia zero resistance" (rz) program was swabs (nasal, pharyngeal, axillary and rectal) were routinely performed to all patients admitted, besides diagnostic cultures when needed. furthermore, we analysed other pathological variables and comorbidities. the difference between groups of mrb was made by chi-square test for qualitative variables and the kruskal-walls test for the continuous ones. statistical significance was set at p < . . results: admitted. in patients were identified one or more mrb ( in total). patients ( , %) were esbls carriers, ( , %) mrsa, ( , %) p aeruginosa, ( , %) acinetobacter spp and ( %) others mrb carriers. in cases ( , %) the presence of a mrb caused infection. nasal swabs detected % of mrb carriers ( % of all mrsa), pharyngeal swabs % ( , % of mrsa), axillary swabs % ( % of mrsa, % of acinetobacter), and rectal swabs % ( % of esbls, , % of acinetobacter). in cases ( %) just the axillary swab was positive, and in cases ( %) the rectal was the only swab able to detect a mrb. diagnostic cultures (blood, urine, bronchoaspirate, surgical wound and others) detected mrb in less than %. the checklist did not detected neither colonization nor infection by mrb in ( %) patients ( % mrsa, , % acinetobacter, % of esbls). all patients with p aeruginosa had rf, but one. there was no statistical significance between groups of mrb and other comorbidities. conclusions: the surface cultures realized at admission detected % of mrb not detected by diagnostic cultures ):e . a enteral paramomycin to eradicate colistin and carbepemenase resistant microorganisms in rectal colonization to prevent icu multiresistant nosocomial infections university hospital of gran canaria dr. negrín, pharmacy department hospital of getafe, intensive care unit microbiology unit, section biology pathology and health products ) received catecholamines and ( %) were immunocompromised. icu mortality was . % and did not differ between esbl carriers and non-carriers. the rate of esbl colonization at admission and esbl acquisition were . % and . %, respectively. escherichia coli was the most frequently observed bacteria. the results of the univariate analysis for esbl acquisition are presented in table . in multivariate analysis, igs-ii and icu length of stay were strongly associated with esbl acquisition (table ). discussion and conclusion: the observed rate of esbl carriage on admission was comparable to other rates in french icus ( %). despite the unfavourable twin-bed architecture of our icu, the incidence of esbl acquisition was . % which was actually lower than transmission rates previously published in other icus. esbl acquisition was strongly associated with icu length of stay and severity score at admission. this study is fully consistent with previous ones challenging the geographic isolation in a non-epidemic setting and suggests that environmental contamination may not play a substantial role in the transmission of esbl-pe wipo was diagnosed with lus if, on at least one upper or lower part of both sides, the lus profile moved from a (normal) to b (interstitial oedema) or from b to "b+", where b+ consisted in at least a doubling of the b lines number. the reference diagnosis of wipo was established on other criteria by experts blind for lus. results: wipo occurred in ( %) sbt. among cases with wipo, the lus profile did not change during sbt in one case, changed for lus signs of pulmonary oedema in cases (true positives) and changed but without typical lus signs of wipo in one case university hospital of lausanne, intensive care and burn unit saint michael's hospital and keenan research centre, interdepartmental division of critical care a introduction: many different tools are found to predict weaning success us) assessed excursions of the right hemi-diaphragm could be a useful measurement for prediction success in weaning from mechanical ventilation (mv us was performed after patient met weaning criteria (according to local protocol) and it was decided to discontinue mv. patients with neuromuscular disorders and diaphragmatic paralysis were excluded. measurements were performed once on pressure support ventilation (ps ≤ cmh o, peep ≤ cmh o). the right hemi-diaphragms of patients were evaluated by m-mode ultrasonography (esaote mylabgamma ac - mhz convex probe). the average diaphragm excursions value (de avg ) was estimated from sequential measurements. the rapid shallow breathing index (sbi), dynamic compliance (c dyn ), minute ventilation (m v ) and spontaneous tidal volume (v t spont) were obtained from the ventilator (servo i , maquet) table ) with best de avg cut-off value . mm (sensitivity % , specificity %). conclusions: our findings suggest that right hemi-diaphragm excursions assessed with m-mode ultrasonography is more accurate predictor of weaning success than other common weaning criteria weaning from mechanical ventilation diaphragm dysfunction assessed by ultrasonography: influence of weaning from mechanical ventilation a cycling-off guided by real-time waveforms analysis (intellisync+): pilot study on next-generation psv anesthesia and intensive care methods: in patients under psv, intellisync + was compared to to default setting, ets opti decreased cycling delay and unassisted efforts at ps basal, but these favorable effects were not maintained at ps + . further optimization (ets opti ) decreased cycling and trigger delay but did not affect unassisted efforts. when intellisync + was activated, cycling delay was shorter and values of trigger delay and unassisted efforts were at least as low as with optimized settings of ets. table summarizes the results obtained in the conditions tested. conclusions: bedside optimization of ets guided by waveforms on the ventilator screen improved pvi. increase of pressure support level worsened pvi and mandated re-optimization of ets a characteristics and factors associated with prolonged weaning. a sub-analysis of the wind study g upres ea irib saint michael's hospital and keenan research centre, interdepartmental division of critical care objectives: to determine a predictor of weaning success with a faster reaction time than respiratory rate & pulse rate. methods: patients ( male, female) on mv > days were included in our study diagnosed with sepsis (n = ), pneumonia (n = ), pancreonecrosis (n = ), obesity hypoventilation syndrome (n = ), intestinal obstruction (n = ). oxygen consumption (vo ) monitoring in different stages of mv support reduction was recorded using e-covx evaluation of mortality over time in patients receiving mechanical ventilation the use of mechanical ventilation in intensive care unit in russia: national epidemiological survey ruvent- a prospective, blinded evaluation of indexes proposed to predict weaning from mechanical ventilation a randomized, controlled trial of the role of weaning predictors in clinical decision making cpf) using ventilator built-in flow-meter to predict extubation success: a single centre study f. gobert , , h inclusion criteria were: age > years, intubation > h, no withdrawal decision of life supporting care, eligible for scheduled weaning trial and then scheduled extubation, mechanical ventilation from evita xl ventilator (dräger, germany) and patient's agreement to participate. once daily checked criteria for weanibility were present, patients were switched to a standardised pressure support ventilation (inspiratory pressure = cmh o, peep = cmh o, fio = . ) for h (if no chronic respiratory failure-crf), h (if crf) or h (if neuromuscular crf). the procedure of cpf measurement was explained to the patient, who was encouraged to cough as strong as possible just before extubation. cpf measurements were done by freezing ventilator screen and scrolling the cursor to the maximal value of cpf during expiration and tidal volume (tv) in preceding inspiration. three measurements were averaged. early extubation success rate was defined as the proportion of patients who were alive and not reintubated h after scheduled extubation. median values were compared by using non parametric tests. diagnostic performance of cpf and tv was assessed by using area under curve (auc) of the roc method. after having defined cut-off values for cpf and tv, we described the performance of a test combining cpf and tv values to predict the early extubation outcome. results: during the study period, patients were admitted to our icu of who were intubated and patients included (fig ). between the patients who succeeded and the patients who failed extubation, median cpf was − . l/min and − . l/min, respectively (p = . , fig a), median tv . l and . l, respectively (p = , , fig b), and auc averaged . and . , respectively (fig a). bi-dimensional analysis showed a synergistic effect of cpf and tv to predict early extubation success (fig b). the combination of thresholds (cpf < − l/min and tv > . l) grant acknolwedgment the study has been supported by the sigrid juselius foundation, päivikki and sakari sohlberg foundation the third international consensus definitions for sepsis and septic shock acute renal failure in critically ill patients: a multinational, multicenter study relation between mean arterial pressure and renal function in the early phase of shock: a prospective, explorative cohort study grant acknolwedgment this study is supported by the national key technology r&d program of china conclusions: in patients with chronic renal impairment who undergo cardiovascular surgery requiring cpb, a lower level of preoperative shp is independently associated with higher risk of paki. a urinary angiotensinogen as a possible predictor of acute kidney injury in severe sepsis s we aimed to compare the incidence of aki according to rifle (risk, injury, failure, loss of kidney and end-stage kidney disease united kingdom intensive care medicine experimental ):a introduction: cytokine elimination during continuous hemofiltration (chf) depends largely on the character of the filter membrane a references ( ) (kidney disease outcomes quality initiative. kdigo clinical practice guidelines for acute kidney injury antithrombin supplementation for anticoagulation during continuous hemofiltration in critically ill patients with septic shock: a case-control study acquired deficit of antithrombin and role of supplementation in septic patients during continuous veno-venous hemofiltration the influence of venovenous renal replacement therapy on measurements by the transpulmonary thermodilution technique effect of the venous catheter site on transpulmonary thermodilution measurement variables the influence of haemodialysis on haemodynamic measurements using transpulmonary thermodilution in patients with septic shock: an observational study when drugs disappear from the patient: eliminaiton of intravenous medication by hemodiafiltration cardiac arrest in intensive care unit: case report and future recommendations omni® (b. braun, melsungen, germany), a new third generregional citrate anticoagulation. we collected patients' characteristics, filter life time, circuit pressures, interruption of therapy duration and reasons (alarm types), achieved and targeted renal dose, metabolic parameters (serum creatinine and potassium levels and arterial base excess). in addition, we adminof total therapy time) in cvvhd-citrate mode. mean achieved renal dose was . ml/kg/hr corresponding to % of the targeted dose in cvvh-heparin mode and . ml/kg/hr corresponding to % of the targeted dose in cvvhd-citrate mode. in both rrt modes, excellent metabolic control and adequate fluid balance were achieved. overall, the interface, design and ease of use were evaluated by users as excellent. conclusions: crrt in both cvvh and cvvhd modes could be provided using omni® in a safe and efficient way in ten critically ill patients. users provided positive feedback regarding therapy setup, management and user interface. a intermittent haemofiltration outside itu led by the intensive care team. experience at a tertiary cardiothoracic centre s following modification of the aquarius haemofilter (nikkiso), we designed and implemented a protocol for rca with stand alone citrate administration pre filter (acd-a (acid citrate dextrose formula-a) containing mmol/l of citrate) and post dilution cvvhf using calcium containing replacement fluid (accusol containing . mmol/l ca) and, when needed, supplementary calcium depending on systemic ica. the protocol can deliver or mls/kg/hr of crrt. we compare the efficacy of this new protocol, which we have initially implemented in patients with a relative contraindication to heparin, to a historical cohort of patients who received crrt with prostacyclin and or pre-dilution cvvhf but would not have been contraindicated for rca. we also present relevant biochemical data. methods: a prospective audit of the first adult critically ill patients receiving rca with post dilution cvvhf. crude comparison was made with a historical group of consecutive critically ill patients who received crrt without heparin prior to the introduction of the rca protocol. patients were excluded from the rca protocol and the comparison if they had, severe acute liver injury. data is presented as median (range) with non parametric analysis and filter survival as a kaplan meier for the event´filter clotting´and censored for medical cessation or technical failure. results: there were filters used in patients who received rca and in in the comparison group respectively. one patient ( filters) from the rca group was excluded from the filter survival analysis due to a triglyceride level of . mmol/l, causing repeated filter failure epidemiology of acute kidney injury in critically ill patients: the multinational aki-epi study conclusions: there is no relationship between copd patients, bmi, age and extubation failure. this new formula combine parameters, dtf*rsbi, as a good parameter for extubation.methods: we used the administrative claims data of all diagnosis procedure combination (dpc) hospitals in japan from april , to march , , and retrospectively reviewed the number and outcome at discharge of patients who were on ecmo support. results: we identified , patients who received ecmo support during the -year study period. the average age was . , and only . % of the patients were under years old. the most common diagnosis was acute coronary syndrome, followed by cardiac arrest and pulmonary embolism. the overall survival rate at discharge was . % [ %ci . - . ]. among the , acute care dpc hospitals, ecmo support was provided in hospitals ( . %), and therefore the annual ecmo patient volume per hospital was . , which is much lower than international standards for ecmo centers. adjusted odds ratio for discharge alive stratified by annual ecmo volume per hospital were . [ %ci . - . ] and . [ %ci . - . ] for medium ( hospitals treating to patients) and high volume centers ( hospitals treating or more patients), respectively, compared with low volume centers ( hospitals treating or less patients). conclusions: ecmo support was administered to many adult cardiac patients, and provided in a substantial proportion of acute care hospitals in japan. no significant patient volume effect for survival discharge was found. funding from the american nurses association impact grant is gratefully acknowledged. history and icu related data were analyzed. basal fracture risk before ci was calculated using the frax tool (https://www.shef.ac.uk/frax). in january , referent family doctors were contacted by phone to check out new bf occurred during the years after icu discharge. data are expressed as median (min-max) or percentages. unpaired data were compared using mann-whitney test (p < . = significant). results: from the patients admitted in , had an icu los ≤ d, were < y, died in icu or died after an icu los ≤ d and were lost to follow-up. we analyzed patients who were alive in january and patients who died outside icu during the fup after an icu los > d. regarding alive patients ( % males), admission was mainly related to cardiovascular, respiratory and neurological failure, or trauma. age was ( - )y, simplified acute physiologic score (saps ii) was . ( - ), icu los was ( - )d. according to the frax tool, the -y probability of major osteoporotic bf (major frax risk) was . ( - )%. nine patients ( men) developed bf in . ( - ) months after ci, equivalent to a % risk of new bf y after ci. a context of fall at home was noted in every case. age, icu los and saps ii of these patients were not statistically different from non-fractured patients. their major frax risk was ( - )%, significantly higher than non-fractured patients (p = . ). finally, among the dead patients, only one y man experienced hip fracture at the th month after ci. conclusions: present incidence of new bf in the y following severe ci with a prolonged icu stay is similar to previously published data [ ]. patients who experienced new bf after ci had a higher frax risk than the non-fractured patients. influence of ci or icu stay on bf risk is thus questioned. however, to be relevant, our results need to be compared to a control population: this work is ongoing. conclusions: we detected a rise in pro-adrenomedullin levels after cardiac surgery. the results suggest that am could be useful for lcos prediction. more data are necessary to confirm the role in the prediction of relevant outcomes. conclusions: the icu stay and early complications evaluated not differ between the two groups , except for acute renal failure and higher mortality, despite the use of shorter times in cardiac surgical in octogenarians. there is a progressive decrease in coronary artery bypass surgery in recent years in this group probably in favor of percutaneous techniques.high-risk patients who require intensive perioperative management,should be identified to reduce the incidence of postoperative complications.conclusions: previous renal replacement treatment and the colonized patients' long stay at icu increase the transformation of the vre colonization into vre infection. strategies to reduce the duration of icu stay of vre-colonized patients are the main objects to controlling vre infection rate. identification of sirs/sepsis signs by ward nurses reduces -days mortality in patients with sepsis m. torsvik , l.t. gustad , , i.l. bangstad , l.j. vinje , j.k. damås , , , e. solligård , , , a. mehl , , nord university, faculty of health science, levanger, norway; nord-trøndelag hospital trust, levanger hospital, internal medicine, levanger, number of patients had ulceration at the site of the suction port but did not suffer any complication as a result. drainage of pleural effusion with small bore tube in mechanically ventilated patients s.j. lee , y.s. cha , w.-y. lee correlate with decannulation failure but future studies are necessary in this field. objectives: to weight all sharps containers in a cardiac intensive care over a one-week period. to then review the financial implications of the cost of this waste. to review ways to redistribute this waste.methods: all closed sharps containers were weighed. research the cost implications of different waste types from the waste management team within the trust. look into ways of reducing this waste. results: a total of items where weighed, totaling . kg, costing £ . . this can be broken down in six l chest drain boxes, weighing . kg, costing £ . . four l sharps bin, weighing . kg, costing £ . . l sharps bin, weighing . kg, costing £ . , and thirty-nine l sharps bins, weighing . kg, costing £ . . this would take eight weeks to produce a tonne. producing around . tonnes a year costing £ , . . compared to other types of waste: sharps containers: £ per tonne clinical waste: £ per tonne domestic waste: £ per tonne recycling: £ per tonne clinically objects that aren't sharps are placed in sharps bins, for example arterial blood gas syringes, this item could be put into a clinical waste bin. while this suggests education is needed there are other methods to reduce sharps bin wastage. these include: having needle only sharps bins, and solidifying chest drain bottles post removal.conclusions: this cardiac intensive care unit produces a volume of high-cost waste. a large proportion of this waste can be redistributed to other types of waste. this could make the unit more efficient, and reduce it's environmental burden. this audit suggests that it should be looked at other types of waste and other departments in the same manner on other units. in the bloodstream infection density related to hemodialysis catheter in the hospital moyses deutsch was . , which represents patient in its entirety. due to this high rate, it was necessary to review all related process through institutionalized and supervised practice, minimizing the risks of hemodialysis procedure and maintenance of the catheter, in order to directly reduce the length of hospital stay, morbidity and hospital costs. objectives: objective of this study was to evaluate the application of strategies according to ihi to reduce infection of the bloodstream related to cvc hemodialysis. methods: the study was conducted in a -bed, medical-surgical icu. criteria for infection catheter related bloodtream infection are those from the cdc. strategy was to implement the permanent education of employees, highlighting the importance of prevention of infections;training of new employees as the hemodialysis routine and safe and aseptic techniques; optimize other measures that can reduce the risks, such as early removal of invasive devices.raise awareness of nursing staff about the importance of their role in the prevention of infection, such as maintenance of the catheter with use of aseptic techniques; disseminate monthly for teams infection rates; make benchmarking with other services; the goals were the icu team adhesion of % achieved in six month after bundle implementation and % after one year of follow up. from june on, the icu a effect of therapeutic hypothermia on mitogen activated protein kinase pathway in the brain tissue of a swine cardiac arrest model y. c objective: to investigate the change in mitogen-activated protein kinase pathways in the brain tissue after therapeutic hypothermia in swine cardiac arrest model. design. prospective animal study setting. university animal laboratory subjects. male domestic pigs (n = ) interventions: after the return of spontaneous circulation by cardiopulmonary resuscitation following min of no flow time induced by ventricular fibrillation, pigs were randomly assigned to one of four groups (sham, normothermia, hr of therapeutic hypothermia, hr of therapeutic hypothermia). therapeutic hypothermia (core temperature - °c) was maintained and the pigs were then rewarmed for hr. at hr after the return of spontaneous circulation, the pigs were sacrificed and brain tissues were harvested. measurement and main results: we measured the tissue levels of p , jnk, and erk pathway expressions in swine brain hippocampus of the four groups. the phosphorylated p to p ratio and phosphorylated jnk to jnk ratios were significantly increased in all of the intervention groups, relative to the sham group. but the phosphorylated erk to erk ratio was increased only in the therapeutic hypothermia groups (p-value = . in the hr of therapeutic hypothermia group and p-value = . in the hr of therapeutic hypothermia group, both compared to the sham group). conclusions: normothermia activated the p and jnk pathway. and did not activate the erk pathway in ischemia-reperfusion injury after cardiac arrest. therapeutic hypothermia, however, did not attenuate the activation of the p and jnk pathways, but activated the erk pathway, which seemed to be dose dependent with the duration of therapeutic hypothermia. effect of permissive hypercapnia on outcome of cardiac arrest in a porcine model of cardiopulmonary resuscitation g. babini , g. ristagno figure ). pigs in the hypercapnic group showed a trend towards longer survival. etco and pco were significanlty higher in the hypercaninc group compared to the normocpanic one (table ). ph and po trended to be lower in the hypercapnic group during the hrs of observation. hypercapnia was associated with significantly higher mean arterial pressure during the post-resuscitation (pr) period ( lesser neuronal degeneration was seen in the frontal cortex in the hypercapnic group compared to the normocapnic one (figure ) . neurological recovery was equivalent in the two groups ( figure ). conclusions: permissive hypercapnia after resuscitation was associated with better mean arterial pressure and lesser neuronal degeneration in pigs. grant support. laerdal foundation for acute care, norway introduction: pain is the main indication for utilisation of the physician staffed prehospital emergency service in germany. data from switzerland showed that oligoanalgesia (inappropriate treatment of pain with nrs > ) is common in trauma patients. objectives:( ) determination of the frequency of oligoanalgesia in trauma patients at our prehospital emergency service location in objectives: assessment of characteristics and outcomes of patients who suffer cardiopulmonary arrest resuscitated in a tertiary hospital, inside and outside intensive care unit, according to utstein style.methods: a prospective cohort study was performed according to utstein style. every arrest occurred in the hospital "virgen de las nieves" (granada, spain) for a period of years (july/ -june/ ) were included. all arrest occurred in all areas of the hospital were included, except those in operating rooms and anesthesia recovery room (not attended by the resuscitation team) and those commenced in the prehospital setting. we also excluded patients in whom no resuscitation attempt was made or those suspended either by existence of a living will, by orders dnr or considered futile. the variables were grouped according to the location (inside or outside the icu). chi test was performed when the dependent variable was qualitative and a t-student test when it was quantitative.results: during this period a total of patients suffered at least one episode of arrest and they were resuscitated. most frequent sex was male ( . %) with a median age years ( . ± . years; interquartile - years). the cardiac origin was the most common aetiology ( . %). the icu was the area most frequent location ( . %). when comparing the characteristics of icu arrests with the rest of the hospital, significant differences were observed. it was most likely to have a shockable initial rhythm (χ : . ; p = . ), younger age ( , ± , vs , ± , years; t = , ; p = , ), shorter interval to defibrillation ( , ± , vs , ± , min; t = , ; p = , ), shorter period until start of resuscitation ( , ± , vs , ± , min; t = , ; p < , ) and shorter total duration ( ± , vs , ± , min; t = , ; p < , ). however, no differences were found in coronary aetiology, sex, recovery of spontaneous circulation and hospital survival ( . % vs . % in icu).conclusions: despite higher frequency in initial shockable rhythms and lower intervals until defibrillation and resuscitation in the icu, no differences were found in initial recovery or hospital survival. delayed onset of cardio-pulmonary resuscitation (cpr) does not induce hyperfibrinolysis in a piglet model of ventricular fibrillation -a pilot study in göttingen minipigs n. introduction: pulmonary arterial hypertension (pah) is a disease with gradually increased pulmonary vascular resistance and pressure, often leads to right ventricular (rv) failure and death. excessive proliferation of pulmonary arterial smooth muscle cells (pasmcs) is regarded as the major cause of the remodeling of pulmonary artery, whereas the underlying mechanism is largely unclear. caffeic acid phenethyl ester (cape) is the main component of propolis, which is known as a versatile compound of antimitogenic, anticarcinogenic and anti-inflammatory potentials. objectives: to investigate the effects of cape on the improvement of the hemodynamic function in pah animal model and to explore the underlying mechanisms in in vitro pasmcs. methods: animal model of pah symptom was induced in - grams sprague-dawley rats by subcutaneous injection of monocrotaline (mct, mg/kg). weeks later, the mct-induced pah rats received intraperitoneal administration of cape with various dosages of or mg/kg once per day, for further weeks. hemodynamic functions, including rv systolic pressure (rvsp) and fulton index, were measured before sacrifice. the lung tissues were harvested for examining the vascular remodeling of pulmonary artery. to investigate the molecular mechanisms, in vitro cultured human pasmcs challenged with either % oxygen level or recombinant human pdgf ( ng/ml), followed by the treatment of cape in or mm. the change of expression level and phosphorylation of the cellular signaling molecules, including erk, akt, nf-kb, or hif- a, were analyzed by semi-quantitative pcr and western blotting, respectively. results: in mct-induced pah rats, cape significantly improved the hemodynamic values of rvsp, fulton index, and attenuated the severity of pulmonary vascular remodeling. furthermore, the administration of cape critically reduced the expression levels of hif- a, nf-kb and pdgf molecules in the lung of mct-induced pah rats. in vitro assay showed that an increased expression level of hif- α and pdgf genes in hpasmcs was observed under hypoxia or pdgf stimulation, which was significantly suppressed following cape treatment. for chemical inhibition, we indicated that cellular signaling molecules erk, akt and nf-kb were involved in the up-regulation of hif- a and pdgf genes, which were responsible for the proliferation of hpasmcs exposed to hypoxia or pdgf stimulation. in addition, cape also significantly promoted the number of apoptotic cells and the number of cell arrested in g phase of hpasmcs by tunel assay and sa-b-galactosidase staining, respectively. conclusions: we showed evidence that the natural compound cape could provide therapeutic benefits on the reversal of experimental pah rats. importantly, the results further indicated that the hif- a-mediated pdgf expression is a positive feedback mechanism underlying the pathogenesis of pah, which was regulated by the akt/erk/nf-kb signaling. right ventricular arterial coupling after cardiac surgery: a preliminary report p. introduction: right ventriculo-arterial coupling (rvac), defined as the ratio of end-systolic elastance (rees) to pulmonary arterial elastance (rea) is considered a sensitive method to assess right heart performance [ ] . objectives: in this study we aim to identify the feasibility of measuring rvac in hemodynamic deranged patients undergoing complex/ emergency cardiac surgery using cardiopulmonary bypass (cpb) as an experimental model of further hemodynamic impairment. objectives: this study aims to determine the frequency of the vre colonization and the transformation into infection and the risk factors, which lead to infection. methods: the patients who were hospitalized for at least hours in tertiary mixed type icu between and and had vre colonization and vre infection during or following their hospitalization were included in the study and their medical records were examined retrospectively. vre rectal swab sample was taken from each patient at his arrival and once a week afterwards. when negativity was detected in the rectal swab sample, which had been taken total times successively from those with positive vre; that patient was considered vre negative. their demographic data, apa-che ii scores, invasive procedures, treatments (corticosteroid, antibiotics, etc.), nutrition types, laboratory results and icu outcome were recorded. results: vre colonization was detected in of patients ( . %) admitted to icu. vre infection developed in of vre-colonized patients ( . %). among these infected patients; it was (n = ) . % primary bloodstream infection, (n = ) % urinary tract infection, (n = ) % . pneumonia. in vre colonized patients ( . %) and infected patients ( %), the most frequent factor was e. faecium. in % of the vre-colonized patients, vre became negative in their stay at icu. previous renal replacement treatment was significantly higher in statistical terms in the vreinfected group ( . %) when compared to vre-colonized group ( . %) (p < . ). in the vre-infected group, colonization with vre lasted longer than week in patients ( . %) were determined. demographic data, apache ii scores, treatments, nutrition types, previous antibiotic usage and types, invasive procedures, laboratory results and icu outcome were similar between the vre-colonized and infected patients.objective: to assess the value of enteral paramomycin to decontaminate patients with rectal colistin and/or carbepemenase resistant microorganisms colonization to prevent the development of icu nosocomial infections methods: all consecutive patients admitted to the icu from october to september , expected to require tracheal intubation for longer than hours, were given sdd with a -day course of intravenous cefotaxime, plus enteral colistin, tobramycin, nystatin in an oropharyngeal paste and in a digestive solution. oropharyngeal and rectal swabs were obtained on admission and once weekly. rectal swabs colonized by colistin and/or carbepemenase resistant microorganisms were treated with enteral paramomycin gram every hours a day, in order to eradicate them and prevent nosocomial infections. categorical variables were summarized as frequencies and percentages and the continuous ones as medians and interquartile ranges (iqr) or means and standard desviations. statistical significance was set at p ≤ . . results: we applied paromomycin treatment to colonized patients with rectal colistin resistant microorganisms. all of them had colonization by extended spectrum beta-lactamases (esbls). also, all of them but two were klebsiella pneumonia. out of these two, one patient was colonized by enterobacter spp and other one by escherichia coli. demographic data and type of admission are shown in fig. . forty out of ( , %) of the studied patients the rectal swab became negative. five out of the patients were colonized by carbapenemases producing microorganisms and one of these died with persistent multirresistant rectal colonization. only out of the patients that negativized the colonization received concurrent susceptible iv antibiotics. only of the paromonycin treated patients developed a mediastinitis infection due to one of the treated microorganisms. finally, patients died in the icu. conclusion: our data show that enteral paramomycin is effective in treating rectal colistin and/or carbepemenase resistant microorganisms colonization allowing clinicians preventing the development of icu nosocomial infections. introduction: diaphragmatic thickness increases as lung volume increases towards tlc. it has been shown that in healthy subjects, diaphragmatic thickness, increases as lung volume increases, above . of the vital capacity (vc). in mechanically ventilated patients, different levels of peep are used to improve oxygenation. there is no information about the diaphragmatic thickness when in icu patients, lung volume increases with peep towards tlc. methods: in patients with acute respiratory failure (arf) and lower lobe atelectasis detected by lung echo, two levels of peep ( and ± cmh o) are used to increase lung volume and to improve oxygenation. end expiratory lung volume (eelv), and diaphragmatic thickness was measured at baseline (zeep) and at the two levels of peep. eelv was measured with a nitrogen indirect dilution method and diaphragmatic thickness at the zone of apposition with echography using a mhz linear probe. statistical analysis was performed by one way anova and normal distribution by colmogorof-smyrnof test. results: patients ( m and f) with a mean age of ± were studied. diaphragmatic thickness at baseline was , cm and eelv at ml ( %) of the predicted ( ml). at the intermediate and high level of peep diaphragmatic thickness did not change significantly ( . and . cm, respectively, p = . ) and eelv increased at % ( ml) and % ( ml) of the predicted. the increase in lung volume induced by peep was at % and % of the predicted vc ( ml). mean pao /fio ratio did not change significantly conclusions: mechanically ventilated patients for arf have a severe reduction in their eelv or frc. the use of peep reestablishes partially the eelv, but not to his normal levels(predicted frc). despite high levels of peep, diaphragmatic thickness remained constant because the increase in eelv never attained the % the vital capacity.introduction: the majority of patients entering the weaning process from mechanical ventilation (mv) in the intensive care unit (icu) will have a short and simple weaning (sw) successfully terminated within hours, while other may take up to one week (difficult weaning) or longer. studies have shown that using a sedation or a weaning protocol could reduce the length of mechanical ventilation and the weaning duration. objectives: to describe factors associated with sw and particularly assess if sedation and weaning protocol are associated with the proportion of patients having a sw. methods: we used the data from the wind (weaning according new definition) study, a prospective multicenter observational study performed in france ( icus), spain ( icus) and switzerland ( icu) from april to august . ventilation and weaning modalities were daily assessed until discharge in all intubated patients admitted to the participating icus. we defined ) weaning attempt (wa) as a spontaneous breathing trial (sbt) or an extubation attempt (with or without sbt), ) successful weaning as an extubation without death or invasive mechanical ventilation within days. we considered patients as having a sw if weaning was successfully terminated within h following their first wa. having a protocol for sedation or for weaning (or both) was asked to each center. quantitative and qualitative variables are presented as mean (standard deviation), median [interquartile range] or number (percentage) as appropriate. comparisons of proportions were made using chi or exact fisher tests and continuous variables were compared using student t-test or wilcoxon rank sum test as appropriate. we performed a multivariable analysis of factors associated with sw by means of a logistic regression, forcing both sedation and weaning protocols in the final model. all statistical tests were two-sided and p values of . or less were considered significant. results: among the patients included, patients entered the weaning process and we only kept in the present analysis the patients who did not have any decision of withholding or withdrawing mechanical ventilation. among these patients, ( %) had a sw and ( %) had a weaning duration longer than hours. main clinical characteristics are shown in table . conclusions: in this study of patients with a daily assessment of the weaning process, hospitalization in an icu using a sedation protocol or a weaning protocol (as declared by the center) was not associated with a higher proportion of patients having a simple and short weaning. admission for planned surgery, younger age, lower sofa score at admission and shorter duration of ventilation before any weaning attempt were associated with a higher proportion of simple and short weaning. this study benefited of a grant of the non-profit association départementale des insuffisants respiratoires (adir) of the haute normandie, france. introduction: during weaning from prolonged ventilation overload of diaphragm as main breathing muscle should be avoided. clinical criteria are used for determining the end of the spontaneous breathing trial (sbt) in the context of a discontinuously concept for weaning. in addition the patients subjective feeling of breathing exhaustion plays an important role. in incommunicable patients lacks this possibility for feedback.continuous monitoring of diaphragm electrical activity could give information of respiratory muscle effort during sbt. objectives: in tracheotomized patients undergoing prolonged weaning the relationship between the protocol-based definition of the end of a sbt and the course of the electrical activity of the diaphragm (eadi) should be examined. methods: prospective observation study conducted in a beds intensive care unit in an early rehabilitation clinic. patients that were not communicable because of stroke ( ), cerebral hypoxaemia ( ), traumatic brain injury ( ) have been included. using an eadi-catheter usually applied in nava (neurally adjusted ventilatory assist)-ventilation, peak of diaphragm electrical activity (eadi peak) was continuously recorded minutes before disconnection from ventilator up to minutes after reconnection. the weaning protocol contained two possibilities for terminating of the sbt: reaching clinical signs of ventilation exhausting or reaching a previously fixed time limit. results: median duration of mechanical ventilation at study start was days and days at successful weaning ( / patients, died). sbt have been recorded, terminated because of exhaustion, by time limit. median duration over all was minutes (exhaustion: / time limit: ). with multiple regression analysis, the relationship between the duration of the sbt and the eadi peak was examined. looking at all sbt, which were terminated due to exhaustion, shows that the duration of the sbt has a highly significant impact on eadi ( p < . ). the mean increase of eadi peak was . μv (absolute) and . (relatively). in sbt terminated because the time limit has been reached, there was no significant correlation between the time and course of eadi peak. conclusions: continuous recording of the electrical diaphragmatic activity during weaning of prolonged ventilation in incommunicable patients can be used as supplementary parameter in monitoring the respiratory function. introduction: patient-ventilator asynchronies are associated with poor outcome. it was suggested that bedside analysis of ventilator waveforms may help detecting different types of asynchrony and setting properly the ventilator [ ] . objectives: to test accuracy of a "waveform" method, based on specific signs on airway pressure (paw) and flow curves, in detecting spontaneous respiratory activity and asynchronies in patients under pressure support ventilation (psv).methods: recordings ( min each) of esophageal pressure (pes), paw and flow were obtained in obstructive ( %) and restrictive ( %) patients under psv with clinical evidence of poor patient-ventilator interaction. tracings of breaths were visually analyzed for detection of spontaneous respiratory activity both with pes (reference method) and without pes (waveform method) by different operators. breaths were defined as assisted, unassisted or autotriggered, and assisted breaths as delayed triggered, early cycled or delayed cycled. the waveforms method was applied in a selection of tracings ( min, breaths) by different operators for assessment of inter-rater agreement. results: the reference method detected autotriggered ( . %), unassisted ( . %) and assisted ( . %) breaths; among assisted breaths, delayed triggered ( . %), delayed cycled ( . %) and early cycled ( . %). table shows sensitivities and specificities ( % ci) of the waveform method in evaluating patient-ventilator interaction. the waveform method detected the start of patient's inspiration and expiration with a bias of − and − ms and a precision (± . sd) of and ms respectively. absolute agreement among operators was almost perfect for unassisted breaths, strong for delayed triggered, delayed cycled and early cycled breaths, and weak for autotriggered breaths. conclusions: the waveforms method is a reliable, accurate and reproducible method to assess patient-ventilator interaction and could help optimal setting of the ventilator. automation of this method may allow continuous monitoring of ventilated patients and/or improved breath triggering and cycling.methods: we studied a group de mechanically patients during the weaning time, at pressure support ventilation (psv) with different levels of assistance (high - cmh o, medium - cmh o, low - cmh o). esophageal, gastric, airway pressure, and airway flow were registered, samplig hz. we determined the phase difference (Φ) relationships between the neuronal times obtained from derivative flow versus esophageal or gastric signal respect to machine cycle, by calculating the phase delay, dividing by the cycle time of ventilator* °. times (t) definitions: t = onset inspiratory effort, t / = effort maximum. data were analyzed by descriptive statistical methods and are expressed as mean ± sd, medians, interquartile range (irq, - % quartile), and coefficient of variation (cv). the comparisons were performed by mann-whitney test. the relationships between measurement methods was examined using single linear regression and bland-altman analysis. results: patients were studied. for all data angle phase Φ median (irq): t : , (− , to , ), t / : − , (− , to , ). the mean comparison of t and t / between pes and df did not showed statistical differences for any level of support, and correlation r > , . the cv for all data at the t of pes and df: % and %, respectively; and for the t / of pes and df: % and %, respectively; without differences between levels of assistance. table below show results from bland-altman analysis. figure show representative tracing of df with well-defined inflection points (arrows) at t and t / , as the onset inspiratory flow and transition from inspiratory to expiratory flow. conclusions: the derivative of flow signal is useful to measure with accuracy neuronal and cycling times, it´s more homogeneous and precise than obtained for esophaeal or gastric pressure for all levels of assistance. the derivative of flow signal is a non-invasive signal which can be calculated easily and useful by conventional ventilator. introduction: sepsis has been defined as organ dysfunction as a result of the inappropriate host response to infection. [ ] renal function is often injured at the early stage of sepsis. [ ] autoregulation, which plays an important role in maintaining an adequate renal blood flow against changes in blood pressure, could be impaired during sepsis, [ ] thus resulting in aki if blood pressure fluctuates greatly. objectives: to investigate if there is any relationship between blood pressure variability (bpv) and aki in septic patients. methods: clinical data of patients admitted to our bed medical icu between / and / were reviewed. continuous records of blood pressure were analysed. blood pressure variability was calculated as the coefficient of variation (cv) of mean arterial pressure in the first h of admission. aki was defined by the kdigo definition according to creatinine change and urine output criteria. [ ] results: adult patients with sepsis (age: . ± . years old; apache ii score: . ± . ; male: . %) who stayed at icu for more than three days were identified. aki was presented in ( . %) of them (stage : n = ; stage : n = ; stage : n = ). the bpv was . ± . % for the patients with aki versus . ± . % for the others (p < . ). icu mortality was . % for the aki group compared to difference was not statistically significant regarding creatinine level on admission (p = . ). moreover, there was a positive correlation between uancr ratio on admission with akin staging and creatinine level of the all studied patient in the follow up days. the cutoff value of uancr on admission to predict later occurrence of aki during icu stay was . ng/mg: at this level, ( . % sensitivity and . % specificity). conclusions: urinary angiotensinogen is a new promising biomarker in early prediction of aki in patients with severe sepsis. acute kidney injury in patients with severe sepsis or septic shock: a comparison between the "risk, injury, failure, loss of kidney function, end-stage kidney disease" (rifle), acute kidney injury network (akin) and kidney disease improving global outcomes an st and polymethyl methacrylate (pmma) membranes have strong adsorption capacity. cytokines play important roles as the main mediators affecting critically ill patients. however, differences in the cytokine elimination by specific membranes during chf have not yet been fully investigated. objective: the objective of this study was to determine the elimination of cytokines by an st and pmma membrane filters during chf in a pig sepsis model. methods: piglets (n = ) weighing - kg were anesthetized and administered μg/kg endotoxin. the baxter sepxiris (an st membrane) and the toray hemofeel . w (pmma membrane) were used as hemofilters. samples were taken at , , , and hours after endotoxin administration, and the inlet plasma, outlet plasma, and filtrate concentrations of tnf-α, il- β, il- , and il- were measured. clearance values were calculated for each cytokine. results: endotoxin administration induced increases in the inlet plasma concentrations of all cytokines measured. the an st membrane filter showed higher adsorption and clearance of il- than the pmma membrane filter at hours after endotoxin administration (an st: . ± . ml/min; pmma: − . ± . ml/min; p < . ). however, the pmma membrane filter showed higher adsorption and clearance of il- β than the an st membrane filter. il- did not appear in the filtrate of the pmma membrane filter, while il- was not eliminated in the filtrate of the an st membrane filter. in addition, the filtrate concentration of tnf-α increased after its plasma concentration decreased with the pmma membrane filter. conclusions: shiga et al. previously reported the efficacy of cytokine absorption by an st membrane filters during continuous hemodiafiltration, and matsuda et al. reported the efficacy of cytokine absorption by pmma membranes. however, the cytokine absorption efficacy by these two membrane filters had not been directly compared. the results shown here confirm that there are differences in cytokine adsorption by the an st and pmma membrane filters. introduction: continuous renal replacement therapy (crrt) in intensive care is a cornerstone in the supportive treatment arsenal. its influence on thermodilution cardiac output measurements, and the possible influence of central venous dialysis catheter(cvdc) position, has been studied but the results are of uncertain clinical impact ( ) ( ) ( ) . there have been case reports describing the possibility of direct aspiration into a cvdc of drugs given in adherent central venous catheter(cvc) ( , ) . objectives: the aim of this study was to investigate if different positions of central lines influence infused noradrenaline during continuous renal replacement therapy (crrt) in an experimental animal model. methods: ten anesthetized piglets received a cvc in the right jugular vein and two cvdcs (one via the same jugular vein as the cvdc and the other through a femoral vein). after randomization the crrt was started in either one of the cvdcs and a nitroprusside infusion was started in an auricular vein. the dose was titrated until the mean arterial pressure (map) was mmhg and then kept constant during the rest of the experiment. after reaching the intended blood pressure an infusion of noradrenaline was started and titrated with the goal of increasing the blood pressure to a map of mmhg during minutes. after a washout period the crrt circuit was changed to the other cvdc and the experiment was repeated. results: the median dose of noradrenaline with the crrt in the jugular vein was . (iqr . ) and in the femoral vein . (iqr . ) μg/kg/min (p = . ). conclusions: during crrt, the noradrenaline dose needed to reach a target blood pressure in hypotensive piglets was twice as high with the cvc and cvdc close together, compared with cvc and cvdc on opposite sides of the diaphragm. this suggests that there is a possible clearance of noradrenaline and that the clearance is affected by catheter positioning a first evaluation of omni, a new device for renal replacement therapy p. schlaepfer , , j.-d. durovray , , v. plouhinec , c. chiappa , r. bellomo , a.g. schneider introduction: due to the lack of conventional dialysis facilities in our centre, intermittent renal replacement therapies (irrt) are led and performed by the itu team. this team comprises a group of specialist outreach nurses with the support of intensivists. irrt are performed nocturnally by itu nurses in level areas according to our hospital policy. objectives: to describe the use and results of irrt in level areas in patients that have left itu with established aki. these therapies are directed and performed by specialist intensive care nurses with the support of the itu medical team. methods: retrospective observational study that included those patients admitted to level areas at harefield hospital during that were transferred to level areas still requiring irrt. demographic variables were collected, along with the indication and duration of irrt and results. results: patients were admitted to harefield hospital level areas during , of which patients required continuous renal replacement therapies (crrt). this population included patients admitted after cardiac and thoracic surgery, heart or lung transplantation, mechanical circulatory devices, out of hospital cardiac arrests (oohca) and medical admissions from the cardiology or cardio-thoracic surgical wards. demographic variables were collected, along with the indication and duration of crrt. of those patients still required intermittent renal replacement therapies at their discharge to a level area. of them ( . %) were male and the group was a median age of . years. of them ( %) were hypertensive and ( %) were diabetic. as shown in figure , the most frequent reason for admission to intensive care was cardiac surgery ( . %, patients), followed by lung transplantation, heart transplantation and medical admissions from the transplantation ward. the reasons for admission to intensive care in the general crrt group are also shown in figure . the most frequent indication for initiation of crrt was metabolic acidosis ( . %, patients), followed by a combination of uraemia and fluid overload ( . %, patients), uraemia ( . %, patients) and fluid overload ( . %, patients) as shown in figure . the median time of rrt was days days whilst the median time of filtration in the general rrt group was days. the in-hospital mortality (after discharge from itu) was . % and was . % in the general crrt group. no complications were associated with the use of intermittent renal replacement therapies in level areas. conclusions: the group of patients that required intermittent renal replacement therapies beyond their discharge from itu had longer itu and hospital lengths of stay. these therapies were performed safely in level areas by the itu team, allowing these patients to leave level areas to continue their care. key: cord- - xzc uc authors: nan title: esicm wednesday sessions october date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: xzc uc nan power spectrums for vt and eadi are shown in fig. (ps and nava) for a typical patient. the enlarged section highlights how changes in eadi are highly synchronized with nava ventilation, but less so for ps. table ) and complications of mechanical ventilation ( table ) did not differ significantly between the two studied groups. introduction. high tidal volumes in mechanically ventilated patients with ards lead to baro/bio-trauma and increase mortality. also, it was recently shown that ventilation with high tidal volumes is a risk factor for ''acquired ards'' in a medical population. objective. we evaluated the impact of high tidal volumes after cardiac surgery. method. we analysed the prospectively recorded data of , consecutive patients who underwent cardiac surgery from to . we predefined groups of patients based on the tidal volume delivered immediately after surgery: ( ) low: - . , ( ) ''traditional'': - . , ( ) high: above ml/kg of predicted body weight (pbw). we assessed the risk factors for organ dysfunction (prolonged mechanical ventilation, hypoxemia, hemodynamic failure and renal failure) by univariate and multivariate analysis, including the initial tidal volume in the models. mean tidal volume/actual weight and tidal volume/pbw was . ± . and . ± . in men (p \ . ), . ± . and . ± . in women (p \ . ). patients ( %) were ventilated with low tidal volumes, , ( . %) with ''traditional'' tv and ( . %) with high tv. the mean body mass index in the groups was . ± . , . ± . and . ± . respectively (p \ . ). with increasing bmi, the tidal volume/ actual weight decreased while the tidal volume/pbw increased (figure) . the percentage of women was . , . and . % respectively for low, ''traditional'' and high tv (p \ . ). high tidal volumes were associated with prolonged intubation ([ h) ( . vs. conclusion. traditional and very high tidal volumes are associated with prolonged mechanical ventilation and organ dysfunction after cardiac surgery and use of high tidal volumes is an independent risk factor. ''prophylactic'' protective ventilatory strategy should be provided in this population with inflammatory state at risk to develop ventilator induced pulmonary edema. women and patients with high bmi are more at risk to be ventilated with injurious tidal volumes. introduction. evidence shows that clinicians' non-technical skills (behavioural and cognitive skills) have a significant impact on teamworking, patient safety, efficiency of care provided and potentially patient outcomes ( ) . such skills are key for cardiac arrest teams (cats), which are multi-professional (anaesthetists, physicians and nurses) and normally function under high pressure. to date, most tools to assess nontechnical skills in healthcare have focused on surgery ( ) and anaesthesia ( ) . no validated, robust tools are currently available for assessing non-technical skills in cats. objectives. to develop and validate an observational skill-based clinical assessment tool for resuscitation (oscar). this should be psychometrically robust for use in both training and assessment contexts. methods. oscar was based on a well-validated tool for surgery (otas) ( ) and was developed in phases. six behaviours were included in the assessment: communication, cooperation, coordination, monitoring, leadership and decision-making. observable behavioural exemplars were derived for each one of these behaviours across the three cat subteams-anaesthetists, physicians and nurses (phase ). quantitative expert consensus methodology was employed to assess content and face validity and observability of the exemplars (phase ). two clinician observers used oscar to blindly rate eight cats performance in a series of simulated cardiac arrests. psychometric analyses of these ratings were used to determine observable behaviour applicability, internal consistency, and inter-rater reliability (phase ). . of oscar behaviours demonstrated high internal consistency (cronbach a = . - . ). psychometric analyses dictated removal of three behavioural exemplars (two in anaesthetic group; one in physician group) to significantly improve internal consistency. inter-rater reliability was also high (inter-observer pearson r = . - . , all p \ . ). inter-observer reliability analyses revealed a learning curve between the two observers, with significant reduction in scoring discrepancies from the first to the eighth observed resuscitations. conclusions. oscar is a psychometrically robust (reliable, content-and face-valid) tool for the assessment of teamworking skills in cardiac arrest events. the tool is feasible to use and can be employed for both training and assessment purposes. introduction. different educational methodologies are used to teach basic skills in emergency medicine. high-fidelity patient simulation offers an ideal venue for presentation of critical events that can be managed by medical students without risk to a patient. therefore full scale simulation training could be superior to paper case based seminary rounds to achieve these specific educational objectives. objectives. the aim was to compare simulation to a standard education measured by multiple choice questionnaire. after written informed consent and approval of the institutional research ethics board fifth year medical students were included in the survey. they took part in the compulsory emergency medicine curriculum of charité universitätsmedizin berlin. the students completed a basic multiple question tests on day including questions concerning the topic of ''acute coronary syndrome'' (acs). on day for the topic ''acs'' half the group was assigned a min session simulation training while half the group was assigned a min session paper case training. on day groups were reversed and the topic ''aic'' was taught in either simulation training or paper case seminary round. the test of day was repeated after each training sessions. results of the tests were evaluated using spss(tm) . the mann whitney u test was used to show any significant differences in reaching educational objectives in the test (a \ . was considered significant). there was an even distribution of men and women among the two groups. the test results showed no significant difference between the two groups on day . on day two for the topic ''acs'' the group with simulation training achieved significantly better test results. for the topic ''acs'' on day there was no difference while students received further training in acs not using a high fidelity simulator. the results were not linked to specific teachers. introduction. rapid sequence induction (rsi) involves loss of spontaneous breathing and mandates airway control. steps to reduce adverse incidents include adherence to minimum monitoring standards, appropriate drug selection, access to difficult airway equipment and presence of skilled anaesthetists. there is substantial evidence that appropriate monitoring reduces risk by detecting the consequences of errors, and by giving early warning of patient deterioration. objectives. to assess conduct of emergency anaesthesia (monitoring and drugs) for critically ill patients not in an operating theatre (or) administered by intensive care doctors. methods. prospective analysis of rsi for critically ill patients in a uk nhs acute hospital over month. or based practice was excluded. reason for anaesthesia, location, drugs administered, monitoring modalities, adverse events and access to airway equipment were recorded. results. data from patient episodes were collected: predominantly in the emergency department ( %) and intensive care unit ( %) for respiratory failure ( %), reduced consciousness ( %) and to facilitate investigations ( %) . the most common induction agent was propofol ( %); thiopentone ( %) and etomidate ( %) were less frequently used. suxamethonium ( %) was preferred for initial neuromuscular blockade. during induction most doctors used pulse oximetry, electrocardiography and blood pressure monitoring. only % used capnography. no doctor used minimum monitoring to association of anaesthetists of great britain and ireland (aagbi) standards. rescue airway equipment immediately available is shown in fig. . complications occurred in cases (fig. ) . patients that had a hypotensive episode during induction all had thiopentone or propofol used as induction agents. % of patients had a period of desaturation, and % required more than one attempt for successful intubation. in cases with complications, rescue airway equipment was unavailable in[ and % did not achieve uk minimum monitoring standards. conclusions. shortcomings during emergency anaesthesia were recorded including monitoring, access to rescue airways and physiological disturbance. procedural guidelines and training are to be developed for emergency anaesthesia; access to capnography and alternative airway equipment will be assured. these issues are unlikely to be unique to our trust and assessment of practice is recommended. introduction. critical care echocardiography (cce) is performed and interpreted by the intensivist at the bedside to establish diagnoses and guide the management of patients with circulatory or respiratory failure in the icu. competence in basic and advanced cce has been recently defined [ ] , but no curriculum to reach the required cognitive and technical skills has yet been elaborated. objectives. to assess the efficacy of a limited, tailored training program for noncardiologist residents without experience in ultrasound to reach competence in basic cce. methods. six noncardiologist residents (anaesthesiology: n = , pneumology: n = ) without previous experience in ultrasound participated to the study during two -month periods. the curriculum consisted in h of didactics, h of interactive clinical cases and h of tutored hands-on. color doppler mapping was excluded from the training. after completion of the training program, all eligible patients underwent subsequently a transthoracic echocardiography (tte) performed in random order by a recently trained resident and an experienced intensivist with expertise in cce who was used as a reference. in each patient, the resident and the experienced intensivist answered binary ''rule in, rule out'' clinical questions covered by basic cce [ ] : global left ventricular (lv) size and systolic function (eye-ball evaluation of ejection fraction), homogeneous or heterogeneous lv contraction pattern, global right ventricular (rv) size and systolic function, identification of pericardial fluid and tamponade, and assessment of both the size and respiratory variations of the ivc. in case of undetermined interpretation, the corresponding clinical question was considered not addressed. the agreement between responses to clinical questions provided by the two investigators who independently interpreted the tte study at bedside was used as an indicator of effectiveness of the tested curriculum. proportion of graduates to work within a ''critical care'' setting. the level of support available to trainees may vary with local resources but risk management and national guidelines stipulate that close supervision is provided to junior doctors in high stake decisions and procedures until deemed competent at the relevant tasks . furthermore, substantial ongoing reduction in working hours places further limitations on training; both majors can impact adversely on junior doctors service output and experience. a modified delphi method was used years ago to design a task focused single-day course on the theoretical basis of critical care and provide lab-based training in delphi identified high risk procedures and interventions . objectives. assess the impact of the course on the following: trainee confidence and the start of the ''novice'' critical care post trainee performance in comparison to peers perceived educational benefit from their training post compared to peers methods. junior doctors attending the course were enrolled in the study and matched for graduation year and medical school to junior doctors who did not attend similar training prior to commencing their post. data was collected through anonymous standardized forms on the day of the course, first day of the job, end of week , week and months into the post. trainee confidence and self perceived competence were assessed on a ten point scale. in addition, trainees were requested to maintain a log of interventions: -ultrasound guided central venous catheter insertion, -arterial catheter insertion, -ventilation problem solving. candidates attending the course demonstrated greater confidence at multiple points within their post as well as higher performance, satisfaction and educational value scores. conclusions. critical care trainees benefit from a task focused orientation to the fundamentals of critical care before commencing first post in this setting. . enrolled patients in each group. no differences in age and gender. incidence of vap-study group . % compared to control group . % p value . . vap per , hospital days: control- . % compared to study- . % p value . ; average days in icu control- . compared to study- . , p value . ; average ventilated days, control- . compared to . , p value . ; average antibiotic use in days control- . compared to study- . , p value . . introduction. nosocomial infections are the most common in-hospital complications with high morbidity and mortality. educating healthcare professionals is an important prevention measure. objective. to analyze the impact of a nurse consultant team on nosocomial infections prevention in the icu, the improvement in prevention knowledge of the nurse staff, and its impact in the application of the prevention measures in the daily practice. methodology: the nurse referent team was constituted by nurses. the study subjects were all the staff icu nurses and all the patients admitted during pre and post-intervention phases. the study was conducted in our medical-surgical icu ( beds) in phases: pre-interventional ( / / - / / ) observational. record of the accomplishment of cdc recommended variables about mechanical ventilation associated pneumonia (vap) and catheter related bloodstream infection (cr-bsi) prevention measures. interventional ( / / - / / ) eight educational meetings with the nurses staff groups to teach the most important aspects of the nosocomial infections prevention. before and after lectures every nurses answered an anonymous questionnaire about their knowledge in those subjects. a poster with the most important reminders was place in every icu patient room. post-interventional ( / / - / / ) observational. new record of the same cdc pre-interventional variables. we compared the accomplishment of these variables before and after the interventional phase as well as the number of correct questionnaire answers. statistics were made with spss software. results. during the interventional phase % of the staff nurses attended the educational meetings. the number of correct answers increased significantly after the conference ( . vs. . % p \ . ). regarding to the daily practice, we observed a significant increase in the accomplishment in most of the variables (see table below), while in of them no improve was observed and in the improvement was not statistically significant. during the study period we observed a decrease in the incidence of vap ( . - . episodes/ , mv days) and cr-bsi ( . introduction. glucose variability has been found to be associated with mortality in critically ill patients, independent of mean glucose concentration [ ] . objectives. the aim of this analysis was to assess the impact of real time continuous glucose monitoring (cgm) on glucose variability in critically ill patients receiving intensive insulin therapy (iit). methods. this is the post-hoc analysis of a prospective, randomized, controlled trial [ ] . data of patients admitted to the icu either receiving iit according to a real time cgm system (guardian Ò , medtronic, northridge, ca, usa) (n = ) or according to an algorithm (n = ) with selective arterial blood glucose measurements (simultaneously blinded cgm) for h were analysed. insulin infusion rates were guided according to the same algorithm in both groups. mean glucose and standard deviation, as a marker of glucose variability, were calculated for the first h (glumean , glusd ) and for the whole study period (glu sd ). statistical comparison of parameters between study groups and between icu survivors (n = ) and non-survivors (n = ) was performed using student's t test. results. the variability of sensor glucose during the entire study period was comparable between the real time cgm group and controls ( . ± . vs. introduction. in the gastrointestinal tract, the gut flora which comprises several hundred grams of bacteria is crucially involved in host homeostasis through their metabolic, trophic, and protective activities. however, the immediate changes in the gut flora in critical illness following severe insults are unknown. objectives. to investigate the changes in the gut flora at an early phase of severe insult in critically ill patients. methods. fifteen patients who experienced a sudden and severe insult including trauma, out-of hospital cardiac arrest, and cerebral vascular disease were studied, along with healthy volunteers as the control group. two fecal samples were acquired from the subjects by swabs of the rectum within h after admission to the emergency room (day ). samples were serially collected from patients on day , , , , , and . samples were collected from control subjects. results. total bacterial counts, especially various obligate anaerobes and total lactobacillus, significantly decreased in comparison to those of the control subjects on day . in addition, on day , the total organic acid levels of the patients were significantly lower than those of the control subjects; particularly acetic acid, propionic acid, and butyric acid. the levels of these acids remained low throughout the days period of study. the total bacterial counts did not recover to normal levels during the day study period. obligate anaerobe counts of the patients did not improve until day . total lactobacillus counts were low on day and increased gradually thereafter, but did not attain the levels found in controls. the counts of pathogens (enterococcus and pseudomonas) increased during the study period. conclusions. gut flora in critically ill patients can change drastically immediately after a severe insult, and may not recover for up to days. at the same time, the number of harmful bacteria can increase. total bacteria . ( . - . ) . ( . - . ) . obligate anaerobes clostridium cocades group . ( . - . ) . ( . - . ) . clostridium leptam subgroup . ( . - . ) . ( . - . ) . bacteroides fragilis group . ( . - . ) . ( . - . ) . bifidobacterium . ( . - . ) . (\ . - . ) . atopobium cluster . ( . - . ) . (\ . - . ) . results. mean serum (oh)d level was . ± . ng/ml. by current definitions the majority of patients ( . %) were vitamin d deficient (\ ng/ml) and . % were vitamin d insufficient (c and \ ng/dl). normal (oh)d levels ([ ng/ml) were present in . %. table provides information on clinical and laboratory findings in the three (oh)d groups. both lower (oh)d tertiles were associated with increased hospital mortality after adjustment for age, sex and saps ii. for patients both (oh)d and pth levels were available. adjusting the cox regression analysis also for pth and dialysis status increased the hr for hospital mortality to . ( . - . ) and . ( . and . ) for the two lower (oh)d tertiles. in addition tertiles of pth and serum calcium levels suggested higher mortality rates for patients in the highest pth (p = . ) and those in the lowest calcium tertile (p = . ). our results demonstrate that independent of baseline saps ii, age and sex, critically ill patients with low (oh)d levels seem to be at increased risk for hospital mortality. whether a rapid correction of vitamin d status may be beneficial in the icu setting remains to be further explored in randomized controlled trials. • the autonomic storm after brain death must be early diagnosed and treated with a standardized protocol including hormone therapy introduction. the use of filling pressures of the right atrium and left atrium is normal in the monitoring of critically ill patients undergoing mechanical ventilation. this monitoring is done through an invasive catheter placed in the superior vena cava and pulmonary artery, which is not free of complications. the ability to make measurements of these parameters in a non invasive way, makes the echocardiography an useful and essential tool when monitoring critically ill patients objectives. we focus the study on validate the reliability of noninvasive measurements by echocardiography and invasive measurement catheters of filling pressures methods. we conducted a prospective observational study relating the filling pressures, between central venous pressure (cvp) with the diameter of the inferior vena cava and left atrial pressures with the values of the ratio e/e . the filling pressure variables were only discriminated as high or low. low values were accepted when invasive measurement of cvp was \ and \ mmhg in the lap; and by echocardiography when the diameter of the ivc was\ mm and the ratio e/e \ . high values were accepted when the measurement of cvp was higher than and mmhg in lap and in echocardiography when the diameter of the ivc [ mm and the ratio e/e [ . we collected data from patients in the immediate postoperative period, under mechanical ventilation (vt - ml/kg, fio %, peep ), sinus rhythm, good cardiac function and without postoperative drug support. all of them had a central venous line and right atrium catheter as habitual monitoring of postoperative cardiac patients. we performed an echocardiography when the patient presented hypotension, with low values of cvp and lap, and we repeated the measurements after the infusion of the habitual fluid protocol ( ml hes % in - min). the data we record were: diameter of ivc and ratio e/e by echo and cvp and lap values by invasive catheters. rd esicm annual congress -barcelona, spain - - october s introduction. an attenuated cardio-hemodynamic response to dobutamine is associated with a poor outcome in established human sepsis [ , ] . establishing a sensitive method to identify early cardiac dysfunction in both experimental and human sepsis would be a useful tool to explore timesensitive mechanisms further. objectives. to assess myocardial responsiveness to dobutamine in early sepsis. methods. all procedures were in accordance with uk home office laboratory animal legislation. under isoflurane anaesthesia, male adult wistar rats underwent left common carotid and right internal jugular venous cannulation for blood sampling/continuous bp monitoring and fluid administration respectively. rats received either . ml caecal slurry (sepsis; n = ) or . ml saline (sham; n = ) ip, before fluid resuscitation ( . % saline ml/kg/h) and conscious monitoring was commenced. after h, rats were re-anaesthetized with isoflurane and transthoracic echocardiography was performed. stroke volume was optimised with saline boluses prior to an incremental dobutamine infusion ( . - mcg/kg/ min). data are presented as mean (sd); analyzed with -way anova and post-hoc tukey test. results. figure summarizes hemodynamic changes after sepsis, fluid resuscitation and dobutamine infusion. baseline parameters were similar after echocardiography-guided fluid resuscitation, with contractility and stroke volume restored in septic rats to sham values. septic rats demonstrated an enhanced chronotropic response to dobutamine compared to sham (p \ . ). both peak velocity and cardiac output were attenuated by c % in sepsis (p \ . ). in sepsis, baseline map was higher but neither sham nor septic maps were affected by dobutamine infusion. conclusions. dobutamine stress echocardiography is a sensitive, reproducible, dynamic physiological probe that reveals early cardiac dysfunction in septic rats with apparently similar baseline cardiovascular physiology. introduction. the evaluation of right ventricular (rv) function is clinically useful in patients with acute respiratory distress syndrome (ards) because the presence of rv failure has large prognosis implications. the purpose of the current study was to compare right ventricular myocardial strain imaging parameters with conventional echocardiographic indices evaluating right ventricular function during ards. objectives. we hypothesized that peak systolic strain would be more sensitive than conventional echocardiographic parameters in detecting subclinical right ventricular systolic dysfunction in patients with ards. methods. in total, patients with ards and with normal right ventricle function assessed by two dimensional echocardiography and age matched subjects under mechanical ventilation without heart or pulmonary disease were included in the present study. conventional echocardiography parameters for rv function assessment like rv fractional area change (rvfa) or the tricuspid annular plane systolic excursion (tapse) were measured and compared to tissue doppler imaging parameters with strain value obtained from the right ventricle free wall. . strain values were reduced in the rv free wall of the patients with ards compared with the control group ( . % ± . vs. . % ± . p = . ) moreover no significant difference was observed in conventional two dimensional parameters evaluating rv systolic function between these two groups of patients. in patients with ards a significant relationship was shown between peak systolic strain at basal free wall and arterial carbon dioxide tension (rho = - . p = . ) and with the end inspiratory pressure (rho = - . p = . ). conclusions. during the ards, doppler tissue imaging parameters can determine rv dysfunction that is complementary to conventional echocardiographic indices and is correlated with respiratory parameters. on doppler tissue imaging, patients with ards exhibit abnormal rv systolic function even in patients with normal rv function assessed with conventional echocardiographic parameters. objectives. studying the effect of olv on rv outflow impedance during inspiration and expiration using transesophageal echo-doppler in a trial to differentiate the rv consequence of increasing lung volume from those secondary to increasing airway pressure during mechanical ventilation. methods. thirty stable patients on mechanical ventilation because of different causes were enrolled prospectively in this single center, cross sectional clinical study. each patient was firstly subjected to conventional ventilation (cv) with volume controlled ventilation, followed by open lung concept (olc) ventilation by switching to pressure controlled mode, then recruitment maneuver applied until pao /fio [ torr. hemodynamic (mean arterial pressure ''map'', central venous pressure ''cvp'' and heart rate ''hr'') and respiratory (total and intrinsic peep, peak, plateau and mean airway pressure and total and dynamic lung compliance) measurements were recorded before, min after a steady state of cv and min after a steady state of olc ventilation. also, transesophageal echo doppler was performed at end of inspiration and end of expiration to calculate the mean acceleration (ac mean ), as a marker of the rv outflow impedance, min after a steady state of cv and min after a steady state of olc ventilation. results. during inspiration, ac mean was significantly lower during cv compared to olc ventilation (p value . ). inspiration didn't cause a significant decrease in acmean compared with expiration during olv (p value. ) but did do so during cv. in comparison to baseline and cv, olc ventilation was associated with a statistically significant higher cvp (p value . for both), higher total quasi-static lung compliance (p value . for both) and dynamic lung compliance (p value . for both). moreover, pao /fio ratio of olv was significantly higher than in baseline and cv (p value . for both). conclusions. olc ventilation does not change rv afterload during inspiration and expiration as rv afterload appears primarily mediated through the tidal volume. moreover, olc ventilation provide a more stable hemodynamic condition and better oxygenation and lung dynamics. introduction. among indices provided by the analysis of aortic blood flow through esophageal doppler, mean acceleration (acc) is supposed to reflect the left ventricular (lv) systolic function, but this has been poorly validated. in particular, acc could be influenced by loading conditions of the lv. objectives. to test whether acc actually behaves as an indicator of lv systolic function by testing if . it increased with inotropic stimulation, . it was not altered by fluid loading, . it correlated with the echographic lv ejection fraction (lvef) and it reliably tracked the changes in lvef during therapeutic intervention. in patients with cute circulatory failure (sapsii ± , age ± years, receiving norepinephrine), we administered either a volume expansion ( ml saline over min in patients) or dobutamine ( lg/kg/min in patients). we simultaneously measured acc (cardioq, deltex medical) and lvef at baseline and after therapeutic intervention. results. volume expansion significantly altered neither lvef (from ± to ± %) nor acc (from . ± . to . ± . cm/s ) while dobutamine infusion significantly increased lvef by ± % and acc by ± %. considering the acc/lvef pairs of measurements, an acc \ . cm/s predicted a lvef b % with a sensitivity of % ( % ci [ - %]) and a specificity of % ( % ci [ - %]). the changes in lvef and in acc during fluid and dobutamine administration were significantly correlated (r = . , p \ . ). conclusions. acc fulfilled the criteria required from a clinical indicator of lv global systolic function. a given value of acc allowed detecting a low lvef with a modest accuracy. by contrast, the treatment-induced relative changes in acc were reliable for tracking the treatment-induced relative changes in lvef. objectives. to compare the relationship between systolic or diastolic dysfunction at icu admission and the incidence of cardiologic complications and mortality at sixth months. methods. prospective study of forty consecutive patients diagnosed of acute myocardial infarction (ami) ( nstemi, stemi) who were admitted in the icu of university hospital puerto real (cadiz, spain) from st may to th september . studied variables: age, gender, type of ami (nstemi, stemi), left ventricular ejection fraction (lvef) by biplanar simpson's rule, diastolic function (ratio e/e of the mitral annulus included), incidence of cardiac complications (acute pulmonary oedema, atrial fibrillation with hemodynamic instability and cardiogenic shock) and mortality at sixth month. echocardiographic studies were performed with a ge vivid pro(r) by an intensivist who had performed up to doppler studies in critical patients. all studies were remeasured by a second observer in an echocardiographic workstation with no statistical difference in measured velocities. patients were classified according to their lvef in (a) preserved ([ %), (b) mildly depressed ( - %), (c) moderately depressed ( - %) and (d) severely depressed (\ %); and according to their e/e ratio in (a) normal e/e ratio (\ ) and (b) elevated e/e ratio (c ). the results were statistically analysed with chi-square test and odds ratio calculus. results. diastolic dysfunction measured with e/e ratio was associated with high incidence of cardiac complications (chi test cl % p \ . , or ). systolic dysfunction measured by lvef was also associated with more complications but with less strength of statistical association (chi test cl % p \ . , or . ). there were no significative statistical difference between lvef and e/e ratio in mortality at sixth month. conclusions. in our study, diastolic and systolic dysfunctions in patients with ami at icu admission were associated with high incidence of cardiac complications, with more strength of statistical association in patients with diastolic dysfunction. the small sample volume didn't allow us obtaining significative statistical differences in mortality at sixth months. a new method has been developed to assess global end-diastolic volume (gedv) and extravascular lung water (evlw) from a transpulmonary thermodilution curve. our goal was to compare this new method to the established method currently in clinical use, over a wide range up to extreme pathophysiological conditions. objectives and methods. anesthetized and mechanically ventilated pigs ( - kg) were instrumented with a central venous catheter and a right ( f pulsiocath, pulsion, munich, germany) and a left ( f volumeview, edwards lifesciences, irvine, ca) thermodilution femoral arterial catheter. the right femoral catheter was connected to a picco monitor (pulsion) and used to measure cop, gedvp and evlwp using the old method based on the equation: gedv = cop (mtt -dst). the left femoral catheter was connected to the new ev monitor (edwards) and used to measure coe, gedve and evlwe using the new method based on the equation: gedve = f (s /s ) coe mtt, where s and s are respectively the maximum up-and down-slopes of the dilution curve, respectively. measurements were done during inotropic stimulation (dobu), during hemmorhage (hypo), during fluid overload (hyper), and after inducing oleic acid-acute lung injury (ali). overall, cop and coe ranged from . to . and from . to . l/min, respectively. cop and coe were closely correlated (r = . ), mean bias (± sd) was . ± . l/min and %error was %. gedvp and gedve ranged from to , and from to , ml. gedvp and gedve were closely correlated (r = . ), mean bias was - ± ml and %error was %. evlwp and evlwe ranged from to , and from to , ml. evlwp and evlwe were closely correlated (r = . ), mean bias was - ± ml and %error was %. parameters over the study period are presented in the table (*p \ . intervention vs. base or hyper). introduction. fluid resuscitation is a major therapy in icu. various mechanisms are involved in the regulation of the microcirculation and the macrocirculation. objectives. the goal of this study is to assess the sublingual microcirculatory changes in response to fluid challenge in preload-responsive and non preload-responsive patients. after approval by our local institutional review board, patients in surgical icu have been included in an observational study. each patient was monitored by an arterial catheter and an oesophageal doppler. the decision of fluid infusion was taken by the physician in charge of the patient. preload-responsive patients were defined by variations in cardiac index (ci) c %. sublingual microcirculation videos were obtained using the orthogonal polarized spectral (ops) imaging technology. functional capillary density (fcd, cm cm - ) and microcirculatory flow index (mfi) were collected. the macrocirculatory and microcirculatory measurements were obtained before, during and after the infusion of ml of saline. five sublingual sites were recorded before and after the fluid resuscitation. the ventilator settings and sedative and vasoactive drugs infusion rates were kept constant throughout the procedure. results. patients were admitted in icu for acute brain trauma (n = ), hemorrhagic shock (n = ), septic shock (n = ), acute brain hemorrhage (n = ) and acute pancreatitis (n = ). the average age of the patient was ± . the mean values of ci and mean arterial pressure (map) before the fluid therapy were respectively . ± . l/min/m and ± mmhg. nine patients responded to fluid infusion (ci c %.). about the microcirculation, there was no significant difference between responders (r) and non-responders (nr) concerning the variations of mfi ( . introduction. passive leg raising (plr) was shown to discriminate hemodynamically unstable patients who will benefit from subsequent fluid administration or not. concerned by the possibility of harmful hypotension starting the plr maneuver from a °semirecumbent position, in a previous study, we found that raising patients' legs from a supine position, we were not able to predict fluid responsiveness in a heterogeneous cohort of medical intensive care unit (icu) patients. objectives. to investigate whether starting plr maneuver from a °semirecumbent position would better predict volume responsiveness without harmful hypotension in spontaneously breathing critically ill medical icu patients. methods. fluid responsiveness was tested in consecutive patients ( sepsis, respiratory failure, heart failure, others) with a mean arterial pressure (map) \ mmhg and/or a cardiac index (ci) \ . l/min/m . heart rate (hr), mean arterial pressure (map), global end-diastolic volume index (gedvi), cardiac index (ci) and stroke volume index (svi) were recorded using the picco method. patients were stable in a semirecumbent ( °) position when first measurements were taken (baseline ). for the plr maneuver, patient's bed was tilt to have the lower limbs raised to a °angle while the patient's trunk was then in a supine position. changes after min were recorded. the patient was then brought into a supine position, and heamodynamic measurements were recorded when stable (baseline ). thereafter, ml of . % nacl were administered over min. positive predictive values (ppv) and negative predictive values (npv) of the plr maneuver were calculated using a cut-off value of % increase for ci and svi and % increase for map. results. patients' median age was ( - ) years and their saps score ( - ). all patients received vasopressors and/or inotropes. baseline hemodynamics and changes after plr and fluid challenge are shown in table . results are given as median (range); n/a = not available, *p \ . versus baseline. ppv and npv for ci were and %, for svi and % and for map and %, respectively. conclusions. in our hands, plr was not useful identifying fluid responders in this heterogenous population of severely ill medical icu patients, the starting semirecumbent position being associated with a potentially harmful decrease in map. however, it was helpful to detect patients who will not benefit (or even suffer harm) from further fluid administration. recently, some studies suggested that an impaired diastolic function is a predictive factor of mortality in patient with shock. it is not already known whether fluid infusion could improve diastolic function. objectives. the aim of the study was to determine the impact of rapid fluid infusion on diastolic function. after acceptance by the local ethic committee, icu patients were prospectively included. volume expansion (ve) by ml of saline was performed by the intensivist in charge. transthoracic doppler echocardiography was performed before and after fluid infusion. stroke volume (sv), early diastolic transmitral velocity (e), early diastolic mitral annular velocity (ea) and e/ea ratio (reflect of lv filling pressure) were studied. patients were divided in groups according to their sv' increase: responders (r) (those who increased their sv by at least %) and non-responders (nr). wilcoxon rank sum test was performed to compare data before and after ve. data are presented in median (iqr) results. fifty-three ( %) patients were r and ( %) were nr. in the overall population, ea increased significantly with ve [from . ( . ) to . ( . ) cm/s, p = . ]. in the r group ea increased significantly [from . ( . ) to . ( . ) cm/s, p = . ] and e/ea did not change significantly [from . ( . ) to . ( . ), p = . ]. however in the nr group, ea did not change significantly [from ( ) to . ( . ) cm/s, p = . ] while e/ea increased significantly [from . ( . ) to . ( . ) cm/s, p = . ]. conclusions. according to these results, adequate fluid infusion seemed to enhance lv relaxation without increasing lv filling pressure while inadequate fluid infusion did not affect relaxation but increased lv filling pressure. objectives. the aim of our study is to compare the rapid variation of co measured by vigileo-flotrac Ò with doppler-echocardiography which is considered as a reference method. during the first hours of hospitalisation, we studied mechanically ventilated patients receiving norepinephrine who underwent arterial pressure monitoring via a radial artery catheter. the flotrac Ò pressure sensor and the vigileo Ò monitor were connected to the arterial line. at each fluid expansion or norepinephrine dose modification a transthoracic doppler-echocardiography was performed and co was calculated. variations for co measured by each method were compared. results are presented as median (iqr). linear regression and the bland-altman method were used for statistical analysis. methods. for the in vitro experiments blood of healthy donors was incubated (in the ratio : ) with one of the following solutions: ringer solution, ringer-lactate solution, modified gelatin (gelofusin); hydroxyethyl starch (hes) / . . after incubation, the following parameters of erythrocyte aggregation were measured: t and t -characteristic times of spontaneous erythrocyte aggregation; b-hydrodynamic strength of aggregates; i . -index of strength of the largest aggregates at shear rate . s - . rbc deformability at various shear stresses was determined by ektacytometry. in vivo study on patients with trauma treated randomly with either only crystalloids (group ; n = ), or crystalloids + hes / . (group ; n = ) or crystalloids + gelofusin (group ; n = ) over days, the same parameters as in vitro study were determined at day - . twenty healthy men and women were included as controls. for statistical analysis the statistical package spss version . was used. statistical significance was considered at p \ . . in vitro study in the final analysis effects of different colloids on rbc aggregation and deformability were considered as increasing impact (:), decreasing impact (;) and no impact (-) ( table ) . in vivo study significant microrheological disturbances were detected at day after admission. deformability index was lower in patients compared with controls ( . ± . vs. . ± . ; p = . ). simultaneously, the patients showed erythrocytes hyperaggregation compared with control (;t , ;t ; :i . , :b). in the first group (crystalloids) described violations persisted throughout the study time. in group (crystalloids + hes), the deformability was higher than in the st group, from days till the end of the study, attaining the normal range, and also higher than in the third group (crystalloids + gelofusin). in the third group, deformability index was not significantly different from group . according aggregatometrical data in the first group hyperaggregation syndrome remained the entire period of observation. hes adding (group ) decelerated aggregate formation (:t , :t ; ;i . ). in contrast, modified gelatin adding enhanced erythrocyte aggregation (;t :i . , :b). conclusions. crystalloid solutions are not able to improve microrheological parameters. hes / . increases rbc's deformability and reduced rbc's aggregability. gelofusin increases erythrocyte aggregation and no effect on deformability. introduction. trauma patients often require norepinephrine (ne) infusion and fluid challenge to keep normal blood pressure values. the reliability of dynamic predictors of fluid responsiveness during vasopressors therapy is under debate. we investigated the impact of norepinephrine (ne) infusion changes on pulse pressure variation (ppv) assessed with the mostcare system (vytech health, laboratoires pharmaceutiques vygon, ecouen, france) in intensive care unit patients. this device is a pulse contour method that provides cardiac output and fluid responsiveness variables and does not need any kind of calibration or preloaded data. methods. trauma patients ( female, male, mean age ± ) admitted to a -bed university hospital medico-surgical icu were prospectively enrolled. inclusion criteria were: mechanically ventilated patients (tidal volume [ ml/kg and constant respiratory rate); invasive arterial blood pressure monitoring; ne infusion. ppv values were recorded continuously during three different haemodynamic states: at baseline (t ), min after a . lg/kg/min ne increase (t ), min after a further . lg/kg/min ne increase (t ), min following the reduction of ne to t dosage (t ) and min after setting ne to baseline value (t ). during the study neither fluid challenge nor other vasoactive/inotropic drug changes were done. anova test was applied. results. see data in table . at t ne mean dosage was . lg/kg/min (range . - . lg/kg/min). the mean ppv was: at t . ± . %, at t . ± . %, at t . ± . %, at t . ± . %, at t . ± . % (p \ . ). conclusions. our findings demonstrated that ppv was significantly affected by changes in ne: the higher the ne dosage the lower the ppv. changes in arterial tone due to ne infusion can impair ppv reliability in assessing fluid responsiveness in trauma patients. introduction. in mechanically ventilated patients respiratory variation in the arterial pulse pressure (dpp) is a reliable predictor of fluid responsiveness . respiratory variation of pulse oximetry plethysmographic waveforms correlate to dpp and can be calculated automatically in real time (heart-lung index [hli Ò ] from hamilton medical). this prospective study evaluates the relationship between dpp and hli Ò to predict fluid responsiveness. mechanically ventilated patients were investigated; all connected to an hamilton g ventilator and ventilated in adaptive support ventilation (asv), paralyzed and none had severe cardiac dysrhythmia. were eligible for fluid expansion. dpp, hli Ò (obtained from a finger probe pulse oxymeter integrated to the ventilator) and cardiac index (ci from transthoracic echo-doppler), were obtained before and after fluid expansion ( ml/kg of hea over min). ci-responders were defined by % increase from baseline. results. out of the patients were ci-responders and had significantly higher hli Ò before volume expansion ( % ± vs. % ± , p \ . ). before fluid expansion hli Ò was correlated with dpp (r = . , p \ . , fig. ). hli and dpp were significantly correlated with change in ic induced by fluid expansion (r = . and r = . , respectively). objectives. the primary end point of this study was to evaluate the rvd of the ivc in icu patients with spontaneous breathing. methods. icu patient with spontaneous breathing and signs of hypoperfusion (oliguria, mottles, serum lactate level [ mmol/l) were eligible after the approval of the local ethics committee. we excluded patients with acute heart failure with pulmonary edema, moribund and arrhythmic patients. the trans thoracic echocardiographic (tte) evaluation was done by confirmed intensivists (level [ in echocardiography). the aortic diameter measured at the lv outflow chamber and the tvi were measured. the vena cava inferior diameters at inspiration and at expiration were measured on the sub costal view. the rvd of the ivc was defined as the (maximal ivc diameter -minimal ivc diameter)/maximal ivc diameter. these measures were realized at t , before fluid challenge, and after a fluid challenge of ml of hes % ( . / ) over min (t ). patients with an increase of tvi of more than % were considered as responders to the fluid challenge. the measures of tvi and of the rvd of the ivc were validated by an experimented intensivist and echographist (level ) after blinding the patient' name and of the times of measurement. roc curves were constructed, and the cut off was determined as the closest point of the roc curve to the ideal point (sensibility = specificity = ). the values are expressed as median and extremes. objectives. our objective was to test whether non invasive assessment by trans thoracic echocardiography of sub aortic velocity time index (vti) variation after a low volume of fluid infusion ( ml of hydroxy ethyl starch, hes) can predict fluid responsiveness. methods. sub aortic vti was measured by transthoracic echocardiography before fluid infusion (baseline) in sedated patients with acute circulatory failure and low tidal volume mechanical ventilation in whom volume expansion was planned. then, vti was recorded after ml of fluid infusion over min, and after an additional infusion of ml of hes over min. we measured the variation of vti after ml of fluid (dvti ) for each patient. receiver operating characteristic (roc) curves were generated for dvti in all patients. when available, roc curves were also generated for pulse pressure variation (ppv) and central venous pressure (cvp). , volumes (gedvi) and variabilities (svv, ppv) have been suggested to predict volume responsiveness (vr). the final classification of a patient as ''volume responsive'' is usually made by a volume challenge (vc) with an infusion of a pre-defined amount of fluid over a certain time. among many variations of vcs, the infusion of ml crystalloid over min is one of the most established. despite superior predictive capabilities of svv, ppv and gedi compared to cvp and pawp in a number of studies, they fail to predict vr in a substantial number of patients. furthermore, the use of these parameters is limited due to femoral access of the cvc (gedi; cvp) or the absence of controlled ventilation and/or sinus rhythm (svv, ppv). repeated ''exploratory'' vcs with ml/kg might result in volume overload in some patients. objectives. therefore, we investigated the usefulness of a ''small vc'' with . ml/kg crystalloid over min compared to a standard vc with ml/kg over min. in patients equipped with picco hemodynamic monitoring we performed a min vc with ml/kg of crystalloid. during the vc transpulmonary thermodilution (td) was performed at , and min to obtain td-derived ci (ci td ). additionally pulse contour ci (ci pc ) was recorded in intervals of min. introduction. the prevalence of obesity, defined as a body mass index (bmi) c kg/ m , reaches epidemic proportions. it is not only a risk factor for health problems, but also exacerbates illness progression. consequently, the number of obese patients on the intensive care unit (icu) has increased enormously. caring for obese patients can be quite challenging due to the weight and size of this person. the extent of and specific problems associated to the care of obese icu patients are unknown. the aim of this study is to identify and quantify problems nurses face in caring for obese patients on the icu. this study was performed on the icu at the radboud university nijmegen medical centre and contained two parts. in the first part a selection was made of obese patients admitted between and ; these patients were matched with normal weight patients (bmi . - . kg/m ). patients were matched on gender, age, length of icu stay and apache-ii score. all patient files were screened for the presence and intensity of problems in caring for these patients. in the second part nurses were asked in a survey to share their experiences in caring for obese patients. they were asked about the nature, frequency and intensity of the problems they faced. in total, problems were identified in the screened patient files. seventy-two problems ( . %) occurred in care for obese patients and ( . %) in care for normal weight patients. in both groups, most of the problems were related to activities of daily living (adl) such as (re)positioning in bed, transfers and personal care. surprisingly, the intensity of the problems was similar in both groups. most of the problems were moderate (hardly to solve by one person) or severe (only to solve with two persons or special equipment). moderate problems occurred in . % of normal weight patients and in . % of obese patients; severe problems . and . %, respectively. this result was also confirmed by the survey. the nurses qualified most of the problems they were asked about as moderate or severe, and the frequency of the experienced problems was much higher. from the files it appeared that in . % of the obese patients nurses had adl problems. strikingly, in the survey nurses reported that they frequently ( . %) or even always ( . %) experienced adl problems in obese patients. nurses reported and experienced more problems in daily care for obese icu patients compared to normal weight icu patients. although the intensity of the problems with obese patients did not differ from normal weight patients, the frequency in which they occur was much higher. differences between reported problems and the survey suggest an underestimation of problems that can be solved by performing a prospective study. nevertheless, based on these results, and taking into account that obesity will increase in the future, we recommend anticipating to the needs of the nurses whenever possible. introduction. worldwide the number of obese patients (bmi [ ) is increasing rapidly ( ); this also includes patients admitted to the intensive care units (icu). this raises special demands on the staff, the surroundings and the equipment ( ) . often the obese patient is not mobilised according to the clinical standard this causes complications to breathing, circulation and skin etc. furthermore the length of stay in the icu increases and the mortality rises. objectives. the aim of this study therefore was to make clinical guidelines and recommendations for mobilisation of the obese icu patient based on evidence. this will increase the knowledge and importance of mobilisation between staff and on longer term improves the daily average number of mobilisations performed with these patients. a secondary aim is that increased knowledge on this topic will improve the interdisciplinary work between the different professions based on the same overall aim. a systematic review of the literature concerning mobilisation of the obese icu patients was made in the year - . the study is still work in progress analysing the literature to make guidelines and recommendations based on evidence. furthermore evidencebased education of special trained staff in mobilisation has been conducted in january/ february to improve their knowledge of the impacts mobilisation has on the respiration, circulation and skincare etc. the education was planned to aiming at a interdisciplinary audience. results. the preliminary results shows that it is more difficult to care for and mobilise the obese icu patient, because there is lack of space, non-availability of the correct equipment, too few available staff members and a significant negative attitudes among the staff towards the obese patient. recommendations are made within airway, breathing, circulation, nutrition, pain, equipment and patient experience according to the procedure of mobilisation of the obese icu patient. the recommendation was implemented in the already performed education and resulted in a changed attitude among the participant and improved the status of mobilisation in the daily prioritization. this knowledge was obtained in the evaluationinterview conducted approximately one month after the seminar. conclusions. according to the literature mobilisation of the obese icu patient needs special attention towards a safe clinical practise based on evidence with focus on both the patient and the staff. special attention towards this group of patient is created by performing evidence based research resulting in clinical guidelines that has to be implemented through theoretical and practical education on an interdisciplinary level. nurses are constantly exposed to the pain and suffering of those in their care . the primary aim of this study was to investigate the risk of secondary traumatic stress/compassion fatigue (sts/cf-the trauma suffered by the helping professional) and burnout (bo-emotional exhaustion, depersonalization, and reduced sense of personal accomplishment), and the potential for compassion satisfaction (cs-the fulfillment from helping others and positive collegial relationships) among nurses working in icu. an additional goal was to test the relationship of these three constructs to each other. ( ) . the use of closed suction circuits has been suggested beneficial as a prophylactic measure ( ) . objectives. the aim of this study was to compare the incidence of vap and the occurrence of desaturation during suction using either oss or css. we also investigated contamination of the closed suction circuit and the occurrence of adverse events. methods. css were a new product in our clinic. all staff underwent a user course supervised by the manufacturer of the closed circuit. after this, data were collected during four periods in , month css followed by months oss which was repeated twice. during the summer period css were used without any data collection and then followed by two periods of css and oss. all mechanical ventilated patients were consecutively included. a culture of deep endotracheal aspirate and a blind microbiology brush was taken in association with the intubation, after h and every monday. after changing css and in case of extubation, the tip of the catheter was sent for culture. demographic data were retrieved from the hospital database. data were analyzed with descriptive methods. results. the incidences of vap were higher in the css group (table ) . both suction systems showed almost no desaturation during and after suctioning. positive cultures were obtained in % of all the retrieved css catheters. the microbiological flora resembled the species found in the airway cultures. there were no inter patient contamination and neither did the bronchoscopy frequency differ between oss and css patients. in the css group six adverse events were seen; three tube occlusion and three incidences with secretion clogging. conclusions. the use of a css did not prevent vap, in our study. there were no benefit with css other than maybe to protect the staff and our finding of positive culture in % of the cases is in line with earlier studies. objectives. the aim of this study was to determine which intensive care patients the nurses defined as 'difficult' and their experiences in coping with such patients. the study was carried out as a qualitative design with voluntary nurses employed in five intensive care units of a research and training hospital. the data were collected using demographic characteristics form and a semi-structured interview form. interviews with nurses were made individually and face to face. the data were evaluated by using colaizzi's phenomenological data analysis method. as a result of data analysis into two categories and two themes were identified. the categories were ( ) difficult patient definition of the nurses, ( ) the effect of difficult patients on their care, and ( ) how the nurses are affected and cope with difficult patients. the nurses listed their reasons for defining some persons as difficult as difficult physical care of the patients, and the difficulty in communicating due to dementia, agitation, alzheimer's disease or the patient's personal characteristics. the nurses said that they found taking care of patients they found difficult physically and psychologically demanding. they used methods such as finding out the patient's problem and taking appropriate measures, increasing communication with the patient and providing explanations, trying to obtain spiritual satisfaction and transferring the patient's care to another nurse when communication problems were impossible to overcome. intensive care nurses have difficulty in caring for and communicating with some intensive care patients due to the characteristics of the disease, physical/psychological factors and personal characteristics. we found that nurses continued the care of these ''difficult'' patients by focusing on solving their problems, transferring the care to another nurse when necessary or by trying to obtain spiritual satisfaction. methods. teams of three delirium experts visited ten icu's in the the netherlands in which the cam-icu was incorporated in daily practice, twice. these teams consisted of two consultants in either psychiatry, clinical geriatrics or neurology, and either a research-physician (mmjve) or a research-nurse (mvdb). based on cognitive testing, inspection of the files and dsm-iv criteria for delirium, the teams classified patients as awake and not delirious, or delirious or comatose. this classification served as gold standard to which the cam-icu as performed by the bed-side nurses was compared. a simple table was used to calculate the sensitivity and specificity. results. delirium experts performed assessments. ( %) of these patients were assessable for delirium, ( %) patients were excluded because the level of consciousness was too low, and ( %) patients were non-assessable due to other reasons. overall, we found a sensitivity of % ( % ci - %) and a specificity of % ( % ci - %). the strengths of this study include the large numbers, the multicentre design, the extensive evaluations by teams of various delirium experts and the independent assessments of delirium experts and bed-side nurses. a limitations is the time interval between the expert assessment and the administration of the cam-icu (mean min; standard deviation min). there were striking differences in implementation strategies of the cam-icu between the centres. tables , . rd esicm annual congress -barcelona, spain - - october s introduction. presence of expiratory ineffective efforts in mechanically ventilated patients is a common problem associated with increased duration of mechanical ventilation, length of stay and also a higher cost and mortality. nowadays, identification and categorization of expiratory asynchronies can only be done at the bedside with the continuous observation of the ventilator interface. nurses must be skilled to understand non appropriate situations of anomalous patient-ventilator interactions. objectives. we tested the hypothesis that after specific training nurses would acquire enough skills to detect expiratory efforts as intensive care expert physicians would do. training phase: nurses were provided with selected bibliography on patient ventilator interaction and afterwards trained by intensivists with expertise on mechanical ventilation ( h/day during days) on airway pressure, flow and volume waveforms identification and eye interpretation of early and late ineffective expiratory efforts during expiration. validation phase: airflow and airway pressure waveforms were obtained from different icu mechanically ventilated patients using and acquisition and processing biomedical signal software (better care Ò ). one thousand and seven breaths were randomly selected from a total of , , breaths. subsequently, selected breaths were blindly analyzed by trained nurses and intensivists to identify ineffective expiratory efforts. introduction. several publications indicate that manual hyperinflation is a widely used measure in the icu, but more important is the fact that there is no uniformity in the implementation of this measure. this is also on my ward. in literature there are a number of reasons given to start manual hyperinflation: abolish mucus retension, improve oxygenation and removal of atelectasis. the positive effects are improved compliance, improved oxygenation and a decrease in the number of vap's (ventilator associated pneumonia). the negative effects are a decrease in cardiac output due to high peak pressures, an increased risk of baro-/volutrauma and the risk of giving too much tidal volumes. the risk of barotrauma increase with pressures above cmh o. other side effects include the development of a pneumothorax and increased icp (intra cranial pressure). objectives. creating more awareness of the procedure with lower peak pressures as a result. methods. through literature review, clinical courses and the introduction of a pressure gauge achieve greater uniformity and awareness of the procedure. we used a flow analyzer of imt medical, a laptop with flowlab software version . . and an artificial lung to demonstrate how much pressure and volume is generated during manual hyperinflation. conclusions. compliance with bts guidelines could be improved. unsurprisingly co-morbidities were frequent, but did not seem to affect outcome. use of a pneumonia severity assessment tool was sub-optimal, however mean curb- score didn't correlate with that recommended to prompt critical care assessment. apart from functional status, we are unable currently to identify any factors in this age group which can be used to guide critical care admission decision making. conclusions. in our study the incidence of complicated pneumonia was / , patients admitted in picu. in necrotizing pneumonias the blood cultures were more positive than in non-necrotizing patients. although the surgical approach in necrotizing pneumonia is controversial, it resulted in a insignificantly lower mortality rate, comparing with non-necrotizing pneumonias. background. community-acquired pneumonia (cap) of mixed etiology has frequently been described in the literature, but its clinical significance remains unknown. the aim of this study was to describe the prevalence, clinical characteristics, and outcome of severe cap of mixed etiology in icu patients. a -year prospective study was conducted on consecutive patients with severe cap admitted to icu in whom an extensive microbiological investigation was performed. results. patients were included. a single pathogen was detected in ( . %) cases, while two or more pathogens in ( . %) cases. the most frequent pathogens' combinations were those of two bacteria ( . %) and bacterium plus virus ( . %). compared with patients with monomicrobial pneumonia, patients with mixed pneumonia were older, had higher severity score (psi) and were more likely to have previous chronic pulmonary disease (see table below). moreover, mixed cap patients showed similar clinical and analytical data at admission but increases in the frequency of respiratory distress and in length of stay and a trend to higher orotracheal intubation and mortality rates. a mixed etiology was detected in % of cases with cap requiring icu hospitalization and was associated with older age and increased severity. despite similar radiological features (n of involved lobes, pleural effusion) at admission, cap with mixed etiology showed a trend to worse clinical course and outcomes than monomicrobial pneumonia. objectives. to assess the incidence and aetiology of pneumonia in a mixed medicalsurgical icu, in order to develop local epidemiologically guided protocols to reduce antibiotic resistance selection in patients with pneumonia. methods. retrospective observational study on prospectively collected data in a mixed medical-surgical icu of a secondary care italian hospital. at our institution, epidemiological data on infections and data on antibiotic use are recorded since ; in a new electronic recording of icu infections was introduced. type of infection, germ characteristics, clinician diagnosis and antibiotic use were prospectively collected in an electronic database and retrospectively reviewed. antibiotic exposure index was calculated as each antibiotic total amount administered divided by its defined daily dose times total days of admission. between and a total of patients were admitted to our icu. pneumonia was the commonest infectious disease at admission ( cases, % of patients), and the commonest infectious complication during icu stay ( new occurrences, % of total pneumonia patients). table shows major epidemiological findings in the study population. the incidence of acquired pneumonia was remarkable: . cases every , days of mechanical ventilation. the most frequent isolated organisms were s. aureus ( patients) and p. aeruginosa ( patients). methicillin-resistant s. aureus (mrsa) accounted for % of pneumonia caused by s. aureus, and its prevalence matched closely the exposure index to vancomycin. such a high incidence of mrsa is consistent with other records in mediterranean countries. carbapenem-resistant p. aeruginosa was somewhat less of a problem ( % of pneumonia by p. aeruginosa), and was not apparently associated with antibiotic exposure, at least within the unit. conclusions. in our retrospective observational study we found a high incidence of pneumonia at our institution, as well as a high percentage of mrsa, the latter with strong relationship with exposure to vancomycin. new protocols for infection containment and antibiotic usage are urgently needed. introduction. community-acquired pneumonia (cap) carries a high morbidity and mortality. a major problem is the insufficient monitoring of cap by standard chest radiography, as the evaluation depends highly on the observer and the extent of pulmonary infiltration cannot be assessed properly ( ). objectives. the aim of our study was to compare the process of inflammation in cap measured by alveolar nitric oxide (no)-analysis ( ) in exhaled breath and the extent of the inflammatory infiltration by electrical impedance tomography (eit) ( ) in spontaneously breathing patients. after approval of the local ethic committee and obtained written informed consent patients with cap were included in the study. all patients showed an acute pulmonary infiltration in chest x-ray, pulmonary symptoms (coughing, shortness of breath), positive findings in auscultation, leukocytosis, elevated crp and a pneumonia severity index c . no analyses (analyser cld sp, eco medics, dürnten, switzerland) were performed at t (up to h after admission), t ( days after admission) and t ( days after admission. eit measurements (eit evaluation kit, dräger medical, lübeck, germany) were performed at t and t and inhomogeneity of ventilation was assessed by offline analysis. all measurements were made at beside in sitting position. data were compared by t test and regression analysis. results. there was no significant correlation between the alveolar no concentration and the extent of inhomogeneity of the local infiltration measured by eit. also during the study the time course of the inhomogeneity index was not correlated with change in exhaled no. the right/left distribution of the pulmonary infiltration in the chest x-ray and the eit measurement showed a positive correlation (p \ . ; r = . ). conclusions. pulmonary regional infiltration in cap measured by eit can not predict the actual alveolar process of inflammation in the lung. nevertheless the monitoring devices give additional information to better evaluate the time course of inflammation and the dimension of the respiratory dysfunction in diseased lung. organizing pneumonia (op) presenting as acute respiratory failure (arf) is a relatively rare disease, and was only previously specifically reported in small series [ , ] , with mortality up to %. these studies were performed before the publication of international consensus classification of idiopathic interstitial pneumonias in [ ] . objectives. to compare clinical features and prognosis of patients with op with those of patients presenting diffuse alveolar damage (dad), during arf. design: retrospective monocentric study in a university hospital conducted during an yr-period. to determine predictors of niv failure in patients who were intubated for respiratory failure and extubated directly to niv. methods. this is a retrospective analysis of prospectively collected data from january to dec . patients with respiratory failure were mechanically ventilated in a university hospital's medical intensive care unit (icu) and subsequently extubated to niv. physiological and biochemical parameters, using arterial blood gas measurements, were collected at the end of the spontaneous breathing trial and h after the application of niv. failure of niv was defined as respiratory failure requiring re-intubation within h. out of patients, . % were successfully extubated to niv. success rates were . % in patients with chronic obstructive pulmonary disease (copd) and . % in other patients (p = . ). patients who failed niv were more tachypnoeic, acidaemic and hypercapnic pre-niv, and more tachycardic, hypotensive, acidaemic, hypercapnic and hypoxaemic post-niv (p all. ). on logistic regression analysis, three physiologic parameters predicted niv failure: pre-niv respiratory rate (or . , % ci . - . per breaths increase), post-niv heart rate (or . , % ci . - . per beats increase) and post-niv systolic blood pressure (or . , % ci . - . per mmhg decrease). conclusions. physiologic parameters, including the respiratory rate pre-niv, and heart rate and systolic blood pressure post-niv, independently predict niv failure post-extubation. these parameters should be taken into account in the decision to extubate directly to niv. introduction. discontinuation of mechanical ventilation in critically ill patients is a challenging task and involves a careful weighting of the benefits of early extubation and the risks of premature spontaneous breathing trial (sbt). only a few studies have explored indices derived from both heart rate and breathing pattern variability analysis for the estimation of weaning readiness. objectives. to investigate heart rate (hr) and respiratory rate (rr) complexity in patients with weaning failure or success, using both linear and nonlinear techniques from signal processing theory. methods. forty-two surgical patients were enrolled in the study. there were who passed and who failed a weaning trial. signals were analyzed for min during two phases: despite of passing the protocol the decision to extubate was postponed in some patients. to gain insight on the physicians reasons for continuing mechanical ventilation after passing the wean screen protocol. a wean screen protocol was introduced at a mixed medical (neuro-)surgical icu of a teaching hospital in december to april . ventilation practitioners assessed ventilated patients and recorded the physicians reasons for continuing mechanical ventilation despite of passing the wean screen protocol. . patients were ventilated in this period. daily screens were performed, screens were successful. only passed wean screens resulted in extubation. the rate of extubation was %. % screens did not lead to liberation from mechanical ventilation. the extubation rate does not correspond with the findings of the abc trial with an extubation rate of %. table shows the physicians' reasons to continuing mechanical ventilation. it should be noted that all patients with an unsafe airway were patients with a glasgow coma scale (gcs) of b [intracerebral haemorrhage ( %), cerebral infections ( %), post-cpr encephalopathy ( %) and severe brain injury ( %)]. we accomplished a reduction in the use of sedatives (- % midazolam and - % propofol) and morphine (- %) ( table ). the amount of time spend on ventilators decreased, albeit not significantly (p = . ). this was probably due to the vap-ventilatorbundle (introduced last year), the heterogeneity of our cohort and the already short mv-duration. . non-invasive ventilation (niv) has been utilized in selected patients with hypoxemic arf to avert endotracheal intubation, which is related to life-threatening complications. niv has been also proposed to facilitate weaning and extubation in patients with hypercapnic arf. so far, no controlled randomized study has investigated the potential role of niv in weaning patients with hypoxemic arf. objectives. we designed this pilot study to assess safety and feasibility of niv to wean hypoxemic arf patients. twenty mechanically ventilated patients with hypoxemic arf were randomized to receive early extubation followed by niv application via helmet (helmet group) or conventional weaning through the endotracheal tube (tube group). primary outcomes were the duration of invasive mechanical ventilation and the adherence to the study protocol. secondary outcomes were protocol failure (i.e. need for re-intubation), icu and hospital mortality, rate of tracheotomy, duration of continuous intravenous sedation, weaning time, and septic complications. table . weaning through helmet by niv application following early extubation was safe and feasible. overall the adherence to the study design was %. in addition, in the helmet group, there was a significant reduction in the rate of tracheotomy and a trend toward a lower rate of protocol failure, and fewer days on invasive ventilation. there was no difference with respect to days of continuous sedation, icu and hospital mortality, weaning time and septic complications. ( ) . delirium is a common occurence on the icu and is associated with increased length of stay (los) and poor outcomes ( ) . objectives. we developed a combined daily sedation hold, delirium management, and weaning (sdw) protocol and implemented this to reduce icu los and improve outcomes. methods. a sdw protocol was implemented in . we prospectively audited all patients from january to march . delirium was measured using the icdsc. data was analysed using graphpad statistical software. results. consecutive patients were analysed. the incidence of delirium was % ( pts). of these, % ( ) had risk factors for delirium. there was no difference in onset of delirium between sexes, age, type of admission, or severity of illness. however, in patients with delirium, duration of mechanical ventilation (mv) and icu los were significantly longer and there was a trend towards increased hospital los ( conclusions. measuring the linear dependence of variables through time by k and ø may be used to determine non-linear behavior between the variables of the emmv. non-linear behavior during weaning perhaps indicates the dependency of, either the resistance or compliance of the respiratory system, on the ventilatory support (i.e. pi). accordingly, k and ø, estimated at the frequency interval form to (h) - , can provide information concerning to the dynamics of the respiratory system that can be used as a complement to determine the suitability of the mv withdrawal. objectives. to study the potential superiority of aprv on cmv in a subgroup of patients with severe ards. methods. retrospective observational study on patients severe ards who were admitted between july and january to mafraq hospital icu in uae. the diagnosis of ards was based on presence of bilateral infiltrates in cxr and p/f ratio of less than in absence of evidence of elevated left atrial pressure. all patients were managed according to ardsnet guidelines using low tidal volume cmv and iv steroids. criteria for transition to airway pressure release ventilation (aprv) included failure to wean down fio below % after h, hemodynamic instability due to high peep, and failure to maintain plateau airway pressure below cmh o. initial settings of aprv were ph , pl , th , and tl . with titration of fio as required keeping pao more than mmhg. we compared the outcome of cmv and aprv groups with special concern to the duration of mechanical ventilation, requirement for tracheostomy, and survival to icu discharge. twenty four male and females were included in the study with a mean age of years (± ). fourteen out of them fulfilled the criteria and were shifted to aprv within h of initiating mechanical ventilation. ten out of ( %) patients in the aprv arm survived to icu discharge versus out of ( %) patients in cmv group (p . ). survivors in aprv group spent significantly shorter periods of mechanical ventilation compared to survivors in cmv group ( . vs. . days p . ). while out of ( %) survivors in cmv required tracheostomy for prolonged intubation or recurrent lavage, only out of ( %) survivors in aprv group required tracheostomy tube placement (p . ). we concluded that aprv can be effectively used as rescue measure of ventilation in patients with severe ards. although our study does not show any mortality benefit of using aprv over cmv, there was a shorter ventilation days and icu stay using aprv. we strongly recommend further studies to investigate the probability of using aprv as initial mode of ventilation in this subset of patients. weaning from mechanical ventilation is a common daily procedure when caring for critically ill patients, and a lifesaving practice on which nurses are taking an increasing role with the introduction of nurse-led protocols. the literature supports that nurse-led protocols facilitate weaning and increase nurses' input in decision-making. on the other hand, decision-making is a complex function affected by the nature of the task, the decision environment and the characteristics of the decision maker. although the cognitive process of clinical decision-making has been investigated with many different methodologies, little is known about the decision environment and its impact on decisions' during the weaning process. objectives. this paper aims to address one of the factors of the clinical environment and its impact on the decisions when discontinuing mechanical ventilation. methods. this paper is part of a large comparative ethnographic study looking at nurses' input during the weaning process of mechanically ventilated patients. participant observation of critical care nurses took place in an -bedded icu in greece and an -bedded icu in scotland for months each to examine nurses' involvement in the decisions made. in-depth semi-structured interviews with the nurses followed focusing on how nurses perceived their participation in the decisions made. data from field notes and interview transcripts were analysed thematically using the qualitative data analysis software nvivo, version . inter-personal and inter-professional relationships were considered revealing influences of nurses' input in decision-making. clinicians' personality played a significant role in their involvement in decisions, whereas trust and appreciation, the sense of support and the sense of accountability were also considerable dynamics of inter-professional relationships and predisposed decision-making. clinical decision-making is a multi-dynamic process specifically in complex clinical long-term situations such as weaning. aspects of the decision environment, such as the interprofessional relationships should be acknowledged when introducing methods to enhance nurses' role in teamwork and collaborative decision-making in order to improve the weaning process of ventilated patients and their outcome. objectives. the objective of our study was to analyze the temporal trends and outcomes of two cohorts of patients ventilated with psv and pav+. a cohort of consecutive patients who were ventilated with pav+ and another cohort of consecutive patients who were ventilated with psv were compared. all patients had the same inclusion criteria (gas exchange, ventilatory mechanics, peep level, resolution/stabilization of the cause leading to invasive mv and appropriate level of consciousness). both modes were adjusted to predefined clinical criteria (psv to reach a respiratory rate about bpm and pav+ to reach a physiological inspiratory effort introduction. presence of expiratory asynchronies (ea) (ineffective efforts, cough and continued contraction of inspiratory muscles) is a common problem associated with increased duration of mechanical ventilation, longer stay, higher costs and increased mortality. because of the lack of systems that automatically detect and report ea, their identification is currently done by examining ventilator interface at the bedside or by applying dedicated algorithms in investigational conditions. validate the accuracy of linear mathematical algorithms to automatically detect ea built in a new computerized system that grabs and process data from different bedside icu monitors and mechanical ventilators. observational and prospective study in a general icu of beds. two beds were equipped with a software (better care Ò ), a technological platform responsible for data acquisition and synchronization, processing, storing-as non static and processable dicom objects-and also for integrating all this data with health information systems. by using the better care Ò platform, a total of , , breaths from consecutive adult patients were collected with at least h of mechanical ventilation. algorithm # : the ea algorithm consisted in a mathematical analysis of the airflow and airway pressure waveform variations during expiration not followed by a mechanical breath. algorithm # : designed to select , breaths out of the total number. this algorithm sorted and classified the breaths by the percentage of deviation from the expected expiratory curve. the result was , breaths covering most of the shapes the expiratory curve could have. five expert attendant physicians independently analyzed the , selected breaths and classified them as ea or not. the ea algorithm processed the same , selected breaths and assigned a percentage to each one, according to the variation in the shape and direction of the expiratory airflow and airway pressure curves. the expert criterion against the ea algorithm scores was used to construct a logistic regression model. we calculated sensitivity, specificity, positive predictive value and negative predictive value. the predictive performance of ea algorithm was evaluated using roc curves. optimal sensitivity and specificity were achieved by setting the cut-off point at a ea algorithm score of %. a variation in the shape and direction of the expiratory airflow and airway pressure curves [ % compared to the theoretical curve identified an ea with a sensitivity of . %, specificity of . %, a positive predictive power of . % and a negative predictive power of . %. introduction. near-infrared spectroscopy (nirs) in combination with a vascular occlusion test (vot) has been proposed to assess and identify metabolic and microcirculatory alterations during sepsis and shock in critically ill patients. however, to automatize repeated measurements at the bedside, this technique can potentially cause discomfort to the patient. vascular arterial occlusion performed in the finger may be a more attractive method to execute repeated measurements at the bedside because of more tolerability from the patient. we have previously showed in healthy volunteers that nirs can be used on finger to assess the sto response to vot and that min was an adequate occlusion time to provide the best curve fit for nirs dynamic variables . objectives. we aimed to investigate whether sto response to vot obtained from the finger could predict conventional sto response measurements obtained from the thenar of critically ill patients. parameters of sto response were measured with an inspectra spectrometer model (hutchinson technology inc.) equipped with a -mm or a -mm probe. the mm probe was placed over the thenar eminence and the -mm probe was place over the ventral face of the middle finger. we performed in each patient a series of two vascular occlusion tests (vot): one on the finger ( min) followed by one on the arm ( min). the measurements were obtained within h of intensive care admission and every h thereafter until day . vot-derived sto traces were analyzed for baseline, ischemic (rdecsto , %/min) and reperfusion (rincsto , %/s) parameters. we performed paired of nirs measurements in critically ill patients (age ± ; m/ f). although sto did not differ significantly between thenar and finger ( % ± vs. % ± ; p = . ), rincsto and rdecsto were statistically lower in the finger ( . %/s ± . vs. . %/s ± . , p = . ; . %/min ± . vs. %/min ± . ; p = . ). we performed bivariate linear model with correlated errors in which sto outcomes on thenar and on finger were treated as responses. the correlation was significant for sto and rincsto , but not for rdecsto (table ) . furthermore, mixed model analysis showed that thenar-sto as dependent variable could be significantly predicted by finger-sto parameters with estimation coefficient (± se) of . ± . (p = . ), . ± . (p = . ) and . ± . (p = . ) for sto , rincsto and rdecsto , respectively. correlation of sto response: finger vs. thenar a prospective randomized clinical trial performed in icu's of an university and teaching hospital during a . year period, involving septic and non-septic patients, randomized (after stratification) to hemodynamic monitoring, by picco tm or pac with both techniques allowing cardiac output and central/mixed venous o saturation monitoring. methods. hemodynamic management was guided by extravascular lung water index (evlwi) and global end-diastolic volume index (gedvi) in the picco tm group and by the pulmonary capillary wedge pressure (pcwp) in the pac group for consecutive days. primary outcome measures were ventilator-free days (vfd), for which the study was powered, and lengths of stay in icu and hospital. secondary measures were the course of cardiorespiratory parameters, fluid and vasopressor requirements, lactate levels, organ functions and mortality. in the study period, septic and non-septic patients were included. patients received a picco tm and a pac catheter. monitoring arms were comparable at baseline, although sepsis differed from non-sepsis in hemodynamics and severity of lung injury. premorbidity was greater in non-septic patients. the fluid infusions and balances did not differ between monitoring arms, except at t = h when the picco tm group had a more positive balance (p = . ). cardiac index and central venous o saturation increased more in the course of time in the picco tm than in the pac group. the decrease in norepinephrine requirements strongly tended to favor the picco tm group (p = . ). the course of lactate levels and organ failure did not differ between monitoring arms. vfd did not differ among monitoring arms. picco tm monitoring was associated with relatively fewer mechanical ventilation and icu days in sepsis but more in non-sepsis (after day ). the changes in respiratory parameters, sofa and number of catheter-related complications did not differ among the arms of the study. overall, patients ( %) died in the picco tm group before day and ( %) in the pac group (p = . ). conclusion. hemodynamic management guided by picco tm monitoring is safe and results in better tissue oxygenation than guidance by pac, without inducing pulmonary overhydration, in septic and non-septic, critically ill patients. this was associated with fewer mechanical ventilation and icu days in patients with sepsis but more days in patients with non-sepsis (after day ), partly attributable to greater cardiovascular premorbidity in the latter. the major primary and secondary endpoints, vfd and mortality, were not affected. introduction. non-invasive evaluation of endothelial function may be easily accomplished by ultrasound assessment of flow-mediated vasodilation (fmd) of the brachial artery, but this technique has not been fully explored in septic patients. objectives. this prospective study aims to investigate the role o fmd analysis on intra hospital prognosis of patients with severe sepsis and septic shock. adult patients admitted to the intensive care unit with a diagnosis of severe sepsis or septic shock (\ h of duration) were consecutively included. fmd of the brachial artery was measured upon admission and after and h using a high-frequency linear transducer ( . - mhz) according to internationally accepted protocols. a group of apparently health subjects paired for gender and age was used as controls for fmd analysis. patients were followed up to discharge or death. we studied adult patients mean age ± years, females, % on vasopressors with sepsis predominantly of abdominal or respiratory etiology ( %). apache ii risk score was ± and intra hospital mortality rate was %. fmd was similar in patients with or without use of vasopressors at baseline (p = . ). fmd in septic patients was significantly lower than in health controls ( . ± vs. ± %; p \ . ). we observed that survivors depicted a gradual improvement on endothelial function, so that h after sepsis onset fmd was significantly lower in nonsurvivors (- . ± vs. . ± %; p \ . ; time-group interaction p value = . ). conclusions. brachial fmd is altered in septic patients with hemodynamic instability and its improvement may be an early marker of favorable prognosis. introduction. change in pulse pressure variation (dpp) and respiratory variation of the pulse oxymetry plethysmogram (pop) may predict the hemodynamic effect of peep in mechanically ventilated patients [ , ] . reported comparisons [ , ] between pop variations (popv) and co or dpp are based on selection of - consecutive breaths (dpp b) during a ''stable'' period of pop. recently, a fully automatic ventilation mode (intellivent Ò , hamilton medical, switzerland) that incorporates an automatic and continuous popv calculation (hli Ò ) using a dedicated algorithm has been developed. the present study was designed to compare dpp b, dpp calculated with the algorithm as hli Ò (dppalg) and hli Ò. . . sedated icu patients ventilated with hamilton medical s ventilator (with integrated pulse oxymetry (po)) were included (age = ± years, saps ii = ± , no arrhythmia, norepinephrine: . ± . mg/h in patients, map = ± mmhg, vt = . ± . ml/kg). waveforms of po from a finger sensor and of blood pressure from a radial catheter were recorded for - h. from the waveforms, breath by breath (using respiratory flow signal), without pre-selection of stable periods and using known formula [ ] dpp b (averaging breaths without any filtering), dppalg and hli Ò were automatically obtained (matlab Ò ). dpp b was compared to dppalg ( pairs) using mann-whitney t test. pairs of hli Ò and dppalg values (see fig. below) were compared using linear regression and bland-altman method. a dppalg threshold value of % was used to generate hli Ò roc curves. results. dpp b and dppalg were significantly correlated (r = . , p \ . ), but standard deviation of dpp b were higher than the standard deviation of dppalg ( . ± . vs. . ± . %, p \ . ). dppalg and hli Ò were correlated (r = . , p \ . ), mean difference was ± %. hli Ò above % predicted dppalg above % with a sensitivity of % and specificity of % (roc: . ). conclusions. dpp b should be interpreted with caution due to the high variance of this index. in real conditions and during long time monitoring dppalg and hli Ò are in acceptable agreement and hli Ò may help estimating continuously the hemodynamic effects of ventilation. introduction. transthoracic echocardiography (tte) is supposed not to be useful in ventilated patients (pt). echocardiography is usually performed transesophageally in ventilated pt and is thought to be independent of the examiner's skills. we want to demonstrate that tte in ventilated pt could be learned even by medical students with reasonable results and that tte could add useful informations for interpretation of the hemodynamic status. objectives. in a prospective observational study consecutive patients (pt) were enrolled in a -bed medical intensive care unit of a university hospital. inclusion criteria was septic shock according to actual guidelines. transthoracic echocardiography (acuson cv , siemens, germany) was performed by a medical student in each subject on day , day and survival was reported on day . tte-examination was reduced to an apical -chamber view for interpretation of left ventricular global function and calculation of left ventricular ejection fraction (ef) with the simpson method and to a subcostal view in order to examine the diameter of the inferior caval vein (ivc) and to rule out pericardial effusion. each examination was digitally recorded and was interpreted by an experienced cardiologist. every single pt was mechanically ventilated. cardiac output (co) was measured with the transpulmonary thermodilutional technique (picco-catheter, pulsion, germany). the insertion of the picco-catheter took place due to an individual physician's decision. crp was measured as an parameter of inflammation. results. pt, mean age years ± . , male ( %), pt with known coronary artery disease ( %), pt with known dilated cardiomyopathy ( %). mean apache ii-score . ± . . pt died within days ( %). picco-catheter was inserted in pt ( %). tte could be successfully performed in pt ( %). the following values are expressed as mean values ± sd, student's t test, p \ . denotes statistic significance. ef on day . % ± . , ef on day . % ± . , p = . . ivc on day . mm ± . , ivc on day . mm ± . , p = ns. co on day . l/min ± . , co on day . l/min ± . , p = . . crp on day . mg/dl ± . , crp on day . mg/dl±, p\ . . pericardial effusion in no pt. in older pt coronary artery disease is common and ef is at the start of septic shock severely diminished. ef decreased slightly in the early course of septic shock, may be as an expression of septic cardiomyopathy. the ivc diameter did not change and may not be useful as a predictor of preload in ventilated pt. co decreased over time as the hyperdynamic circulation in septic shock is getting normalised. tte adds useful hemodynamic information and should be performed in each ventilated pt. tte could be performed in almost each ventilated pt and is easily learned even by medical students. ( , ) , which can often be caused by anaemia. in current guidelines the transfusion trigger is haemoglobin (hb) \ g/dl, but there is no recommendation for scvo ( ). objectives. the aim of this retrospective study was to evaluate the change in scvo before and after transfusion and to reveal whether co -gap reflects it. methods. over a month period hb, scvo , co -gap and o -extraction ratio (o er) were recorded before and after transfusion. data are presented as median [interquartile range], for statistical analysis wilcoxon, mann-whitney tests and pearson correlation were used as appropriate. results. out of transfusion events the scvo was measured in cases. after transfusion hb increased significantly: . [ . - . ]- . [ . - . ] g/dl, p \ . . the median scvo was %, therefore two groups were created: ''low'' (scvo \ %, n = ); ''high'' (scvo c %; n = ). hb increased significantly in both groups (p \ . ), but scvo conclusions. in the high-group the low hb levels did not cause oxygen debt, as after transfusion hb increased significantly but scvo did not, and o er and co -gap were within the normal range. our results give further support that not only the hb level should serve as a transfusion trigger, but measures of oxygen debt such as scvo and co -gap should also be considered, hence unnecessary transfusions could be avoided. introduction. intellivent Ò is a fully closed loop ventilation designed to keep the patient within target ranges of etco and spo . the system includes an automatic adjustment of peep and fio following the ardsnetwork tables [ ] . if required peep is changed by cmh o every min with a maximal possible value set by the user or depending on an automatic and continuous calculation of the respiratory variations of the plethysmogram from an integrated pulse oxymeter (hli Ò ), i.e. the higher the hli Ò the lower the maximal peep allowed by the system. the present study was designed to estimate whether changes in peep are reflected in hli Ò changes. in sedated icu patients ventilated for min in fully closed loop ventilation with intellivent Ò (hamilton medical s ventilator), episodes of significant changes in peep (c cmh o) were selected and hli Ò values within min before and after peep changes were collected. statistics were done using sigmastats with p \ . as significant. results. changes in peep and in hli Ò are shown in the table ± cmh o ± cmh o ± % ± % p \ . the correlation between change in peep and change in hli Ò is shown on the fig. . conclusions. based on these preliminary data changes in peep are reflected hli Ò changes and may help estimating continuously the hemodynamic effects of ventilation. objectives. we have tested a axis accelerometer sensor for detection of regional left ventricular ischemia. in pigs a -axis accelerometer was sutured to the left ventricular (lv) apical region in left descending coronary artery (lad) supply area accelerometer x-axis measured longitudinal-, y-axis circumferential-and z-axis radial epicardial motions. epicardial displacements were calculated from the acceleration signals and systolic displacements within ms after peak r on ecg was measured. lad was occluded for s to induce regional lv dysfunction. myocardial circumferential strain (shortening) measured by echocardiography in the lv apical anterior region was used to confirm ischemia. the ecg st-segment in lead ii was also monitored. data are presented as mean ± se. early systolic displacement at baseline was ± mm, ± mm and ± in circumferential, longitudinal and radial directions, respectively. lad occlusion induced akinesia in circumferential ( ± mm, p \ . ) and radial ( ± mm, p = . ) directions, whereas longitudinal displacement changed less to ± mm (p = . ). ischemia was confirmed by echocardiography strain, showing lengthening in systole (p \ . ). no significant changes were observer in the ecg st-segment during coronary occlusion (p = . ). introduction. there is increasing evidence to suggest perioperative complications are predictive of long term survival and that reducing them may improve survival rates . goal directed therapy has been shown to reduce mortality and morbidity perioperatively, with those unable to increase oxygen delivery perioperatively having demonstrably worse outcomes. the advent of non invasive tissue oxygenation monitors using near infrared spectroscopy has allowed further study of oxygen flux during goal directed therapy. objectives. to observe changes in tissue oxygenation during an h oxygen delivery targeted post surgical optimisation program and provide long term mortality followup of a surgical cohort of high risk patients. methods. patients undergoing high risk surgery and postoperative optimisation (targeting of oxygen delivery index of [ ml/min/m ) on the tensive care unit at a london teaching hospital were enrolled. each patient underwent a protocolised haemodynamic optimisation protocol as per our standard unit policy for h with consecutive recordings of tissue oxygenation at the thenar eminence using an inspectra monitor. additional variables relating to global and tissue perfusion were measured concurrently. patients were followed up for survival status at . years using routinely available information held within our hospital records. in hospital mortality was . % (n = ), whilst at . years this had increased to % (n = ). there was no significant difference between apii scores ( ) versus . ( ), age . ± . versus . ± . or operation type for survivors and non-survivors at . years respectively. significant differences between groups were found however for admission and mid optimisation protocol ( h) hr and sto (see table there were no significant differences in measured variables for day mortality. conclusions. there appears to be a statistical and clinical difference in hr and tissue oxygenation between the long term survivors of high risk surgery who undergo monitored postoperative goal directed optimisation. introduction. bronchoscopic bronchoalveolar lavage (b-bal) is today the gold standard for sampling of inflammatory markers in the distal airways. nonbronchoscopic bronchoalveolar lavage (n-bal) by ordinary suction catheter has been investigated as a more easily accessible method for alveolar sampling in the setting of acute respiratory distress syndrome (ards). the results, however, were disappointing, probably due to more proximal sampling by the n-bal. to investigate wether n-bal by a catheter with physical properties similar to those of the bronchoscope is comparable to b-bal. methods. b-bal and n-bal by cook's airway exchange catheter was performed with ml normal saline on opposite sides min apart at nine different occasions on anesthetized and intubated pigs. the volume of the recovered lavage was noted, after which the fluid was analyzed for albumin, total cell count, viability and differential cell count. statistical analysis was performed using wilcoxon's rank-sum test. results. n-bal yielded significantly higher albumin content than b-bal ( . ± . vs. . ± . mg/l, p = . ). in all other measurements there were no significant differences between n-bal and b-bal (recovered volume . objectives. we hypothesized that collagen synthesis and degradation are disturbed in acute respiratory failure. in the finnali-study we defined acute respiratory failure as need of noninvasive and/or invasive ventilatory support for more than h ( ). after informed consent we collected blood samples for serum procollagen propeptides i and iii (pinp, piiinp) and ictp levels at study admission, day , and . patients with all four blood samples were included in this substudy. multiple organ dysfunction (mod) was defined as two or more individual organ sofa scores of - at any day during the first week. results. the study population comprised of finnali patients ( ). the mean (sd, range) age was years ( , - ) and the majority were male %. on admission the mean sapsii score was ( , - ). patients ( %) developed mod during the first days. over time piiinp/pinp-ratio first increased and then decreased to baseline by day while pinp/ictp-ratio decreased and then decreased to baseline by day (p \ . and p = . , respectively) ( fig. ). there were no statistical differences in the ratios between patients with or without mod. conclusions. we found that in patients with acute respiratory failure the balance of collagen synthesis was towards degradation of type i collagen and production of collagen type iii. ± ng/ml in the ards group, and significantly higher than the . ± . ng/ml in the ali (not ards) group. the difference in hmgb values in the early stage between the group that died up to the by th day and the surviving group was not significant, but the hmgb values were significantly higher in the group that died until the th day and th day than in the survival group. it was concluded that differences in hmgb values in the early stage after the onset of ali (not ards)/ards are useful as outcome determining factors after days of onset. an inverse correlation was observed between the hmgb values and lung oxygenation, suggesting the possibility that hmbg is involved in the development of respiratory failure. s. shibata , g. takahashi , n. shioya , s. endo akita city hospital, anesthesiology, akita, japan, iwate medical university, emergency medicine, morioka, japan, iwate medical university, critical care medicine, morioka, japan sivelestat sodium hydrate (sivelestat) is a selective polymorphonuclear leukocyte elastase (pmn-e) inhibitor and has also been shown to be effective for pulmonary disorders associated with sirs in clinical patients. blood levels of inflammatory cytokines have been shown to be decreased in patients treated with sivelestat. however, since patients with sirs have already received other drugs, it remains indefinite whether or not sivelestat might suppress the production of cytokines. moreover, it is difficult to clarify any cells releasing cytokines. in the experiment using cells isolated from the blood, intercellular mutual actions and cytokine networks were blocked and the experiment failed to faithfully reproduce the in-vivo condition. objectives. the possibility of sivelestat suppressing the production of cytokines from granulocytes and monocytes was assessed by intracellular cytokine staining using the whole blood culture method and flow cytometry to faithfully reproduce the in-vivo condition. methods. blood samples were collected from healthy volunteers. a vehicle (control group), lipopolysaccharide (lps; lps group), or lps + sivelestat (sivelestat group) was added to the whole blood, followed by the addition of a protein transport inhibitor in each group. after incubation, they were subjected to staining of the cytokines retained in the cells by the addition of an anti-interleukin (il- ) or anti-tumor necrosis factor a (tnf-a) antibody and analysis by flow cytometry. the data were analyzed by the kolmogorov-smirnov test. values obtained [d/s(n)] result from the comparison of the fluorescence histograms of each sample with a control one. addition of sivelestat at low concentrations ( and lg/ml) significantly (p \ . ) suppressed the production of il- from granulocytes induced by a low concentration ( ng/ml) of lps. on the other hand, the granulocytic production of tnf-a induced by a high concentration of lps ( ng/ml) was significantly (p \ . ) suppressed by treatment with sivelestat at high concentrations ( and lg/ml). with regard to the monocytic production of tnf-a and il- induced by lps, there was no significant suppression of either tnf-a or il- production by sivelestat. conclusions. sivelestat, a neutrophil elastase inhibitor, suppressed granulocytic production of il- and tnf-a, suggesting the potential usefulness of sivelestat for the treatment of various morbid conditions involving il- and tnf-a in their onset. introduction. coagulation, fibrinolysis and extravascular fibrin deposition are the hallmarks of the pathogenesis of acute lung injury (ali). pai- has a central role in antagonizing fibrinolysis by decreasing the plasminogen turnover to plasmin. pai- has been suggested as a clinical severity marker of ali. in previous studies it was associated with higher mortality and morbidity in the critically ill. upar is a cell surface receptor activating the serine protease upa. increased expression of upar is found in various stages, including inflammation, tissue remodelling and malignancies, indicating poor prognosis. pai- antagonizes the proteolytic activities of upa and plasmin. objectives. we sought to evaluate the prognostic value of supar and pai- for -day mortality of patients with acute respiratory failure (arf). the finnali-study patients needed invasive or non-invasive ventilation for more than h ( ). blood samples were collected from patients at baseline and on day after baseline. healthy volunteers were also analyzed. sera were frozen at - °c until analyses. concentrations of supar and pai- in blood serum were measured by enzyme linked immunosorbent assay (elisa). data are presented as median (iqr). the prognostic value of supar and pai- for -day mortality was determined with roc analysis. in the critically ill, supar and pai- were . ( . - . ) ng/ml and . introduction. acute lung injury is a common disease in intensive care, associated to various septic or inflammatory diseases. inflammation is part of the defense mechanisms of innate immunity, occurring after tissue injury. objectives. the aim of the project was to decipher the transcriptional changes occurring after the onset of an inflammatory injury by intravenous injection of oleic acid. experimental study of the lung transcriptome after oleic acid injection. thirtysix c bl/ j mice, aged of weeks, were sacrificed at h, h , h, h, h and h after physiological serum or oleic acid injection ( ll) in the caudal vein. left and right lung were separated for mrna extraction and pathological examination. labelled cdna were hybridized on cdna nylon microarray (tagc, marseilles, france) and raw data were extracted from scanned images with bzscan software. raw data were normalized with the quantile method, and supervised analysis was conducted with significance analysis of microarray algorithm within the r statistical suite and bioconductor libraries. after the administration of oleic acid, the mice were tachypneic and prostrated. all survived during the first hours. the pathological analysis of lung tissue revealed an early inflitration of the lung tissue by polynuclear cells, as well as a pulmonary edema. these alterations were not observed after h. the time course analysis of transcriptional lung data identified a thousand genes which expression is modulated after injury. hierarchical clustering identified major groups of genes. the first one ( genes) is composed of genes transiently up-regulated between h and h after oleic acid injection. th second group ( genes) is composed of genes expressed between h and h. the third group ( genes) is composed of genes expressed at the later time points ( h- h). the functional annotation linked these signatures with keywords related to pro-inflammatory response, vascular endothelium modification and lipid metabolism, respectively. rt-pcr analysis of pro-(tnf, il ) and anti-inflammatory (il , il ) markers related the pro-inflammatory phase to the earlier time points ( h- h ) and the anti-inflammatory phase to the late points (after h). conclusions. oleic acid injection in mice induced a transient acute lung injury. this is confirmed by clinical, pathological and transcriptional modifications. the modulation of gene expression after the oleic acid injection revealed an early pro-inflammatory response, followed by an anti-inflammatory response and lipid metabolism modificiations. this model could now be used to describe the specific modulation occuring during pulmonary infection and critical injuries like acute respiratory distress syndrome. introduction. ventilator associated lung injury (vali) is influenced by tidal volumes, airway pressure and cyclic opening of alveoli during mechanical ventilation. preserved spontaneous breathing during partial ventilatory support may be protective, but it is not known whether the transpulmonary pressure generated by spontaneous breathing has the same effect on vali as if generated by the ventilator. to determine whether hemodynamics, respirtory function and vali are influenced by the amount of support provided by pressure support ventilation. after approval from the institutional animal care committee, acute lung injury was induced in anesthetized sd rats by acid aspiration. ten animals each were then ventilated with positive end-expiratory pressure cmh o in pressure control (pc), pressureregulated assist control (ac) or pressure support mode with % (ps ), % (ps ) or % (ps ) pressure support of initial distending pressure needed to maintain tidal volume. pc animals were paralyzed. after h animals were killed and vali determined. results. there were no differences in baseline characteristics. acute lung injury was characterized by a decrease of the p/f ratio from ± to ± mmhg and of the dynamic compliance from . ± . to . ± . ml/cmh o. conclusions. compared to controlled ventilation, preserved spontaneous breathing activity improved hemodynamic stability, respiratory function and lung edema clearance. the reduction in pressure support did not lead to reduced tidal volume, but transpulmonary pressure was preserved by muscular activity of the chest wall. no difference was observed between full or % of pressure support, but further reduction in pressure support resulted in increased wet-dry ratio. objectives. we studied the effects of metabolic acidosis on enzymatic and non-enzymatic no-production in hypoxic and hyperoxic lung regions in a pig model. eighteen healthy anesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (lll) and hyperoxic gas to the rest of the lung. six pigs received hcl infusion (hcl group), six pigs received n w -nitro-l-arginine methyl ester (l-name) and hcl (l-name + hcl group) and six pigs received buffered ringer's solution (control group). no concentration in exhaled air (eno), no synthase (nos) activity in lung tissue, and regional pulmonary blood flow were measured. results. metabolic acidosis, induced by infusion of hcl, decreased the relative perfusion to the hypoxic lll (q lll /q t ) from (± ) to (± )% in the hcl group (p \ . ), and from (± ) to (± )% in the l-name + hcl group (p \ . ), without any measurable significant changes in eno from hypoxic or hyperoxic lung regions there were no significant differences between the hcl and control groups for ca + -dependent or ca + -independent nos activity in hypoxic or hyperoxic lung regions. metabolic acidosis augmented the hypoxic pulmonary vasoconstriction, without any changes in pulmonary enzymatic or non-enzymatic no-production. when acidosis was induced during ongoing nos-blockade, the perfusion of hypoxic lung regions was almost abolished, indicating acidosis-induced pulmonary vasoconstriction was not no dependent. assessing and monitoring biomarkers in acute lung injury (ali) may improve knowledge of its pathogenesis, early recognition, and management and predict remote organ injury and multiple organ failure. objectives. early consents for research are difficult to obtain in patients with or at risk of ali because of the emotional burden of the severity and sudden onset of the disease. however, study samples may be obtained from left-over clinical blood draws, which are readily available if processed adequately. the aim of this study was to compare fresh and ''waste'' blood samples prospectively in a series of consecutive critically ill patients. the hypothesis is that ''waste'' blood samples if appropriately processed provides accurate and reliable results comparable to the gold-standard, which is immediate collection and processing of fresh blood samples. prospective study comparing biomarkers of epithelial injury (srage) and inflammation ( different cytokines/chemokines) in critically ill patients measured on fresh blood or waste blood, kept at degrees celsius for h. an automated system performed a daily screening of adults in the icu with an increased risk for ali (lung injury prediction score, lips) within h of admission and/or on recognition of the diagnosis of ali, using the american-european consensus conference criteria. risks factors for ali include pneumonia, sepsis, pancreatitis, shock, aspiration, high risk surgery and high risk trauma. irb approved the protocol and written consent was obtained from patients or their surrogates. statistical measurements were performed using the bland-altman analysis for correlation between fresh and waste blood sample data. between may and december , patients were enrolled. one patient was excluded due to lack of sample. samples were obtained either at one time point (n = ) or two, on consecutive days (n = ). female/male patient ratio was / . seven of the patients had ali. twenty two patients had risk for ali with a median lips score of (iqr . - . ). sepsis was the most common risk factor, present in patients. in-hospital mortality was % ( / ). the bland-altman plot (mean bias ± se, limits of agreement) showed good correlation for il- ra (- ± . pg/ml, - . to . pg/ml), il- ( . ± . pg/ml, - to . pg/ml), il- (- . ± . pg/ml, - . to . pg/ml), il- (p ) (- . ± . pg/ml, - . to . pg/ml), mcp- (- . ± pg/ml, - . to . pg/ml) and srage (- ± pg/ ml, - to pg/ml) between fresh blood and ''waste'' blood samples. in patients with ali, properly stored blood, drawn for clinical purposes, can be processed within h for research purposes. however, the stability of each biomarker of interest needs to be individually validated before using stored blood introduction. pulmonary surfactant inactivation following acute lung injury might promote alveolar derecruitment and reduce the airspace available for ventilation, making the lung more prone to ventilation-induced lung injury (vili). our aim was to test the potential for a protective effect of exogenous surfactant treatment in a model of acid aspiration and vili. methods. male c /bl mice were anesthetized, mechanically ventilated (vt ml/ kg; rr /min; peep ± . cmh o; fio . ) and immediately subjected to intrabronchial (right) instillation of . ml/kg hcl . m. mechanical ventilation went on for min. min after the acid instillation, mice were treated with exogenous surfactant ( mg of phospholipids/ml) given as bolus of ml/kg in the right bronchus (surf group). we measured oxygenation, lung compliance (measured every min throughout the experiment), macrophage inflammatory protein (mip) in broncho-alveolar lavage (bal) fluid. . pao at the end of the experiment was significantly higher in the surf than in control group ( ± vs. ± mmhg, p \ . ). although surfactant bolus caused a reduction in lung compliance measured and min after treatment, in the surf group compliance restored to ± % of the post injury level, while it decreased in control group to ± % (p \ . ). there were no differences between groups in the dosage of mip- in bal neither in right or left lung. conclusions. exogenous surfactant treatment improved lung function in a murine model of two hit lung injury. grant acknowledgment. introduction. ventilator induced lung injury significantly contributes to the mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. understanding the molecular basis for response to cyclic stretch and its derangement during high volume ventilation is of high priority. objectives. to identify specific molecular regulators involved in the development of ventilator induced lung injury. we undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of cyclic stretch responsive genes using microarray analysis. analysis of stretched vs. non-stretched cells identified significant enrichment for genes containing binding sites for the transcription factor atf (activating transcription factor ). to determine the role of atf in vivo, we compared the response of atf gene deficient mice to wild type litter mates in an in vivo model of ventilator induced lung injury. results. atf deficiency results in increased sensitivity to mechanical ventilation alone or in conjunction with inhaled lipopolysaccharide ( mg/kg) as determined by assessment of lung and bronchoalveolar lavage cell infiltration and pro-inflammatory mediator release, pulmonary edema and indices of tissue injury. the expression of genes containing an atf cis-regulatory region was significantly altered in gene deficient animals. atf protein expression and nuclear translocation is increased after mechanical ventilation. conclusions. atf deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. in our model, atf acts to ''counterbalance'' cyclic stretch and high volume-induced inflammation, limiting its potential to cause additional lung injury and consequently protecting animals from injurious cyclic stretch. objectives. our aim was to evaluate the role of the alveolar macrophages in a murine model of ali, by selective depletion of this type of cells from the air space achieved by clodronate administration. mice were treated (it) with ll of clodronate (clo)-or pbs (pbs)-liposomes. after h mice were anesthetized and ventilated (vt - ml/kg, rr min - , fio . ); in order to induce lung injury ml/kg of hcl ( . m) or air bolus (sham group) was instilled in the right bronchus. mice were ventilated for min, and extubated after awakening. h after injury, animals were sacrificed and broncho-alveolar lavage (bal) and blood gas analysis (fio = . ) were performed. . h after lung injury animals with alveolar macrophages depletion, showed a better oxygenation versus pbs-treated group. however, recruitment of neutrophils in bal was not statistically different between clo_hcl and pbs_hcl group. results. high levels of oc were found in patients treated by mg of ot bid. oc levels ranged from , to , ng/ml in these patients. concentrations of oc were five-to tenfold higher than concentrations reported in healthy volunteers. lesser levels were found in patients treated by mg of ot bid. nevertheless, the patient with the moderate renal failure seemed to accumulate oc (levels ranged from to ng/ml) whereas concentrations reported in the patient with a normal renal clearance were below ( - ng/ml). conclusions. ecmo seemed not to have any influence on oc concentrations while renal insufficiency seemed to be the parameter leading to oc accumulation. as ic was very low and reached even with usual dosage, increasing ot dose to mg bid appeared to be unnecessary. objectives. aim of our study was to evaluate the effect of nursing care on patients undergoing venous-venous ecmo for acute respiratory distress syndrome (ards). methods. we recorded physiological and ecmo parameters (heart rate, arterial blood pressure, mixed venous saturation (svo ), arterial oxygen saturation (spo ), body temperature and extracorporeal blood flow (bf)) before and during daily nursing in patients undergoing vv-ecmo for several days (each patient was followed on average for . days, cases in total). arterial blood gases were also collected before and after nursing care. daily nursing was performed following defined steps (sponge bath, oral hygiene, change position of endotracheal tube, elevation with scooping stretcher for sheets replacement and back hygiene, dressing replacement) in agreement with a standard protocol in use in our department. (expressed as mean ± standard deviation). all patients were affected by ards h n -related. patients were sedated with propofol ( ± mg/h) or midazolam ( . ± . mg/h) plus an opioid drug (fentanyl ± mcg/h or remifentanil . ± . mcg/kg/min or sufentanil . ± . mcg/kg/min). ramsey score before nursing was . ± . . in cases patients were paralysed. in table we summarized the adverse events observed during nursing care, divided into hypertensive or tachycardic episodes, blood oxygen desaturation, reduction in svo or reduction in bf. forty-nine sedative bolus were administered during nursing (mean request for each patient: . ± . ), always after an episode of hypertension or tachycardia (most frequently during elevation with scooping stretcher and changing position of endotracheal tube). although in cases preventive bolus of sedation were administered before nursing, in of those cases ( %), additional bolus were required. we found an inverse correlation between bf and the increase in heart rate, drop in arterial saturation and svo . despite active warming, we observed a drop of . ± . °c (p \ . ) in body temperature. nursing care may have a significant impact on physiologic parameters of patients during vv-ecmo. tachycardia, hypertension and reduction in oxygenation were commonly recorded and were not prevented by pre-nursing bolus of sedation but were attenuated in patients with higher bf. introduction. prone position has been used in cases of ards with refractory hypoxemia but some physiological effects are still unknown. prone position could increase intraabdominal pressure (iap) and could lead to acute renal failure (arf). acute kidney injury in icu is associated with increased mortality. objectives. the aim of this study was to determine whether prone position could increase intraabdominal pressure and possibly promote arf. we studied all adult ards patients who were ventilated using the protective strategy defined by ards network criteria and who needed prone position to improve oxygenation. we collected respiratory data (ventilator parameters and gas exchange) and hemodynamic variables (heart rate, systolic, diastolic and mean arterial pressure). iap was measured using the abdo-pressure tm bladder transducer following world society of acute compartment syndrome recommendations. abdominal perfusion pressure was calculated as mean arterial pressure minus iap. main renal parameters were: filtration gradient (fg), creatinine clearance, fractional excretion of sodium (fena) and urea (feurea). patients were classified according to rifle score after each manoeuvre. all data were recorded in prone and in supine position at least once per day. results. the study included patients ( male) admitted to a medical-surgical icu over a one-year period. their mean age was . ± . and length of icu stay was ± days. all patients had primary ards and had received nephrotoxics. icu mortality reached %. we recorded at least manoeuvres per patient (a, b, c). prone positioning improved pafio ratio from . ± to ± (p = . ). iap showed a small increase from . ± . to . ± . mmhg (a; p = . ), from . ± . to . ± . mmhg (b; p = . ) and from . ± . to . ± . mmhg (c; p = . ). there were no statistically significant changes in hemodynamic parameters or abdominal perfusion pressure. renal function parameters (fg, creatinine clearance, fena and feurea) showed no modification after each prone positioning. in contrast, when patients were classified according to rifle score, we observed a trend towards worsening, though this was not statistically significant. conclusions. prone positioning improved arterial oxygenation in primary ards patients and was associated with an increase in iap. however, creatinine clearance and glomerular filtration remained unchanged. percutaneous extracorporeal life support system (p-ecls) including ecmo becomes widely used in medical and surgical emergent situation, such as refractory cardiogenic shock, cardiac arrest and acute respiratory failure. patients requires highly specialized intensive care and monitoring system. we reviewed our ecls experience and tried to analyze the clinical outcomes, factors for survival and frequently faced problems during management for improving weaning and survival rate (medical vs. surgical patients). introduction. in spite of the huge efforts spent over the last years, conventional treatment of acute hypoxemic respiratory failure (ahrf) is often inadequate and alternative procedures must be instituted. icus skillful in extracorporeal membrane oxygenation (ecmo), as recently shown [ ] , may improve survival of these patients. since we developed a treatment algorithm for ahrf which encomprises: ( ) low flow venous-venous ecmo (lf-ecmo) consisting in a relatively low initial blood flow (bf, - . l/min) to maximize extracorporeal co removal while providing partial oxygenation (if needed, bf can be increased up to . - l/min to keep arterial po above mmhg); ( ) femoral-femoral percutaneous cannulation with - fr cannulas to allow free movements of the neck and increase patient's tolerance; ( ) early institution of spontaneous assisted ventilation (sb) and weaning from sedation and mechanical ventilation (mv) while on ecmo. objectives. to review our last years lf-ecmo activity. methods. study period was january - . lf-ecmo entry criteria were: potentially reversible acute hypoxemic respiratory failure, lis c , no evidence of intracranial bleeding and no absolute contra-indications to heparinization. ecmo was performed with different type of heparin coated hollow-fiber artificial lungs. . we treated patients (mean ± sd, ± . years old, % males, bmi ± , sofa . ± , oi ± ). % of these patients were placed on ecmo at other hospitals and transported to our icu by a dedicated ecmo team. ventilation days before ecmo were ± (range - ). before ecmo vt/kg was ± . and rr was ± : after ecmo beginning vt/kg was unchanged while rr decreased to ± (p\ . ). ecmo was set at bf . ± l/min, gf . ± . l/min, fio . ± . introduction. ventilating patients with acute lung injury (ali) in supine position potentially leads to an impaired pulmonary gas exchange. prone position (pp) is an attractive means to improve ventilation-perfusion (v/q) ratio [ , ] but has several contraindications and showed no improvement in survival so far [ ] . another therapeutical option is an upright position, which is easy to perform and has theoretical advantages over pp: the upward shift of the abdominal compartment is less pronounced, thus increasing thoracoabdominal compliance [ ] . however, to date regimes of an upright position did not tilt patients more than ° [ ] . objectives. we hypothesised that a °standing position (sp) during mechanical ventilation may improve respiratory function. furthermore, we aimed to determine the feasibility of a sp for h during mechanical ventilation. we studied adult patients, receiving mechanical ventilation for more than h in the intensive care unit of an university hospital. after recording baseline data, patients were placed in a °sp with the body entirely straight. further data sets were recorded during h in sp, and after patients position was readjusted to supine position. functional residual capacity (frc) increased immediately after reaching sp (p \ . ) and remained elevated after repositioning to supine position. pao /fio ratio and compliance decreased initially during sp, but increased (p \ . ) after patients were retransferred to supine position. haemodynamic variables remained stable under a moderate increase of doses of catecholamines during the study period. conclusions. changes in respiratory function during sp are probably explained by a downward shift of the diaphragm due to gravitational forces leading to an increased frc but not altering v/q ratio as demonstrated by the pao /fio ratio. after reaching the initial supine position the opening of the lung proved by the elevated frc is the predominant effect now associated with an increase in oxygenation as reflected by the pao /fio ratio due to an optimised v/q ratio. our results are confirmed in a subgroup analysis for patients meeting ali criteria. ventilating patients in sp may be a new therapeutical approach to improve respiratory function in patients with ali. ( ) . there are several clinical trials investigating the efficacy of the free radical scavenger n-acetylcysteine (nac) in ards, but its advantage remains uncertain. objectives. critically appraise and summarize all randomized clinical trials involving intravenous nac administration in adult patients suffering from ards. we included trials involving participants with ards according to the american-european consensus conference criteria ( ) regardless of the underlying cause, and where one of the groups was treated with intravenous n-acetylcysteine in bolus intravenous doses or as continuous infusion, or combination of the two, and the other group was given placebo or standard treatment. conclusions. the main finding of this meta-analysis is that intravenous nac is ineffective in reducing mortality, length of stay or duration of mechanical ventilation in ards. we also found that late administration of nac may be associated with adverse outcome. the mechanism of this potentially deleterious effect remains unclear, but dosing and timing of nac appear to be critical issues. objective. to evaluate if extubation during ecls is harmful or beneficial. a -year-old woman was admitted to our intensive care unit (icu) after removal of a left ventricular assist device. this device was implanted as bridge to recovery for postpartum cardiomyopathy and ventricular function seemed to have recovered sufficiently. however, shortly after icu admittance she developed massive left and right ventricular failure. therefore a centrally cannulated veno-arterial ecls (maquet permanent life support) was implanted as a bridge to transplant. four days later she was extubated while on full ecls support, in order to reduce the risk of ventilator associated pneumonia. while on ecls, the patient was mobilized, practiced with an ergometer and chatted with her family. three days later the patient underwent cardiac transplantation. the postoperative period was characterized by temporary pulmonary failure, due to the combination of lung edema and atelectasis. eventually she made a full recovery. discussion. ecls provides a valuable means as bridge to transplantation, bridge to bridge or bridge to recovery. with the increasing use of ecls for circulatory failure, debate about the necessity of mechanical ventilation during this treatment ensues. ecls is usually applied under deep sedation and controlled mechanical ventilation. discontinuation of sedation possibly prevents intensive care acquired weakness. extubation during ecls may provide better pulmonary perfusion due to negative intra-thoracic pressure. furthermore, the awake and extubated patient is able to mobilize and exercise which may reduce the risk of atelectasis and ventilator associated pneumonia. our patient however developed pulmonary edema and atelectasis after discontinuation of ecls. the edema was probably a consequence of reperfusion injury, due to severely decreased pulmonary flow while on ecls. an absent ventilatory drive while on ecls may have led to hypoventilation while the patient was extubated, resulting in atelectasis. an extensive medline search resulted in one other case report describing an extubated patient on ecls. intermittent non-invasive positive pressure ventilation was used to prevent atelectasis, but the patient developed pneumonia after days of ecls. our patient was successfully extubated while on ecls. however, we conclude that there is insufficient evidence to recommend or oppose extubation of patients on ecls for circulatory failure. severe ards and refractory hypoxemia were defined with a pao / fraction of inspired oxygen (fio ) ratio of b , or uncompensated hypercapnea with a ph of \ . despite receiving optimal conventional treatment. the ecmo can be used as a rescue treatment in these case. objectives. evaluation of severe ards treated with extracorporeal oxygenation (ecmo). all these ards were due to bacterial pneumonia or h n influenza. over the last year (december -january ), the recourse to extracorporeal oxygenation (ecmo) was used in ten patients with severe ards and severe hypoxemia. two groups were defined: bacterial pneumonia with ards (bp group, n = ), and h n influenza with ards (h n group, n = ). all ecmos were implanted at the bedside to facilitate intra-hospital or inter-hospital transfer, because of severe hypoxemia or hemodynamic instability making impossible patient mobilization before ecmo. results. data sets of patients of consecutive patients treated with ecmo were complete and included into analyses. we had no clinical or radiological evidence for thrombosis or clotting within ecmo-circuit with a target-ptt of s. one patient with systemic aspergillosis died because of intracranial hemorrhage. one ecmo circuit had to be replaced due to insufficient oxygenator function after days. further data are presented in tables and . conclusions. in this retrospective analysis of patients who underwent ecmotreatment, ac with low-dose heparin (target-ptt of s) was safe and without any observation of macroscopic thrombosis or clotting within the circuit. transfusion requirements and intracranial hemorrhage were low as compared with previous reports [ , ] . therefore our data suggest that it is possible and safe using ecmo-therapy with low-dose heparin. introduction. in response to h n pandemy, italy and lombardy created a national and a regional icu network, respectively, for treatment of ards patients. our hospital policlinico san matteo of pavia participated with a team for inter-hospital ecmo implantation and subsequent patient transport. objectives. description of the pavia ecmo team and activity analysis. methods. our team is composed by a cardiac surgeon, two intensivists, a perfusionist, an icu nurse, two emergency rescue technicians and a driver. all necessary aids for implantation and intensive care are ranged in three trolleys and three transport bags. equipments are firmly mounted on a two-level steel bridge connected to a spinal board. a portable ultrasonograph is also available. the ecmo team was alerted by the national call center. each mission used two ambulances, and in one case the ambulances were embarked on a hercules c j. from october to december , four patients were implanted and transported, three suffering from h n influenza (including a -kg body weight patient) and one from acute mitral valve rupture. all patients, already mechanically ventilated with maximal support, had veno-venous ecmo implanted by femoro-femoral percutaneous cannulation. the median mission duration was of . h (range - h). all patients were transported to our icu, where the median ecmo duration was of days (range - days). no major managing issue occurred during the ecmo missions, and patient hospital survival was of %. a multispecialist team with good knowledge of ecmo can provide an effective support in severe respiratory failure, with ecmo implantation in peripheral hospitals and subsequent patient transport, thus realizing a fast and safe continuum between phone call activation and admittance to the reference center. introduction. when patients with sever respiratory failure are treated with v-v ecmo the right heart sometimes fails. this is a serious complication with a high mortality. in our unit these patients have been converted to v-a ecmo, although it is not fully agreed upon in the ecmo community due to previously depressing results. objectives. to evaluate the results of conversion to v-a from v-v ecmo in case of right heart failure. retrospective analyses of all patients with severe respiratory failure, treated between and at the karolinska ecmo centre. patients who were converted to v-a ecmo due to right ventricular failure were evaluated. a total of patients ( adults, peadiatric, neonatal) were treated on v-v ecmo for severe respiratory failure. of them ( adults, peadiatric, neonatal) needed conversion to v-a ecmo due to right ventricular heart failure demonstrated clinically by multiorgan failure and verified by echo cardiography. the survival after conversion to v-a ecmo was / ( %) in the adult age group, / ( %) in the peadiatric age group and / ( %) among the neonates. conclusions. given the high risk of fatality if not treated, conversion to v-a from v-v ecmo should be considered when the right ventricle fails. patients on v-v ecmo with right ventricle heart failure have very bad prognosis. it is concluded from the present results that conversion to v-a ecmo can save some of these patients. cardiac surgery and regional hemodynamics: objectives. to test whether tapse and right ventricular systolic (sm) and diastolic (em and am) tissue doppler imaging velocities are related with pulmonary artery systolic pressure (pasp) and length of the weaning process in mechanically ventilated patients with acute heart failure (ahf). methods. rv fractional area change (rvfac), left ventricular ejection fraction (lvef), pasp, tapse, sm, em, am rv tdi velocities, early diastolic mitral e wave and e maximal tdi velocities of the mitral annulus at the lateral wall were obtained at admission by doppler echocardiography in a cohort of patients with ahf, presented with pulmonary oedema, who required positive-pressure ventilation for more than h in the intensive care unit (icu). echo-derived measures were compared between patients with and without pulmonary hypertension, whereas their association with duration of mechanical ventilation and length of the weaning process was tested with multivariate linear and logistic regression analysis. and increased e/e ratio ( . ± . vs. . ± . , p \ . ) compared with subjects with normal pasp (n = ). these variables were negatively associated with duration of mechanical ventilation (r = . , beta slope = - . for tapse, r = . , beta = - . for sm, r = . , beta = - . for em/am, p \ . ) and were proven to successfully discriminate patients with (n = ) and without (n = ) prolonged weaning ([ days of weaning after the first spontaneous breathing trial failure, p \ . for all comparisons). conclusions. we suggest that in critically ill patients with ahf presented with pulmonary oedema, low tapse and rv tdi velocities upon admission are associated with pulmonary hypertension and prolonged length of the weaning process. objectives. the aim of the study was to study changes in cerebral blood flow (cbf), as determined by tcd, during the early postoperative course of cvs and to correlate such changes with post-operative nc. we studied patients undergoing extracorporeal circulation cvs (coronary by-pass, valve replacement or both) between march and march . cbf was assessed by measuring bilateral mca flow velocities by tcd before and , and h after cvs. changes c % between consecutive tcd results were considered significant. demographic and clinical variables, co morbidities, euroscore, sofa, type and duration of surgery and type and severity of nc were also recorded. patients were assigned to groups according to cbf changes from baseline: a) changes b %; b) cbf increases c %, c) cbf decreases c %. nc were classified as major (stroke, tia and coma) and minor (delirium, encephalopathy, transient cognitive impairment). we used descriptive statistics and inference by v , anova and pearson's correlation. of the patients, were excluded ( early post-operative death and due to technical difficulties or incomplete tcd recordings). of evaluable patients, ( %) had no cbf changes (group a), ( %) had increases c % (group b) and ( %) had decreases c % after cvs (group c). a positive correlation was found between cbf changes and duration of circulatory arrest (p \ . ), maximum sofa score (p \ . ), respiratory dysfunction (p \ . ) and duration of mechanical ventilation (p \ . ). neurological complications occurred in patients ( %), of which ( %) were major and were minor ( % introduction. the sole monitoring of macrohemodynamic variables is not always sufficient in the early detection of tissue hypoperfusion, especially in cardiac surgical patients that frequently present with microcirculatory derangements. near infrared spectroscopy (nirs) is an easily applicable non invasive technique that has been used to provide an estimate of tissue oxygenation at the bed side. objective. the aim of our study was to evaluate the effect on outcome of guiding hemodynamic therapy and specifically inotrope titration in cardiac surgical patients postoperatively with nirs. methods. patients operated on with cardiopulmonary bypass were assigned, after stratified randomization (gender, euroscore-cutoff of ), to an intervention (ig) and a control group (cg). postoperatively, following cardiac intensive care (cicu) admission, after initial resuscitation according to cicu protocol, sto (%) was measured in patients of the ig in muscle sites: thenar, masseter and deltoid. if it was less than % in / sites, dobutamine was administered in incremental doses ( . lg/kg/min), with the sto (%) measured every half hour. the interventional period began upon cicu admission and lasted for h, after which both groups were treated according to cicu protocol. primary outcome measured was the oxygen consumption rate at the end of the h intervention period as assessed with nirs vascular occlusion technique. . patients were included in the study ( in the intervention group and in the control group). the groups did not differ statistically significantly regarding age, euroscore, and macrohemodynamic variables postoperatively (with the exception of cvp). microcirculatory parameters upon admission to the cicu also did not differ, excluding masseter sto (%). the oxygen consumption rate and the reperfusion rate increased in the h study period in both groups, without differing statistically significantly between the groups at any time point (cg oxygen consumption rate . ± . upon cicu admission and . ± . h later, ig . ± . and . ± . respectively) (cg reperfusion rate ± upon cicu admission and ± h later and ig ± and ± respectively). as far as outcome parameters were concerned, the groups did not differ statistically significantly in the total hours and total dose of vasopressors ± inotropes received, in the hours of mechanical ventilation, in the duration of cicu or hospital stay, and in sofa scores the days following the operation. conclusion. nirs guided titration of inotropes did not lead to a greater improvement in the microcirculation h postoperatively, or to a better outcome. the limited power of the study prevents definite conclusions on the role of nirs in hemodynamic therapy in cardiac surgery patients. objectives. to estimate the prevalence of pulmonary embolism among mv patients in icu and its association to deep vein thrombosis (dvt). in a monocentric prospective observational study, we included all the patients requiring mechanical ventilation with no previously diagnosed pe, who underwent a thoracoabdominal ct contrast scanner for any medical reason. we used a modified protocol for pe diagnosis with a -multidetector row ct scan read by two independent radiologists. the association with a dvt was explored by performing venous compression ultrasound of four limbs. objectives. the aim of this animal study was to evaluate the effect of intraabdominal hypertension on left ventricular diastolic function. after approval by an institutional animal care committee, rabbits were anesthetised before mechanical ventilation. an intraperitoneal infusion of . % glycine solution was used to increase intraabdominal pressure to mmhg. the right common carotid artery was catheterised in the neck in order to introduce a millar mikro-tip catheter (millar instruments inc., houston, usa) into the left ventricle. heart rate, arterial pressure, central venous pressure, oesophageal pressure and intraabdominal pressure were measured. the s time constant of relaxation which is considered as best index of relaxation was calculated using the derivative method ( ). all haemodynamic measurements were registered at baseline and after inducing intraabdominal hypertension. data are presented as mean (iqr) and were compared using a wilcoxon rank sum test. results. heart rate (from ± to ± beat/min, p = . ), mean arterial pressure (from ± to ± mmhg, p = . ) and dp/dt max (from , ± to , ± mmhg/s, p = . ) were not significantly modified by intraabdominal hypertension. however, the s time constant of relaxation increased significantly (from ± to ± ms; p = . ). conclusions. in this animal model, intraabdominal hypertension impairs left ventricular relaxation. these changes in the condition of the microcirculation have been related to the degree of organ dysfunction and thus patient outcome ie hospital length of stay. near infrared spectroscopy (nirs) is an easily applicable non invasive technique that has been used to provide an estimate of tissue oxygenation at the bed side. objectives. the aim of our observational study was to examine whether impaired tissue oxygenation as assessed with nirs immediately postoperatively correlates with hospital length of stay. patients undergoing a planned cardiac surgical procedure on cpb were included in the study. patients' thenar tissue oxygenation (sto %) was assessed with nirs postoperatively in the cardiac intensive care unit (cicu). results. patients undergoing cardiac surgery on cpb ( male/ female) (age: ± years, euroscore: . ± ; mean ± sd) were enrolled in the study. patients length of stay was . ( - ); median(range). the haemodynamic parameters of our patients upon admission to the cicu were: map ± mmhg, cvp ± mmhg, pcwp ± mmhg, mpap ± mmhg, ci . ± . l/min/m , svr ± dyne x s/ cm , pvr ± dyne x s/cm , hr ± bpm, hb . ± . g/dl, lactate . ± . mg/dl; (all variables expressed as mean ± sd). upon admission to the cicu all patients were mechanical ventilated, under vasopressor ± inotrope support and their central temperature was . ± . ; mean ± sd. the thenar sto % was ± ; mean ± sd. thenar sto % correlated statistically significantly with hospital length of stay (r = . , p = . ). discussion. tissue oxygenation as assessed with nirs reflects the balance between regional oxygen delivery in relation to oxygen utilization. an elevated sto in the presence of normal macrohemodynamics may reflect impaired oxygen consumption and thus an impaired microcirculation. conclusion. patients with impaired tissue oxygenation immediately postoperatively have a longer hospital length of stay. further studies are needed to confirm these results and to investigate the potential benefit from incorporating this information regarding tissue oxygenation in the treatment algorithm. objectives. the goal of this study was to compare two different sedative agents for implantation of crt-ds related to incidence of adverse events and patient's satisfaction. methods. the study included forty-two, asa iii-iv patients, undergoing transvenous implantation of crt-ds under local infiltrative anesthesia with to ml of % lidocaine. intraoperative sedation was established with intermittent boluses of midazolam ( - mg) to achieve desirable level of sedation. before the induction of ventricular fibrillation in order to test the defibrillator function of the crt-d device, patients received an additional bolus of either propofol ( . - . mg kg - , p group, n = ) or etomidate ( . - . mg . kg - , e group, n = ) targeting bis values in the range - . the incidence of apnea, hypotension, nausea, myoclonus, pain at injection site, allergic reactions as well as patient's satisfaction with anesthesia described as feel of well being were registered and compared between groups. results. in subjects ( %) no complications were recorded. myoclonus was registered in patients from e group ( %) and in none from p group (p \ . ). no patients receiving etomidate reported pain at injection site compared to patients ( %) receiving propofol (p \ . ). there was no significant difference in incidence of apnea between two groups ( vs. %, p = . ). two patients in p group ( %) and in e group ( . %) became hypotensive after delivering the hypnotic agent (p = . ). also, there was no statistically significant difference between groups considering the frequency of nausea ( % vs. %, p = . ). all the patients whom propofol had been delivered ( %) reported feel of well being and only four of them filed the same after etomidate ( %) (p \ . ). no allergic reactions and major adverse events were registered. conclusions. implantation of crt-ds and its testing can be successfully performed with administration of both propofol and etomidate as a safe procedure with low per operative morbidity and shorter complication rates. still, treating with propofol tends to be more satisfactory for the patients. introduction. ultra-short-acting b selective adrenergic antagonists are now widely used to control tachycardia and tachyarrhythmia perioperatively. among them, landiolol, a new ultra-short-acting b -blocker, has been reported to exert a more potent negative chronotropic effect with little effect on blood pressure than esmolol ( ). however, detailed mechanisms underlying different cardiovascular actions are still unknown. objectives. in this study we evaluated direct effects of landiolol on cardiac performance and single cell electrophysiology in comparison to those of esmolol. methods. the present study composed of two parts. the first part of the study used isolated guinea-pig hearts which were perfused in the langendorff mode at constant flow with oxygenated tyrode solution at °c. the coronary perfusion pressure (cpp) was continuously monitored throughout the experiment, and intrinsic heart rate (hr) and isovolumetric left ventricular contraction were measured with a thin saline-filled balloon inserted into the left ventricle. the second part of the study was to measure action potentials and ionic currents in ventricular myocytes isolated enzymatically from guinea-pig hearts. comparison of data was conducted by repeated-measure anova with post hoc test (bonferroni's correction). conclusions. esmolol had a more potent negative inotropic effect than landiolol. this effect is, at least in part, derived from shortening of apd. in addition, increase of the coronary resistance would facilitate the negative chronotropic action of esmolol in vivo. conclusions. nma moderates hpv in the conscious spontaneously breathing beagle, but not to the same degree as acz. as compared to acz, the additional methyl-group in nma may impair its capability in vivo to act on a non-ca acz-sensitive cellular receptor or channel or that both, ca-dependent and ca-independent actions of acz yield a greater effect. introduction. tee with bubble test is considered as the ''gold standard'' method to detect a pfo with right to left shunt. tcd is a non-invasive method which has been shown to be as accurate as tee for pfo detection. we conducted a multicenter trial to estimate the prevalence of pfo, the influence of the size of the heart chambers on the prevalence of pfo and the accuracy of tcd as a non invasive method for pfo detection in mechanically ventilated icu patients. one hundred icu patients ( m and f) under mechanical ventilation who needed a tee study for hemodynamic assessment were included in the study. in each patient, the presence of a pfo was detected by tee and tcd. three bubble tests with agitated haemacel Ò were performed by each method, with tee probe at and rotation and with tcd the gate of pulse wave doppler (pwd) at the m segment of the middle cerebral artery (mca). patients without temporal acoustic window to perform tcd were excluded from the study. the size of pfo was classified as grade i, ii and iii according to the number of microbubbles passing from the right to the left atrium and the number of hits (high intensity transient signals) detected with pwd in the mca (grade i: \ microbubbles or hits, grage ii: [ and \ and grade iii: more than microbubbles or hits). for each patient included in the study we measured and correlated the presence of pfo with the tidal volume (v t ), the plateau pressure (p plat ), the compliance of the respiratory system (c rs ) and the size of the right (rv) and left (lv) ventricle. results. mean p a o /fio was (min , max ), mean c rs was ml/cmh o (min , max ), mean v t was ml (min , max ) and mean p plat was cmh o (min , max ). the prevalence of pfo detected with tee was % and with tcd %. there was no pfo detected with tee and missed by tcd. tcd was more sensitive than tee in detecting pfo of grade i ( with tee, with tcd) and ii ( with tee, with tcd), while for grade iii the two techniques had equal sensitivity ( with tee, with tcd). no correlation was found between p plat , c rs , v t and the presence of pfo. on the contrary, a strong correlation was found between rv dilatation and the presence of pfo (p \ . ). conclusions. the prevalence of pfo detected by tcd is very high in mechanically ventilated icu patients and this may have important clinical implications. tcd is more sensitive than tee in detecting a small pfo. the presence of rv dilatation increases the prevalence of pfo. objectives. the aim of our study was to identify in mechanically ventilated patients for ali/ards the prevalence of pfo and to evaluate the factors that may influence the prevalence of pfo. methods. two groups of mv patients, one with ali/ards and one without respiratory failure (rf), were enrolled in the study. all patients underwent a tee study for hemodynamic assessment. in each patient three consecutive bubble tests with agitated haemacel Ò were performed at and rotation of the tee probe. the bubble test was performed through a central line in the inferior or superior vena cava (ivc, svc). a pfo was diagnosed by the presence of microbubbles in the left atrium within five cardiac cycles following the injection. furthermore, in ali/ards patients in whom a pfo was not detected at baseline mv, three consecutive bubble tests during recruitment maneuver at cmh o for s were performed. the compliance of the respiratory system (c rs ), blood gas exchange and the ventilatory settings (p plat , v t ) were recorded in both groups. o, respectively. the presence of rv dilatation was a strong predictor for the fo opening (p \ . ); on the contrary, no statistical significant difference was found between the site of injection (svc vs. ivc), the c rs , v t , and p plat and the presence or absence of a pfo. a high prevalence of pfo was found in ali/ards patients. rv dilatation seems to be the reason of this high prevalence. rv dilation may be due to the lower c rs and higher p plat of the ards patients. introduction. the clinical evaluation of arterial tone is mainly based on the calculation of total systemic vascular resistance (tsvr). however, given the pulsatile nature of arterial flow, this parameter provides an inadequate assessment of vascular tone. another approach proposed would take account of changes in pulse pressure and blood flow, relationship known as arterial elastance (ea). so, for a given stroke volume, the blood pressure generated in the circulatory system will depend on ea ( ). to assess the ability of the dynamic arterial elastance (ea dyn ), defined as the relationship between pulse pressure variation (ppv) and stroke volume variation (vvs), to predict the hemodynamic response in mean arterial pressure (map) to a increase in stroke volume (sv) in hypotensive preload-dependent patients with acute circulatory failure. we performed a prospective clinical study in a -bed multidisciplinary intensive care unit, including patients with controlled mechanical ventilation and monitored with the vigileo Ò monitor, for whom the decision to give fluids was taken due to the presence of circulatory, including arterial hypotension (map b mmhg or systolic arterial pressure \ mmhg), and preserved preload-responsiveness condition, defined as svv c %. dynamic arterial elastance (vpp/vvs ratio), arterial pulse pressure to sv ratio, map/sv ratio, tsvr and map were compared to predict a map increase c % after volume expansion (map-responders). results. at baseline, only ea dyn was significantly different between map-responders and nonresponders. ve-induced increase in map was strongly correlated with baseline ea dyn (r = . , p \ . ) and changes in ea dyn after ve (r = . ; p \ . ). the only predictor of map increase was ea dyn (auc . ± . ; % c.i.: . - ). a baseline ea dyn value [ . predicted an increase c % in map after fluid administration with a sensitivity of . % ( % c.i.: . - . %) and a specificity of % ( % c.i.: - %). conclusions. dynamic assessment of arterial elastance by pvv to svv ratio during controlled mechanical ventilation could be used to predict mean arterial pressure increase after volume loading in hypotensive preload-dependent patients. severe sepsis is one of the major reasons for intensive care unit (icu) admission and leading causes of mortality. some of these score systems have been customized for patients such as apache ii, apache iii, sasp ii and mods. this study is to assess the validity of mortality prediction systems in severe septic patients. objectives. the aim of this study was to compare and evaluate four severity scoring systems in intensive care unit (icu), including apache ii, apache iii, sasp ii and mods in severe septic patient. methods. fifty-six severe septic patients were divided into two groups. one was survival group and the other was non-survival group. besides general data, the continuous surveillance of apache ii, apache iii, sasp ii and mods were recorded by st, rd and th day. results. compared with survival group, mods was significant difference in non-survival group only in st day ( . ± . vs. . ± . , p \ . ) but apache ii, apache iii and sasp ii were significant difference through st, rd and th day(p \ . ). in seven-day comparison, p value of apache iii in non-survival group was the minimum (p = . ) and p value of mods was the maximum (p = . ). in optimal survival evaluation, it seemed that apache iii was the best (apache iii [ apache ii = saspii [ mods). conclusions. in order to evaluate the critical condition and prognosis of severe septic patients, apache iii was the best and apache ii and sasp ii were followed and mods was the worst. objectives. to assess compliance with the cem standards for management of severe sepsis across three ed sites in the west midlands. methods. data was collected retrospectively over months. patients presenting to the ed within this period were assessed for likelihood of severe sepsis by the diagnostic code given to each patient upon leaving the ed. data was analysed using a scanned copy of the ed clerking. patients' notes were assessed for sirs criteria and signs of new infection. if these criteria were met, and organ dysfunction was present, they were included in the audit. results. patients with severe sepsis were identified. of these % were documented as septic by ed staff. the cem standards of care were received in % of patients with a documented diagnosis of severe sepsis in the ed, and % of patients overall. % of patients received the 'treatment' aspects of care: oxygen, iv antibiotics (with blood culture) and iv fluids. % of severely septic patients had no documented consideration of icu referral. conclusions. early recognition of severe sepsis in the ed led to greater performance in meeting the cem standards. although % of patients received observations and % received the treatment interventions, we performed poorly in meeting the remaining cem standards. the trust has developed a severe sepsis proforma which incorporates the cem standards to accurately record the completion of each intervention. a sepsis course for staff has been launched trust wide, and a formal referral process to icu for all severely septic patients is being implemented. objectives. to observe association of body temperature (bt) and antipyretic use with mortality in the critically-ill. a prospective multi-national, multi-center observational study. consecutive patients whose icu stay were expected to be more than h were recruited from centers in japan and centers in korea. patient's bt was prospectively recorded every h until patient's death, discharge from the icu or up to days. information including patient's clinical characteristics at admission, presence of infection, and use of steroids, extracorporeal circuit, and antipyretics were recorded. ( ). while blood culture results take time, treatment for bloodstream infection should be provided swiftly, usually before results are available ( ) . prior treatment with antimicrobials increases the chances of false negative results. haste, poor technique and alteration in commensal flora may increase the chances of falsely identifying pathogens. objectives. we have investigated the utility of blood culture tests in our general critical care unit over year in terms of results yielded and actions prompted. methods. the indication for blood culture was clinician's discretion. all critical care sourced blood cultures for the period oct to sept were reviewed from the microbiology laboratory database. blood culture specimens were collected in bact/alert Ò bottles (biomerieux, durham, nc, usa ). notes review was made of the positive blood culture episodes to determine actions after the results were known. consideration was given to the source of the blood sample: clean stab versus from an intravascular device. categoric data was analysed using the chi-squared test and p value of . was accepted as significant. objectives. we hypothesized that in the emergency department of our hospital many patients with sepsis are not recognized as such. methods. in a retrospective design, patients of an age of years and older who were admitted to the emergency department during a period of months between january-april and diagnosed as having an infection were included. the diagnose infection was made on admission by the emergency department nurse. the included patients were either classified as having sepsis or not having sepsis, according to the sirs criteria. conclusions. h n infection was associated with significant morbidity and mortality. it occurred mainly in young pts with co-morbidities and was associated with severe hypoxemia, a trigger for prolonged mechanical ventilation and frequent use of lung rescue therapies. a significant delay in hospital admission and start of antiviral therapy should also be noted. admission to administration time difference between cycles was . h, with a mean reduction of . h between clinician assessment and prescription time in cycle two. we identified delays against the standard after both cycles of the audit. we demonstrated that the method of prescription should be taken into consideration when prescribing antibiotics in patients with suspected sepsis. there are a multitude of factors that could contribute to a reduction in the clinician assessment to prescription time, which may be investigated in further audits. conclusions. despite high levels of resistance among psa and ab from these icus, cfr for most carbapenem dosing regimens were above the reported susceptibility. doripenem provided greater cfr than meropenem, which was superior to imipenem against these isolates. while higher doses combined with prolonged infusions significantly improved cfr against psa, alternative therapeutic strategies will be required to address these highly resistant ab. grant acknowledgment. the passport study is supported by a grant from janssen-ortho-mcneil. introduction. drug interactions are common, and the effects of these interactions can range from innocuous to deadly. critically ill patients often receive a variety of potent drugs, including antimicrobials, making this population extremely susceptible to drug-drug interactions. therefore, physicians must be familiar not only with the antimicrobial drugs capable of producing adverse drug events, but also their potential drug-drug interactions. there are scarce data about the incidence of these types of drug interactions and the how frequently it might cause adverse events. objectives. the purpose of this study is to evaluate the incidence of potential drug interactions involving antimicrobials and the possibility to cause adverse events. the clinical pharmacist has prospectively analyzed icu prescriptions between january and december with the purpose to identify potential drug-drug interactions involving antimicrobials. the screening was done with the relief from a software (epocrates rx Ò drug reference). the interactions detected were classified in eight groups according to the affected system (neurological, cardiovascular, gastrointestinal, renal, endocrine, hematological, musculoskeletal and others) and through the type of interaction (pharmacokinetic, pharmacodynamic and others). we have identified the most common potential effects, the medications involved and have observed the incidence of adverse drug events. results. the icu admitted patients during the study period. we have analyzed physician orders with prescribed items. we have identified antimicrobial drug interactions ( different interactions) which compound % of the total drug interactions (n = ). the cardiovascular system and the pharmacokinetic interaction were the most potentially affected ( %; %). the most common medications involved were: fluconazole ( %), clarithromycin ( %), levofloxacin ( %); linezolid ( %). the clinical pharmacist has made an intervention regarding medication safety in % (n = ) and the acceptance rate by the medical icu staff was %. we have not been able to identify any adverse drug event caused by drug interaction even with our active search and the spontaneous reports. however, sub notification must be taken into consideration. conclusions. clinicians should be aware of potential drug-drug interactions when making therapy selections for critically ill patients. antimicrobial drugs are susceptible to interact with other drugs, which may increase the risk of adverse drug events. the clinical pharmacist interventions may improve clinical outcomes by optimizing medication use, monitoring potentially preventable adverse drug events and promoting information about this important issue to the icu multi-professional team. introduction. cefazolin is one of the most frequently administered antimicrobial agent for prophylaxis in ''clean'' surgery. its broad spectrum against gram + micro-organisms and its pharmacological characteristics make it an easy-to-use choice to prevent infections caused by staphylococcus aureus and coagulase-negative stapylococci. objectives. the aim of this study is the evaluation of the plasma concentrations of cefazolin administered as a prophylactic antimicrobial agent during cardiac surgery with cpb. adequate cefazolin plasma levels can maintain a tissue concentration high enough to prevent the risk of developing post-operative infections. after obtaining ethical committee approval and personal written consent, two groups of patients were enrolled in this prospective study. the first group, patients, received cefazolin, g, - min before skin incision and g adjunctive dose after h. then, three g doses were administered every h. in the second group of patients the adjunctive g cefazolin dose was given at the beginning of the cpb. blood samples were collected immediately before the first dose and every hour for the whole time of surgery, and, only in the second group, after surgery, at th, th and th hour. plasma cefazolin concentration was determined with a biological radial diffusion assay. results. plasma cefazolin was constantly higher than the mic of the most involved micro-organisms (according to clsi). in the first group, cefazolin concentration suddenly decreased after starting cpb. the g adjunctive dose immediately restored it. the earlier administration of this dose in the second group prevented this sudden fall. plasma cefazolin was maintained at effective inhibitory levels for the whole time of surgery in all patients ([ mcg/ml). during the postoperative period cefazolin decreased slowly, but inhibitory plasma levels were always maintained. the rate of cefazolin clearance was found equal to the creatinine clearance in all patients. perioperative plasma cefazolin concentration conclusions. the administration of cefazolin g every h can guarantee effective inhibitory plasma concentrations during surgery and during the first h after surgery. cpb causes a sudden fall in cefazolin plasma levels. this can be avoided administering an adjunctive g dose immediately before starting cpb. objectives. vancomycin dose regimen was adjusted based on trough plasma levels in burn patients that were distributed according to the extension total burn surface area (tbsa); also pharmacokinetics changes were compared. methods. twenty seven adult burn patients of both sexes, requiring antimicrobial therapy with vancomycin for the control of sepsis were investigated. pharmacotherapeutic follow up was performed in a serial of periods ( observations) for all patients investigated by collection of blood samples, ml each from the venous catheter as follows: st blood sample collection, h after the beginning of drug h infusion and a nd sample blood collection at the trough, immediately before the next dose. if necessary, additional sample blood collections were performed based on the laboratorial data for patients any time, for dose adjustment purpose and optimization of drug therapy. vancomycin plasma concentrations were determined by highperformance liquid chromatography. plasma curve decay was plotted, and pharmacokinetics was analyzed by one-compartment open model against the reference data reported. results. burn patients receiving the empiric dose regimen showed trough plasma level lower than the minimum effective concentration, consequently dose adjustment was required. vancomycin adjusted dose regimen showed statistical significance differences according to tbsa (p \ . ) as follows for daily dose normalized to body weight and expressed by mean ± sd: . ± . mg/kg/day were required for patients with tbsa below %, . ± . mg/kg/day for tbsa - % and . ± . mg/kg/day were required for tbsa above %. relevant changes on pharmacokinetics were observed by drug plasma clearance increased according the increase of tbsa (p \ . ), while the apparent volume of distribution and also the biological half-life remained unchanged. additionally, a weak correlation was observed between vancomycin plasma clearance and creatinine clearance (r = . ; p = . ), probably due to the contribution of the extra-renal clearance on total drug elimination. on the basis of data obtained in the present study and to prevent therapeutic failure and also to reduce the risk of bacterial resistance, dose adjustment in burn patients is recommendable based on vancomycin plasma monitoring and also on the extension of total burn surface area. introduction. the importance of early antibiotic therapy has been recently demonstrated. regarding a rapidly increasing number of obese patients, appropriate drug dosage in these patients is an important challenge of critical care since it has been shown that not only early start of antibiotics but also correct target concentrations decrease mortality. vancomycin is administered according to body weight (bw). nevertheless, little is known about the percentage of obese patients achieving pre-defined target serum levels within h after initiation of vancomycin therapy compared to patients with normal bw. objectives. therefore, it was the aim of our study to analyze the appropriateness of serum vancomycin levels in patients with a bw between and kg. vancomycin is almost entirely excreted by the glomerulus and may be responsible for nephrotoxicity [ ] . however, there is a lack of definitive evidence linking concentrations to either outcome or toxicity [ ] . few reports exist comparing intermittent dosing and continuous infusion. ingram [ ] suggested that whilst associated with a slower deterioration in renal function, there was no difference in the prevalence of nephrotoxicity. similarly, hutschala [ ] demonstrated worsening creatinine in patients following cardiac surgery with both intermittent and continuous infusion but infusion tended to be less nephrotoxic despite receiving higher doses. we wish also to report our experiences with vancomycin infusion in critically ill cardiac patients. methods. we examined retrospective data from , patients treated with vancomycin. we perform adjusted and un-adjusted analysis using sofa on the day of starting vancomycin and total dose received. to assess the differences in either an initial pulmonary or non pulmonary presentation. methods. prospective, observational, multi-center study conducted in intensive care (icu). we reviewed demographic and clinical data for all pandemic h n influenza a infections reported in the esicm h n registry. results. patients were screened from the registry. patients with completed data entry for pulmonary and non pulmonary with outcomes were identified and analysed. all patients had either suspected, probable or confirmed pandemic h n influenza a infection and were being cared for in an icu. % of the patients were male with a median age of (iqr - ) years. the admission mean saps score was ± and the apache ii score was ± . % of the patients subsequently received non invasive ventilation and % received invasive mechanical ventilation. the icu mortality rate was %. the hospital mortality was %. % of patients presented with a pulmonary presentation. % of these were admitted with ards and/or bacterial pneumonia and % with an acute bronchospastic exacerbation. % of patients were admitted to the icu with a non pulmonary presentation. the main reasons for admission in these patients were: cardiovascular instability ( %), altered level of consciousness ( %), renal failure ( %) and acute coronary syndromes ( %). patients with a pulmonary presentation were older, had a increased history of asthma or copd and were more likely to be ventilated. they had a higher mortality rate in the icu. non pulmonary presentations were more likely to suffer from chronic renal impairment. a total of episodes of pandemic influenza a (h n )v infections in critical care setting were analyzed: with bacterial pneumonia ( males and females) and with wheezing or viral pneumonia ( males and females). the mean age was (± ) years in patients with bacterial pneumonia and (± ) in patients viral pneumonia. the mean apache ii score was (± ) and (± ), with a corresponding probability of death of (± )% and (± )%. comorbidities were common, but without significant differences between the two groups (only exceptions pregnancy-more prevalent in patients without bacterial pneumonia-and dialysis dependence-more prevalent in patients with bacterial pneumonia). at icu admission shock and acute renal failure were more common in patients with bacterial pneumonia. in patients without pneumonia; severe hypoxia and ards did not presented significant differences between groups. aims. evaluation if an isocaloric beginning of artificial nutrition in critically ill medical patients is associated with increased nutritional related side effects compared to a hypocaloric start. methods. critically ill medical patients with an expected need for artificial nutrition of [ days were included into this prospective, randomized clinical study. artificial nutrition was started either isocalorically right from the beginning (group a; n = ) or hypocalorically ( % of the energy demands) followed by a stepwise increase over the next days (day : %); day : %) (group b; n = ). nutrition related side-effects were defined as the occurrence of hyperglycemia, hyperlactatemia, hypertriacylglycerolemia, upper digestive intolerance, cholestasis, or diarrhea as well as disturbances of serum electrolytes and were assessed on a daily basis. patients were randomized to receive either an artificial nutrition started isocalorically (group a) or hypocalorically followed by a stepwise increase (group b). of the patients, patients completed the study (group a: n = ; group b: n = ). the calculated, cumulative energy requirements of patients of group a and b were , ± , and , ± , kcal, respectively (p = ns). patients of group a received ± % and patients of group b ± % of the calculated energy requirements (p \ . ). the incidence of nutritional related side effects was not different comparing both groups, except for hypophosphatemia, which was more pronounced in group a. additionally, exogenous phosphate needs were higher in patients of group a. the number of interruptions of the artificial nutrition did not differ between groups. conclusions. an isocaloric start of artificial nutrition provided more energy during the first days of their icu stay than a hypocaloric beginning. there was no difference in the number of interruptions and in the incidence of nutritional related side effects, except hypophosphatemia suggesting the presence of refeeding syndrome. in studies carried on to demonstrate positive effects of glutamine (gln) that has innumerable biological features, the main point of discussion isn't whether gln has positive effects in sepsis but rather the effect difference between different administration routes. only enteral (en.) or parenteral (pn.) administration was analyzed in this respect and no studies on combined administration were performed. the primary endpoint in this study was to analyze the effects of administration of en. and pn. gln together or separately on intestinal mucosa + immune system in the experimental sepsis model. for this purpose villus atrophy, bacterial growth in blood and tissue, levels of blood gln, tnfa and il were examined. the secondary endpoint was to evaluate the different administration models in terms of cost. wistar, adult female rats were used. they were fed standard. sepsis was developed in groups (all rats) by injection of intraperitoneal(ip.) ml ( cfu/ml) e. coli. grup c (n = ):en./pn. isotonic saline ( ml/day; ml/d); grup e (en., n = ):en. gln ( . g kg - day - ) + pn. saline ( ml/d); grup p (pn., n = ):pn. gln ( . g kg - day - gln) + en. saline ( ml/d); group ep (en. ± pn., n = ):pn. gln ( . g kg - day - ) ala-gln = . g kg - day - gln) + en. gln ( . g kg - day - ); were administered. feeding of rats began h (h) after administration of ip e. coli. blood gln (with spectrophotometer), tnfa and il concentrations(with elisa) were examined at the start (baseline levels) and at - h after the experiment started. samples of tissue from mesenteric lymph node, liver, lung, blood and small intestine were collected. ala-gln = . g kg. . rates of reproduction of the strain administered were found lower for group ep than group c (p \ . ). rates of villus atrophy in ileum of group ep, p and e were lower than group c (p \ . ).plasma gln levels were found lower in groups ep and p at h, and higher at h than other groups (p \ . ). when plasma gln levels at h were compared with their baseline levels, significant increases were detected in groups ep and p and significant decreases were detected in groups c and e (p \ . ). serum tnfa and il levels were found lower for groups ep and p at and h when compared between groups (p \ . ). when serum tnfa and il levels at h were compared with their baseline levels, more distinctive increases were detected in groups c and e than other groups (p \ . ). significant positive correlation was determined between tnfa and il levels at h (p \ . ) and h (p \ . ). cost of simultaneous administration of en. and pn. gln was higher than en. administration but close to pn. administration at these doses. methods. medline and embase were searched. hand citation review of retrieved guidelines and systematic reviews was undertaken and academic and industry experts were contacted. only methodologically sound randomised controlled trials (rcts) were eligible for inclusion in the primary analysis. the primary analysis was conducted on clinically meaningful patient oriented outcomes, which included mortality, functional status and quality of life. secondary analyses considered vomiting/regurgitation, pneumonia, bacteremia, sepsis and multiple organ dysfunction syndrome. meta-analysis was conducted using the peto analytic method, which is known to minimize bias in the presence of sparse events. the impact of heterogeneity was assessed using the i metric. results. , unique abstracts were identified, resulting in the retrieval of papers for detailed eligibility review. four rcts were identified to be on topic however one rct reported excessive loss to follow-up such that an intention to treat analysis could not be conducted. analysis based on the three methodologically sound rcts demonstrated the provision of early en was associated with a significant reduction in mortality (or = . , % confidence interval . to . , i = ). no other outcomes could be pooled. sensitivity analysis including all four on-topic rcts (or = . , p = . , i = ), and a simulation analysis conducted using a different analytical method. (or exact = . , % ci . to . ), confirmed the presence of a mortality reduction. conclusions. although the detection of a statistically significant reduction in mortality is promising, overall trial size was small. the results of this meta-analysis should be confirmed by the conduct of a large multi-center trial. reference(s). results. the mean ibp was . ± . and mean igp was . ± . . correlation between the ibp and igp was significant however moderate (r = . ). analysis according to bland and altman showed a bias and precision of . and . mmhg respectively, however the limits of agreement (la) were large and ranged from - . to . mmhg. the median grv proto was ml ( - , ) and median grv classic was also ml ( - , ). correlation between the methods was excellent (r = . ). analysis according to bland and altman showed a bias and precision of - . and . ml respectively and the limits of agreement (la) ranged from - to mmhg. the median drainage time and return times were min ( . - ) and . min ( - ) for grv proto compared to min ( . - ) and min ( - ) for grv classic. a preliminary cost effectiveness analysis shows that the price of measuring grv with the classic method ranges from . € to . € per day, depending on the grv size. price of measuring grv with the gastro pv system is independent of grv size and is estimated at . € per day. the gastro pv system if priced at . € could become cost effective at grv of cc and more. conclusions. the interim results of an ongoing multicentre pilot study show that the gastro pv is a good alternative to the standard method for measuring grv. because the nurse can perform other tasks during drainage and return of the grv, and the fact that the system remains closed during measurement, this could be a major step forward in standardisation of grv measurement. furthermore it allows screening for intra-abdominal hypertension via igp estimation. acknowledgment. the gastro pv devices were provided by holtech medical, free of charge. introduction. the importance of early enteral feeding of the critically ill patient has been well documented. it is the more physiological approach, which is associated with lower rates of infectious complications. early enteral nutrition within h is recommended by the espen guidelines on enteral nutrition. a recent meta-analysis revealed that mortality and the incidence of pneumonia were significantly reduced in patients with enteral nutrition within h. parenteral nutrition may be associated with higher mortality. objectives. evaluation of a new technique for the placement of postpyloric feeding tubes by intensive care physicians. methods. prospective cohort study in critically ill patients subjected to transnasal endoscopy and intubation of the pylorus. attending intensive care physicians were trained in the handling of the new endoscope for transnasal gastroenteroscopy for days. a jejunal feeding tube was advanced via the instrument channel and the correct position assessed by contrast radiography. primary outcome measure was successful postpyloric placement of the tube. secondary outcome measures were time needed for the placement, complications like bleeding and formation of loops and the score of the placement difficulty graded from (easy) to (difficult). data are given as mean values and standard deviation. out of attempted jejunal tube placements, tubes ( %) were placed correctly in the jejunum. the duration of the procedure was ± min. the difficulty of the tube placement was judged as follows: grade : patients, grade : patients, grade : patients, grade : patients. in cases, the tube position was incorrect, and in another cases, the procedure had to be aborted. only in one patient, bleeding occurred that required no further treatment. conclusions. fast and reliable transnasal insertion of postpyloric feeding tubes can be accomplished by trained intensive care physicians at the bedside using the presented procedure. this new technique may facilitate early initiation of enteral feeding in intensive care patients. grant acknowledgment. the authors acknowledge the support of pentax, hamburg, germany, who provided the endoscope used in the study and of fresenius kabi, bad homburg, germany who provided the feeding tubes. a well-nourished condition before prolonged endotoxemia results in a better ability to adapt to endotoxin-induced metabolic deterioration of arginine-nitric oxide metabolism than does reduced caloric intake before endotoxemia ( ). the role of individual organs in the arginine-citrulline metabolism during malnutrition and sepsis is unknown and may be key to direct future interventions. to study the effects of reduced caloric intake and endotoxemia on the citrulline-arginine metabolism in the gut-liver-kidney axis. organ arginine-nitric oxide metabolism was measured by using a primedconstant stable-isotope infusion of [ n ]arginine and [ c- h ]citrulline during conditions; a -day reduced caloric intake feed regimen (starv; n = ), normal control feed regimen (co; n = ), endotoxemia alone (ce) and reduced caloric intake and endotoxemia (re) in. catheters for blood sampling were placed in the abdominal aorta, which, in combination with the catheters in the portal, hepatic and renal veins, served for metabolic measurements across the portal-drained viscera, liver and the kidneys, respectively. results. interestingly, re animals had similar citrulline appearance from the gut ( ± nmol/kg/min) compared to control and animals during ce, but higher in endotoxemia alone ( ± , p \ . ). this was related to a significantly higher no production from the gut in the re group ( , ± vs. ± , p \ . ). in the kidney arginine appearance from citrulline decreased significantly during re compared the control animals ( ± vs. ± nmol/kg/min, p \ . ). in contrast, the liver disposed more arginine in the re group compared to the other conditions, while no production was not higher. conclusions. despite reduced caloric intake prior to endotoxemia, the gut remains capable of increasing release of citrulline, although the capability of the kidney for the de novo production of arginine is severely compromised. metabolic control of the citrullinearginine metabolism in the gut-liver-kidney axis should focus on increasing de novo arginine production from citrulline. objectives. the aim of this study was to measure duodeno-caecal transit times of enteral feed in this patient group using a scintigraphic technique. a prospective observational study was performed in mechanically ventilated critically ill patients ( m, age ± yr, bmi ± kg/m , icu admission day ± , apache ii on study ± ; mean ± sd) and healthy subjects ( m, age ± year, bmi ± kg/m ). after a h fast a ml enteral feed (ensure kcal/min), labelled with mbq m tc-sulphur colloid, was infused into the distal duodenum over min. dynamic anterior scintigraphic images were recorded in min frames for min and the time of first appearance of activity in the caecum was recorded by two blinded operators (kj, ar). data were assessed using mann whitney u test and are presented as median (iqr). introduction. erythromycin, a macrolide antibiotic is widely used as a prokinetic agent in intensive care unit (icu) despite the lack of data supporting its prolonged effectiveness in enteral nutrition (en) intolerant critically ill patients. to evaluate impact on clinical outcome of erythromycin prescription as prokinetic agent in icu. all patients consecutively admitted from january through december mechanically ventilated for more than days and receiving en were included in an observational cohort study. en intolerance was defined clinically as a -hourly gastric residual volume (grv) c ml or vomiting. successful en was defined as a grv\ ml with a feeding rate c ml/h. erythromycin prescription was left to practician appreciation. objectives. this study aims at evaluating the relationship between diarrhoea and en in icu patients. methods. during month, the days with and without diarrhoea (c liquid stools/day) and the characteristics of nutritional support of all patients staying in our icu were recorded. patients staying \ h or presenting an intestinal stomy were excluded. we compared, between days with and without diarrhoea, total energy coverage and energy coverage by en as % of needs, en energy intake and en volume for each patient. needs were estimated as - kcal/kg body weight for women and men, respectively. the relationship between antibiotics, laxative treatment and diarrhoea was also analysed. results are presented as mean ± sd. comparisons were made by mann-whitney test. the risk of diarrhoea with en was calculated by odds ratio and confidence intervals (ci). the study included days of hospitalisation of patients ( ± years, bmi ± kg/m , sofa score at admission ± ). en was present in days of diarrhoea and days without diarrhoea. determining the small bowel function is of great concern in icu patients, because a malfunctioning small bowel may predispose to malnutrition and may increase the risk of sirs. a recently developed test, the citrulline generation test (cgt), measures the enterocytes' capability to convert glutamine into citrulline. the production of citrulline exclusively takes place in functioning enterocytes, therefore this conversion represents small bowel function. objectives. we aimed to define the cgt reference values in 'stable' icu-patients to assess small bowel function. secondly, we wanted to compare four different cgt methods; enteral and iv administration of dipeptiven and measurement of citrulline in both arterial and venous samples. we performed the cgt on stable icu-patients, defined as having respiratory failure but not dependent on vasopressors. they had a normal renal function and were able to tolerate enteral nutrition. a h fast was followed by administration of g of glutamine-alanine (dipeptiven Ò ) either intravenously or enterally, randomly determined. the next day the same test was performed by using the other route. after each administration of dipeptiven, citrulline levels, both arterial and venous, were measured at fixed time points using reverse-phase high performance liquid chromatography (hplc). results. nine females and males were admitted to the icu with either a medical ( ) or a surgical ( ) diagnosis. they had a mean (± sd) age and bmi of . ± years and . ± , kg/m respectively. their median apache ii score was . (iqr = . - . ). on the day the cgt was performed their median sofa score was . (iqr = . - . early post-pyloric feeding has been shown to improve clinical outcomes [ ] . commonly used methods for placing a nasojejunal tube (njt) are blind, endoscopic or fluoroscopic placement. the later two methods are relatively invasive, expensive and can cause delay to feeding, whereas blind placement is often unsuccessful. electromagnetic sensor guided njt insertion is a bedside technique able to confirm successful placement without the need for abdominal x-ray. the system incorporates a liquid crystal display and a receiver unit. the receiver is placed over the patient's xiphoid process and picks up the signal from an electromagnetic transmitter located at the tip of the feeding tube. the screen provides a visual aid to enable the operators to trace the route of the tube tip and identify its' location according to anatomical markers. objectives. we were interested to determine the suitability of electromagnetic sensor guided njt insertion especially in relation to success rate and procedure time. methods. fifty patients were referred for electromagnetic njt insertion on units at the leeds teaching hospitals. insertion time was measured from oesophageal visualisation until post-pyloric placement. various positional manoeuvres were employed along with administration of sedatives, prokinetics and air insufflation when applicable. all insertions were carried out by experienced investigators. all njt insertions were confirmed by abdominal x-ray. data collection included patient demographics, hospitalisation and procedural information. results. forty male and female patients, mean age (range - years), bmi mean ( - ), had attempted electromagnetic njt placement. patients had been hospitalised for a median of days ( - ). indication for njt insertion was either large aspirate and/or reflux ( %). seventy six percent of patients had an artificial airway and % of patients were receiving sedation. forty six percent of patients received metoclopramide and % air insufflation. thirty six percent of patients were moved into either left or right lateral position. successful post-pyloric placement was achieved in % of patients confirmed by additional abdominal x-ray. procedural time varied from to min (mean ). two of the placement failures were due to patient intolerance. conclusions. bedside electromagnetic guided njt placement technique is an acceptable method of placing post pyloric feeding tubes with a high success rate. gastrointestinal failure (gif) score has been suggested ( ). the gif score defines gi failure as the occurrence of feeding intolerance (fi) and intra-abdominal hypertension (iah) simultaneously. to compare the outcome of patients with primary vs. secondary gif. methods. all consecutive, mechanically ventilated (mv) patients treated for at least h during january to december in two icus were studied. gif was defined as gif score equal or above points according to the gif score ( ). points = fi and iah simultaneously; points = abdominal compartment syndrome (acs). fi was defined as the need to stop enteral feeding for any clinical reason (vomiting, high gastric residuals, bowel distension etc). iah was defined as mean intra-abdominal pressure (iap) c mmhg on any day. acs was defined as iap [ mmhg with the new onset organ failure. when gif developed in a patient with primary pathology in abdomino-pelvic region it was classified as primary gif, when occurred without previous pathology in abdomino-pelvic region it was taken as secondary. objectives. in this study the biochemical quality and prion safety of the pharmaceutically licensed plasma octaplaslg Ò was evaluated. the prion reduction factor achieved by western blot was confirmed by animal studies. eighteen consecutive batches of octaplaslg Ò (octapharma ppgmbh, vienna, austria) were tested on global coagulation parameters, fibrinogen levels, activities of coagulation factors and protease inhibitors, activation markers, as well as von willebrand factor multimers. in parallel studies, plasma pool was spiked with exogenous spike material, derived from brains of hamsters infected with hamster-adapted scrapie k, and a down-scale of the octaplaslg Ò manufacturing process was performed. the prp sc reduction factor for the resin was investigated in both western blot and hamster bioassay studies. a reduction factor of c . log prp sc was found for this process step by western blotting. the outcome of the hamster bioassay confirmed that the high level of removal prp sc seen during octaplaslg Ò manufacturing was equivalent to a removal of infectivity ( . log ). in octa-plaslg Ò , a parallel reduction of the s/d virus inactivation step led to significantly higher activities of plasmin inhibitor. our studies demonstrated that the same amounts of prp sc and prion infectivity bind rapidly and with a very high affinity to the chromatography resin. octaplaslg Ò has the same clinical safety and efficacy profile compared to that demonstrated by octaplas Ò over the last years, except for the increased safety margin in terms of prion disease transmission and the possible effect of a significantly increased plasmin inhibitor activity. uniplas Ò is a second generation solvent/detergent (s/d) treated, coagulation active plasma for infusion produced with an implemented prion removal step. it was developed as an alternative to the blood group specific s/d plasma products, octaplaslg Ò and octaplas Ò , in order to obtain an universally applicable (i.e. blood group independent) plasma that can be used without taking into account the blood group of the recipient. due to an initially controlled, optimal mixing of plasma of different blood groups prior to s/d treatment, in uniplas Ò , the blood group specific antibodies (anti-a and anti-b of both igm and igg type) are neutralised and/or removed by free a and/or b substances and red blood cells (rbcs) to a clinical acceptable level with very limited or no complement activation. objectives. in this study an extensive biochemical characterisation of the first uniplas Ò validation batches was performed. methods. three batches of uniplas Ò were produced by octapharmappgmbh (vienna) under production conditions in [ ] [ ] . uniplas Ò batches were tested on all important coagulation factors, protease inhibitors, activation markers, adamts and factor h levels, as well as von willebrand factor multimers. in addition, anti-a and anti-b titres of igm-and igg-type were investigated. finally, complement activation products, as well as key components of the complement system, were measured. results. in uniplas Ò batches, all coagulation factor activities were higher than . iu/ml and all protease inhibitor activities, including protein s and plasmin inhibitor, were higher than . iu/ml. uniplas Ò contained standardised levels of adamts and factor h, within the normal ranges for single-donor freshfrozen plasma. there was no activation of fvii obtained during manufacturing, thrombin-antithrombin (tat)-complex, prothrombin fragments (f + ) and d-dimer levels were within the normal ranges. anti-a and anti-b titres were within the uniplas Ò specification, i.e. anti-a igm and anti-b igm\ : as well as anti-a igg and anti-b igg \ : , respectively. uniplas Ò did not contain an increased amount of immune complexes and the manufacturing of uniplas Ò associated with more complement activation than the one seen for octaplaslg Ò . conclusions. the present study confirmed that uniplas Ò displays the same high quality and clinical efficacy as the s/d treated blood group specific plasma octaplaslg Ò , but with the additional advantage in being a blood group independent universally applicable plasma. most pts received more fluids than calculated by parkland formula ( ± . ml/kg %tbsa). interestingly, nonsurvivors received less ( . ± . vs. . ± . ml/kg %tbsa). gastric decompression, ascites drainage and the implementation of a stool protocol with rectal enemas ( interventions in pts) was able to remove . ± . l of body fluids and this was related to a significant decrease in iap and cvp and an improvement in oxygenation and urine output ( conclusions. pris is a difficult condition to diagnose and routine monitoring of the adverse effects of high-dose propofol remains sub-optimal. hypothermia has been reported to alter propofol pharmacokinetics and we propose that active cooling may increase the risk of developing pris. this may be particularly relevant in patients with tbi who are on high doses of propofol to control icp in addition to concomitantly administered catecholamines to maintain cerebral perfusion pressure. we recommend that further research is required in this area in view of the increasing use of induced hypothermia in icu. objectives. to compare differences in fluid resuscitation based on direct or indirect admissions to the london burns unit. methods. admissions to the burns unit with [ % burned surface area (%bsa) were identified over years. were excluded from analysis due to palliation or death within the first h. sets of notes were randomly selected for analysis of fluid balance in the first h period of fluid resuscitation after the burn injury. results. mean (sd) time from burn injury to arrival at the burns unit was lower for patients transferred direct to the burns hospital rather than via another hospital ( . ± . vs. . ± . min p = . ). mean (sd) error in burn size estimation was lower for patients initially treated by burns specialists versus non-burns specialists ( ± . vs. . ± . %, p = . ). all patients were resuscitated according to the parkland formula calculated at one of , or ml/kg/%bsa. the mean (sd) actual fluid volume differed from the target by . % (± . %); the lower the calculated fluid target, the greater the error between actual and planned resuscitation volumes; there was no difference in accuracy of fluid resuscitation at h between patients initially managed by burns specialists versus non-burns specialists ( . ± . vs. . ± . % respectively, p = . ). conclusions. burned patients transferred directly to specialist burns care receive a faster and more accurate assessment of their burn injury. despite this, we found no difference in fluid targeting errors at h, though this may reflect corrective fluid management on arrival at the specialist centre. echocardiography is an useful and minimally invasive tool that allows to know the heart filling pressures, also it has proven highly accurate in predicting the response to volume in critically ill patients. we try to determinate the response to fluid infusion by static variables as cvp or lap, comparing with the variation of ivc. methods. an observational prospective study with patients undergoing coronary cardiac surgery ( patients were excluded by a no presenting a good echo views), in the postoperative period under mechanical ventilation (vt ml/kg, fio %, peep ). we performed an echocardiography if the patient presented hypotension, just before the habitual fluid load protocol were started ( ml hes % in - min). we collected data before and after the infusion, and determine the responsiveness to volume if the cardiac output increased more than %. data in the report included invasive cvp and lap, and echo measures, ratio e/e', diameter and variations of inferior vena cava (ivc) and variations of stroke volume by echocardiography (Ølvot x vti lvot) and with vigileoÒ system. . the correlation between low values of cvp/lap and volume response was poor, the relationship between cvp below mmhg with increased cardiac output had a correlation (pearson correlation - . ) with a significance ( -tailed) . , and the relationship between lap \ mmhg and an increase in cardiac output had a correlation (pearson correlation . ) with a significance of ( -tailed) . . the measurement of the variation of the inferior vena cava, led us to calculated a cutoff point more sensitive to determine which patients were responders to volume. through the roc curves (sensitivity/specificity), with the area under the curve of . % (se = . %) and with a confidence interval of % (p significance of . ), resulted in a % variations of ivc with a sensibility of % and specificity of % (younden's index of . %). the same calculation, based on kraemer's quality indices (qi) gave us a % of variation in ivc, with a w = . specificity rather than sensitivity (qi . ), and with a w = . sensitivity rather than specificity (qi . ) objectives. to ascertain whether postoperative hypothermia is linked to high or low risk surgical patients. we conducted a prospective systematic analysis looking at the incidence of postoperative hypothermia in adults who underwent general anaesthesia. children age \ , pregnant women and patients undergoing regional anaesthesia were excluded from the survey. to identify the current level of doctors' knowledge on perioperative fluid management. methods. the survey was conducted at george eliot hospital, nuneaton, uk in may . questionnaires consisting of ten multiple-choice questions on basic sciences and clinical scenarios were devised by a consultant anaesthetist. these were personally distributed to doctors of all grades working in anaesthetics and the surgical specialties. doctors were asked to complete the questionnaire within min. of the questionnaires distributed, were completed. results. the mean questionnaire score varied between specialties from % in the anaesthetics department to % for doctors in surgical specialties. the mean score of registrars and fy doctors in surgical specialties was found to be and % respectively. the overall mean score was %. of all doctors surveyed, the daily maintenance water requirement was known by only %, % knew the daily maintenance sodium requirement and % knew that of potassium. the electrolyte contents of . % sodium chloride and hartmann's solution was answered correctly by % and % respectively. there is a significant deficiency in doctors' knowledge on perioperative fluid management. more emphasis on optimal perioperative fluid management is required in undergraduate and postgraduate training. increased awareness of the british consensus guidelines on intravenous fluid therapy for adult surgical patients would aid training. based on this survey, a regional online survey of junior doctors is planned to further identify gaps in perioperative fluid management training. optimal fluid management could also help to reduce prolonged hospital stay which can result from fluid-related complications. objectives. to evaluate dynamic echocardiographic parameters as predictors of volume responsiveness in surgical patients. methods. patients were included in the study after laparotomy surgery performed on the same day ( breathing spontaneously and mechanically ventilated in volume controlled mode with tidal volume of ml/kg). a fluid challenge was performed in spontaneously breathing patients by passive leg raising and infusing saline ( ml/kg). echocardiographic analysis of respiratory changes of inferior vena cava diameter (ddivc) and aortic blood flow (dabf) was performed in all patients. a threshold of % for ddivc was used for classifying patients as volume responders or non-responders. age, sex, gender, bmi, cvp, iap, map, left ventricular ejection fraction, left ventricular systolic and diastolic area, and stroke volume in all patients, as well as itbvi, ci, ppv and svv in patients were measured. a positive correlation with ddivc was established for itbvi (r = . , p = . ), iap (r = . , p = . ) and ef (r = . , p = . ). a positive correlation with dabf was not established for any variable measured. patients ( %) were classified as volume responders and ( %) as non-responders. responders had overall higher iap than non-responders ( . ± . mmhg vs. . ± . mmhg respectively, p = . ). respiratory changes of ivc diameter showed positive correlation with itbvi. so, conclusions about itbvi could be indirectly made from ddivc values in patients who are not being invasively monitored. ppv and svv did not show positive correlation with itbvi. surprisingly, we confirmed a positive correlation between ddivc and iap. we detected patients with high iap, while all the volume responders had overall higher iap. although further investigations are needed to establish how longer duration of high iap may influence ddivc, it seems that ddivc is a good parameter of volume responsiveness during first h after laparotomy surgery. unlike from other studies, we could not establish a positive correlation between dabf and any variable measured. these studies were performed in hypovolemic septic patients, so this could be the reason for such different results. more studies are needed in a larger set of patients undergoing laparotomy surgery to evaluate dabf. introduction. fluid optimization after major cardiac surgery was shown to improve patients postoperative outcome significantly. several hemodynamic parameters were proposed for the guidance of therapy but never compared in a head to head trial. objectives. in this prospective randomized trial patients scheduled for elective cardiac surgery underwent early goal directed fluid therapy guided either by stroke volume variation (svv) or by oxygen delivery index (do i). we hypothesized that while svv is easier to obtain it will not be inferior to do i in outcome parameters. methods. following ethics committee approval and signing of a written informed consent, patients were randomized in two groups to undergo either fluid optimization guided by do i or svv in the first postoperative hours in the icu following elective cardiac surgery (cabg). following a standardized egt protocol the parameters were collected by using hemodynamic monitoring based on a pulse contour analysis and a transpulmonary lithium dilution (lidco plus, lidco,uk). we compared amount and type of volume infused, need and amount of inotropic or vasopressor substances, time spent on ventilator, los in the icu and postoperative complications. statistics were evaluated by using a t test for unpaired samples. table . compared to the do i group fluid optimization using svv showed reduced ventilator times (p = . ) and less complications (p = . ) in the first days after surgery. no differences between the groups were detected concerning the type and amount of volume infused, need for inotropes or vasopressors or the los in hospital conclusions. while svv is less invasive, cheaper and easier to be obtained than do outcome was at least not inferior and even showed improvements in postoperative cardiac surgery patients. rd esicm annual congress -barcelona, spain - - october s introduction. over the years, there have been concerns over incompatibility of transfused blood with various intravenous fluids during blood transfusion, especially related to increased levels of haemolysis. it is often impractical, particularly in an emergency situation, to flush through a giving set with a so-called ''safe'' fluid prior to and after delivering blood. we wanted to investigate whether this is actually necessary and whether the usual fluids used in the perioperative period really do cause any demonstrable alteration in the composition of transfused blood. objectives. the purpose of this study was to expose packed red cells to a variety of different intravenous fluids commonly used during the perioperative period and to measure a number of parameters in the blood following their contact with each different fluid, including a blood film to examine for clumping of cells or haemolysis. a unit of a positive blood was passed through blood giving sets which were primed with various intravenous fluids. after adequate mixing of blood with fluids, samples were collected for full blood count, urea and electrolytes and blood films. one millilitre of mixed blood was taken in each bottle at a time. the intravenous fluids used in this study were normal saline, hartmann's solution, % dextrose, % dextrose, starch and gelatin. there was no significant rise in blood parameters suggestive of haemolysis. the potassium and ldh levels were not significantly different with various fluids. the haemoglobin and haematocrit levels were also comparable to one another. there was no demonstrable changes in blood parameters suggestive of haemolysis, nor were there any change in electrolyte values. this suggests that all of the fluids investigated during this study would be suitable to be used via the same giving set before and after the transfusion of pack red cells. objectives. to assess the compliance with the national guidelines in avoiding inadvertent peri-operative hypothermia in an acute district general hospital in england. we prospectively studied our local practice on maintaining normothermia in consecutive adult surgical patients { men, mean age . years, patients with asa grade ( . %), emergency surgical patients ( . %), patients with significant cardiac disease . %}. we used a questionnaire that was filled pre-operatively by anesthetic nurses, intra-operatively by anesthesiologists, and post-operatively by recovery nurses. patients were recruited from the following surgical subspecialties: general surgery ( %), gynecology ( %), trauma ( %), breast surgery ( %) and orthopedics ( %). day surgery patients were excluded. peri-operative hypothermia was defined as temperature \ °c as per the nice guidelines. results. less than half of our patients ( . %, n = ) had their temperature measured preoperatively, on whom incidence of hypothermia was . % (n = ). only one of these patients was warmed prior to induction. patients requiring emergency surgery and those with asa grade had increased incidence of preoperative hypothermia ( . % and . % respectively, p \ . ). based on nice guidelines, patients needed intraoperative forced air warming but only ( . %) patients received it. intraoperative temperature measurement was made on patients, of whom . % (n = ) were hypothermic. incidence of intraoperative hypothermia was high in surgical procedures lasting longer than min (p \ . ) but was not affected by the use of regional anesthetic techniques. patients had their temperature measured on arrival to recovery of whom ( . %) were hypothermic. patients ( . %) had their temperature measured every min (nice recommendation) and the mean time interval for temperature measurement in recovery was min. patients were still hypothermic on leaving recovery. conclusions. majority of our surgical patients did not receive adequate perioperative care on maintaining normothermia. consequently, the incidence of hypothermia was significant pre-, intra-and post-operatively. we are currently analyzing the data to investigate the effect of hypothermia on duration of recovery stay, length of hospitalization and mortality in our patients. we completed a double-blind randomized trial in patients undergoing cardiac surgery in which we compared fluid resuscitation with a hydroxyethyl starch (hes, % mw pentastarch) and saline. use of hes resulted in markedly less use of catecholamines the morning after surgery. an underlying design principle was that assessment of cardiac index (ci) is essential for a proper fluid protocol. in this analysis we examine that supposition. all subjects had pulmonary artery catheters. patients were consented preoperatively, but randomized post operatively to receive up to blinded ml boluses for predefined hemodynamic targets; ci \ . l/min/m , blood pressure (bp) set by admitting team, cvp \ mmhg, or urine output \ ml/h. hemodynamic measurements were made before and after each bolus. after the study boluses, only saline was used. results. patients received fluids, hes and saline. there were study boluses, hes and saline. of these, boluses ( %) could not be assessed for this hemodynamic analysis (but were still used for the primary outcome) because of protocol violation or missing data. of the rest, ( %) of boluses were given for a low ci; in bp and cvp were also low so that ci was the only trigger in %. a low bp was a trigger in ( %). low cvp was the trigger in ( %). only hes and saline patients required the maximum allowed blinded boluses. at the th bolus, low ci was the trigger for ( %) of hes but ( %) of saline patients. there were that could be evaluated for hemodynamic response based on four possible outcomes of cvp and ci. objectives. the aim of our study was to evaluate the predictive value of cvp with regard to gedi, and to correlate these parameters to cardiac index (ci). conclusions. volume depletion according to gedi was found in more than half the patients. the predictive values of cvp with regard to volume depletion were low gedi and its changes significantly correlated to ci and its changes, which was not observed for cvp. therefore, gedi appears to be more appropriate for volume management during mayor liver resections. introduction. regional anticoagulation with citrate is an effective and established anticoagulation strategy during crrt in critically ill patients, especially in surgical patients with a high risk of bleeding and in case of a heparin-induced thrombocytopenia ( ). however, citrate crrt could be associated with major metabolic derangements such as metabolic alkalosis, hypocalcemia, hypernatremia and citrate toxicity. objectives. the aim of our study was to investigate efficacy, safety and metabolic stability during citrate crrt in critically ill patients with acute kidney injury. methods. the retrospective study was performed in a mixed surgical and trauma icu in a university hospital. patient charts were reviewed for demographic data, the period and dosage of citrate crrt and metabolic parameters. reasons of admission, comorbidities and severity of illness were also evaluated. citrate crrt was performed using commercially available equipment and fluid solutions (multifiltrate Ò with integrated ci-ca Ò -system; fresenius medical care; germany). to maintain stable metabolic and haemodynamic conditions we used an internal standard protocol for citrate crrt. statistical analysis was performed using descriptive methods (mean, median and standard deviation) and a mann-whitney u test where appropriate. p \ . was regarded as statistically significant. conclusions. although minor metabolic imbalances were observed, none led to a termination of citrate crrt and all of them could be managed by adjustments of blood flow and dialysate rates according to a preset protocol. our findings suggest citrate crrt to be a safe and effective strategy for crrt even in patients with hepatic dysfunction. nevertheless, metabolic parameters need to be monitored regularly to avoid severe metabolic derangements. introduction. the liver is central to ammonia metabolism, being the main site of urea cycle enzyme pathways. in acute liver failure (alf) and decompensated chronic liver disease (cld) ammonia dysmetabolism results in hyperammonaemia, thought to be of central importance in the pathogenesis of hepatic encephalopathy and, in alf cerebral oedema [ ] . continuous renal replacement therapy (crrt), commonly used in critically ill patients may be an effective method of clearing ammonia. little is known of the efficacy such techniques have on ammonia clearance. objectives. to quantify the clearance of ammonia using an aquarius haemofilter (ahf) using different renal replacement doses and techniques. methods. patients with a circulating ammonia level[ lmol/l due to commence crrt were enrolled. the ahf was programmed to run in either pre-or post-dilution modes at a blood flow rate of ms/min using a . or . m filter depending on the crrt ultrafiltration (uf) dose, which included , or ml/kg/h (adjusted for ideal body weight). ml of blood and effluent fluid were collected, on ice into lithium/heparin and serum separation tubes, from pre and post filter access points and effluent tubing to calculate urea and ammonia clearance using the cordoba formula [ ] . delta whole body ammonia clearance was determined by measuring arterial ammonia at and min. ammonia measurements were performed using a pocketchem Ò blood ammonia bedside testing machine. results. patients ( alf and cld) were recruited (mean age years, sd ( ), with mean arterial ammonia lmol/l, sd ( ). min whole-body ammonia clearance was - lmol/l, p = . , paired t test). ammonia and urea clearance were correlated (r = . , p = . ); uf rate correlated negatively with filtrate ammonia (r = - . , p = . ) and positively with ammonia clearance (r = . , p = . ). filter ammonia clearance was not dependent on filter size for the standard blood flow rate. pre or post dilution modes did not affect ammonia clearance (p = . , student's t test). a constant filter size and blood flow rate achieved ammonia clearance of ml/min/m for ml/kg/h, ml/min/ m for ml/kg/h and ml/min/m for ml/kg/h (p = . , one way anova). conclusions. ml/kg/h based on ideal body weight appears to be the optimum dose of crrt for ammonia clearance when using a blood flow rate ml/min and a . m filter. filter and delta whole body ammonia clearance may be increased further using the combination of a higher dose ( ml/kg/h) with a larger filter size and higher blood flow rates. introduction. malnutrition is common in intensive care following the catabolic state induced by critical illness. patients who progress from enteral nutrition back to oral feeding are usually in an energy deficit. espen guidelines recommend increasing calorie delivery during the recovery period to cover this anabolic phase. oral nutritional supplements (ons) are widely used to facilitate calorie delivery within the hospital setting however the effectiveness of this strategy is dependent on patient compliance with the products. compliance among the elderly ward-based population has been considered ( ) however that of intensive care patients has not been reported. to evaluate compliance to ons in a mixed medical and surgical adult intensive care unit (icu) in a district general hospital. prospective observational study was conducted over a month period with data compiled from fluid chart analysis and discussions with nursing staff. all adult icu patients prescribed, or offered without prescription, an ons were included until the point they were discharged to the ward. the supplements studied, resource Ò energy, . fibre, fruit and dessert (nestlé nutrition), were selected based on their availability within the trust. patients were offered a choice of flavour. results. data was collected and analysed for patient days. a total of supplements were prescribed. of the prescribed supplements, . % were offered to patients and . % consumed. % were offered the same at nursing discretion based on clinical need and . % were consumed. resource Ò energy was the most frequently prescribed and offered product ( . and . % respectively). most common flavours selected by patients were strawberry and vanilla. resource . fibre was better tolerated ( . %) than resource energy, resource fruit and resource dessert ( . , . and . % respectively). across all products the best tolerated flavours were apricot, chocolate and coffee ( %). the highest calorie supplement, resource Ò . fibre, resulted in the best compliance in both tested flavours. compliance with ons demonstrated here is higher than previous studies ( ) partly attributable to one-on-one nursing of icu patients enabling active encouragement with feeding. nursing staff discretion had better uptake than routine prescription of ons. however, difficulties with ons still remain. interestingly in our study the highest calorie density supplement was tolerated the best and thus giving the most benefit to the patient. despite the difficulties associated with ons uptake we would recommend its regular use on icu with a drive towards the highest calorie supplements being offered. introduction. cirrhosis is a chronic disease and the patient's quality of life is affected in a negative way due to the problems like ascites, jaundice, nutrition deficiency, fatigue, activity intolerance, itching, pain, insomnia, anxiety, hopelessness, work loss and depression. objectives. the aim of this study is to examine the changes in patient's lives that diagnosed with cirrhosis of the liver disease owing to the symptoms they experienced. methods. this research is a qualitative study that has been carried out with inpatients diagnosed with liver cirrhosis in the gastroenterology clinic of a teaching and research hospital. average age of patients was (ranging - ). descriptive characteristics form and semi-structured interview form were used in the data collection. interviews with patients have been performed individually and face to face. the data were evaluated by using colaizzi's phenomenological data analysis method. as a result of the data analysis, three categories and six themes were identified. categories include: (i) problems of symptoms related to the physical limitations (ii) psychosocial issues. patients suffer mostly from fatigue and malaise ( patients), while those in the later stages suffer from, additionally, physical ailments caused by acid. inability to sleep due to anxiety and increase in tendency to sleep in advanced stages have been identified after being diagnosed. the majority of patients were identified to have undergone an anxiety besides having a fatal disease due to concern for the future, being forced to quit the job and being affected by the experiences of the patients in advanced stages. it also has been discovered that the patients had experienced social isolation because of fatigue and weakness in particular. as the result of this study it has been determined that patients with cirrhosis have mainly problems of fatigue, weakness, sleep disorders, anxiety and associated problems. rd esicm annual congress -barcelona, spain - - october s [ ] . while in patients with acute liver failure, elevation of arterial ammonia levels has been linked to cerebral complications and increased mortality, the role of arterial ammonia in hh patients is unknown. our study aims at evaluating arterial ammonia levels in patients with hh. furthermore, we wanted to elucidate the potential consequences of high ammonia levels in these patients. arterial ammonia levels were measured and documented in hh patients without liver cirrhosis who were admitted to the medical icu. icu mortality and overall day-survival were documented. cox regression was performed to describe the impact of ammonia levels on mortality. mann-whitney test was used for comparison of metric variables. results. overall median arterial peak ammonia level in our patients was lmol/l ( . - . lmol/l), whereas median arterial peak ammonia value was significantly higher in icu non-survivors compared to survivors ( ( - . ) vs. . ( . - . ); p \ . ). saps ii and sofa score were significantly higher in icu non-survivors (p \ . and p \ . , respectively). cox regression revealed that arterial peak ammonia levels were significantly associated with higher -day-mortality (p \ . ), even after adjustment for saps ii. median arterial peak ammonia levels in patients with verified brain edema were significantly higher than in patients without ( . lmol/l ( - . lmol/l) vs. . lmol/l ( . - . lmol/l); p \ . ) after exclusion of patients following cardiopulmonary resuscitation with consecutive hypoxic brain damage. our results suggest that increased levels of ammonia are associated with high mortality and can lead to brain edema in patients with hh. % of patients had a diagnosis of sepsis and % of patients were admitted under the neurosurgical team, the latter of which may have contributed to the relatively low anticoagulant use of %. systemic heparinisation was the sole anticoagulant used, but compliance with local protocols was poor with % of appts below the therapeutic range and % of infusions commenced at the wrong rate. % of filter changes were due to clotting and mean filter life was h. despite this, dose delivery was acceptable, with % of prescribed dose delivered. conclusions. as previously reported , our demographic data confirm the relatively poor outcome of patients needing crrt. we have identified areas where care for these patients could be optimised and endeavour to do this locally via improved protocol design and an ongoing educational programme. many of the components of crrt could be incorporated into care bundles, but certain aspects of treatment remain controversial which may be a barrier to their adoption. given the high numbers of neurosurgical patients in our unit, consideration should be given to the use of regional anticoagulation such as citrate. introduction and objectives. accurate prognostic indicators of patient survival in an intensive care unit (icu) help guide clinical decision making. factors known to portend poor prognosis in acutely ill cirrhotics in icu include the need for mechanical ventilation, development of shock, renal failure and sequential increase in the number of failing organs. while serum lactate is now an established marker of survival and/or the need for transplantation in fulminant liver failure, its impact on critically ill cirrhotics is less well known. methods. we retrospectively studied consecutive acutely ill cirrhotics admitted to the icu between and at the royal free hospital, a tertiary referral centre in liver diseases and transplantation. data were collected on demographic variables, aetiology of liver disease, liverspecific prognostic scores [child-turcotte-pugh (ctp), model for end-stage liver disease (meld), united kingdom model for end-stage liver disease (ukeld)], and acute illness scores [acute physiological score and chronic health evaluation (apache ii), sequential organ failure assessment score (sofa) ]. in addition, serum lactate levels at , and h were also recorded. multivariable logistic regression analysis was performed, and the discrimination ability of each of the above-mentioned scoring models in predicting icu and hospital survival of these patients was evaluated using the area under the receiver operating characteristic (roc) curve. conclusions. one third of lt recipients present a documented bacterial infection within year after surgery. we found a high prevalence of ciprofloxacin resistance and a low incidence of s.aureus witch was often resistant to methicillin. non fermentative gram negative bacilli represent % of the pathogens and should be taken in account for treatment of the most severe patients. extracorporeal liver support therapy is in its infancy but is valued as a detoxification treatment option for patients with cirrhosis who have rapid worsening of their liver function. we report the use of prometheus Ò , a new extracorporeal liver support system allowing the removal of protein bound and water soluble toxins by fractionated plasma separation and absorption (fpsa) in a patient with wilson's disease (wd) who developed rapid worsening of their liver function. a -year-old female patient, diagnosed with wd since the age of , was initially treated in an irregular pattern with penicillamine. therapy was discontinued. now, years later, she developed acute decompensated liver failure with hepatic encephalopathy with a meld . liver transplantation (lt) was the treatment option for this patient. but, in this case, the rapid and adverse evolution of the liver failure with renal failure and the unknown waiting time for a emergency liver donor in our country led us to use the extracorporeal liver support therapy. after h min of therapy we reduced the amount of bilirrubin for less than a half, we increase the urinary output and next day the patient went to liver transplant, stable, with a renal function improved. conclusions. acute liver failure due to wd is most of the time fatal without emergency lt. this case report highlights discontinuation of chelants treatment in a patient with wd. as the patient progressed to decompensated liver cirrhosis with encephalopathy, lt was the only treatment option but while we don't get a donnor, we can use, for a short period of time, an extracorporeal liver support therapy as a very useful bridge. results from two studies presented at the recent easl congress have shown that treatment with extracorporeal devices may not confer a survival advantage for severe liver failure patients, despite positive dialysis effects. however, results among a small sub-group of patients show promise like severely ill patients with hepatorenal syndrome type or a meld score over . ( ) . metoclopramide is used to stimulate the upper gi tract and seems to have no effect on colonic motility. objectives. the aim of this in vitro study was to compare the prokinetic potency of those substances. a tissue bath with guinea pig colonic segments fixed on a polyacrylic tray allows the evaluation of the transit time (tt), the time necessary for a wooden pellet to perambulate. a decrease of the tt reflects stimulation, and an increase inhibition of peristalsis. after stable peristalsis activity the effect of increasing concentrations of prucalopride, neostigmine or metoclopramide on tt were evaluated. dose response curves were constructed, two way anova (sigma stat) was used for statistics, p values b . were considered to be significant. effect of prucalopride and neostigmine on motility results. prucalopride stimulates normal peristalsis in vitro only in the highest tested concentration of lm (p \ . ). neostigmine's prokinetic effect was limited to a small concentrations range ( . lm, p \ . ), the concentration of . lm had a moderate, but not statistically significant prokinetic effect and the highest tested concentration ( lm) lead to a complete block of peristalsis (fig. ) . metoclopramide, as expected, was devoid of any effect on colonic motility. conclusions. this experimental setting is a reliable method to evaluate the effect of different substances on colonic motility in vitro. prucalopride's prokinetic activity is concentrations dependent and limited. neostigmine is well known to improve colonic motility, but it seems imperative that the drug's effective dose range be use-higher concentrations have inhibitory effect on peristalsis. objectives. robotic radical prostatectomy involves extreme changes in patient position and often associated with a longer operative time than other commonly performed laparoscopic procedures. this review discusses the anesthetic considerations in robotic radical prostatectomy while analyzing potential risk factors related to pulmonary complications. we retrospectively reviewed the medical records of all the patients who had undergone robotic radical prostatectomy at our institution. among the total patients of , aged to years, patients were capable of spontaneous respiration at the end of surgery (group i) whereas patients needed assist ventilation (group ii). the demographic characteristics, coexisting diseases, anesthesia and operation time, anesthetic agents, the amounts of blood loss, infused fluid and transfused blood products were compared between the groups. results. the mean age of the patients was . ± . years. the mean operation times were . ± . min (range, - min). age, body mass index (bmi) and asa status did not differ significantly between the two groups, whereas operation time, the amount of blood loss and the incidence of transfusion were significantly higher in the group ii. although patients with subcutaneous emphysema and atelectasis needed prolonged ventilator care for h, the incidence of atelectasis and subcutaneous emphysema was similar between the groups. conclusions. prolonged laparoscopic surgery in a steep trendelenburg position has a high possibility of postoperative respiratory insufficiency and the possible contributing factor is a long operation time. objectives. we examined the frequency of postoperative cough reflex and its effect on postoperative clinical outcome retrospectively. we examined the patients who admitted into the icu after the esophagectomy with lymphadenectomy during the period from september, , to february, . in addition to usual criteria for extubation we removed their tracheal tube if the cough reflex was identified when one milliliter of half saline was distilled into their trachea. if the cough reflex was absent until days after the operation the patient underwent tracheostomy and after that they weaned from the ventilator. results. there were patients (f/m / ), and their mean age was . ± . . cough reflex were confirmed by seventh postoperative day in patients ( %) but residual patients underwent tracheostomy because of absence of cough reflex ( introduction. the technique of laparoscopic cholecystectomy carried with carbon dioxide pneumoperitoneum may lead to adverse events in mechanical, hemodynamic and respiratory systems as a consequence of physiopathological changes such as increased intraabdominal pressure. _ it may cause hypoxemia, hypercapnia, hemodynamic instability and impairment of oxygenation. decreased functional residual capacity, ventilation/perfusion imbalance and sympathetic stimulation effects of co that is absorbed from peritoneum are basic problems. in perioperative period, application of mechanical ventilation and anesthesia should be reviewed because of these physiopathological mechanisms. in this study, we aimed to investigate the effects of cmh o peep application on etco , minute ventilation and arterial oxygenation during laparoscopic cholecystectomy operations. for this reason, the study included total patients and they were randomly divided into two groups. same anesthetic protocol was applied in both groups. for general anesthesia induction; mg/kg dose of fentanyl, mg/kg dose of propofol were administered. following this procedure endotracheal intubation was applied with . mg/kg dose of cisatracurium. patients received % o -% n o (mixture with equal amounts) with . - . mac end-tidal sevoflurane for anesthesia maintenance. before co insufflation, respiratory parameters were recorded on the respiratory apparatus adjusting etco - mmhg, respiration rate /min., inspiration/expiration rate : , vt: - ml/kg. patients were ventilated by volume controlled mechanical ventilation. heart beats, mean arterial blood pressure and peripheric o saturation (spo ), etco , minute ventilation(v) and peak airway pressure(p _ ip) values of all patients were recorded just before insufflation (t ). after recording, cmh o peep was applied to the first group (group ). peep wasn't applied to the nd group (group ). these parameters were repeated in periods such as (t ) and (t ) minutes after insufflation, preexsufflation (t ) and postexsufflation (t ) in both groups. before insufflation, respiration rate ( /min) and etco ( - mmhg) values were adjusted as planned in both groups and minute ventilation was also adjusted. at the same time, total insufflated amount of co for distending abdomen was recorded. arterial blood gas analyses were made just before induction (while patients were breathing normal room air, t ), min after induction (t ) and just before the end of the operation (t ). in our study, we found that minute ventilation to stabilize etco - mmhg was significantly increased in group in which peep was not applied (p \ . ). none enhancement was needed in minute ventilation in group and arterial oxygenation was significantly increased in group (p \ . ). aside from the cholesterol lowering effects of statins, as a class of drugs they have been shown to exert anti-inflammatory effects and have the potential to be therapeutic in neuroinflammatory disorders . we tested the hypothesis that atorvastatin improves memory retrieval post unilateral nephrectomy in a murine model. methods. c /bl mice were randomly allocated into groups (n = - /group): control plus placebo, control plus atorvastatin, nephrectomy plus placebo and nephrectomy plus atorvastatin. animals were given either a placebo ( . ml normal saline) or lg in . ml normal saline of atorvastatin by gavage once a day for days. on day all animals underwent fear conditioning training using a conditional stimulus of a db tone and an unconditional stimulus of a . ma electric shock. on day the surgical animals underwent unilateral nephrectomy, whilst the control animals received no surgery. at post-surgical day all animals were tested for hippocampal dependent memory retrieval using the fear conditioning paradigm, with freezing response to the db tone as a marker of memory retrieval. all animals were then terminated. results. surgery evoked a reduction in hippocampal dependent memory retrieval in the nephrectomy plus placebo group as measured by % freezing time (mean ± sd: ± ) when compared to the control plus placebo group ( ± ; p \ . ); a situation mimicking pocd. this change was obviated in the nephrectomy plus atorvastatin group ( ± ; p [ . vs. control plus placebo). conclusions. our data suggested that atorvastatin has the potential to improve postoperative cognitive performance in a murine model of pocd. the proven safety of the drug along with its already widespread use and cost effectiveness would permit rapid instigation of a human randomized controlled trial to explore efficacy in the clinical setting. a. puxty , r. docking glasgow royal infirmary, department of anasethetics, glasgow, uk hypotension in the post-operative period is common but guidelines recommend its prevention/treatment [ ] . epidurals are common practice following major surgery in many institutions and can prevent pulmonary complications [ ] but have also been associated with falls in blood pressure when compared to other analgesic techniques [ ] . fluids therapy is a common intervention for hypotension but fluid overload has been associated with worse outcomes in surgical patients [ ] . we decided to audit the incidence and management of hypotension in the surgical high dependency unit of a large tertiary referral hospital. to determine the incidence and management of hypotension in the surgical high dependency unit in pancreatic, upper gi and lower gi patients. we prospectively looked at patients who underwent major upper gi, lower gi or pancreatic surgery involving epidural analgesia. the first h of care from onset of anaesthesia was closely looked at with regards to fluid management, epidural management and actions taken on episodes of hypotension or severe hypotension (defined as systolic blood pressure of \ and \ respectively). each episode of hypotension was looked at to determine the actions taken at that point. of the patients looked at, were major pancreatic, lower gi and upper gi patients. ( %) had at least one episode of hypotension, with ( %) having at least one episode of severe hypotension. mean fluid in during the first h was ml, with a mean fluid balance of ml. there was no difference between the doses of epidural local anaesthetic in h between the hypotensive and non hypotensive groups (p = . ). management of hypotensive episodes was variable, but the most common intervention at episode one was fluid bolus ( %) and discontinuation of epidural was most common at episode two ( %). use of vasopressors for hypotension was very low with only two infusions being started altogether. conclusions. hypotension is very common in our high dependency unit. fluid balance in our patients was far more positive that we had expected. management of hypotension was variable. we plan to institute a protocol for hypotension and fluid administration to determine if improvements can be made. objectives. to identify predictive factors associated with the need for relaparotomy in patients with ssp. adult ssp patients undergoing laparotomy between and included within a single-center peritonitis registry (perit) were collected. patients subjected to relaparotomy were studied. we excluded patients with severe peritonitis secondary to appendicitis. apache ii and sofa score at icu admission after the initial laparotomy were recorded. variables with a p value. in a bivariate analysis were included in a multivariate logistic regression for further analysis of predictors for need for re-laparotomy. results. two-hundred forty-seven patients were obtained from perit registry. a total of patients with spp were included in the analysis. eighty seven patients ( %) required relaparotomy. median number of re-laparotomies was . most spp were associated to colon (n = , . %), small intestine (n = , . %) and biliary tract (n = , . %) perforations. cultures were positive in . % of first laparotomy: gram negative bacteria were isolated in . %, gram positive bacteria in . % and fungi in . %. hospital mortality was % (n = ). multivariate analysis is described in the table . conclusions. in obese patients scheduled for surgery, the previous use of cpap has not shown an improvement in blood gas parameters. the use of cpap in the hours before and immediately after surgery has not been associated with better postoperative oxygenation. combined icu-surgery dpt. action in these cases seem to contribute to better patient outcomes. objectives. we set out to quantify the intensive care workload and changes to that workload over the first years following the transfer of a specialist bariatric service to our hospital. a prospectively collected bariatric surgical database was cross-referenced to the itu database (ward-watcher) to identify admissions to the -bedded critical care unit of all patients who had undergone any bariatric procedure. for each patient identified; demographics, reason for admission, level of support, length of stay and outcome were recorded. data were grouped into -month periods for trend analysis. research in emergency situations and especially in resuscitation field raises important ethical and regulatory issues. the globalization of the resuscitation science through multicentric trials for example highlights the need for a more consistent approach to regulatory aspects to enable the science to grow while protecting human rights. objectives. the purpose of this analysis is to compare the different regulations approaches in emergency research in north america (canada, usa) and in europe (european directive, france). conclusions. this analysis emphasizes the lack of international standardization of regulatory measures and ethical decisions. however some countries like the us seem to advance in the democratic process by mandating additional regulatory measures (community consultation, public disclosure to the communities) prior to initiation of clinical investigation; nonetheless, there is little evidence of their effectiveness. many challenges are raised. firstly, the variability in regulations, and consequently in local board's assessments, is problematic, pleading for international regulations. secondly, the current heterogeneous ethical review process and demanding unsubstantiated regulatory measures poses a risk to all when it is not evidence based and it is applied inconsistently between countries, within a country and worse at the level of each individual hospital review board. it puts the investigator at risk for unnecessary criticism and the community at risk as it is unknown if we truly consult or inform our target communities about waiver of consent research through our current ethical and regulatory processes. globalization and evaluation of the ethical and regulatory processes are urgently needed; regulatory community has to work towards a standardized evidence-based process upon which to base regulatory decisions. introduction. in research outside the intensive care field it is known that a high score for the psychological factor ''perceived hopelessness'' experienced by healthy individuals increases risk of death several fold. objectives. the aim of this study was to examine if the score of the psychological factor ''perceived hopelessness'' may predict long term mortality (mean or high perceived hopelessness score) when assessed post icu care in former icu patients. methods. prospective, multicenter study in three mixed icu's in sweden. questionnaires, including the -item hopelessness scale, demographic data and previous illnesses, were sent months after discharge to all former adult icu patients who thereafter were followed for another years. a reference group of individuals from the uptake area of the hospitals served as controls. results. ( %) patients returned the questionnaires. the icu patients reported significantly higher mean scores in perceived hopelessness score compared with the general population, . (sd . ) compared with . (sd . ) (p \ . ), and % (n = ) of the icu patients perceived a mean or high hopelessness score compared with % of the general population (p \ . ). the icu patients who died during the follow-up period reported a significantly higher perceived hopelessness score (n = ) . (sd . ) (p \ . ) as compared with those who survived up to years after discharge (n = ) . (sd . ). in a logistic regression model the long term mortality for the icu group was found to be affected by: pre-existing disease [odds ratio (or): . ], age (or: . ) and perceived hopelessness score (or: . ). the new and interesting finding of this study is that icu patients score higher on ''perceived hopelessness'' than a control population and this increase is predictive for the post icu mortality. furthermore, the size of this effect is significant and only exceeded by pre-existing disease and age. we performed a retrospective observational study to evaluate what proportion of met calls was associated with lomt issues. to estimate the proportion of met reviews involving patients with a not-forresuscitation (nfr) order and the timing of met calls in relation to admission and death or discharge from hospital. to compare the patient characteristics and outcome for met calls associated or not associated with lomt issues. we obtained hospital research ethics committee approval. we performed a retrospective observational study involving five-year (august -april ) in a single tertiary australian hospital. we obtained information on demographics, on the met review and hospital outcome. lomt included nfr orders, not for met orders and palliative care plans. results. we analysed met reviews in patients. table and fig. summarize major findings for overall population and the two subgroups of patients with or without lomt. patients with lomt care plan were older, more likely to have medical diagnoses, were reviewed later during their hospital stay and closer to their hospital discharge or death. fewer lomt patients were admitted to icu. hospital length of stay was shorter, mortality in lomt care patients was double that of non-lomt patients. however, more % of patients with lomt were discharged alive from the hospital. conclusions. more than one third of met activations deal with lomt issues. although the mortality of these patients is high, a large proportion survives to hospital discharge. evaluation of the patient experience in intensive care (icu) frequently depends on reports from surrogates such as relatives. there is a concern regarding the validity of the surrogate opinion which might not represent the values of the incapacitated patient and treatment decisions therefore maybe biased [ ] . others have found that there is a strong preference within a population for utilizing relatives as surrogate decision-makers in the event of admission to icu and this attitude is not influenced by ethnicity, religion or education level [ ] . objectives. the objective was to measure the ability of the relative to answer on behalf of the patient. a further wish was to determine the validity of their surrogate responses. a retrospective study, which surveyed relatives of patients who had died within a critical care service during a -year period ( , ) . the item questionnaire allowed for the collection of quantitative and qualitative data with respect for each item to overcome the limitations of the quantitative format which may not be sensitive to all the issues which can surround the provision of end-of-life care [ ] . for items, relatives were asked specifically to grade their capacity to represent the patient. results. quantitative data from the items designed to test the relatives' perception of their ability to act as surrogates indicates that relatives considered they could respond to these items for % (average) of instances. when the relative did answer on the patient's behalf, the level of concordance between the surrogate (relative) and the patient's perceived opinion was % suggesting that when the relative is willing to act as surrogate the response is likely to have validity. (table ) . results from the qualitative data indicates that the low ( %) level of willingness to answer these questionnaire items reflected a reluctance to answer on behalf of a sedated or ventilated patient, rather than an inherent inability to represent the patient. conclusions. the response rate to the items vindicates concerns regarding the ability of relatives to represent the patient in icu settings and supports a need for further study. where the relative is willing to act as surrogate, concordance does exist. qualitative data clarified quantitative results and was instrumental in promoting a better understanding of the concerns of relatives who have a family member admitted to icu. . the majority of patients that died in icu were provided some kind of therapy restriction. an important conflict strains between clinical practise, bioethical principle and jurisdiction laws; the solution of this conflict is more and more urgent. therapy restriction has also important economical aspects since the number and cost of available treatments constantly increase. our survey studied therapy restriction procedures in hungary for the first time. in we performed a survey with questionnaire among intensive care physicians. questionnaires were sent out electronically to registered members of the hungarian society of anaesthesiology and intensive care. respecting anonymity we have statistically evaluated replies ( %) with t test and anova. we grouped intensive care physicians based on gender, years spent in work, religion and type of department they were working, and we compared data from these groups. intensive care physicians generally make their decisions alone, based on the patient's long-term life prospects and physical status ( . / points). they are slightly influenced by the opinion of the patient ( . ), the relatives ( . ) and other medical personnel ( . ). if the physician sees any chance of recovery but the patient or relative requests treatment restriction then . % of physicians that completed the forms would continue therapy against the will of the patient or relative. only . % would accept the patient's/relative's opinion and autonomy in such a case and would stop therapy. in fact . % of physicians would make their decisions without considering or even against the opinion of patient if they think therapy is useless. if there is no chance of recovery despite medical treatment % of physicians stop the treatment, . % would continue it without informing the patient or the relatives, . % informs the relatives but continues useless treatment irrespective of the will of the patient or relative. having analyzed the groups we found two significant differences. in case of useless treatment physicians working in university hospitals more often choose treatment restriction without informing relatives (p \ . ) then those working in non-university hospitals. physicians who declare themselves as atheist rather choose the continuation of treatment without informing relatives (p = . ). conclusions. the hungarian practise of end of life decisions among intensive care specialists is paternalistic, physicians make their decisions alone, do not consider the requests of the patient or relatives. our goal is to strengthen patient autonomy and to support their opinion by training icu physicians. on the other hand it is inevitable to define what useless medical treatment exactly is and to introduce this category in medical ethics and also in jurisdiction practise. objectives. to determine the frequency and processes of eol care at our centre. between october and december , / ( %) patients staying in the icu for more than day, underwent some form of eol care in the icu. icu staff notified investigators whenever an eol decision was made. we recorded demographic details, documentation of the eol care process in the case notes, and interviewed icu staff to determine the eol care processes involved. results. patients ( %) were male, ( %) were females. mean age was . ± years. icu stay was . ± . days, admission apache ii score was . ± . which increased to . ± . on the day of eol care decision. % patients had metastatic cancer. reasons for initiating eol care were refractory acute illness in %, advanced cancer in %, brain death in %, and lack of finances in %. eol discussions were initiated by the family in %, and by the icu medical team in % patients. families wanted to take the patient home to die. the icu consultant was involved in all discussions with the family, the primary consultants in % and primary team residents in %. nurses were involved in only patients. agreement on eolc was reached after discussion in %, discussions in %, and discussions in % of cases. documentation of the eol care process was not done in % cases. withholding of life support (wh) was practised in / patients ( %) and withdrawal of life support (wd) in %. intubation was withheld in . % patients, cardiopulmonary resuscitation in %, inotropes in % and dialysis in %. regarding wd, only / patients were extubated and the ventilator withdrawn in another / patients. inotropes were withdrawn in patients ( %). reduction of fio . without discontinuing mechanical ventilation was the commonest mode of wd, in patients ( %). all patients received morphine infusions during lols/wols. family members were present by the bedside in % cases. conclusions. wh is preferred over wd. documentation of the eol process does not occur in a significant proportion of cases. nurses are rarely involved in the eol care decision making process. legal issues may be barriers to good eolc in our icu, and perhaps in india. objectives. to know the point of view of the staff is essential to understand their beliefs, attitudes and decisions. brazilian private general icu with beds. the following items were analyzed: profile of the interviewed; their opinion about end of life questions: fear of death, fear of experience pain before death, the best place to die, advanced directives, decision-making process, therapeutic withhold of mechanical ventilation, nutrition, fluid management, antibiotics, vasoactives drugs, sedation and analgesia in patients which death is imminent and irreversible. results. about . % of our icu team answered the research (n = ). the mean age is . years (sd . ), . % of female, . % married, . % protestants and . % catholics and icu professional experience of . years (sd . ). using a visual analog scale ( , no fear to , the worst fear possible) the team pointed . as their fear of death; the fear of suffering pain before death was . . for . % of the responders, the best way to die would be with their lovely ones, no matter if at home or at hospital. only . % would prefer to die an icu. the majority of the team ( . %) would share the eol decision-making process with the family instead only by the medical staff ( . %). about . % would leave an advanced directive with their therapeutic preferences like do not resuscitation orders. the icu team agreed on the withdrawal of vasoactives drugs ( . %), antibiotics ( . %), nutrition ( . %) and mechanical ventilation ( . %) in patients out of treatment. our results showed the staff vision about their own death and their opinion about the end-of-life care issues. in developing country as brazil there is a still gap between everyday practice and the current legislation. fortunately, the debate about eol issues has increased in last years. the end-of-life discussions and decisions should begin by respect to points of view of all involved: patients, family, medical staffs with a legal support of the society's beliefs and expectations. prospective observational study conducted in greek multidisciplinary icus. we studied all consecutive icu patients who died, excluding those who stayed in the icu \ h or were diagnosed with brain death. patients comprised the study population [mean age ± (sd) years, mean apache ii score on admission ± ]. results. of patients studied, % received full support including unsuccessful cardiopulmonary resuscitation (cpr). % died after withholding of cpr, % after withholding of other treatment modalities besides cpr, and % after withdrawal of treatment. patients in whom therapy was limited had a longer hospital (p = . ) and icu (p \ . ) stay, a lower admission gcs score (p \ . ), a higher apache ii score h prior to death (p \ . ), and were more likely to be admitted with a neurological diagnosis (p \ . ). patients who received full support were more likely to be admitted with either a cardiovascular (p = . ) or trauma diagnosis (p = . ), and to be surgical rather than medical (p = . ). the most important factors affecting the physician's decision to provide full support were reversibility of illness and prognostic uncertainty; the physician's religious beliefs and legal concerns had minimal impact. the main factors guiding the decision to limit therapy were unresponsiveness to treatment already provided, prognosis of underlying chronic disease, and prognosis of acute disorder; old age was not a determinant, while economic cost and lack of icu beds seem to play no role. relatives' participation in decision-making occurred in % of cases and was more frequent when a decision to provide full support was made (p \ . ). the principal reason for not discussing end-of-life dilemmas with relatives was the fact that the family was thought not to understand ( %) advance directives were rare ( %). icus. however, in a large majority of cases, it involves the withholding of cpr only. withholding of other therapies besides cpr and withdrawal of support are infrequent. physician has a dominant role in decision-making. objectives. the primary objective of this study is to determine the prevalence of inappropriate or non-beneficial care in icu patients as perceived by their icu healthcare providers, as well as the reasons for this perception. second, we want to determine which factors are associated with the perception of inappropriate care. a descriptive survey design is used. a single-day cross-sectional evaluation of perceptions of inappropriate care among , icu healthcare providers in icu centres in european countries will take place on may th . questionnaires will be administered to icu healthcare providers (nurses, head nurses, junior and senior icu physicians) providing bedside care to adult icu patients on that particular day. in this study, inappropriate care is defined as a patient care situation that is similar to one or more of seven scenarios. these scenarios were created based on the literature and a multidisciplinary conference attended by experts in intensive care, geriatrics, and palliative care. . the cross-sectional study will take place on may th . preliminary results will be given at the esicm conference. we have designed a one-day cross-sectional study to record inappropriate or non-beneficial care in european icu's. results will be available for the esicm conference. grant since the introduction of the mental capacity act in the uk in , the impact within research in the intensive care environment has not been elucidated. since many of the patients are incapacitated and therefore unable to consent, it is now stipulated by the ethics committee that the researcher must make reasonable attempts to identify a consultee, failing this, nominate a person unrelated to the research project to be consulted. in order to comply with the mental capacity act, retrospective consent must be obtained, once the patient regains capacity. objectives. the aim of the study was to highlight the difficulties in obtaining retrospective consent, evaluate the methods used and demonstrate the adaptations made to increase retrospective consents. methods. this explorative analysis investigated the process of obtaining consent in patients enrolled in an observational study on critically ill patients. consent was obtained on admission if the patient had capacity. assent from the patient's next of kin or a legal professional representative was obtained before enrolment in patients who lacked capacity. after discharge from icu, a member of the research team re-visited these patients to explain their involvement in the research, its purpose, procedures, implications and any further participation required by the subject. at this point, the patient could consent or withdraw from the study. if the patient decided to withdraw from the study, all data collected and samples stored were destroyed. the researcher visited the patient for a minimum of two visits; firstly to explain the study; secondly to establish if the patient has retained the information and to gain retrospective consent. results. patients were recruited within the time period of which ( . %) died. in ( . %), consent was obtained on admission as the patients had capacity, ( . %) were discharged prior to obtaining retrospective consent, ( %) lacked capacity on the researcher's visits, and patient ( . %) withdrew from the study. patients ( . %) were successfully consented retrospectively. overall, the researchers performed visits to obtain from the patients for whom retrospective consent was required. conclusions. the process of recruiting patients who lack capacity within the intensive care unit is challenging and time consuming. stipulations set by the ethics committee to seek retrospective consent once the patient has regained capacity, has a major impact on research staff time and finances. detailed recommendations as well as guidelines how to assess capacity in the post-icu patient and how the assessment of capacity has to be applied to intensive care research are needed to fully comply with ethical and legal requirements. objectives. we wanted to know if patients expressed to surrogate decision makers, after icu discharge, specific resuscitation directives, and we have investigated any factors related to the patients and their illness or care process that might be associated with this. we reviewed patients admitted in the icu between december and may . a random sample of survivor patients has been defined. seven patients were excluded ( for language barrier, died, were no more reachable). fifty three patients took part in semistructured interview at - month post icu discharge. the questionnaire discussed in detail the aspects of advance directives. patients had also completed a quality of life questionnaire (euroqol d), and we calculated the eq- d visual analog scale. we reviewed medical records in icu data base: age, gender, length of stay, saps ii, bmi, length of ventilator support and central venous catheterization as well as prescription of transfusion, hemodialysis or adrenergic agonist. multivariate logistic regression was practiced to investigate any factor associated to expression of specific resuscitation directives after icu discharge. after icu discharge, % of interviewed survivors expressed specific resuscitation directives to an appropriate identified surrogate (written ''living will'' or oral statement). eq- d visual analog scale was ± . on multivariate regression analysis, only one studied variable was significantly associated to the post-icu expression of specific resuscitation directives: age (odds ratio = . , z = - . , p = . ). conclusions. after icu discharge, a majority of our patients expressed to surrogate decision makers specific resuscitation directives, especially the younger patients. our findings suggest that surviving to icu is an opportunity to specify oral or written directive, and both may help to illuminate future decision making from the patient's perspective. objectives. to explore the issues around eolc provision for cancer patients in a critical care unit through family, professional and patient experiences. to explore how a diagnosis of cancer impacts upon eolc provision for critically ill patients. a heideggerian phenomenological interview approach was undertaken, in order to gain personal experiences. families of those patients who died after decisions to forgo lifesustaining treatment (dflsts) were interviewed. patients who were seriously critically ill (apache ii [ or had received cpr) who experienced critical care were also interviewed, since patients' views about eolc provision are very rarely explored. doctors and nurses also contribute their vision for, and experiences of, eolc in a cancer critical care unit. thirty seven participants were interviewed. tensions between treating families versus treating patients impacted on timeliness of eolc. achieving a good death was possible through caring activities that made best use of technology to prevent prolonged dying. decision-making and eolc could be difficult to separate out which, in turn, affects prospects for eolc. three main themes included: dual prognostication; the meaning of decision-making; and care practices at eol: choreographing a good death. these themes outlined the essence of moving along a continuum toward patients' deaths and the impact that had on opportunities for care and a good death. conclusions. cancer affected the trajectory in unexpected ways. the trajectory could be very quick, especially in unexpected death and some newly diagnosed cancers. even in the face of a life-limiting and serious disease like cancer, death could be unexpected. the rapidity of trajectory related to cancer diagnosis, prognosis, withdrawal and patient demise significantly impacted on the potential for, and timing of, eolc. a sentiment of moving on from historical practices around critical care for cancer patients, and related poor prognoses, was overwhelmingly agreed on but important caveats in cancer prognostication remains. conclusions. these data suggest that oscillation settings of and hz provided more optimal pef/pif ratio ([ . ). our data also suggests that airway clearance using hfcwo may facilitate improved gas exchange in mechanically ventilated patients. further study is required to confirm these results grant acknowledgment. partial funding support in the form of devices was provided by hill-rom inc. a. esquinas , m. folgado , j. serrano hospital morales meseguer, intensive care unit, murcia, spain, hospital virgen de la concha, zamora, spain, hospital reina sofia córdoba, intensive care unit, cordoba, spain objectives: we hypothesized that the use of intrapulmonary percussive ventilation (ipv) could effect hypercapnia/acidosis and airway secretions control during treatment with noninvasive mechanical ventilation (nippv) in exacerbations of copd associated with bronchial secretions. prospective multicenter study. the study was performed in the medical icu of spanish university hospitals members of the spanish ipv working group. we enrolled copd exacerbation patients with secretions and the need for nippv in icu. criteria of exacerbations of copd are: a respiratory frequency c /min, a pao [ mmhg and ph b . . we define two ipv strategies as complementary treatment during nippv to evaluate the effects of ipv. strategy group i: nippv at first line and combination of ipv in early periods without nippv in spontaneous breathing and ph c . . strategy group ii: first line of ipv with mouthpiece/face mask and oxygenation previous to the application of nimv with ph \ . . in both groups daily sessions ipv were applied by for min/ day by mouthpiece or face mask during stay in icu. nippv was applied with bipap ventilator (respironics) and face mask with bipap mode. cardiopulmonary monitoring, clinical and arterial blood gases were evaluated. therapy was considered as successful when patients did not need nippv support and clinical and arterial blood gases returned to baseline. results. patients with copd exacerbation were admitted in icu for nimv, age ± years, male ( %) were excluded for severe hypoxemia (pao :fio b ) associated with pneumonia ( / ) and cardiac insufficiency ( / ). fifty patients were enrolled in the study. -up tilt-table rehabilitation better than sitting in a chair for ventilated adults in intensive care in terms of improving lung function? j. manners , a. thomas , s. boot , g. mandersloot barts and the london school of medicine and dentistry, london, uk physiotherapy intervention is a fundamental part of the patient stay in an intensive care unit (icu) and treatment is often aimed at maintaining/improving respiratory function. physiotherapists use the upright posture to elicit these improvements and sitting in a chair and standing with a tilt-table are commonly used interventions. to date there are no published reports comparing the efficacy of these interventions in ventilated subjects. • to compare the effects of these two positioning techniques employed with icu patients. • to measure changes in respiratory rate, tidal volume and minute volume during these positioning interventions. • to measure functional residual capacity during positioning interventions. • to measure the change in metabolic demand during positioning interventions. methods. convenience sampling of ventilated subjects meeting the inclusion criteria was employed. subjects acted as their own controls undergoing sitting in a trauma chair and standing on a tilt table at degrees in random order on the same day. respiratory rate (rr), tidal volume (v t ), ventilation (v e ) and oxygen consumption (vo ) were measured at minute intervals during baseline and intervention for min. functional residual capacity (frc) was measured once at rest and following each intervention. measurements were recorded using the ''e-covx'' module for the ''ge carestation ventilator''. results. subjects were recruited. no adverse events occurred during interventions. significant increases from baseline rr (p \ . ), v e (p \ . ) and vo (p = . ) occurred during the tilt table intervention. there was an increase in frc during tilting of . l which failed to reach significance. significant increases from baseline rr (p \ . ), vo (p = . ) and a decrease in v t (p = . ) occurred with the chair intervention. conclusions. these interventions are safe in a critical care population. increased muscular activity associated with upright interventions elicited expected elevations in vo . the tilt-table produced an increase in v e driven by an increased rr at the expense of v t . v e was not elevated during chair sitting despite an increased vo and was accompanied by an unexpected decrease in v t. introduction. uk guidelines about rehabilitation after critical illness highlight the need for outcome measures to determine patient progress and efficacy of treatment [ ] . there is no consensus about the most appropriate measures of patient function. the austoms [ ] tool was designed by therapists in australia to measure activity and function across nine scales assessing structural and functional difficulties and ability to perform activities. scales are split into four domains (impairment, activity limitation, participation restriction and distress/wellbeing) and scored from to with . intervals allowed. acceptable inter-rater variation is defined as an absolute difference of . . austoms has not been appraised in patients recovering from critical illness. objectives. to prospectively determine the inter-rater reliability of the austoms physiotherapy scales in adult patients who had undergone cardiothoracic surgery and required critical care admission for over days. methods. the therapy (physiotherapy and occupational therapy) team underwent a h teaching session using the austoms handbook prior to commencing the trial. austoms was then used over eight consecutive weeks during the weekly therapy goal setting meeting. each week a patient was selected to be scored using the most appropriate functional scales. the clinical history was presented to the team by the therapist leading the patient's care. therapists were then asked to independently score patients across the four domains for each scale. reasons underlying differences in scores were explored by group discussion. the difference between the th and th centiles of the initial scores was calculated for each domain as a measure of inter-rater variability. results. - therapists were present at each meeting. respiratory function and musculoskeletal movement related function were the most common scales used. the mean difference between th and th centiles was greater than . (± . ) for all domains. none of the scales/domains showed consistent inter-rater reliability over the week period. overall the activity limitation domains of each scale showed the least inter-rater variance of scores. clinical experience of therapist did not appear to influence scores. conclusions. the austoms outcome measure showed poor inter-rater reliability when evaluated over an week period on our intensive care unit. further work is ongoing to evaluate the ability of austoms to reveal changes over time when scored by therapists. introduction. uk guidelines on the rehabilitation of patients after critical illness highlight the importance of establishing and reviewing individualised rehabilitation goals for all patients that are at risk of developing physical and non-physical morbidity [ ] . our institution's practice is to create objective goals that are smart-specific, measurable, achievable, realistic and timed [ ] . objectives. the aim of this audit was to prospectively collect data regarding the setting of rehabilitation goals in a group of patients admitted to a cardiothoracic intensive care unit. methods. all consecutive patients admitted under the intensive care team in november were included. data regarding the timings of initial physiotherapy assessment, goal setting, and concomitant sedation were collected using a structured questionnaire completed by the treating physiotherapist. results. patients were admitted under the critical care team. patients were assessed by a physiotherapist within h of admission. of these , had smart goals set within a median of days of initial assessment (range - days). there was a correlation between level of consciousness and the number of days taken to set goals. patients who were fully conscious or drowsy on initial contact (n = ) had a smart goal set in a median of days. by contrast patients who were sedated/paralysed on initial assessment (n = ) had goals set in a median of days. initial goal setting did not include other therapists or the family. goals fell in to categories, range of movement, hoisting out to chair for periods of time, sitting on the edge of the bed, transferring out to the chair by standing and mobility goals-i.e. walking set distances. the maximal interval between reviews of the patients' goals was days. most patients had smart goals defined and regularly reviewed. however, despite physiotherapy assessment within h of admission, there was often a delay in setting these objective goals. the need for continuous sedation acted as a barrier to explicit setting of goals. the results emphasised the need to improve patient and family/carer involvement with initial goal setting in order to be compliant with uk standards. objectives. investigation of ems effects on muscle strength and exploration of issues in relation to handgrip dynamometry in icu patients. one hundred seventy two consecutive patients with apache ii score c , were randomly assigned to the ems (n = , age: ± years, apache ii: ± ) or the control (n = , age: ± years, apache ii: ± ) group. ems sessions applied daily in muscles of both lower extremities. the strength evaluation of various muscle groups of the upper and lower extremities was made clinically upon awakening with the mrc scale, ranging from to (normal strength) for each group. the same scale was also employed in the diagnosis of cipnm (mrc \ / ). a subgroup of these patients also performed handgrip dynamometry. results. fifty seven patients (ems: , control: ) were finally evaluated. ems patients scored higher than controls (p b . ) in wrist flexion, knee extension, ankle dorsiflexion and right side hip extension, while they tended to perform higher in all other muscle groups (p: . - . ) ( table ) . grant acknowledgment. this project has been co-financed by e.u. and the greek ministry of development. background. secretion removal is major aim of respiratory physiotherapy in intensive care. manual hyperinflation provides a tidal volume to the lungs that is greater than baseline. it is effective in secretion clearance and is frequently used [ , ] . there is a limited evidence that addressed the effects of combining rib-cage compression and suctioning on oxygenation, ventilation, and airway-secretion removal in mechanically ventilated patients [ ] . objectives. the aim of this study was to investigate the effects of manual hyperinflation administered in combination with expiratory rib-cage compression on lung compliance, gas exchange, and secretion clearance in mechanically ventilated patients. methods. twenty-two intubated, mechanically ventilated, and hemodynamically stable patients were studied. the patients received manual hyperinflation, with or without expiratory rib-cage compression, with a minimum -h interval between the two interventions. manual hyperinflation with or without expiratory rib-cage compression was performed for min before endotracheal suctioning. respiratory mechanics and hemodynamic variables were measured min before (baseline) and then and min after the interventions. arterial blood gases were determined min before (baseline) and min after the interventions. secretion clearance was measured as sputum weight. the two measurements were obtained on the same day. results. no significant differences were observed in gas exchange and secretion clearance between the two interventions (p [ . ). in each case, static lung compliance and tidal volume improved significantly at min post-intervention (p \ . ), whereas at min postintervention, only static lung compliance had improved significantly above baseline (p \ . ). our results suggest that the addition of expiratory rib-cage compression to manual hyperinflation does not improve lung compliance, gas exchange, or secretion clearance in mechanically ventilated critically ill patients. recently, there has been an interest in mobilization of acutely ill patients who are in an intensive care unit (icu). in the literature, the major safety issues while mobilizing critically ill patients has been outlined. cardiac reserve [(cr) (% of age predicted maximal heart rate)] and respiratory reserve [(rr), ratio of partial pressure of oxygen in arterial blood to the inspired fraction of oxygen (pao /fio )] are the important factors that can affect the ability to tolerate the mobilization. patient who has rr more than and cr lower than % is considered to have sufficient reserve to tolerate mobilization [ , ] . objectives. the aim of this study was to compare the effects of mobilization on respiratory and hemodynamic parameters in patients with sufficient and insufficient respiratory and/or cardiac reserve. mobilization events are divided into two groups (sufficient, insufficient) according to the pre-mobilization cr (sufficient, \ %; unsufficient, [ %) and rr (sufficient, [ ; insufficient, \ ). heart rate (hr), systolic/diastolic/mean arterial blood pressure (sbp, dbp, mabp), respiratory rate (rsr) and percutaneous oxygen saturation (spo ) were recorded from the monitor. respiratory and hemodynamic parameters were collected just prior to the mobilization, just after the completion of the mobilization when the patient had been returned the supine position and min of the recovery period and compared between the groups. a total of abdominal surgery patients ( male, female) received mobilization treatments in icu. the mean age was . years, mean body mass index (bmi) was . kg/m , mean apache ii score was . and mean icu stay was . days. mobilization events included ( %) sitting on the edge of the bed, ( %) standing, ( %) walking to chair and sitting in the chair. % ( ) of mobilization events had insufficient rr and % ( ) of mobilization events had sufficient rr. . % ( ) of mobilization events had insufficient cr and . % ( ) of mobilization events had sufficient cr. all respiratory and hemodynamic parameters were found similar in sufficient rr and insufficient rr group at all stages of the mobilizations (p [ . ). spo was higher, while hr and rsr was lower at all stages in sufficient cr group compared to insufficient cr group (p \ . ). resting hr and cr may affect the safety of mobilization, for this reason it is important to consider respiratory and hemodynamic parameters prior to and while mobilizing the icu patients. introduction. obesity is a chronic disease and a major health problem. obesity in critically ill patients is associated with a prolonged duration of mechanical ventilation and intensive care unit (icu) length of stay [ ] . objectives. the aim of this study was to investigate the effects of mobilization on respiratory and hemodynamic parameters in the critically ill obese patients. [ . kg/m )] were included as soon as their cardiorespiratory stability allowed mobilization protocol. mobilization was defined as sitting in the bed, sitting on the edge of the bed, standing, walking to chair and sitting in the chair. heart rate (hr), systolic/diastolic/mean arterial blood pressure (sbp/dbp/mabp), respiratory rate (rr) and percutaneous oxygen saturation (spo ) were recorded from the monitor. respiratory and hemodynamic parameters were collected just prior to the mobilization (supine position), just after the completion of the mobilization when the patient had been returned the supine position and min of the recovery period. all parameters were compared with initial values. the ratio of partial pressure of oxygen in arterial blood to the inspired fraction of oxygen (pao /fio ) was calculated from the arterial blood gas samples before and after the mobilization. introduction. the use of respiratory therapy for patients with a variety of lung disease is a standard in medical care [ ] , including in the intensive care unit (icu) setting [ ] . in this context, it is widely accepted the routine use of physical therapy in several situations in the intensive care, such as the care of critically ill patients not requiring ventilatory support, assistance during the postoperative recovery and the assistance to critically ill patients requiring ventilatory support [ ] . at present definitive recommendations cannot be made regarding the use of respiratory physiotherapy for decreasing relevant clinical outcomes in critical ill patients requiring mechanical ventilation. objectives. this study aimed to determine the impact of providing chest physiotherapy on the duration of mechanical ventilation, intensive care length of stay, intensive care and hospital mortality in mechanically ventilated patients. single-centre, randomized, controlled trial in a university hospital general intensive care unit (icu). were included in the study patients aged more than years, admitted to the icu needing mechanical ventilation for longer than h. physiotherapists provide group intervention (p) with the intensity and frequency of therapy they felt appropriate based on their assessment of the likely treatment benefit. control patients (group c) only received suctioning, decubitus care and general mobilization. results. primary outcomes were icu and hospital mortality regardless of the cause of death. secondary outcomes were length of icu and hospital stay, length of mechanical ventilation, weaning and extubation failure. patients in the p group more frequently achieved parameters to start weaning, but there were no significant differences between p and c groups on weaning and extubation failure, length of mechanical ventilation and length of icu stay. there was fewer hospital, but not icu, mortality in the p group. conclusions. we demonstrated that respiratory physiotherapy decrease hospital mortality and suggest that this effect was, in part, secondary to the effect of the intervention on weaning from mechanical ventilation. introduction. critical illness can cause diverse cerebral dysfunctions ranging from unconsciousness to minor cognitive impairments (mci). severe cerebral dysfunction, as delirium, is known to affect outcome after critical illness but it is uncertain whether minor impairments affect mortality or morbidity [ ] . objectives. the primary aim of this study was to estimate the incidence of mci in a group of general icu survivors immediately after icu stay and three and months after discharge. secondary we wanted to explore if type of cerebral dysfunction after icu discharge affected mortality and morbidity. methods. patients admitted to our general icu were included prospectively. we included patients. / ( %) were delerious and / ( %) were not delerious but had mmse \ after icu stay. of the patients with mmse c , were possible to classify as having mci or not. / ( %, % ci: - %) were found to have a mci after icu discharge. on and months these numbers were respectively: % ( % ci: - %) and % ( % ci: - to %) there was an increased risk of both death and being institutionalised at both and months regarding delirious patients and patients with mmse \ compared to patients with mmse [ . no such differences were found regarding patients with or without mci. (tables and ) . conclusions. the incidence of mci after critical illness is high on discharge but drops on and months after. severe cognitive impairments affect mortality and morbidity, but minor cognitive impairments do not. objectives. this study analyzes mid-term survival and risk factors associated with survival of patients undergoing cardiac surgery in son dureta hospital. methods. patients were consecutively operated from november to december . patients who were discharged alive from hospital were followed until december . we did kaplan-meier survival analysis and logistic regression study of variables associated with mid term mortality. results. in-hospital mortality was . % ( % ci: . - . %). information was available on , ( %) of , patients who survived until hospital discharge. at the end of the follow-up period, observed mortality was . % (ci %: . - . %). survival probability at , and years of follow-up was , and %, respectively. the mean time of follow-up was . years (range . - . ). patients c years showed a lower survival rate than patients \ years of age (log rank \ . ). age c years, history of severe ventricular dysfunction (ef \ %), diabetes mellitus, preoperative anemia and hospital stay were independently associated with mid-term mortality. conclusions. mid-term survival of patients alive after hospital discharge was very satisfactory. mid-term mortality varied according to age and several preoperative chronic diseases. a closed-ended questionnaire was developed by the nurse congress commission of the société de réanimation de langue française (srlf). an invitation to complete it online was sent by email to caregivers registered on the srlf push-list. results were analyzed by icu or by respondent. results. caregivers working in icus completed the questionnaire ( % were nurses, % were doctors, % were nurse's aides, % worked in adult icus and % in pediatric icus). % of adult icus (n = ) had unrestricted policy but % had a visiting time of less than h per day. at the opposite, % of pediatric icus (n = ) had unrestricted policies. % of the respondents working in icus with a visiting time \ h per day considered very useful or essential to enlarge visiting periods but % of them considered this enlargement as unhelpful. at the opposite, % of the respondents working in icus with unrestricted policy found very useful or essential to reduce visiting periods. % of caregivers working in icus with unrestricted policy but only % of caregivers working in other icus thought that an unrestricted policy was able to improve often or systematically the relations with families. moreover, only % of caregivers working in icus with unrestricted policy but % of caregivers working in other icus thought that an unrestricted policy disturbs the organization of care. % of respondents found very useful or essential to give information in a dedicated room whereas it was often or systematically done in only % of icus. identically, % of respondents found very useful or essential to give information to proxies with the patient's nurse whereas it was often or systematically done in only % of icus. some cares were often or systematically programmed for family participation in % of pediatric icus but in only . % of adult icus. indeed, proxies often or systematically participated in nursing in % of pediatric icus but never in adult icus. at the opposite, proxies often or systematically participated in tracheal aspirations in only % of pediatric icus and in . % of adult icus. conclusions. more than half of respondent's adult icus are closed but caregivers working in icus with unrestricted policy perceive it favorably. some improvements are also expected by caregivers on the use of dedicated rooms for information and on the participation of nurses in meetings with families. finally, participation of families to care is not a practice of french adult icu caregivers. methods. included: patients with dysfunction of two or more organs in the first h, admitted and discharged from icu during . excluded: neurocritical and politrauma patients. contact year following discharge; questions were asked concerning symptoms related to a period in intensive care that presented following discharge and which were not present prior to admission. in the case that the patient was not contacted, the next of kin was asked. results. patients included. general characteristics during admission to icu: % male; age . ± . years; sofa* ± . ; apache** ii . ± . ; apache** iv ± . ; length of stay in icu: . ± . days; . % were on invasive mechanical ventilation and . % on non-invasive mechanical ventilation. data collection was carried out over ± . months, on average months (range: - months). . % ( patients) had died at the time of contact. the person contacted was the patient in . % of the cases, the spouse in . % and immediate family (patient's parent/child/sibling) in . % of the cases. . % had difficulty sleeping following discharge from icu with an average time since discharge of . ± . months; . % suffered feelings of sadness and difficulty in finding enjoyment which had persisted for . ± . months; . % had experienced difficulty in concentrating over an average of . ± . months; . % had suffered some form of memory loss after discharge over an average period of . ± . months; . % presented with asthenia over an average of . ± . months; . % had arthromyalgia over a period of . ± . months; . % had experienced changes in appetite over an average of . ± months; . % had changes in intestinal habit over an average of . ± months; of which . % had diarrhoea, . % constipation, and . % both symptoms; . % presented with headache over a period of . ± . months; . % had tremors, that had not previously been present, over an average of ± . months; . % had experienced reduced vision, over an average period of . ± . months; . % presented with speech/ language problems, over an average period of . ± . months; . % exhibited newly presenting changes in micturition, over ± . months. another less frequently occurring symptom was loss of hearing ( . %). conclusions. severely ill patients that are admitted to icu frequently present with ''residual'' symptomatology following discharge, most notably arthromyalgia and asthenia. many of these conditions persist for months. intensive care unit (icu) readmission rates range from to %, in spite of initial recovery from critical illness. previous researches report that the revised acute physiology and chronic healthy evaluation (apache ii) score at either admission or discharge is an important predictor for readmission after icu discharge. however, there are a few papers concerning the association of discharge apache ii score with readmission after discharge from surgical intensive care unit. objective. we compared the ability of the discharge apache ii score with that of the admission apache ii score in predicting readmission, especially early readmission within h, after discharge from icu. conclusion. this study showed that both discharge apache ii score and admission apache ii score are useful predictors for readmission after icu discharge, but discharge apache ii score is only independent factor in predicting early readmission within h after icu discharge. introduction. health related quality of life (hrqol) is decreased in former icu patients. in research outside the intensive care field it is well known that the psychosocial factors, coping strategies and perceived hopelessness affect hrqol. however, the influence of coping and hopelessness on hrqol after intensive care is unknown. objective. the aim of this study was to examine how coping strategies and perceived hopelessness among former icu patients compares to corresponding in a reference group. we also evaluated the effect of coping and hopelessness and icu related factors on hrqol. methods. prospective, multicenter study in three mixed icu's in sweden. patient demographics, length of stay, apache ii score, reason for admission and time on ventilator were collected for all adult patients. questionnaires, including the coping instrument pearling-schooler mastery scale (pms), the -item hopelessness scale, sf- , demographic data and previous illnesses were sent months after discharge from hospital to the patients. the reference group (n = , ) was a random selection of persons from the same catchment area as the study patients. . ( %) icu-patients, - years, returned the questionnaires. the patients reported significantly lower mean scores in coping . (sd . , p \ . ) and higher perceived hopelessness . conclusions. this study indicates that coping strategies and perceived hopelessness are important for the hrqol of previous icu patients. however, the magnitude of these effects are smaller than that of pre-existing diseases. introduction. mortality on a medical intensive care unit (icu) is estimated to occur in about % of patients. its association with age, severity of illness and comorbidities is well established. for other diseases like coronary artery disease it has been shown that pre-existing depression is a risk factor for worse outcome. the role of depression regarding the outcome of icu patients has not been investigated so far. we studied the association between pre-existing depression and mortality in medical icu patients and present preliminary data of this ongoing study. objectives. assessment of a possible association between mortality of icu patients and prevalent depressive mood at time of icu admission. the primary endpoint was -day mortality. methods. prospective cohort study. all patients admitted to a medical -bed icu in a university hospital, older than years, were eligible. postoperative patients and patients who had an expected length of stay below h (survey) were excluded. patients whose cognitive function allowed appropriate comprehension and response answered the hospital anxiety and depression scale (had). prevalent depressive mood at admission was defined by a score c in the depression dimension. all other patients were assessed by observer rating by next-ofkin. in this case the hammond scale, a validated instrument for observer rating of depressive mood (cut-off c ), and a modified version of the had for observer rating (cut-off c ) were used. in addition apache ii, saps ii, sofa, age, sex, comorbidities, reason for admission, length of icu stay and ventilator days were recorded. . by now patients had complete follow up data. of these patients ( %) were classified to have depressive mood at icu admission. in total patients had died by day ( %). the -day mortality was % ( / ) in patients with depressive mood and % ( / ) in patients without (p = . ). patients with and without depressive mood did not differ with respect to age, sex, apache ii, saps ii or sofa score at admission. multiple logistic regression analysis with -day mortality as the dependent variable revealed that prevalent depressive mood at the time of icu admission was an independent risk factor for mortality (table ) . conclusions. pre-existing depressive mood is an independent risk factor for mortality in medical icu patients. introduction. some classical post-icu discharge predictors of death are described, such as age, severity of disease and level of nursing care [ ] . besides these factors, some laboratorial data at icu discharge are potential predictors of post-icu death. objectives. the aim of this study was to investigate whether standard base excess (sbe), ph, lactate, hemoglobin level, creatinine, platelets, leukocytes and albumin at the icu discharge as well as the % decrease on c-reactive protein concentrations (crp [ %) from the day pre-icu discharge to the day of icu discharge may be useful predictors of in-hospital outcome. patients discharged from the icu after at least h of stay were retrieved from our prospective collected data base. a multivariate analysis was performed using a backward-lr binary logistic model taking in-hospital death as a dependent variable and the cited data as independent variables. results. patients were retrieved. the average age was ± years old, mean apache ii score was ± , and the main causes of admission were septic syndromes and respiratory failure. the in-hospital mortality after icu discharge was %. the icu length of stay was ± days. at the time of icu discharge ph was . ± . , sbe was - . ± . mmol/l, lactate was . ± . mmol/l, hemoglobin . ± . , creatinine was . ± . g/dl, albumin was . ± . g/dl, platelets was , ± , /mm , leukocytes was , ± , cells/mm and the number of patients who lowered crp at least % were ( % conclusions. this study demonstrated that sbe, lactate, hemoglobin and albumin concentrations on the day of icu discharge are independent predictors of in-hospital mortality. moreover, the reduction on crp levels above % in the last h of icu stay is a strong predictor of better in-hospital clinical outcome. we suggest that these variables together with the clinical judgment may be taken into account on the icu discharge decision process. readmissions to the intensive care unit (icu) are usually associated with increased morbidity and mortality, and they may evidence the quality of patients' care. the risk for icu readmission varies across studies, and is generally analyzed just before icu discharge, leading to deviation of icu team and patients' daily goals. early prediction may improve the care for patients in risk for icu readmission, and help developing mechanisms for its prevention. objectives. to analyse risk factors for readmission in intensive care unit looking at the first h data after unit admission. methods. the first intensive care unit admission of patients was analyzed from january to december in a medical-surgical unit. readmission to the unit was considered those during the same hospital stay or within months after intensive care unit discharge. deaths during the first admission were excluded. demographic data, acute illness and comorbidity prognostic scores, and use of mechanical ventilation were submitted to uni and multivariate analysis for readmission. numeric variables were expressed as median or percentage. conclusions. age, medical admission, sofa score and respiratory-and/or sepsisrelated admission are early associated with increased icu readmission risk. objectives. the aim of this study was to examine patient perceived hrqol in former icu patients that die in the period from month up to years after discharge from intensive care unit and the hospital. methods. prospective, multicenter study in three mixed icu's in sweden. questionnaires, including hrqol (sf- ), demographic data and previous illnesses, were sent out six, , and months after discharge to all former adult icu patients. data for this study were only collected among those dying before the months post-icu follow-up. of the patients who returned the questionnaires ( . %) died, ( . %) between and months, ( . %) between and months, and ( . %) between and months. the most frequent admission diagnoses were respiratory problems n = ( . %) and gastrointestinal diseases n = ( . %). examining hrqol in the former icu patients the following observations were made: (see fig. ). a pronounced and quantitatively large decrease in hrqol is seen for the surviving patients with pre-existing disease as compare to the previously healthy survivors. although already at a very low value further decreases in hrqol for the patients dying before years post icu is significantly less as compared to the icu patients with pre-existing disease that survives. the decrease is mainly in physical function, role physical function and role emotional function (marked in the figure). conclusions. yes, health related quality of life is extensively affected, mainly in the dimensions physical function, role physical function and role emotional function. importantly, in these two affected physical dimensions a shorter time to death increases such a decrease. the finding further stresses the importance of pre-existing diseases for the final hrqol outcome of former icu patients. introduction. despite initial recovery from critical illness requiring icu admission, many patients remain at risk of subsequent deterioration and death [ ] . recent studies have shown readmission rates ranging between and % [ ] ; this population had mortality rates six times higher and were eleven times more likely to die in hospital [ ] . . to calculate the readmission rate in our mixed icu unit over a months period . to identify risk factors associated with readmission into the icu . to study the outcomes of these readmissions methods. a retrospective observational study, data was collected from an icu computer database (metavision) and analysed manually results. the total number of admissions in this period was , average patient age was ± with . % being males. readmissions constituted . % of the total admissions with . % of those readmitted within h of their initial discharge. % of the initial discharges from the unit were made out of hours i.e. unplanned, presumably due to heavy demand on beds. readmissions were particularly associated with patients discharged to surgical wards . % and the hepatobiliary hdu . %, the latter might reflect the proportion of that particular patients population received. . % of the readmissions required to stay h or less in icu. the overall mortality of the patients requiring more than one admission in this months period was . %. there is an urgent need for expanding icu services in our hospital, i.e. extra beds, staff, outreach teams, etc in addition to investing in nursing capacity building especially in surgical wards. we agree with others studies that compared with the general population, icu survivors report lower hrqol. moreover, a relationship between several factors like sepsis, renal failure, sofa (first and second day score), critical illness polyneuropathy, mechanical ventilation, sedation time, previous psychiatric history and blood products transfusions were found in our study population. conclusions. according to our data, subclavian vein was the most common insertion site used, especially as nd and rd placement and was related with the lower incidence of becteremia episodes. although the risk of placing a cvc for inflection complications is against the risk for mechanical complications, we have to improve our cvc policy, preferring the subclavian or the jugular site of insertion, in order to minimize the infection risk for a nontunneled cvc. objectives. objectives for this study were to determinate the frequency and the risk factors associated with bos. secondarily, we searched several variables as civil status, age, sex, work seniority as potential risk factors. inclusion criteria were to work in critical care unit (ccu) the hospital clínico universidad de chile (hcuch). this unit included subunits: intensive care unit (icu), middle care unit (mcu). the mbi Ò instrument was applied between april to july of . all staff of ccu were asked to response the instrument. as previously reported, bos was defined with high ee, high dp and low pa. risk of bos was anything of the three dimensions positive for bos. we gave information on specifics objectives and the schedule of a future intervention programme. for analysis, comparisons were made based on student t test, chi-square test with yates corrections or fisher exact test as corresponded. for all tests we used confidence interval % with p \ . . a total of mbi Ò tests that included all sub-units in ccu. this is a % of all personal working in the ccu. bos was found in . % of cases. women ( %), unmarried ( %), with an average of age . years old. ( - years old) and with a work seniority younger than years ( %). ee is high ( . %), for nurse and paramedical personals. dp was . and . % to middle level, for nurse and medical doctor, and low pa in % for paramedical personal, with longer work seniority (more than years). risk factors were female gender, unmarried status, childless, middle aged ( - years old) and recent start in the job (stay younger than years). introduction. burnout is a prolonged response to chronic emotional and interpersonal stressors on the job, and is defined by three dimensions: exhaustion, cynism (depersonalization), and inefficacy. icu physicians are exposed to several stress factors and are particularly predisposed to this syndrome. to describe the prevalence of burnout syndrome among intensivists and its relation to their quality of life. methods. an epidemiological cross-sectional survey conducted to evaluate all adult icu physicians in salvador, ba (brazil), from october to december . the quality of life and burnout syndrome were evaluated respectively by the whoqol-bref instrument and the maslach burnout inventory (mbi). burnout was classified into low, moderate and high levels for the three studied dimensions, according the mbi classification, and it was defined by the presence of a high level in at least one dimension. the quality of life was evaluated in four domains: physical, psychological, social relationships and environment, graduated from to , with higher scores denoting higher quality-of-life. [ ] ) has been successfully used to measure nursing workload on an intensive care unit over a -h period. in contrast to intensive care, the nursing care workload on mc is not evenly spread over a twenty four period, but tends to vary between shifts. objectives. the aims of this pilot study were ( ) to assess the fitness of nas as an accurate reflection of nursing workload on an mc unit. ( ) to determine the nursing work load, per patient, per h shift. prior to the commencement of the study all thirty one nurses taking part received instruction in the content and registration of nas. at the end of each h shift, each nurse retrospectively scored their patient(s) using nas. this consists of a check list containing twenty three items giving a possible score between and , where equates to . full time equivalent (fte) intensive care nurse. the nas were entered in to a database and the average scores, per patient, per shift were calculated. three hundred patients were retrospectively scored over a -month period in october and november . not all patients were scored on all three shifts as some patients had been transferred out of the unit before shift end. in addition any incorrectly completed forms were discarded and excluded from the study. methods. this multicenter pilot study included doctors working at (pediatric) intensive care units (icu). subjects were randomly assigned to two groups: one was first tested during day, then during night, while the other was tested in reverse order. the d test of attention [ ] was used to assess attentional performance. total performance (tn-f) score, standardized for age and level of education, was used to express attentional performance. subjective, -to- scores were gathered in two questionnaires. results. figure displays standardized total performance scores of doctors. measured attentional performance showed high intra-and interpersonal variability and did not differ between both shifts (p [ . ). in contrast, doctors expected alertness to be decreased ( . ± . and . ± . (mean ± sd) on subjective -to- scale during day and night shifts, respectively; p \ . ) and the chance of making errors to increase (from . ± . to . ± . (mean ± sd); p \ . ) during night shifts. conclusions. physicians working at icu are aware of the risk of making errors during night shifts. however, we showed that doctors perform equally during night and daytime when confronted with a short-time challenging task. consequently, a discrepancy between measured attentional performance and expected alertness was observed. these results suggest nocturnal alertness might be comparable to daytime during short-lasting tasks that elicit a high level of stress and motivation (e.g. testing, medical emergency). further research is needed to elucidate if longlasting (routine) tasks reflect decreased sustained attention and contribute to medical errors. we studied physicians, the majority of whom were male ( %). mean age and time since graduation were . and years, respectively. high levels of emotional exhaustion, depersonalization, and reduced personal accomplishment were found in . , . , and . %, respectively. prevalence of burnout syndrome, defined as a high score in at least one dimension, was . %, while prevalence was . % for all three dimensions. in conclusion, burnout syndrome was common in this sample of icu physicians. aims. our goal was to assess the physician's opinion about potential competencies of a triage nurse. a representative cross sectional study design was applied with self-fill-in questionnaire about physician's attitude related to skills of triage nurses. the questionnaires were distributed between september and november in (out of ) eds. in this survey physicians' questionnaires were processed. chi-square and student-t test was used for comparison of variables. p values less than . were considered statistically significant. results. . % of physician would support the special training of triage nurse. . % of physician suggests that the nurses use the patient's physical examination regularly in eds. the full time (ft) emergency physician significantly would reduce the basic competencies of nursing (e.g. dressing, feeding of patient, p = . , and p \ . , respectively) than parttime (pt) emergency physicians. significantly greater part of the ft physician would widen the competency of triage nurses in the field of physical examination of nervous system (p \ . ) and cardiovascular system (p = . ) than the pt physician. conclusion. hungarian emergency physician would widen the competency of triage nurse, but only half of physician would like to that nurses apply physical patient examination in practice. the full time physician would give more competencies for triage nurse than part time ones, but the final field of competency will be depended on other factors. healthcare-associated infections (hcai) are estimated to affect . million people worldwide, causing longer hospital stay, increasing hospital costs and excess mortality [ ] . hand hygiene represents the single most effective way to prevent healthcareassociated infections. compliance with hand hygiene amongst healthcare workers (hcw) has been demonstrated to be quite low at % [ ] . to quantify the degree of compliance to hand hygiene norms in the icu and to assess the short term success of strategies to improve hand hygiene compliance. setting. bedded medical-surgical icu in a tertiary care centre. design. prospective observational. method. unobtrusive observer (single person). observed over sessions of h. the compliance was calculated as :number of times the staff performed hand hygiene/number of hand hygiene opportunities. the number of hand hygiene opportunities was based on the who tools [ ] : before touching a patient, before clean/aseptic procedures, after body fluid exposure risk, after touching a patient and after touching patient surroundings. introduction. icu delirium represents a form of brain dysfunction that in many cohorts has been diagnosed in - % of patients receiving mechanical ventilation. delirium is a common but complex clinical syndrome characterized by disturbed consciousness, cognitive function or perception, which has an acute onset and fluctuating course and is associated with poor outcomes. and yet, it can be diagnosed and treated. in the uk, reporting of delirium is generally considered to be poor. in light of updated nice guidelines on delirium due out this year, specialist clinical assessment will soon become gold standard as a means of diagnosing and reducing the prevalence of this condition in the icu setting. nice recommends that cam-icu (confusion assessment method) be used by healthcare professionals who are trained and competent in the diagnosis of delirium. on our -bed unit, we are currently implementing cam-icu assessments to be performed twice daily (at the commencement of each nursing shift) as well as rass (richmond agitation and sedation scale) scoring on an hourly basis for all patients. objectives. to implement training of all our icu nursing staff in the use of cam-icu and rass scoring. to periodically validate and reinforce earlier training, so as to improve assessment and reporting of delirium. methods. our 'delirium group' comprising both nursing and medical staff, taught cam-icu and rass to staff members using multimedia presentations in small groups and/or individual teaching sessions over weeks. scoringofcam-icu andrasswassubsequentlyauditedon occasions post training. discrepancies were discussed and post-audit retraining provided where necessary. results. the following audit and validation data were generated on our unit as documented in table . no statistical analysis was undertaken. we anticipate focusing on the challenges encountered and strategies used in managing this change in our icu practice. methods. the factors causing resistance to change based on multisource data. qualitative technical methods were used: brainstorming and focal groups. the data collection elaboration was created by the collaboration of icu nurse, quality department nurse and external reviewers. finally, the main factors were classified in different categories. each category was scored by to according to gravity and prevention possibility. finally, priority was given to more serious and easier prevention problems. results. the most serious problems for icu professional was the historical factors. the easier solution problems were ''the lack of information'' and all evaluators were agree with it. we arranged the factors in order to the next classification (tables and ). discussion. all investigators were agreed with the low importance of problems with payments and low prevention probability of low organisational flexibility, so they were agreed on not to work about them. the icu professionals were more pessimistic and have lower confidence in prevention possibilities but they showed more confidence about the capacity to learn new skills. they weren't worried about resistance to do experimental things. probably, historic factors play an important role in this pessimistic attitude. on the other side, quality and safety experts have more experience in prevention programs and they put all their trust in its. after doing the analysis, we chose the ''lack of information problem'' to plan prevention activities. we consider it is a serious and real problem but at the same time, easy of prevent. conclusions. the implementation of the patient safety program in the icu means a real cultural change. the priority analysis could help to plan strategies in order to avoid the program failure. objectives. we concerned about whether medical personnel could recognize management of the cuff of artificial airway or not. we asked to doctors and nurses working in intensive care unit of konyang university hospital, daejeon, republic of korea. we asked questions with contents of questionnaire that was composed of methods of set initially, maintenance and appropriate pressure of cuff. results. of medical personnel replied to us. most of them had worked in intensive care unit, so they had placed of artificial airway. . % of them used manometer to adjust the cuff. we could find that nurses had more cognition compared to doctors for it ( vs. %). only . % of doctors described pressure of the cuff in medical record. of medical personnel replied that they knew the appropriate range of cuff pressure. % ( / ) of them replied that the range of cuff pressure was kept with - mmhg and % ( / ) was - mmhg. % of nurses in the icu knew that range of cuff pressure was - mmhg. most of them knew complications of high and low pressure of the cuff. . % of medical personnel monitored the cuff balloon during receiving mechanical ventilation and they used manometer to adjust it. % of nurses knew that the cuff should be adjusted continuously, but % of doctors did. interval measuring the cuff pressure was % of once a day, % of three times a day, % of more than four times a day conclusions. most of the medical personnel knew to keep appropriate cuff balloon to prevent various complications of artificial airway. they had insufficient cognition about maintaining the cuff balloon and appropriate level of cuff pressure. that was more prominent in doctors than nurses interhospital transfer is occasionally required as a consequence of limited therapeutic options or because of a need for a higher intensity of medical care that cannot be given in rural intensive care units. along with the potential benefit for the to be transferred patient, transport may also lead to hemodynamic and pulmonary deterioration. in order to minimize additional risk of interhospital transport of critically ill patients, a mobile intensive care unit with a specialized retrieval team was established in our university hospital-based intensive care unit. from march , transport of the critically ill patients in our adherence region are performed by micu. objectives. in this prospective audit adverse events and patient stability during micu transfers were assessed and compared to our previous data on transfers performed by standard ambulance [ ] . results. interhospital transfers over a -month period were evaluated. systolic blood pressure, glucose and haemoglobin were significantly different at arrival compared to departure, although never significant values for major deterioration were reached. an increase of total number of variables beyond threshold at arrival was found in % of patients, percent exhibited a decrease of one or more variables beyond threshold and thirty percent showed an equal number of trespassed thresholds. there was no correlation between the patients status at arrival and the duration of transfer or severity of disease. icu mortality was %. compared to standard ambulance transfers of icu patients performed in , there were far less adverse events: . vs. %, which in the current study were merely caused by technical (and not medical) problems. although mean apache ii score was significantly higher, patients transferred by micu showed less deterioration in pulmonary parameters during transfer than patients transferred by standard ambulance. conclusion. transfer by micu imposes less risk to critically ill patients compared to transfer performed by standard ambulance and has therefore resulted in an improvement of quality of interhospital transport of icu patients. introduction. previous studies in adult intensive care units (icus) reported rates of pre-mortem to post-mortem discrepancies ranging between and % depending on the population studied. and, most of them were retrospective studies, which included small number of patients. to compare clinical and pathological diagnoses and to determine the types of errors in a large and multidisciplinary icu-patient population. we conducted a prospective study of all consecutive autopsies performed on patients who died in the icu of the hospital universitario de getafe, madrid, spain, between january and december . the diagnostic errors were classified in two categories: class i errors that were major misdiagnoses with direct impact on therapy, and class ii diagnostic errors which comprised major unexpected findings that probably would not have changed therapy. conclusions. this study found significant discrepancies between clinical diagnoses before death and post-mortem findings. this reinforces the importance of the post-mortem examination in detecting otherwise unexpected diagnoses and improving the quality of care of critically ill patients. introduction. unplanned extubation is associated to a high risk of reintubation end correlates with increased risk of nosocomial pneumonia. on the other hand, reintubation significantly increases morbidity and mortality in critical ill patients, increasing the incidence of ventilator associated pneumonia (vap) rate and makes the airway management risky. objectives. the aim of our study was to test the rate of unplanned extubation as well as the reintubation rate in our icu, in order to evaluate the efficiency of our airway and weaning time protocols. methods. during a nearly year's period, patients admitted to the icu, mean age: . years, mean apache ii score: . , mean los: . days, with predicted and actual mortality: . and . % respectively. from these, were intubated and included retrospectively in our study. patients were extubated, while the others either underwent bedside percutaneous tracheostomy or died. we concerned that the number of days of mechanical ventilation were about equal to the number of days of intubation. reintubation was defined as the need to reintubate during the first h after extubation. we recorded four episodes of unplanned extubation. three of them caused by malfunction of the tube due to secretions and airway obstruction and one of them was undesired extubation caused by the patient himself. the total number of days of intubation was , , mean ± sd: . ± . , min: , max: days. therefore the rate of unplanned extubation was . %, while the standard limit is below %. the total number of reintubations was , while the total number of scheduled extubations was . therefore, the reintubation rate was . %, while the standard limit is below %. conclusions.the recorded rate of unplanned extubation was low in our icu patients, below the acceptable limit, assuming that our sedation and airway management policy is effective. on the other hand, the recorded rate of reintubation was high in our study, above the acceptable limit. although a low rate of reintubation might indicate excessively long mechanical ventilation times, this did not recorded to our study. nevertheless, our data suggest that we have to improve further our weaning time protocols, making the extubation procedure safer, and avoiding risk factors for vap. . pvs such as inappropriate enrollment of patients with a contraindication to the study treatment may lead to excess harm in the active intervention group [ ] and failure to deliver the study intervention according to the study protocol may underestimate true treatment efficacy [ ] . full reporting of pvs may aid in the interpretation of rct results however there are no published reviews on this topic [ ] . objectives. to determine reporting rates for key types of pvs and to investigate study characteristics that may be related to reporting. publications were excluded because they were subgroup or economic analyses of a previously published rct [ ] , not a rct [ ] , not published in the target journal [ ] , systematic reviews [ ] , or other reason [ ] . median trial size was participants (range: to , ). / ( %) of rcts were single centre, / ( %) were industry funded and / ( %) reported negative findings. overall / ( %) of rcts reported some form of pv, these included: / ( %) patient compliance; / ( %) discontinuation of study intervention due to safety; / ( %) study intervention-related researcher error; / ( %) inappropriate enrollment and; / ( %) technical errors in randomisation. multi-centre rcts may be more likely to report study intervention-related researcher errors ( % of multi-centre trials vs. % of single centre trials, p = . ). academic trials were less likely to report discontinuation of study intervention due to patient safety ( % of academic trials vs. % of industry trials, p = . ) and were less likely to report technical errors in randomization ( % of academic trials vs. % of industry trials, p = . ). conclusions. multi-centre trials are accepted to be organizationally complex. on-site education may be required to reduce errors in study intervention delivery attributable to the research team. it is possible the apparent excess harm attributable to industry trials is a reporting artifact however, if it is real, it must be addressed. additional research is required to investigate patient safety-related pvs and technical randomization errors, which may be lower in academic trials. to determine the occurrence of harmless incidents and ae related to physician's competences in icus, disclosing their potential risk factors. conclusions. this prospective study was essential to identify the proportion of our icu admissions affected by md-inc and md-ae, disclosing their nature. our md-ae rates, affecting more than % of admissions, were higher than those described in prior general studies, including not only icus. among the detected md-ae, hypoglycemic episodes not related to insulin administration predominated, indicating important deficiencies regarding nutritional support. severity on admission and length of stay were important risk factors for the occurrence of at least one md-ae. a systematic measurement and analysis of unintended events (ue) have been recommended for patient safety and improvement of quality of care in critically ill patients. however, a spontaneous reporting system may be inefficacious in intensive care unit (icu) because of a poor data collection, particularly by physicians staff. objectives. the aim of this study was to evaluate the reliability of a staff spontaneous event report by comparison with events collected by an external observer in a surgical intensive care unit (icu). to facilitate the reporting and the analysis, we identified a series of events with a serial number and a colour code related to their for each of the following macro-phases: icu bed booking, admission procedures, patient stay, discharge and emergency procedures. a specific structured form including ue's code and colour, date and hour of the event and type of patient has been prepared and proposed to staff -week for each month after a proper phase of education. the report was voluntary and anonymous and the data collected during the morning shift from september to december have been compared to those collected from an external observer. in the studied period, healthcare staff reported ues: % collected by nurses, % occurred during the morning shifts and % were classified as moderate or severe. the rate of ue in the morning shift was ues per patient days. the external observer identified events in morning shifts with an incidence of ues per patient days. the violation of isolation rules for patient with multi-drug resistant bacteria infection both by icu staff and surgical consultant was the ue observed more frequently by the staff ( %) and by the external observer ( %). conclusions. the above data indicated that: . in our icu the incidence of ue is very high, particularly for compliance to isolation of infected patients and . the spontaneous reporting system under-estimated largely the real incidence of ues. introduction. importance of renal assessing in intensive care unit (icu) patients is unquestionable for a correct drug dosing, fluid requirements or decisions for renal replacement therapies. serum creatinine (sc) is a very common biochemical parameter in clinical practice for assessment of renal function. many equations have been designed to estimate creatinine clearance based on sc, but their capacities for providing a correct estimate of glomerular filtration rate (gfr) are suboptimal. this is even worse in critically ill patients due to malnutrition and/or immobilization. in clinical practice, despite its limitations, h-urine creatinine clearance (crcl h ) is used as a reference method to determine gfr. data show that cystatin-c could be promising as an endogenous filtration marker in icu settings. objectives. to assess in a medical icu population whether the arnal-dade formula of cystatin-c clearance (cc) developed from serum cystatin-c (scc) shows better predictive performance of gfr than sc-based formulae, as regards to patients' renal function: crcl h c ml/min . m or crcl h \ ml/min . m . results. all formulae showed notable bias from the reference method. interestingly, all equations based on sc-values clearly overestimated crcl h (cg: . %; mdrd: . %; fv-mdrd: . %), whereas cc showed underestimation of these crcl h (cc: - . %). in the crcl h c ml/min . m group (n c = ; patients), cc showed the best correlation indexes (cc-crcl h ; r = . , r = . ), the second most biased (- . %) and the worst precision ( . %). in this group, mdrd was the least biased (- . %) and the most precise ( . %). in the crcl h \ ml/min . m group (n \ = ; patients), cc was the worst correlated with crcl h (r = . , r = . ), in contrast to mdrd (r = . , r = . ). in terms of precision, mdrd showed again better results than cc: . % vs. . %, respectively. conclusions. in our icu population, cc did not demonstrate a clear improvement on the remainder sc-based formulae in either of the two groups according to crcl h . however, in a patient with high mdrd values and suspicion of low gfr, cc could be useful as guidance before obtaining the definitive confirmation by crcl h . introduction. there are well established and robust techniques for measuring and categorizing renal function in people with chronic kidney disease (ckd). a number of rapid bedside estimates of renal function have been devised incorporating routine daily measurements, such as serum creatinine, in combination with demographic data (e.g. cockroft-gault, the mdrd series). the addition of serum cystatin c measurements to some equations may also improve accuracy of estimation. the current and accepted categorical classification of acute kidney injury (aki: akin/rifle) has been useful epidemiologically but does not provide a continuously variable measure of severity of aki which would be valuable for both clinical management and research. objectives. previously published abstracts have suggested a role for egfr in describing renal function in the critically ill but a more comprehensive analysis was needed. methods. ( male) (mean age range - ) critically ill patients with aki were recruited. a h creatinine clearance ( crcl) (previously validated as a measure of renal function in critically ill patients) was measured and simultaneous blood sampling was done for creatinine, urea, albumin and cystatin c. various equations used to estimate gfr were compared to crcl with regression and bland-altman analysis. all patients had a crcl of\ ml min per . m introduction. epithelial-mesenchymal transition (emt), a key process in tissue development and repair, has also been identified as a major mechanism in fibrogenesis. the cytokine tgfb has been shown to induce transformation of epithelial cells into matrixforming and smooth muscle actin (sma)-expressing myofibroblast (mf) via emt. the other prerequisite is an injury-induced loss of intercellular contact, including adherens junctions (ajs). the classical experimental method to induce aj disruption is the uncoupling of e-cadherin-mediated contacts by low calcium medium (lcm). this concept has been termed as the two-hit model of emt ( ). b-catenin, a scaffold protein of the aj, released by cell contact injury, can act as a transcription factor and has been shown to facilitate emt. however, the mechanism whereby cell contact injury promotes emt is not understood. our recent studies have shown that smad , one of the main signal transducers of the tgfb pathway is a strong inhibitor of epithelial sma expression, by interfering with myocardinrelated transcription factor (mrtf) [ ] . the latter is the main driver of the sma promoter, through it association with serum response factor (srf). intriguingly, b-catenin can bind to smad . to clarify the mechanisms whereby aj injury promotes sma expression. methods. ajs were manipulated in kidney tubular cells, either by sirna-mediated downregulation of e-cadherin, b-catenin or through chemical uncoupling of ajs by lcm. protein expression was detected by western blotting and immunofluorescence microscopy, proteinprotein interactions were monitored by co-immunoprecipitation, and the activity of the sma promoter was determined by luciferase reporter assays. knockdown of e-cadherin promoted b-catenin translocation to the nucleus and induced a threefold rise in the tgfb-triggered sma expression. conversely, silencing of b-catenin strongly suppressed the two-hit (tgfb + lcm)-induced activation of the sma promoter, and inhibited sma protein and mrna expression by %. the same stimuli induced strong association of b-catenin with smad . transfection of cells with a b-catenin expression vector dose-dependently prevented the inhibitory action of smad on the mrtfinduced activation of sma promoter. moreover the active (myogenic) mrtf-srf complex was restored, as b-catenin preempted smad 's inhibitory effect on the complex. these studies define a novel mechanism whereby epithelial injury activates the myogenic program, a central process in organ fibrosis. our results imply that b-catenin, liberated from the injured ajs, facilitates the activation of the myogenic program by preventing or mitigating the inhibitory action of smad on mrtf. these hitherto unknown interactions among smad , b-catenin and mrtf represent novel targets to lessen fibrogenesis. introduction. in intensive care unit (icu) patients, kidney function is monitored by the creatinine clearance (crcl). it can be measured by two methods. urinary crcl (ucrcl) is directly measured, using the urinary and serum creatinine. but commonly crcl is estimated from serum creatinine (scr) alone, as estimated glomerular filtration rate (egfr); using equations validated in chronic kidney diseases. there is paucity of literature on validation and comparison of these methods in icu (hoste) . objectives. we compared -h timed ucrcl and egfr in the newly admitted critically ill. we also sought to ascertain the incidence of high crcl and the agreement between methods in this subgroup. conclusion. the use of rifle criteria gives a high incidence of aki in the icu setting. in this unselected population of critically ill pts, cysc seems to be superior to cre in predicting pts who will develop aki and will need rrt during their hospitalization in the icu. early identification of high risk patients may allow potentially beneficial therapies to be initiated early in the disease process, before irreversible injury occurs. introduction. the contrast-induced nephropathy (cin) is consider to be the most frecuence reason of acute renal failure in hospitalized patients. they are defined by a fixed increase ( . mg/dl) o a % rise serum creatinine level after to be exposed h to the contrast. the main complications are kidney and cardiac problems and this will lead to longer hospitalization and increased mortality. objectives. to compare cin occurrence after a injecting a iso-osmolar contrast (ioc, idixanol) or a low-osmolar contrast (loc, iohexol) to a group of patients submitted to coronary angiography, with o without percutaneous coronary intervention (pci). to establish unrelated cin markers and to evaluate the efficiency of the kidney protection protocol used in our hospital. conclusions. the loc was associated to a greater number of cin than ioc. patients who developed cin were significantly longer hospitalized. the use of point giving system that includes cin's predictors like dm, hematocrit \ %, ami, and treatment with diuretics helps us to classify cin risk and use a correct kidney protection protocol. introduction. the incidence of acute renal failure in the intensive care unit (icu) is around % of cases and is related to increase in mortality in patients who required dialysis as far as %. early detection of acute kidney injury (aki), after damage is not on set could be crucial to develop therapeutic strategies to modify the course of injury. blood and urinary concentrations of ngal are early biomarkers of aki ; to date, little information exists regarding ngal usefulness in critically ill patients. objectives. to analyze: . the capacity of urine ngal (ungal) to predict akievaluated by rifle score-in critically ill patients and, . the ungal values in patients with sirs, sepsis or septic shock. methods. ngal was measured in urine sample by an automatic analyzer device (architect ci Ò ; abbott diagnostics) at admission and h later in patients admitted to a general icu. patients were classified both by rifle score at admission and and h later and by ungal concentrations at admission. to the later classification, the cut-point for aki prediction was obtained by roc curve analysis. ungal values at admission were compared in patients with sirs, severe sepsis or septic shock. clinicians were blinded to ngal results. the study included consecutively-admitted patients ( female) with mean age . ± . years, and length of icu stay of . ± days. fifty-four sirs, severe sepsis and septic shock. thirteen patients developed rifle f score, of them at icu admission; extracorporeal renal therapies were required in cases. when patients were classified according to their rifle score at h of admission, ungal values at admission were: ( - ) ng/ml in patients with rifle , ( - ) ng/ml in with rifle r, ( - ) ng/ml in with rifle i and ( - ) ng/ml in with rifle f (p = . ). five patients were excluded, three died before h with ungal ( - , ) ng/ml and two were discharged before h with ungal ( - ) ng/ml. the area under roc curve of ungal at admission for aki prediction was . ( % confidence interval . - . , p \ . ), with an optimal cutoff value of ng/ml with % sensitivity and % specificity. forty-seven patients have ungal b ng/ml. ungal concentrations at admission were ( - ) ng/ml in patients with sirs, ( - ) ng/ml in patients with severe sepsis and ( - ) ng/ml in patients with septic shock (p = . ). conclusions. urine ngal concentrations measured at icu admission appeared as a useful predictor of aki in critically ill patients; in addition, ungal concentrations showed an increasing pattern from sirs to severe sepsis and septic shock. rd esicm annual congress -barcelona, spain - - october s introduction. two previous studies using the rifle criteria in intensive care patients have found the incidence of acute kidney injury (aki) to be and %. however, these studies used calculated basal value of creatinine in a considerable proportion of their patients, which is a possible source of error. objectives. the aim of this study was to investigate the incidence and severity of acute kidney injury in intensive care patients using true baseline creatinine values. objectives. the aim of this study was to define the status of hcy and b vitamins at admission and days of icu stay in critically ill patients, and to evaluate its relationship between them. a prospective study was done on critically ill consecutive patients with inclusion criteria: c years old, sirs and apache ii [ . hcy, b and folic plasma levels were measured by enzymoimmunoassay and enzymatic method. for b , b and b in erythrocyte. permission was obtained from an institutional ethical committee and written informed consent was asked. results. at and days of icu stay and % of patients were b deficient, respectively. and % were b deficient on both times, respectively. folic levels show significant differences between and days of icu stay. we found association between b vitamin and hcy at admission and days. no differences were found between and days hcy values. introduction. cytochrome p a (cyp a), the most abundantly expressed cytochrome p enzymes in liver, are responsible for the metabolism of over % of drugs used across several therapeutic classes. in adults, cyp a is represented primarily by the major isoform, cyp a , and a polymorphically expressed isoform, cyp a . individuals with at least one wild-type cyp a * allele synthesise functionally active enzyme while homozygotes for the * allele are functional non-expressers of the enzyme. the presence of functional cyp a increases the hepatic metabolism of cyp a substrates such as tacrolimus. ckd is known to reduce the hepatic metabolism of drugs via the cyp a enzyme system and we have shown, recently, that aki has a similar effect and that the length of time with aki is the most important variable. we hypothesise that expression of functional cyp a may reduce the impact of aki on hepatic drug metabolism as has been shown to be the case for drug interactions with the imidazole antifungals. methods. ( male) (mean age range - ) critically ill patients with no aki and varying degrees of severity of aki were recruited. midazolam concentration was measured h after intravenous administration as a probe-drug for hepatic cyp a / enzyme activity (t [midazolam] ). this is a validated method for testing cyp a activity in critically ill patients. patients were excluded if they were on any known cyp a / inhibitors. results. two patients with severe aki had unexpectedly high t [midazolam] . figure demonstrates the following: without a cyp a * allele, the rate of midazolam metabolism increased with duration of aki (r = . ; p \ . ) (solid line). patients who had at least one * allele (dashed line) were protected from the inhibitory effect that aki has on hepatic drug metabolism (significant difference between the correlation lines p = . ). if the two major outliers are removed (dotted grey line) from the * /* group (r = . ; p \ . ), the correlation lines remain statistically different (p = . ). conclusions. the presence of an allele which codes for functional cyp a protects critically ill patients from the inhibitory effect of aki on the hepatic metabolism of midazolam. thyroxine replacement therapy has become commonplace in the management of organ donors to reverse hemodynamic instability and homeostasis, yet the pharmacokinetics of thyroxine are unknown in this patient population [ , ] . since t is only available in oral form, we studied the pharmacokinetics of oral versus intravenous t to determine if oral administration is suitable. objectives. ( ) to study the pharmacokinetics of oral versus iv t therapy; ( ) to determine if oral thryoxine therapy is suitable. with ethics approval and signed consent from the substitute decision maker, patients who were determined to be neurologically dead and consented for organ donation, were randomized to receive either an oral or intravenous dose of t ( mcg/kg). all patients received an oral and iv preparation; one of which was a placebo. this study was also double blinded and randomization occurred in blocks of - . free serum levels of t and t were measured hourly until the time of organ procurement. the area under the curves (auc) were determined and compared using. results. there were patients ( males) in the oral versus patients ( males) in the iv group, with an average age of ± vs. ± , respectively. there was no significant difference at baseline or h between groups for hemodynamic variables, free t , free t or tsh levels. the only exception was map where it was higher at baseline in the oral group and there was a significant increase at h in the iv but not the oral group ( - vs. - in the oral). the auc for t was greater for the iv group ( pmol/l/ h) compared to the oral group ( pmol/l/ h). there was no statistically significant difference in any of the levels from to h between the oral and iv groups. oral bioavailability of t was %. conclusions. administration of iv t resulted in a slightly greater auc compared to oral administration. however, oral bioavailability of t in our population was very high, at %. t is currently the recommended thyroid replacement in neurologically dead organ donors. however, intravenous t is unavailable in many jurisdictions. iv t has been used as a substitute. our study shows that in this select population, oral bioavailability is high suggesting that oral t may be a reasonable alternative. further work is needed to determine whether there was a difference in the number and rate of organ retrieval in the oral versus intravenous groups. introduction. specific characteristics of metabolic derangements occurring in critical illness is domination of developing catabolic state particularly in acute necrotizing pancreatitis. as a result, we faced such a problem as developing a clinically apparent protein-calorie deficiency which is resistant to standard nutritional support. the treatment of acute necrotizing pancreatitis in chronic abuse patients is difficult to handle for the clinician and should include sufficient energoplastic supply. objectives. in our research we aimed to assess the efficacy of adding of ornithineaspartate complex in carbohydrate metabolism in chronic abuse patients with acute necrotizing pancreatitis. methods. comparable chronic abuse patients with acute necrotizing pancreatitis (control group n = , mean age . ± . ; ornithine group n = , mean age . ± . ) received early parenteral nutrition from the moment of admission to hospital with universal system ''three-in-one''. ornithine group also received ornithine-aspartate complex by parenteral administration ( g/day). on the second day the patients were admitted parenteral nutrition and tube feeding h/day. the volume of parenteral nutrition was gradually decreasing. biochemical and metabolic endpoints were measured at baseline and on th day (nitrogen balance, amino acids spectrum, plasma whole protein, transferring concentrations, glucose and insulin levels) at the clinical laboratory in all patients metabolic disturbances with protein status and carbohydrate metabolism shifts were revealed. dynamic of the whole protein, albumin/protein ratio and nitrous balance in both group showed similar tendency of metabolic improvement. dynamic of essential and nonessential amino acids concentration remained normal showing adequate energoplastic supply in both groups. glutamine concentration in ornithine group remained stable and even increased by the th day of nutritional support, while in control group glutamine concentration was decreasing, and by the th day of nutritional support it was below normal values. in ornithine group higher levels of endogenous insulin at normal values of glucose and faster fisher index improvement were detected. conclusions. administration ornithine-aspartate complex in therapy of acute necrotizing pancreatitis in chronic abuse patients, probably, may influence on disease outcome. in ornithine group duration of delirium tremens causes was ± days versus control group ( ± days). restoration of metabolic activities confirms adequate nutritional support in both groups but ornithine-aspartate complex adding provides faster improvement of protein and carbohydrate metabolism. objectives. this study was designed to evaluate the nutrition indexes including serum prealbumin level as prognostic indicators of patient recovery in critically ill patients with comparing severity scoring systems. we selected patients over years old, supplied with total parenteral nutrition (tpn) for more than days in surgical intensive care unit, ajou university hospital, suwon, korea. the serum prealbumin, albumin levels and total lymphocyte count were measured at the first, rd, , , , th days of nutrition support care by tpn. we checked apache (acute physiology and chronic health evaluation) ii score, saps (simplified acute physiology score), mods (multiple organ dysfunction score) and sofa (sequential organ failure assessment) score of patients. results. there were male patients and female patients with mean age . years. the mean day of sicu staying was . days. we compared two groups; survivor group (n = ) and non-survivor group (n = ). there were significant statistical differences in icu staying days (p = . ), apache ii score (p \ . ), saps (p \ . ), mods (p = . ) and sofa score (p = . ) between two groups. however, serum prealbumin level (p = . ), albumin level (p = . ) and total lymphocyte level (p = . ) did not showed significant difference between two groups. receiver operating characteristic curve showed low accuracy of serum prealbumin level as a prognostic factor (area = . ). prealbumin level showed correlation with albumin (r = . ), however did not show correlation with apache ii (r = - . ), saps (r = - . ), sofa (r = - . ) and mods (r = - . ). conclusions. nutrition indexes including prealbumin did not correlated with clinical outcome of critically ill patients. introduction. physical function is impaired following critical illness [ ] . anaemia is a common complication of critical illness and has the potential to influence physical function [ ] . it is not known whether anaemia affects the physical components of quality of life, the ability to carry out the activities of daily living (aodl) or the actual physical function of patients during recovery from critical illness. to determine the physical quality of life, ability to perform activities of daily living and actual physical function in a cohort of icu survivors dichotomised on the presence of anaemia at months following icu discharge. one other organ failure were recruited from a general icu population. patients with a preexisting haematological condition were excluded. baseline and characteristics of icu stay were recorded. the patients were assessed with the sf- quality of life questionnaire (pcs), the frenchay activities index (fai) of aodl recalled for pre-morbid status and at and months, and the min walk test ( mwt) for actual physical function at and months following discharge from icu. organotopic measures of haemaglobin, creatinine, serum c-reactive protein and albumin concentration were also recorded. the results were dichotomised on the presence of anaemia at months for statistical analysis. baseline characteristics were compared with student's t test. a way anova was performed on the pcs and fai score as well as comparisons with t test between each time-point. the distance walked as part of the mwt was compared with mann-whitney u test. patients who remained anaemic at months were older, had a longer icu stay and had a greater requirement for inotropes during their icu stay. the pcs score of quality of life and the fai score was significantly impaired in both groups during follow up, but there was no effect of anaemia. the results of the t tests showed that there was a significant difference between the groups at months for pcs but not for fai scores. the distances walked were severely impaired compared to the normal population ( and m at and months for anaemic group and and m for non-anaemic) in both groups was not significantly different between the two groups. the non-anaemic group did increase the distance walked significantly from to months. there was no difference between albumin, crp and creatinine concentrations between the groups. methods. this experiment was divided into two procedures. the first procedure is to choose two kinds of cell strains, including jurkat cell strain (comes from leukemia) and ccrf-cem cell strain (comes from acute lymphocyte leukemia).we cultivate this two kinds of cell strains to mature stage, then inoculate every kind of cell strain into four culture dishes, two culture dishes was stimulated by lg/ml lipopolysaccharide(study group), and the other two culture dishes serve as blank control(not stimulated by lg/ml lipopolysaccharide). eight hours later, we extracted the microrna in each culture dish. the second procedure is to use the technique of gene microarray to analysis the difference expressions of microrna. in the context of a high altitude expedition human subjects can safely be submitted to prolonged hypoxia and the resulting changes in mitochondrial function can be explored in a controlled fashion. the effect of hypoxia on immune cells-key players in the pathophysiology of sepsis-is of particular interest. to measure mitochondrial function of monocytes during prolonged hypobaric hypoxia. methods. serial blood samples were collected and oxygen saturation was measured in twelve climbers before and throughout a high altitude climbing expedition to pik lenin ( , m). measurements were performed at m (baseline) and at the altitudes of , m (day ), m (day ) and , m (day ) above sea level. pure monocytes were isolated by the use of an antibody-antigen mediated immunomagnetic cell isolation procedure and lysed for determination of activities of mitochondrial enzymes cytochrome c oxidase and citrate synthase. repeated measurements anova followed by least significant difference (lsd) post hoc test were used to compare results on different altitudes. mean oxygen saturation was ± % on , m, and decreased to ± % on , m and ± % on , m (p = . ). we observed an increase in citrate synthase activity on all altitudes compared to baseline levels (p = . ). compared to the baseline, prolonged hypobaric hypoxia induced an increase in the mitochondrial respiratory chain enzyme cytochrome c oxidase enzymatic activity only at , m (p = . ). normalization of cytochrome c oxidase enzymatic activity by citrate synthase activity (relative enzymatic activity) yielded a decrease in relative cytochrome c oxidase enzymatic activity during hypoxia on , and , m (fig. ) . expressing cytochrome c oxidase enzymatic activities as a ratio to citrate synthase is intended to act as a safeguard for potential differences in mitochondrial enrichment. conclusions. the data demonstrates that prolonged hypobaric hypoxia leads to a decrease in relative cytochrome c oxidase activity. this is due to an increase in citrate synthase activity as a marker enzyme for the mitochondrial matrix representing mass and/or number of mitochondria which is not counterbalanced by a corresponding increase of cytochrome c oxidase activity. results. glycocalyx degradation was increased in the lps-treated animals ( . lm, p \ . ) compared to controls. intracellular tissue no concentrations were two-to threefold higher in the lps-treated mice compared to controls (liver, kidney, heart, gut). the number of infiltrating mpo-positive cells increased significantly during endotoxemia. levels of both plasma arg and cit were significantly lower in lps-challenged mice than in controls, whereas plasma ornithine levels were significantly higher. conclusions. in this new developed murine sepsis model, the prolonged infusion of lps resulted in increased glycocalyx degradation and associate endothelial leakage. the enhanced no levels correlated with decreased plasma levels of arg and cit. our murine model with prolonged infusion appears applicable as a model for the human clinical situation, enabling adequate investigation of the influences of the arg-no metabolism on endothelial dysfunction in sepsis. critical illness polyneuromyopathy is a muscular weakness occurring in intensive care unit. one of the major risk factor is sepsis. an early decrease in membrane excitability was described [ ] but corresponding mechanisms are imperfectly known. tnfa is released in the first time of sepsis and could be involved in the physiopathology. objectives. the aim of our study was to investigate tnfa effects on muscular voltage gated sodium channels (nav) in an in vitro model. early effects of tnfa on nav were analysed by macro-patch clamp on muscular fibers isolated from rat peroneus longus. measurements were performed on control fibers and after addition of tnfa at concentrations ranging from . to ng.ml - . the effects of chelerythrine, a specific inhibitor of protein-kinase c (pkc), were also tested. experimentations were realised in a laboratory with permission of experimental research on animals and under the supervision of an authorized person (no - ). tnfa produced a concentration-dependant inhibition of nav currents (fig. ) . maximal inhibition ( % of control current) was observed with concentrations from ng ml - and above. this decrease was fast: % of maximum inhibition was observed in less than min. moreover, chelerythrine inhibited tnfa action on nav. conclusions. in our experimental model, tnfa induce a rapid and concentration dependant decrease of muscular nav currents like observed in chronic sepsis [ ] . as this effect is too quick to be a transcriptional one, and as it is blocked by chelerythrine, it can be assumed that tnfa action is mediated by a nav phosphorylation secondary to pkc activation. in conclusion we evidenced that tnfa reduce muscle excitability in the early stages of sepsis. further studies are needed to obtain a precise description of tnfa mechanisms. may also contribute to cell signaling and regulation of the immune response. nad(p)h oxidase in leukocytes and the vascular wall is a major regulated source of o . we hypothesized that mice deficient in the p phox (ko) component of nad(p)h oxidase would have less pulmonary inflammation than wild type (wt). we treated wt or ko mice with iv saline or lps and assessed lung injury by: . wet-dry-weight ratio; . leak of evans blue (eb) labeled albumin; and . histological score for edema. we used myeloperoxidase activity to indicate neutrophil (pmn) accumulation in lungs, and measured accumulation of macrophages and neutrophils in bronchial alveolar lavage (bal). apoptosis was assessed by tunnel staining. we also expression of icam- , an adhesion molecule, and nitric oxide synthase (nos) enzymes, enos and inos (western and northern analysis) as well as nitrotyrosine formation. results. lung injury was increased in both groups. surprisingly there was greater eb leak in ko than wt at h and a greater edema score at and h. pmn and macrophage accumulation in bal were the same in both groups at h but greater in ko mice at h. myeloperoxidase activity was similar at h post lps in ko and wt indicating that similar accumulation of pmn in the lungs. apoptosis was increased in both groups at h, but resolved in wt at h and persisted in ko. nitrotyrosine was increased in both groups but appeared higher in ko. expression of enos and inos increased in both groups but was greater in ko than wt. conclusions. in contrast to our prediction, lung injury was greater in p phox ko mice which indicates that this complex is not essential for lung injury. however, the injury was more severe and prolonged in ko mice indicating that o may regulate the inflammatory response. introduction. septic shock remains the main cause of mortality in the icu, thus a persistent challenge. recently, dna and mrna analysis by microchip and gene expression by real time pcr highlighted proteins s a , s a and their complex, known as the calgranulins, as potential key prognostic markers for this disease: those two proteins, whose expression seems to be restrained to phagocytes cells are newly recognized components in sepsis-induced inflammation. moreover, they were shown to be at significantly higher concentrations in the plasma of septic shock patients that were going to die. in the contrary, those who were to survive saw their plasmatic concentration decrease, all severity scores in between the population being the same. objectives. the aim of this study was to determine the repartition of these proteins in immune cells, their intracellular variation, at baseline and after cell activation and finally to understand the relation between their intracellular and extracellular expression. we used an in vitro model close to the immuno-inflammatory aggression that is septic shock. we stimulated in vitro for , and h whole blood from healthy volunteers using agonists found in the inflammatory storm that is septic shock (lps, fmlp, gmcsf, ifng). we also induced death cell, either using an apoptotic agonist, or by necrosis technics. we then analysed the intracellular variation of the calgranulins using flow cytometry technics. the extracellular quantification was made using elisa methods. all the statistic analysis were made using a mann-whitney test. we showed in this work for the first time that the intracellular repartition of the calgranulins is different depending on the type of cell: the complexe is the main form in the monocyte cytoplasma, whereas s a is the main intracellular form of the pmn. this repartition remains after cell activation. we also checked the absence of calgranulins in lymphocytes. after cell activation we showed that intracellular s a , s a and s a a increased, but at different levels depending on the cell and the agonist used. extracellular s a also raised after cell stimulation, but the concentration found were very low compare to those found in the plasma of septic shock patients. conclusions. together, these results suggest a different regulation depending on the form of the protein and of the cell and thus of proper distinct function of each monomer and of the complex. in the limits of our model the increased concentrations found in the plasma of patients with a septic shock can't be explained by immune cell activation. objectives. although there is no specific antidote for these potent toxins, drugs like penicillin g and silibinin have been used with conflicting evidence. we successfully managed two patients with mushroom poisoning by using silibinin and nac. methods. two members of a family, a mother years old, and her son years old were admitted to our icu h after the ingestion of wild mushrooms. they presented with abdominal cramps, vomiting, profuse diarrhea ([ /day), myalgias, confusion and agitation. the clinical examination showed severe dehydration, tachycardia, oliguria with grade i-ii hepatic encephalopathy. laboratory exams revealed elevation of liver enzymes sgpt: / u/l, sgot: / u/l. coagulation parameters were as following: prothrombin time . / . , factor v \ %/ %, factor vii \ / %. high ammonia levels were noted, reaching and ng/dl, respectively. metabolic acidosis was also present with mild renal dysfunction. the ultrasound performed in both patients showed hepatosplenomegaly. aggressive fluid and electrolyte replacement started upon admission. silibinin was given at a dose of mg/kg/day intravenously, in four divided doses, for three consecutive days, while nac was given as a continuous infusion at a dose of mg/kg for the first hour, mg/kg for the next h, and thereafter mg/kg/day for the following four days. hepatic encephalopathy, mild jaundice and renal dysfunction resolved within h, and liver function tests returned to normal within days. the patients recovered fully and were discharged to a medical ward. recent experimental and clinical studies have shown a strong protective and antioxidant effect against hepatic cell injury in amanita toxicity by the administration of nac and silibinin, either as monotherapy or as a combination therapy. although further clinical research is required to confirm their efficacy in reducing mortality and transplantation rate, nac has been used in our icu in hepatic dysfunction of different etiologies with promising results. we have recently shown that in patients with lactic acidosis due to metformin intoxication (serum drug level = ± lg/ml; therapeutic level is b lg/ml) systemic oxygen consumption (vo ) can be abnormally low despite a preserved global oxygen delivery (do ) ( ). the study, however, suffered from being retrospective. objectives. to prospectively clarify whether metformin primarily impairs vo . methods. eight sedated, paralyzed and mechanically ventilated pigs received a continuous i.v. infusion of metformin, at a rate of . g/h. the amount of metformin administered to each animal ranged from and g. the experiment always finished h after the initiation of drug infusion. use of sedative and neuromuscular blocking drugs, as well as ventilatory setting, were always kept constant. serum metformin concentration was measured at the end of the experiment, using high performance liquid chromatography (hplc). arterial ph, lactatemia, vo (indirect calorimetry) and do (computed from cardiac output measured by pulmonary artery thermodilution) were recorded hourly. data are presented as mean ± sd. statistical testing was performed using the one-way repeated measure anova and the linear regression analysis. metformin infusion produced toxic serum drug levels ( ± lg/ml; n = ). arterial ph drop from . ± . (prior to infusion) to . ± . (end of the experiment) (n = ; p \ . ) and lactatemia rose from ± to ± mmol/l (n = , p \ . ). vo progressively decreased (from ± to ± ml/min; n = , p \ . ) while do did not significantly change over time (from ± to ± ml/min; n = , p = . ). the decrease in vo was proportional to the dose of metformin administered (r . ; n = , p = . ) and to the serum drug level reached by the end of the experiment (r . ; n = , p = . ). conclusions. lactic acidosis develops during metformin intoxication in the presence of a diminished vo but in the absence of any clear evidence of inadequate do . this finding suggests that impaired oxygen utilization, rather than availability, may have a role in the pathogenesis of metformin-induced lactic acidosis. : min) . death was consequent to multiorgan failure, anoxic encephalopathy or capillary leak syndrome if ecls was performed under cardiac massage. four patients presented with documented brain death, allowing organ donation in cases. among these patients, the heart of one flecainide-poisoned patient was successfully transplanted, after normalization of ecg and myocardial function as well as toxicant elimination under ecls. prognostic factors in ecls-treated poisoned patients were as follows: qrs enlargement on admission (p = . ), saps ii score on admission (p = . ), ecls performance under massage (p = . ), arterial ph (p \ . ), lactate concentration ( . [ . - . ] versus . mmol/l [ . - . ], p = . ), as well as red cell (p = . ), fresh plasma (p = . ), and platelet (p = . ) transfusions within the first h. conclusions. to our knowledge, this is the larger series of ecls-treated poisoned patients ever reported. ecls appears to be an efficient salvage technique in case of refractory toxic cardiac failure or arrest, with a % survival rate. our series clearly demonstrate that toxic refractory cardiac failure remains the best indication with a % survival rate. objectives. aim of the study was to investigate the incidence of infections in patients treated with hypothermia while receiving sdd. in this retrospective case control study patients treated with prolonged hypothermia (cases) were identified and patients with severe brain injury were included (controls). propensity score matching was performed to correct for differences in baseline characteristics and clinical parameters. primary outcome was the incidence of infection. the secondary endpoints were the micro-organisms isolated from surveillance cultures and during infection. the demographic and clinical data indicated that the cases and controls were well matched. the length of stay in the icu and duration of mechanical ventilation were comparable between the groups. the overall risk of infection during icu stay was % in the hypothermia groups versus . % in the normothermia group (p = . ). pneumonia was diagnosed in . % of patients in both groups (p = . ). the incidence of meningitis, wound infection, bacteremia, and urinary tract infection was low and comparable between the groups. staphylococcus aureus was most frequently identified as the causative infectious microorganism in both the hypothermia ( . %) and normothermia ( . %) group (p = . ), followed by coagulase negative staphylococci ( . % in the hypothermia and . % in the normothermia patients, p = . ) gram-negative bacteria were isolated from the surveillance cultures in . % of patients treated with hypothermia and . % of patients in the control group (p = . ). colonization of the rectum with gram-negative bacteria was significantly more frequent in patients treated with hypothermia compared with normothermia ( . vs. . % respectively, p = . ). in contrast, colonization of the upper gastrointestinal tract and sputum was comparable between the groups with an incidence of . % in the hypothermia patients versus . % in the normothermia patients (p = . ). use of sdd mitigates the increased risk of infection in patients treated with hypothermia. based on the surveillance cultures, it seems that oropharyngeal decontamination is the most effective part of the sdd regimen in the prevention of pneumonia. introduction. prognostic scores specific for critical patients were developed in order to predict mortality based on physiologic and laboratorial variables. on the other hand, specific scores for burn patients are calculated taking into consideration inhalation injury, age and total burned surface area (tbsa), among others. however, scores utilized in general icu have not been evaluated in burn patients. objectives. therefore, the aim of the present work was to validate apache ii, saps as well as initial sofa in a population of patients with massive burn. these scores were compared to some specific burn patient scores, including absi (abbreviated burn severity index) and estimates of the probability of death. retrospective study employing data collected prospectively from may to february ( months) at an icu specialized in burn patients at a teaching hospital which is considered a reference centre in trauma care. all patients admitted during this period were included. one hundred and fifty-four consecutive patients were studied (male: %; female: %), with averaged age of . ± . years and a hospital stay of . ± . days. mortality rate of our sample was . %. incidence of inhalation injury was % and total burn surface area (tbsa) was the following: . % of patients had % or less; . % had - % of tbsa whereas . % showed % or more. area under curve of receiver operating characteristic (roc) of evaluated indexes is displayed on table . computerized head tomography is routinely performed as a diagnostic tool after the occurrence of neurologic deterioration in the icu adult patients. however, the ct findings in this setting are rarely reported. we hypothesized that the analysis of a series of cranial cts would help to understand the neurologic conditions of the critically ill patients and improve their management. objectives. to analyze, over a three-month period, the head ct scans performed in the adult icu in the albert einstein hospital in são paulo, brazil. methods. all cranial cts performed in the icu patients during the studied period were analyzed by two radiologists from the albert einstein hospital staff from may st to august st, , according to a pre-established protocol: . presence of acute cerebral ischemia; . presence of previous cerebral ischemia; . presence of acute cerebral hemorrhage; . presence of cerebral edema; . cerebral aneurisms; . cerebral tumors and . normal cerebral tomography. we studied ct scans from ( . %) males and ( . %) females, mean age . ± . years. the head ct findings were the following: ( ) presence of acute cerebral ischemia = ( . %); ( ) presence of previous cerebral ischemia = ( . %); ( ) presence of acute cerebral hemorrhage = ( . %); ( ) presence of cerebral edema = ( . %); ( ) cerebral aneurisms = ( . %); ( ) cerebral tumors = ( . %) and ( ) c years c , abc (assessment blood consumption) cp: c and ets (emergency transfusion score) cp: c , c years c . these scales handle the following combinations of variables for calculation: age, sex, type of admission, mechanism, blood pressure, focussed assessment for the sonography of trauma, hemoglobin, orthopedic or pelvic trauma, heart rate. mt was defined as the transfusion of units or more of packed red blood cells in the first h. we study the sensitivity (s), specificity (sp), positive and negative predictive value (ppv, npv), likelihood ratios positive and negative (lhr+ , lhr-) and area under the receiver operating characteristic curve (auroc) of different scales for the predictive power of tm validated in the literature. patients were available for analysis ( . % men, iss ± , blunt trauma . % objectives. we measured patient-reported outcome following surgical management with dc using a quality of life instrument. methods. survivors discharged between and months after severe tat were contacted after obtaining approval by our institutional irb. we excluded patients with neurotrauma. we applied self-response version euroqol questionnaire (eq- d) and visual analog scale (eq-vas: (worst health)- (best health). euroqol it is based on a descriptive system that defines health in terms of dimensions: mobility, self-care, usualactivities, pain/discomfort and anxiety/depression. each dimension has levels of response: no problems (level ), some problems (level ) severe problems (level ). results. thirty four patients were contacted. mean ± sd age was . ± . yrs, male were . % and penetrating trauma occurred in . %. mean ± sd in severity scores were: ati . ± . , iss . ± . and apache ii ± . the median time from discharge was months (iqr - months). the eq- d dimensions in which the largest proportion of patients reported severe problems were usual-activities (work, study) and pain/discomfort . % and . % respectively as shown in the conclusions. survivors of severe trauma and dc, reported acceptable quality of life with minimal limitations with social functioning. a prospective study should assess quality of life in these patients from hospital discharge and systematically over time. introduction. brain tumors surgery is one of the main causes of admittance to the nicu. it is important to know the risk factors associated to hospital mortality of patients admitted to nicu due to this reason. to identify perioperative factors associated to higher hospital mortality in a series of patients admitted to nicu immediately after a bt elective resection. methods. data of patients operated for bt elective resection and consecutively admitted to nicu at imss umae bajío were prospectively obtained. nicu bt database includes perioperative items. we divided the series in two groups: surviving and deceased patients. then, we analyzed the perioperative behavior differences between both groups. either student's t test or chi-square test was used, as it corresponded, for the analysis of differences observed between both groups. values of p lower than . were considered significant. results. the hospital mortality observed in this series of patients was . % ( / ). data of the nine variables showing significant differences between surviving and deceased patients groups are shown in table . even if hypoxic brain injury has been reported as the strongest factor affecting the poor outcome of near-drowning patients, little has been known about prognostic factors affecting the outcomes of those patients receiving mechanical ventilation. to define prognostic factors affecting the outcomes of patients mechanically ventilated after near-drowning. , white blood cell counts (or, . ; % ci, . - . ; p = . ), serum creatinine (or, . ; % ci, . - . ; p = . ), and serum lactic acid (or, . ; % ci, . - . , p = . ) were associated with favorable outcomes, respectively. however, only higher body temperature as a clinical parameter and the level of serum lactic acid as a laboratory parameter were significant predictors of favorable outcomes in multivariate analyses; the or were . ( % ci, . - . ; p = . ) and . ( % ci, . - . ; p = . ), respectively. conclusions. initial body temperature and the level of serum lactic acid were two most important clinical and laboratory prognostic factor in nearly drowned patients. the outcomes were not affected by the degree of initial hypoxemia. to determine the use of automated external defibrillators (aed) and manual defibrillators deployed in the various hospital wards (unmonitored areas) in a university hospital. a prospective study was performed according to utstein style of all cardiac arrests occurred in the hospital during the first months after the implantation of a new protocol of care for hospital cardiac arrest. because of this plan automated external defibrillators were located for hospital wards and common service areas (radiology areas, outpatients, …) where one would expect a lower incidence of cardiac arrests, according to the risk map elaborated previously. in areas of greatest risk manual defibrillators previously existed. all resuscitation attempts in these areas were analyzed, excluding the emergency department because of a separate protocol against the rest of the hospital. special attention was given to the use of aeds by wards staff before the arrival of resuscitation team. also a comprehensive volunteer training program was designed, but it began after the analyzed period was finished. results. during the first months we collected a total of pcr in hospital wards and public areas, with a median age of years and predominantly male ( patients). the most common origin was respiratory ( patients) followed by cardiac ( patients). the most frequent rhythm detected was non-shockable ( patients), only in was shockable and unknown in . before the resuscitation team arrival only two patients had been manually defibrillated and were never used the new aeds. conclusions. the aeds provided in the hospital were completely useless in the first months after placement, probably due to the lack of a comprehensive training plan associated to the population goal. methods. descriptive longitudinal study. patients were studied by encephalic death, as potential donors of organs, alerted to the network of regional transplant (cdtot), by units of intensive care, for months, in barranquilla's city. it was applied qualifying each of the variables in agreement to the vital opposing signs and biochemical tests brought in this moment. . . % of the subjects were male; the average of age was . years (±sd: . ). the values of blood sugar, sodium, osmolaridad, tonicidad, po , fc, pam, and glasgow, determined a score of , qualification that there had patient with encephalic death with the scale mbcm, as a test of certainty of the scale to diagnose encephalic death in total absence of reflections of stem. conclusions. there is recommended the application of mbcm's scale to every neurological patient by diagnosis of encephalic death in proof of certainty, in absence of others. by the high specificity of the already demonstrated scale there is recommended that scores lower than they should restate the qualification. a score of is an encephalic death in absence of reflections of stem. grant acknowledgment. clínica general del norte-cdtot introduction. prospective analysis of tracheostomies performed in patients admitted to a neurotrauma icu, the reasons for its implementation, and intraoperative complications in the first week. methods. all patients admitted to the icu of neurotrauma, which underwent a tracheostomy after admission. data were collected: affiliation, cause of admission, average stay, cause for realization of tracheostomy, tracheostomy time delay from its indication, place of performance of the procedure (icu or operating room), perioperative complications (event at transfer to operating room or during surgery: hypoxia, hypotension, arrhythmia, bleeding, premature extubation, false cannulation, cardiac arrest, pneumothorax or death), and postoperative complications in the first week (bleeding, difficulty in changing cannula, stomal infection, pneumothorax, death). introduction. the s- b protein is a brain-specific protein release from astroglial cells into the circulation after traumatic brain injury (tbi). researches indicate that the s- b serum level could be a useful indicator of tbi severity, however there is not evidence enough about the role of s- b in nonsevere head trauma. the hypothesis that s- b is a useful screening tool to detect brain injury in patients with a normal level of consciousness after a head trauma was tested. a total of patients with the diagnosis of mild tbi without decrease of consciousness (according to the gcs) with at least one neurological symptom or finding like amnesia, headache, dizziness, convulsion and vomits, were prospectively included. we recorded the clinical data on admission and a blood sample before h after tbi, for s- b inmunoluminescence analysis. a routine cranial computed tomography scan (ct) was obtained within h after the injury (categorized in normal or pathological). the diagnostic properties of s- b serum levels. lg/l, for prediction of intracranial lesions revealed by ct were tested with receiver operating characteristic (roc) analysis. seventy of the patients ( . %) were men, with a mean (sd) age of . ( . ) years (range, - years). a total of patients ( . %) had intracranial lesions. serum s- b levels were significantly higher in patients with intracranial lesions than in the remaining patients. the average value of the protein in patients without intracranial lesion was . lg/l with a ci % ( . - . lg/l), and in those with pathological findings in ct was . lg/l with a ci % ( . - . lg/l). significant differences were found between levels of s b protein and the presence of pathological findings in the ct (p = . ) (fig. ) . the roc curve analysis showed that s b protein is a useful tool to discriminate the presence of intracranial injury in ct (auc, . , % ci, . - . , p \ . ). s b analyses with a cut-off level of . lg/l showed a sensitivity % but a specificity . %. we evaluated different cut off values and in our series, the best cut off of the s b protein is at . lg/l with a sensitivity of % and specificity %. (fig. ) conclusion. determination of serum protein s- b is a useful biochemical indicator of brain damage in head trauma. our results show that an increase in the cut-off point of s- b to . lg/l increases its accuracy in the prediction of the existence of macroscopical lesions. key words. protein s- b, brain injury, minor head trauma, cranial computed tomography. critically ill patients with systemic inflammatory response syndrome frequently suffer muscle weakness due to critical illness myopathy (cim) and polyneuropathy (cip). several in vitro studies have shown that the cause of muscle weakness is a loss of membrane excitability accompanied by membrane depolarization [ ] . objectives. we investigated membrane polarization and excitability parameters in muscle and motor nerve in vivo within the first week after intensive care unit (icu) admission. methods. the study was approved by our local ethics committee. patients with sofa scores c on consecutive days underwent nerve conduction studies including direct muscle stimulation to categorize patients as icu-control, cim-(dmcmap \ mv) and/or cippatients (reduced snap amplitude) within the first days after icu admission. to assess excitability parameters we recorded stimulus-response behaviour, threshold electrotonus, current-threshold relationship and recovery cycle from abductor pollicis brevis muscle following stimulation of the median nerve [ ] . data are shown as median and %/ % percentile. conclusions. we describe for the first time that critically ill patients in general show muscle-and nerve membrane depolarization, whereas patients later suffering from muscle weakness due to cim or cim/cip feature additionally reduced membrane excitability. this suggests that membrane depolarization in critically ill patients is caused by energy failure leading to dysfunction of the na-k pump, the motor of membrane repolarisation-whereas reduced membrane excitability in cim or cim/cip needs an additional dysfunction of voltage gated sodium channels for example occurring in the presence of endotoxins [ ] . in intensive care patients with central nervous system (cns) disease, the systemic inflammatory response syndrome (sirs) criteria are often unreliable as a basis for identifying the inflammatory process. even with the presence of some infection they could be signs of the diencephalons-catabolic syndrome. diencephalons-catabolic syndrome like sirs constitutes of hyperthermia over °c, tachypnea of over per minute, tachycardia, and arterial hypertension. thus, sirs symptoms may occur after antibacterial treatment even if there is no infection or inflammation. we suggest a more precise method which could help to avoid the excessive antibacterial therapy and to control it in patients with cns disease-a procalcitonin test. objectives. reduce the use of wide specter antibiotics makes the control over antibacterial therapy in patients with cns diseases more precise; reduce the number of complications related to unnecessarily long antibacterial treatment. after obtaining the informed concern, in our investigation we included patients with different neurological disorders, who had recently transferred neurosurgical operations. all of them demonstrated sirs symptoms on different postoperative terms. when sirs symptoms occurred, we checked the level of procalcitonin in the patient's serum by a semi quantitative method on a disposable brahms pct-q system. the procalcitonin level was determined against a color scale. procalcitonin level over . ng/ml ( patients) considered a sign of infection and in such cases we prescribed antibacterial treatment , mg of selenase for - days. if the test result was negative ( patients) we repeated it in h and in cases with the same results, no antibacterial treatment was administered even if there were sirs symptoms. if pct-q test was negative patients were sedated (fentanyl . - . lg/kg/h and clonidine . - . lg/kg/h) to achieve autonomic stability and attenuate clinical manifestation of sirs. we had not observed any cases of sepsis in both groups of patients. by mince of pct, we had managed to reduce the quantity of wide specter antibiotics, used in neurosurgical patients for . %. conclusions. procalcitonin test in neurosurgical clinic let us determine the necessity of antibacterial treatment reduce the use of wide specter antibiotics, medical costs and prevent the forming of polyresistant infection. l. combe , r. appleton , c. gilhooly , j. kinsella university of glasgow, department of anaesthesia and critical care, glasgow, uk intensive care unit-acquired weakness (icuaw) is increasingly recognised as a common complication of critical illness with potentially prolonged debilitating sequelae. the estimated incidence is % in patients with sepsis, multi-organ failure or prolonged mechanical ventilation [ ] and suggested risk factors include: the systemic inflammatory response syndrome (sirs), sepsis, higher severity of illness, hyperglycaemia, renal replacement therapy and parenteral nutrition. objectives. the aims of this study were to determine the incidence, risk factors and outcomes for patients diagnosed with icuaw in glasgow royal infirmary's (gri) icu. the study was undertaken in two parts, firstly as a case-control study [matched for age (within years), sex and admission apache ii score (within points)] and secondly by comparing identified cases of icuaw to a -month cross-sectional sample ( / / - / / , patients) of gri's icu patients. data for both parts of the study was obtained from two electronic databases, wardwatcher and carevue. carevue was searched to identify patients with icuaw and wardwatcher was used to identify the controls. data collected included: patient and illness characteristics, severity of illness scoring, organ support and treatments provided, laboratory results and outcomes. minitab software was used for statistical analysis. conclusions. the incidence of icuaw was very low, we hypothesise this to be explained by the absence of systematic evaluation of patients for icuaw. the risk factors and outcomes for icuaw were consistent with some of the published literature. prospective study is now planned to systematically evaluate this condition. with increasing age, comorbidity, and socioeconomic deprivation being associated with higher risk pregnancies, there comes a potential higher risk of complications. neurological and neurosurgical complications, which can be particularly devastating during the peripartum period, include those due to medical conditions of pregnancy (hypertensive disease, sepsis, thromboembolic disease, hypoxic-ischaemic brain injury), iatrogenic complications secondary to anaesthetic or obstetric interventions, incidental illness or injury (pharmacological alterations, trauma, tumour), and deliberate self-harm and violence. objectives. to ascertain the frequency of neurocritical care admissions in the west of scotland, the nature of the admission diagnoses, the impact they have on our service (length of stay), and maternal and foetal outcome. methods. using the scottish intensive care society audit group wardwatcher patient database, female patients aged - years old who were admitted to the neurocritical care unit were identified (january -december ). we manually reviewed the electronic admission note for each of these women in order to gain diagnoses; a targeted case note analysis ensued. within the month study period there were a total of admissions to neurocritical care, of whom fulfilled the age and gender criteria; admissions ( . % of total) were for neurological complications in the peripartum period. the age range was to years (median years). three women ( %) were intrapartum ( - weeks gestation) at the time of their admission, and three were postpartum ( day- months). half of admissions were due to incidental illness or injury, a third to pregnancyrelated medical complications, and one case was iatrogenic in nature. length of stay in icu was to days (median . days). one patient sustained a residual facial nerve weakness and deafness. conclusions. this survey provided insight into the incidence and nature of pregnancyrelated pathology requiring acute referral to a regional neurosciences centre. as highlighted in other surveys, there may be many more peripartum patients with neurological complications who are cared for in general critical care units, and do not require admission to a tertiary referral centre [ ] . further work is underway to ascertain the true numbers of neurological complications of pregnancy countrywide. our approach represents a paradigm for the continuing audit of pregnancy-related critical care resource use in scotland. introduction. hypertonic saline has an osmotic effect on the brain because of its high tonicity and ability to effectively remain outside the blood-brain barrier. there may be a minimal benefit in restoring cerebral blood flow, which is thought to be mitigated through local effects of hypertonic saline on cerebral microvasculature. most comparisons with mannitol suggest almost equal efficacy in reducing icp but not compared their effects on eeg. objectives. we aimed to compare the effects of % mannitol, % or % hypertonic saline on hemodynamic parameters, intracranial pressure and electroencephalography in experimental head trauma. bilateral craniotomy were carried out in the parietal region and head trauma was applied for all rabbits. the rabbits were randomly divided into four groups. in group i rabbits were only observed. in group ii: % mannitol, in group iii: % hypertonic saline and in group iv: % hypertonic saline was administered intravenously to achieve similar osmolar load. electroencephalography, mean arterial pressure, heart rate, intracranial pressure were recorded before trauma and and min after trauma. results. increased intracranial pressure was significantly decreased by mannitol, and % hypertonic saline solutions at the end of study (p \ . ). but intracranial pressure values of mannitol and % hypertonic saline groups were lower than the other groups (p \ . ). the electroencephalography scores decreased after trauma in all groups (p \ . ). at end of the study, and % hypertonic saline groups had similar electroencephalography scores with pretrauma scores (p [ . ). the mean arterial pressure and heart rates increased after trauma in all groups (p \ . ). mean arterial pressure values were found lower only in mannitol group at end of the study (p \ . ). our study showed that when used in intracranial hypertension treatment, % hypertonic saline solution is as effective as mannitol, and preserves hemodynamic parameters, and normalizes traumatic electroencephalography abnormalities better than mannitol. objectives. to identify the causes of new onset seizures in patient admitted in medical icu. methods. all the patient admitted in icu and who had new onset seizures were evaluated. the patients were evaluated for metabolic profile. imaging (ct/mri) was done whenever needed. patients with preexisting seizure history were excluded from study. . ( males, females) patients, who had first seizure during hospitalization in icu were included. patients had generalised and one had focal seizures. patients had metabolic abnormalities. ( . %) had evidence of hepatic encephalopathy. ( . %) had only hepatic encephalopathy while rest had associated uremia, hyponatraemia, hypophosphatemia and hypomagnesemia. out of patients, who had renal failure, had evidence of uremia while rest had associated hyponatraemia or hypophosphatemia. only one patient had evidence of hypocalcemia. imaging was done in patients. ( %) had abnormal ct scan results. ( . %) had intracranial hemorrhage, ( . %) had infarct, ( . %) had brain metastasis, had evidence of hydrocephalus and one each had evidence of extradural hemorrhage and tuberculoma. csf analysis was done in ( . %) patients. ( . %) had evidence of tuberculosis and ( . %) had evidence of pyogenic infection. to study the role of various investigations and ct in evaluating these patients. all patients admitted with new onset seizures within h prior to presentation were included. all the patients were questioned and an attempt was made to assign an electroclinical syndrome to seizure. patients were evaluated for metabolic profile, neuroimaging. csf examination was done in those who had persistently altered mental status, infectious symptoms and fever. results. patients were admitted ( . % of total patients who came to emergency) with history of new onset seizures. . % patients were diagnosed to have acute symptomatic seizures and were placed in ilae category . and three patients were placed in ilae category of remote symptomatic seizures. the cause of seizures was established in ( . %) patients and remained unestablished in ( . %) patients. ( . %) patients were diagnosed to have neurocysticercosis. other important causes were acute infarct, uremia, hyponatremia, hypernatremia, viral encephalitis, post partum eclampsia, pyogenic and tubercular meningitis. alcohol withdrawal seizures were seen in . % patients. metabolic derangements were seen in ( . %) patients. computed tomography was done in patients and % had abnormal findings. mri was done in patients and had abnormalities. conclusions. neurocysticercosis was found to be most common cause of seizure activity in our part of country. though metabolic derangement can cause significant proportion of new onset seizure patients routine imaging of brain should be performed in patients with new onset seizures. work environment and organisational issues: - subjective and objective research into the working conditions and their effect on the health and safety of people working in icu, focusing mainly on the natural factors of temperature, humidity, ventilation, lighting and noise (part ) n. karachalios , e.c. katsilaki , d. sfyras general hospital of lamia, icu, lamia, greece the aim of the project is the subjective and objective investigation of the conditions of work and the relation repercussions on the health and safety of people working in the icu, focusing mainly on the natural factors that are likely to cause the sick building syndrome. for this purpose a protocol of research in two phases has been planned. the first included objective measurements, with the use of suitable equipment, of the natural factors of temperature, humidity, ventilation, lighting and noise. the second phase included the subjective estimation of the working people about their own health and conditions of their work, in the particular area of the hospital with the use of substantiated anonymous questionnaire. after the subjective and objective study and analysis of questionnaires and measurements of natural factors, we found that the medium temperature of the icu was °c. the mean relative humidity of the icu was % (highest . % and lowest . %). the mean ventilation rate of the icu was m /h (highest . and lowest \ . m /h). the mean sound pressure was . db (highest and lowest . db). the average lighting was . lux ( lux lowest and lux highest). the objective data seem to keep pace with the subjective opinions of the working people, as they were impressed in the questionnaires of subjective estimate. the objective data were compared with the subjective. the results of the research were also compared with data from the existing bibliography and current legislation, leading to a line of conclusions. ( ) insufficient and bad quality ventilation. ( ) the existing temperature of the environment contributes to the appearance of sick building syndrome. ( ) the working environment is noisy. ( ) the environment of work has problematic or insufficient lighting. ( ) the icu under study is a building area which can be characterized as ''sick'' if immediate action is not taken. background. up to % of critical care nurses test positive for (symptoms of) post traumatic stress disorder (ptsd) [ , , ] . it is assumed that these symptoms are caused by professional involvement in life-threatening events [ ] . in a sample of intensive care nurses, we investigated which work related incidents were perceived as most distressing. method. in interviews, nurses ( % female) were asked to memorize and tell about their most traumatic work related event. all interviews were recorded. after verbatim transcription, the 'most critical events' were extracted and categorized bij two independent psychologists. . none of the nurses reported major life-threatening events such as trauma-related injuries, massive bleeding or seeing patients die as their 'most critical incident'. conclusion. not the major life-threatening events but relatively 'normal work related events' under unusual circumstances are mentioned as most critical by nurses. in contrast to major life-threatening events, these 'normal events' are usually underestimated by colleagues, and thus potentially compromise peer-support. a care bundle refers to evidence based interventions and information grouped together to improve outcomes and consistency of provided care [ , ] . at the icus charge nurses and intensivists as shift leaders are responsible for daily management of unit activities. several immediately made decisions by shift leaders are made under time pressure and high information load with inadequate information. though we have evidence of structure and process based factors such as material and human resources, admission and discharge decisions or bed utilization, the support for information transfer and integration is poor in organizational decision-making concerning these factors. objectives. to identify immediate information needs of charge nurses and intensivists during the management of daily activities at the icu and evaluate how necessary this information is for their decision-making. from september to november , all charge nurses (n = ) and intensivists (n = ) of university affiliated icus providing comprehensive care in finland were surveyed with an on-line questionnaire using statements. the questionnaire was developed based on our previous observation study and statements of our survey regarded information needs related to the icu care activities. a rating scale from to (completely unnecessary-absolutely necessary) was used to assess the necessity of the information. for each statement, a response with mean or over was regarded as necessary information for immediate decisions. results. the response rate was . % (charge nurses . %, intensivists . %). the working experience varied from to years (mean . , sd . ). over % of respondents worked as a shift leader once a week or more often. statements of were valued as a necessary (mean [ or more) for immediate decision-making. absolutely necessary information (mean [ or more) for immediate decision-making were assessed related to the statements. these statements concerned isolations, mechanical ventilation, admissions and discharges, special treatments, patient's condition, and scheduled dates or times for surgery or other procedures. conclusions. both icu charge nurses and intensivists identified several information needs that are crucial for immediate decision-making during the whole icu care process. information needs of the shift leaders differed and they were strongly connected to the needs of one's professional requirements. an integrated overview and summarization of immediately needed information-a care bundle for organizational decision-making-at the icus is highly needed for icu shift leaders. the common interests of both professionals, charge nurses and intensivists, should be emphasized when new technology-based systems are developed. background. the nursing shortage is an international problem that is expected to worsen in the coming years. studies show that one of the main reasons nurses leave the profession is their dissatisfaction with their work environment. structural empowerment and nurse-physician collaboration are two elements of the nurses' work environment that are potentially related to one another according to kanter's theory ( ) . in addition, a nurse's clinical specialization has been found to influence perceptions related to these two concepts. to examine the level of perceived structural empowerment, the perceptions of nurse-physician collaboration and the relationship between these two variables, among intensive care unit (icu) nurses and general ward nurses in israel, and to compare the groups. a descriptive, correlational, comparative study design was used on a sample of icu nurses and nurses from internal medicine and general surgery wards in a large university hospital in israel (response rate %). a three section, self administered questionnaire was used to measure the study variables: the condition of work effectiveness scale-ii (cweq-ii), the collaboration with medical staff scale (cmss) and demographic-professional background. results: perceived structural empowerment was found to be moderate (m = . , sd = . , range = - ). nurses tended to agree that there was nurse-physician collaboration (m = . , sd = . , range = - , = strongly disagree, = strongly agree). a correlation was found between structural empowerment and the nurse-physician collaboration (r = . , p \ . ). a significant difference was found between icu nurses and general ward nurses on their perceptions of nurse-physician collaboration (t ( ) = - . , p \ . ; general wards: m = . , icu: m = . ). no significant differences were found between nurse specialization on perceived level of structural empowerment. conclusion. nurses in this study tended to agree that there was nurse-physician collaboration on their unit/ward. nurses who perceived themselves as having a higher level of structural empowerment, felt that there was a higher level of nurse-physician collaboration. general ward nurses had more positive perceptions about nurse-physician collaboration on their ward as compared to icu nurses. no difference was found between the two groups on the level of structural empowerment. recommendation. the findings of this study can be used as the basis for the design of interventions, aimed at enhancing structural empowerment and nurse-physician collaboration, in order to improve nurses' work environment, as one of strategy to decrease the nursing shortage. further study of additional hospitals in the country is also recommended. teams have expanded and in some hospitals h cover has been instituted. researchers are questioning the validity of outreach services and its impact on patient outcomes. as cco has been viewed as the panacea to all problems, data collection and analysis is fundamental in proving its financial and clinical benefits. objectives. this comparative study aims to evaluate retrospective data from month in and month in . data does not encapsulate patient outcomes; it will compare frequency of referrals and interventions. this data provides an indication to the extent cco has participated in the care of the acutely ill over a given time period. methods. data was collected from the d medicus database collating intervention data. analysis occurred using key interventions using excel software conclusions. whilst the validity of services has been questioned, the data itself indicates that more patients are referred and frequency of interventions has increased. various system changes occurred during this time period such as a change of mews trigger scores, the advent of h cco and courses such as alert and survive sepsis were introduced into the basic training of staff. it must be noted that the intention in the uk for cco was a service that empowered staff through education to undertake this care themselves; therefore the increase in interventions could indicate that the educational approach hasn't made progress. although the study compares interventions, an increase in the type of interventions was also noted such as ward based cco supervised cpap and establishing a picc line service. therefore this highlights the changing application of interventions. further analysis is required to look at the appropriate skills required for the delivery of safe care to the acutely ill in the ward environment. whilst ward staff are increasingly under resourced, both in skills and manpower, cco do provide the skills, knowledge and time to meet the shortfall in safe timely care. introduction. working as a critical care nurse involves situations where teamwork is essential and rapid, effective communication is of importance [ ] . the education to become a specialist icu nurse gives skills and knowledge to manage patients who are critically ill with rapidly changing conditions [ ] . experimental research is one way of contributing to the acquisition of such knowledge. to describe how icu nurses may contribute and perform in the experimental research process, an environment usually unfamiliar to them. we describe our experiences with regard to clinical contribution and our subjective evaluation of involvement in animal experimental research. method. three icu nurses in a swedish hospital were asked to participate in a research project investigating myocardial metabolism in porcine models of shock. the tasks were anaesthesia and pain management, assisting with catheter insertion and haemodynamic monitoring the pigs during the process results. although the situation was new, the nursing role and function in the team were at once similar and different to the daily work situation in the icu. one major skill learnt was the rigour of experimental measurements and sources of error, which is sometimes neglected in clinical care. being able to observe changes due to shock in a controlled setting, we improved our ability to critically 'think ahead' in anticipation of clinical deterioration [ ] . our first-hand experiences at the animal experimental laboratory allayed many anxieties and misconceptions with this type of research. conclusions. the critical care environment demands skills such as the ability to accurately define and change priorities rapidly, good communication and teamwork [ ] . we believe that the experimental research setting is one way of enhancing this ability. in these units patients condition may change rapidly and they may need close inspection as well as emergency response. early warning scoring (ews) system may make early recognition of and response to bad condition possible by observation based on systematic parameters. ews was developed as a simple scoring system to be used at ward level utilizing routine observations taken by nursing staff. ews is based on five physiological parameters; systolic blood pressure, pulse rate, respiratory rate, temperature and avpu score (alert; reacts to voice; reacts to pain; unresponsive). objectives. the aim of this study was to evaluate ews among patients admitted to pacu. methods. ews parameters were recorded four times from patients after their admission to pacu. the first record was taken during the first admission to pacu (ews ), the second (ews ) after min, the third after (ews ) and the fourth record after min. the correlation between variables like differences of four ews, patients age, the asa score, duration of operation were statistically examined. early treatment and recognition of sepsis is a stated aim of the surviving sepsis campaign [ ] but in busy clinical environments the delivery of antibiotics and fluids can often be delayed. we describe the implementation of an audit proforma, based on the survivesepsis.org [ ] resuscitation bundle, as a tool to deliver six aspects of management within h of recognition sepsis. . improve the early recognition and treatment of sepsis in acute medical patients. . provide a sustainable change in the management of septic patients . improve mortality and length of hospital stay methods. the proforma consist of six treatment management steps, based on the survivesepsis.org ''septic six'': oxygen, blood cultures, antibiotics, lactate, iv fluids, strict fluid management. it is triggered by patients satisfying two or more of the systemic inflammatory response syndrome criteria. all management steps should be implemented within h of the trigger time stated on the form. the forms are collected and analysed every month and the results are displayed for staff working on the medical admissions unit and accident and emergency. a total of forms have been collected, % diagnosed with severe sepsis. the progress on all six parameters is shown below. over the initial seven month period we have demonstrated a sustained improvement in the rapid delivery of all six of the management parameters. introduction. the early goal-directed resuscitation has been shown to improve survival in patients presenting with septic shock. a recent systematic review demonstrated the inability of central venous pressure (cvp) to predict the hemodynamic response to fluids infusion, and it should not be used to make clinical decisions regarding fluid management in critical patients. the clinical implication of this fact in septic shock is not well-known. objectives. the aim of this study is to determine if the resuscitation with fluids guided by cvp has clinical implications in patients with septic shock. post-hoc analysis of a patients' cohort with septic shock admitted in the medical intensive care unit since june to june . all of them were treated on basis of a bundle for severe sepsis management. chi-square analysis was used to compare categorical data. continuous data were compared using student's t test. we used multiple logistic regression model to assess the association between the independent variable and mortality, after adjustment for possible confusing factors (we considered variable to be confounding if the estimate of the coefficient changed by more than %). eighty-five patients were studied. % were male. their average age was ± and % had previous chronic diseases. severity scores: apache ii ± , sofa ± and % of patients had multiorganic dysfunction. infectious focus was respiratory in %. cvp mean was ± mmhg, scvo ± % and the mean amount of fluids provided was ± cc. % of patients needed mechanical ventilation. hospital-stay middle was days ( - ) and days in icu conclusions. in our patients' cohort with septic shock treated under the basis of the early goal-directed resuscitation, the volume of fluids infused was associated independently with mortality. a lower fluid administration in the resuscitation probably could be caused by the early reach of a high central venous pressure. blinding of study interventions is necessary to prevent bias in randomized controlled trials (rct). since normal saline and % albumin are packaged in bags and bottles, respectively and they have different color and texture, a blinding procedure is necessary to ensure the fluids appear identical for comparative rcts. objectives. to describe the blinding procedure and evaluate sterility and stability involved in the transfer and storage of study fluids in the precise pilot rct. a standard operating procedure for concealment, meeting pharmacy guidelines and good manufacturing practices was developed by the manufacturing pharmacist at the coordinating centre and used by all participating sites. fluids were transferred with aseptic technique into identical ml bottles under a sterile hood by the pharmacy or transfusion medicine technician then covered with an opaque wrapping. average time to transfer of study fluids from their original packaging was recorded to understand labor involved with creating each study fluid package. yellow intravenous tubing was manufactured to also conceal the fluid color. six blinded bottles of normal saline and % albumin from the participating centers were stored at room temperature for at least months. cultures of the fluids using blood culture media and/or endotoxin levels (measured by commercial assay) were obtained to document sterility of the study fluids. protein electrophoresis was used to assess albumin stability. results. transfer of the study fluids was the responsibility of the research pharmacist/ technician and blood bank at and sites, respectively. average time to transfer containers of normal saline and % albumin into bottles was ± and ± min, respectively. sterility (culture negative and/or endotoxin undetectable) of study fluids was confirmed from all bottles of normal saline and albumin that underwent testing. protein electrophoresis of albumin samples showed a single band suggesting no degradation of albumin during transfer and storage. conclusions. the standardized blinding procedure developed for transfer of study fluids in this pilot rct confirmed sterility and stability of our study fluids for months. these data are important when considering the length of allowable storage time for these study fluids. due to the resources and time involved with the transfer of these fluids for individual sites, this transfer method needs to be incorporated into budgeting and may not be feasible in the context of a large rct. grant acknowledgment. the precise pilot rct was funded by a grant from canadian blood services. covidien, singapore, singapore, yong loo lin school of medicine, national university of singapore, biostatistics unit, singapore, singapore introduction. the surviving sepsis campaign recommends a -h resuscitation bundle and a -h management bundle to improve outcomes in severe sepsis. compliance with and relevance of these recommendations to asian intensive care units (icus) are unknown. objectives. the primary objective of the present study was to assess the compliance of asian icus and hospitals to these bundles. the secondary objectives were to evaluate the impact of compliance on mortality, and the organisational characteristics of asian hospitals which are associated with higher compliance. methods. this was a prospective observational study of patients with severe sepsis who were admitted to the participating icus in july . we recorded the organisational characteristics of participating centres, the patients' baseline characteristics, and the achievement of targets within the resuscitation and management bundles. results. sixteen countries and icus participated, enrolling patients. hospital mortality was . %. achievement rates for the bundle targets were: lactate measurement, . %; blood cultures, . %; broad-spectrum antibiotics, . %; fluids ± vasopressors, . %; central venous pressure, . %; central or mixed venous oxygen saturation, . %; low-dose steroids, . %; drotrecogin alfa, . %; glucose control, . %; lung-protective ventilation, . %. compliance rates for the entire resuscitation and management bundles were . and . % respectively. on logistic regression analysis, achievement of the targets for blood cultures, antibiotics, and central venous pressure independently predicted decreased mortality. high-income countries, university hospitals, icus with an accredited fellowship programme, and surgical icus were more likely to be compliant to the resuscitation bundle. conclusions. compliance to the resuscitation and management bundles is generally poor across asia. given the resource limitations in asia, the most appropriate strategy to improve outcomes in severe sepsis may be to concentrate on ensuring early administration of antibiotics after blood cultures, and appropriate fluid therapy. cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery monitoring brain oxygen saturation during coronary bypass surgery: a randomized, prospective study the work is supported by departmental sources. clinical features and prognosis of organizing pneumonia pre-senting as acute respiratory failure in icu reference(s). . webster nr. ventilation in the prone position prone position in acute respiratory distress syndrome effect of prone positioning on the survival of patients with acute respiratory failure acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome this study was funded by arjo international ag, florenzstrasse d metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports longterm propofol infusion and cardiac failure in adult head-injured patients mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium intermittent haemodialysis versus crrt for arf in the intensive care unit dialysis dose in acute kidney injury: no time for therapeutic nihilism cirrhotics admitted to icu, and when added to the liver-specific scores of meld or ukeld, improves their respective predictive value intensive care, london, uk, royal free hospital epidural anesthesia, hypotension and changes in intravascular volume intraoperative fluid restriction improves outcome after major elective gastrointestinal surgery surrogate designation: can we trust our relatives? does chest physical therapy work? physiotherapy in intensive care: towards an evidence-based practice fisioterapia no paciente sob ventilação mecânica this research was supported by grants from the following brazilian funding agencies/programs: cnpq, capes, fapesc and unesc readmission to surgical intensive care increases severity-adjusted patient mortality physiological scoring systems and audit predicting death and readmission after intensive care discharge a case-control study of patients readmitted to the intensive care unit severity of illness and risk of readmission to intensive care: a meta-analysis a comparison of admission and worst -h acute physiology and chronic health evaluation ii scores in predicting hospital mortality: a retrospective cohort study learning from the past to inform the future-a survey of consultant nurses in emergency care assessing emergency nursing competence post-traumatic stress among swedish ambulance personel levels of mental health problems among uk emergency ambulance workers partial and full ptsd in brazilian ambulance workers: prevalence and impact on health and on quality of life ambulance personnel and critical incidents impact of accident and emergency work on mental health and emotional well being artemis health institute, director, critical care, pulmonology and sleep medicine, gurgaon, india, artemis health institute, nursing, gurgaon, india reference(s) the australian incident monitoring study in intensive care: aims-icu. the development and evaluation of an incident reporting system in intensive care adverse events in critical ill patients ministry of health and social policy communication: a key factor in the patient safety? anemia of the critically ill: acute anemia of chronic disease impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient high dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome: the journal of trauma: injury, infection and critical ca to the staff of the critical care department, faculty of medicine injury severity and quality of life: whose perspective is important? quality of life and persisting symptoms in intensive care unit survivors: implications for care after discharge variations in health-related quality of life in critical patients funded in part by fogarty international center nih grant no. d tw - and clinical research institute-fundacion valle del lili glasgow coma score, use of mechanical ventilation and vasoactive agents, and the occurrence of severe sepsis (according to bone's criteria- ). the causes of admission were divided as: ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, status epilepticus, traumatic brain injury, elective neurosurgeries, and miscellanea. the foci of infection, microbiological data and bacteremia were analyzed from septic patients. numeric data were expressed as median and interquartiles, while categorical data were calculated as percentage. univariate and multivariate (logistic regression) analysis was carried out to point factors associated with hospital mortality. results. we included patients, with median age years (iq range - ) and % were male %) patients, while it occurred during icu stay on ( %) patients. hospital mortality was associated with age, the admission cause (higher for hemorrhagic stroke, traumatic brain injury and status epilepticus), apache ii score, glasgow coma score and severe sepsis on the univariate analysis cnpq perioperative factors associated to higher mortality in patients admitted to the neurological intensive care unit (nicu) immediately after brain tumor (bt) resection saldívar umae (high-specialty medical unit no ) el bajío, imss and nicu, hraeb (high-specialty regional hospital of el bajío) anaesthesiology and intensiv care medizin anaesthesiology and intensive care unit charité universitätsmedizin-berlin, department for anesthesiology and intensive care medicine after approval of the local ethics committee, the pdr icg was measured within h post injury (day ) using the non-invasive limon system (pulsion medical systems of pdr icg to supranormal values higher sofa scores were indirectly associated with lower pdr icg values, particularly for sofa scores[ . when patients were grouped by icu length of stay (\ , c days, corresponding to the mean icu los of the german trauma registry), logistic regression analysis identified pdr icg consumables were provided by pulsion medical systems influence of apoe polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury genetic variation of the apoe promoter and outcome after head injury effects of apolipoprotein e genotype on outcome after ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage the association between apoe « , age and outcome after head injury: a prospective cohort study decreased cerebrospinal fluid apolipoprotein e after subarachnoid hemorrhage correlation with injury severity and clinical outcome « association of ventilation rates and co concentrations with health and other responses in commercial and industrial buildings « sensitivity to noise, personality hardiness, and noise-induced stress in critical care nurses recommended lighting level for offices » the chartered institution of « sick building syndrome, sensation of dryness and thermal comfort in relation to room temperature in an office building: need for individual control of temperature silent misery: most severe critical incidents post traumatic stress disorder in the emergency room: exploration of a cognitive model trauma exposure and post-traumatic stress disorder in intensive care unit personnel increased prevalence of post-traumatic stress disorder symptoms in critical care nurses drivers of quality in health services: different worldviews of clinicians and policy managers revealed systems thinking, system dynamics the fifth discipline: the art and practice of the learning organisation the development of system dynamics as a methodology for system description and qualitative analysis finnish funding agency for technology and innovation nursing activities score tradução para o português e validação de um instrumento de medida de carga de trabalho de enfermagem em unidads de terapia intensiva: nursing activities score (nas) nursing activities score in the intensive care unit: analysis of the related factors the self-perceived health between medical-surgical and crit-ical care nurses in hungary deutsch , i. boncz , a. sebestyen , a. olah university of pecs faculty of health sciences a longitudinal study design was used to explore the self perceived health of inhospital nurses in acute care settings (surgery, casualty, internal medicine, intensive, coronary care, emergency room) in two hungarian factors predicting team climate, and its relationship with quality of care in general practice nurse working conditions, organizational climate, and intent to leave in icus: an instrumental variable approach critical care nurses' work environments: a baseline status report quality of practice in an intensive care unit (icu): a mini-ethnographic case study vasps/intv ). medicinska fakulteten, lunds universitet critical thinking and clinical decision making in critical care nursing assessing and developing critical-thinking skills in the intensive care unit gulhane military medical academy, haydarpasa training hospital, istanbul, turkey, gulhane military medical academy technology as a catalyst to transforming nursing care devices and desire: gender, technology and american nursing surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock division of pulmonary and critical care medicine, seoul, republic of korea, peking union medical college hospital, department of critical care medicine mai hospital, intensive care department, hanoi, viet nam, king saud bin abdulaziz university for health sciences, king abdulaziz medical city, intensive care department dr soetomo general hospital, department of intensive care republic of china, ripas hospital, intensive care unit surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock the surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis great differences in compli-ance with surviving sepsis campaign bundles surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock delayed diagnosis is associated with increased morbidity, mortality and cost in the icu. as the mortality rate of severe sepsis remains unacceptably high, a group of international expert developed guidelines in , termed the surviving sepsis campaign (ssc). the ssc group has introduced the ''sepsis care bundles surviving sepsis campaign guidelines for severe sepsis and septic shock implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality improving outcomes for severe sepsis and septic shock: tools for early identification of at-risk patients and treatment protocol implementation observational, prospective follow-up. patients who were admitted into the intensive care unit in university hospital complex a coruña (chuac) during the months of hospital mortality was surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock early goal-directed therapy in the treatment of severe sepsis and septic shock associated with decreased mortality translating research to clinical practice: a -year experience with implementing early goal-directed therapy for septic shock in the emergency department improvement in process of care and outcome after a multicenter severe sepsis educational program in spain duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock delta co (pvco -paco ) as a prognostic factor in septic shock septic shock using the new device inspectra : relation to macro-and microhemodynamic and outcome c. luengo , , f. vallée , c. damoisel , m. resche-rigon among the techniques assessing microperfusion, near infrared spectroscopy (nirs) gained interest. more than baseline sto values, the reperfusion slope after a vascular occlusion test (vot) nirs parameters, especially the reperfusion slope scvo or svo ); metabolic (ph, base excess and lactate) parameters were collected. microperfusion data consisted in: nirs (baseline sto , occlusion and reperfusion slopes (%/s), automated software); skin laser doppler microflow (baseline flow (tpu), peak flow (tpu) and slope during reperfusion (tpu/s), measured during and after a min vot. survivors (s) and non-survivors ] differed between s and ns at day . macro-hemodynamic and metabolic data did not differ between s and ns plan quadriennal ea svo does not predict fluid responsiveness in critically ill septic patients supported by msm research grant: replacement of and support to some vital organs years) were studied. apache ii and sofa score at study entry were (range: - ) and (range: - ) respectively. the septic syndrome was due to sepsis (n = ), severe sepsis (n = ) or septic shock (n = ). sites of infection included the lung reference(s). . ungerstedt u: microdialysis: principles and applications for studies in animals and man the pathophysiology and treatment of sepsis management of sepsis surviving sepsis campaign guidelines for management of severe sepsis and septic shock relation between muscle na + k + atpase activity and raised lactate concentrations in septic shock: a prospective study long-term continuous glucose monitoring with microdialysis in ambulatory insulin-dependent diabetic patients whether it is worth to correct acidemia by infusion of alkaline solutions is a matter of discussion. there are a number of evidences against the use of alkalinization therapy with respect to the benefits of reversing ph and the side effects of sodium bicarbonate infusion [ ]. nonetheless, as recently shown by means of an on line survey, % of critical care physicians administer base to patients with lactic acidosis mmol/l), animals were randomized to min of: a) sustained lactic acid infusion, a + b) sustained infusion + sodium bicarbonate, o) transient infusion, b) transient infusion + sodium bicarbonate. in the transient infusion (group o and b), at randomization lactic acid was replaced with normal saline. acid-base status and lactate levels were measured over time. in a number of animals phosphofructokinase (pfk) enzyme's activity was also measured. results. following lactic acid infusion blood lactate rose unnecessary use of alkali perturb acid-base status and lactate metabolism potentially overcoming metabolic adaptive strategies. reference(s). . boyd jh, walley kr. is there a role for sodium bicarbonatein treting lactic acidosis from shock? use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey strong ions gap (sig) quantifies unmeasured blood anions and it is calculated by the difference between strong cations and strong anions (all of them, dissociated in blood plasma) retrospective, observational study of all patients with septic shock as defined by the american-european consensus, admitted to the icu from arterial blood gases, albumin, lactate and electrolytes were obtained at admittance and h later; apache and sofa score, central venous saturation and lactate comparison of acid base models for prediction of hospital mortality following trauma forty-five sepsis patients [median age, (iqr, - ) years; admission saps ii, ( - ) pts; severest multiple organ dysfunction syndrome score interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial lambert university of leicester, division of anaesthesia, leicester, uk blood samples were taken: at induction of anaesthesia, at and - h post-cpb. neutrophils were isolated, mrna extracted, dna cleaned and reverse transcribed supported by a grant from the association of anaesthetists of great britain and ireland, and the british journal of anaesthesia/royal college of anaesthetists secretoneurin (sn), a neuropeptide, is specifically expressed in endocrine elevated nucleosome levels in systemic inflammation and sepsis extracellular histones are major mediators of death in sepsis rd esicm asymmetric and symmetric dimethylarginines (adma, sdma) are protein-breakdown markers; both compete with arginine for cellular transport and are excreted in urine. moreover adma, sdma, their ratio (marker of adma catabolism), arginine, interleukin- (il- ), tumor-necrosis-factor-a (tnf-a), c-reactive-protein(crp) on day , , , , and at discharge in consecutive severely-septic patients were measured sdma were higher than normal, adma/sdma ratio was halved, arginine was low. adma was related to total sofa and arginine, inversely related to il- and crp; sdma was related to saps ii, sofa, blood urea, creatinine, arginine. adma/sdma ratio was inversely in non-survivors, creatinine, il- , tnf-a, crp and adma were stable, sdma increased, adma/sdma ratio remained low figure: time course of adma and sdma blood levels (mean ± standard error) during icu stay and the last icu day protein-hmgb- levels as predictors of outcome in patients with sepsis and septic shock hmgb as a predictor of organ dysfunction and outcome in patients with severe sepsis early low dcs counts may be correlated to disease severity and could predict fatal outcome. however, little is known about dc number in other shock than septic. objectives. to evaluate and compare the circulating dcs number in patients with severe sepsis, septic or cardiogenic shock. methods. in a prospective multicentric study ( icu), consecutive immunocompetent patients with severe sepsis (ss), septic shock, cardiogenic shock were included. peripheral blood dc counts, measured by flow cytometry, were evaluated and compared between the three populations at admission and h later. correlation to disease severity evaluated by clinical scores and day mortality was studied. results. patients were included (age ± years, male, sofa d . ± . , saps ii ± ): septic shock, severe sepsis and cardiogenic shock. mortality at d was respectively , and %. patients presented a sepsis associated to cardiogenic shock. at baseline and at day , a dramatic diminution in the numbers of total dcs either myeloid (mdcs) or plasmacytoid (pdcs), was observed in sepsis (severe sepsis or septic shock) compared to cardiogenic shock patients. no difference was seen between severe sepsis and septic shock patients (fig. ). we did not observe any correlation between the number of total dcs at admission or at day and severity of illness scores dc reduced number is a valuable marker of severe sepsis in shock and is not affected by hemodynamic changes. it could not be used as a prognostic marker in severe septic patients. preliminary results from a prospective study assessing the relationship between standard laboratory coagulation and global tests of clot-formation using thromboelastography in patients with fulminant hepatic failure v the routine use of international normalized ratio (inr) to establish the coagulation status in patients with fulminant hepatic failure (fhf) may be misleading. anecdotally, fhf patients, despite a significantly deranged inr, may display a normal or even hypercoagulable state, as recently shown, albeit in an extracorporeal setting, with frequently clotted circuits, despite raised pt we prospectively studied coagulation, demographic, survival and outcome measures of fhf patients (defined by de-novo liver failure, coagulopathy-inr [ . , and encephalopathy) admitted to the royal free hospital liver and/or intensive care unit(s) (icu), a tertiary referral centre in liver diseases and transplantation we present the standard clotting tests and teg results from (of a required ) patients currently enrolled, demonstrating variable degrees of encephalopathy and coagulopathy effect of norepinephrine on cardiac output and preload in septic shock patients apparent heterogeneity in splanchnic vascular response to norepinephrine during sepsis aggressive use of high-dose norepinephrine in the treatment of septic shock norepinephrine requirement is not an independent variable to predict outcome in severe septic shock patients aim. the aim of this study was to measure the level of ptsd among hungarian ambulance workers, and explore factors which can influence it.sample and methods. hungarian ambulance workers were involved to this crosssectional study ( ambulance drivers, ambulance nurses, and ambulance team leaders: medical doctors and ambulance officers). self filling questionnaire were used for data collection, including briere's trauma symptom checklist, and socio-demographic questions. chi square test, independent t test and variance analysis were used for comparison of variables.results. the average ptsd-points of ambulance workers was . there was significant association between level of ptsd and gender: women's average , men's average ptsd-points (p = . ). there were no correlations between level of ptsd and type of settlement, location of ambulance station and level of education. those who would need psychological support (p = . ), and those who had psychologically traumatic experiences in the last years have significantly higher ptsd-points (p = . ).conclusions. hungarian ambulance workers are exposed with many effects which can lead ptsd. professional psychological support is needed in order to cope with ptsd successfully.the results were presented and discussed in our weekly meeting on patient safety and healthcare for all icu personnel. by the end of this year all the recommendations will be implemented in our icu.conclusions. we improved the safety and quality of in hospital transportation of icu patients by performing a prospective risk analysis. bow-tie is a good instrument to identify health care risks. to determine the incidence of phrenic neuropathy associated with the catheterization of internal jugular and subclavian veins, without ultrasound support, in patients admitted to an icu. a prospective study was performed by following patients admitted in the icu between october and may . a normal neurography of both right and left phrenic nerves at the moment of their admission was the main inclusion criteria. after this baseline study, a new neurography was repeated weekly (chen and resman method, sinergy medelec), during their stay and at the moment of being discharge from icu. simultaneously, all vascular subclavian and internal jugular vein catheterization were registered. a final neurography and a fluoroscopy study were performed after being discharged from hospital. results. patients were included and two hundred and ten neurographies of both right and left phrenic nerves were performed. patients did not receive any vascular punctures in the cervical region during the follow up period, acting as control group. patients underwent a total of vascular catheterization, in subclavian vein ( . %) and in internal jugular vein ( . %). a phrenic neuropathy was diagnosed in patients. this represented an incidence of % ( / ) of phrenic neuropathy per patient and % ( / ) related to subclavian and internal jugular vein catheterization. in relation to patients without phrenic nerve injury who underwent subclavian and internal jugular vein catheterization, patients affected of phrenic neuropathy had longer mechanical ventilation time ( ± days vs. ± , p = . ) and longer average stay time in icu ( . ± days vs. ± , p = . ), although these differences have not statistical significance. we did not find significantly differences related to age ( ± vs. ± , p = . ) and apache ii index ( ± . vs. . ± . , p = . ) between both groups (wilcoxon two-sample test). we performed a control neurography of case patients after being discharged from hospital. we checked the cmap phrenic nerve reappearance after weeks and months of being diagnosed its neuropathy, respectively. conclusions. we found an incidence of phrenic neuropathy of % per patient and % related to subclavian and internal jugular vein catheterization, during the follow-up period. the time of reappearance of phrenic cmaps after being detected its neuropathy points to a neuroapraxia or partial axonotmesis as pathogenic type of injury.discussion. phrenic neuropathy has to be considered in cases of difficult weaning of unclear etiology. the catheterization of subclavian and internal jugular veins should be recommended employing ultrasound support. p. merino , m.c. martin-delgado , j. alvarez , i. gutiérrez-cía , Á . alonso-ovies , syrec hospital can misses, icu, ibiza, spain, isde, Á rea de salud, madrid, spain, hospital de fuenlabrada, icu, madrid, spain, hospital clínico universitario, icu, zaragoza, spain introduction. syrec project aims to improve icu patient safety. the project includes an epidemiological study. we present the main results.objectives. to estimate the near miss (nm) and adverse events (ae) rate in spanish intensive care units (icus). we study the incidence and nature. finally, we classify and analyze its severity.methods. multicenter prospective observational cohort study. inclusion criteria: patients admitted to the participant icus during the -h observation period. during this period, nm and ae detected and reported inside and outside icu were included. only outside icus were considered when its were the reason for admission. we evaluate the kind of incident, severity and preventability. data collection studied under the distribution of frequencies.results. , patients were included. , incidents were reported in patients, were nm and ae. risk: the median risk of nm was % versus ae %. . incidents per patient admitted. incidence rate: the incident rate median was . per patients per hour icu stay, the nm of . per patients per hour icu stay and that of ae, . per patients time of stay in icu. the % of the incidents reported have been nm and % ae. this incidents causing temporary damage in the . % of occasions and in the . % permanent damage, compromised the patient's life or contributed to death. classification of incidents (table ) . conclusions. our study shows a high individual risk. our icus services present a highrisk environment. therefore we have to go into the developement of epidemiological studies depth, in order to create further strategies supporting patient safety. restore cardiovascular performance in severe lactic acidotic rats a. kimmoun , n. sennoun , n. ducrocq , b. levy , inserm u , groupe choc, vandoeuvre-lès-nancy, france, chu nancy brabois, intensive care unit, vandoeuvre-lès-nancy, france introduction. lactic acidosis during shock is responsible for myocardial failure, vascular hyporesponsiveness and a decrease in sensitivity to vasopressor agents. sodium bicarbonate is a proposed treatment to correct acidosis, although with deleterious cardiovascular effects. indeed, hypocalcemia and hypercapnia, both powerful myocardial depressants, are the main side effects of the administration of this therapy [ ] . objectives. already studied in experimental models of isolated lactic acidosis, the cardiovascular effects of sodium bicarbonate administration have never been explored after correction for hypocalcemia and hypercapnia. methods. we therefore compared, in a rat model of severe lactic acidosis (ph \ . , hyperlactatemia[ mmol/l) induced by a state of controlled hemorrhagic shock, the cardiovascular effects of: ( ) standard resuscitation plus administration of sodium bicarbonate with correction for calcemia and paco (''adapt'' group, n = ); ( ) standard resuscitation plus administration of sodium bicarbonate without correction for paco and calcium (''nonadpat'' group, n = );( ) standard resuscitation; (''stand'' group, n = ); ( ) standard resuscitation plus calcium administration (''calc'' group, n = ). evaluation at steady and shock state, min and min was focused in vivo on arterial gas and myocardial contractility (emax) by conductance catheter. ex vivo vasoreactivity was tested on mesenteric arteries ( lm) by myography. sodium intakes were equivalent between groups. results. our model displayed a profound acidosis from . to . ± . (p = . ) and hyperlactatemia from . ± . to . ± . mmol/l (p \ . ). emax decreased from . ± . to . ± . mmhg/ll p = . . in the adapt group, at min, ph was normalized at . ± . (p = . ). furthermore, emax was enhanced at ± % (p \ . ) (stand: ± %, nonadapt: ± %, calc: ± %). the cumulative dose of infused norepinephrine was significantly lower in the adapt group ± lg/kg compared to other groups (stand: ± lg/kg, nonadapt: ± lg/kg, calc: ± lg/kg, p = . ). ex vivo mesenteric vasoreactivity in the adapt group was normalized (graph ).mesenteric vasoreactivity to phenylephrine conclusions. in severe lactic acidosis, infusion of sodium bicarbonate after correction of its side effects improves myocardial function and vasoreactivity. [ ] . the prevalence and significance of -hydroxyvitamin d deficiency in the intensive care unit have not been fully determined. a recent study of an unselected group of itu patients [ ] has suggested low itu admission -hydroxyvitamin d levels are common. objectives/hypotheses to be tested. royal free hospital intensive care unit patients exhibit low circulating levels of -hydroxyvitamin d. circulating levels of -hydroxyvitamin d decrease further during the course of hospital admission. admission circulating levels of -hydroxyvitamin d affect itu morbidity and mortality methods. all itu admissions were assessed within h of presentation and patients who were deemed to have the potential to require admission for at least week were included. demographic and clinical data were obtained in a prospective manner. results were recorded from samples obtained at admission, days and days. standard itu nutrition protocols were used. no interventions were performed. results. clinical and outcome data were obtained for patients. no significant differences between apache , saps or apache scores for survivor and non-survivor groups at either itu or hospital discharge were noted. further patients await complete data analysis. % ( of for whom results were available) achieved an adequate ([ nmol/l) circulating hydroxyvitamin d level. patients ( . %) demonstrated levels within the insufficient range ( - nmol/l). patients ( . %) did not have any detectable -hydroxyvitamin d. the remaining patients ( . %) were either in the deficient ( . %, - nmol/l) or severely deficient ( . %, - nmol/l) ranges. admission -hydroxyvitamin d levels in survivors and non-survivors were compared at itu and hospital discharge. no significant differences between the four groups (p [ . , anova) were observed, indicating that in this data set, admission -hydroxyvitamin d levels do not appear to alter or determine clinical course. mean -hydroxyvitamin d levels were compared at admission, day and at day . no significant differences between the three groups (p [ . , anova) were identified. no significant differences between the mean -hydroxyvitamin d levels of the survivors and non-survivors at day or day were apparent (small numbers). admission [ , ] and patients undergoing surgical procedures [ ] . patients with neurological illness can receive significant quantities of ns, chosen primarily for its iso-osmolar properties. objectives. ns is commonly used as maintenance and resuscitation fluid by the anaesthetist, and as intravascular flushes by the radiologist during prolonged interventional neuroradiological (inr) procedures. this pilot feasibility study aimed to ascertain the effect of ns infusion on acid-base measurements in patients undergoing inr procedures under propofol-remifentanil anaesthesia. methods. we collated routine electrolyte, albumin and acid-base data of patients who underwent coil/glue embolisations of intracranial aneurysms and vascular malformations, both before and after the procedure. base excess (be) was partitioned into the effects of sodium chloride difference (na-cl), albumin, lactate and unmeasured anions (uma), using the stewart-fencl-story approach [ ] . all values are reported as medians (ranges objectives. to investigate the erythropoietic response to hight dose of a weekly schedule of recombinant human erythropoietin (rhuepo) in critically ill anaemic septic patients. a total of patients admitted to the intensive care unite (icu) were enrolled in this study, patients were randomized to receive either rhuepo or not, patient did to form the rhuepo group, did not to form the control group.results. the epo treated group of patients showed significant increase in reticulocyte count compared with baseline p \ . , as well as with the control group p \ . . the epo treated group exhibited also a significant increases in hb concentration compared with baseline p \ . as well as the control group . . all patients in the control group received rbc blood transfusion %, while only . % of the epo group did. the epo treated group showed significant decreases in their apache ii score during the study period compared with baseline p \ . as well as with the control group p \ . . the epo treated group showed no significant difference in their sofa score compared with baseline p \ . , however the control group exhibited continuous and significant increase in their sofa score throughout the study period compared with their baseline p \ . , there was no significant difference in the final outcome recovery, mortality or morbidity p . , p \ . respectively.conclusions. the administration of rhuepo to critically ill anaemic septic patients is effective in raising their reticulocytic counts, hb concentrations and in reducing the total number of units of rbcs they require. in addition there was a trend toward better in hospital clinical course, increased recovery and decreased mortality in the rhuepo group.conclusions. anaemia is common following critical illness but does not appear to affect the physical aspects of recovery during medium term rehabilitation. this may be due to an overwhelming degree of symptom burden from other complications of critical illness impairing physical function to such a degree that the effects of anaemia are negligible in the medium term. although decreases in number and function has mainly been described in skeletal muscle, also other organs seem to be affected and it has been hypothesized that mitochondrial dysfunction might be involved in the development of organ failure. to study the effect of plasma of patients with septic shock on mitochondrial function in vitro to potentially later on identify a central factor affecting mitochondria in all tissues during sepsis and leading to multiple organ failure.methods. after sacrificing - week old sprague-dawley rats, mitochondria from soleus muscle were isolated through homogenization and a series of centrifugations. mitochondrial function was assessed by measuring of oxygen consumption, using an oxygraph containing a clarke-electrode, after addition of adp. before these measurements, mitochondria were incubated with plasma from septic patients or healthy volunteers, respectively, for min. in our second series, the mitochondria were incubated with different concentrations of il- , tnf-a or buffer. respiration rates were measured in the presence of adp (state ; a measure for the oxidative capacity to produce atp) and without the presence of adp (state ; a measure for the amount of uncoupling). respiratory control ratio (rcr; a measure for the respiratory efficiency of the mitochondria) was calculated by dividing state by state activity. all measurements were related to citrate synthase activity to compensate for the amount of mitochondria. statistical differences between the groups were analyzed using a student's t test.results. adp dependent (state ) respiration was % higher and rcr % higher in the mitochondria incubated with plasma from the septic patients compared to those incubated with plasma from healthy volunteers (table) . there were no significant differences between the groups incubated with preservation buffer or the different cytokines (table) . introduction. microvascular fluid loss from the intravascular to the interstitial space generates tissue edema and is one of the major challenges in emergency and intensive care medicine. isolation of interstitial fluid (if) from skin makes it possible to study the microcirculation and proteins in this environment both during normal as well as pathophysiological conditions such as acute inflammation.objectives. by studying bio-markers from proteomic analysis by mass spectrometry in an inflammation model, we wanted to find proteomes that could be important in explaining inflammation. we have applied a recently described centrifugation method in a porcine model and compared it with implanted wicks. in nine anesthesized piglets we compared the methods and evaluated the if, by overhydrating the pigs with ml of acetated ringer's solution for h, and thereafter continuously supplemented for h according to fluid losses. if was isolated from implanted dry wicks, wet wicks and by centrifugation of excised skin. the methods were evaluated by the ability to reflect overhydration and to show the expected composition of plasma proteins in if by use of hplc. the if was also processed further with mass spectrometry to find possible tissue degradation or inflammation due to overhydration. statistics: by spss v . and graphpad instat (version . ). significance level: p = . . colloid osmotic pressure in if was significantly lowered after overhydration for all the tree methods. wet wicks p = . , dry wicks p = . , skin samples p = . . hplc of if collected with centrifugation after overhydration, identified peaks representing molecules smaller than albumin. mass spectrometry of the same if identified several proteins associated with inflammation: alpha- -antichymotrypsin and lumican, the latter a protein identified as a modulator of inflammation. we have introduced a new centrifugation method for isolation of if from the skin of pigs. by further analysis of if isolated by centrifugation we were able to distinguish proteins found only in the if of the pigs overhydrated with ringer's acetate. these proteins could be associated with an inflammatory condition in the skin caused by massive overhydration, again causing tissue degradation. identification and validation of proteomic biomarkers can be a useful tool in future treatment of inflammation in general, and in sepsis in special. objectives. to define the pattern of change in metabolites by mrs in experimental sepsis. male sd rats (weight - g) underwent cecal ligation and puncture or sham procedure (n = per group), and h after surgery were euthanized. pulmonary tissue was extracted for magic angle mrs (hr-mas) and processing by the r metabonomic package. a supervised statistical analysis of main components (mc) was performed on the processed spectra.results. the mc analysis discriminated both group (septic and nonseptic) indicating a different metabolite profile. in addition, the analysis of mc loading revealed displacement positions in the discrimination between groups with a variation in the signal intensity of %.conclusions. metabolomic analysis of pulmonary tissue by mrs is a potentially useful technique for the detection of biomarkers in sepsis.grant acknowledgment. introduction. cd + cd + neutrophils are a key subset of phagocytes associated with severe bacterial sepsis [ ] . their characteristics, and potential neuro-immunomodulation, have not been explored in humans neutrophils exposed to septic plasma from icu patients. to assess the effect of adrenergic/cholinergic neurotransmitter molecules on human neutrophil adhesion and activation markers following exposure to human septic plasma. with irb approval, neutrophils were isolated from healthy volunteers (ficoll density gradient separation) and incubated for h with either plasma from healthy volunteers or septic patients plus pathophysiological concentrations of epinephrine (e), norepinephrine (ne) or acetylcholine (ach) and nicotine (nic) to assess potential parasympathetic-related neuro-immunomodulation. flow cytometry (dako cyan) measured expression on neutrophils of cd , cd , cd antibody markers and viability. median values are shown; analyzed by anova.results. neutrophils were unaffected by ne, e, ach or nic after incubation with plasma from healthy volunteers. after incubation with septic plasma, marked neutrophil activation occurred (p = . ). however, nic reduced cd + cd + activation (* fig. a ) by % (median ( - %; th- th centiles); p = . ). nic also attenuated cd expression, suggesting reduced neutrophil adhesion (* fig. b) . neutrophil viability was similar across drug and plasma treatments. conclusions. these preliminary data suggest that nicotine attenuates both the activation and adhesion of human neutrophils exposed to human septic plasma, but does not affect viability. objectives. the aim of this study was to evaluate the potential impact of lag between sepsis initiation and start of treatment on mitochondrial respiration. methods. animals [ . ± . kg] were randomized (n = /group) to a control group (group i) and three groups resuscitated at (group ii), (group iii), and (group iv) hours, respectively, after fecal peritonitis induction. fecal peritonitis was induced with instillation of . g/kg of autologous feces via intra-peritoneal drain. resuscitation was performed according to the ssc and esicm sepsis guidelines for h. respiration of permeabilized skeletal muscle fibers and their isolated mitochondria was assessed at baseline and after , , , and h, when applicable, or before death occurred, if earlier. at the end of the experiment, also isolated brain, hepatic and myocardial mitochondrial respiration was measured using high resolution respirometry (oxygraph- k, oroboros instruments, innsbruck, austria). results. mortality ( %, each) and organ dysfunction was highest in groups iii and iv. in these two groups, different pattern of changes of skeletal muscle mitochondrial complex i-dependent respiratory control ratio (rcr) were observed (table ) . no significant differences between groups were observed for complex i-and ii-dependent rcr values of hepatic, myocardial and brain mitochondrial respiration (fig. ). there were no significant differences between the groups for any of the complexes in permeabilized skeletal muscle fibers mitochondrial respiration (data not shown). conclusions. despite the high mortality observed in groups resuscitated at later time points after induction of sepsis, end organ mitochondrial function assessed using physiological substrates was preserved. despite significant changes in skeletal muscle mitochondrial respiration efficiency in the two groups with the highest mortality, our findings do not support the view that mitochondrial dysfunction plays a major role in the pathogenesis of multiorgan dysfunction in experimental sepsis. grant acknowledgment. swiss national fund, nr: - ; stiftung für die forschung in anästhesiologie und intensivmedizin. adipose tissue is an endocrine organ which produces signalling proteins involved in inflammation and glucose homeostasis [ ] . one of these proteins, adiponectin, promotes glucose utilisation and fatty acid oxidation and thus improves insulin sensitivity via its two receptors, adipor and adipor [ ] . adiponectin expression has been shown to be reduced in type ii diabetes, obesity and endotoxaemia [ , ] . adiponectin also exhibits antiinflammatory properties [ ] . in this study, we have examined whether adiponectin and its receptor gene expression changes in murine adipocytes stimulated by lps. methods. t --l adipocytes were grown in culture media (dmem with % fetal calf serum) until confluent. pre adipocytes were differentiated with the addition of mg/ml insulin, mm dexamethasone and mm ibmx. media was changed every h. cells were treated on day with ng/ml, or mcg/ml lps (escherichia coli, sigma-aldrich). cells were harvested at and h. mrna levels were determined by rt pcr in a . ll reaction volume consisting of . ng of reverse transcribed cdna mixed with optimal concentrations of primers and probe and qpcr tm core kit (eurogentec, uk) in -well plates on a mx p detector. results. cell response to lps was confirmed using il as a reference gene. expression of adiponectin mrna was significantly reduced in cells treated with lg/ml lps harvested at h ( . fold p = . ). there were no changes in cells treated with lower concentrations of lps. there were no changes at h. r gene expression was significantly reduced following treatment with ng/ml lps at h ( . fold p = . ), but treatment with higher concentrations did not change expression. there were no changes at h. r expression levels were significantly reduced at h in the and the mcg/ml groups ( . fold p = . and fold p = . ) respectively. there were no changes at h. discussion. our results add to the evidence that changes occur in the adiponectin system during inflammation. in this model, we observed rapid reduction (at h) in adiponectin at high dose lps, r at low dose lps and r at medium and high doses. there were no changes in expression levels at h. this suggests that a rapid change in the adiponectin system may occur in response to lps but this change is not maintained at h. in a previous study, our group has shown reduced adiponectin gene expression in adipose tissue depots in lps induced endotoxaemia [ ] . it is interesting that different concentrations of lps induce different changes within the adiponectin system. further studies are needed to elucidate whether reductions in both adiponectin and its receptor may contribute to the inflammatory changes and hyperglycaemia commonly observed during sepsis including all co poisoned patients treated with hyperbaric oxygen. following parameters were seized: age, sex, date of admission, sofa, the source of the intoxication, the gravity co score, the initial clinical examination (realized by first aid), biology, the rate of hbco, the murray score and the rate of complication. results. patients were included in the study. the sex ratio was %, the mean age was ± years and the global mortality was , %. among the patients % were poisoned by smoke (s group), % by pure co (c group) and % by exhaust fumes. more than % of the exhaust fumes victims were suicide origin. this characteristic is associated with neurological impairment induce by ingested drugs. then, their neurological status is impossible to link to the co poisoning. we have therefore decided to exclude this group. the sofa score was higher in the s group compared with the c group ( . - . ; p \ . ). a co score equal to was present in versus % respectively in s versus c group (p \ . ). in the under group of patients having a co score at , % ( / ) of co poisoned patients versus . % ( / ) of smoke poisoned patients were ventilated (p \ . ). these patients were intubated either during transport or in the intensive care and none of them received hydroxycobalamine during the first aid (before intubation). the laboratory data showed in the s group a higher lactates level ( . vs. . mmol/l; p = . ) and lower initial pao /f i o ratio ( vs. ; p = . ). nine percent of the s group present a murray score at versus % for c group (p \ . ). pneumonia, shock and death were significantly more frequent in the s group (respectively . vs. . %, p \ . ; . vs. . %, p \ . ; and . vs. . %, p \ . )conclusions. as expected the smoke poisoned group has a higher mortality than pure co group (mortality % vs. overall mortality . %). at equivalent co gravity score, mortality and complications are always more frequent in the smoke poisoned group. the smoke poisoned group has a high risk of degradation. those patients require specific monitoring and support and probably early administration of hydroxycobalamine. hypothesis. at administration and maintaining higher plasma levels of at can reduce the need for inotropes in burn shock patients. we performed a retrospective cohort study of burn shock patients admitted to a single tertiary care center over years period. patients were eligible for inclusion if they were received fluid resuscitation with ringer's solution and colloid according to clinical guidelines. data were abstracted including demographic, burn injury characteristics, resuscitation fluid volume, the type of colloid and the average of plasma at levels within h after burn injury. administration of fresh frozen plasma and/or recombinant human at was defined as at administration. the decisions of at administration and inotropic support (dopamine or dobutamine) were made by the attending intensivists. primary outcome measure was the need for inotropes within h after burn injury. cox regression model was used to estimate the risk reduction by at administration and average of at levels. [ ] . argon, another member of the noble gas family has been reported previously to have a neuroprotective property [ ] . the aim of this study was to investigate whether it attenuates neuronal injury in a rat model of neonatal asphyxia. methods. seven-day-old postnatal sd rats underwent right common carotid artery ligation and then recover with their dim for h. thereafter, they were exposed to % o balanced with nitrogen for min. after h, they were treated with % argon or % nitrogen (positive control group) for min. the cohort pups without intervention served as naïve control. they were perfused days later and their brains were sectioned and stained with . % cresyl violet. microphotographs were taken from ca area of the hippocampus near - . bregma relative to adult brain at magnification. healthy cells were counted in a blind manner and their mean value was used for data analysis. results. the thickness of healthy layers in the right ca area of the positive control group was remarkably reduced compared with other groups (fig. ). quantitative analysis revealed that argon treatment significantly increased healthy cell numbers in the right ca area of hippocampus from . ± . in the positive controls to . ± . (p \ . ) (fig. ). grant acknowledgment. this study was supported by a grant from action medical research, uk. objectives. our objective was to study the mechanisms of death following high-dose citalopram administration in rats. experimental study in sprague dawley rats with intraperitoneal (ip) citalopram administration; determination of the median lethal dose (mld)using the dixon and bruce upand-down method; clinical descriptive study of citalopram-induced features and measurement of alterations in respiratory pattern (arterial blood gases and plethysmography) and biological parameters including blood lactate (scout Ò , ekf diagnostic), plasma and platelet serotonin concentrations (high-liquid performance chromatography-fluorometry); determination of the preventive activity on seizures and death of diazepam, cyproheptadine, and propranolol pretreatments with the determination of their minimal effective dose; comparisons using anova for repeated measurements followed by bonferroni post-test.results. citalopram ip-mld was determined as mg/kg in rats. seizures were significantly increased in rats receiving and % of citalopram mld versus controls (p \ . and p \ . , respectively), while death rate was only significantly increased in rats treated with % of citalopram mld (p \ . ). significant decrease in body temperature was observed after min in rats treated with doses[ % mld in comparison to controls (p \ . ). occurrence of serotonin behavioural syndrome was comparable in all groups. citalopram administration did not result in significant hypoxemia, hypercapnia, and lactate elevation, thus not supporting the hypothesis of the occurence of any significant deleterious cardiovascular effect in citalopraminduced toxicity. however, a significant moderate increase in the inspiratory time (p \ . ) accompanied with an expiratory braking was observed. a significant decrease in platelet serotonin and increase in plasma serotonin concentrations were measured (p \ . ). pre-treatment with diazepam ( . mg/kg) and cyproheptadine ( . mg/kg) of rats receiving a lethal citalopram dose prevented seizures and death, while propranolol was ineffective.conclusions. citalopram respiratory toxicity remains mild, while deaths result from seizures probably related to serotonin toxicity. our observations may be helpful to better understand and manage human citalopram poisonings. objectives. to define the population pharmacokinetics (pk) of phenytoin in the critically ill, in addition to risk factors for sub-therapeutic dosing.methods. free and total ptn concentrations were measured in serum by means of high performance liquid chromatography following microfiltration, two to three times in the first h after a loading dose. population pk modelling, including intra and interindividual variability, were determined using nonmem (r) . in the netherlands the use of diazepam is advised as first line treatment although evidence is not established and mainly provided through case-reports [ ] . to compare the effect of diazepam on mortality in (hydroxy) chloroquine intoxication to standard therapy. we performed an extensive medline search ( -april ) with a manual reference search of identified papers. (hydroxy) chloroquine intoxication studies and case reports in english, dutch or french were evaluated. patients older than years with severe intoxications, based on measured concentrations or life-threatening symptoms, were included. pooled relative risk (rr) for mortality with corresponding % confidence interval (ci) were calculated by means of a fisher exact test. our results were compared with two retrospective and one prospective study.results. there were case reports identified from which case reports met our inclusion criteria. thirteen patients received diazepam of whom two died, compared to twelve patients who did not get diazepam of whom one died. statistical analysis demonstrated that treatment with diazepam was not associated with a lower mortality rate (rr: . ci . - . ; p = . ).although pooling of case reports is debatable, these results were comparable to the retrospective and prospective studies that didn't show any benefit from diazepam in chloroquine intoxication [ , , ] . the positive effect of diazepam may have been underestimated, due to the fact that it has been given only as rescue therapy.conclusions. based on our analysis there is a lack of evidence concerning any antidotal effect of diazepam. good supportive treatment is pivotal. if the clinical manifestations of (hydroxy) chloroquine intoxications require sedation or treatment of seizures, diazepam is a good choice based on its pharmacological profile. a prospective study which compares diazepam to sedativa with similar pharmacokinetic and dynamic profile is required to prove that diazepam has any antidotal effect. introduction. brain is one of the first organs affected in sepsis and evaluation of brain function is difficult since patients are under sedation. it has been shown that mitochondrial dysfunction may play a significant role in the pathogenesis of septic encephalopathy. here we investigated inflammatory and metabolic parameters in a model of polymicrobial sepsis in mouse. methods. sepsis was induced by intraperitoneal injection of feces. animal received imipenem h after the procedure. control animals received intraperitoneal saline and imipenem after h. blood cytokines and serum lactate were measured. the animals were sacrificed by cervical dislocation. brain slices of mcm were used to measure oxygen consumption and glucose uptake.results. interleukin , mip a and interleukin b significantly raised in the first h after sepsis induction (p = . ; p = . ; p = . respectively). in h only mip a was significant higher (p = . ). lactate was elevated and h after sepsis induction (p \ . and p \ . respectively). oxygen consumption increased after h of sepsis and drops under control values h after the induction of sepsis. glucose uptake, measured by the nbdg fluorescence, was higher after h (p = . ) and h after sepsis induction.conclusion. in a murine model of abdominal sepsis, inflammatory markers, lactate production, and brain glucose uptake increased and were parallel to alterations in the mitochondrial oxygen metabolism. introduction. the royal bournemouth hospital has one of the highest out-of-hospital cardiac arrest admission rates in the uk. in , following ilcor/aha guidelines [ ] , a cooling protocol was developed for patients with return of spontaneous circulation after advanced life support for ventricular fibrillation or pulseless ventricular tachycardia. in preparation for potential new ilcor/aha guidelines in , the prospective database of outcomes for these patients was analysed.objectives. to evaluate the outcomes of therapeutic hypothermia for patients with return of spontaneous circulation following cardiac arrest. outcome data from our prospective registry of cooled patients are summarised.results. sixty-three patients were cooled in years (median age years; mode ; range - years). % survived to itu discharge and % to hospital discharge. % of these were discharged home ( % to a rehabilitation hospital before home and one patient to a long term care facility). ninety-five percent of survivors were alive at months and % alive at year with seven status results still pending. median itu length of stay was . days (range - ). six patients required temporary percutaneous tracheostomies for airway protection and weaning from ventilation. median duration from itu to hospital discharge was days (range - ).conclusions. this series is large by comparison to other uk centres. survival to hospital discharge, at months and year were better than other published results. although neurological outcomes were not formally assessed, we believe that the capacity to discharge home is a desirable patient outcome and represents the beneficial neurological effect of our cooling protocol. selection bias will have undoubtedly affected our results. however the age of our patients was higher than in published trials and in other reports is considered an adverse outcome predictor. our data would not support restricting induced hypothermia on the basis of age alone. we consider the itu and hospital lengths of stay required to discharge these patients to be long. these data were not reported in original trials. discharges may obviously be delayed for non-clinical reasons. this aside, neurological recovery progresses for months after cardiac arrest and discharge home may still prove possible if time is allowed. however, post-itu resource implications should be considered when introducing a cooling protocol. introduction. acute ischaemic stroke (ais) is the third largest cause of mortality and the leading cause of chronic disability in the industrialized world. in some parts of europe and the united states - % of patients with ais may be admitted to a neurological intensive care unit (icu) for supportive therapy with - % receiving mechanical ventilation [ , ] . there are currently no agreed uk criteria for the admission of ais patients to critical care.objectives. to review the incidence and outcome of ais in our tertiary icu over the last five years. november and november . ais was classified as thrombo-occlusive or embolic. subarachnoid haemorrhage and primary intracerebral haemorrhage were excluded. demographic and outcome data were recorded and compared against a mean value of all icu admissions.results. ais comprised . % of icu admissions during the study period. demographic data is presented in table as mean ± standard deviation or median (interquartile range) as appropriate. in % ( / ) of hospital ais admissions were admitted to icu. patients had surgical procedures including decompressive craniectomies. % of survivors had a discharge gcs of / . mortality for unselected medical admissions over the study period was %. there are differences of significance in the mortality according to the age, classified by age groups with an age cut off of years (\ years . vs. c years %, p \ . ). apart from the gcs, the rest of the variables analyzed in the ich score are not of significance; supra and infratentorial, presence of intraventricular blood neither on the divided volume over or under cc although, in the latter, a p \ . can be observed and if we only analyze the supraventricular, it comes out as significant. other analyzed data are the time of the surgery, which is not significant, the need for mechanical ventilation, which is ( . vs. . %, p \ . ), and the days of ventilation with a mortality clearly higher on those patients with\ days of ventilation ( %) and on those of shorter stay (lesser then days %).conclusions. let be remarked that the samples have been taken from patients admitted in the intensive care unit, losing a possible sample of less serious patients, and with a higher level of consciousness, what might explain why supra or infratentorial location and the volume don't come out as forecasting factors, since its likely that there are many small infratentorial outside the intensive care unit. we highlight also that the high mortality in the first few days can be caused by those patients who are admitted as donors, developing an encephalic death in the first days, conditioning also the data regarding the mortality on fewer days with ventilation. the finish up, we have to point out the fact that the presence of previous hypertension during the treatment might be a bad forecasting factor that should be deeper studied. to determine whether a delay exists between the time of diagnosis of intracranial haemorrhage and the time of reversal of anticoagulation, in patients presenting within our region. following approval by all audit and haematology departments a month retrospective analysis was performed. we reviewed consecutive patients who received reversal of anticoagulation with pcc and vitamin k having presenting with intracranial haemorrhage whilst on warfarin. time of diagnosis was obtained from the time of scan and time of pcc issue was obtained from the blood bank database. case note analysis was performed to obtain further information.results. patients were identified, in the neurosurgical centre and in peripheral hospitals. the median time from scan to issue of pcc was min. patients were reversed within min and patients waited longer than min to have pcc issued. no adverse thromboembolic events were encountered.conclusions. avoidable delay exists between ich diagnosis and pcc issue. pcc could be stored in the emergency department and a stat dose administered immediately after diagnosis facilitating rapid correction of inr. repeat audit will be required to assess safety and efficacy. objectives. the aim of this study was to compare the functional ability and muscle strength between these two groups of patients. twenty-nine patients were evaluated (m: , f: ) (age: ± years).the diagnosis of critical illness polyneuromyopathy was based on muscle strength measurement according to the medical research council (mrc) of muscle strength methodology. nine patients were diagnosed with critical illness polyneuromyopathy during their icu stay (mrc \ / ).the patients were evaluated with mrc and hand-grip dynamometry (hgd) every days until their discharge from the hospital. the fim scale (functional independence measure) was used to evaluate the functional ability ( - ).the first evaluation was done at the discharge from the hospital and the second one ± months afterwards.results. the patients who developed critical illness polyneuromyopathy had statistically significantly lower mrc ( ± vs. ± , p \ . ) and hgd at icu discharge (left ± kg vs. ± , and right ± kg vs. ± , p \ . ) compared to those who did not. the muscle strength as assessed with the mrc days after icu discharge had statistically significantly lower ( ± vs. ± , p \ . ), just as the second hgd evaluation (left ± kg vs. ± and right ± vs. ± kg, p \ . ).compared to those who did not develop critical illness polyneuromyopathy, the patients who did, had statistically lower fim values during their discharge from the hospital ( ± vs. ± , p \ . )and months afterwards ( ± vs ± , p \ . ).conclusions. the patients who developed critical illness polyneuromyopathy had significantly inferior muscle strength at their discharge from the icu. these patients also had lower functional ability. this functional ability remained defected even months after their discharge from the hospital. these initial findings are suggestive that the appearance of critical illness polyneuromyopathy affects the patients mobility after their discharge either from the icu or from the hospital and persists for several months after icu discharge. further studies are needed to evaluate the effect of this impairment on the quality of life of these patients and also to evaluate therapeutic tools for critical illness polyneuromyopathy. introduction. this poster presents a qualitative system dynamics (sd) analysis of the factors which influence the care of acutely unwell ward patients in new zealand. this systems thinking approach is commonly used in organisational research and offers a way to make sense of complex relationships between variables. this approach has previously been used in health care to demonstrate differences in mental models between policy makers and clinicians (cavana et al., ) . since the factors which influence the care of acutely unwell ward patients are complex and multi faceted the qualitative sd method becomes an ideal analytic approach (e.g. see wolstenholme and coyle, ; senge, ; vennix, ; or maani and cavana, ) .objectives. the aim of this study was to examine the factors which influence the care of acutely unwell ward patients from an organisational perspective. key objectives were to determine the enablers and barriers to care from a nursing, medical and managerial (at ward and executive level) perspective.methods. using a multiple case study approach in four wards in two new zealand hospitals, focus groups and one to one interviews were conducted with key stakeholders identified as nurses, doctors and managers. initial coding of the data generated themes. these themes were then clustered to provide variables which were mapped to generate separate causal loop diagrams (clds) for each of the stakeholder groups to provide the basis for analysis. the clds were compared for characteristics and world views. preliminary results demonstrate a difference between clinical and managerial staff in characteristics and world view regarding the factors which affect the care of acutely unwell ward patients.conclusions. the qualitative sd approach has offered a novel and helpful way to make some sense of the complexity associated with caring for acutely unwell ward patients. organizational responses that may improve care delivery to these patients should be based on frank and open discussions between staff at all levels to ensure a shared mental model as the basis for change. objectives. the aim of the study is to explain the nursing in the technologicallyadvanced intensive care units. in this phenomenologically-designed study, a face-to-face in-depth interview was performed with nurses, who were experienced for - years in the intensive care unit of cardiovascular surgery clinics. during the interviews, a semi-structured form was used. data were analysed using colaizzi's method of data analysis. the study was approved by the ethics committee of the institution.results. according to the nurses, nursing in technologically-advanced environment has three stages. these stages constituted three themes of the study: technology shock (first stage), understanding the technology-supported care (second stage), competency in technological environment (last stage). in the first stage, the nurses focus on themselves and technology; perceive the environment as frightening and complex. in the second stage, nurses gain control on technology, feel themselves safe and recognize their responsibility. in the last stage, the nurses experience anxiety related to their accountability. this anxiety may be motivating but also may be wearisome.conclusions. the nurses passes through three stages in a technologically-advanced environment. helping nurses to pass through these three stages appropriately will increase the contribution of technology to the patient care, more utilization of technology by nurses and more job satisfaction. unexpectedly, the compliance rate with the recommendations was significantly better over night. although the number of nurses is constant in the h, the number of doctors is lower and less differentiated in the night shift. in an attempt to find an explanation for these findings we looked at the patient flow and time span until the first medical observation in the different time periods and we found that over night admissions (between : a.m. and : a.m.) corresponded only to % of all admissions and were seen sooner, which might explain our findings. a. objectives. the purpose of the study was to assess whether the completion of the sepsis resuscitation bundle within the first h after icu admission, but beyond the specific time limit of the various bundle interventions, is related to an improvement in survival in patients with severe sepsis/septic shock. this was a single-center prospective observational study of patients admitted to the medical-surgical icu of an urban tertiary care teaching hospital with severe sepsis/septic shock. patients were recruited from june to november . we assessed the compliance with the different tasks included in the -h resuscitation bundle. furthermore, we ascertained within the first h after icu admission the compliance with those tasks not carried out within their specific time limits; we have called this variable ''bundle improvement at the icu''. results were stratified by the number of tasks of the bundle completed before admission at the icu, and the lag time between the beginning of severe sepsis and admission to the icu. these late completed tasks at the icu were related to hospital mortality by a cox regression model. objectives. the aims of this study were to assess the compliance rate with h bundle as defined in the surviving the sepsis campaign guidelines in patients diagnosed with sepsis regardless of severity and whether compliance affects the rate of mortality and/or hospital stay. we conducted a prospective observational study. we randomly recruited adult patients from acute admissions unit and intensive care in an acute district general hospital in england who met the diagnostic criteria for sepsis. for each patient, compliance with sepsis care bundle was obtained from medical notes. the following components of the h sepsis bundle were assessed: obtaining blood cultures, initiating antibiotic therapy, measuring serum lactate and in the event of septic shock administration of fluid therapy. conclusions. long and unacceptable delays in admission to iccu were identified despite evidence of significant organ dysfunction in many of these patients. with all bundle elements being met for only patient it is apparent that evidence based endpoints aimed at reducing mortality from severe sepsis are not being met despite all the bundle elements being practically deliverable. poor compliance with taking blood cultures prior to antibiotic administration and lack of scvo measurement are areas requiring particular attention. further work is recommended to identify potential contributing factors to non-compliance. introduction. international guidelines recommend that cardiac output measurement is required in addition to arterial pressure monitoring in patients with persistent shock after initial therapy [ ] . nevertheless, these recommendations are not supported by any comparison of arterial pressure and cardiac output for monitoring the effects of the most current treatments like fluid therapy. objectives. to evaluate in which extent monitoring the haemodynamic effects of a standardized fluid challenge with the sole arterial pressure could help for detecting the fluidinduced changes in cardiac index (ci). in critically ill patients with acute circulatory failure deemed at receiving a -ml saline infusion over min, we measured the systolic (sap), diastolic (dap), mean (map) and pulse (pp) arterial pressure and transpulmonary thermodilution ci before and after volume expansion.results. volume expansion significantly increased ci, sap, dap, map and pp by ± %, ± %, ± %, ± % and ± %, respectively. the fluid-induced changes in pp, sap and map were significantly correlated with the fluid-induced changes in ci (r = . , . and . , respectively). the changes (in %) in pp were significantly related to the changes (in %) in stroke volume for all quartiles but with different coefficients of correlation: r = . for the st quartile ( - years), r = . for the nd quartile conclusions. pp and sap were the best arterial pressure values for detecting the fluidinduced changes in ci. using the sole pp for assessing fluid responsiveness led to a non negligible proportion of false negative cases. this supports the recommendation that when a precise monitoring of fluid resuscitation is required, like in refractory shock, a direct assessment of cardiac output is required. objectives. aim of our study is to show that it is possible to reduce high catecholamines in previous improper volume resuscitated patients by forced volume resuscitation combined with active dose reduction and generate the hypothesis of an avoidable catecholamine induced circulation injury. introduction. the sialic acid content of the red blood cell (rbc) membrane decreases early in sepsis [ ] , and this alters the rbc shape and metabolism [ ] . an increased ratio of the rbc proteins band /alpha spectrin was observed in a mouse model of septic shock, suggesting a possible alteration of the rbc membrane integral/peripheral proteins ratio [ ] . as there are interspecies differences in membrane composition, these observations need confirmation in humans. we studied rbcs from patients with (n = ) and without (n = ) sepsis at icu admission and on day in the septic patients. exclusion criteria were recent rbc transfusion, hematologic diseases, cirrhosis and diabetes mellitus. procedures included screening for rbc membrane protein alterations by cryohemolysis test and separation of the rbc membrane and skeletal proteins by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate [ ] . comparison between groups was made by the student's t test or the mann-whitney test. a p value . was considered as statistically significant.results. the hemogram, including reticulocyte count was similar in septic and non-septic patients at icu admission. no significant difference was observed for cryohemolysis test results and the amount of the rbc proteins (table ) . objectives. our purpose was to compare a new method (patrol fr - ) with the reference method (randox tm ) during cbp. patients scheduled for coronary artery bypass (cb) and aortic valve replacement (avr) under cbp were enrolled after written informed consent in this protocol approved by local ethics committee. anesthesia protocol was standardized with systematic use of tranexamic acid. three blood samples were harvested: t = induction; t = min. after cross aorta clamping; t = h after induction. the patrol method was performed after serum exposition to a photosensibilizer agent then to a laser irradiation leading to the formation of free radicals. oxidation by those free radicals of a fluorometric sensor allowed an indirect measure of tas. this measurement in arbitrary unit (au) corresponded to area under curve compared to a control value from a pool serum. a value higher than indicated a lower capacity for the given serum to neutralize free radicals whereas a lower value indicated a higher capacity. the same sample allowed tas determination (lmol/l) with randox tm method. results were expressed as absolute numbers, mean ± sd. tas were compared with anova test; p \ . was significant.results. the seven patients ( male, female; ± years old) enrolled underwent cardiac surgery ( cb and avr) without any problem. there was no variation in tas determination with the randox tm method: t : . ± . ; t : . ± . ; t : . ± . lmol/l. conversely a two fold significant increase was measured during cpb with the patrol method: ti: . ± . ; t : . ± . *; t : . ± . au. *p \ . versus t .conclusions. oxidative stress due to overwhelming release of reactive nitrogen/oxygen species (rn/os) is held largely responsible for sepsis-induced organ failure and mortality [ ] . up-front and/or ongoing distortion of the pro-oxidant/anti-oxidant balance is likely to play an important role in this situation and in ischemia-reperfusion. therefore the patrol test which appeared to be more sensible than the randox tm method could a good tool in these cases and for evaluation of new anti-oxidant treatments in critical care medicine. these results have to be confirmed in a larger population. introduction. sepsis is the leading cause of death in critically ill patients. despite attempts to improve standardized strategies in resuscitation and treatment of sepsis, the morbidity and mortality remain unacceptably high. early diagnosis and stratification of the severity of sepsis is the key to start timely the appropriate treatment. sepsis is the systemic inflammatory response syndrome to infection; it can lead to hypoperfusion and organ dysfunction and at the cellular level to aerobic mitochondrial dysfunction. lactate is the product of anaerobic metabolism and thus may serve as a prognostic factor in this subset of patients.objectives. the authors propose to test the association of the first serum lactate at hospital admission with shock and icu mortality in patients with community-acquired severe sepsis. during the study period , patients were admitted in the unit, of those ( %) had severe community-acquired severe sepsis (cass). crude icu mortality rate among cass was %. considering the model previously described in methods and when the variables were adjusted only gender, age, saps ii, severity of sepsis and serum lactate were retained in the final model for icu mortality and saps ii nad serum lactate for shock (see table ). a first blood lactate level was independently associated with shock and icu mortality in patients community-acquired severe sepsis admitted in intensive care. objectives. the objective of this study was to test whether svo can predict fluid responsiveness in these patients. we studied patients who were monitored with a pulmonary artery catheter for severe sepsis and septic shock. hemodynamic measurements were obtained before (baseline values) and after a fluid challenge with colloids or crystalloids. responders were defined as those with a[ % increase in cardiac index (ci). no additional interventions were performed during the test. student's t test and linear correlation were used for the statistical analysis.results. mean patient age was ± years and the mean sofa score ± . mean arterial pressure was ± mmhg, cardiac index . ± . l/min/m , pulmonary artery balloon-occluded pressure ± mmhg, and heart rate ± bpm. thirty-four patients ( %) responded to the fluid challenge. responders and non-responders had similar baseline svo ( ± vs. ± %, p = . ). baseline svo was[ % in responders ( %) and in non-responders ( %). there was no correlation between changes in ci (%dci) and the baseline svo (fig. ) . sepsis is a disorder of microcirculation [ , ] . although the pathogenesis of microvascular dysfunction in sepsis is extremely complex, neutrophil activation and their interaction with endothelial cells are considered central features of sepsis-induced microcirculatory alterations. to our knowledge, however, no study evaluated the microvascular pattern of septic patients with chemotherapy-induced severe leukocytes depletion.objectives. to assess early microcirculatory response to sepsis in patients with and without drug-induced neutropenia.methods. demographic and hemodynamic variables together with sublingual microcirculation recording (ops-sdf videomicroscopy) were collected in four groups of subjects: septic shock (ss, n = ), septic shock in neutropenic patients (nss, n = ), neutropenia without inflammation (neutr, n = ) and healthy controls (crtl, n = ). except for controls, all measurements were repeated after complete resolution of septic shock and/or neutropenia (tp ). collected video-files were processed using appropriate software tool and semi-quantitatively evaluated (functional capillary density, fcd (cm/cm ); mean flow index, mfi [ ] ) [ ] . conclusions. microvascular derangements in sepsis did not differ between non-neutropenic and neutropenic patients. surprisingly, neutropenia per se without measurable systemic inflammation was also associated with alterations of the sublingual microcirculation. although we cannot exclude the role of residual neutrophils, our data could indicate that leukocytes are not the only and exclusive modulators of septic microvascular dysfunction. in addition, the role and mechanisms of microvascular changes associated with chemotherapyinduced neutropenia warrants further investigation. multiple organ failure is a leading cause of death in critically ill patients. improvements in outcome will most rely on our capacity to measure rapidly accessible biomarkers.objectives. to investigate if the time sequence of reactive oxygen metabolites (roms) production with sofa score could be prognostic for outcome. the study included critically ill patients (from september to december ) who had roms measured (hydroperoxides) during icu stay, when the diagnostic criteria for sepsis (observed n = ), severe sepsis (observed n = ) and septic shock (observed n = ) were present, - days and weeks after the diagnosis (samples n = ); on the same days, the sofa score was calculated. the plasma roms values were assayed by a diacron-italia kit, applied to an automatic instrument (olimpus au ). statistical analysis was performed used mann-whitney test and the linear regression analysis. the roms values and sofa score were inversely correlated (r = . for sepsis; r = . for severe sepsis; r = . for septic shock). the droms (the difference between the first and the last measurement of roms levels in each individual patient) was significantly different between survivors and non-survivors. clinical characteristics of the patients are presented in table . values are presented as median and interquartile rangers. a p value . was considered as statistically significant.conclusions. the plasma roms values decreased when the critically conditions rapidly evolved towards organ failures with higher sofa. to explore: (a) stress neuropeptides (acth, cortisol, prolactin, neuropeptide y (npy) and substance p (sp)) in critically ill subjects and controls, (b) potential association between levels of stress neuropeptides, disease severity and pain. a prospective correlational study, with repeated measurements and cross-sectional comparisons. fifty-three critically ill patients with diverse primary diagnoses and -age and gender-matched healthy controls were studied for days. serum neuropeptides were quantified by elisa (npy, sp) and chemiluminescence immunoassays (acth, cortisol, prolactin). pain levels were assessed by payen and puntillo scales. clinical severity was quantified by multiorgan failure scoring system (mof) and the multiple organ dysfunction score (mods). results. we observed: (a) statistically significant differences between critically ill and control subjects in regard with cortisol (p \ . ), npy (p \ . ) and sp (p \ . ) levels throughout the study. specifically, cortisol levels were higher and npy and sp levels were lower in patients compared to controls, (b) significant bivariate associations between stress neuropeptides (p \ . ), (c) statistically significant associations between acth and pain intensity levels assessed by payen (r = . , p = . ) and puntillo (r = . , p = . ) scales. there was also a constant but not statistically significant (p = . ) trend for lower sp levels in patients receiving opioids than in controls. moreover, npy levels were significantly lower in patients receiving analgesia (p = . ), (d) lower acth and cortisol levels in survivors (p \ . ) (e) at the day of least severity, a significant association between sp levels and mof was observed (r = . , p \ . ).conclusions. (a) despite the fact that npy and sp are stress neuropeptides, their levels appear to be decreased in mods patients. it is worth-exploring whether critical illness may be a state of suppressed activity of some neuropeptides, (b) the observed association between stress neuropeptide levels and survival in critical illness needs to be explore further, (c) bedside measurement of selected neuropeptides in the future may provide an estimation of pain in uncommunicative patients.hence, the study of stress neuropeptides may provide new insight for the management of the critically ill. objectives. the objective of this study was to compare septic and non-septic inflammatory process in critically ill patients with respect to paraoxonase activity, lipid profile and lipid peroxidation markers. methods. analyzed were serum paraoxonase activity, lipid profile, oxidized low density lipoproteins and conjugated dienes in critically patients with sepsis n = ), age/sex/ap-acheii matched critically ill controls with non-septic sirs (n = ) and age/sex matched outpatient controls without inflammation (n = ).results. the activity of pon was lower in septic patients ( . ± . u/ml) as well as in patients with non-septic sirs ( . ± . u/ml) compared to healthy controls ( ± . u/ml). the decrease in paraoxonase activity, high density lipoprotein cholesterol and apolipoprotein a- concentrations was closely followed by the counter increase of serum amyloid a in both groups of patients. there was no difference in paraoxonase activity between septic and non-septic critically ill patients. the concentration oxidized low density lipoproteins and conjugated dienes as markers of lipid peroxidation, were raised in both septic and non-septic sirs critically ill patients as compared with healthy controls. however there was no difference between both critically ill patient groups.conclusions. the decreased activity of paraoxonase in negative correlation with lipid peroxidation markers offers a potentially useful nonspecific marker of inflammation in critically ill patients.grant acknowledgment. objectives. in the present study, we studied the short-term and direct effects of ivig with sepsis.methods. patients was investigated. following the administration of g of ivig for h, we took blood samples immediately following ivig treatment and at h after ivig treatment. blood samples taken at h and just prior to ivig administration were used as controls. while there was no difference between h before and just prior to ivig treatment, statistically significant decreases were observed in the levels of il- after the administration of ivig. no significant changes were observed in the levels of tumor necrosis factor-a and high mobility group box- .changes in serum tnfa, il- , hmgb we confirmed the results of previous animal studies. while we reported that the administration of ivig directly reduces the levels of il- in patients with sepsis, a further prospective study of the ant-cytokine effects following ivig treatment will be conducted in the near future. objectives. to investigate the levels of nucleosome in septic patients and to determine whether nucleosome could serve as a biomarker for sepsis. sixty-four consecutive patients who were newly admitted in surgical intensive care unit at two university hospitals were enrolled in this study. whole blood samples were drawn within h of admission and on the third, fifth and seventh days. a last blood sample was drawn after recovery at icu discharge in survivors or at imminent death in the cases of non-survivors. plasma levels of nucleosome as well as cytokines il- and il- were detected by means of enzyme linked immunosorbent assay. . fifty patients were diagnosed as sepsis and the other fourteen patients were classified as controls. plasma levels of nucleosome were significantly higher in septic patients than in controls (two-way anova, p \ . ), while the levels of il- and il- were comparable between septic patients and controls. the septic patients presented the highest levels of nucleosome on the admission day, which was significantly different from the admission levels of nucleosome in controls ( . ± . vs. . ± . , p \ . ). the plasma levels of nucleosome between survivors and nonsurvivors showed no statistical significance.conclusions. plasma levels of nucleosome may serve as a valuable biomarker for sepsis.introduction. high mobility group box protein (hmgb- ) is a cytokine that can mediate inflammatory response in different conditions included rheumatoid arthritis, infections, sepsis and septic shock. hmgb- released by activated macrophages/monocytes acts as a late mediator of sepsis. studies have shown that serum hmgb- concentrations were elevated in patients with severe sepsis.objectives. in the present study, we evaluated the role of the hmgb- levels at the time of admission at the intensive care unit (icu) as predictor of outcome in patients with sepsis and septic shock.methods. forty-four patients admitted to the icu with sepsis and septic shock was recruited. serum samples were obtained at the time of admission for the determination of hmgb- levels. the results were correlated with the origin of sepsis, severity, organ dysfunction, requirements of mechanical ventilation and vasoactives, days at the icu, comorbidities and mortality at the icu and days after admission. twenty-six patients were male ( . vs. . %). septic shock was present in patients ( . %). the mortality rate at the icu was . % (n = ) and . % (n = ) at day th. hmgb- levels were . ng/ml ± . ( . - . ng/ml). hmgb- levels were significantly higher in non-survivors at the icu than in survivors ( . ng/ml ± . vs. . ± . , p \ . ). higher levels of hmgb- in serum at the admission were correlated with a higher mortality rate in the icu (p \ . ) but not at day th (p = . ). these levels were not correlated with days at the icu, requirements of vasoactives, mechanical ventilation, and apache score.conclusions. the determination of hmgb- levels at admission at the icu in patients with sepsis and septic shock is a good predictor of worse outcome and lethality.introduction. recent experimental and clinical data ( , ) support the hypothesis that costimulatory molecules, such as cd , play an essential role in the innate immune response during sepsis. expression of cd on the surface of monocytes could represent an important pathway in the modulation of the production of several key inflammatory mediators.objectives. to investigate whether the expression of cd molecule on the surface of plasma monocytes differs among the various stages of sepsis. a total of participants ( icu patients with sepsis, icu patients with septic shock and healthy controls) were included in the study (male patients . %, mean age . ± . years). inclusion criteria: icu patients on mechanical ventilation with first episode of sepsis or septic shock during current hospitalization. exclusion criteria: immunosuppression, neoplasia, autoimmune disease, cardiovascular disease. age, gender and comorbid conditions were recorded. a blood sample for quantification of cd expression was obtained at the time of enrollment (day ), and on the fifth day after the onset of sepsis; measurement was made on the same day. cd expression on the surface of plasma monocytes (on days and ) was assessed by flow cytometric analysis. statistical analysis: kruskal-wallis test to identify difference of cd expression among the groups was performed. post-hoc analysis was made by mann-whitney u test between independent groups, using bonferroni correction for multiple comparisons. roc curve analysis was used to determine the accuracy of cd in identifying patients with sepsis or septic shock. patients with sepsis had significantly higher levels of cd (day ) compared with healthy controls subjects ( . ± . vs. . ± . , p b . ). on the contrary, patients with septic shock did not show any significant difference compared with controls. a roc curve analysis for cd (day ) (auc = . , p b . ), revealed that a cut-off value of . could predict patients with sepsis with a sensitivity of % and a specificity of %.conclusions. upregulation of cd expression may reflect a protective phenomenon during sepsis. on the contrary, low cd expression could represent impaired immune function associated with more severe disease. in order to increase the cardiac output in the septic shock patients, according to surviving sepsis campaign team, norepinephrine (ne) or dopamine administration was recommended. the both agents increase the sympathetic tone which antagonize against parasympathetic activity used for gastrointestinal motility (involved gastric emptying). then, it is raised a question whether ne delayed the gastric emptying or not.objectives. this study was aimed to evaluate the gastric emptying in the septic shock patients with norepinephrine. a prospective observational study involved adult septic shock patients, who received ne continuously in icu sardjito general hospital (yogyakarta, indonesia). patients with any head pathologies (trauma, surgical procedures for tumor or bleeding), any gastrointestinal or abdominal pathologies (diarrhea, trauma, surgical procedures for cancer, peritonitis, ileus etc.), and administrations of metochlopramide or alinamin were excluded. nutrition fluids ( ml) was given passively via nasogastric tube, then after min the tube was aspirated. the volumes of aspirates were recorded in % as a gastric residue. once measurement was done with time randomly for every patient. at the measurement time were recorded the dose of ne and the vital signs.results. the gastric residues were . ± . % ( patients), . ± . % ( patients) and . ± . % ( patients) for the doses of ne of . , . and . lg/kg b.w./ min respectively. at the ne doses of . , . and . lg/kg b.w./min, all of the gastric residues were zero ( patients). the correlation between the ne doses and the gastric rescues was statistically significant (p: . ). the mean arterial pressures (map) were . ± . mmhg (ranges from to mmhg. there was no significantly correlation between map and the gastric residues.conclusions. the gastric emptying in the septic shock patients was not disturbed by administration of ne. introduction. anemia is a frequently encountered problem on the intensive care unit. several factor lead to anemia, among which are traumatic blood loss and the drawing of blood for routine laboratory tests. it's not known how this may affect innate immunity. hepcidin is a central regulator of iron homeostasis. it is induced in response to iron and inflammation and reduced in response to anemia and hypoxia. the suppression of hepcidin leads to the internalization and degradation of the iron exporter ferroportin on intestinal cells and macrophages, leading to the uptake of iron from the gut and the release of iron from the macrophages from the reticulo-endothelial system (res). these cells are central to the innate immune response and the altered iron status of these cells due to suppression of hepcidin may affect the inflammatory response of these cells. we tested the hypothesis that phlebotomy in human volunteers would lead to a suppression of the innate immune response. this abstract provides data of a pilot study carried out in subjects. to investigate the effect of phlebotomy on the innate immune response of whole blood in human volunteers.methods. three volunteers were subjected to the letting of ml of blood by phlebotomy. blood for the determination of hemoglobin and iron parameters, leucocyte count and differential, and hepcidin- was drawn at day , and after phlebotomy. further whole blood stimulation was carried out at each time point by adding . ml heparin anticoagulated whole blood to a prepared tube containing endotoxin, pam cis or rpmi as a control. final concentrations of lps and p c were ng/ml and lg/ml respectively. these tubes were incubated at °c for h and centrifuged for min at , g. the supernatant was frozen at - until the measurement of tnf-alfa and il- by elisa. cytokine production was corrected for the number of monocytes present. data are expressed as mean ± sem. hemoglobine decreased from . ± . mmol/l at baseline to . ± at day . it returned to normal at day . there were no apparent changes in serum iron levels. there was however a clear decrease in serum ferritin levels from ± at baseline to ? at day . leucocyte count and differentiation did not show any significant changes. hepcidin was clearly suppressed from to day after phlebotomy (from ± to ± ). tnf-alfa production dropped from to ng/ monocytes at day . il- production dropped from to ng/ monocytes. hepcidin levels correlated well with cytokine production (r . for tnf-alfa, r . for il- ).conclusions. phlebotomy leads to suppression of the innate immune response in whole blood. this could be a result of the intracellular decrease of iron in immune cells due to the systemic suppression of hepcidin. these findings are relevant to critical care patients that are subject to the repeated drawing of blood while their immune system is often compromised. introduction. hypothermia and hyperthermia occur in many pathological states presenting to the emergency department. both these processes are known to significantly impair coagulation pathways but as yet there is little evidence to show what affect they have on the evolving clot structure. previous studies have attempted to determine the effect of temperature on whole blood coagulation using techniques such as thromboelastometry (teg) but its ability to provide meaningful outcomes in terms of clot quality and structure remains elusive. recent studies have highlighted the potential of a new technique, gel point (gp) and fractal dimension (d f ), as a functional biomarker in haemostasis. to explore both the changes in coagulation pathways and their associated effect on clot structure and quality based on the new biomarkers, gp and df. following full ethical approval, healthy whole blood samples were obtained from individuals and tested at temperatures of °c (n - ), °c (n - ), °c (n - ), °c (n - ), °c (n - ). an oscillatory shear technique [ ] using an ar-g instrument (ta instruments) was applied to each sample. the gp, which indicates the formation of the fibrin network, was obtained for each sample using the chambon-winter gel point criterion [ ] . this method provides the basis from which d f can be determined [ ] to interpret the structural properties of the clot network. the results were compared with the standard teg analysis. firstly, results showed a significant progressive change in the clot structure by this new biomarker across the whole temperature range ( - °c). secondly, it also highlighted a significant and meaningful correlation between coagulation pathway change (time to gp, tgp) and the eventual clot outcome (fractal dimension). the tgp of the incipient clot was prolonged and the corresponding d f decreased with reduced temperature values. although, the changes in the coagulation pathway of the teg (r time) and the rheometer (tgp) correlated, the new biomarker, d f , provided additional structural data on the fibrin network formed and highlighted the relationship between coagulation pathway changes and the eventual fibrin clot structure.conclusions. in this study, we describe and quantify for the first time how temperature affects the coagulation pathways and how this impacts on the fibrin clot network, morphology and strength by using the new biomarkers, gp and d f . the potential of these new biomarkers in determining the effects of temperature change in critical illness and injury needs to be evaluated clinically. key: cord- -ppe br z authors: mohammed, amira; f.k. alghetaa, hasan; miranda, kathryn; wilson, kiesha; p. singh, narendra; cai, guoshuai; putluri, nagireddy; nagarkatti, prakash; nagarkatti, mitzi title: Δ -tetrahydrocannabinol prevents mortality from acute respiratory distress syndrome through the induction of apoptosis in immune cells, leading to cytokine storm suppression date: - - journal: int j mol sci doi: . /ijms sha: doc_id: cord_uid: ppe br z acute respiratory distress syndrome (ards) causes up to % mortality in humans and is difficult to treat. ards is also one of the major triggers of mortality associated with coronavirus-induced disease (covid- ). we used a mouse model of ards induced by staphylococcal enterotoxin b (seb), which triggers % mortality, to investigate the mechanisms through which Δ -tetrahydrocannabinol (thc) attenuates ards. seb was used to trigger ards in c h mice. these mice were treated with thc and analyzed for survival, ards, cytokine storm, and metabolome. additionally, cells isolated from the lungs were used to perform single-cell rna sequencing and transcriptome analysis. a database analysis of human covid- patients was also performed to compare the signaling pathways with seb-mediated ards. the treatment of seb-mediated ards mice with thc led to a % survival, decreased lung inflammation, and the suppression of cytokine storm. this was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell rna sequencing. a transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following thc treatment. in addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl l-carnitine in thc-treated mice. thc caused the downregulation of mir- , which correlated with an increase in the pro-apoptotic gene targets. interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (balf) of human covid- patients showed some similarities between cytokine and apoptotic genes with seb-induced ards. collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ards associated with covid- . staphylococcal enterotoxin b (seb) is a superantigen that promotes massive inflammation by triggering a large proportion of t cells expressing certain vβ t cell receptors [ ] . depending on the route of exposure, seb can promote toxic responses, leading to food poisoning, toxic shock syndrome, or acute lung injury (ali). the inhalation of seb promotes ali, a life-threatening condition that is characterized by leukocyte infiltration, pro-inflammatory cytokine production, and the breakdown of the lung barrier. in a c h mouse model, we have previously shown that dual-dose exposure to seb involving the intranasal route followed by systemic exposure triggers acute respiratory distress syndrome (ards), leading to % mortality [ , ] . in humans, ards can be triggered by infectious agents that trigger a life-threatening condition characterized by severe pulmonary inflammation, poor oxygenation, and respiratory failure [ ] . because there are no specific and effective treatment modalities, up to % of ards patients die. interestingly, patients with a severe form of novel coronavirus disease were found to exhibit ards, cytokine storm, and pulmonary failure [ , ] . ∆ -tetrahydrocannabinol (thc) is a psychoactive cannabinoid derived from cannabis sativa that has potential therapeutic value for pain relief, control of nausea and vomiting, appetite stimulation, and its anti-inflammatory properties [ ] . indeed, a previous report from our laboratory showed that exposure to thc prior to the administration of seb can prevent seb-induced ards and associated mortality through the mirna (mir) regulation of regulatory t cells [ ] . in the current study, we tested whether thc administration after exposure to seb would prevent seb-mediated ards; to further understand the mechanisms, we used single-cell rna sequencing (scrna-seq) of cells isolated from the lungs. apoptosis is a form of highly regulated programmed cell death that can be triggered through the intrinsic (mitochondrial) or extrinsic (death receptor-mediated) signaling pathways [ ] . here, we attempted to clarify the role of thc in inducing apoptosis in immune cells as a mechanism of attenuation of ards. our laboratory and others have indicated that thc can induce apoptosis in different cell types [ ] [ ] [ ] . in t cell leukemia (jurkat cell line) cells, for instance, a study from our lab showed that thc can induce apoptosis via cross talk between intrinsic and extrinsic pathways [ ] . thus, in the current study based on single-cell rna sequencing data, we determined whether thc induces apoptosis in activated immune cells in the lungs following seb-induced ards and, if so, whether it was through the death receptor or mitochondrial pathway. single-cell rna sequencing (scrna-seq) is a relatively novel and powerful technique for quantitating the transcriptome of various cell types in tissues based on molecular characteristics rather than on the morphology or proteins in cells [ ] . in the current study, we used this technology to unveil the precise cells and molecular signatures that may be involved in the thc-mediated induction of apoptosis. furthermore, the data were integrated with our findings from metabolomic analysis of serum metabolites, as well as cellular respiration, mitochondrial function, and metabolism. in recent years, mirnas (mirs) have been identified to suppress multiple genes, and thus regulate biological processes [ ] . studies from our lab have shown the ability of thc to suppress neuroinflammation by the downregulation of mir- , which upregulates bcl l [ ] . furthermore, we demonstrated that thc treatment caused the elevation of anti-inflammatory myeloid-derived suppressor cells (mdscs) through the mir- -targeted c/ebpα gene [ ] and via mir- a-targeted nos [ ] . in the current study, we also investigated the role of mirna in the regulation of apoptosis in immune cells induced by thc to attenuate seb-mediated ards. our data demonstrated that thc decreased the expression of mir- - p in seb-activated immune cells, thereby promoting the induction of a number of genes related to the mitochondrial pathway of apoptosis, causing an alteration in metabolism of immune cells, leading to the attenuation of inflammation and ards. it is well known that dual-dose seb exposure in c h mice is fatal due to the massive production of inflammatory cytokines and chemokines that lead to the exponential proliferation of effector t cells and other immune cell phenotypes [ ] . consistent with our earlier published studies, we found that while seb exposure in mice caused a % mortality, treatment with thc led to the % survival of the mice [ , ] . additionally, we found that dual seb exposure versus naïve mice resulted in a massive infiltration of immune cells in the lungs ( figure a) . interestingly, seb+thc mice showed a noticeable reduction in the abundance of infiltrating cells in the lung parenchyma when compared to seb+veh mice ( figure a) . electronic cell-substrate impedance sensing (ecis) was performed to measure the epithelial cell resistance. our data showed that epithelial cells treated with seb+thc had a higher resistance than seb+veh ( figure b) . consequently, seb+veh mice, in contrast to naïve mice, had elevated levels of proinflammatory cytokines ifn-γ, il- β, il- , tnf-α, and il in balf, while thc treatment led to a significant reduction in these cytokines ( figure c ). similar trends for the chemokines, ccl , ccl , and cxcl were also observed ( figure d ). it is well known that dual-dose seb exposure in c h mice is fatal due to the massive production of inflammatory cytokines and chemokines that lead to the exponential proliferation of effector t cells and other immune cell phenotypes [ ] . consistent with our earlier published studies, we found that while seb exposure in mice caused a % mortality, treatment with thc led to the % survival of the mice [ , ] . additionally, we found that dual seb exposure versus naïve mice resulted in a massive infiltration of immune cells in the lungs (figure a) . interestingly, seb+thc mice showed a noticeable reduction in the abundance of infiltrating cells in the lung parenchyma when compared to seb+veh mice (figure a) . electronic cell-substrate impedance sensing (ecis) was performed to measure the epithelial cell resistance. our data showed that epithelial cells treated with seb+thc had a higher resistance than seb+veh (figure b) .consequently, seb+veh mice, in contrast to naïve mice, had elevated levels of proinflammatory cytokines ifn-γ, il- β, il- , tnf-α, and il in balf, while thc treatment led to a significant reduction in these cytokines ( figure c ). similar trends for the chemokines, ccl , ccl , and cxcl were also observed ( figure d ). for in vivo studies, seb-mediated ards was induced in c h/hej mice, then the mice were treated with either vehicle (veh) or thc, as described in methods. for in vitro studies, epithelial cell type ii was cultured, and the resistance was measured after adding splenocytes, which were activated with seb + veh or seb+thc. (a): representative hematoxylin and eosin, h&e images of lung tissue sections. (b): ecis measurement of epithelial resistance, presented resistance is normalized to a pre-treatment time point for comparison of thc effect on barrier function. (c,d): elisa quantification of broncho-alveolar lavage fluid (balf) for cytokines (c) and chemokines (d). vertical bars show data from mice with mean+/-sem. statistical significance is depicted as * p < . , ** p < . , *** p < . , and **** p < . between the groups. to determine whether the decrease in lung infiltration was due to induction of apoptosis, we performed tunel staining by flow cytometry. our data showed that thc induced apoptosis in lunginfiltrating mono-nuclear cells, mncs (figure a ). thc also led to a reduction in the mitochondrial membrane potential by dioc( ) staining (figure b ). to confirm our in vivo results, we examined apoptosis in vitro. to this end, we activated naïve splenocytes with seb ( μg/ml) for h in the presence of either um thc or veh. the cells were then collected and stained with anti-cd and for in vivo studies, seb-mediated ards was induced in c h/hej mice, then the mice were treated with either vehicle (veh) or thc, as described in methods. for in vitro studies, epithelial cell type ii was cultured, and the resistance was measured after adding splenocytes, which were activated with seb + veh or seb+thc. (a): representative hematoxylin and eosin, h&e images of lung tissue sections. (b): ecis measurement of epithelial resistance, presented resistance is normalized to a pre-treatment time point for comparison of thc effect on barrier function. (c,d): elisa quantification of broncho-alveolar lavage fluid (balf) for cytokines (c) and chemokines (d). vertical bars show data from mice with mean+/-sem. statistical significance is depicted as * p < . , ** p < . , *** p < . , and **** p < . between the groups. to determine whether the decrease in lung infiltration was due to induction of apoptosis, we performed tunel staining by flow cytometry. our data showed that thc induced apoptosis in lung-infiltrating mono-nuclear cells, mncs (figure a ). thc also led to a reduction in the mitochondrial membrane potential by dioc( ) staining ( figure b ). to confirm our in vivo results, we examined apoptosis in vitro. to this end, we activated naïve splenocytes with seb ( µg/ml) for h in the presence of either um thc or veh. the cells were then collected and stained with anti-cd and dioc( ) and, likewise, thc led to increased apoptosis and the loss of the mitochondrial membrane potential in seb-activated t cells ( figure c ). furthermore, we tested the direct effect of thc on the proliferative capacity of immune cells in vitro by performing a h-thymidine incorporation assay, specifically by stimulating naïve splenocytes with seb and then treating them with thc or veh for h. as expected, seb activation led to increased proliferation when compared to non-activated t cells, while µm of thc reduced the seb-induced proliferation ( figure d ). we further analyzed lung-infiltrating mncs using mouse transcriptome arrays, and found that thc increased the expression of genes related to apoptosis, such as caspases (casp , casp ); the release of mitochondrial cytochrome c, including mitochondrial apoptogenic protein or cytochrome c oxidase assembly factor (apopt or coa ) and coa ; other mitochondrial cytochrome c oxidases (cox a , cox a , cox ); apoptosis-inducing factor -homologous mitochondrion-associated inducer of death (aifm ); as well as autophagic cell death comprising autophagy-related and (atg and atg ) ( figure e ). these studies suggested thc mediated the induction of apoptosis and autophagic cell death by altering the cytochrome c oxidases of the mitochondrial electron transport chain in mncs infiltrating the lung in seb-induced ards. dioc( ) and, likewise, thc led to increased apoptosis and the loss of the mitochondrial membrane potential in seb-activated t cells (figure c ). furthermore, we tested the direct effect of thc on the proliferative capacity of immune cells in vitro by performing a h-thymidine incorporation assay, specifically by stimulating naïve splenocytes with seb and then treating them with thc or veh for h. as expected, seb activation led to increased proliferation when compared to non-activated t cells, while μm of thc reduced the seb-induced proliferation (figure d ). we further analyzed lung-infiltrating mncs using mouse transcriptome arrays, and found that thc increased the expression of genes related to apoptosis, such as caspases (casp , casp ); the release of mitochondrial cytochrome c, including mitochondrial apoptogenic protein or cytochrome c oxidase assembly factor (apopt or coa ) and coa ; other mitochondrial cytochrome c oxidases (cox a , cox a , cox ); apoptosis-inducing factor -homologous mitochondrion-associated inducer of death (aifm ); as well as autophagic cell death comprising autophagy-related and (atg and atg ) ( figure e ). these studies suggested thc mediated the induction of apoptosis and autophagic cell death by altering the cytochrome c oxidases of the mitochondrial electron transport chain in mncs infiltrating the lung in seb-induced ards. vertical bars in panels a-c show data from mice with mean+/-sem. statistical significance is depicted as * p < . and **** p < . between the groups. in order to elucidate the precise cells and the genes that may be altered in the lungs, we performed scrna-seq. whole lung tissue was collected from seb-administered mice treated with either thc or veh and processed to a single cell suspension for scrna-seq. t-distributed stochastic in order to elucidate the precise cells and the genes that may be altered in the lungs, we performed scrna-seq. whole lung tissue was collected from seb-administered mice treated with either thc or veh and processed to a single cell suspension for scrna-seq. t-distributed stochastic neighbor embedding (t-sne) plots showed that the distribution of the major subpopulations of immune cells in ards were alveolar macrophages, mac a and mac b macrophages, neutrophils, cd + and cd + t lymphocytes, and natural killer (nk) and nkt cells ( figure a ). the enrichment of these inflammatory populations was higher in veh-treated mice than in thc-treated mice ( figure b ). interestingly, a scrna-seq analysis showed an increase in several genes in the seb+thc versus seb+veh groups, which included mitochondria-associated apoptosis regulatory genes. this comprised the elevated expression of bad in the cd + and cd + t cells, nkt cells, as well as mac a and mac b macrophages ( figure c ); bcl associated x apoptosis regulator (bax) in cd + t cells and nkt cells ( figure d ); cox i c in cd + t cells, neutrophils, nk cells, b cells, and alveolar and mac b macrophages ( figure e ); apopt in cd + and cd + t cells, nkt cells, and nk cells ( figure f ); as well as casp in cd + and cd + t cells and mac b macrophages ( figure g ) in the seb+thc treated group when compared to seb+veh mice. additionally, an scrna-seq analysis showed that thc increased the expression of genes involved in the metabolic reprogramming of immune cells, specifically genes encoding the mitochondrial solute carrier family of proteins (slc ) including a phosphate carrier protein, slc a , and an amino acid or iron carrier protein, slc a ( figure h ). neighbor embedding (t-sne) plots showed that the distribution of the major subpopulations of immune cells in ards were alveolar macrophages, mac a and mac b macrophages, neutrophils, cd + and cd + t lymphocytes, and natural killer (nk) and nkt cells (figure a ). the enrichment of these inflammatory populations was higher in veh-treated mice than in thc-treated mice ( figure b ). interestingly, a scrna-seq analysis showed an increase in several genes in the seb+thc versus seb+veh groups, which included mitochondria-associated apoptosis regulatory genes. this given that thc induced apoptosis via the mitochondrial pathway and affected mitochondrial solute transporter proteins, we next performed a real-time cell metabolic analysis of purified t cells. for this purpose, using seahorse technology we determined the oxygen consumption rate (ocr), including first the basal mitochondrial and non-mitochondrial respiration, and, following the sequential addition of oligomycin, an atp synthase inhibitor, the atp-linked respiration and proton leak. next, we treated the cells with carbonyl cyanide- -(trifluoromethoxy)phenylhydrazone (fccp), given that thc induced apoptosis via the mitochondrial pathway and affected mitochondrial solute transporter proteins, we next performed a real-time cell metabolic analysis of purified t cells. for this purpose, using seahorse technology we determined the oxygen consumption rate (ocr), including first the basal mitochondrial and non-mitochondrial respiration, and, following the sequential addition of oligomycin, an atp synthase inhibitor, the atp-linked respiration and proton leak. next, we treated the cells with carbonyl cyanide- -(trifluoromethoxy)phenylhydrazone (fccp), which mimics the physiological stimulation of the respiratory chain, causing the oxidation of all substrates including sugars, fats, and amino acids to obtain maximal respiratory capacity. finally, we added rotenone/antimycin a and respiratory chain complex i and iii inhibitors, respectively, to determine the reserve capacity. our studies on ocr showed that t cells from the seb+thc group had decreased basal respiration, proton leak, atp-linked respiration, maximal respiratory capacity, and reserve capacity when compared to the seb+veh group ( figure a ). we next estimated the dependency of these activated t cells on glucose versus fatty acids as main substrates for their metabolic functions. in order to determine the glucose dependency, we examined the ocr by blocking glucose oxidation in the presence of uk , an inhibitor of mitochondrial pyruvate carrier, followed by the blocking of both fatty acid and glutamine oxidation using etomoxir, a carnitine palmitoyl transferase inhibitor, and bis- -( -phenylacetamido- , , -thiadiazol- -yl)ethyl sulfide (bptes), a glutaminase inhibitor. furthermore, the β-oxidation dependency was studied by examining ocr in the presence of etomoxir, which blocks fatty acid metabolism, followed by the treatment of the cells with bptes and uk , which block both amino acid and glucose oxidation. interestingly, we found that while the ocr was decreased significantly in seb+thc cells, the metabolic activity of the thc-treated cells was independent of glucose utilization ( figure b ). however, these thc-treated t cells trended towards being dependent on the β-oxidation pathway to fulfill their energy demands ( figure c ). in contrast, the seb+veh-treated cells were dependent on glucose oxidation but independent of fatty acid oxidation for their energy demands. furthermore, the metabolomic profile of serum showed that seb+thc mice had elevated levels of carnitine pathway metabolites, which are displayed in a heat map ( figure d ), when compared to the seb+veh group. specifically, the metabolomic analysis showed a significant increase in the serum concentrations of propionyl-l-carnitine (plc) ( figure e ), free carnitine ( figure f ), lysine ( figure g ), and n-acetyl methionine ( figure h ) in seb+thc mice, indicating that there was dysregulation in carnitine metabolism pathway following seb exposure. carnitine is made from amino acids, lysine, and methionine. carnitine transports long-chain fatty acids from the cytosol to the mitochondrial matrix, and is therefore important for β-oxidation. carnitine can be converted to plc. interestingly, plc has been shown to promote the induction of apoptosis [ ] . to test if the effect of thc on metabolism may be contributing to the increased cell death in infiltrating immune cells, we activated naïve splenocytes with seb ( µg/ml) for h in the presence of plc ( µm). the data showed that plc-treated cells had an increased loss in mitochondrial membrane potential and increased apoptosis ( figure i ). next, a h-thymidine incorporation assay confirmed that plc had no significant effect on the proliferation of naïve splenocytes ( figure j ). however, the addition of plc led to a significant suppression of proliferation in seb-activated splenocytes ( figure j ). . statistical significances are depicted as * p < . , ** p < . , and **** p < . between the groups. we performed a mir microarray and found a number of dysregulated mirs in these two groups of mice. ingenuity pathway analysis (ipa) was used to predict the most common pathways involved in modulating the immune cell metabolism and proliferation capacity of lung-infiltrating mncs. we found that mir- - p was downregulated in seb+thc versus seb+veh mice. per the ipa analysis, mir- - p promoted apoptosis induction and inhibited the nfkb signaling ( figure a ). next, we validated the downregulation of mir- expression in lung-infiltrating mncs in seb+thc in the seb+veh group using qrt-pcr (figure b ). to confirm the alignment existence between the mir- and ′utr region of target genes, microrna.org was used (figure c ). furthermore, qrt-pcr validated the upregulation of mir- target genes that regulate apoptosis, including bad (figure d we performed a mir microarray and found a number of dysregulated mirs in these two groups of mice. ingenuity pathway analysis (ipa) was used to predict the most common pathways involved in modulating the immune cell metabolism and proliferation capacity of lung-infiltrating mncs. we found that mir- - p was downregulated in seb+thc versus seb+veh mice. per the ipa analysis, mir- - p promoted apoptosis induction and inhibited the nfkb signaling ( figure a ). next, we validated the downregulation of mir- expression in lung-infiltrating mncs in seb+thc in the seb+veh group using qrt-pcr ( figure b ). to confirm the alignment existence between the mir- and utr region of target genes, microrna.org was used ( figure c ). furthermore, qrt-pcr validated the upregulation of mir- target genes that regulate apoptosis, including bad ( figure d ), bax ( figure e ), hrk ( figure f ), runx ( figure g ), and cox ( figure h ). additionally, we found that nkiras , encoding an inhibitor of nfkb signaling, was elevated in seb+thc versus seb+veh ( figure i ). because patients with a severe form of covid- develop sepsis and ards, we next correlated our study with two available gene expression datasets from the balf of human covid- patients. the datasets were examined for cytokine and apoptotic genes similarly dysregulated between seb+veh and seb+thc using scrna-seq vs. covid- vs. normal control balf samples. venn diagram analysis showed that pro-inflammatory cytokines, including ccl , il rg, and tnfaip , were upregulated in cd + t cells, cd + t cells, and nk cells in the seb-induced ards group and in the balf of patients with the covid- disease (figure a ). additionally, apoptosis pathway genes such as coxiv and bax were down-regulated in the seb-induced ards group and covid patients (figure b ). because patients with a severe form of covid- develop sepsis and ards, we next correlated our study with two available gene expression datasets from the balf of human covid- patients. the datasets were examined for cytokine and apoptotic genes similarly dysregulated between seb+veh and seb+thc using scrna-seq vs. covid- vs. normal control balf samples. venn diagram analysis showed that pro-inflammatory cytokines, including ccl , il rg, and tnfaip , were upregulated in cd + t cells, cd + t cells, and nk cells in the seb-induced ards group and in the balf of patients with the covid- disease ( figure a ). additionally, apoptosis pathway genes such as coxiv and bax were down-regulated in the seb-induced ards group and covid patients ( figure b ). ards is a disorder caused by acute pulmonary inflammation, resulting in severe lung damage. because currently there are no effective pharmacological therapies to prevent this inflammatory condition, ards is characterized by high mortality rates of - % [ ] . risk factors which are associated with the development of ards could be genetic predisposition, obesity, chronic alcohol abuse, and chronic liver disease [ ] [ ] [ ] [ ] . many survivors experience a poor quality of life, depression, anxiety, and post-traumatic stress disorder (ptsd) [ ] [ ] [ ] [ ] . it is interesting to note that while the ards is a disorder caused by acute pulmonary inflammation, resulting in severe lung damage. because currently there are no effective pharmacological therapies to prevent this inflammatory condition, ards is characterized by high mortality rates of - % [ ] . risk factors which are associated with the development of ards could be genetic predisposition, obesity, chronic alcohol abuse, and chronic liver disease [ ] [ ] [ ] [ ] . many survivors experience a poor quality of life, depression, anxiety, and post-traumatic stress disorder (ptsd) [ ] [ ] [ ] [ ] . it is interesting to note that while the majority of covid- patients get milder form of the disease,~ % get a more severe form of the disease and develop ards, characterized by sepsis, cytokine storm, and respiratory and multiorgan failure, and a significant proportion of such patients die [ ] . it is likely that severe infection with the novel virus sars-cov- that causes covid- in the lower respiratory tract may cause dysbiosis, leading to the emergence of pathogenic bacteria such as staphylococcus aureus and streptococcus pneumoniae [ , ] and triggering ards. thus, the current animal studies using seb-induced ards may have some relevance to the ards seen in covid- . interestingly, we found a correlation between the upregulation of inflammatory cytokine genes in both seb-induced ards and covid- disease, which were downregulated with thc treatment in seb mice [ ] . additionally, our analysis showed that genes in the apoptosis pathway, such as coxiv and bax, were downregulated in both seb-induced ards group and covid- group. these data suggested that thc may be used as an immunosuppressive agent to dampen cytokine storm and promote apoptosis in activated immune cells during covid- . these correlations warrant further in-depth study. seb is one of the most important toxin threats in bioterrorism and is listed as a biological-warfare agent, which the centers for disease control (cdc) has classified as a category b priority agent [ ] . investigation from our lab found that seb inhalation caused vascular leak, the massive infiltration of lymphocytes, and cell death in the endothelial cells of the terminal vessels of the lung during ards [ ] . cannabis is the marijuana plant that has more than compounds called cannabinoids. thc is generally the most abundant cannabinoid found in cannabis extracts [ ] . thc is also the main psychoactive compound in marijuana, but is known to have anti-inflammatory properties, and can induce apoptosis and autophagy [ , , ]. in the current study, we found that treatment with thc after exposure to seb can induce apoptosis in activated immune cells in a seb-mediated ards model. in a recent study, we found that thc can reduce the inflammation in the lungs by decreasing the infiltrating immune cells, edema, and congestion [ ] . furthermore, thc decreased pro inflammatory cytokines ifn-γ, il- β, il- , tnf-α, and il , which are the most important cytokines that lead to ards [ ] . we also found a reduction in ccl , ccl , and cxcl which are chemokines that recruit leukocytes, including t cells such as memory t cells and monocytes [ , ] . in the current study, we observed that thc can induce apoptosis in the mncs of the lung by the intrinsic pathway. tunel staining, which depends on terminal deoxynucleotidyl transferase (tdt)-mediated dutp nick-end labeling to detect apoptotic dna fragmentation, was increased significantly after the thc treatment [ ] [ ] [ ] . dioc ( ) is a cationic dye which strongly labels mitochondria. the loss of mitochondrial membrane potential (mmp) is among the changes during the early stages of apoptosis, and a decrease in the mmp in apoptotic cells is associated with a reduction in the expression of dioc ( ), which we observed after thc treatment [ , ] . the dose-dependent decrease in activated t cell proliferation in thc-exposed cells was consistent with its ability to induce apoptosis. in the current study, we sought to identify dysregulated genes by examining the transcriptome in mncs from the lungs in seb+veh and seb+thc groups. interestingly, we found that genes associated with mitochondrial functions, such as mitochondrial apoptogenic protein (apopt ), also known as cytochrome c oxidase assembly factor (coa ); and coa ; mitochondrial cytochrome c oxidases (cox a , cox a , cox ); and apoptosis-inducing factor -homologous mitochondrion-associated inducer of death (aifm ), were upregulated in lung-infiltrating mncs following thc treatment in seb-induced ards. these genes encode for proteins that localize in the mitochondria, where they stimulate the release of cytochrome c and consequently induce apoptosis [ ] . cytochrome oxidase assembly factor genes encode for proteins that are required for the collection of the terminal cytochrome c complex iv or cytochrome c oxidase of the mitochondrial respiratory chain, which transports electrons to molecular oxygen and contributes to atp synthesis [ ] . in addition, autophagy-related and (atg and atg ) were also upregulated following thc treatment. inasmuch as autophagy is a process of the removal of damaged organelles and misfolded or aggregated proteins, it plays a critical role in preventing inflammatory diseases [ ] . specifically, it has been demonstrated that naive t cells exiting from the thymus depend on autophagy-related mitochondrial content reduction [ ] . furthermore, the loss of atg in t cells was shown to result in an inflammatory response and a loss of tolerance [ ] . indeed, the reduction in the expression of atg genes observed in the seb+veh group may be a factor in the induction of inflammatory response. these studies suggested the thc-mediated involvement in apoptosis and autophagy, and, importantly, cytochrome c oxidases of the mitochondrial electron transport chain in mononuclear cells infiltrating the lungs following seb-induced ards. in order to detect genes involved in thc-induced apoptosis in various immune cell subpopulations, we performed scrna-seq. the mitochondrial pathway of apoptosis is influenced by bcl family members bound to the mitochondrial membrane, including both the anti-apoptotic members, bcl- and bcl-xl as well as the pro-apoptotic regulatory proteins, bcl -associated agonist of cell death (bax) and bak, which can induce apoptosis by forming a pore in the mitochondrial outer membrane for the release of cytochrome c and other pro-apoptotic factors to the cytosol [ ] . in contrast, bad heterodimerizes with the anti-apoptotic regulatory protein bcl- and inactivates it, thereby allowing bax/bak to induce apoptosis. in the cytoplasm, cytochrome c along with adenosine triphosphate (atp) binds to apoptosis protease activating factor- (apaf- ) to form a multimeric complex that recruits and activates pro-caspase- to caspase , which in turn activates caspase and induces apoptosis [ ] . caspase- gene was elevated in the cd + and cd + t cells from the seb+thc group, which regulates the inhibition of dna repair and starts dna degradation [ ] . it should be noted that mitochondrial cytochrome c and cytochrome c oxidase subunit iv (cox iv) productivity are early events in the progression of apoptosis onset [ ] . furthermore, apopt , which was elevated in seb+thc when compared to seb+veh, has also been shown to induce apoptosis independent of bax/bak pore formation [ ] . our studies also found that thc caused an alteration in t cell metabolism. a metabolic analysis of seb+thc versus seb+veh t cells detected a reduction in mitochondrial respiration, specifically in basal respiration, maximal respiratory capacity, proton leak, and spare respiratory capacity, while increasing the dependence on the fatty acid metabolism. this observation indicates that thc stunts cell growth based on a previous study which showed that t cell growth and function requires rapid increases in glycolysis and a decrease in lipid metabolism [ ] . during activation, t cells undergo metabolic reprogramming, which is believed to be critical for cells to sustain the biosynthesis of lipids, proteins, and nucleic acids required for cell proliferation. therefore, increased glycolysis is observed in effector and activated t cells [ ] . we also found that thc caused alterations in serum metabolome, specifically elevations in lysine, n-acetyl methionine, carnitine, and propionyl carnitine (plc). lysine and methionine are precursors of carnitine, which is found in animal proteins and plays an important role in fat metabolism by transporting long chain fatty acids from cytosol to the mitochondrial matrix, and is therefore useful in the β-oxidation of fatty acids. l-carnitine has been used in the treatment of cardiovascular diseases, end-stage renal diseases, and other diseases [ ] . n-acetyl-l-methionine is similar to l-methionine both nutritionally and metabolically [ ] . it is used as a dietary supplement. methionine is an essential amino acid required for normal development in humans. methionine deficiency leads to a decrease in liver functions. it is also required for cysteine synthesis. while methionine is required for angiogenesis, high levels may lead to an increase in homocysteine, which is an indicator of cardiovascular disease [ ] . the presence of excess methionine may also lead to dna methylation and the induction of cancer [ ] . propionyl-l-carnitine is a naturally occurring amino acid derived from l-carnitine. plc is used in the treatment of heart failure and peripheral vascular disease. importantly, plc can induce apoptosis through the intrinsic pathway via the activation of bax gene [ ] . our results were consistent with this observation, inasmuch as the addition of plc triggered apoptosis and decreased cell proliferation. we have reported that thc treatment following seb injection alters the expression of mirs in lung-infiltrating immune cells [ ] in this study, we focused on mir- , which was found to be downregulated by thc in lung-infiltrating mncs of mice exposed to seb when compared to mice treated with vehicle. upon a pathway analysis of mirs using ipa, we identified mir- in mncs, which may play a significant role in thc-induced immune suppression via the induction of apoptotic genes bad, bax, activator of apoptosis harakiri (hrk), and apopt . mir- plays an essential role in in various diseases-for instance, tumor suppression in nasopharyngeal carcinoma, and it also inhibits the invasion, migration, and proliferation of squamous cell carcinoma [ , ] . furthermore, mir- can be therapeutic target for gastric cancer because it can induce apoptosis via the activation of the runx gene [ ] . the inhibition of mir- caused pten induction and akt inhibition, thus promoting apoptosis [ ] . mir- can also induce apoptosis in lung epithelial cells and a decrease in cell proliferation during hypoxia [ ] . together, our data indicate that thc may have beneficial effects on ards by promoting immune cell apoptosis via the downregulation of mir- - p. while our studies suggest that thc may be useful in treating ards seen during sepsis, as well as covid- , its clinical use may pose some problems because of its psychoactive properties. however, it is worth noting that thc is approved by the fda to treat nausea and vomiting in cancer patients undergoing chemotherapy and to gain appetite in hiv/aids patients. in this context, it is worth noting that cannabidiol (cbd), a non-psychoactive cannabinoid, may be better suited because cbd also exerts anti-inflammatory properties. a recent study showed that cbd can suppress ards and cytokine storm induced by poly(i:c) [ ] . while we have also shown that cbd is highly effective against a variety of autoimmune diseases [ , ] , it is less potent in suppressing cytokine storm when compared to thc. clearly additional studies are necessary to compare the efficacy of thc and cbd to treat ards and cytokine storm in a variety of clinical models. adult female c h/hej mice were purchased from the jackson laboratory (jax stock # ) (augusta, me, usa). all the delivered mice were kept for one week as an acclimatization period prior to performing any experiments. the animals were housed in maximum of mice per cage under a light/ dark cycle at a temperature of~ - • c and a - % humidity. food and water were available ad libitum. to minimize the microbiome variations from cage/rack to cage/rack due to managerial and housekeeping effects, the experimental mice were selected randomly from different cages to house them in one new cage with a maximum number of mice/cage, and then each cage was blindly assigned for different treatments or kept as a control group according to the experimental design. the person who carried out the experiments was not blinded because of the injection of seb, vehicle, and thc at different times, but most data analyses and experiments were blinded to avoid any bias. the mice were housed in an association for assessment and accreditation of laboratory animal care (aaalac)-accredited, specific pathogen-free animal facility at the university of south carolina school of medicine. all the mouse experiments were performed under protocols approved by the institutional animal care and use committee (aup (old aup) which is renewed as aup - - approved on july , ). all the studies involving animals are reported in accordance with the animal research: reporting of in vivo experiments (arrive) guidelines for reporting experiments involving animals [ , ] . to induce ards, seb was delivered according to the "dual dose" model described previously [ ] . this approach causes a % mortality with a low concentration of seb, and triggers ards in c h/hej mice. in brief, seb dissolved in sterile pbs was administered first by the intranasal (i.n) route at a concentration of µg per mouse in a µl volume. two hours later, a second dose of seb was delivered (i.p) at a concentration of µg per mouse in a µl volume. additionally, thc or vehicle (ethanol) was administered in doses. the first dose of thc ( mg/kg, i.p) was given immediately after the first seb exposure. then, the second and third doses of thc ( mg/kg, i.p) were given after an additional h and h, respectively. the seb-exposed mice that displayed signs of lethargy, hunching, ruffled fur, and respiratory distress were humanely euthanized. the mice were euthanized h post-seb exposure for tissue collection. staphylococcus enterotoxin b (seb) was purchased from toxin technologies (sarasota, fl, usa). delta- -tetrahydrocannabinol (thc) was procured from the national institute on drug abuse at the national institutes of health (bethesda, md, usa). rpmi culture medium, l-glutamine, penicillin-streptomycin mixture, hepes buffer, fetal bovine serum, and phosphate buffered saline (pbs) were purchased from invitrogen life technologies (carlsbad, ca, usa). rneasy and mirnaeasy mini kits, miscript primer assays kit, and miscript sybr green pcr kits were purchased from qiagen (valencia, ca, usa). the iscript and miscript cdna synthesis kits were purchased from bio-rad (madison, wi, usa). epicentre's pcr premix f and platinum taq dna polymerase kits were purchased from invitrogen life technologies (carlsbad, ca, usa). elisa kits for il- , il β, ccl , and ccl (elisa max tm standard set mouse) were purchased from biolegend. seahorse xfp glycolytic rate assay kits and xfp cell mito stress test kits were purchased from agilent technologies (santa clara, ca, usa). lung tissues from mice were fixed in % paraformaldehyde solution, dehydrated in alcohol, and embedded in paraffin. the microtome sections were cut to µm thick, stained with hematoxylin and eosin (h&e), and examined for inflammatory cell infiltrates under cytation cell imaging multi-mode reader microscopy (biotek, winooski, vt, usa). the cytokine concentrations were measured in broncho-alveolar lavage fluid (balf). balf was obtained from euthanized mice by binding the trachea with a suture and excising the lung along with the trachea, as described previously [ ] . then, ml of sterile, ice-cold pbs was injected through the trachea to lavage the lungs. the aspirated balf was centrifuged to obtain supernatants containing cytokines. elisas were performed using elisa max™ standard kits from biolegend (san diego, ca, usa), following the manufacturer protocols. electric cell-substrate impedance sensing (eciszθ) system was used to noninvasively real-time monitor the barrier function of lung epithelial cells type ii (mle ) in the presence of seb-activated splenocytes treated with either thc or veh for h before being co-cultured with mle cells. briefly, mle cells were seeded in rate of × cells/well on gold film electrodes arrays, w e+. once the monolayer of epithelial cells formed, the resistance of this layer was evaluated using a multifrequency test (mft) to find out what current frequency is suitable, then the resistance was recorded for at least h before coculturing these cells with pre-activated splenocytes with seb for h and treated with either thc or veh. the activated splenocytes were washed with rt-pbs twice before being resuspended in µl of complete medium at a concentration of × cells/well. the cells were allowed settle down for min at rt before the re-evaluation of the resistance/capacitance for the next h. a cell-free well was considered as a control, and the barrier resistance values were calculated after being normalized to the resistance of the cells before being wounded with activated splenocytes. apoptosis was detected by apo-direct terminal deoxynucleotidyl transferase dutp nick end labeling (tunel) assay kit (millipore sigma, st. louis, mo, usa). isolated lung mononuclear cells were washed with pbs, fixed with % paraformaldehyde at room temperature for m, and permeabilized with . % tritonx for m. the tunel solution master mix was added to each tube and incubated in a humidified incubator for h. next, the cells were washed twice with pbs then analyzed by flow cytometry. to analyze the mitochondrial membrane potential, lung mononuclear cells were collected and stained with dioc ( ) dye (enzo life sciences). the cells were incubated in dye for m at • c, then washed twice with pre-warmed pbs and analyzed by flow cytometry. to examine the suppressive effect of thc on the t cell proliferation, splenocytes ( × ) from c h naive mice were cultured in the presence of seb ( µg/ml) together with different ratios of thc. [ h]thymidine ( µci per well) was added to the cell cultures, and, after h, the radioactivity was measured using a liquid-scintillation counter (microbeta trilux; perkinelmer, greenville, sc, usa). cd + t cells were purified from splenocytes, as described previously [ ] . in brief, the splenocytes were collected from mice and labeled with pe-conjugated anti-cd antibody (biolegend, clone: a ). immunomagnetic selection was achieved by the use of pe positive selection kit (stemcell technologies; cambridge, ma, usa). a seahorse mito fuel flex test kit and cell mitochondrial stress test kit were used to measure the oxygen consumption rates (ocr) in cd + t cells according to the manufacturer's protocol (agilent, santa clara, ca). purified t cells were seeded in each well of an xfp cell culture mini plate at a density of × cells/well. the xfp cell culture plates were pre-coated with celltak (corning, ny, usa) to allow the t cells to adhere to the bottom of wells. measurements were performed on a seahorse xfp analyzer (agilent, santa clara, ca, usa). the seahorse wave software was used to interpret the acquired data and calculate the ocr of the purified t cells. measurement of glycolysis, tca, and tryptophan metabolites using lc-ms: metabolites were extracted from serum using the extraction procedure described previously [ ] [ ] [ ] [ ] [ ] [ ] . briefly, µl of the serum sample was used for the metabolic extraction. the extraction step started with the addition of µl ice-cold methanol:water ( : ) containing µl spiked internal standards to each cell pellet or tissue sample. ice-cold chloroform and water were added in a : ratio for a final proportion of : : : water:methanol:chloroform:water. the organic (methanol and chloroform) and aqueous layers were mixed, dried, and resuspended with : methanol: water. the extract samples were deproteinized, followed by resuspension and subjected to triple quadrupole mass spectrometer (agilent technologies, santa clara, ca, usa) coupled with a hplc system (agilent technologies, santa clara, ca, usa) via single reaction monitoring (srm). separation of tryptophan metabolites: esi positive mode was used to measure tryptophan. for the targeted profiling (srm), the rp chromatographic method employed a gradient containing water (solvent a) and acetonitrile (acn, solvent b, with both solvents containing . % formic acid). the separation of metabolites was performed on a zorbax eclipse xdb-c column ( × . mm i.d.; . µm, agilent technologies, ca) maintained at • c. the binary pump flow rate was . ml/min, with a gradient spanning % b to % b over a min time period. gradient: min- % b; min- % of b; . min- % b; min- % b; min- % b; min- % b, followed by re-equilibration at the end of the gradient. the tc automated cell counter (biorad) was utilized to measure the cell count and viability of the isolated lung cells. with a target of cells, we loaded them onto the chromium controller ( × genomics). following the manufacturer's protocol, the chromium single cell reagent kits ( × genomics) were used to process samples into single-cell rna-seq (scrnaseq) libraries. the sequencing of those libraries was performed using the nextseq instrument (illumina) with a depth of - k reads per cell. the base call files generated from sequencing the libraries were then processed in the × genomics cell ranger pipeline (version . ) to create fastq files. the fastq files were then aligned to the mm mouse genome, and the read count for each gene in each cell was generated. downstream analysis was completed using seurat suite version . [ , ] within r studio. the data were integrated in seurat using the anchor and integration functions. the integrated data were scaled and a principal component analysis (pca) was completed for dimensionality reduction. clusters were made following the pca analysis by adjusting the granularity resolution to . . we determined the number of principal components (pcs) to utilize the post-jackstraw analysis within seurat to determine the pcs with the lowest p-value. the differential expression was determined for each cluster to determine the cluster biomarkers, and between the disease and treated samples using the default wilcoxon rank sum test. to validate the expression of the selected mir- and associated genes (bad, bax, cox , runx , hrk, and nkiras ), qrt-pcr was performed in lung-infiltrating mncs isolated from seb+veh or seb+thc mice. in brief, the total rna from lung-infltrating mncs was isolated using the mirneasy kit from qiagen and following the manufacturer's instructions. the miscript primer assays kit and the miscript sybr green pcr kit from qiagen were used, and the qrt-pcrs were performed following the protocol of the company (qiagen, valencia, ca, usa). for qrt-pcr, we carried out cycles using the following conditions: m at • c (initial activation step), s at • c (denaturing temperature), s at • c (annealing temperature), and s at • c (extension temperature and fluorescence data collection). snord a was used as the housekeeping mir loading control. to determine the expression of genes, gapdh was used as the loading control. significant differences (p < . ) in expression were determined by the student's t-test with an online mirna database (www.microrna.org). the sequences primers used are described in table . the experimental design and analysis of this study were performed according the recommendations and requirements [ ] . a power analysis was carried out (a = . and − b = . ) to estimate the number of animals used in this study, which yielded a minimum sample size of mice per group. statistical analysis was undertaken only for studies where each group size was at least n = . all the in vitro studies were carried out in triplicate. all the in vivo studies were performed with at least mice in each group, except for the metabolome analysis (n = ). statistical analysis was performed using the data generated for individual mice and not using replicates as independent values. the graphpad prism . software was used in the statistical analysis. a student's t-test was used to compare two groups, whereas multiple comparisons were made using a one-way anova, followed by a post hoc analysis using tukey's method. the post hoc test was performed only if we noted an overall statistically significant difference in the group means. all the statistical analyses were carried out using the graphpad prism v software (san diego, ca, usa). a p value of < . was considered statistically significant. each experiment was performed independently at least three times to test the reproducibility of results. the metabolomics data were log -transformed and normalized with internal standards on a per-sample, per-method basis. statistical analyses were performed with either an anova or t-test in r studio (r studio inc., boston, ma, usa). differential metabolites were identified by adjusting the p-values for multiple testing at an fdr (benjamini hochberg method) threshold of < . . the current study concludes that the treatment of mice with thc post-seb challenge protects mice from seb-mediated toxicity by inhibiting inflammation and ards through the modulation of mirs targeting mitochondria-related apoptotic genes. because seb is a superantigen that drives cytokine storm, our studies revealed that thc is a potent anti-inflammatory agent that has the potential to be used as a therapeutic modality to treat seb-induced ards. importantly, the metabolomic and metabolic profiling indicates profound effects on mitochondrial functions that may be responsible for the anti-inflammatory activity of thc. this study also concludes that thc may mediate its effects through downregulating the expression of mir- - p and the consequent upregulation of apoptotic genes and pathways; thus, targeting mir- - p may constitute another therapeutic modality for the alleviation of ards. using gene expression datasets from the balf of human covid- patients, we found similarities between the cytokine and apoptotic genes with seb-induced ards. thus, our data suggests that thc may be useful in treating ards and cytokine storm seen in covid- patients. w., and g.c. contributed to analyzing the data. n.p.s. contributed to the microarray analysis. n.p. contributed to the metabolome analysis. k.m. analyzed the covid- patient data and revised the first copy of the manuscript, which was approved by all the authors. p.n. and m.n. supervised the work from designing to finalizing the manuscript for journal submission. all authors have read and agreed to the published version of the manuscript. the studies were supported in part by nih grants: p at , p gm , r at , r es , r ai , and r ai were awarded to m.n. and p.n. the ministry of higher education and scientific research (mohesr)/iraq provided support to am. the metabolomics core was supported by the cprit core facility support award rp "proteomic and metabolomic core facility," nci cancer center support grant p ca , intramural funds from the dan l. duncan cancer center (dldcc). this research was supported by nih/nci r ca (n.p.) and nih/nci r ca (n.p.). the funding agencies had no role in the experimental design, data collection and analysis, decision to publish, or preparation of the manuscript. acknowledgments: special thanks to jeffrey a. whitsett from perinatal institute, cincinnati children's hospital medical center, department of pediatrics, division of neonatology, perinatal and pulmonary biology, cincinnati, ohio, for providing us with the mle cell line. the authors declare that they have no conflict of interest. pyrogenic toxins induce toxic shock. toxins resveratrol protects mice against seb-induced acute lung injury and mortality by mir- a modulation that targets tgf-β signalling administration of ∆ -tetrahydrocannabinol (thc) post-staphylococcal enterotoxin b exposure protects mice from acute respiratory distress syndrome and toxicity acute respiratory distress syndrome: advances in diagnosis and treatment poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology marijuana and medicine: assessing the science base: a summary of the institute of tetrahydrocannabinol attenuates staphylococcal enterotoxin b-induced inflammatory lung injury and prevents mortality in mice by modulation of mir- - cluster and induction of t-regulatory cells apoptosis: a review of programmed cell death tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression delta -tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of bcl- and caspase- targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in ∆ -tetrahydrocannabinol (thc)-induced apoptosis of jurkat cells single-cell rna sequencing to explore immune cell heterogeneity microrna in control of gene expression: an overview of nuclear functions combination of cannabinoids, ∆ -tetrahydrocannabinol and cannabidiol, ameliorates experimental multiple sclerosis by suppressing neuroinflammation through regulation of mirna-mediated signaling pathways distinct microrna expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by delta -tetrahydrocannabinol in vivo: regulation of ccaat/enhancer-binding protein alpha by microrna- central roles for il- and mcp- following intranasal exposure to seb: a new mouse model protective effects of delta -tetrahydrocannabinol against enterotoxin-induced acute respiratory distress syndrome is mediated by modulation of microbiota propionyl-l-carnitine reduces proliferation and potentiates bax-related apoptosis of aortic intimal smooth muscle cells by modulating nuclear factor-kappab activity acute respiratory distress syndrome and acute lung injury alcohol abuse enhances pulmonary edema in acute respiratory distress syndrome early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in sweden, denmark, and iceland recent advances in genetic predisposition to clinical acute lung injury psychiatric morbidity in survivors of the acute respiratory distress syndrome: a systematic review one-year outcomes in survivors of the acute respiratory distress syndrome two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome incidence and outcomes of acute lung injury clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis therapeutic and triage strategies for novel coronavirus disease in fever clinics respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia clinical features of patients infected with novel coronavirus in toxins as weapons of mass destruction: a comparison and contrast with biological-warfare and chemical-warfare agents acute lung injury induced by staphylococcal enterotoxin b: disruption of terminal vessels as a mechanism of induction of vascular leak prevalence and correlates of cannabis use in developed and developing countries cannabinoids as novel anti-inflammatory drugs cannabinoid action induces autophagy-mediated cell death through stimulation of er stress in human glioma cells acute lung injury: epidemiology, pathogenesis, and treatment disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury motif chemokine ligand (ccl ) mediates acute lung injury induced by lethal influenza h n virus dna strand breaks occurring during apoptosis-their early insitu detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors delta -tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the cb receptor tetrahydrocannabinol-induced neurotoxicity depends on cb receptor-mediated c-jun n-terminal kinase activation in cultured cortical neurons activation through cannabinoid receptors and on dendritic cells triggers nf-kappab-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation induction of apoptosis in human prostate cancer cell line, pc , by , -diindolylmethane through the mitochondrial pathway early mitochondrial activation and cytochrome cup-regulation during apoptosis inventory control: cytochrome c oxidase assembly regulates mitochondrial translation microcystic adenoma of the pancreas with myoepithelial cells: a hitherto undescribed morphologic feature autophagy and the immune response bax and bak pores: are we closing the circle? cytochrome c promotes caspase- activation by inducing nucleotide binding to apaf increased mitochondrial cytochrome c levels and mitochondrial hyperpolarization precede camptothecin-induced apoptosis in jurkat cells apop- , a novel protein inducing cyclophilin d-dependent but bax/bak-related channel-independent apoptosis cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory cd + t cell subsets a target for the comprehension of immune response toward transplantation l-carnitine and heart disease pharmacokinetics, and regulation of l-carnitine and acetyl-l-carnitine metabolism the role of methionine on metabolism, oxidative stress, and diseases qiu, y. mir- - p regulates nasopharyngeal carcinoma radioresistance by targeting wnt bin vitro molecular mechanism and effect of microrna on proliferation, migration and invasion of esophageal squamous cell carcinoma microrna- regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain mir- inhibits hepatocellular carcinoma growth by targeting the dnmt /pten/akt pathway mir- mediates lung epithelial cell death after oxidative stress cannabidiol modulates cytokine storm in acute respiratory distress syndrome induced by simulated viral infection using synthetic rna. cannabis cannabinoid res cannabidiol attenuates experimental autoimmune encephalomyelitis model of multiple sclerosis through induction of myeloid-derived suppressor cells role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of trpv receptors by cannabidiol animal research: reporting in vivo experiments: the arrive guidelines guidelines for reporting experiments involving animals: the arrive guidelines multiple anti-inflammatory pathways triggered by resveratrol lead to amelioration of staphylococcal enterotoxin b-induced lung injury tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor and induction of myeloid-derived suppressor cells epigenetic loss of aox expression via ezh leads to metabolic deregulations and promotes bladder cancer progression multi-omics integration analysis robustly predicts high-grade patient survival and identifies cpt b effect on fatty acid metabolism in bladder cancer serum metabolic profiling identified a distinct metabolic signature in bladder cancer smokers: a key metabolic enzyme associated with patient survival dimethyl fumarate targets gapdh and aerobic glycolysis to modulate immunity peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in drosophila and mouse large-scale profiling of serum metabolites in african american and european american patients with bladder cancer reveals metabolic pathways associated with patient survival integrating single-cell transcriptomic data across different conditions, technologies, and species experimental design and analysis and their reporting ii: updated and simplified guidance for authors and peer reviewers this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -e l t g authors: jamaati, hamidreza; dastan, farzaneh; tabarsi, payam; marjani, majid; saffaei, ali; hashemian, seyed mohammadreza title: a fourteen-day experience with coronavirus disease (covid- ) induced acute respiratory distress syndrome (ards): an iranian treatment protocol date: journal: iran j pharm res doi: . /ijpr. . . sha: doc_id: cord_uid: e l t g covid- is currently causing concern in the medical community as the virus is spreading around the world. it has a heavy global burden, particularly in low-income countries. the clinical spectrum of covid- pneumonia ranges from mild to critically ill cases and acute respiratory distress syndrome. an expert panel was held and an internal protocol was developed to manage the covid- induced ards according to who recommendations and nih guidelines. different therapeutic regimens were employed on this protocol based on the ards severity and the patients’ special characteristics. the mortality rate, the rate of survivors, and non-survivors were reported. of the suspected cases of covid- admitted to the hospital during two weeks, patients were admitted to icu with diagnosis confirmed by rt-pcr. in total, mortality in the icu was % (n = ) among ards patients over two weeks. covid- induced ards is a major concern. the rapid progression of ards needs specific protocol based on patients’ characteristics and rapid action. in december , the city of wuhan in hubei province, china, became the center of an outbreak of pneumonia of unknown cause. on january , , the chinese health officials confirmed the identification of a novel coronavirus . covid- from wuhan in china is currently causing concern in the medical community as the virus is spreading around the world. so far, , cases of covid- have been clinically confirmed and , deaths have occurred till march , . covid- has a significant burden worldwide as a pandemic disease. the clinical presentation of covid- pneumonia may present from mild to severe illness including acute respiratory distress syndrome (ards). remarkably, the critically ill patients with covid- are more likely to develop ards regarding the cytokine cascade activation over a short period of time ( , ) . the most common complication is ards, which is seen in the covid- patients with high mortality rates. on february , , iran reported its first confirmed cases of covid- and dr. masih daneshvari hospital was selected as a referral center for covid- cases. the hospital was equipped with a special setup to admit covid- cases. on february , , seven patients were admitted to the hospital with the confirmed covid- . in the first h, four cases covid- who were referred from the other hospitals and admitted in the intensive care unit (icu) died due to severe ards. because of the rapid progression of ards, an expert panel was held on february , consisting of all intensivists, infectious disease specialists, pulmonologists, internal medicine specialist, cardiology specialist, and clinical pharmacy specialist. finally, an internal protocol was developed to manage the covid- induced ards according to who recommendations and nih guidelines ( ). different therapeutic regimens were employed on this protocol based on the ards severity and the patients' special characteristics. this protocol is shown in figure . of the suspected cases of covid- admitted to the hospital during two weeks, patients were admitted to icu with diagnosis confirmed by rt-pcr. in total, mortality in the icu was % (n = ) among ards patients over two weeks (table ) . twenty-four patients recovered and were transferred to the ward. thirty patients were under treatment in icu. totally, patients expired during two weeks including cases in icu. the timeline of two-week events is depicted in figure . the patients' vital signs, cbc, serum creatinine, urea, urine output, crp, lft, bilirubin, coagulation parameters, abg, and regular chest imaging must be closely monitored. all of the patients were administered hydroxychloroquine, oseltamivir, and lopinavir-ritonavir before admission to icu based on the ministry of health protocol and recent data regarding covid- treatment ( , ) . oxygen therapy, non-invasive ventilation or invasive mechanical ventilation are considered based on o saturation according to the who recommendations and nih guidelines. the patients were categorized into three groups based on pio /fio . according to berlin criteria, mild, moderate, and severe adrs are defined as pio /fio between and , and , and less than , respectively. invasive mechanical ventilation should be applied to ards patients with persistent hypoxemia. we recommend the administration of vitamin d , thiamine, and selenium in the ards patients according to our protocol. vitamin d deficiency is associated with greater cellular inflammation and cytokine release at h after ards development. thiamine deficiency is also a risk factor for ards development based on several published trials, whereas selenium has a beneficial role in oxidative stress pathways. as we have faced with the rapid progression of ards in our cases, the administration of corticosteroid is recommended for all our patients to inhibit the inflammation process in ards. high doses of dexamethasone as mg daily from day to , then mg daily from day to were administered in all stages of ards, even in the mild cases. this approach was applied based on the study done by villar et al. and the rapid progression of ards in our cases in order not to lose the time ( ) . immunoglobulin therapy ivig is administered in the cases that failed with the above strategies. ivig has controversial effects on the patients with respiratory coronavirus. ivig is applied to treat some diseases, especially primary immune deficiencies, autoimmune neuromuscular disorders, and respiratory failure regarding sepsis. it is considered as an effective agent in the cases of coronavirus associated fulminant myocarditis ( , ) . combination therapy with interferon beta- a and ribavirin in all refractory cases is administered based on data regarding coronavirus treatment and ebola experiences. ecmo is a specialized, resource-intensive, and expensive form of life support. however, it is associated with severe complications including nosocomial infection and hemorrhage. ecmo can serve as a life-saving rescue therapy for refractory respiratory failure in the setting of ards, such as that induced by coronavirus disease (covid- ) ( ) . other therapies stress ulcer prophylaxis, venous thromboembolism prophylaxis, and nutrition management are applied to all of the patients. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study investigators ftls and group tet. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected chloroquine and hydroxychloroquine as available weapons to fight covid- aminoquinolines against coronavirus disease (covid- ): chloroquine or hydroxychloroquine pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy inhibition of human coronavirus nl infection at early stages of the replication cycle covid- , ecmo, and lymphopenia: a word of caution key: cord- -ala ub authors: zhao, xuan; zhang, yi title: mesenchymal stem cells represent a potential therapeutic option for coronavirus disease -related acute respiratory distress syndrome date: - - journal: engineering (beijing) doi: . /j.eng. . . sha: doc_id: cord_uid: ala ub nan a recent clinical study by chen et al. [ ] reported that the transplantation of allogeneic menstrual-blood-derived mesenchymal stem cells (mscs) significantly reduced the mortality of influenza a (h n )-virus-induced acute respiratory distress syndrome (ards) without harmful side effects. this work may simultaneously provide a new insight into the treatment of ards caused by coronavirus disease . ards is characterized by progressive arterial hypoxemia and dyspnea-a severe form of acute lung injury (ali)-and may even cause multi-organ failure [ ] . effective therapies for ards have proven to be clinically challenging because no specific pharmacotherapies have been identified for lung-protective ventilation [ ] . multiple studies have shown that fulminant pneumonia and ards can be induced by various viral infections, such as severe acute respiratory syndrome coronavirus (sars-cov) [ ] , middle east respiratory syndrome coronavirus (mers-cov) [ ] , and h n virus [ ] . most h n patients primarily had viral pneumonia, and some progressed to ards [ ] . ards, lung failure, and fulminant pneumonia are major lung diseases, and h n virus causes extrapulmonary diseases through cytokine storms [ ] . covid- is caused by the novel coronavirus (sars-cov- ), which displays high similarity to sars-cov. an early report on january found that ards was present in % of covid- patients, requiring intensive care unit (icu) admission and oxygen therapy, and that respiratory failure from ards was the leading cause of mortality [ ] . virally triggered acute pro-inflammatory cytokines (interferon (ifn)-α, ifn-γ, interleukin (il)- β, il- , il- , etc.) released by immune effector cells can result in pulmonary edema, dysfunction of air exchange, and ards, similar to the cytokines involved in h n infection [ ] [ ] [ ] . thus, similar complications (e.g., ards and lung failure) and corresponding multi-organ dysfunction with lung inflammatory lesions and structural damage are shared by h n and covid- . early identification and early management of covid- patients might lower the occurrence of ards and the corresponding mortality; however, the incidence rate of ards in severe patients is still high and their prognosis is poor [ ] . this finding is in line with a prior study demonstrating that the quality of life of survivors with ards induced by h n infection was worse than that of those without ards [ ] . hence, it is urgent to develop effective therapies for ards. mscs are key players in stem-cell-based therapeutics in regenerative medicine and immunoregulation [ ] . they can be isolated from a multitude of sources, such as bone marrow, adipose tissues, fetal tissues, menstrual blood, and most types of mesenchymal tissues [ ] . mscs are pluripotential non-hematopoietic cells, which are capable of differentiating into various cell types including myocytes, osteocytes, and adipocytes [ ] . due to the safe, non-immunogenic characterization and great therapeutic potential of mscs, their transplantation has been widely studied as innovative drugs to treat multiple pathologies including ali/ards. mscs can reduce the production of pro-inflammatory cytokines in ards patients [ ] , and facilitate lung tissue regeneration and repair by releasing a large amount of paracrine soluble factors such as vascular endothelial growth factor (vegf) and transforming growth factor-β (tgf-β ) [ ] . mscs can also preserve the vascular endothelial [ ] and alveolar epithelial barrier function [ ] in ards animal models. in addition, mscs can enhance alveolar fluid clearance and increase the phagocytic activity of host immune cells to improve antimicrobial effects [ ] . the general potential therapeutic mechanisms of mscs in the treatment of ards are shown in fig. . it has been demonstrated that mscs have considerable advantages over other immunosuppressive agents (i.e., monoclonal antibody-based drugs, which have a high cost, or glucocorticoid drugs, which carry a high risk of side effects) for ards therapy in clinical practice. these advantages include availability and ease of harvesting, multi-lineal differentiation potential, and safety with no possibility of malignancy [ ] [ ] [ ] . chen et al. [ ] proposed a new strategy to treat h n -induced ards using msc transplantation. the major lung diseases found in h n patients include ards, lung failure, and fulminant pneumonia. in the work of chen et al., the mortality of the msc transplantation group was remarkably reduced compared with the control group ( . % vs. . %), and no infusion-related toxicities or seriously adverse events were found in these moderate-to-severe h n -induced ards patients. during the five years of follow-up, computed tomography checks showed that the radiological changes, including linear fibrosis, bronchiectasia, and isolated areas of pleural thickening, were improved by msc transplantation. furthermore, msc infusion showed no harmful effects in patients during long-term follow-up. this is the first meaningful report demonstrating both the short-and long-term effectiveness of msc transplantation to treat ards caused by virus infection. recently, another report on msc transplantation for the treatment of patients with covid- pneumonia showed that msc transplantation is safe and effective, especially for patients in a severe condition; however, this treatment requires long-term observation to establish its clinical efficacy [ ] . due to the similarity of ards caused by h n and that caused by sars-cov- , the work of chen et al. [ ] may provide the most promising option for the treatment of ards caused by sars-cov- . however, further investigation is needed on how mscs affect the host and how host microenvironments affect msc function. mscs will be a promising therapeutic strategy for the treatment of ards caused by virus infection in future. clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic influenza a (h n ) infection: a hint for covid- treatment. engineering fifty years of research in ards. the epidemiology of acute respiratory distress syndrome. a th birthday review acute respiratory distress syndrome acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome a mouse model for mers coronavirus-induced acute respiratory distress syndrome. a mouse model for mers coronavirus-induced acute respiratory distress syndrome long term outcomes in survivors of epidemic influenza a (h n ) virus infection human infection with highly pathogenic avian influenza a(h n ) virus human infection with a novel avian-origin influenza a (h n ) virus clinical features of patients infected with novel coronavirus in wuhan, china pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology the role of innate leukocytes during influenza virus infection clinical characteristics of coronavirus fisease in china pioglitazone protects mesenchymal stem cells against p-cresol-induced mitochondrial dysfunction via up-regulation of pink- concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing pluripotency of mesenchymal stem cells derived from adult marrow the effect of acute respiratory distress syndrome on bone marrow-derived mesenchymal stem cells allogeneic mesenchymal stem cells transplantation in patients with refractory ra bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury mesenchymal stem cells: mechanisms of potential therapeutic benefit in ards and sepsis usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages the genetic shortcut to antibody drugs nonsteroidal anti-inflammatory drugs and cardiovascular risk-a matter of indication transplantation of ace -mesenchymal stem cells improves the outcome of patients with covid- pneumonia the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. key: cord- - mn b vv authors: diehl, j-l; peron, n.; philippe, a.; smadja, d. m. title: response to damiani and colleagues date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: mn b vv nan we have read with great interest the comment of damiani on our article, retaining the hypothesis of a possible major role of microvascular derangement in the physiopathology of covid- ards. such a hypothesis, supported by a number of arguments such as the rich expression of the sars-cov- ace receptors in lung endothelial cells and dysregulation of the renin-angiotensin system, is now widely mentioned by others, using different approaches such as eit studies [ ] , high-energy ct studies [ ] and histopathology studies [ ] . damiani et al. have put our results in perspective with their own published observations of an inverse relationship between sublingual perfused vessel density and d-dimers in mechanically ventilated patients with severe sars-cov- pneumonia. they also reported a tendency to a decrease in sublingual microcirculation in patients with increased driving pressures. interestingly, we observed in our patients an inverse relationship between circulating endothelial cells (cecs) and total respiratory system compliance (r = − . , p = . ), which could suggest a parallel between microvascular and alveolar insults, perhaps in relation with the hemodynamic consequences of a more severe alteration in respiratory mechanics. to explore if covid- ards patients could exhibit a lung-specific microvascular response to high peep levels, as compared to non-covid- ards patients, seems to be an important field of investigation. one important point is that the very vast majority of studies in covid- ards patients used, by convenience, ventilatory ratio (vr) as a marker of impaired ventilatory efficacy, as mentioned in damiani's comment, rather than dead space measurements. however, it must be pointed out that vr was not originally designed to be used as a surrogate of dead space [ ] . accordingly, although highly significant, we found only a moderate level of correlation between vr and physiological dead space (v d /v t ) [ ] . the level was even lower than the values found in the non-covid- ards literature. we appreciate the opportunity to discuss some very important technical points in relation to capnography methods and the derived indexes. damiani et al. state that our v d /v t measurements could be inaccurate, due to transport delay of gas together with variable sampling flow rate. however, this point (and others also considered as disadvantages of the side stream method) is counterbalanced by specific disadvantages of the mainstream method which could also influence the precision of the results. altogether, it is generally considered that there are advantages and disadvantages of both, the choice between them being of personal preference or from availability (as in our cohort of covid- ards) rather than from strong recommendation [ ] . nevertheless, we agree that knowledge of physiologic and technologic basis of capnography is absolutely mandatory, both for research purposes and also for monitoring of icu patients [ ] . finally, it will be important to further precisely investigate the relationship between dead space measurements, with a special focus on indicators of alveolar dead space, and markers of endothelial dysfunction, such as bio-markers (such as cecs and d-dimers) and innovative methods such as the video-microscopy methods used by damiani and colleagues. ideally, such prospective studies should include covid- ards patients and non-covid- ards patients as a control group. they should include measurements performed at different peep levels. they should also include measurements performed during the full course of invasive mechanical ventilation. *correspondence: jean-luc.diehl@aphp.fr potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease pulmonary angiopathy in severe covid- : physiologic, imaging, and hematologic observations pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- ventilatory ratio: a simple bedside measure of ventilation respiratory mechanics and gas exchanges in the early course of covid- ards: a hypothesis-generating study principles and practice of intensive care monitoring. tobin mj edit an unusual sidestream capnogram publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to acknowledge all nurses, technicians and physicians involved in the george pompidou european hospital for help in taking care of patients and including them in the study. substantial contributions to the conception or design of the work: jld, ds. drafting the work or revising it critically for important intellectual content: all authors. agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors. all authors read and approved the final manuscript. no specific funding. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. patients mentioned in the response were included in the french-covid national cohort after informed consent of proxies or family members by phone, due to quarantine. additionally, proxies or family members gave also an informed consent by phone for a formalized local process of collecting biological samples in relation to cardiovascular, metabolic or renal diseases (comité de protection des personnes ile-de-france ii, irb registration , approval: november , ). not applicable. key: cord- -m n r authors: sole-violan, j; sologuren, i; betancor, e; zhang, s; pérez, c; herrera-ramos, e; martínez-saavedra, m; lópez-rodríguez, m; pestano, j; ruiz-hernández, j; ferrer, j; rodríguez de castro, f; casanova, j; rodríguez-gallego, c title: lethal influenza virus a h n infection in two relatives with autosomal dominant gata- deficiency date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: m n r nan introduction acute myocardial depression in septic shock is common [ ] . myocardial depression is mediated by circulating depressant substances, which until now have been incompletely characterized [ ] . the aim of our study was to observe the eff ects of tnfα on the model of perfused rat heart. methods after profound anesthesia with pentothal, the wistar rats were killed by exsanguination. after sternotomy, the heart was taken and connected to the langendorf column. the apex of the heart was hooked to a strength sensor. biopac student laboratory software was used to record and analyse heart contractions. contractions were recorded every minutes during periods of minutes. control measurements were fi rst recorded. we measured four parameters: heart rate, contraction force, speeds of contraction and relaxation for control, during tnfα ( ng/ml) exposure and after removal of tnfα. we express the variations of parameters as percentage of the control ± sem. a paired t test was used to compare heart rate, contraction amplitude, speeds of contraction and relaxation with tnfα and control measurements and after removal of tnfα. results eight rat hearts wistar (weight = ± g) were studied. see table . heart rate ± * ± introduction traditional whole blood experiments suggest that sepsis causes abnormal red blood cell (rbc) deformability. to investigate this at the cellular level, we employed a novel biophysical method to observe individual rbc membrane mechanics in patients with septic shock. methods we collected blood samples from patients with septic shock until either death or day of admission. thermal fl uctuations of individual rbcs were recorded allowing a complete analysis of rbc shape variation over time. mean elasticity of the cell membrane was then quantifi ed for each sample collected. we recruited nine patients with septic shock. table shows mean rbc thermal fl uctuation and sofa scores. conclusion rbc thermal fl uctuation analysis allows variations in rbc elasticity during sepsis to be quantifi ed at a cellular level. we could not identify any specifi c trend between sepsis severity and erythrocyte elasticity. cells demonstrated both increases and decreases in fl uctuation independent of sofa score. this is contrary to current evidence that suggests rbc deformability is reduced during sepsis. reference introduction whole blood experiments suggest that cardiopulmonary bypass (cpb) causes red blood cell (rbc) trauma and changes in deformability that may contribute to postoperative microcirculatory introduction neutrophil gelatinase-associated lipocalin (ngal)/ lipocalin , known as a sensitive biomarker of acute kidney injury, prevents bacterial iron uptake, resulting in the inhibition of its overgrowth [ ] . we previously demonstrated that this protein was discharged into gut lumen from crypt cells in septic conditions, and inhibited the growth of escherichia coli [ ] . however, it remains unclear which pathway is associated with the upregulation of ngal. we therefore designed the present study to reveal whether the patternrecognition receptor of bacteria, the toll-like receptor (tlr) family, plays a pivotal role for ngal secretion from gut crypt cells. methods with our institutional approval, the ileum and colon of male c bl/ j mice ( to weeks) were everted and washed by ca + and mg + free pbs buff er fi ve times. tissues were incubated with ca + and mg + free pbs containing mm edta for hour to isolate crypt cells of gut. the cell suspension was fi ltered through a cell strainer ( μm) twice, and deposited the crypt cells by centrifugation at ×g. the isolated crypt cells were resuspended in pbs and stained with . % amido black for labeling paneth cells. the × crypt cells were resuspended in ml hbss containing . % fetal bovine serum and % penicillin-streptomycin. the crypt cells were incubated at °c with or without tlr ligands: lipopolysaccharide (tlr ligand, μg/ml) and cpg-dna (tlr ligand, μg/ml). after a -hour incubation period, the crypt cells were deposited and eluted mrna to measure the expression of both ngal and tlr mrna using real-time pcr. results more than to % of collected cells were stained by amido black. lps signifi cantly upregulated the expression of ngal and tlr mrna in ileum and colon crypt cells (p < . ). although the cpg-dna did not upregulate ngal and tlr mrna in ileum crypt cells, the apparent expression of ngal and tlr mrna was found in colon crypt cells (p < . ). conclusion bacterial stimulation of tlr and tlr pathways plays a pivotal role in the expression of ngal mrna in gut, suggesting that ngal, derived from gut crypt cells, could contribute to the regulation of the intraluminal microfl ora in the critically ill. references introduction most individuals infected with the pandemic h n infl uenza a virus (iav) (h n pdm) experienced uncomplicated fl u. however, in a small subset of patients the infection rapidly progressed to primary viral pneumonia (pvp) and a minority of them developed ards. inherited and acquired variability in host immune responses may infl uence susceptibility and outcome of iav infection. however, the molecular nature of such human factors remains largely elusive. methods we report three adult relatives with the autosomal dominant gata- defi ciency. p and his son p had a history of myelodysplastic syndrome and a few episodes of mild respiratory infections. they developed pvp by h n pdm which rapidly evolved to ards. they died at the age of and , respectively. results patients were heterozygous for a novel r l mutation in gata . like other patients with gata- defi ciency, the three relatives had absence of peripheral nk and b cells and monocytopenia. however a high number of plasma cells, which were found to be pauciclonal, were observed in peripheral blood from p during h n pdm infection. p and p had normal levels of immunoglobulins and igg antibodies against common viruses. microneutralization test showed that p produced normal titers of neutralizing antibodies against h n pdm and against the previous annual h n strain. our results suggest that a few clones of long-living memory b cells against iav expanded in p ; and that these cells produced cross-reactive antibodies against h n pdm, similar to those recently described. during the fl u episode p had a strong increase of ifnγ-producing t cells and of ifnγ production. the th -related chemokines cxcl and cxcl , as well as ifnγ, mcp- and il- , were strongly elevated in serum from p and p in the course of h n pdm infection. conclusion gata- defi ciency is the fi rst described mendelian inborn error of immunity underlying severe iav infection. primary immunodefi ciencies predisposing to severe iav infections may debut, even in adults without a history of previous severe infections. the massive ifnγ-mediated cytokine storm may explain the fatal course of h n pdm infection in our patients. introduction adenosine exerts anti-infl ammatory and tissue protective eff ects during systemic infl ammation. while the anti-infl ammatory properties may induce immunoparalysis and impede bacterial clearance, the tissue protective eff ects might limit organ damage. the eff ects of a common loss-of-function variant of the adenosine monophosphate deaminase gene (ampd ), which is associated with increased adenosine formation, in patients with sepsis are unknown. methods in a prospective cohort, genetic-association study, the eff ects of the presence of the ampd gene on immune function, multiorgan dysfunction and mortality in septic patients was studied. pneumosepsis patients (n = ) and controls without infection (n = ) were enrolled. results in pneumosepsis patients and controls, a similar prevalence of the c>t (rs ) mutation in the ampd gene was found. univariate logistic regression analysis showed a tendency of increased mortality in patients with the ct genotype, compared with patients with the cc genotype (or . ; % ci . to . ). moreover, carriers of the ct genotype tended to suff er more from multiorgan dysfunction, or . ( . to . ) and . ( . to . ), for ct and tt, respectively (p = . ). in septic carriers of the ct genotype, the ex vivo production of tnfα by lps-stimulated monocytes was attenuated (p = . ), introduction hypogammaglobulinemia has been frequently found in adult patients with severe sepsis and septic shock. furthermore, it seems that at least a low serum level of igm is correlated with higher mortality in sepsis. the mechanisms of hypogammaglobulinemia in septic shock have not yet been explained. it has been hypothesized that outfl ow of immunoglobulins into the extravascular space due to increased capillary permeability could reduce immunoglobulin serum concentrations. angiopoietin- , which directly disrupts the endothelial barrier, is markedly elevated in sepsis and other infl ammatory states and its serum level has been correlated with microvascular leakage, end-organ dysfunction and death in sepsis. methods in the prospective, noninterventional study, we assessed the correlation between the capillary leakage marker angiopoetin- and serum levels of igg and igm in patients with community-acquired severe sepsis or septic shock on admission. blood samples were obtained during the fi rst hours after admission to hospital. results mean age of patients ( females) was years. median apache ii and sofa scores at admission were and , respectively. the mortality rate was %. thirty-four percent of all patients had level of igg < mg/dl. the median concentration of angiopoietin- in the hypo-igg group was , pg/ml, which was not statistically diff erent (mann-whitney; p > . ) than in the rest of patients with normal levels of igg ( , pg/ml). the concentration of igm < mg/dl was found in only four patients ( %) and all died. pearson's correlation test showed that the correlation between the concentrations of angiopoietin- and igg (correlation coeffi cient . ) or igm (correlation coeffi cient . ), respectively, were not statistically signifi cant (p < . ). conclusion at present the hypothesis that increased microvascular leakage is responsible for hypogammaglobulinemia in septic patients could not be accepted. studies on larger number of patients are needed. in addition, it is necessary to further explore other possible mechanisms, such as increased catabolism and consumption of antibodies or inadequate synthesis of immunoglobulins, which could also be responsible for hypogammaglobulinemia in sepsis. introduction septic encephalopathy is a frequent complication in severe sepsis but its pathogenesis and mechanisms are not fully understood. oxygen supply and utilization are critical for organ function, especially for the brain, a tissue extremely dependent on oxygen and glucose. disturbances in oxygen utilization are common in sepsis and a number of mitochondrial dysfunctions have been described in diff erent tissues in septic animals as well as in septic patients. our group described mitochondrial dysfunctions in the brain during experimental sepsis. methods experimental sepsis was induced by endotoxemia (lps mg/ kg i.p.) in sprague-dawley rats and by polymicrobial fecal peritonitis in swiss mice. brain glucose uptake was observed in vivo in endotoxemic rats using positron emission tomography with [ f]fl uorodeoxyglucose and autoradiography with -deoxy- c-glucose. results mice with polymicrobial sepsis present hypoglycemia, hyperlactatemia and long-term cognitive impairment. we observed a rapid increase in the uptake of fl uorescent glucose analog -deoxy- -(( -nitro- , , -benzoxadiazol- -yl)amino)-d-glucose in brain slices from septic mice in vitro. a similar increase in brain glucose uptake was observed in vivo in endotoxemic rats. remarkably, the increase in glucose uptake started hours after lps injection, earlier than other organs. the brains of mice with experimental sepsis presented neuroinfl ammation, mitochondrial dysfunctions and oxidative stress, but mitochondria isolated from septic brains generated less ros in vitro in the fi rst hours. this led us to investigate the role of nadph oxidase, an enzyme induced during innate immune response, as a potential source of reactive oxygen species in experimental sepsis. inhibiting nadph oxidase with apocynin acutely after sepsis prevented cognitive impairment in mice. our data indicate that a bioenergetic imbalance and oxidative stress is associated with the pathophysiology of septic encephalopathy. we are observing a new metabolic phenotype in the brain during sepsis, characterized by a rapid increase in glucose uptake and mitochondrial dysfunctions that may be secondary to infl ammation and hypoxia. introduction pathophysiology of brain dysfunction associated with sepsis is still poorly understood. potential mechanisms involve oxidative stress, neuroinfl ammation and blood-brain barrier alterations. our purpose was to study the metabolic alterations and markers of mitochondrial dysfunction in a clinically relevant model of septic shock. methods twelve anesthetized (midazolam/fentanyl/pancuronium), invasively monitored, and mechanically ventilated pigs were allocated to a sham procedure (n = ) or sepsis (n = ), in which peritonitis was induced by intra-abdominal injection of autologous feces. animals were studied until spontaneous death or for a maximum of hours. in addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis were assessed at baseline, , , and hours after sepsis induction. after death, brains were removed and brain homogenates were studied to assess markers of mitochondrial dysfunction. introduction identifying a group of patients at high risk of developing infectious complications is the fi rst step in the introduction of eff ective pre-emptive therapies in specifi c patient groups. quantifying cytokine gene expression also furthers our understanding of trauma-induced immunosuppression. our group has already demonstrated that a predictive immunological signature derived from mrna expression in elective thoracic surgical patients accurately predicts pneumonia risk [ ] . methods in total, ventilated polytrauma patients were recruited. mrna was extracted from paxgene tubes collected within hours of the initial insult, at and hours. t-helper cell subtype specifi c cytokines and transcription factors mrna was quantifi ed using qpcr. ten healthy controls served as a comparator. results the median injury severity score (iss) was . time bloods demonstrated a reduction in tnfα † , il- § , il- ‡ , rorγt* and t bet § , and an increase in il- * and il- † mrna levels in comparison with the control group (*p < . , † p < . to . , ‡ p < . to . , § p < . to . ). there was a positive correlation between iss and il- ‡ whilst both il- § introduction measurement of biomarkers is a potential approach to early assessment and prediction of mortality in septic patients. the purpose of this study was to ascertain the prognostic value of proadrenomedullin (padm), measured in all patients admitted to the icu of our hospital with a diagnosis of severe sepsis or septic shock during year. methods a cohort study of patients > years with severe sepsis according to the surviving sepsis campaign, in an icu of a university hospital. demographic, clinical parameters and padm, c-reactive protein and procalcitonin were studied during year. descriptive and comparative statistical analysis was performed using the statistical software packages statistica stat soft inc . and medcalc . . . . results we analyzed consecutive episodes of severe sepsis ( %) or septic shock ( %) in the icu. the median age of the patients was introduction sepsis results from complex interactions between infecting microorganisms and host responses, often leading to multiple organ failures and death. over the years, its treatment has been standardized in early goal-oriented therapies, which may benefi t from circulating biomarkers for early risk stratifi cation. we aimed to evaluate the prognostic value of presepsin (scd -st), a novel marker of bacterial infection. methods we performed a nested case-control study from the randomized controlled albumin italian outcome sepsis (albios) trial, enrolling patients with severe sepsis or septic shock from icus in italy. fifty survivors and nonsurvivors at icu discharge were selected, matched for age, sex, center and time of enrollment after inclusion criteria were present. edta-plasma samples were collected at days , and after enrolment for presepsin (immunechemiluminescence assay pathfast presepsin, url pg/ml, cv %; mitsubishi chemicals) and procalcitonin assay (pct, elecsys brahms cobas® pct, url . ng/ml, cv . %; roche diagnostics). results clinical characteristics were similar between the two groups, except for a worse sofa score at day in decedents. presepsin at day was signifi cantly higher in decedents ( , ( , to , ) pg/ ml, median (q to q )) than in survivors ( , ( to , ) pg/ml, p = . ), while pct did not diff er ( . ( . to . ) vs. . ( . to . ) ng/ml, p = . ). presepsin decreased over time in survivors, but remained elevated in decedents ( ( to , ) vs. , ( , to , ) pg/ml at day , p = . for time-survival interaction); pct decreased similarly in the two groups (p = . ). patients with early elevated presepsin had worse sofa score, higher number of mofs, hemodynamic instability (lower mean arterial pressure at baseline and after hours), and mortality rate at days ( % vs. %, logrank p < . ). the association between presepsin and outcome was more marked in patients with late enrollment ( to hours), and in septic shock. early presepsin had better prognostic accuracy than pct (auroc . vs. . , p = . ), and improved discrimination over sofa score, especially in septic shock. conclusion early presepsin measurements may provide important prognostic information in patients with severe sepsis or septic shock, and may be of crucial importance for early risk stratifi cation. introduction infections are a major complication during the postoperative period after heart transplantation (ht). in our hospital, nosocomial pneumonia is the most frequent infection in this period. the objective of this study is to determine the epidemiological and microbiological characteristics of this disease in our centre. methods a descriptive retrospective study of all medical records of ht performed in a single institution from to followed until june . clinical and microbiological variables were considered. centre for diseases control (cdc) criteria were used to defi ne nosocomial infections. invasive aspergillosis was considered if there were criteria for probable aspergillosis according to idsa criteria. results in hts there were infectious episodes in patients ( . %). eighty-fi ve patients ( . %) died during hospitalization. infection is the second cause of mortality during the postoperative period ( . % of dead patients). the most common locations of infections were pneumonia (n = , . % of infection episodes), bloodstream (n = , . %), urinary tract (n = , . %), surgical site (n = , . %) and intraabdominal infections (n = , . %). patients with pneumonia were treated according to knowledge in a specifi c moment, thus diff erent antibiotics were used. the duration of antibiotic therapy was ± . days. in nine episodes of pneumonia according to the cdc no germ was isolated in the cultures. six of the episodes were polymicrobial infections. the most frequent microbes isolated were e. coli (n = , . % of pneumonia cases), a. fumigatus (n = , . %), s. aureus (n = , . %), p. aeruginosa (n = , . %), p. mirabilis, k. pneumoniae, e. cloacae, e. faecalis, c. glabrata, and s. marcescens (one case each, . %). pneumonia was suspected but not confi rmed in patients. despite this, antibiotic treatment was maintained for a media of . ± . days: wide-spectrum treatments and targeted therapy after knowing the antibiogram. the length of icu stay was . ± . ( to ) days, of hospital stay was . ± . ( to ) days and of mechanical ventilation was . ± . ( to ) days. the mortality of patients with pneumonia was . %. conclusion nosocomial pneumonia is the most frequent infection in our series. despite when infection was not confi rmed, antibiotic therapy was maintained in suspect cases. we found a high incidence of aspergillosis. limitations because of wide duration of this study should be considered. that numbers of cvc, intubation and surgery, the use of muscle relaxant and steroid were independent risk factors for developing vap. ventilator days and icu length of stay were longer in the vap group ( vs. and vs. days, respectively). lastly, the hospital mortality rate was signifi cantly higher in the vap group ( % vs. %, p = . ). conclusion the incidence of vap was . % in the sicu of siriraj hospital, which was comparable with previous reports. bundles of care to prevent vap should include weaning from a ventilator. muscle relaxant and steroid should be administered according to strong indication. meticulous care of the airway should be implemented as protocol in order to prevent complications that can result in the development of vap. reference introduction this is a -year prospective study to determine the incidence, source and etiology of hospital-acquired bloodstream infection (habsi) in the indian context. the resistance pattern was also reviewed. methods a single-centre prospective study in a -bed icu. habsi was defi ned according to current cdc guidelines. hcap, catheterassociated uti (cauti) and skin-related infections causing bsi was also defi ned according to recent guidelines and analysed. results out of positive samples, samples (n = ) were habsi. the microbiological analysis showed % were gram-negative, % were candida and % were gram-positive. the commonest isolate was klebsiella and mrsa was commonest in gram-positive. the source of habsi showed crbsi was the commonest cause at %, which correlates with international data. ventilator-associated pneumonia and cauti caused . % bsi respectively. the resistance pattern among gram-negative bacteria showed multidrug-resistant (mdr) and extreme drug-resistant (xdr) isolates were highest. see tables and . introduction catheter-related bloodstream infection (crbsi) is a complication of central venous catheters (cvcs) with an attributable morbidity, mortality and cost [ ] . we examined patient risk factors for crbsi in an adult parenteral nutrition (pn) population. the study was carried out in a -bed tertiary-referral teaching hospital over a -year study period ( to ). all inpatients referred for pn via cvcs were included. prospectively collected data were recorded in a specifi c pn record. the crbsi audit group met quarterly to review all sepsis episodes, assigning a diagnostic category (crbsi or non-crbsi). patient risk factors for development of crbsi were examined using a logistic regression model to take account of the dichotomous nature of the outcome. odds ratios from a model incorporating demographic and clinical data were tested for statistical signifi cance. introduction many patients develop infections following operations. decreased immune competence has been demonstrated in acute neurological conditions. a strong cytokine-mediated antiinfl ammatory response was observed in stroke patients at infection, although infection due to the decreased proinfl ammatory mediators can be expected as well. to investigate this question the following experiment was performed. methods twenty-two urinary bladder cancer patients with radical cystectomy and lymphadenectomy were studied. blood samples were taken on day (before) and days , , , and after operation as well as on days , , and during follow-up. tnfα, soluble tnfα receptor i and il- levels in sera were determined by hs elisa and/or elisa. plasma acth and cortisol values were measured by ria kits. results from patients, eight deep wound and urine infections were found in days and six urine and wound infections in days after surgery, all survived. all patients were bacterially contaminated, as wound samples taken at the end of operation demonstrated. on day the circulating tnfα values were lower in infected patients. tnf started to increase from day to day , never reaching values of the uneventful healing group. soluble tnf receptor i, il- , acth, and cortisol concentrations did not demonstrate any diff erence on day but from day started to increase transiently, reaching higher levels in septic patients. conclusion a low proinfl ammatory response is a key facilitating factor for the development of infection. measuring serum tnfα levels before and after operations can thus predict the outcome. evaluation during days in may including direct observation of hand hygiene compliance by control nurses and hand cultures of healthcare workers (hcw). based on the who guidelines on hand hygiene in health care [ ] , cleaning of hands with alcohol-based hand rubs (sterillium) was prescribed before touching a patient and before aseptic procedures, after body fl uid exposure risk and after touching a patient and touching his/her surroundings. promotion of the hand hygiene program consisted of lectures and web-based self-learning, posters located near points of care and verbal reminders by control nurses. new observations of hand hygiene by control nurses during days and hand cultures of healthcare providers were performed in september . consumption of alcohol-based hand rub (product volume use per patient-days) was used as a surrogate marker of hand hygiene over time. the diff erence in hand hygiene compliance during the two periods was examined using a chi-squared test. diff erences in hand cultures were examined using a student's t test. time trends in the consumption of alcohol-based hand rub were examined using linear correlation. p < . was considered statistically signifi cant. the study was approved by the institutional ethics review board. results during the survey, in may opportunities to observe hand hygiene were presented and in september. overall compliance improved from . % ( / ) to % ( / ), χ = . (p < . ). in may, hcw had a mean of . ± . colony-forming units (cfu) on their hands compared with . ± . cfu on the hands of hcw in september (p = . ). we also observed an initial increased use of alcohol-based hand rubs from ml per patient-day in may to a maximum ml per patient-day in june, but a decline to ml per patient-day in september, pearson correlation coeffi cient = . (p = . ). conclusion implementation of a new hand hygiene program at our icu resulted in improved hand hygiene compliance and less cfu on the hands of hcw. there was no signifi cant increased use of alcohol-based hand rubs over time. the results indicate that constant awareness is vital for success. reference introduction icu-acquired infection is directly related to hospital mortality. hand hygiene is an eff ective, low-cost intervention that can prevent the spread of bacterial pathogens, including multidrugresistant organisms. historical compliance with hand hygiene guidelines by physicians, nurses and other care providers is poor. methods present expectations by the infection control committee are to 'pump in, pump out' of every room, using % isopropyl alcohol. we performed , observations of hand hygiene in the surgical icu from march through october , and intervened to change behavior by providing monthly feedback to specifi c provider groups and services. we made use of the unit coordinator to measure compliance of all individuals in the icu. results overall compliance by physicians was . %, for nonphysicians was . %. feedback to physicians, individually and by service, dramatically increased hand hygiene compliance, defi ned as both on entry and exit from the patient room, over the study period. see figure . conclusion physician behavior is responsive to monthly feedback that is specifi c to the individual or surgical service. use of the unit coordinator was very eff ective at gathering a very large sample size in a short period of time. introduction the benefi ts of universal glove and gowning (bugg) study is a cluster-randomized trial to evaluate the use of wearing gloves and gowns for all patient contact in the icu. the primary outcome is vre and mrsa acquisitions; secondary outcomes include frequency of healthcare worker visits, infection rates, hand hygiene compliance and adverse events. methods we enrolled icus in states. icus collected nasal and perianal swabs on all patients at admission and discharge/transfer. after a -month baseline period, units were randomized to the intervention arm and required to wear gloves and gowns for all patient contact. an intervention toolkit was created based on site feedback and compliance reports. swab collection compliance was fed back and discussed during site conference calls on a weekly basis. site coordinators monitored compliance with gloves and gowns, hand hygiene and frequency of hcw visits and reviewed patient charts for adverse events. results during the -month study period, , swabs were collected. after the baseline period, we were able to achieve and maintain swab compliance rates between and %. monthly discharge compliance increased by % by the beginning of the intervention period ( figure ). observers found % compliance with universal glove and gowning over , -minute observation periods ( figure ). ninety charts at each site were reviewed for adverse events. conclusion over a diverse group of us hospitals, we achieved high compliance with surveillance cultures and implementing universal gloving and gowning was achieved quickly with high compliance. introduction sepsis accounts for a very high mortality. the surviving sepsis campaign recommends a fi rst hours resuscitative bundle to improve patient outcome. despite this, the bundle is poorly performed because of several organizational and cultural barriers. in recognition of this, we guess that an educational and organizational intervention out of the icus could impact on septic patient outcome. in order to test our hypothesis we carried out, in hospitals, a pre-intervention survey of the human and organizational resources (hor) available in the management of septic patients. the aim is to seek any barrier potentially aff ecting correct guidelines implementation. methods thirty-nine medical wards (mw) and emergency departments (ed) were enrolled. every unit was asked to fi ll in a pre-agreed hor checklist focused on the main requirements suggested by the guidelines. results analysing the human resources available, we see that the bedto-doctor ratio signifi cantly (p < . ) increases from the day to the night shift: from to beds per doctor on the mw (median). otherwise, the ed staff remains roughly the same: from . to . doctors on duty (median). the analysis of the organizational tools (table ) points out a low percentage of hospitals having: a diagnostic and therapeutic protocol for sepsis management ( . %), some hospital empirical antibiotic therapy guidelines ( %) and an infective source eradication protocol ( . %). moreover, just % of hospitals involve an infectious diseases expert in every case of severe sepsis or septic shock. conclusion we guess that the poor availability of hor showed by the hospitals could have a role in the guidelines implementation and in the patient's outcome. only a comparison between these results and data collected from a clinical checklist, focused on sepsis bundle compliance, and from a patient's outcome summary could confi rm our hypothesis. this is the aim for our next part of the study. reference introduction the incidence of patients carrying esbl-positive bacteria in our icu ( in admissions in ) was not considered problematic. however, routine cultures had identifi ed esbl-negative patients who had become colonized with esbl strains during their icu stay. self-disinfecting siphons, preventing bacterial growth by antibacterial coating and intermittent heating, and biofi lm formation by electromechanical vibration, were placed in all sinks in the icu. the aim of the present study was to evaluate the eff ect of this intervention. methods an intervention study in a -bed icu. the intervention involved placement of self-disinfecting siphons (biorec). all patients with an expected icu stay of days or more between january and december were studied. samples of throat, sputum and rectum were taken at admission and twice weekly, and cultured for esbls. between june and october , sinks in patient rooms were cultured regularly for esbls. after the intervention in april , multiple repeat cultures were taken. whenever the species and antibiogram of bacteria cultured from patients and sinks matched, they were typed by aflp. results before intervention multiple esbl-forming strains were found in sinks of all patient rooms. eighteen patients who were esbl-negative on icu admission became colonized with diff erent esbl strains, that were present in sinks of their admission rooms ( figure ). four contaminations were proven by aflp-tying. one patient died of esblpositive e. cloacae pneumonia. after intervention all sinks were negative for esbl strains. no further patients became esbl colonized during the icu stay. conclusion wastewater sinks were the likely source of esbl colonization for icu patients. after placing self-disinfecting siphons introduction the present study investigated the eff ects of a single dose of intraperitoneal (i.p.) igg and iggam administration on various behavioral alterations in a cecal ligation perforation (clp)-induced sepsis model in rats. methods female wistar albino rats ( to g) were divided into fi ve groups (n = ): a naive control group, a sham operated group receiving conventional antibiotic treatment, a clp group receiving clp procedure and conventional antibiotic treatment, and igg and iggam groups which were also applied g/kg, i.p. igg and igam therapy minutes after the clp procedure. ten, and days after the surgery, animals underwent three behavioral tasks: an open fi eld test to evaluate the locomotor activity, an elevated plus maze test to measure the level of anxiety, and a forced swim test to assess the possible depressive state. the results acquired from these tests were used to estimate the eff ect of immunoglobulin therapy on behavioral changes in clp-induced sepsis in rats. in the open fi eld test, the clp group showed a signifi cant decrease in total squares passed on days and . similarly, total numbers of rearing and grooming were dramatically decreased in the clp group in comparison with control and sham groups (p < . ). in the elevated plus maze test, the number of entries to open arms decreased in the clp group. in the forced swim test, there was a tendency for increase in immobility time in the clp group, although the data were statistically insignifi cant. all of these values which were indicating the importance of behavioral alterations were improved on day . immunoglobulin therapy prevented the occurrence of these behavioral changes. especially, animals in the iggam group conserved the values quite near to those of the control group in measured parameters. conclusion sepsis, even though it has been treated with conventional antibiotics, caused a negative eff ect on behavioral parameters. in this study, igg and iggam treated animals in the presence of clp did not show these behavioral changes. therefore our results suggest that a single dose of i.p. igg and iggam treatment, which was applied immediately after the sepsis procedure, prevents behavioral defects observed following sepsis. introduction thrombomodulin is an endothelial cell cofactor and glycoprotein for thrombin-catalyzed activation of protein c. a recombinant human soluble thrombomodulin (rhstm) has been recently developed, and this new agent has a unique amino-terminal structure exhibiting anti-infl ammatory activity including sequestraction and cleavage of high-mobility group box (hmgb- ). methods in this study, patients with septic disseminated intravascular coagulation (dic) were treated with rhstm, which is recomodulin® inj. (asahi kasei pharma co., tokyo, japan). patients with septic dic were treated with to u/kg/day. results there were signifi cant results for improvement of apache ii score and dic diagnostic criteria score for critically ill patients after treatment using rhstm (p < . ). improvement for platelet count and d-dimer level were also observed in this study (p < . ). activation of antithrombin (at) also was signifi cantly increased after treatment (p < . ). hospital mortality was . % in this study. conclusion the rhstm might be one of most important endogenous regulators of coagulation, acting as the major inhibitor of thrombin as well as at iii. this new agent may play an important role in treatment for septic dic. introduction antithrombin iii (at iii) has been known to contribute to anti-infl ammatory response as well as its anticoagulation. our previous introduction sepsis and septic shock are complex infl ammatory syndromes. multiple cellular activation processes are involved, and many humoral cascades are triggered. presumably, endothelial cells play a pivotal rule in the pathogenesis of sepsis, not only because they may infl uence the infl ammatory cascade but also because, upon interaction with excessive amounts of infl ammatory mediators, the function of these cells may become impaired. it is likely that a general dysfunction of the endothelium is a key event in the pathogenesis of sepsis [ ] . hmg-coa-reductase inhibitors have been shown to exhibit pronounced immunomodulatory eff ects independent of lipid lowering. most of these benefi cial eff ects of statins appear to involve restoring or improving endothelial function [ ] . we hypothesize that statins can improve endothelial dysfunction in septic patients. methods a double-blinded, placebo-controlled, randomized trial was undertaken. we enrolled adult patients within hours of severe sepsis or septic shock diagnosis and randomized them to placebo or atorvastatin mg/day for a short term. endothelial dysfunction was assessed measuring plasmatic levels of il- , et- , vcam- by elisa and measuring fl ow-mediated vasodilatation of the brachial artery at basal, and hours after randomization. results we studied patients, in the placebo group (mean age ± years, . % male; apache ii risk score . ± . ) and in the statin group (mean age . ± years, . % male; apache ii risk score ± . ). the baseline characteristics of the placebo group were similar to statin patients as well as the mean length of stay in the icu ( . ± . and . ± days, respectively) and the time on vasopressors ( . ± . and ± . hours, respectively). no signifi cant diff erence was observed on the temporal variation of biomarker levels (il- , vcam- , et- ) between treatment and control groups. the intrahospital mortality rate was % in the statin group and % in the placebo group (p = . ). introduction a novel sorbent hemoadsorption device for cytokine removal (cytosorbents, usa) was developed and successfully tested in animal models of sepsis. the experience in the clinical setting is still limited to case reports. in this fi rst clinical trial, we tested the hypothesis that treatment with sorbent hemoadsorption could safely and eff ectively reduce cytokines in septic patients with acute lung injury (ali). methods ventilated patients fulfi lling the criteria for severe sepsis and ali were enrolled in this multicenter randomized, controlled, openlabel study comparing standard of care with or without hemoperfusion treatment. primary endpoints were safety and il- reduction. treated patients underwent hemoperfusion at fl ow rates of ~ to ml/ minute for hours per day for consecutive days. the overall mean reduction in individual plasma cytokines for the control and treatment groups during the treatment period was calculated using a generalized linear model. results forty-three patients ( treated, control) completed the study and were further analyzed. incidence of organ dysfunction at enrollment (treatment vs. control) was: septic shock ( % vs. %, p = . ), acute respiratory distress syndrome ( % vs. %, p = . ), and renal failure ( % vs. %, p = . ). during treatments no serious device-related adverse events occurred. on average, there were no changes in hematology and other blood parameters except for a modest reduction in platelet count (< %) and albumin (< %) with treatment. hemoperfusion decreased il- blood concentration signifi cantly (- . %, p = . ), with similar reductions of mcp- (- . %, p = . ), il- ra (- . %, p = . ), and il- (- . %, p = . ). the -day mortality ( % vs. % control, p = . ) and day mortality ( % vs. % control, p = . ) did not diff er signifi cantly between the two studied groups. conclusion in this fi rst clinical study of a novel sorbent hemoadsorption device in patients with severe sepsis and ali, the device appeared to be safe and decreased the blood concentration of several cytokines. further research is needed to study the eff ect of the device on the clinical outcome of septic patients. response; and the changes of endotoxin and proinfl ammatory molecules. methods forty septic/septic shock patients with renal failure were enrolled in the study. all patients had preoperative endotoxin > . level/units (eaa spectral d) and were submitted to high-volume hemodiafi ltration ( ml/kg/hour, prismafl ex; gambro) with a new treated heparin-coated membrane (oxiris; gambro). at t (pretreatment) and t ( hours) the main clinical and biochemical data were evaluated. all data are expressed as mean ± sd. one-way anova test with bonferroni correction was used to evaluate the data changes. p < . was considered signifi cant. results table presents the main results of this study. conclusion in septic/septic shock patients with renal failure, crrt with a new treated heparin-coated membrane (oxiris; gambro) is clinically feasible, and has a positive eff ect on renal function and hemodynamics. an adsorbing eff ect on proinfl ammatory mediators may have a role in these results. these data and the trend toward a decrease of endotoxin during the treatment warrant further investigation. reference introduction endotoxin, a component of the outer membrane of gramnegative bacteria, is considered an important factor in pathogenesis of septic shock [ ] . the aim of our study was to determine whether endotoxin elimination treatment added to the standard treatment would improve organ function in patients with septic shock. methods adult patients with septic shock who required renal replacement therapy (rrt), with a confi rmed endotoxemia, and suspected gram-negative infection were consecutively added to the study within the fi rst hours after diagnosis. all patients received full standard treatment for septic shock. endotoxin elimination was performed using the membrane oxiris (gambro, sweden), a medical device for continued rrt with the unique feature of endotoxin adsorbtion. an endotoxin activity assay was used to monitor endotoxin elimination therapy at baseline (t ), hours (t ), hours (t ), hours (t ), hours (t ), and hours (t ). our key indicators were the improvement in hemodynamics and organ function, and decrease of endotoxin activity (ea) in blood. continuous variables are presented as mean values with standard deviations. results high ea level at baseline ( . ± . endotoxin activity units (eau)) signifi cantly decreased during rrt with oxiris membrane to . ± . (t ), . ± . (t ), . ± . (t ), . ± . (t ), . ± . (t ) eau (p < . ). map increased from baseline ± to ± , ± , ± , ± , ± mmhg (p < . ), and the mean norepinephrine use decreased from . ± . to . ± . , . ± . , . ± . , . ± . , . μg/kg/minute (p < . ) at t , t , t , t , t , t , respectively. the sofa score had decreased from ± to ± , ± , ± points (p < . ), and the procalcitonin level declined from ± to ± , ± , ± ± ng/ml (p < . ) at t , t , t , t . conclusion rrt with oxiris membrane resulted in the eff ective elimination of endotoxins from the blood. the therapy was associated with an increase in blood pressure, a reduction of vasopressor requirements, and an improvement of organ function. the application of the endotoxin activity assay was useful for bedside monitoring of endotoxemia in icu patients. introduction severe sepsis and septic shock remain the most serious problem of critical care medicine with a mortality rate of to % [ ] . several studies have demonstrated positive eff ects of selective adsorption of lps on blood pressure, pao /fio ratio, endotoxin removal and mortality [ , ] . the purpose of the study was to evaluate the effi ciency of using the selective adsorption of lps, toraymyxin -pmx-f (toray, japan) and alteco® lps adsorber (alteco medical ab, sweden), in the complex treatment of patients with severe sepsis. methods forty-six patients with gram-negative sepsis in the postoperative period were enrolled into the study. toraymyxin -pmx-f was used in the pmx-f group (n = ), while alteco lps adsorption was used in the alteco lps group (n = ). the clinical characteristics are listed in table . the sofa score, pao /fio , procalcitonin (pct), c-reactive protein (crp), endotoxin activity assay (eaa) was noted before, and hours after the selective adsorption of lps. results at hours after pmx-f, signifi cantly decreased pct from . ( . ; . ) to . ( . ; . ) ng/ml, p = . , decreased crp from ( ; ) to ( ; ) mg/l, p = . and sofa score from . ( , ; . ) to . ( , ; . ), p = . . at hours after alteco lps, signifi cantly decreased pct from . ( . ; . ) to . ( . ; . ) ng/ml. the -day mortality rate was . % (n = ) in the pmx-f group and . % (n = ) in the alteco lps group. introduction corticosteroid (cs) therapy in sepsis remains controversial and was fi rst introduced in sepsis management for its antiinfl ammatory property. cs has found a role in septic shock amelioration with inconsistent outcomes. the surviving sepsis campaign (ssc) includes cs as a level c recommendation in septic shock [ ] . adapting and practicing ssc guidelines vary between critical care units. accordingly, a survey was conducted to elucidate the usage of cs for septic shock by uk critical care physicians (ccps). methods following approval by the uk intensive care society (ics), the survey was publicised on the ics website and its newsletter. results a total of intensivists responded to this online survey. seventy-four ( . %) ccps prescribed cs only if the septic shock is poorly responsive to fl uid resuscitation and vasopressor therapy. six ( . %) initiated cs at the same time as vasopressor therapy. none initiated cs for patients with severe sepsis. no cs other than hydrocortisone is being used. the most commonly used intravenous regimen is mg hourly ( %) followed by mg hourly ( %). only % of ccps would prescribe it by infusion. less commonly used regimens were mg hourly ( %) and mg hourly ( %). only % would consider adding fl udrocortisone. prior to initiating cs, % of ccps would perform a short synacthen test, while % would not. the majority ( %) of ccps would stop cs after resolution of shock state or when vasopressor infusion is terminated whilst % after a fi xed duration. withdrawal of cs also diff ered, in that % tapered/weaned steroids, % stopped it abruptly and % of ccps would base their cs cessation pattern on the clinical context. only % of ccps believe that cs is benefi cial whereas % were unsure of the benefi ts in septic shock. only ( %) responders indicated that their critical care unit had a written protocol for cs in septic shock. conclusion the perceptions, usage and cessation of cs in septic shock vary but do appear to have shifted in the last decade. a uk survey in identifi ed that only % of icus used cs for septic shock and over % perform a short synacthen test [ ] . it appears that many intensivists are using cs for septic shock, despite confl icting outcome data. we all strive to practice evidence-based medicine but until we have a robust, reliable and methodical randomised control trial that attempts to resolve the cs debate, practice will remain diverse on this subject, as refl ected by our survey. references introduction from december to december , patients in scotland presented with confi rmed anthrax infection manifested by soft tissue disease related to heroin injection. these cases represent the fi rst known outbreak of a recently recognized form of anthrax, termed injectional anthrax, which appears to be associated with a high mortality rate ( % in confi rmed cases from the uk outbreak). while epidemiologic data from this outbreak have been published, no report has systematically described fi ndings in patients at presentation or compared these fi ndings in nonsurvivors and survivors. methods to better describe injectional anthrax, we developed a questionnaire and sent it to clinicians who had cared for confi rmed cases during the outbreak. completed questionnaires describing patients, nonsurvivors and survivors, were returned. results in preliminary analysis of categorical data, a signifi cantly (fisher exact test) greater proportion of patients with compared with without the following fi ndings did not survive; history of alcohol use (p = . ); the presence of lethargy (p = . ), confusion (p = . ), nausea (p = . ), abdominal pain (p = . ), or the need for vasopressors (p = . ), oxygen, mechanical ventilation, or steroids (all p = . ) at presentation; and excessive bleeding at surgery (p = . ). initial analysis of continuous data demonstrated that, compared with survivors at presentation, nonsurvivors had signifi cantly (one-way anova) increased respiratory rate, percent neutrophils on complete blood count, hemoglobin, inr, c-reactive protein, and bilirubin and signifi cantly decreased temperature, systolic blood pressure, platelets, sodium, albumin, calcium (corrected for albumin), base excess and bicarbonate (all p ≤ . ). conclusion the implications of the apparent diff erences noted between nonsurvivors and survivors in this survey of cases from the fi rst known outbreak of injectional anthrax require further study. however, these diff erences might inform the design of research during future outbreaks or of methods to identify patients most in need of anthrax-specifi c therapies such as toxin-directed antibodies. introduction based on the results of our previous studies [ ] we have identifi ed clinical risk factors for the emergence of gr(+) infections in our icu and we have developed a new algorithm for combating them. the choice of the particular antibiotic drug is guided by additional risk factors for severity of illness and data on the infectious focus. the response to therapy and its duration are also stated. the aim of the current study was to evaluate the effi cacy and safety of this preemptive approach. methods a randomized prospective controlled trial was carried out from september to september . patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antibiotic therapy was started on the day of inclusion in the treatment group and only with proven gr(+) pathogen in the control group. initial data were gathered on demographics, diagnosis, proven risk factors for sepsis-related mortality, severity of infl ammatory response, ventilator-associated pneumonia and organ dysfunction. dynamics of sirs, cpis and sofa scores, subsequent infectious isolates, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent score values, length of icu stay and the number of ventilator-free days were also comparable between groups. the majority of gr(+) pathogens were isolated between and days of inclusion. no diff erences were found regarding the concomitant gr(-) fl ora and the related antibiotic therapy. the new organ dysfunction severity was similar in both groups (p = . ). the in-hospital mortality was . % in the treatment group versus . % in the control group (p = . ). signifi cant diff erences between the kaplan-meier estimates of survival were also not found (log-rank test p = . ). no major adverse reactions were observed. conclusion the implementation of this new policy failed to reduce the degree of organ dysfunction severity and was not associated with signifi cant survival benefi t. moreover, even though it did not reach statistical signifi cance, a second peak of gr(+) isolates was observed as a possible complication of the preemptive therapy. whether this approach could lead to vancomycin mic creep or there could still be a niche for it later in the course of treatment and/or in nontrauma patients remains to be further explored. reference introduction acinetobacter baumannii (a. baum) is a leading cause of septicemia of patients hospitalized in the icu with high mortality rates. the aim of our study is to investigate the risk factors associated with a. baum bacteremia and its mortality rates. introduction the french military hospital at the kaboul international airport (kaia) base provides surgical care for international force and afghan national army soldiers, and also local patients. the development of multiresistant bacteria (mrb) nosocomial infections has raised a major problem complicating the care of combat casualties [ ] . the aim of this study is to assess the prevalence of mrb carriage on admission to the icu in this combat support hospital. methods we used a prospective observation study on patients admitted to the french military icu in kaia over months (july to september ). all hospitalized patients were assessed for the presence of colonization with mrb: nasal and rectal swabs were performed to identify, respectively, methicillin-resistant staphylococcus aureus (mrsa) and extended-spectrum β-lactamases bacteria (esblb). the following data were recorded for each patient on admission: demographic characteristics, bacteriological results, length of stay, type of previous hospitalization. results sixty-three patients were admitted. the mean length of stay (mls) was ± days, and the mean age was ± ( patients < years). patients were hospitalized for combat-related trauma ( %), noncombat-related trauma, medical pathologies ( %), and postoperative care ( %). they were afghans ( %) or westerners ( %). swabs were not realized for eight patients. forty-three percent revealed an esblb colonization: escherichia coli ( patients), klebsiella pneumoniae (one patient), acinetobacter baumanii (one patient). no patients were colonized with mrsa. ten patients ( %) were directly admitted to the icu, ( %) had been hospitalized before admission, ( %) were transferred after resuscitative and stabilization care in a level unit. for the two last categories, the mls (for previous hospitalization) was respectively ± days and ± hours. among patients transferred after care in a level unit, mls was no diff erent between colonized and noncolonized patients: ± versus ± hours (p = . , mann-whitney test). conclusion in this study, prevalence of colonization with esblb at admission is very high, suggesting a high prevalence of mdr colonization in the local population in afghanistan. it remains important to intensify the prevention policy against mrb cross-transmission in the deployed icu. critical care , volume suppl http://ccforum.com/supplements/ /s introduction the aim of this study is to describe the clinical and epidemiological profi le of icu patients receiving tigecycline (tgc) and to evaluate the potential benefi ts of tgc higher doses. methods all patients admitted to our icu between june and may who received tgc were evaluated. cases were excluded when infections were not microbiologically confi rmed. results over the study period, patients fulfi lled the inclusion criteria: in the sd group ( mg every hours) and in the hd group ( mg every hours). the sd group and the hd group were not signifi cantly diff erent in terms of age, severity of disease, duration of tgc therapy, rate of concomitant other active antibiotic use and of inadequate empirical antimicrobial therapy (iiat) (p = ns). mdr a. baumannii and k. pneumoniae were the main pathogens isolated. the percentage of germs other than a. baumannii and k. pneumoniae was higher in the sd tgc group (p < . ). otherwise infections due to less susceptible germs (tgc mic value ≥ μg/ml) were mainly treated with tgc higher doses (p < . ). no signifi cant diff erences were found in terms of icu mortality (p = . ). the rate of abnormal laboratory measures during tgc treatment was similar between the two groups (p = ns). no patients required tgc discontinuation or dose reduction because of suspected adverse events. in the vap subpopulation ( patients: received sd and hd), the clinical cure rate and microbiological eradication percentage were higher when tgc was used at higher doses ( . % vs. . %; p = . and . % vs. . %; p = . ). table shows multivariate analysis of clinical cure predictors in the vap subgroup. conclusion in critically ill patients, hd tgc use seems to be safe and, combined with other active antibiotics, may increase the rate of mdr germ vap clinical success. iiat and the severity degree of patients' clinical condition still remain major determinants of vap treatment failure. reference introduction amikacin inhale (nktr- , bay - ) is a drugdevice combination in clinical development for adjunctive treatment of intubated and mechanically ventilated patients with gram-negative pneumonia. the product uses a proprietary vibrating mesh nebulizer system (pdds clinical) with amikacin sulfate formulated for inhalation ( . ml of mg/ml amikacin solution) for a -day twice-daily course of therapy. it is designed for use with two delivery systems: one system for intubated patients (on-vent; figure ), and a second handheld (hh) system for patients who are extubated before completing the course of therapy ( figure ). we investigated in vitro the amikacin lung dose delivered by pdds clinical. methods an estimated lung dose (eld) for on-vent setting was measured in vitro after collecting aerosolized amikacin from a fi lter at the end of an endotracheal tube during ventilation. the eld for the hh device was calculated from the fi ne particle fraction (fpf < μm) postmouthpiece, multiplied by the in vitro delivered dose post-mouthpiece. fpf < μm refl ects lung deposition observed during phase clinical trials [ ] . eighty-one nebulizers with volume median diameter (vmd) introduction recent studies demonstrate that a loading dose of mg/kg (total body weight) of amikacin in septic patients is required to reach a suffi cient peak concentration. this study examines parameters infl uencing the relation between amikacin dose and peak concentration. methods in this retrospective study we looked at patients ( peak levels) between and . multivariate linear regression analysis was done for several parameters: administered dose calculated with total body weight, ideal body weight, adjusted body weight, type of intensive care patient, bmi, daily fl uid balance, sofa score and apache score, and patient characteristics were analyzed. results a linear correlation between dose and amikacin peak level was confi rmed (figure ) . a total . % of all amikacin administrations did not result in a therapeutic peak level. the multivariate linear regression analysis showed the best linear correlation with adjusted body weight and sofa score. the comparison of variables between four patient groups, based on the deviation between measured peak level and predicted peak level (according the linear correlation), showed new variables that may infl uence peak level. conclusion this confi rms that low doses (< mg/kg) of amikacin in intensive care patients seldom result in a therapeutic peak level. the proposed loading dose of mg/kg is good for reaching a therapeutic level, although . % remains subtherapeutic. due to the linear correlation, more therapeutic levels may be reached with higher doses ( to mg/kg). new variables need further investigation to explain the high variability in achieved peak level. introduction antibiotic-associated diarrhoea (aad) occurs in as many as % of patients receiving antibiotics, often leading to increased morbidity, prolonged in-hospital stay and additional healthcare resource utilisation. age, antibiotics and prolonged postoperative ward and icu stay have been suggested to be independent risk factors. in such patient populations, probiotics may be used to prevent antibioticassociated diarrhoea, yet they are not routinely recommended as a component of perioperative care. the aim of this study was to model the long-term costs associated with aad and to assess the eff ectiveness of probiotics as a preventive strategy. we developed a simulation model to determine clinical costs and outcomes attributable to aad. to assess the cost-eff ectiveness of probiotics, as part of a perioperative regime, we constructed a decision critical care , volume suppl http://ccforum.com/supplements/ /s s tree. the model observes long-term costs and outcomes of probiotics as compared with conventional therapy, from a societal perspective. input parameters, extracted from meta-analysis, clinical trials and national databases, include incidence numbers, costs and qualityadjusted health states for the remaining life (qalys). outcomes assessed were overall costs attributable to add and the cost-eff ectiveness of probiotics, described as costs/qaly. our results indicate an estimated incremental lifetime cost of £ , . per add patient, largely driven by increased icu length of stay and readmission rates. the addition of probiotics to the standard perioperative regime is associated with a small survival benefi t of . months, yet a cost reduction of £ . /add patient. the main cost was increased duration of icu stay and readmissions, which contribute to % of total expenses. conclusion aad is associated with a signifi cant increase in costs from a societal perspective. the provision of probiotics can achieve substantial cost savings and can be recommended as a cost-eff ective regime in the perioperative setting. preventing add off ers a potentially signifi cant reduction of in-hospital costs and resource expenditures. introduction novel treatment strategies for invasive candidiasis (ic) are constantly emerging. nevertheless, diffi culties in diagnosis pose a challenge on their reliability, effi cacy and safety. we have previously developed and approbated in our icu an algorithm for empirical antimycotic therapy, combining the most signifi cant risk factors for ic with three major clinical criteria for persistent nonbacterial sepsis [ ] . on the other hand, preemptive therapy, based on identifi cation of mycotic antigens and/or anti-mycotic antibodies in serum, is regarded as more reliable, even though it is known for its low sensitivity. the aim of the current study was to compare and evaluate the possible outcome benefi t of our protocol implementation versus detection of galactomanan in patient's serum as a trigger for antimycotic treatment initiation. methods a randomized prospective controlled trial was carried out from september to september . after the implication of the inclusion and exclusion criteria, patients were submitted to block randomization and stratifi ed on the basis of their initial saps ii exp score. antimycotic therapy was started on the day of inclusion in the control group and only with positive galactomanan serum test in the preemptive therapy group. initial data were gathered on demographics, proven risk factors for ic-related mortality, severity of infl ammatory response and organ dysfunction. dynamics of sirs and sofa values, candida colonization index, ventilator-free days, length of icu stay and outcome were followed for each patient. results a total of patients were enrolled. no statistically signifi cant diff erences in their basal characteristics were found. the subsequent sirs and sofa scores showed fi rm dynamics in the control group, although the new organ dysfunction severity was insignifi cantly lower. the length of icu stay and the number of ventilator-free days were comparable. the in-hospital mortality was . % in the preemptive therapy group versus . % in the control group (p = . ). a total of seven adverse reactions were observed among treated patients, yet not associated with higher mortality risk. conclusion the choice of empirical versus preemptive therapy led to earlier and more stable reduction in the degree of organ dysfunction severity. it showed to be at least not inferior if not equal; in terms of survival benefi t and expediency of treatment. moreover, galactomanan detection fails to guide the choice of the individual antimycotic, based on the expected candida spp. reference introduction invasive candidemia is a major cause of increased mortality among icu patients. antifungal agents like liposomale amphotericin b and azoles could not accomplish the claim to be fi rst choice in the treatment of invasive fungal infection (ifi) because of side eff ects and eff ectiveness. especially, cardiothoracic surgery patients as a group of high-risk patients are in a focus for new strategies and agents. a new class of antimycotic agents, the echinocandins, with a low profi le of side eff ects, low interactive potential and high eff ectiveness in the treatment of candidemia, is a powerful option in the treatment of ifi. we report our single-center experience with a modifi ed clinical treatment approach based on clinical score of leon and using echinocandins as fi rst-line therapy for proven and suspected fungal infection. methods from may to october , , patients were treated on our cardiothoracic icu. we evaluated cardiothoracic postoperative patients with proven or suspected ifi or prophylaxis ( figure ). the records were evaluated for cardiothoracic procedures, microbiological and yeast date, cardiothoracic surgery score (casus), icu and clinical data. mean age was . years with % male patients. most patients had combined cabg and valve procedure (n = ), other groups were htx and ltx (n = ), assist therapy (n = ), tavi (n = ) and other procedures. mean predicted mortality using the logarithmic casus score at the onset of ifi was %. c. albicans was isolated in %, c. glabrata in %. length of antifungal treatment using micafungin in cases was ± days. eradication of yeast was successful in % but mortality of all patients remains high at . % but was lower than predicted in the casus score. mortality was not yeast related. conclusion our described treatment approach shows encouraging results for the treatment of ifi especially in high-risk cardiothoracic patients. with fungi [ ] . the relationship between colonization and invasive fungal infection (ifi) in severely ill icu patients with a vad support is not described. this study analyzes the incidence and outcome of fungal infection and colonization in vad patients in bridge to transplantation or in destination therapy. methods we conducted a retrospective review of all vad implantations in our surgical icu between and . the incidence of fungal colonization, antifungal prophylaxis, bacterial sepsis and the mortality of ifi versus no ifi patients were compared. results in the study period, patients with severe heart failure or cardiogenic shock were selected for a vad implantation (nine in destination therapy). the overall mortality rate was % during mechanical assistance. confi rmed (n = ) and highly suspected (n = ) ifi occurred during the icu stay in % of patients who were treated with echinocandins, voriconazole and/or liposomal amphotericin b. the isolated fungi were: six candida albicans, two parapsilosis, one glabrata and one invasive pulmonary aspergillosis. antifungal prophylaxis with fl uconazole was administered to % of patients at mean for days mainly in the more recent implantations. in the no ifi population, % (n = ) had a systemic or vad bacterial sepsis with a mortality rate about %. the mortality without any sepsis was reduced to %. fungal colonization was signifi cantly more present ( % vs. %) before ifi in vad patients. the mortality rate was dramatically higher with ifi ( % vs. %) in accordance with the literature [ ] . see table . conclusion in our center, we observed a high incidence of ifi in icu patients with vad that was associated with a mortality rate of %. screening of fungal colonization appears to be very important during the icu stay for vad patients. trials are needed for investigating the use, the drug choice and the timing of antifungal prophylaxis for such high-risk patients. reference introduction echinocandins are recommended fi rst-line treatment for candidaemia [ ] . a cost-eff ectiveness model developed from a uk perspective examined costs and outcomes of antifungal treatment for candidaemia and other forms of invasive candidiasis based on european clinical guidelines [ ] . methods costs and treatment outcomes with the echinocandin anidula fungin were compared with caspofungin, micafungin, fl uconazole, voriconazole and amphotericin b. the model included non-neutropenic patients aged ≥ years with confi rmed candidaemia/ another form of invasive candidiasis receiving intravenous fi rst-line treatment [ ] . patients were categorised as a clinical success or failure (patients with persistent/breakthrough infection); frequency data for each outcome were taken from a mixed-treatment comparison [ ] . successfully treated patients switched to oral therapy. clinical failures switched to a diff erent antifungal class. it was assumed that second-line treatment duration was equivalent to that of fi rst-line treatment and only two lines of therapy were required to treat infection. other inputs were all-cause -week mortality, cost of treatment-related adverse events (aes) and other medical resource use costs. life-years were calculated using a published model [ ] . antifungal agent-related aes were taken from the product label/literature. resource use was derived from the literature and discussion with clinical experts. drug acquisition/ administration costs were taken from standard uk costing sources. results first-line anidulafungin for treatment of candidaemia was cost-eff ective per life-year gained versus fl uconazole (incremental cost-eff ectiveness ratio £ ). anidulafungin was cost saving versus caspofungin and micafungin in terms of life-years gained due to lower icu costs and a higher rate of survival combined with a higher probability of clinical success. conclusion anidulafungin was cost-eff ective compared with fl uconazole for treatment of candidaemia and was cost saving versus other echinocandins in the uk. european guidelines recommend echinocandins as fi rst-line treatments for candidaemia [ ] ; this model indicates that anidulafungin marries clinical eff ectiveness and cost-eff ectiveness. introduction invasive fungal infections (ifi) aff ect % of icu patients and are increasing in incidence. ifis are associated with a poor prognosis, which is further complicated by diffi culties in identifi cation of fungal organisms by traditional culture methods and the emergence of candida species resistant to triazole therapy [ , ] . this study aimed to assess the prevalence of ifis, the organisms responsible and outcomes of patients aff ected. the majority of patients ( %) were treated with echinocandins, whilst of the nine patients who were initially treated with fl ucanazole, six ( %) required therapy escalation to an echinocandin. the results of our study are consistent with other published data, in that whilst ifi prevalence is low, they are associated with increased morbidity in critically ill patients. this study has led to a change in hospital policy regarding antifungal use in the icu, with echinocandins being fi rst-line in the pre-emptive treatment of ifi. we keenly await the results of the fire study, which will provide important insights to identifi cation of patients at risk of ifis and optimal drug therapy. introduction the aim of this study was to compare self-reported beliefs with actual clinical practice of oxygen therapy in the icu. hyperoxia is frequently encountered in ventilated patients and prolonged exposure has repeatedly been shown to induce lung injury and (systemic) toxicity. methods an online questionnaire for icu clinicians was conducted to investigate beliefs and motives regarding oxygen therapy for critically ill patients. furthermore, arterial blood gas (abg) samples and corresponding ventilator settings were retrieved to retrospectively assess objective oxygenation between april and march in the icus of three teaching hospitals in the netherlands. results analyzable questionnaire responses were received from icu physicians and nurses. the majority of respondents believed that oxygen-induced lung injury is a concern, although barotrauma and volutrauma are generally considered to impose a greater risk in mechanical ventilation. frequently allowed minimal saturation ranges in the questionnaire were to % and to kpa ( figure ). selfreported fio adjustment in hypothetical patient cases with variable saturation levels was moderately impacted by the underlying clinical condition. to study actual clinical practice, a total of , abg samples with corresponding ventilator settings, covering , patient admissions, were retrieved. analysis showed a median (iqr) pao of . kpa ( . to . ), median fio was . ( . to . ), median peep was ( to ). a total . % of all pao registries were higher than previously suggested oxygenation goals ( . to . kpa) [ ] . in . % of cases with pao higher than the target range, neither fio nor peep levels had been lowered when the next abg sample was taken. conclusion most clinicians acknowledge the detrimental eff ects of prolonged exposure to hyperoxia in the icu and report a low tolerance for high saturation levels. however, the self-reported intention for conservative oxygen therapy is not consistently expressed in our objective data of actual clinical practice and a large proportion of patients was exposed to high and potentially toxic oxygen levels. introduction during mechanical ventilation, oxygenation can be infl uenced by adjusting fio and positive end-expiratory pressure (peep). there have been recommendations for how the fio and peep should be set [ ] . however, in a recent audit we found that the compliance of doctors of these recommendations is very low [ ] . conclusion implementing an fpi ≤ -based algorithm signifi cantly reduced the fio and increased the peep applied in mechanically ventilated within the fi rst hours. whether this has any impact on earlier weaning due to reaching the weaning criteria of fio sooner, and as a result shortening the duration of mechanical ventilation, has to be investigated in the future. references system) were applied with the humidifi er to optimize humidication. typeb was used in three patients and typev in four patients. the fl ow was started at l/minute. this fl ow rate was titrated upwards to a maximum of l/minute ( , , , , , l/minute) and the agfr was measured. intratracheal pressure tracing was done over minute. airway pressure measurement was repeated and the maximal expiratory pressure was measured in mmhg. the agfr in the respiratory circuit was almost same in typeb, but there was obvious decrease in the agfr in typev ( . ± . , . ± . , . ± . , . ± . , . ± . , . ± . l/minute at assumed fl ow, , , , , , l/minute, respectively). hfnc signifi cantly increased maximal expiratory pressure in both groups, . ± . , . ± . , . ± . , . ± . mmhg for typev and . ± . , . ± . , . ± . , . ± . mmhg (maximum mmhg) for typeb, when agfr was set at , , , l/minute. higher agfrs were found to result in larger increase in maximum expiratory pressure. the data indicate that hfnc are associated with an increase in intratracheal expiratory pressure. because it was diffi cult to determine end-expiratory pressure, we chose maximal expiratory pressure for a substitute. the reason why agfr in typev was lower than assumed fl ow may be the resistance generated by nc. the larger increase in expiratory pressure in our study than previously reported may be due to the eff ect of high respiratory resistance of japanese who have relatively small airway structure compared with western people. conclusion hfnc are eff ective in providing higher expiratory pressure. it is important to know the fl ow rate is lower than expected when the venturi type is used. results a weaning-induced pulmonary edema was diagnosed in instances (paop signifi cantly increased from . ± . to . ± . in these cases). evlwi, bnp, plasma protein and hemoglobin concentrations signifi cantly increased in these instances ( . ± . %, . ± . %, . ± . % and . ± . %, respectively) while they did not signifi cantly changed in cases without weaning-induced pulmonary edema. the increase of evlwi ≥ . % (+ . ml/kg), an increase in bnp ≥ . % (+ pg/ml), an increase in plasma protein concentration ≥ % and in hemoglobin concentration ≥ % exhibited good areas under the roc curves to predict weaning-induced pulmonary edema ( . ± . , . ± . , . ± . and . ± . , respectively). these areas under the roc curves were not statistically diff erent. the baseline values of evlwi, bnp, plasma protein and hemoglobin concentrations did not predict weaning-induced pulmonary edema. conclusion the increases in evlwi, in plasma protein and hemoglobin concentration and in bnp are valuable alternatives to the pulmonary artery catheter for diagnosing weaning-induced pulmonary edema. the primary aim of this study is to assess the impact of pressure support ventilation (psv) on the rate of pneumothorax and mortality in critically ill patients with lung injury. the secondary aim is to evaluate pressure-volume (p-v) relationships. spontaneous modes of ventilation have been associated with lower rates of atelectasis, less muscle atrophy, better airfl ow distribution and importantly lower sedation requirements, which relates to lower mortality. accordingly, we hypothesized that the use of psv in patients with moderate/severe lung injury would have rates of pneumothorax and mortality within the standard of care. we further hypothesized that given its spontaneous nature, set pressures (peep and ps) but not tidal volume (vt) would be related to airway pressures. methods all adult patients admitted to two surgical/medical icus subjected to invasive mechanical ventilation (mv) were enrolled. patients were stratifi ed by lung injury score (lis) in two groups: < . (lisl); ≥ . (lish). exclusion criteria included pneumothorax on admission, use of other ventilatory strategies, and inability to trigger ventilation. patients were ventilated with psv, and treated only with pro re nata haldol, morphine and clozapine. airway pressures and conclusion we demonstrate that psv in minimally sedated patients with severe lung injury is safe as it is associated with low incidence of barotrauma, atelectasis and mortality, and with ppl and duration of mv within standard of care. we also demonstrate in psv that p-v relationships may diff er and that in this setting higher vt may not be deleterious. introduction the aim of this study is to compare two ventilation strategies, the ardsnet protocol and open lung management, using computer control for hours. the standard therapy for patients with ards does typically apply a mechanical ventilator to support breathing. the cost of therapy is high and it requires much attention from physicians to adjust the proper ventilation settings in a timely manner. a closed-loop ventilation concept has therefore been developed and tested with two induced ards pigs. methods the hardware system is composed of a ventilator (servo ), a spectrophotometry (cevox), a capnography device (co smo+), an electrical impedance tomography device (goe mf ii) and a patient monitor (sirecust). the software is developed with labview . . with approval from the ethical committee, two kg pigs were exposed to surfactant depletion with a warm saline washout to induce ards (pao / fio < mmhg). one pig model was ventilated with an automatic ardsnet protocol and another was automatically ventilated with open lung management. blood gas analysis (bga) was carried out every half an hour. results artifi cial ventilation using the auto ardsnet protocol successfully stabilized oxygenation, minimized plateau pressure (< cmh o), and controlled the ph value for acidosis and alkalosis management. on the other hand, auto open lung management off ers a distinctive result of ventilation. a signifi cant improvement of oxygenation and lung compliance was observed within a few breaths after the recruitment maneuvers. both subjects were ventilated at the same tidal volume of ml/kg and the comparative results of automatic ventilation settings and bga are provided in table for every hours. conclusion the auto open lung management concept gave much better gas exchange than the auto ardsnet protocol. these preliminary results showed a necessity to evaluate the two diff erent ventilation strategies. therefore, further experiments with pig models will be implemented in the near future to obtain results with statistical signifi cance and to ensure the safety of automation in a mechanical ventilation system. intellivent-asv has been developed to provide fully closed loop mechanical ventilation using a ventilation controller keeping etco and spo within expert-based ranges. ventilation of ards patients focuses on delivering adequate oxygenation and allowing elimination of co while protecting the lung. the objectives were to compare intellivent-asv with conventional ventilation on safety and effi cacy, and to compare the number of manual adjustments between the two ventilatory modalities. methods a randomized, controlled study including all consecutive patients receiving mechanical ventilation for at least hours. patients were randomly ventilated either with intellivent-asv or conventional ventilation, with a s (hamilton, bonaduz, switzerland). parameters were adjusted by the clinician in charge of the patient. ventilatory and oxygenation parameters were recorded cycle by cycle during hours and blood gases were performed every hours. results twenty-four patients with ards were included, female, male, median age ( to ) years, apache ii score ( to ), pao /fio at inclusion ( to ). eleven were ventilated in the conventional group and in the intellivent-asv group. the study was stopped for one patient from the intellivent-asv group because of a pneumothorax not caused by ventilation. the delivered vt was slightly higher during intellivent-asv ( . ( . to . ) vs. . ( . to . ) ml/kg, p = . ). the time spent by the various parameters in the suboptimal zone (safety) is the same for the two ventilation modes. the time spent in the optimal zone (effi cacy) is the same for the two ventilation modes, introduction ventilator-induced lung injury (vili) is a well-known side eff ect of mechanical ventilation. the pressures and volumes needed to induce vili in healthy animals are far greater than pressure and volumes applied in clinical practice [ ] . a possible explanation may be the presence of local pressure multipliers (stress raisers). methods we retrospectively analyzed ct scans of patients with ards and ct scans of healthy subjects. a homogeneous lung would have the same gas/tissue ratio in all its regions. if a lung region expands less than the neighbour regions these will be more strained to vicariate the non/less expanding region. we measured the stress raisers by computing the ratio between the gas fraction of the region of interest and the neighbouring regions: if the infl ation would be the same (homogeneity), the ratio will be equal to one; if the infl ation of the surrounding regions would be greater than the region of interest (that is, more strained), the ratio between the two will be greater than one and was taken as a measure of stress raiser. we considered pathological stress raisers as the regions showing infl ation ratio greater than the th percentile of the control group ( . ) and defi ned as the extent of the stress raisers the fraction of lung volume above this threshold. the extent of stress raisers increased with the severity of ards ( ± , ± , ± % of lung parenchyma in mild, moderate and severe ards, p < . ). the extent of stress raisers correlated with the dead space fraction (r = . , p < . ), with the fraction of poorly aerated tissue (r = . , p < . ) and also has a negative correlation with the fraction of well infl ated tissue (r = . , p < . ). the response to peep, passing from to cmh o is minimal (average decrease of stress raiser extent ± %) and inter-individual variability is great (in patients, stress raisers increased passing from peep to peep ). stress raisers turn out to be greater in nonsurvivor patients than in survivor patients ( ± vs. ± % of lung volume, p = . ). the art strategy did not increase the risk of barotrauma (relative risk (rr) = . , % ci = . to . ) in the fi rst days after randomization or the need to initiate or increase vasopressors or mean arterial pressure < mmhg (rr = . , % ci = . to . , p = . ) hour after randomization. however, the art strategy increased the risk for severe acidosis (ph < . ) hour after randomization (rr = . , % ci = . to . , p = . ). conclusion art is feasible. the incidence of adverse events was similar between groups except for severe acidosis hour after randomization. hence we adjusted the study protocol, increasing the respiratory rate (from to /minute) during msarm. introduction cardiac surgical procedures are associated with a high incidence of postoperative complications, increasing costs and mortality. the purpose of this study is to evaluate prospectively the impact of two protective mechanical ventilation strategies, both using low-tidal volume ventilation ( ml/kg/ibw) after cardiac surgery. conclusion the reliability of pressure measurements and also of compliance estimation via the tested catheters is high. only in two catheters was the fi lling volume a critical point for a precise measurement of pressure or for estimation of compliance. immediately after unpacking, adhesion of the balloon material might prevent reliable pressure measurement, therefore before the fi rst measurement overfi lling of the balloon and retention of the excess gas seems strongly recommended. introduction low tidal volume (vt) ventilation in intensive care patients without lung injury attenuates the systemic infl ammatory response [ ] . the contribution of the specifi c organ infl ammatory responses to the systemic picture remains to be elucidated. we investigated the eff ect of low vt ventilation compared with medium high vt on hepatic, splanchnic and cerebral cytokine responses in an experimental large animal postoperative sepsis model. methods twenty pigs, group protective ventilation (pv), were ventilated with low vt ( ml/kg) and peep cmh o while pigs, group control (c), were ventilated with a vt of ml/kg and peep cmh o. catheters were introduced into an artery, the jugular bulb, the hepatic vein and the portal vein. laparotomy for hours simulated a surgical procedure after which baseline ensued and a continuous endotoxin infusion was started at . μg/kg/hour for hours. diff erences were analyzed with anova for repeated measures. results tnfα levels were higher in the hepatic vein than in the artery, the jugular bulb and the portal vein. il- levels were higher in the artery and the jugular bulb compared with the portal and hepatic veins. il- levels were higher in the portal vein compared with the jugular bulb and hepatic vein. the organ-specifi c il- concentrations were all higher than the arterial concentration. comparison between the ventilation groups showed that tnfα, il- and il- in the hepatic vein were higher in group c compared with group pv at the end of the experiment. peak concentrations of tnfα and il- in the portal vein were higher in group c compared with group pv. in this experiment tnfα was mainly generated in the liver while the results point to signifi cant nonhepatic il- and il- production. ventilation with low vt and medium-high peep attenuated hepatic and splanchnic cytokine production compared with mediumhigh vt and lower peep. reference introduction airway pressure release ventilation (aprv) allows spontaneous breathing throughout the ventilation cycle. it increases venous return and cardiac index, which will signifi cantly improve organ perfusion. this is important in septic shock patients to prevent extrathoracic organ system failure secondary to poor perfusion. benefi ts of aprv with cardiovascular changes are noticed in patients with acute lung injury and acute respiratory distress syndrome. it is not well established whether applying aprv will improve the survival outcome for septic shock patients. the primary outcome is whether the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. the secondary hypothesis is whether the use of aprv in septic shock patients improves their survival in the icu. methods after institutional review board approval, we retrospectively analyzed the clinical data of septic shock patients who received ventilator support between january and december at a tertiary care hospital. the cox proportional hazards model was used in adjusting potential confounding factors. the nonparametric wilcoxon rank sum test was used to assess signifi cant outcome diff erences between groups. time to event/survival data will be analyzed using kaplan-meier methods. these analyses were accomplished using sas, version . . results among the patients, were excluded as per the exclusion criteria: incomplete data (n = ), do not resuscitate (n = ), icu readmission (n = ) and head injury (n = ). finally, patients were included, from these received cmv and received aprv. at the beginning of the study, there were no diff erences between the groups in relation to hemodynamic parameters. reversal of shock achieved in less than hours was statistically signifi cant between the groups (aprv, n = ( %) and cmv, n = ( %), p = . ). the proportion of patients recovering from septic shock after initiation of ventilator therapy was higher in aprv than the cmv group ( % vs. %, respectively, p < . ). the mortality rate was signifi cantly higher in cmv (n = , %) as compared with aprv (n = , %) (p = . ). conclusion the use of aprv in septic shock patients restores hemodynamic stability earlier than the cmv mode. there was a signifi cant improvement in icu survival using aprv over cmv. early initiation of aprv in ventilated septic shock patients was associated with a decrease in icu mortality. obese patients are at risk of developing atelectasis and acute respiratory distress syndrome (ards) [ ] . the prone position (pp) may reduce atelectasis, and improves oxygenation and outcome in severe hypoxemic patients in ards [ ] , but little is known about its eff ect in obese ards patients. introduction protective mechanical ventilation (mv) in ards is based on reduced stretch of pulmonary tissue, sometimes resulting in severe hypoventilation that can be avoided when using high respiratory rate. high-frequency positive-pressure ventilation (hfppv) has not been fully explored, especially when associated with other strategies aiming to avoid hypercapnia. methods we induced ards in eight pigs by lung lavage with saline plus hours of injurious mv with low peep and high driving pressure (dp). we then performed a recruitment maneuver (rm) followed by peep titration using the amount of alveolar collapse in electrical impedance tomography (eit). then stabilization during hours with tidal volume (vt) at ml/kg, respiratory rate (rr) breaths/minute and peep selected with the peep-fio table (arma study), which was kept constant during two steps of hfppv with a rr : one without an inspiratory pause (hfppv- ), and one with a pause of % of inspiratory time (hfppv- w/p %). in another hfppv step, we used peep titrated with eit after rm (hfppv- w/rm). during each hfppv step, vt was set to reach a paco of ± mmhg. distribution of regional ventilation was analyzed using eit. equilibrium was considered if paco was stable (< % of variation) for > minutes. results hfppv allowed reduction in paco levels: ( , ) versus ( , ), ( , ), ( , ) mmhg, besides using lower vt: . ( . , . ), . ( . , . ), . ( . , . ) and . ( . , . ) ml/kg during stabilization, hfppv- , hfppv- w/p % and hfppv- w/rm, respectively. it had no signifi cant diff erent results comparing hfppv- with and without an inspiratory pause. hfppv- w/rm allowed a better alveolar homogenization and improvement in oxygenation, shunt, dead space and dp compared with the other steps. see table . conclusion hfppv with a conventional mechanical ventilator is able to maintain stable paco in clinically acceptable values, allowing reductions in vt. hfppv- w/rm and peep titration using eit allowed further physiologic benefi ts in a severe ards model. high-frequency percussive ventilation (hfpv) is a rescue technique for most severe acute lung injury/acute respiratory distress syndrome (ards) patients [ ] , especially with smoke inhalation or respiratory burns [ ] . this study aimed at characterizing hfpv as delivered by percussionnaire vdr ® and at evaluating how hypobarism interferes with hfpv, in order to assess its usability at altitude. methods using a mechanical test lung mimicking ards (compliance ml/cmh o) with two resistance levels ( and cmh o/l/second) and ventilated with vdr ® in a hypobaric chamber, ascents/descents between and , and then and , ft were performed. adjustable vdr ® parameters were modifi ed one at a time at each altitude. besides these parameters (cross-measured with standalone hardware), oxygen consumption of the respirator and three calculated parameters were studied: low-frequency tidal volume (vt, integrated from instantaneous fl ows measured with a fleisch pneumotachograph), end-inspiratory (pmei) and end-expiratory (pmee) mean pressures. pmei and pmee in hfpv refl ect plateau pressure and positive end-expiratory pressure in conventional ventilation. the correction of altitude-induced off set with the modifi cation of working pressure was also tested. results data displayed by vdr ® overestimated pulmonary pressures by more than %, but were reliable for other parameters. during ascent, an off set appeared for all respiratory parameters: vt increased by % and pmei by % between and , ft. during descent, the off set was reversely directed with a % decrease in vt and a % decrease in pmee between , and ft. modifying working pressure adequately corrected pmei and pmee, but not vt. in all cases, manually correcting vdr ® parameters to their ft level also corrected these off sets. multivariate analysis further established that, adjusting for other parameters, vt, pmei and pmee did practically not depend on altitude. oxygen consumption of the respirator was high, l/minute at ft, and stable with altitude. it was reduced with percussive rate and with fio . conclusion hfpv can be safely used at altitude, provided that vdr ®displayed parameters are used to manually adjust settings in order to avoid exposing patients to volutrauma or barotrauma during ascent, and to major hypoventilation and alveolar collapse during descent. the high oxygen consumption is currently the main limit to its use for longrange aeromedical evacuations. the application of peep is commonly used in acute respiratory distress syndrome (ards) and has been shown to improve oxygenation. to identify patients that most benefi t from the application of peep, the discrimination of recruiters and nonrecruiters has been postulated by gattinoni and colleagues [ ] . recently, dellamonica and colleagues [ ] presented a method to predict alveolar recruitment. we hypothesised that the amount of recruitable volume allows the discrimination between ards patients and patients with healthy lungs (hl). methods we recalculated the recruited volume (rv) in patients with ards [ ] according to the method proposed by dellamonica and colleagues during an incremental peep manoeuvre (peep increased until the plateau pressure reached cmh o). rv was calculated as the change in end-expiratory lung volume minus total respiratory system compliance times the peep change (rv = Δeelv -ctot×Δpeep). for comparison, patients with hl undergoing elective surgery in general anaesthesia were measured using the same protocol. results both ards and hl patients exhibited typical p-v curves and stepwise recruitment ( figure ). by raising peep from to cmh o, ards patients recruited ± ml (mean ± sd) and hl patients ± ml. there was a strong correlation (r = . ) of the total rv with the end-inspiratory volume at a plateau pressure of cmh o in both groups; that is, recruitment was found to the same extent in both groups ( figure ). conclusion the relative contribution of rv to lung volume gain is similar in ards and in patients with healthy lungs. our results question the relevance of recruitability as defi ned by dellamonica and colleagues as a typical phenomenon of ards, but support the baby lung concept, as the recruited volume was closely related to the size of the lung. introduction venovenous extracorporeal membrane oxygenation (vv-ecmo) for respiratory failure in the icu is used in a variety of clinical situations and has been demonstrated to signifi cantly improve survival without disability in adult respiratory distress syndrome [ ] . ecmo has been presented as a risk factor for bloodstream infection although recently published data do not support this view or the use of antibiotic prophylaxis [ ] . we aimed to examine vv-ecmo as a risk factor for nosocomial bloodstream infection. a larger study is needed to confi rm such fi ndings and to assess the need for specifi c intervention, namely routine antibiotic prophylaxis. introduction aptt is a common tool for anticoagulation monitor ing during extracorporeal membrane oxygenation (ecmo). thromboelasto graphy (teg) is another available option in this setting. methods a prospective observational study on consecutive patients during venovenous ecmo. anticoagulation was provided critical care , volume suppl http://ccforum.com/supplements/ /s s with unfractioned heparin titrated to an aptt ratio target of . to . kaolin-activated teg (k-teg) was contemporarily measured but did not guide heparin infusion. baseline k-teg reaction time (r) > minutes is accepted for anticoagulation but when it exceeds minutes anticoagulation may be too great [ ] . results mean ecmo duration was ± days. a total of k-tegs were collected. comparison between aptt and k-teg r is reported in table . four patients ( %) had hemorrhagic complications. neither aptt nor k-teg r were signifi cantly diff erent in patients with hemorrhagic events compared with patients without hemorrhagic events but the latter received a signifi cantly lower total heparin dose (p = . ). conclusion anticoagulation was excessive in more than one-half of the samples according to teg monitoring, while negligible based on aptt. reference introduction the usefulness of extracorporeal membrane oxygenation (ecmo) is being rediscovered in the wake of the pandemic of h n infl uenza. however, it has been reported that patients who received ecmo often developed virus-associated hemophagocytic syndrome (vahs), compared with those without ecmo support. although there is ample evidence that extensive cytokine activation is a key factor in vahs, ecmo itself could be a potential trigger to exacerbate the pathology by amplifying cytokine activation. in this study, we investigated whether mediators such as cytokines may be produced by ecmo. methods patients with severe respiratory failure who were placed on ecmo were enrolled between june and july . this study was approved by the ethics committee. blood specimens were drawn from the blood circuit at the inlet of the centrifugal pump (before) and outlet of the hollow fi ber oxygenator (after) at a frequency of three to four times per day. blood il- β, il- , il- , il- , il- , il- , il- , il- , il- (p ), il- , il- , g-csf, gm-csf, ifnγ, mcp- , mip- β, and tnfα were measured globally using a multiplex cytokine bead array system (bio-plex; bio-rad, tokyo, japan). hmgb was measured using an elisa kit (shino-test, tokyo, japan). results two patients with interstitial pneumonia were studied. the ecmo system consisted of a rotafl ow centrifugal pump (maquet japan, tokyo, japan), a biocube tnc coating (nipro, osaka, japan), and a percutaneous cardiopulmonary support system (capiox ebs; terumo, tokyo, japan). the blood fl ow rate was . ± . l/minute. a total of blood sets were collected. in most cases, blood levels of il- β, il- , il- , il- , il- (p ), il- , il- , gm-csf, ifnγ, and tnfα were below the detection limit and did not increase during ecmo. the other mediators were detected at the inlet (before), but no signifi cant increase was observed at the outlet (after) (hmgb , p = . ; il- , p = . ; il- , p = introduction during severe exacerbation of chronic obstructive pulmonary disease (copd) tachypnea, as a consequence of respiratory acidosis, and airfl ow limitation, due to small airway obstruction, lead to lung hyperinfl ation, respiratory distress and gas exchange impairment. invasive mechanical ventilation could worsen lung hyperinfl ation and produce a vicious circle. we investigated whether increasing extracorporeal carbon dioxide removal (ecco cl) could reduce the respiratory rate (rr), so prolonging time for lung emptying and allowing resolution of hyperinfl ation. methods six patients with copd exacerbation with respiratory acidosis (paco ± mmhg, ph . ± . ) and tachypnea (rr ± ) despite maximal non-invasive ventilation underwent venovenous extracorporeal membrane oxygenation (vv-ecmo). all patients were awake and spontaneously breathing an adequate air-oxygen mixture to correct hypoxemia (pao ± mmhg). while keeping the blood fl ow stable ( . ± . l/minute), we changed the gas fl ow of the artifi cial lung to modify the extracorporeal co clearance as a percentage of total patient co production (% ecco cl/total vco ) and we observed the variations of rr. we recorded rr at three levels of gas fl ow in each patient ( figure ) . in all patients rr decreased with the increase of extracorporeal co removal and a negative correlation was found between rr and ecco cl/total vco (r = . , p < . ). in all patients we were able to obtain a reduction of rr below ( ± vs. ± , rr at low gas fl ow vs. rr at maximal gas fl ow, p < . ). the selected maximal gas fl ow was variable between diff erent patients ( . ± l/minute), corresponding to diff erent levels of ecco cl/total vco ( ± %, range to %) and rr response ( ± , range to ). conclusion in patients with copd exacerbation, who failed noninvasive ventilation, vv-ecmo allows one to maintain spontaneous breathing. titration of extracorporeal co removal leads to control rr. this approach could interrupt the vicious circle of dynamic hyperinfl ation and allow the defl ation of lung parenchyma. table presents the main results. the co removal by membrane oxygenator ranged from to ml/minute. all patients survived to the treatment and / were weaned from the ventilator at the end of ecco removal. only one oxygenator was used for every patient without clotting of the circuit or any major bleeding problem. we have previously shown, in an ex vivo porcine model, that lung elastance calculated as the peep change divided by lung volume increase (Δpeep/Δeelv) is closely correlated to conventionally measured lung elastance using oesophageal pressure [ ] . in this study we hypothesize that the successive change in lung volume during a peep-step manoeuvre could be predicted from Δpeep and lung elastance as Δpeep/el. the objective of the study was to validate this hypothesis in patients with acute respiratory failure (arf). methods thirteen patients with arf were studied during an incremental peep trial, - - - - cmh o. Δeelv was determined as the change in expiratory tidal volume following each peep step. conventional calculation of lung elastance was obtained from tidal variation in airway pressure minus tidal variation in oesophageal pressure divided by tidal volume. position of the oesophageal catheter was verifi ed according to baydur [ ] . the measured change in end-expiratory lung volume during the peep-step manoeuvre using spirometry was compared with the end-expiratory lung volume change calculated from el and stepwise changes in peep as Δpeep/el. results there was a close correlation between the measured build-up of end-expiratory lung volume during a peep-step manoeuvre and Δpeep/el where el was conventionally determined using oesophageal pressure measurements (see figure ). conclusion esophageal pressure measurements are diffi cult to perform [ ] and rarely used in routine clinical practice. our fi ndings indicate that a change in peep together with measurements of the resulting change in end-expiratory volume by spirometry in the ventilator could be used to determine lung elastance separately, the relation between lung and chest wall elastance as well as the transpulmonary pressure. references introduction long-term use of mechanical ventilators may lead to ventilator-induced diaphragmatic dysfunction (vidd) and increase the duration of weaning from mv [ ] . it was hypothesized that stimulating the diaphragm during mv may prevent vidd and may lead to early weaning [ ] . in this study, the feasibility of generating coordinated contraction of both diaphragms was investigated using a novel transvenous diaphragmatic pacing system. methods two juvenile pigs were anesthetized with propofol ( to μg/kg/minute) and ventilated (vent) with an assist control mode mv (nellcor puritan bennett ). using fl uoroscopy, a novel multipolar neurostimulation catheter (inspirx rl picc ; respithera, bloomington, mn, usa) was threaded into the left internal jugular vein and advanced to the junction of right atrium and the superior vena cava using a modifi ed seldinger technique. the successful capture of the right and left phrenic nerves was confi rmed by fl uoroscopic visualization. peak airway pressures (pawp) and blood gases were determined after minutes mv (mv), mv and stimulation applied together (mv+stim) and stimulation only (stim). no animal-ventilator dyssynchrony during stimulation (mv+stim) was noted while peak airway pressures were reduced. during stim there was no discernible paradoxical movement of the diaphragm. in addition, pco and po confi rmed that adequate ventilation and oxygenation can be provided by the system, while pawp could be reduced (table ) . introduction retrospective studies suggest that cardiac troponin levels are often elevated in patients with acute exacerbation of chronic obstructive pulmonary disease (aecopd) indicating a poor survival. novel high-sensitivity cardiac troponin (hs-ctnt) assays have better analytical precision than standard troponin (ctnt) assays. we elaborated a prospective cohort study to investigate the prognostic value of this novel biomarker in patients with aecopd. methods fifty-six patients (mean age years, % male) with the fi nal diagnosis of aecopd were enrolled. those who were diagnosed with acute coronary syndromes were excluded. we measured cardiac troponin t with a standard fourth-generation assay and a highsensitivity assay. clinical, electrocardiographic and echocardiographic data were collected at admission and the primary prognostic endpoint was death during days of follow-up. introduction british thoracic society guidelines on communityacquired pneumonia (cap) advocate icu referral for patients with curb score of and . a recently developed scoring system, smart-cop, designed to identify patients at need of intensive respiratory or vasopressor support (irvs), has been validated in a variety of settings. it predicts the need for icu admission (defi ned as need for irvs) with greater accuracy than curb , but is not used routinely in our uk institution. methods we retrospectively analysed critical care admissions of patients with a diagnosis of cap in a uk district general hospital -icnarc-coded diagnoses of pneumonia (bacterial, viral, no organisms isolated) over a -month period (august to january ). we ascertained the curb and smart-cop scores on referral to the icu and matched them in relation to the need for irvs, length of inotropic and ventilatory support and icu length of stay. results our search revealed potential matches. five patients were excluded (not cap) and the notes for seven patients were not available for analysis. we analysed the notes of patients matching our criteria. in this small sample, there was a strong association between increasing smart-cop score and the need for irvs (correlation coeffi cient r = . ). there was also a strong correlation with longer inotropic support (r = . ) and longer ventilatory support (r = . ) with increasing smart-cop scores but a weaker correlation with length of icu stay (r = . ). moreover, none of the patients admitted to the icu had curb score higher than at the time of icu referral. conclusion in our small sample, higher smart-cop score was associated with increased likelihood of irvs. this suggests that a further study with a larger sample size should be performed to investigate whether smart-cop is an improvement on curb in predicting the need for irvs in uk intensive care patients. introduction streptococcal pneumonia remains the most common cause of community-acquired pneumonia (cap), bacterial meningitis and bacteremia. severe pneumonia caused by streptococcal pneumonia frequently exists in the emergency room or icu. we performed this study to evaluate the eff ect of steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation retrospectively. methods we enrolled adults of streptococcal pneumonia patients who required mechanical ventilation. seven of patients (s group) were administered with steroid (hydrocortisone to mg/day), and the remaining six patients received no steroid therapy (ns group). as the conventional therapies, mechanical ventilation was commenced when a patient's pao /fio showed less than or they clinically complained of being short of breath. all patients received appropriate fl uid therapies, vasoactive agents and blood transfusion according to the protocol of early goal-directed therapy in the surviving sepsis campaign guidelines , and also were treated with antibiotics, immunoglobulins ( g/day for days) and sivelestat sodium hydrate ( . mg/kg/day for days). the apache scores in the s group and ns group were ± and ± , sequential organ failure assessment scores were ± and ± , respectively. these scores showed no signifi cant diff erence between the groups. procalcitonin (pct) in the s and ns groups was . ± . and . ± . ng/ml, respectively, and there was no signifi cant diff erence between the groups. pct declined signifi cantly in both groups. pao /fio of the ns group was signifi cantly higher than the s group on icu admission and days after admission, but no signifi cant diff erence on days after icu admission. il- of the ns group declined signifi cantly after icu admission, and the s group also tended to decline. conclusion steroid therapy for severe streptococcal pneumonia patients with mechanical ventilation may have a potential to maintain oxygenation of the lung, but no signifi cant eff ects on changes of infl ammatory markers (il- , crp). introduction electrical impedance tomography (eit) is a non-invasive and nonradiating imaging technique, which can be used to visualize ventilation distribution of the lungs and could distinguish between the dependent (dorsal) and nondependent (ventral) parts. methods the aim of this study was to observe ventilation distribution between dependent and nondependent lung regions, for the individual patient, during three diff erent levels of support during pressure support (ps) and neurally adjusted ventilatory assist (nava) ventilation. ten mechanically ventilated patients in the icu were included. the ratio for dependent/nondependent distribution of ventilation is signifi cantly higher at lower support levels compared with higher support levels in both ps and nava. however, during nava there was signifi cantly less impedance loss between the diff erent levels of assist compared with ps. tidal volumes decreased when decreasing assist levels during ps whereas not during nava ventilation. the electrical activity of the diaphragm decreased in both ps and nava with higher levels of assist. three patients showed an increase in dependent tidal impedance variation (tiv) after lowering the assist level from to cmh o. this increase in tiv did not occur during nava ventilation. conclusion there is more ventilation in the dependent part of the lung, compared with the nondependent part, at lower levels of assist. this could indicate that at higher support levels the contribution of the diaphragm is reduced. during nava ventilation, there is an autoregulation in which the patient is adjusting his tidal ventilation to maintain homogeneous ventilation distribution. in status asthmaticus. our purpose was to analyze bipap use and outcomes for children with status asthmaticus and obesity in our ped. methods patients placed on bipap in the ped for status asthmaticus from january to august were included in the analysis. subjects were divided into moderate and severe exacerbations and then further subdivided into the following growth curve-based weight subgroups: < percentile, to percentile and > percentile. subjects received standard asthma therapies in addition to bipap. data were obtained at the bedside by the respiratory therapist or collected retrospectively by study investigators. data were stored and analyzed using a redcap database. results three hundred and fi fty-nine subjects were analyzed. table shows the time on bipap per visit. children whose weight was > percentile revealed trends towards longer treatment times on bipap compared with the other two groups. we explored the feasibility, reliability and physiological signifi cance of diaphragm thickening on ultrasound. methods five healthy subjects participated. we monitored inspiratory fl ow, volume, esophageal and gastric pressures, and diaphragm electrical activity (by esophageal and surface electromyography) while subjects performed a series of inspiratory maneuvers: tidal breathing, threshold-loaded breathing, a muller maneuver, and inspiration to various lung volumes above functional residual capacity. at the end of each inspiratory eff ort, subjects were instructed to close the glottis and relax the respiratory muscles (so as to maintain lung volume while eliminating diaphragm activation). sonographic images of diaphragm thickening during these maneuvers were obtained using m-mode with a mhz linear array probe placed in the right ninth, th, or th intercostal space between the middle and anterior axillary lines. results diaphragm thickening in the zone of apposition was readily visualized by ultrasound in all fi ve subjects. mean end-expiratory diaphragm thickness was . mm (sd = . mm). during tidal breathing, the diaphragm thickened by a mean of % (sd = %). the bland-altman coeffi cient of reproducibility was . mm; approximately % of measurement variability arose from caliper positioning on the ultrasound machine; diaphragm thickness measurements changed as the probe was placed in diff erent intercostal interspaces. diaphragm inspiratory thickening increased signifi cantly with increasing inspiratory eff ort but also varied with lung volume independent of eff ort. at inspiratory volumes below % of inspiratory capacity, lung volume change contributed minimally to diaphragm thickening. conclusion visualizing diaphragm thickening in the zone of apposition by ultrasound provides a feasible non-invasive technique for monitoring diaphragm activation in healthy subjects. diaphragm thickening primarily refl ects muscular eff ort rather than altered muscle conformation induced by changes in lung volume, especially at lower inspiratory volumes. the theoretical advantages of monitoring the electrical activity of the diaphragm (eadi) and neural triggering of support breaths (nava-maquet) have not yet been shown to translate into signifi cant clinical benefi t [ ] . here we assess the eff ect of eadi monitoring, in patients at risk of prolonged weaning, on outcomes. introduction emergency endotracheal intubation results in accidental oesophageal intubation in up to % of patients often with disastrous consequences. we have previously published a highly specifi c and sensitive novel method to detect endotracheal intubation based on diff erences in ventilation pressure waveforms in the oesophagus and in the trachea in patients with healthy lungs [ ] . a detection algorithm, based on diff erences in compliance/elasticity between the lung and the oesophagus, generated a d-value indicating tracheal intubation if d > . and oesophageal intubation if d < . . the aim of the current study was to validate the algorithm in patients with lung disease. methods after obtaining institutional approval, intubated and ventilated icu patients were included. inclusion criteria were controlled mechanical ventilation and at least mild to moderate lung injury according to a murray lung injury score > . . a connecting piece was placed between the endotracheal tube and the ventilation bag. this piece comprised a thin air-fi lled catheter inserted through the tube lumen at cm from the distal end, and a second catheter located at the proximal end of the tube. we performed three consecutive manual bag ventilations while recording the pressure curves through both catheters. for each ventilation, a d-value was calculated. results mean age (sd) of the patients was ( ) years, % were male. the mean (sd) murray score was . ( . ). pathologies included pulmonary oedema, pneumonia, atelectasis and traumatic lung injury. all d-values are represented in figure . the median (iqr, range) d-value was ( to , . to , ). our algorithm therefore confi rmed a high sensitivity to detect correct endotracheal intubation also in patients with lung disease. under the hypothesis that oesophageal compliance does not increase signifi cantly in patients with lung disease, the specifi city of our algorithm will not be aff ected. the aim was to compare two novel endotracheal tubes (ett), mallinckrodt taperguard (tg, tapered polyvinyl chloride (pvc) cuff ) and kimvent microcuff (mc, cylindrical polyurethrane cuff ), with conventional portex (pt, globular pvc cuff ) in leakages across cuff s (microaspiration) under simulated clinical situations. it has been shown that globular pvc cuff s protect poorly against leakages due to microchannels formed from infolding of redundant cuff material [ ] . we hypothesized that tg and mc better prevent microaspiration, which is a major mechanism of ventilator-associated pneumonia (vap the most common cause of ventilator-associated pneumonia (vap) is aspiration of oral secretion through the endotracheal tube (et). subglottic suction drainage (ssd) has been recommended as a safety measure against aspiration due to its high eff ectiveness. currently, two types of cuff shape -spindle and tapered -are predominant in high-volume, low-pressure (hvlp) ets with ssd. however, the shape most suitable for preventing dripping onto the subglottis has not been determined. the purpose of this study was to determine whether an et with tapered-type cuff can reduce the incidence of vap. methods after approval from the appropriate ethics committee, we conducted a single-institutional prospective randomized clinical trial on the eff ectiveness of using an et with a diff erent cuff type. introduction national audit project (nap ) highlighted the need to improve airway management in icus and key recommendations were the continuous use of end-tidal carbon dioxide (etco ) monitoring, pre-intubation checklists and diffi cult airway trolleys [ ] . this complete cycle audit aimed to quantify the current state of airway management on our icu and the eff ectiveness of implementing the nap recommendations. methods data collection was carried out prospectively for both phases and included documentation of intubation, use of etco and the incidence of serious adverse events (saes). the contents of the intubation boxes were compared against the diffi cult airway society (das) guidelines [ ] . the re-audit was carried out months following the introduction of a pre-intubation checklist, a documentation sticker, a diffi cult airway trolley and standardization of the basic bedside airway boxes with a checklist of contents. a training program in airway management for all icu staff was also introduced. micro-ct scan (skyscan ; bruker, belgium) was performed using a resolution of μm. axial sections of the cm above the cuff were reconstructed, and the volume of secretions was assessed by a density criterion. microbiological cultures of the ett lavage fl uid were then obtained. patient's demographics and clinical data were recorded. in a diff erent set of bench experiments, we injected ml water-based polymer into new etts of diff erent sizes. we measured resistance to airfl ow before and after using an ett cleaning device (airway medix closed suction system; biovo technologies, tel aviv, israel). we also obtained resistance values of intact etts as controls. the studied etts remained in place for a median of days (iqr range to ). the amount of secretions assessed by ct scan was . ± . ml (range . to . ml). secretion volumes were not related to patient severity at admission (saps , p/f ratio) or days of intubation; an inverse correlation with patient's age was present (p = . , r = . ). bacterial growth was present in / ( %) ett fl uids cultures and candida spp. showed an elevated prevalence ( / , %). in the bench tests, the cleaning device reduced resistance to airfl ow (diff erence before and after cleaning . ( % ci = . to . ) cmh o/l/second, p = . ). after cleaning, resistance resulted higher than intact etts, although with a clinically negligible diff erence (diff erence . ( % ci = . to . cmh o/l/second), p = . ). conclusion micro-ct scan is a feasible and promising technique to assess secretions volume in etts after extubation. the use of an ett cleaning device decreases resistance to airfl ow in bench tests; the eff ectiveness of such a device in the clinical setting could be properly assessed by post-extubation ct scan. [ , ] . the objective was to develop and validate a simplifi ed score for identifying patients with di in the icu and to report related complications. methods data collected in a prospective multicenter-study from , consecutive intubations from icus were used to develop a simplifi ed score of di, which was then validated externally in consecutive intubation procedures from other icus and internally by bootstrap on , iterations. in multivariate analysis, the main predictors of di (incidence = . %) were related to the patient (mallampati score iii or iv, obstructive sleep apnea syndrome, reduced mobility of cervical spine, limited mouth opening), to pathology (severe hypoxia, coma) and to the operator (non-anesthesiologist). from the β-parameter, a sevenitem simplifi ed score (macocha score; introduction in mechanically ventilated neonates the fl ow-dependent resistance of the endotracheal tube (ett) causes a noticeable pressure diff erence between airway and tracheal pressure [ ] . this may potentially lead to retardation of the passive driven expiration and dynamic lung infl ation consecutively but more importantly increases . the aim of this study was to evaluate the correlation between nt-probnp and cce and the potential usefulness of such variables during the weaning process from mv. methods twenty-two long-term (> hours) mechanically ventilated patients capable of performing a weaning trial of spontaneous breathing (sbt) were enrolled in the study. inclusion criteria were: age > years and equipment with a standard arterial catheter line. exclusion criteria were: neuromuscular disease, tracheotomy, renal failure, and traumatic brain injury. during the weaning process, nt-probnp plasma levels, cce, and standard hemodynamic and ventilatory data were collected minutes before extubation (t ), hours (t ) and hours later (t ). after removal of tracheal tube, patients with a history of heart failure received continuous positive airway pressure (cpap group). patients with normal cardiac function were maintained with spontaneous breathing (sb group). results sixty-six paired nt-probnp and cce values were obtained. patients in the sb group and in the cpap group were and , respectively. in both groups there was a trend towards an increase in nt-probnp values after extubation, an opposite trend was observed regarding cce values (p < . ). nt-probnp levels showed an increase after extubation (t , t ) compared with t ; conversely, cce showed an inverse trend. overall, a negative correlation was found between nt-probnp and cce values (r = - . , p < . ). signifi cant inverse correlations were found between nt-probnp and cce at t , t , and t (r = - . , - . and - . respectively; p < . ). the overall correlation between nt-probnp and cce was - . in the sb group and - . in the cpap group. standard hemodynamic and ventilatory data did not show signifi cant changes during the study. conclusion nt-probnp correlated well with cce. the latter seems to be an additional attractive index of cardiovascular state that, in association with nt-probnp changes, may provide information about cardiac function on a beat-by-beat basis during weaning process from mv. comparison of outcomes between early and late tracheostomy for critically ill patients k suzuki , s kusunoki , t yamanoue , k tanigawa introduction tracheostomy is one of the more commonly performed procedures in critically ill patients requiring long-term mechanical ventilation. however, the optimal timing or method of performing tracheostomies in this population remains to be established. in the present study, we compared outcomes of early and late tracheostomy in critically adult patients with diff erent clinical conditions. methods all patients needing tracheostomy in the critical care medical center of hiroshima prefectural hospital from january to december were surveyed. patients with tracheostomy who were not indicated for mechanical ventilation were excluded from the subjects. early tracheostomy (et) was defi ned as < days after tracheal intubation and late tracheostomy (lt) was defi ned as ≥ days after intubation. we compared patient characteristics, type of tracheostomy procedure, length of weaning from ventilator and outcomes between the groups. data are shown as the mean ± sd, with unpaired t test and mann-whitney u test used for statistical analyses. statistical signifi cance was accepted at p < . . results one hundred patients were surveyed. the et and lt groups included and patients, respectively. tracheostomy was performed using a percutaneous procedure in patients (et: , lt: ) and a surgical procedure in patients (et: , lt: ). sixty-two patients (et: , lt: ) survived to discharge and patients died in the icu (et: , lt: ). fifty-six patients (et: , lt: ) were weaned from ventilator support and tracheostomy cannula was removed in patients (et: , lt: ). there were no signifi cant diff erences in type of tracheostomy procedure, period from tracheostomy until icu and hospital discharge, rate of patients who could be weaned from ventilator and removed tracheostomy cannula, and icu and hospital mortality between the groups. the length of mechanical ventilation and the time to removal of tracheostomy cannula were signifi cantly shorter in the et group ( ± vs. ± and ± vs. ± days, respectively). conclusion in this retrospective study, early tracheostomy reduced the length of weaning after tracheostomy and the time to removal of tracheostomy cannula, while there were no diff erences in the length of icu stay and patient outcome. in critically ill adult patients who require mechanical ventilation, a tracheostomy performed at an earlier stage may shorten the duration of artifi cial ventilation. a further randomized clinical trial is essential to determine the eff ectiveness and safety of early tracheostomy. reference s variability in the course of blood vessels in the pre-tracheal area. a % risk of clinically relevant bleeding was recently reported for patients undergoing pdt [ ] . we conducted a systematic review of reports evaluating clinical outcomes following use of ultrasound scanning (us) for pdt. methods two investigators performed a search of the literature using the following databases: central, embase, medline and scopus. the following eligibility criteria were used: population including adults > years managed in the icu; use of ultrasound to guide decisionmaking pre-pdt or guide pdt performance; report of clinically relevant outcome measures. nonrandomised controlled trials were classifi ed according to cochrane non-randomised study methods group criteria [ ] and evaluated for risk of bias. results an initial search identifi ed , reports, of which studies met eligibility criteria: eight case series, one randomised controlled trial (rct) and one prospective cohort study, incorporating patients. two studies specifi cally reported data on patients with obesity (n = patients) and one study reported data for a group of patients with spinal cord fi xation (n = ). us was used to guide decision to perform pdt or surgical tracheostomy in fi ve studies, with decision to perform surgical tracheostomy ranging from to % of cases. us was used to guide insertion point in seven studies, and used real-time in four studies. times to perform us-guided pdt were reported in four studies (ranging from to minutes). no studies compared time taken with or without us. data on complications of procedure were reported in nine studies. minor bleeding was reported for eight cases ( . % overall). prolonged bleeding was reported in two cases ( . %). there were no episodes of catastrophic bleeding among cases. high risk of bias was identifi ed in fi ve studies in terms of patient selection. an intervention protocol was not defi ned in three reports. no attempt was made at blinding any aspect of the studies. conclusion use of us guidance could theoretically help minimise risk of haemorrhagic complications during pdt and perhaps reduce time taken to perform pdt. however, there is currently inadequate evidence from controlled cohort studies or rcts to suggest that routine use for pdt in selected or unselected groups improves clinically relevant outcome measure. introduction failed airway situations are potentially catastrophic events and require a correct approach with appropriate tools. recently, ventrain has been presented as a manual device for emergency ventilation through a small-bore cannula, which can provide expiratory assistance by applying the venturi eff ect. methods we used the simularti human patient simulator to evaluate ventrain. initially, we studied the eff ectiveness and security in ventilating and oxygenating the patient. in a second phase, the ventrain performance was compared with what is considered to be the present gold standard (quicktrach ii, portex mini-trach ii seldinger kit, melker emergency cricothyrotomy catheter set). seven anesthesiologists performed an emergency transcricoid ventilation with each device in the same setting. results ventrain provided an average tidal volume of ml and an average minute volume of . l in the considered situation, with a modifi cation of pao from to mmhg and of paco from . to . mmhg. in the second phase, the time needed to obtain an eff ective oxygenation with ventrain was found to be shorter than other devices (median diff erence; vs. minitrach - seconds; vs. melker - seconds; vs. quicktrach - seconds) ( figure ); the ability to remove co resulted bigger (average diff erence: vs. minitrach - . ; vs. melker - . ; vs. quicktrach - . ) ( figure ) and moreover the users judged it more favorably. conclusion in this manikin study, ventrain seemed to be able to appropriately oxygenate and ventilate a patient in a cicv situation. when compared with the best available choices, it has shown not to be inferior. introduction eff ective delivery of aerosolized bronchodilators for patients with asthma is crucial for adequate therapy in critical care and emergent settings. often administered with pressure-metered dose inhalers (pmdis), bronchodilator delivery depends on the correct patient technique during administration [ ] and the ability to measure treatment response, which are diffi cult to monitor at the point of care and particularly so in resource-poor settings where standard inhospital monitoring is unavailable [ ] . methods a point-of-care device for airfl ow measurement during bronchodilator delivery was designed and tested for use in resourcelimited settings. the handheld device was constructed from a clinical aerosol delivery tube with a bidirectional sensor for pressure diff erential detection about the aerosol element ( figure ). the custom low-cost introduction protocol-based care of the tracheostomised patient is important, as adverse events confer a high rate of mortality. little is known regarding the existence of formal evidence-based guidelines on tracheostomy care. the aim of this study was to perform a systematic review for evidence-based guidelines on adult tracheostomy care. methods a systematic search of pubmed, medline, guideline clearinghouses, centres of evidence-based practice, and professional societies' guidelines relating to care of adult patients with a tracheostomy was performed by two reviewers. in addition, a google search of publicly available tracheostomy care guidelines was performed. search terms: (tracheostom* or tracheotom*) and (protocol* or guideline* or standard* or management or consensus or algorithm*). filters: english language, human, from january to date, adult patients. guideline appraisal criteria: the quality of guidelines retrieved was assessed using the appraisal of guidelines research and evaluation ii (agree ii) instrument [ ] . the search results are summarised in table . a total of guidelines were identifi ed. five were found to satisfy the agree ii criteria and only three related to the entire spectrum of tracheostomy management. the majority was informal and was not published or evidence based. conclusion five evidence-based guidelines on adult tracheostomy management were identifi ed. this may represent a paucity of evidence on the subject, suggesting that further clinical trials on the topic are needed to contribute to the evidence base. this also highlights the need for international consensus on the topic, to reduce duplication of eff orts, standardise practice, and improve outcomes. [ ] concluded that the majority of airway-related signifi cant complications in icus resulted from displaced or blocked tracheostomies and recommended together with the intensive care society and the national tracheostomy safety project that each icu in the uk should have an emergency airway management plan and guidelines [ ] . the aim of this survey was to establish whether such guidelines exist and are familiar to those working within the icus of the east of england (eoe), their ease of availability in an emergency and the degree of emergency tracheostomy training within the region. methods data collection was via a telephone survey of icus in the eoe training region during july with one senior icu nurse and one icu trainee questioned per hospital. questions related to the existence and accessibility of guidelines for tracheostomy emergencies, and to the respondent's degree of emergency tracheostomy training and their perceived availability of formal training. results all icus questioned perform and manage tracheostomies. of respondents, knew of guidelines covering all of the emergencies described above and their location. four respondents thought that these guidelines were accessible in an emergency setting, one-half of which were on computer systems requiring a login and search function. with regards to emergency management, respondents felt competent in a tracheostomy emergency; almost exclusively through experience and in-house teaching. no respondents were aware of any formal emergency tracheostomy management courses. conclusion despite national guidance within the uk this survey highlights that implementation and awareness of emergency tracheostomy guidelines in icus in the eoe region is poor, and when present they are not readily accessible in an emergency. emergency training has largely been informal and the availability of formal training courses has not been recognised. in order to improve patient safety there is a need to ensure that emergency tracheostomy management including guidelines, equipment and formalised tracheostomy emergency training are adopted and embraced universally. references introduction a fatal incident related to a blocked tracheostomy tube prompted a review in our trust. to provide safe tracheostomy care, changes in staffi ng, education and operational policies were recommended. training of potential fi rst responders to tracheostomy or laryngectomy emergencies remains outstanding. we aim to quantify the training defi cit. tracheostomies are common in critical care but these patients require ongoing management of an artifi cial airway on discharge to the ward and even the community. in our critical care unit cared for tracheostomy patients, of which were transferred to the wards. the th national audit project highlighted complications including hypoxic brain injury and death [ ] and the national patient safety agency recognised a number of avoidable aspects [ ] . existing guidelines for management of these patients including emergencies are not widely known. methods an anonymous online survey was sent to all trainees who may respond to a tracheostomy emergency in our organisation. trainees in anaesthesia/critical care, general medicine, general surgery, ent, thoracics and a&e were approached. all completed forms were included. we achieved a response rate of % ( / ). respondents comprised: % anaesthesia/critical care, % medicine and % surgery. over one-half ( / ) had managed tracheostomy/laryngectomy emergencies, with % ( / ) of these incidents occurring on the wards and one in an outpatient clinic. only % ( / ) had received any formal training on management of a blocked/misplaced tracheostomy tube and only % ( / ) were aware of any guidelines. one-third of responders lacked confi dence in management of these emergencies and % felt they would benefi t from formal training including simulation. conclusion the population of patients with exteriorised tracheas is increasing and represents a high-risk group. management of airway emergencies in these patients is not part of standard life-support courses. according to our trainees, these scenarios are relatively common and a signifi cant proportion of fi rst responders are poorly equipped to deal with them. our trust will be including specifi c training on the emergency management of neck breathers as part of in-house resuscitation training. we would contend that national resuscitation courses should consider doing the same. introduction usually percutaneous tracheostomy is accomplished via the tracheal tube. some severe complications during percutaneous dilatational tracheostomy (pdt) may be related to poor visualization of tracheal structures. the alternative implies extubation and reinsertion of a laryngeal mask (lma). an accidental extubation as well as an injuring of the vocal cords (because of the infl ated cuff during dislocation) appears impossible in this method. subjectively, the bronchoscopic view obtained via a lma seems to be better than that obtained with an endotracheal tube (et) [ , ] . methods in this prospective observational study, the bedside pdt was performed using the ciaglia blue dolphin method in critically ill patients. the patient's tracheal tube was exchanged for a lma fastrach™ before undertaking pdt. the insertion of the lma, the quality of ventilation, the blood gas values, the view of the tracheal puncture site, and the view of the balloon dilatation were rated as follows: very good ( ), good ( ), barely acceptable ( ), poor ( ), and very poor ( ) . results pdts with lma were successful in . % of the patients (n = ). the ratings were or in % of cases with regards to ventilation and to blood gas analysis, in . % for identifi cation of relevant structures and tracheal puncture site, and in . % for the view inside the trachea during pdt. a rating of was assigned to one patient requiring tracheal reintubation for inadequate ventilation. there were no damages to the bronchoscope or reports of gastric aspiration. conclusion the blue dolphin pdt using a lma showed defi nite advantages regarding inspection of dilation process. this method improves visualization of the trachea and larynx during a video-assisted procedure and prevents the diffi culties associated with the use of an et such as cuff puncture, tube transection by the needle, accidental extubation, and bronchoscope lesions. the lma results as an eff ective and successful ventilatory device during pdt. this may be especially relevant in cases of diffi cult patient anatomy where improved structural visualization optimizes operating conditions. the intensivist performing pdt should be scrupulous when deciding which method to use. in our icu the blue dolphin pdt with lma has become the procedure of choice. introduction acute cor pulmonale (acp) is associated with increased mortality in patients ventilated for acute respiratory distress syndrome (ards). interventional lung assist (ila) allows a lung-protective ventilatory strategy, whilst allowing co removal, but requires adequate right ventricular (rv) function. rv restriction (including presystolic pulmonary a wave) [ ] is not routinely assessed in ards. methods a prospective analysis of retrospectively collected data in patients with echo during ila was performed. data included epidemiologic and ventilatory factors, lv/rv function, evidence of rv restriction and pulmonary hemodynamics. data are shown as mean ± sd/median (interquartile range). results thirty-two patients ( ± years), male ( %), sofa score . ± . were included. pulmonary hypertension (pht) was %, and hospital mortality %. mortality was not associated with age, days on ila, length of icu stay, inotropic support, nitric oxide or level of ventilatory support, but was associated with pressor requirement (p = . ), a worse pao :fio ratio ( . ( . to . ) vs. . ( . to . ), p = . ) and higher pulmonary artery pressures ( . mmhg ( to ) vs. . ( . to . ), p = . ). no echo features of acp were found, with no signifi cant diff erence between rv systolic function, pulmonary acceleration time and pulmonary velocity time integral between survivors and nonsurvivors. the incidence of rv restriction was high ( %), and independent of pht, rv systolic function and level of respiratory support, but correlated with co levels (restrictive . kpa ( . to . ) vs. . ( . to . ), p = . ). see figure . conclusion typical echo features of acp were not seen in this study, possibly because of the protective ventilatory strategies allowed by use of ila. the incidence of rv restriction may refl ect more subtle abnormalities of rv function. further studies are required to elucidate rv pathophysiology in critically ill adult patients with ards. reference introduction global left ventricular electromechanical dyssynchrony (glvd) is uncoordinated lv contraction that reduces the extent of intrinsic energy transfer from the myocardium to the circulation leading to a reduction in peak lv pressure rise, prolonged total isovolumic time (t-ivt) and fall in stroke volume [ ] . this potentially important parameter is not routinely assessed in critically ill cardiothoracic patients. methods a prospective analysis of retrospectively collected data in cardiothoracic icu patients who underwent echocardiography was performed. in addition to epidemiological factors, echo data included comprehensive assessment of lv/rv systolic and diastolic function including doppler analysis of isovolumic contraction/ relaxation, ejection time (et) and fi lling time (ft). t-ivt was calculated as ( -(total et + total ft)) and the tei index as (ict + irt) / et. t-ivt > second/minute and tei index > . were used to defi ne glvd [ ] . data are shown as mean ± sd/median (interquartile range). results a total of patients ( . ± . years), male ( %), apache ii score ( . ± . ) were included. the prevalence of glvd was high ( / , %) and associated with signifi cantly increased mortality, . % vs. % (p = . ). there was no diff erence in requirement for cardiorespiratory support between the two populations, but there were signifi cant diff erences (no glvd vs. glvd) in requirement for , p = . ), mitral regurgitation ( . % vs. . %, p = . ), or any other measures of lv systolic or diastolic function between the two groups. there was good correlation between the two methods used to assess dyssynchrony (lv t-ivt:lv tei index correlation coeffi cient = . , p < . ). conclusion glvd that limits cardiac output is common in the cardiothoracic icu, and signifi cantly related to mortality. when diagnosed, the underlying cause should be sought and treatment instigated to minimize the t-ivt (pacing optimization/revascularization/ inotrope titration/volaemia optimization). references introduction correction of coagulopathy before central venous catheter (cvc) insertion is a common practice; however, when ultrasound guidance is used this is controversial as mechanical complications are rare. studies in oncology patients suggest that cvc placement without prior correction of coagulopathy is safe but no studies are available for critically ill patients and guidelines do not give recommendations [ , ] . we do not routinely correct coagulopathy, even if severe, when ultrasound guidance is used and the purpose of this retrospective study was to evaluate the safety of this practice. methods data for all ultrasound-guided interventions, including complications, are prospectively collected in our department for audit purposes; in this study we involved only cvc insertions in the icu between february and november . electronic medical and laboratory records and paper-based nursing charts were retrospectively studied for all interventions, specifi cally looking for blood results, coagulation abnormalities and intervention-related complications. in the study period, ultrasound guidance was employed for a total of central line insertions in icu patients. coagulopathy was detected in cases at the time of cvc placement ( . %). on the day of cvc insertion, coagulation abnormalities were corrected in cases ( . %); out of patients with severe coagulopathy ( . %) and out of patients with coagulopathy of moderate severity ( . %) had no correction at all. correction was started only after cvc insertion for reasons unrelated to cvc placement in a further eight and two patients with severe and less severe coagulopathy ( . % and . %), respectively. no bleeding complications were observed. conclusion in patients undergoing cvc insertion in our icu, coagulopathy is common. we observed uncomplicated cvc placement in all patients with severe uncorrected coagulopathy and in a further patients with coagulopathy of moderate severity. when combined with other studies, our data suggest that ultrasound-guided cvc placement without routine correction of coagulation abnormalities may be safe in the icu. introduction early bleeding from the exit site after cvc or picc placement is a very common event that causes diffi culties in the patient's care and logistical problems. in our experience, the rate of signifi cant local bleeding after placement of piccs without reverse tapering may be as high as % at hour and % at hours, while the rate of bleeding after placement of a large-bore dialysis catheter is above % at hour. methods the aim of this pilot study was to verify the effi cacy of a cyanoacrylate glue in reducing the risk of early bleeding at the exit site after cvc or picc placement. we studied a group of adult patients consecutively undergoing placement of polyurethane cvcs or piccs without reverse tapering in a non-intensive ward of our hospital. all lines were inserted according to the same protocol, which included % chlorhexidine antisepsis, maximal sterile barriers, ultrasound guidance, ekg guidance and securement with sutureless device. two minutes after placement of the glue, the exit site was covered with a temporary gauze dressing, which was replaced by transparent membrane at hours. all patients were assessed at hour and at hours. results in consecutive patients ( piccs, dialysis catheters and nine cvcs), there was no signifi cant local bleeding at hour or at hours after catheter placement. no local adverse reaction occurred. no damage to the polyurethane of the catheters was detected. conclusion glue is an inexpensive and highly eff ective tool for avoiding the risk of early bleeding of the exit site after catheter placement. we also suggest that in the next future the glue might prove to have benefi cial collateral eff ects on the risk of extraluminal contamination (by reducing the entrance of bacteria in the space between the catheter and the skin), as well as on the risk of dislocation (by increasing the stability of the catheter inside the skin breach). introduction about years ago the use of chest radiographs as the golden standard to ensure correct positioning of central venous catheters (cvc) was questioned. the frequent use of cvcs was also challenged. we decided to retrospectively evaluate our routines in a large surgical unit in a swedish university hospital. methods all x-rays were centrally registered. chest x-ray performed in our unit is almost entirely used to confi rm cvc positioning. the certofi x cvc set for the seldinger technique in combination with certodyn -universaladapter (b braun, germany) is now used as the routine equipment and the right jugular vein is our standard approach. in the total number of x-rays performed in patients at our unit was , , which corresponds to the approximate number of inserted cvcs at that time, since a confi rmatory x-ray was routine. x-rays were rarely performed on other indications in our unit. x-ray costs were at that time approximately € , (~€ /each). the year after, , chest x-rays were performed, refl ecting both the use of intracardiac confi rmation of correct cvc position and also a reduced use of cvcs. this trend has continued over time. in approximately cvcs were inserted at our unit. x-rays were performed in about % of these cases. the cost for a chest x-ray is today ~€ , meaning that x-ray costs were approximately € , . we have not experienced any medical problems when intracardiac ecg was used for positioning confi rmation. on the contrary, aspiration of venous blood without apparent p-waves in a patient with sinus rhythm may suggest improper placement of the cvc; for example, the right brachial vein. conclusion if we had continued to use cvcs at the same frequency as we did years ago, and used x-ray confi rmation in practically all cases, we would have paid approximately € , annually. reduced use of cvcs, in combination with intracardiac confi rmation of cvc positioning, has not only allowed us to reduce costs associated with cvc insertion by more than € , , corresponding to a reduction rate of more than %, but also decreased the patient's exposure to x-ray irradiation. introduction in cases of arrhythmia, the beat-to-beat variation of arterial pressure (ap) may impair the accuracy of automated cuff measurements. indeed, this oscillometric device relies on the detection of arterial wall oscillations. our aim was to determine, in icu patients, whether brachial cuff measurements are really less reliable during arrhythmia than during regular rhythm. methods patients with arrhythmia and carrying an intra-arterial catheter were prospectively and consecutively included in this multicenter study. after each arrhythmic inclusion, a regular rhythm patient was included. a second inclusion was possible in case of change in the cardiac rhythm. three pairs of invasive and brachial cuff (philips® mp monitor) measurements of mean arterial pressure (map) were respectively averaged. some patients underwent a second set of measurements, after a cardiovascular intervention (passive leg raising, volume expansion, initiation of/increase in catecholamine infusion) allowing the assessment of map changes. introduction signifi cant changes in haemodynamics occur after brain stem death (bsd) and there is evidence that yield of transplantable organs may be decreased in donors who remain preload responsive prior to donation [ ] , suggesting that optimisation of the cardiac output (co) may be benefi cial in potential organ donors. we describe current uk practice with regard to co monitoring in this group. methods we reviewed a database of brain-stem-dead potential organ donors collected by specialist nurses in organ donation (sn-od) over a -month period ( april to october ) across multiple uk centres. the database contained data on donor management in the period from initial sn-od review to immediately prior to transfer to the operating theatre. we analysed data on co monitoring and vasopressor/inotrope use. where information was missing/not recorded in the dataset, the treatment referred to was interpreted as not given/not done. fifty-three patients ( . %) had evidence of co monitoring. lidco was the most popular method ( figure ). a total of ( %) patients received treatment with vasopressors and/or inotropes. co data were utilised in a variety of ways ( figure ). conclusion the majority of potential donors require vasopressors and/or inotropes post bsd, but it seems only a minority currently have their co monitored. there is variation in how co data are utilised to direct haemodynamic management. we welcome the development of standardised bundle-driven donor management. reference the indocyanine green plasma disappearance rate (icg-pdr) is a dynamic liver function test that can be non-invasively measured by pulse densitometry. icg-pdr is associated with mortality and other markers of outcome. due to predominant use of icg-pdr in the icu setting, the normal range is based on scarce data available outside the icu and given with to %/minute. methods to prospectively re-evaluate the normal range and to analyze the potential impact of biometric data on icg-pdr, we measured icg-pdr (i.v. injection of . mg/kg icg; limon, pulsion, munich, introduction mixed venous oxygen saturation (svo ) represents a well-recognized parameter of oxygen delivery (do )-consumption (vo ) mismatch and its use has been advocated in critically ill patients in order to guide hemodynamic resuscitation [ ] and oxygen delivery optimization. nevertheless, the pulmonary artery catheter (pac) is not readily available and its use is not devoid of risks. furthermore, its use has been decreasing in recent years in surgical and cardiac surgical patients as the benefi t of guiding therapy with this device is unclear [ ] [ ] [ ] . central venous oxygen saturation (scvo ) has been suggested as an alternative to svo monitoring due to its feasibility in several settings. unfortunately concerns arise from its capability to correlate with svo , the relationship being infl uenced by several factors, such as hemodynamic impairment and pathological process. hemodynamic instability and shock often complicate cardiac surgery, and the svo -scvo relationship has not been specifi cally investigated in this setting. the aim of this study is to compare svo and scvo values in patients with cardiogenic shock after cardiac surgery. methods a prospective observational study was designed and conducted. inclusion criteria were: patients who had underwent elective or urgent/emergent cardiac surgery, with cardiac index (ci) < . l/minute/m estimated by means of a pac, left ventricle ejection fraction (lvef) < %, lactate > mmol/l, age > years. a central venous catheter (cvc) and a pac were inserted for each patient before surgery in the same right internal jugular vein in accordance with standard procedure. proper position of the pac was confi rmed with pressure tracings and chest x-ray. mixed and central venous blood samples were collected from the distal ports of the pac and cvc respectively minutes after icu admission, and every hours for a total of three samples in a -hour period for each patient. all blood samples were analyzed by a co-oximeter (radiometer abl fl ex; radiometer, copenhagen, denmark). statistical analysis was performed by stats direct (ver. . . , cheshire, uk) and graphpad (vers. prism . ; san diego, ca, usa). all data were tested for normal distribution with the kolmogorov-smirnov test. statistical analysis was performed by linear regression analysis. the agreement between absolute values of scvo and svo were assessed by the mean bias and % limits of agreement (loa) ((mean bias ± . )×standard deviation) according to the method described by bland and altman [ ] . results a total of patients were enrolled. in out of cases all three blood samples were collected. in two patients only two blood samples were drawn as they exited the inclusion criteria. linear regression analysis between the two variables resulted in an r of . . bland-altman analysis ( figure ) for the pooled measurements of svo and scvo showed a mean bias and loa of . % (sd of bias . ) and - . to + . % respectively. conclusion scvo has been advocated as an attractive and simple indicator of do -vo mismatch [ ] . its role as a surrogate of the wellestablished svo has been investigated in several settings, and it has been purposed in the hemodynamic resuscitation of critically ill septic patients [ ] . nevertheless, the svo -scvo relationship can be infl uenced by several factors due to scvo dependency from global blood fl ow redistribution that can occur during hemodynamic impairments. it has been shown previously that in healthy people scvo values tend to underestimate svo values, due to the higher oxygen content from inferior vena cava [ ] . during circulatory shock, not homogeneous oxygen extraction and regional blood fl ow methods we assessed the benefi t these tee data provided in the assessment of fi ve domains: hypovolemia, right ventricular dysfunction, left ventricular dysfunction, sepsis, and valvular abnormality. bedside practitioners listed their diagnoses before and after seeing primary tee images perform by trained physicians. we used a to likert scale to assess diff erential diagnosis before and after the tee, comparing changes using a paired t test. results all requests for tee were to access hemodynamic instability. a total of patients were screened and nine were eligible, in which total tee studies were performed. there were no complications with tee and all patients tolerated the long-term placement of the probe well. of the fi ve diagnostic domains studied, right ventricular failure was the most commonly underdiagnosed contributor to the hemodynamic instability among patients prior to tee (p = . ) (figures and ). introduction echocardiography is increasingly utilized by inten sive care physicians in everyday practice. standardization of echocardiographic studies and reporting, quality assurance and medicolegal requirements necessitate establishment of a dedicated system within the critical care setting. we describe the process of setting up a critical care echocardiography (cce) laboratory based on our experience from three separate icus. methods a retrospective review and analysis of the process involved in establishment of echocardiography laboratories within icus. results creating a cce service involves a number of stages and takes several years to achieve. major components include staffi ng, equipment, quality control, study archiving and networking capability. for staffi ng the objective is to identify and recruit staff with adequate training and expertise in cce, providing / specialist cover in addition to supporting and training junior medical and nursing staff . there is further a need to acquire funding for high-quality ultrasound machines and related hardware as well as long-term dicom-based archiving and reporting systems. this should be based on projections of annual volumes of echo studies and corresponding digital storage. networking connectivity is highly desirable, including obligatory back-up solutions and site allocations. a business case incorporating all the above should precede any development as identifi able funding sources and administrative approval are essential. the implementation stage requires the presence of a project leader who can organize the trialing of scanners, archiving, reporting and research systems, ensure compatibility with existing hospital and cardiology networks, and who can assist in individualizing archiving and reporting software refl ecting institutional and icu specifi cs. coordination with the it department is very important. clear contractual vendor obligations for service, maintenance and future upgrades of hardware and software need to be specifi ed. training and credentialing of staff is best achieved within a systematic framework that includes ongoing competency review, education and qa programs. partnership with cardiology may benefi t both groups. major pitfalls are associated with poor initial training, lack of expertise and leadership, and bad vendor contracts. conclusion establishment of a cce laboratory requires careful planning, and allocation of adequate human and fi nancial resources. many potential problems can be identifi ed and prevented in advance. strong expert leadership plays an important role. introduction contrast-enhanced ultrasonography (ceus) is a dynamic digital ultrasound-based imaging technique, which allows quantifi cation of the microvascularisation up to the capillary vessels. as a novel method for assessment of tissue perfusion it is ideally designed for use in the icu. ceus is cost-eff ective and safe and can be repeatedly performed at the bedside without radiation and nephrotoxicity. critical care , volume suppl http://ccforum.com/supplements/ /s methods the frequency of ceus use in the multidisciplinary surgical icu was retrospectively evaluated for the period from september to september . furthermore, contributions of this novel method to the management of critically ill icu patients as well as its accuracy were assessed. results in total, ceus studies were performed in critically ill icu patients. the most frequent indications included: assessment of the liver perfusion, assessment of the pancreas and kidney perfusion after pancreas and kidney transplantation, assessment of the renal perfusion in acute kidney injury (aki), assessment of active bleeding and assessment of the bowel perfusion. in all studies, the correct diagnosis was achieved and the transport of critically ill patients to the radiology department for further diagnostic procedures as well as application of iodinated contrast agents was avoided. in cases signifi cant new fi ndings were detected. twelve of them were missed by conventional standard doppler ultrasound prior to ceus. in assessment of seven cases with aki, impaired or delayed perfusion and microcirculation of the kidney was observed in six patients. in three patients urgent surgical intervention was performed because of ceus results. in three cases active bleeding was excluded at the bedside due to absence of contrast agent extravasation into hematoma (thigh and perihepatic) or into abdominal cavity, without need for complementary ct imaging or angiography. in one case the regular perfusion of intestinal anastomosis was confi rmed with no need for surgical exploration. none of patients undergoing ceus manifested any adverse reactions or developed any complications associated with the imaging technique. conclusion contrast-enhanced ultrasonography clearly improves visualization of the perfusion in various tissues. it is very likely to be superior to standard doppler ultrasound, and is safe and well tolerated in critically ill patients. promising indications for the use of ceus in the icu may be the assessment of kidney microcirculation and assessment of liver perfusion in liver transplant and liver trauma patients. introduction even though invasive hemodynamic devices are usually used for assessment of septic shock victims, they cannot evaluate the heart function. lv dysfunction as well as right heart syndrome are not uncommon in sepsis and critical patients. intensive care ultrasound discloses these data and leads to appropriate treatment. methods the study was a prospective cross-sectional study. the measurement was performed within hours of icu admission. we excluded patients with history of copd and pulmonary hypertension from any diseases. only good-quality images acquired from subjects were included for analysis. the primary objective was to disclose how the hemodynamic changed in septic patients by icu-us. introduction thermodilution (td) is considered a gold standard for measurement of cardiac index (ci) in critically ill patients. the aim of this study is to compare intermittent bolus td ci with intermittent automatic calibration ci (autoci) and two continuous cis obtained by pulse contour analysis with picco (picci) and pulsiofl ex (pucci). methods interim results of an ongoing prospective multicentre study in patients. age . ± . , saps ii score . ± . and sofa score ± . . all patients underwent picco monitoring via a femoral line whilst a radial line was kept in place during four -hour time periods (in the fi rst two periods, the pulsiofl ex was connected to a radial line; in the last two it was connected to a femoral line). in the fi rst and third periods, the pulsiofl ex was calibrated with tdci, for the second and fourth periods pulsiofl ex was calibrated with autoci. simultaneous picci and pucci measurements were obtained every hours while simultaneous tdci and autoci were obtained every hours. we also looked at the eff ects of interventions. in total, cci and tdci values were obtained: paired picci and pucci; paired autoci-tdci measurements. tdci values ranged from . to . l/minute/m (mean . ± . ), autoci from . to . ( . ± . ), picci from . to . ( . ± . ) and pucci from . to . ( . ± ). pearson's correlation coeffi cient comparing mean pucci and picci values per patient had an r of . . comparison between autoci and tdci had an r of . . changes in autoci correlated well with changes in tdci (r = . , concordance coeffi cient = . ), as did changes in pucci versus changes in picci (r = . , cc = . %). changes in picci and pucci induced by an intervention correlated well with each other (r = . , cc = %). the percentage error (pe) obtained by bland and altman analysis and r for the diff erent comparisons are presented in table . the preliminary results indicate that in unstable critically ill patients, ci can be reliably monitored with pulsiofl ex technology via a femoral line. pulsiofl ex was also able to keep track of changes in ci. interim results of an ongoing study on the use of non-invasive hemodynamic monitoring with nexfi n in critically ill patients introduction perioperative goal-directed therapy (pgdt) can substantially improve the outcome of high-risk surgical patients [ ] . but the approach needs an initial investment and increases the staff workload. economic factors might participate in the weak adherence to the pgdt concept. some model studies support pgdt cost-eff ectiveness, but real economic data based on a recent clinical trial are lacking. we performed an economic analysis of hemodynamic optimization using the stroke volume variation trial [ ] in order to elucidate this issue. methods the hospital care invoices of all patients included in the trial were retrospectively extracted. due to the nature of the data we have adopted the healthcare payer's perspective. we performed a comparison of induced costs between the vigileo (n = ) and control (n = ) groups and constructed a cost tree using the study group and complications occurrence as distributive parameters. the incremental cost-eff ectiveness ratio per complication avoided was calculated and, fi nally, diff erent reimbursing categories were assessed as potential cost drivers. results a decreased rate ( vs. patients) and number of complications ( vs. ) were observed in the original trials vigileo group. the mean cost of intervened patient was lower (€ , ± , vs. € , ± , ; p = . ). according to the cost-tree analysis, patients with complications (n = ; %) consumed signifi cantly more resources (€ , ; %). a gain of € per avoided complications confi rms that the lower complications rate was the most important cost driver. both the clinical care for patients costs (€ vs. ; p = . ) and ward stay costs (€ vs. ; p = . ) were decreased by the intervention. on the contrary, the intervention increased anaesthesia costs (€ vs. ; p = . ). conclusion intraoperative fl uid optimization with the use of stroke volume variation and the vigileo/flotrac system showed not only a substantial improvement of morbidity, but was also associated with an economic benefi t. this observed benefi t highly exceed the increased monitoring costs in our trial. introduction hemodynamic monitoring is important in high-risk surgical patients in order to detect and correct circulatory instability, thereby improving outcome [ ] . the extravascular lung water index (evlwi) refl ects pulmonary edema [ ] . the new ev /volumeview (edwards lifesciences) can accurately measure evlwi corrected for the actual volume of lung parenchyma (evlwic). the aim of our study is to prove a stronger correlation between evlwic and pao /fio compared with evlwi in patients undergoing pulmonary resection. methods a prospective observational study. seven patients with lung cancer undergoing pulmonary resection were monitored using the ev plathform. evlwi was assessed by thermodilution at the following time points: after intubation (t ); during single-lung ventilation (t ); after lung resection (t ); after icu admission (t ); hours (t ) and hours after icu admission (t ). evlwic values were also collected at t and t . pao /fio was measured at the same time points. results no signifi cant correlation was found between evlwi and pao / fio (r = - . , p > . ), while a signifi cant correlation was seen between evlwic and pao /fio (r = - . , p = . ; figure ). conclusion despite the small sample size, this study shows that in patients undergoing pulmonary resection the evlwic is more strongly correlated to pao /fio than evlwi. therefore, the ev may be a valuable tool for more reliable hemodynamic monitoring in this subgroup of patients. references or extracardiac arteriopathy) were allocated to gdt or conventional hemodynamic therapy. we excluded patients with endocarditis, previous use of dobutamine, need for iabp, high dose of vasopressors and emergency surgery. the gdt protocol involved hemodynamic resuscitation aimed at a target of a cardiac index > l/minute/m through a three-step approach: fl uid therapy of ml lactated ringer's solution, dobutamine infusion up to a dose of μg/kg/minute, and red blood cell transfusion to reach a hematocrit level above %. results twenty patients from the gdt group were compared with control patients. both groups were comparable concerning baseline characteristics and severity scores, except for a higher prevalence of hypertension and heart failure in the gdt group. intraoperative data showed no diff erence regarding length of extracorporeal circulation, fl uid balance, transfusion or inotropic requirement. patients from the gdt group were given more fl uids within the fi rst hours as compared with the conventional group ( , ml vs. ml, p < . ). gdt patients showed a median icu stay of days ( % ci: to ) compared with days in control patients ( % ci: to ). moreover, hospital stay was less prolonged in gdt patients ( days vs. days, p = . methods sixteen patients were divided into two groups: one group was treated with a restrictive approach (≤ ml/kg/hour), and the other with a liberal approach (> ml/kg/hour). patients were randomly allocated using sealed envelopes. during the thoracic part of the surgical procedure, all patients received one-lung ventilation (olv). in the group treated with a restrictive volume approach, patients received fl uids at the rate of . ± . ml/kg/hour. pao /fio was ± after intubation and ± before extubation. in the group treated with a liberal volume approach, fl uids were replaced at . ± . ml/kg/hour. pao /fio was ± after intubation and ± before extubation. surgery combined with olv was found to signifi cantly aff ect the pao /fio value (anova, f , = . a, p = . , partial η = . ). the average pao /fio level was signifi cantly higher in the restrictive-replacement group than in the liberal-replacement group (anova, f , = . , p = . , partial η = . ). there was no interaction between the groups (anova, f , = . a, p = . , partial η = . ). mean length of stay in the icu was similar between the restrictive-replacement group ( . ± . days) and the liberalreplacement group ( . ± . days) (anova, f , = . a, p = . , partial η = . ). conclusion results from this small sample indicate that esophageal carcinoma surgery by itself had a detrimental eff ect on the pao /fio value, which restriction of perioperative volume did not signifi cantly aff ect. volume restriction also did not aff ect length of stay in the icu. we hypothesized that goal-directed therapy (gdt) is not associated with an increased risk of cardiac complications in high-risk, noncardiac surgical patients. patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery [ ] . augmentation of the oxygen delivery index (do i) with a combination of intravenous fl uids and inotropes (gdt) has been shown to reduce the postoperative mortality and morbidity in high-risk patients [ ] . however, concerns regarding cardiac complications associated with fl uid challenges and inotropes used to augment cardiac output may deter clinicians from instituting early gdt in the very patients who are more likely to benefi t. methods systematic search of medline, embase and central databases for randomized controlled trials of gdt in high-risk surgical patients. studies including cardiac surgery, trauma, and pediatric surgery were excluded to minimize heterogeneity. we reviewed the rates of all cardiac complications, arrhythmias, acute myocardial ischemia, and acute pulmonary edema. meta-analyses were performed and forest plots drawn using revman software. data are presented as odd ratios (ors) ( % cis), and p values. and compared with those calculated with the echocardiographic standard formulation (stroke volume = cross-sectional area×velocity time integral; coecho = sv×heart rate). in every patient co was measured twice: at baseline (t ) and after volume loading ( ml lactate ringer solution) (t ). agreements between covig, comc, and coecho were evaluated by means of simple linear regression (r ) and bland-altman analysis. results twenty patients were enrolled in the study. values of r , bias and limit of agreement at t and t are summarized in table . co values ranged from . and . l/minute (echo), from . to . (vigileo) and from to . (mostcare); the pearson's and bland-altman methods showed poor agreement between coecho and covig, demonstrating a tendency to overestimation (see figure ). the percentage of error (pe) was . % at t and . % at t . on the contrary, mostcare measures showed good agreement with echocardiography (see table ) with a pe of . % at t and of % at t . conclusion vigileo did not prove to be a substitute to the reference system; pre-loaded data, necessary for vascular impedance estimation, may be one of the main limitations that made vigileo measurements less accurate than the mostcare ones. on the contrary, mostcare, an uncalibrated totally independent system, was shown to properly estimate the vascular impedance in these hemodynamically stable patients. further comparisons in unstable conditions are needed to confi rm our observations. references previous studies have found an association between severity of acute infl ammatory states and increased arterial stiff ness but it is not known whether non-invasive pulse waveform analysis could predict development of multiple organ failure in septic patients. the purpose of this study was to evaluate the photoplethysmographic brachial artery pulse wave transit time and augmentation index and their changes in response to induced forearm ischemia in septic icu patients and correlate these indices to the development of subsequent end organ damage. methods a prospective observational study in patients with sepsis within hours of admission. severity of sepsis was assessed with apache ii score (median . ) and sofa score (median . ). threeminute signal recording was done concurrently from the brachial artery at the elbow and the radial artery at the wrist with an originally designed photoplethysmograph at rest and after minutes of induced forearm ischemia. recordings were analyzed to obtain the pulse wave transit time and augmentation index at rest and seconds after induced ischemia. the sofa score was recalculated at hours post recording. results we studied consecutive general icu patients. there was a negative linear relationship between the pulse wave transit time (median . ms) at rest and increase in sofa score in hours (p = . , r = . ). the postischemic pulse wave transit time increased in all patients (median . ms) but no association was found between the proportion of increase and subsequent change in sofa. correlation between rest (median . ) and postischemic (median . ) augmentation index and -hour sofa scores was not statistically signifi cant (r = . , p = . ). conclusion this study indicates that in early sepsis pulse waveform characteristics could predict the risk of developing end organ failure. the pulse wave transit time is more robust than the augmentation index and could be easier to use in patients with poor perfusion. vascular reactivity indices do not seem to have predictive value in this context. reference in clinical practice, blood volumes (bv) are typically measured by thermodilution. recently, contrast-enhanced ultrasound (ceus) has been proposed as an alternative minimally invasive approach for bv assessment [ ] . this method measures bv using a single peripheral injection of a small bolus of ultrasound contrast agent (uca) detected by an ultrasound scanner. by measuring the acoustic backscatter, two indicator dilution curves (idcs) can be derived from two diff erent sites in the circulatory system. idc analysis permits deriving the mean transit time (mtt) the bolus takes to travel between the injection site and two measurement sites. assessment of the bv between these sites is obtained by multiplying the diff erence in mtt (Δmtt) by the blood fl ow. in this study, we compare diff erent volumes in an in vitro set-up by ceus with true set-up volumes and thermodilution acquired volumes. methods the in vitro set-up consisted of a centrifugal pump, a network of tubes with variable volumes, an electromagnetic fl owmeter to measure and adjust the generated fl ow, heating devices to maintain constant temperature ( °c), two thermistors for thermodilution measurement, an ultrasound transducer and a pressure stabilizer. a small bolus of uca diluted in cold saline ( mg sonovue® in ml saline at °c) was injected into the system. the cold uca passage through a fi rst and a second region of interest (roi) was measured simultaneously with the ultrasound transducer and the thermistors. the measurements were performed at diff erent fl ows and volumes. bvs were estimated using the two diff erent approaches, namely ceus and thermodilution. the idcs were processed and fi tted separately with a dedicated model to estimate the Δmtt of the cold uca bolus between the two rois and the two thermistors. all the measurements were repeated three times. results a linear relation between bvs estimated by the two techniques was observed with a correlation coeffi cient of . . the bias of ceus with respect to the true volumes was - . ml; the bias of thermodilution was . ml. the most prominent diff erences between the two techniques were observed in case of high volume and low fl ow, possibly due to diff erent transport kinetics between ucas and heat. the use of cardiac output monitoring has been shown to be benefi cial in the setting of perioperative medicine and critical illness [ , ] . more recently, its application in the setting of major trauma has been described [ ] . here, we describe our preliminary experience of embedding bioreactance fl ow monitoring within the major trauma primary survey of severely injured patients and the subsequent eff ect on patient management. methods institutional ethical approval was obtained. intubated major trauma patients were sequentially enrolled. exclusions included major thoracic burns and children. bioreactance fl ow monitoring (nicom; cheetah) was applied at the same time as ecg leads and the calibration step performed during handover from the prehospital team. time to availability of oxygen delivery data was recorded and trauma team members surveyed regarding for perceived benefi ts and concerns from this monitoring. the infl uence of fl ow monitoring on fl uid resuscitation, time to ct and defi nitive disposal (to or/icu) was measured and compared with a control population matched for injury severity score, age and sex. results cardiac index was available at mean . minutes (median minutes; sd . ), fl uid responsiveness at mean . minutes (median ; sd . ) and oxygen delivery calculation at mean . minutes (median ; sd . ). passive leg raise was not performed in % of patients due to concerns about pelvic or brain injury. volume of fl uid infused (mean vs. ml; p = . ), time to ct (mean . vs. . minutes; p = . ), and time to defi nitive disposal (mean . vs. . minute; p = . ) were all reduced in the fl ow monitored group, although not signifi cantly diff erent when compared with a matched control group (mann-whitney u rank sum). eighty-four percent of trauma team members surveyed felt the fl ow monitoring data to be useful, and only % felt it may impair clinical management. conclusion cardiac index, fl uid responsiveness and oxygen delivery data can be obtained inform a primary survey. rather than introducing delays, the use of fl ow monitoring was associated with a trend towards decreased time to imaging; less fl uid use pre-damage control point and reduced time to defi nitive disposal. further research is required to confi rm benefi ts and mechanism. references introduction pulse pressure variation (ppv) is a dynamic indicator of fl uid responsiveness, which is known to have a low sensibility and specifi city in patients ventilated in pressure support (ps) [ ] . we aim to investigate patient-ventilator asynchrony as a potential source of hemodynamic interference in ps. methods we performed a prospective study including ps ventilated patients who met inclusion criteria for fl uid depletion [ ] . patients who showed an asynchrony index (ai) exceeding % were included in the asynchrony group (ag). the remaining patients were included in the synchrony group (sg) [ ] . beat-to-beat hemodynamic variables were recorded through pram (mostcare; vytech health srl, padova, italy). ppv cutoff of % was used to identify fl uid responders/nonresponders. a fl uid challenge of ml normal saline was given in minutes. an increase of % of cardiac index after minutes indicated fl uid responsiveness. results so far, eights patients showed an ai > % while did not. overall sensitivity was . % versus % in sg; overall specifi city was . % versus . % in ag. overall cohen's k was . % versus . % in ag (see figure ). however, because none of the responders in the ag group was detected by ppv, statistical analysis was not feasible within this subgroup. the mini-fl uid challenge is a widely used strategy to manage fl uid loading in the icu and or. although it might be a rational strategy, data on the mini-fl uid challenge and its reliability are very limited. we investigated the value of changes in pulse contour cardiac output as a result of a mini-fl uid challenge of and ml to predict fl uid loading responsiveness. methods we measured the eff ects after the administration of , and ml bolus colloid infusions on co (modelfl ow (com) and lidco (coli)), cvp and map in patients on mechanical ventilation after elective cardiothoracic surgery. from the data we analysed the smallest volume that was predictive for the eff ects of ml on cardiac output. results coli and com increased after , and ml fl uid loading. best results are observed for changes in com after ml fl uid loading (area under the roc . , % ci between . and . ). a change in modelfl ow co of at least . % has a sensitivity of % and a specifi city of % after ml fl uid loading. sensitivity is % and specifi city % for a similar cutoff in co measured with the lidco device after ml fl uid loading. in our patient population, map and coli did not predict responsiveness with more accuracy than mathematical chance. see figure . conclusion changes in pulse contour co can be used in a mini-fl uid challenge to assess fl uid responsiveness in our postcardiac surgery patients. introduction fluid responsiveness is defi ned based on an arbitrary increase of cardiac output (co) or stroke volume (sv) of to %. we hypothesise that the variation of heart effi ciency (eh) and the slope (s) defi ned by the relative increase of co over the relative increase of mean fi lling pressure (pmsa) can be used as alternative defi nitions of fl uid responsiveness. introduction fluid overload is associated with poor outcome in the critically ill. thus, an accurate predictor of a positive haemodynamic response (increase in stroke volume) to fl uid challenge is vital. methods we studied the predictive value (positive response defi ned as change in stroke volume > % after ml/kg fl uid bolus) of a range of haemodynamic variables: static (cvp, active circulating volume, central blood volume, total end diastolic volume), dynamic (systolic pressure variation, stroke volume variation) and contactility (dp/dt), in a group of ventilated children (median weight kg). variables were measured using transpulmonary ultrasound dilution and pram (an arterial pulse contour method). we performed paired measurements (pre-fl uid and postfl uid challenge), with a sv response rate of %. overall predictive values were poor, but slightly better for static versus dynamic variables (table ) . when sv response was analysed as a continuous variable, the two predictive multivariable variables were change in tedvi and baseline dp/dt (r = . , both p < . ). conclusion the predictive ability for typical static and dynamic haemodynamic variables, when taken in isolation, is poor. however, improved prediction is seen when baseline contractility is taken into account. pressure (map)-guided fl uid therapy on microcirculatory perfusion in patients undergoing abdominal surgery. methods patients undergoing elective abdominal surgery were randomized into a ppv/ci-guided group (n = ) or a map-guided (n = ) group. ppv, ci and map were measured using the non-invasive fi nger arterial blood pressure measurement device ccnexfi n (edwards lifesciences bmeye, amsterdam, the netherlands). tidal volumes were ≥ ml/kg with peep ≥ mmhg. in both groups, map of mmhg was maintained. in the ppv/ci group, an intraoperative algorithm was used keeping the ppv under % and ci above . l/minute/ m using fl uid therapy and dobutamine and noradrenaline infusion, respectively. sublingual microvascular perfusion was measured after anesthesia induction, and every subsequent hour using sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). the perfused small vessel density (pvd) values were offl ine quantifi ed. the fi rst hour during surgery, the ppv/ci-guided group tended to receive more fl uids than the map-guided group ( , ± ml vs. ± ml; p = . ). at this time point, the pvd was slightly lower in the ppv/ci-guided group ( . ± . mm/mm ) when compared with the map-guided group ( . ± . mm/mm ; p = . ). in both groups the pvd remained stable during the fi rst hours of surgery. however, hours after the start of surgery, the pvd in the ppv/ci group restored and tended to be higher than in the map-guided group ( . ± . vs. . ± . mm/mm ; p = . ). after hour of surgery, the administered fl uid volume correlated inversely with pvd (r = - . , p = . ). conclusion goal-directed fl uid management resulted in a higher administered fl uid volume in the beginning of surgery, and this was associated with a slightly reduced microcirculatory perfusion when compared with map-guided fl uid management. microcirculatory perfusion tended to improve as surgery progressed in the goal-directed fl uid therapy group. our fi ndings suggest that goal-directed and mapguided fl uid management are associated with distinct patterns in fl uid resuscitation, which may be of consequence for microvascular perfusion. introduction previous studies demonstrate that loss of glycocalyx integrity is associated with impaired microvascular function. we investigated whether glycocalyx dimensions are reduced in patients undergoing cardiac surgery with or without cardiopulmonary bypass (cpb), and are paralleled by loss of microcirculatory perfusion using in vivo microcirculation measurements. methods patients undergoing on-pump surgery with nonpulsatile (n = ) or pulsatile (n = ) cpb or off -pump surgery (n = ) underwent sublingual sidestream dark-fi eld imaging at baseline, during coronary grafting and upon icu admission to assess perfused microvascular vessel density. glycocalyx integrity was evaluated using the glycocheck measurement software, and expressed as the perfused boundary region (pbr). an increase in pbr represents deeper penetration of erythrocytes into the glycocalyx, and is indicative for compromised glycocalyx thickness. introduction cold exposure can be adapted for exercise or therapeutic purposes, but its impact on microcirculation in healthy humans has not been well defi ned. we hypothesize that whole body cold stress may impair microcirculation. methods seven volunteers were recruited for the water immersion procedure. during the cooling protocol the volunteers every minutes of immersion were asked to step out from the bath and rest for minutes in a room environment and then return to the water bath for the next minutes of immersion. this head-out immersion procedure in bath water at °c continued until the rectal temperature was dropped to . °c or the time of minutes was terminated. maximum cold water immersion time was minutes. before, at the end of whole body cooling and hour after cooling was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. results during cooling and hour after cooling was ended, a signifi cant increase in cardiac output (p = . and p = . ) was observed, but there were no changes in heart rate or mean arterial pressure in comparison with baseline variables. there were no signifi cant changes in ppv, mfi, pvd and tvd of small vessels in comparison with baseline variables during all observational time. conclusion defined cold exposure had no effect on the microcirculation. introduction vasodilation and increased skin blood fl ow (also sweating) are infl uential in heat dissipation during heat exposure and exercise. it is unclear how heat stress infl uences microcirculation. side dark-fi eld imaging visualizes the blood fl ow at the capillary level and helps to assess perfusion heterogeneity. clinical and experimental data show that the sublingual region is clinically relevant for detecting microcirculatory alterations and more represents central microcirculation than cutaneous perfusion. we hypothesize that whole body heat stress may increase capillary density. methods eight healthy men with no history of cold and/or heat injury were recruited to this study. passive body heating was performed by continuous immersion up to the waist in the water bath at °c and continued until rectal temperature reached . °c. before, at the end of whole body heating and hour after heating was ended, systemic hemodynamics and direct in vivo observation of the sublingual microcirculation were obtained with sidestream dark-fi eld imaging. assessment of microcirculatory parameters of convective oxygen transport (microvascular fl ow index (mfi), proportion of perfused vessels (ppv)), and diff usion distance (perfused vessel density (pvd) and total vessel density (tvd)) was done using a semiquantitative method. vessels were separated into large (mostly venules) and small (mostly capillaries) using a diameter cutoff value of μm. results whole body heating resulted in signifi cantly increased heart rate (p = . ) and cardiac output (p = . ) in comparison with baseline variables. one hour after heating was ended, the heart rate introduction serial measurements of lactate over time may be a better prognosticator than a single lactate concentration [ ] . early lactateguided therapy also reduces icu length of stay and icu and hospital mortality [ ] . this study aims to assess the prognostic value of the lactate clearance (lc) in the fi rst hours in surgical patients. methods in a prospective cohort during year, we followed consecutively enrolled patients admitted immediately postoperative to the surgical icu of hospital santa luzia, brasília, brazil. patients were assigned to two groups: lc > % and lc ≤ %. the primary outcome measure was mortality at and days. the secondary outcome included hospital and icu length of stay (los). results a total of patients were followed. in total, . % were male and % underwent elective surgery. the mean age was ± , apache ii score ± , saps ± . the mortality at days was . % (n = ) and the mortality at days was . % (n = ), respectively. hospital mortality was . % (n = ). sixty-one percent (n = ) of the patients had lc > % versus % (n = ) with lc ≤ %. those who had lc ≤ % were older ( ± vs. ± , p = . ) and had greater apache ii score ( ± vs. ± , p = . ) and saps ( ± vs. ± , p = . ). there was no diff erence in icu los ( ± vs. ± days, p = . ) and hospital los ( ± vs. ± days, p = . ). initial lactate levels were lower in the group with lc ≤ % ( . ± . vs. . ± . , p = . ); however, mean lactate was higher in hours ( . ± . vs. . ± . , p = . ). all of the patients who died in the fi rst days had lc ≤ % ( . %, n = , p = . ); this group also had a higher mortality at days ( . %, n = vs. . %, n = ; p = . ). the relative risk for mortality lc ≤ % in and days was . ( % ci: . to . ) and . ( % ci: . to . ), respectively. signifi cant diff erence was observed in the kaplan-meier survival curves for and days (p = . and . , respectively). the sensibility of lc ≤ % was % ( % ci: to %) for -day mortality and % ( % ci: to %) for -day mortality. the specifi city was % ( % ci: to %) for -day mortality and % ( % ci: to %) for -day mortality. conclusion despite initial lactate levels, lactate clearance ≤ % proved to be a good predictor of mortality in and days in surgical patients admitted in the postoperative period to the icu. references introduction the use of peripheral perfusion objective parameters to anticipate successful resuscitation in septic shock has been recently investigated [ ] . the mottling score, a perfusion parameter used for decades, has been proposed to correlate with septic shock survival [ ] , and was tested in this study as a clinical tool in predicting mortality. methods a prospective observational study was conducted, with patients consecutively admitted to a tertiary hospital icu in brasília, brazil. from july to may , all patients diagnosed with septic shock were enrolled. demographic data, diagnoses, shock origin and severity scores were recorded. after initial resuscitation, the score was registered in the fi rst days by the same observer, considering the score on the lower limb without an arterial catheter, or the worst between the lower limbs, and the worst in the days. exclusion criteria were terminal illness with no intervention decision and incomplete methods pigs ( to kg) were randomized into one of the groups: sham (n = ), hs (n = ), lr ( × volume bled; n = ) or terli ( mg bolus; n = ). hs induced to target map of mmhg was maintained for minutes. brain tissue oxygen pressure (pbto ), intracranial pressure (icp), cerebral perfusion pressure (cpp), haemodynamics and blood gas analyses were assessed prior to hs (baseline) up to minutes after treatment. tissue markers of brain oedema (aquaporin- (aqp ) and na-k-cl cotransporter- (nkcc )), apoptosis (pre-apoptotic protein (bax)) and oxidative stress (thiobarbituric acid reactive substances (tbars)) were also measured. results sham animals had no signifi cant changes in the variables assessed. hs resulted in a signifi cant decrease in cpp (mean varied from to mmhg), pbto (from . to . mmhg), icp (from to mmhg) and haemodynamics (map from to mmhg; ci from . to . l/minute/m ), and a signifi cant increase in blood lactate (from . to . mmol/l) and cerebral aqp (mean ± se; ± % of sham), nkcc ( ± % of sham), bax ( ± % of sham) and tbars. fluid resuscitation was followed by an increase in icp (from to mmhg) and a decrease in cpp (from to mmhg), with an increased expression of cerebral aqp ( ± % of sham), nkcc ( ± % of sham) and bax ( ± % of sham introduction shock induces mitochondrial damage, which can lead to tissue injury and infl ammation. resuscitative adjuncts to limit mitochondrial injury may be eff ective to reduce tissue injury and protect against the sequelae of hemorrhagic shock (hs). others and we have demonstrated the protective eff ects of inhaled carbon monoxide (co) or nebulized sodium nitrite (nano ) in models of hs. our aim was to test the hypothesis that co and nano protect against hemorrhagic shock-induced tissue injury/infl ammation by limiting mitochondrial damage and preventing bioenergetic failure. methods twenty anesthetized female yorkshire pigs were subjected to severe hemorrhage until unable to compensate or minutes, and were then resuscitated with volume/pressors. muscle and platelet samples were obtained at baseline (bl) and hours after resuscitation (endobs). animals were randomized to: standard of care (hsr, n = ); hsr+co (co; ppm× minutes, n = ); or hsr+nano (nano ; mg in pbs× minutes, n = ), and sham (n = ). co or nano were initiated ~ minutes before resuscitation. primary endpoints were changes in muscle and platelet mitochondrial respiration between bl and endobs, quantifi ed by muscle respiratory control ratio (rcr, traditional respirometry), and by the change in proton-leak respiration (plr) and mitochondrial reserve capacity in platelets. secondary endpoint was mortality at endobs. results skeletal muscle rcr decreased in the hsr group (p = . ) but not in sham. decrease in rcr was primarily due to decreased adpdependent respiration, without change in state respiration. hsr also resulted in platelet mitochondrial dysfunction as demonstrated by increased plr and decreased reserve capacity. this correlated with increased platelet activation (%cd p+ by fl ow cytometry) in hsr. co or nano treatment prevented these deleterious changes in both muscle and platelet mitochondrial respiration, as well as limited hsr-induced platelet activation. co treatment also improved reserve capacity compared with baseline. mortality was higher in hsr than in co or nano ( vs. and %, respectively). conclusion in severe hs, mitochondrial injury in platelets and muscle was limited by co or nano . although not powered for a secondary endpoint, mortality was double in hsr versus adjunctive therapies. this suggests that co and nano may protect mitochondrial function by maintaining atp-coupled respiration and reserve capacity, and that this may confer a survival advantage. however, further investigations are required. introduction norepinephrine has been widely used in septic shock. however, its eff ect remains controversial. we conduct a systematic review and meta-analysis to compare the eff ect between norepinephrine and other vasopressors. methods the pubmed, embase, and cochrane library databases from database inception until october were searched. we selected randomized controlled trials in adults with septic shock and compared norepinephrine with other vasopressors. the quality of each study included was assessed with jadad score. after assessing for heterogeneity of treatment eff ect across trials using the i statistic, we used a fi xed eff ect model (p ≥ . ) or random-eff ects model (p < . ) and expressed results as the risk ratio (rr) for dichotomous outcomes or the standardized mean diff erence (smd) for continuous data with % ci. results eighteen trials (n = , ) met inclusion criteria, which compared norepinephrine with fi ve diff erent vasopressors (dopamine, vasopressin, epinephrine, terlipressin and phenylephrine). the mean jadad score was . . overall, there was no diff erence in mortality in the comparisons between norepinephrine and vasopressin, epinephrine, terlipressin and phenylephrine (p > . , respectively). however, norepinephrine had a trend in decreasing mortality compared with dopamine (rr, . ; % ci, . to . ; p = . ). there were a decreased heart rate (hr) (smd, - . ; % ci, - . to - . ; p = . ), cardiac index (smd, - . ; % ci, - . to - . ; p = . ) and an increased systemic vascular resistance index (svri) (smd, . ; % ci, . to . ; p < . ) with the treatment of norepinephrine compared with dopamine. conclusion there is not suffi cient evidence to prove that norepinephrine is superior to vasopressin, epinephrine, terlipressin and phenylephrine in terms of mortality. however, norepinephrine is associated with a decreased hr, cardiac index and an increased svri, and appears to have a greater eff ect on decreasing mortality compared with dopamine. introduction vasoplegic syndrome is a common complication after cardiac surgery, with negative impact on patient outcomes and hospital costs. pathogenesis of vasodilatory phenomenon after cardiac surgery remains a matter of controversy. loss of vascular tone can be partly explained by the depletion of neurohypophyseal arginine vasopressin stores. vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its eff ect on vasoplegic shock is unknown. we hypothesized that the use of vasopressin would be more eff ective on treatment of shock after cardiac surgery than norepinephrine, decreasing the composite endpoint of mortality and severe morbidity. methods in this prospective and randomized, double-blind trial, we assigned patients who had vasoplegic shock to receive either vasopressin ( . to . u/minute) or norepinephrine ( . to μg/ kg/minute) in addition to open-label vasopressors. all vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. the primary endpoint was major morbidity according to sts ( -day mortality, mechanical ventilation > hours, mediastinitis, surgical re-exploration, stroke, acute renal failure). secondary outcomes were time on mechanical ventilation, icu and hospital stay, new infection, the time to attainment of hemodynamic stability, occurrence of adverse events and safety. results a total of patients underwent randomization, were infused with the study drug ( patients received vasopressin, and norepinephrine), and were included in the analysis. patients who received vasopressin had a lower rate of morbidity ( . % vs. %, p = . ) as compared with the norepinephrine group. the -day mortality rate was . % in the norepinephrine group and . % in the vasopressin group (p = . ). there were no signifi cant diff erences in the overall rates of serious adverse events ( . % and . %, respectively; p = . ). results patients in the two groups were statistically comparable with respect to sex (p = . ) and age (p = . ). the causes of the syndrome of tako-tsubo were: subarachnoid hemorrhage (six patients) after coronary artery bypass graft (four patients), and polytrauma (two patients). all patients had low cardiac output. in the levosimendan group the ejection fraction at entrance was ± %, after hours ± %, and ± % after hours. in the control group the ejection fraction at entrance was ± %, after hours ± % and after hours ± %. comparing the two groups we reached statistical signifi cance, p = . . conclusion comparing the two groups, we noticed that both started from a low cardiac output. however, in the group who used the drug therapy based on levosimendan we saw a return of systolic function of the left ventricle to near-normal levels within hours, while in the control group there remains a dysfunction in systolic function. we have shown the drug therapy based on levosimendan contributes to improving the systolic function of the left ventricle compared with treatment with dobutamine despite the initial cardiac stunning. reference introduction in the critically ill, the incidence of raised cardiac troponin t (ctnt) levels is high. although the mechanisms of myocardial injury are not well understood, raised ctnt levels are associated with increased mortality. the aim of our study was to determine the incidence, prevalence and outcome of silent myocardial injury as determined by raised ctnt levels and concomitant ecg changes in critically ill patients admitted for noncardiac reasons. methods ecgs were taken and ctnt was measured daily during the fi rst week and on alternate days during the second week until discharge from the icu or death. after completion of the study, all ctnt levels and ecgs were analysed independently and patients were classifi ed into four groups: defi nite mi (ctnt ≥ ng/l and defi nite ecg changes of mi), possible mi (ctnt ≥ ng/l and ischaemic changes on ecg), troponin rise alone (ctnt ≥ ng/l with no ischaemic ecg changes), or normal. all medical notes were reviewed independently by two icu clinicians. results a total of patients were included in the analysis ( % female; mean age . (sd . ); mean apache ii score . ). in total, patients ( %) had at least one ctnt level ≥ ng/l during their stay in the icu. twenty patients ( %) fulfi lled criteria for a defi nite mi, of whom % were septic and % were on noradrenaline at the time (icu and hospital mortality: % and %, respectively). thirty-nine patients ( %) had a possible mi, of whom % were septic and on noradrenaline (icu and hospital mortality: % and %, respectively). sixty-two patients ( %) had a raised troponin without ecg, of whom % were septic and . % were on noradrenaline (icu and hospital mortality: % and %, respectively). twenty-three patients had normal ctnt results and serial ecgs, of whom % had sepsis. icu and hospital mortality was %. only % of defi nite mis and % of possible mis were recognised by the clinical teams at the time. conclusion eighty-four per cent of critically ill patients had a raised ctnt level at some stage during their stay in the icu. more than % of patients fulfi lled criteria for a possible or defi nite mi, of whom only % were recognised clinically. icu and hospital outcome were signifi cantly worse in patients with a ctnt rise. the proportion of patients with sepsis was similar between the patients with a defi nite, possible or no mi. the grace risk score for predicting death within months of hospital discharge was validated and can be used in patients with acs. it would be perfect in the future to include the grace risk score in the medical records of this type of patients. also it would be very interesting to validate this in a multicentric study. figure ). patients in group had more prolonged length of stay in the icu and in hospital than patients in group . after recovery from septic shock we notice a huge accumulated fl uid balance. a more positive fl uid balance was associated with a more prolonged length of stay in the icu and in the hospital. ugib patient needs an intervention or not. however, the intervention which the gbs mentions includes not only endoscopy but also blood transfusion. therefore, we cannot determine whether a ugib patient needs urgent endoscopy or just blood transfusion by gbs alone. we hypothesized that high lactate clearance (clac) would decrease the likelihood of sustained ugib. methods this is a retrospective study. ugib patients, who visited the emergency department (ed) of the national center for global health and medicine from april to march and received urgent endoscopy in the ed, were enrolled. we collected for each patient the gbs, the blood lactate value on arrival in the ed, the blood lactate value after bolus administration of to ml/kg ringer's acetate (initial fl uid therapy) and the report of urgent endoscopy. we classifi ed the severity of ugib according to gbs. a score ≤ was classifi ed as moderate, and a score ≥ was classifi ed as severe. clac was defi ned as the percentage decrease in blood lactate from the time of arrival in the ed to the time when an initial fl uid therapy was fi nished. clac < % was defi ned as low, and clac ≥ % was defi ned as high. whether a patient had sustained bleeding or not was determined based on the report of urgent endoscopy. the relationship between clac and sustained bleeding was examined by fisher's exact test, and p < . was considered statistically signifi cant. results seventy-nine patients were enrolled. fifty-one patients were with moderate ugib, and patients were with severe ugib. as indicated in tables and , there was a signifi cant relationship between clac and sustained bleeding in moderate ugib (p = . ). on the other hand, there was no signifi cant relationship between clac and sustained bleeding in severe ugib (p = . ). introduction the aim of our study was to assess the muscular glucose by microdialysis and its association with mortality in septic shock patients. we conducted a preliminary prospective study. we included septic shock patients hemodynamically optimized according to international recommendations. a microdialysis catheter was inserted in the femoral quadriceps. interstitial fl uid samples were collected every hours for days. the determination of muscular glucose was performed by the cma analyzer (cma/microdialysis ab, sweden). we also performed a dosage of concomitant blood glucose. the study population was divided into two groups according to hospital mortality. statistic analysis: mann-whitney test and chi-squared test: comparisons between groups. quantitative variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate. results we included patients with septic shock. the mortality rate was %. demographics were comparable between groups except for age ( ± vs. ± , dead patients vs. survivors, respectively; p = . ). pneumonia was the major cause of septic shock ( patients). we analysed blood samples and muscular glucose samples. we found a positive association between muscular glucose, blood glucose and mortality. tissue glucose was signifi cantly higher among dead patients compared with survivors at the th hour. comparing all data, muscular glucose (p = . ) and blood glucose (p = . ) were signifi cantly higher in dead patients (table ) . conclusion our data suggest that muscular glucose assessed by microdialysis and blood glucose are associated with mortality in septic shock patients. therefore, muscular glucose may refl ect the metabolic alterations and microcirculatory dysfunction induced by septic shock. methods the audit had the trust audit committee's approval. the existing protocol was used as the benchmark. patients were studied prospectively to assess compliance with the local bowel protocol, incidence of constipation and relationship to weaning from respiratory support and feeding. all hdu and all mechanically ventilated icu patients who stayed on the ward for more than days were included, except for patients after bowel surgery and patients with encephalopathy. results among the hdu and icu patients audited in the royal liverpool university hospital, % and % respectively were constipated. laxatives were prescribed when patients had not opened their bowels for days in % hdu and % icu cases. taking into consideration that the median age, apache ii score and length of stay for constipated and nonconstipated patients were similar, the relationship to feeding and respiratory support were assessed. introduction it was noted on our unit that dislodgement of nasogastric tubes occurred commonly. this can lead to an increased risk of aspiration, interruptions in nutritional support, skin breakdown and radiographic exposure [ ] . it is recommended that the position of nasogastric tubes should be confi rmed by aspiration and ph testing, with radiographic confi rmation used only when this is not possible [ ] . methods we performed a retrospective review of chest x-ray (cxr) requests for the -month period june to august using the trust radiology information system. the proportion of cxr requests for confi rmation of position and patient demographics were measured with an estimation of the fi nancial cost performed. results there were patients admitted to the critical care area in the study period. in total, out of , ( . %) cxrs performed were for confi rmation of position. repeated x-rays were required in some patients (see table ); these patients were older and tended to have a longer length of stay. a mobile cxr costs £ in our trust, if one cxr is accepted per patient with a nasogastric tube; there was an excess of images with a cost of £ , in the -month period. conclusion an excess of cxrs were performed for confi rmation of nasogastric tube in our patient population. the recommended methods for position confi rmation were reinforced amongst medical staff . the high number of repeated imaging for some patients indicates that dislodgement of tubes was also a problem. we propose that nasogastric tubes should be bridled after fi rst dislodgement or at tracheostomy insertion to minimise dislodgement in the future. methods mechanically ventilated, not enterally fed icu patients (n = ) were recruited from an interdisciplinary icu. healthy, overnight-fasted volunteers (n = ) served as reference. a primed constant i.v. infusion of h-labeled phenylalanine (phe) and tyrosine was used to quantify whole-body protein metabolism. patients remained on parenteral nutrition (pn) as clinically indicated; controls received pn starting . hours before starting enteral feeding. intrinsically c-phe-labeled casein was infused for hours by nasogastric tube at . g protein/ hour, together with maltodextrin at . g/hour. protein breakdown, synthesis, net balance, and phe splanchnic extraction were calculated before and at the end of the enteral feeding period, using equations for steady-state whole-body protein kinetics. comparisons were made by wilcoxon matched pairs and mann-whitney u tests; values are reported as mean ± sd. results protein net balance was lower in patients than in the reference group at baseline (- . ± . vs. . ± . mg/kg bw/hour, p = . ), and after enteral feeding (- . ± . vs. . ± . mg/kg bw/hour, p = . ). recovery of labelled phe from enteral feeding into the systemic circulation was higher in the reference group as compared with patients ( . + . % vs. . + . %, p = . ). enteral feeding did not aff ect protein metabolism in the reference group. in patients, protein breakdown became slightly lower during enteral feeding ( . ± . vs. . ± . mg/kg bw/hour, p = . ) and protein net balance became slightly higher (- . ± . vs. - . ± . mg/kg bw/ hour, p = . ). conclusion intrinsically isotope-labelled casein can be used to quantify dietary contribution to protein metabolism in critically ill patients. hypocaloric enteral feeding marginally improved protein balance in these patients. the low recovery of enterally administered labelled amino acid underlines the need to quantify uptake from the gastrointestinal tract when protein turnover measurements are performed in critically ill patients on enteral nutrition. methods this small-scale study of ngt placements during a -week period collated data supplied by questionnaire by healthcare workers responsible for ngt placements. results analysis of adverse incident reports identifi ed no never events of misplaced ngts within the previous years. this audit revealed that the commonest type of ngt was a radio-opaque tube with stylet (corfl o) ( % of placements), with occasional use of the electromagnetic placement system (cortrak) ( % of placements). sizes ( %) and ( %) were most common. tube placement was confi rmed by: x-ray ( %); ph of aspirates ( %); electromagnetic tube placement (one patient). the time taken from decision to place ngt to use varied (range to minutes). little distinction was seen in the time taken to use and ngt confi rmed by aspirate alone ( minutes) or by x-ray ( minutes), although the shortest interval was seen in electromagnetic ngt placement ( minutes). the cost of ngts confi rmed by aspirate alone was low (approximately £ . ), higher with x-ray confi rmation/electromagnetic placement (approximately £ . ). conclusion despite the small dataset the results demonstrate a concerning delay in the application of enteral feeding and/or drug administration. whilst reassuring in the steps taken to avoid never events, this study demonstrates that there may be delays in time-critical administration of enteral medicine or optimal nutritional practices. this study reveals a signifi cant problem with aspirating gastric contents for ph testing, necessitating a large number of x-ray position confi rmations. even if the frequency and volume of gastric aspiration were greater, there is a belief that ph testing may not be suffi ciently accurate (since many factors alter patients' gastric ph). it is possible that new technologies such as electromagnetic ngt placement may allow faster/equally safe practices. further study including cost/benefi t analysis will be needed to confi rm this. reference . eighteen readings were from newly placed ng tubes and readings from old ng tubes. fiftythree per cent of routine ph readings were falsely high; that is, ph or above despite the ng tube being in the stomach (figure ). twentyeight per cent of newly placed ng tubes had falsely high ph readings ( figure ). conclusion in this population of icu patients, routine/daily checks of ng ph aspirate appear to be limited. this is almost certainly due to the use of continuous ng feed together with ppis. the usefulness of ph testing in newly placed ng tubes, however, appears more reliable. introduction sepsis is the most common cause of death in icus [ ] . destruction of intestinal barrier function and increased translocation of bacteria to systemic blood fl ow can lead to sepsis [ ] . probiotics may have benefi cial eff ects in improvement of critically ill patients by modulating intestinal barrier and reduction of infl ammation [ ] . the aim of this trial was to determine the eff ect of probiotic on infl ammatory biomarkers and mortality rate of sepsis in critically ill patients in the icu. methods this double-blind, randomized controlled trial was conducted on critically ill patients admitted to the icu. they were randomly assigned to receive placebo or probiotic for days. the apache score, sequential organ failure assessment (sofa) and systemic concentrations of il- , procalcitonin (pct) and protein c were measured before initiation of the study and on days and . also, day mortality was evaluated for each patient. results il- and pct levels decreased and protein c levels increased signifi cantly in probiotic group over the treatment period (p < . ). there was a signifi cant diff erence in il- , pct and protein c levels of the th day between two groups (p = . , . and < . , respectively). compared with controls, probiotic was eff ective in improving apache and sofa scores in days (p < . ). there was signifi cant diff erence between the probiotic and control group in the -day mortality rate ( % vs. % respectively, p = . ). conclusion probiotics reduce infl ammation and mortality rate in critically ill patients and might be considered as an adjunctive therapy to sepsis. introduction the aim of this study is to establish whether diff erent types of sepsis have an impact on selenium levels. selenium is an essential trace element involved in antioxidant and immunological reactions. selenium levels have been shown to be low in patients with systemic infl ammatory response syndrome and sepsis. selenium replacement has been recommended in patients with sepsis [ , ] . greater than days of supplementation may also help to prevent the development of new infections on icus [ ] . methods this is a prospective survey where selenium levels were collected from patients admitted with septic shock to a tertiary icu, for months from october to march . results selenium levels were measured in patients with septic shock. abdominal and chest sepsis were the main sources of infection. those with an abdominal source of sepsis had the lowest levels, as shown in table . all septic shock patients who had selenium levels taken within the fi rst days of admission had subnormal levels (< . mg/dt), and after days had levels within the normal range, as shown in figure . introduction glutamine regulates many biological functions in preserving the cell, acts as a key respiratory fuel and nitrogen donor for rapidly dividing cells, and modulates the expression of many genes associated with metabolism, cell defences and repair, and cytokine production. in severe thoracic trauma, glutamine supplementation is essential because the body consumes more than it produces and glutamine eff ects become dependent on its route of delivery. methods fifty-two patients to years old with surgery for severe thoracic trauma were assessed in two groups: group a received . to . g/kg/day i.v. glutamine + g enteral glutamine for days, supplementation to enteral nutrition; group b receive only i.v. glutamine supplementation to enteral nutrition . to . g/kg/day for days. weaning time, the duration of p.o. ileus, incidence and time to resolution of vap, glycemic level and the percentage decrease of crp at hours were assessed in both groups. results weaning time and the duration of p.o. ileus were signifi cantly lower in group a; although the incidence of vap is similar in both groups, the time of vap resolution is lower, the glycemic control is better in group a. the percentage of crp decrease is higher in group a. see figure . conclusion glutamine becomes an essential amino acid in severe thoracic trauma and when the patients are fed other than tpn (enteral, oral); although hard evidence is lacking, both administration routes may be effi cient as soon as possible. results total cholesterol (tc) and low-density lipoprotein-cholesterol (ldl-c) levels were less changed signifi cantly in the low ratio group ( ± vs. ± mg/dl, p = . for tc, ± vs. ± mg/dl, p = . for ldl-c) compared with the high ratio group in postoperative patients. other laboratory parameters and adverse events did not show statistically signifi cant diff erences between the groups. see table . introduction the optimal feeding of critically ill patients treated in the icu is controversial. present guidelines for protein feeding are based on weak evidence obtained with suboptimal methods. whole body protein kinetics is an attractive technique to assess optimal protein intake by measuring the eff ect of protein feeding strategies on protein synthesis rates, protein degradation rates and protein balance. here protein kinetics were measured in critically ill neurosurgical patients during hypocaloric and normocaloric parenteral nutrition. methods neurosurgical patients on mechanical ventilation (n = ) were studied. energy expenditure was measured with indirect calorimetry. after that, the patients were randomized to receiving hours of % of measured energy expenditure followed by hours of % or % before %. whole body protein kinetics were measured during the last half hour of the feeding periods using stable isotope-labeled phenylalanine as a tracer. during a continuous infusion of labeled phenylalanine and tyrosine, plasma samples were obtained and later analyzed for the content of the labeled amino acids using mass spectrometry. protein kinetics were calculated using standard steady-state kinetics. in addition, amino acid concentrations were analyzed by hplc. student's t test was used for statistical analyses. the patients received . ± . and . ± . g amino acids/ kg/day (p < . ) on the days with and % of measured energy expenditure respectively. energy expenditures were . ± . and . ± . kcal/kg/day (p = . ) on the and % days respectively. plasma amino acids concentrations were . ± . and . ± . mm (p = . ) on the days respectively. whole body protein synthesis was % lower when % of energy expenditure was given, . ± . versus . ± . mg/kg/hour (p = . ), whilst protein degradation was unaltered . ± . versus . ± . mg/kg/hour (p = . ). also protein oxidation was unaltered . ± . versus . ± . mg/kg/hour (p = . ). this resulted in a % higher whole body protein balance with the normocaloric nutrition, - . ± . versus - . ± . mg/kg/ hour (p = . ). conclusion the protein kinetics measurements and the protocol used were useful to assess the effi cacy of nutritional support in critically ill patients. in the critically ill neurosurgical patients treated in the icu, hypocaloric feeding was associated with a more negative protein balance, while the amino acid oxidation was not diff erent. controlled trial (epanic: clinicaltrials.gov: nct ) [ ] showed that withholding parenteral nutrition during the fi rst week of icu stay whereby tolerating substantial caloric defi cit (late pn) accelerated recovery and shortened weaning time as compared with early parenteral substitution for defi cient enteral feeding (early pn). we examined the impact of late pn, as compared with early pn, on incidence and recovery of icuaw. methods a preplanned subanalysis of adult patients included in the epanic trial. the study was performed between october and november and included those patients who required intensive care for ≥ days as well as a computer-generated, admission categorymatched, random sample of short-stay icu patients, the latter to correct for possible bias evoked by earlier icu discharge in one of the two study groups. assessors blinded for treatment allocation evaluated muscle strength clinically three times weekly from awakening onward and performed nerve conduction studies and electromyography (ncs and emg) weekly. the primary outcome was the incidence of icuaw, diagnosed clinically by the medical research council (mrc) sum score (< / ) [ ] at fi rst evaluation. secondary outcomes included icuaw at worst and last mrc evaluation, recovery from icuaw and incidence of abnormal fi ndings on ncs and emg. all analyses were performed on the total dataset and on a for-baseline characteristics propensity score-matched sample to correct for possible imbalances between the groups. [ ] . plasma total bilirubin was quantifi ed in all patients daily while in the icu. liver enzymes alt, ast, ggt and alp were quantifi ed twice weekly in all patients while in the icu. in a random predefi ned subset of patients, circulating bile salts were also quantifi ed with ms-hplc at baseline and on day , day and the last day in the icu (n = ). gallbladder sludge was evaluated by ultrasound on icu day by blinded assessors (n = ). results from day after randomization until the end of the -day intervention window, plasma bilirubin was higher in the late pn than in the early pn group (all p < . ). in the late pn group, as soon as pn was started on day , plasma bilirubin also fell and the two groups became comparable. maximum levels of ggt, alp and alt during the icu stay were higher in the early pn group (all p < . ). compared with baseline, the circulating glycine and taurine conjugated primary bile salts were elevated on day , day and last day of the icu stay (p < . for all). however, there was no diff erence between the two groups. more patients in the early pn than in the late pn group had gallbladder sludge on day ( % vs. %; p = . ). conclusion tolerating substantial caloric defi cit by withholding pn until day of critical illness increased circulating levels of bilirubin but reduced the occurrence of gallbladder sludge and lowered ggt, alp and alt levels. these results suggest that hyperbilirubinemia during critical illness dies not necessarily refl ect cholestasis and instead may be an adaptive response. additional analyses on a propensity scorematched patient population are ongoing. reference the duration of renal replacement therapy (rrt) [ ] . the impact of the intervention on early markers of catabolism has not been investigated. methods we studied the impact of early versus late pn on daily markers of catabolism in the icu in the total study population and in propensity score-matched subgroups of long-stay patients. in addition, we calculated the net incorporation rate of the extra amino acids supplied by early pn. results plasma urea, the urea/creatinine ratio and nitrogen excretion increased over time in the icu. early pn further increased these markers of catabolism, from the fi rst day of amino acid infusion onward, and only marginally improved the nitrogen balance. also in the group that received pn only after the fi rst week in the icu, ureagenesis was increased by infusing amino acids. over the fi rst weeks, approximately two-thirds of the extra amino acids supplied by early pn were net wasted in urea. the above fi ndings were confi rmed in propensity scorematched subgroups of long-stay patients. the higher urea levels with early pn, rather than the kidney function as such, may have driven the observed longer duration of rrt, as supported by multiple regression analysis. conclusion the extra amino acids supplied by early pn appeared ineffi cient to reverse the negative nitrogen balance, not because of insuffi cient amino acid delivery, but rather because of insuffi cient incorporation with, instead, increased degradation into urea. the substantial catabolism of the extra amino acids, leading to pronounced urea generation, may have prolonged the duration of rrt in the early pn group. introduction muscle weakness of critical illness is associated with prolonged dependency on ventilatory support and delayed rehabilitation. muscle wasting related to poor nutrition has long been considered a major determinant, whereas the importance of myofi ber integrity only recently emerged [ ] [ ] [ ] [ ] . we hypothesized that nutrient restriction early during illness aggravates atrophy while preserving myofi ber integrity by activating the crucial cellular quality control pathway autophagy. the latter could be important to preserve muscle function. methods critically ill patients (n = ) were randomized to early (early-pn) or late (late-pn) initiation of parenteral nutrition to complete failing enteral nutrition, while maintaining normoglycemia ( to mg/ dl) with insulin, in the epanic study [ ] . vastus lateralis biopsies were harvested after week and compared with matched controls (n = ). results as compared with controls, muscle from critically ill patients showed reduced myofi ber density, a shift to smaller (especially type i) myofi bers, lower myosin and actin mrna, upregulated mrna of the ubiquitin ligases muscle-ring-fi nger- and atrogin- , a small increase in the autophagosome formation marker lc -ii/lc -i, and increases in the autophagic substrates ubiquitin and p (all p ≤ . ). late-pn, resulting in a larger caloric defi cit than early-pn, had no substantial impact on atrophy markers. in contrast, late-pn increased lc -ii/lc -i (p = . ), which coincided with less accumulation of ubiquitinated proteins/aggregates (p = . ). fewer patients on late-pn developed muscle weakness as compared with early-pn ( % vs. %, p = . ). in multivariable analysis, a lower lc -ii/lc -i ratio (p = . ) and higher myofi ber density (p = . ) were independently associated with muscle weakness. conclusion early-pn did not counteract muscle atrophy whereas it suppressed autophagy and aggravated weakness. statistically, muscle weakness was not explained by atrophy or wasting but rather by impaired autophagy and preservation of muscle density. thus, tolerating nutrient restriction early during critical illness may preserve myofi ber integrity by activating autophagy. introduction closure of an acute hospitals emergency department (ed) has important ramifi cations for those centres expected to take up the resultant workload. the continued reconfi guration of emergency care is likely to produce an increasing number of these scenarios. little evidence is available to support planning of such initiatives and thus the implications are diffi cult to anticipate. this study aims to demonstrate one hospital's experience of the rationalisation of emergency care and its eff ect on workload. methods this retrospective study was conducted in a large teaching hospital. activity data were analysed for a -month period following the closure of a neighbouring ed. the results were subsequently compared against the year prior to closure. attendance, triage data, admission rates and waiting times were compared across the two periods, as were workload data for all grades of physician. the chisquared test was used to examine diff erences between groups. results in the period studied, the gross attendance fi gure increased by , ( . %), whilst the admission rate rose from to %. following closure of the neighbouring ed, the proportion of highacuity patients attending our institution increased dramatically, with the proportion of category one and two patients (manchester triage scale) increasing by . % (p = . ) and . % (p < . ), respectively. likewise, ambulance arrivals increased out of proportion to the total increase in attendances (p = . ). admissions from the ed to the icu increased by . %. consultants workloads now include % more category and patients (p = . ). conclusion reconfi guration of emergency care can have dramatic implications for existing services; these may not always be anticipated. rationalisation of ed's may result in a concentration of high-acuity patients accompanied by a downturn in the numbers of patients whose presentations are amenable to care delivered in other settings. this abrupt change in case mix requires a re-examination of existing workforces and their seniority. overcrowding estimation in the emergency department: is the simplest score the best? introduction emergency department (ed) overcrowding is a major international problem with a negative impact on both patient care and providers. among validated methods of measurement, emergency physicians have to choose between simple and complex scores [ , ] . the aim of the present study was to compare the complex national emergency department overcrowding scale (nedocs) with the simple occupancy rate (or) determination. we further evaluated the correlation between these scores and a qualitative assessment of crowding. methods the study was conducted in two academic hospitals and one county hospital in liège, chênée and verviers; each with an ed census of over , patient visits per year. samplings occurred over a -week period in january , with fi ve sampling times each day. results ed staff considered overcrowding as a major concern in the three eds. median or ranged from to , while the nedocs ranged from . to . . we found a signifi cant correlation between introduction it is evident that accident and emergency departments are overloaded with patients, which results in delays in healthcare provision [ ] . a large proportion of patients consist of patients with minor illness that can be seen by a healthcare provider in a primary care setting. the aim of the study was to determine the characteristics of patients using gp walk-in services, patients' satisfaction and the eff ect on emergency department (ed) services. methods the survey was conducted in sheffi eld and rotherham walk-in centres over weeks during september and october . a self-reported, validated questionnaire was used to conduct survey on the patients presenting at these centres. we estimated that a sample size of around patients from each centre was required to achieve statistically robust results. a post-visit, short questionnaire was also sent to those who agreed for the second questionnaire and provided contact details. ed data were also obtained from april to march , year before and year after the opening of the gp walk-in centre. data were entered and analysed in pasw statistics . ethical approval of the study was obtained from the nhs ethical review committee. results a total of , patients participated in the survey (rotherham ; sheffi eld ). the mean age of the participants was . years at sheffi eld and . years at rotherham. a higher proportion of users were female, around % at both centres. most of the patients rated high for convenience of the centre opening hours and location (above %, apart from the location of sheffi eld centre, which was rated high by around % of the research participants). overall % patients were satisfi ed with the service at rotherham centre and around % at the sheffi eld centre. based on the estimation of the monthly counts of patients attending ed and the gp walk-in centre, around % monthly reduction in minor attendances at ed was expected. however, ed routine data did not show any signifi cant reduction in minor attendances as a result of the opening of the gp walk-in centre. conclusion these walk-in centres have been shown to increase accessibility to healthcare service through longer opening hours and walk-in facility. although the eff ect on the reduction of patients' load at the ed is not visible as these centres cover a fraction of the population, the centre has a potential to divert patients from the ed. reference overcrowding in emergency departments (eds) is a widely known problem. it causes problems and delays in the ed and has a negative impact on patient safety [ ] . the aim of this study was to analyse whether a reform of emergency care can reduce patient fl ow into the ed. methods a substantial reform of emergency care took place in the province of kanta-häme in southern finland. three separate out-ofhours services in primary healthcare (phc) and one ed in the hospital were combined into one large ed in april . basic principles of the new ed were: the ed is only for those patients who are seriously ill or injured, and need immediate care; phc (healthcare centres) take care of acute ordinary illnesses and nonserious injuries during offi ce hours. to achieve these principles a regional fi ve-scale triage system was planned and implemented. the information plan was established. citizens were systematically informed about the principles of the new ed by mail, articles in the newspapers and interviews in the radio and television. the ed's internet pages were planned and established. the number of patient visits (hämeenlinna region) was analyzed years before and after establishing the new ed. results during the -year period before the establishment of the new ed the mean number of gp patient visits was , ± /month. during the -year period after the reform the number was diminished to , ± /month. this change was not associated with the increase of the patient visits taken care of by specialists and hospital residents. see figure . conclusion an extensive reform of the emergency services can notably reduce patient fl ow into the ed. reference abdominal pain in adolescent females has undergone recent changes with regards to its management under various specialities. the authors report a single-centre audit looking at the correct investigation and management of -year-old to -year-old girls with abdominal pain in the emergency department setting. methods a single-centre audit and retrospective analysis of patients took place using case notes and computerised records. documentation was analysed using statistical analysis and minimum standards were set and reviewed. results after exclusion criteria females between the ages of and presented to the paediatric emergency department in leicester with abdominal pain as the predominant admission symptom during a -month period. documentation of the gynaecological history was poor (menstrual history %, sexual history %, contraception %), as was the performance of basic investigations (urine dipsticks %, pregnancy test %). documentation was analysed with regard to discharge diagnosis. ultrasound investigation was performed on seven of the patients but only once admitted to various specialities. no ultrasound was undertaken upon admission. conclusion improvement in documentation of minimum standards for these patients is needed. a multidisciplinary care pathway could improve outcome. consideration should be given to whether early ultrasound investigation is appropriate and there is a further need for investigation as to whether this would improve longer term outcomes. introduction bipap utilization for the treatment of severe refractory status asthmaticus patients has become an accepted therapy but is not well described for moderate exacerbations. we sought to analyze outcomes from our bipap quality database for children presenting in status asthmaticus at varying levels of severity. methods ped status asthmaticus patients requiring bipap from january to august had a bedside interview and documentation of information at the time therapies were given. incomplete data were collected retrospectively. all data were stored and analyzed using a redcap database. subjects were stratifi ed into severity groups based on asthma score at the time of bipap placement. results there were subjects in the moderate severity group and in the severe group. table shows the groups were well matched and compares other pertinent data. children with severe presentations were placed on bipap sooner (p < . ) and remained on bipap longer (p < . ). the moderate group had a longer wait until bipap placement. tables and demonstrate higher initial bipap (ipap/epap) settings with increasing age and severity. figure trends initiation and termination asthma scores stratifi ed by severity at bipap we present a case series of toxicity due to a novel substance in the uk: eric- . novel drugs of abuse are becoming more common throughout the world, and they represent particular diffi culties in their acute management. a recent report from the european monitoring centre for drugs and drug addiction and europol has reported new psychoactive substances reported via its early warning system. methods this was a retrospective case-note review over a -month period. patients were included if their presentation was due to recent ingestion of eric- . physiological data, symptoms, outcome and destination of the patient from the emergency department were collected. postmortem toxicological analysis was obtained for one of the two patients who died. results forty-one attendances were identifi ed from patients. two patients died and fi ve were admitted to the icu. heart rate and temperature on arrival tended to be above normal (mean heart rate was bpm, with an sd of ; mean temperature was . °c with an sd of . ). in total, . % of attendances included agitation and . % choreiform movements. α-methyltryptamine and -/ -fl uoroephedrine were found in the blood of one of the patients who died. conclusion in this outbreak in the uk, eric- gave symptoms similar to other stimulants known as legal highs, including death. it may have been a novel substance, -/ -fl uoroephedrine. this underlines the need for prospective data collection and early national and international information sharing. introduction thallium is an odorless, tasteless, heavy metal that has been often used for intentional poisonings. in severe patients, thallium poisoning produces neuromuscular symptoms such as extreme pain and muscle weakness. methods five case reports. results all patients worked at a pharmaceutical factory. they joined a tea party held at their workplace at the end of april . the fi ve patients drank tea from a teapot someone had put thallium in. a few days later, they complained of femoral numbness and pain caused by pressure. about a week later, three of fi ve patients had profound hair loss. three weeks after the party, they came to our er. we thought that their symptoms might be caused by some chemicals. we searched the keywords: 'lower extremity pain' , 'hair loss' and 'poison' in the internet. as a result, thallium, mercury, lead, and so forth, were suspicious metals. in those metals, thallium was most likely because it was used in their factory. we immediately examined the blood concentration of several metals and ordered iron(iii)hexacyanoferrate(ii) that is known as the antidote for thallium poisoning. only thallium was positive in the blood metal concentration test. three patients consented to oral administration of an antidote. two patients rejected administration because their symptoms were mild and getting better. all symptoms of all patients gradually disappeared by august. we also followed up the course of blood concentration of thallium. the concentration in three patients who took the antidote was reduced more rapidly than the two patients who did not take it. conclusion all patients recovered without any sequelae. three patients' hair started to grow months from ingestion of thallium, and after half a year their hair was restored to their former state. we had diffi culty ordering iron(iii)hexacyanoferrate(ii) because this is also known as an antidote for cesium. on march a megathrust earthquake and tsunami hit japan and the giant tsunami gave rise to an accident at a nuclear power generation plant. because the rumor of radioactive substances including cesium might be spread was the talk in the city near the nuclear power plant, the authorities put the antidote under heavy supervision. we could also collect the data for the course of thallium concentration. thallium concentration of the patients who had an antidote was reduced more rapidly but these patients had a loose stool, thought to be a side eff ect of this antidote. reference . ± sd . . ± sd . drugs aff ects the central nervous and cardiovascular systems, resulting in severe arrhythmia and death. heart rate variability (hrv) analysis is a non-invasive assessment method that allows evaluation of the cardiac autonomic (sympathetic and parasympathetic) activity. the aim of this study was to evaluate hrv in children requiring icu stay due to tca poisoning. methods twenty children with isolated tca poisoning aged between and years who were hospitalized in the pediatric icu, between march and july , and healthy children as a control group were enrolled. clinical and electrocardiographic (ecg) fi ndings were noted in the tca poisoning group. in both groups, -hour time domain hrv analysis (sdnn, sdann, sdnni, rmsdd, nn , and pnn ) was performed. we also recorded frequency domain analysis results at the fi rst minutes and the last minutes of the -hour record (vlf, nlf, nhf, lf/hf ratio). the average level of tca in the study group was , ± and tca levels were positively correlated with the duration of qrs interval (p < . ). in time-domain nonspectral evaluation, sdnn (p < . ), sdnn (p < . ), rmsdd (p < . ), and pnn (p < . ) were found signifi cantly lower in the tca intoxication group compared with the control group, while nn (p < . ) was signifi cantly higher in value. the spectral analysis (frequency domain) of data recorded at fi rst minutes after intensive care admission showed that the values of the nlf (p < . ) and lf/hf ratio (p = . ) were signifi cantly higher in the tca intoxication group than the controls, while nhf (p = . ) values were signifi cantly lower. the frequency domain spectral analysis of data recorded at the last minutes showed a lower nhf (p = . ) in the tca intoxication group than the controls, and the lf/hf ratio was signifi cantly higher (p < . ) in the intoxication group. sdnn (p < . ), rmsdd (p < . ), sdnni (p < . ), and pnn (p < . ) levels were higher in patients with positive ecg fi ndings than those without positive ecg fi ndings. the lf/hf ratio was higher in seven children with seizures (p < . ). conclusion existing fi ndings give us an idea about hrv's value to determine arrhythmia and predict convulsion risk in tca poisonings. hrv can be used as a non-invasive method in determining the treatment and prognosis of tca poisoning. results hmmd receives an average of cases of stroke monthly, and thrombolysis did not occur before the implementation of the tm project, because of the lack of neurologists available to conduce the cases. after implementation of the tm program, six cases of ischemic stroke were thrombolyzed with alteplase; only one case ( %) progressed to death from septic shock, and one case ( %) presented symptomatic intracranial hemorrhage. conclusion thrombolysis in ischemic stroke reduces % the risk of disability and % the mortality rate. this procedure has been only feasible to be done in the community setting because of the implementation of the tm project, which permits the presence of a real time consultation with a specialized neurological team from a tertiary center. analyses, and then returned home. in total, . % of patients were hospitalized in a medical or surgical department, and . % in the short-term hospitalised unit of the emergency department (stay duration < hours). some . % of patients worsened and were oriented in the icu. a total . % of patients in a cardiac icu. in total, . % of patients had stay duration less than hours in the ed, . % < hours. forty percent of patients supported by fi remen and % supported by private ambulance left the hospital after a single medical consultation. conclusion nearly % of patients calling the french emergency medical dispatching centre are sent to hospital. those transportations are supported for two-thirds of cases by a private ambulance or fi remen ambulance. one out of two patients only receive a simple medical consultation in the ed, and go back home. this may concur to the defi ciency of using general medicine in town. they prefer using emergency services for free. only one patient out of four was hospitalized more than hours. introduction early onset eff ective care in the emergency department (ed) has been reported to have a great infl uence on the intensive care patients' morbidity and mortality [ ] . little is known about the infl uence of the reorganisation of the ed on patient intake to the icus. the aim of this study was to analyse monthly intake of patients from the ed to the cardiac care unit (ccu) and icu before and after the reform of emergency services. methods in kanta-häme central hospital, a new ed started on april . four older emergency rooms were combined into one bigger emergency department and an observation ward was introduced with continuous follow-up of vital signs. this study is a retrospective analysis of the patient intake to the ccu and icu year before and after the reorganisation. using as data the finnish intensive care quality consortium (intensium, finland) database and the cardiac database of the hospital, patient transfer from ed to the icu and ccu was collected and analysed. monthly pre/post comparisons were carried out statistically by a nonparametric wilcoxon signed-rank test. the total decrease in monthly patient infl ow from ed to the icu and ccu was . % (p = . ); that is, from the mean of . ± . to . ± . patients (figure ) < . ) . the result is longer overall hospitalization of patients having wi (p < . ) and a higher number of surgeries (p < . ). after the er, % of patients with wi were hospitalized in the icu ( % of them after surgery) but only % of patients involved in a ca ( % after surgery). as many patients with wi as involved in a ca ( %) were admitted to the ward ( % of patients with wi after surgery but only % of patients with injuries due to a ca). thirty-three per cent of patients involved in a ca returned home and one was transferred, whereas only three patients with wi returned home after being in the er, three patients were transferred and one died in the operating room. observed paediatric mortality in our medical treatment facility was . % ( children out of ): three children died of wi, three due to a ca and one of septic shock due to a medical cause. conclusion war injuries are more prone to cause polytrauma than ca. according to the pts, iss, niss, triss and ascot, children experiencing wi have higher severity scores and predicted mortality rate than others, stay longer in the hospital and have more surgeries. our research indicated that disaster medicine should be established systematically or it is necessary to compile a compendium of disaster medicine from a broad perspective or from a bird's-eye and long-term view. the japanese version was tentatively completed with volumes as of the fi nancial year , of which nearly three-quarters are written in japanese. although this worked partly during the aboveshown catastrophe in japan , several problems are left to be solved; that is, the insuffi cient operation system of the japan dmat or disaster medical assistant team that seemed to have caused a large number of preventable deaths. conclusion the large number of casualties during a major disaster is a global problem, even in the developed countries. when the role of the intensivist is reviewed, many roles were verifi ed to be important; that is, as a leader of a medical team or triage offi cer as well as a professional in the fi eld of specifi c intensive care. however, there are many problems to be solved in the fi elds of disaster medicine. in order to solve the diversifi cation or the various medical problems, it is necessary to compile or systematize a disaster medicine of the world version. the concept of the compendium and our process of trial are shown in relation to intensive care. there are distinct diff erences in the pathophysiology between medical cardiac arrests and tca. traumatic pathologies associated with an improved chance of successful resuscitation include hypoxia, tension pneumothorax and cardiac tamponade [ ] . the authors believe a separate algorithm is required for the management of out-of-hospital tca attended to by a highly trained physician and paramedic team. methods a suggested algorithm for tca was developed based on the greater sydney area helicopter emergency medical service's standard operating procedures and current available evidence. results an algorithm for the general management of tca can be seen in figure . in tca, priority should be given to catastrophic haemorrhage control (tourniquets, direct pressure, haemostatic agents, pelvic and long bone splintage) and volume resuscitation. simultaneous oxygena tion optimisation should occur with proactive exclusion of tension pneumothoraces with bilateral open thoracostomies. cardiac ultrasound (us) should be used to help exclude cardiac tamponade and assist in prognostication. the us presence of true cardiac standstill versus low pressure state/pseudo-pea, and an etco < . kpa carries a grave prognosis in tca. given the high incidence of hypovolaemia, hypoxia and obstructive shock prior to tca, the role of adrenaline and chest compressions are limited. figure shows a suggested algorithm for the management of penetrating tca requiring prehospital thoracotomy. conclusion the suggested algorithm is designed for a highly trained physician-led prehospital team and aims to maximise the number of neurologically intact survivors in out-of-hospital tca. little is known about the benefi t of physician winching in addition to a highly trained paramedic. we analysed the mission profi les and interventions performed during rescues involving the winching of a physician in the greater sydney area hems (gsa-hems). methods all winch missions involving a physician from august to january were identifi ed from the prospectively completed gsa-hems electronic database. a structured case-sheet review for a predetermined list of demographic data and physician-only interventions (poi) was conducted. we identified missions involving the winching of a physician, of which case sheets were available for analysis. the majority of patients were traumatically injured ( %) and male ( %) with a median age of years. seven patients were pronounced life extinct on the scene. a total of poi were performed on patients. administration of advanced analgesia was the most common poi making up . % of interventions. patients with abnormal rtsc scores were more likely to receive a poi when compared with those with normal rtsc (p = . ). the performance of poi had no effect on median scene times ( vs. minutes; p = . ). see tables and . conclusion our high poi rate of % coupled with long rescue times and the occasional severe injuries supports the argument for winching doctors. not doing so would deny a signifi cant proportion of patients time-critical interventions, advanced analgesia and procedural sedation. the aim was to assess the content and state of repair of equipment carried for transfer of critical care patients to other hospitals. by chance, several items of date-expired stock were identifi ed in the transfer kit whilst moving a patient to a tertiary centre. this raised the possibility of a more extensive problem with the equipment bags. due to the geographical location of our district general hospital we undertake around transfers of critical care patients to other hospitals per year ( % by air) and it is clearly important that our equipment is well maintained for these journeys. methods we maintain two identical sets of equipment (syringes, fl uid, airway management items, and so forth) and drug bags to take on transfers; one equipment and one drug bag taken on each trip. the contents of all four bags were checked and itemised. by careful consideration of the aims of the bags (to provide emergency equipment and drugs for managing one patient during an en-route emergency) a new inventory was devised. excess items were removed to lighten the bags and improve accessibility to the essential items. expired stock was removed. a daily checking procedure and tamper-proof seals on the bags were instigated and the bags were reassessed months later. results a total of . % of drug items and . % of equipment items had expired or would do so within days of the initial assessment. the combined weight of one equipment and one drug bag was reduced from to kg ( % reduction) by introducing the new inventory. at reassessment in november , only items of equipment ( . %) were expired or near to expiry and there were no expired drug items ( . % near to expiry). in total, . kg ( small items) of extraneous equipment had been added through over-restocking and was removed. conclusion these bags are designed for a clinician to manage a patient when an emergency arises during transfer of a critical care patient. by the introduction of simple measures, the risks posed by expired items or cluttered equipment bags have almost been eradicated. signifi cant weight savings have been made; this off ers improved ergonomics for staff and is also an important consideration for aeromedical operations. our department was surprised to discover the extent of decline of our equipment and it may be that other departments would fi nd themselves in a similar position. the anaesthetic registrars who routinely escort the transfer patients have a vested interest to maintain this equipment and this has secured their buy-in to the new checking procedure with clear results. conclusion prehospital hyperoxemia did not infl uence the functional neurological outcome. one of the reasons for this fi nding could be the short arrival time to the trauma center where repeated analyses of arterial blood gases were performed. therefore, correction of fraction of inspired oxygen according to the arterial blood gas analysis shortens the time of hyperoxemia, thus reducing neuronal brain damage. introduction severe burn patients are often noted to have subsequent neurocognitive problems. experimentally, we have found striking, prolonged elevations of infl ammatory markers in the brain (for example, il- ) even when the injury occurs in a remote anatomic location. this neuroinfl ammatory response can also be signifi cantly blunted by a single post-burn dose of estrogen. sonic hedgehog (shh), an important signaling protein found in the brain, controls and directs diff erentiation of neural stem cells, infl uencing brain regeneration and repair by generating new neurons throughout life. as estrogens not only blunt infl ammation but also exert an infl uence on a variety of stem cells, we hypothesized that β-estradiol (e ) might aff ect levels of shh in the post-burn rat brain. methods male rats (n = ) were assigned randomly into three groups: controls/no burn (n = ); burn/placebo (n = ); and burn/e (n = ). burned rats received a % ° tbsa dorsal burn, fl uid resuscitation and one dose of e or placebo ( . mg/kg intraperitoneally) minutes post burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrifi ced at hours and at days, respectively (sham group at days only), with four each of the two burn groups sacrifi ced at days. brain tissue samples were analyzed by elisa for shh. results mean levels of shh levels were signifi cantly elevated within hours as much as days post injury in burned animals receiving the β-estradiol (> , pcg/mg) as compared with the placebotreated burned animals (< pg/mg) and controls (< pcg/mg). see figure . conclusion early, single-dose estrogen administration following severe burn injury signifi cantly elevated levels of shh in brain tissue. this fi nding may represent an extremely novel and important pathway for both neuroprotection and neuroregeneration in burn patients. introduction many proposed resuscitative therapies for cardiac arrest and trauma will require the earliest possible intervention and would occur under volatile circumstances, making true informed consent for clinical trials unfeasible. the purpose here was to report our experience using exception to informed consent during the inaugural pilot study of infusing estrogen for acute injury, the so-called rescue shock study. methods fifty patients were enrolled in rescue shock in which estrogen or placebo was infused as soon as possible in the emergency department for trauma patients with a low systolic blood pressure (< mmhg) at two level i trauma centers. they were all treated with a single-dose estrogen or placebo infusion within hours using exception from informed consent following us federal guidelines. results investigator-initiated exception from informed consent studies is feasible, with our fda ind approval obtained in days, irb approval in days, and irb approval in days. community consultation/notifi cation was successfully accomplished with no one opting out and / enrolled patients or their legal representatives were notifi ed of participation (one died unidentifi ed, two died with no known contact). the average number of days to verbal notifi cation of patients or advocates was . days (range to days) as the study team began notifi cation only after the patient or family was able to reasonably understand information about the study. no one decided against continued follow-up. overall, patients and their families were very enthusiastic about participation and the data safety monitoring board had no safety concerns after reviewing all study data. conclusion although delayed notice of participation occurs for many justifi able reasons, the use of exception from informed consent for novel, time-sensitive resuscitation studies is not only crucial, but can be feasible, and well accepted by patients, their advocates and communities at large. introduction patients with severe burn injury experience a rapid elevation in multiple circulating proinfl ammatory cytokines, with the levels correlating with both injury severity and outcome. in animal critical care , volume suppl http://ccforum.com/supplements/ /s s models, accumulations of these cytokines have been observed in remote organs, including the heart, brain and lungs. however, data are lacking regarding the long-term levels of cytokines in the heart following severe burn injury and also how infusion of parenteral estrogen, a powerful anti-infl ammatory agent, would aff ect these levels. using a rat model, we studied the eff ects of a full-thickness thirddegree burn on cardiac levels of il- and tnfα over days with and without β-estradiol infusion. methods a total of male rats were assigned randomly to one of three groups: ( ) conclusion following severe burn injury in an animal model, an early single dose of estrogen can decrease the prolonged let alone the early onset of cardiac infl ammation. based on these data, clinical studies of estrogen infusions should be seriously entertained as estrogen may not only be an inexpensive, simple adjunctive therapy in burn management, it may also obviate the need for many subsequent interventions altogether and even diminish mortality. conclusion the results of this study highlight the risk factors for the development of complications following blunt chest trauma. a risk stratifi cation tool has also been developed that could assist in the prediction of poor outcomes in this patient group. the next stage is to complete a prospective validation study. reference introduction we have reported the risk of chest drain insertion inferior to the diaphragm when using current international guidelines [ ] . another complication is damage to signifi cant peripheral nerves, such as the long thoracic nerve causing winging of the scapula [ ] . we assessed these risks using: the european trauma course method, a patient's handbreadth below their axilla just anterior to the midaxillary line; the british thoracic society safe triangle [ ] ; and the advanced trauma life support (atls) course guidance [ ] . methods we used the above guidelines to place markers (representing chest drains) in the thoracic wall of cadavers bilaterally ( sides), cm anterior to the midaxillary line. subsequent dissection identifi ed the course and termination of the long thoracic nerve, the site of lateral cutaneous branches of intercostal nerves, and their relation to the markers. the long thoracic nerve was found in the fi fth intercostal space in of cases, always in or posterior to the midaxillary line. contrary to the description in grays' anatomy ( th edition) it terminated before the inferior border of serratus anterior. most commonly it was found to end by branching in the fourth (right) or fi fth (left) intercostal space (range third to sixth). lateral cutaneous branches of intercostal nerves were found in the fi fth intercostal space in of cases. contrary to the description in last's anatomy ( th edition) they always passed anterior to the midaxillary line (and marker). conclusion placement cm anterior to the midaxillary line minimises risk to the long thoracic nerve and lateral cutaneous branches of intercostal nerves. we therefore conclude that not all areas of the british thoracic society safe triangle are indeed safe, and anteroposterior placement should follow the european trauma course and atls guidelines: just anterior to the midaxillary line (for example, cm). introduction whole body computed tomography (wbct) appears to be useful for the early detection of clinically occult injury, although its indications have been controversial. the purpose of this study was to develop a clinical prediction score to clarify the indications for blunt trauma patients with multiple injuries (mi) who require wbct. methods we conducted a retrospective study of patients with blunt trauma who underwent wbct at our emergency center between june and july . we chose the presence or absence of mi (injury severity score ≥ ) in need of surgical intervention as the outcome variable. we used bivariate analyses to identify variables potentially predicting the presentation of mi. the predictor variables were confi rmed by multivariate logistic regression analyses. we assigned a score based on the corresponding coeffi cients. results among the patients enrolled, were in the mi group. four predictors were found to be independently signifi cant by the logistic analysis: ( ) body surface wound ≥ regions, ( ) positive focused assessment with sonography for trauma, ( ) white blood cell count ≥ , /μl, and ( ) d-dimer ≥ μg/ml. score was assigned to predictor ( ), score was assigned to predictors ( ), ( ) and ( ). a prediction score was calculated for each patient by adding these scores. the area under the receiver operating characteristic curve was . . no patients with a score of or less had mi (figures and ) . conclusion in patients with a score of or , the presence of mi is less likely. these patients may not require wbct, and selective ct scans of body parts based on clinical presentation should be considered. (figure ) . the most common intervention as a result of the ultrasound was initiation of a pressor infusion ( . %), of which . % were ionotropes. additional therapies included blood transfusion ( . %), heparin ( . %), tpa ( . %), cardiac catheterization ( . %), and surgery ( . %). rosc was achieved in . % of patients; average time to rosc was minutes. a total . % of patients who underwent als were alive at hospital discharge and . % at year. conclusion focused cardiac ultrasound is a feasible adjunct to als resuscitation and may assist in the early identifi cation of reversible causes of cardiac arrest. care must be taken to ensure no interruptions to cardiac compressions are made by performance during pulse checks. further studies are needed to examine the outcomes associated with its integration into resuscitations. introduction in this case report, we describe a patient who presented with a cardiac arrest as a result of an obstructive shock, which progressed into cardiac arrest, caused by an acute para-esophageal gastric herniation. methods our patient, with a medical history of a laparoscopic repair of a symptomatic diaphragmatic hernia months prior, presented herself at the emergency department with pain in the upper abdomen and nausea. the physical examination, laboratory tests and x-ray of the thorax were normal and she was sent home. twenty-four hours later paramedics were summoned to our patient because of increased complaints. on arrival of the paramedics she had a normal electrocardiogram (ecg) and during the transfer from her bed to the stretcher she collapsed due to pulseless electric activity (pea), for which cardiopulmonary resuscitation was started. sinus rhythm and output was regained after several minutes and the patient was transported to the hospital. at arrival in the hospital, the x-ray of the thorax showed an intrathoracic stomach and a signifi cant mediastinal shift to the right. results after emergency laparotomy, which concerned correcting the gastric herniation and resection of an ischemic part of stomach, the patient remained hemodynamically stable. cardiac ischemia was ruled out based on ecg, laboratory fi ndings, cardiac ultrasound and cardiac computed tomography. the ultrasound in the emergency department did show a distended right ventricle and normal left function, which disappeared later (after repositioning the stomach), which is evidence for the mediastinal shift as a cause for the pea. conclusion we are the fi rst to describe a patient requiring cardiopulmonary resuscitation for progressive obstructive shock, due to an intrathoracic stomach. especially after a laparoscopic repair of a diaphragmatic hernia, this is a rare cause for shock and cardiac arrest, which requires a diff erent medical approach. is a key factor in improving survival from out-of-hospital cardiac arrest (ooh-ca). the alert algorithm, a simple and eff ective compression-only telephone cpr protocol, has the potential to help bystanders initiate cpr. this study evaluates the eff ectiveness of the implementation of this protocol in the liege dispatching centre. methods we designed a before-and-after study based on a -month retrospective assessment of the adult victims of ooh-ca in , before the implementation of the alert protocol in the liege dispatching centre, and the prospective evaluation of the same -month period in , immediately after the implementation of this protocol. data were extracted from ambulance, paramedical and medical intervention teams fi les, as well as the audio recordings of the dispatching centre. conclusion in ohca patients with unshockable initial rhythm, prehospital epinephrine administration signifi cantly increased the rate of survival at month after cardiac arrest. the best single predictor for favorable neurological outcomes at month following prehospital epinephrine administration after cardiac arrest was age (< years) followed by total dose of epinephrine ( mg) and then by call-response time (< minutes). [ ] . methods this was a single-center retrospective cohort study of patients who suff ered ohca and were transported to our hospital between april and march . we investigated the patients' characteristics, whether they met the tor criteria, and their outcome at the time of hospital discharge. results a total of patients (mean age, years), % of whom were male, were transported to our hospital after suff ering ohca. cardiopulmonary arrest was witnessed in cases ( %). the aha guidelines for cpr and ecc regarding the criteria for tor were applied in cases ( %), of whom ( %) were dead on arrival, and were successfully resuscitated and admitted. the outcomes for these patients were as follows: died in the hospital, two patients were discharged with a glasgow pittsburgh cerebral performance category (cpc) score of , and one patient was transferred to another hospital with a cpc score of . conclusion in our study, % of the patients who were transported to the hospital after ohca met the criteria for tor. outcomes for patients who met the tor criteria were signifi cantly worse than those who did not meet the criteria ( . % vs. . %, p < . ). in japan, eff orts are made to resuscitate almost all individuals who suff er ohca, but % of those patients die within a day. in light of the fact that even the medical cost for each of these patients who die within a day amounts to us$ , [ ] , the introduction of tor will have a particularly strong impact in japan. introduction detection and treatment of cardiopulmonary arrest and their antecedents may be less eff ective at night and weekend than weekdays because of hospital staffi ng and response factors [ ] . early detection and resuscitation of cardiopulmonary arrest are crucial for better clinical outcome. we conducted our study to evaluate event survival of in-hospital cardiopulmonary arrest after regular working hours in nonmonitored areas of a tertiary-care center. = ) , hypoxia (n = ), cardiac other (n = ), sepsis (n = ), arrhythmia (n = ) and pe (n = ). in two ihca patients more than one likely cause of arrest was reported and in cases no cause was identifi ed. the presenting rhythm was ventricular fi brillation (vf) in . % (n = ), pulseless electrical activity in . % (n = ) and asystole in . % (n = ). a total of . % (n = ) were thrombolysed and one ( . %) patient was referred for emergency pci. conclusion as previously reported [ ] , ihca was associated with a worse prognosis than ohca. the ohca survival rate was better than reported elsewhere [ ] . the percentage of ihca attributed to mi was low. only one ohca patient was referred for emergency pci. routine coronary angiography with ad hoc pci in vf ohca has been associated with increased survival [ ] . greater availability of pci post ohca could further improve mortality in patients with a primary cardiac pathology. further investigation should include management of noncardiogenic cardiac arrest. introduction mild therapeutic hypothermia (mth) is the most powerful therapy to improve survival and neurologic outcome after out-ofhospital cardiac arrest. such benefi t may also occur for unconscious patients after in-hospital cardiac arrest. the aim is to compare -year evolution of neurological outcomes of patients treated with mth after in-hospital versus out-of-hospital cardiac arrest. methods a prospective study of patients treated with mth after cardiac arrest in a community hospital in são paulo, brazil. after return of spontaneous circulation, unconscious survivors received mth using topical ice and cold saline infusions in order to achieve a to °c goal temperature, within hours of cardiac arrest, and maintained in the management of out-of-hospital cardiac arrest (ohca) is not clear cut [ ] . it has historically been used in patients with st elevation on post-resuscitation electrocardiogram (ecg) although this is a poor predictor of acute coronary occlusion after cardiac arrest [ ] . this study investigates the benefi t of pci regardless of post-resuscitation ecg. benefi t is widely claimed for therapeutic hypothermia, so cooling parameters were included. methods we analysed all consecutive adults admitted post ohca to a university hospital icu between january and december . patients received pci regardless of ecg changes. a cox proportional hazards model was used to determine the relationship between pci, cooling and survival to discharge. routinely collected data such as demographics and details of resuscitation (ohca utstein data) were also included. results survival to hospital discharge was % with % of survivors discharged to a neurological rehabilitation centre. multivariate analysis using a cox proportional hazards model showed pci to be an independent predictive factor of survival, unrelated to ecg (hazards ratio, . ; % ci, . to . ). cooling had no signifi cant impact on patient survival. see figure . conclusion in this small retrospective study primary pci appears to be an independent predictor of survival after ohca. this is consistent with other studies suggesting benefi t for primary pci regardless of the post-resuscitation ecg [ ] . cooling was not found to improve survival to discharge but further analysis is required to determine impact on neurological function. introduction sedation and therapeutic hypothermia (th) modify neurological examination and alter prognostic prediction of coma after cardiac arrest (ca). additional tools, such as eeg and evoked potentials, improve prediction of outcome in this setting, but are not widely available and require signifi cant implementation. methods using a new device for infrared pupillometry, we examined the value of quantitative pupillary light reactivity (plr) to predict outcome in comatose post-ca patients treated with th. twenty-four comatose ca patients treated with th ( °c, hours) were prospectively studied. the percentage variation in plr was measured during th ( hours from ca), using the neurolight algiscan® (idmed, marseille, france). for each patient, three consecutive measures were performed and the best value was retained for analysis. the relationship of plr with survival and neurological outcome (cpc scores) at months was analyzed, and the predictive value of plr was compared with that of standard clinical examination (motor response and brainstem refl exes) performed at hours from ca. results quantitative plr was strongly associated with survival (median left-eye plr % ( to %) variation in survivors vs. . % ( to . %) in nonsurvivors, p < . ) and -month neurological outcome ( % ( to %) in patients with cpc to vs. . % ( to . %) in those with cpc to , p < . ). comparable fi ndings were obtained using right-eye plr. a plr > % was % predictive of patient prognosis, with false-positive and false-negative rates of % for outcome. clinical examination was signifi cantly associated with outcome; however, motor response (mr) and brainstem refl exes (brs) yielded higher falsepositive and false-negative rates than plr (table ) . conclusion quantitative plr appears highly accurate and superior to standard neurological examination to predict outcome in patients with post-ca coma. further study is warranted to confi rm these promising fi ndings. acknowledgements supported by grants from the swiss national science foundation (fn _ ) and the european critical care research network (eccrn). figure . mv was associated with a signifi cant reduction of scto from baseline ( % ( to ) to % ( . to . ), p < . ). no signifi cant changes in scto were found after ih ( ( to ) vs. ( to . ), p = . ). conclusion moderate hv was associated with signifi cant reduction in cerebral saturation, whilst ih may be detrimental after ca and th, whilst increasing map to supranormal levels with vasopressors does not improve cerebral oxygenation. these data stress the importance of strict control of paco following ca and th to avoid secondary cerebral ischemic insults. introduction after cardiac arrest, microcirculatory reperfusion dis orders develop despite adequate cerebral perfusion pressure. increased blood viscosity strongly hampers the microcirculation, resulting in plugging of the capillary bed, arteriovenous shunting and diminished tissue perfusion. the aim of the present study was to assess blood viscosity in relation to cerebral blood fl ow in patients after cardiac arrest. methods we performed an observational study in comatose patients after cardiac arrest. patients were treated with hypothermia for hours. blood viscosity was measured ex vivo using a contraves ls viscometer. mean fl ow velocity in the middle cerebral artery (mfvmca) was measured by transcranial doppler (tcd) at the same time points. < . ) . there was a signifi cant association between viscosity and the mfvmca (p = . ). see figure . conclusion viscosity decreases in the fi rst days after cardiac arrest and is strongly associated with an increase in cerebral blood fl ow. since viscosity is a major determinant of cerebral blood fl ow, repeated measurements may guide therapy to help restore cerebral oxygenation after cardiac arrest. in preliminary data, we report that sr > might correlate with bad outcome and that combining nse and sr might improve the predictive value. also, low nse and good initial bis values correlate with preserved cerebral potential and should encourage the clinician. introduction accurate prediction of neurological outcome after cardiac arrest is desirable to prevent inappropriate withdrawal of lifesustaining therapy in patients who could have a good neurological outcome, and to limit active treatment in patients whose ultimate neurological outcomes are poor. established guidelines to predict neurological outcome after cardiac arrest were developed before the widespread use of therapeutic hypothermia. the american association of neurology guidelines [ ] currently recommend that absent or extensor motor scores on day post arrest are reliable indicators or poor neurological outcome with a false positive rate of to %. methods a review of existing literature was undertaken to examine whether the utility of motor scores to predict poor neurological outcome is infl uenced by the use of therapeutic hypothermia. results six studies were identifi ed [ ] [ ] [ ] [ ] [ ] [ ] that investigated the use of motor scores on day post cardiac arrest in patients who had received therapeutic hypothermia. false positive rates (defi ned as -specifi city) for predicting poor neurological outcome were calculable in fi ve of the six studies [ ] [ ] [ ] [ ] [ ] and were %, %, %, % and % respectively. in all studies the fpr for motor scores of extension or worse were signifi cantly higher than the % ( to % % cis) in the aan guidelines. conclusion motor scores at day post cardiac arrest of extension or worse do not reliably predict poor neurological outcome when therapeutic hypothermia has been used. clinical neurological fi ndings may not be valid predictors of poor neurological outcome after therapeutic hypothermia. introduction it has been reported that the young are much more resistant to transient cerebral ischemia than the adult. methods in the present study, we compared the chronological changes of calcium binding proteins (cbps) (calbindin k (cb-d k), calretinin (cr) and parvalbumin (pv)) immunoreactivities and levels in the hippocampal ca region of the young gerbil with those in the adult following minutes of transient cerebral ischemia induced by the occlusion of both the common carotid arteries. in the present study, we examined that about % of ca pyramidal cells in the adult gerbil hippocampus died at days post ischemia; however, in the young hippocampus, about % of them died at days post ischemia. we compared immunoreactivities and levels of cbps, such as cb-d k, cr and pv. the immunoreactivities and protein levels of all the cbps in the young sham were higher than those in the adult sham. in the adult, the immunoreactivities and protein levels of all the cbps were markedly decreased at days post ischemia; however, in the young, they were apparently maintained. at days post ischemia, they were decreased in the young; however, they were much higher than those in the adult. conclusion in brief, the immunoreactivities and levels of cbps were not decreased in the ischemic ca region of the young days after transient cerebral ischemia. this fi nding indicates that the longer maintenance of cbps may contribute to a less and more delayed neuronal death/ damage in the young. delay in reaching target temperature [ ] . we hypothesize that early and rapid induction of hypothermia will mitigate neuronal injury and improve survival in a swine model of tbi. methods twenty domestic cross-bred pigs ( to kg) were subjected to a atm ( ms) lateral fl uid percussion tbi. the brain temperature and icp were measured using camino®. serum biomarkers for neuronal injury -s- β, neuron-specifi c enolase, glial fi brillary acid protein (gfap), and neurofi laments heavy chain -were measured daily using enzyme-linked immunosorbent assay. twelve of the injured animals were rapidly cooled to °c within minutes of the injury using a transpulmonary hypothermia technique [ ] . hypothermia was maintained for hours. eight injured control animals were maintained at °c. in both groups, anesthesia (isofl urane %) was discontinued and the animals were weaned off the ventilator after hours. five days post injury, the surviving animals were euthanized and necropsied. the data were analyzed using a log-rank (mantel-cox) test, and anova. results ten of the hypothermia and four of the eight normothermia animals survived to the end of the -day study (χ = . , df = , p = . ). although the probability of type i error between survival curves was %, the study was clinically signifi cant and showed a clear trend toward improved survival with hypothermia. the intracranial pressures were signifi cantly (p < . ) lower in the hypothermia group. both interventions -that is, general anesthesia and hypothermiamitigated the rise of serum biomarkers following tbi. however, the suppression of biomarkers was sustained during the recovery period only in the hypothermia group. with the exception of the gfap levels, the curves of all biomarkers were signifi cantly diff erent between the groups. conclusion our preliminary fi ndings show early initiation, rapid induction, and prolonged maintenance ( hours) of cerebral hypothermia to lower intracranial pressure, blunt the rise in serum biomarkers, and improve survival following tbi. references introduction traumatic brain injury (tbi) is a contributing factor to approximately one-third of all injury-related deaths in the usa annually. updated statistical records for tbi in egypt are lacking. the current research is aiming to estimate the prevalence of tbi in egypt in order to develop a comprehensive tbi prevention program. methods a -year period (one calendar month every quarter of ) descriptive epidemiological study of moderate and severe tbi cases admitted to the emergency department, cairo main university hospital. the data collection sheet included personal data (age, sex and residency), incident-related data (cause, nature and time of injury) and both clinical and radiological fi ndings. introduction one of the most used prognostic models for traumatic brain injury is the impact-tbi model, which predicts -month mortality and unfavorable outcome. our aim was to study whether adding markers of coagulation improves the model's predictive power when accounting for extracranial injury. methods patients with a tbi admitted to a designated trauma center in / were screened retrospectively and included according to the impact study criteria. the predictive outcome was calculated for included patients using the full impact-tbi model. to assess coagulopathy and extracranial injury we used the prothrombin time percentage (pt), platelet count ( ), and injury severity score (iss introduction evidence suggest that endogenous lactate, produced by aerobic glycolysis, is an important substrate for neurons, particularly in conditions of increased energy demand. this study aimed to examine brain lactate metabolism in patients with severe traumatic brain injury (stbi). methods a prospective cohort of stbi patients monitored with cerebral microdialysis (cmd) and brain tissue oxygen (pbto ) was studied. brain lactate metabolism was assessed by quantifi cation of elevated cmd lactate samples (> mmol/l). these were matched to pyruvate and pbto , and dichotomized as hyperglycolytic (cmd pyruvate > μmol/l) versus nonhyperglycolytic or as hypoxic (pbto < mmhg) versus nonhypoxic. data were expressed as percentages per patient. global brain perfusion (categorized as oligemic, normal or hyperemic) was assessed with ct perfusion (ctp). results twenty-four patients (total , cmd samples) were studied. samples with elevated cmd lactate were frequently observed ( ± % sem of individual samples). brain lactate elevations were predominantly hyperglycolytic ( ± . %), whilst only ± . % of them were hypoxic. trends over time of both lactate patterns are shown in figure . on ctp (n = ; average hours from tbi) hyperglycolytic lactate was always associated with normal or hyperemic ctp, whilst hypoxic lactate was associated with oligemic ctp (table ) . our fi ndings suggest predominant nonischemic lactate release after tbi and identify, for the fi rst time, an association between cerebral hyperglycolytic lactate production and normal to supranormal brain perfusion. our data support the concept that lactate may be used as energy substrate by the injured human brain. in the prehospital setting, it is diffi cult to use the glasgow coma scale (gcs) to evaluate the consciousness state using in pediatric patients with severe trauma. the japan coma scale (jcs) is a consciousness scale used widely in japan and, with its four grades, is simpler and quicker to use than the gcs. this study examined whether our study identifi ed a moderate relation between peep and osnd and a weaker one between ppeak, pm and osnd. thus, in selected cases osnd could serve as a bedside marker of eff ect of airway pressure to icp. yet, larger studies are needed to come to a safer conclusion. reference introduction following primary neurological insult, initial manage ment of traumatic brain-injured (tbi) patients has a clearly defi ned pathway [ ] . however, after arrival at tertiary centers, further manage ment is not standardized. intracranial hypertension (ich), systemic hypotension, hypoxia, hyperpyrexia and hypocapnia have all been shown to independently increase mortality [ ] . despite numerous studies, there is currently no level evidence to support any specifi c management [ ] . our objective was to provide an overview of the current clinical management protocols in the uk. methods thirty-one icus managing patients with severe tbi were identifi ed from the rain (risk adjustment in neurocritical care) study, and a telephone survey was conducted. results a total % of units used a cerebral perfusion pressure protocol for the initial management, with % targeting pressures of to mmhg and % aimed for > mmhg. ninety-one percent of units monitored co routinely with % targeting co of . to kpa (figure ). regarding osmotherapy, mannitol was still the preferred agent, with % of units using it as fi rst line; % used hypertonic saline, while % of units used either depending on clinicians' preference. sixteen percent questioned were currently enrolled on the eurotherm hypothermia trial, while % never used hypothermia and one unit used prophylactic hypothermia routinely. the remaining % of units used hypothermia only to manage refractory ich. conclusion there is no clear consensus on the initial targets used. the surviving sepsis campaign showed that protocol-led care can reduce mortality [ ] . perhaps it is time for a similar approach to be adopted, with specialists coming to together to review the evidence and formulate guidelines that can then be tested. introduction traumatic brain injury (tbi) is a major cause of permanent disability and death in young patients. controversy exists regarding the optimal cerebral perfusion pressure (cpp) required in tbi management. a tool for monitoring autoregulation and determining an optimal cpp is the pressure reactivity index (prx), defi ned as a moving correlation coeffi cient between the mean arterial blood pressure (map) and intracranial pressure (icp) at a frequency of at least hz. this requirement of high frequency has constrained its use to a few academic centers. an association was shown between outcome and continuous optimal cpp based on hours of prx [ ] . we present a novel low-frequency autoregulation index (lax), based on correlations between icp and map at a standard minute-by-minute time resolution. methods a total of patients from the brain-it [ ] multicentre european database had registered outcome and icp and map for the fi rst icu hours. twenty-one tbi patients admitted to the university hospitals of leuven, belgium and tubingen, germany were continuously monitored using icm+ software (cambridge enterprise) allowing for continuous prx calculation. autoregulation indices versus cpp plots for prx and lax were computed to determine optimal cpp every minute during the fi rst icu hours [ ] . results on the brain-it database, lax resulted in an optimal cpp for % of the fi rst hours. table shows recommendations with respect to outcome. in the leuven-tübingen database, prx and lax resulted in % and % recommendations respectively. the average diff erence between methods was . mmhg. conclusion the diff erences in optimal cpps derived from prx and lax were not clinically signifi cant. lax allowed for recommendations to be computed for longer periods. signifi cantly better outcome (table ) was observed in patients for whom optimal cpp derived from lax was maintained. introduction pediatric patients with altered mental status (ams) present with poor histories resulting in delayed testing and potential poor outcomes. non-invasive detection for altered cerebral physiology related to tbi would improve resuscitation and outcome. cerebral rso (r c so ) studies demonstrate its utility in certain neurological emergencies. methods a retrospective analysis of r c so utility in ams. rcso data were collected every seconds for ams patients who had a head ct. patients with a negative head ct were compared with those with an abnormal head ct. roc analysis was performed to fi nd the auc for each summary statistic and performance characteristics. subgroup analysis was done to determine whether r c so predicted injury and location. results r c so readings across , , , and minutes were stable (figure ). r c so readings with one or both sides < % or a wide diff erence between l and r cerebrum was predictive of an abnormal ct scan. a mean diff erence of . was % sensitive for detecting a ct lesion with % specifi city, % ppv, and % npv; a mean diff erence of . was % specifi c for an abnormal head ct. lower mean r c so readings localized to the ct pathology side, and higher r c so readings trend toward the edh group. conclusion cerebral rcso monitoring can non-invasively detect altered cerebral physiology and pathology related to tbi as the cause for pediatric altered mental status. the utility of r c so monitoring has shown its potential for localizing and characterizing intracranial lesions among these altered children. further studies utilizing r c so monitoring as an adjunct tool in pediatric altered mental status evaluation and management are ongoing. introduction fever is a dangerous secondary insult for the injured brain [ ] . we investigated the cerebral and hemodynamic eff ects of intravenous (i.v.) paracetamol administration for the control of fever in neurointensive care unit (nicu) patients. methods the i.v. paracetamol ( g in minutes) was administered to nicu patients with a body temperature (temp.) > . °c. its eff ects on mean arterial pressure (map), heart rate (hr), intracranial pressure (icp), cerebral perfusion pressure (cpp), jugular venous oxygen saturation (sjvo ) and temp. were recorded at the start of paracetamol infusion (t ) and after (t ), (t ) and (t ) minutes. interventions for the maintenance of cpp > mmhg or icp < mmhg were recorded. (figure ). in fi ve cases norepinephrine infusion was started for cpp < mmhg. in another two cases, for the same reason, the norepinephrine dosage was augmented. the proportion of patients who had infusion of norepinephrine increased from . % at t to . % at t (p = . , chi-square for trends). conclusion use of i.v. paracetamol is eff ective in the maintenance of normothermia in acute brain-injured patients. however, adverse hemodynamic eff ects, which could represent a secondary insult for the injured brain, must be rapidly recognized and treated. reference introduction evaluating resource utilization is paramount in critically ill patients with traumatic brain injury (tbi), but little is known on readmissions after hospital discharge. we evaluated rates and determinants of unplanned readmission following tbi. methods we conducted a multicenter retrospective cohort study from april to march . data were obtained from a canadian provincial trauma system, based on mandatory contribution from trauma centres, and a hospital discharge database. patients aged ≥ years with tbi (icd- or icd- codes of - and s , respectively) were included. patients who died during the index hospitalization, who lived outside the province, who could not be linked with the hospital discharge database were excluded. we collected baseline and trauma characteristics, hospital admissions in the months preceding index admission, and readmissions in the following months. primary outcome was unplanned readmission days, months and months post discharge. we evaluated sociodemographic and clinical factors associated with readmissions using a logistic regression model. results among , adult patients with tbi identifi ed in the registry, , patients were included among which , had severe, , moderate and , mild traumatic brain injury. most patients were young (mean age: ± years) and had no comorbidity ( . %). overall, , patients ( . %) were readmitted within days, . % within months and . % within months. at days post discharge, ( . %) were readmitted for a complication. the median length of stay was days (q to q : to ). more than % of patients aged ≥ years with ≥ comorbidity or with ≥ admission prior to index hospitalisation were readmitted. the severity of the tbi was not an independent predictor of readmission. age, highest ais, number of comorbidities, number of admissions prior to index hospitalization, level of index trauma center and discharge destination were associated with readmissions on multivariate analysis. conclusion readmissions in the months following tbi are frequent, but were not found to be associated with the tbi severity. further studies evaluating reasons for readmission are warranted in order to develop strategies to prevent such events. introduction pituitary disorders following traumatic brain injury (tbi) are frequent, but their determinants are poorly understood. we performed a systematic review to assess the risk factors of tbiassociated pituitary disorders. methods we searched medline, embase, scopus, the cochrane library, biosis, and trip database, and references of narrative reviews for cohort, cross-sectional and case-control studies enrolling at least fi ve adults with tbi in whom ≥ pituitary axis was tested and one potential predictor reported. two independent investigators selected citations, extracted data and assessed the risk of bias. we pooled the data from all studies assessing a specifi c predictor, regardless of the pituitary axis being evaluated. when more than one pituitary axis was assessed, we used the data related to hypopituitarism or the data from the most defective axis. when a pituitary axis was evaluated several times, we used assessment farthest from the injury. a meta-analysis was performed using random eff ect models and i was used to evaluate heterogeneity. introduction prevention of secondary neurologic injuries is paramount for improved neurologic outcomes after traumatic brain injury (tbi). evidence suggests that although therapeutic hypothermia (th) lowers intracranial pressure and attenuates secondary cerebral insults after tbi [ ] , it also induces hypotension. brief episodes of mild hypotension in brain-injured patients can trigger secondary injuries, which have been associated with increased mortality in patients with tbi [ ] . vasopressin mitigates hypotension in septic shock and improves coronary perfusion in hypothermic cardiac arrest models [ ] . we hypothesized that a lowdose vasopressin infusion may reduce the cumulative epinephrine dose in hypothermic, brain-injured swine. methods six domestic cross-bred pigs were subjected to epinephrine infusion after general anesthesia, standardized tbi and transpulmonary hypothermia ( °c for hours). all animals received the same care, aiming for a mean arterial pressure > mmhg. at hour , animals received additional vasopressin infusion at . units/minute. we measured the cumulative epinephrine dose for each animal pre and post vasopressin infusion ( figure ) and performed a twosample wilcoxon rank-sum test, comparing the median cumulative epinephrine doses in the two groups. the median cumulative epinephrine dose in the animals that received the vasopressin infusion was mg with a th to th interquartile range (iqr) of to mg. the median cumulative epinephrine dose in the control group was , mg (iqr , to , mg). this was statistically signifi cant (p = . ), based on the wilcoxon rank-sum test. conclusion a low-dose infusion of vasopressin can signifi cantly reduce vasopressor requirements and improves hemodynamics in hypothermic, brain-injured swine. this hemodynamic stability may improve neurological outcomes. introduction severe traumatic brain injury (tbi) is a major cause of death and of severe neurologic sequelae. long-term functional outcome of tbi and its best timing of assessment are not well understood, and may be evaluated too prematurely in clinical studies because of resources required to do so without too much missing data. hence, we conducted a systematic review of studies in severe tbi patients to evaluate the long-term functional outcome. we hypothesized that functional impact measured by the glasgow outcome scale (gos), or the extended version (gose), may plateau after several months in patients with severe tbi. methods we performed a systematic review of randomized controlled trials and cohort studies (prospective and retrospective) in patients with severe tbi. we searched medline, embase, cochrane central, biosis, cinahl and trip database from their inception to december . references of included studies were searched for additional studies. two reviewers independently determined study eligibility and collected data. the primary outcome measure was the proportion of unfavourable functional outcome (gos to or gose to ) at to months, to months, to months and more than months after severe tbi. we calculated freeman tukey-type arcsine squareroot transformations and pooled data using random-eff ect models. heterogeneity was assessed with the i test and sensitivity analyses were based on a priori hypotheses. in total, , studies were assessed for eligibility; studies (n = , ) were included. in the studies using the gos, a poor functional outcome was observed in . % ( % ci = . to . %, i = %), . % ( % ci = . to . %, i = %), . % ( % ci = . to . %, i = %) and . % ( % ci = . to . %, i = %) of patients at to months, to months, to months and beyond months, respectively. in the studies using gose, a poor functional outcome was observed in . % of patients at to months ( % ci = . to . %, i = %) and . % at to months ( % ci = . to . %, i = %). heterogeneity was present in most analyses and was not entirely explained by the planned sensitivity analyses. conclusion considering that the incidence of patients with an unfavourable outcome remained constant at diff erent assessments, a follow-up of severe tbi patients longer than months does not provide incremental information. functional outcomes measured longer than months after the injury may not be warranted in clinical studies. introduction prevention of secondary brain injury is the cornerstone in the management of patients with severe traumatic brain injury (tbi) and raised intracranial pressure (icp). although a variety of monitoring methods are available, due to lack of strong evidence their use varies considerably [ ] . the objective of this survey was to provide an overview of the current practice in monitoring of patients with severe tbi in all neuro-icus across the uk. introduction pulmonary complications are frequently occurring medical complications after aneurysmal subarachnoid hemorrhage (asah) [ ] . early respiratory deterioration (erd) may be associated with delayed cerebral ischemia (dci) or outcome and would then be a potential target for therapeutic interventions. we investigated whether respiratory deterioration within the fi rst hours after admission predicted dci or poor outcome. methods we conducted a retrospective study in consecutively admitted patients with asah, admitted between october and october to the icu of a university hospital. erd was defi ned as increased need for ventilatory support the second or third day after admission (table ) . elective intubation for a surgical procedure was not included as erd. inclusion criteria were availability of detailed information on respiratory status and level of support, admission within hours after hemorrhage and age ≥ years. multivariable survival analysis was used to investigate associations of dci, death and glasgow outcome scale (gos) with erd adjusted for condition on admission, hijdra score, treatment of ruptured aneurysm and pulmonary comorbidity. gos was assessed at to months after the bleed. dci was defi ned as described recently [ ] . results mean age of the patients was . (± . ) and . % was female. a total . % of the patients developed dci. mortality was . %. forty percent of the patients were classifi ed as having erd. erd was not associated with dci (adjusted hr = . ; % ci = . to . ; p = . ). erd showed a trend towards an association with mortality (adjusted hr = . ; % ci = . to . ; p = . ; additionally adjusted for age, and rebleed). a clear association was found between absence of erd and functional outcome with ordinal logistic regression analysis ( . point increase in gos score at to months; % ci = . to . ; p = . ; additionally adjusted for age and rebleed). conclusion erd within hours after admission is associated with increased risk of poor functional outcome after asah, but not dci. further investigations are required to assess whether prevention of erd may improve outcome. introduction elevated intracranial pressure (icp) may have deleterious eff ects on cerebral metabolism and mortality after aneurysmal subarachnoid hemorrhage (sah) [ , ] , but its relevance has not yet been well explored. aims of this study are to track icp changes after sah, to identify clinical factors associated with it and to explore the relationship between icp and outcome. methods a total of consecutive sah patients with icp monitoring were enrolled. episodes of icp > mmhg for at least minutes and the mean icp value for every -hour interval were analyzed. the highest mean icp collected in every patient was identifi ed. icp values were analyzed in relation to clinical and ct fi ndings; -month outcome and icu mortality were also introduced in multivariable logistic models. results eighty-one percent of patients had at least one episode of elevated icp and % had a highest mean icp > mmhg. the number of patients with highest mean icp > mmhg or with episodes of hicp was maximum at day after sah and decreased only after day . neurological status, aneurysmal rebleeding, amount of blood on ct and ct ischemic lesion occurred within hours from sah were signifi cantly related to highest mean icp > mmhg in a multivariable model. patients with highest mean icp > mmhg showed signifi cantly higher mortality in icu. however, icp is not an independent predictor of months unfavorable outcome. conclusion elevated intracranial pressure is a common complication in the fi rst week after sah. it is associated with early brain injury severity and icu mortality. . we systematically reviewed their prevalence, aiming particularly at studies with low risk of bias. methods we searched embase, medline, the cochrane library, trip database, references of included studies and narrative reviews. we included cohort studies, cross-sectional studies and rcts published in any language that tested the integrity of ≥ pituitary axis in adults with asah. studies including more than % of non-aneurismal sah were excluded. studies were considered at low risk of bias if the authors defi ned inclusion/exclusion criteria, avoided voluntary sampling, and tested > % of included patients with proper detailed diagnostic criteria. studies testing all pituitary axes were considered as evaluating hypopituitarism, which was defi ned as the dysfunction of ≥ axis. we used a freeman tukey-type arcsine square-root transformation and pooled prevalences using the dersimonian-laird random-eff ect method. we determined the degree of heterogeneity with i values. results among , citations, we included studies ( , patients). patients were mostly female ( %) aged . ± . . sixteen studies reported the severity of asah, reported the procedure for securing the aneurysm and reported the location of aneurysm. overall, hypopituitarism was observed in . % of patients at shortterm (< months), . % at mid-term ( to months) and . % at long-term (> months) ( table ). there was an insuffi cient number of studies with low risk of bias to perform sensitivity analyses according to study quality. conclusion the exact prevalence of pituitary disorders following asah remains uncertain, mainly due to high heterogeneity and the small number of studies with low risk of bias. however, the prevalence seems to decrease during the recovery phase. the prevalence, risk factors and clinical signifi cance of pituitary disorders in asah will require further rigorous evaluation. is associated with a high morbidity and mortality. although uk anaesthesia guidelines advocate early coiling or clipping of the aneurysm within the fi rst hours of admission for all grades of asah, the optimal timing of treatment and whether this is linked with better neurological long-term outcome are a subject of debate [ ] . we aimed to investigate whether the timing of the occlusion of the aneurysm translates into better outcome. methods a retrospective analysis of prospective collected data in a tertiary neuroscience centre from january to september . all patients were managed according to the local guidelines for the management of asah. outcome was assessed at months using the extended glasgow outcome scale (gose) defi ning good recovery as a gose ≥ and poor outcome as gose ≤ . results a total of patients were included within the study period. three patients were not expected to survive the fi rst hours and were not included in the study. seventeen patients were classifi ed as good grade asah (wfns i to iii) and eight as poor grade (iv to v). twenty-two patients underwent successful coiling while the other three required clipping due to unsuccessful coiling. we did not fi nd any correlation between the timing of coiling/clipping and the -month gose (figure ) . a total % of the patients had a poor -month gose while % had a good long-term functional outcome. the overall mortality rate was %. conclusion overall mortality in patients with asah is low when aneurysm is treated early post rupture of aneurysm. we did not fi nd any correlation between the timing of occlusion of aneurysm and the -month functional outcome. patients underwent neuropsychological evaluation at early (< days, days) and delayed time points ( month, months). patients were tested for language, verbal fl uency, short-term and long-term memory, attention, executive functions, praxis, and neglect. impairments in activities of everyday life were assessed using the activities of daily living scale and the instrumental activities of daily living scale. the sf- was used to assess the quality of life at months. since complications of aneurysm treatment in addition to asah severity may signifi cantly aff ect cognitive status, patients were evaluated according to the world federation of neurological surgeons score after treatment (wfnspt). all wfnspt to patients completed neuropsychological tests at each time point. wfnspt and wfns patients were testable in % and % of the cases respectively at early time points. wfns patients were not testable at any time point. in all testable patients, cognitive functions were severely impaired at early time points. at months in wfns to a good recovery of language defi cits while only a partial recovery of attention, memory and executive functions were observed; at the same time point % of wfns patients became testable, but they had a worse recovery of all cognitive functions. at month after sah less than % of patients return to work, at months approximately %. despite a good recovery of everyday life activities at months, for all patients quality of life was lower than a normal population. conclusion cognitive dysfunction has diff erent time courses after asah: signifi cant defi cits in diff erent cognitive domains, worse quality of life and diffi culties in return to work persist in more than % of patients at months following sah. results pretreatment with mg/kg, but not mg/kg, of asa-da protected against ischemic neuronal death and damage, and its neuroprotective eff ect was much more pronounced than that of asa or da alone. in addition, treatment with mg/kg asa-da reduced the ischemia-induced activation of astrocytes and microglia. conclusion our fi ndings indicate that asa-da, a new synthetic drug, prevents against transient focal cerebral ischemia, which provides a resource for the development of its clinical application for stroke. introduction acute neurological injury is a leading cause of morbidity and mortality in children. global prevalence and regional disparities of etiology, interventions, and outcomes are unknown. the aim of this point-prevalence study was to measure the burden of pediatric neurological injury and to describe variations in interventions and outcomes in icus. methods one hundred and three icus on six continents enrolled subjects on specifi c days in a -year period. included subjects were between ages days and years who were diagnosed with acute traumatic brain injury, stroke, cardiac arrest, central nervous system infection or infl ammation, status epilepticus, spinal cord lesion, hydrocephalus, or brain mass. sites completed a secure web-based case report form that included subject and hospital demographics, details about the neurological disease, interventions, length of stay, and pediatric cerebral performance category (pcpc) score (good outcome = pcpc to ) and mortality at hospital discharge. results of , subjects screened, , ( %) met enrollment criteria. the mean number of subjects enrolled per site for each study day was . . most sites were dedicated pediatric icus with a mean number of icu beds (range to ). icus had resources to invasively monitor intracranial pressure ( %), continuous electroencephalography ( %), invasive and non-invasive brain tissue oxygenation ( % and %), and somatosensory evoked potentials ( %). there were on average icu faculty and six fellows per site, and nearly one-half reported a neurocritical care icu team. subjects were % male and % white, and % had normal pre-admission pcpc scores ( %). status epilepticus and cardiac arrest (both %) had the highest prevalence. sixty-one per cent of subjects were mechanically ventilated during icu admission. icu length of stay was a mean days (median days) and hospital los was a mean days (median days). survival at hospital discharge was % with % of subjects discharged home and % to inpatient rehabilitation. conclusion acute neurological disease is a signifi cant pediatric health issue. these data suggest a vital need for increased research and healthcare resources to assist in the challenge of improving outcomes for these children. the newly approved oral anticoagulant dabigatran has no eff ective antidote. we therefore suspected an overall increase in mortality in patients presenting to the emergency department (ed) with a bleeding complication on dabigatran compared with warfarin or aspirin. methods we conducted a post hoc analysis on a database of all patients admitted to a tertiary-care ed with any kind of bleeding or suspicion of one from march to august who were taking dabigatran, warfarin, or aspirin. the primary endpoint was long-term survival. patients were censored at death or at the end of the study period ( december ). we performed a cox proportional hazard model, controlled for age, to calculate the hazard ratio (hr) for dabigatran versus warfarin and one for warfarin versus aspirin. statistical signifi cance was set at α = . and results are presented with % ci. results in total, patients met the inclusion criteria with a mean follow-up period of year. the mean age was . years and . % were men. a total of deaths ( . %) were recorded within the follow-up period; eight ( %) for dabigatran compared with ( . %) for warfarin and ( . %) for aspirin. the mortality risk for patients on dabigatran was signifi cantly higher than for patients on warfarin: hr = . ( % ci: . to . ), p = . after controlling for age. aspirin had a lower (but not statistically signifi cant) mortality risk compared with warfarin; hr = . ( % ci: . to . ), p = . after controlling for age. the results showed higher overall mortality in patients who presented to the ed with a bleeding complication and were taking dabigatran compared with warfarin or aspirin. physicians should be aware of the potential higher mortality with dabigatran over warfarin when treating a bleeding patient. however, this was a singlecentre retrospective analysis with a small number of patients taking dabigatran (n = ), and further studies are needed to corroborate the results. introduction dose adjustments of low molecular weight heparin (lmwh) based on daily anti-xa measurement by chromogenic assay remain controversial in daily clinical practice. one of the major obstacles is the cost of such a test. an aff ordable and reliable bedside test could change practice to an individual tailored dosing of lmwh. the aim of our study was to evaluate whether a prophylactic dose regimen of mg enoxaparine in cardiac surgical patients increases the anti-xa activity to the level necessary for effi cient prevention of a thromboembolic event [ ] . secondarily we tested whether there was a reliable correlation between a bedside anti-xa measurement compared with a two-stage chromogenic assay at the laboratory [ ] . this was an open, single-centre, prospective, nonrandomized clinical trial at a university hospital. all patients that needed prophylactic dosing of enoxaparine after cardiac surgery were duly informed and after giving written consent we included patients with a mean euroscore of . . the demographic specifi cations, medical and surgical history of all patients were collected. anti-xa activity was measured at three diff erent points in time. we determined baseline, peak and trough anti-xa activity: preoperatively, and respectively hours after the third dose of enoxaparine and minutes before the fourth dose. each measurement was done with both techniques, the two-stage chromogenic assay at the laboratory (biophen®) and the bedside assay (hemochron® jr). results our dose regimen of enoxaparine achieved in one-half of the included patients a suffi cient anti-xa activity for prevention of thromboembolic events. one-half of the patients with insuffi cient anti-xa activity had a body mass index over kg/m . comparison of the bedside assay with the two-stage chromogenic assay by means of the pearson's correlation coeffi cient showed correlation of the two tests if no variables were taken into account. in the bland-altman analysis we could not confi rm this correlation. conclusion the bedside anti-xa activity assay with a hemochron device tends to show some correlation with the two-stage chromogenic assay, but insuffi cient to be used as an alternative, in this small but uniform patient population. use of a standard dosing protocol for enoxaparine administration is prone for underdosage in post-cardiac surgery patients and may increase postoperative morbidity. references introduction we hypothesized that higher doses of enoxaparin would improve thromboprophylaxis without increasing the risk of bleeding. critically ill patients are predisposed to venous thromboembolism, leading to increased risk of adverse outcome [ ] . peak anti-factor xa (anti-xa) levels of . to . iu/ml, hours post administration of enoxaparin, refl ect adequate thromboprophylaxis for medico-surgical patients. methods the sample population consisted of patients, randomized to receive subcutaneous (s.c.) enoxaparin: mg × (control group), versus mg × , mg × or mg/kg × (test groups) for a period of days. anti-xa activity was measured at baseline, and at , , and hours post administration on each day. patients did not diff er signifi cantly between groups. results on day of administration, doses of mg × and mg × yielded similar mean peak anti-xa of . iu/ml and . iu/ml respectively, while a dose of mg × resulted in subtherapeutic levels of anti-xa ( . iu/ml). patients receiving mg/kg enoxaparin achieved near-steady-state levels from day with mean peak anti-xa levels of . iu/ml. steady-state anti-xa was achieved for all doses of enoxaparin at day . at steady state, mean peak anti-xa levels of . iu/ ml and . iu/ml were achieved with doses of mg × and mg × respectively. this increased signifi cantly to . iu/ml and . iu/ml for doses of mg × and mg/kg enoxaparin respectively (p = . ) (figure ) . a dose of mg/kg enoxaparin yielded therapeutic anti-xa levels for over % of the study period. there were no adverse eff ects. introduction unfractionated heparin is preferred over lmwh in icu patients but lmwh is used more frequently in many european icus. thromboprophylaxis with standard doses of nadroparin and enoxaparin has been shown to result in signifi cantly lower anti-xa in icu patients when compared with medical patients [ , ] . methods icu patients (saps ± , mv, n = ; pressors n = ) received , iu (group , n = ) or , iu dalteparin s.c. (group , n = ). twenty-nine medical patients receiving , iu dalteparin served as controls (group ). results group had signifi cantly lower areas under the xa curve (auc) compared with groups and (table ) . diff erences were not signifi cant between groups and . peak anti-xa activities (c max -anti-xa) were delayed (t max -anti-xa) in group compared with groups and (table ) . conclusion in icu patients a s.c. dose of , iu dalteparin results in signifi cantly lower xa activities when compared with normal ward patients. a s.c. dose of , iu dalteparin in icu patients resulted in kinetics and peak anti-xa activities comparable with medical patients receiving , iu dalteparin. introduction anemia is very frequently encountered on the icu. increased hepcidin production is one of the cornerstones of the pathophysiology of anemia of infl ammation. the fi rst-in-class hepcidin antagonist nox-h , a pegylated anti-hepcidin l-rna oligonucleotide, is in development for targeted treatment of anemia of infl ammation. we investigated whether nox-h prevents the infl ammation-induced serum iron decrease during experimental human endotoxemia. methods a randomized, double-blind, placebo-controlled trial in healthy young men. at t = hours, ng/kg e. coli endotoxin was administered intravenously (i.v.), followed by . mg/kg nox-h or placebo i.v. at t = . hours. blood was drawn serially after endotoxin administration for measurements of infl ammatory parameters, cytokines, nox-h pharmacokinetics, total hepcidin- , and iron parameters. the diff erence of serum iron change from baseline at t = hours was defi ned as the primary endpoint. results endotoxin administration led to fl u-like symptoms. infl ammatory parameters (crp, body temperature, leucocytes, and plasma levels of tnfα, il- , il- , and il- ra) peaked markedly and similarly in both treatment groups. nox-h was well tolerated. plasma concentrations peaked at . ± . hours after the start of administration, after which they declined according to a two-compartment model, with a t / of . ± . hours. in the placebo group, serum iron increased from . ± . μg/l at baseline to a peak at t = hours, returned close to baseline at t = hours and decreased under the baseline concentration at t = hours, reaching its lowest point at t = hours. in the nox-h group, serum iron concentrations rose until t = hours and then slowly declined until t = hours. from to hours post lps, the serum iron concentrations in nox-h -treated subjects were signifi cantly higher than in placebo-treated subjects (p < . , ancova). conclusion experimental human endotoxemia induces a robust infl am matory response and a subsequent decrease in serum iron. treatment with nox-h had no eff ect on innate immunity, but eff ectively prevented the infl ammation-induced drop in serum iron concentrations. these fi ndings demonstrate the clinical potential of the anti-hepcidin drug nox-h for further development to treat patients with anemia of infl ammation. the association between haemoglobin concentrations and mortality has been studied in patients with various comorbidities [ , ] . this study aims to determine the association between haemoglobin levels on admission to intensive care and patient length of stay and mortality. methods a retrospective collection of data from patient admissions to a single fi ve-bed icu over a -year period identifi ed , patients between april and november . patients were split into groups according to haemoglobin concentration on admission. the data were analysed to determine whether there was any relationship between haemoglobin concentration at icu admission and any of our outcome measures (unit and hospital mortality, unit and hospital length of stay). results patients with haemoglobin concentrations ≤ g/dl and > . g/dl were used in mortality comparisons. patients with a haemo globin concentration ≤ g/dl had an increase in icu mortality compared with those with haemoglobin levels > g/dl (or = . , % ci = . to . , p < . ). a similar diff erence was seen with hospital mortality (≤ g/dl . % vs. > g/dl . %, p < . ). unit length of stay was signifi cantly longer in patients with admission hb ≤ g/ dl ( . days) compared with an admission hb > g/dl ( . days), p < . . hospital length of stay was also signifi cantly longer in patients with hb ≤ g/dl versus hb > g/dl ( . days vs. . days, p < . ). there was seen to be an inverse correlation between haemoglobin concentration and patient age (r = - . ; p < . ). conclusion haemoglobin concentrations ≤ g/dl on admission to the icu are associated with an increase in icu mortality, hospital mortality, unit length of stay and hospital length of stay when compared with patients admitted with haemoglobin concentrations > g/dl. introduction according to many authors, acute necrotizing pancreatitis (anp) still remains one of the diffi cult problems of abdominal surgery. the complexity of the pathogenesis of the disease, features of the pancreas pathomorphology, abdominal hypertension, and high mortality ( to %) necessitate a search for new ways to treat this disease. the study was conducted in patients with anp, who were divided into two groups according to type of analgesia: epidural or opioids. patients from the fi rst group (n = ) had epidural analgesia by ropivacaine to mg/hour during to days, and from the second group (n = ) opioid analgesia by trimeperidine mg three times a day during the same period. we monitored the level of septic and thrombohemorrhagic complications by clinical and instrumental data, during the month after treatment starting. the hemostatic system was evaluated using indicators of hemoviscoelastography (mednord- m analyzer). results it was found that all patients with anp initially have hypercoagulation and fi brinolysis inhibition. levels of hemostatic disorders correlate with the level of septic complications, treatment in the icu, and mortality. in the fi rst group we noted a deep vein thrombosis, two pneumonia, seven pseudopancreatic cysts and abscesses, two deaths and time of stay in the icu as . days. in the second group: three cases of deep vein thrombosis, four pneumonia, pseudopancreatic cysts and abscesses, two episodes of gastroduodenal bleeding, fi ve deaths and time of stay in the icu as . days. conclusion using epidural anesthesia in patients with anp reduced the number of septic complications on . %, and reduced the mortality rate from . % (second group) to . % (fi rst group). we think that violations of blood coagulation and microcirculation are the basis for ischemia, necrosis in tissues and septic complications. epidural analgesia is an eff ective method to decrease the level of septic and thrombohemorrhagic complications and mortality in anp patients. methods after ethics approval and informed consent, we studied the functional state of hemostasis in a group of healthy volunteers, who were not receiving drugs aff ecting coagulation, and patients with postphlebothrombotic syndrome (ppts). in the ppts patients we conducted baseline studies of coagulation state and daily monitoring of dynamic changes in the functional state of hemostasis, a comparative evaluation of performance low-frequency piezoelectric vibration hemoviscoelastography (lpvh) and platelet aggregation test (pat), standard coagulation tests (sct), and thromboelastogram (teg). we found that lpvh correlated with sct, pat and teg. however, our proposed method is more voluminous: indexes icc (the intensity of the contact phase of coagulation), t (the time for the contact phase of coagulation), and ao (initial rate of aggregation of blood) are consistent with pat; indexes icd (the intensity of coagulation drive), cta (a constant thrombin activity) and cp (the clot intensity of the polymerization) are consistent with sct and teg. in addition, the advantage of this method is to determine the intensity of fi brinolysiswith the indicator iris (the intensity of the retraction and clot lysis). conclusion lpvh allows one to make a total assessment of all parts of hemostasis: from initial viscosity and platelet aggregation to coagulation and lysis of clots, as well as their interaction. these fi gures are objective and informative, as evidenced by close correlation with the performance of traditional coagulation methods. prophylaxis in orthopedics or in cases of acute coronary syndromes. the main drawback of fond is that routine monitoring is not currently available. this could be a problem during the management of critical and surgical patients, especially in cases of old patients and renal failure. the aim of this study is to evaluate the ability of thromboelastography (teg) to determine the level of anticoagulation due to fond in a surgical population. we prospectively analyzed all patients to whom elective major orthopedic surgery was consecutively performed in a -month period. all the patients received fond . mg in the postoperative period according to accp guidelines. native and heparinase (hep) teg (haemoscope corporation, niles, il, usa) tests activated with kaolin were performed using whole blood citrated samples at four times: t , before fond administration; t , hours after administration; t , hours after administration (half-life); t , hours after administration. the following native and hep teg parameters were analyzed: reaction time (r), α angle, maximum amplitude (ma) and coagulation index (ci). these parameters were compared with levels of anti-xa. unvariate analysis and spearman's test were applied to our data. results eighteen patients were analyzed. ten patients met the inclusion criteria. the mean r value increased from t to t . the mean r parameter was in the normal range at any phase of the study and there was no signifi cant diff erences between the r mean value at the diff erent phases. the lowest value of r was at t , which coincides with plasmatic peak concentration of fond. this value did not correlate with anti-xa mean value at t , which showed the highest value at that time. there was signifi cant diff erence between the mean native and hep r value only at t (p < . ), native and hep α angle at t , ma and ma hep at t (p < . ) and ci and ci hep at t (p < . ). only the parameter ma had signifi cant variation over time (p < . ). conclusion r represents the time necessary to thrombin formation and in the presence of fond we hypothesized a prolonged r time. in our population, teg performed with citrated kaolin-activated whole blood was not able to detect prophylatic doses of fond in every phase. on the contrary, levels of anti-xa were able to reveal the exact pharmacokinetics of the drug. further studies including a large number of patients are necessary. introduction coagulopathy, particularly a trend toward hypercoagula bility and hypofi brinolysis, is common in critically ill patients and correlates with worse outcome. available laboratory coagulation tests to assess fi brinolysis are expensive and time demanding. we investigated whether a modifi ed thromboelastography with the plasminogen activator urokinase (ukif-teg) [ ] may be able to evaluate fi brinolysis in a population of critically ill patients. methods ukif-teg was performed as follows: fi rst urokinase was added to citrate blood to give fi nal concentrations of ui/ml, then thromboelastography (teg) analysis was started after kaolin activation and recalcifi cation with calcium chloride. basal teg (no addition of urokinase) was also performed. fibrinolysis was determined by the loss of clot strength after the maximal amplitude (ma), and recorded as ly (percentage lysis at minutes after ma) and as ly (percentage lysis at minutes after ma). results ukif-teg was performed on healthy volunteers and critically ill patients. ly was predicted by ly according to an exponential function, so we used ly as an indicator of clot lysis. basal teg showed increased coagulability and a trend toward less fi brinolysis in critically ill patients compared with healthy volunteers (reaction time . ± . minutes vs. . ± . minutes, p < . ; α-angle . ± . vs. . ± . , p < . ). this reduction of fi brinolysis was more evident at a urokinase concentration of ui/ml (figure ). conclusion ukif-teg could be a feasible point-of-care method to evaluate fi brinolysis in critically ill patients. methods we performed a randomized, double-blind study in patients who underwent cesarean section. patients were divided into two groups: the fi rst group (n = ) received preoperative ( minutes before operation) tranexamic acid mg/kg; the second group (n = ) received preoperative placebo. the condition of hemostasis was monitored by haemoviscoelastography. results all patients included in the study before surgery had moderate hypercoagulation and normal fi brinolysis: increasing the intensity of clot formation (icf) to . % compared with normal rates; the intensity of the retraction and clot lysis (ircl) was . ± . in both groups. at the start of the operation in patients (group ), icf decreased by . % (p < . ), and ircl decreased by . % (p < . ) compared with preoperatively. in group , there was icf decrease by . % (p < . ), and ircl increase by . % (p < . ) compared with preoperatively. at the end of the operation, the condition of hemostasis in both groups came almost to the same value -moderate hypocoagulation, depressed fi brinolysis. in both groups there were no thrombotic complications. intraoperative blood loss in the fi rst group was ± . and in the second was ± . . conclusion using of tranexamic acid before surgery signifi cantly reduces intraoperative blood loss by %, without thrombotic complications. introduction rotational thromboelastography (rotem) can detect dilutive and hypothermic eff ects on coagulation and evaluate corrective treatments. the aim of this in vitro study was to study whether fi brinogen concentrate alone or combined with factor xiii could reverse colloid-induced and crystalloid-induced coagulopathies in the presence and absence of hypothermia. methods citrated venous blood from healthy volunteers was diluted by % using / . hydroxyethyl starch or ringer's acetate. rotem was used to evaluate the eff ect of addition of either fi brinogen concentrate corresponding to g/ kg, or this fi brinogen dose combined with factor xiii equivalent to iu/kg. blood was analyzed at or °c with rotem extem and fibtem reagents. results a signifi cant dilutive response was shown in both groups: hypocoagulation was greater in the starch group. hypothermia lengthened the following: extem clotting time (ct), clot formation time and α angle; fibtem maximal clot formation (mcf). irrespective of temperature, fi brinogen overcorrected ringer's acetate's eff ects on all rotem parameters and partially reversed starch's eff ects on extem ct and fibtem mcf. fibtem demonstrated that factor xiii provided an additional procoagulative eff ect in the ringer's acetate group at both temperatures but not the starch group. the only extem parameter to be improved by addition of factor xiii was mcf at °c. conclusion rotem shows that fi brinogen concentrate can reverse dilutive coagulation defects induced by colloid and crystalloid at both and °c. some additional reversal was provided by factor xiii: higher doses of both fi brinogen and factor xiii may counteract starch's eff ects on clot structure. introduction natural colloid albumin induces a lesser degree of dilutional coagulopathy than synthetic colloids. fibrinogen concentrate has emerged as a promising strategy to treat coagulopathy, and factor xiii (fxiii) works synergistically with fi brinogen to correct coagulopathy following haemodilution with crystalloids. objectives were to examine the ability of fi brinogen and fxiii concentrates to reverse albumininduced dilutional coagulopathy. high and low concentrations of both fi brinogen and fxiii were used to reverse coagulopathy induced by : dilution in vitro with % albumin of blood samples from healthy volunteers, monitored by rotational thromboelastometry (rotem). results haemodilution with albumin signifi cantly attenuated extem maximum clot fi rmness (mcf), α angle (aa), clotting time (ct) and clot formation time (cft), and fibtem mcf (p < . ). following haemodilution, both doses of fi brinogen signifi cantly corrected all rotem parameters (p ≤ . ), except the lower dose did not correct aa. compared with the lower dose, the higher dose of fi brinogen signifi cantly improved fibtem mcf and extem mcf, aa and cft (p < . ). the lower dose of fxiii did not signifi cantly correct any of the rotem parameters, and the high dose only improved extem ct (p = . ). all combinations of high/low concentrations of fi brinogen/ fxiii signifi cantly improved all rotem parameters examined (p ≤ . ). fibrinogen concentration generally had a greater eff ect on each parameter than did fxiii concentration; the best correction of rotem parameters was achieved with high-dose fi brinogen concentrate and either low-dose or high-dose fxiii. conclusion fibrinogen concentrate successfully corrected initiation, propagation and clot fi rmness defi cits induced by haemodilution with albumin, and fxiii synergistically improved fi brin-based clot strength. results iocs was used in severe pphs and severe pph controls were managed without iocs. placenta accreta can be selected as the best indication for rbc restitution. in the , to , ml pph, allogeneic transfusion was decreased in the iocs group: . versus . % (p = . ); prbc: ( to ) versus ( to ) (p = . ). iocs spared blood bank prbc ( , ml); that is, . % of the total transfusion need. no amniotic fl uid embolism has been observed in the group with iocs whereas one case appeared in the control group without iocs. conclusion regarding the literature [ ] [ ] [ ] [ ] and our study, iocs could be used safely in pph during cs. a leukocyte fi lter for retransfusion has been recommended and rhesus isoimmunization must be precluded and monitored by repeated fetal rbc testing. bleeding with the use of a protamine infusion and an abolishment of heparin rebound [ ] . the aim of this study was to see whether the use of postoperative protamine infusions in our cardiac itu was associated with a reduction in heparin rebound and blood loss. methods data from cardiac surgery patients were retrospectively analysed. of these, had routine management with a bolus of protamine to correct the activated clotting time and then expectant management of subsequent bleeding, and had the same but also a protamine infusion of to mg/hour for between and hours postoperatively. blood loss was measured at , , and hours. in all, excessive bleeding was investigated using thromboelastography (teg). rebound heparinisation was determined by a ratio of r-times (heparinase/plain) < . . the mann-whitney u test and the chi-squared test were used to assess statistical signifi cance. results there was no signifi cant diff erence in blood loss between the two groups. blood loss at hour in the infusion and non-infusion group was and ml, respectively (p = . ); at hours: and ml (p = . ); at hours: and ml (p = . ); and at hours: and ml (p = . ). there was also no signifi cant diff erence in those getting heparin rebound with % in the infusion group and % in the non-infusion group (p = . ). conclusion unlike teoh and colleagues [ ] , we did not fi nd an advantage in using protamine infusions. that there were still cases of heparin rebound in the infusion group suggests that the infusion was not as eff ective as expected and/or the dose was inadequate. however, previous studies assessed heparin rebound using isolated clotting parameters [ , ] . here, we used teg. as teg measures the thrombodynamic properties of whole blood coagulation, perhaps it is a more reliable indicator of heparin activity? as a retrospective study, there are limitations; namely, the nonstandardised management of the patients and the potential bias in the anaesthetists' selection of patients for an infusion. this group may be inherently higher risk for bleeding. however, heparin rebound is common and protamine is a simple, relatively safe and low-cost intervention compared with transfusion and so further study is needed. introduction the purpose of this study was to evaluate whether a restrictive strategy of red blood cell (rbc) transfusion was superior to a liberal one for reducing mortality and severe clinical complications among patients undergoing major cancer surgery. methods the trial was designed as a phase iii, randomized, controlled, parallel-group, superiority trial. the inclusion criteria were adult patients with cancer who were undergoing major abdominal surgery requiring postoperative care in an icu. the patients were randomly allocated to treatment with either a liberal rbc transfusion strategy (transfusion when hemoglobin levels decreased below g/dl) or a restrictive rbc transfusion strategy (transfusion when hemoglobin levels decreased below g/dl). the primary outcome was a composite endpoint of death or severe complications. the patients were monitored for days. results a total of , patients were screened for eligibility and met the inclusion criteria. after exclusions for medical reasons or a lack of consent, patients were included in fi nal analysis, with allocated to the restrictive group and to the liberal group. the primary composite endpoint -all-cause mortality, cardiovascular complications, acute respiratory distress syndrome, acute kidney injury requiring renal replacement therapy, septic shock or reoperation at days -occurred in . % of the patients in the liberal strategy group and in . % in the restrictive group (p = . ). the liberal strategy group had a signifi cantly lower -day mortality rate as compared with the restrictive group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). the occurrence of cardiovascular complications was lower in the liberal group than in the restrictive group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). the restrictive strategy group had a higher day mortality rate as compared with the liberal group ( . % ( % ci, . to . %) vs. . % ( % ci, . to . %), respectively, p = . ). conclusion the liberal rbc transfusion strategy with a hemoglobin trigger of g/dl was associated with fewer major postoperative complications in patients undergoing major cancer surgery compared with the restrictive strategy. introduction red blood cell (rbc) transfusion is associated with morbidity and mortality in critically ill patients. congenital cardiac surgeries are associated with high rates of bleeding and consequently with high rates of allogeneic transfusion. we aimed to evaluate the association of transfusion with worse outcomes in children undergoing cardiac surgery. methods we performed a prospective cohort study of patients undergoing cardiac surgery for congenital heart disease. we recorded baseline characteristics, rachs- score, intraoperative data, transfusion requirement and severe postoperative complications as need for reoperation, acute kidney injury, arrhythmia, severe sepsis, septic shock, bleeding, stroke, and death during days. we performed univariate analysis using baseline, intraoperative and postoperative variables. selected variables (p < . ) were included in a forward stepwise multiple logistic regression model to identify predictive factors of a combined endpoint including -day mortality and severe complications. results one hundred and thirty-six patients ( . %) were exposed to rbc transfusion. in the intraoperative room, . % of patients received at least one rbc unit, and in the icu, . % of children were transfused. from all patients, ( . %) presented the combined endpoint. patients with complications had higher rachs- score, were younger ( months ( to ) vs. months ( to ), p < . ), had a lower weight ( kg ( to ) vs. kg ( to ), p < . ), a longer time of surgery ( minutes ( to ) vs. ( to ), p < . ), a longer duration of cardiopulmonary bypass ( minutes ( to ) vs. minutes ( to ), p = . ), a lower svo at the end of surgery ( % (iqr to ) vs. % ( to ), p < . ), a higher arterial lactate at the end of surgery ( . mmol/l ( . to . ) vs. . mmol/l ( to ), p = . ), a lower intraoperative hematocrit ( . ± . % vs. . ± % (p < . )) and a lower hematocrit at the end of surgery ( . ± . % vs. . ± . % (p < . )) as compared with patients without complications. patients with complications were more exposed to rbc transfusion in the intraoperative room ( % vs. %, p = . ) and in the icu ( % vs. . %, p = . ). in an adjusted model of logistic regression, rbc transfusion is an independent risk factor of combined endpoint (or . ( % ci, . to . ), p = . ). conclusion blood transfusion after pediatric cardiac surgery is a risk factor for worse outcome including -day mortality. avoiding blood transfusion must be a goal of best postoperative care. introduction we do not have enough criteria to make a judgment of the need for a massive transfusion (mt) in severe blunt traumatic patients. as a scoring system to predict the need for a mt, we usually use the assessment blood consumption score (abcs) and/or the trauma-associated severe hemorrhage score (tashs). however, for these scoring systems, the procedure is slightly complicated. the aim of this study was to establish a predictor of a mt using coagulation or fi brinolysis markers. methods a retrospective analysis of mt was conducted in patients with severe blunt traumatic injury, which was defi ned as injury severity score (iss) of or more admitted to the icu between june and december . blood samples were collected from patients immediately after arriving at our level i trauma center. we defi ned the patients who received more than unit packed red blood cells (prbcs) within the fi rst hours as a mt group and who received less than units prbcs as a non-mt group. after the demographic data, number of units of prbcs and the need for massive transfusions were recorded and analyzed in each groups, we compared data between two groups. results there were patients who met the inclusion criteria. fifty patients received blood transfusions ( . %; / ). there were patients in the mt group ( . %; / ) and in the non-mt group. the mt group was signifi cantly higher in the ratio of females (p < . ), iss (p < . ), pt-inr (p < . ), aptt (p < . ), abcs (p < . ) and tashs (p < . ) than in the on-mt group. on the other hand, the mt group was signifi cantly lower in ps (p < . ) and fi brinogen level (p < . ) than the non-mt group. in the receiver operating characteristics (roc) analysis, the area under the curve (auc) to distinguish a mt was the highest for tashs ( . , p < . ), followed by fi brinogen ( . , p < . ), and abcs ( . , p < . ). fibrinogen was only a predictor of a mt without a scoring system such as abcs and tashs, and the optimal cutoff value was mg/dl. conclusion we found that the level of fi brinogen was the most valuable predictor of a mt in the coagulation or fi brinolysis markers. it is certain that the level of fi brinogen at admission was not as useful as the tashs about predicting a mt in this study. whereas the scoring systems require the assessment of several factors, the measurement of fi brinogen is simple, easy and quick. we strongly suggest that the level of fi brinogen will be a useful predictor of a mt at in severe blunt traumatic patients. introduction red blood cell (rbc) transfusions are frequent in critically ill children. their benefi ts are clear in several situations. however, issues surrounding their safety have emerged in the past decades. it is important to identify the potential complications associated with rbc transfusions, in order to evaluate their risk-benefi t ratio better. methods a single-center prospective observational study of all children admitted to the pediatric intensive care unit (picu) over a -year period. the variables possibly related to rbc transfusions were identifi ed before the study was initiated, and their presence was assessed daily for each child. in transfused cases (tcs), a variable was considered as a possible outcome related to the transfusion only if it was observed after the fi rst transfusion. results during the study period, admissions were documented, of which were included in the study. among them, ( %) were transfused. when comparing tcs with nontransfused cases (ntcs), the odds ratio (or) of new or progressive multiple organ dysfunction syndrome (npmods) was . ( % ci = . to . , p < . ). this association remained statistically signifi cant in the multivariate analysis for children with admission prism score ≤ (or = . , % ci = . to . , p = . ). tcs were ventilated longer than ntcs ( . ± . days vs. . ± . days, p < . ). this diff erence was still signifi cant after adjustment using a cox model. moreover, we observed an adjusted dose-eff ect relationship between rbc transfusions and length of mechanical ventilation. the picu length of stay was signifi cantly increased for tcs ( . ± . days vs. . ± . days, p < . ), even after multivariate adjustment (hazard ratio of picu discharge for tcs: . , % ci = . to . , p < . ). we also observed an adjusted dose-eff ect relationship between rbc transfusions and picu length of stay. the paired analysis for comparison of pre-transfusion and posttransfusion values showed that the arterial partial pressure in oxygen was signifi cantly reduced after the fi rst transfusion (mean diff erence . mmhg, % ci = . to . , p < . ). the paired analysis also showed an increased proportion of renal replacement therapy, while the proportions of sepsis, severe sepsis and septic shock did not diff er. conclusion rbc transfusions were associated with prolonged mechanical ventilation and prolonged picu stay. the risk of npmods was increased in some transfused children. moreover, our study questions the ability of stored rbcs to improve oxygenation in critically ill children. these results should help to improve transfusion practice in the picu. introduction microcirculatory alterations during sepsis impair tissue oxygenation, which may be further worsened by anemia. blood transfusions proved not to restore o delivery during sepsis [ ] . the impact of storage lesions and/or leukocyte-derived mediators in red blood cell (rbc) units has not yet been clarifi ed [ ] . we compared the eff ects of leukoreduced (lr) versus nonlr packed rbcs on microcirculation and tissue oxygenation during sepsis. methods a prospective randomized study. twenty patients with either sepsis, severe sepsis or septic shock requiring rbc transfusion randomly received nonlr (group , n = ) or lr (group , n = ) fresh rbcs (< days old). before and hour after transfusion, microvascular density and fl ow were assessed with sidestream dark-fi eld imaging sublingually. thenar tissue o saturation (sto ) was measured using near-infrared spectroscopy and a vascular occlusion test was performed. results the de backer score (p = . ), total vessel density (p = . ), perfused vessel density (p = . ), proportion of perfused vessels (p = . ), and microvascular fl ow index (p = . , figure ) increased only in group . the sto upslope (figure ) during reperfusion increased in both groups (p < . ). in group the baseline sto and sto downslope during ischemia increased, probably refl ecting a lower o consumption. conclusion unlike nonlr rbcs, the transfusion of fresh lr rbcs seems to improve microvascular perfusion and might help to restore tissue oxygenation during sepsis. introduction obstetric haemorrhage remains a leading cause of maternal mortality and severe morbidity. cardiovascular and haemostatic physiology alters in pregnancy and massive transfusion protocols have been implemented for obstetric haemorrhage based on limited evidence. the objective of this study was to examine the pattern and rate of blood products used in massive transfusion for obstetric haemorrhage in a tertiary obstetric hospital. methods massive transfusion was defi ned as or more units of red blood cells within hours in accordance with the australian massive transfusion registry defi nition. following ethics approval, all cases fi lling this criterion were identifi ed in the hospital's birthing and blood bank systems. data were extracted from the medical histories and analysed using spss. p < . was considered statistically signifi cant. results twenty-eight women in three years ( to ) underwent a massive transfusion for obstetric haemorrhage, with nine receiving more than units of rbcs in hours. eleven ( %) were admitted to the icu and underwent a hysterectomy, of which six were admitted to the icu. the median estimated blood loss was , ml (iqr , to , ). median blood product delivery was rbc units (iqr to ); ffp units (iqr to ); platelets units (iqr to ) and cryoprecipitate units (iqr to ). one-half of the women received the fi rst four units of rbcs in less than minutes. other blood products were started a median of minutes, minutes and minutes after the rbc transfusion commenced, respectively. eight women had a fi brinogen level < . g/l on the initial coagulation test during the haemorrhage. the remaining women had a median fi brinogen level of . g/l (iqr . to . ). there was no diff erence in the transfusion of rbcs (p = . ), ffps (p = . ) and platelets (p = . ) in women who showed an initial low fi brinogen and those who did not, although there was a diff erence in the number of units of cryoprecipitate (p < . ). the median lowest hb during the haemorrhage was g/l (iqr to ) and median discharge hb was g/l (iqr to ). no blood product reaction was noted and there was one death. conclusion massive transfusion for obstetric haemorrhage involved rapid blood product administration with no consistent pattern in the ratio of products administered. introduction blood transfusions are associated with longer icu and hospital inpatient durations, and an increase in mortality [ ] . this study was undertaken to investigate whether the practice of packed red cell critical care , volume suppl http://ccforum.com/supplements/ /s s (prc) transfusions in the icu was in accordance with the best clinical evidence. a number of studies, most notably the tricc study [ ] , have shown that indications for icu blood transfusions are a haemoglobin (hb) level of < g/dl or evidence of acute haemorrhage [ ] . these criteria were therefore employed. methods this study prospectively examined episodes of prc unit transfusions over a -month period in the icu of a large level trauma centre and a tertiary cardiac unit. the number of prc units transfused in each episode was recorded by nurses, along with the proposed indication and concurrent hb level. the data were analysed to assess the number of transfusions administered contrary to the guidelines, along with the average hb level at which a prc unit was transfused and the average number of units administered per episode. results a total units of prc were transfused in the icu, over episodes during the -month period (excluding immediately postoperative transfusions). ninety-four units ( . %) administered in transfusion episodes ( . %) occurred contrary to the guidelines. in . % of these cases the recorded reason for transfusion was an apparently low hb level. the median (iqr (range)) hb level at which patients were transfused: within guidelines was . g/dl ( . to . ( . to . )); within guidelines, excluding cases of acute blood loss, was . g/dl ( . to . ( . to . )); and outside the guidelines was . g/dl ( . to . ( . to . )). one unit of prc was transfused in episodes ( . %), units of prc were transfused in episodes ( . %), and to units were transfused in episodes ( . %), with two-thirds of the latter due to acute haemorrhage. our results indicate a liberal transfusion threshold currently exists in the icu. patients are frequently receiving excessive prc transfusions for hb levels above the recommended concentration. in the -month study period, these were associated with a cost of approximately £ , . we recommend increased staff awareness of the guidelines to reduce the number of unnecessary transfusions. this would decrease exposure of icu patients to unnecessary risks of blood transfusion, reduce cost of treatment and help to preserve a valuable resource. introduction transfusion-related acute lung injury (trali) has a high incidence in critically ill and surgical patients and contributes to adverse outcome, while specifi c therapy is absent. recently it was demonstrated that complement activation plays a pivotal role in trali. we aimed to determine whether a c inhibitor is benefi cial in a two-hit mouse model of antibody-mediated trali. methods balb/c mice were primed with lipopolysaccharide (lps, from e. coli :b ) that was administered intraperitoneally in a dose of . mg/kg, after which trali was induced by injecting mhc-i antibody against h kd (igg a,k) at a dose of mg/kg. mice infused with pbs or lps served as controls. concomitantly, mice infused with the mhc-i antibody were treated with c inhibitor (cetor®; sanquin, amsterdam, the netherlands) in a dose of iu/kg intravenously. after infusion, mice were mechanically ventilated with a lung-protective pressurecontrolled mode for hours and then sacrifi ced, after which a bronchoalveolar lavage (bal) was done. statistics were analyzed by one-way anova, values expressed as mean and standard deviation. results injection of lps and mhc-i antibodies resulted in trali, indicated by increased levels of protein in the bal fl uid, wet/dry ratios and levels of kc, mip- and il- . c inhibitor cetor® signifi cantly reduced total protein in bal fl uid from ( ) to ( ) μg/ml (p < . ) and tended to reduce the wet/dry ratio from . ± . to . ± . (p = . ). cetor® also reduced balf levels of mip- from ( ) to ( ) pg/ml (p < . ). kc and il- levels were not aff ected. conclusion in a model of antibody-mediated trali, c inhibitor attenuated pulmonary infl ammation. c inhibition may be a potential benefi cial intervention in trali. introduction transfusion-related acute lung injury (trali) is a syndrome that presents as a sudden onset of respiratory distress hours after transfusion of blood products. the diagnosis is based on clinical and radiographic fi ndings. particularly at risk for trali are cardiac surgery patients. however, specifi c patient risk factors and data on outcome are largely unknown. the aim of this study was to investigate incidence, risk factors and outcome of trali in cardiac surgical patients on cardiopulmonary bypass. methods all thoracic surgery patients from a university hospital in the netherlands of years and older admitted to the icu from january until december were screened. included patients were observed during surgery and the fi rst hours on the icu for the onset of possible trali. the canadian consensus conference trali defi nition was used. two independent physicians blinded to the predictor variables scored the chest radiographs for the onset of bilateral interstitial abnormalities on k monitors. when interpretation diff ered, chest radiographs were reviewed by a third physician to achieve consensus. the european system for cardiac operative risk evaluation (euro score) and the american association of anesthesiology (asa) were scored before surgery. by calculating the acute physiology and chronic health evaluation (apache) ii and iv scores the severity of illness was determined on arrival in the icu. in total, , cardiac surgical patients were included. a total of ( . %) patients developed trali within hours following surgery. patients developing trali were older compared with patients not developing trali, mean age respectively and years (p = . ). furthermore, patients developing trali had higher apache ii, apache iv, euro and asa score (p = . , p = . , p = . and p = . introduction volume resuscitation is essential to restore normovolemia during hemorrhagic shock, burns and sepsis. however, synthetic colloids cause dilutional coagulopathy. the aims were to determine whether the natural colloid albumin induces a lesser degree of coagulopathy compared with synthetic colloids, and the comparative eff ectiveness of fi brinogen concentrate to reverse coagulopathy following dilution with these solutions. methods rotational thromboelastometry-based tests were used to examine coagulation parameters in samples from healthy volunteers, in undiluted blood and samples diluted : with saline, was seen for samples diluted with synthetic colloids (p < . ) but not albumin (p = . ). following addition of fi brinogen, fibtem mcf, extem mcf and extem aa were signifi cantly higher, and extem cft was signifi cantly shorter in samples diluted with albumin versus those treated with hes or dextran (p ≤ . ). conclusion hemodilution using albumin induced a lesser degree of coagulopathy compared with the synthetic colloids hes and dextran. in addition, albumin-induced coagulopathy was more eff ectively reversed following addition of fi brinogen concentrate compared with coagulopathy induced by synthetic colloids. comparative assessment of the diff erent fl uid modalities is hampered by a paucity of direct trials. we present a network meta-analysis for assessing the relative eff ectiveness of two fl uid treatments in sepsis when they have not been compared directly in a randomized trial but have each been compared with a common treatment. methods a systematic review of trials sepsis yielded trials for assessment in network meta-analysis. the indirect comparison between albumin, hes and crystalloid was conducted using bayesian methods for binomial likelihood, fi xed-eff ects network meta-analysis with a monte carlo gibbs sampling method. studies in septic patients with crystalloid as a reference treatment compared with any formulation of the colloid treatments albumin or hes were included, as were direct head-to-head trials between the two colloids. results odds ratios between the diff erent treatments were obtained ( figure ). ranking the interventions [ ] demonstrated that albumin ranked highest in lowering mortality at a . % probability compared with . % and . % for crystalloid and hes, respectively. conclusion albumin as a fl uid therapy in sepsis is associated with the lowest mortality of the three modalities studied. (sap), sv and co were recorded directly before the administration of any colloid (t ) and every minutes for the next hour (t to t ). kolmogorov-smirnov was used to test normal distribution of data and anova was used for the statistical analysis. p < . was considered statistically signifi cant. results demographic data and asa classifi cation did not diff er statistically signifi cant among the six groups of the study. co, sv, hr and sap did not show any statistically signifi cant evolution compared with their baseline value during the study period. moreover, there were no statistically signifi cant diff erences among the six study groups with regard to any of the recorded parameters. conclusion according to our results, volume replacement with the six colloids tested in our study did not result in any hemodynamic response. within comparison of these six colloids did not reveal any statistically signifi cant diff erence in any of the parameters recorded according to our protocol. the biochemical characteristics of infused fl uids may be important in regulating acid-base balance, by modifying plasmatic volume and strong ion diff erence. in vitro and animal studies [ , ] have shown that volume and strong ion diff erence of infused fl uids (sidin) as well as the arterial baseline bicarbonate concentration (hco -a) infl uence acid-base variations. our aim was to verify these changes in critically ill patients after surgery. methods an electronic-dedicated database was created to retrospectively collect volume, type of fl uids infused and plasmatic acidbase balance variations in postoperative icu patients from admission to : am of the day after. sidin was calculated as the average sid of all fl uids infused during the whole study period (crystalloids, colloids and blood products). arterial base excess variation (Δbea) was computed as the diff erence between values at : am on the day after and those at entry. we report data from all patients admitted in and ( patients). results nine patients not receiving intravenous infusions were excluded. the remaining population was divided into three groups according to sidin distribution (group , ± ; group , ± ; group , ± meq/l). we observed a progressive increment in Δbea between the groups ( . ± . vs. . ± . vs. . ± . mmol/l, p < . ). we further subdivided each group by the median value of baseline hco -a ( . ( . to . ) mmol/l) and we analyzed the Δbea: we observed a greater increase in patients with lower baseline hco -a (group , . ± . vs. . ± . , mmol/l, p < . ; group , . ± . vs. . ± . , mmol/l, p < . ; group , . ± . vs. . ± . mmol/l, p < . ), as compared with those with higher baseline levels. when the study population was divided into quartiles of the diff erence between sidin and hco -a, Δbea appeared to increase with the rise of such diff erence (p < . ). conclusion sidin aff ects the acid-base status per se and in relationship with hco -a. we verifi ed this hypothesis in critically ill patients, highlighting the importance of the diff erence between sidin and hco -a, which better describes and predicts the acid-base modifi cations to fl uid therapy. introduction fluid resuscitation should improve tissue oxygenation in hypovolemia, besides restoring macrohemodynamic stability [ ] . we evaluated the microvascular response to fl uid challenge with diff erent colloid solutions and its relation to macrohemodynamics. methods an observational study of patients receiving a fl uid challenge ( ml colloids in minutes) according to the attending physician's decision. before and after the infusion, sublingual microcirculation was evaluated with sidestream dark-fi eld imaging (microscan; microvision medical, amsterdam, the netherlands). microvascular fl ow and density were assessed for small vessels [ ] . the cardiac index (ci), intrathoracic blood volume index (itbvi) and extravascular lung water index (elwi) were measured in seven patients with picco (pulsion medical system, munich, germany). results ten patients (two sepsis, four trauma, three intracranial bleeding, one post surgery) received either saline-based hydroxyethyl starch (hes) / . (amidolite®; b.braunspa; n = ) or balanced hes / . (tetraspan®; b.braunspa; n = ). the ci (p = . ) and itbvi (p = . ) tended to increase, the evlwi did not change. microvascular fl ow and density improved in the whole sample. no correlation was found between macro-circulatory and micro-circulatory parameters. balanced hes led to a greater increase in capillary density than nacl hes (figure ). conclusion balanced hes may be more effi cacious than saline-based hes in recruiting the microcirculation, thereby improving tissue o delivery. introduction are safety guidelines being followed when administering procedural sedation in the emergency department? between november and november , the npsa received alerts of patients being given the wrong dose of midazolam for procedural sedation [ ] . in the fi rst years of midazolam use there were deaths, most related to procedural sedation [ ] . methods we searched through the controlled drugs book in resuscitation over a -month period and found a list of patients who had received midazolam or fentanyl. from this, we could make a search for the relevant a and e notes for these patients. from these notes, we looked for (see shorthand in table ): verbal consent documentation (consent), past medical history recorded (pmhx), safe initial dose of midazolam (midaz), pre-procedure monitoring (pre), post-procedure monitoring (post), and monitoring for hour before discharge ( hr). following introduction of a reminder in the controlled drugs book/ sedation room and staff education, the case notes were analysed over another -month period ( sets of notes) to assess practise against safety guidelines. results see table (key for shorthand in methods). conclusion the re-audit notices within the procedural sedation room and controlled drug book front cover served as a reminder of good practise. the visibility of this reminder (within the cd book) helped ensure better adherence to the audit standard. this reminder will now be kept within the cd book. introduction daily sedation interruption and protocol implementation have been recommended to reduce excessive sedation; however, their use has been inconsistent. we hypothesized that the use of an age, kidney and liver function adjusted sedation protocol would be associated with reduced doses and improved outcomes compared with a standard protocol. methods this was a prospective cohort study comparing months of a standard protocol (control group) with months of an adjusted protocol (intervention group). in the adjusted protocol, patients were divided into three categories: category (age < years, and normal kidney and liver function), category (age = to years, or moderate kidney or liver function impairment), and category (age > years, or severe kidney or liver function impairment). the upper limits of analgesics and sedatives doses were determined by age, and kidney and liver function, being lowest in category , and lower in category than category . all consecutive adults mechanically ventilated patients who required infusion of analgesics and/or sedatives for > hours were included in the study. we compared the main outcomes of both groups including average daily doses of analgesics and sedatives; average sedation-agitation scale (sas), pain and gcs scores; mechanical ventilation duration (mvd); sedation-related complications during icu stay; icu and hospital length of stay (los), and icu and hospital mortality. results two hundred and four patients were included in the study (control group = ; adjusted protocol group = ). there was no diff erence in baseline characteristics between the two groups. the adjusted protocol group, compared with the control group, received signifi cantly lower average daily doses of fentanyl ( , ± , μg vs. , ± , μg, p = . ), nonsignifi cant lower average daily doses of midazolam and dexmedetomidine, and a trend toward higher average daily doses of propofol. pain score was higher in the adjusted protocol group ( . ± . vs. . ± . , p < . ) with no diff erence in sas or gcs scores. sedation-related complications during icu stay were not diff erent between the two groups; however, agitation (sas = ) was less frequent in the adjusted protocol group ( % vs. %, p < . ). icu mortality was signifi cantly lower in the introduction the aim of this research was to provide clinically relevant evidence for y-site compatibility of drug infusion combinations used in the picu. pharmacists and clinicians regularly have to interpret limited published data, particularly when more than two drugs are y-sited. the risk of potential incompatibility must be balanced against that of additional line insertion. methods a full -factorial design (total combinations) was used to investigate chemical and physical compatibility of fi ve drugs (clonidine, morphine, ketamine, midazolam and furosemide). the drugs were studied at their highest commonly infused concentrations and exposed to three variations in environmental conditions (diluent: sodium chloride . % or glucose %; temperature or °c; and normal room lighting or blue light phototherapy). chemical stability was assessed using hplc; > % reduction in concentration indicated incompatibility. physical incompatibility was confi rmed by precipitation, ph or colour change. results environmental conditions had no eff ect on the drug mixtures. the precipitation observed in incompatible combinations was due to either a change in ph, or with ketamine the presence of benzethonium chloride. of possible drug combinations, were incompatible. a further three combinations were incompatible at extreme ph, or were of concern and so should be avoided. the incompatible formulations all contained furosemide. all combinations of the sedative agents studied were chemically and physically compatible. conclusion this work provides evidence for y-site compatibility of morphine, midazolam, clonidine and ketamine in any combination, which will potentially reduce the need for extra intravenous lines. furosemide is incompatible with any of these sedative drugs and must be infused via a separate line. these results will aid clinical decisionmaking and help satisfy the requirements of recent uk department of health legislation relating to the mixing of medicines. reference introduction in light of the interest in the relationship between glycemia control in critically ill subjects and outcome, we set up a study to investigate whether benzodiazepine, commonly used in anesthesia and icus, interferes with glucose metabolism and to explore the mechanism. methods a total of sedated and paralyzed sprague-dawley rats ( ± g) were investigated in four consecutive studies. ( ) to investigate the eff ects of diazepam on blood glucose, rats were randomly assigned to intraperitoneal anesthesia with tiopenthal mg/kg (dzp ), tiopenthal mg/kg + diazepam mg/kg (dpz ) or tiopenthal mg/kg + diazepam mg/kg (dzp ). blood levels of glucose (gem premier ; il) were measured at time intervals over hours. ( ) ten animals randomized to dzp or dzp underwent an intravenous glucose tolerance test with glucose bolus ( . g/kg). acute insulin response, the mean value of blood insulin (insulin elisa kit; millipore) from to minutes after glucose bolus, was measured as index of insulin secretion. ( ) a hyperinsulinemic euglycemic clamp obtained by a continuous intravenous infusion of insulin ( mui/ kg/minute) was run in animals randomized to dzp or dzp and the glucose infusion rate (gir, mg/kg/minute) was assessed [ ] . ( ) introduction we report our experience in the use of isofl urane for prolonged sedation in severe ards patients. prolonged sedation in the icu may be diffi cult because of tolerance, drug dependence and withdrawal, drug interactions and side eff ects. inhaled anesthetics have been proposed for sedation in ventilator-dependent icu patients. anaconda is a device that allows a safety and easy administration of inhaled anesthetics in the icu. methods from january to june , patients were sedated with isofl urane by means of the anaconda device. we consider administration of isofl urane as a washout period from common sedative drugs in patients with (at least one of ): high sedative drug dosage (propofol ≥ mg/hour or midazolam ≥ mg/hour) to reach the target richmond agitation sedation score (rass) or inadequate paralysis; two or more hypnotic drugs to reach the target rass (propofol, midazolam, hydroxyzine, haloperidol, diazepam, quetiapine); and hypertriglyceridemia. during isofl urane administration previous hypnotic drugs were interrupted. we retrospectively collected data before, during and after administration of isofl urane: hemodynamic parameters, renal and hepatic function, level of sedation (rass) and sedative drug dosage. all data are reported as mean ± standard deviation, otherwise as median (minimum to maximum). results mean age was ± years and saps ii was . ± ; patients were treated with ecmo for severe ards and four had a history of drug abuse; median icu length of stay was ( to ) days and they were ventilated for ( to ) days. due to severe critical illness, target rass was - for all patients, most of which were also paralysed. isofl urane was administered in nine patients because of a high level of common sedative drugs, in fi ve patients due to the use of two or more hypnotic drugs and in one patient because of hypertrigliceridemia. isofl urane administration lasted . ± . days. during isofl urane administration no alteration in renal function or hemodynamic instability was recorded. after the isofl urane washout period we observed a reduction in sedative drug dosage in patients while two patients were quickly weaned from mechanical ventilation and the target rass raised to . in two patients isofl urane was precautionarily interrupted because of concomitant alteration of liver function and suspected seizures respectively. conclusion inhaled anesthetics could be successfully used in the icu especially in case of an inadequate sedation plan; for example, in patients with a history of drug abuse or young severe ards patients that required deep sedation and paralysis for a long period. introduction pharmacological agents used to treat critically ill patients may alter mitochondrial function. the aim of the present study was to investigate whether fentanyl, a commonly used analgesic drug, interacts with hepatic mitochondrial function. methods the human hepatoma cell line hepg was exposed to fentanyl at . , or ng/ml for hour, or pretreated with naloxone (an opioid receptor antagonist) at ng/ml or -hydroxydecanoate ( -hd; a specifi c inhibitor of mitochondrial atp-sensitive k + (katp) channels) at μm for minutes, followed by incubation with fentanyl at ng/ml for an additional hour. the mitochondrial complex i-dependent, ii-dependent and iv-dependent oxygen consumption rates of the permeabilized cells were measured using a high-resolution oxygraph (oxygraph- k; oroboros instruments, innsbruck, austria). the respiratory electron transfer capacity of intact cells was evaluated using fccp (carbonyl cyanide p-trifl uoromethoxyphenylhydrazone) to obtain the maximum fl ux. results incubation of hepg cells with fentanyl ( hour, ng/ml) induced a reduction in complex ii-dependent and iv-dependent respiration ( figure ). cells pretreated with -hd before the addition of fentanyl exhibited no signifi cant changes in complex activities in comparison with controls. pretreatment with naloxone tended to abolish the fentanyl-induced mitochondrial dysfunction. treatment with fentanyl led to a reduction in cellular atp content ( . ± . in controls vs. . ± . μmol/mg cellular protein in stimulated cells; p = . ). we did not observe any diff erence in basal or fccp-uncoupled respiration rates of cells treated with fentanyl at ng/ml compared with controls (data not shown). conclusion fentanyl reduces cultured human hepatocyte mitochondrial respiration by a mechanism that is blocked by a katp channel antagonist. in contrast, antagonism with naloxone does not seem to completely abolish the eff ect of fentanyl. introduction endothelial dysfunction during endotoxemia is responsible for the functional breakdown of microvascular perfusion and microvessel permeability. the cholinergic anti-infl ammatory pathway (cap) is a neurophysiological mechanism that regulates the infl ammatory response by inhibiting proinfl ammatory cytokine synthesis, thereby preventing tissue damage. endotoxemia-induced microcirculatory dysfunction can be reduced by cholinergic cap activation. clonidine improves survival in experimental sepsis [ ] by reducing the sympathetic tone, resulting in the parasympatheticmediated cap activation. the aim of this study was to determine the eff ects of clonidine on microcirculatory alterations during endotoxemia. methods using fl uorescent intravital microscopy, we determined the venular wall shear rate, macromolecular effl ux and leukocyte adhesion in mesenteric postcapillary venules of male wistar rats. endotoxemia was induced over minutes by intravenous infusion of lipopolysaccharide (lps). control groups received an equivalent volume of saline. clonidine μg/kg was applied as i.v. bolus in treatment groups. animals received either (i) saline alone, (ii) clonidine minutes prior to saline administration, (iii) clonidine minutes prior to lps administration, (iv) clonidine minutes prior to lps administration, (v) clonidine minutes after lps administration or (vi) lps alone. results all lps groups (iii to vi) showed a signifi cantly reduced venular wall shear rate compared with the saline group after minutes. there were no signifi cant diff erences between the numbers of adhering leukocytes in the clonidine/lps groups (iii, iv, v) and the lps group after minutes. macromolecular effl ux signifi cantly increased in all groups over the time period of minutes. after minutes there was no diff erence between the lps group and the clonidine minutes prior to lps administration group (iv) whereas all other groups (i, ii, iii, v) showed a signifi cantly reduced macromolecular effl ux compared with the lps group. conclusion clonidine has no positive eff ect on microhemodynamic alterations and leukocyte-endothelial interaction during endotoxemia. the reduction of capillary leakage in clonidine-treated groups depends on the time interval relative to the initiation of endotoxemia. endothelial permeability and leukocyte activation are regulated by diff erent pathways when stimulated by clonidine during endotoxemia. we conclude that clonidine might have an important time-dependent anti-infl ammatory and protective eff ect on endothelial activation during infl ammation. introduction delivering analgesics via conjunctival application could provide rapid and convenient pain relief in disaster medicine. there are sporadic reports from the usa concerning inhalation administration of aerosol with various drugs producing a wide variety of eff ects from anxiolysis, sedation, and loss of aggressiveness to immobilisation. we attempted to determine in an animal experiment whether conjunctival administration of s+ketamine could produce signifi cant eff ect without side eff ects. methods after ethic committee approval, rabbits were administered conjunctival s+ketamine . mg/kg. measured parameters were spo , blood pressure (bp) and heart rate (hr) before administration and in -minute intervals and immobilisation time (loss of righting refl ex [ ] . we can speculate that the reason for stability of cardiorespiratory parameters was due to the sympathoadrenergic eff ect of ketamine or due to the method of administration. there were no signs of conjunctival irritation in any animal (s+ketamine is a preservative-free solution). conclusion conjunctival s+ketamine . mg/kg in rabbits produced rapid onset without changes in cardiorespiratory parameters and without signs of irritation of the eye. the results of our project warrant further research to increase the variety of drugs and methods of their administration for anxiolysis, sedation and analgesia in disaster medicine. introduction procedural sedation is used in the emergency department (ed) to facilitate short but painful interventions. many patients are suitable for discharge after completion. ideally, the agent used to achieve sedation should not have a prolonged eff ect, allowing safe discharge in the shortest time frame. we hypothesised that propofol, with its short onset and off set, may reduce length of stay (los) in comparison with traditional benzodiazepines. methods data from a prospective registry were analysed for the period august to january . patients who underwent procedural sedation and who were discharged from the ed were identifi ed. individuals were grouped as having received propofol, midazolam or a combination of the two. all were discharged when fully alert and able to eat and drink. demographic details and the type of procedure undertaken were extracted. anova was performed to identify diff erences in the length of stay between groups, in addition to descriptive analysis. results during the study period patients underwent procedural sedation and were discharged from the ed. the median age was years and % were male. the commonest procedure performed was shoulder reduction ( %). in the propofol group (n = ) the mean los was minutes compared with minutes in those receiving midazolam (n = ) and minutes in those receiving a combination (n = ), p = . . there was no diff erence in adverse events between groups. see figure . conclusion propofol is increasingly used in eds for procedural sedation due to its short duration of action. this study suggests that a shorter duration of action and faster recovery may result in a reduced los in the ed. the use of propofol for sedation in intensive care has been associated with the propofol infusion syndrome (pris) characterised by cardiac dysfunction, metabolic acidosis, renal failure, rhabdomyolysis and hyperlipidaemia. we prospectively monitor biochemical markers that we believe demonstrate early signs of this dangerous, often fatal syndrome. when this pre-pris state is identifi ed, propofol is withdrawn whilst the syndrome is still reversible. methods we prospectively audited our monitoring of these markers over a -month period in propofol-sedated patients: propofol infusion rate, creatine kinase (ck), triglycerides (tg), creatinine, lactate, ph and base defi cit. we defi ned the criteria for pre-pris as requiring a ck ≥ mmol/l that had doubled from its base level and a rise in tg ≥ . iu/l; both that followed a trend with propofol dose. conclusion we propose that a paired rise in ck and tg that can be attributed to propofol alone represents a pre-pris state that is at risk of developing into full pris. we noted this in % of our patients, all on modest doses of propofol. it is unclear what proportion of patients will develop the full syndrome as it is not ethically possible to continue propofol in this situation. we advocate daily monitoring of ck and tg to identify pre-pris so that propofol can be reduced or substituted to avoid the morbidity and mortality of the full syndrome. introduction until recently there were no guidelines for the reporting of adverse events (aes) during procedural sedation [ , ] . a consensus document released in by the world siva international sedation task force proposed a benchmark for defi ning aes [ ] . we analysed , cases of procedural sedation in the emergency department. methods the study is based on , patients who received procedural sedation with propofol in the emergency department between december and march . patients were selected and sedated to a strict protocol by ed consultant staff . we applied the ae tool by performing a search through patient records, discussion with consultants performing the sedation and consensus opinion. results from , cases we identifi ed sentinel (six of hypotension, fi ve cases of hypoxia), moderate, minor and three minimal risk adverse events. the study shows a % adverse event rate. this supports use of propofol sedation by emergency physicians but within the limits of a strict governance framework. our safety analysis using the world siva adverse events tool provides a reference point for further studies. introduction physical restraints are used to facilitate essential care and prevent secondary injuries. however, physical restraint may be regarded as humiliating. it may lead to local injury and increase the risk of delirium and post-traumatic stress syndrome. research on physical restraint is scarce. the aim of this study is to investigate the scope of physical restraint use. methods twenty-one icus ranging from local hospitals to academic centres were each visited twice and patients were included. we recorded characteristics of restrained patients, motives and awareness of nurses and physicians. results physical restraint was applied in ( %) patients, ranging from to % in diff erent hospitals. frequent motives for restraint use were 'possible threat to airway' ( %) and 'pulling lines/probes' ( %). restrained subjects more often had a positive cam-icu ( % vs. %, p < . ), could less frequently verbally communicate ( % vs. %, p < . ), and received more often antipsychotics ( % vs. %, p < . ), or benzodiazepines ( % vs. %, p = . ). the use of physical restraint was registered in the patient's fi les in % of cases. of the interviewed nurses, ( %) were familiar with a physical restraint protocol and ( %) used it in any situation. thirty percent of the interviewed physicians were aware of the physical restraint status of their patients. conclusion physical restraint is frequently used in dutch icus, but the frequency diff ers strongly between diff erent icus. attending physicians are often not aware of physical restraint use. introduction physical restraint (pr) use in critically ill patients has been associated with delirium, unplanned extubation, prolonged icu length of stay, and post-traumatic stress disorder. our objectives were to defi ne prevalence of pr use, and to examine patient, treatment, or institutional factors associated with their use in canadian icus. measures aimed at delirium prevention (psychohygiene and early mobilization) were carried only in a small minority or were not documented. to implement protocolled delirium care in the region at study, a multifaceted tailored implementation program is needed. introduction the objective of this study is to investigate the eff ect of intraoperative administration of dexamethasone versus placebo on the incidence of delirium in the fi rst four postoperative days after cardiac surgery. methods within the context of the large multicenter dexamethasone for cardiac surgery (decs) trial [ ] for which patients were randomized to mg/kg dexamethasone or placebo at induction of anesthesia, a monocenter substudy was conducted. the primary outcome of this study was the incidence of delirium in the fi rst four postoperative days. secondary outcomes were duration of delirium, use of restrictive measures and sedative, antipsychotic and analgesic requirements. delirium was assessed daily by trained research personnel, using the richmond agitation sedation scale and the confusion assessment method. medical, nursing and medication charts were evaluated for signs of delirium and use of prespecifi ed medication. analysis was by intention to treat. results of eligible patients, complete data on delirium could be collected in patients. the incidence of delirium was . % in the dexamethasone group and . % in the placebo group (odds ratio = . , % ci = . to . ). no signifi cant diff erence was found on the duration of delirium between the intervention (median = days, interquartile range to days) and placebo (median = days, interquartile range to days) group (p = . ). the use of restrictive measures and administration of sedatives, haloperidol, benzodiazepine and opiates were comparable between both groups. conclusion intraoperative injection of dexamethasone seems not to aff ect the incidence or duration of delirium in the fi rst days after cardiac surgery, suggesting this regimen is safe to use in the operative setting with respect to psychiatric adverse events. reference introduction the beliefs, knowledge and practices regarding icu delirium among icu professionals may vary. this may interfere with the implementation of the dutch icu delirium guideline. we aimed to get insight into potential barriers and facilitators for delirium guideline implementation that may help to fi nd an eff ective implementation strategy. methods an online survey was sent to healthcare professionals from the six participating icus. respondents included icu physicians, nurses and delirium experts (psychiatrists, neurologists, geriatricians, nurse experts). the survey consisted of statements on beliefs, knowledge and practices towards icu delirium. agreement with statements by more than % of respondents were regarded as facilitating items and agreement lower than % as barriers for implementing protocolled care. of the surveys distributed, were completed ( . %). the majority of respondents were icu nurses ( %). delirium was considered a major problem ( %) that requires adequate treatment ( %) and is underdiagnosed ( %). respondents considered that routine screening of delirium can improve prognosis ( %). however, only a minority ( %) answered that delirium is preventable. only % of the respondents had received any training about delirium in the previous years and % of them found training useful. the mean delirium knowledge score was . out of (sd = . ). when all groups were mutually compared, nurses scored lower than delirium experts (anova, p = . ). the respondents ( %; n = ) from three icus indicated that cam-icu assessment was department policy. however, % (n = ) of these respondents felt unfamiliar with cam-icu and only % (n = ) of them indicated that a positive cam-icu was used for treatment decisions. haloperidol was the fi rst-choice pharmacological treatment. only % of all respondents knew that a national icu delirium guideline existed, but in-depth knowledge was generally low. conclusion our survey showed that healthcare professionals considered delirium an important but underdiagnosed form of organ failure. in contrast, screening tools for delirium are scarcely used, knowledge can be improved and protocolled treatment based on positive screening is often lacking. these results suggest that the focus of implementation of icu delirium management should not be on motivational aspects, but on knowledge improvements, training in screening tools and implementation of treatment and prevention protocols. introduction delirium is an acute disturbance of consciousness and cognition. it is a common disorder in the icu and associated with impaired long-term outcome [ , ] . despite its frequency and impact, delirium is poorly recognized by icu physicians and nurses using delirium screening tools [ ] . a completely new approach to detect delirium is to use monitoring of physiological alterations. temperature variability, a measure for temperature regulation, could be an interesting parameter for monitoring of icu delirium, but this has never been investigated before. the aim of this study was to investigate whether temperature variability is aff ected during icu delirium. methods we included patients in whom days with delirium could be compared with days without delirium, based on the confusion assessment method for the icu and inspection of medical records. patients with conditions aff ecting thermal regulation, including infectious diseases, and those receiving therapies aff ecting body temperature were excluded. twenty-four icu patients were included after screening delirious icu patients. daily temperature variability was determined by computing the mean absolute second derivative of the temperature signal. per patient, temperature variability during delirious days was compared with nondelirium days using a wilcoxon signed-rank test. with a linear mixed model, diff erences between delirium and nondelirium days with regard to temperature variability were analysed adjusted for daily mean richmond agitation and sedation scale scores, daily maximum sequential organ failure assessment score, and within-patient correlation. results temperature variability was increased during delirium days compared with days without delirium (mean diff erence = - . , % ci = - . ; - . , p < . ). adjusting for confounders did not alter our fi ndings (adjusted mean diff erence = - . , % ci = - . ; - . , p < . ). conclusion temperature variability is increased during delirium in icu patients, which refl ects the encephalopathy that underlies delirium. opportunities for delirium monitoring using temperature variability should be further explored. particularly, in combination with electroencephalography it could provide the input for an objective tool to monitor delirium. in icu patients, little research has been performed on the relationship between delirium and long-term outcome, including health-related quality of life (hrqol), cognitive functioning and mortality. in addition, results seem to be inconsistent. furthermore, in studies that reported increased mortality in delirious patients, no proper adjustments were made for severity of illness during icu admission. this study was conducted to investigate the association introduction we aimed to clarify the diff erences between primary and secondary acute gi injury. methods a total of , consecutive adult patients were retrospectively studied during their fi rst week in the icu. pathology in the gi system or laparotomy defi ned the primary gi insult. if gi symptoms developed without primary gi insult it was considered secondary gi injury. absent bowel sounds (bs), vomiting/regurgitation, diarrhoea, bowel distension, gi bleeding, and high gastric residuals (grv > , ml/ hours) were recorded daily. results in total, , patients ( . % male), median age years (range to ), were studied. eighty-four per cent of them were ventilated, % received vasopressor/inotrope. median (iqr) apache ii score was ( to ) and sofa on the fi rst day was ( to ). a total . % had primary gi pathology. during the fi rst week % of patients had absent bs, % vomiting/regurgitation, % diarrhoea, % bowel distension, % high grv and % gi bleeding. all symptoms except diarrhoea occurred more often (< . ) in patients with primary gi insult. eighty-fi ve per cent of patients with primary gi insult versus % without developed at least one gi symptom. the incidence of gi symptoms was signifi cantly higher in nonsurvivors. icu mortality was lower in patients with primary than secondary gi injury ( . % vs. . %, p = . ). nonsurvivors without primary gi insult developed gi symptoms later (figure ). conclusion primary and secondary acute gi injury have diff erent incidence, dynamics and outcome. ventilation with relative risk of to % and with mortality of to % [ , ] . one of the promoting factors of vap is the increased ph of the gastric acid, which occurs when h -receptor antagonists (h ra) or proton pump inhibitors (ppi) are used for stress ulcer prophylaxis. the results of this pilot study suggest that there may be no diff erence in the incidence of vap and gi bleeding if stress ulcer prophylaxis is performed by h ra or ppi. as the latter is more expensive, its use as fi rst choice in critical care should be questioned. conclusion depending on resection size liver resection acutely increases portal venous pressure and induces neurohumoral activation resulting in compromised renal function and increased risk of developing aki. introduction severe acute pancreatitis (sap) requiring admission to an icu is associated with high mortality (hospital mortality reached %) and long lengths of stay [ ] . survival among patients with predicted sap at admission has been shown to correlate with the duration of organ failure (of) [ ] . the systemic determinant of severity in a new classifi cation of acute pancreatitis (ap) is also based on identifi cation of patients with transient or persistent of [ ] . methods the aim of the study was to retrospectively determine the predictors of early persistent of in icu patients with sap. the analysis involved patients. the median time interval between the onset of ap and admission was ( ; ) hours. the patients were divided into two groups: the fi rst group (n = ) had transient of and the second group (n = ) had persistent of. the ability of the apache ii score, total sofa score and number of organ/system failure to discriminate transient from persistent of was explored with receiver operating characteristic (roc) curves. results hospital mortality was signifi cantly higher in the second group as compared with the fi rst group ( % vs. %, p = . ); while infectious complications were % versus % (p = . ) and median lengths of icu stay were ( ; ) days for the second group and ( ; ) days for the fi rst group (p = . ). optimum cutoff levels (by roc curve analysis) were apache ii score ≥ (sensitivity . ; -specifi city . ), total sofa score ≥ (sensitivity . ; -specifi city . ), and failure ≥ organs/systems (sensitivity . ; -specifi city . ). see table . introduction the aim of this study was to evaluate the accuracy of thrombopoietin (tpo) plasma levels as a biomarker of clinical severity in patients with acute pancreatitis (ap). tpo is a humoral growth factor that stimulates megakaryocyte proliferation and diff erentiation [ ] . furthermore, it favors platelet aggregation and polymorphonuclear leukocyte activation [ ] . elevated plasmatic concentrations of tpo have been shown in patients with critical diseases, including acs, burn injury and sepsis [ ] . in particular, clinical severity is the major determinant of elevated tpo levels in patients with sepsis [ ] . ap is a relatively common disease whose diagnosis and treatment are often diffi cult, especially in the clinical setting of the emergency department (ed introduction renal ischemia-reperfusion injury (iri) is a common cause of acute kidney injury and occurs in various clinical conditions including shock and cardiovascular surgery. renal iri releases proinfl ammatory cytokines within the kidney. atrial natriuretic peptide (anp) has natriuretic, diuretic and anti-infl ammatory eff ects [ ] and plays an important role of regulating blood pressure and volume homeostasis. the hypothesis was that renal iri induces infl ammation not only in the kidney but also in remote organs such as the lung and heart and anp attenuates renal injury and infl ammation in the kidney, lung and heart. methods male sprague-dawley rats were anesthetized with pentobarbital. tracheostomy was performed and rats were ventilated at vt ml/kg with cmh o peep. the right carotid artery was catheterized for blood sampling and continuous blood pressure measurements. the right femoral vein was catheterized for infusion of saline or anp. rats were divided into three groups; iri group (n = ), left renal pedicle was clamped for minutes; iri+anp group (n = ), left renal pedicle was clamped for minutes, anp ( . μg/kg/minute, for hours minutes) was started minutes after clamp; and sham group (n = ), the shamoperated rats. hemodynamics, arterial blood gas, and plasma lactate levels were measured at baseline and at hour, hours and hours after declamp. the mrna expression of il- in the kidney, lung, and heart were measured. the kidney, lung and heart were immunostained to examine the localization of il- and nf-κb and assigned an expression score. the wet/dry ratio of the lung was also measured. results renal iri induced metabolic acidosis, pulmonary edema, mrna expression of il- in the kidney, lung and heart. renal iri increased immunohistochemical localization of il- in the proximal convoluted tubule of the left kidney and nf-κb in the bronchial epithelial cells of the lung. anp attenuated metabolic acidosis, pulmonary edema and expression of il- mrna in the kidney, heart, and lung. anp decreased immunohistochemical localization of il- in the left kidney and nf-κb in the lung. conclusion these fi ndings suggested that infl ammation within the kidney after renal iri was extended into the lung and heart. anp attenuated metabolic acidosis and infl ammation in the kidney, lung and heart in a rat model of renal iri. anp may attenuate organ crosstalk between the kidney, lung and heart. reference increase in urinary ngal in patients receiving bicarbonate infusion was observed compared with control (p = . ). the incidence of postoperative rrt was similar but hospital mortality was increased in patients treated with bicarbonate compared with chloride ( / ( . %) vs. / ( . %), or . ( . to . ), p = . ). see figure . conclusion on this basis of our fi ndings we do not recommend the use of perioperative infusions of sodium bicarbonate to reduce the incidence or severity of aki in this patient group. figure ). an excellent predictive value was found for ungal/uhepcidin ratio (auc . , figure ). this ratio combines an aki prediction marker (ngal) and a marker of protection from aki (hepcidin), potentiating their individual discriminatory values. contrarily, at icu admission, none of the plasma biomarkers was a good early aki predictor with auc-roc ≥ . . conclusion several urinary markers of acute tubular damage predict aki after cardiac surgery and the biologically plausible combination of ngal and hepcidin provides excellent aki prediction. introduction furosemide is one of the most employed diuretics in the icu for its ability to induce negative water balance. however, one common side eff ect is metabolic alkalosis [ ] . we aimed to describe the time course of urinary excretion and changes in plasmatic acid-base balance in response to the administration of furosemide. methods we connected the urinary catheter of icu patients to a quasi-continuous urine analyzer (kidney instant monitoring®), allowing measurement of ph (phu), sodium, chloride, potassium and ammonium concentrations (na+u, cl-u, k+u, nh +u) every minutes. the study period lasted hours after a single intravenous bolus of furosemide (time ). in patients receiving two or more administrations over a longer period ( ( to ) hours), according to clinical needs, we reviewed data on fl uid therapy, hemodynamics and acid-base balance from the beginning to the end of the observation. results ten minutes after furosemide administration, na+u and cl-u rose from ± to ± and from ± to ± meq/l respectively, while k+u fell from ± to ± meq/l (p < . for all electrolytes vs. time ) with a consequent increase in urinary anion gap (agu = na+u + cl-u -k+u). urinary output increased from ( to ) to ( to ) ml/ minutes (p < . ). after the fi rst hour cl-u remained higher than na+u, which progressively decreased, leading to a reduction in agu and phu over time. in parallel, a progressive increment in nh +u was observed. in patients receiving more than one administration we observed an increase in arterial base excess ( . ± . vs. . ± . mmol/l, p < . ) and plasmatic strong ion diff erence (sidpl) ( ( to ) vs. ( to ) meq/l, p = . ) during the study period. these changes were due to a decrease in plasmatic clconcentration ( . ± . vs. . ± . meq/l, p = . ). plasmatic sodium and potassium concentrations did not change. in these patients, considering the total amount of administered fl uids and urine, a negative water and chloride balance was observed (- ± ml and - ± meq, respectively). conclusion furosemide acts immediately after administration, causing a rise in urinary output, na+u and cl-u concentrations. loop-diureticinduced metabolic alkalosis may be due to an increased urinary chloride loss and the associated increase in sidpl. reference introduction given the signifi cant morbidity and mortality associated with acute kidney injury (aki), there is a need to fi nd factors to help aid decision-making regarding levels of therapeutic support. as a prognostic biomarker, the red cell distribution width (rdw) has attracted interest in the setting of critical care when added to existing scoring systems [ ] . by examining rdw in a previously studied aki cohort, we aimed to evaluate the utility of this routine blood test. methods a cohort of mixed critical care patients who received renal replacement therapy for aki had their demographic and biochemical data retrieved from electronic databases. outcomes were gathered for icu and hospital mortality. incomplete datasets were discarded, leading to complete sets. rdw data were taken from the fi rst sample after admission to the icu, as were all other biochemical values apart from pre-rrt creatinine and potassium. overall cohort characteristics were gathered, and two groups were created: those with a rdw value within normal range (≤ . %) and those with a greater than normal value (> . %). we then further subgrouped rdw to assess the correlation between rising levels and icu mortality. results a total . % of our cohort had a rdw greater than the normal laboratory range at time of icu admission. key baseline characteristics (age, apache ii score, length of stay, icu mortality) did not diff er signifi cantly between patients with normal and abnormal rdw. when subgroup analysis was performed, no statistically signifi cant correlation between rising rdw and icu mortality was found (spearman correlation = . , p = . ). conclusion in this cohort of critically ill patients with aki, rdw was not found to be a predictor of mortality. our results contradict those of recent studies [ , ] . however, both groups of rdw patients in our study suff ered a higher icu mortality than in other studies. to further explain these fi ndings, we intend to perform multivariate logistic regression analysis and assess the eff ect of social deprivation on rdw. introduction intra-abdominal hypertension (iah) is an independent predictor of renal impairment and mortality [ ] . organ dysfunction caused by the pressure eff ect of iah is well understood, but how this is modifi ed in the presence of bowel obstruction is unclear. the aim of this study was to determine how diff erent iah models cause renal dysfunction in a pig model. methods twenty-four pigs were divided into three groups; a control group (n = ), a pneumoperitoneum (pn) (n = ), and an intestinal occlusion (oc) model (n = ). iap was maintained for hours at mmhg during which time creatinine, urea, urine output, potassium, and glomerular fi ltration pressure (gfp) were measured. statistical analysis was performed using repeated-measures anova. results over the fi rst hours there was a statistically signifi cant diff erence between the control group and both iah models for conclusion as expected the iah models resulted in signifi cantly worse renal function after hours. this early renal dysfunction may be as a result of an early infl ammatory process that has been associated with the pathophysiology of acute kidney injury. potassium was signifi cantly elevated in the pn group as compared with the oc group. early changes in potassium levels with iah may be a marker of early renal dysfunction and the usefulness of other renal biomarkers, such as ngal, prompts further investigation. reference introduction oliguria is common in septic patients and is frequently therapeutically addressed with loop diuretics; that is, furosemide. diuretic treatment in shock and hypovolemia is not rational, but can be tried in oliguric patients with normovolemia or hypervolemia and without hypotension. in such patients it still does not always increase dieresis and can also be harmful. the resistive index is a measure of pulsatile blood fl ow that refl ects the resistance to blood fl ow caused by the microvascular bed distal to the site of measurement. it can refl ect functional status of the tissue distal to the point of measurement. we investigated whether measuring the renal resistive index (ri) could be helpful in determining which patients will respond to furosemide treatment. methods we included medical icu patients with sepsis and oliguria (urine output < ml/kg/hour) who were prescribed i.v. furose mide. patients with known chronic renal failure, hypovolemia (cvp < mmhg) or severe hypotension (map < mmhg) were excluded. resistive index ( − (end diastolic velocity / maximum systolic velocity)× ) was measured in at least three segmental arteries of both kidneys, the average of all measurements was reported as the result. repeated assessments were viewed as independent if separated by more than hours. furosemide was given intravenously in the dose of mg after ri measurement. positive response to furosemide was defi ned as doubling of hourly dieresis or achieving urine output > . ml/kg/hour after drug administration. we included patients with a total of measurements. in cases patients had positive response to furosemide. median ri in responders was . (range . to . ) and in nonresponders . (range . to . ); p = . . construction of receiver operating characteristic curve showed % sensitivity and % specifi city for the cutoff ri . . no other measured patient characteristic was found to be predictive of response to diuretic treatment. conclusion our results show that the ri could be used to guide diuretic treatment in nonhypovolemic, nonhypotensive septic patients. further studies are needed to confi rm those preliminary results. introduction as a proof of concept, the potential added value of chitinase -like (chi l ) as a more early and specifi c diagnostic parameter for acute kidney injury (aki) was investigated in adult icu patients that underwent elective cardiac surgery. . conclusion sdma appears to be an accurate and precise estimate of gfr and a more sensitive biomarker of renal dysfunction than scr. we predict sdma will perform better than scr as a biomarker of aki. this forms the basis of a future study. introduction growing evidence hints that bidirectional interaction between heart failure and kidney disease and renal insuffi ciency is a strong predictor of mortality as well as causally linked to the progression of heart failure. neutrophil gelatinase-associated lipocalin (ngal) is an early predictor of acute kidney injury (aki). we evaluated the impact of ngal on morbidity and mortality in patients with acute heart failure. methods seventy-six patients presenting with symptoms consistent with acute heart failure (median age years, % male) were enrolled. plasma ngal levels were measured by an elisa at admission and compared with the glomerular fi ltration rate (egfr) and b-natriuretic peptide (bnp) levels. the primary outcome was aki development defi ned by rifle criteria (fall in gfr > % or creatinine rise ≥ % from baseline, or a fall in urine output < . ml/kg/hour) and secondary outcomes were duration of hospital stay and in-hospital mortality. conclusion ngal is emerging as a promising biomarker of aki in the setting of acute heart failure and elevated ngal levels indicate a poor prognosis in this population regarding morbidity and mortality. introduction aki is a common occurrence in sick hospitalized patients, in particular those admitted to intensive care. published data suggest that to % of all critically ill patients develop severe aki and require initiation of renal replacement therapy (rrt) [ , ] . such patients have high mortality rates often exceeding % [ ] . we aimed to review the outcomes of patients admitted to the icu and required renal replacement therapy for aki. we examined whether aetiology of aki, comorbidity burden, hospital length of stay and treatment in icu had any signifi cant association with survival in the study cohort. methods during , patients were identifi ed to have received rrt with aki who were admitted to the icu at the royal wolverhampton hospitals nhs trust. computerised and paper-based case records were examined for these patients to collect the data. akin classifi cation was used to classify the severity of aki. conclusion individuals who develop dialysis-dependent aki in the icu setting in general terms either die or recover. sepsis is the most common association with death. the need for mechanical ventilation and inotropic therapy are both associated with increased incidence of death. introduction this study was to evaluate the effi ciency of the early start of intermittent substitutive renal therapy in patients with polytrauma complicated by multiple organ failure syndrome. methods forty-two patients with polytrauma complicated by multiple organ failure syndrome were included in the study. the age of the patients was from to years ( . ± . years average). all patients were divided into two equal groups. in the control group (cg) the criteria for the start of the substitutive renal therapy were: hyperkalemia ≥ mmol/l, plasma creatinine ≥ μmol/l, diuresis ≤ ml/hour. in the investigation group (ig) there were subtests to carry out the substitutive renal therapy, allowing one to start it in the earlier period of the multiple organ failure progression. these are increase of na + > mmol/l, osmolarity > mosm/l, elevation of the plasma toxicity according to the average molecule concentration ≥ . , diuresis decrease ≤ ml/hour. these were examined: lethality, quantity of the substitutive renal therapy procedures, mechanical lung ventilation duration (mlv), intensive care and hospital duration. the substitutive renal therapy was carried out by ak- -ultra apparatus (gambro, sweden). the statistical analysis was realized using statistica . and the mann-whitney u test. the average quantity of the substitutive renal therapy procedures in the cg was . ± . , in the ig it was ± . (p < . ). the recuperation of the renal excretory functions was on ± day in patients of the cg, and on ± . day in the ig, from the moment of substitutive renal therapy start (p < . ). lethality in the cg was % (nine patients), and in the ig it was % (six patients, p < . ). the duration of the mlv in the cg and ig was ± . days and ± . , respectively (p < . ). in the ig the duration of the icu was lower by %, hospitality duration was lower by % (p < . ). conclusion the effi ciency of the substitutive renal therapy depends directly on the hydroelectrolytic and metabolic changes and toxicosis degrees in the polytrauma complicated by multiple organ failure syndrome. the early start of the dialysis methods treatment allows one to achieve the earlier recuperation of the renal functions and to decrease the lethality level by %. can treatment with the molecular adsorbent recirculation system be the solution for type- introduction it has been suggested that fl uid balance is a biomarker in critically ill patients [ ] . there is a paucity of randomized trials examining the eff ect of daily fl uid balance on outcomes in patients on continuous renal replacement therapy (crrt). the renal trial did not fi nd mortality diff erence with higher crrt dose [ ] , but did not investigate the eff ect of daily fl uid balance on patient outcomes. a post hoc analysis suggested survival benefi t in patients with negative fl uid balance [ ] . in this study, we hypothesize that daily fl uid balance is an independent predictor of mortality in critically ill patients. we conducted a retrospective cohort study in eight icus of a tertiary academic center. we constructed a robust clustered linear regression model of daily fl uid balance and all-cause hospital mortality among critically ill patients receiving crrt. we adjusted the model for the charlson comorbidity score, the daily sofa scores in the fi rst week after initiation of crrt as well the type of icu. results after adjusting for the type of icu and the daily severity of illness, patients who died had on average ml higher daily fl uid balance compared with patients who survived (p < . , % ci = to , ml, figure ). severity of illness predicted daily fl uid accumulation; each additional point of the sofa score predicted an additional ml of extra daily fl uid (p = . ). balance and intradialytic hypotension with mortality and recovery of renal function. methods we conducted a retrospective cohort study among patients aged ≥ years who had rrt initiated and continued for ≥ days in a level or icu at two academic centres, and had fl uid balance data available. patients with end-stage kidney disease, within year of a renal transplant or who had rrt initiated to treat a toxic ingestion were excluded. we used multivariable logistic regression to determine the relationship between mean daily fl uid balance over the fi rst days following rrt initiation and the outcomes of mortality and rrt dependence in survivors. introduction acute kidney injury (aki) is a common complication of critical illness and sepsis [ ] . dosing of antibacterial agents in septic patients is complicated by altered pharmacokinetics due to both acute renal failure and critical illness [ ] . current dosing regimens for administration of gentamicin and vancomycin to septic patients with aki on continuous venovenous hemofi ltration (cvvh) at a fi ltration rate of ml/kg/hour are missing. methods seventeen septic patients with aki treated with vancomycin and seven patients with gentamicin on cvvh were included. in the vancomycin group, patients received the fi rst dose of . g intravenously followed by . g/ hours if not adjusted. in the gentamicin group, patients received a loading dose of mg followed by a maintenance dose every hours. the vancomycin maintenance dose was optimized to achieve auc - /mic ≥ (cmin > mg/l), gentamicin target was cmax/mic of to . maintenance doses were adjusted according to drug level simulation using a pharmacokinetic programme. the median vancomycin total clearance (cltot) was . and . ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about to % of vancomycin cltot found in a population with normal renal function ( . ml/minute/kg). vancomycin serum concentrations after the fi rst dose were below the required target of mg/l as early as hours in patients. auc - / mic ≥ ratio was achieved in % of patients on the fi rst day. the median gentamicin cltot was . and . ml/minute/kg on the fi rst and second day of the study. crrt clearance accounted for about % of gentamicin cltot found in a population without renal impairment ( . ml/minute/kg). the target cmax/mic ratio was achieved in % of patients after the fi rst dose. conclusion cvvh at a fi ltration rate of ml/kg/hour leads to high removal of both antibiotics. due to rapid change in patient's clinical status it was impossible to predict a fi xed dosage regimen. we recommend administration of unreduced loading dose and: blood sampling as early as hours after fi rst vancomycin dose; blood sampling to minutes after gentamicin administration and before the next dose; and the maintenance dose should be based on druglevel monitoring. crrt. the aim was to evaluate the eff ects on electrolyte and acid-base status of a new rca-cvvh protocol using an mmol/l citrate solution combined with a phosphate-containing replacement fl uid, compared with a previously adopted rca-cvvh protocol combining a mmol/l citrate solution with a conventional replacement fl uid. methods until september , rca-cvvh was routinely performed in our centre with a mmol/l citrate solution and a postdilution replacement fl uid with bicarbonate (hco - , ca + . , mg + . , k + mmol/l) (protocol a). in cases of metabolic acidosis, not related to inappropriate citrate metabolism and persisting after optimization of rca-cvvh parameter setting, bicarbonate infusion was scheduled. starting from september , in order to optimize buff er balance and to reduce the need for phosphate supplementation, a new rca-cvvh protocol has been designed using an mmol/l citrate solution combined with a recently introduced phosphate-containing replacement fl uid with bicarbonate (hco - conclusion protocol b provided a buff er balance more positive than protocol a and allowed one to adequately control acid-base status without additional bicarbonate infusion and in the absence of alkalosis, despite the use of a standard bicarbonate concentration replacement solution. furthermore, the combination of a phosphate-containing replacement fl uid appeared eff ective to prevent hypophosphatemia. introduction the aim of this study was to establish the intraobserver and interobserver variation of ultrasonographic measurements of the rectus femoris muscle cross-section area (rf-csa). muscle wasting is frequent in the icu, aff ecting more than one-half of the patients with severe sepsis [ ] . muscle mass reduces rapidly, and to % is lost within the fi rst week [ ] . to monitor muscle mass, ultrasound has the benefi ts of being both readily available in the icu and non-invasive. ultrasonographic measurement of rf-csa has an almost perfect correlation with mri (mean interclass correlation (icc) = . ) [ ] and rf-csa is linearly related to maximum voluntary contraction strength in both healthy subjects and copd patients (r = . ) [ ] . methods the study had two purposes: to determine the intraobserver variation for rf-csa by one observer scanning healthy adult volunteers three times each at -day intervals; and to determine the interobserver variation for rf-csa by two observers each scanning adult icu patients on the same day. patients were in a supine position, legs in passive extension. the transducer was placed perpendicular to the long axis of the right thigh over the rf, two-thirds of the distance from the anterior superior iliac spine to the superior patellar border [ ] . rf-csa was calculated by planimetry. at each scan, three measurements were made. for intraobserver variation, the × scans were analyzed using the interclass correlation coeffi cient. for interobserver variation, the three measurements from each observer were averaged and compared using bland-altman statistics. results intraobserver variation: healthy adults, age . ± . years, weight . ± . kg, sex three male/ female. icc: . ( % ci: . to . ). interobserver variation: icu patients, age: ± . years, weight: . ± . kg, sex nine male/six female. bland-altman: bias: - . cm , % limits of agreement - . to . cm . conclusion ultrasonographic measurement of rf-csa is easily learned and quickly performed. it has a very low intraobserver and interobserver variation and can be recommended as a reliable method for monitoring muscle wasting in the icu. in artifi cially fed critically ill patients, adipose tissue reveals an increased number of small adipocytes and accumulation of m -type macrophages [ ] . we hypothesized that nutrient-independent factors of critical illness explain these fi ndings, and also that m macrophage accumulation during critical illness may not be limited to adipose tissue. methods we performed a randomized investigation in a septic mouse model of critical illness and a study of icu patient biopsies. in the critically ill mouse, we compared the eff ect of parenteral nutrition (n = ) with fasting (n = ) on body composition, adipocyte cell size, and macrophage accumulation in adipose tissue, liver and lung. fed healthy control mice (n = ) were studied for comparison. in vivo adipose tissue was harvested after week of illness from human patients (n = ) who participated in a rct on early parenteral nutrition versus tolerating nutrient restriction [ ] , adipose tissue morphology was characterized and compared with healthy controls (n = ). results irrespective of nutritional intake, critically ill mice lost body weight, total fat and fat-free mass. part of the fat loss was explained by reduced ectopic fat accumulation. adipocyte cell number and the adipogenic markers peroxisome proliferator-activated receptor γ and ccat/enhancer binding-protein β increased with illness, again irrespective of nutritional intake. macrophage accumulation with predominant m -phenotype was observed in adipose tissue, liver and lungs of critically ill mice, further accentuated by fasting in visceral tissues. macrophage m -markers correlated with chemoattractant factor expression in all studied tissues. in human subcutaneous adipose tissue biopsies of critically ill patients, increased adipogenic markers and m macrophage accumulation were present irrespective of nutritional intake. conclusion adipogenesis and accumulation of m -macrophages are hallmarks of critical illness, irrespective of nutritional management in humans and mice. critical illness evokes macrophage polarization to the m -state not only in adipose tissue but also in liver and lungs, which is further accentuated by fasting. introduction intravenous magnesium sulfate is commonly used in obstetric patients with pre-eclampsia. following a case of acute symptomatic hypocalcemia we retrospectively examined a cohort of patients to investigate the frequency of hypocalcemia. methods obstetric patients were identifi ed from the icu admissions database and divided into two groups -those treated with magnesium (for suspected pre-eclampsia) and those admitted for other obstetric indications (postpartum hemorrhage, infection, etc.). the baseline calcium values were compared, as well as the lowest and discharge values. albumin and magnesium values were also compared. all comparisons used student's t test. results data were collected on parturients admitted over years including ( %) who received magnesium and ( %) who did not. magnesium-treated women were younger (age: ± vs. ± years, p = . ). the baseline calcium concentrations were similar for the two groups ( . ± . vs. . ± . mmol/l, p = . ). patients receiving magnesium had signifi cantly higher magnesium concentrations ( . ± . vs. . ± . mmol/l, p < . ), and signifi cantly lower calcium concentrations during therapy ( . ± . vs. . ± . mmol/l, p < . ). at discharge, the calcium levels were closer (magnesium treated . ± . vs. untreated . ± . mmol/l, p = . ). the albumin concentrations did not diff er between the two groups (magnesium treated ± vs. nontreated ± g/l, p = . ). normal values: calcium . to . mmol/l, magnesium . to . mmol/l, albumin to g/l. conclusion magnesium therapy was associated with hypocalcemia. potential causative mechanisms include a renal excretion interaction and magnesium-induced suppression of parathyroid hormone secretion. physicians should be aware of the potential for symptomatic hypocalcemia during magnesium therapy. introduction disorders of sodium (na + ) and water homeostasis are common in hospitalised patients. hyponatremia in particular has been associated with worse hospital outcome and length of stay [ ] . we aimed to defi ne the incidence of hyponatremia (serum na + ≤ mmol/l) in our intensive care population and to determine whether it was associated with icu outcome or length of stay. methods demographics, apache ii score, outcome data and admission sodium were retrieved from the ward watcher system in the victoria infi rmary icu for , consecutive admissions from january to present. we divided patients into three groups depending on serum na + (≤ mmol/l, to mmol/l, ≥ mmol/l) and compared apache ii score, length of stay and icu outcome between patients with a low versus a normal serum na + . data were analysed using the chi-squared test, student's t test and the mann-whitney test where appropriate. results of the , patients studied, , had apache ii data and serum na + recorded and so were included for analysis. in total, patients ( . %) had a serum na + ≤ mmol/l and , patients ( . %) had a serum na + of to mmol/l. patients with a low na + had a higher mortality (or = . , % ci = . to . , p < . ), a higher apache ii score ( vs. , p < . ) and higher mean age ( years vs. years, p < . ) than patients with a normal serum na + . mean length of stay of patients with low serum na + was also longer ( . days vs. . days) although this was not statistically signifi cant (p = . ). conclusion in summary, hyponatremia is a useful index of severity of illness in our icu population. whether this is a direct adverse eff ect of low serum sodium levels, or if hyponatremia is simply a marker for 'sicker' patients, is not known. reference introduction the anion gap (ag) is used routinely in the assessment of metabolic acidosis, but can be misleading in patients with hypoalbuminemia and other disorders commonly encountered in intensive care. this approach to acid-base analysis relies on assessment of ph, pco , sodium, bicarbonate and chloride, and can lead to underestimation or overestimation of the true electrochemical status of a patient, as it does not include important ions such as lactate, calcium, magnesium, and albumin. the strong ion gap (sig) is an alternative to the ag and is based upon stewart's physical chemistry approach. however, the sig is cumbersome to calculate. as such, a number of shortcut equations have been developed in an eff ort to approximate the sig. we sought to compare three such equations, the kellum corrected anion gap (kellagc), the moviat equation, and ezsig, in an eff ort to evaluate precision and accuracy [ ] [ ] [ ] . methods we conducted a retrospective chart review of consecutive patients admitted to the icu of george washington university medical center from september to march . of the , patients screened, met inclusion criteria, which included availability of all laboratory components to calculate the sig, obtained within hour of each other. demographic data and serum values for ph, pco , albumin, lactate, sodium, potassium, chloride, bicarbonate, magnesium, phosphate, and calcium were collected. the ag, sig, kellagc, ezsig, and moviat equations were subsequently calculated and compared using pearson correlation and bland-altman analysis. results the mean sig was . ± . . mean values for kellagc, moviat, and ezsig were . ± . , . ± . , and . ± . , respectively. pearson correlation coeffi cients for kellagc, moviat, and ezsig when compared with the sig were r = . , p = . ; r = . , p = . ; and r = . , p = . , respectively. in bland-altman analysis, the mean bias for the test equations versus the sig were: kellagc ( . ), moviat (- . ), and ezsig ( . ). conclusion while all three equations correlated highly with the sig, the ezsig and moviat outperformed the kellagc in pearson and bland-altman analysis. the ezsig had a smaller bias than the moviat equation and a slightly better correlation ( . vs. . ). in the assessment of critically ill patients, ezsig is a candidate scanning equation for the measurement of the sig when all sig components are not available. university-affi liated teaching hospital in tunis. patients admitted within the fi rst hours post burn with greater than % total body surface area (tbsa) burned were enrolled in this study from january to june . exclusion criteria were pregnancy, history of adrenal insuffi ciency, or steroid therapy within months prior to burns. a short corticotrophin test ( μg) was performed, and cortisol levels were measured at baseline (cs t ) and minutes post test. adrenal insuffi ciency was defi ned by a response ≤ μg/dl. relative adrenal insuffi ciency was further defi ned by a baseline cortisol > μg/dl. results patients were assigned into two groups: g (rai, n = ) and g (absence ai, n = ). comparative study of the two groups shows the results presented in table . conclusion rai is common in severely burned patients during the acute phase, and is associated with shock. further prospective controlled studies will be necessary to establish risk factors of rai in severely burned patients and its impact on their prognosis. albumin-adjusted calcium concentration should not be used to identify hypocalcaemia in critical illness t steele , r introduction hypocalcaemia is common in critical illness and accurate assessment is crucial. small studies have shown that albumin-adjusted calcium (adjca) does not accurately predict the ionised calcium (ica) concentration in critically ill patients, yet adjca continues to be widely used [ ] . we investigated the reliability of using adjca to identify hypocalcaemia in a large, diverse population requiring intensive care. methods in a retrospective study of patients admitted to the icus of a tertiary care hospital between january and , ica and ph were extracted from routine blood gas results and total calcium, albumin and phosphate from routine biochemistry results. adjca was calculated using a formula derived from and validated on the local population [ ] . sensitivity, specifi city, positive and negative predictive values (ppv and npv) and area under the curve (auc) of adjca for predicting hypocalcaemia (ica < . mmol/l) were calculated. results in total, patients were included. the mean age was ± years, mean weight ± kg, apache ii score ± and most patients suff ered from pneumosepsis. on the fi rst day of intubation, total and free testosterone levels were extremely low in most patients and remained low during the fi rst week (figure ). β-estradiol levels were elevated on day and decreased during the fi rst week. lh and fsh levels were inappropriately low. all lipoprotein fractions and their apo-proteins were reduced as well as -oh-progesterone, dhea and dheas. in contrast, androstenedione (adione) levels were elevated. this suggests preferential and stimulated synthesis of androstenedione ( figure ). the high β-estradiol levels indicate that androstenedione is shunted into the estrogen pathway, a process that requires high aromatase activity. the high estradiol/total testosterone ratio supports this conclusion. conclusion hyperestrogenic hypotestosteronemia is a frequent fi nding in the acute phase of severe sepsis in male patients with respiratory failure. it is suggested to be caused by decreased androgen production and shunting of androgen to estrogen synthesis as a result of increased aromatase activity. the clinical relevance of gonadal hormone substitution needs further study. introduction melatonin could have a meaningful role in critically ill patients, because of its immunomodulatory, antioxidant and sleep regulation properties; it is reduced in critical illness. the purpose of this study is to describe the endogenous blood melatonin values in icu patients and their correlation with clinical parameters. methods seventy-three high-risk critically ill patients mechanically ventilated for > hours were enrolled. blood samples for melatonin assay were collected between the rd and the th day of the icu stay. melatonin was determined by radioimmunoassay and elisa. the peak and the area under the curve (auc) calculated for each patient were correlated with the clinical parameters using the regression for quantiles test. results endogenous melatonin was found lower in critically ill patients compared with healthy subjects (figure ) , although it showed a great individual variability and it generally maintained a night-time increase. in the univariate analysis the peak was found related to: blood creatinine (p = . ); patients in coma (p = . ); hospital mortality (p = . ). the auc was found related to: saps ii (p = . ); creatinine (p < . ); ast (p < . ); alt (p < . ); hospital mortality (p < . ). peak and auc were found higher in nonsurvivor patients. in accord with previous studies, the endogenous blood melatonin was found reduced in icu patients. the higher melatonin peak in renal failure may be due to an increased distribution volume; greater auc in patients with liver failure could be due to a less effi cient removal of the hormone from the systemic circulation. the fi nding of increased peak and auc in nonsurvivor patients could be due to a hormonal response increased by the body stress reaction, potentially similar to cortisol [ ], or to a higher production of a physiological antioxidant [ ] with a decreased ability to use it. introduction metformin intoxication inhibits mitochondrial complex i and oxygen consumption (vo ). succinate bypasses complex i by donating electrons to complex ii. the aim of this study was to clarify whether succinate ameliorates mitochondrial vo of metforminintoxicated human platelets. methods platelet-rich-plasma was incubated for hours with metformin at a fi nal concentration of mg/l (control), . mg/l (therapeutic dose) or mg/l (toxic dose). platelet vo was then measured with a clark-type electrode, in the presence of glutamate plus malate (complex i electron donors) (fi nal concentration: mmol/l for both) or succinate (complex ii electron donor) ( mmol/l), before and after adding cyanide ( mmol/l). mitochondrial (cyanide-sensitive) and extra-mitochondrial (cyanide-insensitive) vo were corrected for platelet count. the main results, from four preliminary experiments, are shown in figure . in the presence of glutamate plus malate, only platelets incubated with a high dose of metformin had a mitochondrial vo signifi cantly lower than controls. in the presence of succinate, mitochondrial vo of controls did not change signifi cantly whereas that of platelets incubated with metformin did. the eff ect of succinate tended to become larger as the dose of metformin was increased from up to mg/l ( . ± . vs. . ± . vs. . ± . nmol/minute* cells) (p = . ). even so, mitochondrial vo of platelets incubated with the highest dose of metformin did not return to the levels of controls. extra-mitochondrial vo was always the same. introduction metformin, widely used as an antidiabetic drug, activates the amp activated protein kinase, a key regulator of the metabolism providing protection under fuel defi ciency. chronic metformin therapy has been shown in long-term follow-up clinical studies to reduce cardiovascular mortality [ ] . in animal experiments, acute metformin pretreatment has been shown to reduce ischemia-reperfusion injury on cardiomyocytes [ ] . we want to evaluate whether outcomes are aff ected in coronary artery bypass grafting (cabg) surgery. introduction metformin, an oral hypoglycemic drug, belongs to the biguanide class and is now generally accepted as fi rst-line treatment in type diabetes mellitus, especially in overweight patients [ ] . in some predisposing conditions, the use of metformin may result in metforminassociated lactic acidosis (mala), a rare adverse event associated with a high mortality rate [ ] . the aim of this study is to assess risk factors and prognostic factors in patients with mala. [ ] . in our study, a higher plasma concentration of lactate represents the main negative prognostic factor, as pointed out by other studies [ ] . the prothrombin activity, which is considered to be a decisive prognostic factor in the study of peters and colleagues [ ] , was not impaired in patients with poor outcome. introduction stress hyperglycemia in the critically ill is a complex process in which insulin signaling is systematically hijacked to provide energy substrate for metabolic priorities such as cell healing or infection containment. fluctuating levels of plasma glucose are associated with increased mortality in the icu [ ] . we develop a multiscale mathematical model that can characterize the severity of stress hyperglycemia based on a fundamental understanding of the signaling molecules involved. methods insulin resistance following insult has been shown to be driven primarily by the immune response via the cytokine il- [ ] . we created a multiscale mathematical model that links circulating glucose and insulin concentration dynamics from the extended minimal model [ ] to a cellular insulin response model [ ] that captures insulinmediated glucose uptake in an insulin-responsive cell. results inhibitory dynamics driven by il- were incorporated into the cellular model to attenuate an insulin signaling intermediate (insulin receptor substrate ) according to the proposed biological mechanisms. the percentage reduction in glucose uptake as a function of il- concentration was fi t to data from patients who underwent elective abdominal surgery [ ] , shown in figure . the overall multiscale model captures decreased insulin signaling as a result of increased il- levels and the subsequent hyperglycemia that may ensue. introduction hyperglycemia is frequently encountered in critically ill patients, and associated with adverse outcome. improvement of glucose protocol adherence may be accomplished using electronic alerts. we confi gured a non-intrusive real-time electronic alert, called a glyc sniff er, as part of our intensive care information system (icis) that continuously evaluates the occurrence of persistent hyperglycemia and hypoglycemia. conclusion a real-time electronic persistent glycemia sniff er resulted in a signifi cantly higher proportion of normoglycemia, without increasing the variability. furthermore, hypoglycemic events occurred less frequently, and were resolved more timely. smart alerting is able to improve quality of care, while diminishing the problem of alert fatigue. introduction a recent study showed that hyperglycaemia (blood glucose ≥ . mmol/l) in nondiabetic patients hospitalised in a medical icu is associated with increased risk of diabetes [ ] . we investigated a large mixed icu population to confi rm these results. methods this study retrospectively included patients with negative history of diabetes admitted to icus during the year . we excluded patients receiving steroids, with newly diagnosed diabetes and those with end-stage disease. patients were followed-up years after index admission. diagnosis of diabetes within months from the index admission was presumed as revealing dm at inclusion, which excluded the patient. patients who were taking glucocorticoids during the followup period were excluded. diabetics were identifi ed from icd- documentation. propensity score for death (pdead) was computed from either sap (mimicii) or apache iii (hidenic) to assess the risk of death. hypoglycemia was defi ned as avg ≤ mg/dl. avg was computed as the area under the glucose curve throughout icu admission. mortality was examined within bins (each bin is categorized by a mg/dl increase in avg) and was compared between adjacent categories using a chi-square test. the same method was repeated among diabetics, nondiabetics, patients with lower (pdead greater than median) and higher (pdead lower than the presence of decubiti on admission to the icu is associated with longer hospitalizations even after adjusting for age, acuity, and organ supportive therapies. du on admission to icu provide a unique, unambiguous marker of increased resource utilization. introduction the aim was to analyze the prognosis of aids patients with organ dysfunctions at icu admission. methods a prospective cohort study, including all patients with hiv/ aids diagnosis, who were admitted to a specialized icu from november until may . patients with less than hours of icu stay were excluded. demographics and nutritional status were collected. the organ dysfunctions were classifi ed according to the sofa score, and categorized as absent ( sofa point), mild ( to points) and severe ( to points). we expressed numeric variables as median and interquartile interval ( % to %). we performed a multivariate analysis of possible variables associated with hospital mortality (p < . ), and we explored the -day, -day and -day survival of patients with and without independent risk factors. we included patients with hiv/aids admitted to the icu. median age was ( to ) years and % were male. severe malnutrition was common ( %). the cd cell count was ( to ) cells/mm and viral load was , ( to , ) copies/ml; % had at least one opportunistic infection; % had used antiretroviral therapy previous to icu admission. mechanical ventilation was used by % of patients and hospital mortality was %. total sofa score was ( to ) points. cardiovascular dysfunction was the most common on the fi rst day of stay ( %), followed by respiratory ( %), neurological ( %), renal ( %), hematological ( %) and hepatic ( %). cardiovascular and renal dysfunctions presented with higher rate of severe dysfunction ( % and %, respectively). rates of neurological (p = . ), renal (p = . ) and hematological (p = . ) dysfunctions were higher in nonsurvivors. age, cd cell count, malnutrition, and opportunistic infections were included in the multivariate analysis. neurological dysfunction was the independent risk factor for hospital mortality (odds . ( . to . )). the presence of neurological dysfunction was dichotomized: associated or not with primary neurological diagnosis; survival was lower in the patients with neurological dysfunction and without primary neurological diagnosis (log-rank test . in the -day and . in the -day analysis). sixty-day survival was similar in primary and secondary neurological dysfunction, but it remained lower than in patients without neurological impairment. conclusion neurological dysfunction was independently associated with hospital survival, mainly in those aids critically patients without primary neuropathy. results a total of charts were reviewed. in total, were categorized into a (n = ), b (n = ) or c (n = ). d (n = ) consisted mainly of patients with hematological malignancies (n = ) and patients with chemotherapy or immunosuppressive treatment (n = ). the groups diff ered in length of stay with a< b< c. during the fi rst days the sofa score was higher in a compared with c and in b compared with c. the duration of antibiotic therapy was longer in both b and c compared with a. there were no diff erences in -day mortality (a: / = %, b: / = %, c: / = %); however, the proportions of patients dying between days and were higher in b ( / = %) and c ( / = %) compared with a ( / = %). conclusion in this retrospective material it was possible to categorize . % of all patients as having primary, secondary or tertiary sepsis. the categories diff ered in clinical picture at presentation as well as in outcome. a prospective study is warranted to validate the results of this study. conclusion older people represent a growing proportion of the population although their representation in the critical care population remained constant in this -year study. these patients had a slightly higher median apache ii score and . % greater critical care mortality than the younger patients. the majority of survivors were able to go home; however, % died within months with signifi cant life expectancy curtailment, surviving on average only . months after discharge; this has not changed in the last years. those who survived this initial period ( %) had a much better outlook. this information may be vital to patients and physicians when discussing admission to critical care. reference methods potential risk factors for psychological problems were prospectively collected at icu discharge. two months after icu discharge icu survivors received the questionnaires post-traumatic stress symptom scale- (ptss- ) and hospital anxiety and depression scale (hads) to estimate the degree of post-traumatic stress, anxiety and depression. of the responders, % had adverse psychological outcome, defi ned as ptss- > and/or hads subscales ≥ . after analysis, six predictors with weighted risk scores were included in the screening instrument: major pre-existing disease, being a parent to children younger than years of age, previous psychological problems, in-icu agitation, being unemployed or sick-listed at icu admission and appearing depressed in the icu. each predictor corresponded to a given risk score. the total risk score, the sum of individual risk scores, was related to the probability for adverse psychological outcome in the individual patient. the predictive accuracy of the screening instrument, as assessed with area under the receiver operating curve, was . . when categorizing patients in three risk probability groups -low ( to %), moderate ( to %) and high ( to %) risk -the actual prevalence of adverse psychological outcome in respective groups was %, % and %. conclusion the preliminary screening instrument may aid icu clinicians in identifying patients at risk for adverse psychological outcome after critical illness. prior to wider clinical use, external validation is needed. the multiorgan dysfunction syndrome (mods) is a dynamic process involving simultaneously or consecutively two or more organ systems [ ] . the organ dysfunction's degree can be assessed by three severity scores (sofa [ ] , mods [ ] , lods [ ] ), but they have some limitations: they do not allow the evaluation of the clinical course of a patient, they are not reliable in populations diff erent from the reference one, and they do not support clinicians' decisions. because mods implies a systemic infl ammatory reaction leading to microcirculatory dysfunction, our hypothesis was that organ failures follow a predictable sequence of appearance. our aims were to verify the presence of more likely organ failure sequences and to assess an online method to predict the evolution of mods in a patient. the high mortality and morbidity rate of mods in icus can in fact be reduced only by a prompt and well-timed treatment [ ] . methods we selected patients consecutively admitted to the icu of sant'andrea hospital from january to june . the inclusion criteria were at least two organ systems with sofa ≥ , icu length of stay > hours. for each patient we calculated the sofa since the beginning of the inclusion criteria and daily for days. for the statistical analysis we used dynamic bayesian networks (dbns) [ ] . dbns were applied to model sofa changes in order to identify the most probable sequences of organs failures in a patient who experienced a fi rst known failure. we created a dbn for the analysis of mods studying the relations between organ failures at diff erent times. the dbn was made so that each organ failure is dependent on the previous one. we also considered a corrective factor to take account that not all patients completed the observation. using software (genie) we obtained the probabilities of the organ failure sequences. conclusion the use of dbns, although with our limited set of data, allowed us to identify the most likely organ dysfunction sequences associated with a fi rst known one. capability to predict these sequences in a patient makes dbns a promising prognostic tool for physicians in order to treat patients in a timely manner, or to test a treatment effi cacy. introduction assessing whether a critically ill patient should be admitted to an icu remains diffi cult and mortality amongst icu patients is high. to render intensive care with no prospect of success is an immense emotional burden for both patient and relatives, and a great socioeconomic burden for society as well. therefore, validated strategies that can help identify patients who will benefi t from intensive care are in demand. this study seeks to investigate whether preadmission quality of life can act as a predictor of mortality amongst patients admitted to the icu. methods all patients (> years) admitted to the icu for more than hours are included. in order to assess preadmission quality of life, the patient or close relatives complete the short-form (sf- ) within hours after icu admission. mortality is evaluated from icu admission until days hereafter. logistic regression and receiver operating characteristic analyses are employed to assess predictive value for mortality using fi ve models: introduction long-term compromise after traumatic injury is signifi cant; however, few modifi able factors that infl uence outcome have been identifi ed. the aim of this study was to identify acute and early post-acute predictors of long-term recovery amenable to change through intervention. methods adults (> years) admitted to the icu, princess alexandra hospital, australia following injury were prospectively followed. data were collected on demographics, pre-injury health, injury characteristics and acute care factors. psychosocial measures (selfeffi cacy (se), illness perception (ip), post-traumatic stress disorder (ptsd) symptoms and psychological distress) and health status (sf- ) were collected via questionnaire , , , and months post injury. outcomes of interest were the physical function (pf) and mental health (mh) subscales of the sf- . regression models were used to estimate predictors of physical function and mental health over a -year period. a subject-specifi c intercept in a mixed model was used to account for repeated data from participants over time. results participants (n = ) were young (median , iqr to years), predominantly male ( %) and spent on average days in the icu and weeks in hospital. response rates were over % at each follow-up, with responders similar to nonresponders except for being generally older. pf and mh scores improved over time, although the averages remained below the australian norms at months. predictors of pf included ip (β = - . , % ci = - . to - . , p < . ), se (β = . , % ci = . to . , p < . ), hospital length of stay (β = - . , % ci = - . to - . , p < . ), never having been married (β = . , % ci = . to . , p = . ), and having injury insurance (β = - . , % ci = - . to - . , p < . ). predictors of mh included ptsd symptoms (β = - . , % ci - . to - . , p < . ), psychological distress (β = - . , % ci = - . to - . , p < . ), se (β = . , % ci = . to . , p < . ), and unemployment (β = - . , % ci = - . to - . , p = . ). conclusion trauma icu patients experience compromised physical function and mental health months after injury. psychological distress, self-effi cacy and illness perception infl uence outcomes and are potentially amenable to change in response to interventions initiated during hospital stay. introduction swiss diagnosis related groups (swissdrg) have been eff ective since january . the infl uence of this new system on patients' discharge characteristics from a large icu is not known. with the introduction of the drg we expect patients to be discharged after a shorter length of stay on the icu and with higher severity of illness. methods the icu of the city hospital triemli in zurich has an interdisciplinary organization with surgical and internal medical patients, with a maximum occupancy of beds and a center function for the surrounding hospitals. in this ongoing prospective observational study, we collect and analyze the anonymized data of all patients discharged from our icu prior to and after the introduction of the swissdrg. the primary endpoint was the length of stay on the icu in hours. the secondary endpoints were the severity of illness of the patients at the time of discharge, detected by the scoring system saps ii as well as measured by the number of readmissions to the icu. initially all patients were analyzed and in a second step only patients within percentiles to were considered. we also analyzed the subgroups of patients referred internally, patients sent back to referring hospital and patients regionalized to a homebase hospital. the statistics have been done with spss and p < . was considered signifi cant. results we present the results of an -month period, months prior to and months after the introduction of the swissdrg. data of , and , patients were analyzed, respectively. when all patients were included, we found prior to and after the introduction of the drgs a comparable length of stay on the icu (mean ± sd of . ± . hours vs. . ± . hours), no diff erence in the severity of illness at discharge detected by the saps ii (mean ± sd of . ± . vs. . ± . ) and the number of readmissions ( vs. ). there was also no signifi cant diff erence when only percentiles to were included or when the three subgroups were analyzed. conclusion up to now, the introduction of the swissdrg has no infl uence on patients' discharge characteristics from a large icu. data assessment will continue and further data analysis has to be performed. there are only few data on the infl uence of drg on icu patients [ , ] . we expect that the introduction of the drg in switzerland will change the number of admissions from external hospitals to a large icu with a centre function and will infl uence the severity of disease of the admitted patients. the icu of the triemli city hospital in zurich has an interdisciplinary organisation with surgical and internal medical patients, with a maximum occupancy of beds and a centre function for the surrounding hospitals of the region. in this prospective ongoing observational study, we collect and analyse the anonymised data of all patients admitted to our icu from an external hospital during months prior to ( january to december ) and after ( january to december ) the introduction of the drg in switzerland. exclusion criteria are admissions by the emergency department, self-assignments into the hospital and internal relocations. the primary endpoint is the number of admissions from an external hospital to our icu. secondary endpoints are the severity of the disease of the admitted patients, detected by the scoring systems saps ii and apache ii as well as the length of stay in external hospitals before admission. the statistical analysis is descriptive. results we present the preliminary data for months (in each case january to october) before and after the introduction of the drg. we observed an increase of . % ( vs. patients) of admissions to our icu after the introduction of the drg. the severity of disease determined by the saps ii score is unchanged (mean . vs. . points, p = . ). the severity of disease determined by the apache ii score is signifi cantly lower ( . vs. points, p = . ). we also noted that after the introduction of the drg the patients were earlier transferred from an external hospital to our icu (mean time until transfer . vs. . hours), but this value was not signifi cant (p = . ). conclusion up to now the introduction of the drg in switzerland has had a complex infl uence on the number and the kind of patients (lwp, n = ); and patients whose waiting time was equal to or less than that period, short waiting period (swp, n = ). results in total, patients were included, of which belonged to the lwp group ( . %). for the entire cohort, the mean apache ii score was ± , the mean age was ± years, and patients were male ( . %). the lwp group did not show diff erence in the apache ii score ( ± vs. ± , p = . ), but was older ( ± vs. ± , p = . ). lwp also had a higher incidence of primary bloodstream infection ( . % vs. . %, p = . ) and catheter-associated urinary tract infection ( . % vs. . %, p = . ). lwp patients had higher mortality ( . % vs. . %, p = . ) and longer icu los ( ± vs. ± days, p = . ). relative risk for death in the lwp was . ( % ci: . to . ). conclusion despite showing no signifi cant diff erences on apache ii scores from the swp group, patients from the lwp group presented greater incidence of primary bloodstream infection, catheterassociated urinary tract infection, higher mortality outcomes and longer icu los. references intensivists are expected to have many roles during and after a major disaster/catastrophe; that is, triage, intensive care, education for people, and so forth. the roles of intensivists against special disaster or nuclear disaster are studied based on actual experiences. methods several disasters are studied. the fukushima daiichi nuclear plant explosion after the higashinihon earthquake was medically reviewed based on the total -day stay on-site in addition to several days around the site. the chernobyl incident was inspected years after the incident. other nuclear disasters are included. results many serious problems were revealed in the medical teams, which are as follows: inappropriate basic preparedness against large special disasters, including nuclear disaster; lack of appropriate education and training for medical teams against nuclear disasterthat is, most members of japan dmat or the disaster medical assistance team are still laypersons; incorrect standard/rules of japan dmat, which were excessively focused upon cure of the usual type of injury and planned short period or nearly hours, which should be abandoned; and insuffi cient consideration to the weak/vulnerable people or cwap, children, (pregnant) women, aged people, and the poor people/sicker patients. many of them died because of an insuffi cient emergency transportation system from their contaminated houses or hospital. conclusion in order to cope with the special disasters, such as nbc or nuclear, biological and chemical disaster, it is insuffi cient to take makeshift measures or use cheap tricks. working out the systematization of disaster medicine, based upon the academic viewpoints and philosophy/reliability, is essential to protect the people and the nation. variation in acute care burden and supply across diverse urban settings s murthy , s austin , h wunsch , nk adhikari , v karir , k rowan , st jacob , j salluh , f bozza , b du , y an , b lee , f wu , c oppong , r venkataraman , v velayutham , d angus the world bank has warned that the rapid growth of the world's urban population can only be accommodated safely if cities adequately develop key infrastructure, such as the provision of acute care resources. yet, even basic descriptive information on urban acute care supply and demand is extremely limited. we therefore conducted a pilot assessment across seven diverse urban settings across the world. we selected a convenience sample of seven large cities with varying geographical and socioeconomic characteristics: boston, paris, bogota, recife, liaocheng, chennai, and kumasi. to estimate acute care supply, we developed an instrument to collect data on acute and critical care infrastructure. we collected data from municipal authorities and local research collaborators. we expressed the burden of acute disease as the number of deaths due to acute illnesses, estimated from the global burden of disease study. results were expressed as acute care supply and acute deaths per , population and acute care supply per acute deaths. the supply of hospital beds varied from . / , population in kumasi to . / , in boston. icu beds with capacity for invasive mechanical ventilation and intensive nursing services ranged from . / , in kumasi to / , population in boston. the number of ambulances varied -fold between cities. the gap between cities widened when demand was estimated based on disease burden, with a -fold diff erence between cities in icu beds/acute deaths. in general, most of the data were unavailable from municipal authorities. conclusion the provision of acute care services, a key aspect of urban infrastructure, varied substantially across the seven diverse urban settings we studied. furthermore, the local municipal authorities generally appeared to have little knowledge of their acute care infrastructure, with implications for future planning and development. resources may not always be allocated by severity of illness, but by custom or habit, particularly if diff erent groups administer bed control and triage. specialty-specifi c diff erences may exist even when a single team controls triage. variability in resource utilization has important implications for cost-containment and triage. methods patients admitted to a single, closed medical/surgical icu with full-time intensivists and unifi ed triage control in a large, university-affi liated hospital were evaluated during to . patients who died in the icu were excluded. the day of discharge (d/c) and severity using apache iv and its related acute physiology score (aps) component were calculated daily for the fi rst days. trend was assessed across days by cuzick's test. results a total of surgical and medical patients met inclusion criteria. in total, . % of surgical and . % of medical patients had an icu los < ; p = . . admission severity was correlated with length of stay, p = . for both medical and surgical patients. medical patients are sicker on admission and d/c from the icu than surgical patients (p < . ) (figure ). conclusion icu utilization diff ered by patient type even with unifi ed triage control within a single unit. surgical patients were less severely ill on admission to and d/c from the icu. a signifi cant percentage of medical and surgical patients are d/c within day and may be more effi ciently served in a less resource-intensive environment. the reasons for the diff erences in icu utilization for surgical versus medical patients require clarifi cation and may have implications for both resource utilization and cost. introduction interest in safety and clinical outcomes of inpatients has been growing in japan, because the , lives campaign was introduced under the japanese patient safety act in . in this act, an introduction of the rapid response system (rrs) was one of the mainstreams to inpatients' care. however, many japanese healthcare providers cannot understand how to achieve the introduction of the rrs, because there are few who have knowledge of the system. therefore, we developed a new introductory training course for the rrs. the educational eff ectiveness was analyzed through the surveillance questionnaires after the course. methods the educational program includes a lecture series con cerning the outline and management methods, introduction of facilities that have already deployed, small group discussions, and teaching methods-of-training for the medical emergency team using a simulator. evaluation was made in the fi ve-point scale by participants ( physicians, nurses and eight other professions) throughout seven courses. the questionnaires are: a. understanding of rrs, b. knowledge acquisition about patient safety, c. expectation for decreasing the cardiopulmonary arrest by rrs, and d. expectation for decreasing the psychological burden by rrs. results seventy-three participants ( . %) answered the questionnaires. the numbers of participants who scored more than four points were as follows: a. was ( . %), b. was ( . %), c. was ( . %), and d. was ( . %), respectively. the majority of participants obtained the correct knowledge, and had a solid understanding for the rrs. it was evident that providing abundant material and didactic lectures traced from the introduction to management, and collecting and resolving the questions, promoted comprehension. however, there is a limitation of whether or not the participants introduce the rrs into their own institutions. it is essential to improve the course and continue to support the activities of the participants. conclusion our training course may promote the introduction and dissemination of the rrs in japan. introduction teaching of medical ethical issues including confi dentia lity and consent have long been a small part of the medical curriculum. these issues are more complex in an icu where patients may lack capacity. documents such as good medical practice , confi dentiality and the mental capacity act give guidance to medical professionals in these matters in the uk. methods a questionnaire was distributed amongst staff in four icus in south london. results were analysed according to level of experience and background (medical/nursing or allied health professional (ahp)). of questionnaires distributed, the response rate was % ( % doctors, % nurses and % ahp). staff with either less than year experience or greater than years experience had the greatest exposure to the mental capacity act and data protection act, suggesting a gap in knowledge in staff with intermediate experience. knowledge of the caldicott principles were unaff ected by experience, with many experienced respondents having 'no idea' . the majority of respondents (unaff ected by experience) felt that when giving information to relatives face to face, relatives should be kept fully informed. when giving information over the telephone, most doctors felt the response should be tailored to the knowledge of the person being spoken to whilst nurses were split between tailoring the response, giving full information, setting up a password system and not giving any information at all. most respondents felt date of birth and hospital number constituted 'patient identifi able information' . however, experienced staff did not appreciate the importance of unusual diagnosis and clinical photographs as also being able to identify patients. similarly, the majority knew that the patient themselves identifi ed the 'next of kin' but % (unaff ected by experience) felt this was decided by the family and felt the family could decide on resuscitation status. when consent is required for an elective procedure in a patient who lacks capacity, doctors tended to have a better understanding of the need to delay the procedure where possible than nurses, the majority of which felt this could be decided by the next of kin or two consultant doctors. most doctors felt that 'acting in the patient's best interests' would mean doing what would give the patient the best outcome rather than doing what the patient would have wanted (unaff ected by experience). the majority of staff , on answering this questionnaire, felt that they lacked suffi cient knowledge on the subject and most felt annual reminders would be useful. the icu is an environment where issues of consent, confi dentiality and disclosure of information occur daily. staff feel they lack knowledge in these areas that is unaff ected by their experience. we need to ensure that all staff have the necessary knowledge to deal with these situations. introduction alcohol-related hospital and icu admissions are known to have a huge impact on healthcare resources in the uk. excessive use of alcohol is independently associated with sepsis, septic shock and hospital mortality among icu patients. this study assesses the relationship between alcohol abuse and intensive care resource utilisation in a mixed medical, surgical and neurosurgical icu. methods a prospective survey of emergency alcohol-related admissions over a -year period was undertaken at a tertiary university adult general and neurosurgical icu. all patients were screened for acute and chronic alcohol abuse on admission. acute alcohol abuse was defi ned as being intoxicated with alcohol at the time of admission and chronic alcohol abuse was defi ned as chronic alcohol use exceeding recommended uk national guidelines on consumption. the amount of alcohol consumption was obtained, diagnosis on admission, icu and hospital mortality, length of stay, and total cost were recorded. all patients were screened for alcohol-related comorbidities. comparative retrospective data were obtained for the same time period for nonalcohol-related emergency icu admissions. data were analyzed using spss. results in total, . % of patients were admitted with a history of acute/chronic alcohol excess. sixty-seven per cent of alcoholrelated admissions were due to acute alcohol excess. neurosurgical patients admitted due to alcohol excess had higher itu mortality than nonalcohol-related neurosurgical patients: . % versus . % (p = . ), respectively. ninety-three per cent of alcohol-related neurosurgical admissions were caused by acute alcohol intoxication. the intensive care cost was signifi cantly higher for alcohol-related (£ , per patient) compared with nonalcohol-related neurosurgical admissions (£ , per patient). of the medical patients admitted, % of these admissions were due to acute alcohol excess. the cost of intensive care treatment was lower for alcohol-related medical admissions. conclusion this is one of the largest studies of alcohol-related admissions to critical care. our survey confi rms that alcohol-related admissions to the icu are commonplace; however, our frequency is signifi cantly less than previously reported. our study reveals interspecialty variations in demographic data, apache ii scores, mortality and cost of admission. neurosurgical alcohol-related admissions bear higher mortality and result in greater resource utilisation relative to nonalcohol-related neurosurgical admissions. alcohol continues to burden both our patients and critical care. during the fi rst three postoperative days, preoperative ahi > was associated with a prolonged weaning time, a reduced oxygenation index (arterial po /fio ), an impaired kidney function, an augmented infl ammatory response and an overall increased length of stay in the icu. the observed association of high preoperative ahi values with postoperative clinical characteristics remained statistically signifi cant throughout the fi rst three postoperative days. conclusion undiagnosed sdb is highly prevalent among cardiac surgical patients. clinical trajectories of individuals with severe sdb are described by a prolonged recovery of pulmonary function, delayed weaning and a pronounced infl ammatory response after surgery. screening for sdb might identify patients that are susceptible for a complicated postoperative course. introduction a literature review was performed to assess whether massage benefi ts patients postoperatively following coronary bypass grafts (cabg) and or valve replacement/repair. a case study on a patient who had suff ered a hypoxic brain post cardiac arrest was conducted. methods a review on medline and cochrane using search terms massage, cardiac and icu identifi ed nine research papers on the benefi ts of massage postoperatively for the aforementioned patient group. other papers were listed but unrelated to cardiac surgery. none of the nine papers identifi ed for this review were icu specifi c in the title but the icu was mentioned in the main text body. for the purpose of this review the selected papers are researching the eff ects of massage on physiological parameters, anxiety, pain, calm and perceived stress indicators in the cabg and/or valve repair/replacement. out of these nine papers, one is british ( ). five are american ( to ), two are brazilian ( ) and one is an indian paper ( ). all papers are randomised control trials (rcts). papers written prior to were excluded from this literature review. introduction vap has continued to be a major cause of morbidity and mortality in critically ill patients in thailand for decades. previous research found that the implementation of vap care bundles and the educational program can reduce vap incidence in the icu [ ] . in this research we aimed to observe the reduction of vap incidence after the implementation of vap care bundles to icu medical personnel. methods inclusion criteria: all adult surgical patients (> years old) who are on ventilatory support in the surgical icu at siriraj hospital. there are two groups, divided into pre-educational group (group i) and post-educational group (group ii) (n = /group). we also observed the adherence rate to vap care bundles according to the educational program. the pretest and post-test to determine the effi cacy of the educational program were done. the vap care bundles consisted of weaning according to weaning protocol, sedation vacation, headof-bed elevation, measurement of cuff pressures four times/day, % chlorhexidine use for mouth care and emptying of ventilator circuit condensate. results there were . and . episodes of vap per , ventilatordays in group i and group ii, respectively (p = . ). the incidence of vap was . % in group i and . % in group ii (p = . ). there was signifi cant reduction in the length of ventilatory support per person (group i = , group ii = (median), p = . , % ci = . to . ) and mortality rate (group i = . %, group ii = . %, p = . ). there was no signifi cant diff erence in loi, loh and atb cost. the pretest scores were . and . on average from medical personnel in group i and group ii, respectively (p = . ). the head-of-bed elevation adherence rate was improved after the educational program (group i = . %, group ii = . %, p = . ). but the adherence to other bundles was not improved. see tables and . introduction following our study of severe sepsis care across three centres [ ] , we aimed to introduce a rapid feedback mechanism into our rolling audit programme. whilst previous audits raised awareness of severe sepsis, only whole organisation performance was reported and no feedback was given to individual clinicians. it is recognised that such feedback loops can improve clinical practice [ ] . methods patients admitted to critical care ( beds, four units) with a primary admission diagnosis of infection were screened for severe sepsis. pre-icu care was then audited against the surviving sepsis guidelines [ ] . time zero is defi ned as when criteria for severe sepsis were fi rst met. an individualised traffi c-light report was then generated and emailed to the patient's consultant and other stakeholders involved in care (figure ). we aimed to report cases within days of critical care admission. a cumulative report is generated monthly to track organisation-wide performance. since november , cases of severe sepsis have been audited and reported back to clinicians. compliance with antibiotics in < hour has risen from to % and compliance with the pre-icu elements of the resuscitation bundle has risen from to % ( figure ). feedback from clinicians has been encouraging as our reports highlight both positive and negative examples of practice. conclusion individualised feedback on sepsis care has led to substantial improvements in guideline compliance. this concept could be translated to other time-dependent patient pathways. introduction when we talk about safety culture, we speak of being aware that things can go wrong. we must be able to recognize mistakes and learn from them, sharing that information fairly and impartially to try to prevent its recurrence. organizations such as the agency for healthcare research and quality (ahrq) have developed tools to help organizations measure their safety culture and there is little information about our country. methods a descriptive survey study. we sent the spanish version of the questionnaire on patient safety culture (ahrq) to the nursing staff of a polyvalent icu of beds in a tertiary hospital. the questionnaire was sent to nurses, receiving correctly answered surveys (response rate of . %). on a scale of to , . points was obtained to estimate the safety climate for staff respondents. the item best scored was teamwork in the unit ( . %). detected as a fortress, 'communication between nurses at shift changes' ( . % positive responses). the worst rating was obtained in the section on human resources, followed by management support in the fi eld of patient safety. conclusion the perception of safety culture in an icu by nursing staff is far from optimal levels. the team work dimension was identifi ed as the most valued by workers, with the transmission of information on shift changes the most valued item. methods to compare our number of admissions, related activity and case-mix indicators year before and after the geographical change was done. we analyzed our whole number of patients admitted to the icu. we used the chi-square test for categorical variables and one-way analysis of variance for quantitative data. minitab and statbas statistical programs were used. we plotted activity data using the barber-johnson diagram. results a total of , cases ( % males; mean age years) were admitted to our icu during the period ( year before and after the transfer). no diff erences between both groups were founded in demographic data, knaus score and nyha status. regarding their origin, we found more patients admitted from other hospital centers ( vs. %; p < . ). apache ii score increased from . to . % (p < . ) and a slight increase change in saps score was also found ( . to . ; p < . there are several defi nitions of level (l ) care, all refer to a group at risk of clinical deterioration on the ward [ ] [ ] [ ] . there is evidence that ward patients who become acutely unwell often receive suboptimal care [ ] . a regional study commissioned by norfolk, suff olk & cambridgeshire critical care network (nscccn) found that a majority of ward patients may be of l dependency and death rates appear to be correlated with l status. we aim to examine the relationship between the ward distribution of illness acuity, staffi ng and patient outcome. methods data were collected as part of nscccn's observational prevalence study in . ward surveys included acuity of illness, staffi ng levels and skill mix. secondary data were obtained from the patient administration system. emergency, oncology, paediatric and maternity units were excluded. results complete datasets were obtained from , patients in wards in our university hospital over two seasons. this constitutes . % of inpatients from those wards. the mean ward occupancy rate was % ( th to th percentile: % to %). at least one l acuity criterion was scored by ( %) patients, with % from geriatrics followed by orthopaedics ( %) and general surgery ( %). each ward had an average of eight qualifi ed nursing staff (range: to ) equating to an average staff :patient ratio (spr) of . . there was no correlation between ward occupancy and nursing staff (pearson correlation, corr: . ), nor between prevalence of l criteria and staffi ng (corr: . ). the admission rate to intensive care was noted to be higher if the patients were nursed in a ward with lower than average spr compared with higher spr ( . % vs. . %, p = . fisher's exact), but this was not statistically signifi cant. senior nursing (band ) staff were part of the skill mix on only nine of ward surveys. conclusion better outcome with improved spr may be unsurprising, although if proven conclusively would signifi cantly inform workforce planning. lack of correlation between staffi ng levels and occupancy or acuity is also interesting given that we know l criteria are associated with worse outcome. introduction prolonged shifts, workload, stress, and diff erent confl icts are associated with burnout, loss of psychological wellbeing, and probably with an inadequate sleep quality (isq). this relevant disturbance leads to deterioration of the work performance, may impair quality of care provided to patients and increases the incidence of serious adverse events. the objective was to determine the prevalence of isq and sleepiness among uruguayan icu workers, and to evaluate risk factors associated with isq. methods a survey was conducted in six uruguayan icus. the sleep quality was evaluated on the basis of the pittsburgh score (ps), and the sleepiness was identifi ed by the epworth scale. isq was defi ned as ps greater than points and sleepiness by an epworth scale higher than points. icu's, patient's, and clinician's characteristics were assessed for their association with the prevalence of isq. all variables with p < . in univariate analysis were included in a model of ordinal regression. p < . was considered statistically signifi cant. results the survey was completed by icu workers. the global prevalence of isq in icu was . %. isq was observed in % of physicians and % of nurses and nurses assistant (p < . ). sleep medication was used by . % of the icu team. univariate analysis showed that isq was signifi cantly associated with sex ( % vs. %, p = . in women and men, respectively), marital status ( % vs. %, p = . in single and couple workers, respectively), more than hours working in the last week ( % vs. %, p = . ) and less than sleeping hours ( % vs. %, p < . ). multivariable analysis demonstrated that a sleep duration less than hours was independently associated with isq (or = . ; % ci = . to . ; p < . ). furthermore, pathologic sleepiness was present in . % of icu workers. sleepiness was independently associated with use of sleep medication (or = . ; % ci = . to . ; p = . ). conclusion the prevalence of isq and sleepiness is very high among icu workers. those disturbances are independently associated with a sleep duration less than hours, and sleep medication use, respectively. these results highlights that strategies to decrease isq and sleepiness in icu clinicians are urgently needed to improve work performance, improve quality of care provided and prevent adverse events. introduction work-related stress is a potential problem among doctors and is associated with anxiety, depression, reduced job satisfaction, days off work, errors and near misses [ ] . to compare stress levels between diff erent groups of doctors and identify causes of stress, we conducted a survey at university hospital lewisham using the uk health and safety executive's management standards (hsems). hsems is a validated tool developed to identify work conditions that warrant interventions to reduce stress levels across organisations [ ] . methods we conducted an anonymous survey of doctors working in anaesthetics, intensive care, general medicine and accident and emergency (a&e) departments over weeks using the hsems question naire. we also surveyed awareness of the trust's stress management services and whether staff had a designated supervisor or mentor. results were analysed using the hsems analysis tool, which rates stressors with a score from to ( represents the lowest amount of stress). we compared the trust's results against hsems national standards. results seventy-two doctors completed the survey. lowest stress levels were found in doctors working in intensive care (n = , mean . , sd . ). this was followed by medicine (n = , mean . , sd . ), anaesthetics (n = , mean . , sd . ), and a&e (n = , mean . , sd . ), which had the highest stress levels. there was no signifi cant diff erence in stress levels between diff erent grades of doctors. when compared with hsems targets, staff relationships and peer support exceeded national standards. however, management of organisational change and demands at work need improvement. the majority of doctors ( %) had no idea what stress management services were provided by the trust. seventy-nine per cent of doctors had an allocated supervisor or mentor, % of those felt able to approach their supervisor. conclusion these survey results provide reassurance that stress levels in intensive care compare well, despite critically unwell patients and higher mortality rates. we identifi ed areas that need improvement within the trust and will present these results to all relevant departments. with the support of hospital management we will initiate hsems-validated measures to reduce stress. introduction although recent reports show an improvement in outcomes for pediatric hematology patients requiring intensive care [ , ] , respiratory failure remains one of the major risks of pediatric mortality. this study was conducted to assess our hypothesis that mortality associated with respiratory failure is higher than that for other organ failures in pediatric hematology patients admitted to our icu. methods a retrospective study analyzed children with hematological disorders admitted to our icu between april and june . all of the included children required emergency admission and invasive mechanical ventilation. those who did not need intubation, or required intubation only for therapeutic intervention and died within hours of icu admission were excluded. the survival group was defi ned as patients who were discharged from the icu, and the nonsurvival group was defi ned as those who died in the icu or within days after discharge from the icu. the pelod score and pim-ii were applied as morbidity scoring systems results twenty-seven patients, including males and nine females, with a median age of . years (range, . to . years) were analyzed. sixteen patients had leukemia, fi ve had hemophagocytic syndrome, six had solid tumors. the average predicted mortality rate was . % in pim-ii. the survival group included patients ( %) and the nonsurvival group included patients ( %). when the survival group was compared with the nonsurvival group, there were no signifi cant diff erences in the systolic blood pressure ( . ± . mmhg vs. . ± . mmhg; p = . ), the proportion of patients requiring continuous renal replacement therapy ( . % vs. . %; p = . ), and pelod score ( . ± . vs. . ± . ; p = . ). in the nonsurvival group, the pim-ii was higher than that in the survival group ( . ± . vs. . ± . ; p = . ); the pao /fio ( . ± . vs. . ± . ; p = . ) and oxygenation index ( . ± . vs. . ± . ; p = . ) were signifi cantly worse in the nonsurvival group than in the survival group. conclusion the data show that respiratory failure is more strongly associated with mortality than other organ failures in pediatric hematology patients requiring intensive care. these results also suggest that mechanical ventilation intervention in patients with respiratory failure must occur earlier to improve the outcomes for these patients. introduction critically ill patients with haematological malignancies (hm) have high hospital mortality [ ] . severity of illness scores may underestimate mortality in such patients [ ] . methods data collection was conducted at three hospitals from to . patients with any active hm condition were matched with two control patients at two hospitals and with one control at christie hospital. control patients had the same apache ii (within points) and admission diagnosis, but no hm. readmissions and planned surgical cases were excluded. results a total of patients with hm were compared with control patients. seventy-four admissions with hm were identifi ed at two hospitals, and each was matched with two control patients. eightynine admissions with hm from christie hospital were identifi ed. these were matched with controls. patients with hm spent signifi cantly longer in hospital before icu admission (table ) . unit and hospital mortality rates were not statistically diff erent between patients with hm and without hm ( table ) . conclusion unit mortality of critically ill patients with hm was similar to those without hm. hospital mortality in patients with hm was higher than those without hm, although not statistically signifi cant. severity of illness at presentation to critical care is the main determinant of outcome in patients with hm. group when requiring emergency admission to the icu in a tertiary cancer centre. methods a retrospective review of medical notes between and . results a total of patients were admitted, of whom had more than one admission. there were episodes in total. leukaemia n = ; lymphoma n = ; myeloma n = . we compared the characteristics of those who survived icu admission with those who failed to survive to discharge from icu. the two populations were similar (age vs. ; males % vs. %). those who survived had a lower apache ii score on admission ( vs. ; p < . ), lower mean organ failure scores ( vs. ; p < . ), lower requirements of inotropes ( % vs. %; p = . ), ventilation ( % vs. %; p = . ) and fi ltration ( % vs. %; p = . ). there was no diff erence in the prevalence of sepsis at the time of admission ( % vs. %). both groups included patients with prior bone marrow transplant ( % vs. %). of note, icu and -month survival were % and %, respectively. these values are lower than those reported in the literature to date. conclusion icu and -month mortalities were % and %, respectively. patients with haematological malignancy stand to benefi t from intensive care, and should be off ered admission based on clinical need. introduction many evidence-based interventions are not delivered to patients [ ] . this may not be due to a clinician's intentional decisions. the aim of this project was to compare the use of starch before and after removing it as an option from an e-prescribing template. methods our e-prescribing software enables users to prescribe intravenous fl uids from a series of menus. one of these is a template that has several fl uids available to use as a bolus when instructed by a clinician. we removed starch as an option from the template in april . starch could still be prescribed elsewhere on the prescribing system. data on the use of starch from november to november were analysed as the mean volume of starch infused per patient per month. the mean of each set of parameters was then compared using a student's t test. results the mean volume of starch per patient administered before and after electronic prescription options were altered was ml and ml, respectively (p = . ). see figure . conclusion despite clinicians intending to reduce the use of starch it was still regularly administered on our icu. the removal of a default prescribing option dramatically reduced the volume of starch used whilst not restricting the ability to make a conscious choice to prescribe it. adjusting default options has potential to infl uence clinical decisions and ensure more reliable, evidence-based care. introduction early detection of sepsis is important for a suffi cient treatment to reduce mortality. we hypothesized that using modifi ed systemic infl ammatory response syndrome criteria over hour using an electronic software program facilitates the clinical diagnosis of sepsis. methods after irb approval and informed consent we enrolled in this prospective, observational, single-center study , consecutive patients (age . ± . , female/male / ) admitted over a -month period to a surgical icu. a total of them met modifi ed systemic infl ammatory response criteria. patients were monitored by an electronic software program using live data from the laboratory and bedside monitors to detect modifi ed systemic infl ammatory response syndrome criteria persisting over hour. the physicians were blinded to the software program alerts that notifi ed in real time when modifi ed systemic infl ammatory response syndrome criteria were detected and persisted over hour, but did not provide treatment recommendations. results there was a total of modifi ed systemic infl ammatory response syndrome criteria alerts. seventy-four were confi rmed as true sepsis cases by physicians. the overall incidence of sepsis was %. patients were categorized into length of stay < hours, to hours and > hours. the overall sensitivity of our system for detecting sepsis was % and the specifi city was %. the positive predictive value is % and the negative predictive value is %. conclusion real-time alerts using an automated, electronic monitoring of modifi ed systemic infl ammatory response syndrome criteria facilitate the clinical diagnosis of sepsis. beds. intentional rounds or proactive patient rounds were recognised by the royal college of physicians and the royal college of nursing [ ] as structured, evidence-based processes for nurses to carry out regular checks with individual patients at set intervals. the senior nursing team decided to adapt this initiative to the intensive care setting in order to address clinical challenges and provide guidance for shift leaders to focus on key elements of care. methods our intentional rounds, performed once per shift (twice daily), include two components. first, pressure area care -this component involves the shift leader checking whether key elements of pressure sore prevention have been performed. these include completion of the waterlow risk assessment tool [ ] , noting the frequency of repositioning, use of lateral positioning and pressure-relieving pads. second, renal replacement therapy rates -this element was identifi ed as an area for focus after we established that our haemofi ltration fl uid use per hour of therapy was twice that of a near identical clinical setting. this pattern continued even after adopting similar therapy guidelines. the shift leader was guided to check whether therapy rates had been adjusted in line with latest biochemical results. the incidence of pressure ulcers in the months since the initiative began has averaged . per month compared with . per month prior to commencement of intentional rounding. added to the rounding tool at the end of september , rrt rates in the preceding months averaged . ml/kg/hour over hours, an . % reduction from the previous average of . ml/kg/hour. if the pattern of rrt was to continue, this could equate to a cost saving of uk£ , per annum. conclusion the use of a modifi ed targeted intentional rounding tool by the nursing shift leader can help ensure that best practice guidelines are adhered to. this strategy can improve patient outcomes and provide potentially signifi cant fi scal benefi ts. references introduction handovers are often associated with poor communi cation. icu patients with multiple complex problems are ideal to study naturally occurring handovers. however, few studies have been conducted in the icu. methods we conducted questionnaires of physicians and nurses involved and observed handovers in real time of medical icu patients over month. we interviewed of physicians and nurses involved ( . %) and observed real-time handovers ( patients, . %) of patients. mean duration of handover was . (± . ) seconds, . % were face to face and . (± . ) distractions per handover were noted, person-to-person calling being the commonest mode of distraction ( . %). nurses received training during induction in signifi cantly higher numbers, covered allied specialties more and reviewed the patients early (all p < . ). perception of the relative importance of diff erent components of the handover varied signifi cantly between donors, recipients, physicians and nurses. both physicians and nurses seldom ( . %) reviewed the available electronic past medical records of the patient before handover, which in addition to training in handover and overall confi dence level in the management following handover are signifi cantly associated with better satisfaction in univariate analysis; only the confi dence level in patient management remained signifi cant after multivariate analysis. however, agreement between donor and recipient on overall satisfaction was poor (p > . ). nursing handovers were signifi cantly longer than physicians' ( . ± . vs. . ± . seconds, p < . ) but are also associated with higher distractions particularly during evening shifts. conclusion a higher percentage of nurses received handover training; nursing handovers are longer and more inclusive of other components of patient management; perceived importance of components of handover varies among healthcare professionals; distractions are common during handovers and associated with longer duration, by nurses and in the evening shifts; and higher confi dence level in patient's management following the handover is associated with better satisfaction. using telemedicine to provide acute burn and critical care consultation on pediatric and adult burn patients in lviv, ukraine, as well as in triage and transport of critically ill patients from lviv to a tertiary-care facility in the usa for further management. methods using a new telemedicine learning center established at city hospital # in lviv, ukraine, consultations regarding acutely injured burn victims occurred between physicians in ukraine and physicians at shriners hospital and massachusetts general hospital in boston. after the initial presentation, each patient was reviewed on a daily basis by physicians in boston. skype, an internet-based communication tool, was used in communication with the burn center in lviv. radiographic images were scanned and digitalized using an electronic scanner, and jpeg image compression was used to facilitate the transmission of radiographic images and patient charts. informed consent and hippa guidelines were followed in transmitting any patient-related information. results since we have provided consultation on patients in lviv, ukraine, ranging in age from months to years. each patient had an average of six consultations. we present two of these cases as examples of the capabilities of our telemedicine program. the fi rst case involved a -month-old female with % tbsa from scald injury, where telemedicine was instrumental in the primary assessment as well as to arrange a direct assessment from a nearby burn surgeon. the second case resulted from a house fi re with multiple casualties, where physicians in boston were able to utilize telemedicine to guide the initial resuscitation and airway management of three critically burned children, as well as to arrange for transport of one of the victims, an -year-old male with % tbsa, from ukraine to the usa for acute management. multiple diffi culties were overcome in implementing the system between the two countries including: time zone diff erences, language barrier, and diff erent approaches to patient care. conclusion we have established a telemedicine program linking physicians in boston, ma, usa with city hospital # in lviv, ukraine to improve care in pediatric and adult burn patients. our program has provided consultation on patients since , and it highlights the capabilities of telemedicine for acute consultation as well as triage and transport of critically ill patients to tertiary-care facilities. introduction during the last few years the frequency of end-oflife decisions (eold) signifi cantly increased in icus. the method of nurse involvement in making eold is diff erent worldwide [ , ] . the purpose of this study was to analyze opinions of nurses about therapy restriction. we have examined with a multicenter study the opinions of the medical stuff about end-of-life care in hungarian icus. methods we performed a questionnaire evaluation among physicians and nurses of icus about infl uencing factors of therapy restriction, the method of the decision-making process, and the frequency of diff erent eold. the questionnaire, containing questions, was delivered electronically to hungarian icus, and then we analyzed the responses anonymously. the retrieved answers ( physicians, nurses) were analysed using a nonparametric student's test. results a total % of the nurse responders work in university clinics, % in regional centrum, % in municipal hospital, % in other icus. the nurses found both human ( . / vs. . / ) and material ( . / vs. . / ) resources more restrictive factors during patient admission than physicians (p = . , p = . ). nurses working in municipal hospital were more strongly infl uenced by lack of material and human resources ( . / , . / ) than nurses working in university clinics ( . / , . / ), p = . , p = . . younger nurses (working between and years) were more interested in the patient's or surrogate's wishes than older nurses (working more than years). religion did not infl uence patient admission and forego therapy; however, religious nurses compared with atheists and nonpracticing believers preferred to prolong therapy against the patient's will (p = . ). nurses felt that physicians slightly involved them in the end-of-life decision-making process ( . / vs. . / p = . ). conclusion we found that the workplace, level of medical attendance, godliness, work experience, and position in medical staff strongly infl uenced making eold. while limitation of the therapy should be team work, nurses felt their opinions were hardly taken into consideration, although nurses seemed to be more realistic in the decision-making process. introduction more than one in fi ve people admitted to an icu will die there. research has highlighted concerns about support for patients and families and decision-making in this context [ , ] . here, we describe the development and evaluation of a tool to improve palliative care in a -bed general icu in a central london teaching hospital. methods medical research council guidance for complex interventions phase to i comprised literature review, theoretical modelling, observation and qualitative interviews and focus groups with staff and families exploring concerns and views of interventions identifi ed in the literature review. phase ii comprised intervention development, implementation and evaluation of tool feasibility and eff ects using staff survey, observation, audit of records and relative survey. results phase i: staff and family members were interviewed. the short time between decisions for treatment withdrawal and death, plus concerns for support management, communication and decision-making, highlighted a need to ensure excellent psychosocial assessment for all. phase ii: as part of integrated care guidelines, we developed the king's psychosocial assessment and care tool (k-pace). k-pace is used for all patients entering the icu, completed within hours of admission. it contains psychosocial assessment of the family and patient needs, and identifi es key individuals for contact. educational training was supported by k-pace and was implemented in two waves. post-implementation survey of icu staff found that most ( %) were aware of k-pace. eighty-two per cent of nurses but only % of doctors had completed the tool. in total, / ( %) family members responded to the survey (additionally three patients responded). there were high levels of satisfaction for symptom control and psychosocial care but concerns continued regarding explanation of treatment and care. conclusion k-pace is a feasible tool to improve the palliative care of patients and their families in the icu. further refi nement is needed and planned, with consideration of roll-out into the wider medical centre. be concerned involving the family's will. especially, stopping or withdrawing therapy is a quite diffi cult operation in japan because of legal issues. our hypothesis is that some diff erence exists in thoughts between physicians and nurses for terminal patients in the icu. the aim of this study is to know their real thoughts. methods a questionnaire survey was performed on physicians and nurses in our medico-surgical icu. the questionnaire consists of questions with fi ve optional answers related to the thoughts of participants about treatment of hopeless or brain death patients. concretely, the questions were; whether to withhold therapy or not, whether to accept to withdraw therapy or not and with family's will, whether to accept to immediately stop therapy and with family's will, whether to positively or not donate organs from a brain death patient, necessity of icu care for brain death patients, and feeling guilty and stress for stopping or withdrawing therapy. the optional answer has fi ve gradations from 'yes' to 'no' for all questions. the participants were asked to answer the questionnaire by expressing themselves without regarding legal issues or the consensus. it was guaranteed to be anonymous for them in the data analysis. the answers were compared between physicians and nurses. the mann-whitney u test was used for statistical analysis. p < . was considered statistically signifi cant. results there were in total participants (response rate . %) with physicians and nurses. withdrawing therapy was signifi cantly accepted in nurses than in physicians ( % vs. %, p = . ), when the family well understood. withholding therapy should not be operated for brain death patients for physicians ( %), while it seemed a diffi cult judgement for nurses ( %, p = . ). icu care for brain death patients is less necessary for physicians than nurses ( % vs. %, p = . ). there were no signifi cant diff erences in other questions between physician and nurses such as feeling guilty or stress for stopping or withdrawing therapy. conclusion some of end-of-life thoughts in the icu showed diff erences between physicians and nurses. introduction optimal patient evaluations of icu rehabilitation therapy remain unclear. methods one hundred icu patients with acute respiratory failure were randomized to receive early rehabilitation (er) or usual-care (uc). cohort (n = ) received er as one physical therapy (pt) session/day versus uc; cohort (n = ) received er as pt/day with the second session resistance training, versus uc. uc was without er. blood was drawn for cytokines through day . cohort underwent strength and physical functional assessments using the short physical performance battery (sppb), a valid and reliable measure of physical function consisting of walking speed, balance, and repeated chair stands. it is a well-studied composite measure in older persons, but has not been used in icu survivors. small changes of . to . points in the sppb have been shown to be clinically meaningful. conclusion in this pilot study, early icu rehabilitation was safe, and was associated with numerically although not statistically shorter hospital stay, greater strength and improved functional scores. particularly, the sppb demonstrated discriminatory ability in groups of icu survivors with low physical function. future early icu rehabilitation studies should consider icu survivor assessments using the sppb due to its ease, reproducibility and discriminatory ability following icu and hospital discharge. of the demographic variables such as sex, age, education, race and length of stay had an eff ect on perceived quality of care. conclusion the cqi 'r-icu' turned out to be a valid, reliable, sensitive and feasible instrument. large-scale implementation is recommended. actual incidence of global left ventricular hypokinesia in adult septic shock sepsis and the heart cardiovascular biomarkers in the icu plasma endothelin- levels in septic patients the role of endothelium and endogenous vasoactive substances in sepsis nicotinic acetylcholine receptor α subunit is an essential regulator of infl ammation cholinergic agonists inhibit hmgb release and improve survival in experimental sepsis thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome infl ammation, stress, and diabetes procalcitonin increase in early identifi cation of critically ill patients at high risk of mortality post-operative hypoalbuminaemia and procalcitonin elevation for prediction of outcome in cardiopulmonary bypass surgery enhanced oxygen delivery by perfl ubron emulsion during acute hemodilution iv perfl ubron emulsion versus autologous transfusion in severe normovolemic anemia: eff ects on left ventricular perfusion and function effi cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial nosocomial infections in a cohort of extracorporeal life support patients the epidemiology and outcome of medical emergency team call patients treated with non invasive ventilation early prehospital use of non invasive ventilation improves acute respiratory failure in acute exacerbation of chronic obstructive pulmonary disease bts guidelines for the management of community acquired pneumonia in adults: update smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia the smart-cop score performs well for pneumonia risk stratifi cation in australia's tropical northern territory: a prospective cohort study application and comparison of scoring indices to predict outcomes in patients with healthcare associated pneumonia eff ects of continuous positive airway pressure in acute asthma noninvasive positive pressure ventilation in status asthmaticus eff ect of nasal continuous positive airway pressure on methacholine-induced bronchoconstriction the royal college of anaesthetists [www.rcoa.ac.uk/nap ] . diffi cult airway society equipment list cochrane handbook for systematic reviews of interventions. version . . . the cochrane collaboration proceedings book of th congress of the society of critical care medicine early goal-directed therapy in the treatment of severe sepsis and septic shock oxygen transport in cardiogenic and septic shock evidence based of the use of the pulmonary artery catheter: impact data and complications the eff ectiveness of right heart catheterization in the initial care of critically ill patients statistical methods for assessing agreement between two methods of clinical measurement use of central venous oxygen saturation to guide therapy comparison of central-venous to mixed-venous oxygen saturation during changes in oxygen supply/demand systematic review and meta-analysis on the use of preemptive hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients intraoperative fl uid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized study accidental catheter removal in critically ill patients: a prospective and observational study national patient safety agency: reducing harm caused by the misplacement of nasogastric feeding tubes. npsa/ /psa . nhs national patient safety agency: reducing the harm caused by misplaced nasogastric feeding tubes. npsa/psa ./psa . npsa epidemiology of severe sepsis in the usa: analysis of incidence, outcome, and associated costs of care post-injury multiple organ failure: the role of gut probiotics in the intensive care unit measures of crowding in the emergency department: a systematic review measuring and forecasting emergency department crowding in real time promoting global research excellence in severe sepsis (progress): lessons from an international sepsis registry interhospital transfer of critically ill patients: demographic and outcomes comparison with nontransferred intensive care unit patients outcomes of patients admitted to tertiary intensive care units after interhospital transfer: comparison with patients admitted from emergency departments outcome of critically ill patients undergoing interhospital transfer brain tissue oxygen monitoring and hyperoxic treatment in patients with traumatic brain injury association between early hyperoxia and worse outcomes after traumatic brain injury both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury focused assessment with sonography in trauma (fast): should its role be reconsidered? it's higher than you think: chest drains and the th ics tube thoracostomy: complications and its management bts guidelines for the insertion of a chest drain american college of surgeons committee on trauma: advanced trauma life support for doctors, course manual. chicago: american college of surgeons american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care heart rate response to hemodialysis-induced changes in potassium and calcium levels survival in cancer patients undergoing in-hospital cardiopulmonary resuscitation: a meta-analysis acute intrathoracic gastric herniation as a rare cause of cardiac arrest dw hoelen references . kern kb: optimal treatment of patients surviving out-of-hospital cardiac arrest immediate coronary angiography in survivors of outof-hospital cardiac arrest immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest hypothermia for neuroprotection in adults after cardiopulmonary resuscitation investigation and early management of head injury. london: national collaborating centre for acute care updates in the management of intracranial pressure in traumatic brain injury guidelines for the management of severe traumatic brain injury bundled care for septic shock early prognosis in traumatic brain injury: from prophecies to predictions one-year extended glasgow outcome scale and hospital mortality predictors in patients with severe traumatic brain injury in brazil r turon , fr ferreira , d prado bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors prophylactic anticoagulation with enoxaparin: is the subcoutaneous route appropriate in the critically ill? s -s . p massive blood transfusion for obstetric haemorrhage s simmons graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial the rule regulating ph changes during crystalloid infusion in vivo conditioning of acid-base equilibrium by crystalloid solutions: an experimental study on pigs mixing of medicines prior to administration in clinical practice: medical and non-medical prescribing procedural sedation goes utstein: the quebec guidelines barriers to propofol use in emergency medicine international sedation task force: adverse event reporting tool to standardize the reporting and tracking of adverse events during procedural sedation: a consensus document from the world siva international sedation task force mediators infl amm acute kidney injury in an infant after cardiopulmonary bypass predictive power of serum cistatin c red cell distribution width improves the simplifi ed acute physiology score for risk prediction in unselected critically ill patients red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy incidence and prognosis of intraabdominal hypertension in a mixed population of critically ill patients: a multiplecenter epidemiological study eff ect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients acute renal failure in critically ill patients: a multinational, multicenter study impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome cirrhotics admitted to intensive care unit: the impact of acute renal failure on mortality hyponatraemia as a risk factor for hospital mortality albumin-adjusted calcium is not suitable for diagnosis of hyper-and hypocalcemia in the critically ill derivation and internal validation of an equation for albumin-adjusted calcium conclusion succinate ameliorates (but does not return to normal) references . uk prospective diabetes study group p root cause analysis of hypoglycemic events in critically ill patients a mcdonald offi ce of national statistics population data sccm/esicm/accp/ats/sis international sepsis defi nitions conference the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome the logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit visualizing multiple organ failure: a method for analyzing temporal and dynamic relations between failing systems and interventions modelling gene expression data using dynamic bayesian networks disaster medicine compendium team japan critical care university of toronto, canada; intensive care national audit & research centre oswaldo cruz foundation, rio de janeiro, brazil; peking union medical college hospital standards for consultant staffi ng of intensive care units. ics & ibticm standards eff ectiveness of an educational program to reduce ventilatorassociated pneumonia in a tertiary care center in thailand: a -year study multi-departmental system analysis is needed for evaluation of severe sepsis care: a multi-centre study audit and feedback: eff ects on professional practice and health care outcomes surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock levels of critical care for adult patients acutely ill patients in hospital. nice guideline . nice an acute problem? ncepod hse management standards and stress-related work outcomes references . centre for maternal and child enquiries: saving mothers' lives: reviewing maternal deaths to make motherhood safer: - . the eighth report on confi dential enquiries into maternal deaths in the united kingdom % in non-infected patients, p = . ) and . % were under haart ( . % in patients admitted without infection, p = . ). mean cd count at admission: . ± . cells/mm (vs. . ± . , p = . ) ) and . % renal replacement ( . % in no septic patients, p = . ). mean icu and hospital los was ± . days (p = . ). icu mortality: . % ( % in nonseptic patients, p = . ) conclusion sepsis is a common reason for admission to the icu in hiv patients and is accompanied by high mortality. pneumonia is the most frequent source of infection. septic patients are less frequently under haart and have a worse inmune status (lower cd count and higher viral load). despite a higher apache ii, and a higher need for hemodynamic and respiratory support, there is no statistically signifi cant diff erence in icu and hospital mortality between septic and nonseptic patients p survival of critically ill patients with haematological malignancies compared with patients without haematological malignancy r pugh the outcome of haematological malignancy in scottish intensive care units intensive care unit admission in patients with haematological disease: incidence, outcome and prognostic factors intensive care management of patients with haematological malignancy comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel mm-comorbidity score icu and -month outcome of oncology patients in the intensive care unit assessing the quality of interdisciplinary rounds in the intensive care unit uni-and interdisciplinary eff ects on round and handover content in intensive care units perspective: physician leadership in quality rcn: ward rounds in medicine. principles for best practice. london: royal college of physicians, royal college of nursing the importance of accurate risk assessment and appropriate intervention in tissue viability handover in the emergency department: defi ciencies and adverse eff ects communicating in the 'gray zone': perceptions about emergency physician hospitalist handoff s and patient safety a national survey of end-of-life care for critically ill patients nurse involvement in end-of-life decision making: the ethicus study p alternative to improve palliative care for all patients and families in critical care units: development and preliminary evaluation following mrc guidance of the king's psychosocial, assessment and care tool i higginson, c rumble half the families of icu patients experience inadequate communication with physicians confl icts between physicians' practices and patients' wishes improving the quality of end-of-life care in the pediatric intensive care unit: parents priorities and recommendations on speaking less and listening more during end-of-life conferences evaluating end of life in ten brazilian pediatric and adults intensive care units parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit ) and sepsis (p = . ) were signifi cantly diff erent between responders and nonresponders. responders had a lower mean gcs ( ± vs. ± ), lower amount of edema and were less likely to have had sepsis. in a multiple regression analysis, sepsis, edema, bmi and age explained % of the variance conclusion in patients with a better neurological condition, sepsis and/ or leg edema it was more diffi cult to obtain an adequate quadriceps contraction with nmes. nmes is safe to apply on the icu. references . dh and modernisation agency: the national outreach report. london: nhs modernisation agency pilot study of early rehabilitation strategies in acute respiratory failure d files physical rehabilitation following critical illness long term outcome from critical illness cg critical illness rehabilitation: guideline public health resource unit: critical appraisal skills programme. questions to help you make sense of qualitative research quality measurement at intensive care units: which indicators should we use? handboek cqi ontwikkeling: richtlijnen en voorschriften voor de ontwikkeling van een cqi meetinstrument using the commissioning for quality and innovation (cquin) payment framework -guidance on national goals for refi nement, scoring, and validation of the family satisfaction in the intensive care unit (fs-icu) survey our data showed no benefi t with the use of a potent statin acutely in patients with sepsis or septic shock with regards to improvement in endothelial function. references conclusion the use of the lps-selective adsorption (particularly pmx-f) in patients with severe sepsis leads to improvement of systemic infl ammation and organ dysfunction. references s on these data we will continue to the next phase of this project and test pfc in the prevention of ards alone, and in combination with hs. references conclusion pp seems safe in obese patients and may improve oxygenation more than in nonobese patients. obese patients could be a subgroup of ards patients who may benefi t most from pp. references long-term functional outcome in adults with severe tbi: a meta-analysis m asselin , y lachance , g lalonde introduction two previous classifi cations of acute kidney injury (aki) that are known as rifle criteria and akin criteria have shown that aki is associated with increased morbidity and mortality. diff erences in predicting ability for prognosis, however, have been reported. in , kidney disease improving global outcomes (kdigo) created the new aki criteria, combining rifle and akin criteria. however, such a combination might cause inconsistency among each defi nition in the criteria. we have investigated all of the defi nitions in the new kdigo criteria in detail. methods this is a retrospective historical cohort study including adult patients admitted to the icu (jikei university, tokyo, japan) between january and october . patients undergoing chronic dialysis were excluded. kdigo criteria were applied to all patients to diagnose aki. hospital mortality of patients with aki diagnosed by the defi nitions in the criteria was compared. results a total of , patients were evaluated. aki occurred in . % with standard defi nition of kdigo; . % with creatinine criteria alone; . % with urine output alone. by multivariable analysis, each aki stage was associated with hospital mortality: . %, odds ratio . , for stage ; . %, odds ratio . , for stage ; . %, odds ratio . , for stage . crude hospital mortality stratifi ed by the defi nitions showed increasing trends with stage progression. mortality of the three defi nitions in stage was from . % to . %. stage had two defi nitions and their mortality was . % and . %. stage had fi ve defi nitions and their mortality was from . % to . %. conclusion aki defi ned by the new kdigo criteria was associated with increased hospital mortality. in addition, defi nitions in the kdigo criteria seem to be appropriate because of clear relations between mortality and stage progression. introduction to evaluate whether urinary neutrophil gelatinaseassociated lipocalin (ungal) detects acute kidney injury (aki) earlier than the estimated glomerular fi ltration rate (egfr) in cardiac surgery patients. methods two-hundred and seventy-four adult patients undergoing cardiac surgery were consecutively included from february to december . exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and a previous cardiac catheterism with i.v. contrast use the week before surgery. four serial blood and urine samples immediately before (pre) and after (post) surgery, and day ( d) and days ( d) after surgery were obtained. ungal was measured in an architect (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. delta ungal was defi ned as the diff erence between the pre and the posts concentrations. results one-hundred and eighty-one patients ( . %) were men; mean age was . ± . years. valve replacement was performed in , coronary artery bypass graft (cabg) in , valve surgery + cabg in , cardiac transplant in fi ve, aorta aneurism surgery in nine, and other procedures in eight patients. icu and hospital stays were . ± . and . ± . days, respectively. renal replacement therapy (rrt) was required in patients ( . %) within hours of icu stay and in patients ( . %) within weeks. mortality at days was . %. eighty-six patients ( . %) were diagnosed with aki within hours of surgery. area under the roc curve of post ungal for aki diagnosis was . ( . to . ) (p < . ) at an optimal cutoff value of μg/l, introduction acute renal failure (arf) is a common complication in patients admitted to the icu. sepsis is also a well-known risk factor for the development of arf. the combination of arf and severe sepsis was reported to carry a mortality up to % whereas the mortality of arf alone is to %. the aim of the study is to evaluate the role of renal perfusion scanning in detecting the prognosis and outcome of patients with acute renal failure due to sepsis. methods forty patients with acute renal failure due to sepsis, aged between and years, were enrolled in the study. they were monitored for their icu prognosis and outcome after doing renal perfusion scanning. all patients were subjected to routine icu and laboratory investigations including apache ii and sofa score. results thirty patients had normal renal scan and patients had abnormal renal scan. the mortality percentage was higher among abnormal renal scan cases (three out of , %) compared with cases with normal renal scan (seven out of , . %) with nonsignifi cant p value: . . the median length of stay/day in icu was longer among nonsurvivors than survivors . ± , . ± , p value: . (approaching signifi cance). apache ii score was higher in nonsurvivors than survivors . ± . , . ± . , p value: . . the percentage of mortality among cases that needed mechanical ventilation was higher (nine out of , . %) compared with mortality cases that did not need mechanical ventilation (one out of , . % with p value: . ). conclusion arf may exert an independent adverse eff ect on outcome in septic and septic shock patients. it is also a risk factor for mortality. tc- m dmsa scanning is useful for detecting renal dysfunction and help to predict the outcome and prognosis. reference introduction acute kidney injury (aki) complicates over % of icu admissions. episodes of aki are a major risk factor for development or progression of chronic kidney disease (ckd); however, methods of estimated glomerular fi ltration rate (egfr) may be poorly calibrated to survivors of critical illness who may have reduced muscle mass. we hypothesized that egfr may underestimate rates and severity of ckd in icu survivors. methods a retrospective observational study of renal function in all patients admitted to a london teaching hospital icu for ≥ days and surviving to hospital discharge in . we excluded cases with current or new diagnosis of end-stage renal disease or renal transplant. we assessed aki in icu by kdigo criteria and hospital discharge egfr by the ckd-epi equation. for comparison we assumed a normal gfr in a healthy individual as ml/minute/ . m at age decreasing by . per year over age . results we identifi ed patients, of whom had aki. median age was and % were male. median hospital discharge serum creatinine was μmol/l (range to ), median egfr was signifi cantly higher than predicted normal gfr for age at versus predicted (p < . , median diff erence ). in patients who had not had aki discharge the egfr was versus normal predicted (p < . , median diff erence ), suggesting that egfr could be overestimating true gfr in our population by at least a factor of . ( figure ). applying this correction factor to egfrs of patients who had recovered from aki resulted in % more diagnoses of ckd (egfr < ) at hospital discharge ( vs. ). conclusion egfr may overestimate renal function in survivors of critical illness confounding identifi cation of ckd in this at-risk population. prospective studies with measurement of actual gfr are required to assess the burden of ckd in survivors of critical illness. to analyze whether variables related to cardiopulmonary bypass (cpb) infl uence acute kidney injury (aki) occurrence and urinary neutrophil gelatinase-associated lipocalin (ungal) in cardiac surgery patients. methods a total of adult cardiac surgery patients were consecutively included from february to december . exclusion criteria were absence of diuresis due to end-stage renal disease or chronic renal failure and cardiac catheterism with i.v. contrast in the week before surgery. cpb, when performed, was used as standard cpb (scpb) or minicpb. we obtained four serial blood and urine samples, immediately before (pre) and after (post) surgery, and day ( d) and days ( d) after surgery. ungal was measured by architect (abbott diagnostics). akin criteria were used to diagnose aki. the study was approved by the local ethics committee and all patients gave informed consent. results one hundred and eighty-one patients ( . %) were men; mean age was . ± . years. icu and hospital stays were . ± . and . ± . days, respectively. twenty-eight-day mortality was . %. eighty-six patients ( . %) were diagnosed with aki within hours after surgery. in total, patients required cpb ( scpb, minicpb) and did not (no-cpb). seven no-cpb patients ( . %) developed aki and their median ungal post was ( . to . ) μg/l compared with . ( . to . introduction neutrophil gelatinase-associated lipocalin (ngal), measured early after cardiac surgery, has been demonstrated to predict postoperative acute kidney injury (aki). fluid overload potentially masks a subsequent acute renal function loss through dilution of serum creatinine and maintenance of urine output just above akidefi ning criteria. methods we investigated the early postoperative value of ngal versus that of simultaneously measured serum creatinine to predict subsequent fl uid overload. we studied adult cardiac surgery patients in the control arm of a rct (nct ). severe postoperative fl uid overload was defi ned as positive fl uid balance > % of preoperative body weight within hours after surgery. results severe postoperative fl uid overload was present in % of patients with a mean positive fl uid balance of . ± . l. at icu admission, urine ngal predicted severe fl uid overload (auc-roc . ( % ci = . to . )) ( figure ) and mortality (auc . ( . to . )). serum creatinine measured at the same time did not predict severe fl uid overload (auc . ( . to . )) or mortality (auc . ( . to . )). conclusion early ngal-guided adjustments to fl uid management may reduce organ edema after cardiac surgery. findings should be validated in larger cohorts. survivors of acute kidney injury requiring renal replacement therapy rarely receive follow-up: identifi cation of an unmet need cj kirwan, r taylor introduction acute kidney injury (aki) occurs in more than % of icu admissions, requiring renal replacement therapy (rrt) in around % of cases. there is now increasing evidence that aki is a risk factor for the development and progression of chronic kidney disease (ckd); however, when aki occurs as a complication of critical illness appropriate follow-up may be neglected. accordingly, we reviewed the follow-up of renal function in all patients who received rrt on our icu and survived to hospital discharge. methods a retrospective audit of patients who received rrt in a central london adult critical care unit during . results of patients admitted, received rrt with surviving to hospital discharge. we excluded patients who had end-stage renal disease, renal transplant or known glomerular disease. of the remaining aki patients, median age was (range: to ) and ( %) were male. median discharge creatinine was . μmol/l ( to ). forty-two ( %) were off ered follow-up, but in only six cases ( %) was this to nephrology services. twenty-eight attended follow-up (fi ve to nephrology) at a median time of weeks; however, creatinine was measured at in only and in six of these it had risen (by median . μmol/l). in addition, patients had creatinine measured to months post discharge and in eight it had risen (by median . μmol/l). conclusion follow-up of patients who received rrt for aki in the icu was poor and they were rarely referred to nephrologists. where renal function was measured after discharge, there was evidence of progressive renal dysfunction; however, renal function was often not assessed. we propose an algorithm for clinicians to guide follow-up. see figure . introduction hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. while there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. our algorithm can assist clinicians in maintaining blood glucose ([gbl]) within a desired target range while avoiding hypoglycemia. methods our model predictive control (mpc) algorithm uses insulin and glucose as control inputs and a linearized model of glucoseinsulin-fatty acid interactions. to allow the controller model to learn from data, a moving horizon estimation (mhe) technique tailored the tissue sensitivity to insulin to individual responses. patient data ([gbl] measurements, insulin and nutritional infusion rates) were from the hidenic database at the university of pittsburgh medical center. [gbl] measurements, typically hourly, were interpolated to impute a measurement every minutes. the model captured patient [gbl] via nonlinear least squares by adjusting insulin sensitivity (si) and endogenous glucose production (egp ). the resulting virtual patient (vp) is used to evaluate the performance of the mpc-mhe algorithm. results mpc controller performance on one vp is shown in figure . across a population of vps, the average [gbl] under mpc is . mmol/l, the average minimum is . mmol/l, the population individual minimum is . mmol/l and the average absolute average residual error is . mmol/l from a . mmol/l target. with standard intervention, the vps have an average [gbl] of . mmol/l, an average minimum [gbl] of . mmol/l, and a population minimum [gbl] of . mmol/l. algorithm performance deteriorates signifi cantly if the imputed sampling time exceeds minutes, underlining the importance of dynamic variations in insulin sensitivity in this population. conclusion the mpc-mhe algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of vps. furthermore, the mhe scheme updates patient parameters in real time in response to changing patient dynamics. introduction blood glucose (bg) control reduces morbidity and length of stay, and is standard practice in patients undergoing cardiac surgery [ ] . however, maintaining bg in the target range, while avoiding hypoglycemia, is challenging. continuous glucose monitoring (cgm) is a promising technology that may help address these challenges. we investigated the performance and safety of medtronic sentrino®, a newly developed cgm for critically ill adults, in the cardiac icu. methods adult patients with actual or planned cardiac icu admission at a single tertiary center were approached for participation and signed consent. other inclusion criteria were treatment with i.v. insulin (target bg < mg/dl) and life expectancy > hours. after initiation of i.v. insulin, sentrino® subcutaneous glucose sensors were inserted into patients' anterior thighs with planned study participation of to hours. reference bg was collected according to icu protocol, obtained from central venous catheter and analyzed with bedside blood gas analyzer (bga; i-stat®, abbott, usa). sensor glucose (sg) results were displayed, and its predictive alerts and alarms fully enabled. additional reference bgs were obtained during alarms and calibration. all treatment decisions were based on bga data, not on sg values. results a total of patients were enrolled; all successfully completed the study. mean age was years, % were women, % had diabetes. types of surgery were cabg ( %), valve replacement ( %), combined cabg and valve ( %) and cardiac transplant ( %). sg was displayed % of the time during the study, and paired bg-sg points were used for analysis. overall mean absolute relative diff erence (mard) was . %. no diff erences in cgm system accuracy were seen within subgroups of low versus high society of thoracic surgeons (sts) score (mard . % and . % for sts > % vs. ≤ %, respectively) or hemodynamic status (mard . % and . % for compromised vs. stable hemodynamics). consensus grid analysis showed > % of sg values within a/b zones, and % in d/e zones. no device or study-related adverse events were reported. in total, % and % of clinicians found sentrino® easy to use after one and two patients, respectively. conclusion the sentrino® cgm system demonstrated good analytic and clinically relevant accuracy, excellent reliability and safety in critically ill cardiac patients; and was easy to use and integrate in the cardiac icu. future studies are needed to determine whether cgm can improve bg control and reduce hypoglycemia in this patient group. introduction a large rct showed that tight glucose control (tgc), targeting age-adjusted normal fasting blood glucose levels with insulin infusion, decreased morbidity and mortality in critically children [ ] . however, the incidence of hypoglycemia increased substantially in the tgc group. we aimed to assess the eff ect of tgc on the three domains of blood glucose dynamics (hyperglycemia, hypoglycemia and blood glucose variability) and their independent association with mortality in the pediatric icu. methods this is a preplanned substudy of a published rct in one -bed pediatric icu. seven hundred patients (age to years), admitted to the picu between october and december , were randomized to either tgc ( to mg/dl in infants, to mg/dl in children) or to the usual care tolerating hyperglycemia up to mg/ dl (uc). patients with at least two arterial blood glucose measurements were included (uc n = ; tgc n = ). results mean blood glucose levels were lowered from ± mg/dl in the uc group to ± mg/dl (p < . ). the median number of samples per patient did not diff er between uc ( ( to )) and tgc ( ( to )). tgc lowered the hyperglycemic index, a marker of introduction hiv infection is a major public health problem in the world. the use of prophylaxis against opportunist infection and the introduction of haart in increased life expectancies. the therapeutic use of icu resources for hiv patients has been controversial, questioning the admission of these patients especially in advanced stages of the disease, given the poor prognosis. the aim of this study was to determine the experience of the past years in relation to the income of these patients in an icu. methods a retrospective case series consisting of patients with diagnosis of hiv infection (known or unknown) admitted between january and december . we collected demographic and epidemiological data, process of acquisition of the disease, infection status: known or unknown patient infected, whether or not receiving antiretroviral therapy and whether it was eff ective (undetectable viral load at the time of admission), apache ii, cause of admission, need for mechanical ventilation (mv), pathology related or unrelated to hiv infection and icu mortality. results during this period , patients were admitted to the icu, ( . %) hiv-positive. mean apache ii score . , median age years, % men and % spanish nationality. principal risk behavior: addiction drugs injection ( %). seventeen percent of patients did not know who was infected with hiv at the time of admission to the icu. fifty-three percent were not receiving haart. of the patients treated, % were receiving haart (eff ective in % of cases). sixty percent of the patients came from the emergency department of the hospital. main admission diagnoses: acute respiratory failure caused by infection (streptococcus pneumoniae and pneumocystis jirovecii), neurological disorders (coma for illicit drugs and psychotropic) and septic shock. seventy percent required mv. of patients whose hiv infection was not known, . % were admitted for related pathology. in patients of known infection, the pathology associated with hiv was %. average length of stay was days. icu mortality was %. most frequent causes of death: septic shock and multiple organ failure. conclusion depending on the patient and the cause of admission, icu admission may represent an excellent opportunity as a screening method to determine hiv status. given the greater effi cacy of haart at present, most patients with medical or surgical conditions unrelated to hiv infection will be eligible to join the icu. people with hiv can and should benefi t from using reasonable and individualized care in an icu. references conclusion neither immune status-related variables nor comorbidity or infection focus are mortality predictors. poor nutritional status, delayed icu admission, shock or renal failure increase the icu relative mortality risk. tachycardia, hypotension, hypercapnia, acidosis, and oliguria in the fi rst icu hours increase signifi cantly icu mortality. mechanical ventilation is not a mortality predictor. introduction patients with lung cancer commonly require the icu for a variety of acute illnesses related to the underlying malignancy, treatment, or comorbid conditions. icu admission of patients with nonresectable lung cancer has been criticized based on the high mortality rate in this population. however, recent advances in critical care may have changed this scenario. the aim of this study was to identify factors associated with hospital mortality in this group of patients. methods a retrospective study was conducted in consecutive medical and surgical patients with lung cancer admitted to a university hospital icu in são paulo, between and . a univariate analysis was performed to identify associated variables with hospital mortality. selected variables were included in the multivariate model. results from patients included in the study, were medical admissions ( . %) and were surgical admissions ( . %). four hundred and twenty ( %) patients had metastasis, patients ( %) required the icu because of respiratory failure and ( %) because of septic shock. the icu and hospital mortality rates were . % and %, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of nonsmall-cell lung cancer, higher charlson morbidity index, medical admission, active neoplasm, vasopressor need at admission to and at hours of icu, acute renal failure at admission, non-invasive ventilation or mechanical ventilation need at admission to and at hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of nonsmall-cell lung cancer (or = . ; % ci, . to . , p < . ), medical admission (or = . ; % ci, . to . , p < . ), acute renal failure at admission (or = . ; % ci, . to . , p < . ), non-invasive ventilation at hours of icu (or = . ; % ci, . to . , p = . ) and mechanical ventilation at hours of icu (or = . ; % ci, . to . , p < . ). conclusion hospital survival in patients with lung cancer requiring icu admission was %. our results provide evidence that icu management may be appropriate in patients with nonresectable lung cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction because the prognosis of older patients with cancer may be poor compared with younger patients, it remains controversial whether they benefi t from icu treatment. the objective of this study was to identify factors associated with hospital mortality in older patients with cancer requiring the icu.methods a retrospective study was conducted in consecutive medical and surgical older patients with cancer admitted to a university hospital icu in são paulo, between and . univariate and multivariate analysis were performed to identify associated and independent factors related to hospital mortality. results from , patients with cancer requiring icu at the period, patients were years old or higher. most patients were male ( %), had solid neoplasm ( %), were from medical admission ( %) and % had metastatic disease. the mean age was years (± ). the icu and hospital mortality rates were % and %, respectively. in the univariate analysis, variables associated with hospital mortality were diagnosis of lung cancer, medical admission, active neoplasm, vasopressor need at hours of icu, acute renal failure at admission, mechanical ventilation need at admission to and at hours of icu and a higher admission arterial lactate. by multivariate analysis, risk factors of hospital mortality were diagnosis of lung cancer (or = . ; % ci, . to . , p < . ), medical admission (or = . ; % ci, . to . , p < . ), acute renal failure at admission (or = . ; % ci, . to . , p < . ), mechanical ventilation at hours of icu (or = . ; % ci, . to . , p < . ) and lactate levels at admission (or = . ; % ci, . to . , p < . ). conclusion hospital survival in older patients with cancer requiring icu admission is acceptable. our results provide evidence that icu management may be appropriate in older patients with cancer and appoint risk factors for mortality, helping to better triage cancer patients who will benefi t from icu care. introduction readmission to the icu within hours is an indicator of quality of intensive care and is associated with an increase in mortality. during the last years several groups have published data based on multivariate logistic regression analysis to describe characteristics of patients who needed readmission to the icu. older age, comorbid conditions and severity of illness (apache score) have been among the strongest predictors for readmission. in our icu most patients are in the groups formerly identifi ed as risk groups, which means that stratifi cation and prediction of readmission is diffi cult. because of the unusual high severity of acute and pre-existing illnesses we could not fi nd a data match on comparable patient groups. to investigate whether we could reduce our rate of readmission we therefore decided to perform a qualitative investigation to identify risk factors related to readmission. after identifi cation of the risk factors we will take actions to optimize care and perform ongoing control of the implemented actions to secure that they decreases the rate of readmission. methods retrospective data on patients readmitted to the icu within hours during an -month period (november to june ) were drawn from the critical information system (cis) at icu zit, bispebjerg hospital, denmark. zit is a multidisciplinary unit with beds and to admissions/year and a median saps ii score of . a group of consultants, junior doctors and nurses from the icu and the ward each read the patient fi les with focus on pattern recognition and suggested trigger points to focus on. data on trigger points were then drawn from the cis system and re-evaluated. finally, fi ve key points were identifi ed and serves as basis for future actions. results in a qualitative analysis, readmissions to the icu are related to the following fi ve key points -discharge outside day hours, lack of infection control, stay in icu < days, lung physiotherapy ordinated but not eff ectuated, and several minor organ dysfunctions (atrial fi brillation and acute kidney injury). age, diagnosis, saps ii score or ventilator treatment during intensive care was not diff erent in patients with successful discharge and patients readmitted in this group of patients. conclusion it is possible and suitable to identify key points for future eff orts in a given subgroup of patients using a systematic qualitative approach. conclusion the latest audit follows introduction of a referral system directly to the icu consultant and may account for the reduction in numbers of referrals attended by junior doctors. ed/medicine persist as the main source of referral to the icu. discussion with the referring team consultant may reduce inappropriate referrals. icu staffi ng should not be reduced. [ , ] . this study aims to evaluate the impact of the time elapsed from request until admission to the icu on mortality and icu length of stay (los). methods a retrospective cohort study performed on patients in the icu of hospital regional de samambaia over a period of years, from january to december . the patients were allocated into two groups: patients who waited longer than hours, long waiting period the management of emergency medical admissions has been a subject of recent clinical incidents. there was a high percentage of patients that were referred to the icu by staff in training, and % of referrals were made by junior doctors. consultant physicians had no knowledge of the case in % of referrals. methods a prospective study of cases of referrals and admissions to the icu was conducted at the glasgow victoria infi rmary hospital from to september . a questionnaire was produced relating to the referrals, admissions, seniority involvement, cause of referral, and time of patient review by the icu consultant after icu admission. they were distributed to specialist registrars and the icu consultants. all data were electronically recorded into an excel database. questionnaires that were not completely fi lled were further investigated using patient clinical notes and contact with medical staff . information that may identify a patient or clinician was removed from the questionnaire for confi dentiality purposes. results twenty-one complete questionnaires were collected. fiftyseven percent ( / ) of cases involved admission to the icu. nine percent of the cases involved contacting either a specialist registrar or icu consultant intensivist for assistance in practical procedures. of the patients admitted to the icu, % ( / ) were from medical wards, % were admitted from a&e. consultants were the most common professionals who referred patients to critical care ( %; / ). fourteen percent of cases ( / ) involved the referral of patients into icu by a junior doctor, but only one of the referrals was accepted by the icu intensivist. consultants referred or were aware of the referral in % ( / ) of cases. of admissions, % ( / ) were accepted by the icu consultant and the remaining by the specialist registrars. all accepted were acknowledged by the icu consultant. after admission all of the patients were reviewed by the icu consultant and the time of review after admission was on average hour minutes ( minutes to hours minutes). conclusion there is still an issue with junior doctors referring patients to the icu without the acknowledgement of consultant physicians, resulting in unnecessary admissions and decreased time that icu trainees spend in the icu. there are more appropriate icu admissions when there is involvement with seniority. contact with icu staff to perform practical procedures outside the icu and not about admissions should be explored further. reference introduction the requirements for the intensivist in handling medical technology are constantly growing. it appears necessary to acquire technological competences particularly within the fi elds of medical technology and physics. in the master's degree program 'masteronline physico-technical medicine' , such technical authority is conveyed. to cope with the intensive vocational situation of the physician, this study course follows the blended-learning concept; that is, it is conceived as an online study course with small portions of intermittent presence phases. within the fi rst year, technical basic skills such as 'measurement technique' , 'informatics' , and 'advanced physics' are covered. subsequently, two of various advanced courses in diff erent fi elds of medical technology ('technology in intensive care medicine' , 'technology in surgery' , 'technical cardiology' , 'radiology' , and other) are selected. methods in a survey, we evaluated the study course. therefore, a questionnaire was distributed among all students including the topics course contents, learning materials, time management, supervision, and overall impression. the students were asked to score their agreement to the statements 'content is well structured' , 'content extent is appropriate' and 'content is relevant for medical purposes' on a scale ranging from (fully disagree) to (fully agree). results the students participated actively in this study course with highest motivation and large commitment. the students' workload was in the targeted range of about hours/week. content structure was scored with . ± . , content extent with . ± . and medical relevance with . ± . . conclusion the blended-learning concept fulfi lls the requirements for occupation-accompanying continued medical education, since it off ers the possibility to study self-employed accessing text documents, lecture recordings, and electronic lectures and to convert in concentrated presence phases this knowledge into practical exercises. the fi rst-hour protocol determines the patient-specifi c resources for the start of an icu stay [ ] . staff resources are decided through triage. task charts direct the start of intensive care. our primary goal is to improve patient care. methods a triage method (red, yellow, green) is used to manage icu resources according to the severity of illness. for example, one doctor and one nurse would admit a stable (green) patient coming from the operating room for postoperative icu care. a patient in septic shock with multiple organ disorder (red), on the other hand, would be admitted by a team of two doctors and three nurses. each staff member has a task chart in a checking-list format. also, an admission chart is used to improve data collection. the use of the protocol started as a pilot study in early . simulation education for staff members started in august and has included video recordings and debriefi ng of each simulated icu admission. primary goal-directed therapy goals have been mean arterial pressure (map > mmhg), spo > %, timing of the laboratory tests, start of antibiotics, and blood glucose level to mmol/l. quality indicators have been followed from the data provided by the finnish intensive care consortium. questionnaires for the staff members have been used to evaluate opinions about the fi rsthour protocol. results according to the questionnaire replies, % (n = / ) of our nurses estimate that the fi rst-hour protocol has improved the starting process of our patients' intensive care. twenty percent (n = / ) of the nurses considered that the protocol has no eff ect, and none thought it to be adverse for patient care. corresponding numbers for our icu doctors were % (benefi cial n = / ), % (no eff ect n = / ) and % (adverse). furthermore, . % (n = / ) of the nurses replied that education of new nurse staff members has improved because of the fi rst-hour protocol. a total of . % (n = / ) thought there has been no eff ect, and none considered the protocol harmful for education. for icu doctors the protocol did not bring either clear educational advantages or disadvantages. the variable life-adjusted display curves (the finnish intensive care consortium) have shown improvement in our patient care after the implementation of the fi rst-hour protocol. however, we cannot determine whether it is a signifi cant factor in our intensive care results. conclusion the fi rst-hour protocol has helped us in resource management, start of the patients' intensive care and education of nursing staff . introduction demand for critical care services is increasing yet a comprehensive understanding of how critical care nurses -the largest group of icu direct care providers -impact outcomes remains unclear. the purpose of this study was to determine how critical care nurse education (hospital proportion of bachelor's prepared icu nurses) and icu work environment infl uenced -day mortality of mechanically ventilated older adults. methods a multi-state cross-sectional nurse survey was linked to hospital administrative data and medicare claims ( to ). the fi nal sample included , mechanically ventilated older adults in hospitals. logistic regression modeling was employed to jointly assess the relationship of critical care nurse education, work environment and staffi ng on -day mortality while adjusting for hospital and patient characteristics and accounting for clustering. results a % increase in the proportion of icu nurses with a bachelor's degree or higher was associated with % lower odds of death while controlling for patient and hospital characteristics. patients cared for in better work environments experienced % lower odds of riskadjusted death than those cared for in poorer icu work environments. conclusion patients cared for in hospitals with a greater proportion of bachelor's prepared icu nurses and in better icu work environments experienced signifi cantly lower odds of death. as the demand for critical care services increases, attention to the education level of icu nurses and icu work environment may be warranted to optimize currently available resources and potentially yield better outcomes. introduction information about big hospital geographical transfer is scarce in the medical literature. on february our hospital (in fact, a big university complex) was transferred from their previous location in the north-center of our city towards a new southern peripheral, geographical location. this transfer has been done without any changes in assisted population or nursing/medical staff . the only change was a slight increase in bed number ( to ). our aim is to analyze changes in activity indexes (length of stay, occupancy rate, and so forth) and case mix (origin, previous quality of life and nyha score, main diagnostic groups, severity scores, in-icu and in-hospital mortality). introduction south-east london (sel) presents unique challenges to healthcare providers due to its diverse demographic. the high levels of poverty, immigration and psychiatric illness impact delivery of obstetric care. these were identifi ed as risk factors for poor outcome in the latest cmace report [ ] . the intensive care national audit and research centre (icnarc) produced data on obstetric critical care admissions in [ ] . we reviewed the obstetric critical care admissions in three sel hospitals and compared this with the national average determined in the icnarc and cmace data. methods all critical care admissions in three high-risk obstetric units in sel ( august to july ) were screened for patients who were currently or recently pregnant. we compared local results with national data by icnarc and cmace. there were obstetric critical care admissions in the sel hospitals within the audited time frame. the mean age was . in icnarc data compared with . in sel. average apache ii scores were lower in sel compared with the icnarc data, but length of stay was greater in sel ( . days) compared with icnarc ( . days). haemorrhage was the most common reason for admission in sel, whilst sepsis was the leading cause of death according to the latest cmace report (figure ). conclusion data from national audits may guide protocol, but services must be tailored to local circumstances. sel has unique population characteristics and obstetric critical care admissions diff er signifi cantly from national statistics; in particular, haemorrhage is over-represented in our region. critical care services were generally required for a short period of time; during this period, routine postpartum care may be omitted as treatment priorities diff er. dedicated critical care services on the labour ward may be a way to combine postnatal care with transient high-dependency requirements. this may enhance patient experience and prove cost-eff ective. introduction adverse drug events (ades) are associated with a substantial increase in morbidity and mortality in any setting. because patients in icus were critically ill with complex diseases and varied organ dysfunction, the incidence of ades on such patients is much more crucial than the counterparts. we thus assessed the nature of ades and their infl uence in icus. methods we conducted a prospective cohort study at icus at three large tertiary-care hospitals in japan. trained research nurses reviewed all medical charts, incident reports and reconciliations from the pharmacy to identify suspected ades as well as the background of patients. ades are any injuries that result from the use of a drug. after suspected ades are collected by research nurses, physician reviewers independently evaluated them and classifi ed them as ades or rule violations. we used the validated methodology [ ] . results we included patients with , patient-days. the median age was years and the median length of stay was days. in total, patients ( %) had at least one ade during their stay in the icu. the median icu stay in patients who had ades was days while days in patients who had no ades (p < . ). the median length of the ade onset days since admission was days. regarding the mortality, patients ( %) were dead during their icu stay: deaths ( %) in patients who had ades and three of deaths were caused by an ade, and deaths ( %) in counterparts (p = . ). there were no signifi cant diff erences of patients' characteristics between patients with ades and without ades (table ) . conclusion ades were associated with longer stay and caused a part of death in icu ( %) although they did not increase the mortality. because the characteristics of patients were not associated with ades, early detection and intervention for ades could be important to improve the morbidity and reduce the death caused by ades in icus. introduction in hungary, despite the high level of social support, the number of organ recoveries from deceased donors has not changed signifi cantly. the donation activity shows a positive relationship with the level of education of staff in icus as well as with their attitude towards transplantation. the aim of this cross-sectional study is to estimate the attitude and knowledge of intensive care specialists and nurses as regard donation and transplantation. methods the self-completed questionnaire that consisted of items was completed at the congress of hungarian society of anesthesiology and intensive therapy in . besides the epidemiological data, the intensive care specialists (n = ) and nurses (n = ) were asked about donation activity, participation in an organ donation course, selfreported knowledge of joining eurotransplant, donor management, legislation, and transplantation. the data were analyzed by spss . . results a total of . % of physicians and . % of nurses attended an earlier organ donation course (p < . ). the average age of those who participated in training was signifi cantly higher among doctors (p < . ). fifty-nine percent of doctors and . % of nurses did not even want to participate in such training. donation activity was higher among staff who joined training (p < . ). independently from accepting the presumed consent legislation ( . %), % of physicians agreed with the hospital practice that requests the adult donor's relatives to consent to organ recovery. this standpoint did not depend on donation activity, participation in an organ donation course, opinion about legislation and the nature of staff . a total . % of participants consented to their organ retrieval after death. the staff who participated in an organ donation course had more knowledge regarding the law and ethics of donation (p < . ), donor management (p < . ), living and deceased donor transplantation (p < . ) and joining eurotransplant (p < . ). older professionals had more information about all fi elds (p < . ). nurses had less knowledge concerning donor management (p < . ), law and ethics (p < . ) and deceased donor transplantation (p < . ) than doctors. conclusion education about organ donation needs to be part of specialist training of intensive care staff , and refresher courses every fi fth year as well. the course should include knowledge regarding brain death, donor management and communication with family. this is the fi rst step to improve the number of transplantations. in the uk, three people die each day awaiting trans plantation, due to the unavailability of donor organs. traditionally, donor identifi cation has been restricted to the icu. however, following the uk organ donation taskforce report in [ ] , a number of emergency departments (eds) have been working with specialist nurses for organ donation (sn:od) to identify potential donors and approach their families for consent in the ed. we present our initial experience after the introduction of a sn:od to an irish teaching hospital's ed. methods we conducted a retrospective review of deaths in our ed during a -month period. for those who died in the ed, case notes were reviewed to identify those suitable for organ donation. referral and donation rates were compared in two cohorts, pre and post introduction of a sn:od. fisher's exact test was used to assess diff erences between groups. results ninety-one deaths occurred in the study period. following introduction of the sn:od, referrals increased from zero to eight. of the eight referred, three received consent and were transferred to the icu, two of whom became successful donors. the number of missed potential donors fell from six to one (p = . ). conclusion introduction of a sn:od and a clinical pathway has led to the identifi cation of previously missed potential organ donors in the ed. several patients have subsequently been admitted to critical care solely to facilitate organ donation. reference introduction admission to hospital overnight has been shown to increase mortality and decrease hospital length of stay [ ] . the objective of this study was to determine whether this relationship is valid in patients admitted to our icu, and whether length of stay was aff ected. methods a retrospective data collection identifi ed , patients admitted to a fi ve-bed icu from april to november . data regarding patient age, sex, apache ii score and icu admission date and time were collected along with the length of stay in the unit and hospital. defi nitions of day and night were set to local icu standards of : am to : pm. patients were then separated into two groups and analysed using analyse-it software for excel. results crude icu and hospital mortality rates in patients admitted during the day and overnight were examined. there was no signifi cant diff erence in unit mortality (day . % vs. night . %, or = . , % ci = . to . , p = . ) or hospital mortality (day . % vs. night . %, or = . , % ci = . to . , p = . ). the mean unit length of stay showed no diff erence in patients admitted during daytime compared with those admitted overnight ( . days vs. . days, p = . ). the mean hospital length of stay was decreased in patients admitted during daytime compared with patients admitted overnight ( . days vs. . days, p = . ). the average age of patients was less in those admitted out of hours (night . years vs. day . years, p = <. ). there was no signifi cant diff erence in apache ii scores of patients between the groups (day vs. night , p = . ). conclusion there is no signifi cant diff erence between the mortality of patients admitted overnight and patients admitted during the day to our unit. the hospital length of stay is increased in patients who are admitted overnight to intensive care; however, icu length of stay is not aff ected. adjustment for other confounders such as current bed occupancy and staffi ng ratios during the entire patient stay may help to understand the diff erences seen in the hospital length of stay. introduction interdisciplinary rounds (idrs) in the icu are increasingly recommended to support quality improvement and to reduce confl icts, but uncertainty exists about assessing the quality of idrs. we developed, tested, and applied a scoring instrument to assess the quality of idrs in icus. methods a literature search was performed to identify criteria for instruments about assessing team processes in the icu. then, videotaped patient presentations led by diff erent intensivists were analyzed by delphi rounds. appropriate and inappropriate behaviors were highlighted. the idr-assessment scale was developed and statistically tested. the inter-rater reliability was evaluated by rating nine randomly selected videotaped patient presentations by three raters. finally, the scale was applied to videotaped patient presentations during idrs in three icus for adults in two hospitals in groningen. results the idr-assessment scale had quality indicators, subdivided into two domains: patient plan of care, and process. the domain patient plan of care refl ects the technical performance from the initial identifi cation of a goal to the evaluative phase. the domain process refl ects the team processes that are important to ensure that the appropriate plan of care is agreed, understood, and executed as planned by all care providers. indicators were essential or supportive. the inter-rater reliability of nine videotaped patient presentations among three raters was satisfactory (κ = . ). the overall item score correlations between three raters were excellent (r = . to . ). internal consistency in videotaped patient presentations was acceptable (α = . ). application to idrs led by diff erent intensivists in three icus in two hospitals demonstrated that indicators could be unambiguously rated. the staff and management of all three icus that were rated had considered their idrs to be adequately performed, and they were surprised by these study results. conclusion this study showed that the quality of idrs can be reliably assessed for patient plan of care and process. the idr-assessment scale had satisfactory inter-rater reliability, excellent overall item score correlations, and acceptable internal consistency. our instrument may provide feedback for icu professionals and managers to develop adjustments in quality of care. testing the idr-assessment scale in other icus may be required to establish general applicability. the development of patient-centered care by interdisciplinary teams in the icu has focused attention on leadership behavior. the purpose of this intervention study was to measure the eff ect of leadership training on the quality of performed interdisciplinary rounds (idrs) in the icu.methods in this nonrandomized intervention study, participants included nine intensive care medicine fellow trainees (intervention group) and experienced intensivists (control group). participants in the intervention and control groups previously were untrained in leading idrs in the icus. after each participant led an idr that was videotaped, the fellow trainees participated in a -day leadership training, which was consistent with principles of adult learning and behavioral modeling. after training, each fellow trainee led another idr that was videotaped. quality of the performed idrs was measured by review of videotapes of the idrs lead by intensivists, including patient discussions subdivided into four icus, and assessment with the idr-assessment scale. results comparison of the intervention versus control groups shows that the intervention group has more yes scores on the idr-assessment scale than the control group. this diff erence was signifi cant in of the, in total, quality indicators. conclusion quality of leadership will be reliably trained and measured in the context of idrs in icus. training in a simulation environment, with real-life idr scenarios including confl icting situations, and workplacebased feedback in the preparation and feedback phases, appears to be eff ective to train leadership behaviour. results over a -month period, teleconsultations ( patients) were done. mean age was . years, . % was male and mean apache ii score was . . a total of . % originated from the icu and . % from the ed. main consultation diagnoses were sepsis ( . %); stroke ( . %); survival from cardiac arrest ( . %); trauma ( . %); and acute myocardial infarction ( . %). tm improved diagnosis in . % and infl uenced the clinical management in . % of the consultations. invasive procedures were indicated in . %. life-saving procedures were tm related in seven patients ( . %): stroke thrombolysis (n = ) and limb amputation (n = ). seven patients ( . %) were transferred and submitted to surgical procedures (heart surgery (n = ), neurosurgery (n = ) and liver transplantation (n = )). the majority of the patients remained at hmmd and were discharged. conclusion a tm program is feasible to be implemented in a community hospital. the major benefi t is expertise medical transfer from the tertiary hospital to the community setting, improving diagnosis and management of critical care patients, and avoiding routine transfer to a major urban center. introduction the purpose of our study was to assess the attitudes of slovenian intensivists towards end-of-life (eol) decision-making and to analyze the decision-making process in their clinical practice. methods a cross-sectional survey among slovenian intensivists and intensive care medicine residents from diff erent icus was performed using a questionnaire containing questions about views on eol decision-making. fisher's exact test and the fisher-freeman-halton test were applied to cross-tabulated data; signifi cance level was set at p ≤ . due to the large number of tested hypotheses. the response rate was . % ( questionnaires were returned out of distributed), which represented roughly the same percentage of all slovenian intensivists. termination of futile treatment was assessed as ethically acceptable (p < . ). the statement that there is no ethical distinction between withholding and withdrawing of treatment could not be confi rmed (the answers 'there is a diff erence' and 'undecided' were less frequent, but not statistically signifi cant; p = . ). a do-not-resuscitate order (dnr) was used more often than other withholding treatment limitations (p < . ). a dnr was used most frequently in internal medicine icus (p < . ; compared with paediatric and surgical icus). withdrawal of inotropes or antibiotics was used more often than withdrawal of mechanical ventilation or extubation ( . % vs. . %; p < . ). withdrawal of mechanical ventilation or extubation was more often used in the paediatric icus ( . %) as compared with the internal medicine icus ( . %) and the surgical icus ( %) (p < . ). over two-thirds ( . %) of intensivists were against termination of hydration, which would be more often used in the internal medicine icus (p < . ). thirty-one percent of intensivists used written dnr orders. conclusion termination of futile treatment was found to be ethically acceptable for slovenian intensivists, although they were not convinced that withholding and withdrawing of treatment were ethically equal. a dnr would be used most often. withdrawal of inotropes or antibiotics would be used more often than withdrawal of mechanical ventilation or extubation. termination of artifi cial hydration would be rarely used in practice. of consultant attendees from the uk, completed the survey ( %). for % of consultants there was no formal institutional protocol for withdrawal of futile therapy. when deciding to withdraw therapy, % of consultants routinely seek and document a second opinion. regarding donation after cardiac death (dcd), % of consultants were happy to delay withdrawal to facilitate successful donation, % have already done so in their practice and % routinely withdraw therapy in theatres rather than on the icu. even if it would impact on the care of other patients, % would delay withdrawal of therapy to facilitate dcd. for patients accepted for dcd, % think that some intensivists withdraw more aggressively (in essence, hasten death) in the hope of improving the likelihood of a successful organ donation and % have felt pressurised to withdraw therapy more quickly than their usual practice. furthermore, % experienced pressure to refer a patient for dcd when it they felt it was not appropriate. conclusion this survey confi rms variation in the practice and attitudes to withdrawal of futile therapy amongst uk consultant intensivists. formal protocols were frequently unavailable to guide withdrawal and second opinions were often not sought. nearly one-half of the intensivists delay withdrawal to facilitate donation, even if this may impact on the care of other patients. many intensivists have felt pressure to refer for donation when they feel this is inappropriate and there is a perception that some intensivists may withdraw care more aggressively in those who are accepted for dcd to improve the likelihood of a successful donation. this survey may help inform debate in this ethically challenging area. reference the research shows that the diffi culty of communi cation is a factor that impacts negatively on the grieving process. moreover, it stresses the importance for parents to rediscuss the moment of their child's death with health professionals. references methods a randomised controlled trial was undertaken in adult survivors of icu admission. they were allocated to receive an -week in-hospital supervised aerobic programme consisting of two cycle ergometry and one unsupervised session per week (exercise group) or no exercise (control group). primary outcomes were the anaerobic threshold (in ml o /kg mass/minute), physical function and mental health scores (sf- questionnaire), measured at weeks and . participants were then allocated to focus groups where the interpretation of experiences was compared with outcomes from the pix study. results fifty-nine patients were recruited to the study. the anaerobic threshold increased at week in the exercise group by a clinically and statistically signifi cant amount of ml o /kg mass/minute ( % ci, to ml/kg/minute). there was further improvement in fi tness levels in both groups by week (although no signifi cant diff erence between groups). no signifi cant diff erence in hrqol measures between groups was demonstrated; however, the exercise group did show an improvement in their mental health scores. the focus groups centred on feelings of isolation, abandonment, vulnerability, dependency and reduced physical activity post hospital discharge. many reported a lack of social inclusion as they did not have the energy or confi dence to venture outside. however, those in the exercise group felt that the rehabilitation programme was motivating, built up confi dence, improved fi tness, helped social interaction and gave them a sense of achievement.conclusion the -week exercise intervention resulted in statistically signifi cant improvements in fi tness at weeks while focus group participants highlighted the positive eff ects of the exercise intervention leading to enhanced energy levels, motivation and achievement. psychological benefi ts of the exercise programme are apparent from the focus group, emphasising the important link between physical and mental health. introduction survivors of critical illness often have a prolonged stay on the icu. these patients may suff er from icu-acquired weakness. it has been shown that reduction in muscle mass and muscle strength occurs early after admission to the icu. however, in the very early stage on the icu, patients are often sedated and not able to participate in any active mobilizations. therefore the use of neuromuscular electrical stimulation (nmes) is becoming a treatment of interest in the icu. the aim was to study the feasibility and safety of nmes in a surgical and medical icu of a large, tertiary referral university hospital. methods fifty patients with an expected prolonged stay on the icu of more days (judged on day ) with no trauma or neurological disease were included. they then received daily a nmes session (duo ; gymna, belgium) for minutes on the quadriceps bilaterally during their entire stay on the icu. the main outcome was the ability to produce a contraction of the quadriceps through nmes. the muscle contraction was quantifi ed on a -point scale: (no contraction palpable and visible) up to (contraction very well palpable and visible). patients were classifi ed as responders when an adequate muscle bulk was obtained in ≥ % of the sessions. the potential factors associated with the feasibility were: gender, age, body mass index (bmi), diagnosis of sepsis, barthel index prior to admission to the hospital, apache ii score, glasgow coma scale (gcs), fi ve questions for adequacy, stimulus intensity and leg edema. a multiple regression analysis was performed to identify the factors determining whether or not a contraction could be expected in a patient. safety of nmes was assessed through heart rate, blood pressure, oxygen saturation and respiratory rate. results in % of the patients we were able to achieve adequate muscle contractions in more than % of the sessions. gcs (p = . ), edemaintroduction trauma is the most common cause of morbidity in young people. it has a high social impact both because of the high cost of the acute treatments and because of the physical and psychological consequences that it may cause. a prospective, observational, singlecenter study on quality of life to months after trauma was carried out. the aim of the study is to evaluate life quality after trauma and to identify the most important needs of the patients, in order to improve the level of care after an icu stay and to implement a faster and more eff ective reintegration into the active and productive society. the aim was to analyse the outcomes and patient satisfaction of a recently implemented icu follow-up clinic. these clinics are national institute for clinical excellence recommended [ ] . methods a retrospective analysis of prospective collected data from january to december . the clinic is run monthly by an icu consultant and a critical care outreach sister. criteria to be invited to the clinic are mechanical ventilation ≥ days. patients fi lled an anonymous satisfaction survey after the clinic. results our attendance rate is % ( patients), which is similar to other series reported in the literature. those patients who attended the clinic required a longer length of mechanical ventilation ( . days vs. . ) and a longer length of stay in the icu ( . vs. ) and in hospital ( vs. ). we identifi ed a wide range of physical and nonphysical morbidities on these patients (figure ). we referred them to the appropriate specialities. patients were very satisfi ed with this new service ( figure ). this study aims to quantify the acute exercise response to early passive and active activities in order to inform exercise prescription when designing rehabilitation programmes for the critically ill. critical care survival is often associated with a poor functional outcome [ ] , with recent investigations presenting the case for early rehabilitation in order to optimise functional recovery [ ] . there, remains, however, a scarcity of research investigating the immediate response to exercise and subsequent exercise prescription, in the acute phase following critical illness. methods this study is a prospective randomised controlled trial with a repeated-measures crossover design. eligible participants, requiring mechanical ventilation for or more days, completed two exercise activities routinely used in early critical care rehabilitation, a passive chair transfer (pct) and active sitting on the edge of the bed (soeob). the oxygen consumption and cardiovascular parameters were measured to quantify and compare the exercise response between the two activities. introduction the aim of this study was to investigate the eff ect of a -week exercise programme on outcomes in post-icu patients. with improvements in intensive care medicine, increasing numbers of patients are surviving catastrophic illness [ ] . severe weakness is common in patients with prolonged critical illness and results in considerable morbidity, mortality and healthcare costs [ ] . the nice guidelines rehabilitation in critical care recommend follow-up for post-icu patients and that further research is needed in this fi eld [ ] . methods patients who have been discharged home from hospital following an icu stay of hours or more were recruited to the study. patients were only excluded if they were not considered safe for exercise. baseline measurements were completed prior to stratifi ed (age, gender, apache ii score) random allocation to either the exercise or control group. outcome measures included cardiopulmonary fi tness ( -minute walk test), balance (berg balance scale), grip strength (jamar grip dynamometer) and hospital anxiety and depression (had score). the exercise group completed a -week supervised exercise programme, twice a week for up to hour. in the seventh week, all patients repeated the baseline measurements. an unpaired student's t test was used to compare any diff erences between the control and exercise groups. results at baseline measurements, there were no statistical diff erences in age, gender, length of stays or apache ii scores between the two groups. results indicate that the exercise group (n = ) had signifi cantly greater improvements in cardiopulmonary fi tness (p < . ) and balance (p < . ) compared with the control group (n = ). greater improvements were also evident in anxiety, depression and grip strength in the exercise group, although not statistically signifi cant. conclusion this pilot study highlights that a -week supervised exercise programme can signifi cantly improve cardiopulmonary fi tness and balance in post-icu patients. further recruitment to the study and -month/ -year follow-up is needed. references introduction intensive care patients suff er psychological and physiological distress that may have debilitating and long-lasting eff ects [ ] [ ] [ ] . healthcare professionals are in a position to help avoid or alleviate this stress [ ] . to action this it is important to identify the main stressors from the patient's perspective. a systematic review was performed to provide a list of what patients consider stressors in intensive care. these were then ranked in order to provide an identifi cation tool that can be used to shape appropriate care. methods a systematic review was performed using medline, cinahl, psych info and academic search complete. grey literature was included and searches were not restricted to type of intensive care or country. criteria were used to fi lter those articles that identifi ed the patients' views of their stressor, not the patient experience. eligible articles were critiqued using the critical appraisal skills programme for qualitative studies [ ] and brought together using a narrative synthesis.all of the reviewed studies used a questionnaire as a means to identify what elements on the intensive care patients found stressful. a list of the top- stressors could then be expressed for each study and compared. from this information, a set of guidelines for best practice were devised. introduction this study describes the development and validation of the consumer quality index relatives in icus (cqi 'r-icu'), which aims to measure the satisfaction of relatives and to identify aspect of care that need improvement in the icu in a reliable and valid way.according to the quality standards of the dutch society of intensive care, every icu needs to record the satisfaction of relatives [ ] . at this moment there is insuffi cient insight into the quality of care off ered to relatives on the icu because an evidence-based dutch measurement instrument is missing. methods the cqi 'r-icu' has been developed based on a scientifi c and standardised method [ ] . a mixed design method is used, consisting of qualitative and quantitative survey studies. factor analyses are carried out to determine the underlying structure of the newly developed questionnaire. multiple regression analysis is used to explore the relationship between demographic variables and the perceived quality of care. results in six hospitals the cqi 'r-icu' is sent to relatives after receiving informed consent (n = ), . % of the respondents are the patient's partner. respondents seem to be most satisfi ed with the presence of a professional at fi rst entrance to the icu. the highest need for improvement scores relate to information about meals, parking and other disciplines (for example, social worker, spiritual worker or psychologist). factor analysis shows that quality of care is determined by four clusters of items: support, communication, general information and organisation. the reliability of the cqi 'r-icu' is suffi ciently high, only communication and support are signifi cant predictors of total quality judgement of relatives (adj. r = . ). in addition, there is a signifi cant diff erence in mean total quality judgement between the six hospitals as well as between the four wards within erasmus mc. none we are conducting a cluster randomized trial with two parallel arms to evaluate strategies to improve family satisfaction with the care that themselves and their critically ill relatives receive in the icus of nonacademic brazilian public hospitals. here we report the results of the baseline phase of this trial. methods in this baseline phase, we interviewed the family member most closely involved with the care of critically ill patients who stayed in the icu for at least hours. we applied a form with questions divided into four domains: overall icu experience, communication, decision-making, and questions related to end-of-life care for patients who died in the icu. each question scored from (very poor) to (excellent). the form was adapted from the family satisfaction with care in the icu (fs-icu ). as many questions assessed the quality of intensivist care or communication, the interview was applied by a psychologist or a nurse. results families of patients were interviewed. a total / ( . %) died in the icu. most respondents were satisfi ed with overall icu experience (mean ± sd score . ± . ). however, family satisfaction with communication ( . ± . ) and decision-making ( . ± . ) resulted in somewhat lower scores. most families of patients who died in the icu ( / ( . %)) considered that their relative's life was neither extended nor shortened unnecessarily. also, most of the families believed that their relative did not suff er or suff ered little in the icu ( / ( . %)) and felt supported by the healthcare team ( / ( . %)). conclusion most families were satisfi ed with the care themselves and their critically ill relatives received in the icu. also, most relatives of patients who died in the icu felt that end-of-life care was adequate. although we believe there is much room for improvement in communication, decision-making and support critically ill patients and their families, as their baseline satisfaction with patient care is quite high, it may be hard to demonstrate substantial improvement after interventions. key: cord- -ehr aaix authors: chang, jae c. title: acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis date: - - journal: clin appl thromb hemost doi: . / sha: doc_id: cord_uid: ehr aaix acute respiratory distress syndrome (ards) is a life-threatening noncardiogenic circulatory disorder of the lungs associated with critical illnesses such as sepsis, trauma, and immune and collagen vascular disease. its mortality rate is marginally improved with the best supportive care. the demise occurs due to progressive pulmonary hypoxia and multi-organ dysfunction syndrome (mods) with severe inflammation. complement activation is a part of immune response against pathogen or insult in which membrane attack complex (mac) is formed and eliminates microbes. if complement regulatory protein such as endothelial cd is underexpressed, mac may also cause pulmonary vascular injury to the innocent bystander endothelial cell of host and provokes endotheliopathy that causes inflammation and pulmonary vascular microthrombosis, leading to ards. its pathogenesis is based on a novel “two-path unifying theory” of hemostasis and “two-activation theory of the endothelium” promoting molecular pathogenesis. endotheliopathy activates two independent molecular pathways: inflammatory and microthrombotic. the former triggers the release inflammatory cytokines and the latter promotes exocytosis of unusually large von willebrand factor multimers (ulvwf) and platelet activation. inflammatory pathway initiates inflammation, but microthrombotic pathway more seriously produces “microthrombi strings” composed of platelet-ulvwf complexes, which become anchored on the injured endothelial cells, and causes disseminated intravascular microthrombosis (dit). dit is a hemostatic disease due to lone activation of ulvwf path without activated tissue factor path. it leads to endotheliopathy-associated vascular microthrombotic disease (ea-vmtd), which orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and mods. thrombotic thrombocytopenic purpura (ttp)-like syndrome is the hematologic phenotype of ea-vmtd. ards is one of organ phenotypes among mods associated with ttp-like syndrome. the most effective treatment of ards can be achieved by counteracting the activated microthrombotic pathway based on two novel hemostatic theories. acute respiratory distress syndrome (ards) is caused by severe pulmonary vascular dysfunction characterized by acute onset of dyspnea, tachycardia, hypoxemia associated with noncardiogenic pulmonary edema, and systemic inflammation. although the exact pathophysiologic mechanism causing pulmonary vascular dysfunction has not been determined yet, it is a circulatory dysfunction often associated with moderate thrombocytopenia [ ] [ ] [ ] and multi-organ dysfunction syndrome (mods). [ ] [ ] [ ] because its pathogenetic mechanism is not clearly recognized, no effective therapeutic agent targeting the underlying pathologic disease has been procured to date. ventilator support, fluid and electrolyte balances, and cardiopulmonary monitoring with the best supportive care have marginally improved the outcome of ards in several decades. mortality rate is still very high. it increases with disease severity. in a multicenter, international, prospective cohort study of patients with ards, unadjusted hospital mortality was reported to be % among those with mild ards, % for those with moderate disease, and % for patients with severe ards. recently, two proposed hemostatic mechanisms have opened the door in the understanding of ards from molecular pathogenesis associated with endotheliopathy that promotes inflammation and coagulation disorder in sepsis and other critical illnesses [ ] [ ] [ ] [ ] ; one is "two-activation theory of the endothelium" in which endothelial pathogenesis activates inflammatory pathway and microthrombotic pathway and the other is a novel "two-path unifying theory" of hemostasis in which hemostasis initiates thrombogenesis and promotes microthrombogenesis, leading to vascular microthrombotic disease (vmtd). , , , these two theories are congruous each other since the endothelium contributes to initial hemostasis and triggers molecular mechanism for thrombogenesis. in endotheliopathy, the pathologic nature of inflammation promoting inflammatory response is recognized and the character of "microthrombi" leading to multiple hematologic phenotypes is identified. in addition, the true mechanism of in vivo hemostasis in vascular injury and three different thrombogenetic mechanisms within hemostasis are uncovered. , through the recognition of endothelial molecular pathogenesis, enough evidences have been accumulated that ards is one of the phenotypes of mods occurring as a result of disseminated intravascular microthrombosis (dit), which is the underlying pathology contributing to endotheliopathy-associated vmtd (ea-vmtd). , [ ] [ ] [ ] the objective of this article is to analyze the clinical, pathological, and hematopathological features of ards and to account for involved pathophysiological mechanisms associated with endothelial dysfunction based on two hemostatic theories. in the end, this author will look into potential therapeutic option for the treatment of ards according to "theorybased medicine" instead of "evidence-based medicine" since clinical trials for ards have completely failed to find an effective therapeutic regimen. the most common underlying condition in ards is severe infection (eg, sepsis/septic shock with or without severe pneumonia) due to various microbic pathogens, which include bacteria, viruses, fungi, rickettsia, and parasites. ards also occurs in association with trauma to the chest/lungs and head/brain, , complications of surgery, pregnancy and transplant, [ ] [ ] [ ] [ ] [ ] certain drug, toxin, chemicals and venom exposure, and thrombotic thrombocytopenic purpura (ttp)-like syndrome. , [ ] [ ] [ ] in addition, it also has developed in association with disseminated intravascular coagulation (dic). [ ] [ ] [ ] some clinicians have interpreted dic was the cause of ards, but others proposed it was the result of complication of ards. regardless, enough evidences have been presented that ards is a clinical disorder of pathologic hemostasis associated with activated coagulation system such as dic. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] however, this author has placed quotation marks on "dic" because recent reinterpretation has identified the current concept of "dic" was ill-founded because it was based on the hemostatic mechanism of activated tissue factor (tf) path, , , , , , which will be discussed briefly later in this article. nonetheless, ards is one of the major organ phenotypic disorders among mods contributing to the death associated with microthrombosis in critically ill patients due to diseases such as sepsis, trauma, and immune disorders. as shown in table , although ards often occurs in association with a variety of sepsis, it can be preceded by pneumonia as seen in severe respiratory distress syndrome (sars) due to sars-cov and middle east respiratory syndrome (mers) due to mers-cov as well as bacterial, fungal, and parasitic pneumonia, especially pneumococcal in particular. the clinical feature of developing pneumonia before sepsis suggests organotropism plays an important role in certain pathogen as shown by sars virus possessing specific affinity to the lungs. , sometimes ards occurs following blood transfusion, which is called transfusion-related acute lung injury (trali) that is characterized by acute noncardiogenic circulatory disorder of the lungs following blood product transfusions. , sepsisassociated ards, notwithstanding the absence of pneumonia, not uncommonly develops with other organ dysfunction such as encephalopathy, hepatic failure, acute renal failure, and acute necrotizing pancreatitis. , this multi-organ involvement suggests ards may not be primary disease but is likely a part of ongoing systemic pathogenetic mechanism due to infection or other critical illnesses as illustrated in table . , now, the underlying physiologic alteration of mods in sepsis and other critical illnesses is identified as circulatory dysfunction occurring as a result of ea-vmtd. [ ] [ ] [ ] this is an extremely important concept in the understanding for the pathogenesis of mods as well as ards because we now know that the culprit of mods is dit, , [ ] [ ] [ ] [ ] [ ] which pathogenesis based on "two-activation theory of the endothelium" as shown in figure . , clinical and pathological features. the clinical features of ards are characterized by ( ) acute onset of noncardiogenic respiratory distress, ( ) bilateral pulmonary infiltrates, and ( ) evidence of diffuse circulatory obstruction of pulmonary vasculature. in addition to acute respiratory distress, hematologic features of ards include thrombocytopenia, , , - mods, , - , - dit, , , , "dic," , , [ ] [ ] [ ] and ttp-like syndrome, [ ] [ ] [ ] as presented in tables and . these manifestations seemed to be consistent with a hemostatic disorder, which is now recognized as ea-vmtd. , , until recently, it was debated whether ards was the cause of thrombocytopenia, inflammation, mods, and "dic," or was rather the result of another pathological condition producing those hematologic phenotypes. in later discussion, this dilemma will be further explored once the pathophysiological mechanism of ards is established. the pathological features of ards are characterized by ( ) diffuse alveolar damage associated with injury to alveolar lining and endothelial cells (ecs), ( ) exudative pulmonary edema, and ( ) hyaline membrane formation. [ ] [ ] [ ] these pathologic changes are very similar, if not identical, in each ards caused by different pathogens and insults, including pneumonia-initiated sars and mers. , one unique abnormality is hyaline membrane formation/deposits. this pathologic feature appears to be similar to that of vmtd associated with ttp and ttp-like syndrome, which microthrombi are characterized by hyaline thrombi composed of unusually large von willebrand factor multimers (ulvwf) and platelets. even though ards develops in association with divergent etiologies from sepsis to envenomation, its pathologic and clinical features are remarkably similar among different underlying diseases. [ ] [ ] [ ] diffuse alveolar damage was the histologic changes in most patients with ards and its progression included phases of exudative, proliferative, and fibrotic changes that correlated with the time rather than its specific causes. these findings are consistent with the hypothesis that pathogenesis of ards is not due to multifactorial processes primarily involving the lungs, but is the result of one pathophysiologic mechanism affecting the lungs and multiorgans. consumptive thrombocytopenia in critically ill patients. as in other critical illnesses, thrombocytopenia commonly occurs in ards during the course of the disease. - even after the known causes of thrombocytopenia such as heparin-induced thrombocytopenia, transfusion and drug-related thrombocytopenia, bone marrow suppression, and other identifiable thrombocytopenia are excluded, the mechanism of undetermined thrombocytopenia cannot be clearly accounted for in most of the cases. thus, this has been designated as thrombocytopenia in critically ill patients (tcip). , , recently, in critical illnesses such as sepsis and trauma, thrombocytopenia is suspected to be associated with endotheliopathy that initiates microthrombogenesis and forms microthrombi. the platelet consumption occurs when ulvwf released from endotheliopathy recruit platelets to form platelet-ulvwf complexes, , , which become microthrombi strings and platelets are consumed. this concept of tcip is direct and unequivocal evidence that endotheliopathy promotes in vivo hemostasis. thrombocytopenia in critically ill patient usually presents with mild to moderately decreased platelet count, and bleeding has not been a significant issue in the care of critically ill patients. according to hemostatic principles (table ) , blood vessel damage limited to ecs in endotheliopathy figure . endothelial molecular pathogenesis of ards and mods in critically ill patients. based on "two-activation theory of the endothelium. reproduced and modified from chang. endothelial molecular pathogenesis of ards as one organ phenotype among various mods is succinctly illustrated. the underlying pathologic nature of ards is a hemostatic disease due to endotheliopathy that promotes activation of two molecular pathways. one is inflammatory pathway, which releases cytokines and provokes inflammation, including fever, malaise, and myalgia. the other is microthrombotic pathway, which causes exocytosis of ulvwf and platelet activation and triggers much more deadly dit via microthrombogenesis, leading to eavmtd/dit. disseminated intravascular thrombosis orchestrates consumptive thrombocytopenia, maha, mods, and ttp-like syndrome. ards indicates acute respiratory distress syndrome; dit, disseminated intravascular thrombosis; ea-vmtd, endotheliopathy-associated vascular microthrombotic disease; ecs, endothelial cells; hc, hepatic coagulopathy; maha/amaha, microangiopathic hemolytic anemia/atypical microangiopathic hemolytic anemia; mods: multi-organ dysfunction syndrome; mof, multi-organ failure; tma, thrombotic microangiopathy; sirs, systemic inflammatory response syndrome; ttp, thrombotic thrombocytopenic purpura; ulvwf, unusually large von willebrand factor multimers activates ulvwf path, but tf path is not activated if subendothelial tissue (set)/extravascular tissue (evt) illustrated in figure is not compromised. , , as the hemostatic nature of microthrombosis associated with critical illnesses has not been recognized to date, tcip has been benignly neglected although bone et al in late s had observed thrombocytopenia was a significant component when he described thrombocytopenia in ards. now, tcip is found to be consumptive thrombocytopenia caused by microthrombogenesis that leads to ea-vmtd/dit. more recently, the significant role of the platelet has been recognized in the care of patients with critical illnesses and ards. the degree of thrombocytopenia in sepsis was associated with increased severity and higher mortality , and thrombocytopenia was an increased risk and predictive for patient mortality in ards. thrombotic thrombocytopenic purpura-like syndrome. when mild to moderate thrombocytopenia was present in ards, this author often found masked microangiopathic hemolytic anemia (maha) in hematologic evaluation. , microangiopathic hemolytic anemia was less prominent in ards with fewer schistiocytes than that in acquired immune ttp, and also with mild to moderate anemia. if, however, the evidence of hemolysis were evident with reticulocytosis, hypohaptoglobinemia, increased lactic acid dehydrogenase, and indirect hyperbilirubinemia, , , it was called atypical maha, which is more common in ttp-like syndrome (ie, ea-vmtd). in the literature, case reports described the association between ards and ttp-like syndrome. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in this author's experience, ards with coexisting ttp-like syndrome responded dramatically when therapeutic plasma exchange (tpe) was employed in very early stage of ards. , the reasons why the diagnosis of ttp-like syndrome has been masked in ards were due to inconspicuous schistocytosis and unsuspected diagnosis as well as major attention for the patient care directed to respiratory distress in real-time clinical practice. more likely, it was also due to diametrically different pathogeneses between ttp and ttp-like syndrome, in which clear distinction has not been recognized until recently. it was also caused by the fact that ards has never been considered to be a hemostatic disease, and further ttplike syndrome was unknown to be caused by endotheliopathy. table . three essentials in normal hemostasis. ( ) hemostatic principles ( ) hemostasis can be activated only by vascular injury. ( ) hemostasis must be activated through ulvwf path and/or tf path. ( ) hemostasis is the same process in both hemorrhage and thrombosis. ( ) hemostasis is the same process in both arterial thrombosis and venous thrombosis. in clinical medicine, all patients with ards should be evaluated with a high index of suspicion to look for atypical maha as well as thrombocytopenia. unexplained thrombocytopenia and firm evidence of hemolysis even with minimal or no schistocytes in repeated blood film examination may still be consistent with ttp-like syndrome. multi-organ dysfunction syndromes. in late s, vesconi et al suspected that ards was caused by pulmonary vascular microthrombosis following very elegant investigation demonstrating pulmonary microvascular occlusive lesions in balloon occlusive pulmonary angiography in patients with severe adult respiratory distress. in the study, multiple pulmonary artery filling defects were detected, which findings were interpreted to be consistent with vascular microthrombosis. however, the concept of microthrombosis was not defined yet in coagulation community. nonetheless, the thesis of microvascular thrombosis or vascular microthrombosis can explain the compromised vascular circulatory function of the lungs and occlusive lesions in pulmonary angiography better than any of other propositions. proposed theories for the pathogenesis of ards have included pulmonary vascular endothelial injury leading to endothelial dysfunction due to inflammatory cytokines or activated immune cells, upregulation of adhesion molecules such as soluble vascular adhesion molecule and e-selectin, underexpression of vascular endothelial cadherins, , interactions between neutrophils and cytokines promoting transendothelial migration of cytokine-primed neutrophils, and neutrophil extracellular traps (nets) provoking coagulation and microcirculatory failure. [ ] [ ] [ ] however, these theories could not define how and what molecular changes occur to lead to ards and produce increased capillary permeability that was considered to be the hallmark of ards. more importantly, these theories cannot answer why inflammation in ards is frequently associated with simultaneous hematologic syndromes and mods. , , the proposition of microthrombosis was a very important thesis because for the first time the potential hemostatic nature of ards was suggested. vascular microthrombosis or microvascular thrombosis has been well recognized as the underlying disease of ttp and more recently as that of ttplike syndrome, which occurs in ea-vmtd as well as "dic." although the molecular mechanism of ards has remained elusive, later khadaroo and marshall correctly understood that vascular microthrombosis could contribute its clinical expression not only as ards in the lungs but also as mods in other vital organs. in addition to common association of ards and mods, the similar, if not the same, pulmonary pathologic changes from different pathogens and noninfectious critical illnesses support the mechanism that each of clinical figure . schematic illustration of cross section of blood vessel histology and hemostatic components. the blood vessel wall is the site of hemostasis (coagulation) to produce hemostatic plug in vascular injury to stop hemorrhage from external vascular injury. it is also the site of hemostasis (thrombogenesis) to produce intravascular blood clots in intravascular injury to cause thrombosis. its histologic components can be divided into the endothelium, tunica intima, tunica media, and tunica externa, and each component has different function contributing to molecular hemostasis. as shown in the illustration, endothelial injury triggers exocytosis of ulvwf from ecs, set injury promotes the release of stf from tunica intima, tunica media, or tunica externa, and evt injury induces the release of etf from the outside of blood vessel wall. these depths of blood vessel injury contribute to the genesis of different thrombotic disorders such as microthrombosis, macrothrombosis, and fibrin clot disease/hematoma. this concept is important in the understanding of endotheliopathy leading to ards, which leads to lone activation of ulvwf to produce microthrombi strings in ecs. ards indicates acute respiratory distress syndrome; ecs, endothelial cells; etf, extravascular tf; evt, extravascular tissue; rbc, red blood cell; set, subendothelial tissue; stf, subendothelial tf; tf, tissue factor; ulvwf, unusually large von willebrand factor multimers. phenotypes of mods occurs as a result of the same systemic disease of vmtd, as displayed in figure . for example, similar to the organ phenotype of hemolytic uremic syndrme (hus) in the kidneys, the organ phenotype of ards in the lungs is caused by microvascular thrombosis, which is also characteristic of ttp, ttp-like syndrome, "dic," and thrombotic microangiopathy. in this context, it can be concluded that ards, hus, and every organ syndrome in mods are also the manifestations of ea-vmtd/dit, as illustrated in figure and further elaborated in figure . indeed, ards is just one phenotype among mods associated with increased microvascular permeability due to vmtd involving multiorgans. , , , , this is also true for the current biorgan designation syndromes such as hepatorenal syndrome, cardiopulmonary syndrome, pulmonary-renal syndrome, hepatic encephalopathy, cardiorenal syndrome, and others. it should be emphasized that ards is not the cause of mods, but all the organ phenotypes of mods as well as ards are collateral syndromes provoked by vmtd. next important question is how clinical expression of vmtd can be so variable in the development of mods among every individual patient as shown in figure . this will be discussed in the heading of tropism and endothelial heterogeneity within pathophysiological mechanisms involved in ards. systemic inflammatory response syndrome. the american college of chest physicians and the society of critical care medicine introduced definitions for systemic inflammatory response syndrome (sirs), sepsis, severe sepsis, septic shock, and mods in early s. the idea proposing the term sirs was to recognize it as a clinical response to a nonspecific insult of either infectious or noninfectious origin. however, sirs couldn't be defined as a disease entity and thus has remained to be just as a complex clinical syndrome associated with sepsis and noninfectious critical illnesses because the pathogenesis of sirs has not been clearly established. it generally has been considered to be expression of self-defense mechanism against overwhelming pathologic insults. over the past decades, it has become evident that endotheliopathy plays a major role in sepsis with inflammation and coagulation. in generalized endotheliopathy, sirs commonly occurs in association with ards, which is manifested by combined severe inflammation via cytokine release and microthrombosis via microthrombogenesis that often leads to mods. [ ] [ ] [ ] [ ] [ ] in severe ards, inflammation coexists with other the pathogenesis of mods seen with ards is summarized. any organ can be involved by vmtd in association with/without ards. however, mods is much more common in vital organs, especially in the lungs with ards, the brain with cnsd, and the kidneys with acute renal failure. please note that ards has shown to be associated with the every illustrated organ syndrome. aai indicates acute adrenal insufficiency; alf, acute liver failure; anp, acute necrotizing pancreatitis, ards, acute respiratory distress syndrome; arf, acute renal failure; cnsd, central nervous system dysfunction; dit, disseminated intravascular microthrombosis; ea-vmdt, endotheliopathy-associated vascular microthrombotic disease; fhf, fulminant hepatic failure; hcps, hantavirus cardiopulmonary syndrome; he, hepatic encephalopathy; hps, hantavirus pulmonary syndrome; hrs, hepatorenal syndrome; hus, hemolytic uremic syndrome; mods, multi-organ dysfunction syndrome; nomi, nonocclusive mesenteric ischemia; pdis, peripheral digit ischemic syndrome; rml, rhabdomyolysis; spg, symmetrical peripheral gangrene; wfs, waterhouse-friderichsen syndrome. organ phenotypes such as encephalopathy, acute renal failure, myocardial infarction, pancreatitis, fulminant hepatic failure, adrenal insufficiency, and others. , , thus, sirs can be best defined as combined syndrome of severe inflammatory response from activated inflammatory pathway and organ dysfunction from activated microthrombotic pathway as a result of generalized systemic endotheliopathy. however, we have to understand that inflammation and microthrombosis in endotheliopathy are two separate processes, although their crosstalk mechanism has been popularized. their molecular pathogeneses are independent, which is illustrated in two-activation theory of the endothelium ( figure ). this is the very reason why clinical trials based on antiinflammatory regimens have had no impact on coagulation system and has failed to improve the outcome as demonstrated in the management of sepsis-associated coagulopathy. in clinical practice, inflammation alone is not the major factor causing poor outcome of the patient, but clinical severity of mods caused by vmtd is the main culprit for the demise in severe sepsis. disseminated intravascular coagulation. "disseminated intravascular coagulation" has occurred with ards with or without sepsis. , , [ ] [ ] [ ] it has been considered be the most serious coagulopathy not only in sepsis but also in other human diseases, which is estimated to occur in about % to % of patients with sepsis. a study in japan found that a diagnosis of dic complicated about . % of admissions to university hospitals. according to nih national heart, lung, and blood institute, dic is a condition in which blood clots form throughout the body's small blood vessels. these blood clots can reduce or block blood flow through the blood vessels, which can damage the body's organs. generally clinicians and pathologists defined dic as a widespread hypercoagulable state that can lead to both microvascular and macrovascular clotting and compromise blood flow, ultimately resulting in multiple organ dysfunction and mods. the truth is the coagulopathy of "dic" couldn't be precisely defined because the concept of microthrombosis and its thrombogenesis had not been identified yet. it is because the physiological mechanism of in vivo hemostasis has been incompletely understood. for example, what is the role of von willebrand factor (vwf) in the thrombogenesis and coagulation? also, what is the role of the platelet in coagulation cascade? what is the difference between fibrin clots of activated tf path and thrombosis of deep vein thrombosis (dvt)? what is the difference between microthrombi and macrothrombus? why is microthrombosis disseminated, but is dvt localized? what is coagulation? and how is it different from thrombogenesis? all of these questions seem to be philosophical ones but are urgently needed practical questions in the patient care. there is no simple answer on the difference between dvt and dic. the former responds to anticoagulation, but the latter does not. why is it? current dilemma is that "dic" is found to be incorrect in its character and also in accepted contemporary pathogenetic mechanism according to this author's interpretation. [ ] [ ] [ ] [ ] [ ] the reinterpretation of "dic" based on "two-path unifying theory" of hemostasis and the mechanism of thrombogenesis clearly support that it occurs as a result of activated ulvwf path. [ ] [ ] [ ] [ ] [ ] the credibility of "dic," which coagulopathy has been blamed to microthrombi composed of platelet-ulvwf complexes via microthrombogenesis by some and to fibrin clots made of fibrin, platelet, and coagulation factors through uncontrolled activation of tf-initiated path by others, is seriously undermined because of the irreconcilable conflict between microthrombi and fibrin clots. [ ] [ ] [ ] [ ] [ ] in in vivo hemostatic process, microthrombi and fibrin clots can be easily differentiated as illustrated in figure a and b. the true character of blood clots in "dic" is the same microthrombi occurring in vmtd as seen in ttp and ttp-like syndrome. also, the pathophysiological mechanism of "dic" is not tf/fviia complex-activated coagulation cascade but instead is partial hemostasis due to lone activation of ulvwf path. since "dic" (ie, microthrombosis) occurs as the result of endotheliopathy alone without the damage of set/evt, , , tf path is not activated. this author has derived two theories of "two-activation theory of the endothelium" and "two-path unifying theory" of hemostasis from the analysis and interpretation of pathological, clinical, laboratory, and molecular characteristics between "dic" and "ttp-like syndrome" and elaborated these hypotheses in previous publications. [ ] [ ] [ ] [ ] [ ] therefore, i shall not repeat them again. in short, it can be affirmed that "dic" is exactly the same to ea-vmtd/dit, which hematologic phenotype is ttp-like syndrome. in summing up, the concept of "dic" has been built on the following faulty pathophysiologic mechanism of hemostasis. comments are followed after each statement. "dic" is uncontrolled "tf path" initiated coagulation disorder occurring in sepsis and other critical illnesses. (instead, it is "ulvwf path" initiated microthrombotic disorder.) "dic" is triggered by inflammation, leading to pathologic "fibrin clots" through "crosstalk" between inflammation and coagulation. (instead, it is triggered by microthrombogenesis, leading to pathologic "microthrombi strings" and "no crosstalk" is involved.) "dic" is caused by microvascular thrombosis initiated by "tf/fviia complex". (instead, it is caused by vascular microthrombosis initiated by "platelet-ulvwf complex.") "dic" "consumes coagulation factors and platelets in clotting process." (instead, it is the result of "released ulvwf from injured ecs that consume platelets in formation of microthrombi strings.") acute "dic" is characterized by thrombocytopenia, maha, mods, and severe hemorrhagic syndrome figure . a, normal hemostasis based on "two-path unifying theory." reproduced and updated with permission from chang. in normal hemostasis, two different thrombotic paths, microthrombotic (ulvwf) and fibrinogenetic (tf), are involved in normal hemostasis, but later the paths must unify to conclude normal hemostasis with passive role of nets; it stops the bleeding in external bodily injury and produces the thrombosis in intravascular injury. however, in the different level (depth) of intravascular injury, thrombogenesis takes two different paths. if the level of intravascular injury is confined to the endothelium, lone ulvwf path becomes activated and causes microthrombosis (ie, ea-vmtd) because tf path is not activated. on the other hand, if the level of intravascular injury extends from the endothelium to set/evt, tf path becomes also activated and causes macrothrombosis (eg, dvt). in another theoretical situation, if only set/evt is injured, available tf is supposed to activate lone tf path. however, in pathologic hemostasis, aberrant tf activation occurs and produces fibrin clots (ie, true dic) in apl due to tf expression in intravascular space from leukemic promyelocytes. acute promyelocytic leukemia causes consumption coagulopathy due to lone activation of tf path. this logic is based on "two-path unifying theory." please note different thrombotic disorders via microthrombogenesis, fibrinogenesis, macrothrombogenesis) in the figure, which are annotated in bold face. each pathogenesis occurs when ulvwf path, tf path, or combined paths are activated depending upon the levels of damage in intravascular injury (endothelium and set/evt). the characters of microthrombi, fibrin clots, and macrothrombus from different paths are very different and produce distinctly different clinical thrombotic disorders. b, three paths in thrombogenesis based on "two-path unifying theory." reproduced and updated with permission from chang. traditionally accepted hemostasis has been based on the concept of primary hemostasis in a local vascular injury followed by secondary hemostasis forming fibrin clots. however, this concept cannot explain microthrombi and thrombus formation. therefore, novel "two-path unifying theory" of hemostasis was derived from the vascular physiologic logic of hemostasis based on hemostatic principles and essential components participating in hemostasis and known works of many dedicated coagulation scientists. please note that there are different thrombogenetic paths in "two-path unifying theory" (macrothrombogenesis, microthrombogenesis, and fibrinogenesis) as annotated in bold face. each thrombogenetic path occurs when ulvwf path, tf path, and/or combined paths are utilized depending upon the vascular levels of damage in intravascular injury, which include the endothelium, set, and evt. the characters of the thrombus/blood clot from different paths are unique and produce distinctly different clinical thrombotic disorders. the pathogenesis ards is via microthrombogenesis due to lone activation of ulvwf path, which promotes microthrombi strings made of platelet-ulvwf complexes in pulmonary vasculatures. apl indicates acute promyelocytic leukemia; dic, disseminated intravascular coagulation; dvt, deep vein thrombosis; ea-vmtd, endotheliopathy-associated vascular microthrombotic disease; evt, extravascular tissue; set, subendothelial tissue; tf, tissue factor; ulvwf, unusually large von willebrand factor multimers. associated with "consumption coagulopathy" with depletion of fviii and fv. (instead, acute "dic" is characterized by "hepatic coagulopathy" with markedly increased fviii, markedly decreased fvii, and decreased fii, fv, fix and fx.) chronic "dic" is characterized by thrombocytopenia, maha, and mods without coagulopathy. (yes, the statement is true, but then it is the same picture to "ttp-like syndrome.") "dic", ttp, hus, ttp-like syndrome, and thrombotic microangiopathy are similar but "different diseases." [ ] [ ] [ ] [ ] [ ] [ ] (instead, all of them are the same disease called "ttplike syndrome" except ttp [ga-vmtd and aa-vmtd]. ) "dic" did not respond to any therapeutic agent utilized in clinical trials. but the reason is unexplained. (yes, the statement is true. the reason was the clinical trials were designed based on incorrect pathogenetic mechanism. but it is expected to respond to antimicrothrombotic therapy.) on the other hand, ea-vmtd/dit occurs due to microthrombogenesis as a result of lone activation of ulvwf path of hemostasis. from these statements, we can conclude as follows: "dic" is incorrect in its concept but is consistent with ea-vmtd/dit. , - chronic "dic" is incorrect term, which should be ea-vmtd/dit without hepatic coagulopathy. acute "dic" is incorrect term but is consistent with ea-vmtd/dit with hepatic coagulopathy. traditionally, dic has included ( ) "dic" that is associated with sepsis, trauma, and other critical illnesses and ( ) true dic that occurs in acute promyelocytic leukemia (apl) and rare cases of certain snake venom bite. the former is microthrombotic disease due to microthrombi strings (ttp-like syndrome) and the latter is hemorrhagic disorder due to fibrin clots (fibrin clot disease). since "dic" has been reappraised as ttp-like syndrome (ie, ea-vmtd/dit), once we move "dic" to the column of dit, the leftover is true dic that occurs in apl in which fibrin clots are formed by fibrinogenesis via extrinsic coagulation cascade from activated aberrant tf path. , finally, sepsis-associated coagulopathy (ie, microthrombopathy) seen in ards can be readily understood as ea-vmtd/ dit, which clinical phenotype is ttp-like syndrome with or without hepatic coagulopathy. on the other hand, aplassociated coagulopathy via fibrinogenesis can be understood as true dic (disseminated fibrin clot disease). this brief note on dic and "dic" seems to be a very complex conceptual issue at this time for readers, but the comprehension would become simple and clear once two theories (figures and a and b) are understood with the help of figure . it is no wonder why we could not unmask the true identity of "dic" term used more than years to date. succinctly speaking, ards is an organ phenotype of hemostatic disease occurring as a result of generalized endotheliopathy (ie, ea-vmtd/dit), leading to lone activation of ulvwf path that promotes microthrombotic pathway (ie, microthrombogenesis) and orchestrates consumptive thrombocytopenia, maha, mods, and ttp-like syndrome. , , generalized endotheliopathy also activates inflammatory pathway independent of microthrombotic pathway. the pathophysiological mechanisms involved in ards can be summarized as follows. complement activation in ards has been well recognized more than decades. [ ] [ ] [ ] however, its relationship between ards and complement activation has not been explored even though the role of c b- was suspected to contribute to its pathogenesis and c a in highly pathogenic viral infections was also implicated in acute lung injury. the activation of complement system is one of the key events in defense mechanism against sepsis. its protective function for host rapidly identifies and eliminates invading pathogen. opsonization of foreign surfaces by covalently attached c b fulfills major functions: cell clearance by phagocytosis, amplification of complement activation by the formation of a surface-bound c convertase, and assembly of c convertases. cleavage of c induces the formation of a multiprotein pore complex c b- (ie, membrane attack complex [mac]), which leads to cell lysis. even though its major role is protective function for host through innate immune defense, complement activation could promote destructive action to innocent bystander of the endothelium of the host, leading to endotheliopathy and neutrophil extracellular traps (netosis), which may impact the course of sepsis and other critical illnesses. membrane attack complex exerts deleterious effects to host's ecs unless cd glycoprotein is adequately expressed in ecs and protects them by inhibiting c polymerization from mac. , if cd is downregulated due to either gene mutation or acquired disease, perhaps activated complement could more readily exert destructive effect to the host's ecs causing endotheliopathy in critical illnesses. when mac attacks the membrane of ecs, channel (transmembrane pores) formation develops on the endothelial membrane and triggers endotheliopathy. [ ] [ ] [ ] [ ] considering the role of the complement in ards as well as in sepsis, endothelial dysfunction via activation of complement cascade is suspected to be the major component contributing to pathologic hemostasis of ards. the endotheliopathy in ards activates major molecular mechanisms; one is severe inflammation caused by inflammatory cytokines released from the endothelium and the other is hypoxic organ dysfunction caused by partial hemostasis via microthrombogenesis as illustrated in figure b . endothelial dysfunction has long been known to be the key modulator in the pathogenesis of ards as well as sepsis and critical illnesses. , [ ] [ ] [ ] [ ] the markers such as various cytokines and coagulation participants indicating endothelial damage were significantly altered in patients with critical illnesses compared with controls, which included vwf, fviii and endothelial procoagulants. recently, in view of the role of endotheliopathy and concept of vmtd based on novel in vivo "two-path unifying theory" of hemostasis, ards pathogenesis has been assured to be the result of pathologic hemostasis. [ ] [ ] [ ] , , in ards, heterogeneous expression of cell adhesion molecules by ecs was also noted in human pulmonary vasculatures. although e-selectin and vascular cell adhesion molecule were not expressed on ecs of normal lungs, immunochemical studies showed strong expression of both molecules on the larger vessels of the lungs supporting induction or upregulation in ards. , perhaps adhesion molecules could play a secondary role through endothelial heterogeneity and netosis in the phenotypes of ards-associated mods. it is now confirmed that ards is not the primary disease causing various organ dysfunction syndromes but is the secondary syndrome due to one of hypoxic organ dysfunction resulting from microthrombosis caused by endotheliopathy just like other mods as illustrated in figure . this concept of mods promoted by one pathogenetic mechanism (ie, microthrombogenesis) provoked by generalized endotheliopathy bespeaks of the following important implications in the understanding of ards and mods: acute respiratory distress syndrome is not the primary disease but is secondary clinical syndrome associated with one of different underlying causes (eg, sepsis, trauma, complication of pregnancy, surgery and transplant, cancer, drug/toxin, autoimmune disease, and others). both ards and other mods occur as a result of the same underlying pathophysiological mechanism, which is now identified to be microthrombogenesis due to generalized endotheliopathy, leading to vmtd. both ards and other mods are the phenotypes of ea-vmtd/dit. both ards and other mods would respond to the same treatment based on the same pathophysiological mechanism. certainly, the conceptual relationship between ards and mods guides us to the better understanding of endothelial molecular pathogenesis because the endothelium is distributed to the entire organ system and tissue of human body and protects from internal disease and external bodily injury through hemostasis and circulatory homeostasis. in endothelial pathogenesis of vmtd, the organ phenotype expression is variable among different hosts by the same pathogen or toxin as well as different pathogens or toxins, which variable expression in turn produces unusual exotic manifestations of mods. these phenotypes are likely to develop due to two main endowed biological mechanisms: endothelial heterogeneity of host - and organotropism of pathogen or toxin. [ ] [ ] [ ] [ ] variable clinical organ phenotypic syndromes occur as seen in the same type of the pathogen. examples are hanta virus, causing cardiopulmonary syndrome in the heart and lungs, shiga toxin-producing escherichia coli, presenting with encephalopathy and hus in the brain and kidneys, and neisseria meningitides, inciting waterhouse-friderichsen syndrome and meningitis in the adrenals and meninges. of course, a same organ phenotype can occur due to different types of pathogen. one of the interesting observations in ards is the common occurrence of combined syndrome of ards and acute necrotizing pancreatitis. , [ ] [ ] [ ] the character of this biorgan attraction of vmtd in a particular patient is similar as seen in combined syndromes of hepatic encephalopathy, cardiopulmonary syndrome, hepatorenal syndrome, pulmonary-renal syndrome, and others. the circulatory dysfunction and pathologic findings of diffuse alveolar damage in ards and necrotizing pancreatic damage in acute pancreatitis certainly support that biorgan syndromes are caused by the same pathogenetic mechanism associated with vascular microthrombosis. endothelial heterogeneity and/or tropism select the organ localization of microthrombi, but vascular microthrombosis inflicts physical damage to the organs. in clinical practice, oversimplified designation of organ phenotypes such as encephalopathy and rhabdomyolysis as well as ards might have interfered detecting the underlying etiology and mechanism of multi-organ syndromes as well as vmtd. some authors have claimed one organ phenotypic syndrome such as ards has caused several other organ dysfunctions, including pancreatitis, encephalopathy, renal failure, or hepatic failure. however, it should be understood that ards and additional organ syndromes begin with an equal footing in systemic vmtd, but the severity of selective organ damage is determined by the localization through selectivity of endothelial heterogeneity and tropism. since ards is not the primary disease, the term extrapulmonary manifestations or extrapulmonary phenotypes of ards are misrepresentation. it is this author's opinion that this conceptual misunderstanding has contributed to the delay in recognizing the pathophysiological mechanisms of ards as well as that of other mods such as hus, fulminant hepatic failure, acute pancreatitis, biorgan syndromes, and others. although ards was suspected to be associated with pulmonary vascular microthrombosis, it has taken several decades to recognize microthrombosis is a distinctly different disease from macrothrombosis seen in dvt and pulmonary embolism (pe). even though ards is different from dvt and pe, clinicians still might equate the character of microthrombosis in ards to that of dvt because we have known only one chang mechanism for thrombosis, which is the "blood clot" due to activated tf/fviia path. it is about time we accept the microthrombosis of ards is the product of different hemostasis from macrothrombosis of dvt or pe. this distinction certainly support new concept of mods, including encephalopathy, hus, acute necrotizing pancreatitis, diffuse myocardial ischemia, fulminant hepatic failure from dvt and pe. multiorgan dysfunction syndrome is caused by microthrombosis the same as in ards as a result of microthrombogenesis. , the term of microthrombogenesis is defined in previously mentioned two hemostatic theories. both theories are congruent to each other, although the "two-activation theory of the endothelium" represents endothelial molecular pathogenesis following exocytosis of ulvwf in endotheliopathy ( figure ) and the "two-path unifying theory" elaborates in vivo hemostatic process following intravascular injury via the release of ulvwf ( figure b ). in essence, microthrombogenesis in endothelial molecular pathogenesis and in vivo hemostasis is identical, but the former is the expanded version of ulvwf path illustrating how vmtd orchestrates clinical and pathological phenotypes via endotheliopathy. hemostasis based on "two-path unifying theory". both ttp and ttp-like syndrome are characterized by dit involving the vital organs. so is true with "dic," thrombotic microangiopathy, hus, and ards. therefore, all of them should be classified as vmtd. as discussed earlier in the reinterpretation of "dic", "dic" is the same disorder as ea-vmtd/dit, which hematologic phenotype is ttp-like syndrome. contemporary theory of tf/fviia-initiated coagulation cascade or cell-based coagulation theory cannot explain how microthrombi strings composed of platelet-ulvwf complexes is the same as fibrin clots within intravascular space. this conceptual conflict between activated tf path and activated ulvwf path has alerted this author with the insights that there must be at least two different paths of hemostasis. the existence of two utterly different characters of blood clots-microthrombi and fibrin clots-have contributed to the redrawing of the framework on two different thrombogenetic mechanisms: microthrombogenesis of ulvwf path and fibrinogenesis of tf path. the former assembles microthrombi strings as seen in vmtd such as ttp, ttp-like syndrome, "dic", hus, ards, and the latter generates fibrin clots as seen in apl and certain envenomation. then, next question is what is the character dvt and arterial thrombus seen in aortic aneurysm since they are neither microthrombi nor fibrin clots. instead, they are obviously macrothrombus, containing fibrin clots and platelets. therefore, it has to be concluded that both ulvwf path and tf path must be involved in the formation of macrothrombosis such as dvt and arterial thrombosis. through this elucidation, two-path unifying theory is borne out to explain not only "two-path unifying theory" of hemostasis but also three paths of thrombogenesis, which includes microthrombogenesis, fibrinogenesis, and macrothrombogenesis ( figure a and b) . finally, in vivo hemostatic mechanism, including the additional role of netosis at the unifying stage of activated ulvwf path and activated tf path, has been indirectly discovered. the present hallmark of ards is vascular microthrombosis (ie, vmtd) as seen with sepsis. sepsis is characterized by generalized endotheliopathy without compromise of set/ evt, which is also the same in ards. hemostatic involvement in sepsis is lone activation of ulvwf path on ecs, leading to formation of microthrombi, but bleeding does not develop because set and evt damage do not occur and tf path is not activated. unlike localized macrothrombosis (eg, thrombus of aortic aneurysm, acute ischemic stroke, and dvt), disseminated microthrombosis (ie, dit) presents with many intriguing features such as ards and hus as well as a variety of hematologic syndromes, including thrombocytopenia, maha, ttp-like syndrome, and "dic." [ ] [ ] [ ] , , according to "two-path unifying theory" of hemostasis, , two thrombotic/coagulation pathways, which are ulvwf and tf paths, are initiated in normal hemostasis but later the two paths must unify to conclude normal hemostasis with passive role of nets. hemostasis stops bleeding in external bodily injury but produce thrombosis in intravascular injury. in the different level (depth) of intravascular injury as presented in tables and , different paths of thrombogenesis take place depending upon what component(s) of vascular wall is damaged ( figure ). if the intravascular damage is confined to the ecs (level ), lone ulvwf path becomes activated and causes microthrombosis (ie, vmtd such as tia, ttp-like syndrome, ards, and mods) because tf path is not activated. on the other hand, if the intravascular damage extends from the ecs to set (level ), both ulvwf path and tf path become activated and cause macrothrombosis (eg, dvt; acute ischemic stroke) as illustrated in hemostatic theory ( figure a and b). , in addition, if the damage extends from the ecs to beyond vessel wall including set and evt (level ), both ulvwf path and tf path become activated and form macrothrombosis with additional evt bleeding (eg, thrombohemorrhagic stroke), which is summarized in tables and . for example, for stroke, this concept is very important in the understanding of thrombogenesis, not only in making the diagnosis but also in planning for the treatment. also, in another situation, if the ecs, set-and evt are damaged by obtuse external trauma, bleeding occur into evt in smaller vessels, but without bleeding into the damaged vascular lumen. tissue factor is released and mixed with blood in evt to activate fvii to trigger the activation of tf/vii path. it causes only "hematoma" without significantly breached ecs because ulvwf path is not activated. this logic is based on "twopath unifying theory." please see figure b , showing three different thrombogenetic processes: microthrombogenesis, fibrinogenesis, and macrothrombogenesis, which are annotated in bold/shaded face. each thrombogenesis occurs when ulvwf path, tf path, or combined paths are activated depending upon the levels (depth) of damage in intravascular injury. the characters of microthrombi, fibrin clots, and macrothrombus from different paths are very different and produce distinctly different clinical thrombotic disorders. among these characters, ards is a hemostatic disease made of "microthrombi strings." molecular pathogenesis based on "two-activation theory of the endothelium". the endothelial molecular pathogenesis triggering inflammation has been well known and documented in medical literature, but its molecular pathogenesis promoting microthrombogenesis has not been understood until recently. although the underlying pathology of ards is vmtd, the pathophysiological mechanism of endotheliopathy causing vmtd has remained in mystery, which is the very reason why progress has not been made in the treatment for ards. nor is the comprehensible pathogenesis of microthrombosis orchestrating hematologic expressions, including thrombocytopenia, maha, mods, and ttp-like syndrome. since sepsis is the initiating cause of microthrombosis and ards is the manifestation of organ phenotype of microthrombosis, sepsis and ards often coexist. further, thrombocytopenia, maha, mods, ttp-like syndrome, and sirs may occur simultaneously in both sepsis and ards. the "two-activation theory of the endothelium" , succinctly explains this pathogenesis of ea-vmtd/dit and identifies dit as a disease promoting all the clinical and hematologic syndromes. the proposed thesis of endothelial molecular pathogenesis in ards is endotheliopathy that initiates two important molecular events: ( ) release of inflammatory cytokines (eg, interleukin (il)- , il- , tumor necrosis factor a, adhesion molecules, and others) , , - and ( ) activation of the platelet and exocytosis of ulvwf. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the former triggers inflammation, which process is called "activation of inflammatory pathway," and the latter mediates microthrombogenesis, which triggers "activation of microthrombotic pathway." these two independent pathways are the essence of the "two-activation theory of the endothelium." the manifestation of activated inflammatory pathway is fever, myalgia, arthralgia, and malaise, but that of activated microthrombotic pathway produces microthrombi strings composed of platelet-ulvwf complexes leading to vmtd. the activation of endothelial inflammatory pathway occurs due to cytokines in both septic and nonseptic critical illnesses. in sepsis-associated ards, the inflammation is accentuated, perhaps through additional loop of activated circulating immune cell pathway (eg, macrophages, monocytes, neutrophils, and lymphocytes) interacting with activated ecs. this pathway further upregulates the expression of inflammatory response, sometimes causing "cytokine storm." this additional mechanism may explain why more severe inflammation occurs in sepsis than in trauma. on the other hand, the activation of the microthrombotic pathway is promoted by excessively exocytosed ulvwf from injured ecs. following the endothelial release, ulvwf become anchored to injured ecs as long elongated strings. [ ] [ ] [ ] if in addition to the excess of ulvwf, the protease adamts , which cleaves ulvwf to smaller molecular weight vwfs, is underexpressed due to additional underlying heterozygous gene mutation, [ ] [ ] [ ] it is more likely to promote ea-vmtd/dit. this endothelial molecular pathogenesis through activation of inflammatory pathway and microthrombotic pathway clearly explains every hematologic feature and organ phenotypic syndrome occurring in ards. in the past several decades, many proposals for redefinition of ards have been forwarded to identify the pathophysiological mechanism and to improve the outcome of the disease with better classification and therapeutic design. [ ] [ ] [ ] [ ] [ ] [ ] however, medical community's task finding the answer on the pathogenesis of ards has been far from over. now, the recognition of ards as an expression of hemostatic disease that is characterized by vmtd has widely opened the door not only in the understanding of this lifethreating phenotype organ syndrome but also in redefining other clinical mods. additionally, with the identification of different thrombogenetic mechanisms of microthrombosis, fibrin clot disease, and macrothrombosis, various thrombotic disorders could be more precisely defined through the submechanisms of in vivo hemostasis. , acute respiratory distress syndrome is the most prominent organ phenotype syndromes developing in sepsis and other critical illnesses among mods. thus, once we understand ards as an organ phenotype syndrome of the lungs in vmtd, we should be able to understand the organ syndromes due to vmtd occurring in the brain, heart, liver, pancreas, muscles, adrenals, and others. it also affirms generalized ea-vmtd/dit is the underlying disease, and ards and other organ syndromes are the manifestations of each specific organ phenotype in ea-vmtd/dit. to make the matters simpler, the diagnostic evaluation and therapeutic approach are the same in every phenotype of mods. finally, we should be able to treat all the patients with every organ phenotype syndrome, combined biorgan syndrome and mods due to ea-vmtd/dit with the same regimen focused on microthrombogenesis. table summarizes the identity of ards defined through clinical, etiologic, pathogenetic and phenotypic features of ea-vmtd. the pulmonary physiologic alteration of hypoxemia, increased capillary permeability and circulatory failure, pathologic changes of diffuse alveolar damage, exudative pulmonary edema, and hyaline membrane formation are the result of pulmonary vascular microthrombosis. thus, the therapy for ards should directly target the pathogenesis producing vmtd. the berlin definition of ards addressed limitations of the american-european consensus conference definition, but poor reliability of some criteria may have contributed to underrecognition and antipathy by clinicians. no pharmacologic treatments aimed at the underlying pathology have been shown to be effective to date, and management remains supportive with lung-protective mechanical ventilation. in addition to cardiopulmonary evaluation for physiological changes due to respiratory distress as well as assessment of the underlying disease, the proper diagnostic approach of ards should start with hematological evaluation. first of all, every patient with ards should be evaluated for the potential of unrecognized ttp-like syndrome, which had been previously defined as "dic". , , unexplained thrombocytopenia, after the exclusion of known causes of thrombocytopenia, should be an initial clue suggesting ongoing microthrombogenesis, leading to ea-vmtd/dit. an additional finding of maha even with minimal degree of schistocytosis, if present, should confirm the diagnosis of ttp-like syndrome. , to look for schistocytes and evidence of hemolysis, blood films should be examined daily for several consecutive days by an experienced hematologist. unlike antibody-associated ttp (aa-vmtd, acquired ttp), schistocytes are fewer in ards, , perhaps due to difference in force of shear stress in the pulmonary vasculature. in critical care settings, in the past, its hemostatic nature could have been missed due to inattention to blood films and low index of suspicion even though an evaluation for unexplained thrombocytopenia and anemia could have been attempted. , , in ards, thrombocytopenia and intravascular hemolysis (ie, anemia, reticulocytosis, increased lactic acid dehydrogenase, indirect hyperbilirubinemia, and hypohaptoglobinemia with negative coombs tests) might be the sufficient criteria to establish the diagnosis of ttp-like syndrome to begin life-saving tpe at the earliest possible time. to solidify the concept that the underlying pathology of ards is ea-vmtd/dic, this author recommends to determine ( ) adamts activity and its autoantibody status, ( ) adamts gene mutation study, and ( ) fibrinogen quantitation, fviii and vwf activity in circulation, and coagulation factor assay for liver-dependent factors (ie, fii, fv, fvii, fix, and fx) to determine the cause of coagulopathy (ie, hepatic coagulopathy). the diagnostic assessments are summarized in table . since ards is one of mods, clinicians should stay vigilant with close clinical monitoring for developing additional organ phenotypes of mods as illustrated in figure . reflection on past clinical trials. more than a half century since the term ards coined, extensive controlled clinical trials have conducted for ards to evaluate the effects of pharmaceutical agents, such as statins, b agonists, anti-inflammatory agents, and corticosteroids, [ ] [ ] [ ] [ ] nutritional supplementation, such as glutamine, selenium, omega- fatty acid, [ ] [ ] [ ] and antioxidant therapy such as n-acetyl cysteine , in prevention and treatment. unfortunately, all of the trials failed to significantly benefit the patient with ards. the fact that the pathophysiologic mechanism of ards has not been clearly recognized and the failure of therapeutic regimens to restore the physiologic alteration of ards from endotheliopathy certainly indicates that the pathogenesis of ards is yet to be discovered. this author is confident that novel hemostatic "two-path unifying theory" and "twoactivation theory of the endothelium" uncover this long hidden mystery of the pathogenesis of ards and should yield effective therapeutic regimens sooner than later. therapeutic plasma exchange. in addition to the best supportive care with proper antibiotics, ventilator support, and appropriate fluid and electrolyte balance for ards, it is obvious that therapeutic approach should target the pathogenesis itself. since this newly recognized concept of the pathogenesis is a hemostatic disease called pulmonary vascular microthrombosis (ie, ttp-like syndrome as a result of ea-vmtd/dit) that is caused by the lone activation of ulvwf path, the therapeutic design should be utilizing the inhibition of vascular microthrombogenesis. at present, the only available antimicrothrombotic regimen is tpe. the rationale is microthrombosis produced by excessive production of ulvwf from endotheliopathy and relative insufficiency of adamts perhaps due to unsuspected gene mutation should respond to additional supply of ulvwfcleaving adamts from exchange of normal donor plasma. indeed, ttp-like syndrome associated with ards has shown excellent response to tpe when employed in very early stage. , , since the lungs are the very organ responsible for oxygen supply to other organs, ards is the most important organ phenotype among mods that could hasten the demise of the patient due to severe hypoxemia. at this time, the earliest intervention utilizing tpe is the only potentially effective treatment to save lives. otherwise, once the patient is entrenched in mechanical ventilation with volume overload following intravenous fluid and blood transfusions, the recovery from ards may become remote even with tpe. just as in sepsis and septic shock, tpe has been used sporadically in ards even without understanding of the concept of microthrombogenesis and vmtd and has shown significant benefit with safety in case reports and limited clinical series. [ ] [ ] [ ] [ ] [ ] [ ] antimicrothrombotic therapy. both ttp and ttp syndrome, including "dic," have shown the beneficial effect with tpe, which is a surrogate for replacement therapy of adamts despite its technical limitations and inconvenience. theoretically, the most efficient therapeutic regimen would be antimicrothrombotic agents, which could include recombinant adamts and possibly n-acetyl cysteine. , - both agents are neither approved nor utilized for human use as defined antimicrothrombotic agents, although adamts is in clinical trials for ga-vmtd. if we can prove their benefit for ards, the therapeutic potential to save so many lives for patients with ea-vmtd/dit in critical care medicine would be immeasurable. the worsening thrombocytopenia (ie, tcip) is the most important laboratory sign suggesting progression of ards. in this situation, platelet transfusion might be tempting, but it is contraindicated in ea-vmtd/dic because platelet transfusion would further promote microthrombogenesis and intensify mods associated with dit as well as maha and also may provoke trali syndrome. if hepatic coagulopathy coexist with ards, its coagulopathy could rapidly progress to combined microthrombo-hemorrhagic syndrome, which will demand a specialized care of coordination with a coagulation specialist. at last, the pathogenesis of ards is identified to be a hemostatic disease occurring due to lone activation of ulvwf path of hemostasis as a result of endotheliopathy in critically ill patients. its underlying pathology is ea-vmtd/dit and clinical phenotype is ttp-like syndrome. generalized endotheliopathy activates the inflammatory pathway and microthrombotic pathway, triggering ea-dit/vmtd. the former provokes inflammation, and the latter promotes consumptive thrombocytopenia, ttp-like syndrome, and hypoxic mods. systemic inflammatory response syndrome is combined syndrome from two independently activated endothelial molecular pathogeneses. acute respiratory distress syndrome is the pulmonary organ phenotype among various ttp-like syndromes. acute respiratory distress syndrome responds to the tpe if initiated in very early stage of the disorder. potentially effective targeted therapeutic strategy should be explored with antimicrothrombotic agents at the earliest possible time to save lives. the author expresses sincere appreciation to miss emma nichole zebrowski for her insights on the structural function of the blood vessel wall in in vivo hemostasis and excellent illustrative art works of figure . the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. orcid id jae c. chang https://orcid.org/ - - - thrombocytopenia in critically ill patients due to vascular microthrombotic disease: pathogenesis based on "two activation theory of the endothelium thrombocytopenia is associated with acute respiratory distress syndrome mortality: an international study platelets in the pathogenesis of acute respiratory distress syndrome acute respiratory distress syndrome and multiple organ failure ards and the multiple organ dysfunction syndrome. common mechanisms of a common systemic process acute respiratory distress syndrome and multiple organ dysfunction: a story of intricate relationship epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries hemostasis based on a novel "two-path unifying theory" and classification of hemostatic disorders ttp-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease thrombogenesis and thrombotic disorders based on "two-path unifying theory of hemostasis": philosophical, physiological and phenotypical interpretation disseminated intravascular coagulation: is it fact or fancy? sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease a thought on possible pathogenesis of ebola viral hemorrhagic disease and potential treatments: could it be thrombotic thrombocytopenic purpura-like syndrome? acute lung injury and the acute respiratory distress syndrome in the injured patient adult respiratory distress syndrome: a complication of induced hypertension after severe head injury preoperative and intraoperative predictors of postoperative acute respiratory distress syndrome in a general surgical population ards in pregnancy acute respiratory distress syndrome in pregnancy acute respiratory distress syndrome after liver transplantation: etiology, prevention and management acute respiratory failure in kidney transplant recipients: a multicenter study respiratory failure as a result of drugs, overdoses, and poisonings respiratory dysfunction in thrombotic thrombocytopenic purpura acute respiratory distress syndrome as a major clinical manifestation of thrombotic thrombocytopenic purpura various clinical manifestations in patients with thrombotic microangiopathy adult respiratory distress syndrome and disseminated intravascular coagulation complicating heat stroke disseminated intravascular coagulation in the pathogenesis of adult respiratory distress syndrome: . experimental study coagulation abnormalities in acute lung injury and sepsis viral hemorrhagic fevers due to endotheliopathyassociated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on "two activation theory of the endothelium long-term outcome of acute respiratory distress syndrome caused by severe acute respiratory syndrome (sars): an observational study molecular pathology of emerging coronavirus infections platelet and trali: from blood component to organism transfusion-related acute lung injury (trali): a serious adverse event of blood transfusion benchto-bedside review: brain-lung interaction in the critically ill-a pending issue revisited early hepatic dysfunction is associated with a worse outcome in patients presenting with acute respiratory distress syndrome: a post-hoc analysis of the acurasys and proseva studies acute kidney injury in children with acute respiratory failure acute pancreatitis and acute respiratory distress syndrome complicating plasmodium vivax malaria acute lung injury and ards in acute pancreatitis: mechanisms and potential intervention the risk factors, incidence, and prognosis of ards following septicemia thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis sepsisassociated disseminated intravascular coagulation and thromboembolic disease combination therapy with sivelestat and recombinant human soluble thrombomodulin for ards and dic patients systemic inflammation and disseminated intravascular coagulation in early stage of ali and ards: role of neutrophil and endothelial activation the pathologist's approach to acute lung injury acute respiratory distress syndrome and diffuse alveolar damage. new insights on a complex relationship lung pathology of severe acute respiratory syndrome (sars): a study of autopsy cases from singapore a decade after sars: strategies for controlling emerging coronaviruses current understanding of the pathophysiology of thrombotic thrombocytopenic purpura clinical features of severe wasp sting patients with dominantly toxic reaction: analysis of cases chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies pulmonary pathology of acute respiratory distress syndrome ards and diffuse alveolar damage: a pathologist's perspective thrombocytopenia in critically ill patients: clinical and laboratorial behavior and its correlation with short-term outcome during hospitalization how do we approach thrombocytopenia in critically ill patients? platelets in critical illness acute respiratory distress syndrome and nonocclusive mesenteric ischemia as major clinical manifestations of thrombotic thrombocytopenic purpura: complete remission following exchange plasmapheresis thrombotic thrombocytopenic purpura (ttp) presenting as acute respiratory distress syndrome (ards) thrombotic thrombocytopenic purpura as a complicating factor in a case of polymyositis and sjögren's syndrome fulminant respiratory failure. a manifestation of thrombotic thrombocytopenic purpura severe hypoxemic respiratory failure and thrombotic thrombocytopenic purpura diffuse alveolar hemorrhage: a lifethreatening condition in thrombotic thrombocytopenic purpura (ttp) pulmonary microthrombosis in severe adult respiratory distress syndrome chemokines in acute respiratory distress syndrome soluble vascular cell adhesion molecule- (svcam- ) is elevated in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome vascular endothelial cadherin expression in lung specimens of patients with sepsis-induced acute respiratory distress syndrome and endothelial cell cultures interactions between neutrophils and cytokines in blood and alveolar spaces during ards neutrophil extracellular traps (nets) are increased in the alveolar spaces of patients with ventilator-associated pneumonia targeting neutrophil extracellular traps in acute lung injury: a novel therapeutic approach in acute respiratory distress syndrome? the acute respiratory distress syndrome: pathogenesis and treatment acute respiratory distress syndrome: pathophysiology and therapeutic options the acute respiratory distress syndrome why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? implications for management definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis disseminated intravascular coagulation (dic). statpearls [internet role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy platelet count and prothrombin time help distinguish thrombotic thrombocytopenic purpura-hemolytic uremic syndrome from disseminated intravascular coagulation in adults sepsis-induced disseminated intravascular coagulation with features of thrombotic thrombocytopenic purpura: a fatal fulminant syndrome disseminated intravascular coagulation and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome thrombocytopenia in the icu: disseminated intravascular coagulation and thrombotic microangiopathies-what intensivists need to know thrombotic thrombocytopenic purpura or disseminated intravascular coagulation? indian venom concentrations and clotting factor levels in a prospective cohort of russell's viper bites with coagulopathy association of complement activation and elevated plasma-c a with adult respiratory distress syndrome. pathophysiological relevance and possible prognostic value activation of the complement system in the adult respiratory distress syndrome accentuated formation of the terminal c b- complement complex in patient plasma precedes development of the adult respiratory distress syndrome the role of c a in acute lung injury induced by highly pathogenic viral infections complement evasion by human pathogens netosis, complement, and coagulation: a triangular relationship complement-mediated injury and protection of endothelium: lessons from atypical haemolytic uraemic syndrome interactions of soluble cd with the terminal complement complexes. cd and c compete for a nascent epitope on c cd expressed by human endothelial cells functions as a protective molecule against complement-mediated lysis cd : its role in complement regulation and potential for therapeutic use the role of the endothelium in severe sepsis and multiple organ dysfunction syndrome endothelial pathomechanisms in acute lung injury endothelial cell activation and blood coagulation in critically ill patients with lung injury the pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities heterogeneous expression of cell adhesion molecules by endothelial cells in ards clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury using cultured endothelial cells to study endothelial barrier dysfunction: challenges and opportunities the endothelium in acute lung injury/ acute respiratory distress syndrome endothelial cell heterogeneity. cold spring harb perspect med molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration location, location, location: five facts about tissue tropism and pathogenesis tropism and replication of middle east respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: an in-vitro and ex-vivo study host cell proteases: critical determinants of coronavirus tropism and pathogenesis tropism and infectivity of a seasonal a (h n ) and a highly pathogenic avian a (h n ) influenza virus in primary differentiated ferret nasal epithelial cell cultures pathophysiology of pulmonary complications of acute pancreatitis pancreatitis-associated acute lung injury: new insights acute respiratory distress syndrome in pancreatitis thrombosis and platelets: an update endothelial biomarkers in human sepsis: pathogenesis and prognosis for ards molecular and immune biomarkers in acute respiratory distress syndrome: a perspective from members of the pulmonary pathology society a pathophysiologic approach to biomarkers in acute respiratory distress syndrome functional architecture of weibel-palade bodies regulation of von willebrand factor secretion from endothelial cells by the annexin a -s a complex von willebrand factor remodeling during exocytosis from vascular endothelial cells weibel-palade bodies: unique secretory organelles within endothelial cells unwinding the von willebrand factor strings puzzle cleavage of ultra-large von willebrand factor by adamts- under flow conditions generation and breakdown of soluble ultralarge von willebrand factor multimers immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation reduced adamts in children with severe meningococcal sepsis is associated with severity and outcome adamts deficiency in severe postpartum hellp syndrome ul haq a. deficiency of adamts- in pediatric patients with severe sepsis and impact on inhospital mortality the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition a universal definition of ards an attempt to validate the modification of the american-european consensus definition of acute lung injury/acute respiratory distress syndrome by the berlin definition in a university hospital acute lung injury epidemiology and natural history network. a clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy acute respiratory distress syndrome: advances in diagnosis and treatment postoperative thrombotic thrombocytopenic purpura following cardiovascular surgeries statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials randomized, placebo-controlled clinical trial of an aerosolized b -agonist for treatment of acute lung injury steroids for acute respiratory distress syndrome? inhaled nitric oxide for acute respiratory distress syndrome (ards) in children and adults glutamine supplementation for critically ill adults selenium supplementation for critically ill adults enteral omega- fatty acid supplementation in adult patients with acute respiratory distress syndrome: a systematic review of randomized controlled trials with meta-analysis and trial sequential analysis effects of nacetylcysteine treatment in acute respiratory distress syndrome: a meta-analysis antioxidant treatment with n-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebocontrolled study use of therapeutic plasma exchange as a rescue therapy in ph n influenza a-an associated respiratory failure and hemodynamic shock plasmapheresis in severe acute pancreatitis, a phase i study plasmapheresis in the treatment of hypertriglyceridemic pancreatitis with ards acute respiratory failure in patients with guillain-barré syndrome and myasthenic crisis treated with plasmapheresis in the intensive care unit effect of plasma exchange in acute respiratory failure due to anti-neutrophil cytoplasmic antibody-associated vasculitis coagulopathy in malaria willebrand factor in experimental malaria-associated acute respiratory distress syndrome beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura n-acetylcysteine reduces the size and activity of von willebrand factor in human plasma and mice key: cord- -vvhq vgp authors: blot, mathieu; jacquier, marine; aho glele, ludwig-serge; beltramo, guillaume; nguyen, maxime; bonniaud, philippe; prin, sebastien; andreu, pascal; bouhemad, belaid; bour, jean-baptiste; binquet, christine; piroth, lionel; pais de barros, jean-paul; masson, david; quenot, jean-pierre; charles, pierre-emmanuel title: cxcl could drive longer duration of mechanical ventilation during covid- ards date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: vvhq vgp background: covid- -related ards has unique features when compared with ards from other origins, suggesting a distinctive inflammatory pathogenesis. data regarding the host response within the lung are sparse. the objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ards etiology (i.e., covid- vs. non-covid- ). methods: bronchoalveolar lavage fluid and plasma were obtained from control, non-covid- ards, and covid- ards patients. clinical data, plasma, and epithelial lining fluid (elf) concentrations of inflammatory mediators and cell-free mitochondrial dna were measured and compared. results: covid- ards patients required mechanical ventilation (mv) for significantly longer, even after adjustment for potential confounders. there was a trend toward higher concentrations of plasma ccl , cxcl , cxcl , cd ligand, il- , and gm-csf, and elf concentrations of cxcl , cxcl , granzyme b, trail, and egf in the covid- ards group compared with the non-covid- ards group. plasma and elf cxcl concentrations were independently associated with the number of ventilator-free days, without correlation between elf cxcl- and viral load. mitochondrial dna plasma and elf concentrations were elevated in all ards patients, with no differences between the two groups. elf concentrations of mitochondrial dna were correlated with alveolar cell counts, as well as il- and il- β concentrations. conclusion: cxcl could be one key mediator involved in the dysregulated immune response. it should be evaluated as a candidate biomarker that may predict the duration of mv in covid- ards patients. targeting the cxcl -cxcr axis could also be considered as a new therapeutic approach. trial registration: clinicaltrials.gov, nct since december , the world is experiencing an outbreak of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ). clinical, radiological, and biological differences have been found between covid- -related acute respiratory distress syndrome (ards) and ards from another origin. indeed, the sudden clinical deterioration observed week after symptom onset, together with deep hypoxemia contrasting with "normal" (> ml/cmh o) lung compliance, and the higher incidence of thromboembolic events suggest that sars-cov- is driven by a unique pathogenesis resulting in an atypical form of ards [ , ] . notably, mechanical ventilation appears to be required for twice as long in covid- than in non-covid- ards patients [ , ] . it has been established that the virus invades type alveolar cells and ciliated epithelial cells that express ace [ ] . subsequently, as they die, infected cells release virus particles and intracellular components including molecules likely to act as alarmins (i.e., danger signals), as reflected by rising lactate dehydrogenase (ldh) levels in the plasma [ ] . the ensuing recruitment and activation of immune cells lead to lung damage [ ] . for now, several studies have established that the hyperinflammatory response (namely the cytokine storm) induced by sars-cov- is associated with disease severity and could contribute to the development of ards [ , ] . in addition, since most patients need to undergo mechanical ventilation in this context, ventilator-induced lung injury (vili) could exacerbate tissue damage as well as local and systemic inflammation, thus acting as a "second hit." our team has previously shown that mitochondrial alarmins (i.e., mitochondrial dna) are released by human epithelial cells submitted to cyclic stretch, and these alarmins are also recovered from bronchoalveolar lavage (bal) fluid obtained from either ventilated rabbits or ards patients. by promoting chemotaxis and activation of polymorphonuclear neutrophils (pmns), mitochondrial alarmins are thought to represent proximal endogenous mediators of vili and ards when they are released by injured alveolar cells [ , ] . the aim of our study was to compare cytokine response patterns, in both alveolar and systemic compartments, between covid- -related ards and non-covid- -related ards (i.e., ards complicating pneumonia from another origin). in addition, we sought to establish the extent to which the immune signature could be associated with clinical evolution according to ards etiology. this is an ancillary study of the ongoing prospective pneu-mochondrie study (clinicaltrials.gov nct ) which started in june in three intensive care units and the department of pneumology at the university hospital of dijon (france). patients were eligible if a bal was considered necessary by the attending physician and if they had ( ) pneumonia (≥ acute signs including cough, purulent sputum, dyspnea, chest pain, temperature < °c or ≥ . °c, and novel radiological pulmonary infiltrate); ( ) ards (according to the berlin definition) [ ] ; ( ) requiring mechanical ventilation (mv); and ( ) bal was performed within h of the start of mv. covid- ards patients were eligible if they tested positive for sars-cov- by reverse transcriptase polymerase chain reaction (rt-pcr) for at least one respiratory sample. the control population consisted of outpatients without fever during the last days, not under mechanical ventilation, and undergoing a bal for a condition not related to acute infection (evaluation of a pulmonary nodule, chronic interstitial syndrome, or unexplained chronic pulmonary sign). seven control patients and bacterial ards patients were prospectively included between june , , and january , ( weeks before the pandemic covid- started in burgundy, france). fourteen covid- ards patients were included between march and april , . oral consent was obtained from the patients or their legal representatives. approval was obtained from the ethics committee (comité de protection des personnes sud-est iii; - b), and an amendment was obtained to include supplementary patients with covid- -related ards. demographic data, comorbidities, clinical and biological parameters, and severity scores (sequential organ failure assessment (sofa) [ ] and the new simplified acute physiology score (saps ii) [ ] ) were calculated on the first day of ards. septic shock was defined as persistent hypotension requiring vasopressors and a serum lactate level > mmol/l despite adequate volume resuscitation. clinical outcomes were recorded up to days after the start of ards: -day mortality; number of hospital-, icu-, and ventilatorfree days; and hospital-acquired complications (ventilatory-acquired pneumonia (vap), thrombo-embolic disease). the "ventilator-free days" outcome was defined as the number of days alive from day of ards to day during which the patient was breathing without mv. dedicated clinical research assistants collected all data using a standardized electronic case report form. automatic checks were generated for missing or incoherent data. all abnormal data were controlled by a physicianscientist. the concentration of inflammatory cytokines and mitochondrial alarmins (cell-free mitochondrial dna concentrations) was measured within both the systemic and alveolar compartments. bronchoalveolar lavage was performed by fiberoptic bronchoscopy as part of standard care with sterile saline at °c. the ten first milliliters of aspirated fluid, reflecting a bronchial sample, was not considered for the study. ten milliliters of bal fluid (balf) was dedicated to the study, transported at °c, and used within h of collection. fifty microliters of whole balf was homogenized with μl of thrombo-plus (sarstedt) before cell count by light microscopy. bal was filtered through a -μm cell strainer (fisher) and centrifuged at ×g for min at °c to remove mucus and cells. the supernatant was then centrifuged again at ×g for min at °c to remove the remaining debris and stored at − °c until use. in addition, three additional blood tubes (edta) were collected just before the bal procedure (with a maximum delay of h), as part of standard care, and then centrifuged at ×g for min at °c and stored at − °c until use. forty-five analytes were quantified in the plasma and balf using human xl cytokine magnetic -plex luminex® assay (r&d systems, usa) according to the manufacturer's instructions: c-c motif chemokine ligand (ccl) , ccl , ccl , ccl , ccl , ccl , ccl , cd ligand, fractalkine, c-x-c motif chemokine ligand (cxcl) , cxcl , cxcl , epidermal growth factor (egf), fibroblast growth factor (fgf), fms-like tyrosine kinase ligand (flt l), granulocyte colony-stimulating factor (g-csf), granulocytemacrophage colony-stimulating factor (gm-csf), granzyme b, interferon (ifn)-alpha, ifn-beta, ifn-gamma, interleukin (il)- α, il- β, il- ra, il- , il- , il- , il- , il- , il- , il- , il- , il- , il- , il- , il- a, il- e, il- , programmed death-ligand (pdl ), platelet-derived growth factor (pdgf)-aa, pdgf-ab/bb, transforming growth factor (tgf)-α, tumor necrosis factor (tnf)-α, tnf-related apoptosis inducing ligand (trail), and vascular endothelial growth factor (vegf). for mitochondrial dna isolation, collected conditioned media from the plasma and balf were first centrifuged at ×g for min to remove cell debris, followed by dna extraction using qiagen dneasy kit (qiagen, valencia, ca, usa). quantitative pcr was performed on a steponeplus™ real-time pcr (applied biosystem), using sybr green reagent (powerup®, thermo) with one-tenth and one-fiftieth dilutions of the final product of plasma and balf respectively, using mitochondrialspecific pcr primers for cytochrome c oxidase subunit iii (coxiii) and nadh dehydrogenase subunit i [ ] , in reference to a standard curve of human mitochondrial dna to quantify the amount of mitochondrial dna, amplified as previously reported [ , , ] . rna extraction was performed on a nuclisens® easy-mag® platform (biomerieux, marcy-l'Étoile, france), from μl of cell-free balf, and according to the manufacturer's instructions. two target genes were amplified and tested simultaneously, namely the rnadependent rna polymerase (rdrp) ip and ip regions [ ] . amplification was performed using quantstudio rtpcr systems (thermo fisher scientific, waltham, ma, usa). quantification of the number of rna copies was done according to a scale ranging from to copies/ml. all positive balf samples were quantified and expressed as the number of rna copies/μl. to correct for dilution of balf, the elf concentration of all analytes or sars-cov- was calculated by multiplying the balf concentration with a dilution factor and using urea, according to the formula [analyte] elf = [analyte] balf × [urea] plasma /[urea] balf , as described by rennard et al. [ ] . determination of the urea concentration in balf and plasma was performed using the liquid chromatography tandem mass spectrometry (lc-msms) method, adapted from han et al. [ ] with modifications. plasma ( μl) or balf ( μl) were extracted with ml of cold ethanol containing ng or ng of c and n urea used as internal standard, respectively. high-performance liquid chromatography (hplc) was performed on an agilent lc system coupled to a qqq mass spectrometer. the analysis was conducted in a positive selected reaction monitoring mode. calibration curves using authentic urea standards (santa cruz, dallas, usa) dissolved in water were prepared. linear regression was used for calculations. collected data were described according to the covid- status of the ards (i.e., non-covid- or covid- ) and for the control group. continuous variables were expressed as median and inter-quartile ranges (iqr) and categorical variables as number and percentages. the univariate analysis consisted of comparisons between variables, according to the covid- status, performed using the chi-square test (fisher's exact test if conditions were not met) for percentages and wilcoxon mann-whitney test for medians and iqrs. subsequently, the association between covid- s non-covid- ards and the number of ventilator-free days was assessed using two multivariate median regression models including some other clinically relevant explicative variables: (i) age, septic shock (yes/no) and pao /fio (model ) and (ii) age and baseline sofa score (model ). then, cytokines were presented by boxplots to visualize potential associations between cytokines and covid- status (those for which differences were observed according to the covid- status or according to physiopathological considerations). finally, multivariate median regression models were built to test the association with the most pertinent clinical outcome associated with covid- status in univariate analysis comparison, including the five most relevant covariates (i.e., covid- status and the cytokines that differed the most between covid- and non-covid- ards patient, either clinically or with a p value below . ) and treatments that differ between both groups. in order to avoid overfitting, the choice of variables was not only made on the p value but also considering statistical (i.e., collinearity) and physio-pathological considerations. model variability explicative power was quantified using the r coefficient. then, mitochondrial dna levels were compared between controls, non-covid- , and covid- ards patients using a kruskal-wallis analysis of variance test. to account for multiple comparisons, the p value was adjusted for a false discovery rate (fdr) using the benjamini and hochberg method. correlations were sought using the spearman test between the concentration of cytokines, mitochondrial dna, and outcome, and also elf concentrations of sars-cov- , and depicted with a heatmap representation and scatter plot. all tests were two-tailed. a p value lower than . was considered statistically significant. all analyses were performed using the stata ( . , stata corporation, college station, tx, usa) or prism software (graphpad prism®, version . , san diego, ca, usa). twenty-eight patients were enrolled in this study ( in the control group, in the non-covid- ards group between june and january , and in the covid- ards group between march and april ). the control patients were outpatients suffered from sarcoidosis (n = ), pulmonary langerhans histiocytosis (n = ), pulmonary carcinoma (n = ), scleromyositis (n = ), focal bronchiectasis (n = ), or unknown cause (n = ), and none had any evidence of current infection or acute disease. bacterial pneumonia was proven in five patients from the non-covid- ards group (pseudomonas aeruginosa (n = ), legionella pneumophila (n = ), mycoplasma pneumonia (n = )), while co-infection occurred in only one covid- ards patient (staphylococcus aureus). while demographic and comorbidity data were not statistically different, baseline severity according to the sofa score in particular was found to be lower in covid- ards patients (p = . ), with a trend toward less frequent septic shock (p = . ) and a marginally lower baseline arterial lactate levels (p = . ) at the onset of ards (table ) . according to the berlin criteria, ards severity was marginally significantly different between non-covid- and covid- patients, with a median baseline pao : fio of as low as . (iqr = . - . ) and . (iqr = . - . ) mmhg, respectively (p = . ). moreover, we found no difference in terms of ventilator settings or lung mechanics. procalcitonin tended to be only slightly higher in covid- ards patients than in the other ards patients ( . [ . - . ] vs. . [ . - . ] μg/l, respectively; p = . ) ( table ) . the -day mortality rate reached % in the non-covid- group and % in the covid- group (table ) . however, the number of ventilator-free days was significantly lower in covid- patients, compared to non-covid- patients ( [ - ] vs. [ ] [ ] [ ] [ ] [ ] ; p = . ), along with a higher rate of ventilator-acquired pneumonia ( ( %) vs. ( %); p = . ). covid- etiology remained associated with a fewer ventilator-free days within the days following admission, even after adjustment on age and baseline severity (i.e., septic shock and pao :fio (model ; p = . ) or baseline sofa score (model ; p = . )) (supplementary tables and ). plasma cytokine levels are shown in fig. and additional table . covid- ards patients had significantly higher plasma concentrations of ccl (p = . ) and non-significantly higher plasma concentrations of cxcl (p = . ), cxcl (p = . ), cd ligand (p = . ), il- (p = . ), and gm-csf (p = . ) compared with non-covid- ards patients. at the same time, we observed lower concentrations of plasma il- (p = . ), trail (p = . ), and g-csf (p = . ). plasma cxcl concentration was independently associated with a greater number of ventilator-free days, after adjustment for the covid- etiology, submission to non-invasive ventilation (niv) prior to intubation, exposure to multiple antibiotics, cxcl , ccl , and cd ligand plasma concentrations (p = . ) ( table ) . interestingly, cxcl levels were highly correlated with those of gm-csf (r = . ; p < . ) and il- (r = . ; p < . ). epithelial lining fluid cytokine levels are shown in fig. and additional table . a trend toward higher elf concentrations of cxcl (p = . ), cxcl (p = . ), granzyme b (p = . ), trail (p = . ), and egf table ) . we also addressed the magnitude and impact of mitochondrial dna released into both the systemic and alveolar compartments during non-covid- and covid- ards. plasma and elf concentrations of mitochondrial dna were significantly higher in ards patients, regardless of covid- involvement (fig. a-d) . figure ) . the same results were observed when only covid- ards patients were considered (additional figure ) . however, neither plasma nor elf mitochondrial dna concentrations were correlated with the number of ventilator-free days. finally, sars-cov- concentrations were measured, and correlations with cytokine levels were sought in the alveolar compartment. first, the sars-cov- genome was detected in covid- ards patients with a median of , (iqr = - , , ) copies per microliter of elf. there was a strong negative correlation with elf il- (r = − . ; p = . ) and ccl (r = − . ; p = . ), while no correlation was observed with elf cxcl (r = − . , p = . ) (fig. a, b ). our findings suggest that covid- ards is associated with prolonged mechanical ventilation in comparison with non-covid- ards patients, regardless of the baseline characteristics. this comprehensive evaluation of systemic and pulmonary immune response showed that the higher cxcl concentrations in both the systemic and alveolar compartments of patients with covid- ards were associated with a longer duration of mechanical ventilation. interestingly, alveolar concentrations of sars-cov- were not correlated with alveolar cxcl concentration. finally, in both covid- and non-covid- patients, higher mitochondrial dna concentrations in the plasma and elf compartment were highly correlated with alveolar inflammation, as assessed by balf cell count and elf il- and il- β concentrations. this result highlights the key role of mitochondrial alarmins in ards and vili. ards is the leading cause of death during covid- . given the increasing number of cases, and especially the protracted duration of ards, attention was rapidly focused on the number of required icu beds, ventilators, and intensivists [ ] . however, covid- -associated ards, despite meeting the berlin definition, is now considered "atypical" with peculiar features such as the discrepancy between the relatively well-preserved lung mechanics and the depth of hypoxemia [ ] . our findings support these observations since we show that patients with covid- ards received prolonged mechanical ventilation when compared to non-covid- ards patients, regardless of baseline severity. in the most severe forms of sars-cov- , common features including systemic cytokine storm (including macrophage activation syndrome), organizing diffuse alveolar damage (acute fibrinous and organizing pneumonia (afop)) with excessive immune cells infiltration into the lung (in particular t cell infiltration), and thrombosis have been reported, but these features have also been observed in patients with sars-cov- infection and middle east respiratory syndrome (mers) [ , [ ] [ ] [ ] . we assume that this atypical dysregulated immune response may cause the lung immunopathology that leads to the protracted and inflammatory nature of covid- ards. since there is no available effective direct anti-viral treatment so far, mitigating the "cytokine storm" through immune modulation is a promising therapeutic avenue. however, it is worth noting that most of the currently tested immunomodulatory agents (especially anti-il- , anti-il- β, and anti-tnfα) have been put forward despite gaps in our understanding of the immune response behind covid- ards, especially within the pulmonary compartment. however, assessing the alveolar compartment is challenging in severe ards patients. to the best of our knowledge, there is currently no published study comparing cytokine concentrations in bronchoalveolar lavage fluid obtained from either covid- or non-covid- ards patients, and basically, data regarding inflammation within the alveolar space of the former patients are sparse [ ] . we report herein new insights into this issue. we show that plasma cxcl , cxcl , ccl , cd ligand, il- , and gm-csf concentrations and elf cxcl , cxcl , granzyme b, trail, and egf concentrations were found in greater concentrations in covid- than in non-covid- ards patients. interestingly, almost all of these mediators are chemokines or cytokines involved in either recruitment or activation of t lymphocytes (ccl , cxcl ) and/or monocytes/macrophages (gm-csf). others are associated with anti-inflammation (il- and trail) or endothelial dysfunction (cd ligand, egf). among them, we found that cxcl was the most likely to account for the protracted nature of covid- ards in both the systemic and the alveolar compartments. cxcl (or inf-γ-induced protein (ip- )) is secreted upon inf-γ stimulation by various cell types (endothelial cells, fibroblasts, monocytes/macrophages, and t lymphocytes) and promotes chemoattraction for activated t lymphocytes, natural killer cells, and monocytes through cxcr [ ] . interestingly, plasma concentrations of cxcl have been previously reported at high levels in sars-cov- [ ] , respiratory syncytial [ ] , and influenza infections [ ] , and significantly associated with a higher risk of death in ards associated with a/h n influenza infection [ ] . yang et al. recently reported that among inflammatory mediators measured in covid- patients, the plasma concentration of cxcl was highly associated with disease severity, especially the murray score, and could independently (see figure on previous page.) fig. boxplot graph depicting plasma concentration of cytokines. plasma cytokines were measured in covid- ards (n = ), non-covid- ards (n = ), and control patients (n = ). covid- ards patients had significantly higher plasma concentrations of ccl and non-significantly higher plasma concentrations of cxcl (p = . ), cxcl (p = . ), cd ligand (p = . ), il- (p = . ), and gm-csf (p = . ) compared with non-covid- ards patients. we observed lower concentrations of plasma il- (p = . ), trail (p = . ), and g-csf (p = . ). the mann-whitney u test was used for comparison between non-covid- and covid- ards patients (pneumochondrie study, - ) predict covid- disease progression [ ] . interestingly, ichikawa et al. showed that the cxcl -cxcr signaling pathway was critical in viral and non-viral ards pathogenesis. moreover, they showed that lung injury could be prevented, and therefore, survival improved, when the cxcl -cxcr axis was blocked [ ] . since our results emphasize the involvement of the cxcl -cxcr signaling axis in the pathogenesis of the most severe forms of covid- infection, this axis represents a potential therapeutic target. corticosteroids that showed beneficial effects in the most severe forms of covid- [ ] may act upstream from cxcl through inhibition of the th pathway. however, specifically blocking cxcl (e.g., eldelumab/mdx- ) or cxcr may be a promising therapeutic approach. interestingly, lev et al. reported that upon the administration of corticosteroid, a significant decrease of cxcl levels was observed in covid- patients [ ] . in addition, if validated in larger cohorts, plasma cxcl measurement could be helpful in predicting the risk of prolonged mv. since plasma cxcl- and gm-csf were strongly correlated (r = . , p < . ), the latter was also highly associated with a longer duration of mechanical ventilation. the most severe forms of covid- were associated with macrophage activation syndrome, characterized by a fulminant hypercytokinemia with multiorgan failure [ ] . gm-csf has recently emerged as a potential therapeutic target, since it plays a pivotal role in initiation (monocyte activation and macrophage transformation) and perpetuation of the immune response and could represent the link between t cell-driven acute pulmonary inflammation and self-amplifying cytokine loop leading to monocyte/macrophage activation [ , ] . interestingly, an anti-gm-csf therapy (lenzilumab) has been previously evaluated in severe covid- and associated with improved clinical outcomes, oxygen requirement, and cytokine release [ ] . still, a cautious approach is required since any immune modulation is likely to alter the body's antimicrobial defenses. this point is particularly relevant, since deep dysfunctions of the myeloid and lymphoid responses have also been described in covid- patients, with a decrease of hla-dr expression on monocytes [ ] and t cell exhaustion [ ] . interestingly, no correlation was found between the alveolar viral load of sars-cov- and elf cxcl , suggesting that activation of the cxcl -cxcr axis may play a role in the dysregulated immune response independently from viral clearance. thus, its blockage might not compromise the host's ability to bring the virus under control. in contrast, we observed a strong negative correlation between elf concentrations of sars-cov- and il- , suggesting that il- production within the alveolar compartment is associated with effective viral clearance. in addition, dampening inflammation in a context of high immune suppression level is not always a hazardous route. in the setting of chimeric antigen receptor t (car-t) cell therapy, gm-csf inhibition reduces cytokine release syndrome and neuro-inflammation but enhances antitumoral cart-t cell function [ ] . moreover, the il- blocker partially rescues immune dysregulation caused by sars-cov- [ ] . nevertheless, as advocated for sepsis [ ] , immune profiling (including cxcl measurement) may serve for the selection of patients that could be eligible for immunotherapy. finally, it is worth noting that higher viral alveolar loads were associated with more severe ards in terms of blood oxygenation and remote organ failure [ ] , highlighting the need for drugs likely to prevent covid- replication in addition to therapies targeting host response. in addition to our findings regarding the cxcl -cxcr axis, we observed that the released amount of mediators involved in chemotaxis and/or activation of pmns (i.e., il- , il- β, il- , and tnf-α) was similar when ards was caused by sars-cov- . moreover, alveolar cell counts and elf concentrations of il- and il- β were highly correlated with the release of mitochondrial dna, whose levels were significantly increased in both the systemic and pulmonary compartments of ards patients, regardless of etiology. it is worth noting that cell-free mitochondrial dna release can elicit neutrophil-mediated lung injury through the promotion of il- and il- β secretion by activation of the tlr- (toll-like receptor ) and the nlrp- (nod-like receptor pyrin domain ) inflammasome pathways, respectively [ , ] . this finding suggests that systemic and pulmonary immune response could be triggered in part by the release of endogenous mediators originating from injured alveolar cells. this reaction may be subsequent to a twohit lung injury (i.e., infection of alveolar epithelial cells and ventilator-induced lung injury), as suggested by previous clinical and experimental findings from our group [ , ] . surprisingly, we observed a trend toward lower elf concentrations of il- in covid- patients compared with non-covid- ards patients (p = . ), thus challenging the interest of anti-il- therapies in severe covid- pneumonia. these results are in line with retrospective observations by sinha et al., showing that plasma il- concentrations were lower in the severe form of covid- as compared to those reported in ards from another origin and arguing that the term "cytokine storm" may be misleading in covid- ards [ ] . finally, it is worth noting that early bacterial coinfection was unlikely in covid- ards patients from our cohort, in accordance with previously published data [ , ] . one could argue that previous exposure to antibiotics has led to false-negative results. more interestingly, it ascertains the safety of introducing new therapies (i.e., including those targeting cxcl- ) likely to dampen the host inflammatory response at this stage of the viral disease. this statement has to be mitigated by the fact that vap complicated ards in % of the covid- patients, as compared to % in patients with ards from another origin. although the longer duration of mv could account at least in part for such an obvious difference, one cannot exclude that vap occurrence reflected exhaustion of the lung immune defense following the strong activation of the cxcl -cxcr axis. moreover, the impact of blocking this critical pathway remains uncertain regarding the risk of subsequent bacterial infection. our study has some limitations. first, the origin of non-covid- ards was mainly gram-negative bacteria, which is not representative of all ards of pulmonary origin. as a result of the difficulty in obtaining balf, the small sample size prevented us from performing a mortality analysis and resulted in a lack of power for some comparisons. as a result, our findings should be taken cautiously, and new studies are required in order to ascertain our hypothesis. however, pulmonary compartment assessment remains challenging, and there is currently no published data comparing balf in covid- and non-covid- ards patients. moreover, the criteria of inclusion of our control group remain questionable, and non-infected icu patients under mv would have been preferred but not possible given ethical concerns related to the fiberoptic procedure, which could not be considered as part of standard care. one can also argue that in the context of such an emerging disease, some treatments likely to influence the release of cytokines could have been given to the covid- patients prior to the study inclusion. however, such treatments (i.e., hydrocortisone and hydroxychloroquine) were administrated prior to blood and balf collection in a small number of patients. moreover, the time elapsed between treatment administration and sampling was quite short, making unlikely any impact on cytokine concentrations (additional table ). finally, the specific impact of mechanical ventilation on pulmonary immune response cannot be evaluated since patients with less severe disease who did not require mv were not included. this study provides new insights into the peculiar pathogenesis of covid- ards. first, cxcl may represent the dysregulated immune response that drives the duration of mv in covid- ards patients. cxcl appears to be a potential biomarker for the duration of mv, and the cxcl -cxcr signaling axis may be a potential therapeutic target in covid- ards. this target seems all the more interesting since no correlation was found between alveolar concentrations of cxcl and sars-cov- clearance. apart from those particular features, covid- and non-covid- ards share the wellknown involvement of both il- and il- β within the airway, potentially driven by the release of endogenous mediators originating from injured alveolar cells (e.g., mitochondrial alarmins). supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file : table . model : factors associated with the number of ventilator-free days in the patients with ards (multivariate median logistic regression; pseudo r = . ; n= , pneumochondrie study, - ). table . model : factors associated with the number of ventilator-free days in the patients with ards (multivariate median logistic regression; pseudo r = . ; n= , pneumochondrie study, - ). table . plasma concentrations of cytokines. table . epithelial lining fluid concentrations of cytokines. figure . heatmap of the spearman correlation (r) between epithelial lining fluid (elf) concentrations of mitochondrial dna (nadh i and cytochrome c), elf concentration of cytokines, and outcomes for the ards patients. spearman correlations: p< . *; p< . ** between each cytokine and the elf concentration of nadh i mitochondrial dna. figure . heatmap of the spearman correlation (r) between the epithelial lining fluid (elf) concentrations of mitochondrial dna (nadh i and cytochrome c), the elf concentration of spearman correlations: p< . *; p< . ** between each cytokine and the elf concentration of nadh i mitochondrial dna abbreviations ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage balf: bronchoalveolar lavage fluid; ccl: c-c motif chemokine ligand; covid- : coronavirus disease ; cxcl: c-x-c motif chemokine ligand cxcr : cxc chemokine receptor ; dna: deoxyribonucleic acid ecmo: extracorporeal membrane oxygenation; elf: epithelial lining fluid egf: epidermal growth factor; fgf: fibroblast growth factor; flt l: fms-like tyrosine kinase ligand; g-csf: granulocyte colony-stimulating factor; gm-csf: granulocyte-macrophage colony-stimulating factor; icu: intensive care medicine iqr: interquartile range; mv: mechanical ventilation; nadh i: nicotinamide adenine dinucleotide i; nlrp : nod-like receptor pyrin domain fio : arterial pressure of oxygen/oxygen inspiratory fraction; pd-l : programmed death-ligand ; pdgf: platelet-derived growth factor rdrp: rna-dependent rna polymerase; rt-pcr: reverse transcriptase polymerase chain reaction; saps ii: simplified acute physiology score ii sars-cov- : severe acute respiratory syndrome coronavirus sofa: sequential organ failure assessment; tgf: transforming growth factor tnf: tumor necrosis factor; trail: tnf-related apoptosis-inducing ligand; vap: ventilator-acquired pneumonia high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study management of covid- respiratory distress epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study sars-cov- entry factors are highly expressed in nasal epithelial cells together with innate immune genes clinical characteristics of refractory covid- pneumonia in wuhan, china. clin infect dis covid- : immunology and treatment options clinical features of patients infected with novel coronavirus in wuhan plasma ip- and mcp- levels are highly associated with disease severity and predict the progression of covid- mitochondrial alarmins are tissue mediators of ventilator-induced lung injury and ards mechanical ventilation and streptococcus pneumoniae pneumonia alter mitochondrial homeostasis acute respiratory distress syndrome: the berlin definition the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine a new simplified acute physiology score (saps ii) based on a european/north american multicenter study circulating mitochondrial damps cause inflammatory responses to injury detection of novel coronavirus ( -ncov) by real-time rt-pcr estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution candidate reference measurement procedure for determination of urea in serum by liquid chromatography-tandem mass spectrometry covid- in critically ill patients in the seattle region -case series covid- does not lead to a "typical" acute respiratory distress syndrome postmortem examination of patients with covid- pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology complex immune dysregulation in covid- patients with severe respiratory failure association of covid- inflammation with activation of the c a-c ar axis characterization of cytokine/chemokine profiles of severe acute respiratory syndrome plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome respiratory syncytial virus-induced chemokine production: linking viral replication to chemokine production in vitro and in vivo the serum profile of hypercytokinemia factors identified in h n -infected patients can predict fatal outcomes angiogenic and inflammatory markers in acute respiratory distress syndrome and renal injury associated to a/h n virus infection cxcl -cxcr enhances the development of neutrophil-mediated fulminant lung injury of viral and nonviral origin dexamethasone in hospitalized patients with covid- -preliminary report real-time ip- measurements as a new tool for inflammation regulation within a clinical decision support protocol for managing severe covid- patients. medrxiv gm-csf-based treatments in covid- : reconciling opposing therapeutic approaches therapeutic blockade of granulocyte macrophage colony-stimulating factor in covid- -associated hyperinflammation: challenges and opportunities first clinical use of lenzilumab to neutralize gm-csf in patients with severe covid- pneumonia. medrxiv severe immunosuppression and not a cytokine storm characterize covid- infections gm-csf inhibition reduces cytokine release syndrome and neuroinflammation but enhances car-t cell function in xenografts the immunopathology of sepsis and potential therapeutic targets pneumochondrie study group. alveolar sars-cov- viral load is tightly correlated with severity in covid- ards oxidized mitochondrial dna activates the nlrp inflammasome during apoptosis is a "cytokine storm" relevant to covid- ? bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid- antimicrobial prescribing bacterial and fungal coinfection among hospitalized patients with covid- : a retrospective cohort study in a uk secondary-care setting publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors acknowledge all the members of the pneumochondrie study group (françois aptel, auguste dargent, marjolaine georges, marie labruyère, laurent lagrost, audrey large, serge monier, jean-baptiste roudaut, charles thomas). we thank hélène choubley from the lipidomic analytical platform of the university of burgundy and serge monier and anabelle sequeira from the cytometry core facility which are supported by the following institutions: conseil régional de bourgogne franche-comté and feder. we thank alexandra lamotte-felin, lydie rossie, and aurélie degot from the cic-ec (cic-ec ) and solenne villot and mathilde audry from the intensive care medicine research team. we thank suzanne rankin for the editing assistance, maud carpentier from the drci (direction de la recherche clinique et de l'innovation), shaliha bechoua (centre de ressources biologiques), and cécile pitoiset and magali darnio for the technical assistance (virology). we thank the patients. all data are available on demand.ethics approval and consent to participate approval was obtained from the ethics committee (comité de protection des personnes sud-est iii; - b), and an amendment was obtained to include supplementary patients with covid- . oral consent was obtained from the patient or their legal representatives. all authors consented for the publication. we declare no competing interests. received: august accepted: october key: cord- -rxudwp v authors: barbas, carmen sílvia valente; matos, gustavo faissol janot; amato, marcelo britto passos; carvalho, carlos roberto ribeiro title: goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome date: - - journal: crit care res pract doi: . / / sha: doc_id: cord_uid: rxudwp v this paper, based on relevant literature articles and the authors' clinical experience, presents a goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome (ards) that can help improve clinicians' ability to care for these patients. early recognition of ards modified risk factors and avoidance of aggravating factors during hospital stay such as nonprotective mechanical ventilation, multiple blood products transfusions, positive fluid balance, ventilator-associated pneumonia, and gastric aspiration can help decrease its incidence. an early extensive clinical, laboratory, and imaging evaluation of “at risk patients” allows a correct diagnosis of ards, assessment of comorbidities, and calculation of prognostic indices, so that a careful treatment can be planned. rapid administration of antibiotics and resuscitative measures in case of sepsis and septic shock associated with protective ventilatory strategies and early short-term paralysis associated with differential ventilatory techniques (recruitment maneuvers with adequate positive end-expiratory pressure titration, prone position, and new extracorporeal membrane oxygenation techniques) in severe ards can help improve its prognosis. revaluation of ards patients on the third day of evolution (sequential organ failure assessment (sofa), biomarkers and response to infection therapy) allows changes in the initial treatment plans and can help decrease ards mortality. acute respiratory distress syndrome (ards) is due to an increase in the pulmonary alveolar-capillary membrane permeability causing lung edema rich in protein and consequently acute hypoxemic respiratory failure in genetically susceptible patients exposed to determined risk factors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . a recent study showed that the del/del genotype (patients homozygous for the base pair deletion in the promoter of nfkb ) is associated with an age-dependent increase in odds of developing ards (or . , % ci . - . ) and patients with the del/del genotype and ards also have increased hazard of -day mortality (hr . , % ci . - . ) and more organ failure (p < . ) [ ] . all age groups may be affected, although the syndrome has a higher incidence and mortality in older people [ ] . the most common precipitating causes of ards are pulmonary infections, nonpulmonary sepsis, shock, gastric aspiration, thoracic trauma, fat embolism, near drowning, inhalational injury, cardiopulmonary bypass, drug overdose, acute pancreatitis, and high-risk trauma (especially traumatic brain injury) [ ] . recent epidemiological studies suggested a variety of intrahospital risk factors for ards development such as multiple blood products transfusions, mechanical ventilation with high tidal volumes, excessive fluid resuscitation, and hospitalacquired pneumonia as well as high-risk surgeries (especially aortic vascular, cardiac, and acute abdomen); all risk factors are potentially preventable. chronic alcohol abuse, chronic liver disease, immunosuppression, hypoalbuminemia, and obesity are also all associated with the development of ards, whereas diabetes mellitus appears to be protective [ ] . after exposure to a risk factor, there is an important activation of neutrophils and release of harmful mediators including cytokines (such as interleukins , , and and soluble tumor necrosis factor-alpha receptors), proteases, reactive oxygen species, and matrix metalloproteinases leading to future damage. an overwhelming pulmonary inflammatory process is initiated leading to alveolar epithelial and vascular endothelial injury. alveolar epithelial injury of type i cells contributes to the pulmonary edema and the breakdown of this epithelial barrier exposes the underlying basement membrane, predisposing to bacteremia and sepsis. injury to type ii alveolar cells leads to an impairment of surfactant function with consequent collapse of the lungs. histopathologically there is diffuse alveolar damage with neutrophil infiltration, alveolar hemorrhage and hyaline membrane formation [ ] [ ] [ ] [ ] [ ] . there are localized destruction and occlusion of the vascular bed of the lungs by intravascular thrombosis and an increment of the anatomical dead space resulting in an increase of arterial carbon dioxide associated with a poor outcome. fibrosis can be evident histologically as early as one week after the onset of ards and procollagen iii peptide, a precursor of collagen synthesis, can be elevated in bronchoalveolar lavage fluid of ards patients at the time of tracheal intubation, its increment being associated with a poor ards prognosis. vascular injury and remodeling may lead to pulmonary arterial hypertension which may compromise right ventricular function associated with a poor clinical outcome [ ] . incorporation of modified risk factors such as acute increase of respiratory rate, presence of tachypnea, detection of pulse oximeter desaturation, increased necessity of oxygen supplementation, presence of low ph, acidosis, or hypoxemia in an arterial blood gas sample in clinical practice can improve the clinicians' ability to perform early diagnosis and prompt therapeutic intervention in ards [ ] . the presence of these modified risk factors may alert physicians to avoid secondary hospital exposures, such as blood products transfusions, excessive fluid administration, infusion of potentially toxic drugs, high tidal volume mechanical ventilation, and gastric aspiration. implementation of ventilator associated pneumonia prevention bundles decreases the incidence of vap and can lower the incidence of ards [ ] . implementation of automated ards electronic screening in usa hospitals such as "assist" (electronic alert from laboratory when the arterial blood gas analysis shows hypoxemia and the radiology department when chest x-ray shows bilateral pulmonary infiltrates) to identify intubated patients with ards in medical and surgical icus showed a sensitivity of . % ( % ci, . - . %) and specificity of . % ( % ci, . - . %) when compared to a manual screening algorithm that had a sensitivity of . % ( % ci, . - . %) and specificity of . % ( % ci, . - %) in icu patients over a -week period during enrollment in ardsnet trials [ ] . the results of this study indicated the advantages of having an in-hospital automated screening of ards over manual screening. the automated screening can increase the chances of ards diagnosis, alert the clinicians, and elicit the rapid response from the hospital team of intensivists to initiate clinical protocols and ards therapeutic interventions [ ] . most hospitals and intensive care units worldwide use the standard criteria for the diagnosis of acute lung injury (ali)/ards: presence of acute hypoxemia (pao /fio less than mmhg or . kpa for ali or less than mmhg or . kpa for ards), bilateral infiltrates seen on a frontal chest radiograph that are consistent with pulmonary edema, and no clinical evidence of left atrial hypertension, or (if it is measured) a pulmonary artery wedge pressure (pawp) of less than mmhg according to the - american-european consensus conference on ards (aecc) [ , ] . this definition aimed to simplify and standardize the diagnosis of ards worldwide. however, in clinical practice, in order to detect and diagnose ali/ards cases, physicians must focus on patients' complaints, physical examination alterations, patients at risk of developing the disease, or patients presenting finger pulse oximeter desaturation. following the ali/ards clinical suspicion, physicians should order an arterial blood gas analysis and a chest radiograph to be able to confirm the ali/ards diagnosis. recent updates of ards definition such as the delphi consensus [ ] or the berlin definition [ ] were published in order to improve ards diagnosis criteria. the berlin definition reclassified ards as mild (pao /fio < or . kpa), moderate (pao /fio < or . kpa), and severe (pao /fio < mmhg or . kpa) and removed the term ali and the necessity of a swan ganz catheter to access pawp. acute time frame was specified as the onset within week of a known clinical insult or new or worsening respiratory symptoms chest radiography criteria were clarified and bilateral opacities consistent with pulmonary edema were maintained as the main radiological criteria of ards, but it was recognized that these findings could be demonstrated on ct scan instead of chest radiograph. the recent berlin definition of ards is a decisive step forward in refining the diagnosis of the syndrome, but pao /fio is influenced by ventilator settings and this fact should be considered; bilateral pulmonary infiltrates can be the result of a wide variety of acute lung diseases that should be better investigated. left and right ventricular function, pulmonary artery pressures, and volemic status could be better evaluated by bedside echocardiography and extravascular lung water can be measured using picco catheter, in order to evaluate the degree of pulmonary edema. predictors of mortality should be calculated at icu admission. with the information, the icu team can program a more careful treatment plan according to disease severity. the berlin definition shows better predictive validity for mortality compared to the aecc definition, but the absolute value of the area under the receiver operating curve is still too small ( . ), suggesting that some factors are still missing. further discussion and research are needed before we reach a comprehensive definition of ards. critical care research and practice the typical findings of ards in a computer tomography reveal a heterogeneous bilateral pulmonary infiltrate predominantly in gravity-dependent regions of the lungs and more preserved lungs in nondependent lung regions. using quantitative analysis of the ct scan, the gravity-dependent pulmonary ards infiltrate is typically nonaerated lung tissue consistent with compressive atelectasis [ , ] . lung weight assessed by ct scan is increased in ards and is correlated with the severity of the syndrome [ ] . the finding of concomitant interstitial infiltrates suggests viral or mycoplasma, chlamydia or opportunistic pulmonary infections, or drug-induced lung disease. the differential diagnosis of bilateral pneumonia, alveolar hemorrhage, and acute interstitial lung disease such as acute interstitial pneumonia, hypersensitivity pneumonitis, acute eosinophilic pneumonia, and bronchiolitis obliterans with organizing pneumonia can be suggested by the characteristic ct scan findings of each specific disease [ ] . the results of stepwise lung recruitment maneuvers as well as positive end-expiratory (peep) titration to keep the lungs open with minimal collapse can be assessed by computer tomography analysis [ ] . this strategy is aimed at opening up the lungs and keeping the lungs open [ ] as quickly and early as possible as postulated by lachmann [ ] in order to have a huge improvement in lung function and avoid potential ventilator-induced lung injury. recently, our group reported the experience with maximal recruitment strategy (mrs) in patients with ards. mrs consisted of -minute steps of tidal ventilation with pressure-controlled ventilation, fixed driving pressure of cmh o, respiratory rate of breaths/minute, inspiratory/expiratory ratio of : , and stepwise increments in peep levels from to cmh o (recruitment phase). after that, peep was decreased to cmh o and, then, from to cmh o (peep titration phase) in steps of cmh o, each one lasting minutes. at each of the steps computer tomography image sequences from the carina to the diaphragm were acquired during an expiratory pause of - seconds. lung collapse was assessed online by visual inspection, for immediate clinical decision, and offline for quantitative measurements. mrs showed a statistically significant decrease in nonaerated areas of the ards lungs that was accompanied by a significant increment in oxygenation. the opening plateau pressure observed during the recruitment protocol was . (± . cmh o), and the mean peep titrated after mrs was . (± . cmh o). mean pao /fio ratio increased from (± ) to (± ; p < . ) after mrs and was sustained above throughout seven days. nonaerated parenchyma decreased significantly from . % (interquartile range (iqr): . to . ) to . % (iqr: . to . ) (p < . ) after mrs. the potentially recruitable lung was estimated at % (iqr: to ), (figure ). icu mortality was % and hospital mortality was %. the independent risk factors associated with mortality were older age and higher driving pressures (or higher delta pressure control). there were no significant clinical complications with mrs or barotrauma [ ] . a better evolution of these ards patients with less necessity of oxygen supplementation in the recovery phase of the disease and a better quality of life must be tested in prospective, controlled clinical trials. a recent metaanalysis showing beneficial effects on mortality using higher peep levels compared with lower peep in ards patients corroborates the results of our clinical case series of ards patients submitted to mrs [ ] . ards is a biphasic disease that progresses from an acute exudative phase, characterized by epithelial and endothelial injury, neutrophilic aggregation, formation of hyaline membranes, alveolar edema, and hemorrhage, to an organizing phase, characterized by regeneration and healing via resolution or repair with persistent intra-alveolar and interstitial fibrosis [ ] . it is crucial to make the diagnosis of ards in the acute phase (preferably less than hours) in order to make it possible to open up the lungs with recruitment maneuvers and keep the lungs open with sufficient peep levels to enable a more homogenous ventilation, minimizing the possible ventilator-induced lung injury (vili) triggers and allowing the recovery of the lungs [ ] [ ] [ ] . a recent study analyzing patients with ards graded into six findings according to the extent of fibroproliferation at the ct scan showed that higher ct scores were associated with statistically significant decreases in organ-failure free days as well as ventilator free days and were an independent risk factor for mortality (or = . , % ci . - . , p < . ) [ ] . positron emission tomography with ( f) fluorodeoxyglucose (fdg-pet) detects inflammatory cells and can assess lung inflammation in ards lungs helping in the understanding of ards physiopathology [ ] [ ] [ ] . lung ultrasonography is a new helpful tool that can be performed at bedside without radiation exposure. thoracic ultrasound is widely used for diagnostic and therapeutic intervention in patients with pleural effusion and pneumothoraces. the assessment of lung recruitment and peep titration in ards patients at bedside using lung ultrasonography is a new promising technique [ ] . currently, the two main limitations of this technique are its inability to detect lung overdistension and its operator-dependent characteristic. thoracic electrical impedance tomography (eit) is a highly promising imaging technique to apply at the bedside for peep titration in ards patients. new automated tools permit the calculation of the percentage of collapsed as well as overdistended lung tissue at decremental peep levels after lung recruitment maneuvers ( figure ). the regional distribution of collapse and overdistension may provide insights about the lung pathology. this technique permits daily peep adjustments at the bedside and verification of tidal volume distribution, avoiding excessive end-expiratory collapse or tidal overdistention [ ] [ ] [ ] [ ] . one of the main sofa score during first days after mrs * p < . advantages of this technique is the possibility of around the clock monitoring. further studies are needed to evaluate the clinical impact of these bedside techniques in ards patients' prognosis. randomized trials suggested that patients with acute hypoxemic respiratory failure are less likely to require endotracheal intubation when noninvasive ventilation (niv) is added to standard therapy [ ] . however, most of these studies analyzed mixed causes of acute hypoxemic respiratory failure and reported the highest intubation rates for patients with ards ( to %) and that the presence of ards was one factor independently associated with niv failure and higher mortalities rates ( to %). recently, zhan and colleagues [ ] analyzed patients with ards randomly allocated to receive either noninvasive ventilation or high-concentration oxygen therapy through a venturi mask. noninvasive positive pressure ventilation decreased the respiratory rate and improved pao /fio with time. the proportion of patients requiring intubation and invasive mechanical ventilation was significantly lower in the noninvasive ventilation group (one of versus of ; p = . ). therefore, noninvasive ventilation can be used as a first ventilatory support technique in selected patients with mild/moderate ards and a hemodynamic stable condition to avoid endotracheal intubation. a larger randomized trial, however, is required, with the need for intubation and mortality as the outcome of interest. a close-monitored initial trial of noninvasive ventilation should be considered in most mild/moderate ards patients, mainly the immunosuppressed ones with pulmonary infection in order to avoid intubation and invasive mechanical ventilation. however, early detection of collapse was more prominent in the right lung. after analyzing the sequence of eit images, the peep selected for this patient was cmh o, believed to represent the best compromise between collapse and overdistension. according to the ardsnet peep/fio table, this patient had been ventilated with a peep = cmh o in the previous hours. the patient was weaned from ventilator days later. niv failure must be recognized, and a prompt intubation and mechanical ventilation must be provided in order to avoid complications. protective ards mechanical ventilation strategies with tidal volumes equal to or less than ml/kg of predicted body weight have been traditionally associated with reduced mortality (when compared with ml/kg of predicted body weight) [ , ] . a recent meta-analysis, however, scrutinized the specific role of various ventilatory strategies used in randomized trials on lung protection (like plateau-pressure limitation and higher peep use) and showed that tidal volume per se is not exactly the most important parameter to prioritize. [ ] demonstrated decreased lung inflammation with this protective ventilatory strategy. although these results are encouraging, the physiologic background supporting the use of p-v curves to titrate peep lacks consistency nowadays. in many different situations, investigators have reported a large dissociation between closing pressures of the lung and the calculated value for the inflection point obtained from the inspiratory p-v curve. in general, patients with high values of inflection point tend to have a more severe disease, and this may explain the relative success of this strategy. nevertheless, we will probably use better tools to titrate peep in the next few years. a more consistent use of the p-v curve has been demonstrated for the analysis of lung recruitability [ , ] . airway pressure release ventilation is a modified form of continuous positive airway ventilation (cpap) described by stock and dows in that uses fairly high prolonged cpap levels with short and intermittent releases of the airway pressure to low cpap levels allowing ventilation and co clearance. this mode of ventilatory support enhances oxygenation by augmenting alveolar recruitment and requires less sedation when used in ards patients compared to conventional mechanical ventilation [ , ] . bipap ventilation combined with lung recruitment maneuvers can also be used in ards patients. wang and colleagues compared this modality of ventilatory support with assist/controlled volume ventilation in a prospective, randomized trial of ards patients showing a better pao /fio ratio, pulmonary compliance, and a shorter duration of mechanical ventilation [ ] . pressure support ventilation (psv) along with sufficient peep levels should be used as early as possible in ards patients to avoid respiratory muscle dystrophy and to decrease mechanical ventilation duration [ ] . the reason for the improvement in oxygenation obtained with psv in ards has been challenged in the recent years [ , ] . the apparent improvement in recruitment seems to have been overstated and there is evidence that it is related to an increased perfusion of better ventilated lung areas, but not to decreased lung collapse. growing concerns related to excessive tidal recruitment or excessive dyssynchrony during this mode of ventilation will have to be better addressed in the next years [ ] . the advantages of using assist modes are to keep the respiratory muscles' activity, but sometimes it is difficult to synchronize the patients to the ventilators. recently, neurally adjust ventilation (nava) was used in ards experimental models [ ] and ards patients [ ] demonstrating that the ventilation cycle and the magnitude of assist breath in nava matched the patients' breath pattern better than in psv, nava improving patient-ventilator synchrony compared to psv. high frequency oscillatory ventilation (hfov) is an alternative mode of ventilatory support that can improve oxygenation by means of a higher mean airway pressure coupled with small tidal volumes generated by a piston pump oscillating at a frequency of - hz and a higher respiratory rate. however, to date there are few studies involving a small number of patients comparing hfov to conventional ventilation. a recent meta-analysis suggested a trend towards mortality benefit and more ventilator free days. however, the results of this analysis should be interpreted cautiously as the main study contributing to its results used high tidal volume in the control group rather than protective lung ventilation strategy [ ] . the use of the position change (supine to prone) leads to consistent improvement in arterial oxygenation in ards patients. large randomized, controlled trials have consistently showed improvement in oxygenation without reduction in duration of mechanical ventilation or survival benefit. a recent meta-analyses suggest survival benefits in ards patients [ ] or, more specifically, in a subgroup of patients with severe ards (pao /fio < mmhg) [ ] . in our experience, the prone position can be an acceptable alternative to improve oxygenation in severe ards patients with arterial pulmonary hypertension and right ventricular dysfunction, which associated with the use of inhaled nitric oxide, can minimize intrathoracic pressures to facilitate right ventricular performance. the principles of a protective ventilation with proper peep titration and minimum driving pressures should also be pursued during prone positioning protocols. clinical studies suggested that elevated pulmonary artery systolic pressure in ards patients was associated with an adverse prognosis [ ] . these data have been further supported by a more recent analysis of hemodynamic data from the ardsnet fluids and catheter therapy trial (factt) [ ] . the investigators assessed the transpulmonary gradient (tpg) (mean pa pressure-pulmonary capillary occlusion pressure (pcop)) and the pulmonary vascular resistance index (pvri) in a group of patients randomized to receive a pulmonary artery catheter to guide their ards management. of note, all patients received a consistent protective ventilator strategy with target tidal volume ∼ ml/kg ideal body weight and plateau pressures maintained < cmh o. the highest recorded daily value of tpg and pvri was used for the analysis. in the population of patients randomized to receive a pulmonary artery catheter for ards management, none of the baseline measures of cardiopulmonary dysfunction, including central venous pressure, pa systolic, or diastolic pressure, pulmonary capillary occlusion pressure (paop), or cardiac index distinguished survivors from nonsurvivors. in the pulmonary artery catheter population, % demonstrated an elevated transpulmonary gradient (tpg > ). patients with a tpg > mmhg had a significantly greater mortality rate than patients with a tpg < mmhg ( % versus %; p = . ). patients with a persistently elevated tpg through day of therapy had a significantly greater mortality than patients with an elevated tpg at day - which subsequently normalized. in multivariate analysis, pulmonary vascular dysfunction as represented by an elevated tpg and pvri remained an independent predictor of an adverse outcome in the ards population. these data further support an important predictive role for pulmonary vascular disease in ards outcome [ ] . in the largest published echocardiographic series of ards, % of patients receiving a consistent lung protective ventilation strategy (mean peep of cmh o and mean plateau pressure (pplat) of cmh o) had evidence for acute cor pulmonale. in this population, % demonstrated evidence of a moderate-to-large patent foramen ovale [ ] . the incidence of right to left shunting increased to % in patients with echocardiographic evidence of acute cor pulmonale. increase of oxygenation and co removal by making the ards patients' blood pass throughout a membrane oxygenator outside the body is the principle of extracorporeal membrane oxygenation that can be applied venousvenous (good for oxygenation and co removal), arterialvenous (good for co removal), and venous-arterial (good for cardiovascular support). early clinical trials of ecmo employed primarily an arterial-venous strategy with larger bore catheters for patients with intractable hypoxemia [ ] . more modern investigations have used a safer venous-venous access approach [ , ] . a recent uk prospective, randomized, clinical trial (cesar) showed a survival advantage in the ecmo group ( % for ecmo versus % for controls). nevertheless, the study was criticized as there was no standardized protocol management for the control group and some patients in the ecmo arm did not receive the proposed treatment [ ] . the authors of cesar trial also recommended transferring adult patients with severe but potentially reversible respiratory failure and a ph less than . on optimal conventional management, to a center with an ecmo-based management protocol to significantly improve survival without severe disability. the authors demonstrated that this strategy is also likely to be cost effective in settings with similar services to those in the united kingdom [ ] . another recent approach for application of extracorporeal carbon dioxide removal new devices (ecmo-r) in ards patients is the demonstration that in severe ards even the low tidal volume ventilation with ml/kg of predicted body weight can cause tidal hyperdistension in the nondependent regions of the lungs accompanied by plateau airway pressures greater than cmh o and elevated plasma markers of inflammation. in this group application of ecmo-r could allow the authors to decrease the tidal volume to less than ml/kg with a consequent plateau pressure less than cmh o that was associated with a lower radiographic index of lung injury and lower levels of lung-derived inflammatory cytokines. however, prognostic implication of this new ecmo-r devices application in clinical practice is still under investigation [ ] . pumpless interventional lung assist (ila) is also used in patients with ards and is aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. ila serves as an extracorporeal assist to support mechanical ventilation by enabling low tidal volume and a reduced inspiratory plateau pressure in extremely severe ards patients. zimmermann and colleagues used ila in severe ards patients and observed a decrease in paco allowing the decrease in tidal volume and plateau pressure (ultraprotective ventilation) with a hospital mortality rate of % [ ] . some authors suggest the use of combined ventilatory strategies in patients with ards. bingold and colleagues [ ] successfully used superimposed high-frequency jet ventilation (shfjv) in combination with continuous positive airway pressure/assisted spontaneous breathing (cpap/asb) in five patients with h -n -associated ards to improve oxygenation. varpula and colleagues [ ] demonstrated a significant improvement in oxygenation in ards patients, when they compared apvr associated with prone ventilation to simv-pressure control/pressure support group. aprv after h appears to enhance improvement in oxygenation in response to prone positioning. rival and colleagues [ ] examined the effects of the prone position associated with a recruitment maneuver consisting of cmh o extended sigh in pressure control, in ards patients. the combination of both ventilatory techniques led to the highest increase in pao /fio ratio without significant clinical side effects. lubnow and colleagues [ ] examined the effects of days of the combination of high-frequency oscillatory ventilation (hfov) and extracorporeal carbon dioxide removal with the interventional lung assist (ila) in severe ards patients who failed conventional ventilation. they observed an increase in pao /fio ratio and ph and a decrease in paco . weaning from hfov/ila was successful in patients. the -day mortality rate was %, and hospital mortality rate was %. in conclusion, combined ventilatory strategies can be applied in severe ards patients, but the best match among all the available ventilatory techniques is still a matter of debate. pulmonary infection and sepsis are the most important triggering factors of ards. pulmonary infection has been associated with a higher risk of ards progression in comparison to nonpulmonary infection in at risk populations [ ] . a wide variety of organisms can invade the respiratory tract and trigger host innate and acquired immune system initiating the inflammatory cascade of ards, sepsis, and multiple organ failure [ ] . it is particularly pertinent to investigate the etiology of pulmonary infection on the first day assessing a nasal swab for a respiratory virus detection (influenza, adenovirus) lower respiratory tract secretion or a bronchoalveolar lavage fluid (balf) for bacteria (especially multiresistant species), other viruses as herpes and cytomegalovirus, coronavirus, or metapneumonic virus [ ] . opportunistic agents such as pneumocystis jiroveci must be investigated in immunosuppressed patients. urinary screening for legionella species is decisive, because if positive, specific therapy must be introduced [ ] . the assessment of balf on the first as well as on the third day of mechanical ventilation is of the utmost importance not only in terms of assessment of etiology of pulmonary infection but also of the assessment of proinflammatory mediators of ards (il- , il , il , il , soluble tumor necrosis factor-alpha receptors (stnfr), and soluble intercellular adhesion molecule- ) and mediators of ventilator-induced lung injury (that can also be obtained in the plasma) such as stnfr, il , il , and il- , indicators of epithelial cell injury (soluble advanced glycation end-product receptors-srage), and surfactant protein-d, components of the coagulation system (protein-c and plasminogen activator inhibitor ) [ , ] . elevated levels of procollagen peptide iii in lavage fluid from patients on day of ards were independent risk factors for mortality [ ] . procalcitonin (pct) and c-reactive protein (crp) are progressively being used in critical care setting in order to diagnose pulmonary infection and sepsis and to guide the antibiotic therapy. procalcitonin levels correlated with severe sepsis and bacteraemia [ ] . a pct-based algorithm guiding initiation and duration of antibiotic therapy in critical ill patients with suspected bacterial infections was associated with a % relative reduction in antibiotic exposure with no significant increase in mortality [ ] . the persistence of an elevated serum crp in critical ill patients with ards may alert the intensivist to a possible persistent infection or inflammatory process. at this moment, a new workup for infection and change in antibiotic therapy could help improve the patient's evolution. early and quick administration of antibiotics in sepsis and septic shock as well as early goal resuscitative measures for septic shock or early goaldirected therapy decrease mortality in this high mortality critically ill conditions [ , ] . we also suggest that preventive measures to avoid gastric aspiration (elevated decubitus, intermittent check for residual gastric content during diet infusion) and to avoid ventilation associated pneumonia (wash hands, elevated decubitus, special endotracheal tubes) should be implemented. the resolution of pulmonary edema is central to recover from ali as it entails regression of air space inflammation and restoration of a functioning alveolar-capillary membrane. accordingly, elevated extravascular lung water measured using this technique early in the course of ali/ards, particularly if indexed to predicted body weight, was associated with a poor prognosis [ ] . a study analyzing the evolution of ards patients showed that unknown-site infection (adjusted hazard ratio (hr) . , % ci . - . ) and multiple site infection (adjusted hr . , % ci . - . ) were associated with increased mortality [ ] . in ards patients it is of considerable significance to evaluate the source of infection as well all organs and systems affected by the sepsis syndrome in order to map the organism (number of nonpulmonary organ failures), to calculate the prognostic indices (acute physiology and chronic health evaluation (apache) and simplified acute physiology score (saps)) and to plan the multiorgan system approach to treat the disease. the higher the number of multiple organ failure associated with ards, the higher the hospital mortality. trauma patients with ards are associated with lower mortality and oliguricrenal failure, while septic shock patients are associated with the highest hospital mortality rates, suggesting that during the first day of hospitalization these ards patients should be stratified and treated according to the severity of the syndrome and associated comorbidities [ ] . in our case series of patients with early severe ards the mean apache ii score was . ± . (predicted mortality of %), median sofa score (day ) was ( to ), median nonpulmonary organ failure was ( to ), sepsis was present in % of our patients, and septic shock in %, vasopressors were used in . % of our patients, and continuous renal replacement therapy was used in . % of our patients. apache ii and day sofa score were not associated with hospital mortality, but day sofa score was [ ] (figure ) showing that a revaluation of the ards patients especially the ones with multiple organ failure and maintenance of sofa score higher than at day has to be considered in order to evaluate hidden sources of infection or to change the antibiotics according to day collected cultures. in moderate-severe ards patients (pao /fio < ), a phase iv randomized controlled trial comparing cisatracurium to placebo for hours showed an improved critical care research and practice adjusted -day survival rate and increased ventilator-free in the cisatracurium group without a significant increase in muscle weakness. short-term paralysis may facilitate patient-ventilator synchrony in the setting of lung protective ventilation. short-term paralysis would eliminate patient triggering and expiratory muscle activity. in combination, these effects may serve to limit regional overdistention and cyclic alveolar collapse. paralysis may also act to lower metabolism and overall ventilatory demand [ ] . inhaled nitric oxide is an endogenous vasodilator that reduces v/q mismatch and improves oxygenation by pulmonary vasodilation in alveolar units that are ventilated, reducing pulmonary vascular resistance in patients with ards. a cochrane review of clinical trials with patients showed only a transient improvement in oxygenation with no benefit regarding length of icu or hospital stay, ventilator-free days or survival. an increased renal impairment was observed in the inhaled nitric oxide-treated group [ ] . the effects of steroids in the late-stage fibrotic phase of ards (after days of onset) were tested in a phase iii study of the ards network. the study showed no mortality benefit in the treatment group, with a higher mortality in patients treated days after onset [ ] . recently, seam and colleagues tested the effects of methylprednisolone infusion in early ards patients compared to placebo. they observed that methylprednisolone therapy was associated with greater improvement in lung injury score (p = . ), shorter duration of mechanical ventilation (p = . ), and lower intensive care unit mortality (p = . ) than in the control subjects. on days and , methylprednisolone decreased interleukin- and increased protein-c levels (p < . ) compared with control subjects [ ] . from the available evidence, low-dose steroids ( - mg/kg/methylprednisolone) may be considered in patients with severe early ards. nevertheless, it is not recommended to initiate corticosteroids beyond days after the onset of ards. ketoconazole, lisofylline, sivelestat, n-acetylcysteine, and exogenous surfactant are not recommended as treatment for ards patients [ ] . cumulative positive fluid balance is associated with worse clinical outcomes in patients with ards. a phase iii study conducted by the ards network (the factt study) compared liberal versus conservative fluid strategy in patients with acute lung injury. they observed an improvement in oxygenation, lung injury score (lis), and shortened duration of mechanical ventilation without any increase in other organ failure in the conservative group, despite no difference in hospital mortality [ ] . beta-agonists were investigated in multicenter, prospective, randomized trials in their aerosolized presentation (the alta study) and their intravenous presentation (the balti- study). both studies showed no mortality benefit and betaagonists are not recommended as part of therapy for patients with ards [ ] . the omega study [ ] , a randomized, double-blind, placebo-controlled, multicenter trial analyzed patients with early acute lung injury allocated to receive either twicedaily enteral supplementation of n- fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. enteral nutrition, directed by a protocol, was delivered separately from the study supplement. the patients that received enteral supplementation had fewer ventilator-free days ( versus . , p = . ), more days with diarrhea ( versus %; p = . ), and no difference in the adjusted -day mortality ( . % versus . %; p = . ). more recently, a randomized, open-label, multicenter trial, the eden study [ ] , reported patients with acute lung injury, randomized to receive either trophic or full enteral feeding for the first days. initial trophic enteral feeding did not improve ventilator-free days, -day mortality, or infection complications but was associated with less gastrointestinal intolerance. finally, based on relevant literature articles and the authors' clinical experience, we suggest a goal-oriented management for critically ill patients with ards that can help improve clinicians' ability to care for these patients (as shown below). patients with ards. correct ards diagnosis. acute onset, increase respiratory rate, pulse oximeter desaturation and hypoxemia (pao /fio < ). (i) if possible, get a computer tomography (improved diagnosis accuracy, permits differential diagnoses, and helps to set recruitment maneuvers and adequate peep levels). (ii) lung ultrasound, fdg-pet ct, electrical impedance tomography, and pressure-volume p × v curves can help assess the correct diagnosis and set protective mechanical ventilation. (iii) get nasal swab and inferior respiratory tract secretion for infection diagnosis or a bal (infection diagnosis and proinflammatory mediators and procollagen iii measurements). (iv) get hemocultures and blood for infection detection. start resuscitative measurements for septic shock and start appropriate antibiotics. critical care research and practice (v) assessment of prognostic indices (apache, saps) and sequential organ failure assessment (sofa) score. standardize initial mechanical ventilation for blood gas measurements. tidal volume: ml/kg predicted body weight, peep of cmh o, rr = . classify ards severity. mild: pao /fio < , moderate: pao /fio < , and severe: pao /fio < . (i) if possible, get a doppler echocardiogram to assess left ventricular function, right ventricular function, systolic pulmonary artery pressure, and vena cava compressibility. (ii) measure extravascular lung water, if available. (a) in cases of severe ards consider recruitment maneuvers and adequate peep titration. (b) in cases of severe ards with right ventricular dysfunction and pulmonary artery hypertension consider prone position and inhaled nitric oxide. (c) in cases of excessive co retention: paco > mmhg and ph < . consider intratracheal gas insufflation and extracorporeal co removal. (i) early recognition of ards modified risk factors and avoidance of aggravating factors during hospital stay such as high tidal volume ventilation, multiple blood products transfusions, excessive fluid administration, ventilator associated pneumonia, and gastric aspiration prevention could help decrease its incidence. (ii) an early extensive clinical, laboratory, and imaging evaluation of "at risk patients" allows a correct diagnosis of ards, assessment of comorbidities, calculation of prognostic indices (apache, saps, sofa), stratification of the severity of ards, and planning a careful treatment. (iii) rapid administration of antibiotics and resuscitative measures in case of sepsis and septic shock associated with protective ventilatory strategies and early shortterm paralysis associated with differential ventilatory techniques (recruitment maneuvers with adequate peep titration, prone position, and new ecmo techniques) in severe ards can help improve its prognosis. (iv) revaluation of ards patients on the third day of evolution (sofa, biomarkers, and response to infection therapy) allows changes in the initial treatment plans and can help decrease ards mortality. (v) fibroproliferative changes on high-resolution ct in ards can predict mortality and ventilator dependency. acute respiratory distress in adults an expanded definition of the adult respiratory distress syndrome the acute respiratory distress syndrome comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings acute respiratory distress syndrome: a historical perspective acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions acute pulmonary edema development of a clinical definition for acute respiratory distress syndrome using the delphi technique acute lung injury and the acute respiratory distress syndrome: a clinical review acute lung injury and acute respiratory distress syndrome: diagnostic hurdles genetic variants in the angiopoietin- gene are associated with increased risk of ards acute respiratory distress syndrome and acute lung injury acute respiratory distress syndrome: a clinical review acute respiratory distress syndrome: pathophysiology and therapeutic options an nfkb promoter insertion/deletion polymorphism influences risk and outcome in acute respiratory distress syndrome among caucasians incidence and outcomes of acute lung injury early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study diffuse alveolar damage, the pathological basis of adult respiratory distress syndrome the role of intra-alveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage the acute respiratory distress syndrome ards and diffuse alveolar damage: a pathologist's perspective clinical year in review iii: asthma, lung transplantation, cystic fibrosis, acute respiratory distress syndrome performance of an automated electronic acute lung injury screening system in intensive care unit patients introducing automated acute lung injury/acute respiratory distress syndrome electronic screening in intensive care unit practice: is it the future? the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition lung structure and function in different stages of severe adult respiratory distress syndrome what has computed tomography taught us about the acute respiratory distress syndrome? reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome mechanical ventilation in acute respiratory failure: recruitment and high positive end-expiratory pressure are necessary open up the lung and keep the lung open how large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography state-of-the-art mechanical ventilation understanding and avoiding ventilatorinduced lung injury: lessons from an insightful experimental study best strategy to recruit primary ards: what to look for fibroproliferative changes on high-resolution ct in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study imaging in acute lung injury and acute respiratory distress syndrome assessment of lung inflammation with f-fdg pet during acute lung injury lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: a [ f]-fluoro- -deoxy-dglucose pet/ct study bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment electrical impedance tomography bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography a unified approach for eit imaging of regional overdistension and atelectasis in acute lung injury whither lung eit: where are we, where do we want to go and what do we need to get there? does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? a systematic review early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial ventilation with lower tidal volumes as compared with traditional tidal volumes for acute critical care research and practice lung injury and the acute respiratory distress syndrome pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis effects of superimposed driving-pressure on mortality in patients with acute lung injury or acute respiratory distress syndrome effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial a scanographic assessment of pulmonary morphology in acute lung injury: significance of the lower inflection point detected on the lung pressure-volume curve influence of tidal volume on alveolar recruitment: respective role of peep and a recruitment maneuver airway pressure release ventilation in acute respiratory distress syndrome airway pressure release ventilation: an alternative mode of mechanical ventilation in acute respiratory distress syndrome comparison of the effects of bipap ventilation combined with lung recruitment maneuvers and low tidal volume a/c ventilation in patients with acute respiratory distress syndrome pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support noisy pressure support ventilation: a pilot study on a new assisted ventilation mode in experimental lung injury spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury effects of neurally adjusted ventilatory adjusted ventilatory assist on prevention of ventilator-induced diaphragmatic dysfunction in acute respiratory distress syndrome rabitts effects of neurally adjusted ventilatory assist on patientventilator synchrony in patients with acute respiratory distress syndrome high frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ards): systematic review and meta-analysis an updated study-level meta-analysis of randomised controlled trials on proning in ards and acute lung injury prone positioning improves survival in severe ards: a pathophysiologic review and individual patient metaanalysis hemodynamic profile in severe ards: results of the european collaborative ards study comparison of two fluid-management strategies in acute lung injury pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome extracorporeal membrane oxygenation in severe acute respiratory failure. a randomized prospective study clinical review: extracorporeal membrane oxygenation extracorporeal membrane oxygenation for ards in adults efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial tidal volume lower than ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study superimposed highfrequency jet ventilation combined with continuous positive airway pressure/assisted spontaneous breathing improves oxygenation in patients with h n -associated ards combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury prone position and recruitment manoeuvre: the combined effect improves oxygenation combination of high frequency oscillatory ventilation and interventional lung assist in severe acute respiratory distress syndrome clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ards virus-induced acute respiratory distress syndrome: epidemiology, management and outcome biomarkers of acute lung injury: worth their salt? type iii procollagen peptide in the adult respiratory distress syndrome. association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial early goal-directed therapy in the treatment of severe sepsis and septic shock early interventions in severe sepsis and septic shock: a review of the evidence one decade later extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury the influence of infection sites on development and mortality of ards predictors of hospital mortality in a population-based cohort of patients with acute lung injury neuromuscular blockers in early acute respiratory distress syndrome inhaled nitric oxide for acute respiratory distress syndrome (ards) and acute lung injury in children and adults efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome randomized, placebo-controlled trial of an aerosolized beta- adrenergic agonist (albuterol) for the treatment of acute lung injury omega- (n- ) fatty acid, gamma-linoleic acid (gla) and anti-oxidant supplementation in acute lung injury (omega trial) initial trophic vs full enteral feeding in patients with acute lung injury: the eden randomized trial the authors would like to thank adriana pardini for revision of the language. key: cord- -h jgwe z authors: gattinoni, luciano; coppola, silvia; cressoni, massimo; busana, mattia; rossi, sandra; chiumello, davide title: reply by gattinoni et al. to hedenstierna et al., to maley et al., to fowler et al., to bhatia and mohammed, to bos, to koumbourlis and motoyama, and to haouzi et al. date: - - journal: am j respir crit care med doi: . /rccm. - le sha: doc_id: cord_uid: h jgwe z nan reply by gattinoni the strong controversies raised by our -word letter ( ) reflect the underlying conflict through which medical knowledge and science proceed: on one side, the need for evidence regarding a treatment, for which the apex is randomized trials, and on the other side, the need for evidence to elucidate the mechanisms of disease, for which the apex is the reproducible observation of phenomena and their interactions ( ) . as suggested by fowler and colleagues, in a pandemic the real problem is to "balance the tradeoff between learning (evidence of mechanism) and doing (evidence of response to treatment)." in any case, the process of acquiring knowledge about a novel disease or treatment ideally begins with observations (generating the hypothesis) and ends with the experiments (to prove or disprove the hypothesis). however, as evidenced by this correspondence, our scientific community seems divided into two broad categories: on one side are the believers that coronavirus disease (covid- ) pneumonia must be defined as acute respiratory distress syndrome (ards)-and that is it. if so, we have nothing to learn about its respiratory treatment, just to do (lung-protective strategy, positive end-expiratory pressure [peep]-fi o table, etc.) ( ) . on the other side are the believers that covid- is a specific disease that is somehow different from ards, with manifestations that may change over time. as such, we have much to learn regarding mechanisms and what a "lungprotective" approach should mean in this setting ( ) . it is from collecting hundreds of consistent observations (the sodespised anecdotes) from milan, parma, turin, and london that we proposed two phenotypes, which represent the extremes of a broad spectrum of the respiratory manifestations in covid- pneumonia: an early phenotype, l (i.e., the "atypical" ards of our letter, characterized by lower elastance, lower _ va/ _ q, lower recruitability, and lower lung weight), and a late phenotype, h (i.e., the typical ards, characterized by higher lung elastance, higher right-to-left shunt, higher recruitability, and higher lung weight) ( ) . dr. bos, dr. maley and colleagues, and dr. haouzi and colleagues in their letters conclude, as do many others in our scientific community, that covid- pneumonia is not atypical but fits the conventional ards definition and that higher respiratory system compliance (crs) may be a normal finding in the syndrome. dr. bos, in particular, reports a "striking similarity" between the common presentation of patients with severe covid- pneumonia and the ards originally described by ashbaugh in , namely, "acute onset of tachypnea, hypoxemia and loss of compliance." actually, the l patients presenting to the hospital are in % of the cases eupneic, with a respiratory rate of approximately breaths/min (approximately breaths/min in the ashbaugh paper [ ] ) with near a normal crs of . ml/cm h o (, ml/cm h in ashbaugh [ ] ). maley and colleagues suggest that our small cohort ( patients with a mean crs of . . because the disease is the same all around the world, the observations also should be similar. actually, we believe that the apparent contradictory results stem from the time of observation, with type l being more likely early on and type h being more likely in the late phase. we suspect that many icus are treating patients at a more advanced h stage. the pivotal role of time is demonstrated in figure , in which we show, in a series of patients, that crs, measured at cm h o of peep is a function of the days elapsed from the initial symptoms ( figure a) , regardless the venous admixture ( figure b) . the striking feature of the covid- pneumonia in the l state is not the crs per se but the remarkable hypoxemia associated with a lung gas volume far greater than what is found in the ards "baby lung." because the gas and ventilation side are relatively preserved, the hypoxemia must primarily derive from the perfusion side ( ) . indeed, a growing number of observations show endothelial involvement ( ) , which initiates hypercoagulability ( ) , and the lung perfusion dysregulation that causes severe hypoxemia because of _ va/ _ q mismatch. however, as pointed out by bhatia and mohammed, microthrombosis are likely part of this phenomenon. in this context, hedenstierna and colleagues suggested that inhaled nitric oxide could be of interest to correct hypoxemia. this is rational and certainly possible, but only further observations may tell us the value of inhaled nitric oxide in the different stages of the disease. given that the hypoxemia is mainly determined by a pathology on the endothelial side of the alveolar membrane, the use of exogenous surfactant suggested by koumbourlis and motoyama lacks physiological rationale. thus, so far, we have learned that covid- is a systemic disease in which the viral assault is primarily focused on the endothelium, which accounts for both the pulmonary vascular dysregulation and the hypercoagulable state. are these insights sufficient to rethink and change our practice, and if so, at which stage? fowler and colleagues, recognizing the difficulties of promptly organizing randomized controlled trials, propose a direct acyclic graph to evaluate the hypothetical risks and benefits of conventional therapies for the two extreme phenotypes. in the meantime, how should we manage type l patients? the transition from l to h status, in which the ards criteria and therapies fully apply, may be due both to the natural course of the disease and to the patient self-induced lung injury ( ) . there is little that can be done to alleviate the first factor, but we can certainly intervene to prevent patient self-induced lung injury. if, despite noninvasive support, the patient continues to make vigorous inspiratory efforts, we believe that mechanical ventilation should be applied without delay. during the mechanical ventilation of these early phase l patients, higher peep is not advisable despite the severe hypoxemia because recruitability is relatively low, the lung is already full of gas, and the consequences on hemodynamics may be remarkable. we also proposed in these l patients a vt higher than ml/kg, provoking a strong disagreement by maley and colleagues, for whom the conventionally low vt ventilation is the precise strategy for gentle lung ventilation. however, in those patients with higher crs, the tradeoff is between possible ventilator-induced lung injury and possible hypoventilation, with an increased need for sedation and risk of atelectasis. we believe that in the l patients the risk of ventilatorinduced lung injury is minimized, as plateau, driving pressure, and mechanical power are far from their conventionally accepted thresholds. in addition, we would like to respectfully remind our correspondents that in three large randomized controlled trials, no differences were found between patients treated with . ml/kg versus . ml/kg ideal body weight (ibw) ( ), . ml/kg versus . ml/kg ibw ( ), . ml/kg versus . ml/kg ibw ( ) . ards is of fundamental importance in the icu community, which developed in parallel to the understanding of the syndrome ( ) . many people have argued that the term "ards" is too generic because it encompasses too many conditions and etiologies to have any credible diagnostic and prognostic validity. it is therefore ironic to see how many try to turn strongly in favor of preserving the diagnosis of ards in covid- disease, particularly because covid- is a single-etiology disease (unlike ards), and the ventilatory management is independent from the degree of hypoxemia (unlike ards). standard ards treatment in such cases should be deeply reconsidered, taking also in account that the mortality rate in different icus around the world ranges from % to % (personal communications). because the disease is the same, this disparity underlines the impact of treatment. n covid- does not lead to a "typical acquiring knowledge in intensive care: merits and pitfalls of randomized controlled trials respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study management of covid- respiratory distress covid- pneumonia: different respiratory treatment for different phenotypes acute respiratory distress in adults hypoxaemia related to covid- : vascular and perfusion abnormalities on dual-energy ct. lancet infect dis [online ahead of print endothelial cell infection and endotheliitis in covid- hypercoagulability of covid- patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis mechanical ventilation to minimize progression of lung injury in acute respiratory failure tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome: the multicenter trail group on tidal volume reduction in ards evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients fifty years of research in ards why is acute respiratory distress syndrome so important for critical care? reply by pan et al. to haouzi et al. we appreciate dr. haouzi and his colleagues for their interest in our research letter ( ) . they reanalyzed our reported data and found a possible but nonsignificant coupling between lower compliance and greater alveolar po (pa o )-pa o gradient. they then suggested that positive end-expiratory pressure (peep) should be titrated by reaching the highest compliance and lowestwe want to point out that a possible association between compliance and pa o -pa o gradient among different patients makes physiological sense but may not be applied for peep titration in a given individual; the peep providing the highest compliance can be completely different from the peep providing the lowest pa o -pa o gradient. actually, we have observed that patients with coronavirus disease (covid- )-associated acute respiratory distress syndrome (ards) from wuhan often present "better" compliance and "worse" pa o -pa o gradient at low peep. we thus will discuss the optimal compliance and the optimal pa o -pa o gradient as two respective peep strategies.titrating peep by the optimal compliance has been proposed for several decades, but years of research have shown many pitfalls and limitations. ) plateau pressure can be measured by performing varied durations of end-inspiratory occlusion, and the pressure value can change according to viscoelastic properties, pendelluft, or simply the presence of leaks. this technical issue is not trivial. a preset . -to . -second end-inspiratory pause minimizes this issue, providing more reliable plateau pressure as an indicator of the maximal lung distension ( ). ) some physiological studies using electrical-impedance tomography suggested that a high peep guided by "best" compliance of the whole respiratory system can be substantially higher than the peep based on regional compliance or on the dorsal fraction of ventilation reaching % and that the chest wall could play a role in these discrepancies ( ) . ) in contrast, when substantial tidal recruitment is present at low peep, compliance may be increased by this tidal recruitment ( ). using this "best" compliance would therefore favor ongoing repeated recruitment and collapse. ) the optimal compliance approach has been tested in a large randomized controlled trial, showing no benefit on outcome ( ) .the pa o -pa o gradient can be a useful physiological indicator during clinical practice, but we cannot rely on it for peep titration because of the following considerations. key: cord- -h lwzpl authors: zhang, john j y; lee, keng siang; ang, li wei; leo, yee sin; young, barnaby edward title: risk factors of severe disease and efficacy of treatment in patients infected with covid- : a systematic review, meta-analysis and meta-regression analysis date: - - journal: clin infect dis doi: . /cid/ciaa sha: doc_id: cord_uid: h lwzpl the coronavirus disease (covid- ) pandemic spread globally in the beginning of . at present, predictors of severe disease and the efficacy of different treatments are not well-understood. we conducted a systematic review and meta-analysis of all published studies up to march , which reported covid- clinical features and/or treatment outcomes. studies reporting patients were included. pooled rates of intensive care unit (icu) admission, mortality and acute respiratory distress syndrome (ards) were . %, . % and . %, respectively. on meta-regression, icu admission was predicted by raised leukocyte count (p< . ), raised alanine aminotransferase (p= . ), raised aspartate transaminase (p= . ), elevated lactate dehydrogenase (ldh) (p< . ) and increased procalcitonin (p< . ). ards was predicted by elevated ldh (p< . ), while mortality was predicted by raised leukocyte count (p= . ) and elevated ldh (p< . ). treatment with lopinavir-ritonavir showed no significant benefit in mortality and ards rates. corticosteroids were associated with a higher rate of ards (p= . ). a pandemic of coronavirus disease caused by the novel severe acute respiratory syndrome coronavirus (sars-cov- ) spread from asia to the rest of the world in the first three months of . the consequences for human health, the global economy and normal functioning of society have been unprecedented. covid- causes infection in any age group, though severe disease is more common in older adults [ ] . the clinical spectrum of disease ranges from asymptomatic or subclinical infections to organ dysfunctionshock, acute respiratory distress syndrome (ards), acute cardiac injury, and acute kidney injury (aki)and death [ ] . as of may , , there was a total of , , confirmed cases globally. of the , , cases that had an outcome reached, , had resulted in mortality [ ] . the growth curve of covid- academic literature since the first report of this outbreak from wuhan, hubei province, china in december has been exponential [ , publications found on the national institutes of health covid- portfolio and publications found on pubmed on may , using the search string 'coronavirus disease or sars-cov- ']. however, systematic reviews which consolidate these findings remain scarce, with none focused on understanding the predictors for severe disease including the effects of different experimental antiviral and immune-modulatory treatments [ ] . to address this gap in the literature, we conducted a systematic review, meta-analysis and meta-regression to ) investigate the predictive value of laboratory investigations for severe disease and adverse outcomes, and ) evaluate the efficacy of antivirals and corticosteroids for covid- . m a n u s c r i p t reviews and meta-analyses (prisma) guidelines [ ] . all titles and abstracts were screened independently by two reviewers (jjyz and ksl) against a set of pre-defined eligibility criteria. potentially eligible studies were selected for full-text analysis. disagreements were resolved by consensus or appeal to a third senior reviewer (bey). agreement among the reviewers on study inclusion was evaluated using cohen's kappa [ ] . all original studies reporting the clinical characteristics (symptoms and signs, laboratory investigations and radiological findings) and treatment outcomes of patients with covid- were included in our meta-analysis. case reports and series with a sample size of < were excluded per recommendations by the cochrane statistical methods group and in accordance with methodologies of previously published meta-analyses [ ] [ ] [ ] . other exclusion a c c e p t e d m a n u s c r i p t criteria included non-english articles, non-original research papers, laboratory-based and epidemiological studies with no clinical characteristics reported, as well as non-human research subjects [see supplementary table ] . the quality of included studies was assessed using the joanna briggs institute (jbi) checklist for prevalence studies and the jbi checklist for case series [ ] . full details are in supplementary tables and . in summary, these tools rated the quality of selection, measurement and comparability for all studies and gave a score for prevalence studies (maximum of ) and case series (maximum of ). two researchers (jjyz and ksl) assessed the quality of all included studies and discussed discrepancies until consensus was reached. data were extracted on the following variables: study details, sample size of study, method of diagnosis, age, gender, coexisting medical conditions, clinical symptoms, laboratory investigations, radiological findings, treatment details and patient outcomes. primary outcome measures were intensive care unit (icu) admission rate, mortality rate and the event rate of ards. icu admission was used as a surrogate marker for severe infection. secondary outcome measures included other morbidities such as respiratory failure, septic shock, coagulopathy, acute cardiac injury, aki and secondary infection, as well as length of hospital stay (los) and discharge rate at the point of study completion. a c c e p t e d m a n u s c r i p t to account for intra-study and inter-study variance, random effects models were used for meta-analyses of variables and end points [ ] . pooled proportions were computed with the inverse variance method using the variance-stabilizing freeman-tukey double arcsine transformation [ ] . confidence intervals (ci) for individual studies were calculated using the wilson score confidence interval method with continuity correction. the i statistic was used to present between-study heterogeneity, where i ≤ %, between % and %, between % and %, and ≥ % were considered to indicate low, moderate, substantial, and considerable heterogeneity, respectively [ ] . p values for the i statistic were derived from the chi-square distribution of cochran q test. for pooling of means of numerical variables, we computed missing means and standard deviations (sds) from medians, ranges (minimum to maximum) and interquartile ranges (iqrs) using the methods proposed by hozo et al. and wan et al [ , ] . summary-level meta-regression was performed using the mixed-effects model after computation of the sd of freeman-tukey double arcsine transformed proportions. publication bias of studies was assessed using funnel plots, where an asymmetrical distribution of studies was suggestive of bias [ ] . quantitative analysis of funnel plot asymmetry was done using egger's regression test, based on a weighted linear regression of the treatment effect (expressed as a freeman-tukey double arcsine transformed proportion) on its standard error [ ] . the grade approach was used to evaluate the quality of evidence for each outcome [ ] . all statistical analyses were performed using r software version . . (r foundation for statistical computing, ), with the package meta [ ] . p-values less than . were considered statistically significant. all included studies were non-randomized, retrospective observational studies. studies reported data from china, with one each from singapore, south korea and hong kong. details of included studies are reported in supplementary table . of the prevalence studies, studies attained a full score of on the jbi checklist for prevalence studies, two studies attained a score of and one study attained a score of [see supplementary table ]. of the nine case series, studies attained a full score of , one study attained a score of and one study attained a score of [see supplementary table ]. of the total patients, were male ( . %) and were female ( . %). a c c e p t e d m a n u s c r i p t the most common blood abnormalities observed were elevated c-reactive protein (crp) ( . %), decreased albumin ( . %), elevated lactate dehydrogenase (ldh) ( . %) and lymphopenia ( . %). the most common radiological abnormalities seen on chest computed tomography (ct) scan were bilateral infiltrates ( . %), ground glass opacities ( . %), interlobular septal thickening ( . %), subpleural lines ( . %) and consolidation ( . %). in terms of treatment, type of antivirals used included combinations of oseltamivir, ganciclovir, lopinavir, ritonavir, ribavirin and arbidol. type of antibiotics used comprised moxifloxacin, ceftriaxone and azithromycin. table funnel plots and egger's regression test were done to assess for publication bias for icu admission, mortality and ards rates. there was no evidence of publication bias for icu admission (p = . ), mortality (p = . ) and ards (p = . ) [see supplementary figure ]. at baseline, the quality of evidence derived from a review of covid- studies was assessed as low, owing to their observational nature. the quality of evidence for respiratory failure was rated down to very low for imprecision, due to the large confidence interval range and the relatively small sample size analyzed. despite considerable study heterogeneity demonstrated by the i values for most outcome measures, there was no rating down due to inconsistency, as the heterogeneity could likely be explained by differences in patient demographics, diagnostic criteria, treatment methods and management protocols given that covid- is a newly emergent disease. meta-regression was performed to identify risk factors of icu admission, ards and mortality [ table ]. fourteen studies with a total of patients reported icu admission rates. subgroup analysis was performed for studies with the use of corticosteroids reported. sixteen studies with a total of patients reported the use of corticosteroids. pooled mortality rate in these patients was . % ( % ci: . - . ) and pooled ards rate was . % ( % ci: . - . ). meta-regression demonstrated a significant association between corticosteroids use and higher rate of ards (p = . ) [fig. a c c e p t e d m a n u s c r i p t our meta-analysis provides an in-depth analysis of the key epidemiological features, clinical characteristics, laboratory investigations, radiological findings, treatment details and outcomes of covid- from published literature. we identified elevated ldh as a significant predictive marker of ards, and found that both elevated leukocyte count and elevated ldh predict mortality. treatment with the anti-retroviral drug lopinavir-ritonavir was not associated with significant benefit, while corticosteroids were associated with possible harm. early recognition of severe infection may allow early intervention with supportive measures and therapeutics and improve outcomes [ ] . our meta-regression identified five significant markers of icu admission: raised leukocyte count, raised alt and ast, in addition to elevated ldh and finally increased procalcitonin. while . % of patients had a raised leukocyte count in our meta-analysis, the degree of leukocytosis was modest (pooled mean leukocyte count was . x /l). raised alt and ast in severe covid- disease may be a result of liver damage caused by the direct binding of sars-cov- to angiotensinconverting enzyme positive cholangiocytes [ ] . in our analysis, ldh was the only marker that significantly predicted all three measured outcomes: icu admission, ards and mortality. ldh is released from cells upon damage to their cytoplasmic membrane, and is not only a metabolic but also an immune surveillance prognostic biomarker [ , ] . ldh increases the production of lactate, which leads to enhancement of immune-suppressive cells and inhibition of cytolytic cells [ ] . these changes could weaken the immune response mounted against the viral infection, resulting in more severe disease in patients with elevated ldh. increased procalcitonin may have been a marker of bacterial co-infection, thereby resulting in complications of covid- disease and hence a higher rate of icu admission in these patients [ ] . interestingly, lymphopenia was not found to be a significant predictor of icu admission, mortality and ards in our meta-analysis. a possible explanation may be that we analyzed lymphopenia as a dichotomous variable without taking into account a c c e p t e d m a n u s c r i p t the degree of lymphopenia i.e. the numerical value of lymphocyte count, which lies on a spectrum and could affect disease severity among patients with lymphopenia. the results of randomized clinical trials of covid- interventions are of critical importance as only weak evidence supports the currently available repurposed and novel antivirals [ ] . among the patients with antiviral use reported in our meta-analysis, overall rates of mortality, icu admission and ards were . %, . % and . %, respectively. we found no overall benefit from treatment with lopinavir-ritonavir, in line with a recent randomized controlled trial however, this trial demonstrated that lopinavir-ritonavir treatment granted a significant reduction in icu length of stay in survivors. further trials (nct and nct ) are in progress to assess the efficacy of both lopinavir and ritonavir in reducing the covid- viral load, and we look forward to future developments to provide recommendations on the use of antiviral therapy [ , ] . severe covid- is associated with a dysregulated host inflammatory response, suggesting immune modulators as an attractive treatment modality [ ] . corticosteroids were used during the sars-cov outbreak, however, in a meta-analysis only four studies provided conclusive data, and all four indicated possible harm [ , ] . these harms included risks of prolonged viremia, corticosteroid-induced diabetes, avascular necrosis and psychosis [ , , ] . our meta-analysis suggested that the use of corticosteroids is associated with disease severity (icu admission) and higher ards rates. it is not clear if this effect is a consequence of corticosteroid treatment, or confounding by indication bias where sicker patients are more likely to receive corticosteroids. an rct of corticosteroids in severe respiratory viral infections has long been called for, and at least one clinical trial in covid- (nct ) is ongoing [ ] . a c c e p t e d m a n u s c r i p t sars-cov- -induced pneumonia is marked by a cytokine stormhyperactivation of effector t cells and excessive production of inflammatory cytokines, particularly interleukin- (il- ) [ ] . blockade of il- function using tocilizumab, a specific monoclonal antibody against its receptor appears to be useful in alleviating hyperinflammation symptoms in severe cases [ , ] . selective janus kinase-signal transducer and activator of transcription (jak-stat) inhibitors such as baricitinib may also be beneficial, though clinical trials are required and any benefit is likely to be greatest in combination with an effective antiviral [ ] . to the best of our knowledge, this is the first systematic review and meta-analysis of covid- to describe specific laboratory predictors of severe disease and adverse outcomes. our study is also the first meta-analysis to evaluate the efficacy of antivirals and corticosteroids. careful attention should be given to the management of patients with raised leukocyte count, raised alt and ast, elevated ldh, increased procalcitonin and raised leukocyte count as these factors predict icu admission, mortality and ards. in terms of treatment efficacy, the use of corticosteroids in covid- patients is significantly associated with higher rates of ards. compared to other antivirals, the use of lopinavir and ritonavir is non-superior in terms of lowering mortality rate. further prospective studies are vital to clarify our findings. a c c e p t e d m a n u s c r i p t no funding was used for the production of this work. all authors have no potential conflicts of interest to disclose. m a n u s c r i p t a c c e p t e d m a n u s c r i p t figure sw epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and metaanalysis preferred reporting items for systematic reviews and meta-analyses: the prisma statement a coefficient of agreement for nominal scales extracorporeal membrane oxygenation in pregnant and postpartum women with h n -related acute respiratory distress syndrome: a systematic review and meta-analysis extracorporeal membrane oxygenation in pregnant and postpartum women: a systematic review and meta-regression analysis excluding small studies from a systematic review or metaanalysis the methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review a basic introduction to fixed-effect and random-effects models for meta-analysis metaprop: a stata command to perform metaanalysis of binomial data cochrane handbook for systematic reviews of interventions version . . . the cochrane collaboration estimating the mean and variance from the median, range, and the size of a sample estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials bias in meta-analysis detected by a simple, graphical test grade: an emerging consensus on rating quality of evidence and strength of recommendations how to perform a meta-analysis with r: a practical tutorial clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study specific ace expression in cholangiocytes may cause liver damage after -ncov infection lactate dehydrogenase, a risk factor of severe clinical characteristics and prognosis of community-acquired pneumonia in autoimmune disease-induced immunocompromised host: a retrospective observational study elevated lactate dehydrogenase (ldh) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. cancer biomarkers : section a of disease markers procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis pharmacologic treatments for coronavirus disease (covid- ): a review a trial of lopinavir-ritonavir in adults hospitalized with severe covid- the efficacy of lopinavir plus ritonavir and arbidol against novel coronavirus infection (elacoi) comparison of lopinavir/ritonavir or hydroxychloroquine in patients with mild coronavirus disease (covid- ) the trinity of covid- : immunity, inflammation and intervention sars: systematic review of treatment effects corticosteroid therapy for critically ill patients with middle east respiratory syndrome factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients glucocorticoid therapy for novel coronaviruscritically ill patients with severe acute respiratory failure (steroids-sari) clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china covid- : consider cytokine storm syndromes and immunosuppression tocilizumab treatment in covid- : a single center experience covid- : combining antiviral and antiinflammatory treatments a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -jvnjzjds authors: radnis, caitlin; qiu, sunny; jhaveri, miral; dasilva, ivan; szewka, aimee; koffman, lauren title: radiographic and clinical neurologic manifestations of covid- related hypoxemia date: - - journal: j neurol sci doi: . /j.jns. . sha: doc_id: cord_uid: jvnjzjds the novel coronavirus sars-cov- is known to cause hypoxemia and acute respiratory distress syndrome (ards) in a significant portion of those with severe disease. survivors of critical illness and ards often experience neurocognitive impairment but, to date, there is scant literature correlating radiographic hypoxic brain injury to hypoxemia related to ards. in this case series, we describe three cases of hypoxic brain injury seen on magnetic resonance imaging (mri) in patients with hypoxemia secondary to covid- -related ards. the lack of severe observed hypoxemia in two of the cases suggests that unrecognized or asymptomatic hypoxemia may play a role in hypoxic brain injury related to covid- . the novel coronavirus sars-cov- emerged in december as a highly contagious virus, with an estimated doubling time in the early stages of . - . days [ ] . the incidence of covid- infections varies widely even within the united states, with a range of . to . cases per , in early april [ ] . sars-cov- has been shown to cause critical illness in between - % of infected patients [ , ] . of patients with severe disease, approximately % had acute respiratory distress syndrome (ards), . % required invasive mechanical ventilation, and % had pneumonia [ ] . with the rising worldwide prevalence of covid- infections, a significant proportion of the global population will require monitoring in an intensive unit care (icu) and will develop ards. ards is the development of an acute onset of new or worsening respiratory symptoms with radiographic evidence of bilateral opacities which cannot otherwise be explained by fluid overload or cardiac failure [ ] . the hallmark of this syndrome is hypoxemia, with severity determined by the ratio of arterial oxygen tension to fractional inspired oxygen (pao /fio ) and a minimum positive end expiratory pressure of five [ ] . there is significant mortality and longterm morbidity associated with ards. survivors of ards are known to develop long-term functional disability for years after the event [ ] . despite advances in treatments, the overall mortality rate is approximately % [ ] . the prevalence of neurocognitive impairment after critical illness is well established [ , ] . in particular, survivors of ards seem to be at increased risk of cognitive impairment [ ] [ ] [ ] . between - % of patients who survived ards had neurocognitive impairment at hospital discharge and nearly half had persistent deficits at one year in the areas of memory, processing speed, executive functioning, and attention [ , ] . while the mechanisms underlying neurocognitive dysfunction in survivors of critical illness are not well understood, many factors are thought to contribute including hypotension, sedation, delirium, hyperglycemia, and cerebral microhemorrhages [ , [ ] [ ] [ ] [ ] . hypoxemia and the duration of hypoxemia have been linked to poor cognitive outcomes in critically ill patients [ , ] . brain atrophy on mri has been reported as a consequence of critical illness and brain volume loss has been observed on computed tomography (ct) in ards survivors [ , ] . a recent autopsy case series found evidence of hypoxic changes in the brain tissue of patients who had succumbed to covid- , but there was no report of whether these patients developed ards, duration of mechanical ventilation if required, whether extracorporeal membrane oxygenation (ecmo) was used, presence or absence of cardiac arrest, or cause of death [ ] . to date, there is scant literature linking hypoxemia to radiographic findings of hypoxic-ischemic brain injury in survivors of ards. in this case series, we describe three cases of hypoxic brain injury seen on mri, along with clinical correlations, in patients with hypoxemia secondary to covid- related ards. notably, none of these patients experienced cardiopulmonary arrest. this is a retrospective review of patients admitted to our tertiary care center with ards due to severe covid- infection who were evaluated by the general neurology team after a consult was requested for encephalopathy or other neurologic deficit. each patient included underwent brain mri as part of the neurologic work up and all were found to have evidence of hypoxicischemic injury. patients selected were neurologically intact prior to hospitalization with covid-j o u r n a l p r e -p r o o f journal pre-proof . all patients had gcs with no apparent encephalopathy prior to intubation, and all were able to provide their own history on initial presentation to the hospital. exclusion criteria included cardiopulmonary arrest during the hospitalization or any history of hypoxic-ischemic injury prior to hospitalization. our institution based respiratory therapy protocol dictates that all ventilated critical care patients be assessed daily for spontaneous awakening and spontaneous breathing trials, and if appropriate trials completed per a "wake up and breathe" protocol [ ] . . cases . case -year-old obese female with a history of asthma, obesity, gastroesophageal reflux disease, and vitamin d deficiency presented with shortness of breath and self-reported oxygen saturation of % measured with home oxygen monitor. she was intubated on the day of admission due to worsening hypoxia and dyspnea and met criteria for severe ards. hospital course was complicated by cytokine release syndrome (treated with tocilizumab), gastrointestinal bleeding, and dysphagia requiring percutaneous endoscopic gastrostomy tube placement. she intermittently required vasopressor therapy but did not have prolonged episodes of hypotension. table summarizes degree and duration of hypoxemia. after days of mechanical ventilation, she was successfully extubated. two days after cessation of sedative medications and one day post extubation, neurology was consulted due to encephalopathy and semi-continuous right facial twitching. given initial concern for seizures, she was started on levetiracetam with slight improvement in the movements, though the movements continued to wax and wane. continuous video electroencephalography (eeg) showed continuous irregular generalized slow wave activity, without any seizures or epileptiform activity, verifying these movements were not seizures but rather dyskinesias or myoclonus. aside from these movements, cranial nerves were intact, she was awake and alert but non-verbal, and had no spontaneous movements of her extremities. mri brain demonstrated symmetric t flair hyperintensities with mild restricted diffusion in the bilateral globus pallidi extending to the adjacent posterior limb of the internal capsules and along the cerebral peduncles, suggesting hypoxic ischemic injury ( fig a) . the suspected dyskinesias versus myoclonus were thought to be related to these radiographic changes. at time of discharge to an acute inpatient rehabilitation facility, she was alert, followed simple commands, communicated via head nodding, had minimal verbal output, and was able to flicker her toes bilaterally but had no movement of her arms. as she was noted to have more proximal than distal weakness, there was likely a component of intensive care unit-acquired weakness (icu-aw), in addition to resolving encephalopathy. -year-old female with history of obesity and prior abdominal gunshot wound presented with shortness of breath and cough. she was intubated the day after admission due to progression of hypoxemic respiratory failure and failure of high flow oxygen supplementation. table summarizes the degree and duration of hypoxemia. her hospital course was complicated by recurrent fevers, lower extremity deep vein thrombosis (dvt), and acute renal failure requiring renal replacement therapy. hypotension was also present and attributed to cytokine release syndrome (crs), which was treated with vasopressor therapy and tocilizumab. she initially failed extubation after days on mechanical ventilation but was later extubated successfully after a total of days on mechanical ventilation. five days after extubation, the patient remained poorly interactive, prompting a neurology consult. on exam she was awake and alert, non-verbal with intact cranial nerves, minimal spontaneous movement, and no motor response to noxious stimulus. mri brain was completed and demonstrated symmetric confluent t hyperintensities in the subcortical white matter along bilateral perirolandic regions at the vertex, and in the corona radiata and centrum semiovale with questionable t hyperintensity in the bilateral lentiform and caudate nuclei (fig b) . upon discharge to an acute inpatient rehabilitation facility she was awake, alert and oriented to person, place and time. her motor exam was significant for profound proximal weakness, with preservation of distal extremity strength. similar to the previous patient, there was improvement in encephalopathy and weakness likely secondary to icu-aw . case -year-old male with history of diabetes presented to an outside hospital with cough, fever, diarrhea and abdominal pain. based on outside hospital records, his oxygen saturation on presentation was % on room air. he was quickly placed on a non-rebreather mask with improvement in oxygen saturation to %. at that time, he was noted to be in mild distress but alert and oriented to person, place and time with a normal motor exam. he was intubated on the day of admission due to worsening hypoxemia (pao on non-invasive ventilation) and transferred to our center six days later for escalation of care. abg prior to transfer demonstrated pao of requiring fio of % and peep of . the patient's full outside hospital course was not included in available records, but oxygen saturation prior to transfer ranged from - % and no episodes of hypotension were recorded. see table for description of hypoxemia while at our center. his course was complicated by superimposed ventilator associated pneumonia, high fevers, opioid withdrawal syndrome and acute renal failure requiring renal replacement therapy. he was initially extubated after days on mechanical ventilation but then reintubated days later for inability to protect his airway. he was ultimately extubated after total days on a mechanical ventilation neurology was consulted on day of admission due to persistent encephalopathy precluding extubation. on neurologic examination while intubated and off sedation, he was noted to open eyes to verbal stimulus but did not follow any commands, had intact brainstem reflexes, and did not demonstrate purposeful or spontaneous movements. mri brain demonstrated symmetric and diffuse cortical, subcortical, thalamic and cerebellar ill-defined t flair hyperintensities likely consistent with hypoxic ischemic injury (fig c) . there were also a few parenchymal microhemorrhages in both a central and peripheral distribution. the patient was transferred back to the outside hospital after he no longer required icu level care. at time of discharge from our icu the encephalopathy was improving, he was awake, alert and oriented to person and able to follow commands. the motor exam had also improved and no abnormal movements were noted. table . oxygenation and blood pressure characteristics. *p/f ratios were only included when fio was provided with arterial blood gas lab draw.**based on ardsnet goal of pao - mmhg [ ] . ***duration is an estimate determined by time of next abg result demonstrating improved oxygenation. ****spo range obtained from vitals charted throughout admission. *****map from blood pressure cuff, arterial map> at the time. ******autonomic instability defined as labile blood pressures requiring intermittent vasopressor therapy as well as antihypertensive therapy this case series aims to describe the clinical and radiographic characteristics of patients with hypoxemia following severe covid- infection. all patients included required prolonged mechanical ventilation, as well as use of vasopressor therapy due to hypotension. there were no documented episodes of hypoglycemia in any patients that were included in this study. two of three patients had one documented pao level below the ardsnet goal of mmhg [ ] . interestingly, despite the lack of severe observed hypoxemia in two of the three patients, these patients developed hypoxic brain injury. the same two patients developed crs requiring tocilizumab, a monoclonal antibody against the il- receptor. the development of hypoxic brain injury despite a lack of severe observed hypoxemia may reflect a proposed theory of hemoglobinopathy [ ] , contributing to what may present as "silent hypoxemia," where patients with covid- related pneumonia have hypoxemia with mild or j o u r n a l p r e -p r o o f absent clinical manifestations [ ] . this is evidenced by the patients in case and who presented with low oxygen saturations, seemingly out of proportion to their symptoms. while these patients may not be initially symptomatic, perhaps prolonged unrecognized periods of hypoxemia can later lead to these findings. hypoxemia in severe covid- has been proposed as one of several mechanisms responsible for neurologic sequelae [ ] . hypoxemia likely increases risk for neurocognitive impairments, but there are a multitude of other risk factors including prolonged hypotension and large cumulative doses of sedation needed for ventilator synchrony [ ] . we propose that crs may be a contributing factor to the prolonged encephalopathy reported in two of the patients. leukemia patients that develop crs secondary to chimeric antigen receptor (car) t cell therapy often present with aphasia and encephalopathy [ ] . however, it is unclear whether car-t cell therapy itself or crs is more contributory. this neurotoxicity does not respond well to treatment with tocilizumab, which is thought to be due in part to the inability of tocilizumab to cross the blood brain barrier [ ] . similarly, in severe covid- , encephalopathy and slow neurologic recovery may be in part related to crs, but minimal neurological improvement may be noted despite treatment with tocilizumab. while only present in one of the patients discussed in this case series, cerebral microhemorrhages have been documented sequalae of both covid- and critical illness in general [ , ] . these findings, in addition to the other factors discussed, may have contributed to the patient's prolonged encephalopathy. neurologic recovery of patients who develop hypoxic-ischemic brain injury is typically prolonged, with the greatest improvement seen within the first three months after injury [ ] . some degree of cognitive deficit is often permanent, though the functional impact varies widely [ ] . as more patients develop and recover from severe covid- infection, we can expect to see many more patients with the long-term neurocognitive sequelae that are well known to follow other critical illness and in particular ards. neurorehabilitation after hospitalization will be important to improve the functioning and quality of life of these patients. although this study is limited in scope due to its size and retrospective design, it provides novel information regarding hypoxic-ischemic brain injury in covid- related ards. although the findings of hypoxic-ischemic brain injury may be generalizable to all causes of ards, there may be features specific to covid- related ards. as mentioned, crs may be involved in this relationship and perhaps potentiate susceptibility to ischemic injury. future studies may assess in greater detail the pattern or degree of hypoxic ischemic injury on mri and long-term neurocognitive outcomes. this case series also highlights the need for further research into covid- related pneumonia and ards. we may need to better identify thresholds for acceptable levels of hypoxemia, as well as continue monitoring for long term neurologic and cognitive outcomes. high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus geographic differences in covid- cases, deaths, and incidence -united states clinical characteristics of coronavirus disease in china acute respiratory distress syndrome the berlin definition of ards: an expanded rationale, justification, and supplementary material functional disability years after acute respiratory distress syndrome lessons to learn from epidemiologic studies in ards long-term neurocognitive function after critical illness longterm cognitive impairment after critical illness neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome the adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms twoyear cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome duration of delirium as a predictor of long-term cognitive impairment in survivors of critical illness the impact of high versus low sedation dosing strategy on cognitive dysfunction in survivors of intensive care units: a systematic review and meta-analysis critical illness-associated cerebral microbleeds neuroimaging findings in patients with covid- the association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the visions cohort magnetic resonance imaging study brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome neuropathological features of covid- efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome covid- : attacks the -beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism critical care crisis and some recommendations during the covid- epidemic in china the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak-a n update on the status astct consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells cytokine release syndrome cognitive sequelae of hypoxic-ischemic brain injury: a review key: cord- -yt lafin authors: mcgurk, kevin; riveros, toni; johnson, nicholas; dyer, sean title: a primer on proning in the emergency department date: - - journal: j am coll emerg physicians open doi: . /emp . sha: doc_id: cord_uid: yt lafin historically, the prone position was used almost exclusively in the icu for patients suffering from refractory hypoxemia due to acute respiratory distress syndrome (ards). amidst the severe acute respiratory syndrome coronavirus (sars‐cov‐ ) pandemic, however, this technique has been increasingly utilized in settings outside of the icu, particularly in the emergency department. with emerging evidence that patients diagnosed with covid‐ who are not intubated and mechanically ventilated may benefit from the prone position, this strategy should not be isolated to only those with critical illness. this is a review of the pertinent physiology and evidence supporting prone positioning along with a step‐by‐step guide meant to familiarize those who are not already comfortable with the maneuver. placing a patient in the prone position helps to improve ventilation‐perfusion matching, dorsal lung recruitment, and ultimately gas exchange. evidence also suggests there is improved oxygenation in both mechanically ventilated patients and those who are awake and spontaneously breathing, further reinforcing the utility of the prone position in non‐icu settings. given present concerns about resource limitations because of the pandemic, prone positioning has especially demonstrable value as a technique to delay or even prevent intubation. patients who are able to self‐prone should be directed into the ''swimmer's position'' and then placed in reverse trendelenburg position if further oxygenation is needed. if a mechanically ventilated patient is to be placed in the prone position, specific precautions should be taken to ensure the patient's safety and to prevent any unwanted sequelae of prone positioning. acute onset: within week of known clinical insult or new/worsening respiratory symptoms. chest imaging bilateral opacities not fully explained by effusions, lobar/lung collapse or nodules seen on chest radiograph or ct. etiology of edema not fully explained by other causes such as cardiac failure or fluid overload. severe ards mm hg or less peep, positive end-expiratory pressure; pao ; partial pressure of arterial oxygen; fio , fraction of inspired oxygen; ards, acute respiratory distress syndrome; ct, computed tomography commonly deployed in the ed, including the prone position. this is especially true as prone positioning has been increasingly utilized in awake, spontaneously breathing patients. , although there are growing data to support the early use of prone positioning in patients with coronavirus disease (covid- ) , many emergency physicians may be unfamiliar with the maneuver or how to successfully utilize it. this article is intended as a primer on both the literature behind prone positioning and its safe application in eds unaccustomed to its use. the mechanism underlying the beneficial effects of prone positioning has become clearer as the understanding of normal and abnormal lung physiology has evolved. while in the supine position under normal conditions, the lung parenchyma is subject to the forces of gravity and constrained by the anatomical shape of the thorax. during inspiration, recruited alveoli are inflated and gas exchange occurs. the magnitude of lung ventilation is affected by the degree of inflation at both the level of the individual alveolus as well as the sum expansion of the entire lung. in the supine position, alveoli in the most dependent dorsal regions are often collapsed due to compression by overlying lung tissue. further compression of these regions occurs from weight placed on lung tissue by the heart and abdomen. ards is an acute, inflammatory lung injury defined by the berlin criteria as shown in table . this syndrome is known to lead to hypoxemia, diminished lung aeration, and edema. the compressive effects of supine positioning are magnified in lung tissue affected by ards because of this edema and the corresponding increased weight of lung parenchyma. this results in less alveolar expansion in dorsal regions as compared to those in the ventral areas and subsequently less gas exchange occurs in these regions. this has been corroborated by imaging studies of patients with ards, which have documented dense consolidation in the dorsal lung regions when patients are supine. , because the dorsal regions of the lung contain more lung tissue as compared to the ventral regions, prone positioning improves ventilation by allowing for a more homogenous distribution of compressional forces on alveoli thereby improving ventilation and oxygenation. , , perfusion in the lungs is also greater in dorsal regions compared with ventral regions even while prone, and the combination of increased recruitment in these dorsal regions with greater perfusion leads to improved ventilation-perfusion matching and improvement in hypoxemia ( figure ). , , the effect of the prone position on alveolar size at functional residual capacity (frc) and frc plus tidal volume (vt). in the supine posture, at frc, the most dependent alveoli are small because of higher pleural pressures, compression from the heart, and extrinsic compression from abdominal contents as compared with the prone posture. during tidal breathing, the distribution of local ventilation is more uniform in the prone posture because the alveolar volumes are more uniform at the initiation of each breath. this allows tidal volumes to be more evenly distributed throughout the lung, leading to less alveolar stress and lung injury. as prone positioning has been primarily studied and applied in patients with ards, it was traditionally reserved for intubated and mechanically ventilated patients with moderate to severe disease. , [ ] [ ] [ ] , with emerging evidence that patients diagnosed with covid- who are not intubated may benefit, this maneuver should not be isolated to only those with critical illness. , , although there are other disease states for which prone positioning has been used successfully, including non-ards associated acute hypoxemic respiratory failure and pediatric bronchiolitis, this is significantly less studied and should not be routinely used in the ed without specialty consultation. , there is no general consensus on absolute contraindications to for patients who cannot self-prone, or more staff members will usually be required to safely turn the patient with on each side and at the head of the bed. this maneuver should be practiced before implementation in your department to ensure the safety of the patient and staff members. with the necessary staff in place, the following steps should be followed - : . disconnect or cap all non-essential lines and medical devices. secure all remaining lines, drains, and tubes as necessary. ensure there is adequate tubing length to allow for patient repositioning. affix any urinary catheter to the medial leg. (figure ) . if there is an insufficient response in oxygenation after proning, consider adding a larger degree ( to degrees or more) of vertical tilt/reverse trendelenburg. [ ] [ ] [ ] in limited studies, oxygenation has been shown to improve with the combination of both prone and upright positioning. although proning in reverse trendelenburg has been the subject of less-dedicated scholarship, it is also an easily executed and low-risk adjustment to trial. existing research shows little or no effect on patient hemodynamics when adding this vertical tilt to the prone position. if a patient has unilateral or asymmetric lung disease, lateral positioning (starting with the less-diseased side down) is a reasonable alternative. for beds likely to be used for patient proning (ie, a high acuity/resuscitation portion of the ed, ward for patients with covid- , etc) consider placing a second top sheet prior to the patient using the bed. when a patient cannot self-prone, the lower of the sheets can then serve as a''slide sheet'' reducing the number of steps necessary to safely position him or her. eds are likely to have neither the mattresses nor headrests specific to prone positioning that might be found in icus or operating rooms. as such, ed staff must remain mindful of anatomic regions at greatest risk for pressure damage or nerve injury. [ ] [ ] [ ] [ ] [ ] this is especially true in sedated or paralyzed patients. specific attention should be paid to the nose and eyes, breasts, elbows/cubital tunnel, pelvis, and the dorsum of the foot. patients with silicone breast implants may be at increased risk for breast tissue damage or necrosis in the prone position. for patients who require central venous access or arterial monitoring, consider insertion sites that are less likely to occlude and will remain more accessible for medication administration or blood draws once prone. proper equipment, preparation, and personnel it can be done safely either via ground or aeromedical transport over long distances with few or no complications. [ ] [ ] [ ] [ ] prone positioning, in the appropriate clinical context, has been shown to be a safe and efficacious maneuver. once relegated exclusively to the icu for those with critical illness, prone positioning can be performed in the ed for both awake, spontaneously breathing patients and those requiring mechanical ventilation. as the medical community navigates the unique challenges posed by the covid- pandemic, prone positioning represents a readily implemented and potentially beneficial treatment option for hypoxic patients in the ed. kevin mcgurk md https://orcid.org/ - - - improved oxygenation in patients with acute respiratory failure: the prone position a novel coronavirus from patients with pneumonia in china efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study lower mortality of covid- by early recognition and intervention: experience from jiangsu province gas exchange in the prone posture efficacy of prone position in acute respiratory distress syndrome patients: a pathophysiology-based review acute respiratory distress syndrome prone positioning in acute respiratory distress syndrome. semin respir critl care med effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome treatment of ards with prone positioning guidelines on the management of acute respiratory distress syndrome prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: a retrospective study respiratory parameters in patients with covid- after using noninvasive ventilation in the prone position outside the intensive care unit early self-proning in awake, non-intubated patients in the emergency department: a single ed's experience during the covid- pandemic early prone position at the emergency room in acute respiratory distress syndrome: a pilot study prone position augments recruitment and prevents alveolar overinflation in acute lung injury prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis physiological effect of prone position in children with severe bronchiolitis: a randomized cross-over study (bronchio-dv) prone position for acute respiratory failure in adults formal guidelines: management of acute respiratory distress syndrome the pragmatics of prone positioning safe prone checklist: construction and implementation of a tool for performing the prone maneuver. rev bras ter intensiva patient positioning in anaesthesia guidance for prone positioning in adult critical care. london: intensive care society the prone position during surgery and its complications: a systematic review and evidence-based guidelines short-term effects of combining upright and prone positions in patients with ards: a prospective randomized study acute effects of upright position on gas exchange in patients with acute respiratory distress syndrome positioning of patients with acute respiratory distress syndrome: combining prone and upright makes sense bilateral breast necrosis after prone position ventilation ultrasound-guided central venous catheterization in prone position ultrasound-guided central venous catheterization in the prone position reverse cpr: a pilot study of cpr in the prone position optimizing prone cardiopulmonary resuscitation: identifying the vertebral level correlating with the largest left ventricle cross-sectional area via computed tomography scan part : electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing cardiopulmonary resuscitation in adult patients in prone position transport of a prone position acute respiratory distress syndrome patient transport of mechanically ventilated patients in the prone position safe long-distance interhospital ground transfer of critically ill patients with acute severe unstable respiratory and circulatory failure ards with severe hypoxiaaeromedical transportation during prone ventilation a primer on proning in the emergency department key: cord- -x ffw authors: damiani, elisa; carsetti, andrea; casarotta, erika; domizi, roberta; scorcella, claudia; adrario, erica; donati, abele title: comment on “respiratory mechanics and gas exchanges in the early course of covid- ards: a hypothesis-generating study” date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: x ffw nan we have read with great interest the article by diehl et al. on the evaluation of respiratory mechanics and gas exchanges in patients with acute respiratory distress syndrome (ards) due to covid- that was recently published in the annals of intensive care [ ] . in patients with moderate-to-severe ards, the authors observed high physiological dead space (v d /v t ) and ventilatory ratio (vr). several hypotheses are made to explain the pathogenesis of increased v d /v t , namely pulmonary embolism, alveolar overdistension, increased instrumental dead space, and diffuse microcirculatory dysfunction [ ] . even if alveolar overdistension due to high peepprotective ventilation, with regional compression of alveolar vessels, is likely to exert a major impact on lung mechanics in ards, the hypothesis of a contributing role of microvascular derangement is particularly captivating. lung injury in ards (and covid- pneumonia) seems mainly driven by a dysregulation of the reninangiotensin system, leading to increased vascular permeability, inflammation, pneumocyte apoptosis, and fibrosis [ ] . pulmonary microvascular injury, with leaky blood vessels, interstitial oedema, microthrombosis, and heterogeneous perfusion, may be the first responsible for ventilation/perfusion mismatch and increased dead space in ards. in patients with early moderate or severe ards, ospina-tascon et al. showed an inverse correlation between v d /v t and sublingual microcirculatory blood flow distribution [ ] . in their study, diehl et al. reported an elevation of markers of endothelial damage and thrombosis (i.e., circulating endothelial cells and d-dimers); however, they did not show any statistical correlation with variables of respiratory mechanics and/ or gas exchange [ ] . in a recent report, we described the sublingual microcirculation of mechanically ventilated patients with severe sars-cov- pneumonia and showed an inverse correlation between perfused vessel density (pvd) and d-dimers [ ] . this relationship was confirmed in sars-cov- patients on veno-venous extracorporeal membrane oxygenation [ ] . unfortunately, we could not evaluate the relationship with physiological dead space, because v d /v t data were not available for our cohort. we calculated the vr for patients who were not receiving extracorporeal membrane oxygenation (median vr = . [ . - . ]); however, we could not find any significant correlation with d-dimers (spearman's rho = − . , p = . ) or microcirculatory variables (spearman's rho for pvd = . , p = . ). the extremely low sample size significantly limits these analyses. this comment refers to the article available at https ://doi.org/ . /s - - - . taken together, all these data would suggest a connection between microvascular dysfunction, coagulopathy, and increased physiological dead space in the genesis of respiratory failure in covid- pneumonia. nonetheless, the cause-effect relationship remains to be proven. an altered sublingual microcirculation could just be an epiphenomenon of a hemodynamic compromise in patients with worse respiratory mechanics: in our cohort, sublingual microvascular perfusion tended to decrease with increasing driving pressures [ ] . further investigations are imperative to gain a more comprehensive understanding of the pathophysiology of covid- and select the best treatment strategy. appropriately designed clinical and laboratory-controlled studies are needed to prove any causal relationship between microvascular derangements and increased dead space ventilation. finally, a consideration must be made regarding the article by diehl et al. [ ] : the authors used side-stream capnography, which may be inaccurate for calculations of v d /v t as compared to main-stream capnography. the transport delay of the gas in the sampling tube with axial mixing of the gas residing in the tube, together with the variable sampling flow rate resulting from the alternating positive airway pressure during mechanical ventilation, leads to underestimation and distortion of the capnogram, with consequent inaccurate v d /v t calculations. respiratory mechanics and gas exchanges in the early course of covid- ards: a hypothesis-generating study angiotensin system and its opposing arm in sars-cov- related lung injury microcirculatory dysfunction and dead-space ventilation in early ards: a hypothesis-generating observational study microvascular alterations in patients with sars-cov- severe pneumonia sublingual microcirculation in patients with sars-cov- undergoing veno-venous extracorporeal membrane oxygenation publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. all authors equally contributed to the study's conceptualization, methodology, and analysis. ed, ac, ec wrote the manuscript. rd, cs, ea, and ad revised the manuscript critically. all authors read and approved the final manuscript. none. ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests.received: july accepted: october key: cord- -u uf e authors: gage, ann; higgins, andrew; lee, ran; panhwar, muhammad siyab; kalra, ankur title: reacquainting cardiology with mechanical ventilation in response to the covid- pandemic date: - - journal: jacc case rep doi: . /j.jaccas. . . sha: doc_id: cord_uid: u uf e nan the incidence has been even higher in the italian series, with up to % of infected patients in lombardy developing ards ( ) . it is likely that many american physicians will be called on to treat pneumonia, hypoxemic respiratory failure, and ards, regardless of their specialty. ards is a life-threatening form of lung injury. this lung injury can be the result of primary pulmonary parenchymal injury such as pneumonia or aspiration or from a systemic process such as sepsis or trauma. increased capillary permeability leading to inflammation is the inciting factor for ards. damage to the capillary endothelium and alveolar epithelium results in protein accumulation within the alveoli, activation of proinflammatory cytokines, and then pulmonary fibrosis. this cascade leads to loss of functional lung tissue. chest radiography demonstrates bilateral opacities. as ards progresses, lung compliance decreases, hypoxemia ensues, and patients can progress to ventilator dependence ( , ) . in practice, ards is defined by the berlin definition. blockade may also be considered ( ). it should be noted that mild ards may be managed with noninvasive forms of ventilation. however, during the present pandemic, modifications to usual critical care may be necessary. given concern for viral transmission, current recommendations advise to breaths/min); this may then be adjusted based on the patient's arterial pco ( figure ). after initial stabilization, it is critical to appropriately titrate settings to minimize ventilator-induced lung injury. one of the most common methods for doing this is careful monitoring of the plateau pressure ( figure ) . although the peak inspiratory pressure represents the pressure to which the proximal large airways are exposed, the plateau pressure is representative of the pressure present in the alveoli at end inspiration, and thus is an indicator of transpulmonary pressure, lung overdistention, and ventilator-induced lung injury. plateau pressure is measured after a . -to . -s inspiratory pause maneuver. if the plateau pressure is > cm h o, consider further reducing the delivered tidal volume. it is also important to monitor the patient's driving pressure, or difference between the peep and plateau pressure, as increased driving pressures have been associated with higher mortality in ards ( ). with a basic understanding of these fundamentals, it is possible for all cardiologists to provide safe and effective care for our patients with covid- . as many of us prepare to use skill sets long forgotten, it will be important to remember to ask for help when needed. one of the few bright spots in this pandemic has been the resurgence of interdisciplinary team- clinical characteristics of coronavirus disease in china covid- and italy: what next? acute respiratory distress syndrome: advances in diagnosis and treatment acute respiratory distress syndrome: pathophysiology and therapeutic options ards definition task force acute respiratory distress syndrome: the berlin definition surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis care for critically ill patients with covid- for the acc critical care cardiology working group. positive pressure ventilation in the cardiac intensive care unit driving pressure and survival in the acute respiratory distress syndrome key words acute respiratory distress syndrome, coronavirus, coronavirus disease- , mechanical ventilation key: cord- -mai eggf authors: bai, lu; gu, li; cao, bin; zhai, xiao-li; lu, min; lu, yong; liang, li-rong; zhang, lei; gao, zi-fen; huang, ke-wu; liu, ying-mei; song, shu-fan; wu, lin; yin, yu-dong; wang, chen title: clinical features of pneumonia caused by influenza a(h n ) virus in beijing, china date: - - journal: chest doi: . /chest. - sha: doc_id: cord_uid: mai eggf background: data on symptoms and radiographic changes in patients with pandemic influenza a(h n ) (a[h n ]) pneumonia during convalescence have not been reported. methods: during october , , and january , , adult patients with pneumonia with laboratory-confirmed or clinically suspected a(h n ) infections were observed for clinical characteristics, high-resolution chest ct scan, and lung function test changes during acute and -month convalescent phases. results: of the case subjects, the median age was (interquartile range [iqr], - ) years, . % were men, and . % had at least one underlying medical condition. sixty-two patients started oseltamivir therapy within a median of (iqr, - ) days from the onset of illness, and received iv corticosteroids. ards developed in patients, and were treated initially with noninvasive positive pressure ventilation (nppv). in this group, nppv was successful in patients ( . %). nine patients died at a median of (iqr, - ) days after onset of illness. multivariate cox regression identified two independent risk factors for death: progressive dyspnea after resolution of fever (relative risk, . ; % ci, . - . ; p = . ) and a higher apache (acute physiology and chronic health evaluation) ii score on presentation (relative risk for each point, . ; % ci, . - . ; p < . ). at -month follow-up of survivors with a(h n ), ground-glass opacities were still present, although diminished, in . %, and diffusing capacity for carbon monoxide was mildly reduced in . %. conclusions: ground-glass opacities and decreased diffusing capacity were the main abnormalities observed at -month follow-up of survivors of a(h n ). the clinical spectrum of this disease has ranged from self-limited illness to respiratory failure and death. in our initial report of the a(h n ) virus infection in china, the majority of patients had mild illness. , since the fi rst report of pneumonia caused by the a(h n ) virus in mexico, severe cases have been documented throughout the world. as of march , , Ն , laboratoryconfi rmed cases of death have been reported by the six world regions. in mainland china, there were . , confi rmed cases up to february , , including deaths. many studies have been published on the clinical manifestations of a(h n ) pneumonia during the acute phase of illness, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] but no information has been reported on symptoms and radiographic and lung function changes in convalescence. we studied clinical manifestations during the acute phase, antiviral and corticosteroid therapy, noninvasive positive pressure ventilation (nppv), and the histopathologic changes of a fatal case. survivors were followed up after discharge for a period of months. we believe patient follow-up and further investigation at follow-up were carried out according to clinical need, so written informed consent was not sought. high-resolution ct (hrct) scanning was ordered only in those with persisting symptoms, chest signs, or radiologic fi ndings on discharge or on last visit. no contrast was given with ct scan, and the possible radiation harm was also explained to patients. lung function tests (lfts) were ordered in those patients still attending at months. the ethics board committee at beijing chao-yang hospital approved the study design. the severity of lung changes was evaluated initially and on follow-up examinations. each lung was divided into three zones. the number of abnormal zones and the changes in ground-glass opacities (ggos), consolidation, reticular-nodules, and interlobular septal thickening were evaluated by hrct scanning. all evaluations were performed by two radiologists who were blinded to the clinical information. lfts, including lung volume, spirometry, and diffusing capacity for carbon monoxide (d lco ) were performed months after the onset of symptoms. all lfts were performed in accordance with recommended standards. d lco was measured with a singlebreath technique, adjusted for hemoglobin and alveolar volume. lft measurements were considered abnormal if they were , % of the predicted value. continuous variables were summarized as means ( sd) or medians (interquartile range [iqr] ). differences between groups were assessed using the x test or fisher exact test for categorical variables and the mann-whitney u test for continuous variables. we used univariate and multivariate cox regression to identify independent predictors of mortality. all analyses were performed by spss software,version . (spss inc; chicago, illinois). a p value Յ . was considered statistically signifi cant. from october , , to january , , a total of , cases of infl uenza-like illness were reported in our hospital, of which were laboratory-confi rmed a(h n ) cases. during the epidemic, a total of patients were eligible for this study, including patients with laboratory-confi rmed a(h n ) and three patients with high clinical suspicion for a(h n ) infection. among the patients, were hospitalized, and were treated as outpatients. median age was years, . % were men, and . % had at least one underlying medical condition ( table ) . dyspnea persisted in . % of patients after resolution of fever. smokers were more common in the ards group ( p . ), and moist rales and wheezing were signifi cantly more frequent in this group. although leukocyte counts were similar in the two our work can help optimize treatment, and also lead to a better understanding of the symptomatic, radiologic, and lung functional changes during the convalescent period. data were collected retrospectively and prospectively on all patients with confi rmed a(h n )-related pneumonia treated at beijing chao-yang hospital between october , , and january , . the diagnosis of pneumonia was based on respiratory symptoms combined with a new infi ltrate on chest radiograph. real-time reverse transcriptase polymerase chain reaction (rt-pcr) assay was used to confi rm the diagnosis of a(h n ) infection. patients presenting with pneumonia with high clinical suspicion of a(h n ) infection but negative rt-pcr test results for a(h n ) were also included in this study. children younger than years of age were excluded. most patients were hospitalized for treatment, whereas those who presented with less serious illness and did not need oxygen supplementation were treated as outpatients under home quarantine. treatment decisions for all patients were made by their attending physicians. hospitalized patients were discharged when their temperatures had returned to normal for at least days, most infl uenza-like symptoms had disappeared, and they were clinically stable. information recorded included demographic data, underlying medical conditions, symptoms, signs, laboratory and chest radiograph fi ndings before therapy and during follow-up, and the clinical course, treatment, and adverse events during hospital stay. apache (acute physiology and chronic health evaluation) ii scores were determined in all patients to assess the severity of illness. during hospitalization, clinical data were collected retrospectively from medical records. zones on chest radiograph ( p . ) than did those who were outpatients. sixty-two of patients started oseltamivir therapy within a median of (iqr, - ) days from the onset of illness. dosages and duration of antiviral therapy are listed in table . thirty-one patients received iv corticosteroids for a median duration of (iqr, - ) days, with a dose of methylprednisolone, - mg/kg/d. adverse effects involving hallucinations and disorientation occurred in three male hospitalized patients to h after beginning corticosteroids or oseltamivir. two of the three patients received both drugs, and the other one received only oseltamivir. symptoms groups, lymphocyte counts were signifi cantly lower and serum potassium levels signifi cantly higher in the ards group. patients with ards also required more frequent use of higher doses of oseltamivir, longer duration of oseltamivir treatment, and more frequent use of corticosteroids and vasopressors, and more frequently had positive bacterial and fungal cultures. the most common initial radiologic fi ndings on hrct scan were bilateral ggos involving several zones with or without associated multifocal areas of consolidation. centrilobular nodules were also common, and small pleural effusions were present in . % of patients ( fig ) . in patients without ards, those who were hospitalized more frequently had diarrhea ( p . ), moist rales ( p . ), a lower serum albumin level ( p . ), and more involved lung ; without ards group (n ); with ards group (n ). g chest radiograph was performed within wk after onset of symptoms. total (n ); without ards group (n ); with ards group (n ). h high-resolution chest ct scanning was performed at a median (interquartile range, - ) days after onset of symptoms. total (n ); without ards group (n ); with ards group (n ). disappeared to days after stopping corticosteroids and oseltamivir or lowering the dose of oseltamivir. among patients with ards, required ventilation support, all of whom were initially treated with nppv. in this group, nppv succeeded in ( . %) (duration . . days) and ( . %) failed and were intubated at a median of (iqr, - ) h after admission; the last one refused intubation and died. among the patients who were intubated, eight died. patients who failed nppv treatment had higher apache ii scores on presentation (median [iqr, [ ] [ ] [ ] [ ] ) compared with those who succeeded table ) , who was treated successfully with oseltamivir and noninvasive positive pressure ventilation. a, initial high-resolution ct (hrct) scan obtained days after onset of illness shows bilateral extensive ground-glass opacities (ggos) and multifocal consolidation that had a predominant subpleural distribution. b, hrct scan obtained days after onset of illness shows ggos, interlobular septal thickening, and reticular nodules pattern (arrows). c, on day , only ggos are seen. d, at a -month visit, ggos are still present but are much improved. e and f, the same scan as a shows centrilobular nodules in the left upper lobe (arrows in e) and a very small amount of right pleural effusion (arrow in f). (median [iqr, [ ] [ ] [ ] ; p . ). barotrauma occurred in two patients, one during extracorporeal membrane oxygenation therapy. sputum or transtracheal aspirate specimens obtained for bacterial culture were positive in patients ( table ) , including acinetobacter baumannii, four; klebsiella pneumoniae, four; pseudomonas aeruginosa, two; enterobacter aerogenes , one; escherichia coli, one; staphylococcus aureus, one; and a spergillus spp, six . only one patient had a positive sputum culture within the fi rst h of hospitalization ( klebsiella pneumoniae ). all other positive bacterial or fungal cultures were obtained Ն h after hospitalization. an autopsy was performed on a -year-old previously healthy man who was admitted days after onset of symptoms and died of severe ards on day of hospitalization ( fig ) . gross examination of lung tissue revealed prominent congestion and consolidation, with increased weight (left, g; right, , g). an abscess was seen in the right lower lobe that among the patients, nine died, of whom eight had hemorrhagic respiratory secretions. one -yearold man died of severe hemoptysis within h of admission. the death rate among patients with ards was . % ( / ). the main cause of death was refractory hypoxemia. two factors were found to be independently associated with death: progressive dyspnea after resolution of fever (relative risk, . ; % ci, . - . ; p . ) and a higher apache ii score on presentation (relative risk for each point, . ; % ci, . - . ; p , . ) ( table ) . of the survivors, had one or more follow-up visits. among who completed the -month visits, symptoms reported at the last visit included exertional dyspnea (four), hair loss (two), and cough (one). the duration of symptoms was as follows: sputum . . days, bloody sputum . . days, fatigue . . days. a -year-old female patient who was previously healthy still had a low platelet count of , per mm at days after the onset of illness. changes in lung abnormalities from initial to follow-up hrct scan examinations are shown in table . among the patients who completed their -month visit, still showed lesser degrees of ggos ( fig ) . in those who had ards (n ), "involved zones" were signifi cantly ( p . ) more frequent than in those without ards (n ). lfts were performed at visit for patients ( table ). all had been hospitalized, and there was no statistical difference in clinical and laboratory characteristics between these patients and those in whom lfts were not obtained. impairment of d lco was the most common ( / [ . %]) abnormality detected. data are presented as median (interquartile range) unless otherwise indicated. a(h n ) infl uenza a(h n ). see table our series of cases of a(h n ) identifi ed two independent risk factors associated with fatal pneumonia: progressive dyspnea after resolution of fever and a higher apache ii score on presentation. three months later, ggos of less severity were still present on chest radiographs in . % of patients ( / ) . lfts revealed decreased d lco ( , % predicted) in eight ( . %) of the patients tested. the clinical characteristics of a(h n ) pneumonia we described during the acute phase were similar to those reported by others. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in this report, most patients complained of dyspnea, which usually occurred within week after illness onset. dyspnea continued to progress after resolution of fever in . % of the patients, a fi nding that has not been reported by others. in this report, the success rate for nppv was . %, which is much higher than that reported by others ( . %- . %). , [ ] [ ] [ ] although the death rate ( / [ %]) in patients who received invasive ventilation in our study was higher than that reported in another study, among patients with ards, the death rate was . %, similar to other reports. , , [ ] [ ] [ ] [ ] [ ] moreover, although nppv was used widely in the ward specifi cally set aside for patients infected with a(h n ), none of the doctors and nurses who were in direct contact with these patients developed respiratory symptoms or infl uenza-like illnesses. therefore, we believe that with proper infection-control procedures, nppv can be used successfully and safely for treating patients with a(h n ) pneumonia complicated by ards. it has been reported that % to % of autopsied patients with a(h n ) had evidence of bacterial coinfection. , streptococcus pneumoniae, streptococcus pyogenes , and s aureus were the most predominant pathogens. however, in our study, community-acquired bacterial infection (defi ned as sputum collected within h of hospitalization) was detected in only one of patients ( k pneumoniae ). the low yield of gram-positive bacteria before or within h of hospitalization may be due to the widespread use of prophylactic antibiotic therapy. in contrast, nosocomial infection was common in the patients ( / [ . %]), and gram-negative bacilli were the predominant causative pathogens. aspergillus spp was also seen. progressive a(h n ) infection, intubation, a prolonged hospital stay, iv antibiotic use, and use of oral or iv corticosteroids may be risk factors for nosocomial infection caused by gram-negative bacilli and aspergillus spp. we showed that symptoms and laboratory abnormalities in survivors of a(h n ) virus infection returned to normal within month of the onset of illness. nonetheless, ggos were still found at months, although no fi brotic changes were seen. in survivors of a(h n ) virus infection, persistent radiologic abnormalities including ggos, often with a reticular pattern, have been seen as long as year after illness onset. in survivors of severe acute respiratory syndrome (sars) followed for year, marked improvements in pulmonary fi brosis have been seen, but some patients still had residual changes. because this kind of fi brosis was reversible, it has been suggested that these fi ndings were partially caused by postinflammatory atelectasis rather than by genuine fi brosis alone. the resolution of lung abnormalities in patients with a(h n ) viral pneumonia seemed better than that seen in patients with sars and infl uenza a(h n ) infection. impairment of d lco was the most common ( / [ . %]) abnormality in lung function testing months after the onset of illness, followed by restrictive defects ( / [ . %] ). the d lco fi ndings were similar to the fi ndings of one study of patients with sars at -month follow-up visits. the impairment of d lco in survivors of sars persisted for year in . % of patients reported by other investigators. although the number of cases with lfts in our series is limited (only cases, of whom eight had a reduction of d lco ), it seemed that patients who had bilateral ggos on hrct scan were more likely to have an impaired d lco . during the convalescent period of ards, ggos may consist of intralobular fi brosis that is below the limits of resolution of hrct scanning. a longer follow-up study is needed to determine whether lung function abnormalities in patients infected with a(h n ) are irreversible and radiologic changes persist over time. to our knowledge, this is the fi rst report of symptoms and radiographic changes in patients with a(h n ) pneumonia during the convalescent period. there were several limitations. first, it is a singlecenter study with a limited number of patients. second, monthly follow-up visits were offered to all patients when they were discharged but some of the patients felt that was inconvenient and did not come back. as a result, out of survivors had one or more follow-up visits. third, most patients had underlying medical conditions that could have contributed to the lung function abnormalities. in conclusion, we found that progressive dyspnea after resolution of fever and a higher apache ii score on presentation were independent risk factors associated with death in patients with a(h n ) viral pneumonia. at the -month follow-up visit of survivors of a(h n ) pneumonia, some degree of ggos persisted in most patients and decreased d lco was common. clinical management of human infection with pandemic (h n ) : revised guidance. world health organization web site national infl uenza a pandemic (h n ) clinical investigation group . clinical and epidemiologic characteristics of early cases of infl uenza a pandemic (h n ) virus infection, people's republic of china national infl uenza a pandemic (h n ) clinical investigation group of china . clinical features of the initial cases of pandemic infl uenza a (h n ) virus infection in china iner working group on infl uenza . pneumonia and respiratory failure from swine-origin infl uenza a (h n ) in mexico utah due to novel influenza a(h n ) infection anzic influenza investigators . critical care services and h n infl uenza in australia and new zealand severe acute respiratory syndrome: temporal lung changes at thin-section ct in patients bacterial coinfections in lung tissue specimens from fatal cases of pandemic infl uenza a (h n )-united states pulmonary pathologic fi ndings of fatal pandemic infl uenza a/h n viral infections radiological features of lung changes caused by avian infl uenza subtype a h n virus: report of two severe adult cases with regular follow-up dynamic changes of serum sarscoronavirus igg, pulmonary function and radiography in patients recovering from sars after hospital discharge severe acute respiratory syndrome: thin-section computed tomography features, temporal changes, and clinicoradiologic correlation during the convalescent period pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome the -year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors acute respiratory distress syndrome: imaging of the injured lung pandemic (h n ) . world health organization web site ministry of health of the people's republic of china . pandemic h n in china. ministry of health web site h n semicyuc working group . intensive care adult patients with severe respiratory failure caused by infl uenza a (h n )v in spain pandemic influenza a (h n ) virus hospitalizations investigation team . hospitalized patients with h n infl uenza in the united states hospitalised adult patients with pandemic (h n ) infl uenza in melbourne, australia california pandemic (h n ) working group . factors associated with death or hospitalization due to pandemic infl uenza a(h n ) infection in california predictors and outcomes of respiratory failure among hospitalized pneumonia patients with h n infl uenza in taiwan canadian critical care trials group h n collaborative . critically ill patients with infl uenza a(h n ) infection in canada critically ill patients with infl uenza a(h n ) in mexico clinical fi ndings and demographic factors associated with icu admission author contributions: dr bai: contributed to data collection and analysis and the fi rst draft of the manuscript. dr gu: contributed to data collection and analysis. dr cao: contributed to data collection and analysis, the fi rst draft of the manuscript, and revision of the manuscript . dr zhai: contributed to radiologic evaluation and review and revision of the manuscript. dr m. lu : contributed to postmortem examination and review and revision of the manuscript. dr y. lu: contributed to lung function testing and review and revision of the manuscript. dr liang: contributed to statistical analysis and review and revision of the manuscript. dr zhang: contributed to radiologic evaluation and review and revision of the manuscript. dr gao: contributed to postmortem examination and review and revision of the manuscript. dr huang: contributed to lung function testing and review and revision of the manuscript. dr liu: contributed to infl uenza virus testing and review and revision of the manuscript. dr song: contributed to data collection and review and revision of the manuscript. dr wu: contributed to data collection and review and revision of the manuscript. dr yin: contributed to data collection and review and revision of the manuscript. dr wang: contributed to data analysis and careful revision of the manuscript. financial/nonfi nancial disclosures: the authors have reported to chest that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article . other contributions: all work was performed at the beijing chao-yang hospital, capital medical university and the school of basic medical sciences, peking university, bejing, china. we key: cord- - kxwkcbl authors: overholt, kalon j.; krog, jonathan r.; bryson, bryan d. title: dissecting the common and compartment-specific features of covid- severity in the lung and periphery with single-cell resolution date: - - journal: biorxiv doi: . / . . . sha: doc_id: cord_uid: kxwkcbl as the global covid- pandemic continues to escalate, no effective treatment has yet been developed for the severe respiratory complications of this disease. this may be due in large part to the unclear immunopathological basis for the development of immune dysregulation and acute respiratory distress syndrome (ards) in severe and critical patients. specifically, it remains unknown whether the immunological features of the disease that have been identified so far are compartment-specific responses or general features of covid- . additionally, readily detectable biological markers correlated with strata of disease severity that could be used to triage patients and inform treatment options have not yet been identified. here, we leveraged publicly available single-cell rna sequencing data to elucidate the common and compartment-specific immunological features of clinically severe covid- . we identified a number of transcriptional programs that are altered across the spectrum of disease severity, few of which are common between the lung and peripheral immune environments. in the lung, comparing severe and moderate patients revealed severity-specific responses of enhanced interferon, a /iκb, il- , and il- pathway signatures along with broad signaling activity of ifng, spp , ccl , ccl , and il across cell types. these signatures contrasted with features unique to ards observed in the blood compartment, which included depletion of interferon and a /iκb signatures and a lack of il- response. the cell surface marker s pr was strongly upregulated in patients diagnosed with ards compared to non-ards patients in γδ t cells of the blood compartment, and we nominate s pr as a potential marker for immunophenotyping ards in covid- patients using flow cytometry. highlights covid- disease severity is associated with a number of compositional shifts in the cellular makeup of the blood and lung environments. transcriptional data suggest differentially expressed cell surface proteins as markers for covid- immunophenotyping from balf and pbmc samples. severity-specific features covid- manifest at the pathway level, suggesting distinct changes to epithelia and differences between local and systemic immune dynamics. immune-epithelial cellular communication analysis identifies ligands implicated in transcriptional regulation of proto-oncogenes in the lung epithelia of severe covid- patients. network analysis suggests broadly-acting dysregulatory ligands in the pulmonary microenvironment as candidate therapeutic targets for the treatment of severe covid- . december , the virus had spread to every major country on earth [ , , , ] . the pandemic disease caused by sars-cov- , termed coronavirus disease (covid- ) , has diverse clinical presentations ranging from asymptomatic infection, to moderate symptomatic infection with possible pneumonia, to severe respiratory distress, to critical respiratory failure, septic shock, and/or multiple organ dysfunction or failure [ , , , ] . a hallmark of severe and critical covid- cases is a rampant dysregulation of the immune system concomitant with the development of a hypoxemic respiratory condition widely characterized as acute respiratory distress syndrome (ards) [ , , , , ] . the serological profile of severe covid- patients largely resembles the cytokine profile of ards [ ] and has been characterized by high levels of many cytokines including il- , il- , il- , il- , il- , ccl , ccl , tnf-α, and ifn-γ [ , , , , ] . post-mortem examinations of covid- patients reveal the aftermath of these disease dynamics: diffuse alveolar damage, multi-organ infiltration of lymphocytes and alveolar macrophages [ , , , ] , and pneumocyte hyperplasia and peribronchiolar metaplasia in the epithelium resembling adenocarcinomas [ , , ] . these morphological findings suggest local and systemic activation and infiltration of inflammatory immune cells that may contribute to the inflammatory injuries of the respiratory system consistent with ards phenotypes in severe covid- [ ] . while months of clinical observations in hospitals across the world have led to consistent descriptions of covid- severity at a clinical level [ , , ] , the biological underpinnings of immune hyperactivation in severe and critical covid- are only beginning to be defined. bulk rna sequencing (bulk rna-seq) and single-cell rna sequencing (scrna-seq) studies have identified stark transcriptional differences between bronchoalveolar lavage fluid (balf) and peripheral blood mononuclear cell (pbmc) samples in hospitalized covid- patients, indicating that immunological responses may be highly compartment-specific [ , ] . a number of recent studies have compared severe patients to healthy control subjects in an effort to define immunological hallmarks of disease severity in both the lung and peripheral circulation using scrna-seq. these studies have identified that severe disease in the lung compartment is associated with lymphopenia, t cell hyperactivation, and inflammatory macrophage polarization, while severe disease in the blood is associated with lymphopenia, suppression of type i and type ii interferon activity, and decreased monocyte hla class ii expression [ , , , ] . although these studies describe immunological dysregulation in severe covid- patients requiring intensive care, they do not explore immunological features distinguishing covid- patients who experience moderate or non-ards pathology from those who progress to life-threatening disease courses. single-cell resolution studies specifically comparing disease severity strata are needed to reveal the immunological mechanisms responsible for severity-specific immune dysregulation and to identify signatures of disease severity that may inform covid- patient triage and treatment. while many studies have endeavored to apply transcriptional profiling to understand the cellular dynamics underlying coronavirus infection, to our knowledge, a single integrative study comparing responses across the spectrum of disease severity in both the lung and blood compartments has not yet been reported. isolated analyses of balf samples have shown neutrophil and proliferating t cell enrichment in severe over moderate patients accompanied by cd + t cell lymphopenia, a shift towards inflammatory macrophage polarization, and increased transcriptional expression of a variety of cytokines [ , ] . previous investigations focusing only on peripheral blood responses have shown various compositional shifts between severe and moderate disease including cytopenias of monocytes, natural killer (nk) cells, dendritic cells (dcs), and t cells, [ , , , , ] accompanied by increases in plasmablasts, b cells, and neutrophils [ , , , ] . serum cytokine levels are reportedly altered between severe and moderate patients, including increased il- , il- , and tnf-ɑ [ , ] and deficient ifn-α and ifn-γ [ ] , while blood single-cell transcriptional analyses have shown alteration of the tnf-α/nf-κb pathway, interferon signatures, and hla class ii expression [ , , , ] . while individual studies have increased our understanding of severe covid- in the lung and blood separately, transcriptional dynamics have not been leveraged to propose detectable cell surface markers correlated with the level of a patient's disease severity in cell types of either compartment. another large gap in the literature persists regarding the transcriptional similarities and differences between the local and peripheral immune environments. critically, dysregulated biological pathways and their correlation with clinical severity levels remain poorly understood in immune cells of both compartments. immuneepithelial signaling dynamics at the site of local infection likely play a supporting role in severe responses but have also not been rigorously described. an overarching unaddressed question is the possibility for therapeutic interventions to affect the lung and blood compartments differently; thus, generating comparative transcriptional data will be useful for determining efficacious treatment strategies for severe in this study, we present comparisons between immunological signatures of covid- based on clinical severity level in both the lung and blood compartments using identical methods. we re-analyzed two publicly available scrna-seq datasets: one containing balf cells from donors stratified by the original authors as "moderate" and "severe" covid- patients as well as healthy control subjects, obtained from liao et al. [ ] , and one containing pbmcs from donors stratified by the original authors as "non-ards" and "ards" patients as well as healthy control subjects, obtained from wilk et al. [ ] for both of these datasets we conducted identical pre-processing, integration and analysis in order to obtain comparable results. we first evaluated differential gene expression and pathway-level changes across the disease severity stratifications mentioned above for each cell type in the balf and the pbmc datasets. next, we leveraged differential expression data to identify cell surface proteins that could be promising markers for covid- severity immunophenotyping. finally, we investigated ligand-receptor interactions implicated in regulating severity-specific immunophenotypes using nichenet network analysis [ ] and we propose multiple 'pan-ligands' as potential key regulators specific to severe disease. our integrative analysis adds to a growing knowledge-base and contributes to a finer understanding of the mechanisms that drive ards-related immune dysregulation in severe covid- . our findings may guide future work informing potential interventional strategies to improve patient outcomes as the covid- pandemic continues to unfold. severe covid- has been thought to result in profound immune dysregulation at both a local and systemic level. here, we performed a re-analysis of single-cell rna sequencing (scrna-seq) data to identify common and compartment-specific signatures of covid- disease severity. we used identical methods to separately analyze multi-donor scrna-seq datasets from bronchoalveolar lavage fluid (balf) and peripheral blood mononuclear cells (pbmcs) in covid- patients classified by severity strata as well as healthy control subjects to investigate severity-specific immune dysregulation in the lung and periphery. balf and pbmc raw gene-barcode matrices were downloaded from separate studies in the geo [ , ] . the balf dataset consisted of patients ( severe and moderate) and healthy control donors, while the pbmc dataset consisted of patients ( patients with ards, patients without ards, where one patient who was sampled twice fell within both groups at different stages of the disease course) and healthy control donors. we performed our analyses on balf and pbmc datasets separately with the goal of identifying common and compartment-specific gene signatures. to analyze the compositional changes in cell populations occurring during severe covid- , we first sought to identify clusters in transcriptionally heterogeneous scrna-seq data of the lung. after preprocessing raw balf gene-barcode matrices, a filtered dataset consisting of , cells was clustered using seurat and visualized by uniform manifold approximation and projection (umap), as shown in figure a . a total of clusters were identified showing distinct separation in a two-dimensional umap space. annotation of these clusters based on the expression of canonical cell type markers showed the presence of myeloid cells, lymphoid cells, and epithelial cells, closely matching the cell types found by the original publication [ ] . of annotated cell types, contained cells from moderate, severe, and control donors, with the exception of plasma cells which were not recovered from moderate donors ( figure s a ). compositional changes across disease severity categories were assessed by z-scored percentages of cell types in each donor sample. analyzing balf compositional changes showed trends of increased donor specific percentages of nk cells, mixed t cells, and plasmacytoid dendritic cells (pdcs) in moderate donors over control and severe donors as displayed in the figure a heatmap. we next preprocessed raw pbmc gene-barcode matrices, resulting in a filtered dataset of , cells. the blood single-cell landscape was visualized by umap ( figure b) . a total of clusters were identified, showing distinct populations in a two-dimensional umap space. annotation of these clusters revealed the presence of myeloid cells and lymphoid cells, roughly matching the cell types found by in the original publication using a different method [ ] . we termed the blood cells observed in this dataset as "pbmcs", although cell type annotation revealed the presence of anuclear platelets and erythrocytes, as well as polymorphonuclear basophils and neutrophils. all annotated cell types contained cells from ards, non-ards, and control donors ( figure s d ). cluster (cd +/cd d+/ighg +) was annotated as probable doublets using the marker gene panel shown in figure s f . analyzing pbmc compositional changes across severity categories using z-scored percentages as described above, we observed trends indicating a decrease in erythrocyte and cd + effector memory t cell percentages as well as an expansion of plasma cells and proliferating plasma cells in both ards and non-ards patients compared to control donors. to examine the population of nk and t cells in the balf at finer resolution, we performed iterative data integration on the "nk", "mixed t", and "proliferating t" populations, using severe donors, moderate donors, and healthy control donors. severe donor s and healthy control donor hc were omitted as a consequence of having too few nk and t cells to allow integration and alignment. after reintegration, a total of , nk and t cells were visualized via umap ( figure c) . a total of clusters were identified, which were annotated according to distinct cell type labels with additional cluster labeled as "uncertain" and clusters (cd d+/cd +) and (cd d+/fcgr b+) classified as probable doublets using the marker gene panel shown in figure s i ). analyzing nk and t cell compositional changes across severity categories, we observed trends indicating expansion of cd + naive t and cd + effector treg cells in moderate donors compared to severe and control donors. the distinctive heterogeneity observed in mononuclear phagocytes (mps) of the balf seen in figure a led us to address severity-specific changes in individual mp populations. we again performed iterative data integration on clusters identified as mps in the original balf dataset ( figure a) . following iterative data integration using severe donors, moderate donors, and healthy controls, a total of , mp cells were visualized by umap ( figure d ). the mp clusters were left unannotated in further analysis. the clusters were evaluated using a panel of balf marker genes to identify probable doublets (figure s l), and clusters (cd +/cd d+) and (cd +/ighg +) were classified as such. analysis of compositional changes of mp clusters across disease categories showed more pronounced compositional changes than we observed in the balf in general. clusters , , and (expressing chemokines ccl , ccl , ccl as well as spp ) appear to be expanded in severe donors compared to moderate and control donors, while clusters , , and (expressing mrc , c qa, and fabp ) appear to be expanded in control donors compared to moderate and severe donors. cluster (expressing hladqa and hladqa ) appears to be uniquely expanded in moderate donors compared to control and severe donors. cellular markers corresponding to clinical categories of covid- disease severity have not yet been rigorously characterized. here, we sought to leverage transcriptional differences across severity strata to identify surface-bound proteins in both the lung and blood that could be used as markers for immunophenotyping. to nominate putative cell surface markers, we conducted differential gene expression analysis between severe and moderate patient groups for lung (balf) cells and between ards and non-ards patient groups for blood (pbmc) cells and selected significant differentially expressed genes (degs) with a fold change (fc) cutoff of |log fc> |. figure a shows significantly up-and downregulated transcripts for pdcs in the balf, one of lung cell types studied. from the large number of significant degs, we observed the upregulation of areg and cd , which were verified as cell surface protein-coding genes using the cell surface protein atlas [ ] . the areg and cd transcripts show robustly increased expression in pdcs in severe compared to moderate disease ( figure b ) and compared to pdcs in healthy control subjects ( figure s a) . we additionally showed that areg and cd are not upregulated in moderate disease compared to controls ( figure s a ). the expression of areg and cd was cross-referenced with bulk rna-seq blood data from the human immune cell atlas (figure s c) , and expression of these transcripts in various subtypes of dcs was verified [ , ] . differential expression of transcripts coding for cell surface proteins was evaluated for every cell type in the balf, resulting in a matrix of potential severity-specific surface markers for each cell type ( figure c) . upregulation of the areg gene was also observed in myeloid dendritic cells (mdcs, also known as conventional dendritic cells), indicating a possible conserved response across dc subtypes. extending our analysis beyond immune cell types and relaxing the stringency cutoff of |log fc> |, we made the interesting observation that epithelial (club and ciliated) cells demonstrate significant upregulation of icam and ldlr, the two main entry receptors for respiratory rhinoviruses. we confirmed that markers identified as differentially regulated between severe and moderate disease were not differentially regulated in the same direction between moderate disease and control ( figure s b) , with the exception of hladra and vamp on mps and ccr on mdcs, indicating that all other identified cell surface protein transcripts in figure c are unique markers of severe disease. we also sought to identify ards-specific cell surface markers in the blood in order to nominate immunophenotyping markers on cells that may be accessible through a blood draw. in gamma delta t (γδ t) cells, we observed ards-specific differentially expressed genes including the surface marker s pr (figure d) , a g-protein coupled receptor that interacts with multiple inflammatory pathways such as jak/stat and mtor/pi k/akt [ , ] . s pr expression was robustly upregulated in ards compared to non-ards patients ( figure e ) and ards compared to control (figure s d) , and additionally did not show upregulation between non-ards patients and controls. similarly to our analysis of the balf, we analyzed differential expression of surface protein genes in every cell type of the pbmc pool, and the matrix of potential markers is shown in figure e . we found that s pr was also differentially expressed in cd + effector t cells, and its general expression on t cells was verified in bulk rna-seq data ( figure s f ). immunoglobulin heavy chain genes also appeared to be differentially expressed in unexpected blood cell types. in both balf and pbmcs, we observed that increasing disease severity was associated with the common downregulation of hla class ii genes hladqa and hladqa on cd + monocytes and balf mps and hladra on cd + monocytes and balf mps. overall, these results suggest cell surface proteins whose transcripts are differentially expressed across disease severity categories as candidate immunophenotyping markers in cells of the lung and blood. to complement our transcriptomic analysis, we employed gene ontology (go) analysis to identify the biological functions of degs ( figure s g -i). go analysis of the degs in balf and pbmcs shows differential expression of transcripts belonging to ontologies of the innate immune system, cytokine signaling, and adaptive immune cell proliferation and activation. to probe the molecular mechanisms of severe covid- at a broader scale, we sought to utilize the large number of differentially expressed transcripts to identify biological pathways that are altered across the spectrum of disease severity in the local lung microenvironment (balf) and systemic circulation (pbmcs). significant transcriptional changes in cells of the balf were abundant in all cell types with the exception of plasma cells. we first directed our attention to the epithelium, where substantial morphological damage and histological atypia were observed in deceased covid- patients [ , , , , ] . at the level of individual gene regulation, we first noted a surprisingly strong significant upregulation of fos and jun, which code for proteins implicated in the development of cancer ( figure a) . additionally, we noted a strong significant downregulation of the tumor suppressor gene c orf . when comparing ciliated cells between moderate disease and healthy control subjects ( figure s a ), we did not observe differential expression of proto-oncogenic transcripts. we next leveraged gene set enrichment analysis (gsea) to dissect pathway-level regulation. gsea provides positive and negative enrichment readouts; here, we define pathways with positive normalized enrichment score as "enriched" and those with a negative normalized enrichment score as "depleted". gsea revealed the enrichment of pathways involved in the innate immune response, general inflammatory response, and, surprisingly, oncogenic signaling in severe versus moderate donors. specifically, we observed the significant enrichment of the epithelial-tomesenchymal transition, k-ras, pi k/akt and p pathways in addition to the tnf-α signaling via nf-κb and il- /stat pathways. when we increased this analysis to include all of the cell types found in the balf (figure a we next investigated pathway-level changes occurring in pbmcs and found that differential gene expression between ards and non-ards patients supported the detection of statistically enriched pathways through gsea. we first examined cd + blood monocytes, a cell type whose severe disease response could be compared to that of balf mps. in ards patients, cd + monocytes demonstrated pronounced downregulation of isg , tnfaip , and nfkbia compared to non-ards patients, manifesting in the depletion of the ifn-α, ifn-γ, and tnf-α signaling via nf-κb pathways ( figure b ). expression of the immunoglobulin g and m heavy chains appeared to be altered at the transcriptional level but did not contribute to significantly enriched pathways. when expanding this analysis to all pbmc cell types ( figure b ), we observed a striking depletion of ifn-α, ifn-γ, and tnf-α signaling via nf-κb pathways in a conserved trend across nearly every cell type. the il- /stat and il- /jak/stat pathways did not appear to be significantly altered in the majority of cell types. comparing pbmcs of non-ards donors to healthy controls revealed a strong enrichment of the ifn-α, ifn-γ, and tnf-α signaling via nf-κb pathways, as well as some inclusion of the il- /stat and il- /jak/stat pathways ( figure s b ). interestingly, comparing ards donors to healthy controls showed that these same pathways exhibited weaker enrichment ( figure s e ). to establish a comparison between blood monocytes and balf mps and explore the heterogeneity of balf mps observed in our dataset, we analyzed differential expression and pathway-level responses across of the clusters resulting from iterative data integration of the mp population. two clusters containing probable doublets were excluded from the analysis, namely cluster (cd +/cd d+) and to nominate potential transcription factors related to differentially expressed gene sets, we sought to identify transcription factors linked to deg lists using the encode and chea chip-x databases. consistent with the identified activity of the il- /jak/stat pathway, we observed enrichment of stat in many cells of the balf (figure s g ). cebpb and cebpd appeared to be depleted in the pbmc but enriched in the balf, and opposite directionality of these genes was observed between mps and cd + monocytes in particular. nelfe appeared to be enriched in t cells of the balf and pbmc (figure s g-h) , representing a commonality between the lung and blood responses to increasing disease severity. following the identification of severity-specific pathway-level regulation differentiating severe and moderate disease courses, we sought to construct a putative network for how these transcriptional programs could be induced by soluble and surface-level cell-cell interactions. specifically, we aimed to identify ligands acting as potential key regulators of severe disease in many cell types of the lung in order to nominate targets for further study as therapeutic options for severe covid- . figure a shows a flow diagram detailing the steps carried out to nominate severity-specific "pan-ligands" local to the site of viral infection. briefly, differential gene expression between moderate and severe donors was first evaluated for each cell type in the balf. we classified these transcripts as "target genes" whose differential expression is potentially regulated through ligand-receptor interactions [ ] . next, we employed nichenet to identify potential ligands linked to regulation of these differentially expressed target genes [ ] . we applied two filtering criteria to nominate potential ligands: ligands should ( ) act on over one-third of the cell types in the balf and ( ) be differentially expressed by at least one cell type in severe disease. to follow up on our observation of areg upregulation in pdcs during severe disease, we used nichenet to nominate potential soluble or cell-surface mediators of pdc differential gene expression. ligand activities were ranked using a nichenet-generated pearson correlation coefficient indicating the correlation between the target genes of a given ligand and the list of differentially expressed target genes in the "receiver" cell ( figure b ). the receptors for the top predicted ligands anxa , spp , tnf, csf, cxcl , ifng, cd lg, itgb , cd , icam , adm, and il all showed non-zero expression in pdcs. to identify which genes may be regulated by top-ranked ligands, putative ligand-gene interactions were scored by nichenet according to "regulatory potential", a graph-based likelihood for a ligand to regulate a particular target gene [ ] . we next sought to identify candidate "sender cells" expressing these ligands ( figure s a) . we found that mps and neutrophils expressed transcripts for pdc ligands, and we chose to further investigate these relationships. ligand-mediated cell-cell interactions between mps, neutrophils, and pdcs are visualized in the network diagram in figure b . as shown, the differential expression of areg is potentially regulated by il- and spp from mps, and il -β from neutrophils, although the receptors for il- and il -β could not be verified at the transcript level in pdcs in our dataset. additionally, given the enrichment of oncogenic pathways in epithelial cells of the balf, we identified cell types and signaling molecules potentially regulating epithelial degs. we applied the nichenet procedure outlined above for pdcs to club and ciliated cells of the balf, resulting in the ligandgene regulatory matrix shown in figure c . the ligands il b, il a, tnf, ifng, apoe, il rn, osm, edn , lif, mif, csf , spp , cd , ccl , vegfa, and ccl show potential for regulating differential expression, and receptors for all of these ligands were manually verified at the transcript level in club or ciliated cells. interestingly, fos and jun are among the genes potentially driven by the proposed ligands. as mps and neutrophils appear to express the ligands of interest (figure s b) , we investigated the role of these cells in regulating epithelial gene expression, visualized in the network diagram in figure c (at larger scale in figure s e ). as shown, mps may induce both fos and jun through il -α, while neutrophils may induce both fos and jun through il -β, tnf, and ifng, with additional regulation of jun by edn . finally, we aggregated ligand-receptor relationships across all of the cell types in the balf and proposed broadly-acting "pan-ligands" possibly contributing to the induction of transcriptional programs in the lung microenvironment. following the procedure described above ( figure a ) using each cell type in the balf as a receiver, we identified a list of potential pan-ligands and developed a ligand-receiver cell correlation matrix (figure s c ). this matrix was subsequently filtered to preserve ligands acting on over one-third of cell types in the balf (≥ cell types) with > % receptor expression and thresholded pearson correlation values. of these candidates, we selected ligands differentially expressed between severe and moderate disease in one or more balf cell types ( figure s d ) to further filter the ligand-receiver matrix. interestingly, the il transcript was not found to be differentially expressed in any of the balf cell types and failed at this filtering step. after filtering, we arrived at a list of differentially expressed pan-ligands implicated in broad severity-specific responses across cell types in the lung, consisting of ifng, il , ccl , ccl , and spp . these ligands were differentially expressed in at least one balf sender cell type and act on over one-third of the cell types in the balf (figure d ), indicating these ligands should be further investigated to elucidate their role in the life-threatening immunopathology of severe covid- . in the course of a severe sars-cov- viral infection, acute pulmonary damage has been observed concomitantly with elevated cytokine levels in serum and infiltration of macrophages and lymphocytes into multiple organs, indicative of both local and systemic immunological responses [ , ] . to better understand these dynamics, we leveraged scrna-seq data from balf and blood to compare severity-specific shifts in cellular composition at the local and systemic levels. in balf, compositional analysis indicated expansion of nk cells, t cells (general t cell population, cd + naive t cells, and cd + effector treg cells), and pdcs in moderate patients compared to both severe and control patients. although severityspecific compositional changes in balf samples remain largely unaddressed in the literature [ ] , the severity-specific lymphopenia of nk cells and cd + naive t cells that we report in balf agrees with findings from compositional studies of pbmcs [ , , ] . we additionally report severity-specific compositional shifts in lung mp populations and identify clusters expressing mrc , c qa, and fabp suggesting an m macrophage-like phenotype expanded in control subjects. moderate donors showed expanded clusters expressing hladqa and hladqa , indicating increased antigen presentation through hla class ii. expanded clusters in severe donors expressing spp as well as various chemokines including ccl , ccl , and ccl are likely associated with an m macrophage-like phenotype, in agreement with previous analyses [ ] . strong macrophage expression of osteopontin, the gene product of spp , has been previously observed during influenza a infection, suggesting that macrophages in severe covid- may be following a similar viral response to influenza [ ] . compositional changes were not readily apparent in pbmcs when comparing ards patients to non-ards patients, although we observed an expansion of multiple plasma cell types in ards patients compared to healthy control subjects, consistent with previous reports [ , , , ] . despite recent advances, the immunological signatures of severe covid- remain largely uncharacterized in both the lung [ , ] and systemic circulation [ , ] . in particular, a need exists to define markers of severity that can be used to assess patient disease trajectory in a clinical setting for the purposes of triage or to inform the use of immunomodulatory treatment strategies [ ] . here, we leveraged balf and pbmc transcriptional data to nominate cell surface proteins that could be incorporated into a flow cytometry panel for covid- patient immunophenotyping. notably, in balf samples we observed upregulation of areg in pdcs and mdcs of patients undergoing a severe disease course compared to patients who experienced moderate disease. the areg transcript was verified to be expressed by dendritic cells in bulk rna-seq data [ , ] , has been previously shown to orchestrate tissue homeostasis during influenza infection [ , ] , and has been previously labeled in flow cytometry studies [ ] . additionally, timp , vamp , and il r were strongly differentially expressed in balf mps during severe disease and have been previously documented to play a role in the immune response to respiratory viral infections. timp has been shown to promote deleterious immune responses in the lung during murine influenza infection [ ] , vamp is implicated in signaling pathways regulating influenza viral replication in vitro [ , ] , and il r encodes a decoy receptor for il -β that is upregulated during severe influenza [ ] . all of the balf identified surface markers in figure c with the exception of vamp , hla-dra, and ccr were specifically differentially expressed between severe and moderate donors but not between moderate and control donors (figure s b) . investigating cell surface markers in pbmcs, we found that il r on nk cells as well as s pr (cd ) on γδ t cells differentiate ards from non-ards covid- blood samples. il- stimulation through il- r has been shown to promote nk cell survival by inhibiting apoptosis [ , ] . s pr is a particularly interesting marker due to previous literature documenting its role in stimulating highly inflammatory pathways such as jak/stat and mtor/pi k/akt. additionally, suppression of the s pr cognate ligand s p decreased mortality rates during influenza infection in mice [ , , ] . all of the identified pbmc surface markers in figure f were specifically differentially expressed between ards and non-ards donors but not between non-ards and control donors ( figure s e ). our investigation revealed a small number of common surface markers of interest between balf and pbmc samples, namely hladqa and hladqa on mps/cd + monocytes and hladra on mps/cd + monocytes; these hla class ii transcripts are downregulated with increasing severity level in both compartments. similar observations of a severity-specific loss of hla-dr on cd + monocytes and t cells have been previously observed in recent scrna-seq and flow cytometry studies [ , , , , , ] . together, these findings suggest transcripts that should be studied further at the protein level as potential markers of a severe or ards disease course for immunophenotyping patients through balf sampling or a convenient blood draw. cell type-specific immunopathological responses in severe covid- have been investigated at both local and systemic levels in recent studies comparing severe patients to healthy controls [ , , , , , , , , , ] . we sought to build on this knowledge by determining the cell-type specific biological responses that differentiate more finely stratified disease severity levels in the lung and systemic circulation. in myeloid and lymphoid cells of the balf, we observed a concerted enrichment of the tnfα signaling via nf-κb pathway in severe compared to moderate donors, indicating the upregulated expression of factors such as nfkbia and tnfaip in severe disease. we further noted il- and il- signaling pathway enrichment in cell types including mps, mast cells, and neutrophils. il ra expression was observed in mast cells, il r was expressed in mps, mast cells and neutrophils, and neither the il nor il transcripts were well-captured in the dataset. ifn-α (type i) and ifn-γ (type ii) pathway responses showed mixed enrichment and depletion, with type i and ii interferon signaling apparently decreased in a majority of balf t cell subtypes. these data are consistent with previous observations of low expression of ifng and tnf in cytotoxic t lymphocytes of balf derived from severe patients [ ] . mps in the balf demonstrated a nearly homogenous enrichment of the il- , il- , and tnf-α signaling via nf-κb pathways across the diversity of clusters. when we compared disease strata based on ards diagnosis in pbmcs, fewer pathways demonstrate enrichment with increasing disease severity. nevertheless, a striking depletion of the type ii interferon response was observed in nearly every cell type studied, along with a broad depletion of the type i interferon response and tnf-α signaling via nf-κb pathways (including downregulation of tnfaip and nfkbia). this result corroborates a previously reported correlation between suppressed type i and ii interferon responses and disease severity in a study of pbmcs that was not specific to cell type [ ] , as well as extending findings of increased interferon response in monocytes during moderate disease but not severe disease [ , ] . our findings do not preclude the observation of increased tnf-α signaling in the bloodstream of severe and critical covid- patients [ ] , as tnfaip depletion has been shown to cause increased tnf-α expression [ ] . we next examined the similarity of pathway-level changes across the severity stratifications provided in the balf and pbmc datasets. comparing balf and pbmc responses to increasing disease severity level in consanguineous cell types showed shared suppression of the type i interferon response in cd + naive, cd + effector, and γδ t cells and of the type ii interferon response in mature b, proliferating plasma, cd + naive, cd + effector, and γδ t cells. for other cell types including mps/monocytes, nk and cd + effector t cells, the type ii interferon response appears to be increased in cells of the lung but decreased in the blood. moreover, our analysis identifies divergent severity-specific responses in the balf and blood in terms of the tnf-α signaling via nf-κb pathway for nearly all cell types. notably, the concerted tnf-α/nf-κb pathway enrichment across balf cell types is indicative of a strong upregulation of tnfaip and nfkbia. conversely, the depleted pathway across pbmc cell types corresponds to tnfaip and nfkbia downregulation. the a protein encoded by tnfaip is an nf-κb inhibitor that functions as a "brake" on antiviral signaling and inflammatory responses [ , , , ] whose deletion in mouse models improved survival during influenza infection [ ] . tfnaip differential expression was largely co-directional with nfkbia (coding for iκbα), a gene whose upregulation is a key feature of the human blood response to sars-cov as well as the lung response to sars-cov and mers-cov infection [ ] . our results suggest that the a /iκbα axis likely plays a role in sars-cov- infection as well, with tnfaip inhibiting nf-κb-mediated antiviral responses during severe disease at the site of local infection yet promoting a systemic inflammatory response through its absence during ards in the periphery. we note in this compartmental comparison that the balf and pbmc clinical stratifications represent different parts of the disease severity spectrum. therefore, we interpret differences in compartmental responses with respect to relative levels of clinical severity rather than absolute severity stages. taken together, our data suggest that transcriptional programs are differentially induced with increasing covid- severity, while the specific responses are nuanced according to cell type and local versus systemic immune environment. in epithelial cells of the balf, we detected the surprising upregulation of fos and jun, along with the downregulation of c orf in severe compared to moderate donors. due to the involvement of these genes in oncogenic programs, we further investigated pathway-level alterations in epithelial cells and detected the enrichment of epithelial-to-mesenchymal transition, k-ras, pi k/akt and p pathways. we note that a separate analysis of epithelial cells from the same balf dataset failed to detect differential enrichment of these pathways through gsea when comparing control samples to pooled moderate and severe samples [ , ] , likely as a result of this pooling and using a much shorter list of statistically tested genes (a single set of genes common to all epithelial cells compared to sets of , genes for ciliated cells and , genes for club cells). our results may be cautiously interpreted as providing evidence for the molecular underpinnings of the morphological changes known to occur in the severely damaged lung epithelia of severe covid- patients, previously described as cellular proliferation resembling atypical adenomatous hyperplasia, in situ adenocarcinoma, or even invasive adenocarcinoma [ ] . following the observation of pathways enriched in the epithelia of severe covid- patients, we employed ligand-receptor network analysis to nominate potential immune-epithelial communication networks that may explain transcriptional differences between severe and moderate disease courses. we identified ligands implicated in driving the differential expression in ciliated and club cells, of which il b, tnf, and ifng are predicted to regulate fos and jun, with il a additionally regulating jun. exploring the expression of these ligands across the diversity of balf cell types indicates that mps and neutrophils may act as "sender cells" signaling to the epithelium, as suggested in recent reports [ , , ] . in particular, aberrant neutrophil responses have been implicated in severe covid- through a number of studies focusing on either the lung or the blood [ , , , , , ] . on further analysis, we our analysis of the transcriptional regulation of cell surface proteins implicated areg as a potential marker unique to severe disease in pdcs. this finding appears consistent with previous literature showing that amphiregulin aids in the maintenance of epithelial integrity and tissue repair during infection or injury, [ , ] as patients with severe covid- experience extreme pulmonary damage. expanding on this knowledge, we utilized ligand-receptor network analysis to provide orthogonal information suggesting how pdc differentially expressed genes, including areg, may be regulated through soluble or cell-surface mediators. nichenet revealed that mps and neutrophils appear to signal to pdcs through spp /il and il b respectively to regulate the expression of areg as well as various other genes. spp in particular appears to be better-evidenced than il and il b as its active receptors cd and itgb are present on over % of pdcs in severe donors. our network analysis suggests that the expansion of a population of spp -expressing mps during severe disease, observed here and in liao et al. [ ] , may partly account for the upregulation of areg by pdcs. we recommend further study of the potential for areg induction by spp in addition to investigation of areg surface expression as a marker of severe disease. immune blockades, including the il- r antagonist tocilizumab, are a class of treatments currently under clinical use and research for covid- intended to dampen the hyperactive immune response by targeting key nodes in a signaling network [ , , ] . here, we sought to utilize ligand-receptor network analysis to nominate ligands as potential key regulators of severity-specific dysregulation in the lung microenvironment during severe covid- . our analysis suggests ifng, il , ccl , ccl , and spp as candidate "pan-ligands" that may induce transcriptional regulation in over one-third of cell types identified in the balf during severe disease. notably, we did not identify il as a potential pan-ligand as its differential expression between moderate and severe patients in our study was not statistically significant in any cell type. all of the pan-ligands we report have been previously implicated in sarsr-cov infection, with il- , ccl , and ifn-γ having been detected in serum from covid- patients [ , , ] , spp upregulation measured in microarrays from sars-cov-infected nonhuman primates, and ccl , ccl , il , and ifng upregulation detected in single-cell or bulk rna-seq from the lungs of covid- patients [ , , , ] . importantly, our data supports accumulating evidence for a nuanced interferon response in covid- depending on disease severity, cell type, and local versus systemic immune environment, as discussed above [ , , , , , , ] . we suspect that treatment strategies consisting of a direct type ii interferon blockade (nih clinical trial nct ) [ , ] could exert different effects systemically and locally depending on the patient's clinical condition when administered. taken together with previous findings, our data suggests ifng, il , ccl , ccl , and spp as candidate targets for the treatment of severe covid- that warrant further study. in summary, our findings emphasize unique roles for the cells of the lung microenvironment and systemic circulation in the immunopathology of ards and severe covid- . we recommend further investigation of differentially expressed cell surface markers to determine their utility in immunophenotyping patients according to suspected disease course to aid in triage or to inform optimal treatment options. our transcriptional analyses show that pathway enrichment differs between cells of the lung and blood, with concerted immunological responses within each compartment mirroring viral respiratory diseases including influenza, sars, and mers. finally, we nominate a small number of broadly-acting ligands as potential drivers of severity-specific transcriptional regulation in the severely damaged lung microenvironment of covid- patients. all single cell rna-sequencing (scrna-seq) data used in this analysis were obtained from publicly available datasets. balf scrna-seq gene-barcode matrices from covid- patients ( severe and moderate), and healthy control subjects were obtained from the geo under accession number gse . [ ] scrna-seq data from an additional healthy balf donor was obtained from the geo under accession number gsm . [ , ] severity-level stratifications for balf donors (severe/moderate/healthy) were used exactly as provided in the original manuscript. out of severe balf donors were invasively ventilated, with the exception of s . gene-barcode matrices obtained from the geo were preprocessed using seurat (v. . . ) in r (v. . . ). matrices were filtered to preserve cells with a umi count over , , gene count between and , , and expression of less than % mitochondrial rna. for pbmc data, cells were additionally filtered to preserve cells expressing less than % s rna and less than % s rna. gene-barcode matrices unique to each donor were subsequently normalized using the 'normalizedata' function and the , most highly variable genes (features) were identified via the 'findvariablefeatures' function using a variance stabilizing transformation. individual donor datasets were subsequently aligned and integrated using the standard seurat v multi-donor integration workflow, finding pairwise anchors using the 'findintegrationanchors' function acting on dimensions with default parameters (k.filter= ), then applying the 'integratedata' function on dimensions. multi-donor integration and all further analyses were performed separately on balf and pbmc datasets. following integration, "raw" rna expression values were normalized using log-normalization via the 'normalizedata' function and the , most variable features were identified using 'findvariablefeatures'. raw expression levels were left unscaled so that scaling could later be applied as needed (e.g. for generating marker gene heatmaps). in parallel, "integrated" expression values were scaled using the 'scaledata' function, regressing out umi count, number of genes, and percent rrna. pbmc data contained rrna transcripts to regress, whereas balf data did not. dimensionality reduction via principal component analysis (pca) was carried out using the 'runpca' function and the first principal components were retained. this reduction was projected onto the entire dataset prior to clustering. clustering was performed by finding nearest neighbors using the 'findneighbors' function in seurat acting on dimensions, then running the louvain algorithm via the 'findclusters' function with a resolution parameter of . . the resulting clustered datasets for balf and pbmc were separately visualized by uniform manifold approximation and projection (umap) acting on the first principal components. cell type annotation was conducted using the resultant clusters for balf and pbmc data. clusters were annotated according to the average expression levels of canonical marker genes identified in the original papers for the balf and pbmc datasets [ , ] , the broader literature, and the human protein atlas [ ] . clusters deemed identical by similar presence of marker genes were merged during annotation. a list of the marker genes used for cell type annotation is available in supplemental figure s , along with a visualization of expression levels. following cell type annotation for the balf, populations annotated as mononuclear phagocytes (consisting of one merged cluster) and t/nk cells (consisting of clusters annotated as "nk", "proliferating t" and "mixed t" cells) were separately re-integrated to enable clustering at a finer resolution. for mononuclear phagocytes, iterative data integration was performed using the integration procedure described above, with a k.filter parameter of for 'findintegrationanchors' and a resolution parameter of . for 'findclusters'. the resulting fine-scale mononuclear phagocyte clusters were left unannotated during further analysis, but were tested using the balf marker gene panel to identify probable doublets. for t and nk cells, iterative data integration was performed using the integration procedure described above, with a k.filter parameter of and a resolution parameter of . . in order to filter anchors for t/nk re-integration, one healthy control donor (hc , cells) and one severe donor (s , cells) with small numbers of t/nk cells were excluded from the integration and subsequent analysis. t and nk cell fine-level clusters were annotated according to a panel of canonical t and nk cell marker genes, available in supplemental figure s . the original integration of pbmc mutli-donor datasets allowed cell type annotation at a fine level and did not require iterative data integration. compositional changes across disease severity categories were assessed for balf and pbmc datasets separately using: ) donor-specific fractional contributions to each cell type in the total pool of cells recovered from all donors, ) donor-specific percentages of cell types comprising each pool of cells recovered from individual donor severity conditions (severe, moderate, or healthy control for balf, ards, non-ards, or healthy control for pbmcs), and ) percentages of cell types in each donor sample z-scored across donors. here, we did not employ low-powered statistical tests but instead sought to use method to highlight donor-to-donor variation in cell type composition and identify robust trends across donors indicating possible expansion or cytopenia. differential expression analysis was performed in seurat using the 'findmarkers' function utilizing model-based analysis of single-cell transcriptomics (mast) statistical framework through the "mast" r package (v. . ) [ ] . differential expression analysis was conducted for all cell types in the integrated balf dataset across three permutations of donor groups: severe vs. moderate, moderate vs. control, and severe vs. control. for all cell types in the pbmc dataset, differential expression analysis was conducted across three permutations of donor groups: ards vs. non-ards, non-ards vs. control, and ards vs. control significantly differentially expressed genes (degs) are indicated by having a mast adjusted p< . and a natural log fold change threshold of . was applied. the identification of cell surface markers indicative of severe disease was performed by crossreferencing all degs across disease severity levels in the integrated balf and pbmc datasets with entries in the cell surface protein atlas (cspa) [ ] . degs were considered to be differentially expressed surface markers if they were included in the "high confidence" cspa category and showed significant differential expression (adjusted p< . ) with an absolute value average natural log fold change greater than . (or log fold change > ). differentially expressed surface markers were further analyzed to verify low expression in moderate or non-ards and control donor samples. finally, differentially expressed surface markers were verified to be expressed in the cell type indicated by our data by cross referencing with the immune cell atlas human bulk rna-seq data [ , ] . gene set enrichment analysis (gsea) [ ] was performed using the "fgsea" package (v. . . ) [ ] in r. differentially expressed gene lists generated using mast were ranked by -log (p) multiplied by the sign of the average natural log change, as previously demonstrated in debski et al. and riemand et al. [ , ] , using the mast adjusted p-value. average natural log fold change was used to break ranking ties and this value also served as an input to gsea to quantify the correlation between the gene and phenotype, as -log (p) values become arbitrarily large. gsea results were interpreted according to normalized enrichment score (nes) and an adjusted p-value, with a p< . significance threshold. pathways with positive nes were defined throughout the text as "enriched" and pathways with negative nes were defined as "depleted". further analysis of significantly differentially expressed genes was performed using the "enrichr" (v. . ) package in r. gene ontology (go) analysis was conducted on the degs between the severe and moderate samples for both the balf and pbmc, evaluating the go "biological function" annotations representing large scale biological programs. transcription factor (tf) analysis was similarly conducted on the deg list to query the regulation of tfs identified by the encode and chea chip-x databases [ , ] . go and tf results were ranked based on the enrichr 'combined score' metric and significance was determined using an adjusted p-value threshold of p< . . to investigate the intracellular interactions potentially contributing to the observed differential gene expression between the severe and moderate sample populations in the balf, we employed the ligand-receptor interaction tool nichenet via the "nichenetr" package (v. . . ) in r. [ ] differentially expressed target genes between severe and moderate disease in a "receiver" cell population of interest were identified using the 'findmarkers' function in seurat with criteria of p< . , average natural log fold change > . , and expression in over % of the receiver cells. concurrently, a list of potential receptors expressed in over % of cells in the severe disease receiver population was generated using nichnet. a list of "sender" cells was created comprising all cell types in the balf, including the receiver cell type to account for the possibility of autocrine signaling. for each sender cell population, potential ligands were inferred using the nichnet ligand-receptor network applied to genes expressed in over % of the severe disease sender population. ligand activities were predicted using the 'predict_ligand_activities' function in nichenet, and the top ligands were selected by pearson correlation coefficient. differentially expressed target genes ranking among the most strongly predicted targets of the top ligands were given a "regulatory potential" interaction score. the upper % of targets by regulatory potential were visualized for plasmacytoid dendritic cells (pdcs), and the upper % of targets were visualized for epithelial cells (ciliated cells and club cells). to specifically analyze signaling from mononuclear phagocytes and neutrophils, differentially expressed target genes ranking among the most strongly predicted targets of the top ligands were used, with the upper % of these targets according to regulatory potential visualized in circos plots. non-signaling molecules and molecules acting on non-coding rna targets were manually removed. receptors for the top ligands were identified using the cellphonedb web server [ ] , and non-zero expression was verified in the severe disease receiver cell population of interest using seurat. identification of potential broadly acting "pan-ligands" was conducted by replicating the above nichenet procedure iteratively using each cell type of the balf as a receiver. for each receiver cell type, ligands with positive pearson correlation were filtered based on ) either belonging to the list of top ligands or having a pearson correlation greater than . , and ) presence of the corresponding receptor in over % of cells (manually validated using cellphonedb [ ] ). only ligands meeting these criteria for over one-third of cell types in the balf were preserved for further analysis. of these, the ligands differentially expressed in severe disease compared to moderate disease in at least one balf cell type were classified as potential pan-ligands. differential gene expression was analyzed using the "mast" package statistical framework through the 'findmarkers' function in seurat. differential expression statistical significance was qualified using the mast false discovery rate (fdr) adjusted p-value, with a significance threshold of p< . . pathway enrichment was analyzed using the standard gsea method in the "fgsea" package. statistical significance of normalized enrichment scores was qualified using the fgsea fdr adjusted p-value, with a significance threshold of p< . . differential gene expression relevant to ligand-receptor interactions was evaluated using the nichnet pipeline implementing the wilcoxon rank sum test through the 'findmarkers' function in seurat. statistical significance was qualified using the 'findmarkers' bonferroni-adjusted pvalue, with a significance threshold of p< . . go and tf analysis was conducted using the "enrichr" package, and statistical significance was qualified using the enrichr adjusted p-value based on fisher's exact test, with a significance threshold of p< . . ligand's ability to induce the differential gene expression measured in the corresponding "receiver" cell. a new coronavirus associated with human respiratory disease in china the proximal origin of sars-cov- cross-country comparison of case fatality rates of covid- /sars-cov- . osong public health and research perspectives covid- : specific and non-specific clinical manifestations and symptoms: the current state of knowledge characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster pathological findings of covid- associated with acute respiratory distress syndrome planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases cytokine profile in plasma of severe covid- does not differ from ards and sepsis covid- pneumonia: ards or not? an inflammatory cytokine signature helps predict covid- severity and death covid- : consider cytokine storm syndromes and immunosuppression imbalanced host response to sars-cov- drives development of covid- aveolar macrophage activation and cytokine storm in the pathogenesis of severe covid- pulmonary post-mortem findings in a large series of covid- cases from northern italy. the lancet infections disease postmortem examination of patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region characteristics and outcomes of critically ill patients with covid- in washington state transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in covid- patients comprehensive transcriptomic analysis of covid- blood, lung, and airway tocilizumab treatment in severe covid- patients attenuates the inflammatory storm incited by monocyte centric immune interactions revealed by single-cell analysis blood single cell immune profiling reveals the interferon-mapk pathway mediated adaptive immune response for covid- single-cell analysis reveals macrophage-driven t cell dysfunction in severe covid- patients ellebedy ah ( ) targeted immunosuppression distinguishes covid- from influenza in moderate and severe disease single-cell landscape of bronchoalveolar immune cells in patients with covid- cross-talk between the airway epithelium and activated immune cells defines severity in covid- in-depth phenotyping of human peripheral blood mononuclear cells in convalescent covid- patients following a moderate versus severe disease course complex immune dysregulation in covid- patients with severe respiratory failure a single-cell atlas of the peripheral immune response to severe covid- terrier b ( ) impaired type i interferon activity and exacerbated inflammatory responses in severe covid- patients immunologic perturbations in severe covid- /sars-cov- infection emergence of low-density inflammatory neutrophils correlates with hypercoagulable state and disease severity in covid- patients nichenet: modeling intercellular communication by linking ligands to target genes a mass spectrometric-derived cell surface protein atlas immune cell atlas single-cell rna-seq reveals new types of human blood dendritic cells, monocytes, and progenitors h n avian influenza infection altered expression pattern of sphiogosine- -phosphate receptor in balb/c mice the alliance of sphingosine- -phosphate and its receptors in immunity osteopontin modulates the generation of memory cd + t cells during influenza virus infection deep immune profiling of covid- patients reveals patient heterogeneity and distinct immunotypes with implications for therapeutic interventions emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair new fronts emerge in the influenza cytokine storm il- promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-egfr interactions timp- promotes the immune response in influenza-induced acute lung injury integrative gene network analysis identifies key signatures, intrinsic networks and host factors for influenza virus a infections patient-based transcriptome-wide analysis identify interferon and ubiquination pathways as potential predictors of influenza a disease severity interleukin- expression and its effect on natural killer cells in patients with multiple sclerosis endothelial cells are central orchestrators of cytokine amplification during influenza virus infection sars-cov- activates lung epithelia cell proinflammatory signaling and leads to immune dysregulation in covid- patients by single-cell sequencing immune cell profiling of covid- patients in the recovery stage by singlecell sequencing longitudinal peripheral blood transcriptional analysis of covid- patients captures disease progression and reveals potential biomarkers the tumor necrosis factor alpha-induced protein (tnfaip , a ) imposes a brake on antitumor activity of cd t cells a /tumor necrosis factor α-induced protein in immune cells controls development of autoinflammation and autoimmunity: lessons from mouse models. front immunol a and cell death-driven inflammation a deficiency in lung epithelial cells protects against influenza a virus infection network-based analysis of comorbidities risk during an infection: sars and hiv case studies neutrophils in cystic fibrosis display a distinct gene expression pattern the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease should we stimulate or suppress immune responses in covid- ? cytokine and anti-cytokine interventions proliferating spp /mertk-expressing macrophages in idiopathic pulmonary fibrosis mast: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell rna sequencing data gene set enrichment analysis: a knowledge-based approach for interpreting genomewide expression profiles fast gene set enrichment analysis etiology matters -genomic dna methylation patterns in three rat models of pathway enrichment analysis and visualization of omics data using g:profiler, gsea, cytoscape and enrichmentmap an integrated encyclopedia of dna elements in the human genome chea: transcription factor regulation inferred from integrating genome-wide chip-x experiments cellphonedb: inferring cell-cell communication from combined expression of multi-subunit ligand-receptor complexes all data used in the study are available in the geo under accession numbers gse , gsm , and gse . all code used for analysis will be made available in a public repository. the authors have no conflict of interest to declare. key: cord- -ksoonwf authors: liu, shan; peng, danyi; qiu, huijun; yang, ke; fu, zhou; zou, lin title: mesenchymal stem cells as a potential therapy for covid- date: - - journal: stem cell res ther doi: . /s - - - sha: doc_id: cord_uid: ksoonwf the outbreak of novel coronavirus disease (covid- ) worldwide is becoming rapidly a major concern. the number of severe cases has increased dramatically worldwide, while specific treatment options are scarce. the main pathologic features of severe or critical covid- were consistent with acute lung injure (ali)/acute respiratory distress syndrome (ards), characterized by cellular fibromyxoid exudates, extensive pulmonary inflammation, pulmonary edema, and hyaline membrane formation. mesenchymal stem cells (mscs) can balance the inflammatory response and has been mentioned to be effective on ali/ards from both infectious and noninfectious causes previously, presenting an important opportunity to be applied to covid- . in this commentary, we summarize the clinical trials of mscs treatments on ali/ards and raise mscs as a hopefully alternative therapy for severe or critical covid- . severe acute respiratory syndrome coronavirus (sars-cov- ) disease (covid- ) is a newly-recognized infectious disease. it has rapidly transmitted and become a major concern all over the world. as of april , , the total number of patients has risen sharply to , , worldwide, with , ( . %) deaths [ ] . apart from supportive care, oxygen supply in mild cases, and extracorporeal membrane oxygenation and low-dose corticosteroids in critical cases, intravenous remdesivir and convalescent plasma might be the effective potential therapy for sars-cov- infection. however, randomized clinical trials are needed to further evaluate the safety and efficacy of them in covid- treatment. the specific and novel therapeutic methods for this disease are still being explored. the main pathologic features of severe or critical covid- contain hypoxemia, diffuse alveolar damage with cellular fibromyxoid exudates, extensive pulmonary inflammation, pulmonary edema, and hyaline membrane formation. the pathologic changes are similar with acute lung injure (ali)/acute respiratory distress syndrome (ards) [ ] , also observed in sars and middle eastern respiratory syndrome (mers) coronavirus infection. however, more serious inflammatory exudation, pulmonary edema and inflammatory cytokine storm, and milder pulmonary fibrosis and consolidation were observed in severe or critical covid- than those in sars. mesenchymal stem cells (mscs), which originate from bone marrow, fat, umbilical cord, placenta, and other tissues, have abundant supply, differentiation potential, powerful immunoregulation, and endogenous repair mechanisms. as one of the most widely studied adult stem cells in regenerative medicine, mscs produce meaningful therapeutic outcomes for the treatment of pulmonary, cardiovascular, neurological, liver, and kidney diseases. the immune-regulation of mscs depends mainly on modulating activation and effector function of immune cells, suppressing lung-infiltrated cells, and enhancing the resolution of pulmonary edema [ ] . the incomplete revealed mechanisms but critical roles of mscs on anti-inflammatory effects imply that mscs is a potential therapy for severe and critical covid- . mscs have been identified to efficiently cure ali/ ards from both infectious and noninfectious causes, mediated primarily by paracrine mechanisms based on the released extracellular vesicles (evs), such as microvesicles and exosomes [ ] . in the cargo of the evs, more than unique gene products and more than mir-nas have been identified by mass spectrometry analysis. either the mirnas or the transcripts are enriched in the regulators of the immune system [ , ] . detailed, mscs can alter the behavior of both adaptive and innate immune cells. they can release keratinocyte growth factor, prostaglandin e , granulocyte-macrophage colony-stimulating factor, and il- and il- to facilitate the phagocytosis and alternative activation of alveolar macrophage, alter the cytokine secretion profile of dendritic cell subsets, and decrease the release of interferon γ from natural killer cells. il- , transforming growth factor β, and tryptophan catabolizing enzyme indoleamine , -dioxygenase secreted from them can also suppress the proliferation of t cells and change the cytokine secretion profile of t cell subsets [ ] . moreover, the proliferation, differentiation, and chemotactic properties of b cells were impaired by mscs as well [ ] . except for the immune regulatory effects, mscs can enhance restoration of capillary barrier [ ] , inhibit bacterial growth [ ] , and restore alveolar atp [ ] . all the functions mentioned above might also be effective on ards induced by covid- infection. some clinical trials for evaluating the efficacy and safety of msc treatment on ali/ards have begun. the inclusion criteria are according to the berlin definition of ards [ ] in common, while the start trial [ ] had a more strict definition of moderate-to-severe ards with categories: ( ) positive pressure ventilation by an endotracheal or tracheal tube with a pao /fio ratio of < with at least cm h o positive end-expiratory airway pressure, ( ) bilateral infiltrates consistent with pulmonary edema on the frontal chest radiograph, ( ) without clinical evidence of left atrial hypertension or a pulmonary arterial occlusion pressure ≤ mmhg, and ( ) categories - must be present within a -h time period and at the time of enrolment. exclusion criteria included patients younger than years, pre-existing severe disease of any major organs, pregnancy, malignant disease, severe chronic respiratory disease, recent deep vein thrombosis or pulmonary embolism, human immunodeficiency virus infection, or if informed consent could not be obtained. in addition, the patients in whom more than h since first meeting the berlin definition for ards had also been excluded in the start trial to avoid enrolling patients with late ards. the completed clinical trials demonstrate that mscs are well tolerated without adverse effects in ali/ards (table ) [ , ] . additionally, acute graft-versus-host-disease (gvhd) is a lifethreatening complication of allogeneic hematopoietic stem cell transplantation due to its inflammatory storm. a meta-analysis revealed that infused mscs could reduce acute gvhd grade and increase overall survival [ ] . the therapeutic effects of mscs on ali/ards and gvhd with powerful inflammatory balance are solid proofs for the application of mscs on other originated ali/ards. furthermore, msc treatment significantly ameliorates ali/ards induced by h n avian influenza virus [ ] and h n [ ] in mice, and even influenza virus in pig [ ] , indicating the possible efficacy of mscs on viral ali/ards. importantly, mscs can cure the patients with severe refractory ards [ ] , who failed to improve after both standard life support measures including mechanical ventilation and additional measures including extracorporeal ventilation, pointing that msc could be used for serious viral ali/ards. some chinese research groups triggered the clinical studies on mscs treating critical covid- (table ). in the trigged clinical trials, the inclusion criteria for severe or critical covid- include respiratory rate (rr) ≥ times/min, pulse oxygen saturation (spo ) at rest ≤ %, partial pressure of pao /fio ≤ mmhg, requirement for mechanical ventilation, shock, etc. as of february , , four patients with severe covid- were recovered and discharged by mscs therapy in china [ ] . therefore, we believe that mscs would be a new effective therapeutic method for severe or critical covid- . according to world health organization [ ] , the management of covid- has mainly focused on infection prevention, case detection and monitoring, and supportive care. however, no specific anti-sars-cov- treatment is recommended because of the absence of evidence. most importantly, the current guidelines emphasize that systematic corticosteroids should not be given routinely for covid- treatment, which was also the recommendation in a comment in the lancet [ ] . evidence shows that mscs can be used as a treatment without the occurrence of severe adverse events. in conclusion, it might be noteworthy to test the safety and efficacy of msc transfusion in covid- patients, especially for the severe or critical cases. availability of data and materials please contact us for the detailed data. ethics approval and consent to participate not applicable. not applicable. the dynamic data for covid- epidemic worldwide incidence and outcomes of acute lung injury mesenchymal stem cell-based therapy of inflammatory lung diseases: current understanding and future perspectives clinical application of mesenchymal stem cell-derived extracellular vesicle-based therapeutics for inflammatory lung diseases mesenchymal stem cell secretes microparticles enriched in pre-micrornas proteolytic potential of the msc exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome human mesenchymal stem cells modulate allogeneic immune cell responses human mesenchymal stem cells modulate b-cell functions conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide ll- mitochondrial transfer from bone-marrowderived stromal cells to pulmonary alveoli protects against acute lung injury acute respiratory distress syndrome: the berlin definition mesenchymal stem (stromal) cells for treatment of ards: a phase clinical trial allogeneic human mesenchymal stem cells for treatment of e. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung fifty years of research in ards. cell-based therapy for acute respiratory distress syndrome. biology and potential therapeutic value mesenchymal stromal cells for the prophylaxis and treatment of graft-versus-host disease-a meta-analysis mesenchymal stromal cell treatment prevents h n avian influenza virus-induced acute lung injury in mice human mesenchymal stromal cells reduce influenza a h n -associated acute lung injury in vitro and in vivo mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model in vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome news conference for joint prevention and control measure of covid- by china's state council clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected clinical evidence does not support corticosteroid treatment for -ncov lung injury publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we apologize to the authors whose work has not been cited here owing to space limitations.authors' contributions sl and dp contributed to the study design, data analysis and interpretation, and writing of the manuscript. hq collected the data mentioned in the article. ky revised the manuscript. zf and lz contributed to the study design, financial support, data analysis and interpretation, and writing, editing and revising and final approval of the manuscript. the author(s) read and approved the final manuscript. key: cord- - ls tkr authors: nelson, brian c; laracy, justin; shoucri, sherif; dietz, donald; zucker, jason; patel, nina; sobieszczyk, magdalena e; kubin, christine j; gomez-simmonds, angela title: clinical outcomes associated with methylprednisolone in mechanically ventilated patients with covid- date: - - journal: clin infect dis doi: . /cid/ciaa sha: doc_id: cord_uid: ls tkr background: the efficacy and safety of methylprednisolone in mechanically ventilated patients with acute respiratory distress syndrome due to coronavirus disease (covid- ) are unclear. in this study, we evaluated the association between use of methylprednisolone and key clinical outcomes. methods: clinical outcomes associated with the use of methylprednisolone were assessed in an unmatched, case-control study; a subset of patients also underwent propensity-score matching. patients were admitted between march and april , . the primary outcome was ventilator-free days by days after admission. secondary outcomes included extubation, mortality, discharge, positive cultures, and hyperglycemia. results: a total of patients met inclusion criteria. propensity matching yielded a cohort of well-matched pairs. groups were similar except for hydroxychloroquine and azithromycin use, which were more common in patients who did not receive methylprednisolone. mean ventilator free-days were significantly higher in patients treated with methylprednisolone ( . ± . versus . ± . ; p = . ). the probability of extubation was also increased in patients receiving methylprednisolone ( % versus %; p = . ), and there were no significant differences in mortality ( % versus %; p = . ). in a multivariable linear regression analysis, only methylprednisolone use was associated with higher number of ventilator-free days (p = . ). the incidence of positive cultures and hyperglycemia were similar between groups. conclusions: methylprednisolone was associated with increased ventilator-free days and higher probability of extubation in a propensity-score matched cohort. randomized, controlled studies are needed to further define methylprednisolone use in patients with covid- . in december , the outbreak of a novel respiratory virus named severe acute respiratory syndrome coronavirus (sars-cov- ) in wuhan, china marked the beginning of a global pandemic that has since led to over four million cases and , deaths worldwide [ ] . the clinical manifestations of coronavirus disease are varied and range from asymptomatic disease to acute respiratory distress syndrome (ards) with septic shock and multiorgan failure [ , ] . the reported mortality among critically-ill patients with covid- has varied significantly. an early study reported . % mortality among critically-ill patients [ ] , while a more recent study reported an overall mortality of . % in a critically-ill cohort [ ] . emerging data and analogy to other coronaviruses indicate that a dysregulated immune response to sars-cov- infection results in a cytokine storm-like syndrome that precipitates the severe clinical manifestations in covid- [ ] . corticosteroids inhibit expression of the cytokines involved in the inflammatory response [ ] and may improve outcomes in patients with severe ards [ , ] . consequently, there is considerable interest in using corticosteroids to treat severe covid- . more data are needed to further define the role of corticosteroids in emerging coronavirus infections. prior studies on the use of corticosteroids in severe acute respiratory syndrome coronavirus (sars) and middle eastern respiratory syndrome coronavirus (mers) were inconclusive. these studies failed to show improved mortality, and one study showed delayed viral clearance [ , ] . early reports out of wuhan, china describing the effect of corticosteroids in covid- have demonstrated variable results [ , ] . the recently published recovery trial demonstrated improved mortality in patients that received dexamethasone; however, it did not examine other corticosteroids and included all hospitalized patients, including patients who were not critically ill [ ] . we sought to further evaluate the effect of corticosteroids in cases of severe covid- and to assess adverse effects, such as hyperglycemia and secondary infections. in this retrospective, observational, case-control study, we investigated the effect of methylprednisolone on critically-ill, mechanically ventilated patients with a c c e p t e d m a n u s c r i p t study design. this study retrospectively evaluated consecutive adult patients with covid- pneumonia requiring intubation and mechanical ventilation. all patients were admitted to a quaternary care medical center in new york city, comprised of a large academic hospital and a smaller community hospital, between march , and april , . the study was approved by the columbia university irving medical center institutional review board with a waiver for informed consent. patients were eligible for inclusion if they tested positive for sars-cov- by reverse transcriptase polymerase chain reaction (rt-pcr) of nasopharyngeal and/or oropharyngeal swab specimen within hours after admission and subsequently required mechanical ventilation. patients were excluded if they died less than five days after hospital admission, if they weighed more than kg, or if they received steroids other than methylprednisolone for greater than hours. patients more than kg were excluded to account for our weight-based dosing protocol that recommended a maximum dose of mg. those who died prior to hospital day five were excluded because most patients in the study period were not evaluated for steroid treatment until at least four days into their hospital course. those included in the methylprednisolone group received greater than hours of methylprednisolone initiated within the first days after admission. our hospital dosing protocol for methylprednisolone was one mg/kg/day with a max dose of mg per day, with recommended duration of five days, although the course could be extended at the discretion of the treating physician. our protocol also recommended that steroids only be started in patients at least five to seven days after symptom onset and only in those with evidence of systemic inflammation. early in the pandemic, our hospital guidelines permitted the use of hydroxychloroquine and azithromycin for patients with vital sign abnormalities or risk factors for disease progression. this recommendation was later removed after publication of new findings showing minimal benefit with these agents [ ] . the primary outcome evaluated was ventilator-free days at hospital day . ventilator-free days were defined as days after extubation, with days prior to intubation not included. patients who died within days were assigned zero for this outcome, as were those who were not extubated during the follow-up period [ ] . secondary outcomes included extubation, death, and hospital discharge at both and days after admission. extubation was defined as either removal of the endotracheal tube or discontinuation of mechanical ventilation without relapse in patients who had undergone tracheostomy. safety outcomes were also assessed, including hyperglycemia and all positive clinical cultures (except for coagulase-negative staphylococcus isolated from a single blood culture). hyperglycemia was defined as days with a blood glucose ≥ mg/dl during the first days, chosen to reflect the time period during which most patients received steroids. positive cultures from any source during the first days served as a proxy for secondary infections, given the difficulty of discerning between colonization and infection in this patient population. data points collected at the time of admission included patient demographics, chronic comorbidities summarized using the charlson comorbidity index (cci) [ ] , laboratory values, and the reported date of symptom onset. the sequential organ failure assessment (sofa) score [ ] was calculated on the day of intubation. days from admission to intubation were also documented. the use of additional agents with antiviral and immunomodulatory effects targeting sars-cov- was also noted. pao /fio (pf) ratios, highsensitivity c-reactive protein (crp) values, and use of vasopressors were recorded during the first hours after admission. statistics. patients who received methylprednisolone were analyzed as cases, and those who did not served as controls. we performed unmatched, case-control analysis of all patients meeting criteria for inclusion. we then used propensity scoring to create well-matched groups by using : nearest-neighbor matching without replacement. covariates included in the propensity score matched analysis were the following: body mass index ≥ kg/m , age ≥ years, gender, admission crp ≥ mg/l, admission d-dimer ≥ one mcg/ml, pf ratio < at hospital day two, sofa score on the day of intubation, cci score, and days from symptom onset to admission. dichotomous cutoffs were chosen in order match specific populations (i.e. elderly or obese a c c e p t e d m a n u s c r i p t patients) or because our system reported laboratory values with a specified upper limit that precluded continuous analysis. patients who did not have a match within . propensity score standard deviations were excluded from the analysis. categorical variables were compared using the chi-square test or fisher's exact test as appropriate. continuous variables were compared using the mann-whitney u test. variables with p values < . in univariable analysis were considered for inclusion into a multivariable linear regression model identifying factors associated with ventilator-free days. methylprednisolone use was also included a priori. statistical analyses were performed using ibm spss statistics, version (spss inc., chicago, ill., usa). patient characteristics. patients with covid- who required mechanically ventilation were identified during the study period. of these, were excluded from the analysis: died within five days of admission; seven received other steroids; four received methylprednisolone starting more than days after admission; and one weighed > kg. a total of patients were included in the overall analysis. other key variables such as age, bmi, gender, cci, sofa score, and days from symptom onset to admission were similar between groups (table ) . clinical outcomes. within the matched cohorts, the primary outcome of ventilator-free days was significantly higher in the steroid group (mean ± standard deviation, . ± . versus . ± . ; p = . ) ( table ). the probability of extubation by day was significantly higher in patients who received steroids ( % versus %; p = . ), and there was a statistically non-significant trend toward reduced mortality ( % versus %; p = . ). mortality was still numerically lower at the end of the -day follow-up period but the difference remained non-significant. there were also no significant differences in hospital discharge between those who received steroids and those who did not at day ( % versus %; p = . ) or day ( % versus %; p = . ). regarding safety outcomes, the proportion of patients with positive cultures was similar between steroid and control patients at hospital day ( % versus %; p = . ). days with blood glucose values ≥ mmol/l over the first days were also similar ( [iqr, - ] versus [ , ] ; p = . ). in a multivariable, linear regression model including matched pairs (table ) , the use of methylprednisolone was found to be independently associated with a higher number of ventilator-free days (p = . ) after controlling for lactate dehydrogenase (ldh). the use of hydroxychloroquine, azithromycin, or tocilizumab was not significantly associated with the primary outcome. after controlling for age, sofa score, white blood cell count (wbc), ldh, and d-dimer, the use of methylprednisolone (p = . ) was independently associated with improved outcome within the overall cohort, while treatment with hydroxychloroquine, azithromycin, or tocilizumab was not. a c c e p t e d m a n u s c r i p t our study evaluated the association of methylprednisolone treatment with duration of mechanical ventilation and mortality in intubated, critically-ill patients with covid- . all patients had bilateral infiltrates and hypoxemic respiratory failure consistent with ards. we observed an increase in the number of ventilator-free days and the likelihood of extubation, as well as a statistically non-significant trend towards improved mortality, in the corticosteroid group when compared to control patients in a propensity-matched cohort by day . numerically fewer patients died by day but the difference was not statistically significant. few patients were discharged by day , but there was a trend toward earlier discharge by hospital day in those who received methylprednisolone. conflicting results on the benefit and safety of corticosteroids in other viral pneumonias led to early recommendations by the who against routine use in the management of covid- [ ] . a systematic review found that corticosteroids used to treat influenza were associated with increased mortality [ ] . in a study of patients with mers-cov, there was no effect of corticosteroids on mortality, and there was a delay in viral clearance [ ] . a systematic review of the literature on corticosteroid use in sars-cov yielded inconclusive results, with some studies trending towards harm [ ] . steroid dosing regimens have varied significantly among studies. for example, in one study sars-cov patients, doses as high as mg of methylprednisolone per day were used [ ] , while in another study of patients with ards receiving less potent corticosteroid doses, treatment duration was as long as days [ ] . several other studies have shown no mortality benefit associated with corticosteroids in patients with ards, and one larger study found an increase in mortality when methylprednisolone was initiated more than two weeks after the onset of ards [ , ] . corticosteroids and other immunomodulators have also been studied as a potential treatment for ards. prior studies have shown that infection with sars-cov and mers-cov can result in a cytokine release syndrome leading to massive inflammatory cell infiltration, acute lung injury, and ards [ ], and a similar process has been theorized as the cause of ards in covid- [ ] . recent studies have shown improved outcomes in patients with ards who received corticosteroids [ , ] . in one multicenter, randomized, controlled trial, a c c e p t e d m a n u s c r i p t mechanically ventilated patients with ards who received dexamethasone had a significant increase in the number of ventilator-free days and a significant reduction in mortality compared to the control group [ ] . in a small, observational study among patients with ards from severe covid- , treatment with methylprednisolone reduced mortality from . % to . % [ ], although these results should be interpreted with caution given the limited quality of the trial design. most recently, the recovery trial found that patients with covid- who received dexamethasone six mg daily for days experienced a mortality benefit. although this benefit was greatest in the subset of patients that required mechanical ventilation, the trial only evaluated outcomes through hospital day and did not assess other corticosteroids, such as methylprednisolone [ ] . the earlier time to recovery seen in our study suggests that corticosteroids may have a favorable effect on the hyperinflammatory state in patients with covid- . we observed a significant increase in both ventilator-free days and in the likelihood of extubation by day . there was also a numerical increase in earlier discharge by day , but this difference was not statistically significant. additional studies examining the pathophysiology of ards in covid- are needed to determine the interplay between the immune response and disease progression and how this is affected by different management strategies. concerns have been raised regarding the incidence of hyperglycemia in patients who are treated with corticosteroids [ , ] . our study did not detect a difference in days with blood glucose values ≥ mmol/l by day . an additional concern is the potential for secondary infections. this finding was noted in a review of patients with influenza pneumonia who were treated with corticosteroids [ ] , although another study found that corticosteroids did not increase the type or incidence of infectious complications among patients with ards admitting to intensive care [ ] . our study did not detect a difference in incidence of positive cultures at day in patients who received methylprednisolone compared to those who did not. a c c e p t e d m a n u s c r i p t the optimal dose and duration of methylprednisolone treatment in patients with viral pneumonia and ards remains unknown. our hospital protocol for use of methylprednisolone in treatment of covid- was one mg/kg/day with a maximum daily dose of mg, with median duration of four to six days. the corticosteroid regimen used in our study was similar to regimens used in prior studies that found improved clinical outcomes in patient with ards [ , ] . the recovery trial used a dexamethasone dose that was approximately half the equivalent methylprednisolone dose used in our patients with a duration of days compared to the four to six days use in this study there are several limitations to our study. first, our study only included patients with covid- requiring mechanical ventilation, which limits the generalizability to less critically-ill patients. however, several recent studies have highlighted the benefits of early corticosteroids in patients with moderate covid- [ , , ] . our study was conducted at a single hospital center with limited sample size, and efforts at propensity matching to reduce selection bias may not have accounted for all the variables determining which patients received corticosteroids. rapidly changing practice patterns at our hospital throughout the course of the pandemic may also have influenced our results. during the second month of the pandemic, there was a higher threshold for intubation. however, in our study the timing of intubation was similar between groups, reflecting the overall early enrollment of these patients. similarly, the threshold to admit patients was also raised later in the outbreak, which may have resulted in prolonged time to admission, although no differences were noted between groups in our study. our hospital guidelines regarding management of covid- were updated several times during the period of our study, as reflected in the differences seen in the use of hydroxychloroquine and azithromycin. these treatments had no significant associations the primary outcomes in multivariable analysis. finally, there were also changes to the prevention and management of venous thromboembolism during the study period. however, none of those changes were routine or protocolled at the time. our ability to distinguish true infection from colonization or contamination was limited by chart review and by diagnostic limitations in the setting of the pandemic. thus, we defined any positive culture as a possible proxy for infection (except for coagulase-negative staphylococcus isolated from a single blood culture). although we observed a trend towards improved mortality both at day and day in patients treated with methylprednisolone, our study may have been underpowered to detect a significant difference in a c c e p t e d m a n u s c r i p t mortality between the two groups. given the limitations of our study design, a randomized-controlled trial is needed to better able to evaluate survival benefits associated with methylprednisolone. in conclusion, our study adds to a growing body of literature regarding the use of corticosteroids for treatment of covid- . we found that treatment with methylprednisolone increased the number of ventilator-free days and probability of extubation compared with a propensity matched control group among patients with severe covid- requiring mechanical ventilation, but we did not detect a significant difference in mortality. a randomized-controlled trial is necessary to further define the role of methylprednisolone in this emerging disease. a c c e p t e d m a n u s c r i p t coronavirus disease . who . available at asymptomatic cases in a family cluster with sars-cov- infection presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study icu and ventilator mortality among critically ill adults with covid- understanding sars-cov- -mediated inflammatory responses: from mechanisms to potential therapeutic tools corticosteroids in severe pneumonia effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial systematic review of treatment effects corticosteroid therapy for critically ill patients with middle east respiratory syndrome early, low-dose and short-term application of corticosteroid treatment in patients with severe covid- pneumonia: single-center experience from wuhan dexamethasone in hospitalized patients with covid- -premliminary report outcomes of hydroxychloroquine usage in united states veterans hospitalized with covid- reappraisal of ventilator-free days in critical care research a new method of classifying prognostic comorbidity in longitudinal studies: development and validation the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine clinical management of severe acute respiratory infection when covid- is suspected corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome effect of hypercortisone on development of shock among patients with severe sepsis hydrocortisone therapy for patients with septic shock early short course corticosteroids in hospitalized patients with covid- effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with covid- a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -fzm f authors: nasir, n.; mahmood, s. f.; habib, k.; khanum, i.; jamil, b. title: treatment of ards and hyperinflammation in covid- with il- antagonist tocilizumab: a tertiary care experience from pakistan date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: fzm f cytokine release syndrome in covid- is characterized by hyperinflammation which manifests as ards, multi-organ failure, and high inflammatory parameters. tocilizumab, an il- antagonist has been used in covid- acute respiratory distress syndrome (ards) with conflicting results from different parts of the world. we conducted a retrospective descriptive study from feb to may on covid- patients with ards and hyperinflammation characterized by raised crp and/or ferritin. a total of patients with covid- were admitted out of which had ards. thirty patients had both ards and hyperinflammation and received tocilizumab. the mean age was . years (sd: . ) and the majority were male ( %). the mean crp pre-treatment was . mg/l and post to hours of tocilizumab treatment was . mg/l. twenty-one patients ( %) also received concomitant intravenous methylprednisolone. of the patients, died and recovered. ten patients required intensive care unit admission and nine developed nosocomial infections. covid- associated aspergillosis was diagnosed in three patients post tocilizumab treatment. mortality was significantly higher in patients who developed a nosocomial infection and who required intermittent positive pressure ventilation (ippv). our study is the first to describe the treatment outcomes with tocilizumab from a low-middle income country. the availability and cost of tocilizumab in our region which makes it imperative to understand its potential for use in our setting. our study supports the use of tocilizumab in a select patient population with covid- and recommends monitoring of nosocomial infections and opportunistic infections. covid- was announced as a pandemic by the world health organization in march and since then it has infected , , people globally and resulted in , deaths as of date . the life-threatening manifestation of covid- is acute respiratory distress syndrome (ards) and is associated with significant morbidity and mortality . the underlying pathogenesis of ards involves a dysregulated immune response leading to a cytokine release syndrome (crs), referring to an excessive and uncontrolled release of pro-inflammatory cytokines. crs in covid- is characterized by hyperinflammation which manifests as ards, multi-organ failure, and high inflammatory parameters . key in the development of the crs is an exaggerated release of the proinflammatory cytokine interleukin- (il- ) and elevated il- levels correlate with ards . marked elevation of c-reactive protein (crp) (whose expression is propelled by il- ) also serves as a biomarker to assess the severity of clinical crs and studies have used crp and ferritin as surrogate markers of hyperinflammation , . given the pivotal role of il- ; it has been postulated that targeting il- with available il- inhibitors like tocilizumab may lead to clinical suppression of the crs . data from clinical studies have been conflicting with regards to the efficacy of tocilizumab in covid- ards. while limited studies from china have shown improved outcomes in covid- patients with hyperinflammation and ards , a study from italy did not show significant mortality benefit . while randomized controlled trials are awaited, there is an urgency to explore therapeutic options that can help to avert icu admissions, especially given the limited capacity in resourceconstrained settings. hence, we would like to report our clinical experience of the management of ards and hyperinflammation with the il- inhibitor tocilizumab which will be the first from a lower-middle-income country (lmic). we conducted a retrospective descriptive study on covid- patients with ards and hyperinflammation admitted to the aga khan university hospital (akuh); a -bedded tertiary care hospital. cytokine storm or hyperinflammation was defined as either a serum crp ≥ all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . mg/l or a ferritin ≥ ng/mlor both . ards was defined as per who definition as having "onset within week of a known clinical insult or new or worsening respiratory symptoms, chest imaging (radiograph, ct scan, or lung ultrasound) with bilateral opacities, not fully explained by volume overload, lobar or lung collapse, or nodules and respiratory failure not fully explained by cardiac and pao /fio < mmhg" . patients were excluded if they had transaminitis (alt of greater than times upper normal limit) and/or ongoing bacterial infection or tuberculosis. demographics and clinical data from the hospital medical records were collected using a structured proforma. the outcomes assessed included in-hospital mortality, length of stay, and development of nosocomial infection during hospitalization. the study was submitted for ethical approval to the akuh ethical review committee and received exemption (erc reference number: - - ). the data was anonymized, and no personal identifiers were recorded. categorical variables such as gender, development of nosocomial infection were described as proportions, and continuous variables like age and length of hospital stay were described using mean, median, and interquartile range (iqr) values. proportions for categorical variables as mentioned above were compared using the χ test or fisher exact test where appropriate. statistical analysis was performed using stata ver . a p-value of less than . was considered statistically significant. a total of patients of covid- were admitted from feb th to may th , out of which met who criteria for ards. of these, patients with ards who also met the criteria for hyperinflammation and qualified to receive tocilizumab. the clinical characteristics and outcomes of these patients are summarized in table . the mean age was . years (sd: . ) and the majority were male ( %). none of the patients had a rheumatological illness. the median dose of tocilizumab was mg (range: - mg). no adverse effects were observed during or post-infusion. twenty-one patients ( %) also received concomitant systemic steroids (intravenous methylprednisolone). of the patients, died and recovered while information was missing on patients who left against medical advice. the all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . in a recent debriefing, who has raised alarm over the numbers of cases that are exponentially increasing in the lower-middle-income countries (lmics). it is a major cause of concern particularly since the capacities of developed countries have been overwhelmed. since the development of a vaccine is unlikely in the near future, the focus has been on treatment and compassionate use of certain medications. tocilizumab is a monoclonal antibody targeting the receptor of il- ; a pro-inflammatory cytokine involved in the pathogenesis of ards seen with covid- . data is urgently needed from developing countries as a "one-size fits all" strategy cannot be used in resource-constrained regions where healthcare capacities are already overstretched . moreover, whether tocilizumab is a cost-effective option in developing countries also requires exploration because of the differences in case fatality rates from the different parts of the world suggesting that same approaches may not be regionally relevant. we conducted an observational study describing patient outcomes in those critically ill patients of covid- who received tocilizumab intravenously for hyperinflammation and ards. most of the data regarding its off-label use in covid- has been from studies conducted in china and parts of europe ( table ). the age and gender distribution of our patient population were similar to those reported in studies from china and italy , . the mortality data has been conflicting from italy with colaneri m et al. reporting no benefit whereas the sciascia s et al. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. showing reduced mortality in those who received treatment with tocilizumab . on the other hand outcomes have been consistently reported to be good in studies from china, at the time of submission, some had not been peer-reviewed and others did not take into account concomitant treatments , . our study has reported a mortality of % which is similar to other studies, but we also report concomitant use of systemic steroids in % of the patients which may have contributed in immunomodulation. none of the studies so far have reported nosocomial infection or aspergillus infection or colonization. since il- antagonism can potentially predispose to worse outcomes in infections, this is an important observation in our study and can have implications in developing countries where there is a higher incidence of multi-drug resistant infections. our study is limited because of small sample size and single-center design but this is expected given the availability and cost of tocilizumab in our region which makes it imperative to understand its potential for use in our setting. all the studies exploring outcomes with tocilizumab are limited due to their small sample sizes and observational design highlighting the need for randomized controlled trials. however, given the rapidity of the spread of covid- infection, real-time data is needed particularly from lmics which are about to see the peak in the number of cases. our study supports the use of tocilizumab in a select patient population with covid- and recommends monitoring of nosocomial infections and opportunistic infections in covid- patients who receive the medication which may lead to adverse outcomes in these patients. all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint supplemental material figure legend figure : comparison of c -reactive protein levels before and after administration of intravenous tocilizumab in patients who died versus survived all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . covid- : who declares pandemic because of "alarming levels" of spread, severity, and inaction covid- coronavirus pandemic cytokine release syndrome in severe covid- dysregulation of immune response in patients with covid- in wuhan, china. clinical infectious diseases advances in the research of cytokine storm mechanism induced by corona virus disease and the corresponding immunotherapies. zhonghua shao shang za zhi= zhonghua shaoshang zazhi= chinese journal of burns interleukin- blockade with high-dose anakinra in patients with covid- , acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease pharmacologic treatments for coronavirus disease (covid- ): a review the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality tocilizumab for treatment of severe covid- patients: preliminary results from smatteo covid registry (smacore). microorganisms clinical management of severe acute respiratory infection (sari) when covid- disease is suspected the lancet infectious d. covid- : endgames. the lancet infectious diseases tocilizumab treatment in covid- : a single center experience pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe covid- effective treatment of severe covid- patients with tocilizumab tocilizumab in severe covid- pneumonia and concomitant cytokine release syndrome tocilizumab therapy reduced intensive care unit admissions and/or mortality in covid- patients key: cord- -kuvnwdn authors: ikegami, saya; jitsuiki, kei; nagasawa, hiroki; nishio, ryota; yanagawa, youichi title: suspected virus-inducing severe acute respiratory distress syndrome treated by multimodal therapy including extracorporeal membrane oxygenation and immune modulation therapy date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: kuvnwdn a -year-old man who had been feeling general fatigue was found in an unconscious state on the same day. he had no remarkable medical history. on arrival at the hospital, his glasgow coma scale was e v m ; he had tachycardia and hypertension, was afebrile, and in a severe hypoxic state. his pao( )/fio( ) (p/f) was under , even with tracheal intubation with % oxygen. chest x-ray and ct revealed a bilateral ground-glass appearance with consolidation. cardiac echo initially showed hyper-dynamic wall motion. the main results of a blood analysis suggested an acute inflammatory reaction, rhabdomyolysis, and pancreatitis. the microscopic findings of sputum and a rapid test for bacterial and viral infections were all negative. as he showed deterioration of p/f, venovenous extracorporeal membrane oxygenation (ecmo) was started. he also showed hypotension and therefore underwent vasopressor and steroid administration. due to concerns of pneumonia, he received meropenem and azithromycin in addition to the infusion of γ-globulin and glycyrrhizin. the results of a covid- test, culture of sputum, and collagen disease test were all negative. the serum virus neutralization assay as a serological test for coxsackievirus b showed a four-fold increase in titer. the multimodal therapy mentioned above resulted in the improvement of his general condition, including acute respiratory distress syndrome (ards). in this report, we discuss the benefits of ecmo and immune modulation therapy in the treatment of severe ards. acute respiratory distress syndrome (ards) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and the need for mechanical ventilation [ ] [ ] [ ] [ ] . the pathology of ards is diffuse alveolar damage, such as the rapid development of capillary congestion, atelectasis, intraalveolar hemorrhaging, and alveolar edema, followed days later by hyaline-membrane formation, epithelial-cell hyperplasia, and interstitial edema [ ] . ards occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents, or severe trauma and is present in roughly % of all patients in intensive-care units worldwide [ ] . although much progress has been made in improving supportive care for ards, effective pharmacological therapies have not yet been identified, and mortality remains high at %- % in most studies [ ] . we report a case of suspected virus-inducing severe ards treated by multimodal therapy including extracorporeal membrane oxygenation (ecmo) and immune modulation therapy that led to a favorable outcome for the patient. a -year-old man felt generalized fatigue and took the day off from work. his son called him on the same day, but he did not respond. when the son visited his house, he found the patient unconscious and called an ambulance. he had no remarkable medical history. he was a neversmoker and drank g of ethanol per day. he worked as a truck driver and lived with his only son after his divorce. his work zone was not located in any of the districts that were reported to have covid- infections. when the emergency medical technicians checked him, he had a tonic convulsive posture with severe hypoxia, and he was transported to our hospital under bag-valve-mask ventilation with high-concentration oxygen. on arrival, his glasgow coma scale was e v m . a physical examination revealed the following findings: blood pressure of / mmhg; heart rate of beats per minute; a respiratory rate of breaths per minute; spo of % under room l per minute of oxygen; and body temperature of . °c. a venous route was immediately secured, followed by endotracheal intubation. an arterial gas analysis revealed the following findings: ph: . ; pco : . mmhg; po : . mmhg; base excess - . mmol/l; and lactate: mmol/l. electrocardiography revealed sinus tachycardia. a chest x-ray revealed a bilateral ground-glass appearance ( figure ). cardiac echo showed hyper-dynamic left-ventricular wall motion. whole-body ct revealed a bilateral ground-glass appearance in the ventral lung fields and bilateral consolidation in the dorsal lung fields ( figure ). the image shows a bilateral ground-glass appearance in the ventral lung fields (arrow) and bilateral consolidation in the dorsal lung fields (asterisks) the pancreas was normal. the main results of a blood analysis were as follows: wbc count: , /μl (neutrophil %, lymphocyte %, monocyte %); hemoglobin: . g/dl; platelet count: . × /μl; total protein: . g/dl; albumin: . g/dl; glucose: mg/dl; hba c: . %; total bilirubin: . mg/dl; aspartate aminotransferase: iu/l; alanine aminotransferase: iu/l; lactate dehydrogenase: , iu/l; blood urea nitrogen: . mg/dl; creatinine: . mg/dl; amylase: (pancreas %) iu/l; creatine phosphokinase (ck): , iu/l; sodium: meq/l; potassium: . meq/l; chloride: meq/l; brain natriuretic peptide: . pg/ml; c-reactive protein: . mg/dl: prothrombin time international normalized ratio: . ; activated partial thromboplastin time: . ( . ) seconds; fibrinogen: mg/dl; ddimer: . μg/ml; human immunodeficiency virus (hiv) antibody: negative; pneumococcal urinary antigen test: negative; legionella urinary antigen test: negative; rapid influenza diagnostic test: negative; microscopic finding of sputum: negative: and urine drug screening test: negative. later, β-d glucan, rheumatoid factor, and anti-neutrophil cytoplasmic antibody were all found to be negative. he received a tentative diagnosis of pneumonia of unknown causes accompanying severe ards, rhabdomyolysis, and pancreatitis. as he showed deterioration of pao [pao /fio (p/f) = ] and a murray score of . , he underwent mechanical ventilation under . fio and cmh o with positive end-expiratory pressure (peep) and received indwelling venovenous ecmo (mera centrifugal blood pump system has-cfp; mera nhp exelung nsh-r hpo- wh-c; senko medical instruments, tokyo, japan) with the right jugular vein (return side, fr) and right femoral vein (drainage side, fr) as the exit. as this event occurred during the night shift, we did not attempt supine therapy before introducing venovenous ecmo. he also showed hypotension and therefore underwent infusion of noradrenalin followed by vasopressin and mg of hydrocortisone. due to concerns of pneumonia, he received . g of meropenem and mg of azithromycin in addition to an infusion of g of γ-globulin and ml of glycyrrhizin as antibacterial and antivirus treatments respectively. after the induction of ecmo, the mode of mechanical ventilation was changed to a lung rest setting ( . fio and cmh o with peep). additional cardiac echo showed diffuse hypokinesis with a % ejection fraction, and troponin t became positive [ pg/ml (normal range: < pg/ml)] on the first hospital day, and so he was diagnosed with myocarditis as a complication. on the second day, his blood pressure increased, resulting in a reduction in the vasopressor administration. his p/f remained under . on the third day, inflammatory data remained high, and hence azithromycin was replaced with levofloxacin. however, this led to skin reddening and he was switched back to azithromycin. a complication of anemia, thrombocytopenia, and coagulopathy required blood transfusion. a polymerase chain reaction (pcr) test for covid- using sputum through the endotracheal tube without bronchoalveolar lavage (performed twice) and initial cultures of sputum, urine, and blood were all negative. on the fifth day, the inflammatory data remained moderate, and hence meropenem was replaced with linezolid and piperacillin/tazobactam. on the same day, in an attempt to withdraw ecmo, the mechanical ventilation setting was changed from to cmh o for peep and from . to . for fio . this resulted in the p/f increasing to over . after the circulation flow of ecmo was reduced from to l/minute, the p/f remained over ; hence ecmo was ceased, and the cannulations were removed (figure ). as the patient was thought to require long-term mechanical ventilation, he underwent tracheostomy on the eighth hospital day. sedative administration was ceased, and a negative water balance was targeted by limiting the infusion volume and the use of diuretics. he showed a transient decrease in his p/f by the formation of atelectasis due to bloody sputum; however, the average p/f improved day by day. on the th hospital day, his p/f exceeded under cmh o for peep and . fio ; hence mechanical ventilation was ceased (figure ). the patient was managed by extracorporeal membrane oxygenation and mechanical ventilation with the lung rest setting on the third day and was withdrawn from mechanical ventilation on the th day day (left) shows bilateral ground-glass appearances. day (middle) shows the deterioration of bilateral radiolucency. day (right) shows clear lung fields he recovered his ability to excrete sputum by himself, and tracheal cannulation was removed on the th hospital day. even after ceasing all drugs for lung and inflammation, his pneumonia, rhabdomyolysis, and pancreatitis did not recur. he was discharged on the nd day on foot. the troponin t level remained high ( pg/ml) even after the ck level normalized, so he was followed up as an outpatient. the serum virus neutralization assay performed as a serological test using pair serum samples with a more than two-week interval for coxsackievirus b showed a four-fold increase in titer (from x to x ). finally, the troponin t level returned to the normal range and showed no subsequent complications. risk factors of direct lung injury involving ards include pneumonia (bacterial, viral, fungal, or opportunistic), aspiration of gastric contents, pulmonary contusion, inhalation injury, and near-drowning, while those of indirect lung injury involving ards include sepsis (nonpulmonary source), non-thoracic trauma or hemorrhagic shock, pancreatitis, major burn injury, drug overdose, transfusion of blood products, cardiopulmonary bypass, reperfusion edema after lung transplantation, and embolectomy [ , ] . the risk factor in the present case was unspecified pneumonia, and an unspecified virus was considered the most likely cause based on the negative results of all cultures, β-d glucan, and rapid test for bacteria and influenza. concerning covid- , while an outbreak had been reported in tokyo at the time, our patient did not live in a covid- -infected district; in addition, two tests for covid- were negative, and ct showed subpleural sparing with a ground-glass appearance, which is not common for covid- . accordingly, the possibility of covid- -related pneumonia was considered to be low. based on our investigations for virus infection, we suspect that coxsackievirus b might have been the responsible virus. however, there are few reports concerning coxsackievirus b infection with pulmonary involvement, and there have been no reports of ards induced by coxsackievirus b [ ] . accordingly, this might be the first case report of severe ards in an adult induced by coxsackievirus b infection. as we did not perform a direct examination of a pulmonary specimen, the possibility of co-infection with multiple viruses or reactivation of coxsackievirus b cannot be excluded. there are two main treatments for ards: treating the main cause of ards or offering supportive therapy for the severely injured lungs. supportive therapy involves oxygen and mechanical ventilation. according to the berlin definition, severe ards requires mechanical ventilation with a high peep and a high concentration of oxygen. when conventional mechanical ventilation fails to improve the arterial oxygenation and/or eliminate carbon dioxide, ecmo is indicated. another indication is circulatory and/or cardiac failure. the conventional ventilation mode can cause ventilator-induced lung injury, such as volutrauma, atelectrauma, and/or biotrauma. in addition, the continuous inspiration of high-concentration oxygen can also injure the lungs. the induction of ecmo helps avoid such mechanical-and oxygen-induced lung injuries by using the lung rest setting, allowing patients time to recover from their lung injuries [ ] [ ] [ ] . as the present case also showed marked hypoxia despite mechanical ventilation with a high concentration of oxygen and high peep, ecmo was introduced, and the lung rest setting was selected. the severity of ards depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, and the repertoire of specific immune cells that control the substances. therefore, treatment with systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) as soon as possible may reduce aberrant immune responses in the early stage of ards [ ] . the results from clinical trials have often been controversial; however, the administration of steroids may shorten the duration of mechanical ventilation, duration of hospitalization, and improve oxygenation, probably because of the wide spectrum of potentially desirable effects, including antiinflammatory, antioxidant, pulmonary vasodilator, and anti-edematous [ , , ] . lee et al. noted that early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) along with antibiotics or antivirals could halt the progression of pneumonia and induce a rapid recovery of pulmonary lesions in patients with ards [ ] . furthermore, macrolides also induce a broad range of immunological mechanisms that result in immunomodulatory effects; hence macrolide therapy can also help reduce mortality in patients with ards [ ] . accordingly, the variety of supportive therapies offered for ards may explain the favorable outcome in the present case. viral pneumonia was thought to be the most likely cause of ards in the present case. respiratory viruses are a common cause of severe pneumonia and ards in adults [ , ] . initially, the present case was suspected of having covid- infection, but this diagnosis was not supported by pcr performed twice. the percentage of patients with ards for which no causative organism has been identified despite bronchoalveolar lavage or pcr testing remains high (> - %) [ ] . although antiviral therapy is available for some respiratory viral infections, most viruses do not have any specific treatment. one of the antivirus therapies used in the present case was glycyrrhizin. glycyrrhiza glabra roots contain glycyrrhizic acid (glycyrrhizin), which is effective against viruses [ ] . glycyrrhizin inhibits the growth and cytopathology of several unrelated dna and rna viruses while not affecting human cell activity or their ability to replicate [ ] . glycyrrhizin is therefore now applied in the treatment of a variety of viral infections [ ] . traditional chinese medicines such as glycyrrhizin may also be effective against covid- infection [ ] . in addition, macrolide and γ-globulin can also exert an antiviral effect [ ] . these unspecific antiviral therapies may be useful treatments for the main cause of ards, which may have resulted in the favorable outcome obtained in the present case. the present case showed pneumonia, pancreatitis, rhabdomyolysis, and myocarditis. the involvement of two pathogens (salmonella typhi and mycoplasma) that have been reported to accompany such complications was not found in the present case [ , ] . however, cases of pneumonia, rhabdomyolysis, myocarditis, and pancreatitis induced by coxsackievirus b have been reported [ ] [ ] . accordingly, this virus may have been the causative pathogen of these complications in the present case. we presented a case of suspected virus-inducing severe ards that was treated by multimodal therapy including ecmo and immune modulation therapy. the wide range of supportive therapies and unspecific antiviral therapies offered for ards may have resulted in the favorable outcome obtained in the present case. human subjects: consent was obtained by all participants in this study. the review board of juntendo shizuoka hospital issued approval . this case study was approved by the review board of juntendo shizuoka hospital. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: this work was supported in part by a grant-in-aid for special research in subsidies for ordinary expenses of private schools from the promotion and mutual aid corporation for private schools of japan. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. acute respiratory distress syndrome: the ikegami et al berlin definition acute respiratory distress syndrome definition, causes, and pathophysiology acute respiratory distress syndrome acute respiratory distress syndrome coxsackie b pneumonia in an adult extracorporeal life support for adults with respiratory failure and related indications: a review extracorporeal membrane oxygenation for acute respiratory distress syndrome: eolia and beyond referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) pneumonia, acute respiratory distress syndrome, and early immune-modulator therapy corticosteroids in acute lung injury: the dilemma continues the immunomodulatory effects of macrolidesa systematic review of the underlying mechanisms viral pneumonia and acute respiratory distress syndrome glycyrrhizic acid inhibits virus growth and inactivates virus particles research progress of glycyrrhizic acid on antiviral activity traditional chinese medicine for covid- treatment therapeutic control of viral infections: chemotherapy, interferon and gamma globulin salmonella typhi infection complicated by rhabdomyolysis, pancreatitis and polyneuropathy rhabdomyolysis associated with infection by mycoplasma pneumoniae: a case report tumor necrosis factor and coxsackie b rhabdomyolysis development of potential antiviral strategy against coxsackievirus b key: cord- -iiqyzqsb authors: li, jin-ze; meng, shan-shan; xu, xiu-ping; huang, yong-bo; mao, pu; li, yi-min; yang, yi; qiu, hai-bo; pan, chun title: mechanically stretched mesenchymal stem cells can reduce the effects of lps-induced injury on the pulmonary microvascular endothelium barrier date: - - journal: stem cells int doi: . / / sha: doc_id: cord_uid: iiqyzqsb mesenchymal stem cells (mscs) may improve the treatment of acute respiratory distress syndrome (ards). however, few studies have investigated the effects of mechanically stretched -mscs (ms-mscs) in in vitro models of ards. the aim of this study was to evaluate the potential therapeutic effects of ms-mscs on pulmonary microvascular endothelium barrier injuries induced by lps. we introduced a cocultured model of pulmonary microvascular endothelial cell (ec) and msc medium obtained from mscs with or without mechanical stretch. we found that wright-giemsa staining revealed that msc morphology changed significantly and cell plasma shrank separately after mechanical stretch. cell proliferation of the ms-msc groups was much lower than the untreated msc group; expression of cell surface markers did not change significantly. compared to the medium from untreated mscs, inflammatory factors elevated statistically in the medium from ms-mscs. moreover, the paracellular permeability of endothelial cells treated with lps was restored with a medium from ms-mscs, while lps-induced ec apoptosis decreased. in addition, protective effects on the remodeling of intercellular junctions were observed when compared to lps-treated endothelial cells. these data demonstrated that the ms-msc groups had potential therapeutic effects on the lps-treated ecs; these results might be useful in the treatment of ards. to date, the emerging virus sars-cov- is causing a worldwide public health emergency; % critically ill patients developed acute respiratory distress syndrome (ards) [ ] . despite numerous efforts towards reducing mortality in established ards, in hospital mortality still remains near % [ ] . the main pathophysiology associated with ards in critically ill patients is the failure of pulmonary microvascular endothelium barrier integrity [ ] . therefore, maintaining the integrity of the endothelium barrier is critical for ards treatment. mesenchymal stem cell (msc) therapy is a potential method to treat ards [ ] , and our previous studies [ , ] have shown concrete benefits both in vitro and in vivo. however, clinical trials of allogeneic msc transplantation have provided conflicting evidences. in one trial, msc treatment in patients with ards produced a short-term improvement in oxygenation [ ] . yet, another trial demonstrated no significant difference in the -day mortality between patients treated with mscs and a control group ( % in the msc group versus % in the placebo group) [ ] . when injected intravenously, mscs preferentially homed to the lungs and engrafted at sites of injury in the pulmonary microvascular endothelium layer [ ] . the therapeutic function of mscs presents from the beginning of their engraftment on the endothelium layer to their merger with the layer [ ] . during this period, mscs are not only affected by biochemical factors but also by different kinds of mechanical stimulation coming from the microenviroment they have lived in [ ] . better integration of experimental and clinical data could provide further insight into the use of msc-based therapy in this setting. mechanical stimulation on the lung tissue exists constantly in physiological and pathological states, such as ards [ , ] . when utilized with mechancial ventilation to maintain essential oxygenation of ards patients, mechanical stimulation conducted through the lung tissue microenvironment varies from mild to severe levels and generates different degrees of lung compliance [ , ] . mechanical stretch may approximate the mechanical ventilation with low tidal volumes that are commonly used in the lungprotective mechanical ventilation required to treat ards previously [ ] and nowadays [ ] . when mscs are introduced into the lung microenvironment to treat ards, they have to encounter different degrees of mechanical stimulation. evidences have shown that mechanical stimulation can affect behavior of mscs, such as morphology [ ] , adhension [ ] , and differentiation [ , ] . therefore, mechanical stretch on mscs could play an important role on the treatment of lps-induced ec injuries. the aim of the this study was to present evidences of ms-msc therapeutic effects on ec injuries treated by lps. to test this hypothesis, we conducted a cocultured model of the ec and msc medium obtained from mscs with or without mechanical stretch. and, we evaluated the repair ability of the medium from mscs or ms-mscs on lps-induced ec injuries. first passage human bone marrow mesenchymal stem cells (mscs) were obtained from sciencell research laboratories (san diego, california, usa). the cells were characterised by the supplier. mscs were maintained in the mesenchymal stem cell medium (mscm; %fbs, % mesenchymal stem cell growth supplement, and % penicillin/streptomycin solution). the media were purchased from sciencell research laboratories (san diego, california, usa). cells were cultured at °c in an incubator with an atmosphere of % co air. every to days, cells were passaged when they reached - % confluency and passages from to of the cells were used for all experiments. mscs were preconditioned by mechanical stretch (ms) in vitro with a bioflex strain unit (bioflex, flexcell international corporation, hillsborough, nc, usa) as described previously [ ] . mscs were seeded onto a six-well plate containing flexible collagen type i-coated silicone rubber membranes at the bottom of each well and incubated at °c in % co atmosphere with % humidity (bioflex, flexcell international corporation, hillsborough, nc, usa). mscs were cultured for or days to reach - % confluency and subjected to mechanical stretch of % or % elongation for h or h using a computer-controlled vacuum stretch apparatus (fx- tension plus system, flexcell international corporation, hillsborough, nc, usa). the untreated msc group did not receive mechanical stretch and was incubated in the same incubator. mscs and supernatant from all groups were collected at scheduled time points and prepared for use in this study. supernatants from the stretched msc and control groups were collected and centrifugated to remove dead cells and cell debris. cell and dermal fibroblast culture. first passage human pulmonary microvascular endothelial cells (ecs) and human dermal fibroblasts (hdf) were obtained from sciencell research laboratories (san diego, california, usa), and the cells were cultured in an endothelial cell medium (ecm; %fbs, % endothelial cell growth supplement, and % penicillin/streptomycin solution) and fibroblast medium (fm; %fbs, % fibroblast growth supplement, and % penicillin/streptomycin solution), respectively. all mediums were purchased from sciencell research laboratories (san diego, california, usa). cells were cultured at °c in the incubator with an atmosphere of % co air. every to days, cells were passaged when they reached - % confluency. system. ecs at a density of , per well were seeded in the upper chambers ( . μm pore size polyester membrane from corning, inc.) and cultured for to days to produce a confluent monolayer, and mscs were seeded in the lower chambers,. then, cells were treated with lps ( ng/ml, sigma) for hours before permeability was tested, as previously described [ ] . after adding μl kda fluorescein isothiocyanate-(fitc-) dextran (sigma-aldrich) to each upper insert and incubating for minutes in an incubator, μl medium from the upper and lower chambers was withdrawn. then, the medium was transferred to a -well plate and read using excitation and emission wavelengths of nm and nm, respectively. to observe cell morphology, cells were stained with wright-giemsa stain (sigma aldrich) according to the manufacturer's protocols as previously described [ ] . after air drying the wells, mscs were inspected under a light microscope (olympus, tokyo, japan). assay. untreated and mechanically stretched mscs were seeded at cells per well onto well plates and cultured in an incubator with a humidified atmosphere of % co at °c. μl of cell counting kit- (cck- ) solution (beyotime, china) was added per well, and cells were cultured for hour at °c, before measuring absorbance at nm with a microplate reader. . . identification of mscs by flow cytometry. untreated and mechanically stretched mscs were identified by flow cytometry (bd bioscience, san diego, ca) as described previously [ ] . harvested mscs were washed with pbs and resuspended to × cells/ml, and μl of cell suspension was incubated with fluorescein-conjugated monoclonal antibodies against cd , cd , and cd (bd pharmingen, san diego, ca), respectively. samples were mixed in the dark stem cells international for minutes, then resuspended and centrifuged at rpm for minutes at room temperature. supernatants were removed, and cells were resuspended with pbs to μl for flow cytometry analysis. . . enzyme-linked immunosorbent assay. the supernatants from all msc groups were collected and centrifuged to remove cell fragments. levels of tumor necrosis factor (tnf-α), interleukin- (il- ), and interleukin- (il- ) in the culture medium were detected by elisa (excellbio, shanghai, china). all tests were performed according to the manufacturer's instructions. all samples were examined in duplicate. ecs were seeded in the upper chamber in -well culture plates ( . μm pore size polyester membrane from corning, inc.) and cultured for to days to produce a confluent monolayer. then, cells were treated with lps ( ng/ml, sigma) for hours before permeability was tested, as previously described [ ] . after adding μl kda fluorescein isothiocyanate-(fitc-) dextran (sigma-aldrich) to each upper insert and incubating for minutes in an incubator, μl medium from the upper and lower chambers was withdrawn. then, the medium was transferred to a -well plate and read using excitation and emission wavelengths of nm and nm, respectively. an annexin v-fitc assay kit (sigma-aldrich) was used to assess the percentage of ecs undergoing apoptosis, according to the manufacturer's instructions. ecs were harvested and washed with pbs and suspended in x binding buffer at a cell concentration of × cells/ml. then, μl propidiumiodide solution (pi) and μl annexin v-fitc conjugate (annexin v) were added to each sample and gently mixed. after minutes incubation in the dark at room temperature, samples were analyzed using a flow cytometer (bd biosciences, usa). western blotting was used to detect the expression of ve-cadherin and connexin- on ecs as previously described [ ] . total proteins from ecs after different treatments were extracted with ripa lysis buffer (beyotime institute of biotechnology, shanghai, china) supplemented with mmol/l phenylmethylsulfonyl fluoride (pmsf), and then separated with % sodium dodecyl sulphate-polyacrylamide gel electrophoresis and transfered onto polyvinylidene fluoride membranes (beyotime, china). afterwards, membranes were blocked in % bsa for hours at room temperature and incubated at °c overnight with primary antibodies against ve-cadherin (abcam) or connexin- (cell signaling technology). the next day, membranes were washed in tbs-t and incubated in hrpconjugated secondary antibody (boster biotechnology, wuhan, china) for hour at room temperature. then, ecl (beyotime, china) was applied to detect the bands with a chemiluminescence imaging system (chemiq mini; ouxiang, china). . . immunofluorescence staining. in a transwell system, ecs were seeded on the upper inserts and cultured to form a confluent monalayer for or days. after treating with lps for hours, cells were then washed with cold pbs and fixed with % paraformaldehyde for minutes. samples were permeabilized with . % triton x- for minutes, blocked with % bovine serum albumin (bsa), and incubated overnight with ve-cadherin primary antibody (ab) ( : rabbit polyclonal anti-ve-cadherin) (abcam, ab , ireland) at °c. after incubation for hours, samples were incubated with a secondary fitc-conjugated goat anti-rabbit igg ( : alexa fluor igg) (biosciences, ireland) and stained with (vwr, ireland) for h at room temperature. cell nucleis were stained with dapi (vwr, ireland) for min at room temperature, washed in pbs, and imaged using confocal microscopy (leica sp , ireland). . . statistical analyses. statistical analyses were performed using the spss . software package (spss inc., chicago, il, usa). results were presented as the mean ± standard deviation. group comparison was analyzed by one-way analysis of variance, followed by tukey's test. p < : was considered statistically significant. to determine if mscs protected ecs from lps-induced injury, we used a transwell coculture system (figure (a)) to assess paracellular permeability when mscs were added at varying seeding concentrations, from × cells per well to × cell per well. permeability significantly decreased when mscs were plated at × cell per well (figure (b); * p < : ) and decreased further as the density of mscs increased. this suggested that the therapeutic effect of mscs on endothelial cell permeability improved as the density of mscs increased. mscs were seeded on six-well mechanical stretch plates with collagen type i-coated flexible silicon rubber membranes placed at the bottom of each well and were preconditioned by mechanically stretching these plates during cell culture (figures (a) and (b) ). an example of a six-well mechanical stretch plate is presented in figure (c). mscs were plated on the silicon rubber membrane and stained with wright-giemsa stain. a schematic view of a well under mechanical stretch is presented in figure (d). the first column shows the side view of two wells containing either untreated or mechanically stretched mscs. the second column presents an illustration of untreated or mechanically stretched mscs, respectively. stem cells international following treatment (figure (a) ). cells in all groups remained firmly adhered to the seeding surface. compared to untreated mscs, the ms-mscs showed signs of atrophy, appearing thinner and flattened, and have increasingly shrunk in a time-and magnitude-dependent manner. moreover, cell proliferation significantly increased in the ms- % groups (figure (b); * p < : ) but decreased in the ms- % groups ( * * p < : ). proliferation in the ms- %- h group was significantly lesser than that in the ms- %- h group ( * p < : ). these data suggest that ms affected the morphology and proliferation of mscs significantly. markers on mscs. surface markers on mscs served as an index parameters for the identification of mscs [ ] . to determine if surface marker expression changed when mscs were preconditioned to mechanical stretch, we used flow cytometry to analyze major surface markers of mscs for identification, such as cd , cd , and cd ( figure ) . the results showed no statistical change in the expression with high levels of cd and cd expressions on nearly % of cells in all treatment groups and low levels of cd expression on fewer than % of cells for all treatment groups. the results suggest that ms did not alter the expression of surface markers. studies have shown that ms can induce biological function change [ ] . to evaluate the effects of ms on the inflammatory function of mscs, we examined the inflammatory mediators tnf-α, il- , and il- presented in the msc supernatants by enzyme-linked immunosorbent assay. the results showed that tnf-α and il- increased statistically as time and magnitude of mechanical stretch increased (figures (a) and (b); * p < : ), but the ms- %- h group did not produce significant differences when compared to the untreated msc group. however, il- did not significantly change in all groups ( figure (c) ). these results showed that ms could statistically increase the tnf-α and il- levels. stem cells international in assessing the integrity of the pulmonary microvascular endothelium barrier [ ] . we introduced a transwell coculture system to evaluate the effects of ms-mscs on the paracellular permeability of lps-treated ecs. treatment with lps significantly increased the paracellular permeabil-ity of the pulmonary microvascular endothelium barrier (figure (a); * * p < : ). and mscs significantly attenuated the increased paracellular permeability induced by lps (figure (a); * p < : ), while hdf showed no effect on the increased permeability. these results suggested that lps is a useful agent to induce injury and apoptosis on pulmonary microvascular endothelial cells [ ] . in this study, we applied the flow cytometry to evaluate the effect of mscs on apoptosis of ecs treated with lps (figure (a) ). lps could significantly induce the apoptosis of ecs both in early and late states (figures (b) and (c); * * p < : ), but mscs decreased the apoptosis of lps-treated ecs ( * p < : ). furthermore, the ms- %- h msc group could significantly attenuate both early and late apoptosis of ecs ( * p < : ), similar to the untreated msc group (figure (b) ). however, the ms- %- h group significantly decreased early apoptosis ( * p < : ) but not late apoptosis of ecs, although it showed a trend towards attenuating apoptosis (figure (c) ). intercellular junction proteins play an important role in maintaining the integrity of the pulmonary microvascular endothelium barrier. ve-cadherin [ ] and connexin- [ ] present critical effects on regulating the permeability of the barrier. to investigate the effects of ms-mscs on endothelium barrier integrity, we examined the expression of these two key proteins. compared with the lps-treated ecs, mscs increased the expression of ve-cadherin and connexin- (figures (b) and (c); * * p < : ). we also applied immunofluorescent staining to detect the protein expression of ecs and observed the cells under confocal microscopy. the results showed that ve-cadherin located on the surface of ecs were destroyed after lps treatment, thus leading to the loss of integrity of the pulmonary microvascular endothelium barrier (figure ). these data indicated that ms-mscs restored the intercellular junction of lpstreated ecs. ards is the leading cause of mortality in icu patients [ ] and featured with acute diffuse lung injury, which results in severely injured lung compliance and increased pulmonary vascular permeability [ ] . msc is a promising method to restore endothelial function [ ] , but when engrafted on the alveolocapillary barrier, the efficacy of mscs under mechanical stretch in the context of decreased lung compliance remains unproven. our study tried to reveal the effect of mechanically stretched mscs on restoring the injured alveolocapillary barrier. we applied a mechanical stretch system to simplify yet still mimic the mechanical microenviroments present within the lung in a simplified way. we demonstrated that mechanical stretch could impact msc morphology and biological function in a time-and magnitude-dependent manner and that ms-mscs could restored the increased permeability of endothelial cells induced by lps. the alveolocapillary barrier provides an essential function in regulating the diffusive exchange of molecules. loss of barrier integrity could lead to excessive leakage of fluid and proteins from the vasculature to the alveoli, producing the pulmonary edema common in ards [ ] . sepsis plays a major role in extrapulmonary edema, and the endothelial barrier stands as the first line of defense in keeping lps out of the vascular system [ ] . studies have demonstrated that endothelial injury is a more important consideration in extrapulmonary ards than pulmonary ards [ , ] . as a major factor driving sepsis and lethal septic shock, lps has been studied in in vivo, in vitro, and ex vivo settings [ , ] . hereby, we adopted lps and a transwell coculture system to investigate the effects of mscs on the permeability of the alveolocapillary barrier. we found that increased permeability by lps was significantly decreased by mscs as the cell density increased accordingly. manipulation of mesenchymal stem cell functions is important for tissue engineering and regenerative medicine. heterogeneous mechanical properties of the alveolocapillary barrier in ards caused a complicated microenviroment for the engraftment of mscs [ ] . so, we used an apparatus to mimic and simplify the mechanical properties within the lung tissue in clinical field, as % mechanical stretch for physical stimulation and % for severe pathological status. our previous research had applied this method and acquired positive therapeutic results of pulmonary fibrosis investigation [ ] . in this study, we tried to discover evidences of mechanically stretched mscs in restoring increased permeability of endothelial barrier induced by lps. while mscs injected via the bloodstream preferred to engraft on and merge into the injured sites of the pulmonary microvascular endothelial barrier [ ] . studies have proved that mscs can coexist with endothelial cells and other kind of cells in the barrier for about to hours. [ , ] therefore, we investigated mscs under these time durations of % and % mechanical stretch as used previously [ ] . we demonstrated that mechanical stretch affects cell morphology and cell proliferation, suggesting that mechanical stretch is important for the maintenance of msc functions. the most attractive charateristics of mscs are the stemness and self-renewal. these properties make them a promising therapeutic tool in many clinical field, such as the kidney [ ] , liver [ ] , and lung [ ] . the stemness of ms-mscs is analyzed by the expression of surface markers. when under the mechanical stretch modes in this study, whether mscs could maintain their stemness is crucial for the lps-treated ec therapy. the expression of cd , cd , and cd did not change with the intervention of different mechanical stretch patterns. all groups exhibit similar expression of the surface markers. the results indicate that, in h with the maximum ms- %, the mscs could maintain the stemness. increased permeability resulted from the disruption of the pulmonary endothelial barrier [ ] . ec apoptosis played stem cells international a vital role in ec barrier integrity [ ] we have been proved that mscs without mechanical stretch could repair the injured ec barrier in a cell density-dependent manner. nowadays, tissue engineering shows great impact on msc therapy and achieved great advances [ ] . mechanical stretch, a method to mimic the mechanical properties of the lung tissue, played an important role in the microenviroment where mscs engrafted. novel strategies to isolate the mechanical factor could shed some light on msc application. our results indicated that lps can induce both early and late apoptosis, and mechanically stretched mscs decreased ec apoptosis but decreased slightly as the time and magnitude of ms increased. thus, mechanical stretch may account for the restoring effect on the injured ec barrier through ec apoptosis. constant remodeling of intercellular junctions to regulate the transendothelial permeability is essential in maintaining endothelium barrier functions. treatment with lps can also alter the apoptotic status of endothelial barrier cells and badly damage the paracellular architecture of causing the endothelial barrier to function abnormally and producing pulmonary edema [ ] . of the intercellular juntion proteins, vecadherin and connexin- are vital for the barrier integrity and could act as index parameters to evaluate the disruption of barrier [ ] . the results presented that endothlial barrier integrity was severely damaged by lps, but ms-mscs increased ve-cadherin and connexin- expressions, which favored the integrity of the endothelial barrier. therefore, ms-mscs restored the increased permeability of the endothelial cell partially by remodeling of ve-cadherin and connexin- . the following limitations to this research should be noted. the mechanical stretch system that we used in this study applies a vacuum to generate mechanical stretch, but as the culture medium is flowing between the mscs, other categories of mechanical stimulations, including shear force and pressure force, are not absent and may influence cells in some level. these forces could also produce a biological response and may thus affect msc function. however, by their nature, these three forces are often mixed together and are difficult to study separately. this could be addressed in future studies. in conclusion, our experiments reveal that ms-mscs statistically improved the increased permeability of the ec barrier induced by lps, through decreasing the apoptosis of ecs and increasing the remodeling of intercellular junctions. these findings provide additional in vitro evidences for the therapeutic potential of mscs and may be useful for the clinical utilization of mscs. endothelial cells ards: acute respiratory distress syndrome mscs: mesenchymal stem cells ms: mechanical stretch lps: lipopolysaccharide elisa: enzyme-linked immunosorbent assay fitc: fluorescein isothiocyanate tnf-α: tumor necrosis factor-alpha il: interleukin ve-cadherin: vascular endothelial-cadherin. the data used to support the findings of this study are included within the article. the authors declare that they have no competing interests. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study mind the gap: mechanisms regulating the endothelial barrier fifty years of research in ards. cell-based therapy for acute respiratory distress syndrome. biology and potential therapeutic value the hepatocyte growth factorexpressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo mtor/stat- pathway mediates mesenchymal stem cell-secreted hepatocyte growth factor protective effects against lipopolysaccharideinduced vascular endothelial barrier dysfunction and apoptosis treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (start study): a stem cells international randomised phase a safety trial mesenchymal stem cells migration homing and tracking characterization of key mechanisms in transmigration and invasion of mesenchymal stem cells alveolar dynamics during mechanical ventilation in the healthy and injured lung the micromechanics of lung alveoli: structure and function of surfactant and tissue components why the impact of mechanical stimuli on stem cells remains a challenge ventilator management ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation mechanically induced formation and maturation of d-matrix adhesions ( dmas) in human mesenchymal stem cells response of mesenchymal stem cells to the biomechanical environment of the endothelium on a flexible tubular silicone substrate mechanical stimulation induces morphological and phenotypic changes in bone marrow-derived progenitor cells within a three-dimensional fibrin matrix mechanical stress and the induction of lung fibrosis via the midkine signaling pathway co-regulation of transcellular and paracellular leak across microvascular endothelium by dynamin and rac fip is required for the cellautonomous maintenance of fetal hematopoietic stem cells minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement interaction between mesenchymal stem cells and endothelial cells restores endothelial permeability via paracrine hepatocyte growth factor in vitro preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock asef mediates hgf protective effects against lps-induced lung injury and endothelial barrier dysfunction endothelial connexin mediates acidinduced increases in pulmonary microvascular permeability epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries mesenchymal stem cells: mechanisms of potential therapeutic benefit in ards and sepsis respiratory distress syndrome, stat-pearls human lipopolysaccharide models provide mechanistic and therapeutic insights into systemic and pulmonary inflammation report from an nih-nhlbi workshop extravascular lung water in critical care: recent advances and clinical applications mechanisms differential role for p -catenin in regulation of tlr signaling in macrophages stem cells, cell therapies, and bioengineering in lung biology and diseases mesenchymal stem cell-based therapy for kidney disease: a review of clinical evidence strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis treatment of acute lung injury: clinical and experimental studies acute respiratory distress syndrome: advances in diagnosis and treatment modulating the stem cell niche for tissue regeneration signaling mechanisms regulating endothelial permeability the authors would like to thank dr. ruoyu hu for his valuable support. key: cord- - qgk authors: roehrig, stefan; ait hssain, ali; shallik, nabil al hamid; elsaid, ingi mohamed a.; mustafa, salma faisal; smain, osama a. m.; molokhia, ashraf abdulla; lance, marcus d. title: flow controlled ventilation in acute respiratory distress syndrome associated with covid- : a structured summary of a study protocol for a randomised controlled trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: qgk objectives: this study aims to demonstrate the positive effects on oxygenation of flow-controlled ventilation compared to conventionally ventilated patients in patients suffering from acute respiratory distress syndrome (ards) associated with covid- .we define ards according to the “berlin” definition integrating the oxygenation index (p/f ratio), the level of positive end expiratory pressure (peep), radiological and clinical findings. trial design: this is a prospective, randomized ( : ratio), parallel group feasibility study in adult patients with proven covid- associated ards. participants: all adult patients admitted to the icu of hamad medical corporation facilities in qatar because of covid- infection who develop moderate to severe ards are eligible. the inclusion criteria are above years of age, proven covid- infection, respiratory failure necessitating intubation and mechanical ventilation, ards with a p/f ratio of at least mmhg or less and a minimum peep cmh o, bmi less kg/ m . the following exclusion criteria: no written consent, chronic respiratory disease, acute or chronic cardiovascular disease, pregnancy or need for special therapy (prone position and/or extracorporeal membrane oxygenation). intervention and comparator: after randomisation, the group a patients will be ventilated with the test-device for hours. the settings will be started with the pre-existing-peep. the upper pressure will be determined to achieve a tidal volume of ml/kg lean body mass, while the respiratory rate will be set to maintain an arterial ph above . . in group b, the ventilator settings will be adjusted by the attending icu team in accordance with lung-protective ventilation strategy. all other treatment will be unchanged and according to our local policies/guidelines. main outcomes: the primary end point is pao . as this is a dynamic parameter, we will record it every - hours and analyse it sequentially. randomisation: the study team screens the ventilated patients who fulfil the inclusion criteria and randomise using a : allocation ratio after consenting using a closed envelope method. the latter were prepared and sealed in advance by an independent person. blinding (masking): due to the technical nature of the study (use of a specific ventilator) blinding is only possible for the data-analysts and the patients. numbers to be randomised (sample size): the sample size calculation based on the assumption of an effect size (change in pao ) of . sds in the primary endpoint (pao ), an intended power of %, an alpha error of % and an equal sample ratio results in n= patients needed to treat. however, to compensate for dropouts we will include patients in each group, which means in total patients. trial status: the local registration number is mrc- - with the protocol version number . the date of approval is (th) april . recruitment began th may and is expected to end in september . trial registration: the protocol was registered before starting subject recruitment under the title: “flow controlled ventilation in ards associated with covid- ” in clinicaltrials.org with the registration number: nct . registered on may . full protocol: the full protocol is attached as an additional file, accessible from the trials website (additional file ). in the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. the pandemic of a newly upcoming viral disease which is associated with covid- puts the whole world's health system under pressure. patients suffering from this disease mainly develop respiratory symptoms, which can lead to severe acute respiratory distress syndrome (ards) necessitating icu, admission in - % of the cases admitted to hospital. in addition to these symptoms, patients show lymphopenia, cardiac symptoms and altered coagulation profiles. although those patients are treated in the icu the mortality is up to % due to multiorgan failure [ , ] . the aim of this study is to show non-inferiority of flow-controlled ventilation [ , , ] compared to standard (lung protective ventilation) [ , ] . after admission to the icu, the patients will receive information about the study and informed consent will be taken. upon reaching the criteria for moderate to severe ards (p/f ratio below mmhg and peep above cmh o) the patients will be randomized. in the treatment group (group a) the ultra-thin ventilation tube will be placed through the existing tube. then flow-controlled ventilation will be applied for hours. in the other group (group b) ventilation will be performed according to the lung protective strategy. all other treatment will be unchanged. data-collection will be started hour after initiation of the study. primary end point is pao . dr the pandemic of a newly upcoming viral disease which is associated with covid- puts the whole world's health system under pressure. patients suffering from this disease mainly develop respiratory symptoms, which can lead to severe acute respiratory distress syndrome (ards) necessitating icu admission in - % of the cases admitted to hospital (scc-guideline). in addition to these symptoms, patients show lymphopenia, cardiac symptoms and altered coagulation profiles. although those patients are treated in the icu the mortality there is up to % due to multiorgan failure [ , ] . currently, there is no proven therapeutic strategy next to symptomatic treatment. although the severely ill patients will need intubation and invasive ventilation according to ards treatment strategies including low tidal volumes and low end-expiratory pressures, not all patients recover their pulmonary function [ , ] . flow control ventilation (fcv) is a recently developed ventilation strategy which allows to keep the intrapulmonary pressures low while achieving optimal gas exchange [ ] . it had been proven in animal models to improve pulmonary function and oxygenation [ ] and in cases with ards [ ] . flow controlled ventilation mode is a unique ventilation technique in which inspiration as well as expiration are controlled i.e. actively performed. this is achieved by generating a continuous flow into the patient's lungs during inspiration or a continuous (negative) flow, sucking gasses out of the patient's lungs. the continuous flow without ventilation pauses, results in linear increases and decreases in intratracheal pressures [ figure ]. as a result, the mean airway pressure will be higher compared to conventional large bore volume controlled ventilation or pressure controlled ventilation (pcv). therefore, the bronchiole and alveoli will be kept open during ventilation facilitating oxygen uptake to the blood. moreover, the continuous gas flow enhances gas mixture in the lungs also improving gas exchange. altogether, fcv results in more efficient ventilation as compared to conventional ventilation techniques. evone® is the only commercially available ventilator applying fcv ventilation mode, thus directing the inspiration as well as the expiration [ figure ]. evone's fcv® ventilation mode is based on a controlled inspiration and expiration flow from a set peep to a set peak pressure and vice versa. the inspiratory flow is continuously controlled by advanced mass flow regulators; the expiratory flow is controlled by regulated suctioning. evone is to be used in combination with tritube [ figure ], an ultra-thin endotracheal tube (outer diameter . mm/ inner diameter . mm), enabling highly accurate intra-tracheal pressure measurements and securing the airway with an inflatable high volume -low pressure cuff because fcv ventilation requires a sealed airway. with an outer diameter (od) of only . mm, tritube® is an ultrathin ventilation tube, intended to obtain endotracheal access to the airway and to ventilate an adult patient [ figure ]. tritube has three lumina: a ventilation lumen -with murphy eye and an inner diameter (id) smaller than mm; a cuff lumen -to inflate and deflate the high volume, low pressure cuff; and an intra-tracheal pressure measurement lumen -for continuous intra-tracheal pressure measurements. tritube (including its cuff) is completely manufactured of polyurethane. additionally, tritube has a malleable stylet to facilitate intubation [ , ] . this study aims to demonstrate the positive effects on oxygenation of flow-controlled ventilation compared to conventionally ventilated patients (pressure control ventilation) in patients suffering from ards associated with covid- . primary outcome: we choose as the primary endpoint arterial oxygen partial pressure (pao ). • minute volume • arterial co (paco ) • tube obstruction by secretion hmc-irb,mrc- - , apr - apr we will collect demographic data (age, sex, bmi), co-morbidities and clinical data (need for special intervention, e.g. "proning") drugs used and fluids administered. next to the vital parameters (blood pressure, heart frequency and body temperature) the oxygenation parameters (bga) will be collected - hourly according to clinical standard. kidney-function parameters (creatinine, urea), liver function tests and whole blood counts and immune-parameters like interleukin (il- ) will be recorded. cardiac enzymes will be collected (troponin, bnp) will be evaluated and reported on clinical need. all of these parameters are reported routinely on daily base for clinical purpose. demographic parameters: • • i: e ratio • abg this is a prospective, randomized feasibility study in adult patients with proven covid- associated ards. we define ards according to "berlin" definition integrating the oxygenation index (p/f ratio), the level of peep and clinical findings [ , ] . we will use an envelope method to randomize patients into the flow-control ventilation group (group a) while all other patients will receive standard treatment (pressure control ventilation-group b). due to the nature of the investigation (we use a special device and tube) blinding of the study groups will not be possible. the study will be performed in hmc facilities hosting covid- patients. after admission to the icu for covid- associated respiratory disease, the patients (or their relatives) will be approached, informed about the study and if agreed informed consent will be taken. upon intubation the severity of the disease will be assessed thrice daily. when the patient fulfils the criteria for moderate to severe ards (p/f ratio between mmhg and mmhg with peep of minimal cmh o and below mmhg with a minimal peep cmh o, respectively) randomization will be performed. hereafter the group a patients will receive the ultra-thin tritube through the existing tube. this does not need exchange of the tube, so it does not generate additional risks for the staff in terms of aerosols. for the safety of the staff, only the investigators will be in the room and perform the change to the tritube. this will be done under full ppe. via the existing tube the ultra-thin tritube will be inserted. for this purpose, the existing tube will be clamped, and the ventilator will be set on hold. then the connector with the inlet for the tritube will be connected and the tritube will be inserted. hereafter, the clamp will be removed, and the ventilator will be re-started. then the tritube will be advanced, blocked and connected to the evone-ventilator. the ventilator settings will be started with the pre-existing-peep and the standard ventilator will be set on hold. the upper pressure will be determined to achieve a tidal volume of ml/kg lean body mass, while the respiratory rate will be set to maintain an arterial bga?? above . ph. in this group the ventilator settings will be adjusted by the icu team (respiratory therapist) in agreement with lung-protective ventilation strategy [ a, ]. all other treatment will be unchanged and according to our local policies/guidelines. in all groups the first clinical data collection starts after hour of initiation of the "new" ventilation strategy. the study ends at hours after insertion of the tritube or if the patient deteriorates needing pronepositioning or ecmo therapy. all adult patients admitted to the hospital (hmgh, hgh) because of covid- infection who develop a moderate to severe ards are eligible. we want to ensure there is no risk for our patients. therefore, we propose a review of our first patients regarding quality and safety by a dmsb. if the irb agrees we could provide names of intensive care doctors experienced in research. study duration and timelines expected duration of the study: months start time: asap (april ) data collection: month data-analysis: months preparing a publication: months hmc-irb,mrc- - , apr - apr demographic data, laboratory data, vital parameters and clinical data will be collected via the electronic patient chart (cerner). we will maintain privacy for the subject throughout data collection by carrying out data collection in private rooms. data confidentiality will be maintained by the use of study ids rather than any identifying data. all data will be entered into a secure database, which is password protected with restricted access, only assigned by the research team. each subject will be assigned an alphanumeric study id, to ensure data confidentiality. the link between the identifier and the study code will be deleted at the end of the study and the anonymized data set will be kept for at least years after study completion per mrc policy. after explaining the project details, a written informed consent will be obtained from patient/ or family member if the patient is not able to give consent. the family member chosen for the consent will be the one who is patient's next of kin. subjects can withdraw from the study at any point and this will not be held against them. they will be informed during the consent process of this and will be asked to contact the research team so that the investigator can withdraw them from the study. if a subject should withdraw, the data and samples collected will be destroyed, unless they have already been analyzed or processed or coded. power-calculation: in order to keep the total number of patients small we will match the patients according to age, co-morbidities inhaled oxygen fraction and we regard this investigation as a feasibility study. therefore, the sample size calculation based on the assumption of an effect size (change in pao ) of . sds in the primary endpoint (pao ), an intended power of %, an alpha error of % and an equal sample ratio results in n= patients needed to treat. however, to compensate for dropouts we will include patients in each group, which means in total patients. data analysis: categorical data will be presented as number and percentage, while interval data will be presented by median and interquartile range (iqr). normally distributed data will be analyzed by using two-tailed unpaired students t-test. continuous variables with skewed distribution will be analyzed using mann-whitney u testing and dichotomous variables by means of fisher's exact test. a p-value < . is considered significant. all data analyses will be done using spss version v (ibm corp, armonk ny, usa). graphs will be constructed using graphpad prism (graphpad prism version . a for windows, graphpad software, san diego ca, usa). although we do not expect adverse events we will follow and report all adverse effects to ensure safety for the patients. • the study will only be conducted after review and approval from mrc and ethical committee of irb. • all participating patients/or patient's family member will be asked for informed consent after explanation of the project and giving written information. • there will be no change in treatment plan with the exception of the ventilation. • we will maintain privacy for the subject throughout data collection by carrying out data collection in private rooms or areas that are partitioned. • data confidentiality will be maintained by the use of an individual study id which is stored in a key file together with the identifier separately and safely. all collected data will be stored under the nominator of the study id. all information is stored in a secured computer file in a locked office in hgh. • all research is done under recognition of the helsinki declaration and under full adherence to the moph regulations in qatar. we rely on our own staff and devices hmc financial support for additional devices might be needed. we are planning to present this study in local or international conference and published it in indexed journal (not decided) after completion of study. . study population and study setting/ location error! bookmark not defined. data collection, data management & confidentiality not defined. hmc-irb case-fatality rate and characteristics of patients dying in relation to covid- in italy clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study acute respiratory distress syndrome: new definition, current and future therapeutic options guidelines on the management of acute respiratory distress syndrome flow-controlled ventilation during ear, nose and throat surgery: a prospective observational study flow-controlled ventilation attenuates lung injury in a porcine model of acute respiratory distress syndrome: a preclinical randomized controlled study flow-controlled ventilation -a novel approach to treating severe acute respiratory distress syndrome ventilation for low dissipated energy achieved using flow control during both inspiration and expiration improved lung recruitment and oxygenation during mandatory ventilation with a new expiratory ventilation assistance device key: cord- - hs jm authors: cruces, pablo; retamal, jaime; hurtado, daniel e.; erranz, benjamín; iturrieta, pablo; gonzález, carlos; díaz, franco title: a physiological approach to understand the role of respiratory effort in the progression of lung injury in sars-cov- infection date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: hs jm deterioration of lung function during the first week of covid- has been observed when patients remain with insufficient respiratory support. patient self-inflicted lung injury (p-sili) is theorized as the responsible, but there is not robust experimental and clinical data to support it. given the limited understanding of p-sili, we describe the physiological basis of p-sili and we show experimental data to comprehend the role of regional strain and heterogeneity in lung injury due to increased work of breathing. in addition, we discuss the current approach to respiratory support for covid- under this point of view. severe acute respiratory syndrome coronavirus (sars-cov ) pandemic has pushed health systems' response to its maximum capacity. in many countries, the surge of cases has exceeded the facilities, technological, and human resources availability at all levels of care. intensive care units have been overcrowded due to swarming of severe cases in a few weeks, where acute respiratory failure (arf) and acute respiratory distress syndrome (ards) are the main cause of admission. protective lowtidal volume (vt) mechanical ventilation (mv), including delivering a physiologic low vt adjusted by ideal body weight, is currently the standard of care for patients requiring invasive respiratory support, like moderate and severe ards. the surge of patients presenting with sars-cov has led to an unprecedented demand of mechanical ventilators, surprising the whole world with a shortage of equipment unthinkable just months ago. due to high demand of invasive mv in many hospitals, mechanical ventilators have become a scarce or nonexistent resource, and other respiratory support strategies have been used, including high flow nasal cannula (hfnc), non-invasive ventilation (niv), and other alternative devices. specific indications for their use are not well defined, consensus guidelines are controversial and frequently they are not followed in clinical practice. the risk of healthcare professional's infection due to aerosolization was suggested as a strong contraindication for hfnc and niv at the beginning of pandemic, contributing in some degree to the shortage of invasive mechanical ventilators. as pandemic reached peak of cases, use of non-invasive devices became widespread. cohort studies form china, italy and north america [ ] [ ] [ ] , showed niv use between and % of patients, but when considering single center and small case series it ranges from to %. although non-invasive respiratory support may prevent invasive mv, failure of this approach may lead to morbidity and mortality [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . some patients will remain dyspneic, breathing spontaneously, with or without respiratory support. currently, indirect information suggests that vigorous and dysregulated respiratory effort may be a promoter of lung injury, a phenomenon known as "patient self-induced lung injury" (p-sili) [ ] [ ] [ ] . biomechanical framework for amplification of lung damage: stress and strain the lung can be described as a pre-stressed network of viscoelastic tissue elements deformed by surface tension and the action of respiratory musculature. this characteristic allows deformation in a time-dependent manner upon applied pressure and return to its initial configuration once the pressure is relieved [ ] . breathing produces a phenomenon of continuous cyclic strain deformation throughout life, where the applied pressure is inspiratory pressure. in biomechanical terms, deformation in the lung is measured in terms of strain, defined as the relative change in volume normalized by a reference volume. this biomechanical property can be defined for the whole lung (global strain) as the ratio between the vt and a reference volume, usually the volume of air at the end of passive expiration, and the functional residual capacity (frc). correspondingly, the force acting on a surface unit, producing its deformation, is the stress. the transpulmonary pressure corresponds to the stress in the lung. strain and stress in the lung tissue are closely related to each other through a constitutive relation (stress = tissue elastance*strain). both are considered to play an important role in the onset and development of ventilator induced lung injury (vili). high values (non-physiological) of strain, measured as pulmonary tissue deformation relative to volume change, are known to be harmful to the lung and to increase mortality in ards patients under mv [ ] . indeed, improved clinical outcomes observed in ards patients due to lower vt corresponds to a reduction of the lung deformation because of mv [ ] . these compelling and well-established findings have directed the attention of several groups to understand the regional mechanisms of deformation in mechanically ventilated patients. understanding the global strain in the lung has allowed the identification of thresholds of safer vt to prevent vili, currently present in guidelines and consensuses [ ] . in injured lungs, there is a wide spectrum of tissue aeration, producing inhomogeneity of ventilation. lung inhomogeneity has been recently proposed as a vili promoter in ards patients, given the fact that lung injury can occur despite the use of recommended vt and pressures, parameters that are considered to be safe in the ventilation of healthy lungs. the concept of stress raisers may explain these findings. the term stress raisers refer to those additional regional factors capable of intensifying the damage. stress raisers produce amplification of the stress applied in certain localized regions of the lung, like the areas of high inhomogeneity of ventilation [ ] [ ] [ ] [ ] . the deleterious effects of high regional strain in the lung was confirmed recently in a swine model of injurious mv, where lung zones of increased regional strain had a spatial correlation with areas of tissue inflammation [ ] . this study highlights the relevance of a better understanding of the spatio-temporal progression of regional strain, supporting that strain is a relevant and prominent determinant of vili [ ] [ ] [ ] . the heterogeneous distribution of opening pressures throughout the lung results in an overstretch of the aerated lung zones ("baby lung") and also in collapsed (poorly aerated) regions due to repetitive cycles of recruitment-derecruitment. the generation of injurious mechanical forces is inevitable when invasive mv is applied, due to the heterogeneous nature of ards and the inflation/deflation dynamics of the lungs. there is a coupling between the applied mechanical stimuli and the biochemical response of lung cells, a biological process called mechanotransduction [ , ] . mechanotransduction can be a pathway of lung injury when the mechanical stimuli are excessive, triggering an inflammatory response in the lung. amplification of lung damage, i.e., vili, depends on the level of energy dissipated by the lung parenchyma and its deformation. the lung does not discriminate the origin of these forces that can be generated by mv or by the respiratory muscles. in this way, biomechanical mechanisms that cause p-sili can occur with or without mv. there is strong evidence that spontaneous ventilation during mv has a role in progression of lung injury [ ] . although spontaneous breathing has proved beneficial in the treatment of mild ards patients, opposite effects occurred when lung injury was severe. spontaneous breathing amplified the damage in severe lung injury, increasing transpulmonary pressures, atelectasis, cyclic collapse, and histological signs of damage [ ] [ ] [ ] [ ] [ ] . the paradox of spontaneous breathing and lung damage can be explained by the solid-like biomechanical behavior of injured lungs. some of the mechanisms described for lung injury from spontaneous effort are increased lung stress/strain, increased lung perfusion, and patient ventilator asynchrony. the generation of vigorous diaphragm contractions induces high negative pleural pressures that will be dissipated along the visceral pleura surface in a homogeneous shape (fluid behavior) in case of healthy lungs, but this dissipation is uneven in case of ards lungs and stress is concentrated in the interphase of collapsed and ventilated lung (solid behavior). this increment in local lung stress has been associated with higher lung inflammation in the dependent lung regions in experimental models. in addition, increment of venous return and oscillations in pulmonary blood flow could favor lung edema production, and finally patient-ventilator dyssyncronies as reverse triggering are associated with increments of vt that may induce vili [ , , ] . there has been a particular emphasis on interventions to prevent mv in recent years, such as hfnc and niv, maintaining spontaneous ventilation and avoiding vili [ ] [ ] [ ] [ ] [ ] . experimental studies and indirect clinical information have given a counter point to this approach, suggesting that spontaneous unregulated ventilatory effort for extended periods of time can also induce progression of the lung damage [ , ] . in spite of these facts, it may be counterintuitive the current recommendation to avoid or deliberately delay the start of the mv. currently, the knowledge of p-sili in extubated patients is limited. p-sili occurs in healthy lungs without mv, in some conditions, like an intense increase in minute ventilation ( e). stress failure of blood-gas barrier after forced training in racehorses was described by west et al. in [ ] . similar findings have been described in elite athletes after prolonged high intensity exercise (i.e., triathletes, marathon runners, and swimmers), which in fact can led to pulmonary edema, in absence of cardiac alterations. after intense exercise, bronchoscopic samples have found higher concentration of red blood cells, total proteins, albumin, and inflammatory cells (neutrophils), mimicking the findings in other mammals [ ] [ ] [ ] [ ] . these alterations can be correlated to the ones described by mascheroni et al. in an experimental ovine study [ ] . the authors observed a serious deterioration in pulmonary function after . - h of pharmacologically induced hyperventilation in spontaneously breathing animals without lung disease. these alterations were prevented by mv and sedoparalysis. this study confirms that vigorous spontaneous ventilation can affect the lung and controlled mv can prevent or attenuate the damage of the lung in this setting [ ] . the alterations in lung function in this experiment were inversely proportional to the exposure time to hyperventilation. as authors point out, they could not discriminate if only the "mechanical stress" was responsible for these observations. off note is that during the observation period, animals were intubated (infraglotic artificial airway) and without positive pressure ventilation. this experimental design may have contributed to the deterioration of lung function by promoting lung atelectasis. for example, hedenstierna et al. described that perioperative atelectasis collapse can easily reach % of the total lung tissue after a few minutes even in uneventful anesthesia [ ] . atelectasis could contribute to p-sili by two main mechanisms: reduction of frc and subsequent increment in dynamic strain during tidal ventilation and generation of heterogeneous lung tissue [ , , , ] . recently, we developed a d tomographic study that employs image-based biomechanical analysis [ ] to unveil the volumetric distribution of regional deformation of the whole lung in subjects without mv. in healthy sedated rats under (unassisted) spontaneously breathing, we observed volumetric regional strain and strain heterogeneity, quantifying the magnitude of these deformation indices and its progression in time [ ] . given the fact that regional strain and heterogeneity are present during a normal respiratory cycle without harming the lung leads to the question: why p-sili does not develop in normal lungs deformed by physiologic vt? the answer probably is related to many factors, as the amount transpulmonary pressure generated, alveolar-capillary barrier indemnity and the magnitude and topographic distribution of dissipated energy on the lungs. a possible explanation might be that the susceptibility to p-sili depends on the size of the frc, prior to injury induced by high global strain. loss of normally aerated lung volume has two main effects: less lung available for tidal deformation and increased force of diaphragmatic contraction. for a same vt, a lung with lower frc is inherently more susceptible to global regional strain. reduced lung volume has important effects on diaphragm position and function. cephalad displacement results in a greater curvature of the diaphragm and an increase in the size of the zone of apposition. further, diaphragmatic fibers are lengthened, augmenting its capability of generate force during the contraction. if respiratory neuromuscular function is intact, then increased drive translates into stronger diaphragm contraction and larger "swings" of negative pressure. this has been demonstrated in laboratory studies, in which spontaneous effort was greater in more severe lung injury. stronger spontaneous effort is linearly related to larger degrees of pendelluft, as well as greater tidal recruitment and regional strain (fig. ) . in a follow-up experimental study, we compared animals with acute lung injury under controlled mv and spontaneously breathing without mv. lung injury was induced by lung lavage in rats, followed by h of spontaneous breathing or low vt-mv. micro-ct images were acquired at the beginning and at the end of the observation period, and d regional strain maps were constructed. we found a marked tomographic progression of the nonaerated-tissue compartment, and a reduction of the normal-tissue compartment, in accordance to de-recruitment phenomenon. additionally, we found a significant progression of regional fig. regional volumetric strain maps in a -h murine model of patient self-inflicted lung injury randomized to two groups: group i: subjects with induced lung injury on low tidal volume mechanical ventilation at the beginning of the experiment (t ) and at the end of the experiment (t ) (upper left and right panels). group ii: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) at the beginning of the experiment (t ) and at the end of the experiment (t ) (lower left and right panels). progression of regional strain and heterogeneity in time is observed in spontaneous breathing, which reaches volumetric strain levels of up to %. regional strain distribution remains more uniform and homogeneous in low tidal volume mechanical ventilation volumetric strain and heterogeneity after spontaneous breathing. in contrast, low vt-mv had limited progression of the regional strain and heterogeneity at the end of the study (fig. ) [ ] . lung heterogeneity has been associated with ards severity and mortality [ ] . peri atelectatic alveoli, as mead et al. described in a theoretical model of alveolar interdependence, can concentrate tension until times in comparison with the global tension applied to the system [ ] . some years ago, our group showed that the peri-atelectatic region in a rat-model of injurious mv presented more inflammation and alveolar disruption than the rest of lung [ ] . if we project the alveolar interdependence to heterogeneous lung with multiple collapsed regions, we can explain this as a trigger of inflammation during spontaneous ventilation. our group is currently working on topographic correlation of areas of strain and inflammation in the p-sili model. we measured gene expression pathways on lung tissue homogenate and lung histology. preliminary results are supportive of our hypothesis. regions-ofinterest (roi) with high regional strain had increased expression of genes involved in apoptosis, il- signaling, g-protein signaling, activation of ligand-activated ion channels, coagulation, and inflammation, among others, compared to rois with low regional strain (taqman™ array rat inflammation -well plates, cat. no. , thermo fisher scientific, usa) (fig. ) . a similar gene expression was identified in areas of high stretch in mechanically ventilated rats in a high global lung strain model [ ] . off note is that in our p-sili model, animals under spontaneous breathing had higher degree of histopathological damage compared to low vt-mv, specifically alveolar wall disruption and hemorrhage, hyperemia, and leucocyte infiltration (fig. ) . interestingly, although fig. variation of gene expression in high strain and low strain regions of the lung in a murine model of patient self-inflicted lung injury. a representative images of in vivo/ex vivo fit between tomographic maps of regional strain and d digitized frozen lungs. red areas represent high strain regions, while the green/blue areas represent low strain regions in spontaneous breathing. low and high strain regions from the same frozen lung were cut, homogenized, and the rna purified. b gene expression variation of inflammation/pathological mechanotransduction between regions of high and low regional strain. the genes that increased their expression in regions of high deformation were tnf superfamily member b (tnfsf b, > times), interleukin- receptor subunit beta (il rb, > times), phosphodiesterase a (pde a,~ times), hydroxytryptamine receptor a (htr a), plasma kallikrein (klkb ), and leukotriene c synthase (ltc s). these genes are involved in apoptosis, il- signaling, g-protein signaling, activation of ligand-activated ion channels, coagulation, and inflammation, respectively biomechanical phenomena and gene expression are regional, lung damage was diffuse. a possible explanation for this is that many of the biomarkers mentioned are water soluble and easily diffusible in plasma and respiratory secretions, so they can be secreted locally, but their consequences are more diffuse, and even at distance. rationale of non-invasive support in arf due to sars-cov : hypothetical fear vs common practice gattinoni et al. recently described two phenotypes in patients with sars-cov , "non-ards" type (or type l), and ards, type (or type h) [ , ] . type refers to initial covid- pneumonia, characterized by low elastance, low v/q ratio, low lung weight, and low recruitability. on the contrary, type fulfills classic criteria of ards. in a small case series of patients, the authors described that patients switched from type to type after week of non-invasive support. authors proposed that facing high respiratory drive, p-sili is responsible to progression from type to type covid- phenotypes. our initial experimental data suggest that one mechanism of the clinical observation of gattinoni et al. may be due to regional lung volumetric deformation and pathological mechanotransduction induced by high strain-spontaneous breathing. as the lung does not discriminate the origin of the force that produce volumetric deformation, whether that can be generated by mechanical ventilation (vili) or the respiratory muscles. under this point of view, this last mechanism can be more precisely describe as "effort-induced lung injury", instead of p-sili. as some authors have pointed out, the type and type phenotypes are an oversimplification of arf due to sars-cov , as it is not possible to attribute to a single mechanism the complexity of covid- . thus, respiratory support, non-invasive and invasive, cannot be decided on a single parameter to prevent potential complications and decrease morbidity and mortality. pathophysiology of covid- respiratory failure [ ] explains why patients with covid- usually present with moderate to severe hypoxemia, so it seems appropriate to use standard oxygen therapy, hfnc and niv as initial respiratory support. due to the discordance of hypoxemia and respiratory distress, it is important to have in mind that previous studies that showed that stratified by severity hypoxemia high vt (greater than . ml/kg [ ] or ml/kg [ ] ) predicts failure of niv support. niv failure has been associated to mortality [ ] , where high global strain may have a role on progression in lung injury. interestingly, a study showed that the use of the helmet as an interface for niv was associated with a better outcome than the traditional interface. whether the possibility to deliver higher peep could be part of the explanation is not known [ ] . high peep could reduce the respiratory drive, the negative pressure swings and global/regional strain due to caudal displacement and shortening of the diaphragm muscle. in this way, sartini et al. recently described the effects of niv and prone position cycles in patients with covid- respiratory failure [ ] . they found a significant decrease fig. representative images of lung histology of a -h murine experimental study where subjects were randomized to three groups: group i: subjects with normal (uninjured lungs) on spontaneous breathing (no mechanical ventilation) (a, b). group ii: subjects with induced lung injury on low vt mechanical ventilation (c, d). group iii: subjects with induced lung injury on spontaneous breathing (no mechanical ventilation) (f-j). in the first image set, no edema or perivascular infiltration is appreciated at × (a) and × (b). in the second image set, minimal amount of perivascular fluid is occasionally observed at × (c-e). in the third image set, we observed alveolar wall disruption and hemorrhage at × (f), perivascular edema and hemorrhage at × (g), intense hyperemia in lung parenchyma vascular bed with signs of initial perivascular edema and leucocyte infiltration at × (h), intense hyperemia and perivascular accumulation of leucocytes at × (i), and perivascular accumulation of polymorphonuclear cell leucocytes and lymphoid cells at × (j) in respiratory rate and an improvement of oxygenation parameters. it is impossible to asses isolated respiratory function in covid- respiratory failure as well as other causes ards patients. a clear example in the study of carteaux et al. where immunosuppression and severity also where associated to niv failure [ ] . as explained before, hypoxemia is infrequently the primary cause of respiratory distress, so it is important to consider other factors as well as non-respiratory organ disfunctions, like acute kidney injury, myocardial, and severe endothelial dysfunction; all of which are common in sars-cov [ ] [ ] [ ] [ ] . the correct assessment of these factors gives a unique opportunity to non-respiratory treatments for covid- . hfnc has shown remarkable results as primary respiratory support in de novo arf [ ] , improving oxygenation and decreasing escalation of care and intubation rate when compared to standard oxygen therapy [ ] [ ] [ ] . the benefit may result from the decrease of the anatomic dead space, reducing the ventilatory demand and work of breathing (wob) [ ] . in covid- , hfnc has been shown to be safe, well tolerated and it has a synergistic effect when combined with other treatments like prone position [ ] [ ] [ ] [ ] [ ] . prone position has been extensively studied in patients with ards and invasive mv, showing an improvement of oxygenation due to many mechanisms, like improving frc, ventilation/perfusion heterogeneity, diaphragm motion in dorsal regions, increasing regional ventilation in dependent lung regions, among others [ , ] . some principles of prone position can be applied to awake extubated patients, but physiology is still not known in depth. it has been demonstrated as a safe intervention, and currently, it is widely used in emergency room, general wards as well as icu settings [ , [ ] [ ] [ ] [ ] . the physiological concepts of hfnc, niv, and prone position can also be applied to patients with hypoxemic arf secondary to sars-cov infection. comorbidities are highly relevant in the selection of the selected noninvasive support strategy (i.e., morbid obesity, copd, chronic heart failure). awake prone position could attenuate p-sili by reducing distending pressures, and negative swings of intrathoracic pressure, and more importantly, an increase in frc. theoretically, these mechanisms can improve alveolar interdependence phenomena by decreasing global strain and heterogeneity. a pragmatic approach to arf due to sars-cov some authors have highlighted the importance of a physiologic approach to sars-cov arf [ ] [ ] [ ] [ ] [ ] . we strongly recommend a conservative approach to respiratory failure due to sars-cov . hypoxemia alone (as well as all derived parameters, like p/f ratio) should not precipitate intubation, and pao as low as to mmhg can be tolerated when there is no evidence of low end-organ perfusion or signs of dysoxia. all obvious indications of invasive mv, like hemodynamic instability, alteration of consciousness, should be carefully assessed over time. in our experience, in most of these patients, intubation can be prevented using timely non-invasive support, and treating identified or suspected complications early. a special consideration is to prevent fluid overload in these patients, although most of the time initial presentation is some degree of dehydration when acute kidney injury is not present. off note is that ctscans do not change our usual management. when patients develop an increase of wob (respiratory rate greater than breaths per minute, increase of respiratory muscles work, severe dyspnea and shortness of breath), a promptly evaluation of secondary causes is assessed and treated [ ] [ ] [ ] [ ] , including end-organ failure, early suspicion of bacterial superinfection, and thromboembolic events. this is in line with the concept of multidimensional dyspnea assessment coined by banzett et al. [ , ] . we acknowledge that there is no clear threshold to decide invasive mv, even considering hypoxemia and increased wob. a special limitation is that there is no standardized measurement of respiratory distress in covid- respiratory failure. given these facts, there are many aspects of p-sili still in debate and our current understanding is very limited on the role of p-sili in progression of lung disease [ ] . the tipping point might be the tolerance of the patient to noninvasive measures and the response to treatment, although it is also a subjective decision. mv is a lifesaving intervention in many situations, but it carries a high risk of complications. p-sili during mv can occur in situations where high respiratory drive cannot be controlled. a short course of deep sedation and neuromuscular blocker (nmb), with daily assessment of discontinuation (nmb-holiday) is recommended [ , ] . weaning in arf-covid- also needs a special consideration. we have observed many situations where increase wob due to high e demand, unrelated to the course of covid- pneumonia, can prompt weaning failure, prolonging mv duration, or ultimately extubation failure. usual situations include severe fever due to systemic unresolved inflammation, delirium, superinfection, drug withdrawal, and acidosis. clinicians need to prevent them before weaning and extubation (i.e., early initiation of antipsychotics, early discontinuation of benzodiazepines infusions, temperature control, etc.). all of these aspects are used to grasp our gestalt of arf due to sars-cov . it includes a multisystemic evaluation (not only respiratory system) to decide appropriate respiratory support, invasive or non-invasive, and correction of other factors that increased e demand and wob [ ] . after intubation, usual care to prevent complications are instituted [ , ] , and conditions for success weaning and extubation are assessed daily, to prevent an excessive duration of mv and morbidity and mortality associated [ , , ] . to our understanding, p-sili might be one of the many factors that can explain progression of lung disease in covid- . we showed preliminary experimental data that regional lung strain and heterogeneity can be identified in acutely injured lungs under unassisted spontaneous breathing. they are capable to induce progression of lung collapse, inflammation, and progressive alterations of lung mechanics. early use of controlled low vt mv may prevent this progression. given the current pandemic due to sars-cov and shortage of medical resources, like mechanical ventilators, the physicians must balance the interventions on respiratory support based on the pathophysiology of arf, but also they must take into account that progression of disease severity might be a consequence of inadequate respiratory support in subjects with high work of breathing, even when it is not primary driven by respiratory failure. clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region icu and ventilator mortality among critically ill adults with coronavirus disease clinical characteristics of coronavirus disease in china non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure association between noninvasive ventilation and mortality among older patients with pneumonia effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial noninvasive ventilation of patients with acute respiratory distress syndrome. insights from the lung safe study failure of high-flow nasal cannula therapy may delay intubation and increase mortality cardiac arrest and mortality related to intubation procedure in critically ill adult patients: a multicenter cohort study clinical practice and risk factors for immediate complications of endotracheal intubation in the intensive care unit: a prospective, multiple-center study covid- pneumonia: different respiratory treatments for different phenotypes? mechanical ventilation to minimize progression of lung injury in acute respiratory failure ventilation-induced lung injury exists in spontaneously breathing patients with acute respiratory failure: yes spontaneous breathing in early acute respiratory distress syndrome: insights from the large observational study to understand the global impact of severe acute respiratory failure study balancing forces: architectural control of mechanotransduction lung stress and strain during mechanical ventilation: any safe threshold? the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome lung inhomogeneity in patients with acute respiratory distress syndrome the future of mechanical ventilation: lessons from the present and the past regional physiology of ards the role of three-dimensionality and alveolar pressure in the distribution and amplification of alveolar stresses does regional lung strain correlate with regional inflammation in acute respiratory distress syndrome during nonprotective ventilation? an experimental porcine study the link between regional tidal stretch and lung injury during mechanical ventilation deterioration of regional lung strain and inflammation during early lung injury mechanotransduction in the lungs towards prevention of ventilatorinduced lung injury: is mechanotransduction the answer? the comparison of spontaneous breathing and muscle paralysis in two different severities of experimental lung injury spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury fifty years of research in ards. spontaneous breathing during mechanical ventilation. risks, mechanisms, and management when to promote spontaneous respiratory activity in acute respiratory distress patients? the role of spontaneous effort during mechanical ventilation: normal lung versus injured lung spatial patterns and frequency distributions of regional deformation in the healthy human lung spontaneous effort causes occult pendelluft during mechanical ventilation high-flow nasal oxygen therapy and noninvasive ventilation in the management of acute hypoxemic respiratory failure high-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients with acute respiratory failure: a systematic review and meta-analysis of randomized controlled trials high flow nasal cannula oxygen versus noninvasive ventilation in adult acute respiratory failure: a systematic review of randomized-controlled trials the clinical practice of high-flow nasal cannula oxygen therapy in adults: a japanese cross-sectional multicenter survey can high-flow nasal cannula reduce the rate of endotracheal intubation in adult patients with acute respiratory failure compared with conventional oxygen therapy and noninvasive positive pressure ventilation?: a systematic review and meta-analysis stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage highly athletic terrestrial mammals: horses and dogs intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes airway inflammation in nonasthmatic amateur runners bronchial epithelial damage after a half-marathon in nonasthmatic amateur runners acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study mechanisms of atelectasis in the peri-operative period reabsorption atelectasis in a porcine model of ards: regional and temporal effects of airway closure, oxygen, and distending pressure lung stress and strain during mechanical ventilation: any difference between statics and dynamics? improving the accuracy of registration-based biomechanical analysis: a finite element approach to lung regional strain quantification mapping regional strain in anesthetized healthy subjects during spontaneous ventilation progresión de la deformación regional pulmonar y heterogeneidad es mayor en respiración espontánea en comparación con ventilación mecánica controlada en lesión pulmonar aguda experimental stress distribution in lungs: a model of pulmonary elasticity non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation covid- pneumonia: ards or not? severe covid- disease: rather avds than ards? failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume predictors of intubation in patients with acute hypoxemic respiratory failure treated with a noninvasive oxygenation strategy respiratory parameters in patients with covid- after using noninvasive ventilation in the prone position outside the intensive care unit kidney disease is associated with in-hospital death of patients with covid- management of acute kidney injury in patients with covid- covid and heart failure: from infection to inflammation and angiotensin ii stimulation. searching for evidence from a new disease endothelial cell infection and endotheliitis in covid- high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure high-flow nasal cannula in critically ill subjects with or at risk for respiratory failure: a systematic review and meta-analysis early high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure in the ed: a before-after study physiologic effects of high-flow nasal cannula in acute hypoxemic respiratory failure prone positioning in high-flow nasal cannula for covid- patients with severe hypoxemia: a pilot study efficacy and safety of early prone positioning combined with hfnc or niv in moderate to severe ards: a multi-center prospective cohort study early self-proning in awake, non-intubated patients in the emergency department: a single ed's experience during the covid- pandemic prone positioning in conscious patients on medical wards: a review of the evidence and its relevance to patients with covid- infection use of prone positioning in nonintubated patients with covid- and hypoxemic acute respiratory failure prone positioning in acute respiratory distress syndrome prone position for acute respiratory distress syndrome. a systematic review and meta-analysis basing respiratory management of covid- on physiological principles acute respiratory failure in covid- : is it "typical a proposed lung ultrasound and phenotypic algorithm for the care of covid- patients with acute respiratory failure respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study caution about early intubation and mechanical ventilation in covid- multidimensional dyspnea profile: an instrument for clinical and laboratory research the affective dimension of laboratory dyspnea: air hunger is more unpleasant than work/ effort validation of the swedish multidimensional dyspnea profile (mdp) in outpatients with cardiorespiratory disease neuromuscular blockers in the acute respiratory distress syndrome: a meta-analysis guidelines on the management of acute respiratory distress syndrome a systematic review of the impact of sedation practice in the icu on resource use, costs and patient safety publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank the plataforma experimental bio-ct, faculty of dentistry, from universidad de chile (fondequip eqm ), for performing the μ-ct analysis. authors' contributions pc and fd conceived the idea of the manuscript. pc took the lead in writing the manuscript, in consultation with fd. jr, deh, and pi were the main reviewers of p-sili during mechanical ventilation section, in consultation with pc and fd. deh and pi were responsible of preliminary results of volumetric strain deformation section. pc and be were the primary reviewers of p-sili without positive pressure ventilation, in consultation with fd. cg analyzed and wrote the preliminary results of histology, in consultation with pc and fd. fd, pc, be, and deh contributed to the discussion in accordance with the preliminary results. all authors were involved in manuscript preparation, and they provided critical feedback to the analysis and discussion. pc and fd are the guarantors of and take responsibility for the content of the manuscript. all authors made substantial contributions to the research, provided final approval of the version to be published, and have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. all authors have read and approved the manuscript. fondo nacional de desarrollo científico y tecnológico grant (fondecyt) # to pc, be and deh. ethics approval and consent to participate not applicable consent for publication not applicable the authors have no conflict of interest to disclose. key: cord- -ov gkgpc authors: bonizzoli, manuela; arvia, rosaria; di valvasone, simona; liotta, francesco; zakrzewska, krystyna; azzi, alberta; peris, adriano title: human herpesviruses respiratory infections in patients with acute respiratory distress (ards) date: - - journal: med microbiol immunol doi: . /s - - -z sha: doc_id: cord_uid: ov gkgpc acute respiratory distress syndrome (ards) is today a leading cause of hospitalization in intensive care unit (icu). ards and pneumonia are closely related to critically ill patients; however, the etiologic agent is not always identified. the presence of human herpes simplex virus , human cytomegalovirus and epstein–barr virus in respiratory samples of critically ill patients is increasingly reported even without canonical immunosuppression. the main aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of ards patients hospitalized in icu. the presence of this group of herpesviruses, in addition to the research of influenza viruses and other common respiratory viruses, was investigated in respiratory samples from patients hospitalized in icu, without a known microbiological causative agent. moreover, the immunophenotype of each patient was analyzed. herpesviruses dna presence in the lower respiratory tract seemed not attributable to an impaired immunophenotype, whereas a significant correlation was observed between herpesviruses positivity and influenza virus infection. a higher icu mortality was significantly related to the presence of herpesvirus infection in the lower respiratory tract as well as to impaired immunophenotype, as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in conclusion, these results indicate that herpesviruses lower respiratory tract infection, which occurs more frequently following influenza virus infection, can be a negative prognostic marker. an independent risk factor for icu patients with ards is an impaired immunophenotype. human herpes simplex virus (hsv ), human cytomegalovirus (hcmv) and epstein-barr virus (ebv) are wellknown members of the herpesviridae family, which are highly prevalent and ubiquitous. primary infection takes place in the majority of cases early in the life and is followed by a lifelong latent infection, from which reactivation may occur with viral shedding at least in the saliva. the outcome of reactivation strongly depends from the host immunological status. in immunodepressed patients, all these three viruses may cause severe diseases, which may be different depending on the virus and on other factors, including host defences. mostly, hcmv and also hsv may cause severe respiratory diseases, whereas the role of ebv in pneumonia is debated [ ] . in addition to a direct involvement of these viruses in respiratory diseases, their detection has been associated with other clinical aspects, which may promote viral reactivation or which outcome may be influenced by viral reactivation. an increasing number of papers report the presence of hsv , hcmv and ebv in respiratory samples of critically ill patients even without canonical immunosuppression [ ] [ ] [ ] [ ] [ ] . in patients requiring mechanical ventilation, herpesviruses, mainly hsv and hcmv, may be frequently detected from either upper or lower respiratory tract abstract acute respiratory distress syndrome (ards) is today a leading cause of hospitalization in intensive care unit (icu). ards and pneumonia are closely related to critically ill patients; however, the etiologic agent is not always identified. the presence of human herpes simplex virus , human cytomegalovirus and epstein-barr virus in respiratory samples of critically ill patients is increasingly reported even without canonical immunosuppression. the main aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of ards patients hospitalized in icu. the presence of this group of herpesviruses, in addition to the research of influenza viruses and other common respiratory viruses, was investigated in respiratory samples from patients hospitalized in icu, without a known microbiological causative agent. moreover, the immunophenotype of each patient was analyzed. herpesviruses dna presence in the lower respiratory tract seemed not attributable to an impaired immunophenotype, whereas a significant correlation was observed between herpesviruses positivity and influenza virus infection. a higher icu mortality was significantly related to the presence of herpesvirus infection in the lower respiratory tract as well as to impaired immunophenotype, as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in conclusion, these results indicate that herpesviruses lower respiratory tract infection, which occurs samples [ , ] . it has been suggested that the presence of hsv in the respiratory samples of icu patients correlates with the duration of tracheal intubation [ ] . the detection of hsv in the lower respiratory tract of icu patients is reported with a variable frequency, from to % depending on the population and the diagnostic method used [ , , ] . moreover, it is not always clear whether the demonstration of hsv dna in lower respiratory tract samples of non-immunocompromised ventilated patients is the consequence of a contamination from mouth or throat or is the result of local viral reactivation [ , , , ] . some studies showed that there was a significant association between an hsv viral load > . copies/ml of bal and admission to the icu (p < . ), mechanical ventilation (p < . ) and death (p < . ) [ , , ] . active hcmv infection, either restricted to the lower respiratory tract or involving both the lower respiratory airways and the systemic compartment, has been shown to occur frequently during critical illness in adult hcmv-seropositive patients [ ] , and has been associated with prolonged icu hospitalization, extended periods of mechanical ventilation, higher rates of nosocomial infection and overall mortality [ , [ ] [ ] [ ] [ ] . the role of ebv presence in respiratory tract of icu patients is not clear. high degree of variability concerning the prevalence of ebv in bal samples from patients admitted in icu is reported in the literature [ , [ ] [ ] [ ] [ ] . ards is today a leading cause of hospitalization in icu. ards and pneumonia are closely related to critically ill patients [ ] ; however, it is not always identified the etiologic agent. in most cases, bacterial infections are the main causative agent of pulmonary infections that evolve into framework of ards; more recently, viral infections, mainly related to influenza viruses, represent a new category of emerging cause of ards, and also viruses belonging to other families, in association or not to bacterial infections, may be involved. in still other cases, the causative agent remains unrecognized [ ] . furthermore, the critically ill patients develop a state of immunosuppression, which can promote the onset and exacerbation of viral infections [ ] . the aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of patients hospitalized in icu and to assess the diagnostic and prognostic value of these findings. patients' characteristics, with attention to their immunological setting, were analyzed together with the virological data. institutional internal committee approval was waived for this study as it involved retrospective analysis of anonymous, routinely collected, group data. during the period september -may , patients with diagnosis of ards were admitted to icu (intensive care unit of emergency department-careggi teaching hospital, florence-italy), from different clinical setting. for out of these patients, the causative agent of ards was unknown. the following samples were collected for microbiological analysis: • throat swab (ts) and bronchoalveolar lavage (bal) sent to general laboratory for research of common germs; • ts and bal sent to virology laboratory for the detection of influenza virus and other respiratory viruses like adenovirus (adv), parainfluenza viruses - (piv - ), enterovirus/rhinovirus (ev/rhv), respiratory syncytial virus (rsv), human coronaviruses (hcov) group i and group ii, human metapneumovirus (hmpv) and herpetic viruses. for each patient, the following data were collected: • anamnestic data: age, sex, body mass index (bmi), charlson comorbidity index (cci) adjusted for age; • data and severity scores at icu admission: saps ii at admission, sofa at admission, gcs at admission, provenience, length of stay before icu admission; • data related to respiratory samples: sampling timing, positivity for influenza viruses rna as well as for other respiratory viruses genome sequences, hsv /hcmv/ ebv dna; hsv /hcmv/ebv viral load in bal; • immunophenotyping analysis at icu admission; • data related to icu stay: treatment with antiviral, steroid; need for extracorporeal membrane oxygenation (ecmo) support and duration of treatment with ecmo; • outcome data: saps ii at discharge, gcs at discharge, ventilation length of stay (los), icu los, icu mortality, post-icu los, post-icu mortality. in the study period, samples were analyzed with the aim to look for the presence of herpesviruses in patients. all clinical samples were collected using standard techniques [ ] . the throat swab was obtained with a nylon fiber tip (copan eswab™ system) inserted and rotated into the throat of patient. the bal samples were taken with sterile flexible bronchoscope through the oro-tracheal tube or the tracheal cannula; after the assessment of the tracheal-bronchial tree, ml of sterile saline solution was instilled and picked up in a specimen trap (covidien argyle™). the detection and typing of influenza viruses were achieved as already described, using primers and probe sequence as indicated by the us centers for disease control (cdc) [ ] . for the detection of other respiratory viruses, duplex real-time pcr, already described, was used [ ] . the detection of hsv dna, hcmv dna and ebv dna was performed by in-house assays. the in-house assays here described were already used in the laboratory of virology and had shown a performance comparable with commercial assays, at a lower cost. any way the results here reported were confirmed by comparison with commercial, validated assays (realtime q-pcr kit, elitech molecular diagnostics). extraction of viral dnas from clinical samples was carried out using a commercially available kit (hp pcr template preparation kit, roche diagnostics, milan, italy). to detect hcmv, hsv and ebv dna in ts and bal samples, three real-time pcrs were developed, using primers listed in table . the real-time pcrs were performed using x hrm pcr master mix (qiagen, valencia, ca, usa). the reaction volume for each amplification was μl ( . μl of master mix, . μl of each primer [ μm], μl of dna and h o to reach the final volume). after initial activation step, cycles of amplification [ °c for s, °c for s, °c for s (acquiring green)] were performed. for melting analysis, ramp from to °c was used, rising by . °c each step. the reaction was performed on rotor gene (qiagen, valencia, ca, usa). all herpesvirus-positive bal samples were quantified by quantitative real-time pcrs. to perform the calibration curves, serial dilutions of dna calibrator for each virus were used. these calibrators consisted of dna sequences obtained by the cloning the product of the pcr of viral dna of each virus in the pgem-t easy vector system (promega, madison, wisconsin, usa). the plasmid dna was purified by qiaprep spin miniprep kit (qiagen, valencia, ca, usa). the analytical sensitivity of all pcrs was determined using serial dilutions of cloned calibrators, quantified by nanodrop spectrophotometer (thermoscientific, wilmington, de, usa). the real-time pcr for ebv was able to detect copies number/ml. the sensitivity of real-time pcr for hcmv and hsv was copies number/ml. as the volumes and other characteristics of bal samples can vary, each bal sample was quantitatively analyzed also for the β-globin gene, as described below. then, the results obtained for each sample were normalized according to the ratio [sample target ct value × sample β-globin ct value/mean β-globin ct value] [ ] . the detection of β-globin gene was performed using the primers described in the literature [ ] . the sequence of primers was pf gh ′-caadttcatccacgttcacc- ′ and pr pc ′-gaagagccaaggacaggtac- ′. the real-time pcr was performed using x hrm pcr master mix (qiagen, valencia, ca, usa). the reaction volume was μl ( . μl of master mix, . μl of each primer [ μm], μl of dna and h o to reach the final volume). after initial activation step, cycles of amplification [ °c for s, °c for s, °c for s (acquiring green)] were performed. for melting analysis, ramp from to °c was used, rising by . °c each step. the reaction was performed on rotor gene (qiagen, valencia, ca, usa). peripheral blood samples ( µl) were incubated with the appropriate fluorochrome-conjugated mabs (anti-cd , cd , cd , cd , cd , cd and hla-dr) at room temperature for min; red blood cells were then lysed by an appropriate lysing solution ( µl, bd biosciences) and acquired with a bdlsr ii flow cytometer according to manufacturer's instructions (bd biosciences). at least . cells were acquired and analyzed by using the facs diva software (bd biosciences) [ ] [ ] [ ] . the descriptive analysis is presented as mean and percentage frequencies. the mean values of the groups were compared using the student's t test for numeric values and chi-square test for ordinary variables. the analysis of variance (anova) was used for comparison of the four groups divided according to positivity for viral infections. we created a logistic model to search for variables predictors of death and a receiver operating characteristic (roc) curve to identify the cutoff of saps ii and cd + that discriminate for mortality. a p value < . is considered statistically significant. for statistical analysis and graphic representation of data were used software microsoft excel © , graph pad prism . © and pasw . © for windows (ibm corporation, armonk, ny, usa). this study includes patients who, since september to may , were admitted to icu, from different clinical settings (other icus in . %, ward in . % and emergency department in . %; mean hospital stay pre-icu admission was . ± . days). this group represents . % of all patients admitted in icu with diagnosis of ards, without a known microbiological causative agent; within h after icu admission, clinical samples from these patients were sent to the laboratory for the detection both bacterial and viral infections and for immunophenotyping analysis to assess the immunological status of patients. the descriptive analysis of the entire sample of patients is illustrated in table . in . % of cases, patients required extracorporeal membrane oxygenation (ecmo) for severe ards, with hypoxia and/or hypercapnia unresponsive to conventional treatment. the ecmo los was on average . ± . days. one hundred and eight clinical samples from upper and lower respiratory tract from the icu patients were analyzed to detect influenza and other respiratory viruses and a group of herpesviruses (ebv, hcmv and hsv ). a total of patients ( %) were positive for one or more herpesviruses in at least one respiratory sample ( tf only, bal only, both samples). thus, altogether, herpesviruses were present in bal from patients ( %) and in ts from patients ( %). ebv was detected in out of patients ( %), either as a single infection or as mixed infection. in only patients ( %), ebv dna was demonstrated in bal samples. in cases, it was present as a single infection and in the two other as a mixed infection. hcmv was detected in patients ( %), either as single (in patients) or mixed infection (in patients). in seven patients ( %), hcmv dna was demonstrated in bal samples. as regards hsv , viral dna was detected in patients ( %). in of these ( %), it was present in bal. in addition, as bal represents a sample more suggestive of lower respiratory tract infection and/or of more invasive infection/reactivation, to understand better the significance of herpesviruses presence in this site, herpesviruses dna load in bal samples was assessed by quantitative realtime pcrs. ebv dna viral load in bal samples varied between traces (not quantifiable) in one sample to × copies number/ml in another sample with a median value of copies/ml. altogether, ebv dna load (mean ± sd) was , ± , . the range of hcmv dna load varied between traces (not quantifiable) in one sample to × copies number/ml with a median value of copies/ml also in this case. altogether, hcmv dna load (mean ± sd) was ± . the load of hsv in bal samples varied between copies number/ml in one sample only and copies number/ml with a median value of . altogether, hsv dna load (mean ± sd) was , , ± , , . according to herpetic viral infection positivity, patients were divided into groups: group of hcmv-positive patients (n = ); group of ebv-positive patients (n = ); group of hsv -positive patients (n = ); and group of herpesvirus-negative patients (n = ). patients positive for more than herpesvirus have been included in more than one group. the analysis of the groups is shown in table . there were no statistically significant differences in the medical history data, the severity score values at icu admission and the provenience data. no statistically significant difference in corticosteroid treatment and in the need for extracorporeal treatment was observed. outcome data showed no statistically significant differences, except for a higher mortality in icu in patients with herpetic viral infection (hcmv group: . %, hsv group: . %, ebv group: . %, herpesvirus-negative group: . %; p < . ). a significant correlation emerged between influenza virus infection and herpetic viruses coinfection (p < . ). all patients with influenza positivity were treated with oseltamivir. in patients with persistent influenza infection, zanamivir was added. dividing patients into two groups, based on the positivity for influenza virus, no correlation emerged between influenza infection and icu mortality. the statistically significant data observed are reported in table : patients with influenza infection showed higher incidence of herpesviruses coinfection in comparison with patients without influenza ( . vs . %; p = . ); saps ii demission score was ± . for influenza-positive patients, whereas it was ± . for patients without influenza. in addition, the cd + percentage was . ± . for influenzapositive patients and . ± . for influenza-negative patients. this observation is in agreement with the presence of lymphocytosis as a risk factor for icu admission in laboratory confirmed influenza patients [ ] . an additional analysis was performed by dividing patients into two groups on the basis of icu mortality: the group of survivors included patients discharged from the icu; the group of non-survivors included patients died in icu. the statistically significant data are shown in table . icu mortality was significantly associated with herpesviruses infection in the lower respiratory tract. in fact, % of herpesviruses infected patients died in icu only few patients with laboratory confirmed herpesviruses infection were treated with acyclovir/ganciclovir and despite the treatment they died; however, the small number of observations and the lack of virological monitoring does not allow us to tray any conclusion. several immunological parameters were significantly impaired in the group of patients icu died. in particular, a clear reduction in circulating lymphocytes was evident in this group when compared to the group of patients discharged from icu. the cell reduction involves all lymphocytes populations: t (cd +), b (cd +) and nk cells (cd cd / +). these data can account for both extravasation of cells that are recruited in inflamed organs and for cell apoptosis that typically affects hyper-activated lymphocytes. to evaluate the influence on icu mortality of viral coinfections, patients were divided into groups depending on the presence of influenza and/or herpetic infection. anova analysis showed no statistically significant difference in icu mortality. in the group (n = ) with presence of both infections (herpes and influenza), icu mortality was %; in patients with only influenza positivity (n = ), icu mortality was . %, while in patients with only herpetic positivity (n = ), it was . %; icu mortality was . % in patients with no one viral positivity (n = ) (p = . ). even if these differences are not significant, these data add further evidence to the association of icu mortality with herpesviruses infection, whereas icu mortality in patients with only influenza infection is similar to that of patients negative for both viruses. to better investigate the variables most associated with mortality, we built a logistic model with saps ii, herpesviruses positivity and total cd value. candidate variables were chosen as those statistically significant and/or clinically relevant to the outcome. table shows that the only variable significantly associated with mortality is herpetic infection; this indicates that herpesviruses positivity is an independent predictor of death. moreover, we researched a cutoff value for saps ii and cd + (table ; figs. , ). the logistic regression is slightly over-fitted, but the hosmer-lemenshow test is not significant (p = . ), suggesting a good calibration of the model. ards is a relevant disease today, affecting patients of all ages that may require admission to intensive care unit. the mortality for this pathology is still high, despite the implementation of specific therapies in recent years. in patients with ards, bacterial infections are prevalent; however, there are no enough studies that highlight the presence of viral etiology. among respiratory viruses, influenza a viruses, above all of the subtype (h n )pdm , may be associated with ards, as it became evident during and after the last influenza pandemic. some studies report the frequent presence of herpesviruses in respiratory samples of patients with ards [ ] [ ] [ ] [ ] [ ] [ ] [ ] ] . however, the significance of this positivity is still debated. this report concerns a group of patients admitted to icu because of ards with unknown causative agent; of them were infected by influenza virus, as demonstrated by the detection of viral rna in both upper and lower respiratory tract samples. instead, two other patients, influenza negative, were positive in the bal for rhv and adv, respectively. this study confirms that influenza viruses, mainly the h n pandemic subtype, are frequently related to ards requiring icu hospitalization, whereas other common respiratory viruses showed to be involved only sporadically. in of influenza-positive patients, also the dna of one or more herpesvirus was present in the bal, whereas no coinfection with herpesviruses was found in the patients with rhv or adv infection. thus, in bal of patients, dna of herpesviruses alone was found. these data indicate that in / patients viral infections seem to be involved in ards. however, the number of respiratory virus-positive patients could be underestimated because of the time elapsed between the onset of symptoms and the icu hospitalization. in addition, this study concerned the common respiratory viruses, whereas others like bocavirus and mimivirus were not included. moreover, it is possible that other already unknown viruses exist. data on other causative agents as bacteria or fungi have not been considered in this study. in addition to the detection of a direct viral cause of ards, this study highlights the existence of some interaction among different viruses and also among viruses, immune status and outcome of ards. in fact, a significant correlation was observed between influenza infection and herpesviruses reactivation, demonstrated by the detection of the viral dna in the bal. this observation could suggest that the respiratory mucosa damage caused by influenza virus replication can trigger herpesviruses reactivation. as regards each herpesvirus searched in the respiratory tract of the patients included in this study, ebv was the more frequently detected ( %), whereas both hcmv and hsv were present in the respiratory tract of % of patients. however, in bal ebv dna was found in patients only ( %), and hcmv dna and hsv dna were found in ( %) and ( %) patients, respectively. the frequency and dna load of hsv in bal samples were higher than that of hcmv and ebv, and in patients, it was higher than , copies/ml, a value that is reported in the literature [ ] as related to higher mortality. these results are in agreement with those of tachikawa [ ] who reported that reactivation of hsv was predominantly observed in intubated patients regardless of their immune status, whereas reactivation of hcmv and ebv was rare in immunocompetent patients. herpesviruses reactivation, as could be inferred by the detection of viral dna in bal, was not significantly associated with impaired immunophenotype, whereas it showed to be related to icu mortality. in particular, the highest icu mortality was observed among patients with hcmv reactivation, followed by those with hsv reactivation and then by those with ebv reaction. as regards the role of each herpesvirus here considered, the small number of data for each virus does not allow to draw a definitive conclusion. altogether, it seems that ebv may be involved in ards like the two other herpesviruses, with a slightly lower frequency. furthermore, the data analyzed in this study indicate that icu mortality was significantly related to an impaired immunophenotype as patients with poor outcome showed severe lymphopenia, affecting in particular t (cd +) cells, since the first days of icu hospitalization. in the present study, for the first time, as far as we know, several factors, like respiratory viral infections, respiratory infection/reactivation by some herpesviruses and immune status of the patients, have been considered and analyzed together. the results obtained, even if on a small number of patients, suggest that in a situation such complex as ards and in its outcome these factors may act at same time and synergistically: among these, viral respiratory infection, mainly by influenza a(h n )pdm , herpesviruses reactivation (more frequently hsv , hcmv and also ebv), which may be triggered by the influenza infection, and immune factors (as impaired immunophenotype). this study has several limitations which are in part related to its observational nature and the scanty samples number. it emphasizes the importance of bal analysis, whereas the analysis of viremia was performed only in few patients so that we were not able to afford a systematic analysis of these data, which must be implemented in future studies. in addition, it lacks dynamic data on herpesviruses infection, like resolution or persistence of viral infections. in addition, the usefulness of acyclovir/ganciclovir administration needs to be better studied. the data obtained imply that in ards icu patientsinfluenza virus laboratory diagnosis should be performed more frequently and as soon as possible; herpesviruses lower respiratory tract infection should monitored, together with the immunological evaluation. this could allow for a timely anti-influenza treatment which could decrease the influenza virus damage on the respiratory mucosa and eventually decrease the probability of herpesviruses reactivation. data deriving from the study of the immunological setting suggest that the evaluation of the immunophenotype is essential in order to improve the risk stratification in patients affected by systemic virus infection. detection of herpesvirus ebv dna in the lower respiratory tract of icu patients: a marker of infection of the lower respiratory tract? herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation detection of herpes viruses in respiratory secretions of patients undergoing artificial ventilation monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using real-time pcr: a prospective study clinical impact of hsv- detection in the lower respiratory tract from hospitalized adult patients herpes simplex virus the most frequently isolated pathogen in the lungs of patients with severe respiratory distress herpes simplex virus from the lower respiratory tract in adult respiratory distress syndrome herpes simplex virus in the respiratory tract of critical care patients: a prospective study comment on: 'nosocomial viral ventilatorassociated pneumonia in the intensive care unit' by daubin et al herpes simplex virus pneumonia: clinical, virologic, and pathologic features in patients active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients the clinical interest of hsv semi-quantification in bronchoalveolar lavage immunological insights into the pathogenesis of active cmv infection in non-immunosuppressed critically ill patients prevalence and mortality associated with cytomegalovirus infection in non-immunosuppressed patients in the intensive care unit cmv in critically ill patients: pathogen or bystander increased mortality in long-term intensive care patients with active cytomegalovirus infection active cytomegalovirus infection in patients with septic shock epstein-barr virus: years on quantitative detection of herpes simplex virus dna in the lower respiratory tract quantitative detection of epstein-barr virus in bronchoalveolar lavage from transplant and nontransplant patients herpesviruses detection by quantitative real-time polymerase chain reaction in bronchoalveolar lavage and transbronchial biopsy in lung transplant: viral infections and histopathological correlation acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data respiratory microbiology patterns within the first h of ards diagnosis: influence on outcome assessment of immunological status in the critically ill a fiberoptic bronchoscopy technique to obtain uncontaminated lower airway secretions for bacterial culture the who collaborating centre for influenza at cdc atlanta, united states of america. cdc protocol of real time rt pcr for swine influenza a(h n ) detection of respiratory viruses by duplex real time pcr assays in respiratory samples pandemic a(h n ) influenza virus detection by real time rt-pcr:is viral quantification useful? genital human papillomavirus infection in female university students as determined by a pcr-based method mortality prediction to hospitalized patients with influenza pneumonia:po /fio combined lymphocyte count is the answer persistent lymphopenia after diagnosis of sepsis predicts mortality lymphopenia associated with highly virulent h n virus infection due to plasmacytoid dendritic cell-mediated apoptosis of t cells subjects hospitalized with the pandemic influenza a (h n ) virus in a respiratory infection unit: clinical factors correlating with icu admission clinical relevance of herpes simplex virus viremia in intensive care unit patients detection of herpes viruses by multiplex and real-time polymerase chain reaction in bronchoalveolar lavage fluid of patients with acute lung injury or acute respiratory distress syndrome key: cord- -aiap z u authors: short, briana; parekh, madhavi; ryan, patrick; chiu, maggie; fine, cynthia; scala, peter; moses, shirah; jackson, emily; brodie, daniel; yip, natalie h. title: rapid implementation of a mobile prone team during the covid- pandemic date: - - journal: j crit care doi: . /j.jcrc. . . sha: doc_id: cord_uid: aiap z u purpose: the coronavirus disease (covid- ) is associated with high rates of acute respiratory distress syndrome (ards). prone positioning improves mortality in moderate-to-severe ards. strategies to increase prone positioning under crisis conditions are needed. material and methods: we describe the development of a mobile prone team during the height of the crisis in new york city and describe characteristics and outcomes of mechanically ventilated patients who received prone positioning between april , and april , . results: ninety patients underwent prone positioning for moderate-to-severe ards. sixty-six patients ( . %) were men, with a median age of years (iqr – ), and the median pao( ):fio( ) ratio was (iqr – ) prior to prone positioning. patients required an average of ± . prone sessions and the median time of each prone session was h (iqr . – . ). by the end of the study period, proning was discontinued in sixty-seven ( . %) cases due to clinical improvement, twenty ( . %) cases due to lack of clinical improvement, six ( . %) cases for clinical worsening, and ten ( . %) cases due to a contraindication. conclusion: the rapid development of a mobile prone team safely provided prone positioning to a large number of covid- patients with moderate-to-severe ards. during the coronavirus disease (covid- ) pandemic, an overwhelming majority of those requiring icu level of care had acute hypoxemic respiratory failure requiring mechanical ventilation for acute respiratory distress syndrome (ards) ( ). ards is common. in one large observational study, . % of patients requiring mechanical ventilation for acute respiratory failure met criteria for ards. mortality from ards depends on severity, and ranges from - % ( ) . prone positioning, when used in conjunction with low tidal volume ventilation, has been shown to significantly reduce mortality in moderate-to-severe ards ( ) ( ) ( ) . despite the evidence, the use of prone positioning in moderate-to-severe ards remains low ( , ) . barriers to implementation of prone positioning include lack of provider recognition of ards, uncertainty of evidence, and resource utilization ( , ) . our medical intensive care unit (micu) instituted a prone positioning program in for the management of moderate-to-severe ards. the micu prone program was a nursing-led initiative that trained micu nurses in safe manual placement of patients with ards in the prone position. indications for proning were based on prior evidence ( ), including patients with the covid- prone team at newyork-presbyterian -columbia university irving medical center was developed as a dedicated mobile team comprised of a micu clinical nurse specialist (cns), occupational therapists (ots), and physical therapists (pts), who were redeployed to this role from their usual clinical jobs. twelve ots and twelve pts were trained to be part of the team during the height of the pandemic. they all had cardiopulmonary rehabilitation experience, and most have worked with icu patients as part of our early mobilization program. in addition to knowledge of body mechanics and positioning critically ill patients, they had experience in securing airways, lines, drains, and monitoring devices in an icu setting. the covid- prone team covered separate icus, a combined total of covid icu beds. their day-to-day availability increased based on demand, up to days a week, from am to pm at the peak, for days. if a patient needed to be emergently repositioned outside of the covid- prone team hours, they were repositioned by micu nurses. in the event of cardiac arrest, if a patient could not be safely placed in the supine position, the protocol specified the prone position should be maintained for cardiopulmonary resuscitation in an effort to minimize risk of ventilator circuit disconnect with the associated risk of aerosolization of viral particles ( , prone positioning. all patients requiring proning during this time were proned by this team, including within the micus. during this same period, patients were admitted to our hospital with covid- requiring invasive mechanical ventilation. baseline characteristics of these patients are shown in table . the majority of patients who required prone positioning were men ( . %), with a median age of years (range - ). there was a high prevalence of comorbid hypertension ( . %) and diabetes ( . %). all of the icus, including those newly created during the covid- pandemic, had patients treated by the covid- prone team. by the end of the study period, proning was discontinued in sixty-seven ( . %) cases due to improvement in gas exchange, in twenty ( . %) cases due to lack of clinical improvement, in six ( . %) cases for clinical worsening and in ten ( . %) cases due to the development of a contraindication. thirty-six patients died and remained alive ( table ) the rapid implementation of the mobile covid- prone team that travelled to multiple icus at our institution during the height of the covid- pandemic, increased the ability to prone patients with moderate-to-severe ards. in a -day period, patients were proned by this team with individual proning sessions. after implementation of the covid- prone team, more patients who met criteria for prone positioning were actually proned, as patients intubated were proned between march , and march , ( ) compared to during the study period. by utilizing ots and pts who were familiar with critical illness and positioning patients, and by developing a careful but efficient training program, the covid- prone team was able to safely provide an evidence-based intervention to critically ill patients with ards in a variety of icu settings. prone positioning has been shown to have a mortality benefit in patients with moderate-tosevere ards, but has been underutilized due to provider under-recognition of ards, frequent misunderstanding of its indications, disbelief in quality of evidence, and resource utilization, which during times of crisis is more pronounced ( , ) . during the covid- pandemic, the concentration of patients with moderate-to-severe ards increased considerably. this increase this study has several limitations. while we are able to describe the characteristics of the patients treated, we have limited data to define the overall population of moderate-to-severe ards patients in our hospital during the study period. it is unclear what proportion of patients with moderate-to-severe ards received this therapy when indicated. also, with limited data on the incidence of moderate-severe ards in our hospital prior to the covid- pandemic, it is unclear if our proning rate changed with this implementation. however, prior to covid- , proning was only available to patients in the micus therefore limiting this treatment to the capacity of the micu. lastly, our outcomes data is limited by the study duration. at the end of the study, forty-five patients were still hospitalized, therefore the outcome of these treated patients is yet to be determined. however, of the fifty-four patients whose hospital survival is yet to be determined, thirty-six ( %) patients had prone therapy stopped due to clinical improvement. the feasibility and success of the covid- prone team has created the possibility of sustaining and even expanding prone positioning capabilities across our hospital network in case of a future crisis. further education and training can be disseminated to nurses and clinicians working in non-medical icus, utilizing some of the training materials and personnel in the covid- prone team. during the covid- pandemic, the rapid development and implementation of a mobile prone team allowed for increased capacity to prone patients with moderate-to-severe ards in icus beyond the micus to meet the surge of critically ill patients during the height of the pandemic. this was done effectively and with tolerable adverse outcomes. (iqr - ) bmi= body mass index; sofa = sequential organ failure assessment; icu=intensive care unit; cc/kg=centimeters per kilogram; cm h = centimeters of water; peep=positive end expiratory pressure; fio =fraction of inspired oxygen; pao = partial pressure or arterial oxygen epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries mercat a, investigators of the apronet study group trntrrdlsfda-r, the etg. a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study prone positioning in severe acute respiratory distress syndrome prone ventilation reduces mortality in patients with acute respiratory failure j o u r n a l p r e -p r o o f journal pre-proof and severe hypoxemia: systematic review and meta-analysis acute respiratory distress syndrome: advances in diagnosis and treatment reverse cpr: a pilot study of cpr in the prone position zelop cm, topjian a. interim guidance for basic and advanced life support in adults, children, and neonates with american association for respiratory care, american college of emergency physicians, the society of critical care anesthesiologists, and american society of anesthesiologists: supporting organizations: american association of critical care nurses and national ems physicians neuromuscular blockers in early acute respiratory distress syndrome surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region covid- does not lead to a "typical" acute respiratory distress syndrome figure : number of interventions per day: daily number of interventions completed by the prone team. includes placing in both the supine and prone position. x axis represents dates in we would like to acknowledge the physical therapist, occupational therapists and nurses who worked tirelessly on the covid- prone team for their extraordinary efforts throughout this pandemic. we would also like to acknowledge our fellow healthcare workers for their dedication to outstanding patient care during this unprecedented pandemic and express our profound sympathy to our patients, their families and the community for all those who suffered during the pandemic. j o u r n a l p r e -p r o o f key: cord- - dergkha authors: wang, tiehua; liu, zhuang; wang, zhaoxi; duan, meili; li, gang; wang, shupeng; li, wenxiong; zhu, zhaozhong; wei, yongyue; christiani, david c.; li, ang; zhu, xi title: thrombocytopenia is associated with acute respiratory distress syndrome mortality: an international study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: dergkha background: early detection of the acute respiratory distress syndrome (ards) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (icu). however, no reliable biomarkers are currently available for accurate early detection of ards in patients with predisposing conditions. objectives: this study examined risk factors and biomarkers for ards development and mortality in two prospective cohort studies. methods: we examined clinical risk factors for ards in a cohort of patients in beijing, china who were admitted to the icu and were at high risk for ards. identified biomarkers were then replicated in a second cohort of , patients in boston, usa. results: of patients recruited from participating hospitals in beijing, developed ards. after multivariate adjustment, sepsis (odds ratio [or]: . , % ci: . – . ), pulmonary injury (or: . ; % ci: . – . ), and thrombocytopenia, defined as platelet count < × ( )/µl, (or: . ; % ci: . – . )were significantly associated with increased risk of developing ards. thrombocytopenia was also associated with increased mortality in patients who developed ards (adjusted hazard ratio [ahr]: . , % ci: . – . ) but not in those who did not develop ards(ahr: . , % ci: . – . ). the presence of both thrombocytopenia and ards substantially increased -daymortality. sensitivity analyses showed that a platelet count of < × ( )/µlin combination with ards provide the highest prognostic value for mortality. these associations were replicated in the cohort of us patients. conclusions: this study of icu patients in both china and us showed that thrombocytopenia is associated with an increased risk of ards and platelet count in combination with ards had a high predictive value for patient mortality. acute respiratory distress syndrome (ards), the most severe form of acute lung injury (ali), is caused by several direct and indirect insults to the lung,life threatening and often lethal. ards usually requires mechanical ventilation and admission to an intensive care unit (icu); ards is a major cause of icu morbidity and mortality worldwide [ ] . emerging viral diseases such as severe acute respiratory syndrome (sars) coronavirus, h n avian-origin influenza virus, and h n swine-origin influenza virus not only possess the potential for pandemic spread, but also cause ards [ ] [ ] [ ] .these factors highlight the need for additional research to improve understanding of the pathogenesis of ards, with the ultimate goal of developing specific treatment [ ] . ards is associated with several clinical disorders, including direct pulmonary injury from pneumonia and aspiration and extra-pulmonary injury from sepsis, trauma, and multiple transfusions [ ] . although low tidal volume ventilation, neuromuscular blockers and prone positioning ventilation have advanced treatments [ ] [ ] [ ] , there are currently no reliable predictive markers for early detection of ards in predisposed individuals. nonetheless, many efforts have been mounted to identify biologic markers, or biomarkers, for ards in critically ill patients, including studies of pulmonary edema fluid, blood, and urine [ ] [ ] [ ] . recent advances on the pathophysiological mechanisms underlying ards have identified several clinical biomarkers to assess disease severity and outcome, including specific cytokines and their receptors (il- , il- , soluble tumor factor receptors i and ii), products of epithelial and endothelial injury [receptor for advanced glycation end-products (rage), surfactant protein d, icam- , and von willebrand factor antigen], and markers of altered coagulation (protein c and plasminogen activator inhibitor- ) [ ] . however, no individual biomarker is strongly associated with outcomes and thus cannot provide sufficient discriminating power for either diagnosis or prognosis. biomarker discovery and validation requires patient samples and must be combined with comprehensive clinical data collected from properly designed trials in different populations. given the acute onset and rapid clinical progress of ards, a prospectively enrolled cohort study in multicenter icus is suitable for more complete and unbiased ards/ali research [ ] . using a protocol modified from a molecular epidemiology ards study established in boston, ma (boston cohort) [ ] , we established a multicenter ards cohort in beijing, china (beijing cohort) in . the overarching objectives of establishing this prospective cohort are to validate relevant biomarkers to ards, as well as genetic polymorphisms, discovered in previous usa studies in chinese population, and discover new biomarkers of ards with a comprehensive sampling protocol. in this report, we present initial results on the clinical factors associated with ards development and mortality in individuals with or at risk for ards. associated clinical factors were replicatedin the boston cohort. this study was approved by the institutional review boards(irbs) of the peking university third hospital, beijing friendship hospital, china-japan friendship hospital, beijing chao-yang hospital, and harvard school of public health and a written informed consent was obtained from each subject or an appropriateproxy of the patient. four medical and surgical icus within four tertiary hospitals participated in the study; hospitals covered the metropolitan area of beijing, china and included peking university third hospital in the northwest ( beds), beijing friendship hospital in the south ( beds), beijing chao-yang hospital in the east ( beds), and china-japan friendship hospital in the northeast ( beds). as an international collaboration, we used a modified study protocol for recruitment as previously described [ ] . briefly, we screened each icu admission for eligible subjects, which were defined as critically ill patients with at least one predisposing condition for ards: ) sepsis; ) septic shock; ) trauma; ) pneumonia; ) aspiration; ) massive transfusion of packed red blood cells (prbc; defined as . prbc units during the hours prior to admission); or ) severe pancreatitis. to avoid interference in biomarker research from certain clinical conditions, exclusion criteria included: ) age , years; ) history of chronic lung diseases, such as interstitial pulmonary fibrosis or bronchiolitis; ) history of pneumonectomy; ) treatment with immunomodulating therapy other than corticosteroids, such as granulocyte colony stimulating factor, cyclophosphamide, cyclosporine, interferon, or tnf-a antagonists; ) presence of other immunodeficient conditions, such as hiv infection, leukemia, or neutropenia (absolute neutrophil count , /ml); ) history of solid or bone marrow transplant other than autologous bone marrow transplant; and ) directive to withhold intubation. sepsis and septic shock were defined by the american college of chest physicians/society of critical care medicine (accp/sccm) consensus conference [ ] . after enrollment, subjects were followed daily for the development of ards, as defined by the american-european consensus committee (aecc) as follows [ ] : a) evidence of hypoxemia with pao /fio # mm hg; b) evidence of bilateral infiltrates on chest radiographs; and c) absence of left atrial hypertension with pulmonary arterial occlusion pressure # mm hg or no congestive heart failure. controls were identified as at-risk patients who did not meet criteria for ards during the icu stay and had no prior history of ards. infiltrates on chest radiographs were defined as opacities that could not be explained completely by pleural effusions, mass, body habitus, or collapse. upper zone redistribution and pulmonary vascular congestion were not considered infiltrates. two pulmonary and critical care physicians interpreted daily chest radiographs; any disagreement went to a third intensivist for arbitration. all physicians underwent a consensus training session on the radiologic criteria for ards. all were blinded to the clinical status of the patients. we collected clinical data by chart review, including demographic information of age, gender, race, height, weight and medical history of ards, diabetes, tobacco and alcohol abuse, and liver disease. baseline clinical information, worst vital signs, and laboratory testing results in the first hours of icu admission were collected for calculation of the acute physiological and chronic health evaluation (apache ii) score for severity of illness [ ] . we also collected ventilatory parameters including the requirement and mode of mechanical ventilation, pao /fio ratio, positive end-expiratory pressure, tidal volume, and peak and plateau pressures. all enrolled patients were followed until one of the following situations occurred: hospital discharge, death, or days after study entry. starting in late , based on finding from ards network trials, chinese icus universally adopted lower tidal volume for mechanical ventilation [ ] . baseline characteristics were compared between groups with fisher's exact test or chi-square test for dichotomous or categorical variables and with student's t test or mann-whitney test for continuous variables. for risk analysis of ards development, we initially used a logistic regression model with a backward stepwise elimination algorithm to select clinical risks or predictors from the univariate analyses with p, . ; the final logistic regression models also included predictors from backward elimination. for mortality analysis, we used the log-rank test as a univariate measure of association and employed cox proportional hazards models to investigate each clinical variable's effect on clinical outcome. we used the time-dependent receiver operating characteristic (roc) method to determine the best cut-off value of thrombocytopenia in the prediction of prognosis of critically ill patients by exploring the area-under-the-curve (auc) values at -day mortality, and selected the maximal sumof sensitivity and specificity [ ] . all analyses were performed with the sas statistical software package (version . , sas inc., cary, nc), and p, . was considered statistically significant. between july and april , we recruited patients with at least one predisposing condition for ards from the participating hospitals in beijing, china. the majority of patients were male (n = , %) and the mean age was years (median: ; interquartile range: - years) ( table ). median apache ii score was (interquartile range: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and median length of time in the icu was . days (interquartile range: - days). mechanical ventilation was used on patients ( %) for a median length of six days (interquartile range: - days). thirtynine patients had diabetes, and one patient had chronic kidney disease. during hospitalization, ( %) patients developed ards;among identified cases, ( %) and ( %) of the ards patients were diagnosed within the first and hours of icu admission, respectively. there were no significant differences in age, gender, smoking status, and initial apache ii score between ards patients and at-risk non-ards patients (table ). in addition, the major physiological variables during the first hours of icu admission were comparable, except that patients who developed ards had higher respiratory rates (p = . ). although not significant, ards patients were in the icu longer (ards median = days; non-ards median = days; p = . ) and on mechanical ventilation longer (ards median = days; non-ards median = days;p = . ) than non-ards patients. low tidal volume (, ml/kg) was used in treating patients with mechanical ventilation. although patient specific data was not available, protocolled low tidal volume ventilation was standardized in study icus. among predisposing conditions for ards in all enrolled patients, sepsis and/or septic shock (n = , %) were the most [ ] were associated with development of ards.respiratory rate (. breaths/min), aspiration, and . risks for ards were also evaluated in model selection but were eliminated during model selection (not significant). apache ii score (removing age and gender components), age, and gender were forced in as covariatesbut not significant in logistic regression analyses. known factors related to ards, including septic shock, diabetes, and alcohol use, were also tested either by forcing as covariates, individually or combined into the model, and did not change the significant associations of sepsis, direct pulmonary injury, and thrombocytopenia with the development of ards (data not shown).because drinking habits in china differ from those in the u.s.,and it was difficult to develop a comparable criterion for alcohol abuse, we did not including alcohol abuse as risk factor in the analysis. we further conducted a stratified analysis and found that thrombocytopenia was significantly associated with ards in both the beijing cohort (univariate analysis, p = . ) and the boston cohort (univariate analysis, p, . ) (table s ), which has ards and , non-ards patients recruited at massachusetts general hospital in boston, usa [ ] , in the subgroup patients with septic shock, but not in non-septic shock subgroup (p = . and p = . , respectively). some patients had already developed ards before icu admission, and this subgroup caseswas usually mixed with those patients who were diagnosed ards during the first hours of icu admission, together accounting for a total of % ards in the beijing cohort and % in the boston cohort ( of identified cases). since the thrombocytopenia was defined by the lowest platelet counts during the first hours of icu admission in these cohorts, some patients developed thrombocytopenia before the onset of ards, who were difficult to be distinguished within this subgroup ards, and could interfere with the finding that thrombocytopenia was associated with development of ards. we then performed a nested analysis on a clean subgroup patients, by removing ards patients who were diagnosed during the first hours of icu admission, and found that thrombocytopenia was still significantly associated with ards risk (or = . ; % ci = . - . ; p = . ). because of the small sample size of the beijing cohort, we further conducted the sensitivity test in the boston cohort in ards cases and , non-ards patients after removing ards patients who were the -day mortality rate for all patients was %, and the development of ards did not increase mortality risk (table ) . among predisposing conditions for ards, septic shock was associated with increased mortality (p = . ), but pancreatitis was associated with decreased mortality (p = . ) in ards patients ( table ). in contrast, pneumonia (p = . ) and external pulmonary injury (p = . ) had higher mortality rates in non-ards patients. univariate examination of demographic characteristics and physiologic variables in the first hours of icu admission revealed that higher apache ii scores and older age were associated with increased mortality for both ards and non-ards patients ( table ) . thrombocytopenia was significantly associated with mortalityof ards (p = . ) but not non-ards (p = . ) patients. in contrast, high serum creatinine levels (. . mg/l) were associated with higher mortality in non-ards (p = . ) but not ards (p = . ) patients. there were no statistically significant differences between survivors and nonsurvivors for gender, history of diabetes, and tobacco or alcohol use. in multivariate analysis, apache ii score was consistently associated with increased mortality in ards, non-ards, and all patients (table ) . thrombocytopenia was a mortality covariate for ards and all patients, but not for non-ards patients (table ) . when replaced with coagulation points of the sequential organ failure assessment score (sofa), thrombocytopenia remained associated with higher mortality in ards [adjusted hazard ratio (ahr) = . ; % ci = . - . ; p = . ]and all patients (ahr = . ; % ci = . - . ; p = . ), but not in non-ards patients (ahr = . ; % ci = . - . ; p = . ). to replicate our findings, we analyzed data from the boston cohort. although univariate analyses identified more physiologic variables in the first hours of icu admission and ards-predisposing conditions significantly associated with mortality (table s and s ), multivariate analyses identified apache ii score and thrombocytopenia as major risk factors for mortality in ards, non-ards, and all patients ( table ) . we also found similar results when thrombocytopenia was replaced with coagulation points of the sofa score (data not shown). we further investigated the interaction between thrombocytopenia and ards on mortality of all patients by creating a combined covariate of the boston and beijing cohorts. in both univariate ( figure ) and multivariate (figure ) analyses, the combination of thrombocytopenia and ards had consistently higher patient mortality. taking advantage of the size of the boston cohort, we conducted a sensitivity analysis to determine the optimal platelet count for prognosis.with adjustmentsfor age, gender, apache ii score, and sepsis, a platelet count of /mlhad the maximal roc value (auc = . ; sensitivity = . ; specificity = . ; p = . ). a sensitivity analysis confirmed a platelet count of /ml by considering a series of stepped ( /ml)cut- this prospective multicenter cohort was established using a modified protocol originally implemented in the boston cohort [ ] . among at-risk icu patients, % developed ards during icu admission, and a majority of those patients ( %) developed ards within the first hours of admission. these observations are consistent with previous reports in the mostly-caucasian boston cohort [ ] . moreover, the profiles of baseline physiologic variables and the major clinical risk factors between ards and atrisk non-ards patients are similar to previous reports from chinese [ , ] andamerican [ ] icus.furthermore, the observation of high baseline respiratory rate (. breaths/min) associated with ards cases was consistent withthe findings from several previous studies [ ] [ ] [ ] . in this cohort, in addition to sepsis and direct pulmonary injury, thrombocytopenia was associated with the development of ards.enhanced platelet activation resulting in platelet deposition within the damaged pulmonary microvasculature has been supported by several clinical and preclinical studies of ali [ , ] , and thrombocytopenia has been reported as a key feature of sars [ ] . in the boston cohort, thrombocytopenia (named hematologic failure) was also identified as a risk factor for ards in multivariate analysis [ ] . in another cohort of ali in rochester, minnesota (mayo clinic), however, researchers did not observe significant difference of platelet count between ali and non-ali patients with septic shock [ ] . since the rochester cohort only focuses on a subgroup icu patients with septic shock, our stratified analysis revealed that thrombocytopenia was significantly associated with ards in both the beijing cohort and the boston cohort in the subgroup patients with septic shock, but not in non-septic shock subgroup. the different results might be explained by that the beijing cohort and the boston cohort focused on ards, which is the most severe form of ali. a major finding of this study is the association ofthrombocytopenia with increased ards mortality. extensive evidence demonstrates that platelet count and function are independently associated with increased icu morbidity and mortality [ ] . although thrombocytopenia is a well-established prognostic marker for mortality in patients with sepsis and septic shock [ ] , which are risk factors for developing ards, thrombocytopenia has been inconsistently associated with ards mortality in two previous studies with small patient series representing noncontemporary treatment eras [ , ] . besides apache ii score, thrombocytopenia was the only risk factor for ards mortality identified in the beijing cohort. further, this association was replicatedwitha larger population and different ethnicities in the boston cohort. these results provide strong evidence that thrombocytopenia is a prognostic marker for ards mortality. in both beijing and boston cohorts, the combination of thrombocytopenia and ards further increased risk of -day mortality among critically ill patients. thrombocytopenia in icu patients is caused by multiple factors [ ] and is considered a marker of illness severity with multiple organ dysfunction scores (mods), simplifiedacute physiology scores (saps), and apache scores.sepsis alone can cause moderate thrombocytopenia, as maladaptive platelet-neutrophil interactionssignificantly increase platelet activation and aggregation, as well as tissue injury [ ] . the lung epithelium is central to both the pathogenesis and resolution of ards, and intra-alveolar coagulation changes (e.g., platelet-fibrin deposition and pulmonary vascular thrombi) are hallmarks of pathologic changes in ards [ ] . thus, thrombocytopenia likely contributes to the development of ards; in return, the coexistence of ards may aggravate thrombocytopenia to increase mortality of critically ill patients. we used the same platelet count criterion from the boston cohort (, /ml)to define thrombocytopenia [ ] . although platelet counts are routinely measured daily in the icu, the epidemiology of thrombocytopenia in critically ill patients has not been well studied. further, illness severity scoring systems inconsistently consider platelet count;for example, the sofa score incorporates platelet count, whereas the apache score does not. different platelet count thresholds have been used in epidemiological studies for the prevalence, incidence, risk factors, and consequences of thrombocytopenia among critically ill patients [ ] . currently, the rand/ucla appropriateness methodrecommends a platelet count threshold of , / ml, or a . % decrease in platelet counts, for epidemiological research of thrombocytopenia [ ] . taking advantage of a large patient population in the boston cohort, we conducted a sensitivity analysis and determined that platelet count (, /ml) was a significant prognostic marker for ards. we further replicated this cut-point value in the beijing cohort. there were some differences between the beijing and boston cohorts. when evaluated individually, there were different association profiles for thrombocytopenia and ards with mortality of all patients with at least one risk factor for ards. thrombocytopenia was significantly associated with higher mortality in the beijing cohort, but not the boston cohort. conversely, ardswas associated with higher mortality in the boston cohort, but not the beijing cohort. it is unexpected that ards did not increase mortality in the beijing cohort, and. it is counter-intuitive that in the univariate analysis thrombocytopenia would be associated with increased mortality in the ards group but not in the non-ards group given that thrombocytopenia is a marker of severity of illness in critical care populations generally. however, the raw numbers were in the direction of higher mortality with lower platelets in the non-ards group, these findings could be explained by the limitation of multiple subgroup analysis in a relatively small dataset. moreover, for several known risk factors or comorbidities of ards [ , [ ] [ ] [ ] , such as septic shock, pneumonia, pancreatitis, trauma, multiple transfusions, and diabetes, we did not observe significant different between ards and non-ards patients in the beijing cohort. due to the relative scarcityand high cost of medical resources to the general chinese population, the participating hospital icus in the beijing cohortmay have admitted more severely ill patients, resulting in less difference in illness severity between ards and non-ards patients. accordingly, although most physiologic variables of the first hours of icu admission, including apache score, were comparable between ards and non-ards beijing cohort patients, thrombocytopenia (platelet counts , /ml) was more common in the beijing cohort than the boston cohort ( . % vs. . %, respectively; p, . ). it is also possible that different ethnicities account for the observed differencesbetween cohorts. based on the boston cohort, our study protocol was modified by the inclusion of severe pancreatitis as a predisposing condition for ards. severe pancreatitis is a well-established risk factor for the development of ards [ ] and is frequently observed in critically ill patients in china. in the beijing cohort, we identified ( . %) cases of severe pancreatitis, similar to a previous report of . % in a large chinese icu survey [ ] . about % of severe pancreatitis cases eventually developed ards during icu admission. severe pancreatitis was not associated with ards risk, but was associated with lower mortality. however, the beijing study is limited by a small sample size. with the patients' enrollment keeps, we will further evaluate severe pancreatitis as a clinically important factor in the development and outcome of ards. this study describes the successful establishment of a prospective, multicenter cohort study of critically ill patients at-risk for ards in beijing, china. initial characterization of the clinical factors associated with ards risk and mortality revealed an association between thrombocytopenia and ards mortality. we replicated these findings in the larger and more diverse boston cohort, suggesting that the beijing cohort can provide comprehensive data and samples to identify biomarkers for the early diagnosis, prognosis, and treatment of ards. epidemiology of acute lung injury and acute respiratory distress syndrome interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome newly recognized causes of acute lung injury: transfusion of blood products, severe acute respiratory syndrome, and avian influenza future research directions in acute lung injury: summary of a national heart, lung, and blood institute working group the acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome plasma protein c levels in patients with acute lung injury: prognostic significance elevated plasma levels of soluble tnf receptors are associated with morbidity and mortality in patients with acute lung injury higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury the pathogenetic and prognostic value of biologic markers in acute lung injury clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion sepsis change bundles: converting guidelines into meaningful change in behavior and clinical outcome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination apache ii-a severity of disease classification system ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury time-dependent roc curves for censored survival data and a diagnostic marker management of thrombocytopenia in the icu (pregnancy excluded) prognostic significance of elevated cardiac troponin-t levels in acute respiratory distress syndrome patients epidemiological investigation on acute respiratory distress syndrome occurring in intensive care units in beijing from retrospective analysis on acute respiratory distress syndrome in icu risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation* intravascular coagulation associated with the adult respiratory distress syndrome the risk factors, incidence, and prognosis of ards following septicemia the severe acute respiratory syndrome thrombocytopenia and prognosis in intensive care multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome adult respiratory distress syndrome. prognosis after onset adult respiratory distress syndrome. sequence and importance of development of multiple organ failure. the prostaglandin e study group coagulopathy in critically ill patients: part : platelet disorders beyond thrombosis: the versatile platelet in critical illness the epithelium in acute lung injury/ acute respiratory distress syndrome the frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review acute lung injury and ards in acute pancreatitis: mechanisms and potential intervention risk factors for the prognosis of acute kidney injury under the acute kidney injury network definition: a retrospective, multicenter study in critically ill patients the authors would like to thank michelle gong, ednan k. bajwa, and taylor thompson from the molecular epidemiology of ards project for help in study design and preparation of study protocols. key: cord- -kpjp sx authors: li, xu; ma, xiaochun title: acute respiratory failure in covid- : is it “typical” ards? date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: kpjp sx in december , an outbreak of coronavirus disease (covid- ) was identified in wuhan, china. the world health organization (who) declared this outbreak a significant threat to international health. covid- is highly infectious and can lead to fatal comorbidities especially acute respiratory distress syndrome (ards). thus, fully understanding the characteristics of covid- -related ards is conducive to early identification and precise treatment. we aimed to describe the characteristics of covid- -related ards and to elucidate the differences from ards caused by other factors. covid- mainly affected the respiratory system with minor damage to other organs. injury to the alveolar epithelial cells was the main cause of covid- -related ards, and endothelial cells were less damaged with therefore less exudation. the clinical manifestations were relatively mild in some covid- patients, which was inconsistent with the severity of laboratory and imaging findings. the onset time of covid- -related ards was – days, which was inconsistent with ards berlin criteria, which defined a -week onset limit. some of these patients might have a relatively normal lung compliance. the severity was redefined into three stages according to its specificity: mild, mild-moderate, and moderate-severe. hfno can be safe in covid- -related ards patients, even in some moderate-severe patients. the more likely cause of death is severe respiratory failure. thus, the timing of invasive mechanical ventilation is very important. the effects of corticosteroids in covid- -related ards patients were uncertain. we hope to help improve the prognosis of severe cases and reduce the mortality. in december , an outbreak of coronavirus disease (covid- ) , which was caused by severe acute respiratory syndrome coronavirus (sars-cov- ), broke out in wuhan, china [ ] [ ] [ ] . the world health organization (who) declared it a significant threat to international health [ ] . covid- was of clustering onset and mainly affected the respiratory system with some patients rapidly progressing to acute respiratory distress syndrome (ards); other organ functions were less involved [ , ] . these patients were likely to be admitted to the intensive care unit (icu) and might die. the elderly and those with comorbidities are at highest risk of death. the death appeared to be related to ards [ ] . although several studies have reported the clinical features of covid- [ , [ ] [ ] [ ] [ ] [ ] [ ] , our understanding about it remains limited [ ] . can we consider all the cases of acute respiratory failure associated with covid- as ards? the answer is probably no. based on current reports and our experience in the management of covid- -related ards patients, we realized that there are many differences between covid- -related ards and ards caused by other factors as defined by berlin criteria, and therefore differences in treatment. thus, we aimed to describe the characteristics of covid- -related ards and to elucidate the differences (fig. ). ards occurs as a result of an acute systemic inflammatory response, which can be caused by insults to the lung, either direct or indirect. the early exudative stage presents diffuse alveolar damage with destruction of epithelial and endothelial cells. covid- mainly affected the respiratory system with minor damage to other organs. studies reported that acute myocardial injury ( . - %) and acute renal injury ( . - %) could occur in severe patients. the reported incidence of ards was . - %, higher than that of other organ injuries [ , [ ] [ ] [ ] [ ] . the most common respiratory symptom of covid- is dry cough ( . - %) [ , [ ] [ ] [ ] [ ] . sputum production was less. it suggested that injury to the alveolar epithelial cells was the main cause of covid- -related ards, and endothelial cells were less damaged with therefore less exudation. endothelial cells line the inner surface of blood vessels in all organs. it was possible that due to less damage to the endothelial cells, other organ functions were less involved in covid- patients. the respiratory system was mainly involved in covid- patients as mentioned above. some patients had a low oxygenation index, indicating severe respiratory failure. chest imaging findings suggested the involvement of both lungs. chest computed tomography (ct) scans usually showed multifocal bilateral patchy shadows and/ or ground-glass opacities; some patients showed a mixed pattern of ground-glass opacities and consolidation [ ] . the ct results indicated diffuse and severe lung injury. however, the clinical manifestations were relatively mild in some patients. these patients might have no complaint of dyspnea, no significant increase in respiratory rate, and no respiratory distress. hemodynamics and indexes of tissue perfusion such as lactate were also relatively stable. the clinical symptoms were inconsistent with the severity of laboratory and imaging findings. however, these patients may deteriorate rapidly and need to be monitored closely. blood carbon dioxide levels may be a meaningful indicator for invasive mechanical ventilation. timing of onset the ards berlin criteria defined that for a patient to be diagnosed as having ards, the onset must be within week of a known clinical insult or new or worsening respiratory symptoms [ ] . the reported onset of covid- -related ards was similar in different studies. huang et al. [ ] first reported cases of covid- in which the median time from onset of symptoms to ards was . days ( . - . ). subsequently, wang et al. [ ] reported cases of covid- in which the median time from the first symptom to ards was . days ( . - . ). zhou et al. [ ] reported the median time from illness onset to ards was . days ( . - . ). studies by chen et al. [ ] and guan et al. [ ] did not report the onset of ards. as the onset time of covid- -related ards was - days, it suggested that the -week onset limit defined by ards berlin criteria did not apply to covid- -related ards. it reminded us to pay more attention to the development of ards in patients with the course of more than a week, so as to treat timely. not all the cases of acute respiratory failure caused by covid- were ards. the typical ct findings of covid- showed bilateral ground-glass shadow with a peripheral lung distribution [ ] . although there was consolidation and exudation, it was not a "typical" ards image. ards is a condition associated with many disease processes, resulting in reduced lung compliance and severe hypoxemia [ ] . lung compliance might be relatively normal in some covid- -related ards patients who met ards berlin criteria. this was obviously inconsistent with ards caused by other factors. in addition, the lung compliance was relatively high in some covid- -related ards patients, which was inconsistent with the severity of hypoxemia. according to the berlin definition, ards is divided into three stages based on oxygenation index (pao /fio ) on positive end-expiratory pressure (peep) ≥ cmh o: mild ( mmhg < pao /fio ≤ mmhg), moderate ( mmhg < pao /fio ≤ mmhg), and severe (pao / fio ≤ mmhg) [ ] . ards classification determines both the severity of the disease and choice of treatment protocol. a previous study reported that more than % of patients with moderate and severe ards according to the berlin definition did not show diffuse alveolar damage [ ] . in fact, the specific ranges under which the hypoxemia is evaluated differ among clinicians. from the perspective of therapy, the intensity of adjunctive treatment varies according to the degree of hypoxemia. thus, we need a more suitable classification of ards severity that can accurately identify patients for a specified therapy. till now, the clinical features of covid- -related ards are still unclear. there are no specific monitoring and implementation protocols. under the current situation, a number of designated hospitals and dozens of medical teams from different provinces have participated in the treatment. the unified ards treatment standard is needed in order to improve the uniformity and thus reduce the mortality. therefore, experts from the national health commission of china developed a standard treatment protocol for covid- based on their experience. covid- -related ards was divided into three categories based on oxygenation index (pao /fio ) on peep ≥ cmh o: mild ( mmhg ≤ pao /fio < mmhg), mild-moderate ( mmhg ≤ pao /fio < mmhg), and moderate-severe (pao /fio < mmhg) [ ] . the new stratification for covid- -related ards determines personalized treatment for different patients. in fact, a number of ards treatments, including prone positioning and neuromuscular blockers, are recommended for patients with pao /fio less than mmhg. this indicates that berlin classification is not suitable to define the severity of ards and accurately guide the corresponding treatments. hypoxemic respiratory failure in ards generally results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. compared to standard oxygen therapy, high-flow nasal oxygen (hfno) reduces the need for endotracheal intubation in ards patients [ ] . who recommended that hfno should only be used in selected patients with hypoxemic respiratory failure [ ] . studies indicated that hfno is more suitable for patients with mild ards. however, according to clinical situations, hfno can be safe in both mild and mild-moderate covid-related ards patients, and even some moderate-severe patients. some patients with an oxygenation index of mmhg can remain relatively stable with the support of hfno. this is clearly inconsistent with the stratified treatment strategies of ards caused by other factors. although covid- may be associated with myocardial injury and arrhythmia as reported [ , , ] , there is currently no evidence that myocarditis is the cause of death. the respiratory system is the most commonly involved for covid- , and some cases can rapidly progress to ards, which requires venous-venous extracorporeal membrane oxygenation (v-v ecmo) in the most severe cases. to date, no patients with severe arrhythmia or acute heart failure due to acute myocarditis have been reported to require venous-arterial ecmo (v-a ecmo) treatment. cardiac injury was diagnosed by elevation of cardiac biomarkers in serum or new abnormalities in electrocardiography and echocardiography. however, serum lactate dehydrogenase (ldh) and creatine kinase-mb were elevated more commonly than hypersensitive troponin i in covid- patients as reported [ , ] . the pathological findings of a covid- -related ards patient by xu et al. [ ] indicated that there were no obvious histological changes seen in heart tissue. therefore, the diagnosis of acute myocardial injury needs further consideration. thus, the more likely cause of death is severe respiratory failure. therefore, the timing of invasive mechanical ventilation is very important. since severe covid- patients may deteriorate rapidly, patients receiving hfno should be closely monitored and cared for by experienced personnel capable of endotracheal intubation at any time. currently published studies did not report the proportion of different respiratory support according to covid- -related ards classification. further research is expected to provide more evidence for the use of hfno in covid- -related ards patients. corticosteroids are considered a potential treatment for ards because of their role in reducing inflammation and fibrosis. although the use of corticosteroids in ards patients remains controversial, treatment with corticosteroids is currently the only pharmacological intervention that may reduce morbidity and mortality. it is reported that treatment with high-dose corticosteroids for a prolonged period of time could accelerate the improvement of ards [ ] . furthermore, methylprednisolone shortened periods of need for invasive mechanical ventilation and lowered mortality in ards patients [ ] . however, who recommended that systemic corticosteroids should not be routinely administered to covid- or covid- -related ards patients [ ] . studies reported that less than half of the covid- patients were given systemic corticosteroids, mostly in severely ill patients with ards [ , , ] . low-to-moderate dosage was administered depending on the severity of the disease, for as short time of treatment as possible. although it has been reported that treatment with methylprednisolone may be beneficial for covid- -related ards patients [ ] , the effect of corticosteroids in such patients is still uncertain and needs to be further evaluated. in particular, the use of corticosteroids may affect virus clearance in covid- patients. further evidence is needed to evaluate the role of systemic corticosteroid therapy and its impact on long-term prognosis in this group of patients. covid- is highly infectious and can lead to fatal comorbidities especially ards. there are currently no recommended specific anti-covid- treatments, so supportive treatment is important. fully understanding the characteristics of covid- -related ards is conducive to early identification and precise treatment. we hope to help improve the prognosis of severe cases and reduce the mortality. clinical features of patients with novel coronavirus in wuhan genomic characterization and epidemiology of novel coronavirus: implications of virus origins and receptor binding a novel coronavirus from patients with pneumonia in china world health organization. coronavirus disease (covid- ) outbreak a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster importation and human-to-human transmission of a novel coronavirus in vietnam coronavirus in china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention ct imaging features of novel coronavirus ( -ncov) acute respiratory distress syndrome: the berlin definition comparison of the berlin definition for acute respiratory distress syndrome with autopsy respiratory treatment procedures in patients with severe novel coronavirus infected pneumonia: an expert opinion. chin j crit care intensive care med effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials clinical management of severe acute respiratory infection when novel coronavirus ( -ncov) infection is suspected: interim guidance pathological findings of covid- associated with acute respiratory distress syndrome prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ards risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. both authors had their substantial contributions to the conception or design of the work or the acquisition and interpretation of data. xl drafted the work. xcm revised it critically for important intellectual content. both authors read and approved the final manuscript. the authors declare that they have no competing interests.received: march accepted: april key: cord- - i atc authors: barnes, betsy j.; adrover, jose m.; baxter-stoltzfus, amelia; borczuk, alain; cools-lartigue, jonathan; crawford, james m.; daßler-plenker, juliane; guerci, philippe; huynh, caroline; knight, jason s.; loda, massimo; looney, mark r.; mcallister, florencia; rayes, roni; renaud, stephane; rousseau, simon; salvatore, steven; schwartz, robert e.; spicer, jonathan d.; yost, christian c.; weber, andrew; zuo, yu; egeblad, mikala title: targeting potential drivers of covid- : neutrophil extracellular traps date: - - journal: j exp med doi: . /jem. sha: doc_id: cord_uid: i atc coronavirus disease (covid- ) is a novel, viral-induced respiratory disease that in ∼ – % of patients progresses to acute respiratory distress syndrome (ards) triggered by a cytokine storm. in this perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (nets)—may contribute to organ damage and mortality in covid- . we show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to covid- . we discuss prior reports linking aberrant net formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. if our hypothesis is correct, targeting nets directly and/or indirectly with existing drugs may reduce the clinical severity of covid- . and phagocytosis (schönrich and raftery, ) . however, neutrophils have another much less recognized means of killing pathogens: the formation of nets (brinkmann et al., ) . nets are web-like structures of dna and proteins expelled from the neutrophil that ensnare pathogens (fig. ) . expelling dna to the extracellular space is not widely recognized as a critical immune function. yet, even plants have specialized cells that kill soil pathogens by this mechanism (wen et al., ) . net formation is a regulated process, although the signals involved are incompletely understood. key enzymes in the formation of nets are: neutrophil elastase (ne), which degrades intracellular proteins and triggers nuclear disintegration; peptidyl arginine deiminase type (pad ), which citrullinates histones to facilitate the decondensation and release of the chromosomal dna; and gasdermin d, which generates pores in the membrane of the neutrophil, thereby facilitating cell membrane rupture and the expulsion of dna and the associated molecules kaplan and radic, ; papayannopoulos, ; papayannopoulos et al., ; rohrbach et al., ; sollberger et al., ) . although nets are beneficial in the host defense against pathogens, collateral damage from sustained net formation also stimulates many disease processes, including those that occur during viral infections (schönrich and raftery, ) . indeed, excessive net formation can trigger a cascade of inflammatory reactions that promotes cancer cell metastasis, destroys surrounding tissues, facilitates microthrombosis, and results in permanent organ damage to the pulmonary, cardiovascular, and renal systems (jorch and kubes, ; kessenbrock et al., ; papayannopoulos, ; fig. ) . importantly, these are three commonly affected organ systems in severe covid- (bonow et al., ; chen et al., b) . prior reports extensively link aberrant net formation to pulmonary diseases, particularly ards. indeed, net levels in plasma are higher in patients with transfusion-associated ards than in subjects without ards (caudrillier et al., ) . furthermore, neutrophils from patients with pneumonia-associated ards appear "primed" to form nets, and both the extent of priming and the level of nets in blood correlate with disease severity and mortality (adrover et al., ; bendib et al., ; ebrahimi et al., ; lefrançais et al., ; mikacenic et al., ) . extracellular histones, likely partly originating from nets, are elevated in the bronchoalveolar lavage fluid and plasma of ards patients (lv et al., ) . naked histones are toxic to cells, and there is strong experimental evidence supporting a role for histones in ards and sepsis (wygrecka et al., figure . neutrophils in an autopsy specimen from the lungs of a patient who succumbed from covid- . (a) extensive neutrophil infiltration in pulmonary capillaries, with acute capillaritis with fibrin deposition, and extravasation into the alveolar space. an image was chosen to emphasize the capillary lesions. (b) neutrophilic mucositis of the trachea. the entire airway was affected (images by a. borczuk, weill cornell medical center). both specimens originate from a -yr-old male of hispanic decent with diabetes, end-stage renal disease on hemodialysis, heart failure, and hepatitis c on ledipasvir/sofosbuvir therapy. he declined medical intervention, was therefore not intubated, and died in the emergency room h after presentation, shortly after developing fever. there was no evidence of sepsis in this patient clinically, premortem cultures were negative, and the autopsy was performed within h of death. similar neutrophil distribution, but with less extensive infiltration, was observed in the two additional autopsies analyzed to date. these other two cases had longer duration of symptoms. scale bars: µm. . excess net formation can drive a variety of severe pathologies. in the lungs, nets drive the accumulation of mucus in cf patients' airways. nets also drive ards after a variety of inducers, including influenza. in the vascular system, nets drive atherosclerosis and aortic aneurysms, as well as thrombosis (particularly microthrombosis), with devastating effects on organ function. ; xu et al., ) . it is therefore likely that nets, as a source of extracellular histones, contribute to ards and sepsis (chaput and zychlinsky, ; lefrançais and looney, ; xu et al., ) . in animal models of lung injury, nets develop in response to a variety of ards-inducing stimuli, and preventing or dissolving nets reduces lung injury and increases survival (caudrillier et al., ; lefrançais et al., ; liu et al., ; narasaraju et al., ) . the mucous secretions found in the airways of covid- patients (mao et al., preprint) are reminiscent of those seen in cf patients (martínez-alemán et al., ) . the cause and origin of these secretions are unclear. however, in cf, mucous secretions impair gas exchange and have been shown to contain extracellular dna, in part originating from nets released in response to persistent lung infections. furthermore, the excessive formation of nets with increased ne makes the mucus thick and viscous (manzenreiter et al., ) , not only impairing ventilation but also facilitating the colonization of bacteria. such colonization further promotes neutrophil recruitment and net formation, increasing mucus viscosity and consequently lowering the patient's respiratory function. if the mucous secretions in covid- contain nets, they may play similar roles as they do in cf: impairing gas exchange and facilitating secondary infections. nets and excessive thrombosis acute cardiac and kidney injuries are common in patients with severe covid- and contribute to the mortality of this disease (bonow et al., ) . d-dimer (a fibrin degradation product indicative of hyperactive coagulation) has emerged as a reliable marker of severe covid- . high blood levels of nets may explain these findings: intravascular nets have been shown to play a vital role in initiating and accreting thrombosis in arteries and veins . for example, in severe coronary artery disease, complexes of nets are elevated, and net levels positively associate with thrombin levels, which predict adverse cardiac events (borissoff et al., ) . in addition, autopsy samples collected from septic patients show that nets infiltrate microthrombi (jiménez-alcázar et al., ) . thus, when nets circulate at high levels in blood, they can trigger the occlusion of small vessels, leading to damage in the lungs, heart, and kidneys (cedervall et al., ; fuchs et al., ; laridan et al., ; martinod and wagner, ) . in mouse models of septicemia, intravascular nets form microthrombi that obstruct blood vessels and cause damage to the lungs, liver, and other organs (jiménez-alcázar et al., ) . mechanistically, nets activate the contact pathway of coagulation (also called the plasma kallikrein-kinin system) via electrostatic interactions between the net histones and platelet phospholipids (oehmcke et al., ) . histones can also promote platelet activation by acting as ligands for the toll-like receptors on platelets (semeraro et al., ) . at the same time, ne (which is bound in its active form to nets) likely also plays an important role by digesting the major coagulation inhibitors antithrombin iii and tissue factor pathway inhibitor (massberg et al., ) . furthermore, there is almost surely a feedback loop whereby pro-coagulant activity (e.g., that of thrombin) leads to platelet activation, and activated platelets then further enhance net formation (caudrillier et al., ; clark et al., ; fuchs et al., ; massberg et al., ; sreeramkumar et al., ; von brühl et al., ) . dissolving nets with dnase i restores normal perfusion of the heart and kidney microvasculature in animal models (cedervall et al., ; jansen et al., ; nakazawa et al., ; raup-konsavage et al., ) . based on the above findings, we argue that targeting intravascular nets may similarly reduce thrombosis in patients with severe covid- . severe covid- is associated with a cytokine storm characterized by increased plasma concentrations of il β, il , il , il , il , il , il , ifnγ, ifnγ-inducible protein , monocyte chemoattractant protein (mcp ), g-csf, macrophage inflammatory protein α, and tnfα mehta et al., ; ruan et al., ; wu and yang, ; zhang et al., ) . these inflammatory mediators regulate neutrophil activity and induce the expression of chemoattractants (molecules that increase the trafficking of neutrophils to sites of inflammation). moreover, cytokine storms lead to acute lung injury, ards, and death (channappanavar and perlman, ; chousterman et al., ) . it is especially noteworthy that nets can induce macrophages to secrete il β and that il β enhances net formation in various diseases, including aortic aneurysms and atherosclerosis (kahlenberg et al., ; meher et al., ; sil et al., ; warnatsch et al., ) . together, these data suggest that under conditions in which the normal signals to dampen inflammation are lost, such as during a cytokine storm, a signaling loop between macrophages and neutrophils can lead to uncontrollable, progressive inflammation. indeed, a correlation between nets and il β exists in severe asthma (lachowicz-scroggins et al., ) . if a net-il β loop is activated in severe covid- , the accelerated production of nets and il β could accelerate respiratory decompensation, the formation of microthrombi, and aberrant immune responses. importantly, il β induces il (dinarello, ) , and il has emerged as a promising target for covid- treatment (mehta et al., ; xu et al., preprint) . il can signal via classic and trans-signaling (calabrese and rose-john, ) . in classic signaling, il binds to a complex of the transmembrane receptor il rα with the common cytokine receptor gp . in trans-signaling, soluble il rα (sil rα) binds il to initiate signaling via gp . trans-signaling is strongly associated with pro-inflammatory states (calabrese and rose-john, ) , and lower levels of sil rα are associated with better lung function in, e.g., asthma (ferreira et al., ; hawkins et al., ) . neutrophils can shed sil rα in response to il (marin et al., ) , which is abundant in the covid- -associated cytokine storm (wu and yang, ; zhang et al., ) . together, these findings lead us to speculate that antagonizing il- trans-signaling and/or il β could be effective indirect strategies for targeting neutrophils and nets in severe covid- . due to the clear similarities between the clinical presentation of severe covid- and known netopathies-ards and microthrombosis-we propose that excess nets may play a major role in the disease. our understanding of net formation and function is incomplete, but drugs that target nets exist or are in development (fig. ) . these drugs include inhibitors of the molecules required for net formation: ne, pad , and gasdermin d. for example, endogenous inhibitors of net formation, which may function by inhibiting pad , have been isolated from umbilical cord plasma (yost et al., ) , and these are in development for the treatment of inflammatory syndromes such as covid- . clinical development of inhibitors against ne is the most advanced, and importantly, they could inhibit both the formation of nets, where ne activity is part of the signaling mechanism, and the toxic activities of ne on the nets. the ne inhibitor sivelestat was approved to treat ards in japan and south korea, but it did not increase survival after ards in a meta-analysis of clinical trials (tagami et al., ) . however, a new generation of potent ne inhibitors, including lonodelestat (pol ), alvelestat, chf , and elafin, have undergone phase i testing. as a result, it may be possible to expedite their development as treatments for covid- . gasdermin d inhibitors remain in preclinical development, but an existing drug-disulfiram, used to treat alcoholism-has been reported to inhibit gasdermin d and limit lung injury in animal models (hu et al., preprint) . finally, colchicine is another existing drug that could inhibit both neutrophil recruitment to sites of inflammation and the secretion of il β, and trials using colchicine in covid- are underway (clinicaltrials.gov identifiers: nct , nct , nct , nct ). a recombinant dnase i (dornase alfa), delivered by inhalation, is approved to dissolve nets in the airways of patients with cf to clear mucus and improve symptoms (papayannopoulos et al., ) . additionally, an actin-resistant dnase (prx- / alidornase alfa) has been tested in cf patients in phase i and ii trials with encouraging results (clinicaltrials.gov identifiers: nct , nct ) and could potentially be more potent than dornase alfa. other engineered dnase proteins, such as dnase -like , which is being developed to dissolve nets (fuchs et al., ) , could enter clinical development soon. we propose that dnases may help dissolve the mucous secretions of covid- patients as they do in cf patients, improving ventilation and reducing the risk of secondary infections. dornase alfa is normally administered through nebulizers, but in many medical centers, these are avoided in covid- due to the risk of aerosolizing sars-cov- and endangering healthcare workers. however, approaches exist that deliver aerosols in closed circuits for mechanically ventilated patients (dhand, ) . for nonintubated patients, therapies can be safely nebulized in negative pressure rooms. in addition to their possible effects on mucous secretions, dnase treatments may also prevent the further progression to ards, as dnase i delivered through the airways increases survival in relevant animal models (lefrançais et al., ; thomas et al., ; zou et al., ) . in addition to directly targeting nets, the net-il β loop could be antagonized with approved drugs against il β, such as anakinra, canakinumab, and rilonacept. trials are now being launched to test the efficacy of anakinra in covid- (clinicaltrials.gov identifiers: nct , nct , nct ). dornase alfa, sivelestat, and anakinra have excellent safety profiles. none of the drugs that currently are available to target nets are specific. nevertheless, collectively, there are multiple individual or combinatorial-and likely safe-therapeutic strategies available to antagonize nets in covid- patients today, and nets themselves may be an appropriate biomarker to follow studies to test their efficacy. nets can be detected in tissues by immunohistochemistry and in blood by sandwich elisa (caudrillier et al., ; figure . approaches to targeting nets. nets can be targeted by existing drugs through several means. ne, pad , and gasdermin d inhibitors will prevent net formation. dnase has been used safely to digest nets in the mucous secretions of the airways of cf patients. colchicine inhibits neutrophil migration and infiltration into sites of inflammation. il β blockers will prevent an inflammatory loop between nets and il β. of these approaches, trials to treat covid- with colchicine and anakinra are already ongoing or being launched (clinicaltrials.gov identifiers: nct , nct , nct , nct , nct , nct , nct ). jiménez -alcázar et al., ; lachowicz-scroggins et al., ; park et al., ) . as samples from patients become available, it will therefore be possible to determine whether the presence of nets is associated with severe covid- . if it is, this result would provide rationale for using the above-mentioned net-targeting approaches in the treatment for covid- . though treatments targeting nets would not directly target the sars-cov- virus, they could dampen the out-of-control host response, thereby reducing the number of patients who need invasive mechanical ventilation, and importantly, reducing mortality. nets were identified in (brinkmann et al., ) , and they are often overlooked as drivers of severe pathogenic inflammation. indeed, we posit here that excess nets may elicit the severe multi-organ consequences of covid- via their known effects on tissues and the immune, vascular, and coagulation systems. targeting nets in covid- patients should therefore be considered by the biomedical community. the authors, members of "the network to target neutrophils in covid- ," thank andrew whiteley for organizing the discussions that are summarized in this paper; laura maiorino for generating the illustrations; laura maiorino and stephen hearn for the photomicrograph of nets; and bruce stillman and david tuveson for discussions and critical review of the manuscript. we acknowledge the cold spring harbor laboratory ccsg p ca and microscopy shared resource. biorender was used to generate the illustrations in the figures. we apologize to those with relevant work that was not included in the discussion due to space limitations. disclosures: m.r. looney reported "other" from neutrolis outside the submitted work. r.e. schwartz is a sponsored advisory board member for miromatrix inc. j.d. spicer reported personal fees from bristol myers squibb, personal fees from astra zeneca, personal fees from merck, personal fees from trans-hit bio, and non-financial support from astra zeneca outside the submitted work. c.c. yost reports a grant from peel therapeutics, inc. during the conduct of the study; in addition, c.c. yost authors a us patent (patent no. , , b ) held by the university of utah for the use of net-inhibitory peptides for "treatment of and prophylaxis against inflammatory disorders." peel therapeutics, inc. has exclusive licensing rights. m. egeblad reported "other" from santhera during the conduct of the study; and consulted for cytomx in . no other disclosures were reported. submitted: april revised: april accepted: april programmed 'disarming' of the neutrophil proteome reduces the magnitude of inflammation neutrophil extracellular traps are elevated in patients with pneumonia-related acute respiratory distress syndrome association of coronavirus disease (covid- ) with myocardial injury and mortality elevated levels of circulating dna and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state neutrophil extracellular traps kill bacteria il- biology: implications for clinical targeting in rheumatic disease platelets induce neutrophil extracellular traps in transfusion-related acute lung injury neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology sepsis: the dark side of histones clinical and immunologic features in severe and moderate forms of coronavirus disease noncanonical inflammasome signaling elicits gasdermin d-dependent neutrophil extracellular traps epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study cytokine storm and sepsis disease pathogenesis platelet tlr activates neutrophil extracellular traps to ensnare bacteria in septic blood how should aerosols be delivered during invasive mechanical ventilation? targeting the pathogenic role of interleukin beta in the progression of smoldering/indolent myeloma to active disease markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial functional il r ala allele impairs classical il- receptor signaling and influences risk of diverse inflammatory diseases pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans extracellular dna traps promote thrombosis neutrophil extracellular trap (net) impact on deep vein thrombosis neutrolis, inc. us patent application us / a national heart, lung, and blood institute-sponsored severe asthma research program (sarp). . the il r variation asp( )ala is a potential modifier of lung function in subjects with asthma identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin d clinical features of patients infected with novel coronavirus in wuhan release of extracellular dna influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps host dnases prevent vascular occlusion by neutrophil extracellular traps an emerging role for neutrophil extracellular traps in noninfectious disease neutrophil extracellular trap-associated protein activation of the nlrp inflammasome is enhanced in lupus macrophages neutrophil extracellular traps: doubleedged swords of innate immunity netting neutrophils in autoimmune small-vessel vasculitis extracellular dna, neutrophil extracellular traps, and inflammasome activation in severe asthma neutrophil extracellular traps in arterial and venous thrombosis neutralizing extracellular histones in acute respiratory distress syndrome. a new role for an endogenous pathway maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury neutrophil-to-lymphocyte ratio predicts severe illness patients with novel coronavirus in the early stage neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury extracellular histones are clinically relevant mediators in the pathogenesis of acute respiratory distress syndrome ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy clinical and pathological characteristics of novel coronavirus disease (covid- ): a systematic reviews chemotactic agents induce il- ralpha shedding from polymorphonuclear cells: involvement of a metalloproteinase of the tnf-alpha-converting enzyme (tace) type understanding the entanglement: neutrophil extracellular traps (nets) in cystic fibrosis thrombosis: tangled up in nets reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases novel role of il (interleukin)- β in neutrophil extracellular trap formation and abdominal aortic aneurysms covid- : consider cytokine storm syndromes and immunosuppression neutrophil extracellular traps (nets) are increased in the alveolar spaces of patients with ventilator-associated pneumonia histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic aki excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis activation of the human contact system on neutrophil extracellular traps neutrophil extracellular traps in immunity and disease neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving dnase therapy cancer cells induce metastasis-supporting neutrophil extracellular dna traps neutrophil peptidyl arginine deiminase- has a pivotal role in ischemia/reperfusion-induced acute kidney injury activation of pad in net formation clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet tlr and tlr macrophage-derived il- β enhances monosodium urate crystal-triggered net formation gasdermin d plays a vital role in the generation of neutrophil extracellular traps neutrophils scan for activated platelets to initiate inflammation effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the picco pulmonary edema study extracellular dna traps are associated with the pathogenesis of trali in humans and mice monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan inflammation. neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis extracellular dna is required for root tip resistance to fungal infection risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease th responses in cytokine storm of covid- : an emerging target of jak inhibitor fedratinib antihistone properties of c esterase inhibitor protect against lung injury extracellular histones are major mediators of death in sepsis effective treatment of severe covid- patients with tocilizumab sepsis and ards: the dark side of histones neonatal net-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation the use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the perspectives of clinical immunologists from china clinical and laboratory profiles of hospitalized patients with novel coronavirus disease in hefei functional exhaustion of antiviral lymphocytes in covid- patients clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study neutrophil extracellular traps promote lipopolysaccharideinduced airway inflammation and mucus hypersecretion in mice key: cord- -mudwcypl authors: lauretani, fulvio; ravazzoni, giulia; roberti, maria federica; longobucco, yari; adorni, elisa; grossi, margherita; de iorio, aurelio; la porta, umberto; fazio, chiara; gallini, elena; federici, raffaele; salvi, marco; ciarrocchi, erika; rossi, francesca; bergamin, marina; bussolati, giacomo; grieco, ilaria; broccoli, federica; zucchini, irene; ielo, giuseppe; morganti, simonetta; artoni, andrea; arisi, arianna; tagliaferri, sara; maggio, marcello title: assessment and treatment of older individuals with covid- multi-system disease: clinical and ethical implications date: - - journal: acta biomed doi: . /abm.v i . sha: doc_id: cord_uid: mudwcypl covid- infection is a multisystem disease more frequent in older individuals, especially in those with multiple chronic diseases. this multimorbid and frail population requires attention and a personalized comprehensive assessment in order to avoid the occurrence of adverse outcomes. as other diseases, the covid- presentation in older patients is often atypical with less severe and unspecific symptoms. these subjects both at home and during hospitalization suffer isolation and the lack of support of caregivers. the geriatric care in covid- wards is often missing. the application of additional instruments would be necessary to facilitate and personalize the clinical approach, not only based on diseases but also on functional status. this narrative review starts from diagnostic evaluation, continues with adapted pharmacologic treatment and ends with the recovery phase targeting the nutrition and physical exercise. we developed a check-list of respiratory, gastro-intestinal and other less-specific symptoms, summarized in a table and easily to be filled-up by patients, nurses and general practitioners. as second step, we reported the clinical phases of this disease. far to be considered just viral infective and respiratory, this disease is also an inflammatory and thrombotic condition with frequent bacterial over-infection. we finally considered timing and selection of treatment, which depend on the disease phase, co-administration of other drugs and require the monitoring of renal, liver and cardiac function. this underlines the role of age not just as a limitation, but also an opportunity to increase the quality and the appropriateness of multidisciplinary and multidimensional intervention in this population. (www.actabiomedica.it) these countries differ in terms of percentages of population over , the most afflicted by infection, with italy reaching %. italy for instance has higher life expectancy than the majority of countries affected by covid- infection ( . overall vs . in china) ( ) . these demographic differences could also explain the different outcomes between countries. italy has one of the highest covid- mortality ( , deaths) and case-fatality rate ( . %), much higher than china ( . %). interestingly, the case-fatality rate in italy and china are very similar for age-groups to years, but rates are higher in italy especially among those aged years or older ( % of deaths and % of case fatality rate). this difference can be at least partially explained by the higher number of people aged years or older (n= ), age group having a very high fatality rate ( . %) and not reported in china ( ) . gender issue has been raised by scientists and epidemiologists with men experiencing higher prevalence ( . % in the last italian report) and severity (they die more and at earlier age) of covid- infection than women. many hypotheses have been formulated to explain this difference between two sexes. cov-id- virus can be localized in the testes, which are potential target of sars-cov- infection, and one of the reasons for the rapidly spreading disease. moreover, testosterone, the male hormone, has been shown to upregulate the expression of transmembrane protease, serine (tmrpss ) which is an enzyme involved in the penetration of virus in the lung cells. age is accompanied by changes in immune competence and a higher prevalence of inflammation, socalled "inflammaging" ( ) . the chronic increase in inflammatory cytokines, augmented by covid- infection, may explain the higher tendency for "the cascade leading to pulmonary fibrosis and insufficiency and activation of clotting" and poorer clinical prognosis, especially in multimorbid older persons ( ) . multimorbidity defined by the concomitant presence of two or more chronic diseases, is highly prevalent in older persons, affecting more than % of people aged + ( ) . data collected in . sars-cov- italian patients who died from covid- show that the mean number of diseases is . (median sd ± . ). seventy patients ( . % of sample) had no diseases, ( . %) disease, ( . %) diseases, and ( . %) or more ( ) . cardio-renalrespiratory (heart failure, atrial fibrillation, chronic renal failure, copd), metabolic diseases (obesity and type diabetes), active cancer during the last years and dementia seem to be the clusters more associated with adverse clinical outcomes. as a consequence of multimorbidity, polypharmacy defined as the number of drugs reported at hospital admission and the potential drug-drug interactions require a careful evaluation in older covid- patients. the combination of antiviral and anti-inflammatory drugs (never tested before in these individuals) and the concomitant treatment for other chronic diseases, especially in subjects with smoking exposition or sarcopenic obesity, increase the risk of adverse drug effects. diarrhea, dehydration, acute kidney insufficiency and liver failure can frequently occur and need to be monitored ( ) . diseases, drugs and the primum movens cov-id- are also associated with hyperactive delirium, especially in hospitalized patients with preexisting dementia and cognitive impairment ( ) . this syndrome requires a multidisciplinary evaluation balancing cost/effectiveness of therapeutic treatment (sedation or precipitation of respiratory and cardiac failure) and opens a large window of ethical issues, especially in older patients ( ) . as suggested by nice rapid guideline and the canadian frailty network, the assessment of all adults for frailty, irrespective of age and covid- status, is highly recommended especially at hospital admission ( ) . as already reported for other diseases, the cov-id- clinical presentation in older patients is often atypical with less severe symptoms. these subjects both at home and during hospitalization also suffer the isolation and the lack of fundamental support of formal and informal caregivers required for their safety ( ) . despite the peculiar aspects of older patients and the epidemiology of the phenomenon, the geriatric culture and care in covid- wards is often missing. their application together with additional instruments would be such necessary to facilitate and personalize the clinical approach, not only based on number of diseases but also on functional status of older patient ( ) . this narrative review has the specific aim to address different aspects of covid- multi-system disease starting from diagnostic evaluation, continuing with innovative classification of phases and proposing sequential adapted pharmacological treatment. the document wants also focus on the recovery phase and ethical considerations regarding the risk of limited access of care and accelerated exitus in this vulnerable age-category. the most common symptoms of covid- disease in the adults are represented in table . this table describes a check-list of more frequent symptoms in adults and would be a guide to orient patients and primary care physicians in assessing older patients with suspected covid- infection. the range of symptoms is similar for covid- and influenza infection, although the fraction with severe disease is different. for covid- , actual data suggest that % of infections are mild or asymptomatic, % are severe infections, requiring oxygen and % are critical infections, requiring ventilation. these fractions of severe and critical infection would be higher than influenza infection ( , ) . symptoms can be traditionally classified into two main groups, including respiratory and gastro-intestinal, and a third group of less organ specific. the quality and severity of symptoms can be different in older persons. the most common symptoms are fever ( %), cough ( %), dyspnea ( . %) and muscle/joint soreness ( ) . the rationale of symptoms distribution across organs is partially explained by the concentration of angiotensin-converting enzyme (ace- ) virus receptors, which is particularly higher in the lung and lower in the gut. this can explain why less common symptoms include abdominal pain, vomiting and diarrhea and virus might be detected in stool samples although gastro-intestinal transmission remains to be demonstrated ( ) . it has been also hypothesized that covid- virus can also alter central nervous system directly or alternatively disrupt the gut-barrier permeability and induces the gut-brain link via vagus nerve. this justifies the reduced sense of taste and smell, headache, dizziness and vertigo also observed in covid- patients ( ) . elderly patients, especially with multiple chronic conditions, display less severe and atypical symptoms. the presence of mild symptoms is disproportionate to the severity of their illness ( ) . they might be afebrile, without cough or sputum production, and show higher prevalence of muscle-joint pain, tachypnea, altered mental status or delirium, unexplained tachycardia and decrease in blood pressure ( ) . atypical presentation may be due to several factors, including physiologic changes with age, comorbidities, and inability to provide an accurate history given the constant lack of caregivers during covid- hospitalization ( ) . despite the presence of less severe and atypical symptoms, older patients have a significantly higher mortality. as nicely shown in an elegant retrospective study male sex, time from disease onset to hospitalization, abnormal kidney function, and elevated procalcitonin levels were all significant predictors of increased mortality ( ) . swab and or lung ct scan. the diagnosis of covid- requires the combination of swab and radiologic features. the algorithm initially considers a swab performed with sterile cotton wool suitably rolled around the end of a glass or metal rod, and intended to be swiped on the surface of a natural pharynx and nose cavity. the main nasal swab tests examine the nasopharynx, where the back of the nose meets the top of the throat. this requires a trained hand to perform and some portion of the false negatives arises from improper procedures and poor compliance especially in older adults with acute confusion state ( ) . the pharyngeal and nasal swab, once carried out (in some centers not even getting out of the car but with the prior authorization and appointment of the public health office of the local healthcare companies) is sent to an authorized laboratory where the presence of viral rna or genetic material of the virus is appreciated. in case of positivity, there is the certification that the subject has a covid- infection. but even if done correctly, the swab may produce a negative result. that is because as the disease progresses, the virus passes from the upper to the lower respiratory system. importantly, the swab test has a sensitivity of - % and strictly depends on the timing of assessment. this means that in - % of cases, even in the case of a negative buffer, the presence of the virus cannot be excluded. in these cases, the patient may be asked to try to cough up sputum -mucus from the lower lungs -or doctors may need to take a sample more invasively when a patient is under sedation. radiological findings are useful complements in the diagnosis covid- and in the management of one of its most common complications, pneumonia. the most common computed tomography (ct) findings of the covid- pneumonia are ground glass and/or consolidation, and mainly reflect the diffuse and bilateral alveolar damage and/or organizing interstitial pneumonia. it has also been reported a strong correlation between the severity of ct pulmonary findings and patients' outcome. hence, it has been suggested that chest ct could be used as a reliable diagnostic test in the emergency workup of covid- , complementing pcr. a further confirmation of the covid- infection comes from a chest x-ray or even better from a high-resolution chest ct scan (hrct) which highlights the percentage of lungs and the number of lung lobes affected by the virus. the radiologist, using specific software, processes a visual score or score in percentage. the higher the visual score the greater the severity of the lung involvement of virus. visual scores at the time of admission to the hospital of more than % are usually associated with a bad prognosis and more than % identify a severe disease. another parameter assessed through the ct scan is the number of lung lobes affected by the infection, which can vary from / to / . also in this case, the greater the number of lung lobes involved, the greater the severity of the ongoing lung involvement of virus. the diagnostic process is the first step of clinical assessment of the patient. interestingly the initial hypothesis that the covid- is just an infectious disease has been gradually abandoned. an intriguing recent theory suggests that there are different phases in the same disease ( figure ). the viral disease is limited to phase , where an early infection ( days of duration) predominates and the host fights to solve the infection. however, if the attempt fails, the activation of an exaggerated response is capable to damage different tissues and organs (kidney, liver, myocardium, brain). another interesting theory suggests an early endothelial cell damage induced by covid- as common mechanism of vascular impairment across different organs ( ) . three other phases (mainly depicting the host response to virus) are even more important for the clinical course and the outcomes of the patients. more effective will be the host response to virus, more chances the individuals have to survive. together with clinical evaluation (for instance peripheral capillary oxygen saturation), the functional assessment should also guide clinicians in the admission to intensive care unit (icu), in selecting therapeutic choices, and in predicting clinical and functional responses. both uk and canadian frameworks suggest the usefulness of easy to use instruments such as the clinical frailty scale to assess frailty ( ) . other additional tests include chair stand test (cst) which is one of the best and validated physical performance tests for older people, and it is reported to be associated with muscle strength of the lower leg. the cst is a simple and feasible physical performance test, even for evaluating older people with limited mobility. then, many representative cohort studies have demonstrated that the cst is a predictor of disability and falls in older people ( ) . (figure and table ) phase . infectious-virological phase or early infection phase (max duration days). the virus is present in the upper airways and digestive tract and usually induces specific symptoms (dry cough, fever, fatigue with normal peripheral oxygen saturation, diarrhea, headache, conjunctivitis) in the adult individuals ( ) . the body response produces immune (igm in phase , viral response predominates and respiratory and gastrointestinal symptoms can be treated at home with hydroxychloroquine and antivirals. in phase : pulmonary, fever and dyspnea worsen and rapid diagnosis by ct and hospitalization is required. in phase , pulmonary and hyperinflammatory, clinically represented by ards, corticosteroids and il- receptor antagonists should be started in sub-intensive wards. in phase , thrombotic, anticoagulant therapy should be introduced and admission to icu indicated. there is a transverse phase: bacterial over infection, typically characterized by high fever, increased white blood cells and procalcitonin, where broad-spectrum antibiotic therapy is the choice treatment. legend of figure . both responses, especially if supported by appropriate pharmacological treatment, translate into an infective resolution in % of cases. the different response in older patients and in different categories (fit, frail, disable) is an interesting topic to be investigated ( ) . the phase treatment includes drugs with mixed anti-viral and anti-inflammatory activity (hydroxychloroquine) and antibacterial drug with minimal anti-viral action (azithromycin) ( , ) . these drugs act synergistically on heart rhythm and require, because of the frequent concomitant use and especially in subjects with previous cardiac disease, electrocardiogram (ekg) trace to monitor qtc interval ( ) . low molecular weight heparin, in the presence of good renal and liver function, at prophylaxis doses is also suggested ( ) . in older patients, these specific aspects require additional and careful evaluation given the inadequate formulas currently used to assess for instance renal function ( ) . in about % of cases, the disease ends at this stage and can be managed at home. however, the onset and persistence of symptoms within - days requires an immediate communication to primary care physician (or general practitioner) for a timely diagnosis and therapy. pharmacological treatment must be accompanied by the adoption of home behavioral measures in order to avoid contagion of the other family members. if the fever is persistently higher ≥ °c, especially for more than - days, or if peripheral oxygen saturation drops below % and/or dyspnea increases, we should suspect an exaggerated inflammatory response and the extension to the lung and recommend the hospitalization. the typical serum biomarker picture of this phase could be represented by low wbc, crp and d-dimer mildly increased, normal troponin i hs levels ( table ) . this phase usually occurs after days on average from the onset of symptoms in which the virus migrates to the lower respiratory tract lung. characterizing symptoms lasting days or longer, range from shortness of breath to severe dyspnea and fatigue. this phase can be characterized by low peripheral oxygen saturation (spo < %). endothelial and initial cardiac damage are also possible ( ) . at this stage, hospitalization in semi-intensive wards could be necessary. acute confusional state in older persons is frequently observed and sedative and palliative treatment are important and detrimental confounders. men experience more clinical complications than women. this different exposure can be explained by higher expression pattern of ace receptors in adult human testes at the level of single-cell transcriptome suggesting that this organ is a potential target of sars-cov- infection, and one of the reasons for the rapidly spreading disease ( ) . the typical serum biomarker picture of this phase could be represented by normal wbc, further increase in crp and d-dimer levels, troponin i hs levels that require to be monitored for the potential involvement of myocardium and pericardium ( table ) . phase . pulmonary-hyper-inflammatory phase , which is characterized by systemic symptoms with multi-organ involvement (ards sirs/ shock cardiac failure) ( , ) . individualized treatment in this phase is required, considering for example corticosteroids (methylprednisolone mg/kg/day or dexamethasone at mg/day intravenously), human immunoglobulin, inhibitors of the il- , il- , and jak receptor. this phase requires hospitalization in icus or respiratory intensive care unit ( ) . the typical biomarker picture of this phase could reproduce phase ( table ) . phase . vasculitic-thrombotic phase (coexisting or immediately following the previous phase) consists of endothelial damage, local and diffuse thrombotic phenomena and pulmonary hypertension ( ) . there is the rationale, especially in this phase, to support, at high dosages, and based on weight and renal function, the use of enoxaparin, very known also for its antiviral activity ( , ) . the presence of pulmonary hypertension suggests also the potential usefulness of phosphodiesterase inhibitors releasing nitric oxide such as sildenafil ( ) . the typical serum biomarker picture of this phase could be represented by normal wbc, very-high levels of d-dimer and troponin i hs levels that require to be monitored for the potential occurrence of thrombotic events in different organs ( table ) . the separation of different phases of disease contributes to delineate a specific timing for starting appropriate pharmacological treatment and establishing setting (home and hospital wards) at increased intensity of care. in case of persistent fever, higher than . °c for a time longer than days and peripheral oxygen level lower than % after starting therapy, we should consider and proceed to hospitalization especially in multimorbid older patients with cardiac, respiratory diseases and diabetes. the use of antivirals is poorly supported by randomized controlled clinical trials performed only in adult patients ( ) and should be limited to the initial phase of the disease. antivirals are poorly indicated during phase ( ), and not indicated at all during phases and . vice-versa, the anti-inflammatory-immunosuppressive therapy, are contraindicated during phases and in which the organism/host is elaborating or implementing its defensive strategy. corticosteroids and other anti-inflammatory medications should be also carriedout, once having careful evaluated specific contraindications, during phases and , where the combination anti-inflammatory/ anticoagulant therapy is suggested in case of significant increase of d-dimer and/or positive pulmonary ct with contrast. late phases are usually characterized by exaggerated phase response of the host which is harmful to the host and needs to be attenuated ( , ) . this might be particularly detrimental in older patients where a chronic inflammatory status is often present. every single phase of the pathology is also influenced by the undergoing pharmacological treatment and related side effects. drug-drug interaction deserves particular attention especially in older persons with polypharmacy. all these medications may induce gastro-intestinal symptoms (especially diarrhea) and worsen kidney and liver function. the ekg at the basal entry should be carried out on regular basis to monitor the qtc interval and to exclude the potential myocardial and pericardial damage induced by the infectious process. treatment in this phase, usually lasting about - days, consists of drugs with anti-inflammatory activities. these drugs, such as chloroquine or hydroxychloroquine should be started as soon as possible ( ) . however, their utilization is actually based on in vitro data ( , ) and single open label non-randomized trial conducted in patients with covid- ( ) . antiviral drugs derive their use from trials verifying their effective treatment of other viruses including sars (severe acute respiratory syndrome-related coronavirus) and mers (middle east respiratory syndrome coronavirus). in particular, preliminary genomic studies on -ncov showed that the sequence has similarities with the corresponding sars and mers enzymes, and this justifies why repurposing exiting sars and mers inhibitors for -ncov ( ) . although the use of many anti-viral drugs has been proposed, particular attention received lopinavir/ ritonavir and remdesivir. the first antiviral drug, lopinavir/ritonavir, has specific indication for treat hiv and was also utilized in the for sars. convincing evidence of its therapeutic effects on covid- is lacking. moreover, a recent randomized clinical trial found no different clinical effect compared to standard care on -ncov infection. only in the modified intention-to-treat analysis, which excluded three pa-tients with early death, the between-group difference in the median time to clinical improvement (median, days vs. days) was significant, albeit modest ( ) . another virally targeted agent is the remdesivir, a very promising drug, which is a drug currently being investigated as a potential covid- treatment through several clinical trials. in details, two phase iii randomized, placebo-controlled double-blind, multicenter trials were initiated in early february to investigate remdesivir in two different dosages mg/day and mg/day for days with estimated complete results at the end of april ( ) . finally, the favipiravir, an antiviral drug manufactured by japanese pharmaceutical company fujifilm toyama chemical, was approved for treatment of novel influenza on february , in china, and clinical trials testing this medication are undergoing. preliminary data from patients indicated that favipiravir had more potent antiviral effect than lopinavir/ ritonavir and even with lower side-effects ( ) . however, given that no current definitive specific treatment for covid- infection has been proved based on randomized clinical trial, who has now launched the solidarity trial to investigate four potential treatments: remdesivir, chloroquine/hydroxychloroquine; lopinavir and ritonavir; and lopinavir and ritonavir plus interferon-β. the only limitation of this study is that will not be double blind, but it will include thousands of patients from several countries ( ) . this phase normally is associated in the adults with the presence of persistent high fever. this symptom often requires admission to emergency department and hospitalization for the execution of pulmonary ct scan. this technique is the gold standard for the diagnosis of typical interstitial pneumonia. the most important observation of this infection phase is the rapid progression into pulmonary impairment with a rapid worsening hypoxia. therefore, patients who failed to standard oxygen therapy required an advanced oxygen/ventilatory. patients may also have increased work of breathing, demanding positive pressure breathing assistance, which could be guaranteed by non-invasive ventila-tion (including continuous positive airway pressure [cpap] or bi-level positive airway pressure [bipap]) in patients with hypoxemic respiratory failure. prone ventilation in patients with persistent severe hypoxic failure should be considered. finally, patients who are acutely deteriorating undergo intubation and mechanical ventilation. two thirds of patients who required critical care in the uk had mechanical ventilation within hours of admission ( ) . in this phase, the presence of elevated serum levels of inflammatory cytokines, such as il- could induce pulmonary damage or proliferative pulmonary phase. il- receptor antagonists (e.g., tocilizumab, sarilumab, siltuximab) can be used. in particular, the tocilizumab which is a monoclonal antibody that blocks the il- signalling pathway is currently used to treat rheumatoid arthritis. however, given the limited evidence on the safety or efficacy of the drug in clinical treatment of covid- , the fda launched through a double blind, a randomised phase iii clinical trial as a treatment for severe covid- pneumonia with tocilizumab in combination with standard of care ( ) . acute respiratory distress syndrome (ards) is an acute, diffuse, inflammatory form of lung injury related with high mortality. diagnostic criteria (berlin definition ) include non-cardiogenic respiratory failure, with respiratory symptoms, bilateral opacities on ct scan and presence of a moderate to severe impairment of oxygenation ( , ) . the pao /fio defines the severity of the ards (calculated data with a positive end-expiratory pressure (peep) or continuous positive airway pressure (cpap) ≥ cm h o) in the absence of cardiac failure or fluid overload. • mild ards -pao /fio is > mmhg, but ≤ mmhg. • moderate ards -pao /fio is > mmhg, but ≤ mmhg. • severe ards -the pao /fio is ≤ mmhg ( ) . excessive inflammatory response is an essential characteristic of ards pathophysiology, with an increase of interleukin- beta (il- β), interleukin- (il- ), il- , interleukin- (il- ), interleukin- (il- ), tumor necrosis factor-α (tnf-α) and c-c motif chemokine ligand (ccl ) ( ) . it is known that in patients with ards, elevated plasma il- at baseline predict a poor survival ( ) . also in covid- patients, higher il- levels are associated with an increased risk of hospitalization and other negative outcomes ( ) . at this stage of the disease, patients typically show dyspnea, tachypnea, fever and tachycardia. they can also show severe, acute confusion (especially in older persons), respiratory distress and cyanosis. as lung dysfunction progresses, it is necessary to increase oxygen-therapy until non-invasive mechanical ventilation is required ( , ) . the use of corticosteroids could be beneficial to modulate the excessive immune response, but their use is controversial. a recent study shows that the use of corticosteroids in ards reduced all-cause mortality and duration of mechanical ventilation, and increased ventilator-free days ( ) . in this regard, we hypothesized that patients already taking corticosteroids for other diseases, such asthma, pulmonary fibrosis, rheumatologic diseases and without indication for bacterial over-infections, can take advantage from adequate dosages of corticosteroids. however, future clinical trials are required to verify these aspects. in this phase, convalescent plasma from patients who have recovered from viral infections can be used as a treatment. clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to sars-cov- in patients with covid- have started. a small preliminary case-series of five critically ill patients reported clinical improvement after convalescent plasma transfusions ( ) . another study of patients with severe illness in china noted symptomatic improvement within days. viral load was undetectable within days in % of patients. no serious adverse reaction was noted. covid- and ards can evolve into thrombotic phenomena. prolonged inflammation is responsible for a pro-coagulation state, with activation of the endothelial vasoconstrictors and formation of lung micro thrombi, also found during autoptic examination ( , , ) . intriguingly, sars-cov- can directly infect engineered human blood vessel organoids in vitro. very recent case-series in patients with cov-id- have demonstrated an endothelial cell involvement across vascular beds of different organs especially in those with preexisting thrombotic disease ( , ) . for all these reasons, a vasculitic/thrombotic phase can be hypothesized during covid ards. clinically, episodes of intense dyspnea and respiratory distress may occur. fever can be resolved. the pro-coagulant state is characterized by an increase in the d-dimer, which must therefore be regularly analyzed ( ) . in details, if d-dimer level, normally performed every three days, increase more than times from admission to later check, this parameter represents a good index for identifying high-risk groups of venous thromboembolism and anticoagulant treatment, if not contraindicated, should be prescribed ( ) . respiratory distress syndrome (ards) is a common complication of covid- infection. ozoline and colleagues demonstrated that in patients with ards higher plasma concentrations of tissue factor and plasminogen activator inhibitor- were present at day seven compared to non-ards ( ) . the mechanisms contributing to this lung coagulopathy are localized tissue factor-mediated thrombin generation, and depression of bronchoalveolar plasminogen activator-mediated fibrinolysis, mediated by the pai- increase ( ) . thus, treatment with heparin might be helpful in mitigating this pulmonary coagulopathy. moreover, adjunctive treatment with low-molecular-weight heparin (lmwh) within the initial seven-day onset of ards reduces the risk of -day mortality by % with a meaningful improvement of the pao /fio ratio ( ) . in the same study, the risk of -day mortality was reduced by % as well. in a report from a wuhan university hospital, heparin use was associated with lower mortality in patients with sepsis-induced-coagulopathy (sic) score ≥ ( . % vs . %, p= . ), but not in those with sic score < ( . % vs . %, p= . ). in the same report patients with d-dimer > . ug/ml experienced a % mortality reduction after heparin treatment ( . % vs . %, p= . ) ( ) . another fascinating concept is the antiviral role of heparin which has been studied in experimental models. given its polyanionic nature, heparin can bind to several proteins and thus act as effective inhibitors of viral attachment ( ). one example is in herpes simplex virus infections. heparin competes with the virus for host cell surface glycoproteins inhibiting the virus entrance in the cells. also, in zika virus infection, it prevents virus-induced cell death ( ) . finally, the use of heparin at a concentration of μg/ml halved the infection in an experimental model of cells injected with sputum from a patient with sars-associated cov pneumonia ( ) . however, the clinical benefits in any of these viral infections are yet to be determined. moreover, heparin may also be helpful in microvascular dysfunction and this is of importance given the well-known role of endothelial dysfunction in the cardiac failure, another increasingly recognized complication of covid- . finally, a recent document of the italian national drugs agency ( ) advices to consider the use of lmwh in serious cases of covid- (defined by the presence of one of the following conditions: pao /fio < , respiratory rate > /min and spo < % at rest) when the d-dimer is markedly increased ( - fold) and the sic score is > ( table ) and myocardial infarction or other thrombotic events cannot be excluded. however, high rate of high incidence of venous thromboembolic events may occur in severe covid- patients, irrespective of anticoagulation ( ) . all previous phases of the covid-infection can be complicated by the presence of bacterial over-infection. this condition should be suspected when specific serum biomarkers such as wbc and procalcitonin are pathologically elevated (table ) ( ) . in this case, specific antibiotic therapy should be promptly prescribed, even in accordance with suggested guidelines ( ) . polypharmacy is one of the main characteristics in older subjects. there is an increased risk of adverse events in this specific age-group. although there are no food and drug administration (fda)-approved drugs to prevent or treat covid- , nevertheless pre-liminary clinical research, based on in vitro-data, have suggested the use of pharmacologic agents as chloroquine or hydroxychloroquine, azithromycin, lopinavir/ritonavir and other anti-retrovirals ( ) . some of these drugs may increase risk of qt prolongation, ventricular proarrhythmia and sudden cardiac death. some of the current covid- repurposed drugs have known risk of us food and drug administration adverse event reporting system (faers), long qt syndrome and torsade de points (tdp) and cardiac arrest for azithromycin, and hydroxychloroquine, and possible risk for lopinavir/ritonavir. in the prevention of qtc-prolongation, special attention should go to high-risk patients. age is one of the main determinants of this risk score which has been derived and validated by tisdale et al. ( ) , for prediction of drug-associated qt prolongation among cardiac-care-unit-hospitalized patients. the application of this scale identifies maximum risk score of and three different classes of risk, low (score ≤ points), moderate ( - points) and high (≥ points) ( table ) ( ) . the goal of qtc screening in this setting is not to identify patients whom are not candidates for therapy, but to identify those who are at increased risk for tdp in order that aggressive countermeasures may be implemented. . baseline a. discontinue and avoid all other non-critical qt prolonging agents. b. assess a baseline ecg, renal function, hepatic function, serum potassium and serum magnesium. c. when possible, have an experienced cardiologist/ electrophysiologist measure qtc, and seek pharmacist input in the setting of acute renal or hepatic failure. . relative contraindications (subject to modification based on potential benefits of therapy) a. history of long qt syndrome, or b. baseline qtc > msec (or > - msec in patients with qrs greater than > msec) . ongoing monitoring, dose adjustment and drug discontinuation a. place on telemetry prior to start of therapy. b. monitor and optimize serum potassium daily. c. acquire an ecg - hours after the second dose of hydroxychloroquine, and daily thereafter. d. if qtc increases by > msec or absolute qtc > msec (or > - msec if qrs > msec), discontinue azithromycin (if used) and/ or reduce dose of hydroxychloroquine and repeat ecg daily. e. if qtc remains increased > msec and/or absolute qtc > msec (or > - msec if qrs > msec), reevaluate the risk/benefit of ongoing therapy, consider consultation with an electrophysiologist, and consider discontinuation of hydroxychloroquine ( ) . during covid- infection adult and older patients may also experience a higher incidence of gastrointestinal symptoms including diarrhea. the ongoing treatment with antivirals and anti-inflammatory could worsen this symptomatology, increasing potassium and magnesium deficiency and amplifying the risk already described of cardiac events and arrhythmia. in older patients it is widely observed the chronic, not always appropriate, use of proton pump inhibitors (ppi). one year ppi treatment has been associated with increased risk of all-cause mortality ( ) . authors suggest that magnesium deficiency, clostridium difficile infection and intestinal colonization with multidrug-resistant microorganisms might justify the link between inappropriate use of ppi and mortality ( ) ( ) ( ) . interestingly their chronic use has been associated with malnutrition and functional decline ( , ) , two main aspects to be assessed and monitored in older patients with covid- infection. older age and the presence of multimorbidity are almost invariably associated with impaired nutritional status and sarcopenia ( ) . some studies have demonstrated that hospitalization and associated bed rest even for short time-period ( days) promote detrimental reduction in muscle mass, strength and physical function, with altered aerobic exercise capacity ( , ) . covid- also amplifies these symptoms if we consider that muscle pain and fatigue are frequent symptoms also in older persons. the bed rest and high inflammatory and hypercatabolic status following covid- infection can promote a further reduction in walking speed, stair ascent power and chair stand test. these functional parameters, as well as the loss of strength, may compromise the recovery of functional skills in the elderly and induce the loss of autonomy. although albumin and prealbumin circulating levels should not be considered as nutritional markers in patients with acute inflammatory response, studies have shown an association between low prealbumin levels and increased risk of respiratory failure with increased need for mechanical ventilation ( ) . all infected patients at hospital admission, especially those at nutritional risk should undergo nutritional assessment and receive nutritional support as early as possible. there is evidence that nutritional derangements should be systematically and urgently managed in patients affected by covid- , also considering that the immune response is weakened by inadequate nutrition. nutritional intervention should be complementary to pharmacological treatment and the presence of a standardized protocol would be extremely helpful. for example, in italy, a nutritional protocol has been developed and proposed by university of milan and pavia in lumbardy which is one of the main italian regions affected by the italian covid- crisis ( ) . this is based on systematic supplementation of certain nutrients (e.g. vit. d, whey proteins and omega fatty acids) with anabolic and anti-inflammatory activity, oligo-elements stimulating immune system and particularly indicated in this high systemic inflamma- heart failure one qtc-prolonging drug * a cut-off ≥ can be used to assess moderate-severe risk. modified by reference . tory and catabolic condition. obesity can be considered a specific type of malnutrition, where the excess of macronutrients intake could also be accompanied by micronutrients deficiency ( ) . the centers for disease control and prevention considers those with bmi ≥ kg/m as being at risk for flu complications. during the h n pandemic, obesity was recognized as an independent risk factor for complications from influenza ( ) . it is now well accepted that obesity increases one's risk of being hospitalized with, and dying from, an influenza virus infection, and it can be considered a predictor for poor outcome during covid- infections ( ) . it has been reported that the presence of obesity in a group of metabolic associated fatty liver disease (mafld) patients was associated with a ~ -fold increased risk of severe covid- illness (unadjusted-or . , % ci . - . , p=. ). given the high prevalence of obesity and overweight in european countries ( - %), the challenge for virus pandemics is therefore to protect these subjects ( ) . although the effects of covid- on patients with obesity have not yet been well-described, it is well known the impact of h n influenza the care of patients with obesity and with severe obesity, due to its adverse effect on pulmonary function ( ) . the increased morbidity associated with obesity in covid- infections may be explained by increased inflammatory cytokines, other important determinants of severity infection include basal hormone milieu, defective response of both innate and adaptive immune system and sedentariness. it has been suggested by recent evidences that a large obese population increases the chance of appearance of more virulent viral strain, prolongs the virus shedding throughout the total population and eventually may increase overall mortality rate of an influenza pandemic ( ) . finally, some authors outlined a framework whereby adipose tissue may be as a reservoir for more extensive viral spread with increased shedding, immune activation and cytokine amplification ( ) . even, there are no specific studies on nutrition management in covid- infection, espen promotes considerations based on the best of knowledge and clinical experience. first, patients at risk for poor outcomes and higher mortality following infection with sars-cov- , namely older adults and multimorbid individuals, should be checked for malnutrition through screening and assessment. criteria can be used are the must criteria or, for hospitalized patients, the nrs- criteria. recently it has been introduced the glim (global leadership initiative on malnutrition) criteria for malnutrition diagnosis. obese individuals should be screened and investigated according to the same criteria, as they are malnourished. in a recent review about potential interventions for novel coronavirus based on the chinese experience authors suggested that the nutritional status of each infected patient should be evaluated before the administration of general treatments ( ) . subjects with malnutrition should optimize their nutritional status, ideally by diet counseling from an experienced professional. macronutrients intake proposed by espen are the following. energy needs can be assessed or predicted by equations or weight-based formulae such as: • kcal per kg body weight and day; total energy expenditure for polymorbid patients aged > years; • kcal per kg body weight and day; total energy expenditure for severely underweight polymorbid patients*; • kcal per kg body weight and day; guiding value for energy intake in older persons, this value should be individually adjusted with regard to nutritional status, physical activity level, disease status and tolerance. *the target of kcal/kg body weight in severely underweight patients should be cautiously and slowly achieved, as this is a population at high risk of refeeding syndrome. protein needs are usually estimated using formulae such as: • g protein per kg body weight and day in older persons; the amount should be individually adjusted with regard to nutritional status, physical activity level, disease status and tolerance. • ≥ g protein per kg body weight and day in polymorbid medical inpatients in order to prevent body weight loss, reduce the risk of complications and hospital readmission and improve functional outcome. fat and carbohydrate needs are adapted to the energy needs while considering an energy ratio from fat and carbohydrates between : (subjects with no respiratory deficiency) to : (ventilated patients) percent. also micronutrients, such as vitamins and minerals, should be ensured to potentially reduce disease negative impact, by supplementation and/or adequate provision. low levels or intakes of micronutrients such as vitamins a, e, b and b , zn and se have been associated with adverse clinical outcomes during viral infections ( ) . recently, a chinese review ( ) proposed that also vitamin c, omega- polyunsaturated fatty acids, as well as selenium, zinc and iron should be considered in the assessment of micronutrients in covid- patients. oral nutritional supplements (ons) should be used whenever possible to meet patient's needs, when dietary counseling is not sufficient to reach nutritional goals. individuals infected with sars-cov- outside of the icu should therefore be treated to prevent or improve malnutrition. the oral route is always preferred when practicable. nutritional treatment should start early during hospitalization (within - h) and targets should be met gradually to prevent refeeding syndrome. ons provide energy-dense alternatives to regular meals and may be specifically enriched to meet targets in terms of protein as well as micronutrients (vitamins and trace elements). the daily estimated requirements of these nutrients should be regularly provided. nutritional treatment should continue after hospital discharge with ons and individualized nutritional plans; this is particularly important since preexisting nutritional risk factors continue to apply and acute disease and hospitalization are likely to worsen the risk or condition of malnutrition. according to espen statements, in multimorbid inpatients and in older persons with reasonable prognosis, when nutritional requirements cannot be met by the oral route, enteral nutrition (en) should be preferred to parenteral nutrition (pn), because of a lower risk of complications (related or not related to infectious). pn should not be started until all strategies to maximize en tolerance have been attempted. about the nutritional management of covid- patients admitted to intensive care units, espen guidelines on this specific topic are available giving suggestions on different stages of treatment according to patients' condition and respiration. infected patients not intubated who do not reach nutritional requirements by normal diet, first should be supplemented by ons, then en treatment can be considered. when limitations are present to en, pn can be prescribed. in covid- intubated and ventilated icu patients, enteral nutrition (en) should be started through a nasogastric tube; post-pyloric feeding should be performed in patients with gastric intolerance after prokinetic treatment or in patients at high-risk for aspiration; the prone position per se does not represent a limitation or contraindication for en. patients' energy expenditure can be derived from ventilator (vo , oxygen consumption from pulmonary arterial catheter or vco , carbon dioxide production), and energy is administered according to its value. hypocaloric nutrition (not exceeding % of ee) should be administered in the early phase of acute illness with increments up to and % after day . regarding protein intake, . g/kg protein equivalents per day can be delivered progressively. in obese subjects, . g/ kg "adjusted body weight" protein equivalents per day is recommended. adjusted body weight is calculated as ideal body weight + (actual body weight -ideal body weight) * . . after mechanical ventilation, patients may present swallowing difficulties and texture-adapted food can be considered after extubation. if swallowing is proven unsafe, en should be administered. in cases with a very high aspiration risk, post-pyloric en or, if not possible, temporary pn during swallowing training with removed naso-enteral tube can be performed. hydration status of patients should be considered and assessed after the acute and critical phases. high grade of inflammation and infectious status with long lasting fever period may cause dehydration which needs to be treated before discharge. furthermore, some patients with covid- show intestinal disease, thus nutritional and gastrointestinal function should be assessed for all patients. some authors suggest that nutritional support and application of prebiotics or probiotics should be suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation ( ) . almost no information is available on metabolic and nutritional needs of icu survivors, and known nutritional practices reveal a poor nutritional performance during icu stay and after discharge. a few evidences showed that currently poor nutritional practices are adopted for older patients who leave the icu in the ward, and further research are needed to fill the gap. following hospital discharge, especially patients should comply with high-protein targets either by prolonged tube feeding or by enhanced high-protein oral nutrition (supplement) intake. further, nutritional and metabolic therapies such as anabolic/anti-catabolic agents in the recovery need urgent studies ( ) . nutritional intervention should be combined (whether possible) with physical exercise in order to optimize its anabolic effect ( ) . different phases and week programs could be also followed with the specific aim of recovering physical and motor skills (table ) . phase . recover of orthostatism. once the acute phase has been resolved, the multidomain intervention should include exercise and target the recovery of orthostatic and motor skills. it would be important progressively increase the anti-gravity position starting from the sitting position on the bed with slow exercises and movements to be repeated several times a day, until the complete recovery of the upright position. phase . train balance and coordination of movements. following this first phase, static and dynamic balance exercise should be performed for improving balance impairment. holding on the back of a chair, stand on tiptoe and then return to the starting position, or keep the balance in monopodalic support. phase . regain muscle strength. low intensity muscle strengthening exercises might be useful for recovering strength and functional autonomy, improving stability, balance and reducing the risk of falls. for example, sitting back on a chair, slowly raise left leg until it is fully extended, pause for a breath, then slowly lower left leg back to the ground. this sequence should be repeated times both sides. phase . start endurance training. aerobic exercise, like walking inside the house or stationary bike, can be started after the regaining of motor skills and strength, initially minutes of activity then up to minutes. maintenance: individual multicomponent exercise program. at the end of the total recovery, a multicomponent exercise program can include aerobic, resistance, balance, coordination and mobility training exercises ( ) . twenty minutes of aerobic exercise every day and three days a week of resistance exercises at low and medium intensity should be the ideal choice for older people to enhance the protective role of physical activity ( ) ( ) ( ) . the pathophysiology of the covid- infection especially in older adults requires a dynamic process with important clinical and ethical implications in the hospital and community care. now it is quite clear that the infection produces a systemic disease with different phases at increasing severity of symptoms. older patients infected by covid- often experience atypical and less severe symptoms in older persons, side-effects of the drugs and require specific nutritional and motor treatment for avoiding disability and death. by expanding the proposal of hasan k et al. ( ) , we added to the already known infective, pulmonary and inflammatory, a potential iv phase for emphasizing the presence of a vascular-thrombotic process more frequent during the severe pulmonary disease. we also underlined the bacterial over-infection, which can be transversally present in all phases and requires the need of antibiotic treatment. as addressed by italian ethics committee it is ethically unacceptable, each selective care criterium based on «age, gender, condition and social role……and disability». these principles have been often ignored, especially in older covid- patients. examples reported from the sociologist giuseppe de rita and coming from uk or holland, describe that patients year or older are invited to sign a declaration where they refuse to be cured if another younger patient requires the same treatment. a statement signed on march rd by the european geriatric medicine society (eugms) ( ) suggests that advanced age should not by itself be a criterion for excluding patients from specialized hospital units and care. simplified models of comprehensive geriatric assessment and tailored interventions (including evaluation of frailty, hydration and nutritional with body mass index and cst, social and psychological support, management of polypharmacy) are mandatory to guide appropriate clinical approaches, especially if older subjects are really fit, without any cognitive and motoric dysfunction, and to improve the patient's quality of life ( ) . these principles should be applied to every setting of care including community/primary care, hospital and nursing home placement. innovative organizing multidisciplinary models are especially important during the transition care and coronavirus outbreak, because older people might experience an understandable slowing down of physi-cal and mental capacities in the discharge from acute care with prolonged hospital stays and increased risk of iatrogenic consequences. all the necessary efforts should be made to consider more intermediate care and home care facilities to improve rehabilitation and recovery of older patients. global epidemiology of coronavirus disease (covid- ): disease incidence, daily cumulative index, mortality, and their association with country healthcare resources and economic status case-fatality rate and characteristics of patients dying in relation to cov-id- in italy the origins of age-related proinflammatory state clinical features of patients infected with novel coronavirus in wuhan, china coronary artery disease concomitant with chronic obstructive pulmonary disease national institute for health and care excellence. covid- rapid guideline: critical care in adults clinical characteristics of coronavirus disease in china facing covid- in italy -ethics, logistics, and therapeutics on the epidemic's front line [published online ahead of print loneliness and social isolation in older adults during the covid- pandemic: implications for gerontological social work comprehensive geriatric assessment for older adults admitted to hospital characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical management of severe acute respiratory infection when novel coronavirus ( -ncov) infection is suspected clinical and virological data of the first cases of covid- in europe: a case series remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro severe acute respiratory syndrome coronavirus (sars-cov- ) and the central nervous system the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china a systematic review on the efficacy and safety of chloroquine for the treatment of covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study how to obtain a nasopharyngeal swab specimen endothelial cell infection and endotheliitis in covid- objectively measured physical capability levels and mortality: systematic review and meta-analysis safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of sars-cov- infection hospital-based use of thromboprophylaxis in patients with covid- estimated glomerular filtration rate and functional status among older people: a systematic review clinical and ct imaging features of novel coronavirus disease (covid- ) scrna-seq profiling of human testes reveals the presence of the ace receptor, a target for sars-cov- infection in spermatogonia baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial covid- autopsies the versatile heparin in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up nifedipine and phosphodiesterase inhibitors: rationale for their utilization as adjunctive countermeasures in the treatment of coronavirus disease (covid- ) a trial of lopinavir-ritonavir in adults hospitalized with severe covid- [published online ahead of print compassionate use of remdesivir for patients with severe covid- [published online ahead of print clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- : six million doses of hydroxychloroquine donated to us despite lack of evidence of chloroquine and cov-id- breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of cov-id- associated pneumonia in clinical studies hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial study to evaluate the safety and antiviral activity of remdesivir (gs- ™) in participants with moderate coronavirus disease (covid- ) compared to standard of care treatment favipiravir versus arbidol for covid- : a randomized clinical covid- : trials of four potential treatments to generate "robust data" of what works covid- : what treatments are being investigated? acute respiratory distress syndrome: the berlin definition the berlin definition of ards: an expanded rationale, justification, and supplementary material formal guidelines: management of acute respiratory distress syndrome the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease biomarkers for acute respiratory distress syndrome and prospects for personalised medicine covid- : most patients require mechanical ventilation in first hours of critical care the use of high-flow nasal oxygen in covid- corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials treatment of critically ill patients with covid- with convalescent plasma dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial immunothrombosis in acute respiratory distress syndrome: cross talks between inflammation and coagulation endothelial cell infection and endotheliitis in covid- anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy activation of coagulation and fibrinolysis in acute respiratory distress syndrome: a prospective pilot study. front med (lausanne) bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry heparin prevents zika virus induced-cytopathic effects in human neural progenitor cells coronaviridae and sars-associated coronavirus strain hsr covid- -scheda informativa aifa su eparine a basso peso molecolare high incidence of venous thromboembolic events in anticoagulated severe covid- patients the critical role of laboratory medicine during coronavirus disease (covid- ) and other viral outbreaks a rapid advice guideline for the diagnosis and treatment of novel coronavirus ( -ncov) infected pneumonia (standard version) pharmacologic treatments for coronavirus disease (covid- ): a review development and validation of a risk score to predict qt interval prolongation in hospitalized patients urgent guidance for navigating and circumventing the qtc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease (cov-id- ) ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for covid- . cardiology magazine proton pump inhibitors and risk of -year mortality and rehospitalization in older patients discharged from acute care hospitals adverse events of proton pump inhibitors: potential mechanisms proton pump inhibitors and hypomagnesemia: a metaanalysis of observational studies evaluation of the association between gastric acid suppression and risk of intestinal colonization with multidrug-resistant microorganisms: a systematic review and meta-analysis relationship between use of proton pump inhibitors and igf system in older subjects proton pump inhibitors and functional decline in older adults discharged from acute care hospitals nutrition support in the time of sars-cov- (covid- ) bed rest promotes reductions in walking speed, functional parameters, and aerobic fitness in older, healthy adults functional impact of days of bed rest in healthy older adults nutritional recommendations for covid- quarantine [published online ahead of print geriatric syndromes and sars-cov- : more than just being old covid and the patient with obesity -the editors speak out is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in covid- espen expert statements and practical guidance for nutritional management of individuals with sars-cov- infection [published online ahead of print obesity and its implications for covid- mortality influenza and obesity: its odd relationship and the lessons for covid- pandemic [published online ahead of print back to the future: lessons learned from the influenza pandemic potential interventions for novel coronavirus in china: a systematic review zhejiang da xue xue bao yi xue ban nutrition therapy and critical illness: practical guidance for the icu, post-icu, and long-term convalescence phases exercise and protein intake: a synergistic approach against sarcopenia physical exercise as therapy to fight against the mental and physical consequences of covid- quarantine: special focus in older people a tale of two pandemics: how will covid- and global trends in physical inactivity and sedentary behavior affect one another? considerations for obesity, vitamin d, and physical activity amidst the cov-id- pandemic physical activity for immunity protection: inoculating populations with healthy living medicine in preparation for the next pandemic covid- illness in native and immunosuppressed states: a clinical-therapeutic staging proposal state-ment of the eugms executive board on the covid- epidemic prevalence, incidence, and clinical impact of cognitive-motoric risk syndrome in europe, usa, and japan: facts and numbers update we deeply appreciated our patients and families for their patience and kindness and our nurse coordinator rosetta castellino and her staff for the excellent work and the strong support during covid epidemic. each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article key: cord- -p c fneh authors: bosma, karen j.; taneja, ravi; lewis, james f. title: pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches date: - - journal: drugs doi: . / - - sha: doc_id: cord_uid: p c fneh the acute respiratory distress syndrome (ards) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. critical care technologies used to support patients with ards, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. however, there is still a need for effective pharmacotherapies to treat ards, as mortality rates remain high. to date, no single pharmacotherapy has proven effective in decreasing mortality in adult patients with ards, although exogenous surfactant replacement has been shown to reduce mortality in the paediatric population with ards from direct causes. several promising therapies are currently being investigated in preclinical and clinical trials for treatment of ards in its acute and subacute, exudative phases. these include exogenous surfactant therapy, β( )-adrenergic receptor agonists, antioxidants, immunomodulating agents and hmg-coa reductase inhibitors (statins). recent research has also focused on prevention of acute lung injury and acute respiratory distress in patients at risk. drugs such as captopril, rosiglitazone and incyclinide (col- ), a tetracycline derivative, have shown promising results in animal models, but have not yet been tested clinically. further research is needed to discover therapies to treat ards in its late, fibroproliferative phase. given the vast number of negative clinical trials to date, it is unlikely that a single pharmacotherapy will effectively treat all patients with ards from differing causes. future randomized controlled trials should target specific, more homogeneous subgroups of patients for single or combination therapy. the acute respiratory distress syndrome (ards) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. critical care technologies used to support patients with ards, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. however, there is still a need for effective pharmacotherapies to treat ards, as mortality rates remain high. to date, no single pharmacotherapy has proven effective in decreasing mortality in adult patients with ards, although exogenous surfactant replacement has been shown to reduce mortality in the paediatric population with ards from direct causes. several promising therapies are currently being investigated in preclinical and clinical trials for treatment of ards in its acute and subacute, exudative phases. these include exogenous surfactant therapy, b -adrenergic receptor agonists, antioxidants, immunomodulating agents and hmg-coa reductase inhibitors (statins). recent research has also focused on prevention of acute lung injury and acute respiratory distress in patients at risk. drugs such as captopril, rosiglitazone and incyclinide (col- ), a tetracycline derivative, have shown promising results in animal models, but have not yet been tested clinically. further research is needed to discover therapies to treat ards in its late, fibroproliferative phase. given the vast number of negative clinical trials to date, it is unlikely that a single pharmacotherapy will effectively treat all patients with ards from differing causes. future randomized controlled trials should target specific, more homogeneous subgroups of patients for single or combination therapy. acute lung injury (ali) and the acute respiratory distress syndrome (ards) arise from direct or indirect injury to the lungs, and results in a life-threatening form of respiratory failure. ali/ards is both common and serious: . - . % of patients admitted to an intensive care unit (icu) will be diagnosed with ali or ards, [ ] [ ] [ ] and approximately one-quarter to one-half of these patients will succumb to this disease process. [ , [ ] [ ] [ ] over the past years, ards has been the focus of extensive basic science and clinical research, although no single pharmacotherapy has been shown to reduce mortality in a large, randomized, controlled, multicentre trial of adult patients. the reasons for this are manifold, and include issues of dosing, route of administration and timing of the various interventions tested. more importantly, however, may be the nature of the disorder itself: the diagnosis of ards envelops a heterogeneous group of patients with varying causes and pathophysiological mechanisms at work. the notion that a therapeutic agent that can successfully alter a single biological target in an animal model of ali will reduce mortality in all patients with ards may be unrealistic. nonetheless, there is reason for hope on the scientific horizon. recent advances have been made in our understanding of the pathophysiological mechanisms underlying ali/ards, leading to the identification of potential novel targets for pharmacological intervention. some therapies are best aimed at preventing the development of ards, while others treat the syndrome as it unfolds or aid in its resolution. the challenge lays in identifying the subgroup of patients most likely to benefit from such focused therapy. this paper reviews the current experimental and existing approaches to managing ards, highlighting the pathophysiological basis for their use and potential for future clinical development. ali may occur following a direct insult to the pulmonary system such as aspiration of gastric contents, bacterial pneumonia or viral pneumonitis (e.g. h n influenza virus), or an indirect insult such as the systemic inflammatory response associated with pancreatitis, sepsis or multiple trauma. table i shows common direct and indirect causes of ali/ards. whether this 'first hit' to the lung is direct or indirect, a pulmonary inflammatory response may occur, which often is adaptive and self-limited. however, when coupled with repeated 'hits' to the lung from insults such as injurious mechanical ventilation or other secondary processes such as hypotension, a cycle of intense inflammation and worsening pulmonary injury ensues. the 'multiple hit' theory of ards progression also provides a framework for studying the disease process (figure ). clinically, ali manifests as bilateral airspace disease observed on chest radiograph and hypoxaemia, such that the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao /fio ) is greatly reduced. according to the american european consensus conference (aecc) definition, a chest radiograph consistent with pulmonary oedema and a pao /fio ratio < is sufficient to diagnose ali in the setting of an inciting pulmonary insult and the absence of congestive heart failure. the aforementioned criteria but with a pao /fio ratio < is classified as ards. [ ] although differentiated by the aecc definition, ali and ards are often grouped together for the purpose of clinical trial enrolment and are treated as a single entity throughout this review. although not all patients follow the same clinical course, progression of ali/ards may be considered along a pathophysiological timeline of early, mid and late phases, with considerable overlap between these phases. table ii summarizes the pathogenetic mechanisms at work during each phase, linking each biological pathway to a potential drug therapy. a general overview of the pathophysiology of ards is provided here, with more detailed descriptions of the specific biologic pathways discussed in sections . - . as they pertain to each potential pharmacological therapy. the early phase, within the first hours of the inciting lung injury, is characterized by inflammatory damage to the alveolar-capillary barrier. this results in increased vascular permeability, leading to interstitial and alveolar oedema as proteinaceous fluid fills the alveolar space. this inflammation-induced pulmonary oedema disrupts normal gas exchange and increases the work of breathing, leading to respiratory failure and the need for mechanical ventilation. mechanical ventilation itself may cause secondary insult to the already inflamed oedematous alveoli. during each tidal breath induced by mechanical ventilation, unstable alveoli undergo cyclical collapse and shearing open, termed 'atelectrauma'. furthermore, the non-collapsed alveolar units may receive a greater proportion of the delivered tidal volume, leading to damage due to overdistention or 'volutrauma'. further breakdown of the endothelial-epithelial barrier may occur with atelectrauma and volutrauma, along with the release of local proinflammatory mediators which further b see text for details. aa = arachidonic acid; arb = angiotensin receptor antagonist (blocker); fa = fatty acid; gm-csf = granulocyte macrophage colonystimulating factor; hne = human neutrophil elastase; icam- = intercellular adhesion molecule- ; il- = interleukin- ; mmps = matrix metalloproteinases; nf-kb = nuclear factor-kb; paf = platelet-activating factor; ppar-g = peroxisome proliferator activated receptor-g; rhpaf = recombinant human paf; tnfa = tumour necrosis factor-a. propagate this cycle of ventilator-exacerbated lung injury. [ ] as inflammation ensues, neutrophils are recruited to the lung. damaged endothelial cells exhibit increased activity of the transcription factor nuclear factor-kb (nf-kb), which upregulates the surface expression of intercellular adhesion molecule (icam)- . icam- mediates leukocyte adhesion and migration across the endothelium to the alveolar epithelium. activated neutrophils release proteases, such as matrix metalloproteinases (mmp) and neutrophil elastase (ne), which further damage the alveolarcapillary membrane. [ ] activated neutrophils also contain high levels of arachidonic acid, [ ] which is metabolized into leukotrienes, prostaglandins and thromboxanes. leukotrienes attract more neutrophils, prostaglandins are proinflammatory mediators, and thromboxanes play a role in vasoconstriction and platelet and leukocyte aggregation. neutrophil recruitment and activation may be an adaptive physiological response to injury, or may incite a vicious cycle of inflammation and further damage. [ ] at this stage, patients may recover from the initial insult, with clearance of the pulmonary oedema and restoration of the barrier between capillary endothelial and alveolar epithelial cells, or may progress to the exudative or mid phase of ards. it is not fully understood why two patients exposed to the same insult may have completely different clinical courses; however, genetic factors, [ ] co-morbid illnesses such as diabetes mellitus and alcohol addiction, [ ] nutritional status, medications and exposure to further insults are all likely to play a role. understanding the host and environmental factors that place a patient at high risk of progressing to the exudative phase of ards will facilitate identification of targets for earlier intervention. the exudative or subacute phase typically occurs over the - days following the initial insult. pathologically, this mid phase is characterized by formation of intra-alveolar hyaline membranes rich in plasma proteins, fibrin and cellular debris. [ ] a biopsy of the lungs at this stage will show diffuse alveolar damage and, clinically, the lungs have poor compliance with ongoing gas exchange problems including hypoxaemia and elevated dead space fraction. the inflammatory milieu within the alveoli, coupled with the cyclical opening, stretching and collapsing of alveoli via mechanical ventilation, initiates a number of pathogenic pathways in concert or in series. these include disruption of surfactant function and metabolism, ongoing neutrophil recruitment and activation, along with increased expression and release of inflammatory mediators, imbalance of oxidant and antioxidant activity, and activation of complement and coagulation cascades. each of these pathways is further discussed to provide context for the drugs or therapies aimed at ameliorating these various mechanisms (see section ). interestingly, only a minority of patients will succumb to severe hypoxaemia or hypercarbia, as the major source of mortality is not the pulmonary injury per se, but rather the occurrence of multiple organ failure. in this setting, the injured lung may represent a rich source of inflammatory mediators that could contribute to the development of multi-organ failure. for example, stress failure and necrosis of the endothelial-epithelial barrier may allow various inflammatory mediators, bacteria and endotoxins to quickly spread from the lungs into the systemic circulation. indeed, it is this de-compartmentalization of inflammatory mediators from the lungs into the circulation that is felt to lead to cell apoptosis in distal organs, [ ] and ultimately multiple organ dysfunction syndrome (mods) [ figure ]. [ ] once mods develops, disease is often irreversible and mortality may increase significantly to - %, the latter occurring when three or more organs are involved for a period of more than days. [ ] [ ] [ ] thus, a key to developing novel therapies that will reduce mortality in ards will be identification of the cellular and molecular mechanisms by which ards leads to mods. survivors of the first week of ali/ards may enter the late phase of the disorder, known as the fibroproliferative phase. during days - , the exudates and hyaline membranes become organized, and fibrosis may become apparent. type ii alveolar cells proliferate and line the alveolar walls, fibroblasts migrate and differentiate into myofibroblasts in the interstitial and alveolar spaces, and a collagen-rich extracellular matrix is laid down in the interstitium. [ ] alveoli may be destroyed, pulmonary vascular area may be reduced and chronic inflammation is generally present. patients in the fibroproliferative phase of ards may slowly recover, or may fail to wean from mechanical ventilation and succumb to complications of a lengthy critical illness or pre-existing co-morbid illnesses. pharmaceutical interventions for late ards must interrupt the fibrosing alveolitis and aid in resolution, remodelling and repair of injured lungs. [ ] often, therapies that might be beneficial during the early phase of lung injury are started too late in the course of the disease, when fibrosis is already established, muting their potential efficacy. when tested specifically for the late fibroproliferative phase of ards, anti-inflammatory therapies have yielded disappointing results. basic science research examining mechanisms of idiopathic pulmonary fibrosis may illuminate therapeutic pathways for fibroproliferative ards, but further work is required in this area. although no pharmacological therapies have been proven to reduce mortality in large, randomized controlled trials (rcts) involving adult patients, it appears that improvements in supportive care have reduced mortality to some extent. for example, mortality estimates ranged progression of acute respiratory distress syndrome (ards) to multi-organ failure (mof). initially, inflammatory damage to the alveolar-capillary barrier results in increased vascular permeability, leading to interstitial and alveolar oedema as proteinaceous fluid fills the alveolar space. there, the proteinaceous fluid interferes with the function and metabolism of the endogenous surfactant system. coupled with this, neutrophils that infiltrate lungs are subsequently activated and represent an important source of inflammatory mediators and oxygen free radicals, inducing further epithelial and endothelial cell damage and an altered host immune response. newly secreted mediators and/or spillover of inflammatory mediators from the lung into the systemic circulation ultimately contribute to the development of mof. inflammatory mediators released from organs such as the liver, heart and kidney return to the lung via the systemic circulation and may contribute to further pulmonary inflammation. thus, each new insult to the pulmonary system accelerates the acute lung injury cycle (reproduced from bosma et al. [ ] [ ], with permission). from % to % as reported in the literature in the s and early s [ ] [ ] [ ] [ ] to more recent estimates of - % in observational epidemiological studies [ , ] and - % in large clinical trials. [ , ] although this mortality reduction may in part reflect differences in diagnostic criteria used post publication of the aecc definition, undoubtedly the largest impact has been the move to more 'protective' strategies of mechanical ventilation. in , the national institutes of healthsponsored ards network (ardsnet) trial involving low tidal volume ventilation was published, and now constitutes the standard of care for patients with ali and ards. this trial compared a traditional tidal volume of ml/kg with a lower tidal volume of ml/kg in patients and reported a mortality reduction from % in the control arm to % in the treatment arm. [ ] these results definitively ended the debate fuelled by three previous inconclusive smaller trials regarding lower versus conventional tidal volumes. in terms of furthering ali/ards research, several lessons have been learned from this landmark study. first, ardsnet was set up to conduct well designed, large, phase iii studies with a concerted effort to optimize patient enrolment through involvement of many centres in an organized and cohesive group. [ ] this enabled a study sufficiently powered to realize a mortality difference to be conducted within a reasonable timeframe, and pointed the way for other similarly structured ards research networks to become established. second, the treatment arm was associated with lower oxygenation values than the conventional arm, highlighting the potential danger of relying on oxygenation or other physiological parameters as surrogates for mortality. third, this study demonstrated that a nonpharmacological intervention could alter mortality, indicating that future rcts need to be carefully standardized in all aspects of supportive care in both treatment and control arms. one potential caveat ensuing from this study has been the assumption that any additional proven therapy would reduce mortality across a population as heterogeneous and diverse as that enrolled in the ardsnet low tidal volume trial. this approach may be misguided, as subsequent studies have demonstrated differences between patients with direct and indirect causes of ali/ards in responsiveness to specific therapies. [ , ] research is ongoing to determine whether newer modes of mechanical ventilation, such as high-frequency oscillation (hfo), can further improve outcomes in ards relative to the ardsnet low tidal volume strategy. [ ] in addition, other aspects of supportive care have been evaluated in large clinical trials, some conducted by ardsnet, and have proven effective in reducing morbidity associated with critical illness. these include cautious fluid management, [ , ] adequate nutrition, [ ] prevention of ventilator associated pneumonia, [ ] [ ] [ ] [ ] prophylaxis for deep venous thrombosis [ ] and gastric ulcers, [ ] weaning of sedation and mechanical ventilation as early as possible, [ ] and physiotherapy and rehabilitation. [ ] a recent review of all patients enrolled in ardsnet studies between and showed that these advancements in critical care (aside from lower tidal volume ventilation) are likely responsible for the improved survival in ali/ards patients in clinical trials noted over the last decade. [ ] additional modalities used as 'rescue therapies' for the ards patient at risk of succumbing to severe hypoxaemia or respiratory acidosis have also been tested, including nitric oxide, prone positioning, hfo and extracorporeal membrane oxygenation (ecmo). nitric oxide [ ] and prone positioning [ , ] have not been shown to reduce mortality or duration of mechanical ventilation in patients with ali/ards, and are therefore not recommended for routine use. however, combined together, these therapies may provide a sustained improvement in oxygenation for patients with severe hypoxaemia and a mortality benefit for patients who are failing conventional mechanical ventilation strategies. [ ] [ ] [ ] a clinical trial of hfo for routine care of patients with ards is currently underway, but existing evidence supports its use as salvage therapy if instituted early for patients failing conventional ventilation, [ ] and may have additive benefits when combined with nitric oxide and prone positioning. [ ] finally, ecmo has recently been studied in the cesar trial (see table iii for a list of trial acronyms). [ ] this study showed that transferring adult patients with severe but potentially reversible respiratory failure, whose murray score exceeds . or who have a ph of < . on optimum conventional management, to a centre with an ecmo-based management protocol, significantly improved survival without severe disability. recent evidence suggests ecmo is also useful for rescue therapy for adults with severe ards due to h n -influenza a virus infection. [ ] pharmacological treatments for ali/ards may be employed prior to the onset of ards or in the early, mid or late phases of ards (table iv) . accordingly, their purpose may be to prevent ali in those at risk, mitigate the pathogenic mechanisms responsible for the cycle of lung injury and systemic inflammation in established ards, or aid in lung healing and repair. some therapies, such as corticosteroids, have been studied for prevention of ards, treatment of early ards and treatment of late ards, and are discussed within each context. the concept that ards may be prevented in those at high risk after an inciting insult is not new, but is one that is garnering greater attention in the scientific literature in recent years. since no pharmacological agent has proven effective in treating established ards in adults, attention has turned to prophylactic treatment to prevent the development of ards in those at highest risk. of course, any pharmacotherapy that is initiated prior to the diagnosis of disease must have a very high benefit to risk ratio and be cost effective. as such, it should have the following attributes: (i) be low risk, without serious adverse effects; (ii) be easily and widely applicable; and (iii) be relatively inexpensive. drug classes studied for ards prevention include imidazoles (e.g. ketoconazole), ace inhibitors, thiazolidinediones (e.g. rosiglitazone), chemically modified tetracycline derivatives, antioxidants, and corticosteroids and other immunomodulating agents. over years ago, the first clinical trial examining prophylactic use of ketoconazole to prevent ards in patients at risk was published. [ ] the rationale for using ketoconazole, an antifungal drug with anti-inflammatory properties, was as follows. as mentioned in section , patients with ards have increased levels of arachidonic acid metabolites in their bronchoalveolar fluid. [ , ] metabolism of arachidonic acid leads to the production of leukotrienes, prostaglandins and thromboxanes. thromboxane a is a potent vasoconstrictor, and is involved with platelet and leukocyte aggregation, while leukotrienes act as powerful chemokines to attract neutrophils. ketoconazole is an antifungal agent of the imidazole class which selectively blocks thromboxane synthetase. ketoconazole also inhibits -lipoxygenase, the enzyme necessary to generate leukotrienes, and inhibits procoagulant activity. [ ] in addition to showing promise in preclinical animal studies, when given prophylactically to patients at risk of developing ards, ketoconazole has been shown to reduce the incidence of severe ards in three small trials. a study of patients admitted to a surgical icu showed that in the group treated prophylactically with oral ketoconazole mg/day, of patients ( %) ultimately developed ards, whereas of ( %) patients in the control group developed ards (p < . ). [ ] similar results followed in a study of patients with septic shock admitted to a surgical icu, where the incidence of ards in the group treated with ketoconazole mg/day was % ( of patients) compared with % ( of patients) in the control group (p = . ), and mortality was % versus %, respectively (p = . ). [ ] although both of these studies were conducted prior to the aecc definition, ards was strictly defined in the aforementioned studies, including a pao /fio ratio < or intrapulmonary shunt > % in patients requiring mechanical ventilation and who had diffuse infiltrates on chest radiograph without clinical evidence of heart failure as pulmonary arterial occlusion pressures were < mmhg. building on the results of these two studies, sinuff and colleagues [ ] developed practice guidelines for prophylactic ketoconazole use, and tested the implementation and efficacy of these guidelines in two icus (one control and one active comparator). they reported a significantly decreased incidence of ards in the icu population receiving ketoconazole prophylaxis, although mortality was equivalent within the two units. [ ] in , ardsnet published the karma study evaluating oral ketoconazole versus placebo for patients within hours of an established diagnosis of ali or ards according to the aecc definition. [ ] the study was stopped early after enrolment of patients for failing to show a difference in mortality or ventilator-free days. of note, this study was designed to look at early treatment of ali/ards rather than prevention of ards in patients at risk, and therefore did not necessarily negate the findings of the three previous smaller studies. furthermore, a problem identified in the karma study was that even though blood ketoconazole concentrations were adequate, urinary metabolites of thromboxane were not affected, raising the possibility that the proper dose to achieve an anti-inflammatory effect was not given. however, since the karma f mortality reduction in subgroup of patients with ards, septic shock and relative adrenal insufficiency. g no mortality reduction in larger study, n = (lasrs). il- = interleukin- ; ma = meta-analysis; mc = multicentre; ppar-c = peroxisome proliferator activated receptor-g; rhpaf = recombinant human platelet-activating factor; rsp-c = recombinant surfactant protein-c; sc = single-centre. study showed no difference in mortality, widely considered the most important endpoint to achieve, further research on ketoconazole for ali/ards ceased. [ ] additionally, ketoconazole has numerous drug interactions and requires an acidic milieu to be absorbed via the enteral route, making routine use in the icu complicated. further research should examine whether other drugs in the imidazole class given intravenously have similar anti-inflammatory properties, and also establish the inflammatory dose-response curve for ali/ards. in addition, although the concept that prevention of ards will definitely lead to decreased mortality is intuitive, this still has to be proven in large multicentre clinical trials. the authors are unaware of any studies being conducted in this area presently. angiotensin-converting enzyme (ace) is produced in the lungs and is responsible for converting angiotensin i into angiotensin ii, a peptide active in vasoconstriction and sodiumfluid balance to maintain blood pressure homeostasis. ace inhibitors and angiotensin ii receptor antagonists (blockers; arbs) are classes of drugs commonly used to treat hypertension, and prevent progression of diabetic nephropathy in patients with diabetes. ace inhibitors also help to preserve vascular structure and function, by exerting a protective effect on endothelial cells. endothelial cell damage is the catalyst for the inflammatory and coagulation cascades activated in ali/ards. thus, the protection of endothelial cells offered by ace inhibitors may have a beneficial role in ards. [ ] studies in transgenic mice have shown that ace, angiotensin ii and angiotensin ii receptor type a may promote lung injury, whereas ace , a close homologue of ace, and angiotensin ii receptor type may protect against severe lung dysfunction in models of ards. [ ] the ace inhibitor captopril has been shown to prevent severe lung injury in an oleic acid-induced model in rats. in this model, captopril reduced expression of icam- in lung tissue, indicating a protective effect on endothelial cells, diminished activity of tissue plasminogen activator, involved in coagulation, and blocked nf-kb, the major signal transduction pathway that regulates the expression of multiple early-response genes related to inflammation. [ ] in humans, two small cohort studies have demonstrated that polymorphism of the ace gene increases susceptibility to the development of ards and its outcome. [ , ] two additional studies, published only in abstract form to date, have examined the association between ace inhibitor use and ards. a retrospective cohort study of adult critically ill patients found that . % of patients developed ards after hospital admission, and that preexisting, long-term use of an ace inhibitor or arb was associated with decreased risk of ards development, after adjusting for predisposing conditions (odds ratio [or] . ; % ci . , . ; p = . ). [ ] the second abstract, a case-control study nested within a prospective cohort of critically ill patients at risk for ards, reported that patients on ace inhibitors had a lower prevalence of respiratory failure on admission to icu, but not lower incidence of ards after adjusting for confounders on multivariate analysis. however, among patients who developed ards, ace inhibitor use was associated with lower mortality (adjusted hazard ratio . ; % ci . , . ). [ ] the associations observed in these clinical studies is consistent with preclinical animal data, but requires further research prior to being applicable clinically. [ ] peroxisome proliferator activated receptors (ppars) are ligand-activated transcription factors related to thyroid hormone, steroid and retinoid receptors. [ ] there are three isoforms: ppar-g, ppar-a and ppar-b/d. ppar-g plays a central role in glucose homeostasis. thiazolidinediones, a class of oral antidiabetic drugs, are synthetic ligands for ppar-g. synthetic ppar-g agonists also have anti-inflammatory properties, inhibiting proinflammatory cytokine production and macrophage activation in vitro. [ , ] this action is mediated in part by antagonizing the activity of transcription factor nf-kb. when activated, nf-kb induces overexpression of inflammatory cytokines such as tumour necrosis factor (tnf)-a, which in turn induces upregulation of icam- expression, as well as recruitment and activation of immune cells. icam- , expressed on the surface of endothelial cells, mediates leukocyte adhesion and migration through endothelium into tissues. the anti-inflammatory properties of thiazolidinediones have been demonstrated in vivo in murine models of inflammatory bowel disease [ ] and rheumatoid arthritis. [ ] rosiglitazone is the most potent selective ppar-g of the thiazolidinediones. prophylactic administration of rosiglitazone has been shown to attenuate ali in an animal model of pancreatitis-associated ali. [ ] in this study, rosiglitazone was dissolved and given intravenously to rats minutes prior to induction of acute pancreatitis by sodium taurocholate. compared with control group rats with acute pancreatitis and its associated lung injury, prophylactic administration of rosiglitazone resulted in a significantly lower histological pulmonary injury score, reduced pulmonary expression of tnfa and icam- messenger rna, and decreased lung tissue myeloperoxidase activity, a measure of neutrophil infiltration in the lung. [ ] this suggests that prophylactic rosiglitazone mitigates the ali associated with acute pancreatitis by its anti-inflammatory effect. unfortunately, the safety of rosiglitazone has recently been questioned due to its augmentation of sodium and water retention, leading to increased incidence of congestive heart failure in diabetic patients placed on this drug long-term. [ , ] thus, further animal studies are needed to confirm the effects of rosiglitazone in acute pancreatitis and evaluate potential complications related to its use, prior to proceeding to human studies. during the early phase of lung injury, neutrophils are recruited into the pulmonary vasculature and activated to release proteases, such as mmps and ne, which damage the alveolarcapillary membrane, [ ] resulting in further release of inflammatory mediators. a single laboratory in the state university of new york (new york, ny, usa) has demonstrated in various animal models that blocking the proteases ne, mmp- and mmp- with a unique modified tetracycline can prevent the increased pulmonary vascular permeability that ultimately leads to ards. the same group has developed a 'two-hit' porcine model of sepsis plus gut ischaemiareperfusion injury that parallels the insidious onset of sepsis-induced ards in humans. in this model, anaesthetized yorkshire pigs undergo cross-clamping of the superior mesenteric artery for minutes to induce intestinal ischaemia, followed by intraperitoneal placement of a faecal blood clot. pigs are then awakened, extubated and taken to an animal icu for hours of continuous observation, where they receive intravenous fluids, broad-spectrum antibacterials and pain control medications. when the pao /fio ratio falls below , pigs are anaesthetized and placed back on mechanical ventilation with tidal volumes of ml/kg. in this model, they demonstrated that prophylactic administration of a synthetic, nonantimicrobial derivative of tetracycline called incyclinide (col- ; collagenex pharmaceuticals), prevented the development of both ards and septic shock. [ ] incyclinide has not yet been tested in any human studies of ards prevention; however, the complex model developed by this group contains all the elements of a clinically relevant animal model and, therefore, these results show potential for phase ii studies. oxidative stress is associated with development of ards and mods via direct tissue injury. nathens and colleagues [ ] examined the effect of antioxidant supplementation using atocopherol and ascorbic acid in critically ill surgical patients. in a prospective rct of surgical icu patients (mainly victims of trauma), they found antioxidants did not reduce the risk of developing ards, but did decrease the risk of developing mods, and shortened duration of mechanical ventilation and length of icu stay. [ ] antioxidants supplementation and nutritional strategies are now being studied for critically ill patients with early signs of mods, [ ] but not specifically for ards prevention. antioxidants and nutrition have also been studied for treatment of ards, and are further discussed in this context in section . . . given that excessive and protracted inflammation is the overriding principle responsible for the various pathophysiological mechanisms leading to ards, broad and potent anti-inflammatory drugs, such as corticosteroids, would seem to be a rational choice for prevention. four rcts, published between and , have examined the use of corticosteroids to prevent the onset of ards in patients at risk. a recent meta-analysis of these studies demonstrated that preventive corticosteroids may actually increase the risk of developing ards in critically ill adults. [ ] furthermore, the meta-analysis suggested a weakly increased risk of death associated with preventive corticosteroid therapy in those patients who ultimately developed ards. thus, corticosteroid therapy is not recommended for preventing ards in those at risk. corticosteroid therapy has also been extensively studied for the treatment of established disease in the early and late phases, and is discussed further in these contexts (see the corticosteroids subsection of section . . and section . . ). platelet-activating factor (paf) is a potent proinflammatory mediator that is degraded by the enzyme paf acetylhydrolase. recombinant human paf acetylhydrolase (rhpaf-ah; epafipase) was studied in a phase iib rct to prevent ards in septic patients. [ ] patients with severe sepsis were randomized to receive rhpaf-ah mg/kg, rhpaf-ah mg/kg or placebo. the incidence of ards was not different amongst the three groups, but -day all-cause mortality was significantly decreased in the mg/kg treatment group compared with placebo ( % vs %; p = . ). therefore, although rhpaf-ah does not appear to be an effective prophylactic treatment for ards, it may hold promise for treatment of severe sepsis. the majority of research to date has focused on treating ards once the diagnosis is established. although many studies are designed to treat 'early ards', with randomization occurring within hours of diagnosis, these studies also likely capture many patients in the exudative phase of ards with intra-alveolar hyaline membranes and histological diffuse alveolar damage at the time of enrolment. this problem arises in part because the diagnostic criteria for ards are subjective and lack sensitivity and specificity when compared with pathological diagnosis. [ ] thus, timing an intervention at a certain point after 'diagnosis' could result in the patient receiving treatment in the early, mid or even late pathophysiological stage of ali/ards. some more recent studies are now targeting time after intubation rather than time after diagnosis to achieve more uniform timing of intervention. however, since the acute and exudative phases occur along a continuum and are not generally distinguished clinically, therapies targeting these phases will be considered concomitantly. therapies currently under investigation for early and/or exudative ards include those targeting the disrupted surfactant system, oxidative stress and antioxidant activity, neutrophil recruitment and activation, expression and release of inflammatory mediators, activation of the coagulation cascade, and microvascular injury and leak. treatment of the overall inflammatory response with agents such as corticosteroids has also been studied and is discussed. finally, the only drugs specifically targeting resolution of the alveolar oedema of the acute phase are b -adrenergic receptor agonists (b -agonists). clearance of alveolar oedema depends on the balance between oedema formation and reabsorption. the rate of fluid reabsorption depends on the active transport of sodium and electrolytes; water follows in the direction of the transported electrolytes. the active transport of salt and water occurs via epithelial sodium channels induced via na + /k + adenosine triphosphatase (atpase). [ ] b -agonists are thought to increase alveolar fluid clearance via two possible mechanisms: (i) increasing the levels of intracellular cyclic adenosine monophosphate, which in turn upregulates na + /k + atpase, causing increased sodium transport across alveolar type ii cells; and (ii) reducing alveolar-capillary permeability, thereby decreasing oedema formation. preliminary animal and ex vivo studies demonstrated the potential of b -agonists to accelerate the rate of alveolar fluid clearance. [ , ] a small, single-centre rct randomized patients with ali/ards to receive intravenous salbutamol (albuterol) mg/kg/h or placebo for days. [ ] the primary endpoint of balti- was extravascular lung water measured by the singleindicator transpulmonary thermodilution system (picco Ò ; pulsion medical systems) at day . patients in the salbutamol group had lower extravascular lung water and plateau pressures, although oxygenation did not differ between the treatment and placebo groups. this latter finding was perhaps due to the vasodilatory effects of b -agonists contributing to shunting of oxygen in the capillary bed. there was no difference in -day mortality or ventilator-free days, although the study was not sufficiently powered to detect a difference in these endpoints. [ ] funded by the medical research council, the same investigators in the uk are now conducting balti- , using the same intravenous salbutamol protocol as in balti- , but powered to detect clinically important outcomes. [ ] it will be interesting to determine if the physiological benefits observed in balti- confer a reduction in -day allcause mortality in balti- . aerosolized b -agonists have fewer systemic adverse effects than intravenous preparations. the national heart, lung and blood institute (nhlbi), in conjunction with ardsnet, conducted a study of an aerosolized b -agonist, the alta study. [ ] the study was stopped for futility at the first interim analysis after enrolling patients. [ ] there was no difference in the primary outcome of ventilator-free days to day . this study may have been negative for the following reasons: (i) delivery of nebulized drug to lung injury sites may have been suboptimal, as was the case with aerosolized surfactant; and/or (ii) less severely ill patients with ali (rather than ards with more severe hypoxaemia) may retain adequate alveolar fluid clearance without the need for upregulation with b -agonists. sixty-day mortality in the alta study was . % compared with a -day mortality of % in the severely ill group of patients who received physiological benefit from intravenous salbutamol in balti- . [ ] exogenous surfactant administration has been very successful in treating and preventing neonatal respiratory distress syndrome (nrds). given the physiological and pathological similarities between nrds and ards, exogenous surfactant therapy has been under investigation for treatment of ali/ards for over a decade. although clinical trial results have been largely disappointing, recent studies show promise. the strong scientific rationale for targeting the disrupted surfactant system, as well as lessons learnt from previous trials, therefore merit further attention. endogenous surfactant is composed of % lipids (mainly phosphatidylcholine and phosphatidylglycerol) and % proteins. the role of endogenous surfactant in the healthy lung is to decrease surface tension and thereby prevent alveolar collapse. in addition, surfactant plays a role in suppressing inflammation and scavenging free oxygen radicals. four apoproteins have been identified, termed surfactant protein (sp)-a, -b, -c and -d. whereas the presence of either or both of the hydrophobic surfactant proteins sp-b and -c are important for the biophysical function of surfactant, the hydrophilic proteins sp-a and -d perform the various host defence roles, including modulation of leukocytes, enhancement of the function of phagocytic cells [ ] and regulation of the host's immune system. [ , ] in ali, disruption of the endogenous surfactant system occurs by a number of mechanisms: injury to alveolar type ii cells results in abnormal synthesis and secretion of surfactant, serum proteins that leak into the airspace interfere with surfactant function, serine endopeptidase and phospholipase a cause degradation of surfactant, and, finally, mechanical ventilation, particularly with high tidal volumes, causes conversion of functional surfactant aggregate forms into dysfunctional forms. without optimal surfactant function, there is high surface tension at the alveolar surface in a non-uniform pattern within the lung leading to alveolar instability and collapse. the presence of bacteria within the airspace may also release and activate endotoxins, a process that is augmented in the presence of an abnormal surfactant system. based on the functional importance of the endogenous surfactant system in the normal lung and, more importantly, the consequences of an altered surfactant system in ali/ards, there is good rationale to consider exogenous surfactant administration as a therapeutic intervention in these patients. [ ] in , a phase iii, double-blind rct tested an aerosolized, synthetic surfactant called exosurf Ò (glaxo wellcome) in patients with sepsis-induced ards. [ ] this study showed no significant difference in overall survival, duration of mechanical ventilation or oxygenation between the treatment groups and standard care. it was postulated that this lack of efficacy was due to a low level of alveolar deposition of the aerosolized preparation and/or due to the absence of surfactant proteins in the preparation. [ ] currently, this surfactant preparation is not being evaluated for patients with ali/ards and is no longer marketed in the us. shortly afterwards, a smaller, open-label phase ii clinical trial evaluated tracheal instillation of a liquid bolus of the natural bovine extract surfactant, survanta Ò (ross laboratories), in patients with severe ards. [ ] there was a trend toward decreased mortality in the group of patients receiving up to four doses of phospholipids mg/kg surfactant compared with the patients in the control group ( . % vs . %; p = . ), and no safety concerns were identified. however, survanta Ò contains only very small amounts of sp-b. coupled with concerns regarding resource limitations, no further clinical trials of this exogenous surfactant preparation for adults with ards have been performed. recognizing the importance of surfactantspecific proteins brought progress to clinical surfactant research. in , results were published for two phase iii clinical trials evaluating effect of a liquid, recombinant sp-c (rsp-c) surfactant, venticute Ò (nycomed), instilled intratracheally in patients with established ards. [ ] the two studies enrolled a total of patients within hours of diagnosis of ards and were powered to show a difference in ventilator-free days. although oxygenation was significantly better during the -hour treatment period in the surfactant group, there were no significant differences noted in the number of ventilator-free days or in -day survival. [ ] a post hoc analysis demonstrated that patients with 'direct' causes of ards (i.e. pneumonia, witnessed aspiration of gastric contents or both) had a mortality benefit with surfactant treatment compared with standard care. a followup meta-analysis pooling results of five multicentre studies of rsp-c confirmed this finding: the subgroup of patients with severe ards due to pneumonia or aspiration had decreased mortality when treated with rsp-c ( . % vs . % in the usual care group; p = . ). [ ] subsequently, a prospective phase iii rct evaluating effect of venticute Ò in patients with pneumonia or aspiration of gastric contents was conducted. the study was terminated at patients due to futility. neither these results nor the potential reasons for futility have been published to date. [ ] calfactant (infasurf Ò , ony inc.) is a modified natural surfactant produced by extracting the phospholipids, neutral lipids and surfactantspecific proteins sp-b and sp-c from newborn calf lungs. in in vivo animal lung studies, calfactant has shown greater surface activity than exosurf Ò and survanta Ò , [ ] [ ] [ ] [ ] and the highest level of resistance to inactivation due to its high ratio of protein sp-b to phospholipids. [ ] [ ] [ ] from to , calfactant was used in a multicentre study of ali/ards in the paediatric population week (full-term infants) to years of age. overall, calfactant significantly improved oxygenation and reduced mortality ( % vs %; p = . ), although the greatest impact was observed in the subgroup of patients with direct ali/ards while calfactant had little effect in patients with indirect ali or ards. [ ] indeed, calfactant is the first and only pharmacological agent to demonstrate a mortality benefit for treatment of ali/ards. it is of note, however, that this study differs from other adult studies in that the majority of paediatric patients had direct causes of ards and the most common cause of death was respiratory failure, whereas adult studies have included a larger proportion of patients with indirect causes, such as sepsis, wherein the most common cause of death is multi-organ failure. based on those encouraging results, pneuma pharmaceuticals began conducting a large phase iii multicentre rct of calfactant for direct ards (origin of ards must be infectious pneumonia, aspiration, near drowning, smoke inhalation without pulmonary burn or inhaled industrial gas) in adults and children. a total of patients in two consecutive studies of patients under and over years of age was planned. however, after the first interim analysis in january , the paediatric arm of the study was stopped for futility due to an unexpectedly low mortality rate. recruitment in the adult arm (ages - years) is continuing as the interim analysis did not reveal futility or any safety concerns (wilson d, university of virginia health sciences center, charlottesville, va, usa, personal communication). [ ] since reactive oxygen species also contribute to the tissue damage incurred in ali, antioxidant therapies have also been investigated as therapeutic options for established disease. n-acetylcysteine (nac) is a commercially available antioxidant approved for the treatment of paracetamol (acetaminophen) toxicity. nac is a precursor for glutathione, an antioxidant present in normal lungs and deficient in bronchoalveolar lavage fluid from ali/ards patients. additionally, because of its thiol group, nac can scavenge reactive oxygen species such as hydrogen peroxide and superoxide anion. in an rct of patients, nac and oxothiazolidine carboxylate (procysteine Ò , clintec technologies inc.), another glutathione precursor, were studied for their combined effect in ali/ards but failed to reduce mortality compared with placebo, [ ] negating promising results of three prior small studies. [ ] [ ] [ ] interestingly, recent evidence suggests that genetic diversity may explain variable responsiveness to nac. glutathione-s-transferases (gsts) are enzymes from a complex, multigene family with important roles in oxidative stress pathways. a study by moradi and co-workers [ ] demonstrated that deletion of specific gst gene polymorphisms correlated with mortality and that treatment with nac significantly lowered mortality in these subgroups of patients. these results suggest that patients with gst gene deletions are more vulnerable to oxidative stress contributing to ards and may be in greater need of antioxidant therapy. [ ] antioxidant supplementation to enteral nutrition rich in omega- fatty acids has also been investigated for patients with ali/ards. while the rationale for nutritional antioxidants such as vitamins e and c is to reduce the oxidative stress present in ali, the purpose of the omega- fatty acids is to reduce production of proinflammatory mediators. eicosanoids, such as prostaglandins, thromboxanes and leukotrienes, derived from omega- fatty acids are generally much less proinflammatory than those derived from omega- fatty acids. since omega- fatty acids compete with omega- fatty acids for the same rate-limiting enzymes in the production of eicosanoids, diets with a high proportion of omega- fats are thought to be proinflammatory and prothrombotic. examples of polyunsaturated omega- fatty acids are a-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. [ ] a phase ii study enrolling patients with ali compared an antioxidant enteral feeding formula containing eicosapentaenoic acid, g-linolenic acid and antioxidant vitamins with placebo, and observed improved oxygenation, reduced pulmonary inflammation, fewer days of mechanical ventilation and fewer non-pulmonary organ failures in the treatment arm, although there was no difference in mortality between this approach and the control group. [ ] ardsnet proceeded to conduct the omega study, a phase iii study examining efficacy of omega- and antioxidant supplementation to enteral nutrition. the study was stopped for futility, but results have not yet been published. [ , ] several therapies aimed at modulating neutrophil activity have been studied. to understand why previous clinical trials have been negative and highlight potential targets for novel therapies, it is important to understand the role of neutrophils in propagating lung injury and mods. polymorphonuclear neutrophils (pmns) form the first line of defence against invading pathogens, and neutropenia or defective neutrophil function predisposes the host to increased morbidity. extensive clinical and experimental data support the role of the activated neutrophil in the pathogenesis of organ injury in sepsis. the lung is particularly vulnerable. postmortem studies of patients with ards show massive pulmonary accumulation of neutrophils, with the highest counts in non-survivors. [ ] the pathological impact of neutrophils may be due to their activation, transmigration or delayed apoptosis. however, neutrophil-independent mechanisms of ali must also exist, since ards has been described in neutropenic patients. neutrophil kinetics in the pulmonary circulation differ substantially from that of microvascular beds in the systemic circulation. the pulmonary circulation harbours a large intravascular reservoir of leukocytes, mainly neutrophils, referred to as the 'marginated pool'. [ ] this marginated pool may equal or even exceed the pool of circulating neutrophils and exchanges with the latter as an ongoing phenomenon. thus, it is important to appreciate that circulating neutrophils, when isolated for experimental analysis, may not represent the characteristics of the entire population of neutrophils in the bloodstream. intravital microscopic studies have revealed that, in contrast to the systemic circulation where neutrophil sequestration is almost exclusively confined to the venular compartment, the major site of neutrophil retention in the lung is the alveolar capillary bed. [ ] neutrophil activation can also lead to cytoskeletal changes that reduce cell deformability and slow their transit time through the alveolar capillaries. since one of the earliest manifestations of ards is accumulation of large numbers of neutrophils in the alveolar capillaries, it is possible that the accumulation of neutrophils may initiate selective capillary blockade and arteriovenous shunting leading to hypoxia seen in ards. activated neutrophils also produce human ne (hne), a protease capable of producing tissue damage by means of its degradation of elastin, fibronectin, laminin, collagen and proteoglycans. normally, protease inhibitors impede ne, but in the setting of an overwhelming inflammatory response, neutrophils generate reactive oxidants that inactivate endogenous protease inhibitors, leaving the activity of hne unchecked. this may lead to increased pulmonary inflammation and endothelial cell permeability. [ ] sivelestat (elaspol Ò , ono pharmaceuticals) is a competitive inhibitor of ne. it was launched in japan after a phase iii study demonstrated reduced icu stay and improved pulmonary function in patients with ali associated with the systemic inflammatory response syndrome (sirs). [ ] however, the strive study [ ] was terminated early after randomizing patients from sites in six countries, when the data and safety monitoring board found a trend to increased mortality at days. final analysis revealed no difference in -day all-cause mortality ( % in both groups) or number of ventilator-free days between the treatment group and controls. epi-hne- or depelestat (debiopharm s.a.) is another hne inhibitor currently under development for treatment of inflammatory pulmonary diseases, including ali. in a repeated lung injury rat model depelestat administration afforded a significant protective effect on lung compliance and alveolar inflammation at day compared with the control group. [ ] a phase ii study examining safety and efficacy of intravenous depelestat for patients with ards has been completed, but results have not yet been published. [ ] neutrophil transmigration neutrophil margination allows for a molecular interaction between the cell surfaces of the neutrophil and endothelial cell to occur. subsequently, as a consequence of cell surface integrins and their ligands, neutrophils undergo adhesion with endothelial cells. following adherence, neutrophils must pass through the endothelial monolayer, interstitial tissue and alveolar epithelium to reach the alveolar space. passage of large numbers of activated neutrophils can cause epithelial damage, sloughing and increased permeability both due to mechanical force exerted by neutrophil pseudopodia as well as due to release of toxic substances such as proteinases (e.g. elastases, cationic peptides, defensins, oxidants and mmps). [ ] while there are conflicting reports on the effects of elastase on increased epithelial permeability, cationic peptides such as defensins can cause both epithelial and endothelial cell injury. defensin levels have been found to be greatly elevated in patients with ards and their levels correlate with the severity of lung injury. [ ] neutralizing its effects could be important in the management of ards. ongoing research is examining if defensins can be used to identify patients with ali at an early stage. [ ] delayed apoptosis of neutrophils once egressed into the extravascular space, neutrophils cannot return to the circulation and their elimination is dependant upon their clearance by apoptosis and subsequent recognition and elimination by macrophages and other phagocytic cells. normally, neutrophils are terminally differentiated cells with a terminal half-life of - hours in vivo. upon completion of their lifespan, neutrophils institute a programme of cell death known as 'apoptosis' and are then removed from the circulation by the liver and spleen. apoptosis, as opposed to necrosis, is believed to be crucial for resolution of inflammation as it does not result in loss of cell membrane integrity and bystander tissue damage by release of intracellular enzymes, proteases and reactive oxygen species. [ ] expression of neutrophil apoptosis is delayed in ards. [ ] this is not an unexpected finding, especially since pmn apoptosis is delayed in other critically ill patients with sepsis, trauma and burns. [ , ] apoptosis of neutrophils may be an important consequence in determining the extent of lung injury. for example, it has been shown that the induction of neutrophil apoptosis by the administration of dead escherichia coli prior to reperfusion resulted in significant improvement in lung injury. [ ] induction of neutrophil apoptosis in the alveolar space has the potential for resolution of inflammation in ards, and can be carried out in a number of ways that could include multiple strategies such as ligation of fas, activation of proapoptotic caspases and modulation of mitogen-activated protein kinases or transcription factors such as nf-kb. hastening neutrophil apoptosis in the alveolar space may also decrease the probability of secondary necrosis and further tissue damage in ards. it is intriguing that no significant differences were found between the expression of neutrophil apoptosis in patients at risk and those with established ards, nor did the extent of apoptotic inhibition correlate with overall outcome in ards. [ ] therefore, while it is well established that ards is associated with accumulation of large numbers of neutrophils in alveolar spaces, their contribution to the severity of ards in humans remains uncertain. in summary, targeting neutrophil responses in ards may have therapeutic potential. however, as has been learnt from various ali and sepsis trials in the past, simple strategies to control dysregulated neutrophil behaviour may not be effective. rather, key stages of neutrophil function and kinetics may need to be identified in different clinical phases of ards, and selective immunomodulation strategies may need to be identified for individual patients. in addition to modulation of neutrophil function, there are other facets of the immune and inflammatory response currently under investigation as potential therapeutic targets for treatment of ards. these include modulation of macrophage activity with granulocyte macrophage colony-stimulating factor (gm-csf), inhibition of inflammatory mediators and broad suppression of the inflammatory response with corticosteroids. although most prostaglandins are proinflammatory mediators, prostaglandin e (pge ) has potential beneficial effects in ali, specifically due to its ability to modulate neutrophil activation. however, exogenous pge is associated with several adverse effects and patient intolerance due to haemodynamic instability has been observed. tlc-c- (ventusÔ; the liposome company) is a liposomal dispersion of pge . the development of pge in liposomal form may potentiate its role in neutrophil downregulation, improve peripheral delivery of the drug to the lung and decrease systemic adverse effects, thus providing a good rationale for testing in humans. [ ] a phase iii trial of patients with ards randomized to intravenous tlc-c- at escalating doses for days versus placebo found no difference in duration of mechanical ventilation or -day mortality between the treatment and control groups, although treatment was associated with accelerated improvement in oxygenation. [ ] however, more than % of patients required a dose reduction due to hypotension or hypoxaemia. interestingly, those patients who tolerated and received at least % of the full dose had a shorter duration of mechanical ventilation. a subsequent multicentre phase iii trial of tlc-c- in ards patients [ ] demonstrated no differences in time to liberation from the ventilator or -day mortality; the trend to shorter duration of hypoxaemia in the treatment group failed to reach statistical significance. gm-csf has been shown to stimulate phagocytosis and oxidative functions of host defence neutrophils, monocytes and macrophages. [ ] in addition to its systemic actions, gm-csf may also influence pulmonary host defence by modulating alveolar macrophage function and surfactant metabolism. as noted, apoptosis of neutrophils is an important mechanism by which these cells are cleared from inflamed lung regions, thereby facilitating resolution of inflammation. although both granulocyte colony-stimulating factor and gm-csf are thought to inhibit neutrophil apoptosis, in animal models of lung injury, gm-csf has been shown to help restore capillary barrier integrity, [ ] preserve alveolar epithelial function and improve alveolar fluid clearance. [ ] a pilot study of patients with ards undergoing serial bronchoalveolar lavage found that patients who survived ards had higher concentrations of gm-csf in the bronchoalveolar lavage fluid on day than patients who died. [ ] the authors speculated that gm-csf might improve survival by prolonging the neutrophil lifespan in the alveoli and/or inducing proliferation of alveolar macrophages, thereby improving host defence and reducing infectious complications in this setting. in a phase ii trial, molgramostim (schering-plough), a recombinant human gm-csf, was given intravenously at a low dose ( mg/kg) for days to ten patients with severe sepsis and sepsis-related pulmonary dysfunction (defined as a pao /fio ratio of < with a pulmonary infiltrate on chest radiograph). [ ] the primary outcome was -day survival, and secondary outcomes included oxygenation, occurrence of ards and degree of organ dysfunction at day . there was no difference in -day survival between the treatment and placebo groups, but oxygenation improved in the gm-csf group. ards was present in four of ten patients in the gm-csf group on study entry, but resolved in two of these patients by day , whereas in the placebo group ards was present in three patients on study entry and five patients on day . organ dysfunction was similar between the two groups, with no change between study entry and day . from july to july , the nhlbi enrolled patients who had been diagnosed with ali/ards for at least days into a phase ii rct of recombinant gm-csf (sargramostim [leukine Ò ], genzyme corporation) versus placebo. [ ] the primary outcome was the number of ventilator-free days during days - . secondary outcomes included measures of lung epithelial cell integrity, alveolar macrophage function, changes in severity of respiratory gas exchange, non-respiratory organ failure and incidence of ventilator-associated pneumonia. this study has been completed, but results have not yet been published. [ ] cytokine inhibitors cytokines are glycoproteins that act as messengers to cell surface receptors to promote or diminish the inflammatory cascade. specific cytokines are observed in high amounts in the bronchoalveolar lavage fluid of patients with ards, and are thought to play an important role in propagating lung injury. unsaturated phosphatidic acid plays an important role in intracellular signalling leading to neutrophil accumulation within the lungs, as well as proinflammatory cytokine expression and cell membrane oxidation, all of which leads to lung tissue damage. [ ] lisofylline (cell therapeutics) is a cytokine inhibitor that impedes synthesis of phosphatidic acid- a and, therefore, was thought to hold potential for treatment of ards. however, ardsnet stopped a phase ii/iii trial, the larma study, for futility after the first interim analysis failed to demonstrate any difference in -day mortality, ventilator-free days, organ failures or levels of circulating free fatty acids. [ ] interleukin (il)- is another potent chemoattractant for neutrophils, observed in high levels in patients with early ards [ ] and associated with increased mortality. [ ] anti-il- monoclonal antibody has been shown to reduce pulmonary oedema and neutrophil accumulation in animal models of ards [ , ] but has not yet been tested in humans. finally, tnfa has long been recognized as an important proinflammatory cytokine in ards, but more recent evidence suggests that it actually plays a dichotomous role in both contributing to permeability oedema but also increasing alveolar fluid clearance capacity. monoclonal anti-tnfa antibodies have been tested in patients with sepsis with disappointing results. [ ] given its dual role in alveolar oedema formation and resorbtion, a more sophisticated approach than simply blocking all tnfa activity is likely to be required in ards. studies examining the efficacy of corticosteroids for acute exudative ards have shown conflicting results. in , bernard et al. [ ] published results of a study of patients with ards randomized to high-dose pulse methylprednisolone ( mg/kg every hours for hours) or placebo. there was no difference in -day mortality ( % vs %; p = nonsignificant) but the confidence intervals were wide, suggesting that the study may have been underpowered to detect a small difference in a population with heterogenous outcomes. in , meduri and colleagues [ ] published their results of patients with severe early ards (< hours) from five hospitals randomized to methylprednisolone mg/kg/day for days versus placebo. they found corticosteroids significantly reduced icu mortality ( % vs %; p = . ), duration of mechanical ventilation and length of icu stay. [ ] annane et al. [ ] published a post hoc analysis of ards patients enrolled in an rct of low-dose corticosteroids in septic shock. patients in the treatment group received hydrocortisone mg every hours plus fludrocortisone mg/day for days. although there was no mortality difference for ards patients overall, ards patients with relative adrenal insufficiency and septic shock had significantly reduced mortality when treated with low-dose hydrocortisone ( % vs % in the placebo group; p = . ). [ ] the use of corticosteroids for acute exudative ards remains controversial, although the evidence is more definitive for corticosteroid treatment initiated late for fibroproliferative ards (see section . . ). a study examining low doses of corticosteroids as adjuvant therapy for lung injury associated with h n influenza virus (cortiflu) is planned. [ ] . . activated protein c microvascular injury and coagulation play critical roles in the pathogenesis of ali. plasma protein c levels are decreased in patients with ali, and are associated with higher mortality and fewer ventilator-free days. [ ] recombinant human activated protein c (rhapc; drotrecogin alfa; eli lilly) was tested in a phase iii clinical trial of patients and demonstrated a significant mortality reduction from % to % in patients with severe sepsis. [ ] a phase ii study was sponsored by the nhlbi to determine if drotrecogin alfa increased ventilator-free days in patients with ali (patients with severe sepsis were excluded). the study was terminated by the data safety monitoring board. although drotrecogin alfa significantly increased plasma protein c levels and decreased pulmonary dead space fraction, there was no significant difference in the number of ventilator-free days or in -day mortality ( of vs of patients, respectively; p = . ). [ ] . . hmg-coa reductase inhibitors (statins) hmg-coa reductase inhibitors, commonly known as statins, have recently been proposed as a treatment for ali/ards. the rationale for this is based on animal models suggesting that statins can attenuate organ dysfunction by reducing vascular leak and inflammation. [ ] a prospective cohort study in ireland showed a nonsignificant trend towards lower odds of death in ards patients receiving a statin during their icu admission (or . , % ci . , . ; p = . ). [ ] however, a recently published retrospective cohort study from the mayo clinic (rochester, mn, usa) showed no difference in mortality or organ dysfunction in ards patients treated with statins. [ ] stip is currently enrolling patients admitted to an icu with respiratory distress and a pao /fio ratio < due to the h n pandemic strain of influenza. [ ] patients in this trial will be randomized to receive rosuvastatin mg/day or placebo for days. since this is a specific subpopulation of patients with ali, findings from this study may not be generalizable to other ali subgroups. the sails trial (also rosuvastatin mg/day vs placebo) is also planned but not yet open for recruitment. [ ] patients who survive the early and exudative phases of ards generally enter a period from week to consisting of fibroproliferation and organization of exudative debris within the airspace. this fibroproliferative relatively 'late' phase either slowly resolves or progresses to fibrosis. during this phase, patients are at risk of dying from other complications such as mods, or may fail to wean from mechanical ventilation due to severely impaired respiratory muscle and lung function. those who successfully wean off mechanical ventilation may have residual pulmonary fibrosis and reduced exercise capacity. for resolution to occur, removal of inflammatory cells, cellular debris, and soluble and insoluble proteins needs to take place. as noted in section . . , apoptosis of neutrophils facilitates resolution of inflammation. monocyte and macrophage phagocytic clearance of apoptotic cells appears to be an important mechanism by which neutrophils are cleared from inflamed lung regions. soluble proteins are likely to be primarily removed via paracellular diffusion, but removal of insoluble proteins appears to depend on the function of alveolar macrophages. mechanisms involved in remodelling of hyaline membranes and restoration of a functional alveolar-capillary barrier are incompletely understood at present, but therapeutic interventions aimed at modulation of phagocytosis/apoptosis are being evaluated. to date, far less research has targeted this later phase of the disease, as most trials have focused on earlier preventative processes. fibroproliferative ards is characterized by ongoing inflammation. in addition to being tested for prevention of ards, and treatment of the early and mid exudative phases, corticosteroids have also been tested for efficacy in reversing the fibrosing alveolitis of the late phase of ards. a study by meduri and colleagues [ ] examined the effect of prolonged methylprednisolone therapy ( mg/kg/day for days) on patients with severe ards that was unresolved after days of respiratory failure. although this study demonstrated a significant hospital mortality benefit ( of patients [ %] in the corticosteroid group died vs of [ %] in the placebo group), the significance of these findings was controversial for two reasons: the calculated sample size to demonstrate a % absolute difference in mortality was patients but the study was terminated early after enrolment of patients, and the mortality in the placebo group was slightly higher than anticipated. [ ] to shed further light on this issue, ardsnet specifically designed a study to focus on the late fibrotic stage of the disease, called lasrs. [ ] this study examined the role of corticosteroids in patients in the late phase (> days from onset) of persistent ards. methylprednisolone, dosed at mg/kg/day for days followed by tapering doses until day , was compared with placebo. there was no difference in -or -day mortality rates. methylprednisolone improved oxygenation, respiratory system compliance and blood pressure, resulting in an increased number of ventilator-free and shock-free days; however, a higher rate of neuromuscular weakness and, if initiated more than days after the onset of ards, a significant increased mortality was observed in the methylprednisolone group. therefore, despite the improvement in cardiopulmonary physiology, methylprednisolone does not improve overall mortality in ards and is not recommended for treatment of late ards. given these results, the convincing lack of efficacy for prevention of ali prior to diagnosis and the lack of evidence of benefit in the early phase, corticosteroids cannot be recommended for routine treatment of ali/ards at any stage, at this time. furthermore, it may prove to be exceedingly difficult to determine which individual patient might benefit from corticosteroids and at what specific point to intervene. clearly, the current status of treatment options for patients with ali/ards is suboptimal. at this time, the clinical management of patients with ali/ards involves supportive therapy only. this primarily includes low stretch or 'lung protective' mechanical ventilation, conservative fluid management and adequate nutritional support. although the term 'supportive' may sound somewhat discouraging, these are important observations, not only because they impact on the outcome of patients with ali/ards but also because they should be embraced and implemented as 'standard care' for this patient population. furthermore, any new therapy being tested should be compared with optimal 'standard care'. other methods proposed to offer greater protection to the lungs while providing mechanical support to respiration include hfo and ecmo. studies into these modes are ongoing. although supportive therapies have reduced mortality, there is still significant need for improvements. previous studies have provided important insight into the pathophysiology of ali/ards. research is ongoing into therapies to prevent ali/ards in those at risk, treat it early in its course or aid in its resolution. each of these goals is associated with specific challenges. demonstrating that a prophylactic intervention reduces mortality, morbidity and is cost effective is challenging at best. this is most likely to occur when the risk of acquiring the disease is high, the outcome of the disease is uniformly devastating and treatment for the disease is nonexistent. for some critically ill patients at risk for ards, this may be the case. however, the diagnosis of ali/ards encompasses a very heterogeneous population, with incompletely understood risk factors and non-uniform, diverse outcomes. the greatest likelihood of success for prophylactic therapy will come when we have further delineated the subgroups at highest risk of dying from ali/ards and have accurate diagnostic tests to identify these patients. for ali/ards, specifically targeting the pathogenic mechanisms responsible for the increased risk of death in these patient subgroups would theoretically be high yield. basic science research identifying genetic polymorphisms of patients with highest mortality or greatest need for specific therapies shows great promise in this regard, but is not yet clinically applicable. until then, validating biomarkers and clinical indicators for poor prognosis in ali/ards should remain a primary research goal. finding therapies to treat ards in its late fibroproliferative phase is also in great need. too often patients survive the early and mid phase of ards only to succumb to complications in the late phase or undergo withdrawal of life support as they are unable to be weaned from mechanical ventilation. research into mechanisms of idiopathic pulmonary fibrosis may help identify common pathways to target for therapy. to date, the majority of research has focused on treating ali/ards in its earlier stages, in the hope that the disease process may be reversed prior to the patient entering the fibroproliferative phase. progress in finding therapies to treat established ards has been slow and hampered by a long series of negative clinical trials. however, there are several lessons to be learned from these rcts. first, a 'one-size-fits-all' approach has not worked for pharmacotherapy for ards. in this sense, the syndrome of ali/ards may be likened to cancer. cancer as a broad term signifies the uncontrolled replication of abnormal cells, but there are specific chemotherapeutic treatments for specific types of cancer, depending on its origin. some treatments may be effective for more than one type of cancer, but not for other types, and the magnitude of the benefit might vary according to the type and stage of disease. oncologists would not design a trial enrolling all patients with differing types of cancer and expect to find a single drug that shows a survival benefit. yet, that is what has been attempted with several large ards trials. recent studies have demonstrated that direct ards is likely to respond differently than indirect ards, and in fact within these broad categories, pathogenesis may differ. therefore, different therapies may need to be developed for specific aetiologies such as sepsis-related ards, sirs-related ards and various direct causes of ards. second, a well designed negative rct does not necessarily mean that the therapy tested should be abandoned. it means that the therapy is likely to not be appropriate for widespread application. however, just because a drug does not work for every ards patient does not necessarily mean it should not be used for anyone with ards. for example, there is no evidence for treating all patients with acute ards with corticosteroids, but there is evidence that treating ards patients with relative adrenal insufficiency and septic shock with low doses of hydrocortisone is likely to be beneficial. similarly, nitric oxide should not routinely be applied to all patients with ali/ards, but may be useful in refractory hypoxaemia, particularly in conjunction with other ventilation rescue strategies. third, a negative rct should potentially lead to further research so that we can gain further insight as to why the therapy failed to yield a clinical benefit. thomas edison, when asked why he pursued his quest to invent a functional and practical light bulb after innumerable failed attempts, is reported to have replied, ''i have not failed. i've just found ways that won't work''. ards research should take us from bench to bedside and back to the bench again. basic science can help us understand basic mechanisms of disease, discover why a therapy failed, then provide new ideas to apply to the clinical realm. rcts are necessary to prove benefit and quantify risk prior to changing clinical practice. since we are in urgent need of therapies to treat ali/ ards, it is necessary that rcts continue to advance our clinical care. however, these rcts need to be well founded in basic biology and physiology research, and focused on specific hypotheses regarding mechanisms of disease. continuing to conduct large clinical trials on heterogeneous patients with ali/ards from multiple aetiologies will not only prove ineffective but also add enormous cost to the healthcare system. the most significant and promising finding from an rct to date is that calfactant, the natural bovine surfactant rich in sp-b and -c, reduces mortality in ali from % in the control arm to % in the paediatric population. indeed, calfactant is the first and only pharmacological agent to demonstrate a mortality benefit for treatment of ali/ards. the ongoing cards study will attempt to reproduce that finding in adults with direct causes of ards. [ ] this trial is continuing enrolment after the first interim analysis, with a target completion date of march . great gains have been made in providing supportive management to patients with ali/ards. ongoing and future research efforts will provide important insights into the complex pathophysiologies involved and may provide further rationale for patient-specific therapies and/or combination therapies targeting the various mechanisms contributing to this disorder. understanding who is at greatest risk of succumbing to ali/ards and establishing the optimal time to intervene will be essential to improving mortality for this syndrome. epidemiology and outcome of acute lung injury in european intensive care units: results from the alive study incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three australian states characteristics and outcomes in adult patients receiving mechanical ventilation: a -day international study a simple clinical predictive index for objective estimates of mortality in acute lung injury the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination transepithelial migration of neutrophils: mechanisms and implications for acute lung injury arachidonic acid remodeling in human inflammatory cells migrating to the lung in vivo recent advances in genetic predisposition to clinical acute lung injury chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock pharmacotherapy of acute lung injury and acute respiratory distress syndrome injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework an overview of mortality risk prediction in sepsis multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome a multicenter registry of patients with acute respiratory distress syndrome: physiology and outcome adult respiratory distress syndrome: risk with common predispositions causes of mortality in patients with the adult respiratory distress syndrome improved survival of patients with acute respiratory distress syndrome (ards): - about the ards network effect of recombinant surfactant protein c-based surfactant on the acute respiratory distress syndrome a search for subgroups of patients with ards who may benefit from surfactant replacement therapy the oscillation for ards treated early (oscillate) trial pilot study review of a large clinical series: association of cumulative fluid balance on outcome in acute lung injury. a retrospective review of the ardsnet tidal volume study cohort pulmonaryartery versus central venous catheter to guide treatment of acute lung injury the use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a metaanalysis of outcome data efficacy of an expanded ventilator bundle for the reduction of ventilatorassociated pneumonia in the medical intensive care unit continuous aspiration of subglottic secretions in the prevention of ventilatorassociated pneumonia in the postoperative period of major heart surgery oral decontamination for prevention of pneumonia in mechanically ventilated adults: systematic review and meta-analysis supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial thromboprophylaxis in medicalsurgical critically ill patients stress ulcer prophylaxis in critically ill patients: resolving discordant meta-analyses efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial effects of physical training on functional status in patients with prolonged mechanical ventilation recent trends in acute lung injury mortality: - effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis effect of prone positioning in patients with acute respiratory distress syndrome: a metaanalysis effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis hemodynamic and gas exchange response to inhaled nitric oxide and prone positioning in acute respiratory distress syndrome patients high-frequency oscillatory ventilation in adults: the toronto experience high-frequency oscillatory ventilation for adult patients with ards efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome ketoconazole prevents acute respiratory failure in critically ill surgical patients a double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome development, implementation, and evaluation of a ketoconazole practice guideline for ards prophylaxis angiotensin-converting enzyme inhibitor captopril prevents oleic acid-induced severe acute lung injury in rats rosiglitazone attenuates the severity of sodium taurocholate-induced acute pancreatitis and pancreatitis-associated lung injury chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model randomized, prospective trial of antioxidant supplementation in critically ill surgical patients corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ards) in adults: meta-analysis recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase iib, multicenter, randomized, placebo-controlled, clinical trial ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial the beta-agonist lung injury trial (balti): a randomized placebo-controlled clinical trial randomized, placebo-controlled trial of an aerosolized beta- adrenergic agonist (albuterol) for the treatment of acute lung injury aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome: exosurf acute respiratory distress syndrome sepsis study group bovine surfactant therapy for patients with acute respiratory distress syndrome venticute in patients with pneumonia or aspiration of gastric contents and intubation/ventilation/oxygenation impairment (by /m - ) [clinicaltrials.gov identifier nct effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial a trial of antioxidants n-acetylcysteine and procysteine in ards: the antioxidant in ards study group n-acetylcysteine enhances recovery from acute lung injury in man: a randomized, double-blind, placebo-controlled clinical study glutathione (gsh) repletion by n-acetylcysteine (nac) in patients with the adult respiratory distress syndrome (ards) antioxidant treatment with n-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebocontrolled study effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome: enteral nutrition in ards study group omega study: information update early versus delayed enteral feeding and omega- fatty acid/antioxidant supplementation for treating people with acute lung injuryj or acute respiratory distress syndrome (the eden-omega study neutrophil elastase inhibition in acute lung injury: results of the strive study a phase iii clinical study of neutrophil elastase inhibitor ono- na in sirs patients beneficial effect of an inhibitor of leukocyte elastase (epi-hne- ) in presence of repeated lung injuries liposomal prostaglandin e (tlc c- ) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. tlc c- ards study group a multi-centre, doubleblind, placebo-controlled study of liposomal prostaglandin e (tlc c- ) in patients with acute respiratory distress syndrome a randomized phase ii trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction a randomized trial of gm-csf in patients with ali/ards [clinicaltrials.gov identifier nct national institutes of health. randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome acid aspiration-induced lung injury in rabbits is mediated by interleukin- -dependent mechanisms humanized monoclonal antibody against the chemokine cxcl- (il- ) effectively prevents acute lung injury methylprednisolone infusion in early severe ards: results of a randomized controlled trial high-dose corticosteroids in patients with the adult respiratory distress syndrome effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome randomized clinical trial of activated protein c for the treatment of acute lung injury acute lung injury and the acute respiratory distress syndrome in ireland: a prospective audit of epidemiology and management statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial prostacyclin and thromboxane a formation is increased in human sepsis syndrome: effects of cyclooxygenase inhibition angiotensin-converting enzyme protects from severe acute lung injury angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome chronic use of angiotensin pathway inhibitors is associated with a decreased risk of acute respiratory distress syndrome use of ace inhibitors and development and outcome in ards the peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation ppar-gamma agonists inhibit production of monocyte inflammatory cytokines a novel therapy for colitis utilizing ppar-gamma ligands to inhibit the epithelial inflammatory response ppar y ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice thiazolidinediones in type diabetes: a cardiology perspective long-term risk of cardiovascular events with rosiglitazone: a meta-analysis trial of glutamine and antioxidant supplementation in critically ill patients (redoxs) [clinicaltrials.gov identifier nct comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings lung epithelial fluid transport and the resolution of pulmonary edema alveolar fluid clearance in the resected human lung upregulation of alveolar epithelial active na+ transport is dependent on beta -adrenergic receptor signaling balti- (beta agonist lung injury trial- ) drug study of albuterol to treat acute lung injury (alta) [clinicaltrials.gov identifier nct ]. us national institutes of health, clinicaltrials.gov a role for b agonists in ards: the question remains unanswered surfactant proteins a and d and pulmonary host defense the future of surfactant therapy during ali/ards the role of exogenous surfactant in the treatment of acute lung injury a mutation in the surfactant protein b gene responsible for fatal neonatal respiratory disease in multiple kindreds target disruption of the surfactant protein b gene disrupts surfactant hemeostasis, causing respiratory failure in newborn mice differential activity and lack of synergy of lung surfactant proteins sp b and sp c in interactions with phospholipids surfactant inhibition by plasma proteins: differential sensitivity of various surfactant preparations importance of hydrophobic apoproteins as constituents of clinical exogenous surfactants is outcome from ards related to the severity of respiratory failure? calfactant for direct acute respiratory distress syndrome (cards) the role of glutathione-s-transferase polymorphisms on clinical outcome of ali/ards patient treated with n-acetylcysteine enteral omega- and acute respiratory distress syndrome evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome the marginated pool physiological neutrophil sequestration in the lung: visual evidence for localization in capillaries safety and efficacy study of depelestat in acute respiratory distress syndrome (ards) patients [clinicaltrials.gov identifier nct high concentrations of alpha-defensins in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome biological markers to identify early sepsis and acute lung injury programmed cell death (apoptosis) and the resolution of systemic inflammation the role of apoptosis in acute lung injury delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase- activity inhibition of apoptosis in polymorphonuclear neutrophils from burn patients a novel therapeutic strategy for attenuating neutrophil-mediated lung injury in vivo neutrophil apoptosis in the acute respiratory distress syndrome granulocyte/ macrophage colony-stimulating factor treatment improves alveolar epithelial barrier function in alcoholic rat lung transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice role of interleukin in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis increased interleukin- concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis regulators of endothelial and epithelial barrier integrity and function in acute lung injury low doses corticosteroids as adjuvant therapy for the treatment of severe h n flu (cortiflu) safety and dose relationship of recombinant human activated protein c for coagulopathy in severe sepsis us national institutes of health, clinicaltrials.gov us national institutes of health, clinicaltrials.gov assistant professor, department of medicine, university hospital, windermere road the authors thank jeanette mikulic for her assistance with preparation of the manuscript. no sources of funding were used to assist in the preparation of this review. the authors have no conflicts of interest that are directly relevant to the content of this review. key: cord- - q jdyrh authors: van der stap, janneke; voortman, mareye title: acute respiratoire insufficiëntie date: - - journal: nursing (maarssen) doi: . /s - - -x sha: doc_id: cord_uid: q jdyrh bij covid- raken veel patiënten acuut respiratoir insufficiënt, maar ook bij andere ziektebeelden kan dat voorkomen. in dit artikel lees je wat er gebeurt bij acute respiratoire insufficiëntie en wat je kunt doen. de bijbehorende toets levert accreditatiepunten op. het acute respiratory distress syndrome (ards) is een pulmonale uiting van een systemische inflammatoire respons (hyperactieve ontstekingsreactie). het is een ernstige acute longaandoening, gekenmerkt door diffuse bilaterale infiltraten (beiderzijds ontstekingen in de long), hypoxemie, verminderde longcompliantie (rekbaarheid van de long) en respiratoire insufficiëntie. ards kan optreden in het verloop van uiteenlopende ziekteprocessen (zowel primair in de longen als daarbuiten). de meest voorkomende oorzaak van ards is sepsis. - % van de patiënten met sepsis ontwikkelt een ards. ards wordt ook bij ongeveer % van de covid- -patiënten waargenomen. beademing kan een patiënt met ards ondersteunen, maar het is vooral belangrijk dat de onderliggende oorzaak wordt behandeld. de mortaliteit van ards is de afgelopen jaren gedaald van % naar - %. dat is mogelijk het gevolg van de verbeterde zorg, longbeschermende beademingstechnieken, toenemend gebruik van protocollen en alertheid op infecties en goede voedingstoestand van de ic-patiënt. de mortaliteit is hoger bij patiënten met een hogere leeftijd en multiorgaanfalen. complicaties na ards zijn vooral het gevolg van de mechanische beademing (barotrauma) en het kritieke ziek zijn. daarnaast kan er blijvende schade (fibrose) in de long optreden. onderstaande verschijnselen kunnen wijzen op een (dreigende) acute respiratoire insufficiëntie, dus een levensbedreigende situatie. snel handelen is dan geboden. zoek je verdieping in je vak? doe dan mee aan de nursing challenge: online kennistoetsen van het niveau dat je van nursing gewend bent. acute respiratoire insuffi ciëntie met dank aan dirk van renterghem, longarts, beroepsvereniging belgische longartsen bronnen het acute boekje. respiratoire insufficiëntie leerboek intensive care verpleegkunde deel . houten: bohn stafleu van loghum acute geneeskunde, een probleemgerichte benadering. de editie. amsterdam: reed business nursing challenge: covid- aandachtspunten bij zuurstoftoediening heated humidifi ed high-flow nasal oxygen in adults. mechanisms of action and clinical implications risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china up to date. acute respiratory distress syndrome key: cord- -whvq y p authors: vidali, sofia; morosetti, daniele; cossu, elsa; luisi, maria luisa eliana; pancani, silvia; semeraro, vittorio; consales, guglielmo title: d-dimer as an indicator of prognosis in sars-cov- infection: a systematic review date: - - journal: erj open res doi: . / . - sha: doc_id: cord_uid: whvq y p background: severe acute respiratory syndrome coronavirus (sars-cov- ) stimulates pro-thrombotic changes. this, combined with its tropism for endothelium and lung structures, may explain its association with thrombotic events, reduction of pulmonary gas exchange, acute respiratory distress syndrome (ards) and a composite end-point (intensive care unit, invasive ventilation, death). this study aims to highlight the correlation between elevated d-dimer (an indirect thrombosis marker) and the increased rate of poor prognosis-associated conditions, and to introduce d-dimer-labelled anticoagulant administration as a potentially useful tool to prevent complications and positively influence coronavirus disease (covid- ) course. methods: an online database search (pubmed, google scholar, scopus, web of science and cochrane) was performed between march and april . the most relevant keywords were “d-dimer”, “sars-cov- ”, “covid- ”, “thrombosis” and “ards”. selection was independently conducted by three reviewers. references and previews of accepted articles were evaluated. data inclusion/extraction inaccuracy was limited by the work of three reviewers. selection bias reduction was addressed by thoughtfully designing the search protocol. quality assessment was performed with the newcastle–ottawa scale. the systematic review protocol was not registered because we anticipated the very limited available evidence on the topic and due to the urgency of the study. results: studies were evaluated. good-quality criteria were reached in out of studies. d-dimer was increased and significantly higher in covid- patients compared with healthy controls, in covid- patients with severe disease or a composite end-point compared with non-severe disease, in ards compared with non-ards patients and in deceased ards patients compared with ards patients who survived (all p< . ). covid- patients treated with anticoagulants demonstrated lower mortality compared with those not treated (p= . ). conclusions: correlations exist between covid- infection, severe elevation of d-dimer levels, and increase in the rate of complications and composite end-point. the appropriateness of early and continuous d-dimer monitoring and labelled anticoagulation as management tools for covid- disease deserves accurate investigation, to prevent complications and reduce interventions. in december , rapidly expanding pneumonia clusters of unknown aetiology were detected in the chinese city of wuhan, capital of hubei province. on january , a novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), was declared responsible for the outbreak of the disease, then named coronavirus disease (covid- ) [ ] [ ] [ ] . the number of covid- diagnoses grew rapidly, with fast global spreading of disease: on march , the world health organization declared a pandemic state [ , ] . by april , confirmed cases and deaths were registered [ ] . sars-cov- represents the third coronavirus-mediated threat to global health of the past decades, after sars-cov and middle east respiratory syndrome coronavirus [ ] [ ] [ ] [ ] . sars-cov- is transmitted through respiratory droplets and enters target cells through the angiotensin-converting enzyme (ace ) receptor [ , ] . after an incubation of - days, a symptomatic phase may manifest, with fever, short breath, coughing and possible progression to pneumonia, severe respiratory dysfunction and global deterioration. disease assessment and monitoring is performed, together with serological testing, using plain chest computed tomography (ct) scans, showing bilateral abnormalities (ground-glass, interstitial involvement, crazy paving) in ⩾ % of cases [ ] . severe disease is associated with conditions such as acute respiratory distress syndrome (ards) and with laboratory abnormalities including leukopenia, thrombocytopenia and hypercoagulative state with d-dimer elevation [ ] . among the factors associated with a composite end-point (cep) (defined as intensive care unit (icu) access, invasive ventilation and death) are comorbidities, older age and ards [ ] . similarly, the procoagulant state, particularly d-dimer elevation, has demonstrated an association with ards and a cep [ ] . the aim of this study was to analyse sars-cov- coagulation deregulatory effects, especially referring to d-dimer elevation and its correlation with thrombotic events, ards and a cep. data sources and searches an online database search on pubmed, google scholar, scopus, web of science, and cochrane was performed from march to april . the keywords and their variants (differently combined) used for the search were "covid- ", " -ncov", " novel coronavirus", "sars-cov- ", "d-dimer", "coagulation", "hypercoagulative state", "laboratory analysis", "ards", "haemostasis", "thrombosis", "pulmonary embolism", "disseminated intravascular coagulation (dic)", "heparin" and "anti-coagulation". the inclusion criteria were as follows: covid- populations, presence of laboratory test values including coagulation parameters (d-dimer specifically), and d-dimer correlation with study population characteristics. the exclusion criteria were: patients included in the study who were aged < years, absence of d-dimer values, conference abstracts, commentary abstracts, letters to authors, articles written with a non-arabic alphabet with no available translation, and case reports. pre-published previews of accepted articles were considered as includible. references of included works were also evaluated. the abstracts/full texts of all the studies that emerged from the search were compared to the inclusion criteria. the study search and selection process is schematised in the flow diagram shown in figure . the selection of documents that met the inclusion criteria was independently conducted by three reviewers (s. vidali, m.l.e. luisi and e. cossu). overall quality was evaluated using the newcastle-ottawa scale (nos) [ ] , which includes items about selection, comparability and outcome/exposure. the nos score ranges from to for cohort and case-control studies; publications with a score ⩾ were considered of good quality. for cross-sectional studies the nos score ranges from to ; a score ⩾ points was used to identify studies with good quality. the evaluation was performed by three independent reviewers (s. pancani, d. morosetti and g. consales). a data extraction scheme was designed to address the search questions of this review, consisting of the title of the article, authors, study aim, sample size, mean/median age and sex composition of samples, reference to the mean/median values measured for the d-dimer variable, eventual comparative elaboration and significance, and main findings of the study. the extracted data were compiled into a microsoft excel spreadsheet. selection bias reduction was addressed by thoughtfully designing the search protocol. in addition, multiple different keywords were used to ensure that as many articles as possible were included in the review. inaccuracy in document inclusion and data extraction was limited by the work of three reviewers (s. pancani, d. morosetti and g. consales). disagreements between reviewers were resolved by discussion. the titles, abstracts and manuscripts of the documents that emerged from the search were analysed. articles reporting the differences in d-dimer between healed/survived patients and those who reached a cep or experienced complications such as ards, organ failure or multi-organ failure were included. from the initial search, studies were collected. after excluding duplicates, studies were identified. among them, two case reports and two letters to authors were excluded. articles with no explicit mention of d-dimer values and/or differentiation of this parameter among patient subclasses (healed/dead, severe/ non-severe, etc.) were excluded. one article was excluded due to incongruent d-dimer measurement units. articles were then reviewed: between cohort and case-control studies and three cross-sectional, with a variable number of patients enrolled ( - ). the case-control and cohort studies were demonstrated to reach the criteria for a definition of good quality (all scored ⩾ ); however, the cross-sectional studies did not (none scored ⩾ points). the quality assessment results are illustrated in table . the demographic characteristics and rates of comorbidities, icu admission, complications and death related to the included studies are reported in table . the main d-dimer-associated outcome and complication data of the study populations are summarised in table . chen et al. [ ] ( covid- patients, among whom the characteristics were analysed of healed and deceased) found markedly higher d-dimer levels in the deceased group during hospitalisation than in survivors ( . µg·ml − versus . µg·ml − ); in addition, % of deceased patients versus % of survivors had d-dimer levels > µg·ml − . in the work of han et al. [ ] ( covid- patients, healthy controls), among the infected group, during hospitalisation, mean±sd d-dimer levels were higher than in the control group ( tang et al. [ ] ( covid- patients, received - mg·day − enoxaparin and five received - u·day − of unfractionated heparin) found that the -day mortality of heparin users was lower than that of non-users, in patients who had increased d-dimer values (> µg·ml − , six-fold higher : range - for cohort/case-control, - for cross-sectional; ¶ : range - for all studies; + : range - for all studies; § : range - for cohort/case-control, - for cross-sectional. in the work of zhang et al. [ ] (seven covid- icu patients, who developed critical limb ischaemia), mean d-dimer levels at icu admission were . µg·ml − (range . - . µg·ml − ). at the time of limb ischaemia occurrence, median d-dimer increased to > -fold the normal range and in five patients ( . %) it exceeded the limit of detection (> µg·ml − ). after - days of anticoagulants, d-dimer levels decreased, but remained above the upper limit of normal ( . µg·ml − ) in all patients (lowest value . µg·ml − ). among the seven patients, those meeting the dic diagnosis criteria [ ] passed from % at admission to . % at the time of thrombosis, to . % after anticoagulant therapy [ ] . hypercoagulability, injury of the endothelium and venous stasis, defining the virchow triad, represent the cardinal inducers of thrombus formation. conditions predisposing to thrombosis directly or indirectly involve mechanisms associated with this triad [ ] . the role of inflammation and hypoxia, among the pathogenetic pathways of hypercoagulative states and thrombosis, has been extensively studied [ ] [ ] [ ] [ ] [ ] . it has been demonstrated that inflammatory settings, where the release of cytokines such as interleukin (il)- , tumour necrosis factor (tnf)-α and complement factors is consistent, induce an upregulation of plasminogen activator inhibitor (pai)- with consequent impairment of fibrinolysis. moreover, they cause pro-inflammatory changes of endothelial cells that increase the expression of chemoattractants and adhesion molecules necessary for mononucleate activation and extravascular transformation in macrophages [ , , [ ] [ ] [ ] . mononucleate cells are stimulated by circulating cytokines to produce tissue factor, trigger and initiator of coagulative extrinsic cascades [ , ] . in addition, pro-inflammatory cytokines such as il- and il- , and platelets themselves, induce platelet activation and cooperate in the propagation and maintaining of coagulative mechanisms [ , ] . products of coagulation eventually perpetuate inflammatory pathways through a stimulation of leukocytes, which enhances the production of cytokines such as il- and il- , therefore indirectly perpetrating coagulative mechanisms [ , ] . in a positive loop of reciprocal induction, hypoxia not only is a consequence of vascular occlusion, but can also stimulate thrombus formation and propagation, through the activation of multiple cellular and molecular pathways. these include hypoxia-inducible factors (hifs), more precisely hif and hif [ , , ] . in hypo-oxygenation, nuclear dimerisation of hifs is extremely enhanced, with consequent activation of hypoxia responsive element and transcription of genes coding for molecules directly implicated in coagulative homeostasis such as pai- [ , ] . hypoxia also induces the production of molecules such as early growth response- , tnf-α, il- and other regulators of thrombus formation and reduces that of thrombomodulin, therefore inducing pro-thrombotic changes and progressively reducing the fibrinolytic activity of the endothelium [ , , ] . during sepsis, multiple factors enhancing coagulation are activated. the pathogen-related cellular damage and immune responses stimulate the production of molecules such as the pathogen-associated molecular patterns (pamps). pamps induce the release from damaged cells of dna, histones and pattern-recognising receptors, promoters of both inflammation and coagulation [ , ] . other mediators implicated are represented by neutrophil extracellular traps (nets). when activated by pathogens such as viruses or stimulated by molecules such as endothelial p-selectin, neutrophils can induce netosis, a specific kind of apoptosis. netosis results in the production of extracellular proteins, histones and dna-intertwined compounds implicated in hypercoagulative states by acting as a scaffold for thrombus formation [ ] . pathogenetic mechanisms of sars-cov- infections involve the binding of virus envelope glycoprotein to ace [ , ] . ace can be identified on the cells of multiple tissues, particularly alveolar epithelial, endothelial, intestinal epithelial and others [ ] . the innate tropism for vascular endothelial cells and their consequent damage, together with the intense activation of inflammatory responses and of coagulation pathways, may explain the intense pro-coagulative state [ ] . this predisposes to systemic micro-thrombotic alterations and may give a partial explanation to the consistent rate of multi-organ failure, dic and, based on the consistent involvement of lung structures, of ards in severe covid- patients. d-dimer is an indirect marker of active coagulation and thrombin formation. it is in fact released when plasmin, a fibrinolytic enzyme, cleaves fibrin to degrade clots and represents a mirror of the endovascular thrombotic processes [ ] . the alterations of coagulation factors during sars-cov- infection and specifically that of d-dimer are, as documented in the clinical experiences described here, severe, constant and correlated with prognosis, complications and cep rates. as reported by tang et al. [ ] , mean d-dimer levels in non-survivors were significantly higher compared to survivors and, based on the experience of wang et al. [ ] , those levels continue to increase until death with higher values compared to survivors. additionally, d-dimer appears significantly higher in severe patients compared to non-severe ones, as shown in the study by zhang et al. [ ] . similar results were obtained by huang et al. [ ] , where they classified patients based on whether they were admitted to the icu. among the factors that were demonstrated to be connected to the clinical outcome of covid- patients, the presence of comorbidities may represent a confounding factor for the interpretation of d-dimer and other coagulation parameter alterations, especially considering the heterogeneous aetiology of thrombotic and thrombophilic states. however, as emerged from the article by zhang et al. [ ] , elevations of d-dimer levels were strongly associated with severe forms of covid- and with the presence of a cep (both p< . ). also, in the work of han et al. [ ] , mean d-dimer levels in covid- patients were significantly higher than those in the healthy control group ( p< . ) and increased substantially with the severity of the disease. this hypercoagulative infection-induced state is, as previously mentioned, systemic, and may lead to various clinical manifestations such as limb ischaemia (as documented by zhang et al. [ ] ), dic and, progressively, to coagulation factor deterioration [ ] . however, due to the more consistent tropism of this virus for lung structures, micro-and macro-thrombotic events in this organ should be primarily considered. these conditions represent severe therapeutic challenges and may require non-pharmacological, invasive rescue treatments, such as endovascular interventional ones. these represent an extra vigorous stress on already very fragile patients. in the experience of wu et al. [ ] , d-dimer levels in covid- patients with ards were significantly higher compared to those without ards, and those of deceased ards patients were significantly higher than those of ards patients who survived, with significant association between d-dimer elevation and the development of ards and progression from ards to death. in cases with sudden or progressive oxygen level deterioration, ards-compatible symptoms, signs of right ventricle progressive overload or diffuse perfusion alterations of micro-thrombotic aetiology, the possibility of pulmonary thromboembolism should be considered [ ] . enforcing this theory, recent pathology studies of deceased covid- patients showed the presence of pulmonary small vessel micro-thrombotic alterations [ , ] . although a cost-benefit evaluation of the appropriateness of each medical action should always be performed to reduce infection transmission risk ( pulmonary ventilation/perfusion examinations are, for this reason, not recommended), in cases of d-dimer progressive elevation, decay of respiratory gas exchange, as well as progressive signs of right side congestive heart failure, the hypothesis of a diagnostic investigation with pulmonary angio-ct scan should be considered, in order to promptly detect possible pulmonary embolic states and to perform adequate pharmacological interventions [ ] [ ] [ ] . similarly, in cases of parenchymal function deterioration, limb ischaemic manifestations or matching of dic or sepsis-induced coagulopathy criteria [ ] , parenchymal and peripheral vascular dopplerultrasound evaluation would be useful, allowing the identification and treatment of eligible patients [ ] . the association between sars-cov- infection and coagulation changes is becoming more defined and experience with anticoagulants, especially low-molecular-weight heparin (lmwh), as covid- management drugs is progressively increasing [ , ] . as reported in the study by tang et al. [ ] , the -day mortality of patients with markedly high d-dimer levels treated with therapeutic doses of heparin was lower than that of non-treated patients, with mortality rates that were raised in non-users together with the increase of d-dimer. similarly, yin et al. [ ] described no difference in the -days mortality between covid- heparin users and non-users overall. however, when d-dimer was > . µg·ml − , mortality was significantly lower in covid- heparin users compared to covid- non-users ( p= . ), while no mortality difference was detected between non-covid- heparin users and non-users. anticoagulant therapy therefore represents a valid tool to use in the rehabilitation of the very fragile global homeostasis of the covid- population and has proved its benefits when administered considering patients' clinical characteristics and contraindications [ , , , ] . however, the appropriate time to start therapeutic administration of these drugs, especially aiming to intervene before patients become symptomatic due to major thrombosis-related dysfunction, has not yet been defined. the hypothesis of an early and continuous pro-thrombotic activity of sars-cov- and therefore the appropriateness of an immediate and continuous monitoring of coagulation indicators, such as d-dimer, with consequent labelled administration of adjusted doses of anticoagulants, should be addressed further, in order to prevent worsening of global conditions due to vascular parenchymal or systemic thrombotic dysfunction. as indicated by hunt et al. [ ] and zhou et al. [ ] , prophylactic anticoagulant treatment with lmwh is to be considered, always after making a precise risk stratification (i.e. tracheostomy access management) and an evaluation of possible contraindications (recent or forthcoming surgery, active bleedings, etc.). however, the precise investigation of the correct balance between d-dimer elevation, coagulation asset and doses of anticoagulants, especially in pre-symptomatic conditions, during covid- disease, has not yet been performed and would be of great interest, in order to personalise treatments, to allow a graduated and targeted adjustment of doses, therefore preventing disease-related thrombotic complications and drug-induced severe coagulation disorders. to conclude, after evaluating clinical data reported in the literature, sars-cov- -induced coagulation alterations and consequent micro-and macro-thrombotic events appeared to be an issue of primary importance. this is particularly supported by the evidence of severe elevation of d-dimer levels observed in critically ill covid- patients. treatment schemes with anticoagulant drugs, especially heparin and lmwh, based on monitoring the levels of d-dimer and other coagulation factors, should be further addressed in order to define adequate timing (therapeutic and prophylactic) and efficacy, based on patients' characteristics, clinical presentations and coagulative function. limitations to this work were represented by the actuality of the investigated issue: available data sources are recent and therefore the knowledge on the disease's implication is not global. additionally, both the studies designed specifically to investigate the implications of coagulation and d-dimer in covid- disease and those reporting explicit d-dimer-related data vary widely in terms of measurement protocols and of the investigated d-dimer-related outcomes. despite the presence of these limitations, which are substantially related to the recent presentation of covid- , the examination and re-elaboration of data from clinical observations seems fundamental, in order to highlight infection-related major issues and to consequently produce evidence-based management and therapeutic solutions. clinical features of patients infected with novel coronavirus in wuhan, china cardiovascular considerations for patients, health care workers, and health systems during the covid- pandemic clinical characteristics of coronavirus disease in china epidemiology of covid- in a long-term care facility in king county, washington world health organization. coronavirus disease (covid- ) situation report - risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical management of severe acute respiratory infection (sari) when covid- disease is suspected: interim guidance clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of middle east respiratory syndrome coronavirus infection in the united arab emirates lung pathology of fatal severe acute respiratory syndrome angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus potential effects of coronaviruses on the cardiovascular system: a review the newcastle-ottawa scale (nos) for assessing the quality of nonrandomised studies in meta-analyses. ottawa, ottawa hospital research institute clinical characteristics of deceased patients with coronavirus disease : retrospective study prominent changes in blood coagulation of patients with sars-cov- infection anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up difference of coagulation features between severe pneumonia induced by sars-cov and non-sars-cov analysis of clinical characteristics and laboratory findings of cases of novel coronavirus pneumonia in wuhan, china: a retrospective analysis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical and coagulation characteristics in patients with critical covid- pneumonia and acro-ischemia clinical characteristics of patients infected with sars-cov- in wuhan, china clinical characteristics of death cases with covid- : a retrospective review of medical records in a single medical center clinical features and treatment of covid- patients in northeast chongqing new criteria for sepsis-induced coagulopathy (sic) following the revised sepsis definition: a retrospective analysis of a nationwide survey the stimulation of thrombosis by hypoxia hypoxia and inflammation more than an anticoagulant: do heparins have direct anti-inflammatory effects? virchow's contribution to the understanding of thrombosis and cellular biology hypoxia and thrombosis could hypoxia increase the prevalence of thrombotic complications in polycythemia vera? leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded "cardiovascular continuum the loss of homeostasis in hemostasis: new approaches in treating and understanding acute disseminated intravascular coagulation in critically ill patients coagulation of whole blood stimulates interleukin- beta gene expression role of infectious diseases in the antiphospholipid syndrome (including its catastrophic variant) the impact of the inflammatory response on coagulation regulatory role of cytokines in disseminated intravascular coagulation nf-κb links innate immunity to the hypoxic response through transcriptional regulation of hif- α new horizons in hypoxia signaling pathways molecular regulation of the pai- gene by hypoxia: contributions of egr- , hif- α, and c/ebpα hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis the effect of hypoxia on capillary endothelial cell function: modulation of barrier and coagulant function advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation pamps and damps as triggers for dic the science underlying covid- : implications for the cardiovascular system review of d-dimer testing: good, bad, and ugly disseminated intravascular coagulation in patients with -ncov pneumonia acute pulmonary embolism and covid- pneumonia: a random association? gross examination report of a covid- death autopsy clinical pathology of critical patient with novel coronavirus pneumonia (covid- ) diagnostic evaluation of pulmonary embolism during the covid- pandemic practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- coronavirus disease (covid- ): a clinical update american society of hematology guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism d-dimer is associated with severity of coronavirus disease : a pooled analysis covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up author contributions: s. vidali: conception, design of the work, acquisition of data, draft and substantive revision of the work. d. morosetti: analysis and interpretation of data, substantive revision of the work. e. cossu: acquisition of data, substantive revision of the work. m.l.e. luisi: conception, design of the work, acquisition of data, draft and substantive revision of the work. s. pancani: analysis and interpretation of data, substantive revision of the work. v. semeraro: design of the work, substantive revision of the work. g. consales: conception, design of the work, substantive revision of the work. all have approved the submitted version (and any substantially modified version that involves the author's contribution to the study). all have agreed both to be personally accountable for the authors' own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.conflict of interest: none declared. key: cord- - twwcp authors: combes, alain; peek, giles j.; hajage, david; hardy, pollyanna; abrams, darryl; schmidt, matthieu; dechartres, agnès; elbourne, diana title: ecmo for severe ards: systematic review and individual patient data meta-analysis date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: twwcp purpose: to assess the effect of venovenous extracorporeal membrane oxygenation (ecmo) compared to conventional management in patients with severe acute respiratory distress syndrome (ards). methods: we conducted a systematic review and individual patient data meta-analysis of randomised controlled trials (rcts) performed after jan , comparing ecmo to conventional management in patients with severe ards. the primary outcome was -day mortality. primary analysis was by intent-to-treat. results: we identified two rcts (cesar and eolia) and combined data from patients. on day , of the ( %) ecmo-group and of the ( %) control group patients had died (relative risk (rr), . , % confidence interval (ci) . – . ; p = . ; i( ) = %). in the per-protocol and as-treated analyses the rrs were . ( % ci . – . ) and . ( % ci . – . ), respectively. rescue ecmo was used for ( %) of the control patients ( in eolia and in cesar). the rr of -day treatment failure, defined as death for the ecmo-group and death or crossover to ecmo for the control group was . ( % ci . – . ; i( ) = %). patients randomised to ecmo had more days alive out of the icu and without respiratory, cardiovascular, renal and neurological failure. the only significant treatment-covariate interaction in subgroups was lower mortality with ecmo in patients with two or less organs failing at randomization. conclusions: in this meta-analysis of individual patient data in severe ards, -day mortality was significantly lowered by ecmo compared with conventional management. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. ventilatory management of patients with severe acute respiratory distress syndrome (ards) has improved over the last decades with a strategy combining low tidal volume (vt) ventilation [ ] , high positive end-expiratory pressure (peep) [ , ] , neuromuscular blocking agents [ ] and prone positioning [ ] . however, ventilator-induced lung injury (vili) may persist in these patients since a recent and large epidemiological study showed that their hospital mortality was still % [ ] . recently, even higher mortality was reported for patients with severe acute respiratory syndrome coronavirus (sars-cov- ) infection who needed invasive mechanical ventilation [ ] [ ] [ ] . venovenous extracorporeal membrane oxygenation (ecmo) providing full blood oxygenation, co elimination and combined with more gentle ventilation has benefited from major technological advances in the last years [ , ] . in , favourable outcomes were reported in patients who received ecmo during the influenza a (h n ) pandemic [ ] [ ] [ ] . the conventional ventilator support vs extracorporeal membrane oxygenation for severe acute respiratory failure (cesar) trial [ , ] showed that transfer to an ecmo centre was associated with fewer deaths or severe disabilities at months compared with conventional mechanical ventilation ( % vs. %; p = . ), although month mortality was not significantly reduced ( % vs. %; p = . ). the more recent ecmo to rescue lung injury in severe ards (eolia) trial showed a non-statistically significant reduction in -day mortality with ecmo ( % vs. %; p = . ) [ ] . however, neither trial was separately powered to detect a - % survival benefit with ecmo. we performed a systematic review with an individual patient data meta-analysis of randomised controlled trials comparing ecmo to conventional mechanical ventilation in patients with severe ards. the primary objective was to evaluate the effect of ecmo on -day mortality. secondary objectives included the evaluation of ecmo for other clinical outcomes and in pre-specified subgroups for the primary outcome. this systematic review and meta-analysis followed the preferred reporting items for systematic reviews and meta-analyses for individual patient data (prisma-ipd checklist in etable in the supplement) and the protocol was registered in prospero (crd ) on may st . we included all randomised controlled trials (rcts) evaluating venovenous ecmo in the experimental group and conventional ventilatory management in the control group, that included patients with ards fulfilling the american-european consensus conference definition [ ] or the berlin definition for ards [ ] , and that were published or whose primary completion date was after [ , , ] . this choice was justified by the major improvements in intensive care treatments and in ecmo technology that occurred in the last two decades. additional information on selection criteria is provided in the supplement. we searched medline via pubmed, embase and the cochrane central register of controlled trials (central) from january , to september , using a search algorithm developed for the purpose of this study and adapted to each database (etable in the supplement). we also searched trial registries including clini-caltrials.gov and the international clinical trial registry platform (ictrp) for completed and ongoing trials, conference proceedings of major critical care societies and screened reference lists of identified articles as well as systematic or narrative reviews on the topic (see the supplement). selection was conducted independently by two reviewers (da and ms) on titles and abstracts first and then, on the full text. for each included rct, the corresponding author was contacted to provide fully anonymized individual patient data as well as format, coding and definition of any variables. risk of bias in each trial was evaluated by two independent reviewers (dh and ad) using the updated version of the risk-of-bias tool developed by cochrane [ ] (see the supplement). the primary endpoint was mortality days after randomisation. main secondary endpoints comprised time to death up to days after randomisation, treatment failure up to days, defined as crossover to ecmo or death for patients in the control group, and death for patients in the ecmo group, number of days alive and out-of-hospital between randomisation and day , number of days alive without mechanical ventilation, renal replacement therapy and vasopressor support between randomisation and day . other preplanned secondary outcomes comprised mortality at and days after randomisation, number of days alive and out of the icu between randomisation and day , number of days alive without respiratory failure, neurological failure, cardiovascular failure, liver failure, renal failure and coagulation failure, defined as the corresponding component sequential organ failure assessment (sofa) score greater in this meta-analysis of individual patient data in severe ards, -day mortality was significantly lowered by ecmo compared with conventional management. patients randomised to ecmo had more days alive out of the icu and without respiratory, cardiovascular, renal and neurological failure than between randomisation and day . data related to patients' management, causes of death and safety outcomes were also described (see the supplement). the statistical analysis was performed for each outcome of interest using individual patient data. an intentionto-treat analysis was used for all outcomes, whereby all patients were analysed in the groups to which they were randomised. the measures of treatment effect were risk ratios for binary outcomes, hazard ratios for time-toevent outcomes and mean differences for quantitative outcomes. the primary endpoint was defined as a binary outcome and analysed using both one-step (as primary analysis) and two-steps (as sensitivity analysis) methods [ ] . in the one-step method, we analysed both studies simultaneously to obtain the combined treatment effect with % cis and p-value using a generalized linear mixed effect model to account for the clustering of data within each trial with a random effect. in the two steps method, we first analysed separately each trial using individual patient data before combining them using a random effects meta-analysis model to account for variability between studies. a two-step method was used for all secondary outcomes. heterogeneity was evaluated with the cochran's q-test, i statistic and between study variance τ . survival curves for the time to death up to days were generated using individual patient data and the kaplan-meier method. we conducted sensitivity analyses for the primary outcome in different populations (per-protocol, as-treated). the per-protocol population included all randomised patients having received the treatment attributed by randomisation (i.e., patients having received ecmo in the ecmo arm and patients not having received ecmo in the control arm). the as-treated population compared patients receiving ecmo to those who did not receive ecmo, whatever the randomisation arm. a sensitivity analysis excluding trials at high risk of bias was also planned. we explored whether the effect of ecmo on -day mortality varied according to baseline patient characteristics (see the supplement). for each subgroup, the treatment-subgroup interaction was tested in the one-step model. for quantitative baseline characteristics, we used the median values to define the subgroups. all these subgroup analyses were pre-planned. alpha risk was set at % for the primary outcome. for all secondary outcomes, we did not correct for multiple testing. as such, subgroup and sensitivity analyses should be considered as exploratory. all the analyses were performed with the use of r software version . . (r foundation). from the references identified by the search strategy, we included two randomised controlled trials fulfilling our eligibility criteria-cesar and eolia [ , ] . reasons for exclusion are reported in efig. of the supplement. the two trials provided individual patient data for all randomised patients ( overall, in cesar and in eolia), and there was no eligible trial not providing individual patient data. detailed characteristics of the two trials are reported in etable in the supplement. comparison of patient characteristics at randomisation did not show baseline imbalance between groups (table and etables and in the supplement). the main disorder leading to study entry was severe hypoxia (in % of the patients, with a mean (± sd) pao /fio of ± mm hg). the main cause of ards was pneumonia (> % of the patients) and % had or more organs failing at randomisation. of the patients randomised to the ecmo groups, ( %) received ecmo ( % and % in eolia and cesar, respectively). rescue extracorporeal gas exchange was used for ( %) of the control patients ( patients crossed over to ecmo in eolia, and to pumpless arteriovenous co removal in cesar that was a protocol violation by the conventional management team as rescue extracorporeal gas exchange was not part of the cesar trial design). risk of bias was judged low in both trials (efigure in the supplement). by day , ( %) ecmo-group and ( %) control group patients had died (relative risk, . , % confidence interval . - . ; p = . ) ( table and fig. ). results were similar in the one-step and two-steps models. there was no evidence of heterogeneity across studies (p = . , i = %, τ = . ). the hazard ratio for death within days after randomisation in the ecmo group, as compared with the control group, was . ( % ci . - . ) (fig. ) . the relative risk of treatment failure, defined as death by day for the ecmo-group and death or crossover to ecmo for the control group was . ( . - . ) ( at day post-randomisation ( -day follow-up was not available for the following outcomes in eolia), patients in the ecmo group had more days alive without vasopressors ( vs days, mean difference, days; % ci, to ), renal replacement therapy ( vs days, mean difference, days; % ci - ) and neurological failure ( vs days, mean difference, days; % ci - ) than those in the control group (table and efig. in the supplement). prone positioning and low-volume low-pressure mechanical ventilation were applied to % and % of control group patients, respectively (table ) . multiorgan failure and respiratory failure were the main causes of death in both groups (table ) , while a cannulation-related fatal complication occurred in of the patients who received ecmo. of the patients randomised to ecmo, ( %) died before ecmo could be established. additional data on secondary outcomes are provided in tables and and efig. in the supplement. the relative risks of death at day post-randomisation according to the per-protocol and as-treated analyses were . ( % ci . - . ) and . ( % ci . - . ), respectively (efig. in the supplement). the only significant treatment-covariate interaction identified in subgroup analyses was the number of organs failing at randomisation with rr = . ( % ci . - . ) among patients with - organ failures and rr = . ( % ci . - . ) among patients with or more organ failures, p = . for interaction (fig. ) . there was no evidence to suggest a differential treatment effect for any other subgroups. the summary of findings table reporting the evaluation of the quality of evidence for the seven most important outcomes is presented in etable in the supplement. the level of evidence was high for mortality at days, time to death and treatment failure. in this individual patient data meta-analysis of patients with severe ards included in the cesar [ ] and eolia [ ] randomised trials, there is strong evidence to suggest that early recourse to ecmo leads to a reduction in -day mortality and less treatment failure compared with conventional ventilatory support. patients randomised to ecmo also had more days alive out of the icu and without respiratory, cardiovascular, renal and neurological failure. the benefit of ecmo in severe ards patients has long been debated [ ] [ ] [ ] [ ] . because of highly challenging design and conduct issues, only four randomised trials of extracorporeal life support for adult patients with acute respiratory failure have been performed in the last decades [ , , , ] . our meta-analysis included only the two most recent trials (cesar [ ] and eolia [ ] ) since major advances in icu care and in ecmo techniques have occurred in the past years making the two older trials not relevant for comparison [ , , ] . in addition the two older trials did not use venovenous ecmo. one used venoarterial ecmo [ ] and one used low-flow veno-venous extracorporeal co removal [ ] . characteristics of patients included in eolia and cesar were comparable regarding ards aetiology and disease severity at randomisation. patients were enrolled early after the initiation of invasive mechanical plus-minus values are means ± sd; see etable the supplement for missing data ecmo denotes extracorporeal membrane oxygenation, ards the acute respiratory distress syndrome, pao partial pressure of arterial oxygen, fio the fraction of inspired oxygen, pao /fio the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, peep positive end-expiratory pressure missing data were < % for patients' characteristics at randomisation, except for predicted mortality, respiratory system compliance and murray score (see etable in the supplement) a number of organ failed ( - ) defined as the corresponding component sequential organ failure assessment (sofa) score > b apache (cesar) and saps (eolia) scores were both translated to predicted probability of icu mortality chest radiograph (quadrants infiltrated) . ± . . ± . ventilation and rates of control patients being proned and receiving low-volume low-pressure mechanical ventilation were high. both eolia and cesar trials showed a comparable survival benefit with ecmo, but neither was individually powered to detect a reasonable survival difference between groups. specifically, the data safety monitoring board of eolia, following pre-specified guidance using a sequential design with a two-sided triangular test based on -day mortality, recommended stopping the trial for futility after % of the maximal sample size had been enrolled, because the probability of demonstrating a % absolute risk reduction in mortality with ecmo was considered unlikely. our meta-analysis, which includes a much larger number of patients and shows higher survival with ecmo in both the intention-to-treat and per-protocol analyses provides strong evidence about the benefit of ecmo in severe ards. our results also extend the conclusions of a post-hoc bayesian analysis of eolia indicating a very high probability of ecmo success in severe ards patients, ranging from to % depending on the chosen priors [ ] . our results are consistent with two previous aggregated data meta-analyses in the field: one was a network meta-analysis considering different interventions whose impact is limited by the [ ] and the other focused on ecmo [ ] . our ipd meta-analyses goes beyond these two previous studies and provides a stronger evidence on the benefit of ecmo in ards for the following reasons. ipd meta-analyses provides a higher level of evidence than aggregated data meta-analyses, because they are independent of the quality of reporting in included studies and allow evaluation of other important outcomes such as time to death and number of days without organ failures [ , ] . in this study, we showed that, beyond mortality, duration and severity of organ failures also favoured ecmo, and these results were highly consistent between the two studies. this observation provides insights into the potential pathophysiological mechanisms of ecmoassociated benefits in severe ards [ ] . although extracorporeal gas exchange may rescue some patients dying of profound hypoxemia or in whom high pressure mechanical ventilation has become dangerous, minimization of lung stress and strain associated with positive pressure ventilation may drive most of the improved outcomes observed under ecmo [ ] . ultraprotective ventilation with very low vts, driving pressures and respiratory rates [ ] , and, therefore, minimized overall mechanical power transmitted to lung alveoli [ ] may reduce ventilator-induced lung injury, pulmonary and systemic inflammation and ultimately organ failure leading to death. these data also reinforce the recent recommendation of the world health organization (who) [ ] , and the surviving sepsis campaign [ ] to consider ecmo support in coronavirus disease (covid- )-related ards with refractory hypoxemia if lung protective mechanical ventilation was insufficient to support the patient [ ] . meta-analyses of individual patient data can also explore outcomes in important subgroups and suggest which population may derive the greatest benefit of a specific intervention, which is very limited in aggregated data meta-analyses [ ] . in this study, the mortality of patients with only one or two organs failing at randomisation was almost halved with ecmo ( % vs. %), while it was not substantially different between groups in patients with ≥ organ failures. this finding suggests that veno-venous ecmo may not be able to improve the outcomes of ards patients with severe shock and multiple organ failure. in eolia, patients with baseline pao / fio > mmhg or those enrolled due to severe respiratory acidosis and hypercapnia, seemed to derive the greatest benefit of ecmo [ ] . this analysis has several limitations. first, inclusion criteria were more stringent for the eolia trial, in which, for example, ventilator optimization (fio > %, vt at ml/kg predicted body weight and peep > cm h o) was mandatory before enrolment. however, it should be noted that baseline patient characteristics were comparable regarding ards severity at inclusion (etable in the supplement). second patient management was not similar in the two studies. in cesar, % of patients randomised to the ecmo arm did not receive ecmo and there was no standardized protocol for mechanical ventilation in the control group. conversely, in eolia, % of patients randomised to ecmo received the intervention, the mechanical ventilation strategy in the control group followed a strict protocol, and rescue ecmo was applied to % of control group patients who had developed refractory hypoxemia. however, this meta-analysis showed a significantly lower mortality with ecmo in the per-protocol analysis including only patients in whom ecmo had been initiated in the ecmo arm and patients not having ecmo in the control arm. this analysis minimizes the aforementioned management differences, since the least severe patients who did not receive ecmo after mv optimization in cesar were excluded from the ecmo arm and the most severe patients who needed rescue ecmo in eolia were excluded from the control arm. in contrast, ecmo was not associated with a mortality benefit in the as-treated population, but such an analysis strongly disadvantages the ecmo group, which includes the most severe control patients rescued by ecmo. second, this meta-analysis does not provide detailed data on ecmo-related safety endpoints, since they were not reported in cesar. death directly related to ecmo cannulation was rare in both studies and the rates of stroke and major bleeding were also low in eolia, in which a restrictive anticoagulation strategy was applied [ ] . third, no long-term outcomes beyond day post-randomisation were analysed although the cesar trial [ ] and a retrospective cohort of ards patients [ ] reported satisfactory long-term health-related quality-of-life after ecmo. fourth, only the cesar trial provided a cost-effectiveness analysis that suggested a benefit of the transfer of ards patients to a centre with an ecmo-based management protocol [ ] . our results, showing improved survival, with more days alive out of the icu and without the need for major organ support are in line with cesar's cost-effectiveness data. fifth, many conditions such as mv duration > days prior to ecmo or major comorbidities were exclusion criteria for enrolment in both cesar and eolia. the indication to initiate ecmo should, therefore, be carefully evaluated in these situations. lastly, ecmo should be used in experienced centres and only after proven conventional management of severe ards (including lung protective mechanical ventilation and prone positioning) have been applied and failed [ ] , except when hypoxemia is immediately life-threatening, or when the patient is too unstable for prone positioning [ ] . in conclusion, this meta-analysis of individual patient data of the cesar and eolia trials showed strong evidence of a clinically meaningful benefit of early ecmo in severe ards patients. another large study of ecmo appears unlikely in this setting and future research should focus on the identification of patients most likely to benefit from ecmo and optimization of treatment strategies after ecmo initiation [ ] . the study was supported by the direction de la recherche clinique et de l'innovation (drci), assistance publique-hopitaux de paris (aphp), with a grant from the french ministry of health (crc , # , ). the eolia trial was supported by the direction de la recherche clinique et du développement (drcd), assistance publique-hôpitaux de paris (aphp), with a grant from the french ministry of health (programme hospitalier de recherche clinique number, phrc , ), the eolia trial group, the réseau européen en ventilation artificielle (reva) and the international ecmo network (ecmonet, https ://www.inter natio nalec monet work.org). the cesar trial was supported by the uk nhs health technology assessment, english national specialist commissioning advisory group, scottish department of health, and welsh department of health. see the supplement for the list of eolia and cesar collaborators. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis bedside contribution of electrical impedance tomography to setting positive end-expiratory pressure for extracorporeal membrane oxygenationtreated patients with severe acute respiratory distress syndrome neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in extracorporeal life support for adults with respiratory failure and related indications: a review mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome. an international multicenter prospective cohort extracorporeal membrane oxygenation for pandemic influenza a(h n )-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar) extracorporeal membrane oxygenation for severe acute respiratory distress syndrome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients fifty years of research in ards. is extracorporeal circulation the future of acute respiratory distress syndrome management? rob : a revised tool for assessing risk of bias in randomised trials cochrane handbook for systematic reviews of interventions version - unproven and expensive before proven and cheap: extracorporeal membrane oxygenation versus prone position in acute respiratory distress syndrome ecmo for immunosuppressed patients with acute respiratory distress syndrome: drawing a line in the sand mortality and costs following extracorporeal membrane oxygenation in critically ill adults: a populationbased cohort study less is more: not (always) simple-the case of extracorporeal devices in critical care extracorporeal membrane oxygenation in severe acute respiratory failure. a randomized prospective study randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal co removal for adult respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial assessment of therapeutic interventions and lung protective ventilation in patients with moderate to severe acute respiratory distress syndrome: a systematic review and network meta-analysis venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis individual participant data (ipd) meta-analyses of randomised controlled trials: guidance on their use comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials: an observational study mechanical ventilation for acute respiratory distress syndrome during extracorporeal life support. research and practice mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts world health organization: clinical management of severe acute respiratory infection when covid- disease is suspected. last accessed surviving sepsis campaign: guidelines on the management of critically ill adults extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with covid- : a retrospective cohort study metaanalytical methods to identify who benefits most from treatments: daft, deluded, or deft approach the preserve mortality risk score and analysis of longterm outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome ecmo for ards: from salvage to standard of care? saying no until the moment is right: initiating ecmo in the eolia era prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial we thank mrs elizabeth allen for her help in preparing the data of the cesar trial. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -d e y r authors: knighton, andrew j.; kean, jacob; wolfe, doug; allen, lauren; jacobs, jason; carpenter, lori; winberg, carrie; berry, jay g.; peltan, ithan d.; grissom, colin k.; srivastava, raj title: multi-factorial barriers and facilitators to high adherence to lung-protective ventilation using a computerized protocol: a mixed methods study date: - - journal: implement sci commun doi: . /s - - -x sha: doc_id: cord_uid: d e y r background: lung-protective ventilation (lpv) improves outcomes for patients with acute respiratory distress syndrome (ards) through the administration of low tidal volumes (≤ . ml/kg predicted body weight [pbw]) with co-titration of positive end-expiratory pressure and fraction of inspired oxygen. many patients with ards, however, are not managed with lpv. the purpose of this study was to understand the implementation barriers and facilitators to the use of lpv and a computerized lpv clinical decision support (cds) tool in intensive care units (icus) in preparation for a pilot hybrid implementation-effectiveness clinical trial. methods: we performed an explanatory sequential mixed methods study from june to march to evaluate the variation in lpv adherence across icus in an integrated healthcare system with > mechanically ventilated patients annually. we analyzed key informant interviews of icu physicians, respiratory therapists (rts), and nurses in of the icus using a qualitative content analysis paradigm to investigate site variation as defined by adherence level (low, medium, high) and to identify barriers and facilitators to lpv and lpv cds tool use. results: forty-two percent of patients had an initial set tidal volume of ≤ . ml/kg pbw during the measurement period (site range – %). lpv cds tool use was % (site range – %). this study’s main findings revealed multi-factorial facilitators and barriers to use that varied by icu site adherence level. the primary facilitator was that lpv and the lpv cds tool could be used on all mechanically ventilated patients. barriers included a persistent gap between clinician attitudes regarding the use of lpv and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-rt interaction in ventilation management, and the lack of clear organization measures of success. conclusions: variation in adherence to lpv persists in icus within a healthcare delivery system that was an early adopter of lpv. potentially promising strategies to increase adherence to lpv and the lpv cds tool for ards patients include initiating low tidal ventilation on all mechanically ventilated patients, establishing and measuring adherence measures, and focused education addressing the physician-rt interaction. these strategies represent a blueprint for a future hybrid implementation-effectiveness trial. acute respiratory distress syndrome (ards) occurs when an acute lung injury (e.g., pneumonia, sepsis, trauma) causes bilateral non-cardiogenic pulmonary edema and hypoxemic respiratory failure requiring mechanical ventilation [ ] . an international study in countries found that % of patients admitted to the intensive care unit (icu) and % of mechanically ventilated patients had ards [ ] . during the novel coronavirus (covid- ) pandemic, - % of hospitalized patients and - % of patients admitted to the icu will develop ards [ ] . ards is associated with high morbidity, mortality, and healthcare cost [ , , ] . lung-protective ventilation (lpv), which combines low tidal volume ventilation (ltvv) with step-wise cotitration of positive end-expiratory pressure (peep) and the fraction of inspired oxygen (fio ), improves outcomes for patients with ards in clinical studies [ , ] and is recommended by the american thoracic society (ats) clinical practice guidelines [ , ] as well as in other recent reviews [ , ] . barriers to consistent use of lpv persist and have hindered progress toward improved ards outcomes [ ] . general agreement exists among physicians, respiratory therapists (rts), and nurses that lpv is warranted for patients with ards, although studies demonstrate a substantial divide between belief and actual practice [ ] . identified barriers to the use of lpv include physician's ability to recognize ards in a timely fashion [ , ] , lack of written protocols [ , ] , lack of concordance with clinician perceptions of patient needs [ , , ] , and perceptions by nurses and rts that ltvv is more labor-intensive and that present staffing is inadequate to achieve full adherence [ , ] . intermountain healthcare (intermountain) was involved in early ards network studies [ ] and demonstrated high adherence at one hospital site, but high system-wide adherence was not attained across all sites. we recently deployed an electronic medical record (emr)-integrated lpv clinical decision support (cds) tool to the icus in our system designed to standardize lpv practice across all sites and increase overall lpv adherence. we conducted a mixed methods study to identify barriers to utilization of lpv and the lpv cds tool in patients with ards in preparation for a pilot hybrid implementation-effectiveness trial (nct ) designed to increase adherence to lpv and the lpv cds tool in ards patients. we performed an explanatory, sequential mixed methods study (quant -> qual) from june to march to ( ) measure the variation in adherence to lpv and to the use of the lpv cds tool across icu sites and ( ) understand, through qualitative interviews, the reasons for variation and to identify implementation barriers and facilitators to lpv and lpv cds tool in routine practice for patients with ards at three of those icu sites [ , ] . the research protocol was approved by the intermountain healthcare institutional review board (irb# ). we adhered to published best practices for reporting of mixed methods studies [ , ] and qualitative research [ ] . intermountain healthcare's icus are part of an integrated, -hospital system that includes frontier hospitals, tertiary care centers, and a children's hospital. across the system, roughly adult patients are ventilated annually. approximately % of these ventilated research has shown that lung-protective ventilation (lpv) improves outcomes for patients with acute respiratory distress syndrome and is not consistently applied in intensive care settings. clinical decision support (cds) tools are being evaluated as one mechanism to standardize lpv use. while cds tools may assist in normalizing the use of lpv, we found multi-factorial barriers and facilitators to lpv and to lpv cds tool use in an organization involved in early lpv studies. these findings contribute to recognized gaps in the literature, including detailing barriers to lpv and cds tool use and describing theory-informed, tailored implementation strategies. to initiate the use of the open-loop protocols, physicians must place an electronic order for each protocol component. once ordered, the rt measures patient height and sets parameters for tidal volume, respiratory rate, fio , and peep. the protocol order does not specify the starting settings. however, if the rt does not use an ltvv setting, the protocol will give instructions to the rt to move to an ltvv setting. an arterial blood gas (abg) is obtained within h. oxygenation and ventilation protocols are then run, generating instructions for the rt to adjust or maintain fio , peep, tidal volume, and respiratory rate. the rt must accept or reject each instruction and, if instructions are rejected, provide a reason. the ventilation protocol is intended to run each time an abg result is received. the oxygenation protocol is intended to be run after abg results and also every h based on oxygen saturation measured from pulse oximetry (spo ) during each rt ventilator assessment. during initial deployment, lpv cds tool implementation strategies included didactic education, communications, audit and feedback to physicians and rts, and executive leadership emphasis on compliance. however, some icus were not achieving consistent adherence to the initial set tidal volumes ≤ . ml/kg pbw or consistent utilization of lpv cds tools in mechanically ventilated patients. we used two provisional measures to explore the variation in adherence by site. using an encounter cohort of icu-admitted adult patients (age ≥ years) receiving invasive mechanical ventilation, we calculated the percentage of patient icu encounters that were treated with an initial set tidal volume ≤ . ml/kg pbw. for the second measure, we calculated the percentage of patient icu encounters that were treated using at least one of the four protocols in the lpv cds tool during the stay. the cohort excludes patients who died on the day of admission. the cohort represents data from a restricted study time period from the improvent clinical trial (nct ). the measurement period for cohort identification began on the date the lpv cds tool was deployed at each site (ranging from april to july ) and ended on october , . the calculations were made from data queried from the intermountain emr systems. spearman's rank test was used to observe any initial correlation between the two measures. a twosample test of proportions was used to explore the differences in both measures at the aggregate level by hospital type. we developed an interview guide using a deductive, multi-method approach: a scoping review [ ] [ ] [ ] [ ] to examine the barriers and facilitators to the use of lpv and the lpv cds tool and interventions to improve adherence; a technical expert panel that included critical care physicians, hospitalists/health services researchers, icu nurse managers, emergency department (ed) physician, respiratory therapist (rt), and implementation scientist, to identify already known or suspected barriers to implementation (simultaneous triangulation) [ ] ; and categorization and summary of findings according to the consolidated framework for implementation research (cfir) [ , ] by two experienced implementation scientists (ak, rs). this approach is consistent with the efforts to develop contextual implementation frameworks for complex system interventions [ ] . cfir constructs identified as relevant through both the scoping review and by the multi-disciplinary expert panel formed the theoretical basis for the interview guide questions. common, relevant cfir domains (and related constructs) identified for both lpv and the lpv cds tool included the individual (knowledge and beliefs), intervention (relative advantage, adaptability, design quality, and packaging), and the inner setting (learning climate, compatibility, and available resources). lpv also included intervention (evidence strength and quality) and inner setting domains (tension for change, relative priority, and leadership engagement). the lpv cds tool also included individual (individual stage of change), intervention (complexity), and inner setting domains (goals and feedback). no constructs were initially identified as relevant from the external setting and implementation domains. validated interview questions related to the selected cfir constructs were then drawn from the "barriers to physician adherence to practice guidelines" model and adapted for interdisciplinary interviews to guide the assessment of knowledge, attitudes, and behaviors of sites and individual caregivers regarding lpv use [ ] . to assess the barriers and facilitators of lpv cds tool use, validated questions were adapted from the "unified theory of acceptance and use of technology" (utaut) to explain user intentions to use an information system and subsequent usage behavior [ ] . upon completion, the interview guide and questions were reviewed by the intermountain lead critical care physician (cg) and respiratory therapist (cw) for clarity and relevance. to understand the primary reasons for the variation in adherence at each site using a grounded theory approach [ , ] , key informant semi-structured interviews were conducted using the interview guide with clinicians at intermountain icus. to ensure an information-rich sample [ ] , three pilot icu sites were selected by the research team from the quantitative analysis. the team used a stratified purposeful sampling approach [ ] based upon site adherence ranking (high-medium-low), icu type (medical/surgical, respiratory, cardiac, neurologic, and thoracic), and local leadership support. local leadership support was determined through conversations between the system icu leader and local site icu leaders. given the study focus on patients with ards, site selection was limited to medical/surgical, trauma, and respiratory icu sites. a two-person team of trained, experienced qualitative researchers (ajk, dw) conducted the key informant interviews with a purposive sample of - key informants using a role-based criterion. interview participant roles included the icu physician director, critical care physicians, icu rt manager, icu rts, and icu nurses with the goal to achieve uniform participation at each site across roles, with an option to sample additional roles as needed. for roles that were not limited to a single individual at a site (intensivists, rts, and nurses), interviews continued until thematic saturation was reached (no new ideas emerged during three consecutive interviews for a particular role at a site) [ ] . each interview was min. while adherence data was available to individual sites, the investigators did not present site adherence data in the discussion. research funds were made available on the day of each site visit at all three sites to schedule additional clinical resources to ensure patient coverage. participants at each site were invited to participate on the day of the site visit by the local icu director and rt manager via email or direct conversation, subject to availability. efforts were made to identify individuals within each role that varied in terms of years of their experience and attitudes and beliefs regarding lpv and the lpv cds tool. preliminary assessments of attitudes and beliefs were based upon the local icu director or site rt manager's experience working with each clinician. the qualitative research team met frequently during each site visit to review interview data and to assess thematic saturation more generally and to identify additional interview needs by role. at the end of each site visit, emerging themes and ideas were summarized and shared with system and site clinical leaders and were used to identify follow-up interviews to address the gaps in understanding. a hybrid qualitative content analysis paradigm was applied to interview data, incorporating both directed and open-iterative methods to provide a reflexive approach to identify barriers and facilitators to high adherence to the use of lpv and the lpv cds tool [ ] . a study investigator and experienced qualitative researcher (ak) organized a preliminary codebook by interview guide question number as the unit of analysis. (the interview guide was originally organized deductively by relevant cfir construct.) two research assistants were trained by the study co-investigator on both the clinical and non-clinical aspects of the study, including specific training on the use of the preliminary codebook. the study investigator (ak) then read and conducted line-by-line coding of a preliminary sample of five interviews using the preliminary codebook, allowing for the open coding of new or emerging themes not already captured. the five transcripts were divided between the two research assistants who separately read and independently conducted line-by-line coding using a similar approach. for each coded transcript, the study co-investigator and the independent reviewers compared the results, agreeing on the name and definition of each code. this codebook was then used to assist the researchers in the analysis of the remaining interview data. the study team followed a similar process for the remaining interviews. during the coding process, the coding team met frequently to identify and agree on new or emerging concepts not captured in the current codebook and recoded prior transcripts accordingly. for each coded transcript, the arbitration for discordant coding was done through a discussion between the study coinvestigator and the assigned independent reviewer until consensus was reached. reported implementation barriers and facilitators were then summarized according to the levels of the cfir framework overall, by site and by clinical role [ ] . all coding was done in atlas.ti version . (scientific software development gmbh, berlin, germany). the provisional estimate of the initial set tidal volume ≤ . ml/kg pbw was % system-wide. icu-level adherence estimates ranged from to % (table ) . the estimated lpv cds tool utilization was %, with icu-level utilization ranging from to %. the five tertiary care hospitals accounted for % of the total icu beds and % of all mechanically ventilated patients. non-tertiary hospitals, which represent smaller urban, rural, and frontier coverage areas, had significantly higher rates on both adherence measures (p < . ) and represented % of patient encounters. higher icu-level use of the cds tool in the provisional estimates was positively correlated with the percentage of patients receiving an initial low tidal volume strategy (ρ = . , p = . ). forty-seven key informant interviews were conducted and analyzed at three icu sites with varying levels of adherence. demographic characteristics by role and by site are shown in table . saturation was reached with each role at each site. initial adherence estimates were inconsistent with comments from key informant interviews that an initial set tidal volume of ≤ . ml/kg pbw was the standard practice for patient care at all three sites and that physicians consistently ordered the lpv cds protocols for all mechanically ventilated patients. rts reported that of the four protocols, the oxygenation and ventilation protocols were the most commonly used in actual practice. based upon qualitative analysis of the nurse interviews, the principal finding was that nurse exposure to lpv management and use of the lpv cds tool was limited to coordinating with the rt on nurserelated aspects of care, such as sedation management, at all three sites. nurses consistently stated they had no visibility to barriers and facilitators to lpv and lpv cds use with limited understanding or influence regarding ventilation management activities. nurses consistently reported that ventilation management was the purview of the physician and rt. given this, the results below focus on physician and rt implementation barriers only. implementation barriers and facilitators-individual/ clinician (table ) physicians at all three sites were able to recall the key criteria for the diagnosis of ards. identification of lowto-moderate severity ards cases, shown to be a challenge in prior studies, remained so for physicians and rts in this study. since non-ards mechanically ventilated patients were similarly started with an initial tidal volume setting of ≤ . ml/kg pbw, physicians felt that the detection of ards was less important to initiate a low tidal volume strategy. once mechanical ventilation was initiated, clinicians at the low adherence site more frequently described returning to alternative ventilation and oxygenation strategies that they have used in the past versus applying lpv and lpv cds tool instructions to non-responsive patients. we're happy to try it. but if it doesn't work, we're not going sit and watch our patient languish when we have something in our back pocket that in our experience has worked fine. physician, low-adhering site what we've found is… sometimes we're playing catch-up…for us it's hard to keep at a high fio , at a high peep, for x number of days, when in the past we've had huge changes and differences as soon as we've swapped to an open lung strategy. rt, lowadhering site at the low and moderate adherence sites, uncertainty regarding the purpose and use of each of the four lpv cds tool protocols, including when it was acceptable to depart from the protocol recommendations, was experienced as impinging on clinician self-efficacy. despite the underlying variation in adherence, clinicians at all sites expressed confidence in their ability to use lpv and lpv cds tool technology and expressed the intention to use them to deliver patient care. while clinicians at the low-and moderate-adhering sites resented being told to adopt an intervention that they did not assist in selecting and developing, physicians at all sites felt that the use of the lpv cds tool provided certain advantages relative to no computerized protocol. rts at the high-adhering site felt that the use of the tool actually increased their self-efficacy when implementing an lpv strategy for ards patients. critical care physicians and rts agreed that an ltv setting was beneficial for patients with ards, but there was some i'm always trying to adapt the ventilator as much as possible to the work and breathing of the patient… and trying to stay within their protocols of six mils per kilo. but sometimes it's extremely difficult and near impossible. i worry because i see that patient retracting and fighting against the ventilator and i see more lung injury occurring. rt, low-adhering site this misperception regarding lpv appears associated at least in part with a misunderstanding regarding the role and use of peep strategies in lpv. as intervention facilitators, rts, and critical care physicians felt that the lpv cds tool was easy to use after training and that major changes in the technology were unnecessary. critical care physicians noted the benefit of being able to place a single order to facilitate patient ventilation management with change orders only required on an exception basis for significant departures from the lpv cds protocols. i really love the protocols. i worked at the univer-sity…and i can see the difference between not having protocols and having protocols. [at the university], all the vent changes had to be actively managed by the physicians…and it takes up a huge amount of time…it allows the rts to really just run the protocol. physician, high-adhering site rts at the high-adhering site felt that the lpv cds tool actually made them more responsive to their patient's needs when considering long-term patient health. the way that we do vent checks every two hours… makes a big difference. we're in the patients room more often, having eyes on the patient and seeing what's going on…and then with our experience in the protocols, i think it does help us make those decisions in a faster way to wean patients and get them off the vent. rt, high-adhering site in contrast, rts at the low and moderate adherence sites felt that the use of the lpv cds protocols slowed their response to patient needs and increased their workload. more experienced rts noted that the use of the lpv cds tool was not necessary to adhere to an initial tidal volume setting ≤ . ml/kg, which was inconsistent with the correlation observed in the quantitative data between lpv cds tool use and initial tidal volume setting. more experienced clinicians felt that following implementation barriers and facilitators-organization/ inner setting (table ) clinicians at the low-adhering site resented the perception that the use of lpv and the lpv cds tool was a system-level mandate that limited their autonomy to select ventilation and oxygenation strategies. we've never been asked. we've never been surveyed. we've never been talked to. we've been told. physician, low-adhering site the lack of agreement both within and across sites regarding lpv adherence standards was itself a barrier to adherence. clinicians felt a limited degree of accountability to achieve high adherence without a clear understanding of what constitutes high adherence. the lack of a clear definition of success impacted perceptions of the lpv cds tool, particularly for more influential, experienced rts who were familiar with earlier iterations of the tool or with the use of paper-based protocols. at low-adhering sites, some more experienced rts who had this view actively opposed both routine and consistent applications of lpv as well as utilization of the lpv cds tool. these "anti-champions" often described being historically given substantial autonomy for ventilator management and tended to feel the lpv cds tool reduced their autonomy. informant interviews suggested these clinicians' views were influential, impacting general attitudes among both rts and physicians and low and moderate adhering regarding the benefits of lpv and the lpv cds tool. limited formal training to assist protocol users, including having convenient, accessible resources to obtain answers to questions, exacerbated frustrations. while physicians did not indicate discussing the lpv cds tool frequently with their peers, physician discussions with rts and between rts were commonly reported. primary reasons for discussions centered on understanding and responding to instructions generated by the tool. under the process, the rt needs to log into the emr to conduct the ventilation assessment. once the required ventilation assessment is conducted, the data is automatically loaded into the ventilator protocol. the rt is then required to open another page and click for instructions and then read and accept or reject generated instructions. reasons for declining instructions are documented by the rt using a drop-down list. perceptions of rts from low-performing sites were that the additional steps and documentation in the workflow took too much time. this was particularly true when they had to repeatedly reject an instruction with each ventilation assessment. impact of the initial approach to lpv cds tool implementation (table ) strategies implemented during the initial rollout led to a meaningful increase in adherence rates for both lpv and the lpv cds tool but were not sufficient alone to achieve high adherence. sustainment efforts following the initial rollout at each site included ongoing executive leadership emphasis in team and organization meetings and site-level audit and feedback reporting. the initial lpv cds tool implementation involved the rollout of all four components in a phased manner by individual site following the implementation of the new emr. at the point of this study initiation, the phased rollout was complete and all cds tool protocols had been in place from to months, depending on the site. users struggled to disentangle their sentiments about the lpv cds tool itself from the impact on lpv cds tool users' experience of system downtime and network delays during the broader emr rollout. there was a system rt champion available on site during the lpv cds tool implementation and a system physician champion available by phone. the lack of an organized effort to discern from front-line clinicians what the barriers were, however, impaired the implementation team's ability to understand and address concerns. adherence data was available by site but was only available with a - -month lag, limiting transparency to site and physician-level performance. this study provides a rich understanding of implementation barriers and facilitators to the use of lpv and an lpv cds tool in icus in an integrated system that was an early innovator in the use of lpv strategies, but has yet to achieve consistent high system adherence. this study's main findings revealed multi-factorial facilitators and barriers to use that varied by icu site adherence level. the primary facilitator was that lpv and the lpv cds tool could be used on all mechanically ventilated patients. barriers included a persistent gap between clinician attitudes regarding the use of lpv and actual use, the perceived loss of autonomy associated with using a computerized protocol, the nature of physician-rt interaction in ventilation management, and the lack of clear organization measures of success. while clinicians consistently agreed that a set tidal volume ≤ . ml/kg pbw was optimal for patient care, we found more variation than expected when clinicians were asked to define ltvv and the appropriateness of ventilator modes other than volume control-our system standard-for the delivery of low tidal volumes. consistent with prior studies [ , ] , clinician's failure to recognize less-severe ards cases likely impedes lpv implementation. however, clinicians did not differentiate ards and non-ards patients when ordering the protocols or initiating an initial set tidal volume ≤ . ml/kg pbw but applied the standard to all mechanically ventilated patients. the fact that clinical teams are not required to differentiate ards patients when making decisions to utilize the lpv cds tool or to initiate an initial low tidal volume setting is an important finding that simplifies implementation. this becomes important in situations, such as the covid- pandemic, where icus are experiencing high rates of ards and are likely to benefit from consistent use of lpv [ ] . consistent with earlier studies [ ] , physician and rt statements that lpv strategies were most appropriate for patients with ards and indicated that they were consistently ordered and that an initial ltvv was used were not consistent with the provisional adherence data. this attitude-behavior gap [ ] between intent and actual practice is consistent with earlier studies demonstrating that clinician beliefs and perceived barriers to using lpv were not correlated with lpv initiation [ , ] . several factors may begin to explain this gap. efforts to promote adherence continued between the time when we generated provisional measurement data and when field interviews were conducted. these findings also suggest that non-attitudinal barriers such as perceptions of control; structural elements, such as workflows; and normative influences, including perceptions by the care team regarding patient impact [ ] , may continue to limit the use of lpv. these findings should be addressed in the development of implementation strategies [ ] . the perceived loss of autonomy associated with following the lpv cds protocol tools was difficult for more experienced rts at low-performing sites. under earlier paper-based systems, more experienced rts may have felt empowered to function without physician orders in certain circumstances. under relationship models theory, the traditional interaction between the physician and rt is based upon an authority ranking dyad relationship, asymmetrically ranked in a linear hierarchy with the critical care physician as the authority [ , ] . at the low-performing sites, the traditional interaction was supplanted over time by an informal, negotiated market pricing relationship between the physician and rt. the critical care physician sought to optimize time in exchange for empowering more seasoned rts to act in the patient's interest as the rt saw fit, without always obtaining a physician's order. the development of this informal, mutually protective dyad made it difficult to isolate and address the actual root causes of low adherence. given that positive ventilation management outcomes are associated with the successful interaction of the physician and the rt, implementation strategies that target joint determinants should be considered. for example, using encounter-level data to identify on an exception basis those dyads that have higher nonadherence rates and conducting simulation training with each dyad to ensure that the required interaction is reasonably scripted and understood. the lack of a definition for successful adherence to lpv and use of the lpv cds tool was perceived as a key barrier at low-adhering sites. relevant and timely information about performance on intermediate outcomes provides transparency at both the team level and with accountable system leadership and improves performance [ ] . given the low-volume, high-complexity nature of patient care in the icu [ ] , detailed encounterlevel data enables local teams to review performance on individual cases and diagnose implementation barriers and facilitators in real-life settings [ ] . the lack of a definition of success also impacted perceptions of the lpv cds tool. teams focused on achieving a high adherence to a low initial tidal volume did not see the lpv cds tool as useful in achieving this goal. however, higher-adhering sites described a broader view of the lpv cds tool use benefits that was embedded in the way they do things, introducing a shared language for treating ards and driving their teams toward standardization in practice. this study had certain limitations by design. the study does not establish a clear causal relationship between specific implementation barriers and facilitators and adherence. adherence data available to inform site selection was initially limited to two provisional measures of performance and included all mechanically ventilated patients undifferentiated on ards status. inclusion of all mechanically ventilated patients was likely not a significant weakness, however, as clinicians at all three sites indicated that ordering the protocols and use of an initial low tidal volume setting was the routine goal for all mechanically ventilated patients. given that lpv and the lpv cds tool protocols are used on all mechanically ventilated patients, some comments regarding barriers and facilitators to use may have been referencing all mechanically ventilated patients and not ards patients alone. we were not able to interview all individuals in each role at the three selected sites given practical considerations but relied upon local site leadership to identify people for the team to meet with on the day of the site visit. efforts were made to identify individuals within each role that varied in terms of years of experience and attitudes and beliefs regarding lpv and the lpv cds tool. evidence of saturation at each site mitigated the risk that important perspectives were not captured. further, the field interview team reviewed the site interview list at the beginning of each site visit and debriefed throughout the day to determine if additional individuals should be added. the use of researchers employed by the delivery system may have impacted the results, highlighting potential strengths and challenges of conducting embedded research linked to healthcare improvement [ ] [ ] [ ] . while clear communication regarding the purpose of the interviews was included in the consent process and clinicians appeared forthright, we cannot rule out the possibility that interview participants' comments were influenced by the investigator's institutional alignment. the investigators' individual biases, including the employment relationship, may also impact results. variation in adherence to lpv persists in icus that were early adopters of lpv. multi-factorial strategies usa. population health sciences ut , usa. complex care, division of general pediatrics, boston children's hospital intermountain healthcare, south state street rd floor acute respiratory distress syndrome: the berlin definition epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries interim clinical guidelines for management of patients with confirmed coronovirus disease (covid- recovery and outcomes after the acute respiratory distress syndrome (ards) in patients and their family caregivers ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome. a prospective cohort study liberation from mechanical ventilation in critically ill adults. an official ats/ accp clinical practice guideline summary for clinicians: mechanical ventilation in adult patients with acute respiratory distress syndrome clinical practice guideline acute respiratory distress syndrome ventilator-induced lung injury a critical care clinician survey comparing attitudes and perceived barriers to low tidal volume ventilation with actual practice barriers to providing lung-protective ventilation to patients with acute lung injury underuse of lung protective ventilation: analysis of potential factors to explain physician behavior barriers to low tidal volume ventilation in acute respiratory distress syndrome: survey development, validation, and results patient and intensive care unit organizational factors associated with low tidal volume ventilation in acute lung injury mixed method designs in implementation research research design: qualitative, quantitative and mixed methods approaches the quality of mixed methods studies in health services research standards for reporting qualitative research: a synthesis of recommendations driving pressure is not associated with mortality in mechanically ventilated patients without ards scoping studies: towards a methodological framework scoping studies: advancing the methodology guidance for conducting systematic scoping reviews systematic review or scoping review? guidance for authors when choosing between a systematic or scoping review approach approaches to qualitative-quantitative methodological triangulation fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science a systematic review of the use of the consolidated framework for implementation research contextual frameworks for research on the implementation of complex system interventions. rockville: agency for healthcare and research quality why don't physicians follow clinical practice guidelines? a framework for improvement technology acceptance models in health informatics: tam and utaut. stud health technol inform constructing grounded theory qualitative research and evaluation methods purposeful sampling for qualitative data collection and analysis in mixed method implementation research what is an adequate sample size? operationalising data saturation for theory-based interview studies three approaches to qualitative content analysis surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ). read online: critical care medicine | society of critical care medicine diffusion of innovations the theory of planned behavior the four elementary forms of sociality: framework for a unified theory of social relations a generic model of dyadic social relationships use of process measures to monitor the quality of clinical practice implementing evidence-based clinical practice in the critical care setting the case study approach applied research and development in health care -time for a frameshift the future of health services research: advancing health systems research and practice in the united states the time has come: embedded implementation research for health care improvement the authors would like to acknowledge the physicians, respiratory therapists, and nurses of intermountain healthcare who contributed time and effort to this research, as well as to their tireless efforts to "help our patients live the healthiest lives possible." we also want to acknowledge other participants including dr. kimberly a. brunisholz, phd, mst, who participated in the initial site interviews, as well as brian garate reyes, a research assistant, who supported the coding of qualitative data. that address the distinctive implementation barriers and facilitators of the icu environment at the individual, team, and unit level appear necessary to achieve high adherence. as part of an implementation plan, organizations should consider initiating low tidal volume ventilation on all mechanically ventilated patients, identifying and agreeing upon standard adherence measures and designing education strategies that address physician-rt interaction during the care process. these strategies represent a blueprint for a future hybrid implementation-effectiveness trial. supplementary information accompanies this paper at https://doi.org/ . /s - - -x.additional file . authors' contributions ak, jb, ip, cg, and rs made substantial contributions to the development of the mixed methods study design. ak, dw, la, jj, lc, cw, ip, cg, and rs made substantial contributions to the acquisition, analysis, and/or interpretation of the study data. ak, jk, ip, cg, and rs were the major contributors in writing the manuscript. all authors read and approved the final manuscript. editorial services were not used in the development of this manuscript. not applicable. this study was funded under a u- grant from the national heart, lung, and blood institute (nhlbi) of the national institutes of health (nih) [u hl ]. dr. peltan received additional support from the national institute of general medical sciences (k gm ). dr. knighton received additional support from the national center for advancing translational sciences of the national institutes of health (kl tr ). the funding bodies were not involved in the study and collection, analysis or interpretation of the data, in writing the manuscript. all provisional quantitative data generated or analyzed during this study is included as aggregated in the published article in table . the majority of qualitative data for this study is made available in the publication tables. however, the detailed interview dataset generated and analyzed during the current study is not publicly available due to individual privacy concerns. the study was approved by the intermountain healthcare institutes review board, reference number irb# . all human subjects provided consent to participate in this study and to have their de-identified interview results disseminated for research purposes. all interview participants consented to have their de-identified interview results disseminated for research purposes, including publication. key: cord- -n cppi authors: d’alonzo, daniele; de fenza, maria; pavone, vincenzo title: covid- and pneumonia: a role for the upa/upar system date: - - journal: drug discov today doi: . /j.drudis. . . sha: doc_id: cord_uid: n cppi here, we highlight recent findings on the urokinase plasminogen activator (upa)/upa receptor (upar) system that suggest its potential role as a main orchestrator of fatal progression to pulmonary, kidney, and heart failure in patients with coronavirus. patients with prolonged background inflammation can present with aberrant inflammatory reactions, well recognized as the main factors that can result in death and probably sustained by a dysregulated upa/upar system. supar, the soluble form of upar, represents a biomarker of disease progression, and its levels correlate well with comorbidities associated with the death of patients with coronavirus. new drugs that regulate the upa/upar system could help treat the severe complications of highly pathogenic human coronaviruses (hcovs), including pandemic coronavirus (covid- ). pandemic covid- is of significant concern for the extended mortality, and impactful social and economic consequences worldwide. hcovs include either low pathogenic strains that usually infect the upper respiratory tract. resulting in a mild, cold-like respiratory illness, or highly pathogenic strains, responsible for severe acute respiratory syndrome covs (sars-cov- , and sars-cov- , or covid- ) and middle east respiratory syndrome cov (mers-cov), which mainly infect lower airways and can cause fatal progression [ ] [ ] [ ] . sars-cov- is transmitted primarily through airways; on infection, the incubation period is ~ - days before symptom onset. when admitted to hospital, patients with covid- typically exhibit fever and dry cough; less commonly, they show difficulty in breathing, muscle and/or joint pain, headache/dizziness, diarrhea, nausea, and the coughing up of blood. severe covid- cases progress to acute respiratory distress syndrome (ards), on average around - days after symptom onset [ ] . currently, no definitive cure for sars-covs and mers-cov infections is available. beside the use of antivirals, symptomatic and supportive treatment is a standard of care for patients with hcov. the most commonly prescribed antiviral regimens in clinical settings are ribavirin, interferons and lopinavir, ritonavir, oseltamivir, chloroquine sulfate or hydroxy chloroquine sulfate [ , ] . a variety of other agents, including antiviral peptides, monoclonal antibodies, cell or viral protease inhibitors, have shown some effectiveness in in vitro and/or in vivo models [ ] . clinical trials of these other agents are awaited. mycophenolic acid (mpa) is another potential therapeutic choice [ ] . frequently used as an immunosuppressive drug to prevent rejection in organ transplantation by inhibiting lymphocyte proliferation, mpa also prevents replication of viral rna. however, mpa toxicity appears to exceed its potential benefits. corticosteroids were extensively used during the sars outbreak, generally in combination with ribavirin [ ] . however, the use of corticosteroids in the treatment of hcov-related diseases remains debated [ ] , and alternative anti-inflammatory drugs would be particularly useful, especially when ards occurs. inhibitors targeting coronaviruses were recently reviewed elsewhere [ ] . in this context, studies aiming to explore new approaches for both the early detection and treatment of coronavirus infections can have a significant impact in the fight against the disease. here, we highlight evidence that supports the potential role of upa, its receptor upar, and the associated coreceptors (overall, the upa/upar system) in the pathogenesis of hcov-associated pneumonia and ards. the upa/upar system might represent a new target for therapeutic interventions of the severe complications of hcov infections, and the study of this system might provide an efficient biomarker of disease progression. the pathological and clinical course of the most severe lung injuries induced by hcovs can be divided into three distinct phases. the early phase is characterized by robust virus replication associated with fever, cough, myalgia, and other systemic symptoms that generally improve in a few days. in the second phase, despite a progressive decline in virus titers, recurrence of fever, hypoxemia, and progression to pneumonia-like symptoms occur. during the late phase, ~ % of patients evolve to acute lung injury (ali) and ards, which often results in death [ ] . given the progressive decline in virus titers, the late phase is thought to result from an overexuberant host inflammatory response [ ] . comorbidities are also important factors in the disease progression: chronic obstructive pulmonary disease (copd), diabetes, hypertension, and malignancy were reported as main risk factors for reaching the composite endpoints in the chinese population during pandemic covid- [ ] . similarly, hypertension, obesity, and diabetes were found to be the most common comorbidities for patients with covid- in the new york city area [ ] . all these comorbidities are sustained by a background prolonged inflammation. rapidly replicating pathogenic hcovs can induce pneumonia with a mechanism that involves a massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine production, which in turn can cause ali and ards [ ] . ards is a severe progressive form of lung injury occurring in patients who are critically ill, causing substantial morbidity and mortality [ ] . it is characterized by diffuse alveolar injury, alveolar capillary leakage, neutrophil-derived inflammation, pulmonary edema formation, and surfactant dysfunction [ ] . clinical manifestations of ards include reduced lung compliance, bilateral pulmonary infiltrates, and severe hypoxemia [ ] . despite the latest advances in therapeutic intervention, ards represents a major cause of death in patients with sars-covs or mers-cov worldwide [ , ] . in highly pathogenic hcov infections, an exuberant inflammatory response correlates with the accumulation of inflammatory monocyte-macrophages, lymphocytes, and neutrophils into the alveolar wall and lumina of lungs, triggering an elevation of cytokine/chemokine levels, vascular leakage and impaired t cell activation [ , , ] . among the inflammatory mediators, tumor necrosis factor (tnf)-α, interleukins il- β, il- , il- , il- , granulocyte macrophage-colony stimulating factor (gm-csf), intercellular adhesion molecule (icam)- , substance p, chemokines, vascular endothelial growth factor (vegf), insulin-like growth factor (igf), keratinocyte growth factor (kgf), reactive oxygen species (ros), and reactive nitrogen species (rns) have been shown to have crucial roles in the pathogenesis of ards [ ] . beside immune cell infiltration and 'inflammatory storm', the pathophysiology of ards includes additional molecular mechanisms that lead to apoptosis of alveolar epithelial and capillary endothelial cells, and the development of fibrosis [ , ] . apoptosis of epithelial and endothelial cells compromises the lung microvasculature and alveolar-epithelial cell barrier, causing vascular leakage and alveolar edema associated with tight junction (tj) loss [ ] , ultimately resulting in hypoxemia [ ] . by contrast, the accumulation of macrophages, fibroblasts, and myofibroblasts can lead to an abnormal deposition of collagen i and iii, fibronectin, and other components of the extracellular matrix (ecm) in the alveolar compartment, thus altering the balance between profibrotic and antifibrotic mediators, and leading to a fibroproliferative response [ , ] . evidence demonstrated that dysregulated angiogenic responses mediated by cytokines and growth factors, such as macrophage inflammatory protein- , angiopoietin- and vegf, may contribute to vascular lesions in ards and drive the fibroproliferative response [ , ] . furthermore, in ards lung, damage to vascular endothelial cells promotes coagulation by activating platelets and procoagulant cascades, while reducing anticoagulant pathway and fibrinolysis, finally leading to the formation of microthrombi in the lung vasculature, and the deposition of fibrin in intra-alveolar and interstitial compartment. the procoagulant activity is promoted by inflammatory mediators during the early stages of ards. water channel aquaporins also have an important role in ards, facilitating water permeability between the alveolar compartment and vasculature. up-or downregulation of various aquaporins have been investigated in induced ards animal models [ ] . the physiological and pathological role of the upa/upar system upar (cd ) is a receptor comprising three domains (d-i, d-ii and d-iii) anchored by glycosylphosphatidylinositol (gpi) to the surface of various cell types, including immune cells, especially neutrophils, monocytes, and macrophages [ ] . upar binds upa, and transforms plasminogen into plasmin, which in turn initiates a series of proteolytic cascades to degrade the components of the ecm. this process traces the path of immune cell migration towards a chemotactic gradient. migrating cells undergo profound cytoskeletal rearrangements required for cell movement. leading-edge detachment, cytoskeletal rearrangement, and attachment occur cyclically during cell migration. upar orchestrates this function. upon upa binding, upar changes its conformation and exposes the chemotactic sequence ser -tyr . given its lack of a transmembrane domain, gpi-anchored upar has high mobility on the cell surface and can interact with later partners with the ability to communicate with the internal cell compartment to produce downstream intracellular signaling mediated by effector molecules, such as the focal adhesion kinase, src, and akt. upar binds vitronectin, and multiple cell receptors, such as different types of transmembrane receptor [the formyl peptide receptors (fprs), integrins, and vegfr [ ] ], establishing crosstalk between membrane-bound upar and its co-receptors. fprs are a family of three human receptors (fpr , fpr , and fpr ). fpr was first identified to bind bacterial formyl-methionyl-leucyl-phenylalanine (fmlf). fprs are essential for host defense against the invasion of pathogens, malignancies, and expansion of traumas, whereas abnormal expression of fpr function can be harmful [ ] . fprs are also subject to homologous and heterologous desensitization (of other chemoattractant g-proteincoupled receptors): excessive activation of the receptor by a ligand causes the unresponsiveness of the receptors to subsequent stimulation by the same or other ligands. therefore desensitization of immune-competent cells could be detrimental for host defense [ ] . human mitochondrial formylated peptides derived from cell death activate fpr signaling, and are recognized as key drivers of ali/ards [ ] . fpr inhibitors (such as cyclosporin h) preserve normal neutrophil bacterial phagocytosis or superoxide production in response to infections. therefore, mitigating fpr homologous and heterologous desensitization can protect the host from systemic sterile inflammation and secondary infection following tissue injury or primary infection [ ] . crosstalk between membrane-bound upar and fpr [ ] is particularly important, and a dysregulated upa/upar system has profound effects on cell response to exogenous stimuli. upar interacts functionally with fpr through the ser -tyr sequence located at the hinge connecting the d-i and d-ii domains. physiological proteolysis of upar generates cell-surface truncated forms lacking the n-terminal d-i. cleaved upar does not bind upa and vitronectin, and does not co-immunoprecipitate with integrins, but it still contains and exposes the chemotactic ser -tyr sequence, resulting in the retention of its ability to functionally interact with fprs [ ] soluble upar peptides, bearing the ser -tyr sequence, are also ligands for fprs and induce migration of various cell types [ ] . ser -tyr -dependent signaling is supported by crosstalk between the high-affinity fprs and the αv chain of integrins [ ] . supar is obtained upon cleavage of the gpi anchor. this form regulates the activity of inflammatory chemokine receptors, such as mcp- and rantes receptors, through fpr activation [ ] . the activity of the upa/upar system is mainly modulated by the plasminogen activator-inhibitor (pai- ), which belongs to the serine protease inhibitors (serpin) family. interaction of pai- with upa diminishes the binding affinity of the latter to vitronectin [ ] . furthermore, pai- induces the internalization and degradation of upar-bound upa through the cooperation of low-density lipoprotein receptor (ldlr)-like proteins [ ] . given its role in preventing plasmin formation, pai- acts as the main inhibitor of fibrinolysis. not unexpected, significantly high pai- levels have been detected in patients with sars-cov who have developed ards, because they are associated with a severe hypofibrinolytic state [ ] . the upa/upar system is reported to be dysregulated in several pathologies: cancer, pulmonary fibrosis, kidney disease, coronary artery disease, rheumatoid arthritis, systemic sclerosis, bone destructive disease, lupus erythematosus, alzheimer's disease, psoriasis, and endometriosis (see refs in [ ] ). these pathologies well match the comorbidities of covid- . during the late-phase clinical course of highly pathogenic hcov, comorbidities are important factors in the development of disease complications that often result in death. only in few cases have no comorbidities been reported. the most common comorbidities reported for covid- are copd, diabetes, hypertension, and malignancies, all characterized by a background prolonged inflammation. an upregulated upa/upar system is related to: (i) elevated levels of proinflammatory cytokines/chemokines; ii) epithelial and endothelial cell proliferation and impaired tissue remodeling; (iii) epithelial and endothelial cell apoptosis; (iv) loss of adequate tj-mediated cellcell contact; (v) aquaporins dysregulation; (vi) vegf-dependent compromised microvasculature; and (vii) hypoxia. upar interacts with cell membrane receptors, such as integrins, fprs, and vegfr . fpr is at the forefront in terms of recognizing formyl-peptides released both from bacteria and death host cell digested proteins. a war against the cause of tissue damage begins. fpr immediately communicates with upar, and a multitude of functions to defeat the invader and to repair the injured tissues under attack begin. beside the proteolytic function of upar on upa, essential for tissue remodeling and immune cell migration/activation, corresponding to a recall of reinforcements from the rear, upar back communicates to the cells that the counterattack was launched, to equilibrate proinflammatory/anti-inflammatory signals, avoiding damage from friendly fire, and to upregulate repair functions. in many cases, the repair process completely recovers tissue and organ function. in some cases, the back communication fails, and proinflammatory signals prevail, causing an aberrant immune response. upar is well recognized as the main orchestrator of monocyte-macrophage and neutrophil accumulation in injured tissue. an excessive concentration of signal molecules can desensitize fprs, and communication with upar might be j o u r n a l p r e -p r o o f interrupted. whether this desensitization causes a robust virus titer and expansion remains to be proven. however, fprs antagonists might abrogate desensitization. supar is present in the serum, but it can also be found in the cerebrospinal fluid, urine, saliva, or pleural, peritoneal, and pericardial fluids [ ] . to date, most research has focused on supar levels in the serum. supar levels can easily be determined [ ] , at a relatively low cost, by the use of a commercially available elisa or by turbidimetric immunoassays [ ] . in addition, supar levels are stable in stored plasma and serum samples, and their quantification is reproducible in samples that have been stored for > years at - °c despite exposure to multiple freeze-thaw cycles [ ] . supar has been proposed as a biomarker of immune system activation, and its use is being revised in a variety of diseases, as summarized in table [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . quantification of supar levels has also been proposed for the assessment of severity in several pathologies, including pneumococcal pneumonia [ ] , children with pneumonia [ ] , and idiopathic pulmonary fibrosis (ipf) [ ] . it also predicts the elevated risk of ards in patients with sepsis and is positively associated with inflammation and mortality [ ] . importantly, supar reflects the level of the immune system activation, regardless of its etiology (viral, bacterial, parasitic, or other). figure compares the supar levels in healthy controls and patients and enables the defining of a cut-off limit of ng/ml of supar to alert for the prognosis of severe complications. supar levels during hcov infections have been very recently determined for the first time, revealing even in this case, an activation of the immune system [ ] . evaluation of supar levels in stored samples of sars-cov- and mers-cov could widen the statistical analysis. however, this preliminary study confirms the need to determine the supar levels in serum of patients with hcov to provide important indications for required early admission and treatment in icu. there is a growing number of drugs under development acting as: (i) broad-spectrum antiviral agents; (ii) viral enzyme inhibitors; (iii) interferons; (iv) immunomodulators; (v) corticosteroids; and (vi) vaccines. immunomodulators involving the upa/upar system have been described, and a selection is reported in table [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, therapies capable of restoring to normality a dysregulated upa/upar system are not yet available, although they could be particularly beneficial in reducing icu admission, and in ards therapy. several peptide-based compounds have been found to interfere with a dysregulated upa/upar system in in vivo models of several pathologies of different etiology. some of these compounds have been designed from the chemotactic ser -tyr sequence of upar, based on the finding that even subtle modifications of this sequence can significantly alter upar-mediated recognition processes [ ] . peptides, including pyroglu-arg-glu-arg-tyr-nh (perery-nh ) [ ] , ac-arg-glu-arg-phe-nh (rerf) [ ] , ac-arg-aib-arg-α(me)phe-nh (uparant) [ ] , cyclic head-to-tail ser-arg-ser-arg-tyr (c[srsry]) [ ] , ac-d-tyr-d-arg-aib-d-arg-nh (ri- ) [ ] , and ser-arg-ser(p)-arg-tyr-nh (srs(p)ry) [ ] , were demonstrated to share the same binding site with upar - , thus competing with the latter for binding to transmembrane receptors. as one of the most illustrative examples, uparant (cenupatide) interferes, independently from upa activation, with fprs and integrins, preventing agonist-dependent fpr internalization in endothelial cells, even at nm concentrations. while originally proposed as an antimetastatic agent, uparant was then explored as anti-inflammatory drug and to treat diabetes complications and ocular pathologies [ ] . in cd- mice and wistar rats, intraperitoneal administration of uparant at - mg/kg reduced inducible nitric oxide synthase (inos), cyclo-oxygenase (cox ), and nitric oxide (no) overproduction subsequent to carrageenan-induced paw edema, and zymosan-induced peritonitis [ ] . in genetically modified fatty rats (torii rats) [ ] , subcutaneous administration of uparant at mg/kg (three times a week) prevented the onset of diabetes retinal complications by reducing vascular leakage into the eye. uparant administration prevented the dysregulation of blood-retinal barrier markers (brb), downregulating the levels of transcripts and proteins of brb markers, including the transmembrane components of the interendothelial tjs, claudin- , claudin- , and zonula occludens- . in streptozotocin-induced diabetic nephropathy in sprague-dawley rats [ ] , subcutaneous administration of uparant at mg/kg for days restored vascular permeability integrity, and increased aquaporin- expression in the medulla. in animal model of retinitis pigmentosa [ ] , mg/kg via subcutaneous injection of uparant at postnatal day and continued daily until postnatal day significantly reduced the bax:bcl ratio and active caspase- levels, limiting apoptosis, but autophagy. drugs targeting the dysregulated upa/upar system might represent candidates for the treatment of severe lung injury resulting from hcov infections or of other different etiology. it was demonstrated that uparant is a strong anti-inflammatory drug in animal models, acting with a mechanism different from corticosteroids and nonsteroidal anti-inflammatory drugs [ ] . uparant has the following characteristics that well match with counteracting the pathological signs of ards: (i) reduces inflammatory cell infiltration; (ii) reduces proinflammatory cytokines/chemokines; (iii) abrogates vascular leakage; (iv) significantly reduces edema; (v) inhibits monocyte-macrophage and neutrophil accumulation; (vi) reduces endothelial cell apoptosis; (vii) restores blood barrier integrity, limiting fluid extravasation; (viii) ameliorates hypoxia-induced reaction cascade; and (ix) blocks impaired tissue remodeling. the evidences that mortality in covid- is related to the presence of various comorbidities brought us to investigate the possibility of identifying a key biological process related to these comorbidities. first, literature data suggested that supar levels in serum of patients with different pathologies are elevated (> ng/ml), with good statistical significance, when compared with healthy controls. among these pathologies, there are many corresponding to comorbidities of patients with hcov. therefore, with this review, we are inviting clinical biochemists to study supar levels in patients with hcov. second, we observed from literature data that elevated supar levels in serum are also representative of background prolonged inflammation. in turn, elevated supar levels and prolonged background inflammation mirror a dysregulated upa/upar system. therefore, we propose the upa/upar system as a therapeutic target to reduce mortality of covid- . finally, we highlight the upa/upar system as potential target that has been validated in animal models by the use of uparant. uparant is classified as an anti-inflammatory molecule, acting with a mechanism different from corticosteroid and nonsteroidal anti-inflammatory drugs. uparant has been shown to be effective in various disease models independently from their etiology. however, clinical evidence is awaited. table in the main text. hypothetical model of urokinase plasminogen activator (upa)/upa receptor (upar) system function. upon binding to upar, upa catalyzes the conversion of plasminogen into plasmin, a serine protease involved in extracellular matrix (ecm) degradation and cell motility. plasminogen activator-inhibitor (pai- ) is a negative regulator of the plasminergic system [ ] . upon upa binding to upar, a conformational transition occurs, and the upar - sequence is exposed and can participate in binding with lateral co-receptors. in addition, chymotrypsin and cathepsin g hydrolyze upar at the d-i:d-ii linker region, giving rise to a truncated d-ii d-iii gpi-anchored upar and to the peptide fragment s rsry . furthermore, upar can be detached from the gpi anchor, leading to the full or truncated soluble (su)par form. beside its upstream role in fibrinolysis, upar lacking an intracellular domain forms supramolecular complexes by interacting with transmembrane receptors: formyl peptide receptors (fprs), integrins (mainly, αvβ integrin), and vascular endothelial growth factor receptor (vegfr- ). fpr can also be activated by the peptide fragment s rsry , and formylated mitochondrial or bacterial peptides. vegfr- can also be activated by vegf-a. the activation of these co-receptors subsequently produces intracellular signaling that ends with the synthesis of proangiogenesis and proinflammatory mediators. the upa/upar system is also represented on the cell surface [ , , ] . uparant binds with very high affinity to fpr and with lower affinity to αvβ integrin, and antagonizes upar co-receptor activation, affecting the plasminergic system and fibrinolysis. abbreviations: creb, camp response element-binding protein; fak, focal adhesion kinase; hif- , hypoxia inducible factor ; nf-b, nuclear factor kappa-light-chain-enhancer of activated b cells; src, proto-oncogene tyrosine-protein kinase; stat- , signal transducer and activator of transcription . j o u r n a l p r e -p r o o f -( -hexyl- -methyl- -( -methyl- h-benzimidazol- -yl)- -oxo- h-chromen- -yl acetate) [ ] -aroyl- -hydroxy- -phenyl- h-pyrrol- ( h)-ones fpr [ ] bvt fpr [ ] epidemic and emerging coronaviruses (severe acute respiratory syndrome and middle east respiratory syndrome) sars and other coronaviruses as causes of pneumonia pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology the trinity of covid- : immunity, inflammation and intervention coronaviruses -drug discovery and therapeutic options clinical evidence does not support corticosteroid treatment for -ncov lung injury recent discovery and development of inhibitors targeting coronaviruses clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study comorbidity and its impact on patients with covid- in china: a nationwide analysis presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area past and present ards mortality rates: a systematic review biomarkers in acute lung injury cellular immune responses to severe acute respiratory syndrome coronavirus (sars-cov) infection in senescent balb/c mice: cd + t cells are important in control of sars-cov infection molecular pathology of emerging coronavirus infections role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome the role of apoptosis in the pathophysiology of acute respiratory distress syndrome (ards): an up-to-date cell-specific review the fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance new insights into the mechanisms of pulmonary edema in acute lung injury elevated plasmin(ogen) as a common risk factor for covid- susceptibility anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice specialized pro-resolving mediators regulate alveolar fluid clearance during acute respiratory distress syndrome regulation of cell signaling by upar the interaction of upar with vegfr promotes vegf-induced angiogenesis the contribution of chemoattractant gpcrs, formylpeptide receptors, to inflammation and cancer the cross-talk between the urokinase receptor and fmlp receptors regulates the activity of the cxcr chemokine receptor novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor signalling in acute respiratory distress syndrome chemotactic ligands that activate g-protein-coupled formyl peptide receptors the urokinase receptor takes control of cell migration by recruiting integrins and fpr on the cell surface cross-talk between fmlp and vitronectin receptors triggered by urokinase receptor-derived srsry peptide the soluble d d ( - ) fragment of the urokinase receptor inhibits monocyte chemotaxis and integrin dependent cell adhesion the serpin pai- inhibits cell migration by blocking integrin alphavbeta binding to vitronectin upar: a versatile signalling orchestrator fibrinolytic abnormalities in acute respiratory distress syndrome (ards) and versatility of thrombolytic drugs to treat covid- the upar system as a potential therapeutic target in the diseased eye complexes between urokinase-type plasminogen activator and its receptor in blood as determined by enzyme-linked immunosorbent assay enzyme-linked immunoabsorbent assay detection of a soluble form of urokinase plasminogen activator receptor in vivo hvidovre hospital. methods of selecting and treating subjects with low-grade inflammation and metabolic disorders soluble urokinase plasminogen activator receptor measurements: influence of sample handling urokinase plasminogen activator receptor and its soluble form in common biopsy-proven kidney diseases and in staging of diabetic nephropathy soluble urokinase plasminogen activator receptor associates with higher risk, advanced disease severity as well as inflammation, and might serve as a prognostic biomarker of severe acute pancreatitis the biomarkers supar and blood eosinophils are associated with hospital readmissions and mortality in asthma -a retrospective cohort study soluble urokinase plasminogen activator receptor (supar) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus kinetics of the soluble urokinase plasminogen activator receptor (supar) in cirrhosis neutrophils are a main source of circulating supar predicting outcome in critical illness circulating biomarkers for long-term cardiovascular risk stratification in apparently healthy individuals from the monica cohort soluble urokinase plasminogen activator receptor for the prediction of ventilator-associated pneumonia plasma soluble urokinase-type plasminogen activator receptor level as a predictor of the severity of community-acquired pneumonia soluble urokinase-type plasminogen activator receptor is a novel biomarker predicting acute exacerbation in copd soluble urokinase receptor (supar) predicts microalbuminuria in patients at risk for type diabetes mellitus. sci rep soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type diabetes plasma supar is lowered by smoking cessation: a randomized controlled study serum levels of soluble urokinase plasminogen activator receptor in infants with late-onset sepsis diagnostic accuracy of soluble urokinase plasminogen activator receptor (supar) for prediction of bacteremia in patients with systemic inflammatory response syndrome high pneumococcal dna load, procalcitonin and supar levels correlate to severe disease development in patients with pneumococcal pneumonia the role of the soluble urokinase plasminogen activator (supar) in children with pneumonia radiation induced apoptosis and pulmonary fibrosis: curcumin an effective intervention? serum plasminogen activator urokinase receptor predicts elevated risk of acute respiratory distress syndrome in patients with sepsis and is positively associated with disease severity, inflammation and mortality soluble urokinase plasminogen activator receptor (supar) as an early predictor of severe respiratory failure in patients with covid- pneumonia the formyl peptide receptors: diversity of ligands and mechanism for recognition d-peptide analogues of boc-phe-leu-phe-leu-phe-cooh induce neovascularization via endothelial n-formyl peptide receptor are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury? an urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis uparant: a urokinase receptor-derived peptide inhibitor of vegf-driven angiogenesis with enhanced stability and in vitro and in vivo potency cyclization of the urokinase receptor-derived ser-arg-ser-arg-tyr peptide generates a potent inhibitor of trans-endothelial migration of monocytes retro-inverso urokinase receptor antagonists for the treatment of metastatic sarcomas urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type -triggered cell migration formyl peptide receptors at the interface of inflammation, angiogenesis and tumor growth antagonism of human formyl peptide receptor (fpr ) by chromones and related isoflavones -aroyl- -hydroxy- -phenyl- h-pyrrol- ( h)-ones as n-formyl peptide receptor (fpr ) antagonists a non-peptide receptor inhibitor with selectivity for one of the neutrophil formyl peptide receptors, fpr single amino acid substitutions in the chemotactic sequence of urokinase receptor modulate cell migration and invasion preclinical evaluation of the urokinase receptor-derived peptide uparant as an anti-inflammatory drug diabetic retinopathy in the spontaneously diabetic torii rat: pathogenetic mechanisms and preventive efficacy of inhibiting the urokinase-type plasminogen activator receptor system inhibiting the urokinase-type plasminogen activator receptor system recovers stz-induced diabetic nephropathy the urokinase-type plasminogen activator system as drug target in retinitis pigmentosa: new pre-clinical evidence in the rd mouse model the fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis molecular mechanisms mediating antiangiogenic action of the urokinase receptor-derived peptide uparant in human retinal endothelial cells financial support from campania region, scientific research department, por-fesr − , grant b c (or ) to v.p. is kindly acknowledged for the study on uparant. key: cord- -hhswage authors: meng, lingzhong; qiu, haibo; wan, li; ai, yuhang; xue, zhanggang; guo, qulian; deshpande, ranjit; zhang, lina; meng, jie; tong, chuanyao; liu, hong; xiong, lize title: intubation and ventilation amid the covid- outbreak: wuhan’s experience date: - - journal: anesthesiology doi: . /aln. sha: doc_id: cord_uid: hhswage the covid- outbreak has led to , diagnosed cases and , deaths in mainland china based on the data released on march , . approximately . % of patients with covid- required intubation and invasive ventilation at some point in the disease course. providing best practices regarding intubation and ventilation for an overwhelming number of patients with covid- amid an enhanced risk of cross-infection is a daunting undertaking. the authors presented the experience of caring for the critically ill patients with covid- in wuhan. it is extremely important to follow strict self-protection precautions. timely, but not premature, intubation is crucial to counter a progressively enlarging oxygen debt despite high-flow oxygen therapy and bilevel positive airway pressure ventilation. thorough preparation, satisfactory preoxygenation, modified rapid sequence induction, and rapid intubation using a video laryngoscope are widely used intubation strategies in wuhan. lung-protective ventilation, prone position ventilation, and adequate sedation and analgesia are essential components of ventilation management. t he outbreak of the "coronavirus disease " started in december and quickly became a sweeping and unprecedented challenge to different stakeholders in mainland china. although the epidemic of covid- is not yet over, it has already outpaced the previous severe acute respiratory syndrome (sars) in and middle east respiratory syndrome (mers) in in nearly every respect, except for the mortality rate (table ). as of march , , a total of , patients were diagnosed with covid- , and a total of , patients among those confirmed cases died, corresponding to a mortality rate of . % (http://www.nhc.gov.cn/; accessed march , ) . at the writing of this article on march , , it appears that the momentum of the epidemic in mainland china, especially that in the epicenter of wuhan, hubei province, china, has slowed down. however, the disease is gaining momentum outside of china, and it could ultimately become very severe (https://www.who. int/emergencies/diseases/novel-coronavirus- /eventsas-they-happen; accessed march , ). the concern is whether the covid- epidemic could become a oncein-a-century pandemic. it did not take more than a few days before the healthcare system and providers in the epicenter of wuhan were stunned by the covid- outbreak's scale, speed, severity, and serious threat to healthcare providers themselves. many patients developed serious symptoms, with some of them becoming critically ill. the hospitals were quickly overwhelmed, forcing the administration to lock down the city of wuhan, reactivate the workforce a few days ahead of the most popular holiday in china, lunar new year, reorganize the case flow, convert noninfectious floors and hospitals into infectious ones, build two new hospitals from ground zero, and open fang cang hospitals using the big sport, conference, exhibition, and performance buildings ( fig. ; http://wjw.wuhan.gov.cn/; accessed march , ). the most common and severe complication in patients with covid- is acute hypoxemic respiratory failure or acute respiratory distress syndrome (ards), requiring oxygen and ventilation therapies. some of these critically ill patients required intubation and invasive ventilation. , moreover, although elective surgeries were largely cancelled, emergency surgeries for patients with confirmed or suspected covid- were permitted to proceed. some of these surgeries were performed under general anesthesia with endotracheal intubation. intubating and ventilating special section: patients with covid- who are critically ill or require emergent surgical procedures present some unique challenges to providers. the healthcare system and providers need to be prepared in and outside of china for the covid- outbreak now and for any outbreaks in the future. preparedness is a pressing issue considering that many places and countries in the world are under-resourced, and at the time of writing this article, covid- is quickly unfolding and evolving outside of mainland china. healthcare providers, who are tasked with taking care of critically ill patients, need to perform the best practices of intubation and ventilation tailored explicitly to the victims of this sweeping covid- outbreak and, at the same time, adhere to strict self-protection precautions. wuhan's experience needs to be highlighted and quickly communicated throughout the world. in february , we conducted four webinars specifically discussing the issues related to preparedness, airway management, lung-protective ventilation, the goal of oxygenation, and extracorporeal membrane oxygenation ( fig. ). we summarize the results of these discussions, which were based on firsthand experience with treating critically ill patients in wuhan. covid- has a wide spectrum of clinical severity, ranging from asymptomatic to critically ill, and ultimately death. , , a common and prominent complication of advanced covid- is acute hypoxemic respiratory insufficiency or failure requiring oxygen and ventilation therapies ( fig. ). , a recent report showed that % of patients developed dyspnea, tachypnea with a respiratory rate greater than or equal to per minute, desaturation with peripheral oxygen saturation (spo ) less than or equal to %, poor oxygenation with a ratio of partial pressure of arterial oxygen (pao ) to fraction of inspired oxygen (fio ) less than mmhg, or lung infiltrates greater than % within h. ards occurred in % of the patients hospitalized and in % of the patients admitted to the intensive care unit (icu) in zhongnan hospital in wuhan. organ dysfunction, injury, or failure, excluding the lungs, is common. cardiac injury occurred in %, liver injury in %, and acute kidney injury in % of critically ill patients. neurocognitive impairments occurred in more than one third of patients with advanced covid- . invasive ventilation via an endotracheal tube is common amid this outbreak. it was performed in . % of the , patients with confirmed covid- based on the patient cohort from hospitals in provinces, autonomous regions, and municipalities in mainland china, in % of the patients admitted to the icu in zhongnan hospital in wuhan, and in % of the patients admitted to the icu in jin yin tan hospital in wuhan. although elective surgeries were cancelled in the epicenter of wuhan, emergent surgeries were permitted amid this outbreak. as of february , , a total of emergent surgical procedures, including cesarean sections (classified as emergent surgery amid this outbreak; fig. ), were performed in patients with confirmed or suspected covid- in tongji hospital in wuhan (data from dr. wan). some of these procedures were performed under general anesthesia with endotracheal intubation. the anesthesiologists from the department of anesthesiology at tongji hospital in wuhan performed approximately nonoperating room intubations in patients with confirmed covid- as of february , . this is just a snapshot of the anesthetic practice in the epicenter of wuhan amid this outbreak. currently, we do not have data detailing the total number of patients with covid- who received intubation and invasive ventilation or details about the outcomes associated with and after these invasive interventions. nonetheless, we can attempt to estimate this based on the available data. as of february , , a total of , patients with confirmed covid- have died (http://www.nhc.gov.cn/; accessed march , ). it is assumed that all of these patients died in icus, as most, if not all, of them should have been admitted to the icu before their death. we estimate that, if using a mortality rate of % among patients who were admitted to the icu, a total of , patients would have been admitted to the icu ( , × = , ) as of february , . one recent report showed a mortality rate of . % in patients who were admitted to the icu. the other report showed a mortality rate of % among critically ill patients. we used a mortality rate of % in our estimate. based on the data reporting an invasive ventilation rate of approximately % in patients who were admitted to the icu, , we estimate the decision to intubate can be obvious and require little deliberation, as for patients with cardiopulmonary arrest or a lost or jeopardized airway. it can also be a decision that lacks quality evidence for guidance and, thus, is a decision made at the discretion of the treating physician. in patients with acute hypoxemic respiratory failure due to covid- , it can be challenging when deciding whether to proceed with intubation and invasive ventilation. the chinese society of anesthesiology task force on airway management released a fast-track publication with the recommendation to proceed with endotracheal intubation for patients showing no improvement in respiratory distress, tachypnea (respiratory rate greater than per minute), and poor oxygenation (pao to fio ratio less than mmhg) after -h highflow oxygen therapy or noninvasive ventilation. these criteria should be regarded as empirical as there is no robust supporting evidence. the frontline physicians taking care of critically ill patients in wuhan suggest that intubation and invasive ventilation may have been adversely delayed in some patients. they are concerned that, amid this particular outbreak, intubation is more often used as a salvage therapy than a proactive means of supporting patients whose oxygenation is progressively declining and oxygen debt keeps increasing. the most recent report showed that, among the icu patients who were intubated, ( %) of them died. although most frontline physicians believe the decision of intubation in some critically ill patients with covid- had been adversely delayed, we do not know at this time if early intubation could save more lives. we do know, based on the work performed yr ago by shoemaker et al., that there is a close association between the oxygen debt accumulated over h and the chance of survival in patients undergoing high-risk surgery and icu admission afterward. shoemaker et al.'s work highlights the importance of timely stopping an enlarging oxygen debt using effective oxygenation and ventilation therapies. the decision-making process for nonoperating room intubation used in wuhan is summarized in figure . timely, not premature, intubation is the keyword in decision-making. we added liberal criteria, including spo less than % in room air and a pao to fio ratio less than mmhg, to facilitate preparedness for intubation based on the experience of taking care of critically ill patients in wuhan. this proposal is justified as unprepared emergent intubation carries more risks, including cross-infection. it is also justified by the observation that some patients are relatively asymptomatic although they have a good degree of hypoxemia for inexplicable reasons (referred to as "silent hypoxemia" in wuhan). silent hypoxemia may be responsible for the quick deterioration in some patients because it gives a false sense of well-being when the oxygen debt has been actually and asymptomatically increasing. this algorithm emphasizes vigilance by asking two questions for patients with respiratory distress or hypoxemia. one is whether the condition has been progressively deteriorating or if it is expected to get worse; if the answer is yes, the next question is whether -h high-flow oxygen therapy or noninvasive ventilation is effective. both patients and healthcare workers have to endure enhanced, but distinctive, risks during intubation and ventilation management amid the covid- outbreak. the enhanced risks to patients will be discussed in the coming sections of this article. the enhanced risk to healthcare workers is cross-infection. copyright © , the american society of anesthesiologists, inc. unauthorized reproduction of this article is prohibited. of the hospitalized patients with confirmed covid- in zhongnan hospital in wuhan, ( %) patients were healthcare workers with hospital-associated transmission suspected as the mechanism of infection. five anesthesia providers working in tongji hospital in wuhan were diagnosed with covid- . two providers likely contracted the infection when taking care of patients with covid- in december when the self-protection mandate had not yet been established. the other three providers likely contracted the infection from family members. all five providers have recovered. since the establishment of the self-protection mandate in january , no anesthesia providers in tongji hospital have contracted the infection. dr. shanglong yao, a well-known anesthesiologist and former vice president of the union hospital in wuhan, was diagnosed with covid- , with the infection likely transmitted from his daughter. dr. yao was hospitalized for a prolonged weeks for close observation of the new-onset atrial fibrillation and poorly controlled hypertension. he eventually recovered and was discharged home ( fig. ). these are just some examples of the situations related to the healthcare providers who were infected. it was estimated that, as of february , , a total of , health workers had confirmed covid- and five had died ( . %) in mainland china. the total number of cases of healthcare worker infections could be much more than this estimate. it was an observation that most of these infections occurred at the early stage of this outbreak when the self-protection mandate had not been established and reinforced. the mechanisms of transmission responsible for these infections are unknown; some cases may be nosocomial infections while the remainder may not be work related. we also do not know how many nosocomial infections are attributable to the intubation process or ventilation management. the lesson we learned from the sars outbreak is that, compared with healthcare workers who do not perform intubation or ventilation management, those who perform these tasks have a higher risk of contracting the infection. a systematic review showed that compared with healthcare workers who did not perform aerosol-generating procedures, those who performed tracheal intubation had an increased risk of contracting the sars (odds ratio, . ), as were those who performed noninvasive ventilation (odds ratio, . ), tracheotomy (odds ratio, . ), and manual ventilation before intubation (odds ratio, . ). a separate study found that the protection guidelines failed to thoroughly prevent the transmission of sars to healthcare workers and that % of the interviewed healthcare workers who had intubated patients contracted sars. however, the cause-effect relationship between infection and intubation in these healthcare workers who contracted sars was unknown. despite the enhanced risk to healthcare workers, the potential harm of withholding intubation may outweigh the potential risk of cross-infection in patients who would benefit from invasive ventilation support. whenever intubation and invasive ventilation are needed, they should be timely and effectively provided. the healthcare workers who are involved in caring for patients with known or suspected covid- should strictly adhere to the self-protection mandate (table ) . the self-protection mandate for healthcare workers was quickly established and reinforced throughout different hospitals in wuhan after the recognition of humanto-human transmission of covid- toward the end of january . extensive and efficient education and training were provided to all healthcare workers. at the same time, personal protective equipment that was most needed was delivered to wuhan and the rest of the country where the epidemic was quickly evolving. the contact and airborne precautions, with components of personal protective equipment, are presented in table . the different levels of precautions were scaled per the settings of patient care in wuhan and the rest of china (table ) . full precaution (level iii) is mandatory for any care that involves direct patient contact, including intubation and ventilation management. in china, it is mandatory to strictly follow the personal protective equipment donning process for high-risk exposure in the following order: disposable hair cover, fittested n respirator or equivalent, fluid-resistant gown, two layers of gloves, goggle and face shield, and fluid-resistant shoe covers. before entering an isolation area, an experienced nurse or assistant is responsible for checking the donning process ( fig. ) . it is crucial to make sure the personal protective equipment is donned in the manner that will not interfere with procedures. it is also mandatory to strictly follow the personal protective equipment doffing process after high-risk exposure in the following order: hand hygiene, face shield and goggle removal, fluid-resistant gown removal, outer glove removal, shoe cover removal, inner glove removal, hand hygiene, n respirator or equivalent removal, and hair cover removal. the doffing process should also be supervised, but not facilitated, to reduce the chance of contamination. it is mandatory to report any inadvertent contamination of the skin or mucosa to the hospital infection control office to assess the need for quarantine. a shower and the use of oral, nasal, and external auditory canal disinfectants are recommended after the removal of personal protective equipment. patients with confirmed or suspected covid- should be regarded as having an augmented risk of presenting potentially difficult and complicated intubation for the following reasons. first, when a patient requires intubation for acute hypoxemic respiratory failure, they have minimal to no respiratory reserve, and their compensatory mechanisms have already been exhausted. it is common to see a patient who starts with a dangerously low spo quickly decline after loss of spontaneous breathing, followed by a slow recovery with manual facemask ventilation. second, due to strict infection control and the urgency of intubation, a careful airway evaluation is frequently not possible. third, the personal protective equipment mandated by the level iii scaled precaution makes the performance of the procedure clumsy, which may easily compromise the intubation process. fourth, strict infection and traffic control restrict backup supplies and helpers from being readily available when they are needed. fifth, the psychological pressure related to concerns of cross-infection challenges the providers, which may make an otherwise easy intubation complicated. preparedness minimizes the chance of cross-infection and improves the chance of smooth intubation. the proposed approach to prepare for intubation for patients with confirmed or suspected covid- is summarized in table . we recommend using the acronym oh-ms. maid-oxygen, helper, monitor, suction, machine, airway supplies, intravenous access, and drugs-to facilitate the preparation process for intubation. in wuhan, all portable supplies, needed or potentially needed, are packed in one package. one-time use disposable supplies are preferred. equipment that has to be reused is dedicated for patients with confirmed or suspected covid- . no glitch or imperfection is minor when there is an associated risk. preparedness is even more crucial amid the covid- outbreak, as the chance of contamination may be readily enhanced during the process of a complicated intubation when all attention is devoted to saving a patient's life. an experienced practitioner, instead of students or junior personnel, should be assigned to this job. a careful and efficient airway evaluation, whenever possible, should be performed ahead of intubation. equipment that is used for more than one patient should be cleaned and disinfected before and after each use. the mixture of ethanol and chlorhexidine is recommended as the disinfecting solution for the breathing circuit in china. two single-use filters (pall bb t breathing circuit filter, pall corp., usa), placed in the inhalation and exhalation breathing circuits, are used for infection control in wuhan. this breathing circuit filter appears capable of preventing the spread of influenza a (h n ) virus from intubated patients, and thus is implicated to be equally capable of preventing the spread of the novel coronavirus. in wuhan, most of the patients were on either high-flow oxygen therapy or bilevel positive airway pressure ventilation when the intubation was called. if the patient is on high-flow oxygen therapy, consider using a bag valve mask or a tightly fitting facemask connected to the already prepared ventilator for preoxygenation. if the patient is on a bilevel positive airway pressure machine, continue bilevel positive airway pressure ventilation for preoxygenation (supplemental digital content, http://links.lww.com/aln/c ). increase oxygen flow and use % fio to maximize oxygenation. make sure the airway is patent. it is well advised to apply an oral or nasal airway at the first sign of difficult masking. consider manual positive pressure ventilation using a bag valve mask if preoxygenation fails to improve oxygenation. it was shown that noninvasive ventilation applied for min before tracheal intubation resulted in better oxygenation than a nonrebreather bag valve mask. however, a multicenter randomized trial based on the evaluation of % fio administered with noninvasive ventilation versus that with a facemask for min before tracheal intubation failed to demonstrate any benefits of using noninvasive ventilation as a preoxygenation method to reduce organ dysfunction in hypoxemic, critically ill patients. clearly, there is a gap between improved oxygenation and unchanged outcomes. although the aerosol-generating potential of noninvasive ventilation is a potential concern to some providers, the bilevel positive airway pressure machine is widely used amid this outbreak for patients with acute hypoxemic respiratory failure in wuhan and the rest of china. we would not recommend using bilevel positive airway pressure for preoxygenation in patients who are not on bilevel positive airway pressure ventilation; however, bilevel positive airway pressure ventilation should be continued if it is already in use. after satisfactory preoxygenation, modified rapid sequence induction is the recommended technique for anesthesia induction. midazolam to mg may be considered for extremely anxious patients. intravenous lidocaine, . mg/kg or more, is effective in suppressing coughing during endotracheal intubation. use a small dose of etomidate ( . to . mg/kg) for patients with hemodynamic instability or propofol ( to . mg/kg) for patients with stable hemodynamics for induction. some providers may opt to avoid etomidate due to concerns of adrenal suppression. rocuronium mg/kg or succinylcholine mg/ kg is administered immediately after loss of consciousness. fentanyl to mcg, sufentanil to mcg, or remifentanil . mcg/kg may be used to suppress laryngeal reflexes and optimize the intubation condition. because opioids have the potential to cause coughing, some providers prefer to give opioids after the accomplishment of satisfactory muscle relaxation. the choice and dose of anesthetics should be determined on a case-by-case basis, with the patient's hemodynamic stability, severity of illness, and mental status taken into consideration. vasoactive drugs should be readily available to treat extreme cardiovascular reactions. ventilation through a patent airway and using a small tidal volume should be continued throughout the induction process until the patient is intubated. the goal copyright © , the american society of anesthesiologists, inc. unauthorized reproduction of this article is prohibited. is to have the patient intubated within s after administration of muscle relaxants. the rationale behind modified rapid sequence induction in china is to shorten the period of potentially ineffective ventilation, from the moment of losing consciousness to the moment of successful endotracheal intubation, in critically ill patients with minimal to no oxygen reserve due to covid- . the approach of using modified rapid sequence induction in this patient population may be criticized, as some providers may prefer to proceed with slow and controlled induction if there is no immediate aspiration risk. they may argue that maximizing oxygen reserve, immediately after anesthetic induction but before endotracheal intubation, is warranted in patients with acute hypoxemic respiratory failure. they may also argue that immediately administering muscle relaxants after anesthesia induction, without testing the effectiveness of bag valve mask ventilation, is not well advised. we recognize this potential difference in approaches and leave it open for further discussion. patient coughing during intubation can generate aerosols and should be avoided. gentle airway manipulation is warranted. it is prudent to use video laryngoscopy rather than direct laryngoscopy for intubation because the former increases the distance between the healthcare worker's face and the patient's face, which may minimize the risk of contamination ( fig. ). videoscopes also allow assistants to visualize the airway so that they can better facilitate the procedure. in wuhan, chest auscultation after intubation is not recommended, unless absolutely needed, due to concerns of contamination. capnography, fogging inside of the endotracheal tube, chest movement, spo , the color of the patient's skin and mucous membrane, and vigilance are used to differentiate between a failed and successful intubation. the same precautions should be considered during extubation. measures to prevent patient agitation, coughing, and bucking should be applied. appropriate levels of sedation, such as dexmedetomidine ( . mcg · kg - · h - ) or remifentanil ( to ng/ml target organ concentration) infusion, should be considered. intravenous lidocaine ( to . mg/kg) is effective for cough reduction. , alfentanil ( mcg/kg) is also effective in decreasing coughing and agitation during anesthesia emergence. mechanical ventilation, though vital in supporting respiratory function in patients with acute hypoxemic respiratory failure or ards, may promote lung damage, a phenomenon known as ventilator-induced lung injury. currently, we lack any guidelines or evidence to help us manage invasive mechanical ventilation in critically ill patients with covid- . it is well advised to adopt the guidelines established for patients with ards, , with appropriate modifications based on the firsthand patient care experience in wuhan (table ) . this is justified as % of the icu patients developed ards based on the recent report. the ards lung-protective ventilation guidelines emphasize: ( ) a tidal volume less than or equal to ml/ kg predicted body weight; ( ) a respiratory rate less than or equal to breaths/min; ( ) a plateau airway pressure less than or equal to cm h o; and ( ) a positive end-expiratory pressure (peep) greater than or equal to cm h o. , the tidal volume can be started at ml/kg and then lowered with an ultimate goal of ml/kg. some clinicians believe that, as long as the plateau pressure can be maintained at less than or equal to cm h o, it may be safe to ventilate the patient with tidal volumes greater than ml/kg predicted body weight. the precise tidal volume for an individual patient should be adjusted according to the patient's plateau pressure, selected peep, thoracoabdominal compliance, and breathing effort. it is advantageous to have a driving pressure (plateau pressure minus peep) below to cm h o via tidal volume and peep adjustments in patients who are not spontaneously breathing. in wuhan, patients with acute hypoxemic respiratory failure due to covid- have a poor tolerance to high peep, likely as the result of the direct and severe lung damage by the virus and inflammatory reactions. the plateau pressure reaches to cm h o when the peep is set at cm h o, fio at %, and the tidal volume at ml/kg according to the fio and peep table. the widely used practice in wuhan, after lung recruitment maneuvers, is to set peep at cm h o and titrate down in a decrement of to cm h o each time until the goals of oxygenation, plateau pressure, and compliance are all achieved. the commonly used peep in this patient population is less than cm h o. no mode of ventilation has been suggested to be superior to others. there is literature suggesting that high-frequency oscillatory ventilation may be an option for viral-induced lung injury. however, it may be best to avoid high-frequency oscillatory ventilation in patients with covid- due to concerns of aerosol generation. , , high-frequency oscillatory ventilation has not been used amid this outbreak in wuhan. pressure-regulated volume control ventilation, although increasingly popular in the perioperative arena, has not gained momentum in icus due to the lack of evidence for its outcome benefits. in patients with acute lung injury or ards, the tidal volume can markedly exceed the lung-protective ventilation target during pressure-regulated volume control ventilation, which is not desirable. pressure-regulated volume control is not the preferred mode of ventilation in wuhan. ventilation in the prone position improves lung mechanics and gas exchange and is currently recommended by the guidelines. , the prone position, if planned, should not be a desperate final attempt but should be considered in the early stages of the disease, as the evidence suggests that the early application of prolonged ventilation in the prone position decreases -and -day mortality in patients with severe ards. prone position ventilation is currently widely used for critically ill patients in wuhan ( fig. ). lung recruitment maneuvers, via transient elevations in airway pressure applied during mechanical ventilation, can open collapsed alveoli and thus increase the number of alveoli available for gas exchange. lung recruitment maneuvers do not significantly reduce mortality but may improve oxygenation and shorten the length of hospital stay in ards patients. overall, recruitment maneuvers are not supported by high-quality evidence, and caution should be exercised when using it because it can be irritating, incite coughing, and generate aerosols. adjunct therapies can be considered. many patients with acute hypoxemic respiratory failure due to covid- have breathing overdrive. appropriate sedation and analgesia, such as dexmedetomidine, propofol and remifentanil infusion, are warranted. the outcome evidence related to the use of muscle relaxants has been controversial. , a recent meta-analysis concluded that muscle relaxants improve oxygenation after h, but do not reduce mortality in moderate and severe ards patients. nonetheless, muscle relaxation should be considered in cases of breathing overdrive, patient-ventilator dyssynchrony, and inability to achieve the targeted tidal volume and plateau pressure. it is appropriate to be conservative with intravenous fluids in patients with severe lung injury if there are no signs of tissue hypoperfusion. conservative fluid therapy is the strategy used in wuhan. it is important to avoid corticosteroid treatment, given that this treatment has been shown to increase mortality and hospital-acquired infections in patients with severe influenza. [ ] [ ] [ ] however, the most recent study suggested that early dexamethasone administration may reduce overall mortality and mechanical ventilation duration in ards patients. corticosteroid treatment is currently used in selected patients with severe inflammatory lung injury in wuhan. disconnecting the patient from the ventilator results in loss of peep and atelectasis, and it should be avoided. in-line catheters for airway suctioning and endotracheal tube clamping are recommended before disconnecting breathing circuits. extracorporeal membrane oxygenation was successfully used in patients with severe influenza and may play an important role in select patients. a recent review concluded that the potential of extracorporeal membrane oxygenation in reducing mortality in patients with ards due to h n infection was apparent and that extracorporeal membrane oxygenation should be used as a salvage option in severely hypoxemic ards patients. the conventional ventilation or ecmo for severe adult respiratory failure (cesar) trial showed that there is a potential role for extracorporeal membrane oxygenation-based management protocols in patients with severe but potentially reversible respiratory failure, and these protocols may improve survival without causing severe disabilities. the ecmo to rescue lung injury in severe ards (eolia) trial showed that extracorporeal membrane oxygenation was not able to significantly reduce -day mortality in patients with very severe ards; however, the post hoc bayesian analysis suggested a potential mortality benefit under a broad set of assumptions. extracorporeal membrane oxygenation has been used in some critically ill patients with covid- in wuhan. more than extracorporeal membrane oxygenation cases (combined) have been treated in zhongnan hospital, jin yin tan hospital, and lung hospital in wuhan. the outcomes of these patients remain to be analyzed. the covid- outbreak is a sweeping and unprecedented challenge in china. its impacts are currently rapidly unfolding outside of china. as of march , , covid- was confirmed in , patients and led to , deaths in mainland china. approximately . % of patients with covid- received intubation and invasive ventilation support. how to provide the best practices of intubation and ventilation amid this mass medical emergency is a real but unprecedented question. in this article, we summarize the firsthand experience pertinent to intubation and ventilation management from the physicians who are taking care of the critically ill patients with covid- in wuhan. in patients with acute refractory hypoxemic respiratory failure, timely, but not premature, intubation and invasive ventilation support may be superior to high-flow oxygen therapy and bilevel positive airway pressure ventilation in boosting transpulmonary pressure, opening collapsed alveoli, improving oxygenation, decreasing oxygen debt, and offering a better chance for the lungs to heal. the invasive nature of intubation and ventilation exposes patients to an augmented risk of procedure-related mishaps. at the same time, these procedures present healthcare providers with an enhanced risk of cross-infection; thus, strict self-protection precautions are mandatory. tilation and the goal of oxygenation amid the covid- outbreak. the authors also thank dr ) for their participation in the fourth webinar held on february , , discussing extracorporeal membrane oxygenation amid the covid- outbreak. all these four webinars were organized by dr responding to covid- -a once-in-acentury pandemic? clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in clinical features of patients infected with novel coronavirus in epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention chinese society of anesthesiology task force on airway management: expert recommendations for tracheal intubation in critically ill patients with noval coronavirus disease role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients critical care crisis and some recommendations during the covid- epidemic in china novel coronavirus pneumonia emergency response epidemiology team: [the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review intubation of sars patients: infection and perspectives of healthcare workers should noninvasive ventilation be considered a high-risk procedure during an epidemic? can breathing circuit filters help prevent the spread of influenza a (h n ) virus from intubated patients? noninvasive ventilation improves preoxygenation before intubation of hypoxic patients effect of preoxygenation using non-invasive ventilation before intubation on subsequent organ failures in hypoxaemic patients: a randomised clinical trial critically ill patients with middle east respiratory syndrome coronavirus infection intravenous lidocaine as a suppressant of coughing during tracheal intubation in elderly patients the optimal dose of remifentanil for acceptable intubating conditions during propofol induction without neuromuscular blockade tussive effect of a fentanyl bolus administered through a central venous catheter efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery effects of maintaining a remifentanil infusion on the recovery profiles during emergence from anaesthesia and tracheal extubation bloodpressure and pulse-rate responses to endotracheal extubation with and without prior injection of lidocaine a comparative study between the effects of % endotracheal tube cuff lignocaine and . mg/kg intravenous lignocaine on coughing and hemodynamics during extubation in neurosurgical patients: a randomized controlled double-blind trial alfentanil suppresses coughing and agitation during emergence from isoflurane anesthesia mechanisms of ventilator-induced lung injury european society of intensive care medicine, and society of critical care medicine: an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome lung protective ventilation strategy for the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome ventilatory management of acute respiratory distress syndrome: a consensus of two driving pressure and survival in the acute respiratory distress syndrome pressure-controlled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ali) or acute respiratory distress syndrome (ards) ventilator management for hypoxemic respiratory failure attributable to h n novel swine origin influenza virus high-frequency oscillatory ventilation versus conventional ventilation for acute respiratory distress syndrome nursing and infection-control issues during high-frequency oscillatory ventilation work of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome: a comparison between volume and pressure-regulated breathing modes ventilator management for acute respiratory distress syndrome associated with avian influenza a (h n ) virus infection: a case series prone positioning in severe acute respiratory distress syndrome lung recruitment maneuvers for ards patients: a systematic review and meta-analysis recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation acurasys study investigators: neuromuscular blockers in early acute respiratory distress syndrome early neuromuscular blockade in the acute respiratory distress syndrome neuromuscular blockade in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials esicm h n registry contributors: use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n ) v influenza a infection corticosteroids as adjunctive therapy in the treatment of influenza corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis gonzález-martín jm; dexamethasone in ards network: dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome extracorporeal life support: the next step in moderate to severe ards-a review and meta-analysis of the literature elbourne d; cesar trial collaboration: efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for severe acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial a novel coronavirus outbreak of global health concern a review of isolation gowns in healthcare: fabric and gown properties prone position for acute respiratory distress syndrome. a systematic review and meta-analysis prone-supine ii study group: prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial prone position for acute respiratory failure in adults semi-recumbent position versus supine position for the prevention of ventilator-associated pneumonia in adults requiring mechanical ventilation cov study group: clinical features and viral diagnosis of two cases of infection with middle east respiratory syndrome coronavirus: a report of nosocomial transmission address correspondence to dr. xiong: department of anesthesiology and perioperative medicine, shanghai fourth people's hospital, tongji university school of medicine, shanghai , china. mzkxlz@ .com. information on purchasing reprints may be found at www. anesthesiology.org or on the masthead page at the beginning of this issue. anesthesiology's articles are made freely accessible to all readers, for personal use only, months from the cover date of the issue. the authors declare no competing interests. key: cord- -ezrkg dc authors: myerson, jacob w.; patel, priyal n.; habibi, nahal; walsh, landis r.; lee, yi-wei; luther, david c.; ferguson, laura t.; zaleski, michael h.; zamora, marco e.; marcos-contreras, oscar a.; glassman, patrick m.; johnston, ian; hood, elizabeth d.; shuvaeva, tea; gregory, jason v.; kiseleva, raisa y.; nong, jia; rubey, kathryn m.; greineder, colin f.; mitragotri, samir; worthen, george s.; rotello, vincent m.; lahann, joerg; muzykantov, vladimir r.; brenner, jacob s. title: supramolecular organization predicts protein nanoparticle delivery to neutrophils for acute lung inflammation diagnosis and treatment date: - - journal: biorxiv doi: . / . . . sha: doc_id: cord_uid: ezrkg dc acute lung inflammation has severe morbidity, as seen in covid- patients. lung inflammation is accompanied or led by massive accumulation of neutrophils in pulmonary capillaries (“margination”). we sought to identify nanostructural properties that predispose nanoparticles to accumulate in pulmonary marginated neutrophils, and therefore to target severely inflamed lungs. we designed a library of nanoparticles and conducted an in vivo screen of biodistributions in naive mice and mice treated with lipopolysaccharides. we found that supramolecular organization of protein in nanoparticles predicts uptake in inflamed lungs. specifically, nanoparticles with agglutinated protein (naps) efficiently home to pulmonary neutrophils, while protein nanoparticles with symmetric structure (e.g. viral capsids) are ignored by pulmonary neutrophils. we validated this finding by engineering protein-conjugated liposomes that recapitulate nap targeting to neutrophils in inflamed lungs. we show that naps can diagnose acute lung injury in spect imaging and that nap-like liposomes can mitigate neutrophil extravasation and pulmonary edema arising in lung inflammation. finally, we demonstrate that ischemic ex vivo human lungs selectively take up naps, illustrating translational potential. this work demonstrates that structure-dependent interactions with neutrophils can dramatically alter the biodistribution of nanoparticles, and naps have significant potential in detecting and treating respiratory conditions arising from injury or infections. the covid- pandemic tragically illustrates the dangers of acute inflammation and infection of the lungs, for both individuals and societies. acute alveolar inflammation causes the clinical syndrome known as acute respiratory distress syndrome (ards), in which inflammation prevents the lungs from oxygenating the blood. severe ards is the cause of death in most covid- mortality and was a major cause of death in the influenza epidemic, but ards is common even outside of epidemics, affecting ~ , american patients per year with a ~ - % mortality rate. - ards is caused not just by viral infections, but also by sepsis, pneumonia (viral and bacterial), aspiration, and trauma. , largely because ards patients have poor tolerance of drug side effects, no pharmacological strategy has succeeded as an ards treatment. , [ ] [ ] [ ] therefore, there is an urgent need to develop drug delivery strategies that specifically target inflamed alveoli in ards and minimize systemic side effects. neutrophils are "first responder" cells in acute inflammation, rapidly adhering and activating in large numbers in inflamed vessels and forming populations of "marginated" neutrophils along the vascular lumen. [ ] [ ] [ ] [ ] [ ] [ ] [ ] neutrophils can be activated by a variety of initiating factors, including pathogen-and damage-associated molecular patterns such as bacterial lipopolysaccharides (lps). , after acute inflammatory insults, neutrophils marginate in most organs, but by far most avidly in the lung capillaries. , , , , neutrophils are therefore key cell types in most forms of ards. in ards, marginated neutrophils can secrete tissue-damaging substances (proteases, reactive oxygen species) and extravasate into the alveoli, leading to disruption of the endothelial barrier and accumulation of neutrophils and edematous fluid in the air space of the lungs ( figure a ). , , , [ ] [ ] [ ] targeted nanoparticle delivery to marginated neutrophils could provide an ards treatment with minimal side effects, but specific delivery to marginated neutrophils remains an open challenge. antibodies against markers such as ly g have achieved targeting to neutrophils in mice, but also deplete populations of circulating neutrophils. [ ] [ ] [ ] [ ] additionally, while ly g readily marks neutrophils in mice, there is no analogous specific and ubiquitous marker on human neutrophils. therefore, antibody targeting strategies have not been widely adopted for targeted drug delivery to these cells. as another route to neutrophil targeting, two previous studies noted that activated neutrophils take up denatured and agglutinated bovine albumin, concluding that denatured protein was critical in neutrophil-particle interactions. , nanoparticle structural properties such as shape, size, and deformability can define unique targeting behaviors. [ ] [ ] [ ] [ ] [ ] here, we screened a diverse panel of nanoparticles to determine the nanostructural properties that predict uptake in pulmonary marginated neutrophils during acute inflammation. as a high-throughput animal model for ards, we administered lps to mice, causing a massive increase in pulmonary marginated neutrophils. we show that two initial leads in our screen, lysozyme-dextran nanogels (ldngs) and crosslinked albumin nanoparticles (anps), selectively home to marginated neutrophils in inflamed lungs, but not naïve lungs. in our subsequent screen of over diverse nanoparticles, we find that protein nanoparticles, all defined by agglutination of protein in amorphous nanostructures (nanoparticles with agglutinated proteins, naps), but not by denatured protein, have specificity for lps-inflamed lungs. in contrast to naps, we demonstrate that three symmetric protein nanostructures (viruses/nanocages) have biodistributions unaffected by lps injury. we show that polystyrene nanoparticles and five liposome formulations do not accumulate in injured lungs, indicating that nanostructures that are not based on protein are not intrinsically drawn to marginated neutrophils in acute inflammation. we then engineered liposomes (the most clinically relevant nanoparticle drug carriers) as naps, through conjugation to protein modified with hydrophobic cyclooctynes, encouraging protein agglutination on the liposome surface by hydrophobic interactions. we thus show that supramolecular organization of proteins, rather than chemical composition, best predicts uptake in marginated neutrophils in acutely inflamed lungs. we then demonstrate proof of concept for naps as diagnostic and therapeutic tools for ards. we show; a) in-labeled naps provide diagnostic imaging contrast that distinguishes inflammatory lung injury from cardiogenic pulmonary edema; b) napliposomes can significantly ameliorate edema in a mouse model of severe ards; c) naps, but not crystalline protein nanostructures, accumulate in ex vivo human lungs rejected for transplant due to ards-like conditions. collectively, our results will demonstrate that supramolecular organization of protein, namely protein agglutination, predicts strong, intrinsic nanoparticle tropism for marginated neutrophils. this finding indicates that naps, encompassing a wide range of nanoparticles based on or incorporating protein, have biodistributions that are responsive to inflammation. naps could be useful beyond ards, since marginated neutrophils play a pathogenic role in a diverse array of inflammatory diseases, including infections, heart attack, and stroke. [ ] [ ] [ ] [ ] [ ] but our findings provide a clear path forward for using naps to improve diagnosis and treatment of ards. to quantify the increase in pulmonary marginated neutrophils after inflammatory lung injury, radiolabeled clone a anti-ly g antibody (specific for mouse neutrophils) was administered intravenously (iv) to determine the location and concentration of neutrophils in mice. iv injection of lps subjected mice to a model of mild ards. accumulation of anti-ly g antibody in the lungs was dramatically affected by iv lps, with . % of injected antibody adhering in lps-injured lungs, compared to . % of injected antibody in naïve control lungs ( figure b) . agreeing with previous studies addressing the role of neutrophils in systemic inflammation, biodistributions of anti-ly g antibody indicated that systemic lps injury profoundly increased the concentration of neutrophils in the lungs. , , , single cell suspensions prepared from mouse lungs were probed by flow cytometry to further characterize pulmonary neutrophils in naïve mice and in mice following lps-induced inflammation. to identify intravascular populations of leukocytes, mice received iv fluorescent cd antibody five minutes prior to sacrifice. single cell suspensions prepared from iv cd -stained lungs were then stained with anti-ly g antibody to identify neutrophils. a second stain of single cell suspensions with cd antibody indicated the total population of leukocytes in the lungs, distinct from the intravascular population indicated by iv cd . flow cytometry showed greater concentrations of neutrophils in lps-injured lungs, compared to naïve lungs ( figure c , counts above horizontal threshold indicate positive staining for neutrophils, figure d , rightmost peak indicates positive staining for neutrophils). comparison of ly g stain to total cd -positive cells indicated . % of leukocytes in the lungs were ly g-positive after lps injury, compared to . % in the naïve control ( figure d , center panel). comparison of ly g stain to iv cd stain indicated that the majority of neutrophils were intravascular, in both naïve and lpsinjured mice. in naïve mice, . % of neutrophils were intravascular and in lps-injured mice, . % of neutrophils were intravascular ( figure d , right panel). the presence of large populations of intravascular neutrophils following inflammatory injury is consistent with previously published observations. , , , , histological analysis confirmed results obtained with flow cytometry and radiolabeled anti-ly g biodistributions. staining of lung sections indicated increased concentration of neutrophils in the lungs following iv lps injury ( figure e , left panels). co-registration of neutrophil staining with tissue autofluorescence (indicating tissue architecture) broadly supported the finding that pulmonary neutrophils reside in the vasculature ( figure e , right panels). previous work has traced the neutrophil response to bacteria in the lungs, determining that pulmonary neutrophils pursue and engulf active bacteria following either intravenous infection or infection of the airspace in the lungs. , , we injected heat-inactivated, oxidized, and fixed e. coli in naïve and iv-lps-injured mice. with the bacteria stripped of their functional behavior, e. coli did not accumulate in the lungs of naïve control mice ( . % of initial dose in the lungs, blue bars in figure f ). however, pre-treatment with lps to recapitulate the inflammatory response to infection led to enhanced accumulation of the deactivated e. coli in the lungs ( . % of initial dose in the lungs, red bars in figure f ). with e. coli structure maintained but e. coli function removed, the inactivated bacteria were taken up more avidly in lungs primed by an inflammatory injury. in order to identify nanostructural parameters that correlate with nanoparticle uptake in inflamed lungs, we conducted an in vivo screen of a diverse array of nanoparticle drug carriers. the screen was based on the method used above for tracing inactivated bacteria: inject radiolabeled nanoparticles into mice and measure biodistributions, comparing naïve with iv-lps mice. to validate that the radiotracing screen would measure uptake in pulmonary marginated neutrophils, we more fully characterized the in vivo behavior of two early hits in the screen. lysozyme-dextran nanogels (ldngs, ngs) and poly(ethylene)glycol (peg)crosslinked albumin nps have been characterized as targeted drug delivery agents in previous work. [ ] [ ] [ ] here, ldngs ( . ± . nm diameter, . ± . pdi, supplementary figure a ) and peg-crosslinked human albumin nps ( . ± . nm diameter, . ± . pdi, supplementary figure b) were administered in naïve and iv-lps-injured mice. neither np was functionalized with antibodies or other affinity tags. the protein component of each particle was labeled with i for tracing in biodistributions, and assessed minutes after iv administration of nps. both absolute ldng lung uptake and ratio of lung uptake to liver uptake registered a ~ -fold increase between naïve control and lps-injured animals (figure a , supplementary table ) . specificity for lps-injured lungs was recapitulated with peg-crosslinked human albumin nps. albumin nps accumulated in naïve lungs at . % injected dose per gram organ weight (%id/g), and in lps-injured lungs at . %id/g, accounting for a -fold increase in lung uptake after intravenous lps insult ( figure b , supplementary table ) . single cell suspensions were prepared from lungs after administration of fluorescent ldngs or peg-crosslinked albumin nps. flow cytometric analysis of cells prepared from lungs after np administration enabled identification of cell types with which nps associated. firstly, the total number of cells containing ldngs or albumin nps increased between naïve and lps-injured lungs. in naïve control lungs, . ly g stain for neutrophils indicated that the bulk of ldng and albumin np accumulation in lps-injured lungs could be accounted for by uptake in neutrophils. in figure c and d, counts above the horizontal threshold indicate neutrophils and counts to the right of the vertical threshold indicate cells containing ldngs ( figure c ) or albumin nps ( figure d ). in iv-lps-injured lungs, ldng and albumin np uptake was dominated by neutrophils ( figure c , figure d , upper right quadrants indicate nppositive neutrophils). in lps-injured lungs, the majority of neutrophils, > % of cells, contained significant quantities of nanoparticles, compared to < % in naïve lungs. likewise, the majority of nanoparticle uptake in the lungs (> %) was accounted for by nanoparticle uptake in neutrophils ( figure e , f, g, h, supplementary table ) . for np uptake not accounted for by neutrophils, cd staining indicated that the remaining np uptake was attributable to other leukocytes. co-localization of albumin np fluorescence with cd stain showed that . % of albumin np uptake was localized to leukocytes in naïve lungs and . % of albumin np uptake was localized to leukocytes in injured lungs (supplementary figure c, supplementary figure d ). for ldngs, localization to neutrophils in injured lungs was confirmed via histology. ly g staining of lps-injured lung sections confirmed colocalization of fluorescent nanogels with neutrophils in the lung vasculature ( figure i ). slices in confocal images of lung sections indicated that ldngs were inside neutrophils ( figure j ). intravital imaging of injured lungs allowed real-time visualization of ldng uptake in leukocytes in injured lungs. ldng fluorescent signal accumulated over minutes and reliably colocalized with cd staining for leukocytes ( figure k , supplementary movie ). ldng pharmacokinetics were evaluated in naïve and iv-lps-injured mice (supplementary figure ) . in both naïve and injured mice, bare ldngs were rapidly cleared from the blood with a distribution half-life of ~ minutes. in naïve mice, transient retention of ldngs in the lungs ( . %id/g at five minutes after injection) leveled off over one hour. in iv-lps-treated mice, ldng concentration in the lungs reached a peak value at minutes after injection, as measured either by absolute levels of lung uptake or by lungs:blood localization ratio. ldng biodistributions were also assessed in mice undergoing alternative forms of lps-induced inflammation. intratracheal (it) instillation of lps led to concentration of ldngs in the lungs at . %id/g. liver and spleen ldng uptake was also reduced following it lps injury, leading to a -fold increase in the lungs:liver ldng localization ratio induced by it lps injury (supplementary figure ) . as with iv lps injury, it lps administration leads to neutrophil-mediated vascular injury focused in the lungs. mice were administered lps via footpad injection to provide a model of systemic inflammation originating in lymphatic drainage. ldng uptake in the lungs and in the legs was enhanced by footpad lps administration. at hours after footpad lps administration, ldngs concentrated in the lungs at . %id/g, an -fold increase over naïve. at hours, ldngs concentrated in the lungs at . %id/g (supplementary figure a) . total ldng accumulation in the legs accounted for . % of initial dose (%id) in naïve mice, . %id in mice hours after footpad lps injection, and . %id at hours after footpad injection (supplementary figure b) , indicating ldngs can concentrate in inflamed vasculature outside the lungs. previous work has indicated that nps based on denatured albumin accumulate in neutrophils in inflamed lungs and at sites of acute vascular injury, whereas nps coated with native albumin do not. , we have characterized lysozyme-dextran nanogels and crosslinked human albumin nps with circular dichroism (cd) spectroscopy to compare secondary structure of proteins in the nps to secondary structure of the native component proteins (supplementary figure a-b) . identical cd spectra were recorded for ldngs vs. lysozyme and for albumin nps vs. human albumin. deconvolution of the cd spectra via neural network algorithm trained against a library of cd spectra for known structures verified that secondary structure composition of lysozyme and albumin was unchanged by incorporation of the proteins in the nps. free protein and protein nps were also probed with -anilino- naphthalenesulfonic acid (ansa), previously established as a tool for determining the extent to which hydrophobic domains are exposed on proteins. consistent with known structures of the two proteins, ansa staining indicated few available hydrophobic domains on lysozyme and substantial hydrophobic exposure on albumin (supplementary figure c -d, blue curves). ldngs had increased hydrophobic accessibility vs. native lysozyme whereas albumin nps had reduced hydrophobic accessibility compared with native albumin. therefore, our data indicate that lysozyme and albumin are not denatured in ldngs and albumin nps, but the nps composed of the two proteins present a balance of hydrophobic and hydrophilic surfaces differing from the native proteins. the previous section demonstrates that two different nanoparticles based on protein, shown not to be denatured in cd spectroscopy studies, have uptake in lpsinflamed lungs driven by uptake in marginated neutrophils. we next undertook a broader study considering how aspects of np structure including size, composition, surface chemistry, and structural organization impact np uptake in lps-injured lungs. as examples of different types of protein nps, variants of ldngs (representing nps based on hydrophobic interactions between proteins), crosslinked protein nps, and nps based on electrostatic interactions between proteins were traced in naïve control and iv-lps-injured mice. as examples of nps based on site-specific protein interactions (rather than site-indiscriminate interactions leading to crosslinking, gelation, or chargebased protein nps), we also traced viruses and ferritin nanocages in naïve and lpstreated mice. liposomes and polystyrene nps were studied as examples of lipid and polymeric nanostructures. nanoparticles based on hydrophobic protein interactions ldng size was varied by modifying lysozyme-dextran composition of the nps and ph at which particles were formed. figure , all sizes of ldngs accumulated in lps-injured lungs at higher concentrations than in naïve lungs, with accumulation in injured lungs reaching ~ % of initial dose for all types of ldngs (supplementary table ). variations in size and composition of ldngs therefore did not affect ldng specificity for lps-injured lungs. expanding on data with peg-nhs ester-crosslinked human serum albumin particles, we varied the geometry and protein composition of nps based on peg-nhs protein crosslinking. human serum albumin nanorods (aspect ratio : ), bovine serum albumin nps ( . table ). lysozyme nps accumulated in naïve lungs at a uniquely high concentration of . %id/g, compared to . %id/g in inflamed lungs. degree of uptake in injured lungs, along with injured vs. naïve contrast, did vary with protein np composition. however, acute inflammatory injury resulted in a minimum three-fold increase in lung uptake for all examined crosslinked protein nps, excluding crosslinked lysozyme, which still accumulated in injured lungs at a high concentration ( . % of initial dose). we traced recently-developed poly(glutamate) tagged green fluorescent protein (e-gfp) nps, representing a third class of protein np based on electrostatic interactions between proteins and carrier polymer or metallic particles. negatively-charged e-gfp was paired to arginine-presenting gold nanoparticles ( . ± . nm diameter, pdi . ± . ) or to poly(oxanorborneneimide) (poni) functionalized with guanidino and tyrosyl side chains ( . ± . nm diameter, pdi . ± . ) (supplementary figure d) . for biodistribution experiments with poni/e-gfp hybrid nps, tyrosine-bearing poni was labeled with i and e-gfp was labeled with i, allowing simultaneous tracing of each component of the hybrid nps. the two e-gfp nps, with structure based on charge interactions, had specificity for iv lps-injured lungs. comparing uptake in lps-injured lungs to naïve lungs, we observe an lps:naïve ratio of . for poni/e-gfp nps as traced by the poni component, . for poni/e-gfp nps as traced by the e-gfp component, and . for au/e-gfp nps ( figure c , supplementary figure ). poni/e-gfp particles, specifically, accumulated in lpsinjured lungs at . % initial dose as measured by poni tracing and . % initial dose as measured by gfp tracing, indicating effective co-delivery in the inflamed organ. acute inflammatory injury therefore resulted in a two-to three-fold increase in pulmonary uptake of nps constructed via electrostatic protein interactions. nanoparticles based on symmetric protein organization adeno-associated virus (aav), adenovirus, and horse spleen ferritin nanocages were employed as examples of protein-based nps with highly symmetrical structure (see supplementary figure d for dls confirmation of structure). [ ] [ ] [ ] for each of these highly ordered protein nps, iv lps injury had no significant effect on biodistribution and levels of uptake in the injured lungs were minimal ( figure d table ). therefore, highly ordered protein nps traced in our studies did not have tropism for the lungs after acute inflammatory injury. liposomes and polystyrene nps were studied as example nps that are not structurally based on proteins. dota chelate-containing lipids were incorporated into bare liposomes, allowing labeling with in tracer for biodistribution studies. carboxylate polystyrene nps were coupled to trace amounts of i-labeled igg via edci-mediated carboxy-amine coupling. liposomes had a diameter of . ± . nm (pdi . ± . ) and igg-polystyrene nps had a diameter of . ± . nm (pdi . ± . ) (supplementary figure c -d). liposomes accumulated in inflamed lungs at a concentration of . %id/g, accounting for no significant change against naïve lungs. lps injury actually induced a reduction in the lungs:liver metric, from . for naïve mice to . for lps-injured mice. polystyrene nps accumulated in inflamed lungs at . %id/g ( . % initial dose), so iv lps injury did in fact induce increased levels of np uptake in the lungs, from a concentration of . %id/g in the naïve lungs ( figure e, supplementary figure ). however, neither bare liposomes nor polystyrene nps were drawn to lps-injured lungs in significant concentrations. significantly, isolated proteins did not home to lps-inflamed lungs themselves. we traced radiolabeled albumin, lysozyme, and transferrin in naïve control and iv lpsinjured mice (supplementary figure , supplementary table ). in injured mice, albumin, lysozyme, and transferrin localized to the lungs at low concentrations and no significant differences were recorded when comparing naïve to lps-injured lung uptake. the data presented in figure and supplementary figures - indicate that a variety of protein-based nanostructures have tropism for acute inflammatory injury in the lungs. nps based on agglutination of proteins in non-site-specific interactions (naps, figure a -c, supplementary figures - ) all exhibited either significant increases in lung uptake after lps injury or high levels of lung uptake in both naïve control and lpsinjured animals. nanostructures based on highly symmetrical protein organization had no specific tropism for inflamed lungs ( figure d ). representative nanostructures not based on proteins, bare liposomes and polystyrene beads, did not home to inflamed lungs ( figure e ). we next engineered naps from liposomes, a nanoparticle shown above to have no intrinsic neutrophil tropism. our methods for engineering nap-like liposomes serve to validate the finding that supramolecular organization of protein in nanoparticles predicts neutrophil tropism. liposomes were functionalized with rat igg conjugated via sata-maleimide chemistry (sata-igg liposomes) or via recently demonstrated copper-free click chemistry methods. briefly, click chemistry methods entailed nhs-ester conjugation of an excess of strained alkyne (dibenzocyclooctyne, dbco) to igg, followed by reaction of the dbco-functionalized igg with liposomes containing peg-azide-terminated lipids (dbco-igg liposomes, figure a ). dbco-igg liposomes had a diameter of . ± . nm and a pdi of . ± . and sata-igg liposomes had a diameter of . ± . nm and a pdi of . ± . (supplementary figure c) . in mice subjected to iv-lps, sata-igg liposomes accumulated in the lungs at a concentration of . %id/g ( figure b , yellow bars). dbco-igg liposomes, by contrast, concentrated in the lungs at . %id/g, corresponding to . % of initial dose and roughly matching the accumulation of nm ldngs in the inflamed lungs ( figure b , brown bars). for comparison, bare liposomes, as in figure e , concentrated in the inflamed lungs at . %id/g ( figure b , green bars). for dbco-igg liposomes, the inflamed vs. naïve lung uptake accounted for a twelve-fold change. dbco-igg liposomes specifically accumulated in injured lungs, whereas sata-igg liposomes and bare liposomes did not (supplementary figure , supplementary table ) . it lps instillation also led to elevated concentrations of dbco-igg liposomes in the lungs. biodistributions of the dbco-igg liposomes indicated a pulmonary concentration of . %id/g at hour after it lps, . %id/g at hours after it lps, and . %id/g at hours after it lps (supplementary figure ). even at early time points after direct pulmonary lps insult, dbco-igg liposomes accumulated in the inflamed lungs. results in figure b were obtained by introducing a -fold molar excess of nhs-ester-dbco to rat igg before dbco-igg conjugation to liposomes (dbco( x)-igg liposomes). optical density quantification of dbco indicated ~ dbco per igg following reaction of dbco and igg at : molar ratio (supplementary figure ) . to test the hypothesis that dbco functions as a tag that modifies dbco-igg liposomes for neutrophil affinity in settings of inflammation, we varied the concentration of dbco on igg prepared for conjugation to azide liposomes. dbco was added to igg at -fold, five-fold, and . -fold molar excesses. a -fold molar excess resulted in ~ dbco per igg, a -fold molar excess resulted in ~ dbco per igg, and a . -fold molar excess resulted in ~ dbco per igg (supplementary figure ) . igg with different dbco loading concentrations was conjugated to azide liposomes. dbco-igg liposomes had similar sizes across all dbco concentrations (supplementary figure c) , with diameters of ~ nm and pdis < . . the different types of dbco-igg liposomes were each traced in iv-lps injured mice. titrating the quantity of dbco on dbco-igg liposomes indicated that liposome accumulation in the lungs of injured mice was dependent on dbco concentration on the liposome surface. concentration of dbco-igg liposomes in inflamed lungs attenuated with decreasing dbco concentration on igg (supplementary table , figure c ). therefore, only igg with high concentrations of dbco served as a tag for modifying the surface of liposomes for specificity to pulmonary injury. flow cytometry verified the specificity of dbco-igg liposomes for neutrophils in injured lungs ( figure d -e). as with ldngs and albumin nps in figure c -h, single cell suspensions were prepared from lps-inflamed and naïve control lungs after circulation of fluorescent dbco-igg liposomes. confirming the results of biodistribution studies, . % of cells were liposome-positive in naïve lungs, compared to . % of all cells in lps-inflamed lungs (supplementary figure a-b) . dbco-igg liposomes predominantly accumulated in pulmonary neutrophils after iv lps. there were more neutrophils in the injured lungs and a greater fraction of neutrophils took up dbco-igg liposomes in the injured lungs, as compared to the naïve control ( figure d -e). approximately one half of neutrophils in iv lps-injured lungs contained liposomes. dbco-igg liposomes were also highly specific for neutrophils in inflamed lungs, with ~ % of liposome-positive cells in the injured lungs being neutrophils (supplementary table ). the remaining dbco-igg liposome uptake in the lungs was accounted for by other cd -positive cells (supplementary figure c -e). . % of liposome uptake colocalized with cd -positive cells in lps-injured lungs and . % of liposome uptake in the naïve lungs was associated with cd -positive cells. accordingly, less than % of liposome uptake was associated with endothelial cells (supplementary figure f -g). dbco( x)-igg itself did not have specificity for inflamed lungs (supplementary figure ). uptake of dbco( x)-igg in naïve and injured lungs was statistically identical and the biodistribution of the modified igg resembled published results with unmodified igg. these results verify that dbco-igg modifies the structure of immunoliposomes, but does not function as a standard affinity tag by acting as a surface motif with intrinsic affinity for neutrophils. indeed, cd spectroscopic and ansa structural characterization of dbcomodified igg and dbco-igg liposomes resembled results obtained for ldngs and crosslinked albumin nps. igg secondary structure, as assessed by cd spectroscopy, was unchanged by dbco modification (supplementary figure a) . deconvolution of cd spectra via neural network algorithm indicated identical structural compositions for dbco( x)-igg, dbco( x)-igg, dbco( x)-igg, dbco( . x)-igg, and unmodified igg, showing that igg was not denatured by conjugation to dbco. ansa was used to probe accessible hydrophobic domains on dbco( x)-igg and dbco( x)-igg liposomes (supplementary figure b) . ansa fluorescence indicated more hydrophobic domains available on dbco( x)-igg liposomes than on dbco( x)-igg itself, resembling results for lysozyme and ldngs. therefore, addition of a hydrophobic moiety to protein on the surface of liposomes led to uptake of the liposomes in pulmonary marginated neutrophils after inflammatory insult. this result indicates that hydrophobic interactions between proteins on the surface of functionalized liposomes, like the protein interactions in naps, predict liposome tropism for marginated neutrophils in inflamed lungs. including nps from our four classes of protein-based nps, two non-protein nps (bare liposomes and polystyrene nps), and five types of igg-coated liposomes, we traced nanoparticles in naïve and inflamed mice. direct assessment of naïve-toinflamed shifts in lung uptake led us to identify naps with specificity for inflamed lungs. to verify this assessment and derive additional patterns in the broader data set, we undertook linear discriminant and principal components analyses of the biodistribution data for our nanoparticles, along with three isolated proteins. grouping the nanoparticles and three proteins according to the classes defined in figure and supplementary figures - , we completed a linear discriminant analysis of the naïve-to-inflamed shift for particle retention in the lungs, blood, liver, and spleen (supplementary figure a) . data for particle uptake in each organ was normalized by subtracting and then dividing by the mean uptake over all particles. the first two eigenvectors, dominated by splenic uptake and a combination of liver and lung uptake, respectively, accounted for % of variation in the data. the resulting projection of the data along the first two linear discriminant analysis eigenvectors was analyzed by k-means clustering to confirm the classes of nanoparticle with specificity for the inflamed lungs (supplementary figure b) . indeed, division of the data into two clusters supported the delineation of the nanoparticles with specificity for inflamed lungs. naps, nanoparticles based on protein gelation, crosslinking, and charge association, all aligned in one cluster. as an exception, dbco( x)-igg liposomes were considered as a unique class of particle and the linear discriminant analysis indicated that the inflammation-specific liposomes had in vivo behavior resembling that of ldngs or poni-gfp nanoparticles. this analysis of the liposome biodistributions supports the classification of dbco( x)-igg liposomes as naps. igg-coated polystyrene nanoparticles and dbco( x)-igg liposomes were part of the k-means cluster without inflammation specificity, but data for these two particles resided close to the voronoi boundary distinguishing the two clusters. principal component analysis comparing normalized nanoparticle uptake in inflamed lungs to normalized retention in liver, spleen, and blood provided a reductive metric to compare the distinct in vivo behavior of nanoparticles in the classes identified by linear discriminant analysis. most variation in the biodistribution data was accounted for by an eigenvector closely aligned to variation in pulmonary uptake (supplementary figure a) . data was projected along that first eigenvector and magnitude of the projection was determined for each nanoparticle (supplementary figure b) . first eigenvector projection values were then grouped according to the classes examined above via linear discriminant analysis. only the classes in the inflammation-specific kmeans cluster had positive average first eigenvector projections. all other particle classes had average first eigenvector projections indistinguishable from isolated protein (supplementary figure b) . principal component and linear discriminant analyses of our compiled biodistributions confirmed; a) identification of naps as nanoparticles with distinct tropism for inflamed lungs and; b) alignment of dbco( x)-igg liposome in vivo behavior with that of other naps. computerized tomography (ct) imaging is a standard diagnostic tool for ards. ct images can identify the presence of edematous fluid in the lungs, but ct cannot distinguish between the two major types of pulmonary edema: non-inflammatory cardiogenic pulmonary edema (cpe) and ards-associated edema. we sought to use naps to distinguish inflammatory lung injury from cpe in diagnostic imaging experiments. we induced cpe in mice via prolonged iv propranolol infusion. edema was confirmed via ct imaging of inflated lungs ex vivo and in situ. three-dimensional reconstructions of chest ct images were partitioned to distinguish airspace and lowdensity tissue, as in normal lungs (white, yellow, and light orange signal in figure a ), from high-density tissue and edema (red and black/transparent signal in figure a ). quantification of ct attenuation and gaps in the reconstructed three-dimensional lung images indicated profuse edema in lungs afflicted with model cardiogenic pulmonary edema ( figure a nm ldngs were traced in mice with induced cardiogenic pulmonary edema. ldngs accumulated in the edematous lungs at . %id/g concentration, statistically indistinguishable from lung uptake in naïve mice and an order of magnitude lower than the level of lung uptake in mice treated with iv lps ( figure c ). naïve and iv lps-injured mice were dosed with ldngs labeled with in via chelate conjugation to lysozyme. in uptake in naïve and lps-injured lungs was visualized with ex vivo spect-ct imaging to indicate capacity of ldngs for imagingbased diagnosis of inflammatory lung injury ( figure d ). in signa was colocalized with anatomical ct images for reconstructions in figure d . in spect signal was detectable in lps-injured lungs, but in spect signal was at background level in naïve lungs (supplementary movies and ). reduced spect signal in the liver of lps-injured mice, in agreement with biodistribution data, was also evident in coregistration of spect imaging with full body skeletal ct imaging (supplementary movies and ). therefore, naps with tropism for marginated neutrophils have the ability to detect and assess ards-like inflammation via spect-ct imaging. since those same naps do not accumulate in lungs afflicted with cpe, naps have potential for differential diagnosis of acute lung inflammation against cpe. in recent work, we demonstrated that human donor lungs rejected for transplant due to ards-like phenotypes can be perfused with nanoparticle solutions. these perfusion experiments evaluate the tendency of nanoparticles to distribute to human lungs ex vivo. we used this perfusion method to evaluate nap retention in inflamed human lungs. first, fluorescent ldngs were added to single cell suspensions prepared from human lungs. µg, µg, or µg of ldngs were incubated with x cells in suspension for hour at room temperature. after three washes to remove unbound ldngs, cells were stained for cd and analyzed with flow cytometry ( figure a -b). the majority of ldng uptake in the single cell suspensions was attributable to cd positive cells. ldngs accumulated in the human leukocytes, extracted from inflamed lungs, in a dose-dependent manner, with . % of leukocytes containing ldngs at a loading dose of µg. therefore, our prototype nap was retained in leukocytes from human lungs. to test ldng tropism for inflamed intact human lungs, fluorescent or i-labeled ldngs were infused via arterial catheter into ex vivo human lungs excluded from transplant. immediately prior to ldng administration, tissue dye was infused via the same arterial catheter to stain regions of the lungs directly perfused by the catheterized branch of the pulmonary artery ( figure c ). after infusion of ldngs, phosphate buffered saline infusion was used to rinse away unbound particles. perfused regions of the lungs were dissected and divided into ~ g segments, then sorted into regions deemed to have high, medium, or low levels of tissue dye staining. for lungs receiving fluorescent ldngs, well-perfused and poorly-perfused regions were selected for sectioning and fluorescent imaging. fluorescent signal from ldngs was clearly detectable in sections of well-perfused tissue, but not poorly-perfused tissue ( figure d ). in experiments with i-labeled ldngs, i-labeled ferritin was concurrently infused (i.e. a mix of ferritin and ldngs was infused) as an internal control particle shown to have no tropism for injured mouse lungs. with ldngs and ferritin infused into the same lungs via the same branch of the pulmonary artery, ldngs retained in the lungs at . % initial dose and ferritin retained at . % initial dose ( figure e ). ldng accumulation in human lungs was focused in regions of the lungs with high levels of perfusion stain, with concentrations of . %id/g in the "high" perfusion regions, compared to . %id/g in the "medium" perfusion regions. ferritin accumulation was more diffuse, with . %id/g in the "high" perfusion regions, compared to . %id/g in the "medium" perfusion regions (supplementary figure ) . ldngs, a prototype nap shown to home to neutrophils in acutely inflamed mouse lungs, specifically accumulated in perfused regions of inflamed human lungs, but ferritin nanocages, a particle with no tropism for neutrophils, concentrated at much lower levels in injured human lungs. our data thus indicate that nap tropism for neutrophils in inflamed mouse lungs may be recapitulated in human lungs. previous studies indicate that nanoparticles can interfere with neutrophil adhesion in inflamed vasculature. we designed studies to evaluate whether or not naps mitigate the neutrophil-mediated effects of lung inflammation. namely, we administered ldngs, dbco( x)-igg liposomes, or bare liposomes in mice subjected to model ards and determined whether or not the nanoparticles prevented lung edema induced by inflammation. mice were treated with nebulized lps as a high-throughput model for severe ards. to evaluate physiological effects of the model injury, bronchoalveolar lavage (bal) fluid was harvested from mice at hours after exposure to lps. in three separate experiments, nebulized lps induced elevated concentrations of neutrophils, cd -positive cells, and protein in the bal fluid. in naïve mice, cd -positive cells concentrated at . x cells per ml bal and neutrophils concentrated at . x cells per ml bal. after lps injury, cd -positive cells and neutrophils concentrated at . x and . x cells per ml bal, respectively. in naïve mice, protein concentrated in the bal fluid at . mg/ml and in lps-injured mice, protein concentrated in the bal at . mg/ml ( figure , white and grey bars). vascular disruption after nebulized lps treatment thus led to accumulation of protein-rich edema in the alveolar space. dbco( x)-igg liposomes, ldngs, and bare liposomes were compared for effects on vascular permeability in model ards. nps were administered as an iv bolus ( mg per kg body weight) two hours after nebulized lps administration. as in untreated mice, bal fluid was harvested and analyzed at hours after exposure to nebulized lps. bare liposomes or ldngs did not have significant effects on vascular injury induced by nebulized lps, as measured by either leukocyte or protein concentration in bal fluid ( figure , red and green bars). dbco( x)-igg liposomes, however, had a significant salient effect on both protein leakage and cellular infiltration in the bal ( figure , brown bars). with dbco( x)-igg liposomes administered two hours after nebulized lps, cd -positive cells and neutrophils in bal were reduced to concentrations of . x and . x cells per ml, respectively. protein concentration in the bal was reduced to . mg/ml by dbco( x)-igg liposome treatment. as measured by protection against cellular or protein leakage, relative to untreated mice, dbco( x)-igg liposomes provided . % protection against leukocyte leakage, . % protection against neutrophil leakage, and . % protection against protein leakage. dbco( x)-igg liposomes, without any drug, altered the course of inflammatory lung injury to limit protein and leukocyte edema in the alveoli. our results with dbco( x)-igg liposomes indicate that some naps can interfere with neutrophil extravasation into the alveoli and thus limit edema following inflammatory injury. however, our results with ldngs show that tropism for marginated neutrophils is not alone sufficient to limit the neutrophil-mediated effects of inflammatory lung injury. neutrophils concentrate in the pulmonary vasculature during either systemic or pulmonary inflammation. , , , , these marginated neutrophils can recognize and engulf bacteria. , , therefore, neutrophils surveil the vasculature for potentially pathogenic foreign species, with the pulmonary vasculature serving as a "surveillance hub" in the case of systemic or pulmonary infection and inflammation. , , , our results with e. coli are noteworthy in this context: when e. coli are stripped of functional properties by heat treatment, oxidation, and fixation, but maintain their structure, uptake of the bacteria in the lungs only occurs after systemically prompting neutrophils with an inflammatory signal, lps. inflammation thus leads to pulmonary uptake of the e. colishaped particles. in large part, the overall outcome of this study is an accounting of nanoparticle structural properties that lead to recognition by "surveilling" neutrophils in the inflamed lungs, analogously to e. coli recognition by pulmonary neutrophils. including different liposomal formulations, nanoparticles were screened in our biodistribution studies comparing pulmonary nanoparticle uptake in naïve and lps-inflamed mice. thirteen different nanoparticles exhibited specificity for inflamed lungs over naïve lungs, with flow cytometry data indicating that at least three of those nanoparticle species specifically and avidly gather in neutrophils. the thirteen nanoparticles with specificity for the inflamed lungs have a range of properties. seven different proteins were used in the inflammation-specific particles. the particles have sizes ranging from ~ nm to ~ nm, include both spheres and rods, and have a range of zeta potentials. however, our analyses classify the inflammation-specific nanoparticles as; ) nanoparticles with structure based on hydrophobic interactions between proteins; ) nanoparticles with structure based on non-site-specific protein crosslinking; ) nanoparticles based on charge interactions between proteins. put broadly, these three classes can all be grouped as structures based on protein agglutination, without regard for site-specific interactions or symmetry in the resulting protein superstructure. we define the term nanoparticles with agglutinated proteins (naps) to indicate that particles with tropism for pulmonary marginated neutrophils during inflammation share commonalities in supramolecular organization. we identify naps as a broad class, rather than a single particle type. accordingly, we have presented diverse nap designs, implying a diversity of potential nap-based strategies for targeted treatment and diagnosis of ards and other inflammatory disorders in which marginated neutrophils play a role (e.g. local infections or thrombotic disorders). , , , , the diversity of naps will allow versatile options for engineering neutrophil-specific drug delivery strategies to accommodate different pathologies. in contrast to naps, three particles (adenovirus, aavs, and ferritin) characterized by highly symmetric arrangement of protein subunits into a protein superstructure [ ] [ ] [ ] did not accumulate in the inflamed neutrophil-rich lungs. these three particles have evolved structures that lead to prolonged circulation or evasion of innate immunity in mammals. [ ] [ ] [ ] [ ] it is conceivable that neutrophils more effectively recognize less patterned and more variable protein arrangements that may better parallel the wide variety of structures presented by the staggering diversity of microbes against which neutrophils defend. , to support our conclusions regarding supramolecular organization and neutrophil tropism, we re-engineered liposomes, particles with no intrinsic neutrophil tropism, to behave like naps. protein arrangement on the surface of dbco-igg liposomes was predicted to recapitulate protein agglutination seen in naps based on hydrophobic interactions. introduction of dbco to igg entails conjugation of a highly hydrophobic moiety to hydrophilic residues on the igg. replacing dbco with the less hydrophobic modifying group used in sata-maleimide conjugation abrogates the inflammation specificity observed with dbco-igg liposomes. likewise, titrating down the amount of dbco on the igg, thus limiting the hydrophobic groups on the protein, also ratchets down the targeting behavior of the dbco-igg liposomes. our data therefore points towards hydrophobic interactions between proteins on the liposome surface being a determinant in liposome uptake in neutrophils in the inflamed lungs. essentially, the dbco-igg liposomes may reproduce the hydrophobic interaction structural motif seen in naps produced by protein gelation (i.e. ldngs). nap-liposomes may be particularly attractive for future clinical translatability. liposomes are prominent among fda-approved nanoparticle drug carriers. further, even without cargo drugs, nap-liposomes conferred significant therapeutic effects in a mouse model of severe ards. ldngs, despite high levels of uptake in inflamed lungs, did not have the same therapeutic effect as the nap-liposomes. this result suggests that the composition of the liposomes may be important for their therapeutic effect. among possible mechanisms for the therapeutic effect, we note that lipid rafts are major signaling hubs in neutrophils. , the lipid content of the nap-liposomes (particularly the cholesterol content) may modulate neutrophil lipid rafts dependent on cholesterol. we have also observed that neutrophil content in the inflamed alveoli is markedly reduced by nap-liposomes. in this context, we note published work demonstrating that certain nanoparticles, in a still undetermined manner dependent on particle composition, can drive redistribution of neutrophils from the lungs to the liver. as a major corollary, our findings indicate many protein-based or proteinincorporating nanoparticles developed for therapeutic applications may accumulate in inflamed lungs, even when those nanoparticles were designed to accumulate elsewhere. the variety of protein nanostructures accumulating in inflamed lungs in our data includes particles that have been investigated as targeted drug delivery vehicles where marginated neutrophils are not the intended site of accumulation. , , , , the patterns in our data indicate that future studies may reveal additional nanoparticles that accumulate in the lungs following inflammatory insult. this study therefore serves as evidence that inflammatory challenges may prompt profound off-target changes in the biodistributions of nanomaterials, including dramatic shunting of nanoparticles and any associated drug payload to the lungs. the nanoparticle targeting profiles documented in naïve or, for instance, tumor model studies may be overturned by, for instance, bacterial infection in a patient receiving the nanoparticle. in conclusion, supramolecular organization in nanoparticle structure predicts nanoparticle uptake in pulmonary marginated neutrophils during acute inflammation. specifically, nanoparticles with agglutinated protein (naps) accumulate in marginated neutrophils, while nanoparticles with more symmetric protein organization do not. nap tropism for neutrophils allowed us to develop naps as diagnostics and therapeutics for ards, and even to demonstrate nap uptake in inflamed human lungs. future work may more deeply explore therapeutic effects of naps in ards and other diseases in which neutrophils play key roles. this study also obviates future testing of supramolecular organization as a variable in in vivo behavior of nanoparticles, including screens of tropism for other pathologies and cell types. these studies could in turn guide engineering of new particles with intrinsic cell tropisms, as with our engineering of nap-liposomes with neutrophil tropism. these "targeting" behaviors, requiring no affinity moieties, may apply to a wide variety of nanomaterials. but our current findings with neutrophil-tropic naps indicate that many protein-based and protein-coated nanoparticles could be untapped resources for treatment and diagnosis of devastating inflammatory disorders like ards. lysozyme-dextran nanogels (ldngs) were synthesized as previously described. , kda rhodamine-dextran or fitc-dextran (sigma) and lysozyme from hen egg white (sigma) were dissolved in deionized and filtered water at a : or : mol:mol ratio, and ph was adjusted to . before lyophilizing the solution. for maillard reaction between lysozyme and dextran, the lyophilized product was heated for hours at °c, with % humidity maintained via saturated kbr solution in the heating vessel. dextran-lysozyme conjugates were dissolved in deionized and filtered water to a concentration of mg/ml, and ph was adjusted to . or . . solutions were stirred at °c for minutes. diameter of ldngs was evaluated with dynamic light scattering (dls, malvern) after heat gelation. particle suspensions were stored at °c. crosslinked protein nanoparticles and nanorods were prepared using previously reported electrohydrodynamic jetting techniques. the protein nanoparticles were prepared using bovine serum albumin, human serum albumin, human lysozyme, human transferrin, or human hemoglobin (all proteins were purchased from sigma). protein nanorods were prepared using chemically modified human serum albumin. for electrohydrodynamic jetting, protein solutions were prepared by dissolving the protein of interest at a . w/v% (or . w/v% for protein nanorods) concentration in a solvent mixture of di water and ethylene glycol with : (v/v) ratio. the homobifunctional amine-reactive crosslinker, o,o′-bis[ -(n-succinimidylsuccinylamino)ethyl]polyethylene glycol with molecular weight of kda (nhs-peg-nhs, sigma) was mixed with the protein solution at w/w%. protein nanoparticles were kept at °c for days for completion of the crosslinking reaction. the as-prepared protein nanoparticles were collected in pbs buffer and their size distribution was analyzed using dynamic light scatting (dls, malvern). glutamic acid residues (e -tag) were inserted at the c-terminus of enhanced green fluorescent protein (egfp) through restriction cloning and site-directed mutagenesis as previously reported. proteins were expressed in an e. coli bl strain using standard protein expression protocol. briefly, protein expression was carried out in xyt media with an induction condition of mm iptg and °c for h. at this point, the cells were harvested, and the pellets were lysed using % triton-x- ( min, °c)/dnase-i treatment ( minutes). proteins were purified using hispur cobalt columns. after elution, proteins were preserved in pbs buffer. the purity of native proteins was determined using % sds−page gel. polymers (poni) were synthesized by ring-opening metathesis polymerization using third generation grubbs' catalyst as previously described. in brief, solutions in dichloromethane of guanidium functionalized monomer and grubbs' catalyst were placed under freeze thawing cycles for degassing. after warming the solutions to room temperature, the degassed monomer solutions were administrated to degassed catalyst solutions and allowed to stir for minutes. the polymerization reaction was terminated by the addition of excess ethyl vinyl ether. the reaction mixture was further stirred for another min. the resultant polymers were precipitated from excess hexane or diethyl ether anhydrous, filtered, washed and dried under vacuum to yield a light-yellow powder. polymers were characterized by h nmr and gel permeation chromatography (gpc) to assess chemical compositions and molecular weight distributions, respectively. subsequent to deprotection of boc functionalities, polymer was dissolved in the dcm with the addition of tfa at : ratio. the reaction was allowed to stir for hours and dried under vacuum. excess tfa was removed by azeotropic distillation with methanol. afterwards, the resultant polymers were re-dissolved in dcm and precipitated in anhydrous diethyl ether, filtered, washed and dried. polymers were then dissolved in water and transferred to biotech ce dialysis tubing membranes with a g/mol cutoff and dialyzed against ro water ( − days). the polymers were then lyophilized dried to yield a light white powder. poni polymer/e-tag protein nanocomposites (ppncs) were prepared in polypropylene microcentrifuge tubes (fisher) through a simple mixing procedure. . nmol of kda poni was incubated with . nmol of egfp at room temperature for minutes prior to dilution to µl in sterile pbs and subsequent injection. similarly, . nmol of arginine-tagged gold nanoparticles, prepared as described, were combined with . nmol of egfp to prepare egfp/gold nanoparticle complexes. azide-functionalized liposomes were prepared by thin film hydration techniques, as previously described. the lipid film was composed of mol% dppc ( , dipalmitoyl-sn-glycero- -phosphocholine), mol% cholesterol, and mol% azide-peg -dspe (all lipids from avanti). . mol% top fluor pc ( -palmitoyl- -(dipyrrometheneboron difluoride) undecanoyl-sn-glycero- -phosphocholine) was added to prepare fluorescent liposomes. . mol% dtpa-pe ( , -distearoyl-sn-glycero- phosphoethanolamine-n-diethylenetriaminepentaacetic acid) was added to prepare liposomes with capacity for radiolabeling with in. lipid solutions in chloroform, at a total lipid concentration of mm, were dried under nitrogen gas, then lyophilized for hours to remove residual solvent. dried lipid films were hydrated with dulbecco's phosphate buffered saline (pbs). lipid suspensions were passed through freezethaw cycles using liquid n / °c water bath then extruded through nm cutoff tracketched polycarbonate filters in cycles. dls assessed particle size after extrusion and after each subsequent particle modification. liposome concentration following extrusion was assessed with nanosight nanoparticle tracking analysis (malvern). for conjugation to liposomes, rat igg was modified with dibenzylcyclooctyne-peg -nhs ester (dbco, jena bioscience). igg solutions (pbs) were adjusted to ph . with m nahco buffer and reacted with dbco for hour at room temperature at molar ratios of . : , : , : , or : dbco:igg. unreacted dbco was removed after reaction via centrifugal filtration against kda cutoff filters (amicon [def] . dbcomodified igg was incubated with azide liposomes at igg per liposome overnight at room temperature. unreacted antibody was removed via size exclusion chromatography, and purified liposomes were concentrated to original volume against centrifugal filters (amicon). maleimide liposomes were also prepared via lipid film hydration. lipid films comprised % dppc, % cholesterol, and % mpb-pe ( , -dioleoyl-sn-glycero- phosphoethanolamine-n-[ -(p-maleimidophenyl) butyramide]), with lipids prepared, dried, resuspended, and extruded as described above for azide liposomes. igg was prepared for conjugation to maleimide liposomes by one-hour reaction of sata (n-succinimidyl s-acetylthioacetate) per igg at room temperature in . mm edta in pbs. unreacted sata was removed from igg by passage through kda cutoff gel filtration columns. sata-conjugated igg was deprotected by one-hour room temperature incubation in . m hydroxylamine in . mm edta in pbs. excess hydroxylamine was removed and buffer was exchanged for . mm edta in pbs via kda cutoff gel filtration column. sata-conjugated and deprotected igg was added to liposomes at igg per liposomes for overnight reaction at °c. excess igg was removed by size exclusion column purification, as above for azide liposomes. nm carboxylate nanoparticles (phosphorex) were exchanged into mm mes buffer at ph . via gel filtration column. n-hydroxysulfosuccinimide (sulfo-nhs) was added to the particles at . mg/ml, prior to incubation for minutes at room temperature. edci was then added to the particles at . mg/ml, prior to incubation for minutes at room temperature. igg was added to the particle mixture at igg per nanoparticle, prior to incubation for hours at room temperature while vortexing. for radiotracing, i-labeled igg was added to the reaction at % of total igg mass. the igg/particle mixture was diluted with -fold volume excess of ph . mes buffer and the diluted mixture was centrifuged at xg for minutes. supernatant was discarded and pbs with . % bsa was added at desired volume before resuspending the particles via sonication probe sonication (three pulses, % amplitude). particle size was assessed via dls after resuspension, and particles were used immediately after dls assessment. top e. coli were grown overnight in terrific broth with ampicillin. bacteria were heat-inactivated by -minute incubation at °c, then fixed by overnight incubation in % paraformaldehyde. after fixation, bacteria were pelleted by centrifugation at xg for minutes. pelleted bacteria were washed three times in pbs, prior to resuspension by pipetting. bacterial concentration was verified by optical density at nm, prior to radiolabeling as described for nanoparticles below. bacteria were administered in mice ( . x colony forming units in a µl suspension per mouse). protein, horse spleen ferritin nanocages (sigma), or adeno-associated virus (empty capsids, serotype ) were prepared in pbs at concentrations between and mg/ml in volumes between and µl. films of oxidizing agent were prepared in borosilicate tubes by drying µl of . mg/ml iodogen (perkin-elmer, chloroform solution) under nitrogen gas. alternatively, iodobeads (perkin-elmer) were added to borosilicate tubes (one per reaction). protein solutions were added to coated or beadcontaining tubes, before addition of na / i at µci per µg of protein. protein was incubated with radioiodine at room temperature for minutes under parafilm in a ventilated hood. iodide-protein reacottions were terminated by purifying protein solutions through a kda cutoff gel column (zeba). additional passages through gel filtration columns or against centrifugal filters (amicon, kda cutoff) were employed to remove free iodine, assuring that > % of radioactivity was associated with protein. lysozyme-dextran nanogels, crosslinked protein nanoparticles, e. coli, or adenovirus were similarly iodinated. at least µl of particle suspension was added to a borosilicate tube containing two iodobeads, prior to addition of µci of na i per µl of suspension. particles were incubated with radioiodine and iodobeads for minutes at room temperature, with gentle shaking every minutes. to remove free iodine, particle suspensions were moved to a centrifuge tube, diluted in ~ ml of buffer and centrifuged to pellet the particles ( xg/ minutes for nanogels, xg/ minutes for crosslinked protein particles, xg/ minutes for adenovirus, and xg/ minutes for e. coli). supernatant was removed and wash/centrifugation cycles were repeated to assure > % of radioactivity was associated with particles. particles were resuspended by probe sonication (three pulses, % amplitude) for nanogels or crosslinked protein nanoparticles or pipetting for adenovirus or e. coli. nanoparticle labeling with in in labeling of nanoparticles followed previously described methods, with adaptation for new particles. all radiolabeling chelation reactions were performed using metal free conditions to prevent contaminating metals from interfering with chelation of in by dtpa or dota. metals were removed from buffers using chelex metal affinity resin (biorad, laboratories, hercules ca). lysozyme-dextran nanogels were prepared for chelation to in by conjugation to s- -( -isothiocyanatobenzyl)- , , , -tetraazacyclododecane tetraacetic acid (p-scn-bn-dota, macrocyclics). nanogels were moved to metal free ph . m nahco buffer by three-fold centrifugation ( xg for minutes) and pellet washing with metal free buffer. p-scn-bn-dota was added to nanogels at : mass:mass ratio, prior to reaction for minutes at room temperature. free p-scn-bn-dota was removed by three-fold centrifugal filtration against kda cutoff centrifugal filters, with resuspension of nanogels in metal-free ph citrate buffer after each centrifugation. dota-conjugated nanogels or dtpa-containing liposomes in ph citrate buffer were combined with incl for one-hour chelation at °c. nanoparticle/ incl mixtures were treated with free dtpa ( mm final concentration) to remove in not incorporated in nanoparticles. efficiency of in incorporation in nanoparticles was assessed by thin film chromatography (aluminum/silica strips, sigma) with µm edta mobile phase. chromatography strips were divided between origin and mobile front and the two portions of the strip were analyzed in a gamma counter to assess nanoparticleassociated (origin) vs. free (mobile front) in. free in was separated from nanoparticles by centrifugal filtration and nanoparticles were resuspended in pbs (liposomes) or saline (nanogels). for spect/ct imaging experiments (see spect/ct imaging methods below) with nanogels, µci of in-labeled nanogels, used within one day in labeling as described above, were administered to each mouse. for tracing in-labeled liposomes in biodistribution studies, liposomes were labeled with µci in per µmol of lipid. nanoparticle or protein biodistributions were tested by injecting radiolabeled nanoparticles or protein (suspended to µl in pbs or . % saline at a dose of . mg/kg with tracer quantities of radiolabeled material) in c bl/ male mice from jackson laboratories. biodistributions in naïve mice were compared to biodistributions in several injury models. biodistribution data were collected at minutes after nanoparticle or protein injection, unless otherwise stated, as in pharmacokinetics studies. briefly, blood was collected by vena cava draw and mice were sacrificed via terminal exsanguination and cervical dislocation. organs were harvested and rinsed in saline, and blood and organs were examined for nanoparticle or protein retention in a gamma counter (perkin-elmer). nanoparticle or protein retention in harvested organs was compared to measured radioactivity in injected doses. for calculations of nanoparticle or protein concentration in organs, quantity of retained radioactivity was normalized to organ weights. mice subject to intravenous lps injury were anesthetized with % isoflurane before administration of lps from e. coli strain b at mg/kg in µl pbs via retroorbital injection. after five hours, mice were anesthetized with ketamine-xylazine ( mg/kg ketamine, mg/kg xylazine, intramuscular administration) and administered radiolabeled nanoparticles or protein via jugular vein injection to determine biodistributions as described above. for mice subject to intratracheal (it) lps injury, b lps was administered to mice (anesthetized with ketamine/xylazine) at mg/kg in µl of pbs via tracheal catheter, followed by µl of air. biodistributions of lysozyme-dextran nanogels in it-lps-injured mice were assessed as above hours after lps administration. biodistributions of liposomes in it-lps-injured mice were assessed at , , or hours after lps administration. mice subject to footpad lps administration were provided b lps at mg/kg in µl pbs via footpad injection. biodistributions of lysozyme-dextran nanogels were obtained at or hours after footpad lps administration. lysozyme-dextran nanogel biodistributions were also traced in a mouse model of cardiogenic pulmonary edema. to establish edema, mice were anesthetized with ketamine/xylazine and administered propranolol in saline ( µg/ml) via jugular vein catheter at µl/min over minutes. lysozyme-dextran nanogel biodistributions were subsequently assessed as above. single cell suspensions were prepared from lungs for flow cytometric analysis of cell type composition of the lungs and/or nanoparticle distribution among different cell types in the lungs. c bl/ male mice were anesthetized with ketamine/xylazine ( mg/kg ketamine, mg/kg xylazine, intramuscular administration) prior to installation of tracheal catheter secured by suture. after sacrifice by terminal exsanguination via the vena cava, lungs were perfused by right ventricle injection of ~ ml of cold pbs. the lungs were then infused via the tracheal catheter with ml of a digestive enzyme solution consisting of u/ml dispase, . mg/ml collagenase type i, and mg/ml of dnase i in cold pbs. immediately after infusion, the trachea was sutured shut while removing the tracheal catheter. the lungs with intact trachea were removed via thoracotomy and kept on ice prior to manual disaggregation. disaggregated lung tissue was aspirated in ml of digestive enzyme solution and incubated at °c for minutes, with vortexing every minutes. after addition of ml of fetal calf serum, tissue suspensions were strained through µm filters and centrifuged at xg for minutes. after removal of supernatant, the pelleted material was resuspended in ml of cold ack lysing buffer. the resulting suspensions were strained through µm filter and incubated for minutes on ice. the suspensions were centrifuged at xg for minutes and the resulting pellets were rinsed in ml of facs buffer ( % fetal calf serum and mm edta in pbs). after centrifugation at xg for minutes, the rinsed cell pellets were resuspended in % pfa in ml facs buffer for minutes incubation. the fixed cell suspensions were centrifuged at xg for minutes and resuspended in ml of facs buffer. for analysis of intravascular leukocyte populations in naïve and inflamed lungs, mice received an intravenous injection of fitc-conjugated anti-cd antibody five minutes prior to sacrifice and preparation of single cell suspensions as described above. populations of intravascular vs. extravascular leukocytes were assessed by subsequent stain of fixed cell suspensions with percp-conjugated anti-cd antibody and/or apcconjugated clone a anti-ly g antibody. to accomplish staining of fixed cells, µl aliquots of the cell suspensions described above were pelleted at xg for minutes, then resuspended in labeled antibody diluted in facs buffer ( : dilution for apcconjugated anti-ly g antibody and : dilution for percp-conjugated anti-cd antibody). samples were incubated with staining antibodies for minutes at room temperature in the dark, diluted with ml of facs buffer, and pelleted at xg for minutes. stained pellets were resuspended in µl of facs buffer prior to immediate flow cytometric analysis on a bd accuri flow cytometer. all flow cytometry data was gated to remove debris and exclude doublets. control samples with no stain, obtained from naïve and iv-lps-injured mice, established gates for negative/positive staining with fitc, percp, and apc. single stain controls allowed automatic generation of compensation matrices in fcs express software. comparison of percp anti-cd signal with fitc anti-cd signal indicated intravascular vs. extravascular leukocytes. comparison of apc anti-ly g signal with fitc anti-cd signal indicated intravascular vs. extravascular neutrophils, with percp and apc co-staining verifying identification of cells as neutrophils. similar staining and analysis protocols enabled identification of nanoparticle distribution among different cell types in the lungs. to enable fluorescent tracing, lysozyme-dextran nanogels contained fitc-dextran, dbco-igg liposomes contained green fluorescent top fluor pc lipid, and crosslinked albumin nanoparticles were labeled with nhs ester alexa fluor . alexa fluor labeling of albumin nanoparticles was accomplished by incubation of the nhs ester fluorophore with nanoparticles at : mass:mass fluorophore:nanoparticle ratio for two hours on ice. excess fluorophore was removed from nanoparticles by -fold centrifugation at xg for minutes followed by washing with pbs. nanoparticles were administered at . mg/kg via jugular vein injection and circulated for minutes, prior to preparation of single cell suspensions from lungs as above. fixed single cell suspensions were stained with apc-conjugated anti-ly g or percp-conjugated anti-cd as above. additional suspensions were stained with : dilution of apc-conjugated anti-cd , in lieu of anti-ly g, to identify endothelial cells. association of nanoparticles with cell types was identified by coincidence of green fluorescent signal with anti-cd , anti-ly g, or anti-cd signal. as described previously, thirty minutes after injection of µci of in-labeled nanogels, anesthetized mice were sacrificed by cervical dislocation. mice were placed into a milabs u-spect (utrecht, netherlands) scanner bed. a region covering the entire body was scanned for min using listmode acquisition. the animal was then moved, while maintaining position, to a milabs u-ct (utrecht, netherlands) for a fullbody ct scan using default acquisition parameters ( µa, kvp, ms exposure, . ° step with projections). for naïve mice and mice imaged after cardiogenic pulmonary edema, ct data was acquired as above without spect data. the spect data was reconstructed using reconstruction software provided by the manufacturer, with µm voxels. the ct data were reconstructed using reconstruction software provided by the manufacturer, with µm voxels. spect and ct data, in nifti format, were opened with imagej software (fiji package). background signal was removed from spect images by thresholding limits determined by applying renyi entropic filtering, as implemented in imagej, to a spect image slice containing ngassociated in in the liver. background-subtracted pseudo-color spect images were overlayed on ct images and axial slices depicting lungs were selected for display, with ct thresholding set to emphasize negative contrast in the airspace of the lungs. imagej's built-in d modeling plugin was used to co-register background-subtracted pseudo-color spect images with ct images in three-dimensional reconstructions. ct image thresholding was set in the d modeling tool to depict skeletal structure alongside spect signal. for three-dimensional reconstructions of lung ct images, thresholding was set, as above, for contrast emphasizing the airspace of the lungs, with thresholding values standardized between different ct images (i.e. identical values were used for naïve and edematous lungs). images were cropped in a cylinder to exclude the airspace outside of the animal, then contrast was inverted, allowing airspace to register bright ct signal and denser tissue to register as dark background. three-dimensional reconstructions of the lung ct data, and co-registrations of spect data with lung ct data, were generated as above with imagej's d plugin applied to ct data cropped and partitioned for lung contrast. quantification of ct attenuation employed imagej's measurement tool iteratively over axial slices, with measurement fields of view manually set to contain lungs and exclude surrounding tissue. mice were exposed to nebulized lps in a 'whole-body' exposure chamber, with separate compartments for each mouse (mpc- aero; braintree scientific). to maintain adequate hydration, mice were injected with ml of sterile saline warmed to °c, intraperitoneally, immediately before exposure to lps. lps (l - mg, sigma aldrich) was reconstituted in pbs to mg/ml and stored at - °c until use. immediately before nebulization, lps was thawed and diluted to mg/ml with pbs. lps was aerosolized via a jet nebulizer connected to the exposure chamber (neb-med h, braintree scientific, inc.). ml of mg/ml lps was used induce the injury. nebulization was performed until all liquid was nebulized (~ minutes). liposomes or saline sham were administered via retro-orbital injections of µl of suspension ( mg/kg liposome dose) at hours after lps exposure. mice were anesthetized with % isoflurane to facilitate injections. bronchoalveolar lavage (bal) fluid was collected hours after lps exposure, as previously described. briefly, mice were anesthetized with ketamine-xylazine ( mg/kg ketamine, mg/kg xylazine, intramuscular administration). the trachea was isolated and a tracheostomy was performed with a -gauge catheter. the mice were euthanized via exsanguination. . ml of cold bal buffer ( . mm edta in pbs) was injected into the lungs over ~ min via the tracheostomy and then aspirated from the lungs over ~ min. injections/aspirations were performed three times for a total of . ml of fluid added to the lungs. recovery bal fluid typically amounted to ~ . ml. bal samples were centrifuged at xg for minutes. the supernatant was collected and stored at - °c for further analysis. protein concentration was measured using bio-rad dc protein assay, per manufacturer's instructions. the cell pellet was fixed for flow cytometry as follows. µl of . % pfa in pbs was added to each sample. samples were incubated in the dark at room temperature for minutes, then ml of bal buffer was added. samples were centrifuged at xg for min, the supernatant was aspirated, and ml of facs buffer ( % fetal calf serum and mm edta in pbs) was added. at this point, samples were stored at °c for up to week prior to flow cytometry analysis. to stain for flow cytometry, samples were centrifuged at xg for min, the supernatant was aspirated, and µl of staining buffer was added. staining buffer used was a : dilution of stock antibody solution (apc anti-mouse cd ; alexa fluor anti-mouse ly g, biolegend) into facs buffer. samples were incubated with staining antibody for minutes at room temperature in the dark. to terminate staining, ml of facs buffer was added, samples were centrifuged at xg for minutes, and supernatant was aspirated. cells were resuspended in µl of facs buffer and immediately analyzed via flow cytometry. flow cytometric analysis was completed with a bd accuri flow cytometer as follows: sample volume was set to µl and flow rate was set to 'fast'. unstained and single-stained controls were used to set gates. forward scatter (pulse area) vs. side scatter (pulse area) plots were used to gate out non-cellular debris. forward scatter (pulse area) vs. forward scatter (pulse height) plots were used to gate out doublets. the appropriate fluorescent channels were used to determine stained vs. unstained cells. the gates were placed using unstained control samples. single-stain controls were tested and showed there was no overlap/bleed-through between the fluorophores. final analysis indicated the quantity of leukocytes (cd -positive cells) and neutrophils (ly g-positive cells) in bal samples. human lungs were obtained after organ harvest from transplant donors whose lungs were in advance deemed unsuitable for transplantation. the lungs were harvested by the organ procurement team and kept at °c until the experiment, which was done within hours of organ harvest. the lungs were inflated with low pressure oxygen and oxygen flow was maintained at . l/min to maintain gentle inflation. pulmonary artery subsegmental branches were endovascularly cannulated, then tested for retrograde flow by perfusing for minutes with steen solution containing a small amount of green tissue dye at cm h o pressure. the pulmonary veins through which efflux of perfusate emerged were noted, allowing collection of solutions after passage through the lungs. a ml mixture of i-labeled lysozyme-dextran nanogels and ilabeled ferritin nanocages were injected through the arterial catheter. ~ ml of % bsa in pbs was passed through the same catheter to rinse unbound nanoparticles. a solution of green tissue dye was subsequently injected through the same catheter. the cannulated lung lobe was dissected into ~ g segments, which were evaluated for density of tissue dye staining. segments were weighed, divided into 'high', 'medium', 'low', and 'null' levels of dye staining, and measured for i and i signal in a gamma counter. for experiments with cell suspensions derived from human lungs (chosen for research use according to the above standards), single cell suspensions were generously provided by the laboratory of edward e. morrisey at the university of pennsylvania. aliquots of , cells were pelleted at xg for minutes and resuspended in µl pbs containing different quantities of lysozyme-dextran nanogels synthesized with fitc-labeled dextran. cells and nanogels were incubated at room temperature for minutes before two-fold pelleting at xg with ml pbs washes. cells were re-suspended in µl facs buffer for staining with apcconjugated anti-human cd , applied by -minute incubation with a : dilution of the antibody stock. cells were pelleted at xg for minutes and resuspended in µl pbs for immediate analysis with flow cytometry (bd accuri). negative/positive nanogel or anti-cd signal was established by comparison to unstained cells. singlestained controls indicated no spectral overlap between fitc-nanogel fluorescence and anti-cd apc fluorescence. proteins were prepared in deionized and filtered water at concentrations of . mg/ml for human albumin, . mg/ml for hen lysozyme, and . mg/ml for igg. crosslinked albumin nanoparticles, lysozyme-dextran nanogels, and igg-coated liposome suspensions were prepared such that albumin, lysozyme, and igg concentrations in the suspensions matched the concentrations of the corresponding protein solutions. protein and nanoparticle solutions were analyzed in quartz cuvettes with mm path length in an aviv circular dichroism spectrometer. the instrument was equilibrated in nitrogen at °c for minutes prior to use and samples were analyzed with sweeps between and nm in nm increments. each data point was obtained after a . s settling time, with a s averaging time. cdnn software deconvolved cd data (expressed in millidegrees) via neural network algorithm assessing alignment of spectra with library-determined spectra for helices, antiparallel sheets, parallel sheets, beta turns, and random coil. -anilino- -naphthalenesulfonic acid (ansa) at . mg/ml was mixed with lysozyme, human albumin, or igg at . mg/ml in pbs. for nanoparticle analysis, nanoparticle solutions were prepared such that albumin, lysozyme, and igg concentrations in the suspensions matched the . mg/ml concentration of the protein solutions. protein or nanoparticles and ansa were reacted at room temperature for minutes. excess ansa was removed from solutions by centrifugations against kda cutoff centrifugal filters (amicon). after resuspension to original volume, ansa-stained protein/nanoparticle solutions/suspension were examined for fluorescence (excitation nm, emission - nm) and absorbance ( - nm) maxima corresponding to ansa. for imaging neutrophil content in naïve and iv-lps-injured lungs, mice were intravenously injected with rat anti-mouse anti-ly g antibody (clone a ) and sacrificed minutes later. lungs were embedded in m medium, flash frozen, and sectioned in µm slices. sections were stained with percp-conjugated anti-rat secondary antibody and neutrophil-associated fluorescence was observed with epifluorescence microscopy. similar procedures enabled histological imaging of lysozyme-dextran nanogels in iv-lps-injured lungs. nanogels synthesized with rhodamine-dextran were administered intravenously in injured mice minutes prior to sacrifice. lungs were sectioned as above and stained with clone a anti-ly g antibody, followed by briliant violetconjugated anti-rat secondary antibody. sections of human lungs were obtained after ex vivo administration (see nanoparticle administration in human lungs above) of lysozyme-dextran nanogels synthesized with rhodamine dextran. regions of tissue delineated as perfused and nonperfused, as determined by arterial administration of tissue dye as above, were harvested, embedded in m medium, flash frozen, and sectioned in µm slices. epifluorescence imaging indicated rhodamine fluorescence from nanogels, coregistered to autofluorescence indicating tissue architecture. a mouse was anesthetized with ketamine/xylazine five hours after intravenous administration of mg/kg b lps. a jugular vein catheter was fixed in place for injection of lysozyme-dextran nanogels, anti-cd antibody, and fluorescent dextran during imaging. in preparation for exposure of the lungs, a patch of skin on the back of the mouse, around the juncture between the ribcage and the diaphragm, was denuded. while the mouse was maintained on mechanical ventilation, an incision at the juncture between the ribs and the diaphragm, towards the posterior, exposed a portion of the lungs. a coverslip affixed to a rubber o-ring was sealed to the incision by vacuum. the exposed portion of the mouse lung was placed in focus under the objective by locating autofluorescence signal in the "fitc" channel. with ms exposure, fluorescent images from channels corresponding to violet, green, near red, and far red fluorescence were sequentially acquired. a mixture of rhodamine-dextran nanogels ( . mg/kg), brilliant violet-conjugated anti-cd antibody ( . mg/kg), and alexa fluor labeled kda dextran ( mg/kg) for vascular contrast was administered via jugular vein catheter and images were recorded for minutes. images were recorded in slidebook software and opened in imagej (fiji distribution) for composition in movies with coregistration of the four fluorescent channels. all animal studies were carried out in strict accordance with guide for the care and use of laboratory animals as adopted by national institute of health and approved by university of pennsylvania institutional animal care and use committee (iacuc). male c bl/ j mice, - weeks old, were purchased from jackson laboratories. mice were maintained at - °c and on a / hour dark/light cycle with food and water ad libitum. ex vivo human lungs were donated from an organ procurement agency, gift of life, after determination the lungs were not suitable for transplantation into a recipient, and therefore would have been discarded if they were not used for our study. gift of life obtained the relevant permissions for research use of the discarded lungs, and in conjunction with the university of pennsylvania's institutional review board ensured that all relevant ethical standards were met. error bars indicate standard error of the mean throughout. significance was determined through paired t-test for comparison of two samples and anova for group comparisons. linear discriminant analysis and principal components analysis were completed in gnu octave scripts (adapted from https://www.bytefish.de/blog/pca_lda_with_gnu_octave/, and made available in full in the supplementary materials). findings in this study contributed to united states provisional patent application number / . raw imaging, flow cytometry, gamma counter, and spectroscopy data supporting the findings of this study are available from the corresponding author upon reasonable request. all other data supporting the findings of this study are available within the paper and its supplementary information files. covid- in critically ill patients in the seattle region -case series the influenza pandemic: insights for the st century lung safe investigators; esicm trials group. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries incidence and outcomes of acute lung injury. b. engl nanomedicine for the treatment of acute respiratory distress syndrome. the ats bear cage award-winning proposal the mercurial nature of neutrophils: still an enigma in ards? endothelial nanomedicine for the treatment of pulmonary disease balti- study investigators. effect of intravenous β- agonist treatment on clinical outcomes in acute respiratory distress syndrome (balti- ): a multicentre, randomised controlled trial national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network. randomized, placebo-controlled clinical trial of an aerosolized β -agonist for treatment of acute lung injury neutrophil function in inflammation and inflammatory diseases paradoxical roles of the neutrophil in sepsis: protective and deleterious targeting neutrophils in ischemic stroke: translational insights from experimental studies neutrophil function in ischemic heart disease contribution of neutrophils to acute lung injury neutrophils kinetics in health and disease neutrophil-endothelial cell interactions in the lung the multifaceted functions of neutrophils neutrophils in the activation and regulation of innate and adaptive immunity what drives neutrophils to the alveoli in ards? pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome neutrophil margination, sequestration, and emigration in the lungs of l-selectin-deficient mice ly family proteins in neutrophil biology use of ly g-specific monoclonal antibody to deplete neutrophils in mice neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases therapeutic targeting of neutrophil granulocytes in inflammatory liver disease prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils neutrophil-mediated delivery of therapeutic nanoparticles across blood vessel barrier for treatment of inflammation and infection non-affinity factors modulating vascular targeting of nano-and microcarriers physical approaches to biomaterial design impact of particle elasticity on particle-based drug delivery systems factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles cell-mediated delivery of nanoparticles: taking advantage of circulatory cells to target nanoparticles neutrophil sequestration and migration in localized pulmonary inflammation. capillary localization and migration across the interalveolar septum neutrophil recruitment to the lungs during bacterial pneumonia the lung is a host defense niche for immediate neutrophilmediated vascular protection icam- targeted nanogels loaded with dexamethasone alleviate pulmonary inflammation flexible nanoparticles reach sterically obscured endothelial targets inaccessible to rigid nanoparticles long-circulating janus nanoparticles made by electrohydrodynamic co-jetting for systemic drug delivery applications the transport and inactivation kinetics of bacterial lipopolysaccharide influence its immunological potency in vivo quantitative analysis of protein far uv circular dichroism spectra by neural networks selective staining of proteins with hydrophobic surface sites on a native electrophoretic gel lysozyme-dextran core-shell nanogels prepared via a green process in vivo editing of macrophages through systemic delivery of crispr-cas -ribonucleoprotein-nanoparticle nanoassemblies adeno-associated virus structural biology as a tool in vector development structure of human adenovirus cisplatin encapsulation within a ferritin nanocage: a high-resolution crystallographic study vascular targeting of radiolabeled liposomes with bio-orthogonally conjugated ligands: single chain fragments provide higher specificity than antibodies targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin acute respiratory distress syndrome: diagnosis and management novel role for cftr in fluid absorption from the distal airspaces of the lung red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude neutrophil-particle interactions in blood circulation drive particle clearance and alter neutrophil responses in acute inflammation the tlr -myd pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice adeno-associated viral vectors at the frontier between tolerance and immunity serum ferritin: past, present and future facile double-functionalization of designed ankyrin repeat proteins using click and thiol chemistries a new reagent which may be used to introduce sulfhydryl groups into proteins, and its use in the preparation of conjugates for immunoassay doxil®--the first fda-approved nano-drug: lessons learned lipid rafts regulate lipopolysaccharide-induced activation of cdc and inflammatory functions of the human neutrophil alterations in membrane cholesterol cause mobilization of lipid rafts from specific granules and prime human neutrophils for enhanced adherence-dependent oxidant production generation of targeted adenoassociated virus (aav) vectors for human gene therapy biphasic janus particles with nanoscale anisotropy direct cytosolic delivery of crispr/cas -ribonucleoprotein for efficient gene editing direct cytosolic delivery of proteins through coengineering of proteins and polymeric delivery vehicles antioxidant protection by pecam-targeted delivery of a novel nadph-oxidase inhibitor to the endothelium in vitro and in vivo red: anti-ly g stain. green: tissue autofluorescence. (f) biodistributions of heat-inactivated, fixed, and ilabeled e. coli in naïve (n= ) and iv-lps-injured (n= ) mice tissue autofluorescence). (k) single frame from real-time intravital imaging of ldng (red) uptake in leukocytes (green) in iv-lps-inflamed pulmonary vasculature (blue, alexa fluor -dextran) biodistributions in iv-lps-injured mice for azide-functionalized liposomes conjugated to igg loaded with . , , , and dbco molecules per igg (bars further to the right correspond to more dbco per igg). (d) mouse lungs flow cytometry data indicating ly g anti-neutrophil staining density vs. levels of dbco( x)-igg liposome uptake. (e) flow cytometry data verifying increased dbco( x)-igg liposome uptake in and specificity for neutrophils following lps insult (inset: verification of increased concentration of neutrophils in the lungs following lps key: cord- - lwmzjxz authors: konig, maximilian f; powell, mike; staedtke, verena; bai, ren-yuan; thomas, david l; fischer, nicole; huq, sakibul; khalafallah, adham m; koenecke, allison; xiong, ruoxuan; mensh, brett; papadopoulos, nickolas; kinzler, kenneth w; vogelstein, bert; vogelstein, joshua t; athey, susan; zhou, shibin; bettegowda, chetan title: targeting the catecholamine-cytokine axis to prevent sars-cov- cytokine storm syndrome date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: lwmzjxz the mortality of coronavirus disease (covid- ) appears to be driven by acute respiratory distress syndrome (ards) and a dysregulated immune response to sars-cov- . emerging evidence suggests that a subset of covid- is characterized by the development of a cytokine storm syndrome (css), and interleukin (il)- levels are predictors of covid- severity and in-hospital mortality. targeting hyper-inflammation in covid- may be critical for reducing mortality. catecholamines enhance inflammatory injury by augmenting the production of il- and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha- adrenergic receptor (α -ar) signaling. prophylactic inhibition of catecholamine synthesis with the α -ar antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. these findings offer a rationale for studying α -ar antagonists in the prophylaxis of patients with covid- -css and ards. as high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate covid- severity and reduce excessive mortality are desperately needed. we hypothesize that treatment with prazosin of individuals who test positive for sars-cov- could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. to investigate a potential role for α -ar antagonists in preventing poor outcomes in ards, we conducted a retrospective analysis of hospitalized patients diagnosed with ards. using data from the truven health marketscan research database ( - ), we identified , men (age - ) with ards, of whom patients ( . %) were prescribed α -ar antagonists in the previous year. applying logistic regression models, we found that patients with prior use of α -ar antagonists had lower odds of invasive mechanical ventilation compared to non-users (adjusted or= . , % ci . - . , p= . ). perhaps more importantly, those patients had a ~ % lower incidence of both being ventilated and dying in the hospital (adjusted or= . , % ci . - . , p= . ). by contrast, prior use of beta-adrenergic receptor (β-ar) antagonists was not correlated with either outcome. we extended these analyses to patients admitted with pneumonia. of , subjects in this cohort, , patients ( . %) were taking α -ar antagonist. similar to ards, patients with pneumonia on α -ar antagonists (but no β-ar antagonists) had a lower odds of mechanical ventilation (adjusted or= . , % ci . - . , p< . ) and of both being ventilated and dying in the hospital (adjusted or= . , % ci . - . , p= . ) compared to non-users. mirroring findings from pre-clinical models, these data support a clinical rationale to study α -ar antagonists in the prevention of severe complications of pneumonia, ards, and covid- . prospective, randomized clinical trials of alpha- receptor antagonists (e.g. prazosin) administered prior to the onset of severe symptoms are needed to assess their efficacy in preventing css and reducing mortality in covid- . to be driven by acute respiratory distress syndrome (ards) and a dysregulated immune response to sars-cov- - . emerging evidence suggests that a subset of covid- is characterized by the development of a cytokine storm syndrome (css) that resembles cytokine release syndrome (crs) in chimeric antigen receptor (car)-t cell therapy , , . hyper-inflammation in covid- is associated with elevation of proinflammatory cytokines including interleukin (il)- , il- r, il- , tumor necrosis factor-α, and granulocytecolony stimulating factor , . this is similar to the exuberant cytokine production by lung-infiltrating monocytes/macrophages and pneumocytes observed in sars-cov and mers-cov infection . targeting the hyper-inflammation in covid- may be critical for reducing mortality. il- levels diverge profoundly between non-survivors and survivors in the third week after symptom onset and are predictors of covid- severity and in-hospital mortality , , . tocilizumab, a monoclonal antibody targeting the il- receptor, is currently being investigated for the treatment of patients with covid- -css (chictr , nct , nct ) [ ] [ ] [ ] . pending data from randomized controlled trials, retrospective data from patients with severe or critical covid- treated with tocilizumab suggests that inhibition of the il- signaling axis is highly effective . however, given the cost, immunosuppression, and potential adverse reactions of tocilizumab, this strategy will likely be restricted to select patients in developed countries. we have recently shown that crs observed with bacterial infections, car-t cells, and other t cell-activating therapies is accompanied by a surge in catecholamines . catecholamines enhance inflammatory injury by augmenting the production of il- and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha- adrenergic receptor (⍺ -ar) signaling . prophylactic inhibition of catecholamine synthesis with metyrosine, a tyrosine hydroxylase antagonist, reduced levels of catecholamines and cytokine responses and resulted in markedly increased survival following various inflammatory stimuli in mice. similar protection against a hyper-inflammatory stimulus was observed with prazosin, demonstrating that ⍺ -ar antagonists can also prevent cytokine storm . . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the findings discussed herein offer a rationale for studying ⍺ -ar antagonists in the prophylaxis of covid- -css. however, all drugs can have unanticipated side effects, and the incompletely understood relationship between hypertension and covid- suggests caution in using any agent that impacts blood pressure . prospective, double-blinded clinical trials of ⍺ -ar antagonists in high-risk patients, when administered prior to symptom onset, will therefore be required to assess their utility in preventing covid- -css. prazosin is inexpensive and safe, as has been documented by long-term . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint treatment of millions of patients with benign prostatic hyperplasia, hypertension, and other conditions. we emphasize that the extensive experience with using prazosin for other indications should prioritize -not obviate -rigorous, controlled clinical research rather than indiscriminate off-label use in patients exposed to sars-cov- . such trials could be expeditiously implemented in areas suffering from high infection rates that threaten to overwhelm hospital capacity. we encourage readers to recommend specific populations and trial designs to test the hypothesis proposed herein. *adjusted for comorbid hypertension, ischemic heart disease, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, benign prostatic hyperplasia, and post-traumatic stress disorder identified from health care encounters in the prior year as well as age and year. a . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . coi: in , johns hopkins university filed a patent application on the use of various drugs to prevent cytokine release syndromes, on which v.s., r.b., b.v., k.w.k., and s.z. are listed as inventors. . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china dysregulation of immune response in patients with covid- in wuhan, china clinical features of patients infected with novel coronavirus in wuhan covid- : consider cytokine storm syndromes and immunosuppression clinical and immunologic features in severe and moderate forms of coronavirus disease pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology detectable serum sars-cov- viral load (rnaaemia) is closely associated with drastically elevated interleukin (il- ) level in critically ill covid- patients the potential role of il- in monitoring coronavirus disease chinese clinical trial register (chictr) -the world health organization international clinical trials registered organization registered platform tocilizumab vs crrt in management of cytokine release syndrome (crs) in covid- -full text view -clinicaltrials favipiravir combined with tocilizumab in the treatment of corona virus disease -full text view -clinicaltrials effective treatment of severe covid- patients with tocilizumab disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome covid- and the cardiovascular system key: cord- - s mjcf authors: wrigge, h.; glien, c. title: spezifische therapie des akuten lungenversagens date: - - journal: anaesthesist doi: . /s - - - sha: doc_id: cord_uid: s mjcf due to a high heterogeneity and dynamic changes in the course of acute respiratory distress syndrome (ards), intensive care physicians are faced with extraordinary challenges. while the current definition, pathophysiology and differential diagnoses were previously addressed in this journal, this article focuses on some specific and individualized treatment options. ventilation treatment with limitation of tidal volumes and pressure amplitudes has been shown to be advantageous with respect to mortality. nevertheless, because of the multifactorial etiology of ards in the context of individual circumstances, this strategy needs to be adjusted to each patient’s needs. in recent years it has become increasingly evident that prone positioning, early spontaneous breathing and early mobilization improve the course of the disease. therefore, an individualized treatment should consider these issues and take the characteristics of the patient and the specific disease progression into account. dieser cme-beitrag knüpft an einen beitrag zu pathophysiologie und definition des "acute respiratory distress syndrome" (ards) von dembinski [ ] , die s -leitlinie zur invasiven beatmung [ ] und die s -leitlinie zur lagerungstherapie [ ] an. der fokus liegt auf der individualisierung des "positive endexpiratory pressure" (peep), der indikation und durchführung von rekrutierungsmanövern und der anwendung von bauchlagerung bei der therapie des ards. aus aktuellem anlass wird in übersichtlicher form auf die bisher bekannten spezifika bei der therapie der "coronavirus disease " (covid- ) eingegangen. die allgemeine empfehlung, dass atemzugvolumen (tidalvolumen, vt) auf einen wert von ml/kg des idealen körpergewichts zu normieren, gilt grundsätzlich. allerdings muss beachtet werden, dass es sich nur um eine grobe annäherung an das vermeintliche lungenvolumen des patienten handelt. dabei ist die idee, dass abhängig von körpergröße und geschlecht über das ideale körpergewicht ( infobox ) eine abschätzung des endexspiratorischen lungenvolumens (eelv) oder der funktionellen residualkapazität ermöglicht wird. insbesondere für die faktoren Übergewichtigkeit (adipositas) und schwere lungenerkrankung ist es möglich, dass sich bei gleicher körpergröße und gleichem geschlecht, also vergleichbarem idealen körpergewicht, die lungenvolumina von patienten unterscheiden (abb. ). es erscheint also aus physiologischer sicht sinnvoll, weitere parameter als nur körperlänge und geschlecht zu betrachten. letztendlich stehen die begrenzung der dehnung der einzelnen belüfteten lungenareale und die vermeidung der Überdehnung dieser lungenareale bei der einstellung einer protektiven beatmung im vordergrund des bestrebens. die spezifische dehnung einer alveole hängt vom volumen der alveole und der spezifischen ventilation dieses lungenareals, also dem anteiligen vt, ab. bei gleichem vt entscheidet die anzahl der alveolen, die an der ventilation teilnehmen, damit das eelv, über die spezifische dehnung der einzelnen alveole. schematisch zeigt abb. das eelv von hypothetischen patienten, abhängig vom bmi. beide patienten sind männlich und gleich groß, sodass sich rechnerisch dasselbe idealgewicht von kg ergibt (infobox , der bmi für das idealgewicht ist kg/m ). der klinisch empfohlene bezug des vt auf das idealgewicht (vt/kg idealgewicht) ist eine erste pragmatische näherung, um das geschlechtsund größenabhängige lungenvolumen bei der auswahl des vt zu berücksichtigen. das beispiel zeigt, dass diese einfache abschätzung in der klinischen praxis durchaus zu unterschieden in der wirklichen mechanischen belastung des lungenparenchyms führen kann. wenn, wie in diesem fall, eine reduktion des eelv durch adipositas vorliegt, erhöht sich die mechanische dehnung des geringeren lungenvolumens, dass dasselbe vt aufnehmen muss. dies ist in der unteren reihe der abb. zu sehen; dort ist die inspiratorische ausdehnung des lungenvolumens in dunkelblau dargestellt. das heißt konkret, wenn nur wenige alveolen belüftet sind und an der ventilation teilnehmen können, ist bei gleichem vt die abstract specific treatment of acute lung failure due to a high heterogeneity and dynamic changes in the course of acute respiratory distress syndrome (ards), intensive care physicians are faced with extraordinary challenges. while the current definition, pathophysiology and differential diagnoses were previously addressed in this journal, this article focuses on some specific and individualized treatment options. ventilation treatment with limitation of tidal volumes and pressure amplitudes has been shown to be advantageous with respect to mortality. nevertheless, because of the multifactorial etiology of ards in the context of individual circumstances, this strategy needs to be adjusted to each patient's needs. in recent years it has become increasingly evident that prone positioning, early spontaneous breathing and early mobilization improve the course of the disease. therefore, an individualized treatment should consider these issues and take the characteristics of the patient and the specific disease progression into account. acute respiratory distress syndrome · peep titration · lung recruitment maneuver · prone position · covid- spezifische dehnung dieser alveolen größer. da die compliance des respiratorischen systems (crs) indirekt vom eelv abhängt und einfacher zu bestimmen ist als das lungenvolumen, erscheint die einbeziehung von crs neben der allgemeinen abschätzung des idealen körpergewichts als sinnvoll. hier hat sich in letzter zeit der parameter des "Δ-pressure" oder des "driving pressure" (Δp) bewährt. das Δp beschreibt die druckamplitude, die zur ventilation oder zur applikation des vt erforderlich ist. rechnerisch ergibt sich Δp aus der differenz von pplat und peep oder dem quotienten aus vt und crs: idee bei der anwendung eines peep, den alveolarkollaps in der exspiration zu verhindern und das eelv möglichst ausreichend groß zu halten. somit gibt es ansätze, Δp zur peep-titration zu nutzen, in dem bei einer absteigenden "peep-treppe" während volumenkontrollierter beatmung das peep-niveau gesucht wird, auf dem das konstante vt im niedrigsten Δp resultiert, also die crs am größten ist. die peep-titration durch minimierung des Δp während volumenkontrollierter beatmung ist in abb. gezeigt. der peep wird von einem maximal tolerablen wert (exemplarisch cm h o) schrittweise gesenkt, und nach erreichen stabiler bedingungen (hier idealerweise min, in praxi sollte aber mindestens min gewartet werden) wird jeweils auf dem aktuellen peep-niveau die druckamplitude Δp gemessen, die für die applikation des konstanten vt erforderlich ist. die peep-stufe mit dem geringsten Δp (abb. grüne kurve mit rot markiertem minimum) repräsentiert bei konstantem vt die beste crs und das peep-niveau mit der günstigsten atemmechanik. zur sicherheit kann die nächsthöhere peep-stufe gewählt werden, um einen zeitabhängigen kollaps des lungengewebes zu berücksichtigen. einige faktoren können abweichungen von der beatmungseinstellung nach idealgewicht und peep-tabellen bedingen. die konstitution des patienten spielt eine rolle; insbesondere patienten mit adipositas benötigen aufgrund des hohen gewebsdrucks, der auf den alveolen lastet, auch unter gesunden bedingungen, einen relativ hohen peep [ ] . Ähnlich wie adipositas wirkt sich beispielsweise ein erhöhter intraabdomineller druck etwa im rahmen eines septischen schocks aus, in dem sich teile davon über das zwerchfell auf die pleura übertragen und zu einer kompression, insbesondere der dorsalen abhängigen lungenareale, führen. bei einem höheren druck außerhalb der alveole im verhältnis zum inneren kann es zu kompressionsatelektasen kommen. die genannten faktoren bedingen eine einschränkung der thoraxwand-compliance ("chestwall compliance", ccw), die summiert mit der lungen-compliance (cl) die crs bildet. die frage, ob bei einer eingeschränkten crs eine erniedrigte cl oder (auch) eine erniedrigte ccw vorliegt, kann oft nicht einfach beantwortet werden. die beiden komponenten von crs lassen sich unter berücksichtigung des pleuradrucks trennen, der über die messung des Ösophagusdrucks (pes) abgeschätzt werden kann. hinweise auf einen erhöhten pleuradruck oder pes können klinische aspekte wie adipositas, aber auch ein erkrankungsbedingt erhöhter abdomineller druck sein, der sich teilweise auf den pleuradruck überträgt. weiterhin ist es sinnvoll, sich den mechanismus der lungenschädigung klarzumachen und abzuschätzen, ob das lungengewebe mit dem vorliegenden schädigungsmechanismus rekrutierbar ist. das heißt, die anwendung von höheren beatmungsdrücken führt zur wiedereröffnung von lungengewebe, und dieses kann im anschluss durch einen entsprechenden peep auch offen gehalten werden. dies kann z. b. der fall sein, wenn sich im rahmen der systemischen inflammation eines extrapulmonalen septischen geschehens ein sekundärer lungenschaden mit einem interstitiellen Ödem entwickelt und die konsekutive erhöhung des spezifischen lungengewichts einen nachfolgenden alveolarkollaps bedingt. die in dieser form geschädigte lunge ist häufig, insbesondere in der frühphase, noch rekrutierbar und kann durch anwendung höherer beatmungsdrücke wiedereröffnet und mit einem adäquaten peep offen gehalten werden. anders kann es sich beispielsweise darstellen, wenn im fall einer pneumonie das lungengewebe infiltriert und mit putridem sekret gefüllt ist, das sich auch durch anwendung höherer beatmungsdrücke nicht aus den alveolen verdrängen lässt. damit ist eine rekrutierung durch höhere beatmungsdrücke nur in geringem oder nichtausreichendem maß möglich. in diesen fällen kann die anwendung eines hohen peep sogar dazu führen, dass die bereits rekrutierten und belüfteten lungenareale in der inspiration zusätzlich überdehnt und überbläht werden. wichtig bei der wahl des peep ist die abschätzung oder testung, ob rekrutierbares lungengewebe vorhanden ist oder nicht. zur beurteilung der rekrutierbarkeit kann beispielsweise eine thorax-ct herangezogen werden, da diese aufschluss über art und verteilung der infiltrationen und konsolidierungen im lungenbereich gibt. eine relativ pragmatische methode zur individualisierung des peep wurde vom amerikanischen ards-netzwerk vorgeschlagen [ ] , bei der der peep nach tabellen an- wie auch die s -leitlinie zur beatmung feststellt, gibt es momentan keinen konsentierten weg zur einstellung des peep [ ] . die ergebnisse der weltweit durchgeführten lung-safe-studie [ ] zeigen allerdings, dass in der praktischen anwendung selten ein peep höher als cm h o auch bei patienten mit schwerem ards angewendet wird, was aus sicht des autors auf größere defizite im bereich der individualisierten beatmungseinstellung hinweisen kann. -eine thorax-ct kann zur abschätzung der rekrutierbaren lungenabschnitte herangezogen werden. rekrutierungsmanöver sollen dazu dienen, den kritischen Öffnungsdruck von rekrutierbaren alveolen zu überschreiten, um nachfolgend mit einem peep oberhalb des kritischen verschlussdrucks diese lungenareale offen zu halten. physikalisch beruht dies auf dem laplace-gesetz, wonach ein hohlkörper einen höheren druck zur Öffnung braucht als zum offenhalten. der klinische stellenwert von rekrutierungsmanövern ist hoch umstritten, und die aktuelle s -leitlinie zur invasiven beatmung kann rekrutierungsmanöver beim ards nicht generell empfehlen. in einer metaanalyse untersuchten suzumura et al. [ ] die zu dem zeitpunkt vorliegenden randomisierten kontrollierten studien und kamen zu dem ergebnis, dass sich zwar formal ein vorteil für rekrutierungsmanöver hinsichtlich der krankenhausletalität finden ließ, dass aber die heterogenität der eingeschlossenen studien zu hoch war, um einen endgültigen schluss zu ziehen. in einer späteren randomisierten kontrollierten studie [ ] wurden patienten entweder einer gruppe mit peep-einstellung nach höherer peep-tabelle des ards-netzwerks [ ] oder einer gruppe, die ein rekrutierungsmanöver mit nachfolgender peep-titration gemäß der besten crs erhielt, zugeführt. das initial nach protokoll durchgeführte rekrutierungsmanöver sah einen peep von cm h o und einen pplat von cm oberhalb des peep, also cm h o, vor [ ] . da es im laufe der studie zu todesfällen im rahmen dieses rekrutierungsmanövers kam, wurde das protokoll geändert, und es erfolgte ein abgeschwächtes rekrutierungsmanöver mit einem peep von cm h o und einem pplat von cm h o [ ] . während der studie haben etwa % der teilnehmenden die beiden jeweiligen manöver erhalten; in den restlichen fällen musste das manöver wegen hämodynamischer instabilität bei niedrigeren peep-werten abgebrochen werden. die primäre outcome-variable der studie war die - tage [ ] . bei dieser patientengruppe überwiegen die vorteile der frühmobilisation mit geringerer analgosedierung und früher spontanatmung, auch wenn es hierfür bisher wenige große studien gibt [ ] . gemäß s -leitlinie ist für die praxis wichtig, dass ) die indikation für die bauchlage das schwere ards mit einem pao /fio -verhältnis < mm hg ist, dass ) die bauchlage möglichst für einen zeitraum von mindestens h durchgeführt werden sollte, ) die kontinuierliche laterale rotationstherapie (klrt) oder die inkomplette bauchlage ( °) beim schweren ards nicht gleichwertig wirksam sind, da keine vorteile für das Überleben der patienten gezeigt werden konnten [ ] . diese verfahren sind für ausnahmefälle wie z. b. vorhandensein eines fixateurs externe oder Ähnliches vorgesehen. weiterhin kann beachtet werden, dass eine augmen-tierte spontanatmung auch während der bauchlage möglich ist, obwohl sich die atemmechanik in bauchlage häufig verschlechtert und der anteil der unterstützung oft erhöht werden muss [ ] . nach empfehlung der leitlinie soll die bauchlage bzw. die intermittierende bauchlage beendet werden, wenn es zur anhaltenden verbesserung der oxygenierung in rückenlage kommt, oder wenn die patienten auch in bauchlage mit -h-intervallen nicht zur respondergruppe, d. h. zur gruppe mit verbesserter oxygenierung, gehören. ansonsten gelten auch während der bauchlage die kriterien der protektiven beatmung. beim konzept der frühmobilisation wird eine mobilisation innerhalb von h nach aufnahme auf die intensivstation (its) angestrebt. hierbei wird die passive mobilisation (durchbewegen, passives bettradfahren, kipptisch, stehbrett, rehabilitationsstuhl) unterschieden von der assistierten aktiven mobilisation mit bewegungsübungen in rückenlage, selbstständiger mobilisation im bett, balancetraining, assistiertem bettfahrradfahren und der aktiven mobilisation (sitzen auf der bettkante, stehen, gehen oder aktives bettfahrradüben; [ ] ). abhängig von der erfahrung des durchführenden teams sind diese maßnahmen auch bei beatmeten patienten und auch unter katecholamintherapie oder anderen organersatzverfahren grundsätzlich möglich. in frühen studien konnten schweickert et al. [ ] zeigen, dass die frühmobilisation zu einer früheren selbstständigkeit des patienten führt, weil sie mit einer verringerten analgosedierung, mit weniger delir und anderen vorteilen einhergeht. retrospektive analysen von balzer et al. konnten feststellen [ ] , dass sich die Überlebensrate nach jahren nachhaltig unterscheidet, mit vorteil für die nicht so tief sedierten patienten. spezielle aspekte der beatmung und therapie von covid- -bedingtem acute respiratory distress syndrome eine abschließende bewertung der therapieprinzipien für dieses patientenkollektiv ist zum zeitpunkt der erstellung dieses beitrags noch zu früh, auch weil die evidenzlage noch gering ist. grundsätzlich gelten ähnliche prinzipien wie bei der behandlung der bisher bekannten ards-formen [ ] . es scheint sich aber herauszukristallisieren, dass es verschiedenste verlaufsformen der erkrankung gibt, wie z. b. von gattinoni et al. zusammengefasst [ ] . dabei wird, bezogen auf die merkmale "elastance", ventilation-perfusion-verhältnis, lungengewicht und rekrutierbarkeit, ein l-typ ("low") von einem h-typ ("high") unterschieden; bei den beiden typen sind die genannten merkmale entsprechend verändert. pathophysiologisch scheint die lungenarterienthrombose mit intimaschäden durch das virus selbst eine rolle zu spielen, sodass ein teil der patienten (l-typ) mit einer o -inhalation oder high-flow-sauerstofftherapie cme behandelt werden kann. sowohl nichtbeatmete wie auch invasiv beatmete patienten scheinen häufig von einer bauchlage zu profitieren. insbesondere bei leichten und mittelschweren oxygenierungsstörungen scheint der effekt der bauchlage weniger auf der rekrutierung von lungengewebe als auf einer verbesserung eines missverhältnisses von ventilation und perfusion zu beruhen, was durch vasoregulationsstörungen und thrombotische areale aufgrund der endothelialen schädigung durch das virus bedingt sein kann. das klassische ards mit schwersten konsolidierungen und einem großen verlust von lungengewebe ist bei moderaten verläufen (l-typ) von ards durch covid- weniger stark ausgeprägt. dies erklärt auch die erfolgreiche beatmung mit z. t. moderaten peep-werten. allerdings gibt es auch schwere verlaufsformen mit schwerem interstitiellem lungenödem sowie nachfolgender konsolidierung größerer lungenareale und einem erhöhten lungengewicht (h-typ). auch wenn es erste therapeutische ansätze zur senkung der sterblichkeit von beatmeten patienten mit covid- gibt [ ] , muss das ziel der beatmungstherapie, wenn sie denn nötig ist, sein, den patienten intensivmedizinisch möglichst schonend und ohne weitere zusätzliche komplikationen durch den erkrankungsverlauf zu führen. dabei sind aus sicht der autoren, wenn irgend möglich, die konzepte der frühmobilisation und der frühen spontanatmung bei so geringer analgosedierung wie möglich anzuwenden, um nicht noch iatrogene komplikationen und eine verlängerung der beatmungszeit mit nachfolgenden sekundärpneumonien zu riskieren. nach schweren verläufen auftretende "critical-illness"-myopathie und "critical-illness"-polyneuropathie können das weaning von der beatmung bei covid- -patienten in besonderer weise erschweren. in einzelnen fällen hat sich die "neurally adjusted ventilatory assist" (nava) als verfahren erwiesen, das auch bei extremen atemfrequenzen und extremer muskelschwäche eine adäquate und zeitgerechte unterstützung der spontanatmung liefern kann. ist es wirklich ein akutes lungenversagen?: aktuelle definitionen clinical practice guideline: mechanical ventilation and extracorporeal membrane oxygenation in acute respiratory insufficiency s e guideline: positioning and early mobilisation in prophylaxis or therapy of pulmonary disorders driving pressure and survival in the acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries individualized positive end-expiratory pressure in obese patients during general anaesthesia: a randomized controlled clinical trial using electrical impedance tomography higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial transient hemodynamic effects of recruitment maneuvers in three experimental models of acute lung injury neuromuscular blockers in early acute respiratory distress syndrome early neuromuscular blockade in the acute respiratory distress syndrome potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the lung safe study prone position for acute respiratory distress syndrome. a systematic review and meta-analysis early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome kurzversion s e-leitlinie -"lagerungstherapie und frühmobilisation zur prophylaxe oder therapie von pulmonalen funktionsstörungen combinedeffectsofprone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial early deep sedation is associated with decreased in-hospital and two-year follow-up survival german recommendations for critically ill patients with covid- covid- pneumonia: different respiratory treatments for different phenotypes? dexamethasone in hospitalized patients with covid- -preliminary report zu den kursen dieser zeitschrift: scannen sie den qr-code oder gehen sie auf www.springermedizin.de/kurse-der-anaesthesist spezifische therapie des akuten lungenversagens ? sie behandeln einen -jährigen patienten (körperlänge cm, körpergewicht kg) mit einem schweren sekundären "acute respiratory distress syndrome" (ards; p/f-ratio < mm hg) aufgrund einer verbrennung. im ct zeigt sich ein interstitielles Ödem, aber keine größeren atelektasen. zur aufrechterhaltung eines ausreichenden mittleren arteriellen drucks ist ein mäßiger katecholamin-support erforderlich. aktuell erfolgt eine druckkontrollierte beatmung ("peak inspiratory pressure" [ key: cord- -n vjjw r authors: rai, deependra kumar; sharma, priya; kumar, rahul title: post covid pulmonary fibrosis- is it real threat? date: - - journal: indian j tuberc doi: . /j.ijtb. . . sha: doc_id: cord_uid: n vjjw r after the covid outbreak, there are a growing number of patients worldwide who have survived covid- but continue to battle the symptoms of the illness, long after they have clinically tested negative for the disease. as we move forward through this pandemic, the challenging part is how to manage this covid- sequelae which may vary from mild in terms of fatigue and body aches to lung fibrosis. this review addressed underlying mechanism, risk factors, course of disease and treatment option for post covid pulmonary fibrosis. elderly patient who require icu care and mechanical ventilation are highest risk to develop lung fibrosis. currently, no fully proven options are available for the treatment of post inflammatory covid pulmonary fibrosis. coronavirus disease (covid- ) is caused by a novel coronavirus, known as severe acute respiratory syndrome coronavirus (sars-cov- ). the global pandemic began in wuhan, china, in december , and has since spread worldwide .as of september , , the cases of covid- infection continues to soar worldwide with no peak in sight making total case tally standing at , , including , , active cases, , , cured/discharged/migrated and , deaths, according to the ministry of health and family welfare. while whole medical fraternity and researchers across the world continue to learn more about the novel contagion and its bizarre array of symptoms, it is becoming clear that the battle with covid- is not an easy one. after the covid outbreak, there are a growing number of patients worldwide who have survived covid- but continue to battle the symptoms of the illness, long after they have clinically tested negative for the disease. they are called as long -haulers. as we move forward through this pandemic, the challenging part is how to manage this covid- sequelae which may vary from mild in terms of fatigue and body aches to severe in form of requiring long term oxygen therapy and lung transplantation due to lung fibrosis, significant cardiac abnormalities and stroke leading to significant impairment in quality of health. various studies have reported that around - % of patients who recovered from covid- presents with persistence of at least or more symptoms, even after being declare covid-free. [ ] [ ] considering millions of covid cases worldwide, even small proportion of post covid lung fibrosis is real concern. many active clinical trials and studies are underway to know more about the entity post covid pulmonary fibrosis. this narrative review summarizes current clinical evidence regarding post covid pulmonary fibrosis. this review was performed to address following question for post covid pulmonary fibrosis. there are various mechanisms of lung injury in covid- have been described, with both viral and immune-mediated mechanisms being implicated . pulmonary fibrosis can be either subsequent to chronic inflammation or an idiopathic, genetically influenced and age related fibroproliferative process. pulmonary fibrosis is a known sequela to ards. however, persistent radiological abnormalities after ards are of little clinical significance and have dwindled with protective lung ventilation. it has been found that % of patients with covid- develop ards, and % of ards cases are severe . the prevalence of post-covid- fibrosis will become apparent in time, but early analysis from patients with covid- on hospital discharge suggests that more than a third of recovered patients develop fibrotic abnormalities. the pathological feature of ards is diffuse alveolar damage (dad) which is characterized by an initial acute inflammatory exudative phase with hyaline membranes, followed by an organizing phase and fibrotic phase . previous studies highlight duration of disease is an important determinant for lung fibrosis post ards. this study showed that, % of patients with a disease duration of less than week, % of patients with a disease duration of between weeks and , and % of patients with a disease duration of greater than weeks, developed fibrosis . cytokine storm caused by an abnormal immune mechanism may lead to initiation and promotion of pulmonary fibrosis. epithelial and endothelial injury occurs in the inflammatory phase of ards due to dysregulated release of matrix metalloproteinases. vegf and cytokines such as il- and tnfα are also involved in the process of fibrosis. the reason remains unknown as to why certain individuals recover from such an insult, whereas others develop progressive pulmonary fibrosis due to accumulation of fibroblasts and myofibroblasts and excessive deposition of collagen. although ards seems to be the main predictor of pulmonary fibrosis in covid- , several studies showed that covid induced ards is different (high and low elastance type) from the classical ards. ct findings in many covid cases are also not suggestive of classical ards. along with, abnormal coagulopathy is another pathological feature of this disease. so, mechanism of pulmonary fibrosis in covid- is different from that of ipf and other fibrotic lung diseases, especially with pathological findings pointing to alveolar epithelial cells being the site of injury, and not the endothelial cells. one of the risk factors for the development of lung fibrosis in covid- is advanced age and this finding is same as in mers and sars-cov. [ ] [ ] second risk factor includes increased disease severity which includes comorbidities such as hypertension, diabetes, and coronary artery disease and lab findings like lymphopenia, leukocytosis, and elevated lactate dehydrogenase (ldh) . serum ldh level has been used as a marker of disease severity following acute lung injuries. it is an indicator of pulmonary tissue destruction and correlates with the risk of mortality. according to the world health organization, % of sars-cov- infections are mild, % develop severe symptoms, and % will become critically ill. third risk factor includes prolonged icu stay and duration of mechanical ventilation. while disease severity is closely related to the length of icu stay, mechanical ventilation poses an additional risk of ventilator-induced lung injury (vili). abnormalities of pressure or volume settings underlie this injury leading to a release of proinflammatory modulators, worsening acute lung injury, and increased mortality or pulmonary fibrosis in survivors. smokers are . times more likely to have severe symptoms of covid- and . times more likely to need icu admission and mechanical ventilation or die compared to nonsmokers. [ ] [ ] [ ] the world health organization (who) and the national institute on alcohol abuse and alcoholism (niaaa) have issued communications warning people to avoid excessive drinking, saying it may increase covid- susceptibility and severity. alcohol use disorder increases the risk for complications of covid- . what proportion of covid patient developed lung fibrosis is remains speculative and should not be assumed without appropriate prospective study. but we can extract data from sars and mers pandemic. zhanga etal followed sars patients for years and found . % at beginning of study, . % at one year and . % patients after years had pulmonary lesions visible on ct scans. similar findings were reported for mers also. the follow-up of mers patients for average days showed that lung fibrosis developed in a significant number of convalescents, and risk was found highest with patient who were elderly, hospitalised with severe disease in icu . we have paucity of data for course of post covid pulmonary fibrosis. in one of the study chest ct scan was performed on the last day before discharge, two weeks and four weeks after discharge. compared with the last ct scan before discharge, the abnormalities (including focal/ multiple ggo, consolidation, interlobular septal thickening, subpleural lines and irregular lines) in lungs were gradually absorbed in the first and second follow-ups after discharge. the lung lesions of . % discharged patients were fully absorbed after -week follow-up. it indicated that the damage to lung tissue by covid- could be reversible for the common covid- patients. it also suggested that the prognosis of nonsevere patients is favourable, and the clinical intervention should be conducted in time to prevent common covid- patients from worsening to severe patients another study conducted at italy (between april to may ) assessing persistent symptoms in patients who were discharged from the hospital after recovery from covid- . patients were assessed a mean of . days after onset of the first covid- symptom; at the time of the evaluation, only ( . %) were completely free of any covid- -related symptom, while % had or symptoms and % had or more. none of the patients had fever or any signs or symptoms of acute illness. worsened quality of life was observed among . % of patients. they also found that most common symptom persistent beyond discharge was fatigue ( . %), dyspnea ( . %), joint pain, ( . %) and chest pain ( . %). another follow up study which studied the pulmonary function and related physiological characteristics of covid- survivors three months after recovery enrolled patients and found different degrees of radiological abnormalities were detected in patients. blood urea nitrogen concentration at admission was associated with the presence of ct abnormalities many studies have shown that most common abnormality of lung function in discharged survivors with covid- is impairment of diffusion capacity, followed by restrictive ventilatory defects, which are both associated with the severity of the disease [ ] [ ] both decreased alveolar volume and k co contribute to the pathogenesis of impaired diffusion capacity . at -months after discharge, residual abnormalities of pulmonary function were observed in . % of the cohort which was lower than the abnormal pulmonary function in covid- patients when discharge. lung function abnormalities were detected in out of patients and the measurement of d-dimer levels at admission may be useful for prediction of impaired diffusion defect. currently, no fully proven options are available for the treatment of post inflammatory covid pulmonary fibrosis. various treatment strategies are under evaluation. it has been proposed that prolonged use of anti-viral, antiinflammatory and anti-fibrotic drugs diminish the probability of development of lung fibrosis. however, it is yet to be ascertained whether early and prolonged use of antiviral agents may prevent remodeling of lung or which of the available antiviral is more effective. though risk-benefit ratio should be assessed prior to use, prolonged low dose corticosteroid may prevent remodeling of lung in survivors . anti-fibrotic drugs, such as pirfenidone and nintedanib, have antiinflammatory effects as well and thus they may be used even in the acute phase of covid- pneumonia . pirfenidone exerts anti-fibrotic, anti-oxidative and anti-inflammatory properties. pirfenidone could attenuate ards induced lung injury based on published data showing that pirfenidone reduces lps-induced acute lung injury and subsequent fibrosis by suppressing nlrp inflammasome activation . there are few concerns for use of antifibrotic in acute phase. there are lots of covid patient have hepatic dysfunction in form raised transminases and both antifibrotic pirfenidone and nintedanib also cause hepatotoxicity. nintedanib use associated with increase the risk of bleeding as most of the covid patient are on anticoagulant evidence is also coming for use of pirfenidone, azithromycin and prednisolone in the management of pulmonary fibrosis post-h n ards, based on data from a case report of three patients . now the literature support for use of antifibrotic within the first week of ards onset to prevent consequences such as lung fibrosis. this fact highlights even more the tremendous need for the identification of biomarkers early in the disease course to identify patients who are likely to progress to pulmonary fibrosis. thus, the rationale for using antifibrotic therapy should be personalized and the role of precision medicine assumes prediction of high-risk population, better understanding of pathophysiology and prevention of disease worsening or/and lung fibrosis development. rehabilitation in the acute stage and particularly in the recovery stage is beneficial. it improves respiratory function, exercise endurance, self-care in daily living activities and psychological support . however, scientific research is required for concluding its definite benefits. considering huge numbers of individuals affected by covid- , even rare complications like post covid pulmonary fibrosis will have major health effects at the population level. elderly patient who require icu care and mechanical j o u r n a l p r e -p r o o f ventilation are highest risk to develop lung fibrosis. currently, no fully proven options are available for the treatment of post inflammatory covid pulmonary fibrosis. china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china for the gemelli against covid- post-acute care study group. persistent symptoms in patients after acute covid- sorveglianza integrata covid- in italia overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses sars-cov, mers-cov, and -ncov risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease risk factors associated with disease severity and length of hospital stay in covid- patients acute respiratory distress syndrome and diffuse alveolar damage. new insights on a complex relationship pulmonary fibrosis and covid- : the potential role for antifibrotic therapy use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice follow-up chest radiographic findings in patients with mers-cov after recovery plasminogen activator inhibitor , fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies critical care utilization for the covid- outbreak in lombardy, italy covid- and smoking: a systematic review of the evidence analysis of factors associated with disease outcomes in hospitalized patients with novel coronavirus disease covid- hangover: a rising tide of alcohol use disorder and alcohol-associated liver disease epub ahead of print long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a -year followup from a prospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region chest ct and clinical follow-up of discharged patients with covid- in wenzhou city covid- and risk of pulmonary fibrosis: the importance of planning ahead antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking nlrp inflammasome activation combined pirfenidone, azithromycin and prednisolone in post-h n ards pulmonary fibrosis. sarcoidosis vasc diffuse lung dis how to manage patients after the icu. covid- videos considering millions of covid cases worldwide, even small proportion of post covid lung fibrosis is real concern . elderly patient, severe disease who require icu care and mechanical ventilation are highest risk to develop lung fibrosis at present, no fully proven options are available for the treatment of post covid pulmonary fibrosis antifibrotic in acute phase of severe disease with ards may reduce fibrosis key: cord- -o fnvuw authors: sinaei, reza; pezeshki, sara; parvaresh, saeedeh; sinaei, roya title: why covid- is less frequent and severe in children: a narrative review date: - - journal: world j pediatr doi: . /s - - -y sha: doc_id: cord_uid: o fnvuw background: despite the streaks of severity, severe acute respiratory syndrome-coronavirus- (sars-cov- ) infection is, in general, less frequent and severe in children than in adults. we searched for causal evidence of this mystery. data sources: an extensive search strategy was designed to identify papers on coronavirus disease (covid- ). we searched ovid medline, pubmed, embase databases, and cochrane library and carried out a review on the causes of this dilemma. results: our searches produced relevant articles. the review showed that children accounted for a lower percentage of reported cases, and they also experienced less severe illness courses. some potential explanations, including the tendency to engage the upper airway, the different expression in both receptors of angiotensin-converting enzyme and renin–angiotensin system, a less vigorous immune response, the lower levels of interleukin (il)- , il- , myeloperoxidase, and p-selectin and a higher intracellular adhesion molecule- , a potential protective role of lymphocytes, and also lung infiltrations might have protective roles in the immune system–respiratory tract interactions. finally, what have shed light on this under representation comes from two studies that revealed high-titer immunoglobulin-g antibodies against respiratory syncytial virus and mycoplasma pneumonia, may carry out cross-protection against sars-cov- infection, just like what suggested about the vaccines. conclusions: these results require an in-depth look. properties of the immune system including a less vigorous adaptive system beside a preliminary potent innate response and a trained immunity alongside a healthier respiratory system, and their interactions, might protect children against sars-cov- infection. however, further studies are needed to explore other possible causes of this enigma. the novel coronavirus infection spread rapidly, so that the world health organization (who) declared this epidemic as a pandemic on march , [ ] . according to the preliminary data, the overall case fatality rate is about . % and is significantly higher in older patients [ ] . also, hospitalization rate increases with age, given the increased risk of nasal colonization and secondary infections [ , ] . limited initial data exist on the burden of coronavirus disease in children [ ] . thus far, only a small number of severe acute respiratory syndrome-coronavirus (sars-cov- ) infection have involved children, so that they have accounted for only - % of total patients [ , [ ] [ ] [ ] [ ] [ ] . however, doubt has existed as to whether covid- is really less common in children, and some have believed that children are as likely as adults to become infected, but are less likely to be symptomatic or to develop severe symptoms [ ] . some have attributed this to a lack of real epidemiological studies in children. however, the recent epidemiological studies have shown that although children are more likely to be affected than those reported previously, children are still less likely to be affected than adults. in iceland, researchers screened % of country's population and found that children under years of age had a lower incidence of sars-cov- infection than adults [ ] . although similar epidemiological results, especially those from serological investigations, are emerging in other countries, such as the netherlands, australia, and china, researchers in china found that children were less likely to catch the covid- within households from an affected family member [ ] . similarly, of close contacts in schools in australia, only two students have been identified as secondary cases [ ] . however, these are three ways that researchers have gauged whether children are less frequently infected by sars-cov- infection. the available data also suggest that sars-cov- is less severe in children. in a report, among , cases reported in the united states through april , , children experienced less severe symptoms. fever, cough, or shortness of breath were in % of children compared to % of adults. also, myalgia, sore throat, headache, and diarrhea were less commonly reported by pediatric patients. three deaths were noted among the pediatric patients in this analysis. however, children aged less than year accounted for the highest hospitalization [ ] . dong et al. investigated epidemiological characteristics of suspected pediatric patients. infection was confirmed in % of these patients, whereas . % of them were asymptomatic, or had mild to moderate courses, and . % were asymptomatic [ ] . these data were similar to previous findings that children with covid- may not have reported fever, cough, or sore throat as often as adults [ ] . also, dong et al. revealed that the prevalence of severe and critical disease was . % in children aged less than year, . % in those aged - years, . % in those aged - years, . % in those aged - years, and % in those aged - years [ ] . however, some patients experienced severe courses of illness. severe sars-cov- infection is characterized by a hyperproinflammatory response or cytokine storm state that results to acute respiratory distress syndrome (ards) and multisystem inflammatory syndrome (mis). ards is characterized by hypoxemic respiratory failure with bilateral lung infiltrates often necessitating invasive respiratory support. in contrast, this situation occurs less frequently in pediatric patients [ , ] . in a systematic review of pediatric patients with confirmed covid- , only % were severe (e.g., dyspnea, central cyanosis, and hypoxemia), and . % were critical (e.g., ards, respiratory failure, and shock) [ ] . unexpectedly, there is now a growing cognizance of small reports of pediatric patients with a hyper inflammatory response termed as mis-c or kawasaki-like disease [ , ] . nevertheless, these two entities are not so common, and the most children experience milder illness. for the first time, we reported two pediatric patients with reactive arthritis who presented with limping following sars-cov- infection [ ] . the data on laboratory markers in children also revealed lower lymphocytopenia ( - . %) than adults ( %) in several studies. also, children generally had lower increased c-reactive protein and procalcitonin levels. thus, the overall prognosis of the disease in children is relatively good [ , , [ ] [ ] [ ] . unfortunately, due to the high percentage of missing data, a real statistical evaluation and comparison could not be conducted [ ] . however, it seems that symptoms in children are both less frequent and less severe. in this review, we comprehensively investigated the most likely causes of this enigmatic topic, although all the actual causes remain unclear. an extensive search strategy was designed to identify all relevant papers from beginning to august , . we used ovid medline, pubmed, embase, and cochrane library and carried out a review on the causes of the lower prevalence and less severity of covid- in pediatric patients. the search strategy was constructed based on searching terms novel coronavirus, covid- , sars-cov- with using and/or, also the terms of child, pediatric, newborn, infant, adolescence, adult, age, age groups, severity, epidemiology, prevalence, difference, immune system, etiology, reasons in title, abstract, and key words. the data were screened and extracted independently by two investigators (the first and corresponding authors) and by one highly experienced librarian; then we proceeded to cross check the results. in addition, we increased the references by using an additional snowballing method. after discussion and consensus, the article was written. the inclusion criteria were: ( ) children and adolescents < years of age; ( ) all scientific papers and letters, about covid- ; and ( ) description of the possible causes of lower prevalence and less severity of diseases. the exclusion criterion is that of ≥ years of age. the search found papers. after removing the duplications and less relevant papers, scientific papers and letters ( - , - , - ) were included. however, several speculations were derived from pathophysiology of disease and defensive mechanisms. the results were categorized into two main groups of causes (immunological and non-immunological considerations), and each group included the six subsets described below. all causes are involved in the less severity of illness, but some (as * ) include the simultaneous and parallel causes of less frequency. the first results stem from some considerations that children have a less vigorous immune response to the virus than adults because the cytokine storm is thought to be important in the pathogenesis of severe sars-cov- infections [ ] . these results have been suggested from several studies in which elevated inflammatory markers are less common in children, so they experience milder disease than adults [ ] . children have a more active innate immune response * of course, this is not in conflict with another hypothesis that children have a more active innate immune response that can be one of the early stages of defense [ ] . this can be attributed to the fact that children had more recurrences of recent viral infections [ ] . however, if the disease went further extension, a less vigorous immune response may prevent them from the cytokine storm and help to reduce the severity. jeljeli et al. studied the ontogeny of cytokine production in the response of phytohemagglutinin by aging and found a rapid shift from enhanced interleukin (il)- secretion capacity at birth toward balanced il- /t helper (th) / th /th cytokine levels early in life. this change appears to be an essential precondition to fight pathogens and also avoids overwhelming inflammatory reactions [ ] . schouten et al. discovered an age-dependent difference in levels of biomarkers in the lungs of ards patients. levels of il- , il- , myeloperoxidase, and p-selectin were higher by aging; whereas intercellular adhesion molecule- was higher in neonates [ ] . however, immunosenescence also may be explain covid- age variability. it refers to the gradual deterioration of the immune system (especially adaptive type) brought on by natural age advancement [ , ] . some studies revealed that with aging, there is a gradual decrease of naïve t cell numbers related to the thymic changes, shrinkage in the collection of t cell clones generated in the thymus, and loss of costimulatory receptor cd . all these factors may impair the immunological responses with age [ ] [ ] [ ] . shortening of telomeres, especially t cells with cell divisions, might be associated with impaired immune response to new antigens along with increasing the production of proinflammatory cytokines [ , ] . zhu et al. revealed that among adolescents, the african and the girls had longer telomeres [ ] . these findings along with those of other studies can justify the severity of covid- in males and also by aging [ ] . some have suggested that the constitutional higher percentage of lymphocytes and natural killers (nk) in children may have a defensive role in covid- [ ] . indeed, increasing proinflammatory cytokines associated with neutrophil function with age, associated with severity of ards and may explain, to some extent, the age-dependent difference [ ] . in adult patients lymphocytopenia (especially cd + and cd + t lymphocytes) has been associated with increased severity or worse outcomes [ ] . total leukocyte and neutrophil counts and the neutrophil/lymphocyte ratio can be used as follow-up parameters in covid- [ ] . at least in three cohorts, the majority of pediatric patients had normal leukocytes and lymphocytopenia accounted for only - . % of cases [ , , ] . given the central role of lymphocytes and monocytes in the induction of immune responses, their frequency in peripheral blood might be expected to reflect the state of an individual's immune response to infection [ ] . in addition, since t cells are required for controlling exuberant innate immune responses, the absence of a potent antivirus t cell response in aged hosts could lead to an exuberant response and damage, which is not seen in children [ , ] . wynn and colleagues found that genes in neutrophils, in monocytes, and genes in lymphocytes were up-or down-regulated in pediatric septic shock, referring the data that circulatory lymphocytes are not the main leukocytes population with altered gene profiles during septic shock [ ] . other results for a milder disease in children are linked to a trained immunity that represents an immune memory after antigen exposure [ ] . interestingly, what have shed light on this under representation comes from two studies that revealed multiple high-titer antibodies against respiratory syncytial virus (rsv) and mycoplasma pneumoniae (mp) in the blood of children appears to offer cross protection against sars-cov- infection [ , ] . several studies have shown that children are more susceptible than adults to infection by rsv and mp [ ] [ ] [ ] [ ] . mp has been reported in - % of community-acquired pneumonia cases, and children with - years age are the most susceptible groups. although, this was documented in children under years by the report of - of european epidemic data [ ] . also, rsv is more prevalent in infancy. the who has reported rsv as a causative pathogen for over million new cases of lower respiratory infection episodes, including acute bronchitis in children less than years age [ ] . older siblings are a greater source of spreading infection than adults because they spend significant time in nurseries and schools [ ] . these events can train the immunity of children so that neutralizing cross-reactive antibodies of mp and rsv may be more common in children than in adults. in a retrospective review of all covid- patients treated at wuhan union hospital until march , , mi et al. evaluated the correlation between prior exposures to mp and better clinical response in covid- patients. the immunoglobulin g (igg) positive patients had a higher lymphocyte, monocyte and eosinophil counts and percentages (p < . ) than covid- patients without mp igg. in addition, thrombin time and lactate dehydrogenases were better in this group. furthermore, requirement and use of nasal catheter oxygen mask was significantly lower in covid- patients with mp igg positivity (p = . ). their findings indicate that mp igg positivity is a potential protective factor for sars-cov- infection [ ] . orange et al. showed that the intravenous immunoglobulin (ivig) manufactured from a plasma pool derived from high-titer, anti-rsv plasma donors contains high titers of antibodies to several common respiratory viruses (influenza a, b, human metapneumovirus, parainfluenza , , and , covoc and v e); this study found a direct correlation between antibody responder status of donors to rsv and their responder status to other viruses (p < . ). although, there are, however, a number of considerations, this could be due to higher humoral immune responders in general or especially against intercellular antigens, to diversity in major histocompatibility complex alleles, and finally to donors that might have experienced a greater diversity of viral infection. this can be generalized to the more infections in children and the potential protection effect that results from these infections [ ] . cao and colleagues emphasized the role of trained immunity as a new immune model that represents a cross protection against various pathogens. it can be activated also by some vaccines, such as bacillle calmette-guerin (bcg), by generation of immune memory just like what is seen in mp [ ] . miller and colleagues found that countries without universal policies of bcg vaccination (e.g., usa, italy) have been affected more severely as compared to countries with universal and long-standing bcg policies. also, countries that have a late start of universal bcg policy (e.g., iran in ) had a high mortality, consistent with the idea that bcg protects the vaccinated elderly population. in addition, they found that bcg vaccination reduced the number of reported covid- cases in the country. the combination of reduced mortality and morbidity makes bcg vaccine a potential new tool in the fight against covid- [ ] . however, this cross-protection has been considered, and what argues against this anecdotal assumption is the higher mortality of covid- in countries where bcg vaccine is compulsory [ ] . myśliwska et al. investigated the relationship between nk activity in the vaccinated population and specific immune protection against influenza virus. they concluded that nk cells activation, which was still significantly elevated after month of vaccination, may allow protection against influenza and other respiratory viral infections [ ] . indirect epidemiological analyses also have suggested a protective role of the measles, mumps, and rubella vaccine against covid- [ ] . because the majority of vaccinated individuals had not protective igg titer against measles after years, hanker et al. hypothesized that age-dependent decline in immunogenicity against measles vaccine could be an explanation for the higher occurrence of covid- in adults [ ] . there are several issues at this setting. the results show at least six other considerations including some constitutional and behavioral reasons: ( ) available data suggest that children may have more upper respiratory tract involvement than the lower. thereafter, viral interference in young children leads to a lower viral load [ ] . however, several speculations have emerged at this setting. young children generally, have a healthier respiratory machinery due to their lower exposure to harmful environmental factors. in addition, children have fewer underlying chronic diseases, than what seen in adults [ ] ; ( ) possible reasons for the disparity in severity between adults and children may be related to the difference in distribution, maturation, and functioning of receptors of renin angiotensin system (ras), angiotensinconverting enzyme (ace- ), and altered inflammatory response to virus [ ] . zhu et al. have looked for reasons of this disparity in severity [ ] . ace- is the receptor of viral endocytosis and also alters the ras activity from proinflammatory to anti-inflammatory response [ ] . the ace levels may be altered by several underlying diseases [ ] and by age [ ] in a murine model, although schouten and colleagues found that there is no marked difference in ace and ace- among age groups [ ] . however, this speculation should be investigated; ( ) xie et al. believe that children are less likely to be exposed to the virus. this may be due to fewer outdoor activities and to less international travel. also, xie et al. considered an under-diagnosis of children that might have resulted from their milder symptoms and therefore yielded fewer laboratory tests [ ] ; ( ) in attili and colleague's investigation, age-stratified odds ratios showed that the nasal carriage was higher in adult rabbits [ ] . this result suggested that the presence of the respiratory nasal bacterial colonization might have more impact in the adult population [ ] . in contrast, it is possible that the presence of other viruses in the respiratory tract of young children limits the sars-cov- development by direct virus-virus interactions [ ] . this hypothesis stems from the greater frequency of viral infection in children and also provides a link between the viral load and covid- severity [ ] [ ] [ ] [ ] ] ; ( ) in total, some results suggest that children have specific mechanisms that regulate the interaction between their immunological and respiratory systems, which could be contributing to milder disease. as a result, lymphocytes have participated in the inducible bronchus associated lymphoid structure after that respiratory insult has happened [ ] ; ( ) it was suggested that maturational changes in the axonal transport system may explain the relative resistance to immature mice to poliovirus induced paralysis [ ] . this can be generalized to the issue as a complementary reason. knowledge about neonatal outcomes of sars-cov- infection is relatively limited. immaturity of both innate and adaptive immune systems make this group highly vulnerable to infection [ ] . interestingly, the majority of neonates born to mother with covid- were not infected, and to date few reports have suggested that neonates have been affected by covid- . the possible reasons might be related to surgical delivery and to rapid separation of neonate [ ] . levy found that neonatal antigen presenting cells and plasmacytoid dendritic cells have impaired production of interferonand present a bias against the production of th cytokines [ ] . however, the levels of il- , il- , myeloperoxidase, and p-selectin are higher by aging, whereas intercellular adhesion molecule- is higher in neonates [ ] . therefore, unlike the infants under year that are at higher risk of infection and hospitalization ( . % of pediatric cases and . % of critical cases) [ ] , neonates are less likely to be infected. in contrast, two known ace- and transmembrane protease serine- receptors are widely spread in specific cell types of maternal-fetal interface and might be vulnerable to the neonate affecting by sars-cov- infection. however, on march , the first case report of possible vertical transmission of sars-cov- infection was published [ ] . dong et al. speculated the possibility of maternal fetal transmission of virus by demonstrating a higher igm level and abnormal cytokines hours after birth [ ] . however, two independent manuscripts described elevated sars-cov- specific igm and igg antibodies in the blood of newborns of affected mothers. to date, while maternal infections were observed in the late phase of pregnancy, there may not have been sufficient time for the generation of antibodies. thus, serological investigation for the diagnosis of neonate is still controversial. nevertheless, increased level of igg could be explained by trans-placental transferring from infected mother, while igm strongly indicates a selfimmune response of newborns [ , ] . thus, the elevated igm might suggest that neonate was infected in utero. in any case, the possibility of vertical transmission has been raised. after birth, the neonates might be involved. zeng et al. reported a series of infants from mothers with covid- , while three of whom were symptomatic, with a radiological picture of pneumonia. the weeks neonate developed coagulopathy, associated with sepsis. none of the newborns died. the clinical features of infected newborns might be nonspecific and include acute respiratory distress syndrome, temperature instability, gastrointestinal, and cardiovascular dysfunction [ ] . however, the age-dependent pattern of immune reactions and other physiological elements may influence the response to sars-cov- in the neonatal subpopulation [ ] . although covid- in children appears largely to present with mild features, a very small percentage of children with sars-cov- infection experience mis-c weeks later. however, the mis-c cases usually do not primarily affect the lungs [ ] . the recent reports from european countries and the us followed by growing universal reports support the emergence of this novel phenomenon [ ] . the clinical presentations of this entity are variable and include persistent fever, severe illness, and involvement of two or more organ systems, in combination with laboratory evidence of both inflammation and sars-cov- infection. however, some presentations of mis-c resemble kawasaki disease (kd), toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome [ , ] . of the potential cases reported across hospitals in new york state, patients were classified as confirmed mis-c. the peak in the number of mis-c cases followed the peak in the number of cases of laboratory-confirmed sars-cov- infection by days. the researchers stated that based on molecular and serological results, mis-c is probably a post-infectious, inflammatory process related to covid- [ ] . also, because the majority of patients have had positive serological results for sars-cov- , with a lesser number of positive rt-pcr tests, this condition may be more a postinfection entity rather than one related to acute early infection state. this hypothesis seems to have emerged for two reasons. first, mis-c cases lagged in time compared with the peak of sars-cov- infection. second, children who were involved in mis-c, more often have igg than positive molecular tests. however, mis-c is a delayed immunological response associated with inflammation characterized by elevated levels of proinflammatory cytokines including il- , il- β, il- , tnf-α, and granulocyte colony-stimulating factor. as a hypothesis, because the younger patients have increased number of naïve t cells in different sites to respond to new pathogens [ ] , this may prevent severe respiratory disease in children. thus, a low-level, persistent infection in other sites may accumulate over time in some children, resulting in mis-c [ ] . one compelling alternative hypothesis for this entity stems from the ability of coronaviruses to block type i and iii of interferon responses, that can result from delayed hyper-inflammatory response in whom that have a high viral load or cannot to control the infection [ , ] . a mapping systemic inflammation and antibody (ab) responses in mis-c was conducted. they documented that all mis-c patients had igg against sars-cov- infection. they identified elevated signatures of inflammation (il- , il- ), lymphocytic and myeloid chemotaxis and activation (ccl , ccl , and cub domain-containing protein- ), and mucosal immune dysregulation (il- a, ccl , ccl ). also, a reduction in m-dendritic cells, nk cells, and t cells in blood were seen, suggesting extravasation to affected tissues. also, some disease-associated autoantibodies (anti-la) were seen. these results suggest that autoreactivity secondary to sars-cov- infection and the inflammatory innate immune response may be crucial to the pathogenesis of mis-c [ ] . interestingly, diorio et al. based on the clinical phenotype, hypothesized that children with mis-c are presenting with a syndrome that is distinct from both kd and severe covid- infection. the researchers found that the patients with mis-c had elevated levels of tnf-α and il- , whereas patients with severe or mild covid- had no or minimally elevated levels of these cytokines. this profile for mis-c is distinct from what happens in kd, which is associated with mild elevations of other cytokines (il- , il- , and il- ) and not il- . tnf-α appears to play key role in the pathogenesis of both mis-c and kd. viral cycle thresholds (cts) and burr cells on blood smears also differentiated between patients with severe covid- and mis-c. the high cts associated with mis-c support a postinfectious etiology phenomenon that has previously been postulated but not demonstrated [ , ] . however, children with mis-c have no higher il- level, and this may be due to their higher lymphocyte counts hypothetically. in addition, they showed distinct ab responses as compared to adults with severe covid- causing ards, and to those who recovered from mild disease. patients with mis-c, often generate igg abs specific for spike (s) protein, while adults with covid- showed anti-s, igm, and iga abs, as well as anti-n igg abs. moreover, mis-c patients had reduced neutralizing activity compared covid- cohorts, indicating a reduced protective serological response [ ] . these results suggest a distinct infection course and immune response in children and adults with severe disease. children appear to have a less severe pulmonary manifestation due to all previous reasons, especially a lower gene expression of the ace- receptor. in contrast, adults with severe respiratory failure syndrome due to sars-cov- infection, who typically deteriorate near one week later of illness onset, have a dysregulation of immune system as opposed to direct cellular injury from viral infection. the immune dysregulation in adults that experienced respiratory distress is characterized by lymphopenia and a sustained production of proinflammatory cytokines, such as tnf-α and il- [ ] , giving the basis of immunomodulatory therapies like il- blockade at this situation. although, some suggest more conservative treatments, such as ivig or even corticosteroids for mis-c cases, empirical treatment with immunomodulators, such as anakinra or tocilizumab, as a substituted agent in refractory cases are promising [ , ] . ards is the most severe manifestation of covid- in adults. the survival rate of covid- patients with ards who are admitted to an intensive care unit (icu) is approximately % [ ] . in contrast, this situation is uncommon among pediatric patients and is called pards [ , ] . why some children experience more severe illness? the reasons that children may experience a severe course have not yet been elucidated. here, we summarize some possible causes of this discrepancy. there are some suggestions that several conditions increase the risk of severe disease in children and include hospitalization, mechanical ventilation, congenital heart disease, neurologic, genetic and metabolic conditions [ ] [ ] [ ] . other conditions are related to all ages and include: diabetes mellitus i and ii, immunocompromised due to solid organ transplant and other conditions, cerebrovascular accidents, chronic pulmonary disease (e.g., cystic fibrosis, moderate to severe asthma), chronic kidney disease, liver disease, pregnancy, obesity, smocking, sickle cell disease, thalassemia, and hypertension [ ] . in two multicenter studies of children admitted to picu, of and of had an underlying condition [ , ] . in a systematic review of confirmed pediatric patients, % had an underlying condition. most of them were chronic pulmonary disease ( %), congenital heart disease ( %), immune suppression ( %), and hematological and oncological conditions ( %) [ ] . it has an important role in development and worse outcome of severity, in both pediatric and adult patients. in the largest ards epidemiologic study of adults, . % and in the pediatric acute respiratory distress syndrome incidence and epidemiology study, % of ards cases, had immunosuppression [ , ] . the higher body mass index has been shown to be an independent factor associated with increased risk of ards development. as a paradox, the underweight patients with ards have higher mortality [ ] . in adult population, cigarette smoking is associated with ards in patients with sepsis [ ] . this can be generalized to pediatrics as both active and passive smokers. it seems that infants aged less than year are at higher risk of infection and severity [ ] . in the largest pediatric population-based study to date with patients, the proportion of severe and critical cases was . % under year, suggesting the higher risk of severe respiratory failure in infants. in addition to smaller airways, both immaturity of respiratory tract and immune system, alongside with relatively lower trained immunity might contributed to this severity [ , , ] . pediatric studies have not always observed a marked association between ards and both race and ethnicity, perhaps due to limited sample size. however, african and hispanic ethnicity appears to be major risks in mis-c patients [ ] . to date, several single-nucleotide polymorphisms have been identified by the increased risk of ards. the most significant variants are surfactant protein-b, ace, angiotensin- , and il- r antagonist [ ] . the endothelial protein c receptor and thrombomodulin genes were independent factors associated with mortality [ ] . il- pathway cytokines are associated with ards risk, although this association has not been found in pards studies [ ] . the regulatory gene arylsulfatase-d was linked in and % of ards cases and controls, respectively. also, xk kell blood group complex membr- was present in a minor allele frequency of and % of ards cases and controls, respectively [ ] . it has been shown that there are five variants of cystic fibrosis transmembrane conductance regulator splicing factor gens that independently are associated with pards in african american children without cystic fibrosis. another variant also was identified in caucasian children with cystic fibrosis, without higher risk of ards development [ ] . interestingly, the cluster of mis-c patients in some countries after the peak incidence of coronavirus infection among adults by approximately one month and in contrast no statistically significant difference in japan and korea, suggest a genetic and ethnicity background for these severe cases [ ] . however, at this time the extent to which genetics impacts the development of mis-c is unclear. considering the implications of host genes in the cell entry and replication of sars-cov- and in mounting the immune system response, it appears that several genes might be involved. the variations within ace- gene, the human leukocyte antigen locus, and the genes regulating toll-like receptor and complement pathways seem to influence susceptibility and subsequently the severity of covid- [ ] . in addition to possible involvement of several other genes (e.g., abo blood type and mediterranean fever gene) [ ] , genetic variations in these gateways might be influenced by the societies geographically. using a combinational analysis approach, taylor and colleagues identified protein-coding genes that were highly associated with severe covid- [ ] . ouyang et al. revealed that the number of differentially expressed genes (degs) increased by disease progression and decreased after initial treatment. all down-regulated degs in severe cases mainly involved th activation [ ] . researchers identified the p . gene cluster as a genetic susceptibility locus in severe covid- patients with respiratory failures. the results from comparing severe covid- patients and healthy blood donors indicated that people with blood group a had a % higher risk of infection than others. similarly, they found blood group o was associated with a lower risk of acquiring covid- [ ] . unexpectedly, some children may have more viral loads without any other reasons. the higher exposure with or without high-risk behavior, alongside the more expression of ace- receptors due to the less immaturity, a less previous exposure to coronavirus, influenza and other viruses, not getting the flu vaccine and some other vaccines, a less simultaneous presence of other viruses in body, and a more bacterial nasal colonization, all can be generalized as involved factors at this setting. in addition, some children may have a weaker innate response; while the strong innate response can be due to more exposure to previous viruses and many other reasons. they also, may have a relatively greater adaptive response alongside memory cells like adults [ , ] . there are several potential reasons that children have relatively milder illness. in addition to a fewer outdoor activity, children have a number of characteristics that protect them against sars-cov- infection. they have a healthier respiratory machinery alongside a different expression of receptors in the lower respiratory tract. also, we believe that the collection of immune system specifications including a less vigorous adaptive system beside a preliminary potent innate response, the constitutional higher level of lymphocyte counts, the trained immunity with cross-reactive neutralizing antibodies, the lack effects of aging, and the interaction between the immune system and respiratory tract might be protecting children against sars-cov- infection. although, these findings suggest that covid- is less common and somewhat milder in children compared to adults, there are now some reports of children presenting with severe types of infection such as mis-c. the exact incidence of mis-c following an asymptomatic or even a mildly symptomatic infection with sars-cov- is unclear. however, further investigations are needed to explore other possible causes of less severity of sars-cov- infection in the pediatric population. who. who director-general's opening remarks at the media briefing on covid- characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study nasal colonization rate of community and hospital acquired methicillin resistant staphylococcus aureus in hospitalized children clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster diagnosis, treatment, and prevention of novel coronavirus infection in children: experts' consensus statement the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china coronavirus disease (covid- ) in italy clinical and epidemiological features of children with coronavirus disease (covid- ) in zhejiang, china: an observational cohort study are children less susceptible to covid- ? spread of sars-cov- in the icelandic population household secondary attack rate of covid- and associated determinants in guangzhou, china: a retrospective cohort study report: covid- in schools-the experience in nsw cdc covid- response team. coronavirus disease in children-united states epidemiological characteristics of pediatric patients with coronavirus disease in china sars-cov- infection in children multisystem inflammatory syndrome in children and covid- are distinct presentations of sars-cov- antibody responses to sars-cov are distinct in children with mis-c compared to adults with covid- . medrxiv sars-cov- infection in children and newborns: a systematic review multisystem inflammatory syndrome in us children and adolescents multi-system inflammatory syndrome in children (mis-c) following sars-cov- infection: review of clinical presentation, hypothetical pathogenesis, and proposed management post ncov- limping child: report of two cases and a rapid review laboratory abnormalities in children with novel coronavirus disease clinical features of patients infected with novel coronavirus in wuhan sars-cov- infection in children: transmission dynamics and clinical characteristics pay attention to sars-cov- infection in children covid- : consider cytokine storm syndromes and immunosuppression systematic review of covid- in children show milder cases and a better prognosis than adults clinico-pathogenesis of covid- in children ontogeny of cytokine responses to pha from birth to adulthood age-dependent differences in pulmonary host responses in ards: a prospective observational cohort study age and immunity: what is "immunosenescence immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front immunol impact of stress on aged immune system compartments: overview from fundamental to clinical data efforts of the human immune system to maintain the peripheral cd + t cell compartment after childhood thymectomy age-related decrease in tcr repertoire diversity measured with deep and normalized sequence profiling telomeres shorten during ageing of human fibroblasts association between telomere length and experimentally induced upper respiratory viral infection in healthy adults leukocyte telomere length in healthy caucasian and african-american adolescents: relationships with race, sex, adiposity, adipokines, and physical activity gender and covid- working group. covid- : the gendered impacts of the outbreak will children reveal their secret? the coronavirus dilemma leukocyte subset-derived genome-wide expression profiles in pediatric septic shock t cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of covid- cytokine storm in covid- : pathogenesis and overview of anti-inflammatory agents used in treatment the ratio of monocytes to lymphocytes in peripheral blood correlates with increased susceptibility to clinical malaria in kenyan children covid- in children: current data and future perspectives not so fast: adaptive suppression of innate immunity the influence of developmental age on the early transcriptomic response of children with septic shock therapeutic immunoglobulin selected for high antibody titer to rsv also contains high antibody titers to other respiratory viruses serum mycoplasma pneumoniae igg in covid- : aprotective factor. medrxiv the effect of respiratory syncytial virus on the severity of acute bronchiolitis in hospitalized infants: a prospective study from turkey infection with and carriage of mycoplasma pneumoniae in children increased reports of mycoplasma pneumoniae from laboratories in scotland in and -impact of the epidemic in infants the contribution of child, family and health service factors to respiratory syncytial virus (rsv) hospital admissions in the first years of life: birth cohort study in scotland correlation between universal bcg vaccination policy and reduced morbidity and mortality for covid- : an epidemiological study immunomodulating effect of influenza vaccination in the elderly differing in health status homologous protein domains in sars-cov- and measles, mumps and rubella viruses: preliminary evidence that mmr vaccine might provide protection against covid- . medrxiv measles immunization: worth considering containment strategy for sars-cov- global outbreak covid- in children and altered inflammatory responses possible causes for decreased susceptibility of children to coronavirus the anti-inflammatory potential of ace / angiotensin-( - )/mas receptor axis: evidence from basic and clinical research a dynamic variation of pulmonary ace is required to modulate neutrophilic inflammation in response to pseudomonas aeruginosa lung infection in mice age-associated changes in the vascular renin-angiotensin system in mice. oxidative medicine and cellular longevity the effect of age and sampling site on the outcome of staphylococcus aureus infection in a rabbit (oryctolagus cuniculus) farm in italy virus-virus interactions impact the population dynamics of influenza and the common cold viral dynamics in mild and severe cases of covid- covid- in children: the link in the transmission chain pathogenesis of human poliovirus infection in mice. ii. age-dependency of paralysis lessons learned so far from the pandemic: a review on pregnants and neonates with covid- coronavirus disease (covid- ) and neonate: what neonatologist need to know innate immunity of the newborn: basic mechanisms and clinical correlates vertical transmission of covid- -a systematic review possible vertical transmission of sars-cov- from an infected mother to her newborn antibodies in infants born to mothers with covid- pneumonia neonatal early-onset infection with sars-cov- in neonates born to mothers with covid- in wuhan is it kawasaki shock syndrome, kawasaki-like disease or pediatric inflammatory multisystem disease? the importance of semantic in the era of covid- pandemic multisystem inflammatory syndrome in children in new york state type i and type iii interferons-induction, signaling, evasion, and application to combat covid- imbalanced host response to sars-cov- drives development of covid- mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (mis-c) pathogenesis of kawasaki disease: the central role of tnf-α complex immune dysregulation in covid- patients with severe respiratory failure coronavirus disease case surveillance-united states pediatric critical care and covid- characteristics and outcomes of children with coronavirus disease (covid- ) infection admitted to us and canadian pediatric intensive care units people who are at increased risk for severe illness epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries paediatric acute respiratory distress syndrome incidence and epidemiology (pardie): an international, observational study risk factors and etiologies of pediatric acute respiratory distress syndrome. pediatric acute respiratory distress syndrome, a clinical guide cigarette smoke exposure and the acute respiratory distress syndrome respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology fifty years of research in ards. genomic contributions and opportunities association of common genetic variation in the protein c pathway genes with clinical outcomes in acute respiratory distress syndrome interleukin- receptor antagonist is associated with pediatric acute respiratory distress syndrome and worse outcomes in children with acute respiratory failure identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome-seq association of polymorphisms in genes of factors involved in regulation of splicing of cystic fibrosis transmembrane conductance regulator mrna with acute respiratory distress syndrome in children with pneumonia genetic gateways to covid- infection: implications for risk, severity, and outcomes differential expression of covid- -related genes in european americans and african americans analysis of genetic host response risk factors in severe covid- patients down-regulated gene expression spectrum and immune responses changed during the disease progression in covid- patients genomewide association study of severe covid- with respiratory failure the authors thank the staff and participants of this key: cord- -b uaooh authors: luks, andrew m.; swenson, erik r. title: reply: covid- lung injury and “typical” acute respiratory distress syndrome: the danger of presumed equivalency date: - - journal: ann am thorac soc doi: . /annalsats. - le sha: doc_id: cord_uid: b uaooh nan hypoxemia. a comparison of the two may yet yield answers to questions of great clinical import. for example, in covid- lung disease, a hypoxemic condition that progresses over several days in which many patients do not appear to be in distress, what is more injurious: accepting a lower oxygen saturation as measured by pulse oximetry or initiating invasive mechanical ventilation? with great respect for the authors' well-meaning concern to avoid patient harm, let me be clear about mine: i am concerned that the alveolar filling/collapse, low-compliance pulmonary disease being seen in the intensive care unit is predominantly due to ventilator-induced lung injury rather than to the natural evolution of covid- disease. that is not to say that this iatrogenic lung injury, if confirmed by further data, is avoidable. we are tasked with preserving life, and it is highly likely that to maintain oxygenation at viable levels for life, we must injure lungs along the way and then do our best to heal them, as we are. i suspect that in the coming months, new research will show that covid- mortality is caused by vascular endothelial rather than alveolar epithelial dysfunction. this will likely lead to intense debate over alterations to currently adopted ventilation strategies that have historically been used to treat alveolar filling/collapse disease. to safely ventilate covid- lungs, our oxygenation and ventilation targets may need to change. given their experience in treating a condition of well-tolerated hypoxemia leading to pulmonary vascular dysfunction, these authors are precisely the experts we will need to help redefine those targets. i look forward to once again hearing and heeding their concerns. author disclosures are available with the text of this letter at www.atsjournals.org. we appreciate the opportunity to respond to dr. kyle-sidell's letter regarding our article on coronavirus disease (covid- ) lung injury and high-altitude pulmonary edema (hape) ( ). although we agree it is necessary to identify the best means for treating respiratory failure due to covid- , we believe it is important to highlight some important misconceptions and address broader concerns raised within the letter. with regard to misconceptions, the author writes that our claims about the natural evolution of lung injury in covid- have not been confirmed and are erroneously based on a presumption of equivalence between covid- and other causes of acute respiratory distress syndrome (ards). this statement overlooks the fact that the majority of patients in published series meet the berlin definition of ards ( , ) and that published autopsy results ( , ), early autopsy results in preprint form, and autopsy studies from related coronavirus infections-severe acute respiratory syndrome and middle east respiratory syndrome coronavirus-document the presence of hyaline membranes and other findings consistent with diffuse alveolar damage, the histopathological correlate of the pathophysiology we cite and the hallmark of ards. vascular lesions, including microthrombi, have been noted, but these findings are entirely consistent with prior reports on non-covid ards ( ) . the author also refers to hypocapnic hypoxemia manifesting as hypoxemia out of proportion to dyspnea as a "most striking and unusual similarity" between hape and covid- . in fact, the absence of dyspnea is uncommon in hape, and hypocapnia is a highly common finding in many causes of both acute and chronic hypoxemic respiratory failure. hypoxemia stimulates peripheral chemoreceptor output, which in turn increases minute ventilation. together with stimulation to ventilation from other factors, including fear, fever, sympathetic nervous system activation, and lung inflammation, this augments co elimination from uninvolved areas of the lung and causes hypocapnia. the presence of hypocapnic hypoxemia is nonspecific, and its presence in hape and covid- in no way implies a shared pathophysiology. finally, the author states, without supporting evidence, that patients with covid- have "normal or near-normal pulmonary compliance." to date, only three published reports have documented static compliance in covid- , and in two of them ( , ) the average static compliance was low (, ml/cm h o) and consistent with that seen in prior studies of ards. although the recent letter from gattinoni and colleagues ( ) reports a higher average of m/cm h o, it is apparent from the letter's accompanying figure that some patients had markedly decreased compliance. furthermore, compliance values of ml/cm h o, which are about half those seen in healthy, spontaneously breathing individuals ( cm/h o) and, therefore, not normal, have actually been seen in patients in prior large ards cohorts ( ) . on a broader level, the author seems to imply that all of the severe pathology in covid- lung injury is related to ventilator-induced lung injury (vili) rather than evolution of the disease. there are no published data to support this assertion. the compliance data from the two reports noted above ( , ) were obtained on the first day of mechanical ventilation, which would indicate that severe injury was present in many of these patients at the time of intubation. furthermore, the fact that the majority of patients with other indications for invasive mechanical ventilation do not progress to ards ( ) argues against the notion that vili is an inevitable outcome of mechanical ventilation under all circumstances, including covid- . thus, although vili has long been a clinical concern, the problem is not initiation of mechanical ventilation per se but rather initiation of inappropriate mechanical ventilation strategies, including an overly high tidal volume or distending pressure. although we agree with dr. kyle-sidell about the importance of scientific debate, our ultimate concern with the author's letter and statements in other forums is that these and other claims about covid- pathophysiology, such as the predominance of endothelial over epithelial injury, lack supporting evidence and are contradicted by the published physiologic, histopathologic, and radiographic evidence. in a time of high patient volumes and stress, there arises a risk that clinicians will latch onto such claims and abandon the approach to ards care that has been developed over many years of well-designed, well-controlled randomized clinical trials, which have yielded impressive improvements in mortality and other clinical outcomes. when faced with new diseases and clinical challenges, we should recognize that novel observations and hypotheses are important for advancing care. we must, however, keep the focus on conducting well-designed studies of these ideas so that we can come out on the other end of the pandemic with a solid sense of what does and does not work. action based simply on conjecture and unsubstantiated claims will leave us with more uncertainty and may increase the risk of patient harm. medical thoracoscopy for pleural infection: are we there yet? to the editor: we read, with keen interest, the randomized clinical trial of intrapleural fibrinolytic therapy versus early medical thoracoscopy (mt) for the treatment of pleural infection, which was published in a recent issue of annalsats ( ). we congratulate the authors for conducting a randomized study addressing an important clinical question. the authors have concluded that early medical thoracoscopy may have a role in the management of complicated pleural effusion and empyema, leading to a reduced hospital stay. however, some critical points regarding the reported results need careful consideration and further discussion. the primary outcome chosen for the trial was the duration of hospital stay. this outcome measure is not ideal for a clinical question concerning the use of medical thoracoscopy. other parameters, such as radiologic resolution or referral/need for surgery, would have been more meaningful for assessing the benefit of the intervention proposed ( , ) . even though authors have used the duration of hospital stay as the primary outcome measure, there is no mention of discharge criteria, which should have been objectivized to maintain uniformity. in the inclusion criteria, it is mentioned that patients with not completely drained empyema were enrolled. authors have not mentioned how long they waited for empyema to drain before enrollment. this time duration is vital because a delay in the intervention may be associated with the failure of the intervention. it is also not clear why the authors chose to put a smallsize intercostal tube in all patients before randomization. in patients randomized to the mt arm, the initial tube placement could have covid- lung injury and high-altitude pulmonary edema: a false equation with dangerous implications covid- in critically ill patients in the seattle region: case series respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study pathological evidence of pulmonary thrombotic phenomena in severe covid- post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction the pulmonary vascular lesions of the adult respiratory distress syndrome covid- does not lead to a "typical" acute respiratory distress syndrome proseva study group. prone positioning in severe acute respiratory distress syndrome for ventila group. association between ventilatory settings and development of acute respiratory distress syndrome in mechanically ventilated patients due to brain injury key: cord- -ay af xr authors: tobin, martin j. title: does making a diagnosis of ards in covid- patients matter? date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: ay af xr nan the question "do patients with covid- develop typical ards?" is arousing fevered debate. respondents pivot their answers around the nature of covid- , rather than ards. the controversy unveils riddles at the core of ards. what exactly is ards, and how should a doctor decide whether some patient has ards or another disorder? in the founding report, ashbaugh and petty christened the new disorder a "syndrome" because it encompassed a grouping of clinical and pathophysiologic abnormalities with no known cause. after its baptism, its very existence was called into question. dr. fishman, editor of the first multivolume textbook of pulmonary medicine, denigrated it a "distinctive non-entity." another critic remonstrated that making a diagnosis of "ards is not helpful because it obscures a clinically very important differential diagnosis". that grumbler was dr. murray, who later enumerated a scoring system to adjudge whether or not a patient has ards. dr. murray never explained his volte-face in resurrecting a syndrome he had previously tried to terminate (rip). subsequent panels-american-european consensus committee (aecc) and berlin panelrearticulated criteria for defining ards. designated criteria were chosen with a goal of setting tight boundaries to achieve greater uniformity of patients being enrolled in clinical trials. each new formulation was justified by specifying grave flaws in its predecessor. none of the redefinitions represented a radical change from ashbaugh and petty's initial description. the berlin definition claims that ards can be diagnosed only if onset is within days of a known insult. observing that respiratory failure occurred - days after first symptoms of covid- in chinese series, li and ma concluded that these patients should not be diagnosed as ards. other commentators consider high compliance measurements as grounds for doubting typical ards in covid- patients. the claims and counterclaims fail to acknowledge that ards is a man-made creation. contrast ards with measles, which is caused by a non-redundant etiologic agent (virus), with uniform pathogenesis and a rash so characteristic that diagnosis is self-evident. nosologically, measles constitutes a "natural kind" on etiologic, pathogenetic, and clinical levels. ards does not represent a natural kind on any level. each constituent in ards definitions has fuzzy boundaries. hypoxemia is identified by in ards patients with fixed shunt, alterations in f i o caused pao /f i o to fluctuate unpredictably by more than mmhg. in patients fulfilling all ards criteria, administration of % oxygen for minutes caused pao /f i o to increase such that . % were no longer categorized as ards. when ards-network researchers interpreted chest x-rays according to aecc criteria, agreement was only moderate (kappa= . ) with full agreement on less than half the radiographs. this poor performance was one justification for developing the berlin definition. subsequent evaluation of the berlin criteria found interobserver agreement no better (kappa= . ), with % disagreeing on imaging interpretation. too much attention is focused on the definition of ards. placing it on an altar for veneration is unwarranted. getting pedantic as to whether a covid- patient truly satisfies criteria for ards is a distraction from patient care. definitions beget a sense of finality (often unjustified), and can confine the mind rather than liberate it. few diagnoses dictate an invariant course of action. diagnosing pneumothorax is not inevitably followed by needle drainage-high concentration of oxygen is preferable in certain circumstances. all patients with ards do not require intubation; some are sustained with supplemental oxygen or noninvasive ventilation. a central criticism of ards is its heterogeneity; diagnosing ards may halt the search for the underlying cause. this criticism does not apply to respiratory failure in covid- patients: we know it is caused by sars-cov- and no therapy is effective against the virus. the only consequent of ards diagnosis is avoiding tidal volume ml/kg. given that tidal volume ml/kg is not employed in any patient, making a diagnosis of ards does not impact selection of any ventilator setting. tidal volume ml/kg has not been proven superior to tidal volume ml/kg (or anything in between)-nor is ml/kg appropriate in every patient. decrements in tidal volume are necessarily accompanied by shortening of mechanical inspiratory time. once mechanical inspiratory time becomes less than the patient's neural inspiratory time, double triggering is inevitable. a doctor may set tidal volume ml/kg, but the patient is receiving ml/kg. identifying phenotypes and endotypes arouses much interest-but this is still (sub)group thinking. searching for subgroups is apposite for research investigations but not applicable for individualized care. the mindset for care at the bedside is antithetical to that needed for conducting clinical trials. each patient is unique-even twins from the same ovum are different. respiratory physiology in ventilated patients is complex. it is impossible to predict the net response of multiple counterbalancing reflex pathways incited by a single alteration in a ventilator setting. there is no substitute for making changes and observing the effect on plateau pressure, airway pressure waveform, double triggering, pao , blood pressure and so on. and then iteratively fine-tuning the settings. based on personal experience of teaching residents at the bedside for more than four decades, the cognitive task trainees find most challenging is to separate wheat from chaff-to ward off distractions in a complex case and identify the pivotal factor that will decide a patient's outcome. for the doctor at the bedside of a covid- patient, making a diagnosis of ards is completely irrelevant. no clinical action will follow directly from the diagnosis. the debate presently raging as to whether covid- produces typical or atypical ards is an unfortunate distraction from the central questions that decide a patient's outcome. the cognitive challenges in covid- revolve around interpretation of blood oxygen levels , and deciding whether to insert an endotracheal tube. it is a tragedy to think that some covid- patients were intubated simply because oxygen was being delivered at more than liters/min targeted to a non-scientific pulse oximetry objective. we tend to forget that diseases have no separate existence independent of patients. as doctors we treat patients, not diseases. management requires customized care, tailored to each patient's unique physiological response-not mindlessly following a protocol assembled for an ards cookbook. acute respiratory distress in adults editorial: the adult respiratory distress syndrome (may it rest in peace) acute respiratory failure in covid- : is it "typical variability of indices of hypoxemia in adult respiratory distress syndrome screening of ards patients using standardized ventilator settings: influence on enrollment in a clinical trial interobserver variability in applying a radiographic definition for ards interobserver reliability of the berlin ards definition and strategies to improve the reliability of ards do we need ards? principles and practice of mechanical ventilation basing respiratory management of covid- on physiological principles why covid- silent hypoxemia is baffling to physicians caution about early intubation and mechanical ventilation in covid- abbreviations list: aecc: american-european consensus committee ards: acute respiratory distress syndrome covid- : coronavirus disease fraction of inspired oxygen pao : partial pressure of oxygen in arterial blood peep: positive end-expiratory pressure sars-cov- : severe acute respiratory syndrome coronavirus key: cord- - c yemi authors: ferrando, carlos; suarez-sipmann, fernando; mellado-artigas, ricard; hernández, maría; gea, alfredo; arruti, egoitz; aldecoa, césar; martínez-pallí, graciela; martínez-gonzález, miguel a.; slutsky, arthur s.; villar, jesús title: clinical features, ventilatory management, and outcome of ards caused by covid- are similar to other causes of ards date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: c yemi purpose: the main characteristics of mechanically ventilated ards patients affected with covid- , and the adherence to lung-protective ventilation strategies are not well known. we describe characteristics and outcomes of confirmed ards in covid- patients managed with invasive mechanical ventilation (mv). methods: this is a multicenter, prospective, observational study in consecutive, mechanically ventilated patients with ards (as defined by the berlin criteria) affected with with covid- (confirmed sars-cov- infection in nasal or pharyngeal swab specimens), admitted to a network of spanish and andorran intensive care units (icus) between march and june , . we examined the clinical features, ventilatory management, and clinical outcomes of covid- ards patients, and compared some results with other relevant studies in non-covid- ards patients. results: a total of patients were analysed with complete -day outcome data: ( . %) with mild, ( . %) with moderate, and ( . %) with severe ards. at baseline, defined as the first day on invasive mv, median (iqr) values were: tidal volume . ( . – . ) ml/kg predicted body weight, positive end-expiratory pressure ( – ) cmh( )o. values of respiratory system compliance ( – ) ml/cmh( )o, plateau pressure ( – ) cmh( )o, and driving pressure ( – ) cmh( )o were similar cto values from non-covid- ards observed in other studies. recruitment maneuvers, prone position and neuromuscular blocking agents were used in %, % and % of patients, respectively. the risk of -day mortality was lower in mild ards [hazard ratio (rr) . ( % ci . – . ), p = . ] and moderate ards [hazard ratio (rr) . ( % ci . – . ), p = . ] when compared to severe ards. the -day mortality was similar to other observational studies in non-covid- ards patients. conclusions: in this large series, covid- ards patients have features similar to other causes of ards, compliance with lung-protective ventilation was high, and the risk of -day mortality increased with the degree of ards severity. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. in late december , the chinese center for disease control and prevention (chinese cdc) reported a series of cases of unknown pneumonia which was subsequently termed coronavirus disease , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . the health, social, and economic impact of this disease is unprecedented in our life-time. the covid- pandemic has collapsed health care systems and led to an overwhelming pressure on intensive care units (icus), since many patients developed profound hypoxemia and extensive pulmonary infiltrates requiring intubation and ventilatory support [ ] . recent publications from china and italy have described the epidemiology, clinical characteristics, and prognostic factors of patients who developed acute respiratory distress syndrome (ards) caused by covid- [ ] [ ] [ ] . a number of editorials and anecdotal points of view have suggested that covid- ards has an atypical behavior, since a number of patients with profound hypoxemia had normal or close to normal respiratory system compliance (crs) [ ] [ ] [ ] . however, data confirming this assumption are scarce, and the view that severe covid- causes an "atypical" ards has generated debate. consequently, there is controversy on the most appropriate oxygenation and ventilation strategies without increasing ventilation-induced lung injury or multiorgan damage. it has been long known that patients with ards have markedly varied clinical presentations, and the berlin definition did not include a threshold value for respiratory compliance as a diagnostic criterion for ards, because it did not add to predictive validity [ ] , and it can be difficult to measure accurately in non-passive patients. the clinical features of patients with sars-cov- -induced ards, and the ventilatory management, and patient outcomes have not been well described [ ] . the main objective of this large observational study was to describe the physiologic characteristics over time, the ventilatory management, and outcomes in a large cohort of confirmed ards covid- patients. a secondary objective was to compare respiratory parameters and outcomes of ards covid- patients with ards of other causes, where possible. this is a prospective, multicenter, observational, cohort study that enrolled patients with covid- ards admitted into hospitals from spain and andorra (participating centers are listed in the supplementary file). during the pandemic, there were no specific hospitals that were designated as covid- centers, and thus the distribution of patients among centers was similar to that observed pre-covid- . the study was approved by the referral ethics committee of hospital clínic, barcelona, spain (code number: hbc/ / ). according to spanish legislation, this approval is valid for all participating centers. the informed consent was waived, except in three centers where the institutional review boards requested oral informed consent from patient's relatives. this study followed the "strengthening the reporting of observational studies in epidemiology (strobe)" statement guidelines for observational cohort studies [ ] . data from patients' electronic medical records were reviewed and collected by physicians trained in critical care, according to a previously standardized protocol. each investigator had a personal username and password and entered data into a specifically pre-designed online data acquisition system (covid .ubikare.io). patient confidentiality was protected by assigning a de-identified patient code. all consecutive covid- patients included in the dataset from march to june , were enrolled if they fulfilled the following criteria: ≥ years old, intubated and mechanically ventilated, confirmed sars-cov- infection from a respiratory tract sample using pcr-based tests, and had acute onset of ards, as defined by the berlin criteria [ ] , which includes a new or worsening respiratory symptoms due to covid infection, bilateral pulmonary infiltrates on chest imaging (x-ray or ct scan), absence of left atrial hypertension or no clinical signs of left heart failure, and hypoxemia, as defined by a ratio between partial pressure of oxygen in arterial blood (pao ) and fraction of inspired oxygen (pao /fio ) ≤ mmhg on positive end-expiratory pressure (peep) ≥ cmh o, regardless of fio . exclusion criteria were patients with non-confirmed sars-cov- infection according to who guidance [ ] , patients with no data at baseline, patients with no information on ventilatory parameters, or non-intubated patients. recorded data included demographics [age, gender, body mass index (bmi), comorbidities], vital signs the covid- pandemic has collapsed health care systems and led to a critically overwhelming pressure on intensive care units (icus), since many patients developed profound hypoxemia and extensive pulmonary infiltrates requiring intubation and ventilatory support. covid- patients with ards predominantly presented a typical moderate-to-severe ards. ventilatory management, and -day outcome did not differ from other causes of ards. [temperature, mean arterial pressure (map), heart rate], laboratory parameters (blood test, coagulation, biochemical), ventilatory parameters [tidal volume (vt), inspiratory oxygen fraction (fio ), respiratory rate (rr), peep, plateau pressure (pplat), driving pressure (dp), respiratory system compliance (crs)], the use of adjunctive therapies [recruitment maneuvers (rm), prone position, neuromuscular blocking agents (nmba), extracorporeal membrane oxygenation (ecmo)], pharmacological treatments, disease chronology [time from onset of symptoms and from hospital admission to initiation of mechanical ventilation (mv), ventilator-free days (vfds) during the first days, icu length of stay (los)]. sequential organ failure assessment (sofa) and apache ii scores, patients discharged from icu, patients who had died or still being treated in the icu on june , were also reported. a full data set was obtained on the first day on invasive mv which was defined as baseline. we also collected the "worst" values during the period of invasive respiratory support (maximum or minimum, depending on the parameter). site investigators collected what they considered to be the most representative data of each day from admission to icu discharge, alive or dead. prior to data analysis, two independent investigators and a statistician screened the database for errors against standardized ranges and contacted local investigators with any queries. validated or corrected data were then entered into the database. for the main objective of the study, two descriptive analyses including clinical characteristics, mechanical ventilation data, respiratory parameters, and adjunctive measures were performed. first, we describe patients stratified as mild, moderate, and severe ards based on the berlin criteria. second, we describe patients stratified as having normal crs (≥ ml/cmh o) or low crs (< ml/cmh o) according to baseline values [ ] . patients were considered as having low-crs if < ml/ cmh o on day of invasive mv. descriptive variables are expressed as percentage, mean and standard deviation (sd), or median and interquartile range (iqr), as appropriate. then, we compared variables across groups using student's t test or mann-whitney test and one-way anova or kruskal-wallis test for numerical variables, and chi-squared test or fisher exact test for categorical variables. second, to assess the relationship among ards severity and discontinuation from mechanical ventilation, icu discharge and mortality at day time to event curves were plotted using the kaplan-meier method and analyzed with log-rank test and univariable cox regression analysis. the same analysis was performed for the crs. time to discontinuation from mechanical ventilation/mortality/icu discharge was described using kaplan-meier plot across categories of ards severity, crs, plateau pressure and driving pressure. for the kaplan-meier analyses, patients with the complementary outcome were right-censored at the longest recorded length of stay. additionally, to test differences between groups, we used log-rank test and univariable cox regression model due to the absence of imbalances between groups at baseline (or multivariable, adjusted for ards, in the case of plateau pressure and driving pressure). as a sensitivity analysis, we reported results using competing-risks approach. results are consistent across methods [ ] . we compared our results for crs, pplat, and driving pressure to five studies in the literature [ ] [ ] [ ] [ ] [ ] using one sample student's t test. for the largest study (lung safe), we estimated median crs from supplemental figure e , since it was not explicitly reporter in the study. when mean values of the whole cohort were not reported, we calculated it from the mean values of the study groups. as this is an observational study and no harm is inflicted and no benefit is neglected to patients in the study, we aimed to recruit as many patients as possible, with no pre-defined sample size. all time to events were defined from day of invasive mv. missing data were not imputed. analyses were performed in a complete case analysis basis. all tests were two-sided, and a p-value < . was considered statistically significant. we have applied the benjamini-hochberg corrections procedure, and have marked with an asterisk the p values that were < . after the correction. all analyses were performed with stata version . over a period of days (between march and june , ), mechanically ventilated patients admitted to icus were included in the study and followed for at least days (fig. ). the distribution of included patients among the different participating hospitals is shown in table s . the enrollment and follow-up of patients are still ongoing, and as of june , ( %) patients were still in the icu. demographics, apache ii and sofa scores, vital signs and laboratory findings at baseline are shown in table and table s . the percent of patients with severe, moderate and mild ards was . %, . % and . %, respectively (table ) ; the percentage of severe ards patients was higher than a number of other large observational studies in non-covid- ards patients. the percent of patients with severe ards decreased markedly from day to day and remained at this lower level from day onwards (fig. ). this was paralleled by an increase in the percentage of patients with mild ards. from the patients ( . %) with compliance data, % ( ) were classified as having low crs (tables s , s and figure s ). from these patients, . % were classified as severe, . % as moderate and . % as mild. median time from the onset of symptoms to initiation of invasive mv was (iqr: - ) days, and from hospital admission to initiation of invasive mv was (iqr: - ) days. the median vt at baseline was . (iqr: . - . ) ml/kg predicted body weight (pbw); in % of patients the vt never exceeded ml/kg pbw. the median highest vt, including during the weaning process with assist modes, was . (iqr: . - . ) ml/kg pbw. the median peep at baseline was (iqr: - ) cmh figure s ). continuous nmba were used in % of patients, prone position in %, and rm in %. degree of ards severity was associated with significant differences in the use of prone position (p < . ) and nmba (p = . ), but not rm (table , figure s ). no differences were observed in patients with normal vs low crs (table s and figure s ). the pharmacological treatments received by the patients is shown in table s . mean vfds (to day ) was [iqr: - ] days. as of june , , ( %) patients were discharged from the icu with an icu los of [iqr: - ] days. allcause -day mortality was % ( patients) distributed as % in severe, % in moderate and % in mild ards ( table ). these mortality values were similar to those from four observational studies from the past years (table s ). the probability of discontinuation of mv was not significantly affected by the ards severity (fig. ) . the probability of icu discharge was higher in mild [hazard ratio (rr) . ( % ci . - . ), p = . ], but not in moderate when compared to severe ards (table and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ - . ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . icu length of stay of deceased patients [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . (fig. ) . sensitivity analysis for outcomes are shown in figure s . the icu discharge and risk of -day mortality was not affected by crs (table s and figure s ). the association of driving pressure and pplat on outcomes are shown in figure s . patients classified as moderate ards who, after h of mv moved to mild ards, had a strong trend towards a lower day mortality, than those who remained classified as moderate ards on day , but this association was not statistically significant [hr: . ( % ci . - . ), p value = . ]. in general, being treated in specific hospitals had no impact on outcomes ( figure s ). in this multicenter, observational study in mechanically ventilated patients with covid- ards, predominantly older, male patients with comorbid conditions, with a median icu length of stay of days, the majority had moderate ards, and greater than % had low crs. the values of crs, pplat and driving pressure were very similar to previously published cohorts of ards patients. on average, patients were managed with low vt and moderate peep levels within the standard paradigm of lung-protective vt. adjunctive therapies, such as rms or prone position, were used frequently. mortality at -days was similar to patients with non-covid ards. as previously reported for patients with covid- , the most common comorbidities were arterial hypertension and obesity [ , ] . the main reason for icu admission in our study was acute respiratory failure, although the sofa scores indicated more than one organ dysfunction. hemodynamic impairment requiring vasopressors was the most common associated organ dysfunction, in agreement with the findings of goyal et al. [ ] , where % of their invasively ventilated patients required vasopressors. of note, the median time from symptoms onset to hospital admission was similar to that reported previously [ ] . on average, hypoxia was severe within the range of previous reports on covid- and non-covid- ards patients [ , , ] . the proportions of severe covid- ards patients were greater than those reported in epidemiological studies of non-covid- ards [ ] (table s ). however, we found, as previously reported, a marked redistribution of ards severity h after ards diagnosis [ ] . this reduction in the percentage of patients with severe ards criteria may be related to positive pressure ventilation by itself, to the effectiveness of adjunctive measures, or (unlikely) the natural history of the disease process (fig. ) . although it was not the aim of this analysis, it is important to highlight that some investigators argue that the degree of ards severity is best evaluated h after assessing pao /fio under certain ventilatory settings [ ] . our findings in a cohort of over patients are in line with preliminary studies of covid- ards patients [ , ] . we found no significant differences when baseline crs, pplat and driving pressure were compared to non-covid- ards observational and randomized ards studies (table s ). these comparisons were not based on a formal meta-analysis, and thus, these comparisons serve to demonstrate that there are no differences in these baseline values for covid- ards to non-covid- ards. in general, compliance with lung-protective ventilation was high, independent of the degree of severity of the disease process and somewhat higher on average than in previous observational studies of non-covid- ards patients [ , ] . this finding was likely due to a greater awareness that these patients had ards. as reported in the lung safe study, one of the main problems in not complying with lung protection strategies was the underdiagnosis of ards [ ] . in our cohort, invasive mv was maintained within the limits of lung-protective ventilation, as defined using a vt ≤ ml/kg pbw, pplat < cmh o, and a driving pressure ≤ cmh o [ ] . in our cohort, rms were the most frequent adjunctive therapies used, followed by prone position, and nmba. these findings are in contrast to reported practice in non-covid- severe ards patients [ , , ] . surprisingly, the use of rms was not influenced by ards severity or by crs. both rms and prone ventilation are usually performed to improve arterial oxygenation, and reduce ventilator-induced lung injury [ , ] . the impact of these maneuvers depends on the recruitability of the lung, which has been shown to be variable in covid- ards [ ] . in our experience, respiratory drive in covid- ards patients appeared to be high, despite adequate sedation, making it difficult to maintain low transpulmonary pressures, which could lead to self-inflicted lung injury [ ] . this bedside observation may explain the high number of patients in whom nmba were used. another reason for the high use of nmba could be the large number of patients treated in the prone position; (see figure on next page.) fig. time to event curves using kaplan-meier with univariable cox regression. the probability of discontinuation from mechanical ventilation and the probability of icu discharge increase with decreasing ards. the -day probability of death was higher in severe ards. icu intensive care unit, ards acute respiratory distress syndrome although nmba are not required, they are often used in these patients, as reported in previous studies [ ] . nonetheless, the protective effects of nmba have been seriously questioned in ards [ , ] . the probability of being discharged from the icu was influenced by ards severity but not by crs, as reported in studies of non-covid- ards patients [ ] . all-cause -day mortality was similar or lower than previously published for non-covid (table s ) and covid- ards [ , , ] patients. this study has several strengths. the study was very large with over patients from icus. as well, this is the first study to provide very detailed physiological data and ventilation strategies during the entire ventilatory period in covid- ards patients. however, we acknowledge a number of limitations. first, our study design did not allow us to analyze potential associations of ventilatory strategies with outcomes. second, we were unable to determine why certain therapeutic approaches were used; for example, how peep was adjusted (pragmatic or individualized approach), or why adjunctive therapies (rm, prone position) were applied (usual practice, refractory hypoxemia, etc.), or the indications and timings of ecmo, or corticosteroids. third, cox regression analysis was not adjusted for confounders. the main reasons were the low grade of imbalances in the groups in the relevant baseline variables. fourth, due to the critical moment of the pandemic, and that most participating centers had rapidly reached icu saturation and intensivists were forced to make difficult decisions, we did not collect the total number of patients admitted to participant icus during the study period. finally, it is plausible that due to the burden of care experienced by participating clinicians during the study period, the ventilatory strategy and specifically, the use of adjunctive therapies may not be representative of clinical practice in non-pandemic circumstances. in conclusion, in this large series, covid- ards patients appear to have similar physiological features to other causes of ards including respiratory system compliance, plateau pressure and driving pressure. compliance with lung-protective ventilation was high, and the risk of -day mortality increased with the severity of ards, but was not greater than other studies in non-covid- ards patients. a novel coronavirus genome identified in a cluster of pneumonia cases-wuhan critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical features of patients infected with novel coronavirus in wuhan covid- does not lead to a "typical" acute respiratory distress syndrome covid- pneumonia: different respiratory treatment for different phenotypes? management of covid- respiratory distress ards definition task force et al ( ) acute respiratory distress syndrome: the berlin definition strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected: interim guidance how to handle mortality when investigating length of hospital stay and time to clinical stability epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries open lung approach network et al ( ) open lung approach for the acute respiratory distress syndrome: a pilot, randomized controlled trial effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial national heart, lung, and blood institute petal clinical trials network ( ) early neuromuscular blockade in the acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome clinical characteristics of covid- in new york city clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china the alien study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation resolved versus confirmed ards after h: insights from the lung safe study a clinical classification on the acute respiratory distress syndrome for predicting outcome and guiding medical therapy respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study respiratory mechanics and gas exchange in covid- associated respiratory failure missed or delayed diagnosis of ards: a common and serious problem driving airway and transpulmonary pressure are correlated to vili determinants during controlled ventilation effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis investigators of the apronet study group, the reva network, the réseau recherche de la société française d' anesthésie-réanimation (sfar-recherche), and the esicm trials group et al ( ) a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study recruitability and effect of peep in sars-cov- -associated acute respiratory distress syndrome respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions early paralytic agents for ards? yes, no, sometimes clinical features of patients infected with novel coronavirus in wuhan characteristics and outcomes of critically ill patients with covid- in washington state all authors contributed to the study conception and design. material preparation, data collection and analysis were performed by cf, rm, mm, ag, ea, ca and gm-p. the first draft of the manuscript was written by cf and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. the authors declare no conflicts of interest in relation to this manuscript. the study was approved by the referral ethics committee of hospital clínic, barcelona, spain (code number hbc/ / ). this is an observational study. the need for written informed consent from participants was considered by each participating center. not applicable. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -jj anf g authors: shang, you; pan, chun; yang, xianghong; zhong, ming; shang, xiuling; wu, zhixiong; yu, zhui; zhang, wei; zhong, qiang; zheng, xia; sang, ling; jiang, li; zhang, jiancheng; xiong, wei; liu, jiao; chen, dechang title: management of critically ill patients with covid- in icu: statement from front-line intensive care experts in wuhan, china date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: jj anf g background: the ongoing coronavirus disease (covid- ) pandemic has swept all over the world, posing a great pressure on critical care resources due to large number of patients needing critical care. statements from front-line experts in the field of intensive care are urgently needed. methods: sixteen front-line experts in china fighting against the covid- epidemic in wuhan were organized to develop an expert statement after rounds of expert seminars and discussions to provide trustworthy recommendation on the management of critically ill covid- patients. each expert was assigned tasks within their field of expertise to provide draft statements and rationale. parts of the expert statement are based on epidemiological and clinical evidence, without available scientific evidences. results: a comprehensive document with statements are presented, including protection of medical personnel, etiological treatment, diagnosis and treatment of tissue and organ functional impairment, psychological interventions, immunity therapy, nutritional support, and transportation of critically ill covid- patients. among them, recommendations were strong (grade ), were weak (grade ), and were experts’ opinions. a strong agreement from voting participants was obtained for all recommendations. conclusion: there are still no targeted therapies for covid- patients. dynamic monitoring and supportive treatment for the restoration of tissue vascularization and organ function are particularly important. the outbreak of novel coronavirus pneumonia that was first detected in wuhan in december resulted in a worldwide pandemic. on february , , the world health organization (who) formally named it coronavirus disease . a person with laboratory confirmation of virus causing covid- infection, irrespective of clinical signs and symptoms, is considered as a confirmed case [ ] . globally, more than , , confirmed individuals and over , deaths, across more than countries, territories or areas have been reported [ ] . approximately % of confirmed cases developed severe disease [ ] , while the grand fatality rate was . % [ ] . as the virus continues to spread at an alarming rate, healthcare workers are seeking effective and actionable management for affected patients. in china, physicians have been coping with covid- for over months. most of the people who contracted covid- presented with mild symptoms ( . %), then severe ( . %), and finally critical ( . %) ( table ) [ ] . most of the confirmed cases were between the ages of and ( . %), diagnosed in hubei ( . %), with the overall fatality rate of . %, and . % in health workers [ ] . the case fatality rate for critical cases was . % [ ] . patients with underlying diseases had much higher fatality rates than patients with no underlying diseases ( . % for cardiovascular disease, . % for diabetes, . % for chronic respiratory disease, . % for hypertension, . % for cancer, and . % for none) [ ] . the epidemic outbreak curve peaked around january - , , after which the decline ensued. a recent single-center study found that most critical patients developed organ dysfunction, where % were found to have acute respiratory distress syndrome (ards), % with acute kidney injury (aki), % with cardiac injury, % with liver dysfunction, and % with pneumothorax [ ] . besides these epidemiological findings, chinese experts have gained valuable experience in the management and pathology of this disease. we consider it our responsibility to share these experiences through the expert consensus. chinese specialists in critical care medicine were organized and worked together to develop an expert statement after five rounds of expert seminars and discussions. this statement represents a synthesis of evidence and experts' consensus on critical care, despite the lack of clinical trials. critical cases are characterized by exhibited respiratory failure, septic shock, and/ or multiple organ dysfunction/failure [ ] . in experts' opinion, the patients should also be considered as critical cases if they are suffering from high respiratory frequency (rr ≥ bpm) and low oxygen index (arterial partial pressure of oxygen (pao )/fraction of inspired oxygen (fio ) ≤ mmhg) under high-flow nasal cannula oxygen therapy (hfnc). the experts drew up sections on the management of covid- disease, mostly based on the experience in wuhan. the statements were drawn up by a group of front-line intensive care experts in china who fought against the covid- epidemic in wuhan. the group's agenda was predefined. the expert group first defined clinical questions to be addressed and then designated the experts in charge of each question after a first meeting. all the questions were formulated according to the population, intervention, control, and outcome (pico) format, which helps defining inclusion and exclusion criteria for the literature searches and identifying relevant studies. the quality of evidence was assessed using the methodology described in grades of recommendation, assessment, development, and evaluation (grade). the quality of evidence can be high, moderate, low, or very low. because of the sudden outbreak of a covid- , the proposed question could be the subject of a recommendation as an expert opinion due to inexistent or insufficient literature. in addition, the published data on severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers) and other coronaviruses infections, as well as data on supportive care in the icu from studies on influenza and other respiratory viral infections, ards and sepsis was used as indirect evidence. a total of rounds of expert seminars and discussions were organized to provide trustworthy recommendation on the management of critically ill covid- patients (table ) . we use the wording "we recommend", "recommended", "should" or "should not" for strong recommendations, "should probably", "should probably not" or "should probably be considered" for weak recommendations, and "the experts suggest", "the experts suggest against", "suggested" or "not suggested" for expert opinion. the implications of the recommendation strength are presented in table . the proposed recommendations were discussed one by one. at least % of experts agree to approve a proposal for criteria, and at least % of experts must agree to reach a strong agreement. in the absence of strong agreement, choose to reformulate the proposal and re-rating, in order to reach consensus. only the expert opinions that give strong agreement are retained. the prevention and control of infections, diagnostic strategy, therapeutic management, and transportation of patients were defined. literatures were searched via pubmed and the cochrane library databases. only articles published in english or with an english abstract were included in the analysis focused on recent data according to an order of appraisal ranging from meta-analyses to randomized trials to observational research studies. the study population size and research relevance were considered for each study. according to the grade method and summary of the results, experts drew up statements. of these guidelines, had a high level of evidence (grade ±), had a low level of evidence (grade ±), and were expert opinions. a strong agreement was reached for all statements after two rounds of scoring. as the front-line of the covid- outbreak response, health care workers are exposed to a huge risk of infection. therefore, health care workers must follow the standard precautionary principles and try their best to ensure the personal protection, hand hygiene, ward management, environmental ventilation, and sanitization of the object surface, so as to avoid nosocomial cross-infection. statement implementation of standard precautions, strengthening ward management, and self-management are suggested safety measures for health care workers (expert opinion). rationale averted by the current epidemic situation of covid- , taking proper precautions is essential for avoiding the spread of infection among health care workers. thus, the following points need to be considered. as a high-risk environment, tertiary class protection is suggested for health care workers in intensive care unit (icu). personal protective equipment (ppe) includes disposable surgical cap, n mask, work uniform, disposable medical uniforms, disposable latex gloves, goggles, and full-face shields. full-face respiratory protective devices or powered air-purifying respirators are required when performing aerosol-generating procedures. destroying and disposing of masks properly, putting on and removing ppe, and practicing hand hygiene are necessary to avoid self-contamination. special attention should be paid to details such as the side exposure of the eyes and wrists with glove slippage, as well as the risks of infection while removing some disposable shoe covers [ ] . the hand hygiene system should be strictly implemented table statement timeline march , designating the experts in charge of each addressed question each expert made a detailed outline of their respective question march , discussing and resolving the problems encountered by the experts in the process of making the statements april , ( ) discussing the experts' respective statement and rational after revision; ( ) first round of scoring april , guideline finalization meeting for the second round of scoring table recommendations according to the grade methodology grade + strong recommendation "…we recommend…", "…recommended…" or "…should…" high level of evidence grade + weak recommendation "…should probably…" or "…should probably be considered…" low level of evidence expert opinion recommendation in the form of an expert opinion "…the experts suggest…", "…suggested…", "…the experts suggest against…", or "…not suggested…" [ ] . clinical triage system needs to be established to assess all patients at admission, allow for early recognition of possible covid- cases and immediate isolation of patients with suspected disease in an area separate from other patients (source control). the number of family members and visitors who are in contact with suspected or confirmed covid- patients should be limited or visiting should be prohibited altogether. the proper disposal of clinical waste should be ensured [ ] . health care workers need to self-monitor for signs of illness and self-isolate. if illness occurs, they should report it to managers and stay at home. a sensible diet, proper rest, and adequate exercise are advised to maintain physical and psychological health. health care workers should familiarize themselves with related working procedures so as to avoid mistakes [ ] . proper icu ward setting, necessary equipment and facilities, and strict icu environmental disinfection, are suggested (expert opinion). rationale it is suggested to adjust measures according to the differing conditions so as to set the icu ward rationally. contaminated areas, potentially contaminated area and clean areas need to be strictly divided. the buffer zone should be set between every two areas. posting eye-catching logos on each area is required to prevent straying into the wrong place. different points of access should be set for medical staff and patients, making sure they do not get crossed. for icu, tertiary class protection should be correctly performed in each area, which is of great importance for precaution of covid- [ ] . the use of negative pressure rooms with natural ventilation is recommended by the who guidance to prevent the spread of airborne pathogens among rooms [ , ] . first-aid materials and medicine such as oxygen tank, electrocardiogram (ecg) monitor, defibrillator, injection pump, infusion pump, endotracheal intubation supplies, portable vacuum extractor, noninvasive ventilator, invasive ventilator, hemofiltration equipment, extracorporeal membrane oxygenation (ecmo) equipment and so on should be prepared. other equipment, including air disinfecting machine and air cleaner, as well as medical gas systems including oxygen, compressed air, special gas, and vacuum suction systems, need to be assured too. it is of particular importance to implement effective measures to prevent the spread of covid- in icu. disinfection includes concomitant disinfection and terminal disinfection. concomitant disinfection must be conducted immediately for the materials and environment contaminated by the excretion of the suspected and confirmed patients. following the end of day's work in icu, or the patients' recovery or death in the isolation ward, terminal disinfection needs to be done carefully. key disinfection objects include patients' living supplies such as clothes and quilt, medical supplies, ground and wall space of icu wards, the surface of desks and bed tables, as well as air [ , ] . current evidence indicates that covid- is mainly transmitted from person to person through droplets, contact, and even high concentrations of aerosols [ ] . large amounts of droplets and aerosol are generated by sputum suction in the airway, specimen collection, tracheal intubation, fiber bronchoscopy, tracheotomy, etc. accordingly, surgeons are at a great risk of contamination. in order to avoid occupational exposure, recommendations during the aerosol-generating procedures in covid- patients are the following: statement if possible, covid- patients should probably be admitted to negative pressure rooms (grade +, weak recommendation). rationale negative pressure rooms are aimed to decrease the concentration of severe acute respiratory syndrome coronavirus (sars-cov- ) pathogens. in view of that, the risk of contamination would be decreased during the aerosol-generating procedures in such a setting. during the severe acute respiratory syndrome (sars) epidemic, it was reported that negative pressure settings were effective in preventing cross-contamination and protecting the staff and patients inside the room [ ] . according to who recommendations for covid- patients, such locations should be with a minimum of air changes per hour or at least l/ second/patient with natural ventilation [ ] . the experts suggest that operators wear a portable air-purifying respirator with level iii biosafety protection (expert opinion). rationale an observational study reported that among hospitalized patients diagnosed with confirmed covid- in zhongnan hospital in wuhan in january, , were healthcare workers [ ] . till march , , it has been reported that over health workers were confirmed with covid- , among whom died. the memory of what has happened during the sars outbreak is still fresh. a systematic review showed that the healthcare workers who performed aerosol-generating procedures, including endotracheal intubation (odds ratio, . ), noninvasive ventilation (odds ratio, . ), tracheotomy (odds ratio, . ), and manual ventilation before intubation (odds ratio, . ) were at higher risk of suffering from sars infection compared with the non-performers [ ] . most of the infections among healthcare workers occurred at the early stage of this outbreak when the self-protective directive has not yet been established and reinforced. after confirmation of human to human transmission of sars-cov- , the self-protection for healthcare workers was subsequently established and reinforced from the end of january . level iii biosafety protection is mandatory for intubation according to the guidance of the general office of the national health committee [ ] . ppe donning process should be strictly followed during high-risk operation: disposable hair cover, fit-tested n respirator or equivalent, fluid-resistant gown, two layers of gloves, goggle and face shield, and fluid-resistant shoe covers. the main operator should use portable airpurifying respirator. all the donning processes should be supervised by a professional nurse or assistant. doffing process of ppe after high-risk exposure should also be followed: hand hygiene, face shield and goggle removal, fluid-resistant gown removal, outer glove removal, shoe cover removal, inner glove removal, hand hygiene, n respirator or equivalent removal, and hair cover removal. the doffing process seems to be of greater importance. all the processes should also be supervised so as to reduce the risk of contamination [ ] . the aerosol-generating operations such as tracheal intubation and tracheotomy are suggested to be performed by senior physicians or specialists in the field. an electronic laryngoscope with light emitting diode is suggested during endotracheal intubation. if possible, disposable equipment is suggested to be used. b) fiber bronchoscopy is not suggested for patients without an artificial airway. the operation is suggested to be performed by senior physicians or professionally trained respiratory therapists. a bronchoscope with an external display is suggested for facilitating operations. if possible, the use of a disposable bronchoscope is suggested (expert opinion). rationale large amounts of aerosols generated by incubation can increase the risk of transmission and nosocomial infection [ ] . thus, visual devices are recommended to facilitate the procedure, limit operation time [ ] and ensure the distance between operator and patient. routine fiber bronchoscopy operations are not suggested for covid- patients. meanwhile, most covid- patients have few airway secretions [ ] so that the indication of bronchoscopy should be strictly minimized. according to the recommendations by the centers for disease control and prevention (cdc) [ ] and who [ ] , disposable medical equipment should be used for patient care if possible. statement (a) deep sedation (richmond agitation-sedation scale (rass): - ) is suggested for patients during the procedure of fiber bronchoscopy. (b) the artificial airway is suggested to be connected with a threeway connector allowing access to get into the airway to perform a bronchoscopy. (c) the use of a closed airway suction device is suggested (expert opinion). rationale severe covid- patients with artificial airway tend to suffer from severe hypoxemia [ ] . the patient's secretions, droplets, and aerosols can be widely spread during the operation. patients should be intubated within s [ ] . the procedure of fiber bronchoscopy should be performed gently with great caution in severe covid- patients. during bronchoscopy, following procedures should be followed to avoid aerosols spreading: artificial airway should be connected with a disposable three-way connector to a ventilator, then (a) ventilator needs to be set to standby mode, (b) the artificial airway needs to be briefly clamped, (c) the bronchoscopy should be quickly inserted into the connector, (d) the clamp should be opened, (e) ventilation should be restored [ ] . for the patients requiring mechanical ventilation, it is not advisable to disconnect patients from the ventilator. even though some clinical experts insisted that antiviral therapy is unnecessary for seriously ill patients with covid- since the course of disease in severe types is longer than weeks, multiple virus particles have been found at the lung lesions following histopathological examination. up to date, there is no specific antiviral drug that has been testified and globally recognized effective for treating covid- . in china, several antiviral drugs such as ribavirin, ganciclovir, oseltamivir, arbidol, alpha-interferon, chloroquine, lopinavir-ritonavir, and remdesivir have been used in clinical settings for the treatment of covid- . among them, oseltamivir and arbidol hydrochloride are the most commonly utilized; however, these antiviral drugs were originally designed for influenza, and their efficacy and safety for covid- need to be further investigated. no antiviral drugs are proven effective and should probably be considered for sars-cov- treatment (grade +, weak recommendation). rationale ribavirin is a broad-spectrum antiviral drug. clinical observations have suggested that early use of this drug is efficacious in containing covid- . to avoid possible aerosol transmission, we do not recommend alpha-interferon nebulization for covid- infected patients. according to a very recently published clinical study from france, hydroxychloroquine can significantly reduce viral load in covid- patients, and azithromycin can further enhance this effect [ ] . in this study, combination use of hydroxychloroquine (hcq) and azithromycin for at least days at an early stage could rapidly reduce the nasopharyngeal viral load and decrease the length of hospital stay for infected patients. it should be noted that treatment with higher chloroquine diphosphate (cq) dosage ( mg cq twice daily) is not recommended for severe covid- due to its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir [ ] . nonetheless, a randomized controlled trial (rct) trial conducted by cao et al. suggested monotherapy of lopinavir-ritonavir did not bring about any clinical benefits for severe covid- patients compared with standard supportive care, which may be partly caused by the higher throat viral loads in lopinavir-ritonavir group, delayed treatment initiation [ ] . of note, these clinical studies were limited by relatively small sample sizes. more large-scale and well-designed clinical trials are needed to confirm their potential therapeutic effects. arbidol monotherapy might be better than lopinavir-ritonavir in reducing viral load in covid- patients [ ] . a clinical study from gilead sciences showed that remdesivir could improve clinical conditions in critically ill patients with covid- , and stop patient from receiving invasive mechanical ventilation or ecmo [ ] . however, a recent multicentre study published in the lancet found no benefit of remdesivir in improvement of clinical outcomes for severe covid- [ ] . one recent study published in n engl j med showed that compassionate use of remdesivir improved clinical outcomes in a subset of severe covid- patients [ ] . however, the absence of control groups precludes a final conclusion. the definite therapeutic effectiveness of remdesivir in the treatment of severe covid- needs to be further verified. remdesivir has been approved as a potential treatment for severe covid- patients by the japanese ministry of health, labour and welfare (mhlw) on may , due to the covid- pandemic [ ] . the main side-effects of these antivirals include qt interval elongation, bradycardia, hepatic injury, and obvious gastrointestinal reactions such as serious diarrhea and vomiting which may contributed to disease deterioration. clinical trials testing remdisivir for the treatment of severe covid- patients are underway (nct , nct ). convalescent plasma therapy belongs to passive immunization, which is used for the treatment of virus infections when specific drugs and vaccines are unavailable. convalescent plasma, which has been used for more than one hundred years, can provide specific antibodies to neutralize and eradicate the viruses from the blood circulation. up to date, there is no particular treatment for covid- . in , the who recommended the use of convalescent plasma collected from patients who recovered from the ebola virus infection as an empirical treatment during the outbreak [ ] . during the covid- epidemic period, this method was also recommended by the national health commission of china for the treatment of severe and critical patients [ ] . statement convalescent plasma therapy should probably be used for severe and critically ill patients with covid- (grade +, weak recommendation). rationale convalescent plasma has been testified to suppress viremia, shorten the hospital stay, and reduce mortality during several virus epidemics. in during a spanish influenza pandemic, convalescent plasma reduced the mortality rate by > % in severe patients [ ] . since then, it was also used for prophylaxis or as a treatment for several virus infections such as measles, argentine hemorrhagic fever, influenza, chickenpox, and infection by cytomegalovirus. over the past two decades, its efficacy and safety were confirmed during pandemics of sars, mers, h n and h n avian flu. during the sars pandemic in , eighty patients received convalescent plasma at prince of wales hospital, hong kong. by the nd day, a higher discharge rate was observed in patients (n = ) given convalescent plasma before day than that given plasma after day ( . % vs. . %; p < . ) [ ] . a prospective cohort study conducted by hung et al. showed that convalescent plasma therapy (n = ) significantly reduced mortality compared to the control group (n = ) ( . % vs. . %; p < . ). meanwhile, plasma treatment lowered the upper respiratory tract virus load and decreased serum cytokines levels in patients with severe pandemic (h n ) virus infection [ ] . these studies verified the efficacy of convalescent plasma in patients with virus infections. it has been reported that among three severe mers patients who received convalescent plasma infusion, just two showed neutralizing activity [ ] . among five critically ill patients with covid- receiving mechanical ventilation convalescent plasma infusion, patients were discharged, while clinically ill patients improved and maintained the stable condition till the day after transfusion [ ] . a study performed in severe covid- patients found that convalescent plasma treatment could improve clinical outcomes, improve immune function, and promote absorption of lung lesions [ ] . nonetheless, just like any other treatment, convalescent plasma has its limitations. the main limitation refers to the reported studies, which are not randomized trials, but just prospective cohort studies or case series studies. therefore, it was not possible to eliminate the influence of baseline severity and other treatments when evaluating the effects of convalescent plasma therapy. other limitations include the risk of transmitting infections to transfusion service personnel, the need for adequate selection of donors with high neutralizing antibody titers, and the risk of other transfusion-transmitted infections [ ] . however, regardless of these limitations, since there are still no specific etiological treatments for covid- , and convalescent plasma is available, it is reasonable to use it in the treatment of covid- patients. respiratory failure is the primary organ dysfunction, which worsens the prognosis of covid- patients. oxygen therapy and respiratory support are the key treatments for covid- -induced ards. due to inflammatory and necrosis-induced small airway occlusion, which was confirmed by autopsy of covid- -induced ards, positive pressure ventilation is vital to restore the collapsed airway and improve gas exchanges. however, high end-inspiratory pressure increases stress and strain to normal alveoli and increases the risk of lung injury. oxygen therapy and respiratory support for covid- -induced ards should balance airway recruitment and risk of lung injury (fig. ). indication for hfnc and niv. statement niv and hfnc should probably be used for covid- -induced ards with pao / fio > mmhg (grade +, weak recommendation). rationale noninvasive ventilation support (niv) and hfnc are important treatments for covid- -induced mild and moderate ards. the mechanisms of the two treatments are positive end-expiratory pressure, decreased respiratory workload, decreased incidence of intubation, ease of use, and higher comfort. in a randomized trial of adult patients admitted to the icu for acute hypoxemic, nonhypercapnic respiratory insufficiency, continuous positive airway pressure (cpap) delivered by face mask was associated with an early improvement in oxygenation; however, it was not associated with a reduced need for intubation or with improved outcomes [ ] . a trial that compared hfnc oxygen, standard oxygen via face mask and face mask niv in patients with acute hypoxemic respiratory failure, reported that the intubation rate was significantly lower with hfnc oxygen than with standard oxygen or niv among patients with pao /fio ≤ mmhg at enrollment and, for the whole group (patients with pao / fio ≤ mmhg), patients managed with hfnc had improved survival. there were no differences in outcomes between niv and standard oxygen [ ] . a substudy examined the practice of niv use in ards of lungsafe study reporting that niv was associated with higher icu mortality in patients with a pao / fio < mmhg [ ] . for covid- , there is no sufficient evidence to prove that hfnc is superior to niv. statement when using niv and hfnc, oxygenation and breathing patterns are suggested to be closely monitored, and intubation delays is suggested to be avoided (expert opinion). rationale for all cases with noninvasive support, patients should be closely monitored, as deterioration can abruptly occur [ ] . in china, some patients presented with hypoxemia, later named "silence hypoxemia", since these patients were without corresponding clinical manifestations, e.g., no high respiratory rates, high heart rate, respiratory distress, and other hypoxia symptoms. these patients have a high risk of sudden death and should be closely monitored and timely provided with oxygen therapy. positive responses are usually evident soon after the initiation of niv and hfnc. if there is no substantial improvement in gas exchange and respiratory rate within a few hours, invasive mechanical ventilation should be started without delay. failure to recognize a lack of improvement during noninvasive support may result in further respiratory deterioration and/or cardiac arrest, often with devastating consequences. delayed intubation increases ards mortality; therefore, early recognition of ards severity could avoid delayed intubation. if the use of hfnc fails, endotracheal intubation is unavoidable even with the use of rescue niv [ ] . the indications for hfnc and niv intubation are a higher level of severity (saps ii score > ), hypoxemia (pao /fio ≤ mmhg), hypoxemia that is not improved following niv treatment for h, and strong spontaneous breathing (tidal volume with niv > ml/ kg pbw) [ ] . rox index can be used to predict hfnc failure and intubation for patients with respiratory failure; > . , suggests a high chance of success, < . suggests a high risk of failure, and intubating the patient should be discussed; index between . and . , suggests the patient should be monitored very closely and intubation delays should be avoided [ ] . [ , ] . another trial that employed a multilevel mediation analysis to analyze individual data from patients with ards, who were also included in nine previously reported randomized trials, identified driving pressure as the ventilation variable that best-stratified risk. decreases in driving pressure owing to changes in ventilator settings were strongly associated with increased survival [ ] . low tidal volume ( - ml/kg pbw), limited plateau pressure (< cmh o), and driving pressure (< cm h o) could decrease ards mortality. bedside measurements should probably be used for the evaluation of lung recruitability (grade +, weak recommendation). rationale alveolar collapse is mainly generated by inflammatory lung edema, impairment of chest wall movement, and surfactant deficiency. some reports have shown different effects of recruitment maneuvers in ards patients due to lung recruitability [ ] . from our experience in wuhan, most of the covid- patients had low lung recruitability [ ] . due to the infectiousness of covid- , ct, and the other necessary equipment cannot always be used to evaluate lung recruitability. however, some bedside measurements, such as the pressure-volume curve, recruitment to inflation ratio, and clinical parameters, can be measured by a ventilator and used to evaluate lung recruitability [ ] . based on low lung recruitability in covid- -induced ards, high peep should probably not be used, and peep setting should probably be based on various factors, including gas exchange, hemodynamics, lung recruitability, and driving pressure (grade +, weak recommendation). rationale use of positive end-expiratory pressure (peep) usually improves gas exchange and helps reduce the need for high fio . in addition, appropriate levels may limit vili by maintaining lung recruitment and improving lung homogeneity [ ] . when applied with a constant pplat, peep reduces the driving pressure and keeps the lung recruited. because of the lack of resources, peep selection criteria may include lung recruitability, peep/fio table, respiratory system compliance, optimal oxygenation, and driving pressure [ , , ] . based on the available data, all peep values represent a compromise between the extent of recruitment and overdistension, and hemodynamics. the experts suggest optimizing ventilator settings to improve hypercapnia (expert opinion). rationale in china, hypercapnia has been commonly found in covid- -induced ards. the mechanisms are related to lung injury inhomogeneity and an increase in dead space. firstly, optimization of ventilator setting is important; secondly, the prone position could decrease dead space and improve hypercapnia [ ] ; thirdly, tracheal gas inflation (tgi), which influences sputum drainage, could increase alveolar ventilation and co removal [ ] ; fourthly, extracorporeal life support or co removal equipment could improve hypercapnia. statement we recommend using prone positioning in severe covid- patients to prevent the deterioration of patients' condition (grade +, strong recommendation). rationale prone positioning has a beneficial effect on oxygenation, lung recruitment, and stress distribution. the physiological effects of prone positioning include redistribution of lung densities, often with the recruitment of well-perfused dorsal regions. although prone positioning increases chest wall elastance, this change is usually accompanied by improved lung recruitment, a reduction in alveolar shunt and improved ventilation/ perfusion ratio, subsequent improvement in oxygenation and co clearance, a more homogeneous distribution of ventilation and a reduced vili risk [ , ] . indications for prone positioning include moderateto-severe ards (pao /fio < mmhg), and/or hypercapnia. duration of prone positioning should be more than h, and the termination of prone positioning should be based on the response of oxygenation, lung mechanics, and hemodynamics. because prone positioning could improve lung inhomogeneity, early prone positioning should be provided for covid- infected patients with/without respiratory failure [ , ] since it could prevent respiratory failure. since covid- is highly infectious, implementation of the prone positioning might require more manpower, thus further increasing the workload of medical personnel. pressure injury of the skin and mucous, facial edema, corneal edema, displacement of the catheter, and airway obstruction must be avoided when placing patients in the prone position. most of the covid- patients presented with mild symptoms; however, about % of patients developed into severe cases, % of them were critically ill with mortality estimates of . − . % [ ] [ ] [ ] . mechanical ventilation alone may not be enough to resolve refractory hypoxemia and hypercapnia in these patients. ecmo could be initiated to maintain oxygenation and avoid ventilator-induced lung injury. a cross-sectional study found that ( . %) patients treated with ecmo [ ] . we recommend an early use of ecmo in covid- patients with refractory hypoxemia or hypercapnia who have received invasive mechanical ventilation and prone positioning (grade +, strong recommendation). rationale the appropriate timing of ecmo in covid- patients might be challenging due to enormous demand and uncertainty related to the reversibility of impaired lungs. to guarantee the reversibility of compromised lungs, ecmo should be launched before injurious mechanical ventilation, which is common in critically ill patients with covid- [ , ] . the primary purpose of ecmo is the maintenance of sufficient oxygenation, removal of co , avoidance of high respiratory drive, and sequencing of ventilator-induced lung injury. the following traditional indications for ecmo may be suitable for covid- patients: pao /fio < for over h; pao / fio < for over h; irreversible ph < . for over h. the experts suggest using the traditional indications for ecmo in hospitals with sufficient medical resources. however, for areas with poor medical resources, the indications for ecmo are suggested to be balanced between the available resources and expected outcomes (expert opinion). the who guidance released a statement, in which they suggest referring patients with refractory hypoxemia despite lung-protective ventilation to those settings with expertise in ecmo [ ] . the latest guidance document issued by elso also suggested that ecmo should be considered according to the standard management algorithm for ards in patients with viral lower respiratory tract infections [ ] . however, in reality, numerous patients who met the criteria for ecmo were admitted over a short period, which was beyond the capacity of the medical resource, including workforce and equipment. in this context, the priority of the ecmo supply should be balanced between the available medical resources and disease reversibility. younger patients with minor or no comorbidities should be given the highest priority when resources are limited. despite standard contradictions, patients who fit the criteria below may be excluded: ( ) patients with significant comorbidities; ( ) elderly patients with worsening prognosis; ( ) patients on mechanical ventilation for more than days. prone position, as well as other adjunct therapies should probably be used for critically ill patients even during ecmo (grade +, weak recommendation). rationale ventilation with the prone position, which is currently recommended by the guidelines, can improve lung heterogeneity as well as oxygenation [ ] . it should be considered in the early stages of the disease rather than as a delayed attempt [ ] . prone position ventilation is currently widely applied for severe covid- patients in china [ ] . even if an ultraprotective ventilation strategy is implemented with the aid of ecmo, prone ventilation is considered to benefit the recovery of the lung. elevated myocardial enzymes, such as cardiac troponin t (ctnt), creatine kinase (ck), creatine kinase-mb isoenzyme (ck-mb), have been widely observed in critically ill patients with the covid- , indicating potential myocardial injury. a significant elevation of myocardial enzymes often indicates a poor prognosis. most patients with elevated myocardial enzymes do not present compromised left ventricular systolic function (reduced ejection fraction) or abnormal electrocardiogram. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension is common in some covid- patients. intensive hemodynamic monitoring should probably be considered for patients with hemodynamic instability. ecmo should probably be used for salvage therapy for patients with severe cardiac dysfunction (grade +, weak recommendation). rationale while sars-cov- and mers-cov share similar pathogenicity, it has been shown that mers-cov can induce acute myocarditis and heart failure [ ] . elevation of biomarkers of cardiac injury is common among critically ill patients with covid- and associated with a higher risk of in-hospital mortality [ , ] . reversible subclinical diastolic dysfunction without systolic impairment was observed in sars [ ] . comparable to sars, most covid- patients with elevated myocardial enzymes do not present compromised left ventricular systolic function. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension have been commonly found in covid- patients. from our experience, tachycardia such as sinus tachycardia and atrial fibrillation were also common, while compensatory tachycardia was absent, even in patients with severe hypoxia or hemodynamic collapse. the exact mechanism of myocardial injury in covid- remains unknown. it has been suggested that direct myocardial injury is mediated via angiotensin converting enzyme (ace ). ace -dependent myocardial infection was observed in the murine model infected with sars-cov [ ] . one study published in n engl j med provides evidence that angiotensin-converting enzyme inhibitors (acei)/angiotensin receptor blockers (arb) medications in covid- patients did not show any association with increasing susceptibility to sars-cov- [ ] . in patients with hemodynamic instability, non-invasive or invasive monitoring, such as echocardiography or thermodilution methods, should probably be used to guide fluid therapy or administration of vasoactive agents. in patients with life-threatening cardiac dysfunction, extracorporeal life support might be salvage therapy. statement hypovolemia is common in critical covid- patients, easy-to-implement parameters should probably be considered for the assessment of the patient's volumetric status (grade +, weak recommendation). rationale the use of vasoactive drugs revealed that the incidence of shock in critically covid- patients was %, and % in non-survivor population [ ] . the shock could be the result of hypovolemia, cardiac injury, and sepsis. fever and mouth breathing could cause large amounts of fluid loss in critical covid- patients, while decreased water intake, acute gastrointestinal injury, depression, intubation, and sedation could exacerbate hypovolemia. previous studies reported on the relationship between dehydration and mortality in severe h n patients [ ] . moreover, older age, comorbidities (especially diabetes and cardiovascular disease), lower lymphocyte count, and higher d-dimer levels were identified as risk factors associated with shock [ , ] . cardiac injury was found in % critical covid- patients [ ] , which meant poor fluid responsiveness and the risk of pulmonary edema. for these reasons, the patients' volumetric status, as well as the fluid responsiveness, should be dynamically assessed. one meta-analysis of rcts showed that dynamic assessment of fluid responsiveness could improve the clinically relevant outcomes in icu, such as mortality reduction, reduced duration of icu length of stay, and mechanical ventilation [ ] . considering the limited clinical resources in the covid- pandemic, we recommend using simple bedside assessments, such as passive leg raising (plr), lactate clearance, pulse pressure variation (ppv), and inferior vena cava (ivc) collapsibility or distensibility. a recent meta-analysis determined that the plr induced changes in cardiac output, with a pooled sensitivity of . and a pooled specificity of . [ ] . ppv also accurately predicted fluid responsiveness in critical patients. in a meta-analysis including studies and patients, ppv predicted fluid responsiveness with the pooled sensitivity of . and a pooled specificity of . [ ] . ivc collapsibility resulted as a simple, non-invasive bedside predictor of fluid responsiveness with a sensitivity of . and a specificity of . [ ] . early lactate clearance-directed therapy was associated with reduced in-hospital mortality, shorter duration of mechanical ventilation, and shorter icu-stay [ ] . a recent observational study showed higher serum lactate levels in covid- non-survivors ( . vs. . mm/l) [ ] . besides, additional attention should also be paid to mental states, degree of thirst, oliguria, skin temperature, and prolonged capillary refilling time as well. conservative fluid strategy should probably be considered for covid- patients with ards while ensuring tissue perfusion (grade +, weak recommendation). rationale even though fluid management in covid- remains unknown, it could be assumed that these patients would respond to fluid therapy in the same way as other ards patients. previous studies have shown that higher cumulative fluid balance is related to the higher mortality of critically ill patients, especially in cases of ards [ ] and/or septic shock [ ] . due to pulmonary edema in critical covid- patients [ ] , excessive fluid therapy could increase extravascular lung water and affect gas exchange, resulting in a poor prognosis. one clinical trial found that the conservative fluid strategy improved lung function, shortened the icu-stay length and duration of mechanical ventilation compared with a liberal strategy in patients with acute lung injury [ ] . another study reported that more than half of critically covid- patients were older than years [ ] . when older patients develop cardiac injury and pulmonary edema, they tend to be less responsive to fluid intake [ ] . conservative fluid strategies could reduce the occurrence of positive fluid balance while ensuring tissue perfusion [ ] . although it has been reported that conservative fluid strategy and liberal strategy have a similar incidence of aki and the requirement for renal replacement therapy (rrt) [ ] , it is still necessary to closely monitor the renal function of patients. at the same time, attention should be paid to maintaining electrolyte balance and acid-base balance. rationale to date, there are still no studies on fluid types in covid- patients; thus, our observations are based on relevant studies of critically ill patients in general. a systematic review of studies that included , participants revealed that using colloids (such as starches, dextrans, albumin or fresh frozen plasma, or gelatins) had no difference in mortality in critically ill patients compared to crystalloids [ ] . considering the price and accessibility, fluid resuscitation with crystalloids should probably be used for critically ill patients. one single-center research reported that low serum albumin ( . ± . g/l) was associated with the progression of covid- pneumonia [ ] , while another study found no significant differences between the nonaggravation and aggravation patients in the early stage of the disease [ ] . serum albumin level < g/l was identified as an independent risk factor for the -day mortality in patients with community-onset pneumonia [ ] . based on the previous evidence and our clinical observations, hypoproteinemia is present in most covid- patients; thus, albumin supplement should probably be used for patients with serum albumin levels below g/l. statement psychological and humanistic care should probably be considered for conscious patients with covid- (grade +, weak recommendation). rationale besides experiencing physical impairment and stressful treatments, covid- patients are being subjected to closing monitoring, and are also witnessing various events in the ward such as sudden deterioration of illness, emergency resuscitation procedures and death, all of which could lead to posttraumatic stress disorder, anxiety, and depression according to previous studies [ , ] . it was reported that % to % of sars survivors had symptoms related to posttraumatic stress disorder, anxiety, and depression and that emotional support, such as communication with others and sharing worries could reduce symptom severity [ ] . accordingly, psychological implications should not be ignored in coronavirus patients. psychological health services and humanistic care could have an important role in rehabilitation. the previous study confirmed that citalopram could improve reappraisal ability and anxiety symptoms in children and adolescents [ ] and that olanzapine could improve psychotic symptoms [ ] . therefore, citalopram or olanzapine should probably be used to improve the psychological symptoms in patients or intervention of the psychologists in the isolation ward who would perform psychological assessment and psychotherapy for patients with new coronary pneumonia. the experts suggest assessing patients' sleep quality, implementing comprehensive measures to improve sleep and reduce the incidence of delirium, thus promoting recovery (expert opinion). nonpharmacological strategies and pharmacotherapy, including dexmedetomidine and melatonin, should probably be considered to decrease the incidence of delirium (grade +, weak recommendation). rationale sleep abnormalities, including abnormal sleep architecture, sleep deprivation, and disruption, frequently occur in the icu. numerous factors can affect sleep in covid- patients, such as stress, anxiety, pain, respiratory distress, tachypnea from the underlying hypoxemia, noise levels, stage lighting in the isolation ward, implementation of healthcare, procedures of healthcare workers, and the pathophysiology of the acute illness. sleep abnormalities may not only lead to mental disorders, but could also damage tissue repair, immune regulation mechanisms and cause delirium, all of which are associated with patient's poor prognosis [ , ] . nonpharmacological strategies for preventing sleep disturbances and treating delirium, such as keeping noise levels within and db range (a) during the day, and less than db (a) at night [ , ] , and providing critical patients admitted to the icu with earplugs can significantly improve patient's sleep and reduce the risk of delirium [ ] . however, in patients with sleep disturbances and delirium, pharmacotherapy care may be necessary. medications such as dexmedetomidine [ ] and melatonin [ , ] may promote sleep and decrease the incidence of delirium, although only limited data are available in support of their use [ ] . assessing pain and preferential use of analgesia over sedation should probably be considered for covid- patients (grade +, weak recommendation). rationale pain is defined as an uncomfortable physical and mental experience caused by physical injury, inflammation, or emotional stimuli. covid- patients tend to experience pain due to hypoxia, long-term immobility, inflammatory storm, impairment of heart, liver, kidney, and other organ functions, procedures, and mental stress. opioids, such as remifentanil and sufentanil, are the firstline options for analgesia in icu according to the pain, agitation/sedation, delirium, immobility, and sleep disruption (padis) guidelines [ ] . sufentanil can be used for covid- patients receiving invasive mechanical ventilation during the early stage of severe ards because of its stronger and faster onset of analgesia, and small accumulation [ ] . remifentanil is suitable for covid- patients receiving invasive mechanical ventilation, especially during person-ventilator confrontation [ ] due to stronger respiratory depression. previous research has confirmed that music or relaxation may diminish anxiety and discomfort in some patients [ , ] . therefore, nonpharmacological pain management strategy can be used for conscious patients with covid- or for patients who do not tolerate opioid therapy, such as covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. assessment of the patient's pain is the foundation of pain management. accordingly, a numeric rating scale (nrs) should probably be used for evaluation of pain in all covid- patients able to self-report their pain. behavioral pain scale (bps) and critical-care pain observation tool (cpot) should be used to evaluate pain in critically ill patients unable to express the pain for themselves. the ideal target values are: nrs < points, bps < points and cpot < points. deep sedation should be performed for patients with severe ards, especially those receiving invasive mechanical ventilation, prone position, neuromuscular blockade, or ecmo treatment (grade +, strong recommendation). rationale it is well known that analgesia and sedation can eliminate pain and discomfort, reduce sympathetic nerve excitement, patient's metabolic rate, oxygen consumption, the metabolic burden of various organs, stress, and inflammation. however, plenty of evidence suggests that deep sedation is associated with adverse outcomes, including prolonged mechanical ventilation and icu-stay, higher mortality, lower rates of in-hospital, and -year follow-up survival [ ] [ ] [ ] [ ] [ ] . under 'real-life' conditions in wuhan, deep sedation was extremely important for reducing oxygen consumption and developing tolerance to mechanical ventilation by new coronavirus patients with severe ards who suffered from respiratory distress, tachypnea and respiratory overdrive even after receiving invasive mechanical ventilation. accordingly, deep sedation should be an important part of lung-protective ventilation strategy, especially during the early stage of severe ards. previous studies have confirmed that daily spontaneous awakening trials (interruption of sedatives) lead to better outcomes in patients receiving mechanical ventilation [ ] . however, critically ill patients with covid- have a longer mechanical ventilation time, and daily sedatives interruption is not suggested for patients receiving deep sedation in order to reduce lung damage during early stage of severe ards. midazolam and propofol are the primary medications used for icu deep sedation. the sedation-agitation scale (sas) and rass are the reliable and valid sedation assessment tools used for assessing the depth and quality of sedation in covid- patients. the sas and rass should be used to measure the depth after administering sedatives. the target value is rass - - points, sas points for deep sedation, and sas point. the target value of very deep sedation is rass - point for patients receiving neuromuscular blocking agents [ ] , prone position, or ecmo treatment. we suggest a bispectral index monitoring for patients undergoing very deep sedation, if available. light sedation is suggested for severe covid- patients receiving hfnc oxygen therapy and non-invasive mechanical ventilation, and also for critically ill patients in the recovering stage (expert opinion). rationale agitation and anxiety, which frequently occur in covid- patients, may be associated with adverse outcomes. appropriate sedation can reduce anxiety and agitation while preserving patients' comfort. light sedation can maintain frequent redirection, and increase the physiologic stress response, but not increase the incidence of myocardial ischemia. we suggest the use of light sedation for covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. in addition, light sedation should be given to recovering patients in order to reduce the time of mechanical ventilation and the time of stay in icu [ ] when pao / fio ≥ - mmhg. dexmedetomidine can be used for patients receiving light sedation due to the small respiratory depression. the target value of light sedation is sas - points and rass − to + points. there is some evidence that immunotherapy may be effective against novel coronavirus infection. an article [ ] published on the medrixv website stated that the mortality of covid- patients might be negatively related to the number of lymphocytes in patients. patients tend to be below normal levels and lower level of helper t cells in the severe group. the percentage of naïve helper t cells increased, and memory helper t cells decreased in severe cases. this suggested that novel coronavirus might fight the immune system; thus, early lymphocytes and t lymphoid subgroups testing are required for early intervention, which may help to avoid lymphocyte depletion. currently, there are several available immunomodulatory drugs, including glucocorticoid, thymosin, and immunoglobulin. statement systemic corticosteroids should probably not be used for the treatment of covid- . for critically ill patients with ards at an early stage, corticosteroids should probably be prudently used at a low or moderate dose over the short course if there are no contraindications (grade -, weak recommendation). rationale glucocorticoid use in ards remains a controversial topic. it is well known that corticoids are beneficial in the treatment of ards since they can alleviate inflammatory response and delay fibrosis [ ] . a retrospective study conducted in guangzhou revealed that proper use of corticosteroids in confirmed critical sars patients led to lower mortality and shorter hospitalization stay and was not associated with significant secondary lower respiratory infections or any other complications [ ] . however, there are some inconsistencies in the existing studies. a study involving patients with ards, showed improved oxygenation and lung injury score in less than h but no change in -day mortality [ ] . another study found no differences in overall mortality, while mortality was increased when steroids were started after day [ ] . as for viral pneumonia, a few studies have found that the administration of corticosteroids in patients with influenza pneumonia is associated with increased icu mortality [ , ] . who does not recommend routine use of corticoids in the treatment of covid- , while treatment with methylprednisolone may be beneficial for patients who develop ards, as was shown by a retrospective cohort study of patients with confirmed covid- pneumonia admitted to wuhan jinyintan hospital in china [ ] . given the inconclusive evidence and urgent clinical demand, the guidance published by china national health commission on march , , suggested the use of glucocorticoids over the short time period ( to days) for patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of inflammatory response. the dosage of methylprednisolone should not exceed - mg/kg/day. it should be noted that large doses of glucocorticoid might delay the removal of coronavirus due to immunosuppressive effects. thymosin is a peptide originally isolated from thymic tissue, which was initially selected for its ability to restore immune function to thymectomized mice. thymosin may act on precursor t cells to increase the number of activated t helper cells and expression of th -type cytokines such as interleukin- and interferon-alpha. the activated dcs and th cells then kill bacterial, fungal, or viral infections and lead to the stimulation of differentiation of specific b cells to antibody-producing plasma cells and an improvement in response to vaccines by stimulation of antibody production [ ] . the use of thymosin alpha therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis [ ] . also, it has been observed that lower lymphocytes in covid- patients indicate worse prognosis [ ] . thus, thymosin may theoretically have an effect on covid- , which needs to be further investigated. immunoglobulin may regulate the host's immune response in a variety of ways, but it had no effect on mortality in previous sepsis studies. at present, it is not recommended in the treatment of covid- . a study performed in severe or critical covid- patients showed that tocilizumab treatment could improve clinical outcomes, promote absorption of lung lesions, improve immune function, and reduce inflammatory response [ ] . however, il- inhibitor sarilumab was shown to be ineffective in the treatment of severe covid- , leading to early termination of this clinical trial [ ] . large sample size studies using prospective cohort designs are required to verify the therapeutic effect of il- inhibitors for severe covid- . great attention should be paid to secondary infection since it may worsen the patient's prognosis. however, since the data on the epidemiology of secondary infection in covid- patients are lacking, we can only make some suggestions according to our own experience and some previous studies focused on h n . the experts suggest against using prophylactic antibiotics for covid- patients (expert opinion). rationale due to the nature of virus infection, it is not logical to use prophylactic antibiotics, and there is no evidence that this strategy could reduce the incidence of the secondary infection. on the other hand, according to the management guidelines of covid- from who and china [ , ] , empiric antibiotic treatment should only be used based on the clinical diagnosis (communityacquired pneumonia, healthcare-associated pneumonia or sepsis), local epidemiology and susceptibility data, and treatment guidelines. based on our observations from wuhan, many severe and critical covid- patients did not show any signs of bacterial infection (such as elevated wbc, pct and similar); thus, we do not suggest the routine use of prophylactic antibiotics in covid- patients, especially at the early stage or for non-intubated patients. the experts suggest closely monitoring the signs of secondary infection, especially in critically ill patients with covid- who have been admitted to icu > h (expert opinion). rationale both long course of the disease and immunosuppressive state place the severe and critical covid- patients at a high risk of secondary infection (including bacteria and fungus). unfortunately, the data on the epidemiology of secondary infection in covid- patients are lacking. however, based on the evidence from h n , secondary infection is very common in patients admitted to icu > h [ , ] . although a complete nosocomial infection prevention and control system was set up in wuhan according to the guidelines [ , ] , ventilator-associated pneumonia and hospital acquired pneumonia were very common occurrences in the icu. we suspect this is mainly because the medical staff is wearing heavy personal protective equipment, and heavy workload adhered to the incomplete implementation of these measures. consequently, the strategies for nosocomial infection prevention should be effectively implemented, and multiple site samples (blood, sputum, etc.) should be routinely collected to monitor the signs of secondary infection. in clinical practice, coagulation dysfunction is commonly found in covid- patients, and the symptoms range from mild disorders of coagulation indicators to disseminated intravascular coagulation (dic). the exact etiology of covid- -associated coagulopathy is unclear, diverse and multifactorial, and may include direct attack by the sars-cov- on vascular endothelial cells, cytokine storm-mediated inflammation-coagulation cascades, hypoxia, and complication with sepsis. coagulation dysfunction or thrombocytopenia is closely associated with the severity and poor prognosis in covid- patients [ ] . clinicians should increase awareness of covid- -associated coagulopathy, which in covid- patients is accompanied with the following abnormal coagulation indexes: platelet-lymphocyte ratio < × , the reduction of prothrombin time (pt) and activated partial thromboplastin time (aptt) by more than the lower limit of th percentile or the increase of pt by more than s or aptt by more than s, or the increase of fibrinogen, fibrin degradation product (fdp) and d-dimer by more than the lower limit of th percentile without clinical evidence of primary blood system diseases or chronic liver diseases. routinely assessing the coagulation dysfunction on admission and dynamically monitored thereafter should probably be performed to identify covid- -associated coagulopathy as early as possible (grade +, weak recommendation). rationale according to the available literature, the condition of covid- patients is commonly complicated with coagulopathy, where the symptoms range from mild disorders of coagulation indicators to dic. the increase of d-dimer in covid- patients is very common, accounting for % to . % of all cases [ , , , , ] . the degree of elevation and persistent elevation are indicators of poor prognosis. the nanshan zhong team has reported that among covid- patients in hospitals from provinces ( mild cases and severe cases), the proportion of severely ill patients with d- dimer higher than . mg/l was up to . %, and the proportion for the mild patients was . % [ ] . zhou et al. have demonstrated that among confirmed covid- patients ( deaths, survival), d-dimer > . g/l was an independent risk factor for clinicians to identify patients with poor prognosis at the early stage [ ] . the coagulation parameters (pt and aptt) in covid- patients vary with different severity and the different courses of the disease. covid- patients in the early stage show the activation of the exogenous coagulation system, manifested as decreased pt and hypercoagulable state. along with the progression of the disease, especially when patients develop dic, pt and aptt significantly increase, which is associated with the poor prognosis of patients. tang has reported increased fibrinogen ( . g/l vs. . g/l, p = . ) and fdp values ( . µg/ml vs. µg/ml, p < . ) in covid- patients [ ] , which indicated that instead of hyperfibrinolysis observed in the late stage of dic, fibrinolysis inhibition is the main feature accompanying the progression of covid- . the autopsies of covid- patients have revealed abundant transparent thrombus in the pulmonary alveoli, myocardium, portal area, and renal tubular epithelial cells, thus indicating that fibrinolysis inhibition may have a decisive role in covid- -associated coagulation dysfunction. the incidence of dic is low in covid- patients. it has been reported that among the covid- patients, only patient ( . %) was diagnosed as dic [ ] . however, tang's report has shown that the overall incidence of dic is . %. the existence of dic was more common in fatal cases, where . % met the isth diagnostic criteria for dic; the median time for dic diagnosis after admission was days, whereas among the patients who survived, only patient ( . %) met this criterion [ ] . medical institutes should dynamically detect the pt, international normalized ratio (inr), aptt, d-dimer, fibrinogen, and fdp to identify covid- -associated coagulation disorders, which might be helpful for making timely treatment decisions. it is also suggested to use the isth score system to diagnose covid- -associated dic [ ] ; if possible, sf and pai- should be used to detect the pre-dic status in the shortest possible time. routinely evaluating the risk of venous thromboembolism (vte) and hemorrhage should probably be performed in covid- patients. for critically ill covid- patients with low hemorrhage risk, subcutaneous injection of low molecular weight heparin (lmwh) should probably be used for preventing vte (grade +, weak recommendation). rationale the most common clinical features of coagulopathy in covid- patients are thrombosis in the deep vein or intermuscular vein of the lower extremity, which can be identified by the coagulation parameters and ultrasonic monitoring. it has been reported that the incidence of vte or thrombotic complications in patients with severe covid- admitted in the icu was - % [ , ] . it is necessary to pay attention to the clinical observation of patients with bed rest lasting for more than days and observe whether these patients are experiencing asymmetric pain, swelling or discomfort in unilateral lower limbs or bilateral lower limbs, or local swelling or superficial vein filling in the lateral limbs. especially when patients show chest pain, hemoptysis, dyspnea, or hypoxemia, which cannot be explained by ncp or other basal diseases, we should be alert to the occurrence of pulmonary thromboembolism. for critically ill covid- patients with low hemorrhage risk, a subcutaneous injection of lmwh should probably be used for the prevention of vte. for patients with severe renal dysfunction (creatinine clearance rate < ml/min), unfractionated heparin is recommended. for critically ill patients whose condition is complicated with high hemorrhage risk, intermittent pneumatic compression is recommended for mechanical prevention. mild or moderate covid- patients should probably avoid sedentary lifestyle or dehydration and are encouraged to engage in active activities and to drink more water appropriately. for mild or moderate covid- patients with a high or moderately high risk of vte according to the padua or caprini evaluation model, it should probably be considered to use lmwh for to days until the elimination of risk factors. anticoagulation therapy should probably be used for patients with hypercoagulant state without bleeding risk. lmwh or unfractionated heparin should probably be considered to be the first choice (grade +, weak recommendation). rationale hypercoagulant state is common in covid- patients. meantime, cytokine storm-mediated inflammation-coagulation cascades may have an essential role in covid- -associated coagulopathy. studies have found that in addition to the anticoagulant effect, heparin also has a certain anti-inflammatory effect [ ] . therefore, lmwh or unfractionated heparin is the first choice for anticoagulation: tang et al. have reported that lmwh or unfractionated heparin anticoagulation was associated with improved survival in the patients with a sepsis-induced coagulopathy (sic) score ≥ and in those with d-dimer levels more than times of the upper limit of normal(≥ mg/l) [ ] . it is suggested that lmwh u/kg or unfractionated heparin units subcutaneously twice daily could be given to patients without contraindication once d-dimer ≥ mg/l or sic ≥ . heparin-induced thrombocytopenia (hit) should be prevented during heparin treatment, and platelet counting should be monitored daily. for patients with hit, other anticoagulants, such as agatraban, bevaludine, fondaparinux, and rivaroxaban, could be used. for patients at high risk of bleeding, anticoagulants are not recommend, and chinese traditional medicine could be used to improve blood circulation and dispersing stasis. although diffuse alveolar damage and ards are the main features of covid- , the involvement of the kidney and other organs needs to be considered. aki was associated with a higher risk of in-hospital mortality. clinicians should increase awareness of aki in hospitalized covid- patients. kidney disease: improving global outcomes (kdigo) criteria should probably be used for the diagnosis of aki in covid- patients. measuring serum creatinine every days should probably be performed to avoid a missed diagnosis of aki (grade +, weak recommendation). rationale the incidence of aki in covid- patients varies with different severity of illness: mild cases have an aki incidence of . - %, severe cases have an aki incidence of - . %, and the aki incidence for those critical cases that require to be admitted in icu is up to . - % [ , , , , ] . according to kdigo aki diagnostic criteria, certifying aki is mainly based on changes in scr, and the frequency of scr tests has a substantial impact on the detection rate of aki. in a nationwide cross-sectional survey of hospitalized adult patients in china, the detection rate of aki was only . % by kdigo criteria [ ] . after adjusting for the frequency of scr, the incidence of aki in chinese hospitalized adults rose to . % [ ] . thus, in order to improve early recognition of aki, scr measurements should be performed more frequently throughout the course of the disease. it is necessary to measure scr every days throughout the course of the disease to avoid a missed diagnosis of aki. the experts suggest using standard aki care bundle ( r principle) for covid- -associated aki (expert opinion). rationale the exact pathogenesis of covid- associated aki is unclear. the etiology of kidney impairment in covid- patients, which is likely to be diverse and multifactorial, may include direct attack by the sars-cov- on target cells in the kidney, immune systemmediated damage, disease-related prerenal factors, a complication with sepsis and nephrotoxic drug-related factors [ , ] . covid- associated aki is an independent risk factor for poor prognosis in patients. clinicians should address standard aki following r principle (risk screen, recognition in the early phase, response in time, renal replacement therapy, and rehabilitation of the kidney). aki is significantly more likely to develop in severe covid- patients than in nonsevere patients [ , , , , ] . meanwhile, studies have shown that patients with elevated baseline scr are more likely to develop aki and develop more severe aki [ ] . therefore, we should routinely screen the risk of aki in covid - patients, particularly for severe cases, patients with elevated baseline scr or those having proteinuria and hematuria at admission. optimizing the volume status and oxygenation, maintaining hemodynamic stability, making sure the mean blood pressure above mmhg are the important measures for prevention and treatment of aki. the experts suggest using crrt for the critical cases accompanied by kidgo aki - stages, or cytokine storm syndrome (expert opinion). rationale according to the available literature [ , , , , ] , the percentage of covid- patients who require continuous renal replacement therapy (crrt) is . - %, and particularly the percentage of critical patients admitted in icu that requires crrt is . - . %. indications of the crrt in covid- patients include renal indications and non-renal indications. renal indications include severe aki (kidgo aki - stages) with hemodynamic instability. non-renal indications include complications with severe ards and persistent inflammatory fever, which cannot be controlled not even with glucocorticoid corticosteroid therapy, hypernatremia refractory to conservative medical treatment, volume overload or urine output, which cannot meet the needs of drug infusion and energy supply and diuretic resistance. multiple rct research has indicated that the application of crrt in critical patients in an early phase cannot effectively decrease the mortality rates [ , ] . however, considering the suggestion that restrictive fluid volume management strategy should be adopted for covid- patients complicated by ards based on the premise of sufficient tissue perfusion, we suggest crrt initiation in severe patients within h when they show rank aki under kdigo criteria or accompanied with cytokine storm syndrome. in clinical practice, the doctors in charge should comprehensively evaluate conditions including the covid- patient's level of systemic inflammation, severity and progress of illness, severity, and progress of aki, local medical resources, and the qualification of blood purification operators to give a reasonable choice of crrt application. statement crrt prescription is suggested to be target-oriented based on the patient's condition (expert opinion). rational crrt prescription should be prescribed before the application of crrt on patients, and the prescription must be target-oriented. continuous venovenous hemofiltration (cvvh) global surveillance for human infection with coronavirus disease (covid- ) world health organization. coronavirus disease (covid- ) situation reports clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study national health commission & state administration of traditional chinese medicine. diagnosis and treatment protocol for novel coronavirus pneumonia practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients world health organization, five moments for hand hygiene world health organization, infection prevention and control during health care when covid- is suspected covid- ) outbreak: rights, roles and responsibilities of health workers, including key considerations for occupational safety and health handbook of covid- prevention and treatment surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ). intensive care med world health organization, rational use of personal protective equipment (ppe) for coronavirus disease (covid- ) control measures for severe acute respiratory syndrome (sars) in taiwan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review guideline of prevention and control of novel coronavirus infection within medical facilities chinese society of anesthesiology task force on airway management: expert recommendations for tracheal intubation in critically ill patients with novel coronavirus disease videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a cochrane systematic review interim infection prevention and control recommendations for patients with suspected or confirmed coronavirus disease (covid- ) in healthcare settings recommendations for bronchoscopy procedures in severe covid- patients clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in covid- patients with at least a six-day follow up: a pilot observational study effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus (sars-cov- ) infection: a randomized clinical trial a trial of lopinavirritonavir in adults hospitalized with severe covid- arbidol monotherapy is superior to lopinavir/ritonavir in treating covid- compassionate use of remdesivir for patients with severe covid- remdesivir in adults with severe covid- : a randomised, double-blind, placebocontrolled, multicentre trial compassionate use of remdesivir for patients with severe covid- announces approval of veklury ® (remdesivir) in japan for patients with severe covid- the convalescent sera option for containing covid- meta-analysis: convalescent blood products for spanish influenza pneumonia: a future h n treatment? use of convalescent plasma therapy in sars patients in hong kong convalescent plasma treatment reduced mortality in patients with severe pandemic influenza a (h n ) virus infection challenges of convalescent plasma infusion therapy in middle east respiratory coronavirus infection: a single centre experience treatment of critically ill patients with covid- with convalescent plasma effectiveness of convalescent plasma therapy in severe covid- patients convalescent plasma: new evidence for an old therapeutic tool? treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure noninvasive ventilation of patients with ards: insights from the lung safe study role of noninvasive ventilation in acute lung injury/acute respiratory distress syndrome: a proportion meta-analysis timing of intubation and clinical outcomes in adults with acute respiratory distress syndrome failure of noninvasive ventilation for de novo acute hypoxemic respiratory failure: role of tidal volume an index combining respiratory rate and oxygenation to predict outcome of nasal high-flow therapy a high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome driving pressure and survival in the acute respiratory distress syndrome recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation lung recruitability in sars-cov- associated acute respiratory distress syndrome: a singlecenter, observational study potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome open lung approach for the acute respiratory distress syndrome: a pilot. randomized controlled trial prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis clinical studies of tracheal gas insufflation prone position ameliorates lung elastance and increases functional residual capacity independently from lung recruitment prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: yes protecting the right ventricle in ards: the role of prone ventilation prone positioning in severe acute respiratory distress syndrome coronavirus disease (covid- ) situation reports clinical characteristics of coronavirus disease in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china summary of a report of cases from the chinese center for disease control and prevention patients with covid- in icus in wuhan, china: a cross-sectional study clinical features of patients infected with novel coronavirus in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study elso guidance document: use of ecmo in covid- patients during the pandemic an official american thoracic society/european society of intensive care medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome intubation and ventilation amid the covid- outbreak acute myocarditis associated with novel middle east respiratory syndrome coronavirus association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china left ventricular performance in patients with severe acute respiratory syndrome: a -day echocardiographic follow-up study sars-coronavirus modulation of myocardial ace expression and inflammation in patients with sars renin-angiotensin-aldosterone system blockers and the risk of covid- mortality and severity evaluation by routine pneumonia prediction models among japanese patients with pandemic influenza a (h n ) pneumonia clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review and meta-analysis passive leg raising for predicting fluid responsiveness: a systematic review and meta-analysis does pulse pressure variation predict fluid responsiveness in critically ill patients? a systematic review and meta-analysis diagnostic accuracy of the inferior vena cava collapsibility to predict fluid responsiveness in spontaneously breathing patients with sepsis and acute circulatory failure relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: a meta-analysis extravascular lung water is an independent prognostic factor in patients with acute respiratory distress syndrome sepsis in european intensive care units: results of the soap study pathological findings of covid- associated with acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury colloids versus crystalloids for fluid resuscitation in critically ill people analysis of factors associated with disease outcomes in hospitalized patients with novel coronavirus disease risk factors associated with disease progression in a cohort of patients infected with the novel coronavirus mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: impact of β-lactam plus macrolide combination therapy posttraumatic stress, anxiety, and depression in survivors of severe acute respiratory syndrome (sars) stress and psychological distress among sars survivors year after the outbreak emotional reactivity and regulation following citalopram therapy in children and adolescents with anxiety disorders effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the stop-pd ii randomized clinical trial sleep in the intensive care unit sleep in intensive care unit: the role of environment effects of intensive care unit noise on patients: a study on coronary artery bypass graft surgery patients monitoring sound and light continuously in an intensive care unit patient room: a pilot study the efficacy of earplugs as a sleep hygiene strategy for reducing delirium in the icu: a systematic review and meta-analysis effect of dexmedetomidine added to standard care on ventilatorfree time in patients with agitated delirium: a randomized clinical trial melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial preventive effects of ramelteon on delirium: a randomized placebo-controlled trial melatonin, ramelteon, suvorexant, and dexmedetomidine to promote sleep and prevent delirium in critically ill patients: a narrative review with practical applications interpreting and implementing the pain, agitation/sedation, delirium, immobility, and sleep disruption clinical practice guideline sedation with sufentanil in patients receiving pressure support ventilation has no effects on respiration: a pilot study could remifentanil reduce duration of mechanical ventilation in comparison with other opioids for mechanically ventilated patients? a systematic review and meta-analysis the effect of music on discomfort experienced by intensive care unit patients during turning: a randomized cross-over study comparison of ice packs application and relaxation therapy in pain reduction during chest tube removal following cardiac surgery early deep sedation is associated with decreased in-hospital and two-year follow-up survival early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study sedation and delirium in the intensive care unit: an australian and new zealand perspective sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit a randomized trial of protocoldirected sedation management for mechanical ventilation in an australian intensive care unit mortality of covid- is associated with cellular immune function compared to immune function in chinese han population paralytics, sedation, and steroids in acute respiratory distress syndrome treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome corticosteroid treatment in critically ill patients with severe influenza pneumonia: a propensity score matching study corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection: analytic strategy using propensity scores risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china immune modulation with thymosin alpha treatment the efficacy of thymosin alpha for severe sepsis (etass): a multicenter, single-blind, randomized and controlled trial effective treatment of severe covid- patients with tocilizumab phase / adaptive-designed trial in hospitalized covid- patients invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study management of adults with hospital-acquired and ventilatorassociated pneumonia: clinical practice guidelines by the infectious diseases society of america and the clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: update by the infectious diseases society of america thrombocytopenia and its association with mortality in patients with covid- clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia guidance for diagnosis and treatment of dic from harmonization of the recommendations from three guidelines prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- the role of heparin in sepsis: much more than just an anticoagulant anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy kidney impairment is associated with in-hospital death of covid- patients clinical characteristics of novel coronavirus infection in china acute kidney injury in china: a cross-sectional survey epidemiology and clinical correlates of aki in chinese hospitalized adults diagnosis and treatment of covid- : acute kidney injury cannot be ignored initiation strategies for renal-replacement therapy in the intensive care unit timing of renal-replacement therapy in patients with acute kidney injury and sepsis expert recommendation for novel coronavirus pneumonia patients with blood purification treatment chinese society for parenteral and enteral nutrition. recommendations for parenteral and enteral nutrition therapy in critically ill covid- patients espen guideline on clinical nutrition in the intensive care unit calorie intake of enteral nutrition and clinical outcomes in acutely critically ill patients: a meta-analysis of randomized controlled trial gudielines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition clinical nutrition in critical care medicine-guideline of the german society for nutrition medicine(dgem) recommendations for nutrition therapy in critically ill covid- patients safe patient transport for covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. all the authors have participated in literature retrieval, viewpoint discussion, and writing the manuscript. all authors read and approved the final manuscript. none. not applicable. not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -ypeibwje authors: veronese, nicola; demurtas, jacopo; yang, lin; tonelli, roberto; barbagallo, mario; lopalco, pierluigi; lagolio, erik; celotto, stefano; pizzol, damiano; zou, liye; tully, mark a.; ilie, petre cristian; trott, mike; lópez-sánchez, guillermo f.; smith, lee title: use of corticosteroids in coronavirus disease pneumonia: a systematic review of the literature date: - - journal: front med (lausanne) doi: . /fmed. . sha: doc_id: cord_uid: ypeibwje the aim was to investigate the effectiveness of glucocorticoid therapy in patients with covid- . a systematic search of the literature across nine databases was conducted from inception until th march , following the prisma guidelines. patients with a validated diagnosis of covid- and using corticosteroids were included, considering all health outcomes. four studies with chinese participants were included. two studies reported negative findings regarding the use of corticosteroids in patients with covid- , i.e., corticosteroids had a detrimental impact on clinical outcomes. one study reported no significant association between the use of corticosteroids and clinical outcomes. however, one study, on participants with different stages of pneumonia due to covid- , found that in more severe forms, the administration of methylprednisolone significantly reduced the risk of death by %. the literature to date does not fully support the routine use of corticosteroids in covid- , but some findings suggest that methylprednisolone could lower mortality rate in more severe forms of the condition. coronaviruses are ribonucleic acid viruses. importantly, in humans the viruses may infect the respiratory, gastrointestinal, hepatic, and central nervous systems ( ) . infection with four of the most common coronaviruses strains (hcov- e, hcov-oc , hcov-nl , and hcov-hku ) usually lead to mild, self-limiting upper respiratory tract infections ( ) . however, other coronaviruses, are associated with severe acute respiratory syndrome (sars-cov) and the middle east respiratory syndrome (mers-cov). in march , the world health organization (who) declared the covid- outbreak a global pandemic. covid- is caused by sars-cov- , a variant of coronavirus. as of april , over , , confirmed cases have been diagnosed in more than countries and areas, resulting in about , fatalities thus far ( ) . symptoms of infection are usually nonspecific, and include fever, cough, and myalgia, with diarrhea, with or without the subsequent development of dyspnea ( ) . severe cases that include respiratory distress, sepsis, and septic shock have been increasingly reported ( ) . during the sars-cov epidemic of , therapeutic systemic corticosteroids were administered in patients who were infected and developed severe respiratory disease. in a meta-analysis of corticosteroid use in patients with sars, only four studies provided conclusive data, all indicating higher mortality ( ). one recent systematic review and meta-analysis identified ten observational studies investigating the administration of corticosteroids in , patients affected by influenza ( ). the review identified increased mortality in patients who were given corticosteroids. moreover, the length of stay in an intensive care unit was increased, as was the rate of secondary bacterial or fungal infection. corticosteroids have also been investigated for respiratory syncytial virus (rsv) in clinical trials in children with no conclusive evidence of benefit, and are therefore not recommended ( ) . two recent commentaries published in the lancet between february and march reported that corticosteroids should not be used for the treatment of covid- ( , ) . however, these assumptions are mainly based on the findings of the metaanalyses cited above, on disease caused by similar viruses, but not research on covid- specifically. therefore, the clinical, therapeutic, and side effects of systemic glucocorticoid therapy in covid- patients are currently unclear. given this background, the present review investigates the effectiveness of glucocorticoid therapy in patients with covid- by applying a systematic review of the literature currently available. the main objective is to investigate whether there is a clinical necessity, or therapeutic justification, for the use of systemic corticosteroids in patients with covid- . this systematic review followed the moose and prisma guidelines ( , ) . two investigators (nv and jd) independently conducted a literature search using embase, pubmed, web of science, cnki, medline, cinahl, toxline, and scopus. specific research in chinese database wan-fang of published and unpublished literature was conducted by one author (ly) and checked by another researcher (lz). the database search was run from database inception until th march . all studies reporting information regarding the use of corticosteroids in covid- were included. in pubmed, the following search strategy was used: "(covid- or novel coronavirus-infected pneumonia or novel coronavirus or -ncov or sars-cov- ) and (cortic * or "glucocorticoids" or "steroids" or "corticosteroids" or "hydrocortisone" or "prednisone" or "methylprednisolone" or "dexamethasone" or "prednisolone"). the strategy was then adapted for the other databases. conference abstracts and reference lists of included articles were hand-searched to identify any potential additional relevant articles. any inconsistencies were resolved by consensus with a third author (ls). following the pico framework ( ), we included: participants who had a validated diagnosis of covid- , irrespective of stage, or severity; intervention: use of corticosteroids (no a priori definition of dosage or route was made); comparison: patients affected by covid- not taking corticosteroids; outcomes: all health outcomes were included, due to the anticipated scarcity of data. a priori, both intervention and observational data were considered. two independent investigators (nv and jd) extracted key data from the included articles in a standardized excel database and a third independent investigator (ls) validated the data extraction. for each article, we extracted data regarding authors, year of publication, country, city or region in which the study was conducted, the period of observation, how the diagnosis of covid- was obtained, the stage of covid- infection (asymptomatic forms, pneumonia, acute respiratory distress syndrome (ards), requiring intensive care unit, icu; convalescent), sample size included, number of males and females, mean age and its standard deviation (or similar information such as median and range), the percentage of people treated with corticosteroids in the sample as a whole, and, if possible, the route of administration and type of corticosteroid considered. the dosage of corticosteroids used in these studies was mainly unavailable. data are reported descriptively according to the best evidence synthesis. when possible, numerical data are reported. as shown in figure , among initially included studies ( in english and in chinese), eight were reviewed as full-text and four finally included ( ) ( ) ( ) ( ) . two studies were excluded since they were commentaries ( , ), one excluded as it was a protocol ( ) , and one a letter to editor ( ) . table shows the descriptive characteristics of the four included studies. altogether, chinese participants, mainly males (= . %) of a mean age of years (range: - ), were included. all the studies were conducted between the end of and february . the diagnosis of covid- was made in all the studies using reverse transcriptase-polymerase chain reaction on throat swab samples. three among the four studies included pneumonia at any stage, from mild to more complicated forms, and one convalescent patient. ( , ) reported negative findings regarding the use of corticosteroids in patients with covid- . wang et al. ( ) showed the group treated with corticosteroids experience a doubled risk of being admitted to an icu, while in ling et al. ( ) , the duration of viral rna for oropharyngeal swabs and feces was almost doubled in corticosteroids group than controls. liu et al. did not report any benefit of the use of intravenous methylprednisolone ( - mg/day) on clinical outcomes (i.e., short-term disease progression) in participants ( ) . finally, wu et al. carried out their study among participants with different stages of pneumonia due to covid- , and found that, in more severe forms (i.e., in subjects having ards due to , the administration of standard doses of methylprednisolone significantly reduced the risk of death by % ( ) . in this systematic review including chinese patients, we have for the first time summarized the ultimate available literature regarding the use of corticosteroids in the treatment of a recent viral condition that is spreading on a global scale. overall, two studies reported negative findings regarding these medications, one reported no significant association between corticosteroids and clinical outcomes, and one concluded that methylprednisolone was associated with a significant reduction of mortality in patients with covid- pneumonia developing ards. since covid- was first reported in december , it has attracted global attention owing to its similarity to sars-cov and mers-cov in causing fatal respiratory disease, and its potential for causing large-scale human infection and economic disruption. when considering patients with sars and mers, the use of corticosteroids therapy is still debated ( , ) . corticosteroids therapy was used in the treatment of severe sars because early anecdotal experience supported it, and radiological findings, and histologic features of critically ill patients with sars were similar to those of patients with ards ( , ) . in march , china summarized its experience in the management of sars, and suggested that high-dose glucocorticoids should be used if patients had a fever persisting the duration of viral rna detection for oropharyngeal swabs and feces in the corticosteroid treatment group was longer than that in the non-corticosteroid treatment group, which were vs. . days (p = . ) and vs. days (p < . ). icu, intensive care unit; ards, acute respiratory distress syndrome; covid, coronavirus disease . for more than days, or if radiologic findings were suggestive of persistent lung involvement or progressive deterioration ( ) . one systematic review of studies on patients with sars-cov, including studies documenting glucocorticoid use, found studies that were inconclusive regarding the role of the adjunctive use of glucocorticoids to standard therapy, and four studies demonstrated that the use of systemic glucocorticoids in sars patients may cause possible harm ( ) . moreover, a prospective, randomized double-blinded, placebo-controlled trial compared early hydrocortisone treatment (before day seven of the illness) with a placebo and found that early hydrocortisone therapy was associated with a higher subsequent plasma viral load ( ) . glucocorticoid therapy was also used for critically ill patients with mers. in one study, hypoxemic patients with mers-cov pneumonia who were not showing signs of improvement were given glucocorticoid therapy ( ) . however, the study reported that there was no difference in -days mortality, and these patients were associated with delayed mers-cov rna clearance. this finding is somewhat confirmed in our systematic review on covid- , since one study reported that the duration of viral rna for oropharyngeal swabs and feces was almost doubled in corticosteroids group compared to controls ( ) . among those infected with covid- some develop mild symptoms, however, a significant proportion progress to severe ards and thus require intensive care ( ) . the use of corticosteroids in patients presenting with ards of different etiologies remains controversial owing to mixed results in the existing literature, mainly derived from observational studies ( ) . globally, high-dose glucocorticoids is among the most frequently used adjuncts in ards ( . %) ( ) . systemic corticosteroids have long been used among critically ill patients presenting with ards given their role in lowering the circulating levels of proinflammatory mediators ( , ) . moreover, adequate and prolonged glucocorticoid supplementation have proved to mitigate the critical illness related corticosteroid insufficiency (circi), thus enhancing resolution of lung and systemic inflammation ( ) . one systematic review conducted an analysis of individual patient data from randomized trials, and found that, compared with the placebo group, prolonged glucocorticoid treatment improved clinical outcomes ( ) . a recent individual patient data meta-analysis combined four rcts evaluating prolonged methylprednisolone therapy for ards and reported a significant reduction in mortality, with an increase in ventilator-free days ( vs. , p < . ) ( ) . recent evidence suggests that a subset of patients with severe covid- may have cytokine storm syndrome ( ) , which is a condition frequently related to lung involvement (including ards) ( ) and multi-organ failure. in order to induce immunosuppression to antagonize virally driven hyperinflammation, treatments with tocilizumab (il- receptor blockade) are ongoing in patients in which a hypercytokinemia laboratory pattern is identified. in these patients, a therapeutic role can also be hypothesized for corticosteroids ( ) . animal experiments may also provide evidence for the use of glucocorticoids during the acute phase of severe disease to (i) reduce inflammation, (ii) attenuate acute lung injury, and (iii) improve survival ( ) . however, other studies have failed to provide convincing evidence to prove the efficacy of corticosteroids in decreasing the mortality of ards, thus suggesting that glucocorticoid therapy is not necessary in this condition, and may even aggravate the clinical course of the disease. challenging analytic issues within these studies (including immortal time bias and indication bias from timevarying confounding) make these results inconclusive and larger specifically designed clinical trials are needed to clarify the favorable and unfavorable effects for corticosteroid therapy in ards patients. the present review has summarized the current evidence of corticosteroids on clinical outcomes in covid- to inform clinicians and policymakers on the current state of the literature. importantly, one study identified in this review in patients with ards owing to covid- infection showed that methylprednisolone significantly decreased the risk of mortality. it should be noted that there is currently one ongoing clinical trial that is directly addressing this research question and its results are eagerly awaited ( ) . the present review should be interpreted in light of its limitations. first, only four studies from china were included and heterogeneous data were reported. more research on this topic is needed before concrete recommendations can be made. second, the type and dosage of corticosteroids varied between studies and, except in the case of wu et al. ( ) , corticosteroids were considered as only one class despite having different actions and properties. third, the data are based only on retrospective findings and cohort studies are now urgently needed. finally, existing data comes only from china and, consequently, it is not known if the genetic background of chinese people may modify the results found in the present work and in which direction. in conclusion, the literature available so far does not fully encourage the routine use of corticosteroids in covid- , but some findings suggest that methylprednisolone could lower mortality rate in more severe forms of this condition, such as in ards. findings from future clinical trials that are ongoing are needed to better understand the role of corticosteroids in covid- . all datasets presented in this study are included in the article/supplementary material. emerging coronaviruses: genome structure, replication, and pathogenesis coronaviruses-drug discovery and therapeutic options world health organization a familial cluster of pneumonia associated with the novel coronavirus indicating personto-person transmission: a study of a family cluster a novel coronavirus outbreak of global health concern sars: systematic review of treatment effects the effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis use of corticosteroids in treating infectious diseases clinical evidence does not support corticosteroid treatment for -ncov lung injury on the use of corticosteroids for -ncov pneumonia preferred reporting items for a systematic review and meta-analysis of individual participant data: the prisma-ipd statement meta-analysis of observational studies in epidemiology: a proposal for reporting the pico strategy for the research question construction and evidence search persistence and clearance of viral rna in novel coronavirus disease rehabilitation patients clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial potential benefits of precise corticosteroids therapy for severe -ncov pneumonia corticosteroid therapy for critically ill patients with middle east respiratory syndrome corticosteroid treatment of severe acute respiratory syndrome in hong kong development of a standard treatment protocol for severe acute respiratory syndrome. the lancet a major outbreak of severe acute respiratory syndrome in hong kong our strategies for fighting severe acute respiratory syndrome (sars) effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients clinical features of patients infected with novel coronavirus in wuhan, china. the lancet acute respiratory distress syndrome epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids effect of corticosteroid on lung parenchyma remodeling at an early phase of acute lung injury critical illness-related corticosteroid insufficiency (circi): a narrative review from a multispecialty task force of the society of critical care medicine (sccm) and the european society of intensive care medicine (esicm) prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ards pulmonary involvement in patients with hemophagocytic lymphohistiocytosis clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. key: cord- -ifeulv authors: longobardo, alessia; montanari, cecilia; shulman, robert; benhalim, suzanne; singer, mervyn; arulkumaran, nishkantha title: inhaled nitric oxide produces minimal improvement in oxygenation in covid- related ards date: - - journal: br j anaesth doi: . /j.bja. . . sha: doc_id: cord_uid: ifeulv nan related to covid- ( (- to ) % vs. ( to ) %; p< . ) (figure ; supplementary table ). venous thromboembolism (vte) was diagnosed in ( %) covid- patients. seven patients underwent computed tomography (ct) pulmonary angiography of which patients had evidence of pulmonary emboli. a further patients underwent lower limb doppler ultrasonography, of whom patients had a diagnosis of deep vein thrombosis. only eight ( %) patients with covid- related ards had an increment in pao : fio ratio > % compared to patients ( %) with ards not related to ards (p= . ). baseline pao : fio ratio, dose of ino, use of steroid, prone position ventilation, c-reactive protein, d-dimer levels, n-terminal b-type natriuretic peptide (nt-bnp) levels, fluid balance, driving pressure, days from icu admission to ino, pulmonary compliance, diagnosis of vte, or body mass index did not discriminate between covid- patients who responded to ino or not (supplementary figure ) . the potential benefit of ino in reducing pulmonary shunt in covid- related ards has been postulated. however, we found that the increase in pao :fio ratio in covid- ards patients in response to ino was significantly lower compared to ards patients without ards, consistent with another published series. pulmonary vascular endothelial dysfunction and microthrombi are hallmarks of covid- induced lung damage, and this may impair ino-induced pulmonary vasodilation. , in contrast, patients with coronavirus-related sars, where increased thrombosis was not a hallmark, demonstrated significant pao :fio ratio improvements in response to ino. early in the covid- disease process, hypoxaemia develops despite good pulmonary compliance, and a pulmonary vasculopathy is implicated . later on, compliance decreases to that seen with 'classical' ards. , our covid- patients who received ino did so as a rescue treatment late in the disease, days following icu admission. while no differences were seen in d-dimer values between responders and non-responders, levels were significantly elevated in most patients. the benefits of ino in covid- related ards may extend beyond its effects on pulmonary vasculature . however, the theoretical benefits of ino in inhibiting early stage viral replication is unlikely to have benefitted patients where ino was administered ( - ) days following icu admission. as with all retrospective analyses, we acknowledge the possibility of residual confounding, and that results are associative. the small number of covid- related ards patients included also warrants caution in interpreting the findings. ct imaging was not performed on all patients either due to clinical instability or lack of a clear indication, thus the presence of major emboli may have been missed in some patients. alternatively, lack of identification by ct does not exclude the presence of multiple pulmonary microthrombi contributing to raised pulmonary vascular resistance and right heart dysfunction. echocardiography was not performed systematically to assess impact on cardiac anatomy and function, but nt-bnp levels were significantly elevated and raised pulmonary pressures were commonplace findings when measured. nt-bnp and d-dimer values were not routinely collected in ards patients prior to the covid- pandemic so comparisons cannot be made. in summary, more than half of patients with refractory hypoxaemia secondary to covid- ards did not show an increase in pao :fio ratio in response to ino. this response was much lower compared to a cohort with ards not related to covid- . further work is required to ascertain if this lack of response to ino is diagnostic for degree of pulmonary thromboembolism. study design (na), data collection (al, cm, rs, sb), statistics (na), drafting manuscript (na), finalising manuscript (ms, na). inhaled nitric oxide for acute respiratory distress syndrome (ards) in children and adults patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction treatment of covid- by inhaled no to reduce shunt? inhaled nitric oxide in patients admitted to intensive care unit with covid- pneumonia pulmonary angiopathy in severe covid- : physiologic, imaging and hematologic observations inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in beijing covid- does not lead to a "typical" acute respiratory distress syndrome covid- pneumonia: different respiratory treatments for different phenotypes? nitric oxide dosed in short bursts at high concentrations may protect against covid the authors declare not conflicts of interest.j o u r n a l p r e -p r o o f key: cord- - vcts w authors: chan, kc allen; tang, nelson ls; hui, david sc; chung, grace ty; wu, alan kl; chim, stephen sc; chiu, rossa wk; lee, nelson; choi, kw; sung, ym; chan, paul ks; tong, yk; lai, st; yu, wc; tsang, owen; lo, ym dennis title: absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study date: - - journal: bmc infect dis doi: . / - - - sha: doc_id: cord_uid: vcts w background: it has been postulated that genetic predisposition may influence the susceptibility to sars-coronavirus infection and disease outcomes. a recent study has suggested that the deletion allele (d allele) of the angiotensin converting enzyme (ace) gene is associated with hypoxemia in sars patients. moreover, the ace d allele has been shown to be more prevalent in patients suffering from adult respiratory distress syndrome (ards) in a previous study. thus, we have investigated the association between ace insertion/deletion (i/d) polymorphism and the progression to ards or requirement of intensive care in sars patients. method: one hundred and forty genetically unrelated chinese sars patients and healthy volunteers were recruited. the ace i/d genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. results: there is no significant difference in the genotypic distributions and the allelic frequencies of the ace i/d polymorphism between the sars patients and the healthy control subjects. moreover, there is also no evidence that ace i/d polymorphism is associated with the progression to ards or the requirement of intensive care in the sars patients. in multivariate logistic analysis, age is the only factor associated with the development of ards while age and male sex are independent factors associated with the requirement of intensive care. conclusion: the ace i/d polymorphism is not directly related to increased susceptibility to sars-coronavirus infection and is not associated with poor outcomes after sars-coronavirus infection. the outbreak of the severe acute respiratory syndrome (sars) has made a great impact to the health care systems around the world. the pandemic affected over individuals and resulted in deaths worldwide [ ] . several clinical parameters, including male sex [ , ] , age of over years [ , ] , elevated lactate dehydrogenase activity [ ] [ ] [ ] , low platelet count [ ] and high viral load on presentation [ ] , have been identified to be predictive of the severity of the disease in affected individuals. moreover, it has been postulated that genetic variations of the host and the virus may account for the individual difference in the susceptibility to the infection and the severity of the disease. with regard to viral factors, it has been shown that there is no significant difference in the genetic sequences of viruses causing the two major outbreaks in hong kong, namely the prince of wales hospital and amoy gardens outbreaks, despite the significant difference in the mortality rates and diarrheal rates of the two cohorts [ ] . furthermore, several association studies have been conducted to investigate the possible contribution of host genetic factors in the determination of the susceptibility and prognosis of sars-coronavirus infection. thus, certain human leukocyte antigen subtypes have been shown to be more prevalent in sars patients [ ] and in those who had poorer outcomes [ ] . on the other hand, the polymorphism in the angiotensin converting enzyme ii gene, coding for a functional receptor of the sars-coronavirus, is not associated with the susceptibility or outcome of sars [ ] . recently, it has also been reported that the deletion of the bp alu repeat (d allele) in intron of the ace gene is associated with hypoxemia in sars patients [ ] . however, there are several limitations to this previous study. first, only sars patients were studied. second, hypoxemia was arbitrarily defined as requiring oxygen supplementation. moreover, patients who died were excluded from the study. these factors may be potential confounders to a genetic association study. therefore, in this study, we investigated the association of the ace insertion/deletion (i/d) polymorphism of the bp alu repeat to the susceptibility to sars and the development of adult respiratory distress syndrome (ards) with a larger population. this study was reviewed and approved by the ethical committee of the prince of wales hospital, hong kong. patients who were admitted to the hospitals of the new territories east cluster of hong kong for the treatment of sars were recruited retrospectively. the recruitment of patients depended on the availability of blood samples. all patients, including survivors and deceased patients, with available blood samples were recruited. for geneti-cally related sars patients, only the index case (the first individual who developed symptoms) was recruited. all patients were of chinese ethnicity and fulfilled the world health organisation case definition of probable sars [ ] . three hundred and twenty-six healthy individuals undergoing routine health check were recruited as controls. the control subjects were recruited before the sars epidemic and none of them had respiratory symptoms. all control subjects were ethnical chinese and were not genetically related. the association between genotype and disease outcome was studied in the sars patients. two categories of patients were considered as having a severe disease: ( ) patients who developed ards; and ( ) patients who required admission to the intensive care unit (icu). a patient was classified as having ards if he or she fulfilled all criteria of the joint american/european consensus for ards [ ] , including: ( ) acute onset of respiratory distress; ( ) presence of bilateral infiltrates on chest x-ray; ( ) having a ratio of arterial partial pressure of oxygen to inspired fractional oxygen concentration (pao /fio ) of less than . kpa and absence of clinical evidence of left heart failure. dna was extracted from whole blood using a qiaamp dna blood mini kit (qiagen) with the 'blood and body fluid spin protocol' as recommended by the manufacturer. ace i/d genotypes were determined by polymerase chain reaction amplification. the forward and reverse primers were '-ctggagaccactcccatcctttct- ' and '-gatgtggccatcacattcgtcagat- ', respectively. reactions were set up in a volume of µl containing . µm of each primer, x buffer ii (applied biosystems), mm mgcl , . mm of each dntp, . u taq polymerase (amplitaq gold dna polymerase, applied biosystems) and ng dna. after initial denaturation at °c for min, the reaction mixtures were subjected to cycles of °c for min, °c for min and °c for min, and a final extension at °c for min. this method yielded amplification products of bp for the i allele and bp for the d allele. the products were electrophoresed and visualized in % agarose gels with ethidium bromide. statistical analyses were performed using sigmastat, ver. . ; spss. disease associations were compared by chisquare tests. univariate and multivariate logistic regression analyses were performed to identify predictors of ards or the outcome of sars. one hundred and forty sars patients ( males, females) and healthy individuals ( males, females) were recruited. the mean ages of the sars patients and control subjects were . and . years, respectively (p = . ). seventeen of the sars patients developed ards during the course of their illness. the demographic data of the sars patients who had or had not developed ards are summarized in table . patients who developed ards were significantly older than those who did not develop ards (p < . ). there was no significant difference in gender, smoking habits, hepatitis b status and the presence of comorbidity between the two groups. thirty-five patients required intensive care and sixteen died. patients who required intensive care were significantly older than those with milder disease. the genotypic distributions and allelic frequencies of ace i/d polymorphism in the sars patients and control subjects are shown in table . the genotypic distributions of the sars patients and the healthy control subjects follow the hardy-weinberg equilibrium using chi-square analysis. there was no significant difference in the genotypic distributions (χ value = . , df = , p = . ) and allelic frequencies (χ value = . , df = , p = . ) of the two groups. among the sars patients, we further analyzed the genotypic distributions and allelic frequencies of ace i/d polymorphism in patients who developed ards and in those who did not develop ards in the course of their illness. the results are shown in table a. there was no significant difference in the genotypic distributions (χ value = . , df = , p = . ) and allelic frequencies (χ value = . , df = , p = . ) between the two groups. besides, there was also no significant difference in the genotypic distributions (χ value = . , df = , p = . ) and allelic frequencies (χ value = . , df = , p = . ) between patients who did or did not require intensive care. the results are shown in table b. in the univariate analysis, we did not detect any significant difference in the number of d alleles in the ace polymorphism between patients who did and did not develop ards (p = . , or = . ( % ci: . - . ). following multivariate logistic regression analysis, age was found to be the only significant factor that determined the development of ards in sars patients (table a). in the multivariate analysis for the requirement of intensive care, we have shown that age and male sex are associated with the requirement of intensive care (table b) . the possible contribution of host genetic factors to the susceptibility and outcome of sars-coronavirus infection has been investigated through several association studies [ ] [ ] [ ] [ ] . in contrast to a recent report showing an association between the presence of the d allele of the ace gene and hypoxemia in sars patients [ ] , we have shown that the i/d polymorphism of the ace gene is associated with neither increased susceptibility to sars-coronavirus infection nor progression to ards once infected. in multivariate logistic regression analysis, we have identified that age is the only significant factor associated with the development of ards while age and male sex are independently associated with the requirement of intensive care in sars there are several possible explanations for the discrepancies in our conclusion and that by itoyama et al [ ] concerning the association between ace polymorphism and the outcome of sars. first, the inclusion of subjects within the same family and exclusion of deceased patients by the previous study might cause potential bias, especially when the frequency of the dd genotype was reported to be as low as % in control subjects [ ] . in this study, we have only included the index patient if more than one member in a family developed sars. second, we have used a well defined endpoint of ards instead of the requirement of supplemental oxygen. sars infection commonly leads to respiratory distress and over % of patients were given supplemental oxygen during the course of their illness in our cohort. therefore, it seems to be more appropriate to use ards instead of the requirement of oxygen supplement to define the severity of sars. as ards is the more severe end of the spectrum of disease progression, any potential association between genotype and disease progression would become even more obvious when the most severe cases were considered. similarly, the disease outcome was not associated with ace i/ d genotype when we also used another broader definition for severe disease after sars infection (requiring intensive care or death). previous studies on caucasian populations have suggested that the presence of the d allele of the ace gene is associated with increased incidence of ards [ ] . this effect has been postulated to be related to the higher enzyme activity in individuals with dd genotype [ ] . however, it is unclear whether these observations can also be seen in chinese as the frequencies of dd genotype and d allele of the ace gene are much lower in chinese than in caucasian subjects [ , ] . furthermore, the sarscoronavirus characteristically affects the pneumocytes, and the formation of multinucleated pneumocytes and intrabronchial fibrogranulation (bronchiolitis obliterans organizing pneumonia-like lesions) are commonly observed in the lung biopsies of sars patients in addition to the typical pathological changes of ards [ ] . therefore, it is possible that the pathogenesis and genetic factors predisposing to sars-related ards may be different from ards resulted from other respiratory illnesses. previous reports have highlighted the inconsistency of the results of genetic association studies for complex diseases [ , ] . this inconsistency may be attributable to the difference in the genetic composition of the studied population and study design. here, we showed that both susceptibility and disease outcome of sars infection were not associated with ace i/d polymorphism among chinese patients in contrast to the recent report studying vietnamese patients [ ] . the sample size was definitively larger in our study. two different better-defined criteria were used as indicators of severe disease progression, yet no association was found between disease severity and ace i/d genotype. the d allele which was the hypothetical high risk allele [ ] , did not show any sign of over-representation in the subgroups of patients with severe disease. our analysis indicates that ace i/d polymorphism is not directly related to poor outcomes after sars-coronavirus infection in chinese. cumulative number of reported probable cases of sars severe acute respiratory syndrome: clinical outcome and prognostic correlates hong kong epidemic: an analysis of all patients serum ld isoenzyme and blood lymphocyte subsets as prognostic indicators for severe acute respiratory syndrome quantitative analysis and prognostic implication of sars coronavirus rna in the plasma and serum of patients with severe acute respiratory syndrome genomic characterisation of the severe acute respiratory syndrome coronavirus of amoy gardens outbreak in hong kong association of human-leukocyte-antigen class i (b* ) and class ii (drb * ) genotypes with susceptibility and resistance to the development of severe acute respiratory syndrome association of hla class i with severe acute respiratory syndrome coronavirus infection ace gene polymorphisms do not affect outcome of severe acute respiratory syndrome ace polymorphism and progression of sars who: case definitions for surveillance of severe acute respiratory syndrome (sars) the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome relationship between angiotensin-converting enzyme id polymorphism and vo( max) of chinese males alhenc-gelas f: angiotensin iconverting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in t-lymphocytes angiotensin i-converting enzyme (ace) gene polymorphism and breast cancer risk among chinese women in singapore pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (sars) problems of reporting genetic associations with complex outcomes candidate gene case-control association studies: advantages and potential pitfalls the work is supported by the research fund for the control of infectious disease (rfcid) from the health, welfare and food bureau of the hong kong sar government. we thank coral lee, wb lui and katherine chow for technical support. the pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/ - / / /prepub key: cord- -nyvwv m authors: méry, geoffroy; epaulard, olivier; borel, anne-laure; toussaint, bertrand; le gouellec, audrey title: covid- : underlying adipokine storm and angiotensin - umbrella date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: nyvwv m severe acute respiratory syndrome coronavirus (sars-cov- ) is the third coronavirus leading to a global health outbreak. despite the high mortality rates from sars-cov- and middle-east respiratory syndrome (mers)-cov infections, which both sparked the interest of the scientific community, the underlying physiopathology of the sars-cov- infection, remains partially unclear. sars-cov- shares similar features with sars-cov- , notably the use of the angiotensin conversion enzyme (ace ) as a receptor to enter the host cells. however, some features of the sars-cov- pandemic are unique. in this work, we focus on the association between obesity, metabolic syndrome, and type diabetes on the one hand, and the severity of covid- infection on the other, as it seems greater in these patients. we discuss how adipocyte dysfunction leads to a specific immune environment that predisposes obese patients to respiratory failure during covid- . we also hypothesize that an ace -cleaved protein, angiotensin - , has a beneficial action on immune deregulation and that its low expression during the sars-cov- infection could explain the severity of infection. this introduces angiotensin - as a potential candidate of interest in therapeutic research on cov infections. coronavirus (cov) is a single-stranded rna virus involved in human and animal diseases. the rare event of its transmission from avian and mammalian reservoirs (mostly bats) to the human host has led to widespread epidemics in recent years ( ) . indeed, over the last two decades, three cov outbreaks have forced human populations to change their perspectives regarding the control of emerging diseases and the importance of public health in general. the first outbreak caused by severe acute respiratory syndrome coronavirus (sars-cov- ) occurred between november and july , originating from china and then spreading worldwide ( ) . although the symptoms of sars-cov- infection were in most cases non-specific, including lethargy, myalgia, and headache, the high mortality rate of % in case series was mostly related to respiratory failure due to acute respiratory distress syndrome (ards) ( , ) . the physiopathology underlying the severity of sars-cov- infection remained unclear after the epidemic due to insufficient sampling. a second cov epidemic occurred in with middle east respiratory syndrome (mers)-cov, which has mostly led to small-size outbreaks in the years ever since ( ) . although it did not reach a pandemic status, mers-cov continues to infect humans, and the world health organization identified more than patients who have died of related complications since its discovery ( ) . indeed, mers-cov has a higher mortality rate in case series (case fatality rate of ∼ %), mostly from respiratory failure, which has led to the identification of unique strategies of cov infections to escape the immune response. due to the ending of the sars-cov- epidemic and the somewhat limited number of cases of mers-cov in the recent years, understanding the mechanisms of cov infections in humans has proven to be complex, and the conclusions drawn from in vitro experiments and animal models remain difficult to extrapolate. in november , cases of a pneumonia with atypical features were reported in wuhan, china; in january , sars-cov- was identified as the cause of this new cov-induced disease , which became a worldwide pandemic in the following months ( ) . although the mortality rates of this new covid- are still being debated, ranging between . and . %, it is still lower than those associated with sars-cov- and mers-cov infections. patients suffering from severe sars-cov- infection could be healthy or only have mild comorbidities such as hypertension or diabetes ( ) . most of all, severe cases due to respiratory failure occur - days after the first symptoms ( ) . studies on covid- have progressively stressed its similarities with previous cov infections, mostly sars-cov- , with the same unanswered questions regarding its physiopathology. one notable feature of this disease, already observed in previous cov infections, is the high prevalence of obese patients among the most severe cases. here we seek to explore what underlies the link between immune response and respiratory failure in cov infections on the one hand, and the current observation of obesity as a risk factor for severe outcome in covid- on the other. most of the time, the need for intensive care during covid- is secondary to the onset of ards ( ), as defined by the berlin criteria (bilateral shadowing on lung radiology, rapid deterioration of symptoms, and objective hypoxemia on blood samples). in the first published series, % of these ards cases were accompanied by septic shock or other organ dysfunction ( , ) . the nature of covid- -induced ards is still under discussion. interleukin (il) dosages are usually very high, and hypoxemia is severe in covid- -induced ards, which matches the hyperinflammatory profile described by calfee et al. ( ) . sars-cov- -induced ards was associated with vascular leakage and neutrophilic alveolitis ( ) , both of which are compatible with a hyper-inflammatory profile. in covid- , some experts observed ventilatory abnormalities suggestive of microcirculatory involvement such as hypoxic pulmonary vasoconstriction or distal thrombosis ( , ) . this points to the contribution of several factors in respiratory failure, with experts also citing the possible involvement of genuine viral pneumonia as well as capillary thrombosis by neutrophil extracellular traps (nets) ( ) . the reason for this respiratory outcome is most likely a complex interplay of multiple factors, which derive directly from cov virulence. the membrane protein angiotensin-converting enzyme (ace ) is used as an entry receptor by sars-cov- and sars-cov- ( , ) . it has been reported that sars-cov- has a greater affinity for ace than sars-cov- due to the specific amino-acid composition in the receptor-binding domain of the spike protein ( ) . ace is expressed at varying levels by most cells in the body but primarily in the small intestine, testis, kidney, heart, thyroid, and adipose tissue cells ( ) . the expression of ace in adipocytes seems to be promoted by high fat diets ( ) . in the lungs, it is expressed by % of epithelial cells, increasing with cell differentiation, and it is mainly located on the apical (or luminal) pole, serving as an accessible anchor point to airborne contaminants ( ) . ace is a key enzyme of the renin-angiotensin system, converting angiotensin (ang ) into ang - . ang binds to a receptor, the angiotensin type receptor (at r), a transmembrane g protein-coupled receptor, which is found in a large variety of cells, ranging from smooth muscle cells, endometrium, and myocardium to blood cells, renal interstitial, and glomeruli. the activation of at r has several effects: for example, vasoconstriction, vascular permeability, macrophage maturation, and pro-inflammatory cytokine release. during the resolution phase of the inflammation, ang promotes tumor growth factor beta production and fibroblast proliferation, leading to fibrosis and inadequate healing of the wounded tissue ( ) . an antagonistic pathway of the ang -derived effects results from the binding of ang - to the mitochondrial assembly (mas) receptor. mas receptor is a ubiquitous g-protein-coupled receptor, implicated, among others, in retina development ( ) , muscle wasting ( ) , and benign prostate hyperplasia ( ) . activation of the mas receptor by ang - induces vasodilatation by a nitric-oxide-dependent mechanism ( , ) and reduces oxidative stress induced by ang in vascular injuries ( ) . in macrophages, it promotes an anti-inflammatory profile ( ), for example, by lowering pro-inflammatory cytokine production, notably il- and tumor necrosis factor alpha (tnfα). ang - has also shown beneficial effects in inflammation resolution and fibrosis, notably in kidney and myocardial disease ( , ) . the binding of ace by sars-cov- prevents it from exerting its enzymatic activities, resulting in decreased anti-inflammatory ang - production and the accumulation of pro-inflammatory ang ( , ) . this results in high cytokine titers, neutrophil infiltration, and endothelial dysfunction in the lungs, potentially predisposing for ards. as early as , ace tampering was suggested to be an important mechanism in sars-cov- infection ( , ) . it was only later discovered that cov possesses very specific mechanisms to escape the host's immunity ( ) . these mechanisms, in addition to the pro-inflammatory response secondary to ace binding, might act as a trigger for a sustained and uncontrolled inflammatory response, leading to ards. in general, an efficient antiviral response is driven by t-helper lymphocytes (lth) with a specific polarization such as lth and lth . lth refers to a polarization in which lth primarily promotes cytotoxic lymphocytes (ctl) and natural killers (nk) for the control and destruction of infected cells as well as the release of specific cytokines, such as type interferon (inf- ) by innate immune cells. inf- is produced by infected cells and innate immune cells after recognizing the viral pathogen-associated molecular patterns (pamps), such as single-strained or uncapped rna, using cytoplasmic pattern-recognition receptors (prr). in particular, toll-like receptor (tlr ) induces toll/interleukin- receptor domain-containing adapter-inducing interferon-β (trif). hosts deficient in either tlr or trif are more susceptible to viral injuries and thus more at risk of developing ards during cov infections ( ) . inf- activates the janus kinase-signal transducers and activators of transcription (jak-stat) pathway, resulting in the modulation of hundreds of interferon-sensitive genes and notably in the synthesis of specific cytokines, preferably oriented toward viral control and clearance ( ) . most of these steps, involved in inf- signaling, are blocked by cov infections. this evolution trait is probably due to the presence of a constitutive inf- production in bats (principal reservoir of cov). cov infections are expert evaders of this antiviral response ( ) . their escape plan revolves around three main mechanisms: -first, hiding viral rna from cytoplasmic prr. after entering the cell, sars-cov- shields its rna by forming, inside the host's endoplasmic reticulum, a large network of doublemembrane vesicles isolated from the cytosol ( , ) . the modified capping of the viral rna ′ -o-methylation also prevents the binding to an important cytosolic prr ( ) . -next, direct tampering of the prr-related enzymes. for example, the papain-like protein in cov can modify the ubiquitinylation profile of tlr ( ) or other antiviralrelated prr ( ) . moreover, s protein triggers il- rassociated kinase and peroxisome proliferator-associated receptor gamma, subsequently downregulating interferon regulatory factor activity ( ) . in addition, the jamming of tlr phosphorylation reduces the prr activity, while blocking most of the inf- production pathways. -lastly, the non-structural protein in both mers and sars-cov- can selectively degrade host rna via endonucleolytic activity against which the viral rna is protected ( , ) . the many mechanisms used by cov probably leave the infected cells in a defensive cul-de-sac where they are incapable of developing an efficient antiviral response. on the one hand, viral pamps do not result in inf- production. on the other hand, non-viral pamps such as debris from cell lysis still stimulate the immune response. this could lead to inappropriate cytokine environments that lack inf- and are thus less effective against viruses, as seen in covid- ( ) . indeed, during covid- infection, most patients exhibit a specific cytokine profile, associating innate immunity chemokines (such as monocyte chemoattractant protein and interferon gamma-induced protein (ip- ), which are suggestive of macrophage activation and epithelial suffering), and pro-inflammatory macrophage-produced cytokines such as il- ( ). moreover, cov infections can directly induce the activation of nuclear factor kappa b (nfkb), notably by tampering with the tnf receptor-associated factor pathway (traf ) via its open reading frame a. activation by ubiquitination of traf also promotes the de novo development of the nod-like receptor pyrin domain containing protein (nlrp ) inflammasome and the production of il- β and il- ( ) . this cytokine production promotes macrophage activation and inf- , although it does not salvage a deficient polarization of the adaptive immunity toward lth and its subsequent efficient antiviral response. high plasma levels of il- and the absence of inf- have been noted in severe patients ( ) , illustrating a sustained innate response that fails to achieve viral clearance and triggers ards. however, this sustained inflammation without lth polarization might not be the only profile to bypass the antiviral cul-de-sac. some patients infected by mers-cov demonstrated a polarization of the immune profile toward a lth -mediated response. faure et al. compared two cases of mers with different outcomes ( ) ; the patient with a fatal outcome had an early increase in il- and il- titers (hallmarks of lth polarization), whereas the surviving patient had a spike in inf- but no indication of lth polarization. lth are effective actors in the clearance of extracellular microorganisms such as fungi and bacteria, but poorly effective against viral pathogens ( ) . in general, viral pamps do not usually polarize the immune response to lth . the association of severe outcome and inappropriate cytokine environment in cov infection suggests a link with immune polarization, as a result of the "cul-de-sac" of antiviral response induced by the cov escaping strategies. the resulting inefficient immune profile leads to a sustained viral exposure and persistent inflammatory state. in addition to the pro-inflammatory signals mediated by ace inhibition, this sustained and inappropriate immune activation might be strongly involved in the development of ards. obesity is a common condition, affecting up to % of adults in western countries. it is defined by a body mass index (bmi) > kg/m , irrespective of the location of the adipose tissue. however, all profiles of obesity are not equivalent in terms of their consequences. indeed, abdominal (or visceral) obesity (estimated by the waist circumference or waist-to-hip ratio), in which visceral fat predominates, is more associated with metabolic disorders such as type diabetes or hypertension, compared to "metabolically healthy" obesity, in which subcutaneous fat predominates. early observations in the sars-cov- epidemics suggested obesity to be a risk factor to covd- , or at least to severe forms of the disease ( ) . in our retrospective cohort, we observed more than % of patients with overweight or obesity (n = ) (figure ) . in a retrospective cohort, simonnet et al. showed an increasing risk of intensive care unit (icu) admission in covid- patients as bmi increased, independently of other metabolic disorders ( ) , which was subsequently confirmed by other teams ( , ) . thus, obesity appears to be a risk factor for presenting a severe form of covid- . it should be mentioned that once in icu, obesity is known to confer a survival advantage, termed the "obesity paradox" ( ) . patients with a bmi > kg/m seem to survive mechanical ventilation and severe septic states significantly better than patients with a normal or low bmi ( , ) , presumably due to their elevated muscle mass, which represents a metabolic reserve in the hypermetabolic state of icu patients ( , ) . it is not yet known whether once admitted to icu, obese covid- patients also present a better prognosis than patients of normal body weight. the scientific observations of the last two decades have placed obesity in a complex pathological framework centered around the deregulation of adipocyte, which is far from the naive idea of a simple diet-induced condition ( ). white adipose tissue (wat) is now recognized as an independent endocrine organ, whose main role is to regulate and store the energy provided by food. however, the hormones released by wat, specific to the adipocyte and known as adipokines, reach a large variety of organs and modulate an extensive range of functions, from appetite control to inflammatory response ( ) . leptin is the leading adipokine, whose anorexigen properties regulate satiety and food intake. leptin levels in blood are proportionate to the amount of wat and increase with bmi. interestingly, the leptin receptor (lepr) on immune cells mostly activates jak-stat and nfkb dependent pathways, except in neutrophils, macrophages, and antigen presenting cells, which all express a particular form of lepr. leptin promotes migration in the wat of resident macrophages and induces their polarization toward a pro-inflammatory profile or a classical activated macrophage (m ) profile, and unbalances the lth profiles, by reducing regulatory t-cells and promoting lth polarization ( ) . adiponectin is another adipokine, whose levels increase in proportion to subcutaneous fat but decrease with visceral fat accumulation. it favors whole-body insulin sensitivity, fatty-acid oxidation and diminishes the hepatic neo-glucogenesis pathways ( ) . adiponectin promotes primarily lth polarization, hence antiviral inflammation. other adipokines, such as lipocalin- , down-regulate inflammatory lth altogether by promoting regulatory lymphocytes. adipokines form a large family regularly counting new members over the last few years, all of which reveal complex and multiple implications in the regulation of energy storage and release, adipose tissue regulation and rather ubiquitous cellular metabolism ( ) . unlike subcutaneous fat, visceral fat accumulation, also described as "abdominal obesity, " is characterized by a dysfunctional profile of adipokines associated with a rise in pro-inflammatory signals. the triggers of this dysfunction is believed to be a metabolic stress in the presence of nutrient excess and a hypoxic stress caused by hypertrophic visceral adipocytes, due to an increase in cells' size and low neovascularization, via a mobilization of hypoxia inducible factor ( ) . unlike visceral fat, subcutaneous fat expansion is hyperplasic and is not correlated with low-grade inflammation ( ) . in severe abdominal obesity, the adipokine profile is unbalanced in favor of leptin production and low-grade inflammation at the expense of adiponectin, or lipocalin- . this deregulation of the adipokine profile links various disorders associated with metabolic diseases, such as insulin-resistance, to inflammatory manifestations, as described in rheumatoid arthritis ( ) . ang - takes an active role in regulating the effects of adipokines. its involvement was reviewed by lelis et al., with an exhaustive approach and emphasis on other adipokines that will not be described here, such as sirtuin and resistin ( ) . a strong interest in ang - has already arisen from these observations, particularly in the field of atherosclerosis and non-alcoholic fatty liver disease, in which ang - seems beneficial. in a concise article, mori et al. hypothesized that the disruption of the reninangiontensin system by the virus could impair the energetic functions of these pathways during sars-cov infections ( ) . we suggest that the tampering with such pathways could also lead to abnormalities in the inflammatory response observed in severe cov infections through their influence on immune regulation and cytokine production. adipocyte dysfunction in visceral fat is correlated to lowgrade persistent inflammation, known as meta-inflammation, which is suspected to be the starting point or an early factor in metabolic disorders associated with severe obesity ( ) . this meta-inflammation is mostly driven by the leptinactivated m macrophages in wat. wat-resident macrophages exhibit pro-inflammatory behavior, producing il- β, il- , and tnfα. the precursor of il- β is cleaved into bioactive il- β by the nlrp inflammasome, as a result of the nfkb pathway activation, which is induced by both pro-inflammatory and hypoxic signals originating from the adipocytes ( ). adiponectin can inhibit nfkb activation, but as mentioned above, depending on the obesity severity and profile, the effects of adiponectin can easily be overwhelmed by those of leptin ( ) . leptin also polarizes hematopoiesis directly in the bone marrow, promoting granulocyte, and erythroblast lines (the latter probably acts as a protective mechanism against hypoxia) at the expense of lymphocytes ( ) . when neutrophils are mature and circulating, leptin also promotes their survival on a dosedependent scale ( ) . higher levels of neutrophils have thus been observed in obese patients, possibly making the neutrophil recruitment during an inflammatory process more potent than in patients with a normal bmi ( ) . besides suffering from a pro-inflammatory environment, which favors macrophage activation and neutrophil production, obese patients exhibit abnormal responses to viral infection. as summarized by honce et al., during influenza infections, obese patients tend to have greater neutrophil activation and net development, contributing to capillary damage and thrombosis. such phenomena have been extensively found in covid- patients ( ) . their inflammatory response is also characterized by a lack of inf- production as well as a strong cytokine production, notably il- , ip- , and type inf, which are elevated in severe covid- . interestingly, patients with visceral fat accumulation also tend to have a lower tlr expression in adipocytes, muscle cells, and adipose tissue-resident macrophages, as well as a concomitant lower production of cytokines following exposure to viral pamps ( ) ( ) ( ) . this suggests that their baseline profile resembles that found in severe cov infections, in which the antiviral response is less efficient, but the overall inflammation is higher than in other viral infections. finally, both obesity and metabolic disorders are associated with vascular dysfunction. at the acute phase of lung infection, this could result in microcirculatory abnormalities, as suggested by intensive care physicians, and increased lung edema. patients with visceral fat accumulation, type diabetes ( ), and hypertension are not the only subjects at a higher risk of severe sars-cov- infection. when considering metabolic disorders separately, diabetes, non-alcoholic liver disease, and obstructive sleep disorders have been recently reported as risk factors for a severe outcome ( ) ( ) ( ) . this suggests that the metabolic dysfunction associated with these disorders more than obesity alone might be involved in the severity of the disease in these patients. when comparing the effects of ang - and the inflammatory environment of patients with adipocyte dysregulation and metabolic disorders, an interesting pattern emerges. all the immunological features arising from the adipocyte dysfunction-(i.e., m macrophage polarization with il- and tnfα production), and neutrophil promotion-may contribute to the development of ards and thus be countered by the activation of the ang - /mas receptor axis. ang - also favors figure | impact of severe acute respiratory syndrome coronavirus (sars-cov- ) on pathways promoting acute respiratory distress syndrome (ards). by inactivating the angiotensin conversion enzyme (ace ), sars-cov- leads to an accumulation of angiotensin and a lower dosage of angiotensin - , respectively resulting in the higher promotion and lower inhibition of pro-inflammatory signals. a strong capillary barrier and a beneficial oxidative profile, which are altered in patients with visceral fat activation and could help to prevent ards. this leads us to two hypotheses: either patients with metabolic disorders, primarily visceral fat accumulation, have a constitutional lower titer of ang - , as suggested by some observations ( ) , and a resulting higher inflammation; or the ang - levels in these patients are preserved and restrain the baseline inflammation. in the first case, the inappropriate inflammatory response, added to the diminished activation of tlr in obese patients, leads to unrestrained inflammation. however, if ang - is present in these patients and limits the meta-inflammation, acting as a guardrail, the antagonization of ace by sars-cov- and in addition to the lack of de novo ang - production could exacerbate the meta-inflammation and contribute to the severe septic states of obese patients with covid- , as illustrated in figure . in both cases, the supplementation of ang - in these patients might improve fitness upon sars-cov infection. ace deficiency has already been explored by some research teams to better understand the potential metabolic benefits of conversion enzyme inhibitors used in hypertension, among others. their studies highlighted the association between ace deficiency and higher titers of pro-inflammatory cytokines in obese mice, as well as in mice with glucose intolerance ( ) , which is closely correlated with metainflammation ( ) . other studies correlate ace deficiency with epicardial inflammation ( ) . this suggests that the ang - /mas axis allows a better control of inflammation in obese patients. tlr is a receptor to lps and leads to nfkb activation and (among others) hepatic inflammation. when administered orally to rats fed with a high-fat diet, ang - lowered hepatic inflammation, notably through a modulation of a metabolic pathway involving tlr ( ) . moreover, promoting the effects of the ang - /mas receptor axis using medication also improves the aforementioned cytokines and oxidative stress in obese mice, with a protective effect against diabetic cardiomyopathy ( ) . ang - is already in the spotlight of scientific research given its beneficial effects in preventing the development of metabolic disorders and obesity ( ) . we believe that our literature review highlights the beneficial effects of ang - on metainflammation in preexisting obesity and its potential involvement in inflammatory response and viral clearance, notably against sars-cov- . modulation of the renin-angiotensin system has been mentioned by others to explain the severity of covid- . a recent study found a lower mortality and intubation risk during covid- among elderly patients treated with nifedipine or amlodipine ( ) , although the study sample was small and most of the accessible data do not suggest a strong connection ( , ) . however, these drugs interfere with at r and not with the genuine production of ang - . in obese patients with covid- , this hypothesis should be considered. oral or parenteral ang - supplementation could be a therapeutic option to diminish the low-grade systemic inflammation due to adipocyte dysfunction and attenuate the severity of ace -mediated injuries consecutive to sars infection. parenteral ang - has already been used in human research on account of its property to enhance acetylcholine-mediated vasodilatation in endothelia, with safe outcomes ( ) . covid- is a viral disease with remarkable characteristics given its high severity in obese patients and its ability to tamper ace metabolism. we believe that more than being just an incentive to accelerate research on viral infection, covid- also presents an opportunity to respond to questions that were previously considered to be too intricate or complex, such as non-septic inflammation or the immune system communication underlying metabolic disorders. understanding the multiple and interrelated factors linking sars-cov- infection, angiotensin metabolism, global inflammation, and metabolic disorders such as type diabetes and obesity should provide us with a better insight into the way in which these conditions and physiological states interact outside of an acute aggression. the raw data supporting the conclusions of this article will be made available by the authors within respect of general data protection regulation, without undue reservation. the studies involving human participants were reviewed and approved by comité ethique du centre investigation clinique (cecic). subjects were all informed and did not oppose, written consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. gm and al conceptualized the idea, provided discussion, feedback, and organize the plan of the article. gm, a-lb, oe, and al wrote the paper. gm, a-lb, oe, bt, and al reviewed the different version of paper. all authors contributed to the article and approved the submitted version. this work was supported by the foundation of grenoble alpes university, grenoble, france. severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection severe acute respiratory syndrome) coronavirus as a possible cause of severe acute respiratory syndrome sars: clinical features and diagnosis mers coronavirus: diagnostics, epidemiology and transmission available online at a novel coronavirus from patients with pneumonia in china clinical features of patients infected with novel coronavirus in wuhan intensive care management of coronavirus disease (covid- ): challenges and recommendations epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-cov-infected mice covid- pneumonia: ards or not? clinical phenotypes of sars-cov- : implications for clinicians and researchers targeting potential drivers of covid- : neutrophil extracellular traps a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor characterization of the receptor-binding domain (rbd) of novel coronavirus: implication for development of rbd protein as a viral attachment inhibitor and vaccine expression of the sars-cov- cell receptor gene ace in a wide variety of human tissues ace is expressed in mouse adipocytes and regulated by a high-fat diet ace , angiotensin-( - ) and mas receptor axis in inflammation and fibrosis the expression of masreceptor of the renin-angiotensin system in the human eye expression of the mas receptor is upregulated in skeletal muscle wasting embarking effect of ace -angiotensin - /mas receptor axis in benign prostate hyperplasia clinical characteristics of allergic bronchopulmonary aspergillosis mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation mas receptor mediates cardioprotection of angiotensin-( - ) against angiotensin ii-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress role of the receptor mas in macrophage-mediated inflammation in vivo angiotensin-( - ), adipokines and inflammation sars: future research and vaccine pathogenesis of severe acute respiratory syndrome chemokine up-regulation in sars-coronavirus-infected, monocyte-derived human dendritic cells toll-like receptor signaling via trif contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection regulation of type i interferon responses chapter seven -interaction of sars and mers coronaviruses with the antiviral interferon response sars-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro sars-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking ′ -o-methyltransferase activity sars coronavirus papain-like protease inhibits the tlr signaling pathway through removing lys -linked polyubiquitination of traf and traf the severe acute respiratory syndrome coronavirus nucleocapsid inhibits type i interferon production by interfering with trim -mediated rig-i ubiquitination middle east respiratory syndrome corona virus spike glycoprotein suppresses macrophage responses via dpp -mediated induction of irak-m and pparγ sars coronavirus nsp protein induces template-dependent endonucleolytic cleavage of mrnas: viral mrnas are resistant to nsp -induced rna cleavage middle east respiratory syndrome coronavirus nsp inhibits host gene expression by selectively targeting mrnas transcribed in the nucleus while sparing mrnas of cytoplasmic origin severe acute respiratory syndrome coronavirus orf antagonizes stat function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane plasma ip- and mcp- levels are highly associated with disease severity and predict the progression of covid- a tug-of-war between severe acute respiratory syndrome coronavirus and host antiviral defence: lessons from other pathogenic viruses the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease distinct immune response in two mers-cov-infected patients: can we go from bench to bedside? interleukin- a (il- a), a key molecule of innate and adaptive immunity, and its potential involvement in covid- -related thrombotic and vascular mechanisms early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia high prevalence of obesity in severe acute respiratory syndrome coronavirus- (sars-cov- ) requiring invasive mechanical ventilation prevalence of obesity among adult inpatients with covid- in france obesity and its implications for covid- mortality initiation of nutritional support is delayed in critically ill obese patients: a multicenter cohort study obesity survival paradox in pneumonia: a meta-analysis obesity paradox" in acute respiratory distress syndrome: asystematic review and meta-analysis high-fat feeding protects mice from ventilator-induced lung injury, via neutrophil-independent mechanisms leptin in the interplay of inflammation, metabolism and immune system disorders adiponectin regulation and function adipokines: linking metabolic syndrome, the immune system, and arthritic diseases oxygen deprivation and the cellular response to hypoxia in adipocytes-perspectives on white and brown adipose tissues in obesity an update on immune dysregulation in obesity-related insulin resistance adipokines and inflammation: is it a question of weight? sars-cov- perturbs the renin-angiotensin system and energy metabolism recombinant adiponectin inhibits inflammation processes via nf-kb pathway in acute pancreatitis a role for leptin in sustaining lymphopoiesis and myelopoiesis apoptotic pathways are inhibited by leptin receptor activation in neutrophils neutrophil infiltration and systemic vascular inflammation in obese women impact of obesity on influenza a virus pathogenesis, immune response, and evolution defects in tlr expression and rnase l activation lead to decreased mnsod expression and insulin resistance in muscle cells of obese people decreased tlr in hyperplastic adipose tissue, blood and inflamed adipocytes is related to metabolic inflammation decreased interferon-α and interferon-β production in obesity and expression of suppressor of cytokine signaling diabetes is a risk factor for the progression and prognosis of covid- metabolic associated fatty liver disease increases covid- disease severity in non-diabetic patients coronavirus disease and obstructive sleep apnea syndrome cross talk between angiotensin-( - )/mas axis and sirtuins in adipose tissue and metabolism of high-fat feed mice deficiency of ace in bone-marrow-derived cells increases expression of tnf-α in adipose stromal cells and augments glucose intolerance in obese c bl/ mice tlr links innate immunity and fatty acid-induced insulin resistance ace deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity oral angiotensin-( - ) prevented obesity and hepatic inflammation by inhibition of resistin/tlr /mapk/nf-κb in rats fed with high-fat diet azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ace- /ang - /mas receptor cascade angiotensin - : a peptide for preventing and treating metabolic syndrome nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for covid- interactions of coronaviruses with ace , angiotensin ii, and ras inhibitors-lessons from available evidence and insights into covid- renin-angiotensin-aldosterone system inhibitors in patients with covid- favorable vascular actions of angiotensin-( - ) in human obesity acknowledgments authors thank mrs. victoria grace, from english publications, for the careful editing of the publication. we kindly thank p. audoin, c. clape, a. metz, and i el amrani for their support regarding the reglementary procedures. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © méry, epaulard, borel, toussaint and le gouellec. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -jck zq authors: cheung, oi-yee; graziano, paolo; smith, maxwell l. title: acute lung injury date: - - journal: practical pulmonary pathology: a diagnostic approach doi: . /b - - - - . - sha: doc_id: cord_uid: jck zq a wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. the clinical syndrome of acute onset respiratory distress, dyspnea, and bilateral infiltrates is referred to as acute respiratory distress syndrome. the histologic counterpart of acute respiratory distress syndrome is diffuse alveolar damage, classically characterized by hyaline membranes. other histologic features of acute lung injury include intraalveolar fibrin, organization, interstitial edema, and reactive pneumocytes. diffuse alveolar damage and other histologic features of acute lung injury are nonspecific as to etiology, and once identified require the pathologist to search the biopsy for further features that may help identify a specific etiology. this chapter reviews the temporal sequence of acute lung injury and explores the large variety of specific etiologic causes with emphasis on helpful histologic features to identify. resultant endothelial and alveolar epithelial cell injury is attended by fluid and cellular exudation. subsequent reparative fibroblastic proliferation is accompanied by type ii pneumocyte hyperplasia. , the microscopic appearance depends on the time interval between insult and biopsy and on the severity and extent of the injury. dad is the usual pathologic manifestation of ards and is the best-characterized prototype of acute lung injury. from studies of ards, the pathologic changes appear to proceed consistently through discrete but overlapping phases ( fig. . )-an early exudative (acute) phase ( fig. . a and b) , a subacute proliferative (organizing) phase ( fig. . c) , and a late fibrotic phase ( fig. . ). , , , , the exudative phase is most prominent in the first week of injury. the earliest changes include interstitial and intraalveolar edema with variable amounts of hemorrhage and fibrin deposition ( fig. . ). hyaline membranes (fig. . ), the histologic hallmark of the exudative phase of ards, are most prominent at to days after injury (eslide . ). minimal interstitial mononuclear inflammatory infiltrates ( fig. . ) and fibrin thrombi in small pulmonary arteries (fig. . ) also are seen. type ii pneumocyte hyperplasia ( fig. . ) begins by the end of this phase and persists through the proliferative phase. the reactive type ii pneumocytes may demonstrate marked nuclear atypia, with numerous mitotic figures (fig. . ). the proliferative phase begins at week after the injury and is characterized by fibroblastic proliferation, seen mainly within the interstitium but also focally in the alveolar spaces ( fig. . ). the fibrosis consists of loose aggregates of fibroblasts admixed with scattered inflammatory cells, reminiscent of organizing pneumonia acute interstitial pneumonia (hamman- in experimental ards, the exact time of injury is known, and the entire lung proceeds through the phases at the same time. in a patient who develops diffuse alveolar damage from any cause, the acute lung injury may begin in different areas at different times, so a biopsy specimen may demonstrate injury at various phases in this sequence. ( in ards the inciting event is frequently extrathoracic, and lung injury is therefore superimposed on normal preexisting structure. a b figure . acute respiratory distress syndrome: fibrin thrombi in arteries. acute lung injury results in local conditions that lead to arterial thrombosis. thrombi in various stages of organization may be seen (larger pulmonary artery in part a, smaller pulmonary artery in part b). ( fig. . ); collagen deposition is minimal. reactive type ii pneumocytes persist. immature squamous metaplasia may occur ( fig. . ) in and around terminal bronchioles. the degree of cytologic atypia in this squamous epithelium can be so severe as to mimic malignancy ( fig. . ). the hyaline membranes are mostly resorbed by the late proliferative stage, but a few remnants may be observed along alveolar septa. some cases of dad resolve completely, with few residual morphologic effects, but in other cases, fibrosis may progress to extensive structural remodeling and honeycomb lung. as might be expected, a review of outcomes for survivors of ards revealed persistent functional disability at year after discharge from intensive care. by definition, ards has a known inciting event. the foregoing description is based on a model of ards due to oxygen toxicity, wherein the evolution of histopathologic abnormalities can be studied over a defined time period. , in practice, lung biopsy most often is performed in patients without a known cause or specific time of onset of injury. moreover, with some causes of acute lung injury, the damage evolves over a protracted period of time, or the lung may be injured in repetitive fashion (e.g., with drug toxicity). in such circumstances, the pathologic changes do not necessarily progress sequentially through defined stages as in ards, so both acute and organizing phases may be encountered in the same biopsy specimen. the basic histopathologic elements of acute lung injury are presented in box . . acute fibrinous and organizing pneumonia (afop) is a histologic pattern of acute lung injury with a clinical presentation similar to that of classic dad, in terms of both potential etiologic disorders and outcome. it differs from dad in that hyaline membranes are absent. the dominant feature is intraalveolar fibrin balls or aggregates, typically in a patchy distribution. organizing pneumonia in the form of luminal loose fibroblastic tissue is present surrounding the fibrin (eslide . ). the alveolar septa adjacent to areas of fibrin deposition show a variety of changes similar to those of dad, such as septal edema, type ii pneumocyte hyperplasia, and acute and chronic inflammatory infiltrates. the intervening lung shows minimal histologic changes. afop may represent a fibrinous variant of dad. in some patients, both dad and afop disease patterns may be present simultaneously. , specific causes of acute lung injury infection infection is one of the most common causes of acute lung injury. if the lung injury pattern is accompanied by a significant increase in neutrophils, areas of necrosis, viral cytopathic effect, and/or granulomas, infection should lead the differential diagnosis. among infectious organisms, viruses most consistently produce dad. , occasionally, fungi (e.g., pneumocystis) and bacteria (e.g., legionella) also can cause infections manifesting as dad. some of the organisms that are well known to cause acute lung injury with characteristic histopathologic changes are discussed next. considerable structural remodeling may take place after ards as these atelectatic spaces fuse to form consolidated areas of lung parenchyma at the microscopic level. influenza is a common cause of viral pneumonia. the histopathology ranges from mild organizing acute lung injury (resembling organizing pneumonia) in nonfatal cases to severe dad with necrotizing tracheobronchitis ( fig. . ) in fatal cases. , specific viral cytopathic effects are not identifiable by light microscopy. on ultrastructural examination, intranuclear fibrillary inclusions may be seen in epithelial and endothelial cells. the coronavirus responsible for severe acute respiratory syndrome produces the acute lung injury associated with this disorder. , [ ] [ ] [ ] both dad and afop patterns have been identified in affected patients. on ultrastructural examination, involved lung tissue revealed numerous to moderate numbers of cytoplasmic viral particles in pneumocytes, many within membrane-bound vesicles. [ ] [ ] [ ] the virus particles were spherical and enveloped, with spikelike projections on the surface and coarse clumps of electron-dense material in the center. most had sizes ranging from to nm in diameter, but some were as large as nm. measles virus produces a mild pneumonia in the normal host but can cause serious pneumonia in immunocompromised children. adenovirus is an important cause of lower respiratory tract disease in children, , although adults (particularly those who are immunocompromised) and military recruits also are occasionally affected. the lung shows necrotizing bronchitis, or bronchiolitis, accompanied by dad. the pathologic changes are more severe in bronchi, bronchioles, and peribronchiolar regions ( fig. . a ). two types of inclusions can be observed in lung epithelial cells: an eosinophilic intranuclear inclusion with a halo usually is less conspicuous than the more readily identifiable "smudge cells" (see fig. . b). these latter cells are larger than normal and entirely basophilic, with no defined inclusion or halo evident by light microscopy. on ultrastructural examination, smudge cell inclusions are represented by arrays of hexagonal particles. herpes simplex virus is mainly a cause of respiratory infection in the immunocompromised host. two patterns of infection are recognized: airway spread resulting in necrotizing tracheobronchitis ( fig. . ) and bronchitis and bronchiolitis, and dad. the characteristic histologic feature is the presence of multinucleated giant cells (fig. . a) with characteristic eosinophilic intranuclear and intracytoplasmic inclusions. [ ] [ ] [ ] [ ] [ ] these cells are found in the alveolar spaces and within alveolar septa (fig. . b ). viral inclusions are seen on ultrastructural examination as tightly packed tubules. interstitial (alveolar septal) edema fibroblastic proliferation in alveolar septa alveolar edema alveolar fibrin and cellular debris, with or without hyaline membranes reactive type ii pneumocytes blood-borne dissemination producing miliary necrotic parenchymal nodules. dad and hemorrhage can occur in both forms. , characteristic inclusions may be seen in bronchial and alveolar epithelial cells ( fig. . ). the more obvious type is an intranuclear eosinophilic inclusion surrounded by clear halo (cowdry a inclusion), and the other is represented by a basophilic to amphophilic ground-glass nucleus (cowdry b inclusion). rounded viral particles with double membranes are seen under the electron microscope. , varicella-zoster virus causes disease predominantly in children and is the agent of chickenpox. pulmonary complications of chickenpox are rare in children with normal immunity (accounting for less than % of the cases). by contrast, pneumonia develops in % of adults with chickenpox; immunocompetent and immunocompromised persons are equally affected. , the histopathologic picture in varicella pneumonia ( fig. . ) is similar to that in herpes simplex. although identical intranuclear inclusions are reported to occur, , these can be considerably more difficult to identify in chickenpox pneumonia. cytomegalovirus is an important cause of symptomatic pneumonia in immunocompromised persons, especially those who have received bone marrow or solid organ transplants, and in patients with human immunodeficiency virus infection. [ ] [ ] [ ] the histopathologic findings range from little or no inflammatory response to hemorrhagic nodules with necrosis ( fig. . a) and dad. the diagnostic histopathologic b a with many organisms (see fig. . b). , however, in the mildly immunocompromised patient this feature is not observed or the pathologic changes may be subtle. in such cases, several "atypical" manifestations have been described. , , dad is the most dramatic of these atypical presentations ( fig. . a), with the organisms present within hyaline membranes ( fig. . b) and in isolated intraalveolar fibrin deposits. the grocott methenamine silver (gms) method is routinely used to stain the organisms, which typically are seen in small groups and clusters (figs. . b and . b). , , bacterial infection common bacterial pneumonias rarely cause dad; however, this lung injury pattern has been described in legionnaires' disease, mycoplasma pneumonia, and rickettsial infection. [ ] [ ] [ ] [ ] [ ] pattern, seen in endothelial cells, macrophages, and epithelial cells, consists of cellular enlargement, a prominent intranuclear inclusion, and an intracytoplasmic basophilic inclusion ( fig. . b). hantavirus is a rare cause of acute lung injury. [ ] [ ] [ ] the infection produces alveolar edema, hyaline membranes, and atypical interstitial mononuclear inflammatory infiltrates (fig. . ). [ ] [ ] [ ] spherical membrane-bound viral particles have been found in the cytoplasm of endothelial cells by electron microscopy. pneumocystis jiroveci (previously known as pneumocystis carinii) is the most common fungus to cause dad. [ ] [ ] [ ] the histopathology of pneumocystis infection in the setting of profound immunodeficiency is one of frothy intraalveolar exudates ( [afb] stains or gms or warthin-starry silver stain, etc.) on every lung biopsy specimen exhibiting dad. systemic connective tissue disorders are a well-known cause of diffuse lung disease. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in some cases, lung involvement may be the first manifestation of the systemic disease, even without identifiable serologic evidence. histologic clues that suggest the acute lung injury is secondary to connective tissue disease include associated bronchiolitis (especially if it is follicular bronchiolitis), pleuritis, capillaritis, hemorrhage, and legionella is a fastidious gram-negative bacillus that causes acute respiratory infection in older adults and immunodeficient individuals. , , the histopathologic pattern is that of a pyogenic necrotizing bronchopneumonia ( fig. . a) affecting the respiratory bronchioles, alveolar ducts, and adjacent alveolar spaces. dad is common. , , the rod-shaped organisms (fig. . b) can be identified by dieterle silver stain. of note, in immunocompromised patients, any type of infection can cause dad, with pneumocystis pneumonia being the most common. for this reason, it is essential to use special stains (acid-fast bacilli and small vessel vasculitis ( fig. . b), and pulmonary edema also may be observed. , , immunofluorescence studies demonstrate immune complexes in lung parenchyma, and both immune complexes and tubuloreticular inclusions may be seen on ultrastructural examination. , , rheumatoid arthritis a significant percentage of patients with rheumatoid arthritis have lung disease. , , [ ] [ ] [ ] [ ] many different morphologic patterns of lung disease in rheumatoid arthritis have been described, , , with the rheumatoid nodule being the most specific. acute lung injury has been reported ( fig. . ), referred to as acute interstitial pneumonia in some publications and as dad in others. a cellular lymphoplasmacytic infiltrate. acute lung injury has been reported to occur in the following connective tissue diseases. pulmonary involvement in systemic lupus erythematosus (sle) may manifest as pleural disease, acute or chronic diffuse inflammatory lung disease, airway disease, or vascular disease (vasculitis and thromboembolic lesions). acute lupus pneumonitis (alp) is a form of fulminant interstitial disease (fig. . a) with a high mortality rate. patients present with severe dyspnea, tachypnea, fever, and arterial hypoxemia. alp represents the first manifestation of sle in approximately % of affected persons. , the most common histopathologic feature of this acute disease is dad (eslide . ). alveolar hemorrhage, with capillaritis b a polymyositis/dermatomyositis, a systemic connective tissue disorder, is well known to be associated with interstitial lung disease. , three main clinical presentations are recognized: ( ) acute fulminant respiratory distress resembling the so-called hamman-rich syndrome, ( ) slowly progressive dyspnea, and ( ) an asymptomatic form with abnormalities on radiologic and pulmonary function studies. three major histopathologic patterns have been observed: dad (fig. . a), organizing pneumonia ( fig. . b) , and chronic fibrosis (fig. . c )-the so-called usual interstitial pneumonia (uip) pattern. the rapidly progressive clinical presentation is associated with a dad histopathologic pattern on lung biopsy studies and carries the worst prognosis. dad associated with scleroderma and mixed connective disease also has been described. , many patients with connective tissue disease receive drug therapy during the course of their illness. a large number of drugs, including cytotoxic agents used for immunosuppression, are known to cause dad. in addition, as a desired result of therapy, patients may be immunosuppressed, making the exclusion of infection a high priority in the case of acute clinical lung disease. drugs can produce a wide range of pathologic lung manifestations, and the causative agents are numerous. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the spectrum of drug-induced lung disease runs the entire gamut from dad to fibrosis. between these two extremes, subacute clinical manifestations may include organizing pneumonia, chronic interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension, venoocclusive disease, and granulomatous interstitial pneumonia. , , dad is a common and dramatic manifestation of pulmonary drug toxicity. many drugs are known to cause dad. a few of the more common ones are discussed next. (drug-related lung disease is also discussed in chapter .) as a generalization, marked cytologic atypia and numerous foamy macrophages in the airspaces are histologic harbingers of possible drug reaction. dad frequently is caused by cytotoxic drugs, and the commonly implicated ones include bleomycin (fig. . ), busulfan ( fig. . ) , and carmustine. , , patients usually present with dyspnea, cough, and diffuse pulmonary infiltrates. [ ] [ ] [ ] [ ] [ ] the histologic pattern most commonly is one of nonspecific acute lung injury with hyaline membranes, but some changes may be present to at least suggest a causative agent. for example, the presence of acute lung injury with associated atypical type ii pneumocytes with markedly enlarged pleomorphic nuclei and prominent nucleoli (see fig. . ) is characteristic for busulfan-induced pulmonary toxicity, and, on ultrastructural examination, intranuclear tubular structures have been found in type ii pneumocytes in association with administration of busulfan and bleomycin. [ ] [ ] [ ] [ ] in most cases, the possibility that a drug is the cause of dad can only be inferred from the clinical history. considerations in the differential diagnosis typically include other treatment-related injury or complication of therapy (e.g., concomitant irradiation or infection). for example, oxygen therapy is a well-recognized cause of dad (fig. . ) and also may exacerbate bleomycin-induced lung injury. methotrexate (fig. . ) is another commonly used cytotoxic drug that can cause acute and organizing dad. methotrexate also produces other distinctive patterns, such as granulomatous interstitial pneumonia (see chapter ) that is seldom seen in association with other commonly used chemotherapeutic agents. to complicate matters further, methotrexate also is used in the treatment of rheumatoid arthritis, a disease known to produce dad independently as one of its pulmonary manifestations. , epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be associated with dad. , the increasing use of targeted therapy drugs in cancer patients warrants a notice of this category as a potential cause. amiodarone is a highly effective antiarrhythmic drug that is increasingly recognized as a cause of pulmonary toxicity. , - because patients taking amiodarone have known cardiac disease, the clinical presentation often is complicated, with several superimposed processes potentially affecting the lungs in various ways. clinical and radiologic considerations typically include congestive heart failure, pulmonary emboli, and acute lung injury from other causes. , distinctive features may be present on chest computed tomography scans. the lung biopsy commonly shows acute and organizing lung injury (fig. . a and eslide . ). other patterns include chronic interstitial pneumonitis with fibrosis and organizing pneumonia. characteristically, type ii pneumocytes and alveolar macrophages show finely vacuolated cytoplasm in response to amiodarone therapy (see fig. . b), but these changes alone are not evidence of toxicity because they also may be seen in patients taking amiodarone who do not have evidence of lung toxicity. methotrexate and gold, common agents for treatment of rheumatoid arthritis, are frequently implicated in lung toxicity. methotrexate is discussed earlier in this chapter. organizing dad (fig. . ) and chronic interstitial pneumonia are commonly described pulmonary manifestations of so-called gold toxicity. , , acute eosinophilic pneumonia acute eosinophilic pneumonia was first described in and is characterized by acute respiratory failure, fever of days' to weeks' duration, diffuse pulmonary infiltrates on radiologic studies, and eosinophilia in bronchoalveolar lavage fluid or lung biopsy specimens in the absence of infection, atopy, and asthma. peripheral eosinophilia frequently is described but is not a consistent finding at initial presentation. , acute eosinophilic pneumonia is easily confused with acute interstitial pneumonia because both manifest as acute respiratory distress without an obvious underlying cause. histologically, the disease is characterized by acute and organizing lung injury showing classic features (fig. . ) of ( ) alveolar septal edema, ( ) eosinophilic airspace macrophages, ( ) tissue and airspace eosinophils in variable numbers, and ( ) marked reactive atypia of alveolar type ii cells (eslide . ). intraalveolar fibroblastic proliferation (patchy organizing pneumonia) and inflammatory cells are present to a variable degree. hyaline membranes and organizing intraalveolar fibrin also may be present (fig. . ) . the most significant feature is the presence of interstitial and alveolar eosinophils. infiltration of small blood vessels by eosinophils also may be seen. it is important of special stains applied to tissue sections or cytologic preparations (e.g., afb, gms, or warthin-starry silver stain) also is essential to rule out infectious organisms in this setting. so-called pulmonary hemorrhage syndromes may feature the histopathologic changes of acute lung injury, in addition to the characteristic alveolar hemorrhage and hemosiderin-laden macrophages. in some patients, dad may be the dominant histopathologic pattern. in a study by lombard et al. in patients with goodpasture syndrome, all showed acute lung injury ranging in distribution from focal to diffuse lung involvement. histopathologic examination demonstrated typical acute and organizing dad, with widened and edematous alveolar septa, fibroblastic proliferation, reactive type ii pneumocytes, and, rarely, even hyaline membranes (figs. . and . ). alveolar hemorrhage, either focal or diffuse, was present in all cases. capillaritis, an important finding indicating true alveolar hemorrhage, also was seen, as evidenced by marked septal neutrophilic infiltration. capillaritis was absent in one case for which dad was the dominant histopathologic pattern. microscopic polyangiitis can manifest as an acute interstitial pneumonia both clinically and histopathologically. affected patients have vasculitis as the known cause of acute lung injury. alveolar hemorrhage with arteritis, capillaritis ( fig. . ) , and venulitis may be seen in some cases. polyarteritis nodosa and vasculitis associated with systemic connective tissue disease (notably sle and rheumatoid arthritis) can also show acute lung injury with alveolar hemorrhage as the dominant histopathologic finding. , cryoglobulinemia is a rare cause of acute lung injury and alveolar hemorrhage. [ ] [ ] [ ] radiation can produce both acute and chronic damage to the lung, manifesting as acute radiation pneumonitis and chronic progressive fibrosis, respectively. the effect is dependent on radiation dosage, total time of irradiation, and tissue volume irradiated. concomitant chemotherapy and infections, which in themselves are causes of dad, may potentiate the effect of radiation injury. , , , acute radiation pneumonitis manifests to months after radiation therapy. , with traditional external beam radiation the pneumonitis is typically confined to the radiation field. however, more diffuse radiation pneumonitis can be seen following yttrium -impregnated microsphere chemoembolization for nonoperable hepatic tumors. clinical findings include dyspnea, cough, pleuritic pain, fever, and chest infiltrates. the lung biopsy specimen shows acute and organizing dad. , markedly atypical type ii pneumocytes with enlarged hyperchromatic nuclei and vacuolated cytoplasm constitute a hallmark of the disease (fig. . a) , and increased numbers of alveolar macrophages are seen. foamy cells are present in the intima and media of pulmonary blood vessels in some cases, and thrombosis ( fig. . b) , with or without transmural fibrinoid necrosis, is common. , [ ] [ ] [ ] disease presenting as classic acute respiratory distress syndrome by definition, ards must be associated with an identifiable inciting event. the histopathologic pattern is that of classic dad. the histopathologic changes should be consistent with those expected for the time interval from the onset of clinical disease (see later). in many cases the ards may be caused by a combination of factors, each potentiating the other. for the purposes of illustration, a few thoroughly studied causes are discussed next. to distinguish acute eosinophilic pneumonia from other causes of dad because patients typically benefit from systemic corticosteroid treatment, with prompt recovery. however, before initiation of immunosuppressive therapy, infection should be rigorously excluded by culture and special stains because parasitic and fungal infections also can manifest as tissue eosinophilia. treatment with steroids prior to the biopsy can make the number of eosinophils less impressive. acute interstitial pneumonia, also commonly referred to as hamman-rich syndrome, is a fulminant lung disease of unknown etiology occurring in previously healthy patients. [ ] [ ] [ ] acute interstitial pneumonia is one of the major idiopathic interstitial pneumonias included in the most recent classification scheme for diffuse interstitial pneumonia. patients usually report a prodromal illness simulating viral infection of the upper respiratory tract, followed by rapidly progressive respiratory failure. the mortality rate is high, with death occurring weeks or months after the acute onset. , the classic histopathologic pattern is that of acute and organizing dad, , with septal edema and hyaline membranes in the early phase and septal fibroblastic proliferation with reactive type ii pneumocytes prominent in the organizing phase. in practice, a combination of acute and organizing changes ( fig. . ) often is seen in the lung at the time of biopsy. a variable degree of airspace organization, mononuclear inflammatory infiltrates, thrombi in small pulmonary arteries, and reparative peribronchiolar squamous metaplasia also are seen in most cases. because acute interstitial pneumonia is idiopathic, other specific causes of acute lung injury must be excluded before making this diagnosis. considerations in the differential diagnosis include infection, connective tissue disease, acute exacerbation of idiopathic pulmonary fibrosis (ipf), drug effect, and other causes of dad. most cases of dad are not acute interstitial pneumonia, and detailed clinical information, radiologic findings (localized vs. diffuse disease), serologic data, and microbiologic results will often point to or rule out a specific etiologic condition. use figure . acute interstitial pneumonia (aip). idiopathic aip may take the form of every possible morphologic manifestation of acute respiratory distress syndrome, depending on the timing of biopsy relative to the onset of symptoms. here, a classic pattern of diffuse alveolar damage (dad) with hyaline membranes of variable cellularity is seen (midproliferative phase). interstitial fibroblastic proliferation may be more or less prominent from case to case and should not serve as a qualifying morphologic finding for the diagnosis. aip is nothing more than dad of unknown causation. oxygen is a well-known cause of ards and a useful model for all types of dad. , , oxygen toxicity also is important in that it is widely used in the care of patients, often in the setting of other injuries that can potentially cause ards, such as sepsis, shock, and trauma. exposure to high concentrations of oxygen for prolonged periods can lead to characteristic pulmonary damage. in pratt first noted pulmonary changes due to high concentrations of inspired oxygen. in nash et al. described the sequential histopathologic changes of this injury, later reemphasized by pratt. in neonates receiving oxygen for hyaline membrane disease, bronchopulmonary dysplasia was reported to occur. as might be expected, the features of hyaline membrane disease in neonates and oxygen-induced dad in adults are indistinguishable (see fig. . ). other inhalants such as chlorine gas, mercury vapor, carbon dioxide in high concentrations, and nitrogen mustard all have been reported to cause ards. , , massive extrapulmonary trauma and shock first became recognized as causes of unexplained respiratory failure during the wars of the second half of the th century. a variety of names were assigned to this wartime condition, including shock lung, congestive atelectasis, traumatic wet lung, da nang lung, respiratory insufficiency syndrome, posttraumatic pulmonary insufficiency, and progressive pulmonary consolidation. it which can be performed even on autopsy specimens. other ingested toxins (e.g., kerosene, rapeseed oil) also have been reported to cause ards. pathologist approach to the differential diagnosis of acute lung injury the histologic spectrum encountered in acute lung injury is broad. very early cases may look nearly normal with only mild interstitial and alveolar edema. other more advanced cases are clearly abnormal with fibrin, inflammation, and organization. the basic elements of the acute injury pattern include interstitial edema, alveolar edema, fibrin, hyaline membranes, reactive pneumocytes, and organization (see box . ). acute lung injury is a pathologic pattern and by itself is a nonspecific finding. from a practical perspective, after an acute lung injury pattern is became clear that shock of any cause (e.g., hypovolemia due to hemorrhage, cardiogenic shock, sepsis) could cause ards, and that in most cases, a number of factors come into play. in the typical presentation, dyspnea of rapid onset is accompanied by development of diffuse chest infiltrates several hours to days after an episode of shock. after ards begins, the mortality rate is high. , , paraquat is a potent herbicide that causes the release of hydrogen peroxide and superoxide free radicals, resulting in damage to cell membranes. [ ] [ ] [ ] oropharyngitis is the initial sign of poisoning, followed by impaired renal and liver function. approximately days later, ards develops. the histopathologic pattern in most cases is one of organizing dad (fig. . ). the diagnosis is confirmed by tissue analysis for paraquat, b a raise consideration of immunologically mediated pulmonary hemorrhage. care must be taken not to interpret the pigmented macrophages seen in the lungs of cigarette smokers as evidence of hemorrhage. the hemosiderin in macrophages related to true hemorrhage in the lung (from any cause) is globular, often slightly refractile, and golden-brown in color. , [ ] [ ] [ ] presence of atypical cells. viral infections often produce cytopathic effects, including intracellular inclusions (see chapter ) . examples of intracellular inclusions are the cowdry a and b inclusions seen in herpesvirus infection, cytomegaly with intranuclear and intracytoplasmic inclusions of cytomegalovirus, the multinucleated giant cells of measles virus and respiratory syncytial virus, and the smudged cells of adenovirus infection. , , , , chemotherapeutic drugs such as busulfan and bleomycin often are associated with markedly atypical type ii pneumocytes, which may have enlarged pleomorphic nuclei and prominent nucleoli. , markedly atypical type ii pneumocytes that may be suggestive of a viropathic effect also are seen in radiation pneumonitis. , , presence of foamy cells. alveolar lining cells with vacuolated cytoplasm accompanied by intraalveolar foamy macrophages are characteristic features seen in patients taking amiodarone, and amiodarone toxicity may lead to acute lung injury changes. [ ] [ ] [ ] in some cases of radiation pneumonitis, foam cells are seen in the intima and media of blood vessels. , presence of foreign material. foreign material in the spaces in the form of vegetable matter or other food elements is indicative of aspiration. massive aspiration events may cause dad. other foreign material, such as radiation impregnated beads may also be encountered. presence of advanced interstitial fibrosis. clinical ipf is associated with the changes of uip on pathologic examination (see chapter ), with advanced lung remodeling. of interest, ipf undergoes episodic exacerbation, and on occasion such exacerbation may be overwhelming, with resultant dad. it is prudent to examine lung biopsy sections for the presence of dense fibrosis with structural remodeling (microscopic honeycombing) in cases of dad, to identify the rare case of ipf that manifests for the first time as an acute episode of exacerbation. because the morphologic manifestations of acute diffuse lung disease may be relatively stereotypical, clinicopathologic correlation is often helpful in arriving at a specific diagnosis. a summary of the more important history and laboratory data pertinent to this correlation is presented in box . . identified, careful search for the following additional features often help to narrow the list of possible causes (summarized in immune status acuity of onset radiologic distribution and character of abnormalities history of inciting event (e.g., shock) history of lung disease (e.g., usual interstitial pneumonia with current acute exacerbation) history of systemic disease (e.g., connective tissue disease, heart disease) history of medication use or drug abuse history of other recent treatment (e.g., radiotherapy for malignancy) results of serologic studies: erythrocyte sedimentation rate determination, assays for autoimmune antibodies (e.g., ana, rf, anca, scl- , jo- ) results of microbiology studies one of the first questions to be addressed is whether or not a known inciting event was identified clinically (i.e., is this ards?). next, the results of any sampling procedures to identify infection should be checked, along with application of special stains to the tissue sections, to exclude infection. finally, data regarding related disease, such as infection, autoimmune disease, underlying lung disease, are needed. for example, if the patient is immunosuppressed, infection should always be the leading consideration in the differential diagnosis. another point to keep in mind is that patients with certain diseases may be taking medications with the potential to cause dad (e.g., amiodarone for cardiac arrhythmia). moreover, laboratory studies may reveal antibodies related to connective tissue disease (e.g., antineutrophil antibody, rheumatoid factor, jo- , scl- , antifibrillarin, anti-mpp , ss-a, ss-b). regarding the pathologist's role and responsibility in biopsy cases of acute lung injury, use of special stains for organisms (at a minimum, methenamine silver and acid-fast stains) is indicated. additional stains (auramine-rhodamine, dieterle or warthin-starry silver stain, immunohistochemical stains for specific organisms, or molecular probes) may be used, especially in patients known to be immunocompromised from any cause. the pathology in immunocompromised patients may not show necrosis, neutrophils, or granulomas, all features favoring an infectious etiology. self-assessment questions and cases related to this chapter can be found online at expertconsult.com. acute and fibrinous organizing pneumonia (eslide . ) a. history-a -year-old female presented with acute onset dyspnea. her past medical history was significant for rheumatoid arthritis for which she had recently begun methotrexate. imaging studies show bilateral ground-glass infiltrates in upper and lower lobes. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification, the lung architecture appears preserved without significant fibrosis. at higher power there is an extensive airspace filling process. many airspaces are filled with fibrin and scattered inflammatory cells. in other areas there is light pink material suggestive of edema. finally, some early fibroblastic polyps of organization are present. the interstitium shows diffuse alveolar damage with hyaline membranes (eslide . ) a. history-a -year-old male without significant past medical history presented to the emergency room with acute shortness of breath and cough. a week prior he participated in a half marathon without difficulty. he was taking no medications and had no exposures. his oxygen saturation was % on room air. he progressed to respiratory failure after being admitted to the intensive care unit. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification the biopsy shows preserved lung parenchyma without significant scarring. however, there is a diffuse process that gives the biopsy a "pink" appearance from low power. at higher power, the histologic features of diffuse alveolar damage (dad) are recognized including alveolar wall edema, reactive type-ii pneumocytes, and hyaline membranes. a few foci of organization are also present. a significant inflammatory cell infiltrate is not recognized. there is no pleuritis, hemosiderosis, granulomas, or necrosis. c. diagnosis-diffuse alveolar damage. d. discussion-features of acute lung injury are readily apparent, and the numerous hyaline membranes support a diagnosis of diffuse alveolar hemorrhage. the biopsy is negative for numerous eosinophils, foamy macrophages, alveolar hemorrhage, foreign material, neutrophils, necrosis, and granulomas. therefore the histology does not suggest a particular etiology on this case. acid-fast and fungal stains were negative. extensive serologic screening studies were negative, and cultures are negative to date. because the additional work-up is negative, this case is best categorized as acute respiratory distress syndrome. lung pathology of fatal severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome a major outbreak of severe acute respiratory syndrome in hong kong fatal measles (rubeola) pneumonia in adults isolation of measles virus at autopsy in cases of giant-cell pneumonia without rash persistence of measles virus and depression of antibody formation in patients with giant-cell pneumonia after measles measles and its relationship to giant cell pneumonia (hecht pneumonia) katzenstein and askin's surgical pathology of non-neoplastic lung disease histopathology of fatal adenovirus infection of the respiratory tract in young children bronchiolitis obliterans, bronchiectasis and other sequelae of adenovirus type infection in young children adenovirus infection in the immunocompromised patient viral infections of the respiratory tract fatal adenovirus pneumonia in a newborn identified by electron microscopy and in-situ hybridization herpes simplex virus pneumonia: clinical, virologic, and pathologic features in patients herpes simplex virus infection of the adult lower respiratory tract varicella infection and pneumonia among adults cytomegalovirus pulmonary disease cytomegalovirus pneumonia in bone marrow transplant recipients: miliary and diffuse patterns cytomegalovirus after allogeneic bone marrow transplantation hantavirus pulmonary syndrome is distinguishable from acute interstitial pneumonia hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease. the hantavirus study group hantavirus pulmonary syndrome in the united states. a new pathological description of a disease caused by a new agent lung biopsy in pneumocystis carinii pneumonia. a histopathologic study of typical and atypical features the diagnosis of pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome using subsegmental bronchoalveolar lavage disseminated pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome pneumocystis infection masquerading as diffuse alveolar damage: a potential source of diagnostic error legionnaires' disease. pathological and historical aspects of a new disease legionnaires' disease pneumonia: histopathologic features and comparison with microbial and chemical pneumonias open lung biopsy in mycoplasma pneumoniae pneumonia adult respiratory distress syndrome in q fever the pathology of the legionella pneumonias. a review of cases and the literature pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis pulmonary involvement in the collagen vascular diseases lung biopsy in rheumatoid arthritis st aspen lung conference: overview. chest pulmonary pathology of acute respiratory distress syndrome acute respiratory distress in adults diffuse alveolar damage-the role of oxygen, shock and related factors acute lung injury patterns: diffuse alveolar damage and bronchiolitis obliteransorganizing pneumonia mortality rates for patients with acute lung injury/ards have decreased over time the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition adult respiratory distress syndrome the pulmonary physician in critical care : the pathogenesis of ali/ards atlas of pulmonary surgical pathology one-year outcomes in survivors of the acute respiratory distress syndrome pulmonary pathology of severe acute respiratory syndrome in toronto fatal acute fibrinous and organizing pneumonia in an infant: the histopathologic variability of acute respiratory distress syndrome clinicopathology study of fatal cases of asian influenza pathologic features of lung biopsy specimens from influenza pneumonia cases intranuclear fibrillary inclusions in influenza pneumonia the spectrum of pathological changes in severe acute respiratory syndrome (sars) lung pathology of severe acute respiratory syndrome (sars): a study of autopsy cases from singapore origin and significance of intranuclear tubular inclusions in type ii pulmonary alveolar epithelial cells of patients with bleomycin and busulfan toxicity oxygen-exacerbated bleomycin pulmonary toxicity methotrexate pneumonitis: review of the literature and histopathological findings in nine patients severe acute interstitial pneumonia and gefitinib fatal interstitial lung disease after erlotinib for non-small cell lung cancer amiodarone-associated pulmonary toxicity: a clinical and pathologic study of eleven cases amiodarone pulmonary toxicity. clinical, radiologic, and pathologic correlations amiodarone lung: pathologic findings in clinically toxic patients amiodarone pulmonary toxicity. recognition and pathogenesis (part i) acute amiodarone-induced lung toxicity alveolar-interstitial pneumopathy after gold-salts compounds administration, requiring mechanical ventilation acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure acute eosinophilic pneumonia: histopathologic findings in nine patients a clinical study of idiopathic eosinophilic pneumonia acute eosinophilic pneumonia: a review of cases acute diffuse interstitial fibrosis of the lungs acute interstitial pneumonia. a clinicopathologic, ultrastructural, and cell kinetic study hamman-rich syndrome revisited an official american thoracic society/european respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias acute interstitial pneumonia pathologic approach to pulmonary hemorrhage surgical pathology of the lung in anti-basement membrane antibody-associated goodpasture syndrome six cases of microscopic polyarteritis exhibiting acute interstitial pneumonia the lung in polyarteritis nodosa: a pathologic study of cases alveolar hemorrhage in cryoglobulinemia-an indicator of poor prognosis lung involvement in essential mixed cryoglobulinemia pulmonary hemorrhage in cryoglobulinemia radiation injury in surgical pathology. part i enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer diffuse alveolar damage. surgical pathology of diffuse infiltrative lung disease. orlando: grune and stratton incidence of radiation pneumonitis after hepatic intra-arterial radiotherapy with yttrium- microspheres assuming uniform lung distribution pulmonary effects of radiation therapy radiation effects in the lung pulmonary lesions associated with oxygen therapy and artificial ventilation pathology of pulmonary oxygen toxicity pulmonary capillary proliferation induced by oxygen pulmonary disease following respirator therapy of hyalinemembrane disease. bronchopulmonary dysplasia pulmonary disease in polymyositis/ dermatomyositis: a clinicopathological analysis of autopsy cases interstitial lung disease in polymyositis and dermatomyositis. clinical features and prognosis as correlated with histologic findings pulmonary pathology in patients with systemic autoimmune disease interstitial lung disease in systemic lupus erythematosus interstitial lung disease in collagen vascular disease microangiitis in lupus-induced pulmonary hemorrhage pulmonary lesions and rheumatoid arthritis pulmonary involvement in patients with rheumatoid arthritis open lung biopsy of patients with rheumatoid arthritis potential pathogenesis and clinical aspects of pulmonary fibrosis associated with rheumatoid arthritis rapidly fatal pulmonary fibrosis: the accelerated variation of interstitial pneumonitis polymyositis-dermatomyositis-associated interstitial lung disease organizing diffuse alveolar damage associated with progressive systemic sclerosis pulmonary disease complicating intermittent therapy with methotrexate desquamative interstitial pneumonia following chronic nitrofurantoin therapy pulmonary changes induced by amphophilic drugs large-dose bleomycin therapy and pulmonary toxicity. a possible role of prior radiotherapy pulmonary disease induced by drugs fibrosing alveolitis, bronchiolitis obliterans and sulfasalazine therapy pulmonary injury induced by gold salts treatment chemotherapy-induced eosinophilic pneumonia. relation to bleomycin gold-induced pneumonitis drug-induced pulmonary disease. an update pulmonary drug toxicity: radiologic and pathologic manifestations radiation-induced and chemotherapy-induced pulmonary injury pulmonary toxicity syndrome following cdep (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy drug-induced lung injury katzenstein and askin's surgical pathology of non-neoplastic lung disease drug-induced lung disease: high-resolution ct and histological findings drug-induced pulmonary disease (parts and ) drug-induced interstitial lung disease drug-induced lung disease drug-induced infiltrative lung disease drug-induced lung disease the effect of busulfan on human epithelia effect of long-term administration of busulfan respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia the respiratory syncytial virus and its role in acute bronchiolitis morphology of adenovirus type- infection of human respiratory epithelial cells in vitro acute exacerbation in idiopathic pulmonary fibrosis. analysis of clinical and pathologic findings in three cases improved survival of patients with acute respiratory distress syndrome (ards): - paraquat and the lung pulmonary ultrastructure of the late aspects of human paraquat poisoning paraquat poisoning. an update acute respiratory distress syndrome in mycoplasma pneumonia: a case report and review can show a bronchovascular distribution c. is associated with mechanical ventilation d. shows microcysts mantled by giant cells e. all of the above answer: e . peripheral cysts in hypoplastic lung tissue have been associated with: a. cri du chat syndrome b. holoprosencephaly c. beckwith-wiedemann syndrome d. down syndrome e. cornelia de lange syndrome answer: d acinar pulmonary dysplasia: a. features cystic change and enlargement of all lobes b. accounts for one of the most common surgical specimens in pediatric lung pathology hyperplasia: a. refers to an increased number of alveoli relative to the corresponding conducting airways which of the following is not in the macroscopic differential diagnosis of cystic lung lesions in children? a. adenomatoid malformation b. intralobar sequestration c. congenital lobar overinflation d. lymphangioleiomyomatosis e. pneumatocele answer: d . pulmonary sequestration is characterized by: a. communication with second-order bronchial lumina b. solely systemic vascular supply c. exclusive extralobar localization d. densely apposed, atelectatic airspaces e. multifocal aggregates of eosinophils answer: b . extralobar pulmonary sequestrations may occasionally contain which one of the following heterotopic tissues? a. bone b. glial nodules c. hepatoid anlage d. striated muscle e. enteric-type epithelium answer: d . congenital malformations of the pulmonary airways: a. are most often seen in stillborns or newborns b. represent malformations of each bronchopulmonary segment c. may be difficult to subclassify in fetal lungs d. must be distinguished from pleuropulmonary blastoma e. all of the above answer: e . which one of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? a. striated muscle b. cartilage c. mucinous epithelium d. embryonic-type mesenchymal tissue e. lymphoid aggregates answer: c .e . which one of the following storage disorders does not usually involve the lung parenchyma? a. niemann-pick disease b. gaucher disease c obliterative bronchiolitis in children can be associated with all of the following except: a. adenovirus b. influenza c. stevens-johnson syndrome d. paragonimiasis e. graft-versus-host disease answer: d acute eosinophilic pneumonia (eslide . ) a. history-a previously healthy -year-old female presented to the emergency room with acute-onset shortness of breath and cough. she was initially evaluated and admitted to the medicine floor for presumed pneumonia. however, she quickly deteriorated and was transferred to the medical intensive care unit and required intubation. imaging studies showed bilateral ground-glass opacities without lobar distribution. additional history obtained from the patient's roommate revealed the patient was recently treated with sulfamethoxazole and trimethoprim for a urinary tract infection. b. pathologic findings-the overall architecture of the lung appears intact, but there is a diffuse acute lung injury pattern including alveolar wall edema, airspace fibrin, organization, and scattered hyaline membranes. pneumocytes show marked reactive atypia. there are numerous eosinophils in the airspaces, embedded within the fibrin, and within the interstitium. numerous airspace macrophages are also present. no necrosis or granulomas are identified. c. diagnosis-acute eosinophilic pneumonia. d. there are four key histologic features in acute eosinophilic pneumonia, all of which are satisfied in this case. i. alveolar septal edema ii. eosinophilic airspace macrophages iii. tissue and airspace eosinophils iv. reactive atypia of type-ii pneumocytes there is a differential diagnosis for the acute eosinophilic pneumonia pattern of injury including drug reaction, infection, connective tissue disease, smoking related, and idiopathic. rigorous exclusion of infection is imperative and requires both infectious stains on the tissue blocks and culture studies. recognition of this injury pattern is of particular importance as these patients typically respond dramatically to high-dose steroids and have a better prognosis than that of diffuse alveolar damage. in this patient the exposure to a sulfa drug in the days prior to presentation was the likely etiology. she was treated with steroids, dramatically improved, and was discharged in days. amiodarone-induced diffuse alveolar damage (eslide . ) a. history-a -year-old male presented to the emergency room with acute shortness of breath first noted the evening prior. his past history was significant for a deceased donor renal transplant days prior to presentation for end-stage renal disease secondary to diabetes. he also had a history of hypertension and atrial fibrillation. imaging studies showed bilateral ground-glass opacities in the upper and lower lobes. b. pathologic findings-from scanning magnification there is preserved architecture without significant fibrosis. there is diffuse alveolar wall thickening, mostly by edema. overlying pneumocytes show reactive epithelial changes. numerous hyaline membranes and focal fibrin in airspaces are present. some airspaces are filled with numerous macrophages showing finely vacuolated cytoplasm. some acute lupus pneumonitis (eslide . )a. history-a -year-old african-american female presented with the emergency room with cough and shortness of breath. upon further questioning, she reported some blood-tinged sputum. the patient was febrile, and chest imaging studies showed bilateral ground-glass infiltrates without lobar distribution. serologic studies revealed an elevated erythrocyte sedimentation rate and c-reactive protein and positive antinuclear antibodies and anti-double-stranded dna antibodies. a surgical lung biopsy was performed. b. pathologic findings-the biopsy shows preserved lung architecture with a diffuse abnormality from scanning magnification. there is extensive alveolar wall edema with numerous foci of hyaline membranes. patchy organization is present, along with a relatively diffuse lymphoplasmacytic interstitial infiltrate. c. diagnosis-acute lupus pneumonitis. d. discussion-based on the histologic features alone, this biopsy is diagnostic of diffuse alveolar damage. however, the clinical history is required to arrive are a more specific diagnosis of acute lupus pneumonitis. the biopsy does show a mild increase in lymphoplasmacytic interstitial inflammation that would be unusual for most cases of idiopathic acute respiratory distress syndrome.edema and a mixed lymphoplasmacytic infiltrate. no hemorrhage, necrosis, or hyaline membranes are present. c. diagnosis-acute fibrinous and organizing pneumonia (afop). d. discussion-afop presents in the same fashion as diffuse alveolar damage (dad) and the differential diagnosis for afop and dad is the same, including drug reaction, toxin exposure, connective tissue disease, infection, and as an idiopathic reaction. they both represent forms of acute lung injury. in this case the degree of lymphoplasmacytic inflammation in the interstitium raises the possibility of a background connective tissue disease. additional history revealed she had recently cut her methotrexate dose in half to save money. she had also recently experienced inflammatory flares in her joints. all of these factors support a diagnosis of afop related to rheumatoid arthritis. a definitive etiology for afop is identified in a minority of patients.pneumocytes show similar cytoplasmic vacuolization. there is no necrosis, neutrophils, or hemorrhage. c. diagnosis-diffuse alveolar damage (dad) with foamy macrophages.a drug reaction leads the differential diagnosis. d. discussion-based on the presence of the patchy but marked cytoplasmic vacuolization in the macrophages and pneumocytes, a drug reaction is the most likely etiology for the dad pattern. in particular, amiodarone is a commonly used drug that causes this cytoplasmic vacuolization, even in the absence of associated lung injury. this was communicated to the clinical services who identified the patient was indeed taking amiodarone, even on the day of transplant. amiodarone-induced lung injury is associated with prolonged use of the drug and with an inciting event (such as a major operation). this patient had been on amiodarone for several years. following clinicopathologic correlation, this case is best diagnosed as amiodarone-induced dad. the patient was treated with pulse high-dose steroids and eventually had a full recovery. key: cord- -nxtfhxjd authors: mauri, tommaso; spinelli, elena; scotti, eleonora; colussi, giulia; basile, maria cristina; crotti, stefania; tubiolo, daniela; tagliabue, paola; zanella, alberto; grasselli, giacomo; pesenti, antonio title: potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease date: - - journal: crit care med doi: . /ccm. sha: doc_id: cord_uid: nxtfhxjd severe cases of coronavirus disease develop the acute respiratory distress syndrome, requiring admission to the icu. this study aimed to describe specific pathophysiological characteristics of acute respiratory distress syndrome from coronavirus disease . design: prospective crossover physiologic study. setting: icu of a university-affiliated hospital from northern italy dedicated to care of patients with confirmed diagnosis of coronavirus disease . patients: ten intubated patients with acute respiratory distress syndrome and confirmed diagnosis of coronavirus disease . interventions: we performed a two-step positive end-expiratory pressure trial with change of cm h( )o in random order. measurements and main results: at each positive end-expiratory pressure level, we assessed arterial blood gases, respiratory mechanics, ventilation inhomogeneity, and potential for lung recruitment by electrical impedance tomography. potential for lung recruitment was assessed by the recently described recruitment to inflation ratio. in a subgroup of seven paralyzed patients, we also measured ventilation-perfusion mismatch at lower positive end-expiratory pressure by electrical impedance tomography. at higher positive end-expiratory pressure, respiratory mechanics did not change significantly: compliance remained relatively high with low driving pressure. oxygenation and ventilation inhomogeneity improved but arterial co( ) increased despite unchanged respiratory rate and tidal volume. the recruitment to inflation ratio presented median value higher than previously reported in acute respiratory distress syndrome patients but with large variability (median, . [ . – . ]; range, . – . ). the fio( ) needed to obtain viable oxygenation at lower positive end-expiratory pressure was significantly correlated with the recruitment to inflation ratio (r = . ; p = . ). the ventilation-perfusion mismatch was elevated (median, % [ – %] of lung units) and, in six out of seven patients, ventilated nonperfused units represented a much larger proportion than perfused nonventilated ones. conclusions: in patients with acute respiratory distress syndrome from coronavirus disease , potential for lung recruitment presents large variability, while elevated dead space fraction may be a specific pathophysiological trait. these findings may guide selection of personalized mechanical ventilation settings. a ccording to reports from china, about % of hospitalized patients ( , ) and up to % of critically ill patients ( ) with the novel coronavirus disease (covid- ) develop the acute respiratory distress syndrome (ards), which markedly increases the risk of death ( ) . the majority of patients with ards due to covid- require intubation and invasive mechanical ventilation ( ) ( ) ( ) . even though the overflow of patients due to the outbreak and the need for patients isolation limit the application of refined diagnostic procedures ( ) , bedside characterization of ards pathophysiology is essential to inform the management of these critically ill patients ( ) . available data seem to indicate that ards due to covid- might present heterogeneous characteristics. the lung morphology is characterized by coexisting signs of alveolar damage and interstitial injury: ground-glass opacity with or without consolidation and septal thickening are common findings on ct images ( ) . furthermore, progression of pulmonary injury is characterized by specific alterations of the pulmonary vasculature tree, with dynamic increase in the size of vessels ( , ) . in this study, we assessed the respiratory mechanics, gas exchange, ventilation inhomogeneity, potential for lung recruitment, and ventilation/perfusion mismatch by electrical impedance tomography (eit) in a cohort of intubated patients with ards from covid- . the study hypothesis was that heterogeneous findings could indicate the need for personalized treatment and that physiologic measures at low positive endexpiratory pressure (peep) might already yield useful guidance. we conducted a prospective physiologic study on intubated patients admitted to the general icu of maggiore policlinico hospital, milan, italy. inclusion criteria were: intubated patients with confirmed infection by novel coronavirus (severe acute respiratory syndrome coronavirus ) and diagnosis of ards on the day of the study, scheduled to undergo a peep trial for clinical reasons. exclusion criteria were: age less than years, hemodynamic instability, history of severe chronic obstructive pulmonary disease, pregnancy, contraindications to the use of eit (e.g., presence of pacemaker or chest surgical wounds dressing). the ethical committee of the hospital approved the study (reference _ ) and informed consent was obtained according to local regulations. after enrollment, we collected sex, age, body mass index, comorbidities, days of intubation, sequential organ failure assessment score, clinical peep level, and the severity of ards. we placed an eit dedicated belt containing electrodes around the patient's chest at the fifth or sixth intercostal space and connected it to an eit monitor (pulmovista ; dräger medical gmbh, lübeck, germany). eit data were generated by application of small alternate electrical currents rotating around patient's thorax, continuously registered at hz during all study phases and stored for offline analysis. patients were connected to a ventilator (servo i; getinge ab, göteborg, sweden) and ventilation mode (seven on volumecontrolled ventilation, three on pressure support ventilation), tidal volume (vt), support, and respiratory rate (rr) were left as selected by the attending physician throughout the whole study. all patients were deeply sedated and kept in the semirecumbent position, seven patients on controlled ventilation were also paralyzed. the study consisted of two crossover steps (i.e., all patients undergoing both phases) performed in random order for minutes: during the last minutes of each phase, we collected arterial blood gas analysis, and we performed end-inspiratory and endexpiratory occlusions to measure the plateau pressure (pplat) and the total peep (peep tot ), carefully checking muscles relaxation in patients on pressure support ( ) . vt as average value from breaths was collected, too. then, we calculated: ) the driving pressure (dp) as (pplat-peep tot ) ) the respiratory system static compliance (crs) as vt/dp ) the ventilatory ratio, as previously described, with higher values indicating less efficient co clearance ( ) we horizontally split the eit images into two contiguous regions of interests of the same size: nondependent from halfway up and dependent from halfway down. then, from offline analyses of eit data obtained during the last minutes of each study phase, we measured: ) the relative pixel-level ventilation (v pixel ) ) the percentage of vt distending dependent lung regions at each peep level (dorsal fraction of ventilation), with values nearer to % indicating more homogenous ventilation distribution ( ) ) the global inhomogeneity (gi) index, with higher values indicating less homogenous ventilation ( ) ) changes in end-expiratory lung volume at higher peep (Δeelv eit ) ( ) ) lung recruitment at higher peep (recr eit ) as the increase in eelv measured by eit minus the change in eelv predicted from the respiratory system compliance measured at peep low (i.e., recr eit = Δeelv eit -Δeelv crs = Δeelv eit -[crs at peep low × Δpeep]) ( ) ) the recruitment to inflation (r/i) ratio, calculated as the compliance of the recruited lung (c recr = recr eit /Δpeep) divided by the compliance of the baby lung (crs at peep cm h o). higher values of the r/i ratio indicates larger potential for lung recruitment ( , ) in paralyzed patients (n = ), during the peep cm h o step, after assessing lung mechanics, we performed a second endinspiratory occlusion lasting seconds and, seconds after the start, we injected a bolus of ml of % nacl solution via the central venous catheter. then, from the offline analysis of the eit data recorded during the saline bolus injection, we measured ( fig. ): ) the pixel-level relative regional pulmonary perfusion (q pixel ): the cardiac region was removed from the images and the slope of the eit signal deflection during the saline bolus injection in each pixel was normalized to the overall detected signal, yielding the relative q pixel ( ) ) ventilation-perfusion (v/q) mismatch: if the amount of the v pixel or q pixel was less than or equal to % of the highest pixel-level value measured in that patient for that study step, then the pixel was classified as either nonventilated or nonperfused, respectively. then, v/q mismatch was quantified as the percentage of pixels that were classified as ventilated but not perfused (dead space fraction) plus the percentage of those perfused but not ventilated (shunt fraction). in this way, v/q mismatch ranged between % and %, with higher values indicating more mismatch ) to quantify the relative contribution of the dead space versus shunt fraction to v/q mismatch, we calculated the dead space to shunt ratio as the dead space fraction divided by shunt fraction. values higher than indicates more relevant role of dead space in determining v/q mismatch and vice versa sample size was similar to previous physiologic studies ( , ) . comparisons between the two peep levels of normally distributed variables were performed by repeated measure t test, while non-normally distributed variables were compared by wilcoxon signed rank test. normality was tested by the shapiro-wilk test. association between two variables was assessed by spearman regression coefficient. a level of p value of less than . (two-tailed) was considered as statistically significant. normally distributed data are indicated as mean ± sd, while median and interquartile range are used to report non-normally distributed variables. statistical analyses were performed by sigmaplot . (systat software, san jose, ca). patients were years old ( - yr old), four were obese but comorbidities were few. patients were studied days ( - d) after intubation and, under clinical settings, three patients had mild, five patients moderate, and two severe ards ( table ) . when looking at average values, increasing peep by cm h o did not affect the respiratory mechanics: the respiratory system compliance remained relatively high, keeping the dp below safe threshold despite intermediate vt ( table ) . at peep high , oxygenation improved, albeit by small extent ( table ) and arterial co tension significantly increased at constant vt and rr (table ) due to significant increase in dead space as assessed by the ventilatory ratio ( table ) . measures of ventilation inhomogeneity by eit improved, too: dorsal fraction of ventilation became closer to % and the gi index decreased (table ) . at peep high , the global increase in lung volume (Δeelv eit ) was of ml ( - ml), of which ml ( - ml) was due to recruitment (recr eit ). potential for lung recruitment measured by eit through the r/i ratio showed relatively high median values of . ( . - . ), but with extremely large variability, as indicated by range of . to . . the r/i ratio was not correlated with the days of ventilation (r = . ; p = . ), while we disclosed significant correlation between the r/i ratio and the fio at peep low (r = . ; p = . ). table summarizes patient-level values of ventilation and perfusion measured by eit at peep low in seven paralyzed patients. the percentage of pixels with v/q mismatch was % ( - %): six out of seven patients had quite large v/q mismatch with values higher than %. the dead space fraction was much more relevant than the shunt fraction in all but one patients and the dead space to shunt ratio was, indeed, . ( . - . ) ( table ) . study main findings can be summarized as follows: in a population of patients with ards from covid- , potential for lung recruitment presents high inter-individual variability; higher r/i ratio values or higher fio 's needed to maintain viable oxygenation at lower peep could be used to identify patients with larger potential for lung recruitment; ards from covid- is characterized by elevated ventilation-perfusion mismatch, with larger prevalence of ventilated nonperfused lung units (dead space) in comparison to perfused nonventilated units (shunt). potential for lung recruitment might be a crucial physiologic measure in ards patients ( ) for two main reasons. from a clinical perspective, previous studies showed that higher potential for lung recruitment is an independent predictor of mortality in ards ( ) . from a physiologic point of view, application of higher peep levels in patients with larger potential for recruitment could enhance lung protection through decreased atelectrauma ( ) . however, likewise many other pathophysiological features (e.g., hyper-vs hypo-inflammatory condition) ( ) , previous observations suggested that potential for lung recruitment can be highly variable in ards, possibly identifying specific ards subphenotypes with higher versus lower recruitability ( ) . our population of covid- patients with ards confirmed that physiologic variability and need for personalized treatment are hallmarks of ards ( ) . potential for lung recruitment in our population ranged from . (meaning that the baby lung size increased only by % with a peep change of cm h o) to . (with an increase of the baby lung of %). these data generate the hypothesis that histopathological characteristics of ards from covid- may be extremely heterogeneous in terms of the most represented lesions (e.g., interstitial vs intra-alveolar edema, reduced aeration vs fibrosis). this variability may be a consequence of the viral load, of the individual inflammatory response, or a mix of both. our data suggest that potential www.ccmjournal.org xxx • volume xx • number xxx for lung recruitment should be assessed in each patient with ards from covid- , for example, to guide personalized titration of peep. the r/i ratio can be computed at the bedside by eit or by other simpler and less expensive methods ( , ) . alternatively, impairment of oxygenation measured at low peep could be used to predict recruitability. the average physiologic effects of higher peep in this population were somehow conflicting: the r/i ratio was higher than previously reported in ards patients ( ) , ventilation inhomogeneity decreased and oxygenation improved, but at the same time, the ventilatory ratio increased, suggesting higher dead space. higher peep usually worsens co clearance by causing dash indicates data is not relevant for this variable, which is descriptive and not quantitative. regional overdistension and diversion of perfusion from ventilated areas. of note, overdistension and recruitment coexist to an unpredictable extent in ards ( ) . presence of vasodilation of pulmonary vessels ( ) and micro-thrombosis might have further complicated the dynamics of perfusion redistribution at higher peep. compression of dilated vessels in affected lung regions might represent an alternative to recruitment for explaining the peep-induced improvement in oxygenation. furthermore, higher peep could worsen the right heart function, decreasing the cardiac output and reducing shunt ( ), further improving oxygenation. thus, average effects of higher peep in this population could already suggest some predominance of detrimental (increased dead space, overdistension, poor right heart function) versus potentially beneficial (recruitment, improved homogeneity) physiologic effects. derangements in gas exchange during ards are caused by regional mismatch between ventilation and perfusion. in this cohort of covid- patients, ventilation/perfusion mismatch was elevated and mainly due to nonperfused but ventilated units (dead space fraction). these observations add to those from previous studies indicating that elevated d-dimers are an independent predictor of mortality ( ) and that pulmonary vessels are enlarged ( ) in covid- patients with ards. inflammatory diffuse micro-thrombosis leading to elevated d-dimers, higher pulmonary vascular resistance and larger dead space fraction might be the underlying mechanism of the observed alterations, thus representing a key pathophysiological trait of ards from covid- . specific treatments limiting the detrimental effects of dead space ventilation and diffuse micro-thrombosis (e.g., % co inhalation or pulmonary vascular vasodilation) ( ) could be tested in these patients. this study has few limitations: first, the population was small, but we performed multiple refined physiologic measures, and given the rapid spread of covid- cases worldwide, we wanted to present our results early to support formulation of more solid clinical and research hypotheses. second, the time we left patients at each peep level was short, albeit similar to previous studies ( ) and longer than the one used in the first study reporting the methodology to assess the r/i ratio ( ) . third, patients were studied at different time points along their clinical time course, and this likely corresponded to different phases of the inflammation process, further increasing heterogeneity. however, potential for lung recruitment was not correlated with days from intubation, likely indicating that intubation might not be an accurate estimate of the highest severity reached by this syndrome. fourth, albeit eit measures of change in lung volumes, recruitment and ventilation-perfusion mismatch have been validated ( , ) , only half of the lung parenchyma lies within the imaging field ( ) . fifth, we did not perform echocardiography to precisely assess the right heart function and the cardiac output at the two peep levels, thus leaving to speculation part of the explanations for our findings. potential for lung recruitment in patients with ards from covid- is highly variable and simple bedside estimates of recruitability should guide personalized mechanical ventilation settings. elevated ventilation-perfusion mismatch due to high dead space fraction could be a specific characteristic of this syndrome and inform the development of effective treatments. clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult in patients with covid- in wuhan, china: a retrospective cohort study washington state -ncov case investigation team: first case of novel coronavirus in the united states a personalized approach to the acute respiratory distress syndrome: recent advances and future challenges radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study covid inmi study group: -novel coronavirus severe adult respiratory distress syndrome in two cases in italy: an uncommon radiological presentation covid- ): role of chest ct in diagnosis and management plateau and driving pressure in the presence of spontaneous breathing physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome regional ventilation displayed by electrical impedance tomography as an incentive to decrease positive end-expiratory pressure evaluation of an electrical impedance tomography-based global inhomogeneity index for pulmonary ventilation distribution bedside assessment of the effects of positive end-expiratory pressure on lung inflation and recruitment by the helium dilution technique and electrical impedance tomography implementing a bedside assessment of respiratory mechanics in patients with acute respiratory distress syndrome potential for lung recruitment estimated by the recruitment-to-inflation ratio in acute respiratory distress syndrome. a clinical trial measurement of relative lung perfusion with electrical impedance and positron emission tomography: an experimental comparative study in pigs topographic distribution of tidal ventilation in acute respiratory distress syndrome: effects of positive end-expiratory pressure and pressure support lung recruitment in patients with the acute respiratory distress syndrome lung opening and closing during ventilation of acute respiratory distress syndrome development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials azurea network: personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in france (the live study): a multicentre, single-blind, randomised controlled trial regional distribution of gas and tissue in acute respiratory distress syndrome. iii. consequences for the effects of positive end-expiratory pressure. ct scan ards study group. adult respiratory distress syndrome influence of cardiac output on intrapulmonary shunt massive pulmonary infarction during total cardiopulmonary bypass in unanesthetized spontaneously breathing lambs electrical impedance tomography in perioperative medicine: careful respiratory monitoring for tailored interventions we thank dr. laurent brochard for sharing his stimulating ideas and dr. luciano gattinoni for critical revision of the article. we are grateful to eckhard teschner from drägerwerk ag & co. kgaa, lubeck, germany, for providing the electrical impedance tomography perfusion software tool free of charge. for information regarding this article, e-mail: tommaso.mauri@unimi.it key: cord- -fziv a k authors: chiang, chi-huei; shih, jen-fu; su, wei-juin; perng, reury-perng title: eight-month prospective study of patients with hospital-acquired severe acute respiratory syndrome date: - - journal: mayo clinic proceedings doi: . / . . sha: doc_id: cord_uid: fziv a k objective to define the clinical characteristics and clinical course of hospital-acquired severe acute respiratory syndrome (sars). patients and methods this -month prospective study of patients with hospital-acquired sars in taipei, taiwan, was conducted from april through december . results the most common presenting symptoms in our patients with hospital-acquired sars were fever, dyspnea, dizziness, malaise, diarrhea, dry cough, muscle pain, and chills. lymphopenia and elevated serum levels of lactate dehydrogenase (ldh) and c-reactive protein (crp) were the most common initial laboratory findings. initial chest radiographs revealed various pattern abnormalities and normal results. five of the patients required mechanical ventilation. the need for mechanical ventilation was associated with bilateral lung involvement on the initial chest radiograph and higher peak levels of ldh and crp. clinical severity of disease varied from mild to severe. at months after disease onset, patients with mild or moderate sars had normal findings or only focal fibrosis on chest high-resolution computed tomography. however, bilateral fibrotic changes remained in the patients who had recovered from severe sars, of whom had mild restrictive ventilatory impairment. one patient with severe sars died; she was elderly and had other comorbidities. five additional patients had reduced diffusing capacity. conclusion the clinical picture of our patients presenting with hospital-acquired sars revealed atypical pneumonia associated with lymphopenia, elevated serum levels of ldh, rapid clinical deterioration, and lack of response to empirical antibiotic therapy. substantially elevated levels of ldh and crp correlated with severe illness requiring mechanical ventilatory support. in those receiving mechanical ventilation, pulmonary function was only mildly reduced at to months after acute illness, consistent with the natural history of acute respiratory distress syndrome due to other causes. the most common presenting symptoms in our patients with hospital-acquired sars were fever, dyspnea, dizziness, malaise, diarrhea, dry cough, muscle pain, and chills. lymphopenia and elevated serum levels of lactate dehydrogenase (ldh) and c-reactive protein (crp) were the most common initial laboratory findings. initial chest radiographs revealed various pattern abnormalities and normal results. five of the patients required mechanical ventilation. the need for mechanical ventilation was associated with bilateral lung involvement on the initial chest radiograph and higher peak levels of ldh and crp. clinical severity of disease varied from mild to severe. at months after disease onset, patients with mild or moderate sars had normal findings or only focal fibrosis on chest high-resolution computed tomography. however, bilateral fibrotic changes remained in the patients who had recovered from severe sars, of whom had mild restrictive ventilatory impairment. one patient with severe sars died; she was elderly and had other comorbidities. five additional patients had reduced diffusing capacity. the clinical picture of our patients presenting with hospital-acquired sars revealed atypical pneumonia associated with lymphopenia, elevated serum levels of ldh, rapid clinical deterioration, and lack of response to empirical antibiotic therapy. substantially elevated levels of ldh and crp correlated with severe illness requiring mechanical ventilatory support. in those receiving mechanical ventilation, pulmonary function was only mildly reduced at to months after acute illness, consistent with the natural history of acute respiratory distress syndrome due to other causes. although several case series of sars have been reported, - to our knowledge, a prospective clinical study including long-term follow-up assessment by chest radiography, chest high-resolution computed tomography (hrct), and pulmonary function testing has not been reported, particularly for hospital-acquired cases. this prompted us to study prospectively the presenting manifestations and the eventual clinical outcome of patients with hospital-acquired sars. this study was approved by the ethics committee of the veterans general hospital, taipei, taiwan. the index patient with sars visited the emergency department of hospital a on april , , and hospitalacquired infections spread in hospital a (a community hospital). subsequently, index patients with sars seen at hospital-acquired sars in taipei, taiwan hospital b (another community hospital) resulted in additional cases of hospital-acquired sars. hospitals a and b were closed subsequently. the taipei veterans general hospital (hospital c), the largest tertiary and national teaching hospital in taipei city, was ordered by the government to admit the patients with hospital-acquired sars from hospitals a and b. two hospital staff members (a physician and an emergency department nurse) at taipei veterans general hospital also acquired the sars infection. we conducted the initial management and data-collecting protocol on april , , and enrolled these patients from april to may , ; follow-up extended through december . all patients met the world health organization case definition, established on april , , for sars - : fever (temperature ≥ °c), cough or shortness of breath, and pulmonary infiltration in the absence of an alternative diagnosis to explain the clinical presentation, combined with a history of direct exposure to sars or returning from a sars-infected area. although the initial chest x-ray films were normal in patients, radiographic abnormalities were noted on films obtained to days later. all of these patients with sars were admitted to the isolation wards at taipei veterans general hospital. we classified the severity of sars into groups on the basis of the oxygenation status of the patients at enrollment: mild was defined by a normal pao , moderate was defined by an abnormally low pao but a pao /fraction of inspired oxygen (fio ) ratio of mm hg or higher, and severe was defined by a pao /fio ratio lower than mm hg. (patients with severe sars developed adult respiratory distress syndrome [ards] and required mechanical ventilation.) for all patients, hematologic (complete blood cell counts with differential leukocyte count and coagulation profile) and biochemical (electrolytes, liver and renal function, creatine kinase [ck], lactate dehydrogenase [ldh]) tests were performed every days during hospitalization. chest radiographs were obtained every days during hospitalization and monthly after hospital discharge. chest hrct was performed every months. blood samples, throat swabs, and/or sputum were collected on the first day of admission. molecular diagnosis of sars was performed by extracting the viral rna according to a viral rna kit (qiagen, hilden, germany), followed by the use of a -step reverse transcriptase-polymerase chain reaction (rt-pcr) kit with coronavirus-specific primers (roche, mannheim, germany) to carry out rt-pcr. the pcr products were observed through . % agarose gel electrophoresis ( figure ). the primers of rt-pcr were cor-p-f (+) ′ctaacatgcttaggataatgg ′ and cor-p-r (-) ′caggtaagcgtaaaactcatc ′. the product size (cor-p-f /cor-p-r ) was base pairs. management protocol all patients received oral ribavirin at mg/d for days, intravenous injection of levofloxacin at mg/d for days, and intravenous immunoglobulin at g/kg per day for days after symptom onset. in cases of acute lung injury (pao /fio ratio < mm hg), methylprednisolone at mg/kg per day was administered intravenously, and the dosage was tapered subsequently according to clinical response. the criteria for tracheal intubation and mechanical ventilation included an absolute indication, pao /fio ratio less than mm hg, and a relative indication, pao /fio ratio of to mm hg. mechanical ventilation was used with a low tidal volume ( - ml/kg), plateau pressure lower than to cm h o, and adequate positive endexpiratory pressure to lessen the likelihood of barotrauma. after discharge from the hospital, patients were followed up as outpatients with chest radiography, hrct, and pul-figure . reverse transcriptase-polymerase chain reaction (rt-pcr) was used to diagnose the severe acute respiratory syndrome (sars) coronavirus in patient . the pcr products were observed through . % agarose gel electrophoresis. as shown in the s column, rt-pcr was done with the serum from this patient on hospital day , and results were positive; product size was base pairs (bp). however, the same procedure was repeated with the serum from this patient on hospital day , and results were negative, as shown in the s column. this finding indicated that the virus was present in the blood during the initial phase but had disappeared in the late phase of disease. monary function tests (automated body plethysmograph autobox dl, sensormedics, loma linda, calif). the impairment of pulmonary function was assessed according to the guidelines of the american thoracic society. the pulmonary function test result was interpreted as within normal limits if the total lung capacity (tlc), forced vital capacity (fvc), forced expiratory volume in second (fev ), and diffusing capacity were greater than % of the predicted normal value and the fev /fvc ratio was greater than . . continuous data are expressed as the mean ± sd or a percentage. the wilcoxon rank sum test was used to determine whether there was an association between any of the clinical and laboratory variables and mechanical ventilation. the fisher exact test was used to determine whether there was an association between categorical variables. p<. was regarded as statistically significant. statistical analysis was performed with systat software (version . , spss, chicago, ill). the mean ± sd age of the patients with hospitalacquired sars was . ± . years (median, years; in patients ( %), the initial chest radiographs appeared normal, but radiological opacities were noted within days of admission ( chest radiographs revealed maximal infiltrates at a mean ± sd of . ± . days (range, - days) after onset of fever. the pattern of radiographic lung involvement varied dramatically among the patients. in patients with only a focal opacity on initial chest radiographs, progression to bilateral lung involvement was seen, including ards in patient (figure ). in patients presenting with bilateral lung involvement on initial chest radiographs, continued radiological deterioration was seen, with of these patients developing ards (figure ). there was a significant association between bilateral lung involvement and development of ards (p=. ; fisher exact test). thus, patients presenting with bilateral or multifocal involvement on initial chest radiography appeared to be at an increased risk of developing ards compared with those presenting with only a focal opacity. initial laboratory findings included leukopenia, lymphopenia, thrombocytopenia, anemia, leukocytosis, and elevated serum levels of ast, alt, ldh, ck, and crp. lymphopenia and elevated ck and ldh levels were the most common. the peak elevation of serum ldh (occurring a mean of days after onset of fever) and crp (a mean of days after onset of fever), maximal lymphopenia (a mean of days after onset of fever), and maximal infiltrates on chest imaging (a mean of . days after onset of fever) appeared to coincide within a -hour period during the course of illness in patients with severe sars. higher peak levels of crp and ldh were significantly associated with the need for mechanical ventilation (table ) . treatment outcome during hospitalization, of the patients needed supplemental oxygen therapy. of these patients, ( % of the total ) had progression to ards and required mechanical ventilation. the clinical course of the patients was generally characterized by defervescence and gradual clinical improvement as well as normalization of blood cell counts and diminishing lung infiltrates during a course of weeks of inpatient management. in this cohort of patients, died. this patient was elderly and had comorbidities, including diabetes mellitus and congestive heart failure. her illness progressed to ards and was complicated by bilateral pneumothorax and multiorgan failure (respiratory, heart, and renal failure). the mean ± sd duration of hospitalization for the entire cohort was ± . days. in the patients with ards who required mechanical ventilation (excluding the patient who died), the duration of hospitalization was . ± . days. at discharge from the hospital, chest imaging showed normal results in patients and residual infiltrates in patients. only patient had continuing need for supplemental oxygen therapy at the time of hospital discharge. hair loss and joint pain occurred in patients with severe sars but resolved within months. generalized anxiety disorder persisted in patient and required medical attention. of the survivors, refused follow-up assessment of pulmonary function because they had recovered fully and had no residual functional impairment. the patients subjected to follow-up pulmonary function testing months after discharge were who survived ards and who did not have ards; in of these patients, results were normal (table ). mild restrictive impairment was observed in only patient who had survived ards associated with sars; this patient required episodes of mechanical ventilation. a reduced diffusing capacity was found in additional patients. the mean ± sd diffusing capacity of ards survivors who also had sars was reduced to . %± . % of the predicted normal value but was . %± % of that predicted in sars patients who did not have ards. figure . images of patient who had severe acute respiratory syndrome complicated by acute respiratory distress syndrome. left, chest radiograph on day reveals bilateral consolidation and infiltrates (endotracheal tube was placed for mechanical ventilation). middle, chest radiograph performed months after hospital discharge shows residual fibrotic infiltrates in the lower lung zones. right, high-resolution computed tomography performed months after hospital discharge reveals patchy ground-glass opacities and fibrotic infiltrates. results of pulmonary function testing showed mild restrictive ventilatory impairment with a total lung capacity of %, forced expiratory volume in second of %, and diffusing capacity of lung for carbon monoxide of %. in the survivors, chest hrct performed months after hospital discharge showed normal results in , focal fibrosis in , multifocal fibrosis in , and multifocal fibrosis with ground-glass opacities in with ards associated with sars. our study population of patients with hospital-acquired sars included health care workers. in taiwan, the outbreak of hospital-acquired sars infection occurred initially in hospital a and then in hospital b. these unfortunate events occurred because the health care workers at these hospitals had not been informed of sars, and infection control measures had not been instituted in these hospitals. thus, most cases of sars in taiwan were related to hospital exposure. health care workers in the hospitals became infected because of their prolonged exposure to and close contact with patients harboring sars. at initial presentation, the main symptoms of sars in our patients were fever, dyspnea, diarrhea, and dry cough. our patients experienced diarrhea more commonly than sars patients reported in other studies. , however, as many as % of the patients in the sars outbreak in the amoy gardens in hong kong also had diarrhea, contributing to a significant virus load being discharged in the sewage. in addition, ( %) of our patients had mildly elevated serum aminotransferase levels during hospitalization, and patients experienced nausea and vomiting. our clinical findings are consistent with those of zhang, who noted that the sars virus can involve the digestive system. lymphopenia and elevated serum levels of ldh and crp were the most common laboratory findings in our patients. some patients had increased levels of ast, alt, and ck, as well as thrombocytopenia and anemia. although the symptoms and laboratory findings of sars are nonspecific, the constellation of these features should alert medical practitioners to the possibility of sars. lymphopenia was an extremely common finding in our patients, as reported in previous studies ( . %- . %). , , depletion of lymphocytes may be secondary to the direct effect of the virus on the lymphocytes, the effect of various cytokines involved in sars, or a stress response. , similar to findings in other reports, , , some of our patients with sars had thrombocytopenia. wong et al reported evidence of active bone marrow with normal megakaryocytes as part of postmortem findings in patients with thrombocytopenia; these findings favor an immune cause of thrombocytopenia. similar to previous reports, [ ] [ ] [ ] our results show that the primary radiological appearance of sars is focal airspace shadowing (hazy/ground-glass opacities or consolidation predominantly affecting the lower lobes) or an interstitial pattern. although the initial radiographic appearance may be normal in some patients, all our patients had radiological abnormalities within or days of presentation, with increasing extent of involvement and consolidation. radiological opacities progressed from focal to multiple, from unilateral to bilateral, or from focal to bilateral diffuse lung involvement. abnormalities seen on chest x-ray films were the most severe at a mean of . days after onset of fever. compared with patients who had only unilateral focal lung infiltrates, those with bilateral or multifocal pulmonary infiltrates on initial presentation had a higher risk of developing respiratory failure. radiologically, sars may be indistinguishable from bacterial bronchopneumonia or viral infections. therefore, the clinical and radiological characteristics of sars do not appear to be helpful in differentiating sars from other pathogens involved in atypical pneumonias. on the basis of the aforementioned findings, we suggest that atypical pneumonia with lymphopenia, elevation of ldh levels, rapid clinical deterioration, and lack of response to empirical antibiotic therapy must raise the suspicion of sars, especially in the context of suspected exposure. we evaluated the patients' clinical and laboratory data to determine which factors correlated with a need for mechanical ventilation. high serum ldh levels are often associated with other forms of lung tissue damage. the crp level generally correlates with the severity of inflammation. therefore, peak ck and ldh levels might reflect severity of inflammation and damage in the lungs, respectively. not surprisingly, we found that bilateral lung involvement on the initial chest x-ray film and higher serum peak levels of ldh and crp were associated with the need figure . serial radiographic studies of patient , a -year-old nurse from hospital b, who had severe acute respiratory syndrome complicated by acute respiratory distress syndrome. upper left, chest radiograph on admission shows bilateral consolidation and infiltrates involving the right upper lung, right lower lung, and left lower lung. upper middle, chest radiograph on hospital day shows progression of infiltration associated with development of severe hypoxia; mechanical ventilation was needed. upper right, chest radiograph on hospital day shows gradual resolution of consolidation and lung fibrotic infiltrates. lower left, chest radiograph months after disease onset shows near-normal findings, except for mild fibrotic lesion in left lower lung. lower middle and lower right, high-resolution computed tomography performed and months, respectively, after hospital discharge shows ground-glass opacities in the bilateral lower lung and fibrotic infiltrates in the left lower lung. compared with -month scan, the -month scan shows that the area of ground glass was smaller but denser and reveals a fibrotic lesion. at -month follow-up, results of pulmonary function testing showed a total lung capacity of %, forced expiratory volume in second of %, and diffusing capacity of lung for carbon monoxide of %. for mechanical ventilation. our findings are similar to those reported by lee et al, who noted that high peak serum ldh levels were an independent predictor of an adverse outcome. our treatment protocol included an initial regimen of broad-spectrum antibacterial and antiviral therapy. when severe refractory hypoxemia occurred, mechanical ventilation was initiated by using a protective ventilatory strategy, and intravenous methylprednisolone therapy was administered. in our cohort of patients, only patient died. the clinical course of this elderly patient was complicated by ards, superimposed bacterial infections, and multiorgan failure. according to previous reports, old age, diabetes mellitus, hepatitis, and other comorbidities (chronic obstructive pulmonary disease, cancer, or cardiac disease) increase the risk of a poor outcome. our patient who died had risk factors: old age, diabetes mellitus, and congestive heart failure. in previous reports, the overall mortality rate has ranged from . % to . %. , variable mortality rates were associated with variations in age, comorbid disease states, access to medical support care, and the approach to medical management. age appears to affect the mortality rate associated with sars, which has been estimated to be a mean of . % (range, . %- . %) for patients younger than years and . % (range, . %- . %) for patients older than years. five of our pa-tients ( %) developed ards and required mechanical ventilation compared with % and % reported in previous studies. , preliminary results from our treatment regimen, which resulted in a relatively low mortality rate, appear promising but need further evaluation in clinical trials. in this -month follow-up evaluation of patients with sars, of survivors had residual focal, multifocal, or bilateral lung infiltrates on chest hrct. only patient had mildly restrictive pulmonary impairment, and other patients had a decreased diffusing capacity. all our patients who survived ards had abnormal diffusing capacity that was reduced compared with that in our sars patients who did not have ards. orme et al found that approximately % of their ards survivors who did not have sars had reduced diffusing capacity. our study found no evidence of pronounced airway obstruction in sars survivors, an outcome similar to that reported by aggarwal et al and schelling et al. in the latter study, surviving sars patients not experiencing ards had no long-term airflow limitations. in contrast, orme et al reported that % of their ards survivors who did not have sars had longterm airflow obstruction. although the discrepancy of airway obstruction is unclear, it might be due to patient selection bias because some ards survivors had a history of chronic airway disease. in our study, sars-ards survivor ( %) had long-term mildly restrictive pulmonary impairment with reduced tlc. the main reason for impaired pulmonary function might be the same as for all ards survivors, regardless of whether they experienced sars. the reduced tlc and reduced fvc were due to lung fibrosis and neuromuscular weakness, respectively. our findings in sars-ards survivors showed only mild reductions in pulmonary function to months after the acute severe illness, consistent with the natural history of ards survivors in other studies. , sars is highly infectious among close contacts. although the predominant pathology of sars involves the lungs, other organs can be involved with the sars coronavirus. an accurate and rapid diagnostic test will be of great importance for managing this disease in the future. until such a diagnostic test is available, a clear picture of the clinical presentation of sars should help physicians recognize this condition. early recognition, prompt isolation, and appropriate supportive therapy are the keys to reducing the mortality and morbidity associated with this potentially deadly infection. the clinical course of our patients with hospital-acquired sars consisted of atypical pneumonia associated with lymphopenia, elevated serum levels of ldh, rapid clinical progression, and lack of response to empirical antibiotic therapy. substantially increased levels of ldh and crp correlated with severe disease that required mechanical ventilation. in those who needed mechanical ventilatory support, pulmonary function was only mildly decreased to months after onset of sars. available at: www.who .int/csr/don/ _ _ /en. accessibility verified september , . . world health organization. cumulative number of reported cases (sars): from identification of a novel coronavirus in patients with severe acute respiratory syndrome update: outbreak of severe acute respiratory syndrome-worldwide severe acute respiratory syndrome-taiwan a cluster of cases of severe acute respiratory syndrome in hong kong a major outbreak of severe acute respiratory syndrome in hong kong canadian severe acute respiratory syndrome study team. identification of severe acute respiratory syndrome in canada acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome hku/uch sars study group. clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study outbreak of severe acute respiratory syndrome (sars) at amoy gardens, kowloon bay, hong kong: main findings of the investigation clinical features and short-term outcomes of patients with sars in the greater toronto area haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome analysis of static pulmonary mechanics helps to identify functional defects in survivors of acute respiratory distress syndrome pulmonary function and health-related quality of life in a sample of long-term survivors of the acute respiratory distress syndrome the clinical pathology of severe acute respiratory syndrome (sars): a report from china we are indebted to the frontline medical and nursing staff who demonstrated selfless and heroic devotion to duty in the face of this sars outbreak despite the potential threat to their own lives and those of their family members. key: cord- -otf ruvj authors: prohaska, stefanie; schirner, andrea; bashota, albina; körner, andreas; blumenstock, gunnar; haeberle, helene a. title: intravenous immunoglobulin fails to improve ards in patients undergoing ecmo therapy date: - - journal: j intensive care doi: . /s - - - sha: doc_id: cord_uid: otf ruvj background: acute respiratory distress syndrome (ards) is associated with high mortality rates. ards patients suffer from severe hypoxemia, and extracorporeal membrane oxygenation (ecmo) therapy may be necessary to ensure oxygenation. ards has various etiologies, including trauma, ischemia-reperfusion injury or infections of various origins, and the associated immunological responses may vary. to support the immunological response in this patient collective, we used intravenous igm immunoglobulin therapy to enhance the likelihood of pulmonary recovery. methods: ards patients admitted to the intensive care unit (icu) who were placed on ecmo and treated with (ivig group; n = ) or without (control group; n = ) intravenous igm-enriched immunoglobulins for days in the initial stages of ards were analyzed retrospectively. results: the baseline characteristics did not differ between the groups, although the ivig group showed a significantly reduced oxygenation index compared to the control group. we found no differences in the length of icu stay or ventilation parameters. we did not find a significant difference between the groups for the extent of inflammation or for overall survival. conclusion: we conclude that administration of igm-enriched immunoglobulins as an additional therapy did not have a beneficial effect in patients with severe ards requiring ecmo support. trial registration: clinical trials: nct ; retrospectively registered. acute respiratory distress syndrome (ards) is characterized by pulmonary inflammation that can be caused by pulmonary and extrapulmonary origins. sepsis, bacterial pneumonia, polytrauma, and aspiration pneumonia are the most common causes of ards [ ] . predictors of survival include age, the type of underlying medical condition, the severity of pulmonary injury, the presence of extrapulmonary organ dysfunction, and ongoing sepsis [ ] . currently, clinical attempts to rescue ards patients include individualized ventilation and fluid management, adequate infection control, including early application of broad-spectrum anti-infectives, neuromuscular blockade using cisatracurium, sedation strategies, prone positioning, and finally extracorporeal membrane oxygenation (ecmo) to ensure oxygenation [ ] [ ] [ ] . although the incidence of ards is relatively high, with five to eight cases per , european inhabitants and even more in the usa, the various pathomechanisms are only partially understood, resulting in different experimental approaches to understand immune responses during early ards [ ] . one well-described issue is decreased immunoglobulin levels in patients with severe infection [ ] as an element of the immunological response in the initial phase of inflammation in response to sepsis [ ] . therefore, one approach to support critically ill patients is intravenous administration of igm-enriched immunoglobulins since this could potentially decrease the severity of inflammation. although this treatment was omitted in recent sepsis guidelines due to a lack of supporting evidence in high-quality trials [ ] , several studies, including one meta-analysis, describe beneficial effects of immunoglobulins in acute pneumonia induced by drug-resistant bacterial infections [ ] [ ] [ ] . furthermore, several case reports describe beneficial effects of antiviral therapy in combination with intravenous immunoglobulin therapy in immune-compromised patients [ ] [ ] [ ] . based on these data, we treated patients with ards requiring ecmo therapy with igm-enriched immunoglobulins immediately after intensive care unit (icu) admission. the objective of this study was to investigate whether intravenous immunoglobulin administration could improve the clinical course of ards in patients treated with ecmo. therefore, mortality, the duration of ecmo therapy, the incidence of renal replacement therapy, the duration of vasopressor and anti-infective therapy, length of stay in the icu, and length of stay in the hospital were analyzed retrospectively in ards patients requiring ecmo therapy. the study was approved by the local research ethics committee of the university hospital and the eberhard-karls university tübingen, germany. patients with severe ards treated with ecmo therapy between january and january at our institution were analyzed retrospectively. in all patients, ecmo therapy was required due to hypoxia and/or increased pulmonary resistance precluding protective lung ventilation. ecmo therapy was performed according to the guidelines of the extracorporeal life support organization (elso) using ila-active systems (novalung, stolberg, germany [ ] . fifty-seven patients were analyzed. twenty-eight patients were treated with igm-enriched immunoglobulins (pentaglobin®; biotest; dreieich, germany) (ivic-group). pentaglobin is an igm-enriched polyvalent immunoglobulin preparation derived from a plasma pool. it contains mg of igm, mg of iga, and mg of igg ( % igg , % igg , % igg , and % igg ) per millilitre. the indication for igm-enriched immunoglobulin (ivig) treatment was determined at the discretion of the treating intensivist. ivig was applied if a viral infection or an infection due to multi-resistant gram-negative bacteria (mrgn) was suspected. ivig dosing was performed according to the instruction of the manufacturer: . ml/kg/h (up to ml) as the initial dose, followed by . ml/kg/h for h until a total dose of mg/kg was achieved. twenty-nine patients did not receive immunoglobulins (control group). vasopressors (norepinephrine; arterenol® sanofi-aventis; germany) were used after volume resuscitation according to the sepsis guideline ( ) . renal replacement therapy was performed with citrate anticoagulation (multifiltrate, fresenius medical care, bad homburg v.d.h. germany) in patients with acute renal failure. data were retrospectively extracted from an ardsspecific database at our institution. since the electronic patient management system was changed during this time frame, not all required data were available for all ards patients. mrsa and vre screening was performed routinely in all patients admitted to the icu. to identify causal infections, bronchoalveolar lavage (bal) samples, blood cultures, urinary samples, and perioperative samples were analyzed. in patients at risk, pcr for atypical pathogens was also performed in bal samples. infection was defined as > colony-forming units (cfu) in bal and/or urinary cultures. for blood cultures, any replicate of bacterial growth was defined as infection. during flu season, influenza infection was detected by pcr. bal samples were also analyzed for other viral pathogens, such as cytomegalovirus (cmv) and herpes simplex virus (hsv). positive findings for these viruses were confirmed by cell cultures. patients with unknown pathogens and immune suppression were additionally screened for other pathogens. anti-infective therapy was applied according to the local guideline considering local resistance patterns. categorical data are reported as numbers and percentages, and continuous data are summarized with the median and range (i.e., the minimum and maximum values) unless otherwise indicated. to compare categorical variables or outcomes, such as the occurrence of infection or in-hospital death, between the ivig group (n = patients) and the control group, which included patients who did not receive ivig therapy, the chisquared test was used. for inter-group comparisons of continuous data, the two-tailed two-sample t test was generally performed. if the original data exhibited a lognormal distribution, e.g., icu length of stay (los), then raw data were log-transformed prior to analysis with the t test. a p value < . was assumed to indicate a statistically significant difference between the groups. the data analysis was performed using jmp® . statistical software (sas institute inc., cary, nc, usa). a total of patients with ards requiring ecmo therapy between and were analyzed retrospectively. twenty-eight patients were treated with igm-enriched immunoglobulins (ivig) for days according to the manufacturer's instruction (ivig group), and patients did not receive ivig therapy (control group). no adverse events were reported after ivig application. the median age of both groups was years, ranging from to years in the control group and from to years in the ivig group. the median simplified acute physiology score (saps) and acute physiology and chronic health evaluation (apache) score were comparable between both groups ( table ). the median apache score in the ivig group was vs. in the control group. in % ( / ) of the ivigtreated patients and % ( / ) of the control patients, the apache score was equal to or greater than . regarding preexisting disease, diabetes mellitus, cardiac disease, immune suppression, and malignancy were more common in the ivig group (table ) . five patients in the control group suffered ards of extrapulmonary origin (three patients with pancreatitis and two with polytrauma). the initial pao /fio ratio in the ivig group was significantly lower than that in the control group (ivig, median vs control, ; t test, log-transformed data, p = . ). seventy-five percent of the ivig-treated patients had severe ards, % had moderate ards, and no patient showed mild ards. in the control group, % of patients had severe ards, % had moderate ards, and % had mild ards. the ecmo duration was shorter in the control group ( - days; median days) compared to that in the ivig group ( - days; median days) and could be reduced earlier in the control group (median days) than in the ivig group (median days). the duration of ventilator support was longer in the ivig group ( - h; median h) compared to that in the control group ( - h; median h; t test, logtransformed data, p = . ). five patients in the control group and three patients in the ivig group were extubated before ecmo was discontinued. ten patients in the control group and seven patients in the ivig group suffered anemia due to bleeding complications, including cerebral hemorrhage (control: n = ; ivig: n = ) ( table ) . all patients suffered from septic shock requiring vasopressor therapy (control, - days vs. ivig, - days). renal replacement therapy was more often required in the control group ( % vs. %; p = . ; pearson's chi-squared test). hepatobiliary dysfunction was comparable between both groups (control, %; ivig, %). in % of the control patients and % of the ivig-treated patients, one or more pathogens could be identified as the cause of pulmonary inflammation. in ( %) patients in the control group, bacterial pathogens such as legionella (n = ; %), streptococcus pneumoniae (n = ; %), pneumocystis jirovecii (n = ; %), and e. coli (n = ; %) were identified in bal samples. none of the control patients showed multidrug-resistant bacteria in any samples. in % ( of ) of the control patients, a viral pathogen was detected in bal samples: influenza (n = ; %) and herpes virus (n = ; %). herpes virus infection included hsv (n = ; %) and cmv (n = ; %). herpes viral infection was confirmed by cell-based culture. in five of the control patients, fungal infection was diagnosed via blood culture (n = ), abdominal sample (n = ), and bal (aspergillus, n = ). in nine control patients, no causal pathogen could be identified ( %). two of the ivig patients were infected with resistant bacteria ( mrgn stenotrophomonas maltophilia and mrsa). in ivig patients, bacterial pathogens such as legionella (n = ; %), streptococcus pneumoniae (n = ; %), pneumocystis jirovecii (n = ; %), and mycoplasma (n = ) were identified in bal samples. viral infections were more frequent in the ivig group (p = . ; pearson's chi-squared test), especially influenza infection (p < . ). in more than half of the ivig patients, viral pneumonia was diagnosed according to the results of bal samples, radiological findings, and clinical symptoms. one or more of the following viruses could be detected in bal samples: influenza (n = ; %) and herpes virus (n = ; %). herpes virus infection included hsv (n = ; %), cmv (n = ; %), and hhv (in bal and blood; n = ). in of the ivig-treated patients, fungal infection was diagnosed in urinary tract (n = ) and abdominal samples (n = ). in addition, one patient suffered aspergillosis pneumonia. in three ivigpatients, no causal pathogen could be identified ( %). the duration of anti-infective treatment was significantly longer in the ivig group than that in the control group (control, median days; - days; ivig, median days; - days; t test, log-transformed data, p = . ). six patients in the control group and four patients in the ivig group underwent anti-infective treatment before admission to the icu. excluding these patients, the duration of anti-infective therapy relative to los in the icu was not significantly different between the groups (control median, % fraction of los icu; ivig, % of los icu). patients treated with ivig stayed for a median of . days in the icu ( to days) and . days in the fig. ). forty-three percent ( out of ) of these patients died; three patients died within the first week due to cerebral hemorrhage (n = ) or multiorgan failure due to septic shock (n = ). the control patients spent a median of days in the icu ( to days) and days in the hospital ( to days); % ( out of ) of these patients died. five patients died during within first week due to cerebral hemorrhage, heart failure, subarachnoidal bleeding (polytrauma), and hypoxic brain injury h after admission, and others died of multiorgan failure due to acute pancreatitis. lymphocyte levels were analyzed retrospectively when available. initially after admission, lymphocyte levels were not different between the groups (control alive . % ± . ; control dead . % ± . ; ivig alive . % ± . ; ivig dead . % ± . ). however, lymphocyte levels were higher in survivors compared to those in non-survivors (fig. ) . the increase in lymphocytes was more prominent in survivors compared to that in non-survivors (control alive . ± . ; ivig alive . ± . ; control dead . ± . ; ivig dead . ± . ; fig. ). in addition, in patients treated with ivig, this increase during treatment was more prominent than that in the control group in the first days (fig. ). since we did not evaluate differential blood counts routinely, limited data were available for determining significant difference. the purpose of this analysis was to systematically investigate the potential effect of igm-enriched immunoglobulins on the outcomes of ards patients requiring ecmo therapy. we analyzed patients; patients were treated with igm-enriched ivig, and patients did not receive ivig therapy. of all patients suffering from septic shock, % of the ivig-treated patients and % of the control patients had severe ards of various origins. however, although the ivig group had a lower pao /fio ratio and required longer ventilation support, longer vasopressor therapy, and longer anti-infective therapy and included mrgn-infected patients, outcome parameters such as los in the icu, los in the hospital, and mortality were not significantly different between the groups. in several studies, hypogammaglobulinemia and overexpression of genes encoding immunoglobulin segments were identified in patients with septic shock [ , , ] . therefore, ivig treatment could be a logical requirement in these patients. we included ivig therapy in our ards patients based on these considerations, although we did not measure immunoglobulin levels before treatment. indeed, in a recent retrospective analysis of patients, high igg levels were associated with high mortality in sepsis patients [ ] . pcr analysis showed an early molecular response to igm in the blood of patients with sepsis [ ] . igm levels remain low in non-surviving sepsis patients, whereas igm levels increase transiently in surviving patients [ ] . single studies and metaanalyses have shown beneficial effects of ivig therapy in patients with sepsis [ ] [ ] [ ] . however, ivig treatment remains controversial. randomized studies have not shown any beneficial effect of this intervention in patients with sepsis or sepsis-associated conditions [ ] . therefore, ivig therapy is not currently recommended in the latest sepsis guidelines [ ] . immunoglobulins interact with cd t-lymphocytes during bacterial eradication. in severe sepsis, b and t cells are depleted due to apoptosis [ ] . since our analysis is retrospective, we could not measure hla-dr expression or cytokine profiles in these patients. however, we found a trend of increased lymphocytes in non-survivors compared to survivors, which may reflect why we did not see any beneficial effect of ivig therapy. although immunoglobulins may play an important role in the innate immune response during ards, nonspecific immunoglobulins may not be as effective in a lymphopenia environment. lymphopenia has been described in ards patients and in animal models after viral infection or mycoplasma infection and affects all lymphoid tissue [ ] [ ] [ ] . however, in our small group of [ , ] , but whether this variability in response is due to genetic alterations [ ] , immune evasion by bacteria [ ] , or different stages of sepsis is unknown. this study has some limitations. it is a retrospective analysis of a limited number of ards patients. since we changed our ecmo system during the study period, we only included patients treated with the one system to exclude any impact of system differences. furthermore, since ivig was ordered by a physician primarily when a viral infection or mrgn infection was suspected, the ivig group included more patients with these infections. however, this may reflect true clinical circumstances in that the cause of disease is typically not determined at admission. ards is a multifactorial disease with a heterogeneous pathogenesis and variable timing and clinical presentations. therefore, one specific therapy is unlikely to improve outcomes. rather than excluding single therapeutic options, identifying patients' risk factors and the individual ards stage may be more important for successful outcomes. we report here in our retrospective analysis that intravenous igm administration in the initial stages of severe ards did not improve overall outcomes or the severity of disease. the acute respiratory distress syndrome the alien study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation the standard of care of patients with ards: ventilatory settings and rescue therapies for refractory hypoxemia neuromuscular blockers in early acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome transcriptomic evidence of impaired immunoglobulin g production in fatal septic shock immunologic alterations and the pathogenesis of organ failure in the icu treatment of neonatal sepsis with intravenous immune globulin protective effects of intravenous immunoglobulin and antimicrobial agents on acute pneumonia in leukopenic mice iv immunoglobulin for acute lung injury and bacteremia in pseudomonas aeruginosa pneumonia mantaring jb rd. intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin first report of severe parainfluenza virus b and rhinovirus c coinfection in a liver transplant recipient treated with immunoglobulin the human metapneumovirus: a case series and review of the literature early levels in blood of immunoglobulin m and natural killer cells predict outcome in nonseptic critically ill patients assessment of plasmatic immunoglobulin g, a and m levels in septic shock patients serum igg levels and mortality in patients with severe sepsis and septic shock : the sbits data quantification of igm molecular response by droplet digital pcr as a potential tool for the early diagnosis of sepsis kinetics of circulating immunoglobulin m in sepsis: relationship with final outcome use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock a case of acute respiratory distress syndrome associated with novel h n treated with intravenous immunoglobulin g early therapy with igm-enriched polyclonal immunoglobulin in patients with septic shock surviving sepsis campaign: international guidelines for management of sepsis and septic shock sepsis-induced apoptosis causes progressive profound depletion of b and cd + t lymphocytes in humans clinical diagnosis of pandemic a(h n ) influenza in children with negative rapid influenza diagnostic test by lymphopenia and lower c-reactive protein levels. influenza other respir viruses clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza a (h n ) virus isolated from humans subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy the role of genetics and antibodies in sepsis immunoglobulins and their receptors, and subversion of their protective roles by bacterial pathogens none. this work was supported by a grant of the deutsche forschungsgemeinschaft to peter rosenberger dfg-ro / - . the datasets obtained and/or analyzed during the current study are available from the corresponding author upon reasonable request. authors' contributions sp prepared the manuscript and analyzed the data. as and ab are responsible for the data acquisition. ak is responsible for the data acquisition and analysis. gb is responsible for the data analysis. hah is accountable for all the aspects of the work and for ensuring that the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. all authors read and approved the final manuscript. the ethics committee of the university hospital tuebingen (eberhard-karls universität tübingen; ethik-kommission; gartenstraße ; tübingen, germany) approved the study. the project number is / /bo . informed consent was not required from the patients involved into this retrospective analysis. this proceeding was approved by the local ethics committee (project number / /bo ) of eberhard karls university tuebingen since extraction of pseudonymous medical records provides structured data and therefore legally permits evaluation of the data for research. not applicable. the authors declare that they have no competing interests.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- -a as bx authors: combes, alain; schmidt, matthieu; hodgson, carol l.; fan, eddy; ferguson, niall d.; fraser, john f.; jaber, samir; pesenti, antonio; ranieri, marco; rowan, kathryn; shekar, kiran; slutsky, arthur s.; brodie, daniel title: extracorporeal life support for adults with acute respiratory distress syndrome date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: a as bx extracorporeal life support (ecls) can support gas exchange in patients with the acute respiratory distress syndrome (ards). during ecls, venous blood is drained from a central vein via a cannula, pumped through a semipermeable membrane that permits diffusion of oxygen and carbon dioxide, and returned via a cannula to a central vein. two related forms of ecls are used. venovenous extracorporeal membrane oxygenation (ecmo), which uses high blood flow rates to both oxygenate the blood and remove carbon dioxide, may be considered in patients with severe ards whose oxygenation or ventilation cannot be maintained adequately with best practice conventional mechanical ventilation and adjunctive therapies, including prone positioning. extracorporeal carbon dioxide removal (ecco( )r) uses lower blood flow rates through smaller cannulae and provides substantial co( ) elimination (~ – % of total co( ) production), albeit with marginal improvement in oxygenation. the rationale for using ecco( )r in ards is to facilitate lung-protective ventilation by allowing a reduction of tidal volume, respiratory rate, plateau pressure, driving pressure and mechanical power delivered by the mechanical ventilator. this narrative review summarizes physiological concepts related to ecls, as well as the rationale and evidence supporting ecmo and ecco( )r for the treatment of ards. it also reviews complications, limitations, and the ethical dilemmas that can arise in treating patients with ecls. finally, it discusses future key research questions and challenges for this technology. in a prospective international study conducted in icus across countries, acute respiratory distress syndrome (ards) represented . % of total intensive care unit (icu) admissions [ ] . over the past two decades, inhospital mortality from ards has remained very high at approximately % [ ] . despite strong experimental and clinical evidence [ ] that lung protection improves outcomes in ards, it remains underutilized [ ] . with the ultimate goal of protecting the injured lung, and improving oxygenation, there has been increasing adoption of extracorporeal life support (ecls) in adult patients with very severe ards. advances in supportive care, innovations in technologies and insights from recent clinical trials have contributed to improved outcomes and a renewed interest in the scope and use of ecls [ ] [ ] [ ] . this narrative review provides a summary of some physiological concepts related to ecls, as well as the rationale and evidence supporting the two main forms of ecls for the treatment of ards: extracorporeal membrane oxygenation (ecmo) and extracorporeal co removal (ecco r). we also highlight evidence on complications, limitations, and the ethical dilemmas that can arise in treating patients with ecls. finally, we discuss future key research questions and challenges for this technology. membrane oxygenators are artificial "organs" designed to replace the lungs' gas exchange function by supplying oxygen and removing carbon dioxide (co ) from blood. full-flow venovenous ecmo (vv-ecmo), bicaval dual-lumen jugular vv-ecmo, and ecco r are modalities of ecls for severe ards (fig. ) . during full-flow vv-ecmo venous blood is typically withdrawn from the inferior vena cava through the femoral vein, and then reinjected into the jugular vein (v f -v j ecmo) or the contralateral femoral vein (v f -v f ecmo) after passing through the membrane oxygenator [ ] . the high blood flow (commonly - l/min) and diffusion of gases between blood and the "sweep gas" flowing through the membrane lung's fibers provide oxygen and remove carbon dioxide directly from blood, hence allowing lower intensity mechanical ventilation. bicaval, dual-lumen jugular vv-ecmo was initially considered promising given the single jugular cannulation. however, ecmo blood flow rates (q ecmo ) are limited by the diameter of the shared lumen for drainage, and its effectiveness is very dependent on optimal placement of the reinfusion port so that oxygenated blood is directed toward the tricuspid valve, limiting its use in some patients during the acute phase of ards. in a recent large international report, it was used in only % of patients as the primary ecls approach [ ] . this review provides a summary of physiological concepts related to ecls, as well as the rationale and evidence supporting the two main forms of ecls for the treatment of ards: extracorporeal membrane oxygenation (ecmo) and extracorporeal co removal (ecco r). it also highlight evidence on complications, limitations, the ethical dilemmas in treating patients with ecls and discusses future key research questions and challenges for this technology. fig. three different modalities of ecls for acute respiratory distress syndrome. a femoro-jugular venovenous extracorporeal membrane oxygenation (vv-ecmo) which enables full oxygenation and carbon dioxide removal in the acute phase of ards. typical mechanical ventilation settings (eolia settings) aim to further protect the lung by reducing vt, rr, and ∆p; b dual-lumen jugular vv-ecmo is an alternative cannulation strategy; c extra-corporeal co removal, which may facilitate lung-protective ventilation by allowing a reduction of vt, pplat, rr, ∆p and mechanical power (supernova pilot settings) by ensuring partial carbon dioxide removal with marginal oxygenation in mild-to-moderate ards. vcv volumecontrolled ventilation, peep positive end-expiratory pressure, vt tidal volume, pplat plateau pressure, bipap/aprv biphasic positive airway pressure/ airway pressure release ventilation, rr respiratory rate, ∆p driving pressure, fr french, ards acute respiratory distress syndrome, ecls extracorporeal life support, mv mechanical ventilation, fdo fraction on oxygen in the sweep gas, mo, membrane oxygenator, qecmo (q e ) ecmo flow in l/min. major changes between the three settings are highlighted in bold font. a modified eolia settings with a set rr lower than in eolia. decreasing respiratory rate (< - breaths/min) to reduce mechanical power seems desirable, although it may be achieved in most ards patients only with deep sedation and neuromuscular blockade understanding the physiological determinants of gas exchange is crucial for optimal application of ecmo. the oxygen content of blood is dependent on haemoglobin level, the partial pressure of oxygen (po ), the oxyhemoglobin dissociation curve, and to a lesser extent, the dissolved oxygen. this has implications for the minimal blood flow required to provide full oxygenation (if required) [ ] , which is on the order of + liters per minute. the ability to oxygenate blood largely depends on the size and properties of the membrane oxygenator, q ecmo , and the difference in po between the blood flowing into the oxygenator and the po of the gas delivered to the membrane lung (sweep gas), typically oxygen or a blend of oxygen and air. the linear relationship between q ecmo and oxygen transfer favors the use of large drainage cannulas ( ) ( ) ( ) ( ) ( ) ( ) ( ) to provide full oxygenation support. the drained venous blood oxygen saturation (i.e., pre-oxygenator oxygen saturation), is the second major component determining oxygen transfer during ecmo. it is affected by the recirculation (i.e. reinfused oxygenated blood which is withdrawn through the drainage cannula before it can circulate through the lung). recirculation can be minimized either by femoral-jugular cannulation with a sufficient distance between the two tips of the cannulas, or using a properly positioned jugular dual-lumen cannula [ ] . because the (well-oxygenated) blood returned to the right atrium from the membrane oxygenator mixes with the remaining native venous return, an increase in cardiac output at constant ecmo flow rates will result in decreased systemic arterial oxygenation when native lung gas exchange is sufficiently impaired. in a physiological study performed in ten severe ards patients receiving v f -v j ecmo, q ecmo /cardiac output ratio ≥ % was associated with adequate blood oxygenation and oxygen delivery [ ] . other factors that affect systemic oxygenation include the complex interplay between intrapulmonary shunt, oxygen fraction to the native lung, oxygen fraction to the membrane lung, and total oxygen consumption [ ] . at any given blood flow, carbon dioxide removal is more efficient than oxygenation. at physiological levels, the carbon dioxide content of a given volume of blood is substantially higher than the oxygen content, and thus, for a given ecmo flow rate a greater percent of the patient's co production can be removed compared with the percentage of the oxygen consumption that can be provided [ , ] . as well, co is more soluble than o , allowing it to diffuse across the membrane circuit with greater efficiency. to understand the performance of available ecco r devices, it is important to understand that co removal will increase with increases in co blood content, the partial pressure of venous co (pvco ), artificial lung surface area, as well as increases in sweep gas and blood flow through the membrane lung, although with ceiling effects for both. blood flow rates of - l per minute (l/min) may be sufficient to fully remove the entire co production of most patients, but insufficient to provide the patient's full o consumption. for a given membrane lung size and blood flow rate, co removal will be increased with increasing sweep gas flow rate up to ~ - l/min [ ] ; a high pco will increase the gradient for diffusion of co out of the membrane; and artificial blood acidification can increase the amount of co available to the membrane [ , ] . historically, ecmo was restricted to patients dying from refractory hypoxemia [ , ] ; however, recently it has become the standard of care in experienced icus for patients with very severe ards [ ] . beyond its ability to rescue patients with very severe gas exchange abnormalities not responding to standard treatment, the ecmo to rescue lung injury in severe ards (eolia) trial strongly suggested that the main benefit of ecmo is through ameliorating ventilator-induced lung injury (vili) [ ] . patients who were enrolled in the eolia trial due to severe respiratory acidosis (arterial ph < . with paco ≥ mmhg for > h), rather than solely due to severe hypoxemia, appeared to benefit most [ ] , likely due to a reduction in ventilator-induced lung injury (vili) secondary to decreased tidal volume (vt), respiratory rate (rr), plateau pressure (pplat), driving pressure (∆p), and mechanical power [ , , ] . ecmo has a number of beneficial effects. minimizing hypoxemia decreases tissue hypoxia, which may reduce organ dysfunction including neurocognitive sequelae [ ] . ecmo decreases respiratory acidosis and right ventricular afterload and, therefore increase cardiac output [ ] . moreover, ecmo may reduce diaghragmatic myotrauma, by improving blood gases, hence decreasing respiratory drive. keeping patients ambulatory when ecls is used as a bridge to lung transplantation has been reported, but it is as yet unclear whether such a strategy is beneficial in ards patients [ ] . if this strategy is applied, then close monitoring of respiratory drive [ ] appears desirable to prevent additional lung injury due to patient respiratory effort [ ] . ideally, ecmo should be used in patients meeting eolia criteria (tables and ) after proven conventional management (including lung protective mechanical ventilation [ ] and prone positioning [ ] ) for severe ards have been applied and failed [ , ] . less frequently, rescue ecmo may be deployed when a patient is too unstable for prone positioning, or when this is the only way to facilitate safe transport from a non-expert centre that is unable to apply evidence-based conventional practices [ ] . lastly, employing ecmo when severe right heart failure, or other severe decompensation occurs, so-called salvage ecmo (referred to as "rescue" in eolia) should be avoided, where possible, as it is associated with higher mortality [ ] . when ecls is applied at relatively low blood flow (e.g., - ml/min) it can provide substantial co elimination (~ - % of total co production), albeit with marginal improvement in oxygenation. under these conditions, the technique is referred to as extra-corporeal co removal (ecco r). the rationale for using ecco r in ards is to facilitate lung-protective ventilation by allowing a reduction of vt, pplat, rr, ∆p and mechanical power [ ] ; the extent of lung protection depends on the volume of co that can be removed by the device [ ] . there is currently limited evidence to support the use of ecco r for ards outside the research setting [ , ] . first successfully deployed in a patient with ards in , ecmo gained momentum due to two unrelated events in : ( ) the influenza a(h n ) pandemic, in which national observational cohorts from france [ ] , italy [ ] , united kingdom (uk) [ ] , australia and new zealand [ ] , reported unexpected low mortality ( - %) in severely ill ards patients treated with ecmo; and, ( ) publication in of the cesar trial conducted in the uk [ ] , which evaluated a strategy of transfer to a single-center which had ecmo capability versus a strategy in which patients were treated conventionally at designated treatment centers ( table ). the primary endpoint (composite of mortality or severe disability six months after randomization) was lower for the patients randomized to the ecmo group ( % vs. %, p = . ). however, the study had numerous methodological issues. for example, many patients randomized to the ecmo arm did not receive ecmo (by design) and lung protective ventilation was not mandated in the control group. the more recent multicenter, international eolia [ ] trial has helped to define the role and safety of ecmo in managing severe ards, despite the fact that it was not "traditionally positive" [ ] . patients who fulfilled inclusion criteria ( table ) were randomized to standard of care, including protocolized mechanical ventilation (n = ), or to ecmo (n = ) with protocolized reduction of ventilator pressures, volumes, and respiratory rates. ninety percent of standard care patients and % of ecmo patiens received a trial of prone positioning at some time during their course. cross-over (i.e., receiving ecmo in the standard care group) was restricted to patients who were profoundly hypoxemic or hemodynamically unstable. the trial was stopped early for futility; there was an non-significant % absolute difference in -day mortality (p = . ). ecmo-treated patients had a significant reduction of cardiac failure, renal failure, and need for dialysis. there was a similar incidence of hemorrhagic stroke in the two groups. following the publication of eolia, goligher et al. re-analysed the results of the trial using a bayesian approach, [ ] which demonstrated a high likelihood of a table proposed indications and contraindications to ecmo for ards a after proven conventional management (including lung protective mechanical ventilation, prone positioning and possibly neuromuscular blockade) for severe ards have been applied and failed. less frequently, rescue ecmo may be deployed when a patient is too unstable for prone positioning, or when this is the only way to facilitate safe transport from a non-expert centre that is unable to apply evidence-based conventional practices b with respiratory rate increased to breaths per minute and mechanical ventilation settings adjusted to keep a plateau airway pressure of ≤ cm of water [ ] . patients randomised to ecmo had more days alive out of the icu and without respiratory, cardiovascular, renal and neurological failure. the eolia trial [ ] , the post hoc bayesian analysis [ ] , and systematic reviews and meta-analysis [ , ] all consistently supported the use of venovenous ecmo in adults with severe ards treated in expert centers. as stated in the editorial addressing the bayesian analysis, it is no longer a question of "does ecmo work? because that question appears to be answered but by how much does ecmo work, in whom, and at what cost?" [ ] . ecmo has played an important role during previous respiratory viral outbreaks [ ] . in a non-randomized study, transfer to an ecmo center was associated with lower hospital mortality compared with matched non-ecmo-referred patients [ ] . similarly, a retrospective chart review of middle east respiratory syndrome coronavirus (mers-cov) patients with refractory respiratory failure reported a lower in-hospital mortality rate in patients who received ecmo compared with those who received conventional oxygen therapy [ ] . due to resource and human constraints, ecmo cannot easily be employed extensively in such outbreaks. widespread application of proven conventional management approaches (i.e., protective mechanical ventilation, and prone positioning) before ecmo, and strict selection of patients most likely to benefit [ , ] are all key since any health system could be rapidly overwhelmed if large numbers of patients require ecmo. a recent study reported results on patients under the age of who fulfilled eolia trial criteria and received ecmo for very severe covid- -related ards [ ] . contrary to results early in the pandemic suggesting dismal outcomes for ecmo-treated covid- patients [ ] , the estimated probability of death days post-ecmo initiation was % ( % ci - %) [ ] . these results were similar to those from the eolia trial ( % at day ) [ ] and from the large prospective lifegard registry ( % at day ) [ ] . a large (n = ) registry study of ecmo for covid- involving predominantly respiratory failure, yielded an estimated cumulative incidence of in-hospital mortality of . % ( % ci . - . ) at days after initiation of ecmo, offering provisional support for the use of ecmo in highly selected patients with covid- [ ] . a very recent study identified a subgroup of patients with covid- -related ards characterised by low static compliance of the respiratory system and high d-dimer concentration that have a markedly increased mortality compared with other patients ( % vs. %) [ ] . these patients may potentially be considered for wider use of ecmo. investigation of the potential benefits of ultra-protective ventilation [ ] have led to renewed interest in ecco r. the technique has markedly improved in recent years [ ] , using more biocompatible circuits [ , ] , duallumen heparin-coated catheters with a diameter closer to dialysis catheters than to ecmo cannulas [ ] , and ultrasonography-guided catheter insertion. ecco r allows for a reduction in vt, pplat, ∆p [ ] , mean minute ventilation [ ] , and therefore enhances protective or ultra-protective ventilation [ ] . an increase in positive end-expiratory pressure (peep) to counteract derecruitment, induced by the tidal volume reduction [ ] , appears desirable. in this context, ecco r may be associated with a significant reduction of systemic and pulmonary inflammatory mediators [ ] . the strategy of ultraprotective lung ventilation with extracorporeal co removal (supernova) pilot study included patients with moderate-to-severe ards in icus. ecco r allowed a significant decrease in mechanical power with reductions of pplat ( to cmh o), vt ( to ml/kg), rr ( to breaths/min), and minute ventilation ( to l/min) [ ] . despite the significant reduction of minute ventilation, ph was maintained > . , and the increase in paco was < % from baseline. however, this strategy may not benefit all patients equally [ , ] , as the lung-protective benefits of ecco r increase with higher alveolar dead space fraction, lower respiratory system compliance, and higher device performance [ ] . therefore, these patients [ ] should preferentially be enrolled in randomized controlled trials, and worsening hypoxemia, reported in up to % of patients [ ] should be addressed. the hypoxemia can be secondary to a decreased mean airway pressure, and a lower ventilation-perfusion ratio, or due to a lower partial pressure of alveolar oxygen due to a decreased lung respiratory quotient and hypoventilation in the native lung [ ] . the co removal performance and device-related adverse events differ across available ecco r devices [ ] . the supernova pilot study used three different devices [ ] . a lower incidence of membrane clotting was reported with two higher flow ( - ml/min) devices ( %), with significantly higher rates of adverse events with the low blood flow device ( - ml/ min), despite similar anticoagulation regimens [ , ] . although theoretically very appealing, the impact on outcomes of a strategy combining ultra-protective ventilation and ecco r is unknown, as only physiological proof-of-concept and feasibility studies are available; randomized controlled trials are ongoing ( table ) . interestingly, the xtravent study, which used a pumpless arterio-venous ecco r device in moderate ards, observed similar mortality between the intervention group ( patients ventilated with ml/kg predicted body weight (pbw) and ecco r) and the control group ( patients ventilated with ml/kg pbw) [ ] . of note, in a post hoc analysis, the treated subgroup with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao /fio ) < mmhg achieved earlier weaning than the controls. the main goals of ecmo are to provide adequate gas exchanges while minimizing vili. in the acute phase of ards, using a large venous drainage cannula-a prerequisite for high q ecmo (> l/min)-enables adequate oxygenation while applying "ultra-protective lung ventilation". how much the intensity of mechanical ventilation should be decreased, and whether or not we should maintain the lungs open to avoid complete lung collapse, are still a matter of debate [ , ] . some degree of ventilation, while maintaining peep ≥ cmh o, during ecmo improved survival in a retrospective study [ ] . on the other hand, a larger reduction in mechanical ventilation intensity through lower driving pressure [ ] was associated with lower mortality and near-apneic ventilation resulted in fewer histological lesions of lung injury in an animal model [ ] . similarly, decreasing respiratory rate (< - breaths/min) to reduce mechanical power seems desirable [ , ] , although it may be achieved in most ards patients only with deep sedation and neuromuscular blockade. this strategy may be less appropriate as the patients' course progresses as it may delay physical and cognitive rehabilitation. future trials should assess these strategies in severe ards patients during ecmo. several techniques have been used to optimize lung recruitment while minimizing lung injury during ecmo. first, individualization of peep during ecmo using transpulmonary pressure measurements [ ] or electrical impedance tomography (eit) [ ] appear promising. second, some centers currently perform prone positioning during ecmo with a goal of reducing vili [ , ] . two recent retrospective series of severe ards patients showed that prone positioning, while on-ecmo demonstrated higher ecmo-weaning and survival rates [ , ] . however, randomized controlled trials of prone positioning during ecmo are needed before recommending this practice routinely. lastly, the use of pressure-controlled ventilation [ ] may allow for easy detection of patient recovery by observing increases in vt during ecmo. when the patient is stabilized, preventing diaphragm atrophy by introducing spontaneous breathing activity may be desirable. however, even during this rehabilitation phase of severe ards, the respiratory drive of the patient may still be (too) high, which may be controlled by increasing sweep gas flow which lowers paco [ ] ; the efficacy of this maneuver may be assessed by measurement of patient effort and work of breathing. ventilation strategies on ecmo integrating repiratory drive monitoring deserve investigation. patients receiving ecmo may also benefit from less sedation and early rehabilitation, and retrospective studies have found that rehabilitation, including mobilization, during ecmo was feasible and safe, even in patients with very high severity of illness [ , ] . in some circumstances, severe hypoxemia persits under vv-ecmo. this situation requires a multi-step approach [ ] that should begin with a complete circuit check, followed by ensuring adequate positiniong of cannulas to minimize blood recirculation and optimize the ratio of ecmo blood flow to cardiac output. moderate hypothermia to decrease tissue oxygen utilization (with a depressant effect on cardiac output). short-acting beta-blockers have been used for refractory hypoxemia to decrease the extracorporeal blood flow-to-systemic blood flow ratio (q e :q s ) [ ] , which will improve arterial oxygenation but will simultaneously decrease cardiac output, and therefore will have an overall variable effect on tissue oxygen delivery and so should be approached with caution if oxygen delivery is not directly measured, especially given the very limited data supporting this approach. packed red blood cells may be transfused with the idea of maximizing oxygen delivery. however, the optimal transfusion threshold for these patients has not been established and transfusion is associated with adverse outcomes in the setting of ards [ ] . prone positioning (pp) during ecmo may also be effective by increasing the proportion of poorly-aerated areas in dependent lung regions [ ] . further data are needed to better understand the risk-tobenefit ratio of this intervention. ecmo weaning, which is typically performed before weaning from mechanical ventilation [ ] , should be tested when native lung function has sufficiently recovered allowing adequate oxygenation and safe (or protective) mechanical ventilation settings (e.g., ventilator fio ≤ %, sweep gas flow < l/min, and vt ≥ . ml/ kg pbw with pplat ≤ cmh o or ∆p ≤ cmh o) and involves regular trials with the sweep gas turned off. a detailed ecmo weaning algorithm is proposed in fig. . based on eolia, current weaning success criteria for safe decannulation from ecmo [ ] are: pao ≥ mmhg, sao ≥ %, with fio ≤ %; paco ≤ mmhg or ph ≥ . , with respiratory rate ≤ /min; pplat ≤ cmh o; and no signs of acute cor pulmonale. modern management of vv-ecmo with heparincoated surfaces and high q ecmo have allowed for a substantial decrease in systemic anticoagulation [ ] . unfractionated heparin (target aptt - s) or anti-xa activity ( . - . iu/ml) are commonly used [ ] . however, these may need to be revised upwards in high inflammatory syndromes or infections associated with vascular injury, such as covid- -related ards, although the data on this are not clear [ ] . close daily monitoring to reduce ecls-related complications is mandatory, and requires intensive education and training (fig. ) . although relatively infrequent in the eolia trial [ ] , intracranial hemorrhage is associated with poor outcomes. the rapidity with which co is reduced after ecls initiation has been implicated in development of neurological complications and the sweep gas flow through the oxygenator should be adjusted to avoid a drop in paco > mm hg/h over the first -h of ecmo in most patients [ , ] . similarly, interactions between the blood, the pump, and the artificial surfaces of the circuit and membrane generate blood trauma and activate coagulation and fibrinolysis pathways associated with increased inflammatory responses. daily monitoring of platelet count, fibrinogen, anticoagulation levels and other parameters are aimed at recognizing the onset of complications such as clotting, bleeding and hemolysis, and the need to change portions of the circuit. in addition, thrombosis and hemolysis appear to be more frequent with low-flow ecmo or ecco r. the clotting risk is directly related to the type of device, the extracorporeal blood flow, and the size of the cannulas [ ] . lastly, the ecls population may be particularly susceptible to nosocomial infections because of concomitant critical illness, indwelling catheters, and prolonged hospitalization. management of infections during ecls is more challenging due to alterations in pharmacokinetics of antimicrobial agents in the presence of an extracorporeal circuit [ ] . an analysis of the international elso registry reported an association between higher annual ecmo volume and lower case-mix-adjusted mortality for ecmotreated neonates and adults [ ] a position paper [ ] by an international group of experts advocated for a regional and inter-regional ecmo network of hospitals around an ecmo referral center with a mobile ecmo unit to retrieve the most severe patients. patients supported with ecmo generally have prolonged icu and hospital lengths of stay [ , , ] , which likely contribute to worse pulmonary function, quality of life, and psychological status. however, the long-term prognosis after ecmo for ards has been insufficiently evaluated. patients in the ecmo arm of [ ] . venovenous ecmo can be associated with complex ethical dilemmas, particularly in situations where patients are unlikely to recover sufficiently to transition to conventional mechanical ventilation, and are not candidates for lung transplantation [ ] . in these circumstances, criteria regarding continuation or withdrawal of ecmo are not strictly established and may differ among caregivers, ecmo centers, and countries. in a recent survey of physicians from countries across continents, these decisions were strongly influenced by whether a patient's or surrogate's wishes were known, the level of consciousness of the patient, and perceived "futility" of the clinical situation [ ] . weighing the potential benefits and risks of ecmo using predictive survival models [ , ] , and improving doctor-patient/surrogate communication surrounding the benefits and limitations clinical management and daily monitoring of ecmo for ards. vv-ecmo venovenous extracorporeal membrane oxygenation, vcv volumecontrolled ventilation, peep positive end-expiratory pressure, vt tidal volume, p plat plateau pressure, rr respiratory rate, ∆p driving pressure, bipap/ aprv biphasic positive airway pressure/airway pressure release ventilation, p high high pressure, p low low pressure, ufh unfractionated heparin, aptt activated partial thromboplastin time, pk/pd pharmacokinetic/pharmacodynamics, rass richmond agitation-sedation scale, p . drop in airway pressure observed during the first ms of an inspiratory effort made against the occluded airway opening, pven venous pressure (i.e. inlet pressure) on ecmo, part arterial pressure (i.e., outlet pressure) on ecmo, ∆p on ecmo trans-membrane oxygenator pressure gradient or pressure drop, i.e., the difference betweenthe pressure of the blood at the inlet and at the outlet of the membrane lung, usually - mmhg. a modified eolia settings with a set rr lower than in eolia of ecmo before its initiation are crucial. shared decision-making with patients and family regarding end-oflife decisions on ecmo are recommended [ ] . the eolia trial took . years to enroll patients. given the logistical hurdles, a new randomized controlled trial comparing ecmo versus conventional mechanical ventilation management seems highly unlikely. the major question now is rather: "how to provide better ecmo care?". the management of mechanical ventilation during ecmo warrants further investigation. studies are needed to investigate the impact of strategies such as larger reductions in mechanical ventilation intensity, frequent use of prone positioning, close control of respiratory drive, and ecmo without invasive mechanical ventilation. more work is needed to decrease the burden of ecmo-induced coagulopathy and associated bleeding, which is particularly important for ecco r. this includes work on improved biocompatible materials to reduce hemorrhagic or thrombotic adverse events; on pump technology to minimize shear stress, and hemolysis especially at low flows [ ] . beyond safety, the degree of benefit of ultra-protective ventilation remains to be proven [ ] and large clinical trials to investigate the impact of ecco r for ards on outcomes are urgently needed (table ) . moreover, future research should focus on the selection of patients who will most likely benefit from the use of extracorporeal support [ , ] . importantly, research networks, such as the international ecmo network (ecmonet; www.inter natio nalec monet work.org), and large ecmo registries, such as the registry of the extracorporeal life support organization (elso; www.elso.org), will be critical to achieving these future research aims. although vv-ecmo is now a safe and viable strategy for severe ards when performed in experienced centers, it should not be a substitute for proven conventional ards management. therefore, the initial management of patients with severe ards should always include lung protective ventilation and prone positioning, unless contraindicated or not technically feasible [ ] . future efforts in the field should focus on the improvement of ecmo care and elucidation of ecco r on patient-centred outcomes [ ] . epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries acute respiratory distress syndrome network ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome less is more: not (always) simple-the case of extracorporeal devices in critical care extracorporeal gas exchange: when to start and how to end? extracorporeal life support: the university of michigan experience the extracorporeal life support organization maastricht treaty for nomenclature in extracorporeal life support. a position paper of the extracorporeal life support organization mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome. an international multicenter prospective cohort blood oxygenation and decarboxylation determinants during venovenous ecmo for respiratory failure in adults recirculation in venovenous extracorporeal membrane oxygenation extracorporeal life support for adults with respiratory failure and related indications: a review extracorporeal carbon dioxide removal for lowering the risk of mechanical ventilation: research questions and clinical potential for the future blood acidification enhances carbon dioxide removal of membrane lung: an experimental study respiratory electrodialysis. a novel, highly efficient extracorporeal co removal technique extracorporeal membrane oxygenation in severe acute respiratory failure. a randomized prospective study ecmo for ards: from salvage to standard of care? extracorporeal membrane oxygenation for severe acute respiratory distress syndrome breathing and ventilation during extracorporeal membrane oxygenation: how to find the balance between rest and load the adult respiratory distress syndrome cognitive outcomes study right ventricular unloading after initiation of venovenous extracorporeal membrane oxygenation early mobilization of patients receiving extracorporeal membrane oxygenation: a retrospective cohort study respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions spontaneous breathing during extracorporeal membrane oxygenation in acute respiratory failure prone positioning in severe acute respiratory distress syndrome the standard of care of patients with ards: ventilatory settings and rescue therapies for refractory hypoxemia applying precision medicine to trial design using physiology. extracorporeal co removal for acute respiratory distress syndrome efficacy and safety of lower versus higher co extraction devices to allow ultraprotective ventilation: secondary analysis of the supernova study extracorporeal co removal: the minimally invasive approach, theory, and practice extracorporeal membrane oxygenation for pandemic influenza a(h n )-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis the italian ecmo network experience during the influenza a(h n ) pandemic: preparation for severe respiratory emergency outbreaks referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) extracorporeal membrane oxygenation for influenza a (h n ) acute respiratory distress syndrome efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial learning from a trial stopped by a data and safety monitoring board extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial ecmo for severe ards: systematic review and individual patient data meta-analysis venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis time for clinicians to embrace their inner bayesian?: reanalysis of results of a clinical trial of extracorporeal membrane oxygenation extracorporeal membrane oxygenation for severe middle east respiratory syndrome coronavirus predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score the preserve mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with covid- : a retrospective cohort study poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports extracorporeal membrane oxygenation support in covid- : an international cohort study of the extracorporeal life support organization registry pathophysiology of covid- -associated acute respiratory distress syndrome: a multicentre prospective observational study ventilator-induced lung injury low-flow assessment of current ecmo/ecco r rotary blood pumps and the potential effect on hemocompatibility feasibility and safety of lowflow extracorporeal co removal managed with a renal replacement platform to enhance lung-protective ventilation of patients with mild-tomoderate ards lower tidal volume strategy (≈ ml/kg) combined with extracorporeal co removal versus 'conventional' protective ventilation ( ml/kg) in severe ards: the prospective randomized xtravent-study low respiratory rate plus minimally invasive extracorporeal co removal decreases systemic and pulmonary inflammatory mediators in experimental acute respiratory distress syndrome ventilator-related causes of lung injury: the mechanical power feasibility and safety of extracorporeal co removal to enhance protective ventilation in acute respiratory distress syndrome: the supernova study determinants of the effect of extracorporeal carbon dioxide removal in the supernova trial: implications for trial design feasibility and safety of lowflow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome understanding hypoxemia on ecco r: back to the alveolar gas equation should patients with acute respiratory distress syndrome on venovenous extracorporeal membrane oxygenation have ventilatory support reduced to the lowest tolerable settings? no should patients with acute respiratory distress syndrome on venovenous extracorporeal membrane oxygenation have ventilatory support reduced to the lowest tolerable settings? yes mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome: a retrospective international multicenter study associations between ventilator settings during extracorporeal membrane oxygenation for refractory hypoxemia and outcome in patients with acute respiratory distress syndrome: a pooled individual patient data analysis : mechanical ventilation during ecmo near-apneic ventilation decreases lung injury and fibroproliferation in an acute respiratory distress syndrome model with extracorporeal membrane oxygenation mechanical ventilation strategy guided by transpulmonary pressure in severe acute respiratory distress syndrome treated with venovenous extracorporeal membrane oxygenation bedside contribution of electrical impedance tomography to set positive end-expiratory pressure for ecmo-treated severe ards patients prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial prone positioning in severe ards requiring extracorporeal membrane oxygenation intensive care physiotherapy during extracorporeal membrane oxygenation for acute respiratory distress syndrome recent developments in the management of persistent hypoxemia under veno-venous ecmo low-dose versus therapeutic anticoagulation in patients on extracorporeal membrane oxygenation: a pilot randomized trial the early change in paco after extracorporeal membrane oxygenation initiation is associated with neurological complications brain injury during venovenous extracorporeal membrane oxygenation ecls-associated infections in adults: what we know and what we don't yet know association of hospitallevel volume of extracorporeal membrane oxygenation cases and mortality. analysis of the extracorporeal life support organization registry position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients mortality and costs following extracorporeal membrane oxygenation in critically ill adults: a population-based cohort study long-term outcomes of pandemic influenza a(h n )-associated severe ards understanding ethical decisions for patients on extracorporeal life support practice patterns and ethical considerations in the management of venovenous extracorporeal membrane oxygenation patients: an international survey low-flow assessment of current ecmo/ecco r rotary blood pumps and the potential effect on hemocompatibility feasibility and safety of ultra-low tidal volume ventilation without extracorporeal circulation in moderately severe and severe ards patients ecmo for immunosuppressed patients with acute respiratory distress syndrome: drawing a line in the sand saying no until the moment is right: initiating ecmo in the eolia era extracorporeal organ support: from technological tool to clinical strategy supporting severe organ failure we thank savannah soenen for the creation of the figures. drafting of the manuscript: c, s, s, b. critical revision of the manuscript for important intellectual content: all authors. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.received: september accepted: october key: cord- -ex nh yi authors: coperchini, francesca; chiovato, luca; croce, laura; magri, flavia; rotondi, mario title: the cytokine storm in covid- : an overview of the involvement of the chemokine/chemokine-receptor system date: - - journal: cytokine growth factor rev doi: . /j.cytogfr. . . sha: doc_id: cord_uid: ex nh yi in - a new coronavirus named sars-cov- was identified as the causative agent of a several acute respiratory infection named covid- , which is causing a worldwide pandemic. there are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the acute respiratory distress syndrome (ards). sars-cov- showed phylogenetic similarities to both sars-cov and mers-cov viruses, and some of the clinical features are shared between covid- and previously identified beta-coronavirus infections. available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ards. chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. this review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to sars-cov- infection. basic and clinical evidences obtained from previous sars and mers epidemics and available data from covid- will be taken into account. in early december , several pneumonia cases of unknown origin were observed in wuhan (china). the pathogen was identified as a novel enveloped rna β coronavirus that was named severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . the virus showed phylogenetic similarities to both sars-cov and mers-cov viruses. in view of its similarities to bat coronaviruses, it was postulated that bats could have been the primary hosts of sars-cov- . this hypothesis suggested that the infection originated via transmission from wild animals illegally sold in the huanan seafood wholesale market. on january, th , , the world health organization (who) declared coronavirus disease (covid- ) a public health emergency of international concern, and on march th , who director general referred to covid- as a pandemic. as of may th , , the number of confirmed cases of covid- has exceeded million worldwide, with more than , covid- -related deaths. the epidemic has put public health systems under severe strain both in western countries and in the developing world. sars-cov- displays a more efficient transmission pattern when compared with sars-cov and mers-cov [ ] , retaining a high transmission rate also in the asymptomatic incubation period [ ] . the clinical spectrum of covid- syndrome varies remarkably, going from asymptomatic forms to acute bilateral pneumonias requiring hospitalization. common presenting symptoms include fever, fatigue and dry cough, while laboratory tests often show lymphopenia and elevated lactate dehydrogenase levels. chest computed tomographic scans show a typical pattern of bilateral patchy shadows or ground glass opacity. a significant percentage of cases requires admission to intensive-care-units (icu) due to acute respiratory distress syndrome that requires mechanical ventilation support. a subgroup of patients with severe covid- can experience the so-called "cytokine storm syndrome", characterized by a fulminant and fatal hyper-cytokinemia associated with multi-organ failure. the term "cytokine storm" has become increasingly used not only by authors of scientific articles but also by popular media. it is likely that the widespread use of this term is related with its rather immediate meaning, which actually recalls the role of the immune system in producing an uncontrolled and generalized inflammatory response [ ] . it seems not casual that the term cytokine storm was first employed in describing j o u r n a l p r e -p r o o f the events modulating the onset of the graft-versus-host disease [ ] , a condition characterized by an impressively powerful activation of the immune system. cytokine storms characterize a wide spectrum of infectious and non-infectious diseases, and since , it was associated to the avian h n influenza virus infection [ ] . apart from the immediate significance of the term cytokine storm, the biological and clinical consequences of this immune system hyperactivity are by far less known, making it worthwhile to be briefly overviewed. there are several similarities in the clinical features between covid- and previously identified beta-coronavirus infections. shared clinical findings include that most patients present with fever, dry cough, dyspnea, and bilateral ground-glass opacities on chest ct scans [ ] . however, the physiopathology of the mechanisms through which sars-cov or mers-cov sustain high pathogenicity are yet to be completely unveiled. since the first reports on covid- disease, it appeared clear that acute respiratory distress syndrome (ards) accounted for a significant number of deaths among infected patients and that ards should be regarded as the hallmark immune-mediated clinical consequence in sars-cov- , similarly to what described for sars-cov and mers-cov infections [ ] . acute respiratory distress syndrome (ards) is a devastating event, with an estimated mortality of approximately %, defined as the presence of bilateral lung infiltrates and severe hypoxemia. ards can occur in a variety of clinical situations, including pneumonia, sepsis, pancreatitis, blood transfusion. ards pathogenesis involves inflammatory injury to the alveolo-capillary membrane, which results in increased lung permeability and the exudation of protein-rich pulmonary edema fluid into the airspaces, leading in the end to respiratory insufficiency [ ] . as shown by previous data in the literature, increased circulating levels of pro-inflammatory cytokines (eg, interferon γ, interleukin (il-) b, il- , il- ) and chemokines (cxcl , and ccl ) are associated with pulmonary inflammation and extensive lung involvement in sars patients, similarly to what happens in mers-cov infection [ ] . as far as covid infection is concerned, huang et al recently reported that infected patients also show high levels of pro-inflammatory cytokines and chemokines [ ] . the demonstration of increased levels of il- b, ifnγ, cxcl , and ccl strongly pointed toward an activation of t-helper- (th ) cell function. more importantly, the so called "cytokine storm" emerged as a main factor driving a more j o u r n a l p r e -p r o o f severe clinical course. this concept originated from the observation that covid- patients requiring icu admission displayed higher concentrations of cxcl , ccl and tnfα as compared to those in which the infection was less severe and did not require an icu admission. to further complicate the issue, it should be highlighted that, in patients with sars-cov- infection, at difference from sars-cov infection, there is also an increased secretion th -immune-oriented cytokines such as il- and il- , whose main effect is to suppress inflammation [ ] . taken together, these data clearly indicate that, in sars-cov infection, ards is the ultimate result of a cytokine storm. in this scenario, the release by immune effector cells of large amounts of proinflammatory cytokines (ifnα, ifnγ, il- β, il- , il- , il- , il- , tnfα, tgfβ) and chemokines (cxcl , cxcl , cxcl , ccl , ccl , ccl ) precipitates and sustains the aberrant systemic inflammatory response [ , , , ] . the cytokine storm is readily followed by the immune system "attacking" the body, which in turn will cause ards and multiple organ failure, the final result being death, at least in the most severe cases of sars-cov- infection [ ] . the cytokine storm, and the consequent ards, results from the effects of a combination of many immune-active molecules. interferons, interleukins, chemokines, colony-stimulating factors and tnf-alpha represent the main components involved in the development of the cytokine storm and will be briefly overviewed. -interferons, a family of cytokines with a central role in virus-directed innate immunity binds specific receptors and result in the expression of genes encoding protein with anti-viral or immunomodulatory properties. this sequence of events supported the therapeutic use of ifns in some viral diseases such as chronic hepatitis, but also in non-viral conditions including leukemia and lymphoma, melanoma and multiple sclerosis [ , ] . -tumor necrosis factor α (tnfα) is a pyrogen cytokine released from immune cells in the acute phase of inflammation and infection. it is a central cytokine in viral diseases and is associated with a number of chronic inflammatory and autoimmune diseases [ ] . j o u r n a l p r e -p r o o f -colony-stimulating factors (csf). these proteins are associated with inflammatory conditions and are components of an amplification cascade which ultimately increases cytokine production by macrophages at sites of inflammation, this effect perpetuates the inflammatory reaction [ ] . -interleukins are a family of cytokines involved in immune cells differentiation and activation. they mediate the traffic of immune cells to the site of the infection, induce the increase of the acute phase signaling, activate epithelial cells and mediate the production of secondary cytokines [ ] . among them, interleukin- (il- ) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. il- is crucially involved in acute inflammation due to its role in regulating the acute phase response [ ] . it is produced by almost all stromal cells and b lymphocytes, t lymphocytes, macrophages, monocytes, dendritic cells, mast cells and other non-lymphocytic cells, such as fibroblasts, endothelial cells, keratinocytes, glomerular mesangial cells and tumor cells [ ] . the production of this cytokine is increased by il- β and tumor necrosis factor (tnf-α) [ ] . il- may also be responsible for the activation of t helper (th ) cells in the dendritic cell-t cell interaction [ ] . in covid- affected patients, a high th cells activation could result from a virus-driven increased production of il- by the immune system. il- plays a key role in the pathogenesis of the cytokine storm owing to its pleiotropic properties. several studies showed that the serum levels of il- are increased in covid- patients and that its circulating levels are positively related to disease severity [ , , ] . for this reason, high serum il- levels were suggested as predictors for disease severity [ , ] . indeed, in animal models of sars-cov infection, the inhibition of the transcription factor of il- and, in turn of its production, was associated with reduced mortality [ ] . during the present covid- pandemic, the use of tocilizumab as a therapeutic agent was proposed. tocilizumab is a humanized anti-il- receptor igg monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases [ ] . by blocking the il- -receptor interaction, tocilizumab inhibits the il- -mediated signal transduction. although clinical data on the use of tocilizumab in covid- patients derive from small series, some authors recommend its use in critically ill covid- patients with significantly elevated il- levels. [ ] -chemokines are a large family of cytokines characterized by a powerful chemotactic effect. chemokines j o u r n a l p r e -p r o o f act as chemo-attractants in the migration of the immune system cells, but they are also involved in several other processes including the development and function of innate and adaptive immune system, embryogenesis, and cancer metastasis [ , ] . they are promptly secreted by a variety of cells in response to viral or microbial infections [ ] . chemokines act as powerful chemoattractants which recruit inflammatory cells to migrate from the intravascular space across the endothelium and epithelium into the inflammation site, according to a chemokine gradient [ ] . the role of one specific chemokine, cxcl (previously referred to as interferon-γ inducible protein of kda, or ip- ), has been highlighted in ards in both experimental models and in patients. indeed, in a mouse model of il- -induced ards, an up-regulation of the mouse cxcl analogue mob- mrna was observed at initiation of lung injury [ ] . several studies also showed that the intratracheal injection of mob- in mice induced pulmonary migration of leukocytes in the alveolar space, with massive recruitment of neutrophils, especially monocytes. this event was rapidly followed by microvascular injury and pulmonary edema typical of ards [ , ] . cxcl signaling appears to be a critical factor for the onset of ards, as shown in mice models of ards induced by either acid aspiration or by viral infection (with influenza h n virus). briefly, ichikawa et al, demonstrated that wild-type mice developing ards had increased levels of cxcl mainly due to an increased secretion by infiltrating neutrophils, which induced an autocrine loop mechanism on the chemotaxis of inflamed neutrophils, leading to fulminant pulmonary inflammation. on the contrary, cxcl and/or its receptor cxcr knock-out mice showed decreased lung injury severity and increased survival in response to both viral and non-viral lung injury [ ] . moreover, cxcl expression in the lung was significantly up-regulated after induction of ards with lipopolysaccharide (lps) in a mouse model of lung injury, and the neutralization of cxcl with anti-cxcl antibody lead to amelioration of lung injury [ ] . cxcl (also referred at as il- ) is another chemokine considered as a potential prognostic bio-marker for ards clinical course [ ] . indeed, cxcl levels were found to be elevated both in plasma [ ] [ ] [ ] [ ] and in the broncho-alveolar lavage fluid [ ] [ ] [ ] of patients with ards. a direct role of cxcl in the progression of ards was proven in rabbit with acid-induced ards lead to a -fold increase in cxcl levels in the j o u r n a l p r e -p r o o f alveolar fluids. of note, pre-treatment with an anti-cxcl antibody prevented the development of the typical acute lung injury [ ] . although chemokines are crucially involved in the regulation and maintenance of immune responses, their role in the onset of the coronavirus-induced cytokine storm is still poorly investigated. chemokines are a family of low molecular weight proteins expressed, both constitutively and in an inducible manner, by several types of cells. chemokines play an important role in the inflammatory response by attracting leukocytes to sites of infection. these small proteins also contribute to the homeostatic circulation of leukocytes through tissues [ ] . at present, chemokines and chemokine receptors have been recognized and classified. chemokines are named according to the most recent nomenclature, which classifies them according to their chemical structure, the c, cc cxc and cx c families [ ] . the binding of chemokines to their receptors is responsible for their chemoattractant ability. the chemokine receptors belong to the seven-transmembrane-spanning, g-protein-coupled receptors, which are expressed primarily on leukocytes but also on other cells, e.g., endothelial cells [ ] . the many functions of chemokines include the control of cell proliferation and differentiation, the regulation of angiogenesis and immune and inflammatory responses, tumor growth and metastasis [ ] [ ] [ ] . most recently, several studies investigated the involvement of chemokines in coronavirus-related infective disease. it emerged that specific chemokines could play a crucial role in the development of covid- -related symptoms, thus confirming what previously known for other types of coronaviruses, such as sars and mers. [ , ] . these findings could be somehow expected in view of the well-known role of chemokines in viral infections. before addressing the specific relationship between chemokines and coronavirus infections, it is mandatory to briefly overview the general role of chemokines in viral infections and how viruses contrast the actions of chemokines. viruses are infectious agents of small size and simple composition that can multiply only in living cells of animals, plants, or bacteria. all viruses contain a nucleic acid, either -dna (deoxyribonucleic acid) or -rna (ribonucleic acid), and several proteins. viruses should not even be considered organisms since they are not free-living (i.e., they require a host cell), thus viruses need to elude the host immune defense to infect its cells in order to reproduce and survive. [ ] . the chemokine/chemokine receptor-related immune defenses are the main obstacles to be by-passed by viruses. some chemokines play a direct anti-viral effect by inducing an array of phenomena that lead cells to determine an "anti-viral "state. these phenomena include activation of apoptosis or direct killing of infected cells by activated immune cells. chemokines also recruit immune cells to the site of infection, which will fight against the intruder [ ] . viral infections are associated with enhanced expression of several chemokines, in particular the interferons-inducible ones. interferons, which can be produced by any mammalian cell, are involved in the rapid and efficient host innate response against viruses. a powerful ifn response triggered by the first contact with a virus can slow down viral multiplication and "buy time" for the organism to establish a more efficient adaptive immune response [ ] . ifns can stimulate surrounding cells to express potent antiviral proteins including enzymes, transcription factors, cell surface glycoproteins, cytokines and chemokines [ , ] . moreover, they can inhibit cell proliferation, regulate apoptosis and modulate the immune response [ ] . among interferons-induced molecules, the chemokine cxcl is currently regarded as a main player in the organism anti-viral response [ ] , and particularly in respiratory tract infections. several studies demonstrated that cxcl levels, as evaluated in serum, bronchial-alveolar washing fluid or nasal secretions, consistently correlate with the severity and duration of acute respiratory tract infection due to viral infections. [ ] [ ] [ ] also the chemokine cxcl , is involved in inflammation and immune cell trafficking in the context of viral infections. cxcl plays a major role in the initial control of respiratory tract infection due to its chemotactic activity for neutrophils and monocytes [ ] . cxcl levels in the nasal washing fluid correlate with symptoms severity during acute respiratory tract infections [ ] . although in the majority of cases a strong chemokine action can efficiently contrast viral infections, some viruses acquire the capacity of escaping j o u r n a l p r e -p r o o f this surveillance system. furthermore, viruses can use the chemokine system network for their own favor by several strategies: -some viruses "mimic" the components of the chemokine system by producing molecules that are very similar to chemokines and can interact with their receptor. these molecules generate an incongruous signal leading to a disorganized immune response to viruses [ ] . -inhibition of the interferon-induced anti-viral response. several viruses do impair the intracellular receptors devoted to pathogen recognition, such as toll like receptors and intracellular rna sensors. [ ] taken together, the above data indicate that viruses can interfere with the chemokine/chemokine-receptors system using their own properties to modify intracellular signaling with the final result to further disseminate the infection. the strict relationship between conaviruses infection and chemokines has been thoroughly investigated during both the sars-cov and the mers-cov epidemics, while some initial data are available regarding sars-cov- and its related syndrome, covid- . since the first reports of sars, it seemed clear that the severe clinical manifestations of the disease could not be ascribed only to the viral activity per se, but that an immune-mediated mechanism rather than a direct virus-induced damage would drive the clinical progression [ ] . indeed from the physio-pathology point of view, the most interesting observation was the demonstration that viral titers seemed to paradoxically diminish during the most severe phase of the disease both in humans and in several animal models [ ] . data in vivo studies showed that several circulating chemokines (cxcl , ccl and cxcl ) and inflammatory cytokines (il- , il- and il- ) were elevated in patients with sars-cov [ , ] . cxcl was also considered an excellent prognostic marker for sars disease progression [ , ] . in particular, jiang et al showed that cxcl serum levels were significantly increased during the early stage of sars, and remained elevated until resolution. moreover, persistently elevated cxcl serum levels during follow-up were predictive of a worse outcome of the infection [ ] these findings prompted further in vitro studies aimed at investigating the relationship between sars and the chemokine system. spiegel et al, demonstrated that, in addition to its direct effect on epithelial lung cells, sars-cov could also enter macrophages and dendritic cells [ ] . this appeared crucial as viral entrance in these cells lead to an abortive infection (e.g. the virus enters the host-cell but cannot successfully complete replication). yet the virus elicited the secretion of pro-inflammatory chemokines by dendritic and macrophages cells [ ] . this finding was confirmed in vivo because the serum levels of a wide spectrum of cytokines and chemokines produced by dendritic cells and macrophages were elevated in sars-cov infected patients [ ] . furthermore, the infection with sars-cov of human primary myeloid-derived dendritic cells was followed by an impaired defensive ifnβ response, which was paralleled by a moderate up-regulation of pro inflammatory cytokines (such as tnf-α and il- ) and a much more significant up-regulation of inflammatory chemokines (such as cxcl , ccl , ccl , and ccl ) [ ] . the authors suggested that the lack of response to antiviral interferons in the presence of chemokine up-regulation could represent a further mechanism of immune evasion by sars-cov [ ] . in line with this hypothesis, the direct exposure of lung epithelial cells [ ] or peripheral blood mononuclear cells (pbmcs) [ ] coming from sars infected patients to viral proteins (such as s-protein and n-protein) induced a prompt release of several chemokines, including cxcl and cxcl . in vitro gene-expression studies also reported that pbmc from normal healthy donors inoculated with sars-cov showed an early enhancement in the expression of several chemokines belonging both to the cc family (ccl , ccl , ccl , ccl , ccl , and their receptors j o u r n a l p r e -p r o o f ccr , ccr ) and of the cxcl family (cxcl and il- ) [ ] . additional data came from animal models of sars-cov infection. in mice infected with sars-cov, the clinical features of the syndrome showed an age-dependent increase in severity (similarly to what observed in humans), which was related to an increased level of pro-inflammatory cytokines and chemokines, paralleled by a reduction in t-cell responses [ ] . another study showed that in mice infected with sars-cov, robust virus replication accompanied by delayed type i interferon secretion caused a rapidly fatal pneumonia. this delayed type i-interferon signaling promoted the accumulation of pathogenic inflammatory monocyte-macrophages, with resulting increase in cytokine (il- ) and chemokine (ccl ) lung levels, vascular leakage, and impaired virus-specific t cell responses. [ ] . these data suggest that coronaviruses, and in particular sars-cov, have a peculiar ability to counteract the antiviral ifn response, pointing toward the fact that the severity of disease might be due to immune dysregulation, rather than to the level of viremia. this dysregulation would be characterized by an insufficient type i interferon response (too little and too late), paralleled by an aberrant pro-inflammatory chemokine secretion by alveolar macrophages, dendritic cells and pneumocytes [ , ] . in vitro data suggest that this class of viruses, and in particular sars-cov, uses several strategies to avoid type i ifn response, both passive and active [ , ] . -passive mechanisms include the induction of double membrane vesicles (dmv) at perinuclear sites within the cytoplasm where rna synthesis takes place. this strategy may help to hide and protect rna replication intermediates from being sensed by intracellular rna-sensors, thus avoiding the activation of the ifn cascade [ , ] . -active mechanisms include a direct action of viral proteins on transcription factors and intracellular signaling molecules that regulate the ifn cascade. in particular, the sars-cov protein orf is able to inhibit the action of interferon regulatory transcription factor- (irf- ), a transcription factor of the ifn genes [ , ] . the fact that sars-cov infection would upregulate the transcription of cxcl , while significantly down-regulating ifns signaling, could seem paradoxical. however, transcriptional enhancement of cxcl could be due to a direct effect on the nuclear factor kappa-light-chain-enhancer of activated b cells (nf-kb) [ ] triggered by sars-cov [ ] , even if other authors did not confirm this early observation [ ] . similarly, the up-regulation of the cxcl gene expression, could be due to a direct effect of the virus at the cellular level. indeed, intestinal and lung cells lines infected by sars-cov, promptly increase their secretion of cxcl [ ] . this observation would fit with the notion that the expression of cxcl is dependent on the transcription factor activator protein (ap- ), which was shown to be strongly upregulated by sars-cov [ , ] . during the mers-cov epidemics, several studies were aimed at understanding the pathogenic mechanisms underlying the severe and often fatal pneumonia were performed. available data suggest that mers-cov infection shares some immunological aspects of sars-cov infection, in terms of involvement of the chemokine system. first, an increase in the serum levels of cxcl when compared to controls was observed also in mers-cov patients. more importantly, a persistent cxcl increase was associated with disease severity [ ] . in this regard, the case of two paradigmatic patients diagnosed with mers-cov is worth noting. one had a fatal outcome and experienced an impaired ifn response together with a relevant increase in serum cxcl levels. the other one, with a favorable outcome, displayed an up-regulation of ifns and irf and a less pronounced increase of serum cxcl levels [ ] . in vitro studies also support the relevance of chemokines in mers-cov patients. a study evaluated the expression of several chemokines and cytokines in cell lysates of polarized airway epithelial cells infected with mers-cov or sars-cov. the results showed that cxcl was up-regulated to a greater extent by mers-cov infection as compared with sars-cov. at difference, ccl and cxcl were more strongly up-regulated by sars-cov than mers-cov [ ] . in addition, in dendritic cells infected with mers-cov, a significant down-regulation of ifn response paralleled by a striking elevation of cxcl was observed [ ] . a strong induction of cxcl secretion was observed also in monocyte-derived macrophages infected with mers-cov [ , ] . interesting data come also from an experimental mouse model of mers-cov infection, in which a significant increase in cxcl expression was observed in lung and brain tissue after infection with mers-cov [ ] . briefly, the inoculation of the two viruses in ex vivo human lung tissue explants showed that sars-cov- was more capable, as compared with sars-cov, in both infecting and replicating in human lung. furthermore, sars-cov- infection was less able to trigger the expression of any ifns, suggesting that sars-cov and sars-cov- might differ in their ability to modulate the production of pro-inflammatory cytokines and chemokines. as an example, it could be worth highlighting that sars-cov infection upregulated out of the pro-inflammatory factors evaluated, while sars-cov- upregulated only five of them, (namely, cxcl , il , ccl , cxcl , cxcl ). interestingly, cxcl transcription was upregulated only by sars-cov, but not sars-cov- infection, while the opposite was observed for cxcl [ ] . the potential involvement of the chemokine system during sars-cov- infection was already evident from the first covid- series described by chinese physicians in early january . it was reported that several pro-inflammatory cytochines and chemokines, including cxcl , cxcl , ccl , tnfα and ifnγ j o u r n a l p r e -p r o o f were higher in the plasma of covid- patients as compared to healthy controls. more importantly, among infected patients, cxcl , ccl and tnfα circulating concentrations (but not those of ifnγ) were found to be significantly higher in patients requiring admission to intensive care units as compared to patients experiencing a less severe clinical course [ ] . j o u r n a l p r e -p r o o f sars-cov- , and its related syndrome covid- , have been known to the scientific community since less than months. clearly much is yet to be understood, and the challenge for the next future will be to increase our understanding the physiopathology of this novel infectious disease. hopefully, the advances in our comprehension of the mechanisms sustaining the clinical course and patients-related factors driving the final outcome will be helpful in developing effective preventive strategies and/or therapeutical options. based on current knowledge, the "cytokine storm" appears as one of the most dangerous and potentially lifethreatening event related to covid- sustaining its major clinical consequences. the immune mediated events related to the response to sars-cov- infection, and the role of the chemokine/chemokine receptor system, will be further and more extensively characterized with the final goal to identify targeted therapeutic strategies. although lessons from the previous sars and mers epidemics can be drawn, there is still much to do in order to conclude whether sars-cov- virus behaves in the same way of its predecessors or if it is characterized by peculiar specificities. clearly, the hide-and-seek challenge between the virus and our immune defenses will also help us understanding the extremely variable spectrum of clinical manifestations of covid- , which appears to range between asymptomatic cases to possibly lethal bilateral pneumonia with multi-organ failure. coronaviruses: an overview of their replication and pathogenesis the severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia clinical features of patients infected with novel coronavirus in the reproductive number of covid- is higher compared to sars coronavirus the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application into the eye of the cytokine storm cytokine storm of graft-versus-host disease: a critical effector role for interleukin- human infection by avian influenza a h n pathological findings of covid- associated with acute respiratory distress syndrome role of chemokines in the pathogenesis of acute lung injury pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality human immunopathogenesis of severe acute respiratory syndrome (sars) the mercurial nature of neutrophils: still an enigma in ards? clinical uses of interferons interferons at age : past, current and future impact on biomedicine an endotoxin-induced serum factor that causes necrosis of tumors colony-stimulating factors in inflammation and autoimmunity evolutionary divergence and functions of the human interleukin (il) gene family interleukin- and its receptor: from bench to bedside il- as a keystone cytokine in health and disease il- : regulator of treg/th balance the role of cytokines including interleukin- covid- induced pneumonia and macrophage activation syndrome-like disease hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease (covid- ): a meta-analysis interleukin- as a potential biomarker of covid- progression inhibition of nf-κb-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival role of chemokines in thyroid cancermicroenvironment: is cxcl the main player? role of chemokines in endocrine autoimmune diseases chemokine receptors: interaction with hiv- and viral-encoded chemokines transepithelial migration of neutrophils: mechanisms and implications for acute lung injury mob- expression in il- -induced ards: regulation by tnf-alpha the novel chemokine mob- : involvement in adult respiratory distress syndrome mob- and tnf-alpha interact to induce microvascular lung injury neutralization can ameliorate lipopolysaccharide-induced acute respiratory distress syndrome in rats biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis national heart, and lung institute acute respiratory distress syndrome network, use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury plasma cytokines il- , il- , and il- are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury pathogenetic and predictive value of biomarkers in patients with ali and lower severity of illness: results from two clinical trials inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome interleukin- and development of adult respiratory distress syndrome in at-risk patient groups elevated levels of nap- /interleukin- are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality acid aspiration-induced lung injury in rabbits is mediated by interleukin- -dependent mechanisms chemokine/chemokine receptor nomenclature international union of basic and clinical pharmacology chemokine and chemotactic signals in dendritic cell migration chemokines and t lymphocytes: more than an attraction role of chemokine receptors in thyroid cancer and immunotherapy coronavirus infections and immune responses virus classification -where do you draw the line? expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function the interferon response circuit: induction and suppression by pathogenic viruses the interferon in tlr signaling: more than just antiviral links between innate and adaptive immunity via type i interferon inverse interference: how viruses fight the interferon system serum ifn-γ-induced protein (ip- ) as a biomarker for severity of acute respiratory infection in healthy adults host response cytokine signatures in viral and nonviral acute exacerbations of chronic obstructive pulmonary disease serum ip- as a biomarker of human rhinovirus infection at exacerbation of copd the pneumococcal polysaccharide capsule and pneumolysin differentially affect cxcl and il- release from cells of the upper and lower respiratory tract association of interleukin- and neutrophils with nasal symptom severity during acute respiratory infection viral mimicry of cytokines, chemokines and their receptors interferon and cytokine responses to sars-coronavirus infection clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome what does the peripheral blood tell you in sars? an interferon-gamma-related cytokine storm in sars patients characterization of cytokine/chemokine profiles of severe acute respiratory syndrome interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells chemokine up-regulation in sars-coronavirus-infected, monocyte-derived human dendritic cells pathogenesis of severe acute respiratory syndrome expression profile of immune response genes in patients with severe acute respiratory syndrome induction of il- release in lung cells via activator protein- by recombinant baculovirus displaying severe acute respiratory syndrome-coronavirus spike proteins: identification of two functional regions a human in vitro model system for investigating genome-wide host responses to sars coronavirus infection age-related increases in pgd( ) expression impair respiratory dc migration, resulting in diminished t cell responses upon respiratory virus infection in mice dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-cov-infected mice coronavirus replication complex formation utilizes components of cellular autophagy ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex severe acute respiratory syndrome coronavirus orf antagonizes stat function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane severe acute respiratory syndrome coronavirus open reading frame (orf) b, orf , and nucleocapsid proteins function as interferon antagonists one nucleotide in a kappab site can determine cofactor specificity for nf-kappab dimers infection of cultured intestinal epithelial cells with severe acute respiratory syndrome coronavirus sars coronavirus and innate immunity inhibition of cytokine gene expression and induction of chemokine genes in nonlymphatic cells infected with sars coronavirus activation of ap- signal transduction pathway by sars coronavirus nucleocapsid protein clinical progression and cytokine profiles of middle east respiratory syndrome coronavirus infection distinct immune response in two mers-covinfected patients: can we go from bench to bedside? perfluoroalkyl acids: a review of monitoring and toxicological findings productive replication of middle east respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response active replication of middle east respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection the characteristics of hdpp transgenic mice subjected to aerosol mers coronavirus infection via an animal nose-only exposure device comparative replication and immune activation profiles of sars-cov- and sars-cov in human lungs: an ex vivo study with implications for the pathogenesis of covid- clinical and immunological features of severe and moderate coronavirus disease transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in covid- patients the laboratory tests and host immunity of covid- patients with different severity of illness at present she is attending the phd couse in experimental medicine at the university of pavia and she is researcher at the unit of endocrinology of ics maugeri spa -i.r.c.c.s, pavia. her research fields are: clinics of thyroid disease, role of chemokines in autoimmune endocrine disorders and thyroid cancer at present her position is: associate professor in endocrinology at university of pavia. she works at the unit of internal medicine and endocrinology, ics maugeri spa -i.r.c.c.s, pavia. her main research fields are: physiopathology and clinics of thyroid diseases key: cord- -bnjupaik authors: deliwala, smit s.; ponnapalli, anoosha; seedahmed, elfateh; berrou, mohammed; bachuwa, ghassan; chandran, arul title: a -year-old male with a fatal case of covid- acute respiratory distress syndrome (cards) and ventilator-induced lung injury (vili) date: - - journal: am j case rep doi: . /ajcr. sha: doc_id: cord_uid: bnjupaik patient: male, -year-old final diagnosis: acute respiratory distress syndrome (ards) • covid- •multi organ failure/septic shock • pneumothorax symptoms: cough • dyspnea • fatigue • myalgia medication:— clinical procedure: mechanical ventilation • thoracentesis specialty: critical care medicine objective: unknown ethiology background: covid- patients that develop acute respiratory distress syndrome (ards) “cards” behave differently compared to patients with classic forms of ards. recently cards phenotypes have been described, type l and type h. most patients stabilize at the milder form, type l, while an unknown subset progress to type h, resembling full-blown ards. if uncorrected, phenotypic conversion can induce a rapid downward spiral towards progressive lung injury, vasoplegia, and pulmonary shrinkage, risking ventilator-induced lung injury (vili) known as the “vili vortex”. no cases of in-hospital phenotypic conversion have been reported, while ventilation strategies in these patients differ from the lung-protective approaches seen in classic ards. case report: a -year old male was admitted with covid- pneumonia complicated by severe ards, multi-organ failure, cytokine release syndrome, and coagulopathy during his admission. he initially resembled cards type l case, although refractory hypoxemia, fevers, and a high viral burden prompted conversion to type h within days. despite ventilation strategies, neuromuscular blockade, inhalation therapy, and vitamin c, he remained asynchronous to the ventilator with volumes and pressures beyond accepted thresholds, eventually developing a fatal tension pneumothorax. conclusions: patients that convert to type h can quickly enter a spiral of hypoxemia, shunting, and dead-space ventilation towards full-blown ards. understanding its nuances is vital to interrupting phenotypic conversion and entry into vili vortex. tension pneumothorax represents a poor outcome in patients with cards. further research into monitoring lung dynamics, modifying ventilation strategies, and understanding response to various modes of ventilation in cards are required to mitigate these adverse outcomes. the cluster of pneumonia cases associated with the novel coronavirus (covid- ) or severe acute respiratory syndrome coronavirus (sars-cov- ) that emerged from wuhan, china and spread rapidly across continents was labeled by the world health organization (who) as a global pandemic. as of may , , . million cases of covid- were present in the united states (us), with roughly deaths [ ] . covid- pneumonia seems to behave differently from other viral types of pneumonia, with large swings in respiratory functioning, inferring that not all previous practices can be adopted, and new strategies are needed to mitigate the high mortality rates ( % to %) seen in advanced cases [ , ] . supplemental oxygen use was seen in . % of infected patients, with . % requiring mechanical ventilation and less than % requiring advanced therapies such as extracorporeal membrane oxygenation (ecmo); however, these numbers may likely be underrepresented with preventative measures such as social distancing and stay-at-home executive orders leading to reluctance and delay in receiving care [ ] . the progression of covid- to ards ("cards") represents a life-threatening sequela, with its ability to lower blood oxygenation levels and induce systemic hypoxemia and multi-organ failure [ , ] . despite cards meeting the berlin diagnostic criteria, its trajectory is characterized by severe hypoxemia with near-normal respiratory compliance, unlike its classic form [ , ] . patients with cards can present within a broad spectrum from perceived normal breathing ("silent hypoxemia") to floored respiratory compromise with a wide array of overlapping features in between [ ] . recently, cards phenotypes have been parsed out, type l and type h, with each one having its distinct pathophysiological pathway. understanding these nuances are vital to providing appropriate treatment and avoiding sub-optimal outcomes [ ] . we present a case of cards with subsequent sequelae and numerous challenges in management. we aim to strengthen the existing literature, explore the cards phenotypes, and discuss therapeutic and ventilator strategies to counteract the unique lung injury seen in covid- pneumonia that progress to ards. a -year-old male with a history of asthma, previous gunshot wound, and obesity, presented to the hospital with dyspnea, cough, fatigue, and myalgias. he used tobacco products and worked at an auto-parts manufacturing unit. on arrival, he was febrile, tachycardic, and tachypneic requiring supplemental oxygen. he appeared ill with a high work of breathing and a productive cough. workup revealed lymphopenia to . k/ul, thrombocytopenia to k/ul, and an unremarkable chest radiograph ( figure ); the patient was transferred to the intensive care unit (icu) with a high suspicion for covid- . testing for sars-cov- was completed using a nasopharyngeal swab transported in an m viral tube to the state department of health and human services. samples were tested on the sars-cov- real-time polymerase chain reaction (rt-pcr) abbott id now™ point-of-care system under the food and drug administration (fda) emergency use authorization (eua). computed tomography (ct) of the chest could not be performed due to concern for virus transmission and environmental contamination due to high demands and short downtime for decontamination. by day , the patient required higher flow rates on a non-rebreather mask, and by day , persistent fevers, tachypnea, and new consolidative changes in the right middle and lower lung zones were noted. he was empirically started on broad-spectrum antibiotics with hydroxychloroquine. foregoing bi-pap or c-pap due to concerns for aerosolization, he was placed on mechanical ventilation. his chest x-ray by day revealed extensive consolidative infiltrates bilaterally and a pao /fio (pf) ratio of consistent with severe acute respiratory distress syndrome (ards) (figure ). testing for sars-cov- came back positive, confirming covid- pneumonia. over the following days, he went into septic shock requiring vasopressor support, while previously sent cytokine labs, including an interleukin- (il- ) of pg/ml, were consistent with cytokine release syndrome. he was given a dose of tocilizumab mg. on day , extensive acute deep vein thromboses (dvts) was discovered in his left upper extremity with d-dimer levels over µg/ml. his previous prophylactic dose of enoxaparin was increased to a therapeutic dose. his fevers did not abate, requiring cooling, neuromuscular blockade, and deep sedation. ards strategies, including low tidal volumes, proning, recruitment maneuvers, diuretics, nitric oxide, and vitamin c, were used despite his rising pressures. during these periods, he exhibited high plateau pressures, often over cm of h o. worsening status prompted consideration of transfer to a specialized ecmo center. however, surrounding centers had limited the inflow of patients adhering to strict infection control measures, while judicious resource allocation and logistical challenges made transportation unfeasible. on day , after a sudden episode of desaturation, a chest x-ray revealed left-sided tension pneumothorax in the left mid and lower lung fields ( figure ) with a chest tube draining ml of serosanguineous fluid mixed with blood clots intermittently blocking output with persistent air leaks. fluid characteristics were not obtained, and his overall clinical trajectory began declining. a family discussion was held to discuss his poor prognosis and address the goals of care. his code status was changed to do-not-resuscitate (dnr) with an emphasis on comfort measures. he eventually desaturated and went into asystole, passing away after spending days in the hospital. trends in oxygenation in our patient can be seen in table . ards can be mitigated by opening collapsed alveoli with higher positive end-expiratory pressures (peeps), recruiting maneuvers, or proning. in contrast, these high pressures are poorly tolerated, leading to the use of low tidal volumes to minimize ventilator-induced lung injury (vili). despite this, high rates of barotrauma were reported from the previous sars epidemic [ ] . covid- patients complicated by ards ("cards") can present despite lacking traditional risk factors such as advancing age, pre-existing co-morbidities, or an advanced lung pathology [ ] . despite the initial insult being the inoculation of sars-cov- , cards can occur from injuries from either the gas or vascular side of the alveoli [ ] . approaching cards from the gas side cards is defined by phenotypes based on its clinical trajectory. "type l" has a relatively compensated clinical state while "type h" resembles full-blown ards ( table ). our patient, initially a type l, had scattered infiltrates with rising minute ventilation over days. type l patients are perceived to be breathing normally ("silent hypoxemia") and often respond to supplemental oxygen. at the same time, deep swings in respiration can induce patient self-inflicted lung injury (p-sili), triggering an inflammation cascade and a rapid downward spiral towards progressive pulmonary injury and pulmonary shrinkage, known as the 'vili vortex' towards full-blown ards [ ] . evidence of transformation to type h by day was noted by his rising plateau and driving pressures, lower static compliance, and low pf ratios signifying a bulkier lung. refractory hypoxia, fevers, and systemic insults led to a dependency on high peeps and fio to maintain oxygen saturation above %. post-mortem studies reveal numerous thromboses in covid- patients with d-dimer serving as a surrogate marker of pulmonary endothelial damage, promoting ventilation-perfusion mismatches and subsequent hypoxemia [ , , ] . dvts were noted in over % of patients, suggesting that coagulopathy may be an independent risk factor for poor prognosis [ ] . our patient reflected coagulopathy and vasoplegia with rising d-dimer levels in the days leading up to his dvt, while the development of cytokine release syndrome and coagulopathy signaled his growing disease burden. once this occurs, vasoregulation is altered due to the failure of hypoxic vasoconstriction from the endothelial damage resulting in significant hypoxemia. if the respiratory drive is not altered by oxygen administration, the generated inspiratory increases transpulmonary pressures across vascular channels, risking vili. this can also serve as a learning point, that early intubation strategies can help minimize the powerful respiratory effort leading to vasoplegia. if uncorrected, high plateau pressures reflecting high trans alveolar pressures can increase thoracic compliance leading to high oxygen and peep requirements that can redirect blood to damaged parts with high permeability affecting hemodynamics and contributing to type h conversion. the accepted thresholds for vili protection include a plateau pressure of cmh developed spontaneous pneumothorax with a % drop in his pf ratio because of his high plateau pressures, respiratory swings, and inflammation. the incidence of pneumothorax has been reported to be roughly % in covid- patients [ ] , although these represented spontaneous cases from the community, unlike our case which was a consequence of progressive lung injury and the inability to liberate the patient from the vili vortex. the development of pneumothorax after intubation can portend a poor prognosis in patients with cards [ ] [ ] [ ] . categorizing lung injury from covid- into cards type l or type h can help unwanted practices and initiate targeted ventilator approaches to correct the underlying mismatch. the surviving sepsis campaign recommended that mechanically ventilated covid- patients be managed similarly to other patients with respiratory failure in the icu, although with the growing body of evidence, cards is displaying a distinct course [ ] . the essential contributors to cards and entry into the vili vortex are ) sars-cov- burden, ) ventilator responsiveness, and ) time of symptom onset [ ] . the paucity of reported cases brings into light the importance of isolated reports in guiding therapy in the current climate. this case represents the first reported cards patient that developed a pneumothorax as a consequence of his phenotype conversion. in previous cases of sars patients, pneumothorax was noted at - days after the initial diagnosis [ ] , suggesting that a sustained period of lung inflammation serves as a pre-requisite, a similar time course as our patient recently a scoring system was proposed to predict the risk of developing critical illness in covid- , allowing early interventions and resource allocation to mitigate the high disease burden [ ] . covid- patients that develop ards ("cards") come in phenotypes: type l and h. type l is often stable while type h presents like full-blown ards. these patients require different ventilator strategies with the goal of avoiding conversion to type h and limiting vili. in these cases, pneumothorax may represent an indicator of a poor outcome. an interactive web-based dashboard to track covid- in real time respiratory support in novel coronavirus disease (covid- ) patients, with a focus on resource-limited settings respiratory conditions in coronavirus disease (covid- ): important considerations regarding novel treatment strategies to reduce mortality covid- : timing is important management of covid- respiratory distress covid- pneumonia: different respiratory treatments for different phenotypes? critically ill patients with severe acute respiratory syndrome clinical phenotypes of sars-cov- : implications for clinicians and researchers autopsy findings and venous thromboembolism in patients with covid- driving pressure and mechanical power: new targets for vili prevention a comparison of oesophageal and central venous pressures in the measurement of transpulmonary pressure change emergency tracheal intubation in patients with covid- in wuhan, china: lessons learnt and international expert recommendations sars-cov- infection associated with spontaneous pneumothorax covid- with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) severe acute respiratory syndrome complicated by spontaneous pneumothorax development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid- none. key: cord- -iheq ub authors: de jong, audrey; wrigge, hermann; hedenstierna, goran; gattinoni, luciano; chiumello, davide; frat, jean-pierre; ball, lorenzo; schetz, miet; pickkers, peter; jaber, samir title: how to ventilate obese patients in the icu date: - - journal: intensive care med doi: . /s - - -x sha: doc_id: cord_uid: iheq ub obesity is an important risk factor for major complications, morbidity and mortality related to intubation procedures and ventilation in the intensive care unit (icu). the fall in functional residual capacity promotes airway closure and atelectasis formation. this narrative review presents the impact of obesity on the respiratory system and the key points to optimize airway management, noninvasive and invasive mechanical ventilation in icu patients with obesity. non-invasive strategies should first optimize body position with reverse trendelenburg position or sitting position. noninvasive ventilation (niv) is considered as the first-line therapy in patients with obesity having a postoperative acute respiratory failure. positive pressure pre-oxygenation before the intubation procedure is the method of reference. the use of videolaryngoscopy has to be considered by adequately trained intensivists, especially in patients with several risk factors. regarding mechanical ventilation in patients with and without acute respiratory distress syndrome (ards), low tidal volume ( ml/kg of predicted body weight) and moderate to high positive end-expiratory pressure (peep), with careful recruitment maneuver in selected patients, are advised. prone positioning is a therapeutic choice in severe ards patients with obesity. prophylactic niv should be considered after extubation to prevent re-intubation. if obesity increases mortality and risk of icu admission in the overall population, the impact of obesity on icu mortality is less clear and several confounding factors have to be taken into account regarding the “obesity icu paradox”. electronic supplementary material: the online version of this article ( . /s - - -x) contains supplementary material, which is available to authorized users. obesity (defined by a body mass index (bmi) ≥ kg/ m ) is a disease caused by excess or abnormal distribution of fat tissue and resulting in chronic diseases related to chronic inflammation and metabolic dysfunction [ ] . obesity has become a global epidemic with prevalences rising both in developed and developing countries. front runners in are the united states of america (usa, %) and australasia ( %), with a prevalence expected to increase in the usa until % by [ ] , whereas european countries have prevalences between and %. the percentage of patients with obesity in the intensive care unit (icu) can be expected to increase concomitantly or even more since obesity increases the risk for a more severe disease course with more need for icu admission and mechanical ventilation [ ] as has been shown in trauma [ ] , traumatic brain injury [ ] patients, out-of-hospital cardiac arrest [ ] , during the h n pandemic [ ] and recently also in patients affected by coronavirus disease (covid- ) [ ] [ ] [ ] [ ] . obesity, especially abdominal obesity (android fat distribution) and severe obesity [ ] , results in altered respiratory anatomy and physiology and, therefore, complicated airway management and adapted ventilator settings during mechanical ventilation. obesity appears to be associated with an increased risk of acute respiratory distress syndrome (ards) [ ] and infection, mainly pneumonia [ ] , probably related to an imbalanced production of adipokines [ ] . in ventilated patients, obesity increases icu length of stay and the duration of mechanical ventilation [ ] . the phenomenon whereby obesity increases morbidity but seems to protect against mortality in selected critically ill patients, known as "obesity paradox", has been evocated in patients with ards [ ] and in those on mechanical ventilation [ ] , even if it remains highly debated. this narrative review will summarize current insights into the impact of obesity on the respiratory system and the measures to be taken to optimize airway management and mechanical ventilation in icu patients with obesity. the patient with obesity suffers from increased respiratory workload and impaired gas exchange. both disturbances reduce physical capacity and health margin if exposed to respiratory stress. a basic triggering factor is reduced lung volume, caused by cranial displacement of the diaphragm by increased tissue mass in the abdomen, and by increased chest wall tissue. the decrease in resting lung volume after normal expiration, functional residual capacity (frc), is - % per kg/m increase in bmi [ ] . the consequence of the increased tissue mass will be greater in the supine than upright position, due to a stronger cranial displacement of the diaphragm. in addition, a further decrease in the frc can be seen during anesthesia with loss of respiratory muscle tone and, most likely, in icu by the use of sedatives and muscle relaxants. the fall in frc promotes airway closure and atelectasis formation, as will be discussed later, and an illustration of one representative case with no ventilation in the dorsal part of the lung, likely because of dependent atelectasis formation [ ] , is shown in fig. . there are several causes of increased work of breathing in the patient with obesity. one is the increased displacement of tissue during the breathing, both in the abdomen and in the lung and chest wall. another is increased airway resistance because of smaller airway dimensions, and increased asthma incidence. finally, increased tissue resistance adds to the work of breathing [ ] . the patient with obesity may easily develop respiratory fatigue on physical exercise and, in the most severe cases, already at rest. it is often assumed that chest wall elastance or its inverse, chest wall compliance, is affected by obesity. however, the increased weight of the abdomen and of the chest wall requires work when moving the tissue, but when the move is over, no additional pressure is required [ ] . end-inspiratory and end-expiratory pauses should be long enough when measuring chest wall compliance. lung compliance, on the other hand, is reduced [ ] . the decreased lung volume may require pressure during inspiration to open closed units, and that may be recorded as a decrease in compliance. airways may close in dependent lung regions during an expiration, a normal age-dependent phenomenon. in patients with obesity, using non-invasive ventilation (niv) is advised both to prevent and treat acute respiratory failure. when invasive mechanical ventilation is needed, pre-oxygenation with niv and appropriated choice of intubation devices will decrease complications. during invasive mechanical ventilation, patients with obesity are more prone to lung collapse and require higher peep to avoid it; low v t is calculated on predicted body weight. when acute respiratory distress syndrome occurs, careful recruitment maneuver might be used associated with prone positioning. fig. impedance changes due to regional ventilation in a patient with obesity. thoracic transversal electric impedance tomography images show impedance changes due to regional ventilation summarized for tidal ventilation cycles in a patient with a body mass index of kg/m . images were recorded during spontaneous breathing before intubation (a) and about h after extubation (c) in a patient without lung pathology. note the ventral shift of ventilation during mechanical ventilation with a positive end-expiratory pressure (peep) of cmh o (b), which is likely due to atelectasis formation in dependent lung areas. obviously, the peep level was insufficient to keep the lung open while this has been known for many years, a more extensive, indeed complete airway closure has been shown during the last few years in anesthetised patients with obesity [ ] or icu patients with obesity on mechanical ventilation. this means that a certain airway pressure is needed to start inflation of the lungs and it is not caused by a time-dependent intrinsic positive end-expiratory pressure (peep). where the complete closure occurs is not clear but may be in the most central airways and not in the periphery. the latter would require simultaneous closure of thousands of airways, as recently discussed [ ] . hopefully, the morphology behind complete closure can be demonstrated in the near future. a consequence of the classic airway closure is impeded ventilation where the closure occurs and the decrease in ventilation will be larger the longer the closure lasts during the respiratory cycle. if airways are continuously closed, as can be seen during anesthesia and most likely in icu, the alveoli distal to the closure will collapse because of gas absorption [ ] . the higher the oxygen concentration is in the inspired gas, the faster is the collapse. with pure oxygen, it can take a few minutes and with air, a couple of hours. the complete closure, on the other hand, will delay onset of inspiration without affecting the distribution per se. uneven ventilation distribution caused by airway closure will occur primarily in dependent lung regions. perfusion of the lung, on the other hand, increases down the lung independent of anatomy. regions that are poorly but still ventilated will cause ventilation-perfusion mismatch and regions that collapse because of continuous airway closure will cause shunt [ ] . both impede oxygenation [ ] and a large shunt may even impair carbon dioxide (co ) elimination. with an extreme shunt, oxygenation is poorly or not at all improved by increasing oxygen in the inspired gas. finally, in patient with obesity, there is significant heterogeneity in both resistance and compliance, therefore, inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows known as pendelluft effect. however, the patients with obesity are not a homogeneous group regarding the physiological modifications, the level of obesity and the fat distribution (gynoid versus android) being confounding factors that should be taken into account. although hypoxemic acute respiratory failure (arf) is not the first cause of arf in the patient with obesity [ , ] , hypoxemia is frequent as it is favored by increased oxygen consumption or work of breathing and atelectasis formation, especially in cases of patients with morbid obesity and during arf [ ] . non-invasive strategies should first optimize body position with reverse trendelenburg position, "beach chair position" or sitting position, which improve respiratory compliance and gas exchange in patients with morbid obesity [ , ] . in patients having postoperative hypoxemia or arf, non-invasive ventilation (niv) is recommended with moderate certainty of evidence, justified by a decreased need of intubation, mortality and morbidity as compared to standard oxygen [ , ] . an observational study including patients with arf after abdominal surgery reported that niv avoided intubation in % of cases [ ] . in a post hoc analysis of a large trial of postoperative thoracic patients [ ] , it was shown that among the patients with obesity (mean bmi of kg/m ), niv was not superior to high-flow nasal cannula oxygen therapy (hfnc), with treatment failure occurring in % and % in niv and hfnc groups, respectively. therefore, niv could be considered as the first-line therapy in patients with obesity having a postoperative arf [ ] , but further studies are needed to confirm the role of continuous positive airway pressure (cpap) and/or hfnc in this setting [ , ] (table ) . data addressing the management of hypoxemic arf with non-invasive ventilatory/oxygen strategies are scarce, especially in patients with obesity. the recent international guidelines failed to offer a recommendation on the use of niv in hypoxemic arf [ ] . one large trial has compared niv with standard oxygen and hfnc in non-selected patients with hypoxemic arf [ ] . results showed lower mortality rates with hfnc than niv, thereby suggesting deleterious effects of niv. similarly, an observational study including patients with bmi > kg/m showed that, after adjustment on high severity scores, hypoxemic arf caused by pneumonia was associated with niv failure [ ] . however, according to physiological abnormalities in patients with obesity, niv could play a role, especially in patients with morbid obesity, through peep that may improve oxygenation and lung volume or alveolar recruitment [ ] . finally, possible use of niv or hfnc as alternative to standard oxygen in patients with obesity and hypoxemic arf is not determined, and future trials are needed (table ) . hypercapnic arf in patients with obesity can not only be part of the clinical course of cardiogenic pulmonary edema, pneumonia, asthma, and exacerbation of chronic lung diseases, but also may be due to exacerbation of obesity hypoventilation syndrome (ohs) [ ] . positive airway pressure, i.e. cpap (refer to one level of airway pressure) or niv (refer to two levels of airway pressures), is the recommended ambulatory treatment for ohs patients [ ] . similarly, niv is the usual treatment applied in ohs exacerbation, but no trial has evaluated its benefit as compared to other oxygen strategies. niv brings together potentially beneficial physiological effects, including peep preserving upper airway patency and pressure support to control central hypoventilation. however, an observational study including severely patients with obesity reports a lower bmi ( kg/m ) in patients with niv success versus kg/m in those who failed niv [ ] . in this setting, niv may be an appropriate treatment, but hfnc interspaced between niv sessions should be evaluated. in addition to the pathophysiological modification of the respiratory system discussed above, patients with obesity have peculiar morphological alterations potentially associated with difficulties during mask ventilation and airway management: reduced neck mobility, limited mouth opening, increased size of pharyngeal and glossal soft tissues, unfavorable conformation and positioning of the larynx, increased neck circumference and decreased thyromental distance [ ] . moreover, patients with obesity have a high incidence of obstructive sleep apnea [ ] , which is directly related to many of the complications occurring during airway management of this sub-population of critically ill patients [ ] . obesity contributes to airway compression through increased airway fat deposits [ ] , and placing the patient with obesity recumbent may lead to sudden death [ ] . it is very important to encourage upright positioning and avoid supine positioning. overall, obesity, especially super obesity (bmi ≥ kg/m ) with android fat distribution, is an important risk factor for major complications, morbidity and mortality related to intubation procedures in the icu [ ] . most of the literature existing on the airway management of patients with obesity is related to the operating room setting [ ] . in this context, several strategies are often recommended, including the adoption of ramped position using specific devices or pillows/blankets under the patient's head and shoulder, pre-oxygenation with positive pressure ventilation [ ] and the use of videolaryngoscopes [ ] . however, compared to the elective surgical patient with obesity, the intubation of the critically ill patient has profound differences in indications, timing and co-existing conditions; therefore, caution should be applied when translating in the icu the recommendations based on evidence in the operating room. in the icu, the incidence of difficult intubation is double compared to the or and the occurrence of severe complications is dramatically higher [ ] . pre-procedural patient preparation is key to successful intubation. an ideal preparation aims at prolonging timeto-desaturation, which in patients with obesity is mainly related to the rapid loss of frc after sedation. concerning positioning, a randomized controlled trial questioned the usefulness of the ramped position applied in critically ill patients [ ] ; however, the study included a large proportion of patients without obesity. therefore, patient positioning should be individualized on the patient anatomy, based also on the intensivist's expertise. a semi-sitting position during pre-oxygenation could help to decrease positional flow limitation and air trapping [ ] . conventional bag-mask ventilation can result in rapid desaturation in patients with morbid obesity. several studies confirmed that pre-oxygenation with cpap or niv improves oxygenation allowing a longer time window for intubation [ , ] . for these reasons, positive pressure pre-oxygenation should be considered the reference in critically ill patients with obesity, considering that obesity carries an intrinsic increased risk for difficult mask ventilation. hfnc might also have a role [ ] , especially in rapid sequence intubation in non-severely hypoxemic patients, where avoidance of bag ventilation might be desirable but is associated with higher incidence of severe desaturation [ ] . however, the value of hfnc value in patients with obesity must be clarified, and cannot replace a preoxygenation using positive pressure [ ] . the intubation maneuver should be always considered as potentially difficult in patients with obesity [ ] , with older age, higher bmi, high mallampati and macocha scores and reduced neck mobility being independent risk factors for both difficult mask ventilation and intubation. a meta-analysis in surgical patients with obesity suggested an advantage of videolaryngoscopes over direct laryngoscopy [ ] . in icu patients with obesity, it seems reasonable to consider the use of videolaryngoscopes by adequately trained intensivists, especially in patients with several risk factors. obesity is associated with abdominal and thoracic tissue mass, which transmit additional hydrostatic pressure via the chest wall and diaphragm to the pleural space and, thus, the alveoli. if pleural pressure is higher than intraalveolar pressure, the alveoli will collapse, and compression atelectasis will occur predominantly in dependent lung areas, where hydrostatic pressure is highest. for example, functional residual capacity is impaired by up to % in non-ventilated subjects with obesity in the supine position [ ] and total lung and vital capacity are reduced as well. induction of anesthesia with muscle relaxation following pre-oxygenation with % o further reduces end-expiratory lung volume (eelv) by about %, if a positive end-expiratory pressure (peep) of cmh o is used after initiation of mechanical ventilation (fig. ) [ ] . the main mechanism of gas exchange impairment is, therefore, shunt (atelectasis) in patients with obesity [ ] . because the opening pressure of alveoli is higher than the pressure needed to keep them open, application of an initial recruitment maneuver (rm) followed by adequate peep after intubation or disconnection of the patient from the ventilatory circuit seems intuitive. due to the high pleural pressure in patients with obesity, opening pressures up to cmh o applied during a rm in patients with obesity without lung injury may not result in full lung recruitment [ ] . potential side effects of applying such high airway pressures include a decrease in venous return and, thus, cardiac preload with a drop in cardiac output and systemic blood pressure. in addition, barotrauma such as pneumothorax or pneumomediastinum especially in patients with pre-existing structural lung damage such as emphysema, and a mechanically triggered boost of pre-existing lung inflammation may occur. thus, rm is not generally recommended, and their use remains a decision based on individual risk/benefit considerations. in mechanically ventilated patients, peep is used to keep alveolar pressure above the closing pressure of alveoli thereby maintaining end-expiratory lung volume (eelv) and arterial oxygenation. in another words, peep does not strictly induce alveolar recruitment but peep avoids alveolar derecruitment by maintaining open alveoli. thus, protective ventilation strategies may improve clinical outcomes even in patients without ards [ ] . due to the superimposed pressure transmitted by adipose tissue on the pleural space, closing pressures in patients with obesity are higher and lungs of these patients are more prone to such complications (fig. ) . despite these considerations, routinely used peep levels applied for ventilation of patients with obesity are often not higher than in normal weight patients [ ] . in previous studies, different methods to find the individualized "best" peep in patients with obesity have been used. these approaches targeted improvements in oxygenation, lung mechanics, and regional ventilation distribution. in patients undergoing bariatric surgery, individualized peep resulted in a range of peep levels between and cmh o with a median of cmh o [ ] and restored eelv to the same level before intubation and initiation of mechanical ventilation. other studies regularly found peep levels > cmh o [ , ] . however, a large trial of ventilation in patients with obesity during anesthesia did not demonstrate a difference in postoperative pulmonary complications for constant peep levels of versus cmh o [ ] . the peep levels in this pragmatic study, however, were not aiming at and resulting in full lung recruitment. as mentioned above, use of higher airway pressures is often associated with hemodynamic depression and higher requirements for fluids and vasopressors [ ] . at least in the perioperative setting, evidence from meta-analyses and clinical trials are somewhat conflicting regarding improved clinical outcomes [ , ] . limiting tidal volume (v t ) has been shown to reduce ventilation-associated lung injury and inflammation in non-selected patients with and without ards. the idea of normalizing v t for predicted body weight (pbw) is based on the expected lung volume (dependent on patient's height and sex) and aims to limit the v t /eelv ratio, i.e., mechanical lung strain. as mentioned above, eelv is regularly below the values in a normal weight population. thus, referencing v t to pbw per se can result in higher strain than in normal weight patients. if pbw is not formally calculated but just estimated, there is a tendency to overestimate pbw and, thus, v t in patients with obesity [ ] . positioning patients with obesity in ramped or sitting positions and even early mobilization may facilitate unloading the diaphragm from increased abdominal pressure and may thereby improve aeration of dependent lung areas. early implementation of spontaneous breathing activity can preserve diaphragmatic tension, redistribute ventilation to dependent lung areas [ ] , may avoid diaphragmatic muscle atrophy caused by muscle relaxation [ ] and reduce duration of mechanical ventilation [ ] . anzueto et al. [ ] and karla et al. [ ] showed that ards patients with obesity were ventilated with higher v t (per kg of pbw) compared to ards patients without obesity. it is tempting to speculate that the amount of atelectasis was different between patients with and without obesity and that the higher v t was chosen by the clinicians to maintain an adequate alveolar ventilation. a study by grasso et al. [ ] tempted to confirm this hypothesis by reporting a decrease in the use of extracorporeal membrane oxygenation (ecmo) in patients with abdominal hypertension by increasing the airway pressure-often above cmh o-based on a transpulmonary pressure target. interestingly, in the study by karla et al. [ ] , the airway plateau pressure and driving pressure were similar between patients with and without obesity. of note, in both studies, the outcome was similar between the two groups. similarly, de jong et al. [ ] , in ards patients with obesity did not find any difference in driving pressure between survivors and non survivors [ ] . when ards patients with obesity were compared to patients with ards but with a normal bmi, it was found that the two groups had similar recruitability and changes in oxygenation when peep was increased from to cmh o [ ] . in these two groups, abdominal pressure and chest wall elastance were also similar. in contrast, fumagalli et al. [ ] found an impressive improvement in oxygenation and lung elastance using higher peep ( cmh o) compared to lower peep ( cmh o). the higher peep was selected according to transpulmonary pressure, while the lower peep was selected according to a peep/fio table. once again, the abdominal pressure was not measured (or reported). the same authors in a retrospective study of patients with severe ards found better gas exchange, respiratory mechanics, and survival in patients treated according to a personalized approach (based on transpulmonary pressure) compared to patients treated with a standard protocol [ ] . the personalized approach resulted in much higher peep levels of cmh o compared to cmh o used in the standard approach. a retrospective analysis of the alveoli trial showed improved outcome using peep cmh o compared to cmh o [ ] . in this trial, however, patients with a weight > kg/cm of height and bmi usually > kg/m were not included. we may wonder why the reported effect of different levels of peep differs among studies. we have to note that the bmi of the population of the different studies was kg/ m , as in the study of chiumello et al. [ ] and likely in the alveoli study [ ] , versus a bmi higher than kg/m in the study by fumagalli et al. [ ] . given such a different bmi, it is likely that the abdominal pressure and mechanical impairment were different in the different populations. the normalized mechanical power, that has been shown being strongly associated with mortality [ ] , was not monitored. moreover, rm was not consistently used, and their use and timing remain a matter of debate in ards patients with and without obesity [ ] . a peep decremental trial preceded by a rm may decrease lung overdistension and collapse in ards obese patients [ ] . in ards patients with severe obesity (bmi = ± kg/ m ) [ ] , rm was performed during pressure controlled fig. effect of obesity in main pressures of the respiratory system. the respiratory system includes the lung and the chest wall, and the airway pressure is related to both transpulmonary and transthoracic pressures, which differ in the patient with obesity compared to the patient without obesity. the relative part of pressure due to transthoracic pressure is often higher in the patient with obesity than in the patient without obesity (elevated pleural pressure, which can be estimated by esophageal pressure). the plateau pressure represents the pressure used to distend the chest wall plus lungs. in patients with obesity, elevated plateau pressure may be related to an elevated transthoracic pressure, and not an increase in transpulmonary pressure with lung overdistension. frc functional residual capacity ventilation with delta pressure of cmh o, peep was increased until a plateau pressure of cmh o for min. after, the ventilator mode was switched to volume controlled ventilation ( ml/kg of pbw), and the peep dropped by cmh o every s. the optimal peep was determined by the peep value with the best compliance of the respiratory system plus cmh o. finally, a second lung rm was performed and the selected optimal peep was set. required peep was increased to [ , ] cmh o above traditional ardsnet settings with improvement of lung function, oxygenation and ventilation/perfusion matching, without impairment of hemodynamics or right heart function. moreover, in a retrospective study [ ] , the same authors also reported that patients treated with rm and with higher peep were weaned from vasopressors agents faster (and improved survival) than patients who were treated with low ardsnet peep table. future investigations would be beneficial to clarify the lungheart interaction when high airway pressure is used in the settings of high pleural pressure. given that the setting of mechanical ventilation (v t , peep) and the indicators of ventilator-induced lung injury (mechanical power, driving pressure) are crucially dependent on chest wall elastance, it is our opinion that it is difficult to propose any treatment if key variables such as transpulmonary pressure and intra-abdominal pressure are not measured or ignored (fig. ) . prone position [ ] also deserves attention in patients with ards and obesity. the safety and efficiency of this therapeutic were similar between patients with and without obesity, and the ratio of alveolar pressure in oxygen over fraction of inspired oxygen (pao /fio ) was significantly more increased after prone position in patients with obesity compared to patients without obesity [ ] . prone position is a therapeutic of choice in patients with severe ards and obesity, and the mechanisms of action, caution and clinical effects are detailed in fig. . in case of severe ards after failure or inability to use prone positioning and neuromuscular blockers, veno-venous extracorporeal membrane oxygenation (ecmo) can also be safely used in ards obese patients [ , ] . the spontaneous breathing trial should be clearly separated from the level of pressure support and peep set before extubation and the respiratory support following extubation. a physiological study specifically assessed the inspiratory effort during weaning of mechanical ventilation in critically ill patients with morbid obesity [ ] . the main result of this study was that for patients with obesity, t-piece and pressure support ventilation + peep cmh o were the weaning tests predicting post-extubation inspiratory effort and work of breathing the most accurately [ ] . if the work of breathing is closely the same between t-tube and after extubation [ ] , the patient with obesity remains prone to atelectasis, and therefore, atelectases should be avoided as much as possible. that is s why after a t-tube, the obese patient should be reconnected to mechanical ventilation, as already demonstrated in patients without obesity [ ] , and put again under pressure support with sufficient peep and pressure support. similarly, following extubation, as detailed below, preventing atelectasis has to start as soon as possible, using cpap or niv. moreover, to perform extubation as soon as possible, sedation should be stopped as early as possible and benzodiazepines avoided, even more than in patients without obesity due to prolonged release of drugs in patients with obesity [ ] . prophylactic niv after extubation decreases the risk of arf by % and length of icu stay [ ] . in hypercapnic icu patients with obesity, using niv after extubation is associated with decreased mortality [ ] . a randomized controlled trial performed in patients with morbid obesity undergoing bariatric surgery found an improvement of ventilatory function when cpap was implemented immediately after extubation as compared to cpap started min after extubation [ ] (table ). in case of positive pressure therapy already used at home, it should be reintroduced as early as possible in the icu as soon as higher levels of assistance requiring the use of an icu ventilator are no longer needed. home positive pressure therapy could also be introduced in icu for selected patients with obesity. cpap is indicated for use in patients with severe obstructive sleep apnea syndrome, as first-line therapy in these indications. in the case of combined obstructive apnea syndrome and moderate hypercapnia between and mmhg, a cpap device will be offered as first-line therapy, and a niv device, allowing ventilation at pressure levels, will be offered in case of failure. if there is a history of respiratory decompensation with acute hypercapnic respiratory failure, hypercapnia greater than mmhg and/or no associated obstructive sleep apnea syndrome, a niv device will be offered [ ] . hfnc was not found to be superior to standard oxygen to prevent extubation failure in post-cardiac surgery patients with obesity [ ] . among cardiothoracic surgery subjects with obesity with or without respiratory failure, the use of continuous hfnc compared to niv did not result in a worse rate of treatment failure [ ] (table ) . similarly, in the study by hernandez et al. [ ] including % of patients with obesity, among high-risk adults who have undergone extubation, preventive hfnc was not inferior to preventive niv for reducing reintubation rate and postextubation respiratory failure. in a randomized controlled trial of the same team comparing hfnc to standard oxygen [ ] in high-risk non-hypercapnic patients including % of patients with obesity, the study was stopped due to low recruitment after patients, without any difference in extubation failure rate found between the two groups. the specificities of weaning and extubation in icu patients with obesity are summarized in supplemental table . a summary of the main respiratory physiological modifications and some suggestions for mechanical ventilation in critically ill patients with obesity are proposed in fig. . in the general population, obesity is one of the top risk factors of chronic diseases and a risk factor for death. consistent with this trend in the general population, the number of obese patients admitted to the icu is rapidly increasing [ ] . obesity decreases life expectancy in the population, and obesity in childhood is now a healthcare crisis for our next generation with unknown consequences. there are overwhelming scientific data on overall mortality/morbidity, the healthcare system shortcomings to deliver adequate care, and the social discrimination and injustice that individuals with obesity are subject on daily basis. however, in icu, patients with obesity may be more likely to develop ards, but their survival sometimes appeared to be better, a phenomenon called the 'obesity paradox' [ ] . patients with obesity have immunological and pulmonary mechanics differences compared to patients without obesity detailed in the supplemental content (see supplemental content ). these differences are increased for patients with higher level of obesity. furthermore, clinicians may overestimate the lung size of patients with obesity, by considering real instead of pbw, and use higher v t during mechanical ventilation, risking ventilator-induced lung injury. the mentioned patient factors may also cause respiratory muscle fatigue and difficult weaning. indeed, meta-analyses show that in close to , ards patients, obesity is linked to a higher risk of developing ards and patients with obesity need mechanical ventilation for a longer period of time, compared to critically ill patients without obesity [ , ] . as a consequence, icu-length of stay is also prolonged in patients with obesity, while hospital length of stay is not [ , ] . while patients with obesity are on mechanical ventilation for a longer period of time, these meta-analyses also demonstrate a survival advantage for patients with obesity. this observation is coined the 'obesity paradox' as a survival benefit may appear counterintuitive in view of the detrimental alterations in respiratory function as described above. several reasons to explain the obesity paradox in ards patients with obesity have been put forward. apart from the described immunological differences, patients with obesity have more metabolic reserve and may, therefore, tolerate the catabolic stress of critical illness during ards better, because of energy stores in the form of adipose tissue. it is important to also address the possibility that patients with obesity may have a lower threshold for icu admission, e.g., because of the need of more nursing staff not available on the ward or monitoring purposes. this would mean that patients with obesity admitted to the icu are less sick and therefore may show a better survival because of selection bias, not representing a real phenomenon. as in the meta-analyses, adjustments for covariates like disease severity were not possible; this may appear plausible. in a large study in over , icu patients, however, the obesity paradox remained present even when adjusted for several covariates including disease severity [ ] . also, patients with obesity may have been misclassified as ards if atelectasis is interpreted as bilateral infiltrates. using a causal inference approach to reduce residual confounding bias due to missing data, it was found that the survival of patients without obesity would not have been improved if they had obesity [ ] , findings which question the obesity paradox. in summary, patients with obesity are more likely to develop respiratory complications, including arf and ards. considering some physiological studies, for non-invasive management, using niv has to be considered both for preventing and treating arf, even if the level of proof is low, especially in comparison with hfnc. airway management in critically ill patients with obesity poses specific challenges, and adequate patient evaluation, pre-oxygenation and choice of intubation devices might improve outcomes. after intubation procedure for invasive mechanical ventilation, patients with obesity being more prone to lung collapse require higher peep to avoid it. low v t according to pbw should be used both in non-ards and ards fig. main respiratory physiological modifications and suggestions for mechanical ventilation in critically ill patients with obesity. the main respiratory physiological modifications (functional residual capacity decreased, abdominal pressure often increased, pulmonary and chest wall compliance often decreased, cephalic ascension of diaphragm, oxygen consumption and work of breathing increased) lead to shunt via atelectasis and gas exchange impairment. comorbidities are often associated with obesity: obstructive apnea syndrome and obesity hypoventilation syndrome. consequences on airway management, potentially difficult, include the preparation of adequate material for difficult intubation as videolaryngoscopes, preoxygenation with noninvasive ventilation in a semi-sitting position, considering adding apneic oxygenation (optiniv method), rapid sequence induction and recruitment maneuver following intubation after hemodynamic stabilization. ventilatory settings include low or limited tidal volume ( - ml/kg/pbw or less), moderate to high peep ( - cmh o) if hemodynamically well tolerated, recruitment maneuver (if hemodynamically well tolerated, in selected patients), monitoring of esophageal pressure if possible, use of prone positioning in a trained team in case of severe ards, without contra-indicating ecmo. after extubation, cpap or niv should be considered early, as implementation of positive pressure therapies at home after evaluation. pbw predicted body weight, peep positive end-expiratory pressure, ards acute respiratory distress syndrome, ecmo extracorporeal membrane oxygenation, cpap continuous positive airway pressure, niv noninvasive ventilation, hfnc high-flow nasal cannula oxygen patients. rm is not systematically recommended, and their use remains a decision based on individual risk/ benefit considerations. prone positioning should be used in severe ards patients with obesity. body-mass index and all-cause mortality: individual-participant projected us state-level prevalence of adult obesity and severe obesity obesity in the critically ill: a narrative review prevalence of cardiovascular and respiratory complications following trauma in patients with obesity isolated severe blunt traumatic brain injury: effect of obesity on outcomes obesity was associated with worse neurological outcome among japanese patients with out-ofhospital cardiac arrest obesity is associated with higher risk of intensive care unit admission and death in influenza a (h n ) patients: a systematic review and meta-analysis comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease : a systematic review and meta-analysis increased mortality in patients with severe sars-cov- infection admitted within seven days of disease onset how important is obesity as a risk factor for respiratory failure, intensive care admission and death in hospitalised covid- patients? results from a single italian centre implications of obesity for the management of severe coronavirus disease pneumonia the role of visceral adiposity in the severity of covid- : highlights from a unicenter cross-sectional pilot study in germany obesity paradox" in acute respiratory distress syndrome: asystematic review and meta-analysis body mass index and the risk of infection -from underweight to obesity obesity altered t cell metabolism and the response to infection is body mass index associated with outcomes of mechanically ventilated adult patients in intensive critical units? a systematic review and meta-analysis the effects of body mass index on lung volumes individualized positive end-expiratory pressure in obese patients during general anaesthesia: a randomized controlled clinical trial using electrical impedance tomography physiology of obesity and effects on lung function the effects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia airway closure during surgical pneumoperitoneum in obese patients airway closure, more harmful than atelectasis in intensive care? respiratory function during anesthesia: effects on gas exchange oxygenation impairment during anesthesia: influence of age and body weight impact of obesity in mechanically ventilated patients: a prospective study outcomes of morbidly obese patients requiring mechanical ventilation for acute respiratory failure the impact of morbid obesity on oxygen cost of breathing (vo( resp)) at rest effects of sitting position and applied positive end-expiratory pressure on respiratory mechanics of critically ill obese patients receiving mechanical ventilation the effects of the reverse trendelenburg position on respiratory mechanics and blood gases in morbidly obese patients during bariatric surgery official ers/ats clinical practice guidelines: noninvasive ventilation for acute respiratory failure effect of noninvasive ventilation on tracheal reintubation among patients with hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive pressure ventilation high-flow nasal cannula therapy versus intermittent noninvasive ventilation in obese subjects after cardiothoracic surgery noninvasive respiratory support in the hypoxaemic peri-operative/periprocedural patient: a joint esa/esicm guideline use of nasal high flow oxygen during acute respiratory failure prevention and care of respiratory failure in obese patients high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure determinants of noninvasive ventilation success or failure in morbidly obese patients in acute respiratory failure noninvasive ventilation and alveolar recruitment maneuver improve respiratory function during and after intubation of morbidly obese patients: a randomized controlled study evaluation and management of obesity hypoventilation syndrome. an official american thoracic society clinical practice guideline perioperative care of the obese patient respiratory management of the obese patient undergoing surgery mechanical ventilation in obese icu patients: from intubation to extubation pathophysiology of sleep apnea cardiac arrest and mortality related to intubation procedure in critically ill adult patients: a multicenter cohort study difficult intubation in obese patients: incidence, risk factors, and complications in the operating theatre and in intensive care units videolaryngoscope versus macintosh laryngoscope for tracheal intubation in adults with obesity: a systematic review and meta-analysis a multicenter, randomized trial of ramped position vs sniffing position during endotracheal intubation of critically ill adults positive end-expiratory pressure during induction of general anesthesia increases duration of nonhypoxic apnea in morbidly obese patients nasal high-flow preoxygenation for endotracheal intubation in the critically ill patient: a randomized clinical trial bag-mask ventilation during tracheal intubation of critically ill adults focus on noninvasive respiratory support before and after mechanical ventilation in patients with acute respiratory failure prevention of atelectasis in morbidly obese patients during general anesthesia and paralysis: a computerized tomography study protective versus conventional ventilation for surgery: a systematic review and individual patient data meta-analysis intraoperative ventilation settings and their associations with postoperative pulmonary complications in obese patients noninvasive monitoring of lung recruitment maneuvers in morbidly obese patients: the role of pulse oximetry and volumetric capnography positive endexpiratory pressure optimization using electric impedance tomography in morbidly obese patients during laparoscopic gastric bypass surgery effect of intraoperative high positive end-expiratory pressure (peep) with recruitment maneuvers vs low peep on postoperative pulmonary complications in obese patients: a randomized clinical trial a trial of intraoperative lowtidal-volume ventilation in abdominal surgery spontaneous breathing with airway pressure release ventilation favors ventilation in dependent lung regions and counters cyclic alveolar collapse in oleic-acid-induced lung injury: a randomized controlled computed tomography trial nava in acute respira-tory failure (naviator) network ( ) neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial influence of body mass index on outcome of the mechanically ventilated patients higher class of obesity is associated with delivery of higher tidal volumes in subjects with ards ecmo criteria for influenza a (h n )-associated ards: role of transpulmonary pressure impact of the driving pressure on mortality in obese and non-obese ards patients: a retrospective study of cases driving pressure in obese ventilated patients: another brick in the (chest) wall effect of body mass index in acute respiratory distress syndrome transpulmonary pressure describes lung morphology during decremental positive end-expiratory pressure trials in obesity a lung rescue team improves survival in obesity with acute respiratory distress syndrome high positive end-expiratory pressure is associated with improved survival in obese patients with acute respiratory distress syndrome mechanical power normalized to predicted body weight as a predictor of mortality in patients with acute respiratory distress syndrome effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis lung recruitment in obese patients with acute respiratory distress syndrome lung rescue team investigators ( ) high pleural pressure prevents alveolar overdistension and hemodynamic collapse in ards with class iii obesity a prospective international observational prevalence study on prone positioning of ards patients: the apronet (ards prone position network) study feasibility and effectiveness of prone position in morbidly obese patients with ards: a case-control clinical study class iii obesity is not a contraindication to venovenous extracorporeal membrane oxygenation support lack of association between body weight and mortality in patients on venovenous extracorporeal membrane oxygenation spontaneous breathing trial and post-extubation work of breathing in morbidly obese critically ill patients reconnection to mechanical ventilation for h after a successful spontaneous breathing trial reduces reintubation in critically ill patients: a multicenter randomized controlled trial immediate interruption of sedation compared with usual sedation care in critically ill postoperative patients (sos-ventilation): a randomised, parallel-group clinical trial noninvasive ventilation for prevention of post-extubation respiratory failure in obese patients continuous positive airway pressure via the boussignac system immediately after extubation improves lung function in morbidly obese patients with obstructive sleep apnea undergoing laparoscopic bariatric surgery how can i manage anaesthesia in obese patients? direct extubation onto high-flow nasal cannulae post-cardiac surgery versus standard treatment in patients with a bmi >/= : a randomised controlled trial effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial high-flow nasal cannula to prevent postextubation respiratory failure in high-risk non-hypercapnic patients: a randomized multicenter trial intensive care in the obese the obesity paradox in surgical intensive care unit patients body mass index is associated with hospital mortality in critically ill patients: an observational cohort study the obesity paradox in critically ill patients: a causal learning approach to a casual finding key: cord- -aurm i authors: schenck, edward j.; hoffman, katherine; goyal, parag; choi, justin; torres, lisa; rajwani, kapil; tam, christopher w.; ivascu, natalia; martinez, fernando j.; berlin, david a. title: respiratory mechanics and gas exchange in covid- –associated respiratory failure date: - - journal: ann am thorac soc doi: . /annalsats. - rl sha: doc_id: cord_uid: aurm i nan the coronavirus disease (covid- ) pandemic has dramatically increased the number of patients requiring mechanical ventilation for respiratory failure. several case series with data on ventilator variables from small cohorts have been reported ( - ). however, differences in respiratory mechanics between those with early mortality and successful extubation have not been explored. in this study, we report physiologic and clinical information from a large group of patients with covid- during the first week of mechanical ventilation. this single center cohort study of patients with covid- , with a positive rt-pcr for severe acute respiratory syndrome coronavirus (sars-cov- ), treated with mechanical ventilation was performed at new york presbyterian hospital-weill cornell medicine from march st, through april th, . care of the patients was at the discretion of the treating intensivists. daily briefings were held with critical care leadership to inform best practices as patient load increased. volumecontrolled ventilation was suggested as first choice with a target tidal volume of - cc/kg of ideal body weight and a plateau pressure < cm h o ( ). positive end-expiratory pressure (peep) was selected by the treating physicians. neuromuscular blockade was suggested for patients with severe hypoxemia or ongoing ventilator dyssynchrony. prone positioning was suggested if the partial pressure of o :fraction of inspired o (p:f) ratio remained under despite optimization of ventilator settings over the first hours. pressure-targeted ventilation was considered if patients experienced dyssynchrony when sedation was weaned. we extracted demographic and chest x-ray findings at baseline. data were extracted from the electronic medical record from days , , and of mechanical ventilation. set fraction of inspired oxygen, plateau pressure, extrinsic peep, set tidal volume, and minute ventilation were recorded. in patients treated with pressure-targeted ventilation, the distending pressure was used to estimate a plateau pressure. volumetric capnography was not available; therefore, a surrogate of dead space, called the ventilatory ratio, was used ( ) . the ventilatory ratio is an independent predictor of survival in acute respiratory distress syndrome (ards) ( , ) . we compared the distributions of each individual parameter at days and between those who remained intubated, those successfully extubated, and those who died. we also examined changes over the three time points across the total cohort. we compared the distributions of each individual variable using nonparametric kruskal-wallis tests, with a false discovery rate correction for multiple testing. all analyses were performed using r (version . . ; r foundation for statistical computing, https://www.r-project.org/). the study was approved by the institutional review board at weill cornell medicine with a waiver of informed consent (no. - ). data are presented as median (interquartile range). table summarizes demographics, comorbidities, and intensive care unit treatments for this cohort. a total of patients had ventilator data available. the median age was ( - ) years, and men made up % of the cohort. bilateral infiltrates were present on the first available chest film in % of patients. a total of ( %) patients was treated with prone positioning, and ( %) patients were treated with neuromuscular blockade during the course of mechanical ventilation. during the observed time period, patients were successfully extubated and died. among the remaining intubated, the median duration of mechanical ventilation was ( - ) days. ventilator variables for the cohort are summarized in table . on day , the median p:f ratio was ( - ). this increased modestly over the first days. the median plateau pressure was ( - ) cm/h o on day and remained constant. the median tidal volumes were . ( . , . ) ml/kg of ideal body weight on day , and decreased over the observed period. the median driving pressure was . ( . - . ) cm/h o, and decreased. the median extrinsic peep was ( - ) cm/h o, and increased. the median static compliance was ( - ) ml/cm h o, and remained constant. the median ventilatory ratio was . ( . - . ), and increased over the observed period. table displays differences in ventilator variables between those who remained intubated, those successfully extubated, and those who died. there were no differences in any ventilator variables observed on day in any group. however, on day , the minute ventilation was higher in those who died compared with the other groups (corrected q , . ). on day there was a trend for higher ventilator ratio (corrected q = . ) and a lower p:f ratio (corrected q = . ) in those who died compared with those who remain intubated or were extubated. this study of patients demonstrates that respiratory failure related to covid- meets the criteria for moderate to severe ards, given the initial median p:f ratio of . these data compliment other early reports ( , , ) . there was also a high use of rescue therapies, such as prone positioning and a prolonged duration of mechanical ventilation. this severe morbidity occurred despite the use of a lung-protective ventilation strategy, as evidenced by the median plateau pressures and tidal volume. an important question is whether or not covid- is a distinct form of ards that requires a different treatment strategy ( ) . importantly, ards is not a single disease. rather, patients with ards have diverse pathology, and the syndrome's definition is used to identify eligibility for therapeutic trials. in this cohort, the baseline extrinsic peep, driving pressure, and static compliance were similar to ards network trials, and the recent worldwide observational study, lungsafe (large observational study to understand the global impact of severe acute respiratory failure) ( ) ( ) ( ) . however, the variability of the respiratory compliance is considerable, as % of patients have a compliance greater than ml/cm h o, which suggests significant heterogeneity. the duration of mechanical ventilation was prolonged in those that remained intubated, which is longer than in other studies of ards ( ). surprisingly, there were no observed differences between those with early mortality compared with those that remained intubated or were successfully extubated in this cohort. however, on day , increasing minute ventilation and ventilatory ratio were seen in those who died, along with a p:f ratio that failed to improve. these findings suggest the potential for differential patient trajectories within this disease. there are a number of limitations of our study. first, the three time points of our study are only snapshots of the dynamic nature of covid- respiratory failure. moreover, the majority of patients in this cohort were still receiving mechanical ventilation at the time of this analysis. a more definitive comparison of covid- respiratory failure with other forms of ards would require rigorous comparison with a contemporary control group. our analysis of respiratory system compliance does not account for the effects of peep titration. moreover, we lack volumetric capnography, and therefore cannot assess the effects of metabolic rate on gas exchange. we would expect that metabolic rate would vary greatly during fever and neuromuscular blockade ( ) . a more complete characterization of gas exchange in covid- would require direct measurement of the dead space and shunt fraction. another limitation of our study is the incomplete standardization of ventilator practice without the use of a formal peep titration table. conclusions. patients in this cohort of covid- respiratory failure meet criteria for moderate to severe ards, and had baseline respiratory mechanics that were comparable to those in patients enrolled in prior therapeutic trials and observational studies of ards. baseline respiratory mechanics were not different between those who died and those extubated or who remained intubated. differences in these groups developed over time, suggesting differential trajectories of covid- -associated respiratory failure. author disclosures are available with the text of this letter at www.atsjournals.org. ventilatory ratio in hypercapnic mechanically ventilated patients with covid- -associated acute respiratory distress syndrome covid- does not lead to a "typical" acute respiratory distress syndrome respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study fifty years of research in ards: respiratory mechanics in acute respiratory distress syndrome ventilatory ratio: a simple bedside measure of ventilation physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome covid- lombardy icu network. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region management of covid- respiratory distress lung safe investigators; esicm trials group. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries national heart, lung, and blood institute petal clinical trials network. early neuromuscular blockade in the acute respiratory distress syndrome: reply acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome the effect of mechanical ventilation on oxygen consumption in critically ill patients yr, mean (sd) driving pressure cm h o, median (iqr) pa o /fi o , mm hg, mean (sd) compliance, ml/cm h o, mean (sd) . ( . ) severity ct, %, median (iqr) . ( - ) nonfocal morphology, n (%) definition of abbreviations: ct = computed tomography fi o = fraction of inspired oxygen pa o = arterial oxygen tension peep = positive end-expiratory pressure sd = standard deviation this article is open access and distributed under the terms of the creative commons attribution non-commercial no derivatives license the authors thank all of the nurses, respiratory therapists, and physicians who courageously expanded their roles during this surge. this work was made possible through data provided by the to the editor:guidance on the best provision of care for patients with coronavirus disease (covid- ) is urgently needed. recently a strong argument in defense of an evidence-based approach was made in annalsats ( ), and we fully support the given line of reasoning. most patients in the intensive care unit (icu) with severe covid- meet the criteria for acute respiratory distress syndrome (ards), and proven therapies for ards not related to covid- are likely effective in these patients as well. however, ards is known to be a heterogeneous syndrome. over the past decade, several biological, physiological, and morphological subphenotypes have been identified that may predict treatment effects and can be used as treatable traits ( ) . for example, patients with a focal lung morphology seem to respond better to prone positioning, but their lungs are not as recruitable as those of patients with a nonfocal lung morphology ( ).it has been postulated that patients with covid- -related ards can develop typical ards (recently called "h type," characterized by high elastance, high shunt, and high lung weight) or have an atypical presentation (recently called "l type," characterized by low elastance, low shunt, and low lung weight) ( ). as with the abovementioned morphological subphenotypes, some investigators have speculated that these subphenotypes require different ventilator strategies. patients with h-type ards may benefit from lower tidal volumes and higher positive end-expiratory pressure (peep), and patients with l-type ards may benefit from higher tidal volumes and lower peep ( ) .several steps have to be taken before subphenotypedirected treatment can be implemented in clinical practice ( ) . the ultimate test would be a head-to-head comparison of subphenotype-directed treatment with standard of care in a randomized controlled trial. but before this step can be considered, it is important to validate the basic assumptions underlying the subclassification of patients. we hypothesized that patients with a low elastance (i.e., with a high respiratory system key: cord- - n tj authors: marini, john j.; dellinger, r. phillip; brodie, daniel title: integrating the evidence: confronting the covid- elephant date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: n tj nan coronavirus disease (covid- ) is an unfamiliar illness with potentially devastating consequences. the pandemic is unfolding at different rates with wide geographic separation and seemingly erratic expression. there is well-justified urgency to describe the inconsistently expressed features of this new viral disease and implement strategies to avoid and treat it [ ] [ ] [ ] [ ] . because covid- -related illness is caused by a single virus, it seems reasonable to assume a degree of uniformity across populations. yet, some observations are universal while others apparently conflict. in this urgent situation, we feel impelled to skip steps in the traditional methodology of first making careful observations and then conducting evidence-building research to inform rational management. we have been down this road before of needing to act while not fully understanding a new pathogen variant. but this sars-cov- /covid- seems different. this time around, the disease may infect anyone and most organ systems and is readily and rapidly transmitted. we have a right to be frightened of this novel virus. mastering the entirety of medicine is impossible; practicing doctors are trained to diagnose (label) by interpreting observations using their prior education and experience, and then manage on that basis. we have a natural tendency to 'force-fit' newly encountered fragments of unfamiliar information into our existing constructs and understandings. (in psychology, this is known as the barnum effect [ ] .) although usually a functional approach to decision-making when dealing with too little information, we may unintentionally make errors when the disease seems as alien and multifaceted as covid- . the acute respiratory distress syndrome (ards) that figures so prominently in severe cases of covid infection may seem familiar but has historically predisposed to such logical missteps [ ] . ards itself was originally perceived as a high permeability edema and low lung compliance condition that disrupted function of all alveolar units and resulted primarily from surfactant deficiency [ ] . cause and histologic manifestations went hand-inhand. this simple perception provided for adult patients a convenient explanation that paralleled that of the infant respiratory distress syndrome, a condition for which the root cause mechanism had already been confirmed [ ] . indeed, for some years after its initial description, the designation of 'adult respiratory distress' reflected this flawed theory of cause and effect. more recently, considerations of lung compliance and underlying pathology have yielded to a broader definition of ards based on a relatively acute onset of a known precipitant that impairs oxygenation and produces otherwise unexplained multi-lobar infiltrates [ ] . airspace flooding, collapse, and consolidation are envisioned to parallel (more or less) the severity of oxygenation impairment [ , ] . most often, this view serves reasonably well. as pathologic severity increases, key definitional features of ards (extensive infiltrates, hypoxemia) usually proceed in synch, serving to guide clinical treatment and prognosis by gas exchange criteria. accordingly, choices for positive end-expiratory pressure (peep), tidal volume, and prone positioning are made with the intention of improving oxygenation and recruiting lung units while avoiding ventilator-induced lung injury (vili). clinical trials and guideline tables for mechanical ventilation in ards are, for better or worse, keyed to the severity of oxygenation deficit [ ] . at the bedside, vili risk is *correspondence: marin @umn.edu indexed by plateau pressure, driving pressure, and more recently by mechanical power [ ] . certain features of covid- -associated ards (what has been termed "cards") seem to challenge that useful conceptual framework. specifically, lung compliance may be well preserved in the early and mild stages of cards (at least in a subpopulation of these patients), because severe hypoxemia may not originate at first primarily from airspace filling and lung unit drop-out-though these do occur to some modest extent-but rather from a microvascular attack that dysregulates ventilation/perfusion matching in well-ventilated lung units and increases dead space [ ] . when simpler measures fail, the familiar initial response is to improve oxygenation-use higher peep and lower tidal volumes, offsetting any hemodynamic consequences. yet, it stands to reason (though still unproven) that because these lungs are initially gas filled and unexpectedly flexible for the severity of hypoxemia, such actions might needlessly accentuate the underlying problem and increase iatrogenic risk without proportionate benefit [ , ] . in more severe cases and at a later stage, however, those same actions become quite appropriate. in summary, it is not yet known whether standard evidence-based approaches to ards management apply equally well at all stages and severities of cards. progress in understanding the biological mechanisms of covid- has been quite rapid, but there remain many unknowns regarding its expression and management. in confronting covid- , there have been shared experiences and points of agreement (table ) , but the varied and puzzling expressions of covid- have challenged the uniformity of our perceptions and in some cases stimulated brisk controversy [ ] [ ] [ ] [ ] . for example, we argue: does intense, sepsis-like cytokine release drive shock? [ ] . should we manage cards as routine ards? [ ] . the basis of such disagreements may lie less with the soundness of the observations among reports and more with patient vulnerability to attack by covid- and its rapidly evolving pathophysiology. the validity of any given observation and inference for management may depend strongly, for instance, on when in the course of the encounter the observation was made (fig. ) . in a sense, with covid- , we intensivists are like the blind people of an ancient indian parable who stumble upon an unfamiliar animal, an elephant. each individual forms a different image of the unseen beast from the part his or her own hands happen to fall upon that resembles the familiar. the individual tactile sensations are undeniable, and each interpretation and extrapolation to characterize the elephant is understandable-but ultimately, incomplete. puzzling or contested features a the virus is easily spread and by multiple routes (droplet, aerosol, contact) what explains striking geographic differences of incidence? many infected persons are asymptomatic, a smaller number require hospitalization, and even fewer develop respiratory failure what explains highly variable mortality rates, site-to-site? children are affected less often and usually less severely than adults, yet may have rare post-infectious complications related to previous vascular invasion are there different covid- genetic types and virulence, perhaps due to its rna mutations? mortality rates are higher among those with diabetes, hypertension, chronic heart or lung disease, the elderly, and the morbidly obese can we develop an effective vaccine against variants of covid and distribute it worldwide? how long will such a vaccine be effective? so-called 'silent hypoxemia' may precede overt respiratory distress are there inflammatory versus non-inflammatory phenotypes of cards? unusually high minute ventilation and high dead space may be evident from the outset what role does 'cytokine storm' play in the clinical presentations of covid- ? abrupt deterioration often occurs after days of smoldering infection do symptomatic patients who present with severe hypoxemia sort into "l and h" phenotypes? respiratory system compliance is not invariably low in the presence of severe hypoxemia do patients progress to diffuse airspace disease via patient self-inflicted lung injury (psili)? incidence of blood clotting appears to be high in hospitalized covid- patients does the fact that cards patients meet the berlin definition mean that these patients will respond to standard approaches and guidelines for ards? early ct infiltrates occurring in severely hypoxemic patients are often scant, peripheral, and characterized by atypical 'ground glass' or 'crazy paving' does disrupted vasoregulation with minor shunt explain the severity of early hypoxemia? prone positioning and peep improve pao /fio should full anticoagulation be routinely implemented? respiratory failure often resolves slowly in the most severely ill who do survive which available drugs and proposed anti-viral approaches for covid- treatment hold the most potential for benefit or risk? so it may be with covid- . well-meaning authors may advocate for individual interpretations, but our current views of the entire problem are obscured and our answers half-finished. although pathogenesis is becoming progressively clear and many clinical trials of promising treatments and vaccines have been initiated, we are still at the stage of gathering fundamental observations from which a unified theory of pathogenesis might be constructed, and around which logical and effective treatment approaches might coalesce. the scientific process is self-correcting; over time, varied high-quality scientific and clinical observations will eventually be drawn together into a coherent, unified entity. although urgency demands that we test especially promising and logical treatment options, for the present time, it seems prudent for the medical community to collate valid observations and experiences from all quarters, form the right image of a dynamic entity, and then devise an appropriate strategy to modify supportive care as we proceed to develop effective countermeasures. as the rajah said to the bickering blind men when advising them to humbly reflect before drawing conclusions: "the elephant is a very large and rather strange animal. each man touched only one part. perhaps if you put the parts together, you will eventually see the truth. " sars-cov- : first do no harm learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by -ncov remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial convalescent plasma as a potential therapy for covid- barnum effect" revisited: cognitive and motivational factors in the acceptance of personality descriptions covid- does not lead to a "typical" acute respiratory distress syndrome acute respiratory distress in adults hyaline membrane disease acute respiratory distress syndrome: the berlin definition reclassifying acute respiratory distress syndrome do the nih ards clinical trials network peep/fio tables provide the best evidence-based guide to balancing peep and fio settings in adults? static and dynamic contributors to ventilator-induced lung injury in clinical practice. pressure, energy, and power management of covid- respiratory distress potential for lung recruitment and ventilation-perfusion mismatch in patients with the acute respiratory distress syndrome from coronavirus disease against pandemic research exceptionalism the perils of premature phenotyping in covid: a call for caution covid- pneumonia: different respiratory treatments for different phenotypes? key: cord- -o qfugjw authors: nye, steven; whitley, richard j.; kong, michele title: viral infection in the development and progression of pediatric acute respiratory distress syndrome date: - - journal: front pediatr doi: . /fped. . sha: doc_id: cord_uid: o qfugjw viral infections are an important cause of pediatric acute respiratory distress syndrome (ards). numerous viruses, including respiratory syncytial virus (rsv) and influenza a (h n ) virus, have been implicated in the progression of pneumonia to ards; yet the incidence of progression is unknown. despite acute and chronic morbidity associated with respiratory viral infections, particularly in “at risk” populations, treatment options are limited. thus, with few exceptions, care is symptomatic. in addition, mortality rates for viral-related ards have yet to be determined. this review outlines what is known about ards secondary to viral infections including the epidemiology, the pathophysiology, and diagnosis. in addition, emerging treatment options to prevent infection, and to decrease disease burden will be outlined. we focused on rsv and influenza a (h n ) viral-induced ards, as these are the most common viruses leading to pediatric ards, and have specific prophylactic and definitive treatment options. acute respiratory distress syndrome (ards) was first described in in adults presenting with tachypnea, hypoxemia, and decreased pulmonary compliance ( ). since then, the understanding, diagnosis, and management of ards has advanced greatly, with most research performed in adults. for more than two decades, pediatric health-care providers have relied heavily on adult-derived diagnostic criteria ( , ). in recent years, the pediatric acute lung injury consensus conference (palicc) has provided age-specific diagnostic and management guidelines for pediatric ards ( , ). with these new pediatric-specific recommendations, future research in pediatric ards looks promising, as new areas for investigation have been identified ( ). one area of interest warranting further exploration is the role of viral infection in the development and progression of pediatric ards. while some information is available specific to pediatrics, much of our understanding continues to be derivative from adult data. this review outlines what is known about ards attributable to viral infections, specifically respiratory syncytial virus (rsv) and influenza a (h n ) virus, as well as viral-specific treatment options. epidemiology of rsv and influenza-induced ards accurate incidence outcomes reporting for pediatric ards are limited by the changing definition for ards. studies using the american european consensus conference (aecc) definition ( ) outlined epidemiology and outcomes for both acute lung injury (ali) and ards as separate viral infection and pediatric ards frontiers in pediatrics | www.frontiersin.org november | volume | article entities ( ). however, both the berlin definition ( ) and the palicc recommendations ( ) no longer identify ali as a separate entity, instead categorizing ards as mild, moderate, or severe. since these guidelines are recent, few studies have been conducted to determine the incidence of ards utilizing these new criteria ( , ) . in addition, management for ards has also changed over the years, with improved outcomes demonstrated with lung-protective mechanical ventilation strategies ( , ). pediatric studies conducted using the aecc definition define an incidence ranging from . to . per , children for all causes of ali/ards, with the predominant etiology reported to be secondary to pneumonia, with or without systemic infection ( ). in a more recent study, using the berlin definition, barreira et al. reported that ards accounts for % of all picu admissions, and was associated with a high mortality rate of . % ( ). while the overall incidence of respiratory virus infection, in particular rsv and influenza a (h n ) virus, leading to lower respiratory tract disease is widely studied ( , ), the frequency of progression to pediatric ards has yet to be clearly determined. respiratory syncytial virus infection has been recognized as an important cause of lower lung disease. in an earlier study, dahlem et al. reported . % of ards cases due to rsv-related infection, but specific mortality for this group was not reported ( ) . in a more recent study by . % of patients admitted to the picu with ards tested positive for rsv, with a reported mortality of . % ( ). a -year study in the netherlands by schene et al. analyzed patients mechanically ventilated for rsv with ( %) patients progressing to ards ( ). of those with ards, % were found to have a bacterial coinfection. the mortality rate was not used as a measure of outcome and therefore not reported. since the beginning of the influenza a (h n ) virus pandemic of , influenza-related respiratory failure has become a notable cause of ards ( ). during the pandemic and postpandemic era, it is clear that children are particularly vulnerable to disease even if they had been previously healthy ( ). in alone, more than , cases were reported, with an estimated % of cases occurring in patients less than years of age ( ). in previous years, influenza-related pediatric deaths averaged annually but increased to during the pandemic ( ). while post-pandemic studies suggest a decrease in influenza a (h n ) virus disease severity and burden ( , ), it continues to be a significant cause of severe illness and pediatric ards ( ). in a retrospective analysis of adult patients within the german ards network, investigators reported that % of ards patients were influenza a (h n ) virus positive ( ). in another pediatric study in india, kinikar et al. reported that % of patients hospitalized with confirmed influenza a (h n ) virus developed ards ( ). in this study, of the children who died were found to have histologic pulmonary findings reflective of ards at autopsy. in argentina, farias et al. studied patients admitted with respiratory failure due to influenza a (h n ) virus and found ( %) met criteria for pediatric ards, % of whom died within days after picu admission ( ). the second, less common novel influenza virus, avian influenza a (h n ) virus, was first identified in ( ) and remains a common cause of severe respiratory disease ( ). kawachi et al. reviewed pediatric patients with ards over a ½-year period in vietnam and found ( . %) of the patients to have confirmed infection with the highly pathogenic influenza a (h n ) virus ( ). they described rapid progression of disease to ards with nine ( %) resulting in death. further investigation has led to improved understanding of transmission, predominantly direct avian-to-human transmission with significant risk in handling sick or dead poultry. type pneumocytes and macrophages are the primary lung target ( ). together, these studies demonstrate that rsv and influenza virus infection play a role in the development of pediatric ards. however, to better understand the disease burden, future studies should seek to more clearly identify the rate of occurrence of primary viral-induced ards, as well as incidence of secondary viral-induced lung injury. furthermore, in patients who have a coinfection with a bacterial pathogen, it may be hard to determine whether the virus or bacteria played the inciting role in the development and progression of pediatric ards. taken together, the overall mortality attributable to either rsv or influenza is relatively similar; thus, it is more likely the syndrome of ards and associated pathology that is responsible for outcome. while rsv and influenza a (h n ) virus are the most commonly reported viruses leading to pediatric ards, other viral pathogens are worth mentioning. typically viral infections leading to respiratory failure in the icu are separated as community acquired and nosocomial ( ). community acquired viral infections include both seasonal and pandemic pathogens ( ). seasonal viruses most commonly include rsv, non-pandemic influenza, rhinoviruses, parainfluenza, adenovirus, coronaviruses, and human metapneumovirus (hmpv). seasonal viruses remain the most frequent cause of childhood community acquired pneumonia ( ). the most common etiology of pediatric ards is primary pneumonia, with or without systemic infection ( ). it can then be assumed that viral infections may play an important role in development of pediatric ards. however, determining an accurate estimate of the disease burden of viral-induced pediatric ards will be difficult, as many simple viral infections can progress to coinfection with the second virus or a bacterial pathogen. as will be detailed below, with the development of multiplex pcr diagnostic platforms that identify multiple viral agents, further insight into coinfections will develop. a single-center adult study reported seven patients developing ards from adenovirus, four of whom died ( ). hung and lin described a case of a -month-old male with adenoviral ards requiring extracorporeal membrane oxygenation (ecmo) ( cases of severe disease in immunocompetent patients are becoming increasingly reported ( ). at an international level, community acquired, novel pathogens have been recognized as a significant cause of ards in the last - years ( ). in , the world health organization (who) developed a panel of experts to prioritize emerging pathogens to likely cause severe outbreaks in the near future, and for which little or no preventative or curative treatments are available ( ). the list includes two novel coronaviruses, severe acute respiratory syndrome (sars)-cov and mers-cov, which are widely recognized as noteworthy causes of ards. in , sars-cov led to the development of sars in china ( ). affecting patients of all ages, sars led to significant mortality worldwide within a few months ( ). a large number of infected patients developed severe complications, with % developing ards ( ). however, reported sars cases have ceased since as the spread of infection has subsided ( ). more recently, the second novel coronavirus, mers-cov, led to the middle east respiratory syndrome ( ). clinical symptoms range from mild upper respiratory symptoms to severe pneumonia and ards, septic shock, and multi-organ failure ( ) and carry an estimated mortality of % ( ) . this virus continues to be a substantial etiology of ards with high mortality as no definitive prevention or treatment other than supportive care has been identified ( ) . with the unpredictable nature of epidemics and pandemics, these novel viruses illustrate the need to improve our understanding of viral progression to ards in order to advance management and reduce mortality. aside from community acquired viral infections, nosocomial infections are an important cause of respiratory illness, and can lead to ards in both adults and children. in mechanically ventilated adults, reactivation of latent herpes simplex virus (hsv) in the oropharynx can potentially lead to lower respiratory tract infection and ards ( , ) . however, the pathogenicity of reactivated hsv lower respiratory tract infection may not be that straightforward as it remains unclear whether hsv contributes to worsening illness or whether reactivation occurs due to the underlying critical illness ( ). schuller et al. found higher levels of clinical severity and mortality in critically ill immunocompetent adults with hsv- infection compared to immunocompromised patients with hsv- ( ). the true extent of hsv reactivation in critically ill children leading to respiratory illness has yet to be studied. hennus et al. described two previously healthy children presenting with respiratory failure due to human herpes virus (hhv- ), and later workup revealed an immunodeficiency in both patients ( ) . a separate pediatric case reported a child with hsv ards resulting in need of extracorporeal support ( ) . these cases illustrate the rare, but possible severe infection and progression to ards from hsv- . finally, many seasonal and pandemic viruses are a potential nosocomial infectious risk secondary to either a health-care provider or air-ventilation transmission. in a study over two influenza seasons in germany, huzly et al. reported a rate of nosocomial transmission of % ( - ) and % ( - ) ( ) . specific guidelines are available to help prevent transmission of infectious pathogens through isolation precautions ( ) . however, dhar et al. found that an increased number in patients placed on contact isolation led to a decrease in compliance with isolation precautions ( ) . decreasing nosocomial transmission within care areas for critically ill patients is an important area for improvement. the palicc has recently provided guidelines for diagnosing pediatric ards ( ). the new guidelines define important diagnostic criteria, including age, timing, origin of edema, imaging, and oxygenation. patients with perinatal lung disease are excluded, and pards criteria must be met within days of a clinical insult. the cause of respiratory failure must not be explained by heart failure or fluid overload, and must be evidenced by new pulmonary infiltrate(s) on chest radiograph consistent with parenchymal disease. finally, the use of oxygenation index is preferred over the pao :fio (pf) ratio in determining the severity of pards in mechanically ventilated patients, while the pf ratio or spo :fio (sf) ratio may be used in patients requiring non-invasive ventilation ( ). the same clinical guideline is used in the diagnosis of viral-induced pediatric ards. currently, there are several different types of laboratory tests that are commercially available for diagnosis. most clinical laboratories utilize antigen detection tests, which consist of multiple steps to accurately identify a single virus ( ) , with or without cell culture. it is worth noting that over the past years, the development and refinement of real-time reverse transcriptase polymerase chain reaction (rt-pcr) has enhanced the clinician's ability to diagnose an array of viruses rapidly and accurately. multiplex rt-pcr testing analyzes a single sample for multiple viral agents and subtypes simultaneously, producing sensitive and specific results in a short period of time ( ) . even with the influenza a (h n ) virus pandemic, the centers for disease control and prevention (cdc) quickly modified standard pcr assays to detect the new virus ( ) . a challenge to routine rt-pcr testing in all patients who present with viral symptoms is the prohibitive cost, need for specialized equipment, and the relatively longer time between sampling and availability of results ( ) . furthermore, pcrs detect viral genes that are used as a surrogate measurement of whole virions. in some instances, viral gene detection may actually reflect non-replicating, non-infectious virions. newer rapid point-of-care pcrs are currently being developed, but their implications for clinical decision making remain uncertain ( ) . in addition, rapid antigen detection tests (radt) are also available commercially for detection of both rsv and influenza virus infection in the outpatient and emergency department settings ( , ) . however, in a recent study by moesker et al., radts were found to have relatively low sensitivity compared to rt-pcr testing which limits their use for clinical decision making ( ) . nonetheless, radt maybe a valuable tool, especially during an outbreak, because it is a point-of-care test that is easy to use with a rapid turnaround time ( ) . since clinical symptoms for different viral respiratory infections are often the same, and with the limitations of our current testing methods, it is critical that clinicians obtain microbiology data early, especially in the risk population ( ) ( ) ( ) ( ) . there is also a large variability of disease severity in children infected with rsv or influenza a (h n ) virus. in rsv infection, development of lower respiratory track disease in premature infants, with or without chronic neonatal lung disease is associated with a significantly higher risk of hospitalization, intensive care unit admission, need for mechanical ventilation, and death ( , [ ] [ ] [ ] [ ] . in a study of , children with lower respiratory infection due to rsv, rodriguez et al. reported age less than months, history of prematurity, chronic respiratory disease or congenital heart disease, and coinfection with adenovirus were significant predictors of increased disease severity ( ) . similar predictors exist for children infected with influenza a (h n ) virus, including age less than years, a history of chronic lung disease, congenital heart disease, and immune compromise ( table ) ( ) . it is therefore prudent that clinicians should conduct laboratory evaluations early in the illness for viral infections in these at-risk populations presenting with respiratory failure and ards. in contrast to clinical predictors of disease severity, the contribution of viral factors to disease burden remains unclear. in rsv infection, although earlier studies suggested no correlation between viral load and disease severity ( , ) newer findings suggest otherwise. studies by both devincenzo et al. and houben et al. reported a direct correlation between viral load and disease severity in infants with primary rsv infection ( , ) . el saleeby et al. also reported that viral load is independently associated with increased risk of patients with rsv requiring prolonged hospitalization or intensive care, or to develop respiratory failure ( ) . the relevance of viral load in influenza a (h n ) virus infection is unclear. launes et al. found that in children who had more than days of symptoms, a higher influenza a (h n ) viral load at diagnosis correlated with an increased risk of requiring mechanical ventilation ( ) . similarly others have found that patients with systemic symptoms and pneumonia had higher viral load when compared to those with uncomplicated upper respiratory tract infections alone ( ) . as would be expected children have a higher influenza a (h n ) viral load compared to adults because of less exposure to influenza antigens. however, this finding did not correlate with the occurrence of disease complications ( ) . both rsv and influenza a (h n ) virus result in a broad spectrum of disease, ranging from mild upper respiratory symptoms to fulminant respiratory failure and ards ( , ) . this high degree of variability may be due to the pathogenicity of the viral pathogen, host immune response, or a combination of both ( ) . human rsv consists of subgroups a and b and primarily infects humans. the rsv genome encodes different proteins involved in transmission, infection, evasion of host response, and replication ( ) . infection is typically restricted to respiratory epithelial cells, including both type i and type ii alveolar pneumocytes, from the trachea to the level of bronchioles. infection leads to epithelial and interstitial inflammation with progression to inflammatory infiltrates and epithelial sloughing ( ) . after infection and viral replication, rsv causes epithelial cells to fuse, forming a syncytium from which the virus spreads from cell to cell ( ) . those infected epithelial cells are then destroyed, releasing inflammatory cytokines and chemokines that ultimately attract additional inflammatory cells and degrade capillary integrity ( ) . disruption of the alveolar-capillary barrier results in leakage of plasma proteins into interstitial tissue and within the alveoli, finally interfering with surfactant function ( ) . with an understanding of the pathophysiologic process of rsv, it is no surprise that progression to ards is a potential end point. aside from viral pathogenicity, host immune-mediated factors also contribute to disease severity. a rapidly progressive area of research is in understanding the role of biomarkers not only in the diagnosis and prognosis of ards, but also in potential therapeutic options to alter such biomarkers ( ) . inflammatory proteins in the matrix metalloproteinase (mmp) family have been shown to be elevated in pediatric ali ( ) with a specific increase in mmp- production in rsv infection. blocking mmp- in vitro and in vivo resulted in decrease in viral load ( ) . in addition, activation of several chemokine and interleukin subtypes, as well as tumor necrosis factors, has been shown to positively correlate with severity of illness in children with rsv ( ) . in their study, fernandez et al. discovered that higher levels of soluble interleukin- (il- ) positively correlated with both disease severity and duration of supplemental oxygen in infants with acute rsv infection ( ) . a separate study confirmed this associate with increased levels of il- in nasopharyngeal secretions ( ) , but the pathogenicity of this correlation has yet to be determined. antigenic variability exists with both influenza a (h n ) virus and the resultant immune-mediated response. like influenza b and c, influenza a is made up of structural proteins and two groups of surface glycoproteins, hemagglutinin (ha), and neuraminidase (na). these glycoproteins are responsible for attachment and entry into cells, viral spread throughout the respiratory tract, and are capable of a large degree of variability ( ) . waterfowl serve as the largest natural reservoir for influenza a subtypes ( ) . the avian-to-human leap can occur through direct transmission ( ) or, alternatively, through pigs ( ). although transmission from pigs to humans is a rare event, it occurred in the pandemic ( ) a small outbreak in new jersey in ( ) and the most recent pandemic of influenza a (h n ) starting in ( ) . influenza a (h n ) virus primarily targets alveolar epithelial cells that serve as first-line defense against respiratory infections ( ) . histological evaluation of fatal cases of influenza a (h n ) virus infection revealed diffuse alveolar damage with inflammation, fibrosis and edema, disruption of surfactant production, and detection of viral antigens throughout the lung parenchyma ( ) . like rsv, this pathogenic can process rapidly progresses to refractory hypoxemia and ards ( ) . in addition to viral pathogenicity, disease severity of influenza a (h n ) virus infection is also closely associated with host response ( ) . in both healthy patients and those with comorbidities, influenza a (h n ) virus can lead to an exaggerated inflammatory response with dysregulation of local and systemic chemokine and cytokine production ( , ) . in a study specifically in the pediatric population, takano et al. found a positive correlation with disease severity and elevated levels of serum interferon gamma, several interleukin types, and monocyte chemoattractant protein- (mcp- ) ( ) . some studies suggest that these elevations may be adequate immune response to infection ( ) , but further exploration of the inflammatory response in influenza a (h n ) virus infection is likely to yield development of potential interventions to prevent disease progression to ards. the treatment of ards has significantly evolved over the past several decades. perhaps the greatest improvement in management developed from studies involving lung-protective ventilation ( ). other interventions such as inhaled nitric oxide ( ) , fluid management ( ), use of steroids ( ) , and prone positioning ( ) are being further investigated and validated. however, specific treatment for rsv infection remains lacking. despite the substantial short and long-term morbidity and mortality associated with rsv disease in children, the current management for rsv infection consists of supportive care, in the form of oxygen supplementation, adequate hydration, and mechanical ventilation for those who develop respiratory failure. multiple therapeutic strategies have been explored with very limited success, and a vital need remains for an effective disease treatment. interventions for either virus can be separated into primary prevention of infection, typically through vaccination, and reduction of infectious burden once transmission has already taken place. primary prevention through vaccination continues to be a major area of research and potential advancement for both rsv and influenza a (h n ) virus. to date, no rsv vaccine has proven efficacious. while significant research has been devoted to vaccine development, major obstacles specific to rsv, such as young age of infection, lack of persistent immunity, and poorly validated animal models make it difficult to find an effective and safe solution ( ) . one current prospect, medi- , a liveattenuated, intranasal vaccine providing protection against both rsv and parainfluenza , although safe in children ages - , has yet to show a beneficial immunogenic response in infants ( ) . other more recent advances continue to focus on live-attenuated vaccines, as well as chimeric live vectors ( ) , with varying antibody response between children ( , ) . while vaccine development continues, prophylactic use of polyclonal rsv intravenous immunoglobulin (respigam) or human anti-f monoclonal antibodies (palivizumab and motavizumab -which is not yet licensed for use) in high-risk infants has been shown to reduce the risk of rsv-associated acute lower respiratory tract infections and disease severity ( ) . palivizumab is a human, monoclonal antibody targeted to block viral infected cells from fusing with adjacent cells ( ) . palivizumab has been shown to be most effective in high-risk populations, specifically premature infants and those with chronic lung disease or congenital heart disease ( ) . the use of palivizumab as treatment for rsv infection in mechanically ventilated pediatric patients has not been shown to be effective ( ) . furthermore, studies have also shown that palivizumab prophylaxis in these patients has a limited effect on the total disease burden of rsv infection, including overall rsv-related hospital admissions and resource utilization ( , ). although not approved for use in the united states, motavizumab, the second-generation derivative of palivizumab, decreased viral load compared with placebo ( ) . however, in a more recent study of hospitalized rsv infected infants treated with motavizumab or placebo, no antiviral effect was demonstrated ( ) . furthermore, both therapies produce only temporary, passive immunity ( ) . the influenza a (h n ) virus was a novel strain, leaving children and young adults with little if any preexisting antibodies and without adequate protection with the seasonal influenza vaccine alone ( ) . a new influenza a (h n ) virus vaccine was rapidly developed and has subsequently been shown to be safe and effective at providing adequate immunological response ( , ) . one post-pandemic study showed a correlation with higher rates of influenza a (h n ) virus infection, compared with other influenza types, along with increased icu admissions for countries with limited numbers of the population having received influenza a (h n ) virus vaccination ( ) . in addition to general supportive care, the second goal of therapy in viral infection focuses on reducing the infectious burden and, theoretically, subsequent viral sequelae. currently, inhaled ribavirin is the only approved antiviral treatment for rsv infection in children ( ) but its use is associated with potential teratogenicity, and its efficacy remains uncertain ( ) . ribavirin directly and indirectly inhibits replication of both dna and rna viruses, including rsv ( ) . studies in infants found a decrease in mortality and respiratory deterioration, and a decrease in days of hospitalization and days of mechanical ventilation in ventilated infants ( ) . luo et al. reported an adult case of severe rsv infection progressing to ards that was successfully treated with inhaled ribavirin ( ) , but overall effectiveness in treatment of viral pediatric ards has yet to be determined. in addition to its use in rsv, ribavirin has also been used in treatment of severe influenza a (h n ) virus infection ( ) . ribavirin can be given orally but is typically aerosolized when used for respiratory viral infections. however, safety considerations regarding potential teratogenicity and exposure to health-care workers during administration ( ) limit its use. the american academy of pediatrics does not recommend the routine use of ribavirin to treat rsv infection, reserving its use for patients with potentially life-threatening disease ( ) . several small molecule inhibitors that interfere with rsv f protein (mdt- and jnj- ) ( ) including the gs- that was recently evaluated in a challenge safety study of healthy adults ( ) . in this study by devincenzo et al., treatment resulted in decreased viral burden and severity of clinical disease. the use of these small molecule inhibitors in the context of pediatric subjects who develop ards remains untested at this point. neuraminidase inhibitors (which prevent the release of influenza virions), including oral oseltamivir, inhaled zanamivir and laninamivir, and parenteral peramivir, remain first-line interventions for influenza. only oseltamivir, peramivir, and zanamivir are available in the united states. perhaps the most widely used, oseltamivir results in a significant decrease in duration of symptoms as well as severity of illness with early treatment (< h of symptoms) ( ) . use of oseltamivir in severe cases of influenza a (h n ) has become standard practice ( , ), although some studies have shown increased resistance ( ) . randolph et al. conducted a retrospective study of children admitted to the picu with confirmed influenza a (h n ) infection ( ) . overall, ( . %) required mechanical ventilation, but the rate of progression to ards was not reported. although % were treated with oseltamivir, there was no association with improved mortality. farias et al. found a reduced mortality in patients with pards from influenza a (h n ) if oseltamivir was administered within the first h ( ). while further studies are needed to look at the effectiveness of antiviral medications in the treatment of viral-induced ards, in recent years, investigators are also focusing on the potential benefits of immune modulation. with enhancement in research surrounding viral pathogenicity and host immune response, potential targets of intervention will hopefully be identified. aside from viral-specific therapies, ecmo has been utilized as rescue therapy for severe respiratory failure in pediatrics for more than years, with more than % survival ( ) . the overall use of ecmo for treatment of ards has increased with improvement in mortality ( ) . the recent palicc recommendations conclude that ecmo should be considered for treatment of pards when lung-protective strategies have failed, when the cause of respiratory failure is thought to be reversible, or when the child may be suitable for lung transplantation ( ) . the use of ecmo in pediatric respiratory failure due to rsv is well reported ( , ) . in their retrospective review of children requiring mechanical ventilation for rsv bronchiolitis, flamant et al. reported the use of ecmo in patients ( ) . in this study, the median duration of ecmo was . ( - ) days with a survival rate of . %. on the other hand, the use of ecmo in pards due to influenza a (h n ) virus is sparsely reported ( , ) and most of our understanding stems from adult studies. in a study in australia and new zealand during the influenza a (h n ) pandemic, adult patients with influenza-induced ards were treated with ecmo ( ) . the median duration of ecmo was ( - ) days. when the report was submitted, ( %) patients had survived to icu discharge, with deaths and patients remaining in the icu, of whom remained on ecmo. in their study in the united kingdom during the same pandemic, noah et al. discovered a decrease in mortality for patients with ards due to influenza a (h n ) who were referred and transferred to an ecmo center compared with matched non-ecmo-referred patients ( ) . in this study, patients received ecmo with a mortality rate of . %. expanded use of ecmo within the pediatric population for influenza a (h n ) virus induced ards has yet to be investigated. however, the use of ecmo in refractory cases or rsv or influenza a (h n ) virus induced ards should be considered when applicable. while it is clear that viral infections are an important cause of pediatric ards, the exact disease burden remains unknown. with more definitive diagnostic criteria, clinicians now have a wide array of research possibilities regarding pediatric ards, both retrospective and prospective. further studies to expand our understanding of viral-induced pediatric ards will be of great benefit, both in understanding the epidemiology and viral-specific treatment options available. in addition, an improved comprehension of viral transmission, pathogenicity, and host response will be particularly important in times of pandemics, either from known or novel viruses. finally, continued efforts in prevention and treatment of viral infections will likely be of greatest advantage to decrease viral progression to pediatric ards. sn, rw, and mk contributed to the conception, writing, and final edits of this manuscript. this work was funded by the national institutes of health (nichd k hd and k hl - ) to mk. middle east respiratory syndrome acute management and long-term survival among subjects with severe middle east respiratory syndrome coronavirus pneumonia and ards herpes simplex virus in the respiratory tract of critical care patients: a prospective study herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation vandenbroucke-grauls cm. herpes simplex virus type and respiratory disease in critically-ill patients: real pathogen or innocent bystander? herpes simplex virus from respiratory tract secretions: epidemiology, clinical characteristics, and outcome in immunocompromised and nonimmunocompromised hosts life-threatening human herpes virus- infection in early childhood: presenting symptom of a primary immunodeficiency? treatment of acute pulmonary failure with extracorporeal support: % survival in a pediatric population characterisation of nosocomial and community-acquired influenza in a large university hospital during two consecutive influenza seasons guideline for isolation precautions: preventing transmission of infectious agents in health care settings contact precautions: more is not necessarily better multiplex pcr for typing and subtyping influenza and respiratory syncytial viruses multiplex real-time pcr assay for detection of influenza and human respiratory syncytial viruses emergence of a novel swine-origin influenza a (h n ) virus in humans the influenza virus: disease, diagnostics, and treatment evaluation of novel second-generation rsv and influenza rapid tests at the point of care accuracy of rapid influenza diagnostic tests: a meta-analysis antigen-based assays for the identification of influenza virus and respiratory syncytial virus: why and how to use them in pediatric practice diagnostic performance of influenza viruses and rsv rapid antigen detection tests in children in tertiary care world health organization. who recommendations on the use of rapid testing for influenza diagnosis comparison of human metapneumovirus, respiratory syncytial virus and rhinovirus respiratory tract infections in young children admitted to hospital role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study predictors of rsv lrti hospitalization in infants born at to weeks gestational age: a large multinational study (poni) populations at risk for developing respiratory syncytial virus and risk factors for respiratory syncytial virus severity: infants with predisposing conditions children's hospital respiratory syncytial virus database: risk factors, treatment and hospital course in infants and young children birth weight and hospital readmission of infants born prematurely respiratory syncytial virus and premature infants born at weeks' gestation or earlier: hospitalization and economic implications of prophylaxis readmission with respiratory syncytial virus (rsv) infection among graduates from a neonatal intensive care unit predictors of severity and mortality in children hospitalized with respiratory syncytial virus infection in a tropical region clinical features of severe influenza a (h n ) virus infection illness severity, viral shedding, and antibody responses in infants hospitalized with bronchiolitis caused by respiratory syncytial virus type and type cytokine imbalance in acute respiratory syncytial virus bronchiolitis respiratory syncytial virus load predicts disease severity in previously healthy infants disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community respiratory syncytial virus load, viral dynamics, and disease severity in previously healthy naturally infected children viral load at diagnosis and influenza a h n ( ) disease severity in children correlation of pandemic (h n ) viral load with disease severity and prolonged viral shedding in children distinct differences in clinical manifestation and viral laboratory parameters between children and adults with influenza a(h n ) pdm infection -a retrospective comparative analysis acute respiratory distress syndrome caused by respiratory syncytial virus viral and host factors in human respiratory syncytial virus pathogenesis respiratory syncytial virus: virology, reverse genetics, and pathogenesis of disease the histopathology of fatal untreated human respiratory syncytial virus infection in vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo novel pathways in the pathogenesis of respiratory syncytial virus disease surfactant abnormalities in infants with severe viral bronchiolitis biomarkers in pediatric ards: future directions matrix metalloproteinase activity in pediatric acute lung injury matrix metalloproteinase- mediates rsv infection in vitro and in vivo novel inflammatory markers, clinical risk factors and virus type associated with severe respiratory syncytial virus infection plasma interferon-gamma, interleukin- and soluble markers of immune activation in infants with primary adenovirus (adv) and respiratory syncytial virus (rsv) infection correlation between inflammatory mediators in the nasopharyngeal secretion and in the serum of children with lower respiratory tract infection caused by respiratory syncytial virus and disease severity molecular character of influenza a/h n : implications for spread and control evolution and ecology of influenza a viruses adaptation of avian influenza a virus polymerase in mammals to overcome the host species barrier the pig as a mixing vessel for influenza viruses: human and veterinary implications updating the accounts: global mortality of the - "spanish" influenza pandemic swine influenza a outbreak swine influenza a (h n ) infection in two children -southern california differential susceptibilities of human lung primary cells to h n influenza viruses pandemic influenza a (h n ): pathology and pathogenesis of fatal cases in the united states pneumonia and respiratory failure from swine-origin influenza a (h n ) in mexico influenza virus pathogenicity regulated by host cellular proteases, cytokines and metabolites, and its therapeutic options three fatal cases of pandemic influenza a virus infection in shenzhen are associated with cytokine storm antibody and inflammatory response-mediated severity of pandemic (ph n ) influenza virus cytokine and chemokine response in children with the pandemic influenza a (h n ) virus infection monocyte chemoattractant protein contributes to an adequate immune response in influenza pneumonia role of inhaled nitric oxide in the management of severe acute respiratory distress syndrome comparison of two fluid-management strategies in acute lung injury efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome prone positioning in severe acute respiratory distress syndrome biological challenges and technological opportunities for respiratory syncytial virus vaccine development phase-i study medi- , of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza- virus in seropositive children live-attenuated respiratory syncytial virus vaccines a gene deletion that up-regulates viral gene expression yields an attenuated rsv vaccine with improved antibody responses in children enhanced neutralizing antibody response induced by respiratory syncytial virus prefusion f protein expressed by a vaccine candidate antibodies for prevention and treatment of respiratory syncytial virus infections in children development of a humanized monoclonal antibody (medi- ) with potent in vitro and in vivo activity against respiratory syncytial virus effectiveness of palivizumab in preventing rsv hospitalization in high risk children: a real-world perspective comparison of intravenous palivizumab and standard of care for treatment of respiratory syncytial virus infection in mechanically ventilated pediatric patients impact of palivizumab on admission to the icu for respiratory syncytial virus bronchiolitis: a national survey safety and antiviral activity of motavizumab, a respiratory syncytial virus (rsv)-specific humanized monoclonal antibody, when administered to rsv-infected children motavizumab treatment of infants hospitalized with respiratory syncytial virus infection does not decrease viral load or severity of illness safety and effectiveness of palivizumab in children at high risk of serious disease due to respiratory syncytial virus infection: a systematic review serum cross-reactive antibody response to a novel influenza a (h n ) virus after vaccination with seasonal influenza vaccine safety and immunogenicity following administration of a live, attenuated monovalent h n influenza vaccine to children and adults in two randomized controlled trials a novel influenza a (h n ) vaccine in various age groups pandemic vaccination strategies and influenza severe outcomes during the influenza a(h n )pdm pandemic and the post-pandemic influenza season: the nordic experience a controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection safety issues related to the administration of ribavirin broad-spectrum antiviral activity of virazole: -beta-d-ribofuranosyl- , , -triazole- -carboxamide ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children inhaled ribavirin therapy in adult respiratory syncytial virus-induced acute respiratory distress syndrome virological clearance rate of high-dose oseltamivir or triple-combination antiviral therapy in complicated pandemic influenza a (h n ) infection respiratory syncytial virus small molecules vp- and jnj- inhibit respiratory syncytial virus fusion by similar mechanisms oral gs- activity in a respiratory syncytial virus challenge study use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment h n influenza and experience in three critical care units systematic review of influenza resistance to the neuraminidase inhibitors critically ill children during the - influenza pandemic in the united states probability of survival after prolonged extracorporeal membrane oxygenation in pediatric patients with acute respiratory failure. extracorporeal life support organization extracorporeal membrane oxygenation for ards: national trends in the united states extracorporeal support in children with pediatric acute respiratory distress syndrome: proceedings from the pediatric acute lung injury consensus conference role of ecmo in the treatment of respiratory syncytial virus bronchiolitis: a collaborative report use of extracorporeal membrane oxygenation in the treatment of respiratory syncytial virus bronchiolitis: the national experience, to severe respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to extracorporeal membrane oxygenation continued high incidence of children with severe influenza a(h n )pdm admitted to paediatric intensive care units in germany during the first three post-pandemic influenza seasons mechanically ventilated children with pandemic influenza a/h n : results from the national pediatric intensive care registry in japan extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome referral to an extracorporeal membrane oxygenation center and mortality among patients with severe influenza a(h n ) the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -md f p authors: carver, catherine; jones, nicholas title: cardiac injury and ards meta-analysis validity – correspondence in response to santoso et al. date: - - journal: am j emerg med doi: . /j.ajem. . . sha: doc_id: cord_uid: md f p nan in the course of writing a rapid review for the university of oxford, we came across an interesting and timely systematic review and meta-analysis in the american journal of emergency medicine by and colleagues ( ). this paper was of note to us because it included a meta-analysis on acute respiratory distress syndrome (ards) and cardiac injury, based on two papers -one by shi ( ) and another by wu ( ). on reading the paper by wu, we have significant concerns about the inclusion of this study in santoso's meta-analysis as we believe it currently underpins an inaccurate conclusion that cardiac injury is not significantly associated with increased risk of ards in covid- by santoso. in figure in santoso, they describe wu as cases of ards ( cases of ards with cardiac injury, and cases of ards with no cardiac injury). when we examined the wu paper, we found a composite outcome of respiratory failure, ards and sepsis was reported, totalling cases across the different troponin levels ( table in wu) . further, when we studied table in wu, patients are described as having respiratory failure/ards/sepsis. this is broken down as with respiratory failure and with ards or sepsis. even if one assumes that all of those cases were ards, that gives a total of ards cases in this paper, contrasting with the used for santoso's meta-analysis. there are conceivable alternative explanations for these figures, for instance perhaps all of the respiratory failures were caused by ards and wu used a counterintuitive way of presenting the data by separating these out from the ards or sepsis cases. however, from what we currently have access to, it seems most likely that santoso's meta-analysis for ards has been based on composite endpoint data. this is concerning, particularly when there is evidence ards was a minority diagnosis. moreover, the conclusion of santoso runs counter to shi's jama cardiology paper, which was the other paper included in santoso's meta-analysis, which did report on purely ards cases and cardiac injury and did find a statistically significant association. cardiac injury is associated with mortality and critically ill pneumonia in covid- : a meta-analysis association of cardiac injury with mortality in hospitalized patients with covid- in wuhan heart injury signs are associated with higher and earlier mortality in coronavirus disease (covid- ). medrxiv screening and data extraction in santoso were performed by two authors, which is good practice and reduces the probability of a simple error. we are therefore curious to learn whether the authors had contact with wu et al and have insights into the wu data that are not immediately apparent to readers. if so, we would appreciate santoso et al sharing this information publicly as it would inform our research and no doubt that of others.we look forward to having our confusion addressed by the authors and thank them for their work. key: cord- -llucxztc authors: Öztürk, selçuk; elçin, ayşe eser; koca, ayça; elçin, yaşar murat title: therapeutic applications of stem cells and extracellular vesicles in emergency care: futuristic perspectives date: - - journal: stem cell rev rep doi: . /s - - - sha: doc_id: cord_uid: llucxztc regenerative medicine (rm) is an interdisciplinary field that aims to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. stem cells, which are undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered as an important part of the rm approaches. they have been widely investigated in preclinical and clinical studies for therapeutic purposes. extracellular vesicles (evs) are the vital mediators that regulate the therapeutic effects of stem cells. besides, they carry various types of cargo between cells which make them a significant contributor of intercellular communication. given their role in physiological and pathological conditions in living cells, evs are considered as a new therapeutic alternative solution for a variety of diseases in which there is a high unmet clinical need. this review aims to summarize and identify therapeutic potential of stem cells and evs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, acute respiratory distress syndrome and burn injury. diseases that affect militaries or societies including acute radiation syndrome, sepsis and viral pandemics such as novel coronavirus disease are also discussed. additionally, featuring and problematic issues that hamper clinical translation of stem cells and evs are debated in a comparative manner with a futuristic perspective. [figure: see text] regenerative medicine (rm) is an emerging interdisciplinary field aiming to repair, replace or regenerate damaged or missing tissue or organs to function as close as possible to its physiological architecture and functions. there have been tremendous advancements in this evolving discipline in the past decades including small molecule drugs, cell and gene therapies, and tissue and organ engineering. however, the main focus of rm has been human cells particularly stem cells for years, which may be somatic, adult stem, embryo-derived or reprogrammed cells [ ] . stem cells, which are defined as undifferentiated cells retaining self-renewal potential, excessive proliferation and differentiation capacity into offspring or daughter cells that form different lineage cells of an organism, are considered among landmark steps in the evolution of cell-based rm approaches. their distinctive characteristics make them an ideal source for replacing and/or regenerating damaged tissues [ , ] . briefly, they are classified according to their tissue of origin and differentiation ability. embryonic stem cells (escs) and induced pluripotent stem cells (ipscs) are considered as pluripotent, which means that they can differentiate into all cell types from ectodermal, endodermal, and mesodermal origin, whereas hematopoietic stem cells (hscs) and mesenchymal stem cells (mscs) are examples of multipotent cells that can differentiate into various cell types of a single germ layer [ ] . the main goal of stem cell therapies can be summarized as the replacement of dysfunctional or dead cells and tissues with physiologically functioning cells, prevention of further damage, microenvironment modification of the tissue such as antiinflammatory and immunosuppressive activity, and activation of self-regenerative and reparative mechanisms [ , ] . for these reasons, they have been investigated extensively in various experimental studies and in phase- / clinical trials of cancer, cardiovascular diseases, immune system disorders, neurological diseases, liver, lung, kidney, orthopedic, ocular, urological, skin diseases, etc. [ ] [ ] [ ] . although most preclinical studies have demonstrated encouraging results, translation of stem cell therapies into clinics and success in clinical trials have not been at the desired level yet. except for a few wellestablished indications such as hematological cancers, stem cell therapies have not exactly improved patient outcomes and cured the disease. unfortunately, evidence mostly coming from small, uncontrolled trials and a few well-controlled, randomized clinical studies have still been somewhat not fully satisfactory [ ] . extracellular vesicles (evs) are small sized, lipid membrane enclosed, heterogenous membrane vesicles secreted from all cell types, and they comprise three subgroups according to their biogenesis namely exosomes, microvesicles and apoptotic bodies. briefly, exosomes are - nm sized vesicles resulting from intraluminal budding of multivesicular bodies and fusion of these multivesicular bodies with cell membrane via the endolysosomal pathway. microvesicles are - nm sized vesicles secreted from cell surface by budding of the cell membrane. apoptotic bodies, which are out of scope of this review, are - nm sized vesicles and released from the cell surface through outward budding of apoptotic cell membrane [ ] . there are various isolation methods for evs with their inherent principles, advantages and disadvantages, which are reviewed in detail elsewhere [ ] . in addition, lack of individual markers for ev subtypes and their overlapping characteristics regarding size, density and composition make the nomenclature problematic. in this context, the term "extracellular vesicle" is suggested for use as a generic nomenclature to describe vesicles isolated from body fluids and cell cultures by the international society for extracellular vesicles [ ] . however, nomenclature issue is still a matter of debate in the scientific community and exosomes, microvesicles and evs have been frequently used interchangeably in the biomedical literature since years [ ] . therefore, we chose not to strictly distinguish them and preferred to use the definition "extracellular vesicle" in this review unless otherwise stated in the related article. evs carry various types of cargo between cells which make them vital mediators of intercellular communication. ev cargo encapsulated within a lipid membrane consists diverse combinations of proteins, lipids, peptides, carbohydrates and nucleic acids including dna, mrna, microrna (mirna) and long noncoding rna, allowing transmission of biological signals between cells. they represent the native characteristics of donor cell resulting with de novo gene expression, posttranslational modification or new transcript translation in the recipient cell [ ] . not only they regulate the physiological processes in cells, they are tightly linked to various disease pathogenesis. evs are secreted by all cell types in the organism and can be detected in all body fluids, which make them an attractive source for biomarker investigations. because they carry cargo between cells, they can be ideal candidates to be utilized as carriers for drug delivery [ , ] . in addition, their inherent role in pathological conditions highlight their potential role as novel targets for therapeutic interventions as cell-free therapies in various diseases [ , , ] . given the prolonged human life and survival expectancy, the number of people requiring emergency care and emergency department admissions are increasing all over the world [ , ] . these mostly include trauma patients, cardiovascular disease, neurological disease patients and patients suffering from organ failures such as acute respiratory failure or thermal burns. in addition, biological or chemical threats causing mass casualty situations such as pandemics, sepsis, and radiation related incidents are significant issues for communities, militaries and local medical systems. although rm approaches including stem cell applications and ev based therapies are in their infancy hitherto, they promise as novel therapeutic targets from a futuristic perspective (fig. ) . in this context, this review aims to summarize and discuss the therapeutic potential of stem cells and evs in patients suffering from diseases requiring acute emergency care. trauma related injury is a significant cause of mortality and disability all over the world. despite the reductions in mortality from cancer and cardiovascular diseases in the last years, death rates from trauma have remained constant. however, there have been significant achievements in the management of trauma patients including timely prehospital care, rapid diagnostic tests, hemorrhage control, transfusion and surgical approaches. traumatic brain injury (tbi), spinal cord injury (sci), chest trauma, abdominal trauma and musculoskeletal injuries are among subtypes of traumatic injuries. the most common causes of death from traumatic injuries include tbi and hemorrhagic shock [ , ] . besides being an important civilian health issue, trauma related injuries are also a significant concern for militaries in time of war [ ] . in general, trauma causes structural damage to tissues, disrupts perfusion and provokes inflammation subsequently resulting with irreversible tissue damage, loss of organ function and finally death. host defense response, which involves local and systemic release of acute phase proteins, proinflammatory cytokines, metabolites and hormonal mediators, plays major role in the clinical outcomes including mortality after trauma [ ] . optimal healing in a tissue after a traumatic injury can be provided by the reversal to preinjury situation and function without scarring and is associated with the nature and degree of the traumatic injury, intrinsic biological activity and regenerative capacity of the affected tissues. theoretically, optimal healing can be accomplished by optimizing the healing process through augmenting patient biology. due to their abilities to modulate inflammation, cell death, vascular dysregulation and tissue damage, which also underlies the complex and heterogeneous pathogenesis of traumatic injury, stem cell therapies may hold a promise for promoting organ and tissue repair after a traumatic process including civilian as well as military populations [ ] [ ] [ ] . for these purposes, the therapeutic potential of stem cells have been widely investigated in various preclinical models of trauma such as tbi, sci, musculoskeletal injury, circulatorypulmonary tissue injury, skin injury, postinjury organ failure and ocular-auditory injuries with encouraging results [ ] [ ] [ ] [ ] [ ] [ ] . mscs from various tissue sources and donor types have been the most investigated cell type in animal models of trauma. their beneficial effects in trauma can be summarized as migration and integration into the site of injury and respond to immunostimulatory molecules defined as damageassociated molecular patterns. besides, they generate an anti-inflammatory and pro-regenerative microenvironment through secreting factors that activate the growth and differentiation of adjacent cells, stimulate angiogenic activity, regulate functions of endothelial cells and fibroblasts, and inhibit fibrosis [ ] . a previous systematic review and meta-analysis study investigating the efficacy of msc transplantation in animal models of tbi suggested that mscs might have beneficial effects on locomotor recovery [ ] . likewise, systemic and local administration of allogeneic bone marrow (bm)-mscs promoted fracture healing in rats [ ] . percutaneous intraspinal injection of autologous neurogenically-induced bm-mscs provided clinical benefits in paraplegic dogs lacking deep pain perception after spinal trauma in a study performed by our research team previously [ ] . our research group also demonstrated that msc infusion is associated with improved local inflammation and histological findings in rats subjected to polytrauma model comprising bone fracture and liver trauma [ ] . clinical data of stem cell therapies in trauma patients mostly come from tbi and sci patients. a phase- clinical trial investigating autologous bm-derived mononuclear cell (bm-mnc) infusion in pediatric tbi patients indicated that fig. main pathological conditions requiring acute emergency care that can benefit from stem cell therapies or extracellular vesicle therapies in the future harvesting and infusion of stem cells is safe in children with no infusion related toxicity or death [ ] . a retrospective analysis of this study with age-and severity-matched control group demonstrated that stem cell therapy is associated with lower treatment intensity required to manage tbi in children [ ] . another phase- / a trial conducted by the same group evaluated the safety and efficacy of autologous bm-mnc infusion in adult tbi patients and demonstrated the safety and feasibility of cell treatment. there was a potential signal of treatment effect regarding structural preservation and down-regulation of inflammatory biomarkers after cell infusion [ ] . autologous bm-msc therapy was also proven to be safe and effective when administrated through lumbar puncture in the subacute stage of tbi [ ] . there are also ongoing clinical trials evaluating the therapeutic effects of stem cells in tbi patients in which the results are highly anticipated and briefly summarized in the related papers [ , ] . there have been numerous clinical studies testing stem cells for neuronal repair in sci patients. human escderived oligodendrocyte progenitor cells were transplanted to sci patients into the site of injury in a phase- trial sponsored by geron corp., but the study was halted. although complete results have not been published, it was announced that there were no safety issues regarding cell treatment. the study has been in progress under the direction of another company [ , ] . besides, bm-mscs have been investigated in many clinical trials of sci with diverse study designs and outcomes. although no adverse reactions or side effects were reported, favorable outcomes were limited in these studies compared to expectations. among these studies, few of them appeared to encourage cell therapy in sci patients. there are also ongoing clinical trials which will probably improve our knowledge about the clinical effects of stem cells in sci treatment [ ] . increasing line of evidence suggests that beneficial effects of stem cell therapies are mediated through evs and their mirnas released from the transplanted cells. this evidence raises the possibility that instead of cell transplantation, evs can be used for the treatment of several traumatic injuries as cell-free agents. evidence demonstrating that severe traumatic injury is associated with elevation of circulating procoagulant and proinflammatory evs underlies the significance of evs in trauma patients [ ] . however, our understanding about their therapeutic role in trauma comes from animal model studies. for example, a recent study showed that administration of exosomes derived from human bm-mscs improve functional recovery of injured animals after tbi [ ] . likewise, exosomes from bm-mscs improved fracture healing in a rat model of femoral nonunion through enhancing osteogenesis and angiogenesis [ ] . due to encouraging preclinical data coming from several works, they have been suggested as an alternative cell-free treatment in several subtypes of trauma including bone fractures [ ] and neurotraumas [ , ] . the mechanisms underlying the beneficial effects of evs in trauma may be the modulation of immune system and systemic inflammatory response that occurs in the acute phase of trauma. besides, increased angiogenesis and vascular density, prevention of cell death, transfer of their cargo between cells, stimulating endogenous reparative mechanisms might mediate their therapeutic functions [ ] . however, lack of clinical data especially in polytrauma patients hampers to make a clinical judgement about possible therapeutic applications of evs in traumatic injuries. coronary heart diseases including acute myocardial infarction (ami) and the leading heart failure (hf) are the main causes of mortality all over the world and constitute a major problem of global health causing frequent acute hospital admissions and hospitalizations. although long term survival of ami and hf patients has improved thanks to improvements in coronary interventions, medical treatments and surgical therapies, prognosis is still poor and admission to emergency departments, hospitalization rates and economic costs are high [ , ] . the main pathophysiological mechanism of poor outcomes in ami and hf patients is the lack of adequate cardiomyocyte renewal capacity in the failing heart and formation of a fibrotic scar tissue in the infarcted myocardium with progressive cardiomyocyte death subsequently resulting with pump failure. besides, none of the current treatment strategies except heart transplantation can reverse these mechanisms back and induce a true regeneration in the heart [ , ] . in recent decades, cell-based therapies including skeletal myoblasts, bm-derived stem cells, mscs, cardiac progenitor cells and pscs have been investigated in order to generate new and functional myocardial tissue and/or activate endogenous repair mechanisms in the heart. after encouraging preclinical studies with small and large animal models, the regenerative potential of these cells have been tested in multiple clinical trials with miscellaneous results and heterogenous outcomes which may be attributed to diversities in study designs such as cell types, cell preparation techniques, delivery route, dose, timing of application, study endpoints and followup methods of patients. in brief, there have been no safety issues regarding these cell therapies, but their efficacy has mostly been neutral or at most marginally positive outcomes [ ] [ ] [ ] . among adult tissue sources, mscs preferably obtained from bm or adipose tissue might be promising due to their high secretory profile and paracrine effects. in addition, cardiac cells derived from pscs may provide superior benefits when compared to other cell types although comparative studies are needed to support this hypothesis. it should also be kept in mind that the use of pscs are restricted due to ethical issues and/or teratoma formation risk although they have a robust differentiation potential than other cell types [ , ] . evidence mostly coming from large animal models also points to arrhythmogenic potential of cardiomyocytes derived from pscs [ ] . a recent phase- study investigated the safety of fibrin patch embedded cardiac progenitor cells derived from human escs in six severe hf patients. the results of the study demonstrated short-and medium-term safety and technical feasibility of the surgical procedure pioneering future efficacy studies [ ] . initially, the hypothesis that the transplanted stem cells reach their target tissue, differentiate into cardiomyocytes, engraft into the host myocardium electromechanically and improve cardiac functions was thought to be the main mechanism for therapeutic effects of stem cells. however, subsequent researches demonstrated that cardiac differentiation and engraftment of stem cells into the myocardial tissue are very rare [ , ] . the recognition that stem cells secrete a variety of evs that act in a paracrine manner and these evs mediate the beneficial effects of stem cells has shifted the stem cell paradigm into a new concept defined as "paracrine hypothesis" [ ] . exosomes, specifically secreted from pscs and mscs, were shown to exert regenerative effects in the heart and vasculature by modulating apoptosis, inflammation, fibrosis and angiogenesis [ ] . besides, beneficial effects of these secretomes released from other stem cell populations such as cardiac and endothelial progenitor cells (epcs) in the cardiovascular system were demonstrated. accordingly, they have been suggested as a potential cell-free therapy to regenerate the diseased heart instead of stem cell applications [ , ] . cardioprotective effects of evs and exosomes have been investigated in several preclinical models including mi [ ] [ ] [ ] and chronic hf [ , ] rendering the potential of these cell-free agents as therapeutic biological medications. besides, a recent study compared the cardiac regenerative effects of intramyocardially-injected ipscs and ipscderived evs in a murine mi model and demonstrated that ipsc-derived evs are safer than ipsc injection in regard to teratoma formation. on the other hand, ipsc-derived evs exhibited superior cardiac repair effects than ipscs in terms of left ventricular function, angiogenesis, reduction of apoptosis and hypertrophy [ ] . an immunocompetent mouse mi model study to investigate the immunological effects of evs obtained from human cardiac progenitor cells demonstrated that intramyocardial delivery of these evs does not induce an allogenic immune response and likely to have a systemic antiinflammatory effect. however, the hypothesis that whether the systemic delivery of evs would trigger similar antiinflammatory effects with positive outcomes on heart functions needs to be tested in future studies which might intensify and accelerate the clinical translation of therapeutic ev applications [ ] . accumulating evidence suggests that cardioprotective effects of evs are mostly mediated through specific mirnas [ ] . they carry information and mediate the cross-talk between cells in tissue of interest such as cardiomyoctes, stem cells, endothelial cells, smooth muscle cells, fibroblasts and others to modulate cellular changes and disease phenotypes. there are numerous cardiac-related mirnas in the heart, which are secreted from various sources of cells with varying functions such as enhanced cardiomyocyte survival and functions, attenuation of cardiac fibrosis, induction of angiogenesis, inhibition of apoptosis and oxidative stress, and regulation of sarcomeric genes and ion channel/automaticity genes [ ] [ ] [ ] [ ] . stroke is a serious neurological condition with high mortality and disability rates worldwide [ ] . ischemic stroke, which occurs suddenly due to thromboembolic occlusion of a major artery that supplies blood to the brain, represents the most common type and requires restoration of blood flow immediately. thrombolytic agents and endovascular mechanical thrombectomy are the only treatment options to achieve recanalization with their limited therapeutic time window and side effects such as risk of hemorrhage [ ] . on the other hand, hemorrhagic stroke occurs secondary to rupture and bleeding of a vessel in the brain and requires immediate surgery to remove clots and blood and decrease intracranial pressure [ ] . irrespective of stroke origin, the integrity of neurovascular unit, which includes numerous cellular components and tissue-related proteins, is impaired in the early times of stroke leading to disruption of blood-brain barrier (bbb) and ischemic cell damage. from a pathophysiological perspective, a series of molecular and cellular pathways are activated during this process such as inflammation, apoptosis and oxidative stress-related pathways subsequently resulting with neuroinflammation, neurodegeneration and irreversible tissue injury. the aforementioned therapies can improve neurological functions and mortality in the acute phase of stroke but their therapeutic effects are limited in the subacute and chronic stages [ ] . it is known that some stroke patients show spontaneous recovery owing to limited plasticity and remodeling capacity of the brain. therefore, activation of intrinsic reparative processes in the brain may promise as a therapeutic strategy for stroke theoretically. there is also increasing evidence that stem cells, particularly neural stem cells located in the brain niches, contribute to remodeling and recovery processes by activating angiogenesis, neurogenesis and neuroprotection after stroke, subsequently provoking improved neurological outcomes [ , ] . in this context, stem cell therapies with their wider therapeutic window may represent a new treatment paradigm to ameliorate the subacute and chronic phases of stroke. beyond stem cells, exosomes are known to regulate intercellular communication between neurovascular system and other system cells and contribute to brain repair processes after stroke putting forward them as promising cell-free agents in stroke therapy [ , , ] . the regenerative potential of various types of stem cells, with different sources, dosages, delivery routes, application times and end-points has been investigated in preclinical animal models and human clinical trials with the expectation that these cells would successfully engraft into the damaged brain tissue, differentiate into functional neuronal and vascular system cells and promote full recovery after stroke. a recently published systematic review of studies testing stem cells in rodent ischemic stroke models and randomized human clinical trials encompassing ischemic stroke patients treated with autologous stem cells with at least one year follow-up period demonstrated that stem cell therapies show beneficial effects in terms of behavior and histological outcomes in rodents. pooled data of human clinical trials failed to show functional recovery although there were some improvements in terms of neurological outcomes [ ] . likewise, translational deficiency was observed from animal models to clinical studies in a systematic review and meta-analysis study investigating the efficacy of mscs in subacute or chronic ischemic stroke [ ] . therapeutic applications of evs for stroke may confer some pros when compared to stem cell applications, which are discussed in detail in the subsequent sections of this paper and related review articles. emerging evidence indicates that the neurorestorative effects of stem cells are mediated through release of exosomes and their mirna cargo instead of integration into neural networks [ , , ] . besides, exosomes mediate dynamic cross-talk between neural system cells and endothelial cells [ ] . comparative studies of stem cells and evs in stroke treatment mostly come from animal models. a previously published study demonstrated that msc-derived evs have similar functional tissue regeneration capacity as mscs in mice subjected to stroke [ ] . another rat stroke model study indicated that msc-derived evs possess better rehabilitation effects than msc treatment in stroke repair which might be due to higher bbb permeability of evs compared to mscs [ ] . in a recent study, systemic application of msc-derived exosomes loaded with mirna- was shown to stimulate cortical neural progenitors to obtain neuronal identity and ameliorate ischemic injury by cortical neurogenesis in mice subjected to stroke suggesting a great potential for clinical translation [ ] . accordingly, a phase - clinical trial (nct ) aims to investigate the safety and efficacy of allogenic bm-msc-derived exosomes genetically enriched with mirna- in ischemic stroke patients. the primary endpoint is safety including treatment-related adverse events in months such as deteriorating or recurrent stroke, brain edema, seizures and hemorrhagic transformation. the secondary endpoint is efficacy measured by the improvement in the modified rankin score at months. the results of the study have not been posted yet and are awaited. acute respiratory distress syndrome (ards), in other words acute respiratory failure, is a life-threatening acute lung injury characterized by diffuse alveolar damage and hypoxemia in the lungs with high morbidity and mortality rates [ ] . among several inciting events such as toxic substance inhalation, trauma, burns and pneumonia, sepsis is the most common cause of ards. a complex interaction between the immune system and the alveolar-capillary barrier, and widespread uncontrolled inflammation in the lungs underlies the pathophysiology of the disease. treatment of ards patients relies on supportive strategies such as mechanical ventilation, fluid management, neuromuscular blockade and prone positioning, because there is no specific pharmacological therapy proven to be effective and reduce mortality in this patient group [ , ] . in fact, numerous pharmacological agents such as surfactant, nitric oxide, corticosteroids, antifungals, phosphodiesterase inhibitors, antioxidants and immune modulating agents have been attempted in acute lung injury and/or ards with unfavorable outcomes and no effect in mortality [ ] [ ] [ ] . therefore, novel therapies for treating or preventing ards are highly needed. stem cells yield substantial promise as a novel treatment strategy for ards patients due to their differentiation abilities to various cells, immune system modulation and antiinflammatory characteristics [ ] . for this purpose, various type of stem cells such as mscs, epcs, escs, ipscs have been investigated in preclinical models with encouraging results. among all cell types, mscs obtained from different sources mostly bm and umbilical cord (uc) have attracted much more attention than other cell types. mscs have been shown to modulate anti-inflammatory and antiapoptotic pathways, ameliorate epithelial and endothelial cell recovery, and increase microbial and alveolar fluid clearance in several animal models of ards. these beneficial effects of mscs resulting with improved lung and distal organ functions and survival have moved msc therapies to a clinical stage [ , , ] . a previous case report of an ards patient demonstrated short term beneficial effects of uc-msc treatment although the patient could not survive in the long-term period [ ] . likewise, allogeneic bm-mscs were demonstrated to improve hemodynamic status and multiorgan failure of two severe ards patients who did not respond to treatments such as mechanic ventilation and extracorporeal membrane oxygenation. besides, clinical improvement of these patients was shown to be mediated through reduction of several pulmonary and systemic inflammatory markers [ ] . a previous phase- trial of allogeneic adipose tissue-derived msc treatment in ards patients demonstrated safety of systemic infusion with limited efficacy [ ] . according to the results of another phase- dose escalation trial, allogeneic bm-msc infusion was well-tolerated and there were no infusion related adverse events in moderate to severe ards patients [ ] . subsequently performed phase- a trial by the same group with a single intravenous infusion dose ( x cells/kg) of allogeneic bm-mscs demonstrated safety of the treatment. when it comes to efficacy, there were no differences between the placebo and cell-treated groups in terms of clinical outcomes. however, there was a tendency for improvement in oxygenation index in cell-treated group. according to biomarker measurements, endothelial injury was significantly improved in cell-treated patients, and msc viability after thawing emerged as a potentially important factor for the efficacy of cell treatment [ ] . although stem cells promise an emerging role for ards treatment, it is known that secretion of soluble mediators acting in a paracrine manner such as evs, which are also highly abundant in the conditioned medium of stem cells, mediate the therapeutic effects of these cells. besides, evs secreted from various type of cells are closely linked with the pathogenesis of ards. therefore, in recent years there has been a growing interest in exploring the effects of evs specifically derived from mscs in ards treatment. the biological rationale for the therapeutic use of these cell-free agents is comparable to stem cells including immune modulation and antiinflammatory effects, promoting alveolar epithelium and endothelium repair, alveolar fluid clearance improvement, antimicrobial effects and inhibition of lung fibrosis [ , ] . preclinical studies investigating evs in ards as a therapeutic approach are in their infancy yet but several encouraging reports indicate that evs derived from stem cells confer similar beneficial effects when compared to administration of stem cells themselves [ ] [ ] [ ] . management and treatment of ards has attracted much more interest than previous times because of the pandemic of novel coronavirus disease (covid- ) pneumonia, which has spread worldwide in a very short time. clinical course of this viral infection may progress to ards and death, and there is no effective pharmacological therapy or vaccine yet. increased inflammatory situation with cytokine activation named as cytokine storm underlies the pathogenetic mechanism of infection. due to close intersection between the disease pathogenesis and mechanism of action of stem cells regarding immune modulation and anti-inflammatory activity, stem cells and/or their secretomes have been considered as a possible therapeutic agent for covid- pneumonia [ , ] . a recent case study of a severe covid- pneumonia patient reported improved clinical course and inflammatory biomarker levels after human uc-msc infusion [ ] . likewise, clinical grade msc infusion was reported to be safe and effective in a pilot study including seven covid- pneumonia patients. laboratory tests of these patients demonstrated improved inflammatory status and according to in-vitro tests infused mscs were not infected with the virus [ ] . in addition to these reports, there are several registered clinical studies to test stem cells, specifically mscs obtained from diverse sources, in covid- pneumonia patients. among these recorded studies, two of them (chictr and nct ) aim to investigate therapeutic potential of exosomes [ , ] . the results of these studies are highly anticipated. in parallel with ards, treatment of sepsis and septic shock is an unmet medical need. despite intensive efforts to decrease morbidity and mortality associated with sepsis, there is no specific therapy yet and management includes symptomatic approaches. in addition, it is the most common cause of ards. altered immune homeostasis with a hyperinflammatory response and subsequent immune suppression are the main pathophysiological processes during the initiation and progression of the disease [ ] . mscs have been supposed to have beneficial effects in sepsis through different ways depending on the origin such as bacterial or viral sepsis. their immune and inflammation modulating capacity, antibacterial actions and organ protective effects, which have been demonstrated in various animal models of sepsis with varying outcomes, yield msc therapies as an attractive cure for sepsis and septic shock [ ] . a recent pilot clinical trial showed that single dose msc administration was safe and well-tolerated in neutropenic patients with septic shock. although msc therapy was associated with improved outcomes such as faster hemodynamic stabilization, vasodepressor withdrawal, improvement in respiratory failure and decrease in neutropenic period, it did not prevent death from the sepsis related organ failure [ ] . however, a meta-analysis study evaluating the efficacy of msc therapies in animal models of sepsis demonstrated lower mortality rates underlining the potential therapeutic effects of mscs in sepsis and the need for future studies [ ] . on the other hand, evs as cell-free agents and/or drug carriers may have therapeutic functions in sepsis. animal model studies are promising but the need for further preclinical and clinical data comes to the fore [ ] . radiation-related nuclear accidents or weapons have been a growing concern worldwide since the past century due to the fact that they are associated with high morbidity and mortality rates in affected societies [ ] . acute radiation syndrome (ars) refers to a wide spectrum of clinical conditions occurring in stages during hours to weeks after a large portion of the body is exposed to a high dosage of ionizing radiation thereby altering organ and tissue functions at varying levels. although bm toxicity and myelosuppression have been considered as the major causes of morbidity and mortality, ars is also accompanied by gastrointestinal failure, neurological damage and multiorgan dysfunction. from a pathophysiological point of view, acute ionizing radiation exposure disrupts physiological recovery of cellular systems through the depletion of radiosensitive stem cells and genotoxic damage [ , ] . it is also a challenging issue for health care providers to identify and appropriately treat highly exposed victims in a real-life situation where a large number of community are exposed to high doses of radiation and exceed the limited capacity of local medical systems [ ] . management of ars generally includes prophylaxis and therapy of infections, detoxification, parenteral nutrition, topical and surgical therapies for damaged skin, correction of secondary toxic metabolic disturbances, and bm transplantation including growth factors and hsc transplantation in selected patients [ ] . given that exposure to high doses can be fatal in hours to weeks, palliative care may also be required. prognosis mostly depends on recovery of the bm and cell transplantation should only be considered if growth factors fail to reconstitute the hematopoietic system [ ] . beyond the preclinical animal model studies demonstrating favorable effects of stem cell therapies in ars [ ] [ ] [ ] , our understanding about the clinical outcome of stem cell transplantation in ars patients mostly comes from previous tragic nuclear accidents and natural disasters. clinical data of these victims concluded that the survival benefit of cell transplantation is limited probably due to late administration time, graft rejection, accompanying organ failures and inhomogeneous radiation exposures [ , ] . therefore, hsc transplantation is only recommended if severe aplasia persists despite cytokine treatment in ars patients [ , ] . despite these limitations, stem cells have an immense potential to combat the early and late complications of radiation exposure. besides taking a role in hematopoietic system reconstitution, they can also impact the recovery of neurological, pulmonary, gastrointestinal system organs and cutaneous wounds, which are highly affected after radiation exposure in acute and long term. mscs isolated from the bm and uc have been at the forefront of investigations [ , ] . local autologous bm-msc administration was associated with a favorable clinical outcome and no recurrence of radiation inflammatory waves during eight month follow-up of a patient suffering from ars with very severe radiation burns [ ] . currently, there is not any stem cell product approved by the regulatory authorities for radiation injuries to use in the context of a mass casualty incident. however, intramuscular injection of human placenta-derived plx-r cells developed by pluristem therapeutics, inc. was associated with improved survival in mice after radiation injury suggesting that plx-r cells may be beneficial for ars treatment [ ] . similarly, clt- cells derived from myeloid progenitors and developed by cellerant therapeutics, inc. improved survival in irradiated mice suffering from hematopoietic and gastrointestinal subsyndromes of ars even cell treatment initiated days after irradiation [ ] . these two "off-the-shelf" products developed by different companies appear to be promising for future clinical applications of ars after a mass casualty radiological or nuclear incident. our knowledge about the therapeutic role of evs in ars is limited yet and entirely origins from preclinical studies. however, there is a growing body of evidence that these cell-free agents play role in radiation-induced genomic instability and bystander effects suggesting a possible pathogenetic effect of these molecules in radiation injury [ ] [ ] [ ] . exosomes derived from bm-mscs and endometrial regenerative cells were demonstrated to increase proliferation of thymidine-incorporated hscs in a previous experimental work [ ] . human neural stem cell-derived microvesicles were able to reverse or prevent radiation-induced cognitive dysfunction in brain-irradiated mice suggesting a possible therapeutic effect of microvesicles for radiation-induced injury in the brain [ ] . culturing macrophages with exosomes derived from lipopolysaccharide-primed mscs was shown to improve survival through hematopoietic system recovery in a mouse model of ars [ ] . in the light of these data, it might be reasonable to suggest that evs may be an attractive approach in ars treatment with the help of future studies as discussed in a workshop held in france in july cosponsored by national institute of allergy and infectious diseases and institut de radioprotection et de sûreté nucléaire [ ] . burns exert significant consequences in the community including death, disability, economic and social loss. a significant portion of burn cases occur in low-to middle-income countries. there are various types of burns according to the origin, but thermal burns are the most common type of burn injuries [ ] . in addition, thermal burns are a significant cause of morbidity during war time accounting approximately % to % of conventional war casualties [ ] . appropriate wound healing of the damaged skin constitutes an important part of the healing process in acute full-thickness burns. skin grafts and skin substitute products containing somatic cells are widely used for this purpose with their inherent limitations such as lack of enough skin to cover the burns and/or effectiveness. considering the challenges of available therapies and systemic consequences of burns, it is evident that rm approaches to treat acute burn injuries are essential [ ] . cutaneous tissue maintains robust regeneration capacity and various stem cell types such as interfollicular epidermal stem cells, hair follicle stem cells, sebaceous gland stem cells, melanocyte stem cells and neural progenitor cells that reside in different compartments of the skin [ ] . skin wound healing includes coordinated complex series of overlapping events occurring in four phases namely hemostasis, inflammation, proliferation and remodeling. stem cells of the skin and other organs play role at all these stages in a coordinated fashion to regenerate the skin. however, several factors influence this process such as the degree and size of burn, patient related conditions such as age, immune status and comorbid situations, and materials covering the burn wounds [ , ] . in this context, autologous or allogenic stem cell therapies might emerge as a promising and effective treatment strategy both for wound healing and systemic effects of the burns such as inflammation, hypermetabolism and immune suppression. various stem cell types from different sources, especially mscs have been investigated for this purpose [ ] . a phase- clinical trial (nct ) collaborated by united states department of defense aims to investigate the safety of allogenic msc application to second degree burn wounds. in addition, the study aims to investigate maximum safe dose that will be used in phase- investigations. the estimated study completion date is february and the results have not been posted yet. another phase - clinical trial (nct ) aimed to investigate the safety and efficacy of allogeneic human uc-mscs and human cord blood mncs in patients with acute moderatesevere full thickness burn but the results have not been published although the estimated study completion date was july . in addition to these studies, there are several clinical trials evaluating therapeutic effects of stem cells in cutaneous burn injury patients recorded in the national institute of health clinical trials website with various study protocols, cell types and outcomes, in which the results are highly anticipated. evs and their related mirnas are known to modulate therapeutic effects of stem cells. therefore, they have been suggested as alternative cell-free agents for the treatment of burn injuries. similar to stem cells, various evs have been demonstrated to play role in the pathophysiological processes of burn wound healing at all stages. their therapeutic role has also been tested successfully in various animal model studies, being msc-derived exosomes or evs the prevailing source of origin [ , ] . a phase- clinical trial (nct ) aiming to investigate the beneficial effect of plasma-derived exosomes in cutaneous wound patients with ulcer is currently in enrollment status. although the study protocol does not specifically include acute burn injury patients, the results of this study may shed light on our knowledge about possible therapeutic potential of evs in cutaneous burn injury patients. rm holds an immense potential for a variety of diseases in which there is a high unmet clinical need. despite the relatively slow rate of translational success from laboratory to clinics, expectations, optimism and excitement surrounding this field remain great. rm involves cell and gene therapies, and tissue engineering applications, however stem cells have been at the center of interest for years because of their biological potential [ , , ] . on the other hand, secretomes of cells namely evs have attracted great attention as therapeutics in recent years and have been suggested as alternative to stem cell therapies as cell-free agents [ , ] . there are many challenges that need to be addressed in order to improve translation of stem cell therapies and evs into clinical practice with sustainable and clinically significant benefits. however, it is obvious that both stem cell therapies and ev therapies are in their infancy ages with their inherent and/or similar pros and cons which are briefly summarized in table . bioprocessing of stem cells for transplantation relies on successful isolation from the donors and this can be achieved by either an autologous or allogeneic source. in autologous transplantation, stem cells are obtained from the patients' own tissue which does not carry a risk for immune rejection but need sufficient time in order to obtain high quality cells with adequate numbers. in addition, isolation procedure involves an invasive and painful procedure and obtaining cells with high quality may be problematic because of impaired stem cell functions in patients with comorbid diseases and genetic alterations. this limitation might be specifically evident in aged and frail patients. on the other hand, allogeneic stem cells are isolated from healthy individuals and expanded in large numbers and efficient quality. they can be stored and administered as "off-the-shelf" products, which make them an attractive option for acute emergency conditions and mass casualty settings and enable diverse and multiple dosing strategies (fig. ) . however, allogeneic cell transplantation requires immunological matching between host and donor [ ] . it is reasonable to question which stem cell source is superior to another. for example, comparison of autologous and allogeneic stem cells in large animal models of ischemic heart disease showed similar effect size [ ] . likewise, allogeneic and autologous bm-mscs compared in randomized clinical trials demonstrated no significant difference in terms of safety and improvement in left ventricular ejection fraction in ischemic cardiomyopathy and nonischemic hf patients [ , ] . a preclinical meta-analysis study of stem cells for experimental stroke showed that autologous cells were better than allogeneic cells to ameliorate infarct volume, whereas allogeneic cells were better for improving functional outcomes [ ] . according to another meta-analysis study investigating mscs in locomotor recovery of rat models of sci, cell source was a significant predictor of improved outcome as autologous and allogeneic cells performed better than xenogeneic and syngeneic cell sources [ ] . such comparative studies have not been performed with regards to ev therapies yet. although first clinical studies tested autologous dendritic cell-derived exosomes in cancer patients [ , ] , the field has shifted to allogeneic sources and most companies are developing allogeneic products because of difficulties of harvesting autologous evs in sufficient quantities [ , ] . in this context, a previous clinical case of a graft-versus-host disease patient refractory to steroid therapy indicated promising outcomes after allogeneic mscderived ev administration [ ] . stem cells are a group of heterogeneous cells that have the ability to self-renew and differentiate into mature cells through asymmetric cell division [ ] . among all stem cell types, mscs are numerically the most used cell type in preclinical and clinical settings. they are considered as the ideal cell type for transplantation. this may be due to their pleiotropic properties such as antiapoptotic, antifibrotic, anti-inflammatory and angiogenic activities, growth factor production, and immune system modulation in addition to their differentiation capacity to various cells of lineages. their immune privileged abilities also render mscs an ideal source for allogeneic applications [ , ] . mscs can be obtained from various sources of tissues in the body including but not limited to bm, adipose tissue and uc. when compared among themselves, adipose tissuederived mscs seem to be ahead because of higher number of cells per gram of tissue, higher cell proliferation rate compared to others and technical convenience to obtain cells [ ] . in the light of these advantages, it is reasonable to suggest that adipose mscs may be an ideal source for acute emergency conditions as well as autologous applications. however, tissue source of mscs may be a challenging task for translational activity. for example, a recent study demonstrated that mscs obtained from adipose tissue are more efficient than those obtained from uc and endometrial tissue in terms of in-vitro and in-vivo angiogenic activity [ ] . likewise, neuro-regenerative potential of mscs derived from human bm, adipose tissue and wharton's jelly was shown to be non-equal in a recent study. although bm-mscs were inefficient than other cell types in terms of neurotrophic growth factor secretion and gene expression, secretome of all cell lines had pronounced neurotrophic potential regarding composition and in-vitro paracrine activity [ ] . pscs, namely escs and ipscs, hold the potential to differentiate into all cells in the organism and are considered as the future of cell transplantation. however, they possess two despite the fact that escs are obtained from an embryo, there remain ethical problems and restrictions with their use. in fact, ipscs were generated to overcome ethical issues surrounding escs but both of these cell types also carry a risk for teratoma formation which limit their translation into clinics [ ] [ ] [ ] . preclinical data suggest that mscs derived from ipscs have superior effects than bm-mscs to attenuate lung disease in rats [ ] . the first human clinical trial using ipscs focused on macular degeneration, but the trial was suspended because of legal issues after the first patient was treated with autologous ipscderived retinal pigment epithelium cell sheet. in addition, genetic alterations were detected in the ipscs of the second patient and transplantation was canceled. there was no safety concern including tumor formation and immune rejection at months of follow-up of the treated patient [ ] . however, the study group revised the study protocol and announced that they implanted ipsc-derived retinal pigment epithelial cells obtained from an allogeneic donor to a man first time [ ] . when it comes to acute emergency situations such as critical organ injuries including mi, stroke, trauma, or mass casualty settings including radiation injury, burns, pandemics and combat injuries, ipsc biobanking can be an alternative solution to obtain sufficient numbers of cells in short times. biobanking of allogeneic stem cells may also help to reduce costs, by eliminating the need to prepare limited doses of cells for each patient. however, immunogenicity still remains as a drawback tried to be solved through donors who are homozygous at human leukocyte antigen alleles namely "super donors". fortunately, encouraging efforts have come from the united states, european union, and japan in recent years in order to expedite approval processes for translation of stem cell therapies into the clinics including pscs [ , ] . significant limitations exist while considering the optimal dose, transplantation route and timing of administration for stem cell therapies and ev-based therapeutics. for example, a dose of four million cells is considered as effective for intravenous transplantation in a stroke rat weighing g, which corresponds to million cells in a kg man suffering from stroke. if cells are transplanted through stereotaxic route, k cells in a g rat is considered as effective dose, which is equivalent to million cells in a kg stroke patient [ ] . however, most of the clinical trials investigating stem cells in stroke patients use cells below these doses and vary among each other [ ] . it should also be kept in mind that higher number of cell transplantation does not mean more improved o u t c o m e s . f o r i n s t a n c e , t h e l o w e s t n u m b e r o f transendocardially injected mscs were associated with the greatest improvements in left ventricular volume and ejection fraction in a dose escalation study of ischemic cardiomyopathy patients [ ] . there are a wide range of transplantation routes for stem cells and evs varying according to disease characteristics but the optimal route for a specific disease is not fully known yet. according to a previous rat study of ventilator-induced lung injury, intratracheal msc application was found to be as effective as intravenous msc therapy [ ] . on the other hand, msc transplantation through intravenous route was found to be more effective compared to intraperitoneal route for improving liver injury in a rat polytrauma model [ ] . although intravenous injection is the most common way of transplantation, it is evident that stem cells are trapped in lungs and eliminated from circulation, which is named as "pulmonary first-pass effect". in a previous rat tbi model study, a significant proportion of mscs were localized into the lungs at hours of intravenous infusion and less than % of the cells reached the arterial system. moreover, this study demonstrated that very few proportion of cells ( . %) reached into the cerebral tissue [ ] . however, this problem might be achieved through multiple infusions instead of single bolus administration [ , ] . despite the fact that evs can easily cross the bbb and they do not carry a risk for vascular obstruction, they promise for systemic applications in neurological diseases such as stroke and tbi compared to stem cells [ , , , ] . a recent study found that biodistribution of evs can be affected by varying dosages, routes of injection, and cellular origin of evs [ ] . organ specific applications such as intracoronary route for cardiac diseases or intratracheal and inhalation route for lung diseases may be an alternative solution regarding the limitations of systemic infusions. in addition, topically applied allogeneic msc-derived evs are being planned to be tested in a phase- / a trial of a rare genetic skin disorder (nct ) [ ] . combination of stem cells and evs with tissue engineering modalities such as scaffold-based technologies, cell sheets and injectable biomaterials might be promising strategies for local or percutaneous applications specifically in cardiac diseases [ , ] . optimal time window for application is not well-defined, however it may depend on disease characteristics and availability of donors. for example, delivery of stem cells at early times may be beneficial to decrease proinflammatory processes which occur at the first days of tbi [ ] . likewise, a clinical study testing allogeneic multipotent adult progenitor cells in acute stroke patients showed that patients treated before hours were more likely to benefit from cell therapy [ ] . one potential limitation of early treatment is the harsh microenvironment at the injury region surrounded by toxic and inflammatory cells that may attenuate the therapeutic effects of cells. in addition, if cell treatment is planned at early times as in such diseases exemplified in this paper, use of autologous sources may not be possible because of time needed for harvesting procedure [ , ] . beside the invaluable contribution of animal model studies to understand disease pathogenesis, and stem cell and ev biology, an important aspect is the ability to test the efficacy of the products before moving to clinical trials. however, it is evident that translational success obtained from clinical trials has been modest despite the encouraging data coming from animal models [ ] . several reasons exist for this discrepancy mostly regarding methodological and interpretative issues observed in preclinical and clinical studies. lack of animal models that exactly match phenotypically and physiologically with the related human disease with similar organ size is a significant limitation. it is known that cellular functions of stem cells such as homing and niche activities, intercellular contact, cytokine and growth factor secretion may differ among various species [ , ] . likewise, biological functions of evs obtained from mscs of different species such as human and murine may vary [ ] . publication bias is a significant problem for both preclinical and clinical studies, which may result with inaccurate interpretation of efficacy and decelerate the translational process [ , ] . the most relevant example of this effect comes from animal stroke studies leading to overstatement of efficacy [ ] . in fact, registration to public databases such as clinicaltrials.gov are encouraged to reduce bias in clinical studies in line with the declaration of helsinki-ethical principles for medical research involving human subjects, but publication and reporting of results are not at desired levels [ , ] . similarly, there are now public based platforms for preclinical studies including preclinicaltrials and animal study registry in order to reduce bias. however, it should be noted that neutral or negative results do not impress researchers, sponsors, authors, peer reviewers and editors, and such papers are most likely to be rejected by the journals [ ] . diversities in study protocols, outcomes, patient populations and interpretation may be another significant hurdle of clinical translational in rm therapies. for instance, according to an analysis of autologous bm-derived stem cell clinical studies for ischemic heart disease, a significant proportion of studies contain factual discrepancies regarding the enhancement in ejection fraction [ ] . fortunately, strategies for standardization of clinical trials of stem cells and evs are being developed [ , ] . such efforts are also being performed to standardize design, organization and reporting of in-vitro research and animal model studies [ , ] . stem cells tend to lose their biological functions after isolation and long term culture in-vitro. furthermore, when they are injected into the body, they challenge with a harsh microenvironment accompanying death signals because of the inadequate interaction between the cells and surrounding extracellular matrix (ecm). therefore, various strategies have been developed in order to enhance survival, engraftment rate, immunosuppressive, immunomodulatory and regenerative functions of stem cells, and improve their efficacy. preconditioning with physical, chemical and biological factors, genetic modification, and optimization of culture conditions are the prevailing strategies [ ] . combinatory approaches using tissue engineering and biotechnology applications might also enhance the therapeutic activity of stem cells. for example, in a study performed by our research group, encapsulation of bm-mscs in platelet rich plasma-derived fibrin microbeads yielded accelerated regeneration period with better myofiber orientation in volumetric muscle loss injury of rats [ ] . furthermore, mscs seeded on decellularized bovine small intestinal submucosa contributed healing process of a critical-sized full-thickness skin defect in rodents [ ] . similar approaches can also have beneficial effects on evs such as increased production in numbers or improved functions [ ] . for instance, a tbi rat model demonstrated that cultivating human mscs in three-dimensional collagen scaffolds yielded enhanced exosome number and therapeutic outcomes compared to exosomes derived from mscs cultured in two-dimensional conventional conditions [ ] . besides, overexpression of specific mirnas and transcription factors, or gene editing may be a feasible approach to improve beneficial effects of evs. mscs overexpressing particular mirnas were shown to have neuroprotective and cardioprotective effects in animal models [ ] . indeed, cultivation of macrophages with exosomes obtained from lipopolysaccharidetreated mscs increased secretion of cytokines and expression of growth factors. these macrophages improved survival in mouse with ars [ ] . genetically modified cell lines such as nt n, ctx e and sb have been widely investigated in preclinical and clinical studies of stroke. there were no safety concerns in clinical trials of these cell lines but genetic stability including ectopic tissue formation and tumorigenesis are potential caveats before moving into clinics [ ] . on the other hand, genetically engineered evs in contrast to naive evs may allow for production of more potent and disease-specific subset of evs with specific therapeutic effects. these engineered evs may be translated into novel strategies for effective use in clinics and may be the treatment choice of future [ ] . however, genetic modification of evs by using viral capsids may provoke an adverse immunological reaction, which can be avoided by using chemically synthesized peptides [ ] . for example, modification of msc-derived exosome surface by a functional chemically synthesized cyclopeptide provided more efficiently targeting of ischemic region compared to unmodified exosomes in a mouse model of cerebral ischemia [ ] . furthermore, genetically modified allogeneic mscderived exosomes enriched with mirna- are being tested in acute ischemic stroke patients in a phase- / clinical study (nct ). the recognition that homing and migratory effects of stem cells are limited, and paracrine mediators secreted from cells constitute their major regenerative functions has highlighted a new perspective into rm therapeutics. subsequently, there has been a shift of interest from cell transplantation to conditioned medium and/or ev-based therapeutics. conditioned medium from bm-mscs overexpressing akt mediated cardioprotective effects both in-vitro and in-vivo [ ] . multidimensional protein identification technology and cytokine antibody array analysis of the conditioned medium of mscs derived from escs demonstrated various gene products associated with cardiovascular biology, bone development and hematopoiesis suggesting a therapeutic potency of conditioned medium without cell transplantation [ ] . moreover, microvesicles derived from human mscs were as effective as their parent stem cells in mice suffering from severe bacterial pneumonia [ ] . cell-free therapies may have several advantages in contrast to cell applications. there is a thrombogenic potential of stem cells in the vasculature as well as arrythmia in the heart, ossification and calcification. in addition, cryopreservation may decrease viability of stem cells. on the other hand, cell-free applications do not require robust and expensive strategies for isolation and expansion, which make them an attractive source in acute conditions or military applications. in general, there are two types of cell-free products namely conditioned medium concentrates, which also contain evs, and evs free from soluble factors such as growth factors [ ] . at this point, one can ask whether conditioned medium or evs have more therapeutic potential. although it is difficult to give a definite answer, a previous study of hyperoxia-induced bronchopulmonary dysplasia demonstrated that ev deficient conditioned medium has no therapeutic effect, whereas both evs and conditioned medium containing evs improved lung inflammation and morphologic alterations [ ] . in addition, utilization of evs as biomarkers and their abilities as drug delivery systems put evs a step forward in rm [ , ] . when compared to stem cells, ev transplantation seem to be less risky than live stem cells. they cannot replicate and the risk of transformation into malign cells is less. due to the fact that they are smaller in size, the risk of elimination in the vasculature is less and they can easily pass the bbb, a property which makes them an ideal source for drug carrying and/ or transplantation in neurological diseases. besides, they do not evoke an immune response after transplantation, so there is no need for immunosuppression [ , , ] . they can also display systemic beneficial effects even in local applications as demonstrated in a recent mouse mi model study [ ] . although they have similar functional effects, their content such as mrna, mirna and proteins may vary compared to their parent cells. for example, comparative analyses of adipose tissue-derived mscs and their evs demonstrated diverse genetic cargo including mrna and mirna, and protein contents that play role in angiogenesis, adipogenesis, apoptosis, regulation of inflammation, blood coagulation and ecm remodeling [ , ] . moreover, protein levels and surface markers also differ between evs and their parent cells [ , ] . a rat mi model study showed superior beneficial effects of msc-derived exosomes in contrast to mscs in cardiac repair. this superiority was attributed to differences in expression profiles of several mirnas from that of mscs detected through mirna sequence analysis, raising the possibility that evs can be used alone and are superior to mscs in promoting cardiac repair [ ] . a recent cutaneous wound model study reported that intradermal injection of evs derived from adipose and bm-mscs were superior to stem cell injection invivo. furthermore, adipose msc-derived evs enhanced wound closure better than their bm-derived counterparts suggesting diverse therapeutic effects of evs obtained from different sources in an organism [ ] . at this point, it is reasonable to speculate that one size does not fit all in ev-based therapies. among diverse cell sources, evs derived from mscs are the most investigated type of evs compared to other cell sources such as pscs. for example, comparison of exosomes obtained from ipsc-derived mscs and synovial membranederived mscs yielded greater therapeutic effect of ipscderived msc exosomes in an osteoarthritis model [ ] . however, evs derived from pscs may be tumorigenic despite their high regenerative capacity because they carry the characteristics of their parent cells. on the other hand, superior safety profile regarding teratoma formation and therapeutic effect of ipsc-derived evs in contrast to ipscs were shown in terms of cardiac repair [ ] . given their inherent role in pathological processes and systemic effects, ev applications can induce spreading of tumor growth, autoimmunity, neurodegenerative diseases, prion diseases or viral infections because they are able to transfer their contents to recipient cells. exosomes derived from mscs of multiple myeloma patients had decreased tumor suppressor mirna- a expression levels compared to normal msc-derived exosomes. besides, exosomes derived from multiple myeloma patients expressed higher levels of oncogenic proteins, cytokines, and adhesion molecules, and promoted tumor growth, whereas exosomes of normal mscs inhibited the growth of multiple myeloma cells [ ] . actually, it should be kept in mind that this feature of evs makes them highly suitable candidates for drug delivery, particularly therapeutic nucleic acid delivery. however, risk of tumorigenesis remains as a concern because of systemic and diverse effects of their cargo though their acellular nature [ ] . the mechanism of action of evs has not been wellunderstood yet but it is thought that they perform their functions through mirnas. the proportion of mirnas accounts for less than % of total rna cargo in evs but they are considered as the leading molecules in regulating functions of evs. it is also evident from multiple knockdown experiments that diverse mirnas might take role for the same effect in different tissues. indisputably, there may be contribution of other components such as proteins and lipids, which are highly abundant in the ev cargo [ ] . on the other hand, the content and function of evs may depend on the metabolic properties of the donors and/or conditioned medium, which might make donor selection and manufacturing process more problematic [ , , ] . in addition, systemic effects of mirnas should be kept in mind if systemic therapy is the preferred route. for example, mirna- regulates brainheart interaction after ischemic stroke [ ] . mirnas involved in cancer pathogenesis should also be kept in mind [ ] . these limitations highlight the significance of tissue specific applications. furthermore, short half-life, off-target effects and insufficient endocytosis remain as major limitations of evs that need to be improved during clinical translation process [ , ] . there exist significant limitations while considering the isolation, characterization, tracking procedures and clinical grade production of ev-based therapeutics. there are various isolation and characterization methods of evs such as ultracentrifugation, density gradient, filtration, size exclusion chromatography, precipitation, magnetic based capture or combinatory methods, while ultracentrifugation is the most commonly used technique for isolation according to a worldwide survey. techniques for characterization also vary but western blotting is the most preferred method [ ] . however, it is not surprising that the other techniques are also widely used in different studies all over the world [ , , ] . on the other hand, efforts to standardize these procedures and confusions regarding the nomenclature are ongoing [ ] . likewise, databases built up to provide information about the composition and functions of evs such as exocarta, evpedia, and vesiclepedia will likely to contribute to clinical translation process [ ] . when it comes to clinical-grade large scale production, evs must be produced and stored under current good manufacturing practice (cgmp) conditions in order to meet market demands. this includes a strict workflow including manufacturing through bioreactors, quality analyses and screening, and preservation in appropriate conditions in order to maintain the stability and integrity of evs. similar strict production flows are also relevant for clinical-grade stem cell production but evs have a simplified cold chain process when compared to stem cells. because of the acellular nature of evs, lower risk of spontaneous dna transformation might be an advantage during cryopreservation [ ] . despite limitations discussed above, evs have moved to clinical studies rapidly. results coming from oncological patients were encouraging in terms of safety and shed light on future studies [ , ] . moreover, administration of evs derived from uc-mscs was safe and ameliorated the inflammatory immune status and improved the kidney functions in a clinical study [ ] . clinical case report of a graft-versus-host disease patient also demonstrated improved outcomes after ev therapy [ ] . in addition, several clinical trials have been designed and conducted in order to investigate therapeutic potential of evs in various diseases including cancer, type diabetes, pleural effusion, ulcers, ischemic stroke, bronchopulmonary dysplasia, etc. however, there is an inevitable need for well-designed, well-conducted clinical trials in order to expedite clinical translation of ev-based therapeutics for acute emergency and/or mass casualty situations. rm with personalized biologics are the future of medicinal sciences. although they are not considered as a drug or pharmacologic agent yet, stem cells promise a potential for the treatment of various diseases with unmet clinical needs. on the other hand, their secretomes namely evs have been the new therapeutic target due to the fact that they are the prominent components that regulate functions of stem cells. both stem cells and evs have demonstrated their therapeutic potential in preclinical models of various diseases but there are many limitations and caveats that need to be considered and improved during the translational process. they are also in their infancy ages and well-designed clinical trials will help to identify their therapeutic activity in human beings. this review aimed to summarize and understand the therapeutic potential of stem cells and evs in diseases requiring acute emergency care such as trauma, heart diseases, stroke, ards and burn injury. diseases that affect militaries or societies including ars, sepsis, and viral pandemics such as covid- have also been discussed. in addition, featuring and problematic issues which hamper clinical translation of stem cells and evs have been debated with a futuristic perspective. their advantages and disadvantages have been discussed in a comparative manner by keeping in mind the need for future studies and with the belief that these rm therapies will help to prolong human life and improve quality of life in the near future. consent for publication this manuscript has been approved by all authors. the authors are alone responsible for the content and writing of the paper. lancet commission: stem cells and regenerative medicine regenerative medicine stem cells applications in regenerative medicine and disease therapeutics stem cell therapies in clinical trials: progress and challenges trends in mesenchymal stem cell clinical trials - : is efficacy optimal in a narrow dose range? clarifying stem-cell therapy's benefits and risks extracellular vesicles: biology and emerging therapeutic opportunities isolation of extracellular vesicles: general methodologies and latest trends minimal information for studies of extracellular vesicles (misev ): a position statement of the international society for extracellular vesicles and update of the misev guidelines extracellular vesicles or exosomes? on primacy, precision, and popularity influencing a choice of nomenclature advances in therapeutic applications of extracellular vesicles the challenges and possibilities of extracellular vesicles as therapeutic vehicles demand at the emergency department front door: -year trends in presentations the danish national patient register icu management of trauma patients detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the resuscitation outcomes consortium incidence of primary blast injury in us military overseas contingency operations: a retrospective study pathophysiology of polytrauma trauma and stem cells: biology and potential therapeutic implications cellular therapies in trauma and critical care medicine: forging new frontiers stem cell applications in military medicine the potential of stem cells in treatment of traumatic brain injury prospective applications of induced pluripotent stem cells in military medicine application of stem cells in tissue engineering for defense medicine modeling trauma in rats: similarities to humans and potential pitfalls to consider systematic review and meta-analysis of efficacy of mesenchymal stem cells on locomotor recovery in animal models of traumatic brain injury systemic and local administration of allogeneic bone marrow-derived mesenchymal stem cells promotes fracture healing in rats the use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma mesenchymal stem cell transplantation in polytrauma: evaluation of bone and liver healing response in an experimental rat model autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children treatment of severe adult traumatic brain injury using bone marrow mononuclear cells autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury stem cells for traumatic brain injury embryonic stem cell pioneer geron exits field, cuts losses mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy changes in the pattern of plasma extracellular vesicles after severe trauma systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under d and d conditions improves functional recovery in rats after traumatic brain injury exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion stem cell-derived exosomes: a promising strategy for fracture healing exosomes -beyond stem cells for restorative therapy in stroke and neurological injury systemic immune response to traumatic cns injuries-are extracellular vesicles the missing link? the global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries heart failure as a general pandemic in asia the evolution of the stem cell theory for heart failure translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types cell therapy trials for heart regenerationlessons learned and future directions stem cells and the heart-the road ahead human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts extracellular vesicles and cardiovascular disease therapy exosomes generated from ipsc-derivatives: new direction for stem cell therapy in human heart diseases beneficial effects of exosomes secreted by cardiac-derived progenitor cells and other cell types in myocardial ischemia exosome secreted by msc reduces myocardial ischemia/reperfusion injury induced pluripotent stem cell (ipsc)-derived extracellular vesicles are safer and more effective for cardiac repair than ipscs acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts cardioprotective role of extracellular vesicles: a highlight on exosome beneficial effects in cardiovascular diseases cardioprotective micrornas: lessons from stem cell-derived exosomal micrornas to treat cardiovascular disease induced pluripotent stem cell (ipsc)-derived exosomes for precision medicine in heart failure extracellular vesicle microrna transfer in cardiovascular disease factors influencing the decline in stroke mortality: a statement from the fibrinolysis: strategies to enhance the treatment of acute ischemic stroke intracerebral haemorrhage stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms exosomes in stroke pathogenesis and therapy exosome therapy for stroke stem cell therapy for ischemic stroke: from bench to bedside from the lab to patients: a systematic review and meta-analysis of mesenchymal stem cell therapy for stroke extracellular vesicles improve poststroke neuroregeneration and prevent postischemic immunosuppression application of mesenchymal stem cell-derived extracellular vesicles for stroke: biodistribution and microrna study exosome mediated delivery of mir- promotes neurogenesis after ischemia incidence and outcomes of acute lung injury the standard of care of patients with ards: ventilatory settings and rescue therapies for refractory hypoxemia prospects and progress in cell therapy for acute respiratory distress syndrome personalized pharmacological therapy for ards: a light at the end of the tunnel pharmacotherapy of acute lung injury and acute respiratory distress syndrome nonventilatory treatments for acute lung injury and ards clinical review: stem cell therapies for acute lung injury/acute respiratory distress syndrome -hope or hype? current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome intratracheal administration of umbilical cord bloodderived mesenchymal stem cells in a patient with acute respiratory distress syndrome in vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study mesenchymal stem (stromal) cells for treatment of ards: a phase clinical trial treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (start study): a randomised phase a safety trial therapeutic potential of mesenchymal stem/stromal cellderived secretome and vesicles for lung injury and disease mesenchymal stem cells-derived extracellular vesicles in acute respiratory distress syndrome: a review of current literature and potential future treatment options therapeutic use of mesenchymal stem cell-derived extracellular vesicles in acute lung injury mesenchymal stem cell infusion shows promise for combating coronavirus (covid- )-induced pneumonia mesenchymal stromal cell secretome for severe covid- infections: premises for the therapeutic use clinical remission of a critically ill covid- patient treated by human umbilical cord mesenchymal stem cells transplantation of ace -mesenchymal stem cells improves the outcome of patients with covid- pneumonia mesenchymal stem cells for coronavirus (covid- )-induced pneumonia: revisiting the paracrine hypothesis with new hopes? mesenchymal stem cell therapy for covid- : present or future sepsisinduced immunosuppression: from cellular dysfunctions to immunotherapy concise review: mesenchymal stromal/stem cells: a new treatment for sepsis and septic shock? the results of the single center pilot randomized russian clinical trial of mesenchymal stromal cells in severe neutropenic patients with septic shock (rumcess) efficacy of mesenchymal stem cell therapy for sepsis: a meta-analysis of preclinical studies functional significance of exosomes applied in sepsis: a novel approach to therapy medical response to a radiologic/nuclear event: integrated plan from the office of the assistant secretary for preparedness and response, department of health and human services radiation emergencies: evaluation, management, and transplantation acute radiation syndrome (ars) -treatment of the reduced host defense health effects in those with acute radiation sickness from the chernobyl accident the radiation protection and therapy effects of mesenchymal stem cells in mice with acute radiation injury radiation rescue: mesenchymal stromal cells protect from lethal irradiation marrow stromal cell infusion rescues hematopoiesis in lethally irradiated mice despite rapid clearance after infusion cellular therapies for treatment of radiation injury: report from a nih/niaid and irsn workshop cellular therapies for treatment of radiation injury after a mass casualty incident european consensus on the medical management of acute radiation syndrome and analysis of the radiation accidents in belgium and senegal emerging therapy for improving wound repair of severe radiation burns using local bone marrowderived stem cell administrations mitigation of lethal radiation syndrome in mice by intramuscular injection of d cultured adherent human placental stromal cells myeloid progenitors: a radiation countermeasure that is effective when initiated days after irradiation extracellular vesicles transfer nuclear abl-dependent and radiation-induced mir- c into unirradiated cells to cause bystander effects possible role of exosomes containing rna in mediating nontargeted effect of ionizing radiation extracellular vesicles mediate radiationinduced systemic bystander signals in the bone marrow and spleen endometrial regenerative cells and exosomes thereof for treatment of radiation exposure cranial grafting of stem cellderived microvesicles improves cognition and reduces neuropathology in the irradiated brain macrophages educated with exosomes from primed mesenchymal stem cells treat acute radiation syndrome by promoting hematopoietic recovery initial evaluation and management of the critical burn patient burn support for operation iraqi freedom and related operations stem cells in skin regeneration, wound healing, and their clinical applications stem cell therapy: a new treatment for burns? pharmaceuticals (basel) skin tissue regeneration for burn injury mesenchymal stromal cells-exosomes: a promising cellfree therapeutic tool for wound healing and cutaneous regeneration mscexosome: a novel cell-free therapy for cutaneous regeneration a brief definition of regenerative medicine cardiac stem cell characteristics in physiological and pathological conditions similar effect of autologous and allogeneic cell therapy for ischemic heart disease: systematic review and meta-analysis of large animal studies comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the poseidon randomized trial randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: poseidon-dcm trial stem cell-based therapy for experimental stroke: a systematic review and meta-analysis mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: systematic review with meta-analyses of rat models vaccination of metastatic melanoma patients with autologous dendritic cell (dc) derived-exosomes: results of thefirst phase i clinical trial a phase i study of dexosome immunotherapy in patients with advanced non-small cell lung cancer exosome redux msc-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue human adipose mesenchymal stem cells show more efficient angiogenesis promotion on endothelial colony-forming cells than umbilical cord and endometrium a comparative analysis of multipotent mesenchymal stromal cells derived from different sources, with a focus on neuroregenerative potential mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage autologous induced stem-cellderived retinal cells for macular degeneration japanese man is first to receive 'reprogrammed'stem cells from another person induced pluripotent stem cells: the most versatile source for stem cell therapy the challenge of bringing ipscs to the patient one, two, three steps toward cell therapy for stroke concise review: stem cell therapy for stroke patients: are we there yet? effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilatorinduced lung injury intravenous mesenchymal stem cell therapy for traumatic brain injury pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting translational applications of tissue engineering in cardiovascular medicine extracellular matrix and regenerative therapies from the cardiac perspective safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (masters): a randomised, double-blind, placebo-controlled, phase trial strategies for improving animal models for regenerative medicine can animal models of disease reliably inform human studies? systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice publication bias in reports of animal stroke studies leads to major overstatement of efficacy trial publication after registration in clinicaltrials.gov: a cross-sectional analysis all preclinical trials should be registered in advance in an online registry discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (damascene): weighted regression and meta-analysis the consensus of the task force of the european society of cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update applying extracellular vesicles based therapeutics in clinical trials -an isev position paper improving animal research reporting standards: harrp, the first step of a unified approach by iclas to improve animal research reporting standards worldwide minimum information and quality standards for conducting, reporting, and organizing in vitro research preconditioning influences mesenchymal stem cell properties in vitro and in vivo encapsulation of bone marrow-mscs in prp-derived fibrin microbeads and preliminary evaluation in a volumetric muscle loss injury rat model: modular muscle tissue engineering decellularization of bovine small intestinal submucosa and its use for the healing of a critical-sized full-thickness skin defect, alone and in combination with stem cells, in a small rodent model current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy evidence supporting paracrine hypothesis for akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice conditioned medium of mesenchymal stromal cells: a new class of therapeutics early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor tsg- integrated transcriptomic and proteomic analysis of the molecular cargo of extracellular vesicles derived from porcine adipose tissue-derived mesenchymal stem cells microrna and mrna cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells comparative proteomic analysis of stem cell rev and rep extracellular vesicles isolated from porcine adipose tissue-derived mesenchymal stem/stromal cells proteomic analysis of microvesicles derived from human mesenchymal stem cells mirna-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair extracellular vesicles derived from mesenchymal cells: perspective treatment for cutaneous wound healing in pediatrics comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membranederived mesenchymal stem cells for the treatment of osteoarthritis bm mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression the metabolic syndrome modifies the mrna expression profile of extracellular vesicles derived from porcine mesenchymal stem cells mir- affects brain-heart interaction after cerebral ischemic stroke cancer hallmarks and micrornas: the therapeutic connection prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey to protect and to preserve: novel preservation strategies for extracellular vesicles umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -hffj s o authors: schmidt, matthieu; hajage, david; lebreton, guillaume; monsel, antoine; voiriot, guillaume; levy, david; baron, elodie; beurton, alexandra; chommeloux, juliette; meng, paris; nemlaghi, safaa; bay, pierre; leprince, pascal; demoule, alexandre; guidet, bertrand; constantin, jean michel; fartoukh, muriel; dres, martin; combes, alain; luyt, charles-edouard; hekimian, guillaume; brechot, nicolas; pineton de chambrun, marc; desnos, cyrielle; arzoine, jeremy; guerin, emmanuelle; schoell, thibaut; demondion, pierre; juvin, charles; nardonne, nathalie; marin, sofica; d'alessandro, cossimo; nguyen, bao-long; quemeneur, cyril; james, arthur; assefi, mona; lepere, victoria; savary, guillaume; gibelin, aude; turpin, matthieu; elabbadi, alexandre; berti, enora; vezinet, corinne; bonvallot, harold; delmotte, pierre-romain; de sarcus, martin; du fayet de la tour, charlotte; abbas, samia; maury, eric; baudel, jean-luc; lavillegrand, jean-remi; ait oufella, hafid; abdelkrim, abdelmalek; urbina, thomas; virolle, sara; deleris, robin; bonny, vincent; le marec, julien; mayaux, julien; morawiec, elise title: extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with covid- : a retrospective cohort study date: - - journal: the lancet respiratory medicine doi: . /s - ( ) - sha: doc_id: cord_uid: hffj s o summary background patients with covid- who develop severe acute respiratory distress syndrome (ards) can have symptoms that rapidly evolve to profound hypoxaemia and death. the efficacy of extracorporeal membrane oxygenation (ecmo) for patients with severe ards in the context of covid- is unclear. we aimed to establish the clinical characteristics and outcomes of patients with respiratory failure and covid- treated with ecmo. methods this retrospective cohort study was done in the paris–sorbonne university hospital network, comprising five intensive care units (icus) and included patients who received ecmo for covid- associated ards. patient demographics and daily pre-ecmo and on-ecmo data and outcomes were collected. possible outcomes over time were categorised into four different states (states – ): on ecmo, in the icu and weaned off ecmo, alive and out of icu, or death. daily probabilities of occupation in each state and of transitions between these states until day post-ecmo onset were estimated with use of a multi-state cox model stratified for each possible transition. follow-up was right-censored on july , . findings from march to may , , patients with covid- were treated in our icus. complete day- follow-up was available for patients (median age [iqr – ] years and [ %] men) who received ecmo. pre-ecmo, ( %) patients had been prone-positioned; their median driving pressure was (iqr – ) cm h o and pao /fio was ( – ) mm hg. at days post-ecmo initiation, the estimated probabilities of occupation in each state were % ( % ci – ) for state , % ( – ) for state , % ( – ) for state , and % ( – ) for state . ( %) patients had major bleeding and four ( %) had a haemorrhagic stroke. patients died. interpretation the estimated -day survival of ecmo-rescued patients with covid- was similar to that of studies published in the past years on ecmo for severe ards. if another covid- outbreak occurs, ecmo should be considered for patients developing refractory respiratory failure despite optimised care. funding none. the outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ) rapidly evolved into a worldwide pandemic, with more than million cases of covid- as of july , . in france, many disease clusters were identified early in march, , with paris and its surrounding area (greater paris) reporting the most cases. covid- can lead to acute respiratory failure requiring intensive care unit (icu) admission and mechanical ventilation. however, its most serious forms can rapidly evolve to severe acute respiratory distress syndrome (ards) with profound hypoxaemia and death, despite lung-protective mechanical ventilation, including prone-positioning. , in , the extracorporeal membrane oxygenation (ecmo) to rescue lung injury in severe ards (eolia; n= ) trial showed that although mortality in the ecmo group was lower at % compared with % in the control group, the difference was not significant (relative risk · [ % ci · - · ]; p= · ). a post-hoc bayesian analysis of eolia data later showed a high likelihood of an ecmo survival benefit for severe ards, as defined by the eolia entry criteria. accordingly, inter national organisations , and experts in the field , recom mended ecmo for patients who were critically ill with covid- following the initial outbreak in china, further stating that it should be provided in high-volume specialised centres, and a mobile ecmo team should retrieve patients on ecmo from other centres. however, survival was very low in chinese case series of ecmo-treated patients with covid- , , raising concerns about the usefulness of ecmo in this setting. we aimed to establish the characteristics and outcomes of patients who received ecmo for laboratory-confirmed sars-cov- infection in the paris-sorbonne university hospital network icus, the principal hospital referral network for icu care in greater paris, including one of the largest european ecmo centres (pitié-salpêtrière hospital). this retrospective cohort study was done in the paris-sorbonne university hospital network icus (three at la pitié-salpêtrière hospital, one in saint-antoine hospital, and one in tenon hospital), which cared for patients with covid- with severe ards. all consecutive adult patients with laboratory confirmed sars-cov- infection, documented by real-time rt-pcr on nasopharyngeal swabs, or lower respiratory tract aspirates, and who received venoarterial-ecmo or venovenous-ecmo for severe ards were included. patients who received ecmo for isolated refractory cardiogenic shock were excluded. ecmo support was provided at pitié-salpêtrière and tenon hospital icus, while saint-antoine hospital icu cared for patients either before ecmo cannulation or after ecmo decannulation. the sorbonne-university ethics committee (cer-su- - ) approved the protocol. in accordance with the ethical standards of french legislation (committees for the protection of human subjects), informed consent for demographic, physiological, and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. only non-opposition of the patient or their legal representative for use of the data was obtained. in a context of ecmo resource constraints, all ecmo proposals in greater paris were centralised at pitié-salpêtrière hospital. once contacted, indications for ecmo were evaluated in a staff meeting, including at least two intensivists. patients eligible for ecmo had to fulfill ards criteria, and one of the following disease severity criteria, despite ventilator optimisation (fraction of inspired oxygen [fio ] ≥ %, tidal volume set at ml/kg predicted bodyweight, and positive end-expiratory pressure [peep] ≥ cm of water): ( ) partial pressure of arterial oxygen (pao ) over a fio ratio of less than mm hg for more than h; ( ) pao /fio less than mm hg for more than h; or ( ) arterial blood ph less than · with a partial pressure of arterial carbon dioxide (paco ) of mm hg or more for h or more. physicians were strongly encouraged to use neuromuscular blocking agents and prone-positioning before ecmo. ecmo contraindications were: age older than years, severe comorbidities (eg, advanced cardiac, respiratory, or liver failure; metastatic cancer; or evidence before this study covid- can lead to acute respiratory failure requiring intensive care unit (icu) admission and mechanical ventilation. however, its most serious forms can rapidly evolve to severe acute respiratory distress syndrome (ards) with profound hypoxaemia and death, despite lung-protective mechanical ventilation, including prone-positioning. extracorporeal membrane oxygenation (ecmo) efficacy in this setting is unknown. we searched pubmed for full papers in any language published in peer-reviewed journals up to july , , with the terms "ecmo" and " novel coronavirus", " -ncov", "covid- ", or "sars-cov- ". we identified articles that reported cases of patients infected with sars-cov- who received ecmo for acute respiratory failure. however, these studies included only a limited number of patients (n= to n= ), with limited information on patient characteristics, management, and outcomes. very few of them reported patient survival beyond day post-ecmo onset, precluding any conclusion regarding the usefulness of ecmo in this setting. this retrospective study, with patients included and a complete follow-up until day post-ecmo initiation is, to our knowledge, the largest to date reporting the outcomes after rescue ecmo for the most severe forms of covid- ards, in the paris-sorbonne university hospital network (paris, france), the principal hospital referral network for icu care in greater paris, including one of the largest european ecmo centres (pitié-salpêtrière hospital). our patients' pre-ecmo characteristics indicated extreme ards severity (median pao /fio , [iqr - ] mm hg) although % had been prone-positioned before ecmo onset. the estimated probability of death days post-ecmo initiation was % ( % ci - ). ( %) had major bleeding and four ( %) patients had a haemorrhagic stroke. contrary to preliminary results that indicated dismal outcomes with - % mortality of patients with covid- given ecmo, the estimated % probability of day- mortality for our patients on ecmo was similar to those ecmo-treated in the eolia trial or the large prospective lifegard registry. should another covid- wave occur, ecmo should be considered early for patients developing profound respiratory failure, despite optimised conventional care, including pronepositioning. longer-term follow-up of these patients is now needed to evaluate covid- 's potential pulmonary, physical, and psychological sequelae. haematological malignancies), cardiac arrest (except when cardiopulmonary resuscitation was provided immediately and the low-flow time was < minutes), refractory multiorgan failure or simplified acute physiology score (saps) ii more than , irreversible neurological injury, and mechanical ventilation for more than days. once the indication was approved, the pitié-salpêtrière mobile ecmo retrieval team (mert), comprising a cardiovascular surgeon and a perfusionist, was sent to the patient's bedside for ecmo cannulation, as described previously. , our mert was available h per day, days a week. once ecmo had been implanted, the patient was transferred by a service d'aide medicale d'urgence ambulance with the mert to one of the paris-sorbonne university hospital network icus. ecmo cannulation was done percutaneously under ultrasonography guidance by a cardiovascular surgeon wearing full personal protective equipment (ie, respirator ffp or n mask, gown, goggles, and gloves). for venovenous-ecmo, blood drainage with a large cannula ( ) ( ) ( ) ( ) ( ) inserted into the common femoral vein, and returned through the right internal jugular vein was strongly recommended. for venoarterial-ecmo, a venous drainage cannula ( ) ( ) ( ) ( ) ( ) ( ) ( ) was inserted into the common femoral vein, an arterial return cannula ( ) ( ) ( ) ( ) ( ) into the common femoral artery, and an additional anterograde perfusion cannula was systematically inserted into the superficial femoral artery to prevent leg ischaemia. pump speed was adjusted to obtain blood-oxygen saturation at more than %. optimal cannula positioning was verified by ultrasonography and chest x-ray. following early reports of severe covid- associated coagulopathy [ ] [ ] [ ] and frequent thromboembolic events on ecmo, inclu ding massive pulmonary embolism, , we decided to increase the targeted activated partial thromboplastin time for anticoagulation of venovenous ecmo with unfractionated heparin to - s or anti-xa activity · - · iu/ml (respective values were - s or · - · iu/ml in the eolia trial ) before we treated our first patients with covid- ards. plasma-free haemoglobin and plasma fibrinogen concentrations were monitored daily. the haemoglobin threshold for red blood cell transfusion was - g/dl (or ≤ g/dl when hypoxaemia persisted); platelet transfusions were discouraged except for severe thrombocytopenia (< × cells per l) or thrombocytopenia of more than × cells per l with bleeding. to enhance protection against ventilator-induced lung injury, ultraprotective lung ventilation on ecmo was recommended, , by targeting lower mechanical power delivered to the lungs and lower tidal volume, respiratory rate, and airway and driving pressures. early prone-positioning on ecmo was encouraged in the absence of haemodynamic instability and contraindications for prone-positioning (ie, massive haemoptysis requiring an immediate surgical or interventional radiology procedure; deep venous thrombosis treated for less than days, or single anterior chest tube with air leaks). , , patients were assessed daily for possible ecmo weaning with use of the eolia clinical and physiological criteria. , information recorded before ecmo comprised age, sex, body-mass index, comorbidities, saps ii, sequential organ-failure assessment score, respiratory extracorporeal membrane oxygenation survival prediction score, date of first symptoms, and hospital and icu admissions. information collected before ecmo implantation comprised previous rescue therapies, the date mechanical ventilation started, ventilator settings (mode, peep, fio , respiratory rate, tidal volume, plateau pressure [p plat ]), arterial blood-gas parameters, and routine laboratory values. driving pressure (Δp) was defined as p plat minus peep and mechanical power (j/min) was calculated as follows : ventilatory ratio was calculated as : an expanded dataset including mechanical ventilation settings, arterial blood gases, adjuvant therapies on ecmo, and ecmo-related complications was noted daily from day - , then every days until ecmo day , ecmo weaning, or death, whichever occurred first. ecmo-related compli cations and organ dysfunction included major bleeding, blood-cell transfusions, massive haemolysis, ecmo-circuit change, severe thrombocytopenia (< × cells per l, occurring during the first study profile for patients included in this study, and their outcomes at july , . icu=intensive care unit. ecmo=extracorporeal membrane oxygenation. days of ecmo), stroke, renal replacement therapy, proven pulmonary embolism, pneumothorax, ventilatorasso ciated pneumonia, bacter aemia, and cardiac arrest. major bleeding was defined as requiring two or more units of packed red blood cells due to an obvious haemorrhagic event, necessitating a surgical or interventional pro cedure, an intracerebral haemorrhage, or a bleed causing a fatal outcome, while massive haemolysis was defined as plasma-free haemoglobin of more than mg/l associated with clinical signs of haemolysis. patient outcomes comprised the following endpoints: on ecmo, in the icu and weaned off ecmo, alive and out of icu, or died on days , , , , , , and after ecmo implantation. time spent in each state was calculated for the whole population of patients, with right-censoring of patients who did not reach the final absorbing state at later timepoints (day , , or ). other outcomes comprised icu and ecmo-related complications. patient characteristics are expressed as n (%) for categorical variables, mean (sd) for continuous variables, or median (iqr), as appropriate. to better describe patients' trajectories in the icu over time, a multi-state model chronic respiratory disease, copd, or asthma ( %) ( %) time from first symptoms to icu admission, days ( - ) ( - ) ( - ) ( - ) time from first symptoms to intubation, days ( - ) ( - ) ( - ) ( - ) time from intubation to ecmo, days ( - ) ( - ) ( - ) ( - ) states: in the icu and weaned off ecmo and alive and out of the icu. because patients could die at any time during follow-up, either in the icu or after discharge, the died state is the only final absorbing state (the final state that a patient can enter that once entered cannot be left). in this four-state model (appendix p ), each box represents a state and each arrow represents possible transitions from one state to another. after assessing patient status, participants who did not reach the final absorbing state were right-censored at the end of the observation period (july , ). a cox model stratified on each possible transition was fitted to estimate transition (from one state to another) and state occupation (for each of the four states) probabilities over time; the percentages of patients occupying each possible state were represented simultaneously over time with a stacked probability plot and reported with their % ci on days , , , , , , and post-ecmo initiation. another figure (appendix p ) individually displays all possible transition probabilities from one state to another over time. mean state occupation times (ie, the expected length of stay in each possible state of the multi-state model) was also reported at the same timepoints. finally, median on-ecmo time and length of icu stay were established. all the analyses were computed at a two-sided α level of % with r software, version . . . there was no funding source for this study. the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. among the consecutive patients ( figure ) data are median (iqr) or n (%). ecmo=extracorporeal membrane oxygenation. icu=intensive care unit. pao /fio =ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen. paco =partial pressure of arterial carbon dioxide. resp=respiratory extracorporeal membrane oxygenation survival prediction. sao =arterial oxygen saturation. sofa=sequential organ-function assessment. copd=chronic obstructive pulmonary disorder. *of the patients discharged from the icu, on july , , were still hospitalised or in a rehabilitation centre and returned home. †of the five patients still in the icu, on july , , one remained on ecmo. ‡patients missing data. data missing for - patients, except for lymphocytes (n= ). §defined as haematological malignancies, active solid tumour, or having received specific anti-tumour treatment within year, solid-organ transplant or infected with hiv, long-term corticosteroids, or immunosuppressants. ¶defined as plateau pressure minus positive end-expiratory pressure. ||mechanical power (j/min)= · × tidal volume × respiratory rate × (peak pressure - / × driving pressure). if not specified, peak pressure was considered equal to plateau pressure. saps ii median score ). their pre-ecmo characteristics according to their endpoint state on july , , are reported in table . briefly, pre-ecmo rescue procedures consisted of prone-positioning (n= , %), continuous neuromuscular blockers (n= , %), and nitric oxide (n= , %). median peep was (iqr - ) cm h o, driving pressure was ( ) ( ) ( ) ( ) ( ) ( ) cm h o, and mechanical power was · ( · - · ) j/min. at cannulation, the median pao /fio was (iqr - ) mm hg and paco was ( - ) mm hg. for comparison, detailed characteristics of patients with covid- in our cohort and in the eolia trial group are reported in the appendix (pp - ). femoral-jugular cannulas were inserted in ( %) patients, mostly with a large ( fr) drainage cannula, a median (iqr - ) days after endotracheal intubation. the mert brought ( %) patients from non-ecmo centres. ecmo support successfully lowered tidal volume, respiratory rate, and plateau pressure during the h following its initiation: median · (iqr · - · ) ml/kg for tidal volume, ( - breaths per min for respiratory rate), and ( ) ( ) ( ) ( ) cm h o for plateau pressure (table , appendix pp - ). consequently, the mechanical power delivered to the lungs dropped to · (iqr · - · ) j/min. arterial blood gases also normalised rapidly on ecmo (appendix pp [ ] [ ] . on ecmo, ( %) patients were prone-positioned, ( %) received continuous neuromuscular blockers, five ( %) nitric oxide, and ( %) high-dose corticosteroids (table ) . median activated partial thromboplastin time ratios rose progressively over days - on ecmo: · (iqr · - · ) on day , · ( · - · ) on day , and · ( · - · ) on day . on july , , median follow-up was (range - ) days. complete follow-up on days was available for patients post-ecmo implantation, -day herein, we describe a large case series of patients who received ecmo support for the most severe forms of covid- ards. they were treated in the paris-sorbonne university hospital network icus, comprising five intensive care units, which are experienced in managing ards and ecmo. ecmo indications were based on the eolia trial selection criteria with an upper age limit of years, and patients received highly standardised ecmo care and general icu care. granular information on patients' pre-ecmo characteristics, daily management, and outcomes were analysed. contrary to preliminary results from other studies that indicated dismal outcomes with - % mortality of patients who had covid- and were treated with ecmo, , the estimated % probability of day- mortality for our patients on ecmo was similar to those treated with ecmo in the eolia trial ( % at day ) or the large prospective lifegard registry ( % at day ). the pre-ecmo characteristics of our patients with covid- indicated great ards severity before ecmo support was initiated. their mean pao /fio ( [sd ] mm hg) was lower than for patients in the eolia ( [ ] mm hg) or lifegard ( [ ] mm hg) trials, while pre-ecmo respiratory system compliance, driving pressure, mechanical power, and other respiratory and ventilatory parameters were similar in all three studies. notably, our patients with covid- had lower respi ratory system compliance and higher driving pressure than previously reported for most patients with covid- receiving mechanical ventilation, , indicating extensive sars-cov- -induced alveolar damage. according to guidelines from and for the optimisation of care for the most severe ards forms, , % of our patients benefited from prone-positioning before ecmo (compared with % in eolia and only % in lifegard ). beyond providing adequate oxygenation, high bloodflow ecmo achieves a homogeneous ultraprotective ventilation strategy, most frequently using bilevelpositive airway pressure or airway pressure-release ventilation modes, with tight control of the driving pressure. , our patients' pre-ecmo median mechanical power reached · (iqr · - · ) j/min, although a higher mortality risk for patients with ards whose value exceeded · j/min has been suggested. following ecmo initiation, tidal volume, driving pressure, and respiratory rate were markedly reduced in our patients, resulting in a major decrease of the median mechanical power to · (iqr · - · ) j/min, as previously reported. in addition, ecmo prone-positioning, used for % of our patients with covid- (vs only % of patients treated with ecmo in the eolia trial), sofa score on ecmo day * ( ) ( ) ( ) ( ) ( ) ( ) ( ) sofa score on ecmo day † ( ) ( ) ( ) ( ) ( ) ( ) aptt have contributed to improving their outcomes. indeed, a retrospective series of patients with severe ards showed that on-ecmo prone-positioning obtained higher ecmo weaning and survival rates. an autopsy-based histological analysis of the pulmonary vessels of patients with covid- showed widespread thrombosis with microangiopathy, with alveolar capillary microthrombi being nine times more frequent in patients with covid- than in those with influenza. consistent with other series, , , , we also observed an unusually high on-ecmo rate of proven pulmonary embolism ( %), an event not reported for the patients treated with ecmo in the eolia trial. those thromboembolic events occurred, despite an early increase of our anticoagulation target for patients with covid- receiving venovenous ecmo support, suggesting that other strategies, beyond systemic anti coagulation, are warranted to care for sars-cov- induced lung endothelial injuries. it should also be noted that haemorrhagic stroke occurred in % of our patients, which was more frequent than in the eolia trial ( %). the higher anticoagulation regimen, and specific sars cov- -associated vasculitis and critical illness associated microbleeds could explain this finding. however, the frequency of severe haemorrhagic events requiring transfusion in our study was similar to those of patients treated with ecmo in the eolia trial. compared with the eolia trial of patients with severe ards ( % bacterial and % viral pneumonia) treated with ecmo, has been proposed in patients with septic shock with severe myocardial dysfunction and decreased cardiac index, which was not the case in our patients. lastly, our antibiotic-treated ventilator-associated pneumonia rate was higher ( %) than for patients in the eolia trial ( %), and might reflect the longer mechanical ventilation or specific sars-cov- induced immunoparalysis. it should also be noted that few of our patients received high-dose corticosteroids. we acknowledge several limitations to our study. first, our results have to be considered preliminary, as some patients remained in the hospital and day- post-ecmo outcomes were not available for all patients. however, we used a time-to-event analysis, which allowed estimation of the probabilities of remaining on ecmo, ecmo weaning, icu discharge, or death over time, taking into account the fact that some patients' follow-up was censored. also, on july , , we carefully updated follow-up of all included patients to ensure the absence of informative censoring for unbiased estimations. second, our patients were treated in a high-volume ecmo university hospital network experienced in the care of the most severe forms of ards that might limit the generalisability of our observations. third, indication for ecmo and other selection and information biases might have existed due to the limited size of our cohort of patients. fourth, although the characteristics and outcomes of our ecmo-supported patients with covid- were similar to those reported in a series of ecmo-treated patients with severe ards before the pandemic, we were not able to compare our patients' outcomes to those of patients with covid- who were not ecmo-supported. fifth, only data for thrombo cytopenia occurring during the first days of ecmo were collected, which might have underestimated the actual rate of this complication. lastly, we did not collect data for patients' viral load and cannot ascertain the potential benefits of prone-positioning on ecmo, which might represent areas for future studies. in conclusion, the survival of ecmo-rescued very sick patients with covid- was similar to that reported in studies on ecmo support for severe ards published in the past few years. , should another covid- wave occur, ecmo should be considered at an early stage for patients developing profound respiratory failure, despite optimised conventional care, including prone-positioning. longer-term follow-up of these patients is also needed to evaluate the potential pulmonary, physical, and psychological sequelae of covid- . epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region extracorporeal membrane oxygenation for severe acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) extracorporeal life support organization coronavirus disease interim guidelines: a consensus document from an international group of interdisciplinary extracorporeal membrane oxygenation providers preparing for the most critically ill patients with covid- : the potential role of extracorporeal membrane oxygenation planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ards) due to coronavirus disease (covid- ): pooled analysis of early reports extracorporeal membrane oxygenation for coronavirus disease -induced acute respiratory distress syndrome: a multicenter descriptive study covid- , ecmo, and lymphopenia: a word of caution clinical management of severe acute respiratory infection when covid- disease is suspected the berlin definition of ards: an expanded rationale, justification, and supplementary material emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-rescue program) retrieval of severe acute respiratory failure patients on extracorporeal membrane oxygenation: any impact on their outcomes? systemic inflammatory response syndrome is a major contributor to covid- -associated coagulopathy: insights from a prospective single center cohort study abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical features of patients infected with novel coronavirus in wuhan, china severe pulmonary embolism in covid- patients: a call for increased awareness high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study mechanical ventilation management during extracorporeal membrane oxygenation for acute respiratory distress syndrome. an international multicenter prospective cohort prone positioning and extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: time for a randomized trial a new simplified acute physiology score (saps ii) based on a european/north american multicenter study the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/ failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. the respiratory extracorporeal membrane oxygenation survival prediction (resp) score ventilator-related causes of lung injury: the mechanical power physiologic analysis and clinical performance of the ventilatory ratio in acute respiratory distress syndrome tutorial in biostatistics: competing risks and multi-state models clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- pneumonia: different respiratory treatments for different phenotypes? an official american thoracic society/european society of intensive care medicine/ society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome formal guidelines: management of acute respiratory distress syndrome extracorporeal life support for adults with respiratory failure and related indications: a review driving pressure and survival in the acute respiratory distress syndrome mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis pulmonary embolism in patients with covid- : awareness of an increased prevalence venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock ms, gl, am, gv, dl, eb, ab, jc, pm, sn, pb, pl, ad, bg, jmc, mf, md, and ac were involved in data generation. ms, dh, and ac were involved in analysis of the data. ms, dh, and ac wrote the manuscript. all authors contributed to the revision, and read and approved the final version of the manuscript. ac takes responsibility for the integrity of the work as a whole, from inception to published article. ms reports lecture fees from getinge, drager, and xenios, outside of the submitted work. ad reports personal fees from medtronic, baxter, hamilton, and getinge; grants, personal fees, and non-financial support from philips; personal fees and non-financial support from fisher and paykel; grants from french ministry of health; grants and personal fees from respinor; grants and non-financial support from lungpacer, outside of the submitted work. jmc reports personal fees and nonfinancial support from drager, ge healthcare, sedana medical, baxter, amomed, fisher and paykel healthcare, orion, philips medical, and fresenius medical care, and non-financial support from lfb and bird corporation, outside of the submitted work. md received fees from lungpacer (expertise, lectures). ac reports grants from getinge, personal fees from getinge, baxter, and xenios, outside of the submitted work. gv reports grants and personal fees from biomérieux, grants from sos oxygène, and grants from janssen, outside of the submitted work. all other authors declare no competing interests. individual patient data reported in this article will be shared after de-identification (text, tables, figures, and appendices), beginning months and ending years after article publication, to researchers who provide a methodologically sound proposal and after approval of an internal scientific committee. proposals should be addressed to alain.combes@aphp.fr. to gain access, data requestors will need to sign a data access agreement. the data from this study are not currently part of any other international collection of data. key: cord- - lx fkv authors: bagate, françois; tuffet, samuel; masi, paul; perier, françois; razazi, keyvan; de prost, nicolas; carteaux, guillaume; payen, didier; mekontso dessap, armand title: rescue therapy with inhaled nitric oxide and almitrine in covid- patients with severe acute respiratory distress syndrome date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: lx fkv background: in covid- patients with severe acute respiratory distress syndrome (ards), the relatively preserved respiratory system compliance despite severe hypoxemia, with specific pulmonary vascular dysfunction, suggests a possible hemodynamic mechanism for va/q mismatch, as hypoxic vasoconstriction alteration. this study aimed to evaluate the capacity of inhaled nitric oxide (ino)–almitrine combination to restore oxygenation in severe covid- ards (c-ards) patients. methods: we conducted a monocentric preliminary pilot study in intubated patients with severe c-ards. respiratory mechanics was assessed after a prone session. then, patients received ino ( ppm) alone and in association with almitrine ( μg/kg/min) during min in each step. echocardiographic and blood gases measurements were performed at baseline, during ino alone, and ino–almitrine combination. the primary endpoint was the variation of oxygenation (pao( )/fio( ) ratio). results: ten severe c-ards patients were assessed ( males and females), with a median age of [ – ] years. combination of ino and almitrine outperformed ino alone for oxygenation improvement. the median of pao( )/fio( ) ratio varied from [ – ] mmhg at baseline, to [ – ] mmhg after ino (p = . ) and [ – ] mmhg after ino and almitrine (p < . ). we found no correlation between the increase in oxygenation caused by ino–almitrine combination and that caused by proning. conclusion: in this pilot study of severe c-ards patients, ino–almitrine combination was associated with rapid and significant improvement of oxygenation. these findings highlight the role of pulmonary vascular function in covid- pathophysiology. severe acute respiratory syndrome coronavirus (sars-cov- ) which is responsible for the coronavirus disease (covid- ) pandemic is causing a massive influx of patients presenting with severe acute respiratory distress syndrome (ards) to intensive care units (icus) worldwide [ ] . for the most severe cases, refractory ards may lead to a discussion regarding the use of extracorporeal membrane oxygenation (ecmo), an expensive and invasive life support resource, available in limited numbers in expert centers [ , ] . since the possibilities cannot fit with the large-scale outbreaks, alternative solutions should be proposed [ ] . some authors have hypothesized that potential relatively preserved respiratory system compliance (crs) despite severe hypoxemia in covid- patients suggests a possible hemodynamic mechanism for ventilation/perfusion (va/q) mismatch as hypoxic vasoconstriction alteration [ ] . the sars-cov- uses angiotensin converting enzyme (ace ) receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, but the ace receptor is also widely expressed on endothelial cells, including the heart, kidney, intestine and lung. the presence of viral elements within endothelial cells with an accumulation of inflammatory cells, suggest that sars-cov- infection may induce endotheliitis altering vascular reactivity [ ] including the hypoxic vasoconstriction or other vasomotion control. the combination of inhaled nitric oxide (ino), a selective pulmonary vasodilator, and almitrine, a specific pulmonary vasoconstrictor, was proposed several decades ago as to improve va/q mismatch. it was spectacular in many ards patients with maintained vasodilation in ventilated zones receiving ino and reduced perfusion in poorly or non-ventilated zones after almitrine treatment [ ] [ ] [ ] . in the particular context of covid- , we hypothesized that ino-almitrine combination could improve arterial oxygenation in severe covid- ards (c-ards) by a redistribution of the pulmonary blood flow towards ventilated areas. intubated patients with laboratory-confirmed covid- , who met the criteria for ards (berlin definition) [ ] with persistent severe hypoxemia (pao / fio < mmhg), were prospectively included at the medical icu of henri mondor university hospital (creteil, france). sars-cov- infection was confirmed by real-time reverse transcriptase-polymerase chain reaction (rt-pcr) assay of nasal swabs or lower respiratory tract samples (bronchoalveolar lavage or endotracheal aspirate). age lower than years, acute cor pulmonale defined as septal dyskinesia with dilated right ventricle (end-diastolic right ventricle/left ventricle area ratio > . ), pulmonary embolism, hyperlactatemia (> mmol/l), hepatic insufficiency, and ecmo support were exclusion criteria. respiratory settings and ards management were in accordance with french guidelines [ ] . the study was approved by the ethics committee of the french intensive care society as a component of standard care, and patient consent was waived as per french law. families were given information about the study. enrolled patients were sedated and received neuromuscular blockers to maintain a volume-control mechanical ventilation adapted to keep the tidal volume around ml/kg of predicted body weight (pbw) and the paco below mmhg. after hemodynamic and ventilatory optimization, prone positioning was tested because of persisting severe hypoxemia (pao /fio < mmhg). after a proning session lasting to h, the patients were put back to supine position and the ino ( ppm) alone followed by ino associated with mcg/kg/min of almitrine (vectarion ® , servier, suresnes, france) were tested. the fio was settled at to limit heterogeneity within patients and to look at the effect of the drugs on true qs/qt, eliminating mostly the low va/q zones. the effect on arterial oxygenation was evaluated at least after min in each condition: supine baseline, ino, and ino plus almitrine. because of the potential negative impact of right ventricle afterload increase during almitrine, the right ventricular function was assessed by echocardiography along with arterial blood gases at baseline, during ino alone, and with ino-almitrine combination. patients who had a pao /fio ratio that increased by at least % or by mmhg as compared to the baseline situation were considered "responders" [ ] . the assessment of respiratory mechanics included the following measurements. plateau pressure and total peep were assessed during an end-inspiratory ( . s) and end-expiratory ( - s) occlusion maneuver, respectively. the driving pressure and the crs were computed as the difference between plateau pressure and total peep and tidal volume divided by the difference between plateau pressure and total peep, respectively. the potential airway closure phenomenon was detected by measuring the airway opening pressure during a low flow (≤ l/ min) insufflation and potential for lung recruitment was assessed by the mean of the recruitment-to-inflation ratio (r/i ratio) computation, as previously described by chen et al. [ ] . a r/i ratio < . was used to characterize a poorly recruitable patient. trained operators (competence in advanced critical care echocardiography) performed transthoracic echocardiography in the supine position at baseline, and during ino and almitrine administration. they focused on global function (velocity-time integral of left ventricular outflow tract, cardiac index), and the right ventricle function as previously proposed [ ] . because of severe hypoxia, all patients had a detection of potential shunting across patent foramen ovale in four-chamber view after injection of sterile-modified fluid gelatine solution (plasmion, fresenius-kabi, sevres, france) aerated with room air to generate microbubbles as previously proposed [ ] . the following data were collected at inclusion: age, gender, body mass index, past medical history, standard treatments, charlson comorbidity index, sequential organ failure assessment (sofa) score [ ] , simplified acute physiologic score (saps) ii [ ] , and the need for vasopressors. in addition, the need for ecmo support, limitation of life-sustaining therapies and icu mortality were collected during hospitalization. statistical analyses were performed with the jmp software (version ; sas institute inc, cary, nc) and graph-pad prism software (version ; graphpad software inc., la jolla, ca, usa). the primary endpoint of this study was the variation of oxygenation (pao /fio ). data were presented as median with interquartile range or number with percentage. multiple paired values were compared using friedman test followed by paired wilcoxon test with benjamini-hochberg correction. spearman's test was used to assess correlation. for all tests, a two-way p-value < . was considered statistically significant. as a pilot study, ten severe c-ards patients were assessed (seven males and three females), with a median age of [ - ] years. median time since endotracheal intubation was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days, allowing to mix potential different hypoxic mechanisms. clinical characteristics, comorbidities, standard treatments and organ failures at inclusion are presented in table . as shown in additional file : table s , the gas exchange response of the last prone position the day before the protocol was favorable (increase in pao /fio of at least % or mmhg) in most ( / , %) patients; overall, the pao /fio ratio increased from [ - ] mmhg (supine) to [ - ] (prone), p < . (additional file : table s ). respiratory mechanics in supine position after proning are reported in additional file : table s . the median values of crs and driving pressure were [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ml/cmh o, and [ ] [ ] [ ] [ ] [ ] mmhg, respectively. r/i ratio was < . in / ( %) patients, indicating limited recruitability in a majority of patients. in supine position, patients were still severely hypoxic with median pao of [ - ] mmhg at fio of ( table ) . on supine position, only the addition of almitrine to ino increased significantly pao from baseline ( fig. ) , with no significant changes in pulmonary blood flow and other hemodynamic and echocardiographic variables ( table ). pao increased by more than % in seven of ten patients with ino-almitrine combination (additional file : figure s ). one non-responder had an intra-cardiac shunt related to patent foramen ovale. the response to ino + almitrine did not correlate with the benefit on pao induced by prone positioning (ρ = − . , p = . ). similarly, the baseline respiratory mechanics were not associated with the ino-almitrine response (additional file : table s ). although the study was not designed to evaluate the impact on outcome, it is important to report that six out of ten patients had a refractory hypoxemia (pao / fio < mmhg), which could not be treated by almitrine due to the shortage of drug reserve. one patient benefited from ecmo support with a favorable final outcome, the five remaining could not be treated by ecmo and died during icu stay. the main findings of this pilot study were as follows: i) only the combination of ino and almitrine improved the arterial oxygenation in severe c-ards patients; ii) in vitro studies suggested a direct antiviral effect of ino on the sars-cov replication cycle [ , ] . during the first sars-cov outbreak in , a pilot study reported the efficacy of ino in a limited series of severe patients, with reversal of pulmonary hypertension, improved hypoxemia and shortened duration of mechanical ventilation [ ] . some authors suggested that ino could be used as a rescue therapy during the current pandemics [ , ] , inasmuch as covid- is characterized by major pulmonary vascular dysfunction with endothelialitis, and thrombosis [ , ] . in our case series, ino alone had a negligible effect on oxygenation. in addition, in the absence of rv dysfunction, ino did not change the rv d echocardiographic measures. these results confirm the adequate exclusion of patients with pulmonary hypertension and/or rv dysfunction, to safely use almitrine. ongoing randomized controlled trial testing ino will probably shed light on its usefulness in a broader population of patients with c-ards [ ] . some authors have hypothesized that in some patients with c-ards (especially those with low elastance-"l type"), hypoxemia was not completely explained by pulmonary shunt resulting from diffuse alveolar damage [ ] . the respiratory mechanics of our selected patients did not fully match with the proposed "l type", described by gattinoni et al. [ ] , but was in accordance with a recent larger cohort of critically ill adults with covid- [ ] . the frequency of vascular and perfusion abnormalities [ ] and pulmonary embolism incidence seems higher in covid- pneumonia as compared to classical ards [ ] . there is also a specific pulmonary procoagulant pattern [ ] , causing alveolar capillary microthrombi, as revealed by post-mortem studies [ , ] . more interestingly, ackermann et al. reported [ ] the presence of intussusceptive angiogenesis. these anomalies may alter hypoxic pulmonary vasoconstriction, a possible mechanism for va/q mismatch and hypoxemia during c-ards. addition of almitrine to ino in patients with c-ards has the potential for restoring vascular homeostasis, in particular hypoxic pulmonary vasoconstriction [ ] . the first reported study on almitrine in severe hypoxia in covid- patients [ ] showed a highly significant increase in p/f ratio with almitrine, independently from the dose used ( or mcg/kg/min). because the level of pvo entering the pulmonary circulation is a major controller of hypoxic pulmonary vasoconstriction [ ] , they measured the svo , that increased significantly. recently, barthélémy et al. [ ] described the effect of almitrine in critically ill covid- patients. in this study, almitrine ( μg/kg/min) globally increased oxygenation within h of infusion start. however, the studied population was heterogeneous, and the effect of prone position was not reported. another study reported the effect of ino ( to ppm in patients), almitrine ( . mg/ kg over min in patients), or both ( patients). surprisingly, the authors failed to observe any oxygenation improvement, with all patients investigated in prone position [ ] . taken together, previous reports and our study suggest a beneficial effect mainly during almitrine infusion in c-ards in the supine position. in our study, since pulmonary blood did not change, it is reasonable to consider that the drugs combination creates pulmonary resistance gradient favoring the perfusion of ventilated areas reducing the va/q mismatch [ ] . these data are consistent with previous larger studies in non-covid ards [ , , ] . moreover, a recent preliminary study in non-covid ards patients with veno-venous ecmo support, might renew the interest for almitrine [ ] . the role of ino and almitrine in the therapeutic arsenal of ards is not yet completely clear, but it is reasonable to consider ino and almitrine as potential rescue therapies that might be applied in case of persisting severe hypoxemia despite prone positioning and before considering ecmo [ ] . our study suffers from several limitations. first, it is a pilot study on a small cohort, with no control group of ards not resulting from covid- , making the results only exploratory. however, our c-ards patients were homogeneous in terms of severity and selection. second, because of limited drug availability, we did not evaluate the prolonged effect of this therapeutic combination. thus, full interpretation on efficacy and tolerance is not possible. we did not observe adverse events on this short duration of administration. at least for a short duration, almitrine did not cause hyperlactatemia, hemodynamic instability (by favoring acute cor pulmonale), or hepatic disturbances [ ] . third, we could not standardize the timing of evaluation referring to prone position. a potential impact of additive effects of prone position and ino-almitrine on arterial oxygenation cannot be ruled out [ ] . fourth, ventilation in fio may theoretically increase the alveolar partial pressure in oxygen and inhibit or at least decrease hypoxic pulmonary vasoconstriction in non-or hypo-ventilated areas. however, an fio of was used for the following reasons: i) the level of hypoxia for almost all patients necessitated very high fio close to ; ii) the fio of allows measuring hypoxia mainly related to true qs/qt and not low va/q zones. it is then more rigorous to compare the results of modification of true shunt instead of global venous admixture containing also low va/q; iii) the gas equation used to calculate the p/f ratio may introduce large bias as previously shown. in this small series of severe c-ards patients, the ino-almitrine combination was associated with rapid and significant improvement of oxygenation, which was not observed with ino alone. these findings highlight the role of pulmonary vascular vasoreactivity in covid- , which could partially be corrected by almitrine. this may help to avoid the ecmo or delay the time at which ecmo can be initiated. this aspect could only be evaluated in a randomized clinical trial in presence or not of almitrine. more work is warranted to test whether the prolonged use of these medicines could alter the long-term outcome of such patients. supplementary information accompanies this paper at https ://doi. org/ . /s - - - . additional file : table s . blood gas before and after the last proning session in ten patients with severe acute respiratory distress syndrome secondary to coronavirus disease . additional file : figure s . individual values of the ratio of oxygen partial pressure to inspired oxygen fraction in arterial blood in patients with severe acute respiratory distress syndrome secondary to coronavirus disease , according to position (prone or supine) and administration of inhaled nitric oxide with or without almitrine. * , # and & denote a p value < . for paired wilcoxon (with benjamini-hochberg correction) following friedman test, as compared to supine (before prone), supine (after prone), and supine with ino, respectively. red lines: "almitrine non-responders"; blue lines: "almitrine responders"; solid lines: "prone responders"; dashed lines: "prone non-responders". additional file : table s . respiratory mechanics in supine position in ten patients with severe acute respiratory distress syndrome secondary to coronavirus disease . table s . correlations between respiratory mechanics and oxygenation response to the combination of inhaled nitric oxide and almitrine in ten patients with severe acute respiratory distress syndrome secondary to coronavirus disease . a novel coronavirus from patients with pneumonia in china joint society of critical care medicine-extracorporeal life support organization task force position paper on the role of the intensivist in the initiation and management of extracorporeal membrane oxygenation planning and provision of ecmo services for severe ards during the covid- pandemic and other outbreaks of emerging infectious diseases preparing for the most critically ill patients with covid- : the potential role of extracorporeal membrane oxygenation covid- does not lead to a "typical" acute respiratory distress syndrome endothelial cell infection and endotheliitis in covid- . the lancet intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome. the no almitrine study group inhaled nitric oxide and vasoconstrictors in acute respiratory distress syndrome additive effect on gas exchange of inhaled nitric oxide and intravenous almitrine bismesylate in the adult respiratory distress syndrome acute respiratory distress syndrome: the berlin definition formal guidelines: management of acute respiratory distress syndrome efficacy of prone position in acute respiratory distress syndrome patients: a pathophysiology-based review potential for lung recruitment estimated by the recruitment-toinflation ratio in acute respiratory distress syndrome a clinical trial prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine a new simplified acute physiology score (saps ii) based on a european/north american multicenter study inhibition of sars-coronavirus infection in vitro by s-nitroso-n-acetylpenicillamine, a nitric oxide donor compound nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus inhalation of nitric oxide in the treatment of severe acute respiratory syndrome: a rescue trial in beijing could nasal nitric oxide help to mitigate the severity of covid- ? microbes infect nitric oxide inhalation as an interventional rescue therapy for covid- -induced acute respiratory distress syndrome. ann intensive care pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- high risk of thrombosis in patients with severe sars-cov- infection: a multicenter prospective cohort study protocol of a randomized controlled trial testing inhaled nitric oxide in mechanically ventilated patients with severe acute respiratory syndrome in covid- (sars-cov- ). intensive care critical care med covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med epidemiology, clinical course, and outcomes of critically ill adults with covid- in new york city: a prospective cohort study hypoxaemia related to covid- : vascular and perfusion abnormalities on dualenergy ct pulmonary embolism in covid- patients: awareness of an increased prevalence the procoagulant pattern of patients with covid- acute respiratory distress syndrome pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction almitrine as a non-ventilatory strategy to improve intrapulmonary shunt in covid- patients hemodynamic, gas exchange, and hormonal consequences of lbpp during peep ventilation efficacy of almitrine in the treatment of hypoxemia in sars-cov- acute respiratory distress syndrome effect of almitrine bismesylate and inhaled nitric oxide on oxygenation in covid- acute respiratory distress syndrome nitric oxide and almitrine: the definitive answer for hypoxemia inhaled no and almitrine bismesylate in patients with acute respiratory distress syndrome: effect of noradrenalin evaluation of almitrine infusion during veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome in adults intravenous almitrine bismesylate reversibly induces lactic acidosis and hepatic dysfunction in patients with acute lung injury publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are very indebted to all physicians and nurses of the henri mondor medical intensive care unit for their help for the care of covid- patients. authors' contributions fb, st and amd designed the study and wrote the manuscript. fb, pm and fp collected the data. kr, ndp, gc and dp designed the study. all authors read and approved the final manuscript. the present study has been conducted without any financial support. all data generated and analyzed during the study are included in the published article and can be shared upon request. all authors helped to revise the draft of the manuscript. all authors read and approved the final manuscript. the study was approved by the institutional ethics committee of the french intensive care society as a component of standard care and patient consent was waived as per french law. information about the study was given to families. not applicable. the authors declare that they have no competing interests.author details ap-hp, hôpitaux universitaires henri-mondor, service de médecine intensive key: cord- -f n hk authors: khan, hafiz muhammad waqas; parikh, niraj; megala, shady maher; predeteanu, george silviu title: unusual early recovery of a critical covid- patient after administration of intravenous vitamin c date: - - journal: am j case rep doi: . /ajcr. sha: doc_id: cord_uid: f n hk patient: female, -year-old final diagnosis: covid- symptoms: cough • fever • shortness of breath medication: — clinical procedure: — specialty: critical care medicine objective: unusual clinical course background: coronavirus disease (covid- ) continues to spread, with confirmed cases now in more than countries. thus far there are no proven therapeutic options to treat covid- . we report a case of covid- with acute respiratory distress syndrome who was treated with high-dose vitamin c infusion and was the first case to have early recovery from the disease at our institute. case report: a -year-old woman with no recent sick contacts or travel history presented with fever, cough, and shortness of breath. her vital signs were normal except for oxygen saturation of % and bilateral rhonchi on lung auscultation. chest radiography revealed air space opacity in the right upper lobe, suspicious for pneumonia. a nasopharyngeal swab for severe acute respiratory syndrome coronavirus- came back positive while the patient was in the airborne-isolation unit. laboratory data showed lymphopenia and elevated lactate dehydrogenase, ferritin, and interleukin- . the patient was initially started on oral hydroxychloroquine and azithromycin. on day , she developed ards and septic shock, for which mechanical ventilation and pressor support were started, along with infusion of high-dose intravenous vitamin c. the patient improved clinically and was able to be taken off mechanical ventilation within days. conclusions: this report highlights the potential benefits of high-dose intravenous vitamin c in critically ill covid- patients in terms of rapid recovery and shortened length of mechanical ventilation and icu stay. further studies will elaborate on the efficacy of intravenous vitamin c in critically ill covid- . coronavirus disease (covid- ) , which is caused by severe acute respiratory syndrome coronavirus- (sars-cov- ), was first reported on december , in a group of patients who presented with atypical pneumonia in wuhan, hubei province, china [ , ] . since the first report of the disease, more than million cases have been reported worldwide, with the united states as the epicenter of this pandemic, with more than million confirmed cases and more than deaths as of april , [ ] . studies from various countries have reported that covid- is associated with rapid spread, acute respiratory distress syndrome (ards), saturated capacity of intensive care units, and high mortality [ , ] . there are still no targeted therapeutic options available for sars-cov- , and symptomatic management is the mainstay of treatment in ards associated with covid- . the mortality rate associated with ards is up to %, which is almost equal to the % case fatality rate reported in patients with severe covid- disease requiring critical care management [ , ] . multiple studies have found that high-dose intravenous vitamin c reduces systemic inflammation in multiple ways, including attenuation of cytokine surge, and prevents lung injury in severe sepsis and ards [ , ] . we describe a case of covid- with septic shock and ards who received high doses of intravenous vitamin c and was the first case to be able to be taken off of mechanical ventilation (mv) early and recover from the disease at our institute. a -year-old white woman presented to the emergency department with a -day history of low-grade fever, dry cough, and shortness of breath (sob). she had been admitted to another hospital for an elective right total knee replacement week ago, with an uneventful post-operative course. she went to the hospital in a healthy state, stayed in a private room, and denied any recent sick contacts or travel history. upon review of systems, the patient reported pain, redness, and swelling in the right knee, which was unchanged since the surgery. the past medical history was pertinent for essential hypertension, obesity, myasthenia gravis (mg) in remission, and osteoarthritis. the physical examination revealed a body temperature of . °c, blood pressure of / , pulse of beats per minute, respiratory rate of breaths per minute, and oxygen saturation of % while breathing ambient air. lung auscultation revealed bilateral rhonchi with rales. chest radiography (cxr) was performed, which reported patchy air space opacity in the right upper lobe suspicious for pneumonia ( figure ). the remainder of the examination was unremarkable. a rapid nucleic acid amplification test (naat) for influenza a and b was negative. given community transmission of covid- , a nasopharyngeal swab specimen was obtained and sent to the state laboratory for detection of sars-cov- . the patient was admitted to the airborne-isolation unit following the centers for disease control and prevention (cdc) recommendations for contact, droplet, and airborne precautions [ ] . the patient was initially started on broad-spectrum antibiotics with cefepime and levofloxacin for pneumonia in the high-risk setting of recent hospitalization for knee surgery after drawing blood and sputum cultures along with supportive care with l of supplemental oxygen. on day , the patient also developed mild diarrhea, generalized weakness, and fatigue. she was evaluated by neurology and started on g/kg intravenous immunoglobulin for days due to mild mg exacerbation and a pending mg crises. the arterial blood gases (abgs), complete blood count, and basic metabolic profile studies were monitored during hospitalization and are presented in table . the laboratory data on day showed mild absolute lymphopenia and anemia, while the abgs revealed a ph of . , pco of . mmhg, po of . mmhg, and bicarbonate of . mmol/l. on day , the creatinine kinase and lactic acid were normal, while the lactate dehydrogenase, ferritin, and interleukin- were elevated at units per liter, nanograms per milliliter, and picograms per milliliter, respectively. on days through of hospitalization, the patient reported progressively increasing sob, and the oxygen requirements increased up to l high-flow nasal cannula. on day , the nasopharyngeal swab results came back positive for sars-cov- by reverse-transcriptase polymerase chain reaction (rt-pcr). the patient was started on oral hydroxychloroquine mg once and started on mg twice a day, along with azithromycin mg once a day intravenously, zinc sulfate mg times a day, and oral vitamin c g twice a day. the blood and sputum cultures did not grow any organisms and broad-spectrum antibiotics were discontinued. on day , the patient's sob worsened rapidly, and oxygen requirements went up to l. upon physical examination, the patient was drowsy, in moderate distress, and was unable to protect the airways. the blood pressure was / mmhg with the heart rate of beats per minute, temperature °c, and a respiratory rate of breaths per minute. the cxr revealed bilateral alveolar infiltrates due to pneumonia and interstitial edema, consistent with ards ( figure ). given her rapid deterioration, she was intubated on an emergent basis and started on pressure-regulated volume-controlled mechanical ventilation. the patient was started on norepinephrine . mcg/kg/min for septic shock and was titrated accordingly to maintain mean arterial pressure more than mmhg, along with colchicine . mg twice a day to address the cytokine storm given the elevated interleukin- levels. on day [mechanical ventilation (mv) day ], she was started on high-dose vitamin c g per h as a continuous intravenous infusion. her clinical condition started to improve slowly and norepinephrine support was stopped on mv day . the cxr on day showed significant improvement of the pneumonia and interstitial edema (figure ) . a spontaneous breathing trial with continuous positive airway pressure/pressure support (cpap/ps) with the settings of positive end-expiratory pressure (peep) of mmhg, ps above peep of mmhg, and a fraction of inspired oxygen of % was successfully tolerated by the patient. the abgs revealed a ph of . mmhg, pco of . mmhg, po of . mmhg, and bicarbonate of . mmol/l. because of her remarkable clinical and radiological improvement, she was extubated to l of oxygen with a nasal cannula on day of illness (mv day ). her breathing status continued to improve in the following days, with oxygen saturation of % on day of illness while breathing ambient air, and a cxr revealed almost complete resolution of the infiltrates (figure ) . the patient received a total of days of treatment with hydroxychloroquine and azithromycin along with days of colchicine during hospitalization. high-dose vitamin c infusion and oral zinc sulfate were continued for a total of days. she received inpatient physical and occupational rehabilitation after being transferred from the critical care unit to an isolation room. she still positive by rt-pcr for sars-cov- on day of illness and was discharged from the hospital in stable condition with an additional days of quarantine. sars-cov- continues to spread across the world causing severe illness in the form of septic shock, multiorgan failure, ards, and death. the virus was first named -ncov when the initial cases of atypical pneumonia in china were found to be associated with a novel coronavirus [ ] . it was later named sars-cov- as it was found to cause ards, requiring high-support mechanical ventilation and associated high mortality [ , ] . thus far, there are no specific targeted therapies with proven efficacy available for the treatment of critically ill patients with ards. in our case, the patient was treated with high-dose vitamin c as a continuous intravenous infusion and was the first covid- patient to be able to be taken off mechanical ventilation early and recover from the disease at our institution. many decades of research have shown that vitamin c is an essential component of the immune cell function and has a critical role in a variety of immune system mechanisms [ ] . patients with vitamin c deficiency can develop fatal scurvy and are highly susceptible to a variety of infections, including pneumonia [ ] . vitamin c enhances neutrophil motility, phagocytosis, microbial killing by activating reactive oxygen species, and apoptosis, and prevents oxidative damage by its antioxidant properties [ ] . it also promotes b and t lymphocytes proliferation and antibody production [ ] . recent data have shown that vitamin c also prevents the production of pro-inflammatory cytokines, including il- , which causes lung injury and leads to ards; this is a component of the cytokine release syndrome that is observed in critically ill covid- patients [ ] . the attenuation of these immune functions by microorganisms leads to a severe inflammatory state and tissue necrosis resulting in multiorgan failure and ards, requiring mechanical ventilation and icu care. various studies have shown that up to % of critically ill covid- patients require invasive mechanical ventilation in the icu [ , ] . a recent meta-analysis of multiple trials showed that vitamin c reduces the duration of mechanical ventilation and the length of icu stay in patients with severe sepsis and ards [ ] . this finding was also confirmed recently in a randomized clinical trial by fowler et al. involving patients with sepsis and ards who received high-dose intravenous vitamin c up to g per day and showed significant improvement in -day mortality and shortened duration of icu stay [ ] . based on the above data, vitamin c has been increasingly used recently in the treatment of covid- disease, and peng et al., from wuhan university, initiated a phase ii trial to study the efficacy of vitamin c infusion in the treatment of ards associated with sars-cov- , in which patients receive g of intravenous vitamin c per day for a total of days [ ]. vitamin c infusion was not part of the treatment for covid- at our institute as it has not been approved as a standard treatment for sars-cov- . the present patient received high-dose vitamin c infusion due to family request after the development of ards and mv initiation. according to a study by bhatraju et al., who investigated covid- in critically ill patients in the seattle region, the median length of icu stay and duration of mv were and days, respectively [ ] . in our case, the length of icu stay and duration of mv were only and days, respectively. our case was also the first to be able to be taken off of mv early in our covid- icu unit and to recover from the disease at our institute. the length of icu stay and duration of mv in the present patient were also lower than in covid- patients who did not receive vitamin c infusion at our institute. the rest of the hospital course of our case was uneventful and the patient was discharged home in stable condition. vitamin c is a pivotal component of the immune system, with proven antioxidant and anti-inflammatory properties and has been tested in numerous studies for its role in severe sepsis and icu care, especially when used as a continuous high-dose intravenous infusion. high-dose intravenous vitamin c treatment in our case was associated with fewer days on mechanical ventilation, shorter icu stay, and earlier recovery compared to the average length of mechanical ventilation, disease duration, and icu stay in critical covid- patients at our institute. our results show the importance of further investigation of intravenous vitamin c in the form of randomized controlled trials for the treatment of sars-cov- to accurately assess its efficacy in critically ill covid- patients requiring mechanical ventilation and icu care. world health organization: pneumonia of unknown etiology coronavirus covid- global cases dashboard clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study critical care utilization for the covid- outbreak in lombardy, italy: early experience and forecast during an emergency response epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries characteristics and outcomes of critically ill patients with covid- in washington state ascorbic acid attenuates lipopolysaccharide-induced acute lung injury phase i safety trial of intravenous ascorbic acid in patients with severe sepsis novel-coronavirus selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses hemilä h: vitamin c and infections vitamin c and immune function ascorbic acid is a potent inhibitor of various forms of t cell apoptosis caveolin- -mediated internalization of the vitamin c transporter svct in microglia triggers an inflammatory phenotype covid- in critically ill patients in the seattle region -case series clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan vitamin c can shorten the length of stay in the icu: a meta-analysis effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial we thank all the intensive care units (icu) critical care nurses at mclaren-flint/michigan state university hospital for their untiring efforts in taking care of our patient during this difficult period of the pandemic. key: cord- -c co cfq authors: lin, shi-hui; zhao, yi-si; zhou, dai-xing; zhou, fa-chun; xu, fang title: coronavirus disease (covid- ): cytokine storms, hyper-inflammatory phenotypes, and acute respiratory distress syndrome date: - - journal: genes dis doi: . /j.gendis. . . sha: doc_id: cord_uid: c co cfq abstract coronavirus disease (covid- ) was first identified in china at the end of . acute respiratory distress syndrome (ards) represents the most common and serious complication of covid- . cytokine storms are a pathophysiological feature of covid- and play an important role in distinguishing hyper-inflammatory subphenotypes of ards. accordingly, in this review, we focus on hyper-inflammatory host responses in ards that play a critical role in the differentiated development of covid- . furthermore, we discuss inflammation-related indicators that have the potential to identify hyper-inflammatory subphenotypes of covid- , especially for those with a high risk of ards. finally, we explore the possibility of improving the quality of monitoring and treatment of covid- patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper- and hypo-inflammatory subphenotypes of covid- . however, there is currently little clinical data available in regard to evidence for cytokine storms in covid- . the expression levels of interleukin- receptor (il- r) and il- in the sera of critical care cases were found to be significantly higher (p < • ) than those of severe cases of in contrast, there were no statistically significant differences in serum tumor necrosis factor alpha (tnf-α, il- , il- , or il- between these two groups (p > • ). [ ] however, following initially high expression of th cytokines (e.g., interleukin (il)- β, interferon (ifn)-γ, interferon-inducible protein (ip ), and monocyte chemoattractant protein- (mcp ) th cytokines (e.g., il- and il- ) may subsequently suppress inflammation during sars-cov- infection. [ , ] furthermore, other observational covid- studies have suggested that cytokine storms (comprised of il- β, il- ra, il- , and il- ) may be associated with disease severity.[ , , ] for example, higher concentrations of granulocyte colony-stimulating factor (gcsf), ip , mcp , mip a, and tnf-α were found in patients who required admission into an intensive care unit (icu). [ , ] taken together, we posit that cytokine storms may be associated with the severity of covid- . however, it is not feasible to conduct a prospective study of covid- at present, and current evidence for cytokine storms in covid- has been derived from small sample sizes. it is also important to consider that patients at different phases of inflammation when corresponding samples are collected will likely also contribute to increased variability of cytokine storm metrics. however, the close relationship between cytokine storms and ards strongly suggests that excessive and maladaptive cytokine release contributes to the unfavorable initiation, strengthening, and promotion of ards in covid- . some other biological indicators are also closely related to hyper-inflammatory subphenotypes of ards. as a novel indicator of inflammation, endocan is a promising biomarker to predict disease severity and mortality in patients with ards. [ ] a decrease in the plasmatic endocan cleavage ratio (ecr) is associated with hyper-inflammatory phenotypes of ards. also, a change in ecr < - • % is the optimal cutoff value for the diagnosis of a hyper-inflammatory subphenotype (sensitivity of • ; specificity of • ). [ ] early vascular injury and disrupted alveolar-capillary barrier integrity can also reflect differences in subtypes of inflammatory responses. early-onset ards is associated with higher levels of the biomarkers srage and ang- . [ ] subphenotypes with higher ang- levels, which are characterized by higher inflammatory biomarkers and hypotension, may reflect more endothelial permeability and predilection for extravascular fluid accumulation that responds favorably to fluid restriction. [ ] however, uncertainty remains regarding how diverse initial environmental injuries result in a sequence of events culminating in the clinical syndrome of ards, involving various molecular pathways along with a general imbalance between injurious and reparative mechanisms. classification of patients with ards into hyper-and hypo-inflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapies. [ ] therefore, further elucidation of phenotypes and identifying treatable traits represent the future of personalized medicine for ards. in covid- , there is also suggestive evidence of hyper-inflammatory subphenotypes of ards. clinical evidence helps to progress patient-level and population-level decision making. therefore, we need to build upon prior experience and identify similarities versus differences among covid- patients. [ ] from the evidence that we were able to retrieve, we found that during the time from the onset of symptoms to mv, which was reported to be • days ( • - • days),[ ] if patient was identified as having a hyper-inflammatory subphenotype of covid- and given targeted therapy, this approach would be expected to ameliorate the probability of the patient progressing to a severe or critical condition. therefore, the key treatment for ards, a key factor in covid- deterioration, is closely related to the identification and monitoring of hyper- inflammatory subphenotypes. it is difficult to distinguish the hyper/hypo inflammatory subphenotypes of covid- since there is currently little data on this phenomenon. c-reactive protein (crp) levels of most patients are above the normal range.[ , ] additionally, hypersensitive crp (hs-crp) has also been found to be increased. the authors declare that there are no competing interests regarding the publication of this paper. pathological findings of covid- associated with acute respiratory distress syndrome. the pulmonary pathology of early phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer. journal of thoracic oncology : official publication of the international association for the study of lung cancer covid- ): a critical care perspective beyond china clinical characteristics of coronavirus disease in china. the new england journal of ang lw, mak tm et al: epidemiologic features and clinical course of patients infected with sars-cov- in singapore investigators c: high-flow nasal therapy in adults with severe acute respiratory infection: a cohort study in patients with influenza a/h n v lung injury prediction scores: clinical validation and c-reactive protein involvement in high risk patients lung endothelial cell antigen cross- presentation to cd (+)t cells drives malaria-associated lung injury the emergence of pathogenic tnf/inos producing dendritic cells (tip-dcs) in a malaria model of acute respiratory distress syndrome (ards) is dependent on ccr . mucosal immunology th /treg cells as a risk indicator in early acute respiratory distress syndrome. critical care angiotensin-converting enzyme in lung diseases. current opinion in pharmacology clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury circulating il- ra and il- levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series corticosteroid therapy in patients with primary viral pneumonia due to pandemic (h n ) influenza. the journal of infection corticosteroid therapy for critically ill patients with middle east respiratory syndrome on the use of corticosteroids for -ncov pneumonia dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. the lancet respiratory medicine zhongguo wei zhong bing ji jiu yi xue = chinese critical care medicine = zhongguo weizhongbing jijiuyixue efficacy of xuebijing injection () on cardiopulmonary bypass- associated pulmonary injury: a prospective, single-center, randomized, double blinded trial remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro cytokine release syndrome: who is at risk and how to treat. best practice & research clinical haematology effects of human interleukin- on ventilator-associated lung injury in rats. inflammation influenza and sars-coronavirus activating proteases tmprss and hat are expressed at multiple sites in human respiratory and gastrointestinal tracts cov- cell entry depends on ace and tmprss and is blocked by a clinically proven key: cord- - hdeuweo authors: torrego, alfons; pajares, virginia; fernández-arias, carmen; vera, paula; mancebo, jordi title: bronchoscopy in patients with covid- with invasive mechanical ventilation: a single-center experience date: - - journal: am j respir crit care med doi: . /rccm. - le sha: doc_id: cord_uid: hdeuweo nan to the editor: severe coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) infection leads to acute respiratory distress syndrome and hypoxemic respiratory failure ( ) . the university hospital de la santa creu i sant pau serves an area of downtown barcelona, spain, of about , citizens. the first case of covid- at our hospital was detected on march , . the first two cases in the icu were detected on march , and the number of beds dedicated to intensive care multiplied by four, with new icu admissions and patients requiring mechanical ventilation between march and april . during this period, patients were discharged, died, and were still in the icu. bal, bronchial wash, and protected specimen brush are bronchoscopic procedures used to provide microbiological samples from lower respiratory airways. however, because of the risk of viral transmission, bronchoscopy is not routinely indicated for the diagnosis of covid- ( ) . bronchoscopy in critically ill patients with covid- has been required to manage complications (atelectasis, hemoptysis, etc.) as well as to obtain samples for microbiological cultures and to assist in the management of artificial airways (guide intubation and percutaneous tracheostomy) ( ) . because no series of intubated patients with covid- submitted to bronchoscopy has been published so far, we describe our experience in performing flexible bronchoscopies in patients with covid- with severe acute hypoxemic respiratory failure requiring invasive mechanical ventilation during the first weeks of the epidemic outbreak. between march and april , , a total of bronchoscopies were performed in patients with covid- . eight patients required two bronchoscopies. indications for bronchoscopy were as follows: radiological and/or clinical deterioration suggesting possible superinfection ( / ) as well as airway secretion management with/without atelectasis ( / ). intensivists indicated procedures . days (range, - ) after intubation. at the time of indication, the median fi o was . (interquartile range [iqr], . - . ), the median positive end-expiratory pressure was cm h o (iqr, - ), and the median pa o /fi o ratio was (iqr, - ). procedures were performed in either supine ( / ) or prone ( / ) position, under usual intravenous sedation and with pressure-controlled ventilation mode. disposable scopes were used in all cases (ambu ascope broncho, large . / . . ambu a/s), and minimal staff attended the procedure bedside (one expert bronchoscopist occasionally accompanied by a staff intensivist). one out of two bronchoscopists got infected with sars-cov- and developed covid- . as a consequence, our colleague had to be replaced by another bronchoscopist during the third week. before the procedure, all the necessary equipment and materials were prepared outside the patient room, including saline, syringes, mucoactive drugs, microbiological recipients, connections, and bronchoscopy system (scope and screen). a negative-pressure room was not always available for the procedures owing to the variety of locations adapted for intensive care support. as recommended ( ), level iii of personal protective equipment was used, including n or fpp mask, goggles, double gloves, and a plastic protective gown including head and neck cover. bronchoscopic examination included orotracheal tube positioning check, direct inspection of tracheal and bronchial mucosa, suctioning of secretions, and mucoactive agent instillation if necessary (hypertonic saline combined with hyaluronic acid), and in cases, a mini-bal with -ml saline aliquots at room temperature was performed just before the end of procedure for microbiological sampling. the bronchial segment to the duration of the procedures was never more than minutes. before the procedure, fi o was increased so as to reach a peripheral oxygen saturation of %- %. bronchoscopy was well tolerated in most cases. a transient drop in oxygen saturation as measured by pulse oximetry (sp o ) below % was occasionally observed during the procedure. in those patients, the bronchoscope was removed for a few seconds until sp o recovery (i.e., . %). major desaturation did not force the abortion of any procedure. the mini-bal was not associated with a greater number of complications as compared with patients in whom bal was not performed. apart from transient drops in sp o , no other complications were detected during the procedures. bronchoscopy results showed normal or mildly hyperemic bronchial mucosa. the presence of white and gelatinous secretions, difficult to suction, was observed in % ( / ) of patients. in cases, mucohematic plugs occupying the main or lobar bronchi were observed and removed after instillation of saline and a mucolytic agent. figure shows examples of the described findings, which to the best of our knowledge have not been reported in peer-reviewed journals. the fact that we used closed-circuit suctioning systems together with heat and moisture exchangers (edithflex hme; vyaire) may also help explain why this complication was encountered so often. because our usual way to provide proper inspired gas conditioning is the use of heated humidifiers, we cannot ascertain if thick secretions are due to the viral infection per se or the change in our humidification strategy. nevertheless, in past scenarios in which our patients used the same kind of passive humidification, this observation was uncommon. the main results are summarized in table . regarding bal results, / ( . %) had positive cultures for pseudomonas aeruginosa (n = ), staphylococcus aureus (n = ), klebsiella aerogenes (n = ), enterobacter cloacae (n = ), enterococcus faecalis (n = ), escherichia coli (n = ), streptococcus anginosus (n = ), or prevotella melaninogenica (n = ). these results are similar to microbiological flora usually observed in ventilator-associated pneumonia ( ) . as a result of bal, a new antibiotic was prescribed in / ( %) patients. the present isolates do not differ from those obtained during nonepidemic periods (tables and ). bal processing did not yield mycobacteria, fungi (including aspergillus sp., verified by microbiological culture), or other viruses. bal galactomannan was determined in only one patient. in summary, in critically ill, mechanically ventilated patients with covid- , thick hypersecretion in the airway is the most common complication observed, and these patients can benefit from specific bronchoscopy management. guided mini-bal can be of help to confirm a clinical suspicion of superinfection. however, with this observational study, it is impossible to weigh the benefits of bronchoscopy against the potential harms to the patient and the bronchoscopist. a different study design would have been required to address the influence on patient-centered outcomes. n to the editor: most patients admitted to the icu with a severe presentation of coronavirus disease (covid- ) fulfill the acute respiratory distress syndrome (ards) criteria ( ) and require invasive mechanical ventilation ( ) . in such patients, knowledge of respiratory mechanics and potential for lung recruitability may provide valuable information to guide adjustments in ventilator settings. some authors have regularly reported from their clinical experience that the key feature of covid- respiratory mechanics would be an uncommon association of severe hypoxemia and preserved respiratory system compliance, altogether with poor recruitability ( ) ( ) ( ) . however, a dramatic decrease in respiratory system compliance has also been reported in severe acute respiratory syndrome coronavirus (sars-cov- )-related ards ( ). gattinoni and colleagues recently proposed to reconciliate these different observations, hypothesizing that the different phenotypes may result from interactions between the time course and severity of the disease and the patient's ventilatory response, with an early l phenotype (low lung elastance, low recruitability) and a late h phenotype (high lung elastance, high recruitability) ( ) . however, physiological descriptions of covid- -associated ards and its comparison with non-covid- classical ards remain scarce in the literature. the aim of the present study is to describe the respiratory mechanics and lung recruitability of patients with covid- -associated ards, to compare it with that of non-covid- -associated ards, and to explore their possible relation with covid- phenotypes. this is an ancillary report of an ongoing prospective monocentric observational study on respiratory mechanics in patients with ards, conducted in the henri mondor university hospital medical icu, créteil, france (institutional review board -a - ). inclusion criteria were age . years and presence of ards according to the berlin definition ( ). exclusion criteria were intubation for more than hours prior to icu admission. all consecutive patients with covid- included in this study are reported here and compared with consecutive patients without covid- who were previously enrolled. written informed consent was waived owing to the observational nature of the study. the ventilator was set by the attending physician. during the first hours of invasive mechanical ventilation, the ventilator's settings were collected and the respiratory mechanics and lung recruitability were assessed once in supine position. thus, airway and esophageal (when available) pressures were recorded during a . -second end-inspiratory and a -to -second end-expiratory occlusion maneuver, at the positive end-expiratory pressure (peep) level previously set by the physician. the potential airway closure phenomenon was detected by measuring the airway opening pressure during a low flow (< l/min) insufflation, as previously described ( ). the potential for lung recruitment was assessed by the mean of the recruitment-to-inflation ratio (r/i ratio) computation, as previously detailed ( ). by default, r/i ratio was assessed between and cm h o of peep. however, in case of airway closure, the low peep was set above the airway opening pressure. comparisons were made using nonparametric tests. a p , . was considered significant. thirty consecutive patients with non-covid- -associated ards and consecutive patients with covid- -associated ards were included in the report. patients without covid- were enrolled between january , , and march , , and those with covid- were enrolled between march , , and april , . five patients with covid- and five without covid- experienced prone position before inclusion in the study. etiologies for non-covid- -associated ards were as follows: pneumonia (n = , of which were related to respiratory viruses), pulmonary vasculitis (n = ), and noncardiogenic shock (n = ). a bacterial coinfection was documented in four patients with covid- at the time of inclusion. patients with and without covid- did not author contributions: a.-f.h.: data collection, data analysis, data interpretation, and writing. f.p.: data collection and data interpretation. s.t.: data collection, data analysis, and data interpretation. n.d.p. and k.r.: data interpretation. a.m.d. and g.c.: study design, data collection, data analysis, data interpretation, and writing. all authors helped to revise the draft of the manuscript. all authors read and approved the final manuscript. originally published in press as doi: . /rccm. - le on june , covid- lombardy icu network. baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region american association for bronchology and interventional pulmonology (aabip) statement on the use of bronchoscopy and respiratory specimen collection in patients with suspected or confirmed covid- infection handbook of covid- prevention and treatment bronchoscopy in ventilator-associated pneumonia: agreement of calibrated loop and serial dilution estudios microbiológicos broncoscópicos en pacientes de uci con vmi: experiencia de año key: cord- -fliudtls authors: singh, gurmeet; brodie, daniel title: commentary: protecting the right ventricle in covid- ards - more data required date: - - journal: j thorac cardiovasc surg doi: . /j.jtcvs. . . sha: doc_id: cord_uid: fliudtls nan oxy-rvad has been proposed for covid- -associated ards as superior to mechanical ventilation and, by implication, ecmo, because it provides rv support. more data are required before adoption. if the oxy-rvad approach is rational and feasible, is it advisable? one issue raised by dr. joyce is cost. clearly, any future study of an oxy-rvad in this setting, as with ecmo, should be accompanied by detailed cost-benefit analyses. so, while this too may be feasible, it must be seen as an additional experiment. as dr. joyce says: "anecdotal evidence should always be viewed with a degree of skepticism." we agree. the experience described is intriguing, but preliminary, with insufficient data to guide clinical practice or broader recommendations. as we learn more about covid- - associated rv failure, the specific need in this context may become clearer. notwithstanding the separate issue of extubating patients during ecmo (or oxy-rvad) support, the broader hypothesis may be applicable to any severe ards patient with concomitant severe rv dysfunction. clearly, more data are needed, and we look forward to dr. joyce's planned multicenter randomized clinical trial. experts' opinion on management of hemodynamics in ards patients: focus on the effects of mechanical ventilation acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial right ventricular unloading after initiation of venovenous extracorporeal membrane oxygenation mechanical ventilation: a necessary evil? mechanical ventilation to minimize progression of lung injury in acute respiratory failure key: cord- -lk upygf authors: lepper, philipp m.; muellenbach, ralf m. title: mechanical ventilation in early covid- ards date: - - journal: eclinicalmedicine doi: . /j.eclinm. . sha: doc_id: cord_uid: lk upygf nan "it is not enough to do your best, you must know what to do, and then do your best." ¡ w. edwards deming a hallmark of acute respiratory distress syndrome (ards) is severe impairment of gas exchange. mechanical ventilation to ensure oxygenation and carbon dioxide clearance is a cornerstone of the treatment of severe respiratory failure. over the past five decades, significant progress has been made in defining principles and practices of invasive mechanical ventilation (imv) in ards. respiratory failure due to coronavirus disease (covid- ) sparked a debate on when and how to apply imv in these patients, as it has been proposed that severe covid- causes "atypical" ards [ ] . as published in eclinicalmedicine, mittermaier and colleagues [ ] investigated the effects of imv, positive end-expiratory pressure (peep) and prone positioning (pp) on oxygenation and lung recruitability in patients with covid- -related ards (cards). all three interventions led to markedly improved oxygenation in cards. initiation of imv also led to a significant reduction in opacity indices assessed by chest x-ray indicating lung recruitability. this recruitment could not be further increased by pp. despite low numbers in the groups, it becomes clear that peep and pp are able to improve oxygenation in cards. peep has been used in the first description of ards and led to an increase in p a o or oxygen saturation in five of the twelve initial patients treated this way [ ] . peep to increase functional residual capacity (frc) and thus keep small airways and alveoli open (leading to a reduction of lung inhomogeneity) is now a universal accepted principle of ards treatment. the practice to set peep right in patients with ards is in contrast somewhat vague. it has been suggested that lungs in cards patients with high compliance are mainly open, thus peep could be set at lower levels and pp might not bring the desired benefits [ , ] . the present study indicates that also cards requires peep levels we are accustomed to from usual ards. importantly, from the present study [ ] we again learn that peep should be applied in an individualized manner. the amount of recruitable lung, an important determinant of harm and benefit from peep, varies considerably across patients with ards and more peep does not necessarily translate into improved gas exchange [ ] . in the present study, pulmonary compliance was relatively preserved but increasing frc by high peep levels led to significantly improved oxygenation. peep above a certain level might be harmful by increasing dead space, reducing venous return and hence cardiac output leading to reduced net oxygen delivery [ ] . this might also be true in patients with ventilation-perfusion (v/q) mismatch as seen in pulmonary embolism or altered hypoxic pulmonary vasoconstriction. in this sense it is difficult to predict peep effects in individual patients as the clinical presentations of these patients are manifold. interestingly, after careful titration, optimal peep in study patients was always lower than the initially applied peep [ ] . the data suggest that in some patients, even lower levels of peep would have been acceptable with regard to oxygenation possibly giving more protection to the right ventricle. nevertheless, peep is a titrated therapy that should be integrated into a cards ventilation strategy [ ] . such a strategy must also include pp. pp is associated with improved outcomes in patients with moderate to severe ards [ ] without the need to change the ventilator to more invasive settings. just by changing the body position, collapsed alveoli in dependent lung zones are recruited, v/q mismatching is decreased and lower concentrations of oxygen may be used [ ] . in their study, mittermaier and colleagues [ ] presented the effects of pp over a period of a least h. however, pp probably did not change opacity indices in chest x-rays, as covid- may cause a very dissiminated infestation of the lungs. the present study does not answer the question of whether peep applied by non-invasive ventilation (niv) can improve oxygenation in a similar way as imv. thus, the current data leave it open when to start imv, directly or after niv. but it adds to the reports indicating that the pathophysiological changes in human lungs due to cards can be treated similarly as ards induced by other infectious agents. stage adjusted, this treatment should include titrated peep, pp and extracorporeal membrane oxygenation (ecmo) [ ] . there is definitely a lot to learn about cards, and it seems that the treatment principles are the same as in usual ards. the practices will be informed be a plethora of studies, and the study by mittermaier et al. [ ] is one of those helping to guide the way. covid- does not lead to a "typical" acute respiratory distress syndrome evaluation of peep and prone positioning in early covid- ards acute respiratory distress in adults covid- pneumonia: different respiratory treatments for different phenotypes? oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. a secondary analysis of the lovs and express trials optimum end-expiratory airway pressure in patients with acute pulmonary failure higher vs. lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis prone positioning in severe acute respiratory distress syndrome prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome clinical features, ventilatory management, and outcome of ards caused by covid- are similar to other causes of ards the authors have nothing to declare. key: cord- - v i authors: lv, dandan; xu, yiming; cheng, hongqiang; ke, yuehai; zhang, xue; ying, kejing title: a novel cell-based assay for dynamically detecting neutrophil extracellular traps-induced lung epithelial injuries date: - - journal: exp cell res doi: . /j.yexcr. . sha: doc_id: cord_uid: v i acute lung injury (ali) and its more severe form, acute respiratory distress syndrome (ards) are common lung disorders characterized by alveolar-capillary barrier disruption and dyspnea, which can cause substantial morbidity and mortality. currently, a cluster of acute respiratory illnesses, known as novel coronavirus ( -ncov)-infected pneumonia (ncip), which allegedly originally occurred in wuhan, china, has increased rapidly worldwide. the critically ill patients with ards have high mortality in subjects with comorbidities. previously, the excessive recruitment and activation of neutrophils (polymorphonuclear leukocytes [pmns]), accompanied by neutrophil extracellular traps (nets) formation were reported being implicated in the pathogenesis of ali/ards. however, the direct visualization of lung epithelial injuries caused by nets, and the qualitative and quantitative evaluations of this damage are still lacking. additionally, those already reported methods are limited for their neglect of the pathological role exerted by nets and focusing only on the morphological features of netosis. therefore, we established a cell-based assay for detecting nets during lung epithelial cells-neutrophils co-culture using the xcelligence system, a recognized real-time, dynamic, label-free, sensitive, and high-throughput apparatus. our results demonstrated that lung epithelial injuries, reflected by declines in cell index (ci) values, could be induced by lipopolysaccharide (lps)-activated pmns, or nets in a time and dose-dependent manner. nets generation was verified to be the major contributor to the cytotoxicity of activated pmns; protein components of nets were the prevailing cytotoxic mediators. moreover, this cell-based assay identified that pmns from severe pneumonia patients had a high nets formative potential. additionally, acetylsalicylic acid (asa) and acetaminophen (apap) were discovered alleviating nets formation. thus, this study not only presents a new methodology for detecting the pathophysiologic role of nets but also lays down a foundation for exploring therapeutic interventions in an effort to cure ali/ards in the clinical setting of severe pneumonia, including the emerging of ncip. initiation and progression of ali/ards. hence, there is a need for a simpler, objective, and quantitative approach for detecting nets, as well as evaluating lung epithelial disruption caused by nets. in this study, we describe the optimization and validation of a novel lung epithelial cell-based assay to analyze the damage caused by nets on lung epithelial barriers using the xcelligence system. till now, this label-free, real-time, and dynamically analytic apparatus has been widely used in evaluating chinese compound medicines or modern pharmaceuticals, monitoring epithelial barrier function, and detecting t cell activation or nk cell killing. the advantages of this system are its high sensitivity, accuracy, effects. moreover, the protein components of nets were the prevailing cytotoxic mediators. we compared the consistency of this novel cell-based nets detection methodology with other common analytical approaches. more encouragingly, the feasibility and practicality of this assay helped to distinguish nets formation differences between pmns from severe pneumonia patients and healthy controls, and seem a or pmn samples were subjected to washing three times with . m sodium cacodylate buffer and fixing in . % glutaraldehyde in . m sodium cacodylate buffer for h. secondary fixation with . % osmium tetroxide was performed for min prior to sequential dehydration with increasing concentrations of ethanol. samples were dried at the critical point using a co drier, mounted onto an aluminum stub, and sputter-coated with / gold-palladium. a thin strip of colloidal silver was painted at the sample edge to dissipate sample charging. samples were imaged with a field emission scanning electron microscope nova nano (thermo fei). live-cell imaging this experiment was conducted using a nikon a r confocal microscope equipped with phase-contrast microscopy and a temperature-control to maintain incubation at °c. pmns with different treatments (medium, μg/ml lps, μm dpi, and μg/ml lps + μm dpi) were re-suspended in rpmi without phenol red containing μm sytox green (s , thermo fisher). then, these suspensions were cultured in a mm -chamber glass-bottom dish (d c - - . -n, cellvis) ( × /ml, μl/chamber). after min, images were randomly taken under low-light illumination at min intervals for a total of h. the procedure used in this study was modified from that described previously. - pmns ( × /ml) stimulated by different concentrations of lps were re-suspended in rpmi without phenol red containing μm membrane-impermeable dna dye sytox green (s , thermo fisher). then, these suspensions were seeded in a -well black plate (whb- , whb) ( μl/well), usually in quadruplicates, and cultured at °c in the dark. extracellular dna released from pmns were quantified by measuring fluorescence values at sequential time points in a microplate fluorescence reader at / nm. following pmns incubation in a -well plate ( × /ml, ml/well), μl culture medium per well was carefully aspirated and μl ×ripa buffer ( s, cell signaling technology) was added into the wells supplemented with edta-free protease inhibitor tablets and phosphatase inhibitors (roche diagnostics). after lysis on ice for min, the total pmn lysates were collected and sonicated on ice for s. the protein concentrations were quantified using the bca assay (beyotime) before solubilizing in ×loading buffer, and regulation of neutrophil extracellular trap formation by anti-inflammatory drugs regulated poly i:c-induced neutrophil extracellular traps and acute lung injury partly protein-based therapies for acute lung injury: targeting neutrophil extracellular traps neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury new insights into the mechanisms controlling neutrophil survival modulation of granulocyte survival and programmed cell death by cytokines and bacterial products matters of life and death. how neutrophils die or survive along net release and is we would like to thank ms. shuangshuang liu for instructing the application of nikon a r confocal microscope throughout the study. thanks to editage (www.editage.cn) for english language editing. key: cord- -uy ew ki authors: singer, benjamin d.; jain, manu; budinger, g. r. scott; wunderink, richard g. title: a call for rational intensive care in the era of covid- date: - - journal: am j respir cell mol biol doi: . /rcmb. - le sha: doc_id: cord_uid: uy ew ki nan as intensive care physicians, we have been trained to treat viral pneumonia and its attendant complications of acute respiratory distress syndrome (ards) and multiorgan failure. the coronavirus disease (covid- ) pandemic has challenged our profession to revisit its paradigms. specifically, do mechanical ventilation strategies optimized in ards trials still apply to this disease? is our policy of waiting for proof of benefit before instituting novel therapeutics still sensible? in this commentary, we make the case that the icu is already optimized for the care of patients with covid- and that departures from our standard of care require evidence, not vice versa. we have learned from decades of critical care research and experience that protocol-driven, physiologically based management strategies result in improved patient outcomes, particularly for ards ( ) . the berlin definition established criteria for ards based on its acute clinical presentation in the presence of hypoxemia and radiographic pulmonary edema not arising entirely from hydrostatic mechanisms ( ) . we, along with other intensivists, have observed that some patients with covid- -induced ards exhibit higher than expected lung compliance that seems out of proportion to the degree of shunt physiology. importantly, although experience has shown that stiff lungs are a common finding in patients with ards in general, measures of static respiratory system compliance are not included in the berlin definition. ards is a syndrome, not a disease, and is heterogeneous by its nature. regardless, findings in covid- have led some to believe that covid- -related respiratory failure is an ards variant ( ). a worrisome corollary of this belief is that the accumulated database of proven ards management strategies (e.g., intubation and low-tidal-volume ventilation, prone positioning, and surveillance for nosocomial infections) can be disregarded. in fact, the patients enrolled in the arma (ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress) trial of low-tidal-volume ventilation and the proseva (proning severe ards patients) trial of prone positioning exhibited myriad etiologies, compliances, and shunt fractions but nevertheless benefited from the targeted interventions ( , ) . we should not deny the benefits proven by rigorous randomized controlled trials to our patients with covid- . biological plausibility is insufficient justification to administer a medication to a critically ill patient outside of a clinical trial. indeed, our specialty's history is littered with examples of agents that carried a strong mechanistic rationale and even positive in vitro signals yet failed or were shown to be harmful in clinical trials, such as surfactants, n-acetylcysteine, statins, and b-agonists, to name a few in ards alone ( ) . currently, numerous agents are being administered to patients with covid- outside of controlled trials, including hydroxychloroquine, azithromycin, doxycycline, remdesivir, lopinavir-ritonavir, heparin, low-molecular-weight heparin, tissue plasminogen activator, glucocorticoids, tocilizumab, eculizumab, ifn-b, ifn-g, il- inhibitors, mesenchymal stem cells, convalescent plasma, nitric oxide, vitamin c, and others. we do not suggest that physicians never use unproven medications off-label or off-trial; in the icu, we frequently must give therapies based on strong signals in disease processes that are similar to the one in front of us. in contrast, the routine use of the agents listed above for covid- -outside of controlled trials-strains credulity. many of these compounds have failed in trials of viral infection and ards. continued use of lopinavir-ritonavir is even more shocking in light of a negative randomized controlled trial in covid- that was published early in the pandemic ( ). why are physicians abandoning standards of critical care in the era of covid- ? emotion, stress, fatigue, and political proclamations amplify our innate desire to help our patients and try something-anything-that might provide benefit and give hope to providers and patients alike. this data-free approach will ultimately harm more patients than it helps, as one-off administration of medications ruins clinical equipoise about their use. when a medication is administered to a patient who then improves, the natural human bias is to believe that the drug caused the improvement. nevertheless, if the patient succumbs to the disease, our biases do not confirm the counterfactual logic. instead, we believe that the disease was too severe for the drug to overcome, while we minimize the possibility that the drug was ineffective or toxic. the only known strategy to overcome these biases lies in the scientific method and the application of controlled trials to determine whether an agent is effective and the degree to which it is harmful. the possibility of persistent covid- is real, and the emergence of new viral pandemics in the future is certain. for our patients' sake, we need to know what works and what does not. the straw man argument-that patients with covid- improve with protocol-driven supportive care-needs to serve as a null hypothesis to be rejected or accepted in controlled trials. to act as if we know otherwise is irrational, hubristic, and reckless. pending data from ongoing clinical trials, we must resist the innate human desire to act on emotion and instead rely on our creed: first, do no harm. n to the editor: respiratory syncytial virus (rsv) infection is a major cause of severe respiratory disease in infants and in immunocompromised and older adults. rsv infects virtually all children by - years of age, resulting in nearly million hospitalizations and , in-hospital deaths annually, mostly in developing countries ( ) . there is no approved vaccine against rsv infection. passive prophylaxis with the anti-rsv antibody palivizumab is the only intervention licensed for the prevention of severe rsv disease in high-risk individuals ( , ) . rsv-specific serum igg antibodies are present in most children and adults, reflecting the universality of rsv infection throughout life. neutralizing antibodies remain a commonly accepted measure of protective immunity in vaccine trials ( ) . however, igg antibodies might influence the course of rsv disease, not only by acting as neutralizing antibodies but also by activating effector functions through the receptors for the fc portion of igg (fcgrs) ( , ) . these receptors are widely expressed in myeloid and b cells. whether t cells express fcgrs is still controversial, but recent studies strongly suggest that a minor fraction of t cells express fcgrii (cd ) ( - ). we show in the present study that severe rsv infection in infants is associated with a marked upregulation of cd on t cells. moreover, we found that cd ligation improves the activation of cd and cd t cells from hospitalized infants. our study included infants (median age, mo [interquartile range, - . ]; male, %) admitted to "pedro de elizalde" children's hospital, buenos aires, argentina, with rsv infection confirmed by direct immunofluorescence of nasopharyngeal aspirates. the local institutional review board approved the study, and written informed consent was obtained from parents. all infants had a clinical disease severity score (modified tal score) greater than or equal to and needed o . those admitted to the pediatric icu required mechanical ventilation (n = ). blood samples were collected at enrollment, usually - days after the onset of symptoms. age-and sex-matched infants admitted for scheduled surgery were included as healthy control subjects (n = ). they had no airway infections for a -week period before the study or any episode of severe rsv infection in their past. peripheral blood mononuclear cells were obtained from blood samples ( . - . ml) by using ficoll-hypaque gradient (ge healthcare life sciences). cd , cd , and/or cd t cells were sorted with a facsaria fusion flow cytometer (bd biosciences). purity was . %. to perform real-time qrt-pcr, total rna was extracted using the purelink-rna mini kit (thermo fisher). cd a and cd b isoforms were quantified as described previously ( ). antibody-dependent enhancement assays were performed using rsv (subtype a, strain long) expanded in hep- cells (american type culture collection) and purified by ultracentrifugation on a % sucrose layer. phytohemagglutinin (pha)-stimulated isolated t cells ( /ml, mg/ml; sigma-aldrich) were challenged with rsv (multiplicity of infection, . ) previously preincubated or not with subneutralizing concentrations of intravenous immunoglobulin ( mg/ml; universidad nacional de córdoba) for days. the percentage of infection was determined by flow cytometry. t-cell functional assays were performed using sorted t cells ( /ml) incubated with anti-cd monoclonal antibody ( mg/ml; stemcell technologies). cross-linking of cd was induced by antimouse igg f(ab ) ( mg/ml; jackson immunoresearch). next, cells were stimulated with pha and cultured for days. cytokines were quantified in cell supernatants (biolegend). degranulation of cd t cells was evaluated by flow cytometry. statistical analysis was achieved using graphpad prism version software. p , . was considered statistically significant. lung safe investigators; esicm trials group. epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in countries ards definition task force. acute respiratory distress syndrome: the berlin definition covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome proseva study group. prone positioning in severe acute respiratory distress syndrome pharmacological agents for adults with acute respiratory distress syndrome a trial of lopinavir-ritonavir in adults hospitalized with severe covid- key: cord- -q hjtsgi authors: roy, a.; behera, s.; pande, a.; bhattacharjee, a.; bhattacharyya, a.; baidya, d. k.; anand, r. k.; ray, b. r.; subramaniam, r.; maitra, s. title: physiological effect of prone positioning in mechanically ventilated sars- cov- infected patients with severe ards: preliminary analysis of an observational study date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: q hjtsgi prone position ventilation has been shown to decrease mortality and improve oxygenation in ards patients. with best of our knowledge, no study reported physiological effect of prone position in sars- cov- infected ards patients. in this prospective observational study, data of n= consecutive laboratory confirmed sars- cov- patients with severe ards as per berlin definition was included. data of patients analyzed with a median (interquartile range, iqr) age of ( . - ) y and median (iqr) p/f ratio of ( - ) with a median (iqr) peep of ( - ) before initiation of prone position. seventy-five percentage ( % ci . - . ) patients were prone responders at h prone session and ( % ci . - . ) % patients were sustained responders. there was a significant decrease in plateau airway pressure (p< . ), peak airway pressure (p< . ) and driving pressure(p< . ) and increase in static compliance (p= . ), p/f ratio (p< . ), pao (p= . )and spo (p= . ) at h and h since initiation of prone session and also after return of supine position. prone position in sars- cov- infected severe ards patients is associated with improvement in lung compliance and oxygenation in two- third of the patients and persisted in half of the patients. since the diagnosis of first case in december , sars-cov- has infected more that million and caused fatality in more than , people worldwide. early data from china reported that around % of all laboratory confirmed cases become critically ill. [ ] . although the overall case fatality rate (cfr) ranges between . to . %, mortality in critically ill can reach % [ ] . early reports from italy indicated that among the different phenotypes of ards in sars-cov- pneumonia that have been proposed, the 'l' phenotype has normal lung compliance and lung weight but leads to hypoxemia due to the loss of hypoxic pulmonary vasoconstriction, later it progresses to 'h' phenotype with low compliance and increased lung weight [ ] . prone position ventilation has been shown to decrease mortality and improve oxygenation in ards patients. in mechanically ventilated patients of severe ards with pao /fio (p/f) ratio < , prone position for at least days decreased -day mortality by almost % [ ] . prone position reduces lung strain and stress, leads to more homogenized distribution of lung aeration and recruitment of dorsal alveoli, thus, leading to improvement in oxygenation [ ] . with best of our knowledge, no study reported physiological effect of prone position in sars-cov- infected ards patients. hence, in this preliminary analysis of an observational study, physiological effect of prone position in sars-cov- infected severe ards patients have been reported. permission from the institute ethics committee was obtained before recruitment of first patient and consent was obtained from legally acceptable representative of all recruited patients. in this prospective observational study, data of n= consecutive laboratory confirmed sars-cov- patients with severe ards as per berlin definition was included. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint as per icu protocol, in the absence of contraindication, all mechanically ventilated ards patients with pao / fio < were placed in at least h/day prone position for consecutive days till the criteria is met. demographic characteristics, baseline respiratory mechanics and blood gas data were collected before initiation of prone position, after h and h of prone position and after h of return of supine position. positive end expiratory pressure (peep) was titrated as per ardsnet protocol peep-fio table. prone responders were defined by % increase in pao / fio ratio during the prone session and sustained responders were defined by % increase in pao / fio ratio h after return of supine position. all collected data were entered in a microsoft excel datasheet. categorical data were presented as as absolute numbers or percentages and non-parametric data were presented as median and iqr (inter-quartile range). unrelated data (between prone responders and nonresponders) were compared by mann-whitney u test or chi-square test as applicable. in this observational study, data of patients analyzed with a median (iqr) age of ( . - ) y and median (iqr) predicted body weight of ( - . ) kg. baseline respiratory mechanics data is presented in table . all included patients had severe ards with median (iqr) p/f ratio of ( - ) with a median (iqr) peep of ( - ) before initiation of prone position. median (iqr) sofa score was . ( . - ) at the time of inclusion. seventyfive percentage ( % ci . - . ) patients were prone responders at h prone session and ( % ci . - . ) % patients were sustained prone responders after return to supine position. prone responders had significantly higher baseline respiratory compliance (p= . , . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint mann whitney u test) but all other respiratory and blood gas variables were similar between responders and non-responders. there was a significant decrease in plateau airway pressure (p< . ), peak airway pressure (p< . ) and driving pressure(p< . ) and increase in static compliance (p= . ) at h and h since initiation of prone session and also after return of supine position. change in respiratory mechanics parameters from baseline are reported in figure . p/f ratio (p< . ), pao (p= . ) and spo (p= . ) increased from baseline and persisted in supine position also (figure ). noradrenalin requirement didn't change during the prone session (p= . ). percentages of changes in static compliance significantly correlated with p/f ratio after return of supine position (r = . , p= . ) but not at h (p= . ) and h (p= . ). percentages of changes in p/f ratio and driving pressure at h (r =- . , p= . ) and after return of supine position (r =- . , p= . ) were significantly correlated; but no correlation was found at h (p= . ). we have found that around % of the sars-cov- infected patients with severe ards responded with h prone position in terms of oxygenation. overall there is improvement in lung mechanics in terms of static compliance, driving pressure and plateau pressure without any changes in the hemodynamic support. in our series, all the included patients had 'stiff lung' as evident by low static compliance. previous studies reported a variable change in . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint respiratory system compliance in prone position in ards patients [ ], whereas we have found a significant decrease in driving pressure and static compliance. recruitment of the dorsal lung region was the biologically plausible mechanism of improvement in static compliance as both driving pressure and compliance were correlated with change in p/f ratio [ ] . we have found that these correlations were present even after return of supine position which indicated a sustained lung recruitment in sars-cov- infected patients. determination of baseline static compliance is important as it was a predictor of absence of response from prone position and these patients may be subjected to extra-corporeal membrane oxygenation early in the course of disease. our study has few limitations such as sample size was small, and we couldn't assess the effect of prone position on chest wall and lung compliance separately as esophageal manometry was not used. prone position in sars-cov- infected severe ards patients is associated with improvement in lung compliance and oxygenation in two-third of the patients and persisted in half of the patients. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted september , . characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study. the lancet respiratory medicine baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region prone positioning in severe acute respiratory distress syndrome prone position reduces lung stress and strain in severe acute respiratory distress syndrome . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintthe copyright holder for this this version posted september , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint key: cord- -bfqsyiyf authors: goette, andreas; patscheke, markus; henschke, frank; hammwöhner, matthias title: covid- -induced cytokine release syndrome associated with pulmonary vein thromboses, atrial cardiomyopathy, and arterial intima inflammation date: - - journal: th open doi: . /s- - sha: doc_id: cord_uid: bfqsyiyf coronavirus disease (covid- ) is a viral disease induced by severe acute respiratory syndrome–coronavirus- (sars-cov- ), which may cause an acute respiratory distress syndrome (ards). first reports have shown that elevated levels of inflammatory cytokines might be involved in the development of organ dysfunction in covid- . here, we can present a case of cytokine release syndrome induced by sars–cov- causing multiorgan failure and death. of note, we can report on pulmonary vein thromboses as potential source of cerebrovascular embolic events. furthermore, we present a specific form of an isolated inflammatory atrial cardiomyopathy encompassing atrial myocardium, perivascular matrix, as well as atrial autonomic nerve ganglia, causing atrial fibrillation, sinus node arrest, as well as atrial clot formation in the right atrial appendage. an associated acute glomerulonephritis caused acute kidney failure. furthermore, all the described pathologies of organs and vessels were associated with increased local expression of interleukin- and monocyte chemoattractant protein- (mcp- ). this report provides new evidence about fatal pathologies and summarizes the current knowledge about organ manifestations observed in covid- . cytokine release syndrome (crs) is a well-described pathological state which may occur after therapy with genetically modified t-cells. in general, crs is characterized by elevation of several biomarkers such as interleukin (il)- , il- , and tumor necrosis factor (tnf)-α. furthermore, ferritin, ddimer, and c-reactive protein (crp) are elevated. clinically, crs causes fever, nausea, tachypnea, and mental status changes. in more severe forms, crs is associated with mechanical ventilation, hypotension requiring vasopressor therapy, organ dysfunction, and shock. in addition to cancer therapy, diseases like viral infections have been described to trigger a release of cytokines. [ ] [ ] [ ] the novel coronavirus disease (covid- ) is a viral disease induced by severe acute respiratory syndrome-coronavirus- (sars-cov- ) that may cause an acute respiratory distress syndrome (ards). at present, the role of crs in covid- and covid- -induced ards is not fully understood. , , in the present case, we can correlate the clinical course of a covid- patient with systemic biomarkers and histopathological results. ► atria ► covid ► fibrillation ► pathology ► stroke coronavirus disease (covid- ) is a viral disease induced by severe acute respiratory syndrome-coronavirus- (sars-cov- ), which may cause an acute respiratory distress syndrome (ards). first reports have shown that elevated levels of inflammatory cytokines might be involved in the development of organ dysfunction in covid- . here, we can present a case of cytokine release syndrome induced by sars-cov- causing multiorgan failure and death. of note, we can report on pulmonary vein thromboses as potential source of cerebrovascular embolic events. furthermore, we present a specific form of an isolated inflammatory atrial cardiomyopathy encompassing atrial myocardium, perivascular matrix, as well as atrial autonomic nerve ganglia, causing atrial fibrillation, sinus node arrest, as well as atrial clot formation in the right atrial appendage. an associated acute glomerulonephritis caused acute kidney failure. furthermore, all the described pathologies of organs and vessels were associated with increased local expression of interleukin- and monocyte chemoattractant protein- (mcp- ). this report provides new evidence about fatal pathologies and summarizes the current knowledge about organ manifestations observed in covid- . we report on a -year-old male patient with a positive polymerase chain reaction (pcr) nasal swap for sars-cov- , who was hospitalized due to high-grade fever and bilateral lung infiltrates (►fig. ). due to rapid deterioration of respiration and development of ards, mechanical ventilation of the patient was initiated. on admission to intensive care unit (icu), the patients also developed atrial fibrillation (af), which had never been recorded before in this patient (►fig. ). due to rapid ventricular rates during af, the patient was electrically cardioverted and placed on amiodarone intravenous (iv). anticoagulation was initiated with unfractionated heparin iv with partial thromboplastin time at approximately seconds. venovenous hemofiltration was initiated because of acute kidney failure with anuria. even after prone positioning and relaxation, gas exchange deteriorated. lowest ph was . with a co of . of note, il- reached a maximum level of , pg/ml (normal value: - pg/ml), d-dimer was > mg/d: ( - mg/dl), fibrinogen maxed at mg/dl ( - mg/dl), crp at . mg/dl ( - . mg/dl), ferritin , ng/ml ( - ng/ml), procalcitonin at . ng/ml ( - . ng/ml), lactate dehydrogenase reached , u/l ( - u/l), von willebrand factor (vwf) (fviii:c)-activity was % (coagulation), vwf-activity was % (turbidimetry), and vwf antigen was % (turbidimetry). angiotensin ii levels were > ng/ml ( - ng/ml), angiotensin converting enzyme (ace) decreased to u/l ( - u/l), adamts (a disintegrin and metalloproteinase with a thrombospondin type motif, member ) protease activity was reduced to %. the patient's blood group was a rhesus factor positive. antipospholipid antibodies could not be detected, homocysteine levels were normal with . µmol/l, and serial heparin-induced thrombocytopenia (hit) screening tests were negative. at this point, crs was diagnosed. , after initiation of mg/day prednisolone, the patients gradually improved. at day , a puncture tracheotomy was performed. the procedure was uneventful. but hours later, the patients developed a sinus node arrest with asystole of > seconds (►fig. ). left ventricular function was not compromised with a normal ejection fraction on echocardiography. a temporary pacemaker wire was inserted through the left jugular vein after two more episodes of sinus node arrest for > seconds. on day , a computed tomography (ct) scan of the brain and chest revealed that the patient had suffered multiple pulmonary embolisms (►fig. a) and multiple thromboembolic strokes of which the largest was in the right posterior hemisphere (►fig. b). due to repetitive episodes of sinus node arrest, a permanent pacemaker was consecutively implanted. twenty-four hours after pacemaker implantation, the patient developed a fatal hemorrhagic shock due to a massive pulmonary bleeding. autopsy confirmed a severe form of sars-cov- induced ards (►fig. a). of note, total lung weight was kg. immunohistochemistry revealed local overexpression of il- (►fig. b) and mcp- (►fig. c) in pulmonary macrophages and alveolar epithelial cells type ii. furthermore, arterial endothelial damage, necrosis, fibrinous exsudation, and inflammatory infiltrates of the intimal layer were present, that is, in the left carotid artery (►fig. c). atypical locations of thrombus formation included a pulmonary vein of the right lung (►fig. d) and the right atrial appendage. histologically, not only subendothelial vascular walls but also atrial walls were invaded by inflammatory cells. interestingly, il- overexpression could be found within vascular thrombi, adherent endothelial cells, and fibroblasts (►fig. a). in the right atrium signs of inflammatory microangiopathy ("small vessel disease," ►fig. b) in conjunction with mild lymphocytic myocarditis and early myocardial necroses were present (►fig. c). interestingly, as a possible cause for af and sinus node dysfunction, histological examination also revealed that ganglionated right atrial plexi were infiltrated by lymphocytes and virus-infected ganglial cells could be observed (►fig. d). in the kidneys a glomerulonephritis with cytopathogenic effect of the podocytes, tubular epithelial necroses with cytopathogenic effect of tubular cells (►fig. a, b) and interstitial nephritis could also be detected (►fig. c). furthermore, involvement of the liver was also shown by overexpression of mcp- in kupffer's cells (►fig. d). in summary, the present case shows that severe covid- induces crs associated with ards, acute kidney failure, liver pathologies, vascular intimal inflammation, pulmonary arterial, and venous thromboses and an inflammatory atrial cardiomyopathy. in particular, the presence of unusual clot formation in the right atrial appendage, but also loosely detached clots within the pulmonary venous system are novel findings, since the latter might be a source of systemic stroke in covid- patients. of note, the venous clots could not be detected by conventional contrast ct scans, which revealed the presence of embolisms in the pulmonary artery in the presented patient. in covid- patients with ards, there are inflammatory infiltrates of alveolar and interstitial tissue, increased vascular permeability, as well as microcirculatory flow abnormalities, due to thrombus formation within the capillaries. ards appears to occur in to % of covid- patients. a recent, to date only on preprint servers and not yet peer reviewed large scale study with a genome-wide association analysis including , patients and , , single-nucleotide polymorphisms identified blood group a rhesus factor positive, the blood group of our patient, as a risk marker for respiratory failure in covid- patients. ellinghaus et al also found a protective effect for blood group o. increased activation of the clotting system appears as one hallmark of covid- . there is growing evidence for an impact of the activated coagulation factor x (fxa) in inflammatory lung diseases. a study investigated the effects of fxa on epithelial lung cells (a cell line). of note, fxa increases expression of cytokines in alveolar epithelial cells, which can be prevented by an inhibitor of protease-activated receptor , vorapaxar. interestingly, the presented patient developed arterial and venous pulmonary microthrombi in the circulatory tree and pulmonary bleeding due to increased capillary permeability. these venous and arterial thrombotic vascular occlusions in the lungs were found despite the constant use of effective heparin iv in the current case. further studies are warranted to assess the effect of fxa inhibitors to prevent clot formation in the lungs of covid- patients. viral infections, such as sars-cov- , may induce systemic inflammatory pathways. activation of host immune systems can cause activation of the plasmatic clotting system resulting in thrombogenesis called thromboinflammation or immunothrombosis. , importantly thrombotic complications have been described in to % of covid- cases. the clotting system can be activated by multiple procoagulant pathways. activated platelets, mast cells, and tissue factor or fxii may induce the intrinsic coagulation pathway. cytokines may cause endothelial injury with endothelial and intimal necrosis and expression of adhesion molecules, which might later on be associated with thrombocytopenia. , subsequent decline in clotting factors occurs with enhanced fibrinolysis during severe infections, which is also characterized by elevated ddimers. activation of the clotting system with decline of clotting factors and thrombocytopenia has been described to occur in patients in later stages of covid- . , massive systemic inflammation has been described in patients with sars-cov- infections. this cytokine release syndrome (crs) is characterized by elevated levels of il- , increased crp, ferritin, and elevated fibrinogen. a report of covid- patients in china found elevated plasma concentrations of inflammatory markers in particular in patients with severe infections. in covid- , elevated d-dimer levels have been associated with thromboembolism and worse prognosis. [ ] [ ] [ ] tang et al showed elevated fibrinogen levels. another study found elevation of fibrinogen, d dimer, and il- levels in patients with covid- -induced ards. in covid- patients, . % of nonsurvivors and . % survivors met the criteria of disseminated intravascular coagulation. initial results have described antiphospholipid antibodies as a cause of coagulopathy in some patients. unlike other rna viruses inducing hemorrhagic manifestations (hemorrhagic fever viruses), sars-cov- has not been reported to result in significant bleeding. however, the present case showed fatal diffuse pulmonary bleeding, which is one of the first descriptions that covid- might cause substantial hemorrhagic manifestations besides thrombogenesis in arteries, veins and as in our case in the heart. recent reports have shown the occurrence of an "endotheliopathy," which contributes to microcirculatory changes in sars-cov- infections. the receptor for viral adhesion is the ace- receptor, causing inflammatory cell infiltration, endothelial cell apoptosis, and microvascular prothrombotic effects. the ace receptors are expressed in different organs like lung, heart, kidneys, and endothelial cells. thus, sars-cov- can effect endothelial cells in many different organs via ace binding. this finding is supported by the present case because we found a generalized inflammation of the vascular endothelium but also the vascular intima causing endothelial shedding, thrombus formation and diffuse bleeding, particularly in the lungs. recent reports suggest that viral inclusions within endothelial cells and sequestered mononuclear and polymorphonuclear cellular infiltration might induce endothelial apoptosis. nevertheless, crs has been clearly described to cause massive endothelial dysfunction and microcirculatory flow abnormalities associated with multiple clots within the capillaries. as a result, microcirculatory dysfunction in solid organ may occur causing organ failure in patients with covid- . in the present case, we can clearly show that the intima of the carotid arteries is substantially invaded by inflammatory cells causing necrosis of the intima and endothelial denudation. of note, we can show overexpression of cytokines in areas of vascular necrosis and thrombosis. thus, the vascular alterations are much more complex than isolated endothellopathy. furthermore, we can show for the very first time that the atrial tissue of the right atrium is affected by the systemic inflammatory process as well. in the present case, we can show that covid- can induce the occurrences of ards, which was associated with pulmonary embolism, as well as thrombogenesis, in pulmonary veins and the right atrial appendage. thus, further studies are warranted to assess the use of antiplatelet therapy and/or oral anticoagulant therapy in patients with this condition to prevent organ ischemia. the term "atrial cardiomyopathy" has been introduced by a worldwide consensus document in the year . inflammatory changes of atrial tissue have been described in the presence of various form of myocarditis or toxic agents. here, we can describe for the first time that covid- induces an inflammatory atrial cardiomyopathy that caused sinus node dysfunction and af. in the present case, it remains unclear if af was causally related to the occurrence of stroke, since severe changes at the endothelium could be documented in the carotid artery and thromboses were also found in the pulmonary veins and the right atrial appendage. in contrast to the significant atrial alterations, histological exam of left ventricular tissue showed only mild subendothelial scarring without significant lymphocytic infiltration. accordingly, left ventricular function was normal throughout the course of hospitalization monitored by echocardiography. studies have recently described mild lymphocytic myocarditis and signs of epicarditis in the ventricles of covid- patients. to our knowledge, however, the manifestation of covid- in cardiac ganglionated plexi with clinical manifestation of sick sinus syndrome has not been described before. it remains unclear at this point if parts of right atrial clots may have contributed to embolic events in the pulmonary arteries. several reports have shown an increased rate of pulmonary thromboembolic events, stroke, and systemic embolism in covid- . neurologic manifestations might occur in up to %. these events appear to be related to activation of the plasmatic clotting system, platelet activation, and vascular intimal dysfunction or endothelial denudation causing local thrombus formation and organ ischemia. the present case further suggests that af and the development of pulmonary vein thrombosis might also be additional factors that may contribute to the development of stroke in covid- patients. there are rare reports on patients with pulmonary arteriovenous shunts, which might become clinically apparent by repetitive cerebral strokes. thus, the pulmonary venous system might be the source of thrombus formation with cerebral clot embolization. the present case also shows that covid- -induced ards is associated with massive clotting in the pulmonary microcirculation. in addition, clot formation may also occur in pulmonary veins, and therefore, pulmonary venous clots might be a source for systemic embolism and stroke in covid- . in the lack of an effective vaccine for preventing severe medical conditions associated with sars-cov- infections (►fig. ), several novel therapeutic approaches have been proposed, encompassing antivirals, antimalarials, and immunomodulators that have shown activity against sars-cov- . , in particular, hydroxychloroquine, remdesivir, interferon β- b, lopinavir-ritonavir, ribavirin, favipiravir, arbidol, tocilizumab, and bevacizumab have been investigated. mostly, however, these therapies have been evaluated in single cases or small-scale studies. remdesivir (gilead science), a nucleotide analogue prodrug that inhibits viral rna polymerases, was originally evaluated for treatment in ebola virus disease, but it has also shown in vitro activity against sars-cov- . preliminary data show that remdesivir may be beneficial in the early phase of sars-cov- infection. hung et al have recently evaluated a combined antiviral and imunomodulator therapy with interferon β- b, lopinavir-ritonavir, and ribavirin in a multicenter, open label, randomized phase-iib trial in covid- patients. the authors conclude that early treatment with the triple combination therapy may successfully reduce viral shedding and hence hospitalization duration. zhagn et al reported on successfully treating a severely ill covid- patient with dose adjustment methylprednisolone according to inflammation parameters and t-cell count. in our case, however, despite early initiation of corticosteroid therapy, the patient developed a severe form of crs with highly elevated il- levels. early reports show that tocilizumab, an il- inhibitor, may be beneficial in this patient population. [ ] [ ] [ ] furthermore, due to the observed alterations at the arterial, venous, and atrial endothelium further studies are warranted to assess the optimal anticoagulative strategy including different anticoagulants and potential combinations of anticoagulants with antiplatelet drugs. covid- is associated with development of crs, which contributes to fatal damage of solid organs. massively increased il- levels and mcp- appear a systemic blood marker of crs. in addition to covid- -induced ards, crs might be associated with pulmonary artery, as well as vein thromboses, atrial fibrillation, sinus node dysfunction, right atrial clot formation, and inflammatory invasion of autonomic atrial nerve ganglia. furthermore, hepatitis and glomerulonephritis might occur at a very early stage of the disease leading to acute organ failure within days of covid- (►fig. ). studies are warranted to examine, if therapeutic agents against crs-like il- receptor antagonist tocilizumab and/or anticoagulants plus antiplatelet therapy are useful to treat patients with severe covid- . current concepts in the diagnosis and management of cytokine release syndrome cytokine release from human peripheral blood leucocytes incubated with endotoxin with and without prior infection with influenza virus: relevance to the sudden infant death syndrome porcine reproductive and respiratory syndrome virus infection triggers hmgb release to promote inflammatory cytokine production covid- : a new virus, but a familiar receptor and cytokine release syndrome cytokine release syndrome in severe covid- cytokine release syndrome in severe covid- : interleukin- receptor antagonist tocilizumab may be the key to reduce mortality postmortem examination of patients with covid- ecmo for ards due to covid- the abo blood group locus and a chromosome gene cluster associate with sars cov- respiratory failure in an italian-spanish genome-wide association analysis coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mers-cov and lessons from the past the procoagulant pattern of patients with covid- acute respiratory distress syndrome activated clotting factor x mediates mitochondrial alterations and inflammatory responses via protease-activated receptor signaling in alveolar epithelial cells will complement inhibition be the new target in treating covid- -related systemic thrombosis? immunohaemostasis: a new view on haemostasis during sepsis thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up polyphosphate modulates blood coagulation and fibrinolysis inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis derangement of the endothelial glycocalyx in sepsis abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy clinical characteristics and outcomes of older patients with coronavirus disease a single-centered, retrospective study clinical features of patients infected with novel coronavirus in wuhan, china levi msubcommittee on disseminated intravascular coagulation. differential diagnoses for sepsis-induced disseminated intravascular coagulation: communication from the ssc of the isth how i treat disseminated intravascular coagulation causes of elevated ddimer in patients admitted to a large urban emergency department coagulopathy and antiphospholipid antibodies in patients with covid- viral hemorrhagic fever-a vascular disease? endothelial cell infection and endotheliitis in covid- covid- and its implications for thrombosis and anticoagulation document reviewers. ehra/hrs/aphrs/solaece expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication cardiac involvement in a patient with coronavirus disease (covid- ) neurologic manifestations of hospitalized patients with coronavirus disease pulmonary arteriovenous malformations: endovascular therapy covid- pandemic: an overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics cardiovascular considerations in treating patients with coronavirus disease (covid- ) compassionate use of remdesivir for patients with severe covid- triple combination of interferon beta- b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with covid- : an open-label, randomised, phase trial dynamic inflammatory response in a critically ill covid- patient treated with corticosteroids tocilizumab in severe covid- pneumonia and concomitant cytokine release syndrome successful treatment of cytokine release syndrome with il- blockade in a patient transitioning from immune-checkpoint to mek/braf inhibition: a case report and review of literature tocilizumab for the treatment of severe coronavirus disease key: cord- -nupi f authors: villar, jesús; confalonieri, marco; pastores, stephen m.; meduri, g. umberto title: rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by coronavirus disease date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: nupi f nan between % and % ( ) ( ) ( ) . ards may require weeks of mechanical ventilation (mv) and is associated with an unacceptably high mortality rate. worldwide, thousands of patients are denied lifesaving support for lack of mechanical ventilators. this is unprecedented global emergency without a workable solution. thus, any intervention directed at decreasing duration of mv and mortality could have a great impact on public health and national security. corticosteroids have been off patent for greater than years, they are cheap and globally equitable. since the first clinical description of ards ( ) , corticosteroids are the most broadly used medication specifically targeted at treatment. translational research has established a strong association between dysregulated systemic inflammation and progression (maladaptive repair) or delayed resolution of ards. in patients with ards, glucocorticoid receptor-mediated down-regulation of systemic and pulmonary inflammation is essential to restore tissue homeostasis and accelerate resolution of diffuse alveolar damage and extrapulmonary organ dysfunction. this can be significantly enhanced with prolonged low-to-moderate dose corticosteroid treatment (cst) ( ) . the recent publication of a large confirmatory trial ( ) provides stronger evidence that prolonged low-to-moderate dose cst is effective and safe for nonviral ards (mostly caused by bacterial pneumonia and sepsis). in , the corticosteroid guideline task force of the society of critical care medicine (sccm) and the european society of intensive care medicine (esicm) released guidelines for cst in critically ill patients including those with ards ( ) . the analysis to support the task force's recommendations was limited to nine randomized controlled trials (rcts) that investigated methylprednisolone (n = ) ( ) and hydrocortisone (n = ) treatment in ards for a duration of at least days. the task force found moderate quality/certainty of evidence for a reduction in the duration of mv (mean difference, . d; % ci, . - . d) and improved www.ccejournal.org • volume • e survival (relative risk, . ; % ci, . - . ) and therefore made a conditional recommendation for methylprednisolone treatment ( ) . the high benefit/risk (therapeutic index) associated with the intervention supported their recommendation. except for transient hyperglycemia (mostly within the hr following an initial bolus), cst was not associated with increased risk for neuromuscular weakness, gastrointestinal bleeding, or nosocomial infections (very low certainty evidence) ( ) . importantly, the survival benefit observed during hospitalization persisted after hospital discharge with follow-up observations extending up to days ( , , ) , months ( ), months ( ), or year (limit of measurement) ( ) . however, most trials were less than patients and performed before the implementation of lung-protective mv. a larger confirmatory rct in patients receiving low tidal volume (ltv) ventilation was missing. clinical investigators in spain recently completed a large confirmatory rct (efficacy study of dexamethasone to treat the acute respiratory distress syndrome [dexa-ards]) enrolling patients with moderate-to-severe ards and receiving ltv ventilation ( ) . early administration of dexamethasone for days led to a significant reduction in duration of mv (mean difference, . d; % cis, . - . d) and all-cause mortality (mean difference, . %; % cis, . - . %), without increasing rate of complications. this latest rct provided consistent evidence similar to what was observed in the previous meta-analyses. the aggregate data from rcts (n = , ) clearly demonstrate that cst is associated with a sizable reduction in duration of mv and hospital mortality. figures and show the impact of prolonged cst on reduction of ventilator dependence and hospital mortality (number needed to save one life is seven). canadian investigators are working on an updated meta-analysis. the dysregulated inflammation and coagulation observed in covid- ( ) is similar to that of multifactorial medical ards, where ample evidence has demonstrated the ability of prolonged cst to down-regulate inflammation-coagulation-fibroproliferation and accelerate disease resolution ( ) . additionally, the ct findings of ground-glass opacities ( ) and the histological findings of hyaline membrane and inflammatory exudates ( ) are compatible with corticosteroid-responsive inflammatory lung disease. a recent study ( ) showed that covid- is associated with a cytokine elevation profile that is reminiscent of secondary hemophagocytic lymphohistiocytosis, a condition responsive to cst. the who statement ( ) of not recommending the routine use of corticosteroids for treatment of viral pneumonia outside clinical trials relies on incomplete evidence. if the evidence favors the use of corticosteroids in nonviral ards, why does the who not recommend cst for covid- -associated ards? there are limitations on the evidence approach used by who to reach a categorical decision with potentially serious public health repercussions. the who's brief argument to support the recommendation is mainly based on the risk of decreased viral clearance reported in one observational study ( ) and inconclusive evidence from retrospective observational studies without a predesigned study protocol and subjected to cofounding (imbalances in baseline characteristics and postbaseline time-dependent patient differences that influence the decision to prescribe corticosteroids), and hidden bias ( ) . a more recent high-quality meta-analysis found a high correlation between cst and potential confounders for measured outcomes, such as disease severity and comorbid illnesses. therefore, confounding by indication is likely to be a significant bias in studies which only provided unadjusted effect estimates. additionally, time to hospitalization, antiviral use, presence of respiratory failure prior to corticosteroids, and the rationale for corticosteroid use or treatment regimen were sparsely reported across studies ( ) . what "kills" covid- patients is dysregulated systemic inflammation. there is no evidence linking delayed viral clearance to worsened outcome in critically ill covid- patients, and it is unlikely that it would have a greater negative impact than the host own "cytokine storm" ( ) . in a recent commentary regarding the use of corticosteroids in contemporary severe viral epidemics (such as severe acute respiratory syndrome coronavirus, middle east respiratory syndrome coronavirus, or influenza), coauthored by a member of the who panel on clinical management for novel coronavirus ( -ncov), it states that there are "conclusive data" to expect that patients with covid- ards will not benefit from corticosteroids ( ) . this interpretation is biased and without evidence-based support ( ) . first, their "conclusive" statement rested on only four small studies without including results from another publications ( ) . six of the studies in the referenced meta-analysis did not describe the cst used ( ) . second, they ignored the positive findings of two large studies ( , patients with severe acute respiratory syndrome [sars] [ ] and , patients with influenza h n pneumonia [ ] ) that evaluated the impact of time, dose, and duration of cst and reported a significant reduction in mortality with dosage and duration similar to the one recommended by sccm and esicm task force ( ) . in the sars study, after adjustment for possible confounders, cst was day -to icu discharge: infusion is obtained by adding the daily dosage to cc of normal saline and run at cc/hr. if necessary, infusion can be changed to bolus every hr ( / daily dose) or in the last d very hr ( / daily dose). five days after the patient can ingest medications, methylprednisolone is administered orally in one single daily equivalent dose. enteral absorption of methylprednisolone, and likely other corticosteroids, is compromised for days after extubation. if between days to , the patient is extubated, the patient is advanced to day of drug therapy and tapered according to schedule. monitor anti-inflammatory response with daily measurements of c-reactive protein levels in addition to severity scores of acute respiratory distress syndrome and multiple organ dysfunction. rapid tapering can be associated with reconstituted systemic inflammation in the presence of suppressed adrenal function with worsening lung physiology and increased mortality risk ( ) . urgent reinstitution of corticosteroid treatment is necessary to be followed after improvement by slow tapering. b, dexamethasone treatment. patients in the dexamethasone group received an iv dose of mg once daily from day to day , which was reduced to mg once daily from day to day . treatment was maintained for a maximum of d after randomization or until extubation (if occurring before day ). an updated protocol mandates to give dexamethasone for a maximum of d after randomization, independently of the intubation status. this protocol does not mandate further tapering for few days to minimize the risk for reconstituted systemic inflammation. safe and decreased the risk for death by % (hazard ratio [hr], . ; % ci, . - . ) ( ) . in the h n study, , patients received corticosteroids and , did not receive it. subgroup analysis among patients with pao /fio less than mm hg ( vs mm hg), low-to-moderate-dose cst significantly reduced both -day mortality (adjusted hr [ahr], . ; % ci, . - . ) and -day mortality (ahr, . ; % ci, . - . ) ( ) . early evidence from few observational studies on covid- ards is available. in a recent report in covid- patients with ards from a single center in wuhan, china, the administration of methylprednisolone (dosage similar to protocol recommended by the sccm and esicm task force [ ] ) was associated with reduced risk of death (hr, . ; % ci, . - . ; p = . ) ( ). in a letter to lancet "on the use of corticosteroids for -ncov pneumonia, " shang et al ( ) provide a compelling argument from intensivists in the frontline of the outbreak in china that deserves consideration. the letter includes a summary of the expert consensus statement on the use of corticosteroids in -ncov pneumonia from the chinese thoracic society. finally, the italian national institute for the infectious diseases "l. spallanzani" released updated recommendations for covid- clinical management that included the use of methylprednisolone or dexamethasone for covid- -associated ards ( ) . in conclusion, this is a critical moment for the world, in which even industrially advanced countries have rapidly reached icu saturation and intensivists are forced to make difficult ethical decisions that are uncommon outside war zones. although there is a wide divergence of opinion in the literature on whether corticosteroids should be used in patients with covid- , the two largest studies on h n and sars (n = , ) ( , ) lend support to its use. however, the lack of sufficient evidence is not tantamount with negating the plausible efficacy of corticosteroids in covid- -associated ards. the stronger evidence for nonviral ards, the early reports from china, and the recommendations from the frontlines of china and italy should be considered. inconclusive clinical evidence should not be a reason for abandoning cst in covid- -associated ards. rcts are in progress (nct , nct , nct , and nct ) and results will not be available for months. until then, there is no justification based on available evidence and professional ethics to categorically deny the use of cst in severe life-threatening "cytokine storm" associated with covid- in hospitals not involved in a rct. figure shows the protocols most commonly used in patients with nonviral ards rcts. this material is the result of work supported with the resources and use of facilities at the memphis va medical center. dr. villar is funded by grants from the instituto de salud carlos iii, madrid, spain (cb / / , pi / ), the european regional development's funds, and the asociación científica pulmón y ventilación mecánica. canary islands, spain. dr. meduri received support for article research from the veteran administration. the remaining authors have disclosed that they do not have any potential conflicts of interest. epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan, china risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china idiopathic pulmonary fibrosis in adult respiratory distress syndrome. diagnosis and treatment guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (circi) in critically ill patients (part i): society of critical care medicine (sccm) and european society of intensive care medicine (esicm) ards network: dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network: efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome methylprednisolone infusion in early severe ards: results of a randomized controlled trial covid- : consider cytokine storm syndromes and immunosuppression activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy severe covid- pneumonia: assessing inflammation burden with volume-rendered chest ct pathological findings of covid- associated with acute respiratory distress syndrome coronavirus disease (covid- ): situation report- . available at corticosteroid therapy for critically ill patients with the middle east respiratory syndrome the influence of corticosteroid treatment on the outcome of influenza a(h n pdm )-related critical illness corticosteroids as adjunctive therapy in the treatment of influenza: an updated cochrane systematic review and meta-analysis clinical evidence does not support corticosteroid treatment for -ncov lung injury on the use of corticosteroids for -ncov pneumonia the effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis clinical recommendations from an observational study on mers: glucocorticoids was benefit in treating sars patients national influenza a(h n )pdm clinical investigation group of china: effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza a(h n )pdm viral pneumonia national institute for the infectious diseases "l. spallanzani", irccs. recommendations for covid- clinical management treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience an exploratory reanalysis of the randomized trial on efficacy of corticosteroids as rescue therapy for the late phase of acute respiratory distress syndrome key: cord- -q igdvq authors: ryan, donal; frohlich, stephen; mcloughlin, paul title: pulmonary vascular dysfunction in ards date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: q igdvq acute respiratory distress syndrome (ards) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension (ph). multiple factors may contribute to the development of ph in this setting. in this review, we report the results of a systematic search of the available peer-reviewed literature for papers that measured indices of pulmonary haemodynamics in patients with ards and reported on mortality in the period to . there were marked differences between studies, with some reporting strong associations between elevated pulmonary arterial pressure or elevated pulmonary vascular resistance and mortality, whereas others found no such association. in order to discuss the potential reasons for these discrepancies, we review the physiological concepts underlying the measurement of pulmonary haemodynamics and highlight key differences between the concepts of resistance in the pulmonary and systemic circulations. we consider the factors that influence pulmonary arterial pressure, both in normal lungs and in the presence of ards, including the important effects of mechanical ventilation. pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient (tpg) depend not alone on the intrinsic properties of the pulmonary vascular bed but are also strongly influenced by cardiac output, airway pressures and lung volumes. the great variability in management strategies within and between studies means that no unified analysis of these papers was possible. uniquely, bull et al. (am j respir crit care med : – , ) have recently reported that elevated pulmonary vascular resistance (pvr) and tpg were independently associated with increased mortality in ards, in a large trial with protocol-defined management strategies and using lung-protective ventilation. we then considered the existing literature to determine whether the relationship between pvr/tpg and outcome might be causal. although we could identify potential mechanisms for such a link, the existing evidence does not allow firm conclusions to be drawn. nonetheless, abnormally elevated pvr/tpg may provide a useful index of disease severity and progression. further studies are required to understand the role and importance of pulmonary vascular dysfunction in ards in the era of lung-protective ventilation. acute respiratory distress syndrome (ards) is characterised by diffuse alveolar damage and is frequently complicated by pulmonary hypertension [ ] . the single biggest advance in the management of ards has been the institution of lung protective ventilation (ardsnet) [ ] . however, mortality remains unacceptably high, ranging from the % to % reported in randomised controlled trials up to % in published observational studies [ , ] . intensivists and researchers have long been aware of the occurrence of pulmonary hypertension and cor pulmonale in ards. however, there has been uncertainty about the underlying pathophysiology and the link between the degree of pulmonary hypertension and outcome from ards. is pulmonary hypertension simply an indicator of the severity of lung injury or is it part of the underlying pathophysiological process contributing to the development of ards? recent studies have pointed to the importance of pulmonary vascular dysfunction (pvd) in predicting mortality from ards [ ] , but the exact mechanism by which pvd and mortality are linked is not known. the focus of this review is to examine the nature of the relationship between pulmonary hypertension/pvd and mortality in ards. studies were identified after a literature search using key terms (ards or acute respiratory distress or ali or acute lung injury) together with any of the following: pulmonary haemodynamics, pulmonary artery pressure, pulmonary vascular resistance, pulmonary vascular dysfunction, right ventricle, right ventricular failure, acute cor pulmonale, or pulmonary artery catheter. the references of articles found in this manner were also examined for similar studies. manuscripts that reported a relationship between pulmonary haemodynamics and mortality in ards/ali were included. in addition, papers that reported a relationship between right ventricular failure/right ventricular dysfunction and outcome were included. we have included definitions of commonly used terms in this article in table . many indices of pulmonary haemodynamics have been measured in patients with ards. pulmonary arterial pressure, wedge pressure and pulmonary vascular resistance have all been reported as well as measures of right ventricular function. the two most commonly reported measures are pulmonary arterial pressure and pulmonary vascular resistance. a number of studies (table ) have documented the changes in pulmonary haemodynamic measurements in patients with ards. all measurements were derived from the use of pulmonary artery catheter except for the study by cepkova [ ] , where pa systolic pressures were estimated using echo. some of these studies are small, and the majority were conducted before the widespread introduction of low tidal volume ventilation. nevertheless, certain observations can be made from the data. mild to moderate elevations in mean pulmonary artery pressure (mpap) are seen in most patients with ards [ , ] . squara et al. found moderate elevation in mean pulmonary pressure in patients, h after the diagnosis of ards [ ] . patients with worse pao /fio ratios had higher mpap than those with better oxygenation ( . ± . vs. . ± . mmhg, p = . ). systolic pulmonary arterial pressure (pap) was deemed to be of 'independent and sustained prognostic significance during the course of ards'. in a later study, osman et al. also found mpap to be an independent predictor of mortality in a multivariate model [ ] . other studies either found pap not to be predictive of death or else did not specifically examine for a relationship [ , [ ] [ ] [ ] [ ] ] . in patients with severe ards, beiderlinden et al. [ ] found an incidence of pulmonary hypertension of . % but did not find any association between pulmonary hypertension and death. hemilla et al., in a review of patients with severe ards who subsequently received ecmo, found evidence of moderate pulmonary hypertension using pulmonary artery catheter data acquired prior to the institution of extracorporeal support [ ] . again, direct measurements of pap were not identified as being of prognostic significance. pulmonary vascular resistance (pvr) is known to be elevated in patients with ards (tables and ). zapol and jones were the first to document that raised pulmonary vascular resistance was a common finding in patients with severe respiratory failure [ ] . they observed that pulmonary vascular resistance tended to fall in survivors but remained elevated in those who died. this is the only study to report pulmonary haemodynamic indices longitudinally. zapol and jones subsequently documented a threefold elevation in pvr in patients with ards [ ] . these in a secondary analysis of the haemodynamic data from the fluid and catheter treatment (factt) trial of patients with ards who were managed with a pulmonary artery catheter, bull et al. showed that the transpulmonary gradient (mpap-pulmonary arterial occlusion pressure (paop)) and the pulmonary vascular resistance index (mpap-paop/ci) were the only pulmonary haemodynamic indices that showed a significant difference between those who died and those who survived. multivariate analyses showed them to be independent predictors of mortality in ards [ ] . they used the term 'pulmonary vascular dysfunction' to describe these two variables. covariates in their multivariate analyses included sex, race, age, apache ii score, the presence of shock at baseline, level of positive end-expiratory pressure (peep), the pao :fio ratio and fluid treatment strategy. they did not find any difference in p:f ratios, pasp, padp, mpap, paop or cardiac index between those who survived with ards and those who did not. the pplat and peep levels were not different among the groups. it is worth noting that % of the screened patients were excluded because they had a pulmonary artery catheter in place at the time of randomization and that % of the enrolled patients showed a paop > mmhg at enrollment, therefore not meeting the abc definition of ards. this may have explained why the pap-paop gradient may have been significant, when pap was not. there are marked differences among these studies, with some showing that pulmonary arterial pressure is independently associated with mortality, and in others' findings, it is not. similarly, increased pvr was found to be a predictor of adverse outcome in some studies and not in others. before considering these discrepancies in more detail, it is helpful to examine the relationship between pap and pvr in healthy subjects and to look at the pathophysiology of elevated pulmonary vascular resistance. there is a complex, non-linear relationship between pulmonary arterial pressure and pulmonary vascular resistance in normal, non-diseased lungs. in the lungs, the pvr is conventionally calculated as follows: where pvr = pulmonary vascular resistance, mpap = mean pulmonary arterial pressure, lap = left atrial pressure and co = cardiac output. in the systemic circulation, an ohmic relationship between driving pressure and flow through the blood vessel provides a reasonable approximation ( figure a ). in such a system, the plot of pressure against flow is a straight line passing through the origin and the resistance to flow is well characterised as the ratio of the arterial pressure to the flow (cardiac output) at all points along the pressure flow line. in contrast, the blood flow through the lungs is not well described by a linear relationship passing through the origin but by a curvilinear plot that has a positive intercept on the pressure axis ( figure b ). this curvilinear relationship arises because of the marked distensibility of the pulmonary vasculature. an increase in pulmonary arterial pressure results in an increased flow due both to the higher driving pressure and the distension of the vessels so that the diameter of the vascular lumen is increased. thus, increases in pulmonary arterial pressure have a disproportionate effect on pulmonary blood flow. as a consequence, a reduction in cardiac output leads to an increase in the ratio of the pressure drop across the pulmonary circulation (pap-lap) to flow, even though there is no change in vasomotor tone ( figure b ). blood flow through the lungs also depends on the transmural pressure in the pulmonary vessels (pressure within lumen minus airway pressure) to a much greater extent than in systemic vessels. airway pressure can have a marked effect on pulmonary blood flow, as originally determined by west [ ] . lung volume has an important effect on pvr which is independent of vascular transmural pressure. whittenberger et al. [ ] described how low (near residual volume) lung volumes were associated with a slight elevation in pvr (extra-alveolar vessels are narrowed) and high lung volumes (near total lung capacity) were associated with the highest pvr (alveolar capillaries are stretched). this contributes to in the systemic circulation, the mean pressure (p)-flow (q) plot is well described as a linear (ohmic) relationship. the two points identified (open circles) show a normal cardiac output and a reduced cardiac output, respectively, in the hypertensive condition. at each of these cardiac outputs, it is clear that the ratio of p to q is the same and therefore can be used to easily characterise the resistance of the systemic circulation. (b) in the pulmonary circulation, the plot of mean pressure against flow is curvilinear with an intercept on the pressure axis that is equal to left atrial pressure. the blue curve represents a normal pressure flow curve (healthy lung), while the red curve represents pressure flow curve in the presence of hypoxic pulmonary hypertension. the two points identified (open circles) show a normal cardiac output and a reduced cardiac output, respectively, in the hypertensive condition. at each cardiac output the pulmonary vascular resistance, (ppa-lap)/q, is illustrated as the slope of the straight dashed line. even though the two points are each on the same pressure flow curve, the calculated pulmonary vascular resistance is different at the different cardiac outputs. psa, systemic arterial pressure (mean); ppa, pulmonary arterial pressure (mean); q, cardiac output (flow). a marked elevation in pulmonary vascular resistance, even if the vascular transmural pressure is kept constant [ ] . pulmonary arterial pressure is not only affected by changes in pulmonary vascular resistance but also changes in right ventricular (rv) output. rv output, in turn, is affected by factors that are extrinsic to the lung. it is evident, even from this brief summary, that pulmonary arterial pressure and pulmonary vascular resistance cannot be used as interchangeable measures of the state of pulmonary haemodynamics in patients with ards. for a comprehensive review of this problem of interpreting changes in pulmonary vascular resistance, the reader is referred to the work of vesprille and naeije [ , ] . many of the candidate mechanisms that explain an elevation in pvr in ards have been recently reviewed [ ] . we will highlight the pathophysiology of some of these mechanisms. bradford and dean were among the first to recognise that hypoxia resulted in sustained elevations in pulmonary arterial pressure [ ] . the mechanisms that underlie hypoxic pulmonary vasoconstriction (hpv) are complex and primarily relate to intracellular increases in calcium concentration and rho kinase-mediated sensitisation in pulmonary arterial smooth muscle cells [ ] [ ] [ ] [ ] . hpv causes an increase in pvr to % to % of baseline when healthy volunteers are exposed to hypoxia (po mmhg) [ ] . marshall et al. have shown that when hpv is acutely reduced in ards by the administration of % inspired oxygen, pulmonary arterial pressure was reduced by the order of % to % from its peak [ ] . this may be an underestimate of the extent of hpv in the lung, as it does not take into account the contribution of hpv in non-ventilated lung units. to assess the contribution of non-ventilated lung units to hpv, benzing et al. took a group of patients with severe ards treated by veno-venous extracorporeal lung assist and ventilated them with an fio of . for a period of min prior to taking measurements (thereby minimising hpv in ventilated lung units). they then manipulated the mixed venous partial pressure of oxygen (pvo ) by adjusting the proportion of blood flow diverted through the oxygenator in order to assess hpv in non-ventilated regions. when pvo was high ( . ± . mmhg), the total lung pvr was (± ) dyne.s.cm − .m and increased by . % to (± ) dyne.s.cm − .m when pvo was reduced to low values ( . ± . mmhg) [ ] , clearly demonstrating that hpv in non-ventilated lung units contributes significantly to the increase in pulmonary vascular resistance in ards. in addition to the influence of hpv, disruption of the endothelium in ards results in an alteration in the normal balance of mediators of vasodilation (no, prostacyclin) and vasoconstriction (thromboxane, leukotrienes, endothelin, serotonin, angiotensin ii) favouring vasoconstriction. these factors have been reviewed recently [ , ] . tomashefski et al., in a landmark post-mortem study of patients with ards, found that patients had evidence of microthrombi. nineteen had macrothrombi in the pulmonary arterial and capillary vessels [ ] . they also found endothelial injury in all stages of ards in all cases on both standard histological preparations and electron microscopy. there is now ample evidence supporting the concept of lung injury causing local, as opposed to systemic, coagulation in ards [ , , ] . tissue factor (tf) is released from endothelial cells that have been injured, in response to a variety of proinflammatory stimuli [ ] . tf is a strong activator of the extrinsic clotting cascade. increased activation of procoagulant processes occurs in the lung in ards and does not result from the systemic activation of coagulation (such as is seen in sepsis) [ , ] . animal data suggest that blockade of the tf-factor viia-factor xa complex may reduce the degree of pulmonary hypertension in ards [ ] . levels of protein c, a natural anticoagulant, are also reduced in ards [ ] while levels of plasminogen activator inhibitor- are increased in ards patients, and both are prognostic of increased mortality in ards [ ] . more recently, biomarkers of coagulation and inflammation have been shown to provide good discrimination for the diagnosis of patients with ards [ , ] , and analysis of sars-cov infection in laboratory models has shown that the delicate balance between coagulation and fibrinolysis is shifted towards fibrin deposition during infection leading to ards [ ] . therapies targeting this pulmonary coagulopathy may also have an anti-inflammatory effect and attenuate the severity of ards [ ] . therefore, ards represents a procoagulant, antifibrinolytic phenotype and results in the local formation of microthrombi, which may, in turn, act to increase the pulmonary vascular resistance by the mechanical obstruction of blood flow. fibroproliferation is a characteristic of the late stage of ards, and is present in approximately % of patients who die of this condition [ ] . it is associated with increased mortality, and the presence of fibrosis on thin cut ct scan has been used to predict outcome in ards [ , ] . in a small post-mortem study of the lungs of patients who had died with 'severe respiratory failure' , zapol et al. demonstrated that there is increasing destruction of the capillary bed as ards progresses, which may contribute to elevations in the pvr of the same patients measured ante-mortem [ ] . many mediators have been linked to the fibroproliferative response, but those that have an association with vascular effects include angiotensin ii and vascular endothelial growth factor (vegf) [ ] [ ] [ ] . tomashefski et al. [ ] noted that there was electron microscopy evidence for extensive vascular remodelling in ards. the intermediate phase was characterised by fibrocellular obliteration of the arteries, veins and even lymphatic vessels. in the late stage, vascular remodelling was associated with distorted, tortuous arteries and veins. these tortuous channels were concentrated in regions of dense or irregular fibrosis. the number of capillaries was reduced, and they were often dilated. muscularisation of the arteries was identified in the intermediate phase and was very marked in the late phase. this mechanical disruption of the course of blood vessels is likely to contribute to the sustained elevation in pvr seen in non-survivors. a key difference between normal lungs and injured lungs in ards is the use of mechanical ventilation in the latter, requiring the application of peep and positive inspiratory plateau pressures. when peep is applied to a diseased lung, the change in pvr is determined by the balance between overdistension of lung units and recruitment of areas with previously low numbers of open alveoli. when the number of open alveoli increases following a recruitment manoeuvre and application of high peep, then pvr may even fall in keeping with whittenberger's-u shaped relationship between pulmonary vascular resistance and lung volume. any increase in ventilated alveolar area may also reduce hpv. canada et al., found that the pulmonary vascular resistance index (pvri) was lowest at cm h o in the normal lung but cm h o had to be applied to the injured lung in order to achieve minimal pvri [ ] . above 'optimal peep' levels, the pvr increased, presumably due to compression of intra-alveolar capillaries by the increased airway pressure resulting in an increase in zone and characteristics [ , ] . there are very few studies which have measured pulmonary vascular resistance in ards patients ventilated with lower tidal volumes, perhaps due to the reduction in the use of the pulmonary artery catheter just as lung-protective ventilation was gaining widespread acceptance [ ] . limitation of plateau pressures has, however, been shown to be associated with lower rates of right ventricular failure than in historical studies [ , ] . the application of higher tidal volume to the patients in these studies was associated with a significant increase in right ventricular afterload [ ] . there is currently no evidence to suggest that one mode of ventilation has more or less effect than any other mode on pulmonary vascular haemodynamics. any effect of the mode of ventilation on pvr is likely to be related to the amount of peep and plateau pressure that is applied. why do the studies of pulmonary haemodynamics report inconsistent relationships with mortality? as is apparent, pvr is directly influenced by factors that are intrinsic to the lung and can be increased by the pathophysiological insults that occur in ards. in contrast, pap is affected both by factors extrinsic to the lung (e.g. rv output preload and contractility) and by factors intrinsic to the lung (pvr). in clinical practice, there is considerable variability in the preload of patients with ards. both volume loading and venous tone have a considerable influence on the amount of venous return reaching the heart. the presence of sepsis and the use of vasopressors will both affect venous tone. likewise, raised intra-thoracic pressure can have a compressive effect on the intra-thoracic veins, including the superior and inferior venae cavae [ ] and limit venous return in patients with ards. sepsis-induced cardiac dysfunction may result in rv impairment in as many as % of patients [ ] . the studies in table have reached different conclusions about the significance of pap and pvr and their relationship to outcome in ards. what might account for these differences? all except one of the studies quoted are observational in nature and did not employ standard patient management protocols. the studies were not designed to answer specific questions about the nature of pulmonary haemodynamics in ards, and the data were drawn from patients who were managed differently in terms of mechanical ventilation (mode and pressures applied), fluid status and vasopressor use, all of which adds to the statistical noise when trying to draw useful conclusions. bull et al.'s data came from patients who all had a standardised approach to ventilator management (in particular the use of low tidal volume ventilation), pulmonary artery catheter data acquisition as well as fluid management. bull et al.'s study, the largest in the modern era of 'protective ventilation' found no association between pap and outcome but showed a highly significant and independent link between two indices of pulmonary vascular dysfunction (mpap-paop and pvri) and mortality. pvr is primarily affected by factors that are intrinsic to the lung, while pap is influenced by both pvr and rv preload and contractility. when the variability in management was controlled for (as in bull et al.'s study), the measured pvr was more likely to have reflected the vascular changes induced by the disease process in ards. this is because the protocol standardised many of the extrinsic factors (airway pressure, tidal volume, fluid loading) that can influence pa pressure independently of changes in pulmonary vascular resistance. importantly, in this wellcontrolled study, indices of elevated pulmonary vascular resistance were found to independently predict greater mortality in ards. this highly significant association between mortality and measures of pulmonary vascular resistance, in a carefully controlled study, raises the question as to whether pvd directly causes increased mortality or is it associated with mortality. there are two potential mechanisms by which an elevation in pvr could cause mortality in ards. either it results in right ventricular failure, with subsequent multi-organ dysfunction or it exacerbates the acute lung injury directly. the right ventricle is more sensitive to acute increases in its afterload than the left ventricle. we know from studies of major pulmonary embolism, that a normal right ventricle cannot acutely generate pulmonary pressures greater than mmhg (mean) and quickly fails in this clinical context [ ] . is the same true for patients with ards? sustained pulmonary hypertension may result in right ventricular failure (rvf) in ards patients [ ] . over the years, the incidence of right ventricular dysfunction (rvd) has declined as improvements in mechanical ventilation have been adopted and lessened the intrathoracic airway pressure in patients with ards [ , ] , but rvd is variably defined and diagnosed among studies which makes comparison difficult. clinically, right ventricular failure has no agreed definition, but criteria (using pulmonary artery catheter data) include pulmonary hypertension associated with an rv cardiac index < . l min − m − and a right atrial pressure > mmhg [ ] . using these criteria, osman et al. found an incidence of right ventricular failure of . % in patients with ards [ ] . the presence of rvf was not associated with death. in bull et al.'s analysis of patients with ards, they reported an incidence of right ventricular failure (rvf) of % (using monchi's definition of right atrial pressure > pulmonary artery occlusion pressure [ , ] ); rvf was not predictive of mortality. the presence of rvf can also be inferred using echocardiographic criteria. acute cor pulmonale (acp) has been defined as the presence of rv dilation (ratio of rv end-diastolic area to left ventricle end-diastolic area > . ) in association with dyskinesia of the interventicular septum in response to an increased afterload [ ] . jardin et al. originally described the two-dimensional echo characteristics in a group of patients with acute respiratory failure, showing that the right ventricular enddiastolic area increased as the pvri (measured using a pac) increased and rv stroke volume declined [ ] . vieillard-baron et al. have demonstrated an incidence of echocardiographic cor pulmonale of % in a study of patients with ards [ , ] . however, acp was found to be reversible in those patients whose ards resolved, and it did not have a negative prognostic significance. similar results were found by cepkova in a study of patients with acute lung injury [ ] . in a retrospective analysis of patients with ards admitted to their unit since , jardin's group found a correlation between increasing levels of plateau pressure and the incidence of acute cor pulmonale [ ] . as measured plateau pressure increased, the incidence of acp rose up to % with plateau pressures of > cm h o. while they also noted an association between the presence of acp and mortality in the overall group, this did not hold true when the airway pressure was aggressively limited, in line with current practice [ ] . vieillard-baron's group [ , , , , ] have suggested that the increases in rv afterload due to elevations in peep and plateau pressure, as well the underlying lung injury, result in rv dysfunction that is sufficient to increase mortality. this reflects what we know of the pathophysiology of pulmonary embolism, but the evidence is not as definitive in ards. the presence of acp has not been consistently demonstrated to be associated with excess mortality in ards in the modern era of protective ventilation. perhaps this is because the authors modified their approach to mechanical ventilation in these studies when acp was recognised, in order to limit the distension of the right ventricle by reducing the airway pressures (peep and plateau) and putting the patient in a prone position [ , ] . recent echocardiographic derived data on right ventricular dysfunction from boissier et al. [ ] suggest that even when tidal volume and plateau pressure are limited in line with best practice, the incidence of acp in ards is still % and is independently associated with mortality in spite of greater use of prone positioning and nitric oxide. lheritier et al. [ ] found a similar incidence of acp ( . %) in moderate to severe ards patients ventilated with a lung protective strategy, but they could not find an association between the presence of acp and outcome. in both studies, the groups with acp had a higher use of nitric oxide and prone positioning compared to those without acp. it is unclear what accounts for the different findings in these studies. the relationship between acp/rvd and outcome in ards is therefore unclear, and it remains to be determined. it is worth asking the question as to whether there is a plausible mechanistic basis that would allow pulmonary vascular dysfunction to worsen ards. high-altitude pulmonary oedema (hape) is a condition that occurs in previously healthy individuals within to days after rapid ascent above altitudes of , to , m [ , ] . while it is not a form of ards, it is a severe form of non-cardiogenic pulmonary oedema, which can develop in susceptible individuals ( % to % of the normal population) in the presence of hypoxia alone [ ] . individuals who develop hape have an increased degree of hpv compared to unaffected members of the population. pulmonary artery pressure at an altitude of , m is about % to % higher in individuals who are prone to hape compared with non-susceptible controls, and this higher pressure precedes oedema formation [ ] . the increase in hpv can also be demonstrated at low altitude in susceptible individuals exposed to a brief hypoxic challenge [ , ] . lowering pulmonary artery pressure during the ascent to high altitude can prevent hape. a non-specific pulmonary vasodilator (nifedipine) [ ] or the phosphodiesterase- -inhibitor tadalafil [ ] reduced the prevalence of pulmonary oedema in hape-susceptible individuals after rapid ascent to , m from % to about %. this suggests that excessive hpv may contribute to the development of acute oedema, possibly by redistributing pulmonary blood flow away from areas with high degrees of hpv to other sections of the lung, with resultant hyper-perfusion, endothelial injury and capillary leak. this causes a secondary inflammation which is clinically indistinguishable from ards [ ] . the finding that a subset of the population is prone to the development of non-cardiogenic pulmonary oedema, as a result of exposure to hypoxia alone, is of relevance to our understanding of ards. ards is characterised by heterogeneous areas of alveolar hypoxia and inappropriate vascular responses to these areas of hypoxia may partially explain the finding that individuals with pulmonary vascular dysfunction have worse outcomes in ards. there is, as of yet, no evidence to support this hypothesis in the general population who present with ards. is pvd a marker of the severity of ards? as patients recover from ards, there is resolution of the pulmonary vascular dysfunction. many of the mechanisms of pvd in ards (the release of multiple vasoactive mediators, vascular remodelling and the formation of vasoocclusive microthrombi) are caused by the disruption of the normal endothelial-inflammation-coagulation pathways. pvd may be a good summative index of vascular damage from these mechanisms. nuckton et al. has previously reported that an increased dead space fraction was associated with increased mortality in ards [ ] , which they postulated might be due to injury to the pulmonary capillaries from inflammation and thrombosis and obstruction of pulmonary blood flow in the extraalveolar pulmonary circulation. there is evidence that extra-pulmonary organ dysfunction in ards is caused by the systemic inflammatory response, which in turn is driven by the initiating pulmonary injury [ ] . if pvd is primarily a downstream result of the activation of the inflammatory-coagulation cascade in the lung, then, the reason it is associated with mortality in ards may be because it reflects the severity of the underlying inflammatory process. this hypothesis may also help to explain why pvd is associated with mortality in wellcontrolled studies of patients with ards whereas right ventricular dysfunction has not been consistently shown to be associated with mortality. ards studies are rarely adequately powered to look at mortality as they do not recruit sufficient numbers of patients to be able to draw valid conclusions. using pvd as an index of disease severity might allow researchers an additional way to stratify the severity of lung injury and to test the efficacy of new treatments for ards by measuring the change in pvd, which is known to improve as the patient recovers from lung injury. in order to develop new treatments for ards, we need better methods for examining their efficacy. using pvd as an endpoint might improve the predictive value of phase ii trials prior to embarking on full scale clinical studies of new treatments. assessment of pulmonary vascular resistance may be possible using non-invasive echocardiographic technology [ ] which would increase the applicability of this approach and may be worth pursuing. pulmonary vascular dysfunction is an independent predictor of mortality in ards. an examination of the physiology of pulmonary haemodynamics in ards helps to explain why it may be a clearer mortality signal, when compared to the inconsistent link between mortality and pulmonary arterial pressure or right ventricular dysfunction. further study is needed to determine precisely the dominant pathways involved in causing pvd in ards. this is an area of research that may yet lead to greater understanding of the complex interplay between the pulmonary circulation, endothelial dysfunction and activation of the inflammatory-coagulation cascades that underlie ards. abbreviations acp: acute cor pulmonale; ards: acute respiratory distress syndrome; co: cardiac output; hpv: hypoxic pulmonary vasoconstriction; lap: left atrial pressure; mpap: mean pulmonary arterial pressure; no: nitric oxide; p:f: ratio of partial pressure of oxygen to fraction of inspired oxygen; pplat: plateau pressure; pac: pulmonary artery catheter; padp: pulmonary arterial diastolic pressure; paop: pulmonary arterial occlusion pressure; pap: pulmonary arterial pressure; pasp: pulmonary arterial systolic pressure; peep: positive end-expiratory pressure; pvd: pulmonary vascular dysfunction; pvr: pulmonary vascular resistance; rv: right ventricle; rvd: right ventricular dysfunction; rvf: right ventricular failure; tpg: transpulmonary gradient. the authors declare that they have no competing interests. authors' contributions dr was responsible for writing, editing and reviewing the majority of the manuscript. sf wrote and reviewed the section on high-altitude pulmonary oedema. pmcl was responsible for the concept for the review, editing and final review of the manuscript. all authors read and approved the final manuscript. the acute respiratory distress syndrome acute respiratory distress syndrome network (ardsnet): ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome incidence and outcomes of acute lung injury has mortality from acute respiratory distress syndrome decreased over time? a systematic review pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury hemodynamic profile in severe ards: results of the european collaborative ards study esc committee for practice guidelines (cpg): guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (esc) and the pulmonary dead space fraction and pulmonary artery systolic pressure as early predictors of clinical outcome in acute lung injury pulmonary hypertension in severe acute respiratory failure pulmonary hypertension in acute respiratory failure the adult respiratory distress syndrome. a report of survival and modifying factors extracorporeal life support for severe acute respiratory distress syndrome in adults french pulmonary artery catheter study g: incidence and prognostic value of right ventricular failure in acute respiratory distress syndrome prevalence of pulmonary hypertension associated with severe acute respiratory distress syndrome: predictive value of computed tomography diagnosis and assessment of pulmonary arterial hypertension the pulmonary physician in critical care. : the pulmonary circulation and right ventricular failure in the itu is there a safe plateau pressure in ards? the right heart only knows early predictive factors of survival in the acute respiratory distress syndrome. a multivariate analysis acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis a: prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome prevalence and prognostic value of acute cor pulmonale and patent foramen ovale in ventilated patients with early acute respiratory distress syndrome: a multicenter study vascular components of ards. clinical pulmonary hemodynamics and morphology regional differences in the lung influence of state of inflation of the lung on pulmonary vascular resistance effect of lung inflation on pulmonary vascular resistance by arterial and venous occlusion versprille a: pulmonary vascular resistance. a meaningless variable pulmonary vascular resistance. a meaningless variable? pathophysiology of pulmonary hypertension in acute lung injury the pulmonary circulation hypoxic pulmonary vasoconstriction hypoxic pulmonary vasoconstriction-invited article hypoxic pulmonary vasoconstriction: mechanisms and controversies inhibition of rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation time course of the human pulmonary vascular response to hours of isocapnic hypoxia role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. . pathophysiology hypoxic pulmonary vasoconstriction in nonventilated lung areas contributes to differences in hemodynamic and gas exchange responses to inhalation of nitric oxide pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome the pulmonary vascular lesions of the adult respiratory distress syndrome endothelial pathomechanisms in acute lung injury endothelium: interface between coagulation and inflammation regulation of endothelial cell coagulant properties. modulation of tissue factor, plasminogen activator inhibitors, and thrombomodulin by phorbol -myristate -acetate and tumor necrosis factor elevated levels of plasminogen activator inhibitor- in pulmonary edema fluid are associated with mortality in acute lung injury the alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons protein c and thrombomodulin in human acute lung injury national heart lung and blood institute acute respiratory distress syndrome clinical trials network: pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/ acute respiratory distress syndrome acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome dos santos cc: advances in mechanisms of repair and remodelling in acute lung injury pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. a study in mechanically ventilated patients prediction of prognosis for acute respiratory distress syndrome with thin-section ct: validation in cases vascular obstruction causes pulmonary hypertension in severe acute respiratory failure vascular endothelial growth factor (vegf) in acute lung injury (ali) and acute respiratory distress syndrome (ards): paradox or paradigm? effects of vascular endothelial growth factor on hemodynamics and cardiac performance vascular endothelial growth factor: a possible mediator of endothelial activation in acute respiratory distress syndrome pulmonary vascular resistance correlates in intact normal and abnormal canine lungs positive end-expiratory pressure redistributes perfusion to dependent lung regions in supine but not in prone lambs pulmonary artery catheters: evolving rates and reasons for use why protect the right ventricle in patients with acute respiratory distress syndrome? role of the venous return in critical illness and shock: part ii-shock and mechanical ventilation actual incidence of global left ventricular hypokinesia in adult septic shock major pulmonary embolism pathophysiology of right ventricular failure two-dimensional echocardiographic evaluation of right ventricular size and contractility in acute respiratory failure clinical significance of elevated b-type natriuretic peptide in patients with acute lung injury with or without right ventricular dilatation: an observational cohort study impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome prone positioning unloads the right ventricle in severe ards prevention of high-altitude pulmonary edema by nifedipine high-altitude illness the physiologic basis of high-altitude diseases abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema pulmonary edema of high altitude. ii. clinical, aerohemodynamic, and biochemical studies in a group with history of pulmonary edema of high altitude both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial adult respiratory distress syndrome secondary to high altitude pulmonary edema pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy echocardiography based estimation of pulmonary vascular resistance in patients with pulmonary hypertension: a simultaneous doppler echocardiography and cardiac catheterization study pulmonary vascular dysfunction in ards. annals of intensive care convenient online submission rigorous peer review immediate publication on acceptance open access: articles freely available online high visibility within the fi eld retaining the copyright to your article submit your next manuscript at springeropen.com key: cord- -uwae authors: evrard, bruno; goudelin, marine; montmagnon, noelie; fedou, anne-laure; lafon, thomas; vignon, philippe title: cardiovascular phenotypes in ventilated patients with covid- acute respiratory distress syndrome date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: uwae nan ). the higher prevalence of lv failure and lower cardiac index in patients with flu-related ards is presumably related to septic cardiomyopathy since they sustained associated septic shock more frequently than covid- patients. depressed indices of rv systolic function and elevated central venous pressure reflecting systemic venous congestion reflect the higher prevalence of rv failure in flu ards patients (table ). this presumably results from the lower p/f, higher driving pressure, and lower respiratory-system compliance observed in this group. covid- patients with acp tended to have lower respiratory-system compliance than their counterparts, presumably due to distinct ards phenotypes [ ] . this pilot study is limited by its small sample size and the retrospective comparison with historical flu-related ards patients. this first study assessing hemodynamically ventilated covid- patients with tee shows a lower **calculated as the tidal volume divided by the driving pressure (difference between the inspiratory plateau pressure and positive end-expiratory pressure) ***one patient was diagnosed with a tako-tsubo syndrome during transesophageal echocardiography examination performed shortly after tracheal intubation, after days of high-flow nasal cannula; full recovery of left ventricular systolic function was documented under mechanical ventilation days later ****measured using the doppler method applied at the left ventricular outflow tract *****as per april , with still patients hospitalized in the intensive care unit, of them being invasively ventilated prevalence of lv and rv failure than in flu-related ards patients. whether herein reported cardiovascular phenotypes are influenced by the type of covid- ards remains to be determined [ ] . these preliminary data warrant confirmation in large-scale multicenter cohorts. funding none ethics approval and consent to participate local ethical committee approval # - - , which waived the need for informed consent. all patients agreed on the use of anonymized information as per the french law on the general data protection regulation (gdpr). author details abbreviations: rr respiratory rate, peep positive end-expiratory pressure, cvp central venous pressure, rveda right ventricular end-diastolic area, lveda left ventricular end-diastolic area, rvfac right ventricular fractional area change, tapse tricuspid annular plane systolic excursion, tr tricuspid regurgitation, ivc inferior vena cava, lvef left ventricular ejection fraction *calculated as the tidal volume divided by the driving pressure (difference between the inspiratory plateau pressure and positive end-expiratory pressure) **measured using the doppler method applied at the left ventricular outflow tract clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a singlecentered, retrospective, observational study description of the acute covid- cardiovascular syndrome the impact of novel coronavirus on heart injury: a systematic review and meta-analysis. prog cardiovasc dis cardiovascular clusters in septic shock combining clinical and echocardiographic parameters: a post hoc analysis acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical impact covid- pneumonia: ards or not? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - ityxc authors: gupta, ashim; kashte, shivaji; gupta, manu; rodriguez, hugo c.; gautam, shraddha singh; kadam, sachin title: mesenchymal stem cells and exosome therapy for covid- : current status and future perspective date: - - journal: hum cell doi: . /s - - -w sha: doc_id: cord_uid: ityxc acute respiratory distress syndrome (ards) is the main cause for the covid- infection-related morbidity and mortality. recent clinical evidences suggest increased level of cytokines and chemokines targeting lung tissue as a prominent etiological factor. the immunomodulatory effect of mesenchymal stem cells (mscs) as the alternative therapy for the treatment of inflammatory and autoimmune diseases is well known. several studies have also revealed that similar therapeutic impacts of parent mscs are also exhibited by mscs-derived extracellular vesicles (evs) including exosomes. in this review, we explored the therapeutic potential of both mscs and exosomes in mitigating the covid- induced cytokine storm as well as promoting the regeneration of alveolar tissue, attributed to the intrinsic cytokines and growth factor present in the secretome. the preliminary studies have demonstrated the safety and efficacy of mscs and exosomes in mitigating symptoms associated with covid- . thus, they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of covid- . however, more preclinical and clinical studies are warranted to understand their mechanism of action and further establish their safety and efficacy. the novel corona virus disease has grown to be a global public-health emergency since the first case was detected in wuhan, china, in december . the novel corona virus or sars-cov- as named by the international committee on taxonomy of viruses has over million confirmed cases worldwide and has claimed over , lives [ ]. after months from the first covid diagnosis, we neither have an effective antiviral medication nor a vaccine available to deal with this emergency. once infected, a patient mainly relies on their immunity to resist sars-cov- , with supportive treatment given if complications occur [ ] . it has been confirmed that the first step in the sars-cov- pathogenesis is specific recognition of the angiotensin i converting enzyme receptor (ace ) by the viral spike protein [ ] , leading to an immune system overreaction causing damage to the body. the immune system overreaction in covid- patients is associated with production of large amounts of inflammatory factors, causing a cytokine storm including an overproduction of immune cells like effector t cells and natural killer cells [ , ] . intensive care unit (icu) admission rates are just over % from confirmed covid- diagnosis [ ] , and more than half of these icu patients showed higher plasma levels of granulocyte colony-stimulating factor (gcsf) and tumor necrosis factor alpha (tnf-α). increased gcsf and tnf-α have been found to produce a cytokine storm, leading to acute respiratory distress syndrome (ards) [ ] . covid- infected patients showed high circulating levels of proinflammatory cytokines including gcsf, ip , mcp , mip a and tnf-α levels, and the levels were higher in patients admitted to the icu. as cytokine storm is the cause behind extensive lung damage that even leads to death, eliminating the cytokine storm and supressing superinflammatroy immunological response coupled with repair and regeneration of the lung tissue can be an effective treatment modality for covid- [ ] . current treatments and clinical interventions for covid- associated acute lung injuries include respiratory support (non-invasive ventilation and mechanical ventilation), antipyretic and non-specific antiviral drugs, corticosteroids, and immunoregulation [ ] . with very high fatality rate seen among the critically ill icu patient population that are unresponsive to the aforementioned treatment modalities, new approaches are required to mitigate the symptoms associated with covid- infection [ , ] . cell-based therapies strive to treat or prevent injury and disease by naturally repairing, restoring, and/or regenerating damaged or diseased organs and tissues [ , ] . this field has exploded in recent years to meet the needs of patients with both complex and common medical problems [ ] . some cell-based therapies aim to slow or stop degenerative or pathophysiologic processes that ultimately present themselves as symptomatic conditions [ ] . other regenerative therapies activate the body's endogenous repair system by influencing the behaviour of somatic and progenitor cells to stop degenerating and start regenerating [ , ] . in the case of pneumonia, acute lung injury (ali) [ ] , acute respiratory distress syndrome (ards) [ , ] and sepsis studies investigating therapy using mesenchymal stem cells (mscs) have demonstrated safety and some positive effects on these conditions [ ] . a recent study conducted in beijing you'an hospital, capital medical university, china used mscs in patients with covid- pneumonia. the results demonstrated that symptoms such as fever, shortness of breath and low oxygen saturation disappeared and or improved - days' post treatment [ ] . several institutes worldwide are putting their best efforts to come up with a novel therapeutic option with good clinical safety and efficacy to help patients affected by covid- . an early first attempt in china utilizing mesenchymal stem cells demonstrated potential to improve symptoms associated with covid- [ ] . other studies also showed efficacy of intravenous administration of mscs in boosting body's immune response against covid- associated infection [ ] . the mechanism of action was ascribed to the accumulation of intravenously administered mscs into the lungs and help build up regenerative cells locally, which can potentially protect the epithelial cells of the lungs, and prevent lung damage [ ] . the efficacy of mscs can be attributed to their trans-differentiation; secretion of growth factors, cytokines and extracellular vesicles including exosomes and associated paracrine effect; and mitochondrial transfer [ , ] . in addition to the stem cell therapy, a cell-free approach like the use of exosomes and associated bioactive molecules are leading the way to treat several pathologies. the exosomes produced by mscs possess hypoimmunogenic properties are enclosed in a lipid bilayer making them extremely stable and are able to migrate to the target organ of damage instead of merely accumulating via blood flow. these extracellular vesicles are identified to be the primary factors responsible for paracrine effects detected in all types of stem cells and for the transfer of genetic material from stem cells to the tissue-specific cell that needs regeneration [ ] . in search of a ultimate viable solution to the harrowing covid- , when scientists around the world are working on a number of vaccines and treatments for covid- , mesenchymal stem cells and their exosomes are emerging as a promising therapeutic option without any major adverse effects. the combinatorial strategy of antiviral drugs along with immunomodulatory, tissue protective and healing potential of stem cells and their exosomes may reduce the severity of the covid- . a call for an urgent development on the mscs and their exosome-based therapeutics specifically targeted towards ards to ensure the health and survival of human being is strongly recommended. the therapeutic potential of mscs due to their regenerative properties is well investigated in various degenerative and inflammatory disorders. mscs are immunoprivileged cells, due to the low expression of class ii major histocompatibilty complex (mhc-ii) and co-stimulatory molecules in their cell surface [ ] . mscs are known to hold an immunoregulatory capacity and elicit immunosuppressive effects by inhibiting t-cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic t-cells [ ] by interfering with various immune response pathways by means of direct cell-to-cell interactions and soluble factor secretion [ ] . profound immunomodulatory effects of mscs on t and b cells and natural killer (nk) cells are mediated by regulatory t cells. mscs are able to suppress in vitro t-cell proliferation induced by cellular or non-specific mitogenic stimuli through the secretion of various soluble factors that include tgf-β, hcf, pce- , ido, hla-g and no. the effect of these suppressive factors is upregulated by pre-sensitization of mscs with tnf-α, and ifn-γ. mscs polarizes t cells toward a regulatory phenotype that serve to decrease il- and tnf-α, which is an important mechanism by which mscs dampen inflammation [ ] . in addition, pretreatment of mscs with ifn-γ has been shown to also suppress b cells [ ] . mscs with the help of dendritic cells (dc) or monocytes are found to produce anti-inflammatory cytokines such as il- that downregulates the human leucocyte antigen (hla) class i [ ] and exert protective effects including direct regeneration and secretion of multiple paracrine factors such as antibacterial peptides [ ] . interleukin- (il- ) plays an essential role in maintaining the immunomodulatory property of regulatory dc. while, regulatory dc play an important role in controlling immune homeostasis and can possess an immunosuppressive ability to induce specific immune tolerance and dampen th type inflammation [ ] , mscs have the ability to induce mature dendritic cells (dc) into novel jagged- dependent regulatory dendritic cell population [ , ] . all these interactions with different dendritic cells lead to a shift of the immune system from a th response toward an anti-inflammatory th response [ ] . cell-based therapy have gained a status as a promising therapeutic field, to cure incurable diseases like diabetes, cardiovascular diseases, neurodegenerative diseases, muscular degenerative disorders, cancers [ ] , liver injuries [ ] , hematopoietic and immune system disorders, metabolic disorders [ ] , graft-versus-host disease, sepsis and ards [ ] due to their immunomodulation properties. since the first observation of pluripotent undifferentiated cells resistance to murine polyomavirus infection [ ] , many researchers have explored the same against a variety of viral infections like human immunodeficiency virus- (hiv ) and human immunodeficiency virus- (hiv ) [ ] , hepatitis b virusrelated acute-on-chronic liver failure (hbv-aclf) [ ] , myxoma virus [ ] , retrovirus [ ] , cytomegalovirus [ ] , etc. with reference to the embryonic and adult stem cells. it was observed that the intrinsic expression of interferon stimulating genes (isg) makes pluripotent and multipotent stem cells resistant to viral infections [ , ] . it was further observed that isg of stem cells gets this defence mechanism from interferon-induced transmembrane (ifitm) family of proteins [ , ] . although, stem cell therapy is not a method to eradicate or cure sars-cov- , there are few evidence-based studies that support the concept that infected patients may be more likely to combat and survive the infection [ , ] . this can be attributed to the rejuvenation and regeneration properties of stem cells such as their ability to reduce inflammation, secrete cell protective substances, transfer mitochondria, decrease cell death, anti-oxidative effects, and improve overall immune function [ ] . in addition, there is direct evidence that stem cells protect against the influenza virus (a/h n ) infection, by helping reverse lung injury [ ] . owing to their anti-inflammatory, immunomodulatroy and homing properties as well as regenerative potential, mscs have attracted the attention of many scientists as a cell based therapy for the treatment for covid- [ ] . leng et al. conducted a clinical trial pilot study (chictr ) using human umbilical cord-derived mscs (hucmscs) in seven covid- patients for days. post-treatment, population of cd + cd c + cd b mid regdcs dramatically increased. the levels of tnf-α decreased significantly, while levels of il- increased in the msc treatment group compared to the placebo control group. the gene expression profile showed that mscs were ace − and tmprss − suggesting mscs were free from covid- infection. this study concluded that the intravenous transplantation of mscs was safe and effective for treating patients with covid- pneumonia, especially patients whose condition was critically severe. these results can be attributed to immunomodulatory role of mscs in reversing the lymphocytes subsets [ ] . in another single case study, intravenous allogenic hucmscs infused in a -year-old female critically ill of covid- revealed that the pneumonia was greatly relieved and the patient recovered from icu after days. no huc-msc-related side effects were observed. after first infusion, the serum bilirubin, c-reactive protein (crp) and aspartate aminotransferase (ast)/ alanine aminotransferase (alt) were gradually reduced. after days, second administration was done and the white blood cells (wbcs) and neutrophil count decreased to the normal level, and the lymphocyte count increased to the normal level. administration of hucmscs led to reduction in inflammation and recovery of antiviral immune cells and organs. in addition, it may have led to homing of hucmscs to repair the injured tissues and neutralize the inflammatory cytokines such as g-csf and il- by expression of their receptors [ ] . it indicates that mscs therapy might be an ideal choice to treat critically ill covid- patients. covid- is associated with a number of complications with ards being the leading cause of the deaths. ards is known to be associated with protein-rich pulmonary edema and acute respiratory failure, characterized by acute inflammation and injury to the lungs and epithelia [ ] . the primary treatment of covid- remains supportive, involving lung protective ventilation and fluid conservation. ards is an important cause of morbidity and mortality with no definitive therapy [ ] . the pathophysiology of ards involves an imbalance between proinflammatory and anti-inflammatory mediators. therefore, regulation of those mediators, specifically cytokines, has been targeted as a potential therapeutic approach [ ] . there are several studies that have demonstrated the therapeutic potential of mscs for patients suffering with ards because of their specific immunomodulatory properties [ ] . mscs have been reported to treat impaired alveolar fluid clearance, decrease the lung permeability, combat infection and regulate inflammation in patients suffering from ards [ ] . mscs also have the ability to secrete a variety of soluble paracrine factors, including key antiinflammatory cytokines such as interleukin- (il- ) and il- receptor antagonist (il- ra) [ ] . a preclinical study showed that human bone marrowderived mesenchymal stem cells (bmmscs) were activated with the serum obtained from patients suffering from ards. these activated mscs were more efficient in reducing lung inflammation compared to untreated mscs. it resulted in increased expression of il- and il- ra, which was associated with enhancement of their protective capacity by reduction of the lung injury score, development of pulmonary edema and accumulation of bronchoalveolar lavage inflammatory cells and cytokines [ ] . in another study, bmmscs were preconditioned with serum obtained from patients suffering with ards and activated. these activated mscs secreted higher levels il- ra and il- , dampened the secretion of proinflammatory cytokines, exhibited upregulation of toll-like receptor (tlr- ) and vascular endothelial growth factor (vegf) genes, and triggered a strong immunomodulatory response via higher secretion of prostaglandin e (pge ). when these activated allogenic mscs were administered in ards porcine models, it suppressed proinflammatory cytokine levels and promoted secretion of anti-inflammatory mediators [ ] . thus, activation of allogenic mscs through incubation in an environment previously exposed to mscs may induce stronger immunomodulatroy effects in patients compared with infusion of nonactivated mscs [ ] . additionally, clinical trials such as stem cells for ards treatment (start) trial, a multicentre, open label, dose escalation, phase i clinical trial (nct ), utilized a single intravenous dose of bone marrow-derived mesenchymal stem cells (bmmscs) which was given to nine moderate to severe ards patients. the results demonstrated no prespecified infusion-associated events or treatment-related adverse events. msc infusion was well tolerated in all patients [ ] . furthermore, in a double blinded, multicentre randomized phase a trial (nct ), one intravenous dose of bmmscs was studied. among patients screened, were eligible and received treatment. the msc dose was safe in patients with moderate to severe ards. there was no infusion-related haemodynamic or respiratory adverse events. it was concluded that larger trials will be needed to test further efficacy of mscs for ards [ ] . ards, lung failure and fulminant pneumonia are major symptoms associated with h n infection. in a single-centre and open-label clinical trial (ntc ; chictr-occ- ), mscs were transplanted into h n induced ards patients. in this clinical trial, patients with h n -induced ards were included as control group without mscs transplantation. the treatment group included patients with h n -induced ards with allogenic menstrual blood-derived msc transplantation. results showed that the treatment group had a significantly lower mortality rate compared to the control group. the study also reported that msc transplantation did not result in harmful effects in human body within the -years follow-up period. msc transplantation significantly improved survival rate of h n -induced ards patients in both preclinical and clinical studies [ ] . considering that h n and coronavirus share similar complications such as ards and corresponding multi-organ failure, msc-based therapy could be a potential alternative for mitigating covid- [ ] . another known and safe source of mscs is adipose tissue. adipose-derived stem cells (ascs) expresses a large amount of anti-inflammatory properties and can be obtained from a minimally invasive aspiration procedure [ ] . ascs secret factors that induce proliferation of vascular endothelial cells and angiogenesis that include vegf and pdgf [ , ] . along with their immunosuppressive activity due to the secretion of tgf- , hgf and inf-y, they can potentially improve the pulmonary function of covid- patients [ ] . recently, there was a phase i, single-centre, doubleblinded, placebo-controlled clinical trial (nct ) that assessed the safety of ascs in the treatment of ards [ ] . the trial concluded that ascs were safe with minimally adverse events and had potential to improve oxygenation in patients with moderate ards [ ] . the results from this study are promising; however, more studies will be required to establish safety and efficacy of ascs to treat patients infected with ards and covid- . both sars-cov- and the middle east respiratory syndrome coronavirus have been known to induce acute liver injury (ali). studies have shown that patients with covid- ali have an incidence rate as high as %. ali induced by viruses can progress rapidly to acute liver failure (alf) [ ] . ali involves the infiltration of immune cells such as t cells, b cells and natural killer cells (nk). immunosuppressive treatments and decreased inflammation reportedly promote repair after ali [ ] . mscs have shown a ray of hope in repairing and regenerating liver tissues and in treatment of liver diseases [ ] . a preclinical study demonstrated that ali was significantly alleviated and survival rate of mice was improved post-treatment with mscs. the results indicated that the mscs modulated the hepatic immune system in terms of the distribution of immune cell subsets and phenotype of single cells. during the injury phase, mscs exhibited a systemic response by reducing the number of ly c low cd + t rm cells, conventional nk cells*, and igm + igd + b cells and increasing the number of immunosuppressive monocyte-derived macrophages. during recovery phase, mscs promoted the retention of ly c low cd + t rm cells and maintained activity of immunosuppressive monocytederived macrophages [ ] . another study demonstrated that the efficacy of msc-based therapy is enhanced with lipid conjugated heparin coating; and the human adipose derived stem cells (hadscs) delivered to the damaged liver resulted in significantly improved recovery from alf in a mouse model. results from this study showed that the intravenous administration of hadscs lowered the elevated serum levels of aspartate transaminase (ast) and alanine transaminase (alt). a significantly increased level of human hepatic growth factor (hhgf), a representative secretome from hadscs, significantly reduced the levels of macrophage and cyp e [ ] . in another preclinical study, bone marrow-derived mesenchymal stem cells (bmmscs) were transfused in alf rat models. the results demonstrated that bmmscs inhibited neutrophil infiltration, oxidative activity and hepatocyte apoptosis. the bmmscs also ameliorated alf by increasing the expression of heme oxygenase (ho- ) [ ] . ho- is known to possess the ability to reduce polymorphonuclear neutrophils (pmns) infiltration and function, and thus, can play a vital anti-inflammatory and anti-apoptic role [ ] . another preclinical study utilizing transplantation of hucmscs in an ali mice model, demonstrated the ability of these cells in decreasing the levels of hepatocellular necrosis and lobular neutrophilic infiltration, leading to significant hepatoprotective effects. no adverse effects, systemic toxicity or neoplastic finding related to hucm-scs transplantation was observed [ ] . in a similar study, intravenous administration of mscs in an intoxicated and burn mice model resulted in less cellularity, limited apoptosis, and slight reduction in the proinflammatory cytokineinterleukin- (il- ) and the neutrophil chemokine-kc (cxcl ) levels in the lung tissue. msc treatment had more dramatic anti-inflammatory effects on systemic and hepatic inflammation. in summary, the results of this study indicated that msc treatment can diminish systemic inflammation, lessen hepatic damage, and decrease liver and lung apoptosis and inflammation [ ] . exosomes are the tiny packets filled with cellular proteins and nucleic acid materials (e.g. mrna & mirna) released by stem cells [ ] . literature have demonstrated powerful regenerative potential of exosomes, ranging from immunemodulatory properties, anti-inflammatory properties, etc. [ ] . although exosomes have been discovered almost years ago, it is only recently that scientists have generated immense interest for being one of the most promising, acellular alternatives to cellular therapeutics, due to their demonstrated aptitude [ ] . exosomes were first identified to be secreted from nanovesicles of sheep reticulocytes, at the time of their maturation; the experiment was performed in the year , soon after which, exosomes were studied rapidly, as the secretions of all the cells including immune cells, like b and t lymphocytes and are found to be necessary for cellular communications [ ] . typically, exosomes are of the size of - nm and are found to be secreted through inward budding of the endosomes. once released by the cells, they get entry into another cellular microenvironment, by fusing to the plasma membrane [ ] . studies have further indicated that increased cellular interaction, through cell to cell communication, is one of the most unique functions of exosomes [ ] . other than that, disposal of unwanted proteins, transfer of genetic material, elicitation of the immune response, reduction in inflammation, etc. are also identified to be some of the functional attributes of exosomes, depending upon the cell of origin [ , ] . majority of the studies focusing on msc-derived exosomes have demonstrated regenerative potential, immune-modulatory functions, anti-inflammatory effects, similar to their parents, i.e. mesenchymal stem cells [ , ] . in preclinical set up, msc-derived exosomes have demonstrated aptitude as an acellular alternative to cell-based therapy, against acute respiratory distress syndrome (ards) [ ] . these studies have further confirmed that post-exosomal infusion, the associated cytokine storm and pro-inflammatory signalling biomolecules were considerably reduced that were primarily responsible for ards pathogenesis [ ] . further analysis confirmed that the exosomes also increased the level of anti-inflammatory signalling mediators that can reduce the severity of the lung injury through increase permeability and functional aspects of alveolar epithelium [ , ] , as a result of which, the exchange of oxygen-rich air is easily facilitated. further deep diving into the same, the ability of exosomes to transfer mitochondria to alveolar cells further increased their survival rate, and thus, facilitated cellular regeneration. these effects have paved the way towards the therapeutic use of this novel acellular alternative [ ] . beyond their effects in preclinical model of acute lung disorders, msc-derived exosomes were also found to be responsible for direct inhibition of viral multiplication [ , ] . with several studies investigating the bio-distribution of this cellular cargo in preclinical setup, it has been quite evident that these exosomes have the potential to alter a variety of different pathways to facilitate active cellular communication. the intrinsic component of the exosomes, mirnas, are reportedly found to be the key component that is responsible for many physiological processes, like development, epigenetic alterations, immune regulations, etc. [ ] . by using near ir dyes, several studies have figured out different techniques to track in-vivo biodistribution of exosomes upon systemic delivery in different animal models [ , ] . several studies have confirmed their reachability to different organs, like in intra-cerebral haemorrhagic rat models, exosomes could reach to the brain upon the intravenous administration [ ] . intravenous administration of exosomes in a mouse model with acute kidney injury shows their accumulation in the kidneys, further confirming exosomes strong paracrine pathways for instant reachability to the site of injury [ ] . multiple studies have demonstrated that mirnas secreted by exosomes are very crucial for accelerated lung recovery, particularly in patients suffering from viral infections like influenza, hypoxia-induced pulmonary hypertension, ventricular induced lung injury, etc. wang et al. observed and studied active regulation of mirnas during early and late-stage repair of lung damage in the mouse model. this study further indicated that certain mirnas like mir- , mir- , let- and mir- played a major role in lung regeneration, immune-regulation, and immune-modulation [ ] . alipoor et al. presented strong experimental evidence that stem cell-derived exosomes can deactivate the signalling pathways associated with hypoxia that can also facilitate reduced hypertension and inflammation, specifically evident in the respiratory disorders [ ] . beyond their effects in a preclinical model of acute lung disorders, msc-derived exosomes are also found to be responsible for direct inhibition of viral multiplication. studies have confirmed that msc-derived exosomes secrete mirna, which acts as a silencing complex and further alters the expression of the cellular receptors through epigenetic changes that help in blocking the entry of many rna viruses like influenza, hepatitis c and also coronavirus [ , ] . in a pig model of influenza, intra-tracheal administration of msc-derived exosomes, hrs post-infection, significantly reduced virus shredding [ ] . several pre-clinical and clinical studies have explored the potential of mscs and exosomes for treating covid- including management of associated cytokine storm. though the results are promising, the limited literature still warrants more studies to establish safety and efficacy of mscs and exosomes to treat and manage symptoms associated with covid- infection. eventually, multi-center, controlled, randomized trials will be needed to adequately assess the future of mscs as well as exosomes in the treatment of covid- . as of july , , there are on-going studies related to use of stem cells (table ) and on-going studies related to use of exosomes (table ) registered on clinicaltrials.gov. covid- is currently one of the biggest socio-economic and public health dangers that we have seen. with the hope of vaccine that will eradicate the viral infection still in the distant future, there is an urgent need for treatments that are not only efficacious but safe. preliminary studies have demonstrated the safety and efficacy of mscs and exosomes in mitigating symptoms associated with covid- . they can be used on compassionate basis, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of covid- , but more preclinical and clinical studies are required to understand their mechanism of action and establish their safety and efficacy. stem cell -based therapy for coronavirus disease transplantation of ace -mesenchymal stem cells improves the outcome of patients with covid- pneumonia primer cytokine storms: understanding covid- the possible pathophysiology mechanism of cytokine storm in elderly adults with covid - infection: the contribution of " inlame -aging care for critically ill patients with covid- mesenchymal stem cells in the fight against viruses: face to face with the invisible enemy presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area bioinspired engineering for liver tissue regeneration and development of bioartificial liver: a review stem cell therapy: a hope business or a magic wand? mesenchymal stem cells modulate the immune system in developing therapeutic interventions human umbilical cord-derived mesenchymal stem cells in acute liver injury: hepatoprotective efficacy, subchronic toxicity, tumorigenicity, and biodistribution treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (start study): a randomised phase a safety trial mesenchymal stem (stromal) cells for treatment of ards: a phase clinical trial regenerative abilities of mesenchymal stem cells through mitochondrial transfer clinical remission of a critically ill covid- patient treated by human umbilical cord mesenchymal stem cells typical"' acute respiratory distress syndrome immunosuppressive properties of mesenchymal stem cells: advances and applications immunomodulation by mesenchymal stem cells and clinical experience current status of potential therapeutic candidates for the covid- crisis mesenchymal stem cells induce mature dendritic cells into a novel jagged- -dependent regulatory dendritic cell population neoplastic differentiation: interaction of simian virus and polyoma virus with murine teratocarcinoma neither human immunodeficiency virus- (hiv- ) nor hiv- infects most-primitive human hematopoietic stem cells as assessed in long-term bone marrow cultures ex vivo virotherapy with myxoma virus does not impair hematopoietic stem and progenitor cells embryonic stem cells use zfp to silence retroviral dnas human cytomegalovirus infection of human embryonic stem cell-derived primitive neural stem cells is restricted at several steps but leads to the persistence of viral dna ifitm-family proteins: the cell's first line of antiviral defense charles stem cells intrinsic immunity shapes viral resistance of stem cells human mesenchymal stromal cells reduce influenza a h n -associated acute lung injury in vitro and in vivo activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin ( il ) - and il- rn levels mesenchymal stem cells reconditioned in their own serum exhibit augmented therapeutic properties in the setting of acute respiratory distress syndrome clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic inluenza a (h n ) infection: a hint for covid- treatment. engineering regenerative capacity of adipose derived stem cells (adscs), comparison with mesenchymal stem cells (mscs) concise review: adipose-derived stem cells (ascs) and adipocyte-secreted exosomal microrna (a-se-mir) modulate cancer growth and promote wound repair engineered fat graft enhanced with adipose-derived stromal vascular fraction cells for regenerative medicine: clinical, histological and instrumental evaluation in breast reconstruction adipose-derived stromal stem cells (ascs ) as a new regenerative immediate therapy combating coronavirus (covid- ) -induced pneumonia treatment of acute respiratory distress syndrome with allogeneic adiposederived mesenchymal stem cells: a randomized, placebo-controlled pilot study immunomodulatory effect of mesenchymal stem cells in chemical-induced liver injury: a high-dimensional analysis significantly enhanced recovery of acute liver failure by liver targeted delivery of stem cells via heparin functionalization mesenchymal stem cells increase expression of heme oxygenase- leading to anti-inflammatory activity in treatment of acute liver failure mesenchymal stem cell treatment attenuates liver and lung inflammation after ethanol intoxication and burn injury extracellular vesicles: novel mediators of cell communication in metabolic disease immune regulatory targets ofmesenchymal stromal cell exosomes/ small extracellular vesicles in tissue regeneration exosomes: looking back three decades and into the future exosomes: biogenesis, biologic function and clinical potential mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome: concise review review article mesenchymal stem cellbased immunomodulation: properties and clinical application therapeutic use of extracellular vesicles for acute and chronic lung disease exosomal micrornas derived from umbilical mesenchymal stem cells inhibit hepatitis c virus infection the biology of extracellular vesicles: the known unknowns advances in analysis of biodistribution of exosomes by molecular imaging emerging potential of exosomes for treatment of traumatic brain injury mechanisms underlying cell therapy for tbi msc-derived exosome as a novel therapy for tbi mesenchymal stem cell derived extracellular vesicles ameliorate kidney injury in aristolochic acid nephropathy exosomes in respiratory disease mesenchymal stem cell-derived extracellular vesicles attenuate influenza virusinduced acute lung injury in a pig model conflict of interest the authors declare that they have no conflict of interest. key: cord- - opvzrj authors: curley, gerard f.; laffey, john g. title: future therapies for ards date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: opvzrj nan despite more than randomized clinical trials (rcts) of multiple potential therapies, the only interventions for acute respiratory distress syndrome (ards) that reduce mortality are those that minimize ventilator-induced lung injury [ ] . this 'translational failure' may have a number of explanations. firstly, ards is a syndrome, and interventional trials in ards generally include a heterogenous patient group with a wide spectrum of disease etiology and disease severity. second, deficits exist in our understanding of key aspects of the pathogenesis of ards. notwithstanding these challenges, a number of promising therapies are currently under investigation for ards, and offer hope for the future. aspirin platelets are important in ards pathogenesis. in preclinical studies, aspirin reduces thromboxane a , p-selectin, and platelet-derived chemokine (e.g., ccl and cxcl ) production, reduces platelet-neutrophil aggregates and neutrophil extracellular traps, and enhances anti-inflammatory lipid mediators such as -epilipoxin a . aspirin reduces the risk of developing ards in critically ill patients [ ] . a clinical study of aspirin in human volunteers undergoing endotoxin inhalation (arena nct ) and a rct of aspirin for ards prevention [ ] are ongoing (table ) . hmg coa-reductase inhibitors (statins) exert diverse 'pleiotropic' effects beyond their 'pharmacologic' effect in cholesterol reduction, including anti-inflammatory and endothelial protective effects. results from both preclinical and observational studies support a potential role for statins in ards. simvastatin improved pulmonary and systemic organ function in a phase / rct in ards [ ] , but two larger phase / trials of statin therapy, carried out in ireland/uk [ ] and the usa [ ], respectively, did not demonstrate benefit. rosuvastatin, a hydrophilic statin, did not improve clinical outcomes in sepsis-associated ards and may have increased hepatic and renal dysfunction [ ] . the lipophilic statin simvastatin did not worsen hepatic or renal function, it non-significantly reduced mortality, but it did not increase the number of ventilator-free days (vfd, the primary outcome) [ ] . a definitive large trial of simvastatin, powered for mortality as a primary outcome, may be warranted. activation of coagulation plays a key role in the pathogenesis of ards, resulting in alveolar fibrin deposition which impairs gas exchange. in pre-clinical studies, heparin has been found to reduce alveolar fibrin deposition and exert anti-inflammatory effects. in one small rct, heparin decreased the number of vfd in patients at risk for ards [ ] . further studies investigating the efficacy of nebulized heparin in patients at risk of ards (actrn ) ( table ) are underway. interferon beta (ifn-b) increases endothelial expression of cd , the rate-limiting enzyme in the conversion of adenosine monophosphate to adenosine, which in turn binds to pulmonary a b receptors and exerts multiple protective effects in pre-clinical models. in a recent openlabel dose-escalation study, only two ( %) of ards patients treated with lg per day of ifn-b- a died by day , compared to a % mortality in a parallel control group [ ] . although the study was not randomized or blinded, and there were some baseline differences between the treated and control cohorts, further investigation of ifn-b for ards is warranted. tumor necrosis factor receptor blockade tumor necrosis factor (tnf) exerts its effects by binding to one of two tnf receptors, designated tnfr and tnfr . tnf-activated pro-inflammatory pathways and the programmed cell death pathways that result in tissue injury are largely mediated through tnfr , while tnfr signaling plays a role in tissue repair and angiogenesis. promising pre-clinical data support the efficacy of anti-tnfr monoclonal antibodies [ ] . in one study, inhaled anti-tnfr antibodies decreased the pulmonary inflammation induced by endotoxin in healthy volunteers [ ] . early phase studies in ards patients are awaited. angiotensin converting enzyme angiotensin-converting enzyme (ace) cleaves angiotensin-i to generate angiotensin-ii, which causes vasoconstriction, inflammation, and increased vascular permeability via type (at r) and type receptors. ace- , a homolog of ace, cleaves a single residue from ang-ii to generate ang - [ ] , which blocks many at r-mediated actions. imai et al. [ ] found that ace, ang-ii, and at r function as lung injury-promoting factors, whereas ace- protects the lung from injury. ace is a receptor for severe acute respiratory syndrome-coronavirus (sars-cov), while sars-cov induces downregulation of ace , which is an important step in the development of severe lung failure [ ] . in addition, mortality is increased in patients with ards who have the ace dd phenotype, which results in greater ace activity [ ] . a human phase i/ii clinical trial of recombinant human ace therapy in patients with early ards is in progress (nct ) ( table ) . adrenomedullin adrenomedullin (am), an endogenous amino acid peptide belonging to the calcitonin gene-related peptide family, is expressed in multiple tissues, including endothelial cells, and plays a crucial role in endothelial barrier integrity. am acts via binding of the calcitonin receptorlike receptor, thereby raising intracellular camp levels in endothelial cells and reducing myosin light chain (mlc) phosphorylation. thus, am may prevent endothelial contraction and intercellular gap formation [ ] . am expression is upregulated in inflammatory diseases including ards and sepsis, and endogenous am may contribute to the protection of vascular function in inflammation [ ] . am therapy reduces pulmonary permeability injury and decreases inflammation in experimental ards and sepsis. the committee for orphan medicinal products of the european medicines agency (ema) recently recommended am as an orphan drug for the treatment of ards (ema/comp/ / ). clinical trials with am are in the planning stage. keratinocyte growth factor (kgf) is a fibroblast growth factor expressed predominantly by mesenchymal cells, and its receptor (kgfr) is expressed on epithelial cells and macrophages. results from pre-clinical studies suggest that intra-tracheal kgf reduces lung injury induced by hyperoxia, ventilator-induced lung injury, and bacterial pneumonia. in a recent study, kgf treatment (palifermin Ò ) increased markers of type ii alveolar epithelial cell proliferation and increased alveolar concentrations of reparative proteases and the anti-inflammatory cytokine il- ra following endotoxin inhalation by volunteers [ ] . a phase ii clinical trial of palifermin Ò in ards has recently been concluded (isrctn ), and the results are awaited (table ) . mesenchymal stem/stromal cells mesenchymal stem/stromal cells (mscs) can regulate both the innate and adaptive immune systems and can modulate macrophage phenotype, inhibit the production of inflammatory cytokines by activated cd and cd t cells, and stimulate the generation of foxp ? regulatory t cells, potentially reducing pro-inflammatory cytokines in ards [ ] . mscs directly attenuate bacterial sepsis, the commonest and most severe cause of ards, by enhancing macrophage phagocytosis and increasing antimicrobial peptide secretion, thereby increasing bacterial clearance [ ] . mscs also repair the injured lung following ventilation-induced lung injury, via paracrine mechanisms [ , ] . a recent pilot study of msc therapy for ards demonstrated no adverse effects [ ] . a phase / , open-label, dose-escalation, multi-center clinical trial of allogeneic bm-mscs in patients with moderate to severe ards is underway in the usa (nct ) ( table ) . although there have been many failed therapies to date, new therapies based on improved understanding of the mechanisms implicated in the development of ards are emerging, and may provide a treatment option in the near future. effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of published randomized trials and meta-analyses prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study us critical illness and injury trials group: lung injury prevention with aspirin study group (usciitg: lips-a) ( ) lung injury prevention with aspirin (lips-a): a protocol for a multicentre randomised clinical trial in medical patients at high risk of acute lung injury a randomized clinical trial of hydroxymethylglutarylcoenzyme a reductase inhibition for acute lung injury (the harp study) simvastatin in the acute respiratory distress syndrome rosuvastatin for sepsisassociated acute respiratory distress syndrome nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial the effect of intravenous interferon-beta- a (fp- ) on lung cd expression and on acute respiratory distress syndrome mortality: an open-label study selective inhibition of intra-alveolar p tnf receptor attenuates ventilatorinduced lung injury a novel tnfr -targeting domain antibody attenuates pulmonary inflammation in a human model of lung injury, via actions on the lung micro-vascular endothelium angiotensin-converting enzyme protects from severe acute lung failure a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury ace i/d but not agt (- )a/g polymorphism is a risk factor for mortality in ards adrenomedullin and endothelial barrier function keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury therapeutic potential and mechanisms of action of mesenchymal stromal cells for acute respiratory distress syndrome effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilator-induced lung injury mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study acknowledgments j. laffey and g. curley are funded by the key: cord- -rdwvsm s authors: wu, chaomin; hou, dongni; du, chunling; cai, yanping; zheng, junhua; xu, jie; chen, xiaoyan; chen, cuicui; hu, xianglin; zhang, yuye; song, juan; wang, lu; chao, yen-cheng; feng, yun; xiong, weining; chen, dechang; zhong, ming; hu, jie; jiang, jinjun; bai, chunxue; zhou, xin; xu, jinfu; song, yuanlin; gong, fengyun title: corticosteroid therapy for coronavirus disease -related acute respiratory distress syndrome: a cohort study with propensity score analysis date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: rdwvsm s background: the impact of corticosteroid therapy on outcomes of patients with coronavirus disease (covid- ) is highly controversial. we aimed to compare the risk of death between covid- -related ards patients with corticosteroid treatment and those without. methods: in this single-center retrospective observational study, patients with ards caused by covid- between january , , and february , , were enrolled. the primary outcome was -day in-hospital death. the exposure was prescribed systemic corticosteroids or not. time-dependent cox regression models were used to calculate hazard ratios (hrs) and % confidence intervals (cis) for -day in-hospital mortality. results: a total of patients [ . ± . years old (mean ± sd), . % males] were analyzed. the median of sequential organ failure assessment (sofa) score was . (iqr . – . ). of these cases, ( . %) patients had invasive mechanical ventilation. the number of patients received systemic corticosteroids was ( . %), and ( . %) received standard treatment. the maximum dose of corticosteroids was . (iqr . – . ) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was . ( . – . ) days in total. in cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within days after adjusting for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (hr . ; % ci . , . ; p = . ). corticosteroids were not associated with delayed viral rna clearance in our cohort. conclusion: in this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within days in covid- patients who developed ards. the world health organization (who) declared that the outbreak of severe acute respiratory syndrome coronavirus (sars-cov- ) constitutes a pandemic [ ] . since the first confirmed case on january , , the virus has been emerged in countries. more than , , laboratory-confirmed cases were reported, with an average mortality approaching . % as of july , [ ] . the spread of sars-cov- has led to serious socioeconomic consequences worldwide. currently, there is no specific treatment or vaccine for coronavirus disease . up to % of the covid- patients developed acute respiratory distress syndrome (ards) [ ] [ ] [ ] as a consequence of cytokine storm. ards was the major cause of morbidity [ ] . adjunctive corticosteroids may be theoretically beneficial [ ] , and has been widely used by clinicians to suppression of hyperinflammation in covid- patients, especially those with critical illness [ , , ] . however, there was comprehensive controversy on its efficacy [ , ] , due to the results of observational studies that showed corticosteroid treatment was associated with increased mortality and nosocomial infections for influenza and delayed virus clearance for severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers) [ ] . in the early pandemic of covid- , lower mortality was reported among the critically ill subgroup of sars patients treated with corticosteroids in a retrospective study [ ] . since then, evidence is growing that corticosteroid treatment is beneficial for some covid- patients. the randomized evaluation of covid- therapy (recovery) trial from the uk reported reduced mortality in patients treated with oral or intravenous dexamethasone mg/d for up to days [ ] . the efficacy was significant only in severe patients who receiving oxygen or invasive mechanical ventilation. a prospective meta-analysis of rcts of critically ill patients with covid- also showed the association between systemic corticosteroids and lower all-cause mortality [ ] . other two randomized controlled trials (rcts) did not show benefit on mortality from intravenous dexamethasone or methylprednisolone treatment, but corticosteroid treatment increased ventilator-free days and number of days alive in patients with moderate to severe ards [ , ] . a meta-analysis of corticosteroids on the mortality of ards showed beneficial effects of corticosteroids on short-term mortality may be counteracted by the delayed onset of adverse effects [ ] , such as secondary infection due to immunosuppression and altered tissue repair. a follow-up period of days in these randomized trials may underestimate the late adverse effects of corticosteroids on all-cause mortality. in addition, most of the aforementioned trials studied dexamethasone, and evidence for methylprednisolone was limited. in this observational study, we thoroughly examined the associations of corticosteroid treatment with -day in-hospital mortality among a population of covid- patients who have developed ards. this single-center, retrospective, cohort study was conducted at the jin yin-tan hospital, wuhan, china. we identified all adult patients with confirmed covid- according to who interim guidance [ ] and patients were admitted between january , , and february , . then, we identified those who developed ards according to the who definition for analysis [ ] . among these patients, have been described previously by wu et al. [ ] , and participated in the open-label trial of lopinavir-ritonavir [ ] . to avoid the influence of early mortality before cortical steroid presenting treatment efficacy, patients who died or discharged within days on hospital admission were excluded. other exclusion criteria were: ( ) participating in any double-blind clinical trial, ( ) under long-term corticosteroid therapy for at least month as part of treatment for chronic underline diseases, or ( ) could not provide valid medical history because of mental disease. the jin yin-tan hospital ethics committee approved the study (no. ky- - . ) and granted a waiver of informed consent from study participants. in jin yin-tan hospital, systemic corticosteroids were considered if patients had progressive respiratory failure or laboratory findings indicated the presence of hyperinflammatory response. in patients receiving mechanical ventilation, preventive ventilation strategy of tidal volume - ml/kg of predicted body weight, inhale positive airway pressure < cmh o, and peep > cmh o was followed. administration of corticosteroids was defined as systemic use (oral or intravenous) of corticosteroids, including methylprednisolone, dexamethasone, hydrocortisone, and prednisone. the primary outcome was keywords: corticosteroids, coronavirus disease , severe acute respiratory syndrome coronavirus , mortality, propensity score, methylprednisolone -day in-hospital mortality. patients were followed to death or discharge from hospital up to days since hospital admission (last clinical outcome was observed on march , ). the secondary outcomes were time to sars-cov- viral clearance since symptom onset. data on demographics, medical history, laboratory findings, chest radiology, medication use, and clinical outcomes were extracted retrospectively from electronic medical records using a standardized data collection form. all data were checked independently by two physicians (dh and xc). from january , , to monitor the clearance of viral rna, sars-cov- rna was tested using polymerase chain reaction from throat-swab specimens for every other day after clinical remission of symptoms, including fever, cough, and dyspnea [ ] . viral clearance was defined as two consecutive negative results. the definitions of ards and other diseases were described in emethods (additional file ). baseline characteristics were compared between patients with and without corticosteroid treatment. data were reported as percentage for categorical variables and as mean ± standard deviation (sd) or median with interquartile range (iqr, - %) for continuous variables. categorical variables were compared by fisher's exact test or pearson chi-square test, as appropriate, and continuous variables were compared by mann-whitney u test or student's t test. to reduce the effect of steroids treatment bias and potential confounding factors, we performed propensity score analysis [ ] to adjust the differences in baseline characteristics. for each patient, a propensity score indicating the likelihood of receiving systemic corticosteroid treatment was calculated by a logistic regression model. the model included pre-selected baseline variables based on the clinical guidelines from national health commission of china, which recommended corticosteroids for patients with progressive respiratory failure and hyperinflammation response. specifically, spo /fio ratio and respiratory rate were included for indicating severe respiratory failure; temperature, heart rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at hospital admission were included for indicating systemic inflammatory response syndrome; age and sex were included as basic characteristics of each patient. the outcome variable was whether or not the patient received corticosteroid therapy in the current hospital stay. goodness of fit was evaluated by the c-statistic and the hosmer-lemeshow test. the effect of corticosteroid treatment on risk of -day in-hospital all-cause death was analyzed using a series of cox proportional-hazard regression models. first, we constructed a univariable cox regression model on hospital death by days since hospital admission with corticosteroid treatment treated as a time-varying covariate. then, we constructed a multivariable cox model of -day hospital death with corticosteroid treatment as time-varying covariate and incorporated the individual propensity score into the model as a covariable to calculate the propensity adjusted hazard ratio (hr). in the final model, the effects of corticosteroids on -day in-hospital death were adjusted for propensity score of corticosteroid treatment, as well as the following pre-selected covariates: age, sex, sequential organ failure assessment (sofa) score at hospital admission, comorbidities (diabetes, hypertension, coronary artery disease, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation) in hospital [ ] . several sensitivity analyses were performed to assess the robustness of our findings. to test whether the findings were influenced by the time point of baseline variables used in propensity score analysis, cox proportional-hazard regression models were repeated in sensitivity analyses: ( ) comparing patients receiving corticosteroids within days after hospital admission versus no corticosteroids; ( ) comparing patients receiving corticosteroids versus no corticosteroids using ards onset date as baseline, where values of spo /fio ratio, respiratory rate, temperature, heart rate, respiratory rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at ards onset were used; ( ) comparing patients receiving corticosteroids within days after ards diagnosis versus no corticosteroids with ards onset as baseline. to test whether the findings might be influenced by ards definition, we conducted survival analysis using the same model among patients diagnosed with ards by berlin definition [ ] . the difference between berlin definition and who definition was that the latter included patients with spo /fio ≤ when pao is not available, and did not restrict to ventilated patients. differences in the time to sars-cov- rna clearance were analyzed using cox proportional-hazard regression adjusted for the same covariables with corticosteroid therapy as a time-varying covariate. patients died without viral shedding or discharged alive before they had two consecutive negative sars-cov- rna tests were censored. the associations between c-reactive protein with corticosteroids treatment after ards onset were analyzed using the interaction between corticosteroids and days after ards onset based on a linear regression model. results were analyzed with sas (version . , sas institute, cary, nc). unadjusted and adjusted hazard ratios and their % confidence intervals (cis) were reported. two-sided p values less than . were considered statistically significant. a total of patients with covid- were screened for the study. forty patients were excluded for participating in any double-blind clinical trial (n = ), death or discharge from the hospital within days after hospital admission (n = ), underwent long-term corticosteroid therapy for chronic kidney disease or rheumatic disease (n = ), or no valid medical history provided because of mental disease (n = ). from patients remained, patients were identified as ards (additional file : fig. s ). baseline characteristics of the ards patients at hospital admission by receiving systemic corticosteroid treatment are shown in table . in the entire cohort, the mean age was . ± . years, and ( . %) patients were male. ( . %) were treated with nimv, ( . %) with imv, and ( . %) with ecmo. all but one of the patients reached end point of decease ( . %) or discharge ( . %) during the follow-up period of days. the median duration of follow-up was . (iqr . - . ) days. a total of ( . %) ards patients had a prescription of systemic corticosteroids. corticosteroids were more likely prescribed to the younger (p = . ) and males (p = . ). corticosteroids group had lower lymphocyte count and higher levels of crp and lactate dehydrogenase at hospital admission than non-corticosteroids group, indicating a propensity in prescribing corticosteroids to patients with more severe immune dysfunction and inflammatory response ( table ). the -day hospital death in patients who ever used corticosteroids was higher than the patients who did not use corticosteroids among patients prescribed corticosteroids, methylprednisolone was the most frequently administered corticosteroids ( / , . %) ( table ) in the logistic regression model generating propensity score, the pre-selected variables most closely correlated with prescription of systemic corticosteroids included age, blood lymphocyte count, heart rate and crp (etable , additional file ). the multivariable regression model of propensity for corticosteroid treatment had area under the receiver operating characteristic curve (roc) of . . in survival analysis, univariable time-dependent cox regression model showed the prescription of corticosteroids was associated with a lower risk of death (hr . ; % ci . , . ; p = . ) ( table ). in full model adjusted for age, sex, sofa score, propensity score, comorbidities, antiviral drugs, and respiratory supports, the association remained (hr . ; % ci . , . ; p = . ) (fig. ) . in sensitivity analysis, narrowing to patients meet the berlin definition of ards did not alter the association between corticosteroids and lower risk of death (hr . ; % ci . , . ; p = . ). the hr of corticosteroids on risk of death was constant when using hospital admission as baseline and excluding patients received corticosteroids days after hospital admission (hr . ; % ci . , . ; p = . ). when using ards onset date as baseline, the associations between corticosteroids and the risk of death were also significant ( blood crp level decreased among corticosteroids group on the first days after ards onset (fig. ) , all of the models assessed the effects of corticosteroids as a time-varying covariate ards acute respiratory distress syndrome, fio fraction of inspired oxygen, sofa sequential organ failure assessment, spo pulse oxygen saturation a adjusted for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities (diabetes, hypertension, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation). propensity score was calculated by a non-parsimonious logistic regression model that included: age, sex, sofa score, temperature, respiratory rate, spo /fio ratio, blood lymphocyte count, blood neutrophil count, and level of c-reactive protein at hospital admission b using values of spo /fio ratio, respiratory rate, temperature, heart rate, respiratory rate, sofa score, blood lymphocyte count, blood neutrophil count, and level of crp at ards onset while an increase was found in non-corticosteroids group. crp levels were significantly lower in corticosteroids-treated group after days of ards onset (p for interaction = . ). in this observational study, prescription of low-to-moderate dose systemic corticosteroids was associated with lower risk of -day in-hospital death among covid- patients who developed ards. the efficiency of corticosteroids was further supported by the reduction of crp, as the marker for suppressed systemic inflammation responses. no associations between corticosteroid treatment with viral shedding were found in our study. our study demonstrates the association between corticosteroid treatment with long-term ( days) risk of death in severe covid- patients. it is biologically plausible that suppression of inflammatory response by corticosteroids may be beneficial for patients with ards, which was caused by dysregulated systemic inflammation [ ] [ ] [ ] and proved the main cause of death. the recov-ery trial and a metanalysis of ongoing rcts showed reduced -day mortality and longer ventilation-free days in patients with corticosteroid treatment [ ] . we used -day in-hospital death as primary endpoint. to our knowledge, it was longer than previously reported rcts. the results showed significant association between corticosteroids and risk of death, which further provide evidence on the long-term benefit of corticosteroids. it was compatible with studies that indicated corticosteroid treatment was not associated with increases in secondary infections in covid- -related ards patients [ , ] . type, dosage, and duration of corticosteroids therapy were fundamental variables of corticosteroid treatment regimens. different from the most of the published rcts using dexamethasone, most of the patients in our study were treated with methylprednisolone. methylprednisolone is a rapid onset glucocorticoid with shorter half-life and less mineralocorticoid effects than dexamethasone, which indicate shorter effects on systemic immunity and preventing corticosteroids-related fluid retention. meduri et al. [ ] firstly promoted the early use of corticosteroids in ards. they found that methylprednisolone reduced the duration of mechanical ventilation, icu stay, and icu mortality in early severe ards patients. in our study, a similar maximum dose (equivalent to methylprednisolone of - mg/kg) of corticosteroids was used, which was also close to the dose in recovery trial and recommended by society of critical care medicine (sccm) and european society of intensive care medicine (esicm) for ards patients [ , ] . our results were in line with the rcts of covid- [ , ] and previous studies of other ards patients, which showed low-dose corticosteroid treatment (equivalent to methylprednisolone of - mg/kg) accelerates the resolution of ards [ , , ] , indicating low-dose methylprednisolone as an alternative to dexamethasone in covid- -related ards. higher dose may increase risks of cox regression model with corticosteroid treatment was time-varying variable, adjusting for age, sex, sofa score at hospital admission, propensity score of corticosteroid treatment, comorbidities (diabetes, hypertension, chronic pulmonary disease, chronic renal or liver disease, solid malignant tumor, hematologic malignancy, and immunosuppressive status), antiviral treatment (lopinavir-ritonavir, oseltamivir, and ganciclovir), and respiratory supports (high-flow oscillation oxygen, noninvasive mechanical ventilation, and invasive mechanical ventilation). propensity score was calculated by a non-parsimonious logistic regression model that included: age, sex, sofa score, temperature, respiratory rate, spo /fio ratio, blood lymphocyte count, blood neutrophil count, and level of c-reactive protein at hospital admission. ards, acute respiratory distress syndrome; sofa, sequential organ failure assessment immune-suppression and corticosteroid-induced complications [ ] [ ] [ ] . in this cohort, tapering strategy was performed as has been suggested by the guidelines for the ards-related corticosteroid insufficiency (circi) to reduce deterioration from the development of a reconstituted inflammatory response and febrile response. of note, a randomized trial included mild covid- patients using a similar dose and shorter course of methylprednisolone ( . mg/kg twice daily for days) than in the regimens of our study found no benefit on mortality. more research is needed to determine the best duration of corticosteroid therapy. a recent analysis of four trials showed prolonged corticosteroids therapy reduced mortality [ ] . however, chronic side effects of corticosteroids including secondary infection and osteoporosis may occur in prolonged course of treatment. delayed virus clearance was reported in corticosteroidtreated patients with both sars, mers, and influenza [ ] [ ] [ ] , which was a major concern for the immune suppressive effects of corticosteroids, albeit its uncertain clinical relevance. we found no difference in viral shedding duration from symptom onset between corticosteroid and non-corticosteroid groups, which may explain the heterogeneity in efficacy of corticosteroids between covid- and other virus infections. of note, positive sars-cov- test results have been reported after two consecutive negative results [ ] . viral tests of throat swabs were not monitored after two consecutive negative tests in our cohort. more evidence is needed for assessing the effects of corticosteroids on clearance of sars-cov- rna. we used rigorous statistical method to control for survival and indication bias. survivors-treated bias exists in observational studies that assess exposure after the start of follow-up, where only patients survived long enough had an opportunity to receive the intervention. therefore, the patients died early are more likely to be misclassified to the no-treatment group, leading to overestimation of the effectiveness of medicine [ ] . this study was specifically designed to address survivors-treated bias of corticosteroid treatment, by using a time-dependent variable for corticosteroids initiation to define corticosteroids group and non-corticosteroids group [ ] . in addition, there was a propensity of clinicians to give corticosteroids to patients who were critically ill in non-randomized clinical condition. the imbalance in baseline characteristics may introduce confounders in comparison of mortality between corticosteroids and non-corticosteroids group. in this cohort, lymphopenia and elevation of crp and lactate dehydrogenase levels were more severe in patients who received corticosteroids therapy. propensity score is a validated method to account for baseline confounding and control selection bias in this case [ ] . in this study, we performed a rigorous propensity adjustment analysis accounting for the baseline variables related to propensity of corticosteroid treatment. these added to the strength of our results that found associations between corticosteroid treatment and risk of death. our study had some limitations. first, unlike randomized controlled trials, the selection bias and potential confounding effects might exist. we used propensity analysis rather than standard multivariable analysis to rigorously adjust for selection bias, and time-dependent model to avoid survivors-treated bias. nonetheless, only measured factors were controlled for due to the nature of observational study design. second, secondary infections were not monitored in this study, because microbiological culture results needed for definite diagnosis of secondary infection were possibly affected by antibiotic treatment the patients received simultaneously. to include the delayed effects of secondary infections on mortality, a longer follow-up period of days was used. third, this study was single center and patients were sicker and transferred from other hospital, so might lacking of generality. forth, some of the patients were treated with lopinavir-ritonavir; it might be a confounder because the efficacy of lopinavir-ritonavir in covid- was unclear. fifth, our cohort was collected in the early outbreak of covid- ; thus, the mortality was relatively higher than other studies, which limited generalization of our results. our findings suggest administration of low dose of corticosteroids might reduce the risk of death in covid- patients who developed ards. supplementary information accompanies this paper at https ://doi. org/ . /s - - - . additional file : emethods, etable and , and efigure were included. director-general's opening remarks at the media briefing on covid- - coronavirus disease (covid- ) situation report- clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china on the use of corticosteroids for -ncov pneumonia clinical evidence does not support corticosteroid treatment for -ncov lung injury corticosteroid administration for viral pneumonia: covid- and beyond treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience dexamethasone in hospitalized patients with covid- -preliminary report association between administration of systemic corticosteroids and mortality among critically ill patients with covid- : a meta-analysis effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and covid- : the codex randomized clinical trial methylprednisolone as adjunctive therapy for patients hospitalized with covid- (metcovid): a randomised, double-blind, phase iib, placebo-controlled trial exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected a trial of lopinavir-ritonavir in adults hospitalized with severe covid- aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: a propensity analysis convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold open access which fosters wider collaboration and increased citations maximum visibility for your research: over m website views per year • at bmc, research is always in progress. learn more biomedcentral.com/submissions ready to submit your research ready to submit your research ? choose bmc acute respiratory distress syndrome: the berlin definition methylprednisolone infusion in early severe ards: results of a randomized controlled trial corticosteroid guideline task force of s, esicm: guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (circi) in critically ill patients (part ii): society of critical care medicine (sccm) and european society of intensive care medicine (esicm) the clinical practice guideline for the management of ards in japan prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients corticosteroid therapy for critically ill patients with middle east respiratory syndrome viral loads and duration of viral shedding in adult patients hospitalized with influenza dynamic profile of rt-pcr findings from covid- patients in wuhan, china: a descriptive study a most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies quantifying the impact of survivor treatment bias in observational studies invited commentary: propensity scores national institutes of health nhl, blood institute an: comparison of the spo /fio ratio and the pao /fio ratio in patients with acute lung injury or ards publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - rji p authors: robba, chiara; robba, chiara; battaglini, denise; ball, lorenzo; patroniti, nicolo’; loconte, maurizio; brunetti, iole; vena, antonio; giacobbe, daniele; bassetti, matteo; rocco, patricia rieken macedo; pelosi, paolo title: distinct phenotypes require distinct respiratory management strategies in severe covid- date: - - journal: respir physiol neurobiol doi: . /j.resp. . sha: doc_id: cord_uid: rji p coronavirus disease (covid- ) can cause severe respiratory failure requiring mechanical ventilation. the abnormalities observed on chest computed tomography (ct) and the clinical presentation of covid- patients are not always like those of typical acute respiratory distress syndrome (ards) and can change over time. this manuscript aimed to provide brief guidance for respiratory management of covid- patients before, during, and after mechanical ventilation, based on the recent literature and on our direct experience with this population. we identify that chest ct patterns in covid- may be divided into three main phenotypes: ) multiple, focal, possibly overperfused ground-glass opacities; ) inhomogeneously distributed atelectasis; and ) a patchy, ards-like pattern. each phenotype can benefit from different treatments and ventilator settings. also, peripheral macro- and microemboli are common, and attention should be paid to the risk of pulmonary embolism. we suggest use of personalized mechanical ventilation strategies based on respiratory mechanics and chest ct patterns. further research is warranted to confirm our hypothesis. presentation of covid- patients are not always like those of typical acute respiratory distress syndrome (ards) and can change over time. this manuscript aimed to provide brief guidance for respiratory management of covid- patients before, during, and after mechanical ventilation, based on the recent literature and on our direct experience with this population. we identify that chest ct patterns in covid- may be divided into three main phenotypes: ) multiple, focal, possibly overperfused ground-glass opacities; ) inhomogeneously distributed atelectasis; and ) a patchy, ards-like pattern. each phenotype can benefit from different treatments and ventilator settings. also, peripheral macro-and microemboli are common, and attention should be paid to the risk of pulmonary embolism. we suggest use of personalized mechanical ventilation strategies based on respiratory mechanics and chest ct patterns. further research is warranted to confirm our hypothesis. . within few weeks, outbreaks of so-called novel coronavirus (ncov) infection had spread worldwide. on february , , the world health organization announced coronavirus disease as the name of this new disease, and exactly one month later, declared the situation a pandemic [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . as of april j o u r n a l p r e -p r o o f , the pandemic is ongoing in the majority of countries [ , ] . data from china suggest that % of patients who require intensive care unit (icu) admission share similar comorbidities, such as diabetes and preexisting heart disease . although an extensive literature is available to guide management of the acute respiratory distress syndrome (ards), covid- is a new viral infection of the lower respiratory tract whose pathophysiology and treatment are still poorly understood. more than % of confirmed covid- cases present as a mild febrile illness. however, a small proportion of patients will experience critical illness, with many of these requiring mechanical ventilation . in one study conducted in wuhan, . % of patients hospitalized for covid- develop acute respiratory failure, with a fatality rate of . % . the median time from symptom onset to respiratory failure was days . at icu admission, most covid- patients present acute onset of hypoxemic respiratory failure, with oxygen saturation (spo ) levels below % . risk factors associated with respiratory failure and death include older age, neutrophilia, coagulation dysfunction, organ failure, and elevated d-dimer . at autopsy, the lungs of patients with confirmed sars-cov- infection exhibit slurry within the alveolar cavity, fibrinous exudation, and proliferation of type ii alveolar epithelial cells and macrophages. moreover, alveolar septal vascular congestion, edema, vascular thrombi with focal intraparenchymal hemorrhage, and hemorrhagic infarction are common, suggesting an important role of the vascular compartment and lung perfusion in the pathophysiology of covid- . to date, the respiratory management of covid- has relied on the general principles of ards management; however, computed tomography of the chest may provide interesting insights into the pathophysiology and individualization of mechanical ventilation in these patients. the aim of this manuscript is to provide brief guidance for respiratory management before, during, and after mechanical ventilation in covid- patients, based on the literature and our direct experience with this population. furthermore, we describe three distinct phenotypes of covid- pneumonia, j o u r n a l p r e -p r o o f represented by distinct patterns of chest ct findings, their pathophysiological correlations, and their implications for management. computed tomography (ct) of the chest is essential to understand the diversity of pathological findings and optimize and individualize therapy for covid- patients ( fig. ) [ ] [ ] [ ] [ ] [ ] . typical chest ct findings in covid- include bilateral infiltrates with multiple ground-glass opacities or consolidation, but no edema . some patients exhibit asymmetrical edematous lesions and atelectasis, or scattered fibrosis . given the low resolution of plain radiography, we recommend that chest ct be performed in all severe patients. however, unfortunately, ct scanning is not available in all emergency departments, and may require transfer of the patient to a radiology suite. lung ultrasound is a developing technique which has been used extensively in ards patients over the last decades and may be useful for safe, noninvasive bedside diagnosis of covid- pneumonia; specific lung ultrasound patterns have been described . nevertheless, this technique has several limitations, such as the need for formal training, interobserver variability, and limited accuracy (particularly in obese patients and in the presence of subcutaneous emphysema). to date, there have been few reports of chest ct findings in . ct imaging demonstrates five stages according to the time since onset and disease progression: ) very early stage (asymptomatic, positive nasopharyngeal swab): single, double, or scattered focal ground-glass opacity, nodules located in central lobule surrounded by patchy ground-glass opacities, patchy consolidation and air bronchogram sign; ) early phase: monitoring of chest ct features is of extreme importance in these patients to personalize treatment strategies and mechanical ventilator settings (fig. ) . in particular, chest ct scan can help in the assessment of areas of atelectasis or overperfusion and shunting, as well as evaluation of the risk of pulmonary embolism. we have identified three main chest ct patterns in covid- patients, representing three different phenotypes: ) multiple, focal, possibly overperfused ground-glass opacities mainly in the subpleural region; ) inhomogeneously distributed atelectasis and peribronchial opacities; and ) a patchy ards-like pattern. these differing phenotypes are attributable to different pathophysiological mechanisms, and therefore require different ventilatory strategies; however, the phenotypes we propose seem to be in agreement with gattinoni et al. (gattinoni et al., a) (gattinoni et al., b) , who proposed a phenotype l (low elastance, low ventilation to perfusion ratio, and low lung reclutability) compatible with our phenotype , a phenotype h (high elastance, and simil ards pattern), compatible with our phenotype , and a transitioning phenotype, which reflects the evolution of the disease. supplemental oxygen is recommended in covid- patients if the peripheral saturation of oxygen (spo ) is below %, and spo should be maintained no higher than % (alhazzani et al., ) . few data are available on the efficacy of noninvasive support-which includes continuous positive airway pressure (cpap), noninvasive ventilation (niv), and high flow nasal oxygen (hfno)-in covid- pneumonia. in patients with influenza a(h n ) infection, noninvasive positivepressure ventilation was associated with a high incidence of failure ( - %), and patients who failed noninvasive support experienced a higher mortality rate than those treated with early j o u r n a l p r e -p r o o f mechanical ventilation (kumar et al., ) ] . the experience in covid- patients from wuhan was similar, with a high rate of noninvasive support failure and need for intubation and mechanical ventilation in % of cases; nevertheless, there was no difference in mortality between patients receiving noninvasive vs invasive ventilation . in general, noninvasive ventilatory management carries a high risk of generating negative (and unmeasured) intrathoracic pressures, and is thus potentially counterproductive (brochard et al., ) . noninvasive support also presents a higher risk of viral spread through mask leaks, with increased risk of transmission ( fig. ) . furthermore, delayed intubation increases the risk of clinical deterioration and the need for emergency airway management. in general icu patients, hfno has been shown to decrease the need for tracheal intubation in acute hypoxemic respiratory failure when compared to conventional oxygen therapy, without impacting mortality (rochwerg et al., ) . a randomized controlled trial comparing niv and hfno in patients with hypoxic respiratory failure showed that hfno was able to reduce mortality at days without affecting the need for intubation ( % vs %, p= . ) (frat et al., ) , while a meta-analysis comparing hfno vs niv demonstrated that hfno is able to significantly decrease the need for intubation (ni et al., ) . therefore, in adults with covid- and acute respiratory failure, hfno should be preferred over niv. both niv and hfno are being used extensively in covid- patients, especially in cases of milder disease or to buy time before invasive ventilation is commenced. however, the potential advantages of using niv or hfno in these circumstances have to be balanced against their risks. when a patient presents with severe respiratory failure or on a downward spiral that suggests intubation will be inevitable, noninvasive respiratory support should not be attempted [ ] . when hypoxemia and respiratory failure persist or worsen after oxygen therapy or within a short time ( hour) of placement of hfno or niv support, or in case of persistent hypercapnia, organ failure, coma, risk or aspiration, or hemodynamic instability, invasive mechanical ventilation should j o u r n a l p r e -p r o o f be implemented as soon as possible (fig. ) . hypoxemic respiratory failure and need for invasive ventilation should be considered when patients receiving standard oxygen therapy exhibit tachypnea (> bpm) and hypoxemia (spo < % or partial pressure of oxygen (pao ) < mmhg) with oxygen administered via a facemask and reservoir bag (gas flow of ~ l/min, fraction of inspired oxygen (fio ) . - . ). similarly, when a patient under hfno support with fio > % and gas flow > l/min or niv experiences persistent respiratory failure or deteriorates acutely, mechanical ventilation should be promptly initiated . fig. presents our algorithm for trialing cpap and indications for centralization and intubation of patients with covid- respiratory failure. according to our experience, phenotype is likely to be found when patients are promptly intubated and receive only brief or no noninvasive respiratory support. patients who receive prolonged noninvasive ventilation are likely to develop phenotype or , thus becoming more difficult to ventilate, with lower compliance and worse deterioration of oxygenation. the process of endotracheal intubation is considered to pose a high risk of aerosol-based transmission [ , ] . some hospitals have created dedicated spaces for planned airway management of covid- patients (such as airborne infection isolation rooms); negative pressure ventilation rooms with an antechamber are ideal to minimize exposure during the procedure, whereas positive-pressure areas must be avoided (zuo et al., ) . the intubation team should start the maneuver only after appropriate airborne/droplet protections are in place and all team members are wearing adequate personal protective equipment (ppe). airway devices, venous access devices, anesthetics, suction, ventilators, and basic monitoring should be guaranteed and readily available before starting. a rapid difficult-airway assessment should be done to recognize those at risk for difficult airway management. intubation should be performed by the most experienced clinician, with the help of another doctor, and the most familiar airway device should be the first choice for intubating (zuo et al., ) . preoxygenation with % fio for minutes before induction of anesthesia could be useful. pre-oxygenation should be j o u r n a l p r e -p r o o f performed, using a well-fitting occlusive face mask attached to a manual ventilation device with an oxygen source (zuo et al., ) . a viral filter must be inserted between the facemask and manual ventilation device to minimize aerosolization. the viral filter should be applied directly to the face mask, since the greater the number of connections between the facemask and filter, the greater the risk of disconnection on the patient side and subsequent aerosolization of the virus (zuo et al., ) . after intubation, if using a humidified ventilator circuit, the viral filter used for intubation will need to be removed promptly; if a dry circuit is used, a combined heat-moisture exchanger (hme) and viral filter can be left in place, but this means that nebulization cannot be administered without breaking the circuit (to place a nebulizer between the patient and the hme). if the viral filter has been removed, the ventilator should be placed on standby for all circuit disconnections. each disconnection from the ventilator should occur with the tube clamped to minimize the risk of aerosolization. with relatively well-maintained lung mechanics (good compliance) but severe hypoxemia, which could be consequent to impaired lung perfusion. moreover, chest ct patterns differ among patients and over time. as noted above, we have found that chest ct findings in covid- fall into three different phenotypes, each warranting unique mechanical ventilation settings and management strategies, which should thus be individualized based on clinical and ct features (fig. , additional file , fig. s ). in phenotype , lung compliance is preserved or even elevated; chest ct shows no or few alveolar areas to recruit, but rather high-perfusion areas (fig. , additional file , fig. s a ). in these cases, the main cause of hypoxemia seems to be not atelectasis, but impaired distribution of lung perfusion and shunting. moderate peep levels may therefore be able to redistribute pulmonary blood flow from damaged to non-damaged lung areas; however, higher peep levels can impair cardiac function, thus increasing the need for fluids and vasoconstrictor drugs without having important effects on oxygenation. tidal volumes > ml/kg should also be considered. in phenotype , atelectasis is inhomogenously distributed. moderate to high peep can be therefore useful to improve lung recruitment, as well as lateral or prone positioning (fig. , additional file , fig. s b ). in phenotype , general principles applied to ards management should be used, including low tidal volume (< ml/kg) and peep titration according to peep/fio table and respiratory mechanics [ , ] (fig. , additional file , fig. s c ). prone positioning can have an important role in severe ards to redistribute pulmonary blood flow, reduce atelectasis, and improve oxygenation (fig. ) (guérin et al., ) . in a meta-analysis including more than patients with moderate to severe ards, prone ventilation for at least hours had a beneficial effect on mortality (five randomized controlled trials; relative risk . , % confidence interval . to . ); however, no effect on mortality was detected when prone ventilation was used for less than hours (sud et al., ) . a recent study showed that prone ventilation has been frequently used in covid- patients ( . %) . however, based on the foregoing, we do not recommend prone positioning of covid- patients with phenotype . it should be reserved for phenotypes and , to redistribute pulmonary blood flow and reduce atelectasis. in short, the recommendation to use prone positioning is associated with chest ct features and should be individualized and reevaluated in each patient over time. it is fundamental that a protocol for prone positioning by available and that proning be performed by specifically trained personnel to avoid risks of infection or accidental endotracheal tube disconnection from the ventilator (alhazzani et al., ) . inhaled nitric oxide (ino) can theoretically have an important role as rescue therapy to improve lung perfusion, but the effect of ino is balanced by the lung anatomical pattern as well as by regional perfusion. recently published guidelines (alhazzani et al., ) did not recommend j o u r n a l p r e -p r o o f routine use of ino in covid- patients with respiratory failure. in phenotype , ino may potentially improve oxygenation by acting on lung perfusion (fig. ) , but no data are available from this population. continuous infusion of neuromuscular blocking agents (nmba) should be reserved for covid- patients in which intermittent dosing may not suffice, such as: patients undergoing prone positioning, persistent ventilator asynchrony, and those with high plateau pressures (alhazzani et al., ) . recruitment maneuvers (rms) are not routinely recommended in covid- patients [ , ] . in a systematic review and meta-analysis including , patients, traditional rms significantly reduced mortality, whereas incremental peep titration rms increased death rate. patients with phenotype are likely not to benefit from rms, whereas in phenotype and rms may help improve oxygenation. when needed, traditional rms along with higher levels of peep should be preferred over incremental peep-based rms (gattinoni et al., ) . finally, in mechanically ventilated covid- patients with refractory hypoxemia despite conventional treatment and prone positioning, veno-venous (vv) extracorporeal membrane oxygenation (ecmo) can be considered as an option. however, given the need for resources, training, and associated risks, it should be used as rescue therapy only, in carefully selected patients. patients with covid- often present in a hypercoagulable state. thromboembolic events, ranging from microemboli to massive pulmonary embolism, are common and can contribute to respiratory failure, as well as precipitate clinical deterioration (additional file , fig. s ) . in a preprint study [ ] , decreased platelet counts, increased fibrinogen and d-dimer levels were observed in out of patients, and prolonged prothrombin time was detected in . %. in this context, early coagulation screening, serial echocardiography, and ct pulmonary angiography can provide important information, particularly in more severe cases with sudden respiratory or hemodynamic deterioration. in a recent retrospective study of patients with , d-dimer and fibrinogen correlated linearly with ct imaging score and changed dynamically according to disease progression. therefore, although the literature is lacking on this specific topic, strict monitoring and early anticoagulation should be considered to mitigate multiorgan damage in severe covid- . changes in pleural pressure (ppl) and transpulmonary pressure can be detrimental to hemodynamics. the increase of ppl after application of positive airway pressure has the effect of decreasing left ventricular afterload and blood pressure. of note, if ppl exceeds pulmonary venous pressure, west zone conditions arise due to microvascular collapse; likewise, if ppl and interstitial pressures overcome pulmonary arterial pressure, pulmonary blood flow is obstructed (west zone ). in both conditions, alveolar pressure represents the driver that boosts right ventricle afterload (vieillard-baron et al., ) . during controlled mechanical ventilation, peep and tidal forces increase pulmonary vascular resistance and ppl, thus influencing mean alveolar pressure (which can be clinically approximated to mean airway pressure). it can also be influenced by longer duty cycles and higher driving pressures (vieillard-baron et al., ) . high mean arterial pressure can increase west zone conditions, thus increasing dead space and shunt fraction. in some cases, elevated right-side pressures may overdistend the right ventricle, thus causing stiffness of the left ventricle in an interdependent manner. such condition needs to be evaluated by changes in venous saturation of oxygen (svo ), and arterial saturation (sao ) (vieillard-baron et al., ) . cardiac injury is common after covid- , occurring in - % of cases. it is heralded by increased levels of troponin and nt-probnp, and is associated with poor outcome . patients with a history of cardiovascular conditions, such as hypertension or diabetes, are at j o u r n a l p r e -p r o o f higher risk. we suggest close monitoring of cardiac function and serial echocardiography in all patients with covid- . although in most cases covid- patients present with isolated viral pneumonia, septic shock may occur and should be promptly recognized and treated. if fluids are needed, isosmotic crystalloids are preferred vs colloids; albumin may be considered as a resuscitation fluid; conservative fluid management should be adopted, and vasopressors should be administered if necessary to improve microcirculation, titrated to a target mean arterial pressure of mmhg with lactate ≥ mmol/l. empiric antibiotics targeting any suspected potential bacterial superinfection should be administered as soon as possible. systemic corticosteroids are controversial in severe ards; methylprednisolone can be used as appropriate for patients with rapid disease progression or severe illness. according to severity, to mg of methylprednisolone per day can be considered, and the total daily dose should not exceed mg/kg. in a recent study , methylprednisolone therapy decreased the risk of death in covid- patients with respiratory failure. however, due to lack of evidence, the routine use of corticosteroids should be avoided. short courses ( - days) can be considered according to clinical status and chest imaging [ ] . corticosteroids might be especially useful in patients with a heightened inflammatory response; therefore, pcr and interleukin (il)- levels should be considered when deciding whether to start steroids in these patients. the weaning process should follow the general criteria for weaning in any type of respiratory failure. as specific criteria for extubation of covid- patients have not yet been established, generic guidelines (popat et al., ) should be followed. fig. presents our algorithm for weaning and extubation. patients can be eligible for a trial of extubation once they are well awake, j o u r n a l p r e -p r o o f exhibit good cough reflexes, and have stable hemodynamic and ventilatory parameters. at this stage, a spontaneous breathing trial (sbt) is performed before considering endotracheal tube removal. niv and hfno can be considered after extubation . patients should ideally be non-infective prior to extubation, but this is likely to be unfeasible. when patients are still at risk of transmission, few recommendations are available to reduce the risk of infection; these include placement of a simple oxygen mask on the patient immediately after extubation to minimize aerosolization, the use of high peep levels, and avoidance of cough. if feasible, separate beds should be reserved for patients suitable for extubation trials (regardless of whether they are still positive for sars-cov- ) to reduce the risk of reagudization and, ultimately, reinfection of other patients. the novel severe acute respiratory syndrome caused by sars-cov- progresses incredibly quickly and is associated with high fatality rates. although the pulmonary pattern of critically ill patients with covid- has been defined as ards, it does not always represent or even resemble ards. chest ct scan features differ among patients, establishing distinct phenotypes; over time, these and might guide therapy and ventilator settings. further studies are warranted to provide additional insight on the respiratory management of patients with severe covid- . cr, db, prmr and pp participated in the design of the review, and write the manuscript; lb, np, ml, and ib contributed discussing different parts of the mechanical ventilation strategies. all authors read and approved the final manuscript. not applicable j o u r n a l p r e -p r o o f the authors declare that they have no competing interests ) phenotype : good compliance, but severe hypoxemia. peep should be set with the aim to redistribute pulmonary flow and reduce shunting. in this case, using the principles generally applied in ards, and thus setting the peep according to the best driving pressure, will probably lead to use of lower peep (as the compliance is good), resulting in less oxygenation. ino could be considered in these cases, and prone positioning can redistribute perfusion, but is generally not very useful at this stage. j o u r n a l p r e -p r o o f fig. : genoa algorithm for the advanced respiratory management of patients with covid- related respiratory failure. this algorithm establishes objective tests which can be performed at bedside to determine whether a patient can be managed on oxygen alone, thus rationalizing ventilator and ppe use, and provides clear steps for escalation to cpap and intubation. neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure lung recruitment in patients with the acute respiratory distress syndrome covid- pneumonia: different respiratory treatments for different phenotypes? covid- does not lead to a "typical" acute respiratory distress syndrome cardiovascular implications of fatal outcomes of patients with coronavirus disease critically ill patients with influenza a(h n ) infection in canada the effect of high-flow nasal cannula in reducing the mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with conventional oxygen therapy and noninvasive positive pressure ventilation. a systematic review and meta-analysis findings of lung ultrasonography of novel corona virus pneumonia during the - epidemic difficult airway society guidelines for the management of tracheal extubation risk factors for noninvasive ventilation failure in critically ill subjects with confirmed influenza infection the response of milan's emergency medical system to the covid- outbreak in italy effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis ards guidelines jama -ards the berlin definition experts' opinion on management of hemodynamics in ards patients: focus on the effects of mechanical ventilation clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan risk factors associated with acute clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study a pathological report of three covid- cases by minimally invasive autopsies clinical characteristics of patients infected with sars-cov- in wuhan expert recommendations for tracheal intubation in critically ill patients with noval coronavirus disease phenotype : atelectasis and derecruitment are predominant. in this case, high peep and prone positioning can recruit non-aerated areas of the lung. recruitment maneuvers (rms) may play a role in these cases phenotype : typical ct pattern of moderate-to-severe ards, with alveolar edema and low compliance key points summarizing our recommendations for the respiratory management of covid the authors thank mr. filippe vasconcellos (são paulo), brazil, for his assistance in editing the manuscript. key: cord- - ks bopm authors: nejatifard, marzieh; asefi, sohrab; jamali, raika; hamblin, michael r.; fekrazad, reza title: probable positive effects of the photobiomodulation as an adjunctive treatment in covid- : a systematic review date: - - journal: cytokine doi: . /j.cyto. . sha: doc_id: cord_uid: ks bopm background covid- , as a newly-emerged viral infection has now spread all over the world after originating in wuhan, china. pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ards) in up to one –third of the cases. pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. the anti-inflammatory effect of the photobiomodulation (pbm) has been confirmed in many previous studies. therefore, this review study was conducted to evaluate the direct effect of pbm on the acute lung inflammation or ards and also accelerating the regeneration of the damaged tissues. the indirect effects of pbm on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. methodology the databases of pubmed, cochrane library, and google scholar were searched to find the relevant studies. keywords included the pbm and related terms, lung inflammation, and covid- -related signs. studies were categorized with respect to the target tissue, laser parameters, and their results. results seventeen related papers were included in this review. all of them were in animal models. they showed that the pbm could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (tnf-α), interleukin beta (il- β), interleukin (il- ), intracellular adhesion molecule (icam), reactive oxygen species (ros), isoform of nitric oxide synthase (inos), and macrophage inflammatory protein (mip- )). conclusion our findings revealed that the pbm could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. pbm can increase the oxygenation indirectly in order to rehabilitate the affected organs. thus, the infra-red lasers or light-emitting diodes (leds) are recommended in this regard. coronaviridae is a family of the enveloped rna viruses, which can infect the humans or other mammals. the two beta corona viruses known as sars cov and mers cov are among some of the well-known viruses within this family. in the recent decades, two epidemics of the acute respiratory syndrome (ars) including severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) have occurred. mild to severe pneumonia was the main feature of these syndromes. beginning in december , a novel type of coronavirus was emerged in wuhan, china that caused a disease known as corona virus disease (covid- ) ( ) . high transmissibility is the hallmark of this virus. the rapid worldwide distribution of the covid- led to the declaration of a pandemic by the world health organization (who). epidemiologic data have shown that the median age of the patients is between - years old ( ) . high fever, myalgia, dry cough ,and dyspnea are the most common clinical symptoms of the disease ( ) . pneumonia is the hallmark of this infection. it can be distinguished from other probable types of pneumonia by the "crazy paving" lesions observed in the chest ct scans. they are the bilateral ground glass opacities in the parenchyma of the lungs ( ) . diarrhea, sputum production, headache, haemoptysis, rhinorrhea, sneezing and sore throat are other common symptoms of this disease ( , ) . clinical data have suggested that the pneumonia could cause dyspnea in roughly half of the patients (liu, ) . one -third of the patients may develop the acute respiratory distress syndrome (ards) and require admission to an intensive care unit (icu). invasive mechanical ventilation is needed in and % of the patients who are candidates for the extracorporeal membrane oxygenation (ecmo). older or smoker patients are more likely to require the invasive life support ( ) . lower blood oxygenation and tissue hypoxia can be expected following the damage to the respiratory system. concomitant tissue hypoxia can lead to a subsequent damage to the heart or central nervous system, considering their sensitivity to the blood oxygen supply. the paraclinical findings include the hypoalbuminemia, leukopenia, lymphopenia, and low platelet counts. increased serum level of c-reactive protein, aminotransferase ( ) ,and lactate dehydrogenase (ldh) can be seen in these patients. the number of cluster of differentiation (cd ) cells may be reduced during the course of the disease ( ) . levels of some inflammatory cytokines, such as il- b, il- , interferon-gamma (ifnγ), interferon-gamma-inducible protein- (ip ) and monocyte chemotactic protein- (mcp ) increase in the serum. these cytokines increase the number and function of t helper type (th ) lymphocytes. meanwhile, activation of t helper type (th ) lymphocytes following the release of interleukin (il- ) and interleukin (il- ) could also be expected. in the patients with severe disease admitted to the icu, high levels of granulocyte colony-stimulating factor (gcsf), ip , mcp , macrophage inflammatory protein a (mip a) ,and tnfα have been commonly found ( ) . in a recent study, it was suggested to consider a "cytokine storm" in the covid- . cytokine storm results in an influx of a lot of immune cells into the infection site, damage of the vascular barrier or capillaries, and may also lead to the multi-organ failure. an increase was observed in the level of many cytokines in the covid- disease including il- β, interleukin (il- ), interleukin (il- ), interleukin (il- ), il- , fibroblast growth factor (fgf), g-csf, granulocyte macrophage colony-stimulating factor (gm-csf), ifn-γ, ip- , mcp- , mip- a, macrophage inflammatory protein b (mip -b), platelet-derived growth factor (pdgf), tnf-α, and vascular endothelial growth factor (vegf). il- , tnf-α, and il- are the most important pro-inflammatory cytokines. it was found that the il- has a pivotal role in the covid- disease especially it is associated with higher mortality. ( ) although, the clinical features of the covid- are less severe than the sars or mers, it is more easily transmitted. the mortality rate of the covid- is equal to - %, while it is equal to and % in the sars and mers, respectively. presently, there is no gold standard treatment protocol available for the covid- . supportive protocols are recommended most often. there is a considerable controversy about the beneficial effects of the antiviral medications and corticosteroids, although dexamethasone has been shown to be effective in reducing the deaths recently. the efficacy of the lopinavir plus ritonavir ( ) has also been reported in treating the mers. in the meantime, remedesivir ( , ) has been indicated to have a good antiviral effect in treatment of the sars/mers. since, the corticosteroids can alleviate the inflammation and subsequent injury, they are also recommended for the severe cases in which standard supportive procedures were not adequate. however, there is no evidence stating that the steroids can reduce the mortality rate in ards in general ( ) . corticosteroids can prolong the virus clearance ( ) and might cause immune suppression with concomitant susceptibility to the secondary infections ( , ) . hyperglycemia, heart attack, hypertension, and gastrointestinal bleeding are some important side effects of the corticosteroids. ( ) . it should also be mentioned that nearly half of the covid- patients have underlying systemic diseases like diabetes, hypertension, and cardiovascular diseases. therefore, corticosteroid prescription might worsen the patient's underlying systemic disease. another point is the existence of genetic polymorphisms, which can influence the patients҆ response to the corticosteroids. this issue might explain why some patients with ards may experience harmful outcomes after steroid administration ( ) . the pandemic of covid- underlines the importance of supportive protocols, which can reduce the inflammation in the severe cases. as previously mentioned, comprehensive evaluation of the patients҆ medical history is necessary to catalogue the underlying systemic diseases and the used medications. the situation is challenging in emergencies where there are many infected patients along with a shortage of medical services as observed in the covid- pandemic. at the moment, there is no definitive treatment, so the therapeutic protocols should be confined to supportive treatments in order to alleviate the inflammation. photobiomodulation could be a promising novel treatment approach. in this non-invasive method, light-emitting diodes or low-level lasers are used to irradiate on the tissue in order to activate the cellular photo-acceptors. irradiation is absorbed by the internal photo-acceptors like porphyrins, cytochrome c oxidase, and light -sensitive ion channels. cytochrome c oxidase is unit iv of the mitochondrial respiratory chain, absorbing the red and near infrared wavelengths. this leads to higher electron transport, increased mitochondrial membrane potential and increased production of the adenosine triphosphate (atp). light-sensitive ion channels absorb the photons, which increases the concentration of the intracellular calcium (ca +) ions. these processes activate several signaling pathways via reactive oxygen species (ros), cyclic adenosine monophosphate (camp), nitric oxide (no) ,and ca + ( , ) (figure ). these pathways influence the cellular processes like proliferation and differentiation, and can also influence other processes like inflammation as histamine release, prostaglandin production, or cyclo-oxygenase expression ( ) ( ) ( ) ( ) . in this way, pbm can be helpful in accelerating the regeneration processes like wound healing and reducing the inflammation ( ) . pbm has mainly local effects and can be irradiated just to a target organ without any side effects on the distant areas. considering the anti-inflammatory and biostimulatory effects of the pbm, it seems to be a reasonable approach to be applied in controlling the covid- symptoms especially in the cases with ards. therefore, this study was conducted to evaluate the direct effect of the pbm on the acute lung inflammation or ards and accelerating the regeneration of the damaged tissue. moreover, the indirect effects of the pbm on modulation of the immune system or blood flow oxygenation within the tissues were also investigated. our search was categorized based on the common covid- symptoms including respiratory problems and also paraclinical changes influencing the blood cells or cytokines. the review strategy was constructed according to the preferred reporting items for systematic reviews and meta-analyses (prisma) checklist. the databases of medline, pubmed, cochrane library, and google scholar were comprehensively searched to find the relevant studies. initially, there were no time or language limitations, in order to avoid missing any relevant papers. in the next step, the non-english papers were excluded from the study. the included papers were evaluated for the effect of light therapy, pbm, or low -level laser therapy on the lung inflammation, ards, lymphocytes, neutrophils, and lung parenchyma. papers were categorized with respect to the type of light source, wavelength, target tissue/ organ, light source parameters, and pbm results. references in all of the included papers were also reviewed. totally, available papers were retrieved from the pubmed database. twelve papers were excluded due to non-english language and three papers were duplicates. there were available papers on the cochrane library and none of them were related. search in the google scholar database yielded papers. fig. shows the final included papers in the form of a diagram. there were some related studies evaluated the effect of the pbm on the chronic respiratory inflammation (such as chronic obstructive pulmonary disease (copd) and asthma). table shows the related papers included in this study. all the studies confirmed that the pbm can reduce the lung inflammation, neutrophil recruitment, and pro-inflammatory cytokine production. during the clinical course of the covid- disease, dyspnea can start as early as days after the infection. coughing is a major sign, indicating an inflammatory reaction in the respiratory system. sputum production is another common sign of the disease. ground glass opacities can be found in the chest radiographs and there are more of them in the severe cases. ards may occur after days and it can be observed in one-third of the patients. it is a life-threatening condition, which might require invasive mechanical ventilation in % of the patients and extracorporeal membrane oxygenation (ecmo) in % of the patients. elderly patients and smokers are more likely to require the invasive life support ( ) . although, there is no definititive treatment protocol for the covid- disease yet, supportive care is the mainstay for management of the covid- infection. chloroquine, kaletra ( ), remedesivir ( , ) , tocilizumab, favipiravir ( ) ,and a combination of lopinavir and ritonavir ( ) are some of the treatment options in this regard, but no definite effect has been observed on the patients҆ survival after treatment with these medications ( ). corticosteroids are the most common anti-inflammatory option. inhibiting the edema formation, leukocyte extravasation, fibrin deposition, capillary dilation, and phagocytosis are some of positive effects of the corticosteroids. reduction of inflammation can also be induced by triggering the apoptosis of the eosinophils and lymphocytes ( , ) . it should be considered that prescription of the corticosteroids should be confined to the icu-admitted cases with ards ( ). they may lead to higher susceptibility to the secondary infections ( , ) and delay the viral clearance ( ). chan et al., suggested that the corticosteroids should only be used in the severe ards cases where standard supportive measures are insufficient. corticosteroids should not be prescribed when there is a remaining infection ( ) . also, genetic polymorphisms play a pivotal role in the patient's response to the corticosteroids. a wide range of adverse reactions make the use of corticosteroids questionable in the ards induced by the covid- . other potential side effects of the corticosteroids may affect other organs especially the liver and kidneys as major organs for metabolism. other side effects include the hyperglycemia, polyneuropathy in the patients staying in the icu for a long time, higher risk of necrotizing myopathy, risk of secondary infections, delayed wound healing, suppression of calcium absorption leading to the osteoporosis and avascular necrosis of the hip, and gastrointestinal ulcers ( ) . also, the corticosteroids may have negative interactions with other medications taken by the patients. this situation is more noticeable in the covid- patients where nearly half of them are older and usually have underlying systemic diseases like diabetes, hypertension, cardiovascular diseases, etc., requiring the additional medications or have compromised immune systems. moreover, covid- sharply lowers the blood oxygenation, which can directly damage the pulmonary tissues or indirectly damage the other organs like the heart or brain by inducing the hypoxia. our experience in the recent covid- pandemic suggests that the clinicians should consider a comprehensive evaluation of the patient's medical condition, medications, systemic diseases, genetic polymorphisms that may affect the drug reactions. these factors make it complex for the clinicians to manage an emergency like the covid- , involving large numbers of the infected people along with insufficient medical services. as mentioned above, there is not yet any definite treatment for the covid- therefore, every possible intervention ,which may help to reduce the inflammation and restore the respiratory system or other impaired tissues could be tried for managing the covid- progression. this could be achieved by direct rehabilitation of the damaged tissue, or indirectly by increasing the oxygenation and blood flow. so, reducing the inflammation and aiding the tissue regeneration are the major goals of the clinicians. it is important for the clinicians to choose the treatment modalities with the least drug interactions or side effects. photobiomodulation is an innovative approach in this regard. it is a non-invasive approach in which the leds or low -level lasers are used to produce the red or near-infrared (nir) light absorbed by the cellular photo-acceptors. this light absorption produces the ros , such as singlet oxygen, hydrogen peroxide (h o ), and superoxide ( - ). these ros affect many cellular processes ,such as proliferation, differentiation ( , , ( ) ( ) ( ) , adenosine triphosphate (atp) formation ( , ) and also can reduce the inflammtion ( ). so, pbm is a helpful approach when the cellular function is impaired especially by the hypoxia ( ). previous studies have shown the advantages of the pbm including anti-inflammatory effects and acceleration of the wound healing ( ) . these features operate alongside the general effects of the pbm for balancing the metabolic, analgesic, and immunomodulatory conditions. one advantage of this approach is that it is applied locally without any systemic side effects on the other organs ( ). based on the aforementioned advantages of the pbm and the current lack of established treatments for covid- disease, it seems that the pbm could be helpful in controlling the covid- disease as an alternative or adjunctive treatment, particularly in the severe cases with ards. table shows the related papers used the pbm for treatment of lung inflammation or ards. the majority of studies have used the red diode lasers ( and nm) with an energy density within the range of - . j/cm and power density within the range of . - mw/cm . three papers ( , , ) have used the infra-red lasers ( and nm) with an energy density within the range of - j/cm and there was not sufficient information about the power density except in one paper ( . mw/cm ( )). all the papers have shown the anti-inflammatory effects of the pbm including reducing the lung edema, cytokines in the bronchoalveolar lavage (bal) fluid, neutrophil influx, myeloperoxidase (mpo) activity, and damage to the endothelial cytoskeleton. the mechanisms of action of the pbm involve many factors related to the inflammation such as: -activating the interferons (ifns) having a pivotal role in the defense against viruses and the modulation of the immune system. huang et al., ( ) found a higher level of ifn-γ in the covid- patients. ifn-γ has antiviral and anti-tumor activity, and also increases the t lymphocytes and natural killer cells. it can regulate the immune system reactions. ifnα and ifn-β stimulate the natural killer cells and macrophages, they can also stimulate the lymphocytes and macrophages in order to improve the antiviral or anti-tumor activity ( - ). -pbm can also activate the phagocytes engulfing and removing the microorganisms (like bacteria or viruses) as well as apoptotic cells ( , ). -pbm can increase the micro and macro-circulation in order to increase the tissue or organ resistance against the external harmful factors ( ). -it also can increase the oxygen saturation of the tissues, which in turn increases the cell metabolism and capacity for proliferation or regeneration of the damaged tissue ( ). based on table , there are several cytokines influenced by the pbm. according to the literature, pbm can reduce the expression of tnf-α mrna and its production levels ( , , , , , ( ) ( ) ( ) ( ) ( ) . neutrophil adhesion and activation can be influenced by the tnf-α and also il- generation can be stimulated by the tnf-α. moreover, tnf-α can promote the coagulation and edema in the acute lung inflammation ( , ). (il- β) il- β, as the main inflammatory cytokine contributes to the initiation of inflammation. neutrophils are the main source of this cytokine and it increases the survival rate of the neutrophils in a reciprocal manner. severe cases of ards with poor prognosis show higher levels of il- β. many studies have confirmed its effects in the acute lung inflammation. it has been found that the pbm can reduce the production of this cytokine ( , , , ) . mafra de lima et al., ( ) revealed that the il- β expression and concentration were not reduced by the energy dose of j/cm , but on the other hand, they were reduced by higher doses ( , and . j/cm ). therefore, it is necessary to provide a sufficient energy dose to the target tissue, especially the lung parenchyma. laser irradiation will be attenuated by the passage through overlying tissue, such as intercostal muscles and skin. -interleukin- (il- ) pbm can reduce the il- levels during the acute lung inflammation or ards ( - ). this cytokine prolongs the duration of inflammation ( , ) and is related to the poor prognosis in ards ( , - ). studies have shown that the low -level laser can increase the il- generation. il- , as an anti-inflammatory cytokine can modulate the production of other inflammatory cytokine or reduce the tissue injury. it has been suggested that there is a balance between the tnf and il- production ( ) . so, the tnf production can be reduced by promoting the il_ formation by the pbm. this protective effect has been demonstrated in several studies ( , , , ). it has been found that the pbm increases the il- production. in contrast, two studies ( , ) have shown that the low -level laser does not influence the il- production. neutrophil recruitment and their chemotaxis from the bloodstream to the lung parenchyma is one of the hallmarks of the acute lung inflammation or ards . there are some cytokineinduced neutrophil chemoattractants (cincs) present on the neutrophils and endothelial cells. cd integrin is present on the polymorphonuclear leukocytes (pmns). however, icam- is a related adhesion molecule on the endothelial cells. it has been shown that the pbm reduces the icam- expression ( , , ) . it has been suggested that the inhibitory effect of the pbm on icam- expression may be related to the suppression of tnf-α and il- β production. this may be another mechanism by which the pbm reduces the lung inflammation. there are two approaches to deliver the light used in the pbm. this involves a direct irradiation of the target organs ( ). in the covid- disease, the lungs can be irradiated through the chest skin or through the back area when the patient is in the prone position. studies on the transcranial irradiation have demonstrated that the light can penetrate through the scalp and skull to reach the brain ( ). as mentioned above, red and nir wavelengths have been used in this regard. pbm should irradiate through the interchondral space so that, the laser clusters are applied over the entire surface of the thorax. infrared wavelengths (e.g., nm) are suggested for the pbm, because less laser irradiation will be absorbed by the overlying tissues. infrared lasers have lower tissue absorption compared to the red lasers. high-intensity laser therapy (hilt) may be helpful to achieve deeper penetration of the laser light to the underlying tissues, especially lung tissues. hilt has been shown to reduce the inflammation by a non-invasive approach ( ). the lack of any long-term toxicity, gene mutations, and damage to other organs are among the potential advantages of this approach. there has not been any bacteremia observed after irradiation, which is beneficial for the immune-suppressed patients. this approach increases the oxygenation of the red blood cells, and influences the biomarkers in order to indirectly decrease the inflammation or regenerate the damaged tissues. this approach can be carried out intravenously, transmucosally, or transcutaneously over the superficial arteries. blood vessels in the easily accessible areas like the nasal mucosa, under the tongue, behind the knee, or on the wrist can be irradiated with the laser or leds. oxygenation can be increased by the green lasers however; viruses could be cleared by the blue laser irradiation. red lasers improve the atp production. ( , ) therefore, using visible lasers is recommended in this approach with an adjusted dosage. two studies have supported the use of this approach ( , ). they have shown that the laser parameters (wavelength, energy density, etc.) have a critical role in the therapeutic effects ( ). it has been shown that the pbm could reduce the ros production in the neutrophils in peripheral blood ( ), and pbm could regulate the immune system by increasing the lymphoctes and neutral killer cells involved in the defense against the viruses ( ). there was just one clinical study which successfully treated a female patient with ards following a secondary viral infection ( ) . clinicians used the pbm ( nm and mw) in order to reduce the lung inflammation. laser was delivered to the skin between the ribs. this study was a casereport, so it was excluded from our study. other immunomodulatory effects of the pbm may be expected by irradiating the lymphoid tissues like the thymus, spleen, bone marrow ,or the lymphatic system. despite the lack of available studies on the pbm effects on the covid- , but it is assumed that the pbm may be a helpful adjunctive treatment in management of the covid- disease. pbm can reduce the lung edema, neutrophil influx and promote the regeneration of the lung tissue and better oxygenation for all the related organs. infra-red lasers are recommended because of their higher ability for penetration into the lung tissue. dosimetry of . - . j/cm energy density is suitable for the red lasers and an amount of . - . j/cm is a suitable dose for the infra-red lasers. continous mode irradiation at different points of the respiratory system may be helpful in management of the covid- pneumonia. pbm may be used as a preventive approach in the high -risk patients who could receive pre-treatment pbm while being still at a relatively mild stage of the disease. also, pbm may be considered as a therapeutic approach in the hospitalized patients before their condition worsens sufficiently to require the icu admission. therefore, randomized clinical trials should be carried out on the pbm effects for the covid- disease, and indeed some have already been started in various parts of the world. clinical features of patients infected with novel coronavirus in wuhan, china. the lancet infection. covid- , sars and mers: are they closely related? clinical microbiology and infection clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury the covid- cytokine storm; what we know so far treatment of middle east respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β b (miracle trial): study protocol for a randomized controlled trial broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov use of glucocorticoids in the critical care setting: science and clinical evidence immune regulation by glucocorticoids the laser therapy handbook. grangesberg, sweden: prima books ab proposed mechanisms of photobiomodulation or low-level light therapy effect of photobiomodulation on mesenchymal stem cells biological responses of stem cells to photobiomodulation therapy effect of lllt ga-al-as ( nm) on lps-induced inflammation of the airway and lung in the rat low-level laser therapy induces dose-dependent reduction of tnfα levels in acute inflammation low level laser therapy (lllt) decreases pulmonary microvascular leakage, neutrophil influx and il- β levels in airway and lung from rat subjected to lps-induced inflammation low level laser therapy (lllt): attenuation of cholinergic hyperreactivity neutrophil-derived il- β is sufficient for abscess formation in immunity against staphylococcus aureus in mice infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an exvivo perfused swine model anti-inflammatory mechanisms of apolipoprotein ai mimetic peptide in acute respiratory distress syndrome secondary to sepsis impact of human interleukin- on vector-induced inflammation and early graft function in rat lung transplantation repeated transcranial low-level laser therapy for traumatic brain injury in mice: biphasic dose response and long-term treatment outcome the beneficial effects of high-intensity laser therapy and co-interventions on musculoskeletal pain management: a systematic review comparative in vitro study: examining nm laser and nm ultraviolet interaction with blood acute respiratory distress syndrome successfully treated with low level laser therapy this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. key: cord- -adlp rjy authors: de rivero vaccari, juan carlos; dietrich, w. dalton; keane, robert w.; de rivero vaccari, juan pablo title: the inflammasome in times of covid- date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: adlp rjy coronaviruses (covs) are members of the genus betacoronavirus and the coronaviridiae family responsible for infections such as severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers), and more recently, coronavirus disease- (covid- ). cov infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ards). however, covs, such as covid- , also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (il)- β and its downstream molecule il- . the inflammasome is a multiprotein complex involved in the activation of caspase- that leads to the activation of il- β in a variety of diseases and infections such as cov infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in covid- patients. here we review the literature regarding the mechanism of inflammasome activation by cov infection, the role of the inflammasome in ards, ventilator-induced lung injury (vili), and disseminated intravascular coagulation (dic) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in covid- patients. symptoms and systemic complications associated with these infections in order to develop better therapies against covid- . here we review the literature on the role of the inflammasome in cov infections, which includes how covs activate inflammasomes upon infection, the role of the inflammasome in acute respiratory distress syndrome (ards), how ventilator-induced lung injury (vili) activates the inflammasome, how the inflammasome plays a role in the systemic complications associated with covid- , and how the inflammasome is involved in the process of disseminated intravascular coagulation (dic). the inflammasome is a multiprotein complex of the innate immune response initially described as a regulator of caspase- activation and processing of the pro-inflammatory cytokines interleukin (il)- β and il- ( ) . these multiprotein complexes are comprised of three basic components: ( ) a sensor such as a nod-like receptor (nlr) or an aim- like receptor (alr) ( ) the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (asc) and ( ) the inflammatory cysteine aspartase caspase- . inflammasomes are named after their sensor proteins which include nlrp , nlrp , nlrp , nlrc , and aim , with nlrp being the most extensively studied inflammasome to date ( ) . in addition to its role in cytokine production, the inflammasome is also involved in the cleavage of gasdermin-d (gsdm-d) in the cell death process of pyroptosis ( ) . gsdm-d is cleaved at the linker region between the amino (n) and carboxy (c) terminus by either caspase- and/or caspase- or - in humans (caspase- in rodents), resulting in freeing of the n-terminus from autoinhibiting the c-terminus, which allows formation of a pore by the n-terminus (gsdm-d-n) in the cell membrane (figure ) ( ) . inflammasomes were initially described for their role in mounting an innate immune response against bacterial ( ) , viral ( ) , and fungal ( ) infections as well as in autoimmune diseases ( ) . however, lately, most attention has been paid to the role of inflammasomes in diseases such as rheumatoid arthritis ( ) , gout ( ) , diabetes ( ) , heart disease ( ) , renal diseases ( ) , hepatic diseases ( ) , psoriasis ( ) , vitiligo ( ) , multiple sclerosis ( , ) , alzheimer's disease ( ), parkinson's disease ( ), as well as central nervous system (cns) injury ( - ), among others. each inflammasome is activated by different ligands which can either be endogenous or exogenous. endogenous ligands are referred to as damage/danger-associated molecular patterns (damps), and exogenous ligands are referred to as pathogenassociated molecular patterns (pamps). examples of damps include adenosine tri-phosphate or mitochondrial dna ( ). however, in the context of covid- , sars-cov- represents a pamp capable of activating the inflammasome. during viral infections, inflammasomes play a role in the response to influenza virus ( ), encephalomyocarditis virus ( ) the process of inflammasome activation involves a twostep process (figure ). the first step is referred to as signal and represents the priming step of inflammasome activation in which a pamp or damp binds to a pattern recognition receptor (prr) such as toll-like receptor (tlr)- to stimulate the synthesis of pro-il- β and pro-il- in a nuclear factor (nf)-κb-dependent manner ( ). once these pro-inflammatory cytokines are formed, then a second signal is needed to induce inflammasome formation and subsequent processing of pro-il- β and pro-il- into its active forms which are then secreted by different mechanisms. one of these mechanisms includes the gsdm-d pore, which is formed by the n-terminus of gsdm-d that is inserted in the membrane (gsdmd-n) following gsdm-d cleavage ( ). inflammasome formation involves a process in which the sensor molecule such as nlrp oligomerizes and then the adaptor protein asc is recruited into the complex, followed by incorporation of caspase- , which is then autoproteolytically cleaved into its active form. this cleaved or active form of caspase- then exerts its catalytic activity on the pro-inflammatory cytokines that after their release perpetuate the inflammatory response ( ). although there is no unifying consensus regarding the mechanism of inflammasome activation, various processes have been proposed to contribute to the second signal of inflammasome activation such as high extracellular k + concentration, k + efflux, mitochondrial dysfunction, formation of reactive oxygen species (ros), oxidized mitochondrial dna, lysosomal degradation, and ca + imbalance (figure ) ( , ). viroporins are hydrophobic proteins that facilitate release of viral proteins from infected cells by modifying the cell membrane, figure | mechanisms of inflammasome activation. inflammasome activation in general relies on two signals for its activation. first, a pamp binds to a prr resulting in synthesis of nlrp and pro-il- β. then a second signal leads to inflammasome assembly, leading to the activation of caspase- , processing of pro-il- β into il- β and pyroptosis. the second signal may come from a variety of pathways including k + efflux. lysosomal rupture or mitochondrial dysfunction. mitochondrial dysfunction results in release of ros, ca + and mitochondrial dna (mtdna), all of which have been shown to activate the inflammasome. pyroptosis occurs as a result of caspase- -mediated cleavage of gsdm-d at the linker region of gsdm-d. following gsdm-d cleavage, the amino terminus of gsdm-d (gsdm-d-n) forms a non-selective pore at the cell membrane through which il- β is then released. and they are involved in the activation of inflammasomes. viroporins are associated in viral pathogenesis, and their low ionic selectivity makes them ideal candidates for ionic exchange, which is critical for viral infection and inflammasome activation (figure ) . when viroporins are blocked or deleted, the severity of infections tends to decrease ( ), making viroporins attractive for the development of therapies to prevent exacerbation of the inflammatory response associated with viral infections ( table ) . the e glycoprotein of cov forms a membrane pore that allows the passage of ions ( ). mice infected with e protein viruses developed pulmonary edema ( ), which is characteristic of ards, and a main cause of death associated with cov infections ( , ). in addition to edema following pore activity mediated by the e protein, high levels of the inflammasome-mediated proinflammatory cytokine il- β have been detected in the lung parenchyma ( ). this finding suggests the involvement of the inflammasome in the mechanism of cov infection. lack of ion exchange through the e protein following sars-cov infection results in lower levels of il- β and lower immunerelated pathology. the events associated with over-activation of the immune response tend to be more damaging to the host than the response associated with cell death in the host induced by the virus ( ). thus, a modulation of the immune inflammatory response is as critical, if not more, than preventing cell death induced by viruses. this observation makes the inflammasome, the master regulator of il- β, a key target for cov infections. in addition to the role of viroporin e in ca +mediated inflammasome activation, the accessory protein a, which potentially acts as a k + channel, has also been shown to activate the nlrp inflammasome (figure ) ( ). like viroporin e, sars-cov open reading frame a (orf a) acts as an ion channel (na + , k + , ca + ) ( ). however, in regards to inflammasome activation, it seems that orf a promotes nlrp inflammasome activation by modulating the ubiquitination of the inflammasome adaptor protein asc and the production of pro-il- β by activation of nf-κb, which is independent of the ion-channel role that orf a plays. furthermore, release of active il- β following activation of the nlrp inflammasome is dependent on tumor necrosis factor (tnf) receptor-associated factor (traf ) ( ). however, a similar effect was not detected for the aim inflammasome. the effects of orf a on the priming (signal ) and the processing (signal ) of pro-il- β on inflammasome activation suggests a mechanism by which one protein is responsible for both signaling events needed for inflammasome activation, unlike other infectious mechanisms that rely on lipopolysaccharide (lps) for the priming step (step ) and adenosine tri-phosphate (atp) for the activation step (step ) (figure ) . interestingly, orf a is also able to process pro-il- β in an asc-dependent but nlrp -independent manner ( ). shi et al. showed that orf b triggers nlrp inflammasome activation and il- β release by binding to the leucine rich repeat (lrr) domain of nlrp , resulting in macrophage pyroptosis ( ). in this study, the authors demonstrated that orf b formed insoluble protein aggregates. moreover, orf b aggregates seemed to interact with nlrp and asc forming a single speck (figure ) . considering that asc specks have prionoid properties that interact with other pathogenic protein aggregates such a amyloid-β, resulting in a more exacerbated inflammatory response, a deeper understanding regarding the role of orf b aggregates following cov infections would be beneficial to understanding the innate immune response mounted by these infections ( ). in the lungs when the s protein of sars-cov- binds to the ace receptor, the virus is internalized by endocytosis, leading to translation and rna replication of genomic and sub-genomic rna including orf a, orf b, and the viral structural proteins (n, s, m, and e proteins). the e protein is involved in ca + release from the golgi apparatus. this ca + has the potential to activate the inflammasome. in addition, orf a interacts with traf to ubiquitinate asc, and orf b interacts with nlrp , resulting in inflammasome activation and pyroptosis. il- β is released through the gsdm-d-n pore during pyroptosis, while na + and h o molecules enter the cell, resulting in cell swelling, which then manifests as pulmonary edema. furthermore, orf a also acts in the cell membrane as a k + channel, which causes an ionic imbalance also capable of promoting inflammasome activation, and mitochondrial dysfunction produces ros that also contribute to inflammasome activation. consistent with previous studies regarding the mechanisms of inflammasome activation, it has been shown that ca + imbalance is a common denominator in a variety of viral infections that result in inflammasome activation such as influenza ( ) , and encephalomyocarditis virus ( ) . ionic imbalance has been associated with inflammasome activation in the lung following infections ( ) , and consistent with this finding is a recent study by nieto-torres et al. showing that e protein from sars-cov makes a ca + permeable channel in the endoplasmic reticulum (er)/golgi intermediate compartment (ergic)/golgi membrane that results in nlrp inflammasome activation and increased levels of il- β (figure ) ( ). the macrodomain of sars unique domain (sud) known as sud-mc is involved in the activation of the chemokine cxcl and il- β in lung epithelial cells as determined by the levels of il- β in bronchioalveolar lavage fluid (balf) ( ) . this process is mediated by the nlrp inflammasome in a c-jun-dependent pathway. however, a similar effect was not detected in nlrp knockout mice, indicating that nlrp is the main inflammasome responsible for this sud-mc-mediated effect. in contrast, the inflammasome also plays a protective role following murine cov infection ( ) . the mouse hepatitis virus (mhv) strain-a (mhv-a ) is a positive-strand rna virus, like sars-cov- , that is used to study cov infections with effects in the cns, liver, spleen, and lungs. using this model, zalinger et al. illustrated that inflammasome activation contributes to control of viral replication through il- . il- knockout mice presented poor survival and increased viral replication ( ) . furthermore, il- was involved in production of interferon (ifn)-γ in activated t-cells. the authors showed that caspase- and caspase- knockout mice were more susceptible to mhv infection. nonetheless, survival increased in il- knockout mice when compared to wildtype, even when the viral load was higher in the il- knockouts ( ) . therefore, as a result of the different effects of each inflammasome signaling protein on viral load and survival, care must be taken when considering therapies that aim to block inflammasome activation for in certain infections, the lack of inflammasome activation may result in death, which is probably due to the negative consequences associated with a suppressed immune response ( ) . accordingly, asc and caspase- have been shown to be necessary for protective adaptive immunity against influenza. however, in that study, a similar role was not found for nlrp ( ), yet other reports have shown an important involvement of nrlp following influenza infection ( , ) , which adds further complexity to the understanding of inflammasome signaling following viral infections. mhv strain- (mhv- ) causes a viral fulminant hepatitis that results in production of fibrinogen-like protein- (fgl ), a monocyte/macrophage-specific procoagulant ( ) . this procoagulant effect may contribute to pathomechanisms that trigger dic. guo et al. showed that mhv- infection increased the levels of il- β in the serum and liver of mice. they also showed that the levels of fgl from macrophages was diminished in il- r knockout mice, and this finding was consistent with decreased infiltration of cd + gr- high neutrophils. in addition, ros derived from the nadph oxidase complex (nox) resulted in nlrp inflammasome activation; thus, nlrp and caspase- knockouts showed lower levels of il- β ( ) . the inflammatory response following cov infection has an anti-viral and a pro-viral role. in regard to the anti-viral response, inflammation restricts viral replication and infection. however, inflammation plays a pro-viral role when it acts to release virions. current understanding of sars-cov- infection indicates that the virus infects the cell through angiotensinconverting enzyme- (ace ) receptors in host cells by binding to the s glycoprotein. ace is part of the renin-angiotensin system (ras) and is involved in the regulation of blood pressure and fluid homeostasis ( ) . recently, shao et al. demonstrated that ace receptor stimulation results in nlrp inflammasome activation in podocytes; thus, leading to cell death. interestingly, this effect did not affect blood pressure ( ) . however, whether sars-cov- binding through the s glycoprotein to ace results in inflammasome activation has yet to be determined. in addition, binding of angiotensin ii receptor (at ) also results in nlrp inflammasome activation ( ) . interestingly, bats that are known to be infected by several covs such as ebola, mers, sars-co-v, and potentially sars-cov- remain asymptomatic following infection even in the presence of high viral loads in blood and tissues ( ) . it has been suggested that covid- was passed to humans by an intermediate host between bats and humans, similar to previous cov infections that were transmitted to humans through camels (mers) or civets (sars-cov). nevertheless, the intermediate host for covid- remains unknown. recently, ahn et al. showed that following infection with mers-cov, bats are able to fight cov infections with lower levels of nlrp inflammasome activation when compared to humans, without affecting viral load ( ) . therefore, the molecular mechanism employed by bats to limit the damaging effects of cov infections should be explored to develop better interventions for the care of covid- -positive patients. traditionally, acute lung injury (ali) is defined by pulmonary infiltrates and edema present in the chest as determined by radiography procedures in the absence of left atrial hypertension, or a pulmonary wedge pressure lower than mmhg and an arterial oxygen to inspired oxygen fraction (pao /fio ) lower than mmhg ( ) . on the other hand, when the pao /fio is below mmhg the ali is referred to as ards ( ) . hence, according to this definition ards is a more severe form of ali. however, the modern definition of ards, eliminates the use of ali for humans, and limits its use to animal studies. moreover, this modern definition of ards divides ards into mild ( - mmhg), moderate ( - mmhg) and severe (below mmhg) based on the berlin definition ( ) . more recently, ards has been stratified based on different phenotypes such as those that are physiologically derived, which separates patients according to the pao /fio ratio, the pulmonary dead space, the ventilator ratio, and the driving pressure ( , ) . the clinically derived phenotype considers whether the etiology is direct (pulmonary origin) or indirect (extrapulmonary origin) ( , ) . the biologic phenotype relies on biomarkers associated with ards and considers whether there is a hypo or hyperinflammatory response, which can be used as a guide for potential therapies ( , ) . examples of these inflammatory markers that are associated with the cytokine storm are il- , il- , il- , and tnf. in addition, other markers associated with ards are proteins of endothelial injury such as surfactant protein-d or coagulation-associated proteins such as plasminogen activator inhibitor- and protein c. moreover, recently it has been shown that increased levels of il- were consistent with increased mortality in sepsis-induced ards ( ) . therefore, the hyperinflammatory phenotype is characterized by increased inflammation, less ventilator-free days, and increased mortality when compared to the hypoinflammatory phenotype ( , ) . thus, supporting a strong role for the inflammatory response in ards that is capable of determining favorable or unfavorable outcomes depending on whether there is hyperinflammation or hypoinflammation. finally, another phenotype that has been described is the omics derived phenotype which stratifies patients based on genomewide association and microrna transcriptomic analysis ( , ) . of the well-known covs (hcov-oc , hcov-nl , hcov-hku , mers-cov, sars-cov, and sars-cov- ), sars-cov- has garnered especial attention due to the level of infectivity as well as lethality in vulnerable populations. the acute stage of cov infections is characterized by infiltration of immune cells into lung tissue, whereas the post-acute stage is characterized by pulmonary fibrosis ( ) . covid- , like other cov infections, causes ali with high viral titers, high levels of the inflammatory cytokines il- β and il- as well as infiltration of macrophages and neutrophils into the lungs ( ) . high mobility group box protein (hmgb ), which activates the inflammasome in the lungs leading to ards/ali ( ) , is upstream of il- release ( ), and has been suggested to play a key role in the inflammatory response occurring in the lungs of covid- patients ( ) . covid- infections are associated with bacterial and viral pneumonia. pneumonia following cov infection can be either viral that may result in secondary bacterial pneumonia, or due to a combination of viral and bacterial pneumonia, however, the combined type has a lower incidence. following sars-cov infection, secondary bacterial (methicillin-resistant staphylococcus aureus) pneumonia has been described with ventilator-associated pneumonia (vap) ( ) . although the role of the inflammasome in viral pneumonias has not been thoroughly examined, several studies point to inflammasome activation after bacterial infections by different organisms. for instance, nlrp , asc, and caspase- are upregulated following streptococcus pneumoniae (s. pneumoniae) infection, resulting in production of il- β ( ) . the authors showed that nlrp knockout cells were able to produce il- β. however, asc knockouts significantly decreased the levels of il- β ( ), pointing to the possibility that even if the nlrp inflammasome is blocked, other inflammasomes that require asc may compensate for the role of nlrp such as the aim inflammasome or other nlr-dependent inflammasomes, yet nlrp knockout mice are more susceptible to the effects of pneumococcal pneumonia infection than wild types. moreover, levels of infiltrated leukocytes into the lungs was not affected by knockdown of nlrp , but pulmonary edema did increase in the nlrp knockout mice as determined by decreased dynamic lung compliance, which probably explains why nlrp knockouts were more likely to die. however, a better measure of edema would have been the determination of the wet to dry lung ratio or balf total protein. similarly, mice deficient in nlrp are also susceptible to the effects of α-hemolysin-expressing staphylococcus aureus (s. aureus) in murine pneumonia and are able to produce il- β, suggesting that other inflammasomes besides nlrp may be involved in the innate immune response to s. aureus pneumonia ( ) . on the other hand, knocking out the nlrc inflammasome has been shown to be protective following pseudomonas aeruginosa (p. aeruginosa) pneumonia as determined by improved bacterial clearance, decreased mortality and decreased lung damage ( ) . in this study, the authors suggested that the inflammasome may not be needed to fight the infection. however, the inflammasome seemed to play a role in increasing levels of il- β and il- , resulting in decreased bacterial clearance and increased lung toxicity. in contrast, during influenza a infection, the aim inflammasome is activated, leading to lung injury and mortality ( ) . moreover, in this study the authors showed that aim knockout mice presented less ali and increased survival without affecting viral load in the lungs ( ) . mechanical ventilation is used as a treatment for ards in order to expand collapsed alveoli. the high pressure generated by mechanical ventilation leads to vili ( ) . vili has been described in sars ( ) and covid- ( ) . wu et al. showed that this process was mediated in part by the nlrp inflammasome by sensing lung alveolar stretch ( ) , suggesting that stretch-injury in vili activates an innate immune response that was partially mediated by the inflammasome. in addition, activation of the nlrp inflammasome by stretched injury seems to be regulated by an interaction between nek- and nlrp , which can be treated with glibenclamide (glyburide) in mice ( ) . furthermore, a study by dolinay and colleagues showed upregulation of il b in a rodent model of vili ( ) . the mrna transcript levels of caspase- , il- β, and il were higher in patients with sepsis/ards when compared to patients with systemic inflammatory response syndrome and controls ( ) . moreover, deletion of il- and caspase- were shown to be protective following vili, and delivery of a neutralizing antibody against il- resulted in decreased neutrophil counts in balf ( ) . moreover, another complication associated with mechanical ventilation in covid- patients is vap ( , ) . in general, vap takes place in ∼ % of patients who undergo mechanical ventilation for over h ( ) , resulting in ∼ % mortality rate ( ) . escherichia coli (e. coli), klebsiella pneumoniae, p. aeruginosa, acinetobacter baumannii, and s. aureus are the main causative organisms of vap ( ) . mortality in the intensive care unit associated with vap is usually related to multi-drug resistant pathogens, and early diagnosis of vap by proper identification of the causative agent is paramount to increase patient survival ( ) . in a study analyzing balf and serum from patients suspected to have vap and age-matched volunteer controls, it was found that il- β and il- in balf were higher in the vap suspected cases when compared to controls ( ) . it has been suggested that a major contributor to poor outcomes in patients with covid- is an exacerbated immune response ( ) . this heightened immune response is characterized by unusually high levels of inflammatory cytokines such as il- β (the main cytokine activated by the inflammasome together with il- ), il- , monocyte chemoattractant protein- (mcp- ), macrophage inflammatory protein- α (mip a), il- , il- , il- , tnf, granulocyte-macrophage colony-stimulating factor (gm-csf), cc-chemokine ligand (ccl ), ccl , cxc-chemokine ligand (cxcl ), and the soluble form of the α-chain of the il- receptor, among others ( , ) . the exacerbated immune response is referred to as cytokine storm syndrome or cytokine release syndrome (crs). however, despite the increased levels of a variety of cytokines in covid- patients, those protein levels seem to be to times lower in covid- patients than in patients with ards ( ) . thus, crs may not fully explain the poor outcomes experienced by covid- patients and further investigation into the inflammatory response in these patients is granted. the heightened inflammatory response in covid- patients presents with decreased cd- + t cells in blood (lymphopenia) probably due to infiltration of these cells into tissues or due to a response to the steroid treatment given to these patients ( ) . in post-mortem studies, lymphocytic cell death has been detected in the lymph nodes and spleen, which could also explain the lymphopenia. crs may result in hemophagocytic lymphohistiocytosis (hlh) or macrophage activation syndrome (mas), leading to high fever, high levels of ferritin, and hypertriglyceridemia ( ) . symptoms of crs range from mild to high fever, fatigue, headache, rash, arthralgia, myalgia, hypotension, circulatory shock, vascular leakage, dic, and multi-organ dysfunction syndrome (mods) ( ) . patients with crs also present with cytopenia, and elevated c-reactive protein (crp), creatinine levels, liver enzymes, and d-dimer values. additionally, von willebrand factor (vwf), a marker of endothelial activation is also increased in crs and has been described in covid- patients ( ) . this suggests that endothelial cells may be an attractive therapeutic target for the treatment of covid- -related hyperinflammation, especially in cases presenting capillary leakage, hypotension and coagulopathy. il- is induced by il- β, the main cytokine activated by the inflammasome ( ) . therefore, inhibition of the inflammasome could be expected to help treat patients with crs. il- , the other cytokine controlled by inflammasome activation is also elevated in patients with crs ( ) . since there is no fda-approved drug that directly inhibits the inflammasome, to this extent, anti-il- and anti-il- β signaling therapies are being tested in patients with covid- ( , ) . increased il- levels lead to vascular leakage, dic and myocardial dysfunction ( ) . in addition, type i ifn signaling has been reported to be decreased in patients with covid- ( ) . it is possible that decreased type i ifn signaling in the presence of an exacerbated inflammatory response may be related to increased inflammasome signaling ( ) . however, viral infections are capable of generating high levels of type i ifn, and deletion of ifnar , a receptor involved in type i ifn signaling, or downstream type i ifn signaling pathways increases the replication, dissemination and lethality associated with viral infections ( ) , indicating that type i ifn are also involved in viral clearance. in a mouse model of s. suis infection, lin et al. studied the systemic effects of streptococcal toxic-shock-like syndrome (stsls) on cytokine production. stsls is characterized by fever, blood spots (purpura), hypotension, shock and mods, similar to what is seen in patients with crs. in that study, the nlrp inflammasome was activated by s. suis leading to production of il- β, resulting in crs ( ) , further highlighting that the inflammasome is a contributor to the effects of crs following infections. thus, the cytokine storm results in mods, which can severely affect patients by inducing an inflammatory response that spreads to other organs beyond the lungs. as a result, a concern in covid- patients is not only what happens due to the pulmonary infection but also the non-respiratory manifestations associated with the inflammatory response caused by sars-cov- infections. in addition to the respiratory effects associated with covid- , other manifestations affecting a variety of organ-systems have been recognized ( table ) . patients with pre-existent cardiovascular conditions tend to have worse outcomes due to covid- than patients who do not present a cardiovascular comorbidity, including hypertension. due to the manifestation of a cardiovascular involvement in more severe cases, it is likely that the effects on the heart are due to sequelae associated with the crs. thus, a reduction and control of the cytokine storm may alleviate the deleterious effects in these patients. covid- exacerbates underlying cardiovascular conditions such as ischemic heart disease and chronic heart failure ( ) . in addition, it may cause myocardial injury, myocarditis, arrhythmia, acute coronary syndrome, cardiogenic shock, stroke, venous thromboembolism, and pulmonary embolism ( ) . non-ischemic events in the heart, such as pressure overload, activate the inflammasome in the heart probably as a result of ros production following stimulation of β-adrenergic receptors, resulting in higher levels of nlrp and asc as well as production of il- from myocardial cells ( ) . similarly the inflammasome was shown to be involved in cardiac arrhythmias ( ) , and higher levels of il- β and il- have been associated with hypertension ( ) . in a mouse model of hypertension, the inflammasome is activated in the kidneys, resulting in production of il- β but not il- ( ); whereas inhibition of the inflammasome resulted in lower blood pressure ( ) . taken together, considering the exacerbated inflammatory response that covid- patients present, the effects of the inflammasome on the cardiovascular system could explain, in part, some of the adverse cardiovascular events seen with covid- ; however, a direct role between inflammasomes and cardiac complications has not been tested in an animal model of cov infections. problems with the gastrointestinal system such as diarrhea, abdominal pain, vomiting and lack of appetite have been described in covid- patients. in some cases, these symptoms occur even in the absence of any respiratory symptoms, and sometimes correspond to a longer time between disease onset and hospitalization when compared to patients who do not present any digestive symptoms ( ) . lack of appetite may be associated with the anosmia that characterizes some of the symptoms experienced by some patients. however, the cause of digestive symptoms in some covid- cases is not well-understood, yet it is possible that the effects are due to an alteration of the intestinal microbiome by the infection, or the result of the effects of the virus binding to the liver, which expresses ace receptors. accordingly, pan et al. suggest that an alteration in the gut-lung axis ( ) may be responsible for the digestive symptoms in some covid- patients, which could also explain how a problem affecting the lungs also affects the gastrointestinal system ( ) . similar to covs, enteroviruses are also positive-sense single stranded rna viruses, and several enteroviruses have been shown to activate the inflammasome by acting on nlrp , caspase- , asc, il- β, and gsdm-d ( ) , indicating that the inflammasome can be activated by infections that affect the gastrointestinal system, and that the machinery responsible for the inflammatory response mediated by the inflammasome is present in the gastrointestinal system. however, whether covs activate the inflammasome directly in the gastrointestinal tract is yet to be determined. it is possible that the ionic imbalances associated with sars-cov- infections also results in inflammasome activation in the gut ( ) , moreover, there is ample evidence on inflammasome regulation of the inflammatory response in intestines in chronic diseases like chron's disease and colitis ( ) , further highlighting the relevance of this innate immune complex in inflammatory events in the gastrointestinal tract. in the liver, covid- increases the levels of alanine aminotransferase (alt) and aspartate aminotransferase (ast), particularly in severe cases ( ) . although no-link between inflammasome and liver problems have been described following cov infections, previous studies have shown that inhibition of the nlrp inflammasome lowers the levels of alt and ast, improving outcomes in liver fibrosis and nonalcoholic steatohepatitis (nash) in mice ( ) , suggesting that inflammasome inhibition may be beneficial to control the effects caused by covs infections in the liver. the pancreas also expresses ace receptors, making the pancreas a target for cov infections. previously, sars-cov was shown to damage pancreatic islet cells leading to diabetes ( ) . furthermore, following covid- , there is an association between poorer outcomes and diabetes. however, poorer outcomes in diabetics seemed to be less frequent in older individuals and those with hypertension ( ) . however, the mechanism for this finding is presently unknown. it is possible that medications used to treat these patients also might serve to treat some of the symptoms associated with covid- , including hyperactivation of the immune response. in addition, nlrp inflammasome proteins are elevated in monocyte-derived macrophages and peripheral blood mononuclear cells from patients with diabetes ( ) . acute pancreatitis, which has been described in covd- patients and is worse in diabetics, also activates the nlrp inflammasome ( ) . thus, a heightened inflammatory response in patients with diabetes could be a risk factor in patients with diabetes and covid- . cerebrovascular complications, convulsions, encephalitis, change in mental status, confusion, headaches and febrile seizures as well as taste (hypogeusia/ageusia) and smell (anosmia/hyposmia) dysfunction have been described in patients with covid- ( , ) . although, the mechanism of taste and smell dysfunction is not known, it is possible that the virus binds to ace in the oral mucosa ( ) , affecting this sensing function. although smell and taste dysfunction are common in several upper respiratory infections, it seems that in covid- , these are even more prevalent ( ) . moreover, covs have been detected in the cerebrospinal fluid (csf) of patients with sars-cov ( ), suggesting the possibility of a similar neurological involvement in patients with covid- . in addition, sars-cov- has been shown to affect human neural progenitor cells and brain organoids ( ), indicating the possibility of direct infection by cov in brain tissue. inflammasomes have been shown to be activated in a variety of diseases and injuries affecting the cns ( , - ). thus, the cns is capable of mounting an immune response through the inflammasome. recently a mechanism was described by which inflammasome proteins are carried in extracellular vesicles (ev) to the lungs from the brain following brain injury, thus inducing ali ( ) . therefore, it is also possible that the lung secretes inflammasome proteins in extracellular vesicles that are carried to the cns following infection, causing neurological symptoms. although ev are capable of carrying viral components ( ) , whether ev are secreted during covid- as part of the neuro-respiratory lung axis is yet to be determined. studies indicate that patients with severe covid- may present conjunctivitis ( ) , and covs have been previously detected in tears ( ) . covs gain direct access to the conjunctival mucosa as the viral particles from an infected patient travel in droplets that reach the eye. however, how cov reach the tear film in the absence of direct access from the virus to the conjunctival mucosa is yet to be fully elucidated. evidence from feline cov suggests that infected macrophages and monocytes extravasate immune tissues and cause endothelial cell dysfunction that leads to vasculitis ( ) . it is the vasculitis that is believed to be an underlying contributor to the ocular manifestations seen following feline cov infections, which include conjunctivitis, retinal vasculitis, pyogranulomatous anterior uveitis and choroiditis with retinal detachment ( ) . in addition, in mouse cov, inflammation in the eye results in optic neuritis and retinal degeneration that affects photoreceptors and ganglion cells ( ) . although conjunctivitis remains the only ocular manifestation widely reported in regards to covid- , it is possible that figure | role of the inflammasome on clot formation. thrombin binds to a gpcr in platelets, resulting in ros-dependent activation of the inflammasome and release of il- β into the cell. il- β stimulates production of il- . il- stimulates tissue factor (tf) to convert prothrombin into thrombin. tf-containing microvesicles are released by pyroptosis following inflammasome activation. thrombin then converts fibrinogen into fibrin, leading to fibrin cross-linking, clot formation and dic. other conditions may arise upon closer examination of covid- patients. moreover, in goblet cells of the conjunctiva s. aureus activates the nlrp inflammasome as well as the purinergic receptors p x and p x which have been shown to be involved in inflammasome signaling ( , , ) . in addition, s. pneumoniae and p. aeruginosa activate the nlrc inflammasome in corneal ulcers ( ) . thus, the ocular surface has the inflammasome machinery necessary to mount an innate immune response against conjunctivitis in the presence of covid- . however, further studies are needed to understand the type of conjunctivitis present in covid- patients. acute kidney injury (aki) is a significant problem in patients with covid- ( ) . patients develop aki during hospital admission and when disease is severe, such as in patients with ards or on mechanical ventilation, as well as in patients with hypertension or diabetes ( ) . it is possible that in covid- , the exacerbated inflammatory response or vascular thrombosis can damage the kidneys. in addition, ace receptors are present in the kidney, making this organ a potential direct target of sars-cov- infection. a potential contributor to the exacerbated inflammatory response is the inflammasome that besides being involved in crs, it is present in the kidneys where it contributes to inflammation in several renal diseases and complications, inhibits tlr and tlr , which have been described in inflammasome activation ( ) ( ) ( ) anakinra il- receptor blocker ( ) tocilizumab therapeutic monoclonal antibody that blocks il- signaling ( ) including aki ( ) . previously, the zika virus has been shown to induce aki through nlrp inflammasome activation ( ); however, whether sars-cov- is responsible for inducing aki through the inflammasome in covid- has yet to be tested. severe cases of covid- may present with coagulation complications that manifest as thrombi, high levels of d-dimers (a sign of fibrin degradation), prolonged prothrombin time, and low platelet count (thrombocytopenia) that may lead to dic. thrombi in covid- patients have been described in the lungs, heart, brain, liver, kidneys and lower limbs ( ) . dic tends to present in cases of sepsis where it blocks microvessels and leads to organ dysfunction. in addition to dic, some patients with covid- may present pulmonary embolism ( ) and deep vein thrombosis ( ) . the nlrp inflammasome has been described as a signaling intermediate between inflammation and thrombosis by modulating clot retraction and platelet spreading ( ) . nlrp knockout mice present abnormal hemostasis and arterial thrombosis, probably as part of a mechanism that involves binding of thrombin to g protein-coupled receptors (gpcr), which stimulates ros production in platelets. ros activates the inflammasome, resulting in il- β signaling that is followed by platelet spreading and clot retraction ( ) . il- stimulates tissue factor (tf) to transform prothrombin into thrombin. thrombin then converts fibrinogen into the fibrin that is characteristic of thrombi. thus, there is a clear association between the inflammasome and clot formation. furthermore, inflammasome activation causes release of microvesicles containing tf by pyroptosis, resulting in systemic coagulation and death ( ) , which provides a mechanism by which dic may contribute to the poor outcomes experienced by covid- patients (figure ) . to date, therapies intended to treat covid- include remdesivir or favipiravir to control translational replication of viral rna, tocilizumab to block the il- receptor, bevacizumab to block vascular endothelial growth factor (vegf), anakinra to block il- receptor activity, lopinavir or ritonavir to target proteolysis, losartan to target ace receptors, corticosteroids such as dexamethasone to target the exacerbated inflammatory response, heparin to treat dic and intravenous immunoglobulins to target crs, or convalescent plasma, among others ( ). thus, great efforts are being undertaken to develop therapeutics against the pulmonary and systemic manifestations of covid- . this review highlights the inflammasome as a target to interfere with different aspects associated with this pandemiccausing virus. however, care must be taken since inflammasome signaling may be necessary to fight the actual viral infection, while at the same time inflammasome activation may be responsible for the hyperactivated inflammatory response that leads to sepsis, dic, aki and death. mechanisms employed by bats to dampen cov infections indicate that inflammation signaling pathways are probably better targets than reduction of viral load in controlling covid- . thus, a better understanding of the role of inflammasomes and inflammatory processes in covs and those regulating viral load are critical for development of therapeutics to treat these diseases, and although to date there are no fda-approved drugs that directly target the inflammasome, in regards to inflammasome signaling and therapeutics that can be considered for covid- treatment, potential therapies that are currently being manufactured for the treatment of inflammasome-related diseases include mcc that interferes with nlrp inflammasome activation by binding to the nacht domain of nrlp , hence preventing its oligomerization ( ) , as well as ic , a monoclonal antibody with intracellular and extracellular action that interferes with asc speck formation ( ) ( table ) . on the other hand, there are some therapies that are already fda-approved and have been shown to interfere with inflammasome signaling activation which are already being considered for the treatment of covid- such as enoxaparin ( , ) , anakinra ( ) , tocilizumab ( ) , and dexamethasone ( , ) . moreover, another drug that is already approved by the fda that can also be used to inhibit the inflammasome is ifn-β ( ) , which is already used to treat multiple sclerosis ( ) , and is currently being tested for its effects on covid- patients ( ) . moreover, tlr and tlr , which have been implicated in inflammasome signaling ( ) have been suggested to play an underlying role in covid- severity ( ) . tlr / are activated by single stranded rna viruses like sars-cov- , and in addition to their role on inflammasome activation ( ) , these prr are better known for their involvement in type i ifn synthesis and a variety of ifn stimulated genes (isg), which when deregulated are capable of contributing to an exacerbated inflammatory immune response ( ) . as a result, m , a tlr / inhibitor, is currently being tested in clinical trials for the treatment of severe symptoms of covid- as a potential treatment for crs ( ) ( table ) . given the number of people that have been affected with covid- worldwide, a better understanding of the systemic effects associated with covid- during and after infection resolution is of paramount importance, and given the possibility that cov infections may become a seasonal infection similar to influenza virus infections, it remains critical to identify fda-approved and future novel therapeutics that can be used for the treatment of cov infections and the associated systemic manifestations. jpdrv and jcdrv designed the structure of the review and performed the literature search. all authors contributed to the writing of this article. this work was funded by an r grant from the nih/ninds to rwk and jpdrv (r ns - ). vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease a -amino acid fragment of the sars coronavirus s protein efficiently binds angiotensin-converting enzyme protein interactions during coronavirus assembly the coronavirus e protein: assembly and beyond a review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme- and furin identification of a novel coronavirus in patients with severe acute respiratory syndrome characterization of a novel coronavirus associated with severe acute respiratory syndrome novel human coronavirus. (sars-cov- ): a lesson from animal coronaviruses the inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proil-beta activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury gasdermin d is an executor of pyroptosis and required for interleukin- beta secretion pyroptosis is driven by non-selective gasdermin-d pore and its morphology is different from mlkl channel-mediated necroptosis a poxvirus-encoded pyrin domain protein interacts with asc- to inhibit host inflammatory and apoptotic responses to infection an essential role for the nlrp inflammasome in host defense against the human fungal pathogen candida albicans nalp forms an il- beta-processing inflammasome with increased activity in muckle-wells autoinflammatory disorder genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis. (the swedish tira project) intracellular innate immunity in gouty arthritis: role of nalp inflammasome activation of the nlrp inflammasome by islet amyloid polypeptide provides a mechanism for enhanced il- beta in type diabetes monosodium urate. (msu) crystals increase gout associated coronary heart disease. (chd) risk through the activation of nlrp inflammasome renal involvement in autoinflammatory diseases and inflammasome-mediated chronic kidney damage role of nlrp inflammasome in the progression of nafld to nash genetic support for the role of the nlrp inflammasome in psoriasis susceptibility nlrp haplotypes associated with vitiligo and autoimmunity increase interleukin- beta processing via the nlrp inflammasome inflammasome proteins as biomarkers of multiple sclerosis ic : a novel anti-asc monoclonal antibody improves functional alzheimer's disease influenza virus activates inflammasomes via its intracellular m ion channel encephalomyocarditis virus viroporin b activates nlrp inflammasome ion flux in the lung: virus-induced inflammasome activation sars unique domain. (sud) of severe acute respiratory syndrome coronavirus induces nlrp inflammasome-dependent cxcl -mediated pulmonary inflammation role of the inflammasome-related cytokines il- and il- during infection with murine coronavirus the nlrp inflammasome mediates in vivo innate immunity to influenza a virus through recognition of viral rna hyperactivation of the nlrp inflammasome protects mice against influenza a virus infection via il- beta mediated neutrophil recruitment the fgl /fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis the nlrp inflammasome and il- beta accelerate immunologically mediated pathology in experimental viral fulminant hepatitis the vasoprotective axes of the reninangiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases angiotensin ii stimulates the nlrp inflammasome to induce podocyte injury and mitochondrial dysfunction sars-cov- infection and overactivation of nlrp inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells bat coronaviruses and experimental infection of bats, the philippines dampened nlrp -mediated inflammation in bats and implications for a special viral reservoir host the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition phenotypes in acute respiratory distress syndrome: moving towards precision medicine ards subphenotypes: understanding a heterogeneous syndrome association of elevated plasma interleukin- level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy stability of ards subphenotypes over time in two randomised controlled trials pathology and pathogenesis of severe acute respiratory syndrome immune response, inflammation, and the clinical spectrum of covid- neural-respiratory inflammasome axis in traumatic brain injury high mobility group protein. (hmg- ) stimulates proinflammatory cytokine synthesis in human monocytes extracellular hmgb : a therapeutic target in severe pulmonary inflammation including covid- ? recognition and management of respiratory coinfection and secondary bacterial pneumonia in patients with covid- the nlrp inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia staphylococcus aureus alpha-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the nlrp inflammasome activation of inflammasome signaling mediates pathology of acute p. aeruginosa pneumonia aim inflammasome is critical for influenza-induced lung injury and mortality a -year-old male with a fatal case of covid- acute respiratory distress syndrome. (cards) and ventilator-induced lung injury. (vili) critically ill patients with severe acute respiratory syndrome activation of nlrp inflammasome in alveolar macrophages contributes to mechanical stretchinduced lung inflammation and injury nek mediated assembly and activation of nlrp inflammasome downstream of potassium efflux in ventilator-induced lung injury inflammasome-regulated cytokines are critical mediators of acute lung injury covid- : an alert to ventilatorassociated bacterial pneumonia clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study ventilator-associated pneumonia ventilator-associated pneumonia. a multivariate analysis microbial etiology and prognostic factors of ventilator-associated pneumonia: a multicenter retrospective study in shanghai diagnostic importance of pulmonary interleukin- beta and interleukin- in ventilator-associated pneumonia covid- : consider cytokine storm syndromes and immunosuppression clinical features of patients infected with novel coronavirus in wuhan is a "cytokine storm" relevant to covid- ? cytokine release syndrome adamts activity, von willebrand factor, factor viii and d-dimers in covid- inpatients il) beta induction of il- is mediated by a novel phosphatidylinositol -kinase-dependent akt/ikappab kinase alpha pathway targeting activator protein- identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor t-cell therapy for acute lymphoblastic leukemia induction of pro-inflammatory cytokines. (il- and il- ) and lung inflammation by coronavirus- . (covi- or sars-cov- ): anti-inflammatory strategies il- blockade with anakinra in acute leukaemia patients with severe covid- pneumonia appears safe and may result in clinical improvement impaired interferon signature in severe covid- host-directed therapy of tuberculosis based on interleukin- and type i interferon crosstalk type i interferons in viral control and immune regulation an nlrp inflammasome-triggered cytokine storm contributes to streptococcal toxic shock-like syndrome. (stsls) il- cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult enhanced cardiomyocyte nlrp inflammasome signaling promotes atrial fibrillation increased serum levels of interleukin- beta in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice pharmacological inhibition of the nlrp inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension emerging pathogenic links between microbiota and the gut-lung axis interactions between enteroviruses and the inflammasome: new insights into viral pathogenesis nlrp inflammasome blockade reduces liver inflammation and fibrosis in experimental nash in mice diabetes aggravates acute pancreatitis possibly via activation of nlrp inflammasome in db/db mice traumatic brain injury-induced acute lung injury: evidence for activation and inhibition of a neural-respiratory-inflammasome axis staphylococcus aureus activates the nlrp inflammasome in human and rat conjunctival goblet cells host response and bacterial virulence factor expression in pseudomonas aeruginosa and streptococcus pneumoniae corneal ulcers zika virus infection induces acute kidney injury through activating nlrp inflammasome via suppressing bcl- cardiovascular implications of the covid- pandemic: a global perspective clinical characteristics of covid- patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study cyclic nucleotides, gut physiology and inflammation colitis induced in mice with dextran sulfate sodium. (dss) is mediated by the nlrp inflammasome covid- and the liver-related deaths to come binding of sars coronavirus to its receptor damages islets and causes acute diabetes diabetes mellitus is associated with increased mortality and severity of disease in covid- pneumonia -a systematic review, meta-analysis, and meta-regression upregulated nlrp inflammasome activation in patients with type diabetes taste and smell dysfunction in covid- patients central nervous system manifestations of covid- : a systematic review high expression of ace receptor of -ncov on the epithelial cells of oral mucosa acute-onset smell and taste disorders in the context of covid- : a pilot multicentre polymerase chain reaction based case-control study detection of sars coronavirus rna in the cerebrospinal fluid of a patient with severe acute respiratory syndrome sars-cov- infects human neural progenitor cells and brain organoids extracellular vesicles and viruses: are they close relatives? conjunctivitis and covid- : a meta-analysis the severe acute respiratory syndrome coronavirus in tears morphologic features and development of granulomatous vasculitis in feline infectious peritonitis ocular manifestations of feline infectious peritonitis can the coronavirus disease . (covid- ) affect the eyes? a review of coronaviruses and ocular implications in humans and animals p x receptors influence inflammasome activation after spinal cord injury acute kidney injury in critically ill patients with covid- role of the nucleotide-binding domain-like receptor protein inflammasome in acute kidney injury coexistent covid- pneumonia and pulmonary embolism: challenges in identifying dual pathology incidence of asymptomatic deep vein thrombosis in patients with covid- pneumonia and elevated d-dimer levels nlrp regulates platelet integrin alphaiibbeta outside-in signaling, hemostasis and arterial thrombosis inflammasome activation triggers blood clotting and host death through pyroptosis emerging therapies for covid- pneumonia mcc directly targets the nlrp atp-hydrolysis motif for inflammasome inhibition after years of regulating immunity, dexamethasone meets covid- dexamethasone alleviate allergic airway inflammation in mice by inhibiting the activation of nlrp inflammasome enoxaparin attenuates acute lung injury and inflammasome activation after traumatic brain injury attention should be paid to venous thromboembolism prophylaxis in the management of covid- the role of interferons in inflammation and inflammasome activation interferon beta- a for covid- : critical importance of the administration route a tolllike receptor , , and antagonist inhibits th and th responses and inflammasome activation in a model of il- -induced psoriasis presence of genetic variants among young men with severe covid- targeting human tlrs to combat covid- : a solution early identification of covid- cytokine storm and treatment with anakinra or tocilizumab effect of genetic polymorphisms on therapeutic response in multiple sclerosis relapsing-remitting patients treated with interferon-beta figures in this manuscript were created using biorender.com. key: cord- -w qkjz authors: chen, wei; chen, yih-yuan; tsai, ching-fang; chen, solomon chih-cheng; lin, ming-shian; ware, lorraine b.; chen, chuan-mu title: incidence and outcomes of acute respiratory distress syndrome: a nationwide registry-based study in taiwan, to date: - - journal: medicine (baltimore) doi: . /md. sha: doc_id: cord_uid: w qkjz most epidemiological studies of acute respiratory distress syndrome (ards) have been conducted in western countries, and studies in asia are limited. the aim of our study was to evaluate the incidence, in-hospital mortality, and -year mortality of ards in taiwan. we conducted a nationwide inpatient cohort study based on the taiwan national health insurance research database between and . a total of , ards patients ( % male; mean age years) were identified by international classification of diseases, th edition coding and further analyzed for clinical characteristics, medical costs, and mortality. the overall crude incidence of ards was . per , person-years, and increased from . to . per , person-years during the study period. the age-adjusted incidence of ards was . per , person-years. the overall in-hospital mortality was . %. in-hospital mortality decreased from . % in to . % in (p < . ). the in-hospital mortality rate was lowest ( . %) in the youngest patients (age – years) and highest ( . %) in the oldest patients (> years, p < . ). the overall -year mortality rate was . %, and decreased from . % to . % during the study period. patients who died during hospitalization were older ( ± versus ± , p < . ) and predominantly male ( . % versus . %, p < . ). in addition, patients who died during hospitalization had significantly higher medical costs ( versus us dollars, p < . ) and shorter lengths of stay ( versus days, p < . ) than patients who survived. we provide the first large-scale epidemiological analysis of ards incidence and outcomes in asia. although the overall incidence was lower than has been reported in a prospective us study, this may reflect underdiagnosis by international classification of diseases, th edition code and identification of only patients with more severe ards in this analysis. overall, there has been a decreasing trend in in-hospital and -year mortality rates in recent years, likely because of the implementation of lung-protective ventilation. a cute respiratory distress syndrome (ards) is a syndrome of acute respiratory failure that is characterized by alveolar-capillary barrier leakage, lung edema formation, pulmonary epithelial cell death, and an acute inflammatory response that manifests with poor lung compliance, hypoxemia, and bilateral infiltrates on chest radiograph. , a variety of clinical disorders are associated with the development of ards, including pneumonia, aspiration of gastric contents, sepsis, trauma, and the transfusion of blood products. acute respiratory distress syndrome is a major clinical problem that contributes to the death of more than , people annually in the united states. , in addition, patients who survive ards have reduced exercise capacity and health-related quality of life and have increased costs and use of health care services during the years after discharge from the intensive care unit. [ ] [ ] [ ] [ ] [ ] although this syndrome has a considerable impact on public health, relevant large-scale epidemiologic investigations have been rare in recent years. before , when a uniform definition of ards was not in place, several studies showed that the incidence of ards was approximately . to . per , person-years. [ ] [ ] [ ] [ ] after the american-european consensus conference published a uniform definition for ards in , several studies conducted in the united states, australia, and europe showed that the incidence of ards was as high as . to per , person-years. [ ] [ ] [ ] [ ] [ ] subsequently, rubenfeld et al conducted a prospective population-based cohort study in hospitals in and around king county, washington, and found that the incidence of ards was . per , person-years in the united states and that the incidence was age dependent and increased from per , person-years for those to years of age to per , person-years for those to years of age. epidemiological studies conducted in asia, however, are limited. because race may be a risk factor for development of ards and there has been no large-scale study of ards conducted in a predominantly asian population, we conducted a retrospective cohort study using nationwide population-based data from the national health insurance research database (nhird) of taiwan. the aim of our study was to investigate the incidence, medical costs, in-hospital mortality, and -year mortality of ards during a -year period. we conducted a population-based study using data obtained from all admission records of the nhird. in taiwan, the national health insurance program, implemented in , provides compulsory health insurance that covers more than % of the population. national health insurance research database includes almost all outpatient and inpatient medical records, including information on patient characteristics, such as age, sex, dates of clinical visits, date of admission, and diagnostic codes. the cases of ards were obtained from whole-population inpatient data in nhird between and and were defined using international classification of diseases, th revision, clinical modification (icd- -cm) codes. this study has been reviewed and approved by the institutional review board of the ditmanson medical foundation chia-yi christian hospital, taiwan. patients who were hospitalized with a diagnosis of ards (icd- -cm codes . , . ) for the first time between and were enrolled in the study. patients whose sex was not identified or who were less than years old were excluded from this study because ards in children has different epidemiology and outcomes. , demographic characteristics, resource utilization, clinical features, in-hospital mortality, and -year mortality were studied. because participation in the national health insurance system in taiwan is mandatory, patients who withdrew from the system for at least months were regarded as dead. the date of withdrawing is regarded as the date of death. age at the time of the first diagnosis was categorized into groups: to , to , to , to , to , to , and over years old. comorbidities that were recorded included pneumonia (icd- -cm codes - ), sepsis (icd- -cm codes . , . , . , . , . , and . ), trauma (icd- -cm code . ), and acute pancreatitis (icd- -cm code . ). the incidence rates (per , person-years) of ards were calculated from to and were plotted for each age group and calendar year for both sexes. the number of ards patients was used as the numerator of the incidence rate, and the total population of taiwan was used as the denominator. the total population for each year was obtained from the department of statistics in the ministry of the interior of executive yuan in taiwan. the age-adjusted incidence rate per , person-years was age-adjusted to the world population in . we tested for temporal trends in ards incidence by poisson regression analysis. differences in demographic characteristics, clinical features, and resource utilization of patients by survival status were tested with student t test or the wilcoxon rank sum test for continuous variables and the x test for categorical variables. we also reported in-hospital mortality and -year mortality across each calendar year, and the temporal trend was tested by the cochran-armitage trend test. data analysis was performed with spss software, version of the spss system for windows (version . : ibm corporation, somers, ny). a -tailed p value less than . was considered statistically significant. a total of , newly diagnosed ards patients ( . % male; mean age years) were enrolled in the study. among them, . % (n ¼ , ) died during hospitalization. patients who died during hospitalization were older ( ae versus ae years, p < . ) and more likely to be male ( . % versus . %, p < . ). in addition, patients who died during hospitalization had significantly higher medical costs ( versus us dollars, p < . ) and shorter lengths of stay ( versus days, p < . ) than patients who survived. the most common etiologic comorbidities for ards were pneumonia ( . %), followed by sepsis ( . %), and trauma ( . %). some patients had more than one etiologic comorbidity. there were significant differences in etiology by hospital mortality status ( table ). the estimated incidence of ards from to is shown in figure a . the incidence of ards during the study period for total male and female populations was . , . , and . per , person-years, respectively. the ageadjusted incidence of ards was . per , personyears. the incidence increased from . to . per , person-years in the total population (p < . by trend test). it also increased from . to . per , person-years in the male population and from . to . per , personyears in the female population (fig. a) . figure b shows the age-and sex-specific incidence rates for ards in taiwan. overall, the incidence rate increased from . per , person-years in the group of to years of age to an estimated . per , person-years in the group of years of age and above. the age-specific incidence rates increased with advancing age, with a sharp increase occurring in patients over the age of that was evident in both men and women. as shown in figure , men had higher incidence of ards than women in all age groups. the overall in-hospital mortality rate of ards patients during the study period was . %. figure a shows a significant trend of a decreasing in-hospital mortality rate, from . % in to . % in (trend test, p < . ) in the overall population, and similar trends in both sexes. an abrupt decrease in the in-hospital mortality rate in was coincident with an outbreak of severe acute respiratory syndrome that year. figure b shows a significant increase in in-hospital mortality rate from . % in the group of to years of age to . % in the group of years of age and above (trend test, p < . ). the pattern of -year mortality of ards was very similar to that of in-hospital mortality in this study (fig. ) . the overall -year mortality rate of ards was . %. we observed a trend of decreasing -year mortality rates from . % in to . % in in patients with ards (trend test, p < . ). there were no sex differences in -year mortality. to our knowledge, this is the first large epidemiological study of ards in a predominantly asian patient population. the average incidence of ards was . per , person-years, and increased from . to . per , person-years during the study period. the average in-hospital mortality rate was . % and decreased significantly from . % to . % during the study period. the in-hospital mortality rate was lowest ( . %) in the youngest patients (age - years) and highest ( . %) in the oldest patients (age > years, p < . ). the overall -year mortality rate was . %, and decreased from . % to . % during the study period. this study used international classification of diseases, th edition (icd- ) coding to identify patients admitted with a new diagnosis of ards. several previous studies have used the icd- coding system to investigate the incidence and outcomes of ards. reynolds et al reported that the estimated incidence of ards in maryland was in the range of to cases per , people and the mortality rate was % to %, using icd- codes . and . . other studies have also used the icd- coding system to determine the incidence or prevalence of ards in particular populations, such as those with traumatic brain injury, spinal cord injury, and subarachnoid hemorrhage. because the icd- coding system is linked to the taiwanese healthcare reimbursement system, the accuracy of icd- coding is quite precise. indeed, more than studies using the taiwan nhird have been published, including a number of important epidemiologic observations. [ ] [ ] [ ] [ ] [ ] in the case of ards, the specificity of icd- coding is likely improved by the fact that the diagnosis is typically made only by intensivists or pulmonologists. we, however, acknowledge that reliance on icd- coding to identify patients with ards likely underestimates the true incidence of ards, especially with regard to mild or moderate ards. this may explain why the observed incidence of ards in this study is lower than that reported by rubenfeld et al in a study that used prospective ards phenotyping by trained investigators. overall, the in-hospital mortality in this cohort was considerably higher than mortality reported in other large cohorts. , there are several potential explanations. one possibility is that use of icd- coding identifies a more severely ill group of patients than other methods of ards phenotyping. the in-hospital mortality rate in ( %) in the current study is very close to the mortality reported for patients with severe ards in the report of the berlin definition of ards, ( %), which accounted for approximately one-third of the total study participants in the berlin study. , one possible interpretation is that the taiwanese study population is representative of severe ards and that icd- coding missed many of the less severe mild and moderate cases. if this were the case, then the calculated incidence of all ards in taiwan might be closer to per , person-years, which is close to the recent report in the united states. in support of this estimate, moss et al used multiple-cause mortality data to analyze the incidence of ards in a population that was more likely to be in the severe stage of the disease. that study showed that the incidence of ards was to per , person-years, which is very close to our finding. another potential explanation for the high mortality in the taiwanese cohort is that factors related to health care delivery or patient race lead to the differences in observed outcomes. as shown in figure , men had higher incidence of ards than women in all age group. one potential explanation is that the rate of alveolar fluid clearance is faster in women with acute lung injury compared with men, which might lead to more rapid resolution of pulmonary edema. in addition, cigarette smoking has recently been shown to be a risk factor for ards , and men are -fold more likely to smoke than women in taiwan. unfortunately, the nhird does not contain information about patient smoking. although a number of experimental studies have shown promising benefits in treating ards, no clinical studies have demonstrated an effective pharmacologic treatment. the reported mortality of ards ranges from % to % depending on the patient population. several studies have shown a decrease in ards mortality over time, [ ] [ ] [ ] mainly because of the implementation of new ventilator strategies. a protective lung strategy could reduce the risk of further lung injury, systemic inflammation, and subsequent multisystem organ failure in ards patients. , [ ] [ ] [ ] interestingly, in the current study, there was an abrupt decrease in mortality in , which coincided with the outbreak of severe acute respiratory syndrome in asia and an increase in incidence of ards (fig. a) . a possible explanation may be that physicians in taiwan that year were more aware of ards and provided better care and were more adherent to low tidal volume ventilation in ards patients. this study has both strengths and limitations. the major strengths include the large number of ards patients in the nhird as well as the long period of follow-up. to our knowledge, this is the first nationwide epidemiological study of ards, and the follow-up period is the longest available, so we can clearly see the trend of the disease. the limitations of the study are inherent to icd- database without any specified definition of ards and retrospective in nature. we did not have detailed data for definition of ards, such as the chest radiograph reports, ratio of arterial oxygen partial pressure to fractional inspired oxygen, and utility of positive end-expiratory pressure. in addition, major indexes as acute physiology and chronic health evaluation score, sequential organ failure assessment score, or lung injury score were lacking. second, because we were limited to the icd- coding data for each admission, we could not identify the actual etiologies of ards in this study. finally, no clinical data such as arterial blood gas analyses were available to grade the severity of ards. in conclusion, we provide the first study of large-scale epidemiological data for ards in asia. the incidence of ards may be underestimated because of the use of icd- coding in the nhird and severe ards may be overrepresented. nevertheless, the study provides valuable new information on the incidence and outcomes of ards in an asian patient population. consistent with findings in other countries, there has been a decrease in in-hospital and -year mortality rates in recent years that likely reflects the benefits of lung protective mechanical ventilation. acute respiratory distress syndrome: the berlin definition the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination the acute respiratory distress syndrome incidence and outcomes of acute lung injury clinical epidemiology of acute lung injury and acute respiratory distress syndrome: incidence, diagnosis, and outcomes impact of distinct definitions of acute lung injury on its incidence and outcomes in brazilian icus: prospective evaluation of , patients one-year outcomes in survivors of the acute respiratory distress syndrome functional disability years after acute respiratory distress syndrome adult respiratory distress syndrome: a systemic overview of incidence and risk factors incidence of the adult respiratory distress syndrome in the state of utah adult respiratory distress syndrome: how many cases in the uk? incidence, severity, and mortality of acute respiratory failure in incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in sweden, denmark, and iceland. the arf study group incidence of ards in an adult population of northeast ohio incidence of acute lung injury in the united states acute respiratory distress syndrome: an audit of incidence and outcome in scottish intensive care units incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three australian states incidence and outcome of acute lung injury and acute respiratory distress syndrome in the surgical intensive care unit sex, race, and the development of acute lung injury pediatric acute lung injury: prospective evaluation of risk factors associated with mortality pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the pediatric acute lung injury consensus conference critically ill patients with severe acute respiratory syndrome acute respiratory distress syndrome: estimated incidence and mortality rate in a millionperson population base impact of acute lung injury and acute respiratory distress syndrome after traumatic brain injury in the united states acute respiratory distress syndrome and acute lung injury in patients with vertebral column fracture(s) and spinal cord injury: a nationwide inpatient sample study acute lung injury in patients with subarachnoid hemorrhage: a nationwide inpatient sample study association between nucleoside analogues and risk of hepatitis b virus-related hepatocellular carcinoma recurrence following liver resection risk of ovarian cancer in women with pelvic inflammatory disease: a population-based study physician's case volume of intensive care unit pneumonia admissions and in-hospital mortality increased risk of cirrhosis and its decompensation in chronic hepatitis c patients with new-onset diabetes: a nationwide cohort study long-term clinical outcome of major adverse cardiac events in survivors of infective endocarditis: a nationwide population-based study relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the berlin definition an attempt to validate the modification of the american-european consensus definition of acute lung injury/acute respiratory distress syndrome by the berlin definition in a university hospital race and gender differences in acute respiratory distress syndrome deaths in the united states: an analysis of multiple-cause mortality data ( - ) alveolar fluid clearance is faster in women with acute lung injury compared to men cigarette smoke exposure and the acute respiratory distress syndrome active and passive cigarette smoking and acute lung injury after severe blunt trauma smoking behaviour in taiwan the acute respiratory distress syndrome epidemiology of acute lung injury and acute respiratory distress syndrome mortality rates for patients with acute lung injury/ards have decreased over time eight-year trend of acute respiratory distress syndrome: a population-based study in olmsted county, minnesota improved survival of patients with acute respiratory distress syndrome (ards): - acute respiratory distress syndrome: epidemiology and management approaches the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury key: cord- -dgy qbl authors: tomazini, b. m.; maia, i. s.; bueno, f. r.; silva, m. v. a. o.; baldassare, f. p.; costa, e. l. v.; moura, r. a. b.; honorato, m.; costa, a. n.; cavalcanti, a. b.; rosa, r.; avezum, a.; veiga, v. c.; lopes, r. d.; damiani, l. p.; machado, f. r.; berwanger, o.; azevedo, l. c. p. title: covid- -associated ards treated with dexamethasone (codex): study design and rationale for a randomized trial. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: dgy qbl objectives: the infection caused by the severe acute respiratory syndrome coronavirus (sars-cov ) spreads worldwide and is considered a pandemic. the most common manifestation of sars-cov infection (coronavirus disease - covid- ) is viral pneumonia with varying degrees of respiratory compromise and up to % of hospitalized patients might develop acute respiratory distress syndrome (ards). several clinical trials evaluated the role of corticosteroids in non-covid- ards with conflicting results. we designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within days after randomization in adult patients with moderate or severe ards due to confirmed or probable covid- . methods: this is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including patients with early-onset (less than h before randomization) moderate or severe ards, defined by the berlin criteria, due to covid- . eligible patients will be randomly allocated to either standard treatment plus dexamethasone (intervention group) or standard treatment without dexamethasone (control group). patients in the intervention group will receive dexamethasone mg iv once daily for days, followed by dexamethasone mg iv once daily for additional days or until intensive care unit (icu) discharge, whichever occurs first. the primary outcome is ventilator-free days within days after randomization, defined as days alive and free from invasive mechanical ventilation. secondary outcomes are all-cause mortality rates at day , evaluation of the clinical status at day assessed with a -level ordinal scale, mechanical ventilation duration from randomization to day , sequential organ failure assessment (sofa) score evaluation at h, h and days and icu-free days within . ethics and dissemination: this trial was approved by the brazilian national committee of ethics in research (comissao nacional de etica em pesquisa - conep) and national health surveillance agency (anvisa). an independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. results will be submitted for publication after enrolment and follow-up are complete. mechanical ventilation duration from randomization to day , sequential organ failure assessment (sofa) score evaluation at h, h and days and icu-free days within . this trial was approved by the brazilian national committee of ethics in research (comissão nacional de Ética em pesquisa -conep) and national health surveillance agency (anvisa). an independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. results will be submitted for publication after enrolment and follow-up are complete. keywords: coronavirus, ards, corticosteroids, covid- , critical care, dexamethasone. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . the disease spread worldwide, and after three months, countries in all continents, except antarctica, had registered cases . considering all cases of covid- , estimates suggest that % will develop respiratory failure , while in hospitalized patients, up to % might develop acute respiratory distress syndrome (ards) , which is the leading cause of death in this population . corticosteroids, due to its anti-inflammatory effects , may be a suitable therapy for these patients and have been tested in different scenarios of ards . a recent trial showed that early use of dexamethasone is safe and reduces the duration of mechanical ventilation in ards patients without covid- . however, data suggest that corticosteroids use might increase viral load in patients with sars-cov- infection and mers infection , while a meta-analysis showed that corticosteroids are associated with increased mortality in influenza pneumonia . early use in less severe cases and late use in the course of ards might be responsible for the detrimental effects in this population. current guidelines recommend against using corticosteroids in patients with covid- outside clinical trials . furthermore, evidence suggests that patients with severe covid- might have a hyperinflammatory state known as cytokine storm. the cytokine profile in these patients resembles the one found in secondary hemophagocytic lymphohistiocytosis (shlh) , with increased levels of interleukin (il)- , il- and tumor necrosis factor alpha. corticosteroids are one of the therapeutic cornerstones for treating shlh. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . therefore, we propose a pragmatic, randomized, open-label, controlled clinical trial, comparing standard treatment versus standard treatment added to early administration of dexamethasone for days in patients with moderate and severe ards due to covid- . we used the recommendations for interventional trials (spirit) guideline for this report , which is presented in the appendix i of the electronic supplementary material (esm). the steering committee members are shown in the appendix ii of the esm. this manuscript refers to the fifth version of the protocol. the covid- -associated ards treated with dexamethasone: codex is a pragmatic, prospective, randomized, stratified, multicenter, open-label, superiority, controlled trial including patients with moderate or severe ards due to confirmed or probable covid- in intensive care units in brazil. we hypothesize that early administration of dexamethasone increases the number of days alive and free of mechanical ventilation in adult patients with moderate or severe ards due to sars-cov . the trial is registered with clinicaltrials.gov (nct ). our primary objective is to evaluate the effectiveness of early intravenous (iv) dexamethasone administration on the number of days alive and free of mechanical ventilation within days after randomization in adult patients with moderate or severe ards due to confirmed or probable covid- . ventilator-free days (vfd) is defined as being free from invasive mechanical ventilation for at least h (successful extubation) . if the patient is re-intubated within h of the extubation it will be treated as zero vfd; if . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint re-intubated after h, the h period will be counted as vfd. patients discharged from the hospital alive before days are considered alive and free from mechanical ventilation at day . non-survivors at day are considered to have zero vfd. secondary objectives are to evaluate the effect of dexamethasone treatment plus standard treatment versus standard treatment alone on the following: • all-cause mortality rates at days after randomization • number of days of mechanical ventilation from randomization to day • icu free days within days • change in the sequential organ failure assessment (sofa) score h, h and days after randomization the planned study duration is five months, being three months of recruitment, one month of follow up and one month for data analysis and manuscript writing. the first patient was enrolled on april th . the final report and publication are expected to be available on the second half of . we will include critically ill patients with ards due to confirmed or probable covid- admitted to the icu. probable covid- is defined by the presence of symptoms, which are contemplated in the inclusion criteria, travel or residence in a city where community transmission is reported or contact with a confirmed case in the last . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint days prior symptoms onset and radiological imaging findings compatible with covid- at the time of inclusion. after patients have been enrolled, the steering committee suggested specific changes on both inclusion and exclusion criteria. the timing of ards diagnosis for inclusion changed from h to h. the rationale for this modification was due to most centers receiving patients intubated in the icu already with ards diagnosis and more than hours of mechanical ventilation, which shortened the time window for recruitment. additionally, given the widespread use of corticosteroids before icu admission in brazil, we allowed inclusion of patients who have previously received one day of corticosteroids during hospital stay, which was not allowed at first. the exclusion criteria were refined by adding three more criteria: use of immunosuppressive drugs, cytotoxic chemotherapy in the past days, and neutropenia due to hematological or solid malignancies with bone marrow invasion. each patient must fulfil all the following inclusion criteria to be eligible for enrolment: • age ≥ years old • intubated and mechanically ventilated • moderate or severe ards according to berlin criteria (table ) • onset of moderate or severe ards in less than h before randomization exclusion criteria are: • pregnancy or active lactation • known history of dexamethasone allergy • daily use of corticosteroids in the past days . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint • indication for corticosteroids use for other clinical conditions (e.g refractory septic shock) • patients who did use corticosteroids during hospital stay for periods equal or greater than two days • use of immunosuppressive drugs • cytotoxic chemotherapy in the past days • neutropenia due to hematological or solid malignancies with bone marrow invasion • patient is expected to die in the next hours • consent refusal for participating in the trial patients are eligible for enrolment if all the inclusion criteria and none of the exclusion criteria are met. patients are being randomized in a : ratio to one of the two groups (figure ): standard treatment plus dexamethasone (intervention group) and standard treatment without dexamethasone (control group). the randomization list is generated by an independent statistician in random blocks of and in order to preserve the allocation concealment and is stratified by center. randomization is performed by an online web-based central, available h a day. the group treatment is disclosed to the investigator only after all information regarding patient enrolment is recorded in the online system. patients are screened for enrolment by the principal investigator and the research team at each study center. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint this is an open-label trial where the investigators, caregivers and patients are not blinded regarding the intervention. all statistical analyses will be performed in a blinded manner with respect to group allocation. each icu enrolling patients in the trial are encouraged to follow the best practice patients in the intervention group are receiving after randomization dexamethasone mg intravenously once daily for days, followed by dexamethasone mg iv once daily for additional days or until icu discharge, whichever occurs first. patients in the control group are not receiving dexamethasone. although we are not controlling the ventilatory strategy in both groups, physicians are encouraged to comply with the following ventilator strategy: tidal volume (vt) of - ml/kg of predicted body weight (pbw), a plateau pressure < cmh , driving pressure < cmh , respiratory rate to maintain arterial ph > . and fio and peep to keep spo ≥ % or pao ≥ mmhg. sedation drugs and the use of other strategies for ards management such as use of neuromuscular blocking agents, prone positioning, nitric oxide and extracorporeal membrane oxygenation (ecmo) are left to physicians' discretion and are registered daily on the study's electronic case report form (ecrf). each center is encouraged to follow institutional guidelines for liberation of mechanical ventilation. the study timeline is shown in figure . . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the main analysis will be based on the intention-to-treat principle, with additional sensitivity analysis regarding the covid- infection status (confirmed vs not confirmed). the most common adverse effects of corticosteroids use are hyperglycemia and possible increase in infections rates. data on glycemic control is collected daily until day and data on the development of new infections is collected daily until day . for any other adverse events a specific form is available on the ecrf and the data is sent in real time to the coordinating center. adherence to protocol and corticosteroids use in both groups is accessed daily. the use of corticosteroids in the control group is not forbidden since critically ill patients might . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint have another indication for corticosteroid use during their icu stay. however, any use of corticosteroids for treating ards and or refractory hypoxemia in the control group is considered protocol deviation. changes in dosage of dexamethasone or early interruption in the intervention group will also be considered protocol deviation. if during the trial the patient is deemed to not have covid- infection, which is defined by a negative laboratory tests along with negative evaluation by the adjudication committee, the study drug will be stopped, data on these patients will be collected until day and will be included in the final analysis. however, giving the epidemiological context and inclusion criteria, it is expected that only a minority of patients will be in this group. all centers will receive an initial training session before initiating recruitment to ensure consistency of the study procedures and data collection. unidentified patient data will be collected through an electronic online data capture tool (redcap) . demographic and baseline data, height, simplified acute physiology score (saps) , use of corticosteroids prior the randomization, and the hscore (table ) for diagnosis of secondary hemophagocytic lymphohistiocytosis are collected for all patients. the sofa score is collected on days , , and . data from gas exchange, lung mechanics, hemodynamic, laboratory data, use of neuromuscular blocking agents, prone positioning and use of extracorporeal membrane oxygenation (ecmo) are collected prior randomization and until day . the use of mechanical ventilation or any other ventilation/oxygen support (high flow nasal cannula, non-invasive ventilation, use of supplementary oxygen) and data on the -point ordinal scale (table ) are collected daily until day or until hospital discharge . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . all data are collected through the ecrf and periodically data quality checks will be performed by the trial management committee. database lock will be carried out after the -day outcome is obtained for all patients. database access will be granted only to steering committee members and statisticians before the main results are published. we plan to share data with other ongoing clinical trials on the same topic for individual patient´s metanalysis. we plan to upload the study dataset to a public database months after database lock. there is a lack of reliable data available in patients with ards due to covid- to allow an accurate sample size calculation. we therefore used data from a randomized controlled trial in non-covid- ards patients , a well-designed multicenter trial that is representative of ards outcomes in brazil, to calculate the sample size. we assumed a mean of vfd at days of days ± days (standard deviation) in the control group. with a two-sided type i error of . and power of % to identify a difference in three days free of mechanical ventilation between groups, a sample size of patients would be needed. however, in the end of may , before the first interim analysis, after discussing the protocol with the data monitoring committee (dmc), the steering committee decided . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint to increase the sample size based on the following rational: given the uncertainty regarding the normality of distribution of vfd, based on the pitman asymptotic relative efficiency , the sample size should be increased by % to preserve study power coupled with a % increase considering possible lost to follow-up and withdrawal of consent. therefore, a final sample size of patients is needed. also, due to the lack of data about ventilator free days in covid- patients, the sample size will be updated using the pooled standard deviation of ventilator free days of the first interim analysis, unless by the time of the first interim analysis all patients have been recruited. the minimal clinically important difference of three days for vfd was chosen based on other trials along with what is perceived as a significant improvement to the in-hospital complications, costs, and intensive care unit availability, especially in countries with limited resources. two interim analyses are planned for safety and efficacy evaluation, after patients and patients with the complete follow up to the primary outcome. based on the results of these interim analyses, the dmc will decide if there is proof beyond a reasonable doubt that the intervention is effective or not safe in this population. the stopping rule for safety will be a p-value < . and for efficacy p-value < . (haybittle-peto boundary). the haybittle-peto boundary is a conservative stopping rule at interim analysis that has minimal impact in increasing type i error in two-arm trials . the interim analyses will be performed by an external and independent dmc. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint main analyses will follow the intention-to-treat principle. for the primary outcome, a generalized linear model will be built with beta-binomial distribution or zero/one inflated beta distribution, with center as random effect and adjusted for age, corticosteroid use before randomization and pao /fio ratio. the effect size will be estimated as mean difference, the respective % confidence interval, and hypothesis testing. missing data on the primary outcome will be dealt with using multiple imputation techniques. for details regarding the analysis of the secondary outcomes and other analysis, please refer to the statistical analysis plan (sap) on the appendix iii of the esm. the significance level for all analyses will be . . there will be no adjustment for multiple testing. all analyses will be performed using the r software (r core team, vienna, austria, ). we plan to perform subgroup analysis for the primary endpoint, including interaction parameters in the main model to: • age (< and ≥ ) • pao /fio ratio (≤ and > ) • saps (< and ≥ ); • duration of symptoms at randomization, days (≤ and > ) • duration of moderate / severe ards to randomization, hours (≤ h and > h to h) • position at randomization; (prone or supine) • hscore (≥ and < ) • use of corticosteroids before randomization • use of vasopressors at randomization . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we will perform the following pre-specified sensitivity analysis: patients with laboratory confirmed covid- , patients with laboratory confirmed and probable covid- , per-protocol analysis (patients that received the proposed treatment in the intervention group and patients that not received corticosteroids in the control group) and an as-treated analysis (considering patients which received any dose of corticosteroids in the control group). we plan to collect blood samples for transcriptomic studies after randomization and after days to evaluate if the treatment effect of dexamethasone changes based on the genetic expression of leukocytes and to follow patients for a period of months in order to perform future analyses on clinical outcomes and quality of life. the steering committee is constituted by the study investigators of the coalition covid- brazil iii and will be responsible for the development of the study protocol, manuscript drafts and study submission to publication. all other study committees will report to the steering committee. i. conduction of the study: creating the electronic case report forms (ecrf), designing the investigator manual and the operations manuals, managing and controlling data quality. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint ii. research center management: selecting and training the research centers, assisting the center in regulatory issues, monitoring recruitment rates, monitoring follow-up, sending study materials to research centers. iii. statistical analysis and reporting: completing the statistical analyses and helping to write the final manuscript. the adjudication committee is responsible for evaluating all laboratory negative cases of covid- . based on the epidemiology, clinical findings and radiological imaging, the committee will classify patients as probable or negative cases of covid- . the data monitoring committee is composed by an external statistician and experts in critical care medicine independent of the study's investigators (see esm appendix iv for further information). the dmc will be responsible for the interim analysis and will provide guidance to the steering committee regarding the continuation and safety of the trial after the interim analyses based on the evidence of significant differences between intervention or control group regarding ventilator free days at day , mortality or adverse events. the trial was designed according to the guidelines for good clinical practice and followed the principles of the declaration of helsinki and was approved by the brazilian national committee of ethics in research (comissão nacional de Ética em pesquisa -conep). all protocol amendments must be approved by conep before its implementation. given the growing number of covid- cases in brazil, most hospitals have adopted total restriction policies in icu visitation in order to contain viral spreading. also, we expect that virtually none of the patients will be able to give consent due to their . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint clinical condition. therefore, the conep allowed for different approaches in obtaining the consent from the patients' legal representatives, such as consent by email or any other digital format and by voice or video. patients will be included in the study only after the informed consent form is obtained by the study's investigators. patients and their legal representatives can withdrawal from the study at any time and for any reason. patients' next of kin are assured that this withdrawal will not have any impact regarding the patients' care. before withdrawal patients or their legal representative will be asked if data can continue to be collected, despite receiving the study interventions. patients who withdrawal consent from the study will not be replaced by other participants. the study will be submitted for publication after completion irrespective of its findings. the manuscript elaboration will be an inalienable responsibility of the steering committee. the main paper will be authored by the steering committee members plus the principal investigators of the -top enrolling sites, which can contribute intellectually to the manuscript. this is the first randomized controlled trial evaluating the efficacy of early dexamethasone administration in moderate and severe ards caused by the sars-cov virus. corticosteroids have been used in ards treatment for almost years . however, there is still controversy around the efficacy of this treatment. the literature suggests a potential benefit of early administration in more severe cases with a possible influence on the outcome depending on the ards cause (bacterial vs. viral pneumonia, primary vs. secondary ards). also, most of the published data is from small, retrospective studies in heterogeneous populations. . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint the most common adverse effects of corticosteroids use is hyperglycemia, but as shown in a recent trial , patients receiving dexamethasone had a similar frequency of hyperglycemia ( %) as compared to controls ( %). also, the trial showed no difference in new infections in the icu between groups. our trial has significant strengths compared to the published literature. the study population will be homogenous comprising only critically ill patients with moderate or severe ards. we offer a precise and reproducible intervention protocol and we will include patients in the early phase of ards. early ards phase probably coincides with a later phase in the disease process, which might reduce the risk of increased viral replication induced by the study drug as suggested by previous authors for mers virus and sars-cov infection . we acknowledge our trial has some limitations. it is an open-label trial, which can interfere in the use of other immunomodulatory therapies such as the use of convalescent plasma, tocilizumab or hydroxychloroquine, especially in the control group. however, we choose an objective primary outcome with clear definitions, which reduces the influence of the open label nature in the outcome assessment. if we confirm our hypothesis of benefit of using dexamethasone in ards due to sars-cov infection, the consequences for public health will be enormous, especially considering the covid- pandemic. given the unprecedented impact in global health and the lack of icu beds in most countries during the pandemic, an increase in days alive and free of mechanical ventilation should help unburden the health care systems worldwide and will represent a noteworthy improvement in ards treatment. hospitalized, not requiring supplemental oxygen. hospitalized, requiring supplemental oxygen. hospitalized, requiring non-invasive ventilation or nasal high-flow oxygen therapy hospitalized, requiring invasive mechanical ventilation or ecmo death . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint world health organization. who director-general's opening remarks at the media briefing on covid- - a novel coronavirus from patients with pneumonia in china world health organization. coronavirus disease (covid- ) situation report - : who characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease antiinflammatory action of glucocorticoids--new mechanisms for old drugs efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial effects of early corticosteroid treatment on plasma sarsassociated coronavirus rna concentrations in adult patients corticosteroid therapy for critically ill patients with middle east respiratory syndrome the effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis infectious diseases society of america guidelines on the treatment and management of patients with covid- anzics covid- guidelines version : anzics; covid- : consider cytokine storm syndromes and immunosuppression adult haemophagocytic syndrome spirit statement: defining standard protocol items for clinical trials epidemiology of weaning outcome according to a new definition. the wind study protocolo de manejo clínico para o novo coronavírus ( -ncov) acute respiratory distress syndrome: the berlin definition correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases the redcap consortium: building an international community of software platform partners research electronic data capture (redcap)--a metadata-driven methodology and workflow process for providing translational research informatics support effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial statistical methods based on ranks: holden-day enteral omega- fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury maximal recruitment open lung ventilation in acute respiratory distress syndrome (pharlap) assessing the impact of efficacy stopping rules on the error rates under the multi-arm multi-stage framework r: a language and environment for statistical computing r foundation for statistical computing development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome respiratory function of blood in the acutely ill patient and the effect of steroids key: cord- -ujnhjy s authors: baer, brandon; mccaig, lynda; yamashita, cory; veldhuizen, ruud title: exogenous surfactant as a pulmonary delivery vehicle for budesonide in vivo date: - - journal: lung doi: . /s - - - sha: doc_id: cord_uid: ujnhjy s background: lung inflammation is associated with many respiratory conditions. consequently, anti-inflammatory medications, like glucocorticoids, have become mainstay intrapulmonary therapeutics. however, their effectiveness for treating inflammation occurring in the alveolar regions of the lung is limited by suboptimal delivery. to improve the pulmonary distribution of glucocorticoids, such as budesonide to distal regions of the lung, exogenous surfactant has been proposed as an ideal delivery vehicle for such therapies. it was therefore hypothesized that fortifying an exogenous surfactant (bles) with budesonide would enhance efficacy for treating pulmonary inflammation in vivo. methods: an intratracheal instillation of heat-killed bacteria was used to elicit an inflammatory response in the lungs of male and female rats. thirty minutes after this initial instillation, either budesonide or bles combined with budesonide was administered intratracheally. to evaluate the efficacy of surfactant delivery, various markers of inflammation were measured in the bronchoalveolar lavage and lung tissue. results: although budesonide exhibited anti-inflammatory effects when administered alone, delivery with bles enhanced those effects by lowering the lavage neutrophil counts and myeloperoxidase activity in lung tissue. combining budesonide with bles was also shown to reduce several other pro-inflammatory mediators. these results were shown across both sexes, with no observed sex differences. conclusion: based on these findings, it was concluded that exogenous surfactant can enhance the delivery and efficacy of budesonide in vivo. inflammation is associated with many respiratory conditions, including asthma, pneumonia, bronchopulmonary dysplasia, chronic obstructive pulmonary disease, and acute respiratory distress syndrome (ards). however, the effectiveness of anti-inflammatory medications, such as glucocorticoids, is location specific for these conditions in terms of airway (bronchi) or airspace (alveolar) involvement [ ] . in asthma, for example, inflammation is observed primarily in the small airways, which allows for a more direct delivery of therapeutics, as evidenced by the effectiveness of standard inhalers [ , ] . on the other hand, in other conditions, such as ards and pneumonia, inflammation occurs in the more distal, alveolar, regions of the lung, where the large surface area, and associated regions of alveolar edema or airway collapse may contribute to an inability of airwaydelivered therapies to reach distal lung units, to provide effective anti-inflammatory functions [ , , ] . in these clinical scenarios, alternative strategies are required to deliver therapeutic concentrations of anti-inflammatory medications to these peripheral sites within the lung. one such approach, is with the use of exogenous surfactant as a delivery vehicle for glucocorticoids such as budesonide. exogenous surfactant is a complex mixture of lipids and specialized proteins, usually obtained from natural sources such as cows or pigs [ ] . the endogenous material, produced by type ii alveolar cells in the lung, has been well studied and serves a vital biophysical role in reducing surface tension, thereby stabilizing the alveoli during normal breathing [ , ] . the discovery of surfactant deficiency in preterm infants led to the development of exogenous surfactant therapy [ ] . given intratracheally, exogenous surfactant spreads throughout the lung, improving lung function and has resulted in significant reductions to infant mortality due to prematurity [ , ] . it is suggested that the spreading properties of exogenous surfactant could improve glucocorticoid delivery to peripheral sites of inflammation in the lung. in support of this notion, exogenous surfactant has already been shown to enhance the delivery of glucocorticoids to remote sites using in vitro approaches [ , ] . similarly, in vivo studies, including those modeling ards, have observed improved drug distribution and anti-inflammatory effects for glucocorticoids delivered by a surfactant vehicle [ ] [ ] [ ] . in addition, it has been shown that through these properties, exogenous surfactant can re-open collapsed airways, overcome regions of edema, and thereby efficiently spread to the deeper, more remote sites of inflammation even in an injured lung [ ] . together, this data highlights the potential for exogenous surfactant to provide these locally acting anti-inflammatory drugs' access to remote regions of the lung otherwise inaccessible to therapeutics. when combined with the efficacy of glucocorticoids, the innate biophysical properties of surfactant suggest that utilizing exogenous surfactant as a vehicle for budesonide would improve its effectiveness for treating remote inflammation in the lung. it was therefore hypothesized that fortifying an exogenous surfactant with budesonide would enhance efficacy for treating pulmonary inflammation in vivo. heat-killed bacteria (hkb) was created from a lab strain of pseudomonas aeruginosa (atcc ), purchased from sigma-aldrich (oakville, on, canada). using measurements of optical density, the bacteria were diluted in saline to × colony-forming units (cfu) per ml, before being heated at °c for min. a commercially available preparation of budesonide ( . mg/ml), suspended in deionized water, was obtained from astrazeneca (södertälje, södermanland, sweden). bovine lipid extract surfactant (bles) at mg/ml phospholipid concentration was obtained from bles biochemicals (london, on, canada). using saline; these preparations were combined and diluted to mg/ml and µg/ml for bles and budesonide, respectively, with drug vehiculization being verified through the wet bridge transfer system as described previously [ ] . all animal work was carried out in accordance with guidelines and regulations set forth by the western university council for animal care. for breeding, two adult male and seven adult female wistar rats ( g) were purchased from charles river (st-constant, qc, canada). acclimatization to the animal care facility and breeding were carried out as previously described [ ] . once pregnant, rats were housed individually and received standard chow. immediately after birth the litters were culled to pups in order to limit the effect of litter size on outcomes. to initiate pulmonary inflammation, male or female offspring were weighed, anesthetized, and intratracheally instilled with µl of hkb ( × cfu/ml) or saline per gram of body weight at - days of age. in animals randomized to a treatment group, this first instillation was followed thirty minutes later by a second instillation of either budesonide ( µg/ml) or bles/budesonide ( mg/ml; µg/ml). to minimize the potential effects of any distinct litter, only or animals per litter were randomized to any individual experimental group. animals were monitored for h following instillation, before being euthanized by intraperitoneal injection of sodium pentobarbital and exsanguination, by severing the descending aorta. after this, a bronchoalveolar lavage (bal) was performed as previously described [ ] , before the lungs were excised, divided into four pieces and snap frozen in liquid nitrogen to be stored at - °c. inflammatory cell counts and differential cell analysis of the lavage were done as previously described [ ] . briefly, lavage volume was recorded and centrifuged at ×g for min to obtain a cell pellet. this pellet was resuspended and used for cell counting and differential cell analysis to obtain the number of inflammatory cells and neutrophils in the lavage fluid. protein content of the lavage fluid was also measured using a micro bca protein assay kit from pierce biotechnology (rockford, il, usa), per manufacturer's instructions. a multiplexed immunoassay kit was utilized per manufacturer's instruction (r&d systems, minneapolis, mn) to measure the concentrations of tnfα, il- , mip- , and gro/kc. a bio-plex readout system was utilized from bio-rad (santa rosa, ca, usa) and cytokine levels (pg/ml) were automatically calculated from standard curves using bio-plex manager software (v. . . , bio-rad). an aliquot of the ×g supernatant was also analyzed through a duck-chong phosphorous assay as previously described [ ] . briefly, the total amount of surfactant in the lavage was determined through the measurement of phospholipid-phosphorus [ , ] . the remainder of the supernatant was then centrifuged at , ×g for min to obtain a pellet of the active form of the surfactant, the large aggregates (la). this resuspended pellet, as well as the , ×g supernatant containing the small aggregates (sa), was also analyzed for phospholipid-phosphorus [ , ] . frozen lung tissue was utilized for myeloperoxidase (mpo) activity as previously described [ ] . briefly, pieces of frozen lung were weighed and then homogenized in . m potassium phosphate buffer (ph ; sigma-aldrich) using a pt homogenizer. using a high-speed centrifuge, the lung homogenate was spun at ×g for min at °c, with the resulting pellet being resuspended in % hexadecyltrimethylammonium hydroxide detergent solution. this mixture was then re-homogenized, before being sonicated at °c and % amplitude for s. the resulting preparation was spun at , ×g for min at °c. the supernatant was then aliquoted into a -well plate at mg/ml and mixed with an mpo cocktail containing , ′, , ′-tetramethyl-benzidine. hydrogen peroxide was then added to each well and the plate was incubated at °c for min. sulfuric acid was used as a stop solution and the plate was read at nm using an imark plate reader (bio-rad). mpo activity (units/ mg) was calculated from standard curves (sigma-aldrich). all data points shown represent one male or female rat. statistical significance was determined by two-way analysis of variance (anova) followed by a tukey-kramer post hoc test to determine differences among experimental groups. results were considered statistically significant with a p-value of less than . . some of the overall characteristics of the experimental groups are shown in table . prior to the first instillation, body weights were found to be similar among the experimental groups. there were also no significant differences across experimental groups for the protein content of the bal. the phospholipid composition of surfactant, including total surfactant, as well as the large aggregate and small aggregate subfractions, was significantly higher in male and female rats receiving bles/budesonide compared to all other treatment groups. to evaluate the anti-inflammatory effects of delivering budesonide with an exogenous surfactant in vivo, standard inflammatory markers were analyzed using the bal and frozen lung tissue. the instillation of hkb resulted in a significantly higher number of inflammatory cells compared to saline (fig. ) . the instillation of budesonide following the inflammatory insult of hkb did not have a significant effect on the number of inflammatory cells as compared to the saline or hkb instilled groups. instillation of bles/ budesonide resulted in significantly lower numbers of (fig. a) . additionally, the number of neutrophils was significantly lower in animals administered bles/budesonide compared to those given budesonide alone. the instillation of hkb ( . ± . for males and . ± . for females) or hkb followed by budesonide ( . ± . for males and . ± . for females) also resulted in significantly higher mpo activity compared to saline ( . ± . for males and . ± . for females; fig. b ). however, only the animals instilled with bles/budesonide ( . ± . for males and . ± . for females) had significantly lower mpo activity compared hkb or budesonide groups. in a separate cohort of animals, the effect of hkb with or without a second administration of bles ( mg/ml) was tested. in these animals, the number of neutrophils in the lavage was . ± . (n = ) for the hkb group and . ± . (n = ) for the hkb plus bles group. additionally, mpo activity for the hkb group was . ± . (n = ), while hkb plus bles group had . ± . (n = ). for both measurements, the values were not statistically significant and were similar to values in the hkb group of the first cohort. the instillation of hkb or hkb followed by budesonide was also shown to result in significantly higher levels of all pro-inflammatory cytokines tested compared to the saline group (fig. a-d) . compared to animals administered hkb, those receiving a second instillation of bles/budesonide showed significantly lower il- and tnf-α concentrations (fig. a, b) . furthermore, the bles/budesonide group showed significantly lower concentrations of tnf-α and gro/kc than the budesonide group (fig. b, c) . although the bles/budesonide group showed lower levels of mip- and gro/kc relative to hkb and budesonide groups, the levels were still significantly higher than the saline group (fig. c, d) . this study tested the hypothesis that fortifying an exogenous surfactant preparation, bles, with budesonide would enhance the efficacy for treating pulmonary inflammation in vivo. overall, our results supported this hypothesis. specifically, bles was shown to enhance the anti-inflammatory effects of budesonide in a rat model of lung inflammation by reducing the number of neutrophils, as well as the concentrations of a several pro-inflammatory mediators in the bal. furthermore, combining budesonide with bles was also shown to be beneficial for reducing mpo activity in the lung tissue. it should also be noted that these results were displayed across both sexes. based on these observations, it is concluded that utilizing exogenous surfactant as a pulmonary vehicle for budesonide enhanced its ability to treat lung inflammation. to address our hypothesis, we utilized an experimental in vivo model, where hkb was instilled into the lungs of young rats. the rationale for the use of young rats was practical in nature to limit animal usage, as these animals were also utilized for a separate experiment (see disclosures). the hkb solution contains a mixture of bacterial components, including lipopolysaccharides, that caused a rapid inflammatory response as evidenced by the significant increases in neutrophil counts, mpo activity and inflammatory cytokine concentrations as compared to animals not receiving hkb. the experimental treatment tested was bles/budesonide for which intratracheal instillation was confirmed via the increased surfactant levels in the bal fluid following the experiment. it should be noted that our experimental design did not include a bles only treatment. however, an additional experiment with pups revealed that bles alone did not impact the inflammatory response induced by the instillation of hkb. based on these considerations, we deem the experimental approach as an appropriate test of our hypothesis. an important aspect of this study was the evaluation of a potential glucocorticoid-based treatment strategy in both males and females. although the objective of this manuscript was not to understand the underlying pathways leading to potential sex differences, numerous studies have demonstrated the role of sex in patient sensitivity to glucocorticoid treatment [ ] [ ] [ ] [ ] [ ] . unfortunately, these previous studies have also been inconsistent with respect to their findings. for example, when developing guides to predict responsiveness among asthmatic children, both wu et al. ( ) and galant et al. ( ) found that the female sex was associated with a higher likelihood of responsiveness to inhaled glucocorticoid therapy [ , ] . on the contrary, some clinical trials and epidemiological studies have observed beneficial effects for daily glucocorticoid treatment in males, but not females [ , ] . for the current model of pulmonary inflammation, the instillation of hkb was found to result in a similar inflammatory response among males and females. moreover, no sex differences were found for the responsiveness of rats to either of the glucocorticoid treatments. since sex hormones have been shown to play such an essential role in inflammatory responses, this lack of differences may be related to the young, sexually immature age of the animals [ ] . despite these findings, the extensive role sex hormones play in modulating inflammatory pathways combined with the variability shown in human studies suggests that sex must be considered when evaluating new glucocorticoidbased treatment strategies [ ] . several previous studies have explored different aspects of utilizing an exogenous surfactant as a drug delivery vehicle for glucocorticoids, such as budesonide [ , [ ] [ ] [ ] [ ] . for example, numerous in vitro studies have characterized the successful incorporation of budesonide into exogenous surfactants, demonstrated their ability to transport budesonide across air-liquid interfaces, and even showcased their ability to improve the drug's anti-inflammatory effects at a distal site, without interfering with the biophysical function of surfactant [ , , ] . in animal experiments, recent data have demonstrated that intratracheally instilling budesonide with an exogenous surfactant enhanced its biodistribution within the lung [ ] . moreover, a rabbit model of meconium aspiration illustrated how the prophylactic administration of surfactant and budesonide could alleviate inflammation more effectively than budesonide or surfactant alone [ ] . our study adds to these previous observations by comparing the therapeutic effects of budesonide delivered by surfactant to budesonide or surfactant alone, when they are administered after a broad inflammatory insult. the current study also investigates these therapeutic effects across both male and female animals, as well as expanding beyond the general markers of inflammation normally analyzed for this treatment strategy. specifically, it uses outcomes such as mpo activity, neutrophil counts, and chemokine concentrations to focus on neutrophilic inflammation, which have been suggested to be a critical aspect of disease progression for ards [ ] when combined with this previous data, our study further supports the use of exogenous surfactant as a delivery vehicle for budesonide in the treatment of pulmonary inflammation. from a clinical standpoint, this study builds on previous work in the neonatal population. specifically, it adds to previous clinical studies that explored exogenous surfactant or glucocorticoids as preventative treatments for poor pulmonary outcomes and respiratory conditions like bronchopulmonary dysplasia [ , ] . for example, there are a number of clinical trials which have found that administering surfactant multiple times or using it as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia [ , ] . similarly, there have also been clinical trials that have found intratracheal instillations of budesonide, with a surfactant vehicle helped to prevent the development of chronic lung disease among preterm infants [ ] . the current manuscript expands these prophylactic approaches in premature lungs, by demonstrating anti-inflammatory effects of this treatment strategy, subsequent to the pulmonary inflammation, in both males and females. to extrapolate our data to the clinical arena, there are a variety of respiratory conditions that may benefit from an anti-inflammatory exogenous surfactant; however, its potential for treating ards is of particular interest. over the course of , ards has become a well-known syndrome as it is the critical pulmonary complication resulting from severe acute respiratory syndrome coronavirus- infections known as covid- . however, even before the emergence of covid- , ards was the most common cause of death in the icu, with no effective pharmacological therapies available [ ] [ ] [ ] [ ] . importantly, it has been shown that disease severity and progression are directly associated with the accumulation of neutrophils into the alveolar space [ , ] , and many aspects of the pathophysiology of ards, such as edema formation and surfactant dysfunction, are consequences of excessive inflammation in the lung [ ] . this has provided a strong rationale for glucocorticoid-based treatments, as evident by numerous clinical trials for ards and an ongoing trial for covid- patients [ ] [ ] [ ] . unfortunately, to date, these highly effective anti-inflammatory medications have failed to prevent ards or show mortality benefits [ , ] . one interpretation of this data is that the efficacy of the glucocorticoids is limited by suboptimal drug delivery. based on our data, it is tempting to speculate that exogenous surfactant as a delivery vehicle will allow glucocorticoids to become an effective treatment option for ards. it should be noted that there are several limitations to our study. first, this study only explored the benefits of one surfactant-glucocorticoid preparation. the improvements observed for budesonide when administered with an exogenous surfactant suggest therapeutic value in exploring a similar approach for other glucocorticoids or antiinflammatory medications. to this end, our lab intends to perform more elaborate in vivo studies with multiple commercially available glucocorticoids, like dexamethasone and hydrocortisone, to further explore the benefits of surfactant delivery. secondly, although our study shows clear benefits for treating lung inflammation with a surfactantbudesonide preparation, it is important to understand the limitations of our model and the extensive subsequent research that would be needed to translate this therapy to the clinical setting for ards. for example, based on the results of a recent study with this model, four main cytokines were selected to be measured [ ] . however, there are a wide array of cytokines and inflammatory mediators increased in ards patients, not to mention the numerous other patient outcomes that have been shown to be important in disease progression [ , ] . moreover, our model of pulmonary inflammation did not imitate the pulmonary edema or airway collapse observed in many respiratory conditions. the current study did measure protein content in the bal; however, its unchanging level across treatment groups suggests that a stronger stimulus is required to disrupt the alveolar capillary barrier. there is strong scientific evidence that exogenous surfactant can overcome regions of edema and airway collapse; however, future studies will be needed to evaluate this treatment strategy under inhibitory conditions and determine its efficacy for other important outcomes [ , ] . in conclusion, this paper demonstrates that the use of exogenous surfactant as a delivery vehicle for budesonide can make it more effective for treating lung inflammation. further, we propose that this novel treatment strategy can overcome the delivery challenges associated with respiratory conditions like ards and treat the neutrophilic inflammation underlying the disease. with no effective pharmacological options currently available for this condition, direct delivery with exogenous surfactant offers an intriguing method for mainstay medications to start effectively treating this devastating disease. drug delivery to the lungs: challenges and opportunities recent advances in aerosolised drug delivery the acute respiratory distress syndrome inflammation and immunity in ipf pathogenesis and treatment pulmonary surfactant: functions and molecular composition new insights into exogenous surfactant as a carrier of pulmonary therapeutics current perspectives in pulmonary surfactant-inhibition, enhancement and evaluation surfactants: past, present and future exogenous surfactant therapy in : what is next? who, when and how should we treat newborn infants in the future? the wet bridge transfer system: a novel tool to assess exogenous surfactant as a vehicle for intrapulmonary drug delivery efficient interfacially driven vehiculization of corticosteroids by pulmonary surfactant budesonide added to modified porcine surfactant curosurf may additionally improve the lung functions in meconium aspiration syndrome biophysical and chemical stability of surfactant/budesonide and the pulmonary distribution following intra-tracheal administration maternal protein restriction during perinatal life affects lung mechanics and the surfactant system during early postnatal life in female rats the antibacterial and anti-inflammatory activity of chicken cathelicidin- combined with exogenous surfactant for the treatment of cystic fibrosis-associated pathogens the effect of diet-induced serum hypercholesterolemia on the surfactant system and the development of lung injury a rapid method of total lipid extraction and purification a rapid sensitive method for determining phospholipid phosphorus involving digestion with magnesium nitrate voluntary running exercise protects against sepsis-induced early inflammatory and pro-coagulant responses in aged mice a simple prediction tool for inhaled corticosteroid response in asthmatic children the bronchodilator response as a predictor of inhaled corticosteroid responsiveness in asthmatic children with normal baseline spirometry lung function decline in asthma: association with inhaled corticosteroids, smoking and sex markers of differential response to inhaled corticosteroid treatment among children with mild persistent asthma airway responsiveness in mild to moderate childhood asthma: ssex influences on the natural history sex and inflammation in respiratory diseases: a clinical viewpoint glucocorticoids, sex hormones, and immunity the pathogenic involvement of neutrophils in acute respiratory distress syndrome and transfusion-related acute lung injury intratracheal administration of budesonide-surfactant in prevention of bronchopulmonary dysplasia in very low birth weight infants: a systematic review and meta-analysis bronchopulmonary dysplasia: an update of current pharmacologic therapies and new approaches intratracheal administration of budesonide/surfactant to prevent bronchopulmonary dysplasia postnatal steroids in extreme preterm infants: intra-tracheal instillation using surfactant as a vehicle a follow-up study of preterm infants given budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches the berlin definition of ards: an expanded rationale, justification, and supplementary material intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep receptor recognition by the novel coronavirus from wuhan: an analysis based on decadelong structural studies of sars coronavirus the mercurial nature of neutrophils: still an enigma in ards? death to the neutrophil! a resolution for acute respiratory distress syndrome? effect of dexamethasone in hospitalized patients with covid- : preliminary report the acute respiratory distress syndrome: from mechanism to translation pharmacological treatments in ards; a state-of-the-art update killing of p. aeruginosa by chicken cathelicidin- is immunogenically silent, preventing lung inflammation in vivo biomarkers in acute lung injury: insights into the pathogenesis of acute lung injury cytokine balance in the lungs of patients with acute respiratory distress syndrome exogenous surfactant as a drug delivery agent acknowledgements the authors acknowledge the funding from the ontario thoracic society and the lawson health research institute internal research funds. brandon baer is supported by an ontario graduate studentship. conflict of interest the authors declare that they have no conflicts of interest. data reported in the manuscript on the response of male and female rats administered only saline or hkb are also utilized in another manuscript as control animals to examine the effect of fetal growth restriction on inflammation (https ://doi.org/ . /cjpp- - ). animals were fully randomized for both studies. key: cord- -f o authors: martin-loeches, i.; lisboa, t.; rhodes, a.; moreno, r. p.; silva, e.; sprung, c.; chiche, j. d.; barahona, d.; villabon, m.; balasini, c.; pearse, r. m.; matos, r.; rello, j. title: use of early corticosteroid therapy on icu admission in patients affected by severe pandemic (h n )v influenza a infection date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: f o introduction: early use of corticosteroids in patients affected by pandemic (h n )v influenza a infection, although relatively common, remains controversial. methods: prospective, observational, multicenter study from june through february , reported in the european society of intensive care medicine (esicm) h n registry. results: two hundred twenty patients admitted to an intensive care unit (icu) with completed outcome data were analyzed. invasive mechanical ventilation was used in ( . %). sixty-seven ( . %) of the patients died in icu and ( . %) whilst in hospital. one hundred twenty-six ( . %) patients received corticosteroid therapy on admission to icu. patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (copd), and chronic steroid use. these patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (hap) [ . % versus . %, p < . ; odds ratio (or) . , confidence interval (ci) . – . ]. patients who received corticosteroids had significantly higher icu mortality than patients who did not ( . % versus . %, p < . ; or . , ci . – . ). cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly associated with mortality [hazard ratio (hr) . , % ci . – . , p = . ] but was still associated with an increased rate of hap (or . , % ci . – . , p < . ). when only patients developing acute respiratory distress syndrome (ards) were analyzed, similar results were observed. conclusions: early use of corticosteroids in patients affected by pandemic (h n )v influenza a infection did not result in better outcomes and was associated with increased risk of superinfections. by pandemic (h n )v influenza a infection, although relatively common, remains controversial. methods: prospective, observational, multicenter study from june through february , reported in the european society of intensive care medicine (esicm) h n registry. results: two hundred twenty patients admitted to an intensive care unit (icu) with completed outcome data were analyzed. invasive mechanical ventilation was used in ( . %). sixty-seven ( . %) of the patients died in icu and ( . %) whilst in hospital. one hundred twenty-six ( . %) patients received corticosteroid therapy on admission to icu. patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (copd), and chronic steroid use. these patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (hap) [ . % versus . %, p \ . ; odds ratio (or) . , confidence interval (ci) . - . ]. patients who received corticosteroids had significantly higher icu mortality than patients who did not ( . % versus . %, p \ . ; or . , ci . - . ). cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly [ ] , and argentina ( %) [ ] . the efficacy of systemic corticosteroids has been extensively studied in acute respiratory distress syndrome (ards). while they clearly have a role in situations where ards has been precipitated by a corticosteroidresponsive process (e.g., acute eosinophilic pneumonia), the value of corticosteroid therapy in most other cases remains uncertain [ ] . in the s and early s, empirical corticosteroids were widely used to treat ards; however, corticosteroid therapy in this setting subsequently became less frequent after several studies found that they had no benefit and may actually cause harm [ , ] . since then, several meta-analyses and reviews have been published offering conflicting perspectives regarding corticosteroid treatment for ards [ ] [ ] [ ] [ ] . the most common pulmonary presentation of patients affected by pandemic (h n )v influenza a infection is rapidly progressive viral pneumonia with bilateral alveolar infiltrates on chest radiography, and ards [ ] . the presentation of ards with severe refractory hypoxemia has been particularly common in patients with this disease process and might be linked to an abnormal immune response [ ] . several published reports of pandemic (h n )v influenza a infection [ , ] have reported use of empirical corticosteroid therapy in more than half of these patients, both as primary therapy and as rescue therapy for patients with severe ards. recent guidelines for management of human infection with pandemic (h n )v influenza a infection recommend that corticosteroid therapy should not be used routinely, although low doses may be considered for patients in septic shock who require vasopressors and have suspected adrenal insufficiency [ , ] . data supporting this guidance, however, remain scarce and controversial [ ] . a single prospective interventional study with only patients by quispe-laime et al. [ ] demonstrated that a prolonged low to moderate dose of corticosteroid treatment was associated with significant improvement in lung injury and multiple organ dysfunction scores and reduced hospital mortality rate. the main objective of this study is therefore to assess the effect on survival of early corticosteroid therapy compared with those who did not receive corticosteroids or received them subsequently as rescue therapy, in a cohort of patients hospitalized with severe presentation of pandemic (h n )v influenza a infection in the icu. data for this study were obtained from a voluntary registry instituted by the european society of intensive care medicine (esicm). the registry contains data from patients admitted to the icu with confirmed, probable or suspected pandemic (h n )v influenza a infection. all reports notified before february were eligible for inclusion. ethical approval was sought and obtained where necessary prior to any patients being entered into the registry. all patients enrolled were recorded into the registry in an anonymous format. the need for informed consent was waived due to the observational nature of the study and the fact that this activity was an emergency public health response. the inclusion criteria for this study consisted of: fever ([ °c); acute illness; respiratory symptoms consistent with cough, sore throat, myalgia or influenza-like illness; and acute respiratory failure requiring icu admission with confirmed, probable or suspected pandemic (h n )v influenza a infection, according to case definitions developed by the world health organization (who) [ , ] . a ''confirmed case'' was defined as an acute respiratory illness with laboratory-confirmed pandemic (h n )v influenza a virus infection with real-time reverse-transcription polymerase chain reaction (rt-pcr) or viral culture [ ] . all tests and procedures were ordered by attending physicians. the definitions of community-acquired pneumonia and hospital-acquired pneumonia were based on american thoracic society and infectious disease society of america guidelines [ ] . primary viral pneumonia was defined in patients presenting during the acute phase of influenza virus illness with ards and unequivocal alveolar opacification involving two or more lobes with negative respiratory and blood bacterial cultures. secondary bacterial pneumonia was considered in patients with confirmation of influenza virus infection who showed recurrence of fever, increase in cough, and production of purulent sputum with in addition positive respiratory pathogens or blood cultures [ ] . microbiological confirmation of hap was based on standardized procedures at each investigator site. acute renal failure was defined as need for renal replacement therapy following the international consensus conference [ ] . obese patients were defined as those with body mass index (bmi) over kg/m [ ] . icu admission criteria and treatment decisions for all patients, including determination of need for intubation and type of antibiotic and antiviral therapy administered, were made by the attending physician. the following information was also recorded: demographic data, comorbidities, time of illness onset and hospital admission, time to first dose of antiviral therapy, microbiologic findings, and chest radiographic findings at icu admission. intubation and mechanical ventilation requirements, adverse events during icu stay (e.g., need for vasopressor drugs, or renal replacement techniques), and laboratory findings at icu admission were also recorded. to determine illness severity, the simplified acute physiology score (saps ) [ , ] and the acute physiology and chronic health evaluation (apache) ii score [ ] were determined in all patients within h of icu admission. in addition, organ failure was assessed using the sequential organ failure assessment (sofa) scoring system [ ] . systemic corticosteroid use was considered when dosages equivalent to [ mg/day methylprednisone or [ mg/day prednisone were given at icu admission. patients who received corticosteroid therapy on icu admission were compared with those who did not receive corticosteroid therapy or who received them subsequently as rescue therapy for unfavorable clinical progression. discrete variables are described as counts (%) and continuous variables as mean with standard deviation (sd) or median with th to th interquartile range (iqr), as appropriate. unless otherwise stated, all statistical tests were two sided and p \ . was considered significant. differences in categorical variables were calculated using the two-sided likelihood ratio, chi-square test or fisher's exact test, and the mann-whitney u test or kruskal-wallis test was used for continuous variables, when appropriate. cox proportional-hazards regression analysis was used to assess the impact of independent variables on icu mortality across time. variables significantly associated with mortality on univariate analysis were entered into the model. to avoid spurious associations, variables entered into the regression models were those with a relationship on univariate analysis (p b . ) or a plausible relationship with the dependent variable. results are presented as hazard ratio (hr) and % confidence interval (ci). potential explanatory variables were checked for collinearity prior to inclusion in the regression models using tolerance and variance inflation factor. data analysis was performed using spss . (spss, chicago, il, usa) for windows. two hundred twenty patients with completed outcomes from the esicm h n registry were analyzed in this study. all patients had suspected, probable or confirmed pandemic (h n )v influenza a infection and were being cared for in an icu. one hundred ninety-four were confirmed ( . %), were probable ( . %), and patients were suspected ( . %) for pandemic (h n )v influenza a virus. of these, patients were male ( . %) with median age of (iqr - ) years, and ( . %) were under years of age. the mean saps score was . ± . and the mean sofa score was . ± . on admission. mechanical ventilation was used in ( . %) of the patients, ( . %) with invasive modes and ( . %) noninvasively; ( . %) of the patients having noninvasive modes of ventilation subsequently required invasive ventilation. all patients received antiviral therapy. oseltamivir administration delay after illness onset did not differ between early corticosteroid uses. ards was present in . % patients. comorbidities were present in ( . %) patients. obesity (n = , . %), asthma (n = , . %), and chronic obstructive pulmonary disease (copd, n = . %) were the main comorbidities reported. one hundred twenty-six ( . %) patients received early corticosteroid therapy at icu admission. patients surviving the icu stay and receiving corticosteroids early on icu admission had mean duration of corticosteroid therapy of . ± . days. icu length of stay in survivors did not differ in patients who received early corticosteroids compared with those who did not ( . ± . versus . ± . days, p = . ). patients who received early corticosteroid therapy were significantly older ( [ ( %) versus ( . %), p \ . ] more frequently than patients who did not. patients who received early corticosteroid therapy were sicker than those who did not receive them according to saps data ( . ± . versus . ± . , p = . ). no differences were found between patients who were or were not treated with early corticosteroid therapy regarding prevalence of ards ( . % versus . %, p . ). mechanical ventilation was based on lung protective strategies. for the entire cohort, tidal volume was . (iqr . - . ) ml/kg ideal body weight (ibw). we did not find any differences between tidal volume in patients who received early corticosteroid therapy compared with those who did not [ . (iqr . - . ) versus . (iqr . - . ) ml/kg ibw, p = . ]. additional demographic data and clinical characteristics of patients with pandemic (h n )v influenza a with and without early corticosteroid therapy are presented in table . hospital-acquired pneumonia was clinically suspected in patients ( . %), with microbiological documentation in patients ( . %) patients. patients who received early corticosteroid therapy had hap more frequently than patients who did not [ . % versus . %, p \ . ; odds ratio (or) . , ci . - . ]. since the severity of illness of patients who received early corticosteroid therapy was higher, multivariate regression analysis adjusting for severity was performed and confirmed the higher incidence of hap in patients who received early corticosteroid therapy [or = . %, confidence interval (ci) . - . ; p \ . ]. pseudomonas aeruginosa (n = , . %) was identified as the most prevalent pathogen, followed by acinetobacter baumannii (n = , . %) and streptococcus pneumoniae (n = , . %) ( table ). in total, patients died on the icu ( . %) and ( . %) whilst in hospital. nonsurvivors presented with significantly higher saps score at admission ( . ± . versus . ± . , p \ . ) and higher sofa score ( . ± . versus . ± . , p \ . ) when compared with survivors. the characteristics of the patients who died are shown in table . patients who received early corticosteroid therapy on icu admission had significantly higher icu mortality than those who did not ( . % versus . %; or . , ci . - . ; p \ . ). this association with increased mortality was not present when mortality data were adjusted for increased severity of illness (saps ) and other known confounding variables (age, copd, asthma, and chronic steroid use) [hazard ratio (hr) . %, ci . - . ; p = . ] (fig. ) . similar findings were found when repeating the analysis for only the cohort of patients who presented with ards (hr . , % ci . - . ; p = . ). this analysis of a large, cohort, prospective, multicenter research study suggests that prompt use of corticosteroid therapy on icu admission does not result in a reduction of mortality for critically ill patients admitted with pandemic (h n )v influenza a infection. furthermore, there is also not a beneficial effect of early corticosteroid therapy when given to the more severe end of the spectrum of patients requiring invasive mechanical ventilation for ards. another important finding of this study was that patients receiving early corticosteroid therapy had increased likelihood of developing superadded bacterial infection. endogenous glucocorticoids as end-effectors play a role in inhibiting inflammation [ ] but are not always effective in suppressing the ''cytokine storm'' driven by copd chronic obstructive pulmonary disease systemic inflammation, even though cortisol levels have been correlated with grades of illness severity and mortality [ ] . with the concept of critical-illness-related corticosteroid insufficiency (circi) [ ] and the results of clinical trials showing respiratory immune and hemodynamic benefits, corticosteroid therapy has re-emerged as a promising adjunct for treatment of severe sepsis. severe bacterial pneumonia is associated with relative corticosteroid insufficiency as well as a plethora of other pulmonary and systemic effects [ ] . this inflammatory cascade can be partially blocked by administration of systemic corticosteroid therapy [ ] . the more severe the presentation, the worse the inflammatory crisis, therefore previous authors have suggested that steroid therapy should be more effective in more severely ill patients [ ] [ ] [ ] . this is not what was shown in the present study. recent guidelines for management of community-acquired pneumonia suggest the benefit of systemic corticosteroid therapy for patients with severe presentation [ ] . this has been shown in one small randomized controlled study with hydrocortisone treatment, terminated prematurely due to % mortality in the intervention arm and a significant reduction in length of hospital stay [ ] . more recently, snijders et al. [ ] conducted a randomized controlled trial in hospitalized patients with cap. these patients were randomized to receive either mg prednisolone for days or placebo added to antibiotic therapy. this study did not show any differences in clinical outcomes in either the overall population or those with severe pneumonia. additionally, late clinical failure ([ h after hospital admission) was more common in the prednisolone group than in the placebo group. data supporting use of corticosteroid therapy in patients affected by primary viral pneumonia are limited [ ] [ ] [ ] to the current pandemic. the innate antiviral host response is based on early elevated expression of cxcl , ccl , and ccl in sars-cov and human respiratory syncytial virus (hrsv)-infected patients [ ] [ ] [ ] . use of corticosteroid therapy is a double-edged sword. li et al. [ ] reported that high doses of corticosteroids decrease immunity by reducing cd , cd , and cd levels in patients with sars and result in an increase in secondary infections; moreover, tsang et al. [ ] found an increase in -day mortality in the same subset of patients. nevertheless, the exact mechanism of corticosteroid therapy needs to be further elucidated due to the fact that there is no evidence of benefit in sars in the early phase when sars-cov replication is still ongoing. lee et al. [ ] found that sars-cov load was significantly higher in the second and third week of illness in patients who received initial corticosteroid therapy. recent results from the corticus study [ ] do not support routine use of corticosteroid therapy in patients with septic shock, because they showed only a beneficial effect of stress doses of corticosteroids in decreasing time to shock reversal [ ] but not on -day mortality, an effect at least in part explained by an increased risk of superinfection. use of corticosteroid therapy also exerts a decisive influence on the immune function of macrophages and granulocytes, the main cell host defenses against bacteria [ ] . in the present study there was significant incidence of nosocomial infections that resulted in twofold higher incidence of hospital-acquired pneumonia in patients who received corticosteroid therapy. incidence of hap due to pseudomonas aeruginosa was . % and due to acinetobacter baumannii was . % in the corticosteroid group. additionally, one of the most intriguing observations was that four patients developed ventilator-associated pneumonia (vap) due to aspergillus spp., three of whom were receiving corticosteroid therapy. the present study has several potential limitations that should be addressed. first is that only patients treated with early corticosteroid therapy on icu admission were considered in the treatment group. the control group comprised patients who did not receive early corticosteroid therapy and those who received them subsequently as rescue therapy. use of corticosteroid therapy after icu admission was not considered in the treatment group, since this subgroup of patients would be considered as receiving rescue therapy due to unfavorable clinical progression. no data were available to subanalyze the role of rescue therapy; nevertheless, the multivariate analysis was adjusted for severity as well as other confounding factors to avoid a potential bias that might invalidate our final conclusions. secondly, this is an observational, noninterventional study, in which the participating icus from countries in the world were self-selected. prescription of corticosteroids was chosen in accordance with local protocols. to correct for differences in different corticosteroid therapies, treatment class was homogenized so that systemic corticosteroid use was considered when dosages equivalent to [ mg/day methylprednisone or [ mg/day prednisone were given acutely on icu admission, as reported in previous studies [ ] . thirdly, in spite of the fact that microbiological confirmation based on current infectious disease society of america (idsa)/ american thoracic society (ats) guidelines [ ] would be preferable, bronchoscopic procedures were not performed routinely because of severe hypoxemia complicating ards (h n )v episode and safety concerns regarding generation of aerosols. finally, dosing of oseltamivir was left to the discretion of the attending physician and was not standardized. it is crucial to note that underdosing is a common problem in patients with severe sepsis and mechanical ventilation who have a high volume of distribution and low enteral absorption [ ] . ariano et al. [ ] recently reported that dosage of mg twice-daily achieved plasma levels that were comparable to those in ambulatory patients and were far in excess of concentrations required to maximally inhibit neuraminidase activity of the virus. there is little definitive evidence of either benefit or harm from early corticosteroid use as routine adjunctive treatment in patients affected by pandemic (h n )v influenza a infection. nevertheless, the results drawn from this study show that such early use did not result in better outcomes and may be associated with increased risk of superadded infections. conflict of interest authors declare no conflict of interest regarding the present manuscript. loreto vidaur (hospital donostia antonia socias (hospital son llàtzer) estevão lafuente (uci, ch tâmega e sousa, penafiel), fernando rua (sci, ch do porto alessandro amatu (fondazione irccs policlinico san matteo, rianimazione), giorgio berlot (cattainara (trieste)), federico capra marzani maurizia capuzzo (azienda ospedaliero-universitaria di ferrara) rebecca cusack (southampton), rhiannon jackson (frimley park hospital nhs trust) jeronimo nahuel chaparro fresco marìa fernanda garcía (hospital eugenio-neumologia) gustavo paredes niall kavanagh (st. luke's general hospital) unisa-hospital geral do grajaú), vicente souza dantas elin helset sigurdur e. sigurdsson (fsa) radka valkova (icu infection's department, masaryk's hospital simone rosseau (charité), jens krassler (fachkrankenhaus coswig gmbh alejandro barrionuevo poquet (hospital nacional carlos alberto seguin escobedo) saber barbar yaron barlavie (rambam hospital), moshe hersch (shaare zedek medical center) hervé zender (hôpital neuchâtelois institute for pulmonary diseases of vojvodina), ilons schaffer (hospital health center kikinda) eleni mouloudi (hippokrateion general hospital thessaloniki) critical care services and h n influenza in australia and new zealand pandemic influenza a(h n ) in argentina: a study of patients on mechanical ventilation eosinophilic alveolitis in acute respiratory failure. a clinical marker for a non-infectious etiology ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock high dose corticosteroids in patients with the adult respiratory distress syndrome nonventilatory treatments for acute lung injury and ards steroid treatment in ards: a critical appraisal of the ards network trial and the recent literature do glucocorticoids decrease mortality in acute respiratory distress syndrome? a meta-analysis use of corticosteroid in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis pandemic (h n ) influenza (''swine flu'') in australian and new zealand intensive care th and th hypercytokinemia as early host response signature in severe pandemic influenza critically ill patients with influenza a(h n ) in mexico who guidelines for pharmacological management of pandemic influenza a(h n ) and other influenza viruses clinical aspects of pandemic influenza a (h n ) virus infection corticosteroids for h n associated acute lung injury: is it just wishful thinking? h n influenza a virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment infection prevention and control in health care for confirmed or suspected cases of pandemic (h n ) and influenza-like illnesses. world health organization novel influenza a (h n ) pregnancy working group. h n influenza virus infection during pregnancy in the usa infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults viral pneumonia due to influenza and parainfluenza viruses and adenoviruses. in: marrie j communityacquired pneumonia acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs saps -from evaluation of the patient to evaluation of the intensive care unit. part : objectives, methods and cohort description saps -from evaluation of the patient to evaluation of the intensive care unit. part : development of a prognostic model for hospital mortality at icu admission apache ii: a severity of disease classification system the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure the hypothalamicpituitary-adrenal axis and immunemediated inflammation a -level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin american college of critical care medicine ( ) recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the american college of critical care medicine role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study corticosteroid effects on cell signalling corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review the effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis safety and efficacy of corticosteroids for the treatment of septic shock: a systematic review and meta-analysis infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study efficacy of corticosteroid in community-acquired pneumonia-a randomized double blinded clinical trial summary of probable sars cases with onset of illness from epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china update: outbreak of severe acute respiratory syndrome-worldwide human immunopathogenesis of severe acute respiratory syndrome (sars) interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome fatal outcome of human influenza a (h n ) is associated with high viral load and hypercytokinemia glucocorticoid in the treatment of severe acute respiratory syndrome patients: a preliminary report coronavirus-positive nasopharyngeal aspirate as predictor for severe acute respiratory syndrome mortality effects of early corticosteroid treatment on plasma sars-associated coronavirus rna concentrations in adult patients hydrocortisone therapy for patients with septic shock organ dysfunction/failure in patients with septic shock: results of the corticus study compartmentalized cytokine production within the human lung in unilateral pneumonia effects of systemic steroids in patients with severe community-acquired pneumonia guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcareassociated pneumonia bench-to-bedside review: appropriate antibiotic therapy in severe sepsis and septic shock-does the dose matter? enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (h n ) influenza key: cord- - sf i r authors: barthélémy, romain; blot, pierre-louis; tiepolo, ambre; le gall, arthur; mayeur, claire; gaugain, samuel; morisson, louis; gayat, etienne; mebazaa, alexandre; chousterman, benjamin glenn title: efficacy of almitrine in the treatment of hypoxemia in sars-cov- acute respiratory distress syndrome date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: sf i r nan am received speaker's honoraria from novartis, orion, and servier and fees as a member of the advisory board and/or steering committee from adrenomed, sanofi, roche, abbott, and teen . bc received fees as a member of an advisory board from roche diagnostics. the other authors have not disclosed any potential conflict of interest. research letter dear editor, critically ill covid- patients frequently present profound hypoxemia with acute respiratory distress syndrome (ards) requiring mechanical ventilation (mv) . according to recently published covid- guidelines , ventilatory support aims at increasing alveolar oxygen partial pressure with non-invasive methods and eventually mv. ventilator settings are optimized in order to recruit collapsed alveoli and reduce ventilator-induced lung injury. however, in sars-cov- ards, it has been hypothesized that recruitment strategies may be hazardous because of a preserved compliance and a poor response to peep whereas physiological measurements rather show increased intrapulmonary shunt . abnormal pulmonary vascular dilation and increased perfusion surrounding areas of lung opacity have been identified with dual-energy ct imaging, suggesting that insufficient hypoxic pulmonary vasoconstriction (hpv) may plays a major role in the onset of hypoxemia . almitrine, a drug that used to decrease intrapulmonary shunt by enhancing hpv, improves gas exchange in ards . we hypothesized that almitrine could improve hypoxemia in sars- cov- ards patients. this monocenter retrospective study aimed to evaluate the association between almitrine introduction and improvement of oxygenation in sars-cov- ards. the study was conducted in a -bed icu (hôpital lariboisière, paris, france) fully dedicated to the covid- outbreak. the medical records of all patients admitted between march th and april th were reviewed. inclusion criteria in the study were: admission for respiratory failure, a diagnosis of ards according to berlin criteria , laboratory confirmed sars-cov- infection, almitrine infusion in icu. the primary endpoint was the arterial oxygen partial pressure (pao ) to fraction of inspired oxygen (fio ) ratio between baseline value and peak value during the st - th hour timeframe after introduction of almitrine. pao /fio ratio was measured with fio . the other endpoints were incidence of treatment failure at h, h, h and h, and safety. treatment failure was defined as death, or the need for additional rescue therapy. increase in right atrial pressure (rap) and lactate during the first hours and peak values for liver tests during the first h were reported as safety data. this study was approved by an institutional ethics committee: institutional review board (irb ) of hupnvs, paris university. patients were managed according to local protocol based on international guidelines . intrapulmonary shunt is confirmed after exclusion of a patent foramen ovale. pleural effusions are considered for drainage. hemodynamic optimization is performed to address low pvo effect. early respiratory management includes limitation of tidal volume and plateau pressure, systematic neuromuscular blockade and prone positioning session of at least h. peep is individualized to improves oxygenation without deteriorating compliance and cardiac output. in case of persistent refractory hypoxemia, we usually consider almitrine infusion (initial dose µg.kg − .min − ) and/or inhaled nitric oxide (ino). almitrine and ino use are decided after collegial discussion on a case-by-case basis. if severe hypoxemia persists despite the latter treatments, extracorporeal membrane oxygenation (ecmo) team is called to evaluate the indication of the device. continuous variables before and after almitrine infusion were compared by a wilcoxon rank sum test for paired data. all statistical analyses were performed using r statistical software version . . . patients eighty-six patients were admitted to our icu during the studied period. nineteen of the patients that met inclusion criteria had complete data and were analyzed ( eighteen patients ( %) had at least one session of prone positioning before almitrine. the median pao /fio ratio increased from [ - ] at baseline to [ - ] after almitrine (p= . ) (figure ). this is the first study describing therapeutic effects of almitrine in sars-cov- ards. in our observational study, almitrine was associated with an increase in pao /fio ratio after treatment. however, this improvement of hypoxemia seems to be heterogenous amongst patients. furthermore, despite an associated improvement in pao /fio ratio, the majority of patients receiving almitrine went on to needing additional rescue interventions or died. this may be explained by the fact that, in our study, almitrine has been used as a rescue therapy in severe patients with worsening hypoxemia and very low pao /fio ratio. even though this is a small sample study without control group, our data shows that enhancing hpv is an encouraging strategy to reduce hypoxemia in sars-cov- ards. this could at least be helpful to secure intra-or inter-hospital transfers in the most severe patients, or gain precious time until a more invasive life support is available. the ideal time to start almitrine also remains to be determined. almitrine could be used earlier in the treatment of sars-cov- hypoxemia to reduce the need or duration of mv, a scarce resource in the setting of worldwide outbreak. however, improvement in hypoxemia is not necessarily associated with improved outcome. on the other hand, almitrine has been identified as a potential candidate against targeted proteins of sars-cov- with expected inhibitory effect . altogether, we believe that almitrine should be evaluated in clinical trials aiming at improving patient centered outcome for covid- patients. in this monocenter retrospective study, we found that almitrine at the dose of µg.kg − .min − was associated with an increased pao /fio ratio in the following hours in sars-cov- ards patients. -cumulative incidence of treatment failure (n) baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease covid- pneumonia: different respiratory treatments for different phenotypes? intensive care med lung recruitability in sars-cov- associated acute respiratory distress syndrome: a single-center, observational study analysis of therapeutic targets for sars-cov- and discovery of potential drugs by computational methods key: cord- - v yw pl authors: trahtemberg, uriel; slutsky, arthur s.; villar, jesús title: what have we learned ventilating covid- patients? date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: v yw pl nan the angiotensin-converting enzyme (ace ) receptor is the functional sars-cov- receptor, and along with the transmembrane serine protease (tmprss ) is required for viral entry into cells [ ] . the ubiquity of this receptor can explain many manifestations of covid- . the lung is a prime target for sars-cov- because of its huge surface area which is in direct contact with the inspired air (and possible sars-cov- virions), and the expression of ace in surfactant-producing alveolar type-ii cells. infection of the latter likely explains the atelectasis and pneumonia observed in covid- patients. ace expression in many cell types can also explain other organ involvement in covid- (e.g., heart, kidney, blood vessels, skin), and perhaps some of the more unique findings including anosmia (olfactory support cells) and "happy hypoxemia" (carotid body). the available pathological findings of covid- ards suggest diffuse alveolar damage along with pulmonary vasculature involvement [ ] , which have been recognized as important features of ards for decades. widespread pulmonary macro/microthrombi are commonly found in autopsies of patients with ards from any etiology at any phase of the disease. the biggest controversy is whether the pathophysiology of covid- ards is different from non-covid- (classical) ards. a number of editorials, opinion pieces, and small reports have suggested that covid- ards is atypical, since some patients with severe hypoxemia had relatively normal respiratory compliance, with implications for ventilatory management [ , ] . however, the heterogeneity of classical ards is well documented, and alterations of gas-exchange and respiratory system compliance in covid- ards [ ] [ ] [ ] appear comparable to, and within the range of values reported for classical ards [ ] , including in a case series published in [ ] . some of the differences found may be due to differences in setting peep, reinforcing the need to individualize peep, as opposed to using a "onesize-fits-all" approach [ ] . although some patients with covid- can be managed with supplemental oxygen and non-invasive ventilation, patients with severe respiratory failure require endotracheal intubation and invasive mechanical ventilation. some authors have recommended early intubation to avoid the risk of patient self-induced lung injury [ , ] , or that measurement of "esophageal pressure swings is crucial" to decide when to intubate [ ] . however, a paucity of data exists to justify this approach, and there are very compelling reasons to oppose a policy of early intubation [ ] . until more data are available on this issue, we recommend using similar criteria regarding intubation that are used for classical ards [ ] . there is significant variability in ventilatory practice when treating patients with ards. since, as discussed above, covid- ards is similar to classical ards, the foundations of ventilatory management should also be similar: provide lung protective ventilation [ ] . although there is no unique recipe on how best to ventilate an ards patient, protective ventilation with low tidal volumes ( - ml/kg predicted body weight), plateau pressures < cmh o and driving pressures < cmh o, is strongly associated with improved outcomes in ards patients. patients with moderate-to-severe ards (pao / fio ratio < mmhg) should be ventilated in the prone position unless there are contraindications. prone positioning reduces the pleural pressure gradient and leads to more uniform distribution of ventilation and lung strain, usually leading to an improvement in oxygenation and, most importantly, decreasing ventilatorinduced lung injury. it has been suggested that prone positioning should be minimized in covid- ards patients with higher compliances, based on the argument that the putative different respiratory physiology makes prone ventilation unlikely to be beneficial [ ] . however, although there is great heterogeneity, covid- ards patients appear to have similar recruitability [ ] . the oxygenation response to prone positioning appears similar to non-covid- ards: ziehr et al. found that pao /fio increased from a median of mmhg in the supine position to mmhg in the prone position [ ] . early in the pandemic, a number of small case reports suggested that mortality of patients treated with ecmo was > %. however, recent studies suggest that covid- patients placed on ecmo have reasonable outcomes. in a series of patients with severe covid- ards treated with ecmo, estimated -day mortality ( %) was similar to previous studies of severe classical ards [ ] . a recent study using the extracorporeal life support organization (elso) registry examined the outcomes of covid- patients who received ecmo [ ] . in the subset of patients with ards (n = ), the vast majority of whom received vvecmo, the cumulative -day hospital mortality was %, a figure similar to the % -day mortality in the eolia trial [ ] . as with virtually all studies, in covid- there was an increased mortality with increasing age. these data suggest that vvecmo is a viable therapy in covid- patients with very severe ards, and for now it seems reasonable to use eolia inclusion criteria to identify suitable candidates in centers experienced with the use of ecmo. covid- ards is ards, a syndrome which, notwithstanding the significant heterogeneity, has been amenable to significant improvements in its management. in the same vein, subphenotypes should be properly defined and management changes should be clearly demonstrated [ ] ; everything else is speculation. recent studies demonstrating that corticosteroids decrease mortality in ventilated covid- patients are an excellent example of validating proposed management changes [ ] . although the data are still limited and we have much to learn in this ongoing pandemic, we have enough evidence at this point to recommend that the ventilatory management of patients with covid- ards should be similar to other causes of ards, tailored to the specific patient. how severe covid- infection is changing ards management angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- management of covid- respiratory distress covid- pneumonia: different respiratory treatments for different phenotypes? pathophysiology of covid- -associated acute respiratory distress syndrome: a multicentre prospective observational study respiratory physiology of covid- -induced respiratory failure compared to ards of other etiologies clinical features, ventilatory management, and outcome of ards caused by covid- are similar to other causes of ards compliance phenotypes in early ards before the covid- pandemic lung recruitment in patients with the acute respiratory distress syndrome covid- -associated acute respiratory distress syndrome: is a different approach to management warranted? caution about early intubation and mechanical ventilation in covid- respiratory pathophysiology of mechanically ventilated patients with covid- : a cohort study extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with covid- : a retrospective cohort study extracorporeal membrane oxygenation support in covid- : an international cohort study of the extracorporeal life support organization registry extracorporeal membrane oxygenation for severe acute respiratory distress syndrome covid- -related acute respiratory distress syndrome: not so atypical association between administration of systemic corticosteroids and mortality among critically ill patients with covid- : a meta-analysis key: cord- -p gvpe i authors: kaur, savneet; tripathi, dinesh m.; yadav, angeera title: the enigma of endothelium in covid- date: - - journal: front physiol doi: . /fphys. . sha: doc_id: cord_uid: p gvpe i coronavirus disease (covid- ), caused by severe acute respiratory syndrome–related coronavirus- (sars-cov- ) has affected millions of people globally. clinically, it presents with mild flu-like symptoms in most cases but can cause respiratory failure in high risk population. with the aim of unearthing newer treatments, scientists all over the globe are striving hard to comprehend the underlying mechanisms of covid- . several studies till date have indicated a dysregulated host immune response as the major cause of covid- induced mortality. in this perspective, we propose a key role of endothelium, particularly pulmonary endothelium in the pathogenesis of covid- . we draw parallels and divergences between covid- -induced respiratory distress and bacterial sepsis-induced lung injury and recommend the road ahead with respect to identification of endothelium-based biomarkers and plausible treatments for covid- . endothelium is a highly specialized and dynamic organ which serves numerous roles in both physiology and pathophysiology (galley and webster, ) . being the first organ to perceive any damage to the underlying tissue, it effectively adapts and mounts compensatory responses to any chemical, mechanical and cellular injury. the pulmonary endothelium that shields the lungs comprises of both macro or microvascular endothelial cells with considerable phenotypic and functional heterogeneity (aird, ) . pulmonary microvascular endothelial cells (mec) are an integral part of the alveolar (epithelial)-capillary (endothelial) barrier formed by tight junctions and adherens junctions in the lungs. this impermeable alveolar-capillary barrier strictly restricts vascular fluid fluxes across the lung epithelium and hence the integrity of this barrier is utmost to prevent pulmonary edema, congestion and respiratory failure (millar et al., ) . in the current perspective, we envisage a key role of mec in the pathogenesis of coronavirus disease caused by the novel coronavirus, severe acute respiratory syndrome-related coronavirus- (sars-cov ). covid- has a wide clinical spectrum ranging from asymptomatic to mildly symptomatic forms to severe clinical conditions such as respiratory failure, sepsis and multiorgan dysfunction syndromes (mods) . most of the hospitalized critically ill covid- patients have pneumonia with abnormal chest ct scans and acute respiratory distress syndrome (ards) seems to be the major causes of death in these patients (yang f. et al., ) . ards is nothing but a reflection of severe mec dysfunction involving changes in vascular permeability, inflammation, accumulation and extravasation of leucocytes, activation of procoagulant pathways and disruption of alveolarcapillary barrier (matthay et al., ) . evidence from several studies have indicated that patients with covid- exhibit most of these attributes. lung pathology from covid- patients has depicted that along with pulmonary type alveolar epithelial cells, endothelial cells in the systemic venules are also desquamated and an inflammatory reaction is present in blood vessel walls (vasculitis), suggestive of intense vascular reactions (ding et al., ) . lung autopsies from covid- patients also show massive neutrophil infiltration in pulmonary capillaries, acute capillaritis and extravasation of neutrophils into the alveolar space (fox et al., ; liu et al., ) . pulmonary neutrophilia is predictive of poor clinical outcomes and also neutrophil-to-lymphocyte ratio is an independent risk factor of disease severity in these patients ). an inflamed/injured endothelium due to increased expression of adhesion molecules, including e-and p-selectins, loss of cadherin junctions and hence altered vascular permeability promotes the adhesion and migration of neutrophils. neutrophilia can induce injury to the endothelium-epithelial alveolar barrier, causing further damage to the lungs. a recent report has illustrated that neutrophil extracellular traps (nets) are enhanced in hospitalized covid- patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. the study has also documented that sera from individuals with covid- trigger net release from control neutrophils in vitro (zuo et al., ) . nets are extracellular dna fibers of neutrophils carrying nuclear proteins, such as histones and bactericidal proteins. net formation in the lungs is documented in bacterial sepsis and thrombosis, however, their role in viral infections is not very well known except for a report which has shown their presence in influenza virusinduced pneumonia in vivo (narasaraju et al., ) . nets represent one of the powerful host mechanisms to damage the microbes. they are, however, suicidal, if present in excess as they can attach to the capillary endothelium, collate with the platelets to induce coagulation and thus cause damage to the alveolar-capillary barrier, leading to vascular leakage, edema and finally ards (sørensen and borregaard, ) . ascertaining the role of nets as markers of covid- disease severity needs further systematic studies and targeting of nets to rescue the lung endothelium represents a worthwhile therapeutic option in covid- . several studies have indicated the presence of atypical manifestations of ards in some severe patients of covid- . they exhibit near normal pulmonary compliance of > ml/cmh o with severe hypoxemia, which seems to emanate due to impaired hypoxic pulmonary vasoconstriction (hpv) and ventilation/perfusion (v/q) mismatch (gattinoni et al., ). an impaired hpv in these patients point toward mec dysfunction in the lungs as recent studies have postulated that the alveolar ion channels in the endothelial cells of the alveolarcapillary barrier are sensors of oxygen/hypoxia that propagate the messages along the vascular endothelium and initiate arteriolar vasoconstriction or hpv (grimmer and kuebler, ) . these patients show features of vasoplegia or persistent hypotension as observed in sepsis patients with atypical ards, indicative of a primary insult to the pulmonary endothelium (gattinoni et al., ) . lung histology in covid- patients with severe respiratory failure also indicates that covid- has features distinct from typical ards (klok et al., ) . the pulmonary abnormalities in these patients comprise of thrombotic microvascular injury in the alveolar capillaries, with fewer signs of viral cytopathic or fibroproliferative changes. pulmonary thromboembolic complications with a distinct pro-coagulant profile, elevated d-dimer levels and angiogenesis is a common finding in many severe cases of covid- patients (ackermann et al., ; ranucci et al., ) . increased ratio of angiogenic factor, soluble fms-like tyrosine kinase (sflt- )/plgf (placental growth factor) ratio in covid- positive patients as compared to patients with covid- negative pneumonia, and healthy donors is recently documented (giardini et al., ) . the use of the s-flt /plgf ratio in covid- as a clinical tool to stratify the intensity of endothelial dysfunction has been proposed in this study. a healthy lung endothelium has an inhibitory effect on inflammation and coagulation while a procoagulant phenotype is a hallmark of an injured endothelium in sepsis and ards both (millar et al., ) . these studies along with the fact that the pulmonary epithelium is more resistant to injury than the endothelium signify that sars-cov- -induced ards and associated coagulopathy may be caused by a direct endothelial infection by the virus in the lungs (matthay et al., ) . another study on a few post-mortem biopsies has, however, illustrated that sars-cov- nucleocapsid protein immunopositivity is not observed in the mecs and is present only in lung pneumocytes and ciliated epithelial cells (schaefer et al., ) . interestingly, in this study, five patients also exhibit blood clots in the pulmonary vasculature. in absence of a direct pulmonary endothelial involvement and viral infection, this may be explained as diffuse pulmonary intravascular coagulopathy, which is distinct from sepsis-induced disseminated intravascular coagulation (marchandot et al., ; mcgonagle et al., ) . however, an absence of viral positivity in the mecs in this study can also be attributed to technical limitations. further studies and sensitive imaging techniques are needed to delineate if sars-cov causes a direct endothelial injury as seen in sepsis-induced ards or a direct epithelial injury as in typical ards. both these conditions have different pathological hallmarks and hence can be dissected. a direct endothelial injury can be characterized by increased levels of angiopoetin- , von willebrand factor (vwf), soluble thrombomodulin, interleukin , soluble icam- indicating massive endothelial stimulation and damage, while direct epithelial injury can be identified by high plasma levels of surfactant protein-d and receptor for advanced glycation end products (hendrickson and matthay, ) . in case of direct injury to mec, sars-cov- should enter the lungs via the mecs. angiotensin-converting enzyme (ace ), the type i integral transmembrane protein, a functional receptor for sars-cov and a potential receptor for sars-cov- is highly expressed in the mec, along with the lung epithelial cells (hamming et al., ; hoffmann et al., ) . although the contribution of ace in the pathogenesis of covid- is not known, yet it has been delineated that sars-cov infection downregulates ace and worsens lung injury that is reversed by treatment with angiotensin receptor blockermediated upregulation of ace (imai et al., ) . this study and several others show a protective role of ace in ards and lung injury. a recent study has also revealed that the use of human recombinant soluble ace prevented host cell binding to sars-cov- , probably by viral binding to proteins in solution rather than those on host cells (monteil et al., ) . however, the precise in vivo role of mec-specific ace vis-à-vis circulating ace levels in covid- infection and/or severity, especially in context of their vascular effects demand stringent evidencebased studies. besides ace , other receptors such as cd l and vimentin that have been proposed to serve as putative receptors of sars viruses are also expressed in mec (jeffers et al., ; yu et al., ) . another possibility worth mentioning is that sars-cov- may also be transported to mec via air-borne particulate matter with a diameter of . micrometers (pm . ) or smaller. these fine air particles can easily reach the smallest of the human airways, cross the alveolar-capillary barrier, deposit on vascular endothelium via specific receptors, modulate vascular permeability and facilitate systemic inflammation, also leading to coagulation (wang et al., ) . recent reports have indeed shown a positive correlation between the increased presence of air pollutants (pm . ) and covid- spread and lethality (fattorini and regoli, ) . although the air-borne spread of sars-cov- via pm and its direct entry into mec remains to be established, it would be interesting to unravel molecular mechanisms if and how sars-cov- survive and thrive in the mec. covid- infection also seems to mount an attack and exacerbate endothelial damage in other vascular beds (sardu et al., a) . active sars-cov- replication in human capillary organoids that closely resemble human capillaries has been demonstrated, suggestive of the fact that the virus could directly infect ace -positive blood vessel cells (monteil et al., ) . presence of viral elements within the endothelial cells and diffuse endothelial inflammation has been documented in post-mortem biopsies of lung, heart, kidney, skin and liver (colmenero et al., ; varga et al., ) . these studies suggest that a direct sars-cov- infection facilitates endothelial injury in other vascular beds besides the lungs. however, since these are post-mortem biopsies of patients with respiratory failure, it is probable that endothelial damage at this phase is because of an overwhelmed host inflammatory response, rather than viral replication and increased viral loads in the endothelial cells. a high mortality rate and poor clinical outcomes due to covid- infections in aged subjects and patients with comorbid conditions including diabetes, obesity and hypertension may also be because of an underlying endothelial dysfunction . indeed, certain features of endothelial dysfunction such as altered permeability, imbalance between vasoconstrictors and vasodilators, markers of procoagulation that are well known to be present in all the above conditions, would serve as key indicators for identifying those subjects who are at a higher risk of developing severe form of the disease. large-vessel stroke has been described in young patients of covid- with a mean stroke scale of indicating a large area of ischemia. all of them had to be given clot retrieval therapy, anticoagulation and antiplatelets (oxley et al., ) . three patients in this study had diabetes indicating that an underlying endothelial damage might be one of the key reasons of sars-cov- -induced stroke in these patients. stroke and thrombotic events in brain could also be, however, ascribed to viral infection-induced thrombophilia. the nucleocapsid and spike proteins of the sars-cov- have been speculated to contribute to a pro-thrombotic state due to their modulation of clotting pathways in the lungs via dysregulation of ace (mcgonagle et al., ) . the organotropism of sars-cov- beyond the respiratory tract has been seen in autopsy studies. besides lungs, viral loads and extensive inflammation have been spotted in the kidneys, liver, heart and brain implicating direct viral tissue damage (puelles et al., ) . given the dissemination of the virus to other organs and presence of mods in some patients, li et al. ( ) has conceived the term "viral sepsis" for severe covid- infections. although systemic inflammation may also occur in the wake of an exuberant host cytokine response, given the presence of viral elements in extrapulmonary tissues, it is reasonable to hypothesize that sars-cov- infection might be spreading through the blood cells and the endothelial route may be one important factor facilitating this viral spread via blood. however, this hypothesis needs further investigations as studies have reported less or even negligible amount of viral rnaemia in infected patients wölfel et al., ) . more advanced and sensitive diagnostic techniques and the culture of sars-cov- in blood cells would be needed to confirm the hematogenous spread of viral infection. here, it is also to be noted that most of the severe covid- patients with ards develop bacterial coinfections in the hospitals, thus complicating the true clinical picture (zhou et al., ) . it is thus pertinent to clearly distinguish patients with only sars-cov infections from those having sars-cov plus secondary bacterial infections. a distinguishing marker could be serum procalcitonin (pct) levels. unlike patients with bacterial sepsis, pct values would remain within the reference range in viral sepsis including severe covid- patients as pct synthesis is known to be inhibited by interferon-gamma released during viral infections (lippi and plebani, ) . a recent elegant study has identified unique immune signatures in severe covid- patients, characterized by a high sustained cytokine production of interleukin- (il- ), a pleiotropic cytokine with multiple effects in these patients, distinct from patients with bacterial sepsis. covid- patients also show il- -mediated low hla-dr expression and lymphopenia (giamarellos-bourboulis et al., ) . further such large-scale studies would shed light on how covid- -mediated sepsis is similar and/or different from bacterial sepsis to avoid overlapping of the two distinct diseases. directly or indirectly, endothelial cells and particularly mecs are a crucial link between sars-cov- and host immune responses and thus may serve many roles in determining the disease severity and mortality in covid- (figure ) . as the clinical, pathological and molecular features of covid- patients are unfolding in investigational studies, several researchers are hypothesizing and reviewing a vascular-centric pathogenesis of covid- . a summary of such recent reviews and short reports is provided in table (alvarado-moreno and majluf-cruz, ; amraei and rahimi, ; cure and cure, ; froldi and dorigo, ; guler et al., ; gupta et al., ; gustafson et al., ; mangalmurti et al., ; marchetti, ; mondal et al., ; panfoli, ; pons et al., ; sardu et al., b; teuwen et al., ) . hence, undoubtedly, an assessment of endothelial dysfunction in patients with covid- to stratify the patients based on severity holds immense relevance. circulating biomarkers such as endothelin- , e-and p-selectins, vwf and soluble adhesion molecules that signify endothelial dysfunction may appear as early biomarkers of viral infection and probable organ dysfunction (goshua et al., ) . pulmonary endothelium has the highest expression of the angiogenic factors like, vascular endothelial growth factor (vegf) and a dysregulated pulmonary angiogenesis is a well-known mediator of acute lung injury (wada et al., ) . figure | probable interactions of sars-cov- with pulmonary microvascular endothelial cells (mecs). sars-cov- may interact with the mecs directly via ace receptor or indirectly affecting a multitude of endothelial-mediated functions including changes in intercellular permeability, expression of selections, adhesins and ve-cadherins, changes in expression of angiogenic and other functional receptors such as vegfr / , pdgfbr, s p / , pecams, icams, vcam causing neutrophilia, formation of neutrophil extracellular traps (nets), inflammation, hypercoagulation and hypoxia. hypoxia causes induction of hypoxia-inducible factors (hif- ) and angiogenesis. ros from activated neutrophils induces expression of transcription factors, nrf and nfk-b, causing further inflammation. these changes in mecs result in an increase/decrease of vaso-active mediators like nitric oxide (no), endothelin- , oxygen sensing machinery, impaired hypoxic vasoconstriction and v/q mismatch. in inflammatory states, the mecs are also subjected to disturbed blood flow (shear stress). mes dysfunction may also cause an increase in the expression of pd-l , leading to t cell lymphopenia. these drastic changes in the capillary endothelium disrupts the alveolar-capillary barrier, causing edema and finally respiratory distress. frontiers in physiology | www.frontiersin.org table | summary of studies hypothesizing an endothelial-specific pathogenesis of covid- . major views type of study study (references) the endothelium is a key target organ in covid- and a major determinant of disease severity. review (sardu et al., b) . deaths occurring in mexico at younger age as compared with other countries may be related to the high frequency of vascular risk factors and the consequent endothelial dysfunction. alvarado-moreno and majluf-cruz, . key role of endothelial dysfunction during sars-cov- infection, as a direct target of the virus and inflammatory cytokines. review pons et al., . binding of virus to ace -positive endothelial cells may cause production of ros, which cause these cells to acquire a pro-thrombotic and pro-inflammatory phenotype, predisposing patients to thromboembolic and vasculitic events and to disseminated intravascular coagulopathy. short report panfoli, . comparative study between various coronavirus reveals similarities in entry and pathogenesis of sars-cov- along with sars and mers in various aspects of multi organ involvement and systematic vasculitis along with similarities in immune-pathogenesis. the involvement of multiple organs in covid- indicates that endothelial injury leading to visceral vasculopathy may be the inciting factor in the disease progression. review mondal et al., ) . vascular-centric pathology of covid- -induced ards. complement pathway activation and ace dysregulation contributing to vascular injury and thrombosis in covid- . hypothesis and review mangalmurti et al., ) . passing of sars-cov- from the respiratory epithelium to the endothelium for viral dissemination. cytokine-driven vascular leak in the lung alveolar-endothelial interface promotes acute lung. review gustafson et al., . ace and ras signaling, as a possible link between the pre-existing endothelial dysfunction and sars-cov- induced endothelial injury in covid- associated mortality. key roles of endothelial cell-expressed cell adhesion molecules including cd l/l-sign and cd /dc-sign in sars-cov- infection. amraei and rahimi, . serum angiotensin ii levels are increased with ace blocking by covid- . angiotensin ii stimulation and local stimuli such as h + ion and hypoxia activate na + /h + exchanger (nhe) in both vascular endothelium and platelets. covid- can lead to thrombosis by causing nhe activation. letter cure and cure, ) . apoptotic processes in the ace -positive lung microvascular bed endothelium or coronary endothelium by sars-cov- . increased d-dimer may be the result of apoptotic endothelial cell induced coagulopathy. letter guler et al., . endothelial damage mediated by complement activation, inflammation, hypoxia, platelets, and abl tyrosine kinases as relevant cause of death in patients with covid- . review marchetti, ) . endothelial cells play a central role in the pathogenesis of ards and multi-organ failure in patients with covid- . review teuwen et al., . increased mortality in young males in italy linked to the diversity in sex-hormones. activation of endothelial estrogen receptors increases nitric oxide and decreases ros, protecting the vascular system of females from angiotensin ii-mediated vasoconstriction, inflammation, and ros production. hypothesis froldi and dorigo, ) . extrapulmonary organ-specific pathophysiology and clinical presentation of covid- . central role of endothelial damage and thrombo-inflammation. review gupta et al., ros, reactive oxygen species; ace , angiotensin converting enzyme ; ards, acute respiratory distress syndrome. an evaluation of angiogenic factors and their soluble receptors, particularly svegfr and angiopoetin- , might be of prognostic significance in these patients. circulating endothelial progenitor cells (epcs) may also be used to assess/predict covid- disease severity and progression in longitudinal studies as altered levels of epcs have been demonstrated in patients with both acute lung injury and bacterial sepsis (witzenrath, ) . identification of biomarkers and molecular mechanisms underlying covid- -induced endothelial injury should lead to new pharmacological targets to ameliorate several processes starting from vascular permeability to neutrophil accumulation, angiogenesis, pro-coagulation tov/q mismatching in covid- pathogenesis. meanwhile, a variety of currently used or investigational drugs such as statins, tyrosine kinase inhibitors, atrial natriuretic peptide, s p agonists that exert endothelial protective or repair effects may be explored for their effects in covid- . dexamethasone, a synthetic corticosteroid and other anti-inflammatory drugs that are already used in many inflammatory diseases including sepsis and ards seem to be a ray of hope in mitigating mortality in critically ill patients of covid- (ledford, ) . dexamethasone and other steroids are also known to inhibit endothelial activation and levels of soluble vcam and e-selectins in both in vitro and in vivo models of sepsis (zielińska et al., ) . the precise effects of steroid treatment on endothelial function in covid- patients with varying severity thus warrant in-depth investigations. to summarize, the pulmonary endothelium seems to be standing at the crossroads of covid- , forming the very crux of this baffling disease. endothelial dysfunction may be both a cause and/or effect of severe covid- . it is thus imperative to have further insights into this entity to embark upon newer prognostic markers and effective treatment options for covid- and in fact for viral sepsis in general. the original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- phenotypic heterogeneity of the endothelium: ii. representative vascular beds covid- and dysfunctional endothelium: the mexican scenario covid- , renin-angiotensin system and endothelial dysfunction sars-cov- endothelial infection causes covid- chilblains: histopathological, immunohistochemical and ultraestructural study of paediatric cases covid- may predispose to thrombosis by affecting both vascular endothelium and platelets the clinical pathology of severe acute respiratory syndrome (sars): a report from role of the chronic air pollution levels in the covid- outbreak risk in italy pulmonary and cardiac pathology in covid- : the first autopsy series from new orleans endothelial dysfunction in coronavirus disease (covid- ): gender and age influences physiology of the endothelium covid- pneumonia: different respiratory treatments for different phenotypes? complex immune dysregulation in covid- patients with severe respiratory failure increased sflt /plgf ratio in covid- : a novel link to angiotensin ii-mediated endothelial dysfunction endotheliopathy in covid- -associated coagulopathy: evidence from a single-centre, cross-sectional study the endothelium in hypoxic pulmonary vasoconstriction is the reason of increased d-dimer levels in covid- because of ace- -induced apoptosis in endothelium? extrapulmonary manifestations of covid- overcoming barriers: the endothelium as a linchpin of coronavirus disease pathogenesis tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis endothelial biomarkers in human sepsis: pathogenesis and prognosis for ards sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor clinical features of patients infected with novel coronavirus in wuhan angiotensinconverting enzyme protects from severe acute lung failure cd l (l-sign) is a receptor for severe acute respiratory syndrome coronavirus confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis coronavirus breakthrough: dexamethasone is first drug shown to save lives sars-cov- and viral sepsis: observations and hypotheses procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis neutrophilto-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with covid- covid-ards clarified: a vascular endotype? covid- related coagulopathy: a distinct entity? covid- -driven endothelial damage: complement, hif- , and abl are potential pathways of damage and targets for cure acute respiratory distress syndrome immune mechanisms of pulmonary intravascular coagulopathy in covid- pneumonia the pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities covid- : are we dealing with a multisystem vasculopathy in disguise of a viral infection inhibition of sars-cov- infections in engineered human tissues using clinical-grade soluble human ace excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis large-vessel stroke as a presenting feature of covid- in the young potential role of endothelial cell surface ectopic redox complexes in covid- disease pathogenesis the vascular endothelium: the cornerstone of organ dysfunction in severe sars-cov- infection multiorgan and renal tropism of sars-cov- . n. eng the procoagulant pattern of patients with covid- acute respiratory distress syndrome hypertension, thrombosis, kidney failure, and diabetes: is covid- an endothelial disease? a comprehensive evaluation of clinical and basic evidence is covid- an endothelial disease? in situ detection of sars-cov- in lungs and airways of patients with covid- neutrophil extracellular traps-the dark side of neutrophils covid- : the vasculature unleashed endothelial cell infection and endothelitis in covid- the role of angiogenic factors and their soluble receptors in acute lung injury (ali)/acute respiratory distress syndrome (ards) associated with critical illness particulate matter disrupts human lung endothelial cell barrier integrity via rho-dependent pathways endothelial progenitor cells for acute respiratory distress syndrome treatment: support your local sheriff! am virological assessment of hospitalized patients with covid- analysis of deceased patients with covid- prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and meta-analysis clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study surface vimentin is critical for the cell entry of sars-cov bacterial and fungal infections in covid- patients: a matter of concern endothelial response to glucocorticoids in inflammatory diseases neutrophil extracellular traps in covid- sk developed these perspectives. sk and dt together drafted the manuscript. ay provided support in conceiving and designing the figure under the supervision from dt. sk finalized the manuscript. all authors contributed to the article and approved the submitted version. the authors would like to thank dr. atampreet singh (department of neurology, fortis hospital, noida, india) for his valuable inputs and discussions while writing of this manuscript. key: cord- - k soh l authors: chaudhary, sachin; natt, bhupinder; bime, christian; knox, kenneth s.; glassberg, marilyn k. title: antifibrotics in covid- lung disease: let us stay focused date: - - journal: front med (lausanne) doi: . /fmed. . sha: doc_id: cord_uid: k soh l after decades of research, two therapies for chronic fibrotic lung disease are now approved by the fda, with dozens more anti-fibrotic therapies in the pipeline. a great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease (covid- ) and its accompanying acute respiratory distress syndrome (ards), few have emerged as effective. historically, survivors of severe viral pneumonia and related acute lung injury with ards often have near full recovery of lung function. while the pathological findings of the lungs of patients with covid- can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. there is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently fda-approved anti-fibrotic therapies. given the relatively favorable outcomes of survivors of virus-mediated ards and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in covid- -associated lung disease. the coronavirus (sars-cov- )-driven coronavirus disease (covid- ) pandemic and its deadliest complication, acute respiratory distress syndrome (ards), have fundamentally changed our world. clinicians are piecing together the puzzle that is covid- . information on disease pathogenesis and possible therapies surfaced initially, much out of necessity, from social media, listservs, case reports, and non-peer reviewed observations. now, months since the initial description in wuhan, china, with almost million infected worldwide and about half a million deaths, the clinical and the scientific communities have learned much and pivoted to high-quality evidence for the management of covid- patients. strong scientific rationale must be articulated before approaching critically ill, consent-weary patients and their families to enroll in clinical trials ( ) . along the way, there have been a few missteps. a recent review has shed light on the potentially dangerous treatment decisions when equating ards seen in covid- infection to the mechanistically distinct physiology of high-altitude pulmonary edema ( ) . despite robust in vitro mechanistic rationale, hydroxychloroquine has failed to protect against respiratory viruses in previous studies ( ) and yet again has not proven effective in covid- ( , ) . among the many excellent ongoing studies with good preclinical data in appropriate animal models, some arising directly from recent clinical observations, we were surprised to see studies proposing to use the fda-approved anti-fibrotic therapies (nintedanib nct and pirfenidone nct ) for idiopathic pulmonary fibrosis (ipf) in covid- patients. we acknowledge that some patients with severe, prolonged viral pneumonia and ards will die as a consequence of inflammation-induced fibrosis. we also recognize that clinical and experimental data suggest overlapping mechanistic pathways with inflammatory scar and ipf ( , ) . the survivors of ards, regardless of cause, clearly have important long-term limitations. muscle weakness, exercise limitation, physical and psychological sequelae, and decreased physical quality of life are well known ( ) . however, lung function upon recovery is often normal or well preserved and improves over time ( ) , arguing against a need for fibrosis-preventive therapies. therefore, covid- associated lung fibrosis does not seem to be the next phase of this pandemic requiring preventive or curative interventions ( ) . in this review, we posit that, unlike patients with ipf, the covid- survivors will follow a familiar course of intense pulmonary inflammation, leading to mild scarring and near-normal lung function recovery over time. ards is a form of severe acute lung injury characterized by its acute onset, bilateral pulmonary infiltrates, severe hypoxemia, and noncardiac pulmonary edema. in most cases, this is accompanied by intense neutrophilic alveolitis ( ). mechanical ventilation is needed as supportive therapy for patients with ards and can perpetuate lung injury ( ) . ards is also characterized pathologically by an initial exudative and inflammatory phase, followed by a fibroproliferative phase and, in non-survivors, end-stage fibrotic lung. with supportive measures, including low-tidal-volume ventilation, to minimize ventilator-induced lung injury and fibrosis, ards outcomes are improved ( ) . cabrera-benitez describes a "fibrosis paradox, " where those patients who die of ards had a prolonged course and evidence of pulmonary fibrosis. in contrast, ards survivors have relatively little evidence of fibrosis when biomarker measurement, lung function testing, or imaging is performed ( ) . fibrosis on biopsy correlated with poor outcome in a diverse ards cohort, but most patients had mild to no fibrosis ( ) . in an autopsy study of ards, fibrosis was noted in % of patients with disease of < week in duration, % of patients with disease of - weeks in duration, and of patients with disease lasting longer than weeks. fibrosis was more frequent in ards of pulmonary origin than that of extrapulmonary origin ( ) . nevertheless, survivors of ards have a favorable pulmonary prognosis. in one study, forced expiratory volume in the first second (fev ), forced vital capacity (fvc), and lung diffusing capacity for carbon monoxide (dlco) were mildly reduced, with > % of survivors showing normal or mild abnormalities on chest imaging at -month follow-up ( ). herridge et al. followed patients for years and noted normal or near-normal volumetric and spirometric test results by years. the results of the min walk tests were near normal. the most common finding in patients who had a chest ct available was minor, nondependent pulmonary fibrotic changes ( ) . many of the studies enrolled patients at a time when low-tidal-volume ventilation, perhaps the best therapy available for preventing and treating ards, was in its early stages of being consistently employed in intensive care unit (icu) care. the majority of ards studies include a heterogeneous patient population in which the onset and the etiology of ards are ill defined. in contrast, the onset of a viral illness and its course are often known. clinical, physiological, and radiological follow-up studies of patients with ards have been conducted in previous viral pandemics. although it is difficult to tease out ards patients from icu patients with severe viral pneumonias in the literature, studies of patients with ards due to influenza h n and h n strains have shown that, although functional impairment occurs, residual spirometric and radiological abnormalities are often inconsequential clinically, with evidence of distortion of septal lines, parenchymal bands, and bronchiectasis. pulmonary function inevitably improves over time ( , ) . in some studies, mild diffusing abnormalities persist in ards patients despite the normalization of fev and fvc ( ) . covid- , like other novel coronaviruses-severe acute respiratory syndrome (sars, to ), middle east respiratory syndrome (mers, - )-is associated with high mortality from ards and multi-organ system failure. fewer studies are available for outcomes in mers, but similar to other causes of viral-induced lung injury, mers survivors have a reduced quality of life ( ) , and the pulmonary sequelae from mers are mild. in a cohort of less severely ill mers pneumonia patients, only the subgroup with severe pneumonia showed an abnormal mean diffusing capacity, which was mildly reduced at % of predicted normal ( ) . in a study of patients with a median follow-up time of days, the follow-up chest radiographs were normal in % of patients. those with lung scarring ( ) of varying degrees were older, and no patients were followed for year to determine if those with acute findings had improved over time. in a few case reports of patients who died of mers, the predominant finding at autopsy was diffuse alveolar damage ( ) . several longitudinal studies have examined the long-term outcomes in sars survivors. it is estimated that up to % of patients with sars required icu admission, with % meeting the criteria for ards. these patients have a significant impairment in health status at year, which show modest correlations but are out of proportion to nearnormal pulmonary function. less than % of patients had severely reduced dlco, and none were hypoxemic on the -min walk test ( , ) . in a study by xie et al., % of sars survivors had residual radiographic abnormalities on follow-up. the findings included interstitial thickening, groundglass opacification, bronchiectasis, and signs of volume loss. forty patients underwent high-resolution computed tomography imaging examination after approximately month, with over half of them showing an improvement ( ) . in another study, the predominant ct findings were air trapping and groundglass opacities in % of patients. reticulation and parenchymal bands were also common, followed by bronchiectasis in % of patients and honeycombing in one patient. in the subgroup of patients with ards, the ground-glass and interstitial opacity scores decreased significantly, although there was no significant change in air trapping at to months ( ) . in survivors of sars followed for years, pulmonary interstitial damage and functional decline caused by sars mostly recovered within years after rehabilitation ( ) . the histopathology of sars has been extensively reviewed in autopsy series with limited information in sars survivors. the lungs in sars predominantly show diffuse alveolar damage and follow similar injury patterns, as seen in ards of other causes, with hyaline membranes and fibrinous tissue in alveolar spaces. the extent of fibrous organization correlates with the length of the disease. active pulmonary injury, however, can be seen for months, and fibrin balls within airspaces with features of organizing pneumonia are unique ( ) . although it is too early to reliably define the long-term outcomes in patients recovering from a severe covid- infection, patients with severe pneumonia have near-normal spirometry and moderate decreases in diffusing capacity ( ) . radiographically, the viral lung injury shows patterns similar to sars, with some patients developing predominant ground glass infiltrates evolving to linear bands and architectural distortion ( ) . covid- is unique in that ards can be atypical, with severe hypoxemia at times being associated with near-normal respiratory system compliance in some patients. despite sharing the same viral etiology, these severely hypoxemic patients may present quite differently, thus requiring different management algorithms ( ) . even as these subtypes are being identified and histopathological studies are emerging, the exact mechanism of lung injury in covid- remains unclear. autopsy data are now available from multiple centers. common findings emerge from these reports, including dad (the histopathological correlate of ards) at different stages in all patients ( ) . thickened alveolar septa with perivascular lymphocytic-plasmocytic infiltration are common and reflect a viral etiology of ards. there are also novel findings showing enhanced microthrombi, endothelialitis, and vascular involvement in covid- as compared to other etiologies of ards ( , ) . until recently, one finding that has lacked emphasis, frequency, and consistency in these reports is pulmonary fibrosis. a recent systematic review by polak et al. summarizes the pathological findings from both autopsy and biopsy reports. in lung samples from patients, were ante-mortem, including three lung transplant explants. the majority of these patients did not survive to be discharged from the hospital. the histological patterns identified in the cohort were reactive epithelial changes with dad in % and microvascular damage with microthrombi and organizing pneumonia in %. the fibrotic pattern was seen in % and occurred approximately weeks after the illness, with % showing some evidence of microcystic honeycombing ( ) . although it is clearly too early to comment on the longterm functional outcomes in covid- patients, a personalized approach given the unique pathologic findings, physiology, and phenotypes is warranted ( ) . nevertheless, we speculate that the lung function deficits will improve as recovery ensues and that survivors who develop lung scarring, much like other viral etiologies of ards, will overwhelmingly have minimal pulmonary physiological consequences. our perspective is that the survivors of post-viral ards recover with mild residual pulmonary deficits and that interventions to prevent these mild abnormalities are unnecessary during the covid- pandemic. despite overlapping pathways, the timing, etiology, prognosis, and mechanistic underpinnings of post-viral scarring are quite different than chronic fibrosing interstitial lung disease. ipf is progressive and eventually fatal in most patients ( ) . pulmonary fibrosis secondary to autoimmune causes such as rheumatoid arthritis and scleroderma may similarly progress and can be treated with an approved anti-fibrotic therapy. patients with connective tissue diseases who develop lung fibrosis have a relatively poor prognosis ( ) . in contrast, while postinflammatory changes can be seen in some ards survivors, progressive fibrosis has not been an important characteristic in ards related to respiratory infections and viral pneumonias. our recent understanding of the pauci-immune mechanism of ipf differs substantially from the intense inflammatory response noted in ards and viral pneumonias. moreover, viral inflammation induces robust t cell responses that can persist for months ( ) . it is quite possible that a significant subset of patients with covid- have ards physiology (or atypical ards with relatively normal lung compliance) due to highintensity lymphocytic alveolitis. this contrasts with other causes of ards in which an intense neutrophilic alveolitis is the rule. comparisons have been made between ards-related fibrosis in humans and the intense inflammation and scarring in the bleomycin mouse model, a model in which young mice resolve their fibrotic lung disease ( ) . age and underlying lung diseases may be important risk factors for enhanced fibrotic responses following ards. in the late stages of ards, diffuse alveolar damage with excessive and abnormal deposition of extracellular collagen matrix predominates as a consequence of the known acute inflammatory insult. interstitial and intra-alveolar fibrosis is often noted to varying degrees. the elevated levels of nt-pcp-iii, which is derived from the cleavage of procollagen iii, may be a useful biomarker to stratify therapies in critically ill patients with different phenotypes ( ) . fibrosis from ards, in contrast to ipf, does not progress nor lead to a dominant pattern of honeycombing. although the etiology of ipf remains obscure, the pathogenesis is best understood as a consequence of repetitive injuries followed by dysregulated repair processes, facilitated by telomere shortening, not intense inflammation ( ) ( ) ( ) . an excellent and thought-provoking review by george et al. highlights many nuances related to the care of ipf patients in the context of covid- ( ) . caring for patients with an underlying fibrotic lung disease is complex. the currently available antifibrotics have pleiotropic effects, allowing for many hypotheses related to their potential utility in other disease processes. it is clear that studies will proliferate as commercial interests grow and the pandemic continues in the absence of effective anti-virals and vaccines. the currently approved anti-fibrotics are meant for chronic disease management and by no means are curative nor do they reverse fibrosis. as such, despite the enthusiasm to study these medications, we believe that there is insufficient scientific rationale to do so, given the favorable course and the low prevalence of clinically meaningful scarring in survivors. the number of patients suffering from covid- is accumulating and will be millions worldwide. certainly we must evaluate patients, prospectively and retrospectively, to define the scope and the burden of residual pulmonary deficits and the fibrotic changes to determine their clinical significance. however, we find ourselves asking: is it worth spending valuable time, resources, and scientific energy studying anti-fibrotic therapies in acutely ill, consent-weary patients that truly need a targeted antiviral treatment or trial? the responsible answer is "no." let us keep our focus during the pandemic. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. all authors have contributed to the conception and design of the work, were involved in drafting and revising the content, gave final approval of the version to be published, and agree to be accountable for the integrity and all aspects of the work. pseudoscience and covid- -we've had enough already covid- lung injury and high altitude pulmonary edema: a false equation with dangerous implications chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial observational study of hydroxychloroquine in hospitalized patients with covid- a randomized trial of hydroxychloroquine as postexposure prophylaxis for covid- the role of epidermal growth factor receptor (egfr) signaling in sars coronavirus-induced pulmonary fibrosis pulmonary fibrosis and covid- : the potential role for antifibrotic therapy long-term outcome after the acute respiratory distress syndrome: different from general critical illness? canadian critical care trials, functional disability years after acute respiratory distress syndrome pulmonary fibrosis secondary to covid- : a call to arms? ventilator-induced lung injury ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. a study in mechanically ventilated patients chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies quality of life, pulmonary function, and tomographic scan abnormalities after ards long term outcomes in survivors of epidemic influenza a (h n ) virus infection. sci rep post-ards pulmonary fibrosis in patients with h n pneumonia: role of follow-up ct long-term outcomes of pandemic influenza a(h n )-associated severe ards quality of life reported by survivors after hospitalization for middle east respiratory syndrome (mers). health qual life outcomes correlation between pneumonia severity and pulmonary complications in middle east respiratory syndrome follow-up chest radiographic findings in patients with mers-cov after recovery histopathology of middle east respiratory syndrome coronovirus (mers-cov) infection -clinicopathological and ultrastructural study the -year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors the longterm impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status follow-up study on pulmonary function and lung radiographic changes in rehabilitating severe acute respiratory syndrome patients after discharge pulmonary sequelae in convalescent patients after severe acute respiratory syndrome: evaluation with thin-section ct long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a -year follow-up from a prospective cohort study pathology and pathogenesis of severe acute respiratory syndrome abnormal pulmonary function in covid- patients at time of hospital discharge clinical features of patients infected with novel coronavirus in wuhan covid- pneumonia: different respiratory treatments for different phenotypes? postmortem examination of patients with covid- pulmonary post-mortem findings in a series of covid- cases from northern italy: a two-centre descriptive study pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- a systematic review of pathological findings in covid- : a pathophysiological timeline and possible mechanisms of disease progression time to consider histologic pattern of lung injury to treat critically ill patients with covid- infection idiopathic pulmonary fibrosis connective tissue disease-associated interstitial lung disease: a focused review t cell metabolism in chronic viral infection exploring animal models that resemble idiopathic pulmonary fibrosis type iii procollagen is a reliable marker of ards-associated lung fibroproliferation telomerase and telomere length in pulmonary fibrosis the role of telomerase and telomeres in interstitial lung diseases: from molecules to clinical implications telomeres in interstitial lung disease: the short and the long of it conflict of interest: sc received consulting and speaking fees from boehringer ingelheim, genentech, and veracyte. mg serves on the advisory board for bellerophon therapeutics.the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © chaudhary, natt, bime, knox and glassberg. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -l hkn li authors: luyt, charles-edouard; bouadma, lila; morris, andrew conway; dhanani, jayesh a.; kollef, marin; lipman, jeffrey; martin-loeches, ignacio; nseir, saad; ranzani, otavio t.; roquilly, antoine; schmidt, matthieu; torres, antoni; timsit, jean-françois title: pulmonary infections complicating ards date: - - journal: intensive care med doi: . /s - - -z sha: doc_id: cord_uid: l hkn li pulmonary infection is one of the main complications occurring in patients suffering from acute respiratory distress syndrome (ards). besides traditional risk factors, dysregulation of lung immune defenses and microbiota may play an important role in ards patients. prone positioning does not seem to be associated with a higher risk of pulmonary infection. although bacteria associated with ventilator-associated pneumonia (vap) in ards patients are similar to those in patients without ards, atypical pathogens (aspergillus, herpes simplex virus and cytomegalovirus) may also be responsible for infection in ards patients. diagnosing pulmonary infection in ards patients is challenging, and requires a combination of clinical, biological and microbiological criteria. the role of modern tools (e.g., molecular methods, metagenomic sequencing, etc.) remains to be evaluated in this setting. one of the challenges of antimicrobial treatment is antibiotics diffusion into the lungs. although targeted delivery of antibiotics using nebulization may be interesting, their place in ards patients remains to be explored. the use of extracorporeal membrane oxygenation in the most severe patients is associated with a high rate of infection and raises several challenges, diagnostic issues and pharmacokinetics/pharmacodynamics changes being at the top. prevention of pulmonary infection is a key issue in ards patients, but there is no specific measure for these high-risk patients. reinforcing preventive measures using bundles seems to be the best option. acute respiratory distress syndrome (ards) regroups a wide range of diseases whose consequence is lung inflammation, alveolar damage and pulmonary edema [ ] . whatever the initial lung injury, patients with ards are prone to develop secondary pulmonary infection, namely ventilator-associated pneumonia (vap). recent data from the center for disease control and prevention suggest that vap rates are not dropping in the usa despite patients with ards exemplify the apparently paradoxical immune state of critically ill patients, whereby activated immune cells mediate organ damage while manifesting impaired antimicrobial defenses [ ] . impaired cellular functions have been identified across both the innate and adaptive arms of the immune system [ , ] , and appear to be stereotyped rather than specific to any precipitating cause of ards [ ] . this apparently paradoxical state is due to the ability of pro-inflammatory and tissue damage molecules to drive immune dysfunction [ , ] . dysfunctional immune cells are found in the lung as well as peripheral blood [ ] . interestingly, lung mucosal immune defects are protracted after the cure from primary inflammation, thus increasing the susceptibility to hospital-acquired pneumonia and ards for weeks after systemic inflammation [ ] . following experimental pneumonia, pulmonary macrophages and dendritic cells demonstrated prolonged suppression of immune functions which increased the susceptibility to secondary infection [ ] . expansion of immuno-modulatory regulatory t cells (t reg ) is also seen and may mediate impaired innate as well as adaptive immune function [ ] . patients with suspected vap, including those with ards, demonstrated impaired phagocytic function of alveolar neutrophils, which interestingly appeared to be mediated by different mediators than those driving dysfunction in the peripheral blood [ ] . while we have a growing understanding of the mediators driving dysfunction, and the intracellular mechanisms which drive them [ ] , we do not as yet have proven therapies although there are multiple potential agents [ ] . when aiming at modulating immunity during inflammation, it is important to differentiate innate and adaptive immune cells responses. while exhaustion and apoptosis seem to be central to lymphocyte defects observed in critically ill patients [ ] , some innate immune cells undergo reprogramming involving epigenetic reprogramming and increased cellular metabolism, a phenomenon so-called trained immunity, resulting in high production of inflammatory cytokines such as il- and tnfα during secondary immune challenge [ ] . while glucocorticoids are classically considered as immunosuppressive drugs, it has been shown that they can prevent the immune reprogramming observed after inflammatory response [ ] , thus limiting the susceptibility of patients admitted to the intensive care unit (icu) to respiratory complications such as pneumonia or ards and improving outcomes of patients with ards [ ] . part of the complexity of pulmonary super-infections arises from the interaction between the injured host with their pulmonary microbiome. although considerably less abundant and diverse than the better studied gastrointestinal microbiome [ ] , the pulmonary microbiome is increasingly well defined and undergoes significant changes during critical illness and ards [ ] . the major role of respiratory microbiota on mucosal immunity and respiratory functions in health suggests that its alterations could be involved in the respiratory complications observed in critically ill patients [ ] . indeed, mechanically ventilated patients experience a reduction in diversity of pulmonary microbes and an increase in enteric-type organisms, even in the absence of overt infection [ ] . early alterations of the lung microbiome, notably increased bacterial burden and biofilm formation, enrichment with gut-associated bacteria and loss of diversity, are associated with the risk of ards and the duration of mv support in critically ill patients [ ] . pre-existing dysbiosis, such as that induced by tobacco smoke, may also influence the development of ards following major trauma [ ] . alongside changes in bacterial species, it is common to find reactivation of latent herpesviridae such as herpes simplex virus (hsv) and cytomegalovirus (cmv) [ ] . the drivers of these changes are incompletely understood but are multi-factorial, with possible mechanisms illustrated in fig. [ , , ] . adding further complexity is the potential for microbes themselves to drive further immune dysfunction [ ] . vap should therefore be conceptualized as less a de novo infection by an exogenous pathogen, but rather a dysbiotic response to critical illness with overgrowth of specific genera of bacteria [ ] . appropriate antibiotic therapy targeting the dominant species, those frequently detected by culture, is key in certain patients but risks exacerbating dysbiosis and further harm to the patient [ ] . what remains to be proven is whether interventions to restore symbiosis, i.e., to increase bacterial diversity rather than only eliminating dominant species, can improve outcomes [ ] . although the experience of fecal transplantation in clostridium difficile associated diarrhea suggests that microbial transplantation may be an effective form of therapy [ ] , negative experience of probiotics in pancreatitis and recent examples of 'probiotic' bacteria causing infections sound a note of caution [ , ] . developing effective therapies for respiratory dysbiosis will require tools to profile the host peripheral pulmonary superinfections in ards patients considerably impact patients' prognosis which is favored by altered local and systemic immune defenses. the poor outcome of ards with pulmonary superinfections is probably related to the lack of early accurate diagnostic methods and difficulties in optimizing therapy. and pulmonary immune cell function and the pulmonary microbiome [ ] . hyperoxia is common in patients receiving mv for ards. a secondary analysis of the lung safe trial [ ] reported that % of the analyzed patients had hyperoxia on day , and % had sustained hyperoxia. while two randomized controlled trials found beneficial effect of avoiding hyperoxia [ , ] , a recent large international multicenter trial demonstrated no effect of conservative oxygen therapy in a cohort of critically ill patients [ ] . however, a subsequent sub-study raised the possibility of clinically important harm with conservative oxygen therapy in patients with sepsis [ ] . oxygen toxicity is mainly related to the formation of reactive oxygen species (ros), especially during hypoxia/ re-oxygenation and long exposure to oxygen. high level of inspired oxygen is responsible for denitrogenation phenomena and inhibition of surfactant production promoting expiratory collapse and atelectasis [ ] . absorption atelectasis occurs within few minutes after pure o breathing. in mechanically ventilated patients, atelectasis seriously impairs cough reflex and mucus clearance resulting in abundant secretions in the lower airways and higher risk for vap. prolonged hyperoxia also impairs the efficacy of alveolar macrophages to migrate, phagocyte and kill bacteria, resulting in decreased bacterial clearance [ ] . hyperoxemia markedly increased the lethality of pseudomonas aeruginosa in a mouse model of pneumonia [ ] . additionally, o can cause pulmonaryspecific toxic effect called hyperemic acute lung injury (hali) (fig. ) . although earlier studies reported a link between high fio and atelectasis, further studies are required to evaluate links between hyperoxia and mortality or vap. in a single center cohort study of patients, among whom ( %) had vap, multivariate analysis identified number of days spent with hyperoxemia [or = . , % ci: ( . - . ) per day, p = . ], as an independent risk factor for vap. however, the study was retrospective, performed in a single center, and the definition used for hyperoxia (at least one pao value > mmhg per day) could be debated [ ] . in the recent hypers s randomized controlled trial [ ] , the percentage of patients with atelectasis doubled in patients with hyperoxia compared with those with normoxia ( % vs. %, p = . ). however, no significant difference was found in vap rate between hyperoxia and control group ( % vs. %, p = . ). however, vap was not the primary outcome of this trial, and there is no clear definition of icu-acquired pneumonia. further well-designed studies are required to determine the relationship between hyperoxia and vap. prone position is recommended in patients with severe ards and is commonly used in this population. there is a rationale supporting a beneficial effect of prone position on the incidence of vap, as it facilitates secretion drainage and allows atelectasis resolution. previous human and animal studies have clearly showed a link between atelectasis and vap, and reported that efficient secretion drainage might result in lower incidence of vap [ ] . on the other hand, prone position might facilitate microorganisms' dissemination and increase microaspiration of contaminated secretions. the results of studies on the relationship between prone position and vap should be interpreted with caution, because of some limitations such as observational design, small number of included patients and confounding factors. five recent studies were performed in patients with protective lung mv, including four randomized controlled studies and one large observational cohort. mounier et al. [ ] reported no significant reduction of vap incidence in a large cohort (n = ) of hypoxemic patients positioned in the prone position, as compared to those who did not receive this intervention [hr . ( % ci . - . )]. one randomized controlled trial reported reduced risk for vap in multiple trauma patients who were subjected to intermittent prone position, as compared to those who did not (p = . ) [ ] . however, the incidence of vap was very high in the control group ( %), and the number of included patients was small (n = ). three other randomized controlled trials reported no significant relationship between prone position and vap [ , , ] . however, these studies lack information on efficient preventive measures of vap, such as the use of subglottic secretion drainage or continuous control of tracheal cuff pressure, and vap was not their primary outcome. in summary, available data do not support a significant relationship between prone position and vap, although it has demonstrated beneficial effects on mortality in severe ards. the diagnosis of lung infections in patients with ards is challenging [ ] . the diagnosis of pneumonia, the dominant respiratory infection of concern in ards, is ultimately a histopathological diagnosis which requires the presence of airspace inflammation and an infecting organism. however, obtaining lung tissue for diagnosis is seldom practical or desirable in ventilated patients [ ] . the clinical features of systemic inflammation and localizing chest signs such as crepitations and bronchial breathing are non-specific and insensitive. while radiological evidence of airspace infiltration is useful, the gold standard of computed tomography is not practical for most patients, leading practitioners to rely on plain radiographs and ultrasound, and even computed tomography cannot always reliably distinguish between infective and non-infective causes of airspace infiltration [ , ] . use of clinical and radiographic criteria alone are likely to significantly overestimate the rate of pneumonia and lead to excessive, potentially harmful, use of antibiotics [ ] . it is also important to recall that pneumonia itself is the commonest precipitant of ards, which, together with the bilateral radiographic alterations in ards patients, creates an additional challenge for the ascertainment of a "new or worsening pulmonary infiltrate", a condition required for clinical diagnosis of vap [ ] . another challenge is the distinction between ventilator-associated tracheobronchitis (vat) and vap. vat is defined as a lower respiratory tract infection without involvement of the lung parenchyma (and therefore without new/progressive chest x-ray infiltrate). the distinction between vat and vap in ards patients remained challenging given the poor accuracy of chest radiograph to detect new infiltrates. obtaining samples from the lungs for microbiological culture is crucial to the establishment of infection. however, there is considerable variability in the timing and type of specimen obtained in practice [ ] . the identification of infection can be complicated by colonization of the proximal airways, which happens rapidly after intubation and is frequent in ards patients [ ] . it is important to differentiate between colonization (presence of bacteria, even at a high burden, in the respiratory tract without lung infection), a harmless phenomenon, and infection. although protected deep lung sampling by broncho-alveolar lavage or protected specimen brush reduces the risk of false positives relative to endotracheal aspirate, this has not been convincingly demonstrated to alter outcomes although observational data suggest they can safely reduce antibiotic use [ ] . although falsepositive results from proximal colonization are a significant problem, intercurrent use of antibiotics is common in ards patients and increases the risk of false-negative culture. this is, increasingly, being addressed by the use of culture-independent molecular technique; however, the utility of the tools available is limited by their restricted range of organisms covered and the risk of over-sensitive detection of irrelevant organisms driving inappropriate use of antimicrobials [ ] [ ] [ ] . physicians should be aware of this particular point and therefore interpret with caution the results of these tests. there are very few prospective studies demonstrating the impact of molecular diagnostics on patient management and the results of forthcoming trials are awaited. antigen detection in the lower respiratory tract can also aid diagnosis, especially with organisms such as aspergillus where culture and pcr are imperfect [ ] . the value of aspergillus sp. and aspergillus fumigatus pcr is promising, but remain to be evaluated in ards patients. in patients with ards and bilateral radiographic infiltrates, there remains a question of which region to sample invasively. while trials have not been undertaken to answer this question definitively, observational data suggest that in the presence of bilateral infiltrates, unilobe sampling is sufficient and minimizes risk of lavage volume and duration of bronchoscopy [ ] . the host response makes up the crucial second component of any infection syndrome, and therefore host biomarkers can be of use in diagnosing infection in ards. laboratory hematological features of inflammation, including leucocytosis, neutrophilia and elevated c-reactive protein, are not specific to infection and can occur in sterile precipitants of ards [ ] . the inflammatory response in pneumonia is highly compartmentalized and alveolar cytokines and other alveolar markers are the most discriminant for pneumonia (table ) [ ] . notably, although alveolar cytokines demonstrated excellent assay performance, measurement of pulmonary cytokines did not alter antimicrobial prescribing in a recent randomized trial [ ] . this illustrates that the challenges in diagnosis lie not only with the technology, but also the behavioral response to results. peripheral blood markers have the advantage of avoiding the need for bronchoscopic sampling and are therefore easier to obtain; however, they are generally less able to discriminate pneumonia from other infections table summary of host-based biomarkers for diagnosis of pneumonia in ards ards acute respiratory distress syndrome, rct randomized controlled trial, strem soluble triggering receptor expressed on myeloid cells, vap ventilator-associated pneumonia, hla human leukocyte antigen interleukin- /interleukin- validated in multi-center cohort [ ] but did not influence practice in an rct [ ] strem- initial report, but not validated in follow-up study [ , ] exhaled breath markers experimental with technical variation currently limiting implementation [ ] pentraxin- meta-analysis suggested alveolar levels superior to plasma levels with moderate diagnostic performance, no rct testing influence on practice [ ] and many lack sensitivity and or specificity for infection (table ). in summary, the diagnosis of pulmonary infection in ards is challenging, and existing techniques are imperfect and risk both inadequate and overtreatment. a combination of clinical, biological and radiological assessment, combined with microbiological sampling from the lungs, remains the current gold standard (fig. ) . the development of molecular diagnostics focusing on both host and pathogen offers great promise, but their impact on patient management and outcomes remains to be convincingly demonstrated. the most common bacterial causes of vap include enterobacterales, pseudomonas aeruginosa, staphylococcus aureus, and acinetobacter among the general population of mechanically ventilated patients [ ] . the pathogens associated with vap in ards are similar to those seen among non-ards patients who develop vap (fig. ) [ , , ] . moreover, patients with ards undergoing extracorporeal membrane oxygenation (ecmo) demonstrate the same breakdown of pathogens with pseudomonas aeruginosa and staphylococcus aureus predominating [ ] . one important element, regardless of the specific causative bacteria seen in vap, is that antibiotic resistance is increasing in vap as well as in other nosocomial infections. in , the tigecycline evaluation and surveillance trial described important european changes in antimicrobial susceptibility between and , with increases in the rates of esbl-positive escherichia coli (from . to . %), mdr acinetobacter baumannii complex (from . to . %), esbl-positive klebsiella pneumoniae (from . to . %), and methicillin-resistant staphylococcus aureus (mrsa) (from . to . %) [ ] . similar worrisome trends for bacterial susceptibility to available antimicrobials have been reported by other investigators as well [ , ] . most worrisome is the increasingly recognized presence of resistance to new antibiotics specifically developed to treat vap [ ] . prior antibiotic exposure and subsequent changes in the host's airway microbiome due to dysbiosis seem to drive the prevalence of antibiotic-resistant bacterial causes of vap (fig. ) [ , ] . the presence of invasive devices such as endotracheal tubes and antibiotic administration promote pathogenic bacterial colonization due to the overwhelming of local defenses, resulting in the development of an intermediate respiratory infection termed vat [ ] . vat represents a compartmentalized host response associated with a better overall prognosis compared to vap, but vat can prolong the duration of mv and icu length of stay [ ] . if the aforementioned response is not compartmentalized, progression to vap is likely and potentially other organ failure including ards may occur [ ] . one of the major fears concerning nosocomial pulmonary infections in ards at the present and into the future is the increasing presence of novel pathogens and infections with microorganisms for which limited treatment options exist. as we increasingly treat older and more immunocompromised hosts with ards, the likelihood for emergence of novel pathogens and infection with pan-resistant microorganisms will increase. early identification of such emerging pathogens in ards is critical. the importance of early identification of novel pathogens is necessary to facilitate epidemiologic surveillance, curtailing pathogen spread, and providing early treatment as illustrated by recent nosocomial outbreaks of middle eastern respiratory syndrome coronavirus, sars-cov- and pan-resistant escherichia coli [ ] [ ] [ ] [ ] . in the future, metagenomic next-generation sequencing should allow earlier and more targeted treatments for novel pathogens causing ards or complicating the course of patients with ards. such technology will allow earlier pathogen identification and accelerate the workup and treatment for both infectious and noninfectious causes of diseases complicating ards [ ] . although the majority of respiratory infections in ards patients are caused by bacteria, icu-induced immunoparalysis may induce infection with unusual pathogens. although invasive pulmonary aspergillosis (ipa) has been reported mainly in immunocompromised patients, lower respiratory tract colonization with aspergillus has been more frequently associated with ards than in other patients invasively ventilated in icu [ ] . the mechanism of damage involves the combination of alveolar damage (induced by ards) and a dysregulation of the local immune response, together with sepsis-induced immunosuppression, innate immunity and antigen presentation impairment, accounting for the development of ipa in previously colonized patients [ , ] . co-infection with influenza has been reported as a risk factor for ipa [ ] . contou et al. reported isolation of aspergillus in the lower respiratory tract in almost % of patients with [ ] . bar graphs depicting the percentages of the most frequently isolated microorganisms in icu-acquired pneumonia episodes for (red bars) and for patients with acute respiratory distress syndrome (ards) (blue bars). total number of isolates , and , respectively ards ( % had putative or proven ipa) [ ] . an important finding from this study was that the median time between initiation of mv and first sample positive for aspergillus spp. was only days. moreover, a post-mortem study in ards patients found that % of deceased patients had ipa manifestations [ ] . if aspergillus is identified as a pathogen in an immunocompetent patient, it is recommended to screen for any kind of immunosuppression (humoral, cellular or combined, complement, etc.). viruses may also be responsible for infection in ards patients. because of immunoparalysis following the initial pro-inflammatory response to aggression, latent viruses such as herpesviridae may reactivate in icu patients [ ] . hsv and cmv are frequently recovered in lung or blood of icu patients (up to %, depending on the case mix), their reactivation being associated with morbidity and mortality [ , , ] . however, the exact significance of these reactivations is debated: these viruses may have a true pathogenicity and cause lung involvement [ , ] , thereby having a direct role in morbidity/mortality observed with their reactivation; or they may be bystanders, their reactivation being only secondary to disease severity or prolonged icu stay. to date, the answer is not known, data regarding a potential benefit of antiviral treatment being controversial. for hsv, the most recent randomized control trial found no increase in ventilator-free days in patients having received acyclovir, but a trend toward lower -day mortality rate (hazard ratio for death within days post-randomization for the acyclovir group vs control was . ( % ci . - . , p = . ) [ ] . for cmv, two recent randomized clinical trials (rcts) were performed: the first one showed that valganciclovir prophylaxis in cmv-seropositive patients was associated with lower rate of cmv reactivation as respiratory microbiome dysbiosis is also demonstrated as a prerequisite for most cases of vap and vt compared to placebo, but not with better outcome [ ] ; and the second one showed that, as compared to placebo, ganciclovir prophylaxis did not lead to lower il- blood level at day , but patients having received ganciclovir had trend toward lower duration of mv [ ] . besides latent viruses, respiratory viruses (rhinovirus, influenza, adenovirus…) have been recently found to be responsible for nosocomial infection in ventilated or non-ventilated patients [ ] . however, like herpesviridae, their true impact on morbidity/mortality is not known. in summary, hsv and cmv may cause viral disease in ards patients, and respiratory viruses may be responsible for hospital-acquired pneumonia; however, the true impact of these viral infections on outcomes remains to be determined. veno-venous extracorporeal membrane oxygenation (vv-ecmo) is now part of the management of refractory ards [ , ] . these very sick patients are at high risk for developing typical icu-related nosocomial infections (e.g., vap or bloodstream infections), in addition to ecmo-specific infections, including localized infections at peripheral cannulation insertion sites. bizzarro et al. reported a high prevalence rate of nosocomial infection of % in a large international registry of ecmo patients [ ] , pulmonary infection being the most frequently reported. this high prevalence may be explained by underlying comorbidities, concomitant critical illness, prolonged mechanical support, mv and icu stay as well as impairment of the immune system by the extracorporeal circuitry through endothelial dysfunction, coagulation cascade, and pro-inflammatory mediators release [ ] . while the rate of pulmonary infection on ecmo has not been thoroughly compared with a population with the same critical illness but in the absence of ecmo, vap was reported in out of patients receiving ecmo ( % vv-ecmo) by grasseli et al. [ ] . among patients who underwent va-ecmo for > h and for a total of ecmo days, ( %) developed nosocomial infections, corresponding to a rate of . infectious episodes per ecmo days. vap was the main site of infection with episodes occurring in patients after a median ± standard deviation of ± days [ ] . vap and resistant organisms are therefore common in that population [ ] [ ] [ ] . the duration of ecmo has been frequently associated with a higher incidence of vap [ , ] , even if a causal relationship is impossible to establish. indeed, longer ecmo runs could be a direct consequence of infectious complications rather than a risk factor. however, it seems clear that ecmo patients who acquired vap had longer durations of mv and ecmo support and a higher overall icu mortality [ , , ] . similarly, immunocompromised patients and older age were consistently found as risk factors associated with infections on ecmo [ , ] . the clinical diagnosis of pulmonary infection in ecmo patients is challenging, since they may have signs of systemic inflammatory response, possibly triggered by the ecmo itself, whereas fever could be absent if the temperature is controlled by the heat exchanger on the membrane. in addition, the common application of an ultraprotective ventilation aiming to rest the lung on vv-ecmo and frequent pulmonary edema on va-ecmo make the interpretation of new infiltrates on chest-x ray, which are commonly used to suspect a vap, difficult. beyond the diagnosis challenge of pulmonary infection on ecmo, the changes of pharmacokinetics/pharmacodynamics (pk/pd) of antimicrobial agents could also contribute to delaying appropriate antimicrobial treatment and consequently increase the burden of infections. an increase in the volume of distribution by ecmo as well as the severity of the underlying illness and drug clearance impairment through renal or liver dysfunctions complicates the management of antibiotics and antifungal therapies [ ] . while waiting for large in vivo studies aiming to report the respective pk/pd of antimicrobial agents on ecmo, avoiding lipophilic agents (i.e., more likely sequestrated on the ecmo membrane) [ ] and therapeutic drug monitoring are warranted. apart from bacteremias/fungemias, most infections are in interstitial or tissue spaces and hence the efficacy of a drug should be related to drug concentrations and actions in those tissues [ ] . drugs will cross the body membranes (move from intravenous compartment into tissue compartments) if there is an intrinsic "carrier mechanism", or if the compound is either a small molecule or is lipophilic [ ] . hydrophilic antimicrobials are found in extravascular lung water, but for relevant lung tissue penetration the lipophilic drugs are most important [ ] [ ] [ ] [ ] . large molecules such as vancomycin, teicoplanin, aminoglycosides and colistin will have poor lung tissue concentrations when given intravenously (elf/plasma concentration ratio << ) [ , ] . betalactams penetrate into lung parenchyma better than other hydrophobic antibiotics [ ] . elf/plasma concentration ratio for glycylcyclines (e.g., tigecycline) is around . lipophilic compounds such as macrolides, ketolides, quinolones, oxazolidinones, antifungals and antivirals will have good lung tissue concentrations (elf/plasma concentration ratio > ) after intravenous administration [ ] . oxazolidinones (linezolid), glycylcyclines (tigecycline) and sulfonamides (cotrimoxazole) may be effective in the treatment of mdr pathogens; however, there is no ards-specific lung pk (elf/plasma concentration) data for these drugs. although newer antimicrobials (ceftolazone-tazobactam, meropenem-vaborbactam, plazomicin) have activity against drug-resistant gram-negative pathogens, there are limited alternatives against drug-resistant acinetobacter baumaniii such as cefiderocol which is undergoing phase clinical trials. the advent of newer generation of delivery devices and mdr organisms has led to a renewed interest in the field of nebulized antimicrobials [ ] , although recent trials in pneumonia have failed to demonstrate clinical benefits [ , ] . ards is often associated with multiple organ dysfunction syndrome. hence, the possibility of achieving high intrapulmonary concentrations with limited systemic side effects is appealing. although recent wellconducted rcts argued against systematic use of nebulized antimicrobials in nosocomial pneumonia [ , ] it may still have a place in the treatment of severe lung infections due to mdr bacteria. in this view, selecting the correct antimicrobial formulation and dosing (table ) is an essential first step, as well as the best device, namely vibrating mesh nebulizer [ ] . clinical pk data available for some nebulized antibacterial, antiviral and antifungals confirm high pulmonary and low systemic exposure [ ] . sputum pk studies report high variability and are difficult to interpret [ ] . however, lung deposition of nebulized antimicrobials is influenced by many factors, including specific ventilator settings. ventilator settings and procedures usually recommended for improving aerosol delivery (high tidal volume, low respiratory rate and low inspiratory flow, systematic changes of expiratory fil-ters…) are difficult to implement in patients with ards, at least those with the most severe forms. ards is a heterogeneous lung condition causing inhomogeneous ventilation distribution potentially affecting drug delivery at the affected site. increased lung inflammation can also increase systemic concentrations by increased diffusion across the alveolo-capillary barrier, thus influencing the nebulized drug dosing [ ] . further pk studies investigating nebulized antimicrobial in ards are required for recommending dosing regimens in this condition. areas of investigation such as pulmonary nanomedicine and targeted delivery using intracorporeal nebulization catheter, while still investigational, have the potential to overcome many of these barriers and enhance lung tissue antimicrobial concentrations [ ] . nosocomial infections may contribute to the mortality related to ards given that such infections are responsible for worsening hypoxemia and causing sepsis. as such, the prevention of these infections must be reinforced to avoid straining the prognosis of patients suffering from ards. however, interpreting the vap prevention literature in this context is challenging because ( ) no studies have been conducted expressly in ards patients; ( ) several preventive measures have been shown to reduce the rate of pulmonary infection, but many less have demonstrated an impact on patient prognosis [ ] . that being said, the general strategy for preventing pulmonary infection applies also in ards patients. however, some preventive measures deserve a special focus in the context of ards patients (fig. ) : ( ) oral care with chlorhexidine is suspected to worsen respiratory failure; ( ) selective digestive decontamination (sdd) deserves to be discussed in such high-risk patients, as it has been proven to be effective in reducing mortality in icu patients and likely lowers vap rates. there is no single preventive measure that will completely avert pulmonary infection in patients suffering from ards and patients must be approached with a package or bundle of preventive measure [ ] provided that an early weaning strategy is part of the bundle [ ] . other preventive measures and notably some expensive medical devices such as automated endotracheal tube cuff pressure monitoring or endotracheal tube allowing subglottic secretion drainage have not been proven effective on patient's outcomes (mortality, duration of mv, antibiotic use), but could be dedicated to these high-risk patients. however, translating research into an efficient bundle of care to prevent pulmonary infection remains a challenge and behavioral approaches to implement the measures are as important as the measures themselves [ ] . chlorhexidine-gluconate (chg) use for oral care in icu patients may be harmful despite previous consistent data showing its beneficial effect in preventing vap [ ] . oral mucosa adverse events with % (w/v) chg mouthwash in icu are frequent, but often transient. adverse events described were erosive lesions, ulcerations, plaque formation (which are easily removed), and bleeding mucosa in of patients ( . %) who received % (w/v) chg [ ] . a systematic review and meta-analysis by labeau et al. in evaluated the effect of oral decontamination with chx [ ] . twelve studies were included (n = ). overall, chx use resulted in a significant risk reduction of vap (rr = . , % ci . - . , p = . ). favorable effects were more pronounced in subgroup analyses for % chx (rr = . , % ci . - . ) and for cardiosurgical patients (rr = . , % ci . - . ). however, a recent metaanalysis suggested that oral chg paradoxically increased the risk of death, which may have resulted from toxicity of aspirated chg in the lower respiratory tract [ ] . consequently, it remains unclear whether using chg for oral care affects outcomes in critically ill patients. selective digestive decontamination (sdd) remains definitely a matter of controversy [ ] . on one hand, it reduces the mortality in mechanically ventilated patients, while on the other hand its use is limited by the potential fig. prevention of pulmonary infections in ards patients: from highly recommended preventive measures to a cautious or even a not recommended use of inducing more bacterial resistance. however, in ards patients at high risk of mortality with high level of bacterial resistance, sdd deserves to be evaluated. the better understanding of ards phenotype may offer an opportunity to develop more selective preventive measures in the future. pulmonary superinfections of ards patients considerably impact patients' prognosis. it is favored by altered local and systemic immune defenses. the poor outcome of ards with pulmonary superinfections is probably related to the lack of early accurate diagnostic methods and difficulties in optimizing therapy. this article reviewed the available knowledge and revealed areas for future investigations in pathophysiology, diagnosis, treatment and prevention. potentials for improvements are numerous in all the fields: to improve knowledge about the host factors (both systemic and local) favoring superinfections. to identify early the disequilibrium between the host and the microbiota that may promote pneumonia in ards patients. to identify early criteria for suspicion of vap and vat. to determine the appropriate time to perform bacteriological samples, and in particular develop a morphological way to unmask areas of pneumonia at the bedside. to identify new diagnostic tests providing accurate and early diagnosis of pneumonia. to develop accurate early methods of pathogen identification and to distinguish patients infected and simply colonized (especially for viruses and fungi). to evaluate the impact of new molecular methods in diagnosing pneumonia in ards patients and improve prognosis. to evaluate the impact of tdm monitoring of antimicrobials on the prognosis of ards patients with pneumonia. to develop non-antibiotic therapies in the future, including vaccines, monoclonal antibodies and phage therapy. evaluate the benefit on antimicrobial consumption and prognosis of the use of sdd in ards patients in icus with a high level of bacterial resistance. acute respiratory distress syndrome changes in prevalence of health care-associated infections in us hospitals ventilator-associated pneumonia and icu mortality in severe ards patients ventilated according to a lung-protective strategy ventilator-associated pneumonia in ards patients: the impact of prone positioning. a secondary analysis of the proseva trial ventilator-associated pneumonia in adults: a narrative review the role of neutrophils in immune dysfunction during severe inflammation immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach cell-surface signatures of immune dysfunction risk-stratify critically ill patients: infect study c a mediates peripheral blood neutrophil dysfunction in critically ill patients trauma-induced damageassociated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient contribution of dendritic cell responses to sepsis-induced immunosuppression and to susceptibility to secondary pneumonia alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis local modulation of antigen-presenting cell development after resolution of pneumonia induces long-term susceptibility to secondary infections c a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling immunosuppression in patients who die of sepsis and multiple organ failure trained immunity and local innate immune memory in the lung dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial harnessing the microbiome for lung health enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome the lung microbiota of healthy mice are highly variable, cluster by environment, and reflect variation in baseline lung innate immunity the dynamics of the pulmonary microbiome during mechanical ventilation in the intensive care unit and the association with occurrence of pneumonia lung microbiota predict clinical outcomes in critically ill patients lung microbiota is related to smoking status and to development of acute respiratory distress syndrome in critically ill trauma patients herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients antibiotic treatmentinduced secondary iga deficiency enhances susceptibility to pseudomonas aeruginosa pneumonia pathophysiological role of respiratory dysbiosis in hospital-acquired pneumonia antimicrobialassociated harm in critical care: a narrative review duodenal infusion of donor feces for recurrent clostridium difficile probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in icu patients hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the lung safe study effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-icu randomized clinical trial hyperoxia and hypertonic saline in patients with septic shock (hypers s): a two-bytwo factorial, multicentre, randomised, clinical trial conservative oxygen therapy during mechanical ventilation in the icu conservative oxygen therapy for mechanically ventilated adults with sepsis: a post hoc analysis of data from the intensive care unit randomized trial comparing two approaches to oxygen therapy (icu-rox) adjunct therapies during mechanical ventilation: airway clearance techniques, therapeutic aerosols, and gases inhibition of extracellular hmgb attenuates hyperoxia-induced inflammatory acute lung injury hyperoxia exaggerates bacterial dissemination and lethality in pseudomonas aeruginosa pneumonia hyperoxemia as a risk factor for ventilator-associated pneumonia study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients prone positioning in acute respiratory distress syndrome: a multicenter randomized clinical trial effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial prone positioning improves oxygenation in post-traumatic lung injury-a prospective randomized trial diagnosis of ventilatorassociated pneumonia in critically ill adult patients-a systematic review and meta-analysis a national survey of the diagnosis and management of suspected ventilator-associated pneumonia quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia usefulness of point-ofcare multiplex pcr to rapidly identify pathogens responsible for ventilator-associated pneumonia and their resistance to antibiotics: an observational study s pan-bacterial pcr can accurately identify patients with ventilator-associated pneumonia performance and impact of a multiplex pcr in icu patients with ventilator-associated pneumonia or ventilated hospital-acquired pneumonia invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study pneumonia in acute respiratory distress syndrome. a prospective evaluation of bilateral bronchoscopic sampling the pathogenic involvement of neutrophils in acute respiratory distress syndrome and transfusionrelated acute lung injury diagnostic importance of pulmonary interleukin- beta and interleukin- in ventilatorassociated pneumonia biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (vaprapid ): a randomised controlled trial and process evaluation microbial cause of icu-acquired pneumonia: hospital-acquired pneumonia versus ventilator-associated pneumonia multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome. incidence, prognosis, and risk factors. ards study group nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation antimicrobial susceptibility among european gram-negative and gram-positive isolates collected as part of the tigecycline evaluation and surveillance trial geographical and temporal variation in the frequency and antimicrobial susceptibility of bacteria isolated from patients hospitalized with bacterial pneumonia: results from years of the sentry antimicrobial surveillance program ( - ) antimicrobial resistance higher mics (> mg/l) predict -day mortality in patients with lower respiratory tract infections caused by multidrug-and extensively drug-resistant pseudomonas aeruginosa treated with ceftolozane/tazobactam composition and dynamics of the respiratory tract microbiome in intubated patients how can we distinguish ventilator-associated tracheobronchitis from pneumonia? host-pathogen interaction during mechanical ventilation: systemic or compartmentalized response? lower respiratory tract infection and short-term outcome in patients with acute respiratory distress syndrome a candida auris outbreak and its control in an intensive care setting early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia escherichia coli harboring mcr- and blactx-m on a novel incf plasmid: first report of mcr- in the united states middle east respiratory syndrome clinical metagenomic sequencing for diagnosis of meningitis and encephalitis aspergillus in the lower respiratory tract of immunocompetent critically ill patients immune correlates of protection in human invasive aspergillosis increased incidence of co-infection in critically ill patients with influenza aspergillus-positive lower respiratory tract samples in patients with the acute respiratory distress syndrome: a -year retrospective study ards: a clinicopathological confrontation cytomegalovirus reactivation in critically ill immunocompetent patients epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock cytomegalovirus reactivation in icu patients acyclovir for mechanically ventilated patients with herpes simplex virus oropharyngeal reactivation: a randomized clinical trial safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial effect of ganciclovir on il- levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: a single-center retrospective study formal guidelines: management of acute respiratory distress syndrome extracorporeal membrane oxygenation for severe acute respiratory distress syndrome infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults extracorporeal life support and systemic inflammation nosocomial infections during extracorporeal membrane oxygenation: incidence, etiology, and impact on patients' outcome nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation ventilator-associated pneumonia in patients assisted by veno-arterial extracorporeal membrane oxygenation support: epidemiology and risk factors of treatment failure infections acquired by adults who receive extracorporeal membrane oxygenation: risk factors and outcome six-month outcome of immunocompromised severe ards patients rescued by ecmo. an international multicenter retrospective study pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men the effect of pathophysiology on pharmacokinetics in the critically ill patient-concepts appraised by the example of antimicrobial agents intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by gram-negative bacilli: a systematic review penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents a research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models a randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: iasis trial inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumonia (inhale): a doubleblind, randomised, placebo-controlled, phase , superiority trial fundamentals of aerosol therapy in critical care clinical pharmacokinetics of inhaled antimicrobials aerosolized antibiotics for ventilator-associated pneumonia: lessons from experimental studies feasibility and safety of targeted cisplatin delivery to a select lung lobe in dogs via the aeroprobe intracorporeal nebulization catheter ventilator-associated pneumonia and its prevention management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the brief summary of french guidelines for the prevention, diagnosis and treatment of hospitalacquired pneumonia in icu. ann intensive care : changes in knowledge, beliefs, and perceptions throughout a multifaceted behavioral program aimed at preventing ventilator-associated pneumonia prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta-analysis oral mucosal adverse events with chlorhexidine % mouthwash in icu reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation: systematic review and meta-analysis antipathy against sdd is justified: yes soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia soluble triggering receptor expressed on myeloid cells- in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia the potential role of exhaled breath analysis in the diagnostic process of pneumonia-a systematic review diagnostic value of pentraxin in respiratory tract infections: a meta-analysis. medicine (baltimore) :e a biomarker panel (bioscore) incorporating monocytic surface and soluble trem- has high discriminative value for ventilator-associated pneumonia: a prospective observational study the current status of biomarkers for the diagnosis of nosocomial pneumonias maintenance treatment with inhaled ampicillin in patients with cystic fibrosis and lung infection due to methicillin-sensitive staphylococcus aureus use of inhaled ampicillin-sulbactam against multiresistant acinetobacter baumannii in bronchial secretions of intensive care unit patients aerosolized ceftazidime prophylaxis against ventilator-associated pneumonia in high-risk trauma patients: results of a double-blind randomized study aerosolized ceftazidime for prevention of ventilator-associated pneumonia and drug effects on the proinflammatory response in critically ill trauma patients nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by pseudomonas aeruginosa nebulized imipenem to control nosocomial pneumonia caused by pseudomonas aeruginosa levofloxacin inhalation solution (mp- ) in patients with cystic fibrosis with pseudomonas aeruginosa reduction of bacterial resistance with inhaled antibiotics in the intensive care unit aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study for nebulized antibiotics in ventilator-associated pneumonia ( ) ventilator-associated pneumonia caused by multidrug-resistant gram-negative bacteria: understanding nebulization of aminoglycosides and colistin inhaled aztreonam lysine for chronic airway pseudomonas aeruginosa in cystic fibrosis key: cord- -uyze dtu authors: earhart, alexander p.; holliday, zachary m.; hofmann, hunter v.; schrum, adam g. title: consideration of dornase alfa for the treatment of severe covid- ards date: - - journal: new microbes new infect doi: . /j.nmni. . sha: doc_id: cord_uid: uyze dtu nan where it can lead to mucus plug clearance and accelerated recovery in humans and mice ( , ) . a controlled clinical trial for treating ards with dornase alfa is currently underway ( ). in the critical care setting, rare and minor adverse effects associated with dornase alfa include voice alteration and rash ( ) . the cellular and molecular mechanism proposed for dornase alfa activity in severely distressed lungs of cf and many ards patients is as follows. inflammation results in neutrophilia and neutrophil infiltration in the lungs, where these cells produce nets, largely comprised of sticky, large chromosomal dna that physically reinforces airway mucus viscosity and accumulation ( , ) . thick mucus that clears poorly can lead to airway obstruction, bronchiectasis, lung injury, hypoxia, and respiratory failure. dornase alfa facilitates airway clearance by breaking up reinforcement of mucus by nets, by far the greatest source of extracellular dna in inflamed lungs ( , ) . neutrophil and mucus-mediated airway exclusion pathway with striking similarities to that described above (figure ). unlike mild covid- often associated with fever and upperairway symptoms, patients with severe covid- often progress to an ards condition: hypoxemic respiratory failure associated with neutrophilia and neutrophil infiltration in the lungs, thick mucus in bronchi, and bronchiectasis ( - ). because lung neutrophilia in ards is generally known to involve high net production ( ), we feel it is rational to hypothesize that nets contribute to severe pathology in covid- . indeed, lung neutrophilia and net production have been shown to contribute to the development of ards in other severe viral respiratory infections, including h n influenza ( ) . we postulate that nebulized dornase alfa may effectively treat a deleterious effect of nets in the airways and thus promote recovery in patients with covid- -related ards ( figure ). dornase alfa can be easily administered to mechanically ventilated patients and is well tolerated in icu settings. anecdotally, a covid- patient who had been intubated five days was given three days of nebulized dornase alfa ( . mg twice daily) with continued standard icu care. improvement in oxygenation and lung compliance were observed comparing before versus after the three-day period (changes: p/f, to ; fi , % to %; peep, to ). four additional days were followed by extubation and six more days in hospital before the patient was considered recovered and discharged home. at this juncture of a rapidly evolving pandemic associated with high mortality in severely ill patients and the concepts discussed above, we suggest consideration to include inhaled dornase alfa in clinical trials for severe covid- associated with ards. dornase alfa for cystic fibrosis. the cochrane database of systematic reviews use of dornase alfa in the management of ards recombinant human deoxyribonuclease shortens ventilation time in young, mechanically ventilated children. pediatric pulmonology protocol for traumadornase: a prospective, randomized, multicentre, double-blinded, placebocontrolled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients net balancing: a problem in inflammatory lung diseases understanding the entanglement: neutrophil extracellular traps (nets) in cystic fibrosis. frontiers in cellular and infection microbiology chest ct manifestations of new coronavirus disease (covid- ): a pictorial review analysis of clinical characteristics and laboratory findings of cases of novel coronavirus pneumonia in wuhan, china: a retrospective analysis. respiratory research targeting potential drivers of covid- : neutrophil extracellular traps excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis figure . model of how dornase alfa-sensitive nets from neutrophils may reinforce mucus accumulation, rigidity, and airway occlusion in severe covid- . (a) viral infection causes lung-infiltrating neutrophils produce nets whose large quantities of chromosomal, extracellular dna are susceptible to degradation by dornase alfa (recombinant human deoxyribonuclease i, right). (b) close up view of alveoli dornase alfa treatment (right) reduces net-mediated reinforcement of mucus making it less rigid (lighter yellow) and facilitating mucus clearance, thus reducing lung injury and increasing gas exchange. (c) the rate at which recovery from severe covid- occurs naturally (left, thin arrow) might be increased by dornase alfa treatment (right, thicker arrow) key: cord- -v sb rc authors: gardin, chiara; ferroni, letizia; chachques, juan carlos; zavan, barbara title: could mesenchymal stem cell-derived exosomes be a therapeutic option for critically ill covid- patients? date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: v sb rc coronavirus disease (covid- ) is a pandemic viral disease originated in wuhan, china, in december , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ). the severe form of the disease is often associated with acute respiratory distress syndrome (ards), and most critically ill patients require mechanical ventilation and support in intensive care units. a significant portion of covid- patients also develop complications of the cardiovascular system, primarily acute myocardial injury, arrhythmia, or heart failure. to date, no specific antiviral therapy is available for patients with sars-cov- infection. exosomes derived from mesenchymal stem cells (mscs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. here, we briefly introduce the pathogenesis of sars-cov- and its implications in the heart and lungs. next, we describe some of the most significant clinical evidence of the successful use of msc-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill covid- patients. the novel coronavirus ( -ncov) has reached pandemic proportions across the world after originating in wuhan, the capital of china's hubei province, in december [ , ] . initially called -ncov, the world health organization (who) subsequently adopted the official name severe acute respiratory syndrome coronavirus (sars-cov- ) for indicating the virus, and the term coronavirus disease (covid- ) for identifying the virus-associated disease [ ] . as of may , the who has reported almost , , confirmed cases of covid- with , confirmed deaths in countries/areas/territories worldwide [ ] . the clinical spectrum of covid- is highly variable-in addition to mild, severe, and critical forms, asymptomatic or paucisymptomatic infections have been described as well [ , ] . milder clinical conditions are commonly characterized by fever, dry cough, myalgia or fatigue, headache, and mild pneumonia, whereas the severe form of the disease is associated with dyspnea, acute respiratory distress syndrome (ards), and hypoxemia (low level of oxygen in arterial blood) [ , ] . the most critical cases experience respiratory failure requiring mechanical ventilation and support in the intensive care mice was correlated with myocardial disfunction [ ] . considering the similarity with sars-cov, it has been speculated that sars-cov- infection might also down-regulate ace expression in lung and heart, thus leading to the pathological processes of lung and cardiac injuries [ ] . to date, no experimental or clinical data have evidenced that using acei/arb therapy makes patients more susceptible to the virus. therefore, several leading cardiovascular societies have strongly urged to not discontinue intake of ras inhibitors in the event the patient develops covid- [ , ] . j. clin. med. , , x for peer review of regulated after sars-cov infection in mice, and this was accompanied by increased pulmonary vascular permeability and pulmonary edema [ ] . similarly, cardiac ace down-regulation following sars-cov infection in mice was correlated with myocardial disfunction [ ] . considering the similarity with sars-cov, it has been speculated that sars-cov- infection might also downregulate ace expression in lung and heart, thus leading to the pathological processes of lung and cardiac injuries [ ] . to date, no experimental or clinical data have evidenced that using acei/arb therapy makes patients more susceptible to the virus. therefore, several leading cardiovascular societies have strongly urged to not discontinue intake of ras inhibitors in the event the patient develops covid- [ , ] . , angiotensin ( - ); at r, ang ii type receptor; aceis, angiotensin-converting enzyme inhibitors; arbs, angiotensin receptor blockers; ards, acute respiratory distress syndrome. green arrows indicate that aceis/arbs increase ace levels in the heart, therefore increasing the susceptibility of cardiac cells to sars-cov- infection [ , ] . blue dotted hammerhead indicates the hypothetical effect of sars-cov- on ace expression in lung and heart, which is based on the reported effect of sars-cov in the same body districts [ , ] . mscs are thought to prevent or reduce the cytokine storm in covid- patients, owing to their powerful anti-inflammatory and immunomodulatory functions [ ] . mscs exert these effects by directly interacting with different cells of innate and adaptive immunity, including t cells, b cells, dendritic cells (dcs), macrophages, and natural killer cells, and by indirectly releasing many types of inflammatory mediators by paracrine secretion [ ] [ ] [ ] [ ] . many studies have described a differential regulation by mscs on the different t cell subsets [ ] [ ] [ ] [ ] [ ] . mscs inhibit effector t (teff) cell proliferation induced by mitogens or alloantigens by causing cell cycle arrest at the g phase [ , ] . another explanation for this immunosuppressive capacity is the loss of cd , the alpha-chain of the il- receptor, which is cleaved from the activated t cell surface by msc-secreted matrix metalloproteinases [ ] . this leads to blockage of the il- cytokine signaling pathway required for t cells activation, expansion, and differentiation. interestingly, such t cell-suppressing properties of mscs seem to require the presence of inflammatory cytokines in the microenvironment, which provoke the production of several t cell-attracting chemokines and inducible nitric oxide synthase figure . schematic diagram showing the renin-angiotensin system (ras) cascade and the effects on the cardiovascular system and lung. ace , angiotensin-converting enzyme ; ace , angiotensin-converting enzyme ; ang i, angiotensin i; ang ii, angiotensin ii; ang ( - ), angiotensin ( - ); at r, ang ii type receptor; aceis, angiotensin-converting enzyme inhibitors; arbs, angiotensin receptor blockers; ards, acute respiratory distress syndrome. green arrows indicate that aceis/arbs increase ace levels in the heart, therefore increasing the susceptibility of cardiac cells to sars-cov- infection [ , ] . blue dotted hammerhead indicates the hypothetical effect of sars-cov- on ace expression in lung and heart, which is based on the reported effect of sars-cov in the same body districts [ , ] . mscs are thought to prevent or reduce the cytokine storm in covid- patients, owing to their powerful anti-inflammatory and immunomodulatory functions [ ] . mscs exert these effects by directly interacting with different cells of innate and adaptive immunity, including t cells, b cells, dendritic cells (dcs), macrophages, and natural killer cells, and by indirectly releasing many types of inflammatory mediators by paracrine secretion [ ] [ ] [ ] [ ] . many studies have described a differential regulation by mscs on the different t cell subsets [ ] [ ] [ ] [ ] [ ] . mscs inhibit effector t (teff) cell proliferation induced by mitogens or alloantigens by causing cell cycle arrest at the g phase [ , ] . another explanation for this immunosuppressive capacity is the loss of cd , the alpha-chain of the il- receptor, which is cleaved from the activated t cell surface by msc-secreted matrix metalloproteinases [ ] . this leads to blockage of the il- cytokine signaling pathway required for t cells activation, expansion, and differentiation. interestingly, such t cell-suppressing properties of mscs seem to require the presence of inflammatory cytokines in the microenvironment, which provoke the production of several t cell-attracting chemokines and inducible nitric oxide synthase (inos) from mscs, so that t cells migrate into proximity of these cells [ ] . at the same time, mscs have been shown to induce the survival and expansion of regulatory t (treg) cells, a subset of t cells involved in the suppression of proliferation and cytokine production by teff cells [ ] . therefore, treg cells foster the msc-mediated immunosuppressive effect. in addition to directly interacting with t cells, mscs also modulate the adaptive immune response by acting on antigen-presenting cells (apcs), such as dcs, monocytes, and macrophages, by shifting them to regulatory phenotypes characterized by t cell-suppressive properties [ , ] . the spectrum of regulatory factors secreted by mscs is collectively defined as the msc secretome, and include a complex array of soluble molecules, such as anti-inflammatory cytokines, angiogenic growth factors, antimicrobial peptides, and lipid mediators. a growing body of evidence nowadays suggests that some of these molecules are packaged into cell-secreted vesicles, known as extracellular vesicles (evs) [ ] [ ] [ ] . besides apoptotic bodies, the two main types of evs released by mscs include exosomes and microvesicles (mvs). exosomes ( - nm) are derived by fusion of multi-vesicular bodies with the plasma membrane, whereas mvs ( - nm) are formed by cellular membrane budding, and contain cellular cytoplasm. all these evs are released into the extracellular microenvironment, where they exert biological effects in a paracrine and endocrine manner, similarly to the soluble components. for this reason, a broader definition of mscs secretome encompasses the entire spectrum of bioactive factors secreted by mscs, which consists of both the soluble and the extravesicular elements. it has now been demonstrated that mscs are also able to transfer functional mitochondria or mitochondrial dna (mtdna) to target cells, thus rescuing aerobic respiration in cells with non-healthy mitochondria or regulating t cell functions [ , ] . following systemic injection, some mscs accumulate in the lung, where they release these soluble mediators, potentially recovering the pulmonary microenvironment, protecting alveolar epithelial cells, and counteracting pulmonary fibrosis, thus resulting in a final improvement of lung function [ ] . moreover, distant injured organs, such as the cardiovascular system, can also benefit from them, by virtue of the secretory abilities of these cells. to date, two studies have investigated the employment of mscs in severely affected sars-cov- patients, with both reporting remarkable reversal of symptoms within a few days [ , ] . in one of these works, the levels of biochemical indicators of liver and myocardium damage (aspartic aminotransferase, creatine kinase activity, and myoglobin) returned to reference levels days after msc treatment [ ] . the authors demonstrated that the cells expressed high levels of anti-inflammatory and angiogenic factors, such as transforming growth factor-beta (tgf-β), hepatocyte growth factor (hgf), leukemia inhibitory factor (lif), fibroblast growth factor (fgf), vascular endothelial growth factor (vegf), epidermal growth factor (egf), brain-derived neurotrophic factor (bdnf), and nerve growth factor (ngf), further demonstrating their potent immunomodulatory abilities. it has been reported that mscs are generally resistant to viral infections compared to their differentiated progeny, probably due to intrinsic expression of ifn-stimulated genes (isgs) [ ] . among these genes, those coding for proteins of the interferon-induced transmembrane (ifitm) family prevent viruses from traversing the lipid bilayer of the cell and accessing the cytoplasm, thus impairing viral infection [ ] . these antiviral proteins limit infection in cultured cells by many viruses, including sars-cov, dengue virus, ebola virus, influenza a virus, and west nile virus. however, some studies have reported that human mscs are permissive to other viruses, for example avian influenza viruses h n and h n and respiratory syncytial virus (rsv), losing vitality and compromising their immunomodulatory activities [ , ] . in the case of sars-cov- , the advantage in using mscs seems to be additionally related to the absence of ace receptors on the cell surface, which precludes their recognition by the virus. notably, in the study of leng and coworkers, the cells remained negative for ace also after transplantation in infected patients [ ] . although mscs seem to be refractory to sars-cov- infection, in order to bypass the impact of viruses on mscs, an interesting therapeutic strategy could consider the use of the msc secretome. among the bioactive factors released by mscs, evs, exosomes in particular, have gained remarkable interest in recent years because they enable more efficient communication and targeting than soluble molecules [ ] . evs, by virtue of their lipid bilayer membrane, better protect their molecular cargo of proteins and genetic material from environmental degradation (i.e., from trypsin or nuclease digestion) when compared to soluble molecules. encapsulation within evs may also facilitate delivery and targeting of these bioactive factors to distant recipient cells, mediated by binding of the ev surface proteins to cells that express appropriate receptors [ ] . msc-derived exosomes offer several advantages over traditional cell-based therapies. first, exosomes are considered safer than cells, because they are biocompatible, non-immunogenic, and lack the potential for endogenous tumors and emboli formation [ ] . in addition, exosomes are physiologically more stable than cells, because their multiple membrane adhesion proteins allow for efficient binding in the target tissues during transplantation. thanks to their resistant membrane, exosomes maintain their integrity during freezing and thawing procedures, making long-term storage without biological degradation possible [ ] . in this context, a process has recently been proposed that combines ultrafiltration and lyophilization and is able to convert msc secretome into a freeze-dried, ready-to-use powder [ , ] . the same research group also suggested the possibility to administer evs by inhalation in the treatment of respiratory diseases [ ] . this route of administration would benefit from lower invasiveness and pain, faster onset of action, and use of lower doses to achieve the same therapeutic effect when compared to oral or injection therapies. in this regard, a pilot clinical trial (nct ) will be conducted in china for exploring the safety and efficiency of aerosol inhalation of msc-derived exosomes in comparison to conventional treatment in severe patients with covid- . another advantage of msc-derived exosomes over whole-cell therapy is that, to improve their therapeutic potential, exosomes could potentially be modified with various types of cargos, including mrna, microrna (mirna), and proteins, tailored to the disease process of interest [ ] . in one pioneering work, exosomes incorporating the s protein have been explored as a novel vaccine approach against sars-cov infections [ ] . the immunogenicity and efficacy of the s-containing exosomes were tested in mice, where they induced neutralizing antibody titers. finally, from an economical point of view, msc-derived exosome therapy might enable development of cheaper treatments other than the expansion and maintenance of individualized clonal cell populations [ ] . this aspect is particularly important when a global pandemic has to be managed, as in the case of covid- . in section , we provide an overview of the currently available evidence on the effects of msc-derived exosomes in pre-clinical models of lung and heart injuries, which are the body districts most affected by sars-cov- . diabetes mellitus (dm) represents the most common inflammatory and chronic metabolic disorder worldwide, and continues to increase in number and significance-it is estimated that there will be million persons with dm by [ ] . type diabetes mellitus (t dm) accounts for - % of all cases of diabetes and results from a progressive defect in insulin production and insensitive response of the body to insulin [ ] . accumulating evidence shows that such a state of insulin resistance (ir) is closely related with obesity [ ] . obesity, mainly visceral adiposity, is, indeed, one of the most important comorbidities in diabetic patients. people with diabetes have a higher overall risk of infections that result from compromised innate cell-mediated immunity; impaired phagocytosis by neutrophils, macrophages, and monocytes; and impaired neutrophil chemotaxis and bactericidal activity [ ] . regarding covid- , it is currently unknown whether patients with diabetes have a higher susceptibility to the virus; nonetheless, there is evidence of higher risk for both infection and disease severity [ ] . as stated above, there is growing interest in the use of msc-derived evs as a therapeutic tool for the management of several diseases. however, because ev cargo usually reflects parent cell characteristics, and these are influenced by the metabolic state of source cells, it is reasonable to consider the risks associated with the employment of msc-derived evs from patients with coexisting metabolic disorders such as t dm. in effect, clinical studies have found differences in the number and composition of evs isolated from the adipose tissue of obese patients and from animal models of obesity [ ] [ ] [ ] [ ] . for example, msc evs isolated from a swine model of metabolic disorder were found to be enriched with mrnas associated with inflammation, such as those coding for the integrin family proteins, or proteins of the fgf signaling [ ] . these msc-derived evs also showed a distinctive mirnas cargo, being enriched in mirna-targeting genes involved in the development of metabolic disease and its complications, including diabetes, obesity, and insulin signaling [ ] . apart from influencing the mrna and mirna content, metabolic disorder also alters packaging of proteins into porcine msc-derived evs, promoting the inclusion of pro-inflammatory proteins, such as those involved in acute inflammatory response, cytokine production, and leukocyte transendothelial migration [ ] . the limitations of these works reside in the small sample size and short duration of metabolic disease compared to the human condition; therefore, further studies would be needed to draw clear conclusions. however, in humans also, analysis of adipose tissue-derived evs demonstrated that obesity alters their cargo of mrnas, mirnas, and proteins [ ] . in particular, the differentially expressed mirnas contained in the isolated evs stimulated up-regulation of wnt/β-catenin and tgf-β signaling pathways, which are related to inflammation, into a lung epithelial cells. overall, these observations suggest that diabetes and metabolic disorders might alter the msc-derived ev cargo, which in turn might compromise their anti-inflammatory and immunodulatory potential both in the endogenous microenvironment and after autologous transplantation. acute lung injury (ali) and ards are major causes of respiratory failure in critically ill ventilated patients, with an estimated -day mortality rate of % [ ] . ards is also one of the most common complications in severely affected covid- patients. the term ards is often used interchangeably with ali; nevertheless, ards should be reserved for the most severe form of the disease [ ] . bacterial or viral infections are the most common causes of ali and ards; however, they can also be initiated by aspiration of gastric contents, toxic inhalation, lung contusion, or trauma [ ] . the acute phase (the first - days) of the diseases is characterized by injury to both the pulmonary endothelium and the alveolar epithelium, the two barriers forming the alveolar-capillary barrier. in healthy lung microvessels, the pulmonary endothelium is maintained by vascular endothelial cadherin (ve-cadherin), an endothelial-specific adherens junction protein, whereas the alveolar epithelial barrier has e-cadherin junctions and is substantially less permeable than the endothelial counterpart [ , ] . during lung injury, ve-cadherin bonds are destabilized by increased expression of thrombin, tnf-α, vegf, and signals from leukocytes. at the same time, e-cadherin epithelial junctions are disrupted by neutrophil migration, which causes injury, apoptosis, and membrane denudation. this ultimately results in increased epithelial permeability, leading to accumulation of protein-rich edema fluid in the alveoli, and in turn to an impairment in gas exchange and to hypoxemia [ ] . dysregulated immune activation has also been implicated in the pathogenesis of ali/ards. in the air space, macrophages release pro-inflammatory cytokines and chemokines, which act locally to stimulate chemotaxis and activate neutrophils. activation of neutrophils leads to the release of numerous cytotoxic products, such as reactive oxygen species, cationic peptides, eicosanoids, and proteolytic enzymes, which may further damage the alveolar epithelium [ ] . resolution of ali/ards aims at removing alveolar edema fluid, repairing the epithelial and endothelial barriers, and removing inflammatory cells and exudate from the air spaces [ ] . to date, management of ali/ards includes lung protective ventilation, prone positioning, neuromuscular blockade, and extracorporeal membrane oxygenation. mechanical ventilation represents the mainstay treatment in ali/ards, and consists in the application of positive-end expiratory pressure for optimizing arterial oxygenation. it has been evidenced that ventilation with a low tidal volume ( ml/kg) gives better results when compared to traditional tidal volume ( ml/kg) [ ] . indeed, the use of lower tidal volumes during ventilation may reduce injurious lung stretch and the release of inflammatory mediators. prone positioning enhances arterial oxygenation by improving alveolar ventilation/perfusion matching. nevertheless, this treatment should be used with caution and should be reserved for patients with critical hypoxemia, since it does not improve survival or decrease the duration of lung ventilation. all these therapeutic options remain primarily supportive; on the other hand, alternative treatments with glucocorticoids, surfactants, inhaled nitric oxide, antioxidants, protease inhibitors, or other anti-inflammatory agents had proven unsuccessful in reducing mortality or improving ali/ards outcomes [ ] . in terms of promising novel strategies, msc-based approaches have been explored for the management of ali/ards. the benefit of msc therapy appears to be related to a decrease in pro-inflammatory cytokines and to an increase in anti-inflammatory cytokines, particularly il- [ ] . mscs release prostaglandin e , which in turn stimulates secretion of il- by monocytes and alveolar macrophages [ ] . moreover, administration of mscs seems to be effective in normalizing lung endothelial and epithelial permeability to protein, as well as in reducing pulmonary edema and increasing the rate of alveolar fluid clearance [ ] . recently, msc-derived exosomes have been demonstrated to have comparable and even greater effects than cells themselves in improving inflammation and injury in a variety of pre-clinical lung disease models, including ali/ards (table ) . for the completeness of information, we have to specify that some of these works take into account the entire spectrum of evs that, in addition to exosomes, also includes mvs. this is because as of yet there are no standardized methods for isolation, quantification, and characterization of evs, or for discriminating mvs and exosomes. consequently, in the majority of these pre-clinical studies, evs, exosomes, and mvs are collectively referred to as evs. msc-derived evs have been proven to be beneficial in both bacteria-and virus-induced ali/ards. a large number of studies have employed an endotoxin-mediated in vivo model to investigate the effects of msc-derived evs for ali/ards. in one of the first works, ali was induced in c bl/mice using the intratracheal (it) instillation of endotoxin ( mg/kg) from escherichia coli (e. coli) [ ] . mvs were isolated from the conditioned medium of human bone marrow-derived mscs with two sequential ultracentrifugations at , × g for h. then, ul of mvs, corresponding to the vesicles released by × mscs, were administrated intratracheally or intravenously in mice. after h, msc-derived mvs reduced lung inflammation and reduced edema to the same levels as mscs themselves, which were used as a positive control. furthermore, mvs also decreased the influx of neutrophils and mip- levels in the alveolar fluid, indicating a reduction in inflammation. surprisingly, the therapeutic effects of the mvs were comparable, regardless of route of administration. the authors suggested that the mechanism underlying the therapeutic effect of mvs might be in part mediated by the transfer of keratinocyte growth factor (kgf) mrna into the injured alveolar epithelium, with subsequent expression of the protein. kgf is an epithelial-specific growth factor released from mscs, which has been shown to reduce lung edema and inflammation in various ali models [ ] [ ] [ ] . in the same study, the effect of mvs was additionally evaluated in raw . cells, a mouse macrophage cell line. treatment with µl of msc-derived mvs to endotoxin-stimulated raw . cells reduced the levels of tnf-α and mip- , and concomitantly increased the production of the anti-inflammatory cytokine il- at , , and h compared with endotoxin-stimulated mouse macrophages [ ] . in the work of tang and colleagues, ali was induced in c bl/mice by the instillation of lipopolysaccharide (lps) from pseudomonas aeruginosa at mg/kg intratracheally [ ] . mvs released from human bone marrow mscs were isolated by two sequential ultracentrifugations at , × g for h, then intratracheally administrated in endotoxin-injured mice. it administration of msc-derived mvs improved the lung inflammation induced by lps in mice, including the influx of white blood cells and neutrophils, and mip- secretion. in that study, the authors found that the transfer of angiopoietin- (ang- ) mrna by mvs was essential for the reduction of inflammation and the restoration of alveolar-capillary barrier. ang- plays a key role in vascular stabilization, since it reduces endothelial permeability and suppresses leukocyte-endothelium interactions [ ] . furthermore, msc-derived mvs showed immunomodulatory effects on raw . cells in vitro by inhibiting tnf-α mrna production and promoting the mrna levels of il- after h [ ] . collectively, these two studies suggest that the beneficial immunomodulatory effect of msc-derived mvs in ali is strongly dependent on kgf and ang- mrna transfer into injured endothelial cells. it has been demonstrated that, apart from mrnas, the therapeutic effect of evs is also mediated by the transfer of functional mitochondria to target cells. mscs have been reported to naturally transfer mitochondria to recipient cells through different mechanisms-incorporated within evs, via cell-to-cell contact through tunneling nanotubes, or through direct release of naked mitochondria into the extracellular microenvironment [ , ] . in the work of phinney and colleagues, transmission electron microscopy images evidenced structures consistent with the morphology of mitochondria inside mvs over nm in size, previously isolated from the conditioned medium of human mscs after centrifugation at , × g for h [ ] . the authors found that these mitochondria were loaded in the cytoplasm into lc -containing mvs, which migrated towards the cell periphery and were incorporated into outward budding blebs in the plasma membrane. the msc-derived mvs contained functionally active mitochondria that were taken up by macrophages and resulted in improved bioenergetics after oxidative stress increment. in particular, the transfer of human msc-derived mitochondria involved fusion with mitochondria inside macrophages, suggesting that the mitochondrial membrane was not collapsed. the same study also confirmed that mitochondria were not packaged within exosomes; rather, exosomes were able to deliver mtdna, which in mammals has an average size under nm [ ] . in the context of lung injury, the group of morrison and colleagues revealed that msc-derived evs protected mice against lps-induced ali by altering alveolar macrophage (am) polarization from the pro-inflammatory m phenotype towards the m anti-inflammatory phenotype [ ] . in detail, evs were obtained from human bone marrow mscs after ultracentrifugation at , × g for h. these were used for pre-treating am, which were then intranasally administrated to lps-injured mice. the msc-derived evs increased phagocytic activity by macrophages and reduced their secretion of tnf-α and il- , two major pro-inflammatory cytokines related to ards severity [ , ] . the transfer of functional mitochondria contained in evs, associated with the promotion of oxidative phosphorylation, was supposed to be the mechanism responsible for the observed effects in macrophages [ ] . the work of monsel and colleagues was the first to evaluate the effect of msc-derived mvs in an infectious ali model [ ] . indeed, the authors instilled live e. coli bacteria into the trachea; then, they intravenously administrated ul of mvs, corresponding to the vesicles released by × human bone marrow mscs. mv injection improved survival and reduced the bacterial load, as well as the influx of white blood cells, neutrophils, and mip- levels, in the injured alveolus of c bl/mice. the authors reported that the effect was in part mediated by kgf mrna shuttled by the vesicles into target cells, as described in their previous study [ ] . in addition to testing in mice, the effect of msc-derived mvs was also investigated in human monocytes and at cells. mv treatment increased the percentage of phagocytosis of human monocytes against e. coli bacteria, thus reducing the bacterial count, and decreased tnf-α secretion. furthermore, mvs showed a beneficial effect on injured human at cell metabolism through the restoration of intracellular atp levels to control levels. in these primary in vitro cultures, the uptake of mvs was mediated by cd , which was essential for the observed therapeutic effects. cd is the hyaluronic acid receptor expressed in almost every cell type including mscs [ , ] . the results of this work suggested that mvs, similarly to their parent cells, act through different mechanisms on the basis of anti-inflammatory, anti-microbial, and metabolomic effects. msc-derived evs have also shown reparative properties on microvascular endothelial and epithelial cells, which are often severely injured in the lung during ali, and are associated with increased mortality in ards patients. hu and coworkers investigated the effects of mvs isolated from human bone marrow mscs on human lung microvascular endothelial cells (hlmvecs) in vitro [ ] . the cells were injured by cytomix, a mixture of the most biologically active cytokines found in ali pulmonary edema fluid (il- β, tnf-α, and ifn-γ at ng/ml), and simultaneously exposed to increasing doses ( or ul) of mvs using a transwell co-culture system [ ] . administration of msc-derived mvs restored protein permeability of hlmvecs by preventing the reorganization of cytoskeleton protein f-actin into "actin stress fibers" and the loss of tight and adherens junction proteins (zonula occludens- and ve-cadherin, respectively) following inflammatory injury. the internalization of mvs via cluster of differentiation (cd) receptor, as well as the subsequent transfer of ang- mrna into injured hlmvecs, were required for the observed therapeutic effects. the study of khatri and colleagues is interesting because ards was induced in pigs after infection with a mixed swine (h n , h n ) and avian (h n , h n ) influenza viruses (swiv) [ ] . pigs are often used as large animal pre-clinical models for several human diseases, including respiratory diseases, due to their close similarity in anatomy, physiology, and immunology to humans [ ] . in addition, influenza virus pathogenesis and clinical signs are similar to those observed in humans. in that work, evs ( µg/kg) isolated from swine bone marrow mscs with two ultracentrifugation steps at , rpm for min were intratracheally administrated in pigs h after swiv inoculation. msc-derived evs were found to inhibit influenza virus replication and shedding in pigs days post-infection. as in other studies, evs also modulated inflammatory cytokine and chemokine production in the lungs, as demonstrated by reduction in tnf-α and cxcl protein levels, and increase in il- protein levels. unfortunately, there are not yet pre-clinical data on the effects of msc-derived ev administration in models of coronavirus respiratory infection, mostly due to the lack of an established animal model [ ] . from the studies discussed above, it emerged that the rationale for using msc-derived exosomes, mvs, or evs in ali/ards is based on several processes, many of which are shared with those identified in the parent mscs. these include immunomodulation and anti-inflammatory properties on host tissue, reduction of the permeability of alveolar epithelium and endothelium, improvement of alveolar fluid clearance, enhancement of macrophage phagocytosis, and tissue repair through direct mitochondrial transfer with host cells (figure ). reduction in tnf-α and cxcl protein levels, and increase in il- protein levels days post-infection. [ ] potential therapy in the management of other lung diseases, such as bronchopulmonary dysplasia, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, and asthma, which have been recently revised in worthington [ ] and behnke [ ] . moreover, in these lung diseases, the most common effects of msc-derived evs were decreased inflammation and restoration of the lung architecture, achieved through the reduction of fibrosis and increase of vascularization and alveolarization. [ , , , ] , reduction of the permeability of alveolar epithelium and endothelium [ ] , improvement of alveolar fluid clearance [ ] , enhancement of macrophage phagocytosis [ ] , and tissue repair through direct mitochondrial transfer with host cells [ ] . acute myocardial injury has been described as the most common cardiovascular complication in covid- patients [ ] . myocardial injury is defined as an elevation in serum levels of highsensitive cardiac troponin (ctn) above the th percentile upper reference limit, although over the years it has also been identified through an increase in different cardiac enzymes and/or electrocardiographic abnormalities [ ] . the injury is considered acute if there is a dynamic rise and/or fall of ctn values. when acute myocardial injury is caused by myocardial ischemia, it is designated as acute myocardial infarction (ami). on the contrary, myocardial injury not related to ischemic events may arise secondary to many cardiac conditions, such as myocarditis [ ] . [ , , , ] , reduction of the permeability of alveolar epithelium and endothelium [ ] , improvement of alveolar fluid clearance [ ] , enhancement of macrophage phagocytosis [ ] , and tissue repair through direct mitochondrial transfer with host cells [ ] . apart from ali/ards, there have been several investigations using msc-derived evs as a potential therapy in the management of other lung diseases, such as bronchopulmonary dysplasia, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, and asthma, which have been recently revised in worthington [ ] and behnke [ ] . moreover, in these lung diseases, the most common effects of msc-derived evs were decreased inflammation and restoration of the lung architecture, achieved through the reduction of fibrosis and increase of vascularization and alveolarization. acute myocardial injury has been described as the most common cardiovascular complication in covid- patients [ ] . myocardial injury is defined as an elevation in serum levels of high-sensitive cardiac troponin (ctn) above the th percentile upper reference limit, although over the years it has also been identified through an increase in different cardiac enzymes and/or electrocardiographic abnormalities [ ] . the injury is considered acute if there is a dynamic rise and/or fall of ctn values. when acute myocardial injury is caused by myocardial ischemia, it is designated as acute myocardial infarction (ami). on the contrary, myocardial injury not related to ischemic events may arise secondary to many cardiac conditions, such as myocarditis [ ] . analyzing several reports from china, a considerable proportion of patients ( - . %) presented elevated ctn levels, and most of them required icus and showed higher in-hospital mortality [ , [ ] [ ] [ ] . the mechanisms of myocardial injury are not well established but likely involve direct or indirect processes and/or their combination (figure ) . myocardial infection by sars-cov- resulting in cardiomyocyte death and inflammation has been proposed as a possible direct mechanism, although, to date, there are no data demonstrating the presence of sars-cov- within myocardial tissue [ ] . nevertheless, a previous autopsy study in patients who died from sars identified the viral rna in % of the post-mortem human heart samples, providing evidence for direct myocardial injury by the virus [ ] . in addition, patients carrying sars-cov in their hearts died considerably earlier, suggesting that viral infiltration in the myocardium was associated with a more aggressive course of illness. systemic inflammatory response or respiratory failure and hypoxemia can represent indirect mechanisms leading to increased cardiac stress and myocardial inflammation [ , ] . in a couple of studies, biopsies taken from heart tissue of covid- patients evidenced mononuclear inflammatory infiltrates, mainly associated with regions of cardiomyocyte necrosis, which identifies myocarditis according to dallas criteria [ ] [ ] [ ] . nevertheless, acute lymphocyte infiltrates were not observed in the myocardium of sars-cov- -infected patient autopsy. died considerably earlier, suggesting that viral infiltration in the myocardium was associated with a more aggressive course of illness. systemic inflammatory response or respiratory failure and hypoxemia can represent indirect mechanisms leading to increased cardiac stress and myocardial inflammation [ , ] . in a couple of studies, biopsies taken from heart tissue of covid- patients evidenced mononuclear inflammatory infiltrates, mainly associated with regions of cardiomyocyte necrosis, which identifies myocarditis according to dallas criteria [ ] [ ] [ ] . nevertheless, acute lymphocyte infiltrates were not observed in the myocardium of sars-cov- -infected patient autopsy. other aspects of covid- in cardiac involvement include blood pressure abnormalities and arrhythmias, ranging from tachycardia and bradycardia to asystole [ ] . very recently, it has also been suggested that there is a link between sars-cov- infection and kawasaki disease (kd), especially in pediatric patients [ ] . although kd is a disease of unknown etiology, infections are considered to be one of the predisposing factors [ ] . the disease predominantly affects children under years of age and causes inflammation in the walls of medium-sized arteries, primarily the coronary arteries, those that supply blood to the heart muscle. consequences of ami are loss of cardiomyocytes and adverse remodeling of the extracellular matrix, which contribute to the reduction of pumping of the heart and further heart failure. nowadays, the best therapeutic strategy for reducing ami is timely and effective myocardial other aspects of covid- in cardiac involvement include blood pressure abnormalities and arrhythmias, ranging from tachycardia and bradycardia to asystole [ ] . very recently, it has also been suggested that there is a link between sars-cov- infection and kawasaki disease (kd), especially in pediatric patients [ ] . although kd is a disease of unknown etiology, infections are considered to be one of the predisposing factors [ ] . the disease predominantly affects children under years of age and causes inflammation in the walls of medium-sized arteries, primarily the coronary arteries, those that supply blood to the heart muscle. consequences of ami are loss of cardiomyocytes and adverse remodeling of the extracellular matrix, which contribute to the reduction of pumping of the heart and further heart failure. nowadays, the best therapeutic strategy for reducing ami is timely and effective myocardial reperfusion. however, this treatment induces oxidative stress and inflammation, thus leading to further cardiomyocyte death, myocardial remodeling, and decreased cardiac function, a phenomenon known as myocardial reperfusion injury [ ] . over the last years, management of ami using stem cell therapy was found to prevent myocardial cell apoptosis, promote local neoangiogenesis, and reduce the local inflammatory response [ ] [ ] [ ] . similarly to what was described above for lung injuries, the beneficial effect of stem cells seems to be largely attributable to the secreted evs. since the first description of the therapeutic potential of msc-derived exosomes in a mouse model of myocardial ischemia/reperfusion (i/r) injury in , several studies have subsequently reported cardio-protective effects of msc-derived evs in ami animal models (table ) [ ] . in one of these works, a single intravenous (iv) injection of msc-derived exosomes in a mouse ami model led to decreased infarct size, enhanced nicotinamide adenine dinucleotide (reduced form) (nadh) and atp levels, and reduced oxidative stress, which are hallmarks of reperfusion injury [ ] . all these events seemed to be associated with the exosome-mediated activation of the pro-survival phosphoinositide -kinase/protein kinase b (pi k/akt) signaling pathway, which resulted in an enhancement of myocardial viability and prevented adverse remodeling after myocardial i/r injury. importantly, intact but not lysed exosomes were responsible for the improved cardiac function after ami induction. another important mechanism by which msc-derived evs contribute to ischemic myocardial repair is through stimulation of neovascularization, as shown in the work of bian and colleagues [ ] . neovascularization refers to processes, such as vasculogenesis, angiogenesis, and arteriogenesis, that are associated with migration and proliferation of endothelial cells. in line with these findings, ma and coworkers also demonstrated that exosomes isolated from akt-transfected mscs accelerated angiogenesis in a rat myocardial infarction model [ ] . the authors suggested that platelet-derived growth factor d (pdgf-d), which was enriched in msc-derived vesicles, was mainly responsible for the akt exosome-mediated improvement of myocardial repair. a more recent study by xuan and colleagues identified notch as a potent modulator of angiogenesis and cardiomyocyte proliferation into ischemic mice hearts following coronary heart ligation [ ] . the role of notch signaling in inducing cardiac angiogenesis during ischemia and enhancing survival of cardiac cells is well established [ ] . the injection of msc-derived evs over-expressing notch intracellular domain (nicd) in ischemic myocardium led to decreased infarct size, improved cardiac function, and increased arteriole density in the peri-infarct area, month after ami [ ] . moreover, teng and coworkers indicated that the beneficial effect of msc-derived exosomes on infarcted rat hearts is mainly dependent on their angiogenesis-promoting activity [ ] . in their study, the authors proved that exosomes also act by restraining the inflammatory response. in agreement with the results of arslan and colleagues, they also demonstrated that fresh exosomes achieved a better therapeutic effect with respect to frozen exosome preparations. several studies agree that reduced fibrosis and apoptosis of myocardial cells are other important effects of the ev-mediated ischemic cardiac repair [ ] [ ] [ ] [ ] . in particular, zhao and coworkers showed that human umbilical cord msc-derived exosomes improved cardiac function and reduced cardiac fibrosis by preventing cardiomyocyte apoptosis and promoting cell proliferation in the border zone of infarcted rats [ ] . the effect mediated by exosomes was attributed to the up-regulation of the anti-apoptotic protein b cell lymphoma (bcl- ) in the myocardial cells. other works have proposed that specific functional mirnas contained into evs and shuttled to target injured cells are primarily responsible for the beneficial effects. for example, feng and colleagues found that mir- was up-regulated in msc-derived evs, and it possibly reduced cardiac apoptosis and fibrosis in an ami mouse model via inhibition of methyl cytosine-phosphate-guanine (cpg)-binding protein (mecp ) expression [ ] . in that study, the authors isolated evs from mscs subjected to ischemic pre-conditioning, which is an effective approach to potentiate survival and regeneration of these cells in an ischemic environment. yu and coworkers identified mir- a as the molecular mediator able to restore cardiac function and reduce infarct size in a rat model of ami [ ] . the cardio-protective role of mir- a was mediated by down-regulation of target genes, phosphatase and tensin homolog (pten), and bcl- interacting mediator of cell death (bim) in cardiomyocytes and subsequent activation of the akt and extracellular signal-regulated kinase (erk) signaling pathways. in their study, exosomes were isolated from mscs over-expressing gata binding protein (gata- ), a transcription factor able to regulate mirna expression in mscs and increase their survival in an ischemic environment [ ] . apart from observing reduced cardiac fibrosis and reduced inflammation in infarcted rat hearts days after exosome injection, shao and colleagues identified a panel of mirnas, which were similarly up-or down-regulated in mscs and the derived exosomes [ ] . on the other hand, other mirnas, such as mir- and mir- , resulted as being differentially expressed between exosomes and mscs, with this potentially explaining why msc-derived exosomes demonstrated superior beneficial effects when compared with treatment with their parent cells. several studies have demonstrated that autophagy also has an important role in mediating the therapeutic effects of msc-derived exosomes. autophagy is known to be an important mechanism in cardio-protection, and dysregulated autophagy is associated with a variety of cvd [ ] . in particular, it has been demonstrated that exosomes reduce apoptosis and the myocardial infarct size, as well as improve cardiac function by inducing cardiomyocyte autophagy both in vitro and in vivo [ , ] . collectively, the described studies documented reduction in infarct size with improved recovery of cardiac function, reduction of fibrosis and apoptosis, stimulation of angiogenesis, and decreased infiltration of macrophages and other immune cells into the injured heart regions following treatment with msc-derived evs (figure ) . when comparing the properties of exosomes recovered from different mscs sources, those isolated from adipose tissue samples exhibited the strongest cardio-protective effects [ ] . [ ] ischemia/reperfusion; left coronary artery; intravenous; glucogen synthase kinase- ; c-jun nterminal kinase; acute myocardial infarction; left anterior descending; platelet-derived growth factor d; cardiac mscs over-expressing notch intracellular domain; methyl cytosine-phosphateguanine binding protein ; b cell lymphoma ; phosphatase and tensin homolog; phosphatebuffered saline; microtubule-associated protein light chain beta. collectively, the described studies documented reduction in infarct size with improved recovery of cardiac function, reduction of fibrosis and apoptosis, stimulation of angiogenesis, and decreased infiltration of macrophages and other immune cells into the injured heart regions following treatment with msc-derived evs (figure ) . when comparing the properties of exosomes recovered from different mscs sources, those isolated from adipose tissue samples exhibited the strongest cardioprotective effects [ ] . [ , , ] , reduction of cardiac fibrosis, reduction of cardiomyocyte apoptosis [ , , , , ] , promotion of angiogenesis [ ] [ ] [ ] ] , and induction of cardiomyocytes autophagy [ ] . [ ] ischemia/reperfusion; left coronary artery; intravenous; glucogen synthase kinase- ; c-jun n-terminal kinase; acute myocardial infarction; left anterior descending; platelet-derived growth factor d; cardiac mscs over-expressing notch intracellular domain; methyl cytosine-phosphate-guanine binding protein ; b cell lymphoma ; phosphatase and tensin homolog; phosphate-buffered saline; microtubule-associated protein light chain beta. the recent coronavirus covid- global pandemic has driven the need for novel urgent therapies. mscs and their derivatives are being evaluated for the treatment of a number of diseases that currently have limited or no therapeutic options. msc-derived evs (exosomes and mvs) have recently attracted great attention because, similarly to their parent cells, they possess strong anti-inflammatory, immunomodulatory, and pro-angiogenic abilities, just to name a few. however, compared to mscs themselves, evs hold many biological and technological advantages. ev administration is considered safer than msc transplantation, lacking some of their negative side-effects, and they are more stable than mscs themselves, allowing for easier handling and storage. over the last years, a plenty of pre-clinical studies in animal models have demonstrated that the administration of msc-derived evs significantly reduced lung inflammation and pathological impairment subsequent to different types of lung injury, as well as resulted in improved cardiac function after acute myocardial injury. however, several challenges still need to be overcome to make the transition from animal models to humans possible. for example, standardized techniques for isolation, characterization, and quantification, as well as criteria for establishing dose, quality control, and storage conditions of msc-derived evs, are required before these can be advanced to the clinic. to date, it is difficult to compare and analyze studies employing msc-derived evs since there is a large degree of heterogeneity in ev preparations, and because msc-derived evs differ depending on tissues and donors from which the cells are isolated. regarding covid- , the lack of an established animal model of coronavirus-induced lung injury requires a more prudent and careful use of msc-derived evs. in this context, a significant issue is to establish under what circumstances and with what criteria to administer msc-derived evs. for example, which population among covid- patients to target and when to start ev administration. moreover, there remains the challenge to clarify the optimal route of ev administration that, in the case of lung diseases, mostly occurs through it instillation or iv injection, although the possibility of ev inhalation has recently been explored. to date, no studies have investigated the biodistribution and the in vivo metabolic fate of evs following it instillation. on the other hand, systemic iv injection has been shown to deliver evs primarily to the spleen and liver, then to the gastrointestinal tract and lungs, followed by renal and hepatic clearance in mice [ , ] . apart from the administration route, another major issue concerns the optimal ev therapeutic dose. considering that the average therapeutic dose of mscs for treating lung injuries is × cells/kg per body weight, the amount of cells required to generate enough evs to achieve the equivalent effect of mscs is generally - times higher [ ] . this necessitates large scale production of msc-derived evs. although this could be implemented with the use of bioreactors for msc expansion, different bioreactor culture conditions would result in alterations of ev content, which in turn may impact on the therapeutic efficacy. another challenge to consider for the administration of msc-derived evs to covid- patients is the need to manufacture a safe and reproducible therapeutic product. since the production of evs requires the use of living cells, these have to be cultured under good manufacturing practice (gmp)-compliant procedures to preserve the quality and safety standards criteria. therefore, ev production must follow the same rigorous scientific and ethical guidelines that apply to mscs, and any therapy based on msc-derived evs needs to be approved by the national regulatory agencies to demonstrate its safety and efficacy. in light of these observations, in our opinion, the use of msc evs could be contemplated to treat critically ill patients with ards requiring mechanical ventilation or icu support, or patients with recognized risk factors, such as pre-existing cvd, or cardiovascular complications, for whom standard therapeutic approaches have not proven resolutive. the authors declare no conflict of interest. a pneumonia outbreak associated with a new coronavirus of probable bat origin characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention coronavirus disease (covid- ) pandemic. available online high proportion of asymptomatic and presymptomatic covid- infections in travelers and returning residents to brunei evidence supporting transmission of severe acute respiratory syndrome coronavirus while presymptomatic or asymptomatic clinical features of patients infected with novel coronavirus in expanded umbilical cord mesenchymal stem cells (uc-mscs) as a therapeutic strategy in managing critically ill covid- patients: the case for compassionate use the use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the perspectives of clinical immunologists from china immune cell profiling of covid- patients in the recovery stage by single-cell sequencing does comorbidity increase the risk of patients with covid- : evidence from meta-analysis cardiovascular disease and covid- clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in inside the heart of covid- epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of coronavirus disease in china covid- and the cardiovascular system mesenchymal stem cells and management of covid- pneumonia clinical evidence does not support corticosteroid treatment for -ncov lung injury on the use of corticosteroids for -ncov pneumonia coronaviruses and the cardiovascular system: acute and long-term implications treatment for emerging viruses: convalescent plasma and covid- recommendations for investigational covid- convalescent plasma chinese clinical trial registry coronavirus disease (covid- ) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus infection tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis angiotensin converting enzyme : sars-cov- receptor and regulator of the renin-angiotensin system high expression of ace receptor of -ncov on the epithelial cells of oral mucosa the ace /angiotensin organ-protective effect of angiotensin-converting enzyme and its effect on the prognosis of covid- effect of angiotensin-( - ) on reperfusion arrhythmias in isolated rat hearts. braz cardioprotective effect in myocardial ischemia/reperfusion. hypertension chronic angiotensin-( - ) prevents cardiac fibrosis in doca-salt model of hypertension expression of an angiotensin-( - )-producing fusion protein produces cardioprotective effects in rats angiotensin-( - ) attenuates lung fibrosis by way of mas receptor in acute lung injury - ) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation the angiotensin-converting enzyme /angiogenesis-( - )/mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension angiotensin-converting enzyme protects from severe acute lung failure covid- ): do angiotensin-converting enzyme inhibitors/angiotensin receptor blockers have a biphasic effect? effect of angiotensin-converting enzyme inhibition and angiotensin ii receptor blockers on cardiac angiotensin-converting enzyme upregulation of angiotensin-converting enzyme after myocardial infarction by blockade of angiotensin ii receptors antihypertensive treatment with acei/arb of patients with covid- complicated by hypertension a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury sars-coronavirus modulation of myocardial ace expression and inflammation in patients with sars position statement of the esc council on hypertension on ace-inhibitors and angiotensin receptor blockers hfsa/acc/aha statement addresses concerns re: using raas antagonists in covid- human bone marrow stromal cells inhibit allogeneic t-cell responses by indoleamine , -dioxygenase-mediated tryptophan degradation nitric oxide plays a critical role in suppression of t-cell proliferation by mesenchymal stem cells therapeutic potential of autologous adipose-derived stem cells for the treatment of liver disease albumin-impregnated bone granules modulate the interactions between mesenchymal stem cells and monocytes under in vitro inflammatory conditions human bone marrow stromal cells suppress t-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific t cells to their cognate peptide mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex mesenchymal stem cells differentially mediate regulatory t cells and conventional effector t cells to protect fully allogeneic islet grafts in mice mesenchymal stem cells: mechanisms of inflammation bone marrow mesenchymal stem cells induce division arrest anergy of activated t cells mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase- and - mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide human mesenchymal stem cells alter antigen-presenting cell maturation and induce t-cell unresponsiveness effects of mesenchymal stromal cells on regulatory t cells: current understanding and clinical relevance antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide ll- harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease intravenous hmscs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein tsg- mitochondrial transfer between cells can rescue aerobic respiration mitochondrial transfer from mscs to t cells induces treg differentiation and restricts inflammatory response clinical remission of a critically ill covid- patient treated by human umbilical cord mesenchymal stem cells intrinsic immunity shapes viral resistance of stem cells ifitm-family proteins: the cell's first line of antiviral defense isolation and characterization of chicken lung mesenchymal stromal cells and their susceptibility to avian influenza virus respiratory syncytial virus-infected mesenchymal stem cells regulate immunity via interferon beta and indoleamine- , -dioxygenase harnessing the mesenchymal stem cell secretome for regenerative urology exosome: a novel approach to stimulate bone regeneration through regulation of osteogenesis and angiogenesis bioprocessing of mesenchymal stem cells and their derivatives: toward cell-free therapeutics pilot production of mesenchymal stem/stromal freeze-dried secretome for cell-free regenerative nanomedicine: a validated gmp-compliant process freeze-dried and gmp-compliant pharmaceuticals containing exosomes for acellular mesenchymal stromal cell immunomodulant therapy mesenchymal stem/stromal cell secretome for lung regeneration: the long way through "pharmaceuticalization" for the best formulation exosomal vaccines containing the s protein of the sars coronavirus induce high levels of neutralizing antibodies idf diabetes atlas: global estimates for the prevalence of diabetes for and pharmacologic approaches to glycemic treatment mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies covid- and diabetes covid- and diabetes: is there enough evidence? metabolic syndrome interferes with packaging of proteins within porcine mesenchymal stem cell-derived extracellular vesicles the metabolic syndrome modifies the mrna expression profile of extracellular vesicles derived from porcine mesenchymal stem cells the metabolic syndrome alters the mirna signature of porcine adipose tissue-derived mesenchymal stem cells metabolic syndrome induces release of smaller extracellular vesicles from porcine mesenchymal stem cells adipocyte-derived exosomal mirnas: a novel mechanism for obesity-related disease past and present ards mortality rates: a systematic review the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation the acute respiratory distress syndrome the acute respiratory distress syndrome ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice bone marrow stromal cells attenuate sepsis via prostaglandin e( )-dependent reprogramming of host macrophages to increase their interleukin- production allogeneic human mesenchymal stem cells for treatment of e. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung human mesenchymal stem cell microvesicles for treatment of escherichia coli endotoxin-induced acute lung injury in mice intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats keratinocyte growth factor protects against pseudomonas aeruginosa-induced lung injury keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by ang- mrna cell-based angiopoietin- gene therapy for acute lung injury mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury artificial mitochondria transfer: current challenges, advances, and future applications mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle micrornas super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtdna mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer high bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin- , interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis il- but not gm-csf correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice hyperbaric oxygen therapy improves the osteogenic and vasculogenic properties of mesenchymal stem cells in the presence of inflammation in vitro mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells acute lung injury edema fluid decreases net fluid transport across human alveolar epithelial type ii cells mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model swine models, genomic tools and services to enhance our understanding of human health and diseases current status of cell-based therapies for respiratory virus infections: applicability to covid- therapeutic use of extracellular vesicles for acute and chronic lung disease msc based therapies-new perspectives for the injured lung universal definition of myocardial infarction clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study cardiovascular implications of fatal outcomes of patients with coronavirus disease clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- and the heart cardiac and arrhythmic complications in covid- patients pathological findings of covid- associated with acute respiratory distress syndrome a pathological report of three covid- cases by minimally invasive autopsies myocarditis: the dallas criteria covid- and kawasaki disease: novel virus and novel case viral infections associated with kawasaki disease myocardial ischemia-reperfusion injury: a neglected therapeutic target potent endothelial progenitor cell-conditioned media-related anti-apoptotic, cardiotrophic, and pro-angiogenic effects post-myocardial infarction are mediated by insulin-like growth factor- intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction cardiac stem cell therapy to modulate inflammation upon myocardial infarction exosome secreted by msc reduces myocardial ischemia/reperfusion injury mesenchymal stem cell-derived exosomes increase atp levels, decrease oxidative stress and activate pi k/akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model exosomes derived from akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor d. stem cells transl extracellular vesicles from notch activated cardiac mesenchymal stem cells promote myocyte proliferation and neovasculogenesis. front notch signaling promotes angiogenesis and improves cardiac function after myocardial infarction mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting mecp via mir- exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury exosomes secreted from gata- overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic micrornas for cardioprotection mirna-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair enhanced mesenchymal stem cell survival induced by gata- overexpression is partially mediated by regulation of the mir- family novel therapies targeting cardioprotection and regeneration exosomes derived from mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via ampk and akt pathways bone marrow mesenchymal stem cell-derived exosomes protect against myocardial infarction by promoting autophagy exosomes derived from adipose tissue, bone marrow, and umbilical cord blood for cardioprotection after myocardial infarction extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- -fdnmeuh authors: tzotzos, susan j.; fischer, bernhard; fischer, hendrik; zeitlinger, markus title: incidence of ards and outcomes in hospitalized patients with covid- : a global literature survey date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: fdnmeuh nan systems and to inform critical care clinicians. this information should enable the prediction of requirements for hospital resources and thereby facilitate planning an appropriate and timely response in the future. we carried out regular searches of pubmed using combinations of the search terms "ards," "covid- ," "clinical characteristics," "clinical features," "clinical findings," "icu," "incidence," "outcome," and "prevalence" (last search july , ). over publications were retrieved from which only studies reporting consecutively hospitalized patients, and giving numbers for ards patients and outcomes, were selected. meta-analyses were excluded. seventeen studies reporting results from hospitalized covid- patients in five countries fitted the inclusion criteria (tables and ). limitations are that seven studies did not define ards and only one study classified patients as mild, moderate, and/or severe; the patient sample is comparatively small: twelve of the studies had less than patients. furthermore, there was heterogeneity in types of data gathered by each research group, hence for many of the studies, patient numbers did not permit calculation of all parameters (tables and ) . there is variability between individual studies with respect to frequency of ards, rates of icu admission, and mortality among patients. calculation of weighted averages for these parameters incorporating data from individual studies for which data is available indicate that among hospitalized covid- patients, approximately / ( %) develop ards, / ( %) require transfer to patient numbers for chen t study not included an icu, / ( %) receive imv, and / ( %) die (table ). for covid- patients transferred to an icu, nearly / ( %) receive imv and / ( %) have ards ( table ). the mortality rate of icu covid- patients is % and of those who receive imv %; the mortality rate in covid- -associated ards is %, and the incidence of ards among non-survivors of covid- is % ( table ). the high incidence of ards among covid- patients revealed in our survey is consistent with the results of postmortem examinations of patients with covid- , in which the predominant finding is diffuse alveolar damage, the most frequent histopathologic correlate of ards. for as long as there is neither a safe and efficacious vaccine nor therapy for severely affected covid- patients, standard supportive care with lung-protective mechanical ventilation will be the cornerstone of treatment for these patients [ , ] . the implications of these survey results are important and demonstrate the considerable challenges posed by the "covid- crisis" to icu practitioners, hospital administrators, and health policy makers. susan data generated or analyzed during this study are included in this published article. ethics approval and consent to participate not applicable all authors have approved the manuscript for submission. for study reference see table characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention mechanical ventilation in covid- : interpreting the current epidemiology risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china acute respiratory distress syndrome: the berlin definition covid- -associated acute respiratory distress syndrome: is a different approach to management warranted? treatment for severe acute respiratory distress syndrome from covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions sjt conducted the literature search and survey. sjt, bf, and hf evaluated and contributed to the interpretation and presentation of the data. sjt drafted the manuscript; bf, hf, and mz revised the final version of the manuscript. the authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -xenq xj authors: chen, hsing i title: acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations date: - - journal: j geriatr cardiol doi: . /sp.j. . . sha: doc_id: cord_uid: xenq xj acute lung injury (ali) or acute respiratory distress syndrome (ards) can be associated with various disorders. recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ali or ards caused by various disorders. this literature review includes a brief historical retrospective of ali/ards, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of no, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ali/ards. acute lung injury (ali) or acute respiratory distress syndrome (ards) is a serious clinical problem with high mortality. [ ] in animals and humans, ali can be induced by various causes such as brain injury, [ ] [ ] [ ] [ ] enterovirus, [ , ] japanese b encephalitis, [ ] and coronavirus. [ , ] the risk factors for ards included septicemia, acid aspiration, infection, traumatic injury, fat embolism, ischemia/ reperfusion, and other caused. [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our cardiopulmonary laboratory has carried out experimental studies and clinical investigations on ali and ards since . [ ] [ ] [ ] , , ] the purposes of this review article are: ( ) to describe in brief the historical perspective of ards and ali; ( ) to draw attention of an important clinical issue of neurogenic ali; ( ) to present the experimental studies and clinical investigations from our laboratory from to ; ( ) to elucidate the functional role of nitric oxide (no) and other mediators involved in the pathogenesis of ards/ali; ( ) to define the risk factors for ards and ali; and ( ) to discuss the pathogenetic mechanisms and therapeutic regimen for ards/ali. ali or pulmonary embolism (pe) has been reported in humans and animals with intracranial disorders such as head trauma, brain tumor, intracranial hypertension or cerebral compression. early studies in our laboratory demonstrated that acute pe of hemorrhagic and fulminant type occurred accompanying severe hypertension and bradycardia (cushing responses) in rats following cerebral compression (cc) or intracranial hypertension (ich). the lung pathology was characterized by intravascular congestion and disruption of pulmonary large and small vessels leading to severe alveolar hemorrhage (alveolar flooding). these changes was prevented by spinal transection, sympathectomy and sympathoadrenergic blocking agents, but was not affected by decerebration, adrenalectomy, vagotomy and atropine. these results suggest that sympathetic nervous system is pivotal in the neurogenic pe. brain areas above the medulla oblongata and parasympathetic nervous system play little role. [ ] a series of studies was carried out to elucidate the hemodynamic events involved in the neurogenic pe. in anesthetized rats, we measured the aortic and pulmonary blood flow and used techniques of right and left heart bypass. the imbalance in the right and left ventricular output was characterized by a rapid and dramatic decline in aortic flow accompanying a gradual decrease in pulmonary arterial flow. in rats with a right heart bypass, ich produced severe pulmonary hypertension and pe. in the left heart-bypassed rats, ich induced systemic hypertension, http://www.jgc .com; jgc@mail.sciencep.com | journal of geriatric cardiology whereas no significant changes occurred in the lungs. [ ] in anesthetized dogs with a total heart bypass preparation, ich produced constriction of the systemic and pulmonary resistance and capacitance vessels. [ ] [ ] [ ] [ ] the implications of these findings are: ( ) central sympathetic activation elicits increase in the systemic and pulmonary vascular resistance associated with decreases in vascular capacity in both circulations; ( ) the major cause of volume and pressure loading in the pulmonary circulation is acute left ventricular failure resulting in a marked decrease in aortic flow; and ( ) systemic venous constriction causes a shift of blood from the systemic to the pulmonary circulation ( figure ) . a schematic representation summarizes the neural and hemodynamic consequence caused by cerebral compression (figure ). spectral analysis of the aortic flow and pressure wave was employed to evaluate the hemodynamics of steady and pulsatile components. in anesthetized dogs, ich caused significant increases in characteristic impedance, pulse wave reflection and total peripheral resistance with decrease in arterial compliance and cardiac output. the ventricular work was elevated. [ ] clinical study in patients with head injury of various severities, analysis of the heart rate variability with frequency analysis revealed increased low frequency percentage, and low to high frequency ratio with decrease in high frequency. the findings indicate augmented sympathetic and attenuated parasympathetic drive. these autonomic functional changes were related to the severity of brain-stem damage. [ ] these two studies further support the contention that central sympathetic activation is involved in the cushing pressor response and consequent hemodynamic and autonomic alterations. in s, my associates and i were interested in the study of chest disorders. we developed an isolated perfused rat's lung in situ preparation ( figure ). previous method involved removing the isolated lungs from the body and placing the organ on a force-displacement transducer to record the changes in lung weight and these procedures were rather complicated and unstable. our in situ preparation does not require removing the lungs. instead, the isolated lungs were left in situ. the whole rat was placed in a scale platform to measure the change in body weight (bw). since the lungs are completely isolated from the body, the changes in bw reflect the lung weight (lw) changes. the preparation can be accomplished in min. we used a digital-analogue converter to transfer the weight change from the scale platform to a recorder. the lw thus could be continuously monitored during the experiment. in this model, we can obtain the lung weight gain, lw/bw ratio, the changes in pulmonary arterial, capillary and venous pressures, the microvascular permeability (capillary filtration coefficient, k fc ), protein concentration in bronchoalveolar lavage (pcbal), dye leakage, and exhaled nitric oxide (no). the concentration of nitrate/nitrite, methyl guanidine (an index for hydroxyl radical), proinflammatory cytokines [tumor necrosis factor α (tnf α ) and interleukin- β (il- β )] and other factors in the lung perfusate can also be detected. early animal experimentations investigated the pathogenesis, modulators and mediators involved in the ali induced by phorphol, air embolism, platelets, hypoxia, ischemia/reperfusion, endotoxin [lipopolysaccharide (lps)]. the major finding is that cyclooxygenase products of arachidonic acid, thromboxane a in particular is involved in the ali and pulmonary hypertension caused by phorbol, platelets and air embolism. [ , ] furthermore, we found that l-arginine and inhaled no enhanced the lung injury caused by air embolism, while blockade of no synthase (nos) with n ω -nitro-l-arginine methyl ester (l-name) attenuated the ali. [ ] the result suggests that no is also involved. during the summers from  , we encountered a total of children suffering from hand, foot, and mouth figure . isolated and perfused lung in situ preparation. the system consists of a perfusion pump with heat exchanger and a venous reservoir. the rat is artificially ventilated. pulmonary arterial pressure (pap) and venous pressure (pvp) are monitored with transducers. the whole rat is placed on a balance platform to record the body weight change. since the lung is isolated from the whole body, the change in body weight reflects the lung weight change. disease. [ ] chest radiography on admission revealed clear lung. however, out of cases developed severe dyspnea, hyperglycemia, leukocytosis, and decreased blood oxygen tension. arterial pressure (ap) and heart rate (hr) fluctuation ensued. spectral analysis of the ap and hr variabilities showed elevation in sympathetic activity at the onset of respiratory stress. thereafter, parasympathetic drive increased with declines in ap and hr. these children died within h after the onset of ards. before death, chest radiography revealed severe lung infiltration. similar to japanese b encephalitis, destruction of the medullary depressor area caused initial sympathetic activation. reversetranscriptase polymerase chain reaction (rt-pcr) found marked inos mrna expression in the lung parenchyma, suggesting inos may also be involved in the pathogenesis of ards in patients with enterovirus infection. furthermore, we have reported ards in patients with leptospirosis. [ ] in leptospirosis-induced ards, histochemical stain demonstrated spirochetes bacteria in the alveolar space. the pathology included alveolar hemorrhage, myocarditis, portal inflammation and interstitial nephritis. antigen retrieval immunohistochemical stain disclosed inos expression in the alveolar type cells, myocardium, hepatocytes and renal tubules. spectral analysis of ap and hr variabilities indicated decreased sympathetic drive with increased parasympathetic activity. the changes in autonomic functions led to severe hypotension and bradycardia. biochemical determinations suggested multiple organ damage. the pathogenesis of lung and other organ injury might also involve inos and no production. [ , ] in subjects with scrub typhus, orientia tsutsugamushi infection caused alveolar injury. marked inos expression was found in the alveolar macrophages with increase in plasma nitrate/nitrite, suggesting that no production from the alveolar macrophages accounts for the ali. [ ] the victim from rabies was a woman bitten by a wild dog. in addition to sign of hydrophobia, hypoxia, hypercapnia, hyperglycemia and increased plasma nitrate/nitrite were observed. the woman died of alveolar hemorrhage shortly after admission. [ ] recently, we encountered five cases with long-term malignancy. these subjects displayed signs of respiratory distress following an episode of hypercalcemia. two cases died of ards after the plasma calcium was increased above mmol/l. search of literatures revealed that holmes et al. [ ] reported a patient who died of ards following a hypercalcemia crisis caused by a parathyroid adenoma. we conducted animal experiments in whole rodent and isolated perfused rat's lungs. our results indicated that hypercalcemia (calcium concentration > mmol/l) caused severe ali in conscious rats and isolated lungs. immunohistochemical staining showed inos activity in the alveolar macrophages and epithelial cells. reversetranscriptase polymerase chain reaction (rt-pcr) found marked increase in inos mrna expression in lung parenchyma. hypercalcemia also increased nitrate/nitrite, methyl guanidine, proinflammatory cytokines and procalcitonin. pretreatment with calcitonin or l-n ( iminoethyl)-lysine (l-nil, an inos inhibitor) attenuated the hypercalcemia-induced changes. we proposed that hypercalcemia produced a sepsis-like syndrome. the ali caused by hypercalcemia may involve no and inos. [ , ] in addition to the aforementioned animal experimentations and clinical observations that no production through the inos may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (lps, endotoxin) provoked systemic hypotension, endothelial damage and ali accompanied by increased plasma nitrate/nitrite and expression of inos mrna, tnf α and il- β . the lps-induced changes were abolished by nonspecific and specific inos inhibitors such as n ω -monomethyl-l-arginine (l-nmma), l-name, aminoguanine and dexamethosone. [ ] this study suggested that no/inos, tnf α and il- β were involved in the endotoxemia-induced ali. generation of no from the activated neutrophil caused alveolar injury from smoke inhalation. [ ] experiments in many laboratories using specific inos inhibitors and/or inos-knockout animals have supported the contention that no/inos is responsible for the oxidative stress and endothelial damage in the ards/ali caused by endotoxin, ozone exposure, carrageenan treatment, hypoxia, acute hyperoxia, bleomaycin administration, acid aspiration and other causes. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our laboratory further provided evidence to suggest that the no/inos system is involved in the pathogenesis of ali caused by air embolism, [ ] fat embolism, [ ] [ ] [ ] ischemia/ reperfusion, [ ] [ ] [ ] oleic acid [ ] and phorbol myristate acetate. [ ] in these recent studies, various insults caused increase in nitrate/nitrite in plasma or lung perfusate, upregulation of inos mrna in lung parenchyma accompanied with elevation of proinflammatory cytokines such as tnf α , il- β and il- . lin et al. [ ] have suggested that an increase in inos mrna triggers the release of proinflammatory cytokines in septic and conscious rats. the inflammatory responses results in multiple organ damage including ali. inhibition of inos with s-methylisothiourea (smt) or l-nil attenuated the inflammatory changes, release of no and cytokines and prevented the organ dysfunction and ali. [ ] in animal experiments and clinical investigations, the risk factors causing ali/ards include head injury, intracranial hypertension, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] sepsis, [ , , , , , , , [ ] [ ] [ ] [ ] and infections. [ ] [ ] [ ] [ ] [ ] [ ] , , [ ] [ ] [ ] ] pulmonary embolic disorders journal of geriatric cardiology | jgc@mail.sciencep.com; http://www.jgc .com such as fat and air embolism are less common causes. [ , , , , [ ] [ ] [ ] ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as pulmonary artery thromboendarterectomy, thrombolysis after pulmonary embolism and lung transplantation. [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] gastric aspiration occurs frequently in surgical patients under anesthesia and other causes such as blunt thoracic trauma, impaired glottis competency, and pregnancy. [ , , ] it is one of the major causes of acute respiratory syndrome (ards). [ , ] intratracheal instillation of hydrochloric acid (hci) or gastric particles has been employed as experimental model of acute lung injury (ali). [ , [ ] [ ] [ ] in addition, amphetamine, phorbal myristate acetate, oleic acid have been employed for the induction of ali. [ ] [ ] [ ] [ ] [ ] phorbol myristate acetate (pma, -o-tetradecanoyl-phorbol- -acetate), an ester derivative from croton oil has been used to induce ali. [ , , , ] experiments in vivo and in vitro have demonstrated that pma is a strong neutrophil activator. [ ] [ ] [ ] [ ] activation and recruitment of neutrophil that lead to release of neutrophil elastase and other mediators may play an initial role in the pathogenesis of ali. [ , ] the oleic acid-induced ali has several clinical implications. first, the blood level of oleic acid was significantly elevated in patients with ards. [ , ] second, the proportion of oleic acid incorporated into surfactant phospholipids was also increased in patients with ards and sepsis. [ , ] these observations have provided evidence to suggest that serum level of oleic acid as a prediction or prognostic factor for ards. [ , ] early studies focused on the potential toxic effects of high oxygen fractions on inspired air. [ ] ventilator-induced ali was attributed to the deleterious effects on capillary stress due to alveolar overdistension. cyclic opening and closing of atelectatic alveoli during mechanical ventilation might cause lung injury and enhance the injured alveoli. recent evidence indicated that over distension coupled with repeated collapse and reopening of alveoli initiated an inflammatory cascade of proinflammatory cytokines release. [ , [ ] [ ] [ ] in spite of the risk factors and causes, the pathophysiology of ards/ali has generally considered to be initiated by formation of alveolar edema (even hemorrhage) that is enriched with protein, inflammatory cells or red blood cells. after damage of alveolar-capillary barrier, impairment of gas exchange occurs, with decrease in lung compliance and increases in dispersion of ventilation and perfusion and intrapulmonary shunt. hypoxia, reduction in arterial oxygen partial pressure to fraction of oxygen in inspired air pao /fio , hypercapnia ensued despite ventilation with high oxygen. [ , , , , , ] in addition to the potential toxic effects of no and free radicals, certain chemokines, cytokines, neutrophil elastase, myeloperoxidase and malondialdehyde have been shown to be associated with several types of ards/ali. [ , , , , [ ] [ ] [ ] the balance between proinflammatory and anti-inflammatory mediators is regulated by transcriptional factors mainly nuclear factor-Κ b (nf-Κ b). [ ] pulmonary fluid clearance and ion transport are important factors to determine the extent of lung edema. regulator factors include cystic fibrosis transmembrane conductance regulators, sodium-and potassium-activated adenosine triphophatase (na + -k + -atpase), protein kinases, aclenylate cyclase, and cyclic adenosine monophosphate (camp). [ , , , ] the treatment of ards/ali is difficult and complex. several review articles and monographs have addressed the issue of possible therapeutic regimen. the modalities include extracorporeal membrane oxygenation, prone position, mechanical ventilation with appropriate tidal volume and respiratory pressure, fluid and hemodynamic management and permissive hypercapnic acidosis. [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] other pharmacological treatments are anti-inflammatory and/or antimicrobial agents to control infection and to abrogate sepsis, adequate nutrition, surfactant therapy, inhalation of no and other vasodilators, glucocorticoids and other nonsteroid anti-inflammatory drugs, agents that accelerate lung water resolution and ion transports. [ , , [ ] [ ] [ ] [ ] [ ] although most animal experimentations on these pharmacological options showed favorable results, the effectiveness and outcomes in clinical studies or trials were conflicting. beta agonists to facilitate water removal and ion transport have been shown to be promising. these agents may also stimulate secretion of surfactant and have no serious side effects. there were several reports on the pharmacological and molecular actions of beta agonists, surfactant and vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme (ace). [ , , ] in addition to the experimental studies and clinical investigations on the pathogenesis of ali/ards, our laboratory has carried out several experimentations on the therapeutic regimen for this serious disorder. in conscious rats, regular exercise training attenuates septic responses such as systemic hypotension, increases in plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, creatinine, amylase, lipase, asparate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactic dehydrogenase, tnf α, and il β . exercise training also abrogates the cardiac, hepatic and pulmonary injuries caused by endotoxemia. [ ] insulin exerts anti-inflammatory effects on the ali and associated biochemical changes following intravenous administration of lipopolysaccharide (lps). [ ] propofol ( , -diisopropylphenol) has been commonly used for sedation in critically ill patients. [ ] this anesthetic has rapid onset, short duration and rapid elimination. [ ] propofol protects the anesthetized rats from ali caused by endotoxin. [ ] in conscious rats, oleic acid results in sepsis-like responses including ali, inflammatory reactions and increased in neutrophil-derived factors (neutrophil elastase, myeloperoxidase and malondialdehyde), nitrate/nitrite, methyl guanidine, inflammatory cytokines. it depresses the sodium-and potassium-activated atpase, but upregulates the inos mrna expression. pretreatment and posttreatment with propofol alleviates or reverses the oleic acid-induced lung pathology and associated biochemical changes. [ ] pentobarbital, an anesthetic agent commonly used in experimental studies and a hypnotic for patients improves the pulmonary and other organ functions following lps administration. it also increases the survival rate. [ ] a later study by yang et al. [ ] further revealed that pentobarbital suppressed the expression of tumor necrosis factor α , which might result from decrease in the activities of nuclear factor-κβ and activator protein and reduction in expression of p mitogen-activated protein kinase. in vivo examination of cytotoxic effects of lps disclosed that lps caused multiple organ dysfunctions. these changes were attenuated by pentobarbital. pentobarbital also reduced the cell aptosis caused by deforoxamine-induced hypoxia. nicotinamide or niacinamide (compound of soluble b complex) abrogates the ali caused by ischemic/reperfusion or endotoxin by mechanism through inhibition on poly (adp-ribose) synthase or permerase cytoxic enzyme and subsequent suppression of inos, no, free radicals and proinflammatory cytokines with restoration of adenosine triphosphate atp. [ , ] n-acetylcysteine, an antioxidant and cytoprotective agent with scavenging action on reactive oxygen species and inhibitory effects on proinflammatory cytokines ameliorated organ dysfunctions due to sepsis in conscious rats. [ , ] in a similar endotoxin-induced ali model, we found that n-acetylcysteine improved the lps-induced systemic hypotension and leukocytopenia. it also reduced the extent of ali, as evidenced by reductions in lung weight changes, exhaled no and lung pathology. in addition, n-acetylcysteine diminished the lps-induced increases in nitrate/nitrite, tnf α , and il β [ ] in isolated lungs, n-acetylcysteine attenuated the ali caused by phorbol myristate acetate. [ ] in a recent study, we reported that posttreatment with n-acetylcysteine prevented the ali caused by fat embolism. [ ] our series of experimental studies provided results in favor of n-acetylcysteine. the conflicting results and practice guidelines from clinical studies in the recommendation of n-acetylcysteine in critically ill patients [ , ] were commented and analyzed by molnár. [ ] the clinical application of results from animal studies requires further investigations. ards or ali is a serious clinical problem with high mortality. the risk factors leading to ali/ards include head injury, intracranial disorders, sepsis and infections. pulmonary embolic disorders such as fat and air embolism are less common causes. ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as lung transplantation. gastric aspiration occurs frequently in several conditions such as anesthesia, trauma and pregnancy. the ventilator-induced ali has been attributed to the deleterious effects on capillary stress due to alveolar overdistension. in experimental studies, phorbol myristate acetate and oleic acid have been employed to induce ali. the pathogenesis of ards/ali is complex. experimental studies and clinical investigations from our and other laboratories have indicated the detrimental role of nitric no through inducible no synthase (inos). activation and recruitment of neutrophils that lead to release of neutrophil elastase, myeloperoxidase, malondialdehyde and proinflammatory cytokines may play an initial role in the pathogenesis of ali/ards. the possible therapeutic regimen for ali/ards include extracorporeal membrane oxygenation, prone position, fluid and hemodynamic management and permissive hypercapnic acidosis etc. other pharmacological treatments are antiinflammatory and/or antimicrobial agents, inhalation of no, glucocorticoids, surfactant therapy and agents that facilitate lung water resolution and ion transports. adrenergic beta agonists are able to accelerate lung fluid and ion removal and to stimulate surfactant secretion. there are reports on the actions of vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme. our laboratory has reported experimental studies on the effectiveness of several regimen for ali/ards. in conscious rats, regular exercise training alleviates the endotoxin-journal of geriatric cardiology | jgc@mail.sciencep.com; http://www.jgc .com induced ali. propofol and n-acetylcysteine exert protective effect on the ali causes by endotoxin, oleic acid and phorbol myristate acetate. we have also provided evidence that insulin possesses anti-inflammatory effect. pentobarbital is capable of reducing the endotoxin-induced ali and associated changes. in addition, nicotinamide or niacinamide (soluble b complex) abrogates the ali caused by ischemia/ reperfusion or endotoxemia. these nonpharmacological and pharmacological therapeutic strategies require further investigations for clinical application. acute respiratory distress syndrome pulmonary edema and hemorrhage resulting from cerebral compression pulmonary edema and hemorrhage as a consequence of systemic vasoconstriction centrogenic pulmonary hemorrhagic edema induced by cerebral compression in rats. mechanism of volume and pressure loading in the pulmonary circulation clinical features and risk factors of pulmonary oedema after enterovirus- -related hand, foot, and mouth disease mechanism of fulminant pulmonary edema caused by enterovirus acute pulmonary oedema: rare causes and possible mechanisms a major outbreak of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada a novel coronavirus associated with severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport static inflation attenuates ischemia/reperfusion injury in an isolated rat lung in situ endotoxin-induced acute lung injury and organ dysfunction are attenuated by pentobarbital anaesthesia clinical and pathological features of fat embolism with acute respiratory distress syndrome effects of nitric oxide synthase inhibitor on acid aspiration-induced lung injury in rats nitric oxide in the cardiovascular and pulmonary circulation--a brief review of literatures and historical landmarks pathophysiological mechanism of lung injury in patients with leptospirosis nitric oxide in systemic and pulmonary hypertension neural and hemodynamic mechanisms of neurogenic pulmonary edema a scintiphotographic study of pulmonary edema and hemorrhage induced by cerebral compression and norepinephrine participation of regional sympathetic outflows in the centrogenic pulmonary pathology the cushing responses in the systemic and pulmonary circulation: the role of adrenal glands, bronchial circulation and pulmonary innervation systemic and pulmonary hemodynamic responses to intracranial hypertension effects of intracranial hypertension on steady and pulsatile haemodynamics in dogs sympathetic and parasympathetic activities evaluated by heart-rate variability in head injury of various severities cyclooxygenase pathway mediates lung injury induced by phorbol and platelets air embolism-induced lung injury in isolated rat lungs the involvement of nitric oxide and beta-adrenergic pathway signalling in pulmonary oedema and fluid clearance pulmonary pathology in patients associated with scrub typhus acute respiratory distress syndrome associated with rabies pulmonary oedema in hypercalcaemic crisis acute respiratory distress syndrome associated with hypercalcemia without parathyroid disorders the detrimental role of inducible nitric oxide synthase in the pulmonary edema caused by hypercalcemia in conscious rats and isolated lungs effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats role of neutrophils and nitric oxide in lung alveolar injury from smoke inhalation endogenous nitric oxide and the pulmonary microvasculature in healthy sheep and during systemic inflammation role of inducible nitric oxide synthase in endotoxin-induced acute lung injury effect of aminoguanidine on lung fluid filtration after endotoxin in awake sheep nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. possible role of interleukin- inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis effects of acute hypoxia and lipopolysaccharide on nitric oxide synthase- expression in acute lung injury pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase proinflammatory role of inducible nitric oxide synthase in acute hyperoxic lung injury inhibition or knock out of inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury nitric oxide modulates air embolism-induced lung injury in rats with normotension and hypertension niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin nitric oxide mediates acute lung injury caused by fat embolism in isolated rat's lungs n-acetylcysteine attenuates acute lung injury induced by fat embolism nitric oxide mediates lung injury induced by ischemia-reperfusion in rats inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion protective effects of propofol on acute lung injury induced by oleic acid in conscious rats the involvement of nitric oxide, nitric oxide synthase, neutrophil elastase, myeloperoxidase and proinflammatory cytokines in the acute lung injury caused by phorbol myristate acetate inducible nitric oxide synthase mediates cytokine release: the time course in conscious and septic rats edema and congestion of the lungs from intracranial hemorrhage pulmonary oedema and intracranial lesions increased intracranial pressure and pulmonary edema. . clinical study of patients the hemodynamic response of dogs and monkeys to increased intracranial pressure mechanisms of neurogenic pulmonary edema hemodynamic study of acute neurogenic pulmonary edema in children the lung is the major site that produces nitric oxide to induce acute pulmonary oedema in endotoxin shock n-acetylcysteine abrogates acute lung injury induced by endotoxin propofol exerts protective effects on the acute lung injury induced by endotoxin in rats physiological and chemical indicators for early and late stages of sepsis in conscious rats clinical year in review iii: asthma, lung transplantation, cystic fibrosis, acute respiratory distress syndrome the acute respiratory distress syndrome unravelling the fat embolism syndrome pulmonary embolism pulmonary reimplantation response in single-lung transplantation reperfusion pulmonary edema after pulmonary artery thromboendarterectomy aspiration pneumonitis and aspiration pneumonia reperfusion pulmonary edema after thrombolytic therapy of massive pulmonary embolism aspiration during anaesthesia: a computer-aided study of , anaesthetics clinical significance of pulmonary aspiration during the perioperative period improved survival of patients with acute respiratory distress syndrome (ards): - acute lung injury in the medical icu: comorbid conditions, age, etiology, and hospital outcome inhibition of acid-induced lung injury by hyperosmolar sucrose in rats surfactant alterations in acute inflammatory lung injury from aspiration of acid and gastric particulates evaluation of exogenous surfactant in hcl-induced lung injury free radicals mediate amphetamine-induced acute pulmonary edema in isolated rat lung effects of an endogenous nitric oxide synthase inhibitor on phorbol myristate acetate-induced acute lung injury in rats oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome? comparative effects of vaporized perfluorohexane and partial liquid ventilation in oleic acid-induced lung injury n-acetylcysteine attenuates the acute lung injury caused by phorbol myristate acetate in isolated rat lungs pentoxifylline rescue preserves lung function in isolated canine lungs injured with phorbol myristate acetate a novel oral neutrophil elastase inhibitor (ono- ) inhibits human neutrophil elastase-induced emphysema in rats pretreatment with fk improves survival rate and gas exchange in canine model of acute lung injury cepharanthin, an alkaloid from stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis neutrophils and acute lung injury neutrophils mediate acute lung injury in rabbits: role of neutrophil elastase an increase in serum c unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia bronchoscopic administration of bovine natural surfactant in ards and septic shock: impact on biophysical and biochemical surfactant properties pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. i. light microscopy ventilator-induced lung injury cellular stress failure in ventilator-injured lungs acute respiratory distress syndrome: a historical perspective the acute respiratory distress syndrome acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management leukocyte elastase: physiological functions and role in acute lung injury roles of neutrophil elastase and superoxide anion in leukotriene b -induced lung injury in rabbit chemokines in acute respiratory distress syndrome transcriptional mechanisms of acute lung injury alveolar epithelial fluid transport in acute lung injury: new insights mechanisms of pulmonary edema clearance perspective on lung injury and recruitment: a skeptical look at the opening and collapse story critical care in ajrccm alveolar recruitment in acute lung injury prone position augments recruitment and prevents alveolar overinflation in acute lung injury hypercapnic acidosis attenuates endotoxin-induced acute lung injury protective effects of hypercapnic acidosis on ventilator-induced lung injury permissive hypercapnia: role in protective lung ventilatory strategies hypercapnia via reduced rate and tidal volume contributes to lipopolysaccharide-induced lung injury permissive hypercapnia impairs pulmonary gas exchange in the acute respiratory distress syndrome nonventilatory treatments for acute lung injury and ards ventilatory management of acute lung injury and acute respiratory distress syndrome acute respiratory distress syndrome: pharmacological treatment options in development pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome inhaled nitric oxide therapy in adults exercise training attenuates septic responses in conscious rats vascular endothelial growth factor and related molecules in acute lung injury angiotensin-converting enzyme protects from severe acute lung failure insulin attenuates endotoxin-induced acute lung injury in conscious rats comparison of propofol and midazolam for sedation in critically ill patients an update of its use in anaesthesia and conscious sedation the reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model n-acetylcysteine ameliorates lipopolysaccharide-induced organ damage in conscious rats post-treatment with n-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats n-acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study antioxidant supplementation in sepsis and systemic inflammatory response syndrome n-acetylcysteine as the magic bullet: too good to be true experimental studies and clinical investigations were supported in part by grants from the "national science council". the grant no. this fiscal year is nsc - -b- - -my . the author is grateful to ms. s. y. huang for the assistance in typing an editing. i appreciate the long-term coworkers involved this and other studies in my laboratory. key: cord- -dep v pt authors: whyte, claire s; morrow, gael b; mitchell, joanne l; chowdary, pratima; mutch, nicola j title: fibrinolytic abnormalities in acute respiratory distress syndrome (ards) and versatility of thrombolytic drugs to treat covid‐ date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: dep v pt the global pandemic of coronavirus disease (covid‐ ) is associated with the development of acute respiratory distress syndrome (ards), which requires ventilation in critically ill patients. the pathophysiology of ards results from acute inflammation within the alveolar space and prevention of normal gas exchange. the increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. a consistent finding in ards is the deposition of fibrin in the air spaces and lung parenchyma. covid‐ patients show elevated d‐dimers and fibrinogen. fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. tissue factor (tf) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor (pai‐ ) from lung epithelium and endothelial cells create a hypofibrinolytic state. prophylaxis treatment of covid‐ patients with low molecular weight heparin (lmwh) is important to limit coagulopathy. however, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. in this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tpa), to treat covid‐ associated ards. tpa is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in phase ii clinical trial. nebulizer plasminogen activators may provide a targeted approach in covid‐ patients to degrade fibrin and improving oxygenation in critically ill patients. in early december multiple cases of pneumonia of unknown aetiology were reported in wuhan, hubei province, china [ ] [ ] [ ] . in january the world health organisation declared that this was caused by a new type of coronavirus, (sars-cov- ). the spread of sars-cov- has been exponential resulting in a global pandemic with more than two million confirmed cases. while most people with covid- develop only mild illness, characterised by a fever and continuous cough [ ] , approximately % develop severe disease that requires hospitalisation and oxygen support and % require admission to intensive care. covid- patients with respiratory distress present primarily with severe hypoxemia, yet respiratory system compliance can vary from near normal to exceptionally low [ ] . in severe cases, patients with covid- develop a type of acute respiratory distress syndrome (ards), sepsis and multiorgan failure. older age and co-morbidities are associated with higher mortality [ ] . a hallmark of ards is increased alveolar-capillary permeability triggered by exudation of fluid rich in cells and plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors [ , ] (figure ). this leads to recruitment of inflammatory leukocytes, including neutrophils [ ] alveolar macrophages [ ] , monocytes and platelets, which propagate the local inflammatory response [ ] . fibrin deposition in the air spaces and lung parenchyma, are consistently observed with ards and contributes to hyaline-membrane formation and subsequent alveolar fibrosis [ ] [ ] [ ] [ ] . this promotes the development and progression of respiratory dysfunction and right heart failure [ ] . fibrin deposition is the net result of an alteration in the balance of the coagulation and fibrinolytic pathways, and several therapeutic strategies have been explored to target the dysfunction of these systems in ards [ ] [ ] [ ] [ ] . recent case studies describe fibrin deposits in biopsies of lung tissue from patients with covid- [ , ] , with ards commonly reported [ , ] . consistent with this large numbers of infiltrating immune cells have been found in covid- positive lung tissues, particularly monocytes and macrophages, [ , [ ] [ ] [ ] alongside the formation of fibrin, [ , , ] proteinaceous hyaline membranes and pulmonary fibrosis [ , ] . ct scans of covid- patient's lungs reveal characteristic ground glass opacities (gco), indicating partial filling of the bronchoalveolar airspace with exudate [ , ] . the timing of the accidental sampling in the covid- patients with lung cancer suggests these early fibrin lung depositions present prior to clinical symptoms of pneumonia [ ] . therefore, biomarkers to allow early identification of these changes would be highly beneficial in early diagnosis and timely treatment of covid- patients. this review will focus on the molecular mechanisms and role of inflammatory cells in underpinning fibrin deposition and persistence in the lungs of critically ill covid- patients and discuss potential therapeutic strategies to help support these patients. this article is protected by copyright. all rights reserved sequestration of leukocytes, particularly neutrophils, within the microvasculature of the lung is central to the development of ards, leading to a massive insult to the alveolar-capillary membrane, unrestricted inflammation and microthrombus formation (reviewed by [ ] ). neutrophils, resident alveolar macrophages and monocyte-derived macrophages, as well as recruited monocytes, infiltrate the lungs, enhance lung injury, and play a key role in the pathogenesis of ards [ ] [ ] [ ] [ ] . release of proinflammatory cytokines, including macrophage inflammatory protein (mip- ), interleukin (il- ), interleukin- (il- ), interleukin- (il- ) and tumour necrosis factor  (tnf-), encourage ongoing infiltration of immune cells from the intravascular compartment to the alveolar airspaces [ ] [ ] [ ] . indeed, these proinflammatory cytokines are used as biomarkers of ards and have been suggested to be important in progression of covid- associated ards [ ] . accumulation of coagulation factors in the lungs can also drive ards through the activation of proteaseactivated receptors (pars) which are expressed on cells in the lungs including alveolar epithelial cells, fibroblasts, monocytes and macrophages [ , ] . par signalling induced by tissue factor, coagulation factor xa, factor viia or thrombin can augment fibrosis in addition to driving fibrin generation. fibrosis is characterised by fibroblast migration, proliferation and deposition of collagen in the intra-alveolar spaces. par- can be acted upon in fibroblasts by both thrombin and factor xa to promote their proliferation, induce production of pro-collagen and amplify expression of various growth factors including connective tissue growth factor (ctgf) [ , ] . par signalling can enhance inflammation in acute lung injury (ali) by increasing the expression of pro-inflammatory cytokines, including il- [ ], il- , [ ] [ ] [ ] and platelet derived growth factor [ ] . accumulation of neutrophils in the lungs further contributes to the pathophysiology of ards [ ] . neutrophils release their dna alongside their nuclear and cytoplasmic contents into the extracellular environment during the cell death process, netosis. these web like cellular extrusions, termed neutrophil extracellular traps (nets) form a scaffold of chromatin decorated with cytoplasmic and granule proteins and histones. nets play a role in the fight against invading pathogens. however, if not tightly regulated, nets can contribute to the pathogenesis of non-infectious diseases where they can exacerbate coagulation and inflammation [ ] and have recently been reported as a contributing player in the pathogenesis of ards and ali where they cause further damage to the lungs [ , ] . net production has accepted article been identified in the lungs during ards, where levels of nets are greatly increased in the bronchoalveolar lavage (bal) of both ards patients and mouse models of induced ali and ards [ , [ ] [ ] [ ] . increased nets correlate with the severity of ards [ , ] and disease severity is reduced in mouse models when nets are degraded using dnase [ ] . a hypercoagulable state exists in the lungs of ards patients, leading to the deposition of fibrin in the intra-alveolar space [ ] (figure ). inflammation modulates coagulation by activating c-reactive protein (crp), thereby augmenting tissue factor exposure on monocytes and alveolar macrophages [ , ] which in turn promote thrombin generation and deposition of fibrin. hepatic synthesis of fibrinogen, an acute phase protein, is increased - -fold in plasma during infection [ ] and local synthesis in the lung epithelium is evident during pneumonia [ ] thereby further exacerbating fibrin deposition. fibrin deposition augments inflammation and fibrosis as well as damaging lung surfactant [ , , ] . this is coupled with a hypofibrinolytic state in the alveolar space, where fibrinolytic inhibitors have been shown to be elevated. levels of thrombin activatable fibrinolysis inhibitor (tafi) and protein c inhibitor were found to be significantly elevated in the bronchoalveolar fluid of patients with interstitial lung disease when compared to healthy controls [ ] . furthermore, it has been reported that α -macrogloblin levels are increased in obstructive lung disease, which may correlate with the increase in plasminogen observed in the bal of ards patients [ , ] . however, the principal fibrinolytic inhibitor described in the pathogenesis of ards is plasminogen activator inhibitor (pai- ), which is known to be elevated in severe acute respiratory syndrome coronavirus (sars-cov) and ali [ , ] . in ards, crp promotes local release of pai- from endothelial cells [ , ] . additionally, infiltration of platelets, the major circulating pool of pai- , may result in local release. we have recently shown that a significant amount of this active pai- remains associated with the stimulated platelet membrane [ , ] . attenuation of the plasminogen activation system leads to abnormal turnover of fibrin in the alveolar space. plasma pai- levels have been reported as an independent risk factor for poor prognosis and mortality in ali [ , , , [ ] [ ] [ ] [ ] . prabhakaran et al [ ] reported a significant increase in pai- antigen and activity in plasma and the edema fluid in ali, with evidence of significant pulmonary production [ ] . a clear role for pai- as a prognostic marker in ards was confirmed by a prospective observational study this article is protected by copyright. all rights reserved which demonstrated -fold higher levels in patients who progressed to ards than those with uncomplicated aspiration pneumonitis ( vs. ng/ml, respectively) [ ] . importantly, a hypofibrinolytic state and increased pai- was observed in the sars-cov epidemic in and [ ] . gralinski et al used a non-biased systems biology approach to study the dysfunctional fibrinolytic pathway in an infection model of sars-cov [ ] . fibrin persistence was mediated by overexpression of pai- which overcomes local upa and tissue-type plasminogen activator (tpa) [ ] . sars-cov infected cells contain high levels of tgf-β , which in turn stimulates expression of extracellular matrix protease inhibitors, including pai- [ ] which has been specifically linked to ards induced by sars-cov [ ] . these studies illustrate a clear role for pai- in the aetiology of ards and suggest it is a key protein contributing to abnormal turnover of fibrin in the alveolar space. plasma pai- has been reported as a potential biomarker for predicting disease progression in ali to ards, with one study concluding that pai- antigen > ng/ml was a % positive predictor for mortality [ ] . similar pathology of fibrin depositions in the lungs has been identified in covid- [ , ] , suggesting pai- may be a useful prognostic marker for patients at risk of developing ards and thus requiring critical care and ventilation. a common finding with covid- patients requiring hospitalisation is increased levels of d-dimers and and fibrin degradation products (fdp) which are associated with a higher risk of mortality [ ] . prothrombin time and activated partial thromboplastin time show a mild elongation [ ] . coupled with the fact critically ill covid- patients will be immobilised, there is an increased risk of hospital-associated venous thromboembolism (vte) [ ] . these findings have led to a recent recommendation for prophylactic anticoagulant therapy with low molecular weight heparin (lmwh) for patients hospitalised with covid- , without contraindications, to limit the extent of the coagulopathy [ , ] . heparin treatment (both unfractionated and lmwh) reduces inflammatory biomarkers [ ] , and therefore may be beneficial in reducing the inflammatory state in covid- this article is protected by copyright. all rights reserved anticoagulant therapy is essential to limit ongoing fibrin deposition and microthrombi formation in ards and treat the systemic prothrombotic complications in these patients. however, lmwh will be ineffective in clearing fibrin clusters deposited in the alveolar space. there is therefore a requirement to readdress the balance of fibrinolysis in the lung, either by enhancing plasminogen activation or downregulating fibrinolytic inhibitors. the significant increase in pai- in ards and ali curtails local upa, but also tpa, activity [ , , , ] . in a pig model of trauma, administration of tpa or upa prevented development of ards, with animals displaying normal pao [ ] . a phase clinical trial revealed a significant improvement in pao at hours in out of patients with severe ards secondary to trauma or sepsis following administration of upa or streptokinase [ , ] . these patients had a pao of less than mmhg, usually considered fatal, which increased to . mmhg following thrombolytic therapy with an overall % survival rate and no incidence of bleeding [ ] . the use of tpa to treat ards in covid- patients has recently been proposed by moore et al [ ] . an initial case report from patients from the current sars-cov- pandemic, demonstrates a transient improvement in p/f ratio in cases and sustained % improvement in case following administration of a mg bolus of intravenous tpa followed by a further mg infusion [ ] . the authors suggest that there is a precedent for increasing the dose of the bolus of tpa whilst maintaining heparin infusion, as the anticoagulant is effective against submassive pulmonary embolism [ , ] . in addition to readdressing the fibrinolytic balance, administration of tpa to ards patients may confer anti-inflammatory effects, as it has been shown to suppress neutrophil activation in a rat model of ali induced by il- α [ ] . a major consideration in anticoagulant or thrombolytic therapy is the undesirable complication of bleeding. in respiratory medicine, treatments are often delivered as aerosolised protein therapeutics as diffusion of proteins from the blood to the lungs can be limited [ ] . interestingly, nebulised anticoagulant therapy with antithrombin or heparin has been shown to reduce lung injury without an increase in systemic bleeding in animal models [ ] [ ] [ ] and ali patients [ ] . however, as discussed, heparin will prevent further fibrin deposition but will be ineffective in the removal of pre-existing fibrin. a recent publication compared the efficacy of the nebulised form of the plasminogen activator, streptokinase and nebulised heparin in the treatment of ards [ ] . the primary outcome in this trial was the change in pao /fio ratio, which was significantly higher in the streptokinase group from day to day , compared to the heparin and standard-of-care groups. importantly, icu mortality was significantly lower in streptokinase patients compared to other groups [ ] . a case report [ ] describes a young woman with ards who was resistant to conventional therapeutics and was treated with nebulised and intravenous tpa, followed by continuous treatment with nebulized unfractionated heparin. the patient this article is protected by copyright. all rights reserved stabilized following fibrinolytic treatment and demonstrated a significant enhancement in pulmonary gas exchange. plastic bronchitis is a condition that can develop from several respiratory disorders, resulting in casts of compacted mucous that have been shown to contain fibrin [ ] . plastic bronchitis is primarily observed in children and has been described in cases of influenza a (h n ) [ , ] and human bocavirus [ ] . nebulised tpa has been shown to be effective in preventing recurrent cast formation in plastic bronchitis [ ] . reports thus far are from single case studies, however, there is an ongoing phase ii clinical trial of nebulised tpa (platypus; alteplase, nct ) for treatment of plastic bronchitis. these data clearly indicate that use of nebulised fibrinolytics could allow a more targeted approach to correct the haemostatic imbalance that results in fibrin deposition, while limiting the risk of systemic activation of fibrinolysis that may trigger unwanted bleeding ( figure ). inhaled tpa is absorbed into the vasculature thus increasing fibrinolytic capacity in the plasma [ ] and the potential to lyse the microthrombi observed in covid- patients. however, it is conceivable that intravenous infusions of tpa may be necessary to disperse larger thrombi in the circulation. a potential caveat of a nebulizer formulation is that aerosolised proteins are susceptible to degradation so the formulation and excipient used must be considered [ ] . however, in the case of tpa, an extreme advantage is that a formulation of nebulised alteplase has been developed and is currently being tested in a phase ii clinical trial [ ] . the covid- global pandemic has necessitated a demand for novel therapeutics to limit the complications of ards and/or reduce the burden on ventilatory support in intensive care units. the indication that fibrin deposits occur prior to symptoms [ ] of the disease, suggests that targeting the fibrinolytic system to promote fibrin resolution could limit severity and improve pulmonary function. given the urgent time scale of the clinical requirement, repurposing of existing therapies, such as nebulised tpa, to promote fibrin dissolution in the lung and improve oxygenation is a pragmatic approach in addressing the ards complications associated with covid- . this article is protected by copyright. all rights reserved outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle bin cao. clinical features of patients infected with novel coronavirus in wuhan alimuddin zumla, eskild petersen. the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china covid- does not lead to a "typical" acute respiratory distress syndrome clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy lung parenchyma remodeling in acute respiratory distress syndrome pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. a study in mechanically ventilated patients nf-kappab regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome the role of macrophages in the pathogenesis of ali/ards accepted article this article is protected by copyright. all rights reserved depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome intravascular coagulation associated with the adult respiratory distress syndrome pathophysiology of acute lung injury and the acute respiratory distress syndrome the acute respiratory distress syndrome tissue plasminogen activator (tpa) as a novel treatment for refractory covid- associated acute respiratory distress syndrome (ards)? j trauma acute care surg anticoagulant therapy in acute lung injury emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia--a review bench to bedside: targeting coagulation and fibrinolysis in acute lung injury immunostaining in the lung of a patient with covid- pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan pathological findings of covid- associated with acute respiratory distress syndrome zhonghua bing li xue za zhi = chinese journal of pathology zhonghua bing li xue za zhi = chinese journal of pathology radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study acute respiratory distress syndrome high levels of interleukin- in the blood and alveolar spaces of patients with pneumonia and adult respiratory distress syndrome phenotypic characterization of alveolar monocyte recruitment in acute respiratory distress syndrome pulmonary macrophage subpopulations in the induction and resolution of acute lung injury role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ali subsequent to septic challenge inhibition of alveolar neutrophil immigration in endotoxemia is macrophage inflammatory protein independent interleukin- and development of adult respiratory distress syndrome in at-risk patient groups relative production of tumour necrosis factor alpha and interleukin in adult respiratory distress syndrome tissue factor-dependent coagulation protease signaling in acute lung injury proteinase-activated receptors in fibroproliferative lung disease thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor- factor xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via par activation accepted article this article is protected by copyright. all rights reserved activation of protease-activated receptor (par)- , par- , and par- stimulates il- , il- , and prostaglandin e release from human respiratory epithelial cells tissue factorfactor viia-specific up-regulation of il- expression in mda-mb- cells is mediated by par- and results in increased cell migration activation of protease-activated receptor (par)- , par- , and par- stimulates il- , il- , and prostaglandin e release from human respiratory epithelial cells thrombin stimulates production of interleukin- in human umbilical vein endothelial cells factor xa is a fibroblast mitogen via binding to effector-cell protease receptor- and autocrine release of pdgf neutrophil extracellular traps in immunity and disease maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury neutrophil extracellular traps (nets) are increased in the alveolar spaces of patients with ventilator-associated pneumonia extracellular traps are elevated in patients with pneumonia-related acute respiratory distress syndrome neutrophil extracellular traps contribute to the pathogenesis of acid-aspiration-induced ali/ards alteration of surfactant function due to protein leakage: special interaction with fibrin monomer therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome diagnostic and prognostic utility of tissue factor for severe sepsis and sepsis-induced acute lung injury serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome acute phase reactants in inflammation and infection induction of fibrinogen expression in the lung epithelium during pneumocystis carinii pneumonia surfactant incorporation markedly alters mechanical properties of a fibrin clot fibroblast migration in fibrin gel matrices thrombinactivatable fibrinolysis inhibitor and protein c inhibitor in interstitial lung disease alpha -macroglobulin in patients with obstructive lung disease, with and without alpha -antitrypsin deficiency local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury elevated levels of plasminogen activator inhibitor- in pulmonary edema fluid are associated with mortality in acute lung injury pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome functional plasminogen activator inhibitor is retained on the activated platelet membrane following platelet activation plasminogen associates with phosphatidylserine-exposing platelets and contributes to thrombus lysis under flow accepted article this article is protected by copyright. all rights reserved increased plasminogen activator inhibitor- concentrations in bronchoalveolar lavage fluids are associated with increased mortality in a cohort of patients with pseudomonas aeruginosa bronchoalveolar levels of plasminogen activator inhibitor- and soluble tissue factor are sensitive and specific markers of pulmonary inflammation alveolar plasminogen activator inhibitor- predicts ards in aspiration pneumonitis plasminogen activator inhibitor (pai- ) predict a poor prognosis in clinical acute lung injury expression of elevated levels of proinflammatory cytokines in sars-cov-infected ace + cells in sars patients: relation to the acute lung injury and pathogenesis of sars severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with smad and modulates transforming growth factor-beta signaling abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated intravascular coagulation of patients infected with covid- anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy isth interim guidance on recognition and management of coagulopathy in covid- anti-inflammatory effects of heparin and its derivatives: a systematic review haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis the severe acute respiratory syndrome coronavirus a protein up-regulates expression of fibrinogen in lung epithelial cells accepted article this article is protected by copyright. all rights reserved a major outbreak of severe acute respiratory syndrome in hong kong extravascular coagulation and fibrin deposition in acute lung injury coagulation, fibrinolysis, and fibrin deposition in acute lung injury prevention of adult respiratory distress syndrome with plasminogen activator in pigs a brief overview of acute respiratory distress syndrome treatment of severe acute respiratory distress syndrome: a final report on a phase i study tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism tissue plasminogen activator (tpa) inhibits interleukin- induced acute lung leak heuze-vourc'h n. designing inhaled protein therapeutics for topical lung delivery: what are the next steps? effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies streptokinase versus unfractionated heparin nebulization in patients with severe acute respiratory distress syndrome (ards): a randomized controlled trial with observational controls inhalation/intravenous recombinant tissue plasminogen activator and inhaled heparin in a patient with acute respiratory distress syndrome management of plastic bronchitis with nebulized tissue plasminogen activator: another brick in the wall plastic bronchitis in three children associated with influenza a(h n ) virus infection bronchial casts and pandemic (h n ) virus infection human bocavirus dna detected in a boy with plastic bronchitis meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury with thanks to wai-lum sum from medical illustration at the university of aberdeen with help in compiling figure of the manuscript. njm and pc conceived the idea. csw, gbm, jlm and njm all wrote and edited the manuscript. this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved key: cord- - oo vnq authors: byrne, j. d.; shakur, r.; collins, j.; becker, s. l.; young, c. c.; boyce, h.; traverso, c. title: prophylaxis with tetracyclines in ards: potential therapy for covid- -induced ards? date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: oo vnq there is an immediate need for therapies related to coronavirus disease (covid- ), especially candidate drugs that possess anti-inflammatory and immunomodulatory effects with low toxicity profiles. we hypothesized the application of pleiotropic tetracyclines as potential therapeutic candidates. here, we present a retrospective multi-institutional cohort study evaluating ventilatory status in patients who had taken a tetracycline antibiotic within a year prior to diagnosis of acute respiratory distress syndrome (ards). the primary outcomes were the need for mechanical ventilation and duration of mechanical ventilation. the secondary outcome was the duration of intensive care unit (icu) stay. data was evaluated using logistic regression and treatment effects regression models. minocycline or doxycycline treatment within a year prior to ards diagnosis was associated with a % reduced likelihood for mechanical ventilation during hospital stay. furthermore, tetracycline antibiotic therapy corresponded to significant reductions in duration of mechanical ventilation and icu stay in ards patients. these data suggest tetracyclines may provide prophylactic benefit in reducing ventilatory support for ards patients and support further evaluation in a randomized prospective trial. severe acute respiratory syndrome coronavirus (sars-cov- ) is the causative agent of the covid- disease. one of the most significant clinical pathologies attributable to sars-cov- are its effects on the pulmonary system, with critical cases progressing to hypoxemic respiratory all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint of failure and the development of ards [ , ] . to date, there remains no substantive therapy for ards, and management continues to be largely supportive [ ] . given the immediate need for therapies related to covid- , especially candidate drugs which possess demonstrated antiinflammatory and immunomodulatory effects with low toxicity profiles, we hypothesized the application of the pleiotropic tetracyclines as potential therapeutic candidates. tetracyclines have demonstrated potent anti-inflammatory effects in addition to their antibacterial properties, including inhibition of t-cell proliferation and reduction of inflammatory cytokines, and have been used in the treatment of human immunodeficiency virus and malaria [ ] . however, tetracyclines relative efficacy in ards patients remains undetermined. in this retrospective multi-institutional cohort study, we aimed to assess whether prophylactic use of either minocycline, doxycycline, or tetracycline could reduce the concomitant requirement for ventilatory support and duration of icu stay among ards patients. minocycline (p = . ) or doxycycline (p = . ) treatment within a year prior to ards diagnosis was associated with a % reduced likelihood for mechanical ventilation during hospital stay (figure , a) . similarly, treatment effects regression modeling indicated that minocycline (p = . ), doxycycline (p = . ), and tetracycline (p < . ) therapy corresponded to significant reductions in duration of mechanical ventilation in ards patients. duration of icu stay for patients who were previously administered minocycline (p = . ) or tetracycline (p = . ) was significantly reduced (figure , b) . of the three tetracycline antibiotics studied, there was no significant effect in timing of administration compared to diagnosis of ards, except for doxycycline (figure , c) . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint our results proffer the potential for tetracyclines to provide prophylactic benefit in reducing ventilatory support and duration of icu stay for ards patients. despite the retrospective nature and small sample size, we envisage implications for prophylactic tetracycline therapy in patients with ards secondary to covid- . the temporal relationship with tetracycline antibiotics' conditioning of the immune system has been previously demonstrated in numerous clinical settings, including multiple sclerosis, rheumatoid arthritis, major depressive disorder, and inflammatory bowel disease [ ] [ ] [ ] [ ] [ ] . our findings are further supported by known anti-inflammatory and anti-viral effects of these antibiotics through mechanisms including downregulation of cd ligand on t-cells, induction of apoptosis in mast cells, and reduction in metalloproteases through zinc chelation [ ] . coronaviruses rely on metalloproteases for viral proliferation, and appear to increase mast cell proliferation in the respiratory submucosa, thus contributing to the local inflammation of lung tissue [ ] . as tetracycline antibiotics are well tolerated and orally bioavailable, randomized prospective trials should be possible to further test their efficacy as a prophylactic therapy, specifically in patients at risk for the sars-cov- infection and development of ards. we performed a retrospective -year cohort analysis using the partners healthcare research patient data registry to identify patients diagnosed with ards to yield a total of , patients. from these patients, we then identified a subset of , , and patients who had taken minocycline, doxycycline, and tetracycline, respectively, within a year prior to diagnosis of ards all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july , . table ). these patients were compared to a control dataset of patients diagnosed with ards that had not taken these antibiotics within a year of diagnosis. analyses were performed using a logistic regression model to estimate the adjusted odds ratios (aor) and confidence intervals (ci) to measure association between treatment (minocycline, doxycycline, or tetracycline within a year prior to ards diagnosis) and outcome of mechanical ventilation. covariates including comorbid conditions, age, sex, smoking status, date of diagnosis, and immunosuppression, were adjusted in the model. furthermore, we used treatment effects regression models to estimate the regression coefficient for the effect of minocycline, doxycycline, and tetracycline on the outcome of mechanical ventilation and duration for both mechanical ventilation and icu stay. the effect of timing of these drugs compared to the diagnosis of ards were also compared. these models incorporated propensity score matching for age, sex, immunosuppression status, comorbid conditions, smoking status, and date of diagnosis. appropriate institutional review board approval (# p ) was granted by the partners review board. informed consent was waived due to the retrospective nature of the research. further, all methods were performed in accordance with the relevant partners review board guidelines and regulations. clinical characteristics of coronavirus disease in china risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease understanding a heterogeneous syndrome minocycline attenuates hiv infection and reactivation by suppressing cellular activation in human cd + t cells trial of minocycline in a clinically isolated syndrome of multiple sclerosis the clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study minocycline in active rheumatoid arthritis minocycline alters behavior, microglia and the gut microbiome in a traitanxiety-dependent manner immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution all rights reserved. no reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint of all rights reserved. no reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted july , . competing interests: there is no competing interest.additional information: availability of data and materials: the authors declare that the data supporting the findings of this study are available within the paper and its supplementary information files. ethics approval and consent to participate: appropriate institutional review board approval (# p ) was granted by the partners review board. informed consent was waived due to the retrospective nature of the research. all rights reserved. no reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted july , . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity.the copyright holder for this preprint this version posted july , . . https://doi.org/ . / . . . doi: medrxiv preprint key: cord- -npfoircv authors: blair, robert v.; vaccari, monica; doyle-meyers, lara a.; roy, chad j.; russell-lodrigue, kasi; fahlberg, marissa; monjure, chris j.; beddingfield, brandon; plante, kenneth s.; plante, jessica a.; weaver, scott c.; qin, xuebin; midkiff, cecily c.; lehmicke, gabrielle; golden, nadia; threeton, breanna; penney, toni; allers, carolina; barnes, mary b.; pattison, melissa; datta, prasun k.; maness, nicholas j.; birnbaum, angela; fischer, tracy; bohm, rudolf p.; rappaport, jay title: acute respiratory distress in aged, sars-cov- infected african green monkeys but not rhesus macaques date: - - journal: am j pathol doi: . /j.ajpath. . . sha: doc_id: cord_uid: npfoircv sars-cov- induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. among those persons with serious covid- disease, acute respiratory distress syndrome (ards) is a common and often fatal presentation. animal models of sars-cov- infection that manifest severe disease are needed to investigate the pathogenesis of covid- induced ards and evaluate therapeutic strategies. here we report ards in two aged african green monkeys (agms) infected with sars-cov- that demonstrated pathological lesions and disease similar to severe covid- in humans. we also report a comparatively mild covid- phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged agms and four rhesus macaques (rms) infected with sars-cov- . we found dramatic increases in circulating cytokines in three of four infected, aged agms but not in infected rms. all of the agms showed increased levels of plasma il- compared to baseline, a predictive marker and presumptive therapeutic target in humans infected with sars-cov- infection. together, our results show that both rm and agm are capable of modeling sars-cov- infection and suggest that aged agms may be useful for modeling severe disease manifestations including ards. sars-cov- induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. among those persons with serious covid- disease, acute respiratory distress syndrome (ards) is a common and often fatal presentation. animal models of sars-cov- infection that manifest severe disease are needed to investigate the pathogenesis of covid- induced ards and evaluate therapeutic strategies. here we report ards in two aged african green monkeys (agms) infected with sars-cov- that demonstrated pathological lesions and disease similar to severe covid- in humans. we also report a comparatively mild covid- phenotype characterized by minor clinical, radiographic and histopathologic changes in the two surviving, aged agms and four rhesus macaques (rms) infected with sars-cov- . we found dramatic increases in circulating cytokines in three of four infected, aged agms but not in infected rms. infection with sars-cov- and the development of covid- is accompanied by a mild respiratory disease for most individuals. however, a small subset progress to develop severe respiratory disease which, in some cases, is fatal . the most severely affected individuals often present with a fever, cough, dyspnea, and bilateral radiographic opacities that, in the majority of critically ill patients, progresses to acute respiratory distress syndrome (ards) . the onset of ards is often associated with an increase in circulating pro-inflammatory cytokines often referred to as a "cytokine storm" , . worsening of disease can be seen in the context of declining viral loads and markedly elevated cytokines suggesting a role for these inflammatory responses in disease progression and immunopathology . research into the causes and mechanisms of the most severe manifestations of covid- is needed to facilitate the development of prophylactic and therapeutic approaches that can prevent this life-threatening outcome. nonhuman primates (nhps) are ideally suited to model respiratory human viral infections because of the similarities to human respiratory anatomy and immunologic responses when compared to other animal species. several nhp species have been successfully employed to model pathogenesis - and test vaccine candidates [ ] [ ] [ ] [ ] for sars-cov- . these prior studies have shown nhps are susceptible to infection and develop mild to moderate disease, but none has been able to recapitulate the rapid clinical deterioration seen in people with severe disease and ards. age is a well-established risk factor for severe disease and death in humans infected with sars-cov- , , ; therefore, older rm and agms were challenged with sars-cov- j o u r n a l p r e -p r o o f via two routes (aerosol and mulitroute) to see if a similar more severe disease phenotype was observed in aged cohorts after aerosol exposure. this report describes the sudden and rapid health deterioration of two out of four aged agms experimentally infected with sars-cov- . the two affected animals developed ards, and elevated circulating cytokines similar to the complications reported in - % of covid- patients . the institutional animal care and use committee of tulane university reviewed and approved all the procedures for this experiment. the tulane national primate research center is fully accredited by the aaalac. all animals were cared for in accordance with the ilar guide for the care and use of laboratory animals th edition j o u r n a l p r e -p r o o f animals and procedures a total of eight animals, four aged (≈ years of age), wild-caught agm ( m, f) and four, adult ( - years of age) rm ( m, f) were used in this study. animals (n= ) were exposed to sars-cov- either by small particle aerosol or multiroute combination. the animals (agm , agm , rm , rm ) were exposed by aerosol and received an inhaled dose of approximately x tcid . the other four animals (agm , agm , rm , rm ) were exposed by inoculating a cumulative dose of . x pfu through multiple routes (oral, ml; nasal, ml; intratracheal, ml; conjunctival, µl per eye). animals were observed for days including twice daily monitoring. pre-and postexposure samples included blood, csf, feces, urine, bronchioalveolar lavage, and mucosal swabs (buccal, nasal, pharyngeal, rectal, vaginal, and bronchial brush). blood was collected at postexposure days - , , (aerosol) or (multiroute), , , , and at necropsy. csf, feces, urine, bronchioalveolar lavage, and mucosal swabs were collected at post exposure days - , , , , and at necropsy. physical exam, plethysmography, and imaging (radiographs and pet/ct) occurred days prior to exposure and then weekly thereafter. animals were euthanized for necropsy after three weeks post exposure, or when humane end points were reached. samples from the left anterior and caudal lung lobes were collected fresh and in media for further processing. all right lung lobes were infused and stored in fixative for microscopic evaluation. the remainder of the necropsy was performed routinely with collection of tissues in media, fixative, or fresh frozen. pulmonary pathology was scored using two separate random forest tissue segmentation algorithms trained by a veterinary pathologist in an unblinded fashion to recognize fibrin and j o u r n a l p r e -p r o o f edema and cellular inflammation using halo software (indica labs, albuquerque, nm). tissue sections from each of the right lung lobes was segmented using the trained algorithms to quantify the percentage of tissue effected by fibrin and edema or cellular inflammation. the percentage of inflammation was converted to a pathology score based on the following scoring system: fibrin and edema score = - %, = - %, = - %, = - %, => % and cellular inflammation score = - . %, = . - %, = - %, = - %, => %. the "histopathology score" was made by summating the fibrin and edema and cellular inflammation scores for each lobe. the reaction master mix were added using an x-stream repeating pipette (eppendorf, hauppauge, ny) to the microtiter plates which were covered with optical film (cat. # ; thermo fisher), vortexed, and pulse centrifuged. the rt-qpcr reaction was subjected to rt-qpcr a program of, ung incubation at °c for minutes, rt incubation at °c for minutes, and an enzyme activation at °c for minutes followed by cycles of a denaturing step at °c for seconds and annealing at °c for seconds. heatmaps were generated using the 'pheatmap' package in r . data were normalized by dividing raw values at week and necropsy by baseline values for each animal, followed by the application of log . values below the limit of detection were replaced with the lowest limit of detection value based on the standard curve for each run, or with the lowest value detected during the run, whichever was smaller. polar coordinate plots were generated using the 'ggplot ' package in r , using the same normalized data shown in the heatmap. scatterplots were drawn using raw data points and display pearson's correlation coefficients. serum samples collected at preinfection and weekly post-infection were tested for binding igg antibodies against sars-cov- s /s proteins using an elisa kit from xpressbio (cat# four, aged, agms and four rm, thirteen to fifteen years of age, were exposed by two routes to sars-cov- isolate usa-wa / . four animals (agm , agm , rm , rm ) were exposed via small particle aerosol and four animals (agm , agm , rm , rm ) were exposed via multiple route installation (table ) . sars-cov- rna was detectable in swabs obtained from mucosal sites in all eight animals ( figure ). the highest levels of viral rna were detected in the pharynx and nasal cavity (figure , b and c). rectal swabs contained high viral rna loads similar to reports in humans ( figure f figure s ). the day prior ( -and dpi) all animals underwent a complete physical evaluation and an extensive sample collection protocol including fluid, stool, swab, and bronchial brush collection, no remarkable findings were noted at that time in any of the animals. in the hours following sample collection ( dpi for agm and dpi for agm ) both animals developed mild tachypnea that progressed to severe respiratory distress that included dyspnea, tachypnea, hypothermia, and an spo of % (supplemental figure s ). no significant clinical findings were observed in any of the remaining animals after dpi. thoracic radiographs for agm and agm revealed a diffuse alveolar pattern throughout the right lung fields and a lobar sign in the caudal dorsal lung field. in agm the left caudal lung lobe also contained a mild alveolar pattern. these findings were in stark contrast to the radiographs from the day before highlighting the rapid disease progression (figure , a and b ). rm had a focal pulmonary scar in the right caudal lung lobe surrounded by acute hemorrhage (supplemental figure s e ). the lungs of the remaining animals (agm , rm , rm , and rm ) were grossly normal. histopathologic findings in the lungs of agm and agm were similar and characterized by alveoli that were filled with fibrin, hemorrhage, and proteinaceous fluid ( figure a ). alveoli were multifocally lined by hyaline membranes and/or type ii pneumocytes, consistent with diffuse alveolar damage ( figure b ). alveoli contained rare multinucleated syncytial cells j o u r n a l p r e -p r o o f ( figure c ). fluorescent immunohistochemistry identified low numbers of sars-cov- infected cells in agm , but not agm . (figure d ). the animals that survived to study endpoint exhibited minimal to mild interstitial inflammation (supplemental figure s and s ) . three out of four rhesus macaques (rm , rm , and rm ) had microscopic evidence of aspiration pneumonia characterized by foreign plant material within bronchioles. histopathologic lesions in other tissues were mild and interpreted as not significant in all eight animals (supplemental table s ). a group of cytokines similar to those observed in human covid- was upregulated in the two animals that progressed to ards (agm and agm ) at the time of necropsy compared to baseline levels ( figure a and supplemental figure s . apart from the severe phenotype observed in two of the animals, our findings are otherwise consistent with prior studies with the surviving agms showing mild clinical disease, pathology, and prolonged viral shedding , . the rms in our study also exhibited mild clinical disease and pathology with shorter viral shedding from mucosal sites compared to the agms. these findings show that even in the absence of severe disease both agm and rm have utility for testing sars-cov- vaccines and therapeutics two of the agms in our study developed widespread radiographic opacities and severe respiratory distress (sp %) that progressed over a -hour period. taken together with the postmortem findings of diffuse alveolar damage and no evidence of congestive heart disease, these findings are consistent with a diagnosis of ards in both agm and agm . of note, both of the animals that developed ards did so within hours following routine sampling procedures which included anesthesia and bronchoalveolar lavage. it has been our experience that these procedures are well tolerated, and procedure-related complications are exceedingly rare (fatal complication within -hours of procedure after of , procedures in animals ranging from - years of age, unpublished data). furthermore, agm and agm previously underwent the same routine sampling procedures one and three times (respectively) without j o u r n a l p r e -p r o o f complication. in our previous experience fatal complications have only occurred in animals that were severely debilitated at the time of the procedure and even in these rare cases the pathologic lesions were distinct (no evidence of diffuse alveolar disease) from the two agms reported herein. therefore, in our experience, routine sampling procedures do not cause the severe covid- phenotype observed in agm and agm , even in the rare cases where fatal complications occur. further, dramatic increases in plasma cytokines compatible with cytokine storm were found in the aged agms that progressed to ards. proinflammatory cytokines including tnfα, il- β, il- , il- , g-csf, mcp- , and mip- have been shown to be elevated during the acute phases of acute lung injury (ali) . in human covid- , circulating il- has been shown to correlate with radiographic abnormalities of pneumonia . indeed, overexpression of several of these cytokines were observed in both animals that progressed to ards. this differed from the cytokine profile in the agms and rms that reached study endpoint. interestingly, at dpi all four agms had increased levels of ifnγ, with the two agms that progressed having the highest plasma concentration. thus, elevated ifnγ in plasma could be explored as a potential predictive biomarker for advanced disease in people. several factors may have contributed to the severe disease phenotype observed in the agms in our study. age , weight , and sex , have been identified as potential predisposing factors for developing severe disease in humans. all of the agms included in our study were aged, with an estimated age of years old. both animals that progressed to severe disease were also female j o u r n a l p r e -p r o o f and low weight. this differs from what is reported in covid- patients in which male gender , and obesity have been shown to have a higher prevalence of severe disease. the agms used in this infection study were also imported from nondomestic sources and although the animals were housed for months at the tnprc and deemed clinically healthy at the time of initiation of the study, there may have been historical factors that predisposed them to enhanced covid- disease. this study demonstrates that following exposure to sars-cov- aged agms develop a spectrum of disease, from mild to severe covid- , which in some cases progress to ards. the cytokine expression profile in the two animals that developed ards is similar to that seen in the severe human disease phenotype. our data suggest that both rm and agm are capable of modeling mild manifestations of sars-cov- infection and that aged agms may additionally be capable of modeling severe disease manifestations including ards. characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology coronavirus pathogenesis cross rw: establishment of an african green monkey model for covid- sars-cov- infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species respiratory disease in rhesus macaques inoculated with sars-cov- sars-cov- infection of african green monkeys results in mild respiratory disease discernible by pet/ct imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts comparative pathogenesis of covid- , mers, and sars in a nonhuman primate model development of an inactivated vaccine candidate for sars-cov- dna vaccine protection against sars-cov- in rhesus macaques an alphavirus-derived replicon rna vaccine induces sars-cov- neutralizing antibody and t cell responses in mice and nonhuman primates disparities in age-specific morbidity and mortality from sars-cov epidemiological, clinical characteristics of cases of sars-cov- infection with abnormal imaging findings prevalence and severity of corona virus disease (covid- ): a systematic review and meta-analysis committee for the update of the guide for the care and use of laboratory animals national research council: guide for the care and use of laboratory animals severe acute respiratory syndrome coronavirus from patient with coronavirus disease, united states the automated bioaerosol exposure system: preclinical platform development and a respiratory dosimetry application with nonhuman primates pheatmap: pretty heatmaps. r package version wickham h: ggplot : elegant graphics for data analysis detection of sars-cov- in different types of clinical specimens temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study clinical features of patients infected with novel coronavirus in local inflammatory responses following bronchial endotoxin instillation in humans obesity study g: high prevalence of obesity in severe acute respiratory syndrome coronavirus- (sars-cov- ) requiring invasive mechanical ventilation sex-and gender-specific observations and implications for covid- gender differences in patients with covid- : focus on severity and mortality we would like to acknowledge natalie thornburg at the ncird for her help acquiring and characterizing the viral stock used in this infection study. key: cord- -m rnze authors: chen, yuntian; wang, yi; zhang, yuwei; zhang, na; zhao, shuang; zeng, hanjiang; deng, wen; huang, zixing; liu, sanyuan; song, bin title: a quantitative and radiomics approach to monitoring ards in covid- patients based on chest ct: a retrospective cohort study date: - - journal: int j med sci doi: . /ijms. sha: doc_id: cord_uid: m rnze rationale: acute respiratory distress syndrome (ards) is one of the major reasons for ventilation and intubation management of covid- patients but there is no noninvasive imaging monitoring protocol for ards. in this study, we aimed to develop a noninvasive ards monitoring protocol based on traditional quantitative and radiomics approaches from chest ct. methods: patients diagnosed with covid- from jan , to mar , were enrolled in this study. quantitative and radiomics data were extracted from automatically segmented regions of interest (rois) of infection regions in the lungs. ards existence was measured by pa /fi < in artery blood samples. three different models were constructed by using the traditional quantitative imaging metrics, radiomics features and their combinations, respectively. receiver operating characteristic (roc) curve analysis was used to assess the effectiveness of the models. decision curve analysis (dca) was used to test the clinical value of the proposed model. results: the proposed models were constructed using ct images from patients. the median age was , and the male proportion was . %. the training dataset and the validation dataset were generated by randomly sampling the patients with a : ratio. chi-squared test showed that there was no significant difference in baseline of the enrolled patients between the training and validation datasets. the areas under the roc curve (aucs) of the traditional quantitative model, radiomics model and combined model in the validation dataset was . , . and . , respectively. accordingly, the sensitivities were . , . and . , while the specificities were . , . and . . the dca curve showed that when threshold probability for a doctor or patients is within a range of to . , the combined model adds more net benefit than “treat all” or “treat none” strategies, while the traditional quantitative model and radiomics model could add benefit in all threshold probability. conclusions: it is feasible to monitor ards from ct images using radiomics or traditional quantitative analysis in covid- . the radiomics model seems to be the most practical one for possible clinical use. multi-center validation with a larger number of samples is recommended in the future. the coronavirus disease (covid- ) caused by novel coronavirus sars-cov- has been spreading rapidly in the world [ , ] . compared with the previous respiratory epidemics, there are some new characteristics of covid- and new patient management challenges. for instance, studies ivyspring international publisher indicated that covid- patients could be asymptomatic and highly contagious in the early stage, resulting in difficulty for early diagnosis [ , ] . fortunately, since the disease outbreak, there a good few early diagnosis models on covid- were published [ , ] . some studies indicated that computed tomography (ct) findings might be earlier than the symptom onset in covid- patients [ ] , and hence ct imaging had become a major complementary tool for diagnosis and assessment of covid- [ ] . however, there were still a lot that radiologists could do in covid- management, such as monitoring of the disease progression or prediction of the patients' prognosis. one of the challenges in treatment of covid- is how to decrease the mortality rate and improve treatment outcome. acute respiratory distress syndrome (ards) is the major cause of severe cases, and early detection and early treatment of ards patients could improve the outcome [ , ] . however, it is a tough task for clinicians to be conscious of early ards existence in covid- because there could be no symptom deterioration or abnormalities of laboratory tests before the mild ards existence [ ] . the most reliable way to overcome this difficulty is to perform arterial gas blood analysis frequently, which was the gold standard of the ards diagnosis, but the arterial puncture was an invasive procedure and could cause extra risk for complications. ards is caused by the injury of alveolar-capillary membrane [ ] , which could result in imaging feature changes captured using quantitative analysis from chest ct images [ ] . therefore, it is possible to use the traditional quantitative chest ct metrics, such as volume and density to monitor the existence of ards. however, to our knowledge, no studies have used quantitative results to monitor the ards in covid- , while few quantitative results were used in some diagnosis models [ ] . it should be noted that computing the aforementioned quantitative changes is not trivial by traditional methods. radiomics method thus is ideal to be used in this situation for extracting rich image features. such kind of method refers to extracting a large number of imaging features in the high-content manner, and use high-dimensional feature selection and classification methodologies for analyzing the relationship between imaging features and clinical factors [ ] . radiomics methods have been successfully applied in various applications including some infectious diseases [ ] [ ] [ ] [ ] [ ] . however, there is no radiomics-based study for early detection of ards in covid- patients. in this study, we use quantitative data analysis of chest ct images to detect the existence of ards during the covid- treatment. the imaging data were analyzed by traditional and radiomics approaches, respectively, and their performances were validated and compared using the datasets collected from our hospital. all covid- patients treated in chengdu public health center between jan , and mar , were enrolled in our study. the diagnosis of covid- was based on a positive result highthroughput sequencing or real-time reversetranscriptase-polymerase-chain-reaction (rt-pcr) assay of nasal and pharyngeal swab specimens [ ] . after collecting the ct imaging and clinical management data, a subset of patients were excluded according to the following criteria: (i) age < yearsold; (ii) incomplete medical records; (iii) cases with no arterial blood analysis result corresponding to respective ct images. the research protocol was approved by the appropriate ethics review board of our hospital, and patient informed consent form was waived because only anonymized data were used, and no diagnosis and treatment for patients has been altered due to this retrospective study. clinical data, such as age, sex, arterial blood analysis results and the numbers of comorbid were obtained from the medical records. the comorbid diseases included: copd, hypertension, hyperlipemia, cerebral infarction, coronary heart disease, cardiac dysfunction iii-iv, liver dysfunction, diabetes, chronic kidney disease and, malignant tumor. the ards existence was measured by the result of arterial blood analysis. if the pa /fi of the artery was < , the patient was considered as with ards. non-contrast chest ct examinations were performed for each patient when their doctors deemed it was necessary to assess their respiratory status. ct examination was prohibited when the patient could not get rid of the ventilator. details of ct scanning were provided in supplementary materials (table s ). qualitative assessment was performed by two independent radiologists after each ct examination, including the change of volumes, density and location of lesions. infection regions were segmented by a pulmonary pneumonia-dedicated multi-task deep learning algorithm, trained by using over multi-center ct scans (united imaging intelligence) based on vb-net [ ] . its accuracy was tested by two expert radiologists with years (zixing huang) and years (bin song) experience in chest ct interpretation. more detailed information of segmentation algorithm was shown in the supplementary material (table s ) . the following traditional quantitative metrics were calculated to quantify infectious regions of the image of each patient: the entire pipeline for the traditional quantitative covid- extraction was shown in figure . a two-step logistic regression was performed to explore the relationship between traditional quantitative metrics and ards existence. first, a univariable logistic regression was performed on all clinical and quantitative imaging features. then a multivariable logistic regression was performed on factors whose p value < . in the first regression. finally, a linear combination of the above significant factor was applied to build a traditional quantitation predictive model. the radiomics workflow is presented in figure . rois were the same regions used for traditional quantitative assessment, which were segmented automatically. texture extraction was performed using pyradiomics in python . . all radiomics features were based on image biomarkers standardization initiative (ibsi). in summary, imaging features were extracted from individual ct, including first-order features, shape features, glrlm features, gldm feautures, glszm features, glcm features and ngtdm features. radiomics features were all normalized by standardscaler in both datasets. then, a two-step high-dimensional data reduction was performed. first, minimum redundancy and maximum correlation of feature selection (mrmr) was performed to eliminate the redundant and irrelevant features, and features were retained. then, the least absolute shrinkage and selection operator (lasso) logistic regression algorithm was applied to choose the optimized subset of features to construct the final model. a linear regression was performed by combination of selected features that were weighted by their respective lasso results. a risk score, called radiomics score was calculated by the formula for each patient to refer the risk of ards existence. a radiomics model was constructed based on the radiomics score. finally, a combination of quantitation and radiomics model was constructed based on the multivariable regression result of the selected quantitative variable and radiomics scores. the predictive performance of the constructed models was assessed by roc, where auc was calculated for the quantification in both training set and validation sets. also, dca was performed by calculating the net benefits for a range of threshold probabilities in the training and validation sets. continuous variables were reported as the mean (standard deviation) or median (interquartile range [iqr] ). student's t-test or mann-whitney u test was used to compare between-group differences (presence and non-presence of primary composite endpoints) based on distributions. categorical variables were presented as n (%) and compared using chi-square (χ ) test or fisher's exact test. the lasso logistic regression model was performed with penalty parameter tuning, which was conducted by -fold cross-validation by minimum criteria. back-ward step-down selection was applied to the multivariable model. all statistical tests were performed using r statistical software version . . . "mrmre" package was used for the mrmr reduction; "glmnet" package was used for the lasso logistic regression; "proc" package was used for roc curves plotting; "dac.r" package was used for dac analysis. statistical significant was considered when a two-sided p < . . totally, covid- patients were enrolled in our study. patients were excluded due to age < . patients were excluded because of incomplete medical records. finally, patients were included in their study. there were ct scans for these patients, and ct scans had corresponding arterial blood gas analysis results. the median age of patients was (iqr: . - . ), male proportion was . % ( / ). among these patients, . % ( / ) patients were mild, patients were severe and . % ( / ) patients were transferred into icu. the median time from symptom onset to admission was days (iqr: - days). the median number of cts during the admission was ( ) ( ) ( ) . the most common initial symptom was fever ( . %, / ) and cough ( . %, / ). the most common comorbidity was hypertension ( / , . %). the detail of patients characterize was shown in table . among ct scans, . % ( / ) were shown to have ards existence at that moment. qualitative assessment showed that . % of ct results were better than the previous ones, while . % ct images showed significant deterioration of infection. quantitative assessment of ct showed the mean infectious proportion of the lung was . ± . %. the mean density of infection regions was - . ± . hu. the largest component of the infection region was zone (hu < - ), which composed . ± . % of infection region among all patients on average. the mean infection area proportion of inner zone of lung was . % ± . %, while the mean proportion of peripheral zone of lung was . % ± . %. more information on the area proportion of different density interval region could be achieved in table . Χ test was applied to all clinical data to assess the distribution of each factor in mild group and severe group. the factor with p value< . was put into further logistic regression. the χ result showed that male proportion (p= . ), chronic kidney disease (p= . ), coronary heart disease (p= . ), cardiac dysfunction (p= . ), copd (p= . ), and hypertension (p = . ) met the above criteria. a multiple variable backward step logistic regression was applied to all traditional metrics with all the above including clinical variables. the regression result showed that male (p= . ), existence of hypertension (p= . ), total infection proportion (p< . ), age (p= . ) and area proportion of zone (ct value > hu) were significantly related to the ards existence. the regression result was visualized in figure . the training sets and validation sets were generated by random sampling from the ct image cohort with a ratio of : .the χ test showed that there was no difference (χ < . , p-value= . ) of the number of ards existence case in train sets ( / ) and validation sets ( / ). there was no difference between training sets and validation sets (table s ) . a total of imaging features were extracted from each ct image. after mrmr reduction and lasso regression, features were selected to calculate the radiomics score (figure ) . the details of radiomics score calculation method were demonstrated in the supplementary material. the wilcoxon test showed that the distribution of radiomics score was significantly different in both training sets and validation sets (figures & ) . age, total volume, area proportion of zone and radiomics score were selected to construct the combined model. the auc in training set of quantitation model, radiomics model and combined model was . , . and . respectively, while the auc of the above three models in validation sets was . , . and . , respectively (figure ). the radiomics model had the highest accuracy ( . % in training sets and . % in validation sets) and sensitivity ( . % in training sets and . % validation sets), while the combined model had the highest specificity ( . % in training sets and . % in validation sets). delong's test showed there was no difference in auc between every two of roc. more information on each model was demonstrated in table . the dca curve showed that when threshold probability for a doctor or patients is within a range of to . , the combined model adds more net benefit than "treat all" or "treat none" strategies, while the traditional quantitation and radiomics model could add benefit in all threshold probability (figure ) . . radiomics score distribution in the training sets. " " group represents the cases without ards existence. " " group represents the cases with ards existence. ns, *,**,***,**** means the p value of wilcox test between two group > . , < . , < . , < . , < . respectively. figure . radiomics score distribution in the validation sets. " " group represents the cases without ards existence. " " group represents the cases with ards existence. ns, *, **, ***, **** means the p value of wilcox test between two group > . , < . , < . , < . , < . respectively. the y-axis represents the net benefit. the red, green and orange line represents the traditional, radiomics and combined model, respectively. the blue line represents the hypothesis that all patients had ards. the black line represents the hypothesis that no patients had ards. the x-axis represents the threshold probability. the threshold probability is where the expected benefit of treatment is equal to the expected benefit of avoiding treatment. for example, if the possibility of ards existence of a patient is over the threshold probability, then a treatment strategy for ards should be adopted. ards existence is the major reason for ventilation care in covid- patients. besides, the current experience showed that earlier treatment of ards is one of the key measures to decrease the modality [ ] . thus, early identification of ards existence could be beneficial to the covid- patients. in this study, we constructed different models by using the quantitative, radiomics and combined data. to the best of our knowledge, it was the first study to use the traditional quantitative and radiomics metrics to monitor the ards existence in covid- . our results showed that used radiomics or quantitative metrics to monitor the ards existence was feasible, which had expanded the effectiveness of ct scans during the covid- treatment, although it is still in controversy for reasons of availability, cost, and increased risk of cross-infection and radiation dosage [ ] . there had already been some constructed model based on deep-learning to predict the prognosis of covid- patient [ ] . currently, all of the above models were based on the initial ct of the patient. usually, this strategy did not cause significant bias because all patients were accepted similar treatment following the treatment guideline. however, as for covid- patients, the treatment varies in different countries, different regions, even in the different patients of the same hospital because some drugs were proven to be ineffective after initial application. in this condition, the treatment strategy would cause significant heterogeneity. thus, we used individual ct results during the patients' treatment instead of the initial ct to construct the model. our results showed that radiomics or traditional quantitative post-analysis on a ct image could add extra information of disease condition in covid- patients. the traditional quantitation and radiomics data of chest ct had the potential to become a noninvasive method for ards screening. the dca curves showed that radiomic or traditional quantitative model could add benefit to patients whatever the threshold probability, which means the model is better than the "treat all" or "treat none" strategies definitely. the noninvasive ards monitor method could benefit covid- patients in many ways. firstly, there are some patients with ards but without obvious respiratory symptoms, which was reported in some published studies . those patients could get earlier oxygen treatment and may have a better prognosis. besides, the monitor method could also decrease the number of arterial punctures, which was an invasive procedure. although there was no difference in auc among the three models, the radiomics model should be the most practical model for monitoring ards existence in covid- . because for the traditional quantitation and combined model, the sensitivity was low ( . and . , respectively), while the specificity was high ( . and . , respectively). in contrast, the radiomics model had a relatively high sensitivity ( . ) and low specificity ( . ). every model is not perfect, but sensitivity was much more important than specificity in ards monitoring because false-negative will cause delay of oxygen treatment to patients while false positive cause an unnecessary extra arterial puncture, which was much less harmful than the former. our traditional quantification result was homologous with the clinical findings. in our quantification result, the significant variable included: male (p = . ), existence of hypertension (p = . ), total infection proportion (p < . ), age (p = . ) and area proportion of zone (ct value > hu). age and total infection proportion was the risk factor reported in many previous covid- studies [ ] . the higher risk in male proportion might come from the higher smoking history of the male, which was reported as risk factor of bad prognosis of covid- patients in previous study [ ] . the probable mechanism of higher ards rate in patient with hypertension was that after covid- infection, the virus could combine with the ace receptor, resulting in a decrease in the number of ace . thus, when persons with hypertension get infected by covid- , their ace receptor level will become extremely low since they have lower ace receptor than those without hypertension [ ] , which could be a significant risk factor for lung failure [ ] . finally, the infection regions with ct value > was highly related to the ards existence. the region with ct value > hu is seldom seen in pneumonia, it could refer to the dense fibrous tissue in the lung, which could be a sign of lung failure [ ] . there were also several limitations in our study. the results could be influenced by the cohort retrospective nature. a larger sample of external validation is needed to acquire high-level evidence before clinical application. besides, the cost-effective between radiation dose, medical cost and patients benefit should be analyzed further. also, we had to mention that there is no "one fits" all analysis approach as performance of various ml workflows has been shown to depend on application and/or type of data. thus, current study may change and improve by using different machine learning algorithms. a noninvasive ards existence monitoring model was constructed by using quantitative and radiomics analysis of chest ct images for covdi- patients. experimental results showed that the radiomics model was the most promising model for ards monitoring. multi-center validation with a large number of samples is recommended in the future work. supplementary figures and tables. http://www.medsci.org/v p s .pdf clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan, china rapid asymptomatic transmission of covid- during the incubation period demonstrating strong infectivity in a cluster of youngsters aged - years outside wuhan and characteristics of young patients with covid- : a prospective contact-tracing study sars-cov- viral load in upper respiratory specimens of infected patients development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel sars-cov- a tool to early predict severe corona virus disease (covid- ) : a multicenter study using the risk nomogram in wuhan and guangdong, china ct imaging and clinical course of asymptomatic cases with covid- pneumonia at admission in wuhan the role of imaging in novel coronavirus pneumonia (covid- ) risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china acute respiratory distress syndrome imaging in acute respiratory distress syndrome a quantitative approach for the analysis of clinician recognition of acute respiratory distress syndrome using electronic health record data radiomics: the bridge between medical imaging and personalized medicine deep learning radiomics of shear wave elastography significantly improved diagnostic performance for assessing liver fibrosis in chronic hepatitis b: a prospective multicentre study next-generation radiogenomics sequencing for prediction of egfr and kras mutation status in nsclc patients using multimodal imaging and machine learning algorithms radiomic machine-learning classifiers for prognostic biomarkers of head and neck cancer noninvasive o methylguanine-dna methyltransferase status prediction in glioblastoma multiforme cancer using magnetic resonance imaging radiomics features: univariate and multivariate radiogenomics analysis a comparative study of machine learning methods for time-to-event survival data for radiomics risk modelling diagnosis and management of covid- disease large-scale evaluation of v-net for organ segmentation in image guided radiation therapy ct screening for early diagnosis of sars-cov- infection prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal sex differences in severity and mortality among patients with covid- : evidence from pooled literature analysis and insights from integrated bioinformatic analysis a crucial role of angiotensin converting enzyme (ace ) in sars coronavirus-induced lung injury hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for covid- idiopathic pulmonary fibrosis: recent advances on pharmacological therapy the authors have declared that no competing interest exists. key: cord- - trr d u authors: ventura, francesco; bonsignore, alessandro; gentile, raffaella; de stefano, francesco title: two fatal cases of hidden pneumonia in young people date: - - journal: j forensic sci doi: . /j. - . . .x sha: doc_id: cord_uid: trr d u abstract: acute respiratory distress syndrome (ards) is a severe lung disease characterized by inflammation of the lung parenchyma leading to impaired gas exchange. this condition is often lethal, usually requiring mechanical ventilation and admission to an intensive care unit. we present two fatal cases of hidden pneumonia in young people and discuss the pathophysiological mechanism of ards with reference to the histological pattern. a complete forensic approach by means of autopsy and histological, immunohistochemical, and microbiological, examination was carried out. in both cases the cause of death was cardio‐respiratory failure following an acute bilateral pneumonia with diffuse alveolar damage and ards associated with sepsis and disseminated intravascular coagulation. our cases suggest on one side the importance of an early diagnosis to avoid unexpected death while on the other that the diagnosis of ards has to be confirmed on the basis of a careful postmortem examination and a complete microscopy and microbiological study. acute respiratory distress syndrome (ards) is a severe lung disease characterized by inflammation of the lung parenchyma leading to impaired gas exchange with concomitant systemic release of inflammatory mediators by local epithelial and endothelial cells, causing inflammation, hypoxemia resulting often in multiple organ failure (mof), and disseminate intravascular coagulation (dic) ( ) . this condition is often lethal, usually requiring mechanical ventilation and admission to an intensive care unit ( ) . physiopathologically when the endothelium of lung capillaries and the alveolar epithelium are damaged, plasma and blood flood the interstitial and intra-alveolar spaces. such a change implies decreased lung compliance, pulmonary hypertension, reduced functional capacity, compromised ventilation ⁄ perfusion ratio, and hypoxemia ( ) . acute respiratory distress syndrome can occur within - h of an injury or attack of acute illness. in such a case the patient usually presents with shortness of breath and tachypnea, usually associated with hypoxemia, petechiae in the axillae, and neurologic abnormalities such as mental confusion ( ) . typical histological presentation involves diffuse alveolar damage (dad) and hyaline membrane formation in alveolar walls ( ) . hyaline membranes, especially, as a result of the acute inflammatory processes in the alveolar compartment ( ) is the histological hallmark of ards. if the underlying disease or injurious factor is not removed, the amount of inflammatory mediators released by the lungs in ards may result in a systemic inflammatory response syndrome (or sepsis if there is lung infection) ( ) . the evolution toward shock and ⁄ or mof follows the same pathophysiological path of sepsis ( ) . it is estimated that ards is caused by septic shock-characterized by leukocytosis or leukopenia, fever, hypotension, and the identification of a potential source of systemic infection with positive blood cultures for pathogenous agents-in more than % of cases ( ) . pneumonia is thought to be the most common lung disease leading to ards as it determines a direct lung injury in the immunocompetent host ( ) . in cases of severe ards the survival rate is % with appropriate and early treatment, but if the ards-induced severe hypoxemia is not recognized and treated or if the disease reaches medical attention only in the terminal phase then cardio-respiratory arrest occurs in more than % of patients ( ) . we present two fatal cases of hidden pneumonia in young people who died within a few hours. the clinical presentation, the radiological and laboratory findings in one case, and the postmortem examination with histological, immunohistochemical, and microbiological exams in both cases, led us to conclude for an acute cardio-respiratory failure secondary to bilateral pneumonia with dad and consequently ards associated with sepsis and dic. the features of the disease are discussed with reference to the histological and immunohistochemical evaluation. a -year-old man was found dead at home by his girlfriend who was sleeping with him. the night before he went out with his friends and came back home late. his friends reported that nothing ''strange'' happened during the evening he spent with them. the day after, in the afternoon, when he should wake up his girlfriend saw the presence of foam around his mouth and nose and when she tried to wake him up he did not respond. so she called the emergency services who could do nothing but declare him dead. he took psychodrugs and was known to be a drug addict and a heavy drinker. family history was reported negative for sudden death. death scene investigation was unremarkable. a complete postmortem examination was performed days after death. external examination did not show any visible sign of injury. the internal examination revealed polyvisceral stasis, diffuse microthrombosis, cerebral and pulmonary edema. free citrine liquid was found on both sides of the pleural cavities. a marked lung congestion and the release of foamy material were bilaterally observed. ''hydrostatic docimasia'' for large and small fragments was bilaterally positive in all fields. also known as ''the flotation test,'' or ''the lung test,'' this old test is still in use to check if there are areas of increased density within the adult lung parenchyma. in these cases lung specimens, being not inflated with air, do not float. such is the case of pneumonia ( ) . the microscopic histological study, performed using formalinfixed paraffin-embedded tissue sectioned at lm and stained with hematoxylin-eosin (h&e), revealed the typical findings of dad: alveolar septa mildly thickened by edema and capillary congestion, alveolar edema, hyaline membranes lining the denuded alveolar walls, hyperplastic type ii pneumocytes, alveolar infiltrates of polymorphonuclear neutrophilic leukocytes, pigmented macrophages, monocytes and plasma cells (fig. a) , fibrin thrombi in small arteries. in some fields, numerous endoalveolar erythrocytes were also observed. bronchial walls presented epithelial denudation, inside the lumen there were infiltrates of leukocytes, mostly neutrophils, and a moderate quote of eosinophilic amorphous material. all these findings were suggestive for a typical dad in the early exudative phase, confirmed by the positive results to immunohistochemical dye for surfactant apoprotein (pe- ) that outlines hyperplastic type ii pneumocytes ( ) . fungal infections were not found on slides by grocott staining. gram staining did not give evidence for bacterial colonies. the examination of other histological samples was unremarkable. the lung samples were also examined under a confocal laser scanning microscope ( ) , and a three-dimensional reconstruction was performed (fig. ) . additional microbiological tests ( ) to identify possible pathogenous agents were carried out through isolation of nucleic acids from formalin-fixed paraffin-embedded tissue sections. to control the course of extraction and check for pcr inhibitors, a fragment of the homo sapiens beta-globin gene was amplified. the purified dna sample was negative for all bacterial cultures. the positive result for beta-globin demonstrated that the dna extraction procedure was efficient in extracting amplifiable dna from the sample. toxicology was negative for drugs and alcohol. thus, viral infection was a diagnosis of exclusion, according with recent literature which reports a prevalence of viral etiologies in communityacquired pneumonia up to % ( ) and an extremely high incidence of lung injury and ards arising from coronavirus and avian influenza virus infection ( , ) . a -year-old previously healthy man presented to the hospital with a -h history of sore throat, fever, and cough. the clinical prodromes were followed by the acute onset of increasing shortness of breath quickly progressing in acute respiratory failure with hemoptysis. chest x-ray demonstrated bilateral diffuse airspace opacification; the high-resolution ct (hrct) confirmed the presence of bilateral, symmetric diffuse ground-glass attenuation associated with liquid in pleural cavities. the patient was admitted to the intensive care unit with severe leukopenia, but he got worse and after few hours died. two postmortem blood cultures were positive for group a beta-hemolytic streptococcus which is well known for causing invasive disease leading to death even though diagnosis is not always made in life, as in this case ( ) . no other pathogenous agents were present. an autopsy was performed within h after death. external examination was irrelevant. internal examination revealed an increased consistency and weight of the lungs ( g the left and g the right respectively) with positive hydrostatic docimasia in all fields and intense congestion which was ascribed to a bilateral pneumonia. the examination of other organs was unremarkable except for intense polyvisceral stasis. the histological examination of lung specimens (one sample per lobe and more samples in increased thickening pulmonary areas as common practice), performed by using the same method described earlier for the previous case, showed alveolar septa that mildly thickened by edema and capillary congestion, alveolar edema, hyaline membranes coating alveolar septal surfaces, flattened pneumocytes, alveolar infiltrates of polymorphonuclear neutrophilic leukocytes, pigmented macrophages, monocytes and plasma cells, fibrin thrombi in small arteries (fig. b) . all these findings suggested a typical dad, confirmed by positive results to immunohistochemical dye for surfactant apoprotein (pe- ) (data not shown) ( ) . in the kidneys was found a thrombotic microangiopathy compatible with dic. the lung samples were examined under a confocal laser scanning microscope, and a three-dimensional reconstruction was performed ( ) . the silent (case ) and the paucisymptomatic (case ) presentations, and the histological and immunohistochemical findings led us to the diagnosis of ards supporting the conclusion that both were affected by a quite rare type of pulmonitis definable as hidden pneumonia. acute respiratory distress syndrome is a pathological entity arising from multiple pulmonary or extrapulmonary causes ( ) . generally, patients with ards report a short prodromal illness characterized by few symptoms like fever and cough, followed by the acute onset of progressive shortness of breath which rapidly evolves to respiratory failure ( ) . chest radiographs typically show bilateral diffuse airspaces opacifications ( ) . chest hrtc scans are significative for bilateral ground-glass attenuation ( ) . the histological features of ards, investigated from open lung biopsies or autopsies, are those of dad, a nonspecific pattern of acute lung injury ( ) . acute respiratory distress syndrome has a poor prognosis, with reported mortality rates still appearing to be higher than % ( ) . the first case concerns a -year-old man found lifeless at home by his girlfriend. at autopsy polyvisceral stasis, diffuse microthrombosis, free citrine liquid on both sides of the pleural cavities, a marked lung congestion, and the release of foamy material were found. hydrostatic docimasia for large and small fragments was bilaterally positive in all fields. the histological evaluation of lungs samples stained with h&e, also examined under a confocal laser scanning microscope, gave evidence of a pattern of dad. the presence of hyperplastic type ii pneumocytes and hyaline membranes was confirmed by the positive reaction of the immunohistochemical dye for surfactant apoprotein (pe- ). additional tests were carried out to identify possible pathogenous agents through microbiological studies but all the cultures showed no bacterial growth. toxicology was negative for drugs and alcohol. the second case involves a -year-old previously healthy man who presented, after a -h history of sore throat, fever, and cough, an acute onset of increasing shortness of breath rapidly progressing in acute respiratory failure with hemoptysis. chest x-ray and hrct showed the typical pattern of ards, with bilateral, symmetric, diffuse ground-glass attenuation. despite admittance to the intensive care unit, the patient died after few hours. two blood cultures were positive for group a beta-hemolytic streptococcus. the macroscopical and histological patterns were similar to that of case . in both cases the cause of death was attributed to an acute cardio-respiratory failure secondary to acute bilateral pneumonia and consequently ards, sepsis, and dic. these cases demonstrate how ards can rapidly lead to death in young patients that can generally be successfully treated in case of pneumonia. in the first case the postmortem diagnosis of ards and sepsis with dic ( ) was made exclusively on the basis of a careful postmortem examination and a complete histological study. therefore, the authors underline that forensic pathological procedures should be applied in all cases of sudden death using systematic practical investigations to find the cause of death, more so in fatal cases involving young people. just in this way it is possible to perform an adequate differential diagnosis when sudden cardiac death is more likely to be expected because of the young age of the patient. the second case, which has attracted the medicolegal interest because of medical liability profiles that were assumed as fault for doctors, suggests that clinicians should be suspicious of all community-acquired pneumonia ( ) , especially in young people, because rigorous diagnosis as well as early and appropriate therapy is mandatory to avoid unexpected death ( ) . particularly, from a forensic point of view, in such cases the authors suggest the importance of taking postmortem bacterial and viral cultures. last, the forensic community should not forget the role played by ards as a potential cause of sudden and unexpected death in previously healthy young people. a shock toxin that produces disseminated intravascular coagulation and multiple organ failure low-tidal-volume ventilation in the acute respiratory distress syndrome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination irwin and rippe's intensive care medicine, th edn abbas ak robbins and cotran pathologic basis of disease nonhomogeneous immunostaining of hyaline membranes in different manifestations of diffuse alveolar damage the acute respiratory distress syndrome mechanisms of sepsis-induced organ dysfunction sepsis definitions conference a multicenter registry of patients with acute respiratory distress syndrome. physiology and outcome effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome in: chapman hc, editor. a manual of medical jurisprudence, insanity and toxicology an immunohistochemical study in a fatal case of acute interstitial pneumonitis (hamman-rich syndrome) in a -year-old boy presenting as sudden death using new technology to answer old questions in forensic investigations the microbiology of the autopsy viral community-acquired pneumonia in nonimmunocompromised adults writing committee of the world health organization (who) consultation on human influenza a ⁄ h . avian influenza a (h n ) infection in humans acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data acute deaths in nonpregnant adults due to invasive streptococcal infections pulmonary and extrapulmonary forms of acute respiratory distress syndrome comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings diagnostic imaging of idiopathic adult respiratory distress syndrome (ards) ⁄ diffuse alveolar damage (dad) adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: ct, clinical, and functional correlations pulmonary pathology of acute respiratory distress syndrome epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study post-mortem diagnosis of sepsis update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults incidence, clinical course, and outcome in patients with acute respiratory distress syndrome the authors thank prof. vittorio fineschi for his help in histological and immunohistochemical studies. they also thank margherita neri, m.d. and irene riezzo, m.d. for their excellent technical assistance in confocal microscopy. finally the authors thank claudio giacomazzi, m.d. for his help in microbiological studies. key: cord- -gsl nv authors: pariani, elena; martinelli, marianna; canuti, marta; jazaeri farsani, seyed mohammad; oude munnink, bas b.; deijs, martin; tanzi, elisabetta; zanetti, alessandro; van der hoek, lia; amendola, antonella title: influenza and other respiratory viruses involved in severe acute respiratory disease in northern italy during the pandemic and postpandemic period ( – ) date: - - journal: biomed res int doi: . / / sha: doc_id: cord_uid: gsl nv since pandemic, international health authorities recommended monitoring severe and complicated cases of respiratory disease, that is, severe acute respiratory infection (sari) and acute respiratory distress syndrome (ards). we evaluated the proportion of sari/ards cases and deaths due to influenza a(h n )pdm infection and the impact of other respiratory viruses during pandemic and postpandemic period ( – ) in northern italy; additionally we searched for unknown viruses in those cases for which diagnosis remained negative. respiratory samples were collected from sari/ards cases and analyzed by real-time rt-pcr/pcr to investigate influenza viruses and other common respiratory pathogens; also, a virus discovery technique (vidisca- ) was applied on those samples tested negative to all pathogens. influenza a(h n )pdm virus was detected in . % of specimens, with a case fatality rate of . %. the impact of other respiratory viruses was . %, and the most commonly detected viruses were human rhinovirus/enterovirus and influenza a(h n ). vidisca- enabled the identification of one previously undiagnosed measles infection. nearly % of sari/ards cases did not obtain a definite diagnosis. in clinical practice, great efforts should be dedicated to improving the diagnosis of severe respiratory disease; the introduction of innovative molecular technologies, as vidisca- , will certainly help in reducing such “diagnostic gap.” most cases of influenza a(h n )pdm infection have a mild outcome; however some present as severe acute respiratory infection (sari) and require admission to intensive care unit (icu) [ , ] . the main reason for admission to icu is a pulmonary inflammatory syndrome characterized by diffuse alveolar damage (acute respiratory distress syndrome: ards), which can be fatal. since the beginning of pandemic, international health authorities recommended monitoring severe and complicated cases of influenza infection [ , ] . considering the serious outcome of these respiratory diseases, the contribution of other respiratory pathogens besides a(h n )pdm should be envisaged [ ] . additionally, in clinical practice, a specific causative agent which explains the respiratory symptoms is often unidentified, owing to the lack of sensitive tests or the presence of an asyet unknown pathogen. the recently developed vidisca- (virus discovery using cdna amplified fragment-length polymorphism combined with roche- high-throughput sequencing) is a sensitive sequence-independent virus discovery technique which can be used to reveal as-yet unknown viruses [ , ] . this study aimed at evaluating the proportion of sari/ards cases and deaths due to a(h n )pdm infection and assessing the impact of other respiratory pathogens during pandemic and postpandemic period ( ) ( ) ( ) in northern italy as well as searching for unknown viruses in those cases for which diagnosis remained negative. to this end, common respiratory pathogens were investigated and vidisca- methodology was applied on samples which remained negative for all tested pathogens. in the capacity of reference laboratory operating within influnet network [ ] , our laboratory is in charge of carrying out the virological surveillance of severe forms of influenza infection in lombardy (nearly million inhabitants). from october , , to april , , respiratory samples were collected from patients hospitalized due to severe respiratory illness. of these, . % were males with a median age of . years (iqr: . years; range: month- years); . % were children ≤ years and . % were ≥ years. data on comorbidities presence were available for nearly % of study patients: . % reported medical conditions [ , ] ; in detail, . % had weakened immune system (due to cancer, hiv/aids, or long-term steroid treatment), . % heart disease, . % asthma/chronic lung disease, and . % neurological/neurodevelopmental conditions. out of patients, ( . % males; . % aged ≤ years, . % aged - years) were sari cases who required admission to icu and extracorporeal membrane oxygenation (ecmo) therapy, and ( . % males; . % aged ≤ years, % aged - years) were ards cases, as defined by the european consensus conference [ ] . nine ards patients (median age: . years, iqr: . years) died during hospitalization: case fatality rate (cfr) in our ards series was . % ( / ). no sari case was fatal. respiratory specimens (paired nasal/oral swab and bronchoalveolar lavage) were collected from each sari/ards case. nucleic acids were purified by nuclisens easymag (biomérieux, france) and analyzed by real-time rt-pcr assay to identify influenza virus. in detail, a one-step realtime rt-pcr assay was performed to simultaneously detect influenza viruses type a and b [ ] . the subtyping of influenza a positive samples was carried out by a one-step realtime rt-pcr assay using specific primer/probe sets for the hemagglutinin gene [ ] . the clinical specimens that resulted negative to influenza virus detection were then screened by real-time rt-pcr/pcr for a panel of respiratory pathogens (respiratory mws r-gene real-time pcr, biomérieux, france) to detect respiratory syncytial virus (rsv) a and b; human metapneumovirus (hmpv) a and b; human rhinovirus (hrv) and enterovirus (hev); adenovirus (adv); human bocavirus (hbov) - ; human coronavirus (hcov) e, nl , oc , hku ; human parainfluenza virus (hpiv) - ; chlamydophila pneumoniae; mycoplasma pneumoniae. cases which resulted negative to all diagnostic assays were further investigated by vidisca- technique. this is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors, and subsequent amplification by pcr combined with high-throughput sequencing flx/titanium system (roche, usa) [ ] . influenza a(h n )pdm virus was detected in . % ( / ) of sari/ards cases ( . % males; . % aged ≤ years, . % aged - years). moreover, the presence of another condition possibly increasing the risk for developing influenza-related complications [ , ] forty-six ( / : . %) sari/ards cases (including two fatalities) resulted negative to all diagnostic assays ( . % males; . % aged ≤ years, . % aged - years) and were further investigated by vidisca- [ , ] . vidisca- revealed no sequence reads that could belong to a novel virus or viral variant in any of the specimens; however it enabled the identification of one case of undiagnosed measles, thus increasing the proportion of cases with a diagnosis to . % ( / ). hence, the overall proportion of cases with unknown diagnosis was . % ( / ); most ( / : . %) cases that could not be diagnosed were ards and two ( / : . %) were fatal. figure summarizes study results. during pandemic and postpandemic period, several pathogens cocirculated and were associated to severe respiratory infections; however, influenza a(h n )pdm virus had the greatest impact ( . %) in our sari/ards series. more than half ( . %) of a(h n )pdm infection resulted in ards. it is interesting to note that most ( . %) severe respiratory diseases due to a(h n )pdm infection were identified among - -year-old individuals. the a(h n )pdm case fatality rate in our ards series was . % fatal cases in young adults, and . % did not belong to any at-risk category [ , ] . this data is in agreement with other studies; van kerkhove et al. have reported a median age of years among fatal laboratory-confirmed a(h n )pdm cases [ ] . mccallum has described that during the pandemic only % of laboratory-confirmed cases and % of laboratory-confirmed deaths were among persons years of age or older [ ] . the global pandemic mortality (glamor) project has evaluated that although the pandemic mortality estimate was similar in magnitude to that of seasonal influenza, a marked shift toward mortality among persons years of age occurred, so that many more life-years were lost [ ] . such an age shift has been documented as well by several studies on a(h n )pdm mortality [ ] [ ] [ ] . the proportion of sari/ards cases associated with respiratory viruses other than a(h n )pdm was significantly lower ( . % versus . %, value < . ). severe respiratory diseases associated with respiratory viruses other than a(h n )pdm were detected more frequently among children ≤ years ( . % versus %, value = . ). this piece of evidence is in accordance with the results of other studies reporting a notable burden of respiratory viruses in children under years [ ] [ ] [ ] . studies published to date have suggested that influenza viruses and rhinoviruses are the leading causes of severe respiratory disease leading to hospitalization [ , ] , similarly to what was observed in our sari/ards series, where hrv/hev were the most common identified viruses along with influenza viruses. also influenza a(h n ) virus played a significant role in our sari cases and caused ards in one patient with a weakened immune system due to hiv/aids. overall, the proportion of sari/ards correlated to an influenza a virus infection was . % ( / ), thus emphasizing the central role of influenza a virus in severe respiratory infection [ , ] . the use of molecular assay has notably contributed to identifying pathogens possibly involved in severe respiratory disease, thus allowing getting to a diagnosis of viral infection in nearly % of study sari/ards cases. other studies that have not used nucleic acid amplification assays have typically reported that - % of cases of acute respiratory infection have a viral etiology [ ] . in addition, it is noteworthy that vidisca- enabled the identification of one measles infection that escaped clinical diagnosis in one sari case. hence, measles infection should be considered in complicated pulmonary disease, as also suggested by others [ ] , since measles virus is not generally included in respiratory diagnostic panels. during pandemic and postpandemic period, several pathogens cocirculated and were associated to severe respiratory infections, with influenza a(h n )pdm virus having the greatest impact. nearly % of sari/ards cases did not obtain a definite diagnosis, and among these cases two were fatal. in clinical practice, great efforts should be devoted to improving diagnosis of severe respiratory infec-tions and to reducing such "diagnostic gap. " the advantage from relying upon more accurate diagnosis could benefit the patient, in terms of receiving the more appropriate antiviral drugs, and could provide more detailed information on viruses circulating in the community, thus making public health authorities aware so as to adjust their policies accordingly. vidisca- proved to be a sensitive and specific methodology that can be successfully applied to surveillance of viral respiratory infections that represent an ever-changing field due to the continuous emergence of new viruses (i.e., influenza a(h n ) and a(h n ) viruses, mers-cov). pandemic novel h n influenza: what have we learned h n influenza pandemic: field and epidemiologic investigations in the united states at the start of the first pandemic of the st surveillance of severe disease due to influenza in europe surveillance of severe forms of influenza a(h n )pdm infection a sensitive assay for virus discovery in respiratory clinical samples identification of a new human coronavirus the american-european consensus conference on ards: definitions, mechanisms, relevant outcomes, and clinical trial coordination world health organization (who) global influenza surveillance network (gisn), "manual for the laboratory diagnosis and virological surveillance of influenza protocol cdc protocol of real-time rt pcr for swine influenza a(h n ) performance of vidisca- in feces-suspensions and serum risk factors for severe outcomes following influenza a (h n ) infection: a global pooled analysis epidemiological characteristics of the influenza a(h n ) pandemic in the western pacific region global mortality estimates for the influenza pandemic from the glamor project: a modeling study mortality burden of the a/h n pandemic in mexico: a comparison of deaths and years of life lost to seasonal influenza mortality burden of the a/h n influenza pandemic in france: comparison to seasonal influenza and the a/h n pandemic all-cause mortality during first wave of pandemic (h n ) epidemiology and etiology of childhood pneumonia in : estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for countries global burden of childhood pneumonia and diarrhoea surveillance for hospitalized acute respiratory infection in guatemala incidence and characteristics of viral community-acquired pneumonia in adults the role of viruses in the aetiology of community-acquired pneumonia in adults incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: results from the severe influenza pneumonia surveillance (sips) project viral infection in patients with severe pneumonia requiring intensive care unit admission community-acquired pneumonia viral etiologies of acute respiratory infections among hospitalized vietnamese children in ho chi minh city the authors declare that there is no conflict of interests regarding the publication of this paper. key: cord- - ru s a authors: convertino, irma; tuccori, marco; ferraro, sara; valdiserra, giulia; cappello, emiliano; focosi, daniele; blandizzi, corrado title: exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in covid- patients date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: ru s a sars-cov- complications include pneumonia and acute respiratory distress syndrome (ards), which require intensive care unit admission. these conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. particularly, since pneumonia and ards are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-il- , anti-tnf, and jak inhibitors are currently studied. in this article, we discuss the potential advantages of the most promising pharmacological approaches. lymphocytopenia. in patients requiring icu admission, an increase in neutrophil count, d-dimer, blood urea, and creatinine levels have been detected as well as more severe lymphocytopenia. this condition is defined as a "cytokine storm" and is associated with high circulating levels of interleukins (il)- , il- , il- , il- , granulocyte colonystimulating factor (g-csf), kda interferon-gammainduced protein (ip- ), monocyte chemo-attractant protein- (mcp- ), macrophage inflammatory protein α (mip- α), and tumor necrosis factor (tnf) [ , ] . in particular, in ards patients, a strong depletion of peripheral blood t cells, along with a decreased recruitment of lymphocytes and neutralizing antibodies and an increased production of cytokines, was detected in the lungs [ ] . this network of pathogenic factors is thought to drive a severe immune-mediated interstitial pneumonia and a delayed pulmonary clearance of covid- [ ] . current evidence supports a close relationship between cytokine storm and disease severity. indeed, icu patients displayed higher serum levels of cytokines (g-csf, ip- , mcp- , mip- α, and tnf-α) than those not requiring icu. for instance, il- and tnf-α levels in icu patients were significantly higher when compared with non-icu ones [ ] . patients with fatal outcome had higher serum concentrations of il- than those survived: the il- median levels reported by zou et al. were . pg/ml (iqr . - . ) and . pg/ml (iqr . - . ), respectively, p < . . similar findings were showed by ruan et al. . pg/ml (iqr . ) in dead patients versus . pg/ml (iqr . ) in discharged ones [ , ] . furthermore, a significantly close relationship between il- levels in critical covid- patients with fatal outcome ( . pg/ml, iqr . - . ) and rnaemia was found, in particular, the . % of patients with il- > pg/ml had positive levels of rnaemia, r . . this suggests that high serum il- along with rnaemia could be predictors of mortality [ ] . additionally, not only critically ill patients with ards have been associated with high cytokine serum levels but also non-severe patients with covid- . indeed, il- median serum levels were . pg/ml (iqr . - . ) in severe patients compared with . pg/ml (iqr . - . ) in those with mild disease, p . [ ] , and . pg/ml (iqr . - . ) in patients with spo ≥ % in comparison with . pg/ml (iqr . - . ) in those with spo < %, p < . , as well as the tnf-α levels ( . pg/ml, iqr . - . even in the conditions with spo ≥ %) [ ] . these data were confirmed by qin et al.; il- median serum levels in severe and non-severe patients were . pg/ml (iqr . - . ) and . pg/ml (iqr . - . ), respectively; and tnf-α median serum levels were . pg/ml (iqr . - . ) in severe patients and . pg/ml (iqr . - . ) in non-severe ones [ ] . based on this knowledge, it has been proposed that the modulation of the above cytokines could represent an interesting approach to improve the prognosis of patients with covid- pulmonary complications, both pneumonia and ards. recently, the food and drug administration has allowed the emergency use of a device aiming at purifying blood of icu patients from the cytokine storm [ ] . several drugs, endowed with modulating activity on cytokine pathways, including anti-il- , anti-tnf, and janus kinase (jak) inhibitors, currently approved for the treatment of immune-mediated inflammatory diseases, have been suggested or could be yet taken into account for experimental use in covid- patients with ards and/or pneumonia ( fig. ). tocilizumab is a humanized, immunoglobulin g κ (igg κ) anti-human il- receptor (il- r) monoclonal antibody approved for some immune-mediated inflammatory rheumatic diseases. clinical evidence supports the view that this drug is an effective therapeutic option, with a good risk-benefit profile, in cytokine storm syndromes [ ] . in china, its off label use has been tested in icu ards patients with favorable results after - h in / patients [ ] . moreover, a multicenter randomized clinical trial in covid- patients with ards, treated with tocilizumab at a dose of ~ mg/kg once, and an additional same dose when fever persists within h after the first administration, has been approved in china [ ] . the italian medicine agency has recently authorized a trial on the use of tocilizumab in covid- patients with ards [ ] . this initiative was pushed on also by promising results published on italian newspapers. particularly, some patients treated with tocilizumab at the "pascale" cancer institute in naples showed disease improvements within h and one of them did not require mechanical ventilation days after starting tocilizumab [ ] . another monoclonal antibody belonging to anti-il- drug class, siltuximab, currently approved in multicentric castleman disease with hiv-negative and human herpesvirus- negative, is under investigation for ards in covid- patients. in particular, an observational case-control study evaluating siltuximab in icu patients with ards-related covid- is performing at papa giovanni xxiii hospital in bergamo, italy [ ] . preliminary results have shown promising outcomes as the clinical improvement in the % of treated icu patients [ ] . in addition, a multicenter open-label randomized clinical trial is studying the benefit risk profile of siltuximab, as a single therapeutic option or in combination with anakinra, at a single dose of mg/kg, in comparison with tocilizumab or anakinra, alone or in combination, in ards patients with covid- [ ] . evidence suggested a higher binding affinity to il- involving siltuximab than tocilizumab but less insights are currently available on the effects of siltuximab in cytokine storm [ ] . based on the results expected with tocilizumab and siltuximab, other anti-il- drugs, currently approved for rheumatoid arthritis, namely sarilumab and sirukumab, could be studied in ards and pneumonia patients with covid- . notably, sarilumab has higher affinity for its target and a longer half-life than tocilizumab; thus, a sustained therapeutic effect could be achieved by administration of only one single dose [ , ] . on march th , , a clinical trial evaluating the efficacy and safety of high dose and low dose of sarilumab in covid- patients was started [ ] . subsequently, further clinical trials have followed, investigating the benefit risk profile of sarilumab in patients with covid- related ards, at a dose of mg or mg, as single or repeated administration, subcutaneously or intravenously [ ] [ ] [ ] [ ] . sirukumab neutralizes il- specifically and directly by preventing its binding to its membrane receptor [ ] , and thus, it leads to a subsequent suppression of il- biological actions. in a phase i trial, sirukumab showed linear pharmacokinetics with long half-life, low immunogenicity, and a good safety profile [ ] . accordingly, it could represent a promising pharmacological option for counteracting the high il- levels occurring in ards patients. anti-tnf drugs, including infliximab, adalimumab, etanercept, golimumab, and certolizumab, could be tested also for covid- -related ards and pneumonia. in china, a clinical trial on adalimumab in covid- patients was recently approved [ ] . infliximab, adalimumab, and golimumab are igg monoclonal antibodies, while etanercept is a fusion protein of two human tnf type receptor moieties linked with the fc region of a human immunoglobulin, and certolizumab is the pegylated fab domain obtained from a humanized anti-tnf igg monoclonal antibody [ ] . differences in the inhibitory mechanism were shown among these drugs, due to their different molecular binding patterns with tnf sites [ ] . all anti-tnf drugs display higher binding affinity to soluble tnf than its membrane-bound form, with golimumab and etanercept showing the highest level [ ] . greater binding avidity to soluble tnf was reported for etanercept than infliximab and adalimumab [ ] . heterogeneity was also found in the neutralizing activity of anti-tnf drugs to soluble tnf, while that to transmembrane tnf was comparable [ ] . infliximab and adalimumab displayed a greater binding activity for fcγrii and fcγriii than etanercept, but the latter was able to bind fcγri with higher affinity [ ] . fcγrs play important roles in the modulation of immune responses, which rely on cytokines and vasoactive mediators [ ] . in addition, a review showed that the proteins coded by the virus alter the complement system control and thus contribute to lung viral damages [ ] . out of the anti-tnf drugs, the igg monoclonal antibodies have a complement-dependent cytotoxicity activity [ ] that could be explored in the covid- infection. the known differences in pharmacokinetics and pharmacodynamics among anti-tnf drugs support the need for testing these agents in covid- -related ards and pneumonia patients without particular priorities, in order to identify the best option. other selection criteria, including the administration route, the possible positive or negative interactions resulting from combination with other drugs (i.e., hydroxychloroquine) and the costs (i.e., the use of biosimilar anti-tnf available) should be considered. anti-jak drugs (such as ruxolitinib, tofacitinib, baricitinib, oclacitinib, fedratinib, upadacitinib, and peficitinib) [ ] should be considered also among the options for clinical investigations in covid- -related ards and pneumonia patients. jaks are involved in jak/stat signaling associated with the receptors of a large variety of cytokines. in particular, stat- and stat- pathways are activated by binding of il- to its receptor (il- r) [ ] . tofacitinib acts as a non-selective inhibitor of all known jaks (jak , jak , jak , tyk ) with moderate specificity for jak and jak . baricitinib inhibits selectively jak and jak [ ] . both are approved by the european medicines agency (ema); baricitinib for rheumatoid arthritis and tofacitinib for both rheumatic disorders and ulcerative colitis. ruxolitinib is a jak / jak inhibitor approved by the food and drug administration (fda) for psoriasis, myelofibrosis, and rheumatoid arthritis. upadacitinib (anti-jak ), fedratinib (anti-jak ), and oclacitinib (anti-jak ) were approved by fda for rheumatoid arthritis, myelofibrosis, and dermatitis, respectively [ ] . peficitinib (anti-jak ) was approved for rheumatoid arthritis only in japan [ ] . tofacitinib and upadacitinib showed potent inhibitory activities on jak / -dependent cytokines, both pathways being involved in lymphocyte activation. tofacitinib, baricitinib, and upadacitinib displayed also inhibitory actions on the jak /tyk -dependent signaling of il- , gm-csf, and g-csf. tofacitinib was shown to act as the most potent inhibitor of g-csf (jak /tyk ). moreover, tofacitinib, baricitinib, and upadacitinib inhibited il- and interferon (ifn) γ (jak / ), as well as il- and ifn-α (jak /tyk ), with tofacitinib appearing as the strongest inhibitor of il- , ifn-γ, and il- signals [ ] . evidence suggests that baricitinib, fedratinib, and ruxolitinib are also inhibitors of numb-associated kinases (nak), involved in viral endocytosis and replication. baricitinib showed the highest affinity for aak than ruxolitinib and fedratinib. thus, besides exerting putative anti-inflammatory effects in ards patients, it is expected also to reduce viral infectivity [ , ] . of note, a clinical trial on such antiviral effect is going to start with ruxolitinib [ ] , and an open-label trial is evaluating its efficacy and safety at a dose of mg twice a day in covid- patients with ards [ ] . furthermore, an expanded access program of the mg ruxolitinib formulation is ongoing in severe covid- patients with ≥ years old [ ] . finally, an open label clinical trial is evaluating the benefit risk profile of baricitinib at a dose of mg a day for days in moderate and severe adult covid- patients [ ] . whenever jak inhibitors could be identified as an effective pharmacological option in covid- -related ards and pneumonia, their cost and safety issues, particularly the risk of thromboembolic events for some of them, should be taken into account [ ] . several drugs targeting cytokine pathways hold the potential for providing benefits in covid- -related ards and pneumonia. anti-il- , anti-tnf, and anti-jak medications, currently available for treating other immunedependent inflammatory diseases, are expected to exert favorable effects in this setting, based on their mechanism of action. in the current emergency situation and without reliable therapeutic options, their benefit riskprofile will likely be favorable. cost and safety will be a priority at a later phase of the epidemic, when more robust data will be available. the epidemiology and pathogenesis of coronavirus disease (covid- ) outbreak a systematic review on the efficacy and safety of chloroquine for the treatment of covid- coronavirus infections and immune responses the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak -an update on the status the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease dysregulation of immune response in patients with covid- in wuhan, china clinical features of patients infected with novel coronavirus in wuhan clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china. intensive care med detectable serum sars-cov- viral load (rnaemia) is closely correlated with drastically elevated interleukin (il- ) level in critically ill covid- patients diagnostic utility of clinical laboratory data determinations for patients with the severe covid- clinical features of cases with coronavirus disease in wuhan, china covid- ) update: fda authorizes blood purification device to treat covid- | fda current concepts in the diagnosis and management of cytokine release syndrome urgente un protocollo per estendere uso del farmaco -la repubblica covid- : consider cytokine storm syndromes and immunosuppression aifa e istituto nazionale per lo studio e la cura dei tumori di napoli avviano uno studio per l'utilizzo di tocilizumab nella malattia covid an observational case-control study of the use of siltuximab in ards patients diagnosed with covid- infection -full text view -clinicaltrials.gov positive early data from siltuximab covid- trial -pharmatimes treatment of covid- patients with anti-interleukin drugs -full text view -clinicaltrials.gov current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor t-cell therapy profile of sarilumab and its potential in the treatment of rheumatoid arthritis favipiravir combined with tocilizumab in the treatment of corona virus disease -full text view -clinicaltrials.gov evaluation of the efficacy and safety of sarilumab in hospitalized patients with covid- -full text view -clinicaltrials.gov cohort multiple randomized controlled trials open-label of immune modulatory drugs and other treatments in covid- patients -sarilumab trial -corimuno- -sari -full text view -clinicaltrials.gov anti-il treatment of serious covid- disease with threatening respiratory failure -full text view -clinicaltrials.gov treatment of moderate to severe coronavirus disease (covid- ) in hospitalized patients -full text view -clinicaltrials.gov sarilumab covid- -full text view -clinicaltrials.gov il- targeting compared to tnf targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab pharmacokinetics, pharmacodynamics and safety of a human anti-il- monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study regulation of interferon production as a potential strategy for covid- treatment tumor necrosis factor antagonist mechanisms of action: a comprehensive review comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor α-associated diseases from a molecular view characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor differences in binding and effector functions between classes of tnf antagonists fcγ receptors as regulators of immune responses the cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factorα new players in the field of immune-mediated diseases, beyond rheumatoid arthritis differential activation of jak enzymes in rheumatoid arthritis and autoimmune disorders by pro-inflammatory cytokines: potential drug targets comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a bayesian network meta-analysis of randomized controlled trials food and drug administration peficitinib: first global approval. drugs comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations covid- : combining antiviral and anti-inflammatory treatments baricitinib as potential treatment for -ncov acute respiratory disease covid- registered trials -and analysis -cebm treatment of sars caused by covid- with ruxolitinib -full text view -clinicaltrials.gov ruxolitinib managed access program (map) for patients diagnosed with severe/very severe covid- illness -full text view -clinicaltrials.gov restrictions in use of xeljanz while ema reviews risk of blood clots in lungs | european medicines agency publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable.authors' contributions ic, mt, and cb contributed to the idea; ic, mt, sf, gv, ec, df, and cb to the data searching and interpretation; and ic, mt, and cb to the redaction of the manuscript and ic, mt, sf, gv, ec, df, and cb reviewed the final version. the authors read and approved the final manuscript. no funding has been received to perform this article.availability of data and materials not applicable. key: cord- -w bdg authors: kloc, malgorzata; ghobrial, rafik m. title: the multiple sclerosis (ms) drugs as a potential treatment of ards in covid- patients date: - - journal: mult scler relat disord doi: . /j.msard. . sha: doc_id: cord_uid: w bdg we encourage studies on the effectiveness of multiple sclerosis drugs for the treatment of ards in covid- infection. these drugs, through the inhibition of the rhoa/actin-dependent expression of virus receptors in the macrophages and macrophage recruitment to the lungs, have the potential to inhibit cytokine storm of long macrophages, reduce or eliminate ards and improve the outcome of covid- infection. improve the outcome of covid- infection. the main and most deadly symptom of the sars-cov- infection is acute respiratory distress syndrome (ards) in the lungs of covid- patients. ards is caused by the hyperactive immune response and the production of cytokine storm by the lung macrophages. the entry of the virus to the lung epithelial cells and lung macrophages depends on the ace receptor expressed on the surface of these cells. the immune factors (cytokines and chemokines) released from the infected cells recruit additional immune cells, including monocytes and macrophages from the bone marrow and blood, to join the fight against infection. this avalanche (cytokine storm) of immune factors is extremely damaging for the lung tissues and, ultimately, leads to lung failure ( - ). thus, the potential drugs which could reduce or eliminate ards should be targeting the ace receptors and macrophage response. research in our laboratory has been, for years, focused on the prevention of long term (chronic rejection) of transplanted organs. during these studies, we showed that chronic rejection depends on the macrophage entry into the allograft and that the application of the inhibitors of small gtpase rhoa pathway prevents macrophage infiltration and inhibits chronic rejection ( ) ( ) ( ) . the rhoa pathway regulates actin cytoskeleton in all eukaryotic cells, and as such also regulates actin-dependent cell movement and recycling and expression of macrophage receptors, which home macrophages to the graft. in our search for clinically applicable rhoa pathway inhibitors we found that drugs clinically approved for the treatment of multiple sclerosis (ms), fingolimod and siponimod, also inhibit rhoa and rhoa/actin-dependent macrophage receptors recycling, and expression, and can be potentially used as an anti-chronic rejection therapy in human transplantation ( , ) . our center is initiating the clinical trial on the effect of fingolimod in kidney transplantation patients. because these clinically approved drugs inhibit, via rhoa/ actin pathway, macrophage movement, and expression of macrophage receptors, they have also a potential to inhibit ace receptors expression and the recruitment of macrophages to the lungs of the covid- patients, which in turn would decrease cytokine storm and attenuate ards. editorial: alveolar macrophages in lung inflammation and resolution alveolar macrophages alveolar macrophages: plasticity in a tissue-specific context cytokine storm in covid- and treatment triptolide mitigates radiation-induced pneumonitis via inhibition of alveolar macrophages and related inflammatory molecules alveolar macrophage activation and cytokine storm in the pathogenesis of severe covid- structural basis for the recognition of sars-cov- by full-length human ace macrophage/monocyte-specific deletion of rhoa down-regulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts macrophages and rhoa pathway in transplanted organs screening rhoa/rock inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts inhibition of rhoa and mtorc /rictor by fingolimod (fty ) induces p -activated kinase , pak- and amplifies podosomes in mouse peritoneal macrophages siponimod (mayzent) downregulates rhoa and cell surface expression of the s p and cx cr receptors in mouse raw . macrophages gene signatures of sars-cov/sars-cov- -infected ferret lungs in short-and long-term models key: cord- - hg be authors: flinspach, armin niklas; zacharowski, kai; ioanna, deligiannis; adam, elisabeth hannah title: volatile isoflurane in critically ill coronavirus disease patients—a case series and systematic review date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: hg be objectives: the ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. although the potential benefits of sedation with volatile anesthetics in coronavirus disease patients are currently being discussed, the use of isoflurane in patients with coronavirus disease –induced acute respiratory distress syndrome has not yet been reported. design: we performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. setting: the study was conducted with patients admitted between april and may , to our icu. patients: we included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus infection. intervention: even with high doses of several iv sedatives, the targeted level of sedation could not be achieved. therefore, the sedation regimen was switched to inhalational isoflurane. clinical data were recorded using a patient data management system. we recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. measurements & main results: mean age (four men, one women) was . (± . ) years. the mean duration of isoflurane sedation was . (± . ) hours. our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. deep sedation as assessed by the richmond agitation and sedation scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of iv sedation was possible within the first minutes. no adverse events were detected. conclusions: our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease infection. volatile isoflurane was able to achieve the required deep sedation and reduced the need for iv sedation. objectives: the ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. although the potential benefits of sedation with volatile anesthetics in coronavirus disease patients are currently being discussed, the use of isoflurane in patients with coronavirus disease -induced acute respiratory distress syndrome has not yet been reported. design: we performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. setting: the study was conducted with patients admitted between april and may , to our icu. patients: we included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus infection. intervention: even with high doses of several iv sedatives, the targeted level of sedation could not be achieved. therefore, the sedation regimen was switched to inhalational isoflurane. clinical data were recorded using a patient data management system. we recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. measurements & main results: mean age (four men, one women) was . (± . ) years. the mean duration of isoflurane sedation was . (± . ) hours. our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. deep sedation as assessed by the richmond agitation and sedation scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of iv sedation was possible within the first minutes. no adverse events were detected. conclusions: our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease infection. volatile isoflurane was able to achieve the required deep sedation and reduced the need for iv sedation. key words: acute respiratory distress syndrome; coronavirus disease ; critical care; deep sedation; severe acute respiratory syndrome coronavirus ; volatile sedation t he ongoing coronavirus pandemic poses new and unprecedented challenges for the healthcare system. severely affected patients may require elaborate critical care treatment including ventilation and extracorporeal membrane oxygenation (ecmo), demanding a sophisticated sedation regime. to facilitate ventilator synchrony and prone positioning during critical care treatment of coronavirus disease (covid- ) patients, deeper sedation levels are often indispensable. based on recently published data and our own experiences regarding the need for unusually high doses of sedation in these patients, special considerations are warranted ( ) . in this regard, the potential benefits of sedation using volatile anesthetics in covid- -induced acute respiratory distress syndrome (c-ards) have been increasingly discussed ( , ) . several studies have demonstrated the safe use of volatile anesthetics in critically ill patients, leading to a decreased duration of mechanical ventilation when treating classical acute respiratory distress syndrome (ards) ( ) ( ) ( ) ( ) ( ) ( ) . known pharmacologic benefits of volatile anesthetics include a low accumulation and metabolism rate (isoflurane: . %), bronchodilatory effects, and antiepileptic properties, which may be favorable for patients who fail to achieve adequate sedation or suffer from severe bronchospasm ( , ) . according to german national taskforce guideline (delirium, analgesia and sedation taskforce ), the use of volatile anesthetics for moderate-to-deep sedation is recommended in critically ill patients with (ards) ( ) . as deep sedation is crucial and repeatedly required in critically ill covid- patients, we assessed the use of isoflurane in patients with severe c-ards ( , ) . this is a retrospective, observational study conducted at university hospital frankfurt. the study was approved by the institutional ethic board of the university of frankfurt (no - ). the need for informed consent from individual patients was waived due to the nature of a retrospective review. we included five patients admitted to the icu who were previously diagnosed with severe acute respiratory syndrome coronavirus (sars-cov- ) infection or who tested positive for covid- during treatment. no other than the five patients with covid- included within this article were treated with volatile sedatives. sars-cov- infection was detected by real-time reverse transcriptase polymerase chain reaction (rt-pcr) testing of nasal and oropharyngeal swabs. the rt-pcr tests were based on the recommended standard of the world health organization and targeted the sars-cov- e-gene as a first-line screening, followed by confirmatory rdrp gene testing ( ) . all patients received mechanical ventilation using an icu ventilator (elisa ; löwenstein medical, bad ems, germany) and intensive care treatment according to current recommendations for managing c-ards ( ) ( ) ( ) . sedation generally consisted of the administration of benzodiazepines and central α receptor agonists, supplemented by esketamine or propofol as indicated. no specific covid- treatment protocols were defined, and treatment was solely at the discretion of the attending physicians, as was the decision to use volatile anesthetic for balanced sedation, performed as combination of isoflurane with sufentanil. in all patients undergoing ecmo therapy, an ultraprotective lung ventilation concept with a targeted volume of less than or equal to ml kg - was used ( ) . volatile sedation under such therapy has already been successfully demonstrated in ards patients up to tidal volumes of ml ( ) . clinical data were continuously recorded using a patient data management system (metavision . ; imdsoft, tel aviv, israel). we recorded demographic data, laboratory results, ventilation variables, sedative dosages, clinical satisfaction of sedation level assessed by the richmond-agitation-sedation scale (rass), prone positioning, duration of volatile sedation, and outcomes. sedation depth was determined by rass, including the occurrence of asynchronous respiratory episodes and vegetative agitation (tachycardia, hypertension, sweating, tachypnea, and tears in the eyes not otherwise explained) ( ) . we defined a clinically satisfactory sedation with predominantly synchronous ventilation and the absence of vegetative agitation. the target sedation depth was a rass less than - ; depending on the treatment, a rass of - was defined as the target for patients in prone position or under ecmo therapy ( , ) . adequate ventilator synchrony was defined as clinical predominant absence of asynchronous phases observing the respiratory volume pressure curves by the attending staff. "triggering of stress response" was defined as follows: suboptimal sedation, resulting in high blood pressure and/or tachycardia and/or repeated coughing. patients were observed with special regard to the occurrence of the following possible complications: • occurrence of an intolerance reaction or anaphylaxis; • occurring of acute renal failure under isoflurane therapy; • liver dysfunction measured by laboratory liver function tests; • hemodynamic instability represented by clinical features of circulatory shock including hypotension, abnormal heart rates, arrhythmias, cold extremities, and/or advanced heart failure or necessity of resuscitation; and • ventilator-associated events, that could not be clinically attributed to a deterioration of covid- infection according to the center of disease control ventilator-associated event protocol ( , ) . for inhalational isoflurane sedation, we used a minimum alveolar concentration (mac)-driven application device (mirustm; pall medical, dreieich, germany). the anesthetic conserving device enables automated end-expiratory control of volatile anesthetics and consists of an anesthetic reflector to conserve and readminister up to % of expiratory isoflurane. the system monitors the end-tidal anesthetic concentration and performs an automatic dose correction to achieve a selected target mac. combining this system with a passive scavenging system (flurabsorbtm; sedana medical, uppsala, sweden) connected to the expiratory limb avoids ambient pollution of volatile anesthetics in the icu ( ) . the patient demographic and clinical characteristics at admission, as well as the therapeutic interventions, are presented in table . to provide an overview of hemodynamic and respiratory stability using isoflurane, please see figure b -d. a -year-old woman had fever and chills for days before she presented herself to a local healthcare provider. intubation was necessary due to the respiratory failure. due to a persisting failure of adequate sedation, volatile sedation with isoflurane (mac = . ) was initiated and enabled cessation of all iv sedatives, with a distinct improvement in ventilator synchrony. after days of inhalational sedation, laboratory findings revealed a pulmonary bacterial superinfection accompanied by deterioration of the respiratory mechanics, leading to the implantation of a venovenous ecmo system. due to gradually decreasing tidal volumes (< ml), sufficient sedation could no longer be achieved, and the sedation regimen had to be switched back to iv pharmaceuticals. a -year-old man was admitted to the emergency department with an -day history of fever accompanied by shortening of the breath and fatigue. subsequently, the patient developed refractory hypoxemia requiring mechanical ventilation and sedation. during the further course of treatment and despite dose adjustments, sedation goals were very difficult to achieve. additionally, episodic airway obstruction occurred, resulting in a switch to isoflurane (mac . ) in combination with sufentanil. the use of the concept of balanced anesthesia enabled adequate sedation, and broncho-obstructive episodes were resolved as the pulmonary compliance increased within the first hours accompanied by improved oxygenation (fig. a) . furthermore, a substantial improvement in ventilator synchrony in pressure-controlled ventilation mode was observed. following a marked improvement in the patient's condition, sedation was switched back to clonidine and midazolam for the successful performance of a percutaneous tracheostomy. thereafter, the sedation was discontinued, and the patient was transferred to an acute rehabilitation center. the third patient was a -year-old man with severe hypoxemia requiring mechanical ventilation. he was transferred to our tertiary university hospital owing to his numerous comorbidities (table ) and persistent respiratory failure. in addition to moderate c-ards, the patient suffered from severe cardiac decompensation and sepsis. aortic valve endocarditis caused by an infection of his implanted pacemaker was detected to be the underlying cause. following cardiac surgery, hemodynamic and respiratory condition improved substantially (fig. ) . however, suboptimal sedation was observed with triggering of stress responses leading to repetitive desaturation, thus initiating isoflurane sedation (mac . ). iv sedation was rapidly discontinued. highly effective sedation (rass - /- ) was achieved under a balanced sedation regime, and the spontaneous respiratory rate decreased from to min - . therefore, the targeted mac was set to . , and analgesia with sufentanil was discontinued. additionally, a reduction of the respiratory minute volume from to l min - was recorded, leading to hypercapnia, which resulted in respiratory acidosis with decreased catecholamine responsiveness. because the respiratory mechanics improved rapidly, deep sedation was no longer required, and successful extubation was achieved on day after discontinuing the inhalational sedation. the patient presented an adequate neurologic status and could therefore be transferred to the normal ward a few days later. a -year-old man with confirmed sars-cov- infection. therefore, endotracheal intubation for invasive ventilation and prone positioning were required. the patient was transferred to our tertiary university hospital for urgent initiation of venovenous ecmo. after the commencement of ecmo therapy and prone positioning, suboptimal sedation was observed despite unusually high doses of iv sedation. concurrently, several bronchospastic episodes were observed. by switching the sedation to isoflurane (mac . ) and sufentanil, stable hemodynamics and adequate sedation were achieved (fig. , b and d) . despite the improved sedation levels and the associated increased respiratory synchrony, the tidal volumes gradually decreased, resulting in insufficient volatile sedation. the sedation regime was then switched from inhaled isoflurane back to an iv sedation method. a -year-old patient presented to our emergency department due to increasing dyspnea, and covid- was diagnosed. after days of invasive ventilation, the implementation of venovenous ecmo was necessary. due to concomitant acute renal failure, renal replacement therapy was initiated. the deep sedation required for venovenous ecmo therapy and prone positioning was impossible with iv sedation. after initiating isoflurane sedation (mac . ) in addition to sufentanil, a marked improvement in respiratory synchrony and adequate sedation levels were achieved. after days of ecmo therapy, the tidal volume gradually decreased up to ml despite ventilator adjustments, resulting in inadequate volatile sedation. the sedation was therefore switched back to iv sedation with clonidine and sufentanil. during the observation period, the mean rass was assessed as - , - , and - for . %, . %, and . % of the time, respectively (data not shown). as reported, cases and showed a considerable clinical improvement of the bronchial-obstructive episodes. this case series of five patients demonstrates the feasibility of using isoflurane for the inhalational sedation of critically ill covid- patients. to the best of our knowledge, no studies have investigated the effect of isoflurane sedation in patients suffering from c-ards so far, and it remains understudied whether the observed pathophysiologic pulmonary abnormalities, such as exudative and proliferative phases of a diffuse alveolar injury, might have an impact on the feasibility of volatile sedation ( ) ( ) ( ) . as increasingly discussed, inhalation of volatile anesthetics might be of some benefit in covid- -infected patients ( , ) . at present, sedation regimens for covid- patients are based on the standard guidelines for critical care and on previous experiences in treating patients with "classic" ards. although the surviving sepsis campaign recommends considering the use of neuromuscular blocking agents (nmbas) for deep sedation in cases of persistent ventilator dyssynchrony and prone positioning, more detailed recommendations for pharmacologic sedation are not yet available ( ) . nmbas were applied in our therapy concept in the first hours after intubation ( ) ( ) ( ) . the application of nmbas has not been necessary in any of the patients included in this study after the initiation of inhalational sedation. this enabled patients to breathe spontaneously during most of the treatment period. the role of spontaneous breathing during mechanical ventilation in ards has not yet been conclusively clarified and is still discussed ( , ) . since the net impact depends on the severity of the lung damage, the optimal ventilation strategy regarding the ventilation mode has to be considered individually. several authors have recommended deep sedation for these patients, especially to minimize the potential aerosol generation from coughing and thus protect medical personnel and to provide optimal patient care ( , , ) . in contrast to patients with "classic" ards, the experiences of our department and others highlight that a large proportion of covid- patients may require unusually high sedation levels ( , ) . the underlying reasons for these high sedation requirements are not yet understood but may be related to younger age and good health of some patients prior contracting covid- . however, in regard to our data, this assumption does not correspond to the patients we observed and requires further research. inhalational sedation may therefore be a suitable and promising alternative for patients with c-ards, also in light of the reported shortage of sedative pharmaceuticals ( , ) . additionally, there may be further beneficial effects regarding the frequently observed need for long-term ventilation in c-ards patients and the associated facilitation of ventilator synchrony, prone positioning, and ecmo therapy that requires deeper sedation levels ( ). however, it has to be mentioned that regardless of the volatile conserving device used, the required components are not very common in intensive care medicine and therefore represent the primary limitation for widespread use. a conceivable elimination of this limitation can be overcome by the pandemic-related use of anesthesia circuit components from the operating room ( ) . our experience with the use of volatile sedation in five patients with c-ards was in line with previous studies on the use of isoflurane in critically ill patients ( , ) . we did not observe any renal or hepatic toxicity, as it has been described for volatile sedation ( , ) . in fact, we were able to rapidly and closely control the depth of sedation; this has also been reported in previous patient cohorts ( ) . as presented, our experiences reinforce that the use of volatile sedation depends on achieving an adequate tidal volume. to maintain an adequate respiratory uptake of isoflurane, a sufficient respiratory minute volume is essential and may be limited by a lung-protective ventilation strategy, especially during ecmo treatment. rand et al ( ) and meiser et al ( ) showed that volatile sedation is feasible in patients undergoing ecmo therapy these studies demonstrated that despite ultraprotective ventilation with low tidal volumes and poor lung function, adequate sedation with volatile anesthesia could be achieved. however, all patients presented in this study who underwent ecmo therapy suffered from extensive covid- -associated lung damage, which resulted in low tidal volumes applying ultraprotective lung ventilation. tidal volume less than ml precluded sufficient sedation with volatile anesthetics, resulting in a switch back to iv sedation. the feasibility of administering volatile anesthetics during a cardiopulmonary bypass has already been demonstrated; however, this has not yet been described for the ecmo circuit in icus but should be considered as a future therapeutic approach, especially in regard to our observations ( ) . in addition to the predominantly favorable effects of isoflurane in the treated patients, respiratory depression related to the pharmacodynamics of inhalational anesthetics was observed in one patient (case ) as a result of volatile sedation at the end of a prolonged weaning process ( ) . in line with current recommendations, we therefore suggest adhering to bedside sedation algorithms and verifying the safety criteria to avoid inappropriate deep or prolonged sedation when applying volatile sedation in covid- patients ( ) . we observed a reduced need for opioid sedation during treatment and an improved lung function with regard to the pao /fio ratio. most notably, in cases and , volatile isoflurane successfully resolved the multiple broncho-obstructive episodes. in regard to the proven impact of underlying respiratory diseases and their attribution to a worse progression and outcome of covid- , volatile sedation could be beneficial in improving the covid- -associated lung injury ( ) . some limitations must be taken into account when interpreting our results. although relevant sequestration through the polymethylpentene membrane of modern oxygenators has not yet been demonstrated, the transient absorption of gaseous isoflurane from the polyvinylchloride tubes of the ecmo circuit may impact the patient ( , ) . furthermore, the small number of five patients displaying different comorbidities and age does not allow a detailed analysis of the dynamics of sedation or pharmacokinetic mechanisms in critically ill covid- patients. additionally, we did not consider the interindividual dynamics of ventilation, sedation, and lung mechanics when interpreting the data. due to the short and limited observation time, we carefully avoid to overclaim our findings. the authors feel confident that the observations obtained within this study are applicable to patients suffering from covid- requiring critical care. further research and long-term observational studies of covid- patients who receive isoflurane sedation are necessary to clarify the pharmacodynamic mechanisms and clinical effects in order to establish a dose-response relationship. in this first report of applying volatile sedation in patients with c-ards, we demonstrated the feasibility of isoflurane sedation in five cases. the use of volatile isoflurane achieved the required deep sedation and even a reduction of iv sedation accompanied by improved pulmonary function. drs. flinspach and deligiannis contributed to clinical data collection. drs. flinspach and adam contributed to article writing. drs. flinspach, zacharowski, and adam contributed to critical revision and article drafting. all authors reviewed the article for important intellectual content and approved the final version. supported, in part, by institutional and/or departmental sources. the authors have disclosed that they do not have any potential conflicts of interest. for information regarding this article, e-mail: armin.flinspach@kgu.de sedation of mechanically ventilated covid- patients: challenges and special considerations sevoflurane, a sigh of relief in covid- ? sedating ventilated covid- patients with inhalational anesthetic drugs the use of volatile anesthetic agents for long-term critical care sedation (valts): study protocol for a pilot randomized controlled trial volatile isoflurane sedation in cerebrovascular intensive care patients using anaconda(®): effects on cerebral oxygenation, circulation, and pressure perioperative anesthesia clinical trials group: volatile-based short-term sedation in cardiac surgical patients: a prospective randomized controlled trial survival after longterm isoflurane sedation as opposed to intravenous sedation in critically ill surgical patients: retrospective analysis prolonged isoflurane sedation of intensive care unit patients with the anesthetic conserving device halogenated volatile anesthetics in the intensive care unit: current knowledge on an upcoming practice isoflurane therapy for severe refractory status asthmaticus in children evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. revision (das-guideline ) -short version sedation for critically ill patients with covid- : which specificities? one size does not fit all the use of volatile anesthetics as sedatives for acute respiratory distress syndrome interpreting diagnostic tests for sars-cov- management of covid- respiratory distress german recommendations for critically ill patients with covid- proseva study group: prone positioning in severe acute respiratory distress syndrome mechanical ventilation in patients subjected to extracorporeal membrane oxygenation (ecmo) inhalative sedation with small tidal volumes under venovenous ecmo sedation practice in intensive care evaluation study investigators; australian and new zealand intensive care society clinical trials group: early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study* effect of extracorporeal membrane oxygenation use on sedative requirements in patients with severe acute respiratory distress syndrome developing a new, national approach to surveillance for ventilator-associated events: executive summary cdc: ventilator-associated event (vae). . available at the scavenging of volatile anesthetic agents in the cardiovascular intensive care unit environment: a technical report pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- covid- pneumonia: different respiratory treatments for different phenotypes? postmortem lung findings in an asthmatic with coronavirus disease (covid- ) surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) the role of neuromuscular blockers in ards: benefits and risks prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: we are not sure prone positioning and neuromuscular blocking agents are part of standard care in severe ards patients: yes fifty years of research in ards. spontaneous breathing during mechanical ventilation. risks, mechanisms, and management long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury intubation and ventilation amid the covid- outbreak: wuhan's experience società italiana di anestesia analgesia rianimazione e terapia intensiva (siaarti) airway research group, and the european airway management society: the italian coronavirus disease outbreak: recommendations from clinical practice fda: current and resolved drug shortages and discontinuations re ported to fda anesthesia and intensive care ventilators: differences and usability in covid- patients methoxyflurane nephrotoxicity. a study of dose response in man current state of critically ill patients sedation with volatile anesthetics. its role in renal and hepatic toxicity volatile anesthetics. is a new player emerging in critical care sedation? inhaled sedation in patients with acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation an innovative technique to improve safety of volatile anesthetics suction from the cardiopulmonary bypass circuit mechanisms of actions of inhaled anesthetics american college of critical care medicine: clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit effect of chronic obstructive pulmonary disease and smoking on the outcome of covid- reduced sevoflurane loss during cardiopulmonary bypass when using a polymethylpentane versus a polypropylene oxygenator sorptive loss of volatile and gaseous anesthetics from in vitro drug application systems key: cord- -d g toc authors: yu, feng; zhu, jing; lei, ming; wang, chuan‐jiang; xie, ke; xu, fang; lin, shi‐hui title: exploring the biomarkers associated with different host inflammation of acute respiratory distress syndrome (ards) from lung metabolomics in mice date: - - journal: rapid commun mass spectrom doi: . /rcm. sha: doc_id: cord_uid: d g toc rationale: the aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ards) for the identification of biomarkers for predicting severity under different inflammatory conditions. methods: cecal ligation and puncture (clp) and lipopolysaccharide (lps)‐intratracheal injection induced acute lung injury (ali). a mouse model was used to explore lung metabolomic biomarkers in ali/ards. the splenectomy model was used as an auxiliary method to distinguish between hyper‐ and hypo‐inflammatory subtypes. plasma, lung tissue and bronchoalveolar lavage fluid (balf) samples were collected from mice after clp/lps. the severity of lung injury was evaluated. expression of tumor necrosis factor‐α (tnf‐α) in mice serum and lung was tested by elisa and pcr. polymorphonuclear cells in balf were counted. the lung metabolites were detected by gc/ms, and the metabolic pathways predicted using the kegg database. results: the lps/clp‐splen group had more severe lung injury than the corresponding ali group; that in the clp‐splen group was more serious than in the lps‐splen group. tnf‐α expression was significantly elevated in the serum and lung tissue after lps or clp, and higher in the lps/clp‐splen group than in the corresponding ali group. the level of tnf‐α in the clp‐splen group was elevated significantly over that in the lps‐splen group. both these groups also showed significant neutrophil exudation within the lungs. during differential inflammation, more differential metabolites were detected in the lungs of the clp‐group ali mice than inthe lps group. a total of compounds were detected in the lungs of the clp and clp‐splen groups. contrastingly, compounds were detected in the lungs of the lps and lps‐splen groups. the lps‐splen and clp‐splen groups had significant neutrophil exudation in the lung. random forest analysis of lung‐targeted metabolomics data indicated ‐hydroxyphenylacetic acid, ‐aminocyclopentanecarboxylic acid (acpc), cis‐aconitic acid, and hydroxybenzoic acid as strong predictors of hyper‐inflammatory subgroup in the clp group. furthermore, with splenectomy, differential metabolic pathways between the clp and lps groups were revealed. conclusions: hyper‐inflammatory subgroups of ards have a greater inflammatory response and a more active lung metabolism. combined with host inflammation background, biomarkers from metabolomics could help evaluate the response severity of ards. acute respiratory distress syndrome (ards) is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue [ ] . although years have passed since the first description of ards [ ] , the overall mortality is still more than % [ , ] . unfortunately, it is a clinical feature of very different mechanisms, with complex syndromes, and biological and clinical heterogeneity. because of the heterogeneity of the host response, it is difficult to found the key to curing every patient with ards. the clinical and biomarker characteristics of ards patients demonstrated hypo-inflammatory and hyper-inflammatory effects [ ] .specific subsets of critically ill patients have higher risk of disease-related outcome or differential responses to therapy [ , ] .therefore, the different inflammatory sub-phenotypes of ards may indicate varied risks related to the disease [ ] . metabolic phenotypes, which represent different pathways important to the pathophysiology of ards, could potentially be used to identify the subgroup that may benefit from certain targeted therapies [ ] . about one third of hyper-inflammatory ards patient have a higher plasma level of inflammatory biomarkers [ ] . some biological indicators, such as endocan [ ] , srage and ang- [ ] , are closely related to the hyper-inflammatory subphenotype of ards. tnf-α is an important inflammatory factor that can induce t cells to produce various inflammatory factors, and then promote the occurrence of inflammatory reactions. it has been reported that tnf-α is a potential biomarker for acute respiratory distress syndrome, as well as for mortality in patients with obesity and coronavirus (covid- ) [ ] . in addition, studies have found that -hydroxybenzoic acid has anti-catabolism and anti-inflammatory effects, and prevents the upregulation of pro-inflammatory markers, including metalloproteinases and cyclooxygenase [ ] . whether acps, as a small molecule, also has such potential needs further study. thus, classification of patients with ards into hyper-and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy [ ] . metabolism has increasingly been acknowledged as a potential target for therapies aimed at modulating the immune system either to enhance or to suppress immunological responses [ ] . due to the coupling of inflammation with metabolism, the novel "inflammation-immunitymetabolism axis" may be another useful way to propose new therapeutic implications and deeper understanding for ards. metabolomics is a rapidly expanding field of systems biology that provides the ability to generate a "snapshot" measurement of all small molecules and this article is protected by copyright. all rights reserved. metabolites in a given sample [ , ] . the burgeoning field of metabolomics lies in its application to acute lung diseases, specifically pneumonia and ards [ ] . the application of untargeted metabolomics for biomarker discovery is well suited to the complexity of ards because metabolomics can detect several hundreds of metabolites, depending on the analytical platform, from a single sample, with minimal bias and no prior knowledge of the sample composition [ , , ] .we have found that specific compounds related to hypoxia may serve as early biomarkers for ards, while metabolites with significant correlations with the partial pressure of arterial oxygen (pao )/percentage of inspired oxygen (fio ) may play a role in determining its severity [ ] . however, it is difficult to find specific metabolic evidence in clinical samples related to differences in inflammatory hosts. the spleen is a site where immune responses that are deleterious to the host can be regulated [ ] . the white pulp of spleen is a secondary lymphoid organ with key functions in immune response initiation and regulation. various immune cells (macrophages, dendritic cells, subsets of b and t lymphocytes) of the white pulp trap antigens and generate an antigen specific response against invading pathogens (bacteria, viruses and fungi). patients without a spleen (resulting from traffic accidents, trauma, etc.) have severe inflammation and a high risk of death in sepsis. therefore, we think that patients without a spleen may form acute lung injury (ali) models with "all or nothing" different subtypes of inflammatory hosts. we have also confirmed that this ali lack-of-spleen model will not die quickly as a result of complete immunodeficiency [ ] . in order to explore differences of metabolism in host inflammation of ards, we established a special ali mode (with spleen or without spleen, induced by lipopolysaccharide (lps)-tracheal infusion, or cecal ligation and puncture (clp). gc/ms metabolomics was then used to determine the endogenous metabolites in the lung tissues. c bl/ mice (male, - weeks old) from the laboratory animal center of chongqing medical university (cqmu, chongqing, china) were usedthe . previous studies had shown that estrogen provides a protective effect in ards [ ] . as, however, the role of hormones is not the research aim in this study, we chose only male mice for the studies [ ] .the mice were acclimatized to the new environment for seven days at °c with a free access to water and food and with a h light/dark cycle before experiments. the study was performed according to international, national and institutional rules concerning animal experiments, clinical studies this article is protected by copyright. all rights reserved. and biodiversity rights. the study protocol was approved by the ethics committee of our institute. the abdominal incision was then closed. in a "sham" operation on mice, the abdominal wall was cut, the spleen was only slightly spit, and there was no resection. the mice were given subcutaneous injections of ceftriaxone ( ug/g) for three days after surgery. fourteen days later, these splenectomy mice were used to establish the model [ ] . lps-induced ali was performed to establish an ali mouse model, using the same anesthesia method as described above. a mg/ml solution of lps was injected into mice through intratracheal instillation, and the control group was injected with the same volume of sterile phosphate-buffered saline (pbs) [ ] . the mice were randomly divided into three groups: control group (n= ), lps group (lps, n= ), and splenectomy group (lps-splen, n= ). the nice were euthanized by carbon dioxide box anesthesia h, h, and h after being challenges with lps or pbs, and blood and lung tissues were harvested for analysis. mice were randomly divided into three groups: control group (n= ), clp group (clp, n= ), and splenectomy group (clp-splen, n= ) and the anesthesia method was followed as previously described. the mice were positioned in dorsal recumbency. after shaving and this article is protected by copyright. all rights reserved. aseptic preparation of the surgical site, a ventral midline incision ( cm) was made to allow exteriorization of the cecum. the cecum was identified and was penetrated through-andthrough with a -gauge needle with a - silk suture at % from the tip. after being punctured, the cecum was gently squeezed to extrude a small amount of feces and returned to the abdominal cavity. the abdominal incision was then closed. sham-operated control mice (sham group) were subjected to the same surgical laparotomy after anesthesia, where the cecum was exteriorized and manipulated as described but not ligated or punctured. immediately after surgery, the animals were resuscitated with ml/kg saline injected subcutaneously [ ] . at the end of the experiment, the mice were euthanized by carbon dioxide box anesthesia h, h, and h after the clp procedure to collect whole blood and lung tissues for analysis. lung tissue samples were collected h post challenge with lps or clp. the superior lobe of the right lungs was fixed with % formalin in pbs for h, dehydrated in a graded ethanol series, and embedded in paraffin. paraffin sections were then stained with hematoxylin and eosin (h&e) followed by microscopic assessment and photographic documentation. lung injury scores were estimated; the higher the score, the more severe the injury. the four following indicators of lung injury were used to arrive at this score: alveolar congestion; bleeding; gap or vascular wall neutrophil infiltration or aggregation; and alveolar septal thickening or transparent membrane formation. the marking system was: marks, no or very slight damage; mark, mild injury; marks, moderate injury; marks, severe injury; and marks, very severe damage. the cumulative increase in the number of lesions related to the total score yields the pathological score of lung injury. the blood vessels leading to the lungs and the left bronchus were ligated h post challenge with lps or clp. μl of pbs was injected into the right lung through the trachea and, seconds later, the pbs was removed and the bronchoalveolar lavage fluid (balf) was collected. these lavages were carried out twice, and a total of μl of balf was collected. the serum, balf, spleen, and lung tissues were harvested for analysis. blood and lung tissue samples were taken h post challenge with lps or clp. blood was drawn from mice and allowed to coagulate for h at room temperature. the serum was then obtained by centrifuging the blood samples at °c for min at , ×g. the lungs were this article is protected by copyright. all rights reserved. ground in pbs ( mg tissues/ μl pbs). the serum and lung homogenate were then aliquoted and kept frozen at - °c until analysis. the tumor necrosis factor-α (tnf-α) levels were measured by elisa. total cellular rna was extracted from lung tissue using trizol reagent accompanied by dnasei digestion. quantitative real-time polymerase chain reaction (qrt-pcr) for mouse tnf-α was performed using specific primers (designed and synthesized by takara for s. gene expression normalized to gapdh was used to determine relative target gene expression by the ΔΔc(t) method. twenty mg of prepared mice lung tissue was added to fresh tubes, followed by the addition of μl of the internal standard, l-alanine- , , , -d ( mm). after adding μl of cold methanol-water ( % v/v), the tissues were homogenized and centrifuged ( , × g, min) to collect the supernatant. the lung tissue was dried using a speedvac and stored at - °c prior to derivatization. the volatilities of extracted metabolites were lowered using methyl chloroformate (mcf) derivatization, based on the protocol of smart et al [ ] . in brief, μl of sodium hydroxide ( m) was added to the speedvac-dried samples. ml of methanol and μl of pyridine were also added as the methyl group donor and catalyst, respectively. the reaction was started by adding μl mcf, followed by seconds of vortexing and subsequently adding another μl of mcf, followed by seconds of vortexing. in order to isolate derivatized metabolites from the reactive mixture, μl of chloroform and μl of sodium bicarbonate ( mm) were added and vortexed for seconds. the chloroform phase was isolated, and excess water was removed by adding anhydrous sodium sulfate. this article is protected by copyright. all rights reserved. the derivatized samples were analyzed using a gas chromatograph (agilent, santa clara, ca, usa) fitted with a zb- capillary column ( m × μm id × . μm with a -m guard column; phenomenex, torrance, ca, usa) coupled to an agilent msd single quadrupole mass spectrometer operating in electron ionization mode at ev. the gc and ms procedures followed the protocol outlined by smart et al. [ ] the isolated chloroform phase was injected at °c in pulsed splitless mode with helium carrier gas at a flow rate of ml/min. the program temperature was as follows: initial temperature of °c, ramped at °c/min to °c, then at °c/min to °c, and finally at °c/min to °c. the auxiliary temperature, quadrupole mass analyzer temperature, and source temperature were set to , , and °c, respectively. the mass range was m/z - , the scan speed . m/z units/s and the solvent delay . min. compound deconvolution and identification were performed by the automated mass spectral deconvolution and identification system (amdis; nist, gaithersburg, md, usa) software, using our internal methyl chloroformate derivatization mass spectra library of metabolite standards. the compounds were identified based on two criteria: > % match with the library spectrum and within a -min bin of the respective chromatographic retention time. the relative abundance of the metabolites was extracted via our in-house massomics software, using the peak height of the highest reference ion mass. the metabolite values were normalized by the abundance of the internal standard (l-alanine- , , , -d ) and total ion count, in order to correct for experimental variability. the metabolomics data have been deposited to the embl-ebi metabolights database (doi: https://doi.org/ . /nar/gks .) [ ] with the identifier mtbls . the abundance of identified compounds was adjusted to a gaussian distribution via log transformation prior to statistical analysis. multivariate analysis of anova followed by tukey's hsd test was performed in r. the predicted metabolic activities were determined using our pathway activity profiling r package based on the kegg online database. the relative metabolic activities were transformed to have a mean of zero and a standard deviation of one (z-score). subsequently, the metabolic pathways were classified according to their cellular processes, and only the predicted metabolic pathways with p values and q values less than . were displayed. the metabolic activities were first normalized by log transformation and pareto scaling, followed by ranking of the metabolic pathways using a random forest model to capture their contribution to the classification accuracy demonstrated in a vip plot. the metabolic network was constructed according to a pathway-based framework provided by this article is protected by copyright. all rights reserved. metscape that connected the kegg human metabolic pathways with our identified metabolites via the kamada-kawai layout, which relates the layout of metabolites to minimize metabolic reactions between metabolites within a metabolic network. all the illustrations and figures displayed were plotted using the ggplot r package, graphpad prism (graphpad software, san diego, ca, usa), and spss . (ibm, amonk, ny, usa). mice (with or without splenectomy) were euthanized h post challenge with lps or clp. the administration of lps or clp led to severe lung injury, compared with the controls ( figure a ). the lung injury scores showed that splenectomy can aggravate lung injury directly in either the lps or the clp group, p < . ( figure a ). all parts of the lung injury degree index, such as thickened alveolar wall, hemorrhage in the alveolus, alveolar collapse, and inflammatory cell infiltration in the lps-splen group or clp-splen group, were more severe than in the corresponding ali group. moreover, the lung injury in the clp-splen group is more serious than in the lps-splen group, p < . ( figure a ; supplementary table , supporting information). the concentrations of tnf-α were significantly elevated in the serum and lung tissue after lps or clp compared with the controls, p < . ( figures b and c ). in addition, the expression of tnf-α in the lps-splen or clp-splen groups was higher than in the corresponding ali (lps or clp) groups. the levels of tnf-α in the clp-splen group were significantly elevated compared with the lps-splen group, p< . ( figures b and c ). subsequently, infiltration of neutrophils was confirmed with neutrophil numbers in balf ( figure d ). after splenectomy, the lps(splen) and clp(splen) groups have significant neutrophil exudation in the lungs ( figure d ). the pls-da and leave-one-out cross-validation results are shown in figure . the supervised pls-da showed that the four different groups were well-clustered, with specific metabolic profiles for each ( figure b ). after anova was performed for the clp and clp-splen groups, a total of compounds were detected in the lungs, including metabolites from organic acids ( / , . %), amino acids ( / , . %), amino acid derivatives ( / , . %), and others ( figure a; supplementary figure , supporting information). in the random forest (rf) analysis the "mean decrease accuracy" indicates how much a certain metabolite contributes to separation of the groups, and the overall "predictive accuracy" is this article is protected by copyright. all rights reserved. indicative of the accuracy of a set of metabolites in discriminating spleen status [ ] . rf analysis of lung-targeted metabolomics data defined a set of metabolites that constitute the best predictors of differences in host inflammation status: in particular, increased hydroxyphenylacetic acid, -aminocyclopentanecarboxylic acid (acpc), and cis-aconitic acid, tridecane and hydroxybenzoic acid were strong predictors of the hyper-inflammatory subgroup in clp-induced ali ( figure b ). after anova was performed for the lps and lps-splen groups, only compounds were detected in the lungs. the organic acids ( / , %) make up the largest category among the subgroups of different inflammation in ali, which was induced by lps ( figure c ). consequently, under differential inflammation (hyper-vs hypo-), the lungs of clp-induced ali will detect more differential metabolites than the lpsinduced ali lungs ( figures a and c ). detailed information on this is displayed in supplementary table (supporting information). when clustering the hyper-inflammatory and hypo-inflammatory classes separately, difference in the lung metabolites between clp and lps were found. under splenectomybased conditions, there were differential metabolites between the clp and lps groups; the organic acids ( / , . %) and tca cycle inter mediates ( / , . %) were the two largest categories ( figure d ). under no-splenectomy-based conditions, there were only differential metabolites between the clp and lps groups and the organic acids ( / , . %) formed the largest category ( figure e ). while identifying the linked metabolic pathways, the anova test was used to extract significant pathways from them. for the clp and clp-splen groups, the kegg alignment revealed pathways that were linked to the above-detected metabolites. amino acid metabolism ( / , . %), chemical structure transformation maps ( / , . %), biosynthesis of other secondary metabolites ( / , . %), metabolism of other amino acids ( / , . %), and carbohydrate metabolism ( / , . %) were the first five largest categories ( figure a ). for the lps and lps-splen groups, however, only pathways linked to the above-detected metabolites were revealed from kegg. the benzoic acid family, bisphenol degradation, and folate biosynthesis were revealed in the h-post-lps-intervention group. in addition, tropane, piperidine and pyridine alkaloid biosynthesis, biosynthesis of phenylpropanoids, and phenylalanine metabolism were revealed in the h-post-lpsintervention group ( figure b ). the hyper-inflammatory and hypo-inflammatory groups were this article is protected by copyright. all rights reserved. then clustered to predict the metabolic pathways separately. under splenectomy-based conditions, there were differential metabolic pathways between the clp groups and the lps groups ( figure c ). however, we cannot find differential metabolic pathways between the clp groups and the lps groups under no-splenectomy-based conditions. ards is a clinically and biologically heterogeneous disorder associated with effects such as trauma, shock, infection, and sepsis. failure of clinical therapeutic trials prompted the investigation and subsequent discovery of two distinct phenotypes of ards (hyperinflammatory and hypo-inflammatory) that have different biomarker profiles and clinical courses and respond differently to management strategies [ ] . the hyper-inflammatory subgroup (about one third of all) shows t higher mortality, higher severity of illness, and worse clinical outcomes [ ] . even in covid- , the hyper-inflammatory response is closely related to the ards of critical covid- pathogenesis [ ] . a major issue is that ards is such a heterogeneous, multi-factorial, end-stage condition that the strategies for "lumping and splitting" are critical [ ] . metabolic phenotypes, representing different pathways important in the pathophysiology of ards, can be used to identify the subgroups [ ] . they can also help distinguish the subphenotypes of ards (hypo-inflammatory and hyper-inflammatory) and identify the risk of developing ards, diagnosis, risk stratification and monitoring. the use of metabolomics as a possible diagnostic tool for ards has been investigated in several studies, including exhaled breath and oedema fluid analyses. we previously found that phenylalanine, aspartic acid, and carbamic acid levels were significantly different in the plasma samples of ards patients [ ] . four metabolites (ornithine, caprylic acid, azetidine, and iminodiacetic acid) could serve as metabolic phenotypes to potentially predict the severity of ards [ ] . due to the limitations of the research conditions, it is difficult to distinguish the subtypes of inflammation solely by metabolomics. the spleen performs vital hematological and immunological functions. removal of the spleen had already been established as a routine technique to treat splenic trauma and other diseases affecting the spleen [ ] . however, splenectomized (asplenic) or hyposplenic individuals have an increased risk of infections [ ] , and this can lead to severe sepsis known as overwhelming post-splenectomy infection (opsi), which has a very high mortality rate [ ] . a previous study showed that a higher charlson comorbidity index score was significantly associated with severe sepsis/septic shock post-splenectomy [ ] . moreover, splenectomy can this article is protected by copyright. all rights reserved. alter the serum cytokine profile, exacerbating the systematic inflammatory responses and injury to multiple organs [ ] . the spleen is necessary for the recruitment of classical monocytes and neutrophil extravasation into the injured lungs [ ] , and it can play an important role in intestinal ischemia-reperfusion (iir)-induced ali [ ] . furthermore, the spleen coordinates interleukin(il)- -dependent il- production, which reduces lung injury during experimental acute kidney injury(aki) [ ] . splenic factors also exacerbate sap-associated lung injury [ ] . in animal experiments, the splenectomy model can be used as an auxiliary method to distinguish high and low inflammatory subtypes. therefore, an ali animal model of host inflammation differentiation can be established after carrying out a splenectomy. the splenectomy model, which could demonstrate the significant involvement of autoimmunity, plays an important role in the experiment. however, it has a higher mortality rate under experimental conditions, and this mortality rate is significantly increased when combined with the clp model [ ] . in our study, this mortality rate was very high after conducting the splenectomy followed by clp and the passage of time (from to h). in order to ensure the homogeneity of experimental mice in metabolic analysis, the same batch of mice was used to establish models synchronously, such that they would have an effective cluster effect. it was difficult to achieve a greater number of animals at each time point and in each group because of the extremely high mortality rate, and because of the existing limitations of these special animal models. ideally, more mice (over ) in each group would be beneficial for repetitive data collection. we found that the clp-splen and lps-splen groups had more severe lung damage than the corresponding non-splenectomy ali group ( figure a) . moreover, the lps-splen and the clp-splen groups showed significant neutrophil exudation in the lungs after splenectomy; however, the changes in the clp-splen group were more significant ( figure d ). possible causes may be that splenectomy did not affect neutrophil extravasation in the lps models of lung injury, as was confirmed by rieg et al [ ] , or because of tnf-α-induced adhesion of monocytes to endothelial cells and leukocyte transmigration in ali. we found that the expression in lps-splen or clp-splen group was higher than in the corresponding ali group, and that the levels of tnf-α in the clp-splen group were significantly elevated, compared with the lps-splen group, p< . (figures b and c) . cd receptor [ ] .the sensitizing effect of lps stimulation aggravates lung damage [ ] . lbp may play an important role in augmenting tnf-α expression by alveolar macrophages in the lung [ ] : the duration of clp action is prolonged, the stimulatory effect persists, and tnfα expression is higher than with lps-intratracheal injection (figures b and c) . on the other hand, the cholinergic anti-inflammatory pathway is completely inhibited following splenectomy [ , , ] . although, splenectomy itself was not associated with increased serum il- or lung injury, the absence of a counter anti-inflammatory response by splenic il- production results in a high proinflammatory response and lung injury [ ] . based on the difference of inflammation (after splenectomy) in ali, the metabolomic differences of lung tissues could be identified. pca and opls-da were used for discriminant analysis, and univariate statistical analysis was used to screen important differential metabolites in untreated(hypo-inflammatory) or splenectomy-treated(hyper-inflammatory) ali mice, which had been subjected to different modeling methods (lps or clp). a total of compounds and pathways were found in lungs, differing between hyper-and hypo-inflammatory in clp groups ( figures a and a) . however, only compounds and pathways were found to differ in the lungs between hyperinflammatory and hypo-inflammatory in lps (figures c and b ). this suggests that nonpulmonary ards (such as clp) has more active lung metabolomics changes that are involved in inciting the differences of host inflammatory response. moreover, continuous stimulation of clp promoted inflammation and injury to the lungs. organic acids form the largest group of differential metabolites in clp and lps under differential inflammatory conditions, and can be attributed to defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. related physiological analysis had found that sepsis experienced a highly catabolic status. many proteins decompose into amino acids to supply energy, which seemed to be relevant to poor prognosis [ , ] . thus, the concentration of amino acids and its derivatives ( / , . %) demonstrated a notable upward tendency in the clp group ( figure a ). among the metabolic pathways, this category, including amino acid metabolism ( / , . %) and metabolism of other amino acid ( / , . %), also dominates ( figure a ). interestingly, rf analysis of lung-targeted metabolomics data showed that the metabolic biomarker group with products was a strong predictor of the hyper-inflammatory subgroup in clp-induced ali ( figure b ). -hpa, as one of the major metabolites in polyphenols, is a necessary adaptive response of microbiota to the stress-induced changes in inflammation [ ] . -hpa could be a biomarker for quantifying leukocyte-mediated damage [ ] , and it has been confirmed to participate in the intermediate step of tyrosine degradation [ ] . acpc is a this article is protected by copyright. all rights reserved. nonmetabolized amino acids. amino acid transport by system "a" is sodium-dependent and results in a high intracellular-to-extracellular gradient [ ] . apac was also shown to have a high affinity for the "a" transport system of endothelial cell membranes [ ] . sepsis specifically decreases cell membrane potential and inhibits the amino acid transport system a [ ] . this is probably because of the reduction in the pulmonary absorption of amino acids in ards. hypoxia cause an imbalance of the nadph/nadp+ and nadh/nad+ ratios, accompanied by the accumulation of intermediates of the tca cycle, such as cis-aconitic acid, as was found by rf analysis. ane may be a substance derived from environmental factors. exposure to fuels and heavy metabolites ( -tridecanone, -tridecanol, and -tetradecanol) was observed only in the lung tissues, possibly indicating that metabolism occurred in the lungs [ ] . however, the aliphatic compound n-tridecane showed no cytotoxic effects on chemoattractant protein- (mcp- ) and il- production [ ] . we therefore believe that tridecane cannot be a member of metabolic biomarker group. low-molecular-weight phenolic acids (phas) are the products of the degradation of aromatic amino acids and polyphenols by the intestinal microflora [ ] , and all phas have an impact on mitochondria and neutrophils. low-molecular weight phas of microbial origin participate in the regulation of the ros production in both the circulation and tissues, thereby affecting the level of oxidative stress [ ] . therefore, there may be a group of metabolic biomarkers related to inflammation, hypoxia, infection, etc. between the hyperinflammatory and hypo-inflammatory subgroups of ards. the etiology has also become a variable. when we clustered the hyper-inflammatory and hypo-inflammatory separately, there were differential metabolites and differential metabolic pathway between the clpgroups and the lps-group in hyper-inflammatory subgroup ( figures d and c ). in the hypoinflammatory subgroup, there were only differential metabolites between the clp and the lps groups ( figure e ), although no different metabolic pathways could be found in this study. overall, the hyper-inflammatory subgroups of ards were observed to exert more abundant metabolism changes in the lung. metabolomics has the potential to improve our understanding of ards biology. from the analysis of lung metabolomics, the difference of host inflammatory response is a key link in determining the severity of ards. hyper-inflammatory subgroups of ards have a heavier inflammatory response and a more active lung metabolism. combined with host inflammation this article is protected by copyright. all rights reserved. acute respiratory distress syndrome: the berlin definition acute respiratory distress in adults acute respiratory distress syndrome current incidence and outcome of the acute respiratory distress syndrome biomarkers for acute respiratory distress syndrome and prospects for personalised medicine toward smarter lumping and this article is protected by copyright smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design acute respiratory distress syndrome (ards) phenotyping coronavirus disease (covid- ): cytokine storms, hyper-inflammatory phenotypes, and acute respiratory distress syndrome genes dis. . epub ahead of print heterogeneous phenotypes of acute respiratory distress syndrome after major trauma endocan levels in peripheral blood predict outcomes of acute respiratory distress syndrome il- a and tnf-α as potential biomarkers for acute respiratory distress syndrome and mortality in patients with obesity and covid- regulation of inflammatory response in human osteoarthritic chondrocytes by novel herbal small molecules host-response subphenotypes offer prognostic enrichment in patients with or at risk for acute respiratory distress syndrome metabolic pathways involved in regulatory t innovation: metabolomics: the apogee of the omics trilogy metabolic consequences of sepsis-induced acute lung injury revealed by plasma ¹h-nuclear magnetic resonance quantitative metabolomics and computational analysis metabolomics and its application to acute lung diseases the emerging field of quantitative blood metabolomics for biomarker discovery in critical illnesses explore potential plasma biomarkers of acute respiratory distress this article is protected by copyright syndrome (ards) using gc-ms metabolomics analysis the spleen in local and systemic regulation of immunity il- interferes with splenic t cells in a clinical and experimental model of acute respiratory distress syndrome role of extracellular signal-regulated protein kinase (erk) in beta-estradiol-mediated attenuation of lung injury after trauma-hemorrhage reversing established sepsis with antagonists of endogenous high-mobility group box effect of splenectomy on antitumor immune system in mice analytical platform for metabolome analysis of microbial cells using methyl chloroformate derivatization followed by gas chromatography-mass spectrometry metabolights--an open-access general-purpose repository for metabolomics studies and associated meta-data the metabolic footprint of aging in mice recent advances in understanding and treating acute respiratory distress syndrome post-splenectomy sepsis: preventative strategies, challenges, and solutions a single-center prospective cohort study on postsplenectomy sepsis and its prevention. open forum infect dis a new role for the spleen: aggravation of the systemic inflammatory response in rats with severe acute pancreatitis spleen-derived classical monocytes mediate lung this article is protected by copyright ischemia-reperfusion injury through il- β splenectomy attenuates intestinal ischemiareperfusion-induced acute lung injury the spleen as a bidirectional signal transducer in acute kidney injury the effects of heparin and splenectomy on survival and plasma fibronectin levels in rat peritonitis lipopolysaccharide binding protein enhances the responsiveness of alveolar macrophages to bacterial lipopolysaccharide. implications for cytokine production in normal and injured lungs the effect of splenectomy on endotoxin-induced acute lung injury and its potential mechanism in rats. the chinese journal of trauma splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis the spleen: the forgotten organ in acute kidney injury of critical illness splenectomy exacerbates lung injury after ischemic acute kidney injury in mice reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? metabolomic analysis of the effects of adipose-derived mesenchymal stem cell treatment on rats with sepsis-induced acute lung injury gut-brain axis: how the microbiome influences anxiety and depression the metabolism and de-bromination of bromotyrosine in vivo association of the tyrosine/nitrotyrosine pathway with death or icu admission within days for patients with community acquired pneumonia aminocyclopentane carboxylic acid and alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and diethylenetriaminepentaacetic acid in morphologically defined tumor regions effect of sepsis on amino acid transport system a and its response to insulin in incubated rat skeletal muscle metabolites from inhalation of aerosolized s- synthetic jet fuel in rats il- from lung epithelial cells exposed to volatile organic compounds toxic effects of microbial phenolic acids on the functions of mitochondria effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils we are very grateful to the laboratory of lipid & glucose metabolism at the first affiliated hospital of chongqing medical university to provide laboratory facilities. the authors declare no conflict of interest. this article is protected by copyright. all rights reserved. lungs from each experimental group were processed for histological examination after h&e staining. lps-and clp-induced mice exhibited obvious lung injury, p < . . lung injury scores were estimated by the method of mikawa, based on the following four indicators of lung injury score: alveolar congestion; bleeding; gap or vascular wall neutrophil infiltration or aggregation; alveolar septal thickening or transparent membrane formation. these were scored as marks: no or very slight damage, mark: mild injury, marks: moderate injury, marks: severe injury, marks: very severe damage. the number of lesions of the total score is the pathological score of the ali. the lung injury of clp-splen group is more serious than that of the lps-splen group, p < . .(b)(c) tnf-α in serum or lung of mice was detected by elisa or pcr. tnf-α was significantly elevated in the serum and lung tissue after lps or clp, compared with controls, p < . . expression of tnf-α in the lps-splen group or clp-splen group, was higher than in the corresponding ali (lps or clp) group. the levels of tnf-α in the clp-splen group were elevated significantly, compared with the lps-splen group, p< . .(d) infiltration of neutrophils was confirmed with neutrophil numbers in balf. after splenectomy, the lps(splen) group and the clp(splen) group have significant neutrophil exudation in the lung. ****p < . ,*p < . , by two-way anova followed by a lsd multiple comparisons test. each group n = , experiments are repeatable and most representative one was shown.this article is protected by copyright. all rights reserved. key: cord- - xqft authors: rello, jordi; belliato, mirko; dimopoulos, meletios-athanasios; giamarellos-bourboulis, evangelos j.; jaksic, vladimir; martin-loeches, ignacio; mporas, iosif; pelosi, paolo; poulakou, garyphallia; pournaras, spyridon; tamae-kakazu, maximiliano; timsit, jean-françois; waterer, grant; tejada, sofia; dimopoulos, george title: update in covid- in the intensive care unit from the hellenic athens international symposium date: - - journal: anaesth crit care pain med doi: . /j.accpm. . . sha: doc_id: cord_uid: xqft the international web scientific event in covid- pandemic in critically ill patients aimed at updating the information and knowledge on the covid- pandemic in the intensive care unit. experts reviewed the latest literature relating to the covid- pandemic in critically ill patients, such as epidemiology, pathophysiology, phenotypes of infection, covid- as a systematic infection, molecular diagnosis, mechanical ventilation, thromboprophylaxis, covid- associated co-infections, immunotherapy, plasma treatment, catheter-related bloodstream infections, artificial intelligence for covid- , and vaccination. antiviral therapy and co-infections are out of the scope of this review. in this review, each of these issues is discussed with key messages regarding management and further research being presented after a brief review of available evidence. the covid- is an ongoing global pandemic caused by sars-cov- . elderly patients with underlying chronic diseases are considered of high risk for death, like immunocompromised but younger people without major underlying diseases may also present lethal complications [ ] . covid- must be regarded as a systemic disease involving multiple human systems due to the uncontrolled systematic inflammatory response resulting from the release of large amounts of pro-inflammatory cytokines and chemokines by immune effector cells, named "cytokine storm" [ ] . for this reason, we propose the new definition as sars-cov- multiple organ disease syndrome (sars-cov- mods) [ ] . in this situation the treatment with immunomodulatory agents (corticosteroids, tocilizumab, anakinra, sarilumab, etc.) has been widely used, although more laboratory and clinical evidence is required [ ] . a major problem of the coronavirus pandemic is the considerable burden imposed on national health systems worldwide due to the hyperacute outbreak and the proportional increase of patients requiring intensive care unit (icu) support in an extremely limited period of time, while outcomes vary according to the burden of the disease in each country. the pandemic has caused also a major global social and economic disruption while misinformation about the virus has circulated through social and mass media. in this article, through an international webinar meeting which took place in athens greece on september th, , we report an update on information and knowledge on covid- pandemic issues in the icu. j o u r n a l p r e -p r o o f epidemiology infection, caused by sars-cov- , has led to a global pandemic. the clinical and pathological features of acute infection have been extensively published, with a wide spectrum of disease seen, from asymptomatic infection to mild self-limiting symptoms to acute respiratory failure requiring invasive mechanical ventilation (mv) [ ] . the most common clinical finding is fever, cough and fatigue with some laboratory findings such as increased serum ferritin, d dimers and c reactive protein (crp) [ ] . it affects more older adults and there is also a high fatality rate in this subset of patients. acute respiratory distress syndrome (ards) is the primary cause of death in covid- [ ] and a recent scope review found that for covid- , < % of patients were reported as experiencing bacterial/fungal coinfection at admission, but development of secondary infections during icu admission is common [ , ] . patients who do not develop a bacterial infection present high initial crp levels and low procalcitonin (pct) levels, decreasing progressively, with implications on antimicrobial stewardship. therefore, empirical antimicrobial therapy with low serum pct in icu patients should not be indicated. crp does not have predictive value for bacterial infections in icu patients with sars-cov- infection. consideration of superinfection and prompt appropriate use of antibiotics should be considered if pct increase after some days of mv. covid- infection has shown a great variability in terms of mortality in different regions around the globe. an observational study conducted in the us found an excess of , ( % prediction interval, , - , ), more deaths than would typically be expected at the same time of the year [ ] . indirect deaths caused by cardiovascular events, delayed cancer care, or malnutrition may be a serious concern. persistent symptoms after hospital discharge also represent a significant burden after acute covid- in the icu. sars-cov- is an enveloped, positive-sense, single-stranded rna viruses of ~ kb, only able to synthesise proteins but creating a wide variety of signs and symptoms. coronaviruses, and especially sars-cov- , penetrate the epithelial cells via the angiotensin converting enzyme (ace ). the serine transmembrane serine protease in the host cell further promotes viral uptake by cleaving ace and activating the sars-cov- s protein. after entry, sars-j o u r n a l p r e -p r o o f cov- can shut down the effective ifn type antiviral pathway. the virus uses the intracellular machinery to multiply and disseminate into the airway [ ] . the virus mainly spread from the lung but could disseminate to all tissues that express ace (mainly small bowel and colon, brain, heart, kidney and skin); during autopsies, the virus is found in many organs [ ] . critically ill mechanically ventilated patients showed rnaemia for days in median [ ] . the absence of normal th response leads to pyroptosis of the epithelial cell (with massive proinflammatory reactions, recruitment of blood monocytes into the lungs and neutrophils attraction and activation (reactive oxygen species , proteases production and cell death by neutrophil extracellular traps (netosis)), leading to a "cytokine storm" [ ] . the lack of cytokine at a transcriptional level in the blood, contrasting with high level of protein, suggest a compartmentalisation of the response starting into the lung and spreading into other tissues [ ] . the abnormal th response is unable to clear the pathogen and leads to an abnormal activation of cd + t cells with massive decrease, partial differentiation, and exhaustion. the cd + response is anarchic with plasmablast proliferation. the high level of production of sars-cov- antibodies contemporaneously to virus persistence is supposed to enhance the inflammatory reaction and to abrogate the wound healing response (mcp- and interleukin (il)- production and proinflammatory monocytes/macrophage recruitment) [ ] . endothelium is activated, through the ace receptor with expression of tissue factor, platelet activation and increased von willebrand factor (vwf) and factor viii (fviii) levels, all of which contribute to thrombin generation and fibrin clot formation. thrombin, in turn, causes inflammation through its effect on platelets which promote net formation in neutrophils. it also activates endothelium through the protease-activated receptors (par) receptor, which leads to c a release and monocyte activation. vasculitis is associated with a prolonged procoagulant and anti-fibrinolytic states that explain the high risk of arterial and vein thrombosis [ , ] . presentation of covid- is characterised by different clinical phenotypes [ ] , with different severity-of-illness and outcomes, with specific biomarkers. phenotype is characterised by mild symptomatic patients without hypoxemia and radiological abnormalities. phenotype presents as hyper-inflamed and hypovolaemic patients, presenting mild hypoxemia and/or small opacities on chest x-ray. exposed to rapid deterioration risk, close spo j o u r n a l p r e -p r o o f monitoring is needed. manifested as "bronchopneumonia pattern" of jin et al. [ ] these patients have a median il- under pg/ml. phenotype is characterised by greater hypoxemia (pao /fio < ), respiratory rates > per minute, il- values > pg/ml, being a possible progression from type . an "organising pneumonia pattern" of jin and "phenotype " of robba et al. [ ] is present. phenotype and are characterised by severe hypoxemia requiring intubation. phenotype is characterised by hypoxic vasoconstriction, micro-embolic lesions, normal lung compliance, lower lobes oedema with ground glass opacities; consider ino, prostacyclin, normal tidal. computed tomography (ct) scan is consistent with as "progressive organising pneumonia pattern" of jin, "type l" of marini and gattinoni [ ] and "phenotype - " of robba. phenotype represents an advanced stage of ards, typically in patients with delayed intubation; it totally fits the severe ards criteria. patients may benefit from positive end-expiratory pressure (peep) levels > cm h , prone positioning, land low tidal volumes. ct documents the "diffuse alveolar damage pattern" of jin, "type h" of marini and "phenotype - " of robba. a comprehensive categorisation is required, based on physiology, ct scan findings and clinical presentation, to achieve a personalised treatment, indeed. as the ace-ii receptor to which sars-cov- binds is widely found throughout the body, including the lung alveolar epithelial cells, enterocytes of the small intestine, arterial and venous endothelial cells and arterial smooth muscle cells [ ] , it should not be surprising that covid- is a disease more than just the lungs. after the lungs, the heart is the most frequently involved organ. a variety of pathologies can impair cardiac function, both primary (i.e. myocarditis) and secondary (myocardial infarction, arrhythmia, cytokine-induced suppression, etc.) [ ] . assessing the cause of cardiac involvement is complicated by the frequent comorbid heart disease in patients with severe disease and the variety of cardiotoxic medications that have frequently been used in combination (e.g. ritonavir, hydroxychloroquine, alpha interferon, high dose methylprednisolone, etc.) [ ] . however, rates of myocarditis are quite significant and a cause for concern regarding long term consequences in covid- survivors [ ] . widespread thrombotic disease in the venous and arterial system due to the endotheliitis, despite prophylactic low molecular weight heparin therapy [ ] , is the other hallmark of covid- . primary j o u r n a l p r e -p r o o f neurological disease other than stroke is rare, and most renal disease is secondary to systemic insults rather than primary. j o u r n a l p r e -p r o o f the prompt and reliable diagnosis of covid- cases is challenging for several reasons and is mainly based on molecular assays. the aims of real-time rt-pcr are to perform early, rapid and accurate diagnostics and also guide patient care and management as well as epidemiological strategies. the most common specimens used are nasopharyngeal and oropharyngeal samples, while tracheal aspirate, bronchial specimens or bronchoalveolar samples are occasionally collected from intubated patients. the molecular diagnosis nowadays mainly relies on real-time rt-pcr techniques, which are considered reference ones, as they present high sensitivity and specificity and are compatible with automation. in a lesser extent, other pcr assays, such as nested pcr, rt-lamp, rt-iipcr or the genxpert assay may be used [ ] . the rna extraction techniques were initially manual and later evolved to automated, with rt-pcr set up to be prepared manually and rt-pcr to be run in separate thermal cyclers. all these steps were later incorporated in fully automated instruments, such as the sample-to-result instrument neumodx system. a very recent evolution in the molecular diagnosis is the application of real-time rt-pcr in saliva, which can be effectively used for the detection of respiratory viruses [ ] . saliva has the obvious advantages to be easy to collect, unaffected by collection process, advantageous for individuals with physical or mental handicaps, stable at room temperature for extended periods, not dependent on swabs that are in shortage, of low-risk for exposing laboratorians to hazardous samples, can be obtained while social distancing and can reduce the need for personal protective equipment since it is self-collected. the global pandemic manifested as covid- pneumonia has raised important challenges to physicians working in icus. in fact, patients with covid- pneumonia present heterogeneous clinical manifestations; further, significant proportion of these manifestations develop severe hypoxemic respiratory failure requiring invasive mv. different factors have been identified to predict those patients who will require mv, like elevated il- in the serum, deterioration of oxygenation (mainly pao /fio lower than ), presence of heart disease and older age [ ] . at histopathological analysis, early presentation is characterised by lymphocytic alveolitis. recent evidence reported pneumo and vascular lysis, alveolar cell infiltration, alveolar mucinosis, and j o u r n a l p r e -p r o o f further fibrosis [ , ] . it is mandatory to understand better the peculiarities of covid- pneumonia pathophysiology, in order to optimise mv. different radiologic phenotypes have been identified by ct scan [ ] : phenotype with multiple, focal over-perfused ground-glass opacities, associated with normally aerated areas; phenotype , with atelectasis and peri-bronchial opacities, heterogeneously distributed and hypo-perfused, associated with phenotype ; phenotype , with patchy ards-like pattern, heterogeneously distributed, with hyper and hypo-perfused areas, associated with radiologic phenotype . radiologic phenotype is likely to be treated by noninvasive respiratory support, while phenotype , more often needs invasive mv. in icu, among intubated critically ill patients, most of them are characterised by phenotype , and only a minority as phenotype or . in normal lungs, the standard lung weight is around g, while in traditional ards, the lung weight is on average around g, with an excess tissue mass of g. similarly, in covid- patients with phenotype , average lung weight is around g, with an excess tissue mass of g. thus, the excess tissue mass is similar in traditional ards as well as in covid- pneumonia phenotype . in traditional ards, the distribution of regional perfusion is mainly distributed on the dependent lung regions, where atelectasis and the majority of non-aerated lung tissue is located. on the contrary, in covid- pneumonia, the distribution of blood flow is nongravitational, prevalent in non-dependent lung regions, with better aeration. areas of hypoperfusion are distributed mainly in dependent lung non-aerated regions. thus, hypoxia is mainly due to the following mechanisms: first, lower ventilation-perfusion (̇⁄ ), in aerated (non-dependent) and poorly aerated lung regions due to increased perfusion; second, higher shunt in non-aerated lung tissue with micro-thrombosis and vascular lysis effect, which may be even partially protective; and, third, lower alveolar-capillary diffusion. it has been hypothesised that in patients with high compliance and low ̇⁄ , hypoxemia is primarily due to the ̇⁄ mismatch related to the loss of the lung perfusion regulation, with a lower amount of non-aerated tissue and less alveolar recruitability. in contrast, in patients with lower compliance with a major loss of aeration, the recruitability and the response to peep has been suggested to be higher. the application of higher levels of peep is associated with larger recruitment in traditional ards as compared to severe covid- pneumonia, radiological phenotype or , but not with the respiratory mechanics. traditional ards is characterised by a diffuse damage of the alveolar capillary membrane, leading to oedema and atelectasis in the most dependent lung regions, in supine position. thus, traditional ards is characterised by increased excess tissue mass, highly recruitable by increasing levels of pressures. on the contrary, covid- pneumonia is characterised by alveolar infiltration, leading to different increased excess tissue mass, yielding to phenotypes to , less recruitable by increasing pressures. for these reasons, we suggest to minimise lung inflation at end inspiration and expiration, j o u r n a l p r e -p r o o f minimising oxygenation [ ] and optimising the level of haemoglobin, according to the optimal oxygen transport [ ] . severe covid- pneumonia is a typical "primary" ards, with pneumocytes and vascular lysis, to be ventilated at lower pressures both at end inspiration and expiration with minimal oxygenation. in conclusion, "less is more" in ventilating critically ill patients with severe covid- pneumonia. [ ] . progression from lower respiratory tract infection to srf necessitating mv is taking place either through over-production of il- β and development of macrophage activation syndrome or through over-activation of the il- receptor pathway leading to a unique pattern of monocyte dysregulation. in this pattern, the expression of the human leukocyte antigen dr on monocytes is decreased, which is associated with defective antigen presentation and subsequent lymphopenia. in parallel, monocytes maintain their potential for the over-production of pro-inflammatory cytokines [ ] . this leads to the hypothesis that early treatment with a biological that can provide effective blockade of pro-inflammatory responses and enhance anti-inflammatory responses may prevent progression into srf and mv. results of the prospective ana-covid openlabel trial in patients have shown that early treatment with anakinra may achieve this goal [ ] . anakinra is the recombinant receptor of il- . early recognition of the risk of a patient for progression into srf using the biomarker supar (soluble urokinase plasminogen activator receptor) [ ] and start of anakinra to prevent mv is the rational of the on-going save trial (eudract number - - , www.clinicaltrials.gov nct ). tocilizumab which blocks il- receptor is also proposed [ ] with intravenous use being suggested to be superior to subcutaneous administration [ ] . although the roche press release of the first results from the phase iii covacta trial is not favouring early administration in all patients, some systematic reviews suggest potential mortality benefit in some cohorts with acute respiratory failure [ ] . sarilumab is also effective in blocking il- receptors and may have similar effects. promising results were provided with the use of low-dose dexamethasone in the recovery trial. when given at mg once daily either orally or intravenously for days, significant decrease of mortality was found. the recommended patient population is either for patients with severe disease in need for oxygen (e.g. oxygen saturation less than %) or under mv [ ] . the european medicines agency human medicines committee (chmp) endorsed on the th of september the administration of dexamethasone in adults and adolescents (from years of age and weighing at least kg) who require supplemental oxygen therapy (oxygenation requirements to maintain spo above % or who underwent mv). in all cases, the recommended dose is mg once a day up to days. use of intravenous steroids is also recommended in the recent american thoracic and european respiratory society guidance [ ] for patients who underwent mv, require oxygen supplementation or require extracorporeal membrane oxygenation. it is also supported by recent meta-analyses [ ] , although more research is required on the interaction with antivirals, anticoagulation, specific subsets like diabetes or older than years, suggesting the need for a precision prescription approach [ ] to be more selective in reducing potential harm and optimise benefits. finally, interactions between il- r blocking therapy and steroids need to be elucidated. plasma from patients who have overcome covid- infection, referred to as convalescent plasma, is a treatment option, which has been recently approved by the food and drug administration for use in patients with sars-cov- infection [ , ] . this approval was based on preliminary results from clinical studies that showed a significant clinical and biochemical improvement of patients, reduction in hospitalisation days and survival benefit [ ] . in greece, a phase clinical study for the use of convalescent plasma in hospitalised patients with covid- (nct ) has been performed. to date, possible donors were tested for the presence of igg/iga antibodies against the spike protein of sars-cov- (s domain). median time from the day of the first symptom or pcr positivity (for asymptomatic patients) till the day of screening was days. igg antibodies were detected in ( %) donors. plasmapheresis was performed in the first donors, at a median time of days (range: - ) after screening. there was a significant reduction in the titter of igg and iga antibodies between the days of screening and plasmapheresis [ ] . this rapid reduction of anti-sars-cov- antibodies in this cohort has also been described in other studies [ ] and reveals a time pattern of reduction. however, it remains unknown whether neutralising antibodies share the same model or if this reduction affects the host immunity against sars-cov- . this result also suggests that, when indicated, plasmapheresis has to be performed as soon as the patient has recovered from covid- . significant improved clinical outcomes with convalescent plasma therapy has been restricted to patients not requiring mv. [ , ] . as multiple factors interfered with standard hai prevention protocols, it was imperative to quickly recover icu standards of care and "adapt recommendations to exceptional care conditions" [ ] . italian group (siaarti) responded to this challenge with guidance on vascular approach in covid- patients [ ] . the effect of central line bundle enhancement was well demonstrated by swiss researchers back in [ ] . moving forward, taking care of three key elements at all times will probably further minimise hai risk: well-trained people, high compliance to updated evidence-based protocols and utilisation of reliable and easy to use technology. needless to say, maintaining sufficient stock is of paramount importance. scientists and pharmaceutic industry are racing to produce a safe and effective vaccine against sars- science, developed a vaccine based on adenovirus (ad ), which was already given limited approval in china [ ] . the gamaleya research institute has developed gam-covid-vac, using a combination of ad and ad . renamed as sputink-v, it was given limited approval in russia before entering phase iii trials [ ] . johnson  johnson, in partnership with the beth israel deaconess medical center, is testing another ad vaccine. astrazeneca and the university of oxford is testing a vaccine based on a chimpanzee adenovirus called chadox ; safety concerns of potential neurotoxicity (transverse myelitis case) have suspended trials in some countries, whereas in others they resumed [ ] . the artificial intelligence (ai) and data science community has supported the global response to the covid- outbreak, with the number of published ai and machine learning studies related to covid- exceeding thousand. the contribution of ai to the fight against covid- is briefly classified in (i) biomedicine and pharmacotherapy, (ii) modelling of the outbreak (identification, tracking and prediction), and (iii) detection and diagnosis. in biomedicine and pharmacotherapy deep, neural networks were used for dna microarray and genomic sequence analysis, while in the modelling of the outbreak machine learning models like long short-term memory (lstm) have been used [ ] . regarding detection and diagnosis, studies have used machine learning algorithms to predict the criticality of covid- positive patients using clinical features and identifying which of them have statistically significant hazard errors [ , ] . other studies have used cough and/or breath sound data to identify covid- , as in [ ] . the most popular ai-based covid- identification approach is using chest x-ray or ct images with cnn models [ ] . the conducted studies have shown the j o u r n a l p r e -p r o o f contribution of ai and data science to the fight against covid- pandemic, however more standardised datasets and clinical validation of the models' performance are further needed. j o u r n a l p r e -p r o o f management and understanding of sars-cov infection has evolved during the six first months of the pandemic. in spite of early reports calling for icu preparedness [ , ] , many icus in western countries were overwhelmed in march-april , with patients exposed to adverse events due to compassionate administration of drugs with weak evidence [ ] , with need of implementing icu admission triage algorithms [ ] and lack of targeting management based on clinical phenotypes. whereas some icus reported similar mortality to primary influenza pneumonia requiring mv [ ] , these conditions were responsible for a large amount in preventable deaths. better understanding of early micro-thrombosis [ ] , refining strategies of oxygenation and intubation criteria (using high flow nasal therapy with awake prone position), and use of immunomodulatory agents have been associated with a shift in the management of critically ill patients, with a lower burden of deaths among hospitalised patients. further research in form of randomised clinical trials is required to improve the understanding of the interactions between antivirals, steroids and other immunomodulatory agents, and to determine the effects on different subpopulations. clinicians and researchers have focused on the acute phase of severe covid- , but continuing monitoring [ ] after icu and hospital discharge for long-lasting complications is advised. in addition, assessment of anxiety, sleep disturbances, depression and post-traumatic distress syndrome in icu survivors needs to be investigated. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical features of patients infected with novel coronavirus in wuhan, china multiple organ dysfunction in sars-cov- : mods-cov- complex immune dysregulation in covid- patients with severe respiratory failure characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention the epidemiology and clinical information about covid- estimates of the severity of coronavirus disease : a model-based analysis bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support covid- antimicrobial prescribing biomarkers for antimicrobial stewardship: a reappraisal in covid- times? estimation of excess deaths associated with the covid- pandemic in the united states impaired type i interferon activity and inflammatory responses in severe covid- patients histopathological findings and viral tropism in uk patients with severe fatal covid- : a post-mortem study risk factors for sars-cov- detection in blood of critically ill patients pathological inflammation in patients with covid- : a key role for monocytes and macrophages t cell responses in patients with covid- endothelial cell infection and endotheliitis in covid- clinical phenotypes of sars-cov- : implications for clinicians and researchers a pattern categorization of ct findings to predict outcome of covid- pneumonia distinct phenotypes require distinct respiratory management strategies in severe covid- management of covid- respiratory distress tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis description and proposed management of the acute covid- cardiovascular syndrome covid- : first do no harm outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease (covid- ) confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis diagnostic strategies for sars-cov- infection and interpretation of microbiological results comparison between saliva and nasopharyngeal swab specimens for detection of respiratory viruses by multiplex reverse transcription-pcr. j clinical characteristics, management and in-hospital mortality of patients with coronavirus disease fibrotic progression and radiologic correlation in matched lung samples from covid- post-mortems pneumolysis and "silent hypoxemia" in covid- . open science framework close down the lungs and keep them resting to minimize ventilator-induced lung injury neurological manifestations of severe sars-cov- infection: potential mechanisms and implications of individualized mechanical ventilation settings haematological characteristics and risk factors in the classification and prognosis evaluation of covid- : a retrospective cohort study thrombosis risk associated with covid- infection. a scoping review covid- and coagulation: bleeding and thrombotic manifestations of sars-cov- infection thromboembolism and anticoagulant therapy during the covid- pandemic: interim clinical guidance from the anticoagulation forum prevention, diagnosis, and treatment of vte in patients with coronavirus disease : chest guideline and expert panel report lung and kidney perfusion deficits diagnosed by dual-energy computed tomography in patients with covid- -related systemic microangiopathy characterization of the inflammatory response to severe covid- illness soluble urokinase plasminogen activator receptor (supar) as an early predictor of severe respiratory failure in patients with covid- pneumonia anakinra for severe forms of covid- : a cohort study tocilizumab therapy of covid- : a comparison of subcutaneous and intravenous therapies beneficial and harmful outcomes of tocilizumab in severe covid- : a systematic review and meta-analysis dexamethasone in hospitalized patients with covid- -preliminary report updated guidance on the management of covid- : from an association between administration of systemic corticosteroids and mortality among critically ill patients with covid- : a meta-analysis steroids and covid- : we need a precision approach, not one size fits all convalescent plasma for the treatment of covid- : perspectives of the national institutes of health treatment guidelines panel the emerging role of convalescent plasma in the treatment of covid- effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening covid- : a randomized clinical trial loss of anti-sars-cov- antibodies in mild covid- rapid decay of anti-sars-cov- antibodies in persons with mild covid- impact of sars-cov- on hospital acquired infection rates in the united states: predictions and early results severe covid- and healthcare-associated infections on the icu: time to remember the basics? sustained reduction of catheter-associated bloodstream infections with enhancement of catheter bundle by chlorhexidine dressings over years coronavirus vaccine tracker -the new york times n.d safety, tolerability, and immunogenicity of a recombinant adenovirus type- vectored covid- vaccine: a doseescalation, open-label, non-randomised, first-in-human trial safety and immunogenicity of an rad and rad vector-based heterologous prime-boost covid- vaccine in two formulations: two open, non-randomised phase / studies from russia safety and immunogenicity of the chadox ncov- vaccine against sars-cov- : a preliminary report of a phase / , single-blind, randomised controlled trial an mrna vaccine against sars-cov- -preliminary report artificial intelligence (ai) and big data for coronavirus (covid- ) pandemic: a survey on the state-of-the-arts a machine learning-based model for survival prediction in patients with severe covid- infection early triage of critically ill covid- patients using deep learning exploring automatic diagnosis of covid- from crowdsourced respiratory sound data covid- detection from chest x-rays using transfer learning with deep convolutional neural networks coronavirus disease (covid- ): a critical care perspective beyond china strengthening icu health security for a coronavirus epidemic adult icu triage during the coronavirus disease pandemic: who will live and who will die? recommendations to improve survival sars-cov- in spanish intensive care units: early experience with -day survival in vitoria key: cord- -f pbd authors: bosteels, cedric; maes, bastiaan; van damme, karel; de leeuw, elisabeth; declercq, jozefien; delporte, anja; demeyere, bénédicte; vermeersch, stéfanie; vuylsteke, marnik; willaert, joren; bollé, laura; vanbiervliet, yuri; decuypere, jana; libeer, frederick; vandecasteele, stefaan; peene, isabelle; lambrecht, bart title: sargramostim to treat patients with acute hypoxic respiratory failure due to covid- (sarpac): a structured summary of a study protocol for a randomised controlled trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: f pbd objectives: the hypothesis of the proposed intervention is that granulocyte-macrophage colony-stimulating factor (gm-csf) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post covid- , and can promote lung repair mechanisms, that lead to a % improvement in lung oxygenation parameters. sargramostim is a man-made form of the naturally-occurring protein gm-csf. trial design: a phase academic, prospective, arm ( : ratio), randomized, open-label, controlled trial. participants: patients aged - years admitted to specialized covid- wards in belgian hospitals with recent (< weeks prior to randomization) confirmed covid- infection and acute respiratory failure defined as a pao /fio below mmhg or spo below % on minimal l/min supplemental oxygen. patients were excluded from the trial in case of ( ) known serious allergic reactions to yeast-derived products, ( ) lithium carbonate therapy, ( ) mechanical ventilation prior to randomization, ( ) peripheral white blood cell count above . /μl and/or active myeloid malignancy, ( ) high dose systemic steroid therapy (> mg methylprednisolone or equivalent), ( ) enrolment in another investigational study, ( ) pregnant or breastfeeding or ( ) ferritin levels > μg/ml. intervention and comparator: inhaled sargramostim μg twice daily for days in addition to standard care. upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ards) and initiation of mechanical ventilator support within the day period, inhaled sargramostim will be replaced by intravenous sargramostim μg/m( ) body surface area once daily until the day period is reached. from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim, based on the treating physician's assessment. intervention will be compared to standard of care. subjects progressing to ards and requiring invasive mechanical ventilatory support, from day onwards in the standard of care group will have the option (clinician's decision) to initiate iv sargramostim m μg/m( ) body surface area once daily for days. main outcomes: the primary endpoint of this intervention is measuring oxygenation after days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of pao /fio and through measurement of the p(a-a)o gradient (pao = partial alveolar pressure of oxygen, pao =partial arterial pressure of oxygen; fio = fraction of inspired oxygen). randomisation: patients will be randomized in a : ratio. randomization will be done using redcap (electronic iwrs system). blinding (masking): in this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. numbers to be randomised (sample size): a total of patients with confirmed covid- and acute hypoxic respiratory failure will be enrolled, in the active and in the control group. trial status: sarpac protocol version . (april ). participant recruitment is ongoing in belgian hospitals (i.e. university hospital ghent, az sint-jan bruges, az delta roeselare, university hospital brussels and zna middelheim antwerp). participant recruitment started on march (th) . given the current decline of the covid- pandemic in belgium, it is difficult to anticipate the rate of participant recruitment. trial registration: the trial was registered on clinical trials.gov on march (th), (clinicaltrials.gov identifier: nct ) - retrospectively registered; https://clinicaltrials.gov/ct /show/nct ?term=sarpac&recrs=ab&draw= &rank= and on eudract on march th, (identifier: - - ). full protocol: the full protocol is attached as an additional file, accessible from the trials website (additional file ). in the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. the primary objective is to investigate whether the administration of inhaled sargramostim (leukine®) at a dose of mcg daily during days improves oxygenation in covid- patients with acute hypoxic respiratory failure. the secondary objectives are: -to study if early intervention with sargramostim is safe (number of aes/saes) -to study if early intervention with inhaled sargramostim affects clinical outcome defined by duration of hospital stay, -point ordinal scale, clinical sign score, sofa score, news score -to study if early intervention with sargramostim affects the rate of nosocomial infection -to study if early intervention with inhaled sargramostim affects progression to mechanical ventilation and/or ards -to study if treatment with sargramostim affects all-cause mortality rate at and weeks post inclusion -to study if treatment with sargramostim affects features of secondary haemophagocytic lymphohistiocytosis, defined by hs score -to study if treatment with sargramostim has a favourable effect on long term - week follow up . . subjects . . . number of subjects a total of patients with confirmed covid- and acute hypoxic respiratory failure will be enrolled, in the active and in the control group. confirmed covid- patients with acute hypoxic respiratory failure admitted to the covid- isolation ward. inclusion and exclusion criteria the following patients will be enrolled: -recent (≤ weeks prior to randomization) confident diagnosis of covid- confirmed by antigen detection and/or pcr, and/or seroconversion or any other emerging and validated diagnostic test. -in some patients, it may be impossible to get a confident laboratory confirmation of covid- diagnosis after h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. in those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (< h) chest-ct scan (confirmed by a radiologist and pulmonary physician as probable covid- ), a patient can be enrolled as probable covid- infected. in all cases, this needs confirmation by later seroconversion. -presence of acute hypoxic respiratory failure defined as (either or both)  saturation below % on minimal l/min o  pao /fio below -admitted to specialized covid- ward -age - -male or female -willing to provide informed consent exclusion criteria -patients with known history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product. -mechanical ventilation before start of study -patients with peripheral white blood cell count above . per microliter and/or active myeloid malignancy -patients on high dose systemic steroids (> mg methylprednisolone or equivalent) -patients on lithium carbonate therapy -patients enrolled in another investigational drug study -pregnant or breastfeeding females (all female subjects regardless of childbearing potential status must have negative pregnancy test at screening) -patients with serum ferritin > mcg/ml (which will exclude ongoing hlh) . . study interventions confirmed or highly suspect covid- patients with acute hypoxic respiratory failure (saturation below % on minimal l/min o or pao /fio < ) will be randomized to receive sargramostim mcg twice daily for days as a nebulized inhalation on top of standard of care (active group), or to receive standard of care treatment (control group). upon progression of disease requiring initiation of mechanical ventilatory support within the day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim mcg/m body surface area once daily until the day period is reached. from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim, based on the treating physician's assessment. in the control group with progressive disease requiring mechanical ventilatory support, from day onwards, the treating physician will have the option to initiate iv sargramostim mcg/m body surface area once daily for days. safety data, including blood leukocyte counts, will be collected in all patients. efficacy data will also be collected and will include arterial blood gases, oxygenation parameters, need for ventilation, lung compliance, organ function, radiographic changes, ferritin levels, triglyceride levels, etc. as well as occurrence of secondary bacterial infections. patients will stop the investigational drug if there is unacceptable toxicity according to investigator's judgement. / . . . imps and dosage leukine® (sargramostim) prepared and administered for inhalation using nebulizer leukine for injection is a sterile, preservative-free lyophilized powder that requires reconstitution with ml normal saline solution. once reconstituted, leukine can be inhaled as an aqueous aerosol using either a vibrating mesh nebulizer (philips innospirego) or jet nebulizer, per manufacturer instructions. (nebulizers studied include: akita apixneb, pari lc-plus set, pulmoaide, pan lc, aeroneb solo device). use reconstituted leukine® solution for inhalation within hours following reconstitution and/or dilution. nebulizing is preferably done in an isolation negative pressure chamber, and if not, personnel should use an ffp mask. patient should self-administer the medication and where possible, the room should not be entered within one hour after administration. for patients that are on a mechanical ventilator and cannot be treated with leukine® inhalation:  the recommended dose is mcg/m /day administered intravenously over a -hour period once daily for up to days.  for intravenous injection: administer leukine injection in . % sodium chloride injection, usp. dilute leukine for intravenous infusion in . % sodium chloride injection, usp. if the final concentration of leukine is below mcg/ml, add albumin (human) at a final concentration of . % to the saline prior to addition of leukine to prevent adsorption to the components of the drug delivery system. to obtain a final concentration of . % albumin (human), add mg albumin (human) per ml . % sodium chloride injection, usp (e.g., use ml % albumin [human] in ml . % sodium chloride injection, usp). . . . schematic overview of the data collection & interventions . . study duration the total treatment duration of the study is days, and the entire study duration is - weeks to final follow up visit. sargramostim (leukine®) is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhugm-csf, sargramostim) and the only fda approved gm-csf (leucine package insert). gm-csf, a pleiotropic cytokine, is an important leukocyte growth factor known to play a key role in haematopoiesis, effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity ( ). since its initial fda approval in , over , patients have received leukine®, providing extensive clinical and post-marketing data in a broad range of treated individuals -from preterm neonates to the elderly and including males and females -representing a well-characterized safety profile for leukine®. leukine® administered as a subcutaneous or intravenous injection is approved for six indications including use as a medical countermeasure for radiation exposure. the us government currently holds leukine® in the strategic national stockpile. leukine® may benefit patients with beginning signs of acute respiratory distress syndrome (ards) due to covid- infection. gm-csf is a critical cytokine for the health of lungs. the alveolar macrophages are dependent on gm-csf for differentiation and normal functioning. in addition, gm-csf is an immunomodulator that plays a critical role in host defense by promoting differentiation of dendritic cells, and stimulating antiviral immunity ( - ). as described in detail below, it is being studied as an adjuvant therapy in the management of lifethreatening infections to boost the hosts innate immune response to fight infection, reduce the risk of secondary infection, and in varied conditions to prevent infection during critical illness ( ) ( ) ( ) ( ) . in addition, it has been studied in pulmonary conditions that affect alveolar macrophages, such as autoimmune pulmonary alveolar proteinosis ("apap"), with beneficial outcomes ( , ) . we propose based on preclinical and clinical data and the safety data from more than , adult and pediatric patients treated with leukine®, that patients with beginning signs of acute lung injury and/or ards due to covid- infection be given leukine®. ards due to covid- carries a high mortality rate ( ) and leukine® may confer benefit by both active management of this complication as well as in prevention of secondary infections. in animal models of postviral ards and mortality, gm-csf has demonstrated immunomodulatory effects that improve the clinical response and symptoms associated with influenza and other viral respiratory infections ( ) ( ) ( ) , and represents a promising candidate for the prevention of ards in patients with covid- . the proposed development plan was guided by three specific considerations: the biology and effects of gm-csf on the lung, specifically alveolar macrophages and epithelial cells, as well its immunomodulatory activities in stimulating antiviral immunity make gm-csf a critical cytokine for healthy pulmonary function and defence. detailed studies have shown that gm-csf is necessary for the maturation of alveolar macrophages from fetal monocytes and the maintenance of these cells in adulthood ( ). gm-csf has a wide array of effects on myeloid cells. gm-csf has been shown to be a myelopoietic growth factor that has pleiotropic effects not only in promoting the differentiation of immature precursors into polymorphonuclear neutrophils, monocytes/ macrophages and dendritic cells, but also in controlling the function of fully mature myeloid cells ( ) . gm-csf is also known to reverse immunoparalysis seen in sepsis by immune activation, resulting in beneficial outcomes ( ). there is a large body of evidence generated with gm-csf in animal studies suggesting the potential use in ards and infections ( ) . for the purpose of brevity, we will point to the data that reflects the potential value in viral lung infections and preventing secondary bacterial infections and progression to ards: halstead and colleagues demonstrated that in vivo high airway levels of gm-csf profoundly rescue mice from lethal influenza pneumonia. while in vitro gm-csf is canonically described as an m polarizing cytokine, their data demonstrated that in vivo, during influenza a virus infection, gm-csf instead temporizes the type ii interferon-induced m polarization of airway macrophages and reduces inflammation induced damage ( , ) . unkel and colleagues demonstrated gm-csf-dependent cross-talk between influenza virus infected alveolar epithelial cells and cd + dendritic cells is crucial for effective viral clearance and recovery from injury and thus pointing to the potential use of gm-csf treatment in severe influenza virus pneumonia ( ) . investigations have shown that gm-csf conferred resistance to influenza in mice via alveolar phagocytes and through alveolar macrophages which became more resistant to influenza-induced apoptosis. delivery of intranasal gm-csf to wild-type mice also conferred resistance to influenza ( ) . there is evidence that inhaled gm-csf prevents bacteremia in post influenza bacterial pneumonia primarily through locally-mediated improved lung antibacterial resistance to systemic bacteremia during influenza a viral infection ( ) . conclusions: gm-csf confers resistance to influenza by enhancing innate immune mechanisms that depend on alveolar macrophages, which are dependent on gm-csf for their health and normal functioning. pulmonary delivery of this cytokine has the potential to reduce morbidity and mortality due to viral pneumonia. this is summarized in the diagram below: / . experience: use of leukine® has beneficial effect in the treatment of conditions that are similar to ards seen with covid- . a small ( patient) double blind randomized placebo controlled clinical trial of low-dose ( mcg/kg daily for days) intravenous gm-csf treatment in adult patients with severe sepsis and respiratory dysfunction, led to the conclusion that gm-csf treatment was associated with improved gas exchange and might play a homeostatic role ( ) . in a phase ii study, patients with severe sepsis with respiratory dysfunction were randomized to gm-csf ( mcg/m intravenously daily for days) or placebo. the results showed an improvement in day mortality on gm-csf; this did not reach statistical significance due to the small sample size ( ). herold and colleagues used leukine® by inhalation route on a compassionate basis in six patients with moderate to severe community-acquired pneumonia or ventilator-associated pneumonia ards who were not improving despite all measures and at least days of mechanical ventilation ( ) . mcg of leukine® were applied by aeroneb solo device (covidien, neustadt, germany) at an interval of hours. compared to historical controls, the authors observed significant improvement in oxygenation and lung compliance with gm-csf therapy. this resulted in improved morbidity using standard scoring systems and of the six patients recovered and were discharged from the hospital. there is an ongoing study of inhaled gm-csf across multiple centers in germany (gi hope; nct ) recruiting patients with diagnosis of pneumonia associated ards. there is a large body of evidence of inhaled leukine® in autoimmune pulmonary alveolar proteinosis (apap), which results in accumulation of surfactant in alveolar sacs with resultant hypoxia. tazawa and colleagues conducted a phase ii study of inhaled leukine® at pulmonary centers throughout japan in patients with unremitting or progressive apap with hypoxia and symptoms ( ) . patients received mcg daily by inhalation, using an lc-plus nebulizer with a manual interrupter valve connected to a pari turbo boy compressor, for days and this cycle was repeated every other week for six cycles (total weeks). the treatment was well tolerated with no serious adverse events. adverse events were reported in just of the patients oxygenation, radiological changes as well as symptoms. following these results, a larger randomized phase study (page study) was conducted by the japanese investigators in centers. patients with mild to moderate apap with hypoxia were randomized to receive placebo or leukine® ( patients) at a dose of mcg twice a day for days followed by a week of no treatment. this two-week cycle was repeated times over a period of weeks. the treatment was again well tolerated with no significant differences in adverse events between the two groups. the gm-csf treated patients had significantly improved hypoxia parameters and radiographic changes ( ) . this clinical experience of use of leukine® in viral pneumonia suggests salutary effects. in addition, these studies establish the safety of inhaled leukine® and provide evidence for activity of inhaled leukine®. . expediency: toxicology, pharmacologic and safety data supports the immediate clinical use of leukine® in hypoxic respiratory failure with acute lung injury leading to ards due to covid- . investigator brochure is available and contains detailed information on toxicity. risk/benefit assessment covid- poses a very significant risk of mortality of - % and this percentage rises to mortality of % in patients with co-morbidity ( , ) . of all infected patients, some - % develop severe respiratory symptoms necessitating hospital admission. around % of infected patients will require invasive mechanical ventilation, and many of those ( - % will die). the current world-wide pandemic of covid- is putting unforeseen stress on the entire primary, secondary and tertiary medical system, leading to unseen triage of patients that potentially benefit or not from admission to icu units when they develop respiratory failure. gm-csf (sargramostim, leukine®) has been given systemically to almost . patients in the past. it is therefore a well characterized product. inhalation of gm-csf has also been used to treat patients with interstitial lung disease and reduced oxygen saturation (i.e. partial acute hypoxic respiratory failure) with few significant side effects above the placebo arm. the protocol is set up to give twice daily inhalation with gm-csf, followed by intravenous administration if the patient would move to the icu unit on mechanical ventilation. although gm-csf has been given systemically and via inhalation to patients with pneumoniaassociated ards, there are no current data on the safety profile of this drug in patients with covid- . given the severity of the clinical syndrome caused by covid- , and the prior triage of patients before hospital admission to the covid- ward, this trial will be performed in a hospital setting on a covid- ward with close monitoring of vital parameters (continuous ecg, oxygen saturation, temperature, vital clinical signs), which will allow intermediate intervention should serious side effects occur. once on the icu unit, patients will be intensively monitored for all vital parameters, as part of the routine icu monitoring. there are currently no treatments directed at improving lung repair and local immunity in covid- patients, and no treatment that attempt to halt the progression from manageable acute hypoxic respiratory failure to ards. preventing such progression to ards could have a huge impact on the foreseeable overflow of the icu units. we therefore believe the benefits of administering inhaled gm-csf treatment in early stage covid- acute hypoxic respiratory failure outweighs the risks associated with a phase imp administration via a different route and unknown indication. there is a large number of covid- infected patients that are currently being hospitalized across the globe. in just days time, our covid- ward at ghent university hospital has admitted confirmed cases, of which a significant portion ( %) already fulfill eligibility criteria for the current proposed protocol. we therefore believe that given the current ascending part of the epidemiology curve, with numbers of patients rising sharply, there will be no shortage of patients that are eligible. partner therapeutics has offered to give (free of charge) enough gm-csf to treat patients for a day period and an additional controls for days (should deterioration occur). there are large / amounts of gm-csf in the united states strategic national stockpile, so should this therapy work, there might be immediate worldwide application of a gm-csf inhalation therapy. primary objectives this is phase academic, prospective, randomized, open-label, interventional study designed to investigate the efficacy of sargramostim (leukine®) in improving oxygenation and short-and long-term outcome of covid- patients with acute hypoxic respiratory failure. there are currently no treatments directed at improving lung repair and local immunity in covid- patients, and no treatment that attempt to halt the progression from manageable acute hypoxic respiratory failure to ards in patients with covid- infection. justification for our objective is that preventing progression from early acute hypoxic respiratory failure to ards could have a huge impact on the foreseeable overflow of the icu units, that is already happening in some countries and is bound to happen on a global scale. the outcome of our study could thus have large impact from a medical, ethical and economic perspective. the hypothesis of the proposed intervention is that gm-csf has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post covid- , and can promote lung repair mechanisms, that lead to a % improvement in lung oxygenation parameters. this hypothesis is based on experiments performed in mice showing that gm-csf treatment can prevent mortality and prevent ards in mice with post-viral acute lung injury. to address our hypothesis, we will randomize patients with confirmed covid- with acute hypoxic respiratory failure (saturation below % on minimal l/min o or pao /fio < ) to receive sargramostim mcg twice daily for days as a nebulized inhalation on top of standard of care (active group), or to receive standard of care treatment (control group). upon progression of disease requiring initiation of non-invasive or invasive mechanical ventilatory support within the day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim mcg/m body surface area once daily until the day period is reached. to measure the effectiveness of sargramostim on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after days of inhaled (and intravenous) treatment through assessment of pretreatment and post-treatment ratio of pao /fio and through measurement of the p(a-a)o gradient, which can easily be performed in the setting of clinical observation of patients admitted to the covid - ward or icu covid- unit. during the day treatment period, we will perform daily measurements of oxygen saturation (pulse oximetry) in relation to fio , and the slope of alterations in these parameters could also be an indicator that our hypothesis is correct. comparison will be between active group a receiving sargramostim on top of standard of care and control group b receiving standard of care. data from the wuhan covid- epidemic show that patients that deteriorate are facing a prolonged period of mechanical ventilation. therefore, from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim, based on the treating physician's assessment. this group will be called group c. in the control group, for patients with / progressive disease requiring (non)-invasive mechanical ventilatory support, from day onwards, the treating physician will have the option to initiate iv sargramostim mcg/m body surface area once daily for days. this group will be called group d. comparisons of group a (early day intervention with sargramostim) with group d (late day intervention with sargramostim) will also be very informative. secondary objectives -to study if early intervention with sargramostim is safe (number of aes/saes) -to study if early intervention with inhaled sargramostim affects clinical outcome defined by duration of hospital stay, mean change in -point ordinal scale between day and day mean change in clinical sign score between day and day time to clinical sign score < maintained for h mean change of sofa score between day and day or between day and day . mean change news score score between day and day or between day and day . tine to news score less than for at least h to measure the effectiveness of sargramostim on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after days of inhaled (and intravenous) treatment through assessment of pretreatment (day ) and post-treatment (day ) ratio of pao /fio and through measurement of the p(a-a)o gradient, which can easily be performed in the setting of clinical observation of patients admitted to the covid - ward or icu covid- unit. preferentially, this measurement should be done in the upright position, while breathing room air for a minimum of minutes.. if this is impossible due to need for supplemental oxygen, fio and oxygen supplementation method should be recorded in patient record, so that a-a gradient can be normalized for age expected normal a-a gradient while on supplemental oxygen use. during the day treatment period, we will perform daily measurements of oxygen saturation (pulse oximetry) in relation to fio , and the slope of alterations in this parameters could also be an indicator that our hypothesis is correct. if the patient leaves hospital prior to the day analysis point, oxygenation at day of discharge will be used as value for measuring primary endpoint. -to study if early intervention with sargramostim is safe (number of aes/saes) although sargramostim has been given previously by inhalation to patients with ards and interstitial lung disease, data on safety in patients with covid- infection are currently lacking. since we are randomizing against days of no sargramostim treatment, comparison of aes and saes between group a and group b will be very informative. -to study if early intervention with inhaled sargramostim affects clinical outcome defined by length of hospital stay mean change in -point ordinal scale change between day , day and -to study if early intervention with sargramostim affects the rate of nosocomial infection patients with viral respiratory infection are at risk of secondary bacterial infections. as part of routine clinical care, sputum samples will be collected in patients suspected of secondary bacterial pneumonia, and checked for the presence of bacteria. -to study if early intervention with inhaled sargramostim affects progression to mechanical ventilation and/or ards decreasing oxygenation often leads to the need for non-invasive or invasive mechanical ventilation, and if severe enough to a diagnosis of ards. we will therefore as a secondary endpoint also study if early intervention with inhaled sargramostim prevents progression to criteria-defined ards (according to the american-european consensus conference (aecc) diagnostic criteria for ards: acute onset; ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao /fio ) of or less, regardless of positive end-expiratory pressure; bilateral infiltrates seen on frontal chest radiograph; and pulmonary artery wedge pressure of mm hg or less when measured, or no clinical evidence of left atrial hypertension), requiring high-flow oxygen devices, non-invasive mechanical ventilation, mechanical ventilation, by measuring the day from admission when this diagnosis is made or therapies are initiated. -to study if treatment with sargramostim affects all-cause mortality rate at and weeks post inclusion. -to study if treatment with sargramostim affects features of secondary haemophagocytic lymphohistiocytosis. a large subset of patients with severe covid- developing respiratory failure might have a cytokine storm syndrome, designated as secondary haemophagocytic lymphohistiocytosis (shlh). shlh is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinemia with multi-organ failure. cardinal features of shlh include unremitting fever, cytopenias, and hyperferritinaemia; hypertriglyceridemia, pulmonary involvement can present as ards. a cytokine profile resembling shlh is associated with covid- disease severity, characterised by increased interleukin (il)- , il- , granulocyte-colony stimulating factor, interferon-γ inducible protein , monocyte chemoattractant protein , macrophage inflammatory protein -α, and tumour necrosis factor-α. predictors of fatality from a recent retrospective, multicentre study of confirmed covid- cases in wuhan, china, included elevated ferritin (mean · ng/ml in non-survivors vs · ng/ml in survivors; p< · ) and il- (p< · ), suggesting that mortality might be due to virally driven hyperinflammation. to address the effect of sargramostim treatment on shlh, we will measure levels of ferritin, these chemokines and cytokines at the beginning of the trial day and after the initial day treatment. pbo including leukocytes and lymphocytes are performed on a routine clinical basis in these patients. -to study if treatment with sargramostim has a favourable effect on long term - week follow up at - weeks after discharge from hospital, patients will be seen on routine check-up by pulmonologist, who will perform a clinical exam, pulmonary function tests (including fvc, tlc and diffusion capacity), and a laboratory (ferritin, lymphocytes, leukocytes). this is phase academic, prospective, randomized, open-label, interventional study designed to investigate the efficacy of sargramostim (leukine®) in improving oxygenation and short-and long-term outcome of covid- patients with acute hypoxic respiratory failure. there are currently no treatments directed at improving lung repair and local immunity in covid- patients, and no treatment that attempt to halt the progression from manageable acute hypoxic respiratory failure to ards in patients with covid- infection. justification for our objective is that preventing progression from early acute hypoxic respiratory failure to ards could have a huge impact on the foreseeable overflow of the icu units, that is already happening in some countries and is bound to happen on a global scale. the hypothesis of the proposed intervention is that gm-csf has profound effects on antiviral immunity, can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post covid- , and can promote lung repair mechanisms, that lead to a % improvement in lung oxygenation parameters. this hypothesis is based on experiments performed in mice showing that gm-csf treatment can prevent mortality and prevent ards in mice with post-viral acute lung injury. we will randomize patients with confirmed covid with acute hypoxic respiratory failure (saturation below % on minimal l/min o or pao /fio < ) to receive sargramostim mcg twice daily for days as a nebulized inhalation on top of standard of care (active group), or to receive standard of care treatment (control group). upon progression of disease to requiring invasive mechanical ventilatory support within the day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim mcg/m body surface area until the day period is reached. dosing of inhaled and systemic sargramostim are based on prior experience of this drug in patients with pulmonary alveolar proteinosis (inhaled) and with pneumonia associated ards (inhaled and intravenous). the inhaled route is preferred first, because high local concentrations of gm-csf have a favourable effect on lung immunity, lung homeostasis and lung repair. the switch to intravenous treatment with deterioration requiring initiation of mechanical ventilation is necessitated by the fact that patients with covid- poorly tolerate ventilation in the absence of high level positive end expiratory pressure (peep), especially when they develop ards. for giving the sargramostim via inhalator in a ventilated patient, this would involve peep-free ventilation for at least - minutes, which will not be tolerated in covid- associated severe hypoxic respiratory failure and/or ards according to expert opinion (prof. dr. pieter depuydt, intensive care unit, uz ghent). to measure the effectiveness of sargramostim on restoring lung homeostasis, the primary endpoint of this intervention is measuring oxygenation after days of inhaled (and intravenous) treatment through assessment of pretreatment and post-treatment ratio of pao /fio and through measurement of the p(a-a)o gradient, which can easily be performed in the setting of clinical observation of patients admitted to the covid - ward or icu covid- unit. supplemental oxygen use will be recorded, and if needed a-a gradient will be normalized against expected age-and supplemental oxygen dependent a-a gradient. during the day treatment period, we will perform daily measurements of oxygen saturation (pulse oximetry) in relation to fio , and the slope of alterations in this parameters could also be an indicator that our hypothesis is correct. if the patient leaves hospital prior to the day analysis point, oxygenation at day of discharge will be used as value for measuring primary endpoint. comparison will be between active group a receiving sargramostim on top of standard of care and control group b receiving standard of care. data from the wuhan covid- epidemic show that patients that deteriorate are facing a prolonged period of mechanical ventilation. therefore, from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim, based on the treating physician's assessment. this group will be called group c. in the control group with progressive disease requiring invasive mechanical ventilatory support or developing ards, from day onwards, the treating physician will have the option to initiate iv sargramostim mcg/m body surface area once daily for days. this group will be called group d. comparisons of group a (early day intervention with sargramostim) with group d (late day intervention with sargramostim) will also be very informative. the subject has completed the study if he or she has completed all phases of the study, including the last visit (week - clinical follow up visit) or the last scheduled procedures, as described in this protocol (see section " . study specific procedures"). overall, the end of the study is reached when the last study procedure for the last subject has occurred: last subject, last visit (lslv). as soon as the whole study has ended (cfr. the definition above), the co-ordinating investigator shall notify the hiruz clinical trial unit, so that the competent authority and the ethics committee can be informed in a timely manner according to the regulatory requirements (within days after end of the study, or if the study had to be terminated early, this period must be reduced to days and the reasons should clearly explained). there is a large number of covid- infected patients that are currently being hospitalized across the globe. in just days time, our covid- ward at ghent university hospital has admitted confirmed cases, of which a significant portion ( %) already fulfill eligibility criteria for the current proposed protocol. we therefore believe that given the current ascending part of the epidemiology curve, with numbers of patients rising sharply, there will be no shortage of patients that are eligible. we estimate the study to terminate in weeks, including last clinical follow up visits. the following patients will be enrolled recent (≤ weeks prior to randomization) -confident covid- diagnosis confirmed by antigen detection test and/or pcr and/or positive serology, or any emerging and validated diagnostic laboratory test for covid- within this period. -in some patients, it may be impossible to get a confident laboratory confirmation of covid- diagnosis after h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. in those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (< h) chest-ct scan (confirmed by a radiologist and pulmonary physician as probable covid- ), a patient can be enrolled as probable covid- infected. in all cases, this needs confirmation by later seroconversion. -presence of acute hypoxic respiratory failure defined as (either or both) saturation below % on minimal l/min o pao /fio below -admitted to specialized covid- ward -age - -male or female -willing to provide informed consent -patients with known history of serious allergic reactions, including anaphylaxis, to human granulocytemacrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product. -mechanical ventilation before start of study -patients enrolled in another investigational drug study -pregnant or breastfeeding females (all female subjects regardless of childbearing potential status must have negative pregnancy test at screening) -patients with peripheral white blood cell count above . per microliter and/or active myeloid malignancy -patients on high dose systemic steroids (> mg methylprednisolone or equivalent) -patients on lithium carbonate therapy -patients with serum ferritin > mcg/ml (which will exclude ongoing hlh) / . . . screen failures screen failures are defined as subjects who consent to participate in the clinical study but are not subsequently randomly assigned to the study intervention or entered in the study. a minimal set of screen failure information will be kept to ensure transparent reporting of screen failure subjects. there is a large number of covid- infected patients that are currently being hospitalized across the globe. in just days time, our covid- ward at ghent university hospital has admitted confirmed cases, of which a significant portion ( %) already fulfill eligibility criteria for the current proposed protocol. similar numbers of patients are currently being seen in all centers.. we therefore believe that given the current ascending part of the epidemiology curve, with numbers of patients rising sharply, there will be no shortage of patients that are eligible. the number of subjects that will be included in this study is: . these are divided into following sub-groups: group a : active sargramostim treatment group, treatment for initial days, no deterioration after days number of patients : group b : control group : no treatment with sargramostim in first days number of patients : group c and d : data from the wuhan covid- epidemic show that patients that deteriorate are facing a prolonged period of mechanical ventilation. therefore, from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim sargramostim mcg/m body surface area once daily, based on the treating physician's assessment. this group will be called group c. it is estimated that some % of patients might deteriorate and require noninvasive or invasive mechanical ventilation, giving potentially rise to patients that progress from group a to group c, if the clinician decides to move forward with the drug. in the control group progressing to requiring invasive or non-invasive mechanical ventilatory support, from day onwards, the treating physician will have the option to initiate iv sargramostim mcg/m body surface area once daily for days. this group will be called group d. it is estimated that some % of patients might deteriorate to mechanical ventilation or ards, giving potentially rise to patients that progress from group a to group c, if the clinician decides to move forward with the drug comparisons between group a (early sargramostim) versus group b (no sargramostim) at day will be important for reaching primary endpoint, and for key secondary endpoints. comparisons of group a (early day intervention with sargramostim) with group d (late day intervention with sargramostim) will also be very informative for secondary endpoint analysis. subjects are free to withdraw from participation in the study at any time upon request. an investigator may discontinue or withdraw a subject from the study for the following reasons: • allergic reactions (anaphylactic shock) to sargramostim • pregnancy  progression to non-invasive or invasive mechanical ventilation and/or ards between screening and randomization • significant study intervention non-compliance • if any clinical adverse event (ae), laboratory abnormality, or other medical condition or situation occurs such that continued participation in the study would not be in the best interest of the subject • if the subject meets an exclusion criterion (either newly developed or not previously recognized) that precludes further study participation in all cases, the reason why subjects are withdrawn must be recorded in detail in the ecrf and in the subject's medical records. if a patient decides to leave hospital before day of the study, for example because of clinical improvement, the oxygenation parameters at day of discharge will be used to calculate the primary endpoint measurement. the following actions must be taken if a subject fails to return to the clinic for a required study visit (visit at - weeks post end of study) : • the site will attempt to contact the subject and reschedule the missed visit within weeks and counsel the subject on the importance of maintaining the assigned visit schedule and ascertain if the subject wishes to and/or should continue in the study. • before a subject is deemed lost to follow-up, the investigator or designee will make every effort to regain contact with the subject (where possible, telephone calls and, if necessary, a certified letter to the subject's last known mailing address or local equivalent methods). these contact attempts should be documented in the subject's medical record or study file. • should the subject continue to be unreachable, he or she will be considered to have withdrawn from the study with a primary reason of lost to follow-up. subjects will be recruited at the covid- hospitalization ward at the participating centers. the study will be proposed by the treating physician to all subjects with pcr-confirmed covid- infection and a presence of acute hypoxic respiratory failure. there will be no compensation for study participation. partner therapeutics inc. is providing sargramostim to the study subjects, free of charge. since this is a hospital based trial, taking place over a minimum of five days in which patients are severely ill, we suspect the retention in the trial to be high. patients will be informed about the study by the treating physician. after receiving full explanation, having received sufficient time to considerer the trial, asking questions and receiving satisfying responses to all questions, patients will be asked to sign icf. a serum pregnancy test will be done (female patients only). medical history will be checked for review of exclusion criteria and relevant subject information. patients will be continuously monitored on the covid- ward. exams (standard of care) include, but are not limited to: -ecg -chest x-ray, and ct-scan -laboratory tests for leukocyte formula, kidney and liver function, ferritin levels -vital signs -pulse oximetry, arterial blood gas, capnography as soon as all in-and exclusion criteria are checked and patient is considered eligible, patient can be randomized. there is no minimal window to randomize the patient. the producer and distributor of leukine® is partner therapeutics inc, an integrated commercial-stage biotech company focused on the development and commercialization of therapeutics that improve health outcomes in the treatment of cancer. the distribution of imp will be done by tanner pharma. for inhalation: leukine® is a sterile, preservative-free lyophilized powder that requires reconstitution with ml normal saline solution, to reach a concentration of , mcg/ml. once reconstituted, leukine® can be inhaled as an aqueous aerosol using either a vibrating mesh nebulizer or jet nebulizer, aerosolizing ml twice daily. reconstituted leukine® solution for inhalation should be used within hours following reconstitution and/or dilution. dosage for inhalation: mcg twice daily via nebulizer. nebulizing is preferably done in an isolation negative pressure chamber, and if not, personnel should use an ffp mask. patient should self-administer the medication and where possible, the room should not be entered within one hour after administration. for intravenous injection: leukine® injection in . % sodium chloride injection, usp. dilute leukine® for intravenous infusion in . % sodium chloride injection, usp. if the final concentration of leukine® is below mcg/ml, add albumin (human) at a final concentration of . % to the saline prior to addition of leukine to prevent adsorption to the components of the drug delivery system. to obtain a final concentration of . % albumin (human), add mg albumin (human) per ml . % sodium chloride injection, usp (e.g., use ml % albumin [human] in ml . % sodium chloride injection, usp). once diluted for infusion, leukine® is stable for h. dosage for intravenous injection: mcg/m /day over a -hour period for up to days. no dose adjustments and interruptions are permitted during this trial. in case of anaphylaxis or severe ae, the drug will be immediately interrupted. leukine® will be administered for days, with a possible day extension to a maximum of days in case of progression of disease and need for mechanical ventilation. . . . packaging and labeling of the imp leukine® (sargramostim) for injection is a sterile, preservative-free, white lyophilized powder supplied in a carton containing five mcg single-dose vials. leukine® (sargramostim) injection is a sterile, clear, colorless solution preserved with . % benzyl alcohol supplied in a carton containing one mcg/ml multiple-dose vial and a carton containing five mcg/ml multiple-dose vials (ndc - - ). storage and handling : leukine should be stored at °c. drug will be labeled by pharmacy uz ghent (for uz ghent enrolment) for inhaled or intravenous use. store leukine® vials refrigerated at °c- °c ( °f- °f) in the original carton to protect from light. do not freeze or shake. do not use beyond the expiration date printed on the vial. leukine® is to be shipped refrigerated at °c- °c ( °f- °f). the medication will be delivered to the pharmacy of the participating centers. temperature during shipment and storage is to be monitored continuously. whenever a temperature deviation occurs, partner therapeutics inc. should be contacted. partner therapeutics inc. might allow further use of the medication vials depending on the duration and intensity of the temperature excursion. the co-ordinating investigator should be informed of this deviation as well. to date, there have been no new safety signals associated with leukine® (sargramostim). observed side effects with aerosolized leukine® at mcg dose and in at least one evaluation have included: bronchospasm, cough, dyspnea, a decrease in vital capacity and/or forced expiratory volume associated with bilateral infiltrates, pleural effusions, increased phlegm, throat irritation, and back pain. there are no restrictions regarding concomitant/rescue medication. patients will be informed about the study by the treating physician. after receiving full explanation, having received sufficient time to considerer the trial, asking questions and receiving satisfying responses to all questions, patients will be asked to sign icf. the icf process will be performed before any other study related procedure. in this open label trial patients will be randomized in a : ratio. randomization in belgium will be done using redcap (electronic ivrs system). this is a hospital based intervention trial, in which patients with covid- will be treated at least for days with sargramostim. patients with covid- infection and respiratory failure are severely ill, and will require multiple daily clinical exams, blood sampling, vital parameter measurements, blood oxygenation measurements, and chest x-rays. these are all part of the clinical management plan of the patients, and data stored in the electronic patient file will be used as part of the assessment of efficacy and safety profile of sargramostim. on screening, blood sample will be taken, preferentially during routine blood sampling, to determine exclusion criteria (pregnancy, high ferritin level). on day , prior to sargramostim treatment in group a, and during the day in group b control patients, a tube of blood serum ( ml) and an edta tube ( ml) will be collected for measuring blood cytokine and chemokine levels, and activation of immune cells in selected centers. also in each center, an arterial blood gas determination via arterial puncture will be taken. this sample should be taken in an upright position, while breathing room air for a minimum of minutes.. if this is impossible due to dependency on supplemental oxygen, fio , oxygen flow rate, and method of oxygen delivery should be noted in the patient file. if arterial blood gas is taken within h before first dose administration, as described in point° the arterial blood gas of screening can be used as d value. on day or on day of discharge before day , a tube of blood serum ( ml) and an edta tube ( ml) will be collected for measuring blood cytokine and chemokine levels, and activation of immune cells in selected centers. also in each center, an arterial blood gas determination via arterial puncture will be taken. on days - , patients in group a will inhale sargramostim mcg twice daily for days as a nebulized inhalation using a philips innospire go portable mesh nebulizer on top of standard of care. this device is a handheld mesh nebulizer that can be fitted with a facial mask. patients will be instructed prior to receiving the first dose on how to use this simple device, by a physician. this procedure is finished in - minutes, and will be performed twice daily, in the morning (between a.m. and a.m.) and evening (between p.m. and p.m.). upon progression of disease requiring initiation of invasive mechanical ventilatory support within the day period, in patients in the active group, inhaled sargramostim will be replaced by intravenous sargramostim mcg/m body surface area once daily until the day period is reached. this administration will occur via a centrally placed catheter or peripheral catheter, that will be in place as part of routine medical care at the icu. on a final clinical visit between week - an additional serum tube ( ml) and an edta tube ( ml) will be taken in selected centers. . patient demographics age, sex, ethnicity, day of admission . day of covid- pcr positivity, and conversion to negative . patient biometry weight, length, bmi, body surface area . clinical and laboratory parameters on screening day and during trial -first day of illness, potential source of infection -clinical examination findings (cyanosis, crepitation's and rales, heart murmurs, peripheral edema) -vital signs (temperature, blood pressure, heart rate, breathing rate) -pulse oximetry data (sao ) -clinical blood gas sampling (pao , paco , hco ) -clinical chemistry sampling (ferritin, leukocyte formula, platelets, kidney and liver function, fibrinogen, triglycerides) -chest x-ray and/or ct characteristics and radiology clinical report -in case of admission to icu : invasive monitoring data (arterial blood pressure, pcwp, continuous o saturation, continuous ecg, ventilatory parameters (tidal volume, fio , peep pressure, peak pressure, minute ventilation) . all standard care drugs used during the trial and on day of enrolment of the trial, including oxygen flow rate. . basic clinical data on prior medical history (prior lung diseases, smoking history, prior lung function measurements (preferentially within preceding years), prior gas exchange measurements) and medication use will be collected from electronic medical record. . study specific measurements . sampling in selected centers only: d : serum blood sample ml, edta blood sample, ml d or discharge before day : serum blood sample ml, edta blood sample, ml w - follow-up visit : serum blood sample ml, edta blood sample, ml these samples are to be taken on d and d (or discharge if before day ) and on final follow up visit between week and . there's no time window allowed. in selected centers samples will be taken during hospitalization together with the blood draw for standard of care. after clotting for - minutes the samples will be processed at rpm or g during minutes at room temperature. aliquots will be filled and frozen at - °c until further analysis. centrifugation and storage will be done by qualified personal. edta blood samples will be processed to purify peripheral bloodmonocytes and stained for flow cytometric analysis of number of monocytes, hla-dr expression on monocytes and dendritic cells, and lymphocyte activation. multiple cytokines and chemokines will be measured by multiplex bead based elisa assay. flow cytometry will be performed on paraformaldehyde fixed samples. development of anti-drug antibodies (ada) will be measured using protocol developed by partner therapeutics on serum samples taken at day and follow up visit. serum samples and frozen pbmcs will be stored at temperature monitored facilities of the participating research centres. . storage conditions: - °c. initially samples will be stored for the use as described within this protocol. if at a later time point samples will be stored for future use, they will be stored in fagg certified biobank the outcome(s) on which the sample size calculation is based upon, is the primary endpoint measurement of oxygenation, defined as ratio of pa /fio and p(a-a)o . sample calculation and power analysis have been performed using genstat. the target difference is the difference measured at the primary endpoint (at day ) between the control and the treated group. given a sample size of patients each, a minimal improvement of % in the treated group relative to the control group will be detected as significant at a significance level of , with a power of . . the error variance was set at units, corresponding with a standard deviation of units. the statistical test to be used will be an f-test. a two-sample t-test is expected to give similar results. the statistical analysis will be performed by gnomixx, a biostatistics consultancy company based in ghent (dr marnik vuylsteke). http://www.gnomixx.com/ subjects that are included in the study , will be assigned a unique study number upon their registration in redcap.. on all documents submitted to the coordinating center, sponsor or ci, patients will only be identified by their study number. the subject identification list will be safeguarded by the site. the name and any other directly identifying details will not be included in the study database. an electronic data capture (edc) system, i.e. redcap, will be used for data collection. data reported on each ecrf should be consistent with the source data. if information is not known, this must be clearly indicated on the ecrf. all missing and ambiguous data will be clarified. only the data required by the protocol are captured in the ecrf. the ecrfs and the database will be developed, based on the protocol. the final ecrf design will be approved by the co-ordinating investigator. all data entries and corrections will only be performed by study site staff, authorized by the investigator. data will be checked by trained personnel (monitor, data manager) and any errors or inconsistencies will be clarified. the investigator must verify that all data entries in the ecrf are accurate and correct. redcap is provided and maintained by vanderbilt university; a license for use was granted to the health, innovation and research institute (hiruz). redcap is a web-based system. the study site staff is responsible for data entry in redcap. the data is accessed through a web browser directly on the secure redcap server. the server is hosted within the uz ghent campus and meets hospital level security and back-up requirements. privacy and data integrity between the user's browser and the server is provided by mandatory use of transport layer security (tls), and a server certificate issued by terena (trans-european research and education networking association). all study sites will have access to redcap. site access is controlled with ip restriction. the investigator and sponsor specific essential documents will be retained for at least years. at that moment, it will be judged whether it is necessary to retain them for a longer period, according to applicable regulatory or other requirement(s). direct access will be granted to authorised representatives from the sponsor, host institution and the regulatory authorities to permit study-related monitoring, audits and inspections. login in redcap is password controlled. each user will receive a personal login name and password and will have a specific role which has predefined restrictions on what is allowed in redcap. furthermore, users will only be able to see data of subjects of their own site. any activity in the software is traced and transparent via the audit trail and log files. term definition adverse event (ae) any untoward medical occurrence in a subject to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product. an adverse event, the nature or severity of which is not consistent with the applicable product information (e.g., investigator's brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product). adverse reaction (ar) an untoward and unintended response in a subject to an investigational medicinal product which is related to any dose administered to that subject. the phrase "response to an investigational medicinal product" means that a causal relationship between a study medication and an ae is at least a reasonable possibility, i.e. the relationship cannot be ruled out. all cases judged by either the reporting medically qualified professional or the sponsor as having a reasonable suspected causal relationship to the study medication qualify as adverse reactions. a serious adverse event is any untoward medical occurrence that:  results in death  is life-threatening  requires inpatient hospitalisation or prolongation of existing hospitalisation  results in persistent or significant disability/incapacity  consists of a congenital anomaly or birth defect other 'important medical events' may also be considered serious if they jeopardise the subject or require an intervention to prevent one of the above consequences. note: the term "life-threatening" in the definition of "serious" refers to an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. an adverse event that is both serious and, in the opinion of the reporting investigator, believed with reasonable probability to be due to one of the study treatments, based on the information provided. a serious adverse reaction, the nature and severity of which is not consistent with the information about the medicinal product in question set out:  in the case of a product with a marketing authorisation, in the summary of product characteristics (smpc) for that product  in the case of any other investigational medicinal product, in the investigator's brochure (ib) relating to the study in question attribution definitions an adverse event is considered associated with the use of the drug if the attribution is possible, probable or definitive. an adverse event which is not related to the use of the drug. an adverse event for which an alternative explanation is more likely -e.g. concomitant drug(s), concomitant disease(s), and/or the relationship in time suggests that a causal relationship is unlikely. an adverse event which might be due to the use of the drug. an alternative explanation -e.g. concomitant drug(s), concomitant disease(s), -is inconclusive. the relationship in time is reasonable; therefore the causal relationship cannot be excluded. an adverse event which might be due to the use of the drug. the relationship in time is suggestive (e.g. confirmed by dechallenge). an alternative explanation is less likely -e.g. concomitant drug(s), concomitant disease(s). an adverse event which is listed as a possible adverse reaction and cannot be reasonably explained by an alternative explanation -e.g. concomitant drug(s), concomitant disease(s). the relationship in time is very suggestive (e.g. it is confirmed by dechallenge and rechallenge). ae's will be recorded from the first drug administration until the end of the study, as defined in section . . special attention will be given to those subjects who have discontinued the study for an ae, or who experienced a severe or a serious ae. all ae's should be recorded in the patient's file and in the crf. sae's occurring during the entire study period will be reported as below. all serious adverse events (initial and follow up information) and pregnancies occurring during this study must be reported by the local principal investigator within hours after becoming aware of the sae to: -the local ethics committee (it is the responsibility of the local pi to report the local sae's to the local ec) -hiruz ctu of the university hospital ghent -the national coordinating investigator (in case of multicenter studies) the company partner therapeutics that provides the imp this reporting is done by using the appropriate sae form. for the contact details, see below.  study team informs company that provides the imp susar notify to hiruz ctu within hours after becoming aware of the susar  hiruz ctu will submit to the central ec.  hiruz ctu will submit to the famhp  study team informs company that provides the imp in case the (su)sar occurs at a local participating site, the local pi or study team should also contact: -the local ethics committee -the co-ordinating investigator . . events, excluded from reporting covid- infection is a very recent syndrome, on which few data are available. normal symptoms and natural disease course symptoms that will not be reported as adverse events are dyspnea, coughing, malaise, fever, drop in oxygen saturation, progression to respiratory failure, progression to ards, severe drop in blood pressure in the icu,progression to multi-organ failure. all study medication is registered and used in current practice. despite the known safety profile of the study medications and study design, a dsmb is foreseen. the coordinating investigator will provide dsurs once a year throughout the clinical study, or on request, to the competent authority (famhp in belgium), ethics committee and sponsor. this dsur will include all sae's (who were not categorized as sar's and were not immediately reported to the ec). the report will be submitted within days after the start of the study, and will subsequently be submitted each year until the study is declared ended. hiruz ctu can provide a template that can be used to complete this dsur. monitoring/auditing/inspection . . monitoring monitoring of the study will be performed in compliance with gcp e (r ) and the applicable regulatory requirements. the study team will be trained in an initiation visit by the monitor. a training and delegation log will be held. a detailed description of the monitoring tasks can be found in the latest version of the (study-specific) 'monitoring plan'. monitoring services will be provided by hiruz ctu. all relevant contact details (e.g. primary contact person, can be found in the 'monitoring plan'. monitoring services will consist of the following (non-exhaustive list): -review of informed consents and the followed process -check on recruitment status -checking for protocol deviations/violations -checking gcp compatibility -check on safety reporting compliance -imp handling and storage -review of study data … this study can be inspected at any time by regulatory agencies during or after completion of the study. therefore access to all study records, including source documents, must be accessible to the inspection representatives. subject privacy must be respected at all times, in accordance to gdpr, gcp and all other applicable local regulations. the investigator/study team should immediately notify the sponsor if he or she has been contacted by a regulatory agency concerning an upcoming inspection. sponsor and all investigators agree to take any reasonable actions to correct protocol deviations/violations noted during monitoring/inspection, in consultation with the monitoring team. all deviations must be documented on a protocol deviation log by the study team that is kept available at any time for monitoring/inspection purposes. under emergency circumstances, deviations from the protocol to protect the rights, safety or well-being of human subjects may proceed without prior approval of the sponsor and the ec. ethical and legal aspects . the study will be conducted cfr the latest version of the ich e (r ) gcp guidelines, creating a standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical studies that provides assurance that the data and reported results are accurate and that the rights, integrity and confidentiality of study subjects are protected. eligible subjects may only be included in the study after providing written (witnessed, if needed) ethics committee-approved informed consent, or, if incapable of doing so, after such consent has been provided by a legally acceptable representative(s) of the subject. informed consent must be obtained before conducting any study-specific procedures (as described in this protocol). prior to entry in the study, the investigator must explain to potential subjects or their legal representatives the study and the implication of participation. subjects will be informed that their participation is voluntary and that they may withdraw consent to participate at any time. participating subjects will be told that their records may be accessed by competent authorities and by authorized persons without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) and/or regulations. by signing the informed consent form (icf), the subjects or legally acceptable representatives are authorizing such access. after this explanation and before entry to the study, written, dated and signed informed consent should be obtained from the subject or legally acceptable representative. the icf should be provided in a language sufficiently understood by the subject. subjects must be given the opportunity to ask questions. the subject or legally acceptable representative will be given sufficient time to read the icf and to ask additional questions. after this explanation and before entry to the study, consent should be appropriately recorded by means of either the subject's or his/her legal representative's dated signature or the signature of an independent witness who certifies the subject's consent in writing. after having obtained the consent, a copy of the icf must be given to the subject. in case the subject or legally acceptable representative is unable to read, an impartial witness must attest the informed consent. subjects who are unable to comprehend the information provided or pediatric subjects can only be enrolled after consent of a legally acceptable representative. any significant change or addition to the protocol can only be made in a written protocol amendment that must be approved by the central ethics committee (and the famhp if applicable). only amendments that are intended to eliminate an apparent immediate safety threat to patients may be implemented immediately. notwithstanding the need for approval of formal protocol amendments, the investigators are expected to take any immediate action, required for the safety of any subject included in this study, even if this action represents a deviation from the protocol. these actions should always be notified to the sponsor. all study data will be handled in accordance with the law on general data protection regulation (gdpr) and institutional rules [belgian law dated on july and aug. ]. the collection and processing of personal data from subjects enrolled in this study will be limited to those data that are necessary to fulfill the objectives of the study. these data must be collected and processed with adequate precautions to ensure confidentiality and compliance with applicable data privacy protection laws and regulations. appropriate technical and organizational measures to protect the personal data against unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. sponsor and site personnel whose responsibilities require access to personal data agree to keep the identity of subjects confidential. the informed consent obtained from the subject includes explicit consent for the processing of personal data and for the investigator/institution to allow direct access to his or her original medical records (source data/documents) for study-related monitoring, audit, ethics committee review and regulatory inspection. this consent also addresses the transfer of the data to other entities, if applicable. privacy and confidentiality of data generated in the future on stored samples will be protected by the same standards applicable to all other clinical data. stored samples will be pseudonymized throughout the sample storage and analysis process and will not be labeled with personal identifiers. the sponsor has taken a no fault insurance for this study, in accordance with the relevant legislation (article , belgian law of may , critical issues that significantly affect patient safety, data integrity and/or study conduct should be clearly documented and will be communicated with the coordinating investigator, hiruz ctu and possibly both the applicable ethics committee(s) and competent authority. (please contact hiruz ctu asap in case of a serious breach: hiruz early determination of the study (in a specific center or overall) may be necessary in case of major noncompliance. . . end of study notification if all subjects have completed the study, a notification of the end of the study should be submitted to the (central) ethics committee and famhp. this notification should be made within days of the end of the clinical study the cloning of gm-csf alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via gm-csf gm-csf treatment prevents respiratory syncytial virus-induced pulmonary exacerbation responses in postallergic mice by stimulating alveolar macrophage maturation yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages a review of gm-csf therapy in sepsis a randomized phase ii trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction a randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis inhaled gm-csf for pulmonary alveolar proteinosis pathological findings of covid- associated with acute respiratory distress syndrome gm-csf overexpression after influenza a virus infection prevents mortality and moderates m -like airway monocyte/macrophage polarization lower respiratory tract delivery, airway clearance, and preclinical efficacy of inhaled gm-csf in a postinfluenza pneumococcal pneumonia model lung epithelial gm-csf improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy? the pleiotropic effects of the gm-csf rheostat on myeloid cell differentiation and function: more than a numbers game frontline science: coincidental null mutation of csf ralpha in a colony of pi kgamma-/-mice causes alveolar macrophage deficiency and fatal respiratory viral infection alveolar epithelial cells orchestrate dc function in murine viral pneumonia gm-csf in the lung protects against lethal influenza infection pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (sars) screening follow-up ( - weeks after d ) d d d (or discharge before day ) informed consent x inclusion/exclusion criteria check serum pregnancy test x vital signs (incl. height and weight)* ° this sample should be taken in an upright position, while breathing room air for a minimum of minutes.. if this is impossible due to dependency on supplemental oxygen, fio , oxygen flow rate, and method of oxygen delivery should be noted in the patient file. § if arterial blood gas is taken within h before first dose administration, as described in point° the arterial blood gas of screening can be used as d value ∞ patients randomized in the treatment group will receive inhaled sargramostim from d untill d . in case of progression requiring mechanical ventilation within the first days, iv sargramostim can be initiated until the day period is reached. from day onwards, progressive patients in the active group will have the option to receive an additional days of iv sargramostim, based on the treating physician's assessment. patients in the control group will have the option to receive days of iv sargramostim in case of progression requiringmechanical ventilation, based on the treating physician's assessment.order of assessments: imp should always be administered after other assessments, where possible. there are no subject restrictions during this trial.in case the coordinating investigator, in consultation with hiruz ctu, decides the sae is a susar (suspected unexpected serious adverse reaction), hiruz ctu will report the susar to the central ec and the famhp within the timelines as defined in national legislation. the coordinating investigator reports the susar to all local pi's. in case of a life-threatening and fatal susar the entire reporting process must be completed within calendar days. in case of a non life-threatening susar the reporting process must be completed within calendar days. notify to hiruz ctu within hours after becoming aware of the sae  hiruz ctu will submit to the central ec this study will be registered at clinicalstudies.gov, and results information from this study will be submitted to clinicalstudies.gov. in addition, every attempt will be made to publish results in peerreviewed journals. appendices appendix : uspi (us package insert) key: cord- -jxigsdzh authors: gattinoni, luciano; camporota, luigi; marini, john j. title: covid- phenotypes: leading or misleading? date: - - journal: eur respir j doi: . / . - sha: doc_id: cord_uid: jxigsdzh comment to an editorial where we invite the authors to express with clarity the risks they are referring to and how their argument is furthering the cause of patients and clinicians. we read the editorial by bos et al [ ] with a mixture of interest, irritation and serious concern. our interest derives from a simple fact: the debate on terms like 'typical ards' or 'atypical ards' is not just question of semantics, but these terms represent concepts linked to specific clinical, mechanical and radiological criteria, and not merely based on the severity of gas exchange. it should not be a surprise to the authors that different radiological patterns and mechanical characteristics should suggest different ventilatory strategies, each with possible benefits and harm. the management of individual patients needs to take into consideration various factors, and not just the gas exchange that currently defines ards. this is precisely the point of bringing attention to the novel 'l & h' phenotypes of covid- that bracket the extremes of the clinical encounter [ ] . usually, there is overlap, depending in large part on disease duration. the 'l & h' were not intended to be tightly prescriptive nor mutually exclusive 'bins' into which each patient falls, as we clearly stated [ ] . rather, the object was to alert clinicians in order to avert potential harm from assuming usual ards associations between hypoxemia and mechanics at all stages. in so doing, we hoped to help prevent use of high peep when there is no benefit, and equally important, to avoid maintaining low pressures when higher pressures can be beneficial. the irritation derives from the fact the authors seem to have deliberately decided to ignore the pathophysiological 'evidence' readily available and ventured into a philosophical and semantic discourse against 'premature phenotyping', and in so doing committing the greater sin of 'premature adjudication'. after reading sentences such as "…by needlessly clouding the clinical picture, false phenotypes … upon inspection of patient data, simply do not exist" , it is not clear to us -and without a doubt to most readers -what sort of clear, and self-evident truth we (and other authors) have been trying to cloud. the fact that covid- patients with similar oxygenation efficiency may have markedly different compliance (and vili risk) is apparent to any clinician who has ever looked after a number of these patients. the reasoning put forward by the editorialists seems purely argumentative and inflammatory, as it seems to imply that what we propose is based on non-existent data, i.e., a perception that we invented. our concern derives from noting that the observations of bos and colleagues are expressed with a tone which goes beyond healthy and reasonable scientific debate. we note also with concern the conclusions of the editorial: "by prematurely phenotyping patients with covid- , we expose ourselves and our patients to considerable and preventable risk" and we invite the authors to express with clarity the risks they are referring to and how their argument is furthering the cause of patients and clinicians. time and emerging literature will undoubtedly demonstrate where "truth" lies. the perils of premature phenotyping in covid: a call for caution covid- pneumonia: different respiratory treatments for different phenotypes? management of covid- respiratory distress key: cord- -z vxamvp authors: gagiannis, daniel; steinestel, julie; hackenbroch, carsten; schreiner, benno; hannemann, michael; bloch, wilhelm; umathum, vincent g.; gebauer, niklas; rother, conn; stahl, marcel; witte, hanno m.; steinestel, konrad title: clinical, serological, and histopathological similarities between severe covid- and acute exacerbation of connective tissue disease-associated interstitial lung disease (ctd-ild) date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: z vxamvp background and objectives: understanding the pathophysiology of respiratory failure in coronavirus disease (covid- ) is indispensable for development of therapeutic strategies. since we observed similarities between covid- and interstitial lung disease in connective tissue disease (ctd-ild), we investigated features of autoimmunity in sars-cov- -associated respiratory failure. methods: we prospectively enrolled patients with rt-pcr-confirmed sars-cov- infection and patients with non-covid- -associated pneumonia. full laboratory testing was performed including autoantibody (aab; ana/ena) screening using indirect immunofluorescence and immunoblot. fifteen covid- patients underwent high-resolution computed tomography. transbronchial biopsies/autopsy tissue samples for histopathology and ultrastructural analyses were obtained from / cases, respectively. results: thirteen ( . %) patients developed acute respiratory distress syndrome (ards), and five patients ( . %) died from the disease. ana titers ≥ : and/or positive ena immunoblots were detected in / ( . %) covid- patients with ards, in / ( . %) covid- patients without ards (p = . ) and in / ( %) patients with non-covid- -associated pneumonias (p = . ). detection of aabs was significantly associated with a need for intensive care treatment ( . vs. %; p = . ) and occurrence of severe complications ( vs. %, p = . ). radiological and histopathological findings were highly heterogeneous including patterns reminiscent of exacerbating ctd-ild, while ultrastructural analyses revealed interstitial thickening, fibroblast activation, and deposition of collagen fibrils. conclusions: we are the first to report overlapping clinical, serological, and imaging features between severe covid- and acute exacerbation of ctd-ild. our findings indicate that autoimmune mechanisms determine both clinical course and long-term sequelae after sars-cov- infection, and the presence of autoantibodies might predict adverse clinical course in covid- patients. coronavirus disease , caused by severe acute respiratory syndrome coronavirus (sars-cov- ), has caused or contributed to hundreds of thousands of deaths and led to almost complete shutdown of social and economic life in many countries ( ) . based on what is currently known about epidemiology, covid- is associated with a mortality rate between and % ( ) . major cause of death in covid- infections is acute respiratory failure (acute respiratory distress syndrome, ards), but the exact mechanism of how covid- leads to ards is unclear. in most reported morphological analyses, the authors describe diffuse alveolar damage (dad) with an early edematous phase followed by hyaline membrane formation, desquamation of pneumocytes, and an increased interstitial mononuclear infiltrate in severe sars-cov- infection ( ) . in one case, tian et al. report loose intra-alveolar fibromyxoid proliferation reminiscent of organizing pneumonia (op) ( ) . such combined histological patterns of (organizing) dad and op, summarized by some authors under the term acute fibrinous organizing pneumonia (afop), have also been observed in interstitial lung disease associated with systemic lupus erythematosus (sle), dermatomyositis, and progressive systemic sclerosis (pss) ( ) ( ) ( ) . this is of special relevance since both organizing dad as well as ctd-ild may evolve to pulmonary fibrosis, and long-term effects of covid- are so far unknown. only recently, upregulation of fibrosis-associated gene expression in covid- has been described ( ) . most ctds are defined by the presence of specific antinuclear autoantibodies (anas), several of which have been identified and summarized under the historic term extractable nuclear antibodies (enas), such as anticentromer antibodies (cenp-b), pm-scl, ss-b/la, jo- , and scl- ( ) . only recently, the presence of such autoantibodies has been described in cases of severe covid- , but the exact relevance of this finding remains unclear ( , ) . taken together, since available data suggests histomorphological as well as pathophysiological similarities between covid- associated ards and lung manifestations of autoimmune disease, we hypothesized that a dysregulated immune response upon sars-cov- infection might show similarities to acute exacerbation of ctd-ild which might shed some light on the mechanism of lung damage in covid- . in this prospective trial we consecutively included all patients with positive sars-cov- -rt-pcr (mucosal swab, pharyngeal or bronchoalveolar lavage) admitted to the bundeswehrkrankenhaus (armed forces hospital) ulm in march and april after obtaining informed consent. suspected cases without rt-pcrconfirmed sars-cov- infection were excluded from the study. a group of patients with non-covid- -associated pneumoniae served as control group for serological analyses (supplementary table ). patients or their relatives had given written informed consent to routine diagnostic procedures (serology, bronchoscopy, radiology) as well as (partial) autopsy in the case of death, respectively, as well as to the scientific use of data and tissue samples in the present study. this project was approved by the local ethics committee of the university of and conducted in accordance with the declaration of helsinki. we collected clinical information from electronic patient files. data included disease-related events, preexisting comorbidities, imaging, treatment approaches (supplementary table ) , and clinical follow-up. the "berlin definition'' was used to categorize ards ( ) . the horovitz quotient (pao /fio ) was assessed in all ards cases based on arterial blood gas analysis. during icu treatment, ventilation parameters, duration of invasive ventilation, catecholamine support, prone positioning, murray lung injury score and the need of additional temporary dialysis were continuously assessed (supplementary table ) ( ) . a profitable trial of prone positioning was defined by an increasing horovitz quotient of mmhg or more. one entire trial covered h of sustained prone positioning. blood samples for serology and monitoring of laboratory values were taken at hospital admission and during ward/icu treatment, respectively. laboratory values included possible predictors of outcome in covid- patients such as lymphocyte count, fibrinogen, d-dimers, ferritin, lactate dehydrogenase (ldh), and bilirubin. we also assessed troponin-t levels as a marker for cardiac events and infection-associated parameters (neutrophils, interleukin- (il- ), creactive protein (crp), and procalcitonin (pct)). cut-off values, median, and range for these parameters are summarized in supplementary table . ana/anca/ena testing initial screenings for ana and anca (p-anca, c-anca, x-anca, anti-pr , anti-mpo) were performed by iif using patient sera on hep- cells and primate liver tissue slides (ana) as well as ethanol-and formol-fixed granulocytes and purified pr- and mpo antigens (anca) on glass slides (euroimmun ag, lübeck, germany) according to the manufacturer's protocols ( , ) . in all cases, presence of specific anti-ena autoantibodies (anti-sm, anti-ss-a/ro, anti-ss-b/la, anti-scl- , anti-centromere, anti-jo , anti-mi- , anti-u -rnp, anti-ro- , anti-pm-scl, anti-cnp b, anti-pcna, anti-dsdna, anti-nucleosome, anti-histone, anti-ribosomal pprotein, anti-ama-m ) was assessed by semiquantitative immunoblot (anti-ena profile ; euroimmun ag, lübeck, germany) irrespective of the initial screening result. following previously published guidelines, ana titers ≥ : with or without positive ena immunoblot or ana titers of : with positive ena immunoblot were regarded as positive ( , ) . laboratory testing was performed by investigators who were blinded to patient status, and in cases with unclear/borderline results in either ana screening or ena subtyping, tests were repeated on a new sample, and results were verified by an external reference laboratory. quality and reliability of ana/ anca/ena testing in our institution have been evaluated through regular interlaboratory ring trials. imaging was performed on a somatom force scanner (dual source scanner * slices, siemens, erlangen, germany) in accordance to the guidelines of the german radiological society and our hospital's covid- guidelines, using low-dose ct (computed tomography) with high-pitch technology ( ) . the following parameters were used: tube voltage: kv with tin filtering, tube current: mas with tube current modulation. in two cases examination was performed as a non-contrast enhanced full-dose protocol because of suspected ild, in one case as a contrast-enhanced ct scan to exclude pulmonary thromboembolism. x-ray examinations were performed at the respective wards as bed-side x-ray examinations (mobilett mira max, siemens, erlangen, germany) as a single anterior-posterior view. the ct images were evaluated according to the expert consensus statement of the rsna and classified as typical, indeterminate, atypical, and negative appearance for covid- ( , ) . lung tissue specimens were obtained as transbronchial biopsies in four cases. in three deceased patients, partial autopsies were performed, and lung, heart, and liver tissues were sampled extensively. specimens were stained with hematoxylin-eosin (he), phosphotungstic-acid-hematoxylin (ptah), elasticavan-gieson (evg) and masson-goldner (mg). furthermore, immunohistochemistry for cd , cd , ck , cmv, and ebv was performed using prediluted antibodies on a ventana benchmark autostainer (roche tissue diagnostics, mannheim, germany) following routine protocols. lung, heart, and liver tissues were immersion-fixed with % paraformaldehyde in . m pbs, ph . . after several time washing in . m pbs, tissue was osmicated with % oso in . m cacodylate and dehydrated in increasing ethanol concentrations. epon infiltration and flat embedding were performed following standard procedures. methylene blue was used to stain semithin sections of . µm. seventy to ninetynanometer-thick sections were cut with an ultracut uct ultramicrotome (fa. reichert) and stained with % aqueous uranylic acetate and lead citrate. samples were studied with a zeiss em electron microscope (fa. zeiss) coupled to a megaview iii soft imaging system camera analysis ® software both from fa. (soft imaging system gmbh). descriptive statistical methods were used to summarize the data. medians and interquartile ranges were used to announce results. absolute numbers and percentages were employed to represent categorial variables. student's t-test was used for the comparison of continuous variables, while chi-square-test/fisher's test was used for categorial variables. all statistical analyses were conducted using graphpad prism (graphpad software inc., san diego, ca, usa). a p-value < . was regarded as statistically significant. baseline clinical characteristics of sars-cov- infected patients are briefly summarized in table , and we show a timeline of the complete study cohort with all relevant events in figure . clinical characteristics of non-covid- -associated pneumonia patients (controls) are summarized in supplementary table . median age at initial diagnosis was . years (range, - years). the majority of patients were male ( / cases; . %). most frequent preexisting comorbidities were cardiovascular risk factors ( / , . %) and established cardiovascular disease ( / , . %). preexisting rheumatic disease was present in / cases ( . %): one patient (# ) had rheumatoid factor-positive rheumatoid arthritis, the other patient (# ) had a history of rheumatic disease and associated treatment which could not be evaluated in more detail. treatment approaches and drug-related toxicities are summarized in supplementary table . bacterial superinfection was suspected in / ( . %) cases by clinical course, imaging, and laboratory values. antibiotic treatment approaches are summarized in supplementary table . there was an overall high rate of complications compared to regular (non-covid) ards patients (supplementary table ). one patient was temporarily transferred to another hospital because vv-ecmo (veno-venous extracorporeal membrane oxygenation) was required. after a median follow-up period of . days (range, - days), five patients ( . %) had died from the disease. thirteen of covid- cases ( . %) and / patients ( %) with non-covid- -associated pneumonia presented with or developed ards according to the "berlin definition'' ( ) , and intensive care unit (icu) treatment was required in / ( %) of covid- patients, and one patient with non-covid- associated pneumonia. covid- patients who developed ards were significantly older, and most of them were male (p = . and p = . , table ). furthermore, these patients presented with more preexisting comorbidities (p = . ). ards was significantly associated with icu treatment, occurrence of severe complications and (invasive) ventilation in covid- positive patients (p < . , p = . and p < . , respectively). the murray lung injury score was calculated for all patients who underwent invasive ventilation and revealed moderate or severe ards in / cases ( . %) ( ) . all five covid- -associated deaths occurred in the ards group. laboratory values for ldh, crp, and il- were significantly higher in the group of covid- -positive patients who developed ards compared to covid- patients with mild clinical course. however, ldh, crp, and il- values were not significantly different between covid- ards patients and patients with non-covid- -associated pneumonia (each p > . , table and supplementary table ). initial ana screening by iif showed titers ≥ : in all covid- ards patients ( %) but in / ( . %) covid- patients without ards. among the group of non-covid- -associated pneumonias, the initial ana screening by iif showed titers ≥ : in / patients ( %). anca screening was completely negative in all investigated covid- cases but positive in / patients ( %) with non-covid- -associated pneumonia. specific autoantibodies could be detected by ena immunoblot in / covid- ards patients ( %) but in / covid- non-ards patients ( . %) and / patients ( %) with non-covid- -associated pneumonia. one patient from the ards group (# , ana titer : ) showed borderline positivity for anti-rna polymerase iii (rp ) autoantibodies only after reference laboratory testing and was therefore classified as negative. the distribution and type of ana/ena among the different subgroups are shown in figure a , while representative images of iif and ib are shown in figure b . pm-scl was the most commonly detected autoantibody ( / cases) and could only be detected in the covid- ards group. taken together, applying established diagnostic criteria for ana/ena screening as described above ( ) detection of ana was associated with higher age and male sex, although not significant. ana positivity, however, was associated with a necessity of assisted/invasive ventilation, icu treatment (both p = . ) and occurrence of severe complications (p = . ). typical or atypical patterns in ct supplementary table ; **, case-related complications are summarized in supplementary table ; ***, patient was transferred to another institution because vv-ecmo was required; ****, patient w/chronic lymphocytic leukemia (cll) and antibody deficiency syndrome. rheumatoid factor was positive in this case. [ ] [ ] [ ] [ ] [ ] [ ] [ ] specific enas: anti-ss-b, anti-pm-scl, anti-jo, anti-cenp, anti-scl- , anti-nucleosome, anti-dsdna. imaging were not different between patients with and without anas. while there were no significant differences in serum levels of crp and il- , ldh levels were significantly higher in the ana+ group (p = . ). the association between ana status and disease-specific survival did not reach statistical significance (p = . ) ( table ) . "typical" radiologic covid- patterns were found in . % of patients (ards: . %/non-ards: %). these included ground glass opacities (all "typical" cases), consolidation and (c)op-like pattern ( figure ). atypical/negative patterns were found in . % of ards patients and % of non-ards patients. bronchoscopy with transbronchial biopsy (tbb) was performed in four patients (cases # , , and ) before (# ) and after (# , , ) an established diagnosis of covid- , respectively ( figure ). from three of these patients (# , , ) , additional post-mortem tissue samples were obtained during a partial autopsy procedure. in all samples, we observed reactive pneumocyte changes ("napoleon hat sign") consistent with viral infection (figure ) . however, there was a marked variance in the histologic appearance between different patients, between tbb and autopsy samples from the same patient and between autopsy samples from different regions of the lung. in addition to hyaline membrane formation consistent with diffuse alveolar damage (classic dad), there was also early septal thickening and intra-alveolar fibrinous plug formation with partial fibromyxoid change, reminiscent of acute fibrinous organizing pneumonia (afop) (# , figure a ). ultrastructural analyses of tissue samples from the same patient showed widening of alveolar septa with activated fibroblasts and early deposition of fine collagen fibrils. in patient # , where biopsies were obtained on day after initial diagnosis, there was a pattern of organizing dad with parenchymal collapse and entrapment of fibrin ( figure b ). tissue samples from autopsy from the same patient showed areas of beginning, patchy fibrosis with a foreshadowing of honeycombing. in all autopsy samples, there was capillary congestion with formation of microthrombi especially in late-stage disease (supplementary figure ) . in the present study, we found overlapping serological, clinical, radiologic, and histopathological features of severe covid- and lung manifestation of autoimmune disease (ctd-ild). we show that presence of anas is significantly associated with the development of ards, necessity for icu treatment and invasive ventilation as well as occurrence of severe complications in these patients; noteworthy, every patient in the present study who presented with or developed ards had detectable autoantibodies. with respect to baseline clinical characteristics, the investigated cohort is comparable to previous reports ( , ) . our result of autoantibodies in patients with severe covd- is in line with first results from other groups ( , , ) ; however, we are the first to put this observation into context with clinical, imaging, and histopathology findings. furthermore, we confirm the association between higher age, male sex, and elevated ldh with severe course of covid- in line with literature data ( ) . given the fact that only hospitalized patients were included, it is not surprising that the mortality rate ( . %) was higher compared to the general population. imaging and histopathological data in the present and in previous studies show that presentation of covid- in the lung is heterogeneous and evolves over time ( , ( ) ( ) ( ) . overall diversity of these changes, including (organizing) diffuse alveolar damage, fibromyxoid plugging and interstitial thickening are reminiscent of exacerbation of ctd ( , ) . however, it has to be clearly acknowledged that the histopathological spectrum of virus-induced dad is wide and also includes findings that have recently been described to be specific for covid- , such as endothelialitis and (micro-)thrombotic events. our finding that significant ana titers and/or detection of specific autoantibodies are found in most patients who develop ards raises the question if there is a comparable mechanism of lung damage between sars-cov- infection and exacerbating autoimmune disease. in / covid- patients with specific enas who developed ards, detected autoantibodies were anti-pm-scl or anti-scl- ; if the borderline positivity for rp in patient # was included, / specific enas in our cohort would be associated with a form of sclerosing ctd, as these autoantibodies (as well as similar hr-ct) patterns have previously been described in dermatomyositis, (progressive) systemic sclerosis and ctd-overlap syndromes ( , ) . of note, a significant proportion of anti-pm-scl-/anti-scl- positive patients develop pulmonary fibrosis, raising the question of long-term effects of severe covid- in these patients ( ) . the possibility of progressively evolving fibrosis would be supported by our findings from histopathology and electron microscopy, where we observed organization and pseudo-honeycombing as well as interstitial fibroblast activation with collagen deposition. another parallel between ctds and covid- are the vasculitis-like changes, vascular dysfunction or microangiopathies that have been described in a subset of patients ( ) ( ) ( ) . while thromboembolic complications occurred in only two patients in our cohort (both ana-positive), it would be of great interest to screen patients with more widespread vascular or cutaneous involvement for the presence of ana. anca screening, however, was completely negative in our cohort of covid- patients. since it is well-known that ana screening can be false positive in severely ill patients or patients who undergo icu treatment, a possible epiphenomenon has to be discussed very frankly. according to a recent publication, a there is no cross-reactivity between anti-sars-cov- igg/igm and ctdassociated autoantibodies ( ) . however, to enhance test validity in the present study, we a) doubled the recommended threshold for ana screening ( ) from : to : and b) figure b for histology) weeks after onset of the disease and ecmo therapy. in addition to diffuse ground glass opacities, a mixture of bronchiectasis, cysts and airtrapping is evident. additional pneumothorax and mediastinal emphysema are visible. performed additional immunoblot for specific ena in all patients, thus adding an independent methodological approach combining high sensitivity and specificity ( , ) . moreover, we included a non-covid- pneumonia control group in which ana titers ≥ : could be detected in two patients. specific autoantibodies against ama-m (associated with primary biliary cirrhosis) and ro (associated with sle) were detected in two additional patients. laboratory values in the pneumonia control group (ldh, crp, il- ) were not significantly different compared to covid- ards cases. while it is conceivable that ana titers rise and specific autoantibodies may appear in severely ill patients in general, we think that the observed clustering of high ana titers with specific, sclerosis-associated autoantibodies in the covid- ards group is reliable, raising the question of how these autoantibodies arise in the context of sars-cov- infection. a recent preprint suggests significant extrafollicular b cell activation with an excessive production of antibody-secreting cells (ascs) in critically ill sars-cov- patients ( ). this mechanism is highly similar to the development and progression of sle, and these asc might represent a possible source of the autoantibodies we report here ( , ) . we do not assume that these autoantibodies were already present in predisposed patients prior to infection, because only two patients in our cohort had any clinical history of rheumatic or autoimmune disease. however, in light of our results, there are interesting parallels between the reported epidemiology of severe covid- and the presence of autoantibodies in the general population. autoantibody titers above : and : can be detected in . and % of otherwise healthy individuals ( ) , reflecting reported proportions of severe ( %) and critical ( %) course of covid- ( ) . preliminary reports from the u.s. suggest that the covid- -associated death rate among african americans is significantly higher compared to the general population ( ) , while at the same time ana titers in african americans exceed those of americans with another ethnic background ( ) . it would be interesting to screen patients for class i and class ii major histocompatibility complex antigens to see whether it is possible to identify patients with an enhanced risk for development of autoantibodies and severe course of the disease. there is an ongoing debate with regard to a possible dysregulation of the immune system by sars-cov- , and it has been discussed whether anti-inflammatory drugs might be beneficial to prevent potentially harmful hyperinflammation ( ) . our hypothesis of sars-cov- -induced immune dysregulation closely correlates with results from the wuhan cohort reported by wu et al., in which methylprednisolone treatment was associated with a more favorable outcome among the patients who had already developed ards ( ) . a recent report from japan described high anti-ssa/ro antibody titers in two patients with severe covid- pneumonia, one of which responded well to corticosteroid therapy ( ) . moreover, first results from the uk recovery trial (eudract - - , press release from oxford university on june , ) indicate a significant benefit for dexamethasone, a drug that is also in use for the treatment of ssc, in mechanically ventilated patients. it would furthermore be interesting to evaluate if patients with sle-like ana pattern (anti-ds-dna) profit from hydroxychloroquine, while patients with an ssc-like ana pattern (anti-scl- , anti-cenp) might respond to figure a for imaging) days after admission shows septal thickening without fibrinous exudate. tissue samples from the autopsy ("a") of the same patient with reactive pneumocyte changes ("napoleon hat sign", arrowhead), ball-like fibrin (yellow circle) and alveoli with plug-like fibromyxoid organization (right). electron microscopy shows widening of alveolar septa with activated fibroblasts (asterisk) and deposition of collagen (silvery filaments in inter-alveolar septum). (b) transbronchial biopsies in a -year-old man (patient # , ana : , positive for scl- ; see figure d for imaging) show alveolar fibromyxoid plugs with entrapment of fibrin ("bx", left; arrowhead). other areas from the same sample show parenchymal collapse with granulation tissue around residual fibrin (yellow circle). ck immunohistochemistry highlights pneumocyte lining of collapsed alveoli. right: tissue samples from autopsy ("a") show interstitial fibroblast activation (arrowhead) and pseudohoneycombing. scale bar, µm. cyclophosphamide. in line with that, one case report described a mild clinical course of covid- in patient with established anti-scl- -positive ssc under treatment with the antiinterleukin (il) receptor blocker tocilizumab ( ) . the correct timing and dosing for any immunosuppressive or antifibrotic treatment approach in response to a viral infection however remains unclear. possible limitations of this study include its limited sample size and the lack of randomization. a further limitation of this study is the possibility of selection bias, which could not be ruled out on account of the study design. our observation of ctd-associated autoantibodies together with the ctd-like radiologic and histopathologic lung findings in severe cases of covid- point towards a possible dysregulation of the immune response upon sars-cov- infection that might fuel organizing pneumonia and trigger interstitial fibrosis, with deleterious effects on the functional outcome in long-term survivors. early detection of the reported autoantibodies might identify patients who profit from immunosuppressive and/or anti-fibrotic therapy to prevent the development of respiratory failure and fibrosis in covid- . all datasets presented in this study are included in the article/ supplementary material. the studies involving human participants were reviewed and approved by the ethics committee of the university of ulm (ref. no. - ). the patients/participants or their relatives provided their written informed consent to participate in this study. written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. functional exhaustion of antiviral lymphocytes in covid- patients case-fatality rate and characteristics of patients dying in relation to covid- in italy pathological findings of covid- associated with acute respiratory distress syndrome pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer organizing diffuse alveolar damage associated with progressive systemic sclerosis acute fibrinous and organizing pneumonia in systemic lupus erythematosus: a case report and review of the literature fatal acute fibrinous and organizing pneumonia in a child with juvenile dermatomyositis pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- international recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies clinical and autoimmune characteristics of severe and critical cases of covid- high prevalence of antinuclear antibodies and lupus anticoagulant in patients hospitalized for sars-cov pneumonia the berlin definition of ards: an expanded rationale, justification, and supplementary material an expanded definition of the adult respiratory distress syndrome automated indirect immunofluorescence evaluation of antinuclear autoantibodies on hep- cells autoimmune features in covid- -induced respiratory failure frontiers in immunology | www europlus ™ anca biochip mosaic: pr and mpo antigen microdots improve the laboratory diagnostics of anca-associated vasculitis from ana to ena: how to proceed? sars-cov- /covid- : empfehlungen für die radiologische versorgung-eine stellungnahme der deutschen röntgengesellschaft (drg), der deutschen gesellschaft für neuroradiologie (dgnr), der gesellschaft für pädiatrische radiologie (gpr), der deutschen gesellschaft für interventionelle radiologie (degir), des berufsverbands der neuroradiologen (bdnr) und des berufsverbands der radiologen (bdr). röfo-fortschritte auf dem gebiet der röntgenstrahlen und der bildgebenden verfahren radiological society of north america expert consensus statement on reporting chest ct findings related to covid- . endorsed by the society of thoracic radiology, the american college of radiology, and rsna -secondary publication risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with covid- time course of lung changes on chest ct during recovery from novel coronavirus (covid- ) pneumonia pulmonary post-mortem findings in a large series of covid- cases from northern italy interstitial pneumonia with autoimmune features: clinical, radiologic, and histological characteristics and outcome in a series of patients role of autoantibodies in the diagnosis of connective-tissue disease ild (ctd-ild) and interstitial pneumonia with autoimmune features (ipaf) good outcome of interstitial lung disease in patients with scleroderma associated to anti-pm/scl antibody interstitial lung disease associated with anti-pm/scl or anti-aminoacyl-trna synthetase autoantibodies: a similar condition anti-pm-scl antibody in patients with systemic sclerosis symmetric cutaneous vasculitis in covid- pneumonia post-mortem examination of covid patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggesting vascular dysfunction complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases detection of igm and igg antibodies against sars-cov- in patients with autoimmune diseases evaluation of a line immunoblot assay for detection of antibodies recognizing extractable nuclear antigens critically ill sars-cov- patients display lupus-like hallmarks of extrafollicular b cell activation. medrxiv ( ) : epstein-barr virus infection, vitamin d deficiency, and steps to autoimmunity: a unifying hypothesis autoantibodies to killer cell immunoglobulin-like receptors in patients with systemic lupus erythematosus induce natural killer cell hyporesponsiveness range of antinuclear antibodies in "healthy" individuals characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention covid- and african americans risk factors for ana positivity in healthy persons covid- : risk for cytokine targeting in chronic inflammatory diseases? high levels of anti-ssa/ro antibodies in covid- patients with severe respiratory failure: a casebased review covid- in a patient with systemic sclerosis treated with tocilizumab for ssc-ild the authors would like to thank all patients and their families for their consent to the use of data and images in the present study. we further thank judith bauer, md and stephan opderbeck, md for providing clinical data. the authors are grateful for the outstanding quality of care of covid- patients provided by the team of the intensive care unit (icu) at the bundeswehrkrankenhaus ulm. the study was supported by the german registry of covid- autopsies (deregcovid). the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fimmu. . /full#supplementary-material key: cord- -x h dhn authors: ge, huiqing; pan, qing; zhou, yong; xu, peifeng; zhang, lingwei; zhang, junli; yi, jun; yang, changming; zhou, yuhan; liu, limin; zhang, zhongheng title: lung mechanics of mechanically ventilated patients with covid- : analytics with high-granularity ventilator waveform data date: - - journal: front med (lausanne) doi: . /fmed. . sha: doc_id: cord_uid: x h dhn background: lung mechanics during invasive mechanical ventilation (imv) for both prognostic and therapeutic implications; however, the full trajectory lung mechanics has never been described for novel coronavirus disease (covid- ) patients requiring imv. the study aimed to describe the full trajectory of lung mechanics of mechanically ventilated covid- patients. the clinical and ventilator setting that can influence patient-ventilator asynchrony (pva) and compliance were explored. post-extubation spirometry test was performed to assess the pulmonary function after covid- induced ards. methods: this was a retrospective study conducted in a tertiary care hospital. all patients with imv due to covid- induced ards were included. high-granularity ventilator waveforms were analyzed with deep learning algorithm to obtain pvas. asynchrony index (ai) was calculated as the number of asynchronous events divided by the number of ventilator cycles and wasted efforts. mortality was recorded as the vital status on hospital discharge. results: a total of , , respiratory cycles in , h were analyzed (average: cycles/min) for seven patients. higher plateau pressure (coefficient: − . ; % ci: − . to − . ) and neuromuscular blockades (coefficient: − . ; % ci: − . to − . ) were associated with lower ai. survivors showed increasing compliance over time, whereas non-survivors showed persistently low compliance. recruitment maneuver was not able to improve lung compliance. patients were on supine position in , h ( %), followed by prone positioning ( h, %), left positioning ( h, %), and right positioning ( h, %). as compared with supine positioning, prone positioning was associated with . ml/cmh( )o ( % ci: . to . ; p < . ) increase in lung compliance. spirometry tests showed that pulmonary functions were reduced to one third of the predicted values after extubation. conclusions: the study for the first time described full trajectory of lung mechanics of patients with covid- . the result showed that prone positioning was associated with improved compliance; higher plateau pressure and use of neuromuscular blockades were associated with lower risk of ai. the novel coronavirus disease (covid- ) imposes an important and urgent threat to global health ( , ) . a substantial proportion of covid- cases will develop severe acute respiratory distress syndrome (ards) that requires invasive mechanical ventilation (imv). the mortality rate of such patients can be as high as % ( ), depending on comorbidities and the available medical resources. mechanical ventilation is an important strategy to treat such patients; and lung mechanics can have both prognostic and therapeutic implications. lung compliance is an important mechanical parameter that should be monitored during imv. for example, lung recruitment maneuver (rm) has been used to improve lung compliance in severe ards ( ) . there is also evidence in general ards population that poor lung compliance without improvement during imv is associated with poor clinical outcome ( ) . patient ventilator asynchrony (pva) is another important parameter that should be stressed during imv. risk factors of pva has been widely investigated, including hours of the day, use of sedatives, ventilation mode and tidal volume ( , ) . while several studies showed that pva was associated with clinical outcome, others did not ( , ) . there is preliminary opinion suggesting that lung mechanics of covid- induced ards can be quite different from general ards ( ) . however, there is no empirical data on the lung mechanics in covid- patients on imv. furthermore, previous studies are limited in several aspects. first, there is no continuous pulmonary mechanics evaluation, including the response of lung recruitment during imv, all events during prone ventilation. second, most techniques for the detection of pva and other parameters requires physical presence of an expert physician at the bedside and is thus only feasible during short periods ( ) ( ) ( ) . in addition, most studies explored risk factors for pva in a fixed-time model ( ) . in reality, both risk factors and pva and compliance were time-varying ( ) . in order to make this gap end, the purpose of the study were -folds: ( ) to describe the lung mechanics of covid- patients by analyzing high-granularity ventilator waveform data; ( ) to explore whether the lung compliance can be influenced by clinical factors, such as recruitment maneuver (rm) and body positioning; ( ) to identify risk factors for pva during imv in covid- patients; and ( ) to describe post-extubation lung functions for survivors with spirometry test. abbreviations: ai, asynchrony index; wob, work of breathing; peep, positive end expiratory pressure; dt, delayed triggering; iee, ineffective effort during expiration; iqr, interquartile range; covid- , coronavirus disease ; pva, patient-ventilator asynchrony; ards, acute respiratory distress syndrome; imv, invasive mechanical ventilation. the study was conducted in the first people's hospital of jingmen. clinical data and ventilator wave data were retrospectively collected. all ventilator parameters were collected as longitudinally in hourly basis using a ventilator information system (respcare tm , zhiruisi tech. co., ltd., hangzhou, china). the impact of rm and positioning on lung compliance was explored in mixed linear model. the study was approved by the ethics committee of the first people's hospital of jingmen (approval number: ) and the ethics committee of sir run run shaw hospital ( - ). individual patient data were de-identified before analysis. informed consent was waived as determined by the irb due to retrospective nature of the study design. all covid- patients treated with imv were included for analysis. covid- was confirmed by one of the following criteria: ( ) novel coronavirus nucleic acid was positive as confirmed by real time (rt)-pct in respiratory or blood specimen; and ( ) genetic sequencing showed highly homogenous sequence with the known novel coronavirus ( ) . for adults with covid- and acute hypoxemic respiratory failure despite conventional oxygen therapy (< %), we would start using high-flow nasal cannula (hfnc) or non-invasive ventilation (niv). if the condition further deteriorated and the oxygenation saturation could not be maintained above % with hfnc or niv, imv would be started ( ) . patients were excluded if ( ) they were younger than years old; ( ) patients with do-not-resuscitate order and ( ) with terminally ill disease; ( ) patients with incomplete record of waveform data. demographic data including age and sex were collected as time-fixed data. hospital mortality was obtained on discharge. pulmonary functions including forced vital capacity (fvc), forced expiratory volume (fev ), fev /fvc ratio, peak expiratory flow (pef), peak inspiratory flow (pif), maximal inspiratory pressure (mip), maximal expiratory pressure (mep) were measured for hospital survivors. ventilator parameters including lung compliance, measured peep, plateau pressure, tidal volume, work of breathing (wob), and peak flow rate were measured based on pressure and flow waveforms. details of the measurement approaches are described in the esm. interventions including rm, positioning, sedatives and neuromuscular blockades were recorded in our analysis. date and time of these interventions used to match to a period when ventilator parameters and lung mechanics were recorded. the body position was recorded as one of supine, right, left and prone positions at a specific time. non-supine position was applied during daytime, and the specific positioning (prone, right or left) was determine at the discretion of the attending physician and respiratory therapist depending on the improvement in oxygenation. prone positioning was applied for at least h one day. rm could be accurately identified from ventilator waves as those with more than cmh o sustained inflation maintained for at least s, the upper limit pressure was cmh o ( ). we developed an interpretable deep learning approach to detect double triggering (dt) and ineffective inspiratory effort during expiration (iee). individual deep learning models were developed under all ventilation modes. under each ventilation mode, two models were established for detecting dt and iee. each model uses the raw ventilator waveforms (airway pressure and flow) as input for a binary classification (pva or non-pva). it is also capable of explaining the classification by highlighting the segments that contributes mostly to the results. datasets were annotated by a group of clinical professionals for training and validating the models based on our previously proposed approach ( ) . the accuracy reached above % for both types of pva in all the ventilation modes. asynchrony index (ai) was calculated as the number of asynchronous events divided by the number of ventilator cycles and wasted efforts ( ) . details of the algorithm development is described in the electronic supplemental material. ventilator parameters were described for each individual patient by median and interquartile range (iqr) ( ) . temporal trends of ventilator parameters were visualized with scatter plots and described with locally weighted scatterplot smoothing (lowess) curves ( ) . these curves were drawn for each individual patient and survivors and non-survivors were denoted with different colors. risk factors for iee and dt were explored with mixed negative binomial regression models, which was a generalization of the poisson regression allowing for the conditional variance exceeds the conditional mean ( ) . random-effects was allowed for intercepts to account for between-subject variance. predictors of iee and dt included compliance, plateau pressure, peep, tv, respiratory rate, peak flow rate, wob, sedatives, and neuromuscular blockades. we reported relative risk (rr) for the risk estimate associated with a unit change of these predictors. risk factors for ai was explored with mixed linear effect model because the response variable ai was in linear scale. we reported coefficient and % confidence interval (ci) to represent how ai increased with a unit change in predictors. factors that can influence lung compliance was explored with a mixed-effects linear model. factors including age, sex, rm, peep, ai, and body position were included in the model. all statistical analyses were performed with rstudio (version . . ) . a two-tailed p < . were considered as statistical significance. a total of patients with full record of ventilator waveforms were included for analysis. there was no excluded patient due to predefined exclusion criteria. four patients died and three survived to hospital discharge ( ; p < . ] than non-survivors. survivors were more likely to adopt prone position than non-survivors ( vs. %; p < . ). all rm was performed in non-survivors. more neuromuscular blockades were used in non-survivors ( table ) . patients were on supine position in , h ( %), followed by prone positioning ( h, %), left positioning ( h, %), and right positioning ( h, %). survivors showed increasing compliance over time, whereas non-survivors showed persistently low compliance ( figure a) . plateau pressure, peep and tidal volume are shown in figures b-d. wob and respiratory rate did not show difference between survivors and non-survivors in temporal pattern (figures e,f) . temporal trends of pva were not different between survivors and nonsurvivors (figure ). risk factors for pva (iee and dt) were investigated in the mixed negative binomial regression models. higher plateau pressure (rr: . ; % ci: . - . ; p < . ) and respiratory rate (rr: . ; % ci: . - . ; p < . ) was associated with less iee. however, greater tidal volume and wob were associated with more iee. in contrast to iee, higher respiratory rate was associated with increased risk of dt (rr: . ; % ci: . - . ; p < . ). higher plateau pressure (coefficient: − . ; % ci: − . to − . ) and neuromuscular blockades (coefficient: − . ; % ci: − . to − . ) were associated with lower ai. sedatives had no significant impact on pvas ( table ) . in multivariable mixed-effects linear model, we found two variables were significantly associated with lung compliance. each cmh o increase in peep was associated . ml/cmh o decrease in lung compliance ( % ci: − . to − . ; p < . ). as compared with supine positioning, prone positioning was associated with . spirometry tests were performed in survivors at day , , and after extubation. it showed that fvc was consistently decreased for the three measurements. fev /fvc was decreased in patient ( . at day and . at day ); but was preserved in the study integrated high-granularity ventilator waveform data with clinical variables to describe the temporal change of lung mechanics of critically ill patients with covid- . at the time of intubation, the lung compliance was similar in survivors and non-survivors; but the survivors showed gradually improved compliance. prone positioning is effective in improve lung compliance. two types of pva, iee, and dt, were identified with deep learning algorithm. higher plateau pressure and use of muscular relaxant were associated with lower risk of pvas. spirometry tests showed that pulmonary functions were significantly compromised after recovery from covid- induced ards. long-term follow up for the change of pulmonary functions would be relevant. although the lung compliance was similar at the time of intubation, survivors showed gradual improvement in lung compliance, while non-survivors showed persistently low lung compliance. this is consistent with other studies that lung compliance was an independent predictor of mortality ( , , ) . an important finding in our study was that rm was not effective in improving lung compliance, which is in contrast to findings from general ards patients. although the effect of rm on mortality was conflicting in general ards, it has been consistently reported to be able to improve lung compliance ( ) ( ) ( ) . for example, kung and colleagues observed that the respiratory system compliance was significantly higher in the rm group from day to ( ) . there is evidence that direct/pulmonary ards is more responsive to rm than indirect/extrapulmonary ards. while only % patients with lower percentage of recruitable lung were caused by pulmonary ards, % patients with higher percentage of recruitable lung caused by pulmonary ards (p = . ) ( ) . thus, covid- induced ards is pulmonary ards but is less responsive to rm as shown in our study. the second reasons may be due to the fact that we only employed sustained inflation rm. since there are many types of rm, it is largely unknown whether other types of rm can be effective in improve lung compliance in covid- patients. finally, the ards in covid- may be due to viral, bacterial, or any kind of lung insults. thus, the rm should not be able to demonstrate the benefits in this group of patients. pvas are commonly observed in patients with imv, especially those with protective ventilation strategy. our study observed that ai was . % (iqr: . - . ) in overall observed hours. non-survivors had more ai than survivors, indicating ai is a risk factor for mortality, which was consistent with other studies ( ) . ventilator parameters can have differing effects on different pva types. for example, while higher respiratory rate was associated with lower risk of iee, it was associated with higher risk of dt. use of neuromuscular blockades was associated with lower risk of both iee and dt. however, we did not observe significant effect of sedatives on ai. other studies have shown that propofol or other sedatives can reduce ai ( , ) . it is not surprising to observe that neuromuscular blockades are associated with significantly reduced risk of pvas. post-extubation pulmonary function has never been reported for covid- patients. our results indicated that pulmonary functions can be significantly compromised in a short period. the fvc is reduced to one third of the predicted value. other pulmonary function parameters, such as pef and mip were also reduced by one third of the predicted value. boucher and coworkers observed that the pulmonary function can be significantly compromised in pediatric ards in short follow-up period ( ) . in adult patients with general ards, the fvc can recover to . ± . and . ± . l at and months follow up ( ), which is significantly higher than that in our study. however, since we did not obtain the long term follow up data, it is largely unknown whether covid- can have long-term effect on pulmonary functions. several limitations should be acknowledged in the study. first, the sample size was limited, which prohibited patient-level analysis. the effect of prone-positioning on mortality outcome could not be analyzed with sufficient statistical power. thus, further large-scale studies are needed to validate our findings. however, our data is rich with high-granularity waveform data, which allows for patient-hour analysis for epidemiological analysis. second, we only developed deep learning algorithms for identifying two types of pva. there are other types of pvas, such as reverse triggering and short/long cycling. however, these analyses are not applicable in pressure-controlled ventilation and pleural pressure is required for reverse triggering ( ) . third, the impact of sedative on pvas were estimated without the dosing of sedatives. we only recorded the use of sedatives as a binary variable. such treatment would lose some information but is easy to interpret because different sedatives imposes challenge to standardize the dose. finally, the pulmonary function was measured in a short period of time; long-term follow up data may provide important information for critically ill covid- patients. in conclusion, the study for the first time described full trajectory of lung mechanics of patients with covid- . the result showed that prone positioning was associated with improved compliance; higher plateau pressure and use of neuromuscular blockades were associated with lower risk of ai. rm was not associated with improvement on compliance. the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. the study was approved by the ethics committee of the first people's hospital of jingmen (approval number: ) and the ethics committee of sir run run shaw hospital ( - ). informed consent was waived as determined by the irb due to retrospective nature of the study design. clinical characteristics of coronavirus disease in china epidemiologic characteristics of early cases with novel coronavirus ( -ncov) disease in republic of korea clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis estimated dead space fraction and the ventilatory ratio are associated with mortality in early ards identifying and managing patient-ventilator asynchrony: an international survey patient-ventilator asynchrony during daily interruption of sedation versus no sedation protocol asynchronies during mechanical ventilation are associated with mortality clusters of ineffective efforts during mechanical ventilation: impact on outcome covid- does not lead to a "typical" acute respiratory distress syndrome defining patient-ventilator asynchrony severity according to recurrence patient-ventilator asynchronies during mechanical ventilation: current knowledge and research priorities effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study predictors of asynchronies during assisted ventilation and its impact on clinical outcomes: the episync cohort study time-varying covariates and coefficients in cox regression models a rapid advice guideline for the diagnosis and treatment of novel coronavirus ( -ncov) infected pneumonia (standard version) surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) optimal duration of a sustained inflation recruitment maneuver in ards patients detection of patientventilator asynchrony from mechanical ventilation waveforms using a twolayer long short-term memory neural network univariate description and bivariate statistical inference: the first step delving into data lowess: a program for smoothing scatterplots by robust locally weighted regression a flexible mixed-effect negative binomial regression model for detecting unusual increases in mri lesion counts in individual multiple sclerosis patients impact of lung compliance on neurological outcome in patients with acute respiratory distress syndrome following out-of-hospital cardiac arrest driving pressure is associated with outcome during assisted ventilation in acute respiratory distress syndrome effects of stepwise lung recruitment maneuvers in patients with early acute respiratory distress syndrome: a prospective, randomized, controlled trial lung recruitment maneuvers for adult patients with acute respiratory distress syndrome. a systematic review and meta-analysis variation of poorly ventilated lung units (silent spaces) measured by electrical impedance tomography to dynamically assess recruitment lung recruitment in patients with the acute respiratory distress syndrome patient-ventilator asynchrony in adult critically ill patients dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials post-discharge respiratory outcomes of children with acute respiratory distress syndrome driving pressure and long-term outcomes in moderate/severe acute respiratory distress syndrome mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling hg, qp, and zz analyzed and interpreted the results and drafted the manuscript. jz, cy, and lz handled the finnaki data. all authors took part in designing the study, revised the manuscript critically for important intellectual content, read, and approved the final manuscript. the authors would like thank biyun lai and jie pan from college of information engineering, zhejiang university of technology for preparing the data, zhiruisi tech. co., ltd. for donating the respcaretm system and mr. bing li from zhiruisi for deploying the system on the scene to help the current research work. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fmed. . /full#supplementary-material key: cord- -god qzw authors: mao, kaimin; geng, wei; liao, yuhan; luo, ping; zhong, hua; ma, pei; xu, juanjuan; zhang, shuai; tan, qi; jin, yang title: identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of rna sequencing data and geo datasets date: - - journal: aging (albany ny) doi: . /aging. sha: doc_id: cord_uid: god qzw acute lung injury (ali) and acute respiratory distress syndrome (ards) are life-threatening clinical conditions predominantly arising from uncontrolled inflammatory reactions. it has been found that the administration of astaxanthin (ast) can exert protective effects against lipopolysaccharide (lps)-induced ali; however, the robust genetic signatures underlying lps induction and ast treatment remain obscure. here we performed a statistical meta-analysis of five publicly available gene expression datasets from lps-induced ali mouse models, conducted rna-sequencing (rna-seq) to screen differentially expressed genes (degs) in response to lps administration and ast treatment, and integrative analysis to determine robust genetic signatures associated with lps-induced ali onset and ast administration. both the meta-analyses and our experimental data identified a total of degs in response to lps administration, and core degs (timp , ly i, cxcl , irf , cxcl , ccl , isg , saa , saa , tgtp , and gbp ) were identified to be associated with ast therapeutic effects. further, the core degs were verified by quantitative real-time pcr (qrt-pcr) and immunohistochemistry (ihc), and functional enrichment analysis revealed that these genes are primarily associated with neutrophils and chemokines. collectively, these findings unearthed the robust genetic signatures underlying lps administration and the molecular targets of ast for ameliorating ali/ards which provide directions for further research. acute respiratory distress syndrome (ards) is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue [ ] . its less severe form is acute lung injury (ali). most patients need mechanical ventilation for support. the initial acute or exudative phase of ali/ards is characterized by the rapid onset of dyspnea, hypoxemia, respiratory failure, and bilateral infiltrates on chest radiographs that are consistent with pulmonary edema [ ] . ali/ards is common and has been associated with several clinical disorders, such as sepsis; pneumonia; aspiration of gastric contents, aging saltwater, or freshwater; major trauma; transfusion of blood products; acute pancreatitis; and drug reactions (for example, reactions to lipopolysaccharide) [ ] . in the past years, considerable progress has been made in understanding the epidemiology, pathogenesis, and pathophysiology of ards. however, ards is being increasingly recognized as a heterogeneous syndrome, generating momentum for the identification of clinical and biological features for classifying patients into subphenotypes that might be more responsive to specific therapies. lipid a (endotoxin), the hydrophobic anchor of lipopolysaccharide (lps), is a glucosamine-based phospholipid that makes up the outer monolayer of the outer membranes of most gram-negative bacteria [ ] . in recent years, lps, which has been most widely used in drug-associated ali models, can effectively induce a neutrophilic inflammatory response accompanied by an increase in intrapulmonary cytokines. many studies have shown that oxidative stress plays a major role in the pathogenesis of lung injury in a murine model of ali induced by lipopolysaccharide (lps) [ ] [ ] [ ] . in response to the increased formation of reactive oxygen species (ros), thioredoxin interacting protein (txnip) detaches from thioredoxin (trx), binds to the nucleotide-binding domain-like receptor protein (nlrp ), and then activates nlrp inflammasome [ ] . the activation of the nlrp inflammasome results in the maturation and release of pro-inflammatory cytokines, such as interleukin- β (il- β), which further aggravates the production of inflammatory cytokines (tumor necrosis factor-α (tnf-α), il- , inducible nitric oxide synthase (inos), and cyclooxygenase- (cox )) and induces oxidative stress [ ] [ ] [ ] . astaxanthin (ast) is a lipid-soluble, red-orange-colored xanthophyll carotenoid synthesized by many microorganisms and various types of marine life. the main producers of natural ast are microalgae and fungi. aquatic animals such as salmon, red seabream, shrimp, lobster and crayfish, which feed on ast-producing organisms, are significant dietary sources of ast for humans [ ] [ ] [ ] . it has been revealed that ast can prevent inflammatory processes by blocking the expression of pro-inflammatory genes as a consequence of suppressing nuclear factor kappab (nf-κb) activation [ ] . some studies also suggested that ast has a dosedependent ocular anti-inflammatory effect, through the suppression of no, pge , and tnf-alpha production, which is achieved by directly blocking nos enzyme activity [ ] . furthermore, ast has great therapeutic value for lung disease, such as an antifibrotic effect against the promotion of myofibroblast apoptosis based on dynamin-related protein- (drp )-mediated mitochondrial fission in vivo and in vitro [ ] and anti-inflammatory effect against lps-induced ali, as mentioned above [ , ] . however, at the transcriptional level, the mechanism of action of ast in the treatment of ali-/ ards-remains unclear. therefore, we hope to explore the molecular targets of ast against ali-/ ards-through further research, with the purpose of providing a new alternative for the clinical treatment of this acute lung disease. to determine the common molecular signatures underlying lps-induced mouse ali initiation, five microarray datasets were obtained from corresponding independent studies. the characteristics of the studies composing the five gene expression compendiums are listed in table and supplementary table . we extracted and annotated the five microarrays, which yielded a collection of unique genes from samples, including control and lps-induced ali mice. before the meta-analysis study, we comprehensively analyzed the five datasets by identifying the differentially expressed genes in each data set and evaluated overlapping significant genes. the overlapping results were used to generate a venn diagram (figure ), and three genes (ccl , zbp , and cxcl ) were identified in the common region, suggesting that these three genes were significantly correlated with lps management in mice in the five datasets. then, we performed a meta-analysis using networkanalyst (http://www.networkanalyst.ca), which is a comprehensive web-based tool designed to perform meta-analyses of gene expression data [ ] . an overview outlining the procedure of the analysis is presented in figure a . using three meta-analysis approaches, namely fisher's method, fixed effect model and voting count, , and differentially expressed genes, respectively, were identified. among these genes, were identified by all three methods ( figure b ), with ( . %) genes being upregulated and ( . %) being downregulated in the lps group compared with the control group. a full list of the common genes identified by the three meta-analysis methods is presented in supplementary table . a heat map of the top common degs across the five datasets is displayed in figure c . of note, the top upregulated genes (p< . ) were junb, vcam , ehd , ifrd, adm, cd , nadk, litaf, tubb , and ctps. the most significantly downregulated genes (p< . ) among the top common degs were acss and abcd . the merged data from this meta-analysis are listed in supplementary data . to further identify the robust expression signatures in lps-induced ali and investigate the transcriptional changes resulting from treatment of ali with ast, we divided mice into three groups, including the control group, lps group, and ast group. rna-sequencing (rna-seq) was performed to profile differentially expressed genes (degs) associated with lps-induced ali initiation and ast treatment. a total of degs were identified in the lps-induced ali group compared with the control group. among these genes, were table . then, we compared these genes with the degs obtained from the above meta-analysis, and generated two heat-maps of the common degs across the meta-analysis results and our experimental aging data, which are displayed in figure c and supplementary figure . in total, degs were detected in both published data and our experimental data, including upregulated and downregulated degs. to explore the therapeutic effect of ast against ali at the genetic level, we also compared the gene expression profile of the lps-induced ali group with that of the ast treatment group. in total, degs were identified after ast treatment ( figure b table ). we subsequently integrated the rna-seq and microarray meta-analysis data, and core degs (timp , ly i, cxcl , irf , cxcl , ccl , isg , saa , saa , tgtp , and gbp ) that were upregulated in ali models and downregulated significantly after ast treatment were identified ( table ) . to understand the function of the core degs, go enrichment analysis including molecular function (mf), biological process (bp) and cellular component (cc) categories (supplementary table ) was performed using the 'clusterprofile' package in r [ ] . in bp terms, the upregulated genes were associated with "cell chemotaxis," the "chemokine−mediated signaling pathway," and "neutrophil migration" ( figure a ). several studies have shown that neutrophil migration and related chemokine network regulation in the lung play roles in the pathogenesis and development of ali/ards [ ] [ ] [ ] . in the mf category, the core degs were associated with "glycosaminoglycan binding," "chemokine activity," and "receptor-ligand activity" ( figure b ). since glycosaminoglycan-cytokine interactions have been reported to support cellular mechanisms that cause acute inflammation [ ] , ast may affect these interactions by downregulating the genes involved to exert an anti-inflammatory effect. moreover, degs were enriched in the cc category involved in "high−density lipoprotein particles," "symbiont−containing vacuole membranes," and "plasma lipoprotein particles" ( figure c ). to further confirm the differences in the expression of the core degs (timp , ly i, cxcl , irf , cxcl , ccl , isg , saa , saa , tgtp , and gbp ) among the control group, lps group, and ast group, we divided mice into three groups and conducted qrt-pcr and ihc verification ( figure a - k, supplementary figure ). the results demonstrate that the relative expression levels of all genes were significantly upregulated in the lps group compared to the control group. more importantly, the expression levels of the above degs, as analyzed by qrt-pcr, were significantly inhibited after the application of ast. of the core genes, were tested by ihc, and the results were consistent with the qrt-pcr results, which further verifying the data (supplementary figure ) . overall, the rt-qpcr and ihc results were consistent with our integrative rna-seq analysis and metaanalysis, suggesting the critical role that the core dges might play in the mechanism by which ast alleviates ali/ards. as a life-threatening condition, ali/ards is an underrecognized condition, and its treatment is an unmet medical need. it is thought that inflammatory storm is the key factor in the occurrence of ali [ ] , and anti-inflammatory and antioxidant therapy should be the primary objective in ali/ards [ ] . to find the conserved genes responsible for lps-induced ali initiation and the effects of ast treatment, we identified robust changes in gene expression related to ali by meta-analysis and rna-seq using the gene expression omnibus (geo) database and mice, respectively. moreover, we performed functional enrichment analysis of core genes using the gene ontology (go) database to explore the possible molecular mechanisms that mediate the therapeutic effect of ast. before the meta-analysis of the five microarray datasets, we compared the differentially expressed genes in each dataset, and common differentially expressed genes (degs) were found in all five datasets: cxcl , zbp , and ccl . cxcl is abnormally expressed in the lung tissues of patients with idiopathic pulmonary fibrosis (ipf), and its circulating concentration is also highly correlated with the clinical manifestations and disease progression of individual patients. in the lung tissues of patients with ipf, cxcl may promote focal infiltration of nonproliferating b cells through the cxcl -cxcr axis [ ] . zbp is a host protein that was shown to be an innate sensor of viral infection, regulating cell death, inflammasome activation, and proinflammatory responses in a variety of situations, including infection and embryonic development [ ] . a previous study indicated that zbp is abnormally expressed in h n induced pneumonia associated with acute respiratory distress syndrome in mice [ ] . ccl (mcp ), which is elevated in pulmonary fibrosis, has been reported to mediate fibroblast survival through il- [ ] . since fibroproliferation is initiated early in lung injury, it has been observed that ccl is highly expressed in ards statistical analysis of significant differences between groups was achieved with one-way anova using prism software. ****p < . , ***p < . , **p < . , and *p < . were considered statistically significant. aging induced by severe sepsis [ ] . to reduce the study bias and increase the statistical power of individual microarray data, we performed a meta-analysis of five microarray gene expression profiles to assess the differentially expressed genes between lps-induced and control groups. consequently, differentially expressed genes (degs) were identified using three meta-analysis approaches. to further identify the robust expression signature related to lps-induced ali and investigate the transcriptional changes in response to the treatment of ali by ast, we performed rna-seq on three groups of mice and integrated the data with the results of the above mentioned meta-analysis. ultimately, we identified core degs that were significantly associated with ast treatment. saa , ly i, saa , irf , cxcl , ccl , timp , isg , gbp , tgtp , and cxcl were found to be overexpressed in the lps group compared with the control group but relatively downregulated in the ast group. our qrt-pcr and ihc verification of the core genes in the mice suggested that these genes might be the key mediators of the therapeutic effect of ast in ali/ards. among the core genes that were differentially expressed in response to ast mediation, two genes are members of the serum amyloid a (saa) family. saa is a critical acute-phase protein that is often increased by infection, trauma, cancer, or other causes of inflammation and plays an important role in the regulation of inflammatory responses [ ] . recent studies have indicated that an increased level of saa is positively correlated with the disease progression of covid , and can thus be a sensitive indicator for assessing the severity and prognosis of covid- [ ] . in our study, saa was the most significantly inhibited gene by ast application in lps-induced ali mice, and its downregulation was further confirmed by qrt-pcr and ihc. saa , the one of three isoforms of saa expressed in mice, is stimulated intensely in lps-induced acute systemic inflammation, which is consistent with our findings [ ] . high expression of saa in response to acute inflammation may be repressed by an interaction with noncoding rnas. it has been confirmed that mir- b- p may target saa to protect against lps-induced ali [ ] . additionally, lncrna malat can also target saa directly or indirectly to cause many diseases such as inflammation, diabetes and septic cardiomyocytes [ , ] . saa , another member of the saa gene family, is believed to have a pro-inflammatory effect, and its expression may aggravate tissue inflammation and damage [ ] . removing the n-and c-terminal sequences of saa can switch the protein to an anti-inflammatory role [ ] . however, other research has suggested that mice induced to express genetically modified human saa have a partial protective effect against the inflammatory response and lung injury caused by lps [ ] . moreover, saa is the direct target of mir- , which can protect nucleus pulposus cells from tnfainduced apoptosis in intervertebral disc degeneration [ ] . considering that saa might act as a biomarker of inflammatory disease, it is possible, that its downregulation induced by ast may partly indicate the antiinflammatory effect of ast. the deeper molecular mechanism underlying saa action in response to ast application deserves further exploration. interferon regulatory factor (irf ) is considered the master regulator of ifn-α against pathogenic infections [ ] . the excessive activation of irf promotes the development of acute lung injury (ali) caused by influenza a virus (iav), and attenuating irf activity can significantly prevent the progression of iavinduced ali in model mice [ ] . thus, the present finding that irf was upregulated by lps and downregulated in response to ast treatment may suggest that of ast protects against ali. regarding how irf regulates ifn production, mirna may act as an important mediator. previous research has shown that mir- c can downregulate irf and irf expression to mediate influenza a virus-induced ifnβ expression [ ] . additionally, mir- was shown to reduces the antiviral response by attenuating the traf -irf pathway to alter the cellular antiviral transcriptional landscape [ ] . however, whether mirna-irf interactions are involved in the pharmacological mechanism of ast remains to be further investigated. tissue inhibitor of metalloproteinase- (timp ), a member of timp family, is primarily recognized to regulate the degradation of the extracellular matrix by inhibiting the activity of matrix metalloproteinases (mmps) [ ] . it has been reported that an imbalance between mmp and timp plays a pivotal role in the pathogenesis of ards mainly through participating in airway remodeling, thus indicating the function of the mmp /timp ratio in the evolution of pulmonary fibrosis in ards [ ] . indeed, increased systemic levels of timp were proven to be associated with increased -day mortality in ards patients according to a large, prospective, multicenter study [ ] . additionally, other research has demonstrated that increased timp expression promotes an immune response, has a pro-inflammatory effect in the lungs after influenza infection and facilitates an injurious phenotype [ ] . the above observations not only support our present results regarding timp but also provide a considerable explanation for the increase in timp expression after lps application. intriguingly, given that timps are highly expressed in liver fibrosis and that the imbalance of mmps/timps promotes the progression of fibrosis, shen et al. found that astaxanthin is able to repress the activation of hepatic stellate cells (hscs) to ameliorate liver fibrosis through downregulating the expression of nf-κb and tgf-β and preserving the balance between mmp and timp [ ] . hence, it is reasonable to further investigate whether there is a similar mechanism by which ast downregulates the expression of timp to mitigate lps-induced ali. interferon-stimulated gene (isg ), which encodes the ubiquitin-like protein isg , which is primarily induced by type i interferons, is an essential player in regulating host signaling pathways such as damage repair responses and immune responses. isg can be induced by various pathogenic stimuli such as viral and bacterial infections, lipopolysaccharide (lps), retinoic acid, or certain genotoxic stressors [ ] . in accordance with our findings, previous studies have observed increased levels of isg conjugates in macrophages in response to lps treatment [ ] . moreover, research has found that systemic isg (mx , isg , ifit , and ifit ) expression within the first days of ards onset is associated with disease severity and prognosis. this response should be considered along with other identified genetic, environmental, and complex demographic factors as the cause of heterogeneity in ards prognosis [ ] . nevertheless, no data has been reported on the association between isg and ast in the literature. since the excessive recruitment of leukocytes appears to be a central contributor to the pathogenesis of ali, the elevation of proinflammatory cytokines and chemokines is considered the most important factor [ ] . similarly, we found that the expression of chemokines such as ccl , cxcl , and cxcl were increased after lps instillation but decreased after ast treatment. previous reports have documented an increased level of ccl in a mouse model of acute lps-induced lung inflammation [ ] . moreover, the expression of cxcl is also rapidly induced in ali murine models after lps administration [ ] . however, no data has on cxcl expression in ali models has been reported. therefore, we report for the first time the induction of cxcl after lps administration, which provides insights into the role of cxcl in the pathogenesis of ali. furthermore, the observation of decreased expression of ccl , cxcl , and cxcl may hint at the antiinflammatory properties of ast. although the roles of other degs (ly i, gbp , and tgtp ) have been described in many other diseases in detail, their regulatory mechanisms in ali-/ ards-are not fully understood. our results show that these degs are overexpressed to varying degrees in the lps group and that ast can effectively prevent this overexpression. further studies on the roles of these three genes in ali initiation and progression are need. to determine the functional mechanisms of these degs, go enrichment analyses were further conducted. according to the results, terms in biological process category, in cellular component category and in the molecular function category were enriched. the most significantly enriched terms in the bp category were associated with chemokines and neutrophils, indicating the dominant role of neutrophils and related chemokines in the pathogenesis and progression of lps-induced ali. in ali, the excessive recruitment of inflammatory cells and their mediators results in injury to endothelial and epithelial barriers [ ] . thus, agents such as ast, which can exert robust anti-inflammatory effects, may provide potential treatment prospects. despite this, several limitations of the current study need to be addressed. first, our research did not use the ali mouse models induced by other agents; thus, it did not address heterogeneity of ali initiation. second, given that findings in animal models of lps-induced lung injury may depend on the time point at which samples are obtained and physiological data are captured, the dynamic changes in lps-induced ali models may have been ignored to a certain extent [ ] . finally, in-depth research into the underlying mechanisms using knockout-gene mice for each differentially expressed gene will help further our understanding of the role of ast in ameliorating ali/ards. in conclusion, many genes were dysregulated in ali/ards. we not only identified genes that consistently differed in expression in the lps group compared to the control group but also revealed that ast can alleviate the abnormal expression of these genes and thus confer a certain therapeutic effect against ali/ards, suggesting the potential for ast to become a novel treatment for ali/ards. to identify the genes related to lps-induced acute lung injury in mice, five datasets (gse , gse , gse , gse , and gse ) were obtained from geo (gene expression omnibus, http://www.ncbi.nlm.nih.gov/geo) [ ] [ ] [ ] [ ] [ ] . lps and control treatments were used in this study. the detailed information (experimental design, transcriptome analysis, array information, data processing, and platform id) for these datasets can be obtained from the geo repository, and this information is partly aging summarized in table and is described in more detail in supplementary table . then, we conducted a microarray meta-analysis using networkanalyst . (https://www.networkanalyst.ca) [ ] . networkanalyst is a visual analytics platform for comprehensive gene expression profiling and metaanalysis. all gene probes were converted to a common entrez id using the gene/probe conversion tool in networkanalyst. following quantile normalization, all datasets were preprocessed through a log transformation and variance stabilizing normalization (vsn). each dataset was visualized in box plots to ensure an identical distribution among the samples. differential expression analysis was performed independently for each dataset using networkanalyst, with an fdr of . and a significance of p < . . the moderated t-test was based on the limma algorithm. for the meta-analysis, we used fisher's method, the fixed-effect model, and vote counting (combined p < . or vote counts ≥ were considered significant) to identify the differentially expressed genes (degs) and we selected the common degs identified by these three methods as the final degs. male c bl/ j mice ( - g, ~ -weeks-old) were purchased from beijing vital river laboratory animal technology co., ltd. (beijing, china). the mice were housed per cage under a h light/dark cycle in a laboratory at ± °c and % humidity. all experiment protocols conformed to the guidelines of the china council on animal care and use. these animal studies were approved by the institutional animal research committee of union hospital. the mice were randomly allocated into three groups: ( ) the control group (n= ), which was exposed to pbs alone and received an intraperitoneal injection of sterile saline; ( ) the lps group (n= ), which was exposed to pbs containing . mg/ml lps; and ( ) the ast group (n= ), which was intraperitoneally injected with ast ( mg/ml, dissolved in pbs) at a dosage of mg/kg body weight every day before one week of exposure to lps to evaluate its preventive and protective effects [ , ] , and intraperitoneally injected with mg/kg ast ( mg/ml, dissolved in pbs) hours after lps exposure in order to confirm the therapeutic effect of ast [ ] . ast was obtained from sigma-aldrich (st louis, mo, usa). for acute lps exposure, mice were exposed to an aerosol of phosphate buffer saline (pbs) alone or pbs containing . mg/ml lps for h, in a custom-built cuboidal chamber. the lps solution was aerosolized with a constant output ultrasonic nebulizer (model: b, yuwell, china) at a flow rate of ml/h. lps was purchased from sigma-aldrich (extracted from escherichia coli o : b , l ). the chamber was cm long, cm wide and cm high. total rna was extracted from mouse lung tissue samples with trizol® reagent (invitrogen, ca) following the manufacturer's protocol. the concentration and purity of the rna were measured by a nanodrop spectrophotometer (nanodrop technologies, technologies, wilmington, de, usa), the rna integrity was detected by agarose gel electrophoresis, and the rin was determined using an agilent bioanalyzer (agilent technologies, santa clara, ca, usa). the construction of a single library required a total of μg rna with a concentration of ≥ ng/μl and an od / ratio between . and . . then, oligo (dt) magnetic beads were subjected to capture mrnas that contained poly-a tails from the total rna. the resulting mrnas were subsequently randomly broken into small fragments of approximately bp by adding fragmentation buffer. the mrna fragments functioned as the templates for double-stranded cdna (dscdna) synthesis using the superscript double-stranded cdna synthesis kit (invitrogen, ca, usa). under the action of reverse transcriptase, a strand of cdna was synthesized by using random primers with mrna as a template, which was followed by two-strand synthesis to form a stable double-stranded structure. since there was a cohesive terminus in the double-stranded cdna structure, end repair mix was added to patch it into a blunt end, and an a base was added at the 'end to connect the yshaped adaptor. to purify and enrich the dscdna, cycles of pcr were performed, and clean dna beads were used to screen - bp bands. after quantification by tbs (picogreen, invitrogen, ca usa), high-throughput sequencing of the resulting libraries was performed on the illumina hiseq xten/novaseq sequencing platform (san diego, ca, usa), and the sequencing read length was pairedend (pe) . to ensure the accuracy of the subsequent biological information analysis, the raw sequencing data generated from rna-seq was firstly filtered to obtain high-quality sequencing data (clean data) to ensure the smooth progress of the subsequent analysis. quality control of the raw reads was performed using seqprep (https://github.com/jstjohn/seqprep) and sickle (https://github.com/najoshi/sickle). the processes were as follows. the first step was to remove the adapter aging from the reads and the reads that did not insert the fragment due to the self-connection of the adapter. second, bases with a low quality (quality value less than ) at the end of the sequence ( ' end) were trimmed. if there was still a quality value of less than for the remaining sequence, the whole sequence was discarded; otherwise, it was retained. third, reads with n ratios over % and sequences with lengths less than bp after quality trimming were also removed. finally, the error rate (%), q and q values, gc-content (%), and sequence duplication levels of the generated clean reads were assessed [ ] . after filtering the raw data, the clean data were aligned to the mouse reference genome grcm by 'bowtie ' software [ ] . then, read summarization was calculated by the 'feature count' tool. differently expressed genes (degs) between the lps samples and control samples were identified by t-test using the 'deseq ' r package, as were degs between the ast samples and lps samples [ ] . the raw p-value was adjusted to the false discovery rate by the benjamini method, and a false discovery rate (fdr) ≤ . and |log fc|≥ was chosen as the threshold. based on the hypergeometric distribution algorithm, go (gene ontology, http://www.geneontology.org/) biological process (bp), molecular function (mf) and cell component (cc) pathway enrichment analyses were performed using the 'clusterprofler' r package [ ] . a p-value ≤ . was set as the cutoff criterion. to validate the combined findings from rna-seq and microarray meta-analysis, the expression of core degs in the three groups was confirmed. rnaiso plus reagent (takara, tokyo, japan) was employed to extract total rna from mouse lung tissues from each group, and reverse transcription was performed to obtain cdna using primescript™rt master mix (takara, tokyo, japan) along with the gdna eraser kit (takara, tokyo, japan). relative mrna expression levels were determined using rt-pcr performed on bio-rad cfx maestro (bio-rad, usa) with tb green® premix ex taq™ ii (takara, tokyo, japan). all the above experimental steps were performed according to the manufacturer's instructions for the corresponding kit. glyceraldehyde- -phosphate dehydrogenase (gapdh) was selected as the reference, and the primer sequences are presented in supplementary table . qrt-pcr was performed under the following conditions: °c for min, followed by cycles at °c for s, °c for s, and °c for s. each analysis was implemented in triplicate, and the relative expression levels of the target genes were calculated by employing the -ΔΔct method [ ] . inmex and networkanalyst were applied for the network-based microarray meta-analysis. for qpcr data, statistical analysis of differences between groups was achieved by one-way anova using prism software (graphpad software inc., san diego, ca, usa). a twotailed test was used for all data, and differences with a p-value < . were considered significant. first of all, we used the search formula of lps[all fields] and ("lung"[mesh terms] or lung[all fields]) and ("mus musculus"[organism] and "expression profiling by array" [filter] ) to obtain results in geo datasets. by eliminating datasets of mirna sequencings, datasets not related to acute lung injury, and datasets that only researching on rna sequencing of specific cells such as macrophages and type ii alveolar epithelial cells, there were articles remained (gse , gse , gse , gse , gse , gse , gse and gse ). continuing to check the specific description of the sample in articles, we found some datasets were grouped with sample of n< and some mainly studied ali or ards induced by excessive ventilation or non-lps chemicals. in the end, there were datasets (gse , gse , gse , gse and gse ) that met the requirements of integrated analysis. we conducted a microarray meta-analysis using networkanalyst . combined three well-established meta-analysis approaches --fisher's method, fixed effect model, and vote counting. the features and main characteristics are given below (https://www.networkanalyst.ca). ( ) fisher's method (- *∑log(p)) is known as a 'weight-free' method and combines p values from multiple studies for information integration. ( ) effect size is the difference between two group means divided by standard deviation, which are considered combinable and comparable across different studies. in the fixed effects models (fem), the estimated effect size in each study is assumed to come from an underlying true effect size plus measurement error. ( ) vote counting is the simplest method in metaanalysis. differentially expressed gene is first selected based on a threshold to obtain a list of de genes for each study. the vote for each gene can then be calculated as the total number of times it occurred in all de lists. the final de genes can be selected based on the minimal number of votes set by the user. after the mice were sacrificed, the lung tissues were collected. immediately, the tissue was fixed in % paraformaldehyde for hours and embedded in paraffin. the embedded tissue was sliced into µm sections for staining. after the tissue sections were deparaffinized and rehydrated, they were heated in citrate buffer at °c for minutes to restore antigen activity. the sections were then incubated with . % hydrogen peroxide in methanol for minutes to inhibit endogenous peroxidase activity. after blocking nonspecific reactions with % normal bovine serum, the sections were incubated with rabbit polyclonal antibodies specific for ccl ( : , abcam), saa ( : , ab , abcam), ly i ( : , abcam), saa ( : - : , thermo), lrf ( : , thermo), timp ( : , thermo), isg ( : , thermo) and cxcl ( : , abcam). the treated samples were placed at °c for hours. the sections were then washed with pbs and incubated with horseradish peroxidase-conjugated secondary antibodies at °c for hours. the stained sections were imaged under an inverted phase contrast microscope. acute respiratory distress syndrome acute respiratory distress in adults. the lancet, saturday the acute respiratory distress syndrome lipopolysaccharide endotoxins cordycepin inhibits lps-induced acute lung injury by inhibiting inflammation and oxidative stress xanthohumol ameliorates lipopolysaccharide (lps)-induced acute lung injury via induction of ampk/gsk β-nrf signal axis linarin prevents lps-induced acute lung injury by suppressing oxidative stress and inflammation via inhibition of txnip/nlrp and nf-κb pathways curcumin and allopurinol ameliorate fructose-induced hepatic inflammation in rats via mir- a-mediated txnip/nlrp inflammasome inhibition troxerutin protects kidney tissue against bde- -induced inflammatory damage through cxcr -txnip/nlrp signaling astaxanthin: a review of its chemistry and applications astaxanthin, a carotenoid with potential in human health and nutrition biorefinery approach and environmentfriendly extraction for sustainable production of astaxanthin from marine wastes astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing i(kappa)b kinase-dependent nf-kappab activation effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo astaxanthin prevents pulmonary fibrosis by promoting myofibroblast apoptosis dependent on drp -mediated mitochondrial fission astaxanthin alleviated acute lung injury by inhibiting oxidative/nitrative stress and the inflammatory response in mice astaxanthin prevents against lipopolysaccharideinduced acute lung injury and sepsis via inhibiting activation of mapk/nf-κb networkanalyst . : a visual analytics platform for comprehensive gene expression profiling and metaanalysis clusterprofiler: an r package for comparing biological themes among gene clusters inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential evidence for chemokine synergy during neutrophil migration in ards fernández-botrán r. modulation of acute inflammation by targeting glycosaminoglycan-cytokine interactions contribution of neutrophils to acute lung injury antiinflammatory activity of a novel family of aryl ureas compounds in an endotoxin-induced airway epithelial cell injury model c-x-c motif chemokine (cxcl ) is a prognostic biomarker of idiopathic pulmonary fibrosis zbp : innate sensor regulating cell death and inflammation dynamic gene expression analysis in a h n influenza virus mouse pneumonia model the cc chemokine ligand (ccl ) mediates fibroblast survival through il- complement inhibition decreases early fibrogenic events in the lung of septic baboons the cytokine-serum amyloid achemokine network serum amyloid a is a biomarker of severe coronavirus disease and poor prognosis serum amyloid a is a high density lipoprotein-associated acute-phase protein exosomes derived from microrna- b- p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting saa long non-coding rna malat regulates hyperglycaemia induced inflammatory process in the endothelial cells il- induced lncrna malat enhances tnf-α expression in lps-induced septic cardiomyocytes via activation of saa emerging functions of serum amyloid a in inflammation suppression of lipopolysaccharide-induced inflammatory response by fragments from serum amyloid a serum amyloid a promotes lps clearance and suppresses lps-induced inflammation and tissue injury knockdown of mir- protects nucleus pulposus cells from tnf-a-induced apoptosis by targeting serum amyloid a irf : activation, regulation, modification and function attenuation of interferon regulatory factor activity in local infectious sites of trachea and lung for preventing the development of acute lung injury caused by influenza a virus mir- c mediates influenza a virus-induced ifnβ expression by targeting nf-κb inducing kinase mir- attenuates the host response to influenza virus by targeting the traf -irf signaling axis cytokine functions of timp- imbalance between matrix metalloproteinases (mmp- and mmp- ) and tissue inhibitors of metalloproteinases (timp- and timp- ) in acute respiratory distress syndrome patients serum mmp- and timp- in critically ill patients with acute respiratory failure: timp- is associated with increased -day mortality timp- promotes the immune response in influenza-induced acute lung injury isg in antiviral immunity and beyond lipopolysaccharide activates the expression of isg -specific protease ubp via interferon regulatory factor extremes of interferon-stimulated gene expression associate with worse outcomes in the acute respiratory distress syndrome role of chemokines in the pathogenesis of acute lung injury proteinaseactivated receptor- , ccl , and ccl regulate acute neutrophilic lung inflammation extracellular atp mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury molecular dynamics of lipopolysaccharide-induced lung injury in rodents modulation of lipopolysaccharideinduced gene transcription and promotion of lung injury by mechanical ventilation bpifa regulates lung neutrophil recruitment and interferon signaling during acute inflammation altered gene expression profiles in the lungs of benzo[a]pyreneexposed mice in the presence of lipopolysaccharideinduced pulmonary inflammation effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice clara cells attenuate the inflammatory response through regulation of macrophage behavior astaxanthin suppresses cigarette smokeinduced emphysema through nrf activation in mice fastp: an ultra-fast all-inone fastq preprocessor fast gapped-read alignment with bowtie moderated estimation of fold change and dispersion for rna-seq data with deseq analysis of relative gene expression data using real-time quantitative pcr and the (-delta delta c(t)) method the authors declare that they have no conflicts interest. please browse full text version to see the data of supplementary tables to key: cord- -m lkrehi authors: nan title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: m lkrehi nan introduction: veno-venous extracorporeal co removal (ecco r) is a promising new therapeutic option in the critical care setting. we conducted a prospective observational study of the use of ecco r in selected voluntary centers during years aiming to assess the prevalence of the ecco r use mainly among copd and ards patients. patients and methods: two medical devices: hemolung (alung technologies, pittsburgh, usa) and ila activve (xenios novalung, heilbronn, germany) were selected after literature and medico-economic evaluations. a specific medical and nurses training was provided in table characteristics of patients with known or de novo svv (small-vessel vasculitis) admitted to the intensive care unit for acute respiratory failure (arf) all arf (n = ) immune arf (n = ) non immune arf (n = ) p age , introduction: ineffective triggering is frequent during pressure support ventilation (psv). its occurrence is favored by dynamic hyperinflation that may arise when increasing the pressure support level (psl). decreasing the psl however fails to suppress ineffective triggering in a subgroup of patients that are therefore exposed to refractory ineffective triggering. proportional assist ventilation with load-adjustable gain factors (pav +) decreases the incidence of ineffective triggering in unselected patients but its effect on refractory asynchrony during psv is unknown. the main aim of our study was to assess the effect . the median gain during pav + was % [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the asynchrony index was significantly lower with pav + than psv ( % [ ] [ ] [ ] [ ] [ ] [ ] [ ] vs. % respectively, p = . ). moreover, the asynchrony index decreased in every patient with pav + (fig. ) . noticeably, the tidal volume was already protective in psv and decreased even more during pav + ( . ml kg [ . - . ] vs. . ml [ . - . ] respectively, p = . ); and the neural respiratory rate was high in both modes ( cycles min in psv vs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in pav + , p = . ). total esophageal pressure-time product (ptpes) did not significantly differ between the two modes but the ptpes proportion that was wasted in ineffective efforts decreased with pav + ( % [ ] [ ] vs. % , p = . ). conclusion: our preliminary data suggest that: ( ) pav + reduces the incidence of refractory ineffective triggering; ( ) patients exposed to refractory ineffective triggering during psv seem characterized by rapid shallow breathing despite high ventilatory support, questioning the tolerance of both ventilatory modes. results with further inclusions will be presented. introduction: the use of alternatives to carbapenems to treat patients with extended-spectrum beta lactamase-producing gram negative bacilli (esbl-gnb) infections remains controversial. their use in patients with severe infections in the icu has been poorly studied. the aim of this study was to compare the outcome of icu patients having received carbapenems to those having received a carbapenem-sparing agent (csa). the charts of patients with esbl-gnb infection hospitalized in our icu between and were retrospectively reviewed. patients treated with betalactam betalactam inhibitor (bl bli), cefepime or quinolones were considered has having received an alternative to carbapenems (csa). patients having received such a csa were compared to those having received a carbapenems. primary outcome was treatment failure at day , defined as esbl-gnb infection recurrence (relapse with same pathogen) or death, whichever first occurred. results: patients with esbl-gnb infection were included. source of infection was the lung for most of them. characteristics of patients are displayed on table . their median saps ii and sofa scores were and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , respectively, and ( %) were on septic shock. patients received a carbapenem empirically, among whom were switched to a csa agent when antibiogram was available (csa-definite group), whereas carbapenems were pursued in the others (carbapenem-only group), mainly because pathogens were resistant to others antibiotics. among the patients having received a non-carbapenem agent as empirical treatment, pathogen was susceptible to this agent in and they pursued the same treatment (csa-only group), whereas were switched to a carbapenem (pathogens resistant to empirical treatment, carbapenem-definite group). treatment failure were not different among these groups (table ) . globally, patients received a csa as their definite treatment (csadefinite and csa-only groups), whereas received a carbapenems (carbapenems-only and carbapenems-definite groups). whereas duration of antimicrobial treatment was similar ( [ - ] days vs. [ - ] days, respectively, p = ns), treatment failure rate was not higher in the former, as compared to those having received a carbapenems ( vs. %, respectively, p = . ). conclusion: treatment of patients with esbl-gnb severe infection in the icu with a csa seems to be safe when the pathogen is susceptible to this csa. however, mic should be first determined before de-escalating to a csa. larger studies are needed. percentages of samplings which attained the pk pd targets for various crcl with potential suboptimal beta-lactam concentration in critically-ill patients with aki treated either with an early or a delayed rrt strategy. patients and methods: ancillary study in a subset of patients with severe aki (kdigo ), receiving a beta-lactam antibiotic, in a trial comparing two rrt initiation strategies. in this trial, patients from intensive care units were randomly assigned to either an early (immediate rrt) or a delayed (late or no rrt) rrt initiation strategy. beta-lactam residual concentrations were sampled at and h after inclusion. the appropriate concentration was defined as a trough of at least times the minimal inhibitory concentration (clinical breakpoint of eucast). the primary outcome was an adequate plasma concentration of the beta-lactam during the first days. results: among the patients included in the centers participating to this ancillary study, a beta-lactam trough concentration was evaluated in subjects, in the early and in the delayed groups. ninety patients ( . %) had an adequate beta-lactam dosage. rrt initiation strategy had no impact on beta-lactam concentration (p = . ). among the septic shock patients ( % of the sampled patients), ( %) had a correct antibiotic concentration. in contrast, only of the patients without definite sepsis ( . %) had a correct dosage. factors associated with an adequate beta-lactam trough concentration in univariate analysis were admission for a septic shock (p = . ), a higher plasma creatinine level (p = . ), a higher mean arterial pressure (p = . ) and a lower serum bicarbonate level (p = . ) at randomization. a higher sofa score was associated with an adequate beta-lactam concentration near to statistical significance (p = . ). multivariate analysis will be presented. in the context of severe aki, beta-lactam concentration reached a sufficient level in % of septic shock patients. interestingly, rrt initiation strategy was not associated with beta-lactam trough concentration. early rrt did not affect trough concentration of betalactam. we may hypothesize that physicians were highly vigilant and adapted antibiotic administration adequately in these patients. introduction: amikacin infusion requires to target a peak serum concentration (c max ) - times the minimal inhibitory concentration, corresponding to a c max at - mg l − for the least susceptible bacteria. recent study reported that % of critically ill patients do not attain this target with a mg kg dose ( ) . membrane sequestration, alteration of the volume of distribution and lack of data in this population make drugs pharmacokinetics (pk) on ecmo challenging. our study aimed to assess the prevalence of insufficient amikacin c max in critically ill patients on ecmo and to identify relative risk factors. patients and methods: prospective, observational, monocentric study of adult patients on venoarterial (va) or venovenous (vv) ecmo receiving a loading dose of amikacin for suspected gramnegative infections. intravenous amikacin was administered with a loading dose of mg kg of total body weight and c max was measured min after the end of the infusion. independent predicators of c max < mg l − after the first amikacin infusion were identified by mixed model multivariate analysis. results: from january to february , patients (median saps (interquartile range) ( - ); age ( - ) years) under va-ecmo ( %) or vv-ecmo ( %) were included. at inclusion, the sofa score was ( - ) and ( %) patients were on renal replacement therapy. overall icu mortality was %. c max was < mg l − in ( %) of the patients. independent risk factors of amikacin under-dosing were body mass index (bmi) < kg m − (odds ratio (or) . , % confidence interval %ci . - . , p = . ) and a positive h fluid balance (or per ml increment: . , %ci . - . , p = . ) (fig. ). our results were comparable to those observed in patients treated with amikacin without ecmo ( ) . conclusion: this large prospective study suggests that the prevalence and associated risk factors of amikacin under-dosing are similar in critically-ill patients with or without ecmo. the use of a mg kg dose in low bmi patients and in those with a positive -h fluid balance on ecmo is strongly encouraged to obtain adequate therapeutic targets and prevent therapeutic failure. results: fifty patients were included ( with delirium, controls), at day for controls and day for patients with confusion. delirium patients were more severely ill sofa [ ; ] versus [ ; ] (p = . ); with higher rass [ ; ] versus [ ; ] (p = . ). they presented with % bl overdosing versus % in controls (p = . ); with % of bl in therapeutic index: % in controls (p = . ). obesity and renal failure were not associated with bl overdosing but there was a trend with hypoalbuminemia (p = . ). discussion: trend in association of bl overdosing with delirium corresponds to previous studies, and would need a larger scale study to be confirmed. severity differences in groups would need changes in inclusion criteria to obtain homogeneous groups. a possible association of bl underdosing with poor evolution of infection and organ failures would need more precise evaluation. hypoalbuminemia could have an impact on bl overdosing. conclusion: delirium was not associated with bl overdosing but with therapeutic index. a high variability of bl concentrations warrants therapeutic drug monitoring. a larger scale study should include changes in design. feasibility and safety of low-flow extracorporeal co removal with a renal replacement platform to enhance lung protective ventilation in patients with mild to moderate ards schmidt matthieu , jaber samir , constantin introduction: extracorporeal carbon dioxide removal (ecco r) might allow ultraprotective mechanical ventilation with lower tidal volume (vt) (< ml kg ideal body weight), plateau pressure (pplat) (< cm h o), driving pressure, and respiratory rate (rr) to reduce ventilator induced lung injury (vili). the aim of this study was to assess the feasibility and safety of ecco r with a renal replacement platform (rrt) to permit ultra-protective ventilation in patients with mild to moderate acute respiratory distress syndrome (ards). patients and methods: twenty patients with mild (n = ) or moderate ards were included. vt was gradually reduced from to , . and ml kg − and peep adjusted to reach > pplat > cm h o. standalone ecco r (no hemofilter associated on the rrt platform) was initiated when arterial paco increased by more than %. ventilation parameters (vt, rr, peep), respiratory compliance, driving pressure, arterial blood gases, and ecco r system operational characteristics (blood flow, sweep gas flow, and co removal rate) were collected during a minimum of h of ultra-protective ventilation. complications, mortality at day , need for adjuvant therapies and data on weaning from both mechanical ventilation and ecco r were also collected. results: while vt was reduced from to ml kg − and pplat kept below cm h o, peep was significantly increased from . ± . at baseline to . ± . cm h o at vt = ml kg − . as a result, the driving pressure was significantly reduced to . ± . cm h o at vt = ml kg − (p < . ) (fig. ) . no significant differences in rr, pao fio ratio, respiratory system compliance were observed after vt reduction. mean extracorporeal blood, sweep gas flow and co removal were ± ml min − , ± . l min − and ml min − , respectively. mean treatment duration was ± h. main side effects related to ecco r were membrane clotting which occurred in patients after ± h. conclusion: a low-flow ecco r device driven by a rrt platform efficiently removed co while allowing ultra-protective mechanical ventilation settings in patients with mild to moderate ards (clinicaltrials. gov identifier: nct ). morimont philippe , habran simon , desaive thomas , janssen nathalie , amand theophile , blaffart francine , dauby pierre , kolh philippe , defraigne jean-olivier , lambermont bernard introduction: protective lung ventilation (plv) is recommended in patients with acute respiratory distress syndrome (ards) to minimize additional injuries to the lung. however, increased right ventricular (rv) afterload resulting from ards could be enhanced by hypercapnic acidosis resulting from ventilation at lower tidal volume. relative contribution of these factors (ards and plv) in rv afterload is not clearly established. the aim of this study was to compare rv afterload in ards combined with plv to rv afterload in plv alone. patients and methods: this study was performed in an experimental model of severe hypercapnic acidosis performed in series of pigs. in both groups, respiratory tidal volume was decreased by %. in the first group (ards group), an ards (obtained by repeated bronchoalveolar lavage) was performed before reducing ventilation, while in the second group (control group), hypercapnic acidosis was resulting from low tidal volume ventilation alone. results: in both groups, systolic pulmonary artery pressure (paps) significantly increased during plv. this increase was significantly higher in ards group than in control group (fig. ) . severe hypercapnic acidosis occurred in both groups: paco increased from . ± . to . ± . (p < . ) and arterial ph decreased from . ± . to . ± . (p < . ) in ards group while paco increased from . ± . to . ± . (p < . ) and arterial ph decreased from . ± . to . ± . (p < . ) in control group. pao significantly decreased in ards group ( ± to ± . mmhg, p < . ) but did not significantly changed in control group. conclusion: isolated hypercapnic acidosis resulting from plv was clearly responsible for increased rv afterload and this effect was significantly enhanced in ards. pulmonary vasoconstriction resulting from hypercapnic acidosis is strongly enhanced by factors like hypoxia, endothelial injuries or inflammatory mediators in ards. extracorporeal co removal could be the solution to limit afterload burden on the right ventricle when plv is achieved during ards. introduction: prone positioning has been shown to improve mortality in acute respiratory distress syndrome (ards) patients. the respiratory system driving-pressure (dprs) and the transpulmonary driving-pressure (dpl), measured with esophageal manometry, have been shown to be strongly correlated with mortality. the aim of this study was to investigate the evolution of the dpl during prone positioning and its relationship with evolution of oxygenation in ards patients. patients and methods: ten patients with ards equipped with esophageal manometry were enrolled. dprs, dpl and chest wall driving-pressure (dpcw) were measured before and h after prone positioning. respiratory system, pulmonary and chest wall elastance (ers, el, ecw) were calculated at the same time. finally, we studied the correlation between these respiratory variables and oxygenation indicators. patients were classified as responders to prone positioning if the change in the ratio of arterial oxygen partial pressure oxygen inspired fraction (delta.pao /fio ) induced by the manoeuvre was larger than the median value observed in the group. results: in the whole population, median value of delta.pao /fio was . mmhg, and patients were classified as responders and as non-responders. in responders, dpl significantly decreased from . ± . cm h o to . ± . cm h o (p = . ) and el decreased from . ± . cm h o l to . ± . cm h o l (p = . ) after prone positioning. other respiratory variables did not change. in non-responders, respiratory variables did not change. between responders and nonresponders, there was no significant difference between baseline respiratory variables. after prone positioning, delta.pao /fio was not related to baseline respiratory parameters. on the contrary delta. pao /fio induced by prone positioning was strongly correlated with changes in dpl (r = − . , p = . ) and changes in el (r = − . , p = . ). we did not find any correlation between delta.pao /fio and changes in dpcw or changes in ecw. the correlation between delta.pao /fio and changes in dprs (r = − . , p = . ) and changes in ers (r = − . , p = . ) did not reach significance. conclusion: in patients who respond to prone positioning by the highest improvement in oxygenation, dpl significantly decrease after prone positioning. the changes in dpl and the changes in el play a major role in the improvement in oxygenation induced by prone positioning whereas the changes in dpcw and ecw do not. introduction: whereas prone positioning (pp) has been shown to improve patient survival in moderate to severe ards patients, its rate of use was . % in lung safe study. however, lung safe study was not specifically focused on pp. therefore, present study aimed to determine prevalence of use of pp in ards patients (primary endpoint), physiologic effects of and reasons for not using pp (secondary end-points). the apronet study was a prospective international one-day prevalence study performed times in april, july, october and january . at each study day, investigators had to screen every patient staying in icu from to h and to fill electronic crf. for patients with ards (defined from the berlin definition criteria) at each study day oxygenation and ventilator settings were recorded. for those receiving pp these variables were recorded before and at the end of pp session. the reasons for not proning were also collected. values are presented as median ( st- rd quartiles). prevalence rates of pp were compared by using chi square for trend and groups were compared with nonparametric tests. introduction: although acute respiratory distress syndrome (ards) has been largely focused on, few data are available concerning hypoxemia independently of its cause in intensive care unit (icu) patients. a recent prevalence-point-day (ppd) evaluated the patterns and outcomes of hypoxemia in french speaking icus. here, we describe the main etiologies, management and outcomes of the patients of this cohort presenting with severe hypoxemia. patients and methods: a ppd was conducted among french speaking icus during spring . hypoxemia was defined by a pao fio ratio below . we analyzed the data from patients with severe hypoxemia (i.e. with a pao fio ratio < ) and compared their characteristics (causes of hypoxemia, ventilatory and non-ventilatory management) and outcomes to the patients with mild or moderate hypoxemia. results: among the hypoxemic patients the day of the study, ( %) had severe hypoxemia. the main cause of hypoxemia was pneumonia and this diagnosis was more frequent than in mild and moderate hypoxemia. whereas bilateral radiologic infiltrates were present in ( . %) patients, ards was diagnosed by physicians in only ( . %) of them. invasive mechanical ventilation (mv) was used in ( . %) patients. high flow oxygen was administered in ( . %) of them and ( . %) were under non-invasive ventilation (niv) the day of the study. median vt was . ( . - . ) ml kg of ibw. positive end-expiratory pressure (peep) was higher than in mild and moderate hypoxemic patients ( ( - ) vs. ( - ) and ( - ) cm h o respectively, p < . ). median plateau pressure was . ( - . ) and was higher than in mild and moderate groups. median driving pressure was ( - ) cm h o with no difference when compared to other groups. neuromuscular blocking agents were administered in ( . %) patients, inhaled nitric oxide (ino) in ( %) patients and only patients ( . %) were on prone positioning. fourteen ( . %) patients were under extracorporeal membrane oxygenation (ecmo). icu mortality was higher in severe hypoxemic patients as compared to mild and moderate ( . vs. . and . % respectively, p < . ). icu length of stay in icu survivors was not statistically different between groups. conclusion: severe hypoxemia, independently from ards, worsens the prognosis of icu patients. even though ards might be underdiagnosed, a protective ventilation was respected in severe hypoxemic patients. introduction: major changes in septic shock management raise the questions of the relevance of the classical risk factors of nosocomial infections in the current era and the link with the primary infectious insult. we herein investigated the risk factors and the outcomes of icuacquired infections in a recent cohort of septic shock patients. patients and methods: this was a -year ( - ) monocenter retrospective study. all adult patients diagnosed for septic shock within the first h were included. septic shock was defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors. patients who survived the first three days were eligible for assessment of the risk of the first icu-acquired infections. the diagnosis of nosocomial infections were based on current international guidelines. patients were classified according to the development of pulmonary or non-pulmonary icu-acquired infections. the determinants of icu-acquired infections were addressed in a multivariate logistic regression analysis. results: patients were admitted for septic shock. patients remained alive in the icu after the first three days and could then be evaluated for the risk of icu-acquired infections. hence, patients remained free of secondary infections, patients first developed an episode of nosocomial pneumonia and patients first developed an episode of non-pulmonary infection. the mortality rates of patients with icu-acquired pneumonia, non-pulmonary icu-acquired infections and without secondary infections were , and %, respectively (p = . ). in multivariate analysis, the development of icu-acquired pneumonia was independently associated with male gender (or . , ci % [ . - . ], p = . ), renal replacement therapy (or . , ci % [ . - . ], p = . ), platelet transfusion (or . , ci % [ . - . ], p = . ) and a primary pulmonary infection (or . , ci % [ . - . ], p < . ). the development of non-pulmonary infections was independently associated with renal replacement therapy (or . , ci % [ . - . ], p < . ), fresh frozen plasma transfusion (or . , ci % [ . - . ] , p = . ), healthcare-associated septic shock (or . , ci % [ . - . ], p = . ). conclusion: icu-acquired pneumonia occurs preferentially in patients with septic shock of pulmonary origin. in addition, we identified the transfusion of blood products as a risk factor for pulmonary and nonpulmonary nosocomial infections. introduction: human serum albumin is used for the restoration of blood volume, emergency treatment of septic shock patients. several experimental studies suggested that albumin could have additional protective effects on the vascular wall and more specifically on endothelial functions. however, the in vivo effect of albumin in human endothelium remains unknown. the aim of this study is to assess the effect of albumin or saline infusion on skin endothelial function in septic shock patients requiring volume expansion. we performed a prospective randomized monocentric study in an -bed medical intensive care unit. all patients with septic shock who required fluid administration were included between h and h after vasopressor starting. patients were randomized to receive either ml of saline solution . % or ml of albumin %. norepinephrine dose was not modified h before and during the procedure. endothelium-dependant vasodilatation in the skin circulation was assessed by iontophoresis of acetylcholine before and after fluid administration. the improvement of skin blood flow in response to acetylcholine after fluid administration was compared between groups. for each patient, age, sex, saps ii, site of infection, global hemodynamic parameters and clinical microcirculatory parameters were recorded. results are expressed as mean ± sd. qualitative data were compared using chi- or fisher's exact test while quantitative data comparisons used student t test or mann-whitney as appropriate. results: twenty-two patients were included ( women, age: ± , saps ii: ± ). twelve patients received saline and received albumin. apart from age, no statistical difference was found between groups regarding demographic characteristics and baseline hemodynamic parameters. norepinephrine dose and mean volume of infused fluid before inclusion was not different between groups (table ) . before fluid replacement, endothelial response to acetylcholine iontophoresis was not different between groups (auc vs ; p = . ). volume expansion induced a slight increase of systolic arterial pressure, significantly higher in the albumin group ( vs %; p = . ) with no difference regarding cardiac output variations between groups. next, we compared the variations of endothelium response to iontophoresis before and after fluid infusion. the improvement of endothelial response after acetylcholine challenge was significantly higher in the albumin group ( vs %, p = . ). conclusion: in the early stage of septic shock resuscitation, we showed that albumin infusion had protective endothelial effects. this result has to be confirmed in a larger cohort. ] + all p < . ). we found no correlation between cognitive scores at hospital discharge and the severity of eeg-defined encephalopathy during the days of icu or during the first h after admission. however, sepsis survivors' scores were lower than controls' (p < . ) ( table ) . conclusion: in this study, eeg was more sensitive than clinical tools to detect sae but clinical scales correlated with the eeg grade. encephalopathy was not associated with short-term cognitive function. further study and a larger cohort are needed to determine which early eeg introduction: there is growing evidence that corticotherapy improves survival from septic shock. this observational study aimed at evaluating at bedside resistance to corticosteroids in adults with sepsis. patients and methods: participants-icu adults with septic shock or without sepsis admitted to the raymond poincaré university hospital. we also evaluated healthy controls. intervention-resistance to corticosteroids was assessed using a skin test. µl of dermocorticoid cream (class iii, betamethasone) was applied on a cm surface of the skin. at h, two independent physicians scored the blanching of the skin from to - -no blanching + -< % of surface + - to % of surface + - to % of surface, and -blanching beyond application area. cohen's kappa was used to measure concordance. a mean score of < indicated corticoresistance and a score of indicating normal sensitivity to corticosteroids. we also performed a µg acth test. results: we enrolled patients, patients with septic shock ( males, ) and patients without sepsis ( males, ). overall, ( %) with two measurements patients had concordant evaluation of score by the two physicians + while had a difference of -point in scores, resulting in a kappa of . ( % ci . - . ). in patients with septic shock, ( %) have corticoresistance, i.e. a mean score < , ( %) a score of or , and ( %) has normal sensitivity to corticosteroids. in non-septic critically ill, ( %) have corticoresistance, ( %) a mean score of - , and ( %) have normal sensitivity to corticosteroids. hence, as compared to non-septic patients, patients with septic shock were more likely to have corticoresistance (p = . ). discussion: topic application of corticosteroids on the skin results in activation of glucocorticoid receptors present within the vessels. subsequently, activation of lipocortin may inhibit the activity of phospholipase a , regulator of prostaglandins, leucotrienes and platelet activating factor. then, the coupling of alpha adrenoreceptors to their agonists is potentiated, increasing vessels smooth muscles sensitivity to catecholamines. the subsequent local vasocontriction is reflected by skin blanching. thus, the observed lack of skin blanching in septic patients may reflect altered coupling between gluocorticoids and glucocorticoids receptors. conclusion: roughly one out of two adults with septic shock may develop a resistance to corticosteroids as assessed by a skin blanching test in response to betamethasone. introduction: mild therapeutic hypothermia, currently recommended in the management of cardiac arrests with shockable rhythm could promote infectious complications and especially ventilator-associated pneumonia (vap) (mongardon et al. crit care med ). despite high incidence of vap and retrospective trials suggesting a benefit of shortterm ( h) antibiotics in this setting (davies et al. resuscitation ) , systematic use of antibiotic prophylaxis is not recommended in patients treated with mild therapeutic hypothermia after cardiac arrest. the primary objective was to demonstrate that systematic short-term antibiotic prophylaxis with amoxicillin-clavulanic acid can reduce incidence of early vap (< days) in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest. secondary objectives were its impact on incidence of late vap and on day mortality. patients and methods: multicenter two parallel-group doubleblinded randomized trial. adult patients hospitalized in icu, mechanically ventilated after out-of-hospital resuscitated cardiac arrest related to initial shockable rhythm and treated with mild therapeutic hypothermia were eligible. exclusion criteria were pregnancy, need for extracorporeal life support, ongoing antibiotic therapy or pneumonia, known chronic colonization with multiresistant bacteria, known allergy to beta-lactam antibiotics and moribund patients. patients received either intravenous injection of amoxicillin-clavulanic acid ( g mg) or placebo three times a day for days. the primary endpoint was the onset of early vap. all suspected pulmonary infections were adjudicated by a blinded independent committee. results: out of patients included, were finally analyzed, in treatment group and in placebo group (mean age . ± . years, sex ratio = , sofa score . ± . ). characteristics of cardiac arrest were similar in both groups (no flow = . ± . min vs . ± . min, low-flow = . ± . min vs . ± . min). early vap were confirmed, in treatment group vs in placebo group, with an incidence of . vs . %, respectively (hr = . + ic % = [ . + . ], p = . ) (fig. ). the procedure did not affect occurrence of late vap (> days), respectively vs . day mortality was similar in both arms ( . vs . %, p = . ) and no adverse event was related to study treatment. conclusion: short-term antibiotic prophylaxis with amoxicillin-clavulanic acid significantly decreases incidence of early vap in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest related to shockable rhythm. introduction: immunosuppressed (is) patients are prone to develop respiratory failure and to need ventilatory support. invasive ventilation shared a grim prognosis in the past and non-invasive ventilation had been recommended in these patients, however niv efficacy has been recently challenged and the advent of high flow oxygen therapy had brought even more complexity in the management of such patients. using the data from a recent point-prevalence-day of hypoxemia in icu, we compare the frequency, management and outcomes of hypoxemia in is and immuncompetent (ic) patients. patients and methods: the spectrum study was conducted in french-speaking icus in countries during spring . is was retained in case of malignant hemopathy, hiv positivity, immunosuppressive drugs, recent chemotherapy, neutrophil count < . g l. hypoxemia was defined as a pao fio ratio > and separate into severe (> ), moderate (> ) and mild (> ). we focused on the causes of hypoxemia, the ventilatory management and the outcome. results: among the patients included, ( %) were is out of whom ( %) were hypoxemic, proportion similar to the ic patients. mean age and igs- of hypoxemic patients were similar in is and ic patients. hypoxemia was mild in ( %), moderate in ( %) and severe in ( %) is patients with a similar distribution compared to hypoxemic ic patients. the causes of hypoxemia were also similar pneumonia being the leading cause. ( %) hypoxemic is patients fulfilled the berlin criteria for ards in a similar proportion to ic patients. respiratory support used in hypoxemic is patients was ambient air in , low flow oxygen in , high flow in , niv in and invasive ventilation in patients, with a different distribution from the ic patients (more patients on high flow therapy and less invasively ventilated). the day of the study, thoracic ct scan and echocardiography were performed in a similar proportion in is and ic patients whereas broncho-alveolar lavage was more frequently performed in is patients ( vs %, p < . ). finally, as expected, icu mortality was higher in hypoxemic is patients ( vs %, p < . ). conclusion: immunosuppression in the icu seems not to be associated with hypoxemia, severity of hypoxemia or ards. oxygenation management is slightly different from immunocompetent patients with more frequent use of high flow therapy. ( ) mmhg, ph . ( . ). were included in the l/kg/min group and in the l/kg/min group. no difference was observed between groups for baseline characteristics. failure rate was not different between groups- . vs . % + p = . . no center effect was observed for failure. discomfort was more frequent in the l kg min group- vs % + p = . . the length of stay was shorter in the l kg min group- . ( . ) vs . ( ) days + p = . . intubation occurred in patients in the l/kg/min group vs patients in the l kg min group (p = . ). conclusion: hfnc with a flow rate of l/kg/min did not reduce the risk of failure compared to l/kg/min at the initial respiratory management of avb in young infants. comparison of epinephrine and norepinephrine for the treatment of cardiogenic shock following acute myocardial infarction. optima cc study levy bruno introduction: despite the frequent use of vasopressors which are administered in % of patients in cardiogenic shock (cs), there is only limited evidence from randomized trials comparing vasopressor in cs. hence, the optima cc study was designed to compare epinephrine and norepinephrine in cardiogenic shock following myocardial infarction. patients and methods: multicenter, double-blind, randomized trial in french icu. cardiogenic shock patients due to myocardial infarction treated by pci were randomized to receive epinephrine or norepinephrine to maintain map at mmhg. dobutamine was introduced at the physician discretion according to a combination of parameters-echocardiographic parameters, cardiac index, lactate clearance, svo and swan-ganz derived parameters. results: / patients were ventilated ( %). there were no differences in the duration nor in the maximal dose or cumulated dose of epinephrine or norepinephrine. dobutamine was used in / ( %) in the epinephrine group and in / ( %) in the norepinephrine group. there were no differences in the duration, in the maximal or cumulated dose. arterial pressure evolution was similar. heart rate increased significantly in epinephrine group and did not change in norepinephrine group. cardiac index and cardiac power index increased significantly more in the epinephrine group than in the norepinephrine group. cardiac double product, a surrogate of myocardial oxygen consumption increased in epinephrine group and did not change in norepinephrine group. epinephrine use was associated with a lactic acidosis from h to h while arterial ph increased and lactate level decreased in norepinephrine groupepinephrine was significantly associated with an higher incidence of refractory shock- / ( %) versus / ( %) p = . ). the incidence of arrhythmia was identical (epinephrine- % versus norepinephrine- %, p = . ). ecmo was used in / ( %) in the epinephrine group and in / ( %) in the norepinephrine group (p = . ) mortality was / ( %) in the norepinephrine group and / ( %) in the epinephrine group (p = . ) epinephrine use was associated with a trend to an increased risk of death (p = . ) and an increased risk of death plus ecmo (p = . ) at days. there was a trend for an increased risk of death plus ecmo at j (p = . ). conclusion: in patients with cardiogenic shock following myocardial infarction, epinephrine use was associated with a lactic acidosis, an higher incidence of refractory shock and an increased risk of death plus ecmo at j . high dose immunoglobulins in toxic shock syndrome in children: a pilot randomized controlled study (ighn study) javouhey etienne , leteurtre stéphane , tissières pierre , joram nicolas , wroblewski isabelle , ginhoux tiphanie , dauger stéphane , kassai behrouz hôpital mère enfant, bron, france; hôpital jeanne de flandre, lille, france; hôpital du kremlin-bicêtre, le kremlin-bicêtre, france; chu nantes, nantes, france; chu grenoble, la tronche, france; hospices civils de lyon, bron, france; hôpital robert debré, paris, france; hospices civils de lyon, bron, france correspondence: javouhey etienne -etienne.javouhey@chu-lyon.fr annals of intensive care , (suppl ):co- introduction: superantigen toxins synthesized by s. aureus or by s. pyogenes are responsible for toxic shock syndromes (tss) which lethality can reach %. high dose intravenous immunoglobulins (ivig), able to neutralize these toxins, are frequently used even tough evidence of its efficacy is not supported by randomized controlled study (rct) . moreover, ivig are expensive and possibly harmful. before conducting a rct, a pilot study was first designed to assess the feasibility in the context of pediatric critical care. patients and methods: a double blinded rct was performed comparing g kg of ivig to isovolumic % albumin perfusion within the first h of tss in children aged between month to years. a priori criteria to determine the feasibility were defined as a rate of inclusion among eligible patients > %, a rate of protocol's deviations < % (treatment delivery, non-respect of blinding, premature stop), and by the practical and financial aspects of the protocol. secondary objectives were to assess the efficacy of ivig on organ dysfunction (using pelod- score), on mortality at day and their safety. the study was promoted by the hospices civils of lyon, approved by the cpp sud-est and registered at clinical trial (nct ). inform consent from both parents was required before randomization. this study was funded by csl-behring company. results: during the months study period, patients were included in centers. the inclusion rate was of % ( parent's refusals, parents were absent at admission). two patients were wrongly included (pneumococcal shocks), one patient didn't receive the treatment because he was transferred for ecmo in a non-investigator center, three patients were treated after h, and in two patients one bottle of treatment was missing. the blinding was well respected. missing data on the pelod score and mortality was lower than %, and no premature stop was reported. the ecrf completion was judged easy by investigators. the inclusion of children within the first h was judged challenging. the treatment delivery had to be improved, requiring the help of research assistants. seven serious and one severe adverse events were registered, all patients recovered and no death was reported. conclusion: this pilot study suggested that a rct is feasible. it provides crucial information to improve the recruitment, the respect of the protocol and the correct measure of organ failure. however, inclusion of international centers is necessary to attain the sample size required. indirect calorimetry-based method for the work of breathing assessment when compared to esophageal pressure (pes) measurement and electrical activity of the diaphragm (eadi) during a spontaneous breathing trial in continuous positive airway pressure. patients and methods: a prospective single center study. all intubated and mechanically ventilated children > months and < years old, hospitalized in the pediatric intensive care unit were eligible. patients considered as ready to extubate were included. simultaneous recordings of vo , pes and eadi were performed during steps: before, during and after the spontaneous breathing test in continuous positive airway pressure. results: twenty patients, median . months, were included. half of the patients were admitted for a respiratory reason. predicted resting energy expenditure was overestimated as compared to measured resting energy expenditure ( [ - ] vs [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] kcal kg day, p < . ). spontaneous breathing test was associated with an increase in esophageal pressure-time product from to cm h o s min. the same trend was observed in respiratory drive, assessed by eadi which increased from . [ . - . ] to . [ . - . ] . oxygen consumption obtained by ic was higher during spontaneous breathing test as compared to conventional ventilation ( . [ . - . ] vs . [ . - . ] ml kg min) but non significantly. changes in work of breathing as assessed by vo was poorly correlated with measurements from pes and eadi whereas we found a moderate correlation between pes and eadi values. spontaneous breathing test and extubation were successful in ( %) and ( %) patients, respectively. conclusion: during weaning from mechanical ventilation, spontaneous breathing test in continuous positive airway pressure induced an increase in work of breathing, both in respiratory drive, as measured by eadi and in respiratory mechanics, as measured by pes. oxygen consumption measured by indirect calorimetry does not seem to be a reliable tool to assess work of breathing in mechanically ventilated children. ben gheriba khalil , grimaud marion , heilbronner claire , roy emeline , hadchouel alice , renolleau sylvain , rigourd virginie hôpital necker enfants malades, paris, france correspondence: ben gheriba khalil -bg.khalil@gmail.com annals of intensive care , (suppl ): introduction: during the winter season - we had evaluated breastfeeding disruption after hospitalization for bronchiolitis in our hospital in infants under month (n = ). we observed % of mothers whose breastfeeding was stopped of modified. clinical severity had no impact on breastfeeding but % of mothers stated that lack of support and advice was the first cause of breastfeeding disturbance. we conducted this second phase to evaluate the potential impact of actions to promote breastfeeding on unwanted weaning during hospitalization for bronchiolitis. patients and methods: this is a cross sectional study during two epidemic seasons of bronchiolitis in a tertiary care hospital. all patients aged months or younger hospitalized with acute bronchiolitis and receiving at least partial breastfeeding were eligible for the study. patients discharged at home whose parents accepted to be contacted by phone were included. a bundle of actions to promote breastfeeding in patients with bronchiolitis was implemented (posters, flyers, staff training, equipment with breast pumps) between the two epidemic seasons. the data was extracted from the charts and from a phone survey two weeks after discharge to evaluate breastfeeding in eligible patients in our hospital. phase i (before action) had included patients hospitalized between december and march in all wards hosting patients with bronchiolitis. phase ii (after action) included patients hospitalized from october to december . the data from phase ii was compared with data from phase i. results: fifty patients could be included during the second step of the study, with a mean age of days. breastfeeding was exclusive for % of mothers (vs % in phase i). the median length of stay was days (vs days in phase i). twenty-one ( %) patients spent time in picu vs. % in phase i, needed intubation, received non invasive ventilation for a median length of days (vs. days in phase i). the number of patients needing nutritional support was ( %) during phase ii vs. ( %) during phase i. after implementation of our actions, ( %) mothers kept breastfeeding as before (vs. % in the previous epidemic season, p < . ), mothers ( %) stopped, ( %) switched to partial breastfeeding and ( %) reduced without stopping. conclusion: bronchiolitis is a high risk event for breastfeeding disruption but staff training and correct advices and support for mothers during hospitalization seems to diminish that risk. benefits of using a high temporal resolution database in the automatic real-time pediatric ards screening nardi nicolas introduction: pediatric acute respiratory distress syndrome (pards) is frequent in pediatric intensive care units (picu), potentially lethal and the diagnosis is often missed or delayed (palicc ) . in picu, data are usually recorded between to min which leads to only a minority of the arterial partial pressure of oxygen (pao ) that are usable to calculate a valid oxygenation index (oi). if not available, pao should be replaced by the spo if < % to calculate the oxygen saturation index (osi). using a high temporal resolution (htr) database that records data every - s, we aim to develop a relevant clinical algorithm of mass data aggregation to improve pards screening with the automatic oi and osi calculation. patients and methods: all the patients admitted to our pediatric icu between may and august were included. the htr and the electronic medical records (emr) were queried through structured query language (sql) following these steps-( ) data selection ( ) extraction to a linear format ( ) date and time synchronization ( ) data pivoting ( ) aggregation through a -min moving average ( ) hypoxemia calculation. statistical analysis included proportions, correlations and bland-altman analysis. results: between may and august , patients ( stays) were admitted to the picu. approximately million rows were retrieved from the databases including , pao values. the algorithm was able to calculate , ( % of the pao ) oi and osi. the comparison between oi and osi showed that . % of the results were between the limits of agreements (− . + . ), a bias of − . and a correlation r = . . the comparison between the ois from the htr and emr databases showed that . % of the results were between the limits of agreements (− . + . ), a bias of − . and r = . . conclusion: using a mass data aggregation algorithm on a htr database allows more pao to be used to calculate an oi than the usual emr. the oi results differ slightly between the htr and the emr. the accuracy is probably in favor of the htr because of the shorter timelapse between the oi parameters. the osi is possibly a biased oi surrogate and should be interpreted with caution. our next step will be to measure the impact of the algorithm on the pards real-time diagnosis and pards severity categories. introduction: early administration of appropriate antibiotic therapy with adequate concentration is the cornerstone of the severe sepsis and septic shock's treatment. adult studies showed alteration of distribution and elimination which can lead to insufficient drug concentration in septic patients. in children, studies are lacking and antibiotic dosing may be suboptimal. we aim to describe the plasma concentration of the most used beta-lactam in critically ill children, to describe the rate of patients with suboptimal exposure and associating clinical and biological factors. patients and methods: this was a prospective, single center, observational study designed in beds pediatric intensive care unit (picu) and high dependency care at the necker hospital (paris, france) from january to may . were included, children with severe sepsis or septic shock, aged less than years and weighing more than . kg, and receiving one or more of the following antibiotics-amoxicillin, cefotaxime, cefazolin, ceftazidime, piperacillin-tazobactam, meropenem and imipenem for suspected or proven infection. betalactam plasma concentrations were analysed using high performance liquid chromatography. results: we enrolled children (severe sepsis, n = ( . %) + septic shock, n = ( . %)) with a median age of months ( - . bacteria were identified in patients ( . %). a total of blood samples were analysed at a median of days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) following the onset of sepsis. twenty-four patients ( . %) had insufficient concentration (cefotaxime ( %) + piperacillin-tazobactam, ( %) + amoxicillin ( %) + meropenem ( %), cefazoline ( %), imipenem ( %) + ceftazidime ( %)). insufficient concentrations were associated with early measurements (< h from the sepsis' onset) (p = . ) and creatinine clearance increase (p = . ). adequate concentrations were associated with small age (p = . ). in conclusion, current standard beta-lactam dosing in children with severe sepsis or septic shock could be inadequate to reach the target concentrations. that could lead to the risk of clinical and bacteriological failures as well as the emergence of bacterial resistance. further pharmacokinetic studies are mandatory to improve antibiotic therapy in this vulnerable population. introduction: intermittent hemodialysis is a key support therapy in icu. despite protocol-based optimization, intradialytic hemodynamic instability (ihi) remains a common complication and could account for mortality and delayed renal recovery. the identification of patients at high risk for ihi is crucial but remains poorly explored. our objective was to test whether tissue perfusion parameters assessed at the bedside (mottling, index capillary refill time (icrt), and lactate) predict ihi and to develop and to validate a predictive score of ihi. patients and methods: prospective observational study in a -bed medical icu in a tertiary university hospital including hemodialysis sessions performed for acute kidney injury. exclusion criteria were patients with dark skin and dialysis performed in extreme emergency. mean arterial pressure (map), mottling score, icrt, and lactate were recorded just before starting hemodialysis. first episode of ihi requiring therapeutic intervention was recorded , , and min after hemodialysis starting. results: ninety-six hemodialysis sessions performed in patients were recorded. half of the patients received vasopressors (n = , %). ihi occurred in ( %) sessions and was more frequent among patients receiving vasopressors ( vs %, p < . ). mottling were more frequent ( vs %, p = . ), lactate levels higher ( . [ . - . ] vs . [ . - . ] mmol l, p < . ) and icrt longer ( . [ . - . ] vs . [ . - . ] s, p < . ) before sessions with ihi compared to sessions without, independently of map (p < . ). the incidence of ihi increased with the number of tissue perfusion alterations ( , , , and % for , , , and alterations, respectively, p < . ). a tissue hypoperfusion score, defined as icrt (seconds) + lactate level (mmol l) + if mottling presence was predictive of ihi independently of map (or . [ . - . introduction: epidemiological data suggest an increased risk of longterm chronic kidney disease after acute kidney injury (aki). in survivors of out-of-hospital cardiac arrest (ohca), aki is frequent and is associated with numerous factors of definitive renal injury. we made the hypothesis that aki after ohca was a strong risk factor of long-term chronic kidney disease (ckd). we aimed to evaluate renal outcome of ohca survivors according the occurrence of aki in icu. patients and methods: we used the cohort of consecutive ohca patients admitted between and in a tertiary medical icu previously described (geri et al. icm. ) . aki was defined by kidney disease improving global outcomes (kdigo) criteria. long-term creatinine level was the last blood creatinine assessment we were able to retrieve. the main outcome was the occurrence of ckd, defined by an estimated glomerular filtration rate (egfr) lower than ml min . m according to the mdrd equation. long-term mortality was evaluated as well. factors associated with ckd occurrence were evaluated by competing risk survival analysis (fine gray and cox cause specific models providing sub-hazard ratio (shr) and cox sub-hazard (csh)). results: among the ohca patients who were discharged alive, we were able to retrieve the outcome of patients (median age [iqr , ] , . % of male) who were included in the analysis. during a median follow-up time of . [ . - . ] years, ckd occurred in ( . %) patients and ( %) patients died. a previous history of arterial hypertension (shr = . [ . + . ], p = . + csh = . [ . + . ], p = . ), aki during icu stay (shr = . [ . + . ], p = . + csh = . [ . + . ] , p = . ) and an age higher than (shr = . [ . + . ] , p = . + csh = . [ . + . ], p = . ) were independently associated with ckd occurrence. aki was not associated with long-term mortality (shr = . [ . + . ], p = . + csh = . [ . + . ], p = . ). in ohca survivors resuscitated from an ohca, ckd was a frequent long-term complication. aki during icu stay was a strong determinant of long-term ckd occurrence. introduction: many critically ill patients have a moderate to high risk of bleeding but they also require prolonged intermittent dialysis to ensure a negative water balance without hemodynamic adverse events. thus, a heparin-free easy-to-use anticoagulation within the dialysis circuit is needed but, to date, usual protocols (iterative saline flushes, heparin grafted membranes) lead to - % of premature clotting and sessions that last greater than min are rarely achievable. we assessed the safety and efficiency of heparin-free regional citrate anticoagulation of the dialysis circuit using a calcium-free citrate-containing dialysate, with calcium reinjected according to ionic dialysance (an online measure of the instantaneous clearance of small molecules available in most of dialyzers). patients and methods: we prospectively reported the clotting events that occurred during all the heparin-free dialysis sessions that were performed with a regional anticoagulation based on calcium-zero citrate-containing dialysate (citrasate, hemotech, france) between january and august in a -beds icu. results: a total of dialysis sessions were performed in patients (mechanical ventilation n = + norepinephrine n = ). median duration of dialysis was min (iqr, - + maximum min), and median ultrafiltration volume was l (iqr . - . ). when assessed, urea and beta -microglobulin reduction rates were . % ± . % and % ± . %, respectively. postfilter ionized calcium was . ± . and . ± . mmol l at and h, respectively, within the extracorporeal circuit. a major clotting event that led to premature termination of the session occurred in only sessions ( . %) . in these five cases, major catheter dysfunction occurred before clotting within the circuit. prefilter ionized calcium remained within narrow ranges (before after change + . ± . mmol l), and total-to-ionized calcium ratio, a surrogate marker for citratemia, was unchanged and always below . . in sessions, no ionized calcium measurement was required. conclusion: dialysis anticoagulation with calcium-free citrate containing dialysate is an easy-to-use, efficient, and inexpensive form of heparin-free regional anticoagulation. calcium reinjection according to ionic dialysance allows prolonged hemodialysis sessions in critically ill patients without the need to systemically monitor ionized calcium. sessions can be safely extended according to the hemodynamic tolerance to ensure an adequate dose of dialysis and a negative water balance, a major point in patients with severe aki. introduction: brain injury is the first cause of death after cardiac arrest (ca) and multimodal neuroprognostication is a cornerstone of postresuscitation care. among the different usable information provide by electroencephalogram (eeg), the aim of this study was to evaluate the predictive value of eeg reactivity regarding neurological outcome at discharge. patients and methods: using our prospective registry of successfully resuscitated patients admitted to a cardiac arrest center between january and , we studied all consecutive comatose patients still alive at h and in whom at least one eeg was performed during coma. in addition to usual clinical findings, we collected eeg (patterns and reactivity, status epilepticus) and somatosensory evoked potentials characteristics. the eeg reactivity was evaluated by a blinded neurophysiologist and was defined as a reproducible change of the tracing (in amplitude or frequency) provoked by an auditory and a nociceptive standardized stimulation. we evaluated the predictive values of persistent lack eeg reactivity and other indicators regarding their respective ability to predict a favorable or unfavorable outcome. recovery of a level or on the cerebral performance category (cpc) scale at discharge was considered as a favorable outcome, as opposed to recovery of a cpc level - (unfavorable outcome). we included patients who were mostly male ( %), with median age of years. ca occurred in a public place in % of cases, and it was witnessed in % of cases. bystander cpr was initiated in % patients and the initial cardiac rhythm was shockable in % patients. median time to eeg was days ( - ) and % of patients were still sedated during the examination. a favorable neurologic outcome was observed in patients ( %). an eeg reactivity was present in patients ( %) with favorable outcome and in patients ( %) with unfavorable outcome. the positive predictive value (ppv) of a persistent eeg reactivity for prediction of favorable outcome was % . by contrast, the ppv of lost eeg reactivity for prediction of unfavorable outcome was % (ic % - ) with a false positive rate (frp) of . % ( . - . ). eeg electroencephalogram, ssep short-latency somatosensory evoked potentials, ppv positive predictive value, npv negative predictive value, fpr false positive rate in this population of post-cardiac arrest patients, the presence of eeg reactivity was poorly predictive of a favorable neurologic outcome. the absence of reactivity was highly predictive of unfavorable outcome. in combination with other indicators, searching for eeg reactivity may have important implications in the neuroprognostication process. conclusion: this subgroup analyses of a randomized controlled trial, found no survival benefit when comparing crystalloids to colloids in critically ill surgical patients. introduction: goal of a fluid challenge (fc) is in fine to increase the stroke volume (sv) or the cardiac index (ci) when an episode of hypovolemia or a preload dependence status are suspected. fc is one of the most common practices in icus, however, the way to assess the response to fc is not standardized. the present study aimed to evaluate whether the trans-thoracic echocardiographic (tte) assessment of the response to fc immediately at the end of the infusion or delayed min later could affect the results of the fc. patients and methods: prospective, observational, multicentre study including all icu patients in septic shock requiring a fc. were excluded patients with-arrhythmias, poor echogenicity and severe mitral or aortic regurgitation. fc was performed administering ml of crystalloids over min. fluid responsiveness was defined as a > % increase in stroke volume (sv). the following echocardiographic parameters were recorded-e wave, a wave, e a ratio, velocity-time integral (vti), ea wave and sa wave. map, hr and tte variables were collected at baseline (t ), at the end of fluid challenge (t ) and (t ) and min (t ) after the end of fluid challenge. quantitative data are expressed as mean and standard deviation (sd) or median and interquartile (iqr), according to their distribution. qualitative data are expressed as absolute number and frequency (%). results: from may th to january th , a total of patients were enrolled in french icus (mean age- ± years, median igs ii- , median sofa score- [ ] [ ] [ ] [ ] [ ] ). among the ( %) patients responders to fc at t , patients were transient responders (tr), i.e. became non-responders at t ( %, % ci = [ - ]) and ( %, % ci = [ - ])) patients were persistent responders (pr), i.e. remained responders at t . among the non-responders (nr) at t , became responders at t , ( %, % ci = [ . - . ] ). in the subgroup analysis, no statistical difference in haemodynamic and echocardiographic parameters was found between non-responders, transient responders and persistent responders (fig. ) . conclusion: the present study shows that, after a % vti increase at the end of the fc, vti returns to baseline at min in half of the responders. blood volume status (normo or hypovolemia) before initiating the fluid infusion could explain the transient or persistent response to fc observed in septic patients. mottling score is a strong predictor of day- mortality in sepsis patients independently of catecholamine dosing and other tissue hypoperfusion parameters dumas guillaume , joffre jérémie , hariri geoffroy , bigé naike , baudel introduction: sepsis is a frequent critical condition. mottling score, an hypoperfusion parameter, is well correlated with outcome. however, uncertainties persist regarding its value not only as a marker of patient severity but also as an independent predictor of mortality and treatment efficacy. we performed a post hoc analysis of four published prospective studies including sepsis patients with or without shock. we analyzed the relationship between the mottling score (from to ) and day- mortality according to other prognosis covariates such as catecholamine dosing, urine output and plasma lactate levels. first, factors associated with outcome were determined by multivariate analysis. second, mottling score-by-covariate interaction was studied to better understand its effect on mortality. finally, effect of mottling score variation at different time point (h -h -h -h ) was assessed. whereas ecmo was successfully weaned in ( %) patients. proportion of perfused vessel (ppv), perfused vessel density (pvd), micro flow index (mfi) and heterogeneity index (hi) were severely impaired before ecmo. re-establishing high and stable peripheral blood flow with va-ecmo led to a rapid decrease in heart rate and vasoactive inotropic support and significantly improved all microcirculation parameters within h. total vessel density and pvd, measured before and after ecmo initiation, were better in patients successfully weaned from ecmo (p < . ) (fig. ) . conclusion: cardiovascular support with ecmo-va rapidly improved macro and microcirculation in refractory cardiogenic shock patients. total vessel density and perfused vessel density were significantly better in survivors h after ecmo initiation and might therefore help to predict outcomes. further studies are now needed to better define the utility of this technology in larger groups of va-ecmo patients. introduction: thyroid storm is a rare but life-threatening disease related to thyrotoxicosis. it can lead to multiple organ failure including cardiovascular disorders or neurological impairment. to date, data on this disease in icu patients are scarce and limited to case reports. we therefore aimed to describe clinical presentation, outcomes and management of thyroid storm in icu patients. patients and methods: local diagnoses coding database (from january to july ) from french icu were interrogated for main and secondary diagnoses codes including thyrotoxicosis based on the international classification of disease th revision. thereafter two investigators reviewed all the medical records selected. inclusion criteria were thyroid storm based on the diagnostic criteria of the japan thyroid association (t. satoh, endocrine journal ). it combines thyrotoxicosis with elevated levels of free triiodothyronine (ft ) or free thyroxine (ft ) with at least two of the following symptoms-central nervous system manifestation, fever, tachycardia > bpm, congestive heart failure, or total bilirubin level more than micromol/l. clinical presentation, therapy used, and outcome were recorded. results: sixty-two patients (median age years (interquartile range - ) + saps ii ( - ) were included. thyroid storm was the first manifestation of thyrotoxicosis in ( %) patients. graves' disease ( %), amiodarone induced thyroiditis ( %), autoimmune thyroiditis ( %), and toxic multinodular goitre ( %) were the main causes of hyperthyroidism. amiodarone, thyroid hormone toxicity, antithyroid drugs withdrawal or infectious trigger were identified in ( %) patients. organ support including mechanical ventilation, catecholamine infusion, renal replacement therapy and veno-arterial ecmo were used in , , , and patients, respectively. main thyroid storm treatments included antithyroid drugs ( %), betablockers ( %), corticosteroids ( %), and plasmapheresis ( %). lastly, icumortality was %, with multiple organ failure responsible of death in all patients. although its incidence appears low, icu physicians should be aware of the multiple clinical features of thyroid storm. our preliminary data reported various specific therapeutic management of this potentially fatal disease. prompt initiation of targeted therapies is required for atypical hemolytic uremic syndrome (ahus) and thrombotic thrombocytopenic purpura (ttp), but no specific therapy is consensual for shiga toxinassociated hemolytic uremic syndrome (stec-hus). thus, rapid differentiation of stec-hus is mandatory to tailor the initial treatment. furthermore, apart from large outbreaks, characteristic features of this syndrome in adults have not been described. in this study, we retrospectively compared the characteristics of stec-hus, ahus and ttp patients at admission in two expert icus. patient were included if they presented with the triad of mechanical hemolytic anemia, thrombocytopenia and organ damage, and tmas were classified using international criteria. other causes than stec-hus, ahus and ttp were excluded. results: amongst tmas admitted between september and january , stec-hus, ahus and ttp were included. stec-hus patients were older ( ) than ahus ( , p = . ) and ttp patients ( , p < . ). they presented with more frequent digestive symptoms ( versus and % for ahus and ttp, p = . and < . ), but bloody diarrhea was rare ( %) and non-statistically different from other tmas. confusion was more frequent in stec-hus ( %) than ahus patients ( %, p = . ). biologically, stec-hus patients displayed elevated fibrinogen levels ( . vs . and . for a hus and ttp, both p < . ) and severe renal failure. forty-two percent required renal replacement therapy and % were treated with plasma exchange before the distinction from other tmas could be made. only ( %) stec-hus patient died in the icu (fig. ) . conclusion: characteristics supposed to identify stec-hus are largely shared with other tmas. in particular, the differential diagnosis between ahus and stec-hus appears to be more difficult than the stereotypical description derived from pediatric studies. severe hyperglycemia in icu patients: a higher mortality rate and a higher incidence of diabetes in a long-term follow-up study . ], p = . ) but not when admitted for coma, sepsis or cardiac arrest. mortality rate was significantly higher in patients with severe hyperglycemia compared to those without, regardless of preexisting diabetes (hnd hd vs. nhnd nhd groups + p < . ). patients with severe hyperglycemia had a higher incidence of type diabetes at ( vs. % + p = . ) and months ( vs. % + p = . ) compared to those who did not. conclusion: severe hyperglycemia occurring in the first days of icu admission was associated with higher mortality rate and an increased risk of diabetes in the following months regardless of preexisting diabetes. introduction: vitamin d deficiency is frequent in northwestern countries and could represent a modifiable risk factor for critically ill patients, in relation with its pleiotropic effects ( ) . some studies reported an association between oh vitamin d ( oh) deficiency, chronic health status and icu-and hospital-related outcomes. however, a large supplementation study have not been found to improve outcome of patients with moderate oh deficiency (< ng ml) ( ) . the aim of the study is to analyze the relationship between the severity of oh deficiency at icu admission, severity of illness and outcomes and ultimately to identify subgroups of patients in whom the likelihood of benefit of supplementation is larger. patients and methods: consecutive patients admitted over a -month period who stayed at least h in a medical surgical -bed icu were included. in these patients, demographic data, charlson comorbidity score, severity scores (saps and sofa) and -oh (chemiluminescence, diasorin) were collected at admission. icu and hospital length of stay (los) and mortality were recorded. correlations were searched between oh and the different scores, and vital outcomes ( - )). hypothyroidism was unknown before icu admission in % patients. median sofa score at icu admission was ( - ). myxedema coma, circulatory failure, respiratory failure, and severe hypothermia were respectively the main admission reason in , , , and % patients. a precipitating factor such as drugs thyroid toxicity, thyroid hormone withdrawal or infection was found out in only ( %) patients. main causes of hypothyroidism were thyroiditis and thyroidectomy. thirtytwo ( %) patients had alteration of consciousness with a median glasgow score at ( - ). in addition, median heart rate at icu admission was ( - ) bpm while hypothermia < °c was noted in ( %) patients. median tsh level at admission was ( - ) mui l, t and t levels respectively ( - . ) pmol l and ( - . ) pmol l. rhabdomyolysis was frequent with median cpk level ( - ) ui l. organ support including mechanical ventilation, catecholamine infusion and, renal replacement therapy were respectively used in , , and % patients. lastly, % patients received oral levothyroxine whereas the intravenous form was used in others. overall icumortality was %. our preliminary data showed that severe manifestations of hypothyroidism leading to icu admission represent de novo hypothyroidism in two-thirds of patients, leading to a high mortality. introduction: when it comes to infections of the central nervous system (cns), the greatest challenge in the emergency department (ed) is to identify patients that have a rare life-threatening diagnosis. alone or in combination, fever, headache, altered mental status encompass a broad differential diagnosis. antibiotics or antiviral therapy should be given as soon as possible, ideally after both blood and cerebrospinal fluid (csf) have been obtained. early treatment is associated with a lower mortality. patients and methods: we present here, a four-year ( - ) retrospective and monocentric study. during the period of the study, we included all adult patients with the diagnosis of cns infection (positive csf culture). we collected and analyzed all clinical, biological, imaging, treatments and evolution datas during the stay. a total of patients with cns infection have been included for statistical analysis. we analyzed a second group (n = ) with suspected cns infection (negative csf) as a control group. results: in the study population, mean age was ± . years old and the sex-ratio was . . there were no difference between the two groups in terms of clinical signs except for more altered mental status in the control group (p = . ). all patients of the study (n = ) benefited of lumbar puncture (lp) in the ed with an average time of ± min after admission. this delay was the same between the two groups (p = . ) but was significantly higher in the encephalitis subgroup (n = , p = . ). patients who had imaging (ct or mri) during the ed stay had more likely a delay in lp realization ( vs min, p = . ). patients where the cns infection diagnosis was firstly evoke by the triage nurse had lp more quickly (p = . ). the median door to-antibiotic-time was min with no difference between the two groups of the study (p = . ). % of all patients were hospitalized for an average length of stay of . ± . days and % of them were admitted in the icu. the inhospital mortality was % in the study population. introduction: there are numerous causes of acute exacerbations of copd (aecopd), the most common of which are bronchial and or pulmonary infections. viral etiologies may account for % of aecopd, but this rate is likely underestimated because of the limited performance of the conventional diagnostic tests. multiplex molecular diagnostic tests may identify several pathogens including viruses and bacteria, from a single respiratory tract sample, with high sensitivity. using these tests, respiratory viruses are identified in to % of cases, according to the series. the objective of this work was to describe the microbial epidemiology, the management and the outcome of patients admitted to the intensive care unit (icu) with moderate to severe aecopd, in the era of multiplex testing. a prospective non interventional multicenter study conducted in two university-teaching hospitals. in addition to the usual samplings, a nasopharyngeal swab was performed for multiplex polymerase chain reaction (pcr), using respiratory panels fil-marray biomérieux ( viruses and bacteria) or eplex automaton ( viruses and bacteria) depending on the center. the preliminary results involve the patients ( males + years ( - )) included in tenon hospital over a -month period. the mean fev was % ( - ) median % [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . drug therapies included anticholinergics (n = + %) and beta- -mimetics (n = + %), inhaled (n = + %) or oral (n = + %) steroids, and azithromycin (n = + %). a respiratory virus was identified in patients ( %), alone or in combination with a bacterium (n = ). a bacterial pathogen was identified alone times ( %). therapeutic interventions did not differ depending on whether a virus was detected or not-exposure to antibiotics ( ± . vs. . ± d + p = . ), administration of oseltamivir ( / vs. / + p = . ), steroids ( / vs. / + p = . ) and mechanical ventilation ( / vs. / + p = . ). the icu length of stay ( . ± . vs. . ± . d + p = . ) was similar. the icu and d-mortality rates were . and . %, respectively. conclusion: respiratory viruses are frequently involved in moderate to severe aecopd. the respiratory multiplex pcr should be performed in this setting and the results should be taken into account to more adequately use the anti-microbial treatments. introduction: prophylactic non-invasive ventilation (niv) is a well established method for prevention of post-extubation acute respiratory failure in hypercapnic patients. however, its role in the postextubation period, in traumatic brain injury patients, is uncertain. especially, because of effects of the brain injury, on respiration and airway control. we perform a study to assess the impact of prophylactic niv after extubation among patients with severe traumatic brain injury. patients and methods: over a period of year, adult patients with isolated severe traumatic brain injury, who were under invasive mechanical ventilation for more than h were eligible for inclusion in the study. they were randomized, after decision of extubation, to receive conventional therapy or conventional therapy associated with niv. conventional therapy consisted of oxygen delivery by facial mask, semi-recumbent position, mucus suctioning and nebulization therapy. the main objective of the study is to assess the impact on reintubation rate. extubation succes was defined by the absence of need for reintubation within the days. the secondary objective is to evaluate the effect on icu length of stay after extubation. the clinical benefit of non-invasive ventilation (niv) in patients with acute hypoxemic respiratory failure (arf) is being called into question. indeed, in a multicenter randomized trial recently conducted in hypoxemic arf patients (pa fi < ), intubation rate in the niv group was % and intensive care unit (icu) mortality rate was %, numbers higher than in the standard-oxygen group ( ) . an excessive tidal volume under niv is a hypothesis to explain these bad outcomes ( ) . our experience does not seem to support these data. therefore we wanted to-investigate the rate of niv success in hypoxemic arf and global in-icu mortality. estimate the average expired tidal volume and identify predictive factors of niv failure. conclusion: though limited by its design, our study seems to show a similar efficacy of niv following ue as compared to planned extubation, with a safety concern for rescue niv and a potential interest for "prophylactic" niv. further data is warranted. which is yet operator dependent and time-consuming, or by invasive methods including esophageal pressure or diaphragmatic electromyogram measurements. the main purpose of this study was to assess the relevance of curvex as a noninvasive diagnostic and classification tool for asynchronism management. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record consecutive icu patients, over -years. all consecutive patients were recorded for a -hours period during -h following icu admission. all measurements were recorded with the patient laying supine, with a ° bed angulation. raw ventilatory pressure and flow curves were transferred to a centralized server using a dedicated network. the physician in charge of the study was informed of the online analysis on a routine basis. physiological recordings were associated with metadata collection. asynchronisms detection is based on a non-parametric hypothesis testing (random distortion testing), that requires no prior information on the signal distribution. beside asynchrony index monitoring (ai), five asynchronism's types were qualified-ineffective efforts (ie), short cycles (sc), multiple cycles (mc), prolonged inspiration (pi) and premature cycling (pc introduction: international guidelines recommend ultrasound (us) guidance for central venous catheter (cvc) insertion. however, evidence is lacking for several aspects of guidance such as probe shape or whether the needle has to be in plane (ip) or out-of-plane (oop). we assessed these issues in a randomized trial. success at first pass, number of attempts (needle passes), success, times between skin contact and needle skin penetration and between needle skin penetration and liquid back flow in the syringe were recorded. qualitative and quantitative values are expressed as number (percentage), and median (range), and were compared using the wilcoxon matched pairs test and the fisher exact test, respectively. results: for ijv puncture, first attempt success rate was more than % and was neither influenced by probe shape nor approach (table ) . conversely for rav puncture, using lp with ip approach was more frequently successful at first attempt ( vs %, p = . ). time elapsed between needle skin penetration and liquid back flow was shorter for rav puncture using ip approach ( s vs s, p = . ). time elapsed between probe appliance on skin and liquid back flow was significantly shorter with the linear probe for ijv whatever the approach and for rav using ip approach. rav puncture was more frequently impossible with mcp ( vs %, p = . ). arterial puncture occurred more frequently with mcp ( vs %, p = . ). lp use and ip approach were associated with more free event puncture ( ± ) . minimal ani, reflecting intense stress was . (± . ). objective and subjective stress of each team leader is shown in fig. . there was a significant negative linear correlation between minimal ani and maximal hr (rho = − . , p = . ). there was no significant correlation between self-reported stress vas (neither pre hfs or maximal stress) and minimal ani. conclusion: hrv monitoring is a feasible method to evaluate continuous physiological stress for team leaders in highly stressful simulationteaching. upgrading signal connection by bluetooth . or wi-fi could improve the method. focusing on specific stressful time points might improve stress assessment and its correlation with performance. introduction: simulation training has become available in health sciences faculties and proposed in many specialties. intensive care is one of the fields of development of simulation based training. the aim of the present study was to report the experience of the faculty of medicine of monastir simulation center in training medical students and residents in intensive care and to compare their respective perceptions. this was a descriptive study including students ( th year of the medical curriculum) and residents who received training during the last academic year ( ) ( ) , in the simulation center during their icu traineeship. simulation training was based on high-fidelity mannequins for students and seminars with high fidelity and procedural simulation training for residents. three sessions per group were organized for students and a total of five sessions for residents. we collected participant characteristics and used likert scale (from to ) to assess participant satisfaction, simulation fidelity, impact on clinical practice, stress level and instructor behaviors. chi test was used to compare students' and residents' perception of the simulation based-training. results: during the study period students (of the students' whole promotion) and residents actively participated at least in one of the simulation-based training sessions. median students' and residents' ages were respectively years ( - ) and years ( introduction: hospitals are encouraged to edit local antibiotic therapy guidelines. antibiogarde ® is an electronic antibiotic prescription referential developed by a multidisciplinary team of french physicians, regularly updated, and locally customizable, which has been purchased by more than french hospitals. we compared adequacy fig. team leader's objective (heart rate and ani) and subjective stress (declared vas stress) of initial antibiotic prescription by icu clinicians, antibiogarde ® proposal and national or international guidelines. patients and methods: between january and june , initial antibiotic prescriptions in an icu were retrospectively analyzed when microbiologically documented. antibiogarde ® and guidelines proposals were simulated, considering data available at the time of initial prescription. adequacy was defined when all bacteria responsible for infection were sensitive to at least one prescribed proposed antibiotic. national guidelines were used when published after . otherwise, most recent international guidelines were used. results: initial prescriptions were analyzed ( monotherapy) in patients (median age y, median saps ii , median sofa on prescription , icu mortality %, % immunocompromised). main sources of infection were lung (n = ) and intra-abdominal (n = ). leading isolated bacteria were enterobacteriaceae (n = , antibiotic resistance in ), streptococci (n = ), non-fermenting gram negative bacilli (n = , antibiotic resistance in ) and staphylococci (n = , resistance to methicillin in ). in the clinical settings analyzed, there was a proposal by antiogarde ® in ( %) and a guideline available in ( %) (p = . introduction: intubation is plagued with a high morbimortality, especially in emergency situations. it is now acknowledged that a seated position allows for optimized preoxygenation ( ) . however, there is no guideline concerning the patient's position for intubation. the patient is most often laid in a supine position, leading to a higher risk of aspiration ( ) . face-to-face intubation in sitting position (ftfi) would allow for an easier intubation and a lower morbidity. we focused on learning the ftfi technique using the macintosh laryngoscope and the airtraq videolaryngoscope in simulated difficult intubation situation and comparing the performance of the ftfi with the classic technique. the participants would intubate a high-fidelity manikin (simman g, leardal, norway) configured with a tongue edema (cormack b- ). for each trial, time to intubate (tti), success and complication rate, intubation difficulty and glottis exposure were noted. in classic position, three trials were performed with the airtraq followed by the laryngoscope in order to obtain baseline parameters. in ftfi, at least intubations were performed by each participant for each device. the utilization order was randomized. results: thirty physicians, with an experience of at least intubations each, were included. figure shows the learning curves of the ftfi based on the evolution of the tti measured for the airtraq and the laryngoscope. in classic position, the mean tti with the airtraq was . ± . s versus . ± . s with the laryngoscope (p = ns). in ftfi, once the technique mastered, the tti was ± . s with the airtraq versus . ± . s with the laryngoscope (p < . ). success rate, tti, complication rate, intubation difficulty and glottis exposure were better using ftfi versus classic intubation (p < . ). these parameters were even better with the airtraq than with the laryngoscope (p < . ). the learning profile of ftfi is different between the airtraq and the laryngoscope. it could be due to the participants' lesser familiarity with the airtraq. the better performances in ftfi could be due to better ergonomics allowing easier glottis exposure and learning ( ) . conclusion: face-to-face intubation in sitting position is easy to learn. it provides better performances and fewer complications than the classic intubation technique which might result in a lower morbidity. the airtraq provides even better results than macintosh laryngoscope. all participants recommend their colleagues to be trained in face-toface intubation. among non-invasive respiratory support, niv with bilevel pressure was the most frequent (n = , %) before cpap (n = , %) and high flow oxygen (n = , %). the proportion of patients on niv was up to % in the centres hosting more acs patients. conclusion: despite the absence of evidence from randomized controlled trials niv is nowadays commonly used in picu and hdu for scd patients with acs, especially in centres taking in charge a high number of scd patients. future physiological studies and randomized controlled trials might help to choose between the different ventilatory support options for acs. in transfused patients, the pre-transfusion hemoglobin was . ( . - . ) g dl in moderate pards and . ( . - . ) g dl in severe pards. the evolution of hemoglobin, osi, scvo and lactate after the transfusion is reported in the table . in our picu, a relatively restrictive policy of rbc transfusion was observed even in patients with severe pards. decision to transfuse seemed associated with the general severity status of the patient and with the hemoglobin level. further studies are needed to explore the generalizability of these findings, and to investigate the impact of transfusion on oxygen transport consumption balance in pediatric acute respiratory distress. introduction: pharmacokinetic parameters are altered in critically ill patients. for instance, in adult patients, it has been well demonstrated that augmented renal clearance results in subtherapeutic antibiotic concentrations. our objectives were to build a pediatric population pharmacokinetic model for piperacillin, in order to optimize individual dosing regimen. patients and methods: all children admitted in pediatric intensive care unit, aged less than years, weighing more than . kg, and receiving intermittent piperacillin infusions were included. piperacillin was quantified by high performance liquid chromatography. pharmacokinetics were described using the non-linear mixed effect modelling software monolix. monte carlo simulations were used to optimize dosing regimen, in order to maintain plasma concentration above the minimum inhibitory concentration ( mg l − for pseudomonas aeruginosa) throughout the dosing interval ( % ft > mic). results: we included children with a median (range) post natal age of . ( . - . ) months, median (range) body weight of . ( . - ) kg, median (range) pelod- score of ( - ) and median (range) estimated creatinine clearance of ( - ) ml.min - .m - . a one compartment model with first-order elimination adequately described the data. median (range) values for piperacillin clearance and volume of distribution were respectively ( . - ) l h − and . ( . - . ) l. body weight (allometric relationship), estimated creatinine clearance and pelod- severity score were the covariates explaining the estimated between subject variability. a third of the cohort attained the target, according to our dosing regimen and to the european guidelines. to reach the target and according to the simulated dosing regimens, children with acute kidney injury should receive intermittent infusion every h, administered on min. those with augmented renal clearance should receive a continuous infusion. to reach the target, standard intermittent piperacillin dosing regimen in critically ill children is not appropriate. in addition to body weight, dosing regimens should take into account the creatinine clearance. continuous infusion is adequate for children with augmented renal clearance. piperacillin individualized dosing regimens and therapeutic drug monitoring are mandatory in pediatric intensive care unit. introduction: all data support the need for early recognition, evaluation of pain in the nicu. multiparametric analysis including physiological parameters could be useful to have a more objective evaluation of pain in the nicu compared to scales built on external-evaluation. the newborn infant parasympathetic evaluation (nipe ® ) was developed to assess pain in newborns and infant, from preterm to the age of years. patients and methods: we conducted a monocentric, prospective study to compare the instantaneous nipe ® index value (nipei ® ) to the dan scale during acute procedural pain (picc line insertion) in preterm infants (under gw). the operators and the nurse were blinded to the continuous recording of nipei ® during the entire procedure. dan scale was assessed every min by a third person, trained to this scale and blinded to nipei ® . a direct correlation assessment between the dan scale and the nipei ® was performed by calculating the pearson's linear correlation coefficient. the differences between the nipei ® of non-painful (dan < ) and painful (dan ≥ ) infants were estimated by the wilcoxon-mann-whitney test. the usefulness of nipei ® as a new tool for pain assessment in neonates was estimated by the corresponding roc curve. our study was approved by our local ethic institutional review board. results: thirty-five preterm infants were included, nipei ® data were incomplete in infants. fifty percent of newborns were born before gw, and % had non-invasive respiratory support (continuous positive airway pressure cpap). at the time of the procedure, newborns had a median post-natal age of days and a median weight of grams. there was a moderate correlation between the nipei ® index and the dan scores (r = . + p < . ). the median nipei ® index was for non-painful events vs. for painful events, p < . . the area under the roc curve was . . for a threshold of nipei ® < , the sensitivity was . %, the specificity was %. positive likelihood ratio was . and the negative likelihood ratio was . ( fig. ) . we showed a correlation between the dan scale and the nipei ® index for pain assessment in preterm infants. the nipe ® monitor could be a useful and non-invasive tool for pain assessment in neonates. further studies are needed to confirm our results and to define more precisely the place of such monitors for pain evaluation in daily clinical practice in the nicu. introduction: the aim was to identify factors associated with the occurrence of acute pituitary hormone dysfunction in children with moderate to severe tbi and to describe the impact of this dysfunction on the stability of the children. patients and methods: prospective bicenter study including all children aged between month to years, admitted to picu for a moderate-severe tbi and with an expected stay > days. setting-pediatric intensive care units of grenoble and lyon, from to . endocrine explorations at the second morning following admission and h before discharge were performed-cortisol h cycle with free cortisol and acth dosages every h (or h if no central line) + free h urinary cortisol + tsh and t l, h urinary lh and fsh, blood level of testosterone or estradiol for children aged > years, and igf . patients were classified as having cortisol insufficiency if all the cortisol dosages were < nmol l and all acth were < pg l. tsh deficiency was defined as t l < . pmol l and tsh < . mui l. gonadotropin defciency was defined as urinary lh < . ui h and urinary fsh < . ui h for males + urinary lh < . ui h and urinary fsh < . ui h in female. patients with deficiency (acth and any deficiency) were compared to those without deficiency in terms of hemodynamic instability, respiratory instability, neurological and infectious complications for continuous variables means and % confidence interval were calculated and compared by t student test. chi- test was used to compare proportions. results: among the patients evaluated, had acth deficiency, and had at least one acute pituitary dysfunction. comparison of patients who presented acth deficiency with those who were not deficient found no differences in terms of patients characteristics, cause of tbi, level of severity and level of injury. paitents with acth deficiency required more frequently fluid bolus at day ( vs %, p = . ). all the markers of severity were higher and the need of vasoactive drugs were more frequent but the differences were not statistically significant. table shows comparison between patients with at least one pituitary hormone deficiency to those without deficiency. the same result was found. glycemia levels were lower in the group with deficiency. conclusion: we didn't find any predictive factors of pituitary hormone deficiency in children with moderate-severe tbi justifying a systematic screening of those patients. introduction: most intensive care unit (icu) patients cannot make decisions themselves. familiy members are actively involved in the care process as surrogate decision-makers and judges of care quality. however, family satisfaction with care is complex and is not clearly defined. the aim of this study is to evaluate the different procedures (reception book and staff education for aid and relationship) used in a new icu to improve the family care. patients and methods: we included in our study patients who had spent more than h in our department. a questionnairy, adapted to our population, was performed by our staff and validated by the hygiene and quality care departement. we proceded by phone calls, months after the inauguration of our icu. results: sixty-five questionnaires were included (fig. ). the average of age was ± with a sex ratio of . the average of the simplified acute physiology score (sapsii) was ± . the median stay was days [ - ] with a total mortality rate of %. mostly, we interrogated first-degree parents (n = ). only three families recieved reception book at admission. visit in patient room was autorised only for % (n = ) of family members. only four persons said they were disturbed in visit hours for architectural reasons (tight space). disponibility was found excellent in % (n = ) of cases for medical staff, % (n = ) for paramedicals. informations provided by physicians were clear in . % (n = ) of cases. fifteen of the family members ( %) asked psychology support. patients were followed up via phone calls during year after discharge. characteristics on admission and outcomes after discharge were analyzed stratified by ventilation modality niv vs imv. the overall survival was analyzed on the basis of the kaplan-meier curves. results: during the predetermined period of data collection, the follow-up involved patients. patients were treated by niv (group ) and patients needed imv (group ). there was no difference between the groups in age (p = . ), severity of copd (p = . ), physiological reserve at discharge (p = . ) and icu readmission (p = ). short term outcomes were not different between the groups- -month readmission ( . vs % respectively in niv and imv, p = . ) and -month mortality ( introduction: post-intensive care syndrome (pics) has been recently described as a combination of physical, cognitive and mental impairments appearing during a stay in an intensive care unit (icu). the prevention and detection of pics require the participation of each category of healthcare workers. however, the level of knowledge is unknown. we sought to assess the awareness among our icu staff in preparation for a follow-up consultation. the study used a short multiple-choice survey filled on a voluntary basis. all members of the staff were asked to fill the questionnaire over a one-week period. the assessment was composed by seven structured questions which aimed measure basic knowledge of post-intensive care syndrome and general strategies to diagnose that syndrome and the tests used. results: fifth five workers ( % of the staff ) of the department of intensive care answered the questionnaires ( % nurses, % physiotherapists, % physicians). the estimated ranges of prevalence of psychological problems were very low ( - %) for . %, low ( introduction: drafting a death certificate (dc) is a procedure considered as a part of doctor's daily practice, especially in emergency and intensive care departments. this certificate represents a civil, social, epidemiological and medico-legal act. it can engage the liability of the certifying doctor. the objectives of our study were to examine the content of dc drafted in emergency and intensive care departments, assess the quality of writing, and analyze drafting errors. patients and methods: a prospective study extended over a period of months from january to december , including all dc emanating from emergency and intensive care departments and received in the forensic department of habib bourguiba hospital in sfax. results: during the study period, dc meeting the inclusion criteria were collected. although confidential, the medical part of the dc was sealed by the doctor in onlyone third of cases. in the administrative section, nine socio-demographic parameters were studied. in % of the cases, less than four of the nine criteria were found. in the section concerning the certifying doctor data, parameters were screened. . % of the certifying doctors met at least six criteria. the most frequently missing parameter in this section was the identity of the person to whom the certificate was issued. the identity of the doctor was not mentioned in % of the cases. forensic data ( items) was complete in over three quarters of the certificates. nevertheless, in . % of cases, the medicolegal obstacle to burial box was left empty ( . %) or not ticked even if judicial investigation was required ( . %). the section on causes of death was the source of almost all of the drafting errors. we have classified these errors into six major ones, according the classifications reported in the literature. the percentage of certificate without faults was %. the most common major error was insufficient cause of death found in . % of cases followed by incorrect sequence of causes of death ( . %), medicolegal obstacle to burial not ticked although required ( . %), several causes of death mentioned simultaneously ( . %), unacceptable cause of death ( . %) and mechanism of death mentioned instead of the cause of death ( . %). our study showed that the quality of drafting of dc suffered from several insufficiencies, which encourages us to provide more effort in training doctors and to review the current official model of dc. introduction: septic shock is defined as a sepsis with hyperlactaemia greater than mm after correction of hypovolemia requiring vasopressors to maintain mbp > mmhg [ ] . it can be observed in pre-hospital emergency medicine (phem). the use of a reliable portable device for measuring lactate in phem would allow a better evaluation of septic patient facilitating their orientation towards intensive care unit (icu) or emergency department (ed). this portable delocalized biology device must be validated against the laboratory reference method (nfen iso ) [ ] . the aim of this study was to clarify the validity of a delocalized measure of lactatemia. we performed a prospective study including patients admitted into icu for septic shock (cpp number - - sc). lactate was measured in parallel on samples-one capillary with the portable device (lactate statstrip xpress, nova biomedical) and the other venous on a centrifuge tube for plasma analysis (architect c abbott diagnostics). we evaluated the analytical performance (coefficients of variation (cv) for repeatability and reproducibility evaluated at levels of quality control (qc)- . and . mm) and then the concordance between lactate levels measured by the devices and lactate levels measured by laboratory analyzer. results: at the qc concentrations tested, the cvs were in agreement with the limits set by the french society of clinical biology-cv < % for repeatability and < % for reproducibility. an excellent correlation was observed between the measurements-correlation coefficient r = . , slope = . and ordered at the origin = . . the latter suggested a low positive bias of the device not confirmed by bland-altmann graph analysis and graph of the differences. we verified the analytical performance of the device and showed an excellent correlation with the laboratory measurement. the delocalized measure can be used in phem in patients with suspected sepsis syndrome. this measure should allow a more accurate and early assessment of their severity in order to improve triage and hospital orientation between ed and icu. there is an association between mortality at d and hyperoxia in patients admitted in icu for refractory ohca requiring ecpr. these data underline the potential toxicity of high dose of oxygen and suggest that control of oxygen administration in such patients is an important part of the treatment. a value of pao between and mmhg after starting ecpr seems to be a target during treatment of ohca treated by ecpr. introduction: sepsis has been defined as a dysregulated host response to infection leading to life-threatening organ dysfunction (singer m et al., jama ) . a qsofa score relying on simple clinical criteria (respiratory rate, mental status and systolic blood pressure) has been proposed to better identify septic patients with associated higher mortality outside the intensive care unit (seymour cw et al., jama ) . the study aim was to evaluate the ability of qsofa to predict the development of organ failure and increased -day mortality in patients admitted for suspected sepsis in the emergency department (ed). patients and methods: prospective study conducted over a period of months comparing the prevalence of organ failure and -day mortality according to the value of qsofa at admission to the ed between group a (qsofa > = ) and group b (qsofa < ). as part of routine care, an electronic sepsis form was specifically created to identify prospectively and exhaustively all eligible patients on-line. for the purpose of the study, sepsis diagnosis was independently validated off-line by an adjudication committee which included three physicians who reviewed clinical, biological and microbiological data. for each patient, demographic data, source of infection, qsofa and sofa score, biological data and -day mortality were recorded. seventy-six patients of group a ( %) were hospitalized, of whom were admitted to the intensive care unit ( . %), and -day mortality reached . %. in group b, only patients developed an organ failure ( . %) and -day mortality was . % (table ) . the present study confirmed that the qsofa score is a reliable and practical tool to predict the development of organ failure and higher -day mortality in patients with suspected sepsis in the ed. limits of ct scan criteria and intravascular contrast extravasation to define pelvic angioembolization need: a specific assessment on the risk of false- introduction: opening of the mitochondrial permeability transition pore (ptp), triggered by cyclophilin-d (cypd) binding under stress conditions, plays a key role in ischemia-reperfusion injury. we sought to determine, using transgenic mice, whether cypd deletion (cypd −) would improve resuscitability and survival after experimental cardiac arrest (ca). additionally, we compared the protective effects of cypd deficiency with that of targeted temperature management (ttm). patients and methods: anesthetized mice underwent a min asphyxial ca followed by resuscitation (cardiac massage, resumption of ventilation, epinephrine). four groups of animals were studied-sham, control (ctrl), cypd-ca using mice lacking cypd (knockout mice), and ttm-ca with fast hypothermia induced by external cooling at reperfusion ( °c for h). two hours after ca, the following measurements were carried out (n = - group)-echocardiography, cellular damage markers (including s b protein and troponin ic) and mptp opening in mitochondria isolated from brain and heart. additional mice (n = - group) were included in the same groups for survival follow-up ( h and days). results: characteristics of ca were similar among groups. rate of restoration of spontaneous circulation (rosc) was significantly higher in cypd-and ttm groups compared to controls (p < . ). time to rosc was shorter in cypd-versus ttm and ctrl (p < . ). genetic loss of cypd and ttm prevented to a similar extent ca-induced myocardial dysfunction, increase in blood levels of both s b protein and troponin ic (p < . versus ctrl). ca resulted in a significant increase in ptp opening only in mitochondria isolated from brain (p < . versus sham). cypd deletion as well as ttm limited ca-induced ptp opening in brain (p < . versus ctrl). short-term survival ( h) was significantly improved in the cypd-and ttm groups when compared to controls (p < . ). however, only therapeutic hypothermia improved survival at day (p < . versus ctrl). in our murine ca model, genetic loss of cypd increased resuscitability and short-term survival but, unlike therapeutic hypothermia, failed to improve -day survival. introduction: early prediction of neurological outcome of post-anoxic comatose patients after cardiac arrest (ca) is challenging. prognosis of comatose patient relies on multimodal testing-clinical examination, electrophysiological testing and structural neuroimaging (mainly diffusion mri). this prognostication is accurate for predicting poor outcome (i.e. death) but not sensitive for identifying patients with good outcome (i.e. consciousness recovery). resting state functional mri (rs-fmri) is a powerful tool for mapping functional connectivity, especially in patients with low collaboration. several studies showed that rs-fmri can differentiate states of consciousness in chronically brain-damaged patients. a recent study also showed that functional neuroimaging can early detect signs of consciousness in patient with acute traumatic brain injury. however, rs-fmri has not been assessed for the early prognostication of post-anoxic comatose patient. we assessed whole-brain function connectivity (fc) of post-anoxic comatose patients early after ca using rs-fmri. nine patients ultimately recovered consciousness (good outcome) while eight died (poor outcome). we estimated fc for each patient following a procedure previously described. we statistically compared whole-brain fc between good and poor outcome group, to assess which brain connections differed between them. then, we trained a machine-learning classifier (a support vector machine, svm) to automatically predict coma outcome (good poor) based on wholebrain fc of comatose patients. finally, we compared this outcome prognostication based on functional mri to those using standard structural diffusion mri. results: good and poor coma outcome groups were similar in terms of demographics, except for time to rosc. good outcome group showed significant increase in whole-brain fc between most cortical brain regions + with the strongest changes occurring within and between occipital and parietal, temporal and frontal regions ( fig. ). using whole-brain fc and a svm classifier to predict coma outcome yielded to an overall prediction accuracy of . %(auc . ). interestingly, automatic outcome prognostication using functional neuroimaging achieved better results that structural neuroimaging methods like dwi (accuracy . %). conclusion: we used rs-fmri to predict coma outcome in a cohort of post-anoxic comatose patients early after ca. we deliberately chose to include only patients with indeterminate prognosis after standard multimodal testing, to assess the contribution of rs-fmri in the early prognostication of coma outcome. we found that automatic prediction based on functional neuroimaging yielded much better results than current dwi methods, notably for identifying patients who recovered consciousness. outcomes of post-anoxic comatose patients early after ca, using rs-fmri in rcts comparing treatment of severe pneumonia that may influence their ability to demonstrate differences between studied drugs. clinical cure was the most frequently used endpoint but its definition was highly variable. these results are not surprising as far as even guidance from regulatory agencies on how to evaluate hap vap treatments differ. the aim of this work was to reach a consensus on the most appropriate endpoint to consider in future clinical trials evaluating the efficacy of antimicrobial treatment for hap vap, using delphi method. patients and methods: twenty-six international experts from intensive care, infectious disease and from the industry were consulted using delphi method (four successive questionnaires) from january to january . more than % of similar answers to a question were necessary to reach a consensus. results: according to % the experts, clinical cure was the most desirable primary outcome among those found in the literature but two other endpoints were highly rated-all-cause mortality and mechanical ventilation (mv)-free days. consequently, % of the panelists agreed to use a composite endpoints and even a hierarchical composite endpoint to combine these items together in which clinical cure and mv-free days would be assessed at day and clinical cure at day after end of therapy. for vap, mortality was considered as the most clinically significant item by % of the experts, followed by mvfree days and finally clinical cure (fig. ) . for hap, a dual composite endpoint that only included all-cause mortality and clinical cure was chosen ( fig. ). among the various elements of clinical cure definition found in the literature, only three were retained by the experts-resolution at end of therapy of signs and symptoms present at enrolment, no further antimicrobial treatment needed and resolution or lack of progression of radiological signs of pneumonia. finally, we found a consensus on the signs and symptoms that should trigger the suspicion of pneumonia-worsening of gaz exchange, purulent tracheal secretions, hypotension and or vasopressor requirements and fever or hypothermia. we provide here two consensual endpoints (for vap and hap) that would help addressing the efficacy of antimicrobial molecules for hap vap treatment in future clinical trials. (table) . sm-vap were matched with control patients. in univariate analysis, risk factors for sm-vap weremale gender, chronic heart failure, respiratory, cardiovascular and coagulation sofa scores two days before vap, median number of antibiotics used, percentage of time with antibiotics before vap, parenteral nutrition, dialysis, catecholamine use and exposure to ureido-carboxypenicillin, ciprofloxacin, tazobactam or imipenem-meropenem during the week before vap (table) . patients with sm-vap were less likely to receive initial adequate therapy ( vs %, or . , p = . ). there was no statistical difference for icu or d mortality. d mortality was higher for sm-vap (table) . in multivariate analysis, exposure to imipenem-meropenem during the week before vap, respiratory and coagulation sofa scores two days before vap were independent risk factors for sm-vap. sapsii: simplified acute physiology score; sofa: sofa (sequential organ failure assessment); sofa resp: sofa respiratory score; sofa coag: sofa coagulation score; sofa cardio: sofa cardiovascular score conclusion: sm-vap represented . % of vap. we observed no differences in patients characteristics between the groups. imipenem-meropenem use during the week before vap was the most important risk factor for sm-vap. the higher risk of inadequate initial therapy with sm-vap had no impact on d mortality but d mortality was significantly higher. introduction: education of undergraduate students is key to improve hand hygiene (hh) behavioral changes amongst doctors [ . ] . our aim was to evaluate personal feedback using ultraviolet (uv) light inspection cabinets in a years program. our hypothesis was that its use for alcohol hand rub (ahr) application on first year would increase complete ahr application on nd year. patients and methods: this was a simple blind randomized trial comparing hh training with personal feedback using uv cabinet to a control group. on first year, students had access to a theoretical formation then were convened by groups for a demonstration of the correct execution of world health organization's (who) procedure [ ] . before hh training, each group underwent a cluster randomization. in the control group, the student hand rubbed under visual supervision and advises of a trainer. in the intervention group after the same visual assessment, completeness of ahr hand application was recorded under uv light and shown to the student. he was given free access to the uv cabinet to repeat the technique, until perfect application complete under uv light. an enhancement with a scenario-based learning was proposed to both groups. on second year, every student were asked to hand rub with the fluorescent ahr. a supervisor blinded to the group of randomization assessed the quality of the hh procedure visually, the completeness of hand application under uv light and compliance with the who's opportunities for hh during the simulation. results: after randomization students were included in the intervention group and in the control group. on second year, the rate of complete application of the ahr under uv was increased in the intervention group as compared with the control group ( % versus . % p < . ) ( fig. ) despite that visual assessment of hh procedures was similar between the two groups. in a logistic regression model including gender, intercurrent hh formation, intercurrent uv cabinet use, surgical unit traineeship and report of regular use of ahr, the hazard ratio for the intervention was . (ic . - . ). the rate of perfect compliance with the hh opportunities in the intervention group was increased ( . % versus . % p < . ) and the effect persisted in the logistic regression. conclusion: uv cabinets for undergraduate students' hh education improve the technique and the compliance with hh opportunities. included in a multifaceted education program, it must be considered a key tool for training. results: among the patients who underwent ecmo support for more than h, the bsi prevalence was . cases per ecmo days and microorganisms associated were most frequently gramnegative bacilli. as for positive ta cultures, microorganisms associated were oropharyngeal germs and gram-negative bacilli. two risk factors were associated with nosocomial bacteria occurrence in ta cultures-prior antibiotics and duration of mechanical ventilation more than days. we demonstrated a link between "positive ta culture" and "positive blood culture" and we showed a protective effect of using an antibioprophylaxis on "positive ta culture" and "global positive cultures" development. introduction: delirium in the icu is often under-diagnosed despite its related burden and impact on patients' morbidity, mortality and prolongation of hospital length of stay. the aim of this study was to assess the medical and paramedical community beliefs and practices regarding delirium in tunisian icus. patients and methods: between august st and / , healthcare professionals working at the icus of university hospitals of monastir and mahdia (tunisia) were asked to participate in the survey by completing a questionnaire anonymously (that specified participants' characteristics (age, gender, function, years of experience in icu) and their knowledge and perception of delirium in icu. the questionnaire consisted in questions of different types: likert style (: widespread scale in psychometric questionnaires in which the respondent expresses his or her degree of agreement or disagreement with an assertion), multiple choice, ranking and yes/no). results: during the study period, respondents out of ( % female, nurses: %), aged between - years in %, responded to the questionnaire. healthcare professionals experience in the icu was < year in . %; - years in . %, and > years in . %. participants asserted that the "most characteristic signs of delirium" were: insomnia ( %); confusion ( %); agitation ( %) and aggressiveness ( %). three-quarters of participants said they did not systematically search for signs of delirium in their patients. % thought that delirium was "an insignificant problem" or that "it was not a problem". only one and three participants respectively, said they attended a conference and read an article about delirium in icu the last year. half of the respondents felt that the most appropriate treatment for a patient with delirium was restraint. nearly one-third of participants thought that delirium was an under-diagnosed entity and only % felt that it was associated with long-term neuropsychological deficits. factors considered to be determinant in the occurrence of delirium were ards, shock, age, mechanical ventilation, postoperative status in , , , and %, respectively. conclusion: most tunisian healthcare professionals consider delirium as a common, underdiagnosed, and serious problem in the icu. yet, few participants actually monitor this condition. the influence of sedation choice on the delirium occurrence in critically ill poisoned patients: a randomized controlled trial khzouri takoua introduction: delirium is a common manifestation of acute brain dysfunction in critically ill patients. it is associated with a healthcare cost increase, and extension of the hospital stay length. the present study aimed to explore influence of patient characteristics and analgesicsedation on delirium incidence and to analyze its risk factors. patients and methods: it is a prospective single blind randomized controlled trial, started on the first july in a -bed toxicological intensive care unit, including all mechanically ventilated patients requiring sedation who were admitted for acute poisoning. they were randomly divided into two groups g et g receiving respectevily propofol-remifentanil and midazolam-remifentanil. delirium assessment scores were judged not adapted to our population and we retained the diagnosis of delirium on arguments inspired from diagnostic and statistical manual of mental disorders fourth edition (dsm-iv). results: until the th september , patients were included, with patients in g and in g . the two groups were comparable in terms of epidemiological characteristics. delirium was developed in patients ( %) (n = in g and n = in g ) with an average duration of ± h with no difference between the groups ( ± h for g - ± h for g , p = . ). compared to those without delirium, no differences were found in the patient characteristics among these two groups with regard to sex, age, psychiatric history and severity of illness (apache ii, igs ii score) and even with regard to hypnotic choice ( vs p = . ). delirium was associated to prolonged duration of mechanical ventilation ( ± h vs ± h, p = . ) and length of icu stay ( . h vs . h, p = . ) without significant differences. delirious patients had more hypotension (p = . ), and received more atropine ( . ). multiple logistic regression analysis identified atropine (or . , %cl . - . , p = . ) as an independent risk factor for delirium. the diagnosis and prevention of icu delirium are subjects of multiple ongoing investigations. we carried out this study to detect the risk factors of delirium in order to prevent it. it is important to note that our results are influenced by the studied population and are only preliminary. we rely on the study pursuit and the sample enlargement to better inform us as well on risk factors as protective. introduction: background: severe alcohol withdrawal syndrome is a common cause of hospital admission. delirium tremens is a potentially fatal complication of alcohol withdrawal. in severe delirium, very large dosages of benzodiazepines can be required despite well described side effects, such as coma and hypoxic cardiac arrest, although there is no recommendations for standardized treatments. objective -the aim of this study was to describe outcomes and risk factors for complications in patients with severe alcohol withdrawal syndrome treated in intensive care unit with continous infusion of benzodiazepine (bzd). we retrospectively reviewed the medical records of all patients hospitalized for alcohol withdrawal syndrome between and . only those who received continous-infusion of bzd, associated with close clinical monitoring and the evaluation of rass and cushman scores, without systematic recourse to mechanical ventilation, were included. results: we studied patients hospitalized in icu for severe alcohol withdrawal syndrome. the mean age (sd) was . ± . years, mean icu admission saps (simplified acute physiology score) ii score was ± . . all of them have received continous infusion of midazolam, with a median maximum perfusion velocity of mg h (interquartile range, ( , )). the median duration of treatement was days (interquartile range, ( , ) ). thirteen patients ( %) developed pneumonia, and or required intubation, and ( %) have had seizures. no cardiac arrest and death was observed. icu length of stay (los) was days ( , ) (median, interquartile range). patients who requiried intubation and or developed pneumonia, received substantially more bzd (median total dose, mg of midazolam vs. mg in the non-complicated group + p < . ), and their icu los was higher (median, days vs. days + p < . ). endotracheal intubation and or development of pneumonia were associated with a higher maximum perfusion velocity of midazolam (> mg h) (or . , ic % ( . - . ), p = . ). previous episodes of delirium tremens before icu admission were associated with higher complications such as mechanical ventilation and or pneumonia (or . , ic % ( . - . ), p = . ). in severe delirium, very large dosages of benzodiazepines can be used without systematic mechanical ventilation with a low incidence of complications. introduction: delirium is frequent in intensive care unit (icu) patients and is associated with increased mortality, increased hospital stay, increased cost and long term cognitive impairment in survivors. numerous pharmacological and non-pharmacological strategies have been investigated for delirium treatment without success. therefore delirium prevention strategies are recommended by current critical care practice guidelines. among the potentially modifiable risk factors for delirium, the impact of daylight exposure on delirium incidence and or duration has not been studied. the objective of this study was to investigate whether daylight exposition would reduce delirium burden in critically ill patients. we conducted a prospective study in a -bed medical intensive care unit (icu) over a -year period (january -january ). all consecutive adult patients receiving invasive mechanical ventilation (mv) for days or more were eligible for the study. patients were assigned to a room with windows allowing daylight exposure ("light" group) or without window ("dark" group), depending on bed availability. delirium was evaluated with the intensive care delirium screening checklist (icdsc) for a maximum period of days. delirium was defined by a icdsc score ≥ for two consecutive days. agitation was defined by a rass > or = + . the primary endpoint was cumulative incidence of delirium. data are presented as median (interquartile range) or number (percentage). results: a total of patients were included (age- [ + ] years, saps - [ + ], sofa score- [ + ], medical admission- %). of them, patients were admitted to a "light" group and to a "dark" group. incidence of known risk factors for delirium was similar in the two groups. delirium occurred in ( %) patients in the "light" group and in ( %) patients in the "dark" group (p = . ). the duration of delirium was [ + ] days. patients in the "light" group received significantly less neuroleptics to treat agitation than patients in the "dark" group ( vs. %, p = . ). this protective association persisted after adjustment for confounders in multivariate analysis (odds ratio = . + [ . + . ] + p = . ). daylight exposure does not impact on delirium burden in icu mechanically ventilated patients. however, daylight exposure is independently associated with a reduced prescription of neuroleptics to treat agitation. introduction: patients with convulsive status epilepticus (cse) frequently require mechanical ventilation (mv), either for general anesthesia in case of refractory generalized cse, or for airway protection. guidelines for the management of refractory generalized cse currently recommend general anesthesia for - h, followed by gradual withdrawal. our objective is to evaluate the incidence of refractory generalized cse among patients who required mv during pre-hospital management of status epilepticus, and to describe the management of general anesthesia in intensive care unit (icu). this ongoing multicenter retrospective observational study is conducted in french icus. all patients admitted in icu under mechanical ventilation between - - and - - with disease-code "status epilepticus" are included. exclusion criteria are-age < years, post anoxic se, acute traumatic brain injury, initiation of mv in icu, transfer from another icu, inclusion in a therapeutic trial on se, non-convulsive se. collected data include reason for mv, antiepileptic treatment, dosage and duration of general anesthesia, mode of eeg monitoring. outcomes are-relapse of se, mv duration, in-icu length of stay and mortality. results: among the medical files reviewed, met the inclusion criteria and were analyzed, and were excluded. a minority of patients ( . %) had a refractory generalized cse, most patients ( . %) had a non-refractory generalized cse + the others had mostly partial cse. the main reason for intubation was coma (n = , . %). the duration of general anesthesia was not significantly different in refractory cse patients compared to non-refractory cse patients (p = . ). data regarding main outcomes are summarized below-. these preliminary data suggest that the majority of the patients admitted in icu under mv for cse do not have a refractory status. indication of mv is mainly coma without persistent convulsions. the mean duration of general anesthesia before withdrawal is < h, and thus in discrepancy with guidelines, but does not seem associated with a frequent relapse of se. if this low rate of rse for patients admitted in icu and the safety of rapid withdrawal of ga are confirmed, the recommended - h duration of general anesthesia in icu could be challenged. introduction: induced coma in intensive care patients protect them against pain and neurologic disorders. however, a few of them may present a delayed wake-up when the sedation is interrupted. the aim of this work is to assess brain imaging findings in patients with this condition. patients and methods: retrospective review of imaging data of patients ( males and females), aged between and years, admitted in intensive care unit (icu) between june and september , who had sedation or general anesthesia and presented a delayed wake-up. they were explored either by mri (n = ) or computed tomography (ct) (n = ). patients with traumatic lesions were excluded. results: patients were admitted in the icu because of chronic obstructive pulmonary disease exacerbation (n = ), infectious pneumonia or pleural effusion (n = ), acute respiratory failure (n = ), heart disease (n = ). two patients underwent general anesthesia. septic shock and circulatory collapse occurred in and patients respectively. mri and ct showed lesions that may explain the wake-up delay in of and of patients, respectively. brain anomalies included anoxic lesions (n = ) with basal ganglia involvement (n = ), ischemic or hemorrhagic strokes (n = ), hepatic encephalopathy (n = ) and herpetic encephalitis (n = ). conclusion: brain imaging techniques help diagnosing causes of delayed wake-up after induced coma. anoxic lesions and strokes are mostly behind this condition. mri is more accurate than ct. introduction: gastric tubes are common in intensive care units used for enteral feeding, administration of drugs or aspiration of the digestive tract. these tubes offer an excellent tolerance but malposition may have serious consequences that can lead to patient's death. the actualy gold method to confirm their correct placement is chest x-ray. we report a study which evaluate the performance of gastric ultrasonography for the validation of the good positioning of the gastric tube. we carried out a prospective, monocentric study in a medical intensive care units. for each included patient, we compared the results of a gastric ultrasonography to the interpretation of a chest x-ray. results: one hundred and thirteen gastric ultrasonographies were performed from july to may . in cases, ultrasonography concluded that the gastric tube was correctly positioned, confirmed by chest x-ray. in cases, ultrasonography did not visualize the tube in gastric area. among these cases, only malpositions were detected by the chest x-ray. the sensitivity and specificity of gastric ultrasonography were . [ . + . ] and [ . + ]. positive and negative predictive values were and . , respectively. the ultrasonography was performed min [ . + . ] after the gastric tube placement while the chest x-ray was interpreted min [ . + . ] after this same placement (p < . ). our results suggest a good performance of gastric ultrasonography to check the positioning of the gastric tube. this result must be interpreted with caution because of a low power of the study. we planned a multi-center study to confirm our results. giabicani mikhael introduction: prognosis of cirrhotic patients hospitalized in intensive care unit (icu) remains poor. in many icus, cirrhotic patients are widely admitted and revalued after receiving optimal treatments. little is known about risk factors involved in the evaluation of the prognosis at day , except the persistence of organ failure. this susceptibility to organ failure would be related to an alteration of the regulation mechanisms of the systemic inflammatory response. the blood neutrophil-to-lymphocyte ratio (nlr) is an inflammation biomarker reported to predict clinical outcome in unselected critically ill patients and in patients with stable liver cirrhosis, but has never been studied in critically ill cirrhotic patients. the aim of this study was to evaluate the blood nlr as parameter to predict mortality of cirrhotic patients hospitalized > days in icu. retrospective monocentric study including consecutively cirrhotic patients hospitalized in a medical icu from to . for each patient, clinical and biological data at admission and day were collected. nlr at admission ("nlrd "), at day ("nlrd ") and its variation between admission and d ("delta nlr") were calculated. statistical analysis used appropriate non parametric tests and cox regression for survival analysis. the ability of the variables to discriminate survivors from non-survivors was determined using roc curves and a net reclassification index (nri). results: patients (median child-pugh score = [ - ], median meld score = [ - ]) were hospitalized more than days in icu. the major causes for icu admission were sepsis ( . %), gastrointestinal bleeding ( %) or respiratory failure ( . %). patients were followed up for . d . ( %) patients died- ( %) in icu, ( %) after icu discharge and ( %) after hospital discharge. in univariate analysis, factors significantly associated with mortality wereat d , nlr, meld and sofa scores + and between d and d -delta nlr, delta sofa and delta meld. predictors of death in multivariate analysis are shown in table . area under delta nlr roc curve was . (ci = . - . ). nri revealed that delta nlr was more efficient than delta sofa (nri = . %) to identify patients with a % mortality risk at least. conclusion: nlr is a novel inflammation index known to predict poor clinical outcomes. delta nlr is an independent predictor of mortality in critically ill cirrhotic patients and could be more effective than delta sofa in predicting hospital mortality in these patients. severe liver dysfunction acute liver failure related to exertional heatstroke: outcomes, histological features and role of liver introduction: severe acute liver injury and failure (sali alf) is a grave complication of exertional heatstroke (eh). liver transplantation (lt) may be a therapeutic option, but the criteria for, and timing of, transplantation have not been clearly established. the aim of this study was to define the profile of patients who require transplantation in this context. this was a multicentre, retrospective study of patients admitted with a diagnosis of exertional heatstroke-related sali alf with a prothrombin time (pt) lower than %, with or without hepatic encephalopathy. results: male patients (median age- . years) with ali alf related to exertional heatstroke were studied + nine of them ( . %) were listed for emergency lt. the latter differed from those who were not listed with respect to their more severe liver failure after d , a clear deterioration in their pt and alt values between d and d , and more marked organ dysfunction. four of these nine patients were subsequently transplanted. at the time of lt, all had pt levels lower than %, a marked rise in bilirubin levels and required support for at least one organ (or x organs were involved). histological findings on the explanted livers demonstrated massive or sub-massive necrosis and little potential for effective mitosis with a mitonecrotic appearance. the unlisted patients ( . %) were still alive months later and had not experienced any after-effects. conclusion: survival without liver transplantation in patients with heatstroke-related ali alf reaches . %. the indication for liver transplantation is based on an evolving dynamic. the lack of any signs of an improvement in liver function at or after d , in patients presenting with other organ dysfunctions or failure, means that liver transplantation should be envisaged. the peculiar histological features observed on all the explanted livers, and the aspect of abortive mitoses in hepatocytes could be attributed to the effects of heatstroke. . on admission, the mean pt was . % ( - ), the mean total bilirubin was umol l. paracetamol poisoning was the principal etiology with % of the patients- % in the prometheus group versus % in the standard group (p = . ). the hepatic encephalopathy grade was significantly higher in the prometheus group- versus . in the standard group (p = . ). there was no difference between the two groups concerning mortality on day (p = ) or day (p = . ). there was no difference concerning the length of stay in intensive care unit or in hospital between the two groups. patients ( . %) were transplanted. there was a statistical difference between the two groups concerning liver transplantation (p = . )- transplant ( %) in the prometheus group versus transplant ( %) in the standard medical care group. there was a significant improve of encephalopathy after the prometheus session (p = . ). therapy in our icu were included consecutively and prospectively in the cohort. mars ® therapy performed using a double lumen dialysis catheter in the femoral or jugular vein. we used the monitor mars ® tc (teraklin) coupled with the dialysis machine prismaflex ® (gambro). the albumin dialysate circuit consisted of ml of % human albumin and was regenerated by an anion-exchange column and an uncoated charcoal column (diamars ® ie , diamars ® ac ). results: ninety patients were included for sessions. the mean duration was h min (± h min). the population treated consisted of groups-acute-on-chronic liver failure (aoclf), acute liver failure (alf), post-surgery liver failure (post transplantation, post hepatectomy), refractory pruritus and drug intoxication ( fig. ). regarding biological efficacy-total bilirubin was lowered in aoclf and post-surgery groups (p < . ), also in the alf group although not significatively. meld score was lowered in the aoclf and alf group (p < . ). however clinical variables (glasgow score and encephalopathy) didn't improve significatively. in the refractory pruritus group, pruritus decreased in out of patients (p < . ). bile acid levels decreased to . % of its mean baseline level (p < . ). in the drug intoxication group improvement of the richmond agitation-sedation scale (rass) from deeply sedated (rass < = − ) to minimal sedation (rass > = − ) was obtained in out of patients. out of sessions, catheter-related adverse effects were low ( . %), thrombocytopenia was the main adverse effect ( . %). conclusion: we report our mars ® experience with the largest cohort of patients referred from a single hospital. we showed biological efficacy in all indications, although clinical efficacy was uneven. mars ® therapy in patients with refractory pruritus yielded promising results. tolerance was good and the main adverse effect was thrombocytopenia. global transplantation-free survival was low in patients with liver failure, reinforcing the need for a liver transplantation center when using mars ® . introduction: colonoscopy is crucial for the management of lower gastro-intestinal disorders, but its profitability is discussed in critically ill patients, mainly because of the complexity of colonic preparation. as the profitability of colonoscopy in intermediate or intensive care units (cicu) has been scarcely reported ( ), we investigated its indications and usefulness. patients and methods: retrospective bicenter observational study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . main endpoint: diagnostic profitability of cicu in unselected critically ill patients. profitability was a priori defined as "high" if cicu led to adapt ongoing therapies; allowed an endoscopic intervention; or participated in the decision to limit therapeutic effort. secondary endpoints: describe the quality of cicu and its preparation; determine its position in diagnosis strategy; describe its morbidity. ) + investigation of a gram negative bacilli sepsis (n = , %) + sigmoid volvulus (n = , %) + and cancer diagnosis (n = + %). cicu profitability was deemed high in % (n = ), with an endoscopic intervention performed in % (n = ). the cicu lead to antimicrobial adaptation (n = ), emergent surgery (n = ), or to limit therapeutics effort (n = ). in cases ( %) the cicu was considered normal. patients' preparation was rated as good in % (n = ) + and the colonoscopy was complete in ( %). the cicu was mainly performed as a nd ( %) or rd ( %) investigation after an abdominal ct-scan or an upper digestive endoscopy (respectively performed in first instance in and %). three cicu were complicated by hemodynamic and respiratory failures, none were fatal. discussion: in our series of unselected critically ill patients, cicu were mainly performed to investigate lower gastro-intestinal bleeding. despite a low rate of good preparation, cicu is safe and its profitability is high in the majority of cases. conclusion: although performed in poor conditions, cicu seems useful in the diagnostic and the therapeutic management of critically ill patients, and not only in gastro-intestinal bleeding. ( ) church, surgical endoscopy . introduction: accurate pain assessment is associated with better outcomes in intensive care unit (icu) patients. specific scales for noncommunicative patients have been developed and validated but their routine use still remains inaccurate and subjective. analgesia nociception index (ani) is based on high-frequency heart rate variability. this study objective was to assess the correlation between the behavioral pain scale (bps) and ani during care procedures in deeply sedated patients. we conduced a french multicentric prospective observational study with blinded continuous recording of ani during h with spotting of care procedures in patients with rass less or equal to − . we compared pain assessment using bps and ani before (t ) and during (t ) each care procedure. the cares analyzed included prick glycaemia, turning, catheter insertion, dressing change and others. a behavioral pain reactivity (bpr) was defined by a bps elevation of at least point. we analyzed minimal ani values and its variations with calculation of deltaani (anit -anit ). because of the analysis of several cares per patient we used a bonferroni's correction in comparison of bpr and no bpr groups with a significant p value < . for this comparison. for others analyses the p value considered as significant was p < . . correlation between ani and bps was analyzed using a spearman correlation rank test. introduction: the pain associated with burn was one of the most painful injuries to treat. pain was induced by therapeutic acts such as wound debridement, dressing and other painful procedures. burn pain caused changes in neurophysiology and pharmacokinetics that may make standard pharmacologic analgesic therapy less effective than usual.virtual reality has been explored as an adjunct therapy for the management of acute pain for a number of conditions. in our study, we attempt to assess the impact of virtual reality on management of burn pain during dressing changes. patients and methods: before the therapeutic procedure (dressing changes), the concept of virtual reality therapy was explained to the patient (technology and equipment used). the video used was snow mountain. during the act, pain was assessed until the end of the procedure. the assessment of pain was based on visual analog scale (vas). for pain intensity, the scale was most commonly anchored by "no pain" (score of ) and "very intense pain" (score of ). results: during the study period, patients were included. the mean age was ± years. % of our patients were adults aged over years. they were men and women. the average burned surface area was ± %. pain was evaluated before the start of the therapeutic procedure. the mean initial pain severity score was . ± . (range to ). the pain assessment after virtual reality condition showed a significant decrease in the intensity of pain (p < . ). the mean pain decreased from . to . ± . with extremes ranging from to . conclusion: our study supports the use of virtual reality, simple noninvasive, as an adjunct therapy in the management of pain associated with dressing changes in burn patients. introduction: hypno-analgesia (ha) is used in the operating room and for complex pain. before implementation of ha in our intensive care unit (icu), most protocols for algogenic procedures included intravenous or epidural morphine and nitrous oxid. since , many caregivers have been trained, ha has been implemented and patient comfort is evaluated using ) a specific analogic scale of comfort ( to ) before and after the procedure + ) at the end of the procedure, a score of patient and caregiver comfort using a five item questionnaire ( to points). this pilot prospective study compares ha versus the standard protocol in the removal of abdominal drains after digestive surgery. the main objective was to evaluate the patient comfort before after the procedure using a scale of comfort + the secondary objectives were to test the patient and caregiver comfort scores and evaluate in the impact on consumption of analgesic. between may and september , two groups were obtained, according whether the procedure was performed by ha-trained or non-hatrained professionals (depending on caregivers availability in the unit). the number of subjects required to compare scales of comfort before vs. after drain removal was , using a nonparametric wilcoxon-mann-whitney test. results: eighty-eight patients were analyzed. the mean note in the comfort scale remained unchanged after vs. before drain removal in patients without ha (n = , + . points, ± . ), while it increased in patients with ha (n = , + . , ± . + p = . ). using our specific five item comfort score, patients and caregivers had a comparable level of satisfaction in ha and non-ha groups (patients . and . + caregivers- in both). a trend was observed in reduction of the consumption of morphine and nitrous oxid with ha, without altering their comfort. discussion: despite its limitations (mainly, its open non-randomized design), this study suggests that-ha may be used for algogenic procedures and is willingly adopted in icu by patients and professionals + specific scales scores, adapted for ha, may be useful to assess the effectiveness + finally, ha seems to be at least as efficient as classical procedures and could reduce the use of analgesic drugs. conclusion: ha adds value to patients and to all caregivers. prospective randomized studies are needed to valid the comfort scores we proposed, and to prove that ha reduces the consumption of analgesic drugs. introduction: pain has long been a focus of concern for doctors and caregivers. in intensive care unit, the inability to verbalize discomfort and pain are major stressors for patients. music therapy has demonstrated in many international studies its effect on the blood pressure and on the respiratory frequency. in this context, we conducted a study to evaluate the effects of standardized musical intervention on pain during painful cares in vigils patients hospitalized in critical care. patients and methods: design-we conduct a prospective, observational, randomised, single blind, mono center study. painful cares were studied and then distributed in two groups (n = with music, n = without music). the patients were equiped with a bose© helmet, and had or not music therapy during the care. our main criteria was the pain, it has been evaluated by a numeric scale before and after the painful care. we also estimated anxiety with the covi's heteroevaluation scale before and after the car. we also noticed if the care were stopped because of the pain, then we used a semi quantative numeric scale in order to estimate the feeling of the caregiver and the patient on the session. results: concerning pain, there is no significant difference between the two groups (p > . ). however, in the music group, pain decreased by % after the care (p < . ). anxiety was way lower in the music group than in the group without music (p < . ). we also noticed a decrease of % of the anxiety in the music group. the patients and the caregivers' feeling were the same in the two groups, with no significant difference (p > . ). on the other hand, caregivers tended to underestimate the difficulty of the session in comparison with the patients' (p < . ) in both groups. conclusion: music therapy did not improve the pain in a significant way, in the music group versus the group without but allowed a decrease of % of the pain after the care. nevertheless, music reduced by two patients'anxiety. introduction: sedation and analgesia is one of the basic themes in icu as complications associated with excessive sedation negatively impact the morbidity and mortality of patients. the objective of this study is to show that the nurse implementation of a sedation and analgesia algorithm is beneficial to the patient in terms of sedative drugs reduction and thus overall decrease in duration of mechanical ventilation (mv) and the morbidity and mortality which is associated with it, without altering patient comfort and tolerance of the environment. patients and methods: a before and after prospective, observational, non-interventional study was conducted in surgical icu in caen university hospital, between november and april . mechanically ventilated patients under sedation predicted to last h or more were included. during the "before" period, sedation and analgesia was managed by the physician, while during the "after" period, it was managed by the nurses according to the protocol. results: intubated and mechanically ventilated patients were admitted during the study period. among the eligible patients, were included during "before" period and during "after" period. the duration of mv after inclusion was significantly shorter in group "after" ( . [ + ] vs [ + . ] days, p = . ), as the duration of target rass (- à ) was significantly longer ( the patients experienced less of ventilator-acquired pneumonia (vap) and delirium during the "after" period ( vs . %, p = . , and vs . %, p = . , respectively). the nurse implementation of a sedation and analgesia algorithm was associated with a trend towards reduction in duration of mv, icu and hospital length of stay. moreover, prevalence of vap and delirium was reduced, in correlation to the significant decrease in sedative drugs. this type of algorithm is necessary to reduce morbidity and mortality associated with mv. introduction: central venous catheter insertion is a common practice for anesthetists and intensivsts. this invasive procedure generates pain and anxiety for patients. we aim to demonstrate that remifentanil improves the analgesia during scheduled central venous catheter insertion in mindful patients. patients and methods: a prospective, randomized, double-blind, controlled study in patients requiring central venous access. patients were randomly assigned to receive ng ml − remifentanil target controlled infusion (tci) and local anesthesia (la) with lidocaine or placebo and la. all patients were monitored in intensive care or postintervention care unit and systematically received oxygen. patients were asked to assess verbal numeric rating pain scale (vnrps) during the procedure. the primary outcome was the maximal vnrps. secondary outcomes were pain at each step, anxiety, patient satisfaction, operator ease and side effects. results: ninety patients were included ( in each group). all patients were analyzed. remifentanil significantly reduced maximal pain-vnrps ( % confidence interval [ci] - ) vs ( % ci - ) in the placebo group p = . (table ) . we did not observe any adverse event during this study, and there were no significant difference between the groups regarding side effects. conclusion: tci remifentanil is a safe procedure to reduce pain during central venous catheter insertion in awake patients. trial registration-clinicaltrials.gov identifier- , remidolcath. introduction: although guidelines on post-resuscitation care recommend the use of short-acting agents for sedation during targeted temperature management (ttm) after cardiac arrest (ca), the potential interests of this strategy have not been clinically demonstrated. patients and methods: before-after study. we compared two sedation regimens (propofol-remifentanil, period p vs midazolamfentanyl, period p ) among comatose ttm-treated ca survivors. management protocol, apart from sedation and neuromuscular blockers use, did not change between the two periods. baseline severity was assessed with cardiac-arrest-hospital-prognosis (cahp) score. time to awakening was measured starting from discontinuation of sedation at the end of rewarming. awakening was defined as delayed when it occurred after more than h. results: patients ( in p , in p ) were included. cahp score in p and p did not significantly differ (p = . ). sixty percent of patients awoke in both periods ( vs , p = . ). median time to awakening was . (iqr - ) hours in p vs. (iqr - ) hours in p . awakening was delayed in % in p vs. % of patients in p (p < . ). after adjustment, p was associated with significantly lower odds of delayed awakening (or . , % ci . - . + p < . ). patients in p had significantly more ventilator-free days, and lower catecholamine-free days between admission and day . survival and favorable neurologic outcome at discharge did not differ across periods. time course for awakening according to sedation period. these figures report the time course of patients included after discontinuation of sedation. at each time point, we report in the upper part, proportion of patients awoken after discontinuation of sedation, in the lower part, patients who died without awakening, and in the middle part (in white), patients still comatose. red dots indicate, for each period, the last patient awakening (after days in p and days in p ). black dots indicate the median time to awakening (too early to appear for period ). conclusion: during ttm following resuscitation from ca, sedation with propofol-remifentanil compared with midazolam-fentanyl was associated with an earlier awakening, and an increase in ventilator-free days. the new recommendations of the french society of anesthesia-intensive care (sfar) on perfusion and medication errors were revised in to promote proper use relating to drug administration with medical devices. to advance that of inquiry, practices of our intensive care unit (icu) were assessed in order to improve drug administration by central venous catheter (cvc). patients and methods: prospective evaluation by pharmacist resident and technical nurse during seven weeks, using a standard evaluation tool, in a bed icu. drug recommendations and sfar documents from were used as referential of conformity. the following parameters were evaluated- central venous lines mounting, drug administration and identification with a focus on narrow therapeutic index (nti) drugs. results: patients with cvc were analyzed between june and july . entered directly in the icu. were hospitalized for surgical reasons. had triple-lumen cvc. regarding the first parameter, no conformity was found due to lack of line identification ( %) or anti-return valve well positioned ( %). perfusion ramp position was above heart level in %, infusion tubing had contact with floor in %, and absence of plug on non-used lines is found in % of cases. regarding second parameter, non-conformities were due mostly to syringe label-absence of drug's concentration ( %), preparator identification ( %), patient identification ( . %), drug identification ( . %, all concerning propofol), date and time of medication preparation ( %), lack of color code of labels ( %). regarding nti, % were not administrated according to the recommendations-absence of dedicated line ( %), absence of administration on the nearest insertion site of the catheter ( %). conclusion: the evaluation highlight some improvement axis such as complete identification on syringes, sensitizing of icu healthcare team, or homogenization of cvc perfusion system. it calls for a second evaluation round after implementation of improvements. introduction: sedation is a corner stone of the care of patients receiving mechanical ventilation in the icu. sedation was associated with increased comfort and adherence to care, but also with increased morbidity, including delirium, increased duration of mechanical ventilation and length of icu stay. previous studies reported beneficial impact of reduced doses of sedative drugs and careful monitoring of patients comfort and consciousness. our goal was to assess the impact of the introduction of a nurses-dedicated sedation protocol in our icu. patients and methods: this monocentre retrospective before-after study included all the patients admitted in our icu, over two threemonth periods, from july and january , treated with invasive mechanical ventilation for more than h and older than yrs. after the first period, all physicians and nurses were trained to a new sedation management protocol. analysis was performed to assess the prescription and application of the protocol, its impact on the use of sedative drugs, icu length of stay, and duration of mechanical ventilation. major complications were also recorded. results: patients were included- before and after the protocol implementation. patients in both groups had similar baseline characteristics (men vs. %, p = . + mean age ± vs. ± years, p = . + weight . ± . vs. . ± . kg p = . + igs ± vs. ± , p = . + medical admission vs. %, p = . ). recordings of rass and bps did not differ between groups ( ± vs ± , p = + ± vs, ± , p = . ). the duration of sedation was significantly shorter after introduction of protocol ( . ± . vs . ± . , p < . ), as was the duration of mechanical ventilation ( . ± . vs . ± . , p = . ) and icu length of stay ( . ± . vs . ± . , p = . ). there was no difference in major icu complications, nor in mortality between groups ( and %). conclusion: although the implantation of a sedation protocol did not translate in increased recording of rass and bps scores, it was associated with improved outcomes. our data suggest that, more than the protocol by itself, beneficial effects reported after the implementation of a sedation protocol may be ascribed to increased awareness of the care givers and thus better management of sedation. introduction: workload affects the quality of care and the prognosis of critically ills patients. measuring workload in intensive care units (icu) has thus become essential for allowing a better matching between the activities required and the management of resources. in march , the medical icu of the university hospital of monastir (tunisia) moved into new buildings (more space and beds, computerbased prescriptions and monitoring, etc.). the aim of the present study is to compare the level of workload before and after the change of the icu buildings. patients and methods: during the two study periods (period -july-september and period -july-september ) adult patients consecutively admitted, for more than h, in the medical icu for arf and or sepsis were included in the analysis. data collected were the demographic characteristics (age, sex, body mass index (bmi), comorbidities, simplified acute physiology score (saps) iii), the nursing workload measured using the therapeutic intervention scoring system (tiss- ) and hospital survival. results: thirty-six patients ( male) were included in the study ( during period and during the second period). the medians of age, saps iii and bmi were respectively (iqr = ) years, (iqr = ) and . (iqr = . ). the main comorbidities were hypertension, copd and neurological disease respectively in , and %. the demographic characteristics were similar during the two periods. nurse workload was characterized by m tiss- = (iqr = ) and time of nurse's care of min (iqr = ). these two workload indicators were significantly higher during the second period (table ) . during the second period, "standard monitoring" and "frequent dressing changes" (> time day) were the activities with significant increase from, respectively to % (p < . ) and from to % (p < . ). the relocation of our icu in in new buildings was associated with a significant increase of the nurse workload with regard to patients with arf and or sepsis. . bland-altman analysis showed excellent accuracy and precision between recorded and collected data for all tested variables within clinically significant pre-defined limits of agreement. however, ( . %) data were missing and a delay was observed between videotaped and collected times. this delay was less than s and remained stable through all data for each patient. we identified that the missing data were due to a limit in the number of data being processed in the database at the same time and the delay between data presentation and data collection in the database was due to different server time settings. both technical issues were corrected. conclusion: our study identified two issues in the data collection process that slightly limited the accuracy of our high resolution electronic database. we recommend the performance of such validation study before using a high resolution database for clinical or research purposes. introduction: fluid overload, and also its variations, is known to jeopardize the outcome of icu patients. however, fluid balance remains difficult to assess accurately. in that context, our study aims to assess the prognostic value of body weight variations (bwv) from day to day on the -day mortality, length of stay (los) and the occurrence of ventilator-associated pneumonia (vap) and bedsore in critically ill patients with shock. patients and methods: adult patients admitted in icu with shock between and , and requiring mechanical ventilation during the first h, were extracted from a prospective multicenter cohort for a retrospective analysis. bwv was defined as the difference between the body weight of the day of interest and the body weight on admission. case mix, severity on admission, and outcomes were collected. fine and gray sub-distribution survival models were used, with icu discharge as competing event, adjusted on comorbidity and illness severity at admission at each landmark, from day to day . the impact of bwv on icu stay duration was estimated through a multivariate negative binomial regression model. the median age and saps score of the included patients were (iqr, - ) years and (iqr, - ), respectively. the bwv increased from . kg (iqr, - . ) on day to kg (iqr, − . to . ) on day . the day in-hospital mortality, the icu occurrence of bedsore and vap were , and . %, respectively. four categories of bwv were defined according to bwv interquartiles: weight loss, stable weight, moderate and severe weight gain. categories of bwv were independently associated with death on day and day (day : shr . ; % . - . p = . ; day : shr . ; % ci . - . , p = . ) (fig. ) . a weight loss tended to be associated with increased occurrence of bedsore, and weight gain with increased occurrence of vap. the extent of bwv increased the duration of icu stay independently of other severity factors. discussion: bwv may be another clinically relevant tool to assess the risk of death, mostly after day . the increased risk of bedsore in case of weight loss deserved to be confirmed. conclusion: body weight should be daily monitored for better prognostication. bwv-based restrictive strategies should be further evaluated. the clinical effectiveness of multi-layer silicone dressings in preventing icu acquired pressure ulcers: a randomised controlled trial introduction: the development of pressure ulcers (pu) in critically ill icu patients result in additional morbidity and may contribute to mortality in some cases. the minimisation of icu acquired pu remain an international challenge. this paper describes australian research that used multi-layer soft silicone sacral and heel dressings to prevent pu in critically ill patients. patients and methods: a total of critically ill patients were enrolled into an -month randomised controlled trial in one of melbourne's trauma centres. patients were randomised on admission to the emergency department and either had standard pu prevention or standard care plus the application of prophylactic sacral and heel dressings. patients were observed daily for pu development for the duration of their icu stay. results: patients in the dressing group has significantly reduced incidence rate of pu development compared to patients receiving standard pu prevention alone ( . vs . %, p < . ). patients in the dressings group had a relative risk reduction of % and a % absolute risk reduction for developing a pu regardless of their critical illness. results indicate the number needed to treat to prevent one pu was . additionally, we calculated the cost-benefit of this intervention and found the patients treated with prophylactic dressings cost . time less than the standard care group for wound care. discussion: the use of prophylactic dressings to prevent pu at our hospital have proved to be very effective in icu and subsequent studies have confirmed our results. it appears that the main mechanism of pu protection provided by these dressings is the reduction of pressure and shear forces leading to tissue distortion and cell death rather than the previously accepted ischaemic model of pu development. our current policy is now to use these dressings on all patients with a high risk of developing pu. the use of prophylactic multi-layer silicone dressings to prevent pu in critically ill patients is effective but it does not replace standard pu prevention methods. the use of these dressings sould be considered complimentary to best practice in pu prevention. iatrogenic events in intensive care unit: incidence, risk factors and impact on outcome ayed samia , merhebene takoua introduction: iatrogenic events (ies) are defined as harm resulting from medical intervention and health care, and not explained by underlying disease. mortality is reported to be as high as . % in cohorts of hospitalized patients experiencing ie. both length of stay and cost of hospitalization are increased by ies occurrence. we perform this study to determine the incidence, risk factors, and impact on outcome of ies in intensive care unit (icu). patients and methods: all patients admitted more than h to the -bed icu of a teaching hospital were prospectively screened. patients were monitored daily for adverse clinical occurrences. time and data about each ie were collected and they were considered as preventable or life-threatening events. for each patient, the followings were recorded-basic demographic data, indication for admission, severity scores on admission (sapsii and apacheii), need and duration of mechanical ventilation (mv), length of stay (los) in icu, intensive care work load score (omega), global mortality and ies related mortality. results: during the months period, patients were included and ( . %) were judged to have developed an ie while hospitalized. we recorded ies over days in icu so a density incidence of ie for patient-day. ies were considered preventable in % of cases and life-threatening in % of cases. ies occurred in a mean delay of ± days. global mortality rate was . % and ies related mortality rate was . %. patients with ies were significantly severe on admission, with a longer duration of mv and los in icu. omega score was significantly higher. multivariate analysis showed that omega score was the independent risk factor of ies occurrence (or . ic % [ . - . ], p < - ). dead patients were significantly severe on admission and experienced more ies than survivors. omega score, duration of mv and los were significantly higher. in multivariate analysis, ies and life-threatening ies were independent factors of mortality (or . ic % [ . - . ], p < - and or . ic % [ . - . ], p < - respectively). conclusion: ies in icu are common and frequent but one-third is preventable. work load icu score is the independent risk factor of their occurrence. ies impact largely the outcome especially the lifethreatening ones. efforts must be focused on preventing programs to reduce ies and improve the outcome. introduction: based on the recent sepsis- definitions, septic shock is defined by the combination of vasopressor requirement and serum lactate level > mmol/l. however hyperlactatemia and lactate kinetics may result from both increased production and impaired clearance in the critically ill, and may therefore not only rely on the severity of circulatory failure. we herein addressed the determinants of hyperlactatemia (> mmol/l) and the factors likely to impact on early lactate clearance in septic shock. patients and methods: this was a -year ( - ) monocentric retrospective study. all adult patients diagnosed for septic shock within the first h were included. septic shock was defined as a microbiologically proven or clinically suspected infection, associated with acute circulatory failure requiring vasopressors. the first lactate value (l ) was measured at the time of icu admission. hyperlactatemia was defined as a first lactate level > mmol/l. the second value (l ) was measured within h following the first measurement. lactate clearance was calculated as (l -l ) l time between l and l measurements) and expressed in mmol hour. parameters associated with initial hyperlactatemia and lactate clearance were investigated using multivariate logistic regression analysis. introduction: cardiac surgery with cardiopulmonary bypass (cpb) induces immunosuppression which has considerable implications for patients. cpb induces a significant increase in circulating neutrophils. neutrophil activation, associated with production of antibacterial peptides, reactive oxygen species (ros), cytokines, and other inflammatory mediators, as well as release of dna into the extracellular milieu (neutrophil extracellular traps (nets)), plays a central role in innate host defense and modulation of inflammation. however, it has been shown that, in septic shock or systemic inflammation as major surgery, immature circulating neutrophils can induce immunosuppression and increase the risk of secondary infections. staphylococcus aureus (sa) is one of the most commonly encountered bacterial pathogen responsible for poststernotomy mediastinitis, and neutrophils alterations may favor postoperative infections. the main objectives of this study were to evaluate the direct effects of cbp on neutrophils functions and to study the impact of different strains of sa on neutrophils bactericidal functions. patients and methods: blood samples were collected before and h after cardiac surgery with cpb and bone marrow samples were harvested directly after sternotomy, before initiation of cpb, and at the end of cpb, before sternal closure. septic patients were included as controls. circulating neutrophils analysis was performed using flow cytometry. we also studied netosis, ros production and bactericidal activity in isolated neutrophils before and after surgery using two strains of sa-one responsible of postoperative mediastinitis and one isolated from nasal carriage. results: blood cell count with differential demonstrated a significant increase in neutrophils h after surgery. flow cytometry analysis of blood samples indicated neutrophils were matures with a significant increase in degranulation marker (cd b). neutrophils life span was also increased after cbp. flow cytometry analysis of bone marrow samples showed no difference in cell composition and maturation before and after cbp. the neutrophil production of ros was significantly higher after cbp. however, cbp did not impact nets formation, phagocytosis and bactericidial function. moreover, there was no difference regarding the phagocytosis and the bactericidial activity when exposed to the two strain of sa. as expected, immature neutrophils count was significantly increased in septic patients compared to cardiac surgery patients. these results indicate that cbp promotes the recruitment of matures neutrophils via a demargination process. cbp does not induce neutrophil dysfunction. neutrophils should not be targeted to decrease postoperative infection after cpb. introduction: protein tyrosine phosphatase b (ptp b) is a negative regulator of both no production and insulin signaling and has been shown to be an aggravating factor in septic shock. stress hyperglycemia frequently occurs in critically ill patients and is associated with poor outcome. experimental studies on transgenic mice have shown that ptp b deletion resulted in a reduced insulin resistance and in a better survival during experimental model of sepsis. the main objective was to study the correlation between the ptp b gene expression and organ failure (through the delta sofa score between day and day ) or insulin resistance. patients and methods: twenty-seven healthy male volunteers have been included in this clinical trial. the product was administered by continuous intravenous infusion (civ). a single ascending dose design with dose levels was used. cohorts and received a -min single dose of motrem ( and mg and one and two volunteers respectively). then, cohorts to received either a -min loading dose (from . mg kg to mg kg) followed by . -hours maintenance dose (from . mg kg h to mg kg h) of motrem or a matching placebo ( - ratio). all volunteers were carefully monitored. before escalation to the next dose level, safety and pk data of the previous dose level were reviewed by a safety review committee. since immune system is at rest in normal individuals and thus trem- pathway is not activated, no pharmacodynamics parameters were analyzed. the main objectives of this trial was then to study the safety and pharmacokinetic profile of motrem. results: no product related changes in vital signs, clinical nor laboratory parameters were observed. no product-related adverse events were reported. the pk of motrem was linear; the main clearance was estimated at l/h/ kg which is higher than the hepatic blood flow in human (i.e., l/h/ kg) and is therefore indicative of an extensive enzymatic metabolism in blood + effective half-life was calculated to be about min. conclusion: motrem was found to be safe and well tolerated up to the highest dose tested ( mg/kg for a -min loading dose and mg kg h for a . -hours maintenance dose). safety and pharmacokinetics of motrem is currently being studied in septic shock patients in a phase iia randomised, double-blind, two-stage, placebo controlled, international, multicenter clinical trial (www.clinicaltrials.gov nct ). - ) is an immunoreceptor expressed on neutrophils and monocytes macrophages whose role is to amplify the inflammatory response driven by toll-like receptors engagement. the pharmacological inhibition of trem- confers protection in several pre-clinical models of acute inflammation. in this study, we aimed to decipher the role of trem- on the endothelium. we evaluated the expression of trem- in vessels and isolated endothelial cells by flow cytometry, qrt-pcr and confocal microscopy. we generated an endothelium-conditional trem- ko mice and submitted them to polymicrobial sepsis through clp. organs and blood were harvested at different time points and analyzed for cellular content, cytokine chemokine concentrations, and vasoreactivity. survival was monitored for week. results: trem- was expressed in aorta and pulmonary vessels from animals, and inducible after lps stimulation or during sepsis. these results were confirmed in human pulmonary microvascular endothelial cells. the pharmacological inhibition of trem- , using the synthetic inhibitory peptide lr , decreased the lps-induced trem- expression. sepsis induced a profound vascular hyporeactivity in wt animals, both in terms of contractility and endothelium-dependent relaxation. although contractility was still impaired in endotrem- -mice, vasorelaxation was completely restored. soluble trem- concentrations, a marker of trem- activation, were markedly increased in the plasma, the peritoneal lavage fluid and the lungs from wt septic mice compared to control. in endotrem- -mice, strem- level was reduced. plasma concentrations of soluble vcam- and il- were also reduced in endotrem- -animals. we observed an accumulation of neutrophils and inflammatory ly chigh monocytes in the lung of wt septic mice. this accumulation was dampened in endotrem- -mice. by contrast, endothelial trem- deletion favored the accumulation of reparative cells (ly clow monocytes). finally, survival was clearly improved in the endotrem- -group as compared to the wt group. conclusion: we reported that trem- is expressed and inducible in endothelial cells and plays a direct role in vascular inflammation and dysfunction. the targeted deletion of endothelial trem- conferred protection during septic shock in modulating inflammatory cells mobilization and activation, restoring vasoreactivity and improving survival. the effect of trem- on vascular tone, while impressive, deserves further investigations including the design of endothelium specific trem- inhibitors. - . ]. patients suffered from pneumonia, from intra-abdominal sepsis. we measured serum levels of total and free thiamine, thiamine mono di and triphosphate (tmp, tdp and ttp respectively), as well as the erythrocyte transketolase activity and arterial lactate at the time of admission. we also recorded the vital status at the end of the icu stay. results: % of our subjects exhibited particularly low levels of free thiamine (< nmol/l). there was no correlation between free (r = − . ; p = . ), or total (r = − . ; p = . ) thiamine concentration and lactate levels. there was no correlation between tmp (r = . ; p = . ), tdp (r = − . ; p = . ), ttp (r = − . ; p = . ) and lactate levels in the whole population. no correlation was found between the concentration of thiamine derivatives and arterial lactate levels in the subgroup of patients exhibiting the highest levels of lactate (> and > mmol/l). total thiamine and tdp concentration at the time of admission were significantly higher in icu survivors than in non-survivors (p = . and p = . ). during sepsis, we did not find any correlation between thiamine and lactate concentration. lower thiamine diphosphate concentration may be associated with icu-mortality. introduction: a positive fluid balance in sepsis is a determining factor for mortality. in previous experimental studies, sodium lactate has been shown to improve hemodynamic and avoid fluid overload ( ). to understand these beneficial effects, we investigated the impact of sodium lactate on capillary leakage, in comparaison to saline on capillary leak in a rat model. the sixteen sedated, mechanically ventilated rats were challenged with intravenous infusion of e.coli lipopolysaccharide ( mg/kg). two groups of eight animals were randomised to receive a continous perfusion ( ml/kg/h) of sodium lactate . % (treatment group) or . % nacl (control group). in order to inject the same caloric load in the two groups, a . ml/kg/h of either water of % dextrose solution were perfused. mean arterial pressure, heart rate, urine ouput were measured over a min period. an echocardiography was then performed and evans blue ( %, mg/kg) was intravenously injected min before sacrifice. organs were withdrawn and organs wet dry ratio and evans blue dye extravasation were measured. results: fluid balance, organs wet dry ratio and evans blue dye extravasation were not significantly improved in sodium lactate group. hemodynamics parameters were not significantly enhanced after sodium lactate infusion. discussion: previously, lactate administration has improves renal perfusion. in our study, the volume of urine output was decreased in the groups reflecting the severity of our model. and the vascular filling ( . ml/kg/h) higher than in the literature could impact our results. ( ) recently, the pressure electricy index-pmus eadi index (pei) has been described. ( ) the purpose of this study was to assess muscular pressure (pmus) using pei with our nava protocol. patients and methods: observational study, patients recovering from pneumonitis and acute respiratory failure. sbt was pressure support ventilation with cmh of assist and no pep. pei was calculated under nava and during sbt from airway pressure drop during end-expiratory occlusions, muscular pressure (pmus) was estimated from pei ( ) . another index, patient ventilator contribution index (pvbc) was also measured using the inspiratory peak of eadi and vt (inspiratory) during assisted and non-assisted breaths. we calculated pvbc-squared because it has been shown that it is more correlated to pmus ptot. results: results are summarized in the introduction: in icu, intubation is a high risk procedure associated with high morbidity. despite procedure's improvement with systematic application of fluid loading, early use of vasopressors and checklist use, morbidity remains high. first pass success is strongly correlated with adverse event occurrence. a recent study by semler et al. concluded than "sniffing" position is better than "ramped" position to increase first pass success even the primary outcome prespecifiedpulse pressure saturation was not different between the two groups. we conducted a post hoc analysis of the randomized clinical trial macgrath mac video laryngoscope or macintosh laryngoscope for intubation in the intensive care unit (macman) to determine the best position for intubation in the icu. patients and methods: macman was a multicentre, open-label, randomized controlled superiority trial. consecutive patients requiring intubation were randomly allocated to either the mcgrath mac videolaryngoscope or the macintosh laryngoscope, with stratification by centre and operator experience. an only inclusion criterion was-"patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if-contraindication to orotracheal intubation (e.g., unstable spinal lesion); insufficient time to include and randomize the patient (e.g., because of cardiac arrest); age < years; pregnant or breastfeeding woman + correctional facility inmate; patient under guardianship + patient without health insurance; refusal of the patient or next of kin to participate in the study; previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess association between patient position (sniffing or supine) and first pass success. between-groups baseline difference was adjusted for baseline covariates significantly associated with the group membership (p < . ). results: failure of first pass introduction: during acute exacerbation of copd oxygen should be titrated to avoid both hypoxemia and hyperoxia. the recommendations are not followed and automated oxygen titration may be useful in this population. the aim of this study was to evaluate a new device developed to automatically titrate oxygen based on spo target (freeo , oxynov, canada) and to compare oxygenation parameters with usual administration (manual flowmeter). the study is an observational monocentric study. we prospectively included patients hospitalized for acute exacerbation of copd receiving oxygen. written informed consent was obtained from all patient. in the first part of the study, we evaluated oxygen flowrate and spo during min at baseline based on management of the physicians in charge. the oxygenation parameters were compared with automated titration (freeo during h). in the second part of the study, oxygen was delivered with freeo until oxygen weaning or a maximum of h. we evaluated the oxygenation parameters during prolonged utilization, the duration of oxygen administration, a new bluetooth spo connection compared to wire spo connection (evaluated by visual analog scale - ). results: we present preliminary data of copd patients (sex ratio m f = ). mean age (± sd) was ± years, mean fev (± sd) was . ± . l. oxygenation data in both parts of the study are displayed in the table . time in the spo target was significantly increased with freeo in comparison with manual titration and oxygen flowrate was reduced by half. in the second part of the study, the % of time in the spo target with automated oxygen titration was above % and time with hypoxemia and with hyperoxia were low. in patients, we compared comfort with wire spo connection to bluetooth wireless spo connection. the comfort was significantly increased with wireless connection ( . ± . vs. . ± . , p < . ). duration of oxygen administration after inclusion ( . ± . days) and hospital length of stay after inclusion ( . ± . days). conclusion: automated oxygen titration maintains the patients within predetermined spo target more than % of the time and reduces oxygen flowrate in comparison with manual oxygen titration. the second part of the study demonstrates the feasibility to use automated oxygen titration during several days with similar outcomes as previously reported in similar population. there are several limitations of the study and additional evaluations of this device are required. introduction: hyperoxemia occurs up to % of mechanical ventilation days in the icu [ ] and is associated with increased mortality as compared to patients ventilated in normoxemia [ ] . intellivent-asv is a full closed loop ventilation mode adjusting automatically oxygenation's settings fio and peep according to spo for passive and spontaneously breathing mechanically ventilated patients. this post hoc analysis of a monocentric randomized controlled parallel group study compared frequency of hyperoxemia (pao > mmhg and or spo > %) and hypoxemia (pao < mmhg and or spo < %) and the percentage of ventilation time with spo > % and the percentage of ventilation time with spo < % between intellivent-asv and conventional ventilation mode in mechanically ventilated icu patients. the randomized controlled trial was performed in the general icu of hôpital sainte musse, toulon, france. eligible participants were adult aged or over, invasively ventilated for less than h at the time of inclusion with an expected duration of mechanical ventilation of more than h. exclusion criteria were broncho-pleural fistula, ventilation drive disorder and moribund patients. patients were allocated to intellivent-asv group or to conventional ventilation group (volume assist control and pressure support modes) using blocked randomization. the post hoc analysis was performed by the comparison of all arterial blood gases (abg) performed during the study period-the number of abg with hyperoxemia and hypoxemia, the median pao and spo for these arterial blood gases and fio associated were compared according to group. results: patients were included, patients in each group. the total number od abg was (mode conventional) vs (mode intel-livent-asv) (p = ns). the number of abg with pao > mmhg was respectively versus (p = . ) with sao > % was vs (p = . ) with pao < mmhg was vs (p = . ) + with sao < % was vs (p = . ). the percentage of time of ventilation spent with spo > % was % vs (p = . ), and with sao < % was . vs . (p = . ). the continuous control of oxygenation settings provided by intellivent-asv decreases significantly the number of blood gas with hyperoxemia as compared to manual oxygenation setting without increasing the risk of hypoxemia. introduction: in invasively mechanically ventilated patient, dyspnea is frequent and severe. relying on self-report, its measurement remains challenging in patients unable to communicate. a -item observation scale, namely the intensive care-respiratory distress observation scale (ic-rdos), has been proposed as a surrogate of dyspnea-visual analogic scale (d-vas) self-report in intensive care unit (icu) patients [ ] . however this scale has been validated among non-intubated patients and included one item "supplemental oxygen" not thoroughly adapted for intubated population. we sought to develop a dyspnea observation scale more suitable for intubated patients and to evaluate its performance to detect dyspnea. patients and methods: ancillary analysis of data prospectively collected from icu communicative patients enrolled for the validation of the ic-rdos. factorial principal component analysis was first performed to select variables that mostly contributed to the principal axes, among a set of observable variables with possible clinical relevance. to identify the best correlation between these variables and d-vas, were performed an iterative partial least square regression process (pls). iterative pls procedure identified five variables, of which the combination and weighting allowed optimal correlation with d-vas (r = . ; % ci . to . ; p value < . ), which constitute the ic-rdos [ ] . in a first step, we removed "supplemental oxygen", not relevant in intubated patients. we obtained a -items ic-rdos (r = . introduction: lung ultrasound (lus) has emerged in different clinical settings, such as in intensive care medicine (icm). early diagnosis of ventilator-associated pneumonia (vap) remains a challenge to the intensivist. however, scientific evidence is little available on whether lus reliably improves the diagnosis of vap. the aim of this prospective study was to assess whether lus could be an alternative to pulmonary computerized tomography (ct) for assessing diagnosis of vap in icm. patients and methods: twenty-one patients ventilated for duration more than days suspected of vap were included. lus was performed by a well-trained operator who was blinded of the vap diagnosis. the diagnostic gold standard of vap was on the basis of pulmonary ct and positive culture pulmonary. all clinical criteria for the diagnosis were collected the same day of lus and pulmonary ct. the ultrasound exam included anterior, lateral and posterior views from both sides of the chest with superior and inferior views. we classed patient in groups according diagnosis of vap with pulmonary ct (vap + or vap-) and lus (lus + or lus-). lus characteristics of vap diagnosis included profils-asymetric line b (profil a b), without sliding (profil b'), sub pleural consolidation (profil c), consolidation with punctiforme bronchogram (pb), linear air bronchograms (lb) or dynamic bronchograms (lbd), posteror lateral alveolar pleural suffusion (plaps), pleural effusion pathological (pep), shred sign (ss and complications according to insertion site. the advantage of this method is that it gives a pragmatic view of the real clinical situation. patients and methods: ancillary study of the akiki trial, an open pragmatic randomized controlled trial published in , in which patients with severe acute kidney injury were randomly assigned to either an early or a delayed rrt initiation strategy. the present study involved all patients who underwent at least one rrt session. number of rrt catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected. results: among the patients included in akiki, received rrt at least once and patients were finally included in the analysis ( missing data), leading to a total of rrt catheters. femoral site was chosen preferentially (n = , %), followed by jugular site (n = , %) and subclavian site (n = , %). investigating center was the sole factor significantly associated with the choice of insertion site in multivariate analysis (p = . ). higher weight did not affect choice of insertion site. mean duration of catheter use was . (+- . ) days without difference according to site. catheter dysfunction was the main reason for replacement (n = , %). suspicion of infection led to replacement of many catheters (n = , %) but was actually seldom proven (n = , % introduction: long standing dialysis (sled or crrt) allows a better hemodynamic tolerance as well as a greater performance to achieve a negative fluid balance in intensive care unit. dialysis alter hemodynamics mainly by short term variation of blood volume. in this study we took advantage of a continuous monitoring of blood volume during dialysis session to decipher the relationship between the variation of relative blood volume (rbv) with mean arterial pressure (map). this study is observational prospective, including all prolonged (> h) dialysis sessions in saint etienne nephrology intensive care unit between january and june . exclusion criteria were ongoing blood transfusion and blood volume controled ultrafiltration. medical records were compiled along with cardiac ultrasonography at the beginning when available. the statistical analysis was perfomed in two parts. the first part studied the performances of the first hour deltarbv (defined by rbv before minus rbv after h of dialysis) to predict a drop of map below mmhg (hypotension). this analysis excluded sessions with hypotension and intervention during the first hour. the second study was the modelization of the relationship between deltarbv and deltamap for every hour of dialysis without any intervention on blood pressure. both analyses were performed using mixed effects linear and generalized models. fig. vancomycin pk during sled results: a total of sessions on different patients were performed during the period. the characteristics of patients were as follows-sex ratio at , age (sd) . ( . ), weight . kg ( . ), sapsii score . ( . ) . patients on were taken in charge for fluid overload. in the first set of analyses (per sessions), sessions were excluded for intervention in the first hour. the adjusted deltarbv did not predict hypotension during the session (generalized mixed effect model, session and patients set as random effects, estimate . , p = . ). in the second set of analyses (per hour without any intervention), h were analyzed. adjusted deltarbv correlated strongly and inversly with deltamap (linear mixed effect model, random effects were sessions, patients and hour order in the session, estimate . , p < . ). conclusion: in our mostly fluid overloaded patients, the drop of rbv correlated with an increase of map. introduction: kidney transplant recipients (ktr) are at risk of icu admission because of prolonged immunosuppressive therapy and a higher risk of cardiovascular events, severe infections or drug-related toxicities. several retrospectives studies reported the short-term outcome of ktr admitted to the icu, but data concerning the risk of chronic kidney disease and anti-hla immunization are scarce. patients and methods: in this retrospective study, we addressed the in-hospital and long-term mortalities of the ktr admitted in a french icu ( beds) between january and june . predictive factors for death, long-term renal function and hla immunization were identified. results: the main causes for admission were acute respiratory failure ( . %), sepsis ( . %), post-operative period (peritonitis, hemorrhage + %). at the admission, mean age, saps and sofa score were ± years, ± and . ± . , respectively. renal replacement therapy, mechanical ventilation and vasopressors were required in ( . %), ( . %) and ( . %) patients. immunosuppressive regimen was modified in patients ( . % + steroids increase %, calcineurin inhibitors or antimetabolites withdrawal and %, respectively). in-hospital mortality was % ( . and . % at months and ). by multivariate analysis, ebv blood proliferation in the months preceding the admission in the icu, and the saps gravity score at admission independently predicted the in-hospital and long-term mortalities. among the patients alive at month after the admission in the icu and with available data, ( . %) and ( . %) progressed to a more severe ckd stage at months and , respectively. both, the severity of the aki and the preexisting ckd predicted the risk of progression of the ckd. last, de novo anti-hla immunization at month was identified in patients ( . %, donor specific antibodies ( . %)) and was significantly associated with the occurrence of acute transplant rejection (p = . ). in five patients who developed anti-hla antibodies, rbc transfusion during the icu stay was the only immunological trigger identified. discussion: outcome of ktr is closed to the general population admitted in icu and better than other immunocompromised patient, like patients from oncohematology. conclusion: worsening of the renal function and hla immunization are frequent and may impact mid to long-term prognosis because of the high risk of transplant rejection, end-stage renal disease and further transplantation contraindication. introduction: acute kidney injury (aki) is associated with a poor prognosis. although pulmonary embolism (pe) may promote aki through renal congestion or hemodynamic instability, its frequency as its impact on the prognosis of patients with acute pe have been poorly studied. patients and methods: using data from the registro informatizado de la enfermedad tromboembolica venosa (riete) registry, we assessed the frequency of aki at baseline, and its influence on the -day mortality rate of patients with objectively confirmed pe. aki was defined according to the "kidney disease-improving global outcomes" definition. we used multivariate analysis to assess whether or not the presence of aki independently influenced the risk for -day death. the study included , patients with acute pe, of whom ( . %) had aki at baseline. of these, patients ( %) were in stage , ( . %) in stage and ( %) in stage . the proportion of patients with high-risk pe in those with no aki, aki stage , aki stage and aki stage was- . , . , . and %, respectively (p < . ). after days, patients ( . %) had died. overall mortality was- % in patients with no aki, . % in aki stage , % in aki stage , % in aki stage , all p < . ). on multivariable analysis, aki was independently associated with an increased risk of death at days (odds ratio = . + % ci . - . ), after adjusting for the initial severity of pe, age > years, chronic heart failure or chronic lung disease, cancer, anemia and liver cirrhosis. conclusion: one in every - patients with acute pe had aki. moreover aki was an independent predictor of poor outcome in pe patients. this study suggests that pe (and its severity) should be considered as a risk factor for aki and aki may deserve to be evaluated as a prognostic factor in patients with acute pe. introduction: metabolic acidosis is frequently observed as a consequence of global ischemia-reperfusion after out-of-hospital cardiac arrest (ohca). we aimed to identify risk factors and assessing the impact of metabolic acidosis on outcome after ohca. patients and methods: we included all consecutive ohca patients admitted between and . using admission data, metabolic acidosis was defined by a positive base deficit and was categorized by quartiles. main outcome was survival at icu discharge. factors associated with acidosis severity and with main outcome were evaluated by linear and logistic regression, respectively. results: patients ( . % male, median age years) were included in the analysis. median base deficit was . [ . , . ] meq/l. male gender (p = . ), resuscitation duration (p < . ), initial shockable rhythm (p < . ) and post-resuscitation shock (p < . ) were associated with a deeper acidosis. icu mortality rate increased across base deficit quartiles ( . , . , . and . %, p for trend < . ) and base deficit was independently associated with icu mortality (p < . ). the proportion of cpc patients among icu survivors was similar across base deficit quartiles ( . , . , . and . %, p = . ) and . % of patients with a base deficit higher than . meq l survived to icu discharge with a good neurological recovery. severe metabolic acidosis is frequent in ohca patients and is associated with poorer outcome, in particular due to refractory shock. however, we observed that about % of patients with a very severe metabolic acidosis survived to icu discharge with a good neurological recovery. introduction: precarious socio-economic status can directly influence health, need for hospitalisation and mortality, according to a previous study performed in european countries. similar findings have been reported from anglo-saxon countries in the setting of intensive care. due to the different structure of the healthcare system in france, we aimed to investigate whether socio-economic status influences initial severity of disease and months mortality in patients admitted to intensive care in france. patients and methods: prospective, multicentre, cohort study including adult patients admitted to one of participating intensive care units (icus) between and , and presenting failure of one or more major organs. patients were considered to have a precarious socio-economic status if they presented at least one criterion of social vulnerability or a high epices deprivation score. results: data on social vulnerability were available for patients, of whom . % were considered to be socially vulnerable. compared to non-vulnerable patients, socially vulnerable patients were younger ( . vs . years, p = . ), more frequently had chronic disease ( . vs . %, p = . respectively for congestive heart failure and . %vs . %, p = . for chronic respiratory disease), had higher levels of physical dependency ( . vs . %, p = . ), and were more often classed as having long-term health conditions ( . vs . %, p < . ). conversely, non-vulnerable patients had greater severity of disease at admission to the icu than those classed as vulnerable, both in terms of saps ii and sofa scores (respectively . vs . (p = . ) and . vs . (p = . )). findings were similar after adjusting for major confounders (adjusted odds ratio (or) . , % confidence interval (ci) [ . - . ], p = . ). mortality at months was not significantly different between socially vulnerable patients and those not considered vulnerable, respectively . vs . % (p = . ), even after adjustment for initial severity. conclusion: despite less severe disease at admission to the icu among patients considered socially vulnerable, -month mortality did not differ significantly between those who were socially vulnerable and those who were not. these findings suggest that the french healthcare system provides good protection for the most disadvantaged members of society, particularly when they are admitted to the icu. introduction: an approach of the quality of care may involve assessing the patients' satisfaction. however, the extended caregiverpatient and family relationship, specific to the critically ill patients, may also require to assess the proxies' satisfaction. the opinionfamily tool was developed to assess the satisfaction of the critically ill patients' proxies, in an anonymous and continuous fashion. we conducted a study in the icu of tenon hospital (paris, france) between mars and august . the opinion-family questionnaire, built with categories ( items each), aimed to measure the proxies' satisfaction regarding their perception of the quality of care. all the proxies were invited to express voluntarily and anonymously his her degree of agreement as a response to a statement by the selection of the corresponding stars (strongly disagree- star, disagree- stars, neither agree nor disagree- stars, agree- stars, strongly agree- stars) using a secure touch screen disposed in the waiting room of the icu. results: altogether, patients were hospitalised during the study period, and proxies completed the questionnaire. all the responders spoke french. only responders ( %) answered more than one time. of the responders, ( %) were the referring person, ( %) were children and ( %) were spouses. during the study period, ( %), ( %), and ( %) responders had visited their relative to times, to times, and more than times, respectively. the different categories assessed by the opinionfamily tool were related to «the family and the patient» (fig. a) , «the family and the environment» (fig. b) , and «the family and the caregivers-availability, trust, support, and information» (fig. c) . the corresponding levels of satisfaction (responses of at least stars) were respectively , , , , , and %. some items were associated with a poor satisfaction (participation to the care, identification and availability of the caregivers). conclusion: the implementation of the opinionfamily tool allowed a continuous evaluation of the satisfaction of the critically ill patients' proxies. a systematic implementation of this tool in the icus may be useful to the caregivers for a better understanding of the needs of the proxies. in addition, this tool may allow rapid changes in icu organizations and behaviours to improve the proxies' satisfaction, which may ultimately, improve the care of patients. many factors influence end-of-life decisions (eol). we describe eol decisions in patients with acute respiratory failure and their impact on patients' prognosis. patients and methods: an international observational study included all patients with acute respiratory distress over a -month period. icu in countries were involved. demographic, clinical and biological data were compared between patients with and without decision of lst limitation. we also compared surviving patients after lst limitation decision to those who eventually died. results: among the patients, mortality was . %. a decision of lst limitation was reported in patients ( . %). in univariate analysis, patients with lst limitation decision were older and more frequently hospitalized for a medical condition, had a lower body weight, a higher sofa score, and presented active neoplasia immunosuppression or chronic liver failure more frequently (p < . for all). patients admitted after trauma, drug overdose or pulmonary contusion were less subject to have an lst limitation decision (p < . ). in contrast, patients with non-cardiogenic shock were more subject to these decisions (p = . ). eol decisions were less frequent in lower-middle income countries as compared to high and middle-high income countries (p < . ). multivariate analysis will be presented. among patients with an lst limitation decision, survived ( . %). mortality was higher in this group than in the whole study population (p = . ). in univariate analysis, death after decision of lst limitation was associated with admission for a medical condition (p = . ), severe ards, higher inspiratory pressure, non-cardiogenic shock, higher sofa score with or without respiratory component and chronic liver failure (p < = . for all). on the contrary, admission for trauma was associated with survival (p = . ). regarding the patients who died during their hospital stay, did not receive a decision of lst limitation ( . %). decision of lst limitation was more frequent in older patients (p < . ) and in high-income countries. conclusion: decisions of lst limitation are frequent in the icu, and are associated with increased age and medical severity. however, a significant percentage of these patients survived. interestingly, almost half of the patients who eventually died during their hospital stay had not been subject of a decision of lst limitation. evaluation of the decision-making process leading to a decision not to readmit a patient to the intensive care unit during a same hospital stay introduction: the risk-benefit ratio of (re-)admission to the intensive care unit (icu) has been widely discussed in the literature. however, the ethics of non-readmission during a single hospital stay have not been widely addressed. a decision not to re-admit a patient to the icu could be seen as a limitation of therapy, thus falling within the scope of the law dated april , by denying the patient access to potentially-available healthcare resources. in this context, we aimed to-( ) investigate whether decisions not to re-admit patients to the icu are taken in accordance with french legislation + and ( ) identify the characteristics of patients concerned by this type of decision. patients and methods: this study was based on data from the prospective, multicentre ivoire cohort (influence of socio-economic vulnerability on initial severity and prognosis of patients admitted to the icu + phrc-ir ). we identified patients included in two large regional university hospitals in the east of france for whom a decision not to re-admit was taken during a single hospital stay. the decisionmaking process was evaluated based on a questionnaire comprising items developed by a sociologist from semi-directive interviews with clinicians. results: among patients discharged from the icu alive, a decision not to re-admit to the icu during a same hospital stay was noted in the medical file of patients ( . %). this decision was primarily made on the day of discharge ( . %), and those involved in the decision included-the family, an outside consultant, and the patient themselves in , . and . % of cases respectively. the decision was justified in medical terms in . % of cases, and the main reasons cited were-( ) therapeutic impasse ( . %) + ( ) comorbidities ( . %) + ( ) degree of dependence of the patient ( . %). patients concerned by decisions of this type were generally older ( vs . years, p < . ), with more comorbidities (median vs , p = . ), greater loss of dependence according to katz's activities of daily living ( vs , p < . ), and longer duration of life-sustaining therapies ( . vs days, p = . ). conclusion: although the profile of the patients identified in this study likely justified the decision not to re-admit the patient to the icu, there is room for improvement in the decision-making process. introduction: most of organ donors are brain dead patients. in some cases, patients are identified as potential donors before brain death and will undergo intubation and mechanical ventilation for the sole purpose of awaiting brain death. the aim of this study is to evaluate the practices of professionals in charge of potential donors. (table ). in this case, the issue of organ donation was addressed to the relatives before intubation by % of icup and % of non icup (p = . ). % of participants never addressed organ donation before the brain death. for the % who have done so at least once, organ harvesting never happened in % of cases. legitimacy and difficulties ( table )- % of respondents felt that when a decision of treatment withdrawal or withholding is taken, the patient should not go to icu for any reason and % think that these patients should be allowed to die "quietly". the prospect of an extubation if brain death does not occur or in case of organ donation refusal is a problem for % of icup and % of non icup (p = . ). % of icup and % of non icup think they would need to receive training. conclusion: this study shows that pursuing mechanical ventilation for the sole purpose of awaiting brain death and organ harvesting is a common practice, and that intubating a patient for this purpose alone is done in most of cases but could still be more generalized. on the other hand, information to the relatives should be improved. - . ] . the effect of pp on the monitored parameters varies significantly between each patient but also between each session for the same patient. in positive responders, the effect continues statistically for to h depending on the parameter studied- . h for vd vt, . for phase slope, for petco and for cdyn. the maximum effect of prone positioning on selected parameters seems to be obtained after h of therapy. the acute respiratory distress syndrome (ards) is characterized by lung infiltration with activated neutrophils. neutrophil extracellular traps (nets) are antimicrobial structures released by neutrophils. nets have also been associated with tissue damage in experimental models of acute lung injury. whether nets are involved in the pathogenesis of human ards and could be a potential therapeutic target is unknown. we aimed to quantify alveolar nets production in patients with pneumonia and ards and assess its relationship with outcomes. patients and methods: prospective monocentric study. patients admitted in the icu in with pneumonia and moderate severe ards were included. immunosuppressed patients were excluded. nets (dnamyeloperoxidase) levels were measured by elisa in broncho-alveolar lavage (bal) fluid and serum samples of ards patients and in those of control patients (n = ). patients with higher and lower bal fluid nets levels were compared using the median as a cutoff value. results: thirty-five patients with bacterial (n = ), viral (n = ) or non-microbiologically documented (n = ) pneumonia and ards were included. nets levels were significantly higher in bal fluid than in blood of ards but not of control patients (fig. introduction: the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pao fio or p f) is daily used to assess patients' evolution under ventilatory support. some studies reported the reliability of percutaneous oxygen saturation (spo ) to appreciate pao easy to get on bedside. thus two equations have been proposed-rice equation and ellis equation. however, no large prospective study assessed the reliability of such equations to estimate the p f at the bedside in real conditions. using the spectrum (severe hypoxemia-preva-lence, treatment and outcome) study, we aimed to evaluate the reliability of spo obtained by rice and ellis equation. this study is a planned companion of spec-trum study, a recent prevalence-point-day conducted by the srlf trial group in french-speaking icu aiming to report the patterns and outcomes of hypoxemic patients (defined by p f < mmhg). we included in the analysis all patients under mechanical ventilation with spo < % (according to limit of the rice study). spo and fio were measured simultaneously to arterial blood gas were drawn. results: among patients of the spectrum study, were on mechanical ventilation and had undergone arterial blood gas with simultaneously recorded spo and fio . of note, p f was < mmhg for + between and for + and between and for . pairwise correlations of truth p f with estimated p f was good (rice-spearman's rho = . , p < . -ellis-rho = . p < . ). bland-altmann test showed an important variability of results (p f vs rice (figure) - . ± . -p f vs ellis- . ± . ). the variability decreased with lower p f. caution may be used to interpret our results because we did not reported the quality of spo signal at the bedside. conclusion: regarding the variability of the results, whatever the used equation, caution may be used to predict the p f by the spo fio ratio in patients under mechanical ventilation. introduction: morbid obesity and ards both affect respiratory mechanics mainly through their respective impacts on chest wall and lung elastances. we present a unique series of patients combining very severe morbid obesity and moderate to severe acute respiratory distress syndrome (ards). we describe the use of trans-pulmonary pressures (tpp) measurements for optimization of external peep setting. patients and methods: the monocentric observational study was performed in morbidly obese patients admitted for moderate to severe ards. we performed an incremental peep trial ( cm h o steps) with tpp measurement (nutrivent probe, sidam, italy) in a semirecumbent position as previously described. a decremental peep trial after a recruitment maneuver was not performed since the safety of such a maneuver in this specific population is largely unknown. we defined two ways for determination of external peep setting-( ) peep necessary to obtain a positive expiratory tpp and ( ) peep necessary to obtain a plateau pressure between and cm h o (maximal alveolar recruitment express strategy). data are expressed as numbers (%) and medians (interquartile range). statistical analysis was made using the xlstat software. results: we enrolled during years morbidly obese patients (bmi (ir - )) admitted for a moderate to severe ards. clinical characteristics are displayed in table . the express strategy indicated a peep setting of cm h o (ir - ) whereas tpp-guided peep was cm h o (ir - ), p = . . driving pressure was higher in the express strategy peep setting ( . cm h (ir - )) than in the tpp-guided peep ( . cm h (ir . - )), p = . . tpp-guided peep setting was higher than indicated by the express strategy in all but one patient. one patient suffered from transient hypotension when external peep was set at cm h o, while no patient displayed an inspiratory tpp higher than cm h o. additional data will be provided during the meeting-pressure-volume curve at zeep ( patients), crf measurements ( patients) and abg and capnometry values at each peep level ( patients) . in our ards patients with extremely severe obesity, an incremental peep trial with tpp measurements appeared to be safe and indicated a peep setting significantly higher than for the commonly-used ards strategies. such an approach deserves further comparisons with other modalities of monitoring, such as crf measurements, eit studies, etc. severe poisoning by cardiotoxic drugs and circulatory assistance: -year experience at french university hospital tardif elsa , conil jean-marie , georges bernard , marcheix bertrand , crognier laure , bounes fanny , delmas clement chu rangueil, toulouse, france correspondence: tardif elsa -tardif.elsa@gmail.com annals of intensive care , (suppl ):f- introduction: toxicity from cardiac drugs is associated with a large number of fatalities, significant morbidity and healthcare consequences. severity of these poisonings can be explained by a refractory cardiogenic shock not responding to optimal conventional treatment. criteria of circulatory assistance indications remain unclear. the aim of the study was to describe and to compare patients intoxicated by cardiotoxic drug treated with or without veno-arterial extracorporeal membrane oxygenation (va ecmo). patients and methods: retrospective cohort study conducted at french university hospital. all patients intoxicated with cardiotoxic drugs between january and march were included. patients were divided into groups-with and without va ecmo. results: among the patients included in the study, patients were treated with va ecmo ( %) and patients with conventional therapies. ecmo was respectively employed for refractory shock and cardiac arrest in and cases, all patient required vasopressor support. in-hospital mortality was . % and was significantly higher in the ecmo group ( . %). beta-blockers with membrane stabilizing activity and non-dihydropyridine calcium channel blockers poisoning were the most commonly reported in the ecmo group. mean time from hospital admission to initiation of ecmo was h and the average ecmo duration was . days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . no serious adverse reaction was reported during this period. results expressed in median value ± confidence interval conclusion: refractory cardiogenic shock following cardiotoxic drug poisoning requiring circulatory assistance is associated with significant mortality. even if its use seems justified by the literature, the implantation criteria must be specified and this after an optimal conventional treatment to prevent multiple organ failure. the cdv of patients in the edass group was significantly higher (p < . ) at all-time points after the introduction of catecholamines than among those without edass, as early as h from catecholamine initiation (fig. ) . a strategy in two steps (cdv > µg kg at h and or cdv > µg kg at h) was able to predict edass with sensitivity of %, specificity %, positive predictive value % and negative predictive value %. overall, this two-step strategy identified high-risk patients at h, of whom presented edass. conclusion: overall, our results confirm that early death directly attributable to septic shock could be effectively predicted by the cdv in the first hours of treatment. these results will help to select patients eligible for innovative therapies aimed at improving early mortality in septic shock. introduction: in patients with cardiac arrest, end-tidal co (etco ) has been proposed to monitor the efficacy of cardiopulmonary resuscitation (cpr) but uncertainty persists on its interpretation. we hypothesized that exhaled co may also by affected by occurrence of "lung airways" collapse previously noticed during cpr. because this closure may possibly also limit oxygenation + analysis of the entire exhaled co time waveform-may give information of high clinical value to manage cpr. we report preliminary results from a clinical and bench study aimed at describing the pattern of the capnogram during cpr. induces a systemic inflammatory response associated with an immune dysregulation and a significant pulmonary dysfunction which has been well characterized. surprisingly, there are only a few data available on immunological changes induced by ecls. we believe that ecls leads to immune dysfunction that could expose patients to nosocomial infections. patients and methods: a two-phase study was lead. first we analyzed blood cell count with differential (including lymphocyte, neutrophils and monocyte counts) in all patients who received ecls in our institution from to within the first week following ecls initiation. secondly, monocytes, granulocytes, dendritic cells and lymphocytes function were assessed at day , day and day using flow cytometry and functional tests in patients receiving ecls and compared to patients with cardiogenic shock without ecls. results: among patients with elcs we found an early and persistent lymphopenia and a late neutrophilia (found to be associated with poor outcome in critically ill patients). compared to control (n = ), we found in patients who received ecls (n = ) a significant increase in immature granulocytes ( . ± . on day one versus . ± ± , p = . ) and lymphocytes apoptosis. ecls induced changes in myeloid derived suppressors cells proportion ( . % ± . on day three versus . % ± . before ecls, p = . ), which has been recently associated with a higher incidence of nosocomial infections and seems to be major actors of sepsis-induced immune suppression. complement component a receptor (c ar) from the neutrophil cell surface, was also decreased after ecls initiation (ratio of mean fluorescence index . ± . on day one, p = . ) which is a sign of complement-induced neutrophil dysfunction in septic patients. conclusion: ecls induces quantitative and qualitative leukocytes dysfunctions that can lead to a greater susceptibility to nosocomial infections which contribute to the poor outcome observed in several studies. introduction: aspiration pneumonia is a common complication of cardiac arrest. although its real incidence remains undetermined, probabilist antibiotherapy is frequently or even systematically prescribed in these cases. we assessed the incidence of out-of-hospital cardiac arrest-related aspiration pneumonia and the impact of a microbiological documentation in regard to antibiotherapy course. patients and methods: all patients admitted for out-of-hospital cardiac arrest from to were studied. in our icu, aspiration pneumonia is suspected when a clinical syndrome (fever, per resuscitation constatation) and or chest radiography infiltrates were present. in case of suspected aspiration pneumonia, a microbiological documentation was performed before initiation of probabilist treatment with amoxicillin-clavulanate. we retrospectively defined if patients have aspiration pneumonia using the following criteria-per resuscitation constatation, chest radiography infiltrates, fever. the number of microbiological documentation leading to an antibiotherapy modification was recorded as well as pathogens types. data are expressed as numbers (%) and medians (interquartile range). statistical analysis was made as appropriate using the xlstat software. results: patients were studied. clinical characteristics are displayed in table . ( ) received a probabilist antibiotherapy and ( ) were retrospectively considered with aspiration pneumonitia. results of microbiological documentation were ( ) positive microbiological sample and ( ) with a positive threshold whose ( ) were considered colonized (i.e. no clinico-radiological sign). on the entire positive culture sample, ( ) were positive with oropharyngeal flora as unique pathogen, ( ) introduction: this study aimed to assess whether augmented renal clearance (arc) impacts negatively on piperacillin-tazobactam pharmacokinetic pharmacodynamics (pk pd) target attainment in critically ill patients receiving g day by continuous infusion. patients and methods: over an -month period, all critically ill patients treated by piperacillin-tazobactam for a suspected or documented sepsis without renal impairment were eligible. during the first three days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at steady state. the main pk pd outcome investigated in this study was the rate of empirical target non-attainment using a theoretical target mic of mg l − for piperacillin and mg l − for tazobactam. the secondary clinical outcome was the rate of therapeutic failure in microbiologically documented infections, defined as an impaired clinical response with a need for escalating antibiotics during treatment and or within days after end-of-treatment. over the study period, patients were included in the primary pharmacological analysis and in the secondary clinical analysis. using a mic of mg l − for piperacillin, the rate of empirical target non-attainment in the overall population was %, with a strong association with crcl ( fig. introduction: invasive fungal infections are a major burden in solid organ transplantation, especially in patients receiving liver graft. however, their incidence has decreased thanks to the development of an antifungal prophylaxis in the post-transplantation period. in patients at high risk of invasive fungal infection (ifi), this strategy is recommended, whereas its benefit remains controversial in low-risk patients. however, there is no clear definition of these two patients groups. our aim was to provide recent data on epidemiology, mortality and ifi risk factors in the early post-operative course in a population without any antifungal prophylaxis. results: the number of beta-lactam antibiotics was . of these requests, half were for piperacillin ( . %), and onethird were for amoxicillin ( . %). the other dosages were mainly for cloxacillin, cefepime, cefotaxime and ceftriaxone. the results confirmed that serum concentrations of piperacillin ( . ± . vs . ± . mg l − < . ) and amoxicillin ( . ± . vs ± mg l − < . ) significantly were higher in patients with neurological disorders or wakefulness delays. the roc curves allowed the predictive values associated with the presence of neurological disorders attributable to antibiotic treatment, corresponding to residual serum concentrations of piperacillin of mg l − and amoxicillin of mg l − . a predictive value for neurological disorders of these concentrations is proposed for residual serum concentrations greater than mg l − for both antibiotics ( % specificity and sensitivity). conclusion: our results suggest that there is an association between a residual concentration of piperacillin and amoxicillin greater than mg l − and the occurrence of neurological disorders. pharmacological therapeutic monitoring of beta-lactams in critically ill patients may be a useful intervention to optimize the antibiotic regimens and to avoid antibiotic-related toxicities. ( ) ( ) ( ) ( ) ( ) . patients with a gnb-bsi were included and were divided into two groups according to the resistance (r) profile (bsi due to a r isolate or not). the following resistances were considered-all gnb-bsi including pseudomonas spp., acinetobacter spp., stenotrophomonas spp. and enterobacteriacae (eb) for which the following antimicrobial resistances were considered-ticarcillin and ceftazidime (cefta) (pseudomonas (pa)), third generation cephalosporin ( gc) (eb) and imipenem (all gnb). after variable selection using random forest and univariable mixed logistic regression models, a multivariable analyses using a mixed model with a random effect (center). sub-group analyses were performed according to species (pa and eb) and resistance for eb. results: from , patients admitted in an annual median of french icus, experienced an icu-acquired (> h.) bsi, ( %) bsi due to gnb, including ( %) bsi due to r isolates. pa was identified in ( %) (mdr-pa bsis ( %)) and eb in ( %) (mdr-eb bsis ( ( %)). the raw mortality rate was % in the overall population and % in the patient with gnb bsi. it was significantly higher for r gnb bsi ( vs % for susceptible gnb bsi, p < . ). after adequate adjustment in a multivariate analysis, we showed that r-gnb bsi was significantly associated with mortality compared to susceptible strains (fig. ) . by considering species subgroup, the effect was not significant for resistant pseudomonas aeruginosa (p = . ) but remained significant when considering only eb. considering eb resistance, the impact of gc r showed a trend to an increased mortality risk whatever there was no effect of imi r (n = ( %)) on prognosis. limitation-the absence of information about antibiotic consumption may partly explain the remaining significant center random effect in the final models. conclusion: in a large french database, after adequate adjustment on prognostic factors, resistant bgn-bsi was associated with a higher icu mortality than susceptible one. the effect was mainly due to eb gc r. severely injured group versus . ± . days for the non-severely injured patients (p < . ). in multivariate analysis, heart rate (> min) and vittel score (≥ criterias) were related to the probability of belonging to the severely injured group (p = . ). the -hour mortality rate was . % in the ed and the -day mortality rate was . %. the development of a network in the ed hosting non vital polytraumas remains crucial. its primary goal will be to meet technical and time requirements and establish in-hospital triage algorithms based on clinical variables, in order to detect these patients at an early stage and offer them priority care in our overcrowded eds. introduction: the trauma of traffic accidents and particularly cranial trauma are, due to their frequency and severe consequences in both the short and long term, a real public health scourge on a global scale. studies of the epidemiology of cranial trauma by traffic accidents and their prognosis are rare at least in underdeveloped or developing countries. in addition, the impact of extracranial lesions on cranial trauma prognosis has long been discussed. the purposes of our study were to examine the epidemiological aspects and to determine the factors correlated to the immediate and distant prognosis of isolated cranial trauma. patients and methods: retrospective cohort spread over years (from to ) and including patients with isolated cranial trauma by traffic accidents (mean age . years, sex ratio- ). we proposed to study the factors correlated with a poor prognosis in terms of death in hospital and glasgow outcome scale (gos) at months unfavorable in dual analysis (univariate and then multivariate). for the gos study, patients were divided into groups-gos favorable for patients with good recovery (gos = ), recovery with a light handicap (gos = ), gos unfavorable for those having survived with a severe disability (gos = ), a vegetative or pauci-relational state (gos = ) and those who died (gos class ). results: hospital mortality was % and the gos at months was distributed as follows: death ( . %), vegetative state ( . %), severe disability ( . %), mild disability ( %) and good recovery ( . %). the -month gos was deemed unfavorable in . % of the cases. various after effects were observed in survivors: physical ( %) dominated by headache ( . %), sleep disorders ( . %) and epilepsy ( . %); memory disorders ( . %) or concentration ( . %) and finally emotional after effects ( . %) with irritability ( . %) and aggressiveness ( . %). in multivariate statistical analysis, independent predictors of mortality were arterial hypotension, hypoxia extradural hematoma (edh),, acute subdural hematomas (sdh), diffuse axonal injury and ventilator associated pneumonia. those correlated with an unfavorable gos were an age ≥ years, hypotension, cerebral edema, coma duration ≥ . days, edh and h glucose ≥ . mmol/l. conclusion: although the short-term prognosis of head trauma seems to be improved at present, the long-term consequences of cranial trauma remain fairly frequent, and often underestimated, which underlines the importance of their screening and their proper care. the average age of the survivors ( . ± . years) was lower than the mean age of the deceased ( . ± . ). ra was the cause of the trauma in % of the cases followed by the fall found cat % of the patients. prehospital care only concerned % of patients. the univariate analysis showed that the main factors of occurrence of death were age (p = . ), glasgow score (p = . ) anisocoria (p = . ), shock (p = . ) % of deaths were due to intracranial hypertension, haemorrhagic shock in % of patients and ards in % of polytrauma patients. conclusion: the management of polytrauma can not be improvised. the medical teams must be coordinated by an emergency physician in prehospital, a doctor anesthesiologist-resuscitator at the reception. some systematic gestures such as preparation of the reception allow to optimize the management of the time. introduction: benign cranial trauma is a major public health problem due to both its frequency and the health costs it creates. the aim of this study was to identify relevant clinical factors that could predict the achievement of brain ct and situations at risk for neurosurgical care and for which ct was a necessity. patients and methods: this is a month prospective study, including patients with benign traumatic brain injury (glasgow coma score gcs ≥ ), patients under years of age and patients with gcs < were excluded. epidemiological, clinical, paraclinical, therapeutic and evolutionary parameters were studied. a multivariate and univariate statistical study was carried out to reveal the predictive factors of a ct anomaly and the predictive factors for the neurosurgical care. data were entered and analyzed using spss . and excel software. results: the average age of patients was years with a predominance of male, and sex ratio of . . the cause of the btb was mainly represented by the accidents of the public road in . % of the cases. . % of the patients were asymptomatic, the most common symptomatology was dominated by the initial loss of consciousness ( . %), headache ( . %). the glasgow coma score was distributed as follows-gcs ( . %), gcs ( . %) and ( . %). . % of patients had clinical signs of trauma to the skulland or face. brain ct was performed in . % of patients, and . % had abnormal ct. the use of neurosurgical care was of the order of . %. in univariate analysis-the predictive factors for a ct abnormality were the intoxication during the brain trauma, the gcs < , signs of trauma in the skull face, the vomiting, the initial loss of consciousness, the comitial crisis and the predictive factors of neurosurgical care were the gcs < , the anisocoria, headache, the vomiting, the amnesia, the initial loss of consciousness, the comitial crisis, the anormal ct, the extradural hematoma or the subdural hematomat in multivariate analysis-the predictive factors for a ct abnormality were the gcs < , the initial loss of consciousness and the predictive factors for the use of neurosurgical care were the gcs < , signs of trauma in the skull face, the amnesia, the comitial crisis, the hsd. conclusion: an algorithm must be applied in collaboration between resuscitators and neurosurgeons to improve the quality of benign cranial trauma management. prognostic value of hyperchloremia in patients with traumatic brain injury: a prospective observational study taghouti introduction: background-traumatic brain injuries (tbi) are a major public health problem. they are the leading cause of death among those aged less than years. hyperchloremia is a common electrolyte disturbance in patients with tbi. hyperchloremia has been associated with increased morbidity and mortality in critically ill patients + however, its prognostic significance in tbi patients is poorly documented. the aim of this study is to describe the prevalence and outcomes of hyperchloremia in patients with tbi admitted to the intensive care unit. patients and methods: in a prospective design, we included consecutive patients with tbi ( males + median age- years) admitted to the icu in charles nicolle hospital of tunis from mars to september . adult patients (aged ≥ years) with isolated tbi or associated with minor extra-cranial injuries (defined as all non-head abbreviated injury scale < ) were included. hyperchloremia was defined as a chloride level > meg/l. clinical and laboratory variables were compared between survivors (n = ) and non-survivors (n = ). we assessed the association between hyperchloremia -h post-admission and -day mortality. p < . was taken to indicate statistical significance. results: the median sofa score at t was points and the median igs score was points. the median iss was points. there were cases of mild head injury, moderate head injury and severe head injury. the -day mortality was %. hyperchloremia occurred in patients ( %) and the incidence was significantly different between survivors and non-survivors ( vs. %, respectively, p < . ). in addition to hyperchloremia (p = . ), other laboratory variables were associated with -day mortality-hypernatremia (p = . ) and hypoalbuminemia (p = . ). conclusion: hyperchloremia -h post-admission was associated with -day mortality in patients with tbi. this index could be useful prognostic marker. efforts should focus on the prevention of hypernatremia and hyperchloremia in this vulnerable group of critically ill patients. child traumatic brain injury naili amine blida rp, algÉrie correspondence: naili amine -drnailiamine@yahoo.fr annals of intensive care , (suppl ):p- introduction: brain injury in children is common and mild in most cases, but it remains the leading cause of death and disability in children over year of age worldwide. the peculiarity of the child is that he possesses not mature brain and that the consequences of injuries acquired by traumatic brain injury can lead to the loss of capacities, as well as the non-acquisition of function, but above all the risk impact on learning abilities. the objective of the study is to define the incidence rate of cranial trauma in children as well as the mortality and morbidity of this scourge which presents a major public health problem. patients and methods: it is a descriptive retrospective study of a series of children hospitalized in neuro-resuscitation service during the period january to december , , including children admitted for cranial trauma. clinical, para-clinical, etiological and therapeutic data were collected from hospitalization records. results: in a series of children hospitalized during the defined period, children were admitted for cranial trauma, i.e. a frequency of %. the average age was years [ h of life- years], with a sex ration of among the children, had severe head trauma, a rate of % + whose causes are variable- road accidents, domestic accidents, traffic accidents, and obstetric accident, admitted with a pediatric glasgow score between and , and all required mechanical ventilation of the head trauma, were operated for different lesions- extra-dural hematomas, cranio-cerebral wounds, subdural hematomas, decompressive craniectomy, and embarrure. children had died following severe head trauma, i.e. a mortality rate of %, the morbidity rate of head trauma in the tipaza wilaya was . , children year, the average length of stay in intensive care units was days, with several complications of decubitus, and functional due to the primary and secondary lesions of the cranial trauma. the head trauma of the child is a public health problem, its functional prognosis can be dramatic when it is severe, its management must be early and multidisciplinary. introduction: the aim of the study was to identify factors predicting lung contusion in trauma children. patients and methods: retrospective study conducted for a period of years (january , -december , ) in a medical surgical intensive care unit. all trauma patients younger than years were included. two groups were compared-those with lung contusions (c + group) and those without lung contusions (c − group). results: we included patients. the mean (sd) age was . ( . ) years. chest injury was diagnosed in patients ( . %). all our patients needed mechanical ventilation. lung contusions were diagnosed in patients ( % of all patients and . % of patients with chest trauma). in multivariate analysis, independent factors predicting lung contusion were road traffic accident (odds ratio [or], . + % confidence interval [ci], . - . + p = . ), increased pediatric risk of mortality (prism) score (or, . + % ci . - . + p = . ), hepatic contusion (or . + % ci . - . + p = . ), and pelvic ring fracture (or, . + % ci . - . + p = . ). death occurred in patients ( . %). intensive care unit mortality was significantly higher in the c + group (or, . + % ci . - . + p = . ). however, mortality was not differentbetween the groups after adjusting for prism score (or, . + % ci . - . + p = . ) or after adjusting for injury severity score (or, . + % ci . - . + p = . ). conclusion: lung contusion is common in critically ill children with chest trauma. the diagnosis should be considered in patientswith road traffic accident, increased prism score, hepatic contusion, and pelvic ring fracture. introduction: chest trauma is often associated with pleural effusion (hemothorax and or pneumothorax). drainage of the pleural space by a chest tube is a common intervention in such situations. blunt dissection technique with a kelly clamp is preferred to classical trocar techniques to prevent severe complications, like perforation of thoracic or abdominal organs. despite these precautions, malposition remains the most common complication of tube thoracostomy. we investigated a new technique of bougie-assisted chest tube insertion to prevent chest tube malposition after chest drainage of post traumatic pleural effusion. patients and methods: we performed a controlled before-and-after study to assess the ability of a bougie-assisted chest tube insertion technique, compared to a standard blunt dissection technique, to prevent chest tube malposition. for the bougie-assisted group, we used a disposable eschmann-style bougie, commonly used to guide the endotracheal tube during difficult intubations. technique consisted in blunt dissection until the parietal pleura is opened. thoracostomy tube was preloaded onto the bougie and bougie was advanced alongside the finger, with apical or caudal direction after entering the chest cavity, depending on the type of pleural effusion. thoracostomy tube was then advanced forward utilizing a seldinger technique. the primary end point was optimal position of the chest tube. the tube position was blindly assessed on standard chest x-ray. in pneumothorax, optimal position was apical (above the aortic arch), and in hemothorax or mixed-effusion it was basal ( cm above the diaphragm or lower). results: a total of patients were enrolled (bougie-assistedn = + conventional-n = ). chest tubes were optimally position in ( %) in bougie-assisted group and ( %) in conventional group, or . , ic % = [ . - . ], p < . . efficacy of chest drainage (defined on chest x-ray as the absence of visible pleural line for pneumothorax and as a clear costophrenic angle for hemothorax) was assessed in ( %) in bougie-assisted group and in ( %) in conventional group, or . , ic % = [ . - . ], p < . . average procedure time was s ( % ci - s) for bougieassisted group and s ( % ci - s) for conventional group, p < . . no severe complication was observed in both groups. conclusion: bougie-assisted chest tube insertion technique prevents chest tube malposition, is safe, effective and shortens procedure time for the post traumatic pleural effusion drainage. introduction: infectious complications determine the prognosis of burned patients. however, the emergence of bacterial resistance to antibiotics threatens treatment efficacy, which is due to an inadequate antibiotic consumption inqualitative and quantitative terms. the objective of this study was to describe the profil of consumptionand susceptibility to antibiotics. and, to explore the predictive factors for theemergence of mrb in the service of burns and plastic surgery. patients and methods: it is a retrospective study including severe burnedpatients hospitalized for years in the plastic surgery department of theuniversity hospital ibn rochd from january to december . bacterialecology was described, and the distribution of the seeds by group, by species andby period of time was detailed. the ddd jh (daily defined dosage reportedin days of hospitalization) was used to assess the consumption of antibiotics. p correlation coefficients were calculated to explore the association betweenconsumption of antibiotics and the emergence of the bmr (multiresistantbacteria), and identified predictors of this emergence. results: on samples taken, bacterial and fungal strains were identified, with a predominance of p. aeruginosa ( . %), a. baumani i ( %) and s. aureu s ( %), the number of strains increased with the duration of the stay reaching itsmaximum from days in hospital. the ceftazidine ( . ddd dh), imipenem ( . ddd dh), and amikacin ( . ddd dh) were themost used antibiotics during our study, also + the profile of consumption increasedbetween and . bmr were isolated + the eblse were at the top ( . %) follow up of thecrpa ( . %), followed by the irpa ( . %) follow-up of the crab ( . %) then the irab ( . %) and finally the mrsa with a portion of . %. the profile of bacterial resistance has varied significantly for severalantibiotics bacteria pairs. conclusion: it remains difficult to show correlations between antibioticconsumption and bacterial resistance. however, these data are particularly usefulin the epidemiological surveillance of bacteria to better guide probabilisticantibiotic therapy. introduction: eclampsia is a rare but serious threat to maternal and fetal well-being. the aim of this study was to assess the incidence of eclampsia and its morbidity and mortality. patients and methods: we conducted a retrospective survey in a third level tunisian university teaching hospital from january to december . we included all patients with the diagnosis of eclampsia. results: in study period deliveries were registered. women with eclampsia were identified hence the incidence of eclampsia was . per deliveries. the median gestational age at the time of eclampsia was weeks. no maternal deaths due to eclampsia were recorded. the delivery mode was caesarean section in % of eclamptic patients. the recurrence of eclampsia despite magnesium sulfate prevention was observed in % of patients. severe complications of eclampsia were recorded in . % of patients- posterior reversible encephalopathy syndrome, acute pulmonary edema, and hellp syndrome. . % of new born were preterm. there were stillbirths and neonatal deaths. conclusion: the incidence of eclampsia was very high probably due to center effect. it's essential to raise awareness among mothers in the community regarding early signs and symptoms of preeclampsia eclampsia and to design a better tracking system for antenatal care program. introduction: to monitor maternal mortality which is an indicator of the quality of obstetrical care and anesthesia resuscitation, our country worked to set up several programs targeting maternal and child health. the aim of this work was-to evaluate the maternal mortality rate in our department and its evolution. to identify the cause of death and classify it depending on whether it is preventable or not. to spot the deficiencies either in the care management or the organization of the care system. to propose ways to improve our care and to fill the failures. patients and methods: it was a retrospective study about maternal death, performed at the department of gynecology and obstetrics, over a -year period (from to ) , that have reported cases of maternal death according to the world health organization definition. results: the maternal mortality rate (mmr) was . for every , live births. the average age of our patients was . years. the main risk factors for maternal mortality are unfavorable socioeconomic conditions, high-risk pregnancies, multiparity, primiparity and a poor follow-up of the pregnancy. the main causes of maternal death are represented by direct obstetric causes ( %) allocated as followspostpartum hemorrhage ( %), pregnancy toxemia ( %), acute fat hepatic steatosis ( %), infection ( %) and complications of anesthesia ( %). indirect obstetric causes were found in % of deaths. death was considered avoidable in . % of cases. conclusion: at the end of this work, we were able to pull several recommendations in order to reduce m.m.r. health education. facilitate access to care for the parturient, improve care and conditions of childbirth. continuous training of the medical and paramedical staff. introduction: mechanical ventilation can help improve the prognosis of sepsis. while adequate delivery of oxygen to tissue is crucial, hyperoxemia may be deleterious. invasive out-of-hospital ventilation is often promptly performed in life-threatening emergencies. we propose to determine whether the arterial oxygen pressure (pao ) at intensive care unit (icu) admission affects mortality at day (d ) in patients with septic shock subjected to mechanical out-of-hospital ventilation. patients and methods: we performed a monocentric retrospective observational study on patients with septic shock admitted to the icu. pao was measured at icu admission in patients subjected to invasive ventilation before any hospital admission. the primary outcome was mortality at day (d ). results: forty-nine ( %) patients with septic shock were mechanically ventilated before any hospital admission and transferred to the icu. the mean pao at icu admission was ± and ± mmhg for alive and deceased patients at d , respectively. pao was significantly associated with mortality at d (p = . ). using a roc curve, the corresponding auc was . [ . - . ]. for a pao > mmhg, the or for mortality at d was . [ . - . ] (p = . ), whereas for a pao < mmhg, the or was . [ . - . ] (p = . ). conclusion: in this study, we report a significant association between hyperoxemia at icu admission and mortality at d in patients with septic shock subjected to pre-hospital invasive mechanical ventilation. the adjustment of the pao is a crucial prognosis factor in patients with septic shock subjected to invasive out-of-hospital ventilation to avoid the toxic effects of hyperoxemia. however, blood gazometry is hard to get in a prehospital setting. consequently, alternative and feasible measures are needed, such as pulse oximetry, to improve the management of prehospital invasive ventilation. introduction: nowadays, benefit of enhanced ct-scan in positive diagnosis of acute pulmonary embolism (pe) is well established. it also allows evaluation of pe's burden on the right heart and shows several signs of acute cor pulmonale (acp). objectives -we aimed to assess benefits of control ct-scan h after thrombolysis in acute pe. patients and methods: we retrospectively enrolled patients with confirmed pe whom have been thrombolysed between january and august and controled with an enhanced ct-scan h after thrombolysis. assessement criteria were: qanadli obstruction index; signs of acp-right ventricle diameter left ventricle diameter (rvd lvd) and paradoxical interventricular septum (ivs). non inclusion criteria were: lack of initial or control ct-scan. results: during the study period ( years and months) we admitted patients from whom patients had acute pe ( . %). very severe patients that were thrombolysed as rescue therapy without initial ctscan and those who died before control ct-scan were not included. we enrolled patients-high risk mortality pe (n = , . %) and intermediate high risk pe (n = , . %). mean age was years and sex-ratio was . . at admission, mean severity scores were . ± . for saps ii and . ± . for apache ii. evolution criteria are listed in table . conclusion: control ct-scan is highly useful h after thrombolysis. it allows evaluation of response to pharmacological thrombolysis of acute pe and shows significative resolution of arterial obstruction degree and signs of acp. in december , after cancellation of the budget for a christmas tree, the nurses and caregivers of the night team spontaneously made and hung christmas decorations in our intensive care unit to make patients and their families feel better. the context was difficult with controversies around secularity. the town of paray le monial had been forced to remove a nativity scene and the city of melun had been criticized for setting one up. so we found it important to assess the perception of the approach by patients and relatives. patients and methods: decorations -hand-colored patterns about christmas theme printed on a paper decorations brought by the staff or already possessed by the unit-christmas balls, garlands, silver stardecorations made with service equipment-christmas tree consisting of inflated non-sterile gloves, cardboard, figurative nativity scene without a recognizable figure in a cardboard box with cotton, bed sheet to simulate snow. evaluation -all visitors and conscious patients received an anonymous single choice questionnaire with numerical scale and free fields from december th to december st, . results: answers were received, including-no negative opinion. neutral answer by a person who had not noticed the decorations. positive or extremely positive opinions. no answer without data. the comments pointed out the originality, the good idea, the warm comforting side. some asked for more decorations. others found them sober. the results show the good perception of the spontaneous action by the patients and their relatives. there was no negative response, particularly offend persons. however, it is possible that relatives or patients with negative opinions did not dare to express themselves. the initiative demonstrated a good cohesion of the night paramedical team, encouraging the interns and the day teams to take part in the coloring of the decorations. the initiative was initially aimed at the wellbeing of the patients and their relatives. however it has enabled an activity similar to preventing psychosocial risks among the healthcare team, allowing them to adopt a positive attitude in their approach to care. in addition, no significant costs were incurred thanks to the use of cheap materials, mainly recycled cardboard and standard quality white paper. the spontaneous decoration of our intensive care unit by the night care team was very well received by the patients, their families and their relatives. the initiative also made possible to enhance team cohesion and to value it. the associated costs were negligible. ventricular contractions. bp monitoring revealed a greater diastolic bp throughout h as well as during night-time. systolic bp higher than mmhg during sleep time was observed in % of participants. the frequency of arrhythmias and blood pressure variability are correlated with the increase in work stress and conflicts. conclusion: our results highlight the extent incidence of arrhythmia and blood pressure variability during intensive care unit night's shift probably due to the increased neuroendocrine stress response. ( %) and qrs enlargement ( %). ami was responsible for a significantly deeper coma (p < . ) but fewer seizures than clo (p = . ). three patients ( %) died. based on a univariate analysis, factors associated with death were cardiac arrest onset (p = . ), elevated plasma lactate concentration (p = . ), low arterial ph (p = . ), reduced pao fio ratio (p = . ) and prothrombine ratio (p = . ), increased aspartate aminotransferases (p = . ), alanine aminotransferases (p = . ) and serum creatinine concentration (p = . ) as well as marked catecholamine infusion rate (p = . ). the pharmacokinetic study showed significant increase in ami ( h vs. h) and clo ( h vs. h) elimination half-lives in overdose compared to pharmacological conditions, highlighting the contribution of organ failure to the delayed elimination of both toxicants. conclusion: ami and clo poisonings did not disappear and are still responsible for significant morbidities and mortality. ami was responsible for deeper coma with fewer seizures in comparison to clo. ami and clo elimination half-lives were significantly prolonged in overdose due to organ failure. introduction: severe poisonings and fatalities have been attributed to buprenorphine (bup) despite its ceiling respiratory effects, mainly if abused in co-ingestion with benzodiazepines. we previously showed that diazepam (dzp) bup combination induces severe respiratory depression in the rat, while each drug by itself does not. the objective of this study was to investigate the mechanisms involved in this drug-drug interaction using c-bup pet imaging and diaphragmatic electromyography in the sprague-dawley rat. patients and methods: c-bup was administered intravenously, mg kg unlabeled bup intraperitoneally and mg kg dzp subcutaneously. pet acquisition started with c-bup pet injection, min after dzp or its vehicle (veh + n = group) administration. suv normalized time activity curves (tacs) were generated and c-bup binding potential [bpnd, i.e. the ratio of the total receptor density (bmax) on the equilibrium dissociation constant (kd)] were modeled in different brain regions using a simplified reference tissue model with cerebellum as reference region. dem, implanted under anesthesia days before the experiment, was recorded during min in rats receiving veh veh, dzp veh, veh bup or dzp bup (n = group). after filtering and half-wave rectification, the first min auc of diaphragm contraction and workload were determined and compared between the groups. results: tacs and c-bup bpnd were not different between the dzp bup and the veh bup groups in all studied brain regions. diaphragm contraction was significantly increased in the veh bup group in comparison to the dzp bup group (p < . ). diaphragm workload was significantly increased in the veh bup group in comparison to the dzp veh and the dzp bup group (p < . and p < . respectively). discussion: dzp did not affect the c-bup brain distribution and brain binding suggesting that dzp does not affect bup transport across the blood brain barrier and bup receptors density affinity. bup administration induced an increase in diaphragm contraction and workload. this increase was inhibited in the presence of dzp suggesting that dzp bup combination-induced respiratory depression is mostly related to dzp. conclusion: respiratory depression related to dzp bup combination results from a pharmacodynamic drug-drug interaction. introduction: since the banning of dextropropoxyphene from the market, overdoses and fatalities attributed to tramadol, a who step- opioid analgesic, have increased markedly. tramadol overdose results not only in central nervous system (cns) depression attributed to its opioid properties but also in seizures, possibly related to nonopioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced cns toxicity. our objective was to investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose. patients and methods: sprague-dawley rats overdosed with mg kg intraperitoneal (ip) tramadol were randomized into four groups to receive solvent (control group), diazepam ( . mg kg ip), naloxone ( mg kg intravenous bolus followed by mg kg h infusion) and diazepam naloxone combination. sedation depth, temperature, number of seizures and intensity, whole-body plethysmography parameters and electroencephalography activity were measured. for each parameter, we compared the areas under the curves using mann-whitney tests for two-by-two comparisons between the four groups. regarding the effects of treatments on seizures, comparisons were performed using two-way analysis of variance followed by multiple comparison tests using bonferroni's correction. results: naloxone reversed tramadol-induced respiratory depression (p < . ) but significantly increased seizures (p < . ) and prolonged their occurrence time. diazepam abolished seizures but significantly deepened rat sedation (p < . ) without improving ventilation. diazepam naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < . ) but did not worsen sedation. based on the eeg study, tramadol-treated rats experienced electro-clinical seizures as soon as min after the injection, characterized by spike-waves and polyspikes with progressive decreased frequencies and inter-critical phases of slow delta waves until the next crisis. after diazepam naloxone injection, eeg waveforms consisted in hz-alpha rhythms and slow-down theta rhythms of drowsiness. none of these treatments significantly modified rat temperature. conclusion: diazepam naloxone combination is the most efficient antidote to reverse tramadol-induced cns toxicity. our experimental data greatly encourage administering this combination rather than naloxone alone as first-line antidote in tramadol-poisoned patients as an alternative to tracheal intubation. introduction: rubigine ® poisoning is a medical emergency that causes a major public health problem in underdeveloped countries, as it is frequently fatal. this poisoning is rare in france, but frequent in the french overseas departments (dom). the rubigine ® , made of fluoride and used as a rust remover, is the main source of poisoning in the caribbean. in martinique, the exact incidence of this intoxication is unknown, as there is no national and regional register. it could represent up to - % of severe acute poisoning. it was not until april that, following a prefectural order on the declaration, classification, packaging and labeling of substances, the composition of rubigine ® was modified to significantly reduce the mortality induced by its ingestion. the objective of our study was to describe the clinical features and complications that can occur after ingestion of rubigine ® as well as to determine the prognostic factors of death. we conducted a retrospective study over years, from to , including all patients admitted to emergency and intensive care units of the university hospital center (martinique) for acute rubigine ® poisoning. the usual demographic and clinical data were collected and comparisons between surviving and deceased patients were performed using a univariate analysis. results: fifty-five patients (mean age- years ( - ) + sex ratio male female- , ) were hospitalized at the university hospital of martinique. one-quarter of patients had no significant history. the average length of stay was . days ( - ). forty percent of patients experienced hypocalcaemia after initial intravenous calcium supplementation. complications included acute respiratory failure requiring invasive mechanical ventilation ( % of patients, duration of ventilation- . days, ( - )), renal failure ( %, of which % required extrarenal treatment, hemodynamic failure ( %), hepatic failure ( %), coagulation failure ( %), neurological failure ( %) and multi-visceral failure ( . %). three patients presented cardiogenic refractory shock requiring va ecmo ( . %) and another patient with digestive perforation ( . %). the mortality was . %, allowing the identification of prognostic factors of death. conclusion: rubigine ® poisoning is responsible for significant morbidity and mortality, despite optimal management. however, its incidence seems to have decreased sharply in recent years thanks to the strong mobilization and awareness of the population following the implementation of an information system by the university hospital 's clinical toxicology and toxico-vigilance unit, and different preventive measures introduced by the health authorities. introduction: since dextropropoxyphene withdrawal from the market, overdoses and fatalities attributed to tramadol, a who step- opioid analgesic drug, have increased markedly. besides central nervous system depression, tramadol overdose may result in seizures, usually included in the related serotonin syndrome. however, the serotoninergic mechanism of tramadol-induced seizures has been recently questioned. we investigated the effects of various specific pretreatments on tramadol-induced seizure onset and alterations in brain monoamines in the rat. patients and methods: sprague-dawley rats were randomized into five groups (n = group) to be pretreated with various agonists antagonists before receiving mg kg tramadol intraperitoneally- . mg kg ip diazepam + mg kg iv bolus followed by mg kg h infusion naloxone + mg kg ip cyproheptadine, and mg kg ip fexofenadine. seizure severity was graded according to the modified racine score ( ). we measured neurotransmitter concentrations in the frontal cortex using high performance liquid chromatography coupled to flurorimetry or radioenzymatic assay, as required. we used positron emission tomography-computed tomography to investigate interactions of tramadol with gaba-a receptors. the effects of treatments on seizures were compared using two-way analysis of variance followed by multiple comparison tests with bonferroni's correction. the areas under the curves of the effects on monoamine concentrations and the binding potentials in the pet-imaging study were compared two-by-two using mann-whitney u tests. results: diazepam abolished tramadol-induced seizures, by contrast to naloxone, cyproheptadine and fexofenadine pretreatments. interestingly, despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < . ), histamine (p < . ), dopamine (p < . ) and norepinephrine (p < . ) while no significant modifications were observed with the other tested pretreatments. based on positron emission tomography imaging using c-flumazenil fixation in the rat brain, we demonstrated molecular interaction between tramadol and γ-aminobutyric acid (gaba)-a receptors not related to a competitive mechanism between tramadol and flumazenil on the benzodiazepine binding site. our findings clearly ruled out the involvement of serotoninergic, opioidergic, histaminergic, dopaminergic and norepinephrinergic pathways in tramadol-induced seizures while strongly suggested tramadolinduced specific allosteric change in gabaa receptors that could contribute to seizures onset in overdose. conclusion: tramadol-induced seizures in overdose are mainly related to the gabaergic pathway. introduction: heparin-induced thrombocytopenia (hit) is a serious iatrogenic complication of heparinic treatments. the diagnosis of hit is difficult in the resuscitation environment because thrombocytopenia is a frequent and multifactorial phenomenon. the aim of this work was to study the clinical and biological presentation of patients with hit and the consequences attributable to hit on the evolution of patients in terms of morbidity and mortality and to develop a diagnostic strategy for hit for resuscitation patients. this was a retrospective, monocentric, descriptive and evaluative study conducted in our intensive care unit (icu) over a period of years months. an anti-pf antibody test was performed in patients who developed thrombocytopenia or a % drop in their initial platelet kinetics and the clinical picture. results: the incidence of hit was . % in patients hospitalized in icu. the clinicobiological severity scores, the reasons for admission to resuscitation were similar in both groups (hit+ and hit−) as well as the characteristics of the heparins used. the time of occurrence of thrombocytopenia was similar in the two groups. the diagnosis of hit was more often the only plausible diagnosis in the hit+ group. the t's score was significantly higher in the hit+ group. the evolution of the platelet count was similar in the two groups, in the decay phases as well as in the recuperation phase. hit+ patients showed significantly more thrombosis than hit− patients. there was no significant difference between the transfusion needs of hit+ and hit− patients. mortality was identical in both groups, as was the length of stay in icu. conclusion: hit is a rare disease. there was no evidence of a predisposing factor for the occurrence of the disease in a uniform resuscitation population. the diagnosis of hit is based on a cluster of arguments and not on an isolated event. biological tools are indispensable, in a complementary way to the clinical picture. pulmonary embolism in patients with sickle cell disease in intensive care unit: a challenging diagnosis jamoussi amira , zayet souheil , merhebene takoua results: during the study period, a total of patients with scd were admitted. among them, presented with respiratory distress and chest pain and then benefited first of trans-thoracic echocardiography that often showed right ventricle dilation and systolic pap > mmhg (n = ). all the patients underwent enhanced ct-scan and the diagnosis of pe was finally retained in cases ( . %) and hence colliged. the average age was . years ± . [ - years] with a sexratio = . the mean of apach ii score was . scd were diagnosed at the age of . years ± . [ - years] with a regular follow up in %. the reason for admission was acute respiratory failure in all cases. patients had clinical symptoms of pneumonia: pleuritic chest pain (n = ), dyspnea (n = ) and fever (n = ). all patients had a chest x-ray showing an alveolo-interstitial syndrome in cases ( . %) and an associated pneumonia in cases ( introduction: acute chest syndrome (acs) is the most severe complication of sickle cell disease and its evolution is unpredictable. acute pulmonary hypertension (ph) in acs is associated with an increased mortality, but its mechanism remains poorly known. our hypothesis is that acute ph is associated with a biological state of hypercoagulability in acs. in a prospective single center study, all consecutive scd patients with acs admitted to the intensive care unit (icu) of tenon hospital were included. specialized haemostasis dosages were performed on icu admission. a trans-thoracic echocardiogram was also performed on admission, and was repeated at steady state. results: among patients with acs, had a trans-thoracic echocardiogram and had a high echocardiographic probability of acute ph, including patient with bilateral pulmonary embolism and patient who developed multiple organ failure and died. there were no significant clinical, biological or radiological differences between patients with a low-intermediate probability of acute ph and those with a high probability of acute ph+ their evolution was similar. the exploration of haemostasis did not show between-group differences, regarding each parameter of haemostasis. however, when using a hierarchical cluster analysis, distinct profiles of coagulation were evidenced, defining biological classes. the subset of patients with a high echocardiographic probability of acute ph was more frequent in biological classes and which corresponded to hypercoagulability states. acute ph was transient in patients (n = ) with a repeated echocardiography at steady state. conclusion: acute ph may likely occur in patients with acs and a biological condition of hypercoagulability. further studies are needed to confirm these findings. gorham julie were the two independent predictors of survival after hospital discharge. in lung cancer patients admitted into the icu, the mgps is an independent predictor of survival after hospital discharge but not for mortality during icu stay. this inflammatory score could therefore be used as a long-term prognostic marker in this population of patients and would be more reflective of cancer, than reflecting the acute complication leading to icu admission. prospective and multicentric studies must be carried out to validate these results. introduction: recombinant active factor vii is a pro-hemostatic treatment used in obstetric haemorrhage, but no study has made it possible to specify its exact place in the decision algorithm. the objective of our work is to evaluate the efficacy and the benefit risk ratio of recombinant factor viia in the treatment of severe postpartum hemorrhage. we conducted a prospective study at the ibn jazzar university hospital in kairouan during the period from january , to december , . in total, we collected cases of recombinant factor viia in one postpartum haemorrhage. results: the mean age of our patients was + . years. the rate of childbirth was . %. the caesarean was the mode of delivery chosen for patients. the causes of postpartum haemorrhage in our series were-uterine atony in cases, uterine rupture and cervicouterine tear cases each, retroplacental hematoma and placenta accreta cases for each two and placenta praevia in cases. our patients were treated in an intensive care unit and the average hospital stay was . days. sulprostone was reported in cases ( . %), and all patients received a massive transfusion. the average time to administer rfviia was h min. the mean dose of factor vila recombinant was . ± . μg kg. five patients received a single dose, patients received a second injection and patients received doses. clinical efficacy-after a single injection, clinical efficacy with reduction in bleeding was observed in patients, i.e. %. the most frequent complication was insufficiencyrenal in cases including requiring hemodialysis, civd in cases, oap in cases, a multivisceral failure in cases, a septic shock in case and a mesenteric infarction in case. the progression was favorable in patients, while patients died ( . %). conclusion: it is important that new studies be carried out and shared experiences around the world on this drug appear to be effective and prevent invasive actions in the therapeutic arsenal of postpartum heamorrhage. introduction: post-partum haemorrhage (pph) is a life-threatening complication and remains a leading cause of maternal morbidity worldwide. the woman trial* estabished that early administration of tranexamic acid (ta) reduces mortality due to the bleeding in women with pph. our study purpose was to determine the effects of early administration of ta and fibrinogen concentrate on death, hysterectomy and transfusion in women with severe pph. patients and methods: this retrospective, monocentric study was performed in a third level tunisian hospital providing healthcare for more than pregnant women per year. were included in this study women with diagnosis of severe post partum haemorrhage after a vaginal or caesarean delivery from to . patients who received ta and fibrinogen concentrate were assessed in group (g ) and who not in group (g ). results: the incidence of severe pph was / deliveries. women were retained for data analysis g (n = ), g (n = ). anthropomorphic and obstetrics characteristics were not significantly different between the two groups. there was a significant difference between the two groups regarding to transfused units of red blood cells however, no difference in term of the use of frozen plasma and platelets concentrates was observed. perioperative hemoglobin nadir was significantly higher in g . the frequency of hysterectomy and pelvic packing were higher in g (table ) . no thromboembolic events and no haemorrhage related mortality were observed in the two groups. conclusion: in this retrospective study, early administration of tranexamic acid and fibrinogen reduces risk of hysterectomy transfusion. these encouraging results strongly support the need for a large, international, double-blind study to investigate the potential of the association "ta-fibrinogen concentrate" to reduce maternal haemorrhage related morbidity and mortality. introduction: immunodeficiency, acquired or congenital, is the first comorbidity associated with poor outcome in pediatric patients with acute respiratory distress syndrome (ards). the aim of this study was to describe outcome of pediatric patient with hematologic disease hospitalized in our intensive care unit for respiratory failure and to investigate the clinical variables associated with mortality. patients and methods: it was a retrospective monocentric descriptive study including all immunodeficient pediatric patient (malignant hemopathy, congenital immunodeficiency, bone marrow transplanta-tion…) from hematology hospitalized in our beds pediatric intensive care unit with the diagnosis of respiratory failure between january and february . results: fifty one patients were included corresponding to admissions. nighty percent of the patients met criteria for pediatric ards- % were severe, % moderate and % mild. extracorporeal circulation (ecc) was needed for patients. global mortality rate at picu discharge was %. twenty four patients ( %) received noninvasive ventilation (niv). height of them ( %) did not need invasive mechanical ventilation (imv). in patients who received imv, mortality rate was significantly higher if patients received before niv ( vs. %) p = . . all patients who needed imv after more than h of niv died (n = ). mortality was higher in children with griffon versus host disease ( vs. % p = . ). mortality of patients receiving ecc and renal replacement therapy (rtt) was respectively and %. conclusion: in our study, most of the patients hospitalized for respiratory failure met criteria for pediatric ards. if niv decrease imv requirement, it could be associated with higher mortality rate in case of failure. this result support recent recommendation that immunodeficiency is not a sufficient criteria to delayed imv. . flow and airway pressure were recorded at the asl inlet and mouth pressure into the manikin mouth. we defined "device driving pressure" as the peak mouth pressure minus the tele-expiratory mouth pressure. continuous data are reported as mean ± sd. results: as compared to the oxygen mask, vt increased significantly with m-niv and h-niv whatever the simulated respiratory effort ( ± and ± vs. ± ml respectively with the moderate simulated effort, p < . ; fig. ). hfnc and cpap were associated with a slight but non-significant decrease in vt as compared to the oxygen mask. overall, for a given respiratory effort, vt was influenced by the "device driving pressure", which tended to decrease when using hfnc and cpap and markedly increased with m-niv as compared to the oxygen mask. therefore, vt in m-niv with a simulated low effort was significantly higher than vt in cpap and hfnc with a simulated moderate effort ( ± ml, ± ml, and ± ml respectively, p = . for both comparisons). conclusion: in our bench model, the vt value was significantly influenced by the noninvasive ventilatory device. niv was invariably associated with significantly higher vt than with other devices, even when dividing by two the simulated inspiratory effort during niv. introduction: in icu, intubation is a high risk procedure associated with high morbidity. despite procedure's improvement with systematic application of fluid loading, early use of vasopressors and checklist use, morbidity remains high. several recent trials has been conducted with different metrics choose as primary outcome. however any evidence exists to choose one more than another: time to intubation, first pass success, difficult intubation. first pass success sine hypoxia and hypotension (dash- a) has been highlighted recently and choose by the game program without any scientific evaluation. we conducted a post hoc analysis of the randomized clinical trial macgrath mac video laryngoscope or macintosh laryngoscope for intubation in the intensive care unit (macman) to determine the best metric to choose for primary outcome for the next intubation studies in icu. patients and methods: macman was a multicentre, open-label, randomized controlled superiority trial. consecutive patients requiring intubation were randomly allocated to either the mcgrath mac videolaryngoscope or the macintosh laryngoscope, with stratification by centre and operator experience. an only inclusion criterion was-"patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if-contraindication to orotracheal intubation (e.g., unstable spinal lesion) + insufficient time to include and randomize the patient (e.g., because of cardiac arrest) + age < years + pregnant or breastfeeding woman + correctional facility inmate + patient under guardianship + patient without health insurance + refusal of the patient or next of kin to participate in the study + previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess association and prediction of life threatening complication (mild to moderate, severe, mild to severe) by different metric existing-time to intubation, first pass success, difficult intubation, first pass success sine hypoxia and hypotension. each metric was compared with another one. area under curve was built for every metric and all metrics were then compared. results: dash- a was superior to all others metrics included in the analysis for prediction of life threatning complications (all p < . ). failure of first pass conclusion: all metrics are not equal to predict severe life threatening complications during intubation in the icu. in this context, we recommend adoption of definitive airway sine hypoxia or hypotension at first attempt (dash- a) as primary outcome for intubation studies in the icu or as metric indicator tracked in quality improvement program. benbernou soumia introduction: introductionacute respiratory failure (arf) is a common cause of emergency use and one of the major reasons for admission to intensive care unit. it associates a vital risk imposing immediate symptomatic treatments and an etiological approach. [ ] among the etiologies of the arf, acute lung edema (ale), decompensation of chronic obstructive pulmonary disease (copd), chest trauma and pneumonia are the most frequent @it is a life-threatening pathology with a high incidence of mortality, since mortality is reported to be - % [ , ] for arf secondary to cardiogenic ale. the prevalence of arf in algeria remains unknown + the tahina study showed that respiratory diseases were the leading cause of consultation in the hospital [ ] . the the objective of this study is to estimate the frequency of use of the niv and to determine the associated factors of failure of the niv for the adult patients hospitalized for arf in the emergency department of oran hospital from january to november . prevalence of copd was found in the . % of tobacco subjects [ ] . the number of patients hospitalized for chest trauma continues to increase, resulting in an increase in the number of patients admitted for arf secondary to chest trauma. patients and methods: this is an observational and exhaustive study during the month of november, from the files of patients. the population-all subjects over years hospitalized for an arf at the reception and resuscitation units of the emergency department of oran hospital from january to november . results: ninety-seven patients were hospitalized for arf during this period. niv was used for patients. patients were acute lung edema. univariate analysis showed that spo was the only failure factor in this series. the failure rate of this technique was . %. niv is a technique that should be used more in the emergency rooms, which would make it possible to use less intubation specially in indications where the level of proof in the literature is important. demographic characteristics, etiology of exacerbation, comorbidities, the sapsii score, arterial blood gases at admission, respiratory, hemodynamic and neurological parameters, use of noninvasive or invasive ventilation, nosocomial infection, duration of niv, length of stay and mortality. results: during period study patients ( % women with a sapsii score ± ) were included. the etiology of exacerbation was bronchitis in % of cases and pneumonia in %. only patients have niv at home and patients have oxygen. pseudomonas aeruginosa was isolated in cases. twenty percent of the patients had developed a nosocomial infection, acinetobacter baumanii and pseudomonas aeruginosa were isolated in and % respectively. niv was used in patients at admission and the rate of niv failure was %. the duration of mechanical ventilation was ± days and the length of stay was ± days. the mortality was %. niv and oxygen at home were prescribed for patients. in univariate analysis survivors and non-survivors were comparable regarding baseline and clinical characteristics. nosocomial infections ( vs. %), and spassii score were significantly more elevated in non-survivors. in emergency department, the management of hypercapnic acute respiratory failure with hfo is limited. hypercapnia and acidosis remain moderate. patients are old with comorbidities. the mortality rate is high but expected given the number of limitation of active therapy. hfo appears to be effective for a majority of patients, but half of them required niv too. the niv hfo association seems an interesting option. but our methodology is perfectible and would require a randomized control tria. severe chronic obstructive pulmonary disease with chronic respiratory failure in intensive care unit: mortality and prognostic factors arnout chloé , faure morgane , novy emmanuel chu nancy, nancy, france correspondence: arnout chloé -arnout.chloe@gmail.com introduction: last decades, the number of patient with chronic respiratory failure due to chronic obstructive pulmonary disease (copd) admitted in intensive care unit (icu) increased. data about their real prognosis in the icu are lacking. the objective of this study was to evaluate mortality rate at months and to identify prognostic factors of copd patients with chronic respiratory failure, treated with long term oxygen therapy (ltot), admitted in icu. patients and methods: a retrospective cohort study was conducted in the french university hospital of nancy during years - on all copd patients treated with ltot admitted in icu. only the first admission was analysed. patients were included if they had spirometry, blood gas and oxygen flow in the year before admission in icu. other causes of chronic respiratory failure, and patients with tracheostomy before icu admission were excluded of the cohort. hospitalizations were selected using the international classification of diseases, th revision (icd- ). results: one hundred and thirteen patients were included, ( %) died in the first months after icu admission. mortality rate in icu was %. severity of copd was-mean bode score ± . , number of exacerbation per year requiring hospitalization ± . . ltot was used for . ± . years. acute respiratory failure was the main frequent cause- % pneumonia, % acute exacerbation of copd, % acute lung oedema. the sequential organ failure assessment score within the first h of icu admission was ± . need for mechanical ventilation was noted in % of cases and was associated to mortality with an odds ratio of . (ci % [ . - ] p = . ). in presence of other organ failure, mortality rate tends to increase. patients with median pao fio ratio > on first blood gas had a reduced risk of death (or . + ci % [ . - . ], p = . ). conclusion: this is the first study to assess mortality at month of patients with severe copd requiring ltot admitted in icu. severity of hypoxemia and use of mechanical ventilation are two prognosis factor of mortality. the addition of another organ failure seems to increase the mortality rate. severity of the chronic respiratory insufficiency less influenced short and long term outcome. this data have to be included in the global decision to admit a copd patient with ltot in icu. introduction: the remarkable progress in the outpatient care of the asthmatic patient (development and access to inhaled drugs) has made the admission of these patients exceptional in the icu. we have noticed a recent upsurge in asthmatic afmissions in the icu, and are investigating whether this fact was related to modifiable factors (access to adapted drugs) or an increase in the severity of the disease. patients and methods: retrospective, observational, three-center study conducted in three tunisian medical icu from january to july, . were included all consecutive patients admitted for severe acute asthma in three icus. were assessed-patient's demographic characteristics, asthma severity and its actual control based on global initiative for asthma classification (gina) , clinical characteristics of the acute episode, length of icu stay, ventilatory free days and mortality. results: out of the patients admitted within the study period, ( %) had severe acute asthma. the mean age was years (iqr - . ). sex ratio was . asthma was allergic in % with an average ancienty of . years. over all asthma was not very severe with no prior icu admission for acute severe asthma . % were mechanically ventilated at least one time. were classified severe and moderate persistant asthma respectively in . (%) and (%). . % were consideredpoorly controlled. low educational level and socio-economic status are the main determinants of poor control- % of analyzed patients didn't have a social care, and thus no accesse to prescribed anti-asthmatics + % didn't have a regular follow up and . % were jobless. when admitted to the icu- patients ( . %) needed invasive mechanical ventilation, one patient received niv. the mean length of stay was days (iqr . - . ). levels of auto peep and pic pressure at icu admission were respectively (iqr - ) and . (iqr , - . ) cm h o. mortality rate was %. this study suggests that low educational level and socioeconomic status (especially the lack of social care and joblessness) are the main determinants of poor control of asthma and may lead to the increase of rate of icu admission for severe acute asthma requiring mechanical ventilation. introduction: in emergency medicine, the boussignac system (bs) is sometimes used to administer oxygen and continuous positive airway pressure (cpap). in this case, fio value depends on the ratio between o flow and inspiratory flow (if). in some cases, the fio decreases due to the if increase. the aim of this study was to test a modified boussignac system in order to limit the fio decreases during inspiratory flow rate increases. the study was conducted on bench with bs connected to a two compartment adult lung model (dual test lung ® ) (dtl) controlled by a maquet servo i ® ventilator. three minute ventilation (mv- . . l min) with ti ttot = . were investigated. fio and mv measurements were made using an iworx ® ga gas analyzer. with a bs, two peep were analyzed- and cm h o. the bs was supplied by an o flow. in order to increase the fio , we have evaluated the addition of a t piece connected to a nebulizer at the air-room admission of a bs. the aerosol was supplied by an o flow of l min. the o flow was analyzed in continuous with a calibrated mass flow meter (red y vogtlyn ™ ). results: when mv increases, the fio decreases (p < . ). when peep increases, fio increases too (p < . ). the addition of an aerosol (o - l min) to a bs increases the fio (p < . ). however, in this last case, the gap between both fio decreases with increases mv (fig. ) . the addition of an aerosol connected to an o flow rate ( l min) at the entry of a bs limits the fio decreases during the mv increases. introduction: burned patients are at high risk of yeast colonization and thus of invasive fungal infections, particularly to candida (c.) spp., leading to an increase in morbidity and mortality. while pre-emptive antifungal therapy has improved survival, it may lead to an increase in antifungal resistance. the objectives of this work were to describe candida species distribution and to determine the antifungal susceptibility of candida isolates acquired in a burn unit. our study is a retrospective review of severely burned patients admitted to the burn unit of the ben arous traumatology and burns center with one or more positive culture sites for candida, during the -month period from may through august . a total of isolates were thus obtained. the susceptibility to antifungal drugs ( -fluorocytosine, fluconazole, ketoconazole, micronazole, itraconazole, amphotericin b) was determined using the fungitest ® broth dilution method for patients with infected normally sterile body sites or a candida colonization index superior or equal to . . since echinocandin and anidulafungine were recently introduced in tunisia, the susceptibility to these antifungal classes was tested for only one patient from our cohort. results: nasal and buccal sites were the most colonized body sites ( . % each), followed by axillary ( . %) and rectal sites ( . %) and urines ( . %). c. albicans was the predominant species ( . %), followed by c. glabrata ( . %), c. tropicalis ( . %) and c. parapsilosis ( . %). among the strains whose antifungal susceptibility was determined, majority of candida isolates were susceptible to fluconazole ( . %), which is the most frequently used molecule as a pre-emptive treatment in such cases in tunisia due to its availability and its efficiency. on the other hand, . % of the isolates were intermediate and . % were resistant to this antifungal drug, mainly c. glabrata for both groups. as for the other tested azoles, high rates of intermediate strains were noticed ( . % to itraconazole, . % to ketoconazole and . % to miconazole), mostly c. glabrata. only one strain was resistant to amphotericin b, which is not usually used in these cases due to its nephrotoxicity and the frequency of kidney failure in burned patients. our study demonstrates that c. albicans is the most frequent species in burn unit-acquired candidiasis. no major antifungal resistance was observed, apart from high rates of intermediate strains (mainly c. glabrata) to azole class antifungal drugs. introduction: infection, especially bacteremia, is a major cause of morbi-mortality in severely burned patients. mortalityrelated to bacteremia in burn patients was about % [ ] . we performed this study to determine the prevalence, the causative agents and outcomes of bacteremia in burned patients. introduction: carbapenems, the last line of therapy, are now frequently needed to treat nosocomial infections, and increasing resistance to this class of β-lactams limit antibiotic options in critically ill patients especially in burns. the objective of our study was to assess the impact of the detection of carbaménépases in optimizing treatments in burned. patients and methods: a prospective, monocentric study was carried out at the intensive care unit of burn in tunisia over months (march-august ). were included all patients who have had a carbapenemase research. the sample was carried out by rectal swab. all samples were analyzed by polymerase chain reaction (pcr) methods for presence of carbapenemase. during the study period, patients were included. the mean age was ± years. they were men and women. the average burned surface area was ± %. patients were transferred from another hospital structure in % of cases with a delay of h. % of patients had a septic complication with a delay of ± days. antibiotic treatment was empirical in cases. the therapeutic failure rate was %. results of carbame-nepases detected by pcr are detailed in table . in the group of patients pcr (+), the antibiotic treatment was changed in cases. the most association of antibiotics were-tigecycline in combination with colistin or in combination with fosfomycine and fosfomycin in combination with colistin. this leads to reduce therapeutic failure by %. conclusion: detection of carbapenemase in our study was higher ( %), allows us to identify regions with high risk of carbapenemase, improve therapeutic efficacy and strengthen infection control measures by isolation of all carbapenemase producing patient. introduction: icu-acquired bacteraemia is prevalent and poses a grave threat. providing information about the main causative bacterial agents and determination of their susceptibility to antibiotics may improve empiric therapy and early detection of emerging antimicrobial resistance. the aim of this study was to investigate the species distribution and antibiotic susceptibility of isolated strains from blood culture in burn intensive care unit during a five-year period. patients and methods: from january to december , a total of , non repetitive strains were isolated from blood cultures. incubation of blood culture vials and the detection of bacterial growth were performed by the bactec system. all isolated organisms were identified on the basis of standard microbiological techniques. antibiotic susceptibility testing was carried out by the agar disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm and guidelines. data were analyzed using the sir-system. minimum inhibitory concentrations of colistin, imipenem and vancomycin were determined using the etest ® method (biomérieux). results: of the , strains isolated, the most frequently identified species were staphylococcus aureus ( %), acinetobacter baumannii ( %), klebsiella pneumoniae ( %), and pseudomonas aeruginosa ( %). the rate of methicillin-resistant staphylococcus aureus (mrsa) was %. resistance to tigecycline and linezolid was and %, respectively. all strains were susceptible to glycopeptides. in addition, isolated acinetobacter baumanii strains showed high rates of resistant to all tested antibiotics except colistin. eighty per cent of these strains were resistant to ceftazidime and % to imipenem. resistance to rifampicin was % in , and has increased steadily to % by . similarly, high resistance rates were observed among klebsiella pneumoniae and pseudomonas aeruginosa to ceftazidime ( and % respectively), ciprofloxacin ( and %) and imipenem ( and %). conclusion: this study investigated on the local distribution patterns of causative organisms of bacteraemia in burn patients and the corresponding antimicrobial susceptibility profiles. multidrug-resistant pathogens, especially mrsa and acinetobacter baumanii, were the most frequently isolated organisms. hygiene measures and antimicrobial stewardship should be implemented to prevent the spreading of these resistant strains. introduction: pseudomonas aeruginosa is known opportunistic pathogen frequently causing serious infections in burned patients. multidrug resistance in this pathogen is increasing throughout the world and is a major problem in the management of these pathogens. analysis of serotype and resistance profile to antobiotics of p. aeruginosa help to establish a prompt control and prevention program. the aim of this study was to evaluate the frequency of antimicrobial resistance and the prevalence of pseudomonas aeruginosa serotypes isolated in the burn unit. patients and methods: during a period of years (from to ), strains of pseudomonas aeruginosa were isolated from burned patients. conventional methods were used for identification. antimicrobial susceptibility testing was performed with disk diffusion method and susceptibility data were interpreted according to breakpoints recommended by the french society of microbiology (fsm). serotypes were identified by slide agglutination test using p. aeruginosa o antisera (biorad). the imipenem-resistant strains have benefited from a research of carbapenemase production by the edta test. results: in our study period, bacterial isolates were found among which pseudomonas aeruginosa was the second most frequent bacterium isolated from burned patients ( %) after staphylococcus aureus ( %). the most frequent sites were-cutaneus infection ( %), blood culture ( %) and catheter ( %). the most prevalent serotypes were-o ( %), o ( %), o ( %), o ( %) and o ( %). the survey of antibiotic susceptibilily showed high pourcentage of resistance to the different antibiotics- % of strains were resistant to ceftazidim, % to ticarcillin, % to ciprofloxacin, % to amikacin and % to imipenem. among the imipenem resistant strains, % were metallo-beta-lactamase producers. the antibiotic to which p. aeruginosa was the most susceptible was colistin ( %). multidrugresistance was associated with o serotype in % of the cases. the global frequency of serotypes o , o and o was more than %. multidrug resistance and carbapenemase being associated with serotype o . serotyping of the strains isolated from burned patients will help to guide the first antibiotherapy. the dissemination of carbapenemases strains must be contained by implementation of timely identification, strict isolation methods and better hygienic procedures. and respiratory disorders ( . %)…). the therapeutic management was based on per operative resuscitation, organ failure treatment, probabilistic antibiotic therapy and median laparotomy surgery. the main etiologies of abdominal sepsis were-digestive perforations ( . %), purulent effusion ( %), intestinal necrosis ( %), cholecystitis ( . %). the bacteriological profile was -predominance of bgn ( . %) dominated by e. coli ( %) followed by klebsiella pneumoniae and acinetobacter baumanii ( . %), the mean duration of the hospitalization was . ± . days. the mortality rate was %. the main prognostic factors in our study in univariate analysis were-the advanced age, the diabetes, the organ failure, the increased gravity scores, the time to management, the use of catecholamines and the development of septic shock. the multivariate analysis showed a statistically significant association between the development of septic shock, the stercoral effusion, the peptic ulcer perforation, the operator and the therapeutic descalation. the abdominal sepsis is a serious affection, with great mortality. the improvement of its prognosis is based on a revision of the medical and surgical protocols, and an adapted antibiotic therapy depending on the direct examination of the samples, also of the bacterial ecology of the service. introduction: severe acute respiratory infections (sari) are common in critically ill patients. viruses can be found in immuno-competent patients. however, the main problem for viral infections is the diagnosis, isolation of the pathogen is often difficult and the symptoms not specific. the aims of this study were to describing the epidemiological characteristics of viral respiratory infections, to identify factors predictive of a poor outcome. introduction: in septic shock there are physiological changes with an increase in the volume of distribution, with implications for pharmacokinetics of antibiotics that make recommended doses potentially inadequate for target organisms with highest minimal inhibitory concentrations. to cover these bacteria, peak serum concentration (cmax) target is - pg ml. identification of predictive factors for insufficient cmax, in common practice, would make it possible to target the patients at risk in order to optimize dosage of antibiotic to be administered. objective of this study was to determine predictive factors of amikacin's cmax insufficient independently of the dosage. patients and methods: this was a retrospective study carried out between august and november in icu of our hospital. all adult patient receiving an initial injection of amikacin between and mg kg were included. clinical data collected were-amikacin dosage, body mass index (bmi), mechanical ventilation (mv), mean arterial pressure (map), use of noradrenaline and continuous hemofiltration (cvvh). biological elements were collected and for each, the last result in the h prior to admission and that at the patient's entry into icu were added to analysis. a comparison of this clinical and biological variables was made between two groups-the first one with an ineffective cmax of amikacin (< pg ml) and the second with an effective cmax of amikacin (> pg ml). results: patients were selected for statistical analysis. median dosage was . mg kg for a median cmax at . mg l. for patients, cmax was less than mg l and in patients, it was greater than mg l. there was a statistically significant relationship between a cmax greater than mg l and mv, bmi, pct measured before and after admission, albumin after admission, hemoglobinemia, hematocrit level after admission, the rate of urea after admission (table ) . a low bmi was associated with cmax < mg l. discussion: these results remain comparable to those found by taccone in , with dosages of mg kg having only % of the peaks above mg l + comparable also to montmollin's study in . conclusion: mv, bmi, pre-and post-admission pct, and albumin, hemoglobin after admission, hematocrit and urea after admission seems to be predictive criteria for insufficient amikacin's cmax independently of dosage. our study was limited to one icu, a heterogeneous recruitment, and that all samples have been taken at the right time. introduction: this study aimed to assess whether augmented renal clearance (arc) impacts negatively on ceftriaxone pharmacokinetic pharmacodynamics (pk/pd) target attainment in critically ill patients receiving g day by intermittent infusion. patients and methods: over an -month period, all critically ill patients treated by ceftriaxone for a first episode of sepsis without renal impairment were eligible. during the first days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at trough concentrations. the main outcome investigated in this study was the rate of empirical target non-attainment using a theoretical target mic of mg/l. results: over the study period, patients were included ( samples analyzed for therapeutic drug monitoring). the rate of pk/pd target non-attainment was %, with a strong association with crcl (p < . ) ( table ). there was no statistical association between pk/ pd target non-attainment and therapeutic failure. conclusion: when targeting %ft > mic of the less susceptible pathogens, patients with crcl > ml/min are at risk of subexposure in ceftriaxone ( g day). these data emphasize the need of therapeutic drug monitoring in patients with arc, especially when targeting less susceptible pathogens or surgical infections with limited penetration of antimicrobial agents. introduction: the septic shock is a major concern of the intensive care unit in the world because of its frequency and especially of its mortality which remains high in spite of the progress made in the optimizing care. the aim of our work is to analyze the prognosis factors related to death among patients with septic shock in the icu of the military hospital avicenna of marrakesh, and to focus on the physiopathological and therapeutic data of the septic shock in the light of last acquisitions in this field. patients and methods: we proceed to a prospective study including all patients with septic shock at admission to icu or secondary, over a -year period (january -december ). prognosis factors related to death in patients with septic shock were studied in univariate and multivariate analysis. results: eighty-six cases of septic shock were collected from icu admissions, the incidence is . %, the mean age was ± . . the sites of infection most often involved were the abdomen and lung ( %), there was a predominance of gram-negative bacilli, the number of organ failure is in average . ± . . the overall mortality was . %. prognosis factors related to mortality retained after logistic regression are cardiovascular organ failure followed by neurological. indeed, the number of patients with or more failures was ( %) in the group of patients who died. as the second factor influencing the high mortality found severity score . ± . , age is also considered a prognosis factor since of patients were over years. the average age of the deceased was ± years versus ± years in survivors (p < . ), yet the mortality according to the infectious agent was not found as factor influencing mortality (p = . ). conclusion: septic shock is a frequent reason for hospitalization in icu. the improvement of prognosis requires an early and adapted management of sepsis as well as increases efforts for control and prevention of nosocomial infection. introduction: vitamin d deficiency is common in critically-ill patients. in addition to its role in the regulation of phosphor-calcic metabolism, vitamin d is of paramount importance for the immune system. the aim of the current study is to assess the prognostic value of vitamin d deficiency in patients with septic shock. patients and methods: retrospective study conducted over months. all the adult patients with septic shock and vitamin d level screening performed within the first h of admission were included in the study. we excluded patients with chronic kidney disease and those receiving vitamin d supply. two groups were compared: those with a serum vitamin d level < ng/ml (g ) and those with higher level (g introduction: since immunity plays a central role in neoplasms surveillance, it is likely that sepsis induced immune dysfunctions may impact on the underlying malignancy. we developed a research project investigating the reciprocal relationships between bacterial sepsis and cancer. we reported that sepsis-induced immune suppression promoted tumor growth in post-septic mice inoculated with cancer. in a reverse cancer-then-sepsis model we observed that sepsis may conversely inhibit tumor growth. this study aimed at investigating the cellular and molecular mechanisms of sepsis-induced tumor inhibition, and most especially the role of monocytes macrophages and toll-like receptor (tlr) signaling. patients and methods: we used c bl j wild-type (wt), tlr -/-, tlr -/-and myd -/-mice. mice were first subjected to tumor inoculation by subcutaneous injection of mca fibrosarcoma cells. fourteen days after, mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (clp). controls were cancer mice subjected to sham surgery. alternatively, cancer mice were subjected to an i.p. challenge with tlr agonist (lps or heat-killed staphylococcus aureus (hksa)). the distribution of tumor-associated immune cells was assessed by facs at days and following surgery. the activation status of tumorinfiltrating monocytes macrophages was assessed by facs (mhcii, cd , cd , pdl , pd ). f / + cells were purified by facs and we assessed cytokines production (rt-qpcr) and bacteria phagocytosis. we confirmed polymicrobial sepsis dampens tumor growth in wt mice. a similar clp-induced tumor growth inhibition was observed in tlr -/-mice, but neither in tlr -/-nor myd -/-mice. a challenge with lps resulted in a marked anti-tumoral effect, whereas a challenge with hksa had no impact on tumor growth. tumor-infiltrating immune cells analysis retrieved monocytes/macrophages predominance with two different subsets based on f / expression (f / high and f / low). late-onset (day ) tumors from clp-operated mice displayed increased proportions of f / high. as compared to f / low cells, f / high cells displayed a more immature status with a lower expression of cd , mhcii and pdl , and a higher phagocytic activity. interestingly, f / high cells from clp-operated mice exhibited a higher phagocytic activity than those from sham-operated mice. conclusion: polymicrobial sepsis drives a potent antitumoral activity in cancer mice, which is associated with changes in the distribution and functions of tumor-associated monocytes macrophages subsets. our results converge on a critical role of tlr signaling, that should be further investigated. conclusion: post-agressive immunosuppression in icu is not specific to sepsis. in septic shock, the low counts in circulating ilc s could be explained by ilc plasticity (conversion of these cells into ilc s), by migration from the blood or by an exacerbated apoptosis. ilc s expansion, associated with a higher risk of secondary infection, could be promoted by il- , released by tissue injuries. ilc s could activate regulatory t cells via il- . these preliminary results must be confirmed on a larger cohort. they play a suppressive role in the immune system by the secretion of negative regulatory cytokines such as interleukin- or by immune cell contact inhibition. the objective of this pilot study was to develop and test a protocol to determine the breg level in septic patients. the level of breg were measured on whole blood sample by flow cytometry the first day of hospitalisation in septic patients. b cells were identified on the single-parameter expression cd combined with scatter. the breg were identified as subpopulation expressing cd /hicd hi or cd /hicd + (see fig. ). the results were expressed as percentage of the parental lineage gate and absolute value per microliter. this protocol has been optimised in order to be able to transfer technic into clinical practice. results: we include patients hospitalized in intensive care unit with severe sepsis or septic shock. the percentage of cd + cd hic-d hi was . ± . % with a mean of . ± . cells microliter. the percentage of cd + cd hicd + was . ± . % with a mean of . ± . cells microliter. we are able to measure and follow the evolution of breg during severe sepsis or septic shock. because breg could inhibit body immune function, we wish to conduct a prospective study to evaluate the correlation between breg level and the prognosis of patients with sepsis. the neutrophil/lymphocyte ratio (nlr) reflects an inflammatory state. the nlr has recently emerged as a prognostic marker in colorectal cancer patients, acute coronary syndrome and pulmonary embolism (kayrak m, heart lung circ ). the aim of this study was to assess the prognostic value of nlr in patients with septic shock. we performed a prospective observational study in septic shock icu patients within h of admission from january to july in charles nicolle hospital of tunis. exclusion criteria were age < years, pregnancy + oncohematological patients, recent blood transfusion, post-cardiac arrest and brain-death. nlr was measured soon after admission and h, h, and h after. demographic, clinical and biochemical parameters, severity scores, life-support therapies (vasopressors, ventilation), and length of icu stay were recorded. the primary endpoint was -day mortality. results: sixty-five patients ( males, median age, . years) with septic shock were included in the study. the -day mortality was %. the median sofa score at t was points and the median igs score was points. the sources of infection were as follows: the lungs (n = ), the urinary tract (n = ), the central nervous system (n = ), the abdomen (n = ), skin and soft tissue (n = ). the parameters that were identified through univariate analysis to be associated with -day mortality were igs score, lactate level, the nlr elevation at h , h and h . median nlr levels were significantly higher in non-survivors (n = ) than survivors ( introduction: the autonomic nervous system (ans) is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of ans activity and a relation between hrv and outcome has been proposed in various types of patients. we evaluated the feasibility of a automated hrv monitoring, based on standard electrocardiography monitoring, and investigated the different parameters that should be recorded. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record more than icu patients over a -years period. patients and methods: physiological tracings were recorded from the standard monitoring system (intelliview mp philips), using a dedicated network and extraction software (synapse v , ltsi inserm u ) that enables simultaneous recording of different physiological curves, at their native resolution ( hz for ecg, hz for other). raw data were subsequently stored on a dedicated local server, before anonymization and analysis. all consecutive patients were recorded for a -hours period during the -hours following icu admission. all measurements were recorded with the patient laying supine, with a ° bed head angulation. physiological recordings were associated with metadata collection by a dedicated research assistant. hrv parameters were derived from electrocardiography monitoring using kubios hrv premium ( introduction: acute cor pulmonale (acp) is a frequent complication of acute respiratory distress syndrome (ards). it occurs in % of cases and might be associated with an increased mortality rate. it is defined by a ratio of telediastolic surfaces of right ventricular (rv) on left ventricular greater than . and a septal dyskinesia. however, systolic dysfunction defined by the guidelines of the american society of echocardiography has not been well studied in ards and in particular concerning the rv free wall longitudinal strain (rv-fw-ls). the aims of the present study were to identify the prevalence of rv systolic dysfunction and acp in ards, and to evaluate the effects of inhaled nitric oxide (noi) and prone positioning. we prospectively included patients to a mild to severe ards, and proceeded to standardization of ventilation and systematic echocardiography in semirecumbent position, with noi and in prone position. interpretation of examination was blinded to the investigator. we evaluated the presence of acp, systolic dysfunction identified by classical cardiologic criteria (rv fractional area change, rv tei index, tricuspid annular plane systolic excursion, velocity of the tricuspid annular systolic motion) and also by rv-fw-ls. results: sixteen patients were included. thirty-seven percent of patients were in severe ards. the prevalence of acp was % while right ventricular systolic dysfunction was identified in . % of patients with the classic cardiologic criteria and . % with the impairment of rv-fw-ls which represented the most sensitive test for right ventricular dysfunction detection (table ) introduction: the use of extra corporeal membrane oxygenation (ecmo) is increasing. brain complications may occur, resulting in an increased morbidity and mortality. the objective of our study was to analyze the incidence of neurological complications while receiving ecmo, the risk factors, and to describe morbidity and mortality in a large cohort of patients in intensive care unit. patients and methods: this was an observational, mono-centric, -year retrospective study in patients who received ecmo. primary outcome was the occurrence of neurological complication until d after ecmo. results: one hundred and eight patients were included in the analysis. twenty-seven patients ( %) presented a neurological complication. of these, died at d . there were ischemic sequelae ( . %), intracranial haemorrhages ( . %), cerebral edema ( . %) and one other lesion ( . %). the median time before occurence of a neurological complication was days after the implementation of ecmo. multivariate analysis revealed the presence of hyperlactatemia > . mmol l, neurological deficit at the beginning of the management, as well as the history of stroke before the ecmo implementation as predictive factors of neurological complication (or . , . the incidence of neurological complications under ecmo is about % and ischemic sequelae are the most frequent. history of stroke and low cerebral flow associated with ischemia-reperfusion seem to increase the occurrence of these complications and must lead to greater vigilance in these patients. - ] . eighteen patients ( %) survived at icu discharge with a good neurological outcome. by multivariate logistic regression analysis, female sex, initial shockable rhythm, and pre-ecmo arterial blood ph ≥ . were independent predictors of survival with good neurological outcome. all of the patients presenting with cpc score of or at icu discharge had a shockable rhythm and or ph ≥ . before ecls implantation. % of the patients presenting with these criteria had a good neurological outcome at icu discharge. all of the patients presenting with non-shockable rhythm and ph < . before ecls implantation died in the icu. conclusion: about one third of the patients presenting with shockable rhythm and or ph ≥ . before ecls implantation had a good neurological outcome at icu discharge. on the contrary, all of the patients presenting with both non-shockable rhythm and ph < . before ecls implantation died in the icu. these simple parameters might help to identify cardiac arrest patients which could benefit from ecls implantation. radjou aguila introduction: the decrease of lung volume is a keystone for the management of patients under mechanical ventilation in intensive care units. this procedure has not only led to a reduction of morbimortality in ards but also in all patients mechanicaly ventilated in intensive care units as well as in major surjery. nevertheless, the incidence of high volume (vt) on morbimortality is extremely variable (about to %). our main objective is to assess the incidence of high volume ventilation (> ml/kg predicted body weight, pbw) in our hospital intensive care units. moreover we were interested in determining the risk factors of high volume ventilation. we conducted a retrospective observational study from january to march in three intensive care units of a tertiary university hospital. all patients ventilated under sedation in vac mode during the h after admission were included in the study. of the patients admissions during the period, one of them ( %) have no height mentioned in their medical file and were exluded. among the patients considered, ( . %) were ventilated with high vt (fig. ). % of patients had a positive expiratory pressure ≥ cmh o. in multivariable analysis, height (smaller) and weight (lower) are the only associated factors with a high volume ventilation (p < . and p = . , respectively). discussion: the observed incidence on high vt patients is higher than that reported in most papers in literature (jaber et al. %, hess et al. %) . nevertheless, both studies were conducted in operating room with higher vt cut-off ( ml/kg). walkey and al showed that % of patients in ards were ventilated with vt › ml/kg of pbw. moreover, the same associated factors (smaller height and lower weight) have found in the study. older studies revealed higher bmi as factor to high volume ventilation. this difference could be explained by the use of predicted body weight. conclusion: although the growing literature and the recommandations aim to reduce the lung volume between to ml/kg of pbw, still one third of the patients in intensive care units are ventilated with too high lung volume. (fig. ). with either a nc overlap on one nostril or not. results: when the mv increases, the fio decreases. when the mouth opens, the fio decreases. when the prongs are overlapping one nostril the fio decreases slightly (mean ± % in absolute value). statistical differences were found between closed and open mouth and between overlap on one nostril and not (p < . ), except between tmo and cm at two mv ( and l/min) when nc overlap on one nostril (fig. ) . conclusion: when the prongs of nc are not correctly placed in the nostrils, the fio decreases, but this impact is limited in our bench study. the impact of mv increases and mouth opening on the fio values is also important. introduction: the weaning of mechanical ventilation is an essential and delicate phase in the management of a resuscitation patient. the neurosurgical patient presents a number of specific problems, such as impaired control ventilatory control, coughing or the pharyngo-laryngeal intersection. however, it often allows short-term ventilatory withdrawal in the neurosurgical patient, probably largely by the simple fact that it authorizes the definitive cessation of sedation. the objective of the study and demonstrate the place of tracheotomy in neuro-resuscitation patients, and prevent its complications. a retrospective descriptive study of patients hospitalized in the neuro-resuscitation unit during the period january to december , of which patients benefited from surgical tracheotomy, is a frequency of % of all inpatients during this period. clinical, para-clinical, etiological, and therapeutic data were collected from hospitalization records. in a series of hospitalized patients, during the defined period, patients had surgical tracheotomy, a frequency of %, in the literature two studies or the data were extremely variable, with % in the study namen versus . % in the coplin study. of the tracheotomies, were performed by neurosurgeons, and by resuscitators at a frequency of %. the tracheotomy was performed on average days after the intubation of the patients, after verification of the impossibility of the extubation of the latter either for central affection of the ventilatory controls, or reached the mixed nerves and disorders of the laryngo-pharyngeal intersection and according to expert recommendations in -tracheotomy should not be performed in the intensive care unit before the fourth day of mechanical ventilation. different pathologies that patients suffered and required tracheotomy were: post-operative complications of brain tumors (brain stem and mixed nerves) with patients, a rate of %, vascular pathologies (stroke and cvt)), with patients ( %), traumatic pathologies, with patients ( %). cases, %, cases of secondary bleeding of the orifice, cases of tracheal stenosis, and case of tracheomalacia. the decan made after pharyngolaryngeal neurological examination, and according to sfar recommendations experts suggest that a multidisciplinary decanulation protocol available in resuscitation departments. conclusion: tracheotomy in neuro-resuscitation has its place, especially in view of the different complications specific to this type of patient, but no study has demonstrated its improvement in vital prognosis. post-tracheotomy complications can be considerably reduced if the protocols and expert recommendations are applied. introduction: noninvasive ventilation (niv) in intensive care (icu) is associated with the occurrence of frequent asynchronies related to the leaks around the interface, mainly auto-triggering and delayed cycling. their detection requires a respiratory muscles activity monitoring. diaphragmatic ultrasonography is a simple imaging technique available at bedside to assess diaphragm motion. whether diaphragmatic ultrasonography would allow detecting asynchronies due to leaks during niv is unknown. the aim of this study was to assess two methods of diaphragmatic ultrasonography (excursion and thickening), coupled with the airway pressure signal to detect patient-ventilator asynchronies during niv. patients and methods: nine healthy subjects were placed under niv and subjected to intentional inspiratory and expiratory leakage on the ventilator circuit to generate delayed cycling and auto-triggering, respectively. the flow, airway pressure and diaphragmatic electromyogram were collected in order to identify the asynchronies generated by the leaks. in the meantime, an ultrasound recording of the excursion of the right diaphragm and of the thickening of the right diaphragmatic zone of apposition were performed and combined with the display of airway pressure on the ultrasound screen. these records were analyzed a posteriori to define the diagnostic performance [including sensitivity (se), specificity (spe), positive predictive value (ppv), and negative predictive value (npv)] of the excursion and the thickening to detect asynchronies. the experimental setup generated a median of asynchronies per subject (interquartile range - ). auto-triggering was correctly identified by continuous recording of both excursion (se = %, spe = %, ppv = %, and npv = %, fig. a ) and thickening (se = %, spe = %, ppv = %, npv = % + fig. c ). delayed cycling was detected with a slightly lower performance by diaphragm excursion (se = %, spe = %, ppv = %, npv = % + fig. b ) and thickening (se = %, spe = %, ppv = %, npv = % + fig d) . discussion: these encouraging results may be tempered by a variable effectiveness of the technique from one subject to another, in particular concerning the excursion. moreover, their generalization to critically ill patients may depend on several factors including echogenicity, stability and amplitude of the ultrasound signal in this population. conclusion: ultrasound is a simple clinical tool available at the bedside to detect delayed cycling and auto-triggering associated with niv leaks, provided that the airway pressure curve is displayed on the screen of the ultrasound machine. further studies are needed to assess its usefulness in detecting other types of asynchronies and its feasibility in critically-ill patients. introduction: although extra-corporeal co removal (ecco r) is not recommended, strong rational supports the concept. we aimed to describe our single-center experience of ecco r in the setting of mild to moderate acute respiratory distress syndrome (ards) and chronic obstructive pulmonary disease (copd). we performed a retrospective case note review of patients admitted to our tertiary regional intensive care unit (icu) and commenced on ecco r from november to august . demographic data, physiologic data (including ph and partial pressure of carbon dioxide in arterial blood [paco ]) before ecco r starting, and at day were recorded. results: twenty one patients received ecco r. thirteen were managed with hemolung ® device, seven with prismalung ® and one with ila ® . indication for ecco r were copd exacerbation (n = ), mild to moderate ards (n = ), uncontrolled hypercapnia due to pneumonia (n = ), and hypercapnia due to bronchial compression by mediastinal adenopathy (n = ). before starting ecco r, median minute ventilation, ph and paco were respectively . [ . , . conclusion: our observational cohort shows that ecco r therapy is effective to reduce paco and improve ph in the settings of mild ards and copd exacerbation. however, early weaning of sedation and pressure support ventilation might limit the decrease of respiratory rate and tidal volume. introduction: duchenne muscular dystrophy (dmd) is an x-linked recessive genetic disorder, caused by mutations in the dmd gene. respiratory failure is classical in the natural history of this disease. little is known about the diaphragm echographic pattern and the spectrum of patients with diaphragmatic paralysis in this disease. we aimed to assess the relationship between age and diaphragmatic motion and thickening fraction (tf) and to characterize the spectrum of patients with diaphragmatic paralysis. patients and methods: we included retrospectively dmd patients who experienced diaphragmatic echography and spirometry in our institution. diaphragmatic paralysis was defined as a diaphragm with tf < %. results: dmd patients were included in this study. all dmd patients were wheelchair bound. dmd patients had severe respiratory insufficiency with a median vc at % of predicted value [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . . % of patients were on home mechanical ventilation (hmv) and % were invasively ventilated. right diaphragmatic motion at deep inspiration was severely altered with a median of . mm [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . right tf of the diaphragm was severely altered with a median of . % [ . - . ] . . % of patients disclosed a paralyzed diaphragm pattern with a right tf < %. the age was inversely correlated with tf of the diaphragm (r = - . , p . ) and with the right diaphragm inspiration motion (r = − . p < . ). patients with diaphragm paralysis were older with median age at . years [ - . ], with severe respiratory impairment (median sitting cv = %) and median cumulated annual hmv duration at . years. conclusion: in dmd, age is inversely correlated with diaphragm function. diaphragm paralysis is frequent in older adult non-ambulant dmd. . the final probability model included the previous identified factors in addition to age and saps ii score, this model exhibited good calibration (hosmer-lemeshow x , p = . ) and good discrimination (roc-auc, . + % confidence interval, . - . ) (fig. ) . conclusion: our cohort study identified risk factors of icu death, mainly collected at admission among patients with aecopd. the proposed probability model has a good performance in predicting the short-term prognosis. further evaluation in other cohorts is needed. introduction: precarity is a complex notion including several components, and its definition is still debated. it is more subtle than financial poverty alone, and can increase population's health insecurity. we hypothesize that patients with precarity features may have different epidemiologic characteristics and icu outcomes than the general population. the aim of this study was to describe precarity features and outcomes of patients admitted to an icu located in a high poverty rate territory. patients and methods: we conducted a prospective single-center observational study of all patients admitted to icu of the saint-denis general hospital, from february to july . precarity features were classified in categories-absence of health insurance, lack of incomes or minimum allowances, homelessness or social home or hotel, and social isolation (no social link, or associations or neighbors). others social data were collected (speaking fluent french and education level) as well as usual clinical icu data. results: among patients included, precarity features were found in patients ( . %). income precarity was the most common, followed by accommodation precarity, health precarity and relation precarity (table ) . precarity was not associated with hospital mortality ( vs. . %, p = . ). all types of precarity were significantly associated with each other. precarious patients were younger ( vs. years-old, p < . ) and had less comorbidities. we found no differences concerning hospital or icu length of stay ( vs. days, p = . ) or concerning education level between precarious patients and the others. conclusion: our pilot study shows that precarity features are indeed very frequent and are often cumulated. with respect to the small patient sample, precarity does not seems to be associated with hospital mortality or length of stay. further investigations with larger patient samples and multicenter designs are warranted to investigate properly the impact of precarity on icu management and outcomes. introduction: population aging is a global and expanding phenomenon. elderly people are particularly vulnerable, and often need health care. this demographic evolution also affects intensive care units, and years old patient are now frequently admitted-it corresponds to % of admission in france. indeed we have analyzed the change in management of this very elderly people ( years old and more) over the past years in a french medical intensive care unit in a provincial university hospital. patients and methods: a retrospective cohort study was conducted using medical intensive care unit registry for demographic, physiological and diagnostic data from january to december . characteristics and treatment intensity during medical icu stay were specified, and short term and long term mortality were also recorded. results: a total of admissions, including octogenarians and older, were registered during the period. the proportion of very elderly people gradually increase from to %. intensity of treatment (organ support) increased from . from . per patient between the primary and the second part of the period, notably linked to mechanical ventilation ( vs. %, p < . ) and vasopressor infusion ( vs. %, p < . ). even if severity score increased (saps increase from . to . , p < . ), the icu mortality remains constant ( vs. . %). however, we were surprised to observe an increase in year mortality ( to %, p < . ). conclusion: between and , proportion of admission of very elderly people has increased two fold in our icu. although treatment intensity increases for more severe patients, icu mortality remains the same. nevertheless, absence of beneficial effect after year remains questioning. could icu to ward transfers and care course after hospital be optimized? lived alone at home, % in couple or with ther family, ( %) in retirement home and ( %) in nursing home. ( %) had a simplified ald score lower than indicating good functional independence. the more frequent diagnosis were acute pulmonary oedema and exacerbated copd. the mean simplified acute physiology score (saps ii) was ± . the treatment were were invasive mechanical ventilation ( %), only with noninvasive ventilation ( %), vasopressor agents ( %) and ( %) with renal replacement therapy. the average length of stay was . ± . days. after adjustment on sap-sii (without age), those invasive treatments were not associated with mortality no more than age. global mortality rate was %. ( %) were subject of a procedure for limiting therapeutics, among which ( %) died in the unit versus % for the other patients. the decision of therapeutic limitation was associated with severity of illness as measured by the sapsii (p = . ) but not with age. frequency of therapeutic limitation were similar in icu and intermediate care units. the mortality rate is lower than the older studies (s de rooij - %). unlike the study of p. biston ( ) which covers only the most serious cases, the mortality for any type of gravity remains reasonable. the procedure for limiting care were frequent especially for the most severe pathologies but all the patients who a decision of limiting care were stated were not dead. the patients over years old admit in french icu are very chosen. any major treatment appear to enhance mortality. introduction: due to advancements in medical technology and management of illnesses, an increasing proportion of critically ill patients are elderly. few information is available on the prognosis of these patients after icu discharge. the aim of this study was to analyze the clinical characteristics and long-term outcomes of elderly admitted to icu. patients and methods: monocentric, observational prospective study was performed. all elderly survivors (aged ≥ years) after an icu stay in a medical tunisian icu between january and december were included. data collected were: clinical features at admission, acute management procedures, functional characteristics and vital parameters (blood pressure, heart rate, abg's) at icu discharge. patients were followed during year via phone calls. a multivariate regression analysis was used to identify risk factors for one-year mortality. results: during the two-years study period, elderly patients were discharged alive. ( . %) were male. clinical features of elderly survivors were: mean age, . ± . years, median of charlson index, [ - ], chronic respiratory disease, ( . %), hypertension, ( . %) and diabetes ( . %). the most common reason for admission was acute respiratory failure in ( . %) patients and mean saps ii was . ± . . ( . %) patients required invasive ventilatory support, ( . %) vasoactive drugs and ( . %) received renal replacement therapy. the median of icu length of stay was days. the follow up was possible for ( . %) patients. mortality rate at year was . %. predictors of one-year fatal outcome in univariate analysis were as follows-saps ii (p = . ), heart rate at discharge (p = . ), decline in functional status (p = . ), world health organization (who) performance status at discharge (p = . ) and readmission within month (p = . ). multivariate regression showed that saps ii (or, . + % ci [ . - . ] + p = . ), who performance status at discharge (or, . + % ci [ . - . ] + p = . ) and heart rate (or, . + % ci [ . - . ] + p = . ) were independent risk factors of one-year mortality. conclusion: this study suggests that age and comorbidities should not be exclusion criteria for icu admission. in the long-term only saps ii, performance status and heart rate were significantly associated with one-year mortality in the elderly icu survivors. introduction: triage is an act performed at the entrance of emergency departments (ed's), it allows the classification of patients in different categories according to the seriousness and the priorities of treatment. vital emergencies are geared towards resuscitation room. in our ed, triage is not codified and is «done» in most cases by an unqualified staff. the aim of this work is to show the impact of absence of triage on the functionning of the resuscitation room. patients and methods: it's a prospective study, conducted in the ed of a university hospital, over months, including all patients over years old, admitted at the resuscitation room. epidemiological and clinical data of patients, their ccmu classification (classification clinique des malades aux urgences) have been specified, as well as their outcomes. we collected patients. the average age was . years old ( - years), for a sex ratio of . . forty patients ( . %) arrived «standing» at the ed. patients ccmu and represented . % of these admissions. the systolic blood pressure was under mmhg in % of cases, the glasgow coma scale < . in % of cases, and the spo < % in % of cases. mortality was . %. the other patients were admitted at the intensive care unit ( %), at the short stay hospitalization unit ( . %), at the operating room ( . %), or transferred to other departments ( . %). discussion: the patients ccmu and arrived by ambulance, «lying» , were considered as severe. the proximity of the resuscitation room of consultation rooms allows it to be used sometimes in flows' management and as a place of triage. the patients transferred straight to services didn't show signs of vital distress motiving their initial admission at resuscitation room or even at ed. those admitted at the short stay hospitalization unit were steady, but needed complementary examinations, specialized expert advice, or were waiting for a downstream bed. conclusion: a triage system must be introduced at the entrance of our emergency departments. the staff involved in that sorting must be identified, and disposing of a triage scale in order to figure out the degree of priority associated to patients conditions, and direct the ones needing urgent care towards the resuscitation room. results: one hundred patients were included, with average age of . years old ( - ) and sex ratio of . . these patients were brought to emergencies by their family in % of cases. reasons for admissions were varied, severe deterioration of their general condition ( %), alteration of consciousness ( %), respiratory distress ( %), convulsive seizures ( %). therapeutic interventions were cardio-pulmonary resuscitation ( %), fluid volume expansion ( %), mechanical ventilation ( %), administration of vasopressors ( %) and anticonvulsants ( %). mortality at the resuscitation room was %. thirty eight patients were admitted at the intensive care unit, equally at the short stay hospitalization unit (ssu) of ed. two patients returned home at the request of their family. discussion: these results show that ed's remain the last resort in front of oncology patient who is deteriorating, the occurrence of complications, and sometimes, the psychological exhaustion or family's obstinacy. emergencies departments continue admitting patients with terminal cancer, but are not organized for medium and long term care. the creation of a palliative care unit and the organization of home-based care will allow the prevention and treatment of complications as well as a psychological care, thus improving the living quality of these patients and their relatives. refusal of intensive care admission: assessment of a tunisian icu practices merhabene takoua introduction: need of intensive care exceeds its availability in several countries. as a consequence, rationing intensive care unit (icu) beds is common and often leads to admission refusal. purpose-to report refusal determinants and characteristics of patients associated with decisions to deny icu admission. this study was performed at the icu of abderrahman mami hospital, a -bed icu in ariana, tunisia. it was a prospective study enrolled between st january and th december . no predefined admission criteria were determined. decisions to admit are based on a combination of patient-related factors, severity of illness and bed availability. all consecutive patients referred for admission to icu during the study period were included. groups were defined gi-admitted patients and gii-refused patients. the reasons for refusal were categorized as follows: too well to benefit, too sick to benefit, patient or family refusal, necessity of other exploration not available in our institution and unit too busy. results: during the study period, icu admission was requested for patients of whom were admitted ( %). of the patients refused, only were admitted to icu later. refusal of icu admission came in % of cases from the emergency room and wards of our hospital, in % from other hospitals of whom % without icu. reasons of refusal were no beds availability ( . %), too sick to benefit from icu ( %), too well ( . %) and necessity of other exploration ( . %). no differences in demographic characteristic between the two groups were noted. among the refused patients, when compared with admitted patients, we found higher proportions of hematologic malignancies (p < . ) and cardiocirculatory arrest (p = . ). on the other hand, admitted patients were more likely to have cardio-respiratory comorbidities ( / vs. / , p = . ) and more need to mechanical ventilatory support ( vs. , p = . ). conclusion: our study confirms that icu refusal rate still high. it depends on both icu organization and patient characteristics. acute heart failure syndroms in intensive care: clinical features, management and outcome jamoussi amira , ajili achraf , merhebene takoua introduction: classification of acute heart failure (ahf) into clinical scenari (cs) was first proposed to facilitate early management ( ) . a decade after implementation of this approach, epidemiological and evolutive data based on this classification are interesting to investigate. that is why we aim to describe frequencies, management and mortality of each ahf syndrom in intensive care. a prospective study of patients > years with ahf admitted to the medical intensive care unit (icu) of abderrahmen mami hospital from january to august was conducted. patients were classified according to the clinical scenari ( ). clinical, therapeutic and outcome findings were recorded. results: during the study period ( months), we admitted patients in icu from whom ( . %) presented with ahf and then enrolled. the median age was of ± . years and sex-ratio . . a medical history of copd ( . %), hypertension ( . %), diabetes ( . %), ischemic cardiopathy ( %) and valvular cardiopathy ( . %) were noticed. at admission, severity assessement scores were: median apache ii . ± . and median saps ii ± . . clinical and evolutive characteristics according to clinical scenari are listed in table . conclusion: cs and cs are the most frequent ahf syndroms in icu and also have the best outcome. introduction: in cardiac arrest patients resuscitated from an ischemic ventricular fibrillation or tachycardia (vf/vt), both incidence and risk factors of recurrent severe arrhythmia are unclear. whether it is useful to give a prophylactic anti-arrhythmic (aa) treatment during the first hours and days is debated, particularly when a successful coronary reperfusion was provided. we aimed to evaluate the incidence of severe arrhythmia in patients resuscitated from an ischemic vf vt and to identify risk factors for developing arrhythmia during their icu stay. the procat registry captures all data from patients admitted in a tertiary hospital center after a resuscitated cardiac arrest (ca). we selected patients with an initial vf vt caused by an acute coronary syndrome (acs) and who were successfully treated with early percutaneous coronary intervention (pci) on admission. the primary endpoint was the recurrence of major arrhythmia between icu admission and icu discharge. all arrhythmias resulting in ca recurrence and or severe arterial hypotension requiring infusion of vasopressors were classified as major arrhythmias. multivariate logistic regression identified factors associated with the occurrence of major arrhythmias. results: between / and / , consecutive ca patients were included in the analysis. all patients underwent a successful pci of the infarct-related artery on hospital arrival. the only drug used as a prophylactic aa treatment was amiodarone, which was employed in / patients ( %). overall, / patients ( . %) had a major arrhythmia recurrence during their icu stay. a large majority of these major arrhythmia recurrences ( . %) occurred during the first h. characteristics of patients with and without major arrhythmia recurrence are described in the table . in multivariate analysis, public place location (or . [ . - . ], p = . ) and male gender (or . [ . - . ], p = . ) were both associated with a lower risk of major arrhythmia recurrence during the icu stay. prophylactic aa treatment was not associated with a lower risk of recurrences of major arrhythmias (or . [ . - . ], p = . ). conclusion: despite an early coronary reperfusion, more than % of our post-cardiac arrest patients experienced a recurrent severe arrhythmia during the post-resuscitation period, mostly during the first h in the icu. this proportion is much higher than what is reported in common acute coronary syndrome (without cardiac arrest) and further studies are needed to explore protective strategies. introduction: during symptomatic treatment of septic shock, markers of anaerobic metabolism may be used in a goal-oriented strategy. the recent international guidelines for management of sepsis and septic shock suggested guiding resuscitation to normalize lactate as a marker of tissue hypoperfusion. the purpose of this study was to evaluate the kinetics of lactate and other markers during the first three hours and to compare their levels between survivors and non survivors. we conducted a prospective, observational, single-center study of patients admitted to a general icu from the may to august . inclusion criteria were patients age ≥ , intubated and under mechanical ventilation with septic shock as defined by the third international consensus conference. simultaneous sampling of arterial and central venous blood gas were collected at h and h to obtain lactate (mmol/l), and scvo (%). delta pco (mmhg) and delta pco /cavo (mmhg/ml) were computed by our patient data management system and presented as a chart with additional hemodynamic data for clinical decision support. comparisons of values between groups were made by mann-whitney u test as appropriate. p < . was considered statistically significant. all reported p values are two-sided. statistical analysis was performed using systat ver. . . results: we studied intubated septic shock patients aged ± years, saps ii ± , sofa ± . . community pneumonia and peritonitis were the major sources of infection. icu mortality rate was %. all patients received norepinephrine ( . ± . µg/kg/ min), two patients received dobutamine ( . ± . µg/kg/min). the evolution of markers is summarized in table . at h and h , arterial lactate levels were higher in non-survivors than in survivors, but did not decrease at h in both groups. at h there was no statistical difference concerning scvo , delta pco and delta pco /cavo . after three hours of resuscitation, delta pco and delta pco /cavo ratio decreased and scvo increased in survivors. survivors had lower delta pco and delta pco /cavo ratio than non survivors. conclusion: although high lactate level is a key signal of anaerobic metabolism, it did not decrease during the first three hours in this group of severe septic shock patients. instead of using lactate, delta pco and delta pco /cavo kinetics could be integrated in a goaloriented strategy for septic shock resuscitation. introduction: to assess whether, in patients under mechanical ventilation, fluid responsiveness is predicted by the effects of short respiratory holds on cardiac index estimated by oesophageal doppler (cidoppler). patients and methods: in patients, before infusing ml of saline, we measured cidoppler before and during the last seconds of successive -second end-inspiratory occlusion (eio) and endexpiratory occlusion (eeo), separated by min. patients in whom volume expansion increased cardiac index (transpulmonary thermodilution) > % were defined as "fluid responders". results: eeo increased cidoppler more in responders than in nonresponders ( ± vs. ± %, respectively, p < . ) and eio decreased cidoppler more in responders than in non-responders (- ± vs. - ± %, respectively, p = . ). thus, when adding the absolute values of changes in ci observed during both occlusions, cidoppler changed by ± % in responders and ± % in nonresponders. fluid responsiveness was predicted by the eeo-induced change in cidoppler with an area under the receiver operating characteristic (roc) curve of . ( % confidence interval- . - . ) and a threshold value of % increase in cidoppler. it was predicted by the sum of absolute values of changes in cidoppler during both occlusions with a similar area under the roc curve ( . ( . - . )) and with a threshold of % change in cidoppler, which is more compatible with oesophageal doppler precision. in this case, the sensitivity was ( - )% and the specificity was ( - )%. conclusion: if consecutive eio and eeo change cidoppler > % in total, it is very likely that volume expansion will be efficient in terms of cardiac output. the measurement of cardiac output using a signal morphology-based form of impedance cardiography (physioflow ® ) in intensive care unit: comparison with the trans thoracic echocardiography. introduction: in the intensive care units, the cardiac output (co) is one of the main hemodynamic parameters required to manage patients in shock. the physioflow ® is a new non-invasive method using the waveform analysis of the thoracic impedance signal (ti) to assess co. in hemodynamicaly unstable patients, no studies have evaluated the level of agreement between the co estimated by transthoracic echocardiography (co-tte) and that measured using the waveform analysis of thoracic impedance physioflow ® (co-ti). the objective of this study was to evaluate the ability of co-ti relative to co-tte to estimate the absolute co value and detect the expected variation co (v-co) in critically ill patients. patients and methods: fourteen patients sedated and mechanically ventilated, in shock under catecholamines and monitorred with tte and ti physioflow ® were included. hemodynamic datas, stroke volume (sv) and co with two monitoring were performed at baseline min before passive leg raising (plr), s after plr and min after volume expansion (ve) of ml of saline solution. responders were defined by an increase > % of cardiac output (v-co) after plr. results: fourteen pairs of tte and ti measurements were compared. the median (iqr) age was years ( - ), igs was ( - ). only patients were responders after plr. there was a significant correlation between the co-tte and co-ti measurements (r = . , p < . ). the median bias was . l/min and the limits of agreement (loas) were − . and . l/min. there was a significant correlation between v-co-tte and v-co-ti (r = . , p = . ) (fig. ) . the median bias was- . % and the loas for v-co were respectively - . and + . %. conclusion: the co measured with physioflow ® , a signal morphology-based impedance cardiography, is correlated to the co measured with tte. however, the high loa observed in this preliminary study underline the necessity to remain careful and wait for further inclusions. - ] vs. . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days, p = . ). despite imbalancedunderlying characteristics in terms of demographics and comorbidities, in-icu mortality rates were similar between patients ( . vs. %, p = . ). conclusion: prior bb treatment have limited impact on the severity of acute circulatory failure in septic shock and is not associated with increased mortality despite the underlying frailty of patients. introduction: cardiac output monitoring is a key component in the management of critically ill patients. cardiac output estimated by transthoracic echocardiography is documented in patient with atrial fibrillation, but a large part of transpulmonary thermodilution validation studies excluded this specific population. the objective of this study was to evaluate cardiac output mesurement and trend ability by transpulmonary thermodilution relative to transthoracic echocardiography in critically ill mechanically ventilated patients with atrial fibrillation. patients and methods: thirty mechanically ventilated patients requiring hemodynamic assessment were included in a prospective observational study. cardiac output was mesured simultaneously with transpulmonary thermodilution and transthoracic echocardiography. seventy-four pairs of cardiac output measurements were compared. the two measurements were significantly correlated (r = . et p < . ). the mean bias was - . l/min, the limits of agreement were - . and + . l/min, and the percentage error was . %. thirty-four pairs of cardiac output variation measurements were compared. there was no significant correlation between cardiac output variation measurements by transpulmonary thermodilution and transthoracic echocardiography. the mean bias was − . l/ min and the limits of agreement were − . and + . l/min. with a % exclusion zone, the four-quadrant plot had a concordance rate of . %. the polar plot had a mean polar angle of . ° with % confidence interval between − . ° and . °. conclusion: in critically ill mechanically ventilated patients with atrial fibrillation, cardiac output measurements with transpulmonary thermodilution and transthoracic echocardiography are not interchangeable. introduction: basic critical care echocardiography (cce) relies on transthoracic echocardiography (tte). we sought to assess the diagnostic capacity of a next-generation micro-digital broadband beamformer in patients with cardiopulmonary compromise. all patients with acute circulatory respiratory failure underwent two basic tte assessments using successively a next-generation micro-digital broadband beamformer ( elements, - mhz) incorporated in a sector phased array probe with twodimensional, m-mode and color doppler mapping capacities which was connected to a touchscreen interface (lumify, philips), and using a compact full-feature imaging system ( elements, - mhz + cx , philips). tte examinations were independently performed in random order by two intensivists with expertise in cce, within a -min time frame without therapeutic intervention. imaging quality was graded from (no image in the corresponding view) to (clear identification of % of endocardial boarders). the concordance of qualitative data was assessed using the kappa test and agreement of two-dimensional measurements (left ventricular end-diastolic diameter [lvedd], ratio of right ventricular (rv) and lv end-diastolic diameters [rvedd lvedd] + end-expiratory inferior vena cava diameter [dexpivc]) was evaluated using intraclass coefficient correlation (icc). results: thirty consecutive patients were studied, without any exclusion for absence of tte images (age, ± years, sap-sii, ± , % ventilated, % under catecholamines, lactate, . ± . mmol l). the proportion of echocardiographic views eligible for interpretation and mean duration of tte examinations were similar with the miniaturized and full-feature systems ( vs. %, . ± . vs. . ± . min, p = . ). two-dimensional imaging quality grade was lower with the miniaturized system ( system. concordance of two-dimensional measurements was also good-to-excellent (table ) . conclusion: for basic cce use, next-generation micro-digital broadband beamformer appears providing reliable information with good-to-excellent diagnostic capability, accurate two-dimensional measurements, and adapted therapeutic suggestions. these preliminary data require further confirmation. introduction: acute kidney injury (aki) in very old patients (over years) admitted in intensive care unit (icu) is a frequent issue and is known to be associated with a severe prognosis. we aimed at describing the clinical characteristics and prognosis of such a population. the objective of the study was dual: first to evaluate the short and long term mortality of these patients, second to determine the factors associated with a poor outcome. patients and methods: we conducted a descriptive, retrospective and monocentric study based on the hospital records of patients over years with aki admitted in our icu between january and december . the patients were selected according to the kdigo criteria ( ) . survivals at the discharge from hospital, at day and at year were assessed. the factors associated with mortality at year were scrutinized. results: after excluding patients for an initial therapeutic limitation, the data of remaining patients were reviewed. the patients were years old (interquartile range, iqr - ) and were predominantly male gender ( %). saps ii and sofa score at admission were (iqr - ) and (iqr - ) respectively. % of the patients needed for mechanical ventilation and % of them needed for catecholamine use. septic ( %), prerenal ( %), iatrogenic ( %) and cardiogenic injury ( %) were the leading cause of aki. dialysis was performed in % of patients. the overall mortality at the discharge from icu, at day and at year was , and % respectively (fig. ) . neither were the age, the comorbidities, the etiology of aki nor the need for dialysis associated to a significant increase in mortality. a stepwise cox regression analysis revealed saps ii and blood lactate level at icu admission as independent risk factors associated with year mortality. conclusion: aki at admission in icu is associated with a high mortality at year in an elderly population. main long term prognostic factors are linked to the initial severity at icu admission. introduction: the proportion of elderly around the world doesn't stop growing and increases the consumption in health care. however, lots of studies report the impact of the age on the decision to admit a patient to the icu despite no triage recommendation exists. the primary objective was to determine prognostic factors of death for the years and over at admission to the icu and secondly to evaluate their functional prognostic at short and medium term after their exit. patients and methods: prospective and observational study conducted in our icu beds unit from august to february . patients of years and over were listed. the dying patients arriving after a pre-hospital resuscitation for whom no therapeutic plan has been initiated and those admitted for an organ donation were excluded. the primary outcome was the duration between the admission and the potential death during the follow-up. the secondary outcomes were the necessity to entry an healthcare institution or the loss of one autonomy point on the adl french scale after the hospitalization. results: patients of the admissions were included. the igs ii and sofa average scores were respectively . ± . and . ± . . the most common diagnosis were a septic shock ( patients), a cardiopulmonary arrest ( patients), a cardiogenic shock ( patients) and a pulmonary oedema or a lung infection ( patients fig. survival of very old patients with aki in icu (%) each). patients ( . %) died during the follow up- at the icu, during ward and during re-education or after their home return. from a multivariate analysis (table ) , anisocoria, cardiopulmonary arrest and acute kidney injury (aki > ) seem to be independent risk factors of death. patients were alive at the end of the follow up. recovered their previous autonomy, needed a place in a specialized institution. all the other lost a part of autonomy months after their home return with the average loss of one point on the adl autonomy french scale. conclusion: anisocoria, aki and cardiopulmonary arrest seem to be independent risk factors of death for those patients. concerning the survivors, a stay at the icu lead to an increased dependency. other studies have to be led to evaluate which of our patients could have get the best benefit of their stay to prevent from a misuse of the structure. introduction: context-among the severe complications of preeclampsia, acute kidney injury (aki) poses a dilemma if features of thrombotic microangiopathy (tma) are present. although a hellp syndrome is considerably more frequent, ruling out a flare of atypical haemolytic and uremic syndrome (hus) is then of utmost importance. objective-to improve the differential diagnosis procedure in cases of post-partum aki. patients and methods: a hundred and five cases of post-partum aki, admitted in the last years ( ) ( ) ( ) ( ) ( ) in french icu from different regions, were analysed. initial and final diagnosis, renal features, haemostasis and tma parameters were all analysed, paying a special attention to their dynamics within the first days following the delivery. results: the main circumstances of aki were severe preeclampsia (n = ), post-partum haemorrhage (pph, n = ) and primitive tma (n = , including atypical hus and thrombotic thrombocytopenic purpura). among the thirteen cases of renal cortical necrosis, were associated with preeclampsia. congruence between the initial and the final diagnosis was low ( %). thus, none of the women referred to our centers for a suspicion of non-placental tma has received a final diagnosis of non-placental tma (and instead had a pe or a pph). conversely, all women with a final diagnosis of nonplacental tma were referred for a suspicion of pe-related tma, or with a pph which polluted the diagnosis. tranexamic acid was largely used in the context of pph ( %), at a dose up to grams total. taking into account the final diagnosis, we subjectively concluded that plasma exchanges and eculizumab were abusively indicated in and cases, respectively, of typical hellp syndrome. plasma exchanges were in itiated in all cases, a mean h following the admission. dynamics of hemoglobin, haptoglobin, and liver enzymes were poorly discriminant. the dynamic pattern of ldh and of platelets, in contrast, was statistically different between primitive tma-related aki and other groups-at day , platelets increased in preeclamptic women, and in other circumstances, but not in patients with primitive tma. a classification and regression tree (cart) independently confirmed the usefulness of platelets and ldh trajectory in the diagnostic algorithm (fig. ) . conclusion: the trajectory of ldh and platelet count is useful to identify the cause of post-partum aki, and the clinician may reasonably take therapeutic decisions at day post-delivery. introduction: continuous veno-venous hemofiltration (cvvhf) is a common practice in intensive care units (icu). because it is continuous, the choice of anticoagulation is essential-regional anticoagulation fig. analysis of post-partum aki cases with citrate or systemic with unfractionned heparin or low molecular weight heparin (lmwh). filter's lifespan is a major issue regarding filtration's effectiveness and cost. in this study, we compared the filter's lifespan between lmwh and citrate anticoagulation. patients and methods: a monocentric retrospective study was led from january to october . all the cvvhf sessions during this period were included. prismaflex© monitors (hospal) were used. practioners were free to choose between citrate or lmwh defining groups. we aimed a post filter ionized calcemia between . to . mmol/l in citrate group + and a post filter anti xa activity between . to . ui/ml in lmwh. results: cvvhf sessions were included- with lmwh anticoagulation, and with citrate. patients were years old on average, primarly males ( %), with an initial average saps ii score of . icu mortality was %. patients' hemostasis was measured before each cvvhf session, without any significant difference between the groups. global filter's lifespan was h + h in citrate group versus h in lmwh, without significant difference (p = . ) (fig. ) . no serious side effect, especially hemorrhage in the lmwh group, was reported. filtration efficiency, represented by the urea reduction ratio during the first cvvhf session, was similar, % ± % in lmwh group versus % ± % in citrate group (p = . ). conclusion: both anticoagulation-systemic with lmwh or regional with citrate can be used in icu. both methods enable long and comparable filter lifespan, with similar filtration efficiency and without serious adverse events. our results need to be confirmed by a randomized propective study. introduction: arf during the post-partum period is a rare complication. the main etiologies are post-partum haemorrhage (pph) and thrombotic microangiopathy (tma). rrt may be required. the aim of this study was to identify variables associated with rrt in this population admitted in icu. patients and methods: we conducted a study using retrospectively collected data in a cohort of patient with post-partum arf according to the kdigo criteria and requiring icu in the university hospital of lille from until . two groups were compared-rrt and non rrt patients. demographic and obstetrical data as well as data during icu stay and patients' outcome were collected. etiologies of arf, kdigo stage, anuria, hemolysis parameters and biological data at icu admission were studied. comparisons were made using a chi-two or fisher exact test or a mann-whitney u test. odds ratio (or) for the statistically different criteria were studied. results: twenty-two patients requiring rrt were compared to the patients without rrt. the two main etiologies of arf were tma ( . %) and pph ( . %). vaginal delivery was significantly more frequent in the rrt group compared with caesarian delivery (p = . ). use of rtt was significantly increased after pph compared the others etiology of arf (p = . ). in the rrt group, the icu length of stay was longer (p < . ) and igs ii score was higher (p < . ). higher kdigo score was observed in rrt patients (in the rrt group-kdigo = , = %, = %, and without rrt-kdigo = . %, = %, = %, p < . ). anuria h after icu admission was more frequent in cases of rtt ( . % versus . %, p < . ). hemolysis was greater in rrt patients with lower haptoglobin (p = . ) and increased lactate deshydrogenase (ldh) (p = . ). the association with rrt requirement was stronger with the duration of anuria, with an or at h at . [ . - . ] and at h at . [ . - ] . a lower haptoglobin was associated with a higher risk of rtt (or . [ . - . ]), as well as pph (or . [ . - . ] ) and vaginal delivery (or . [ . - . ]). conclusion: hemolysis parameters and anuria seemed useful criteria to identify patients at higher risk of rrt early during their icu admission. introduction: renal replacement therapy (rrt) has three aimsrestoring homeostasis, ensuring survival and preserving the potential for renal recovery. the main indication of rrt in icu is acute renal failure, correlated with a very important rate of mortality despite the progress made in its management. patients and methods: the objective of this work is to take stock of the indications and the objectives of the rrt in icu. through a prospective study, we report a serie of cases, collected at the multipurpose resuscitation unit of the avicenna military hospital in marrakech between september and september . results: the average age of our patients is , ± , years with extremes ranging from to years and a male predominance ( %). the main reasons for admission were hemodynamic distress in . % of cases, followed by septic shock in . % of cases, neurological and respiratory distress were noted in . and . % of cases, respectively. rrt indications were severe acidosis in % of patients, followed by % hyperkalaemia, acute pulmonary edema in %, hemodynamic instability in patients with chronic renal failure in %, acute renal failure in %, and hyperuriaemia in % of cases. the technique chosen is conventional intermittent hemodialysis with a synthetic membrane. the main duration of the sessions was h min ± mn. vascular access was a right internal jugular catheter in . % of patients and left in . %, right femoral catheter in . % of patients and left in . %, arteriovenous fistula (fav) and a tunneled catheter in . and . % of patients. mortality was , %, chronicity progressed in . % of cases and total or partial recovery of normal renal function in % of cases. conclusion: we have a high rate of mortality in our icu that's why we will focus on prevention of risk of renal failure in our patients. introduction: there is limited information on the outcome of acute kidney injury (aki) in patients with traumatic intracranial hemorrhage (tich). tich patient with aki was related high mortality rate. the aim of this study is to estimate the outcome using different renal replacement therapy on the survival rate and rate of long term renal-replacement therapy in adult tich patient. patients and methods: we retrospectively identified a total of tich patients with aki who required glycerol or mannitol therapy admitted to the intensive care unit during a -year period ending dec from the national health insurance research database. demographic data, severity of tich, medication, level of care, type of head surgery were collected. all patients subjects were older than > years. we also excluded patients diagnosed with tich before the cohort entry date, hemodialysis before tich, chronic kidney disease cancer coagulation defects purpura and other hemorrhagic conditions, mortality mechanical ventilation ischemic heart disease before tracking. the primary outcome was overall survival at day . the secondary outcome was the rate of long term hd therapy. results: a total of patients were enrolled. the kaplan-meier estimates of mortality at day did not differ significantly between the continuous veno-venous hemofiltration (cvvh) and hemodialysis (hd) strategies + deaths occurred among patients receiving cvvh-strategy group and deaths occurred among patients receiving hd-strategy group (adjusted hazard ratio: . , % ci . to . ; p = . ). the rate of long term hd was higher in the hd-strategy group than in the cvvh-strategy group ( . vs. . %, p = . ) especially in injury severity score ≥ group (table ) . discussion: in our study, tich patient with aki receving cvvh may have effect on renal blood flow protection or cytokine removal which lower the rate of long term hd. conclusion: these clinical data provides readers interventions to improve outcomes in this population and future study are needed to confirm the result. this study highlights the importance different renal replecement therapy in the tich with aki population (table ) . khaleq khalid , hattabi khalid , bensardi fatima zahra , bouhouri m. a , nciri a , hamoudi d , alharrar r introduction: the combined progress of abdominal surgery and anesthesia lead to more frequent surgical indications, including for fragile patients or serious pathologiespostoperative morbidity and mortality is an element that requires evaluation and analysis in surgical resuscitation. although pathological processes and new therapeutic approaches in surgery are currently well known, data on risk factors for morbidity and mortality are less available. the aim of our work is to evaluate the post-operative morbidity and mortality rate and to identify the main predictive factors. patients and methods: a retrospective-cohort, unicentric study that included all consecutive patients hospitalized in the surgical resuscitation department after abdominal surgery regardless of the operated organ, during years. the structured sheet of data collection included more than items on all perioperative data concerning the patient, the disease, and the operating surgeons. postoperative mortality and morbidity were defined as in-hospital death and complications. a first descriptive analysis of the various parameters collected was carried out a bivariate analysis was then performed to study the factors affecting morbidity and mortality in digestive surgery the comparison was made using the student's t test for quantitative variables and the chi square for the qualitative variables. a difference is considered significant when p < . ( %). results: among patients, the in-hospital death rate was . % and the overall morbidity rate was . %, the mean age was . ± , years with extreme ages of years and years with sex ratio of . . five factors were incriminated in post: operative mortality notably:renal failure p = . , duration of stay p = . , parenteral nutrition p = . , long duration of intubation p = . , perioperative blood transfusion p = . . three factors influencing morbidity were found: duration of stay p = . , parenteral nutrition p = . , long duration of intubation p = . . conclusion: knowledge of the true frequency of both mortality and morbidity is crucial in planning health care and research and identifying risk factors. introduction: tools to quantify and assess bowl management in critically ill are still very limited and often over-looked. with the primary fig. filter's lifespan concern of optimizing patients to preserve life, the problem of bowel care has been given less priority. the aim of this study was to use ultrasonographic measurements of gastric emptying in the critically ill as a tool of measurement of the impact of different specific factors of icu stay on bowl emptying. patients and methods: this is a prospective study conducted in an intensive care unit for months. it included patients. ultrasonic imaging of antral sections was undertaken every min for the first h and every min thereafter until total emptying. correlation analyses were calculated, applying an adjusted significance level (pb < . ) to correct for multiple testing. results: all our patients were above the age of . the median of age was years old . of our patients were male and were female. the total emptying median time was ± min. significant correlation was observed between length of stay and delay in bowl emptying. mechanical ventilation had also significant relation with slower bowl progression and gastric emptying. patients in septic shock had tendencies to earlier delayed bowl emptying compare to others patients included in our study. conclusion: the study we conducted is a pilot study. further studies should be conducted and unltrasonografic gastric assessment could be standardized in protocols to assess clinical decision making and improve nutrition and bowl management in icu patients. introduction: enteral nutrition, via a feeding tube, is often used in intensive care units (icu) to supply artificial nutrition to critically ill patients. the feeding tube is also commonly used to administrate drug therapy as well. however, there is a lack of knowledge of the nurses about this way of administration. this could be a potential source of medicine-related illness. the purpose of this study was first, to evaluate the nurse's knowledge on enteral drug administration, and second, to observe nurses and to evaluate the adequacy of their practices with guidelines, and to report medication-administration errors. patients and methods: this prospective study using the observation technique was conducted in icu (one medical and one surgical). first, a knowledge and practice questionnaire regarding drug administration trough enteral feeding tube was filled by each intensivist nurse. secondly, pharmacist performed observations of nurses during preparation and administration of medications. these practices were compared with the original medical prescription and with the data available in the literature. results: questionnaires were returned. nurses evaluated their knowledge as medium and as inadequate. there was a lack of knowledge on the type of drugs which can be used by feeding tube ( wrong responses). nurses and different drugs were observed during the drug administration phase. no administration totally complied with our institutional protocol, particularly the crush of tablets. when a tablet was crushed, in % an alternative formulation (in syrup for example) existed. the correct administration of drugs in feeding tubes is important and represents a challenge in icu. firstly, crushed tablets is the most frequent cause of obstruction of feeding tubes which have to be changed + secondly, crushed tablets destroys the controlled release of enteric coated dosage forms, resulting in a higher or a lower initial blood level. we have to train nurses for drug administration by feeding tube. on their daily ward, the pharmacist should improve the choice of medication's forms. introduction: acute variceal hemorrhage (avh) is a severe complication of portal hypertension. in addition, the variceal bleeding is still the most common lethal complication of cirrhosis. the most effective modality of treating is based on resuscitation combined with the endoscopic variceal band ligation. the purpose of this preliminary study was to find the factors associated with poor prognosis of avh in cirrhotic patients. patients and methods: this is a retrospective study, spread over months between january and december . are included all consecutive patients with liver cirrhosis hospitalized for variceal bleeding. we exploited the medical records to identify the clinical, biological and endoscopic parameters. results: a total of patients hospitalized for avh occurred during the study period. the mean age at admission was years, and are female. cirrhosis was post viral in % of cases. patients were classified as child-pugh c in % of cases. the median presenting model for end stage liver disease (meld) and clif sofa were respectively and . . twelve ( ) patients received beta-blockers and have required at least one endoscopic variceal band ligation at the time of the bleeding episode. in the acute phase, pharmacological treatment based on vasopressor (sandostatin)) was instituted in all cases and combining with antibiotic prophylaxis (c g or fluoroquinolone) in cases. in cases the endoscopy was made within h, active bleeding at endoscopy was observed in patients. esophageal avarices (ov) were grade i ( patients) grade ii ( patients) and grade iii ( patients). the eradication of varices was obtained in patients ( . % percentage of the cases). the variceal bleeding recurred in of patients ( %of cases) and patients died which within the first days. spontaneous bacterial peritonitis (p . ), hepatic encephalopathy (p . ) and the hemodynamic instability with schok (p . ) are correlated with early mortality at days. hepatic encephalopathy (p . ) and bacteremia (p . ) are corrolated with week motality. non selective betablocker (p . ) and primary use of band ligation when indicated (p . ) are protective factors and parameters of good outcome. conclusion: despite developing of endoscopic tools and respect of actual therapeutic guidelines in avh, the outcome is still poor. the prognosis appears to be dependent on the clinical condition at admission and primary prevention. introduction: the french intestinal stroke center based on a multimodal and multidisciplinary management has been developed to improve survival and intestinal viability. open surgical revascularization was decided for patients unsuitable for radiological revascularization and or suspected of intestinal necrosis. we aimed to study the prognosis of patients suffering from aoami in icu and who have benefited from open revascularization. single-center, observational and prospective study was carried out in a surgical icu of a tertiary center. patients with aoami managed in our intestinal stroke center from to and who underwent open revascularization were included. results: data of patients were collected. patients' characteristics are described in table . all patients had abdominal computed tomography angiography at the diagnosis, and patients ( %) presented signs of intestinal injury. thrombosis was the main mechanism of superior mesenteric artery (sma) occlusion ( patients, %). all patients received antiplatelet therapy, curative unfractionated heparin therapy and digestive decontamination. open revascularization was performed by sma endarterectomy ( patients, %), sma surgical bypass ( patients, %), retrograde open mesenteric stenting ( patients, %) and coeliac artery bypass ( patients, %). three patients ( %) underwent a radiologic endovascular revascularization attempt before open repair. small bowel resection ( cm ) was achieved in patients ( %). four patients ( %) had peritonitis. six patients ( %) had one or more relaparotomy ]), usually for hemodynamic instability ( %). only one patient died in icu ( %). icu lenght of stay was days ] and duration of mechanical ventilation was days [iqr - ]. overall, haemodynamic failure was present in patients ( %). median duration of vasoactive support was days [iqr - ]). severe acute respiratory distress syndrome was observed in patients ( %) and acute kidney injury in patients ( %, including patients who received renal-replacement therapy, %). enteral feeding was initiated in patients ( %) with a delay of . days [ . parenteral nutrition was administered in patients ( %), including patients ( %) without enteral feeding. five patients ( %) were discharged with small bowel syndrome. conclusion: icu patients who underwent open revascularization to treat aoami as part of a multimodal and multidisciplinary management in a dedicated intestinal stroke center have low mortality and intestinal resection rates. larger studies are needed to confirm these results. introduction: precise consequences of late transit in icu remain elusive. we have previously shown that defining late transit by the absence of stool within days after admission was not relevant because it did not identify a group of patients with specific outcome [ ] . to further improve this definition, we investigated the differences in outcome among patients according to their bowel movements frequency. patients and methods: preliminary results of a prospective, two centers, observational study. all patients admitted to icu, with a length of stay (los) of at least h were eligible and included with the following exceptions-abdominal surgery, bowel infection or any baseline condition known to alter transit time. patients were compared according to stool frequency-less than %, between and %, between and % or more than % of icu days. we also tested the former constipation definition of more than days after admission without stool passage. we registered demographic data, time spent under mechanical ventilation (mv), icu los, ventilation associated pneumoniae (vap) and vital status at discharge. results: over months, patients were screened and ( . %) were included, age . ± . years, mean saps ii ± , ( . %) mechanically ventilated. the most frequent exclusion criteria were los < h (n = ). % of the patients had stool less than % of icu days. patients with fewer bowel movements were more likely to be mechanically ventilated, without association with time spent under mv. there was a link between the time to first stool after admission and the stool frequency during icu (p < . vap n(%) ( . ) ( . ) ( . ) ( . ) death n(%) ( . ) ( . ) ( . ) ( . ) discussion: this study is limited by the number of patients leading to an imbalance between subgroups therefore limiting the comparison. conclusion: these preliminary results do not plead for an improvement of the late transit definition based on the frequency of stool. further data is warranted to better define this condition, and the management to provide. introduction: antibiotic therapy during acute exacerbation of copd (aecopd) still controversial and not well supported by clinical evidence. in fact half of these episodes are caused by viruses even during severe episodes with need to ventilator support. procalcitonin is effective to guide antibiotic therapy during acute exacerbation of copd without compromising patients' outcome, its efficacy in the intensive care setting still not well evaluated. we have conducted in a bed icu a before after study. during the first period (january -december ) patients with aecopd were included retrospectively and treated with antibiotics according to anthonisen criteria (control group). in the second period (january -may ) antibiotics were prescribed only if the procalcitonin level was greater than . ng ml (procalcitonin group). results: ninety-two patients were included, in the procalcitonin group and in the control group. antibiotics were administered at icu admission in patients ( %) in the procalcitonin group and in ( %) patients in the control group, p = . . only % of sputum cultures were positive at icu admission. time to recovery was similar between the two groups [ iqr ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , iqr ( - ), p = . ]. other patients' outcomes did not differ between the control group and the procalcitonin group with respectively: the mortality ( . vs. %, p = . ), the incidence of pavm ( vs. %, p = . ) and niv failure ( vs. %, p = . ). readmission to the hospital at day was significantly higher in the control group ( vs. %, p = . ). conclusion: using procalcitonin to guide antibiotic therapy during severe aecopd can reduce the use of antibiotics without compromising patients' outcomes. our study aimed to assess whether arc impacts negatively on cefazolin pharmacokinetic pharmacodynamics (pk/pd) target attainment and clinical outcome in critically ill patients. patients and methods: over an -month period, all critically ill patients treated by cefazolin for a documented respiratory infection without renal impairment were eligible. patients who underwent an empiric antimicrobial treatment > h before introduction of cefazolin were not included. during the first three days of antimicrobial therapy, every patient underwent -hour creatinine clearance (crcl) measurements and therapeutic drug monitoring at steady state. the main outcome investigated in this study was the rate of pk pd target non-attainment defined by an unbound concentration < µg ml (mic value for inoculum > ufc ml). the secondary outcome was the rate of therapeutic failure, defined as an impaired clinical response with a need for escalating antibiotics during treatment and or within days after end-of-treatment. results: over the study period, patients were included ( samples analyzed for therapeutic drug monitoring). in pharmacological analysis, the rate of pk pd target non-attainment was %, with a strong association with crcl (p = . ) ( table ). in clinical analysis, the rate of therapeutic failure was % ( ), with a strong association with inoculum effect (p = . ). there was a strong association between therapeutic failure, crcl > ml min and pk pd target non-attainment adjusted on the inoculum effect (p = . ). introduction: vancomycin has long been used as the standard therapy of infections due to methicillin-resistant staphylococcus aureus (mrsa). the side effects of this drug as well as the increasing resistance and its pharmacodynamics effects have fostered the development of newly active drugs. nevertheless it is still widely prescribed and it stands as the mostly used comparator in randomized study. an assessment of our medical practice regarding its use may enhance compliance to guidelines so as to promote a better use of vancomycin. patients and methods: in our bed hospital, the incidence rate of mrsa fell from . to . per patient days from to whereas the current proportion of mrsa isolates is about %. vancomycin is the most prescribed empirical or targeted antibiotic therapy covering mrsa in our medical intensive care unit of beds even if a shift towards the use of linezolid in nosocomial pneumoniae has been noticed during the last years. key points regarding the proper use of vancomycin have been implemented in our antibiotic stewardship program. moreover courses concerning this topic are provided to our junior doctors. a retrospective review of the quality of antibiotic use has been carried out in courses of vancomycin therapy and the following criteria have been assessed-indication, dosing schedules, serum levels of vancomycin, duration of antibiotic therapy and the overall degree of conformity of the prescription. results: regarding indication, conformity was observed in cases ( %). the dosing schedule was appropriate in cases ( %) only. of the remaining cases ( %), all of them were not adjusted to the serum concentration and in cases ( %) the general dosing recommendation was not respected. the loading dose was inappropriate in cases ( %) and the proper follow up of serum levels of vancomycin has not been carried out in cases ( %). the duration of antibiotic therapy was in compliance with the protocol in cases ( %) and a slight longer duration was observed in cases ( %). finally the overall degree of conformity of the prescription was observed in cases ( %) only. table . in the sfar srlf guideline, the limitation of the echinocandins use to the benefit of ampho deoxycholate explains most of the poor agreement or consensus rate between investigators. the idsa escmid guideline are more helpful to guide indications of empirical treatment which mainly explains their higher rate of both applicability and agreement rate. the rates of agreement do not reflect whether the choice between different class iii antifungal therapies is the best or not. conclusion: the idsa guideline seems to take a broader spectrum of clinical situations into account, particularly in guiding more precisely indications of empirical treatments. escmid or idsa reach more often consensus at the first reading. ( ), and was discovered during a chest x-ray examination for % ( ). diaphragmatic paralysis was confirmed for all cases with chest ultrasound. % of patients ( ) were receiving mechanical ventilation at the moment of the diagnosis. the paralysed hemidiaphragm was left sided in % ( ), and right sided in % ( ). there was no bilateral diaphragmatic paralysis. hemi-diaphragmatic plication was performed in % of the patients ( ), and median time from cardiac surgery to surgical plication was days (range - days). indications for plication were failure to wean from ventilator ( %, ), and respiratory distress ( %, ). plicatured patients were remarkably younger (median age at cardiac surgery- days, range - days) than non-plicatured patients ( . months, range days- years). the median ventilation time after plication was days (range - days). all patients were asymptomatic after diaphragmatic plication. two patients died ( %). cause of death was independant from surgical plication (cardiogenic shock, septic shock). conclusion: diaphragmatic paralysis is a rare but serious complication of cardiac surgery in children. it commonly occurs after open-heart surgery, and specifically after arterial switch operation. plicatured patients were younger than non-plicatured patients and needed more frequently a ventilatory support. a closer monitoring may be required for young patients and mechanically ventilated patients. indeed, both are more likely to be treated by a diaphragmatic plication, reducing mechanical ventilation and intensive care duration. a prospective study. consecutive children aged between days and -year-old admitted to the picu, intubated and mechanically ventilated were eligible and they reached inclusion if they had at least one chest tube. ppl was directly measured by a pressure transducer connected through a needle inserted into the existing chest tube. pes was measured by both a specific probe (gaeltec probe) and by the feeding tube after mobilization (pes-ft). results: patients (median age months (interquartile + - )) were included and exploitable signals were finally available in patients, who were included in the analysis. most of patients (n = ) were admitted after cardiac surgery and had a spontaneous breathing activity. median pes measured by gaeltec probe and by feeding tube was . (interquartile + . - . ) and . ( . - . ) cm h o, respectively. median ppl measured into the chest tube was . ( . - . ) cm h o. bland-altman plots are represented in the figure. conclusion: both ppl measured into the chest tube, pes measured by the gaeltec probe or by the feeding tube are reproducible methods. . respiratory syncytial virus was identified in infants ( %). an initial caffeine citrate loading dose of mg kg was usually administered, followed by a mg kg day maintenance dose, for a median treatment duration of days [ ] [ ] [ ] [ ] [ ] [ ] . therapeutic management (invasive and non-invasive ventilation, nutrition support) and clinical outcomes (death, length of stay) were similar between groups. there was no difference in potential caffeine adverse effects between groups or within the caffeine exposed group pre and post-caffeine administration. conclusion: caffeine treatment of bronchiolitis related apnea seems to be a standard practice in our picu. our study failed to show any influence of caffeine on clinical outcomes in this indication when compared with a small number of patients. further studies are needed to assess the efficacy and safety of caffeine treatment in this indication as well as the appropriate treatment regimen as pharmacokinetic data suggest that higher dose could be of great interest in this non-prematurely born population. introduction: during the last decade, many authors have raised awareness concerning the increasing rate of venous thromboembolism (vte) in critically ill children [ ] . the presence of central venous catheter (cvc) is one of the most important risk factor for venous thrombosis in children [ ] . the purpose of this study was to analyze incidence and risk factors for catheter-related thrombosis in children admitted in our pediatric intensive care unit (picu). patients and methods: all children aged less than years, admitted in the picu from january to june , and receiving at least one tunneled cvc, were included in our retrospective study. those with venous thrombosis unrelated to cvc placement were excluded. catheter-associated venous thrombosis (cavt) was confirmed using doppler ultrasonography. introduction: weaning from the ventilation is a crucial moment in the icu stay. because of the risks of mechanical ventilation (mv), such as ventilator-associated pneumoniae, it is recommended to begin the weaning process as soon as weaning criteria occurs [ ] . however, extubation is also a hazardous period, with to % of subsequent respiratory failure requiring reintubation, harboring a dismal prognosis [ ] . international guidelines display the criteria triggering the extubation. nevertheless, the physician in charge eventually takes the decision to extubate. in this regard, there could be variations from an individual to another. the main goal of our study was to identify the perceived impediments to mv weaning among physicians, from intubation to extubation. patients and methods: prospective single center study in a bed university icu. all patients admitted between february and may and undergoing mv were included. we daily registered the existence of the criteria recommending a spontaneous breathing trial (sbt), the occurrence of a sbt, the items recommending postponing extubation, and the occurrence of an extubation. the estimated reasons for all the aforementioned decisions were asked to the physician in charge. results: patients were included, gathering days of mv and sbt. the average duration of mv was . ± . days. there was one extubation failure requiring reintubation. there were sbt failures. in cases, sbt was a success but did not lead to extubation because of hypotonia, weak cough, subsequent respiratory failure, hemorrhagic bronchial secretions, hemodynamic instability, absence of weaning criteria, drowsiness (all the aforementioned n = ), post sbt hypercapnia (n = ). out of the sbt ( %) were done while one or several weaning criteria were absent. impediments to weaning trials were different according to the time lag since icu admission, with fluid overload, muscular weakness and persistent need for assist control ventilation settings being the most frequent reasons advocated after days (figure). no objective assessment of muscular or cough strength was performed at any time, neither was monitored the rr vt, vital capacity or inspiratory pressure. . % of patients had otolaryngologist follow-up. the overall mortality of the studied population was . % including mortality related to tracheostomy in patients. the tracheostomy for extended mechanical ventilation was significantly associated with an increase of mechanical ventilation duration before tracheostomy (p < . ), duration of mechanical ventilation (p < . ), length of stay in intensive care unit (p < . ) and mortality rate (p = . ). introduction: acute renal failure complicating surgery has a particularly harmful prognosis, with a mortality of % to %. this high mortality rate is attributed to patient-related factors, the severity of the disease and the type of surgery, but not to the acute renal failure itself. the aim of our study is to elucidate the prognostic factors of acute renal failure in the postoperative sepsis in a series of patients. it is a retrospective analytical descriptive study spread over a period of years (from january to december ), observations of postoperative peritonitis were collected in the service of resuscitation of surgical emergencies of chu ibn rochdof casablanca. the statistical analysis was carried out using the spss software. the results are expressed with or and % confidence intervals (ci at %). the results were considered significant when p is < . . the mean age of the patients was ± years with a sex ratio of . ( m ) . renal failure was the most frequent failure after hemodynamic failure, patients were oliguric, anuriques and patients had a preserved diuresis, patients were divided according to the rifle (r %, i %, f %) and akin (i %, ii %, iii %). the predictive factors of acute renal failure ari were studied in univariate and multivariate analysis, factors were retained including catecholamines-or . + ci at % between . and . + p = . + the surgical site-or . + ci at % between . and . + p = . . conclusion: acute renal failure is an independent factor of mortality in the post-operative sepsis, but remains that its presence is a pejorative prognostic factor. this was a retrospective study performed in a large university hospital. all patients receiving the molecule were included in the analysis. indication for sodium lactate, dose, and modality of administration were collected. we also collected clinical and biological variables before sodium lactate infusion, after h (h ), and after h (h ). an analysis of the evolution of these variables at h and h was performed. results: between january and may , patients, aged years, % males, sofa score [ - ], received an infusion of molar sodium lactate ( ml ). main indications for sodium lactate were hyperchloremic metabolic acidosis ( %), vascular filling ( %), mixed acidosis ( %), and intracranial hypertension ( %). % of the patients presented with a chloride sodium ratio > = . at basal time. sodium lactate was associated with a significant increase of mean arterial pressure at h (p = . ) and h (p = . ), a decrease of catecholamine dose (p = . ) and heart rate (p = . ) at h , and an increase of diuresis in the h period following initiation of the treatment (p = . ). we observed an increase of ph, bicarbonate, base excess, and sodium, at h and h (all p < . ). plasma lactate concentration was increased at h (p < . ), but was not different from basal value at h (p = . ). there were no significant variation of plasma chloride. chloride sodium ratio was significantly reduced. plasma sodium > = mmol l and ph > = . at h were observed in % of the patients. this retrospective study reports the largest number of critically ill patients having received sodium lactate. hemodynamic effects observed in this study are concordant with the data of the literature. the metabolic effects observed in this study, with rapid increase of ph, bicarbonate, and base excess, strongly suggest the potential interest of sodium lactate among critically ill patients presenting with acidosis and increased chloride sodium ratio. introduction: acute kidney injury (aki) is a frequent and severe condition in intensive care unit patients that may require renal replacement therapy, most frequently continuous renal replacement therapy (crrt). although hypoglycemia is a well-known complication of crrt using glucose free solutions, euglycemic ketoacidosis (eka) has never been described in this setting. patients and methods: all anuric patients with glucose free crrt solution induced eka (february -may ) were prospectively included and evaluated. ketoacidosis was deemed possible when nonlactic metabolic acidosis did not improve in patients on crrt. because all patients were anuric, we measured ketonemia and used urinary test strip in the effluent fluid. eka diagnosis was retained when arterial serum bicarbonate was < meg/l despite crrt, in the absence of lactic acidosis and in the presence of ketones in the serum or crrt effluent fluid. results: eighteen patients ( % of our patients under crrt in this period) developed eka during crrt using glucose free solution (phoxilium ® ). time between cvvhdf initiation and ketonemia detection was ( - ) days. patient characteristics are presented in the table . half of them had for a medical history of diabetes ( insulindependent). only patients were receiving insulin and most of them had low glucose or food intake. increasing glucose intake and insulin infusion resolved ketonemia in all cases. discussion: we describe for the first time the occurrence of euglycemic ketoacidosis in critically ill patients under crrt using glucose-free replacement solution. common features of the patients were multiple organ failure with anuria, normal glycemia without insulin infusion and low glucose infusion or food intake. critical illness-induced insulin resistance and starvation could altogether contribute to ketoacidosis even if acidosis is unusual in starvation ketosis. by removing substantial amounts of glucose from the blood, crrt with glucose free solution could worsen this condition, mask hyperglycemia and induce euglycemic ketoacidosis. in critically ill patients on crrt using glucose free solution, euglycemic ketoacidosis is common and should be detected, especially in patients with low glucose intake, no insulin infusion and unexplained metabolic acidosis. importantly, the diagnosis can be missed in anuric patients with normal blood glucose and in the absence of known diabetes. since, cvvhdf-induced ketoacidosis may contribute to persistent acidemia and its adverse effects, serum or crrt effluent fluid ketone level should be measured in this setting. . - ] years. main reasons for admission were hypercalcemia (n = ( . %)), followed by acute encephalopathy (n = ( . %)). median saps ii and sofa scores were [ . - . ] and [ ] [ ] [ ] [ ] [ ] respectively. main causes of hcm were hematological malignancies (n = ( %)), solid tumors (n = ( %)), iatrogenic events (n = ( %)) and endocrinopathies (n = ( %)). median calcium levels at admission, at day and at icu discharge were . [ . - . ], . [ . - . ] and . [ . - . ] mmol l respectively. more than half of the patients (n = ( %)) recovered from hcm days after icu admission. acute kidney injury occurred in ( %) patients and ( . %) patients required dialysis. neurological complications concerned ( . %) patients, mainly delirium (n = , . %). digestive events occurred in ( . %) patients. cardiovascular events concerned ( %) patients and consisted in de novo hypertension in ( %) patients, and ekg disturbances in ( %) patients. during icu stay, ( . %) patients required mechanical ventilation and ( . %) patients required vasopressors. volume resuscitation with crystalloids was the first treatment in ( . %) patients, ( . %) received bisphosphonates and ( . %) received corticosteroids. respective icu and hospital mortality were . and . %. there was no correlation between the degree of hcm and icu mortality (p = . ). icu and hospital mortality were associated with the underlying disease (hematological malignancies (p = . )). conclusion: hcm is associated with high mortality rates. the increased mortality is a consequence of the main mechanism, mainly underlying malignancy rather than hcm per se. the course of hcm may be complicated by organ failures that are most of the time reversible with early icu management. introduction: sepsis is one of the leading cause of death among patients with chronic kidney disease (ckd). the mechanisms of this higher mortality remain poorly understood. sepsis and chronic kidney disease are both conditions associated with a higher plasmatic concentration of bile acids. the farnesoid x receptor (fxr) is a key regulator of the bile acid metabolism and has recently been involved in the regulation of the inflammasome during sepsis. we explored the role of fxr in the prognostic of sepsis in an animal model of ckd. patients and methods: sepsis was provoked by the injection of . mg kg of lps weeks after the creation of ckd. the ckd was created by unilateral nephrectomy associated with contralateral thermocauterisation. the mice (c bl j) were randomly assigned to one of the following groups-sham placebo, ckd placebo, sham lps or ckd lps. a fifth group of ckd lps mice received a treatment with sevelamer (a bile acid sequestrant) during weeks. survival of the animals, serum biochemistry and molecular biology in the kidney were performed after sacrifice. results: whereas the sham lps animals survived, all ckd lps animals died during the h following the injection of lps. the plasmatic urea, il beta and tnfa concentrations increased with the creation of ckd (ckd placebo versus sham placebo animals) and with the creation of sepsis (ckd lps versus sham lps groups). whereas the expression of fxr rna did not changed with the injection of lps in the sham animals (sham lps versus sham placebo), the fxr rna decreased with the creation of sepsis in the ckd animals (ckd lps versus ckd placebo groups). the ckd animals treated with sevelamer weeks before the administration of lps (ckd sev lps group) had a lower plasmatic concentration of il b, tnfa and increased the rna expression of fxr in the kidney compared to the ckd lps group. also, the treatment with sevelamer improved the survival of the ckd lps animals. conclusion: our study demonstrates a relation between fxr and the prognostic of sepsis in ckd animals. the exact link and the potential therapeutic interest of targeting fxr and bile acids metabolism in ckd patients remain to be studied. introduction: dysnatraemia, dyskalaemia and hypomagnesemia are frequent metabolic disorders in intensive care, and their causes represent a major concern for the intensivist, especially in urgent conditions. in the diagnostic approach, we often use the urine analysis. although measurement of -hour urine electrolyte excretion ( -hu) is considered the most reliable method, the great burden and difficulty in collecting complete -hour urine has prompted the search for more practical methods, such as spot urine analysis. the aim of the present study was to compare electrolyte excretion in urine samples collected over different time periods, in comparison with a -hour urine sample collection considered as the gold standard method. patients and methods: this prospective and descriptive study included patients admitted in a tunisian medical icu, between september and december . baseline characteristics, medications and laboratory data including electrolytes and renal function parameters were obtained from all patients. multiple urine specimens for analyzing na + k + mg + urea + ca + phosphate + creatinine + proteins and uric acid were obtained from -hour, -hour and -hour urine samples during day and night time, and results were compared with those obtained from the gold standard method ( -hour urine collection). correlation analysis was performed using the spearman test. results: significant correlation was found for all biochemistry parameters between -hour urine results and those obtained from -hour and -hour samples regardless of day or night sampling. a comparative analysis for sodium and potassium is shown in fig. . conclusion: determination of electrolyte excretion from urine samples taken over different time periods, and h, provides a reliable estimation of -hour urine electrolyte excretion. it appears practical for early understanding of the mechanism of electrolyte imbalance. however, further studies are warranted to confirm the usefulness of this approach. use of the procalcitonin assay in an adult emergencies department: retrospective experience of a general hospital of the suburb of paris ( . - . ). other markers of infectious were poorly recorded (fibrinemia in ( . % + . g l [ . - . ] + immature forms on blood count- . %). only ( . %) had blood cultures in the ed ( patient [ ] [ ] ) and ( . %) other(s) microbiological sample(s), mainly urinary ( patients [ . % + among them % considered as positive]). % of blood cultures were positives, mainly for gram negatives ( %). final diagnosis in the ed was considered as infectious disease (id) in only patients ( . %, including sepsis and septic shocks). ( . %) was considered as non-infected (nid) and final diagnosis remains unprecise in ( . %). pct values was of . ( - . ) in the id vs. ( - . ) in the nid (p < . ), wbc was of . in the id vs. . in the nid (p < . ) and crp was of ( . - . ) in the id vs. ( - ) in the nid (p < . ). no correlation was observed between the pct value and admission to dechocage room admission. . identification of the involved drug was obtained in % of the cases, based on qualitative screening. management was mainly supportive and included sedation ( %), naloxone ( %) and flumazenil ( %). tracheal intubation was required in patients ( . %). one cardiac arrest but no death occurred in the ed. forty-three patients ( %) were transferred to the intensive care unit. conclusion: our dataset provides an interesting insight into the drugs involved in and clinical pattern of toxicity outcome of acute recreational drug toxicity presentations at the ed, despite possible under-declaration and coding. classical recreational drugs were more common ( %) followed by prescription drugs ( %) and nps ( %). and drug ( %) consumers + hiv-infected ( %) and depressive ( %) patients) were admitted to the icu. the main declared compounds were methylenedioxypyrovalerone (mdpv + n = ), -methylethcathinone ( -mec + n = ), -methyl methcathinone ( -mmc + n = ) and -methyl methcathinone ( -mmc + n = ), more frequently used in drug mixtures sold as bath salts or in poly-intoxication with conventional illegal drugs (mainly cocaine and gamma-hydroxybutyrate). nps was used in a recreational ( %), chemsex ( %) or solitary practice ( %). binge ( %) and intravenous ( %) self-administration was remarkable. patients presented acute encephalopathy with psychomotor agitation ( %), confusion ( % + glasgow coma score- [ ]), hallucinations ( %), anxiety ( %), seizures ( %), myoclonus ( %) and stereotypes ( %). ecg typically showed sinus tachycardia ( %), qrs qt abnormalities ( %) and atrio-ventricular block ( %). acute cardiac ischemia ( %) and dysfunction ( %), disseminated intravascular coagulation ( %) and multiorgan failure ( results: during the first and the second study periods and patients were respectively admitted in the icu. total micro-organisms density was and . for patients for the first and the second period, respectively (p < . ). acinetobacter spp and pseudomonas aeroginosa were the predominant isolated microorganisms with a respective density of . and . isolates for patients. figure summarizes the patterns of bacterial ecology and resistance in our icu before and after transfer to new buildings, showing a significant decrease in pseudomonas aeroginosa resistance for ticarcillin and ceftazidim, whereas acinetobacter resistant to carbapenems and enterobacteriacae esbl significantly increased. our study suggests that transfer of icu to the new buildings was associated with a decrease of pseudomonas aeroginosa resistance, whereas acinetobacter spp resistance and esbl enterobacteriacae incidence increased. introduction: infections caused by antimicrobial-resistant bacteria (amrb) are one of the main issues in the spectrum of critically ill patients as they are associated with higher mortality, morbidity, and length of stay. thus, an appropriate initial antimicrobial therapy is decisive for better patient outcomes. the aim of the study is to determine the adequacy of first-line antibiotic therapy guided by weekly amrb screenings. patients and methods: a months prospective study was conducted in -bed micu. were included all patients with more than h of icu stay. an amrb screening was conducted upon admission and on weekly basis for all the patients. the choice of antibiotherapy if indicated, was guided by the most recent colonization results. if the patient has received at least one active in vitro antibiotic against the isolated bacteria, the empiric antibiotherapy was considered appropriate. results: patients were included in the study. mean age and saps ii were respectively ± years and ± . the median length of stay was days. ( %) patients were colonized by amrb upon admission. the most frequent isolated microorganisms were-escherichia coli ( %) and klebsiella pneumonia ( %). were assessed hospital-acquired infections (hai)- ( %) in amrb colonized patients and ( %) in uncolonized ones. the antibiotherapy was considered appropriate in infections ( %). out of the colonized patients, ( %) developed hai. ( %) patients had a concordant colonization body site to the infection. of the nosocomial infections, ventilator-associated pneumonias and central venous catheter infections were the most frequent, both at % (n = and n = ) + followed by urinary tract infections % (n = ) and infective endocarditis % (n = ). ( ). overall, the isolates were-extended spectrum betalactamase productrice-enterobacteria ( %), imipenem resistant-acinetobacter baumanii ( %), and multi resistant-pseudomonas aeroguinosa ( %). ni were documented including caused by mdr bacteria and distributed as follows-ventilator acquired pneumonia-vap (n = ), bacteraemia (n = ), vap with bacteraemia (n = ), catheter related infection-cri (n = ), cri with vap (n = ) and catheter-related bacteraemia-crb (n = ). the performance of mdr bacteria-screening in predicting ni was poor with % of sensitivity, % of specificity, . % of negative predictive value (npv), and % of positive predictive value (ppv). nevertheless, the performance of the nasal swab in the prediction of vap was better with % of sensitivity and . % of npv. conclusion: mdr bacteria-screening is useful as it allows to identifying the mdr bacteria-carriers and helps for a rational use of antibiotics in severe ni. however, its diagnostic contribution in the occurrence of ni is poor except the interest of the nasal swab in the prediction of vap owing to its good npv. we aimed at determining the respective weight of these phenomenon and the physiological determinants of the respiratory variations of the ivc diameter. patients and methods: in mechanically ventilated patients (tidal volume- . ± . ml kg of predicted body weight) haemodynamic, respiratory and the intra-abdominal pressure (iap) signals were continuously computerised. cvp, iap and the ivc diameter (transthoracic echocardiography) were recorded during -second end-inspiratory and end-expiratory occlusions separated by s, before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) > % were defined as "responders". the respiratory variations of the ivc diameter, cvp and iap were calculated as the (end-inspiratory-end-expiratory values) mean value. the compliance of the ivc was estimated by the ratio (end-expiratory-end-inspiratory ivc diameter) (end-expiratoryend-inspiratory cvp). results: fluid administration increased cardiac index by more than % ( . ± . to . ± . l min m , p = . ) in patients. the respiratory variations of the ivc diameter predicted fluid responsiveness (area under the roc curve- . ( % ci . - . ), p < . ). before fluid administration, the ratio of changes in ivc diameter over changes in cvp was not different between responders and non-responders ( . ± . vs. . ± . mm mmhg, p = . ). before fluid administration, the respiratory variations of the cvp tended to be higher in responders than in non-responders ( ± vs. ± %, p = . ). the respiratory variations of the ivc diameter were associated with the respiratory variations of cvp (r = . , p = . ) but not with the respiratory variations of iap (r = - . , p = . ). the respiratory variations of the ivc diameter were not explained by a higher ivc compliance but rather by higher respiratory variations of the cvp in responders than in non-responders. interestingly, it seems that iap, the ivc extramural pressure, was not involved in the respiratory variations of the ivc diameter. inclusions are ongoing. during the hospitalization in icu, there was no significant difference between the two groups regarding the proportion of patients with aki through icu discharge. in the intervention group, % of the patients had a glomerular filtration rate lower than ml min . m compared to . % in the control group (p = . ) at day- . we found no significant difference between the two groups neither on hematopoietic effects of epo or serious adverse events. in patients resuscitated from an ohca of presumed cardiac cause, early administration of erythropoietin compared to standard therapy did not confer any renal protective effect. salvetti marie , and the ratio of end-diastolic areas of both the right and left ventricle in the long axis view of the heart (rveda lveda) were measured. a lvef < % defined lv systolic dysfunction, a ci < l min m defined low cardiac output, and a rveda lveda ratio > . (± associated with a paradoxical septal motion in the short axis of the heart) defined rv dysfunction (± acute cor pulmonale). the preload-dependence was evaluated using deltasvc or deltavmaxao. front-line hemodynamic and metabolic parameters were recorded at the time of tee assessment. results: lvef and ci could be simultaneously measured in of patients ( %). patients ( %) had a low ci related to lv systolic dysfunction (lactate- . ± . mmol l), patients ( %) had a low ci and a preserved lvef related to a rv dysfunction or to a sustained preload-dependence (lactate- . ± . mmol l), patients ( %) had preserved ci and lvef (lactate- . ± . mmol l) including only patients ( %) with a hyperkinetic profile (high ci and lvef > %), and patients ( %) had preserved ci but altered lvef (lactate- . ± . mmol l) due to a marked tachycardia. none of the front-line hemodynamic parameters was discriminatory to identify the circulatory profile identified by tee assessment (table) . introduction: aortic end-systolic pressure (esp) is considered as a reliable index of left ventricular afterload. recently, the effective arterial elastance (ea), i.e., the ratio of esp over stroke volume (sv), has also been proposed as a reliable afterload index. our aim was to document peripheral estimates of ea (eapsap) at the bedside in critically ill patients, and to investigate the haemodynamic mechanisms responsible for ea changes after fluid administration (fa). in the validation study, carotid tonometry (complior) was prospectively performed on haemodynamically stable spontaneously breathing patients equipped with an arterial femoral (n = ) or radial (n = ) catheter. ea was defined as the ( . × csap) sv ratio, where csap was the central systolic arterial pressure directly measured from the calibrated carotid waveform. eapsap was calculated as the ( . x peripheral systolic arterial pressure) sv ratio. sv was obtained by transpulmonary thermodilution or transthoracic echocardiography. in the clinical study, we included patients with invasive haemodynamic monitoring (picco- ), in whom fa was planned. results: in the validation study, the complior allowed estimating ea in all patients (ea = . ± . mmhg ml). the (eapsap-ea) bias was smaller at the femoral than radial artery level ( . ± . vs. . ± . mmhg ml, p < . ) and was strongly related to the systolic pressure amplification between the carotid and peripheral artery (r = . , p < . ). ea was more strongly related to sv (r = − . ) than to esp (r = . ) (each p < . ). the four-quadrant plot analysis indicated that patients ( %) exhibited a concordant low ea high sv pattern or high ea low sv pattern, while only patients ( %) exhibited concordant high ea high esp pattern or low ea low esp pattern (p < . ). there was a negative relationship between changes in eapsap and changes in sv in the whole population, in fluid responders (cardiac index increases > % after fa), in pressure responders (mean arterial pressure increases > % after fa) and in non-responders, while no consistent relationship between eapsap and esp changes was documented. conclusion: ea may be reliably estimated at bedside by using the ( . x femoralsap) sv ratio. ea value and ea changes induced by fa were related to sv rather than to esp. thus, ea should be considered as an index reflecting sv rather than left ventricular afterload in critically ill patients. this study included a sham group (n = ), a cpb group (n = ), an ir group (n = ) and a cpb-ir group (n = ). rats were exposed to min of cec, min of left pulmonary ischemia and min of reperfusion. fonctional endothelial dysfunction was evaluated by measurement of the pulmonary artery reactivity. systemic inflammation was evaluated by the plasma assay of il- beta, il- and tnf-alpha. the endothelial glycocalyx was evaluated by plasma assay syndecan- and electron microscopy. the statistics were performed using an anova test, p < . . we showed that cpb associated with ir induce an endothelial vasorelaxation dysfunction mainly mediated by nitric oxyde (no introduction: during circulatory shock, the goal of increasing cardiac output is to correct tissue hypoxia, which can be manifested by an increase in oxygen consumption (vo ) associated with an increase in oxygen delivery. we hypothesized that, in patients in circulatory shock, veno-arterial co gradients (pv-aco ) could be a good predictor of an increase in vo in fluid responders. patients and methods: we included patients with circulatory shock who received a fluid challenge. circulatory shock was defined by the association of vasopressor requirements to maintain mean arterial pressure (map) and a blood lactate concentration ≥ mmol l. we measured cardiac index (ci) and arterial and central venous blood gases and arterial lactate before and after a volume expansion ( ml of plasmalyte ® ). cardiac index (ci) was measured using a pulse contour analysis method (picco + pulsion, munich, germany). ci responders were the patients in whom ci increased (Δci) by > %. in those patients, vo responders were those in whom vo increased (Δvo ) by > %. receiver operating characteristic (roc) curves were performed. the data was presented as median ( th percentile- th percentile). a p < . was considered as statistically significant. introduction: the autonomic nervous system (ans) is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of ans activity and a relation between hrv and outcome has been proposed in various types of patients. while electrocardiographic hrv assessment seems to be the gold standard, we evaluated the feasibility of an automated hrv monitoring based on standard photoplethysmographic monitoring. this project is based on a prospective physiological tracing data-warehousing program (rea stoc, clinicaltrials.gov # nct ) that aims to record more than icu patients over a -years period. introduction: diabetic ketoacidosis is an acute complication of diabetes, defined as metabolic acidosis with a high anionic gap, associating hyperglycemia > mmol l ( g l), positive ketonuria, or superior or equal ketonuria to ++, it is a medical emergency which can occur in a known diabetic patient, or not. objective-to describe the clinical therapeutic and prognostic aspects of diabetic ketoacidosis in the intensive pediatric care unit at the ehs canastel oran, algeria. patients and methods: retrospective study carried out over a period of years. from january , to january , , in the intensive pediatric care service. the data was entered and analyzed using excel . results: cases were retained on hospitalizations per year, % of cases had no history with diabetes, % occurred in known diabetics with insulin, but are not followed medically. our patients were aged from months to years, but the average age of these patients was years and months, with a slight female predominance, coma was preceeded by % of cases polydipsy polyuria syndrome and % weight loss, triggered by an infectious syndrome including % of ent cases, % of respiratory infections and % of cases with digestive infections characterized by fever, abdominal pain, vomiting. the delay between diagnosis and admission to ice was - days. at admission % of patients were scored at on the glasgow scale, with presence of the cough reflex, and % were scored at < requiring tracheal intubation and mechanical ventilation of h with signs of dehydration and ionic disorders, namely hypokalemia and hypernatremia, blood glucose at admission varies between . and g l with glycosuria at +++ and ketonesuria between ++ and ++++ in only % of the patients had metabolic acidosis, a cerebral computed tomography (ct) performed in % of cases found a slight cerebral edema. therapeutic management was the rehydration, correction of metabolic disorders and introduction of insulin into sap, with monitoring and subcutaneous relaying due to ketonuria negativity. the outcome was favorable for all patients. conclusion: diabetic ketoacidosis is a major complication of diabetes which can be avoided by a good prevention campaign and systematic screening of any child suspected of diabetes, recognition of risk situations such as infections and clinical manifestations in order not to delay the management. introduction: scorpion sting is a public health problem world wide with a global distribution of species. in algeria, scorpionic envenomation occupies a prominent place in declarations. in , cases were reported. the objective of our study is to describe the epidemiological, diagnostic, therapeutic and evolutionary characteristics of the scorpion sting in children. retrospective study of cases of scorpionic envenomation hospitalized in the pediatric resuscitation department of the ehs canastel oran conducted during the year the inclusion criteria were the presence of traces with at least one locoregional or general clinical signs. the parameters studied-age, sex, city of origin, time of bite, time of management, initial first aid, time limit for admission to pediatric intensive care, and severity criteria. results: % of these cases were boys and % girls. the mediane age . % of the punctures occurred during the day, the site of the injection was the lower limb in % of the cases and there were bites scorpion cases in the west of algeria and exactly in oran and tiaret. of the cases was the upper limb. the delay of the management was from to h for of the cases who were classified in the third classed according to the clinical signs of gravity. the type of the scorpion was not identified. we can classify all the patients that we received in our service into three classes − % in class i, with local signs such as pruritus, redness, abnormalities and local pain. eva - , calmed by the infusion of mg kg iv of paracetamol and application of xylocaine cream at the site of the sting. introduction: the residence of children in intensive care is most often due to the existence of one or more organ dysfunction which requires heavy treatment (intubation, ventilation, drainage, venous tract) and this in a hostile environment which amplifies the aggression organic. the main objective of our work is to study the consequences of hospitalization of children in pediatric resuscitation. patients and methods: this is a descriptive prospective study on the outpatient consultation file of canastel's ehs multipurpose resuscitation. we studied files and assessed memory, perception of contact and nuisance factors felt by sick children. results: out of children seen in post resuscitation. the sex ratio is . . the average age of children is years ( months- years). the average hospital stay is days. the average gos (glasgow out scale) is . ( ) ( ) ( ) ( ) . the average duration of ventilation is days. % of children had central vascular access. three children describe a total memory of the stay, some memory and none. three children have a good perception about the staff, one child dissatisfied and three others indifferent. the nuisance factors described by the children are pain ( ), cold ( ), noise ( ), hunger ( ) and light ( ) . conclusion: consequences of psychological trauma, insufficiently evaluated especially by the staff, which result in the appearance of psychological disorders (nightmares and anxiety) with sometimes even severe post-traumatic neurosis. hence the need to adapt the environment and mainly noise and respect for sleep. [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the median treatment duration time was at ( - ) minutes. femoral vein was used as vascular access ( %) and most of pe procedures ( %) were performed with citrate anticoagulation. median exchange volume was at [ - ] ml and renal replacement fluid was fresh frozen plasma (ffp) in %, % ffp and % human albumin % in % and human albumin only in % of procedures. adverse effects were observed in less than % of procedures and % were lifethreathening including cardiac arrest, heart rhythm disorders, cerebral oedema and hemolysis. other remaining complications were secondary infections %, hemorrhage %, and pulmonary oedema % in all patients. twenty patients deceaded (icu mortality %). icu and hospital lenght of stay was at ± and ± days respectively. of survived patients still underwent pe after their icu discharge + totally recovered whereas ( %) were on partial remission. conclusion: pe is a routine and feasible technique in icu. this study showed that tpp was the most commonly indication of its use and that outcome was fair. adverse effects frequently occured but most of them were not severe. further studies would benefit form larger cohort to improve indications, delay of initiation and practice of this treatment. renal replacement therapy was required in % of elderly versus % (p = . ). frequency of ttp, hus and ahus was similar beetween groups. tma was more frequently associated with ongoing cancer and drug use in elderly ( vs. %, p < . and vs. %, p < . , respectively). gastro-intestinal bleeding during icu occurred more often among elderly ( vs. % (p = . )). icu mortality rate was higher ( vs. %, p = . ). no difference was found concerning plasma-exchange therapy, steroids use, and rescue treatments for refractory-ttp. discussion: increased complication and mortality rates in the elderly group might be ascribed to more cardiovascular morbidity in this population. the association between tma and ongoing cancer suggests a routine oncological workup among elderly. introduction: neutropenia, defined by an absolute count of polymorphonuclear neutrophils less than < mm , exposes patients to infectious complications that can lead to sepsis or septic shock. the mortality risk is higher. the french guidelines published in were formulated to homogenize the clinical practices and improve survival. we performed a monocentric retrospective study including all consecutive patients admitted to the medical icu of a tertiary hospital to a neutropenia with sepsis or septic shock, between the th of december and the th of december . the study protocol was approved by the local ethics committee ( . ce ) and published on clinical trial (nct ). results: patients were admitted in icu during this period. patients ( %) presented a neutropenia with sepsis or septic shock. among these patients, % had hematologic malignancies and % had solid tumour. patients ( %) was treated empirically with antipseudomonal beta-lactam or carbapenem and aminoglycoside. ( %) skin or suspected catheter-related infections were treated with anti-mrsa (methicillin-resistant staphylococcus aureus), vancomycin or linezolid. adequate antibiotics as described in guidelines was performed to patients ( %). patients ( %) received aminoglycoside ( patients received initial dose in icu, patients complement dose) and ( %) received anti-mrsa with antipseudomonal betalactam or cabapenem. patients ( %) had microbiologically documented infections with, % of bacteria ( % of gram-posit cocci, % of gram-negative cocci, % of gram-negative bacillus), % of fungi and % of viral infection ( table ) . among of them, % ( ) of esbl, % ( ) of mrsa and % ( ) of emerging highly resistant bacteria (bhre). the icu-mortality rate was % ( ) with % of -day mortality ( ). the curves of the cumulative incidence of death risk between d and d were no different according to adequate empirical antibiotic treatment as like french guidelines (fig ) . by multivariate analysis, independent factors of adequate antibiotic treatment were septic shock (or, . + % ci . - . ) and febrile neutropenia > days (or, . + % ci . - . ) at icu admission. conclusion: according to the usual clinical practice, septic neutropenic patients was already treated empirically by bitherapy including antipseudomonal or anti-mrsa if there is a skin or suspected catheter-related infection. adjunction of aminoglycoside in of the symptomatology in case of overdose, make the diagnosis difficult, especially since the drug in question is often unspecified and the toxicological analysis is not exhaustive. introduction: carbon monoxide intoxication is a public health problem in tunisia and around the world. currently, it is unclear the impact of this type of poisoning in our country for lack of declarations. we propose in our work to study the epidemiological characteristics of fatal carbon monoxide intoxications collected in the forensic pathology department of the university hospital in sfax, tunisia, to describe the different steps used in forensic diagnosis of fatal carbon monoxide intoxication and to propose preventive measures to reduce the rate of these intoxications. patients and methods: it is a retrospective study of cases of fatal carbon monoxide intoxications collected in the forensic pathology department of the university hospital in sfax, tunisia during years ( january to december ). commemoratives were collected from medical and police records. a forensic autopsy and a toxicological analysis were carried out in all cases. results: fatal carbon monoxide intoxication is the leading cause of toxic death in sfax during the period of our study. we notice a decrease in the incidence of this type of intoxication. the average age of deaths was years and months with male predominance. the peak frequency of intoxication was in cold season. the most frequent form of intoxication was accidental. the source of carbon monoxide was mainly the defective water heater often placed in poorly ventilated areas. the classic carmine red-color of lividity was found in the majority of cases. myocardial distress, favored by hypoxia, has been reported in two subjects with a pathological coronary artery. the mean hbco level was . %. however, account must be taken of the survival time and the time elapsed between death and dosing of hbco. the incidence of fatal carbon monoxide intoxication has decreased since and the victim profile has not changed too much. the fatal carbon monoxide intoxication is still persists as a public health problem in tunisia. the reduction of its frequency requires the implementation of a well-structured prevention plan based on epidemiological data from a national registry. the identification of these data requires mandatory reporting of this type of intoxication in tunisia. introduction: olanzapine is an atypical antipsychotic drug frequently prescribed in the treatement of bipolar disorder and schizophrenia. acute poisoning with this molecule is rarely reported. through this study we aimed to evaluate the incidence and describe the different clinical features of acute olanzapine poisoning. patients and methods: retrospective analysis of all cases of olanzapine intoxication admitted in -bed teaching icu between january and decembre . inclusion criteria were patient age ≥ year, acute olanzapine intoxication, the intoxication severity was assessed by the poisoning severity score (pss) of the european association of poison centres and clinical toxicologists. the evaluation of electrocardiograms was performed in the first day of hospitalization. the durations of qrs and qtc was measured and arrhythmias and conduction disorders was identified. results: patients were included, the mean age was ± years. they were males and females. long term treatment with olanzapine was noted in patients ( %) who suffered from psychiatic desease. the supposed ingestion dose ranged from to mg. the mean consulting time was ± h after the ingestion. olanzapine was co-ingested with others drugs in patients ( %). co-ingested drugs were-benzodiazepine (n = ), levomepromazine (n = ), serotonin recapture inhibitor (n = ), amitriptilyne (n = ) and biperiden (n = ). the pss was moderate in cases ( . %), severe in cases ( %) and fatal in case. the main clinical signs were tachycardia and miosis in % of cases each of them (n = ), agitation in % of cases (n = ). ecg abnormalities has been detected such as prolonged qtc in cases with a mean duration of ± ms. in the group of monointoxication ( patients) the pss was moderate in cases ( . %), severe in cases ( %) and fatal in one case. the coma glosgow scale was < fig. kaplan-meier survival between admission and -day according to adequate empirical antibiotic therapy guidelines (log rank, p = . ) in cases. mechanical ventilation was required in % of cases (n = %) with a mean duration of ± heures. the mean duration of icu stay was of ± h. twenty three patients recovered during the hospitalisation, one patient died with severe poisoning. conclusion: as showed in this study, acute olazapine poisoning could be severe, and lead to death sometimes. introduction: voluntary drug intoxication (vdi) continues to be a major health problem in many developed and developing countries. in algeria, this has become a worrying concern. awareness-raising is launched to prevent the public from these dangers. vdi are intentional or rarely accidental and can be individual or collective and affect all age groups. the vdi represents the first reason for hospitalization in the emergency department university hospital of oran. in algeria there is no national or regional register of voluntary intoxication. knowledge of the causes of drug poisoning should therefore be extrapolated from foreign studies. to draw up an assessment of the imvs, a retrospective study was carried out over the years ( - ) . this survey consisted of collecting data on the nature of the drug, age, sex, major toxidromes, severe imvs requiring hospitalization in icu, mortality, e.t.c scores and glasgo scores. results: cases of acute poisoning were collected, with a predominance in patients aged between and , a percentage of . %. in addition, most patients were female with . %, a sex ratio of . with p < . . the main toxidromes were-opioid syndrome in % of cases and anticholinergic syndrome in % of cases. etc with a score of > % accounted for % of patients. severe vdi requiring resuscitation hospitalization were %. conclusion: acute poisoning remains high and steady in the oran region and the under- age group represents the most affected category. awareness campaigns must be launched throughout the year to better conserve and store medicines, phytosanitary products and other chemicals. improved socio-economic conditions would help to reduce voluntary intoxication. introduction: scorpionic envenomation is unevenly distributed throughout the world and is particularly frequent in some regions of the world, notably north africa. the purpose of this work is to describe the epidemiological profile of the scorpionic envenomations admitted to the resuscitation department of mahres. patients and methods: a prospective study conducted at the mahres intensive care unit over a period of months ( until ), including all patients admitted for scorpion envenomation. results: we collected cases of patients admitted to the resuscitation department of mahres from to , including cases of scorpionic envenomations, i.e. . %. the median age was years with extremes ranging from to years. the sex ratio was . scorpion stings occurred at night in % of patients, % in the first half of the night (between pm and - pm) and % in the second half of the night ( to h). venom inoculation points were in the lower limbs in % of cases, followed by upper limbs ( %). the color of the incriminated scorpion was yellow in %, black in % and unspecified in % of the cases. for admission classes, there were % class i, % class ii and % class iii. the traditional therapeutic gestures practiced by the patients or their entourage were the laying scarification ( %) and the suction ( %). all patients received anti-scorpion serum, an analgesic, serum and tetanus vaccine. the progression was favorable in all cases after an average hospital stay of ± days. conclusion: scorpionic envenomations are indeed a reality in mahres with a non-negligible frequency despite under-reporting of cases treated by traditional medicine or in other hospitals. they mostly affect young people and the associated clinical manifestations often remain benign. introduction: severe pediatric poisoning is defined by the need for intensive care monitoring due to the nature, quantity of the substance and or clinical manifestations. it is one of the frequent reasons for admission to emergency and resuscitation. the purpose of this work is to identify poisoning in children admitted to pediatric intensive care units in order to assess the frequency, identify the products involved, and the clinical and evolutionary aspects. patients and methods: this is a descriptive study over a -month period in the canastel oran multi-purpose pediatric intensive care unit from july to july . we included all children aged - years admitted for ingestion and inhalation of products toxic. results: children admitted to pediatric intensive care, mean age was years, % under years with extremes of months and years, a female predominance of % was observed with a slight predominance of accidental poisoning ( %) compared to voluntary poisoning ( %). in % the toxic is ingested orally. the most frequent toxicants were drugs with cases ( %), mostly antidepressants and antiepileptics, followed by organophosphates with cases ( %), co cases ( %), petroleum products and plants with cases ( %). the main clinical signs were neurological signs ( %) with predominance of coma and convulsions in cases ( %), respiratory distress was present in cases ( %) and digestive signs cases ( %). for therapeutic management gastric lavage, charcoal and antidotes were the most frequent treatments. the evolution was marked by a mortality of % or a death secondary to a poly-medicinal intoxication voluntary in a girl of years. mechanical ventilation in cases ( %) and an average hospital stay of days. conclusion: acute poisoning is a medical emergency that may require resuscitation. young children are most exposed with drugs are the most frequently incriminated. we propose, as a preventive measure, companions of information on the dangers of toxic products and especially of medicines by the surveillance of the child and the regulation of certain products. introduction: the place of neuron specific enolase (nse) dosing remains uncertain as an indicator of neurological prognosis after a cardiac arrest, the threshold value for predicting an unfavorable evolution being variable from one study to another. our objective was to determine a nse cut-off value predictive of poor neurological outcome after a cardiac arrest. patients and methods: we realized a monocentric prospective trial in a medical icu of a french university hospital from january st to december th . all patients over years old hospitalized for a cardiac arrest in medical icu were included. patients who died during the first h or admitted for cardiac arrest with a neurological cause were excluded. serum nse values (elecsys nse test, cobas ® analyzer) were assessed at h and h after cardiac arrest. somatosensory evoked potentials were recorded between h and h . the primary endpoint was neurological outcome at month using the cerebral performance category scale (cpcs). cpcs or was considered as favorable outcome and cpcs higher than as poor outcome. data were collected using cardiologic or neurologic consultations report, or by phone call to the patient. using a roc curve we determined the nse value at h with higher specificity and acceptable sensitivity. results: we included patients. average age was years old. noflow time and low-flow time were respectively . and min. hypothermia was performed in ( %) patients. patients ( %) died in the icu. the -day and -months survival rates were respectively and % with a favorable outcome of % at months. on the roc curve we found a cut-off value of ng ml with specificity of . ci % ( . - . ) and a sensibility of . ci %( . - . ). area under curve was . ci % ( . - . ). out of the patients with a rising nse between h and h had an unfavorable outcome. among patients with nse > ng ml, the cortical n responses were bilaterally present in of them. conclusion: in our study nse value over than ng ml at h was predictive of poor neurological outcome after cardiac arrest. nse may prove to be a useful marker in patients with present n responses, possibly limiting the duration of hospitalization by introducing therapeutic limitation or withdrawal of support. physicians assessment of prognosis in icu patients with brain introduction: outcome prediction in icu patients with severe brain damage is a difficult task with observed heterogeneity in physicians estimation. the aim of the survey was to evaluate the prognostic estimates and treatment recommendation of intensivists in real patients with various causes of severe brain damage. patients and methods: a web anonymous survey including a summarized clinical report of four patients who stayed in the icu was submitted to french intensivists. patient presented with prolonged hypoglycemic coma, patient with intracerebral hemorrhage, patient with central and extra pontine myelinolysis, patient with a brainstem hemorrhage. all these patients received full treatment in the icu and had a -month follow-up. physicians were provided with the four clinical vignettes including clinical history, brain imaging and other relevant exams (csf, eeg,…), evolution of symptoms within the first days of the icu stay. they had to estimate -month outcome using modified rankin scale (mrs) where a score from to was considered as a good outcome and to as a poor outcome. they had to provide a recommendation about care among the following-full treatment, care limitation, care withdrawal. results: physicians completed the survey. there were ( . %) female. ( %) respondents were residents and ( . %) had a > -year of experience. patients and had a good -month outcome with mrs and mrs respectively while patients and had a poor outcome, both with mrs . correct prognosis estimations were ( %), ( . %), ( %) and ( . %) in patients to respectively. care limitation or withdrawal was recommended by ( . %), ( . %), ( %) and ( %) respondents in patients to respectively. of interest, care withdrawal was recommended by ( . %), ( . %), ( . %) and ( . %) respondents in patients to respectively. univariate analysis did not display any factor related with a good prediction of prognosis. conclusion: in this study, overall predictions were pessimistic with important variations among respondents. although decisions to withdraw life sustaining care were relatively low with regard to estimated prognosis, both inappropriate care limitation leading to self-fulfilling prophecies and unreasonable prolonged life supportive care could result from these estimations. introduction: organ harvesting is a national priority because of the shortage of organs, responsible each year for the lengthening of transplant waiting lists. among the identified potential donors, the main cause of non-harvesting is the refusal of organ donation (od), which exceeds % in france and % in paris area. patients and methods: in a network of hopitals, each procedure on a potential donor by the donor co-ordinator is recorded in a report. after selection of the reports with interviews with relatives about od between and , the data in the reports were collected and a multivariate logistic regression was performed to identify the factors associated with the refusal. results: reports with interviews about od was found. the overall opposition rate is . %. among the children ( . % of cases) the opposition rate is . %. among adults, ( . %) expressed their will about od during their lifetime, with an opposition rate of . % and for the ( . %) of them who never expressed their will, the opposition rate is . %. the factors associated with opposition in multivariate analysis are presented in table . when the deceased had never expressed their will, the reasons given by the relatives to justify the refusal are specified in . % of the reports. these are religious grounds ( %), cultural grounds ( %), respect for physical integrity ( %). in % of the cases, relatives believe that the deceased would have been opposed, and in % of the cases, they choose to refuse because they do not know the deceased's opinion. discussion: french law is based on presumed consent. despite this, it is noted that when patients had never expressed their opinion about od (and therefore had not refused it), the opposition rate reached . % and was comparable to the patients who had expressed themselves. conclusion: in our study, factors related to refusal of od are mainly related to the characteristics of the deceased (religion, culture, history of ethylism) and those of relatives (disagreement, presence of a spouse), but little to the way of doing the interview. however, there is a trend for less opposition when the interview is conducted during the day (between - and - ). on the other hand, when relatives first address the issue of od, the opposition rate is lower. introduction: french intensive care society guidelines and the claes-leonnetti law recommend that intensive care teams organize collegiate and multidisciplinary discussions regarding limitation and withdrawal of care decisions. these moments, coined ethical staffs in our unit, require freedom and safety of speech, which can be difficult to obtain when people are caught in hierarchical and or power relations. we sought to assess the representations, perceptions and opinions of icu personnel regarding ethical staffs. patients and methods: a questionnaire, developed by the icu psychologist, was distributed to the entire unit (secretaries, nurses, nursing auxiliaries, doctors) over a period of months. this -question questionnaire covered session organization and power relations between participants. results: among the questionnaires distributed in the icu, were retrieved and analyzed. medical function was associated by respondents with roles linked with power (leading, knowledge, decision, explanation) whereas paramedical function was associated with roles linked with care (perception, account, spokesperson) (fig. ) . regarding representations of decision making, nurses were considered as decision makers in cases ( %) and doctors in cases ( %). discussion: although ethical staffs are presented as a place where each opinion counts, stereotypes representation appear in the different roles assigned-on one side doctors are in charge of explanation and decision, and on the other side, nurses are taking care of patient's feelings and assume a role of spokesperson. these stereotypes correspond to gender stereotypes assigning women to positions of care, empathy and relationship, and men to more intellectual and leading skills. these gender stereotypes attest a hierarchy internalized by each one, as highlighted by social sciences and gender studies. conclusion: our results highlight the existence of a global idea, shared by the majority-doctors are decision makers and therefore are in a power relation regarding paramedical staff. this hierarchical relationship persists in this moment wished egalitarian (each opinion would count equally). these is a linkage between professional power relations and gender power relations, which show an association between doctor and masculine "qualities" and caretakers and feminine "qualities". these power relations are rarely acknowledged but could have a significant impact on the decision process of these meetings, and should be further investigated. results. despite the diary, % had a qspt score > , indicating a higher post traumatic disorders. patients ( %) presented a anxiety score > and patients ( . %) had a depression score > . these results underline the need of psychological support after the stay. conclusion: many survivors of intensive care unit reported a high level of psychological distress. it seems important offer at this patient a psychological support after an intensive care unit stay. most patients needs return in intensive care unit to understand some elements of hospitalization. actually, this support lack to screening and treatment this psychological morbidity. prevalence and description of the complications following a percutaneous coronary intervention for a myocardial infarction in non-cardiac critically ill patients: a retrospective single-center introduction: type myocardial infarction (mi) is an emergency, which immediate invasive strategy by a percutaneous coronary intervention (pci) is based on guidelines for cardiologic patients. conversely, the invasive strategy remains uncertain for patients hospitalized in the intensive care unit (icu) for a primary non-cardiac disease with mi as a complication, given the ischemic and hemorrhagic risks. we aimed to assess the prevalence of-and describe the major adverse cardiac and hemorrhagic events occurring in the icu after an invasive strategy by pci in this context. we conducted a retrospective single-center -year ( - ) study. all the consecutive icu patients with a suspected mi undergoing a coronarography were screened. patients treated with an invasive strategy (pci performed within days of mi) were included. patients hospitalized in icu for cardiac disease were excluded. the major adverse cardiac events (mace) were defined as post-procedure events occurring in the icu, including death from cardiovascular causes, mi recurrence, need for emergent revascularization and stroke. the major adverse hemorrhagic events (mahe) were defined as post-procedure events occurring in the icu, according to the bleeding academic research consortium. results: icu patients suspected of mi underwent a coronarography. patients ( %) had significant coronary lesions. twelve patients were excluded-tri-truncular coronary involvement (n = ), delayed procedure (n = ), cardiogenic shock (n = ). patients were included ( men, years [iqr - - - ], patients mechanically ventilated, patients with sepsis septic shock, median sofa score at the time of mi [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ). a pci was performed during the first day after diagnosis of mi in patients ( %) (median time- day [iqr - - - ]). a mace occurred in patients ( %), including stroke (n = ) and mi recurrence without revascularization (n = ). no patients deceased from cardiovascular causes in the icu, neither at months post-procedure (table ) . a mahe occurred in patients ( %), of whom had a mace. altogether, the prevalence of major adverse cardiovascular events combining mace and mahe was . ( % ci . - . ). there was no difference between septic and non septic patients regarding the prevalence of mace or mahe. the prevalence of adverse cardiovascular events after an invasive strategy by pci is high in non-cardiac critically ill patients with mi. larger studies are needed to determine which patients may benefit from this procedure. introduction: resuscitated cardiac arrest (ca) lead to immune alteration including lymphopenia, decreased monocyte hla-dr (mhla-dr) expression and dysregulated production of cytokines. in a recent multicenter randomized clinical trial, we tested the hypothesis that cyclosprine a (csa) would limit organ failures following out-of-hospital cardiac arrest (ohca). in a substudy, we aimed to determine the influence of csa on ohca-induced immune dysfunction. this study is a predefined substudy of the randomized cyrus trial (cyclosporine in ca resuscitation). patients with non-shockable ohca randomly received either an intravenous bolus injection of csa ( . mg kg) at the onset of advanced cardiovascular life support (csa group) or no additional intervention (control group). patients from the coordinating center were sampled at admission (d ) and at h (d ). complete blood count, cd + lymphocytes count and mhla-dr were evaluated by flow cytometry. serum levels of il- , il- , il- , il- and tnf&# + were measured by elisa test on frozen samples. results: a total of patients were sampled- patients from the csa group and from the control group. the characteristics of the patients, including resuscitation data, were also similar between the two groups at admission. the severity of organ failure as assessed by the sofa score at admission was similar between groups. all patients introduction: critically ill patients experience major insults that lead to increased protein catabolism and a significant loss of lean body mass with an impact on weaning from the ventilator and muscle recovery. in critically ill patients, severe and persistent testosterone deficiency is very common after icu admission. administration of testosterone may induce skeletal muscle fiber hypertrophy and decreases protein breakdown. the aim of this work is to assess testosterone levels in critical ill patients and to evaluate the safety of testosterone gel administration. this is a single center study realized in a university icu of beds. total testosterone levels were measured in critical ill men with at least one organ dysfunction with sofa > . the study drug was androgel, a formulation of % testosterone in an alcohol-water gel, approved by the ansm for treatment of hypogonadism in men. androgel was applied to the abdomen, shoulders or upper arms once a day at the same time to dry and intact skin during icu stay. the daily dose was mg in men and mg in women daily. patients with history of prostate or breast cancer or psa > ng ml were excluded. results: total testosterone levels were measured in men. median length of stay at the time of measurement was days in icu and days in the hospital. plasma testosterone levels were low in all but patient. median testosterone level was ng dl (normal values - ng dl). testosterone levels were not correlated with score sofa or length of icu stay. we found a moderate positif correlation between testosterone levels and length of hospital stay (r = . =). testosterone gel was administered in men and in women. in these patients, the median score sofa was , icu death occurred in patients ( % icu mortality), median length of ventilation was days and median length of stay in icu days. all patients received mechanical ventilation and vasoactive treatment. patients needed renal replacement therapy. androgel was well tolerated. no ischemic cardiovascular events were described. there was no application site reaction or acne. median length of testosterone gel administration was days. conclusion: critical ill patients have low testosterone levels. testosterone gel may be safely administered during the acute phase in icu. randomized clinical trials are needed to evaluate the impact of testosterone gel on physical performance. introduction: stroke is the leading cause of physical disability and the second leading cause of death worldwide. two thirds of all strokes occur in developing countries and is increasingly a public health problem. the aim of this study was to evaluate the epidemiology of strokes in oran, algeria in order to create a stroke registry. patients and methods: a cross-sectional study was conducted on all patients admitted for stroke at the oran chu between january and september . sociodemographic data, modifiable and nomodifiable risk factors, type of stroke, degree of disability, severity scores (glasgow and nihss) were studied. the spss software, log rank test, was used for data analysis and statistical testing as well as kaplan-meier for survival studies. results: a total of stroke patients were enumerated, aged - years (mean ± sd = . ± . ), . % had an ischemic stroke and % had a haemorrhagic stroke. % of the patients were men and % of the women. high blood pressure, diabetes, emboligenous heart disease and smoking were the most common risk factors. intra-hospital mortality was . % and the overall survival rate at days was %. conclusion: this epidemiological study demonstrates that strokes at oran hospital may be similar to other locations. however, it seems necessary and useful to design a continuous patient registration system. introduction: the prevalence of hyperosmolar states and the relationship with mortality nevertheless remain unquantified and not objectively demonstrated. the aim of this work is to determine whether hyperosmolarity is a prognosis factor, and to assess the impact of hyperosmolarity on the evolution of patients. patients and methods: this is a retrospective descriptive and analytical study performed at the medical intensive care unit at the university teaching hospital ibn rushd in casablanca on the cases admitted during year. we noted epidemiological, clinical, biological and evolutionary parameters of all the patients and divided them into two groups according to their osmolar states, the first non-hyperosmolar group with plasma osmolarity of less than mosm l, called the control group and the second hyperosmolar group, plasma osmolarity greater than or equal to mosm l. results: patients were included. the first group comprised patients ( %) and the second comprised patients ( %). the two groups did not differ significantly about sex and age. hyperosmolar patients had more diabets . %. patients in the two groups did not show significant differences in clinical outcomes, including apache ii and saps ii scores. significant differences are reported between the two groups, in natremia, creatinemia, liver transaminases. the plasma osmolarity was significantly different between the two groups with a mean in the control group of . ± . mol l while in the hyperosmolar group it was . ± . mosmol l (p = . ). the prevalence of hyperosmolar states in the study was % with % mortality. in the control group % were intubated-ventilated + . % received vasoactive drugs and . % received antibiotic therapy. in the control group + %of the patients were complicated by nosocomial infection, . % by septic shock and % diseased by thromboembolic complications. the deceased subgroup used intubation artificial ventilation in . %, vasoactive drugs in %, and antibiotic therapy in . %. in the surviving subgroup, . % only contracted the nosocomial infection. in the subgroup died . % are of mixed hyperosmolar type + . % hyperglycemic hyperuremic + . % hyperglycemic hypernatremic type. conclusion: hyperosmolar states are an independent a prognosis factor. intubation and ventilation, vasoactive drugs and antibiotic therapy increases considerably in hyperosmolar states. furthermore, it induced serious complications as nosocomial infections and septic shocks that further aggravate the prognosis even within hyperosmolar states. introduction: hyperthermia represents a major life-threatening medical emergency, and is also one of the leading causes of death in young athletes worldwide. its incidence is rare and little understood, but its mortality is on the rise. the objective of this study was to describe the population of patients admitted for exertional hyperthermia in martinique and guadeloupe and to determine the prognostic factors. patients and methods: retrospective and prospective study, including all patients admitted for exertional hyperthermia in both emergency and resuscitation services in martinique and guadeloupe from january to june . results were expressed as mean ± sd or %. results: in years, patients were observed (age- ± , men and women), the main antecedents of which were- hypertension, chronic oh, psychoses, stress hyperthermia. ( %) of the patients had seizures initially. the pre-hospital management was < min. nevertheless, ( %) patients were admitted to icu due to organ failure (neurologic %, hemodynamic %, liver %). the progression was favorable, deaths, including fulminant hepatitis and multi-visceral failure. the average length of stay in intensive care units was days (± ). conclusion: despite considerable preventive measures, stress hyperthermia represents a major problem within the military, soldiers and other athletes, with a mortality rate about % in most published series. the most effective method is immersion in ice water. there is an urgent need to provide the region with a clear preventive policy, including a relief action plan, training for doctors, athletes and other health professionals at risk of hyperthermia. chapoutot anne-gaëlle , leteurtre stéphane , chamouine abdourahim ( ) . the university hospital of lille is a pediatric center including several itecus in its pediatric hematology or gastrology departments, and more recently in its pediatric surgical department. moreover, there are - itecu extra-beds within the - bed pediatric intensive care unit (ivecu). the hospital of mayotte has no pediatric ivecu but a polyvalent one for adults, which receives children when necessary, as well as a bed itecu. the aim of this study was to describe prospectively the pediatric population which was admitted in the itecus of lille and mayotte over a one-year period from june to may . patients and methods: in this twin-center, prospective and observational study, data were collected for each patient admitted during the test period in itecus of both lille and mayotte pediatric hospitalsgeneral information about the patient, characteristics of each stay, severity scores on admission, type of treatments implemented, the report of the stay and patient's evolution. a standard declaration was made with an authorization granted by the local commission on informatics and liberty (french commission informatique et liberté, cil). results: during the course of the study, about children were admitted in each center. the collected data allow to describe and compare both populations in terms of severity of each patient's condition. this study based on a very large cohort has permitted to compare the population of a regional hospital with that of a university hospital and to demonstrate that a health-care provision including a pediatric intensive care unit is needed on mayotte island. introduction: simulation in intensive care is an innovative method for teaching. respiratory settings are responsible for some morbi-mortality of our patients. for this reason we develop a simulator of artificial ventilation (simva) and virtual patients. mathematical model resolved differential equations of chest and lung movements in order to match with a clinical data base. the goal of this study was to evaluate and compare virtual patients respiratory mechanic with the results of different protocols of ventilation from large randomised controlled trial-arma ( ) and express ( ). patients and methods: virtual patients had ards, and were defined by different thoracic and pulmonar compliance, total resistance, lung volumes, pressure-volume relation, and pressure and volume recruitment coefficients. ventilatory protocols were high versus low vt (arma study) and max versus min distension according to pep (express study). each virtual patient was titrated on the simulator with the protocols. respiratory frequency was set around cycles minute and adapted to protocols. respiratory mechanic after titration was recorded and compared to results of the studies. results: results are summarised in the table-the difference between virtual and real patients were not significant. vm l/min . ( . ) . ( . ) . ( . ) . ( . ) . ctp: tharacopulmanar compliance (ml/cmh o) discussion: inspiratory plateau pressure and thoraco-pulmonary compliance were able to change according to pep or vt settings within the same range as the large rct studies. mathematical model of recruitment was adapted to create many different results while pep was titrated according to respiratory mechanics with the express protocol. conclusion: simulation of artificial ventilation with a software can be realistic and might be an interesting pedagogical tool to teach interactively and repetidly ventilatory settings and respiratory mechanics interactions in ards without any risk for the patient in our units. introduction: expiratory flow limitation (efl) has previously been investigated in ards patients on zero peep by using negative expiratory pressure (nep) technique on tidal breath. in ards patients with efl peep improved oxygenation from intrinsic peep homogenization rather than lung recruitment. the nep technique is no longer available. as efl should reflect airway closure it is important to assess it. we described a new technique to assess efl. patients and methods: thirty-nine ards patients ( mild, moderate, severe) were investigated at peep and . they were intubated, mechanically ventilated (evita xl) in volume controlled mode (tidal volume ± ml kg predicted body weight) in the semi-recumbent position. airway pressure and flow measured proximal the endotracheal tube were continuously recorded (biopac ). we measured respiratory mechanics by the occlusion technique at each peep and recruited lung volume between peep and by using low flow inflation method associated with measurement in change in end-expiratory lung volume. for the latter, patient was manually disconnected at the end of baseline tidal inflation downstream pneumotachograph to atmosphere til zero flow, then reconnected at previous settings. efl was assessed offline by superimposing flow-volume loops of disconnected and baseline breath. efl was defined if no change in flow occurred over all or part of the disconnected expiration as compared to the baseline breath and no efl (nfl) if any increase in flow during the expiration was present (fig. ) . the percentage of the tidal volume involved in efl was measured. results: efl was present in patients ( %) over % of the tidal expiration. patients with efl had significant higher body mass index ( ± vs. ± kg m , p < . ) and totalpeep at peep ( ± vs. ± cmh o, p < . ) than nfl patients and tended to be more hypoxemic. at peep efl patients had a significant better compliance ( ± vs. ± ml cm h o, p < . ) with no change in recruited lung volume ( ± vs. ± ml) and tended to be more hypoxemic than nfl patients. mortality at icu discharge was % in efl versus % in nfl (p = . ). conclusion: measurement of efl is feasible without the nep technique. at higher peep ards patients with efl markedly improved compliance of the respiratory system not related to lung recruitment. further studies are required to better understand efl in ards patients and to assess its impact on patient outcome. limiting factor being carbon dioxide accumulation and hypercapnic acidosis. extra corporeal carbon dioxide removal (ecco r) intervenes by maintaining ph and pco within physiological ranges. this combination is called ultra-protective ventilation. we report our experience with ecco r in ards and non ards patients with a focus on feasibility and safety. patients and methods: from june to july all patients who have undergone ecco r in our icu were included consecutively and prospectively. venovenous ecco r was used through a dual lumen venous catheter (femoral or jugular). results: nineteen patients underwent ecco r for a total of sessions. ecco r was implemented through a dual lumen venous catheter (femoral or jugular) with different devices-hemolung respiratory assist system ® (alung) (n = ), ila activve ® (novalung) (n = ) and prismalung ® (prismaflex system) (n = ). sessions were (iqr . - . ) days long. catheter diameters were fr (n = ), fr (n = ), fr (n = ) and fr (n = ). thirteen patients suffered from ards and had non ards indications for ecco r, including ultraprotective ventilation. tidal volume decreased during ecco r from . (iqr . - . ) to . (iqr . - . ) ml kg of predicted body weight (p < . ) while ecco r allowed maintaining of ph and pco within acceptable range (fig. ). driving pressure decreased from (iqr - ) to (iqr - ) cm h o (p < . ). the main adverse effect was thrombocytopenia ( patients). six selected patients had no anticoagulation during ecco r because of high bleeding risk. discussion: ultra-protective ventilation was achieved with a decrease of tidal volumes (vt < ml kg) and positive pressures. few data on ecco r are available in patients at high risk of hemorrhagic complications, we report here a subgroup of patients who underwent efficiently ecco r without anticoagulation. six patients underwent ecco r for non ards indications, of them had no structural damages to the lungs which has never been reported and eccor allowed implementing ultra-protective ventilation with no major adverse effect. we report our experience on ecco r for ards and non ards indications. ultra-protective ventilation (vt < ml kg) was safe and feasible. the impact of general practitioners consultation on ards complicating community acquired pneumonia donval ulysse , tadie introduction: community-acquired pneumonia (cap) is a potentially severe infection that results in numerous general practitioner (gp) visits and hospital admissions each year. cap is also the most frequent single cause of acute respiratory distress syndrome (ards). risk factors for development of ards in the course of cap are not clearly defined although prognostic factors associated with mortality have been extensively studied. gp visits, as an early diagnosis and earlier access to antibiotics prescription could significantly affect the course of cap. the aim of the present study was to evaluate the impact of general practitioners consultation on ards complicating cap admitted to our icu. patients and methods: we retrospectively reviewed the medical records of all patients aged over years admitted between october , and december , , for ards complicating community acquired pneumonia with a pao fio ratio < mmhg after at least h of lung protective mechanical ventilation (mv). ventilatory modalities for ards had been protocolized over the study period as our icu was recruiting patients for two consecutive multicenter trials (acurasys and proseva). consequently, the protective ventilatory strategy used in these two clinical trials was applied to every patient with ards. patients were divided into two groups according to whether or not they visited a gp before icu admission. : patients were admitted for ards complicating cap. patients ( %) had visited a gp before admission in icu (gp +) and did not (gp-). analysis of demographic data, respiratory microbiology patterns, ards severity at admission did not show any differences between the two groups. sofa score at admission was significantly higher in gp-compared to gp + patients ( . ( - ) vs. . ( - ) respectively + p = . ) although respiratory sofa scores were not different ( ( - ) vs. ( - ) respectively + p = . ). ( %) gp-( %) and ( %) gp + patients presented septic shock at icu admission (p = . ). multivariate analysis found that gp consultation ( . [ . - . ] + p = . ) with antibiotics prescription ( . [ . - . ] + p = . ) were associated with decreased mortality at day ( fig. ) . in patients admitted to our icu for ards complicating community acquired pneumonia, gp visits prior to icu admission was associated with a better outcome. the beneficial effect may be due to earlier antibiotic prescription which could significantly lowered severe infection and septic shock. introduction: optimal peep level during ards remains controversial because of its beneficial and adverse effects. the optimal level of recruitment and its effect on oxygenation are not well defined and no technique is currently validated. the aim of our study was to evaluate the correlation between the recruited pulmonary volume estimated by a new technique (crf inview ® ) and the evolution of pao as well as the respiratory and hemodynamic tolerance of the application of an increasing levels of peep . patients and methods: a prospective, monocentric study that will last years (january -january ), taking place in the intensive care unit at the military teaching hospital of tunis and including patients if they met standard criteria for ards (berlin criteria). the main criterion for judgment was the correlation between the recruited pulmonary volume estimated by a new technique (crf inview ® ) and the evolution of the pao after application of three increasing levels of peep ( - - ). the other secondary criteria were the respiratory and hemodynamic tolerance of the application of increasing levels of peep measured by the picco ® technique. aimed to investigate the concordance between the onset of three vae tiers and valrti, and their impact on outcomes. we performed a retrospective analysis of prospectively collected data from patients requiring mechanical ventilation for more than days in a -bed mixed icu of a tertiary university teaching hospital, between january and december , . vat and vap episodes were assessed by prospective surveillance of nosocomial infections, according to the american thoracic society criteria. vae were identified retrospectively, according to current cdc definitions. the agreement between vac, ivac, pvap and valrti was assessed by k statistic. the impact of vae and valrti on duration of mechanical ventilation, icu and hospital length of stay and mortality was also assessed for the first episode of vat and vap. results: we included patients ( ventilator days). vap ( . per ventilator-days), vat ( . per ventilator-days) and vae ( . per ventilator-days) were diagnosed. there was no agreement between vat and vae and the agreement was poor between vap and vac (k = . , % ci . - . ), vap and ivac (k = . , % ci . - . ) or vap and pvap (k = . , % ci . - . ). patients who developed vat, vap or vae had significantly longer duration of mechanical ventilation, icu and hospital length of stay, compared to patients who did not, with similar mortality rates. conclusion: vae are not relevant for vat diagnosis and have low agreement with vap, despite their negative impact on ventilation duration, icu and hospital length of stay ( fig. ) . the introduction: post-operative pneumonia (pop) is a frequent and severe complication of major lung resection surgery. in , we changed our surgical antibioprophylaxis protocol from cefamandole to amoxicillin-clavulanate and observed a significant decrease of pop incidence and mortality. in , we additionally implemented in the respiratory intensive care unit (ricu) an antimicrobial stewardship program based on a local antimicrobial guideline and a weekly multidisciplinary review of all antibiotic therapies by ricu physicians, infectious diseases specialists and microbiologists. our objectives were to describe our current epidemiology of severe pop and to assess the quality of antibiotic prescriptions. patients and methods: all patients with severe pop occurring within days after lung resection between january and december were included. we collected data on clinical presentation, results of microbiological investigations, antibiotic regimen and outcomes. the quality of antibiotic use was assessed using indicators previously validated in the literature. results: over patients who underwent major lung resection in our center, matched criteria for severe pop and were included. most were males (n = , %). the median age was years (minimum- + maximum- ). most patients had chronic obstructive pulmonary disease (n = , %) and ( %) a history of non-pulmonary cancer. the resection consisted in lobectomy in % (n = ). the median length of stay in ricu was days ( + ), and -day mortality was % (n = ). respiratory microbiological samples were obtained in all patients, in most cases invasively per bronchoscopy ( %). microorganisms were cultured at a significant level in ( %) patients. predominant species were enterobacteriacae ( %), haemophilus influenzae ( %), staphylococcus aureus ( %) and pseudomonas aeruginosa ( %). microorganisms were sensitive to third generation cephalosporins in ( %) and to piperacillin-tazobactam in ( %). in patients treated empirically, antibiotics were prescribed according to the guideline in % ( ). in documented pop, empiric antibiotics were active against documented micro-organisms in ( %), and were correctly changed to pathogen-directed therapy in ( %). the median duration of antibiotics was of days ( + ). conclusion: ten years after implementation of amoxicillin-clavulanate as surgical antibioprophylaxis, the proportion of enterobacteriacae increased. the -day postoperative mortality rate remained below %. we report high adherence to the guideline for the choice of empirical therapy and treatment duration. the rate of de-escalation to pathogen-directed therapy could however be improved considering the high rate of bacteriologically-documented pop. resistance of pa has reduced between both periods from % to % (p < . ) for ceftazidim, from % to % (p < . ) for cirpofloxacin and from % to % (p < . ) for imipenem. nevertheless, among the cases, the p period did not change the risk of developing an infection (rr = . , ci % . - . ), a vap (rr = . , ci % . - . ), a septicemia (rr = , ci % . - . ) or the mortality rates (rr = . , ci % . - . ). conclusion: colonization and infection with pa are risk factors of increased mortality rates and alos in icu. an antibiotic stewardship program allows to reduce the incidence of patients having a positive sample with pa, and the antibiotic resistance of pa strains, without reducing the infection rate of these patients. impact of a local care protocol on the duration of antibiotic therapy in community-acquired peritonitis: years of experience introduction: the use of antibiotics is a major public health, economic and ecological challenge. in , a french national warning plan was created to manage the use of antibiotics. it advocates monitoring of the prescription of antibiotics and the implementation of measures to assess professional practices. the great majority of guidelines concerning the duration of antibiotic therapy in community-acquired peritonitis are based on studies with low level of evidence. the objective of this study is to evaluate the implementation of a standardized operational report (sor) with a local antibiotic protocol in the management of community-acquired peritonitis at our institution. patients and methods: this is a monocentric, prospective cohort study-before and after the establishment of the sor. the primary endpoint is duration of antibiotic therapy. secondary endpoints are length of hospitalization, infectious complications, mortality, and changes in local bacterial ecology. we have also evaluated retrospectively these different criteria on cohort was constituted since . results: a total of patients were enrolled from january to june and patients from may to may . the duration of antibiotic therapy was decreased by to days in localized peritonitis (p < . ) and to days in generalized peritonitis (p < . ) (figure) . however, the compliance to the protocol was only %, which leads to an increase in the duration of antibiotic therapy and hospital stay when not used (p < . ). the hospital stay decreased from to days in the localized peritonitis (p < . ). amoxicillin clavulanic acid (amc) is the most used antibiotic with an efficiency of %. there was no impact on morbidity and mortality when amc was inadequate. the bacterial ecology was not modified, the rate of extended-spectrum beta-lactamase (esbl) producing enterobacteria (esble) was %. the use of a standardized antibiotic protocol reduced antibiotic therapy duration and hospital stay, particularly in localized peritonitis despite incomplete compliance to the protocol. to achieve full compliance, we need to continue the training of different physicians and continue the spread of the protocol. introduction: bacterial meningitis is an important public health problem because of its frequency and severity. they remain a major cause of mortality and morbidity in developing countries. the aim of our work is to establish the epidemiological characteristics and the prognostic factors . patients and methods: we did a retrospective descriptive and analytical study and we included all the patients admitted for severe meningitis for year in the medical intensive care unit of the university teaching hospital ibn rushd at casablanca-morocco. results: patients were included. the incidence of severe meningtis was . %, the mean age was years old and the sex ratio h f was , . , % were pneumococcal meningitis and % were tuberculosis in univariate analysis, factors influencing mortality significantly-the male sex patients with pulmonary tuberculosis as an antecedent.• a low glasgow score at admission. the presence of a neurological deficit arterial ph, mean (sd) arterial lactate, mean (sd) kidney disease-improving global outcomes chronic kidney disease guideline development work group members. evaluation and management of chronic kidney disease-synopsis of the kidney disease-improving global outcomes clinical practice guideline dramatic increase in venous thromboembolism in children's hospitals in the united states from antithrombotic therapy in neonates and children acute childhood arterial ischemic and hemorrhagic stroke in the emergency department childhood hemorrhagic stroke-an important but understudied problem emergency management of deeply comatose children with acute rupture of a cerebral arteriovenous malformation goulmane mourad -m.goulmane@hotmail.com annals of intensive care we recorded episodes of nosocomial infections-pneumonia (n = , . %), bacteremia (n = , . %), catheter related infections cri (n = , . %) and urinary infections (n = , . %). pathogens isolated were largely dominated by non-fermentent gram-negative bacilli (n = , . %)-acinetobacter baumanii (n = , . %) with % resistance to imipenem and tygecycline, pseudomonas aeruginosa (n = , . %) with . % resistance to ceftazidim and stenotrophomonas maltophila (n = ). other gram-negative bacilli were enterobacteries (n = ), which were wide-spectrum betalactamase secreting (n = ) and carbapenemase (n = ). gram-positive cocci were the second highest (n = , . %)-coagulase negative staphylococcus (n = ) which were resistant to methicilline ( %), enterococcus (n = ) which were resistant to vancomycin (n = , . %), staphylococcus aureus sensitive to methicilline (n = ) and streptococcus (n = ). candida was incriminated in cases of cri we report here that neonates had a reduction in hla-dr expression after cpb, and those with prolonged decreased hla-dr in the early postoperative period (day ) could represent a subpopulation at greatly increased risk of later ni. if confirmed in a larger cohort of patients, our findings could indicate that hla-dr may be a useful biomarker of immunosuppression after cpb in neonates. non-traumatic hemorrhagic stroke (nths) in comatose children: epidemiological features and clinical presentation conclusion: compared to normobaric ltot the fio is lower during niv with the same o flow. compensation for intentional and nonintentional leaks and so an increase of air flow despite a constant o input might explain this. in intermediate care the use of hv for niv may be interesting alternative in which case the clinician must keep in mind that the fio decreases compared to standard oxygen therapy. concerning home usage we hypothesize that this partial removal of o treatment could contribute to the poor results of niv in chronic copd. introduction: in february , we opened a beds-post icu rehabilitation center (service de rééducation post réanimation, «srpr»), dedicated to weaning from mechanical ventilation and global post icu rehabilitation. objectives-description of the characteristics and main outcomes of the patients admitted over the first year of activity. patients and methods: retrospective analysis of data extracted from the medical files. results: patients were admitted times in the unit over its st year, from different icus (median duration of stay in the icu . days (iqr - )). % were ventilated ( % with niv). % had a tracheostomy. % had icu acquired weakness + % were able to walk. an underlying chronic respiratory disease was present in % of cases. % were obese. difficult weaning was found to have one or several respiratory components in % of cases (including post surgery diaphragmatic paralysis), cardiac in %, neurologic in %. significant complications occured in % of cases. median duration of stay was . ( - . ) days. ten patients died in the unit, patients were re-transferred in the icu, where of them died. over half of the patients were discharged at home, in a rehabilitation unit (ssr) or in a hospital ward awaiting a rehabilitation bed. the remaining %, that still needed some form of medical or surgical care were discharged in the ward (fig ) . in intention to treat, successful weaning from invasive ventilation was obtained in % of patients. of the patients discharged alive from the unit after completing the rehabilitation program (n = ), % were completely weaned from mechanical ventilation, % were discharged with niv or cpap + patients ( %) were considered not weanable from invasive ventilation + decanulation of tracheostomy was obtained in % of cases + % of the patients could walk. conclusion: srprs offer a new concept of care for difficult to wean patients, with promising results. introduction: scarce data about patients with prolonged weaning from the mechanical ventilation are available in the literature. patients without successful weaning days after their first weaning attempt were classified in the group of the weaning according new definition (wind) classification ( ) . we here describe specific data concerning weaning and hospital evolution of group patients included in this prospective cohort. among the patients included in the wind study, were classified in the group . additional data concerning comorbidities, cause of weaning failure and hospital evolution were collected for ( %) of these patients. results: these patients had median [interquartile range] duration of invasive mechanical ventilation of [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days and [ ] [ ] [ ] separation attempts. etiology of icu hospitalization was medical in ( %). they had a copd in ( %), hearth disease in ( %) and immusoppression in ( %). we noticed a mean saps ii of ± , a mean sofa d of ± and d of ± . tracheostomy for weaning was performing in ( %). at the end of their follow-up, ( %) were still alive- ( %) were still tracheostomized, still intubated and ventilated, ( %) treated with vni and ( %) were extubated (or decannulated) and breathed without assistance. among the patients still tracheostomized at the end of the follow-up, ( %) were still ventilated (permanently for of them, and partially for ) and ( %) had spontaneous breathing through their tracheostomy. these patients had a total icu length of stay of days. the destination at discharge from the icu is known for only of the survivors- ( %) in medical ward, ( %) in intermediate care units, ( %) in sub acute care, ( %) in icu and in surgical ward. conclusion: a third of the patients of the wind study classified in group and with available additional data died in hospital in months following intubation. at the end of the follow-up, % had spontaneous breathing without assistance, and % were still tracheostomized. among these tracheostomized patients, one third still required mechanical ventilation. ( )-béduneau, g., pham, t. and co ( ) . epidemiology of weaning outcome according to a new definition. the wind study. ajrccm, ( ) , - . introduction: copd patients have often polyglobulia because of associated hypoxemia especially in patients at the stage of chronic respiratory failure. we recently reported that anemia was present in % of patients with severe aecopd admitted to icu without impact on short-term prognosis. the aim of the present study was to assess the long-term impact of haemoglobin (hb) levels on outcomes of aecopd patients. patients and methods: in a prospectively collected database including consecutive patients admitted between and for aecopd in our icu. long-term status of patients following the first icu admission (surviving or deceased) has been verified by consulting the civil status registers. anemia was defined according to who criteria-hb < g dl in males + hb < g dl in females. long-term survival was assessed by kaplan-meier curve. results: the cohort included patients (median age , median ph . , . % males, niv as first ventilator mode in . %). anemia was observed in of the patients ( . %) with median haemoglobin levels at . and . g dl, in patients with and without anemia, respectively. anemia was associated with significantly lower years survival (log rank p = . ) (fig. ). the final model included age, saps ii score, comorbidities, home oxygen therapy, initial ventilatory mode, niv failure and haemoglobin levels. multivariate analysis identified age (or . per year + ic % . - . + p = . ), home oxygen therapy prior to exacerbation (or . + ic % . - . + p = . ), intubation at icu admission (or . + ic % . - . + p < . ), niv failure (or . + ic % . - . + p < . ), and haemoglobin (or . per decrease of g dl + ic % . - . + p = . ) as independently associated factors with years mortality . we conducted a prospective observational study including all patients who visited the sis during the last months. the collection of the usual anonymous demographic, medical and toxicological data was performed by the care-givers and social workers in charge of the drug users. data were declarative and no analytical confirmation was available except for the patients admitted in the icu. results discussion during months, drug users [f m sex ratio . + median age . years ( - ) + patients without resources ( %), without medical insurance ( %), unstable housing homelessness ( %)] visited the sis for drug injection or inhalation, representing , drug use including , inhalations and , injections by drug users day. drug users had no addictology ( %) or sociomedical ( %) follow-up. they were infected by hepatitis virus c ( %) and or hiv ( %). they declared to continue injecting in the public space ( %), sharing material ( %), and needles syringes ( %). the injected inhaled drugs in the sis were skenan ® (morphine, . %), crack ( % including injections), methadone ( . %), buprenorphine ( . %), heroine ( . %), and cocaine ( . %). these drugs were self-administered by polydrug users declaring concomitantly consuming crack ( . %), illicit morphine ( . %), cocaine ( . %), ethanol ( . %), cannabis ( . %), heroin ( . %), illicit methadone ( . %), benzodiazepines ( . %) and illicit buprenorphine ( . %). forty-five patients required a paramedical intervention in the sis resulting in calls to the emergency department and hospital admissions including transfers to the icu in relation to opioid overdose. no cardiac arrest and no death occurred. conclusion: sis visit for recreational drug self-administration rapidly becomes popular among drug users. illicit morphine (skenan ® ) glycemia (mmol/l) . ( - ) . ( - )ketones in the effluent liquid (g/l) . ( . - . ) ( - ) patients and methods: physiological tracings were recorded from the standard monitoring system (intelliview mp philips), using a dedicated network and extraction software (synapse v , ltsi inserm u ) that enables photoplethysmographic recordings from oximetry monitoring at a native resolution of hz. raw data were subsequently stored on a dedicated local server, before anonymization and analysis. all consecutive patients were recorded for a -hours period during the -hours following icu admission. all measurements were recorded with the patient laying supine, with a ° bed head angulation. physiological recordings were associated with metadata collection by a dedicated research assistant.hrv parameters defined in a previous study were derived using kubios hrv premium ( introduction: preventing post liver transplantation (lt) hepatic artery and portal vein thrombosis is challenging and includes enoxaparin administration. enoxaparin pharmacokinetics (pk) has not been investigated in children following lt. between-subject variability and critical illness may alter pk, leading to the risk of subtherapeutic exposure. patients and methods: clinical, biological and kinetic data were retrospectively collected in a single pediatric intensive care unit center from january to july . we described an enoxaparin pk model in children the first week following the lt. anti-xa activity timecourses were analyzed using a non linear mixed effects approach with monolix version r. results: anti-xa activity time-courses were well described by a one-compartment open model with first order absorption and elimination. body weight prior the surgery (bwpreop) and the related postoperative variation (bw(t)) were the main covariates explaining cl and v between subject variabilities. parameter estimates were cli = cltyp*(bwpreop ) + vi = vtyp*(bw(t) ) + where typical clearance (cltyp) and typical volume of distribution (vtyp) were . l h − and . l, respectively. standard dosing regimens of iu kg h were insufficient to reach the target range of anti-xa activity of . to . iu ml. specifically, children ( %) did never attain the target range during the whole period of treatment and all children were at least once under dosed. according to the final results, we simulated individualized dosing regimens within h following the first administration. more than iu kg h are suggested to reach the target range of anti-xa activity of . to . iu ml from the first day. standard enoxaparin dosing regimens is not appropriate to reach the target in pediatric liver transplantation patients. enoxaparin pk modeling should help the physician to achieve the target range from the initial dose and during the maintenance doses. higher dosing regimens, especially in youngest children are suggested to achieve the prophylactic target range. pharmacokinetic analysis of unfractionated heparin in critically ill children during extracorporeal membrane oxygenation: do we achieve the target? introduction: preventing thrombosis in children under extracorporeal membrane oxygenation (ecmo) requiring unfractionated heparin administration. unfractionated heparin pharmacokinetics (pk) has not been well investigated in children under ecmo. we described the unfractionated heparin dosing regimens and resulting anti-xa activities in children with ecmo. patients and methods: this is a single center retrospective study from march to september . were included children (< years old age) who were under ecmo for refractory hemodynamic failure related to (i) myocarditis or (ii) septic shock. anti-xa activity timecourses were analyzed using a non linear mixed effects approach with monolix version r. results: a total of children were included (septic shock, n = + myocarditis + n = with a median age of months ( - ), a median weight of . kg ( . - ) and median admission pelod- score of ( - ). bleeding occurred in children and thrombosis in . an initial bolus of unfractionated heparin ranging from to iu kg was infused and then continued by continuous perfusion with an initial dosing ranging from iu kg h to iu kg h. a total of anti-xa activity measurements were performed between h empirically antibiotics for these patients with severe infection may be recommended. introduction: prognosis of allogeneic hematopoietic stem cell transplant (hsct) recipients admitted to icu has improved with advances in hsct procedures and critical care management, but also with evolution in icu triage policy. our aim was to describe the outcome of hsct recipients admitted to icu according to a wide admission policy. patients and methods: retrospective multicenter study including all consecutive allogeneic hematopoietic stem cell transplant (hsct) recipients admitted to saint-antoine hospital medical icu, paris, france from to january to april . admissions were identified through a systematic review of icu database using icd- codes z and t . data were extracted from medical charts. qualitative and quantitative values are expressed as number and percentage, and median and interquartile range, respectively. comparisons between groups were performed using fisher's exact test and mann-whitney test for qualitative and quantitative variables, respectively. a p-value < . was considered to be significant. results: one hundred seventeen patients- men ( . %), median age [ - ] years-were included in the study. underlying hematological malignancies were: acute myeloid leukemia (n = , . %), myelodysplastic/myeloproliferative neoplasms (n = , . %), acute lymphoid leukemia (n = , . %), lymphoma (n = , . %), other ( . %). complete remission was achieved before hsct in ( %) patients. forty-nine ( . %) patients underwent myeloablative conditioning regimen and ( . %) received haploidentical grafts. twenty-eight ( . %) patients experienced disease relapse after hsct and ( %) graft versus host disease prior icu admission. median saps ii was and sofa score at day one [ - ]. the icu, hospital and -day mortality rates were respectively . , . and . %. in univariate analysis, factors associated with -day mortality were: saps ii (p = . ), invasive mechanical ventilation (p < . ), vasopressors (p = . ) and renal replacement therapy (p = . ). mechanical ventilation was the only independent factor of -day mortality (or . - . ], p < . ) with mortality rate reaching . % and even . % among patients with uncontrolled hematological disease. conclusion: prognosis of unselected hsct recipients admitted to icu remains poor, particurlaly among those receiving mechanical ventilation, and even more if hematological disease is not controlled. these results suggest that the implementation of an icu triage policy determined both by intensivits and hematologists would be helpful to identify good candidates for icu admission. introduction: acute respiratory failure (arf) is a common event in patients with primary malignant brain tumors (pmbt). even if many factors (corticosteroid therapy, swallowing disorders) suggest a specific etiologic spectrum, few data are available regarding its precipitating factors. our first aim was to compare the causes of arf between patients with pmbt and those with other type solid tumors. our second aim was to identify, among pmbt, the factors influencing survival in icu. patients and methods: bicentric case-control study from march to may . patients with pmbt (cases, primary central nervous system lymphoma included) admitted for arf were compared to patients with other kind of solid tumors (controls). the reason for admission "arf" as well as the causes of arf was determined by three experienced respiratory physicians and were required for inclusion: a respiratory rate > cycles/min and a pao /fio < for patients in spontaneous breathing and only a pao /fio < for patients under mechanical ventilation. in both groups were excluded patients with metastatic solid tumors, benign tumors or tumors with more than years of complete remission, recent post-operative patients, and patients with other immunodeficiency. results: a total of cases and controls were included. main patients' characteristics are reported in the table . acute infectious pneumonia was the leading cause of arf in both groups but was more frequent among cases ( vs. %, p < . ). cardiogenic pulmonary edema and exacerbation of chronic respiratory diseases were more frequents in controls ( vs. %, p < . ). pulmonary embolism was similar between the two groups ( vs. %, p = . ). among acute infectious pneumonia, pneumocystis pneumonia (pcp) and aspiration pneumonia were more frequent in cases ( vs. %, p < . and vs. %, p < . respectively). in multivariate analysis cancer progression (or- . %ic [ . - . ], p = . ), need for intubation (or- . %ic [ . - . ], p = . ) and respiratory rate (or- . % ci [ . - . ], p = . ) independently predicted icu mortality of pmbt patients. conclusion: in pmbt patients, the causes of arf differ significantly from other cancer patients. up to % of the admissions was related to preventable causes (pulmonary embolism, pcp) and a curable cause was identified in the majority of cases. our results suggest that pmbt alone is not a relevant criterion for icu recusal. introduction: drug intoxication is a common problem encountered in emergency departments. poisoning remains a major cause of hospitalization for young people, and that of the elderly is constantly increasing. objectives . determine the epidemiological characteristics of addicted patients . know the clinical manifestations of poisoning. patients and methods: a retrospective study of cases of acute poisoning recorded at the university hospital center chuoran between january and december was carried out. seizure on data processing by epi-info version . results: cases of acute poisoning, with an age ranging from to years. female patients predominated with %. people between the ages of and are the people most affected by poisoning. the nature of poisoning is varied. in this series, analgesics were found to be the leading cause of acute intoxication, with cases, % followed by psychotropic drugs ( %), benzodiazepines ( %), neuroleptics ( %), antiepileptics%) and antihistamines ( %). the majority of acute intoxications were managed within an average time of . ± . h with an interval between . and h. in % of cases the poisoning was asymptomatic, there were digestive manifestations in % of patients, % neurological, % cardiovascular and % respiratory. we deplore death in this series secondary to many drug poisoning. conclusion: acute drug poisoning is a common reason for admission to the emergency department of oran university hospital. the large number of drug families offered for sale, as well as the heterogeneity introduction: selective serotonin reuptake inhibitors (ssris) have been considered for their low toxicity comparatively to antidepressant agents. the present study aims to describe clinical features and prognosis of poisoning ssris. patients and methods: a retrospective study of patients admitted to our -bed teaching icu for acute ssris poisoning over a period of years from january to december . ssris poisoning was retained on a history of over dose ingestion, clinical signs and positive urine samples for ssris. results: thirty seven patients were collected, the middle age was ± years with a female predominance ( . %). a psychiatric history with depressive syndrome was noted in . % and a history of suicide in . %. paroxetine was the main invoked drug (n = ), followed by sertaline (n = ), then fluoxetine (n = ), venlafaxine (n = ) citalopram (n = ). the mean supposed ingestion dose was . mg. intoxication was pure in cases and associated with other drugs in cases-benzodiazepines (n = ), klippal (n = ), amisulpride (n = ), non-steroidal anti-inflammatory drug (n = ), prazin (n = ) and promethazine (n = ). neurological examination found drowsiness and mydriasis in % of cases (n = ), coma in . % (n = ), agitation (n = ), tremor (n = ), hyperreflexia (n = ), hypersudation (n = ), fever (n = ) and diarrhea in one patient. the qt was lengthened in five cases. treatment was symptomatic. five patients ( . %) required mechanical ventilation with average of ventilation duration of . h. all patients discharged alive the icu. conclusion: ssris poisoning is mainly manifested by serotonergic syndrome. evolution is favorable in the majority of cases. mechanical ventilation could be required. hemodynamic profile of shocks induced by dihydropyridine calcium channel blocker poisoning khzouri takoua introduction: acute calcium channel blockers (ccb) poisoning remains infrequent despite their increasing use. in our country, dihydropiridines are the most prescribed ones. very few works have studied the hemodynamic profile of acute dihydropyridines poisoning either by invasive means (right cardiac catheterization, transpulmonary thermodilution) or non-invasive (cardiac ultrasound). in this perspective, we carried out this study whose main objective was to illustrate the different hemodynamic profiles of shocks induced by dihydropyridine ccb poisoning. patients and methods: it was an observational retrospective study spread over months from st january to th december in a teaching toxicological icu, including all patients admitted for acute dihydropyridine ccb poisoning, who presented a shock and underwent right hemodynamic exploration.results: during the study period, ccb poisoning accounted for . % (n = ) of all the acute poisoinings requiring hospitalization in our intensive care unit. among them, had taken dihydropyridine which represents . %. four women aged of [ , ] were eligible. all the exposures were single-drug. the dihydropyridines involved were amlodipine in cases with a median value of supposed ingested dose (sid) of . mg and nicardipine in the other two ones, the median sid was mg. the delay of consultation was of . ± h after ingestion. gastrointestinal decontamination was performed in one patient with activated charcoal. the patients developed a shock within h, treated by initial vascular filling on average ml of crystalloids, noradrenaline alone in cases and with a combination of dobutamine in one patient. other adjuvant treatments (high dose insulin, calcium salts) have been used in all patients. their hemodynamic profile evaluation by right-handed catheterization swan-ganz was in favour of vasoplegia in cases with median values of systemic vascular resistances (svr) of dynes.s.cm- , of cardiac output (co) of (l min), and of the arteriovenous oxygen difference of . . the fourth patient's shock had mixed nature with svr of dynes.s.cm- and co of . (l min). all patients were discharged from the icu with a mean length of stay of days. conclusion: the dihydropyridine calcium channel blockers poisoning exposes to the shock risk due to several mechanisms. the clinician must be warned to look for signs of severity and understand its mechanisms by using the hemodynamic study in order to improve its management. goulmane mourad , alachaher djamel , djebli houria introduction: in daily practice, admission to the intensive care unit (icu) usually does not raise any major ethical problems. difficulties arise mainly in acute situations requiring intensive care that have not been anticipated and therefore, not adequately prepared and discussed. we hypothesized that non-admission of a patient to the icu must occur in the following circumstances-( ) with the patient's agreement, expressed either directly or through advance directives (ad), or as relayed by a surrogate or the family + ( ) according to a collegial decision-making process (if the patient is decisionally incapacitated) + and ( ) after seeking the opinion of an external consultant. the decision-making process must be documented in the patient's medical file. patients and methods: prospective, observational study in two hospitals (one large university hospital, one regional non-acamedic hospital) over a period of months. inclusion criteria were-patients aged ≥ years presenting with failure of at least organ that was directly life-threatening and requiring life-sustaining therapies. complete data collection was performed for each patient. results: a total of patients were included ( % from the emergency department and % from medical wards). the decision not to admit the patient to the icu was taken-( ) during night duty for patients ( %) + ( ) by a senior physician in %, and ( ) after clinical examination in ( %). the main reasons justifying the decision not to admit to the icu were-( ) metastatic cancer in patients ( %) + ( ) total loss of autonomy in ( %) + ( ) severe cognitive impairment in ( %) + ( ) premorbid state in ( %) + ( ) chronic organ failure for ( %) + and ( ) presence of ad (written or oral) specifying that the patient did not wish to be admitted to the icu in ( %). this study raises several points concerning the decision-making process for patients requiring intensive care. first, collegiality is observed in almost all situations of non-admission ( %). second, an outside consultant was contacted in around % of cases. third, % of patients had ad. fourth, the family or entourage were consulted in less than % of cases and finally, in around % of cases, the decision-making process was documented. conclusion: this study shows that in emergency situations, it is more difficult to take adequately structured decisions regarding icu admission than, for example, decisions regarding limitation or withdrawal of treatment in the icu. introduction: as known, tracheostomy is performed to improve quality of life (qol) in patients requiring prolonged mechanical ventilation. it is indicated to facilitate care of critically ill patients, in order to minimize risks of oro-tracheal intubation, and enhance recovery, allowing early discharge from icu with home ventilation. we aimed by this study to evaluate long-term survival and qol in tunisian patients discharged from the icu with tracheostomy, as well as related burden assumed by their relatives. patients and methods: patients who were admitted to the icu between and were eligible for inclusion in this retrospective cohort if they had a tracheostomy during their icu stay, and were discharged at home with a tracheostomy canula. for survivors, we used the short form health survey (sf ) to assess their qol at home. we estimated the degree of autonomy using the adl scale. to assess burden assumed by caregivers (family members most of the time) we used the short version of zarit burden interview. exclusion criteria were refusal of the interview or unavailability on the phone call. results: fourteen patients were discharged at home with a tracheostomy canula. only twelve responded to the phone call. four patients died month later. amoung the survivors, the removal of the tracheostomy canula was successful in patients after a mean duration of days. main findings are summarized in table . conclusion: tracheostomy shows good acceptance and acceptable qol. it allowed shorter length of stay in the icu and long-term survival after discharge from the icu, and should be encouraged for tunisian patients. in contrast, the qol of patients' relatives was more affected, with significant burden and work load. introduction: intensive care survivors present often some psychological disorders linked with experience memory loss or nightmares. the use of patient diaries has been developed and implemented by clinical staff to improve the quality of life after intensive care. patients received their diaries at icu discharge. this study was conducted in order to understand the potential benefits for patients the diary on prevalence anxiety, depression and post traumatic disorders during recovery. patients and methods: a structured interview study was administered to adult critical illness survivors who received ≥ h of mechanical ventilation in a medical and surgical intensive care unit. after months, this patients answered at two questionnaire-hospital anxiety and depression scale (had) and a screening instrument for ptsd (qspt). results: from the survivors at months, patients answered the questionnaires. we have two groups- patients had a diary and patients no diary. but these group are so low currently to compare introduction: in ards patients under ecmo common ventilator strategy aims at resting the lung by lowering tidal volume (vt) in the - ml kg predicted body weight range found in the literature analysis. we tested on the bench the not previously explored hypothesis that vt was not delivered in the % accuracy by most of icu ventilators in this low range. patients and methods: pneumatic test lung set at ml/cmh o compliance and cm h o/l/s resistance was attached to any of icu ventilators (v (drager), carescape r (ge healthcare), servo u (maquet), pb (covidien) and g (hamilton)) equipped with heated humidifier (fisher-paykel mr ) set off and adult ventilator circuit (rt evaqua fisher paykel). each icu ventilator was set in btps condition, at peep cm h o and fio . . airway pressure and airflow (hans-rudolph pneumotachograph) were measured (biopac m ) proximal to the lung model. for each ventilator a series of vt ranging from to ml was delivered for breaths each, at then at breaths/min respiratory rate (rr). the relationship of vt measured to vt set was assessed by linear regression over the icu ventilators for each circuit-rr combination. in each model, the change from the mean effect was assessed for each ventilator. for each model we obtained the mean effect of the ventilators then we compared the effect of each ventilator to the mean effect. results: for each combination of f and circuit, the mean slope was significantly lower than indicating that, on average, the set vt was under delivered (table) . there were differences in change in slope from the mean across the ventilators with interaction between ventilators and combinations. as an example, for the adult circuit f , carestation, pb and servo u performed better than g and v . across the combinations, v had consistent negative (greater underestimation than average) slopes and servo u consistent positive (lower underestimation than average) slopes whilst the slope sign in the three others changed direction. biomarkers. yet, hla-dr expression on alveolar monocytes was lower in ards than in controls, consistent with sepsis-induced immunosuppression at the alveolar level. functional differences observed between ards and controls suggested a tolerogenic profile of ards monocytes. introduction: despite their recommendation in the prevention of ventilator-associated pneumonia, oral care is not still clearly standardized. it generally includes a time for oropharyngeal and tracheal suctions which can induce a cough reflex in non-paralyzed patients leading to the mobilization of the endotracheal tube and a consecutively increased risk of tracheal microaspirations. during the oral care procedure, drainage of subglottic secretions at particular times before oro-tracheal suctions is expected to reduce microaspiration. the aim of this study is to assess whether this "optimized" oral care including subglottic drainage can reduce microaspirations. this is an open prospective study, including icu ventilated patients. two procedures have been compared in two randomized cross-over consecutive periods of one day each ( oral cares a day)-on day, they received routine oral care (oral care (o) then tracheal suction (t)) and on the other day they received optimized oral care (subglottic suction (sg ) then o then sg then t). the amylase enzymatic activity has been measured in o, t, sg and sg suctions as a surrogate for the oropharyngeal content. if present in t suctions, it defines microaspiration. since the amylase o content is not similar from a patient to another, the primary outcome was the median amylaset o ratio after routine versus optimized oral care. results: after informed consent, patients were included. were analyzed due to incomplete follow-up in patients. patients (sapsii ± ) were ventilated since . ± . days for a majority of respiratory indications. at day , and patients received routine oral or optimized oral car respectively without significant baseline difference. a trend in the reduction (− %) of amylase t o median ratio was observed after optimized versus routine oral care ( . % [ . - vs. . % [ . - ], p = . . conclusion: despite protection of trachea by the cuff of the endotracheal tube, amylase has been found in tracheal suctions (which represents the last step of oral care). in this pilot study with a limited sample of patients, a trend in the reduction of microaspirations was observed when subglottic suctions were interleaved between oral and tracheal suctions. an increased sample power could show more significant results, but we cannot eliminate that this weak effect could also be due to the inability of subglottic suctions to prevent microaspiration of the oral content. the study has been founded by teleflex. introduction: although necessary, mechanical ventilation can lead to ventilator-induced lung injury (vili) even when using protective ventilation strategies that combine low tidal volume (vt)( ml kg predicted body weight) and plateau pressure (pplat) <= cmh . lower positive pressures and tidal volumes could enhance lung protection + the hla-dr and pd-l expressions were higher on alveolar than on blood monocytes in both ards patients and controls (figure) . yet, hla-dr expression on alveolar monocytes was higher in controls compared to ards patients (p = . ). circulating monocytes had a higher phagocytic activity than alveolar monocytes (p < . ), but no significant difference was observed between ards patients and controls. an lps challenge increased the phagocytic activity of monocytes in controls (p = . ) but not in ards monocytes (p = . ). tnf-α intracellular synthesis was increased after lps exposure in circulating and alveolar monocytes of controls (p < . ) but only tended to do so in ards (p = . ). conclusion: differences in the phenotype of alveolar and circulating monocytes were observed in ards but also in controls, suggesting a physiological lung blood gradient in the expression of these results: until , ten patients were included and analyzed for the study. there was a significant difference between the volumes recruited at the three peep levels (p = . ). the recruitment evaluated was not correlated with pao . there is a significant decrease in cardiac index and pam caused by the increase in peep. conclusion: preliminary results from our study suggest that the estimated recruited lung volume estimated by crf inview ® technology appears to be poorly correlated with measured pao . the hemodynamic repercussions observed should also be considered in order to propose an optimal strategy for the optimal adjustment of peep. were compliant with the re-evaluation. ( %) patients received carbapenems according to the recommendations. a compliant prescription had no impact on hospital or icu length of stay and no impact on duration of mechanical ventilation but seemed associated with increase mortality (p = . ). discussion: the high rate of compliant prescriptions can be explained by the broad indications of carbapenems in the icu, especially in patients with septic shock. the increase mortality of patients with a compliant prescription is probably due to the severity of the infections. in order to achieve % compliance, we could suggested regularly updating the knowledge of carbapenems prescriptions, collaborating with bacteriology and infectiology teams, and establishing a computerized or paper prescription with feedback control. conclusion: the prescription of carbapenems appears most often in accordance with the recommendations in this icu. however, there is a need for improvement. introduction: bacterial infections are frequent triggers for diabetic ketoacidosis and a significant increase in morbimortality is observed in case of delayed antibiotic treatment. however the unnecessary administration of antimicrobial therapy can also lead to bacterial resistance. early sepsis markers are thus particularly useful for patients admitted in icu for diabetic ketoacidosis. patients and methods: we retrospectively studied cases of patients admitted in icu at avicenne french universitary hospital for ketoacidosis defined by ph < . and glycemia > . mmol l. clinical and biological data were analyzed at admission (d ) and on day (d ). results: between and , among patients admitted for diabetic ketoacidosis, were included. twelve out of were infected ( urosepsis, pneumonia, others). demographic data and comorbidities did not significantly differ between the infected and non infected group (ig and nig). antibiotics were administered to patients- ( %) in the infected group versus ( . %) in the non infected group. on d , there was no difference for-ph, temperature, leukocytes, neutrophils-to-lymphocytes count ratio and pct (table ) . on d , temperature, leukocytes, neutrophils-to-lymphocytes count ratio and pct were significantly higher in the ig. in the ig, the biological markers did not vary between d and d , whereas in the nig, leukocytes (p < . ), pnn (p < . ) and neutrophils-to-lymphocytes count ratio (p < . ) significantly decreased. surprisingly average pct levels seem to be particularly high in the nig on do as well as on d . conclusion: at admission, pct as well as other usual markers do not appear to be useful to differentiate infected from non infected patients admitted for ketoacidosis. however, on day , two different patterns can be drawn and help detecting non-infected patients and thus reduce exposure to antibiotics. these results should be confirmed by a prospective study, including a larger number of patients. ventilator-associated events (vae), reflecting worsening oxygenation, are defined as a persistent and significant increase in fio or peep level after a period of stability on the ventilator. vae definition includes ventilator-associated conditions (vac), infection-related ventilatorassociated complications (ivac) and probable ventilator-associated pneumonia (pvap). the relevance of vae for ventilator-associated pneumonia (vap) is low. however, the correlation between the three vac, ivac, and pvap, and the onset of ventilator-associated low respiratory tract infection (valrti), including ventilator-associated tracheobronchitis (vat) and pneumonia (vap), has never been studied yet. we on clinical examination. gravity scores-apache ii and saps ii. for lumbar puncture data, there is the proteinuria, glycorrhaphy resuscitation measures-drug intake and intubationin multivariate analysis, the factors of pejorative evolution-the male sex presence of meningeal syndrome. high proteinorachia. taking vasoactive drugs. the saps ii score. conclusion: according to this work, many factors influence the prognosis of acute meningitis in our population such as severity general scores, hemodynamic state and initial lumbar puncture data. we will need more investigations and prospective multicentric study to have more discrimination parameters. introduction: the emergence of atb-resistant bacteria has become an important public health problem, particularly in resuscitation environments, surveillance and monitoring of atb consumption is essential to combat this threat ecologically and economically. the aim of this work was to evaluate the consumption of atb in surgical resuscitation, to establish the cost, and to list the risk factors for bacterial resistance. patients and methods: it is a retrospective analytical study spread over year, studying patients who have received antibiotic therapy, the data on the consumption of atb were collected from the patient's medical records, the delivered doses were converted into ddd, according to the who standards and the end result is expressed in ddd days of hospitalization. the statistical analysis was carried out by the spss software. results: in our study, the mean age was . ± . , with male predominance + sex ratio . , traumatic pathology is the most common reason for admission, pneumopathy was the most frequent infection. overall atb consumption was . ddd dh, dominated by the class of betalactamins (cephalosporins . ddd dh, carbapenemes . ddd dh), the direct cost of atbs rises to . million dirhams, these are accounting for a large part of the pharmaceutical budget of the ibn rochd university hospital. bacteria found in order of frequency were acinetobacter baummanii, beta-lactamaseproducing enterobacteria, s. aureus and p. aeruginosa. acinetobacter baumannii showed the highest resistance rate. several risk factors for bacterial resistance were studied, notably the correlation between the use of atb and the emergence of resistant strains, only piperacillintazobactam was associated with the emergence of resistant strains of eblse, as well as other factors that were retained as significantly related to bacterial resistance by multivariate analysis-duration of hospitalization and perfusion of albumin. discussion: despite the limited number of studies done on atb consumption, it seemed that our results were similar to other national and foreign studies, the consumption of atbs is increased in hospital giving rise to the appearance of many multi-resistant bacteria. conclusion: in conclusion, resistance to antibiotics is a serious threat to public health both nationally and globally. it is therefore crucial to implement measures to counter this phenomenon + this is only possible through the proper use of atbs and gaits to prevent nosocomial infections. introduction: ventilaor-associated pneumonia (vap), the leading cause of infection in resuscitation, is also the main respiratory complication in cranial trauma. the aim of this study is to determine the specific risk factors for the occurrence of vap in this type of patient in an intensive care unit. patients and methods: we performed a retrospective study in our intensive care unit for an -month period (january , june ). all patients admitted for cranial trauma were included in the study and ventilated more than h in intensive care. vap is defined as late as of the th day of occurrence. the quantitative and qualitative variables studied were recorded at admission and during hospitalization. a univariate and multivariate analysis using the fischer and mann-whitney tests was performed. p is said to be significant if it is < . . results: our study included traumatic brain injury in older adults, of whom ( %) had one or more episodes of vap during their resuscitation. late vap accounted for almost of the cases ( patients). four independent variables were significantly related to the occurrence of vap-advanced age (p = . ), glasgow score (gcs) at admission < (p = . ), diabetes (p = , ), and the use of proton pump inhibitors for the prevention of stress ulcers (p = . ). the duration of intubation ( ± vs. ± days) and on intensive care ( ± vs. ± days) are significantly longer in the case of vap. mortality was significantly higher in vap- versus % (p = . ). the majority of early vap were due to both strepococcus ppneumoniae and haemophilus influenzae. the ecology of late vap was dominated by klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumanii. conclusion: of the four independent risk factors found in our study, glycemic balance and rapid airway safety by orotracheal intubation in the case of initial gcs < represent the relevant prevention axes of vap in traumatic brain injury in older adults. unfortunately, it is accompanied by a significant increase in bacterial resistance to antibiotics, leading to an increase in morbidity and mortality in intensive care units. patients and methods: this is a retrospective study carried out in our intensive care unit, covering all patients hospitalized between january and june and having contracted a nosocomial urinary infection. patients whose hospital stay was less than h and those fig. agreement between vae and lrti diagnostic with a nosocomial urinary tract infection acquired in another service were excluded. results: the study of resistance of the germs responsible for nosocomial urinary tract infection showed that-escherichia-coli was resistant to third generation cephalosporins in % of cases, at imipenem in % of cases, and without resistance to ertapenem and amikacin. pseudomonas was resistant to ceftazidime in % of cases, to imipenem in % of cases and to amikacin in % of cases. acinetobacter baumannii was resistant to imipenem in % of cases and to amikacin in % of cases. enterococcus faecalis had no resistance to vancomycin and ampicillin. staphylococcus aureus was resistant to methicillin in % of cases and without any resistance to vancomycin. mortality directly associated with nosocomial urinary tract infection was %. the comparison with previous studies has shown a significant increase in the bacterial resistance responsible for nosocomial urinary tract infection, which is of interest in monitoring the ecology of intensive care units and the resistance profile as well as the improvement of the management of antibiotics. introduction: nosocomial enterococcus infections are a constant concern in intensive care units due to their increasing frequency and the emergence of resistant strains to vancomycin. the aim of our study was to compare outcome findings of patients with nosocomial enterococcus infections according to their sensibility to vancomycin, and then to investigate predictive factors of mortality. patients and methods: it was a retrospective descriptive study, including all hospitalized patients in intensive care, between january st, and april st, , with nosocomial enterococcus infections. we recorded demographic and clinical findings, severity scores igs ii, apache ii, initial sofa and sofa at the time of infection, microbiological, therapeutic and outcome data. patients infected with vancomycin-susceptible enterococcus (vse) were compared to those having vancomycin-resistant enterococcus (vre) + then we searched for independent risk factors for vre. finally, a multivariate logistic regression was conducted to investigate independent predictive mortality factors. results: during the study period ( years and months), patients presented a nosocomial enterococcus infection with a median age of years [ - ] and a sex-ratio of . . at admission, patients ( . %) had respiratory distress. the median scores of igs ii, apache ii, initial sofa and sofa at the time of infection were respectively + + and . the infection sites were-urinary infection (n = , . %), bacteremia (n = , . %) and central line associated infection (n = , . %). patients had a vre nosocomial infections and vse. a septic shock complicated enterococcus infection in cases including cases of vre and cases of vse (p = . ). vre nosocomial infections were significantly related to arterial (p = . ) and venous (p = . ) femoral catheterization, to a duration of venous femoral catheterization > days (p = . ) and to e. faecium species (p < - ). no independent risk factor of vre was found. the median duration of hospitalization was days and the overall mortality rate was . %. multivariate analysis identified independent predictive factors of attributable mortality-patients in coma (or . + ic % = . - . + p = . ) and the occurrence of septic shock (or . + ic % = . - . + p = . ). conclusion: attributable mortality to nosocomial enterococcus infections was high and independent of the susceptibility of the strain to vancomycin. mortality was independently associated to septic schock occurrence and neurologic dysfonction. introduction: ventilator-associated pneumonia (vap) is defined by a lung infection contracted h after the putting under mechanically assisted breathing. risk factors predisposing to the development of vap among mechanically ventilated patients are many. some are related to the patient as age, history of copd, presence of an altered state of consciousness + others are related to care providing. patients and methods: a prospective nested case control study was conducted from marsh through april . all icu patients mechanically ventilated for more than h with endotracheal intubation or tracheostomy were included. cases of community-acquired pneumonia, non-mechanical ventilated hospital-acquired pneumonia, end-life patients and those aged less than years were excluded. the included patients with vap and those without vap were matched based on the age, the severity score and the comorbidities. for all patients included, preventive measures as assessed by the recent guidelines for preventing vap were applied after an education period of all medical and paramedical staff of the icu. the collected data are-age, comorbidities, admission severity scores, time to onset of vap, prior antibiotic therapy at the onset of vap, need for tracheostomy, duration of mechanical ventilation, length of stay in icu and become. results: during the study period, patients were mechanically ventilated. vap was observed in % of cases. vap was observed in cases with an incidence of % and incidence density of per patient-days of mechanical ventilation (mv). in univariate analysis, significant difference was found between the group with vap and the group without vap regarding admission for poly trauma, acute respiratory failure, the concept of prior antibiotic therapy, the need tracheostomy, the number of days alive without antibiotics and without mv, the duration of mechanical ventilation, length of stay and mortality. multivariate analysis showed that prior antibiotic therapy and the use of tracheotomy were independent factors for developing vap. prolonged duration of mechanical ventilation was an independent predictor of mortality in multivariate analysis with or . + % [ . to . ], p = . . the occurrence of vap was not an independent predictor to mortality. conclusion: the incidence of vap found in our study is similar to that found in the literature. an active strategy of rationalizing the prescription of antibiotics in intensive care units and a well-defined protocol of weaning from mechanical ventilation may reduce the incidence of vap and over-all morbidity and mortality. introduction: hyperoxemia is common in critically ill patients. hyperoxic acute lung injury (hali), reduced bacterial clearance, atelectasis and higher mortality rates were reported in mechanically ventilated patients with hyperoxemia. the aim of our study was to determine the relationship between hyperoxemia and mortality in patients with ventilator-associated pneumonia (vap). this retrospective observational single center study was performed in a -bed mixed intensive care unit (icu) during a -year period, from january to january . all patients with vap were included. vap was defined using clinical, radiological and quantitative microbiological criteria. hyperoxemia was defined as peripheral capillary oxygen saturation-spo ≥ %. spo was hourly collected in all study patients during the whole period of mechanical ventilation. the daily percentage of time spent with hyperoxemia was calculated as the number of hours with hyperoxemia divided by . results: among the patients receiving invasive mechanical ventilation (mv) > h during the study period, the incidence rate of vap was . vap per ventilator-days. patients developed vap and were all included in this study. ( %) vap patients died in the icu. the mean daily time spent with hyperoxemia was %. no significant difference was found in mean percentage of time spent with hyperoxemia between survivors and nonsurvivors at icu admission, before, after or at the vap diagnosis. age, and sequential organ dysfunction assessment (sofa) at the day of vap occurrence were independently associated with icu mortality (or . [ . - . ] per year, p = . + . [ . - . ] per point, p = . + respectively). no significant impact was found of time spent with hyperoxemia before vap occurrence, on mv free days, or icu length of stay (fig. ). discussion: several potential explanations could be provided for the absence of negative impact on mortality of hyperoxemia. first, the definition used for hyperoxemia could be debated, as no consensus exists. however, the definition used in our study was rather stringent and the mean daily time spent with hyperoxemia was in line with that reported by studies. second, the impact of hyperoxemia on mortality could have been confounded by a large number of patients included with pulmonary lesions at admission. third, the number of included patients was small. conclusion: our study found no significant impact of hyperoxemia at icu admission, or during icu stay, on icu mortality in vap patient. results: patients collected during this period. distal protected specimens were performed in patients suspected of vap. the diagnosis of this infection was made. in of them with other diagnostic criteria ( %) which represents an incidence density of . per , days. % of pavm are due to gram negative bacilli. the first germ involved in our series and pseudomonas ( %) followed by klebsielles ( %) followed by acintobacter baumanii ( %) enterobacteries representing the rest. % lung infection with gram-positive cocci (principally sensitive methicillin) pseudomonas was imipenem resistant in . %, baumanii was imipenem resistant in %. the resistance profile of the recovered germs (baumanii and pseudomonas) encourages the utmost rigor in the management of these patients, prevention is better attitude to adopt. introduction: the ventilator associated pneumonia (vap) appear in the second rank of the infections acquired in hospital after the urinary infections. the diagnosis is based on a beam of clinical, biological, radiological and bacteriological arguments. this work consisted of an epidemiologic analysis of the vap and aimed at evaluating of it the frequency, the risk factors, the antibioresistance of the isolated bacteria and the mortality factors. patients and methods: this retrospective study related to patients hospitalized in icu during a period of years from january to december . the study included all patients over years and ventilated more than h and developing vap. results: bgn predominant and represent . % of identified germs, the acinetobacter baumanni leads with . %, followed by klebsiella pneumonia ( . %), followed by pseudomonas aeruginosa ( . %), followed by e. coli ( . %), followed by enterobacter cloacae ( . %) and citrobacter frendi ( . %). the cocci gram positive (cgp) constitue . % of isolated germs of witch . % staphylococcus aureus, . % of non aureus staphylococci, . % streptococcus sp. the polymicrobism was found in % cases. the isolated germs were multiresistants. in this study, we find a very high mortality and a major additional morbidity of the np by prolongation of hospitalization, of mechanical ventilation and a major additional cost.conclusion: it appears in the light of this work that a strategy of prevention based on the strict application of hygiene measurements, the maintenance of the material of ventilation and the respect of care procedures prove to be urgent in our context. introduction: burns induce modification of distribution volume, increased clearance of drugs and decrease of protein binding. amikacin pharmacokinetics (pk) was altered with subthera-peutic serum concentrations. the aim of our study was to assess the pk of amikacin in burns after a loading dose given once a day according to this equation-dose(mg kg) = *pi( * , *dp ) + ( * , * dp ). threshold for therapeutic efficacy was a ratio of ≥ between the concentration achieved h after beginning the infusion (c peak) and the minimal inhibitory concentration (mic) of the isolated pathogen. patients and methods: this study was conducted in burn center in tunis. patients with documented and or suspected infections were included. were excluded pregnant women and patients with renal failure. enrolled patients received amikacin at a loading dose in h infusion. blood samples for pk analysis were assessed during days (total duration of amikacin)-immediately after the end of the first infusion (t ) and min after (t ) at day . for the nd, rd, th and th day, blood samples were taken before the infusion (t ), at the end (t ) and min after the end of it (t ). results: burned patients were included. the mean age was ± years with a body weight of ± kg. the mean dose of amikacin was mg kg day [ - mg kg day]. a peak between and μg/ml was reached in % of cases, corresponding to times the mic, break-points for enterobactericeae and pseudomonas aeuroginosa. total volume of distribution was . l kg ( . - . ) l kg, half-life time (t ) was . h [ . - h] and the amikacin clearance was . l h. a correlation was found between cpeak at day and cpeak at day (r = . ). conclusion: our study shows that an early achievement of an optimal cpeak mic ratio of amikacin was reached in half of cases with a correlation between cpeak in the beginning and at the end of treatment. so, initial cpeak was useful tu adjuste amk therapy in burns and predicts treatment efficacy. *pi-ideal weight + dp -admission weight-ideal weight + dp -actuel weight-admission weight. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - opyo i authors: kappel, coralea; piticaru, joshua; jones, graham; goucher, george; cheon, paul; fischer, marc; rochwerg, bram title: a case of possible fournier’s gangrene associated with proning in covid- ards date: - - journal: can j anaesth doi: . /s - - - sha: doc_id: cord_uid: opyo i nan severe acute respiratory syndrome coronavirus- (sars-cov- ), the virus responsible for the coronavirus disease (covid- ) pandemic, has contributed to significant morbidity and mortality, and presents with a myriad of clinical manifestations. we report a case of a yr old obese male with acute respiratory distress syndrome (ards) secondary to covid- , who went on to develop fournier's gangrene following prolonged and repeated ventilation in prone position (proning). the patient was transferred to our intensive care unit (icu) from a community hospital with pneumonia suspected to be covid- after presenting to the emergency department with fever, dyspnea, dry cough, and diarrhea for several days. his wife had known covid- exposure during a recent international flight. the patient was previously healthy, a lifetime-non-smoker, with a body mass index of . kgÁm - . he initially required % oxygen via high-flow nasal cannula. on day of admission, his nasopharyngeal swab tested positive for sars-cov- , his respiratory status decompensated, he failed a trial of awake proning, and he required intubation for worsening hypoxia. serial chest radiographs showed worsening bilateral patchy airspace opacities consistent with ards. despite optimized positive end-expiratory pressure ( cmh o) and lungprotective ventilation, the patient had ongoing hypoxia with pao /f i o ratios less than , and by day of icu admission was started on a - hrÁday - proning protocol. he required proning for consecutive days for a cumulative exposure of hr. on day of icu admission, he had worsening leukocytosis ( . Ál - ) and severe scrotal edema with slight discolouration. the following day, examination revealed multiple areas of necrotic tissue without crepitus around the glans of the penis, the superior scrotum, and at the base of the penis. intravenous vancomycin and piperacillin/tazobactam were initiated, and the urology service was consulted who made a diagnosis of fournier's gangrene. the patient went to the operating room for an urgent penile and scrotal debridement. intraoperative examination revealed necrosis at the base of the penis, more prominent at the glans penis and a small area of necrosis at the superior scrotum penoscrotal junction. wound cultures initially revealed mixed aerobic organisms on gram stain, although final cultures were negative. the infectious disease team was consulted, and the patient was treated with a nine-day course of antibiotics without further surgical intervention. at the time of writing, he has successfully been liberated from the ventilator with no further urologic concerns. there are numerous well-described complications associated with proning in ards, especially regarding pressure ulceration of the eyes and face. measures such as frequent head repositioning and protocolized turns are used to avoid these complications. interestingly, fournier's gangrene has not been described previously in association with ards or covid- . we hypothesize that this patient had multiple risk factors for this presentation, including obesity, proning (associated with prolonged pressure to the genitals), and critical illness. the prothrombotic and inflammatory nature of covid- , may have also contributed to tissue breakdown and infection. it is also possible this necrosis was due to a macrovascular thromboembolic event. given the risks faced by healthcare workers treating critically ill patients with covid- , they may be tempted to perform limited, focused, or less frequent physical examinations. nevertheless, given the prolonged duration of ventilation required by most covid- patients and the risk of both common and unique complications due to proning (as highlighted by this case), clinicians ought to be increasingly vigilant with monitoring. a prospective survey of early -h prone positioning effects in patients with acute respiratory distress syndrome clinical characteristics of deceased patients with coronavirus disease , retrospective study clinical characteristics of coronavirus disease in china disclosures none. editorial responsibility this submission was handled by dr. gregory l. bryson, deputy editor-in-chief, canadian journal of anesthesia. key: cord- -u gm kyh authors: baksh, mizba; ravat, virendrasinh; zaidi, annam; patel, rikinkumar s title: a systematic review of cases of acute respiratory distress syndrome in the coronavirus disease pandemic date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: u gm kyh the outbreak of coronavirus disease (covid- ) was declared a global pandemic after it spread to countries and has the highest total number of cases worldwide. about % of covid- infections are mild or asymptomatic and never require hospitalization but about % of patients become critically ill and develop acute respiratory distress syndrome (ards). the widely used management for ards in covid- has been in line with the standard approach, but the need to adjust the treatment protocols has been questioned based on the reports of higher mortality risk among those requiring mechanical ventilation. treatment options for this widespread disease are limited and there are no definitive therapies or vaccines until now. although some antimalarial and antiviral drugs may prove effective against severe acute respiratory syndrome coronavirus (sars-cov- ), their safety and efficacy are still under clinical trials. we conducted a systematic review of case reports on ards in sars-cov- infection to summarize the clinical presentation, laboratory and chest imaging findings, management protocols, and outcome of ards in covid- -positive patients. we need more data and established studies for the effective management of the novel sars-cov- and to reduce mortality in high-risk patients. an outbreak of a cluster of cases of pneumonia with an unknown cause was first reported in late december in wuhan in the hubei province of china. this respiratory illness during the coronavirus disease (covid- ) is caused by a novel severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . covid- was declared a global pandemic on january , , after it spread to countries, areas, or territories including the us, where the first case was reported on january , [ , ] . community transmission of covid- in the us was first reported in february that spread widely later on through close person-to-person contact via respiratory droplets, and through the infected surface to a person's eyes, nose, or mouth [ ] . as a result, active surveillance, contact tracing, quarantine, and strict social distancing were implemented worldwide to contain the transmission of the virus [ ] . the overall cumulative covid- incidence in the us was . cases per , population on april [ ] . sars-cov- is a positive single-strand enveloped ribonucleic acid (rna) virus that contains viral membrane e type glycoprotein that binds and enters sensitive cellular receptors by endophagocytosis in organ systems including epithelial cells in the respiratory tract [ ] . the novel beta coronavirus strain that causes covid- is in the same subgenus as the sars virus of the outbreak [ ] . there is only sporadic information on the pathophysiology of the disease at an early and evolving stage of the pandemic outbreak. in previous animal models and human studies on sars pathology, it is mentioned that the sars-cov protein binding to angiotensin-converting enzyme (ace ) could lead to acute lung injury through ace downregulation and angiotensin (at) a receptor stimulation [ , ] . animal studies found that elastase, a major protease induced in lung inflammation, might also be involved in sars pathogenesis [ , ] . clinical pathology of autopsy cases of sars helped in the significant understanding of the nature of the disease. the overall pathological changes in the lungs were of diffuse alveolar damage-causing ards [ ] . microscopic examination of pulmonary lesions revealed extensive bilateral consolidation, hemorrhagic infarction, desquamative pulmonary alveolitis and bronchitis, hyaline membrane formation, and viral inclusion bodies in alveolar epithelial cells [ ] . imaging findings range from no abnormalities to bilateral lung consolidation on chest radiographs or peripheral ground-glass opacities on ct scan [ ] . the included four case reports were published between february and april ; two of them were from china, one was from singapore, and one was from the us [ ] [ ] [ ] [ ] . a total of six patients with covid- were studied for the development of critical illness and/or ards. patients were adults with an age range of to years. the most common initial presentation of covid infection was a history of two to seven days of cough with or without fever, chills, dyspnea, and fatigue [ ] [ ] [ ] [ ] . one of the patients from iran was detected incidentally on a chest ct scan when he presented to the emergency room for follow-up of a two-weekold rib fracture from a fall with pain unresponsive to over-the-counter painkillers [ ] . the course and development of critical illness or ards were similar in most cases with the patient's condition deteriorating within - hours of initial presentation. most of them developed dyspnea and severe hypoxemia with declining oxygen saturation (sao ) during the second week of illness requiring oxygen supplementation or assisted ventilation. the patient who was diagnosed accidentally at early stages of infection was immediately treated with oseltamivir mg twice daily (bid) and hydroxychloroquine mg stat, based on the iranian interim guideline for "clinical management of covid- ", though the patient developed fever and dyspnea three days later [ ] . management was switched to a focused antiviral treatment regimen with oseltamivir mg and lopinavir/ritonavir / mg bid and the patient gradually improved attaining normal oxygen saturation without the need of intubation or supplemental oxygen [ ] . all six patients were tested positive for sars-cov- using the reverse rt-pcr assay of a respiratory specimen. in two of the six cases, a detailed laboratory investigation revealed lymphopenia and elevated c-reactive protein [ , ] . in one of the cases, flow cytometric analysis showed decreased peripheral cluster of differentiation (cd) cells and cd cells [ ] . liver and renal function tests showed an elevated aspartate transaminase/alanine transaminase ratio and lactate dehydrogenase levels, and lung biopsy showed bilateral ards [ , ] . three cases of critically ill, mechanically ventilated patients with ards required continuous monitoring of d-dimer and fibrinogen levels since it involved treatment with a fibrinolytic agent: tissue plasminogen activator (tpa) [ ] . chest x-ray and chest ct scan on admission showed predominant bi-basilar ground-glass opacities in all six patients [ ] [ ] [ ] [ ] . treatment modalities and clinical management options for covid- -induced ards were variable among these patients but mainly supportive and similar to standard ards management. infection control measures that included patient placement in isolation wards and standard contact and airborne precautions were pre-requisite. oxygen supplementation was a standard protocol for most patients who developed dyspnea and hypoxemia. antiviral therapy was tried in three of the six cases mentioned either as lopinavir/ritonavir mg bid or in combination with oseltamivir as / mg bid [ ] [ ] [ ] . one patient died of hypoxemia and sudden cardiac arrest (patient was on the do-not-resuscitate code status), but the other two showed marked improvement after receiving treatment [ ] [ ] [ ] . the other medication commonly used (in four of six cases) was hydroxychloroquine stat mg, in combination with either azithromycin or oseltamivir ( mg) [ , ] . empiric broad-spectrum antibiotics such as moxifloxacin were used in two mechanically ventilated patients to prevent secondary infection; however, one patient developed ventilator-associated pneumonia that necessitated the use of culture-guided antibiotics [ , ] . corticosteroids, such as intravenous methylprednisone, were administered in one patient to decrease lung inflammation [ ] . the study on tpa treatment for covid- -associated ards, which involved measuring the partial pressure of oxygen (pao )/fraction of inspired oxygen (fio ) ratio for oxygenation status, reported one out of three cases had % improvement post-tpa but the effect was transient [ ] . this case series also mentions the use of anticoagulants like heparin with tpa infusion to decrease the risk of bleeding [ ] . there are few in vivo studies on the use of plasminogen activators for the prevention of acute lung injury in animal studies, and so more trials are required to determine the optimal dosing and therapeutic effects of tpa [ , ] . vasopressors such as norepinephrine, phenylephrine, and vasopressin have been proved effective for hemodynamic support, sedation, and chemical paralysis [ ] [ ] [ ] . few studies have summarized the use of non-ventilatory interventions as rescue therapy in non-compliant patients with refractory hypoxemia [ , ] . a descriptive summary of all case reports that met our inclusion criteria is shown in table . demographics initial about % of patients with covid- have mild disease and never require hospitalization, and about % of patients become critically ill, with the risk of ards being highest in icu patients [ , ] . there could be a high risk of mortality (about two-thirds) in ventilated patients according to new data from the united kingdom's intensive care national audit and research center (icnarc), but this was unclear [ ] . other less frequent complications include acute cardiac injury, acute kidney injury, and septic shock, followed by multi-organ failure [ ] . of the six patients in our review, two died from complications within one to two weeks of clinical presentation [ , ] . the reported causes of death included cardiac arrest even after receiving invasive ventilation and chest compression and the other patient in wang et al.'s study died due to multi-organ failure with secondary bacterial infection [ , ] . the other four patients showed a good prognosis with no inpatient death. antiretroviral protease inhibitors, such as lopinavir/ritonavir, and antimalarials like hydroxychloroquine, for which us food and drug administration (fda) has issued an emergency use authorization (eua), were used in all studies but randomized clinical trials (rcts) to assess their efficacy and safety are still ongoing [ ] . sanders et al. suggested that remdesivir can be a promising therapy for covid- as it has already shown broad antiviral activity in both in vitro and in vivo studies against related viruses: middle east respiratory syndrome (mers)-cov and sars-cov [ ] . oseltamivir has no role in covid- treatment and corticosteroids that have been widely used in many patients in china may potentially prolong the course of illness by causing delayed viral clearance [ ] . antimalarial drugs like chloroquine or hydroxychloroquine monotherapy or combination therapy with azithromycin may prove effective, especially in severe disease, but these benefits need to be determined with rcts that are already underway [ , ] . so treatment options are limited and there are no definitive therapies or vaccines until now and additional studies are needed to evaluate their effectiveness [ ] . according to previous reports from china and new icnarc findings from england, mortality was higher among those requiring mechanical ventilation than those who did not and appears higher than that for patients treated in icu for other types of viral pneumonia [ , ] . the widely used management for ards in covid- has been in lines with the standard approach, but treatment protocols need to be adjusted according to the characteristics of disease pathophysiology, making more gradual positive endexpiratory pressure changes for the atypical type of ards seen with covid- [ ] . our systematic review of published cases of ards in covid- -positive patients will help healthcare professionals to clearly understand and implement updated treatment strategies and confront the covid- pandemic and its medical consequences. nonetheless, we need more rcts and treatment guidelines for developing effective management of the novel sars-cov- and thus improve survival and reduce mortality in high-risk and critical patients. in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. novel coronavirus ( -ncov) situation report - covid- ) geographic differences in covid- cases, deaths, and incidence -united states covidview: a weekly surveillance summary of u.s. covid- activity interim clinical guidance for management of patients with confirmed coronavirus disease (covid- ) tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series pathological findings of covid- associated with acute respiratory distress syndrome rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from covid- infection lung involvement found on chest ct scan in a pre-symptomatic person with sars-cov- infection: a case report the clinical pathology of severe acute respiratory syndrome (sars): a report from genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding studies of severe acute respiratory syndrome coronavirus pathology in human cases and animal models covid- -considerations for the paediatric rheumatologist meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury prevention of adult respiratory distress syndrome with plasminogen activator in pigs severe hypoxemic respiratory failure salvage therapies for refractory hypoxemia in ards clinical course and mortality risk of severe covid- higher mortality rate in ventilated covid- patients in large sample clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis information for clinicians on investigational therapeutics for patients with covid- pharmacologic treatments for coronavirus disease (covid- ): a review brief review on covid- : the pandemic caused by sars-cov- . cureus. clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study key: cord- - rqnu bu authors: nan title: th international symposium on intensive care and emergency medicine: brussels, belgium. - march date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: rqnu bu nan the relationship between systemic glycocalyx degradation markers and regional glycocalyx thickness in non-septic critically ill patients is unclear. conjunctival sidestream dark fieldimaging for the purpose of glycocalyx thickness estimation has never been performed. we aimed to investigate whether changes in glycocalyx thickness in conjunctival and sublingual mucosa are associated with global glycocalyx shedding markers. methods: in this single-centre prospective observational study, using techniques for direct in-vivo observation of the microcirculation, we performed a single measurement of glycocalyx thickness in both ocular conjunctiva and sublingual mucosa in mixed cardio surgical (n= ) and neurocritical patients (n= ) and compared these data with age-matched healthy controls (n= ). in addition we measured systemic syndecan- levels results: in the sublingual and conjunctival region we observed a significant increase of the perfused boundary region (pbr) in both neuro critical and cardiac surgical icu patients, compared to controls ( . ], p< , ). we detected a weak correlation between syndecan- and sublingual pbr(r= . , p= . ) but no correlations between global glycocalyx damage markers and conjuctival glycocalyx thickness. conclusions: conjunctival glycocalyx thickness evaluation using sdf videomicroscopy is suitable and is impaired in non-septic icu patients but only measurements in sublingual mucosa are correlating with systemic glycocalyx shedding markers. global glycocalyx damage is more severe in cardiac comparing to neuro critical patients. introduction: endothelial dysfunction plays a major role in the sepsis related organ dysfunction, and is featured by vascular leakage. amp-activated protein kinase (ampk) is known to regulate actin cytoskeleton organization and interendothelial junctions (iejs), contributing to endothelial barrier integrity. we have already demonstrated its role in defence against sepsis induced hyperpermeability [ ] , but the underlying mechanisms remain unknown. this project aims to identify molecular targets involved in the beneficial action of ampk against endothelial barrier dysfunction. methods: experiments have been performed in human microvascular dermal endothelial cells. α ampk activity has been modulated via the use of a specific sirna or treatment by two pharmacological ampk activators (aicar, ). we have investigated the effect of this modulation on the expression/phosphorylation of connexin (cx ) and heat shock protein (hsp ), two proteins playing a key role in maintenance of iejs and actin dynamics respectively. results: we show that α ampk is required to sustain the level of cx expression as it was drastically reduced in cells transfected with a sirna targeting specifically α ampk. regarding hsp , its expression level was not affected by α ampk deletion. however, both ampk activators increased its phosphorylation on ser , in a α ampkdependent manner, while they had no effect on cx . our results also reveal that hsp phosphorylation concurred with the appearance of actin stress fibers at the periphery of cells, suggesting a beneficial role for phsp as well as f-actin stress fibers in vascular barrier function through reinforcing the endothelial tethering. conclusions: our work identifies the regulation of cx expression and hsp phosphorylation as potential protective responses underlying the beneficial action of ampk against endothelial barrier dysfunction. ampk could consequently represent a new therapeutic target during sepsis. introduction: sepsis induced cardiomyopathy (sic) is a serious condition during sepsis with a mortality rate up to % ( ) . sic is clinically manifested with left ventricle impaired contractility ( ) . melusin is a muscle-specific protein involved in sustaining cardiomyocyte survival thorough the activation of akt signaling pathways ( ) . pi k-akt signaling pathway plays a pivotal role in regulating calcium channel activity ( ) . we hypothesized that melusin overexpression could exert a protective effect on cardiac function during septic injury. methods: animals were treated with an intraperitoneal injection of lipopolysaccharide (lps) at mg/kg. sv strain knockout mice (ko) for melusin gene and fvb strain with cardiac-specific overexpression (ov) of melusin were compared. each group was studied together with a control group (wt). hemocardiac parameters were studied at hour and hours through echocardiography. another cohort of animals was sacrificed hours after mg/kg lps treatment and cardiac tissues and blood sample were harvested for wb analysis to quantify the expression of akt, p-akt and cacna c and elisa analysis for troponin levels. results: sv wt, ko melusin and fvb wt mice groups, fractional shortening (fs) was significantly impaired after lps challenge and was associated with compensatory tachycardia (fig. ) . fvb ov mice group didn't show decrease in fs. consistent with the increased akt phosphorylation observed in ov mice, the expression of cacna c was also significantly higher both at basal levels and after lps treatment in ov mice compared to wt mice (fig. ) . troponin levels didn't differ between mice groups after lps treatment conclusion: melusin has protective role in lps induced cardiomyopathy, likely through akt phosphorylation controlling the cacna c protein density. introduction: liver dysfunction is frequent in sepsis, but its pathophysiology remains incompletely understood. since altered liver function has also been described in icu patients without sepsis [ , ] , the influence of sepsis may be overestimated. we hypothesized that sedation and prolonged mechanical ventilation after abdominal surgery is associated with impaired liver function independent of sepsis. methods: sedated and mechanically ventilated pigs underwent abdominal surgery for regional hemodynamic monitoring and were subsequently randomized to fecal peritonitis and controls, respectively (n= , each), followed by h observation. indocyanine green (icg) retention rate minutes after injection of . mg/kg icg (icg r ) was determined at baseline, and , and h after sepsis induction (si), and at the same time points in controls. concurrent with icg r , plasma volume, total hepatic perfusion (ultrasound transit time), and bilirubin and liver enzymes were measured. anova for non-parametric repeated measurements was performed in both groups separately. results: icg r increased over time without significant differences between groups (table ). there was a parallel increase in bilirubin in septic but not control animals. the other measured parameters were similar in both groups at the end of the experiment. conclusion: liver function was impaired under sedation and prolonged mechanical ventilation after abdominal surgery, even in animals without sepsis. the underlying reasons should be further explored. introduction: previous work has shown the cytoprotective properties of antithrombin-affinity depleted heparin (aadh), by neutralization of cytotoxic extracellular histones [ ] , major mediators of death in sepsis [ , ] . aadh was produced from clinical grade heparin, resulting in preparations that have lost > , % of their anticoagulant activity. to gain insight into the mechanisms and the basic pharmacological aspects of aadh protective properties, we performed a systematic analysis of how aadh is tolerated in mice and ascertained its effects in three different in vivo models of inflammation and infection. methods: dose ranging studies, short term and medium term, were performed in c bl/ mice. the effects of i.v. administration of extracellular histones in the presence or absence of aadh were assessed in mice. we further analysed the effect of aadh in models of concanavalin a-and mrsa-mediated lethality. in all studies we assessed clinical signs, lab parameters and histology. results: aadh was well tolerated in both short term and intermediate term (till days) experiments in mice, in the absence of any signs of tissue bleeding. aadh was able to revert the cytotoxic properties of i.v. administered histones. in a concanavalin a mediated model of sterile inflammation, we confirmed that aadh has protective properties that counteract the cytotoxic effects of extracellular histones. in an in vivo lethal mrsa model, for the first time, aadh was shown to induce a survivalbenefit. conclusions: we conclude that aadh contributes to the overall increased survival by means of neutralization of extracellular histones and represents a promising product for further development into a drug for the treatment of inflammatory diseases and sepsis. introduction: urokinase (uk) and tissue plasminogen activator (tpa) mediate thrombolytic actions by activating endogenous plasminogen. thrombomodulin (tm) complexes with thrombin to activate protein c and thrombin activatable fibrinolysis inhibitor (tafi). activated protein c (apc) modulates coagulation by digesting factors v and viii and activates fibrinolysis by decreasing pai- functionality. methods: the purpose of this study is to compare the effects of rtm and apc on urokinase and tpa mediated thrombolysis utilizing thromboelastography. results: native whole blood was activated using a diluted intrinsic activator (aptt reagent, triniclot). the modulation of thrombolysis by tpa and uk (abbott, chicago, usa) was studied by supplementing these agents to whole blood and monitoring teg profiles. apc (haematologic technologies, vt, usa) and rtm (asahi kasai pharma, tokyo, japan) were supplemented to the activated blood at . - . ug/ml. the modulation of tpa and uk induced thrombolysis by apc and rtm was studied in terms of thromboelastograph patterns. the effect of both apc and rtm on plasma based systems supplemented with tpa was also investigated. patients treated with antibiotic therapy were eligible for inclusion. the plausibility of infection (definite, probable, possible, none) was determined based on the centers for diseases control (cdc) criteria. patients with sepsis (definite/probable/possible infection and a sofa score increase of >= ) were screened for death within days and secondary infections h to days after icu admission, using the cdc criteria. hla-dra and cd mrna expressions were determined by reverse transcription quantitative pcr. results: among icu admissions, a blood sample for rna analysis was collected in cases. two hundred fifty-seven patients met the inclusion criteria and provided written informed consent. sepsis was noted in patients. the sepsis patients experienced death in cases ( %), secondary infection in cases ( %), and death and/or secondary infection in cases ( %). table shows the results of hla-dra and cd expression related to death and secondary infections. conclusions: the mrna expression of hla-dra on icu admission was significantly decreased in patients with sepsis who died or contracted secondary infections within days. cd expression was not significantly decreased in patients with negative outcome. introduction: acid-base disturbances are common in patients with infection admitted to the intensive care unit (icu). more attention is given to hyperlactatemia in this patient population as a prognostic factor, although other acid-base disturbances may also have an impact on patient outcomes. our objective is to describe the acid-base profile of this patient population and determine the association between different acid-base abnormalities and icu mortality. methods: retrospective cohort of patients admitted with infection to an intensive care unit. patients were stratified according to ph (< . ; . - . ; > . ) and, then, according to the standard base excess (sbe) (< - ; - -+ ; > + ). in each of these strata and the whole population, the proportions of acid-base disturbances were quantified during the first hours of icu admission. to assess the association between acid-base disturbances and outcome, a logistic regression model was fit, adjusting for age, sex and saps score. results: patients were analysed. ( %) patients were acidemic and ( %) presented with a normal ph. metabolic acidosis (as assessed by sbe) was observed in all subgroups, regardless of ph levels (ph < ). lactic acidosis was observed in % of the whole population; sig (strong ion gap) acidosis, in %; sid (hyperchloremic) acidosis, in %; metabolic alkalosis, in %; and respiratory acidosis, in % of the patients. introduction: sepsis-induced brain dysfunction has been neglected until recently due to the absence of specific clinical or biological markers. there is increasing evidence that sepsis may pose substantial risks for long term cognitive impairment. methods: to find out clinical and inflammatory factors associated with acute sepsis-induced brain dysfunction (sibd) serum levels of cytokines, complement breakdown products and neurodegeneration markers were measured by elisa in sera of sibd patients and healthy controls. association between these biological markers and cognitive test results was investigated. results: sibd patients showed significantly increased il- , il- , il- and c d levels and decreased tnf-α, il- , c a and ic b levels than healthy controls. no significant alteration was observed in neuronal loss and neurodegeneration marker (neuron specific enolase (nse), amyloid β, tau) levels. increased il- β, il- , il- , il- , tnf-α and decreased c d, c a and ic b levels were associated with septic shock, coma and mortality. transient mild cognitive impairment was observed in of patients who underwent neuropsychological assessment. cognitive dysfunction and neuronal loss were associated with increased duration of septic shock and delirium but not baseline serum levels of inflammation and neurodegeneration markers. conclusions: increased cytokine levels, decreased complement activity and increased neuronal loss are indicators of poor prognosis and adverse events in sibd. cognitive dysfunction and neuronal destruction in sibd do not seem to be associated with systemic inflammation factors and alzheimer disease-type neurodegeneration but rather with increased duration of neuronal dysfunction and enhanced exposure of the brain to sepsisinducing pathogens. introduction: high levels of some aromatic microbial metabolites (amm) in serum are related to the severity and mortality of critically ill patients [ ] . several studies have discussed the imbalance and loss of the diversity of gut microbiota but there are practically no data on the gut microbial metabolites in critical conditions, only a little -in healthy people [ , ] . the aim of this work is to analyze the connection between serum and fecal levels of amm in icu patients. methods: simultaneously serum and fecal samples (sfs) from icu patients with nosocomial pneumonia (group i), sfs from icu neurorehabilitation patients (group ii) and sfs from healthy people were taken for gc/ms analyses. the following amm were measured: phenylpropionic (phpa), phenyllactic (phla), p-hydroxybenzoic (p-hba), p-hydroxyphenyllactic (p-hphla), p-hydroxyphenylacetic (hphaa), p-hydroxyphenylpropionic (p-hphpa) and homovanillic (hva) acids. data were presented as medians with interquartile range (ir, - %) using statistica . results: the sum of the level of most relevant metabolites ( amm) -phla, p-hphla, p-hphaa, and hva -in serum samples from group i and group ii were equal to . ( . - . ) μ m and . ( . - . ) μ m, respectively, and were higher than in healthy people - . ( . - . ) μ m (p< . ). we suppose the presence of the correlation of amm profile in blood and intestine. particularly, sfs of healthy people are characterized by the prevalence of phpa; amm are not detected in feces of non-survivors but only hva dominates in their serum in the absence of other (fig. ) . conclusions: the amm profiles in gut and serum are interrelated; amm in serum probably reflect the violation and loss of biodiversity of the gut microbiota in critically ill patients. introduction: since nitrogen oxide (no) is an essential component of the immune system, the dynamics of plasma no concentration was studied in order to predict the development of sepsis [ , ] . methods: with the permission of the ethics committee included the full-term newborns with respiratory diseases on a ventilator, retrospectively divided into two groups (i, n= -sepsis - days; ii, n= without sepsis), at , - , days was studied by elisa the plasma concentration of no, nos- , nos- , adma (multilabel coulter victor- , finland). to select points "cut-off" used the method of roc-lines. results: the statistical power of the study was . % (α< . ). at admission in patients of groups i and ii decrease the concentration of no and increased adma in plasma (p< . ) relative to healthy newborns. after - days, relatively in patients of groups introduction: sepsis-associated disseminated intravascular coagulation (sac) is associated with decreased platelet counts and formation. the widespread activation of platelets contribute to vascular occlusions, fibrin deposition, multi-organ dysfunction, contributing to a two-fold increase in mortality. the purpose was to measure markers of platelet function in the plasma of patients with clinically established sac and to determine association to disease severity and outcome. methods: plasma samples from adult intensive care unit (icu) patients with sepsis and suspected sac were collected at baseline and on days and . dic scores were calculated using platelet count, d-dimer, inr, and fibrinogen. patients were categorized as having no dic, non-overt dic, or overt dic. plasma levels of cd l, von willebrand factor (vwf), platelet factor- (pf- ), and microparticles (mp) were quantified using commercially available elisa methods. results: markers of platelet activation were significantly elevated in patients with sepsis alone and with suspected dic compared to normal healthy individuals on icu day (p< . ). levels of platelet-associated biomarkers were compared between survivors and non-survivors. pf- was significantly decreased in non-survivors compared to survivors (p = . ). patients were stratified based on platelet count and levels of markers were compared between groups. cd l, vwf, pf , and mp showed significant variation based on platelet count, with all markers exhibiting stepwise elevation with increasing platelet count. conclusions: markers of platelet activation were significantly elevated in patients with sac compared to healthy individuals. pf levels showed significant difference based on dic score or mortality, and differentiated the non-survivors compared to survivors. cd l, vwf, pf , and mp showed significant association with platelet count, increasing in a stepwise manner with increases in platelet count (table ) . prognostic value of mean platelet volume in septic patients: a prospective study a chaari king hamad university hospital, bussaiteen, bahrain critical care , (suppl ):p introduction: mean platelet volume (mpv) has been reported as a valuable marker of inflammatory diseases. the aim of the current study is to assess the prognostic value of mpv in septic patients. methods: prospective study including all patients admitted to the intensive care unit (icu) with sepsis or septic shock. demographic, clinical and laboratory data were collected. the mpv was checked on admission and on day . two groups were compared: survivors and non-survivors. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days in survivors and . [ . - ] days in non-survivors (p= . ). conclusions: the decrease of the platelet count but not the increase of the mpv was associated with increased mortality in critically-ill septic patients. endotoxin activity assay levels measured within hours after icu admission affected patients' severity assessments a kodaira , t ikeda , s ono , s suda , t nagura tokyo medical university, tokyo, japan, introduction: sepsis profoundly alters immune homeostasis by inducing first a systemic pro-inflammatory, then an anti-inflammatory state. we evaluate the prognostic value of ex vivo lipopolysaccharide (lps) stimulation of whole blood in septic patients, at day and after intensive care unit (icu) admission. methods: this prospective cohort study included patients with severe sepsis or septic shock admitted to a surgical icu of a university hospital. blood was drawn on day and day , and stimulated ex vivo with lps for hours. tumor necrosis factor alpha (tnf), interleukin (il) , il and il were measured. twenty-three healthy adults served as controls. outcomes were ventilator and icu-free days, sofa score at day and , and need for dialysis during the course of sepsis. results: forty-nine patients were included (mean age ± years). the blood of septic patients was less responsive to ex vivo stimulation with lps than that of healthy controls, as demonstrated by lower tnf, il , il and il release ( fig. ). at day , patients above the th percentile of il release had significantly fewer ventilator and icu-free days than those in the lower th percentile (fig. ) . in contrast, patients in whom il release increased between day and day had significantly lower sofa scores at day and and need for dialysis, and more icu-free days than patients in whom il release decreased (table ) . conclusions: greater lps-stimulated il release in septic patients at day was associated with poorer clinical outcomes and may reflect the severity of the forthcoming immunoparalysis. however, an increase in il release between day and day was associated with favorable outcomes, perhaps signaling immune restoration. introduction: hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (hipec-crs) is a curative treatment modality for peritoneal carcinomatosis. extensive debulking surgery, peritoneal stripping and multiple visceral resections followed by intraperitoneal installation of heated high-dose chemotherapeutic agents, a process leads to a 'high-inflammatory' syndrome. serum procalcitonin (pct), a biomarker for bacterial sepsis, in the heightened inflammatory state after hipec-crs might be of limited utility. our aim is to determine the trends of pct in the early postoperative phase of hipec-crs and to identify trends in patients with and without bacterial sepsis methods: in a case-control design, we reviewed all patients undergoing hipec-crs over a -month period ( ) ( ) ( ) . patients were divided into groups based on whether they developed bacterial sepsis in the first days after surgery (infected v/s non-infected). summary data are expressed as medians and ranges. two-tailed nonparametric tests were performed and considered significant at p values of less than . results: patients' data was analyzed. infections developed in % ( patients) with escherichia coli as the predominant pathogen isolated ( % isolates). pct levels (ngm/ml) were elevated postoperatively in both infected and non-infected patients; day infected . (iqr . introduction: early outcome in cardiac surgery has been an area of growing interest where the given risks raise several predictive models for assessment of postoperative outcome [ ] . procacitonin (pct) emerges as a possible predictive tool in cardiothoracic intensive care unit (cticu).we aim at testing the predictive power of pct for early morbidity, prolonged ventilation, icu and hospital stay, in patients developing early fever after cardiac surgery methods: a retrospective descriptive study done in tertiary cardiac center, enrolling patients who stayed for more than hours post-operatively in the cticu risk stratification included additive euro score and pct immunoluminometricaly prior to surgery and every hours in response to onset of fever. results: we screened consecutive patients who underwent open heart cardiac, of which patients were enrolled in the study. patients were divided into two groups based on the level of pct, those with value > ng/ml (group ) and those with level < ng/ml (group ). patients in group as compared to group , over the postoperative course was associated with prolonged icu stay (p= . ), length of mechanical ventilation (p= . ), length of hospitalization (p= . ), acute kidney injury (p= . ) and culture positivity (p= . ). multivariate analysis showed that pct > ng/ml was was significantly associated with positive cultures. (p= . ) conclusions: a rise of serum pct carries the signals of early icu morbidity and lengths of ventilation, icu stay and hospital stay methods: patients aged ( - ) days ( - days) underwent cardiac surgery with cardiopulmonary bypass for severe congenital heart disease. in the dynamics levels of pct, mr-proadm, ct-proavp and mr-proanp were measured before surgery and on the , , and days after the operation with the kryptor compact plus analyzer. data are presented as medians with interquartile range. the mann-whitney u-test was used to compare the data. values of p < . were statistically significant. results: patients ( %) required alv for more than hours. in this group statistically significant higher levels of pct, mr-proadm and mr-proanp were found throughout the period ( table ). the level of ct-proavp had increased to statistical significance since the day after the operation. patients were in the icu for more than hours. in this group statistically significant higher levels of pct, mr-proadm were found throughout the whole period ( table ). the higher level of mr-proanp was statistically significant on the st and th days after surgery, mr-proanp had a tendency of increasing values on nd and rd days. ct-proavp increased to statistical significance since the nd day after the operation and persisted throughout the studied period. conclusions: pct, mr-proadm and mr-proanp can be used as predictors of prolonged alv for children of the first year of life after cardiac surgery with cardiopulmonary bypass. the level of ct-proavp can be considered since the day after surgery. pct and mr-proadm may be used to predict the los in the icu. mr-proanp and ct-proavp can be considered since the and days after surgery respectively. introduction: early prediction of the risk of death among patients admitted at the emergency department (ed) remains an unmet need. the prognostic performance of hbp that is secreted by neutrophils was prospectively validated in a series of sequential ed admissions. methods: hbp and elements of qsofa were analyzed prospectively in serial ed admissions (main reasons for admission: acute abdominal pain . %; fever . %; vomiting/diarrhea . %; dyspnea . %; neurologic signs . %; non-specific complaints . %; most patients admitted for more than one reasons). upon ed admission patients were scored as low-risk, intermediate-risk and high-risk at the discretion of the physician. hbp was measured in blood samples upon admission by an enzyme immunosorbent assay. results: hbp was significantly greater among patients who died very early (fig. ). in five out of six of patients dying early hbp was greater than ng/ml. we combined hbp more than ng/ml and the presence of one sign of qsofa into a new score; this had . % sensitivity to predict -day mortality. the respective sensitivity of two signs of qsofa was . % (p: . ). the use of this new score allowed better stratification of patients originally considered at the triage as low-risk into high-risk (fig. ) . conclusions: we propose hbp more than ng/ml and one qsofa sign as an early score for -day mortality at the ed. introduction: despite of our growing knowledge in pathophysiology of septic shock still remain one of the most important factors of hospital mortality. it is thought that early diagnosis and treatment at early stage of septic shock would decrease its mortality. there have been on-going studies in recent years which research the usability of heparin binding protein (hbp) in early diagnosis of sepsis [ ] . to seek the usability of c-reactive protein (c-rp), procalcitonin (pct) and hbp biomarker combination in early diagnosis of septic shock. methods: patients, who have the diagnosis of septic shock, that are expected to stay in intensive care unit more than hours, and aged between - are included in the study. data are collected from the patients' blood samples that are drawn on admission, on the th hour, and on the day of discharge or death. results: it has been found in our study that, best "cut-off" value ng/ml, specificity . and sensitivity . for hbp. compared with other biomarkers, hbp was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve (auc) = . ). conclusions: although there have been many biomarkers for early diagnose of septic shock, c-rp and pct are the most common used markers in nowadays' clinical practice. the usability of hbp in early diagnosis of sepsis is still being researched. we concluded that pct, c-rp and hbp biomarker combination is usable to diagnose septic shock at the end of our study. introduction: reduced adamts- and increased von willebrand factor (vwf)/adamts- ratio have been observed in sepsis and are associated with the severity of the disease [ , ] . however, their change during the septic episode and in the event of a change in the clinical status of the septic patients has not been investigated. the aim of the study was to assess the variation of these hemostatic parameters in critically ill patients during the course of a septic episode. methods: we monitored septic patients admitted in the intensive care unit (icu). improved (group a) while deteriorated (group b). we assessed vwf, adamts- and the vwf/adamts- ratio on admission in icu (time point ) and at the time of a change in patients' clinical condition (remission or deterioration, time point ). results: in group a, adamts- and the vwf/adamts- ratio did not significantly change ( . ± . vs . ± . conclusions: hemostatic disorders, as assessed by vwf and adamts- levels were detected in septic patients, while their changes differed according to the evolution of the septic episode. adamts- changes may be associated with outcome. methods: adult patients with at least one sign of qsofa and infection or acute pancreatitis or after operation were prospectively followed-up. blood was sampled the first hours; those with hiv infection, neutropenia and multiple injuries were excluded. sepsis was diagnosed using the sepsis- criteria. soluble urokinase plasminogen activator receptor (supar) was measured by an enzyme immunoassay. results: sixty patients were classified with sepsis using the sepsis- definitions. presence of at least two signs of qsofa had . % sensitivity, . % specificity, . % positive predictive value and . % negative predictive value for the diagnosis of sepsis. the integration of qsofa signs and supar improved the diagnostic performance ( fig. ) . conclusions: conclusions two signs of qsofa have significant positive prognostic value for sepsis but low sensitivity. this is improved after integration with supar. the intelligence- study is supported by the european commission through the seventh framework programme (fp ) hemospec. introduction: sepsis is a frequent reason for admission in the emergency department (ed) and its prognostic mainly relies on early diagnosis. in addition, no validated prognostic tool is currently available. therefore, identification of patients at high risk of worsening in the ed is key. the triage objective was to assess the prognostic value of a blood marker panel to predict early clinical worsening of patients admitted in the ed with suspected sepsis. methods: triage was a prospective, multicenter ( sites in france and belgium) study on biological samples conducted in partnership with biomerieux s.a. patients admitted in the ed with suspected or confirmed community-acquired infection for less than h were included. exclusion criteria were: admission in the ed for more than hours, septic shock at admission, immunodepression, sepsis syndrome days prior to admission. the protocol included clinical and biological time points (h , h , h , h , d ). patients were classified in groups at admission (infection, sepsis, severe sepsis) and divided into evolution/prognosis groups depending on worsening or not from their initial condition to severe sepsis or septic shock and sofa score's evolution. the evolution criteria were centrally evaluated by an independent adjudication committee of sepsis experts including emergency physicians and intensivists. patients were followed up to day for mortality. results: the study duration was years with patients included ( excluded). the centralized analysis is in progress to select the combination of biomarkers with the best prognostic performance comparing both evolution/prognosis groups. currently, patients have been classified as worsening and some results will be available in . conclusions: triage is the largest prospective multicenter study assessing the prognostic value of a panel of blood markers in eds which could help identification of septic patient at risk of worsening at time of admission in the ed and develop specific management. introduction: immune status characterization in intensive care unit (icu) patients presents a major challenge due to the heterogeneity of response. in this study, the filmarray® system was used with customized gene assays to assess the immune profile of critically-ill icu patients compared to healthy volunteers; from within the realism cohort. methods: a customized filmarray® pouch containing assays was designed; target and reference genes. detection and semiquantification of assays from whole blood collected in paxgene tubes occurs in the device within hour. a total of subjects from the realism cohort were tested in duplicates: trauma, septic shock and surgery patients, along with healthy volunteers. the patients' selection was based on hla-dr expression on monocytes, and pha-(phytohaemagglutinin) stimulated t-cell proliferation assay, to have various immune profiles. results: quantification cycle values of the target genes were normalized by the geometrical mean of reference genes to account for the different cell counts among specimens. the number of the cd + cells and hla-dr, determined by flow cytometry, showed good correlation to cd d and cd gene expression, respectively. seven genes showed significant differences in expression levels between the healthy volunteers and patient groups: cd d, cd , ctla & cx cr were down-regulated, while il- , il rn and s a were up-regulated in the patient populations. the use of relative quantitative difference of some markers was able to distinguish and introduction: early, rapid diagnosis is integral to the efficient effective treatment of sepsis; however, there is no gold standard for diagnosis, and biochemical surrogates are of limited and controversial utility. the cytovale system measures biophysical properties of cells by imaging thousands of single cells per second as they are hydrodynamically stretched in a microfluidic channel. this platform has been shown to measure dozens of mechanical, morphological, and cell surface biomarkers of wbc activation simultaneously [ , ] . in this study, we show the performance of the cytovale system in measuring biophysical markers for sepsis detection in the emergency department (ed). methods: we conducted an irb-approved prospective cohort study of emergency department (ed) patients with + sirs criteria and evidence of organ dysfunction. patients were included for analysis. blood samples for the cytovale assay were collected in the ed, and the diagnosis of sepsis was adjudicated by blinded clinician review of the medical record. captured imaging data were analyzed using computer vision to quantify mechanical parameters per cell, and a logistic model was trained to discriminate patients who had sepsis from those who did not. results: we found substantial biophysical differences between cells from septic and non-septic patients as observed at both the single cell level (fig. ) and when looking at the overall leukocyte populations (fig. ) . a multiparameter classification algorithm to discriminate septic from non-septic patients based on biophysical markers currently yields a sensitivity of % with a negative predictive value of %. conclusions: in patients presenting to the ed with of sirs criteria and evidence of organ dysfunction, the cytovale system provides a potentially viable means for the early diagnosis of sepsis via the quantification of biophysical properties of leukocytes. oxidative stress and other biomarkers to predict the presence of sepsis in icu patients v tsolaki, m karapetsa, g ganeli, e zakynthinos icu, larissa, greece critical care , (suppl ):p introduction: early identification of sepsis adds a survival benefit in icu patients. several biomarkers have been evaluated, yet an optimal marker is still lacking [ ] . methods: we prospectively determined oxidative status in patients admitted in a general intensive care unit of the university hospital of larisa. oxidative status was determined measuring the novel static (sorp) and capacity (corp) oxidation-reduction potential markers. other biomarkers (bnp, presepsin, crp) were measured, and the discriminative properties for the detection of sepsis were evaluated. results: oxidative status was evaluated in a hundred and fifty two consecutive patients. patients with severe sepsis and septic shock had significantly higher sorp values than patients without sepsis ( introduction: c-reactive protein (crp), is reported to be an effective marker for the assessment of vascular inflammation activity and acute coronary events prediction [ ] .we hypothesized that preoperative crp elevation is related to the occurrence of postoperative adverse cardiovascular outcomes. methods: we prospectively included patients scheduled to undergo different vascular surgeries from december to september . we assessed demographic data, comorbidities, revised cardiac risk index (rcri) and biomarkers (crp, cardiac troponin high sensitive ths, creatinine and urea) in the preoperative period. we also noted type and duration of surgery, intraoperative blood loss, icu stay and mortality. we evaluated crp as a predictive marker of major cardiovascular events defined as chest pain, ths elevation, electrocardiogram changes, arrhythmia, pulmonary embolism, stroke occuring within postoperative months. results: during our study, patients were scheduled to undergo vascular surgeries. from the patients, % developed adverse cardiac events (table ) . we showed the predictive value of crp in major cardiovascular event in a roc analysis (fig. ) . the cuttoff value of cpr was giving % of sensitivity and % of specificity. conclusions: our study pointed out that crp preoperative elevation could have a very strong predictive value of post-operative cardiovascular events in vascular surgery, this is in line with results showed by previous studies [ ] . introduction: elderly are particularly susceptible to bacterial infections and sepsis, and they comprise an increasing proportion of intensive care unit (icu) admissions. our aim was to evaluate the impact of age on critically ill infected patients. methods: we performed a post-hoc analysis of all infected patients admitted to icu enrolled in a -year prospective, observational, multicenter study involving icus. patients aged < , - and >= years were compared (group a, b, and c). multidrug-resistance (mdr) was defined as acquired non-susceptibility to at least one agent within three or more antimicrobial categories. results: of the patients analyzed, ( . %) were infected on icu admission. of these, ( %) belonged to group a, ( %) to group b and ( %) to group c. group c were more dependent, had higher saps ii and charlson scores (p< . ). icu and hospital length of stay did not differ between groups. microorganism isolation and bacteremia were higher in group b ( % and %, respectively) than groups a ( % and %, respectively) and c ( % and %, respectively; p< . ). septic shock was present in % of patients and was more frequent in groups b ( %) and c ( %) than group a ( %). the most common sources of infections were respiratory and intra-abdominal. isolation of gram-negative bacteria was significantly increased in group b and c (p= . ). the most common isolated bacteria were escherichia coli ( %), staphylococcus aureus ( %) and pseudomonas aeruginosa ( %) for all groups. in total, isolates ( %) corresponded to mdr bacteria, of which % were staphylococcus aureus. age was not a risk factor for infection by mdr. all-cause mortality in icu and hospital was: % and %; % and %; % and % -respectively for groups a, b, and c (p < . ). conclusions: old patients ( - years) were more prone to present with bacteremia, which could account for the increased severity of sepsis and higher all-cause mortality. age was not a risk factor for mdr infection. introduction: the rapid identification of pathogens using patient samples is crucial. delays in this can potentially have serious implications for patients and infection prevention/control [ ] . the aim of this project was to identify the number of microbiology samples sent, the number rejected and reasons for rejection, with the intention to reduce such instances. methods: data was collected retrospectively on icu admissions from january-june to a university hospital in the uk. patients were identified and data collected using the intensive care national audit and research centre (icnarc) database and from electronic patient records. data collected included: demographics, length of stay, microbiology samples sent and details on the rejected samples. results: patients were identified with a total of (median: samples/patient) samples sent to microbiology. were rejected ( %). ( %) patients had at least sample rejected. the median number of samples rejected per patient was (range: - ). the fig. (abstract p ). the area under the curve for crp elevation is . most common samples rejected were urine ( %), blood ( %), faeces ( %) and sputum ( %). ( %) of the samples were resent for testing (median day; range - ). reasons for sample rejection are shown in table . most rejections occurred within -hours of admission ( fig. ) . conclusions: this study confirms a high number of samples are sent to microbiology. although a few are rejected, overall this represents a large number, with most occurring during the first days of admission. reasons for sample rejection are remedial through improved training and vigilance. a bespoke guide to sample collection for microbiology coupled with a training program for healthcare professionals has been introduced with the aim to reduce sample rejections from % to . %. introduction: careful hand hygiene of health-care workers (hcws) is recommended to reduce transmission of pathogenic microorganisms to patients [ ] . mobile phones are commonly used during work shifts and may act as vehicles of pathogens [ , ] . the purpose of this study was to assess the colonization rate of icu hcws' mobile phones before and after work shifts. methods: prospective observational study conducted in an academic, tertiary-level icu. hcws (including medical and nursing staff) had their mobile phones sampled for microbiology before and after work shifts on different days. samples were taken with eswab in a standardized modality and seeded on columbia agar plus % sheep blood. a semiquantitative growth evaluation was performed at and hours after incubation at °c. results: fifty hcws participated in the study ( % of department staff). one hundred swabs were taken from mobile phones. fortythree hcws ( %) reported a habitual use of their phones during the work shift, and of them ( . %) usually kept their mobiles in the uniform pocket. all phones ( %) were positive for bacteria. the most frequently isolated bacteria were coagulase negative staphylococcus, bacillus sp. and mrsa ( %, %, %, respectively). no patient admitted to the icu during the study period was positive for bacteria found of hcws' mobile phones. no difference in bacteria types and burden was found between the beginning and the end of work shifts. conclusions: hcws' mobile phones are always colonized mainly by flora resident on hcw's hands, even before the work shift and irrespective of the microbiological patients' flora. further studies are warranted to investigate the role of mobile phones' bacterial colonization in the icu setting and to determine whether routine cleaning of hcws' mobile phones may reduce the rate of infection transmission in critical patients. methods: sixty samples were collected from aicu (n= ), picu (n= ) and or (n= ) during august to september . samples were randomly selected and taken at the end of the hcws duty with a sterile swab covering all mp surfaces. the inoculation was made into blood sheep and eosyn methilene blue agar for culture. isolated bacteria were identified according to standard microbiological techniques. antibiotic sensitivity testing was performed using disc diffusion method. results: overall mp bacterial colonization rate was %. main results are detailed in table . most common non pathogenic bacteria was staphylococcus epidermidis n= ( %). isolated pathogenic bacteria conclusions: we found high rates of mp colonization with pathogenic bacteria. an educational program is necessary to reduce the contamination and transmission of these high risk microorganisms. introduction: the objective of this study was to evaluate the variability in the dynamics and levels of airborne contamination within a hospital intensive care unit in order to establish an improved understanding of the extent to which airborne bioburden contributes to cross-infection of patients. microorganisms from the respiratory tract or skin can become airborne by coughing, sneezing and periods of increased activity such as bed changes and staff rounds. current knowledge of the clinical microflora is limited however it is estimated that - % of nosocomial infections are transmitted via air. methods: environmental air monitoring was conducted in glasgow royal infirmary icu, in the open ward and in patient isolation rooms. a sieve impactor air sampler was used to collect l air samples every minutes over hour ( : - : h) and hour ( : - : h) periods. samples were collected, room activity logged and the bacterial contamination levels were recorded as cfu/m of air. results: a high degree of variability in levels of airborne contamination was observed over the course of a hour day and a period in a hospital icu. counts ranged from - cfu/m over hours in an isolation room occupied for days by a patient with c. difficile infection. contamination levels were found to be lowest during the night and in unoccupied rooms, with an average value of cfu/m . peaks in airborne contamination showed a direct relation to increased room activity. conclusions: this study demonstrates the degree of airborne contamination that can occur in an icu over a hour period. numerous factors were found to contribute to microbial air contamination and consideration should be given to potential improved infection control strategies and decontamination technologies which could be deployed within the clinical environment to reduce the airborne contamination levels, with the ultimate aim of reducing healthcareassociated infections from environmental sources. new practice of fixing the venous catheter of the jugular on the thorax and its impact on the infection f goldstein, c carius, a coscia quintad'or, rio de janeiro, brazil critical care , (suppl ):p introduction: central line-associated bloodstream infection (clabsi) is an important concern in the icu, mainly in those with a high density of use of central venous catheter. any measures that may have an impact on the reduction of clabsi are important in reducing morbidity and mortality of hospitalized patients. therefore we present a retrospective study comparing the fixation site (neck vs. thorax) of the catheters implanted in the jugular vein, guided by ultrasonography and evaluating its impact on the incidence of clabsi. the purpose of our study was to identify if there is any positive impact on the reduction of clabsi when the catheter is fixated on the thorax. methods: a retrospective unicentric study comparing the infection rates between the year of , when the traditional technique of catheter fixation on the neck was used, and , when % of the catheters were fixated on the thoracic region. the criteria for clabsi were defined by the infection commission of quintad`or hospital and the data on clabsi were provided by the same commission. during this period there were no changes in the team of our unit and the patient's profile was the same. no deep vein catheter impregnated with antibiotics were used in the patients included in the study. the comparison used fisheŕs test as a tool. all the patients hospitalized in the intensive care unit with indication of the central venous catheter of short permanence in the internal jugular vein were included. patients with the central venous catheter of short permanence in other topographies, patients with hemodialysis catheter or with picc were excluded. results: during the year of , internal jugular vein catheters were installed in our unit using the traditional technique, fixing the catheter on the neck. in this period, cases of clabsi were detected. on the other hand, in the year of , internal jugular vein catheters were installed in the same unit, all of them, using the thorax as the point of fixation. although the number of catheters installed this year was higher, there was no case of clabsi. it appears that this position, provides a better fixation of the catheter, avoiding that the bandage gets uncovered. conclusions: during the year of , though there were more patients using deep vein catheters of short permanence, we had less clabsi events on our unity compared to the year of . fisher's exact test identified a p-value of this association of . . fixation of the internal jugular vein catheter in the thorax seems to contribute to the prevention of clabsi. further prospective and randomized studies are required to evaluate the contribution of fixation of the jugular vein catheter in the thorax in the clabsi prevention. introduction: the oral cavity of a patient who has been hospitalized presents a different flora from normal healthy people. after h hours of hospital stay, the flora presents a bigger number of microorganisms that can be responsible for secondary infections, like pneumonia, because of their growth and proliferation. the objective of our study was to assess the dental plaque index on patients on admission to an intensive care unit, and reassess days later, to evaluate the efficacy of oral hygiene. methods: prospective, descriptive and observational study in an intensive care unit of the chp. demographic, admission motive, hospital length of stay, feeding protocol, respiratory support need and oral hygiene protocol data was collected. the greene & vermillion simplified oral hygiene index (iho-s) was used as the assessment tool on the first h and on th day. results: patients were evaluated, of which were excluded for not meeting the minimal dentition. patients had a mean age of , ± , years, , % were males and most of medical and surgical scope ( , % each). mean hospital length of stay was , ± , days. the majority of patients were sedated ( %), under ventilator support ( , %) and with enteric nutritional support, under nasogastric tube feeding. initial iho-s score was , ± , , rising to , ± , (p< , ) days later. conclusions: various studies have proven the importance of a good oral hygiene to avoid bacterial growth and reduce the risk for nosocomial infections. in this study, we've observed a significant worsening of oral hygiene one week after admission. although this could be unimportant for a one week staying patient, it could indicate an increased risk for nosocomial infections for longer staying patients, which could benefit from a more efficient oral hygiene protocol. positive pocket cultures and infection risk after cardiac electronic device implantation-a retrospective observational single-center cohort study p pekić methods: we performed a retrospective observational single-center cohort study on patients who received de novo implantation of pacemaker, cardioverter-defibrillator or cardiac resynchronization therapy device in a two-year period. each patient was implanted using standard aseptic procedure according to local protocol and antibiotic (cefazolin) prophylaxis before the procedure. pocket aspirate was taken after irrigating the wound with normal saline just before device placement. results: we analyzed patients ( . % male, . % female). the most often implanted device was a ddd pacemaker followed by a vvi pacemaker. mean length of hospital stay was . ± . days. there were ( . %) positive cultures with overall ( . %) clinically apparent infections which required prolonged iv antibiotics, removal of device and reimplantation after infection resolution. in regard to microbiology, s. epidermidis ( . %) and coagulase negative staphylococcus ( . %) were the most often finding which is in contrast to the cultures described in the literature. the only statistically significant risk factor for positive pocket culture was male sex and presence of a urinary catheter. invasive vascular devices, previous intrahospital infection, and diabetes were not found to increase the likelihood of positive pocket culture. conclusions: positive pocket cultures after cied implant are a frequent finding mostly due to contamination and colonisation. the risk factors for such a finding differ from the usual and expected clinical circumstances. our results are consistent with those in the literature. it turns out that the most important preventive measure in cied implantation is strict aseptic procedure. introduction: intensive care patients are in constant risk of contamination due to suppression of their immune system, use of invasive procedures and medical equipment and health associated infections (hai). chlorhexidine gluconate (chg) is an antiseptic and disinfectant product. in medical research it has been found that daily chg bathing is affective in reducing levels of skin and central line related infections (climo, ) . it is also referred to in the recommendations of the ministry of health "prevention of septicemia due to central lines" ( ). methods: unit guide lines for patient dry bathing were written in may and thereafter began the implementation and instruction of nursing staff. quality control was inspected by observation. there was a phase questioner that included several categories such as: preparation of the chg solution, staff protection actions, infusions and surgical wound dressings, bathing performance and documentation. results: a gradual rise of %was observed in theperformance ofdry bathing according to the unit guidelines conclusions: % of observed dry baths where performed according to the guide lines. points for improvement: correct care of infusions and surgical wound dressing and verify use of separate wipes for each body part. next we will examine the correlation between the use of dry baths and theextent of infections in the unit. dry baths are nowconsidered an integralpart of the daily nursing routine. they have no substantial costs, help prevent complications from infection and add to the patient's safety. introduction: despite reductions in mortality reported with sdd, concerns about bacterial resistance and alteration of microbiome limit use. a retrospective observational study was conducted into the effect of local sdd protocols on vap rates and resistance patterns. over a -year period, regimens were used dependent on drug availability and hospital antibiotic stewardship concerns. the study was designed to review practice and identify any risks of partial implementation. methods: patients ventilated on a general intensive care were identified via clinical information systems. three periods were reviewed for adherence to sdd protocols, pre sdd (jan -feb ), full (july -sept ) and partial (july -sept ). high-risk patients during both sdd periods also received iv antibiotics for hours. patients admitted with pneumonia or tuberculosis were excluded from vap analysis. remaining patients' records were reviewed and the clinical pulmonary infection score (cpis) calculated for each ventilated day to identify vap rates. positive respiratory microbiological results for all patients admitted to the icu during each time period were reviewed to assess for wider changes in local resistance patterns. results: protocol adherence was assessed in patients during the full sdd period and during the partial ( table ). the number of patients included for analysis of vap rates during each period was pre sdd, during full sdd and during partial sdd. there were no significant changes in resistance patterns or clostridium difficule rates (table ) . conclusions: compliance with the available enteral antibiotics was reasonable but with iv antibiotics was poor. it is accepted that alterations and non-adherence to protocols risk development of resistant bacterial strains. within our unit no decrease in vap rates was seen but reassuringly no increased rates of extended bacterial resistance were identified during the treatment periods. introduction: arterial catheters are commonly used in intensive care units (icu) and are among the most frequently manipulated vascular access devices. our aim was to evaluate the rate of arterial catheterrelated bloodstream infection and colonization. methods: this was a -month, prospective and monocentric cohort study, performed in a multipurpose icu. all arterial catheters, inserted in or presented to the icu, were cultured and assessed for colonization or catheter-related bloodstream infection (crbi). results: we enrolled patients ( . % males, average age ± years, saps ± ) of whom a total of arterial catheters were analyzed for a total of catheter-days. radial arterial catheters were inserted in . % (n= ), femoral arterial catheters in . % (n= ) and other arterial catheters in . % (n= ). signs of dysfunction were found in . % and . %, respectively. radial arterial catheters colonization (n= ) and crbi (n= ) occurred at a rate of . and . / catheter-days. femoral arterial catheters colonization (n= ) and crbi (n= ) occurred at a rate of . and . / catheter-days, respectively. mean catheter time insertion was significantly higher in colonized catheters/crbi ( ± days; % ci: - ) when compared to arterial catheters with negative cultures ( ± days; % ci: - ); p = . ). colonized lines showed acinetobacter baumannii (n= ), staphylococcus epidermidis (n= ), enterococcus spp (n= ) and pseudomonas aeruginosa (n= ). crbi were caused by staphylococcus epidermidis (n= ) and staphylococcus haemolyticus (n= ). conclusions: the incidence of radial arterial catheters colonization and crbi were lower than reported rates in literature. colonization and crbi rates were higher in femoral catheters. femoral catheters showed dysfunction more frequently. prolonged catheterization was associated with colonization and crbi. a multimodality approach to decreasing icu infections by hydrogen peroxide, silver cations and compartmentalization and applying acinetobacter as infection marker introduction: nosocomial infections at the intensive care unit (icu) represent a substantial health threat [ , ] . icu infections are mainly attributed to the extended hospital delay which results in high morbidities and mortalities. methods: a cross sectional study was conducted at the intensive care unit, aseer central hospital, saudi arabia over months period ( ) ( ) . the intervention program included the application of mist of hydrogen peroxide and silver cations, physical separation and compartmentalization of the intensive care unit. the glosair™ system was used to deliver a mist of hydrogen peroxide and silver cations. hydrogen peroxide is an oxidizing agent, which kills microorganisms. results: a total of strains of acinetobacter species were identified from the patients over the months period (fig. ) . the mean infection rates decreased from . in the first three months of the program to in the last three month after continuous. conclusions: the program using the three procedures offered a significant decrease in infections at the icu as measured by acinetobacter count, which is one of the most hazardous nosocomial pathogens. introduction: the efficacy of ß lactam antibiotics is related to the time above mic. continuous or extended infusions can be used to increase the time above mic, especially in patients with normal or increased drug clearance. administering antibiotics by continuous infusion is not a new concept. a review in looks at the outcomes of continuous infusions [ ] . more recently an improvement in mortality has been demonstrated [ ] . our perception was that uptake of this low cost intervention was not common, so we undertook a survey to determine how commonly continuous infusions are used in england. methods: a telephone survey of all intensive care units in england was undertaken. questions included: -are you using continuous or extended antibiotic infusions? -which antibiotics are you using for continuous or extended infusions? -if not currently using has it been considered? data was collected over a week in june . results: there was an % response rate. ( . %) of the units continuously infuse some antibiotics, however . % of those only infuse vancomycin and not ß lactams. only of the total responders ( . %) infuse antibiotics other than vancomycin (i.e. ß lactams). conclusions: the theoretical advantage of continuous infusion of ß lactam antibiotics has been described for over years. there is now evidence that this may improve survival. despite this, uptake in england has been slow. introduction: infections contribute to a significant proportion of morbidity and mortality worldwide. while many infections are successfully managed with antimicrobial therapy, rates of antimicrobial resistance (amr) are increasing. certain patient populations such as those admitted to intensive care units (icu) are at high risk. methods: we conducted a retrospective, observational study of all icu patients at a tertiary referral hospital in rwanda from january through december we collected data on diagnosis, icu length of stay, mortality and hospital length of stay, as well as microorganism, site of culture, amr and antibiotics prescribe. results: overall, patients were admitted to the icu. most patients were admitted from the main operating theater (n= , %).the most common admitting diagnoses were sepsis (n= , %), head trauma (n= , %). a total of samples were collected from patients. the samples were from blood (n= , %), tracheal aspirate (n= , %),. the most common organisms isolated were klebsiella (n= , %), acinetobacter (n= , %), e.coli (n= , %), proteus (n= , %), citrobacter (n= , %), s aureus (n= , %), pseudomonas (n= , %), and other (n= , %). of klebsiella isolates, % and % were resistant to ceftriaxone and cefotaxime, respectively. of e.coli isolates, % and % were resistant to ceftriaxone and cefotaxime, respectively. all acinetobacter isolates were resistant to ceftriaxone and cefotaxime. conclusions: there is an alarming rate of antimicrobial resistance to commonly used antibiotics in the icu. expanding antibiotic options and strengthening antimicrobial stewardship are critical for patient care. the last three days g latten , p stassen zuyderland mc, sittard-geleen, netherlands, introduction: this study provides an overview of the prehospital course of patients with a (suspected) infection in the emergency department (ed). most research on serious infections and sepsis has focused on the hospital environment, while potentially most delay, and therefore possibly the best opportunity to improve treatment, lies in the prehospital setting. methods: patients were included in this prospective observational study during a week period in . all patients aged years or older with a suspected or proven infection were included. prehospital, ed and outcomes were registered. results: in total, patients visited the ed during the study period, of whom ( . %) patients had a (suspected) infection. (fig. ) median duration of symptoms before ed visit was days (iqr - days), with . % of patients using antibiotics before arrival in the ed. most patients ( %) had been referred by a general practicioner (gp), while . % of patients had visited their gp previously during the current disease episode. twenty-two patients ( . %) experienced an adverse outcome (icu admission and/or -day all-cause mortality): these patients were less often referred by a general practicioner (gp) ( . vs. . %, p= . ) and were considered more urgent both by ems and in the ed. conclusions: the prehospital phase of patients with an infection provides a window of opportunity for improvement of care. patients become ill days before the ed visit and . % already visited their gp previously during the current disease episode, while . % is currently using antibiotics. future research should focus on quality improvement programs in the prehospital setting, targeting patients and/or primary care professionals. introduction: worldwide, the prevalence of tetanus has decreased.-however, even if progress has been made in the combat to eradicate tetanus it may be a cause of admission to intensive care.the objectives of our study are to determine epidemiological,clinical and prognostic characteristics for severe tetanus in our unit. methods: we conducted a retrospective study in the medical intensive care unit of ibn rushd hospital in casablanca in morocco from to .we studied the epidemiological,clinical and prognostic characteristics of the patients who were admitted for severe tetanus. results: the incidence of severe tetanus was . % affecting male in %. . % were aged between and years old. in . % there were a integumentary portal of entry. contractures were present in %of the cases. at intensive care unit admission, . % of the patients were sedated. the anti-tetanus vaccination was never updated. according to the dakar score . % of the patients were listed dakar , . % dakar and . % dakar . for the mollaret score, the crude form was found in . %, the acute generalized form was found in . % and the severe form in . % of the cases.mechanical ventilation was necessary in . %. diazepam and baclofen were used in . %, phenobarbital in . % and propofol in . %. a serotherapy was used for all the patients and a preliminary vaccination dose for . %. all the patients received antibiotics, penicillin g . % and metronidazole . %. the mortality was . %. the length of intensive care stay was significantly higher. the need for an intubation,its duration and the occurrence of autonomic dysfunction have significantly influenced the mortality. conclusions: to improve the prognosis in these serious forms of tetanus,it is highly important to identify the warning signs and refer patients in intensive care for early and appropriate management in intensive care. introduction: bloodstream infections (bsis) are associated with increased mortality in the icu. the aim of the study was to evaluate the epidemiology and resistance patterns during the period to . methods: bacteria and fungi isolated from the blood of patients hospitalized in a mixed icu during the study period were retrospectively analyzed. sensitivity testing was performed with disk diffusion (kirby-bauer) and microscan walkaway plus for minimal inhibitory concentrations. results: during the study period patients were hospitalized in the icu. bsis were diagnosed in cases ( . %). the isolated microorganisms were acinetobacter baumannii ( %), klebsiella pneumoniae ( %), other enterobacteriaceae ( %), pseudomonas aeruginosa ( %), stenotrophomonas maltophilia ( %), enterococci ( %), staphylococci ( %) and candida spp. ( %). of the a. baumannii isolates, % were resistant to carbapenems, . % to colistin, and % to tigecycline. of the k. pneumoniae isolates % were resistant to carbapenems, % to colistin, and . % to tigecycline. of the p. aeruginosa species % were resistant to carbapenems and they were all susceptible to colistin. the rate of resistance to vancomycin was % for the e. faecium isolates, . % for the e. faecalis, while the resistance to methicillin of the coagulase negative staphylococci was %. the most commonly isolate species of candida was c. albicans. conclusions: multi-drug resistant isolates, especially a. baumannii and enterobacteriaceae, are a serious problem in our icu. gram positive bacteria are less common, but the resistance of enterococci to vancomycin is significant. antibiotic stewardship and infection control measures should be applied in a more strict way. nosocomial sinusitis in intensive care unit patients i titov introduction: nosocomial sinusitis (ns) is a complication of critically ill patients which develops - h after admission and is mostly linked but not limited to such invasive procedures as nasotracheal intubation and nasogastric tube placement. ns is often overlooked as a source of pyrexia of unknown origin, meningeal manifestations, sepsis and ventilator associated pneumonia in icu patients. ct scanning and sinus puncture are used to confirm the inflammatory process and identify the pathogen behind it. methods: a retrospective case study of . icu patients for a period of - was performed. we have analysed data from the ct scans of paranasal sinuses and bacteriological findings of samples obtained from sinus puncture. results: ( . %) patients were suspected of ns on the - th day of stay in the icu. the ct scan confirmed pathological changes in patients ( . %). hemisinusitis was detected in patients ( . %) and pansinusitis in patients ( . %). there was also an isolated case of maxillary sinusitis in patient ( . %). the pathogenic culture was identified only in ( %) samples, . % of which revealed isolated bacteria and . % a polymicrobial association. gram positive bacteria were detected in . % of cases and gram negative in . %. most cases revealed multiple antibiotic resistance. conclusions: . ns has proved to be largely caused by gram negative bacteria and polymicrobial associations. the use of broad spectrum antibiotics in icu may justify the presence of sterile cultures. .early identification of risk patients in icu as well as the use of screening ct scan may benefit timely diagnosis and adequate treatment of patients. .preventive considerations include: patient's bed head elevation, the use of oral gastric tube in sedated and coma patients on ventilation, nasotracheal intubation only if indicated, removal of nasogastric tube at night, proper hygiene. conclusions: only of , tb patients ( %) required critical care intervention (table ) . those admitted to icu were older and more likely to have pulmonary, cns, miliary or abdominal tb (table ) . mortality was high despite critical care input in a unit familiar with managing tb, and hour access to infectious diseases advice within the trust, likely due to overwhelming organ dysfunction, patient frailty and advanced tb infection. rates of drug resistant tb were low and comparable to uk-wide rates over that period ( % mono-drug resistant, % mdr) thus less likely a contributory factor to the majority of deaths. short term antibiotics prevent early vap in patients treated with mild therapeutic hypothermia after cardiac arrest t daix , a cariou , f meziani , pf dequin , c guitton , n deye , g plantefève , jp quenot , a desachy , t kamel , s bedon-carte , jl diehl , n chudeau , e karam , f renon-carron , a hernandez padilla , p vignon , a le gouge introduction: patients treated with mild therapeutic hypothermia after cardiac arrests with shockable rhythm are at high risk of ventilator-associated pneumonia (vap) [ ] . despite retrospective trials suggesting a benefit of short-term ( h) antibiotics in this setting [ ] , it is not recommended. the primary objective was to demonstrate that systematic antibiotic prophylaxis can reduce incidence of early vap (< days). the impact on incidence of late vap and on day mortality was also assessed. methods: multicenter, placebo-controlled, double-blinded, randomized trial. icu patients > years, mechanically ventilated after out-of-hospital resuscitated cardiac arrest related to initial shockable rhythm and treated with mild therapeutic hypothermia were included. moribund patients and those requiring extracorporeal life supports, with ongoing antibiotic therapy, known chronic colonization with multiresistant bacteria or known allergy to beta-lactam antibiotics were excluded. either iv injection of amoxicillin-clavulanic acid ( g/ mg) or placebo was administered times a day for days. all pulmonary infections were recorded and blindly confirmed by an adjudication committee. results: in intention to treat analysis, patients were analyzed, (treatment group n= ; mean age . ± . years, sex ratio= , sofa score . ± . ). global characteristics of cardiac arrest were similar (no flow= . min vs . min, low-flow= . min vs . min). vap were confirmed incl. early vap, in treatment group vs in placebo group (hr= . ; ic %=[ . ; . ]) (fig. ) . occurrence of late vap ( % vs . %) and day mortality ( . % vs . %) was not affected by the study procedure. conclusions: short-term antibiotic prophylaxis significantly decreases incidence of early vap in patients treated with mild therapeutic hypothermia after out-of-hospital cardiac arrest related to shockable rhythm and should be recommended. introduction: antibiotics are the most commonly prescribed drugs in icu.in the era of antibiotic resistance it is difficult to choose antibiotics during septic episode.the choice antibiotics mainly depends on clinical diagnosis,culture sensitivity and local flora. whether severity of illness really maters is not well known. to study antibiotic prescription pattern and whether the choice of antibiotic varies according to hemodynamic stability in patients admitted in icu.to study of microbiological isolates and their variability according to hamodynamic stability in icu patients. methods: all icu patients of more than years age who received antibiotics and where cultures had been sent were included in the study.patients discharged against medical advice and where treatment had been withdrawn were excluded in this study. this prospective observational study was conducted between july to march .patients were divided into stable and unstable group according to hemodynamic parameter and usage of antibiotics and microbiological isolated were correlated. icu mortality and length of stay were correlated between hemodynamically stable and unstable group. results: sepsis episode were analysed. mean age was years, male predominant, and average apache iv score was (sd ). we had patients in unstable group of which % patients got discharged and % of patients got discharged in stable group. antibiotic combination therapy was used more in hemodynamically unstsble patients(p . ). blbli was used more in stable group. drug resistance in microbiological isolates did not reveal any statistically significant difference among stable or unstable group. conclusions: there is a tendency to administer combination antibiotics in sicker group of patients with hemodynamic instability. prevalence of microbial flora did not show any statistical difference. outcome is worse in hemodynamically unstable patients. the clinical significance of candida score in critically ill patients with candida infection h al-dorzi , r khan , t aldabbagh , a toledo , s al johani , a almutairi , s khalil , f siddiqui , y arabi king abdulaziz medical city, riyadh, saudi arabia, msd, riyadh, saudi arabia, king saud bin abdulaziz university for health sciences, riyadh, saudi arabia critical care , (suppl ):p introduction: candida score (cs) is used to identify patients with invasive candidiasis in the icu, but its clinical use has not become widespread. our objective was to evaluate the clinical significance of cs in a mixed population of icu patients. methods: this was a prospective observational study of critically ill patients who had candida species growth during their stay in any of six different icus of a tertiary-care center. two intensivists classified patients as having candida colonization or invasive candidiasis according to predefined criteria. cs was calculated for each patient on the day of candida species growth as follows: . see text for description point for parenteral nutrition + point for surgery + point for multifocal candida colonization + points for severe sepsis. the receiver operating characteristic (roc) curve was plotted to assess cs ability to discriminate between invasive candidiasis and candida colonization. results: cs was . ± . in patients with candida colonization (n= ) and . ± . in those with invasive candidiasis (n= ) (p< . ). however, only . % of invasive candidiasis cases had cs >= (compared with . % of candida colonization cases; p< . ). the roc curve (fig. ) showed that cs had fair ability to discriminate between invasive candidiasis and candida colonization (area under the curve . , % confidence interval . to . ; p< . ). in patients with invasive candidiasis, cs was similar in hospital survivors and nonsurvivors ( . ± . and . ± . , respectively; p= . ). cs did not discriminate between survivors and nonsurvivors (area under the roc curve . , % confidence interval . to . ; p< . ). conclusions: cs was higher in patients with invasive candidiasis than those with candida colonization. however, its ability to discriminate between these patients was only fair. cs was not associated with hospital mortality. poor reliability of creatinine clearance estimates in predicting fluconazole exposure in liver transplant patients m lugano, p cojutti, f pea asuiud, udine, italy critical care , (suppl ):p introduction: invasive candidiasis (ic) is a frequent complication in liver transplant (lt) recipients, especially during the first - months after lt. fluconazole is a triazole antifungal used for prophylaxis and treatment of ic. due to its renal elimination, dose adjustments are usually based on estimated creatinine clearance (ecrcl). however, the reliability of ecrcl in predicting fluconazole clearance has never been investigated in this population. the aim of this study was to conduct a population pharmacokinetic (poppk) analysis in a cohort of lt patients who underwent therapeutic drug monitoring (tdm) in order to find out which covariates may influence fluconazole pharmacokinetics (pks). methods: this retrospective study included lt patients who were admitted to the intensive care unit of our university hospital between december and may , and who were treated with intravenous fluconazole in the first months after lt. tdm of fluconazole was performed with the intent of attaining the efficacy pharmacodynamic target (auc h/mic > . ). the tested covariates were: age, gender, ckd-epi ecrcl, time from lt, serum albumin and transaminases, saps ii score. poppk was carried out with pmetrics software. results: nineteen patients (mean±sd age, weight and serum creatinine of ± . years, ± . kg, . ± . mg/dl, respectively) with a total of fluconazole trough plasma concentrations were included in the poppk analysis. mean±sd fluconazole distribution volume (vd) and clearance (cl) were . ± . l and . ± . l/h. age and time from lt were the only clinical covariates significantly correlated with fluconazole vd and cl, respectively. conversely, ckd-epi eclcr was unable to predict fluconazole cl. conclusions: ckd-epi eclcr is unreliable in predicting fluconazole exposure in lt recipients. consistently, in this population adaptation of fluconazole dose should be based on measured crcl, and tdm may be helpful in optimizing drug exposure. outcomes of a candidiasis screening protocol in a medical icu m boujelbèn , i fathallah , h kallel , d sakis , m tobich , s habacha , n ben salah , m bouchekoua , s trabelsi , s khaled , n kouraichi introduction: the aim is to determine the incidence, characteristics and risk factors of invasive candidiasis (ic) in critically ill patients by using a weekly screening protocol. methods: a months' prospective study was conducted in a -bed micu. the candidiasis screening consisted of the culture of plastic swabs (from different body sites), urine and respiratory tract samples.it was conducted upon admission and on weekly basis for all the patients. decision to treat was based on clinical and microbiological features. results: patients were included. the colonization rate with candida spp was . %(n= ). screening samples were collected with a positivity rate at . %(n= ). table describes the isolated candida species by site. antifungal resistance was tested in ( %) species. the resistance rate to fluconazole was . %(n= ). the antifungal resistance of candida albicans is detailed in table . ( . %) patients presented an ic with a mean age and mean saps ii at . ± years and ± . respectively. ( %) presented acute renal failure upon admission. . % (n= ) of the patients needed mechanical ventilation. the median length of stay was days [ . - . ] and the mortality rate was . %(n= ). the mean sofa score upon infection was . ± . . the candida score was >= . and the colonization index was >= . in fig. (abstract p ). roc curve for candida score discrimintaing between invasive candidiasis and candida colonization . %(n= ) and . %(n= ) of the patients respectively. only one patient had a positive blood culture. mannan antigen and anti-mannan antibodies were screened only in five patients with a positivity rate at %(n= ). the most isolated species was: candida albicans . %(n= ). multivariate analysis showed that prior use of imipinem more than days was a risk factor for ic (or= . , ci [ . ; . ], p= . ). conclusions: this study showed the ecology and epidemiology of candida species in our micu with an increased ic rate and high mortality. prior imipinem use was a risk factor for ic. introduction: icu-acquired infection is as high as . episodes per patient-days in lower-middle income countries like india (who). almost three times higher than in high-income countries [ ] . candida infection is the rd most commonly acquired nosocomial infection in india burdening the debilitated patient with longer icu stay [ ] . there are no definite guidelines on whether & when to start antifungal treatment, specific to india where ifi risk is high and diagnostic facilities are limited. currently, the intensivists across india are using antifungals, according to their clinical experience and selective application of international guidelines leading to non-uniformity of patient outcomes. in an endeavour to synchronize anti-fungal therapy and educate intensivists from small cities of india, intensivists and infectious disease specialist of international repute were approached to design a module on 'invasive fungal infections -when to start anti-fungals in icu [ fig. ]. the ifi in india was summarised into a compact hour session for dissemination of knowledge using idsa as a reference guideline. intensivists from across india were trained on the module by our faculty. the module was rolled out to intensivists and pulmonologists focussing particularly on the tier- & tier - cities where avenues for learning are limited [ fig. introduction: trichosporon species are fungi found in nature and human normal flora but they can be an opportunistic pathogen, introduction: this study assessed whether empiric combination antibiotic therapy directed against gram-negative bacteria is associated with lower intensive care unit (icu) mortality compared to single antibiotic therapy. methods: retrospective cohort study on prospectively collected data conducted in the icu of a tertiary care hospital in india between july to march . all consecutive infection episodes treated with empiric antibiotic therapy and with subsequent positive culture for gram-negative bacteria were included. primary and secondary outcomes were all cause icu mortality and icu length of stay (los). outcomes were compared between infection episodes treated with single vs.combination antibiotic therapy. results: of total episodes of gram-negative infections . % received combination-antibiotic therapy. baseline demographic and clinical characteristics between single vs. combination therapy groups were similar (mean age: p= . ; sex: p= . ; mean apache iv score: p= . ). overall icu mortality did not significantly differ between single and combination antibiotic groups ( . % vs. %; p= . ). in single antibiotic group, icu mortality was significantly higher for antibiotic-resistant compared to antibiotic-sensitive bacteria ( . % vs. . %, p= . ). in combination group, significantly lower icu mortality was noted if bacteria was sensitive to even one antibiotic compared to pan-resistant bacteria ( . % vs. . %, p= . ). icu los was similar between antibiotic-sensitive bacteria and antibiotic-resistant bacteria, both in single and combination therapy groups (single, antibiotic-sensitive vs. antibiotic-resistant: mean los±sd . ± . vs. . ± days; p= . ; combination, antibioticsensitive vs. antibiotic-resistant: . ± . vs. . days; p= . ). conclusions: irrespective of the number of antibiotics prescribed as empiric therapy, outcome of patients solely depends on the sensitivity pattern of the bacteria isolated. pharmacokinetics of trimethoprim and sulfametrole in critically ill patients on continuous haemofiltration r welte , j hotter , t gasperetti , r beyer , r introduction: the combination of trimethoprim and sulfametrole (tmp-smt, rokiprim®) is active against multi-drug resistant bacteria and pneumocystis jirovecii. in critically ill patients undergoing continuous veno-venous haemofiltration (cvvh), however, its use is limited because of lacking pharmacokinetic data. methods: pharmacokinetics of both drugs were determined after standard doses in patients on cvvh and in critically ill patients with approximately normal renal function. quantification of tmp and smt was done by high pressure liquid chromatography (hplc) and uv detection after pre-purification by solid phase extraction. the total clearance (cltot) was estimated from arterial plasma levels and the haemofilter clearance (clhf) from plasma and ultrafiltrate concentrations. results: six patients on cvvh ( after the first dose, at steady state) and nine patients off cvvh have been enrolled ( after first dose, at steady state). after a single dose, cltot of smt was . ( . - . , median [range]) and . ( . - . ) l/h on and off cvvh, respectively. at steady state, we observed a cltot of . ( . - . ) and . ( . - . ) l/h, respectively, on and off cvvh. steady state trough levels (cmin) of smt amounted to - mg/l in patients on cvvh and - in patients off cvvh. cltot of tmp was . ( . - . ) l/h on cvvh and . ( . - . ) l/h off cvvh after the first dose. at steady state, its cltot amounted to . ( . - . ) and . ( . - . ) l/h on and off cvvh, respectively. cmin was - mg/l on cvvh and - mg/l in patients off cvvh. clhf accounted for - % of cltot of smt and - % of cltot tmp. conclusions: exposure to both antimicrobial agents is highly variable, but comparable in patients on and off cvvh. as considerable amounts of smt and tmp are eliminated by cvvh, no excessive accumulation appears to take place during treatment with standard doses. the positive impact of meropenem stewardship intervention at a brazilian intensive care unit w freitas introduction: loss of colistin as a clinical option has profound public health implications. widespread use of colistin in agriculture and humans has seen the emergence of mcr- mediated resistance amongst south african patients [ ] . we sought to describe the trends of colistin minimum inhibitory concentrations (mic) over two years using data collected by smart. methods: smart monitors the in vitro susceptibility of clinical aerobic and facultative gram-negative bacterial isolates to selected antimicrobials of importance, enabling longitudinal analyses to determine changes over time. the dataset comprised bacterial isolates from four different south african private pathology laboratories and one public sector pathology laboratory from - . the methods used in the study have been described elsewhere [ ] . isolate proportions between years were compared using the chisquared test with yates' continuity correction. ( ) ( ) ( ) ( ) days]; patients underwent renal replacement therapy. the median treatment duration (iqr) was ( - ) days. in . % of cases, antibiotic-therapy therapy combination (phosphomycin and colistin) was chosen. all the patients experienced a clinical response by / hours from the ceftazidime/avibactam commencing. in / bacteraemic patients negativization of blood culture occurred by hours as well as of the rectal swab in / patients. a (b) recurred and a second treatment was given. / ( . %) patients survived, whereas death was caused by multi-organ failure. the susceptibility test of strains showed sensitivity to ceftazidime/avibactam, whereas % of resistance to carbapenems, quinolones and iii/iv generation cephalosporin, tigecycline and piperacillin/tazobactam; . % of susceptibility to fosfomycin and colistin; (v) less than % of suceptibility to aminoglicosides. conclusions: the strains of kp-cp were susceptible to ceftazidimeavibactam despite the high carbapenem-resistance recorded in our icu, because od rare identification of kp-cp vim/ndl +. the preliminary data seems to confirm the efficacy and clinical utility of this antibiotic for the critically ill patients. introduction: multidrug resistant bacteria (mdr) are an increasing problem on intensive care units. lung infections caused by acinetobacter baumannii are frequently difficult to treat. phages have regained attention as treatment option for bacterial infections due to their specificity and effectivity in lysis. the aim of this preclinical study was to determine efficacy and safety of a novel phage preparation in mice. methods: mice were transnasally infected with a mdr a. baumannii strain [ ] and hours later treated intratracheally with a specific phage or solvent. phage acibel [ ] was produced as suspension including efficient depletion of endotoxins. at defined time points, clinical parameters, bacterial burden in lung and bronchoalveolar lavage fluid (balf) and cell influx were determined. further, lung permeability and cytokine release were quantified and histopathological examination was performed. results: mice treated with phages recovered faster from infectionassociated hypothermia. hours after infection, phage treatment led to a reduction in bacterial loads in lungs and balf. in addition, lung permeability and cytokine production were reduced in phagetreated mice. histopathological examination of the lungs showed less spreading of bacteria to the periphery in phage-treated mice, whereas cellular recruitment into the lung was unaffected. no adverse effects were observed. conclusions: for the first time a highly purified phage against a. baumannii was successfully used in vivo. the current preclinical data support the concept of a phage-based therapy against pulmonary a. baumannii infections. introduction: vap is common in critically ill patients and associated with high morbidity and mortality, especially when caused by antibiotic resistant bacteria. recently, phage therapy has emerged as a promising non-antibiotic based treatment of antibiotic resistant bacterial infections. however, proof-of-concept experimental and clinical studies are missing before its wider use in clinical medicine. the goal of this experimental study was to compare the efficacy of phage therapy versus antibiotics for the treatment of mrsa in a rat model of vap. methods: four hours after intubation and protective ventilation, rats were inoculated via the endotracheal tube with - x cfu (ld ) of the mrsa clinical isolate aw . the animals were subsequently extubated. two hours after bacterial challenge, rats were randomised to receive intravenously either teicoplanin (n= ), a cocktail of lytic anti-s. aureus bacteriophages (n= ) or combination of both (n= ). animals served as control (no treatment). survival by hours was the primary outcome. secondary outcomes were bacterial count in lungs, spleen and blood. kaplan-meier estimates of survival were done and multiple comparisons of survival rates performed using the holm-sidak method. results: treatment with either phages, antibiotics or combination of both significantly increased survival ( %, %, % respectively, compared to % survival for controls, p< . ). there were no statistical differences in survival rates between either forms of treatment ( fig. ) . treatments hinder the systemic extension of the infection into the blood and spleen without impacting bacterial counts within the lungs, but the numbers are too small to perform statistical tests (table ) introduction: the aim of the study was comparative evaluation of the clinical and microbiological efficacy of combination of amikacin thru nebuliser aeroneb pro and standard antimicrobal therapy (amtcomb) with standard antimicrobal therapy (amtst) in treatment of ventilator-associated pneumonia (vap) and ventilator-associated tracheobronchitis (vat) caused by multi-drug resistant gram-negative bacteria. methods: in prospective two-center study with retrospective control included patients with vap and vat. in amtst group (retrospective, n= ) we used combination of meropenem g every h iv as continuous infusion, cefoperazon/sulbactam g every h iv as continuous infusion and amikacin g iv every h. in amtcomb group (prospective, n= ) we used combination of amtst and amikacin inhalation mg every h thru nebuliser aeroneb pro. results: in amtcomb clinical cure rate was %, while in amtst . % (p< . ), clinical pulmonary infection score (cpis) on day was ( - ) points in amtst and ( - ) points in amtcomb (p< . ). recurrence of vap/vat was . % in amtst and . % in amtcomb (p= . ). on day infectious agent titer in tracheal aspirate was ( - ) cfu/ml in amtst group, while (no growth- ) cfu/ml in amtcomb (p= . ). microbiological eradication observed in patients in amtcomb vs in patient in amtst and microbiological persistance observed in patients in amtcomb vs patients in amtst (p= . ). in amtcomb on rd day sputum was less purulent (p= . ). amikacin nebulisation didn't led to deterioration of organ dysfunction: on day there was no difference in platelet count, creatinine and bilirubin levels as compared to day (p= . ; p= . , p= . , respectively). conclusions: addition of amikacin inhalation mg every h thru aeroneb pro nebuliser in patients with vap and vat was more efficacious than intravenous standard antimicrobal treatment with comparable safety profile. introduction: the aim of the study was to assess the effectiveness of inhaled colistin (ic) as an adjunct to systemic antibiotics in the treatment of ventilator-associated pneumonia (vap). methods: icu patients with vap were enrolled in this observational study. resolution of vap was assessed as primary endpoint; eradication of pathogens in sputum, weaning time, duration of icu stay and mortality were assessed as secondary outcomes. patients were split into groups: gr. (n = ) -addition of ic to systemic antibiotics without changing the basic regimen; gr. (n = ) -change in systemic antibiotics according to sensitivity. groups were comparable. ic was administered in a dose of million iu tid (xselia pharmaceuticals aps, denmark). statistical analysis was performed using statistica . (m, σ, newman-keuls test; p < . ). results: vap resolution rate was % in gr. (vs. % in gr. , p = . ); eradication of pathogens from sputum by the th day. treatment was achieved in % of gr. and % in the gr. (n = ) (p> . ); in gr. weaning from ventilation was possible earlier than in gr. - . ± . days. in gr. vs. . ± . days. in gr. (p = . ); in gr. duration of icu stay was shorter than in gr. - . ± . days vs. . ± . days. in gr. (p = . ). no mortality differences were detected. conclusions: administration of inhaled colistin million iu tid is effective as an adjunct to systemic antibiotics in the treatment of vap. this modified treatment promotes a more rapid resolution of vap, earlier weaning from ventilator, reduction of the duration of icu stay, with no impact on mortality. the addition of ic to systemic antibiotics should be considered as second-line regimen in vap patients. factors associated with no de-escalation of empirical antimicrobial therapy in icu settings with high rate of multi-drug resistant bacteria c routsi introduction: de-escalation is recommended in the management of antimicrobial therapy in icu patients [ ] . however, this strategy has not been adequately evaluated in the presence of increased prevalence of multidrug-resistant (mdr) bacteria. the aim of this study was to identify factors associated with no de-escalation in icus with high rate of mdr bacteria [ ] . methods: prospective, multicenter study conducted in greek icus over a -year period. patients with laboratory confirmed infections were included. sofa score on admission, on septic episode and thereafter every h over days, infection site(s), culture results, antimicrobial therapy, and mortality were recorded. only the first septic episode was analyzed. in order to assess the factors associated with no de-escalation, a multivariate analysis was performed. results: a total of patients (admission sofa score ± ) were analyzed. % of those had septic episode on icu admission; % patients had an icu-acquired. de-escalation was applied to ( %) patients whereas it was not feasible in patients ( %) due to the recovery of mdr pathogens or it was not applied, although the microbiology results allowed it, in patients ( %). septic shock on the day of septic episode was present in % and % of patients with and without de-escalation, respectively, p= . ). compared to no de-escalation, de-escalation strategy was associated with a shorter duration of shock ( ± vs. ± days, p< . ) and all-cause mortality ( . % vs. . %, p< . ). multivariate analysis showed that the variables associated with no de-escalation were: a deteriorating clinical course as indicated by an increasing sofa score (or . , p< . ) and a lack of de-escalation possibility due to recovery of mdr pathogens (or . , p= . ). conclusions: deteriorating clinical course and mdr pathogens are independently associated with no de-escalation strategy in critically ill patients. conclusions: the qsofa scale in the prognosis of sepsis does not differ significantly from the sirs criteria, but in the prognosis of mortality is significantly better than sirs. qsofa significantly worse in the prognosis of sepsis and death than the sofa scale. the international task force of sepsis- introduced the quick sequential failure assessment (qsofa) score to supersede the systemic inflammatory response syndrome (sirs) score as the screen tool for sepsis. the objective of this study is to prospectively access the diagnostic value of qsofa and sirs among patients with infection in general wards. methods: a prospective cohort study conducted in ten general wards of a tertiary teaching hospital. for a half-year period, consecutive patients who were admitted with infection or developed infection during hospital stay were included. demographic data and all variables for qsofa, sirs and sofa scores were collected. we recorded daily qsofa, sirs and sofa scores until hospital discharge, death, or day , whichever occurred earlier. the primary outcome was sepsis at days. discrimination was assessed using the area under the receiver operating characteristic curve (auroc) and sensitivities or specificities with a conventional cutoff value of . results: of patients (median age, years [iqr, - ]; male, [ %]; most common diagnosis pneumonia, [ %]) who were identified with infection in general wards, ( %) developed sepsis at a median of (iqr, - ) day, patients ( %) and patients ( %) met qsofa and sirs criteria at a median of (iqr, - ) and (iqr, - ) day, respectively. the qsofa performed better than sirs in diagnosing sepsis, with an auroc of . ( % ci, . - . ) vs . ( % ci, . - . ). with a conventional cutoff value of , qsofa had lower sensitivity ( % [ % ci, %- %] vs. % [ % ci, %- %], p < . ) and higher specificity ( % [ % ci, %- %] vs. % [ % ci, %- %], p < . ) than sirs (table ) . conclusions: among patients with infection in general wards, the use of qsofa resulted in greater diagnostic accuracy for sepsis than sirs during hospitalization. qsofa and sirs scores can predict the occurrence of sepsis with high specificity and high sensitivity, respectively. prognostic accuracy of quick sequential organ failure assessment (qsofa) score for mortality: systematic review and meta-analysis introduction: the purpose of this study was to summarize the evidence assessing the qsofa [ ] , calculated in admission of the patient in emergency department (ed) or intensive care unit (icu), as a predictor of mortality. the hypothesis was that this tool had a good prediction performance. methods: systematic review and meta-analysis of studies assessing qsofa as prediction tool for mortality found on pubmed, ovid, embase, scopus and ebsco database from inception until november . the primary outcomes were mortality (icu mortality, inhospital mortality, and -day mortality). studies reporting sensitivity and specificity of the qsofa making it possible to create a x table were included. the diagnostic odds ratio (lndor) was summarized following the approach of dersimonian and laird using the software r ('mada' package). the summary roc curve was created using the reistma model (bivariate model). the revman software was used to organize the data. results: the search strategy yielded citations. of unique citations, met the inclusion criteria ( , patients). the sensitivity and specificity from each study are shown in fig. . the meta-analysis of the dor was . ( % confidence interval (ci): . - . ) and of the lndor was . ( % ic: . - . ) (fig. ) . the pooled area under the summary receiver operating characteristic (sroc) curve was . . the summary estimative of the sensitivity was . and the false positive rate was . , by bivariate diagnostic random-effects metaanalysis. the chi-square goodness of fit test rejects the assumption of homogeneity, and the fit of the model for heterogeneity was better (p-value = . ). conclusions: the qsofa has a poor performance to predict mortality in patients admitted to the ed or icu. introduction: sepsis and septic shock patients are the most common cause of death in intensive care units. [ ] the aim of this study is to quantify the relationship between hours sequential organ failure assessment (sofa) scores change and in-hospital mortality as a treatment outcome in sepsis and septic shock patients. introduction: an outreach team, akin to a rapid response team, is made up of healthcare professionals assembled together for quick and effective reviews in managing of rapidly deteriorating or gravely deteriorated patients [ ] . this study aimed to look at the variety of patient referrals in terms of their severity, patient dynamics, reasons for referral and their subsequent dispositions. methods: patient records were randomly reviewed retrospectively from july to october . data were collated in an excel spreadsheet for comparison and then sorted in accordance with the clinical questions and percentages calculated. results: from the referrals, the severity criteria was done by calculating the national early warning score (news). it was found that % patients had a score of - , % had a score of - , and % scored more or equal to . % of patients were in the age range - years old. % referrals came from the emergency department (ed) where a consultant was involved in the decision of the referral; of this, % were referred during office hours of am to pm where there was greater manpower to aid management. % referrals came from inpatients on the general wards; % were done during office hours. % of referrals were transferred to ic/hd upon review; % were not, from whom died and were later admitted after procedures ( %) or because they deteriorated further ( %). for reasons for referrals and disposition decisions, see fig. . conclusions: despite having no set criteria for outreach team referrals, the accuracy rate was nearly % admissions to ic/hd based on clinician concerns. there was only % re-admission rate having been re-reviewed when the patients had not been deemed suitable for ic/hd admission initially. therefore referrals were done accurately and safely with the protocol of clinician referral openness directly to ic consultants. introduction: prompt recognition of patient deterioration allows early initiation of medical intervention with reduction in morbidity and mortality. this digital era provides an opportunity to harness the power of machine learning algorithms to process and analyze big data, automatically acquired from the electronic medical records. the results can be implemented in real-time. intensix (netanya, israel) has developed a novel predictive model that detects early signs of patient deterioration and alerts physicians. in this study we prospectively validated the ability of the model to detect patient deterioration in real time. methods: the model was developed and validated using a retrospective cohort of consecutive patients admitted to the intensive care unit in the tel-aviv sourasky medical centera tertiary care facility in israel, between january and december . in this study, we tested model performance in real time, on a cohort of patients admitted to the same icu between june and august . significant events that lead to major interventions (e.g. intubation, initiation of treatment for sepsis or shock, etc.) were tagged upon medical case review by a senior intensivist, blinded to model alerts. these tags were then compared with model alerts. [ ] [ ] [ ] [ ] . reviews occurred despite 'low news' (fig. ) . rrt review led to cc admission in ( . %) cases; median [iqr] news [ ] [ ] [ ] [ ] [ ] [ ] . probability of admission increased with higher news (fig. ), however admissions had 'low news'. of these were excluded due to high news trigger in the preceding hrs or post-operative status. the remaining ( . %) represented genuine low news cases; age [ - ], % male, admission apache ii [ - ] and day sofa [ ] [ ] [ ] [ ] [ ] . admission source was emergency department %, medical %, surgical %. diagnoses are shown in table . no low news patients with sepsis were qsofa positive. cc length of stay was [ ] [ ] [ ] [ ] days and icu mortality was . %. conclusions: a high proportion of rrt activity occurs at low levels of abnormal physiology. despite an association between news and cc admission, news fails to trigger for approximately one in ten admitted cases. clinical concern remains an important component of the escalation of acutely ill patients. meanwhile, novel markers of deterioration should be sought and validated. introduction: although rapid response systems are known to reduce in-hospital cardiac arrest rate, their effect on mortality remains debated. the rapid response call (rrc) is a system designed to escalate care to a specialised team in response to the detection of patient deterioration. there are diurnal variations in hospital staffing levels that can influence the performance of rapid response systems and patient outcomes. the objective of this study was to examine the relationship between the time of rrc activations and patient outcome. methods: review of retrospectively collected, linked clinical and administrative datasets, at a private hospital during a -month period. all patients with medical emergency team activation were included. rapid response calls occurring between : - : were defined as 'out of hours'. results: between january and october there were rrc. the trigger for rrcs activation was nurse concern ( ; . %), modified early warning score ( ; . %) and cardiac arrest ( ; . %). rrcs were "out of hours" being the main activation trigger a modified warning score > . "out of hours" patients had higher icu admissions ( . % versus %) and were more likely to have an inhospital cardiopulmonary arrest (or= . , p< . ). conclusions: the diurnal timing of rrcs appears to have significant implications for patient outcomes. out of hours calls are associated to a poorer outcome. this finding has implications for staffing and resource allocation. and septic shock) and severe sepsis (incl. septic shock) using icd- codes coded as primary and secondary discharge diagnoses and procedural ops codes. we assessed incidences and discharge disposition incl. mortality. results: incidences, mortalities and discharge disposition comparing and and the mean annual increase in incidence rates are reported in tables and . conclusions: the annual increase in standardized sepsis incidence rates is greater than in infections, but similar to the increase in infectious disease patients with organ dysfunction, which are less prone to coding incentives than sepsis codes. an increasing number of patients is discharged to nursing homes and hospice. given the alarming increase in sepsis cases and deaths, this analysis confirms sepsis as a key priority for health care systems. introduction: patients with urgent admissions to the hospital on weekends may be subjected to a higher risk of worse outcomes, which may be due to differences in compliance to established processes. because delays to antibiotic administration is an important measure of sepsis protocol efficiency and has been associated to worse outcomes, we aimed to assess the association of the weekend effect (admissions on weekend) with timing to antibiotic administration. methods: patients included in the sepsis protocol in the emergency department (ed) of hospital sao rafael, from january to july were retrospectively evaluated. sepsis protocol is supposed to be activated to every patient with a suspected sepsis diagnosis in the ed. we evaluated the association of weekend (saturday or sunday) admission with timing to antibiotic administration. introduction: current sepsis guidelines emphasize resuscitation of hypotension to a mean arterial pressure (map) of at least mmhg [ ] . a map less than mmhg appears to be associated with poor outcomes in postoperative patients in the intensive care unit (icu) [ ] . however, extent of hypotension in critically ill septic patients during icu stay and its relationship with adverse outcomes is poorly defined. we determined the magnitude of hypotension in icu patients with a diagnosis of sepsis and its association with major complications. conclusions: reduced mortality may be supposed to be correlated to a quicker recovery of organ damage sepsis related. pcrts should be warranted in the future to corroborate these preliminary data. introduction: the pd- /pd-l immune checkpoint pathway is involved in sepsis-associated immunopathy. we assessed the safety of anti-pd-l (bms- , bristol-myers squibb) and its effect on immune biomarkers and exploratory clinical outcomes in participants with sepsis-associated immunopathy. methods: participants with sepsis/septic shock and absolute lymphocyte count <= cells/μ l received bms- i.v. ( - mg; n= ) or placebo (pbo; n= ) + standard of care and were followed for d. primary endpoints were death and adverse events (aes); secondary endpoints were monocyte (m)hla-dr levels and clinical outcomes. methods: this observational study was performed using a prospective, multi-center registry of septic shock. we compared the -day mortality between patients who were excluded from the new definition (defined as < mmol/l after volume resuscitation) and those who were not (lactate level >= mmol/l after volume resuscitation), from among a cohort of patients with refractory hypotension, and requiring the use of vasopressors. results: of patients with refractory hypotension, requiring the use of vasopressors, had elevated lactate levels, while did not have elevated lactate levels (neither initially nor after volume resuscitation), and ( . %) had elevated lactate levels initially, which normalized after fluid resuscitation (fig. ). thus, these patients were excluded by the new definition of septic shock. significantly lower -day mortality was observed in these patients than in those who had not been excluded ( . % vs . %, p= . ). conclusions: it seems reasonable for septic shock to be defined by the lactate levels after volume resuscitation, however due to small sample size further large scale study is needed. results: significant downregulation (p< . ) of about pro-and anti-inflammatory cytokines, including il- , ip- , tnf-a, mip- a, mip- ß, il- , was documented. ifn-g effect on macrophages and dendritic cells was inhibited at the level of phosphorylated stat . ifn-ginduced expression of cxcl and cxcl in macrophages was reduced. patients treated in vivo with higher dosages of apoptotic cells had lower cytokine/chemokine levels compared to those treated with lower levels, and in inverse correlation to agvhd staging. in vitro binding of apoptotic cells to lps was documented. conclusions: the cytokine storm is significantly modified towards homeostasis following apoptotic cell treatment. the mechanism is multifactorial and was shown to include tam receptor triggering, nfkb inhibition, and lps binding. these results together with previous studies showing significantly higher murine survival in sepsis models of lps and cecal ligation puncture suggest that apoptotic cells may be used to treat patients with sepsis. a multicenter clinical trial in septic patients is planned in . moreover, the urine output significantly increased in survival group. conclusions: the present study suggests that cytokine-oriented critical care using pmma-chdf might be effective the treatment of sepsis and ards, particularly,in the treatment of ards associated with aspiration pneumonia in elderly patients. the polymyxin b immobilized fiber column direct hemoperfusion has an effect for septic shock but has no effect on sepsis: a cohort study and propensity-matched analysis k hoshino introduction: overwhelming cytokine release often referred to as "cytokine storm" is a common feature of septic shock, resulting in multiple organ dysfunction and early death. attenuating this cytokine storm early by eliminating cytokines may have some pathophysiological rationale. our aim was to investigate the effects of extracorporeal cytokine removal (cytosorb) therapy on organ dysfunction and inflammatory response within the first hours from the onset of septic shock. methods: patients with: sepsis of medical origin, on mechanical ventilation, noradrenaline > mg/min, procalcitonin > ng/ml and no need for renal replacement therapy, were randomized into cytosorb and control groups. cytosorb therapy lasted for hours. in addition to detailed clinical data collection, blood samples were taken to determine il- , il- ra, il- , il- , il- , tnf-α, pct, crp levels. introduction: blind pericardiocentesis leading to low success rate and high complication rates such as ventricular wall or oesophageal perforations, pneumothorax or upper abdominal organ injury.real time needle visualisation is allowing us to avoid this major complication [ ] . methods: we presented cases of acute traumatic cardiac tamponade secondary to severe chest injury. both patients presented with haemodynamic instability and echocardiographic features of pericardial tamponade. pericardiocentesis under ultrasound guidance at left parasternal area with needle directed from medial to lateral technique were performed (fig. ) . real time needle tip visualisation done throughout the procedure (fig. a) . needle placement in pericardial space was confirmed with agitated saline and guidewire visualisation (fig. b) . pigtail catheter was inserted and blood was aspirated until the patient were haemodynamically improved. repeated ultrasound was done to confirm the absence of ultrasonographic features of tamponade and complications. results: we demonstrated a successful real time needle visualisation ultrasound guided pericardiocentesis in cases acute traumatic pericardial tamponade. procedural time (time from needle piercing the skin to time needle entering the pericardium) in both cases were less than minute. post procedural ultrasound confirmed no major complications. conclusions: the real time needle visualisation using ultrasound was important to reduce major complications during pericardiocentesis. the safety of the highly invasive procedure can be improved with real time needle visualisation. osman a et al. eur j emerg med (in press), introduction: diagnosis of cardiac tamponade post continuous-flow left ventricle assist devices (cf-lvads) is challenging due to missing pulsatility. recent case study of sublingually microcirculation with incident dark-field imaging (idf) provide a new improved imaging for clinical assessment of cardiac tamponade in a patient with cf-lvad. we sought to examine the changes in microvascular flow index (mfi) as a sign of cardiac tamponade following lvad implantation. methods: off-site quantitative analysis of sublingual microcirculation clips with automated vascular analyses software (ava; microvision medical©), and the velocity distributions followed during admission till discharge in patients with end-stage heart failure treated with cf-lvad complicated by cardiac tamponade. results: eleven out of thirty lvad implantations, males, mean age ± years, april to january , (( heart mate (hm ) and heartmate ii (hm ii) (thoratec corp., ca)), were complicated by rethoracotomy due to early postoperative cardiac tamponade within week. there sublingual microcirculation was examined by a novel incident dark-field imaging (idf) before and daily post-lvad implantation. pre-lvad microcirculation was typical for heart failure, characterized by slowly, sludging movement of red blood cells (rbcs), (fig. a arrows) . directly after implantation, a normal microcirculatory flow was seen with a high rbcs velocity (fig. b) . on the day of tamponade the patients were stable except for severe failure of microcirculation as reflected by drop in mfi (fig. c ) and congestion in venules (* in fig. c ). in out of patients there was a significant drop in mfi before tamponade was clinically recognized (p< . ). shortly after rethoracotomy a quick restoration of microcirculatory flow has been found. conclusions: sublingual microcirculation imaging is a simple and sensitive non-invasive tool in early detection of cardiac tamponade. survey on the use of cardiovascular drugs in shock (ucards) - results: a total of physicians responded. as detailed in table , the respondents think that dobutamine is first-line inotrope to increase cardiac pump function (n= , %) and should be started when signs of hypoperfusion or hyperlactatemia despite adequate use of fluids and vasopressors in the context of low left ventricular ejection fraction are present (n= , %). the most accepted target was an adequate cardiac output (n= , %). the combination of noradrenaline and dobutamine was preferred to single treatment with adrenaline mainly due to possibility to titrate individually (n= , %). the main reason for adding another inotrope was to use synergistic effects of two different mechanisms of action (n= , %). according to respondents, phosphodiesterase-inhibitors should be used in the treatment of predominant right heart failure because of prominent vasodilatory effect on the pulmonary circulation (n= , %). they also believe levosimendan is the only inotrope that does not increase myocardial oxygen demand (n= , %). vasodilators are used in cardiogenic shock to decrease left ventricular afterload (n= , %). there is no experience or no opinion about the use of ß-blockers in shock states (n= , %). conclusions: this web-based survey provided latest trends on inotrope use in shock states which showed considerable diversity among respondents in opinions about its use. introduction: recent literature data clearly indicated that in patients with shock the resuscitation of macro-circulation often does not match with microcirculation and tissue perfusion improvement. unfortunately, the bed-side assessment of regional perfusion remains difficult, particulary in critically ill patients. in the last years thermography has been used in different medical fields but no studies have been performed on the use of this technique in critically ill patients. the aim of this study was to evaluate whether thermography is feasible and may provide useful data during resuscitation of patients with septic shock. methods: in patients with septic shock we collected central systemic temperature and infrared images (flir-t digital camera) of limbs at , , and hours after shock occurrence. thermal pattern distribution of the limbs was obtained by a specific analysis of the images (thermacam™researcher p). a systemic to peripheral temperature gradient called "Δ systemic-limb temperature" was calculated for each single temperature data collected. results: macrocirculatory and perfusion parameters improved in all the patients throughout the study period: mean values of noradrenaline dose decreased from . to . γ/kg/min, mean map increased from to mmhg and mean blood lactate decreased from . to . mmol/l. the "Δ systemic-limb temperature" pattern showed an heterogenous time course in the patients with a mean overall increase at and hours (fig. ) . conclusions: as expected, the regional data obtained by thermography did not match with macrocirculatory and systemic perfusion parameters. the significance and the relationship between treatments and data observed will be investigated by appropriate studies. regional differences in the treatment of refractory septic shockan analysis of the athos- data introduction: vasodilatory shock is a common syndrome with high mortality. despite established care protocols, regional differences in treatment remain. we sought to characterize these differences using data from the recently published athos- study [ ] . methods: individual patient data were analyzed at baseline and at h for regional differences in demographics, clinical characteristics, and treatment patterns, and grouped according to four geographical areas: the united states (us), canada (ca), europe (eu) and australasia (au). p-values were calculated by kruskal-wallis tests for continuous data and chi-square tests for categorical data. subsequent temporal analysis compared changes in the treatment of shock, indexed by changes in patient acuity level. results: regional differences existed with respect to bmi (p= . ), albumin (p< . ), cvp (p= . ), meld score (p= . ), apache ii score (p= . ) and sofa score (p= . ). baseline norepinephrine (ne) and ne equivalent doses were significantly higher in eu (p< . and p= . , respectively), and utilization of vasopressin was correspondingly lower (p< . ). at baseline, stress dose steroids were utilized to a greater extent in the us and ca (p= . ). temporal analysis revealed differences in the utilization of vasopressin and steroids with changes in patient acuity: in eu, increasing acuity was associated with a lower utilization of vasopressin, and in ca, increased acuity was associated with a lower utilization of steroids. steroid utilization was higher with increased level of acuity in au and the us. conclusions: significant differences in the treatment of vasodilitory shock exist globally, with important implications: (a) there are introduction: levosimendan is a calcium sensitizer and katp-channel opener exerting sustained hemodynamic and symptomatic effects. in the past fifteen years, levosimendan has been used in clinical practice also to stabilize at-risk patients undergoing cardiac surgery. recently, the three randomized, placebo-controlled, multicenter studies licorn [ ] , cheetah [ ] and levo-cts [ ] have been testing the peri-operative use of levosimendan in patients with compromised cardiac ventricular function. over smaller trials conducted in the past [ ] suggested beneficial outcomes with levosimendan in peri-operative settings. in contrast, the latest three studies were neutral or inconclusive. we aim to understand the reasons for such dissimilarity. methods: we re-analyzed the results of the latest trials in the light of the previous literature to find sub-settings in which levosimendan can be demonstrated harmful or beneficious. results: none of the three latest studies raised any safety concern, which is consistent with the findings of the previous smaller studies. in levo-cts, mortality was significantly lower in the levosimendan arm than in the placebo arm in the subgroup of isolated cabg patients ( fig. ) [ ] . the trend towards both hemodynamic and long term mortality benefits is maintained in recent meta-analyses [ , ] including the three larger recent studies. conclusions: despite the fact that the null hypothesis could not be ruled out in the recent trials, we conclude that levosimendan can still results: patients were included in levosimendan group and in control group. in the whole population, weaning failure incidence and mortality was comparable between the groups (respectively % vs %, pr , and % vs %, pr= , ). higher assistance duration, longer stay under mechanical ventilation and longer duration of stay in critical care unit were observed in levosimendan group. in the post-cardiotomy sub-group (table ) , weaning failure was lower in levosimendan group ( % vs %, pr , ) and levosimendan was an independent protective factor from weaning failure (or , , pr , ). positive impact of levosimendan may be explained in part by his calcium sensitizer effect and by facilitating recovery of myocardial calcium homeostasis in postcardiotomy cardiac stunning. conclusions: levosimendan failed to reduce the incidence of ecmo weaning failure, except for post-cardiotomy population. renal outcomes of vasopressin and its analogues in distributive shock: a systematic review and meta-analysis of randomized trials introduction: venous return (vr) is driven by the difference between mean systemic filling pressure (msfp) and right atrial pressure (rap) and determines the maximum ecmo flow. msfp depends on stressed volume and vascular compliance. it can be modified by absolute blood volume changes and shifts between stressed and unstressed volume. norepinephrine (ne) may increase stressed volume by constriction of venous capacitance and at the same time increase the resistance to systemic flow. we therefore studied the effects of ne on msfp, maximum ecmo flow and the ecmo pressure head (map-rap). methods: msfp was measured with blood volume at euvolemia and ne to ( . , . and . μg/kg/h) in a closed-chest porcine va-ecmo model (n= , central cannulation with left atrial vent and avshunt) in ventricular fibrillation. the responses of rap and vr (measured as ecmo flow, qecmo) were studied at variable pump speeds including maximum possible speed without clinically apparent vessel collapse at constant airway pressure. results: the ecmo pump speed and qecmo showed a strictly linear relationship (r . to . , range over all conditions) despite increased pressure head, indicating that the maximum qecmo was determined by vr alone. ne led to both increases in msfp and qecmo in a dose dependent way, indicating a rightward shift in the vr plot ( fig. ) via recruitment of stressed from unstressed volume ( table , fig. ). this resulted in an increased msfp during ne despite decreased absolute blood volume ( . ± . l vs. . ± . l, p= . ). the reduced blood volume was associated with hemoconcentration suggesting plasma leakage. conclusions: ne shifts the vr curve to the right, allowing a higher maximum ecmo flow. the ne induced increase in msfp results from recruitment of unstressed volume to stressed volume, which may be modified by changes in vascular compliance. the effects on pump afterload were not limiting. introduction: to locate vessels for percutaneous central venous catheterizations, it may be helpful to apply not only real-time ultrasound (us) guidance but also us-assistance vein prelocation. the aim of this study was to evaluate the superiority of two us methods compared to surface landmark methods by reviewing randomized control trials (rcts). methods: as updating an earlier systematic review [ ] , we searched pubmed and central in november . we included rcts which compared the failure rates of internal jugular or femoral venous cannulations among ) real-time us guidance, ) us-assistance vein prelocation and ) surface landmark methods. a frequentist network meta-analysis was conducted using the netmeta package on r. results: out of citations, rcts ( patients) were eligible. the number of studies comparing outcomes between real-time us guidance vs. surface landmark methods, us-assistance vein prelocation vs surface landmark methods and real-time us guidance vs us-assistance vein prelocation was , and . regarding cannulation failure rate, network meta-analysis in a fix-effect model showed that a p-score was lower in the real-time us guidance than us-assistance vein prelocation ( . vs. . ), by reference to surface landmark methods, and also regarding arterial punctures, a p-score was lower in the real-time us guidance than us-assistance vein prelocation ( . vs. . ). conclusions: based on the present network meta-analysis of rcts, pscores of cannulation failure and arterial puncture were lower in the real-time us guidance, suggesting that the us-assistance vein prelocation is superior than the real-time us guidance, both of which achieve lower rates of failure and arterial puncture compared to the landmark methods. we speculates that the inferiority of real-time guidance is associated with difficulties in manipulating the needle together with an echo probe in targeting relatively smaller veins in children. introduction: we present a case report of 'shoshin beriberi' in a young female who was 'fussy with food' that developed an acutely progressive metabolic acidosis and multi-organ failure requiring intensive care support. methods: our patient was a -year-old british woman who presented to the emergency department (ed) with a ten-day history of diarrhea, vomiting and increasing fatigue. she had a past medical history of gastroparesis, polycystic ovary syndrome (on metformin), laparoscopic cholecystectomy and hysteropexy. she lived with her husband and two children who had viral gastroenteritis two weeks previously. results: the patient had a metabolic acidosis (ph . ) with raised lactate (> ) on initial blood gas in the ed. a . % sodium bicarbonate infusion and hemofiltration were commenced overnight. the patient's ph and lactate remained static with an increasing work of breathing over this period. by morning she developed flash pulmonary oedema and hypotension, the first signs of acute cardiac failure. an echocardiogram displayed severely impaired left ventricular function with ejection fraction of %. the patient was intubated and inotropic support was commenced. it was thought that a micronutrient deficiency may have caused a rapid onset cardiac failure. pabrinex (containing ml of thiamine hydrochloride) was commenced and within hours the patient's metabolic acidosis markedly improved ( fig. ). complete reversal of the cardiac failure occurred over hours. conclusions: shoshin is a rare clinical manifestation of thiamine deficiency [ ] . it is an important differential diagnosis to bear in mind after excluding more common aetiologies of heart failure. especially in this case as our patient had no obvious risk factors at the time of presentation. we suggest empiric use of thiamine should be considered in treatment algorithms for young patients presenting with acute cardiac failure. the pateint had provided informed consent for publication. introduction: takotsubo syndrome (ts) is known to be an acute transient cardiac condition accompanied with acute heart failure. ts is often triggered by critical illness but that has been rarely studied in icu practice.therefore, it is known, that the use of catecholamines can directly induce ts, worsen lvot obstruction, and delay spontaneous recovery in ts patients, it is nearly impossible to avoid their administration in critically ill [ ] . methods: we have analyzed medical records from patients with ts, that were revealed during year in our hospital. ts was defined due to mayo criteria, including transient regional wall motion abnormalities, mildly elevated troponin level and no signs of obstructive cad on coronary angiography. results: out of patients who developed ts in icu or iccu, hemodynamic instability occurred in acute phase of ts in ( %) cases. ( %) of patients were admitted to icu in due to septic shock ( patients), major bleeding ( ), cerebral mass lesion ( ) and ards ( ) and required treatment with catecholamines. general mortality rate in ts patients was ( %), and ( %) in critically ill ts patients. mean duration of noradrenalin infusion was , days, dobutamine infusion , days. patients with ts needed more icu resources and longer icu-stay. mortality rate was higher in ts patients ( %) vs the icu-population ( %), p = . . conclusions: ts seems to be an often cause of lv dysfunction and acute heart failure in critically ill. it seems that ts could be a predictor of worse prognosis in critically ill patients. although catecholamine administration may worsen the patient prognosis and induce further ahf in critically ill patients it rearely can be avoided. introduction: previous studies on readmission following lvad implantation have focused on hospital readmission after dismissal from the index hospitalization. since there are very little data existing, the purpose of this study was to examine intensive care unit (icu) readmission in patients during their initial hospitalization for lvad implantation to determine reasons for, factors associated with, and mortality following icu readmission. methods: this was a retrospective, single center, cohort study in an academic tertiary referral center. all patients at our institution undergoing first time lvad implantation from february to march were included. patients dismissed from the icu who then required icu readmission prior to hospital dismissal were compared to those not requiring icu readmission prior to hospital dismissal. results: among lvad patients, ( . %) required icu readmission. the most common reasons for admission were bleeding and respiratory failure (fig. ) . factors found to be significantly associated with icu readmission were preoperative hemoglobin level of less than g/dl, preoperative estimated glomerular filtration rate < ml/min/ . m , preoperative atrial fibrillation, preoperative dialysis, longer cardiopulmonary bypass times, and higher intraoperative allogeneic blood transfusion requirements. mortality at year was . % in patients requiring icu readmission vs. . % in those not requiring icu readmission (age-adjusted or= . , % ci . to . , p= . ). conclusions: icu readmission following lvad implantation occurred relatively frequently and was associated with significant one-year mortality. these data can be used to identify lvad patients at risk for icu readmission and implement practice changes to mitigate icu readmission. future larger and prospective studies are warranted. atrial fibrillation and infection among acute patients in the emergency department: a multicentre cohort study of prevalence and prognosis t graversgaard odense university hospital, odense, denmark critical care , (suppl ):p introduction: patients with infection presenting with atrial fibrillation (af) are frequent in emergency departments (ed). this combination is probably related to a poor prognosis compared to lone af or infection, but existing data are scarce. aim: to describe the prevalence and prognosis for af and infection individually and concomitantly in an ed setting. introduction: its afterload reducing effects make peep the treatment of choice for cardiogenic pulmonary edema. studies indicate that peep may lower coronary blood flow. its effects on left ventricular contractility is unclear. most of the surrogate measures for cardiac contractility are dependent on afterload and contractility assessment under peep may therefore be biased. we have investigated cardiac contractility under peep with the endsystolic pressure volume relationship (espvr) as a load-independent measure of contractility. methods: patients scheduled for coronary angiography were ventilated with cpap and a full face mask at three levels of peep ( , and cmh o) in random order. structural cardiac pathologies were excluded with echocardiography. at every peep level, left ventricular pressure volume loops (millar conductance catheter with inca system, leycom, netherlands) were obtained. the endsystolic elastance was derived from a pv-loop family under preload reduction with an amplatzer sizing balloon in the inferior caval vein. all participants gave written informed consent. the study was approved by the bernese ethics committee. results: women and men with an age ± years were studied. ejection fraction was ± % at baseline. mean espvr at peep levels of , and were . ± . , . ± . and . ± . mmhg/ml (p = . , repeated measurements anova). dp/dt and ejection fraction did not differ between the peep levels (p= . and . ). conclusions: moderate levels of peep did not influence endsystolic elastance. higher peep and patients in cardiogenic shock should be investigated. introduction: we sought to assess the feasibility of d volumetric analysis with transthoracic echocardiography in critically ill patients. we choose a cohort typical of icu where accurate volumetric analysis is important: hypoxic, mechanically ventilated patients. d analysis is enticing in simplicity and wealth of data available. it is accurate in cardiology patients [ ] but has not been assessed in the icu. methods: patients were imaged within hours of admission. inclusion criteria: adult, hypoxic (p:f < ), mechanically ventilated, doppler stroke volume (sv) assessment possible. echocardiography: seimens sc real-time volumetric analysis with standard b-mode and doppler assessment. images unacceptable if > segments unable to be seen in volumetric planes. d left ventricle (lv) and right ventricle (rv) analysis with tomtec imaging and seimens acuson respectively and compared to doppler derived sv. % limit of agreement considered clinically acceptable [ ] . imaging was optimised for volumetric analysis ( - vols/sec). results: patients, in sinus, in af. no significant difference seen between doppler vs d simpson's biplane, d lv or d rv sv estimation. feasibility, sv values and bias are reported in table and fig. . limit of agreement for corrected doppler vs lv d sv = - % to %; rv d sv = - . % to . %. conclusions: d lv and rv volumetric analysis is feasible in majority of patients requiring mechanical ventilation, however lacks agreement with doppler derived stroke volume assessment. although images may appear sufficient, the semi-automated software appears to underestimate stroke volume. further larger studies using thermodilution are warranted. introduction: body position changes such as leg raising are used to determine fluid responsiveness. we hypothesized that the trendelenburg position increases resistance to venous return. together with abolishment of the hepatic vascular waterfall, this may limit the increase in regional blood flow. methods: inferior vena cava (ivc), portal vein (pv), hepatic, superior mesenteric (sma) and carotid artery blood flows and arterial, right atrial (ra) and hepatic (hv) and portal venous blood pressures were measured in anesthetized and mechanically ventilated pigs in supine and °trendelenburg positions. all hemodynamic parameters were measured during end-expiration at cmh o peep, and at inspiratory hold with increasing airway pressures (awp) of , , and cmh o, respectively. paired t test was used to compare pressures and flows in different positions during end-expiration. repeated measures anova was performed to evaluate the effects of awp on hemodynamic parameters. results: trendelenburg position significantly increased ra, hv and pv blood pressures at end-expiration, while qpv and qsma remained unchanged, qha increased and qivc showed a trend to decrease (table ). in both positions, all blood flows decreased with increasing awp, and the difference between ppv and qsma became smaller, indicating splanchnic blood pooling ( table ). in the trendelenburg position, splanchnic blood pooling was less severe compared to supine position. conclusions: trendelenburg position tended to decrease venous return from inferior vena cava. further increases in rap by augmenting awp led to a decrease in all flows and signs of abolished hepatic vascular waterfall. passive manoeuvers to assess fluid responsiveness evoke complex hemodynamic reactions which are not fully understood. introduction: despite of preventive measures, the incidence of deep venous thrombosis (dvt) in icu patients is estimated to range from - %. while clinical diagnostics is unreliable, ultrasound compression test (uct) has proven to be a highly sensitive and specific modality for the recognition of lower extremity dvt [ ] . delegating this competence to icu nurses can increase uct availability and enable preventive dvt screening. therefore, we decided to conduct a clinical study to evaluate the sensitivity and specificity of uct performed by general icu nurse in icu patients compared to an investigation by icu physician certified in ultrasound. methods: prior to the study, each nurse participating in the study completed one-hour training in uct and examined patients under supervision. then, icu patients without known dvt underwent uct in the femoral and popliteal region of both lower extremities performed by trained general icu nurse. on the same day, the examination was repeated by an icu physician. the results of the examinations of each patient were blinded to each other for both investigators until both tests were performed. in case of a positive test, the nurse immediately reported the result to the icu physician. the sensitivity and specificity of the test performed by general nurse was calculated in comparison with the examination by a specialist. results: a total of patients were examined. both lower extremities were examined in all patients. the prevalence of dvt of , % has been found. the overall sensitivity of the examination performed by general nurse was . %, the specificity % with negative predictive value of . %, positive predictive value of % and accuracy of . %. the results of our study have shown that general icu nurses are able to perform bedside screening of dvt by compression ultrasound test with a high degree of reliability after a brief training. methods: a cytosorb® (cytosorbents, new jersey, usa) ha device was inserted within the cpb circuit in ten patients undergoing elective cardiac surgery. one hour after cpb onset, the activity of coagulation factors (antithrombin (at), von willebrand factor (vwf), factors ii, v, viii, ix, xi, and xii) were measured before and after the device. pre and post device measurements were compared using student ttest, a p value < . was considered statistically significant. results: patients' mean age was . ± . years, % were female, the mean euroscore ii was . ± . . procedures were: coronary artery bypass graft (cabg) ( / ), aortic root replacement ( / ) and cabg combined with aortic valve replacement ( / ). mean cpb duration was . ± . min. pre and post ha measurements of coagulation factors activity are presented in fig. . post-device at and fii activity was significantly lower (respectively from . to . , p= . and from . to . , p= . ) compared to predevice measurement. there was no statistically significant difference between pre-and post-ha measurements for all other coagulation parameters conclusions: pre and post ha cytosorb® measurements for coagulation factor activity were not different except for a small decrease in at and fii activity. this might be related with intra-device consumption or adsorption. further analyses accounting for cpb fluid balance, the entire study population and timepoints are pending. introduction: the aim of this study is to evaluate changes in hemodynamics and microvascular perfusion during extracorporeal blood purification with cytosorb in patients with septic shock requiring renal replacement therapy. methods: eight adult patients with septic shock requiring continuous renal replacement therapy for acute renal failure were enrolled and underwent a -hour treatment with the emodasorption cartridge cytosorb. measurements were taken at baseline before starting cytosorb, after h (t ) and h (t ) and included: blood gases, macrohemodynamic parameters (picco ), vasopressor and inotropic dose, plasma levels of cytokines (interleukin [il]- , il , il , il , tumor necrosis factor alpha) and parameters of microvascular density and perfusion (sublingual sidestream dark field videomicroscopy). procalcitonin was measured at baseline and after h of treatment. results: a non-significant decrease in plasma levels of cytokines was observed over time. hemodynamic parameters and vasopressor requirement remained stable. the microvascular flow index increased significantly at t , total vessel density and perfused vessel density increased at t and t ( introduction: objective renal replacement therapy (rrt) with the oxiris filter is used in sepsis septic shock with aki, but few clinical studies compare the adsorbing effect of oxiris filter on the inflammatory mediators to rrt. the aim of this study is -to confirm whether oxiris decreases cytokines and procalcitonin in sepsis septic shock. -this effect is superior to rrt. -this translates in a better cardio renal response. methods: a coohort study and a propensity-matched analysis included patients admitted to three intensive care (aurelia hospital, european hospital, tor vergata -rome) with a diagnosis of septic shock. patients were submitted to rrt with oxiris filter and patients to rrt.il , procalcitonin, the cardiorenal indices and sofa score were compared before (t ) and at the end of the treatments (t ). all data are expressed as mean±sd. anova one way was used to compare the changes of the variables in the time. p< . was considered statistically significant. results: of patients submitted to rrt with the oxiris filter could be matched to septic patients who received rrt. il and procalcitonin decreased in the oxiris group (p< . ) but not in the rrt group.-map increased (p< . ) and noradrenaline dosage decreased in oxiris group (p< . ), but non in rrt group. also pao /fio ratio, diuresis, sofa improved only in the in the oxiris group (p< . ). conclusions: in sepsis/septic shock patients with aki, il and procalcitonin decrease more in the oxirs group then in the rrt group.this is associated with an improvement of the cardio -renal function and the clinical condition.the study confirms that rrt with oxiris filter may be useful in sepsis/septic shock when other convective/diffusive techinques fail. introduction: advos (hepa wash gmbh, munich, germany) is a recently developed ce-certified albumin-based hemodialysis procedure for the treatment of critically ill patients. in addition to the removal of water-soluble and albumin-bound substances, acid-base imbalances can be corrected thanks to an automatically regulated dialysate ph ranging . to . . methods: patients treated with the advos procedure between in the department of intensive care medicine of the university medical center hamburg-eppendorf were retrospectively analyzed. overall treatments in critically ill patients (mean sofa score ) were evaluated. additionally, subgroup analysis for hyperbilirubinemia, respiratory acidosis and non-respiratory acidosis were conducted. results: severe hyperbilirubinemia (> mg/dl) was present in treatments, while and treatments were performed to treat respiratory (paco > mmhg) and non-respiratory (paco < mmhg) acidosis (ph< . ), respectively. mean treatment duration was h. advos procedure was able to correct acidosis and reduce bilirubin, bun and creatinine levels significantly. the subgroup analysis shows an average bilirubin reduction of % per advos multi treatment in the hyperbilirubinemia group ( . mg/dl vs . mg/dl, p< . ). moreover, ph ( . vs. . , p< . ) and paco ( . vs. . mmhg, p< . ) were corrected in the respiratory acidosis group, while in the non-respiratory acidosis group, an improvement in ph ( . vs. . , p< . ), hco ( . vs. . , p= . ) and base excess (- . vs. - . , p= . ) could be observed. there were no treatment-related adverse events during therapy. conclusions: advos is a safe and effective hemodialysis procedure, which is able to remove water soluble and protein bound markers and correct severe acidosis in critically ill patients. score for timely prescribing (stop) renal replacement therapy in intensive care unit -preliminary study of a mneumonic approach introduction: the moment of initiation of renal replacement therapy (rrt) in critically ill patients and a reason for debate, without having objective criteria that indicate it. the objective of this study was to propose a score to help identify the ideal time for the initiation of rrt, and if there is correlation between this score and intensive care unit length of stay and mortality. methods: patients admitted to the intensive care unit, > -yearsold, to whom rrt were indicated by the intensivist. the study protocol was approved by the hospital das forças armadas ethical committe, and written informed consent was obtained from all patients. the stop was assigned according to the presence or not of each of the items (fig. ). they were classified into groups a and b according to fig. , and the group change was recorded. results: patients admitted to icu in the period, excluded for limitation of therapeutic efforts. were admitted to the study, with the mean age of . years; , % males (n= ). distribution among the groups: a (n= , . %), a ( , . %), a ( , . %), b ( , . %), b ( , . %) e b (no patients). there were statistically significant correlation between group change and mortality (p . ), and between the stop and nephrologist agreement (p . ). there was no correlation between stop value and icu los (p , ) or stop and mortality (p . ). conclusions: the stop value is correlated with hemodialysis indication agreement between intensivists and nephrologists, and not correlated with icu los or mortality. the group change was correlated to increased mortality, in the study population. the significance of stop as a tool in determining the moment of initiation of renal replacement therapy remains a work in progress. introduction: liver transplant (lt) in patients with renal dysfunction presents intraoperative challenges and portends postoperative morbidity. continuous renal replacement therapy (crrt) is increasingly used for intraoperative support; however, there is a paucity of data to support this practice. methods: pilot randomized open-label controlled trial in adults receiving cadaveric lt with a modification of end-stage liver disease (meld) score >= and preoperative acute kidney injury (kdigo stage ) and/or estimated glomerular filtration rate < ml/min/ . m . patients were randomized to intraoperative crrt (icrrt) or standard of care. primary endpoints were feasibility and adverse events. secondary endpoints were changes in intraoperative fluid balance, complications, and hospital mortality. analysis was intention-to-treat. results: sixty patients were enrolled, ( %) were randomized ( to icrrt; to control). mean (sd) was age ( ) years, meld was ( ), % (n= ) had cirrhosis; % (n= ) received preoperative rrt; and % (n= ) were transplanted from icu. one patient allocated to icrrt did not receive lt. seven ( %) allocated to control crossed over intraoperatively icrrt ( ( ) min, with only interruptions (all due to access). icrrt fluid removal was . l (range - . ). fluid balance was . l ( . ) for icrrt vs. . l ( . ) for control (p= . ). postoperative crrt was similar ( % vs. %, p= . ). there were no differences in reexploration (p= . ), mechanical ventilation time (p= . ), reintubation (p= . ), sepsis (p= . ), or mortality (p= . ). conclusions: in this pilot trial of high acuity lt patients, icrrt was feasible and safe. these data will inform the design of a large trial to define the role of icrrt during lt. clinicaltrials.gov: nct . the uptake of citrate anticoagulation for continuous renal replacement therapy in intensive care units across the introduction: the purpose of this descriptive study is to report the trend of citrate anticoagulation uptake, used for continuous renal replacement therapy (crrt), in intensive care units (icus) across the united kingdom (uk). citrate anticoagulation has been used in the uk since , but its uptake since then is unknown [ ] . methods: a survey questionnaire targeted pharmacists working in uk adult icus providing crrt. invitations to participate were distributed utilising the united kingdom clinical pharmacy association online forum as a platform for access. survey administration was by self-completion and submissions were accessible over a total of six weeks. basic demographic data, icu specifications, the citrate system in use and implementation details were sought. a descriptive statistical analysis ensued. results: responses were received of which were analysed after duplication removal. trusts, encompassing a total units, in the uk confirmed use of citrate anticoagulation for crrt. units reported a mean of days to implement a citrate system (range to days). prismaflex® (baxter) and multifiltrate (fresenius) were reported as the most commonly used citrate systems; ( . %) and ( . %) units respectively. conclusions: there are icus in the uk [ ] . we conclude that a minimum of units ( %) use citrate anticoagulation for crrt in uk critical care centres. citrate systems of anticoagulation are becoming an increasing popular choice for regional anticoagulation, falling in line with international guidance [ ] . these guidelines were introduced in which corresponds to increase national uptake. introduction: patients requiring renal replacement therapy (rrt) whilst on significant doses of vasoactive medications have often been deemed unsuitable to undergo ultrafiltration (uf). however with better understanding of the pathophysiology of renal injury [ ] in intensive care patients we hypothesise that vasopressor/inotrope requirement will not significantly increase with uf or with a more negative fluid balance (fb). methods: data was retrospectively collected in a general icu/hdu of adult patients requiring acute rrt for acute kidney injury. patients on chronic dialysis were excluded. percentage change in vasopressor index and mean arterial pressure were combined to form the combined percentage change (cpc) which we used as an index of patient stability. results: patients were assessed undergoing a total of rrt sessions. the mean age was with females and males. mean fb for the hours from start of rrt was + mls (range - to + mls). using a model to correct for significant covariates and plotting hour fb against cpc we found no significant effect of fb on stability p= . (fig. ). mean uf volume was mls (range - mls). there was a non linear relationship between uf and stability with moderate volumes improving but larger volumes worsening stability (fig. ). this did not reach statistical significance (p= . ) so may be due to chance but is likely due to a lack of power. conclusions: fluid balance has no effect on cardiovascular stability during rrt in our cohort but there may be a varying effect of uf depending on volume. introduction: exposure of blood to a foreign surface such as a continuous renal replacement therapy (crrt) filter could lead to activation of platelets (plt) and fibrinogen (fib) trapping. thrombocytopenia has been reported in adults on crrt but data in pediatrics are scarce. our institution uses regional citrate anticoagulation (rca) as standard of care with prefilter hemodilution and hf filters (polysulfone, surface area (sa) . m ) regardless of patients' (pts) age and size. as filter sa is relatively larger in younger pts, we aimed to investigate the impact of crrt filter change on hemostasis parameters in infants on crrt in up to first three filter changes. methods: retrospective chart review results: patients < kg were included, age . ( . - ) months, weight . + . kg, with filters. metabolic disease was the most common principal diagnosis ( / , %), liver failure (lf) was the most common comorbidity ( / , %). all patients received prefilter continuous venovenous hemodiafiltration with minimum dose of ml/ . m /h. thrombocytopenia was common at crrt start ( / , %). plts decreased in % filter changes ( / ) by + % (pre vs post plt ( - ) vs ( - ), p< . ). fibrinogen also decreased from ( - ) to ( - ), p< . ; there was no change in ptt, pt, or inr values before and after filter changes. bleeding events were seen in / ( %) of pts ( / of lf pts vs / others, p= . ), but were not more common in pts who had decrease in plts or fib with filter changes ( % with drop in plts vs % without, p= . ; % with drop in fib vs % without, p= . ). conclusions: thrombocytopenia is common in infants on crrt. further decreases in plt and fibrinogen can be seen in with crrt filter changes if the filters are relatively large compared to patient size. bleeding events seems more related to underlying comorbidity, and less to changes in hemostatis parameters observed with filter change but would need to be confirmed with further studies. intensive monitoring of post filter ionized calcium concentrations during cvvhd with regional citrate anticoagulation: is it still required? introduction: the aim of the present study was to evaluate the role of postfilter calcium concentrations (pfca) in terms of safety and efficacy in large retrospective cohort of patients treated with cvvhd and regional citrate anticoagulation. methods: retrospective, observational study at a university hospital with icus. all patients treated with rca-crrt were included in the study. results: among patients treated with rca-cvvh pfca at the start of the cvvhd was available in pts. the pfca concentrations were in target range ( . - . mmol/l) in the majority of patients ( %), whereas % and % of patients had the pfca below or above the target range, respectively. in the further h of cvvhd treatment the propotion of patients with targeted pfca increased to % and remained stable. at the start of the rca-cvvhd there was a significant but weak correlation between the pfca and ionized systemic ca (ica) with a spearman rank-order correlation coefficient (rho) of . (p < . ). the coefficient of variation of pfca concentraions was significantly higher if compared to the coefficient of variation of ica concentration. using per protocol adaptations the incidence of a severe hypocalcemia (< . mmol/l) was low and present only at first hours of therapy: % and % of patients with pfca below the target range and . % and . % of patients with pfca in target range, at h and h respectively (p< . ). there was no correlation between pfca concentrations and filter lifetime. the results of the present study support the previous reports about higher measurements variation of pfca compared to systemic ica ( ). nevertheless due to the weak correlation of ica and pfca as well as a low number of patients with a severe metabolic complication, the results of our study question the necessity of intensive pfca monitoring during rca-crrt. present results need to be validated in further trials. introduction: in critically ill patients, occurrence of pain is frequent and usually correlates with worse outcomes, such as prolonged icu length of stay (los) and mechanical ventilation. in this regard, pain leads to sympathetic activation, inflammatory mediators and therefore, potentially to organic dysfunction. the aim of this study is to evaluate the relationship between acute pain in critically ill patients and their association with acute kidney injury (aki). methods: retrospective cohort with adults patients admitted between june and june , from the icu of hospital sírio libanês hospital in sao paulo (brazil). main exclusion criteria were: length of stay < h, coma and previous aki. the predictor pain was obtained through daily electronic records according to numerical verbal scale ( - ). the outcome was defined as serum creatinine elevation equal to or greater than . mg/dl and/or greater than % increase at any time after the first hours in the icu. the multivariate analysis was performed by binary logistic regression through distinct groups of early or late predictive factors in relation to aki. results: after the exclusion of patients, the incidence of pain with numerical verbal scale equal to or greater than points was . %. the outcome occurred in . % of the cohort. in the binary regression, using the more early predictive factors, sex and pain presented independent relation with the outcome -adjusted or . ( . - . ) and . ( . - . ), respectively (p < . ). in the analysis conclusions: poor management of icu pain is associated to worse outcomes, including increased risk to aki. the search for a better pain management strategy in the icu scenario should therefore be reinforced. introduction: acute kidney injury (aki) is a common complication in hospitalised patients, strongly associated with adverse outcomes [ ] . a lack of baseline incidence and outcome data limits our ability to assess local strategies aimed at improving aki care. methods: in an audit in three linked inner london hospitals we interrogated our electronic patient data warehouse (cerner millennium power insight electronic data warehouse) with a specially written query to identify cases of aki, defined by kdigo creatinine criteria, in patients aged over y admitted for > h during january to june . we excluded palliative care and obstetric patients. in the absence of premorbid baseline (median - d pre-admission) the admission creatinine value was used. end stage renal disease (esrd) and primary sepsis diagnosis was obtained from icd coding. results: of admissions, we excluded with pre-existing esrd (hospital mortality . %) and with fewer than one creatinine result who could not be assigned aki status (mortality . %). of the remaining there were with aki ( . %), with mortality increasing from no aki group ( . %), to aki stage ( . %), and a further increase to aki stages - ( . %) (p< . ) ( table ) . patients with aki were older (p< . ), more likely to be medical than surgical (p< . ), more likely to have a primary sepsis diagnosis (p< . ) and had higher baseline creatinine (median vs p< . ). no known baseline was found in . % of patients with aki, but their mortality did not significantly differ to those with a baseline ( . % vs . %, p= . ). conclusions: an electronic query identified the local burden of aki and it's associated hospital-mortality; such baseline data is essential to assess the effect of quality improvement interventions in aki prevention and care. introduction: acute kidney injury (aki) is a common condition in critically ill patients [ , ] . loop diuretics are generally used as first line treatment. however, controlled trials show controversial results. we ought to search systematically and realize a metaanalysis on the matter. methods: an electronic search of randomized clinical trials in adult patient treated with diuretics for aki compared with standard treatment or a control group was conducted. the primary objective of the analysis was to assess recovery of renal function. secondary endpoints included time to recovery of renal function, need for renal replacement therapy (rrt), mortality in the intensive care unit (icu) and complications. introduction: increased venous pressure is one of the mechanism leading to acute kidney injury (aki) after cardiac surgery. portal flow pulsatility and discontinuous intra-renal venous flow are potential ultrasound markers of the impact of venous hypertension on organs. the main objective of this study was to describe these signs after cardiac surgery and to determine if they are associated with aki. methods: this single center prospective cohort study (nct ) recruited adult patients able to give consent. ultrasound studies were performed before cardiac surgery and repeated on post-operative day (pod) , , and . abnormal portal and renal venous flow patterns are defined in fig. . the association between the studied markers and the risk of new onset of aki in the following hours period following an assessment was tested using logistic regression with a % confidence interval. clinical variables associated with the detection of the signs were tested using generalized estimating equation models. this study was approved by the local ethics committee. results: during the study period, patients were included. the presence of the studied ultrasound signs is presented in fig. . during the week following cardiac surgery, patients ( . %) developed aki, most often on pod ( . %). the detection of portal flow pulsatility and severe alterations in renal venous flow (pattern ) at icu admission (pod ) were associated with aki in the subsequent hours period and was independently associated with aki in multivariable models including euroscore ii and baseline creatinine ( table ). the variables associated with the detection of abnormal portal and renal patterns were associated with lower perfusion pressure, higher nt-pro-bnp and inferior vena cava measurements (table ) . conclusions: abnormal portal and intra-renal venous patterns are associated with early aki after cardiac surgery. these doppler features must be further studied as potential treatment targets to personalize management. introduction: acute kidney injury (aki) is very prevalent after cardiac surgery in children, and associated with poor outcomes [ ] . the present study is a preplanned sub-analysis of a prospective blinded observational study on the clinical value of the foresight nearinfrared spectroscopy (nirs) monitor [ ] . the purpose of this subanalysis was to develop a clinical prediction model for severe aki (saki) in the first week of picu stay. methods: saki was defined as serum creatinine (scr) >/= times the baseline, or urine output < . ml/kg/h for >/= h. predictive models were built using multivariable logistic regression. data collected during surgery, upon picu admission, as well as monitoring and lab data until h before saki onset, were used as predictors. relevant predictors with a univariate association with saki, were included in the models. accuracy of the models was tested using bootstraps, by auroc and decision curves. results: children were enrolled, admitted to the picu of the leuven university hospitals after cardiac surgery, between october and november . patients were excluded. children ( . %) developed saki in the first week of picu stay. a multivariate model with admission parameters (maximum lactate during surgery, duration of cpb, baseline scr, rachs and pim scores), and postoperative measurements (average heart rate, average blood pressure, hemoglobin, lactate), was most predictive for saki ( fig. ) . conclusions: the risk of saki in children after congenital cardiac surgery could be predicted with high accuracy. future models will also include medication data. these models will be compared against and combined with nirs oximetry data to investigate the independent and added predictive value of the foresight monitor. introduction: acute kidney injury (aki) occurs in over % of the patients in the intensive care unit (icu). the predominantly ethiology of aki is septic shock, the most common diagnosis in the icu. aki significantly increases the risk of both morbidity and mortality [ ] . methods: icu patients with septic shock was studied within hrs from admission. patients after cardiac surgery served as control group. all patients were sedated and mechanically ventilated. renal blood flow (rbf) and glomerular filtration rate (gfr) were obtained by the infusion clearance of paraaminohippuric acid (pah) and by extraction of cr-ethylenediamine ( cr-edta). n-acetyl-β -d-glucosaminidase (nag), was measured. results: rbf was % lower, renal vascular resistance % higher and the relation of rbf to cardiac index was % lower in patients with septic shock compared to the control group. gfr ( %, p= . ) and renal oxygen delivery (rdo ) ( %) where both significantly lower in the study group (table ) . there was no difference between the groups in renal oxygen consumption (rvo ) but renal oxygen delivery was almost % lower in septic shock patients. renal oxygen extraction was significantly higher in the study group than in the control group. in the study group, nag was . ± . units/mikromol creatinine more, i.e times the value in patients undergoing cardiac surgery [ ] . conclusions: sepsis related aki is caused by a renal afferent vasoconstriction resulting in a reduced rbf and lowered rdo in combination with an anchanged rvo , this results in a renal oxygen supply/ demand mismatch. introduction: the primary aim was to determine if the addition of daily creatine kinase (ck) measurement was usefully guiding decision making in intensive care units within greater glasgow and clyde. methods: after a change to the daily blood ordering schedule to include ck, a retrospective audit was carried out covering a -month period within intensive care units. all patients with ck > units/ litre were included. basic demographics, apache score and admitting diagnosis were recorded. utility of ck was assessed by determining the associated diagnosis and whether the diagnosis was first considered (diagnostic trigger) due to ck level, clinical suspicion or haematuria. additionally, it was determined if and what actions had been taken based on the raised ck and associated diagnoses. results: data was collected from / / to / / . patients were captured with ck > units/litre from an average combined admission rate of patients/month [ ] . total male patients ( . %) and female ( . %). age range to years (mean . ). apache score range to (mean . ) with estimated mean mortality of . %. patients ( . %) had associated diagnoses with elevated ck including: burns ( . %), compartment syndrome ( . %), myocardial infarction ( . %), myositis/myocarditis ( . %), neuroleptic malignant syndrome ( . %), rhabdomyolysis ( . %), serotonin syndrome ( . %), surgical procedure ( . %). as outlined in fig. the diagnostic trigger was the routine ck measurement in patients ( . %), prior clinical suspicion ( . %), haematuria ( . %) and unclear in ( . %). action was the correlation analysis showed the egfrs from every formula could all to some extent reflect the glomerular function or gfr accurately. the gfr (scys) formula was a quickly and accurate method for estimating gfr and may apply clinically in critically ill patients. perioperative chloride levels and acute kidney injury after liver transplantation: a retrospective observational study s choi introduction: the risk of developing acute kidney injury (aki) after liver transplantation in the immediate postoperative period ranges between to %. most studies in critically ill and surgical patients evaluated the link between chloride-rich resuscitation fluids, not serum chloride levels, and the incidence of aki. the association between preoperative chloride level or difference in perioperative chloride levels and the incidence of postoperative aki after liver transplantation were evaluated. methods: adult patients (>= years old) who underwent liver transplantation at seoul national university hospital between and were included in the retrospective analysis. the difference between preoperative serum chloride level and the immediate postoperative serum chloride level was defined as intraoperative chloride loading. postoperative aki within days of liver transplantation was diagnosed according to the rifle criteria. patients were divided into normochloremia group ( - meq/l), hypochloremia group (< meq/l), or hyperchloremia group (> meq/l) according to their preoperative chloride level. intraoperative chloride loading was defined as the difference between preoperative serum chloride level and immediate postoperative serum chloride level. . ) compared to patients with preoperative normochloremia. meld scores > and age > years were also associated with increased risk of aki. intraoperative chloride loading was not a significant risk factor for aki after liver transplantation. conclusions: preoperative hyperchloremia and hypochloremia were both associated with an increased risk of developing aki in the immediate postoperative period after liver transplantation. introduction: perioperative acute kidney injury (aki) is associated with significant morbidity and mortality [ ] . certain urinary biochemical parameters seem to have a standardized behavior during aki development and may act as surrogates of decreased glomerular filtration rate (gfr) aiding in early aki diagnosis [ ] . aim of this prospective observational study was the evaluation of urinary biochemical parameters as early indicators of aki in a cohort of major surgery patients. methods: patients were studied. aki was defined according to akin criteria within hrs after surgery [ ] . at pre-defined time points (preoperatively, recovery room [rr] and on postoperative days [pod] to ) simultaneous serum and urine samples were analyzed additional studies must confirm these findings and reevaluate these simple parameters as potential aki monitoring tools. urinary liver-type fatty acid-binding protein is the novel biomarker for diagnosis of acute kidney injury secondary to sepsis t komuro, t ota shonan kamakura general hospital, kamakura, kanagawa, japan critical care , (suppl ):p introduction: acute kidney injury (aki) is the predictor of poor prognosis for the patient with sepsis and septic shock. several diagnostic criteria for aki is used on clinical settings, but useful biomarker is not known yet. urinary liver-type fatty acid-binding protein(l-fabp) is associated with kidney function and aki [ ] , but that is not still discussed about aki secondary to sepsis. thus, we conducted the study of the association between urine l-fabp and aki with secondary to sepsis. (fig. ) . the cut-off line of l-fabp was . μg/g cr. conclusions: l-fabp can be the novel biomarker for diagnosis of aki. further investigation need for diagnostic value of l-fabp and usefulness of early intervention for aki used by l-fabp. introduction: biotransformation of -hydroxyvitamin d to active , (oh) d occurs primarily in the kidney. our aim was to explore whether this process was altered in patients with acute kidney injury (aki). methods: consecutive patients admitted to critical care at a tertiary hospital were recruited. the aki group comprised patients with kdigo stage ii or stage iii aki; the non-aki group were patients requiring cardiovascular or respiratory support, but with no aki. vitamin d metabolite concentrations were measured on days , and . statistical analysis included comparison between groups at each time point, and longitudinal profiles of vitamin d metabolites. results: interim analysis of participants ( % of the recruitment target) showed that , (oh) d concentrations were significantly lower in patients with aki at day and day . considering longitudinal changes, -hydroxyvitamin d profiles were not different between the groups ( fig. ) but there was a trend towards a longitudinal increase in , (oh) d in patients without aki, which was not seen in aki patients (fig. ) . conclusions: interim analysis indicates significant differences in concentrations of , (oh) d, but not (oh)d, in critically ill patients with aki. recruitment is ongoing and further results are awaited. introduction: acute renal failure affects from % to % of patients in the intensive care units (icus) and it is associated with excess mortality. hydratation is a useful preventive measure but it is often controindicated in critically ill patients who, on the contrary, often benefit by a strictly conservative strategy of fluid management. fenoldopam, a selective dopamine -receptor agonist, increases renal blood flow and glomerular filtration rate by vasodilating selectively the afferent arteriole of renal glomerulus. the aim of our study is to compare renal effects of fenoldopam and placebo in critically ill patients undergoing a restrictive fluid management. methods: we enrolled patients admitted to our icu. patients were assigned by randomization to study groups: fenoldopam (n= ) and placebo (n= ). fenoldopam was infused continuously at , mcg/kg/ min and equivalent volume for placebo during a period of seven days. creatinine, cystatin c and creatinine clearance were daily measured as markers of renal function. the incidence of aki according to rifle criteria (risk, injury, failure, loss, end stage kidney disease) was also calculated. results: patients with a negative fluid balance at the end of the week (~- ml, p= , ) were included in the analysis, in the placebo group and in the fenoldopam group. there were not significant differences in the trend of creatinine, creatinine clearance, cystatin c and in the incidence of aki between the groups during the week of infusion. conclusions: a continuous infusion of fenoldopam at , mcg/kg/ min does not improve renal function and does not prevent aki in critically ill patients undergoing a strictly conservative strategy of fluid management. introduction: this study aims to evaluate the efficacy of a protocol implemented for dysphagia risk factors [ ] in hospitalized patients in a cicu (coronary intensive care unit). methods: patients hospitalized in the cicu of a medium-sized hospital in presidente prudente, sp, brazil, were subjected to a survey that screened for dysphagia during the period from january of to september of . patients with at least one risk factor for dysphagia were evaluated by a phonoaudiologist and are the subject of this study. the information was statistically analyzed using epi info, version . . . software. considering significant p < . two-tailed, for logistic regressions multivariate estimated in the sample. results: for this study patients were selected, of which . % were male and the mean age was . ± . years. a higher incidence of dysphagia was observed among patients who had at least one of the following risk factors: stroke (odds ratio . p< . ); brain tumor (or . p= . ); chronic obstructive pulmonary disease (copd) (or . p= . ); degenerative diseases (or . p< . ); lower level of consciousness (or . p< . ); ataxic respiration (or . p< . ); aspiration pneumonia (or . p< . ); orotracheal intubation > h (or . p< . ); tracheostomy (or . p< . ); airway secretion (or . p< . ); nasoenteral tube (or . p< . ); gastrostomy (or . p= . ). there was no statistical significance for age > , traumatic brain injury, oropharyngeal surgery and unfavorable dentition. four factors appeared less than times and could not be analyzed (chagas disease, human immunodeficiency virus (hiv), orofacial burn and excess saliva). conclusions: we concluded that the dysphagia triage protocol insertion was effective to identify dysphagic patients and can be used as an additional tool in the intensive care risk management. physiological bases of this age old concept, more recently applied to endotracheal intubation, have never been confirmed by current methods. we therefore decided to study the effects of an apnea oxygenation period under hfnc oxygen therapy by means of a novel modelization of the respiratory system. methods: firstly, an airway model was built with anatomical, physical and physiological attributes similar to that of a healthy subject (fig. ) . this system reproduces the physiological evolution of intrapulmonary gases during apnea by progressively increasing co levels after having cut off previous o supplies (fio %). secondly, the effects of a hfnc apnea oxygenation of l/min with an fio of % were analyzed by collecting intrapulmonary gas samples at regular intervals (fig. ) . results: after minute of apnea oxygenation, intrapulmonary oxygen levels remain stable at %. after minutes, oxygen fraction reaches %, and increases up to % in minutes. regarding co levels, no significant modifications were observed. conclusions: a novel experimental and physiological model of the respiratory system has been developed and confirms the existence of an alveolar oxygen supply as well as the lack of a co washout during hfnc apnea oxygenation. however, these effects are only observed after a delay of about . to minutes. therefore, the clinical interests of this technique to reduce apnea-induced desaturation during intubation of a hypoxemic patient in the icu seem limited without adequate preoxygenation. combination of both preoxygenation and apnea oxygenation by hfnc can most likely explain positive results observed in other clinical studies. effect of % nebulized lignocaine versus % nebulized lignocaine for awake fibreoptic nasotracheal intubation in maxillofacial injuries in emergency department h abbas, l kumar king george's medical university,lucknow,india, lucknow, india critical care , (suppl ):p introduction: topical lignocaine is most commonly used pharmacological agent for anaesthetizing upper airway during fibreoptic bronchoscopy. we compare the effectiveness of two different concentrations, % lignocaine and % lignocaine, in nebulised form for airway anaesthesia during awake fibreoptic nasotracheal intubation in terms of patient's comfort and optimal intubating conditions, intubation time. methods: institutional ethics committee approved the study and written informed consent obtained; patients of either sex, between - years age with anticipated difficult airway planned for intubation were included for this study. patients were randomly allocated into two groups (a and b) based on sealed envelope method; patients and observers were blinded by using prefilled syringes of lignocaine.one group was nebulized with ml of % lignocaine(group a) and other with ml of % lignocaine(group b) in coded syringes via ultrasonic nebuliser for minutes followed by inj midazolam . mg/kg iv and inj fentanyl microgram/kg iv just before the procedure. the fibreoptic broncoscope was introduced via nostril and the other nostril was used for oxygen insufflation ( - l/min). the fibroscope was introduced through the glottic opening and visualising tracheal rings and carina.the endotracheal tube railroaded over the fiberscope and cuff inflated. results: the primary outcome measure was patient's comfort during awake fibreoptic nasotracheal intubation. the mean patient comfort puchner scale score of group a was . ± . and of group b was . ± . . the mean value of puchner scale of group b was significantly higher.the mean procedural time of group b was significantly higher ( . %) as compared to group a (p< . ). the no of intubations attempts did not differ between the two groups. conclusions: % nebulised lidocaine provided adequate airway anaesthesia and optimal intubating conditions, patient comfort, stable hemodynamics. introduction: this systematic review and meta-analysis aims to investigate whether video laryngoscopy (vl) improves the success of orotracheal intubation, when compared with direct laryngoscopy (dl). methods: a systematic search of pubmed, embase, and central databases was performed to identify studies comparing vl and dl for emergency orotracheal intubations outside the operating room. the primary outcome was rate of first pass intubation. subgroup analyses by location, device used, clinician experience, and clinical scenario were performed. the secondary outcome was rate of complications. results: the search identified studies with , emergency intubations. there was no overall difference in first-pass intubation with vl compared to dl. subgroup analysis showed first-pass intubations were increased with vl in the intensive care unit (icu) ( . ( . - . ); p< . ), but not in the emergency department or pre-hospital setting. rate of first-pass intubations were similar with glidescope® and dl, but improved with the cmac® ( . ( . - . ); p= . ). there was greater first-pass intubation with vl than dl among novice/trainee clinicians (or= . ( . - . ); p< . ), but not among experienced clinicians or paramedics/nurses. there was no difference in first-pass intubation with vl and dl during cardiopulmonary resuscitation or trauma. vl was associated with fewer oesophageal intubations than dl (or= . ( . - . ); p= . ), but more arterial hypotension (or= . ( . - . ); p= . ). conclusions: in summary, compared to dl, vl is associated with greater first-pass emergency intubation in the icu and among less experienced clinicians. vl is associated with reduced oesophageal intubations but a greater incidence of arterial hypotension. compared success rate between direct laryngoscope and video laryngoscope for emergency intubation, in emergency department: randomized control trial p sanguanwit, n laowattana ramathibodi hospital, bangkok, thailand critical care , (suppl ):p introduction: video laryngoscope was used as an alternative to intubate in the emergency room, designed for tracheal intubation more success [ , ] . methods: we performed a prospective randomized controlled trial study of patients who had sign of respiratory failure or met indication for intubation from july to june . patients were randomly by snose technique; assigned to video laryngoscope first or direct laryngoscope first. we collect the demographics, difficult intubation predictor, rapid sequence intubation, attempt, cormack-lehane view and immediate complication. primary outcome was first attempt success rate of intubation. results: first attempt success rate of video laryngoscope was . % trend to better than direct laryngoscope was . %, (p= . ), good glottic view (cormack-lehane view - ) of video laryngoscope was . % better than direct laryngoscope . %, and statistically significant (p= . ), no statistical significant in immediate serious complication between direct laryngoscope or video laryngoscope. conclusions: compared to the success rate between using video laryngoscope or direct laryngoscope for intubation, video laryngoscope trend to better success rate, and better glottic view. -year cohort of prehospital intubations and rescue airway techniques by helicopter emergency medical service physicians: a retrospective database study p de jong, c slagt, n hoogerwerf radboudumc, nijmegen, netherlands critical care , (suppl ):p introduction: in the netherlands the pre-hospital helicopter emergency medical service (hems) is physician based and an adjunct to ambulance services. all four hems stations together cover / specialist medical care in the netherlands. in many dispatches the added value is airway related [ ] . as part of our quality control cycle, all airway related procedures were analysed. high quality airway management is characterized by high overall and first pass endotracheal intubation (eti) success [ ] . methods: the hems database was analysed for all patients in whom prehospital advanced airway management was performed in the period - . balloon/mask ventilation, supraglottic airway (sga) devices, total intubation attempts, cormack & lehane (c&l) intubation grades, successful eti, primary and rescue surgical airway procedures and professional background were reviewed. results: in the -year period, there were dispatch calls. in total patients were treated in the prehospital setting by our hems. of those, required a secured airway. eti was successful in of ( . %). in the remaining patients ( fig. ) an alternative airway was needed. rescue surgical airway was performed in . %, . % received a rescue sga, rescue balloon/mask ventilation was applied in . % of cases, was allowed to regain spontaneous ventilation and in . % of patients all airway management failed. hems physicians, ambulance paramedics, hems paramedics and others (e.g. german emergency physicians) had eti first pass success rates of . %, . %, . % and . % respectively (fig. ) . difficult laryngoscopy (no epiglottis visible) was reported in . % of patients (table ) . conclusions: our data show that airway management performed by a physician based hems operation is safe and has a high overall eti success rate of . %. the total success rate is accompanied by a high first pass eti success rate. introduction: incidences associated with endotracheal tubes are frequent during mechanical ventilation (mv) of intensive care unit (icu) patients and can be associated with poor outcomes for patients and detrimental effects on health care facilities. here, we aimed to identify factors associated with event occurrence due to unsafe management of endotracheal tubes (e-umet). methods: a retrospective observational study was conducted in three icus: one surgical icu, one stroke icu, and one emergency department, at a tertiary hospital in japan from april to march . patients requiring mv and oral intubation during their icu stay were included. the primary finding was the incidence rate of e-umet (biting, unplanned extubations, and/or displacement of the endotracheal tube). the patients were divided into two groups: with or without e-umet. to investigate e-umet, potential factors possibly related to its occurrence were obtained from electronic medical records. we conducted univariable and multivariable analyses to investigate e-umet factors. results: of patients, e-umet occurred in ( . %). the mean and standard deviation for age and acute physiology and chronic health evaluation (apache) ii score were ( ) and ( ), respectively. according to a multivariate logistic-regression analysis, significant risk factors associated with e-umet included patients of neurosurgery (odds ratio (or) . ; % ci, . - . ; p= . ), sedative administration (or . ; % ci, . - . ; p< . ), and higher richmond agitation-sedation scale (rass) scores (or . ; % ci, . - . ; p< . ). the use of a restraint (or . ; % ci, . - . ; p= . ) was an independent factor associated with a lower probability of e-umet. conclusions: this study suggests that risk factors associated with e-umet include neurosurgery, higher rass scores, and the administration of sedatives. patients with these factors and longer oral intubation periods might require extra care. introduction: the use of nasal high flow (nhf) as a respiratory support therapy post-extubation has become increasingly more common. nhf has been shown to be non-inferior to niv and reduces escalation needs compared to conventional oxygen therapy. clinical outcomes using nhf in patients with type ii respiratory failure (rf) is less well understood. our aim was to determine if nhf can be used successfully when extubating type ii rf patients compared to type i rf. methods: we conducted a retrospective observational study on the use of nhf as an extubation respiratory support in (n= ) consecutive patients in icu over a -month period. primary outcome was the need for escalation in therapy (niv, intubation and palliation) post extubation. patients were categorised as high risk if they scored >= from: age>= years, bmi>= and >= medical comorbidity. results: analysis was conducted on all fifty-six (n= ) patients. type i rf group was composed of (n= ) patients with a mean age of . (±sd) years. type ii rf group had (n= ) patients with a mean age of . (±sd) years. in type i rf patients ( %) were successfully extubated with nhf compared to patients ( . %) in type ii. in type ii rf the outcomes were more variable with a greater requirement for niv. of these patients % required niv, . % required intubation and . % received nhf therapy for palliation. a higher average bmi ( . vs . kg/m ) was found in unsuccessfully vs successfully extubated patients in type ii rf. in type i rf escalation of therapy was equally distributed with % in each category. conclusions: the use of nhf for respiratory support post-extubation may become standard practice for type i rf in critical care settings. our data suggests that nhf can be used but with caution in type ii rf and clinicians should risk stratify patients to identify those at risk of re-intubation and post-extubation respiratory failure. introduction: pathogenesis of ventilator-associated pneumonia (vap) relies on colonization and microaspiration. oral topical decontamination reduced the vap incidence from to % [ ] . the persistence of antiseptic effect in the oral cavity is questionable; we hypothesize that continuous oral antiseptic infusion may offer a better decontamination. aim of the work: we developed endotracheal tube that allows continuous oral infusion of chlorhexidine (chx), and we want to test the technique versus the conventional on bacterial colonization. (provisional patent: ) methods: a two identical bio models for the upper airways were manufactured by ( dx diagnostics, usa) to adapt the modified and the ordinary endotracheal tubes (ett). the two techniques tested were using six hourly disinfection with chx (group a) versus disinfection through the hours infusion technique (group b). five microorganisms plus mixed bacteria were used and each was tested for five times. normal saline was used constantly to irrigate the biomodels and ten ml aliquot was collected by the procedure end. culturing of the aliquots from decanted broth pre and post disinfection was performed. the time to apply chx by practitioner was also compared. results: there was a trend towards lower bacterial growth in group a in experiments which reach statistical significance only with pseudomonas aeruginosa (p= . ). in one experiment the growth was lower in group b (fig. ) . additionally there was time saving advantage in group b ( ± . versus ± . min, p= . ). conclusions: the novel technique got at least non inferior results, plus time saving advantage. these results may warrant future clinical trial. monitoring airways non invasive online analysing different particle flow from the airways is never done before. in the present study we use a new technology for airway monitoring using mass spectrometric analysis of particle flow and their size distribution (pexa particles in expired air). the exhaled particles are collected onto a substrate and possible for subsequent chemical analysis for biomarkers. our hypothesis was that by analysing the particle flow online, we could optimise the mechanical ventilation. our hypothesis was that a small particle flow would probably be more gentle for the lung than a large particle flow when the lung is squeezed out and the majority of all small airways are open. methods: in the present study we analyse the particle flow from the airways in vivo, post mortem and during ex vivo lung perfusion using different ventilation modes; volume controlled ventilation (vcv) and pressure controlled ventilation (pcv) comparing small tidal volumes( ) versus big tidal volumes( ) at different peep (positive end-expiratory pressure) and after distribution of different drugs in six domestic pigs. results: we found that vcv resulted in a significant lower particle flow than pcv in vivo but in ex vivo settings the opposite was found (fig. ). in both in vivo and ex vivo settings we found that big tidal volume resulted in a larger particle flow than small tidal volumes.air. the opening and the closure of the small airways reflect the particle flow from the airways. we found that different ventilation modes resulted in different particle flow from the airways. we believe this technology will be useful for monitoring mechanical ventilated patients to optimise ventilation and preserve the lung quality and has a high potential to detect new biomarkers in exhaled air. introduction: malaria is a common problem in underdeveloped countries, with an estimated mortality of more than one million people per year. pulmonary involvement is one of the most serious manifestations of plasmodium falciparum malaria. non-invasive ventilation (niv) decreases muscular works and improves gas exchange by recruitment of hypoventilated alveolus. in this context, we analyze the impact of the use of non-invasive ventilation in malaria with pulmonary dysfunction. methods: it's a retrospective cohort study. we analyzed electronic records of patients who were diagnosed with malaria, with acute respiratory failure, who underwent respiratory therapy with niv between - within the intensive care unit (icu). the study variables were: icu mortality, length of hospital stay, niv time and outcome groups. statistical analysis was performed with the pearson correlation coefficient, with significance level of p < . . the statistics were performed using the bioestat . program. results: thirty-one patients were included in the study. four results were analyzed according to table and fig. . % of the patients were discharged from the hospital. pearson's correlation coefficient analysis showed statistical significance in the group (niv/discharge) in the analysis of patients hospitalized versus niv ( % ci = . to . <(p) = . ). conclusions: the use of niv was positive in patients using this resource as first-line treatment of malaria in the fight against respiratory decompensation, with improvement of symptoms. introduction: cpap is used to improve oxygenation in patient with arf. we aimed to determine non-inferiority (ni) of helmet cpap to facemask in arf based on physiological (heart rate (hr) and respiratory rate (rr)) and blood gas parameters (pao and paco ). we also compared patients' perception in dyspnea improvement after cpap using dyspnea scale (visual analogue scale (vas)) and likert score. methods: we randomized patients to helmet (n= ) and facemask (n= ) with . % of arf was due to acute pulmonary edema. cpap was applied for minutes. patients' physiological and blood gas parameters were recorded before and after intervention. patients then marked on dyspnea scale and likert score. ni of helmet would be declared if confidence interval (ci) of mean difference between groups (helmet's mean minus facemask's mean) in improving physiological, blood gas parameters and dyspnea scale was no worse than predetermined non-inferiority margin (nim). secondary outcome was to compare incidence of discomfort and mucosal dryness between groups. methods: this is a single center retrospective study performed in the icu of tel aviv medical center, israel, a tertiary academic referral hospital. using the electronic medical record system and intensix predictive critical care system for analysis, all patients admitted to the icu between . and . were assessed. respiratory deterioration in mv patients was defined as acute adjustment of fio increase > % or peep increase > cmh o that persisted for at least hours. the primary outcome was icu mortality. secondary outcome was length of icu stay (los). a chi square test for trends was used for the significance of mortality data and a one way anova test for los. results: mv patients were admitted to the icu with an overall mortality of . %. mortality and los were tripled in patients who experienced at least one respiratory deterioration when compared to no events ( . % vs. . %, p< . and . vs. . days, p< . respectively) (fig. ) . increased events of respiratory deteriorations showed significant trend of increased mortality (p< . ). conclusions: in mv patients, a single respiratory deterioration event carries a times higher mortality rate and length of stay (los). any additional event further increases both parameters. association of lung ultrasound score with mortality in mechanically ventilated patients j taculod, jt sahagun, y tan, v ong, k see national university hospital singapore, singapore, singapore critical care , (suppl ):p introduction: lung ultrasound is an important part of the evaluation of critically ill patients. it has been shown to predict recruitability in acute respiratory distress syndrome. however, little is known about the application of lung ultrasound in predicting mortality in mechanically ventilated patients. methods: observational study of mechanically ventilated patients admitted to the medical intensive care unit (icu) of a tertiary hospital (national university hospital, singapore) in and . only the first icu admissions of these patients were studied. lung ultrasound was done at six points per hemithorax and scored according to soummer (crit care med ): normal aeration = ; multiple, well-defined b lines = ; multiple coalescent b lines = ; lung consolidation = . the lung ultrasound (lus) score was calculated as the sum of points (score range - ). we analysed the association of lus score with icu/hospital mortality, using logistic regression, adjusted for age and acute physiology and chronic health evaluation (apache) ii score. results: patients were included (age . ± . years; female [ . %]; apache ii . ± . ; sepsis diagnosis [ . %]). icu and hospital mortality were . % and . % respectively. lus score was associated with increased icu (or . , % ci . - . , p= . ) and hospital (or . , % ci . - . , p= . ) mortality, adjusted for age and apache ii score. conclusions: lus score was associated with increased icu/hospital mortality and may be useful for risk stratification of mechanically ventilated patients admitted to icu. introduction: ventilator asynchrony results in morbidities and mortality. the aim of this study was to explore whether and how physicians used patient-ventilator interactions(pvi) to set mechanical ventilators(mv) in thailand. methods: thai physicians treating mv patients were asked to respond to questionnaires distributed in conferences and to e-mails sent. types of asynchronies encountered and frequency of mv adjustment guided by pvi were evaluated. in addition, correlations between physician's knowledge and )confidence to manage asynchronies and )their experience were analyzed. results: two hundred and eleven physicians answered the questionnaires. most of them were medical residents and icu specialists. % of them set and adjusted mv by asynchrony guidance and the majority used waveform analysis to more than a half of their patients. the most and the least common asynchronies encountered were double triggering and reverse triggering, respectively, while the most difficult-to-manage and the most easily managed asynchronies were periodic/?a b show $ #?>unstable breathing and flow starvation, respectively. lack of confidence and knowledge of pvi were the major reasons of physicians who did not perform asynchrony assessment. for knowledge evaluation, more than % of physicians incorrectly managed asynchrony. chest and icu fellows had the greatest skills in waveform interpretation and asynchrony management with the mean score of . from the total , compared with specialist( . ), medical residents( . ), internists( . ) and general practitioner( . ). there were poor correlations between years' experience in mv management and the skill in waveform interpretation (r = . , p= . ) and between physician's confidence in pvi management and the clinical skill (r = . , p< . ) conclusions: the majority of thai physicians realized the importance of pvi, but the skill in asynchrony management was moderate. intensive programs should be provided to improve their clinical performance. methods: six deeply anesthetized swine underwent tracheostomy, thoracostomy and experimental plef with ml/kg of radiopaque saline randomly instilled into either pleural space. animals were ventilated at vt= ml/kg, frequency= bpm, i/e= : , peep= cmh o, and fio = . . quantitative lung computed tomographic (ct) analysis of regional aeration and global frc measurements by nitrogen wash-in/wash-out technique were performed in each of these randomly applied positions: semi-fowler's (inclined °from horizontal in the sagittal plane); prone, supine, and lateral positions with dependent plef and non-dependent plef (fig. ) . results: no significant differences in frc were observed among the horizontal positions, either at baseline (p= . ) or with plef (p= . ) ( fig. a) . however, component sector total gas volume in each phase of the tidal cycle were different within all studied positions with and without plef (p=<. ). compared to other positions, prone and lateral position with non-dependent plef had a more homogenous vt distribution among quadrants (p=. , fig. b ). supine was associated with most dependent collapse (fig. c ) and greatest tendency for tidal recruitment ( % vs~ %, p= . , fig. d ). conclusions: changes in body position in the setting of effusioncaused chest asymmetry markedly affected the internal distributions of gas volume, collapse, ventilation, and tidal recruitment, even when commonly used global frc measurements provided little indication of these important positional changes. of the respondents, % were affiliated with multidisciplinary icus, % with thoracic and/or cardiac icus and % with neuro-icus. most respondents ( %) had completed their specialist training. overall, arterial oxygen tension (pao ) was the preferred parameter for the evaluation of oxygenation (fig. ). the proportions of doctors' preferences for increasing, decreasing or not changing an fio of . in two (out of six) patient categories at different pao levels are presented in table and table . conclusions: this is the largest survey of the preferred oxygenation targets among icu doctors. pao seems to be the preferred parameter for evaluating oxygenation. the characterisation of pao target levels in various clinical scenarios provide valuable information for future clinical trials on oxygenation targets in critically ill icu patients. introduction: sonographic assessment of diaphragmatic excursion and muscle thickening fraction have been suggested to evaluate diaphragm function during weaning trial [ ] . the purpose of this study is to compare these two parameters to predict extubation success. methods: this prospective study was carried out during months from march to november . we enrolled patients who were mechanically ventilated for more than h and met all criteria for extubation. the non inclusion criteria were: age < years, history of neuromuscular disease or severe chronic respiratory failure. we excluded subjects who needed reintubation for upper airway obstruction, neurological or hemodynamic alteration. the scenario involves a patient expected to receive mechanical ventilation for at least hours in the icu. all proportions are percentages of respondents with % confidence intervals. *p < . for comparisons of proportions of "no change" versus adjacent lower pao level (mcnemar's test) introduction: ventilator induced diaphragmatic dysfunction is known to be a contributor to weaning failure. some data suggest that assisted ventilation might protect from diaphragmatic thinning. aims of this study are to evaluate, by ultrasound (us), the change in diaphragm thickness and thickening in patients undergoing controlled and assisted mechanical ventilation (mv) and clinical factors associated with this change. methods: we enrolled patients who underwent either controlled mv (cmv) for cumulative hours or hours of pressure support (psv) if ventilation was expected to last for at least days. patients < years old, with neuromuscular diseases, phrenic nerve injury, abdominal vacuum dressing system and poor acoustic window were excluded. diaphragm thickness and thickening were measured with us as described by goligher and clinical data were collected every hours until icu discharge. results: we enrolled patients, were excluded because they had less than measurements and for low quality images, leaving patients for analysis. as expected, during cmv diaphragm thickening was almost absent and significantly lower than during psv (p< , ). diaphragm thickness did not reduce significantly during cmv (p= . ), but during psv significantly increased (p< . ) (fig. , where "day " represents the first day of psv). during cmv, in / patients diaphragm thickness showed a >= % reduction. they had a significantly higher fraction of days spent in cmv (p= . ) and longer neuromuscular blocking drugs (nbds) infusion (p= . ). during psv, / patients showed an increase in diaphragm thickness >= %. duration of hospital stay was significantly lower for these patients (p . ). differences between the two groups are reported in table . conclusions: longer time spent in cmv and with nbds infusion seems associated with a decrease in diaphragm thickness. assisted ventilation promotes an increase in diaphragm thickness, associated with a reduction in the length of hospitalization. prediction of intrinsic positive end-expiratory pressure using diaphragmatic electrical activity in neutrally-triggered and pneumatically-triggered pressure support f xia nanjing zhongda hospital, southeast university, nanjing, china critical care , (suppl ):p introduction: intrinsic positive end-expiratory pressure (peepi) may substantially increase the inspiratory effort during assisted mechanical ventilation. our purpose of the study was to assess whether electrical activity of the diaphragm (eadi) can be reliably used to estimate peepi in patients undergoing conventional pneumaticallycontrolled pressure support (psp) ventilation and neutrally-controlled introduction: atelectasis develops in critically ill obese patients submitted to mechanical ventilation. the pressure exerted by the abdominal weight on the diaphragm causes maldistribution of ventilation with increased pleural pressure and diminished response to peep. our objective was to analyze the effects of peep in the distribution of ventilation in obese and non-obese patients according to bmi (obese >= kg/m , or non-obese: to . kg/m ), using electrical impedance tomography (eit). methods: we assessed the regional distribution of ventilation of surgical and clinical patients submitted to a decremental peep itration monitored by eit. we calculated the percent ventilation to the nondependent (anterior) lung regions at the highest and lowest peep applied. the highest compliance of respiratory system was consistently observed at intermediate values of peep (between those extreme values), indicating that the highest peep caused pulmonary overdistension, whereas the lowest peep likely caused dependent lung collapse results: were enrolled patients, with non-obese patients ( , ± kg/m ) and obese patients ( . ± . kg/m ). all patients presented progressively decreased ventilation to dependent (posterior) lung regions when peep was lowered (p< . ). obese patients consistently presented higher ventilation to the anterior lung zones (when compared no nonobese), fig. introduction: lung protective ventilation is the mainstay of mechanical ventilation in critically ill patients [ ] . extracorporeal co removal (ecco r) can enhance such strategies [ ] and has been shown to be effective in low flow circuits based on renal replacement platforms [ , , ] . we show the results of a pilot study using a membrane lung in combination with a hemofilter based on a conventional renal replacement platform (prismalung™) in mechanically ventilated hypercapnic patients requiring renal replacement therapy (nct ). methods: the system incorporates a membrane lung ( . m ) in a conventional renal replacement circuit downstream of the hemofilter. mechanically ventilated patients requiring renal replacement therapy were included in the study. patients had to be hypercapnic at inclusion under protective ventilation. changes in blood gases were recorded after implementation of the extracorporeal circuit. thereafter ventilation was intended to be decreased per protocol until baseline paco was reestablished and changes in vt and pplat were recorded. data from patients were included in the final analysis. results: the system achieved an average co removal rate of . ± . ml/min which corresponded to a paco decrease from . ± . to . ± . mmhg (p< . ) and a ph increase from . ± . to . ± . (p< . ) [ fig. ]. after adaption of ventilator settings we recorded a decrease in vt from . ± . to . ± . ml/kg (p< . ) and a reduction of pplat from . ± . to . ± . cmh o (p< . ). these effects were even more pronounced in the "per protocol" analysis [ fig. ]. conclusions: low flow ecco r in combination with renal replacement therapy provides partial co removal at a rate of over ml/min can significantly reduce invasiveness of mechanical ventilation in hypercapnic patients. introduction: in ecco r-crrt, efficiency of co removal is higher positioning the oxygenator (oxy) up-stream than down-stream the haemofilter due to higher blood flow (bf) [ ] . we tested whether this effect was due to lower pre-filter pressure (pfp). methods: ecco r-crrt circuit was tested in-vitro (n= ) with the following settings: l bovine blood; bf ml/min; oxy . m (euroset); cvvh post mode; substitution flow ml/h; uf rate function off; . m haemofilter (diapact®, b.braun avitum); sweep air flow . l/min. pfp was evaluated at baseline, , and hours. co extraction was measured at bf of , and ml/min. sweep air flow/blood ratio was : . co was add to obtain paco of mmhg. co removal rate calculation ( ): co removal rate = (co ecco r inlet-co ecco r outlet)* blood flow (eq. ) co molar volume at °c [l/mol] = ; solubility of co at °c = . mmol/(l*mmhg); hco i = inlet hco concentration [mmol/l]; hco o = outlet hco concentration [mmol/l]; pi co = inlet co partial pressure [mmhg]; poco = outlet co partial pressure [mmhg] equation becomes: co removal rate= x ((hco i + . x pico ) -(hco o + . x poco )) x blood flow (eq. ) results: bf of ml/min was always reached with the up-stream configuration. bf was reduced to ml/min with the down-stream configuration due to high pfp alarm (table ). co removal increased to . ± . to . ± . , and . ± . ml/min, at bf of , and ml/ min (p< . ). conclusions: bf of ml/min can be reached only with the upstream configuration due to lower circuit pfps. bf directly correlates to co removal efficiency. we may speculate that simultaneous use of crrt and lf-ecco r and activation of the uf rate function with the down-stream setting may further increase pfp thus forcing to more enhanced reduction of bf and less effective co -removal. introduction: we describe the use of a novel low-flow ecco r-crrt device (prismalung-prismaflex, baxter healtcare gambro lundia-ab-lund, sweden) for simultaneous lung-renal support. methods: a retrospective review of patients submitted to prismalung-prismaflex due to aki associated to hypercapnic acidosis during the period may -august at prato hospital icu was performed. data collected were: demographic, physiologic, complications, outcome. data were presented as mean ± ds; anova test was used to compare changes of parameters over time; significance was set at p< , . results: we identified patients (mean age ± yr, mean sofa ± ). causes of hypercapnia were moderate ards (n= ) and ae-copd (n= ). in all patients a fr double lumen cannula was positioned and ml/min blood-flow with lt oxygen sweep-gas-flow was maintained; iv-heparin aiming to double aptt was used. haemo-diafiltration (effluent flow ml/kg/hour) was delivered. in all cases prismalung-prismaflex improved respiratory and metabolic parameters (figs. and ) without any complications. all patients survived to the treatment, nevertheless patients ( ae-copd; ards) died during icu stay due to irreversible cardiac complications. in ards cases: patients were successfully weaned from imv, mean duration of the treatment was ± hours, mean duration of imv after ecco r-crrt was ± days. in ae-copd cases: intubation was avoided in patients at risk of niv failure, patients were successfully weaning from imv, mean duration of the treatment was ± hours, mean duration of imv after ecco r-crrt was , ± , days. fig. (abstract p ) . minutes after implementation of the combined renal replacement and ecco r circuit a moderate decrease in paco (- . mmhg) corresponding to a slightly higher ph ( . ) was observed conclusions: the use of prismalung-prismaflex has been safe and effective: it may be argued that it could be due to the low-blood-flow used. the positive results of this preliminary study may constitute the rational for the design of a larger randomized control trial. systemic il- production and spontaneous breathing trial (sbt) outcome: the effect of sepsis introduction: spontaneous breathing trial (sbt), a routine procedure during ventilator weaning, entails cardiopulmonary distress, which is higher in patients failing the trial. an intense inflammatory response, expressed by increased levels of pro-inflammatory cytokines, is activated during sbt. sepsis, a common condition in icu patients, has been associated with increased levels of the pro-inflammatory cytokine il- . il- produced among others by skeletal muscles, has been associated with severe muscle wasting and maybe by icu acquired weakness. we hypothesised that il- increases during sbt, more evidently in sbt failures. we anticipate this response to be more pronounced in formerly septic patients fulfilling the criteria for sbt. methods: sbts of -min duration were performed and classified as sbt failure or success. blood samples were drawn before, at the end of the sbt and hours later. serum il- levels and other inflammatory mediators, commonly associated with distress, were determined and correlated with sbt outcome. subgroup analysis between septic and non-septic patients was performed. )kg/m ) were monitored for . ± . hours. apneas were identified ranging from - s (fig. a) . apneas were observed in % of patients, suggesting low predictability of respiratory insufficiency. the average mv was ± . %mvpred, as patients were often sleeping or mildly sedated. we assessed the effects of each apnea on the temporally associated mv (fig. b) . while apneas ranging in length from - s decrease mv by as much as %, their effect over min is < %. on a min time scale, even s apneas led to lowmv just % of the time (fig. c) . conclusions: while apneas were ubiquitous, they seldom led to lowmv over clinically relevant time scales. large compensatory breaths following an apnea generally restored mv to near pre-apnea levels. nonetheless, some apneas can become dangerous when ignored, as when subsequent sedation decreases compensatory breath size. rvm data provide a better metric of respiratory competence, driving better assessment of patient risk and individualization of care. introduction: diffuse alveolar hemorrhage (dah) is an acute lifethreatening event and recurrent episodes of dah may result in irreversible interstitial fibrosis. identifying the underlying cause is often challenging but is needed for optimal treatment. lung biopsy is often performed in the diagnostic evaluation of patients with suspected dah. however, the role of lung biopsy in this clinical context is unclear. hence, we sought to identify the spectrum of histopathologic findings and underlying causes in patients with dah who underwent lung biopsy, surgical or transbronchial. methods: we identified patients who underwent surgical lung biopsy (n = ) or bronchoscopic biopsy (n = ) in the evaluation of dah over a -year period from to . we extracted relevant clinical pathologic and laboratory data. results: the median age in our cohort was years with % females. serologic evaluation was positive in % of patients (n= ). most common histopathologic findings on surgical lung biopsy included alveolar hemorrhage (ah) with capillaritis in patients of whom six had necrotizing capillaritis, followed by ah without capillaritis in patients. the most common histopathologic finding on bronchoscopic lung biopsy was ah without vasculitis/capillaritis in patients, followed by ah with capillaritis in patients. there were no procedure related complications or mortality observed with either method of lung biopsy. the clinico-pathologic diagnoses in these patients are shown in tables and . conclusions: in patients with dah undergoing lung biopsy alveolar hemorrhage without capillaritis was found to be the most common histopathologic finding followed by pulmonary capillaritis. these histopathologic findings contributed to the final clinico-pathologic diagnoses of granulomatous polyangiitis and microscopic polyangiitis in a substantial portion of cases. future studies are needed to ascertain the benefits vs. risks of lung biopsy in patients with suspected dah. note that, an apnea of -sec will (by definition) drive mv over a -sec window down to , but will only decrease mv over a -sec window down to~ % mvpred and to less than % over a -min window. (c) likelihood of an apnea of specific length to decrease mv below the low mv cutoff over various time windows. note that a single -sec apnea has just a % chance to decrease mv below % in a -sec window and less than % chance to decrease mv below the cutoff over a -min window. even -sec apneas have just % chance of decreasing sustained mv over a -min window below the % mvpred cutoff ( ) granulomatosis polyangitis ( ) ah without capillaritis ( ) antiphospholipid syndrome ( ) microscopic polyangitis ( ) ah with diffuse alveolar damage( ) microscopic polyangitis ( ) ah with pulmonary vascular changes( ) pulmonary hypertension( ) introduction: assessing the sensitivity of the peripheral chemoreflex (spcr), we can predict the likelihood of developing respiratory and cardiovascular disorders. spcr is one of the markers of disease progression and good prognostic marker [ ] . disturbed respiratory mechanics can make it difficult to evaluate. breath-holding test may be helpful in such situation, the results of this test are inversely correlated with peripheral receptor sensitivity to carbon dioxide in healthy people [ ] .the aim of the study was to compare the breath-holding test to single-breath carbon dioxide test in the evaluation of the sensitivity of the peripheral chemoreflex in subjects with copd. methods: the study involved patients with copd with fev /fvc < % of predicted, all participants were divided into two groups depending of disease severity (gold classification, ). in group (mild-to-moderate copd, n= ) all patients had fev >= % and in group (severe-to-very severe copd, n= ) all patients had fev < %. breath-holding test was performed in the morning before breakfast: voluntary breath-holding duration was assessed three times, with min intervals [ ] . a mean value of the duration of the three samples was calculated. the single-breath carbon dioxide test [ ] was performed the next day. the study was approved by the local ethics committee. all subjects provided signed informed consent to both tests. and january . the data was collected from the hospital electronic and paper notes, and data collected was mortality rate, apa-che ii score, icnarc score, type of respiratory support received and whether there was documentation of advanced decisions in case of acute deterioration. results: there were patients admitted to the icu with acute respiratory failure as a complication of pulmonary fibrosis. the median apache ii score was and icnarc standardised mortality ratio was . . nine patients died on icu ( %) and hospital mortality was ten ( %). eight patients ( %) received high flow nasal oxygen, six ( %) received non-invasive ventilation, and two ( %) received invasive ventilation. the median time to death was . days. of patients for whom paper notes were available, no patient had any documented ceiling of care or end of life decisions. conclusions: our study confirmed a very high mortality in this cohort of patients, supporting national guidance that invasive respiratory support has limited value. we advise that frank discussion with patients and their families should happen early after diagnosis, such that end of life plans are already in place in the event of acute deteriorations. introduction: arf is common in critically ill patients. we compared diaphragm contractile activity in medical and surgical patients admitted to icu with a diagnosis of arf. methods: adult medical and major abdominal laparotomic surgical patients admitted to a general icu with a diagnosis of arf were enrolled. arf was defined as a pao /fio ratio<= mmhg/% and need for mechanical ventilation (mv) for at least hours. diaphragmatic ultrasound was realized bedside when the patient was stable and able to perform a trial of spontaneous breathing. a convex probe was placed in right midaxillary line ( th- th intercostal space) to evaluate right hemidiaphragm. diaphragmatic respiratory excursion and thickening were evaluated in m-mode on consecutive breaths and thickening fraction (tf) was calculated. antropometric, respiratory and hemodynamic parameters, saps , sofa score, duration of mv, need for tracheotomy and timing, septic state and site of infection, superinfections, icu and inhospital length of stay (los) and outcome were recorded. patients with trauma and neuromuscular disorders were excluded. p< . was considered significant. results: we enrolled patients: % medical and % surgical, without differences for age, sex, bmi, saps , sofa score, sepsis and superinfections. moderate arf was prevalent in both groups. during diaphragmatic examination, no differences were recorder for respiratory rate, hemodynamic state and fluid balance. surgical patients showed a lower but not significant diaphragm excursion ( . vs . cm), instead tf was significantly reduced ( vs %,p< . ). no differences emerged on duration of mv, but tracheotomy were higher in medical ones ( vs %,p< . ). icu and inhospital los do not differ between medical and surgical patients and mortality rate was respectively % and %. conclusions: in arf, surgical patients showed a lower diaphragm contractility compared to medical ones, maybe due to the combination of anesthetic and surgical effects, but with no influence on outcome. (fig. ) . the slope of the regression line for pes/paw plots was consistently higher for slow compressions ( . ± . ), as compared to fast ones ( . ± . ). a good agreement between Δ pes and Δ paw (fig. ) was found during slow maneuvers, but not during the fast ones. conclusions: slow chest compressions must be used when checking position/inflation of esophageal balloon. the fast maneuver produces hysteresis and underestimation of Δ pes (but not in direct Δ ppl). pes monitoring at high respiratory rates may be problematic. methods: consecutive comatose post cardiac arrest patients were ventilated with volume assist ventilation ( ml/kg ibw, peep cm h o) using elisa eit (lowenstein medical, ge). orogastric tube (nutrivent, sidam, it) was inserted, and eit vest (swisstom ag, ch) was applied in all patients. measurements were performed min after admission and after hrs (fig. ) . optimal peep was defined as lower inflection point using pv curve (pv), positive ptpeep (ptp) and optimal regional stretch/silent spaces (eit) results: methods to determine peep using pv, ptp and eit were comparable in non obese patients (p=ns introduction: the driving pressure of respiratory system (dp) reflects the extent of lung stretch during tidal breathing, and has been associated with mortality in ards patients during controlled mechanical ventilation [ ] . aim of this study was to examine dp during assisted ventilation, and examine if and when high dp occurs in patients in assisted ventilation with pav+. methods: critically ill patients hospitalized in the icu of the university hospital of heraklion, on mechanical ventilation in pav+ mode were studied. continuous recordings of all ventilator parameters were obtained for up to three days using a dedicated software. dp was calculated from the pav+ computed compliance (c) [ ] , and the measured exhaled tidal volume (vt, dp=vt/c). periods of sustained dp above cmh o were identified, and ventilation and clinical variables were evaluated. results: sixty-two patients and hrs of ventilation were analyzed. in half of the patients, dp was lower than cmh o in % of the recording period, while high-dp (> cmh o) more than % of the total time was observed in % of patients. icu non-survivors had more time with high dp than survivors (p= . ). periods of sustained high-dp (> cmh o for > h) were observed in patients. level of assist, minute ventilation, and respiratory rate were not different between the periods of high dp and the complete recordings, while vt was higher and c was lower during the high-dp period compared to the complete recording. the median compliance was below ml/ cmh o during the high-dp period, and above ml/cmh o during the complete recording. conclusions: high dp is not common, but does occur during assisted ventilation, predominantly when compliance is below ml/cmh o, and may be associated with adverse outcome. table summarizes the percent of monitored time with reported data for the two devices. figure depicts mv decrease following propofol and cannula dislodgement fol- fig. (abstract p ) . bland-altman analysis demonstrated that cvp-derived Δppl and Δpes were correlated significantly lowing a jaw thrust. table ) . negative (a-et) pco was strongly associated with good outcome and were significantly associated with overall survival (fig. ) conclusions: in conclusion, the negative arterial to end-tidal co pressure gradient may predict patient survival in some subgroups. introduction: ards may result from various diseases and is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation and surfactant dysfunction. various biomarkers have been studied in diagnostics and prognostication of ards. the purpose of the study was to measure the expression of proinflammatory mediators like il- and tnf, a cellular receptor with a role in innate immunity(tlr- ),and a biomarker of fibrogenesis (mmp- ) in different phases of ards patients. methods: we studied patients admitted to our icu with diagnosis of ards during the month of january . six ml of blood were prospectively collected at two times: during the acute phase and in a sub-acute phase before icu discharge. blood samples were centrifuged to obtain the platelet-rich plasma and plasmatic rna (crna) was isolated from platelets.il- , tnf, tlr- and mmp- expression in crna was determined by the droplet digital™ pcr as copies/ml. results: all patient showed a decrease in il- , tnf, tlr and mmp- levels after the acute phase of ards (fig. ) . patient and were affected by influenza a virus (h n ), patient was admitted for pneumococcal pneumonia and patient was affected by legionella. adequate ethiologic treatment was promptly started in patients with bacterial infection. mean duration of mechanical ventilation was . days. all patient survived icu stay and were discharged from hospital. conclusions: il- , tnf, tlr- and mmp- expression detected by extracted platelets rna, may be a novel tool useful for clinicians indicating persistent inflammation with resulting progressive alveolar fibrosis and impaired lung function. more data are necessary to understand the real clinical significance of this biomarkers and their role in fibroproliferation and progression of ards. introduction: although mesenchymal stem cells (mscs) transplantation has been shown to promote lung respiration in acute lung injury (ali) in vivo, its overall restorative capacity appears to be restricted mainly because of low engraftment in the injured lung. ang ii are upregulated in the injured lung. our previous study showed that ang ii increased mscs migration in an angiotensin ii type receptor (at r)dependent manner [ ] . the objective of our study was to determine whether overexpression of at r in mscs augments their cell migration and engraftment after systemic injection in ali mice. methods: a human at r expressing lentiviral vector was constructed and introduced into human bone marrow mscs. we also downregulated at r mrna expression using a lentivirus vector carrying at r shrna to transduce mscs. the effect of at r regulation on migration of mscs was examined in vitro. a mouse model of lipopolysaccharide (lps) induce ali was used to investigate the engraftment of at r-regulated mscs and the therapeutic potential in vivo. results: overexpression of at r dramatically increased ang ii-enhanced human bone marrow msc migration in vitro. moreover, msc-at r accumulated in the damaged lung tissue at significantly higher levels than control mscs h and h after systematic msc transplantation in ali mice. furthermore, msc-at r-injected ali mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti-inflammatory effects. in contrast, there were less lung engraftment in msc-shat r-injected ali mice compared with msc-shcontrol after transplantation. thus, msc-shat r-injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. conclusions: our results demonstrate that overexpression of at r enhance the migration and lung engraftment of mscs in ali mice and may provide a new therapeutic strategy for the injured lung. introduction: reorganization of endothelial barrier complex is critical for increased endothelial permeability implicated in the pathogenesis of acute respiratory distress syndrome. we have previously shown hepatocyte growth factor (hgf) reduced lipopolysaccharide (lps)-induced endothelial barrier dysfunction. however, the mechanism of hgf in endothelial barrier regulation remains to be unclear. methods: recombinant murine hgf with or without mtor inhibitor rapamycin were introduced on mouse pulmonary microvascular endothelial cells (pmvecs) barrier dysfunction stimulated by lps. then, endothelial permeability, adherent junction protein (occludin), endothelial injury factors (endothelin- and von willebrand factor), cell proliferation and mtor signaling associated proteins were tested. results: our study demonstrated that hgf decreased lps-induced endothelial permeability and endothelial cell injury factors, and attenuated occludin expression, cell proliferation and mtor pathway activation. conclusions: our findings highlight activation akt/mtor/stat- pathway provides novel mechanistic insights into hgf protective regulation of lps-induced endothelial permeability dysfunction. introduction: mechanical ventilation (mv) is a life-saving intervention for critically ill patients, but may also exacerbate pre-existing lung injury, a process termed ventilator-induced lung injury (vili). interestingly, we fig. (abstract p ) . fluorescein isothiocyanate-dextran or fluorescein isothiocyanate-bsa analysis of the effect of hgf on pmvecs permeability fig. (abstract p ) . western blot analysis of hgf on mtor signaling pathway discovered that the severity of vili is modulated by the circadian rhythm (cr). in this study, we are exploring the role of the myeloid bmal , a core clock component, in vili. methods: we employed mice lacking bmal in myeloid cells (lyzmcre-bmal -/-) and lyzmcre mice as controls. at circadian time (ct) or ct , mice were subjected to high tidal volume mv to induce vili. lung compliance, pulmonary permeability, neutrophil recruitment, and markers of pulmonary inflammation were analyzed to quantify vili. to assess neutrophil inflammatory responses in vitro, myeloid cells from bone marrow of wt and bmal -deficient animals were isolated at dawn zt (zeitgeber time ) and dusk (zt ), incubated with dcfh-da and stimulated for min with pma or pbs. neutrophil activation (ly g/cd b expression) and ros production (dcfh-da/ly g+ cells) were quantified. results: injurious ventilation of control mice at ct led to a significant worsening of oxygenation, decrease of pulmonary compliance, and increased mortality compared to ct . lyzmcre-bmal -/-mice did not exhibit any significant differences when subjected to mv at ct or ct . mortality in lyzmcre-bmal -/-mice after vili was significantly reduced compared to lyzmcre controls (ct ). neutrophils isolated from control mice at zt showed a significantly higher level of activation and increased ros production after pma-stimulation compared to zt . ros production of lyzmcre-bmal -/-neutrophils did not differ from zt to zt . conclusions: the lack of the clock gene bmal in myeloid cells leads to increased survival after injurious ventilation and to loss of circadian variations in neutrophil ros production. this suggests that the internal clock in myeloid cells is an important modulator of vili severity. introduction: hemodynamic resuscitation by means of fluids and norepinephrine (ne) is currently considered as a cornerstone of the initial treatment of septic shock. however, there is growing concern about the side effects of this treatment. the aim of this study was to assess the relationship between the hemodynamic resuscitation and the development of the ards. methods: new zealand rabbits. animals received placebo (sham= ) or lipopolysaccharide (lps) with or without (edx-r, n= ; edx-nr, n= ) hemodynamic resuscitation (fluids: ml/kg of ringer's lactate; and later ne infusion titrated up to achieve theirs initial arterial pressure). animals were monitored with an indwelling arterial catheter and an esophageal doppler. respiratory mechanics were continuously monitored from a sidestream spirometry. pulmonary edema was analyzed by the ratio between lung wet and lung dry weight (w/d), and the histopathological findings. results: sham group did not show any hemodynamic or respiratory changes. the administration of the lps aimed at increasing cardiac output and arterial hypotension. in the lps-nr group, animals remained hypotensive until the end of experiment. infusion of fluids in lps-r group increased cardiac output without changing arterial blood pressure, while the norepinephrine reversed arterial hypotension. compared to the lps-nr group, the lps-r group had more alveolar neutrophils and pneumocytes with atypical nuclei, thicker alveolar wall, non-aerated pulmonary areas and less lymphocyte infiltrating the interstitial tissue. in addition, the airway pressure increased more in the group lps-r, and the w/d, although slightly higher in the lps-r, did not show significant differences. conclusions: in this model of experimental septic shock resuscitation with fluid bolus and norepinephrine increased cardiac output and normalized blood pressure but worsened lung damage. obese patients have been excluded from most of the clinical trials testing the effects of peep in ards. we hypothesized that in morbidly obese patients the massive load of the abdomen/chest further increases lung collapse thus aggravating the severity of respiratory failure due to ards. methods: we performed a clinical crossover study to investigate the contribution of lung collapse to the severity of respiratory failure in ards obese patients and to determine the specific contribution of titrated peep levels and lung recruitment to changes in lung morphology, mechanics and gas exchange. patients were studied at the peep (peepicu) levels selected at our institution and at peep levels establishing a positive end-expiratory transpulmonary pressure (peepinc) and at peep levels determining the lowest lung elastance during a decremental peep (peepdec) trial following rm. results: thirteen patients were studied. at peepicu end-expiratory transpulmonary pressure was negative, lung elastance was increased and hypoxemia was present (table ) . regardless the titration technique there was no difference in the peep level obtained. at peepinc level endexpiratory lung volume increased, lung elastance decreased thus improving oxygenation. setting peep according to a peepdec trial after a rm further improved lung elastance and oxygenation. at peedec level after a rm lung collapse and overdistension were minimized (fig. ) . all patients maintained titrated peep levels up to hours without complications. conclusions: in severely obese patients with ards, setting peep according to a peepinc trial or peepdec trial following a rm identifies the same level of optimal peep. the improvement of lung mechanics, lung morphology and oxygenation at peepdec after a rm suggests that lungs of obese ards patients are highly recruitable and benefit from a rm and high peep strategy. introduction: lung protective ventilation (lpv) strategies, principally focused around the use of tidal volumes < ml/kg predicted body weight (pbw) remains an enduring standard of care for ventilated patients. however, implementation of and compliance with lpv is highly variable. we used 'nudge'-based interventions to assess if these can improve lpv. methods: ventilation data analysis over years ( hours in patients) showed patients had been ventilated with a median tidal volume of . ml/kg pbw with a significant proportion receiving over ml/kg pbw (fig. ) , an effect more pronounced in female patients and those with higher bmi. interventions: ) creation of a software tool to easily identify and monitor patients receiving tidal volumes that were too high for their pbw ) attached laminated reference guides to each ventilator to calculate pbw ) presentation, opportunistic education and verbal prompts to relevant clinical care staff regarding importance of lpv and use of pbw rather than actual body weight ) incorporating checking of tidal volumes on a daily ward rounds from junior clinical members results: we collected hourly ventilation data of the patients over a -week period ( hours in patients) following our interventions. there was, overall a statistically significant reduction tidal volume (p< . ). there was improvement in the ventilation of male patients (p< . ) but female patients endured higher tidal volumes. there was a mixed picture in different bmi grades. conclusions: reducing tidal volumes in mechanically ventilated patients can be done through a mix of behavioural and educational interventions, as well as using technological shortcuts. this helps to reduce the effort on the part of clinical staff to adhere to best practices, and ultimately improve patient outcomes. introduction: lung protective ventilation (lpv) using a tidal volume (vt) of - ml/kg ideal body weight (ibw) is recommended in the intensive care unit and theatres to reduce the incidence of pulmonary complications. the aim of this audit was to assess the extent to which lpv is used in theatres in a busy district general hospital and to implement measures to promote adherence to the recommendations. methods: anaesthetists completed questionnaires for all patients undergoing general anaesthesia at northwick park hospital over week. demographics, actual body weight (abw), height, american society of anesthesiologists (asa) score, and procedural information were recorded. ventilatory parameters included the ventilation mode, vt, and positive end expiratory pressure (peep (fig. ) . significantly more females ( %) received vt >= ml/kg than males ( %) (p< . ) (fig. ) . vt was independent of age, asa, bmi, ventilation mode, speciality, and patient position. conclusions: over half of the patients received vt >= ml/kg ibw. females were more likely to be over ventilated. a likely contributing factor is the disparity between abw and ibw in this cohort. we organised staff teaching and constructed ibw charts with the appropriate corresponding tidal volumes to be displayed in all theatres to promote the use of lpv. results: there were significant differences in ards incidence between groups: ards developed in . % of protective mv groups vs. . % of standard mv group (p= . , fisher's exact test). vap patients ventilated in a protective mode presented with lower duration of mv ( . ± . days) and icu stay( . ± . days) than patients with standard mv ( . ± . and . ± . days). there were significant differences in mortality rates between patient groups: . % in protective mv and . % in standard mv (p= . , fisher's exact test). conclusions: protective mv prevents the development of ards in vap septic patients. introduction: reduction of tidal volumes (tv) below ml/kg associated with low driving pressure (dp) might improve lung protection in patients with acute respiratory distress syndrome (ards). the current study tests the combination of coaxial double lumen endotracheal tube (to reduce instrumental dead-space) and moderately respiratory rate (rr) (< bpm) to maintain co at clinically acceptable levels while using ultraprotective tv. the objective is to considerably reduce dp, which has been preconized as an index more strongly associated with survival than tv, per se, methods: juvenile pigs were anesthetized, intubated and mechanically ventilated. severe lung injury (p/f< ) was induced using a double-hit model: repeated surfactant wash-out followed by injurious mechanical ventilation using low positive end-expiratory pressure and high dp (~ cmh o) for hours. then vts of , , and ml/kg were used in random sequence for min each, both using a standard and coaxial endotracheal tube. at each vt level, rr was adjusted to achieve paco = mmhg but not exceeding bpm. lung functional parameters and blood gas analysis were measured at each vt level. statistical analysis was performed using mixed linear model. results: coaxial endotracheal tube, but not the conventional tube, allowed decreasing vt to and ml/kg, while keeping paco at approximately mmhg and rr< bpm, reducing dp of . cmh o and . cmh o, respectively, compared to the conventional vt of ml/kg (fig. ) . conclusions: in this ards model, coaxial tube ventilation associated with moderately high rr allowed ultraprotective ventilation (vt= ml/kg) and reduced dp levels, maintaining paco at acceptable levels. this strategy might have a significant impact on mortality of severe ards patients. the table shows oxygenation and respiratory mechanics. figure : echocardiographically measured right heart function. conclusions: in morbidly obese mechanically ventilated patients with ards an increase in peep by cmh o (from . ± . cmh o to . ± . cmh o) did not impair right heart function, but improved respiratory mechanics and oxygenation. introduction: mechanical ventilation can, while being lifesaving, also cause injury to the lungs. the lung injury is caused by high pressures and mechanical forces but also by inflammatory processes which are not fully understood [ ] . heparin binding protein (hbp) released by activated granulocytes has been indicated as a possible mediator of increased vascular permeability in the lung injury associated with trauma and sepsis [ , ] . we wanted to investigate if hbp levels were increased in bronco alveolar lavage (bal) fluid or plasma in a pig model of ventilator induced lung injury. methods: anaesthetized pigs were surfactant depleted by saline lavage and randomized to receive ventilation with either tidal volumes of ml/kg with a peep of cm h o (controls, n= ) or ml/kg with a peep of cm h o (ventilator induced lung injury (vili) group, n= ). plasma and bal samples of hbp were taken at , , , and hours (fig. ) . results: characteristics of pigs by study group are shown in table . plasma levels of hbp did not differ significantly between pigs in the control and vili group at any time of sampling. hbp levels in bal fluid were significantly higher in the vili group after (p= . ), (p= . ), (p< . ) and (p= . ) hours of ventilation (fig. ) . conclusions: in a model of ventilator induced lung injury in pigs, levels of heparin binding protein in bal fluid increased significantly over time compared to controls. plasma levels however did not differ significantly between groups. (fig. ) . conclusions: this meta-analysis concluded that corticosteroid treatment in ards provided no benefit in decreasing mortality. in addition, this treatment was not associated with increasing risk of nosocomial infection. (fig. ) . the change in the pao /fio ratio was significant [rr( %ci)= . ( . - . ), p= . ] (fig. ) . finally, trial sequential analysis and grade indicated lack of firm evidence for a beneficial effect. conclusions: surfactant administration may improve oxygenation but has not been shown to improve mortality for adult ards patients. large rigorous randomized trials are needed to explore the effect of surfactant to adult ards patients. moderate to severe acute respiratory distress syndrome in a population of primarily non-sedated patients, an observational cohort study l bentsen, t strøm, p introduction: extracorporeal carbon-dioxide removal (ecco r) might allow ultraprotective mechanical ventilation with lower tidal volume (vt) (< ml/kg predicted body weight), plateau (pplat) (< cmh o) and driving pressures to limit ventilator-induced lung injury. this study was undertaken to assess the feasibility and safety of ecco r managed with a renal replacement therapy (rrt) platform to enable ultraprotective ventilation of patients with mild-to-moderate ards. methods: patients with mild (n= ) or moderate (n= ) ards were included. vt was gradually lowered from to , . and ml/kg, and peep adjusted to reach <=pplat<= cm h o. stand-alone ecco r (prismalung, no hemofilter associated with the rrt platform) was initiated when arterial paco increased by > % from its initial value. ventilation parameters (vt, rr, peep), respiratory system compliance, pplat and driving pressure, arterial blood gases, and ecco r-system characteristics were collected during at least hours of ultraprotective ventilation. complications, day- mortality, need for adjuvant therapies, and data on weaning off ecco r and mechanical ventilation were also recorded. results: while vt was reduced from to ml/kg and pplat kept < cmh o, peep was significantly increased from . ± . at baseline to . ± . cm h o, and the driving pressure was significantly reduced from . ± . to . ± . cm h o (both p< . ). the pao / fio ratio and respiratory-system compliance were not modified after vt reduction. mild respiratory acidosis occurred, with mean ph decreasing from . ± . to . ± . from baseline to -ml/kg vt. mean extracorporeal blood flow, sweep-gas flow and co removal were ± ml/min, ± . l/min and ± ml/min, respectively. mean treatment duration was ± hours. day- mortality was %. introduction: there is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ecmo). ecmo is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. this study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ecmo based on thromboelastography (teg) as opposed to an activated partial thromboplastin time (aptt)-based protocol. methods: we performed a multicenter, randomized, controlled trial in two academic tertiary care centers. adult patients with acute respiratory failure treated with veno-venous ecmo were randomized to manage heparin anticoagulation using a teg-based protocol (target - minutes of the r parameter, teg group), or a standard of care aptt-based protocol (target . - of aptt ratio, aptt group). primary outcomes were safety and feasibility of the study protocol. results: forty-two patients were enrolled, were randomized to the teg group and to the aptt group. duration of ecmo was similar in the two groups ( ( - ) days in the teg group and ( - ) days in the aptt group, p= . ). heparin dosing was lower in the teg group compared to the aptt group ( . ( . - . ) iu/kg/h versus . ( . - . ) iu/kg/h respectively, p= . ). safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. as for the feasibility, the teg-based protocol triggered heparin infusion rate adjustments more frequently (p< . ) and results were less frequently in the target range compared to the aptt-based protocol (p< . ). number of prescribed teg or aptt controls (according to study groups) and protocol violations were not different between the study groups. conclusions: teg can be safely used to guide anticoagulation management during ecmo. its use was associated with the administration of lower heparin doses compared to a standard of care apttbased protocol. methods: single-center retrospective study of patients (n= ; ± . years; % males) undergoing vv-ecmo for severe ards. the acp-score ( - ) was calculated immediately before ecmo initiation and at ecmo-day , -day and -day , as follows: pneumonia as cause of ards - point; driving pressure >= cmh o - point; pao /fio ratio < mmhg - point; paco >= mmhg - point. results: longer duration of mechanical ventilation before vv-ecmo was associated with higher acp-scores. patients with higher acp-scores before vv-ecmo also presented longer total duration of mechanical ventilation and hospital stay. after vv-ecmo initiation, acp-scores significantly decreased from . ± . to . ± . , . ± . and . ± . at ecmo-day , -day and -day , respectively. at ecmo-day , patients with higher acp-scores ( - ) presented increased hospital mortality when compared with patients with lower acp-scores ( - ): . vs. . %, respectively (p= . ). at ecmo-day , high driving pressures and low pao /fio ratios were the acp-score determinants that significantly associated with increased hospital mortality. conclusions: in severe ards, vv-ecmo support allowed a significant and sustained acp-score reduction in most patients. this was achieved by artificial lung correction of low pao /fio , hypercapnia and elevated driving pressures. after an initial period of vv-ecmo support, patients with higher acp-scores present higher mortality rates. our results suggest that on-going adjustment of ecmo and ventilation parameters is necessary to maximize outcome. introduction: we sought to use mechanical power to describe "lung rest" in patients with acute respiratory distress syndrome (ards) supported with extracorporeal membrane oxygenation (ecmo). mechanical power describes work done by the ventilator on the patient's respiratory system over time. this concept unifies tidal volume, rate, and total pressure delivered during the ventilatory cycle into a discrete value that may be useful to guide ventilatory support. we hypothesized that initiation of ecmo led to decreased mechanical power delivered to the patient. methods: we reviewed the charts of the three medical intensive care unit patients at our institution supported with ecmo for severe ards. we collected data on plateau pressure, driving pressure, and mechanical power before initiating ecmo, then at < hours, hours, and hours after. we calculated the mechanical power delivered by the ventilator to the patient in joules per minute as . x respiratory rate x tidal volume x (peak pressure -½ x driving pressure) [ ] . results: all patients were alive at discharge and at days. mean pao /fio at ecmo initiation was ± , mean plateau pressure was ± cm water. all patients received neuromuscular blockade at initiation of ecmo. following ecmo initiation, mechanical power decreased by an average of %± % initially, by %± % at hours, and by %± % at hours (fig. ) . by comparison, driving pressure changed by an average value of - . ± . , - . ± . , and - . ± . cm water over those same intervals. average plateau pressure changed by - . ± . , - . ± . , and - . ± . cm water during the same time period (fig. ) . conclusions: in our limited case series, mechanical power decreased significantly following initiation of ecmo in patients with severe ards. we suggest mechanical power may be more useful than changes in driving pressure or plateau pressure when pursuing "lung rest" during ecmo. introduction: it is not clear whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for underlying risk factor and baseline severity of illness. we attempted to assess the attributable mortality of ards by performing a systematic review and meta-analysis. methods: we systematically searched pubmed, embase, scopus and reference lists to identify observational studies reporting mortality rates of critically ill patients with and without ards. all included studies were matched for underlying risk factor. primary outcomes were all-cause in hospital-mortality and short-term mortality (combined day-mortality and intensive care unit-mortality). we calculated pooled risk ratios (rr) and % confidence intervals (ci) with a random-effects model. our meta-analysis was registered with prospero. results: of the initially retrieved articles, studies ( cohorts) involving patients were included. the underlying risk factor was sepsis, trauma and other in , and cohorts, respectively. in-hospital mortality was higher in patients with versus without ards ( cohorts; patients; rr . , % ci . - . ; p< . ). we saw a numerically stronger association between ards and inhospital mortality in trauma (rr . , % ci . - . ; p< . ) than sepsis (rr . , % ci . - . ; p= . ). short-term mortality was higher in patients with versus without ards ( cohorts; patients; rr . , % ci . - . ; p= . ). ards was independently associated with mortality in approximately half of the cohorts which controlled for baseline severity of illness using a multivariable analysis. conclusions: the accumulated evidence suggests that ards is independently associated with mortality after controlling for underlying risk factor; the association is stronger for trauma than septic patients. evidence is mixed as to whether ards is independently associated with mortality after controlling for baseline severity of illness. introduction: evidence is mixed as to whether acute respiratory distress syndrome (ards) is independently associated with mortality after controlling for baseline severity of illness, particularly in patients with sepsis. methods: this was an observational study comparing mortality rates of septic patients with and without ards. subjects for the present study were enrolled in ongoing prospective cohorts of critically ill patients hospitalized in medical intensive care unit (icu) in the united states or south korea. ards was defined using the berlin definition for cases after and the american-european consensus conference definition for cases before . sepsis was defined using the sepsis- definition. baseline severity of illness was assessed using a modified sequential organ failure assessment (sofa) after exclusion of the respiratory component. the primary outcome was inhospital mortality. results: of the critically ill patients enrolled in the cohorts, ( . %) had sepsis and comprised the population of the present study. of the septic patients, ( . %) had ards. patients with versus without ards had higher sofa score; both total (median vs ; p< . ) and modified ( vs ; p< . ). the unadjusted mortality of septic patients with ards was higher than septic patients without ards ( . % vs . %; p< . ). after controlling for baseline modified sofa score, both moderate and severe ards remained significant predictors for in-hospital mortality [odds ratio (or) . ; % confidence intervals (ci) . - . ; p< . and or . ; % ci . - . ; p< . , respectively]. in contrast, after controlling for baseline modified sofa score, mild ards was not associated with in-hospital mortality (or . ; % ci . - . ; p= . ). conclusions: among critically ill patients with sepsis, moderate and severe, but not mild, ards are associated with mortality after controlling for baseline severity of illness. a multicenter study on the inter-rater reliability of heart score among emergency physicians from three italian emergency departments introduction: previous studies suggested that the heart (based on history, ecg, age, risk factors, troponin) score could be a valid tool to manage the patients with chest pain at the emergency department (fig. ). our hypothesis was that there could be heterogeneity in the assignment, because of the history and ecg parameters. for this reason, our objective was to test the heart reliability. there are no published studies on this topic. methods: this is a multicenter retrospective study conducted in italian eds between march and october using clinical scenarios. twenty emergency physicians were included, provided that they had undergone a course on heart score. we used scenarios from a medical database with each scenario including demographic and clinical characteristics. each participant assigned scores to the scenarios using the heart. we tested the measure of interrater agreement using the kappa-statistic, the confidence intervals are bias corrected. a p-value of < . was used to define statistical significance. results: the participants' assignment is shown in fig. . the overall inter-rater reliability was good: kappa = . (ci %; . - . ); with a good agreement between the low and high class of risk but a moderate reliability in the medium class: kappa= . , . and . . we have not found differences of inter-rater reliability among the senior (more than yrs in ed) and junior physicians: kappa= . (ci %; . - . ) and . (ci %; . - - ).the heart score showed the worse value of inter-rater reliability in the history and ecg parameters : k inter = . (ci %; . - . ) and . (ci %; . - . ). conclusions: the heart showed a good inter-rater reliability but a fair agreement in the history parameter. the clinical experience doesn't influence the agreement in the assignment. the main limit of this study lies in using scenarios rather than real patients. introduction: the aim of the experiment was to study the efficacy of preconditioning, based on changes in inspiratory oxygen fraction on endothelial function in a model of myocardial ischemia/reperfusion injury in conditions of cardiopulmonary bypass (cpb). methods: the prospective study included rabbits divided into four equal groups: hypoxic preconditioning; hyperoxic preconditioning (hyperp); hypoxic-hyperoxic preconditioning (hhp); control group. animals were anesthetized and mechanically ventilated. we provided preconditioning, then started cpb, and then induced acute myocardial infarction by ligation of left anterior descending artery. after minutes of ischemia we performed minutes of reperfusion. we investigated endothelial function markers (endothelin- (et- ), asimmetric dimethylarginine (adma), nitric oxide metabolites) at stages before ischemia (after preconditioning in study groups), after ischemia and after reperfusion. results: the level of et- after the stage of ischemia increased in all groups, a significant difference was between hhp and control group (p= . ), then et- increased even more after the stage of reperfusion (p= . hhp vs control group). the concentration of nitrite decreased after the stages of ischemia and reperfusion in comparison with the baseline in all groups. however, the level of nitrite after all types of preconditioning was higher than in the control group (p= . ; . ; . ). the total concentration of nitric oxide metabolites in the study groups was higher than in the control group: before ischemia (after preconditioning) p= . ; after ischemia p= . ; after reperfusion, p= . . concentration of adma was lower in the hhp comparing with the control group at the stages after ischemia (p= . ) and after reperfusion (p= . ). conclusions: hyperp and hhp maintain endothelial function: the balance of nitric oxide metabolites and the reduction of et- hyperproduction in a model of myocardial ischemia/reperfusion injury in conditions of cpb. upscaling hemodynamic and brain monitoring during major cancer surgery: a before-after comparison study introduction: hemodynamic and brain monitoring are used in many high-risk surgical patients without well-defined indications and objectives. in order to rationalize both hemodynamic and anesthesia management, we implemented monitoring guidelines for patients undergoing major cancer surgery. methods: early , and for all eligible patients, we started to recommend (standard operating procedure, sop) cardiac output, central venous oxygen saturation, and depth of anesthesia monitoring with specific targets (map > mmhg, svv < %, ci > . l/min/ m , scvo > %, < bis < ). eligibility criteria were pelvic or abdominal cancer surgery expected to last > hours in adult patients. pre-, intra-, and post-operative data were collected from our electronic medical record (emr) database and compared before (from march to august ) and after (from march to august ) the sop implementation. results: a total of patients were studied, before and after the sop implementation. the two groups were comparable in terms of age, asa score, duration and type of surgery, the surgical possum score was higher after than before ( vs , p= . ). the use of cardiac output, scvo and bis monitoring increased from to %, to %, and to %, respectively (all p values < . ). intraoperative fluid volumes decreased ( . vs . ml/kg/h, p= . ), whereas the use of inotropes increased ( vs %, p= . ). the rate of postoperative delirium ( vs %, p= . ) and urinary track infection ( vs %, p= . ) decreased, as well as the median hospital length of stay ( . vs . days, p= . ). conclusions: in patients undergoing major surgery for cancer, despite an increase in surgical risk, the implementation of guidelines with predefined targets for hemodynamic and brain monitoring was associated with a significant improvement in postoperative outcome. introduction: tissue perfusion and oxygen delivery is low in patients with severe preeclampsia, which would explain multiple organ failure and death in these patients. the aim of this study was to determine the relationship between the base deficit and the risk of adverse maternal and perinatal outcomes. methods: retrospective multicenter cohort study included pregnant patients with severe preeclampsia admitted to six intensive care units at tertiary referral centers during a ten years period in colombia. clinical information was gathered from hospital medical records. the correlation of base deficit with adverse maternal outcomes was evaluated using logistic regression analysis. outcomes were maternal death, acute kidney injury, hellp syndrome, transfusion, eclampsia and extreme neonatal morbidity. results: patients were included in the study, we found a total of ( , %) maternal deaths, the median calculated base deficit obtained was - . meq/l. patients with base deficit greater than - . meq/l had significantly higher mortality rates or . (ci . - . ) p , . this group of patients was also associated with a higher probability of developing a class hellp syndrome or . (ci . - . ) p , . a more mild alteration in the base deficit (greater than - . meq/l) was related to the appearance of kidney injury or . (ci . - . ) p . y complete hellp or . (ci . - . ) p . . conclusions: base deficit is related to worse outcomes in patients with severe preeclampsia. according to our results, a cut-off point greater than - meq/l, there is a higher risk of death and worse outcomes such as class hellp syndrome. comparison of two different laser speckle contrast imaging devices to assess skin microcirculatory blood flow g guven, y ince, oi soliman, s akin, c ince erasmus mc, university medical center rotterdam, rotterdam, netherlands critical care , (suppl ):p introduction: laser speckle contrast imaging (lsci) is a common, non-contact and practical method used to assess blood flow of tissue surfaces. we have lack of knowledge about comparability of different lsci devices due to the arbitrary units (au) used to define blood flux. we sought to examine the linearity between skin blood flux, recorded using two different lsci devices. methods: we performed post-occlusive reactive hyperemia test (porh) on the arm and measured blood flux on the hand using two different lsci devices (moor instruments, devon, uk and perimed ab, järfälla, sweden). all volunteers were measured at baseline, during occlusion and after release of occlusion during the hyperemia phase. the third finger and fourth finger nail were selected for recording blood flux and au were used to express values. results: fifteen healthy, non-smoker male volunteers participated in this study. an excellent correlation was found between the two lsci devices (finger: r : . , p< . & finger nail: r : . , p< . ). data were also assessed in terms of the variability at different stages of the porh test (fig. a-d) . correlation of devices was still high at baseline, first minute of occlusion and in the post-occlusion hyperemia phase. however, in the period between minute after start of the occlusion and the beginning of the hyperemia, correlation was lower for the whole finger (r : . , p= . ) and correlation was lost for fingernail (r : . , p= . ) between the two devices. conclusions: skin blood flux measured with two different lsci devices are linearly correlated with each other. however care should be taken when assessing patients with low blood flux such as occurs during shock and ischemic organs. introduction: the aim of this study was to evaluate the effects of hyperoxia and mild hypoxia on microcirculatory perfusion in a rat model. methods: spontaneously breathing anesthetized (isoflurane) male wistar rats (n= ) were equipped with arterial (left carotid) and venous (right jugular) cannulae and tracheotomy. rats were randomized in groups: normoxiainspired oxygen fraction (fio ) of . ; hyperoxia -fio ; mild hypoxia -fio . . the following measurements were taken hourly for hours: blood gases, mean arterial pressure (map), stroke volume index (svi) and heart rate (echocardiography), skeletal muscle microvascular density (sidestream dark field videomicroscopy). results: at hour, arterial o tension was ± mmhg in normoxia, ± mmhg in hyperoxia, ± mmhg in mild hypoxia (p< . ). hyperoxia induced an increase in map (from ± to ± mmhg at h, p< . ) and a decrease in svi (from . ± . to . ± . ml/kg at h, p< . ), while in mild hypoxia map tended to decrease and svi tended to increase (p> . ). microvascular density decreased in hyperoxia and increased in mild hypoxia (fig. ) . conclusions: in anesthetized rats, microvascular density decreased with hyperoxia and increased with mild hypoxia. introduction: the imbalance between oxygen (o ) delivery and o requirement in patients with sepsis can be assessed by central venous oxygen saturation (scvo ). the low or high scvo may indicate cellular hypoxia or inability to utilize the o . this study aims to determine the relationship between high scvo and mortality in patients with sepsis. methods: a retrospective observational cohort study was done by collecting data (i.e., baseline characteristics, severity of infection and vasopressors) from medical records of >= -year-old patients with sepsis and st scvo measurement within hours of sepsis, who were admitted in a university hospital between and . the patients were stratified by st scvo level (< %, - %, > %) and apache-ii score (<= , > ). the primary outcome was inhospital mortality. results: among patients, those with high scvo ( . %) and low scvo ( . %) were associated with adjusted hazard ratios for death of . ( . - . , p= . ) and . ( . - . , p= . ), respectively, while those with normal scvo ( . %) as control. when the patients were stratified by scvo level and apache-ii score, using patients with normal scvo and low apache-ii score as control, those with high scvo and low apache-ii score, and those with low scvo and low apache-ii score had adjusted hazard ratios of . ( . - . , p= . ) and . ( . - . , p= . ). for those with normal, high and low scvo , and high apache-ii score had adjusted hazard ratios of . ( . - . , p= . ), . ( . - . , p= . ), and . ( . - . , p= . ), respectively. conclusions: the scvo > % with apache-ii score > , but not only scvo > %, is independently related to increased mortality in patients with sepsis. introduction: serum lactic acid levels and scvo are useful predictive parameters for patients with sepsis. however, little is known the differences in the impact of lactate levels and scvo on the prognosis of septic patients. in this study, we investigated these differences by analysing septic patients' characteristics and prognosis. methods: this study is a post hoc analysis of data obtained from a multicentre, prospective, randomized controlled trial, which compared two fluid management strategies for septic patients requiring mechanical ventilation. we categorised patients into the following four groups: scvo >= % and lactic acid levels < mmol/l (hh group); scvo >= % and lactic acid levels < mmol/l (hl group); scvo < % and lactic acid levels >= mmol/l (lh group) and scvo < % and lactic acid levels < mmol/l (ll group). sofa score, saps ii score, lactic acid levels, scvo and bnp were evaluated. primary outcome was -day mortality, whereas secondary outcomes were the duration of mechanical ventilation, administration of crrt, duration of catecholamine therapy and length of icu stay. results: in total, patients were included: hh group (n = ), hl group (n = ), lh group (n = ) and ll group (n = ). no significant differences were observed in terms of patient characteristics. further, -day mortality was % in the lh group, . % in the hh group, % in the ll group and % in the hl group, and there was no significant difference in terms of mortality among the groups. furthermore, there were no significant differences in terms of secondary outcomes. on multivariate analysis using the hl group as reference, the odds ratios for -day mortality in the lh, hh and ll groups were . ( %ci, . - . ), . ( %ci, . - . ) and . ( %ci, . - . ), respectively. conclusions: because -day mortality was higher in the hh group than in the ll group, serum lactic acid levels may have bigger impact on the prognosis of septic patients. introduction: in septic shock endothelial damage can lead to failure of microcirculation and low microcirculatory oxygen saturation. in the skin this is seen as mottling and can be quantified using hyper fig. (abstract p ) . changes in microvascular density spectral imaging. there is insufficient data about associations between skin oxygenation, severity of illness, biomarkers of endothelial damage and mortality in patients with septic shock. methods: this single centre observational study was performed in consecutive intensive care patients with septic shock. within hours of admission hyper spectral imaging of knee area skin was performed and blood was sampled for assay of biomarkers of endothelial cell damage (plasminogen activator inhibitor - (pai- ), soluble intercellular adhesion molecule (sicam- ), soluble vascular cell adhesion molecule (svcam- ), thrombomodulin, angiopoetin- ). nonlinear fitting of optical density spectra was used to calculate relative skin oxy/deoxy hemoglobin concentration and obtain oxygen saturation. the association between skin oxygen saturation, biomarkers, sepsis severity (apache ii, sofa) and -day mortality was analyzed. results: the median (iqr) age of patients was years ( to ), and % were males. the median sofa and apache ii scores were ( to ) and ( to ) and -day mortality rate was %. patients ( %) had mottling. there was a relationship between skin oxygenation, plasma biomarkers (thrombomodulin and svcam- ) and sepsis severity assessed by sofa and apache ii scores, p < . . using logistic regression analysis, skin oxygenation and biomarker concentrations were not associated with -day mortality rate. conclusions: in our cohort of patients with septic shock, skin oxygenation and biomarkers of endothelial injury were strongly associated with initial severity of sepsis but poorly predictive of -day mortality. comparison between ultrasound guided technique and digital palpation technique for radial artery cannulation in adult patients: a meta-analysis of randomized controlled trials s maitra, s bhattacharjee, d baidya all india institute of medical sciences, new delhi, new delhi, india critical care , (suppl ):p introduction: possible advantages and risks associated with ultrasound guided radial artery cannulation in-comparison to digital palpation guided method in adult patients are not fully known. previous meta-analyses included both adult and pediatric patients and long axis in-plane technique and short axis out of plane technique in the same analysis, which may have incurred biases [ , ] . methods: pubmed and cochrane central register of controlled trials (central) were searched (from to th november ) to identify prospective randomized controlled trials in adult patients where dimensional ultrasound guided radial artery catheterization has been compared with digital palpation guided technique. for continuous variables, a mean difference was computed at the study level, and a weighted standardized mean difference (smd) was computed in order to pool the results across all studies. for binary outcomes, the pooled odds ratio (or) with % confidence interval ( % ci) was calculated using the inverse variance method. results: data of patients from studies have been included in this meta-analysis. overall cannulation success rate was similar between short axis out of plane technique and digital palpation [p= . ; fig. ] and long axis in-plane technique with digital palpation. ultrasound guided long axis in-plane approach and short axis out of plane approach provides better first attempt success rate of radial artery cannulation in comparison to digital palpation [p= . and p= . respectively; fig. ]. no difference was seen in time to cannulate between long axis and short axis technique with palpation technique. conclusions: usg guided radial artery cannulation may increase the first attempt success rate but not the over all cannulation success when compared to digital palpation technique. introduction: ultrasound guidance may improve the success rate of vascular cannulation. there is lack of data regarding the utility of usg guided arterial cannulation in critically ill patients in shock. we aim to compare the impact of using real time ultrasound guidance versus palpation method in achieving arterial catheterization in critically ill patients in hypotension. methods: a single center, prospective, randomized trial was performed among critically ill patients aged > years, with hypotension (or requiring vasopressor infusion) and on not previous cannulated radial arteries. patients were randomized in a ratio of : to the ultrasound group or palpation group. under aseptic precautions, arterial puncture was performed using appropriate sized leader cath (vygon, ecquen, france), under real time usg guidance using short-axis out-of-plane view with bevel down. data were recorded and compared between two groups. the unpaired student's t-test or mann-whitney u test were used for continuous variables, and the uncorrected chi-squared or fisher's exact test were used for proportions. results: a total of patients with hypotensive shock requiring radial artery catheterization were randomized into palpation (n = ) and ultrasound (n = ) groups. first pass success rate was significantly higher in ultrasound group as compared to palpation group ( % vs %, p< . ). cannulation time was significantly shorter in ultrasound group ( . vs . ,p< . ). early complications were significantly higher in palpation group compared to ultrasound group ( . % vs . %, p< . ). conclusions: in critically ill patients with hypotension (or requiring vasopressors), ultrasound guidance improved first pass success rate, shortened the cannulation time and reduced the rate of early complications in radial artery catheterizations. relationship between inferior vena cava diameter and variability with mean arterial pressure and respiratory effort b kalin, k inci, g gursel gazi university school of medicine, ankara, turkey critical care , (suppl ):p introduction: there is no consensus on the use of vena cava inferior (ivc) diameter and variability in the assessment of fluid response (fr) in spontaneously breathing icu patients. influence from respiratory effort, experience requirement and measurement problems are reasons for not being preferred. the aim of the study is to investigate the relationship between ivc diameter, variability and spontaneous breathing effort and hypotension measured by ultrasonography in spontaneously breathing intensive care patients methods: the maximum and minimum diameters of the ivc were measured and the collapsibility index (ci) was calculated. measurements were made in d mode on cineloop recordings. diaphragm thickening ratio was used as a measure of respiratory effort. correlations between respiratory effort criteria with ivc minimum diameter and ci were calculated by pearson's correlation coefficient. ivc measurement criterias, such as inspiratory diameter of < cm, %, %, % of the ci were compared with chi square test in hypotensive and non-hypotensive patients. we took two mean arterial pressure threshold for hypotension as and mmhg for this calculation. results: patients were included in the study. for both hypotensive threshold values, there was no significant difference in the rates of hypotensive and non-hypotensive patients with and without a minimum ivc diameter of cm below. even there was no significant relationship between the ci higher than %, % and % and hypotension (p> . ). in spontaneously breathing patients, a significant correlation was found between respiratory effort and ivc ci and ivc diameter < cm conclusions: at the end of the study, there was a correlation between spontaneous breathing effort ivc diameter and ci in the intubed patients. additionally the result that ivc ci is not different even between hypotensive and non-hypotensive patients suggests that this method should be used with caution in predicting fr. introduction: fluid responsiveness in icu patients can be assessed using changes in pulse rate and blood pressure following administration of a fluid bolus, assisted if necessary by cardiac output (co) monitors such as the lidcoplus. this uses pulse contour analysis to estimate stroke volume (sv), with > % change in sv following a fluid challenge (fc) signifying overall benefit. there is no evidence that the use of co monitoring improves patient outcomes and it is unclear if it improves clinical decision making. methods: a lidcoplus monitor was set up with the screen covered. a ml fc was administered over minutes. the heart rate, systolic and mean arterial pressures were recorded before and after the fc. the clinician administering the fc was asked to decide if the patient was fluid responsive. following this decision, the sv change was revealed and the clinician asked again to assess fluid responsiveness. results: forty-five fluid challenges were studied. use of the lidco changed the decision made on occasions (fig. ) . in three patients ( %), this change in decision was appropriate and either corrected a misinterpretation of the haemodynamic data or represented a patient whose only marker of fluid responsiveness was a sv change. in four patients ( %), the lidco changed the decision inappropriately from a correct interpretation of the haemodynamic data. in six patients ( %) the sv change was ignored when it should have changed the initial decision. in the remaining patients ( %) the decision made with the haemodynamic data was in agreement with the sv change and unchanged by revealing the lidco data. conclusions: the use of lidco monitoring only appropriately changed the decision made with information from basic haemodynamic monitoring in % of patients. this augmentation of decision making was only seen in patients whose basic haemodynamic parameters did not respond to fluid. it changed a correct decision inappropriately in %. overall, no improvement in the assessment of fluid responsiveness was seen. introduction: there are accumulating evidences suggesting that intraoperative blood pressure affects postoperative outcome including myocardial injury, acute kidney injury, stroke, and mortality. in a patient undergoing laryngeal microsurgery (lms), blood pressure usually rises sharply due to the stimulation on the larynx. since pulse transit time (ptt) has been reported to reflect arterial blood pressure fairly well, it has possibility to be a marker for blood pressure which reflects beat-to-beat changes in blood pressure and is less invasive than arterial catheterization. methods: intraoperative noninvasive blood pressure (nibp), electrocardiogram (ecg), and photoplethysmogram (ppg) of patients undergoing lms were recorded simultaneously. ptt was defined as a time interval between the r-wave peak on ecg and the point which the maximal rising slope appears on the ppg. the mean ptt values for one minute before and after the increase in blood pressure due to the stimulation on larynx were compared. parameters of ppg such as width, height, maximal slope, minimal slope, and area were also compared. then, correlation between blood pressure and each variable was calculated. results: as the larynx was stimulated by lms, nibps have surged (systolic blood pressure, . p< . ) significantly in most of the patients. systolic blood pressure and ptt were inversely correlated (r = - . , p < . ). minimum slope of ppg also showed good negative correlation with systolic blood pressure (r = - . , p < . ). conclusions: ppt showed good correlation with systolic blood pressure and may have potential to be used as noninvasive continuous blood pressure monitor during a surgery in which blood pressure changes abruptly. introduction: aim of this prospective randomized pilot study was to investigate influence of intra operative restrictive volume approach and post operative lung ultrasound (lus)on prevention and early detection of postoperative interstitial syndrome development methods: cardiac patients who underwent non cardiac surgical procedure were randomly assigned for: group a-liberal volume approach or for group b-combination of restrictive intra operative volume approach and small dose of norepinephrine. all patients post operatively received <= . ml/kg/h fluids, mostly crystalloids. lus was performed before surgical procedure and hours after their admission in icu together with arterial blood gases measurements. the ultrasound characteristic of interstitial syndrome was development of b profile results: before surgery all patients had a profile. twenty for hours later in a group significantly higher number of patients / ( . %) vs / ( . %) in b group,had b profile (p< . ).at the same time there were no significant difference between the groups in amount of patients with pao /fio ratio <= ( patients with positive b lines from a group vs patients from group b).(p> . ) conclusions: intra operative fluid restriction is efficient in prevention of post operative cardiogenic pulmonary edema development. lus is a simple non invasive method for early detection of interstitial syndrome even before development of signs of respiratory deterioration. introduction: the peak rate of left ventricular (lv) pressure (dp/dtmax) has been classically used as a marker of lv systolic function. since measuring lv dp/dtmax requires lv catheterization, other surrogates have been proposed using the peripheral arterial waveform. the aim of this study was to test the performance of lv and arterial (aortic and femoral) dp/dtmax for assessing lv systolic function against the gold-standard (the slope of the end-systolic pressure-volume relationship, emax) during different cardiac loading and contractile conditions. methods: experimental study in pigs. lv pressure-volume data was obtained with a conductance catheter and peripheral pressures were measured via a fluid-filled catheter into the aortic, femoral, and radial arteries. emax was calculated during a transient occlusion of the inferior vena cava. the experimental protocol consisted in three consecutive stages with two opposite interventions each: changes in afterload (phenylephrine and nitroprusside), preload (bleeding and fluid bolus), and contractility (esmolol and dobutamine) (fig. ) . measurements were obtained before and after each hemodynamic intervention. results: emax variations and lv, aortic, femoral and radial dp/dtmax changes throughout the study are shown in fig. . all peripheral artery-derived dp/dtmax underestimated lv dp/dtmax. percentage changes in lv and femoral ddp/dtmax were tightly correlated (r = . ; p< . ). both lv and femoral dp/dtmax were affected by preload changes during fluid infusion. all peripheral dp/dtmax estimations allow to detect lv systolic function changes according to emax during isolated variations in contractility. conclusions: femoral and lv dp/dtmax accurately reflected emax changes, although both were affected by preload changes during fluid administration. fig. (abstract p ) . emax, lv dp/dtmax and aortic, femoral and radial dp/dtmax changes. (table , fig. ). concordance was < % and radial loa was ±< °for all devices; mean polar bias was < °for ft only (table , fig. ) . conclusions: cs, ft and pa are not interchangeable with tptd, because of inaccuracy [ ] . when considering limitations they may be used for trending. introduction: about years ago, the german physiologist pflüger stated that the cardio-respiratory system fulfils its physiological task by guaranteeing cellular oxygen supply and removing waste products of cellular metabolism. methods: the study was performed in early postoperative period after major abdominal surgery in patients. the physical condition of patients corresponded to class of asa. the median age was . ( . - . ) years. duration of the surgery was , ( , - , ) hours. surgery was performed under combined epidural anesthesia with mechanical ventilation. the study was conducted in the following stages: -admission from operating room; -in - hours; - - hours; - - hours; -after - hours after the surgery. results: depend on rate of oxygen extraction index (ero ) groups were revealed: group (n= )low ero (< %) followed by recovery to normal levels to stage - (ero = - %), group (n= )normal level ero ( %) in all the stages, group (n= )high levels ero (> %) with recovery to normal levels to stage , group (n= )high ero (> %) in all the stages. oxygen extraction index at admission to icu after surgery can be normal ( . % of patients), reduced ( . % of patients) or high ( . % of patients). when oxygen extraction ratio is reduced metabolic recovery occurs classically after - hours; when ero is elevated -after hours. core temperature improvement is connected with the restoration of oxygen homeostasis. so, under normal and reduced ero even mild central hypothermia after surgery were not observed, and at an elevated ero moderate hypothermia after surgery was observed with only to - hours post-surgery restoration. conclusions: maintaining an adequate tissue oxygenation is the cornerstone of metabolic response and postoperative recovery in patient after major abdominal surgery. (fig. ) . patients with cso < %time above %h had an odds ratio of hospital survival of . ( %ci . - . , p= . ) (fig. ) . conclusions: cerebral oxygen desaturation below % was significantly associated with outcome in patients undergoing vaecmo. in patients with cso < %time above h%, prognosis was especially poor. prospective trials are needed to evaluate if cso is a viable target for therapeutic interventions. introduction: during the second consensus meeting on microcirculatory analysis the exploration of novel parameters related to physiological function of the microcirculation was proposed. capillary hematocrit (chct) is a direct measure of capillary hemodilution, a potential mechanism of microcirculatory dysfunction in states of shock. our hypothesis was that by application of advanced computer vision (i) chct can be reliably measured in given capillaries, and (ii) change in chct reflects capillary hemodilution induced by cardiopulmonary bypass (cpb). methods: in patients undergoing coronary artery bypass surgery sublingual capillary microscopy videos were recorded before and during cpb primed with hes / . . per-capillary chct was estimated as the product of the number of red blood cells (rbc) and an assumed volume of nl, divided by the capillary volume including plasma gaps. rbc number was assessed by manual counting in the first frame of a given video clip, as well as using a novel advanced computer vision algorithm employing blob detection to calculate the mean per-capillary rbc number in all frames of a given video clip (fig. ) . results: capillaries were analyzed, within a total of and frames using manual and algorithmic analysis. a good correlation was found between both methods for chct (r= . , p< . , fig. ). cpb initiation resulted in an decrease in chct from (mean±sem) . ± . to . ± . , p< . and . ± . to . ± . , p= . in manual and algorithm. conclusions: accurate measurement of chct is possible using advanced computer vision, and it reflects hemodilution induced by initiation of cpb. chct further is a determinant of capillary delivery of oxygen. combined with the assessment of functional capillary volume, blood flow velocity, and capillary hemoglobin saturation, chct may enable direct optical quantification of capillary delivery of oxygen as an integrated functional parameter of the microcirculation. fig. (abstract p ) . prognosis of patients with cso < %time above %h was poor fig. (abstract p ) . detection of single erythrocytes using a novel advanced computer vision algorithm in a representative capillary ribbon extracted from a video frame of the sublingual microcirculation fig. (abstract p ) . the area under cso < % was significantly lower in survivors introduction: cardiac function is known to be impacted by sepsis. passive leg raise (plr) is an effective method to predict fluid responsiveness (fr) or cardiac response to preload expansion. preload functional status and trending cardiac output may identify patient phenotypes with varying cardiac reserve, dysfunction and outcome. methods: patient data were analyzed from a currently enrolling prospective randomized controlled study, evaluating the incidence of fr in critically ill patients with sepsis or septic shock (fresh study, nct ). patients randomized to plr guided resuscitation were classified as plr+ (fluid responsive/preload dependent) if stroke volume (sv) increased >= % when measured with a non-invasive bioreactance device (starling sv, cheetah medical). patients were categorized into different phenotypic cohorts based on changing physiology exhibited on plr and trending cardiac output over the initial hours of therapy. results: a total of plr assessments were performed in patients. overall, % ( / ) of assessments indicated a patient was plr+ after receiving initial resuscitation fluid of~ l. most patients ( %) demonstrated a dynamic physiology with changing plr status occurring > time over hours. there were no differences among the groups with respect to age, gender, or qsofa score (fig. ) . patients in group exhibited a significantly decreased icu stay ( . hours) compared to group ( . hours, p= . ) (fig. ) . patients in group exhibited significantly increased echo evidence of lv/rv cardiac dysfunction ( %), compared to group ( %, p= . ) ( table ) . patients in group exhibited % evidence of echo based lv/rv cardiac dysfunction. conclusions: physiological based resuscitation phenotypes identify significantly different patient groups. patients who are initially not plr+, but then become plr+ with no improved co are significantly more likely to have confirmed lv/rv dysfunction and a significantly longer icu stay. introduction: accurate measurement of a patient's intravascular volume status remains an unsolved clinical problem in the icu setting. in particular, septic and cardio-renal patients often receive volume challenges or diuresis, respectively, with little appreciation of baseline bv or the resulting response. this can lead to volume overload and/or depletion and associated increases in morbidity, mortality and hospital length of stay. methods: we tested the performance of a novel, rapid, minimally invasive technique capable of measuring pv, bv and glomerular filtration rate (mgfr) in human subjects. the method consists of a single iv injection of a large ( kda) carboxymethyl dextran conjugated to a rhodamine-derived dye and a small ( kda) carboxymethyl dextran conjugated to fluorescein. plasma and blood volumes were quantified minutes following the injection of the dye based on the indicatordilution principle. results: this phase b study included normal subjects, chronic kidney disease (ckd) stage iii and ckd stage iv subjects. pv and bv varied according to weight and body surface area, with pv ranging from to mls, and both were stable for greater than six hours with repeated measurements. there was excellent agreement ( fig. ) with nadler's formula for pv in normal subjects. a hour repeat dose measurement in healthy subjects showed pv variability of less than +/- %. following an intravenous bolus of ml % albumin solution the mean +/-(sd) measured increase in pv was . ml +/- . ml post infusion (fig. ) . conclusions: this novel bedside approach allowed for rapid and accurate determination of pv, bv, mgfr (data not shown) and dynamic monitoring following clinical maneuvers such as fluid administration, with a high level of safety, accuracy and reproducibility. this approach should assist the intensivist especially with volume administration and removal in septic and cardiorenal patients. introduction: accumulating evidence shows that fluid overload is independently associated with adverse outcome in children and adults with acute lung injury. fluid restriction initiated early in the disease process may prove beneficial, potentially by diminishing the formation of interstitial edema. the main goal of this study was to determine the short-term biophysical effects of intravenous (iv) fluid restriction during acute lung injury in relation to age. methods: infant ( - weeks) and adult ( - months) wistar rats were mechanically ventilated (mv) hours after intratracheal inoculation with lipopolysaccharide to model acute lung injury. both age groups were randomized to either a normal or restrictive iv fluid regimen during hours of mv. thereafter the rats were sacrificed and studied for markers of interstitial edema formation (wet-dry weight ratios), lung permeability (total protein and alpha- macroglobulin (a m) in bronchoalveolar lavage; bal) and local inflammation (cell counts and cytokines in bal). results: restrictive fluid therapy was not associated with worsening of hemodynamic indices during the period of mv in either infant or adult rats. however, as compared to the normal fluid regimen, restrictive fluid therapy led to lower wet-dry weight ratios of the lungs and kidneys in adult rats (p < . ), but not in infants (figs. and ). no difference was found in total protein and a m in bal between the two fluid regimens in both age groups. also, neutrophil influx in the lungs did not differ between fluid regimens in both age categories, nor did the influx of inflammatory cytokines il- and mip- in bal fluid. conclusions: there is an age-dependent effect of early fluid restriction on the formation of interstitial edema in local and distant organs in the disease process of acute lung injury. further investigation of the effects of fluid therapies in experimental models may help steering towards better treatment in critically ill patients. . ) . in a multivariate analysis fb was independently associated with: group c (p< . ), a history of diabetes (p= . ), the acute physiology and chronic health evaluation iii score (< . ) and the duration of aortic-cross clamp (p< . ). the main findings of this study substantiated the hypothesis that the introduction of continuous fb-tracking throughout the entire care process, is associated with a significant reduction in the administration of fluids in post-cardiac surgery patients, independent of differences in their baseline characteristics. demonstrating that certain organizational changes can influence medical behavior beyond the scope of teaching and instruction, and therefore serves to provide awareness to the current issue known as 'knowledge-to-care gap'. using a protocol for fluid resuscitation: how well is it followed? introduction: positive fluid balance in icu patients has been correlated with worse outcomes [ ] . consequently, we developed a protocol to guide fluid resuscitation. the protocol was introduced in and mandates that fluid responsiveness is assessed when administering fluid boluses. once a patient becomes fluid unresponsive, no further resuscitation fluid should be administered. to assess responsiveness, the protocol advises the use of haemodynamic data such as heart rate and blood pressure as well as the change in stroke volume (sv) measured by a lidcoplus monitor. after years of use and a rolling education program this protocol was felt to be well ingrained in our unit culture. we then assessed how well it was being followed. methods: staff performing fluid challenges were asked to fill out a form recording the haemodynamic and sv data measured before and after a fluid challenge. they were also asked to record their interpretation of just the haemodynamic data and then this data combined with the sv data. results: forty five forms were completed. the protocol was not followed on occasions ( %). four patients who should have been assessed as responsive were deemed to be unresponsive. six patients who should have been assessed as unresponsive were assessed as being responsive. the remaining deviations from the protocol represent misinterpretation of the haemodynamic data but correct use of the sv data to reach a correct final assessment. conclusions: despite being a longstanding ingrained practice in our icu, this review suggests that the protocol for fluid resuscitation is being followed incorrectly approximately a third of the time. this could result in inappropriate under or over administration of iv fluid. we plan to review the educational programme and raise awareness of the protocol to try and improve future compliance. introduction: understanding the effects of therapeutics on the left ventricular (lv) loading conditions is of utmost importance in critically ill patients. the effective arterial elastance (ea=esp/sv, where esp is aortic end-systolic pressure and sv stroke volume) is a lumped parameter of arterial load that has been proposed as an index of lv afterload. we aimed at comparing the effects of fluid administration on esp (i.e., the lv afterload in the pressure-volume phase-plane according to the classic "cardiocentric" framework) and on ea. methods: in mechanically ventilated patients, we recorded ea from the femoral peripheral systolic arterial pressure sap (ea=( . ×femoral sap)/sv) before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) >= % were defined as "responders". introduction: the respiratory variations of the inferior vena cava (ivc) diameter in mechanically ventilated patients with preload responsiveness could be explain by a higher compliance of the ivc and/or higher respiratory variations of the ivc backward pressure, i.e., the central venous pressure (cvp).we aimed at determining the respective weight of these two phenomena. methods: in mechanically ventilated patients, haemodynamic, respiratory and the intra-abdominal pressure (iap) signals were continuously computerised. cvp, iap and the ivc diameter (transthoracic echocardiography) were recorded during end-inspiratory and endexpiratory occlusions, before and after the infusion of -ml of saline. patients in whom fluid administration induced an increase in cardiac index (picco- ) >= % were defined as "responders". the respiratory variations of the ivc diameter, cvp and iap were calculated as (end-inspiratory -end-expiratory values)/mean value. the compliance of the ivc was estimated by the ratio between (end-expiratoryend-inspiratory) values of ivc diameter and cvp. results: fluid administration increased cardiac index by more than % in patients. the respiratory variations of the ivc diameter predicted fluid responsiveness (area under the roc curve: . ( %ci: . - . ), p< . ). before fluid administration, the compliance of the ivc was not different between responders and non-responders ( . ± . vs. . ± . mm/mmhg, p= . ), whereas the respiratory variations of the cvp were higher in responders than in nonresponders ( ± vs. ± %, p= . ). the respiratory variations of the ivc diameter were associated with the respiratory variations of cvp (r= . , p= . ) but not of iap (r=- . , p= . ). conclusions: the respiratory variations of the ivc diameter rather depend on the respiratory variations of the cvp than on the ivc compliance. the iap seems to not be involved in the respiratory variations of the ivc diameter. hours and gedi measured at the same time was examined. since the dataset used in this study consists of repeated measurement data, the analysis used the general linear mixed effect model (glmm). the multivariate analysis adjusted with age, cr, and cardiac index was also conducted. results: of the patients with the total bnp measurements conducted for times and gedi measurements for times, the median of age and saps were (iqr - ) and (iqr - ), and the hospital mortality rate was %. the univariable analysis and the multivariable analysis using glmm respectively found statistically significant differences, with regression coefficient at . %ci . - . (p= . ), and . %ci . - . (p< . ). conclusions: while a positive correlation between gedi and bnp was statistically identified, its effect may be minor in clinical terms, and its significant clinical difference remains unclear. introduction: fluids are a cornerstone of the management of critically ill patients who are at risk of multiple organ dysfunction syndrome. however positive fluid balance (fb) is associated with worse morbidity and mortality in this population, so fluid administration needs to be carefully titrated and the nutritional support products must be taken in consideration. objective: evaluate the impact of nutritional support in the fluid balance in a intensive care unit methods: observational prospective study, conducted in eleven portuguese icus of nine general hospitals. patients with years of age or older were eligible if they were ventilated and had a length of stay (los) in icu greater than days. demographic data, fluid balance along type of nutritional support used in the first days and were collected from the selected patients. results: patients were enrolled, . % were male, the median age - ± ( - ), icu los - . ± . days, mortality rate of . % ( ). % of patients were admitted for medical reasons, . % had normal weight, the remaining patients were either overweight or obese. the average daily fb in the eight days was ± ml, being the maximum at day with + ml, slowly trending down reaching a neutral balance at day and reaching - ml at day . in the first days the majority of the intake is due to resuscitation driven fluids, however the nutritional support contribution rises as the days passes, reaching % at day and % at day ( fig. ) . regarding the administration route, the enteral route was responsible to , % of fluids at day compared to , % of parenteral route. the nutritional support is an factor to take into account regarding fluid balance in intensive care units. in this study after the th day the nutritional support, it was responsible for more than % of the total volume that was delivered to the patient and with an higher impact with the increase in los results: we included patients with mean age years, % male, apache ± , saps ii ± , sofa in admission ± , mechanical ventilation %, continuous renal replacement techniques %. the mean total volume administered during the first days was ± l with a mean dcb of ± l and a mean fluid accumulation of % ± . regarding fluid accumulation: % have < %, % between - % and . % > %. th-day mortality and icu mortality were % i % respectively. during the first week, the percentage of fluid accumulation was significantly higher in non-survivors than in survivors ( . ± . l vs. . ± . l, p . ) (fig. ) . cumulative survival was significantly lower (logrank = . , p= . ) in patients with > % of volume gain since the th day (fig. ) . > % volume gain in the th day is a independently associated variable to mortality after adjusting by age, apache and haemodialysis (or = . ; ci % . - . ; p = . ) ( table ) . conclusions: in septic shock patients, fluid overload more than % since -day of evolution is associated with a higher th-day mortality. its early detection may influence the prognosis and survival. introduction: sepsis is defined as a life-threatening organ dysfunction due to a deregulated host response to infection [ ] . fluid infusion is one of the cornerstones of sepsis resuscitation therapies. one of the major adverse effects reported is fluid overload (fo). the objective of this study was to assess influence of fo on sofa score changes from day to day . methods: this study is a retrospective, multicenter, epidemiologic data analysis. it was performed in three french icus. all adult patients admitted for septic shock, caused by peritonitis or pneumonia and mechanically ventilated, were enrolled. delta sofa score was defined as the sofa score measured on admission minus sofa score measured on day . results: patients met the inclusion criteria of the study. fo occurs in about % of the patients. cumulative fluid balance at day was greater in the fo group ( . versus . ml, p < . ) ( table ) . delta sofa score was higher in the no fo group than in the fo group ( . versus . , p = . ) (fig. ). there was a stepwise decrease of delta sofa score when duration of fluid overload was greater (p = . ) (fig. ) . in linear modelling, association between fo status and delta sofa score was confirmed with an adjusted rr of . [ . - . ] (p = . ) ( table ) . conclusions: ) fo patients had more prolonged multi-organ failure during septic shock; ) the longer the fo is the longer the more multi-organ failure last. , (t ) and (t ) minutes later. cardiovascular parameters were also measured at above time points. biomarker change from baseline (fold-change), indexed to hemoglobin, was compared between groups using mixed effects models (bonferroni-holm corrected p< . ). results: minor differences in measures of shock between groups after fluid administration resolved by t . cryst showed increased fold-change in hyaluronan compared to other groups at t (fwb p= . , hes p< . , gelo p< . ), t (fwb p< . ) and t (fwb p< . ) (fig. ) . gelo had increased fold-change in hyaluronan compared to other groups at t (hes p= . ), t (fwb p< . ) and t (fwb p< . , cryst p= . ), as did fwb at t (hes p= . ). cryst showed increased fold-change in il compared to other groups at t (hes p< . , gelo p= . ), t (hes p= . , gelo p= . ,), t (hes and gelo p< . ) and t (hes and gelo p< . ) (fig. ) , of il at t (gelo p= . ), and of kc at shock (fwb p= . , gelo p= . ), t (fwb p= . , gelo p= . ), and t (gelo p= . ). conclusions: rapid large-volume crystalloid given for hemorrhagic shock was associated with increased hyaluronan, a biomarker of endothelial glycocalyx damage, and inflammation, including increased il , il and kc. introduction: a bi-center randomized controlled trial has recently been published that investigates the impact of the type of fluid (crystalloid versus colloid) on patient outcome following major surgery [ ] . the study used a closed-loop fluid delivery system to eliminate the clinician bias when determining when to deliver fluids. the goal of the current analysis is to compare the immediate hemodynamic response to ml fluid boluses of either a crystalloid or a colloid solution. methods: patient consent was obtained prior to transferring the data from [ ] to edwards lifesciences for further post-hoc analysis. the percent change in stroke volume (dsv) following each ml bolus was tabulated and cross-referenced to the type of fluid. the responder rate and the dsv cumulative distribution function (cdf) were determined for each type of fluid administered. a responder was defined as a dsv >= % for a ml fluid challenge. the mean dsv was compared between the two groups using a student t-test. results: from the datasets reported in [ ] , were used in the analysis. descriptive statistics are summarized in table and the cdfs are plotted in fig. . more crystalloid boluses were administered. in both groups, the responder rate was around %. mean dsv was not significantly different between groups (p = . ). we observed similar responder rates and cdfs with the two fluid types, suggesting that the immediate hemodynamic response to ml fluid boluses is independent from the fluid type. we therefore hypothesized that it is the longer intra-vascular persistence of the colloid that explain the lower number of boluses required to achieve the hemodynamic endpoints targeted in the clinical study [ ] . fig. (abstract p ) . cumulative distribution functions of delta stroke volume for crystalloid and colloid fluid boluses the reduction projected to an average annual saving of , usd ( introduction: colloids are widely used for volume resuscitation. among synthetic colloids, hydroxyethyl starch (hes) is commonly administered. in cardiac surgery, priming of the cardiopulmonary bypass (cpb) circuit with colloids minimizes resuscitation volume and results in less pulmonary fluid accumulation. however, the use of hes has been associated with a higher incidence of renal damage and a higher occurrence of coagulopathy. the aim of this study was to investigate the effect of low dose ( - ml/kg) hes % ( / , ) in cpb pump priming on fluid balance, blood loss, transfusion requirement and occurrence of acute kidney injury. methods: in a pre-post design, data from patients undergoing cardiac surgery with cpb were analyzed. in patients, priming solution consisted of ml balanced crystalloids, ml mannitol %, tranexamic acid g and i.e. heparin. for the other patients, ml of the crystalloids were replaced with hes % ( / . ), the other components were the same. patients were matched : with propensity score method. the primary endpoint was intraoperative fluid balance. secondary endpoints were perioperative blood loss, transfusion requirement and the occurrence of acute kidney injury. results: in total, patients were analyzed. the hes group showed less positive fluid balance than the crystalloid group (p< . ). there was no difference in intraoperative blood loss (p= . ) and transfusion requirement (p= . ). the occurrence of acute kidney injury was not significantly different between the two groups (p= , ). conclusions: low-dose administration of - ml/kg hes % ( / . ) to cpb pump priming decreased intraoperative fluid accumulation without increasing perioperative blood loss and transfusion requirement. there was no effect on the incidence of acute kidney injury. priming cpb pumps with a low-dose of hes % ( / . ) is an important component for a restrictive volume strategy and might safely be used in patients with preexisting renal dysfunction. introduction: most crystalloid solutions used in critically ill patients have a greater chloride (cl) concentration than plasma, which may be detrimental. replacing some cl with bicarbonate (hc ) reduces cl, but may increase partial pressure of carbon dioxide (pc ) in blood. such an increase in pc may be harmful [ ] . the main objective was to determine if a hco balanced fluid resulted in increased paco compared to a conventional balanced fluid. methods: single center randomized controlled trial in an adult icu, comparing balanced fluid (sodium,na= mmol/l, chloride,cl= mmol/l, hco = mmol/l) vs conventional fluid (na= mmol/l, cl= mmol/l, hc <= mmol/l). university ethics committee approval:m . we used the absolute difference between the pco and mmhg as a comparison for the fluid groups. betweengroup comparisons of pc from d -d was done by repeated measures anova. a p value < . was considered significant. results: patients were allocated to the conventional group and to the balanced group. at baseline the groups were well matched (p> . ) for age, weight, gender, severity of illness and organ support. there were no significant differences in pc between the two fluid groups, overall or at d , d or d . the balanced group showed a significant improvement in egfr (scr), between d and d (p= . ) while the conventional group exhibited a significant decline (p= . ). there were no significant differences between the groups with respect to fluid requirements, number of positive blood cultures, icu renal replacement utilization, icu length of stay, icu mortality and day mortality. conclusions: the use of a balanced fluid did not result in an increase in pco and appears to be safe. a beneficial effect on renal function was observed. introduction: the effects of crystalloids and colloids on macro-and microcirculation is controversial. our aim was to compare their effects on microcirculation during free flap surgery when management was guided by detailed hemodynamic assessment. methods: patients undergoing maxillo-facial tumour resection and free flap reconstruction were randomized into a crystalloid (ringerfundin, rf, n= ) and a colloid ( % hydroxyethyl starch, hes, n= ) groups. cardiac index (ci), stroke volume (svi) and pulse pressure variation (ppv) were continuously monitored by a non-calibrated device (pulsioflex -pulsion, maquet). central venous oxygen saturation (scvo ), venous-to-arterial pco -gap (dco ), lactate levels and hourly urine output was also measured, and a multimodal, individualized approach based algorhithm was applied [ ] . microcirculation was assessed by laser doppler flowmetry (periflux ldpm, perimed jarfalla, sweden). measurements were performed at baseline and from the start of reperfusion hourly for hours. for statistical analysis, two-way rm anova was used. results: there was no difference between the groups regarding age, sex, length of surgery (whole population: ± min). patients in the rf-group required significantly more fluid in total (rf: ± , hes: ± ml, p= . ). both groups remained hemodynamically stable (ci, svi, ppv, scvo , dco , lactate and urine output) throughout the study. there was no difference between the rf-, and hes-groups in the laser doppler measurements neither on the control site nor in the flap (fig. ) . conclusions: we found that when hemodynamic management is guided by a multimodal assessment and stability is maintained, there was no difference between crystalloids and colloids in macrocirculation and microcirculatory perfusion. introduction: our aim is to evaluate the impact of crystalloid fluids on immune cells. intensive care unit (icu) patients' inflammatory status can switch from an early pro-inflammatory to a late anti-inflammatory phase, which favors infections. they can receive different crystalloids, either normal saline (ns), ringer's lactate (rl) or plasma-lyte (pl). high chloride concentration present in ns has been associated with various complications [ ] , whereas high doses of nacl have inflammatory effects on immune cells [ ] . however, the immune consequences of crystalloids in humans are ill-defined. methods: using our comprehensive immunemonitoring platform, we assessed the immunological phenotype of peripheral blood mononuclear cells (pbmc) in humans. healthy subjects received a liter of ns, rl and pl. blood samples were taken before and h later. pbmc phenotypes were assessed by flow cytometry and cytokine concentrations were measured by a multiplex assay. off-pump cardiac surgery patients were also randomized to receive either ns, rl or pl during surgery and their stay in the icu. blood samples were drawn at various time-points. all leucocytes were analyzed in a similar fashion. we are still recruiting. results: study of healthy subject's pbmc suggested that rl reduced classical monocytes, whereas ns increased lymphocyte activation and il- and mip- b levels. in cardiac surgery patients, our preliminary results suggested that rl and pl reduced classical monocytes and increased non-classical monocytes compared to ns. neutrophils were also affected differently by crystalloids, where ns seemed to activate them more. conclusions: our results suggest that crystalloids have different immune consequences. a better understanding of their immune modulation will lead to personalization of their use according to the inflammatory status of patients to restore their immune homeostasis. this randomised controlled open-label pilot study included patients presenting to an emergency department with suspected infection requiring a fluid bolus. patients received either a single bolus of ml/kg of . % nacl (isotonic group) or ml/kg of % nacl (hypertonic group). blood biomarker concentrations of glycocalyx shedding (syndecan- , hyaluronan), endothelial activation (sicam- , svcam- ) and inflammation (interleukin- , - , - , ngal, resistin) were measured at t (before fluid) and hour (t ), hours (t ) and - hours (t ) later. changes in biomarker concentrations were compared between study groups using mixed regression models, with fold-change from t reported. differences in fluid volumes were compared using the wilcoxon rank sum test. significance was set at p< . . results: syndecan- concentration in the isotonic group decreased from t to t (fold-change . , % ci . - . ), which was significantly different to the hypertonic group (fold-change . , % ci . - . )(p= . )( table ) . interleukin- concentration decreased in the isotonic group from t to t (fold-change . , % ci . - . ), which was significantly different to the hypertonic group (fold-change . , % ci . - . )(p= . ). otherwise, there were no significant differences in change over time between groups for measured biomarkers. total fluid volume administered between t and t was significantly higher in the isotonic group (p< . ) ( fig. ) but not different for subsequent time periods. conclusions: biomarkers of glycocalyx shedding, endothelial activation and inflammation were not different between patients receiving either . % or % saline. also, % nacl did not reduce administration of additional fluids. introduction: acute changes in pco are buffered by non-carbonic weak acids (atot), i.e., albumin, phosphates and hemoglobin. aim of the study was to describe acid-base variations induced by in-vitro pco changes in critically ill patients' blood and isolated plasma, compare them with healthy controls and quantify the contribution of different buffers. methods: blood samples were collected from patients admitted to the icu and controls. blood and isolated plasma were tonometered at and % of co in air. electrolytes, ph, blood gases, albumin, hemoglobin and phosphates were measured. the strong ion difference (sid) was calculated [ ] and non-carbonic buffer power was defined as β=-Δhco -/Δph [ ] . t-tests and linear regression were used for analysis. results: seven patients and controls were studied. hemoglobin, hematocrit and albumin were lower in patients (p< . ), while sid and phosphates were similar. pco changed from ± to ± mmhg, causing different blood ph variations in patients and controls ( . ± . vs. . ± . , p= . ). patients had lower blood and plasma β ( ± vs. ± , p< . and ± vs. ± , p= . , respectively). figure shows changes in [hco -] and sid induced in blood by pco variations. in both populations, ± % of [hco -] change was due to sid variations, while only ± % to changes in atot dissociation. a significant correlation between hematocrit and Δsid was observed in the whole study population (fig. ) . conclusions: the β of icu patients was lower, likely due to reduced albumin and hemoglobin concentrations. similar pco increases caused therefore greater ph variations in this population. electrolyte shifts, likely deriving from red blood cells [ ] , were the major buffer system in our in-vitro model of acute respiratory acidosis. introduction: there is an increasing trend in the incidence of aneurysmal subarachnoid haemorrhage in hong kong and the disease carries high morbidity and mortality rate. electrolyte disturbance is one of the known complications of sah and the outcomes associated with this are not fully understood. the objective of this retrospective local study is to evaluate the pattern of electrolyte disturbances in patients with sah and their impact on the prognostic functional outcome. methods: patients with spontaneous aneurysmal sah who were admitted to icu at pamela youde nethersole eastern hospital, hong kong between st january and st december were included into this retrospective local study. collected data include demographic details, comorbidities, serum electrolyte levels (sodium and potassium) from day to of admission into icu, radiographic intensity of haemorrhage using fisher scale and the clinical grading of sah using wfns. prognosis of these patients was estimated using the glasgow outcome scale at months after initial insult (fig. ) . results: a total of patients were included in this study. the mean age was , with the majority of patients being female ( . %). the most common aneurysm location was in anterior communicating artery, though poor outcomes were shown significant in patients with posterior circulation aneurysms. whilst early-onset hyponatremia was not correlated with poor outcome, late-onset hyponatremia was associated with better outcome. logistic regression analysis identified independent predictors of poor outcome (table ) . patients who underwent interventional radiological procedure treatment was shown to have better outcome. conclusions: hypernatremia after sah is associated with poor outcome. there does not appear to be significant evidence that hyponatremia has an effect on short-term mortality or certain outcome measures such as gos, and its longer-term effects are not well characterized. fig. note logarithmic transformation of los data). we found a statistically significant difference between the two groups when comparing the length of stay (p < . ). conclusions: dean et al demonstrated no significant difference in the mean length of stay using the same definitions of hypo and eunatraemia as in this study [ ] . even though our data appears to contradict their findings, regarding the statistical significance seen, we feel that this is not significant clinically, given the very similar median times for los between the two groups; the unbalanced design may contribute to the statistical significance. fig. (abstract p ) . length of stay between the two groups (note logarithmic scale for los) fig. (abstract p ). gos at months group consisted of patients with mean age . (sd . ) years and mean sodium . (sd . ) mmol/l with a median los of . (iqr . - . ) days. we found no statistically significant difference (p = . ) between the two groups when comparing the length of stay (fig. ) . conclusions: darmon et al demonstrated prognostic consequences of an admission sodium greater than , eliciting hypernatraemia as a factor independently associated with -day mortality [ ] . in contrast, our study suggests that hypernatraemia (as defined) is not associated with the length of stay, however this result is limited by the unbalanced design of this small study. introduction: our aim is to determine whether auscultation for bowel sounds helps in clinical decision making in icu patients with ileus. ileus can be the consequence of an operation, a side effect of drugs or the result of an obstruction requiring direct operative correction. although auscultation for bowel sounds is routinely performed in the icu and a well-established part of the physical examination in patients with suspected ileus, its clinical value remains largely unstudied. methods: a literature search of pubmed, embase and cochrane was performed to study the diagnostic value of auscultation for bowel sounds. results: auditory characteristics (tinkling, high pitched and rushes) were highly variable in postoperative ileus, mechanical ileus and healthy volunteers. the inter-observer variability for the assessment of the quantity, volume and pitch of bowel sounds was high, with a moderate interobserver agreement for discerning postoperative ileus, bowel obstruction and normal bowel sounds (kappa value . ). the intra-observer reliability of duplicated recordings for distinguishing between patients with normal bowels, obstructed bowels or postoperative ileus was % [ ] . no clear relation between bowel sounds and intestinal transit was found (table ) . sensitivity and positive predictive value were low: respectively % and % in healthy volunteers, % and % in obstructive ileus, and % and % in postoperative ileus ( table ) . conclusions: auscultation with the aim to differentiate normal from pathological bowel sounds is not useful in clinical practice. the low sensitivity and low positive predictive value together with a poor inter-and intra-observer agreement demonstrate the inaccuracy of utilizing bowel sounds for clinical decision-making. given the lack of evidence and standardization of auscultation, the critically ill patient is more likely to benefit from abdominal imaging. introduction: stress ulcer prophylaxis has become a standard of care in intensive care unit (icu). however, it has been proposed that enteral nutrition (en) could play preventive role for gastrointestinal bleeding and some studies revealed no added benefit of acid suppressive drugs to patients on en. based on these backgrounds, we use proton pump inhibitor (ppi) as stress ulcer prophylaxis during starvation period, and discontinue it within hours after commencing meals or en. the aim of this study is to evaluate the applicability of our protocol by reviewing the incidence of upper gastrointestinal bleeding (ugib) in our icu. methods: we conducted a retrospective observational study. all consecutive patients admitted to our icu between april and march were reviewed. patients who had ugib within hours after admission, had previous total gastrectomy, or underwent upper gastrointestinal surgery were excluded. the primary outcome was the incidence of overt or clinically important ugib, and the secondary outcome was protocol adherence. we presented descriptive data as number (percentage) and median (interquartile range). results: a total of patients were included. of those, ( . %) were male, median age was ( - ), and median sofa score was ( ) ( ) ( ) ( ) ( ) ( ) ( ) . of all patients, ( . %) had overt bleeding, and ( . %) had clinically important bleeding. both patients who introduction: patients requiring operative procedures admitted under non-surgical specialties typically experience delays in treatment and fail to meet peri-operative standards with regards to the timing of operative intervention. patients admitted from medicine requiring an emergency laparotomy have an increased mortality when compared to those patients admitted from surgery ( . % v . %) [ ] . methods: we undertook a retrospective case note review of patients requiring a non-elective laparotomy at our hospital during a sixmonth period in . patients were identified using the emergency theatre booking system. data were gathered on admission details, peri-operative care and post-operative stay. results: two main investigators reviewed patients to standardise data extraction. six patients presenting with inflammatory bowel disease were excluded from analysis. most patients ( . %) were admitted through the emergency department; ( . %) of whom were initially admitted under medicine, with only . % of these reviewed by a senior clinician prior to admission (table ). there was no statistically significant difference in mortality between the medicine and surgery groups. there was a trend to increased length of stay in icu and in hospital in the medical group (table ) . conclusions: lack of senior decision making may have a direct impact on patient care due to the inappropriate streaming of patients to medicine. the increased mean length of stay in those patients admitted to medicine may reflect a delay in surgical intervention and therefore a prolonged recovery period. we are introducing an acute abdominal pain screening and immediate action tool to improve identification of these high-risk patients and early involvement of senior decision makers. introduction: biomarkers reflecting the extent of surgical tissue trauma should be investigated in an effort to predict and prevent postoperative complications. the aim of the present study was to investigate blood concentrations of selected alarmins in patients after colorectal surgery in comparison to healthy individuals. the secondary aim was to analyze the relationship between alarmins and inflammatory biomarkers during early postoperative period. methods: the prospective, single-center, observational study consisted of non-surgical (ns) group (n= ) and surgical (s) group (n= ) undergoing colorectal surgery. serum levels of selected alarmins (s a and s a ) and inflammatory biomarkers (leukocytes; c-reactive protein, crp; interleukin- , il- ) were analyzed. results: proteins s a an s a had significantly higher serum values in the s-group during all three days after the surgery. the multidimensional model taking into account age, sex, weight, group and days revealed significant differences between study groups for both proteins s a and s a (p< . , p= . , respectively). biomarkers (leukocytes, crp, and il- ) showed significant differences between study subgroups (p< . , p< . , and p< . , respectively). in s-group, moderate positive correlations were found between s a and all biomarkers: leukocytes (r= . ), crp (r= . ), and il- (r= . ). s a had moderate positive correlation with leukocytes (r= . ). levels of s a also positively correlated with intensive care unit and hospital length of stay (r= . , r= . , respectively) conclusions: protein s a might be considered as early biomarker of first wave of immune activation elicited by surgical injury after colorectal surgery. the increase of the alarmins is reflected by the elevation of routine inflammatory biomarkers. introduction: critical illness-induced liver test abnormalities are associated with complications and death in adult icu patients, but remain poorly characterized in the pediatric icu (picu). in the pepanic rct, delaying initiation of parenteral nutrition to beyond day (late pn) was clinically superior to providing pn within h (early pn), but resulted in a higher rise in bilirubin. we aimed to document prevalence and prognostic value of abnormal liver tests and the impact of withholding early pn in the picu. methods: we performed a preplanned secondary analysis of of the pepanic patients aged days to years, as neonatal jaundice was considered a confounder. plasma concentrations of total bilirubin, alt, ast, γ gt, alp were measured systematically during picu stay. analyses were adjusted for baseline characteristics including severity of illness. results: during the first picu days, the prevalence of cholestasis (> mg/dl bilirubin) ranged between . %- . % and of hypoxic hepatitis (>= -fold uln for alt and ast) between . %- . %, both unaffected by the use of pn. throughout the first week in picu plasma bilirubin concentrations were higher in late pn patients (p< . ), but became comparable to early pn patients as soon as pn was started on day . plasma concentrations of γ gt, alp, alt and ast were unaffected by pn. high day plasma concentrations of γ gt, alt and ast (p<= . ), but not alp, were independent risk factors for picu mortality. day plasma bilirubin concentrations displayed a ushaped association with picu mortality, with higher mortality associated with bilirubin concentrations < . mg/dl and > . mg/dl (p<= . ). conclusions: in conclusion, overt cholestasis and hypoxic hepatitis were rare and unrelated to nutritional strategy. however, accepting a large macronutrient deficit during week increased plasma bilirubin. a mild elevation of bilirubin on the first picu-day was associated with lower risk of death and may represent an adaptive stress response rather than true cholestasis. positive fluid balance is an independent risk factor for intensive care unit mortality in patients with acute-on-chronic liver failure introduction: muscle wasting is a common consequence of disuse and inflammation during admission to intensive care with critical illness. limb muscles are known to decrease in size during critical illness, but less is known about muscles of the trunk. in this study, we tracked how psoas muscle area changes at multiple levels, in a group of patients with acute severe pancreatitis. methods: paired computed tomography (ct) scans were obtained from patients admitted to the royal liverpool university hospital's icu with acute severe pancreatitis. the first scan was within days of admission, and the second took place between to days later. for each scan, three slices were identified: the top and bottom plates of l , and the mid-point of l vertebral body. on each slice, the cross sectional area (csa) of the left and right psoas muscle was calculated using imagej. the difference and percentage change in csa between both scans was calculated. white cell counts and c-reactive protein results were obtained, with peak levels correlated against change in muscle size. results: combined csa of the left and right psoas muscle increased from top to bottom plates and was positively correlated with height (r= . , p< . mid l level)) and weight (r= . , p= . , mid l level) at all three levels. at all three levels, there were significant losses of csa between the two scans (see table ). crp was moderately correlated with percentage change in csa (r= - . , p= . ). increasing weight on admission was associated with greater percentage losses in csa (r= - . , p< . ). wcc did not correlate with change in size. in critically ill patients with acute severe pancreatitis, there are significant losses in both psoas muscles throughout the l level. further prospective studies are required to determine if inflammatory markers and cytokines have a role in these losses, and to determine the functional effects of these losses. introduction: the evidence for penta-therapy for hyperlipidemic severe acute pancreatitis (hl-sap) is anecdotal. the purpose of our study is to evaluate the efficacy of penta-therapy for hl-sap in a retrospective study. methods: retrospective study between january and december in a hospital intensive care unit.hl-sap patients were assigned to conventional treatment alone (the control group) or conventional treatment with the experimental protocol (the penta-therapy group) consists of blood purification, antihyperlipidemic agents, lowmolecular-weight heparin, insulin, covering the whole abdomen with pixiao (a traditional chinese medicine).serum triglyceride, serum calcium, apache ii score, sofa score, ranson score, ct severity index, and other serum biomarkers were evaluated. the hospital length of stay, local complications, systematic complications, rate of recurrence, overall mortality, and operation rate were considered clinical outcomes. results: hl-sap patients received conventional treatment alone (the control group) and patients underwent penta-therapy combined with conventional treatment (the penta-therapy group). serum amylase, serum triglyceride, white blood cell count, c -reactive protein, and blood sugar were significantly reduced, while serum calcium was significantly increased with penta-therapy. the changes in serum amylase, serum calcium were significantly different between the penta-therapy and control group on th day after the initiation of treatment. the reduction in serum triglyceride in the pentatherapy group on the second day and th day were greater than the control group. patients in the penta-therapy group had a significantly shorter length of hospital stay. conclusions: this study suggests that the addition of penta-therapy to conventional treatment for hl-sap may be superior to conventional treatment alone for improvement of serum biomarkers and clinical outcomes. average energy expenditure (ee) for all patients was ± kcal/kg (mean ± sd). there was no difference in the average ee between the patients who survived and those who died: ± and ± kcal/ kg (mean ± sd) respectively (p > . ). however, there was a negative correlation between ee and saps score in the non-survivors groupcorrelation coefficient - . , p < . . the energy deficit (computed by subtracting caloric intake from ee measurement) was similar among survivors and non-survivors, . ± vs . ± kcal/kg, respectively (mean ± sd) (p > . ). the patients who survived had received ± kcal/kg while those who died - ± kcal/kg (mean ± sd) (p > . ). the provision of protein was also similar for both groups: . ± . g/kg for survivors and ± . g/kg for nonsurvivors (mean ± sd) (p > . ). there was no statistically significant correlation between provision of calories and protein and outcomes such as length of hospital and icu stay or duration of mechanical ventilation. conclusions: average energy expenditure in critically ill patients with acute severe pancreatitis roughly equals to aspen estimation of kcal/kg and does not differ among survivors and non-survivors. outcomes such as survival, length of hospital and icu stay and duration of mechanical ventilation were unaffected by caloric nor protein provision in this sample. introduction: disturbances in gastrointestinal motility are common in critically ill patients receiving enteral nutrition. slow gastric emptying (ge) is the leading cause of enteral feeding intolerance (efi), which compromises nutritional status and is associated with increased morbidity and mortality. this phase a study evaluated the efficacy, safety and tolerability of acute tak- (previously td- ), a selective agonist of the hydroxytryptamine receptor ( ht ), compared with metoclopramide in critically ill patients with efi. methods: this was a double-blinded, double-dummy study conducted in mechanically ventilated patients with efi (> ml gastric residual volume) randomized to receive either intervention (tak- . mg over hour and . % saline ml injection qid) or control ( . % saline over hour and metoclopramide mg injection qid). within hour of the first dose, patients received a test meal of ml ensure® and ge was measured using scintigraphy. primary objectives were to evaluate the safety and tolerability of tak- and its effect on ge (% retention at mins) vs control. results: a total of patients (intervention, n = ; control, n = ) were studied. the median ages were and years in these groups, respectively. post-treatment, a -fold greater number of patients had normal gastric retention (< % at mins) in the intervention group vs the control group ( vs ; fig. ). in the intervention and control groups, (table ) . no aes led to treatment discontinuation. conclusions: a greater proportion of patients receiving tak- had normal gastric retention after a single dose compared with those receiving metoclopramide. treatment with tak- was not associated with an increase in aes. these results support further evaluation of tak- in critically ill patients with efi. method to assess gastric emptying in the fed state in enterally tube fed patients: comparison of the paracetamol absorption test to scintigraphy j james introduction: the paracetamol absorption test (pat) is the most common and practical approach for assessing gastric emptying (ge) in critically ill patients. however, current methods require that paracetamol be administered to an empty stomach, removing gastric contents and depriving patients of feeding for several hours. the objective of this study was to develop methods to assess gastric emptying in these patients without interrupting feeding. methods: gastric emptying was assessed in the fed state using pat and scintigraphy in healthy volunteers. paracetamol g in ml was ingested immediately before consumption of a test meal of ml ensure plus containing kcal, . g protein, and . g fat plus mbq of mtc-dpta as a scintigraphic agent. comparisons were made between paracetamol absorption and the time to % and % gastric emptying by scintigraphy at baseline and after administration of ulimorelin μg/ kg, a prokinetic agent known to enhance gastric emptying. blood samples for paracetamol were collected for up to h post administration. values for normal gastric emptying were based on the % confidence intervals for pk parameters. sensitivity and specificity were assessed by receiver operating characteristic (roc) analysis before and after treatment. results: the pat correlated with scintigraphy and pk parameters for normal emptying were determined. cmax and auc were the most sensitive and specific parameters for assessing ge with lowest variability and areas under the roc curve of . and . , respectively. a h sampling period appeared sufficient to distinguish normal from abnormal emptying. conclusions: the pat can be used to distinguish normal versus abnormal ge in the fed state. under the conditions used, patients can receive up to ml enteral feeding over a h test period ( ml/hr). this method can be used to distinguish normal from abnormal gastric emptying in enterally tube fed patients without interrupting feedings. introduction: for mechanically ventillated critically ill patients, the effect of full feeding on mortality is stil controversial. we aimed to investigate the relationship of energy intakes with -day mortality, and nutritional risk status influenced this relationship. methods: this prospective observational study was conducted among adult patients admitted to icu and required invasive mechanical ventilation (imv) for more than h. data on baseline characteristics and the modified nutritional risk in critically ill [mnutric] score was collected on day . energy intake and nutritional adequacy was recorded daily until death, discarge or until twelfth evaluable days. patients were divided into groups: a)received < % of prescribed energy b) received >= % of prescribed energy. results: patients ( % male, mean age . ± . years, mean body mass index . ± . kg/m , mean mnutricscore . ± . ) were included. in the univariate analysis, mnutrİc score was associated with -day mortality. in the multivariable logistic regregression analysis, mnutric score(odds ratio, or . , ci . - . , p < o.oo ) was associated with -day mortality. nutritional adequacy was assessed, median nutritional adequacy was . ( . - . ). in patients with high mnutrİc score ( - ), received >= % of prescribed energy was associated with a lower predicted -day mortality; this was not observed in patients with low mnutrİc score ( - ). conclusions: nearly % of imv required patients admitted to icu were at nutritional risk, mnutrİc score is associated with -day mortality. energy adequacy of >= % of prescribed amounts were associated with decreased mortality in patients with a high mnutrİc score. results: patients included in the study were asa iv. four patients died in the first few days after surgery ( ÷ days). mean length of stay in icu was . ± . days. univariate analysis showed a correlation between hypoalbuminemia and the onset of mof (p = . ); reduction of the lymphocyte count and risk of mof (p = . ). sofa score showed a significant correlation with occurrence of pneumonia (p = . ) and mof (p = . ). including the -day mortality among confounders, albumin and lymphocyte count were the strongest predictors of mof. length of stay in icu and ventilation days did not have statistical significance. bmi showed no predictive value of any outcome. conclusions: our sample was poor but results of our study seem to indicate malnutrition as an independent risk factor for elderly patients undergoing emergency surgery. early multidisciplinairy screening of dysphagia at admission to the emergency departmenta pilot study d melgaard, l sørensen, d sandager, a christensen, a jørgensen, m ludwig, p leutscher north denmark regional hospital, hjørring, denmark critical care , (suppl ):p introduction: dysphagia increase the risk of aspiration pneumonia, malnutrition, dehydration and death. this combined with the fact that patients with dysphagia have a longer stay in the hospital makes early prognosis and appropriate treatment important. knowledge about effect of early dysphagia screening is limited. the aim of this study is to examine the prevalence of dysphagia in the emergency department (ed) population. methods: this study included consecutively hospitalized patients in days from pm- pm at the ed of north denmark regional hospital. the screening took place within hours of admission. inclusion criteria were any of the following: age ≥ years, neurological disorders, alcoholism, copd, pneumonia, dyspnoea, diabetes or unexplained weight loss. a nurse screened patients with a water test and with signs of dysphagia tested by an occupational therapist with the v-vst and the meof-ii. results: of eligible patients ( % male, median age years) ( %) were screened. it was impossible to screen patients ( %) to limited time and patients ( %) due to poor health condition and patients ( %) declined participation. the prevalence of dysphagia in the study population was % ( patients). results from the water test were confirmed with v-vst and meof-ii. in patients with lung related diseases or circulatory diseases was the prevalence respectively % and %. patients, not screened due to poor health condition, were tested during hospitalisation and the prevalence of dysphagia was % in this group of patients. conclusions: the prevalence in ed patients was %. patients transferred to other departments due to poor health condition had a prevalence of %. it is possible to screen patients in the ed. the water test is a useful screening tool in an acute setting. introduction: to improve protein and energy delivery in a nutrition delivery bundle was introduced to a level icu. greater protein and energy intake is associated with improved outcomes in the critically ill [ ] [ ] [ ] [ ] , but only % of prescribed protein and energy is delivered in icus worldwide [ , ] . methods: percentage of target protein and energy delivery was measured via participation in the international nutrition survey (ins) before and after a "nutrition delivery bundle" was introduced by the icu dietitian. the nutrition delivery bundle involved all stakeholders in icu nutrition care (fig. ) and included the following quality improvement measures: increased icu dietetic staffing, update of icu enteral feeding protocol with staff education, use of higher protein formulations, earlier patient nutrition assessment, daily calculation of percentage nutrition delivery, increased nutrition communication through more regular discussion of patient care with medical team, expansion of choice of nasojejunal tube available, monthly reporting of key nutrition performance indicators, improved resources for cover dietitian(s) when icu dietitian on leave (fig. ) . results: prior to a nutrition delivery bundle being introduced the mater misericordiae university hospital (mmuh) icu achieved % of protein and % of energy targets over the first admission days of consecutive mechanically ventilated patients in icu > hrs enrolled in the international nutrition survey. this increased to % of protein and % of energy targets in (table ) . conclusions: a % improvement in protein and energy delivery to critically ill patients was seen after the introduction of a dietitian-led nutrition delivery bundle. introduction: the critically ill polytrauma patient with sepsis presents with variable energetic necessities characterized by a proinflammatory, pro-oxidative and hypermetabolic status. one of the challenges the icu doctor faces is adapting the nutritional therapy based on the individual needs of each patient. through this paper we wish to highlight the trend of energy needs in the case of critically ill polytrauma patients with sepsis by using non-invasive monitoring of respiratory gases based on indirect calorimetry (ge healthcare, helsinki, finland). methods: this is a prospective observational study carried out in the anesthesia and intensive care unit "casa austria", emergency county hospital "pius brinzeu", timisoara, romania. we monitored vo , vco , energy demand (ed), and specific clinical and paraclinical data. we measured energy demand values monitored by direct calorimetry with values calculated based on standard formulas. results: values have been recorded in the study. the mean vo was . ± . ml/min/kg, the mean vco was . ± . ml/min/kg. in regard with energy demand, the mean ed obtained through direct calorimetry was . ± . kcal/day, and those obtained by using mathematic formulas were . ± kcal/day (p < . ). moreover, statistically significant differences have been observed regarding the mean difference between energy demand determined using indirect calorimetry and that determined mathematically, respectively between the enteral and parenteral administered ed. conclusions: continuous monitoring of the energy demand in critically ill patients with sepsis can bring important benefits in regard with the clinical prognosis of these patients through the individualization and adaption of intensive therapy for each patient. introduction: cachexia is defined as a complex metabolic syndrome associated with underlying illness, characterized by loss of muscle with or without loss of fat. in cancer cachexia, reduction in muscle size has been demonstrated to be an independent risk factor for mortality. loss of muscle in icu patients is rapid and extensive and is also associated with mortality risk, but methods to measure muscle mass in these patients are lacking. surrogate methods (dexa, ct, ultrasound, total body water) do not measure muscle mass directly methods: the d -creatine (d -cr) dilution method takes advantage of the fact that % of cr is found in muscle and that muscle mass can be assessed by cr pool size. cr is transported into muscle against a concentration gradient and irreversibly converted to creatinine (crn), which is excreted in urine. a single oral dose of d -cr is transported to skeletal muscle, and measurement of d -crn enrichment in a spot urine sample provides an accurate estimate of skeletal muscle mass. results: the method has been validated in preclinical and clinical studies; in a large longitudinal observation study in older men, d -cr muscle mass was strongly associated with habitual walking speed, risk of falls, and incident mobility limitation; dexa failed to show these relationships. the d -cr method is being used in a nicu study to measure changes in muscle mass in neonates (gates foundation grant). further, this method has been incorporated into a trial assessing the treatment effects of a ghrelin agonist in icu patients with enteral feeding intolerance (nct ). in this trial, the d -cr dose is delivered intravenously and a spot urine sample is collected at baseline and postdose. conclusions: the d -cr method provides a non-invasive, accurate way to assess therapeutic agents that may mitigate the loss of skeletal muscle mass; it is of particular utility in clinical settings where changes in muscle mass are consequential, such as muscle loss during an icu admission. introduction: vitamin c, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, which affects most intensive care unit (icu) patients. while many observational studies have demonstrated that critical illness is associated with low levels of vitamin c, randomized controlled trials (rcts) of high-dose vitamin c, alone or in combination with other antioxidants, yielded contradicting results. the purpose of this systematic review and meta-analysis is to evaluate the clinical effects of vitamin c when administered to various populations of icu patients. methods: eligible trials: rcts comparing vitamin c, by enteral or parenteral routes, to placebo in icu patients. data collection and analysis: we searched medline, embase, and the cochrane central register of controlled trials. after assessing eligibility, data was abstracted in duplicate by two independent reviewers. overall mortality was the primary outcome; secondary outcomes were infections, icu length of stay (los), hospital los, and ventilator days. pre-specified subgroup analyses were conducted to identify more beneficial treatment effects. results: pooling rcts (n= ) reporting mortality, vitamin c was not associated with a lower risk of mortality (risk ratio [rr]: . , % confidence interval [ci]: . - . , p= . , i = %). in a subgroup analysis, trials of lower quality (n= ) were associated with a reduction in mortality (rr . , % ci . , . , p= . ), whereas high quality trials (n= ) were not. no statistical difference existed between subgroups (p= . ). in addition, no effect was found on infections, icu or hospital length of stay, and ventilator days. conclusions: current evidence does not support the hypothesis that vitamin c supplementation improves clinical outcomes of icu patients. introduction: the protein intake for patients who met adequacy for energy was assessed within our cardiothoracic intensive care. nutritional support should aim to provide at least % of calorie requirements to achieve nutritional adequacy with suggested protein requirements of . - g/kg/day [ ] . guidelines highlight the difficulty achieving the correct protein:energy ratio from nutritional support to meet this target especially in the obese population. methods: the audit was registered with clinical governance. data was collected prospectively from patients requiring tube feeding for three or more days from january -october (table ). data included type and volume of feed and calories from other sources. patients who met adequacy for energy (fig. ) introduction: patients admitted to the intensive care unit (icu) are usually at high risk of malnutrition [ , ] . the purpose of our study was to compare the accuracy of nutric score, nrs and sga in predicting los-icu, los-hosp and in-hospital mortality. methods: a total of consecutive patients admitted between march to june in a mixed (medical/surgical) icu were assessed on day of admission using the three screening tools to classify them into high-risk and low-risk of malnutrition. day apache scores and demographic data were recorded. los-icu, los-hosp inhospital mortality and secondary outcomes studied were need for supplemental nutritional support, need for ventilation and need for dialysis in high-risk and low-risk patients by each nutrition assessment tool. results: of the patients studied, ( . %) were males and ( . %) were females. . % males and . % females were found to be at a high risk of malnutrition by at least one of the scores. the mean apache score for patients at high risk (using any one screening tool) was . (sd . ) and . for the low risk group (sd . ; p < . ). the nrs and sga demonstrated statistically significant correlation(p= . ) for length of icu stay for both the high risk and low risk group whereas only the nrs correlated significantly for the length of hospital stay(p= . ). mortality was significantly higher in high risk patients identified using all scores. conclusions: there was a wide difference in the percent of patients identified as high-risk using each of the scores. introduction: nitrogen balance (nb) may be an important tool in the nutritional management of critically ill patients. cancer patients present a special challenge regarding nutrition, due to its peculiar characteristics related to neoplasia and adjuvant treatments. objectives: to evaluate nb in patients with solid cancer in the postoperative period in the icu, analyzing the correlation between nb and the mortality outcome in the icu. methods: retrospective cohort study. we evaluated adult patients (> years) admitted to the icus of two different hospitals, with diagnosis of current cancer in postoperative period (elective or emergency surgeries). patients were excluded if the diagnosis of cancer was not confirmed. nb (measured through analysis of dietary protein intake subtracted from -hour urinary urea plus an estimate of nonurinary losses) was calculated on the st, rd and th icu day. nb was measured only while the patient was in the icu. results: during the study period, patients were included (mean age . , mean apache . , . % male). admission apache ii and abdominal-site surgery were predictors of mortality. the nb of all patients was negative on the st icu day. in the patients who survived, nb of the rd and th day remained stable (negative), whereas in patients who died nb was more positive (fig. ) . there was no difference in the amount of protein ingested on the st day between survivors and deceased patients. conclusions: among adult patients with solid cancer in the postoperative period in the icu, nb was persistently negative in the survivors between st and th icu day, but among the patients who died nb tended to be more positive on the rd day. nb monitoring could allow a more adequate individualization of nutritional management in this group of patients. fig. (abstract p ) . nitrogen balance in st, rd and th icu day introduction: nutritional therapy plays an important role in the treatment of critically ill patients. caloric and protein goals are defined, and artificial nutrition tailored to the targets which are related to outcome [ ] . questions rise about the mean caloric and protein needs of patients, once discharged from icu, and the evolution of body weight, and nutritional adequacy. the aim is to know the ratios between caloric needs and intake of patients with a minimum stay at icu of days. methods: after evaluation of critically ill patients, patients were prospectively followed during their entire hospitalization. data concerning nutritional needs, prescriptions and delivery were collected from the electronic medical file. nutritional calculations of oral intake were done by nubel. ratios were made during the entire stay and body weight was followed up. results: in female and male patients, median age . years (range - year), estimated body weight of . ± kg and actual body weight of . ± kg, a mean caloric need of ± kcal/ day and an effective delivery of ± kcal/day was observed. body weight increased in two patients and decreased in ( %). in ten out of twelve patients, underfeeding was present. one patient with a caloric need of kcal/day received a mean caloric load of kcal/day ( . %). conclusions: the overall observed evolution in body weight was negative in most of the patients. nutritional adequacy was low after icu discharge and never reached target. introduction: severe burn injury can create a rapid-onset, sustained proinflammatory condition that can severely impair all major organs. this massive systemic response has been documented clinically by associated biomarker measurements including dramatic elevations in cytokines such as il- . the severity of multi-organ injury and subsequent development of other systemic complications in burn patients have been well-correlated with il- levels, including the increased risk of sepsis/multi-organ failure and associated morbidity and mortality. considering that estrogen is a powerful and easy to use anti-inflammatory agent, an experimental burn model was created to test the potential value of parenteral β-estradiol (e ) as a feasible and inexpensive early intervention to mitigate the the profound pro-inflammatory response associated with severe thermal injury. methods: male rats (n = ) were assigned randomly into three groups: ) controls/no burn (n = ); ) burn/placebo (n = ); and ) burn/e (n = ). burned rats received a % °tbsa dorsal burn, fluid resuscitation and one dose of e or placebo ( . mg/kg intra-peritoneal) minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrificed at minutes (sham group at days only), with four each of the two burn groups sacrificed at days. tissue samples from major organs and serum were obtained and analyzed by elisa for il- at each of these intervals. results: in the burned rats, β-estradiol decreased the organ levels of il- significantly as measured at both early ( min.) and late ( day) phases post-burn (figs. & . also, sham animal levels were comparable to the estradiol group, conclusions: experimentally, a single, early post-burn dose of estrogen significantly mitigates the associated detrimental inflammatory response in all major organs up to days. in turn, this may present a promising potential therapy to decrease the widespread multipleorgan dysfunction seen in severe burn injury patients. early, single-dose estrogen increases levels of brain-derived neurotrophic factor (bdnf), a neurotrophin for neuronal survival and neurogenesis following indirect brain inflammation caused by severe torso burns introduction: prior studies have found that patients with severe burns may suffer significant neurocognitive changes. while frequently attributed to psycho-social issues, we have found a substantial, rapid and sustained ( min - day) increase in rat brain inflammatory markers (for example, il- ) following remote torso burns that is blunted by a single post-burn dose of estrogen. brain-derived neurotrophic factor (bdnf), one of the most active neurotrophins, protects existing neurons and encourages the growth and differentiation of new neurons and synapses. as estrogens not only blunt inflammation but also exert an influence on cns growth factors, we hypothesized that β-estradiol (e ) might affect levels of bdnf in the post-burn rat brain. methods: male rats (n = ) were assigned randomly into three groups: controls/no burn (n = ); burn/placebo (n = ); and burn/e (n = ). burned rats received a % °tbsa dorsal burn, fluid resuscitation and one dose of e or placebo ( . mg/ kg intraperitoneally) minutes post-burn. eight animals from each of the two burn groups (burn/placebo and burn/e ) were sacrificed at hours and at days, respectively (sham group at days only), with four each of the two burn groups sacrificed at days. brain tissue samples were analyzed by elisa for bdnf. results: mean levels of bdnf were significantly elevated within hours and continued to increase up to days post-injury in burned animals receiving the β-estradiol (> pcg/mg) as compared with the placebo-treated burned animals (< pg/mg) and controls (< . pcg/mg). see fig. . conclusions: early, single-dose estrogen administration following remote severe burn injury significantly elevated levels of bdnf in brain tissue. this finding may represent an extremely novel and important pathway to enhance both neuroprotection and neuroregeneration in burn patients. the value of cortisol in patients with the infection and multiple organ dysfunction. s tachyla, a marochkov mogilev regional hospital, mogilev, belarus critical care , (suppl ):p introduction: hormones changes in patients with infection and multiple organ dysfunction is a topic that hasn't been adequately studied. goal of study: to establish the value of cortisol in patients with infection and multiple organ dysfunction. methods: after approval the ethics committee of the mogilev regional hospital a prospective observational study was performed. the study included patients aged to years. all patients were hospitalized in the intensive care unit with the infection and multiple organ dysfunction. patients with endocrine diseases and receiving glucocorticoids were excluded. cortisol levels were measured on admission and during the course of treatment by radioimmunoassay. in group l (n = ) patients had a low levels of cortisol, in the m group (n = ) -normal cortisol, in group h (n = ) -high cortisol. results: cortisol level was in l-group . ( . , . ) nmol/l, in mgroup . ( . ; . ) nmol/l, in h-group . ( , ; . ) nmol/l. it is found that the mortality was higher in the groups l - . % (p = . ) and h - . % (p = . ), than in the m-group - . %. the mgroup odds ratio equals . at % confidence interval . - . when compared with the h-group. in the m-group in survivors patients (n = ) showed a decrease cortisol with ( . , . ) nmol/l to . ( . , . ) nmol/l (p = . ). while the no survivors patients (n = ) showed increase cortisol with ( . , . ) nmol/l to . ( ; ) nmol/l (p = . ). thus itself cortisol level is not a marker of mortality. receiver operating curve analysis for cortisol was performed: area under the curve equals . at % confidence interval of . - . (p = . ), sensitivity . %, specificity . %. conclusions: in patients with infection and multiple organ dysfunction may be observed disorders in cortisol levels. these disorders require correction to prevent the increased mortality. introduction: the hypothalamic-pituitary-adrenal (hpa) axis is a key regulator of critical illness. cortisol and adreno-corticotrophic hormone (acth) are pulsatile, which emerges from the feed forwardfeedback of the two hormones [ ] . different genes are activated by continuous or pulsatile activation of the glucocorticoid receptor, even when the total amount is the same [ ] . we aimed to characterise the acth and cortisol profiles of patients who were critically ill after cardiac surgery and assess the impact of inflammatory mediators on serum cortisol concentrations. methods: patients with > organ system failure, > days after cardiac surgery were recruited. total cortisol was assayed every min, acth every hour and il , il , il , il , il , tnf-α every hours. cortisol binding globulin (cbg) was assayed at and hrs. the relationship between cortisol and the inflammatory mediators was quantified in individual patients using a mixed regression model. results: all profiles showed pulsatility of both cortisol and acth and there was concordance between the two hormones (see fig. ). one patient died after hours (see fig. ). this patient lost pulsatility and concordance of cortisol and acth. mean cbg was . μ g/ml at the start of sampling and . μ g/ml at the end. there was an association between il (p= . ), il (p< . ), il (p= . ) and serum cortisol levels. there was no association between the other mediators and cortisol. conclusions: cortisol and acth are both pulsatile in critical illness. because pulsatility emerges from the interaction between the two hormones[ ]the premise of a 'disconnect' between the pituitary and adrenal gland is refuted. il , il and il may have roles in the control of cortisol during critical illness. introduction: elevation in plasma cortisol is a vital response to sepsis and partially brought about by reduced cortisol breakdown in which bile acids (bas) may play a role. vice versa, cortisol can also upregulate bas. we hypothesized a central role for the hepatic glucocorticoid receptor (hgr) in cortisol and ba homeostasis and in survival from sepsis. methods: in a mouse model of sepsis, we documented hgr expression and investigated the impact of hepatocyte-specific shrnaknockdown of gr on markers of corticosterone (cort), ba and glucose homeostasis, inflammation and survival. we also compared hgr expression in human septic icu and elective surgery patients. results: in mice, sepsis reduced hgr expression with % (p= . ), elevated plasma cort, bas and glucose and suppressed a-ringreductases. also in human patients, sepsis reduced hgr expression (p< . ), further suppressed by treatment with steroids (p= . ). in septic mice, further and sustained hgr-inhibition increased mortality from % to % (p< . ). at h, hgr-inhibition prevented the rise in total plasma cort, but did not affect a-ring-reductases expression. however, it further reduced cort binding proteins, resulting in elevated free cort equal to septic mice without modified hgr. after days of hgr-inhibition in sepsis, total and free cort were comparable to septic mice without modified hgr, now explained by further reduced a-ring-reductase expression, possibly driven by higher hepatic ba content. hgr-inhibition blunted the hyperglycemic sepsis response without causing hypoglycemia, markedly increased hepatic and circulating inflammation markers and caused liver destruction (p< . ), the severity of which explained increased mortality. conclusions: in conclusion, sepsis partially suppressed hgr expression, which appears to upregulate free cort availability via lowered cort binding proteins and a-ring-reductases. however, further sustained hgr suppression evoked lethal excessive liver and systemic inflammation, independent of cort availability. introduction: cortisol levels have been found to be increased in sepsis patients, and high cortisol levels have been correlated with increased mortality. the purpose of this project is to assess the association of plasma cortisol levels with severity of coagulopathy in a population of patients with sepsis and clinically confirmed dic. methods: citrated, de-identified plasma samples were collected from adults with sepsis and suspected dic at the time of icu admission. platelet count was determined as part of standard clinical practice. pt/inr and fibrinogen were measured using standard techniques on the acl-elite coagulation analyzer. cortisol, d-dimer, pai- , cd l, nlrp , and microparticles were measured using commercially available elisa kits and were performed. dic score was calculated using isth scoring algorithm. results: cortisol showed significant variation based on dic status (kruskal-wallis anova, p < . ). patients with non-overt dic and overt dic exhibited significantly elevated cortisol levels compared to healthy controls (p < . for both groups). cortisol levels showed dic based variations. patients with sepsis and overt dic had elevated cortisol compared to patients with sepsis and no dic (p = . ) (fig. ) . correlations were evaluated between cortisol and hemostatic markers platelets, fibrinogen, inr, d-dimer, and pai- as well as with the inflammatory marker, nlrp and the platelet markers cd l and microparticles. cortisol conclusions: cortisol showed a significant association with hemostatic status in a population of patients with sepsis and welldefined coagulopathy. cortisol levels were significantly elevated in patients with overt or non-overt dic compared to healthy individuals and in patients with overt dic compared to those with sepsis without dic. introduction: in most cases presenting with hypoglycemia in emergency departments (eds), the etiology of the hypoglycemia is almost identified. however, about % of cases, the etiology of hypoglycemia cannot be determined. methods: this is a -year prospective observational study. a total of patients were transported to our ed with hypoglycemia. after the investigation, a rapid acth loading test (synthetic - acth μg iv.) was performed on patients with unexplained hypoglycemia; i.e., μg acth was administered intravenously and blood specimens were collected before loading, at min and min after acth administration. we adopted a peak serum cortisol level < μg/dl or a delta cortisol of < μ g/dl for the diagnosis of adrenal insufficiency. results: among the patients, of ( . %) were using antidiabetic drugs, ( . %) were using hypoglycemia-relevant drugs, ( . %) suffered from digestive absorption failure including malnutrition, ( . %) had been consuming alcohol, ( . %) suffered from malignancy, and ( . %) suffered from insulin autoimmune syndrome. initially, an etiology was unknown in of ( . %) patients. rapid acth test revealed the adrenal insufficiency in ( . %) among them. administration of hydrocortisone in adrenal insufficiency patients promptly improved hypoglycemia. in those patients, serum sodium level was lower (na; vs. meq/l, p< . ) and serum potassium level was higher (k; . vs. . meq/l, p< . ) than in the other hypoglycemic patients, respectively. there was no significant difference in baseline plasma glucose level on ed between the groups of patients ( vs. mg/dl, p= . ). conclusions: the probability of adrenal insufficiency was much greater than that of the better-known insulinoma as a cause of hypoglycemia. when protracted hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using the rapid acth loading test. introduction: sepsis caused have showed serious alternations of thyroid hormones releasing, causing a nonthyroidal illness syndrome. the aim of the study was to measure thyroid hormone levels in septic patients and analyse its relation with clinical state and outcome. methods: prospective study in a cohort of consecutive septic patients. we studied thyrotropin (tsh), free triiodothyronine fraction (ft ) and free thyroxin fraction (ft ) serum levels, apache ii and sofa score. statistical analysis was performed using spss . . results: we analysed episodes of sepsis ( %) and septic shock (ssh) ( %), the median age of the patients was (inter-quartile range, . - ) years; the main sources of infection were: respiratory tract ( %) and intra-abdomen ( %); . % had medical diseases. apache ii score was [ - ], sofa score was [ . - ] and day mortality was . %. our data shown . % with low levels of tsh (< . uui/ml), . % had low levels of ft (< . ng/dl) and . % low levels of ft (< pg/ml). the tsh ( . vs. . uui/ml) and ft ( . vs . pg/ml) concentration of ssh group were significantly lower than those of sepsis group, whereas ft ( . vs . ng/dl) it was not statistically significantly. correlation of ft to apa-che ii (r = − . , p = . ) and sofa score (r = − . , p = . ). the profile of death patients were men ( . %, n = ), with significantly older ( vs. years; p= , ), as well as clinical severity scores, apache ii ( . vs. . ; p< . ) and sofa ( . vs . ; p< , ). non-survivors had significantly lower tsh . vs. . uui/ ml; p= . , and ft . vs. . pg/ml, p= . , however ft did not show statistical significance . vs. . ng/dl, p=ns. conclusions: conclusions: most of our septic patients present an altered thyroid function. our data suggest that tsh and specially ft may be used as a marker of disease severity and a mortality predictor. observational study to evaluate short and long-term bone metabolism alteration in critical patients. introduction: reduction of bone mineral density and/or muscle mass can be short and long-term complications in critical patients admitted in intensive care unit (icu). the study aims to evaluate, during a -month period, the following parameters: ) the alterations of bone metabolism and quantitative and qualitative parameters of bone tissue, ) the proportion of subjects with bone fragility, and ) the identification of specific risk factors. methods: an observational-longitudinal monocentric study is being conducted in adult patients hospitalized in icu. the evaluations performed at baseline, and month visits include analysis of biochemical and instrumental exams. results: a specific clinical-care pathway was created between bone metabolic diseases unit and icu, in order to perform specific anamnestic collection, biochemical analysis of bone metabolism, and instrumental exams. patients were enrolled and evaluated at the baseline visit. biochemical exams, performed within hours of hospitalization, showed that % (n: ) of subjects had a deficit of ohvitamind < ng/dl, associated with normal corrected serum calcium levels and of these % (n: ) had high pth levels. bone alkaline phosphatase was increased in % (n: ) of patients. conclusions: critical patients are "fragile" subjects, which should be monitored with a short and long-term follow-up. the creation of a clinical pathway that includes specialists of bone metabolism may be a virtuous way to identify patients who report bone mass loss and increased fracture risk. this study will allow to implement the knowledge regarding specific risk factors of bone fragility and the most appropriate therapeutic choices as prevention and treatment. a retrospective analysis of predictors for length of intensive care stay for patients admitted with diabetic ketoacidosis a fung, tl samuels, ae myers, pg morgan east surrey hospital, redhill, uk critical care , (suppl ):p introduction: diabetic ketoacidosis (dka) is one of the most common metabolic causes of admission to the intensive care unit (icu). the incidence of dka is quoted as between . - episodes per patients with diabetes mellitus (dm) [ ] . we aim to establish the factors that affect length of stay (los) on icu. methods: we undertook an analysis of patients admitted to icu over the last years with a primary diagnosis of dka. we assessed whether there was an association between the following factors and an increased length of icu stay: age, gender, body mass index (bmi), systolic blood pressure, heart rate, sodium, potassium, haemoglobin and ph. these factors were assessed using multiple linear backward stepwise regression. results: overall, admissions were identified over the time period from the ward watcher database. the median los was . days (iqr . - . ). our analysis demonstrated that length of icu stay (alpha level < . ) was significantly associated with bmi, low systolic blood pressure, and the presence of hyponatraemia or hypernatraemia. conclusions: we found the variables that affect the los for patients presenting to our unit with dka are bmi, elow systolic bp, low sodium and high sodium. we intend to extend this work to include survival analysis with the same subgroup of patients. maximal glycemic gap is the best glycemic variability index correlated to icu mortality in medical critically ill patients t issarawattna, r bhurayanontachai prince of songkla university, songkla, thailand critical care , (suppl ):p introduction: several evidences shown a correlation of glycemic variability (gv) and icu mortality. however, there have been no report of the correlation between various parameters of gv and mortality in medical icu patients. the aim was to determine the correlation between various parameters of gv and medical icu mortality, as well as, to identify the best gv index to predict icu mortality. methods: a retrospective chart review was then conducted in medical icu at songklanagarind hospital. the patient characteristics, causes of admission, apache ii, blood glucose within the first hours of icu admission and icu mortality were recorded. glycemic variability parameters including maximal glycemic gap, standard deviation, coefficient of variation and j-index of blood glucose were calculated. the correlation of those gv index to icu mortality was determined. the roc and auroc of each gv index were then compare to identify the best gv index to predict icu mortality. results: of patients, patients ( . %) were survived ( table ). all gv indexes were significantly higher in non-survival group (p < . ) ( table ). maximal glycemic gap was independently correlated to icu mortality and give a highest auroc compared to others gv. (maximal glycemic gap auroc . ( %ci . - . vs. coefficient of variation auroc . ( %ci . - . ) vs standard deviation auroc . ( %ci . - . ) vs j-index auroc . ( %ci . - . ), (p< . ) (fig. ) . conclusions: maximal glycemic gap independently correlated to icu mortality and was the best gv to predict icu mortality in medical critically ill patients. reliability of capillary blood glucose measurement for diabetic patients in emergency department h ben turkia, s souissi, a souayeh, i chermiti, f riahi, r jebri, b chatbri, m chkir regional hospital of ben arous, ben arous, tunisia critical care , (suppl ):p introduction: acute glycemic disorders should be early diagnosed and treated in emergency department (ed), especially hypoglycemia. can capillary blood glucose (cg) replace plasmatic glucose (pg). the objective of this study was to compare capillary blood glucose with venous blood glucose methods: patients with type diabetes were included. we realize a capillary blood glucose with a glucose meter (acu-check active-roche) and a concomitant determination of venous blood glucose with laboratory machine (synchrony cx delta system beckman coulter). a correlation study (pearson correlation) between the two measurements was evaluated and linear fitting equation was established. the concordance was checked with bland and altman method. results: during the months of the study, patients were included. the average age was +/- years old, with a sex ratio = . majority of patients ( %,n= ) had type diabetes and % was treated with insulin. we found an excellent correlation between the two techniques with a pearson correlation coefficient r= . .topredict the pg from cg, we can use this equation: pg(g/l)= . cg(g/l)+ . (r = . ; p= . ). we noticed a good concordance between the two techniques especially in case of hypoglycemia and moderate hyperglycemia (fig. ) . however, releases were noted with a pg higher than g/l. conclusions: in ed, the measurement of capillary glucose can exempt from venous blood glucose especially in case of hypoglycemia and moderate hyperglycemia. is frequently found in critically ill patients in icu, especially patients who are treated for a long time. this study aims to analyse the comparison between length of stay and dvt incidents in critically ill patients. methods: a cross-sectional study was employed. we include all patients who were years or older and were treated in icu of dr soetomo public hospital for at least days. data were collected from june until june . the patients were examined with sonosite usg to look for any thrombosis in iliac, femoral, popliteal, and tibial veins and well's criteria were also taken. results: thirty patients were included in this study. this study shows that length of stay is not the only risk factor for dvt in patients treated in icu. in our data, we found out that the length of treatment did not significantly cause dvt. other risk factors such as age and comorbidities in patients who are risk factors may support the incidence of dvt events. the diagnosis of dvt is enforced using an ultrasound performed by an expert in the use of ultrasound to locate thrombus in a vein. conclusions: length of treatment is not a significant risk factor for dvt. several other factors still need to be investigated in order for dvt events to be detected early and prevented. [ ] was used to retrospectively study trends and outcomes of cancer patients admitted to the icu between and . logistic regression analysis was performed to assess predictors of -day and -year mortality. results: out of , icu admissions, , hemato-oncological, , oncological and patients with both a hematologic and solid malignancy were analyzed. hematologic patients had higher critical illness scores, while oncological patients had similar apache-iii and sofa-scores. in the univariate analysis, cancer was strongly associated with mortality (or . , table ). over the -year study period, -day mortality of cancer patients decreased by % (fig. ) . this trend persisted after adjustment for covariates, with cancer patients having significantly higher mortality (or= . , %ci: . , . ). between and , the adjusted -day mortality decreased by % every year. over the decade, -year mortality decreased by %. having cancer was the strongest individual predictor of -year mortality in the multivariate model (or= . , %ci: . , . ) (fig. ) . conclusions: between and , the number of cancer patients admitted to the icu increased steadily and significantly, while longitudinal clinical severity scores remained overall unchanged. although hematological and oncological patients had higher mortality rates than patients without cancer, both -day and -year mortality decreased significantly over the study period. introduction: sepsis was redefined in with the introduction of an increase in sequential organ failure assessment Δsofa) score of >= and the quicksofa (qsofa) as screening tools for sepsisrelated mortality. however, the implementation of these criteria into clinical practice has been controversial and the applicability for hematological patients is unclear. methods: we therefore studied the diagnostic accuracy of different sepsis criteria for sepsis and mortality according to definition criteria in a retrospective analysis of hematological patients in an academic tertiary care hospital. patient characteristics and variables were collected in icuand non-icu patients to determine the systemic inflammatory response syndrome (sirs), Δsofa and qsofa. by applying the definition of sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection" [ ] as reference, the scores were evaluated. in patients with sepsis who died, / were sirs-negative, / Δsofa-negative and / qsofa-negative ( fig. and table ). conclusions: in conclusion, these findings suggest that criteria proposed in the sepsis- definition might have limitations as screening fig. (abstract p ) . results of the logistic regression analysis for (a) -day and (b) -year mortality. all covariates were statistically significant except for white race in the -year mortality model. ***p-value< - , **p-value< . , *p-value< . fig. (abstract p ) . longitudinal change in -day mortality for cancer patients (yes) compared with controls (no) over the -year study period. mortality in the cancer group decreased from % to % (- %), while mortality in the control group decreased from to % (- %). enoxaparin pharmacokinetics in patients with augmented renal clearance, preliminary results of a single center study introduction: augmented renal clearance (arc) has being described in some groups of critically ill patients. the aim was to investigate the impact of arc on the pharmacokinetics of enoxaparin. methods: this is a prospective study in a surgical and medical intensive care unit (icu) carried out from august to november . patients < years old, under prophylactic treatment with enoxaparin and normal plasma creatinine, were included. anti-xa activity was measured at second day under treatment. creatinine clearance was calculated from urine sample collected during -hours. arc was defined by a creatinine clearance >= ml/min/ . m . results: thirteen patients aged years old (± . ) were included. six patients developed arc and of them were in therapeutic range. seven patients did not develop arc and of them were in therapeutic range. there was no differences between the two groups in achieving therapeutic range (fisher test, p= . ). we did not observe thromboembolic events. conclusions: we found no relationship between arc and therapeutic failure in patients under prophylactic treatment with enoxaparin. introduction: this study reviewed argatroban use in patients in a tertiary hospital critical care unit. argatroban is a direct thrombin inhibitor approved for use in proven or suspected heparin-induced thrombocytopenia (hit) in patients with renal dysfunction. methods: this was a retrospective cohort study in a medical and surgical icu in a tertiary teaching hospital. data was collected for adult patients treated with argatroban for proven or suspected hit april-august , excluding patients requiring ecmo. we scored patients using the t score and compared this to an elisa immunoassay optical density score which quantifies the pf /h antibody level. also noted was use of continuous haemodialysis and organ failure using the sequential organ failure assessment (sofa), scoring >= defines failure. results: patients were treated with argatroban for proven or suspected hit. / patients had a positive elisa. there was no relationship between t score and elisa optical density (fig. ) . infusions were commenced at either the manufacturer recommended dose of μg/kg/min or a reduced dose of . μg/kg/min. patients receiving the reduced dose had a median of organs failing compared to in the standard regimen. the time taken to the first aptr in range was longer with the reduced dose regimen, however, the time to a stable aptr was less (table ). in patients the dose of argatroban never stabilised. died and was very sensitive to argatroban and required cessation of the infusion for interventions. in the reduced regimen group, there were episodes of bleeding, minor pr bleed in a patient with organs failure and upper gi bleed. conclusions: in this population of icu patients the t score did not correlate with the elisa optical density score, as found previously. patients with multi-organ failure mostly received the reduced starting dose. however, the bleeding events were still confined to this group. this correlates with previous studies that organ dysfunction necessitates a dose reduction for argatroban. results: the mean age in our study group was ± years. the effects of tpe on standard coagulation were increased aptt ( ± to ± s, p= . ) and decreased fibrinogen levels ( ± to ± mg/dl, p= . ). a non-significant decrease in platelet count was observed ( ± to ± /mm , p= . ). on rotem parameters tpe was associated with increased ct in extem ( ± to ± s, p= . ) and intem ( ± to ± s, p= . ) and increased maxvt on extem ( ± to ± s, p= . ) and intem ( ± to ± s, p= . ). all other rotem parameters changed non-significantly. the decrease observed in fibrinogen levels was not associated with a decrease in fibtem mcf ( ± to ± mm, p= . ). conclusions: our results demonstrate that tpe is associated with minimum changes in clot kinetics initiation that do not result in either pro-or anti-coagulant changes. therefore, tpe with fresh frozen plasma can be safely used in normal subjects. introduction: acutely ill patients are prone to critical illness anaemia, a multifactorial condition with potential contribution of iatrogenic anaemia defined as lowered hb due to large/frequent venepunctions. decline in hb is most pronounced in the first days of icu stay. it correlates with the need for rbc transfusion, but the impact on patient outcome is uncertain. the aim of this study was to determine impact of phlebotomy on change in hb (Δhb), and correlation of Δhb with need for transfusion, presence of central venous catheter (cvc) and patient outcome. conclusions: critical illness anaemia is an unexplained phenomenon. impact of phlebotomy is hard to unequivocally determine since there are many confounders. the change in hb levels during icu stay correlates with the need for transfusion that could cause immunomodulation and potentially adverse outcome. every effort should be made to maintain adequate hb levels and lower the risk of iatrogenic anemia. introduction: anemia is prevalent in critically ill traumatic brain injury (tbi) patients and red blood cell (rbc) transfusions are often required. over the years, restrictive transfusion strategies have been advocated in the general critically ill population. however, considerable uncertainty exists regarding optimal transfusion thresholds in critically ill tbi patients due to the susceptibility of the injured brain to hypoxemic damages. methods: we conducted an electronic self-administered survey targeting all intensivists and neurosurgeons from canada, australia and the united kingdom working caring for tbi patients. the questionnaire was developed using a structured process of domains/items generation and reduction with a panel of experts. it was validated for clinical sensibility, reliability and content validity. results: the response rate was . % ( / ). when presented with a scenario of a young patient with severe tbi, a wide range of transfusion practices was noted among respondents, with % favoring rbc transfusion at a hemoglobin level of g/dl or less in the acute phase of care, while % would use this trigger in the plateau phase. multiple trauma, neuromonitoring data, hemorrhagic shock and planned surgeries were the most important factors thought to influence the need for transfusion. the level of evidence was the main reason mentioned to explain the uncertainty regarding rbc transfusion strategies. conclusions: in critically ill tbi patients, transfusion practices and hemoglobin thresholds for transfusion are said to be influenced by patients' characteristics and the use of neuromonitoring in critical care physicians and neurosurgeons from canada, australia and the uk. equipoise regarding optimal transfusion strategy is manifest, mainly attributed to lack of clear evidences and clinical guidelines ( -year) . no significant associations were found between ffp:rbc ratio and mortality rates. patients with higher apache ii score received more platelet transfusions and mortality rates were higher in those who received platelets:rbc ratio > . on multivariate analysis, higher apa-che ii score was an independent predictor of increased mortality. conclusions: the compliance with the recommended : : ratio of blood products was poor. there was no association between transfusion ratios and mortality after adjusting for apache ii score. introduction: the lack of evidence-based medicine supporting the transfusion decision is illustrated by the wide range of blood product use during first-time coronary artery bypass grafting (cabg). use of red blood cells (rbc) ranges from to percent, while the use of platelets range from to [ ] . approximately percent of cabg patients suffer abnormal bleeding, with platelet dysfunction thought to be the most common culprit [ ] . methods: the objective of this study was to evaluate the use of allogeneic blood and blood products among patients undergoing first-time cabg over the past years. the first patients who underwent cabg (on-pump and off-pump) from st of march each year were included for analysis. the percentage of patients receiving rbc, fresh frozen plasma (ffp), platelet and cryoprecipitate during the first hours intra-and postoperatively were analysed. linear regression analysis was performed in each group. results: our analysis shows that the use of rbc decreased over the last years, in contrast to the use of the other investigated products. (see fig. ) the increase of platelets was the most pronounced with a direction coefficient of . and had the least variability (r = . ). (see fig. ) the decrease in rbc was less obvious than the rise in platelet use (direction coefficient of . ) and had a higher variability (r = . ). the consumption of ffp and cryoprecipitate stayed constant (direction coefficient of . and . respectively). the higher incidence of semi-urgent cabg in recent years, which involves continuation of anti-platelet therapy until the day before surgery, can be an explanation for our observed increased use of platelets. the observed decrease in rbc transfusion over the past years might be due to rising awareness of complications associated with red cell transfusion. introduction: red blood cells (rbc) transfusion is frequently required in cardiac surgery and is associated with increased morbidity and mortality rates. the aim of this study is to identify predictors of rbc transfusion for patients undergoing cardiac surgery, emphasizing the use of bioelectrical impedance analysis (bia). methods: this was a retrospective study of patients who underwent elective cardiac surgery between years and in a tertiary reference center. patients' demographic and clinical variables, preoperative bia measurements and postoperative data were analyzed. the univariate and multivariate logistic regression analyses were used to identify the predictors of postoperative rbc transfusion. all of the calculations were performed with ibm spss v. . introduction: red blood cells (rbc) transfusion is a common intervention in cardiac surgery and is associated with higher mortality rates and predisposes serious adverse events. the aim of this study was to determine whether red blood cells (rbc) transfusion is linked to long-term results after cardiac surgery. methods: this observational retrospective study included all of the patients who underwent any of the sts defined elective cardiac surgery types from to . we evaluated - year all-cause mortality rates and secondary postoperative outcomes defined by the sts risk prediction model. patients were categorized according to whether they received rbc transfusions postoperatively; long-term results were compared using cox-regression analysis and kaplan-meier method. introduction: transfusion of packed red cells (prcs) is an important treatment option for patients requiring intensive care but, like all treatments, it is not without risk. these patients, although may be more sensitive to anaemia, are also at increased risk of transfusionrelated complications. we conducted an audit of blood prescribing and administering practices in our intensive care unit. methods: audit proformas were placed in blood prescribing forms for a -month period. all transfusions of prcs were logged over this time, and transfusion triggers, post-transfusion haemoglobin (hb) and whether hb was checked between units was recorded, in addition to other supplementary information. results: over a -month period, transfusion events were recorded, with an average age of the transfused patients of years old (range - years). % of transfusion events were for low hb, % for bleeding and in % of cases the indication was not documented. for patients transfused for a low hb, the mean transfusion trigger was g/l (range: g/l - g/l). only % had a transfusion trigger of g/l or less, and a further % who were transfused for a low hb had a hb of g/l or more. % of transfusion events involved transfusing or more units and, in only % of these cases the hb was checked between units. excluding the two bleeding patients, the mean increase in hb following a single unit transfusion was . g/l (range g/l - g/l), whilst in patients transfused two units, the average increase in hb was g/l per unit transfused (range g/l - . g/l), suggesting single unit transfusions may have greater hb yields. conclusions: our audit demonstrated variability in transfusion triggers and progress needed with administering practices when transfusing multiple units of blood in the non-bleeding patient. we have since implemented measures to meet guidelines in both prescribing prcs with restrictive triggers and in the administration and assessment of hb between units, and will be re-auditing. introduction: there is a perceived increased risk of bleeding in cirrhosis patients undergoing invasive procedures. this lead to a high rate of empirical prophylactic transfusion, which has been associated to increased complications and cost. the best strategy to guide transfusion in these patients remains unclear. our aim was to compare three strategies to guide blood component transfusion prior to central venous catheterization (cvc) in critically ill cirrhosis patients. methods: single center, randomized, double-blinded, controlled clinical trial conducted in brazil [ ] . all cirrhosis patients admitted to the icu with indication for a cvc were eligible. participants were randomized : : to three transfusion strategies based on: ( ) standard coagulation tests (sct), ( ) rotational thromboelastometry (rotem) and ( ) restrictive. the primary outcome was proportion of transfusion of any blood component prior to cvc. secondary outcomes were incidence of major and minor bleeding, icu length of stay (los), and -day mortality. analysis was intention-to-treat. results: participants ( in each group) were enrolled between september and december . most were male ( . %) and listed for liver transplantation. the study ended after reaching efficacy in first interim analysis. there was no significant difference in baseline characteristics among groups. regarding primary endpoint, there was ( . %), ( . %), and ( . %) events in sct, rotem and restrictive groups, respectively (p < . ). there was no difference between sct and rotem groups (p > . ). overall -day mortality was . % and was similar between groups. icu los did not differ between groups. there was no major bleeding. overall minor bleeding occurred in . % with no difference between groups. conclusions: a restrictive strategy is safe and effective in reducing the need of blood component transfusion prior to cvc in critically ill cirrhosis patients. a rotem-based strategy was no different from transfusion guided by sct. introduction: desmopressin (ddavp) is a vasopressin analogue which improves platelet function. its general use as a haemostatic agent is still controversial. the aim of study was to evaluate the effect of prophylactic desmopressin in blood coagulation in patients undergoing heart valve surgery. methods: prospective, randomized, double-blind clinical trial performed at the heart institute of the university of são paulo. a total of adult patients undergoing heart valve surgery were enrolled from february to november . immediately after cardiopulmonary bypass weaning and heparin reversal, patients were randomized in ratio : to intervention group: ddavp ( . μg/kg) or control group. blood samples were drawn at three different times, at baseline (t ), hours (t ) and hours (t ) after study medication. blood coagulation and perioperative bleeding were analysed using laboratorial tests and thromboelastometry, chest tube drainage and requirement of allogenic transfusion within hours. results: a total of patients were allocated to intervention and to control group. blood levels of factor viii at t ( . conclusions: prophylactic use of desmopressin in heart valve surgery does not influence coagulation and thromboelastometric parameters. identifying the impact of hemostatic resuscitation on development of multiple organ failure using factor analysis: results from a randomized trial using first-line coagulation factor concentrates or fresh-frozen plasma in major trauma (retic study) p innerhofer introduction: to clarify how hemostatic resuscitation affects occurrence of multiple organ failure. methods: analysis of secondary endpoints of the retic study [ ] (coagulation factors, activated protein c (apc), thrombin generation, rotem parameters, syndecan- , thrombomodulin (tm) and d-dimer) measured at randomization, and after patients had received ffp or coagulation factor concentrates (cfc) at admission to icu, and hours thereafter. we used factor analysis to reduce the highly interrelated variables to a few main underlying factors and analysed their relation to mof before and after hemostatic therapy. results: the factors concentration, clot and hypoperfusion representing trauma-induced coagulopathy (table ) were comparable between groups at baseline (fig. ) and only high hypoperfusionscore predicted mof, while after therapy a low clot-score also predicted mof. only the changes of the clot-score independently affected occurrence of mof (p= . , adjusted or . , ci . - . ), while changes of concentration (p= . , adjusted or . , ci . - . ) and hypoperfusion (p= . , adjusted or . , ci . - . ) did not. a lower clot-score occurred after ffp transfusion than use of cfc, mainly through persistent thrombocytopenia (platelet count r - ffp vs cfc p< . ) (fig. ) . the higher concentration-score after ffp did not affect mof and ffp had no beneficial effect on fibrinolysis, syndecan- , tm or apc. conclusions: hemostatic resuscitation should augment the factor clot, which is feasible with early fibrinogen administration but not with ffp. the found platelet-saving effect of early fibrinogen administration is important as platelets play a major role in inflammation and transfusion of platelets did not correct thrombocytopenia. introduction: the trauma induced coagulopathy clinical score (ticcs) was developed to be calculable on the site of injury with the objective to discriminate between trauma patients with or without the need for damage control resuscitation (dcr) and thus transfusion [ ] . this early alert could then be translated to in-hospital parameters at patient arrival. base excess (be) and ultrasound (fast) are known to be predictive parameters for emergent transfusion. we emphasize that adding this two parameters to the ticcs could improve its predictability. methods: a retrospective study was conducted in the university hospital of liège. based on the available data in the register (from january st to december st ), the ticcs was calculated for every patient. be and fast results were recorded and points were added to the ticcs according to the ticcs.be definition (+ points if be < - and + points in case of a positive fast). emergent transfusion was defined as the use of at least one blood product in the resuscitation room. the capacity of the ticcs, the ticcs.be and the trauma associated severe hemorrhage (tash) to predict emergent transfusion were assessed. results: a total of patients were included in the analysis. ( %) needed emergent transfusion. the probability for emergent transfusion grows with the ticcs.be value (fig. ) . positive predictive values (ppv) and negative predictive values (npv) of the three scores are displayed in table . conclusions: our results confirm that be and fast results are relevant parameters that can be added to the ticcs for better prediction of the need for emergent transfusion after trauma. fig. (abstract p ) . probability for emergent transfusion with ticcs.be values. fig. (abstract p ) . boxplots show available measurements of extrinsically activated clot firmness at min (exa ), fibrin polymerization at min (fiba ) and platelet count at baseline (r ) and after therapy at admission to icu, and hours thereafter (r to r ) for the cfc (blue, n= ) and the ffp (yellow, n= ) group as well as for patients without (white, n= ) and with (grey, n= ) multiple organ failure. table ) for the cfc (blue, n= ) and the ffp (yellow, n= ) group, as well as for patients without (white, n= ) and with (grey, n= ) multiple organ failure. each factor is given at the measurement time point baseline (r ) and following haemostatic resuscitation at admission to icu, and hours thereafter (r to r ). introduction: the management of the critically ill polytrauma patient is complex and is often a challenge for the intensive care team. the objectives of this study is to analyze the oxidative stress expression in polytrauma cases as well as to evaluate the impact of antioxidant therapy on outcomes. methods: this prospective study was carried out in the clinic for anaesthesia and intensive care "casa austria", form the "pius brînzeu" emergency county hospital, timisoara, romania, with the approval of the hospital's ethics committee. clinicaltrials.gov identifier nct . the patients' selection criteria included an injury severity score (iss) of or higher, and age of or higher. patients were eligible for the study. they were divided in two groups, group a (antioxidant free, control, n= ), and group b (antioxidant therapy, study group, n= ). the antioxidant therapy consisted in continuous iv administration of mg/ h of vitamin c until discharge from icu. the patients included in the study presented with similar characteristics, and no statistically significant differences were shown between group a and b regarding age (p > . ), sex (p > . ), iss upon admission (p > . ), percentage of patients admitted in the icu more than hour post-trauma (p > . ), and associated trauma (p > . ). among patients in group b statistically significant differences were identified regarding the incidence of sepsis (p < . ), multiple organ dysfunction syndrome (p < . ), mechanical ventilation time (p < . ), and mortality (p < . ). no statistically significant differences were shown regarding the time spent in the icu (p > . ). conclusions: following this study we can state that the administration of substances with a strong antioxidant character has positive influences on the outcome of critically ill patients, decreasing the incidence of secondary pathologies as well as mortality rates. icc increased by . %, icd increased by . %, slightly increased ma, and ircl was nearly in the normal range. conclusions: rapid and accurate diagnosis of the coagulation system by lpteg method at different stages of traumatic disease allows for more accurate selection and adjustment of the therapy, which allows improving the prognosis of the disease. introduction: evidence for tranexamic acid (txa) in the pharmacologic management of trauma is largely derived from data in adults [ ] . guidance on the use of txa in pediatric patients comes from studies evaluating its use in cardiac and orthopedic surgery. there is minimal data describing txa safety and efficacy in pediatric trauma. the purpose of this study is to describe the use of txa in the management of pediatric trauma and evaluate efficacy and safety endpoints. methods: this retrospective, observational analysis of pediatric trauma admissions at hennepin county medical center from august to november compares patients who did and did not receive txa. the primary endpoint is survival to hospital discharge. secondary endpoints include surgical intervention, transfusion requirements, length of stay, thrombosis, and txa dose administered. results: there were patients [<=] years old identified for inclusion using a massive transfusion protocol order. twenty patients ( %) received txa. baseline characteristics and results are presented as median (iqr) unless otherwise specified, with statistical significance defined as p < . . patients receiving txa were more likely to be older, but there was no difference in injury type or injury severity score (iss) at baseline (table ) . there was no difference in survival to discharge, need for surgical intervention, or thrombosis (table ) . patients who did not receive txa had numerically higher transfusion requirements and longer length of stay, but these did not reach significance. conclusions: txa was utilized in % of pediatric trauma admissions at a single level i trauma center, more commonly in older patients. though limited by observational design, we found patients receiving txa had no difference in mortality or thrombosis. introduction: the risk of venous thromboembolism (vte) in trauma is greatly increased and one of the leading causes of morbidity and mortality after an accident [ ] . prophylactic measures to prevent vte primarily consist of anticoagulants. in instances in which anticoagulation is contraindicated or inadequate, inferior vena cava (ivc) filters can be used [ ] . however, insertion of ivc filter as a prophylactic measure is controversial as filter-related complications are well documented and increase with treatment time [ ] . the objectives of our study were to evaluate ivc filter insertion indications and filter related complications in pelvic trauma patients. methods: patients with pelvic fractures were operated during the study period / / - / / . all patients who received ivc filter during the period were included into analysis. relevant data was collected from electronic patient journal. results: thirty four patients received retrievable filters during the study period ( males and females) ( table ) . median age of patients was years (range, - ). the predominant indication ( %) was prophylactic insertion. the median indwell time was days (range - days). despite ivc filter insertion one patient experienced lung embolism and another -dvt. in eleven cases ivc filters were tried to be removed at the treating hospital. in two cases filter extraction was unsuccessful and in another two cases filters were left in place due to ivc thrombosis. conclusions: majority of ivc filters were inserted outside guidelines [ ] and proportion of prophylactic indications is significantly higher ( % vs %) than seen in registry studies [ ] . filter related complications were observed in % of patients. more restrictive approach to prophylactic ivc insertion should be exercised. the impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in patients with major trauma admitted to intensive care unit ( conclusions: patients on preinjury anticoagulants and antiplatelet agents showed an increased mortality; this may be the result of the greater incidence of bleeding, the older age and more comorbidities in this groups. is enzymatic debridement better in critically burned patients? introduction: early debridement of burned tissue reduces infection rate, icu stay and mortality. the use of proteolytic enzymes such as bromelain allows a faster, more effective and selective debridement of denatured tissue, preserving and exposing healthy tissues, reducing debridement times compared to standard of care. methods: retrospective observational study performed in the critical burn unit (march to september ) including patients > years old with a total body surface area (tbsa) burned > % and < %, or > years old with a tbsa burned > %, who underwent enzymatic debridement. mean and standard deviation were used for normal quantitative variables and median and interquartile range in the opposite case. qualitative variables were presented by absolute and relative frequencies. results: mean age was . ± . years old, % males, apache ii (ri - ), absi (ri - ). median tbsa burned was % (ri - %), % (ri - ) were deep dermal or full thickness. time until debridement was hours (ri - ). . % (n= ) had incomplete debridement after first application, % (n= ) received regional anesthesia, % (n= ) didn't need blood transfusion. % of patients who didn't have vasopressors prior debridement, needed the use of it with a mean dose of , mcg/kg/min. % of patients with vasopressors prior treatment, required an increase of dose by a mean of . mcg/kg/min. median icu stay was days. mortality was %. conclusions: topical bromelain allows a fast start of tissue debridement with a low rate of failure. the need for fasciotomy and blood transfusion was very low. topical treatment involved a fast and simultaneous debridement of the tbsa burned, generating an inflammatory response that in some cases required vasopressors. . . / ). the bche activity was measured by using point-ofcare-test system (securetec detektions-systeme ag, neubiberg, germany). levels of the routine inflammation biomarkers, i.e. c-reactive protein (crp) and the white blood cell count (wbcc), were measured during the initial treatment period. measurements were performed at the admission, followed by , and -hour time points. injury severity score (iss) was used to assess the trauma severity. results: the observed reduction in the bche activity was in accordance with the change in the crp concentration and the wbcc. the bche activity measured at the hospital admission negatively correlated with the length of the icu stay in patients with polytrauma (r = - . , spearman's rank correlation coefficient). conclusions: the bche activity might be used as an early indicator for the magnitude of the systemic inflammation following polytrauma. moreover, the bche activity, measured at the hospital admission, might predict the patient outcome and therefore prove useful in early identification of the high-risk patients. pharmacological interventions for agitation in traumatic brain injury: a systematic review introduction: among tbi complications, agitation is a frequent behavioural problem [ ] . agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. pharmacological treatments are often considered for agitation management following tbi. however, the benefit and safety of these agents in tbi patients as well as their differential effects and interactions are uncertain. methods: the major databases and the grey literature were searched. we included all randomized controlled, quasi-experimental, and observational studies with control groups. the population of interest was all patients, including children and adults, who have suffered a tbi. studies in which agitation was the presenting symptom or one of the presenting symptoms, studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in tbi patients were included. results: we identified references with our search strategy. two authors screened after removal of duplicates. after searching the grey literature and secondary databases, a total of potential articles were identified. eleven studies in which agitation or an associated behavior was the presenting symptom, studies where agitation was not the presenting symptom but was measured as an outcome variable, and studies assessing the safety of these pharmacological interventions were identified. overall, the quality of studies was weak. in studies directly addressing agitation, pindolol and propranolol may reduce assaults and agitation episodes. amantadine and olanzapine may reduce aggression, whereas valproic acid may reduce agitated behavior. conclusions: there is weak evidence to support the use of pharmacological agents for the management of agitation in tbi. impact of decompressive craniectomy on neurological functional outcome in critically ill adult patients with severe traumatic brain injury: a systematic review and meta-analysis p bonaventure, ja jamous, f lauzier, r zarychanski, c francoeur, a turgeon chu de québec -université laval, québec, canada critical care , (suppl ):p introduction: severe traumatic brain injury is associated with high mortality and functional disability. several interventions are commonly used to control the intracranial pressure to prevent secondary cerebral injuries. among them, decompressive craniectomy (dc) is widely performed; however, its impact on functional outcome is still under debate. our objective was to assess the efficacy and safety of this procedure in adult patients with severe traumatic brain injury. methods: we systematically searched in medline, embase, cen-tral, web of science, conference proceedings and databases of ongoing trials for eligible trials. we included randomized controlled trials of adult patients with severe traumatic brain injury, comparing dc to any other intervention. our primary outcome was the neurological function based on the glasgow outcome scale. secondary outcomes were mortality, intensive care unit (icu) and hospital length of stay, intracranial pressure control, and complications. two reviewers independently screened trials for inclusion and extracted data using a standardized form. we used random effect models to conduct our analyses and the i index to assess heterogeneity. results: we identified citations, from which we included trials for a total of patients. we observed no impact on the [ ] . univariate logistic regression analyses were performed to identify predictors associated with the decision for icp monitoring. results: a total of adult patients were included (tables and ). the risk of poor outcome estimated by the impact model was associated to the decision to monitor icp (fig. ) . icp was more often monitored in patients with severe tbi, with one dilated pupil at admission and positive ct findings (in particular, high marshall scores). conclusions: according to our results, the clinician follows a multifactorial reasoning: the main determinants for the decision to monitor icp are gcs, pupils' abnormalities and, above all, ct findings. future studies will be needed to clarify specific indications for the clinicians in the identification of patients who would benefit from invasive monitoring. trajectories of early secondary insults after traumatic brain injury: a new approach to evaluate impact on outcome. introduction: secondary insults (si) occur frequently after traumatic brain injury (tbi). their presence is associated with a worse outcome. we examined the early trajectories of hypotension (sbp< mmhg), hypoxia (spo < %) and pupillary abnormalities from the prehospital settings to the emergency department (ed), and their relationship with -months outcome. methods: in this retrospective, observational study we included all tbi patients admitted to our neuro intensive care unit (nicu) from january to december . we defined the trajectories of si: -"sustained" if present on the scene of accident and at hospital admission, -"resolved" if present on the scene but resolved in ed, -"new event" if absent on the scene and present in ed, -"none" if no insults were recorded. we investigated the association of si trajectories with -months dichotomized outcome (glasgow outcome scale (gos); favorable= - ; unfavorable= - ). results: patients were enrolled in the final analysis. hypoxia and hypotension were related with unfavourable outcome when introduction: guidelines for management of pediatric traumatic brain injury recommend maintaining intracranial pressure (icp) < mmhg [ ] . use of . % sodium chloride (nacl) is considered safe and effective for management of icp in adults, but evidence for concentrations > % in pediatrics is limited. this study will describe the safety and efficacy of . % nacl in reducing icp among pediatric patients. methods: this retrospective study evaluated patients <= years old who received . % nacl and had continuous icp monitoring. cerebral perfusion pressure (cpp), mean arterial pressure (map), icp, and brain tissue oxygenation (pbto ) were recorded hourly and were compared to baseline for hours after each dose. safety outcomes included peak serum sodium, peak serum chloride, and the incidence of stage acute kidney injury (aki) (serum creatinine elevation >= . mg/dl or >= %) [ ] . results: between august and july , eligible pediatric patients received doses of . % nacl; doses were included in the analysis of perfusion parameters. mean age was . +/- years ( months to years), and the median initial glasgow coma scale score was . subjects received a median of four . % nacl boluses, with a mean dose of . +/- . ml/kg. significantly lower icp and higher cpp (p< . ) were observed at all post-treatment time points (fig. ) ; pbto was also significantly increased during of the hours recorded (p< . ). there was no difference in map. peak post-treatment serum sodium and chloride were +/- meq/l and +/- meq/l, respectively (fig. ) . stage aki was observed in . % of patients, and in-hospital mortality was . %. conclusions: our data suggests that . % nacl is a safe and effective therapy for elevated icp in pediatric patients. methods: we performed a prospective study in adult patients with mild head trauma (gcs and ) qualified for acquisition of urgent head ct scan. the clinical symptoms potentially related to intracranial lesion including abnormal vitals, vomiting, headache, persistent dizziness were recorded. ons as well as head ct were then performed. all ons examinations were executed by an experienced sonographer to eliminating interrater bias. head ct findings were dichotomized as positive or negative finding for ich based on formal radiology reports. the patients' disposition including admission, surgery and safe discharge were followed. results: patients were enrolled for the survey. patients had at least one symptom related to potential intracranial lesion ( . %). the mean onsd was ± mm. patients were found to have ich and underwent neurosurgery thereafter. no significant difference of onsd was found between the groups with and without ich, as well as the group receiving surgery or conservative treatment. with introducing a conventional mm threshold of onsd, the sensitivity, specificity, ppv and npv was . , . , . and . , respectively. while incorporating occurrance of at least one positive clinical symptom with the onsd measurement greater than mm as a composite threshold, the sensitivity, specificity, ppv and npv was . , . , . and . , respectively. conclusions: the diagnostic value of ons in mild head trauma is defective. nevertheless, with the supplemental aid of recognition of clinical symptoms relevant to potential intracranial lesion, the overall accuracy would improve. a correlation between ykl- concentrations in cerebrospinal fluid and marshall classification in traumatic brain injurypreliminary results g pavlov , m kazakova , p timonov , k simitchiev , c stefanov , v sarafian medical university -plovdiv, plovdiv, bulgaria, university of plovdiv, plovdiv, bulgaria critical care , (suppl ):p introduction: establishment of prognostic models in traumatic brain injury (tbi) would improve the classification based on predictive risks and will better define treatment options [ ] . in recent years, one of the most intensively studied glycoprotein is ykl- . it is expressed as a consequence of broad spectrum of inflammatory and malignant diseases [ ] . this is study aimed to investigate the level of ykl- in tbi patients and its relationship with several clinical models. methods: we determined plasma and cerebrospinal fluid (csf) ykl- levels in six ( ) patientson the th and th hour after the tbi. each patient was examined by physical and instrumental methods for somatic and neurological status, clinical assessment and prognostic scales (gcs, marshall classification, apache iii). routine haematological and biochemical tests were also performed. as control served the csf of age-matched suddenly deceased healthy individuals (n = ), which was examined post mortem for ykl- levels. results: we found no significant difference between plasma ykl- levels till th and th in all patients (mean difference ± sd: ± ng/ml ) and calculated cerebral autoregulation (ar) as correlation coefficients (pearson) for each ih wave. z-ratios were divided according to binary ar outcome and correlation calculated with intracranial pressure before, during and after the ih waves. results: our preliminary analysis demonstrated a negative correlation between intracranial pressure and z-ratio in the grouped ih waves with preserved ar, but no correlation in the grouped ih waves with impaired ar (table and fig. ). this indicates a decrease in power in the eeg low frequencies ( - hz) and/or an increase in the eeg high frequencies ( - hz) for increased values of intracranial pressure when ar is preserved. conclusions: features of ih waves differ depending on the ability of the injured brain to autoregulate cerebral blood flow. these features might include different signature of eeg frequency changes. the causative links and clinical significance of the different eeg patterns remain unexplored and might represent a signature of neurovascular coupling. introduction: targeted temperature management of patients who have suffered a traumatic brain injury is often used in the hope of preventing further insult to the brain; however, there is no uniform approach to managing temperature either locally, nationally or internationally, and maintenance of goal temperature in this patient population is often challenging due to hypothalamic injury. we sought to evaluate the feasibility and safety of an esophageal heat transfer device (ensoetm, attune medical, chicago, il) to perform temperature management of patients suffering from traumatic brain injury. methods: this was an irb-approved prospective study of patients undergoing temperature management after traumatic brain injury. patients were treated with an esophageal heat transfer device connected to an external heater-cooler, and maintained at target temperature for at least hours. patient temperature obtained via foley catheter was recorded hourly, and the deviation from goal temperature during treatment reported. results: a total of patients were treated from august to may . temperature targets during treatment ranged from . to . degrees c. maintenance of target temperature was successful, with % of readings within +/- degrees c of target, and % of readings within +/- . degrees c of target. one patient developed a small hydrothorax, not attributed to device use. all patients survived to discharge from the icu, with median cpc of (range to ). conclusions: targeted temperature management of patients with traumatic brain injury using an esophageal heat transfer device was feasible and safe, providing a tight maintenance of goal temperature in this challenging patient population. introduction: traumatic brain injury (tbi) represents a serious problem in europe. it still is the principal cause of death in us and europe. every year in italy people on , suffers of tbi and on , dies. disability and incapacity from tbi provides "strong ethicals, medicals, social and health economy imperative to motivate a concerted effort to improve treatment and preventions" methods: our hospital is the hub for modena's county for tbi and we took part in the past year on european project creactive (collaborative researce on acute traumatic brain injury in intensive care medicine in europa) as branch of italian group giviti (gruppo italiano per la valutazione degli interventi in terapia intensiva). our study concerned about patients with tbi dismissed from icu that "personally" or by the family will accepted the consensus to be included in our follow up conducted after months from the dismissal. we collected clinical data from the admission to the dismissale and measured impact of tbi on all day life with gos-e and qolibri-os using telephonical interview. results: we collected data about patients, answered to the telephonical follow-up and only compilated the qolibri-os. we found out that patients admitted with lower gcs has worst outcome in terms of quality of life. it also appears that anisocoria during icu staying represents an odds ratio for death and is connected with worst quality of life after months from the dismissal (tables & ) . inability to re-start a normal work-activity appeared to be the most important factor on the perception that our patient have of their new lives. conclusions: anisocoria seems to be an indicator of severe brain damage. gcs, despite it's simplicity, still represent the best and easiest way to score tbi. work impairment appear to be the most important disability to determine subjective perception of quality of life after tbi, so efforts have to be made to improve work rehabilitation after the dismissal from hospital. introduction: hyperventilation (hv) reduces elevated intracranial pressure (icp) by changing autoregulatory functions connected to cerebrovascular co reactivity. criticism to hv is due to the possibility of developing cerebral ischemia and tissue hypoxia because of hypocapnia-induced vasoconstriction. we aimed to investigate the potential adverse effects of moderate hv of short duration in the acute phase in patients with severe traumatic brain injury (tbi), using concomitant monitoring of cerebral metabolism, continuous brain tissue oxygen tension (pbro ), and cerebral hemodynamic with transcranial color-coded duplex sonography (tccd). methods: a prospective trial was conducted between may and may at the university hospital of zurich. adults (> years), with non-penetrating tbi, first gcs < , icp-monitoring, pbro and/or microdialysis (md)-probes were included within hours after injury. data collection and tccd measurements took place at baseline (a), at the begin of moderate hv (paco - . kpa) (c), after minutes of moderate hv (paco - . kpa) (d), and after return to baseline (e) (fig. ) . repeated measures anova was used to compare variables at the different time points followed by post hoc analysis with bonferroni adjustment as appropriate. p-value < . was considered significant. results: eleven patients were included ( % males, mean age ± years). first gcs was ( - : median and interquartile range). data concerning paco , icp, pbro , mean flow velocity (mfv) in the middle cerebral artery, and md values are presented in table . during hv, icp and mfv decreased significantly. pbro presented a trend of reduction. glucose, lactate and pyruvate did not change significantly ( table ) . conclusions: short episodes of moderate hv have a potent effect on the cerebral blood flow, as assessed by tccd, reduce icp and pbro , and do not induce significant changes in cerebral metabolism. outcome of pediatric patients six months after moderate to severe tbi -results of creactkids study from three picu in israel paco arterial partial pressure of co , cpp cerebral perfusion pressure (mmhg), icp intracranial pressure (mmhg), pbro brain tissue oxygen tension (mmhg), mfv mean flow velocity in the middle cerebral artery introduction: delirium is a major cause of complications in postoperative patient in icu. risk factors for delirium include poor cerebral hemodynamics and peri-operative cerebral desaturations. intraoperative target cerebral oximetry monitoring may decrease the incidence of postoperative delirium in elective major abdominal surgery patients. methods: a single-blinded, randomised controlled trial in patients undergo elective major abdominal surgery who received postoperative care in surgical icu with age more than years were randomised into two groups. the intervention group was received intra-operative target cerebral oxygen monitoring using cerebral oximetry whereas the control group was not. delirium was assessed in both group at , , hour postoperatively. other risk factors for delirium, mechanical ventilator day, length of icu stay, length of hospital stay and post-operative complication were recorded. results: from august -march , patients who met the criteria were randomised to patients in intervention group and patients in control group. overall incidence of delirium was . % (intervention . % vs control . %, p= . ). baseline cerebral oxygen in intervention group was . ± . %. desaturation below % from baseline was found in from patients ( . %) and was the only significant risk factor associated with delirium (p=. , odd ratio . ). there was no significant different in mechanical ventilator day, icu length of stay, hospital length of stay and postoperative complication between both groups. there was no complication associated with application of the cerebral oximetry probe in the intervention group. conclusions: from this preliminary report can not demonstrated the significant different of intra-operative target cerebral oxygen monitoring by using cerebral oximetry in prevention of delirium. however the reduction of cerebral oxygen more than % from baseline in intervention group showed significantly associated with delirium postoperatively. the set score as a predictor of icu length of stay and the need for tracheotomy in stroke patients who need mechanical ventilation introduction: set score was initially developed as an in-house screening tool based on tracheotomy predictors identified in several retrospective studies. it combined the categories of neurological function, neurological lesions, and general organ function/ procedure, and weighed by allocation of certain point values [ ] . in our study it was very interesting to us to find a tool to judge application of early tracheotomy, and as we have a good culprit number from stroke cases so we decided to try to apply this score in our icu after discussion with the inventor of this score. methods: stroke patients were prospectively included in the study as they were ventilated or were very little potential for ventilation and assessed by the stroke-related early tracheotomy score (set score, table ) within the first h of admission (table ) . endpoints were length of stay and ventilation time (vt) after doing early tracheotomy. we examined the correlation of these variables with the set score using standard analytical methods. results: the set score with a value cutoff point of had a significant effect on decision of making tracheotomy and hence decreasing ventilation time and length of stay in icu, which affected outcome (figs. & ) . conclusions: all efforts must be exhausted in neuro intensie care to decrease the secondary changes of brain injury after stroke,early tracheotomy is a good tool to decrease length of stay in icu and ventilation time in these patients.inventing a tool to judge these decisions of doing tracheotomy was a challenge. set score proved to be valuable.further multi center trials are needed. fig. (abstract p ) . specificity for the cutoff point of set score. cut point of is the best to predict tracheostomy with sensitivity of . % and specificity of . %. cut point of is the best to predict early tracheostomy with sensitivity of . % and specificity of . %. since no patients had score so the previous analysis that consider cut-point of should remain the same but just change the number in the text to contraindication for pharmacological vte prophylaxis ( . %). overall, ncc patients were more likely to receive mechanical ( . % icu days) than pharmacological vte prophylaxis ( . % icu days), however pharmacologic was more likely among younger patients with lower apache ii scores. guideline concordant care varied by recommendation; lower for pharmacological and higher for mechanical vte prophylaxis. conclusions: ncc patients uncommonly receive guideline concordant pharmacological vte prophylaxis. collectively, our findings suggest that current vte prophylaxis prescribing practices may reflect uncertainty around risks associated with vte prophylaxis among ncc patients. methods: we retrospectively analysed prospectively collected data from consecutive ich patients that received dvt prophylaxis in a tertiary hospital. he was defined as an increase of > ml measured using the abc/ method or the semiautomatic software based volumetric approach. using multivariate analysis, we analysed risk factors including early dvt prophylaxis for he> h, hospital mortality and poor -month functional outcome ( m modified rankin score> ). results: patients presented with a median gcs of (iqr - ), hematoma volume of ml (iqr - ) and were y old (iqr - ). % received early dvt prophylaxis, % late dvt prophylaxis and % had unclear bleeding onset. hematoma volume was smaller in the early dvt prophylaxis group with . ml (iqr - . ) vs . ml (iqr - ) in the late prophylaxis group (p= . ) without any other significant differences in disease severity. delayed he (n= / , . %) was associated with higher initial hematoma volume (p= . ) and lower thrombocyte count (p= . ) but not with early dvt prophylaxis (p= . ) in a multivariate analysis adjusted for known risk factors. early dvt prophylaxis was not independently associated with m outcome. conclusions: although limited by the retrospective design, our data suggest that early dvt prophylaxis (< h) may be safe in patients presenting with primary ich, which supports the recommendations given by the neurocritical care society. introduction: there is a paucity of literature describing the relationship between clevidipine and its impact on intracranial pressure (icp). the safety of clevidipine in patients with intracranial hemorrhage is often extrapolated from studies using nicardipine, which has demonstrated a neutral effect on icp [ ] . the objective of this study was to determine if there was a relationship between clevidipine initiation and changes to cerebral hemodynamic parameters. methods: this study was a retrospective analysis of adults admitted to hennepin county medical center between july and july . individuals were included if they had intracranial bleeding and icp data recorded prior to initiation of a clevidipine infusion. baseline demographic data was collected, including age, gender, type of injury, and initial glasgow coma score (gcs introduction: aneurysmal subarachnoid hemorrhage (sah) is an acute cerebrovascular event with high mortality and is an important cause of neurologic disability among survivors. many complications in the course of sah, such as hydrocephalus, also play a role in the poor outcome. the aim of the study was to describe the characteristics of patients with sah admitted to the icu to evaluate the factors associated with outcome. methods: this study was conducted in two reference centersone in rio de janeiro and one in porto alegre. from july to september , every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during hospital stay. the primary endpoint was mortality and dichotomized functional outcome (poor outcome defined as glasgow outcome scale to ) at hospital discharge and months. dichotomous variables were analyzed using two-tailed fisher's exact test. results: a total of patients were included. demographic characteristics are presented in table . frequency of clinical and neurological complications are presented in table . in univariate analysis, factors most frequently seen in patients with unfavorable outcome were seizure ( % vs %, p= . ), hydrocephalus ( % vs %, p< . ), meningitis ( % vs %, p= . ), rebleeding ( % vs %, p= . ), vasospasm ( % vs %, p= . ), pneumonia ( % vs %, p< . ), sepsis/septic shock ( % vs %, p< . ), postsurgical neurological deterioration ( % vs %, p= . ) and delayed cerebral ischemia ( % vs %, p< . ). at months, out of patients with follow-up, % had poor outcome. conclusions: sah is associated with high morbidity. both neurological complications as clinical complications were associated with unfavorable outcomes. therapeutic interventions to prevent those may have an impact on clinical outcomes. introduction: brain tissue hypoxia (brain tissue oxygen tension, pbto < mmhg) is common after subarachnoid hemorrhage (sah) and associated with poor outcome. recent data suggest that brain oxygen optimization is feasible and may reduce the time with brain tissue hypoxia to % in patients with severe traumatic brain injury [ ] . little is known about the effectiveness of protocolized treatment approaches in poor-grade sah patients. methods: we present a retrospective analysis of prospectively collected data of poor-grade sah patients admitted to tertiary care centers where pbto < mmhg was treated using an institutional protocol. treatment options were left to the discretion of the treating neuro-intensivists including augmentation of cerebral perfusion pressure (cpp) using vasopressors if necessary, treatment of anemia and targeting normocapnia, euvolemia and normothermia. the dataset used for analysis was based on routine blood gas analysis for hemoglobin data matched to hourly averaged data of continuous cpp, pbto , temperature and cerebral microdialysis (cmd) samples over the first days of admission. results: patients were admitted with a gcs of (iqr - ) and were (iqr - ) years old. overall incidence of brain tissue hypoxia was %. during this time we identified associated episodes of cpp< mmhg ( %), hyperglycolysis (cmd-lacta-te> mmol/l, cmd-pyruvate> μmol/l; %), pco < mmhg ( %), metabolic distress (cmd-lactate-to-pyruvate-ratio> ; %), pao < mmhg ( %), hb< g/dl ( %), and temperature> . °c ( %) (fig. ). of these variables only hyperglycolysis was significantly more common ( %) during episodes of normal pbto ( % of episodes). conclusions: underutilization of ivt despite the overwhelming evidence that support the effectiveness of such therapy can be partly attributed to the fear of hemorrhagic complications. this fear is not justified by current data. the estrangement of the emergency medicine community regarding ivt and the domination of stroke experts in decision making is also a barrier. regional wall motion abnormalities and reduced global longitudinal strain is common in patients with subarachnoid hemorrhage and associated with markedly elevated troponin k dalla sahlgrenska university hospital, gothenburg, sweden critical care , (suppl ):p introduction: stress-induced cardiomyopathy after subarachnoid hemorrhage (sah) is a life-threating condition associated with poor outcome. regional wall motion abnormalities (rwma) is a frequent finding, however, assessment of rwma is known to be difficult. in the present study we hypothesized that global and regional longitudinal strain (gls and rls) assessed with speckle tracking echocardiography can detect myocardial dysfunction indicated by increased levels of the cardiac biomarker troponin (tnt). methods: this prospective study comprised patients with sah. the tnt was followed daily from the admission up to days postadmission and elevated tnt was defined as > ng/l. a transthoracic echocardiography examination was performed within hours after the hospitalization. the peak gls was determined using the three apical projections and presented as the mean of the segments. reduced gls was defined as > - % and reduced rls was considered present when segmental strain was > - % in > adjacent segments. introduction: deviations from strict eligibility criteria for intravenous thrombolysis (ivt) in ischemic strokes regarding either license contraindications to alteplase or relative contraindications to thrombolysis have been reported in international literature, with conflicting results on patients' outcome.the aim of our study was to evaluate safety and efficacy for patients receiving ivt outside standard inclusion criteria. methods: retrospective analysis of our department's thrombolysis database.we compared patients with strict protocol adherence (strict protocol group) [mean age years and national institutes of health stroke scale (nihss) at admission /range - ] and patients with protocol deviations (off-label group) [mean age years and nihss at admission /range - ],in particular patients > years old, patients with mild stroke-nihss< ,and with symptom-to-needle time - . hours ( patients had deviations). results: patients in the off-label group were older but had no difference in baseline severity scores (sapsii, nihss). they had no statistically significant difference on short-term (nihss at days, need for critical care support, primary adverse event) and long-term (mortality,functional outcome at months) outcome measures when compared to standard protocol patients. conclusions: in accordance with international literature,off-label thrombolysis is save and equally effective to standard protocol thrombolysis.thrombolysis strict protocol needs expansion of inclusion criteria. introduction: most scales (gcs,nihss) don't consider the pathway of secondary acute brain failure (sabf). neuron-specific-enolase (nse) could be usefull in diagnostic and treatment pts. with sabf [ , ] . methods: prospective study incl. pts. with abf. pts. were identical in condition, age and comorbidies. in main group, nse examed and choline alfoscerate was used, pts. was divided into subgroups ia (n= ) with acute ischemic stroke(ais) and ib (n= ) pts. with posthypoxic encephalopathy. the control group (n= ) pts. with ais treated by loc.protocol № . clinical, laboratory, and imaging variables were fully compared. pts. examed by abcde algorithm, gcs and nihss. brain ct, carotid doppler performed. considering criteria:nse(days , , ), neurological status, length of stay in icu (icu los). "ss- . "was used. results: the baseline nse was higher and correlated to nihss ( . ± . , ÷ = . ) in all pts. in ia, ib sbgroups nse decreased for - days vs. control group - days (÷ = . ) and correlated with regression neurological deficit. icu los in main group was . ± . days vs. control group . ± . days. sensitivity and specificity of nse as a marker of brain injury in pts. with ais were and % and in posthypoxic pts. were and %, respectively, which showed nse as eligible diagnostic criterion of posthypoxic cerebral edema. in ia (ais) pts. and ib (posthypoxic edema) were confirmed by increasing nse in fold and -fold respectively more vs. pts. who had only brain ct at first day. nse also correlated with regression neurological deficit and improving of the neurological status. although, two pts. in iib group died with nse - ìg/ml conclusions: . nse is an effective marker of the severity of damages even in the sabf, and shoved efficacy efficacy of treatment. . negative outcome can be in pts. with sabf and more -fold increasing nse and increasing up to - ìg/ml is a mortality predictor. . we included nse in local protocols p n-terminal pro-brain natriuretic peptide as a bio-marker of the acute brain injury introduction: the detection of biomarkers levels facilitates an early diagnosis of brain tissues damage, allows assessing the prognosis of the disease and its outcome, and performs the monitoring of the patient treatment. methods: we studied patients ( m, f.). st group comprised patients with severe brain trauma: asurvivors with good outcome (on glasgow outcome scale groups i-ii) (n= ), bdead or severely disabled (on glasgow outcome scale groups iii-v) (n= ). nd group comprises patients with intracranial and sub-arachnoid hemorrhages: assignment to groups a (n= ), b (n= ) was done using the same criteria as group . rd group comprises patients operated in conjunction with brain tumor. assignment to groups a (n= ) and b (n= ) was done using the same criteria as groups and . we tested the level of n-terminal pro-brain natriuretic peptide in blood ( - pg/ml) between st and rd days after severe brain injury and then every - days for the total duration of days. results: : statistical analysis failed to demonstrate noticeable difference in the level of ntprobnp between groups , , . we detected the differences between subgroups (p< . ). patients from groups a, a, a (n= ) ntprobnp level stayed below pg/ml in cases ( %), in the cases ( %) the level was above pg/ml, but by - th day decreased to the normal values. for patients in subgroups b, b, b (n= ) in cases ( %) ntprobnp level was above pg/ml at least once, in cases ( %) level stayed below pg/ ml but remain high for the entire duration of the study without significant decrease. conclusions: all the patients with acute brain injury show the increased level of ntprobnp above normal values, irrespective of ethiology of injury. in case when ntprobnp level increases above pg/ml and/or does not decrease to the normal values it is possible to predict a negative outcome. introduction: cerebrovascular and coronary artery diseases share many of the same risk factors [ ] . cardiac mortality accounts for % of deaths and is the second commonest cause of death in the acute stroke population, second only to neurologic deaths as a direct result of the incident stroke. methods: this is a prospective observational study from july to april done on adult patients (groupi: pts acute ischemic strokes & group ii: pts as control) in kafr-elsheikh general hospital icu. inclusion criteria: all patients with acute ischemic stroke while exclusion criteria: patients with heart or renal failure/sepsis&septic shock/ischemic heart disease or hemorrhagic stroke,full clinical examination&labs including admission quantitative serum cardiac troponin i elisa immunoassay,ecg, d echocardiography&ct brain on day & ,alberta stroke program (asp) early ct (aspect) to predict neurological outcomes and mortality in patient with acute ischemic stroke within days so survivors vs non-survivors in group were divided to g a & g b respectively. results: dyslipidemia, hypertension, diabetes mellitus were significant comorbidities in all ischemic stroke pts.tlc, urea, inr and troponin were significantly higher in case group vs control group.gcs was found to be lower in non-survivors at day &at rd day follow up while aspect was significantly lower only at rd day follow up.troponin level was significantly higher in non-survivors g b, it was also higher in patents who developed convulsion later during their icu stay& it was significantly inversely correlated to gcs and asp. troponin had sensitivity % and specificity % (roc curve analysis) conclusions: troponin level was predictor for mortality in patient with acute ischemic stroke.it is well correlated to gcs and asp on admission.it was a predictor for occurence of convulsions later in icu stay. introduction: based on examination and treatment of hyperkinetic disorder in patients with uws and mcs, we supposed that hyperkinesis manifesting the formation of the generator of pathologically enhanced excitation in cerebral cortex, basal ganglia, which subsequently causes the formation of hyperkinesis. halogencontaining anesthetic sevoflurane had a good clinical effect in patients with prolonged impairment of consciousness. methods: the study included patients with uws ( -hypoxia, -encephalitis) and patients with mcs ( -hypoxia, -encephalitis). hyperkinetic disorder presenting as permanent myoclonus of arms and legs, face. all patients were performed head mri and eeg (before, during and after anesthesia), crs-r assessment, patients -[ f]-fgd pet. initial anesthesia: propofol - mg/kg, rocuronium bromide (esmeron) , mg/kg, fentanyl - mg/kg and clonidine (clophelin) . - . mg/kg. maintenance of anesthesia is carried out due to the following scheme: inhalation anesthesia using sevoflurane ( . - . vol%, mac . - . ). additionally, during the nd - th hours of medical anesthesia was prescribed the intravenous injection using ketamine - mg/kg/hr. the anesthesia is used during hours. the patients were nurtured by balanced mixtures through nasogastric tube. after hours the patients were gradually transferred to the autonomous breathing. the control clinical and instrumental studies to evaluate the therapy effectiveness (eeg, crs-r) were performed. results: in patients ( mcs, uws) was observed the hyperkinetic disorder regression as decrease of hyperkinesis manifestation, patients didn't have a significant dynamics. conclusions: the artificially formed "pharmacological dominant" (using sevoflurane and ketamine) may decrease the activity of pathological system of the brain, which clinically presented as significant decrease of hyperkinesis manifestation in out patients. -year experience of using benzodiazepines in predicting outcomes and targeted treatment of patients in unresponsive wakefulness syndrome (uws). introduction: we accepted a hypothesis that in some patients uws is a consequence of a pathologic system (ps), that limits the brain functional activity. identification of a ps allow to predict consciousness recovery. eeg registration under benzodiazepines test (bt) has become the method of ps identifying in uws patients. methods: we examined uws patients ( -traumatic, -non traumatic). crs scales assessment, eeg with bt, mri of brain were performed for all patients. the midazolamum was administered iv . mg/kg,.in - min after bzd was recorded eeg for min. the test was considered to be positive if against the background of bzd eeg pattern restructuring was observed: the low-amplitude eeg activity was rebuilt with the advent of alpha-and beta-spectrum.in patients with slowwave activity of theta-and delta-spectrum appeared stable fast forms, and in patients with baseline polymorphic eeg pattern was recorded prevalence of alpha activity and (or) the alpha rhythm. in order to confirm the correlation between the bzd effect and eeg pattern restructuring, flumazenil was administrated at rate of . mg every to minutes until the original eeg pattern has been registered again. results: the bt was true positive (recovery consciousness in - month later) in traumatic and non traumatic patients. true negative (permanent uws month later) in traumatic and non traumatic patients. false positive - traumatic, non traumatic. false negative traumatic, non traumatic patients. sensitivity bt to vs/uws = . % sensitivity to mcs = . % conclusions: our data confirmed the correctness of hypothesis that a ps limits the activity of the brain in patients in a uws. we proposed diagnostic method of a ps activity and suppression. apparently, bzd are the drugs of first stage examination choice in the treatment of uws patients. early identification of sepsis-associated encephalopathy with eeg is not associated with short-term cognitive dysfunction introduction: septic-associated encephalopathy (sae) affects approximately % of septic patients. recent studies showed sae is associated with short-term mortality and long-term cognitive disability. however, diagnosis of sae is one of exclusion and its association with short-term cognitive deficit is uncertain. the aim of this study is to evaluate the sensitivity of clinical examination in detecting sae. the association between sae and short-term cognitive impairment is also assessed. methods: prospective observational study enrolling adult septic patients admitted to a mixed icu. exclusion criteria were: encephalopathy from another cause, history of psychiatric/neurologic disease, cardiac surgery. all patients received continuous eeg monitoring and were assessed for sae for up to days after inclusion. we performed a comprehensive consciousness assessment twice daily during the icu (gcs; full outline of unresponsiveness, four; coma recovery scale-revised, crs-r; reaction level scale , rls ; confusion assessment method for the icu, cam-icu). we defined altered brain function as gcs< , no correlation between cognitive function at hospital discharge and severity of eeg alteration was found. conclusions: eeg was more sensitive than clinical assessment in detecting sae. altered eeg was not associated with short-term cognitive function. analysis of the training needs in italian centers that use brain ultrasound in their daily practices: a descriptive, multicenter study r aspide introduction: as mission of siaarti neuroanesthesia and neuroicu group of study, we are mapping out the brain ultrasound training needs in our centers. although brain ultrasound is widely used to study the intracranial vessels and other issues, it is still not clear the homogeneity of the skills required in both neuro and general icu in italy. the aim of this study is to explore the use of us-tcd and validate a collection of criterea which would prove useful in any future national wide survey. methods: starting from sept. the seven center involved (bologna, catania, pisa, verona, bergamo, cesena, roma) collected clinical and sonographic data, basing on a crf of twenty criteria such as: kind of hospital and icu, number of beds and neuro-patients/year, the physicians specialization trained to perform us-tcd, the kind of us doppler device used and the kind of training course followed. as a second step, data were analyzed by coordination team, as third step, during annual siaarti conference, these centers had a deep discussion on these selected items, further modifying and adapting the content of the items. results: the result is a ready list of items, an available tool for all the participant centers, that are going to start with an internal test survey for a final validation. conclusions: there is more than one path to train a physician on brain us in italy and there are new possible applications, even outside of the neuro sub-speciality. from the preliminary discussion, it is clear that in italy we have a inhomogeneous frame of training and use. this group of study believes that among the anesthesiologists/intensivists, it is possible to find a useful number of physicians interested in training on this topic. the main aim is the production of a validated criterea collection, available for eventually future national survey, useful to help map out the real national training needs in italy on us brain. perinatal neurosurgical admissions to intensive care c nestor, r hollingsworth, k sweeney, r dwyer beaumont hospital, dublin, ireland critical care , (suppl ):p introduction: beaumont hospital is the neurosurgical centre for ireland serving a population of . million. we present data on all perinatal patients who required icu admission for neurosurgical conditions over an year period. our data presents an insight into the incidence and outcome of neurosurgical conditions during pregnancy methods: searching our database identified pregnant and recently pregnant patients admitted to icu with neurosurgical conditions. patient data was collected retrospectively by review of charts and of an electronic database. a further pregnant patients were admitted for neurosurgical intervention but did not require critical care. results: intracranial haemorrhage was the most common diagnosis ( subarachnoid haemorrhage and had intra-cerebral haemorrhage). patients presented with intracranial tumours and patient had a traumatic brain injury. patient was admitted post spinal tumour resection. patient was referred with an ischemic stroke after iatrogenic injury to the carotid and vertebral artery. the requirement for organ support in this cohort of patients was high; % required ventilation and % inotropes. patients underwent neurosurgical intervention & medical treatment. maternal deaths occurred at & weeks gestation. the modified rankin score (mrs) on discharge from hospital was <= for of the surviving patients (median= ). of the pregnancies (all singleton) there were foetal deaths. patient miscarried spontaneously at weeks, had a medical termination of pregnancy at weeks to facilitate chemotherapy and foetus died after maternal death at weeks. the remaining patients delivered normal babies. conclusions: neurosurgical disease requiring icu admission during pregnancy is rare; our data suggest an incidence of case per million population. maternal outcomes were mixed with more than half having a mrs> on discharge. foetal outcomes were good with only one miscarriage and good neurological outcome in all surviving infants. stepwise multivariable analyses that included interaction between time of day and arrest location were performed in a stepwise manner. results: prehospital als (adjusted or, . ; %ci, . - . ) but not good-quality of bystander-performed ccs ( . , . - . ) was associated with sustained return of circulation (rosc). neither provison of good-quality ccs nor prehospital als was a major factor associated with on-month survival. however, good-quality of bystanderperformed ccs ( . , . - . ) in addition to shockable rhythm ( . ; . - . ) and bystander-witnessed ohca ( . ; . - . ) were associated with higher chances of neurologically favourable one-year survival, whereas prehospital als ( . ; . - . ) and elderly ohca ( . ; . - . ) were associated with lower chances of the survival (fig. ) . the impact of good quality ccs on survival were preserved in bystander-witnessed ohcas with shockable initial rhythm. noncentral region (adjusted or for good-quality, . ; %ci, . - . ), lack of bls training experience ( . ; . - . ), elderly-only rescuers ( . ; . - . ), cc initiation following dispatcher-assisted cardiopulmonary resuscitation ( . ; . - . ), and female-only rescuer ( . ; . - . ) were associated with poor-quality ccs. cc quality in athome ohcas remained low throughout the day, whereas that in outof-home ohcas decreased during night-time. conclusions: provision of good-quality ccs before ems arrival but not prehospital als was essential for neurologically favourable survival. new protocol for start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service introduction: healthcare providers including emergency medical service (ems) personnel usually confirm absence of carotid pulse before starting chest compressions. at the end of , ishikawa medical control council implemented new criteria for start of chest compressions encouraging ems to start chest compressions when carotid pulse was week and/or < /min in comatose adult patient with respiratory arrest or agonal breathing. methods: data were prospectively collected for out-of-hospital cardiac and respiratory arrests during the period of - . definitive cardiac arrest was recorded when loss of carotid pulse was confirmed by pulse checks performed every min after the early start of chest compressions. the effect of early chest compressions on the proportions of definitive cardiac arrest was analysed in cases with respiratory arrest and circulatory depression in initial patient evaluation. before/after comparison of neurologically favourable -y survival was performed in cases with ems-witnessed ohca. results: the early start of chest compressions did not significantly prevent definitive cardiac arrest that followed respiratory arrest with circulatory depression in the initial patient evaluation (fig. ) . time interval between start of chest compressions and definitive cardiac arrest confirmation (median; iqr) was ; . - min. the survival rate of all ems-witnessed ohcas after the implementation of new criteria was significantly higher than that before the implementation: adjusted or; % ci, . ; . - . (fig. ) . no complications related to early chest compressions were reported during the study period. conclusions: start of chest compressions before definitive cardiac arrest improved survival from out-of-hospital cardiac arrest witnessed by emergency medical service. healthcare providers including ems personnel should be encouraged to provide chest compressions on cases with respiratory arrest and severe cardiovascular depression. introduction: our study sought to determine if there is a difference in time to tracheal intubation between direct and video laryngoscopy during cardiac compressions. guidelines suggest no more than seconds should be taken to perform intubation to minimise any delay in compressions [ , ] . it is unclear if use of video laryngoscopes results in faster intubation times during cardiac arrest. methods: observational trial involving emergency, anaesthesia and intensive care doctors. participants' baseline data obtained by questionnaire. resusci-anne™ manikin with airway trainer™ head [laerdal] with grade airway was utilised. participants intubated the manikin times, once with each of: macintosh size blade, c-mac video laryngoscope (karl storz, germany) with size blade and portable mcgrath mac enhanced video laryngoscope (medtronic, usa) with size blade. order of laryngoscopes was randomised by computer generated sequence. continuous cardiac compressions were performed throughout attempts. results: total participants. there was a statistically significant difference in time to intubation between the devices using friedman test (p< . ). wilcox signed-rank test demonstrated time to intubation with videolaryngoscopy was longer, c-mac (p= . ) and mcgrath (p= . ) compared with direct laryngoscopy. there was no significant difference between the two videolaryngoscopes (p = . ). when controlled for participants level of seniority and previous experience with device, direct laryngoscopy was still significantly faster than c-mac (p = . ) and mcgrath (p = . ) conclusions: our study showed a disadvantage of video laryngoscopy during cardiac compressions. faster intubation times with direct laryngoscopy could result in less pause in compressions and decrease periods without perfusion. direct laryngoscopy is an appropriate first choice for tracheal intubation during cardiac arrest. introduction: the aim of this study was to describe the coronary angiographic findings in relation to specific ecg changes and comorbidity in survivors after cardiac arrest. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between - from national registries in sweden. unconscious patients with coronary angiography performed within days after return of spontaneous circulation and available ecg were included (fig. ) . results: after exclusion, patients were analyzed (fig. ) , (table ) . ( %) were women and mean age were years. patients without st-elevation were separated into groups with specified ecg changes and comorbidities. differences were observed in the incidence of any significant stenosis, total occlusion and pci performed, between the specified ecg changes, as well as between the comorbidity groups ( introduction: fewer women after return of spontaneous circulation from out-of-hospital cardiac arrest (ohca) are undergoing coronary angiography (cag) with possible percutaneous coronary intervention (pci). the aim was to investigate gender differences in comorbidity, cag findings and outcome after ohca in comatose patients with a shockable first ecg rhythm. methods: a retrospective cohort study of out-of-hospital cardiac arrest patients with data retrieved between - from national registries in sweden (fig. ) . results: there was no difference in age or comorbidity except for men having more ischemic heart disease, . vs . % (p= . ). rates of previous myocardial infarction did not differ, . vs . %. no difference was seen in rates of ecg indicating prompt cag according to guidelines. still, more men underwent cag but no difference in numbers of cag leading to pci was seen (table ) . furthermore, in patients with st elevation or lbbb, no gender difference in cag and subsequent pci was found. men had lower rates of normal cag findings but more triple vessel and left main coronary artery disease ( table ) . year survival did not differ, . vs . %. conclusions: our study suggests, that despite no gender differences in rate of ecg findings indicating a prompt cag, men seems to have a more severe coronary artery disease while women have more frequently normal angiograms. however, this did not influence year survival. introduction: the circadian clock influences a number of cardiovascular physiological processes. a time-of-day variation in infarct size has recently been shown in patients with st segment elevation myocardial infarction. however, there is no clinical evidence of circadian variation in patients with out-of-hospital cardiac arrest (ohca) of cardiac etiology. methods: we performed retrospective analysis using data from japan's nationwide ohca registry from january through december , which includes all ohca patients presented with ventricular fibrillation as first documented rhythm, and consequently confirmed cardiac etiology. in order to eliminate the night and weekend effects, we enrolled only patients suffered ohca in the morning we conduct a retrospective cohort study focusing on the association between ohca outcome and icu bed availability. the ohca data was acquired from a regional emergency operation center, and the icu bed information was obtained from a regional sur it exceeds physiological levels in order to avoid insufficient oxygenation [ ] . hyperoxia has been associated with increased in-hospital mortality, though uncertainty remains about this association. multiwave pulse co-oximetry has safely been studied intraoperatively as a guide to monitor hyper-and hypoxia by calculating an oxygen reserve index (ori) which could add information to pulse oximetry measures when spo is > % [ ] . methods: this is a monocentric prospective study including patients with successful resuscitation following ohca. the aim of our study is to evaluate the feasibility and assess the availability of novel non invasive oxygen and hemodynamic variables. collected data principally concern blood oxygen and circulation such as ori, spo , total hb, perfusion index and pulse rates. recording is ideally started at time of rosc. results: we monitored consecutive patients for a total time of . min during transport from ohca place to the er. spo signal was present for . % of transport time.oxygen reserve index signal was present for . % of the total transport time. pleth variability index (pvi) signal was present . % of the total transport time. sphb signal was present . % of total time from rosc to hospital. the confidence interval for each variable is given in fig. . conclusions: our pilot study shows that noninvasive measurements of hyperoxia, fluid responsiveness and hemoglobin are readily available from the prehospital phase of post-rosc care allowing for early tailored and goal directed interventions. increase in sofa score was associated with € ( % ci - €) increase in the cost per day alive in the first months after ca. the sofa score is a good indicator of disease severity but the overlap between outcome groups does not allow its use for early prognostication in ca patients. the association of sofa and its sub-scores with -month outcome and healthcare costs highlights that in addition to neurologic damage the full spectrum of multiple organ failure affects the survival and morbidity of ca patients. public opinion on cardiopulmonary resuscitation decision and outcome in out-of-hospital cardiac arrest patientsquestionnaire study ty li introduction: metabolomics is a novel approach that can characterize small molecules (metabolites) and has the potential to explore genotype-phenotype and genotype-environment interactions, delivering an accurate snapshot of the subject's metabolic status. in this context, the aim of metabolomics is to improve early diagnosis, classification, and prediction over the development of a pathological condition. to this end, metabolomics have not been used in the characterisation of cardiac arrest (ca), cardiopulmonary resuscitation (cpr) and return of spontaneous resuscitation (rosc). the aim of the present study was to explore whether metabolomics can characterize the ca versus rosc in a swine model of ventricular fibrillation (vf). methods: ten animals were intubated and instrumented and vf was induced with the use of a cadmium battery. vf was left untreated for min and the animals were then resuscitated according to the guidelines. defibrillation was attempted in all animals. venous blood was drown at baseline, min, min, min during untreated ca and finally at min, min, h, h after rosc in order to determine the metabolomic profile during ca and during the early post-resuscitation period. rosc was defined as the presence of an organized cardiac rhythm with a mean arterial pressure of at least mmhg for > min. blood was centrifuged and serum was analysed by high resolution h-nmr spectroscopy. nmr spectral data were submitted to multivariate discriminant analysis. results: eight animals survived the experiment and were included in the analysis. metabolites upregulated in the immediate rosc versus ca were succinate, hypoxanthine, choline and lactate. metabolites upregulated in the hour rosc versus ca were ornithine and alanine. the measured phases are shown in fig. introduction: early outcome prognostication in successfully resuscitated out-of-hospital cardiac arrest (ohca) patients remains challenging. prediction models supporting the early decision to continue with full supportive treatment could be of major interest following ohca. we constructed prognostic models able to predict good neurologic outcome within hours after icu admission. methods: upon icu admission, targeted temperature management at °c, hemodynamic and neuromonitoring (cerebral oxygen saturation measured with near-infrared spectroscopy and bispectral index (bis)) was initiated. prediction models for good neurologic outcome at days post-ca were constructed at hour , , and after admission using variables easily collectable and known to be predictive for outcome. after multiple imputation, variables were selected using the elastic-net method. each imputed dataset was divided into training and validation sets ( % and % of patients, respectively). cut-off probabilities yielding a sensitivity above % were determined and performance of all logistic regression models was assessed using misclassification rates. introduction: in many venues, ems crews limit on-scene care for pediatric out-hospital cardiac arrest (pohca), attempting treatment during transport. hypothesizing that neuro-intact survival can be improved by prioritizing on-site care, strategies were effected to expedite on-scene drug delivery and intubation (with controlled ventilation). methods: from / / to / / , data for pohca cases were collected. in , new training prioritized on-site resuscitation (phase i) using expedited drug delivery and intubation with controlled ventilation (~ breaths/min). training included psychological and skills-enhancing tools to boost confidence in providing on-scene care. in , drugs were prepared while responding (phase ii). american heart association guidelines were used throughout and no other modifications were made. neuro-intact survival in - was compared to phase i & ii outcomes. results: over the . -years, ems faced consecutive pohca cases. the great majority presented in asystole throughout. in those resuscitated, mean time from on-scene arrival to the st epinephrine infusion fell from . min ( - ) to . min (phase i) and . min (phase ii). by , it was min. for resuscitated patients and . min. for all patients. intubation and intraosseous insertion occurred more frequently in phase i/ii, but there were no significant differences in age, sex, etiology, response times, bystander cpr or drug sequencing. neuro-intact survival improved significantly from / in - to . % ( / ) in phase i and . % ( / ) in phase ii (p < . ; -tailed fisher's exact test) (fig. ) . conclusions: although historically-controlled, the sudden appearance of neuro-intact survivors following a renewed focus on rapid on-site care was profound, immediate and sustained. beyond skillsenhancing strategies, physiologically-driven techniques and supportive encouragement from leadership, pre-arrival psychological and clinical tools were also likely contributors to the observed outcomes. fig. (abstract p ) . effecting neurologically-intact survival for children with out-of-hospital cardiac arrest p improved outcomes with a bundled resuscitation technique to enhance venous return out of the brain and into the heart during cardiopulmonary resuscitation pe pepe , ka scheppke , pm antevy , d millstone , c coyle , c prusansky , s garay , jc moore introduction: lowering intracranial pressure to improve brain perfusion during cpr has become a focus for our team. combined with devices that enhance venous return out of the brain and into the thorax during cpr, outcomes have improved using head/chest elevation in the laboratory (fig. ) . this study's purpose was to confirm the safety/clinical feasibility of this new approach involving mechanical cpr at an angle. methods: , consecutive out-of-hospital cardiac arrest (oohca) cases (all rhythms) were studied for . years ( / / to / / ) in an expansive, socio-economically-diverse u.s. county (pop. . mill). in , ems crews used the lucas© and impedance threshold (itd) devices on such patients, but, after april , they also: ) applied o and deferred +-pressure ventilation several min; ) raised the backboard~ °; and ) solidified a pit-crew approach to expedite lucas© placement. neuro-intact survival was not recorded until , so resuscitation by ems to hospital admission was used for consistency. quarterly reports were run to identify any periodic variations or incremental effects during protocol transition (quarter , ). results: no problems were observed with head/torso-up positioning (n= , ), but rates of resuscitation rose steadily during the transition period with an ensuing sustained doubling (fig. ) over the ensuing years when compared to those studied (n= ) prior to the head-up approach (mean . %; range - % vs. . %, range - %; p < . ). outcomes improved across subgroups. response intervals, indications for attempting cpr and bystander cpr rates were unchanged. resuscitation rates in - remained proportional to neuro-intact survival. conclusions: the head/torso-up cpr bundle was not only feasible, but also associated with an immediate, steady rise in resuscitation rates during the transition phase with a sustained doubling of resuscitation rates, making a compelling case that this bundled technique may improve oohca outcomes in future clinical trials. introduction: cardiac arrest (ca) often requires intensive care unit (icu) treatment, which is costly. while there are plenty of data regarding post-ca outcomes, knowledge of cardiac arrest associated healthcare costs is virtually non-existent. methods: we performed a single-center registry-based study to determine expenditure data for icu-treated ca patients between and . healthcare cost evaluation included costs from the initial hospital treatment, rehabilitation costs and social security costs up to one year post-ca. we calculated mean healthcare costs for one year survivors and for hospital survivors who died within the first year after cardiac arrest. we calculated effective costs per independent survivor (ecpis) as an indicator of cost-effectiveness. we adjusted all costs according to consumer price index (cpi) in finland as of . all costs are presented as euros (€). results: we identified , ca patients eligible for the analyses. at one year after ca % of the patients were alive and % were alive and independent in daily activities. one year survival stratified by cardiac arrest location group was % for out-ofhospital ca patients, % for in-hospital ca patients and % for in-icu ca patients. for the whole study population, mean healthcare costs were , € per patient. healthcare costs for hospital survivors were , € per patient and for hospital non-survivors , € per patient. healthcare costs for those who survived to hospital discharge but died within the first year were , € per patient, while for one year survivors they were , € per patient. healthcare costs stratified by ca location are presented in fig. . mean ecpis were , €. conclusions: for icu-treated cardiac arrest patients, the mean ecpis were close to , €. the best prognosis and the lowest costs were observed for out-of-hospital ca patients. introduction: in lithuania the incidence of out-of-hospital cardiac arrest (ohca) is unknown, as there is no official coding for ohca as a cause of death in the national death registry. kaunas emergency medical service (ems) underwent major stepwise changes since , including implementation of medical priority dispatch system and dispatcher-assisted cpr instructions. we sought to describe the epidemiology and outcomes from ohca in kaunas, the second largest lithuanian city. methods: the incidence, demographics and outcomes of patients who were treated for an ohca between st january and st december in kaunas ems, serving a population of almost . million, were collected and are reported in accordance with utstein recommendations. results: in total, ohca cases of ems treated cardiac arrests were reported ( per . of resident population). the mean age was . (sd= . ) years and . % were male. % ohca cases occurred at home and . % were witnessed by either ems or a bystander. in non-ems witnessed cases, . % received bystander cpr, whilst public access defibrillation was not used. medical dispatcher identified ohca in . % of all cases and provided over-the-phone cpr instructions in . % of them. average ems response time ( % fractile) was min. cardiac aetiology was the leading cause of cardiac arrest ( . %). the initial rhythm was shockable (vf or pvt) in % and non-shockable (asystole or emd) in . % of all cases. return of spontaneous circulation (rosc) at hospital transfer was evident in . % and survival to hospital discharge was . %. conclusions: rosc and survival to hospital discharge in kaunas were similar to those reported in united kingdom in [ ] . routine ohca data collection and analysis will allow us to track the efficiency of service improvements and should become a standard practice in all lithuanian regions. outcomes of patients admitted to intensive care following cardiac arrest j mcloughlin, e landymore, p morgan east surrey hospital, surrey, uk critical care , (suppl ):p introduction: patients who have return of spontaneous circulation following a cardiac arrest are haemodynamically unstable and require critical care input. outcomes are often poor, with unadjusted survival to hospital discharge at . %, following an in hospital cardiac arrest [ ] . the aim of the study was to assess the survival of patients admitted to intensive care following a cardiac arrest, reviewing whether age and gender impacted on their outcome. methods: the inarc database for a general intensive care unit (icu) at a district general hospital was reviewed. since , patients were admitted following a cardiac arrest (both in and out of hospital). their age, gender and survival to icu discharge and overall hospital discharge were recorded. results: female patients and male patients of varying ages were admitted to our icu following a cardiac arrest. the mortality for both genders increased with increasing age. overall survival to the time of icu discharge following a cardiac arrest was similar for both females ( . %) and males ( . %). figures (female) and (male) below show the number of patients who survived or died on icu discharge, by age and gender. mortality rates increased when reviewing hospital outcome, as some patients died following discharge to the ward. conclusions: overall mortality in our icu following a cardiac arrest at any age is at least %, with the general trend appearing to rise with increasing age. more male patients were admitted to icu following a cardiac arrest than female, with similar survival rates for both male and female patients. more research could be undertaken to assess whether survival rates following a cardiac arrest have improved since and also to compare outcomes following either an in or out of hospital arrest. introduction: raw simplified eeg tracings obtained by a bispectral index (bis) device significantly correlate with standard eeg [ ] . this study aimed to investigate whether simplified bis eeg tracings can predict poor neurologic outcome after cardiac arrest (ca). methods: bilateral bis monitoring (bis vistatm, aspect medical systems, inc. norwood, usa) was started following icu admission. six, , , , and hrs after targeted temperature management (ttm) at °c was started, raw simplified bis eeg tracings were extracted and reviewed by two neurophysiologists for the presence of burst suppression, cerebral inactivity and epileptic activity. at days post-ca, neurologic outcome was determined using the cpc scale, where a cpc - and cpc - corresponded to good and poor neurologic outcome, respectively. results: of the enrolled ca-patients enrolled, had good and poor neurologic outcome. with a positive predictive value (ppv) of . and a negative predictive value (npv) of . , epileptic activity within - hrs predicted a cpc - with the highest accuracy. epileptic activity within time frames - hrs and - hrs showed a ppv for poor outcome of . and . , respectively. cerebral inactivity within - hrs had a poor predictive power (ppv= . , npv= . ). in contrast, cerebral inactivity between - hrs predicted a cpc - with a ppv of . and a npv of . . the pattern with the worst predictive power at any time point was burst suppression with a ppv of . , . and . at - hrs, at - hrs and at - hrs, respectively. conclusions: based on simplified eeg derived from a bis device, both the presence of epileptic activity at any time as well as cerebral inactivity after the end of ttm can be used to assist with poor outcome prognostication in successfully resuscitated ca patients. the helicopter as first response tool -rio de janeiro fire department experience. (interquartile range= ) min, followed by tih with flights ( %) and median time of (iqr= ) min, and ( %) were neo missions with median time of (iqr= ) min. total time of aircraft usage was higher for tih ( %), followed by neo ( %). evam was the most frequent mission, however it accounted for % of aircraft utilization time, where most victims had traumatic brain injury (tbi) followed by other traumatic injuries ( and cases respectively). tbi victims were predominantly males ( %) with a median age of (iqr= ) years. most commonly, tbi is a consequence of transportation accident ( %), where a motorcycle was involved in %, car collision in % and pedestrian run over % of the cases. conclusions: goa utilizes the air ambulance helicopter as a first response tool in % of total missions, where respect for the trauma golden hour is paramount. traumatic brain injury is the most prevalent diagnosis at the scene of event. therefore, goa training and equipment must be tailored to meet this demand, which translates in stabilization of critical patients outside hospital environment with limited resources. introduction: the intra-hospital transport of critical patients is associated with adverse events and worse outcomes. the objective of this study was to evaluate the safety profile of intrahospital transport after the creation of a specific group for this purpose. methods: evaluated all the transports of critical patients from october to september , in a large hospital, after the creation of a group consisting of intensive care physician, nurse and physiotherapist. clinical and non-clinical complications related to the transport and outcome of the patients were evaluated. results: a total of , transports were performed, . % of the male patients and . % of the patients being hospitalized. . % were under mechanical ventilation and . % under vasoactive drugs. at the time of transport, . % were clinically stable. during transport, . % presented clinical complications, being more frequent hemodynamic instability ( patients) and respiratory failure ( patients). non-clinical complications occurred in patients ( . %), and communication failures were responsible for . % of the occurrences. in cases ( . %) there was worsening of the clinical conditions during transportation, and in only one case this worsening resulted in an increase in the length of stay in the icu and in the hospital, with no correlation with deaths. conclusions: the implantation of a group specialized in critical patients to carry out in-hospital transport made the process safer with complications rates lower than literature and guarantee better quality of care. clinical profile of patients admitted to icu due to acute poisoning mp benitez moreno , e curiel balsera , mc martínez gonzález , s jimenez jimenez intensive care unit, hospital regional universitario carlos haya, malaga, spain; hospital regional universitario carlos haya, málaga, spain critical care , (suppl ):p introduction: patients suffering from acute intoxication, whether voluntarily for autolytic or accidental purposes, often require life support in intensive care units. methods: retrospective observational study of all patients admitted for acute intoxication who required admission to the icu of the regional hospital of malaga between january and august , older than years with admission to the icu for intoxication of any kind. we study patient characteristics in terms of age, sex and medical history, type of toxicity, severity and evolution in our unit. results: we found cases of patients who required admission to the icu due to acute intoxication, of which . % were women. the average age was . (standard deviation . ). the average stay in icu was . (standard deviation . ). . % of patients had a psychiatric history. as other background highlights, . % were addicted to illegal drugs and % were hypertensive. most patients took more than one toxic . % and intoxication was voluntary in . % versus accidental in . % of cases. the toxic was known in %. the most used benzodiazepines in . % of the total. the main cause of admission to the icu was due to neurological deterioration in of the cases registered and mechanical ventilation was necessary in patients. the maximum time in mechanical ventilation was days. the infection occurred in . %, with the majority being respiratory infection. the . % died in icu. the hospital stay presented an average of . days. conclusions: the profile of a patient admitted to the icu due to acute intoxication is that of a woman of middle age and psychiatric history, with voluntary intoxication of several toxic substances and requiring mechanical ventilation for a low level of consciousness for an average of days. the survival is very high and it would be necessary to analyze the possible relapses of these patients. mushroom that break hearts: a case report e karakoc, k demirtas, s ekemen, a ayyildiz, b yelken eskisehir osmangazi university, eskisehir, turkey critical care , (suppl ):p a introduction: because of the high mortality and morbidity mushroom poisoning is a significiant medical emergency [ ] . amanita phalloides (a. phalloides) is responsible for the % of the mortality in adults caused by mushroom poisoning. it causes damage in liver, kidneys and rarely pancreas, causing encephalopathic coma, disseminated intravascular coagulation, hemorrhage, hypovolemic shock and death but its effect on cardiac functions has not been established yet. there are three main groups of toxins;phallotoxins, virotoxins and amatoxins;amatoxin is the common responsible toxin from the fatality. we aimed to present a -year-old woman poisoned by mushroom complicated with hepatic,renal and cardiac toxicity methods: patient with nausea and vomiting started hours after mushroom eating,creatine kinase mb . ng/ml and cardiac troponin i . ng/ml her blood urea nitrogen, creatinine levels and liver enzymes were higher than upper limits in lab tests (table ) ; she was admitted to icu, treated for acute renal failure by hemodialysis.plasmapheresis was applied against potent mushroom toxins. at .day in icu, hypoxemia and severe swelling resistant to ultrafiltration was evaluated as a global left ventricular hypokinesia with ejection fraction(ef) %, end-diastolic diameter of . cm, and systolic pulmonary artery pressure (spap) of mmhg. oxygen was administrated to treatment.urine output improved at .day, three more plasmapheresis sessions were performed. hypoxemia was recovered,liver enzymes and creatinin levels decreased results: at control ef measured was %, end-diastolic diameter of . cm, spap of mmhg.than at the .day patient discharged from the icu.after a year follow up assessment she has no complaints conclusions: one of the major problems for amanita poisoning is diagnosis. patients who had mushroom poisoning should also be evaluated especially in terms of cardiac dysfunction with clinic signs, ecg, cardiac enzyme tests and eco introduction: the characterization of clinical and/or biological variables found in the emergency room predictive of a secondary admission in icu would help to improve the identification of patients at risk of aggravation in order to avoid the associated consequences, such as, an increased mortality and increased hospital stay. methods: this is a retrospective monocentric study of years with patients admitted secondarily to a medical icu within hours of admission to the general wards from the emergency department in the pitié-salpêtrière hospital in paris. each case was matched to controls. different variables were collected in the emergency room. results: patients, of whom were cases and controls were studied. pneumonia is the diagnosis the most frequent in cases followed by sepsis (in and %, respectively). conclusions: the risk of being admitted secondarily to intensive care is higher if patients consult for dyspnea or fever, if they are old smokers, if they have a high igs score, if an arterial blood gas is requested and if an icu medical advice is taken. the meds score under and being an active smoker seems to be protects for the unexpected transfer. introduction: managing the special needs of patients who present with agitation or psychosis can pose a greater challenge to an already busy emergency department as their symptoms can escalate rapidly. traditional antipsychotics used in the ed, such as haloperidol or ziprasidone often do not fully relieve patient's symptoms and may require administration of repeat doses or additional medications such as benzodiazepines to achieve effective results. this can induce excess sedation which can lead to longer length of stay in the ed and requires additional time at the bedside by the ed physicians and staff to manage these patients. adasuve® is an antipsychotic drug that works in a single-use device providing an aerosol form of loxapine that is rapidly absorbed by the lungs which may offer faster symptom relief, allowing subsequent earlier psychiatric evaluation and disposition. methods: to test this hypothesis, data including time of physician assignment and time physician documented discharge disposition and number of hours physician was assigned to the patients was retrospectively collected from patients who arrived to the emergency department presenting with agitation or psychosis that received adasuve or other types of antipsychotic medication such as ziprasidone, haloperidol and benzodiazepines or a combination of the three. results: we found that physicians who administered adasuve spent an average of . hours assigned to their patient compared to . hours when the physician administered any other type of antipsychotic medication. this resulted in a significant . -hour difference (p < . ) between the two groups. conclusions: in conclusion, less time spent assigned to a patient that received adasuve can be attributed to faster symptom relief which allowed the physicians to complete their psychological evaluations and develop dispositions more rapidly than with patients that received other antipsychotic agents. clinical work in language-discordant emergency department introduction: emergency residents are particularly vulnerable to sleep deprivation due to persistent conflicts between work schedule and the biological clock. recent approaches to address fatiguerelated risk mainly focused on reducing work hours and ensuring sufficient recuperation time. such approach has demonstrated its limits due to growing emergency rooms visits and emergency residents' shortage. dawson & mcculloch ( ) introduced the notion of proofing as a complementary approach to manage fatigue-related risk [ ] . fatigue proofing strategies (fps) aim to reduce the likelihood a fatigued operator will make an error, in contrast of reduction strategies (frs) aiming to reduce the likelihood a fatigued operator is working. most formal risk control systems do not encompass the notion of proofing and fps typically develop as informal practices. in this study, we aim to ) identify informal reduction and proofing strategies used by residents and ) to investigate how they relate to fatigue-related risk indicators. methods: first, we organized focus-group with a total of residents in order to identify informal strategies used to manage fatigue-related risk. second, we designed a questionnaire assessing the frequency of use of each reported strategy. introduction: this randomized controlled study assessed the impact of a -hour intravenous medication safety simulation-based learning (sbl) on self-efficacy, stress, knowledge and skills of nursing students. medication administration error is a worldwide concern [ ], that has been linked with a lack of knowledge and skills in safe medication administration among new graduate and student nurses [ ] [ ] [ ] . preventing medication errors could therefore involve training through simulation. methods: participants (n= ) were randomly assigned either to the control group (cg, n= ) or the experimental group (eg, n= ). while cg and eg both had a traditional clinical internship, eg beneficiated in addition the -hour sbl, using standardized patients in the context of an intensive care unit. the two groups were assessed twice: at t and t (four weeks later), through an objective structured clinical examination (osce) and questionnaires. two blinded experts rated the students osce with an evaluation grid. results: mean participants age was , . there were no statistically differences between groups at t . compared to the cg ( %), the eg increased its self-efficacy (+ . %) with a significantly difference (p< . ) at t . the sbl conducted to a greater increase of knowledge and skills in the eg (respectively + %, + %) than in the cg (respectively + % and + %), with a statistically significant difference (p< . ). conclusions: results reinforce the interest of a short sbl using standardized patients to improve medication administration. clinical impact of these observations requires further evaluation to determine potential transfer in clinical settings and retention over time. introduction: medication errors occur frequently in the intensive care unit (icu) and during care transitions. medication reconciliation by a pharmacist could be useful to prevent such errors. therefore, the aim of this study was to determine the effect of medication reconciliation at the icu. methods: a prospective -month intervention study with a pre-and post-phase was performed in haga teaching hospital ( ) and erasmus university medical center ( ). the intervention consisted of medication reconciliation by pharmacists at icu admission and discharge. the severity of potential harm of the medication transfer errors (mte) (pade= ; . ; . ; . ; . ) was scored. primary outcome measures were the proportions of patients with >= mte at icu admission and icu discharge. secondary outcome measures were the proportions of patients with a pade score >= . , the severity of the pades and a cost-benefit analysis. odds ratio and % confidence intervals were calculated. results: table shows patient characteristics. figure shows the primary outcome measures (oradj admission = . [ % ci . - . ] and oradj discharge = . [ % ci . - . ]). the proportion of patients with a pade >= . at icu admission reduced from . % to . % and after icu discharge from . % to . %. the pade reduction resulted in a potential net cost benefit of € per patient. conclusions: medication reconciliation by pharmacists at icu transfers is an effective safety intervention, leading to a significant decrease in the number of errors and a cost effective reduction of potential adverse drug events. introduction: in intensive care unit, administration of numerous drugs in icu patients via a central venous catheter provide a high risk of drugs incompatibilities. it has been reported in experimental studies [ ] that particles issued of drug incompatibilities could induce thrombogenesis, microcirculation impairment and inflammatory response which could aggravate the occurrence of organ dysfunctions [ ] . the objective of this study was to evaluate the occurrence of particles by reproducing in vitro the intravenous system and the drugs combination used in icu for patients suffering either septic shock or acute respiratory distress syndrome (ards). methods: first, we registered during a period of months the most common central venous catheter system used in patients admitted for septic shock or ards in three university hospital in lille. the second part of the study was to reproduce in vitro the previous infusion system in order to quantify the amount of particles generated during a simulated period of hours infusion. the egress of the iv line was connected to a dynamic particle counter qicpic analyser (sympatec inc ; clausthal zellerfeld, germany) (fig. ) . results: the most common intravenous system observed was a three lumen central catheter. the proximal lumen was dedicated for vasoactive agents, the medial lumen for sedation and the distal lumen for the other drugs infused continuously and discontinuously..among the drugs infused via the distal lumen of the central venous catheter, introduction: insufficient identification of possible organ donors in the icu is one of the main factors contributing to the loss of donors after brain death [ ] . up to % of potential donors might not be identified [ ] . the aim of this study was to evaluate how active search of possible brain dead donors affect the potential deceased donor pool. methods: the strategy implemented at university hospital with specialized icus from december to october and data compared to the matching period of the previous year. donor coordinator visited all icus every day and selected patients who met possible brain dead donor criteria: ) gcs <= ; ) severe brain injury. all data registered in original color coded follow-up system according to the patient status. results: a total of patients were identified as possible donors. there was no significant difference of potential donor numbers in study period comparing to previous year ( vs ). main causes of brain death remain intracranial hemorrhage and subarachnoid hemorrhage. the length of hospital stay of potential donors was significantly longer in study period comparing to previous year ( ± . vs . ± . , p= . ). there was no significant difference of donor's demographic data, conversion rates to actual donor or frequency of family refusals and medical contraindications. conclusions: active search of brain dead donors neither increased total number of potential donors nor increased conversion rates and did not change a donor profile in our donor center. longer observational period and more sophisticated follow-up system might be required. a fast hug bid a day keeps the patient ok! e sousa, t leonor, r pinho centro hospitalar de entre douro e vouga, santa maria da feira, portugal critical care , (suppl ):p introduction: regardless the underlying diagnose, providing meticulous supportive care is essential to critically ill patients management. in , vincent jl introduced the fast hug (feeding, analgesia, sedation, thromboembolic prophylaxis, head of bed elevation, ulcer prevention, glucose control) mnemonic for recalling what he considered the key issues to review in daily clinical practice. our intensive care unit (icu) decided to add bid (bowel regimen; indwelling catheter removal; de-escalation of antibiotics) indicators following some published data. since , the adequate use of this mnemonic became an instrument for quality of care evaluation. objectives for each variable were designed; regular annual audits done. the present study aims to audit the use of this mnemonic in a portuguese tertiary hospital icu, in . methods: a prospective observational study was performed. admissions in icu staying at least one h min and h min period, during the first six months of were included. all mnemonic variables were recovered from icu medical record database, as well as demographics, severity scores and clinical information. data was analyzed with microsoft office excel software. results: we included admissions. the predictable global fast hug bid assessment was entries [one per each full day ( h - h ) in the unit, per patient]. the mnemonic was used in about % of the opportunities. the target thresholds were considered as achieved in % of entries (concordance equal or superior to %). looking to individual variables, the best performance was achieved in h and u; worse performance was seen in s. the daily use of this mnemonic aims to revisit important intervention sectors in critical patient. applying the "plan-do-check-act" policy, this study allowed us to identify growth opportunities, reviewing or creating protocols, adopting more frequent training measures and seeking to take this model to other hospital areas. impact of incidents and adverse events in intensive care unit and its characteristics on outcomes e siqueira, l taniguchi, j vieira junior hospital sírio libanês, sao paulo, brazil critical care , (suppl ):p introduction: critically ill patients are usually exposed to adverse events (ae) due to acuity and complexity of care. ae might potentially result in disability or death, and increase in length of stay. our aim was to assess the incidents and ae in a general intensive care unit (icu). methods: this is a prospective cohort study conducted in a private tertiary hospital (hospital sírio-libanês) in são paulo, brazil. all consecutive patients who were admitted to the icu and all incidents and ae reported in the study period were evaluated. univariate and multivariate analysis were used to identify risk factors associated with hospital mortality. results: between may to november we studied patients and reported incidents and ae. overall, patients ( %) experienced some incident or ae during icu stay. we found higher severity of illness (saps of versus ; p< . ), mechanical ventilation (mv), use of vascular lines, drains and catheters, physical restraints, delirium and also an increased length of icu ( vs days; p< . ) and hospital stay ( vs days; p< . ) and hospital mortality ( % vs %; p< . ) among patients who experienced any incident or ae. independent risk factors for hospital mortality in our logistic model were: higher saps , mv and at least one adverse event during the icu stay. mortality was higher among patients who experienced late ae (> hours after icu admission) compared to patients who experienced early ae ( % vs %; p< . ). saps , sofa and mv were predictors of moderate and/or severe ae and a negative correlation between these events and icu occupancy rate was found. conclusions: patients who experienced incident or adverse event during icu stay had poorer outcome. ae, mainly moderate or severe, mv and severity of illness were independent risk factors to mortality. there was a negative correlation between moderate or severe adverse event and icu occupancy rate. monte carlo modelling of patient flow can aid complex intensive care bed and workforce capacity planning. introduction: models for icu populations based on the queuing model use arrival rate, length of stay, and bed number [ , ] . these models lack the complexity of specialised icus with different admission types, and patient subpopulations. results: > % of patients reported satisfaction on all areas except noise, patient facilities for hand hygiene and being informed about timing of operations. staff survey results revealed confusion regarding the interventions that are provided. baseline capacity for new patients was %, bed occupancy varied between and per day (overflow to recovery) with overall capacity at . % and mean length of stay (los) was . days (sd= . , n= , =range - ). following intervention, the los was reduced to . days (sd= . , n= , range - ). new patient capacity was increased to % with a bed occupancy range - . introduction: in clinical practice, when harm or potential harm occurs to patients, this can adversely impact upon the morale of staff involved and thereby affect clinical care delivered to subsequent patients. the personal narratives behind clinical incidents contain learning opportunities and individuals involved may reflect on the course of events and make changes to their practice to avoid recurrence. the aim of this study was to evaluate whether sessions enabling trainees to discuss their mistakes in a confidential environment improved trainee morale and safe clinical practice in an anaesthetic trainee cohort. methods: we conducted a survey amongst anaesthetic trainees in a london teaching hospital before and after a monthly, hour long, confidential, semi-structured, trainee lead "confession session" was introduced. results: initial results demonstrated that % of respondents (n= ) had made a mistake resulting in patient harm with % of these individuals describing negative feelings about themselves as a consequence. additionally, % of respondents had made a mistake causing a near miss, with % of these describing negative feelings as a result. of note, only % of respondents felt comfortable discussing errors with more senior colleagues, whilst % felt comfortable discussing errors with their peers. a follow-up survey identified that % of respondents (n= ) agreed that the session had the potential to improve clinical practice and trainee morale with % agreeing that their own clinical practice had improved from attending the sessions. conclusions: clinical mistakes leading to harm and "near misses" are common and provide opportunities to improve care. this trainee lead "confession session" appears to improve trainee morale and may improve patient care by encouraging trainees to engage in a process that seeks to understand error through sharing stories in a non-judgmental setting. funnel plots for quality control of the swiss icu -minimal data set introduction: a clinical database should be representative of the labelled population and guarantee completeness and accuracy of collected data. without explicit permission of the patients, swiss laws regarding data protection do not allow external audits based on periodic checks of random samples, supposed to give a general pattern of accuracy. to test alternative methods for quality control we introduced the principles of statistical process control to derive funnel plots from the swiss icu -minimal data set (mdsi). the mdsi from all certified adult swiss icus ( and ) was subjected to quality assessment (completeness and accuracy). for the analysis of accuracy, a list of logical rules and cross-checks was developed as e.g. range of saps ii according to age. errors were classified in coding errors (e.g. nems score > points) or implausible data (nems without basic monitoring). we also checked for icus producing significantly more errors -outliers -(> mean ± standard deviations [sd] or > . % confidence interval [ci] of an adapted version of the funnel plots, which allows the presence of trends depending of the icu's size. results: a total of ' patient mdsi ( items/patient; items for trauma patients) from the certified icus.were investigated. we detected ' patients ( . %) with an overall sum of coding errors and ' implausible situations. implausible situations related to supposedly inaccurate definitions (diagnostic and patient's provenance prior to icu admission) and discrepancies in the logical rules between diagnostics and treatments. figure is an example for imprecise coding of the diagnostic: icus declared having treated - % of their patients without a defined diagnosis. conclusions: accuracy of data in mdsi needs further improvement. funnel plots may be useful for meaningful interpretation of data quality and permit to identify icus disproportionately generating inaccurate and/or implausible data. introduction: lung cancer is the leading cause of intensive care unit (icu) admission in patients with the advanced solid tumors. this study was aimed to elucidate the clinical factors associated with icu mortality of advanced lung cancer patients and the effect of intensivist's contribution on their clinical outcomes. methods: we included patients with advanced lung cancer including non-small cell lung cancer (nsclc) with stage iiib or iv and small cell lung cancer (sclc) with extensive stage who admitted to icu from to . multivariate logistic regression analysis was performed to find the variables associated with icu mortality and in-hospital mortality. we applied autoregressive integrated moving average (arima) for time-series analysis of the intenvention of intensivists. results: among total patients with advanced lung cancer, patients ( . %) were admitted icu before introduction of organized intensive care at , and ( . %) were admitted after (fig. ) . the leading cause of admission was the respiratory failure ( . %) and cancer-related event ( . %) in terms of intensivist's and oncologist's perspective. before and after , the -day icu mortality rate was . % and . % (p = . ), and the hospital mortality rate changed from . % to . % (p = . ) (fig. ) introduction: decisions when to refer and to admit patients to the intensive care unit (icu) care are very challenging. demand typically exceeds supply in icu beds, which results in a constant need for evaluation of the processes involved in icu referral and admission with a view to optimising resource allocation and patient outcomes. the aim of this study was to evaluate the theoretical impact of a newly designed triage tool for icu referrals on a cohort of patients referred to icu (fig. ) . methods: we reviewed all patients consecutively referred to our icu, whether admitted or not, in february . demographics, referring speciality, role of the referrer, comorbidities, the presence of advanced disease or terminal illness, the presence of acute organ failure, dnr status, reason for not admitting, and icu mortality were recorded. a retrospective analysis of icu referrals using a pilot triage tool was carried out independently by three authors. results: forty-six patients were referred to our icu over the study period. of these, ( %) were admitted. patients were declined icu if their admission was deemed unnecessary ( %), futile ( %), or were transferred due to bed shortage ( %). of the patients referred, ( %) had an advanced disease or a terminal illness. of those, ( %) were admitted, dnr status was unclear in ( %), family was involved in ( %) and their icu mortality was %. by analysing retrospectively these referrals with the aid of a triage tool, we propose that the overall referrals could have decreased from to ( % percentage difference). dnr status and family involvement would have been clarified in all patients with advanced disease or terminal illness before icu referral. kappa score for inter-rater agreement was . . conclusions: adopting a triage tool for icu referrals could reduce the overall proportion of inappropriate referrals and admissions. end-of-life discussion would also be proactively clarified prior to icu admission. introduction: intensive care unit (icu) admission triage occurs frequently worldwide and often involves decisions with high subjectivity, possibly leading to potentially inappropriate icu admissions. in this study, we evaluated the effect of implementing a decision-aid tool for icu triage on icu admission decisions. methods: urgent icu referrals before (may, to november, , phase ) and after (november, to may, , phase ) the implementation of a decision-aid tool were prospectively evaluated. our primary outcome was the proportion of potentially inappropriate icu referrals (defined as priority b or patients, as described by the or society of critical care medicine [sccm] guidelines) that were admitted to the icu in hours following referral. we conducted multivariate analyses to adjust for potential confounders, and evaluated the interaction between phase and triage priorities to assess for differential effects in each priority strata. results: of urgent icu referrals, ( %), ( %), ( %), ( %) and ( %) were categorized as priorities b, a, , and (sccm ) or ( . %), ( . %), ( %), ( %) and ( %) were categorized as priorities , , , and (sccm ), respectively. overall, ( %) patients were admitted to the icu in hours following referral. the implementation of the decision-aid tool was associated with a reduction of admission of potentially inappropriate icu referrals [adjor ( % ci) = . ( . - . ), p = . ] (fig. ) . there was no difference on hospital mortality for the overall cohort between phase and phase . conclusions: the implementation of a decision-aid tool for icu triage was associated with a reduction of potentially inappropriate icu admissions. introduction: the aim was analyze the icu bed rotation pattern, the epidemiological characteristics of patients and to correlate them with prognostic score after software implementation methods: this is an epidemiological and retrospective study. data were collected between june and november , using epimed® monitor software, applied in an adult icu of a public hospital in bahia/brazil. authorization for collection and use of data was granted by the institution. all patients hospitalized in the period were included regardless of other exclusion criteria. results: during the period evaluated, there were . new hospitalizations, men ( . %) and women ( . %). . % ( ) were in the age group of to years, followed by . % of the patients ( ), who were between and . the mean duration of hospitalization in our unit was approximately , days. during the period covered, . exits occurred: patients ( . %) were introduction: early debriefing after stressful events holds great value in reflection on both an individual and team-based level. our objective was to implement routine structured debriefing sessions for doctors working in intensive care in order to optimise learning and develop strategies to improve practice. methods: % of junior doctors (n= , pre-implementation questionnaire) on the intensive care unit expressed a need for regular debriefing sessions to discuss challenging and complex cases. weekly sessions were implemented and structured using the sharp performance tool [ ] . key learning points were collected and added to a debrief list to track progress and assimilate learning. informal feedback was obtained on a weekly basis with formal feedback assessed following one month of implementation. results: min sessions occurred on a weekly basis supported by a consultant intensivist. desired outcomes included assessment of team performance, identification of key learning points and psychological support. following one month, % doctors involved felt that debriefing sessions were important and should continue. % felt that they left every session with a key learning point applicable to future clinical practice. common themes in perceived benefits included improved team communication and creation of an open environment to address concerns. conclusions: working in intensive care exposes doctors to challenging and stressful situations. implementation of a regular structured debrief session provides an opportunity for clinicians to address concerns, consolidate learning and develop strategies to improve clinical practice. nurse staffing patterns, outcomes and efficiency in resource use in the context of icus with a "low-intensity" nurse staffing: a multicenter study in brazilian icus m soares introduction: studies investigating nurse staffing and outcomes were often conducted in high-income countries with low bed/nurse ratios. our objective was to investigate the association between nurse staffing patterns, outcomes and resource use in brazilian icus. methods: retrospective cohort study in , ( % medical) patients admitted to medical-surgical icus during - . we retrieved patients' data from an icu registry (epimed monitor system) and surveyed participating icus about characteristics related to icu organization. we used multilevel logistic regression analysis to identify factors associated with hospital mortality. we evaluated efficiency in resource use using standardized mortality rates (smr) and resource use (sru) based on saps . results: saps score was ( - ) points and hospital mortality was . %. intensivists were present / in % icus. median bed/ nurse ratio was . ( . - . ) and at least the chief nurse was boardcertified in critical care (bccc) in % icus. bed/nurse technicians ratio was . ( . - . ). adjusting for relevant characteristics at patientlevel (age, admission type, sofa, performance status, comorbidities, hospital days before icu) and icu-level (hospital type, checklist use, / intensivist, protocols), bed/nurse ratio was not associated with mortality [or= . ( % ci, . - . )]. however, mortality was lower in icus with at least the chief nurse bccc [or= . ( . - . )]. in multivariate analysis, bed/nurse ratios <= [or= . ( . - . )] and having the chief nurse bccc [or= . ( . - . )] were associated with higher efficiency. conclusions: in a "low intensity" nurse staffing scenario, bed/nurse ratios were not associated with mortality. however, having at least the nurse chief bccc was associated with higher survival. moreover, bed/nurse ratios <= and presence of chief nurse bccc were associated with higher efficiency in resource use. methods: a systematic search on the value of acute non-physician provider on the icu was conducted. the methodological quality of the included studies was rated using the newcastle ottawa scale (nos). the agreement between the reviewers was assessed with cohen's kappa. results: in total studies were identified. twenty comparative cohort studies were identified which compared non-physicians with either residents or fellows. all studies comprised adult intensive care. most of the included studies were moderate to good quality. a random effects meta-analysis from all studies regarding length of stay and mortality showed no differences between non-physicians and physicians, although there was a trend to better survival when implementing acute non-physician providers in the icu (figs. & ) . mean difference for length of stay on the icu was . ( % ci - . - . ; i = %) and for in hospital - . ( % ci = - . - . ; i = %); while the odds ratio for icu mortality was . ( % ci = . - . ; i = %) and for hospital mortality . ( % ci . - . ; i = ). conclusions: the acute care non-physician provider in the icu seems a promising clinician on the icu with regard to quality and continuity of care. whether they also can reduce mortality remains to be determined by designing studies, which adequately measure the contribution of the non-physician providers in icu care overall and per task. their role in europe remains to be elucidated. burnout and depression in icu staff members n bahgat menoufia university hospital, shibin elkom, egypt critical care , (suppl ):p introduction: family and success in work are the most important sources of person satisfaction in life, chronic prolonged exposure to stressful high workload in intensive care units (icu), create a bad psychological state named burnout syndrome in which person is depressed, exhausted and thinks to leave job. in this study we made a survey on icus staff members in egypt menoufia university hospital to explore and find risk factors increase depression and burnout among nurses and doctor. methods: questionnaires were given to all intensive care staff for estimating the prevalence and associated risk factors of burnout using maslach burnout inventory (mbi) with its three subscales emotional exhaustion (ee), lack of accomplishment (la), and depersonalization (dp). depressive symptoms using the beck depression inventory scale. blood sample was taken for assessing depression biomarkers including il- , tumor necrosis factor (tnf)-alpha, and coenzyme q (coq ), which appears to be one of the most reliable peripheral biomarkers. results: participants were respond in our survey from icu members the response rate was . %, the depression symptoms found increased in nurses more than physicians in icu with more desire to leave the job. there was strong correlation between the degree of depression symptoms and decrease percent of personal accomplishment. impaired personal relationships at work and increased night shifts were major risk factors of burnout syndrome. levels of the proinflammatory cytokine (il and tnf alpha) were elevated in members who recorded sever degree of depression score with decrease in concentration of co-enzyme q . conclusions: the health workers in icu had high liability for depression and burnout syndrome. the risk factors differ between nurses and doctors. il , co-enzyme q and tnf alpha concentrations had god correlation with degree of severity of symptoms. impact of a tailored multicomponent program to reduce discomfort in the icu on post-traumatic stress disorder: a casecontrol study p kalfon , m alessandrini , m boucekine , m geantot , s renoult , s deparis-dusautois , o mimoz , j amour , e azoulay , c martin , t sharshar , m garrouste-orgeas , k baumstarck , p auquier introduction: reducing discomfort during the icu stay should be beneficial on long-term outcomes. the aim of this study was to assess the impact of the implementation of a tailored multicomponent program to reduce discomfort in the icu [ ] on the occurrence of posttraumatic stress disorder (ptsd) months after discharge from the icu. methods: design: case-control study; the cases were patients hospitalized in the icus which implemented the tailored multicomponent program; the controls were patients hospitalized in the icus which did not implement the program. exposition: the tailored multicomponent program consisted of assessment of icu-related self-perceived discomforts by using the iprea questionnaire, immediate and monthly feedback to healthcare teams, and tailored site-targeted measures under control of a duo of local champions. general procedure: eligible patients were recalled months after the icu stay. data collection: sociodemographics, clinical data related to the icu stay, discomfort's levels assessed the day of discharge from the icu, life situation (home/care center), pstd (ies-r) and anxiety-depression symptoms (hads) months after the icu discharge. results: from the eligible cases and eligible controls, cases and controls were included (reason for exclusion: deaths after discharge from the icu, lost to follow-up, patient refusal, cognitive incapacity). a total of . % of the cases and . % of the controls presented certain symptoms of ptsd at months (p= . ). after adjustment for age, gender, iprea score, mccabe score, presence of invasive devices during the icu stay and considering anxietydepression symptoms at months, cases are less likely to have ptsd symptoms than controls. conclusions: our tailored multicomponent program for discomfort reduction in the icu can reduce long-term outcomes as ptsd. diffusion of such a program should be enhanced in the icus paving the way for a new strategy in care management. introduction: cognitive dysfunction is a major factor leading to disability and poor quality of life in icu survivors. in order to identify patients at risk for developing cognitive dysfunction due to critical illness or icu treatment, one has to discriminate between patients with pre-existing cognitive dysfunction and those developing new cognitive dysfunction or worsening of cognitive function during icu treatment. we investigated the incidence of pre-existing cognitive dysfunction in icu patients using the informant questionnaire on cognitive decline in the elderly (iqcode) and its relation with delirium during icu treatment. methods: patients relatives were asked to fill in the iqcode on admission. an overall score on cognitive dysfunction was calculated by the average of the score on each item of the questionnaire. the incidence of delirium was based on the cam-icu score. statistical analysis was performed using the fisher's exact test. p-values of less then . were deemed significant. results: in total consecutive patients admitted to our icu were analyzed, of whom . % (n= ) showed decline in cognitive function prior to icu admission. cognitive function was divided in four groups; no change . % (n= ), slight decline . % (n= ), moderate decline . % (n= ) and severe decline . % (n= ) (fig. ). incidence of delirium is shown in fig. . patients with moderate to severe cognitive dysfunction showed significant more delirium during icu treatment than patients with no change in cognition ( . % and . % respectively, (p= . )). conclusions: almost half of the patients admitted to the icu have cognitive dysfunction prior to icu admission. to assess ones cognitive function after icu treatment one has to take in to account the patients pre-existing cognitive functioning. patients with a moderate to severe pre-existing cognitive dysfunction develop significantly more delirium during icu treatment. introduction: our aim was to identify and analyse patients treated for pocd admitted to a thoracics/urology intensive care unit at university college london, uk. pocd is rising in the ageing high-risk surgical patient. early identification of those at risk and timely intervention could help reduce associated morbidity and mortality [ ] . methods: we identified patients treated with haloperidol, midazolam, lorazepam, olanzapine, clonidine or chlordiazepoxide from our electronic data system. these pharmacological interventions were used as surrogate markers of primarily hyperactive pocd, acknowledging other forms of delirium may be unaccounted for. of admissions ( . %) were shortlisted from august to july . patients were excluded if the drugs had been used for other indications. prevalence of known pocd risk factors were then detailed. on these data we performed a cluster analysis using r. results: of the patients ( . %) suitable for analysis, the mean age was . patients underwent elective procedures. were male and were female. % patients had thoracic surgery. the mean pain score in the first hours post-op was . (sd= . ), (with = no pain, = very severe pain). % had evidence of poor sleep and % evidence of anxiety. in the hours prior to evidence of pocd, the mean pain score remained . (sd= . ), % had evidence of poor sleep and % had evidence of anxiety. % of our population was septic during their itu admission. conclusions: our analysis demonstrates pocd is highly prevalent in male patients over undergoing thoracic procedures. we will now develop a pocd pathway targeting improved postoperative management of pain, sleep, anxiety and infection in this patient population. introduction: our objective was to determine the feasibility of employing family-administered tools to detect delirium in the critically ill. the use of family-administered delirium detection tools has not been assessed in the icu where patients are critically ill and frequently intubated. family members may be able to detect changes in patient cognition and behavior from pre-illness levels earlier than unfamiliar providers. these tools may be a valuable diagnostic adjunct in the icu. methods: consecutive patients and family members (dyads) in the largest adult icu in calgary, canada were recruited (aug. -sept. , ). inclusion criteria were: patients with a richmond agitation sedation scale (rass) >=- ; no primary brain injury and glasgow coma scale score of < ; ability to provide informed consent (patient/ surrogate); and remain in icu for hours. data were collected for up to days. family-administered delirium assessments were completed once daily (family confusion assessment method & sour seven). to assess feasibility, we assessed proportion of eligible patients and percent family member enrollment. barriers to enrollment were categorized. results: of admitted patients with family, ( %) met inclusion criteria and ( %) dyads consented. % of admitted patients did not have family and were thus ineligible. % of enrolled dyads assessed delirium at least once, with a median of (of total) assessments. the most common reason for non-enrollment was refusal by the family, who commonly reported feeling overwhelmed by the icu environment. barriers with nursing staff were encountered, including not providing access to patients and patient exclusion. conclusions: these data suggest that employing family-administered delirium detection tools in the icu is feasible for a subset of the population. future studies will validate the use of these tools in the icu, decrease modifiable barriers to enrollment, and test strategies to overcome attitudinal barriers towards employing these tools. introduction: psychological impact of critical illness and icu stay on patients can be severe and frequently results in acute distress as well as psychological morbidity after discharge [ ] . however, the stressful experience in icu and its influence on patient recovery, remain relatively understudied. we assessed patients in icu for acute distress and psychological symptoms with validated tools. methods: we conducted an observational study in a group of awake icu adult patients admitted in a tertiary centre for at least hours, from january until october , with mixed diagnosis on admission. we collected demographic factors, saps ii at admission, mechanical ventilation, day of sedation, history of psychopathological disorder. un-sedated and alert, critical care patients were assessed with tools such as intensive care delirium screening checklist (icdsc), hospital anxiety and depression scale (hads) and intensive care psychological assessment tool (ipat). results: patients were recruited, (mean age . ± . years, . % males). saps ii at admission was . ± . , . % was mechanically ventilated (mean duration . ± ), mean duration of sedation was . ± . days and a rate of . % had an history of psychopatological disorder. . % of the sample had clinical delirium (icsdc> ) and was not assessed with others tools, . % had subclinical delirium (icsdc <= ). regarding psychological outcomes, . % (mean score . ± . ) reported a score (>= ) on hads that indicates a possible diagnosis of anxiety and . % (mean score . ± . ) of depression. a rate of . % reported a score >= on ipat suggesting an acute distress. conclusions: the study's key finding was that acute psychological distress was high in awake icu patients. further work is needed to determine the efficacy of early psychological interventions to reduce the incidence of acute distress and psychological outcomes after icu stay. introduction: a high percentage of polytrauma patients require surgery within the first hours to stabilize primary traumatic injuries. one of the main intraoperative complications in this type of patients is due to hemodynamic instability [ ] . thus, it is necessary to implement multimodal monitoring involving both hemodynamic monitoring and monitoring of general anesthesia. the objectives of this study were to identify the possible implications of entropy monitoring on hemodynamic stability in critically ill polytrauma patients. methods: prospective observational study, deployed in the clinic of anesthesia and intensive care, emergency county hospital "pius brinzeu" timisoara, romania. clinicaltrials.gov identifier. there were two groups, group a (n = ), in which the depth of hypnosis was monitored through entropy (ge healthcare, helsinki, finland) and group b (n = ). results: the incidence of hypotension and tachycardia episodes was statistically significantly lower in group a, unlike the control group (p < . ). moreover, a statistically significant (p < . ) consumption of inhaled anesthetic agent was recorded in group a compared with group b. consumption of vasopressor was also lower in group a (p < . , difference between means . ± . , % confidence interval . - . ) conclusions: deploying monitoring for the depth of hypnosis in general anesthesia using entropy can significantly increase the hemodynamic stability of critically ill polytrauma patients. introduction: the use of methadone as a potent analgesic has been gaining ground in the intensive care setting, such as where it is possible to properly select the group of patients who will benefit from the drug, as well as monitoring of possible complications. the objective of this study is to evaluate the safety of the use of methadone in critically ill patients in a large hospital. methods: a retrospective analysis of all patients who used methadone in a neurological intensive care unit for a period of four months and the results were evaluated. results: in the four-month period, patients used methadone during intensive care. % of the patients were male, with a medical age of . ± . years. the main indication for the use of the medication was for analgesia in patients who were weaned from mechanical ventilation. the mean time of use was . days. in all cases evaluated, analgesia was effective, with methadone being used alone or in combination with other drugs, according to an institutional protocol. among the complications found, patients presented hypotension ( %); presented bradycardia ( %); presented constipation ( %); had excessive sedation ( %) and had other complications. all complications were reversible. patients of the studied population died, however, without correlation with the use of methadone. conclusions: the use of methadone, in the studied group, was effective in the control of analgesia, with no impact on patient safety when used in a monitored way. introduction: renal colic is a common disorder which presents with dramatic acute pain. providing rapid relief, using effective pain control medications is the clinical priority to treat the patients. this study aims to compare the effect of iv ketorolac versus morphine in releasing renal colic pain by measuring pain severity and duration and also the need for additional doses. methods: we performed a clinical pilot cohort study from during on patients with the clinical diagnosis of renal colic who recruited from the emergency department (ed) of rasool-e-akram hospital and firoozgar hospital. participants who were candidate to receive either morphine or ketorolac were divided into two groups who received either mg ketorolac iv or mg morphine. the pain was evaluated using the visual analog scale (vas) at four time points: before drug injection (vas- ), minutes (vas- ), minutes (vas- ), and minutes (vas- ) after injection. in cases when the pain was not controlled with the first injection of drug beyond minutes; additional doses (rescue) were injected. statistical analyses were performed using spss . results: one-hundred-fifty patients treated with morphine and ones with ketorolac were studiedthe group treated with morphine scored on average . before the injection, which was roughly . points higher than ketorolac. morphine reduced patients' vas scores more intensely (median: , iqr: versus median: , iqr: ; p value< . ). in general, patients treated with morphine were more likely to need a second (rescue) dose, when compared to ketorolac group ( . % vs %, p value= . ). conclusions: morphine is a better option for pain release in cases of renal colic. ketorolac released the pain to an acceptable level; but, because of its slower action time, we recommend it in cases with moderate than severe pains. effect of analgesics on cardiovascular and hormonal response to operative trauma d loncar stojiljkovic, mp stojiljkovic sgh, , serbia critical care , (suppl ):p introduction: objective of this study was to compare the effects of two analgesic regimens, one opioid and one non-opioid, on cardiovascular and hormonal reaction of patients undergoing elective surgery under general endotracheal anaesthesia. methods: a total of elderly patients, asa , scheduled for elective abdominal surgery were assigned to receive on induction a single dose of either fentanyl ( . mg, + . mg) or a fix combination of etodolac and carbamazepine (novocomb, dose mg+ mg iv bolus). haemodynamic parameters and concentrations of prolactin cortisol and growth hormone (gh) [ ] were determined at critical points and h after operation. results: both fentanyl and novocomb blocked the hypertensivetachycardic response to surgical trauma. cortisol was a more appropriate endocrine marker of stress than prolactin or gh since fentanyl as an opioid analgesic increased secretion of prolactin [ ] , while carbamazepine from novocomb did the same with gh [ ] (figs. & ) . conclusions: cortisol plasma concentration correlates positively with cardiovascular parameters in patients undergoing elective abdominal surgery who received fentanyl or novocomb as intraoperative analgesic. its suppression is better marker of analgesia than prolactin and gh. volatile anaesthetic consumption and recovery times after long term inhalative sedation using the mirus system -an automated delivery system for isoflurane, sevoflurane and desflurane introduction: the new mirus system as well as the anaconda uses a reflector to conserve volatile anaesthetics (va) [ , ] . both systems can be paired with icu ventilators, but mirus features an automated control of end-tidal va concentrations (etva). we compare feasibility and recovery times for inhalational long term sedation with isoflurane (iso), sevoflurane (sevo) or desflurane (des). methods: asa ii-iv patients undergoing elective or emergency surgery under general anaesthesia were included. patients were randomized into three equal groups iso, sevo and des. the mirus system was started with a targeted etva of . mac. we used the puritan bennett icu ventilator and performed a spontaneous breathing trial. if successful, the target concentration was set to mac and recovery times measured. results: patients were comparable in demographics, tidal volume, respiratory rate and sedation time (total h: iso ± h; sevo ± h; des ± h; p= . ). in all patients, a mac of . was reached. conclusions: mirus could automatically control end-tidal va concentrations in ventilated and spontaneously breathing patients. the recovery times are only prolonged in the iso group and could be shortened by removing the reflector. the higher etva required for a . mac using des and sevo were associated with an increased va consumption. introduction: intranasal analgesia is increasingly used in order to relieve pain in the emergency department. this non-invasive approach avoids discomfort, stress and risks related to the parenteral route of administration. the objective is to compare intranasal (in) fentanyl versus any parenteral opioid (intravenous, subcutaneous, intramuscular) for the effectiveness of acute pain relief in an adult population. methods: the systematic review was registered in prospero (crd ). the research of articles was conducted through embase, central, and medline databases. randomized clinical trials comparing the effectiveness of in fentanyl to any parenteral opioid for acute pain relief (<= days) in an adult population (>= years old) were considered for inclusion. studies on breakthrough cancer pain were excluded. two different reviewers extracted data and analyzed the quality of the selected articles. the main outcome was the difference between pain levels before and after analgesia. the effect size was approximated using the inverse of variance of standardized mean differences, based on a random-effect model. heterogeneity was quantified using a test of i . results are presented with % confidence interval. results: eight randomized clinical trials with cohorts and a total of patients were selected ( in fentanyl vs control group). selected articles contained a low risk of bias. there is no significant difference between the average levels of pain before and after analgesia comparing the two groups (smd . [ic % - . à . ], p= . ; i = %) (fig. ) . conclusions: in fentanyl is as effective as other parenteral opioid to relieve pain during the first hour of treatment. introduction: the aim of this study is to underline the importance of sedation protocol when performing the pegj procedure in advanced parkinson's disease (pd) patients. research about the use of sedation in endoscopy is getting more and more widespread as to answer to the increasing grade of complexity and duration of endoscopic procedures as to offer comfort to the patient in terms of analgesia, tolerability, and amnesia. sedation is also a way to assure quality and safety examination and to improve its outcome [ ] . methods: this observational retrospective study includes pd patients scheduled for pegj procedure (fig. ) in order to start therapy with duodopa gel. we propose an anesthetic technique (table ) to support pegj with both local anesthesia and moderate sedation so as to provide analgesia and patient's comfort. this technique ensures mean duration of pegj procedure was '± '. mean stay time in recovery room '± '. compared to our old experience, we collected lack of patient's discomfort, anxiety, and memory, high procedure compliance and improvement of the quality of procedure without use of opioids. conclusions: based on our experience, we consider this sedation protocol effective for different reasons: to relieve or abolish patient's discomfort, anxiety, and memory, to ensure compliance with the procedure, to ensure patient's analgesia and patient's safety and, finally to assure procedure's quality and rapid discharge. anyways, a multicentric study should be done to test our protocol. introduction: studies have shown that icu survivors exhibit longterm neurocognitive impairment and perceived reduction in quality of life after icu discharge, but studies examining sleep architecture and sleep disordered breathing (sdb) in icu survivors after icu discharge are scanty. the aim of our study was to assess sleep architecture and sbd in icu survivors. methods: icu survivors were screened for eligibility. inclusion criteria were: age - yrs, mechanical ventilation >= hours, gcs of at the time of hospital discharge. patients with a history of sbd, chronic neuromuscular disorders, chronic restrictive lung disease, congestive heart failure and respiratory failure at hospital discharge were excluded. patients were evaluated within one week after hospital discharge and months later. at both visits patients completed health related quality of life questionnaires (sf and epworth sleepiness scale), underwent a physical examination, lung function tests including maximum inspiratory and expiratory mouth pressures, and an overnight full polysomnography (psg). results: sleep quality at days of hospital discharge is poor, characterized by severe disruption of sleep architecture and excessive sdb, mainly of obstructive type which in % of patients was classified as moderate or severe. although at six months after hospital discharge sleep quality remained relatively poor, significant improvement in n stage and ahi was observed, with more patients to be classified as normal or mild sdb. both at hospital discharge and months later quality of life was reduced but there was no relationship between the health related quality of life and sleep disturbances. conclusions: icu survivors experience significant deterioration in their quality of life status with minor improvement months later and a variety of sleep disturbances that seems to start getting better months later. introduction: disrupted sleep in critically ill patients may be associated with delirium, prolonged stay in icu and increased mortality. polysomnography (psg), the criterion standard method of sleep monitoring, is challenging in icu due to interpretation difficulties, as the patterns defined by the standard classification for scoring sleep are absent in many critically ill patients. the aim of this study was to investigate if the presence of atypical patterns in critically ill patients' psg is associated with poor outcome measured by -days mortality in conscious critically ill patients on mechanical ventilation. methods: psgs (median duration hours) recorded in conscious critically ill mechanically ventilated patients were scored by an expert in sleep medicine blinded to patient characteristics. standard sleep scoring classification was used if possible. otherwise, modified classification for scoring sleep in critically ill patients proposed by watson et al. was applied [ ] . the association of sleep patterns (normal or atypical) and micro-sleep phenomena (sleep spindles and kcomplexes) with days mortality was assessed using weibull model by calculation of hazard ratios (hr). results: hr analysis showed twice as high mortality risk in case of atypical sleep compared to normal sleep; this was however not significant (hr . ; % ci . - . ; p= . ). the presence of sleep spindles in psg significantly reduced mortality risk to / (hr . ; % ci . - . ; p= . ). the presence of k-complexes in psg reduced mortality risk to ½, though not significantly (hr . ; % ci . - . ; p= . ). conclusions: the absence of normal sleep characteristics in psg in conscious critically ill patients on mechanical ventilation is associated with poor short-term outcome. antipsychotics (aps) prescribing in critically ill delirious patients, the reported versus the perceived practice e almehairi , g davies , d taylor introduction: aps are the most commonly prescribed drugs in hyperactive/mixed delirium and agitation in critical care (cc) [ ] . yet evidence in cc is scant, there are known adverse effects (ade) and prescription is out with the european license. meticulous observation of ap selection, prescribing and safety, alongside delirium assessment/plan is essential to gain new knowledge and patients. when accompanied by prescribing clinicians perspective of delirium ap treatment results are more interpretable. we conducted a two-part single centre cohort study that aimed to describe/compare real to perceived delirium assessment/plan, aps prescribing and safety in cc adult patients at gstt. methods: part : a prospective survey, of cc prescribing clinician's beliefs and attitudes to delirium assessment/plan, aps prescribing and safety over previous months. part : a meticulous audit of aps prescribing and safety and delirium/agitation assessment and plan, over period of months. results: part survey. of prescribers ( . %) completed survey. % of reported using aps to treat delirium, with % selecting atypical aps as first option. part audit. there were admissions to cc. aps were prescribed in . % ( prescription), . % ( prescription) were in delirium/agitation patients (table ) . survey (vs.) audit: in the survey % reported daily delirium screening whereas only . % undertook daily screening in audit (fig. ) . higher quetiapine and lower iv haloperidol maximum daily dose were prescribed in audit in comparison with survey reported doses ( table ) . lead ecg was used to monitor ap ade. in survey % reported assessing ecg once or more daily. audit revealed only % actually did so (fig. ) . conclusions: authors believe perceived vs actual can identify key areas for quality improvement (qi). major differences were in delirium assessment/plan and safety monitoring sedation practices in turkish icus, the aim was to provide knowledge on this matter. methods: an electronic survey form was generated with google forms. first part of the form included questions about demographics, and choices and routines of sedation administration. this part mostly contained multiple choice questions, which more than one choice could be indicated. second part was comprised of some statements to investigate the attitudes of physicians, which were indicated on a five-point likert scale. the link for the survey was posted to all email addresses registered in the turkish society of intensive care member database. results: of members, ( %) completed the survey form. demographics are given in table . sedation was generally applied by the physicians ( %). the indications were mechanical ventilation ( %), agitation ( %), seizures ( %), anxiety ( %), delirium ( %). drug choices of the respondents are shown in fig. . sedation level was evaluated daily by % of respondents, mostly using ramsay scale ( %). daily established sedation level was indicated in . %, and daily interruption of sedation was indicated in . % answers. sedation protocol was not used in . % of the answers. analgesics applied commonly, while % routinely evaluated pain and visual analogue scale (vas) was the preferred method in % of the answers. . % of physicians indicated routine use of neuromuscular blockers. in . % answers routine evaluation for delirium was indicated, mostly using cam-icu.when the knowledge of sccm guideline pain, agitation and delirium management, % indicated a positive answer.the respondents indicated their opinion for some comments on sedation, the answers are shown in the table . conclusions: it may be concluded sedation practices may need to be improved by increasing awareness on novel concepts in this area. fig. (abstract p ) . the prediction-corrected vpc plots for dexmedetomidine pk. the vpc plots show the simulation-based % confidence intervals around the th, th, and th percentiles of the pk data in the form of blue ( th) and gray ( th and th) areas. the corresponding percentiles from the prediction corrected observed data are plotted in black color methods: a prospective multinational cohort study was performed in icus in sweden, denmark and the netherlands. all adult patients with an icu stay >= hours were screened for inclusion. primary outcome was psychological problems three months after discharge from the icu, assessed with the questionnaires hospital anxiety and depression scale (hads) and post-traumatic stress symptoms checklist- (ptss- ). a subscale score > in the hads and a score > in the ptss- part b indicate clinically significant symptoms of depression, anxiety and pts and was considered an adverse outcome. we collected data on known risk factors for psychological problems post-icu. univariable and multivariable logistic regression modelling of risk factors was performed in order to create an instrument to be used bedside, predicting individual risk for adverse psychological outcome. results: patients were included and ( %) returned follow-up questionnaires. % of patients scored above the predefined cut-offs having symptoms of depression, anxiety or pts. age, lack of social support, depressive symptoms and traumatic memories at discharge remained significant after multivariable modelling and constituted the screening instrument ( table ) . the predictive value of the instrument was fairly good with an area under the receiver operating characteristics curve (auroc) of % (fig. ) . we developed an instrument to be used at icu discharge, predicting individual patients' risk for psychological problems three months post-icu. the instrument can be used as a screening tool for icu follow-up and enable early rehabilitation. improving the patients hospitalization experience in an intensive care unit by contact with nature w yacov , y polishuk , a geal-dor , g yosef-hay kaplan medical center, rehovot, israel; kaplan medical center, rehovot, israel critical care , (suppl ):p introduction: the intensive care unit is characterized by a noisy and threatening work environment using multi tecnologic equipment.the staff works very intensively caring for very complicated and unstable patients.whilst caring for the patients physical needs one must not forget the patients mentally needs.the improvement of the patients hospitalization experience by changing the environment improves the mood and responsiveness to treatment gives hope for healing to the patient and family. methods: a quality questionare with open questions relating to the subjective sensory experience of the patients and their families. the patients were transferred to the "sun balcony" for a period of - minutes having their families alongside. music was transmitted and the patients were offered food and drinks if their condition allowed. results: the patients reported a significant improvement of hospilizaton experience following their exposure to the "nature environment". patients described the sensory experience as a positive, pleasant, quiet and relaxing experience. the contact with the sun, wind, sky and grass and being outside on the "sun balcony" allows a disconnection from the threatening icu environment. conclusions: the "sun balcony" gave the patients a sense of hope and wish for healing. mobilizing complicated patients to the "sun balcony" is a big challenge which requires planning and preparation by the staff. yet by the proactive and creative thinking of the staff the patients are tranferred to the "sun balcony" to give them encouragement, a feeling of well being and hope for recovering. this intervention is costless and a routine procedure in the intensive care unit. introduction: long-term psychological outcomes of patients(pts) discharged from icu represent an emergent relevant matter of concern.systematic reviews refer prevalence of %- % for anxiety, %- % for depression and %- % for posttraumatic symptoms in ards patients.the onset of psychiatric symptoms after discharge, might be associated with patient's competence to process memories related with hospitalization and with memories. methods: we selected ards pts in icu of a tertiary centre (jan -dec ) at least hour, for months follow-up and pts for months follow-up after discharge. the psychopathological assessment was performed using scale as: impact event scale-revised (ies-r), hospital anxiety and depression scale (hads), icu memory tool (icu-mt). results: mean age was . ± . at months follow-up and , ± , at months. ptsd symptoms was fund respectively in % and . % pts at and months; anxiety symptoms % and . % of pts;depression symptoms in % and . %. significant correlations were fund between psychopathology at months and memories of icu: hads anxiety with delusion memories (r . ,p< . ); hads depression with factual (r . ,p< . ), feeling (r . ,p< . ) and delusion memories (r= . ,p< . ); feeling (r . ,p< . ). at months significant correlations was fund between hads anxiety and feeling memories (r . ,p< . ); ies-r and factual (r . ,p< . ), feeling (r . ,p< . ) and delusion memories (r . ,p< . ). the results of the study confirmed the importance of assessing psychopathology after discharge from icu. the onset of these symptoms appeared to be mediated by specific traumatic memories related with icu hospitalization. the main clinical recommendation emerging from this study is to investigate psychiatric history and develop psychological strategies to manage frightening or delusional experiences during icu stay. introduction: the aging of the population is a fact. the subgroup of very old (>= years (ys)) is the one that increases the most rapidly. intensive care unit (icu) admission of these patients is an ongoing discussion worldwide. our icu has designed the voolcano aiming its characterization and reviewing outcomes, to find some predictive indicators. the purpose of this first analysis is to evaluate specifically the group of very old patients (volds) admitted to a tertiary portuguese hospital icu. methods: retrospective observational study was preformed, included all volds admitted in icu during years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . demographic data, admission diagnosis, severity scores, charlson comorbidity index, length of stay and outcomes were considered. data analysis used spss software. results: we found a total of admissions. the median age was . ys with iqr ; mostly male with medical admission diagnosis (sepsis and respiratory failure due to infection). there was a median acute physiology and chronic health evaluation ii of (iqr ) and simplified acute physiology score ii of (iqr ). median charlson comorbidity index was . (iqr ). median length of stay was . days (iqr . ). concerning outcomes, we found intra-icu mortality of %; intra-hospital after icu discharge mortality of % and mortality after hospital discharge of %. identified as predictors of intra-hospital mortality the use of mechanical ventilation (p < . ), urgent surgical admission or medical admission versus schedule surgical admission (p < . ) and the absence of oncologic disease (p = . ). on multivariate analysis, only mechanical ventilation (p = . , hr . , % c.i. . - . ) and urgent surgical admission versus schedule surgical admission (p = . , hr . , % c.i. . - . ) remain significant. conclusions: recognizing the need to understand what is the biologic|funcional age (opposed to chronologic age) would be beneficial in the selection of volds to icu admission. organ failure and return to work after intensive care s riddersholm , s christensen , k kragholm , cf christiansen , bs rasmussen aalborg university hospital, aalborg, denmark; aarhus univeristy hsopital, aarhus, denmark critical care , (suppl ):p introduction: organ failure is associated with an unfavorable prognosis. nevertheless, the association with capability to return to work remains unclear. therefore, we investigated the association between organ support therapy as a proxy for organ failure and return to work in a nationwide cohort of icu survivors. methods: we linked danish registry-data on icu-and hospitalsurvivors working prior to hospital admission during - , - years of age, with an icu length of stay > hours and not previously treated with dialysis, to data on return to work. we reported cumulative incidences (chance) of return to work with death as competing risk, and compared rate of return to work in adjusted cox regression-models by number of organ support therapies including renal replacement therapy, cardiovascular support and mechanical ventilation and stratified on primary hospital-admission diagnosis. results: of , patients - years of age, % ( , ) survived to hospital discharge (tables and ). among these, the chance of return to work was . % ( % ci [ . - . ]) within two years (fig. (fig. ) . when stratified an increasing number of organ support was associated with a decreased chance of return to work among patients with infection, respiratory failure or trauma but not among patients with neoplasms or endocrine, gastrointestinal and cardiovascular diagnoses. introduction: mortality rates among people with moderate to severe learning disabilities (ld) are times higher than in the general population [ ] [ ] [ ] . this study was designed to examine critical care admissions with learning disabilities in terms of mortality, demographics and reason for admission. methods: data was retrieved for adult patients (> years old) between sept and . the ward watcher database for icus within surrey and sussex healthcare nhs trust was interrogated using search words including, learning disability, cerebral palsy, down's syndrome and autism. results: there were episodes ( . % of all admissions) of patients admitted with ld. % of the ld patients had more than admission. respiratory is the most common system affected ( %). logistic regression suggests survival is highest in those with a neurological reason for admission (p= . ). proportionally ld patients were young compared to the total population (fig. ) . we found that mortality appears to increase rapidly in those over years of age and overall mortality is greater in those with ld (fig. ) . conclusions: from april all uk trusts will be required to complete a detailed review for patients with ld who die whilst in hospital care. this follows mencap's report 'death by indifference' which exposed deficiencies in the care of people with lds who died whilst in nhs care and the subsequent confidential inquiry into premature deaths of people with learning disabilities. in our population, ld patients have an earlier death than the general population and the overall mortality from critical illness is greater. a multidisciplinary approach at the emergency department to admit potential organ donors for introduction: the aim of the present study is to improve the recognition of potential organ donors by implementing a multidisciplinary approach for organ donation at the emergency department (ed) [ ] . methods: in a prospective intervention study, we implemented this approach in six hospitals in the netherlands. when the decision to withdraw life sustaining treatment was made at the ed in patients with a devastating brain injury without contra indications for organ donation, an intensive care unit (icu) admission for end-of-life care was considered. every icu admission for end-of-life care was evaluated. interviews were conducted with emergency physicians, neurologists and icu physicians according to a standardized questionnaire. this interview focused on medical decisions that were made and difficulties arising during hospitalization. results: from january to november data were collected on the number of patients admitted to the ed with acute brain injury. in total, potential organ donors were admitted to the icu for end-of-life care. donation was either requested in the ed ( %), icu ( %), neurology department ( %), or donation was not requested ( %). out of donation requests, families ( %) consented to donation. this led to successful organ transplantations. in four of these patients family consent was obtained to intubate them solely for the purpose of organ donation. the most important points raised during the interviews were: explaining the non-therapeutic icu admission to the family, the location where donation should be requested (ed/icu) and utility of icu resources. conclusions: a close collaboration between the ed, neurology department and icu is necessary and achievable in order not to miss potential organ donors in patients with acute brain injury with a futile prognosis in the ed. introduction: there is a relationships between intensive care patients losing the ability to speak and negative emotions [ ] . nursing care is challenging when patients are unable to verbalise and factors like pain and comfort are misjudged.. our intensive care unit has introduced a communication tool intelligaze grid which enables patients with primary motoric disorders to communicate their needs. a quality improvement study reviewed the methods of communication and interactions that our nurses use for patients who are ventilated. the objective of the study was to promote areas of improvement with communication in the icu. methods: we used a mixed-methods qualitative and quantitative study to evaluate the communication tools used by our nursing staff to interact with ventilated patients. a convenient data sample for all nurses working on particular dates was collected which is % of the nursing workforce. the study has been approved as a quality assurance project by the human research ethics committee of nepean hospital. results: sixty registered nurses ( %) participated in the study. the most common communication tool used with patients was closed yes/no questions( %), followed by hand gestures( %), magnetic writing board( . %), lip reading( . %) and alphabet board( . %). the descriptive analysis identified challenges were levels of sedation, weakness, non-english speaking patients and delirium. a significant finding was that only % of nurses identified the patients message being understood and % acknowledged listening as effective communication. conclusions: communication is a vital aspect of icu nursing and is achieved through dialogue and specialised skills. the study concluded that icu nurses find it difficult to communicate effectively with ventilated patients. the introduction of intelligaze grid has improved patient communication and promotes holistic nursing care. p withdrawn introduction: substantial variability in eolp occurs around the world [ ] . differences in eolp were previously reported in europe in the ethicus i study [ ] . methods: icus worldwide were invited to participate through their country societies. consecutive admitted icu patients who died or had treatments limitations during a month period from . . to . . were prospectively studied. regions included north, central and southern europe (ne, ce, se), north and latin america (na, la), asia (as), australia (au) and africa (af). previous eolp definitions were used [ ] . results: icus in countries participated enrolling , patients. figure shows differences in eolp by region and figure in patient competency by region. conclusions: worldwide differences included more cpr in af, la, and se and less cpr in ne, au and na. there was more withdrawing (wd) in ne and au and less wd in la and af. more patients were competent in au and ne and less were competent in af, se and la. introduction: the decision of end-of-life care in the icu is very tough issue because the law, ethics, traditions and futility should be concerned involving family's will. especially, stop or withdraw therapy is a quite difficult operation in japan because of our traditions. recently there are few legal issues due to some guidelines. our hypothesis is some difference over time exists in thoughts about end-of-life care in the icu. the purpose of this study is to know changing methods: a questionnaire survey, which consists of questions with optional answers related to the thoughts of participants about end-of-life care of hopeless or brain death patients, was performed to nurses and doctors in our icu. the questions were; whether accept to withdraw therapy or not and with family's will, whether positive or not to donate of organs from brain death patient, necessary of icu care for brain death patient, feel guilty and stress for doing stop or withdraw therapy. the optional answer has gradations from 'yes' to 'no' for all questions. it was guaranteed to be anonymous for them in the data analysis. we conducted entirely same survey in . the answers between in and in were fig. (abstract p ) . patient mental compentency by region kidney disease: improving global outcomes acute kidney injury working group references nice clinical guidelines: idiopathic pulmonary fibrosis in adults: diagnosis and management references . zambon et al annual update in inten care references references references damage control management in the polytrauma patient crash- trial collaborators guidelines for the management of severe traumatic brain injury references references references . soar et al; european guidelines for resuscitation we acquired the confirmed date of death from the finnish population register centre database and gross -month healthcare costs from the hospital billing records and the database of the finnish social insurance institution. results: a total of patients were included in the study and were alive at months. median (interquartile range, iqr) -hour sofa score was ( - ) in -month survivors and ( - ) in non-survivors. the sofa score had an area under receiver operating characteristic curve of . ( % ci . - . ) for predicting -month mortality. in multivariate regression model with age and gender, sofa score had an odds ratio, or ( % confidence interval, ci) of . ( . - . ) for predicting -month mortality. all except cardiovascular sub-score also had p predictive factors for secondary icu admission within hours after hospitalization in a medical wards from the emergency room m cancella de abreu hôpital saint antoine p acquired neuromuscular weakness in eldery patients with femoral bone fracture, could we decrease the incidence? d pavelescu, i grintescu, l mirea emergency hospital floreasca p adasuve enables quicker dispositions of acute psychiatric patients in the emergency department k hesse , e kulstad , k netti , d rochford isi web of science and clinicaltrials.gov. data extraction: eligible studies were case reports and randomised controlled trials (rcts) that evaluated the effects of drug incompatibilities in critically-ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. data synthesis: twelve articles met the selection criteria (fig. ). the six articles reporting rcts concern only four rcts. rcts were single-centre studies comparing infusion with or without filter. two of them included adult patients. the others included pediatric and neonatal intensive care unit patients. primary endpoints were systemic inflammatory response syndrome (sirs), organ failure, overall complication rate, bacteremia, sepsis, phlebitis and length of stay. results: the results are mixed with one rct reporting a reduction in sirs, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of stay. the six articles on case reports show different drug incompatibility situations european directorate for the quality of medicines & healthcare of the council of europe. guide to the quality and safety of organs for transplantation p current status and problems of organ transplantation before and after the enactment of the revised organ transplant law in p morale: introducing the anaesthetic trainee confession session results: of total patients admitted during study period, were eligible for study; . % were males and ( %) patients were transferred during after-hour. mean age of two groups (daytime vs. after-hour . ± . vs. . ± . years) was similar(p= . ) methods: retrospective analysis of prospectively collected data between october to february of a tertiary care icu in india. patient data collected on all consecutive icu admissions. primary and secondary outcomes were icu los and hospital mortality respectively. icu patients payer status were categorized as self-paid, corporate (paid-fully or partially-by-employer), and insurance (paid-fully or partially-by-third-party-payer). all analyses were adjusted for illness severity and icu support (vasopressor use, mechanical or noninvasive ventilation, blood transfusion). results: of patients admitted during study period significantly higher number of patients received icu support in self-paid and corporate groups compared to insured group ( . %and . % vs. . %; p= . ) braden scale is predictive of mortality in critically ill patients, independent of its efficiency as a predictive tool of pressure ulcer risk d becker , tc tozo discharged and died ( . %). the turnover rate of the icu was . . the occupancy rate calculated during the period was . %. there were only readmissions ( . %) within hours of admission. regarding the hospital evolution of these patients we had exits in this period, ( . %) were discharge and ( . %) were deaths, of these, ( . %) were after discharge from the icu. the mean saps score was . (ranging from to ). the probability of death, according to the standard equation was . % and the adjusted for latin america of . %. conclusions: the icu has a high occupancy rate and rotation turnover, as well as a higher mortality than predicted by the score. these indicators show the great population demand that we have and alert to the impact on the sustainability of the unit and patient safety methods: research/ethics approvals were obtained. surveys, interviews, round tables, targeted delphi exercises and non-participant observation were conducted across four adult critical care units, involving professionals. these methods were used to describe the baseline 'paper-based' workflow/inter-professional communication systems; and semi-quantitative quality improvement measures. secondly, critical care services worldwide were visited to generate a database of experience, lessons and models of optimised informatics delivery. results: key challenges at baseline in relation to workflow/communication information transfer between different healthcare professionals site visits revealed the importance of human resources; lead time technology advances; the prioritisation of nursing workflow and pharmacy medicines/prescribing database creation/testing and the importance of the hardware interface and ergonomics. improvements included patient safety/experience p work-related stress amongst doctors and nurses in intensive care, a&e, acute medicine, anaesthetics and surgery i lever *, h nawimana introduction: work-related stress is associated with anxiety, depression, days off-work, errors and 'near misses' [ ]. our objective was to references . kerr et al p pre-existing cognitive dysfunction in critically ill patients and the incidence of delirium during icu treatment p validation of the sos-pd scale for assessment of pediatric delirium: a multicenter study e ista , b van beusekom children's hospital, rotterdam, netherlands; umc groningen -beatrix children's hospital p introduction: delirium in critically ill children has gained attention in the last few years and the incidence seems higher than anticipated before. the sophia observation withdrawal symptoms-pediatric delirium (sos-pd) was developed to combine assessment of delirium with iatrogenic withdrawal syndrome, two conditions with overlapping symptoms. the current study evaluates the measurement properties of the pd component (pd-scale) of the sos-pd scale. methods: in a multicenter prospective observational study in four dutch picus, patients aged months to years and admitted for more than hours were included. these patients were assessed with the pd-scale three times a day. criterion validity was established: if the pd total score was or higher the child psychiatrist was consulted to confirm the diagnosis of pd using the diagnostic and statistical manual-iv criteria as the "gold standard". the child psychiatrist was blinded to outcomes of the pd-scale. in addition, the child psychiatrist assessed a randomly selected group of patients to establish false-negatives the pediatric delirium scale had an overall sensitivity of . % and a specificity of . % for a cut off score of points. the positive predictive and the negative predictive value were respectively, . % and . %. the icc of paired nurse-researcher observations was . ( % ci . - . ). in total patients were diagnosed with delirium during the picu stay. conclusions: the pd scale shows a good validity for early screening of pd. so, the pd scale is a valid and reliable tool for nurses to assess delirium in critically ill children p frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically ill neonates, children and adults: a systematic review of clinical trials ma duceppe , m perreault we also examined the grey literature. we included studies reporting frequency, risk factors or symptomatology of iatrogenic withdrawal of opioids, benzodiazepines (or both) in critically ill patients. we considered all study designs except case reports and case series. pairs of reviewers independently abstracted data and evaluated methodological quality using the cochrane collaboration tool, newcastle-ottawa or quadas- . pros-pero (registration number: crd ). results: we identified unique citations through database search and full-texts were assessed for eligibility. thirty-three studies were included; the majority were observational and only a few included adults proportion of perfused small vessels at to p use of methadone in critically ill patients p the use of intranasal fentanyl versus parenteral opioid for acute pain relief in adults: systematic review and meta-analysis p sleep disorders in icu survivors c alexopoulou, a proklou p impact of dexmedetomidine on the duration of invasive mechanical ventilation in pediatric intensive care patients -dexped trial m genest peri-operative dexmedetomidine in high risk cardiac surgerymulticentre randomized double blind placebo controlled pilot trial y shehabi we compared vasopressors, inotropes, pacing and cardiac complications for safety and severe acute kidney injury (aki), dialysis and death (major adverse kidney events make) for efficacy. methods: adults patients undergoing cardiac surgery [combined (valve + coronary bypass) or complex] or with preoperative glomerular filtration rate (egfr) < mls/min/ . m were included. salvage or transplant surgery, dialysis, egfr < mls/min/ . m and those on extracorporeal support were excluded. dex ( . ug/kg/hr) was started at induction of anaesthesia and continued up to hours after surgery. equivalent volume of saline was given to control group. standard intra and post-operative care was provided. results: we randomized patients in the dex group and in the placebo (pgp). the mean(sd) age . ( . ) and egfr . ( . ) in all patients. no significant differences at baseline. in the dex, . % underwent complex surgery vs . % pts in the pgp. the mean(sd) bypass time and aortic clamp was comparable ( ) and ( ) min. the vasopressor requirements methods: nine tracheostomized copd patients ready to be weaned from ventilation were enrolled.for each patient, the sleep architecture was studied by polisomnography (sleep profiler-advanced brain monitoring) performing recordings:basal registration, continuos infusion of propofol or dexmetomidine from pm to am. rass target was - /- . results: the mean dose was . mg/kg/h for propofol and . mcg/ kg/h for dexmedetomidine.quantitative analysis showed, a statistically significant longer total sleep time (tst) and less sleep fragmentation (awakenings/hour) using dexmedetomidine. qualitative analysis showed non statistical differences between the two regimens: longer n and n stage with propofol and a longer n and rem phase with dexmetedomidine. furthermore, a reduced number of dosage adjustment was needed during dexmedetomidine sedation methods: a -year prospective observational cohort analysis was performed. all patients consecutively admitted to the medical or surgical icu or burn unit of a university hospital with an icu-los of >= days were included. qol was assessed at baseline (bl) and at months (m), year (y) and lt (median . years (iqr . - . )) after icu discharge with eq- d and sf- surveys. at lt, questions about daily life were added. in subanalysis, we compared groups (g and g ) based on median icu-los. results: patients ( % men) with a median age of , an apa-che ii score of and a sofa score of at icu admission were included. patients ( . %) were lost to follow-up. median icu-los in the cohort, g and g was (iqr - ), (iqr - ) and days (iqr - ) respectively. during icu stay, g had significantly more and longer need for any type of organ supportive therapy (p< . ) and had higher maximum sofa scores (p< . ). icu, hospital, m, y and lt-mortality rates in the cohort were , , , and % respectively. these rates were similar in g and g and the outcomes were assessed by telephone interviews at month after discharge. factors associated with readmission and post icu mortality are presented as odds ratios. results: during the study period, elderly patients were discharged alive. the follow up was possible for ( . %) patients. predictors of one-month readmission in univariate analysis were coronary disease (p= . ), sapsii (p= . ) and decline in functional status (p= . ). in multivariate analysis ) were the independent predictors of early readmission. mortality rate at month was . %. risk factors of onemonth mortality in univariate analysis were sapsii (p= . ), heart rate at discharge (p= . ), world health organization(who) performance status at discharge (p= . ) and decline in functional status (p= . ). in multivariate analysis p= . ), decline in functional status (or, . ; %ci comorbidities don't have an important impact on short term outcome after critical illness, which is most strongly predicted by severity of illness and physiological reserve at discharge. p characteristics and outcome of elderly patients in intensive care unit i coelho health inequalities & people with learning disabilities in the uk: emerson & baines cipold p comparison of home and clinic follow-up visits after hospital discharge for post-icu patients: a cross-sectional study r rosa , c robinson , p berto , p cardoso , l biason in a post-icu follow-up service which is reference for tertiary hospitals in southern brazil. post-icu patients with a icu stay > h (for medical and emergency surgical icu admissions) or > h (for elective surgical icu admissions) who were discharged alive from the hospital were invited by telephone to participate in a clinic-based multidisciplinary appointment months after icu discharge. home visits were offered to patients who claimed impossibility to attend the clinic appointment due to the severity of their disabilities graph of total mortality in ld vs all patients fig. (abstract p ). graph of admission age in ld vs all patients references p evaluation of family satisfaction instrument in multicultural middle eastern critical care units a p breaking bad news in the emergency department: a randomized controlled study of a training using role-play simulation i bragard , jc servotte , i van cauwenberghe p introduction: this is a randomized controlled study aiming to assess the impact of an e-learning and a -hour role-play training in breaking bad news (bbn) each assessment included a video-recorded role-play with two actors playing the role of relatives, and questionnaires. two blinded experts rated the videos. results: out of participants, % were trainees and % were anaesthesia residents. eg (n= ) and cg (n= ) were not different at baseline on the several variables. there were significant group and time interaction effects. only eg increased their selfefficacy p deficits of end-of-life care (eolc) perceptions among physicians in intensive care units managed by anesthesiologists in germany m weiss , a michalsen , a toenjes p ethicus end-of-life practices (eolp) in worldwide intensive care units (icus)-the ethicus ii study a avidan p multidisciplinary team perceptions about terminal extubation in a teaching hospital in brazil s p changing thoughts about end-of life care in the icu; results of a survey the feel guilty for withdraw therapy in nurses was also significantly decreased in years ( % vs. %, p< . ). conclusions: some of end-of-life thoughts in the icu were shown differences in nurses compared with years ago introduction: workload resulting from in-flight emergencies has not been quantitatively analysed in the literature. for hospitals local to major airports, this may have significant financial implications. methods: review was carried out of all cases admitted to east surrey hospital from gatwick airport over a year period beginning in . data were collected by interrogating the icnarc database. demographics, presenting pathology and length of stay for each patient were recorded. in addition, the cost of care for patients admitted during was calculated using recent median figures for intensive care admission (local ccg rates). results: since , patients were admitted from gatwick airport. this was approximately % of our critical care admissions. the mean (sd) age was . ( . ) years, and the median [iqr] length of stay [ . - . ] days. around % of these patients were non-uk or eu nationals and therefore not entitled to nhs care. reasons for admission included cardiac ( . %), respiratory ( . %), central nervous system ( . %), and gastrointestinal issues ( %). during , patients were admitted resulting in a total of . patient days in critical care. the total cost attributable to this group of patients was calculated to be £ , . conclusions: there is a substantial additional financial burden on hospitals that regularly receive admissions from major airports simply due to their geographical location. there is no additional funding available for providing this service. the pattern of presenting conditions in our population is similar to that seen in previous reports describing inflight emergencies [ ]. given the increasing accessibility of air travel and the economic pressures on healthcare providers, further analysis of the financial impact of this patient group on certain hospitals would be welcome. methods: we developed a monte-carlo simulation [ ] with separate referral rates for emergency, elective, and ventilated patients. bed occupancy is classified according to admission type with a conversion to prolonged ventilated stays at a rate of % [ ]. we used data from our neurointensive care unit to complete the parameters required for the model e.g. beds and , referrals/day. outcome measures were bed occupancy, and failed admissions. we tested two scenarios: increased referral rate ( . /day), and increasing to beds. results: the model simulated our intensive care where we have a high occupancy rate. increasing referral rate led to a consumed icu and an increase in failed admissions (fig. ) . lastly, increasing bed numbers eased pressures with fewer failed admissions. conclusions: we recommend a personalised icu monte-carlo population model for specialist units for a more accurate representation of icu bed occupancy. these icu specific models should be more useful for predicting staff, bed and financial requirements in specialist units where healthcare resources are changing e.g. increasing geographical referral radius. conclusions: better patient flow increased occupancy and standards. staff education and clear protocols are needed to improve patient booking and efficiency. assess stress levels and causes of stress among doctors and nurses at university hospital lewisham and queen elizabeth hospital woolwich. we surveyed staff using uk health and safety executive's management standards (hsems), a -question validated tool which identifies stressful work conditions requiring intervention. methods: we conducted an anonymous survey of doctors and nurses working in intensive care, accident and emergency (a&e), acute medicine, anaesthetics and surgery over six weeks. results were analysed using the hsems analysis tool and broken down into seven areas: job demands, managers' support, peer support, relationships, role, level of control and possibility of change. each area was scored from - ( represents lowest stress). we compared the trust's results against national standards. results: healthcare professionals completed the survey. intensive care had the lowest stress levels and scored above average in all areas (n= , mean . , s.d. . ). this was followed by a&e (n= , mean . , s.d. . ), anaesthetics (n= , mean . , s.d. . ), surgery (n= , mean . , s.d. . ) and acute medicine (n= , mean . , s.d. . ) which had the highest stress levels. when compared to hsems targets peer support exceeded national standards. however, there is a clear need for improvement in staff's ability to control and change their working environment. conclusions: stress levels on intensive care were reassuringly low when compared to other departments as well as national standards. we identified areas that need improvement and with the support of hospital management we will initiate hsems-validated measures to reduce stress. p tools for sepsis-associated mortality in hematological patients and should be studied in larger cohorts.conclusions: our results present clinical data of protocolized pbto -targeted therapy and show that there is room for further optimization. a larger cohort with predefined interventions is needed to proof the effect on longterm outcome after sah. impact of phone cpr on rosc outcome a giugni , s gherardi , l giuntoli introduction: early cardiopulmonary resuscitation (cpr) improves survival in out-of-hospital cardiac arrest, and phone-cpr instructions can increase the number of victims receiving cpr before emergency medical service (ems) arrival. little is known about the impact of cpr phone instructions on the outcome of patients (pts) with return of spontaneous circulation (rosc). the target of this study is to investigate the impact of phone instructions on mortality, and on neurological outcomes of patients who survived an out-of-hospital cardiac arrest. methods: we enrolled pts admitted to icu after rosc following out-of-hospital-cardiac-arrest, from / / to / / ; pts younger than , in-hospital cardiac-arrest-victims, pts who underwent cardiac arrest in health facilities, and missing data records were excluded. written informed consensus was obtained for all pts during follow up. data about comorbility, mortality, neurologic outcome, cpr timing according to utstein style, complications in icu, metabolic state on er admission, were collected. study population was divided into two groups for statistical analysis: pts with immediate cpr guided by phone instructions (phone-cpr group) and those who did not underwent immediate cpr by laic bystanders. data were extracted from icu, ems databases and registered ems phone calls. results: pts met study criteria. phone cpr were given in cases, % of the whole study population. results are summarized in tables and conclusions: phone-cpr significantly reduced cpr-free interval. it correlates with a significative increase in shockable rhythms on ems arrival. there is no significative reduction in mortality and in disability, even if a decrease trend can be observed. phone-cpr seem to be a promising, effective and easy to use tool to improve survival and disability in rosc, and should be widely applied. early hemodynamic complications in cardiac arrest patients-a substudy of the tth- study j hästbacka introduction: our aim was to determine the incidence and severity of hemodynamic complications during therapeutic hypothermia and analyze whether these complications can be predicted from data available on admission. methods: this is a substudy of the tth- study, where cardiac arrest (ca) patients were randomized to receive therapeutic hypothermia treatment for either or h [ ] . hypotension within four days from admission was recorded and defined as mild, moderate, severe or circulatory failure. arrhythmias were recorded and classified as mild, moderate or severe. we calculated the incidence and distribution of severity of the events. we used multivariate logistic regression analysis to test association of admission data with any hypotension or any arrhythmia. results: of all patients, . % had hypotension which was mild in . %, moderate in . %, severe in . % cases. . % had circulatory failure. an arrhythmia was present in % of patients. of these, . % were mild, % moderate and . % severe. bradycardia (n= ), new ca (n= ) and circulatory shock (n= ) were hemodynamic reasons for preterm rewarming. in multivariate analysis age (p= . , or . ) and admission map (p= . , or . ) were significantly associated with hypotensive complications. only use of mechanical compressions was significantly associated with risk for arrhythmia (p= . , or . ). conclusions: hypotension and arrhythmias were frequent in cardiac arrest patients during days - from admission, but mostly mild or moderate in severity. age and admission map were associated with hypotension. only the use of mechanical compressions was independently (negatively) associated with arrhythmias. introduction: in a retrospective study from the pittsburgh clinic, which analyzed survival data from patients admitted to a hospital with a cardiac arrest outside the hospital, it was found that patients with opioid overdose showed significant improvements in neurological status when discharged from the hospital compared with patients who did not receive opioids [elmer j. et al., ] . methods: after local ethic committee approval case-records of patients with cardiac arrest and subsequent resuscitation for the period - in the clinic of traumatology and orthopedics in astana were analyzed. criteria for inclusion in the study were hospital cardiac arrest, trauma to the musculoskeletal system. results: out of case-records, ( . %) patients with out-ofhospital cardiac arrest were excluded. among all hospital stops of blood circulation, we found only successful cpr ( . %). among the patients who were successfully resuscitated, groups were identified: i - patients ( %) who received ketamine or/and opioids before the blood circulation stopped ( - minutes); ii - patients ( %) who did not receive these medicines. the mean age in group i of patients was . ± . years, in group ii - . ± . years (p> . ). patients of the second group had an average life expectancy of . ± . days, with a maximum postresuscitation life of days. patients of the first group were in the hospital for . ± . days (p < . ), with a maximum period of days. in the first group, the final neurologic evaluation according to the glasgow scale was . ± . points, while in the second group it was . ± . points (p < . ). conclusions: a retrospective analysis revealed a better survival and neurological outcome in patients who received ketamine or/and opioids before circulatory arrest.introduction: the revised organ transplant law was enacted in japan in . under the revised law, it is now possible to donate organs with the consent of the family even if the intention of the potential donor is unknown. organs from brain-dead children under the age of can also be donated. methods: the aim of this study was to assess how to provide prompt transplant medical care and improve the donor's condition. this was achieved by clarifying the problems encountered in the process leading to brain-dead organ transplantation at our institute before and after the enactment of the revised organ transplant law. there were cases of organ donation at our institute from january to june . among them, the background factors of cases leading to organ donation were examined. results: the causes of the brain-dead condition were cerebrovascular disease (n = ; subarachnoid hemorrhage, intracerebral hemorrhage), trauma (n = ), suffocation (n = ), cardiopulmonary arrest on arrival (n = ), suicide by hanging (n = ), cardiomyopathy (n = ), and lethal arrhythmia (n = ). the organs donated for transplantation were kidneys, eyes, lungs, livers, hearts, and tissues (i.e., heart valve, bone, and skin). the time lapses were as follows. the number of days from informed consent to family acceptance was . days before the enactment of the revised organ transplant law and . days after the revision. the number of days from informed consent to organ removal was . days before the revision and . days after the revision. even after the enactment of the revised organ transplant law in japan, it still takes about days from informed consent to organ removal, with no current initiatives to shorten the time to organ removal. conclusions: although years have passed since the enactment of the revised organ transplant law in japan, there are still administrative and management problems that need to be addressed to achieve optimal organ transplantation. the financial impact of proximity to a major airport on one critical care unit introduction: in septic patients, increased plasma levels of cell-free hemoglobin (free-hb) are associated with a reduction of perfused vessel density (pvd) of sublingual microcirculation and to adverse outcomes caused by hemoprotein-mediated lipid peroxidation. recent studies show that acetaminophen protects from damage due to lipid peroxidation in sepsis [ ] . the aim of this study is to detect changes in sublingual microcirculation after the infusion of a standard dose of acetaminophen in febrile septic patients. methods: prospective observational study on adult septic patients admitted to our intensive care unit. pre-infusion (t ), minutes (t ) and hours (t ) after the end of the infusion of acetaminophen, sublingual microcirculation was assessed with incident dark field illumination imaging; vital signs, plasma levels of acetaminophen and free-hb were assessed. results: preliminary descriptive analysis on the first patients shows a median sequential organ failure assessment (sofa) score of (interquartile range iqr - ) and baseline temperature of , c°( iqr . - °c). an increase of the proportion of perfused vessels (ppv) was evident both at t and t ( introduction: in common sedation is required during mri for adult uncommunicative patients or those with different psychiatric disorders [ ] . although it can be challenging to obtain the deep sedation level required to prevent the patient's movement while maintaining respiratory and hemodynamic stability. limited access to the patient may pose a safety risk during mri. objectives: to compare efficacy and safety of dexmedetomidine sedation versus propofol during mri in adults.methods: this prospective randomized study was conducted at department of anesthesiology and intensive care at postgraduate institute of bogomolets national medical university (kyiv, ukraine) during - . uncommunicative conscious patients with acute ischemic stroke were included in the study and randomly allocated to groupsdexmedetomidine (d) and propofol (p). the sedation goal was the same in the both group (rass to - ). patients in group d receive dexmedetomidine infusion in dose . conclusions: in this prospective randomized study dexmedetomidine comparing to propofol was associated with higher sedation quality and lower incidence of complication during acute ischemic stroke patients sedation for mri. the usefulness of dexmedetomidine after lung transplantation in intensive care unit. introduction: dexmedetomidine (dex) showed some advantages in the sedation of patients in intensive care unit (icu) [ ] . other studies described efficacity of dex in icu delirium [ ] . the aim of this study was to evaluate the efficacity and safety of dex after lung transplantation in icu. methods: we conducted a prospective monocentric study in our surgical icu between november at november . in the first part of the study (november at november ), lung recipients did not received dex; in the second part of the study dex was used for the sedation in mechanically ventilated patients after lung transplantation. we compared the duration of mechanical ventilation in the two groups and the occurence of adverse effects. results: in total lung recipients were enrolled. there was no difference between the two groups in demographic data, one or double-lung transplants, the cause of lung transplantation and the use of epidural infusion. in the dex group, mechanical ventilation support was hours versus . hours in the other group (p= . ). there was no difference between delirium in the two groups ( / , p= . ). the occurence of adverse events like hypotension and bradycardia was significantly higher in the dex group ( / for hypotension, p= . ; / for bradycardia, p= . ). conclusions: the use of dex after lung transplantation in icu was not more efficience for the mechanical ventilator weaning. lung recipients delirium was significantly the same in the two groups. the most notable effect was the occurence of bradycardia and hypotension in the dex group.introduction: dexped evaluated the impact of a prolonged exposure (>= hours) to dexmedetomidine on the duration of invasive mechanical ventilation (imv), length of picu and hospital stay and use of other sedative agents. methods: dexped is a retrospective cohort study that included patients aged to years, admitted to the picu of the montreal children's hospital between november st and april th , requiring imv and sedative agents for >= hours. patients exposed to dexmedetomidine during imv (n= ) were compared to non exposed patients (n= ) using a propensity score analysis ( : ratio). , and received more opioids and benzodiazepines. however, a secondary analysis redefining exposure as initiation of dexmedetomidine within the first hours from intubation suggested that exposure was associated with a greater short-term probability of extubation, although this study was not powered to perform this analysis. conclusions: dexmedetomidine was associated with a longer duration of imv. however, the association was inversed when patients received dexmedetomidine as a primary sedative agent. it is uncertain whether this difference of associations is due to immortal time bias or clinical features. timing of initiation of dexmedetomidine in relationship to other sedatives may impact patient outcomes and should be considered in the planning of future trials. is an α -agonist which has been increasingly used for analgosedation. despite of many papers published, there are still only a few concerning the pk of the drug given as long-term infusion in icu patients. the aim of this study was to characterize the population pharmacokinetics of dex and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in icu. methods: all the subjects were sedated according to modified ramsay sedation score of - . blood samples for dex assay were collected on every day of the infusion and at the selected time points after its termination. the dex concentrations in the plasma were measured using lc-ms/ms method. the following covariates were examined to influence dex pk: age, sex, body weight, patients' organ function (sofa score), catecholamines and infusion duration. non-linear mixed-effects modelling in nonmem (version . . , icon development solutions, ellicott city, md, usa) was used to analyse the observed data. results: concentration-time profiles of dex were obtained from adult patients ( table ). the dex pk was best described by a twocompartment model (fig. ) . the typical values of pk parameters were estimated as l for the volume of the central compartment, . l for the volume of the peripheral compartment, . l/h ( . ml/min/kg for a kg patient) for systemic clearance and . l/h for the distribution clearance. those values are consistent with literature findings. we were unable to show any significant relationship between collected covariates and dex pk. conclusions: this study does not provide sufficient evidence to support the individualization of dex dosing based on age, sex, body weight, sofa, and infusion duration. seems to reduce the wakefulness time and the sleep fragmentation but, while we haven't found differences in sleep architecture using dexmedetomidine or propofol. introduction: the early mobilization program during intensive care hospitalization presents numerous benefits related to the outcome of the patient. the objective of this study is to evaluate the safety of the implementation of an early mobilization protocol within the first hours of admission and its impact on high functional status of the icu. methods: retrospective study, from march to may , evaluating patients admitted to the neurological icu, assessing the hemodynamic, respiratory and neurological variables in patients submitted to the early mobilization program, consisting of progressive therapeutic activities, including sedestation and orthostatism assisted on the board and evaluated the impact on the functional status/degree of high muscle strength of the icu. results: from march to may , , patients were admitted to a neurological intensive care unit, of whom , were included in the early mobilization program. the mean age of the patients was . years, with saps of . points (estimated mortality risk of . %) and real mortality of . %. during the program, % presented clinical instability, which was promptly reversed in all situations. ninety-one percent of the patients presented maintenance or gain of muscle strength/functional status. conclusions: the application of an early mobilization program within hours of patient admission was shown to be safe, positively influencing the rehabilitation of neurological patients. introduction: given the worldwide rapidly aging of the population, the demand of critical care for elderly is increasing. data on short -term outcomes of elderly patients after icu discharge are sparse. the objective of our study was to assess short term outcomes of elderly after icu discharge and their potential risk factors.introduction: patients aged years or older presently account for approximately - % [ ] of all intensive care unit (icu) admissions in europe. the major challenge nowadays is to admit those elderly patients who will benefit from icu treatment. the objective of this study is to describe the characteristics and outcomes of patients >= years old admitted to the icu. methods: retrospective observational study of all patients aged >= years admitted for > h in . demographic data, admission diagnosis, apache ii and saps ii scores, use of icu resources and mortality were collected. results: patients ( %) were included, with a mean age of , . female gender was more prevalent ( . %). mean length of stay was , days with mean saps ii and apache ii scores of , and , respectively. the most prevalent type of admission was medical, , % (n= ) and from these the main reasons for admission were respiratory disease (n= ; , %) and sepsis (n= ; %). icu mortality rate was , % (n= ), whereas -month mortality was , % (n= ).survival rate was often related with cardiovascular ( [ , %], p<. ) and respiratory diseases ( [ %], p=. ), whereas nonsurvivors were admitted due to sepsis and neurologic causes. mortality rate was independent from the mean length of stay, noninvasive ventilation and renal replacement therapy, but dependent for previously comorbidities. mechanical ventilation was an independent predictive factor of icu mortality (p<. ) and -month mortality (p=. ). conclusions: nearly % of patients aged >= years were discharged alive from icu, and less than % survived months after icu admission.our study revealed a better prognosis for admissions due cardiovascular and respiratory diseases. efforts should be done to identify earlier septic and neurological patients that benefit icu treatment, and reevaluate the critical patient pathway, in this special population.conclusions: more than % of icu-survivors returned to work. overall, the chance of return to work within two years was independent of the number of organ support therapies in patients with at least one organ support therapy. however, in subgroups, the chance of return to work decreased with increasing number of organ-support therapies. factors associated with non-return to work among general icu survivors: a multicenter prospective cohort study r rosa introduction: critical care patients may develop long-term health problems associated to their illness or icu treatments, which may affect their work capacity. unfortunately, studies evaluating the impact of critical illness on work-related outcomes are scarce.therefore, we aimed to investigate factors associated with non-return to work among icu survivors. methods: a prospective cohort study involving icu survivors of brazilian tertiary hospitals was conducted from may to august . patients with a icu stay > h (for medical and emergency surgical icu admissions) or > h (for elective surgical icu admissions) who were discharged alive from the hospital were evaluated through a structured telephone interview months after discharge from the icu. a stepwise multivariate poisson regression analysis adjusted by age, gender and years of education was used to evaluate the association of sociodemographic-and icu-related variables with nonreturn to work. results: in total icu survivors completed the -month follow-up. of these, ( %) were working before icu admission. only of patients ( %) returned to work within the first months after discharge from the icu. percentage of risk of death at icu admission (relative risk [rr], . ; % confidence interval [ci], . - . ), decrease in physical functional status in relation to the pre-icu period measured by barthel index (rr, . ; % ci, . - . ), not having a introduction: the aim of this study was to assess the accuracy of physician's prediction of hospital mortality in critically ill patients in an intensive care unit (icu) scarcity setting. methods: prospective cohort of acutely ill patients referred for icu admission in an academic, tertiary hospital in brazil. physicians' prognosis and other variables were recorded at the moment of icu referral. results: there were analyzed referrals. physician's prognosis was associated to hospital mortality. there were ( . %), ( . %) and ( . %) deaths in the groups ascribed a prognosis of survival without disabilities, survival with severe disabilities or no survival, respectively (p< . ) (fig. ) . sensitivity was %, specificity was % and the area under the roc curve was . for prediction of mortality. after multivariable analysis, severity of illness, performance status and icu admission were associated to an increased likelihood of incorrect classification, while worse predicted prognosis was associated to a lower chance of incorrect classification. physician's level of expertise had no effect on predictive ability. conclusions: physician's prediction was associated to hospital mortality, but overall accuracy was poor, mainly due to low sensitivity to detect mortality risk. icu admission was associated to increased incorrect classification, but there was no effect of physician's expertise on predictive ability. what are physicians in doubt about? an interview study in a neuro-intensive care unit. introduction: inescapable prognostic uncertainty, lack of decisionmaking capacity, risk of death or disability and long recovery trajectories complicate decision-making after traumatic brain injury. methods: to elicit experienced physicians' perspective we interviewed neurosurgeons, intensive care-and rehabilitation physicians from oslo university hospital about being in doubt about whether to offer, continue, limit or withdraw life-sustaining treatment and on how such cases were approached. interviews were audiotaped and transcribed verbatim, coded and analysed using systematic text condensation by a clinician (ar) and a medical ethicist (rf). results: the difficulty of decision-making when there is prognostic uncertainty was acknowledged, leading to adaptive approaches; willingness to change and adjust plans along the way. to have access to different opinions within the physician group was seen as constructive. time-critical decisions were based on team discussions and physician's discretion. none-time critical decisions were reached through a process of creating common ground between the medical team and family. themes physicians where in doubt about or expressed different opinions towards: ) appropriate aggressiveness of treatment in a given situation. ) if and when to initiate discussions on appropriateness of treatment. some believed that even addressing the issue in young patients or if small improvements were seen was inappropriate due to the possibility of late recovery. physicians questioned the value of previously expressed patient's wishes in this context. ) optimal timing and type of decisions. the need for nuanced individualized plans was recognized. to have a plan as opposed to just "wait and see" was seen as especially important in medical unstable patients. conclusions: physicians expressed different views on appropriateness and optimal timing of level of care discussions and decisions in traumatic brain injury. a need for a more structured approach was exposed. fig. (abstract p ) . association of physician's prognosis with hospital mortality (p< . ).introduction: this cross sectional study was designed to investigate the level of family satisfaction in intensive care units in a tertiary hospital in the united arab emirates (uae), which is a multicultural society methods: family members of patients who were admitted to intensive care unit for more than hours or over were included in the study. families were approached with a validated fs -icu family satisfaction survey questionnaire [ ] . one hundred questionnaires were collected over a period of months from january to march in our pediatric medical surgical and cardiac, adult cardiac and adult medical/surgical intensive care units. results: the overall level of satisfaction rate was comparable to other high-income and developed countries with total satisfaction score, medical care score and decision making score of . ± . , . ± . , and . ± . respectively (table ) . conclusions: this is the very first study from the uae demonstrating a high level of patient family satisfaction in both adult and pediatric intensive care units. this study also highlighted areas where further improvement needed to occur.introduction: in order to apprehend the structural aspects and current practice of end-of-life care (eolc) in german intensive care units (icus) managed by anesthesiologists, a survey was conducted to explore implementation and relevance of these items. methods: in november , all members of the german society of anesthesiology and intensive care medicine (dgai) and the association of german anesthesiologists (bda) were asked to participate in an online survey to rate items. answers were grouped into three categories: category reflecting high implementation rate and high relevance, category low implementation and minor relevance, and category low implementation and high relevance. results: five-hundred and forty-one anesthesiologists responded, representing just over / of anesthesiology departments running icu's. the survey revealed new insights into current practice, barriers, perceived importance, relevance, and deficits of eolc decisions. only four items reached >= % agreement as being frequently performed, and items were rated "very" or "more important". items attributed to category , to category , and to category , representing a profound discrepancy between current practice and attributed importance. items characterizing the most urgent need for improvement (category ) referred to desirable quality of life, patient outcome data, preparation of health care directives and interdisciplinary discussion, advanced care planning, distinct aspects of changing goals of care, standard operating procedures, implementation of practical instructions, continuing eolc education, and inclusion of nursing staff and families in the process. conclusions: the survey generated awareness about deficits in eolc matters in critical care. consequently, already available eolc tools have been made available through the website of the german society of anesthesiology and intensive care medicine (dgai): http:// www.ak-intensivmedizin.de/arbeitsforen.html.introduction: this study evaluated differences in eolp after years in european icus that also participated in the ethicus i study [ ] . methods: all previous ethicus i centers were invited to participate in the ethicus ii study. consecutive admitted icu patients who died or had treatment limitations during a month period from . . to . . were prospectively studied. previous eolp and region definitions were used [ ] . eolp in the different regions of the ethicus i study [ ] were compared to the same icus in the ethicus ii study. results: of the original icus participated again in this study. figure shows the differences in eolp by region. figure notes differences in patient mental competency at the time of decision, information about patient's wishes and patient discussions in both ethicus studies. conclusions: changes included less cpr (especially in the south) with more withholding and withdrawing therapies. there was a greater number of competent patients with discussions and knowledge of their wishes.introduction: palliative extubation is performed in patients with terminal ilnesses in which mechanical ventilation might prolong suffering. even though the procedure involves nurses, respiratory therapists and doctors, some professionals feel unconfortable performing a palliative extubation. the concept of withdrawing life support can be easily confounded with euthanasia, specially in low income countries, where there is usually less education on palliative care. methods: a questionary containing open ended questions concerning a hypotetical case of intracerebral hemorrhage and prolonged coma, with potential indication for palliative extubation was applied to members of an emergency department intensive care unit staff ( doctors, nurses, respiratory therapists (rt). results: more than half of the professionals ( %) had never participated in a palliative extubation. four professionals ( %) believed palliative extubation is euthanasia. when asked about their own preferences in such a situation, only two ( %) would like to be tracheostomized. symptoms anticipated by most professionals were dyspnea and respiratory secretions. four ( %) would feel very uncomfortable performing palliative extubation because they either felt to be killing the patient or unable to manage symptoms conclusions: most professionals in this tertiary emergency intensive care unit never witnessed a palliative extubation. however, most of believe this procedure is beneficial. some still cannot understand the difference between palliative extubation and euthanasia. education in palliative care and withdrawal of life support can be helpful to clear concepts and relieve moral distress in the team. key: cord- -b cmviny authors: marchetti, monia title: covid- -driven endothelial damage: complement, hif- , and abl are potential pathways of damage and targets for cure date: - - journal: ann hematol doi: . /s - - - sha: doc_id: cord_uid: b cmviny covid- pandemia is a major health emergency causing hundreds of deaths worldwide. the high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. this review addresses some of the pathways leading to endothelial derangement, such as complement, hif- α, and abl tyrosine kinases. this review also highlights potential targets for prevention and therapy of covid- -related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials. the new coronavirus (sars-cov- ) pandemic has rapidly spread to many countries [ ] and caused several thousand deaths. endothelial derangement and increased permeability are reported to be early hallmarks of organ damage in patients with covid- , such as lungs, kidney, and myocardium. moreover, thrombotic complications are a relevant cause of death in patients with covid- . finally, the interaction of sars-cov- with ace possibly implies alterations of angiotensin ii plasma levels. therefore, the vascular system is increasingly being addressed as a major therapeutic target for defeating covid- [ , ] . the present paper in particular reviews some of the pathways leading to endothelial disruption in the course of covid- infection, namely complement activation, hypoxia, platelets, and thyroxin kinases. furthermore, the paper explores potential therapeutic strategies, particularly commercially available drugs, such as imatinib. complement system is a protein network belonging to both the innate and the adoptive immune system: it has opsonization properties, but it also enhances the activity of antibodies and macrophages in eliminating pathogens and damaged cells. c a anaphylatoxin, a central complement protein, is involved in sepsis and acute lung injury mediated by cc-chemokine receptor [ , ] . c a leads to exaggerated early proinflammatory responses and activation of neutrophils and macrophages (by the activation of pi k/akt and mapk signaling pathways), with subsequent release of histones and reactive oxygen species that ultimately lead to endothelial damage, inflammation, and thrombosis; a functional decline of the innate immune system and multiorgan dysfunction follows [ , ] . moreover, c a is involved in pyroptosis, which is a form of programmed cell death by a lytic modality catalyzed by caspase and aimed at eliminating immune cells infected by pathogens. due to cell membrane break, pyroptosis induces an inflammatory damage and release of caspase, which activates interleukin- . c a itself also causes substantial cardiomyocyte dysfunction, which is reversed by complement blockade [ ] . also, c a complement fraction plays a relevant role in the pathogenesis of infection-related lung injury: high serum c a predicts evolution to ards [ , ] , while both c a and c a increase endothelial permeability and activate endothelial cells, thereby increasing the expression of adhesion molecules and cytokines [ , ] , and the distal complement activation product c b- triggers intracellular fluxes of calcium in epithelial and endothelial cells. the vicious cycle might be sustained by hypoxia, which reduces the expression of cd , a complement regulator, by hif- alpha, il- , and tnfα. this downregulation enhances c a release and caspase deposition onto endothelial cells [ ] . the complement damage may also be triggered by some specific infective agents, such as staphylococcus, that provoke shedding of anti-complement surface proteins cd and cd from endothelial cells thus favoring cell lysis [ ] . complement also proved to be relevant for survival in patients with heart failure and sepsis-related miocardiopathy [ , ] . moreover, tocilizumab proved to reduce c a receptor in myocardial infarction patients; therefore, its anti-cytokine efficacy in covid- may be partly mediated by attenuation of complement hyperactivation [ ] . in fact, sars-cov can directly activate complement system by lectin way and particularly acts onto t-lymphocytes in hypertensive patients, since an increased expression of c a receptor has been reported in treg foxp + lymphocytes from these individuals [ ] . tissue damage by complement activation seems to be a common way to many pathogen viruses, including h n influenza, sars, cov- , and mers-cov [ ] [ ] [ ] [ ] [ ] [ ] . preliminary data show that c a mediates mers-cov and sars-cov- -induced pyroptosis in infected macrophage, dendritic cells, and cd + lymphocytes [ , ] . c knockout mice proved to be resistant to organ damage induced by sars-cov, while the high serum and pulmonary concentrations of c a and c b- reported in mice infected with mers-cov and sars-cov could not cause lung damage if a c a receptor inhibitor was administered [ , ] . inhibition of c a or c a receptor reduced lung damage and prolonged survival also in mice infected with h n influenza virus [ ] . moreover, a reduced mers-cov viral replication was observed after inhibition of c a receptor [ ] . specific inhibition of c a biological activity could gain therapeutic benefit without affecting the protective immune response. in the last few years, several peptide and non-peptide antagonists of c a have been discovered and tested in relevant pharmacological models. treatment with eculizumab, the first-in-class terminal complement inhibitor, reported a rate of meningococcal infection of . / patient years and no deaths in patients temporarily treated with the drugs, i.e., patients with atypical hemolytic uremic syndrome, while the risk of meningococcus-related death was / , patient years in chronically treated individuals [ ] . eculizumab was successfully used to treat virusrelated hemolytic uremic syndrome (cytomegalovirus, human immunodeficiency virus, herpes zoster virus, influenza b virus) with no reported immunosuppressive effects [ ] [ ] [ ] . the solid-c (nct ) expanded access study is currently testing mg administration of eculizumab weekly in patients with covid- ards, and the panamo phase ii study in the netherlands (nct ) is currently testing ifx- , an anti-complement (c a) monoclonal antibody. endothelial cells represent one-third of overall lung cells. baseline endothelial damage may be chronically caused by increased adiponectins in diabetic and obese patients: this effect is related to the activation of inflammosome nlrp and autocrine production of il- β [ ] . additional damage to pulmonary endothelial dysfunctional cells is acutely provoked by infections and in turn causes excess thrombin generation and reduced fibrinolysis [ ] [ ] [ ] . in fact, most dangerous infective agents, such as dengue , adopt an adiponectin-like mechanism of endothelial damage [ ] . thrombin causes further endothelial damage, which can be prevented in vitro by cxcr agonists, such as ubiquitin [ ] . moreover, hypoxia may lead to increased hypoxia inducible factor- α (hif- α) expression and hypercoagulability [ ]. therefore, a higher rate of thrombotic episodes is reported in patients with covid- pneumonia, while increased vascular permeability seems to be strongly related to increased thrombosis. in particular, in patients with lymphopenic pneumonia and organ failure increased vascular permeability was strongly correlated with severe lymphopenia [ ] . lung computed tomography of patients infected with sars-cov- shows an earlier interstitial edema followed by a subsequent alveolar edema, which questioned the similarity of covid- lung damage and ards. in pathology samples from covid- patients, diffuse microcirculatory and macrovascular thrombosis have been detected in lung tissue, which is not typical for ards, and when a few endothelial cells were directly infected by sars, several macrophages were instead [ ] . however, no evidence of vasculitis has been reported by pathologists and no laboratory signs of diffuse intravascular coagulopathy were found in most of the patients, since antithrombin-iii, fibrinogen, and platelet count rarely decline in the first phases of the disease, while d-dimer usually shows a progressive increase during hospital stay and predicts a higher mortality [ ] . angiopoietin , thrombomodulin, icam , endothelin, and e-selectin are usually increased in cases of endothelial damage; however, quantitative data from covid- patients are still awaited. rather, severe early hypoalbuminemia and subsequent increased cpk, myoglobin, creatinine, and uric acid are observed in the majority of patients with covid- , resembling systemic capillary leak syndrome and explaining some cases of renal failure. hypoalbuminemia is also a relevant prognostic factor of the lung injury prediction score in sepsis [ ] . apoptosis of human pulmonary microvascular endothelial cell may be chronically triggered by inflammation, such as in copd, or acutely induced by ards; the latter is mediated by bruton kinase (btk), il- , and macrophage stimulating- , while il- seems protective [ ] [ ] [ ] [ ] . ldh is typically released into the serum by apoptotic endothelial cells [ ] . a different kind of damage to lung microvascular endothelial cells, namely autophagy, may be induced by nadph oxidase during viral infections, but prevented by nadph oxidase as a protecting way against oxidative stress [ , ] . furthermore, endothelial cells of lymph vessels in the lungs are particularly sensible to oxidative stress and might be the most damaged cell population in sars-cov- infection [ ]. several drugs can damage the endothelium. endothelial damage secondary to ponatinib is mediated by notch hyperactivation, but also propranolol and sirolimus inhibit endothelial proliferation and carteolol induces apoptosis in corneal endothelial cells by caspase-and mitochondria-dependent pathways [ ] [ ] [ ] . also, ace , a sars-cov- target, inhibits proliferation of endothelial cells; however, it also reduces endothelial inflammation [ ] . finally, steroids induce apoptosis in bone endothelial cells causing osteonecrosis, but such an effect has not been proven in pulmonary capillary cells. a shorter list of drugs prevent endothelial apoptosis, namely recombinant adenosine deaminase, registered for scid ada deficient patients, casin, and plerixafor, which markedly expand endothelial proliferation in vitro, inducing also tubing and sprouting [ , ]. however, cyclin-dependent kinases are upregulated by plerixafor, and endothelial permeability is therefore reduced [ ] . adrecizumab is a first-in-class monoclonal antibody targeting ad stabilizing plasma bioactive adrenomedullin (bio-adm ®), a key hormone secreted by endothelial cells showing vasoprotective activity, preserving endothelial barrier function (i.e., keeping tight junctions) and preventing vascular leakage (ref shock ) [ ] . conversely, in the interstitium adm has dangerous vasodilatory properties at high concentrations. the ongoing adrenoss- trial (ntc ) has enrolled patients with early septic shock and high serum levels of bio-adm: patients were randomized to receive adrecizumab or placebo in addition to standard care. preliminary data confirmed the treatment safety (bjcp phase i) and showed a trend to a reduced -day mortality as compared with % in the placebo group (www.adrenomed.com). the role of platelets in inducing or amplifying the endothelial damage in covid- patients is unknown. a low platelet count, possibly due to consumption, bone marrow infection, or autoimmune phenomena, was reported to increase covid- mortality rate by five-fold, even though the rates were very heterogeneous among the analyzed studies [ - ]. moreover, the opposite is more common in covid- patients, being its platelet counts quite high or higher than in patients with sepsis or ards; increased serum levels of thrombopoietin caused by pulmonary inflammation have been supposed to explain this phenomenon [ ]. organ damage to skin, cns, heart, and kidney appears to be related to transient thrombotic or ischemic phases (hypoperfusion, hypoxemia). heparin proved to protect tight junctions in alveolar endothelial cells from il- induced hyperpermeability and thus may possibly improve the outcome of covid- patients [ , ] . it also antagonizes histones released from damaged cells by histone methylation and interaction with mapk and nf-kb pathways [ , ]. furthermore, heparin has well-documented anti-inflammatory properties that include binding to inflammatory cytokines, inhibiting neutrophil chemotaxis and migration, neutralizing the positively charged c a, and sequestering acute phase proteins [ ] . heparin polyanionic nature also seems to interact with sars-cov- spike s protein receptor binding domain (https://www.biorxiv.org/content/ . / . . . v .full). several covid- cases reported atypical thromboses (renal veins, uterine veins, mesenteric vessels) and myocardial micro-thrombotic vessels; however, a large portion of thromboembolic events occurred in patients receiving prophylactic heparin doses. furthermore, some centers reported the need for high heparin doses to achieve a target aptt ratio in these patients and no standard level of anticoagulation has yet been established. early, i.e., domiciliary, antithrombotic prophylaxis, and subsequent dose titration according to ards severity still need to be validated, especially in selected patients, such as older patients, those receiving antiplatelet therapies, and those with renal failure. defibrotide and rtpa have also been proposed to rescue patients with severe thrombotic events. full (ufh , u/ day or enoxaparin mg/day) or intermediate (ufh , / day or enoxaparin mg/day) heparin dose was reported to benefit covid- patients with higher platelet counts and higher d-dimer levels [ ] . an english trial is currently assigning patients to either aspirin mg, clopidogrel mg, rivaroxaban . mg, or omeprazole versus standard of care, in order to prevent cardiac complications of covid- (nct ). other antiplatelet agents, such as prasugrel, a p y inhibitor, proved to reduce prostmyocardial infarction inflammation and might be a potential drug to be tested in the context of covid- -induced endothelial inflammation [ ] . also, hypoxia is expected to play a central role in leading inflammation and endothelial activation: cells adapt to hypoxia by activating hypoxia-inducible factors hif- and hif- which in turn induce the expression of a number of genes promoting energy metabolism and cell survival and specifically endothelial cell adaptation (migration, growth, differentiation) (whyte-hypoxia). a transition from hif- to hif- governs adaptation from acute to prolonged hypoxia, despite most genes may be regulated by both [ ] . hif- α upon activation increases the expression of vascular-endothelial protein thyrosine phosphatase, which in turn decreases vecaderin phosphorylation, supporting the integrity of adherens junctions and preventing loss of endothelial barrier function [ ] . contrarily, expression of hif- α in alveolar epithelial cells enhances lung inflammation in a nf-kb mediated way [ ] and favors a cell-mediated inflammation (cd + cd +) and proinflammatory cytokines (il- and tnfα), which proportionately downregulate cd and augment complement-mediated endothelial damage [ ] . moreover, myeloid cell hif- α is a key driver of myeloid cell response in hypoxic and inflammatory microenvironments by modulating cellular energetics, upregulating glycolytic enzymes and glucose transporters to permit atp generation under conditions of hypoxia, and preventing apoptosis of innate immunity cells. in chronic infections, however, hif- α was reported to prevent excessive lymphocyte recruitment into lung interstitium and avert immunopathological consequences to the host [ ] . despite there are no currently marketed drugs achieving a selective control of hif- α, imatinib proved to reduce hif- α levels and pulmonary hypertension caused by chronic hypoxia [ , ] . the activation and damage of pulmonary endothelium is a hallmark of ards, and ace+ circulating endothelial microparticles are markers of pulmonary endothelial injury predicting development of ards in septic patients [ ] . endothelial damage has been shown to induce the recruitment of circulating endothelial cells: circulating mature endothelial cells increased in patients with moderate or severe ards as compared with mild ards or non-ards septic patients [ ] . increased circulating endothelial progenitor cells (epc) proved to positively correlate with survival [ ] . however, also overall cd + cd + circulating cell count is associated with improved survival in sepsis-related ards. inhaled nitric oxide was reported to induce mobilization of endothelial cell progenitors from bone marrow into circulation, contributing to repair lung vascular injury in vivo, while autotransplanted endothelial progenitor cells protected mice from lpsinduced lung injury [ , ] . no data are yet available regarding phase-related mobilization of mature or progenitor endothelial cells during covid- infection. beta-blockers favor migration of endothelial progenitor cells mediated by sdf- thanks to the inhibition of beta adrenergic receptors onto circulating mononuclear cells and bone marrow stem cells [ ] . finally, an increased synthesis of hyaluronic acid seems to explain the huge shift of liquids into the interstitium of patients with sars-cov- -related endothelial damage and respiratory failure. this phenomenon, however, might be counteracted by marketed hymecromone or intranasal hyaluronidase [ ] [ ] [ ] . the permeabilizing action of vegf on the endothelium of the pulmonary capillaries, typical of ards, can be counteracted by inhibiting abl (arg). imatinib is an abl and abl tyrosine kinase inhibitor with ema designation of orphan drug for the treatment of ards (january , ) by virtue of its demonstrated in vitro and in vivo ability to attenuate the expression of vcam- in endothelial cells, restoring ve junctions-caderine and thus reducing the ards secondary to sepsis, mechanical ventilation, and ischemia and mediated by vegf, thrombin, and histamine [ ] [ ] [ ] [ ] . also, the anticytokine action of imatinib, mediated by the inhibition of the nf-kb pathway in myeloid-derived cells, has been widely demonstrated with efficacy in asthma, rheumatoid arthritis, systemic sclerosis, and pulmonary hypertension [ , ] . several cases of acute lung inflammation induced by toxic agents (bleomycin, gemcitabine) or sepsis got rapid clinical improvement after treatment with low doses of imatinb [ , ] . furthermore, the immunomodulatory action of imatinib is proven: the inhibition exerted on c-kit in bone marrow stem cells favors the mobilization of myeloid cells already at low doses [ ] . in primates with concomitant hiv infection and mycobacterium tuberculosis, imatinib has demonstrated an effective action directly to the host [ ] . a phase ii clinical trial (impact-tb, nct ) is enrolling patients with mycobacteriosis tb (± hiv) to concomitant imatinib therapy. finally, a direct anti-viral action of imatinib has also been documented: it appears to inhibit the fusion of sars-cov with the late endosome membrane at micromolar doses (ec . μm/l), a phase necessary for subsequent viral replication [ ] [ ] [ ] . based on the above rational, the counter-covidrandomized, placebo-controlled, clinical trial is currently enrolling in amsterdam (eudract number, - - ). several pathways have been identified as possible drivers in the pathogenesis of sars-cov- : some pathways, such as the complement, may be targeted by available drugs, while some others are orphan of specific therapies, such as hif- α and hif- α. several drugs currently marketed for blood diseases, such as imatinib, ruxolitinib, heparins, tocilizumab, and eculizumab, are currently being tested for patients with covid- symptoms. hematologists, who are expert on such drugs, are therefore called into multidisciplinary teams for managing patient selection and therapy monitoring. while awaiting vaccines and effective antiviral therapies, their expertise needs to be combined with the updated evidence on the pathogenesis of covid- , as they have the chance to contribute to amelioration of patient outcomes. appropriate trial designs still need to be developed in order to address some fundamental issues, such as covid- patient stratification and testing of multiple drugs. furthermore, trials are challenged by heterogeneous support therapies for covid- and partial non-comparability of patients belonging to different clinical centers. nevertheless, most of the above cited candidate drugs have a favorable safety profile, especially in the short term, and are promising tools for defeating covid- . conflict of interest mm has received speaker honorarium from novartis and consultant fees from gilead. ethical approval this article does not contain any studies with human participants performed by any of the authors. epidemiology and clinical features of covid- : a review of current literature coagulation disorders in coronavirus infected patients: covid- , sars-cov- , mersd-cov and lessons from the past severe covid- infection associated with endothelial activation complement as a major induced of harmful events in infectious sepsis experimental design of complement component c a-induced acute lung injury (c a-ali): a role of ccchemokine receptor type during immune activation by anaphylatoxin blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ros, ros-dependent organ injury and coagulopathy new insights into molecular mechanisms of immune complex-induced injury in lung complement-induced activation of mapks and akt during sepsis: role in cardiac dysfunction cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury mannose-binding lectin in severe acute respiratory syndrome coronavirus infection caspase- -dependent pyroptosis of lung epithelial cells protects from melioidosis while caspase- mediates macrophage pyroptosis and production of il- caspase- -dependent pyroptosis of peripheral blood mononuclear cells predicts the development of sepsis in severe trauma patients: a prospective observational study hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants l phosphatidylinositol-specific phospholipase c potentiates lung injury via complement sensitization role of complement c a and histones in septic cardiomyopathy il- receptor inhibition by tocilizumab attenuated expression of c a receptor and in non-st-elevation myocardial infarction complement components sc b- and ch predict prognosis in heart failure patients combined with hypertension deficiency of complement c and c receptors prevents angiotensin ii-induced hypertension via regulatory t cells the comparative pathology of severe acute respiratory syndrome and avian influenza a subtype h n -a review serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with h n influenza the role of c a in acute lung injury induced by highly pathogenic viral infections complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mbio. complement receptor c ar inhibition reduces pyroptosis in hdpp -trangenic mice infected with mers-cov. viruses cell pyroptosis, a potential pathogenic mechanism of -ncov infection p y is involved in emergency hematopoiesis after myocardial infarction primary endothelial cellspecific regulation of hypoxia-inducible factor (hif)- and hif- and their target gene expression profiles during hypoxia hif alpha signaling inhibits adherens junctional disruption in acute lung injury hypoxia-inducible factor (hif)- alpha promotes inflammation and injury following aspiration-induced lung injury in mice pdgfrβ and hif- α inhibition with imatinib and radioimmunotherapy of experimental prostate cancer hypoxia-or pdgf-bbdependent paxillin tyrosine phosphorilation in pulmonary hypertension is reversed by hif- alpha depletion or imatinib treatment increase in circulating ace-positive endothelial microparticles during acute lung injury evaluation of endothelial damage in sepsis-related ards using circulating endothelial cells increased circulating endothelial progenitor cells in septic patients: correlation with survival inhaled no contributes to lung repair in piglets with acute respiratory distress syndrome via increasing circulating endothelial progenitor cells autotransplantation of circulating endothelial progenitor cells protects against lipopolysaccharide-induced acute lung injury in rabbit the role of the beta adrenergic receptor on endothelial progenitor cells dysfunction of proliferation and migration in chronic obstructive pulmonary disease patients accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis differential and opposing effects of imatinib on lps-and ventilator-induced lung injury effective treatment of edema and endothelial barrier dysfunction with imatinib imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury reduction of vascular leakage by imatinib is associated with preserved microcirculatory perfusion and reduced renal injury markers in a rat model of cardiopulmonary bypass beneficial effects of imatinib in a patient with suspected pulmonary veno-occlusive disease possible role of imatinib in clinical pulmonary veno-occlusive disease successful treatment of gemcitabine-induced acute interstitial pneumonia with imatinib mesylate: a case report complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with hodgkin's lymphoma: hope for severe chemotherapy-induced toxicity? low dose of imatinib induce myelopoiesis and enhance host anti-microbial immunity impact-tb: a phase ii trial assessing the capacity of low dose imatinib to induce myelopoiesis and enhance host anti-microbial immunity against tuberculosis. imatinib mesylate per oral as a clinical therapeutic for tb repurposing of clinically developed drugs for treatment of middle east respiratory syndrome coronavirus infection abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus fusion coronavirus s proteininduced fusion is blocked prior to hemifusion by abl kinase inhibitors middle east respiratory syndrome coronavirus: another zoonotic betacoronavirus causing sars-like disease publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -rpyoeg n authors: alberici, federico; delbarba, elisa; manenti, chiara; econimo, laura; valerio, francesca; pola, alessandra; maffei, camilla; possenti, stefano; lucca, bernardo; cortinovis, roberta; terlizzi, vincenzo; zappa, mattia; saccà, chiara; pezzini, elena; calcaterra, eleonora; piarulli, paola; guerini, alice; boni, francesca; gallico, agnese; mucchetti, alberto; affatato, stefania; bove, sergio; bracchi, martina; costantino, ester maria; zubani, roberto; camerini, corrado; gaggia, paola; movilli, ezio; bossini, nicola; gaggiotti, mario; scolari, francesco title: a report from the brescia renal covid task force on the clinical characteristics and short-term outcome of hemodialysis patients with sars-cov- infection. date: - - journal: kidney int doi: . /j.kint. . . sha: doc_id: cord_uid: rpyoeg n the sars-cov- epidemic is pressuring health care systems worldwide. disease outcomes in certain subgroups of patients are still scarce, and data are needed. therefore, we describe here the experience of four dialysis centers of the brescia renal covid task force. during march , within an overall population of hemodialysis patients, sars-cov- rna positivity was detected in ( %). at disease diagnosis, of the ( %) patients (group ) were managed on an outpatient basis whereas the remaining ( %) (group ) required hospitalization. choices regarding management strategy were made based on disease severity. in group , % received antivirals and % hydroxychloroquine. eight percent died and % developed acute respiratory distress syndrome (ards). in group , % received antivirals and % hydroxychloroquine. forty two percent died and % developed ards. overall mortality rate for the entire cohort was %. history of ischemic cardiac disease, fever, older age (over age ) and dyspnea at presentation were associated with the risk of developing ards whereas fever, cough and a c-reactive protein higher than mg/l at disease presentation were associated with the risk of death. thus, in our population of hemodialysis patients with sars-cov- infection, we documented a wide range of disease severity. the risk of ards and death is significant for patients requiring hospital admission at disease diagnosis. the impact of the sars-cov- epidemic in subgroups of patients has yet to be determined. in brescia. italy we have developed a standardized protocol when approaching patients on maintenance haemodialysis (mhd) and kidney transplant recipients, respectively ( ) . reports would suggest a more severe disease course in patients with ckd( ) although outcomes in mhd patients is still unclear with earlier small case series suggesting a milder course ( ) . management of mhd patients in the context of an epidemic poses several challenges: this group of patients usually requires caregiver assistance, transportation from home to the dialysis units as well as spending periods of time in crowded waiting areas before and after treatment ( ) . moreover, mhd patients are usually old and affected by several comorbidities that are known to be associated with high risk of poor outcomes in patients with covid- . the lombardy region in general and brescia in particular have been severely hit by the sars-cov- epidemic and this has generated several logistical and clinical challenges for the dialysis units of the "brescia renal covid task force". here, we describe the characteristics and outcomes of the mhd patients affected by covid- and followed in four dialysis units that are a part of the "brescia renal covid task force". ninety-four patients tested positive for rt-pcr within the overall population of ( %) ( table ) .while centers limited the viral testing only to patients showing symptoms suggestive for sars-cov- infection, the center of brescia performed rt-pcr in its entire mhd population (patients with symptoms and patients without symptoms). the positivity rates were not substantially different between these approaches ( % versus %, respectively). patients testing positive were either triaged to the hospital or back to their dialysis facility based on the clinical judgement of the caring physician according mainly to the severity of the symptoms shown. the main clinical characteristics of the overall mhd population with sars-cov infection and the subgroups managed as outpatient or in hospital are shown in table . the median time from symptoms onset to positive rt-pcr was days (iqr - ). patients that needed to be admitted showed a higher proportion of symptoms compared to the ones not requiring hospitalisation ( % vs %). thirty-seven out of ( %) patients were managed as outpatients, for a median follow-up of days (iqr - ). among the group managed as outpatient, / ( %) were asymptomatic at disease diagnosis, while the remaining patients experienced mild symptoms. among the asymptomatic patients, in / ( %) the chest x-ray was negative, while unilateral and bilateral infiltrates were detected respectively in / ( %) and / ( %). detailed patient characteristics are shown in table . antiviral therapy and/or hydroxychloroquine were employed in / ( %) patients for a median duration of days (iqr - ). antibiotics were employed in / ( %): macrolides in %, cephalosporins in %, carbapenems in %, glycopeptides in %, aminoglycosides in %, beta-lactams in % and fluoroquinolones in %. / ( %) received prophylactic heparin and / ( %) were on acei or arbs. one patient had to withdraw hydroxychloroquine due to vomiting. no other adverse event due to the treatment was documented in this patient group. during follow-up, / ( %) patients experienced a new onset/a worsening of the interstitial pneumonia, / ( %) died, / ( %) developed ards and / ( %) had to be hospitalized. in addition, / patients ( %) developed cough, / ( %) myalgia, / ( %) fever and / ( %) gastrointestinal symptoms during follow up. patients who were asymptomatic at baseline, compared to the symptomatic ones, were less likely to develop ards ( / vs / ), to develop a new onset or a worsening of pneumonia ( / vs / ) and less likely to die ( / vs / ). fifty-seven patients were admitted after a median time from symptom onset and from positive rt-pcr test results of (iqr - ) and days (iqr - ), respectively. median followup was days (iqr . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . detailed characteristics of this population are shown in table . antiviral therapy was employed in / ( %) with / patients ( %) experiencing adverse events: diarrhoea, increase in liver enzymes, prolongation of qtc interval, atrial fibrillation, gastrointestinal bleeding, coagulation alterations and skin rash. the median duration of lopinavir/ritonavir or darunavir + ritonavir and hydroxychloroquine treatments were days (iqr - ) and days (iqr - ), respectively. antibiotics were administered in / patients: macrolides in %, cephalosporins in %, carbapenems in %, glycopeptides in %, aminoglycosides in %, beta-lactams in % and fluoroquinolones in %. thirty one out of ( %) received prophylactic heparin and out of ( %) were on acei or arbs. forty-five out of patients ( %) developed ards; / ( %) died after a median of days (iqr . - . ) from admission and a median of days (iqr - ) from onset of symptoms. eleven out of ( %) patients were discharged after a median of days (iqr . - ) from admission and days (iqr . - . ) from onset of symptoms. among the patients who died, the cause of death was respiratory failure secondary to ards in / ( %), bacterial sepsis in / and sudden death of unknown origin in / . serial chest x-rays were performed in / ( %) patients; among those patients / ( %) showed chest x-ray worsening compared to baseline. dexamethasone was administered to / ( %) patients due to respiratory deterioration; out of of these patients also received tocilizumab. in this group, out of patients ( %) died. out of patients whose response to glucocorticoids was assessable at the moment of data analyses, / showed stabilisation of the po /pif ratio or chest x-ray improvement, while the remaining patients did not improve. regarding the two tocilizumab treated patients, response was assessable only in one with no improvements in chest x-ray or lung function. in univariate analyses, cardiac failure (or . ( %ci . - . ), p= . ), ischemic heart disease (or . ( %ci . - . ), p= . ), fever at disease diagnosis ( . ( %ci . - . ), p= . ), shortness of breath at disease diagnosis ( . ( %ci . - . ), p= . ), myalgia or fatigue at disease diagnosis (or . ( %ci . - . ), p= . ), infiltrates at the baseline chest x-ray (or . ( %ci . - ), p= . ), higher ast levels (or . ( % . - . ), p= . ) and higher crp levels (or . ( %ci . - . ), p= . ) were associated with the risk of developing ards. ischemic heart disease (or . ( %ci . - . ), p= . ), fever at disease diagnosis (or . ( %ci . - ), p= . ), cough at disease diagnosis (or . ( %ci . - . ), p= . ), shortness of breath at disease diagnosis (or . ( %ci - ), p= . ) and higher crp at disease diagnosis (or ( %ci . - ), p= . ) were associated with the risk of death (table ) . two multivariate analyses were performed, one for each outcome of interest (ards and death). in the first model, the characteristics found to be associated with the risk of ards were history of ischemic heart disease (or . ( %ci . - . ), p= . ), fever at disease diagnosis (or ( %ci . - ), p= . ), age at symptoms onset (or . ( %ci - . ), p= . ) and shortness of breath at disease onset (or , ( %ci . - . ), p= . ). in the second model, the characteristics associated with the risk of death were fever at disease diagnosis (or . ( %ci . - ), p= . ), cough at disease diagnosis (or ( %ci . - . ), p= . ) and higher serum crp at disease diagnosis (or . ( %ci . - . ), p= . ) ( table ). sars-cov- infection is challenging health care systems around the world. the predictions regarding covid- associated mortality are changing as new information is gathered although comorbidities such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension and cancer are consistently associated with worse prognosis( , ). we have reported recently that hospitalized kidney transplant recipients tended to have a poor prognosis with a mortality rate of % ( ), while another group observed that when such patients did not require hospital admission they experienced a more favourable outcome ( ) . the prognosis of haemodialysis patients with covid- is still unclear and more data are desperately needed. in our cohort including four centers of the "brescia renal covid task force", we have identified patients with sars-cov- infection. as expected, infected mhd patients not requiring hospital admission experienced a better disease course compared to patients who required hospitalisation. nevertheless, % of the patients treated in the outpatient setting subsequently required admission. there was also substantially less use of antiviral medications in patients managed in the outpatient setting although the proportion of patients receiving hydroxychloroquine was similar between the two groups. this should be taken into account when interpreting the results since it was the managing physicians decision to start medications. while the lower rate of antiviral use was associated with lower incidence of adverse events in the outpatient group, whether this may be the result of less frequent antiviral use rather than a better overall disease profile needs to be clarified. finally, in our cohort, only a few patients were treated with glucocorticoids and tocilizumab, which does not allow us to draw any conclusions on the potential efficacy of these treatments. the disease severity of the sars-cov- infection is highly variable and a significant proportion of infected patients appear to experience only mild disease or no symptoms at all in our cohort. notably, the overall case fatality rate of our population was higher compared to the general italian and chinese population ( % vs . % vs . %) ( , ) . the finding of worse outcome of hemodialysis patients with sars-cov- infection may be explained by high prevalence of comorbidities as well as other risk factors related to end stage renal disease per se ( ). our study also provides some preliminary information on factors associated with the risk of ards and death. the presence of cvd and severe inflammation were predictive of worse outcomes. notably, these factors are not specific for the haemodialysis population since cardiac comorbidities, fever and older age have been already described as prognostic factors in the general population with sars-cov- infection ( , ) . our results should be interpreted with some caution. median follow-up was days, center bias cannot be ruled out, symptoms severity was not collected, and the relatively small sample size of our cohort may have impacted on the generalizability of our analyses. the strengths of our study include a shared management approach characterized by relative data homogeneity and detailed data collection made possible by an unprecedented commitment of the members of our task force. in conclusion, sars-cov- infection in maintenance haemodialysis patients presents with a wide range of symptoms. the data represented herein suggest a strikingly higher mortality rate compared to the general population although the risk factors for disease severity are similar. further data collection and follow up is necessary to have a complete picture of the spectrum of covid- in maintenance dialysis patients. considering the well-known potential of lopinavir/ritonavir and hydroxychloroquine for increasing qtc, a baseline ekg was performed before therapy commencement and, afterwards, every - days; in case of qtc prolongation a reduction or discontinuation of treatment was considered in a case-by-case manner. acute respiratory distress syndrome (ards) and cardiac failure have been defined as reported by others ( , ) . the decision whether or not admitting a patient was taken by the attending physician according to symptoms severity or signs of respiratory failure. ethical approval for this study was obtained according to italian regulations. statistical analysis was performed using r software (https://www.r-project.org) and graphpad prism . results are expressed as the number and percentage for categorical variables and the median (interquartile range [iqr]) for continuous variables. changes in variables were compared by a related sample wilcoxon test, proportions of patients were compared using a chi-squared or fisher test, as appropriate. univariate and multiple logistic regression models were used to assess the ability of some predefined clinical characteristics to predict the risk of ards or death. all the statistically significant predictors at univariate analysis were entered in a multivariate model ( ) . finally, the best multivariate model was identified by adopting a stepwise selection approach. odds ratios (ors) and their % cis were estimated from logistic regression analysis. p values less than . ( -tailed) were considered significant. management of patients on dialysis and with kidney transplantation during the sars-cov- (covid- ) pandemic in brescia chronic kidney disease is associated with severe coronavirus disease (covid- ) infection covid- in hemodialysis patients: a report of cases . . the novel coronavirus pneumoniae emergency response epidemiology team. the epidemiological characteristics of an outbreak of clinical features of patients infected with novel coronavirus in wuhan a single center observational study of the clinical characteristics and short-term outcome of kidney transplant patients admitted for sars-cov pneumonia covid- infection in kidney transplant recipients characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention case-fatality rate and characteristics of patients dying in relation to covid- in italy risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study acute respiratory distress syndrome: the berlin definition accf/aha guideline for the management of heart failure: a report of the american college of cardiology foundation/american heart association task force on practice guidelines epidemiology of covid- in a long-term care facility in king county key: cord- -hpldjsc authors: leisman, daniel e.; deutschman, clifford s.; legrand, matthieu title: facing covid- in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: hpldjsc nan published data [ , ] , anecdotal observations, and discussions with colleagues worldwide indicate that covidinduced respiratory phenotypes are distinct from typical ards in several ways [ ] . covid- patients develop profound hypoxemia early in their disease course. however, overt respiratory dysfunction at these early stages is unusual. pulmonary compliance in intubated covid- patients appears to be only modestly decreased, and patients are therefore relatively easy to ventilate [ ] . gattinoni et al. [ ] described hyperperfusion of poorly ventilated lung, perhaps due to vasodilation and the loss of hypoxic vasoconstriction. while benefit from low-tomoderate levels of peep and prone positioning have been noted, these authors suggest that they result more from hemodynamics effects than lung recruitment [ ] . later in the course of covid- , some patients develop a phenotype more consistent with ards [ , ] . the reported inflammatory response in covid- is also not consistent with either typical ards or cytokine-release syndromes (crs) or "cytokine storm. " qin et al. [ ] report mean interleukin- levels were (sd: - ) pg/ml (normal range: pg/ml). other smaller covid- reports have ranged from to pg/ ml. these findings contrast with interleukin- elevations seen in typical ards and in crs. sinha et al. report mean interleukin- levels of ( - ) pg/ml in "hypoinflammatory" ards [ ] and ( - ) pg/ml in hyperinflammatory ards [ ] , -to -fold higher than reported in the wuhan data. among crs patients, mean interleukin- levels are frequently as high as , pg/ml [ ] . other inflammatory cytokines (e.g., interleukin- , interleukin- β) demonstrate similar patterns. in summary, covid- is associated with only mild inflammatory cytokine elevation and demonstrates physiology and immunology that are difficult to reconcile with ards or crs. an alternative mechanism of disease therefore seems likely. the combination of observed physiology and emerging pathologic evidence points toward a vascular disease process as contributing factor in covid- pathogenesis. pulmonary shunting is consistent with intense vasodilation and endothelial dysfunction. the observation that % of hospitalized patients in rome showed subsegmental vascular enlargement on their admission computed tomography scan supports this view [ ] . reports of increased respiratory dead space suggest lung-vascular thrombosis from thrombotic microangiopathy or pulmonary embolism. the latter was recently reported in up to % of hospitalized covid- patients [ ] . autopsies performed on patients who died early on were indeed notable for lung-vascular congestion [ ] . vascular disease may also explain massive d-dimer elevations, while antiphospholipid antibodies were recently reported in covid- [ ] . a constellation of multi-system organ involvement, low-grade inflammation, lymphopenia, hypercoagulability, and heterogenous microvascular dysfunction is a classic description of many systemic vasculopathies, such as vasculitides (supplement table) . reported findings indicate that immunosuppression, endothelial activation, and direct viral-mediated tissue damage, rather than hyperinflammatory injury, mediate covid-induced organ dysfunction. for example, a recent autopsy study found no renovascular or interstitial inflammation, but noted endothelial activation, occasional frank necrosis, and copious virions in renal tissue [ ] . if direct infection drives injury, vascular tissue is expected to be quite susceptible as it highly expresses angiotensin-converting enzyme- (ace- ), which is essential for coronavirus uptake. sars-cov- initiates cellular infection by binding ace- on the surface of human cells, including endothelial cells (fig. ) [ ] . attachment promotes disordered cytokine paracrine signaling, including both pro-and anti-inflammatory molecules, and pro-apoptotic mediators [ ] . chemokine-mediated lymphocyte recruitment and subsequent infection of lymphocytes, which also express ace- , likely contribute to lymphocyte apoptosis, natural killer and b cell suppression, and t cell exhaustion, as noted by qin et al. [ ] . these findings are consistent with clinical lymphopenia, which correlates with mortality [ ] . viral injury, disordered cytokine release, and damage-associated fig. ( ) the sars-cov- virus infects an endothelial cell by binding to ace- . cellular infection initiates localized inflammation, endothelial activation, tissue damage, and disordered cytokine release. membrane fusion also interrupts angii metabolism, leading to an increase in angii and a decrease in ang ( - ) , augmenting inflammation, endothelial activation, and leukocyte and platelet recruitment. ( ) pulmonary endothelial activation leads to the ace- shedding phenomenon, where ace- is rapidly liberated from the cell membrane. this produces an initial rapid rise in angii, which can induce a positive feedback loop enhancing local inflammation, coagulation, and capillary leak. ( ) the transiently increased ace- dissipates, leading to subphysiologic angii concentrations. low angii in this phase leads to vasodilation, worsened capillary leak, and impaired endothelial conductance and autoregulation. low systemic angii also upregulates ace- , possibly increasing susceptibility to sars-cov- in remote tissue. ace, angiotensin-converting enzyme; angi, angiotensin-i; angii, angiotensin-ii; ang ( - ), angiotensin ( - ); damps, damage-associated molecular pattern molecules molecular patterns (damps) induce localized microvascular inflammation, which triggers endothelial activation, leading to vasodilation and pro-thrombotic conditions. angiotensin-ii (angii) is primarily metabolized by endothelial ace- to the vasodilatory and anti-inflammatory peptide angiotensin ( - ) . in the early phases of infection, ace- consumption by viral entry would be predicted to increase local angii concentration. among the known effects of angii are vasoconstriction, endothelial activation, and pro-inflammatory cytokine release. platelet activation by angii may further enhance a pro-thrombotic milieu. angii also has potent chemotactic effects that may accelerate lymphocyte recruitment and suppression. importantly, admission angii levels in covid- patients are reportedly twice the normal levels [ ] . in addition, pulmonary vascular inflammation specifically leads to a phenomenon known as ace- "shedding, " where endothelial surface-bound ace- is released into the interstitium [ ] . this phenomenon initially produces a sharp increase in local angii that gradually decreases until concentrations are well below physiologic levels [ ] . because angii downregulates ace- expression, transition to a state of angii deficiency is consistent with the increased ace- expression noted at autopsy [ ] . of note, angii reportedly increases microvascular permeability under basal conditions but decreases permeability during inflammation, an effect attributed to the inflammation-induced shift from type- to type- receptor expression [ ] . postulating that covid- is a vascular and hypoinflammatory disease has important implications for ongoing research. however, more evidence is needed to explore vascular injury through biomarkers, imaging, and histology. if covid- is indeed primarily a vascular disorder, early invasive mechanical ventilation should be initiated cautiously. investigations should examine the impact of liberal versus restrictive invasive mechanical ventilation strategies. we reiterate that there is no evidence that covid- patients develop "cytokine storm. " this finding suggests that the use of cytokine-blockade agents should meet with skepticism in the absence of randomized evidence. however, anticoagulation should be a key priority for investigation. similarly, given the putative role of angii deficiency, a randomized trial of angiotensin-ii treatment in covid- patients who have progressed to shock is warranted. illness progression may also be an effect modifier, with potential benefits of anti-inflammation and angiotensin blockade earlier in critical disease and harms at later time points. covid-induced respiratory failure involves physiologic, clinical, and immunologic phenotypes that are not consistent with either ards or cytokine-release syndromes. covid- instead reflects immunosuppression and features compatible with vascular disease. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. covid- does not lead to a "typical" acute respiratory distress syndrome covid- pneumonia: different respiratory treatment for different phenotypes? dysregulation of immune response in patients with covid- in wuhan, china development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials chimeric antigen receptor t cells for sustained remissions in leukemia chest ct features of covid- in findings of acute pulmonary embolism in covid- patients ( / / ) pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer coagulopathy and antiphospholipid antibodies in patients with covid- renal histopathological analysis of postmortem findings of patients with covid- in china composition and divergence of coronavirus spike proteins and host ace receptors predict potential intermediate hosts of sars-cov- coronaviruses: an overview of their replication and pathogenesis clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury responses of serum and lung angiotensin-converting enzyme activities in the early phase of pulmonary damage induced by oleic acid in dogs angiotensin ii type receptor provides an endogenous brake during inflammation-induced microvascular fluid leak key: cord- -pol qm authors: nan title: third international congress on the immune consequences of trauma, shock and sepsis —mechanisms and therapeutic approaches date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: pol qm nan this issue of the journal contains the abstracts for the third international congress on the immune consequences of trauma, shock and sepsis -mechanisms and therapeutic approaches. we hope that the information contained in this special issue will stimulate you to participate in the congress, to contribute to the knowledge being developed in this field and to use this information to help you in providing better care for your patients. we thank the editors and the editorial board and publishers of the journal for their interest and support in preparation of this special issue. we also, on behalf of the scientific committee, welcome you to the third international congress in munich on - march . when, in the mid- s, we thought of having a worldwide congress, we hoped to bring together investigators to discuss this theme. the explosion of knowledge occurring around that time provided an excellent background against which the first conference in provided stateof-the-art information and consensus on factors involved in injury and sepsis. in , the second congress was held at the time of another resurgence of research, study and information on injured and operated patients. it seemed then that there would be a lull in the development of new information and therapy, and that another state-of-the art conference might not be necessary until or . however, the explosion in molecular biology has continued. the wonderful world of cytokines has gone from ill to il- to il- , il- and il- and beyond. the vast amount of information about mediators and their importance in disease is impressive. this has all suggested a magic bullet that might be used to alter or block inflammatory responses. this has not happened, however, and the question is "why not"? our science is powerful, but our therapy is still weak. what are the issues, then, in , to be dealt with at this symposium and congress? ( ) proposals for new terminology. there have been a number of proposals for new terminology and new classifications of injury, sepsis, inflammation and various other problems related to human illness. the question is whether this is the way to go. will this contribute to better clinical trials, information basis and better research? the pros and cons of this development will be reviewed by those making the proposals and those questioning the need for and wisdom of this effort. ( ) magic bullets: the prospect of a magic bullet to deal with inflammation in injury and infection seemed highly promising earlier. many preclinical trials and a lot of animal research suggested the possibility of a great breakthrough in clinical care. what has become, then, of all the expensive and extensive multi-institution randomized, placebo-controlled, double-blind clinical trials of agents that block mediators and endotoxin. many such studies have yielded equivocal, marginal or negative results. the reasons for this and the future of clinical research will be the subject of presentations and discussions to set the stage for further work. ( ) should future clinical trials be based on new classifications of illness such as mods, sirs, apache iii, sap ii, mrm, etc., or should trials be dedicated to specific diseases -urinary tract infections, pneumonia, trauma patients, cardiac surgery and other specific problems, rather than generalized problems of sepsis, the sepsis syndrome and other classifications? in other words, should we now begin to have clinical trials on specific diseases with causes that are known and can be attacked? the causality of disease becomes an important consideration in this regard. ( ) a multitude of potential therapeutic agents has been proposed on the basis of animal studies. how should we decide which of them should be brought to clinical trial? the possibilities are endless as we develop new clinical information about the mechanisms and pathogenesis of human disease. ( ) information on the pathogenic mechanism of disease states and of injury continued to emerge in an explosive fashion, and in light of our gathering knowledge we can look forward to working out a cohesive system of response to injury. ( ) additional information will be provided in plenary sections, many symposia and free communication sessions and posters, which will update the participants on a variety of relevant topics presented by many of the leading in-iv vestigators in these fields. topics will range from molecular mechanisms, such as signal transduction, through the explosive growth of information on the role of cytokines and pathophysiology, to practical considerations in the design of immunomodulatory therapeutic regimens. these merely touch on a few areas, from the basic to the clinical, which will be the subjects of those symposia. all this information will fit into the jigsaw of this exciting area and its stimulus to further research study. this promises to provide an exciting, educational programme with experts and participants from all over the world. we hope it will set the stage for many years to come and will increase our understanding of trauma, shock and sepsis and help us to provide better therapy for those of our patients who are affected by such problems. a. the clinical syndrome of mods versus mof will be reviewed in detail by those who have made these proposals. b. an extensive review of the design and interpretation of clinical trials in patients with shock and injury will be provided. the reasons why so many clinical studies in the recent past have been negative will be reviewed. the therapeutic strategies that are being developed for the treatment or prevention of mods or mof will be the subject of another panel discussion by experts who have been involved in and contributed to this area. a consensus conference or controversy conference will be presented about various aspects of mods or mof, including the benefits of supernormal oxygen delivery, bacterial translocation, parenteral nutrition, the immune response and other aspects. the successes and failures of completed clinical trials will be presented by those who are involved in these clinical trials, with a refreshing review of the problems related to that injury. there will be late news about studies just being completed at present or after the beginning of and where they stand. c. the mechanisms and biochemical profiles of specific organ dysfunction or failure will be reviewed. what are the definitions? what are the mechanisms? how can organ dysfunction and/or failure be defined? an extensive review of the biological mechanisms involved in production of injury by mediators will be presented. a session will be devoted to how future ongoing trials might be better designed and what can be done about the studies recently completed, many of which are negative. d. the immunological or inflammatory pathways resulting in organ injury will be reviewed in detail in presentations and a panel discussion. we look forward to welcoming you to an exciting and rewarding conference, which undoubtedly possesses the potential to become a landmark event and major reference point for any scientific discussion about the complex of host defense dysfunctions following trauma, shock and sepsis. studies over the past years have established that the contact system, which forms bradykin/~, is gax important mediator in hypotensive septicemia. in addition to hradyk{nln, another product of the contact system, kailikrein, can mediate inflammation by virtue of its chemotaetic mad neutrophj/activating properties. using functional and immunochemical tech~ ques, we have demonstrated activation of the contact system in the adult respiratory distress syndrome in typhoid fever and clin/cal sepsis. we have also been able to inhibit the hypotension but not the disseminated intravaseular coagulation in a model of primate sepsis by the use of a monoclonal antibody directed agsi~st factor xii, the initiating protein of the contact system, in volunteers given e. coil endotoxin, who did not develop hypotension, we were also able to demonstrate activation of the contact system with a rise of alpha- macrogiebulin-kalllkrein complex. we have also examined, j~ an i~tensive care situation, patients with sirs. we found that serial measuremezzts of the contact system were useful in eva~u~ting prognosis+ these studies suggest that inhibition of kalllkrein a~d l e r bradykinin actions might be useful i~ obviating many .of the features seen in sepsis and septic shock. dextran sulfate (dxs) activates the contact system and, in vivo, produces transient hypotension. in order to better define the mechanisms underlying the dxs-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor, des-pro -iarg] ]aprotinin (bay ) or the b kinin antagonist, hoe on the hypotensive response to dxs. in the first study, anesthetized miniature pigs ( pigs/group, randomly assigned) were given one of the following treatment protocols: ) dxs ( mg/kg), - ) dxs plus bay ( , , , or rag), or ) saline. dxs alone produced a profound but transient systemic arterial hypotension with a corresponding reduction in plasma kinin-containing kininogen. circulating kinin levels, complement fragment c adesarg and fibrin mom)mer were all increased. bay produced a dose-dependent delay or attenuation in these effects with the highest dose completely blocking dxs-induced hypotension and elevations of kinin, c adesarg and fibrin monomer levels. thus, the effects of dxs are solely dependent on contact system activation and this activation is sensitive to bay . llowev~:r, contact system activation is known to produce changes in a variety of vasoactive mediators, all of which can affect blood pressure. in a second study, two groups of pigs ( /group) were given either dxs alone ( mg/kg) or dxs minutes after a bolus injection of hoe ( #g/kg). dxs alone produced transient hypotenmon. this response was completely blocked by hoe pretreatment. both groups had identical reductions in kinin-containing kininogen. we conclude that dxs-induced hypotension is produced by activation of the contact system which results in the production of bradykinin. liberation of bradykinin is both necessary and sufficient to produce all of the hemodynamic changes observed. dr. matthias siebeck, department of surgery, university of munich, klinikum lnnenstadt, nussbaumstrasse , d- munich, germany in experimental animals exposed to i.v. injection of endotoxin accumulation of leukocytes in various organs as lungs and the liver is a prominent feature. as a part of these morphological changes damages of endothelial ceils are regularly seen. this process, which is a part of endothelial-cellular interaction, leeds to exposure of the sub-endothelial basement membran. the basement membran is known f r its capacity to activate the contact system of plasma. during this cascade activation, coagulation factor xii is converted to the active factor xii. this activation might produce increased plasma kallikrein activities and thereby give release of the vasoactive substance bradykinin. using a porcine model we have noticed that endotoxin infusion ( , mg/kg) induces elevated plasma kailikrein activities within two hours after the start of the infusion. this enzyme activity remained increased during the next hours and reached value of up to u/ . in patients with sepsis we also have observed elevated plasma kallikrein activities with enzyme activities up to u/ . in order to further elucidate the significance of these elevated enzyme activities, we prepared human plasma kallikrein and injected it intravenously in anaesthetized pigs ( ). when very small plasma kailikrein activities ( , u/kg bodyweight) were given intravenously a % decrease in arterial blood pressure was seen in the animals. in the patients with sepsis also decreases in prekallikrein values and functional plasma kallikrein inhibition are frequently seen. furthermore, degradation of high molecular weight kioinogen is found in these patients indicating formation of bradykinin. these experimental and clinical studies underline that contact activation in sepsis might results in the release of very powerful mediator substances which can be of pathophysiological importance in this disease. a number of pathological disorders as reperfusion injury, bone marrow transplantation, polytrauma and septic shock are associated with capillary leakage. as the activation of the complement system and the contact phase play a major role in these diseases we investigated whether cl-lnhibitor (c -inh), which inactivates cl-esterase, kallikrein and clotting factors xii and xl, could abolish vascular leakage. a capillary leakage was induced in rats by the administration of interleukin- ( x iu/kg). the increased vascular permeability was monitored for one hour as the extravasation of fitc marked rat serum albumin from a mesenterial vessel by a video-image processing system. ci-inh (berinert®, behringwerke) given as a single i.v. bolus in concentrations of , or u/kg dose-dependently prevented the capillary leakage. carrageenaninduced inflammation in the rat leads to vascutar leakage and to edematous swelling of the paw. ci-inh in this model leads to a dose-dependent decrease in paw edema formation. finally, we investigated the effect of ci-inh (infusion ( - u/kg x h) on a lps-induced shock in the rat by combination therapy with the antithrombotlc agents antithrombin ill (kybernin®) or rec. hirudin (both substances from behringwerke). in this animal model mortality was % in the untreated control. both antithrombotic agents decreased mortality rates by inhibiting formation of dic; a further significant improvement of survival was achieved by the treatment with ci-inh. thus+ it could be concluded that c -inh has a beneficial effect in diseases associated with a vascular leakage. iclb and laboratory for experimental and clinical immunology, university of amsterdam, the netherlands; thrombosis research center, temple university, penn., usa; oklahoma medical research foundation,. ok. city, usa. to evaluate the contribution of the contact system to activation of other mediator systems in an experimental model of sepsis, we investigated the effect of mab c b which inhibits activation of factor xli, on activation of complement and fibrinolytic cascades and activation of neutrophils in baboons suffering from a lethal sepsis. activation of the complement system was assessed by measuring circulating levels of c b/c and c b/c, and a significant reduction was observed in animals that had received a lethal dose of e. coli together with mab c (treatment group), compared to animals that had received a lethal dose of e. coil only (control group). activation of the fibrinolytic system as reflected by circulating plasmin-= antiplasmin complexes and tissue plasminogen activator, and activation of neutrophils, assessed by measuring circulating elastase-=l-antitrypsin complexes, was also significantly less in the treatment group. we conclude that activation of the contact system protein factor xll during the inflammatory response to a lethal dose of e. coil in this baboon model, modulates directly or indirectly activation of the complement and fibrinolytic systems and that of neutrophils. in a prospective study, plasma levels of c a, c , and c a were measured in patients from an internal intensive care unit. patients were clinically septic defined by the criteria of bone et al.(l) . the remaining patients were critically ill but didn't fulfill the clinical criteria of sepsis. from both groups of patients blood samples were taken over a l days period. during the first days blood samples were drawn every h, on day - every h and the last days once daily. mean plasma concentrations of c a within the first h after clinical onset of sepsis were + pg/ml, whereas non-septic-patients exhibited mean values of only +_ p_g/m/. c levels were lower for septic-patients ( + lag/ml) than for non-septic-patients ( _+ lag/ml). the most profound difference between both groups was found, when the c a/c ratio was compared ( . + . for septic-patients and . _+_ . for the control group). no significant differences between both patient groups were observed in c a plasma levels ( . + . ng/ml in septic-patients vs. . _+ . ng/ml in control patients). in of cases of clinically defined sepsis causative organisms like bacteria, protozoa or fungi could be cultured from blood, bronchoalveolar lavages and/or section materials. application of the complement parameters to survivors (n= ) and non-survivors (n=l ) within the septic-group revealed, that the c a/c ratio could also be used as a prognostic parameter for clinical outcome. the possibility of rapid and easy measurement of c a and c in only - minutes ( ) and the significant difference of the c ajc ratio between the septic and non-septic group renders this parameter a good candidate for early diagnosis of sepsis in the intensive care unit. hirudin, a single polypeptide chain composed of amino acids with cysteine residues (mr daitons), is the most potent and specific thrombin inhibitor, which is now available as a genetically engineered product (rec. hirudin -hbw , behringwerke; marburg). the aim of our study was to establish a rabbit model of tissue factor (tf) induced activation of the extrinsic pathway of coagulation and to evaluate the therapeutic efficacy of rec. hirudin. coagulation was induced in female nzw rabbits by infusion of . p.g/kgxh thromboplastin for hours. development of disseminated clotting was manifested by a decrease of fibrinogen and platelets to . % and , % respectively, and by an increase of fibrin monomers from . to > . ~tg/ml. we administered rec. hirudin to rabbits in different concentrations ( . , . and . mg/kg); treatment started simultaneously with the infusion as an i.v. bolus. rec. hirudin significantly prevented the decrease of fibrinogen, platelets and the increase of fibrin monomers. this effect was dose dependent and long lasting, even hours after the administration of rec. hirudin, clotting was still significantly reduced. as could be drawn from the plasma levels, rec. hirudin had been cleared from plasma at this time. in a post-treatment study we administered rec. hirudin ( . , . and . mg/kg i.v. bolus) as late as hours after the start of tf infusion. at this time there was already a prominent activation of coagulation. even in this post-treatment regimen rec. hirudin significantly prevented disseminated clotting. hence, it was concluded, that rec. hirudin by inkihiting thrombin could be effective in the prevention of coagulation disorders including disseminated intravascular clotting (dic) induced by a septic disease. research laboratories of behringwerke ag, marburg, germany $ novel protease inhibitory activities of the second domain of urinary trypsin inhibitor (r- ) and its effect on sepns-lnduced organ injury in rat atsuo murata , hitoshi toda , ken'ichi uda , hidewaki nakagawa , takesada mori , hideaki morishita , tom yamakawa , jiro hirese , atsushi ni~ , nariaki matsuura osaka university medical school, osaka, mochida pharmaceutical co. ltd. tokyo, wakayama medical schoof, wakayama, japan inhibitory-activities of the second kuntz-type inhibitor domain of human urinary trypsin inhibitor (uti) and its effect on sepsis-induced organ injury in rat were investigated by using the recombinant protein. uti is a glycoprotein with a structure in which kunitz-type inhibitor domains are linked in a row. we isolated the gene encoding the second kunitz-type inhibitor domain of uti, and then constructed expression plasmids by ligating it to the e. coli phoa signal peptide gene. these plasmids expressed the second domain in e. coil strain je which lacks the membrane lipoprotein. the recombinant second domain (r- ) innb[ted trypsin, plasmin, neutrophil elastase and chymotrypsin. in addition it inhibited blood coagulation factor xa and plasma kallikrein in a concentration dependent and competitive manner. the in vivo effect of the recombinant r- was investigated in a rat model of septic shock induced by cecal ligation and puncture. the administration of r- significantly improved the survival rate of the rats and attenuated the pathological changes of lung and iiver. we found out the novel protease inhibitory activities of the second domain of uti and its protective effects on sepsis-induced organ injury. macrophages are known to secrete lysosomal proteinases,mainly cathepsin b and cathepsin l, and also ~-proteinase inhibitor (pi),related to acute phase proteins.disturbances of proteinases/ proteinase inhibitors correlates with inflammatory process,leading sometimes to noncontrol "pathglogical" proteolysis (jochum et ai., ) . the cathepsin l-like and cathepsin b-like activity were measured in serum of patients with chronic bronchitis ( -with obstructive, -with nonobstructive bronchitis),acute bronchitis ( ) and healthy persons.simultaneously the level of~pi was determined in the same groups.cysteine proteinases were measured with help of fluorogenic substrates,as was presented earlier (korolenko et ai., ) , ~pi with help of immune enzyme method. it was shown increase of cathepsin l-like and cathepsin b-like activities during aggravation of chronic bronchitis comparatively to the controls ( - fold) .after treatment there was a tendency to normalization of indices,but the increase was about - % more than the control values.~pi level in this group was also increased (two-fold),in patients with acute bronchitis - - -times more comparatively to the control.it is possible to conclude that chronic bronchitis induced increased secretion both cysteine proteinases and d{pi into blood. some peculiarities of ratio were noted in patients with emphysema. endotoxins are microbial products derived from the outer cell membrane of gram negative bacteria. the active component of endotoxin is lipopolysaccharide (lps), a complex macromolecule consisting of polysaccharide covalently bound to a unique lipid, termed lipid a. now recognized to embody the endotoxic principle of lps, lipid a consists of a/ - diglucosamine backbone, both ester and amide linked fatty acids, some of which are acyloxyacylated, and charged constituents such as phosphate, phosphorylethanolamine and amino arbinose lps, exerts its biological effects in vivo by noncytotoxic interactions with a variety of host inflammatory mediator cells, primarily the mononuclear phagocyte and the endothelial cell, although other host cells also participate. these interactions are modulated by lps-specific binding proteins found in plasma, including lps-binding protein (lbp) scd and perhaps other proteins as well. specific receptors for lps have been identified on mammalian cells which mediate signal transduction via multiple pathways. lps-activated host cells are stimulated to secrete or express multiple proinflammatory mediators, including tnf-a, illa, il- / , ifn-a, il- , il- , il- , paf, pge, ltb and procoagulant activity. the overproduction of these proinfiammatory mediators results in the manifestations of endotoxemia, observed experimentally as fever, hypotension, disseminated intravascular coagulation and death. modulation of activity of these mediators protects animals against lethality. similar pathways are thought to be operative in gram negative sepsis, and control studies with human volunteers support such conclusions. immunotherapeutic approaches in clinical gram negative sepsis have, to date, been less successful. in vitro experiments and studies in animal models have recently shown that several proteinaceous bacterial exotoxins can evoke cytotoxic effects that ultimately lead to cardiovascular collapse and shock. since the possible relevance of bacterial exotoxins in the pathogenesis of septic shock has received very little attention in the past, an attempt will be made here to provide a brief overview of this generaily neglected topic. protein toxins act intracellularly or they dz~nage the integrity and function of the plasma membrane. major representatives of the former group are the adenosine diphosphate (adp)-ribosylating toxins, e.g. cholera and cholera-like toxins, diphtheria toxin), and the neurotoxins. most medically relevant toxins of this category have been studied in great detail. although often responsible for severe and sometimes fatal disease, their association with septic shock is rare. in contrast, experimental evidence is accumulating for a role of membrane<lamaging toxins in the pathogenesis of inflammatory lesions. formation of transmembrane pores is probably the most widespread mechanism via which such physical membrane perturbation can occur ( , ), the present discussion will be restricted to this category of toxins. the author shall first discuss basic properties of pore-forming proteins, and consider the factors that direct their attack to specific targets. thereafter, attention will be drawn to diverse functional consequences that may follow membrane damage so that a general concept of how pore-forming toxins may contribute towards the development of shock will evolve. i. bhakdi, s. and tranum-jensen. j. gram positive bacteria produce exotoxins that, at least in part, exhibit the unusual properties of superantigens. superantigens (sag) activate v/ selectively t cells to produce lymphokines including i - and tnf/lymphotoxin. systemic application of the sag staphylococcal enterotoxin b (seb) to d-galactosamine sensitized mice causes lethal shock within hours. seb reactive v/ + t cells accumulate within - min mrna for the ii- , i - , tnfai~ and ifn- ,. parallel in time high concentrations of bloodborne i - and tnf are noted. anti tnf t~// neutralizing mab protect mice against seb induced t cell dependent lethal shock thus indicating a key role of tnf in effecting lethal toxicity. within - h distinct levels of tolerance to seb become discernable on ligand reactive v/ t ceils, dependent of the dose of seb used. these levels include anergy, t cell receptor downregulation, loss of cd , cd , cd accessory molecules and programmed cell death. m.freudenberg, y.yaegashi, p.nielsen, c.galanos. the sensitivity towards endotoxin (lps) is genetically determined, however it may be increased under different experimental conditions. these include treatment with hepatotoxic agents such as d-galactosamine, and with live (infection) or killed bacteria. it is well established now that d-galactosamine sensitizes to lps by increasing the susceptibility of the host to toxic activity of lps-induced tnf~. sensitization by bacteria, especially by gram-negative once is of especial interest because it implies that infecting microorganisms not only produce lps, but als sensitize the host to its lethal activity. sensitization to lps by bacteria proceeds in all lps-sensitive (lps n) mouse strains that have been investigated so far. it also proceeds in lps-resistant (lps d) c h/hej mice. the absence of sensitization to lps in lps d c bl/ sccr mice was identified as being due to their inability to produce interferon- (ifn?). administration of exogenous ifn? to these mice conferred sensitivity to lps. conversely, administration of anti-ifn? to lpsn; mice inhibited the development of sensitization'by bacteria. it may be concluded therefore that ifn is the mediator of sensitization to lps by bacterial infection. the ifn? defect of c bl/ sccr mice concerns only the ifn response to bacteria, since the response to the t-cell mitogen con a and to cd monoclonal antibodies was not impaired. the ifn?producing cells themselves were shown to be intact. on closer investigation the impaired ifn? response was identified as the result of a defective accessory function of macrophages. macrophages of c bl/ sccr mice are incapable of producing interferon-~ (ifn~) which we could show to be obligatory for the production of ifn? in response to bacteria. although antibiotics are required to clear bacteremia, they do not reverse evolving shock, because endotoxin free in the bloodstream or exposed on the surface of circulating bacteria continues to activate the production of inflammatory mediators, furthermore, antibiotics have been shown to induce release of endotoxin from gram-negative bacteria during the treatment of severe infection. in an in-vitro study, using live escherichia coil, we have observed the release of endotoxin upon treatment with several antibiotics like cefuroxim, imipenem, ceftazidime and aztreonam. incubation with imipenem or ceftazidime induced an early lyeis and a mild rise in endotoxin levels, whereas incubation with cefuroxime or aztreonam resulted in the formation of filaments with a late but dramatic rise in endotoxin levels. in a second study we studied the influence of different antibiotics on the tnf-= production of e.coli stimulated human monocytes. we found again great differences in the production of this important cytokine among the different antibiotics according to their capacity to induce liberation of endotoxin. these differences in the amount of endotoxin release are probably caused by penicillin-binding-proteins (pbp) specificities of the antibiotics with resultant differential morphological changes, in a rat sepsis model treatment with imipenem or ceftazidime resulted in a transient increase in il- levels, whereas treatment with aztreonam resulted in progressively increasing levels of il- and a significant increase in mortality. the increased mortality in pbp- specific aztreonam treated rats might have been the result of filament formation in the abdominal cavity of the septic rats. the endotoxin sequestered at local sites may account for the precipitation of gram-negative shock. finally, we've also demonstrated that in patients under treatment for septic shock endotoxin release can be related to the administration of antibiotics. carbapenem-and cephalosporin-lnduced release of lps from smooth and rough pseudomonas aeruginosa: in-vivo relevance j. jackson and h. kropp, merck research laboratories, rahway, nj b-lactam (cell-wall active) antibiotics are generally deemed the class of antibiotics most responsible for the release of free endotoxin (lps) from gram-negative bacteria due to their cell lytic actions although all antibiotic classes studied thus far induce release of endotoxin. we have recently shown in-vitro that antibiotics within the b-lactam class (i.e. imipenem , meropenem and ceftazidime , with equivalent mics) differ in their propensities to release excessive amounts of lps from both smooth-(s-) and rough-(r-) lps laboratory and clinical and antibiotic-sensitive and -resistant p. aeruginosa isolates and that lps release is independent of cell lysis. additionally, variations in the induction of endotoxin release is antibiotic concentration dependant and correlate with antibiotic penicillin-binding protein (pbp) affinities which result in morphological changes. these studies also show that lps differences measured via chromogenic lps (c-lal) assay correlate with lps lethality in lps-sensitive mice. release of lps was compared to changes in cfus, cell mass, morphology and antibiotic pbp-specificity. corresponding in-vivo studies in cd mice against s-lps p. aeruginosa isolates show that, despite equivalent in-vitro protection, antibiotic efficacy in mice differ as much as -to lo -fold. to establish a possible in-vivo role for antibiotic-induced release of free lps we compared antibiotic efficacy results in mice challenged with virulent parent s-lps and its relatively avirulent r-lps mutant (lacking only its side chain) p. aeruginosa isolates. results show the relevance of quantity and physiochemical composition (bioreactivity) of free lps to virulence and in-vivo antibiotic efficacy. in other in-vivo studies chemical agents that destroy cells (m~) which mediate lps lethality in-vivo were used to pretreat mice prior to antibiotic therapy and bacterial challenge with wild type pseudomonas. we conclude that circumstances in which antibiotic-induced filamentation occurs are also conditions that yield excessive lps release, the in-vivo effects of which are shown through the requirement of larger amounts of antibiotic to afford equivalent protection. bacterial endotoxins have been reported to play a significant role in the pathogenesis of gram negative sepsis by their interaction with, and stimulation of, host inflammatory mediator cells to produce cytokines, biologically active lipid intermediates, and procoagulant activity (tfa). although both microbe-associated and free endotoxin are capable of stimulating mediator production, studies from our laboratory suggest that free endotoxin may be the more potent stimulus for tnf and tfa. further, our studies suggest that the majority of the proinflammatory activity released from antibiotictreated e. coli coisolates with lps by two different fractionation techniques. to assess whether actions of endotoxin directly contribute to lethality in gram negative sepsis, an experimental model was developed in which mice were made hypersusceptihle to the lethal effects of endotoxin by treatment with d-galactosamine (dgaln). challenge of cf- dgaln-treated mice with e. coli olll:b resulted in an lds of approximately . x cfu. resolution of the peritonitis and bacteremia by treatment with cell wall-active antibiotics resulted in an increase in the ldso. ceftazidime and imipenem, which differ in their mechanism of action and in their capacity to effect endotoxin release in vitro, also differed in their in vivo capacity to provide chemotherapeutic protection ( fold vs fold respectively, p< . ). parallel studies with endotoxin hyporesponsive c h/hej mice indicate significantly greater levels of protection with imipenem (> fold vs saline controls). collectively these data suggest that endotoxin may contribute directly to the pathogenesis of experimental gram negative sepsis. bacterial lipopolysaccharides (lps) are the endotoxins of gram-negative bacteria and represent their major surface antigens. lps is made up of three chemically, biologically and genetically disctinct regions, i.e, the o-chain, the core region and the lipid a moiety whereby the latter represents the endotoxic center. it is our current understanding that lps is responsible for many of the pathophysiological events observed during gramnegative infections and that one of the major mechanisms leading to shock and death is the lps-induced activation of macrophages resulting in the production and release of lipid and peptide mediators, among which tumor necrosis factor seems to be the most important. therefore, in the fight against the lethal outcome of gram-negative infections, modern strategies, in addition to antibiotic treatment, aim at i) the neutralization of tumor necrosis factor, ii) the inhibition of the production of tumor necrosis factor or iii) the neutralization of the activation potential of lps for macrophages by monoclonal, preferably human antibodies. the latter approach, to be effective against a broad spectrum of gram-negatives, must be directed against common structures of lps (lipid a and core region). the molecular basis of this approach and the controversy in this field will be discussed. passive immunotherapy has been used since , when von behring described the administration of immune horse serum to treat a patient with diphteria infection. even if this therapy was sometimes successful in bacterial infections, it has been largely replaced by antibiotics. however, antibiotics have their limitations, especially in critically-ill patients. to improve outcome, adjunctive therapies such as immunotherapy with polyclonal and monoclonal antibodies particularly against endotoxin are again considered. the role of humoral immunity in host defenses against bacterial infections is weu known. for instance, tile importance of antibodies in the defense against gramnegative infections has been established clinically by studies relating the outcome of patients with gram-negative bacteremia to tilers of antibodies directed at the offending pathogens at the onset ofbacteremia (mccabe ; pollack ) . ever since we know the role of endotoxins in the pathophysiology of sepsis, antibodies against the s-and r-lps have also been detected in sepsis patients. the aim of the administration of iv/g to the sepsis patient is as follows: ) enhancing of opsonization and phagocytosis(antibactericidai activity) ) synergistic effects with [ - actam antibiotics ) neutralization of endotoxin, the main pathogenic mediator of gram-negative sepsis ) modulation and/or inhibition of cytokine release the enhancement of opsonic-and phagocytic-activity especially with igg via fc and c receptors has been well documented. monoclonal antiendotoxin antibodies, proven in clinical studies, do not appear to neutralize endotoxin in vitro and are not reproducibly protective in animal models of sepsis. also they can not suppress endotoxin-induced tnf-~, il- release in mice (baumgartner , corriveau and danner ) . in conlrast, recent studies of a polyclonal immunoglobulin preparation, containing high levels of antibodies against gram-negative bacteria and their o-antigen of lps in igg, igm and iga classes (pentaglobin®) provide evidence to neutralize endotoxin. this effect is demonstrated in vitro (berger (berger , , in animal models (stephan , berger and also in prospective, randomized, controlled clinical trials (schedel , poynton , behre . furthermore mortali b' was reduced statistically in patients with septic shock and endotoxemia by using this preparation, as has been demonstrated by sehedel. anti-core lps monoolonal antibodies: binding specificity and biological properties f.e. di padova, r. barclay, e.th. rietschel. bacterial lps and cytokines are responsible for the pathological processes of gram-sepsis and are suitable targets for therapeutic interventions. chemical characterization and structural analysis of different lps have revealed common features. the inner core region of lps shows a high degree of similarity among e. coli, salmonella and shigella. among a large number of broadly cross-reactive murine anti-core lps mab one of these igg ak) has been selected and chimerized into a human igglk (sdz - ). in elisa and in immunoblots on purified lps both sdz - and wni - show a strong reactivity with all smooth lps from e. coli and salmonella. reactivity with all the known complete core structures from e. coli and salmonella (ra) is evident. reactivity with re structures or free lipid a is not observed. this mab cressreacts with all clinical e. coli isolates from blood, urine and feces and with other enterobacteriaceae. sdz - and wni - have biological activity as they inhibit the lal assay and the secretion of monokines (il- and tnf) by mouse and human macrophages. moreover, sdz - and wni - inhibit the release of il- and tnf in vivo. in vivo sdz - as well as wni - neutralize the pyrogenic activity of e. coli lps and protect mice from lethality in d-gain-sensitized mice. the possibility to use wni - as a capture antibodies in the immunolimulus assay opens the possibility to differentiate the origin of the lps in patients with endotoxemia. franco di padova, sandoz pharma ag, ch basel, $chweiz $ presentation of lps to cd by lps binding protein peter s. tobias, julie gegner, katrin soldau, lois kline, loren hatlen, douglas mintz, and richard j. ulevitch. the activation of myeloid cells by lipopolysaccharides (lps) has been shown to require the serum glycoprotein lps binding protein (lbp) and binding of lps to membrane bound cd (mcd ). other cells such as human umbilical vein endothelial cells (huvec), smooth muscle cells, and some epithelial cells, which do not express mcd but nevertheless respond to lps in the presence of serum, have receptors for complexes of lps with the soluble form of cd (scd ). these complexes of lps with scd are only formed efficiently in the presence of lbp. we have begun to characterise the mechanisms by which lbp enables lps to bind to cd , either soluble or membrane bound. with the use of fluorophore and radiolabelled reagents we have developed procedures for quantitative measurement of the association of lps with lbp and of lps-lbp complexes with cd . these results show that the delivery of lps to scd is catalysed by lbp, i.e., lbp is not included with the lps-scd complex. in contrast, on the surface of cells, lbp does not dissociate from the cells after lps binds to mcd . the kinetics, equilibria and stoichiometry of these reactions will be discussed in the context of models for cellular activation by lps and cellular uptake of lps. supported by nltt grants gm , ai , ai , gm , and assistance from the pharmaceutical research institute of johnson and johnson. the scripps research institute, imm- , n. torrey pines rd. la jolla, ca usa . modulation of endotoxin-induced cytokine production by lps partial structures h.-d. flad, h. loppnow, t. mattern, and a.j. ulmer department of immunology and cell biology, forschungsinstitut borstel, d- borstel lipid a constitutes the active moiety of endotoxin (lps) of gramnegative bacteria. it activates mononuclear phagocytes to produce cytokines, such as tnf, i _- , and il- , which are the major mediators of the endotoxic effect of lps in vivo. lipid a precursor la (synthetic compound ) does not induce cytokines, but is able to specifically antagonize lps-or lipid a-induced mediator production in human mononuclear cells, vascular endothelial cells, and smooth muscle cells. furthermore, we present evidence for the first time that t-lymphocytes proliferate in response to lps and express mrna for interleukin- and interferon-~ and that these responses are also antagonized by synthetic lipid a precursor la. when comparing the agonistic and antagonistic activity of lipid a and different partial structures at the functional and binding level, the number and length of the fatty acids and the number of phosphoryl groups were pound to be of crucial importance. unexpectedly, lipid a precursor la, although biologically inactive, turned out to be both the most potent antagonist and competitor in inhibiting the binding of lps. taken together, our results provide evidence for a model in which lipid a partial structures compete with lps for specific cell surface receptor(s). in this sense, biologically inactive lipid a analogues may be good candidates as therapeutic agents for the prevention of gram-negative septic shock. two mammalian lipid a-binding proteins have been identified that are believed to have important roles in mediating the host response to endotoxin: lipopolysaccharide-binding protein (lbp) and bactericidal/ permeability-increasing protein (bpi). human lbp shares a % amino acid sequence identity with human bpi. despite the sequence homology, the two lipid a-binding proteins have very different functional activities. lbp is an acute phase serum protein that markedly potentiates the proinfiammatory host response to gram-negative infection by a mechanism which involves binding of the lbp-lps complex to cd receptors on monocytes, neutrophils and endothelial cells. in contrast, bpi is a neutrophil granule protein with potent bactericidal and lps-neutralizing activities. the divergent functional properties of these two lps-bindlng proteins can be explained by the inability of bpi-lps complexes to bind to cell-surface cd receptors. a recombinant protein (rbpi ), corresponding to the amino terminal kd fragment of human bpi, has been shown to retain the potent biological activities of the hdlo protein and may represent a novel therapeutic agent for the treatment of gram-negative infections, sepsis and endotoxemia. for therapeutic effectiveness in many clinical situations, rbpi will have to successfully compete with relatively high serum levels of lbp ( - ~g/mi) for binding to endotoxin and gram-negative bacteria. to evaluate this issue, experiments were conducted to compare the relative binding affinities of rbpi and human recombinant lbp (rlbp) for lipid a. the binding of both proteins to iipid a was specific and saturable with apparent kd's of . nm for rbpi and nm for rlbp. in a competition assay format rbpi was approximately -fold more potent than rlbp in inhibiting the binding of nsi-rlbp to lipid a. these results demonstrate that rbpi has a significantly higher affinity for endotoxin than does rlbp and may explain the potent inhibitory activity of low concentrations of rbpi in a variety of in vitro functional assays for lps activation of cells despite the presence of high lbp levels. for example, rbpi at . ~tg/mi was able to totally inhibit lps-induced tnf release from monocytes despite a -fold weight excess of rlbp over rbpi . and for heparin binding. three separate domains which inhibit the lal reaction to lps and bind to heparin were identified in amino acid regions - , - and - . a single synthetic peptide ( - ) was bactericidal. these results suggest that rbpi contains three separate functional domains which may contribute to its high affmity interaction with gram-negative bacteria and heparin. the individual activity of each domain and the cooperative interaction among domains provide the basis for developing rbpi analogues with increased biologic efficacy. a considerable body of experimental data has accumulated implicating tumour necrosis factor (tnf) as a principal mediator of the pathophysiological features of septic shock. these data prompted the development of clinical strategies designed to limit excess (inappropriate) tnf production. monoclonoal antibodies (mobs) were developed and a phase ii dose escalation trial in patients confirmed that the mab was safe, and suggested that it was having a beneficial effect on certain parameters. preliminary results of a large phase iii study indicated that (a) the mob was safe; (b) that it was of no discernible benefit in non-shocked patients; (c) that it reduced mortality in shocked patients, especially during the first days. an alternative strategy was to take advantage of the high binding affinity of soluble receptors for tnf (stnfr). stnfr-iggfc constructs were made for both the p and p receptors. both were effective in animal models of lps challenge, but when a clinical trial was done with the p stnfr-fc there was unexpected mortality in the treated arm. using an animal model of live e.coli sepsis, we have shown that this may have been due to the release of bound tnf from the construct. plasma enhances while bpi inhibits lps-induced cytokine production from peripheral blood mononuclear cells (pbmc). pseudomonas species produce cytokine-inducing substances which are different from lps as indicated by the fact that polymyxin b blocks only % of the cytokine-inducing activity of these pyrogens. we now tested the effect of plasma and bpi on the il- [ -inducing activity of pseudomonas maltophilia -derived pyrogens (pmp). bacteria were cultured to the log phase and filtered ( kd) to obtain prop. dilutions of pmp or lps were added to pbmc alone or to pbmc in % plasma +/-bpi ( ng/ml). pbmc were incubated for hours at °c and total il-i~ was measured by ria. results: il-i[~ in ng/ml (n= , mear~+sem, *p< . vs control). control . _+ + bpi . + % plas. . _+ + bpi . _+ pmp (ng/ml) lps (ng/ml) . _+ . _+ . _+ . _+. . +. . _+. . _+. " _+ " . _+ " . _+ " . _+. . + _+ _+. * _+ " . +. " . + -+ . -+ " . _+. " cba, c bl/ , balb/c, akr, dba, swiss mice, guinea pigs, rabbits have been used in research work. the toxicity, immunogenicity, mitogenic and immunomodulating activity of lps have been studied. the possibility of reduction of the toxic activity of lps on macroorganism by bioglycansimmunomodulators obtained from sea invertebrates anymals (crenomytilus grayanus, stromhus gigas) have been investigated too. lps has been shown to induce specific antibody response of laboratory animals. cba mice are high responsive to lps. lps stimulates humoral immune response of mice to tdependent and t-independent antigens and suppresses intensity of the delayed hypersensitivity. the small doses of lps stimulate functional activity of macrophages, the large doses of lps -decrease one and show the cytotoxic effect. the bioglycans enhance the resistance of mice to the lethal effect of lads and provide protection - % of mice. one opens possibility to use of bioglicans for reduction of toxinemia in generalizated forms of pseudotuberculosis. thus, lps from y.pseudotuberculosis is immunogen and immunomodulator wich has influence on humoral and cellular factors of immunity and plays the important role in immunopathogenesis of infection. endotoxaemia is implicated in the pathophysiology of obstructive jaundice. the lirnulus lysate (lal) assay is the gold standard method for measuring endotoxin concentrations, but inherent biochemical and technical problems limit the usefulness of this assay. the endocab elisa is a novel assay which measures endogenous antibody (igg) to the inner core region of circulating endotoxins (acga). objectives we evaluated the significance of endotoxaemia in biliary obstruction using the endocab assay and subsequently the specificity of the humoral response to endotoxin compared with an exogenous antigenic challenge [tetamls toxoid (tt) ]. materials and methods in experiment i three groups of male wistar rats ( - g) were studied [no operation (n= ) , sham operation (n= ), and bile duct ligation for days (bdl)(n= )]. plasma was collected and assayed for bilirubin, endntoxin(lal) and acga(endocab). in experiment ii rats were actively immunised with tetanus toxoid ('it) and then randomised to have no op(n= ), sham op(n= ) or bdl(n=i ). blood was taken at this time (to) and days later(t at sacrifice for acga concentrationslendocab] and igg produced to tt(ttab) [elisa] . antibody concentrations are expressed as % increase from control values.results in bdl rats, acga concentrations were significantly increased compared with controlslp< . , mann-whitney]. endotoxin concentrations were sporadically elevated in the jaundiced rats but the rise was not significant. in experiment [i there was no difference between the acga or ttab concentrations in the fllree groups at to, bdl rats had a significant rise in acga concentrations by t [p< , ,paired t-test] and humoral response to tt was significantly impaired in bdl rats compared with control groupslp< . , paired ttest data plasma endotoxin was measured by means of an endotoxinspecific endospecy test after pretreatment of the plasma with a new perchloric acid method that we developed. the normal value of plasma endotoxin is less than . pglml. polymyxin b was administered at a dose of , u every hours. plasma endotoxin rapidly decreased to the normal range in of the patients. body temperature fall significantly. apache ii scores were also significantly improved. tumor necrosis factor-o~ and interleukin decreased in survivors, while in high values tended to persist in patients died. no side effects were observed in any of the patients. in conclusion, intramuscular injection of minute of polymyxin b was useful in the treatment of endotoxemia. - uchimaru, morioka , japan. l e v a n t g r a m n e g a t i v organisms. m e t h o d s : u n d e r general anesthesia, n o r w e g i a n b r e d landrace pigs ( - kg) of either sex, pr group, u n d e r w e n t t r a c h e o s t o m y a n d w e r e v e n t i l a t e d on a / air a n d o x y g e n m i x t u r e a i m e d at m a i n t a i n i n g a n o r m a l p h a n d a isocapnic level. ventilation w a s not readjusted d u r i n g the observation period. the anesthesia w a s k e t a m i n e . m g / k g h a n d d i a z e p a m . m g / k g h i n t r a v e n o u s l y . h e m o d y n a m i c m o n i t o r i n g of m e a n aorta, p u l m o n a r y artery, central v e n o u s a n d p u l m o n a r y capillary w e d g e pressures w a s p e r f o r m e d w i t h a f s w a n -g a n z catheter a n d an aorta catheter. a continous infusion of r i n g e r ' s acetate ( m l / k g h ) w a s g i v e n intravenously. w h e n stabilised, the a n i m a l s w e r e g i v e n . x l cfu of e colt intraperitoneally as a bolus in ml saline, the a n t i b o d y g r o u p received in a d d i t i o n m g / k g e a n t i e n d o t o x i n i n t r a v e n o u s l y over h o u r via a n infusion p u m p at the start of the observation period. the a n i m a l s w e r e observed for hours. results : a t a n d hours, the o x y g e n c o n s u m p t i o n increased by % in the a n t i b o d y treated g r o u p w h e r e a s there w a s a significant fall of % in the sepsis group. in the a n t i b o d y group, the arterial p h a n d the cardiac index were also significantly h i g h e r at the s a m e p o i n t s in time. there w a s no significant difference in arterial po . in severe bacterial infections it would be beneficial to neutralize the plasma endotoxin content with complex forming compounds. the phenothiazines are able to form complexes with endoto×in and the existence of these complexes were already shown in differential speetrophotometry and animal experiments, however, the mechanism of partial neutralization was not clarified. therefore some representative phenothiazines and structurally related compounds were tested for anti-endotoxin activity. the endotoxin neutralizinb effects of several benzophenothiazines were investigated in differential speotrophotemetry, tnf induction and in the conventional limulus test. in animal experiments some beneficial effect of complex forming compounds was found. the benzophenothiazines were not able to inactivate the biological effect of endotoxin in the limulus test. the recent findings indicates that a multifocal effect can be responsible for "anti-endotoxin action in vivo". effects of tnf inducing effect of endotoxin in leukocytes and bypotensiv action in experimental animals were reduced by some phenothiazine derivatives. monophosphoril lipid a was without effect. of microbiology, albert szemt-gydrbyi medical university, odm t~r lo, h- szeged~ hunbary involvement of streptococcus pyogenes erythrogenic toxins in the induction oflstreptococcal toxic shock syndrome heide mgller-alou~* , joseph e. alouf , die [er gerlach , ~atherine fitting., and jean-marc ca~aillon . unit des toxines microbiennes and "unit d'immuno-allergie, institut pasteur, , rue du docteur roux - paris (france) ; institut f~r experimentelle mikrobiologie, jena (germany). superantigen erythrogenic toxin a (eta) is thought to be involved in toxic shock syndrome in humans by inducing massive release of cytokines by patient immune cells. the cytokineinducing capacity of eta w~:s £:ompa~ed to that of lps, a gram-negative bacterial cell wall component. eta elicited weak production of il- d and ~, tnf ~ and il- in purified human monocytes whereas lps stimulated the production of high amounts of these cytokines. in the presence of t cells, eta elicited the production of significant amounts of il-i~, il-i~, il- and il- . however, the most preponderant cytokine was tnf~, which peaked at i ng/ml after stimulation with i ~g eta. comparable amounts of tnfd (ca ng) were induced by .i ~g eta and .i ~g lp$. in contrast to lps, eta was a strong inducer of tnf~ which was produced only in marginal amounts by lps. these results suggest that the septic shock induced by gramnegative bacteria (lps) and by gram-positive bacteria {extracellular superantigens) follows different pathogenic pathways. lps-induced shock is mainly mediated by monocytes and monocyte-produced cytokines (il-i and tnf). the eta-induced shock is mediated by t-cells or depends on t cell help for the production of monocyte-liberated cytokines. production of t cell cytokines such as tnf~ and interferon in addition to the other cytokines contribute very likely to the severity of the toxic-shock resulting from s. auzeus and s. pyogenes infections in humans. the present study was utidertakc~l to cvalu~tlc the effect of soluble chemically modified giucan during septic shock. carboxylnethyl-b-i, -glucan (ram ) was injected twice and h before the shock i.v. in a dose of ing/kg. shock was induced in u~?esthetizcd (sodikm~. l)mntobarbital) rats by i.v. injection of endotoxin of escherichia colli bs, mg/kg. aiiofcmg pretreated ruts survived during first haher ¢ndotoxine, while in controi shock group the lethality was %. the concentration of ~col)terin in serum was significantly elevated hafterthc second cmginjection (appare~tly % if compare with the control rats), but didu't chartged rain and s rain after endotoxin injectjom cardiac output in cmogroup was higher a* the i and min after endotoxine onset ( i % trod ~, respectively of initial level) than in the control shock group ( % and % at the same time). pretreatment of rals with soh~ble giucan w~ts associated with beneficial effects o~ the hepatic c~ergy $ia[tls after h after challenge of endotoxiae: the tissue level of lactale was ahnost twice lower than in the control ruts, me~mthne the tissue atf in cmg pretreated group was higher at %. twice injected macrophage stimuhttor soluble glucan can prevent the endotoxic shock, and extremely ir~creased survival rate after endotoxine injection. the national committee of surgical infections of the spanish association of surgeons have produced a computer program for the collection and analysis of information on surgical infections. the program is suitable for ibm compatible hard disk personal computers and works through the ms-dos system. the main menu is called up on the screen when the operating disk has been installed; it reads as follows: i. new record; . modify records; . erase records; . searches; . reports; . configure; o. ouit. if you ask fdr a new record the screen will prompt you to enter the number of case, record number, hospital, age and sex. the next screen will come up and the words "topographic diagnosis" will flash. a menu of areas or organs will be displayed. then, the words "type of pathology" (inflammatory, neoplastic, traumatic and other). days of postoperative period. type of surgery (programmed and emergency). type of operation (clean, clean contaminated, contaminated and dirty). duration of surgery. this is followed by "order of operation" and the "type of anaesthesia (general, regional or local). you are then required to supply the "diagnostic code of who" (icd ) and the "procedure code of who. analytic and concurrent illnesses (total proteins, albumin, haemoglobin, haematocrit, leucocytes, red corpuscles, glucose and bilirubin). the next screen asks for "risk factors" (obesity, uraemia, neoplasia, malnutrition, urinary catheter, distant infection, artificial valve, immunosuppressive drugs, over years and anergy. this is followed by a screen headed "postoperative complications". "evolution" (the questions asked are drainage, systemic antibiotics, and on each ocasion a choice of antibiotics is displayed), local antiseptics, reoperation, etc. under "microhiology" is a choice of organisms and the chance of identifyin organisms. finally, "sepsis score". our recent work had shown that renshen-fuzi-chaihu mixture could increase the survival rate in experimented study. the purpose of this study was to determine the effect of combined administration of renshen-fuzi-chaihu mixtuer and antibitics (sa) in patients with septic shock. the result showed that, in sa group ( cases), the total effective rate was , %, in the contral group (combined administration of gentamycin and dexamethasone, cases) the total effective rate was %. however the obviously effective rate in sa group % was significantly higher than in contral group % (p<o.os). sa group appeared to be more obvious than the contral group in raising arterial pressure, recovering consciousness and pulse, improving cold lilmbs and reducing fever (p<o.o ). it was found that sa could inhibit the pathogeneses changes of septic shock such as the decreases of superotide dismutase (sod) and glutathione peroxidase (gsh-px) in erythrocytes and the increases of plasma free hemoglobin (phb), plasma malondialdehyde (mda) and -glucuronidase ( -gc) occured in septic shock. sa had stronger effect than gd in inhibiting the changes mentioned above. hence, these results suggest that sa has beneficial effect in the treatment of septic shock. sa could diminish the decrease of the antioxdase activities and inhibit lipid peroxidization and stabilize cellmembrance. this may be one of the principal mechanisms of the beneficial effect of sa in the treatment of septic shock. donna l. lehman, heather a. childers, irshad h. chaudry and alfred ayala. the thymus is thought to be a privileged sight for tcell generation. here the t-lymphocytes are either selected for their potential to recognize and react competently to foreign antigens or de-selected, due to their potential to react to auto-antigens, de-selected. tcells with this latter capacity are thought to be deselected through a process referred to as programmed cell death or apoptosis. while it is known that thymic apoptosis is elevated by a variety of stressers associated with infection and inflammation, little or no information is available concerning its presence in polymicrobial sepsis. it was, therefore, the aim of this study to determine whether thymocytes exhibit increased apoptosis during sepsis. to assess this, thymocytes were harvested from c h/hen mice at i and h following cecal ligation and puncture (clp; to induce sepsis) or sham-clp (sham). thymic yields were assessed and the extent of apetosis determined by staining the cells with propidium iodide (a dna intercalating dye) for facs analysis or by examining the extracted dna electrophoretically for the endogenous endonuclease activity the results (n= /grp) indicate that at i h post-clp there was no marked changes in any of these parameters. however, at h the thymic cell yield from clp mice was significantly decreased (sham: . ! . x l vs clp: . i . x * cells; *,p< . ), the % of cells apoptotic by facs analysis increased from . i . % in sham to . ± . %* in clp, and the septic mouse genomic dna exhibited dna degradation these results indicate that clp, but not simple laparotomy, induces marked thymic apetosis, which may contribute to the lymphocytic immune deficiency seen in these mice the purpose of this retrospective study was to evaluate effectiveness of irrigation to treat septic knee joints from longterm results. from to patients with septic knee joints have been treated. treatment in acute cases started with asp#at[on of the effusion to evaluate for cultures. without awaiting the result treatment was continued with immediate joint irrigation under arthroscopic control. three redon tubes ( ch ) were introduced for continuous irrigation and for intermittent distention of the joint cavity. in case of chronic joint infection additionally all foreign and synthetic material was removed. systemic antibiotics were given. patients could be re -examined with a mean follow-up of years. re-examination showed that immediate arthroscopic lavage started at the onset of septic sings had best results (less signs of osteoarthr[tis, less synovitis, less pain while loading and less range of motion loss ). patients ( %) out of patients with s tre_=.tsd acute se.~tic knee joint had excellent functional recovery, whereas all patients with chronic septic knee joints showed poor results. additionally, in of these patients with chronic septic knee joint after irrigation a further procedure was necessary due to recurrent septic knee joint. the concept that bacteria can translocate across the intestinal mucosa under a variety of circumstances is well established. however, due to the inherent limitations of in vivo studies, the cellular mechanisms underlying the process of bacterial translocation (bt) across the epithelial barrier are poorly understood. this is especially true in those circumstances in which there is no merphologic evidence of mucosal injury. consequently, we have utilized an in vitro cell culture model system to investigate the cellular events involved in the translocation process. in this model system, a polarized monolayer of intestinal cells (caco- cell line) is grown on a micron filter in a two compartment system. after tight junction integrity is established, bacteria are placed in the apical surface chamber and bt across the caco- monolayer is measured by culturing the basal chamber. the results of our studies utilizing the caco- system indicates that; l) several strains of non-pathogenic bacteria will translocate across the caco- monolayer in a time-dependent and dose-dependent fashion. however, the incidence and magnitude of bt are highest for those strains of bacteria (gram-negative enterics) that are most commonly cultured in vivo. ) caco- cells are actively involved in the transcellular passage of bacteria across the caco- monolayer, since inhibition of caco- microtubule or microfilament function decreases the magnitude of st. ) lectin but not integrin receptors are involved in bacterial translocation of e. col~ across the caco- cell monolayer. ) caco- cells have the ability to ingest and kill certain strains of bacteria. the mechanisms involved in caco- bactericidal activity appear similar to that of pmns to the extent that both are oxidant but not nitric oxide mediated. these in vitro studies suggest that caco- cells can function as "nonprofessional" phagocytes and that both bacteria and enterocytes are involved in the translecation phenomenon. bacterial translocation due to gut barrier dysfunction is considered to be a major cause of septic complications and multiple organ failure following trauma, burn injury, hypoxia, shock and shock-like states. the invasion of bacteria into the circulation from the gastrointestinal tract or even from other sources, however, should not necessarily result in systemic infection or organ cohinisation, as long as the humoral and cellular defense mechanisms are not impaired. thus, a reduced res clearance capacity and hepatic clearance function of bacteria and toxins can be observed under the same conditions which enable bacterial translocation from the gut. in order to evaluate the influence of circulatory, metabolic and humorul disorders on the elimination of bacteria out of the blood circulation, a series of experiments were performed in anesthetized and ventilated rabbits which received defined numbers ( . x colony-furming units) of escherichia coli as a bolus injection. in unaffected control animals the intravenously injected bacteria are eliminated about . % within the first minutes and are totaiy cleared within minutes. % offue total cfu counted in the cultures of the organ homogenates were found in liver and spleen, whereas only very low numbers could be detected in the lungs and kidneys. systemic injury of the animals by hemorrhagic shock, endotoxinemia, hypoxia, coagulation disorder, systemic vasoconstriction by norepinephrine and other types of injury reduced the elimination rate of bacteria and changed the pattern and degree of their dissemination and tissue distribution. the bacterial clearance was delayed mostly in rabbits subjected to hypoxemic hypoxia in which about cfu of viable e.eoli per ml blood could still be counted hours following their injection. the number of viable bacteria was some ten powers higher in organs of hypoxic rabbits in comparison to control ardmais, and an excessive colonisation of the lungs and kidneys with % respectively % of the total cfu of the cultared organ homoganates was observed. unilateral iscbemia of the kidney prior to the intravenous injection of e.coli only moderately delayed the bacterial clearance, bowever, caused an intense eohinisation of the affected reperfused organ. in contrast to this, inhalation injury did not promote the accumulation of bacteria in the lungs. conclusion: shock, systemic and local affections reduce the clearance of bacteria from the blood circulation and enable their dissemination and accumulation in vital organs. the degree of this reduction and the organ pattern of the bacterial distribution varies with the type of injury. thus, these factors seem to be essentially involved whether or not bacterial translocation and multiple organ failure will follow the invasion of bacteria into the circulation as in the ease of gut barrier dysfunction. movement of enteric baaterla from gut to extralumeaal sites (bacterial tra~sloeation) m~y play a role ~. nraltipl~ orga~ failure. traumatic stress (shock, hffectiort, and im~lammation) and severe illness are common alateeedents. tnt~st~aal lleus is e common proximme causal factor. we have exanlined the hypothesis that bacterial ttanslecation from the gut in expe~me~tal paaerestitis is due to bacterial overgrowth as a cuas~ucnee of a deere~ae in intestinal transit. ne~rotit_.~g pancreatitls fbliowlng bile duct iigation in the opossum is associated with colonization of the pa,se ~re, aa by gut derived organisms or salmonella of biljary origin in infected animals (previously reported). to ti~rther define the mechanism of transloemdon in panereati* inflammation, pancteatitis was induced hy iigatlon of t~e lower bile duet distal to the pancreatic duets m the rat. intestinal transit, enteric bacteriology, and tromsloeatien of bacteria to mesanterie lymph nodes, blood stream and splanelmie organs wen deletmhaed at (n~ ), g (n ~ ), and (n~ ) hours with the fallowing results: ly~testinai,..transfi". geometric mean of fluorescent marker - % at hour~ with return to % of gut leugth (similar to ~m) at hour~. bacterial overgrowt_hff -increase in total bsctetia ~ad gram negative rod.~ at ,; hours with return to sham control at hours ( log cfu/g veraus log cfu/g ia ileum). translocation to mesenteric nodes - , , and percent at , , and fi hours compared to b in sham controls (n=l of ). conclusion -bacterial translocation following panetoatieobiliary duct ljgation induced panereatitls ha the rat is tighlly linked to intestinal trausit and bacterial overgrowth within the gut lumen. speclrjlation -the ilens in in/~arm~ation may be related to activation of eytokiaes and mediated by nitric oxide. preliminary evidence for this notion will be discussed. in a series of studies we investigated: a) the time course of bacterial translocation (bt), b) the kinetics of lps and cytokine appearance (tnf, il- , soluble tnf receptor [stnf-r] ) in the circulation, and c) the role of lps and/or tnf with regard to haemorrhagic shock (hs) related pathophysiologie alterations and mortality in baboons and/or rats. method: baboons were subjected to femur fracture, soft tissue trauma (acute experiment), and hs ( mmhg mean arterial pressure: map for - h terminated at an accumulated oxygen debt of - ml/kg followed by resuscitation). a chronic model of hs was set up by administration of zymosan activated plasma (zap) before and after hs but without trauma. hs was induced in rats by bleeding the animals to map of - mmhg - rain followed by resuscitation. results and conclusion: in rats, lps increased in the systemic circulation, plasma tnf levels were found to be significantly elevated at min and were still markedly increased at rain postshock. plasma tnf, il- , and stnf-r levels increased already during the shock period in baboons, while tnf was not detectable. our data suggest that haemorrhagic shock may lead to early bt in the intestinal wall (at min following resuscitation in rats subjected to hs for min, similarly at h after the end of oxygen debt period in baboons ) and transient access of gut-derived lps into the circulation (levels became significant at min, while in baboons higher levels up to pg/ml were found at the end of shock and h after reinfusion, partially accompanied by bacteremia). in addition, since the treatment of rats with anti lps measures or anti tnf therapy significantly improved the -hour survival rate it can be assumed that endogenous lps and lps-induced mediator(s), in particular tnf, may lead to organ injury and mortality following haemorrhagic shock. alteration of the mesenteric blood flow and the consequent ischemia / reperfusion injury to the intestine appear to be one of the earliest events in the systemic inflammatory response following severe thermal injuries. the causative relationship between the subsequent disruption of the intestinal integrity and the potentiation of the translocation of indigenous bacteria and/or endotoxins to remote body organs and the systemic circulation has been deeumented in several studies. among other effects, endotoxemia solely or acting synergistically with thermal injuries has been shown to promote bacterial translocation. as these sequences continue without adequate intervention, multiple organ failure and eventually death may become inevitable. hence, the crucial need of treatment modalities with the capacity of modulating the intestinal blood flow and preventing the manifestations of these pathological incidents. although the underlying mechanisms of this process have not yet been fully elucidated, there is accumulating evidence that various interacting vasomediators are involved. the actions of these mediators can probably be modulated by either nonspecific or selective agents. among the nonspecific agents, the composition, volume and timing of the resuscitation fluids appear to play an important role in this process. nitropmsside, a nonspecific vasodilator, has been shown to prevent the decrease of the postbum mesentefic blood flow when selectively infused in the mesenteric artery. the nonspecificity of various vasodialators with their possible undesirable systemic effects emphasizes the importance of the identification and modulation of selective vasomniiators. thromboxane a (txa ) and angiotensin ii (a-ii) appear to be the primary mediators of the postburn vasoconstriction. both mediators were found to be elevated following thermal injuries. in a previous study, pretreatment with oky- , a thromboxane synthetese inhibitor was found to attenuate the postbarn mesenteric vasoconstriction. in a bum/sepsis porcine model the efficacy of dup , an a- receptor antagonist as a posthum treatment modality was evaluated. treatment with dup prevented the early posthum and the late posteodotoxin elevation in the mesenteric vascular resistance and subsequently abrogated the fall in the mesenteric blood flow. the incidence of burn & endotoxin induced bacterial translocation was significantly reduced by dup from % to % (p< . , fisher's exact test). the indigenous flora of the gastrointestinal tract exerts a potent influence on the developmental maturation of normal systemic immunologic responsiveness. moreover, both oral and intraportal administration of experimental antigen is associated with a systemic state of immunologic hyporesponsiveness, known as oral tolerance. since trauma and critical illness are associated with changes in the flora of the gut and with altered systemic immune reactivity, we have hypothesized that the interactions of an altered gut flora with immune tissues in the gut and liver play a role in the pathogenesis of the immunologic derangements of critical illness. prolonged feeding of two clinically relevant killed organisms-pseudomonas and candida-to a rat results in significant impairment of cutaneous delayed hypersensitivity (dh) reactivity. conversely, measures directed against gram negative bacterial overgrowth in experimental peritonitis result in partial restoration of impaired dh reactivity. to ascertain the role of the liver in the pathogenesis of these alterations, we studied the differential immunologic sequelae of portal versus systemic (ivc) infusion of killed bacteria. experimental infusion of live or killed gram negative organisms into the portal vein produces dh suppression in rive, and profound suppression of mitogen-driven lymphocyte proliferation in vitro; systemic administration of the same organism has no effect on these phenomena. suppression is tgf -dependent, and mediated by a soluble factor released by fixed tissue macrophages of the lung and spleen. the suppressive influence appears to be mediated at the level of interactions between il- and its high affinity receptor. release of this factor can be induced by a second circulating factor present in the plasma of portally-, but not systemically-infused animals two hours after bacterial administration. these studies suggest that the release of inducible immunoregulatory factors from the liver, and possibly from the gut, may play a role in the pathogenesis of the profound derangements of systemic immune homeostasis that accompany trauma and critical illness. acad.hospital st. radboud,postbus , lib nijmegen introduction. the central question being tested in this study was whether liposome encapsulated dichloromethylene-diphosphonate (ci mdp) mediated elimination of liver and splenic maorophages would influence zymosan induced systemic toxicity (st) and bacterial lranslocation (bt). materia|s and methods. male swiss (icr) mice were used weighing - g elimination of liver and spleen macrophages was accomplished by intravenous injection of / suspension of ci mdp-liposome suspension. control mice received an i.v. injection with pt phosphate-buffered saline (pbs) . two days later all mice were challenged with an i.p. injection of zymosan suspended in paraffin (z) at a dosage of either mg/g, . mg/g or . mg/g body weight (n= in each group), signs of st and bacterial translocation bt were measured hours later the st was assessed by blindly grading the degree of lethargy, conjunctivitis, diarrhea, and ruffled fur of each mouse on a four point scale. bt to the mesenteric lymph nodes (mln) and systemic organs (liver, spleen, lung and blood) was tested by culturing on blood and macconkey's agar at the time of sacrifice sections of the distal ileum were taken for histology. an additional two control groups (n= in each group) were tested to verify that neither paraffin nor pbs or ci mdpqiposome suspension alone induced bt or st. furthermore survival over a -day period was assessed in a control and macrophage-depleted group with a dose of d mg/g z. results. neither the paraffin nor ci mdp-tiposome suspension induced bt or st the incidence of bacterial translocation to the mln was similar between macrophage depleted and control groups. however, macrophage depletion was associated with a significantly higher incidence of systemic spread of bacteria. data expressed as positive tissues/total tissues tested: / vs. / at . mg/g zymosan (p~o. ); vs. at mg/g zymosan (p~q ); / vs. / st . mg/g zymosan (p~o.o ).the magnitude of bt however did not show any differences. although systemic bt was greater in the macrophage depleted groups, the systemic toxic response was significantly less at doses of . mg/g zymosan ( . -+ . vs. . -+ , p~o. ) and . mg/g zymosan ( . -+ . vs. . -+ . , p<_.o. ) . the day mortality after . mg/g zymosan was % in the control group and % in the macrophage depleted group (p=o. ). histology did not show any differences between the control and macrophage depleted groups. conclusion. the lethal and toxic effects of zymosan in this model appear to be more related to the excessive activation of macrophages than to the systemic spread of bacteria. bacterial translocation (bt) in hemorrhagic shock was studied using a porcine model. in this study three groups were randomized: one control (n= ) and two experimental (n= each). a portal vein catheter was placed and remained in situ hrs. a femoral artery and vein catheter were in place hrs. the arterial eaanula was used for monitoring mean arterial pressure (map) in all animals and to bleed the experimental animals and the venous cannula to repelfuse with ringer's lactate (rl) or autologous blood (ab). baseline samples and values were taken in this period. control animals were observed for a sham shock period of . hrs., given more hours of anesthesia, and studied for further hrs. % of the estimated blood volume was withdrawn from each experimental animal over min. these animals were kept in shock for . hrs. at the end of the shock one group was perfused with rl and the other with ab. two hours later they were extubated and further studied for hrs. samples from portal blood for cultures and measurement of leukotriene b (ltb ), prostaglandin e (pge ), and nitric oxide (no) metabolites were taken from all animals at intervals beyond baseline up to hrs. after hrs. under general anesthesia a second laparotomy was performed and samples for culture from mesenteric lymph nodes (min), liver and spleen were taken; as well as samples for histologic study with light and scanning electron microscopy were taken from jejunum, ileum, and colon. animals were then euthanized. results: significant shock was induced as indicated by map and arterial blood gases. significant bt to min was observed in all groups. no significant bt was observed in cultures from liver and spleen in any of the groups. increased values for ltb , pge and no metabolites were found during the period of shock. these results suggest that the isehemic phenomenon triggers a significant inflammatory response, and that bt to min may be an epiphenomenon without apparent significant influence on the inflammatory response. objective: to study the potential effects and mechanisms of action of systemic administration of monoclonal antibodies anti-endotoxin (ha- a) in a animal model of gut-origin sepsis. materials and methods: exoeriment a. balb/c mice were transfused with allogeneic blood (from c hb-iej mice). five days post-transfusion the animals were gavaged with lxl viable escherichia coil and randomized into groups (n= /group) to receive a sham burn (sb group) or a % thermal injury immediately followed by the systemic administration, via a tail vein, of monoclonal antibodies ( mg/kg) (ha- a group) or a % burn injury and administration of equal volume of sterile saline (c group). all groups were resuscitated by intraperitoneal injection of . ml of saline. the animal survival rate was observed for days post-burn. experiment b, transfusion and burn procedures were identical to experiment a but the mice (n= /group) were gavaged with viable e.coli labeled with mmndium oxine. four hours after burn the mesenteric lymph nodes (mln), liver, lungs and blood were harvested to determine plasma endotoxin levels and the magnitude of transtocation of labeled bacteria as measured by the residual radioactivity (dpm) in the organs. circulating endotoxin levels were determined by limulus colorimetric assay. diamine xidae(dao) is an enzyme existing in the mucosa of small intestines, but its activity is low in the plasma. it is evoked in the blood with the intravenous injection of much heparin. it is well known that da declines under the chronic mueosal injury when the small intestines are cut off or the mucosae become atrophied. aim of this paper is to confirm that da goes up to the measureable level by the intravenous injection of a small amounts of low molecular heparin(lmh objectives: the aims of this study is to investigate the inhibitor" effect of the prolease inhibitor, urinastatin, on endotoxin induced bacterial transleeation in mice. materials and methods:lcr mice were divided in six groups as the fotlows, group i: control mice receiving intraperitoneal injections (ip) of saline . and hr prior to sacrifice, group ih treated mice receiving ip of utinastatin . hr and endotoxin ( mg/kg) hr prior to sacrifice,group ilk sham reated mice receiving ip of saline . hr and endotoxin ( mg/kg) hr prior to sacrifice,group iv: saline control mice receiving ip twice during rain intervals,group v: mice received ip of utinasmtin, and min later they were received ip of endotoxin ( mg/kg), group vi: mice received ip of saline,and min later they received ip of endotoxin ( mg/kg). in group l,ii and ill ,the mice were killed by cervical dislocation.using stetile techniques,a middle-line incision was made and the mesenteric lymph nodes were harvested in order to culture on selective agars for quantitation of bacterial trauslocation. in group iv, v and vi, survival was recorded for days. unnastatin pretreatment could rednce mortality significantly. first surgey, shiga university of medical science, seta ,ohtsu - ,japan increased gut permeability correlates with inflammatory response in multiple trauma aptients. pape, h.-c. dwenger, a. grotz, m. regel, g. purpose: disturbances of intestinal permeability have been advocated as a pathogenetic factor of posttranmatic multisystem organ failure (mof). a close relationship with impairment of the stationary reticulocndothelial system (res) and a systemic inflammatory response (sir) was discussed. these tactors were investigated prospectively in patients with multiple trauma showing posttraumatie complications (multiple organ failure, mof). methods: polytranmatized patients were studied prospectively. according to a mof-score (goris) those with posttrattmatic complications were selected (> points at days), others were excluded. every second day gut permeability according to the ratio of urine concentrations of lactulose and mannitol (l/m) was evaluated (enteral application). at parallel time points res clearance capacity (k-value, invasion constant, normal range . - . mind) was studied after i.v. injection of mbq rotehuman albumin. liver perfusion was calculated from these data, total serum bilirubin (/zmol/l) was documented. serum elastase (#g/l) levels were determined enzymatieally. results . + + liver perfusion did not ehangu, bilirubin showed progressive worsening indicating mof. a positive correlation was present between l/m and k (r= . ) and between l/m and ela (r= . ). conclusions: there is a positive correlation between the time pattern of intestinal permeability dysfunction and res hyperactivity as well as between intestinal permeability and the systemic intlammatory response (elastase levels). the results speak in favor of an interaction between intestinal and extraintestinal inflammatory systems, which in eombiuation are likely to be responsible for post~anmafic complications. endotoxemia, il- release and consecutive acute phase reaction are observed as a host response to surgical trauma. as well vasodilative prostaglandins (pg) and thromboxane (tx) are released after abdominal meaenteric traction (mt). the following hypotension and acute hypoxeraja are duo to prostacyelin (pgiz) arm can be avoided by perioperative cyclooxygenase inhibition. we therefore focused on the effect of pg and tx liberated following mt on the induction of endotoxemia. methods: in a prospective, randomized double-blinded protocol patients, who were scheduled for major abdominal surgery (pancreatic or infrarenal abdominal surgery), were studied. ibuprofen ( mg i.v.) or a placebo equivalent was administered minutes before skin incision. mt was applied in a uniform fashion. baseline values were obtained before induction of anesthesia. further measurements followed before the incision of the peri[onenm (tl) and , , , min, . the plasma concentrations (,pc) of -keto-pgft,, txb: and-ki- -pgf ~ (stable metabolites of pgi , txa and pge~) were determined by ria. we measured endotoxin pc by limulus-amoebocyte-lysate test and il- levels by elisa. data are given as mean+sem (* p< . placebo vs. [ibuprofen] ). results: endotoxin plasma levels increased before incision of the peritoneum tl both in the ibuprofen pretreated and in the placebo group. peak pc were observed minutes after mt. endotoxin pc were significantly higher in the ibuprufen treated group (t . + . e[ . + . ] eu/ml). il- pc demonstrated an increase continuously from t to t (t + [ + ] ng/l) in both groups. after intentional abdominal mesenteric traction we observed a marked increase of -keto-pgf~,, pc up to h after mt in untreated patients with a peak of *[ ] ng/ at tl. also txb: and kh pge pc showed a considerabe increase up to h after mt in the placebo group. in ibuprofen pretreated patients the pg and tx pc remained within the normal range. discussion: our data clearly indicate a significant endotoxemia and il- release following major surgical trauma which is not initiated either by prostaglandin or thromboxane release. moreover endotoxemia is accentuated by ibuprofen pretreatment. therefore we hypothesize that in major abdominal surgery prostacyclin release-after mt may play a crucial physiological role in maintaining splanclmic microcirculation and thus preserving gut mucosal barrier function. objectives of the study it has been shown recently that parenteral and certain euteral diets promote the translocation of gut flora to the mesenteric lymph nodes (mln) and systemic organs, a process termed bacterial translocation (bt). in chow fed rats bt usually does not occur without further promoting factors. the goals of the present study were to determine whether the provision of defined amounts of standard lab chow during iv-tpn administration wotfld redane the incidence of bt, materials und methods male spf spragnle-dawley rats were divided into groups. group received standard laboratory chow feeding ad lib. in group a central venous catheter was placed, ligated and secured by a spring coil tether attached to a swivel allowing free movement in the housing cage and chow was fed ad lib. in group % of the calculated daily required calory intake (drci) ( /kcal/kg) was given by iv-tpn ( % glucose, , % amino acids) and % by limited chow administration. groups and received % and % of the drci by i.v. tpn and % and % respectively by chow feeding. group received iv-tpn only. after days the rats were sacrificed and the mln, liver, spleen and cecum removed aseptically, homogenized and cultured for bt samples of distal ileum were taken for light microscopy. the group with the least amount of chow shown to be protective against bt received the amount of non-fermentable fiber of that chow regimen during iv-tpn feeding and bt was studied. , + , , - , , / + ~ " , -+ , , -+ ~ - , / +~ + _+ , + , , - , -+ + , ~ , , -+ ~ conclusions: the administration of % of drci by chow feeding during iv-tpn significantly reduced the incidence of bt and maintained gut barrier function. the addition of the respective amount of dietary fiber of this group did not prevent iv-tpn-indueed bt. dr. med. m naruhn., dep. of general surgery, eberhard-karls-university, hoppe-seyler-str. previous experimental studies have suggested that a disturbed ecology of the enteric bacterial population might contribute to the development of bacterial translocation from the gut in acute liver failure (alf). in the present study, the effect of oral administration of lactobacillus reuteri r lc and oat fiber on bacterial overgrowth and translocation was investigated in rats with acute liver failure induced by subtotal ( %) liver resection. the oatmeal soup base was anaerobically inoculated with lactobacillae and fermented for hours, after which the animals were fed with either fermented or unfermented oatmeal or saline daily for days prior to the operation. bacterial translocation to mesenteric lymph nodes (mln) and the systemic circulation was determined, as well as the intestinal bacterial flora and enterocyte protein content. the incidence of bacterial translocstion to the systemic circulation was nit in rats subjected to sham operation and saline treatment and % in animals subjected to % bepatectomy and lreatment with fermented oatmeal, while - % and - %, respectively, in rats subjected to hepatectomy and treatment with either saline or unfermented oatmeal. only one rat with fermented oatmeal demonstrated bacterial growth in mln (p < . vs hepatectomy and treatment with saline or unfermented oatmeal). the enterocyte protein content significantly decreased (p < . ) in salinetreated animals following % hepatectomy, while there was no significant difference between bepatectomized animals with oral administration of fermented or unfermented oatmeal. the number of anaerobic bacteria, gram-negative anaerobes and lactobacillus significantly decreased and the number of e.cnli increased in the distal small intestine and colon in hepatectomized animals with enteral saline or unfermented oatmeal as compared with animals subjected to sham operation or bepatectomy with fermented oatmeal. our results thus show that the occurrence of bacterial translocatiou from the gut in % hepatectomy-induced alf could be prevented by enteral administration of fermented oatmeal, maybe partly due to a positive effect on the enteric bacterial ecology. _+ " +_ " . " data=mean_+sd, * stats anova p< . vs control. l+air and lap groups, both exposed to exogenous i.ps shnwm:t m significant increase (p<. ) in lps gut translocation compared to control and l+co . this correlated with a significant increase in peritoneal inflammatory responses (o -,tnf) above that of the control and l+co groups, while mac- and cr opsonized phagocytosis were significantly impaired. the absence of significant differences between l+air and lap groups indicates that lps rather than wound factors is the principle mediator. thus, lps plays a significant role in regulating peritoneal responses in the early post-operative period dept of surgery, rcsi, beaumont hospital, dublin , ireland brlke e, berger d, staneseu a, buttenschsn k, vasilescu c, seidelmann m, beger hg in patients undergoing a colonoscopy, endotoxin, endotoxin neutralizing capacity (enc), thromboxane b o (stabile metabolite of tbmomboxane ~), -keto-prostaglansin, leueotriene c , interleukin and the incidence of bacteremia were determined before and then every five minutes during the procedure. twenty-one of patients showed a significant increase of endotoxin plasma levels during colonoscopy (p= . ), whereas only one patient had a positive blood culture with bacteria obviously derived from the gastro-intestinal tract. the enc decreased significantly five minutes after the beginning of eolonoscopy and was diminished further thereafter. the baseline values were reached after hours. ~hromboxane b o levels also increased after five min. from to pgyml peaking at min. with pg/ml. -keto-prostaglandin,leucotriene c , ii- and crp remained unchanged. a control group of i volunteers who were not subjected to endoscopy, were prepared for eolonoscopy by orthograde lavage. the blood sampling procedure remained identical. no differences were seen in all described parameters for the controls. these data show that the gut barrier can be compromised by mininml invasive procedures, at least, concerning bacterial products. living bacteria, on the contrary, do not pass the gastro-intestinal wall. endotoxin, when determined by enc, is more sensitive than the conventional limulus-amebocyte-lysate test. no acute-phase reaction was induceri by the observed endotoxin translocation. it can be speculated from the dramatically enhanced thromboxane b levels, together with its hemodynamie effects, that the thromboxane release may support translocation of bacterial products. sepsis is common after hemorrhagic shock. this study aims to demonstrate that hemorrhagic shock alone can promote translocation of gut bacteria from intestinal tract to its regional nodes and subsequently to blood. one hundred twenty mice, divided into groups were subjected to , and minutes of %, % and % of hemorrhagic shock. on the specified time, blood cultures were taken and mice were sacrificed. the intestinal tract were histologically examined for any changes which allows translocation and its regional nodes were quantitatively cultured for translocated bacteria. there was a direct relationship between duration and degree of hemorrhagic shock and incidence of translocation (p . ). there was a high incidence of gut bacterial translocation to the mesenteric and mesocolic nodes in all degrees of shock (p . ). bacterial growth in the regional intestinal nodes increased and blood cultures were positive in direct proportion to degree and duration of shock. histologic evaluation of segments of git showed submucosal congestion to allow bacteria normally contained within the gut to cause systemic infections. translocation of gut bacteria in untreated hemorrhagic shock is clearly shown in this study on animal models. in this study, guotobiotic rats with known species of bacteria were subjected to total parenteral nutrition(tpn) and subsequent hemorrhagic shock. the purpose of the study was to observe the impairment of gut barrier function following tpn and hemorrhagic shock and to study the mechanism of enterogenic infection induced by tpn and shock.the results were as follows: .long term( - days) tpn induced impairment of gut barrier function, evidenced by atrophy of intestinal mucosa, significant decrease in diamine oxidase activity of intestinal mucosa and blood, and marked microecologic imbalance of the intestinal mucosa flora with dorminant growth of aerobes and relative decrease in anaerobes. the degree of mucosal damage were proportional to the duration of tpn. .in tpn+shock groups, failure of gut barrier function was found. ri,~ere were further damage in the mucosa, with a large number of gramnegative organisms invading mucosa and submucosa and a significant decrease in dao activity as compared with each relative tpn groups. these changes were significantly correlated with enhanced bacterial translocation, elevation of lps and mda levels in the plasma. these findings suggested that long term standard tpn impaired the gut barrier function, precipitating posttraumatic gut barrier failure. thus infec. fion following shock might be oi'iginated from the gut and it was obviously related to the impaired gut defence resulted from antecedent tpn. the determination of plasma dao activity might provide a valuable tool for the ear. ly diagnosis of gut injut;y during tpn and after trauma. in our earlier studies we have investigated the dynamics of granuloayte infiltration of the ischemic/reperfused s~all intestine (g. illy~s, j. hamar int. j. exp. athol. . . .) . there was a increasing infiltration of the mucosa c m~nating at the d to th hours of reperfusion. in the present series we have studied sc~e of the conseqn/ences and the possible role of this cellular reaction. ~in isehemia was followed by a hour reperfusion in the anesthetized rat. arterial ~/ad mesenteric venous blood samples were collected at m_in, i, ~ , and hours of reperfusion. elastase and lactate concentrations were determined and hamoculture was carried out from the blood samples, and tissue pieces from the heart, lung, liver and kidney were collected for histological analyses at the above mentioned times of reperfusion. all blood samples were free of cell bacteria. staphylococci appeared only occasionally at the th hour in the arterial blood .and at the d and th hours in the venous blood, respectively. arterial and venous elastase activities were high throughout the reperfusion, venous concentrations being higher at all times. lactate concentrations of the arterial and mesenteric venous blood samples increased during shock. ~ranuloeyte infiltration of all organs studied appeared during the d hour and it increased at later times of reperfusion. it is concluded that heavy infiltration of the intestinal mucosa can block bacterial translocation in most of the cases during reperfusion. granulocytes activated either by the reperfused area or by the released cytokines infiltrate other organs contributing by this way to the mesenteric shock s!rndrc~e. intestinal motility plays an important role for maintaining nutrient transport and absorption and for balancing the enteric bacterial population. disturbances of intestinal motility may be one of the earliest notable changes in intestinal function. in the present study, we aimed at determining early alterations in intestinal transit time following ischemia-reperfusion injury induced by occlusion of the superior mesenteric artery in the rat. intestinal ischemia was induced for and minutes by applying a microvascular clip on the superior mesenteric artery followed by reperfusion , and hours after clip removal. intestinal transit time was measured by the propulsion of a radiolabelled solution (cr ). light microscopy was performed on intestinal samples. macroscopical pathological changes were not observed. however, microscopically, mucosal epithelial oedema, degeneration or slight ulceration occurred in rats hours after reperfusion in ischemia- rain group and and hours after reperfusion in the ischemia- rain group. delayed small intestinal transit time was seen from hours and on after intestinal ischemia for both and rain ischemia followed by reperfusion. the distribution of radioactivity demonstrated that most radioactivity was accumulated in the first two segments following intestinal ischemia and reperfusion, significantly differing from what was seen in animals subjected to sham operation (p < . ). the distribution of radioactivity in segments and in the group with repeffusion hours after intestinal iscbemia for rain was significantly higher than that noted in the group with repeffusion hours after intestinal ischemia for min (p < . ). q'he results indicate that a delayed intestinal transit time may be one of the earliest pathophysiological alterations noted, associated with duration of gut ischemia, and a potential factor for the development of bacterial overgrowth, gut barrier failure and bacterial translocation, in hypovolemic conditions. bacterial infections still constitute a major cause of morbidity and mortality in patients with acute liver failure. the present study aimed at evaluating the effect of ethylhydroxyethyl cellulose (ehec) on bacterial translocation following surgically induced acute liver failure. acute liver failure was induced by subtotal hepatectomy ( %) in the rat. water-soluble ehec was administered orally and hours prior to hepatectomy. the incidence of bacterial translocation from the gut to mesenteric lymph nodes (mlns) and systemic and portal circulation was evaluated and the number of isolated bacteria from these samples and from intestinal content were determined. intestinal transit time, bacterial adherence onto the intestinal surface, intestinal mucosal mass, bacterial growth and dna synthesis, bacterial surface characteristics (hydrobiology: hydrophobicity, hydrophilicity and neutrality; surface charges: positive, negative and neutral) were also determined. hepatectomized animals showed a - % translocation rate to mlns or blood and hours after operation, while only - % of rats subjected to sham operation or animals with % hepatectomy and pre-treatment with ehec (p < . ). bacterial overgrowth, increased bacterial adherence onto the intestinal surface as well as decreased intestinal mucosal masses were observed in animals with subtotal liver resection alone, alterations that were prevented by enteral ehec treatment. a delay in intestinal -hour transit time occurred in both groups with subtotal liver resection, with or without enteral ehec. ehec inhibited bacterial growth and dna synthesis, and altered bacterial surface properties following hour incubation with bacteria. in conclusion, the findings in the present study imply that ehec alters enterobacterial capacities for metabolism, proliferation and invasion by effects on e.g. bacterial surface characteristics. furthermore, ehec seems to possess a trophic action on the intestine, rather than exerting its effect by enhancing intestinal motility. department of surgery, lund university hospital, s- lund, sweden disturbances in intracellular calcium signalling can potentially result in impairments of cellular responses vital to the functional integrity of both immune and non-immune cells, and thus contribute to a decrease in host resistance against infection and to multiple organ system failure during sepsis. studies in our laboratory have focused on assessments of intracellular ca ÷ regulation and ca~+-depended cellular responses in the liver, skeletal muscle and splenic tlymphocytes harvested from rats subjected to gram-negative intraabdominal sepsis. cytosolic ca + concentration, [ca *]i, and ca + fluxes were measured by the use of fluorescent ca + chelating dyes (fura- or indo- ) and ca respectively. to assess sepsis-related changes in ca + dependent cellular responses, we measured the acute phase protein response in the liver, the regulation of protein and sugar metabolism in the skeletal muscle, and the proliferation response in the splenic tlymphocytes. altered ca + i signalling with sepsis was correlated with an exaggerated inappropriate acute phase protein response ( % ¢) in the liver, and a blunted insulin mediated sugar utilization ( % ) and increased proteolysis ( % ~) in the skeletal muscle. in t-lymphocytes, a decrease in mitogen induced elevation of [ca +]i by - % was correlated with a significant depression in their proliferative capacity. these studies clearly suggest that altered calcium signalling is correlated with disturbances in cellular responses in both immune and non-immune cells during sepsis. the altered cellular responses adversely effect the outcome of the septic injury. (supported by nih grant gm ). alfred ayala, ping wang and irshad h. chaudry. changes in macrophage capacity to respond to foreign pathogens are thought to be central to the developing immunosuppression associated with traumatic injury. in this respect, the suppression seen in m~ functions following hen (a common component of traumatic injury) may be mediated by the direct or indirect inhibition of their capacity to perceive external stimuli (e.g., opsonized & non-opsonized bacteria, and their cellular components, etc.} due to the breakdown of the receptormediated signal transduction system. results of a number of studies by our laboratory and others indicate that this inability to respond to external stimuli is in part due to the loss of cell surface receptors. decreases have been documented for not only la antigen, but also c b, fc, and tnf receptors following hem in mice. furthermore, studies which have examined second messenger generation in these cells indicate that m~ derived from the peritoneum and spleen exhibit a decreased capacity to mobilize ca + from intracellular stores. this protein kinase dependent process of [ca+ ] i mobilization appears to be linked to the inability to synthesize inositol triphosphate. of interest, the depression in ca + signal generation appears to be inversely related to presence of elevated levels of camp in m~ from hen mice. we have reported that m~ priming agents, such as ifn- (which exhibits salutary effects on m~ function following hem), appear to restore cell signal transductive capacity while reducing the levels of camp. nonetheless, the extent to which depressed receptor signal transduction in hem, is due to receptor loss~dysfunction or elevated antagonistic second messenger levels remains to be determined. conclusions: significant impairment of calcium signaling occurs at all time-points prior to and following pha stimulation in trauma patients. tcell activation failure can, in part, be explained by the inadequacy of this essential intracellular second messenger system. restoration of immunocompetence following trauma will have to address strategies to better assess and restore this vital step in the activation sequence leading to proliferation during the antigen recognition process. patrick a. bseuerle institute biochemistry, albert-ludwigs-university, hermann-herder-str. , d- freiburg, germany the active form of the transcriptional activator nf-~b is a heteredimer composed of a and kda polypeptide. in this form, nf-'<b can bind with high affinity to decameric sequence motifs (consensus: "-gggpunnf'ypycc- ") found in enhancers and promoters of many genes activated upon a wide variety of pathogenic conditions, including viral and bactedai infections, acute phase response, oxidative stress and uv and gamma irradation. clinically important target genes for nf-k:b encode inflammatory cytokines (il- b, tnf, [l- , il- , gm-csf etc), cell adhesion molecules (icam- , elam- , vcam- ), acute phase proteins and immunoregulatory ceil surface receptors. in most cell types, nf-~:b is sequestered in the cytoplasm and, therefore, unable to initiate transcription of these genes. the cytoplasmic form of nf-~:b contains one additionai subunit, referred to as h,;:b. i~b can reversibly suppress dna binding and nuclear uptake of nf-~b by virtue of its association with p . upon stimulation of cells, ikb is proteolytically destroyed, allowing nf-kb to enter the nucleus and activate genes upon binding to transcriptional enhancers. we have demonstrated that various antioxidative compounds inhibit the activation of nf-~b in response to many inducers. moreover, nf-~:b was shown to be activated upon treatment of cell cultures with p.m-amounts of hydrogen peroxide. these data suggested that nf-~b prinicipaliy is an oxidative stress-responsive transcnption factor. the notion is supported by numerous reports on the induction of oxidative stress by many nf-nb-inducing agents. nf-~b activition can likewise be suppressed by protease inhibitors. these drugs apparently inhibit a yet unidentified protease responsible for the inducible decay of inb. we propose to use nf-nb inhibifors as novel drugs with a very broad application under acute phases el inflammation, injury and infection. northern blot experiments revealed that expression of the recently discovered lipopolysaccharide binding protein (lbp), a / kd glycoprotein, in the liver rises substantially during the acute phase response. experiments with an in-vivo acute phase model using new-zealand-white rabbits and also in-vitro experiments employing stimulated hep-g cells showed that lbp transcripts could be induced to ford within hours after induction with cytokines. by using a newly established nonradioactive nuclear run-on technique we show that induction of lbp during the acute phase is transcriptionally regulated. furthermore we screened a human genomic library and were able to clone the lbp gone, containing the promoter . kb upstream. several liver-specific and "acute-phase-typical" potential binding sites were found fn the promoter region and reporter gone assays were set up. several caat-boxes, the il- responsive elements hstf-hsp . and h-apf- rs as well as the transcription factor hnf- and the glucocrticoid-responsive elements oct- -d and gcre were found, which correlates with the induction pattern of lbp mrna in hep-g cells by il- , il- and dexamethasone. pcr-based analysis of the exon-intron pattern of the lbp gene revealed similarities with the genes of two other lps binding proteins, namely bpi and cetp. further analysis of this novel acute phase protein, that also has an important role in endotoxin recognition and immunomodulation will help in understanding the complex acute phase mechanism and potentially lead the way to new therapeutic strategies. lps activation of nucle?/r fa-ctor:~b " (nf:~bj"in cd .transfected fi'broblasts does not appear to require tyrosine kinase activity d. t. golenbock, r. delude, r. savedra, s. vogel and m. j. fenton lipopolysaccharide (lps) is the major constituent of the outer leaflet of gram-negative bacteria. during the course of serious infection, shock may occur as a result of the interaction of lps with macrophage lps receptors. cd , a kda glycosyl phosphatidylinositol (gpi)-linked protein, functions as an lps receptor. a critical issue in lps activation concerns the mechanism by which cd , which has no transmernbrane domain, transduces a sig,nal after lps binding. evidence exists which suggests that cd may signal cells after lps binding by interacting with an lps signal transducer with tyrosine kinase (tk) activity. wild-type chinese hamster ovary fibroblasts (cho) normally do not respond to lps, but can be activated following transfection with cd (cho/cd ). stimulation of cho/cdi with as little as ng of lps/ml resulted in the release of h-arachidonic acid ( h- : ) into the culture supernatant. in addition to h- : release, we examined lps-imiuced activation (transl cation) of the transcription factor nf-~b. similar to lps-induced h- : release, these responses were observed only in cho cells lransfected with cd closely resembling the same response in the marine macrophage cell line raw . . maximum nf-~cb expression occurred at minutes. in contrast to lps-induced h- : release, dexamethasone, cycloheximide, and actinomycin d had no effect on activation of nf-r,.b in cho/cd , suggesting that nf-r,b activation begins early after lps binding to cd and does not require transcription or translation. we then examined cells for lps-induced tk activity by western blotting cellular ly~ates with anti-phcsphot-'rosin:~ anl',bodie~" although tk activity was seen in lps-stimulated raw cells and phorbol ester stimulated cho/cd , lps-induced tk activity in cho/cd was not observed. although the tk inhibitor herbimycin inhibited the release of h- : in cho/cd and raw cells, neither herbimycin nor genestein effectively blocked nf-r,b activation in either cell type. these results suggest that tk activity is involved in a portion of the signaling pathway that is distal to initial signal transduction. the absence of observable lps-induced phosphotyrosine residues in cho/cd cells as well as the failure of tk antagonists to inhibit lps-induced nf-~cb activation suggest that the proposed cd -related lps signal transducer in cho/cd is not a tymsine ldnase. dimished cardiac inotropic function and response to -adrenergic receptor ( -ar) stimulation are frequently seen in septic patients, these cardiac defects are also seen in animal models of entoxemia. to determine the characteristics of the decreased transmembrane signal associated with the decreased beta adrenergic response we measured the force and rate of contraction of atria harvested from sprague-dawley rats exposed to endotoxin ( : gm/kg). to stimulate various components of the transmembrane signal cascade of -ar was isoproterenol (i -ar), acetylcholine (m ach receptor), naf(gs and gi proteins), forskolin (adenylate cyclase), and calcium (intracellular contracttile signal) were used. to eliminate the transmembrane control of calcium and test the intrinsic contractile response, hypothermia ( °c) was used the results showed alterations in the inotropic function with no significant difference in chronotropic response. the inotropic reponse for the endotoxin exposed atria and controls is shown below these results show that there is a transmembrane signal defect both for the i~-ar signal and for ca +. these data indicate that the level of the defect appears to be at the g proteins. ischemia-reperfusion of the rat intestine produces an injmry both to the intestine and to distal organs, notably the lungs and liver. prior studies have shown that h of intestinal ischemia leads to a nemtrophil independent reperfusion injury of the gut. thus, rats rendered neutropenic by pl~l antiserum have been shown to express a severe local gut injury when subjected to ischemia and reperfusion. this gut injury is postulated to he mediated at least in part by the complement system. the soluble (s) cri receptor which binds to c b and cdb was given to rats at a dose of mg/kg by intravenous bolus, min before reperfusion of the ischemic gut. a control group was given pbs buffer. at h of rmperfmsion the animals were sacrificed. pbs treatment led to a significant activation of both classical and alternate complement pathways while scri inhibited both pathways (fall to zero of chbo ). intestinal mucosal injury score, assessed by histological grading was reduced by scri ( . ± . to . _+ . ,p< . ) . intestinal neutrophil sequestration estimated by assay of myeleperoxidase was also reduced ( . ± . to . ± . u/g). c was detected in the gut hy i~unohistochemistry. remote organ injury was modified that is lung permeability (ration of concentration of radiolabelled albumin in broncho-alveolar lavage fluid to that in blood) was reduced ( . ± . x i to . ± . x , p<o. ). however, neutrophil sequestration by the lungs was unaffected. this remote protection is thougth to be related to prevention of ic b deposition on imng andotheli~ which activates adherent neutrophils. these findings support the hypothesis of complement mediated local and remote injury. we postulate that complement fragments may be deposited either as a result of the ischemia induced loss of membrane bound complement regulatory proteins, such as decay accelerating factor or membrane cofactor protein, which allow complement fragments to accumulate on the endothelial cell surface. alternatively, increased expression of p-selectin on the endothelial cell surface may, by means of its complement binding domains, act as a lattice for complement deposition. indeed, p-selectin has been detected on the surface of endothelial cells ans platelet-neutrophil aggregates recovered from the intestine of these animals. ischemia ( hr) followed by reperfusion (dhr) of rat hind limbs resuits in local (muscle) injury as well as in remote (lung) injury, which is characterized by increased vascular permeability (leakage of j sl labeled albumin) and neutrophil accumulation (tissue content of myeloperoxidase, mpo). within minutes of reperfusion following ischemia, tumor necrosis factor-o~ (tnfc , interleukin-i ( l-i) and il- plasma levels increased significantly, reaching maximum levels after hours ofreperfusion. polyclonal antibodies to tnfet and l-i provided significant protection against muscle and lung injury. muscle and lung vascular permeability decreased in anti-tnfct treated rats by % and % respectively and mpo was reduced by % and %. antml- yielded a protection in muscle and lung vascular permeability of . °, and . % respectively whereas muscle mpo was reduced by . % and lung mpo by . °, . these results were confirmed by the use of soluble tnf~ receptor and il-i receptor antagonist (il-ira). when icam-i expression in vivo was examined using mabeled antmcam-i, constititive expression of icam- was evident only in lung but not in muscle. during reperfusion icam- expression increased by . %. treatment with anti-tnfcx or il-ira reduced icam-i upregulation by . °, and . % respectively. frozen sections of normal rat lung revealed no evidence of e-selectin expression, whereas lung sections obtained after ischemia and reperfusion immunhistochemically demonstrated expression of e-sdectin. lungs from rats pretreated with anti-tnfct were negative for e-selectin staining. our data indicate a role for cytokines in the upregulation of adhesion molecules in ischemia/reperfusion injury. adherence of neutrophils to the coronary endothelium is associated with significant myocardial injury following min of ischemia (mi) and . h of reperfusion (r). p-selectin is expressed by activated endothelial ceils and platelets within min and tethers polymorphonuclear leukocytes (pmns) to the endothelium. we examined the cardioprotective effects of a monoclonal antibody (mab) designated pb . to p-selectin in a feline model of mi+r. pb . ( mg/kg) administered rain post-occlusion ( min prior to reperfusion) significantly attenuated myocardial necrosis compared to a non-blocking mab (nbp . ) for p-selectin ( + vs + % of area-at-risk, p< . ). endothelial dependent relaxation to acetylcholine was also significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with pb . compared to nbp . ( + vs + , p< . ). furthermore, pmn adherence to ischemic-reperfused coronary endothelium was significantly attenuated in pb . treated cats ( + vs + pmns/mm z, p< . ). also, normal coronary endothelium activated with thrombin ( u/mt) had increased pmn adherence under conditions of shear stress, an effect which was significantly (p< . ) blocked by pb . , but not by nbp . . furthermore, p-selectin is markedly upregulated - min post-reperfusion in coronary arterial and venous endothelinm. similar results were obtained in a rat model of mesenteric ischemia/reperfusion, including upregulation of p-selectin on mesenteric vascular endothelium. these results demonstrate that tethering of neutrophils to endethelium by p-selectin is an important early consequence of reperfusien injury, and a specific monoclonal antibody to p-selectin exerts significant endothelial preservation and cardioprotection in ischemia and reperfusion states. as recent interest has increased in the role of extracellular matrix proteins in inflammation, we examined the role and relationship of laminin and fibronectin to the processes of cell infiltration in a rat model of heart isografts. changes occurring in this system are on a nonimmunological basis and may be an effect of the initial surgical manipulation and the warm and cold ischemic times of transplantation. lewis (lew) donor hearts were transplanted into lew recipients, naive lew acted as naive controls (nc). grafts were harvested , , , , , , , and h after transplantation (n= /time point) . snap frozen sections of organs were stained for cd- (w / ), cd- (ox ), t-lymphecytes (tl) (ox- ), macrophages (ed , ed ), neutrophils (pmn) (mom), icam-i (iap ), laminin and fibrinogen. results were evaluated visually by counting cells/field of view (cf) for w / , ox , ox , ed , ed and mom, staining for icam , lain and fib was assessed visually using a scale (ve= - ). as early as h after transplantation, fibrinogen and laminin expression increased in i, peaking h after transplantation (ve= . ; nc: ve=i. ) . at and h in i, on both vessels and interstitial cells laminin and fibrinogen expression had declined to baseline (ve=i. ) but rose again at h, peaking at h (ve= ) and remaining elevated thereafter (ve= ). the high expression at h correlated well with the maximal pmn infiltration at that time (cf= ) in i returning to baseline at h (cf= . ) and thereafter. the second peak at h correlated with the onset of macrophage and t-lymphocyte infiltration. thus, laminin and fibrinogen seem to guide leucocyte infiltration following graft ischemia during the time of reperfusion. background. reperfusion of ischemic kidneys with xenogeneic blood leads to activation of endothelial cells and circulating leucocytes with the final consequence of microvascular thrombosis. in concordant systems, the mechanisms of rejection can be studied due to cross-reactivity of mediators with anti-human monoclona~ antibodies. aim of the study. to obtain information about the kinetics of proinflammatory cytokines and production of soluble adhesion molecules in the acute phase of reperfusion, eight kidneys from rhesus monkeys were perfused ex-vivo with human blood (group b/o) for one hour in a closed system. blood levels of il-lb, il- , tnf-a, soluble icam and e-selectin were measured in elisa-technique under steady-state conditions. results. cytokine levels rose significantly within the minute interval (il-lb: , __+ , to , __+ , pg/ml; il- : . - , to , __+ , pg/ml; tnf-a: , __+ , to , + , pg/ml; p< . ). immediately after the beginning of reperfusion, soluble icam- and selectin levels were abnormally high and constantly rising throughout the observation period, reaching significance at minutes. discussion. high levels of proinflammatory cytokines may lead to an induction of adhesion molecules, thus upregulating the leukocyte-endothelial interaction in an complement-independent mechanism. specific pretreatment with monoclonal antibodies against icam- , lfa- or other soluble mediators may be useful in downregulating hyperacute rejection in transspecies transplantation. prolonged ischemia has been associated with later dysfunction of solid organs as it may cause upregulation of adhesion molecules, production of cytokines on vascular endothelium and migration of host cells into the graft. these early events may lead to irreversible organ injury. this study evaluates the effects of global ischemia on early immunohistological changes in cardiac grafts transplanted in rats. isografted hearts (lewis->lewis) were were divided into ischemic and non-ischemic groups (n= /group). all donor hearts were flushed immediately with cold saline. non-ischemic hearts were then transplanted within rain, ischemic hearts were stored in cold ringer's solution for hours before revascularization. representative grafts were removed after . , hrs, and days, and evaluated immunohistologically (cells/field of view=c/f). restitution of ventricular activity was significantly delayed in ischemic grafts ( vs rain). after hrs, all ischemic grafts exhibited an extensive interstitial edema, declining slowly thereafter. at the same time, numbers of pmn peaked ( vs c/f in non-ischemic grafts), whereas edl+macrophages ( vs c/f) and tnfe expression peaked by hrs. by hrs t-lymphocytes began to enter ischemic myocardium and icam- was moderately increased. after days cellular infiltration had returned to baseline, and no differences were seen among both groups after days. global myocardial ischemia inhibits initial graft function, and engenders a brisk inflammatory reponse, primarily pmn and macrophages, with increased mhc class ii and cytokine expression. leukocyte -endothelial interactions are the result of endothelial activation, leukocyte activation or combination of both, which are accompanied by nee-expression, upregulation or shedding of adhesion molecules (selectins, inlegrins). such interactions differ with regard to the stimulus (e.g. thrombin or histamine for p-selectin, endotoxin or tnf/il- for e-selectin), the time course of response (minutes versus hours) and the localisation in different organs. recently assays are available for circulating soluble fragments of the cell bound adhesion molecules e.g. se-seleetin was found to be increased in plasma concurrent with high circulating endoloxin and cytokine levels. the importance of adhesion molecules for the sepsis event is evident, while effectiveness of anti-adhesion inolecu]e therapy is controversial e.g. beneficial anti-e-selectin therapy in baboon bacleremia but deleterious effects of amti-cd treatment in the same model. in other species similar controversial results with anti-cd therapy in sepsis were reported. steven l. kunkel,theodore standiford* and robert m. stricter. the migration of leukocytes to the lung during endotoxemia is dependent upon the coordinated expression of lung vascular adhesion molecules and the subsequent production of appropriate leukocyte chemotactic proteins. in experimental animals, neutrophils accumulate within the lung soon after the administration of endotoxin, while mononuclear cell infiltration occurs in a more distal manner. a kinetic analysis of lung leukocyte levels revealed a -fold increase in neutrophil numbers associated with dispersed lullg tissues hours after lps treatment, while macrophage levels increased by -fold at the hour time point. thus, the recruitment of different leukocyte populations to the lungs during endotoxemia is likely directed by different mechanisms. recent studies have identified a supergene family of small inducible chemotactic cytokines (chemukines) which possesses chemotactic and activating properties for neutrophils. the prototype of this family is interleukin- (il- ). interestingly, a related supergene family has been identified which possesses activity for recruiting mononuclear cells. examples of this group of inflammatory chemukines are monocyte chemotactic protein-i (mcp-i) and macrophage inflammatory protein-i alpha (mip-i). in initial in viva studies we examined whether mip-i was expressed systemically or in a compartmentalized fashion post lps challenge. assessment of plasma cytokine levels revealed maximal tnf levels occurred i hour post lps administration, returning to baseline by hours, while mip-i levels were maximal at hours ( , ng/ml), with a second peak at hours after lps challenge. interestingly, aqueous extracts of liver homogenates from lps treated animals demonstrated no mip-i levels, while aqueous extracts of lung revealed a -fold increase in mip-i levels over control lungs. immunohistochemical analysis of the lungs from hour lps treated animals demonstrated the alveolar macrophage was a rich source of mip-i protein. cell-associated mip-i was also expressed by blood monocytes adherent to the pulmonary vascular endotheliun, however the expression of monocyte-mip-i was observed by hours post lps administration. immunohistochemical analysis also demonstrated that mip-i antigen is associated with the extracellular matrix on the interstitial side of the endothelium. this suggests that the extracellular matrix, which is produced during inflammation, can bind mip-i and this may serve as a depot for the prolonged presence of nip- . in additional studies we have demonstrated that the intratracheal instillation of rmui [ip-l(loong) activation of polymorphonuclear leukocytes by inflammatory stimuli may contribute to the development of multiple organ failure in septic patients. thereby pmnl are proposed to avidly adhere to vascular endothelium causing damage by the subsequent release of toxic agents. as cellular adhesion is primarily mediated by -integrins and lselectins, the present study compares the expression of these adhesionmolecules on pmnl in septic patients and healthy volunteers. methods: expression of -integrins and l-selectins on pmnl was measured in whole blood by flow cytometry using the monoclonal antibodies ib and dreg , baseline values were determined immediatley after drawing blood. in addition cells were incubated min at °c to allow for spontaneous regulation of adhesion molecules. blood specimens from septic patients were obtained during the course of their illness. control values were determined in healthy volunteers. results: baseline expression of -integrins and l-selectins was not signifcantly different in septic and in healthy subjects. in contrast, there was a significant upregulation of g -integrins and shedding of l-selectins of pmnl in septic patients (sp) compared to healthy volunteers (hv). the local or systemic production of inflammatory cytokines, such as tumor necrosis factor alpha (tnfc~), can serve to modulate multiple aspects of neutrophil function. the ability of neutrophils to leave the circulation and migrate to areas of infection is one essential component of host defense. l-selectin, a leucocyte-associated adhesion molecule, is responsible for the initial reversible contact between neutrophils and endothelium and the subsequent roiling action of neutrophils along the vessel wall. in contrast to other adhesion molecules, l-selectin expression is rapidly down-regulated after neutrophil activation. the loss of l-seleclin may thus be a critical determinant of how neutrophils become unbound from their endothelial attachments and enabled to proceed towards an underlying extravascular area of infection. we hypothesize that the shedding of l-selectin is a strictly controlled process, occurring primarily at localized sites of inflammation, which may be modulated by tnf~, a flow cytometric method of staining neutrophhs by monoclonal antibodies in whole blood is described whereby the kinetics of l-selectin shedding may be followed in real time. the dose response and time course of in-vitro l-selectin shedding by neutrophils from normal human subjects was assayed after exposure to n-formyl-methionylleucyl-phenylalanine (fmlp) and tnfc~. either singly or in combination, our results show that l-selectin shedding can be reliably followed over time. a significant percentage of cells shed l-selectin after exposure to pg/ml tnfc~ or nm fmlp (but not at pg/ml tnfc~ or nm fmlp). greater numbers of cells were able to shed their l-selectin when fmlp and tnf~x were presented in combination rather than alone. high levels of tnfc~ did not appear to alter the threshold concentration of fmlp required to induce shedding, we conclude that the extent and rapidity of l-selectin shedding may be modified by different combinations of ligands and that shedding, by vidue of the high concentrations of cytokines or chemotactic factors required, is a process localized to sites of infection or inflammation. we prospectively studied patients with severe sepsis syndrome; group a : septic shock with or without adult respiratory distress syndrome lards) (n = , bacteremia = ); group b : sepsis syndrome without septic shock (n = , bacteremia = ). serial plasma samples obtained on day , , , , and , were assayed using elisas method (british biotechnology), normal control levels of soluble icam- and e-selectin, obtained from healthy volunteers, were respectively ± . ng/ml and ± . ng/ml (mean _+ se), acute lung injury was quantified dally on a tour-point score system (murray, am rev respir dis, ) . compared to control mean values, initial levels of groups a and b were significantly higher for icam- (p < - ) and e-selectin (p < - ). comparisons of group a and [] (* = p< . ; ** = p< . t) soluble icam- levels of group a enhanced significantly (p< . ) during the first hours, and a sustained high levels was of bad prognosis ( % of survivors at day ). the evolution of soluble icam- and e-selectin levels were significantly correlated with murray's score (spearman test : p < . ). conclusion: these results suggest that endothelial adhesion molecules are released into the plasma of patients with severe sepsis syndrome. soluble icam- and e-selectin are correlated with endothelial lung damage, and loam- seems to be a better indicator of the severity of endothelial injury. introductory remarks to anti-adhesion molecule strategies as a therapeutic modality ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the development of antimicrobial therapy represented a major breakthrough in the struggle against disease. it strengthened the notion that disease could be overcome by eliminating foreign invaders threatening the host. this paradigm has proven to be very successful, the threat of many infectious diseases has significantly changed, some have even been eradicated. nevertheless, sepsis has remained a severe condition, increasing in incidence while mortality remained very high. more recently, it has become increasingly clear that besides the nature and treatment of an exogenous agent, the reaction of the host defense itself plays a pivotal role in the outcome of the event. endogenous mediators, such as tnf, il-i, il- and il- , govem many of the actions of the host defense system. while the expression of these cytokines more often than not benefit the host, (over)-expression can cause severe damage. based on this hypothesis,anticytokine strategies, such as those targeted against tnf or il- , have been evaluated for the treatment of sepsis. results of these early studies have not yet indicated success in improving the outcome of the disease. it has been difficult to define a patient population where a benefit could be reproducibly shown. furthermore, it has been documented that synergy between cytokines occurs, but detailed knowledge of the cytokine network is not yet available. it is conceivable, that neutralization of one cytokine prompts the induction of another which will evoke the intended response in the host. recent data obtained in human endotoxemic volunteer models seem to confirm this. if this turns out to be the case, neutralizing a single cytokine may not be a successful approach. cytokines in tum, induce various adhesion molecules, such as icam- . such molecules regulate for instance the neutrophil-endothelial cell interactions, which are thought to play an important role in the pathogenesis of systemic organ injury. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. protective effects have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries. thus, altering the host response by modulating the function of adhesion molecules may attenuate the inadvertent injury caused by inappropriate behavior of host defense cells. targeting cellular surface interactions has been added to the efforts to change the outcome of disease. modulation oftheseprocesses seems very promising, but may temporarily leave the host without effective defense mechanism. great care therefore, must be exerted when studying this powerful two-edged sword in a clinical setting. our knowledge of the role of adhesion molecules in the intlammatory response has increased rapidly due to the availability of new reagents and mice geneticly deficient in adhesion molecules. these molecules are important in interactions of leukocytes with endothelial cells, other leukocytes, platelets, and epithelial cells. when these molecules are engaged, they can also play a role in activating leukocytes and their effector functions. in the venules of the systemic circulation, adhesion often occurs through a series of sequential interactions. initial interactions are mediated by members of the selectin family to loosely associate the leukocytes with the endothelium and are followed by firm adhesion requiring members of the integrin and immunoglobulin family. later interactions with endothelium may require pecam. adhesion molecules are usually required for leukocyte emigration in response to extravascular stimuli and for neutrophil-mediated endothelial cell injury. they are critical for host response in many diseases including infections. however, when the inflammatory response results in damage to host tissues, patients may benefit from blocking the leukocyte response. anti-adhesion molecule agents are an important potential antiinflammatory therapy. the focus of anti-adhesion therapy may be at any step of the sequence. diseases where anti-adhesion molecule therapy may benefit patients include ischemia/reperfusion injury in many organs, ards and mof, and transplantation, both to protect the donor organ from ischemia/reperfusion injury and to inhibit graft vs host disease. many strategies have been considered and include: ) blocking the ability of adhesion molecules to recognize their ligand using antibodies that have been humanized or soluble receptors linked to igg to prolong their circulating halflife, ) blocking the ligands for adhesion molecules using soluble adhesion molecules, peptide analogues, or oligosaccharides, and ) blocking the production of the adhesion molecule using anti-sense oligonucleotides. because the synthesis of adhesion molecules is usually regulated by cytokines, inhibiting the action of cytokines is another potential site for interrupting the adhesion process. although important issues of safety must be evaluated, the potential for modulating the inflammatory response make this an exciting area of improvement in health care delivery. claire m. doerschuk, m.d.; riley hospital for children, room ; barnhill drive; indianapolis, in usa. modulation of neutrophil-endothelial cell adhesion with anti-cdl i/cd monoclonal antibodies as a therapeutic modality. ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the central role of inflammatory cells in the pathogenesis of lung and systemic organ injury is well recognized. binding of neutrophils to endothelial cells and migration into the parenchyma are largely regulated by complementary adhesion molecules. the leukocyte integrins are glycoproteins expressed on the neutrophil surface and in the cytoplasmic granules. integrins consist of a common beta or cluster differentiation (cd) chain covalently linked to one of three different alpha chains (cdlla, cdllb, cdilc) and exist on the cell surface as three distinct heterodimers. cdlla/cd is expressed on all leukocytes, whereas cd b/cd and cd c/cd . are restricted to cells of myeloid origin. cd i / cd interacts with intracellular adhesion molecule- (icam-i), its ligand on endothelial cells. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in a large number of experimental models. protective effects with anti-cd antibodies have been observed in a wide variety of inflammatory, immune, and isehemia-reperfusion injuries, such as arthritis, burns, endotoxic shock, bacterial meningitis, autoimmune diabetes, nerve degenemrion, allograft rejection, allergic asthma, acute lung inflammation, skin lesions, and ischemia-reperfusion models of the intestine, myocardium, lung, skeletal muscle, and central nervous system. protective effects have also been observed in animals resuscitated following hemorrhagic shock. blockage of cd , however, would affect all leukocytes, as would antibodies to cdlla/cdi . targeting cdllb/cd would affect cells of the myeloid lineage only, which could prove to be beneficial. cd b/cd is not only involved in transendothelial migration, but is also implicated in adherencedependent formation of reactive oxygen species. blocking cd lb/cd may therefore not only reduce the numbe r of leukocytes accumulating in the tissue, but also attenuate the oxidant stress of infiltrated neutrophils. anti-cd b treatment has been used effectively to reduce tissue injury initiated by ischemia-reperfusion, complement activation and endotoxemia. altering the host response by modulating the function of adhesion molecules may attenuate the inadvertent injury caused by leukocytes, but may also temporarily leave the host without effective defense machinery. overall, animal studies suggest that it may be safe to inhibit neutrophil adhesion for a limited period of rime. these observations will have to be confirmed in carefully designed clinical trials. c, arbobydrams are ubiquizom constir~uts of cell sv.rfaees, and possess many c~xssfies ttm~ m~,e ~em ide~. canaidates for r~ognifioa mole~ule& in m~y systems whe,~ cer udhesioa ~lays a critical ro~ car~hydram l:~dtag ~otegas have been shown to b~ad tocell surfa~ earbohydzaxes ~nd pzrl~pate in cell-ceil lumtaefion& such sys,.ems include ~rti~za~io=, deveaopmeat, l~thoge~-hcet reeog--ition ~d i~zmmadon_ in particular, tb.z recent di%~ve~ of lhe selec~ and th~ impo.~a~c~ in teukccy~udo~lelium adh~ion has -~f~m av.c~on ok l~in m~ted cell adhe~on. s~vere/poten~s/cs.rbohydr~ l~ga~s hrve ~e~l ~u~ilied for ~he s~lcc~ins. the,~ c~u be broadly di,,sded la~o ~wo m'oups -sibyl l~wis x m~ mh~.~l oligo~chadd~s, ~d sf/~ ca~ohydmma, all ~:~ ~l~dns bind m siflyl l~wis x (sie$ o!igos~ccb.e.rkms, zlthou~ w~ differing avi~re~. 'we have i~¢n~ed the functional g~oups a s~ex ~n~ med/a~ ~he b~u ~di~g of ~h~ c~b hydmm = e-se/sedm we have used ~hat iv.formation to sya~esize sle ~ '~mt gs r.he, t focus on replacing slslic ~sd ~nd fuc s¢ wi~ simpler, more stable strunt~es. a[~ou~a ~ proeer~ is ongoing, we hve been ~ucee,.~ful a~ rep~aein t.ke si~ic a~id. residue wi~ std.fzte. ~ce~ or la~c amd groupa we t'we ex aninad &e ten, bunion of ezed~ hydroxyl group of the fizeose residue ~ billding of e-, l-~nd p-selees..u. we have also found m~fi~fio~ of the reducing end ~¢.cha'i~ ~z increase mtagovsst activity. the, m¢ond. group of figs,rids a.r eontzin su~a~ u a ea.rbohydr~t¢ support,, und seem to bi~.d to t~e sele~ti~s wi~ dlf:ferem characteristics c .an does sle:, s=h compounds are m ogniz~d by l-selects. md p-selectia, bur., in genera/, not e, selecti~ these dam may mdicam r.hat l-and p-s~ ¢at~ h~d via o, second ~te thaz operates lu~.ead of, or in conjunction with ~tc sle" b~ding ~iite. dam rela~&~g to ±e, se two types of ,ml~ liga~ds have beam t~ed to desig~ potential the ~peutics for i~fi~anmat ry disease. lr:rng maimai models of acute lung lu ury we can demo~trate that eompmmds that inhibit seleetiu birding ~ ~i~o hzve ber~ficial effects when uc~d in rive. progressive microvascular damage in the tissue adjacent to a cutaneous burn injury results in extension of burn size. the role of leukocytes in the pathogenesis of microvascular injury was investigated by inhibition of their adherence to the microvascular endothelium using monoclonal antibodies directed to leukocyte cdi or its endothelial ligaud, intercellular adhesion molecule- (icam- , cd ). a model of thermal injury was developed using new zealand white rabbits. two sets of three full-thickness burns separated by two x -mm zones were produced by applying brass probes heated to °c to the animals' backs for sec. cutaneous blood flow determinations carried out with a laser doppler blood flowmeter were obtained for hours. there were five experimental groups: controls given saline alone; animals given monoelonal antibody to the cd r . prior to burn injury (pre-r . ); animals given r . min after burn injury (post-r . ); animals given a monoclonal antibody to icam-i, r . prior to burn (pre-r . ); and animals given the r . min postburn injury (post-r . ). blood flow in the marginal "zone of stasis" between burn contact sites was significantly higher in the antibody-treated animals. administration of the antibodies min after injury was as effective as preburn administration in preserving blood flow. at hr post-burn all antibody -treated animals had blood flow in the areas at risk for progression (i.e., the zone of stasis) at or above baseline levels while the control animals had levels equal to . _+ % of baseline (p < . by analysis of variance and mann-whitney u test). these results indicate that leukocytes play an important role in the pathogenesis of burn wound progression, and that this progression can be attenuated by moduiating adherence to endothelial cells. a wealth of information now supports the hypothesis that inhibition of cell adhesive mechanisms will nter the course of immunologicand inflammatory processes. what remains unclear is whether inhibition of specific mechanisms wfl[ be of therapeutic benefit in any specific human disease. current data derived from animal models are not inconsistent with the hope of therapeutic benefit, but techniques for inhibition (e.g., antibodies, antisense oligonucleotides, inhibitory peptides, inhibitory carbohydrates, smaii synthetic inhibitors, etc), tissue and species differences in the relative contributions of adhesion molecules to the inflammatory process, and the cascade model of adhesive interactions are all confounding issues, making predictions of therapeutic benefit in any specific human disease process very difficult. additional concerns involve the potential roles of adhesive mechanisms in host resistance to infection. as human therapeutictdals are initiated, more exact information on the roles qf specific adhesion molecules in human disease should emerge. inhibition of leukocyte adherence to endothelial cells can represent a novel therapeutic approach to septic shock. we performed a pilot study to evaluate the safety and tolerability to cy- , a monoclonal antibody against human e-selectin, in patients with septic shock. septic shock was defined by clinical signs of sepsis, a documented source of infection, and fluid-resistant hypotension requiring the use of vasopressors. eleven patients entered the study, but patients who died during the first hours were excluded, as this was part of the protocol. cy- was administered as a single intravenous bolus of . mg/kg (n= ), . mg/kg (n= ) or i mg/kg (n= ) mg/kg. the antibody was well tolerated. none of the patients died during the day follow-up period. organ failure was assessed for organs (cns, lungs, liver, kidneys and coagulation). the mean number of organs failing, which was initially . ± . , decreased to . ± . at the end of the study (p<o.o ). these results are therefore encouraging. administration of an antibody to e-selectin in patients with septic shock requires further study. the importance of cytotoxic t lymphocytes (ctl) in the host defense mechanism against viral as well as parasitic and bacterial diseases is becoming increasingly appreciated. the design of vaccines to generate cytotoxic t ceils from nonviable or subunit constructs, however, poses challenges due to the unique characteristics of antigen processing and presentation by class i major histocompatibility complex (mhc) molecules. since the final antigen recognized by ctl are short peptides capable of high affinity binding to class i mhc molecules, we have designed strategies: a) to define the structural characteristics of peptides that are required for their high affinity binding to mhc; and b) to formulate these peptides into immunogenic vaccines that are capable of generating cytotoxic t lymphocytes. the strategy and results to accomplish these two goals will be discussed. amnon altman and erich gulbins ras proteins represent essential intermediates in receptor-mediated growth and differentiation pathways. they couple signals initiated by receptor or nonreceptor protein tyrosine kinases (ptks) at the cell surface to cytoplasmic targets which coordinate signal transduciion to the nucleus. ras also participates in t lymphocyte activation initiated by the antigen-specific t cell receptor (tcr)/cd complex, which leads to lymphokine production and proliferation. receptor ligation causes activation of associated ptks of the src and syk families as the earliest identifiable event in this pathway. the importance of ras in t cell activation is indicated by the findings that an oncogenic ras protein activates the interleukin- (il- ) gene promoter; conversely, a transdominant inhibitory ras mutant inhibits this event and the activation of map kinases. the rate-limiting step in ras activation is the exchange of bound gdp for gtp, which is catalysed by guanine nucleotide exchange factors (gefs). we identified the sh /sh domain-containing vav protein, which is selectively expressed in hematopoietic cells, as a ras-specific gef coupled to several hematopoietic receptors. vav can be activated by two pathways, i.e., by ptk-mediated phosphorylation or by binding of diglyceride second messengers to a cysteine-rich, protein kinase c (pkc)homologous vav domain. these pathways are independent as demonstrated by structure/function analysis and the use of pharmacological inhibitors. the two activation pathways may enable vav to integrate signals from distinct hematopoietic cell receptors, and couple them to ras. t cells express another, ubiquitous ras gef, i.e., sos, which is known to be coupled to activated tpk receptors. t cell activation leads to membrane association of a signaling complex consisting of sos and two other signaling proteins, grb- and shc, via direct binding of the shc sh domain to the tyrosine-phosphorylated chain of the tcr/cd complex. thus, multiple receptors, ptks and ras activators participate in signaling pathways that lead to hematopoieitc cell growth and differentiation. the interactions and function of these various signal transducers will be reviewed. phagocytes. immunity is mediated by specific t lymphocytes, cytokines produced by these specific t cells activate antimicrobial capacities in mononuclear phagocytes, thus contributing to protection. other immune mechanisms also participate in the acquisition of resistance. on the other hand, t cells are also crucial for many pathologic sequelae of intracellular bacterial infections. although ifn-y is central to macrophage activation, synergistic and antagonistic effects with other cytokines occur. the cd/ t cells, representing the major t cell population in experimental mice, are the main mediators of antibacterial immunity; an auxiliary role for y/~ t cells appears likely. the c~// t cell population further segregates into cd t cells which recognize microbial peptides in the context of gene products of the major histocompatibility complex (mhc) and cd t cells which see their peptide in the context of mhc class i. the -y/~ t cells are generally double-negative. knock-out mice in which the genes for various t cell receptor chains, for mhc class i or mhc class ii molecules, for cytokines or cytokine receptors had been deleted, have provided extremely helpful tools for analyzing the role of t cell subsets and cytokines in antimicrobial immunity. using these mutant mice, the role of distinct t cell subsets and cytokines in bacterial elimination and granuloma formation was analyzed in detail. these studies underline the central role of a// t cells and ifn-y in antibacterial immunity and, furthermore, show a distinct function of /$ t cells. moreover, these studies show that the relative contribution of cd or cd t cells to antimicrobial immunity varies in response to different pathogens. apoptosis is an active form of cell death in which the cell participates in its own demise, providing the biochemical pathways that trigger and mediate the complex events of the process. although this phenomenon has been studied for many years, it is only recently that significant progress has been made towards the elucidation of the molecular mechanisms that control apoptosis. once such mechanism came as something of a surprise: in a number of eases, apoptosis can be promoted by the action of the c-myc protein, a protooncogene product that had previously been associated only with cell proliferation (and presumably, survival) . expression of c.myc in cells can cause them to enter an apoptotic pathway or proliferate, mad this "decision" depends upon additional signals, such as growth factors that inhibit apoptosis and allow the ceils to proliferate. thus, c-myc directs cells out of rest and the choice of proliferation or death depends upon the presence or absence of survival signals. other survival signals are generated by oncogene products that can cooperate with my¢, including bcl- and abl there are implications of this interplay between apoptotie and anti-apoptorlc signals in cell iransformation and the resistance of some tumor ceils to therapeutic agents capable of inducing apoptosis. oncogene interactions therefore control the life or death of transformed ceils but also have important roles in normal, development processes. in the immune system, developing t ceils are "screened" for potential self-reactivity by a process of negative selection, in which activation via the t cell receptor (tcr) induces apoptosis. this process can be mimicked in t cell hybridomas, and appears to depend upon the expression of the c-mye protein. evidence that this represents a requirement for the myc/max heterodimer will be presented. as above, these cells are presented with the "choice" to proliferate or die and this depends not only upon myc but also other signals. thus, expression of functional v-an kinase in these ceils can render them resistant to the activation of apoptosis via tcr ligation, surprisingly, bcl- does not appear to be capable of blocking this form of apoptosis, and the reasons for this will provide new insights into the development of the immune system and the process of apoptosis. although the oncogene products discussed here probably do not directly participate in the biochemical process of apoptosis, they represent molecular controls on this complex mechanism. as such, they gave us new ways to look at the life and death of a cell recent attention has focused on macrophage release of cytokines, such as il- , il- and tnf as important mediators of septic shock. however, serum cytokine levels have correlated poorly with outcome of septic shock. the purpose of this study was to compare the functional status of macrophages to serum cytokine levels in early sepsis by an analysis of splenic macrophage protein synthesis during abdominal sepsis. macrophage total protein distribution and biosynthetic activity was assessed by large format -d page, autoradiography of s-labeled proteins and computer assisted densitometric analysis. sepsis was induced in sprague dawley mts by cecal ligation and puncture (clp). untreated and sham operated rats served as controls. splenic macrophages were harvested at and hrs. following clp. serum il- levels were determined at , , and hours by the tdi bioassay. by hrs. % of the clp mls exhibited multi-microbiaj bacteremia. control or sham operated rats did not show bacteremia. clp resulted in a significant % elevation (p < . ) in serum il- levels at hrs. there was no difference in il- at and hrs. when compared to the control groups. d page studies examined splenic macrophage total protein distribution and biosynthetic activity at and hrs. post-clp. at hrs. macrophages from clp rats showed a substantial decrease in total protein pattern ( protein spots vs protein spots) when compared to non-septic control macrophages. a decrease in the number of lower molecular weight proteins (< kd) was observed. at hrs. post-clp, splenic macrophages from clp rats showed a substantial increase in the synthesis of low molecular weight (< kd) proteins, when compared to non-septic controls. we conclude that: l) fulminate abdominal sepsis induces an early ( hrs.) staining with cd and cd mabs will identify two monocyte subpopulations in human blood: a major population of regular monocytes, which strongly expresses the cd antigen (cd ++) and a minor population with weak expression of cd and expression of the cd antigen lcd +/ cd + cells). in healthy control donors(n= ) the latter cells account for + cells/mm and %+ % of the monocytes. in sepsis patients, the cd] +/cd + cells can become a major population with more than % of all monocytes in of patients and with more than cells/mm in of cases. there was no correlation of cd +/ cd + cells to any clinical parameter except for cd +/cd + percentage and body temperature (p= . ). the cd ++ monocytes showed a substanttial decrease in cd antigen density in of patients. three-color-if shows that the cd +/ cd + cells in sepsis patients when compared with the cd ++ monocytes exhibit a higher level of class ii antigen and a lower level of cdiib and cd antigens, consistent with a more mature nature of the cd +/cd + cells. levels of il- were increased in sepsis patients: of patients with high numbers of cdi +/cd + cells ( /mm ) had high levels of il- ( u/ml). these data suggest that septicemia may lead to substantial changes in blood monocyte composition and this may be related to elevated levels of cytokines such as il- . human peritoneal macrophages were exposed to increasing doses of lipopolysaccharide (lps) or a synthetic lipid a analogue (mrl ) and production of the cytokines il-lb, il- , tnf-a and g-csf was assessed at the protein-and mrnalevel. cells were also stimulated with low doses of lps and mrl to study their "adaptation" to a secondary challenge with high doses of lps. tnf-a production after stimulation with lps could be almost completely relieved by preincubation of cells with low doses of lps and similarly, il- production was suppressed. surprisingly, however, "adapted" cells were able to synthesize even larger quantities of of g-csf and il-lb when exposed to a secondary lps challenge. the changes in tnf-a, il- and g-csf protein synthesis could a/so be detected on the mrna level, whereas transcript levels for il-lb remained unaltered as assessed by northern blot analysis. high doses of the synthetic lipid a analogue mrl were also able to "adapt" macrophages for a secondary lps challenge by downregulating tnfa-and il- -production, while priming secretion of g-csfand il-lb as well. taken together, here we describe for the first time the discordant adaptation of human peritoneal macrophages to a secondary lps stimulus in vitro. these findings appear to bear ramifications for the in-vivo endotoxin response during inflammation and gramnegative septicemia. shock states with inadequate cellular oxygen delivery may contribute to macrophage (mo) activation or dysregulation. in this study we compared the effect of transient hypoxia and endotoxin pretreatment (lps ) on mo mediator release with a second endotoxin stimulus (lps ). methods: in vitro cultures of marine peritoneal exudate mo were exposed to hr. of hypoxic or normoxic conditions, then incubated hr under identical normoxic conditions _+ ng/ml of lps pretreatment. during the final hours all m~l were exposed to a range of lps concentrations. m~i supernatants were assayed for tnf, il- , il- , pge , nitric oxide (no), and superoxide release. results: lps markedly inhibited mo tnf release by lps but hypoxia had no effect on lps -triggered tnf release. hypoxia increased mo il- production in the absence of lps , but inhibited lps augmentation seen under normoxic conditions. pretreatment with lps increased no production from lps under normoxic conditions, but bypoxiainhibited this effect. pretreatment with lps signifcantly augmented mo release of il-i and pge , but hypoxia had no significant effect (data not shown) superoxide production was increased by lps under normoxic conditions, but hypoxia significantly inhibited superoxide release (not shown a. lepape, c. docile, f. arpin, m. c. gutowski, v. banssillon and j. bienvenu. i aim of the study. increased levels of tnf are inconsistently correlated with the severity of sepsis. one possible explanation is a decrease ability of ceils to produce eytokines. the objectives of this study were m compare at different levels of of clinical severity the responsiveness of cytokine producing cells. this was evaluated by the response to a stimulation by lps as well as to the inhibitory effect of ptx. the technic used is a whole blood ex-vivo model, as described by desch et al. ( ) . h materials and methods. different groups of icu patients, postoperative (n= ), sepsis (n= ), septick shock (n= ), and healthy control (n= ), were studied. blood was drawn in endotoxio free heparinized robes. stimulation was achieved by addition nf pl oflps ( ng/ml) to id of whole blood in presence of various concentrations of ptx ( , " , - , " , i " m). after hrs incubation at °c, the tubes were centrifuged and supematants frozen at - °c. tnfa and/l were measured by elisa (medgenix r and immunotech r respectively). monocytes were quantified on a technicon h . the results are expressed as median values. non parametric tests are used for testing differences between groups. hi results, tnftx and , , corrected for monocytes count, are given as % of their initial value, the baseline before stimulation or inhibition being %, ) stimulation by lps. the control group is much more stimulated (> % for il , > % for tnfa). blood samples taken postoperatively and in patients with simple sepsis are significantly less stimulated (> % for il , > % for tnfa ). the lowest stimulation was observed in patients with septic shock (median = %), some patients being not stimulated at all. )effects of ptx.the inhibitory effect of ptx on tnftx production is effective in all groups at - m (reduction to less than '¼ of the median values), and is almost complete at " m. the septic shock group has a decreased sensitivity to ptx. il production exhibits a lesser reduction at - m (~ 'a to ½ of the median values), further increased at - m. the septic shock group is again less sensitive to ptx. iv conclusion: the reduced ability of circulating monocytes to produce cytokines during severe infections is confirmed here. ptx is able to reduce significantly tnfc~ at - m and the inhibition is nearly complete at - m. surprisingly, there is a lesser, but significant suppressive action of ptx on il , not found in experiments using purified monocytes. one possible explination could be the interplay between cytokines production. ( ) lymphokine research ( ) cdna sequencing constitutes a powerful method of measuring steady-state mrna levels for all genes transcribed in a given cell or tissue at a particular stage of differentiation. by comparing transcript abundance both prior to and following differentiation, individual genes can be identified whose transcription is regulated both positively and negatively. in order to examine monocyte activation, the human monocyte line thp- was induced with phorbol ester ( h) and activated for h with lipopolysaccharide (lps) after which polya + rna was purified. the rna from control and lps-treated cells were each used to construct a cdna library under identical conditions, and all resulting clones were selected for cdna sequence analysis. each clone sequence was evaluated by matching with both genbank and our own gene databases. very different patterns of gene expression were seen in the two libraries, the latter reflecting very high levels of known inflammatory mediators such as il- and tnf. a second set of libraries were made from umbilical vein endothelial cells (huvec), both with and without lps stimulation, and were analyzed in a similar fashion. the effects of lps induction on specific gene transcription in both cell types will be discussed. t. tadros, md, th wobbes, me) phd, rja goris, md phd to investigate whether the preactivation of regional macrophuges by liposomes containing muramyl tripeptide (mtp-pe) can counteract the detrimental effect of blood transfusions on both anastomotic repair and host susceptibility to infections. methods eighty lewis rats received lmg/kg of either empty or mtp-pe encapsulated liposomes, intraperitoneally (ip). twenty-four hours thereafter, the animals underwent resection and anastomosis of both ileum and colon, and received ml of either saline or blood from brown norway donors,iv. the animals were killed or days after surgery and examined for septic complications and anastomotic repair. the average anastomotic strength, as assessed by bursting pressure (+sd), was significantly diminished in the transfused animals, as compared to the non-transfused animals (ileum;day ; -+ vs + , p< . ). transfused animals pretreated with mtp-pe encapsulated liposomes showed a significant improvement of their anastomotic bursting pressure ( + , p< . vs transfusion). pretreatment with mtp-pe encapsulated liposomes decreased significantly the incidence of anastomotic abscesses in transfused animals ( from % in ileum on day to %, p< . ). conclusions preactivation of regional macrophges by intraperitoneal administration of mtp-pe encapsulated liposomes prevents the detrimental effects of transfusions on anastomotic repair and reduces the incidence of intraabdominal sepsis. academic hospital nijmegen, dept of general surgery, pb i, hb nijmegen, the netherlands. leukemia cell line, teip- . robin s. wa, gner*, perry v. halushka "~, and james a. cook*, departments of physiology , pharmacology "l" and medicine "t, medical university of south carolina, charleston, s.c. . adherence of monoeytes to endothelium and extracella/ar matrix proteins is essential for accumulation at sites of inflammation. txa , an arachidonic acid metabolite, inhibits human monocyte chemotactic responses suggesting that txa may alter monocyte adhesiveness. we selected the thp- cell line, a human monocytic leukemia cell line to further investigate the effect of txa on adhesion. we tested the hypothesis that txa alters lpsinduced adhesion of thp- cells and that txa exerts its effect on adhesion via a camp dependent mechanism. thp-i cells were exposed to s. enteritidis endotoxin (lp.g/ml) _+ the cyelooxygenase inhibitor lndomethacin (in), the txa mimetic i-bop ( . .tm,) or txa receptor antagonists bms and l ( ~m). cells were allowed to adhere for hours and adherent protein/well was determined. lps-induced a significant (p< . ;n= ) increase in adherence of thp- cells (basal, . + . gg protein/well; lps, . +_ . p.g protein/well). the amino acid glutamine is an essential compound for synthesis of purine and pyrimidine basis and therefore necessary for rna-and dna synthesis. in human plasma the concentration of glutamine is between . - . mm, and is reduced in septic patients up to % ( . - . mm). monocytes play a central part in the inunune system and it was of interest, whether glutamine is involved in the modulation of cell surface markers and phagocytosis of these cells. human peripheral blood mononuclear ceils were obtained from ml heparinized blood of apparently healthy donors by ficoll-paque density gradient and isolated by counterflow elutriation. the puritiy was more than %. subsequently cells were cultured in phenolred-free rpmi medium with various concentrations of glutamine ( . , . , . , . , . , , mm) in teflon-fluorinated ethylene propylene bottles to exclude cell adhesion and possible cell activation. aider seven days culture, cell viabilty was determined by trepan blue exclusion and varied between and %, independent of glutamine concentrations. cell surface markers were detected by flow cytometry, noaspecifie phagoeytosis was measured with latex beads and specific phagocytosis with opsonizied e.eoli using a facscan. lower concentrations of glutamine decreased the expression of hla-dr and icam- /cd on monocytes in a dose-dependent manner. the receptor for fc'/rucd as well as the receptors for complement cr /cdllb and cr /cdllc were down-regulated. cr /cd which is only slightly expressed on monocytes was not influenced. furthermore, no effects on the expression of cdi , the receptor for transferrin cd and fc'friii/cd were seen. our data indicate, that lower concentrations of glutamme influence the phenotype of monocytes. we are now interested to study whether glutmnine influences non-specific phagocytosis, or whether specific phagocytosis correlates with the decreased expression of fc'/r and complement receptors. we investigated immunologically more than patients who were admitted to icu because septic syndrom during the last four years. patients were immunologically followed up - times per week until release from icu. the expression of hla-dr antigen on monocytes turned out to be the best prognostic parameter. the persistence (> days) of low hla-dr expression (< %) predicts fatal outcome (mortality > %). the altered phenotype was associated with a functional deactivation of monocytes (diminished apc, ros formation, cytokine secretion). we called this phenomenon "immunoparalysis". ifn-gamma and gm-csf were able to restore the altered phenotype and function in vitro. however, addition of autologous plasma from septic patients with "immunoparalysis" to these cultures prevented the cytokine-induced restitution. the inhibitory activity could not be removed by dialysis. therefore, we started a study to prove the therapeutic efficacy of plasmapheresis. indeed, [ of patients recovered from "immunoparalysis" following repeated plasmapheres; of them survived ( %). patients recovered temporarely and patients did not respond (all died). the survival rate in the control group of septic patients with persistent "immunoparalysis" was of ( %; p< , ). in summary, plasmapheresis in association with immune monitoring may be an alternative strategy to improve survival rate in severe sepsis. taurolidine, a synthetic taurine-formaldehyde derivative has antiadherent, bactericidal and anti-lps properties functioning primarily through binding of the lipid a region of the lps molecule. the active derivative of taurolidine, taurine, modulates calcium channel activity, critical to the initiation of a number of immunostimulatory pathways. we hypothesised that taurolidine may have direct immunostimulatory activity. the aim of this study was to investigate the immune effects of taurolidine on peritoneal macrophage (pmo) function and then determine the role of taurine in this response. study : in vivo stimulation:cd- mice (n= ) were randomized to receive taurolidine ( mg/kg bw/i.p.) or saline cor~trol. peritoneai cells were harvested after hours and were assessed for pm function [superoxide anion generation (o -), nitric oxide (no), tumor necrosis factor (tnf), fc/cr -mediated phagocytic function (phago) study : control pm were harvested and cultured in vitro with taurine ( . mg/ml for hrs), after which time they were assayed for -and tnf release. in vivo stimulation with taurolidine taurolidine has specific immunological effects on m . release of the inflammatory mediators -and tnf, and fc/cr -mediated phagocytosis were significantly increased, while release of the endothelial relaxing factor no was significantly reduced. in addition, the amino acid taurine, which is released as a byproduct of taurolidines breakdown has an immunostimulatory effect on pmo and may be the active moeity of the compound tanrolidine. in sepsis, a number of mediators which affect vasomotor tone and cardiovascular function are produced. inasmuch as sepsis causes decrease in systemic vascular resistance (svr), attention is usually focussed on vasodilators such as lactate, tumor necrosis factor, interleukin-i & , and nitric oxide. but injury and inflammation als cause production of several vasoconstrictors whose effect may not be evident in changed svr, but may significantly affect organ blood flow or function in the paracrine environment. endothelin (et) is a amino acid peptide vasoconstrictor produced by ischemic or injured endothelial cells (ec's). et is also a potent constrictor for renal mesangial and coronary vessels, an endocrine regulator, and a negative cardiac inotrope. systemic et levels increase significantly in hypoperfusion and ischemia. while et is principally produced by ec's, we asked if human monocytes might also produce et and thereby regulate vasomotor tone in areas of inflammation. monocytes from healthy donors were separated on ficoll, resuspended in rpmi + % fetal calf serum and stimulated with i ug/ml endotoxin (lps). et was measured by radioimmunoassay. lps-stimulated monocytes produced ! fm of et/ cells (vs. unstimulated controls of < ). this calculates to - % of the amount of et observed in patients with low cardiac output, sepsis or ischemia. we conclude that et is a cytokine produced by both ec's and monocytes with potent effects on numerous cells and organs in the critically ill. wuppertal , germany we and other authors showed that fatal outcome in septic disease is associated with a decreased capacity of peripheral blood monocytes for the in vitro production of proinflammatory cytokines, especially tnf-alpha. we found that this monocytic deactivation is completed by a persistent and marked decrease of hla-dr expression on monocytes (< % hla-dr+ monocytes) and a diminished antigen presenting activity whereas the capacity to form the antiinflammatory il- receptor antagonist remains high. in order to evaluate the in vivo situation and to determine at which level tnfproduction/secretion is altered we assessed the tnf-alpha mrna expression in freshly isolated peripheral blood mononuclear cells (pbmnc) from septic patients. tnf-mrna was onty rarely detected by semiqaantitative polymerase chain reaction in pbmnc's from septic patients with monocyte deactivation. meanwhile, it was found in almost all pbmncs from septic patients without monocytic deactivation. we wondered, whether il-i , which ,is known to depress monocytic proinflammatoly response and mhc class ii expression, could be one of the mediators in fatal sepsis. in fact, we found that il- message in pbmncs of septic patients peaked in the beginning phase of monocytic deactivation. in further investigations we found that tnf-administration can induce monocytic deactivation in a murine model/n vivo and provoke il- message in human pbmncs in vitro. these results support our hypothesis that an excessive delivery of proinflammatory cytokines in a first phase can induce an overwheiming inhibitory feedback, mediated by immuninhibitory mediators like il-l , which leads to often fatal monocytic deactivation in a second phase. interferon-gamma which is known to counteract il- production and the effects of il- on monocytes restores the function and phenotype of monocytes from septic patients with monoq, te deactivation in vitro and could be a possible therapeutic agent in otherwise fatal sepsis. our laboratory previously reported that lps dependent macrophagederived tnf-a production can be enhanced by pretreatment with lps at substimulatory lps priming doses coincident with a suppression of lps dependent nitric oxide (no) production (zhang and morrison, j. exp. med : , ) . in order to extend the characterization of these lps priming effects in mouse macrophages, we examined the capacity of substimulatory lps to modify lps dependent il- production. macrophages were obtained from peritoneal exudate of thioglycollate treated c heb/fej mice and cultured in rpmi medium containing % fetal bovine serum. macrophages were pretreated with various subthreshold stimulatory concentrations of lps (olll:b ) for hours, washed three times, and then stimulated with the effective stimulatory concentration of lps for hours. the amount of il- in the supernatant was measured by il- dependent cell line (b and td ) proliferation assay. il- was produced by macrophages at lower threshold doses of lps than those required for tnf-o~ or no production. subthreshold doses of lps modulated il- production in a biphasic manner characterized by an initial suppression and then potentiation. higher doses resulted in secretion of il- during the initial incubation with lps and subsequent desensitization. il- , like tnf-~ and no, is, therefore, also affected by lps pretreatment. moreover, tnf-a and il- shared the similar potentiational pathway, but differed by the fact that only il- was inhibited. (supported by r ai and po a .) department of microbiology, molecular genetics and immunology and the cancer center, wahl east, university of kansas medical center, kansas city, ks - . korolenko t.,urazgaliev k.,and arkhipov s. the role of macrophage (mph) stimulation in mechanism of protective effect of new immunomodulators yeast polysaccharides -heteropolysaccharide cryelan and homopolysaccharide mannan rhodexman (both produced by petersburg chem.-pharm. inst.) was studied. in vitro according to nst test incubation of murine peritoneal mphs with cryelan or rhodexman, ~g/ml, min was followed by increase of potencial microbicidic activity of mphs. in vivo mph stimulation by immunomodulators studied included increase rate of carbon particles phagocytosis during single i.v. or i.p. mode of administration to mice - days after (peak at nd day for i.v. and th day for i.p. mode of administration of the same dose of mg/ g b.w.).the preliminary injection of cryelan ( mg/ g, or h before) to mice with acute cold stress (- ° c, h) revealed protective effect restorating the value of depressed phagocytosis up to the normal level;the positive effect on ultrastructure of hepatocytes was noted also.there was no changes of plasma corticosterone level between group with acute cold stress and mice with cryelan + acute cold stress (several fold increase comparatively to the control mice).as was suggested, the mechanism of protection can include mph stimulation and secretion of some acute phase proteins responsible for positive effect of immunomodulators. new yeast polysaccharides cryelan and rhodexman can be used for macrophage stimulation,especially in pathological states. immunomodulators were shown to increase production and secretion of lysosomal enzymes (like zymosan). secreted enzymes,especially cysteine proteinasescathepsins b and l -involve in the process of inflammation;however, excessive release of these enzymes may lead to noncontrolled proteolysis followed by tissue degradation (assfalg-machleidt et al., ) .the effect of zymosan,bcg and new immunomodulator carboxymethylglucan (cmg), second fraction on secretion of lysosomal enzymes by murine peritoneal macrophages was studied. zymosan increased the secretion of n-acetyl-~-d-glucosaminidase and ~-galactosidase into the culture medium ( - fold); bcg possessed similar effect.cmg in the same concentrations ( /~g/ml) increased release of these enzymes only saightly ( . times).it's known that zymosan-induced secretion reflects the enzyme release from formed lysosomes (warren, ) .it was suggested that cmg activated macrophages via interaction with scavenger-receptors,followed by weak secretion of lysosomal enzymes and as a result decrease of tissue damage. in vivo zymosan induced stimulation of mononuclear system of phagocytes followed by increase of cysteine proteinases activity in liver at the th day. in the same time in blood n-acetyl-~-d-glucosaminidase and n-acetyl-~-d-galactosidase activity increased - fold. it was concluded that in drug design it's possible to select such immunomodulators,e.g. cmg,which can activate mononuclear system of phagocytes and do not damage tissue. endothelin-i (et-i) is produced by injured/ ischemic endothelium, mobilizes intracellular ca ++ and is a potent vasoconstrictor. it is also a ca ++ agonist for anterior pituitary or renal mesangial cells and monocytes. et-i causes monocytes to produce interleukin-l, , , prostaglandin e , and substances which trigger neutrophil superoxide production. et-i levels increase in shock and et may play a role in activating leukocytes post shock causing reperfusion injury. but blood flow experiments suggest splanchnic circulation changes more profoundly in shock than peripheral circulation. we therefore asked if et- (or vic), the et which predominates in splanchnic vessels, had any effect on monocyte cytokine production. human monocytes from health~ blood donors were separated on ficoll. . x ucells/ ml in rpmi + % fcs were incubated i min., & hrs. with - m et-i, - m vic or i ug/ml of lps. supernatants were assayed by elisa. we have shown that low dose endotoxin pretreatment (lps ) for hrs markedly inhibits the macrophage (mo) release of tumor necrosis factor (tnf) and increases interleukin- (il-i) in response to a subsequent endotoxin stimulus (lps ). in this study we examined the kinetics of lps inhibition of tnf and augmentation ofil- . methods: murine peritoneal exudate mo from balbc mice were exposed in vitro to medium or ng/ml of lps for intervals of to hours. culture medium was then replaced with , or ng/ml of lps for hrs. tnf and il- in mo supernatants were measured by specific bioassays. during sepsis endotoxin (lps) activates macrophages (mo) to release mediators such as tumor necrosis factor (tnf), interleukin- (il- ), interleukin-i (il-i) and prostaglandin e (pge ). we showed that preexposure to lps (lps ) alters the response of murine m~i to subsequent lps stimulation (lps ). we hypothesized that in vitro cytokine release by lps in human monocytes (mo) is also be altered by preexposure to lpsi. methods: human peripheral blood mo were obtained from healthy volunteers (n= ), cultured in vitro hrs, then pretreated hr _+ lps -cultures were then stimulated with lps and mediators in mo supernatant measured: tnf, il-i, and il- by specific bioassays, pge by immunoassay kit. serum cytokine levels (specific elisa kits) were compared to in vitro supernatant levels. data is expressed as % control_+sem, lps = ng/mh the table shows that all mediators were increased, in the absence of lps . pretreatment with lps resulted in complete inhibition of lps -triggered tnf release. in contrast, lps significantly increased mo secretion of il- , il- and pge (data not shown). serum cytokine levels were as follows: tnf _+ , il-i + , and il- . -+ . ng/ml. these serum levels were low, showed an extremely wide variation, and did not correlate with in vitro lps -triggered mediator production. conclusion: human monoeyte mediator production is differentially regulated by preexposure to lps . provocative in vitro testing of monocytes may ultimately be clinically useful to identify prior in vivo lps exposure or mo macrophages release numerous secretory products involved in host defense and inflammation. activated macrophages with cytokines produced have been implicated in tissue damage in sepsis and multiple organ dysfunction. aimed to elucidate the organ-association phenomena,this study is to compare peritoneal macrophage(pm),alveolar macrophage(am), and kupffer cells(kc) during sepsis in terms of cellular protein contents as symbol of activation by flow cytometry analysis. sepsis were produced by cecal ligatien and perforation (clp) in wistar rats weighing - g.pm were obtained by peritoneal lavage,am by bronchial lavage and kc by incubating the collegenase digested liver with pronase-e. leukocytes have been implicated as a mediator of the microvascular dysfunction associated with reperfasion of ischemic tissues. a role for ieukocytes is largely based on observations that rendering animals anutropenic with anti-neutrophil serum or preventing leukocyte adhesion with monoclonal antibodies attenuates the increased fluid and protein leakage from the vaseulature that is normally observed in postischemic tissues. we have recently undertaken studies designed to determine the relationship between leukocyte-endothelial cell adhesion and albumin leakage ia rat mesenterlc venules exposed ~o ischemia-reperfusion (i/r). leukocyte adherence and emigration as well as albumin extravasafion were monitored in single postcapillary venules using iatravital fluorescence microscopy, lschemia was induced by complete occ!usion of the superior mesenteric artery and ~dl parameters were monitored at various intervals following reperfusion. the magnitude of the leukocyte adherence and emigration, and albumin leakage elicited by i/r was positively con-elated with the duration of ischemia. the albumin leakage response was also highly correlated with the number of adherent and emigrated leukocytes. monoclonal antibodies against the adhesion glycoproteins cd , cdllb, icam- and l-selectin, but not p-or e-selecdn, reduced i/r-induced leukocyte adherence and emigration as well as albumin leakage. phauoidln, an f-aetin stabilizer, largely prevented the emigration (but not adherence) of leukocytes and greatly reduced, the raicrovascular protein leakage. plateletleukocyte aggregates were formed in postischemic vemdes; the number of aggregates was reduced by antibodies against p-selecdh, cdilb, cd , and icam- , but not e-selectin or lselectin. a significant fraction of the mast ceils surrounding the posteapillary venules degranulated in response to ischemia/repeffusion, but mast cell stabilizers did not afford protection against the albumin leakage elicited by i/r. these results indicate that reperfusloninduced albumin leakage is tightly coupled to the adherence and emigration of leukocytes in posteapillary venules. this adhesiomdependent injury response is primarily mediated by cdllb/cdi on activated neutrophils and icam- on venular endothellum, and appears to require l-selecda dependent leukocyte rolling. mast cell degranulation does not appear to conwibate to the vascular pathology associated with i/r. m.d. rod=iek, boston, ma, usa the polymorphonuclear neutrophil (pmn) has long been known to pa~tlcipats in the inflammatory rebpons~ as a phagocyte and killer of invading organisms, but little attention has been given to its potential as a participant in the in~une interaction of lymphocytes and macrophages. we and others have shown that the pmn may have i~m~/nomcdulatory effects both in vitro and in vlvo. more recently it has been proven that the pmn can make mrna for and secrete the proinflammatory oytokines illa, il-ib, tnfs, il- and il- as does the other major circulating phagocyte, the monocyte/macrophags. furthermore it has been shown to make the potentially autoregulatory oytokines gcsf and gmcsf. these functional capabilities suggest that the pmn is not an wend cell ~, but one which has a potential role in regulation cf ~he immune response and that this potential ~cle should no longer be ignored when considering the immune abnormalities existing in patients following majo~ injury or surgery. we have investigated the proinflaznmatory oytokine secretion patter~ by pmn in patients following major ~hermal or tra~matic injury and in volunteers fellowinq endotoxemia. ?ollowing major injury there is variable pmn secretion of these cytokines when stimulated in vlero. following endotoxemia in a group of human volunteers pmn showed a hypo=esponsivenesa to lps hrs following endotoxin infusion followed at hre by an overshoot. pretreatment with steroids modulated this overshoot phenomenon, suggesting that receptors for steroids are involved in the regulation of cytokin® secretlon by fmn. these results sugges~ that the pmn, the most numerous cell in the circulation and the first to respond to an ins~l~ may be a so~rce of the prolnflammatory cytokine cascade following injury that has been recognized as significant in the process which often leads to multiple o;gan failure, the immunosuppresslon which occurs following major thermal injury may predispose these individuals to infection and sepsis, which remain a significant cause of morbidity and mortality. included among the many immune aheratlons are the p integrln (cdlla, b,c/cd ) dependent activities of adhesion, chemotaxls, diapodesls, and phagocytosls. our investigations indicate that, following major thermal injuries, the expression of the [~ integrlns, but not cd , is significantly decreased on neutrophlls (pmns). it remains unclear if pmns from thermally injured patients respond normally to lps, the effects of treatment in vitro with lps and f-met-leu-phe (fmlp) on the expression of cdtlb was examlned on pmns from the peripheral blood of healthy volunteers and non-septic burn patients (> ~; total body surface area, >ls~ full thickness), the pmns were incubated with lps (]ng- p.g/ml) or f'mlp ( " to " m) et oc for mln, in ~; human ab serum, the expression of the ]ntegrins was detected using monoclonat antibodies and flow cytometry. lps and f'mlp resulted in a slight increase ( fold) in the expression of cd b on pmns from burned patients compared to an and fold increase, respectively, on pmns from healthy individuals. this inability of lps or fmlp to increase cd b expression was not due to the amount of lps bound to the two cell populations. because the same defect is seen after either lps or fmlp stimulation, it is speculated that the defect must be in the amount of preformed cd ] b or its transport to the plasma membrane. platelet-activating factor (paf) and neutrophils have been implicated in the patbophysiology of ischemia-repeffusion injury, in addition, paf stimulates neutrophi[ (pmn) oxidative metabolism in vitro. the present study examined the potential role of paf in repeffusion injury in an in viva rabbit model. eight anesthetized rabbi~s underwent retroperitoneal exposure of the infrarenal abdominal aorta after percutaneous insertion of a catheter through the jugular vein into the infrahepatic inferior vena cava. doppler flow probes were placed around the abdominal aorta and the right common femoral artery to assess flow through these vessels. an occlusive ligature was placed around the abdominal aorta (superior to the flow probe) at t = and total occlusion of blood flow to the lower extremities was maintained for g mins., after which the ligature was released allowing for reperfusion of the ischemic lower limbs. effluent blood from the ischemic hind-limbs was collected through the ivc catheter at the times indicated below and assayed for paf by a direct radioimmunoassay. in addition, neutrophil h production was determined by a previously described ' '-dichlorofluorescein flowcytametric assay. _+ amean _+ s.e.m, pg/ml blood; brelative fluoresenee (% of baseline); caortic and femoral artery flow (% of baseline); *p < . vs. baseline; "p < . vs. baseline. a significant elevation of paf was observed in ischemic hind-limb effluent blood at min. after release of the aortic ligature during the repeffusion phase, as compared to baseline levels. in addition, pmn h production was increased by . -fold above baseline values by hour after ligature release during the reperfusion phase. both of these elevations were transient and returned toward baseline by hours post-isehemia. tatar occlusion of hind-limb flow was achieved as evidenced by the absence of aortic or femorat flow at rain. post-ischemia, however after release the ligature a significant reactive hyperemia was observed by mln. into the rapeffusion phase. histolog[c examination of reper[used gastrocnemius muscle revealed moderate pmn infiltration into the interstitium. in conclusion, these data indicate that paf is released into the circulation during repeffusion, and is likely involved as a mediator in the observed pmn oxidative burst activity, thereby contributing to reperfusien injury. following thermal injury and infection granulocyte function ts abnormal. to elucidate the mechanism by which thermal injury and infection affect the granulocyte's ability to polymerize and depolymedze actin, we serially measured f-actin levels in granulocytes from burned patients (mean age , +_ . years, mean burn size . % _+ . %) during the first s weeks post injury. six of the patients had infections during the course of the study, (septicemia, wound invasion and pneumonia). actin levels in granulocytes from eleven healthy volunteers (mean age years) were measured repeatedly and served as controls. lysecl white blood cell preparations were brought to c and incubated with n-formyl-met-leu-phe (stim) or with dulbecco's phosphate unbuffered sellne (unstim). the cells were concomitantly stained and fixed with formaldehyde, lysoleclthln and fiuoresceln phafioidin. actin depolymedzation (depol) was measured by incubating stimulated cells at °c before the stain-fixative was added. baseline (base) f-actln levels were assessed by adding stsln-fixatlve to icecold unstimulated cells. fluorescence was estimated in a facscan and expressed as ilnesr mean channel fluorescence_+ sem (mcf). figure displays granulecyle fectln levels in infected and uninfected patients as compared to controls. f-actln levels were consistently lower in control cells than in those from burned or burn-infected patients under all measured conditions. granulocytes from infected burned patients demonstrated a significant decrement in their ability to depofymerlze f.actin compared to both uninfected burned patients and controls, while there were no significant differences between infected and ,~ uninfected patients in the baseline, unstlmuleted and stimulated conditions. those results indicate la that grsnulocytas from burned and bum-infected patients contain higher levels of polymerized actln than ~ , s control cells. in order to study tumor necrosis factor (tnf) receptor sensitivity in septic critically ill patients we investigated blood samples of such people in reaction of leucocyte migration inhibition. migration of their polymorphonuclear leucocytes (pmns) was studied with stimulation with human recombinant tnf in concentration of . u/ml (recommended by manufacturer is the range of - o/ml) and without such. ten healthy blood donors formed control group. the results obtained showed diminished pmn reactivity to tnf in patients (migration inhibition was absent) oscaring with significantly increased migration ability of their pmns ( . % of that in control group). at the same time normal pmns in control group did show migration changes upon tnf stimulation. considering all the above we come to a conclusion that externally added tnf fails to activate pmns in critically ill patients more than they are by their endogenous tnf. moreover, this tnf no longer serves a positive chemotactic factor for such pmns. these findings may suggest that in critically ill septic patients reactivity of pmns to tnf is deeply altered. tnf receptors of pmns are either exhausted as such by excessive stimulation with endogenous tnf or further transmission of their message is impossible due to "fatigue" of the cell's activation mechanisms. we express our gratitude to reanal factory of laboratory chemicals for generously providing us with a tnf com~rcial sample. ~-sanguis medical, ekaterineburg russia; s-urals med.lnst. activated neutrophils infiltrating the local site of inflammation following trauma release high amounts of destructive lysosomal enzymes into the extracellular space. cytokines were discussed to be involved in regulation of this early process. the task of this investigation was to evaluate the possible regulatory role of interleukin- (il- ) and its potential immunosupressive opponent, the transforming growth factor-&, in regulation of neutrophil degranulation. we analysed the concentration of the al-proteinase-inhibitor complex of the lysosomal elastase as marker for the degranulation of neutrophils as well as the levels of il- and tgf- in the plasma probes of patients undergoing multiple trauma and severe surgeries. the time courses of il- and elastase were found to be highly correlated, wheras the concentrations of the cytokine tgf-e~ were found to be not significantly altered in comparison to the control group. this close temporal correlationship was confirmed by investigation of fluids derived from sites of inflammation. interstingly, the inhibitory potential (~zcproteinase inhibitor, antithrombin iii) was dramatically reduced in the early inflammatory phase. to prove this in vivo findings, the effects of il- and tgf-i~ on the degranulation of isolated human neutrophils of healthy donors was investigated in vitro. pathological high concentrations of rhll- up to u/ml (as detected in fluids derived from local inflammatory site) were found to be capable to induce a significant release of lysosomal elastase in a concentration-dependent manner, whereas the degranulation of neutrophils was uneffected by tgf- . in conclusion, these data suggest a contribution of il- in regulation of neutrophil activation at sides of inflammation. the immunosuppressive cytokine tgf-i&~ seems to have no direct regulatory effect beside its described chemotactic function on neutrephils. postirradiation chan~es of adhesive properties arid supercoiled nucleoid dna structure of blood leukocytes were studied in macaca nemestrina andrats. the dynamics of membrane chan~es after nonlethal irradiation of rats demonstrated the temporary increase of the leukocyte adherence at h followed by return of this parameter to normal levels at h. after lethal irradiation of both animal species the increase in adhesive leukooytes fraction was detected as early as at h. this hi~her index persisted until the end of experiments ( days). the early ( - h) temporary loosin~ of supercoiled dna structure was demonstrated in the leukocytes of nonlethally irradiated animals. this phenomenon seems to be connected with the lymphocyte fraction chan~es. this process was not dependent on altered adhesive properties of leukocyte membranes. the membrane chan~es of leukocytes preceded decondensation of supercoiled dna after lethal irradiation of animals, in this case loosin~ of supercoiled dna pro-~ressively increased at h and at the later terms of postirradiation period. the systemic inflammatory response syndrome (sirs) involves many inanunological reactions of the host including acfivatinn of inflammatory mediator cascades and depression of cellular reactivity in t-lymphecytes ( ). there are reports of nentrophil dysfunction in inflammatory disorders of the skin ( ), are there dysfunctions concerning the unspecific host defense in sirs, as well? in this study, we examined the reactivity of neutrophil granolocytes from patients suffering from sirs. twenty-one patients (apache ii-score ± ) with diagnosis of sirs entered the study. granulocytes were prepared as reported previously ( ) . in parallel, granulocytes from healthy individuals were tested. two granulocyte functians were studied in vitro: . migration of the ceils in a boyden chamber through a filter matrix following stimulation with different receptor dependent stimuli (c a, intefleukin- , platelet-activating-factor, leukotrien b , fmlp). . release of glucuronidase following stimulation with the aforementioned activators. the results demonstrate, that the release of -glucuronidase in patients suffering from sirs was comparable to the enzyme release of granulocytes prepared from healthy individuals. each stimulant induced release of p-glucuronidase in a characteristic dose dependent fashion. all granulocyte preparations from the healthy donors showed a positive chemotaxis response in the migration-assay. in contrast, only ten out of twenty-one patients had granulocytes migrating after stimulation. the two groups of patients displaying reactive or non-reactive granulocytes differed clinically: the nonreactive group consisted of patients with multiple organ failure ( / ) and nonsurvivors ( / ), whereas / patients in the reactive group survived. thus, the in vitro chemotaxis of granulocytes is impaired in a subgroup of patients with sirs. this defect of the non-specific host defense may contribute to poor prognosis and outcome of these patients. dermatol. : - , klinik ffir an~isthesiologie und operative intensivmedizin der cau kiel, schwanenweg , kiel, germany. objectives of the study: major emphasis has been given to the analysis of interactions of antibiotics with microorganisms. effects of antibiotics on cells of primary host defense mechanisms, such as the neutrophils, are less well known. therefore, attention has been focused on clindamycin, a member of the lincoseamide family. materials and methods: the effect of clindamycin (i -i ~g/ml) on granulocyte functions (healthy volunteers) such as random migration, chemotaxis (agarose method), ingestion (radiometric assay), superoxide (cytochrom c reduction) and hydrogen peroxide production (phenol red oxidation), lucigenin-and luminol-amplified chemiluminescence (luminometry) and degranulation (turbidometry with micrococcus lysodeicticus) were investigated in vitro. results: motility and degranulation were inhibited, ingestion of saccharomyces cerevisiae, zymosan-induced lucigenin-and luminol-amplified chemiluminescence, superoxide and hydrogen peroxide production were stimulated in a dose dependent fashion. conclusion: clindamycin has granulocyte function modulating properties. recognition of immunomodulating effects of antibiotics may have therapeutic significance, especially in patients with long-term antibiotic therapy or immune deficiencies. the intense muscle activity (ea) of rats resulted in increase of neutrophil influx in muscles during the recovery. we investigated neutrophil proteinases involvement in neutral proteinases balance of skeletal muscles by na. the rats were submited to swim with the load ( % of body mass) till exhaustion. immediately after na the neutrophil antiserum was injected i.p. to rats of experimental group. saline was injected to control animals° injections were repeated in h of the recovery and cytosol proteolytic activity (ph . ; fitc-casein) was determined. isolated soleus muscles were incubated also in vitro and proteolytic activity of incubation media was measured. it was found that there was - -fold proteinases activity increase in cytosols of all investigated muscles (soleus, white and red portions of quadriceps) of control animals by h of the recovery (the comparison was done with the sedentary rats). in h cytosol proteolytic activity decreased and then increased again by h of the fast. antiserum injections resulted in relible decrease of the proteolytic activities at every investigated time. when incubating m. soleus in vitro the activities of proteinases in incubation media turned out reliably less if soleus muscles were isolated from the animals to which antiserum was injected. the conclusion is that neutrophil proteinases can be involved in the balance of rat skeletal muscle neutral proteinases after ~a. a lot and new clinical problems complicating the outcome of polytrauma, burn and septic patients in surgical intensive care units, have arisen as the care improvement prolonged the patient's survival: a progressive degradation of organ and system functions often develops, usually making its first clinical appearance by ards, followed by the other organ failure (mof) and sepsis symptoms. the clinical picture is polymorphic, the end result of a complex systemic pathophysiological reaction trigg~ed off by trauma consequences (tissues disruption, hypo~xygenatiun and necrosis). nowadays there is not a preventi~ or specific therapy to lower the mortality rate ( - %) and-'mdy-a~ early, aggressive surgical approach .-evacuating haematomas, stopping bleeding, toileting all septic, necrotic foci and restoring anatomic continuity-, seems to be of some help this complex clinical entity has not an univocal denomination yet. the proper labelling of an illness should come from the full understanding of its pathopysiology and suggest the proper treatment choice. clinical and experimental studies demonstrated that pathophysiologic mechanisms involved in the past-traumatic illness, share the same anatomo-pathological elemem: the interstitial edema, due to a generalised endothelial micro circulatory injury. this alteration, as constantly seen in polytrauma patients, develops in a few hours after trauma as a consequence of the deregulation of the homoeostatic and immune mechanisms. in fact the overproduced oxygen free radicals and r~ombinam cytokines (il ,tnf), together with the complement degradation fragments, the proteolytic enzymes and many other mediators are all strongly h~l ~ ,_he e,,j,yheha! ceils. our~osect, atim~,-bnsed on examination of autopsical specimens from polytraanm patients, showed that such endothelial damage, supporting the interstitial edema, is widely and simultaneensly distributed, ensues shortly arer trauma and shows its effects in different organs at different times, only because each apparatus has different fimctienal reserves: the lung is the first organ to fail just because its ah, celocapillary membrane is one of the most delicate bodily structure, and its function is irroplace~le. we think it will be of a great help, in planning a preventive therapy, to chose a denomination focusing the physician's attention on the earl)" generalized endothelial injury and its effects, as in trauma patients it is present -even if latenflysince the first few hours. we would like to see the generalised endothelial microcircolatory injury properly highlighted when considering the best definition and the optimal nomenclature for the post-traumatic s mdrome. the presence of interleukin (il)- in bronchoalveolar lavage fluid of critically ill patients correlates clinically with the development of the adult respiratory distress syndrome lards), and inhibition of il- in animal models can attenuate lung injury. collectively, evidence to date suggests that il- attracts and activates neutrophiis (pmn), which are then responsible for the capillary leak of ards. however, an alternative explanation is that il- is directly toxic to the endothelial cell (ec). in this study, we have hypothesized that il- can disrupt endothelial integrity independent of pmn. meth ods: human umbilical vein (huv) ec monolayers were cultured to confluency on collagen-coated micropore filters. to assess ec integrity, .albumi n leak was quantitated by measuring the counts which crossed the monolayer, using a gamma counter. il- (lpg/ml) was incubated in the culture medium with .albumi n for hrs. the il- dose was not cytotoxic. to determine the involvement of protein synthesis in this process, selected monolayers were pretreated with cycloheximide (ch) prior to .- addition. statistical analysis was performed using anovmfisher plsd. we have previously shown that platelet activating factor (paf) enhances cdt expression and primes pmn's for subsequent generation. both are important steps in pmn mediated injury and are assumed to occur in concert. following major trauma non-specific pmn inflammation is activated, however, unbridled systemic pmn activity needs to be minimized. since circulating catecholamines are high early post-injury, we hypothesised that they downregu/ate cd expression and pmn priming via the [ adrenergic signal transduction pathway. methods: normal human pmns were primed with paf ( ng/ml for min) or pre-treated with - m of isoproterenol (i) or forskoklin (f) for rain and then primed with paf. cd expression was measured by flow cytometry (fig.l) and -generation in response to -rm fmlp was determined as sod inhibitable reduction of cytochrome c ( fig. holler** and georg w. bornkamm* lymphocyte-endothelial interactions are crucial for various immune responses, including cytokine driven inflammatory processes. protein kinase c (pkc)-inhibitors on the other hand are discussed as potential cytokine antagonists. in the present study we investigated the influence of the pkc-inhibitor gf x on cytokine-and endotoxin induced expression of intercellular adhesion molecule (icam- ) and on adhesion of lymphocytes to cytokine activated endothelial cells. we found that tumor necrosis factor alpha (tnfo -and lipopolysaccharide (lps)-induced icam- expression on human endothelioma celts (eahy ) were unaffected by the pkc-inhibitor and thus appeared to be independent of pkc activation. in contrast, gf x significantly reduced icam- expression induced by interferon-y (ifn-?) and interleukin- (il- ). the functional relevance of these findings was evaluated in an adhesion assay using human umbilical vene endothelial cells (huvec) and peripheral blood mononuclear cells (pbmc). in fact, the ifn-? and il- induced adhesion of pbmc to cytokine treated huvec could be downregulated by the pkc-inhibitor, whereas tnfc~-and lps-mediated adhesion was not influenced. additionally, the il- driven icam- expression on eahy cells as well as the il- induced adhesion of pbmc to huvec was found to be tnf-dependent, since both effects could be inhibited by an anti-tnf monoclonal antibody ( f) . these in vitro data further support the idea of examining pkc-inhibitors, such as gf x, for their biological relevance in cytokine related dysregulations. seiffge, d., bissinger, t., laux, v., during inflammation there are some key processes, which occur in the microcirculation: the release of mediators from various cell types, the migration of inflammatory cells towards a chemotactic stimulus in the tissue, the expression of adhesion molecules on different cells, and the extravasation of plasma proteins. the aim of the present study was to elucidate the mediator induced interaction of leukocyte adhesion and plasma leakage in postcapillary venules. using an analogous video-image analysing system we have studied the effect of different mediators on leukocyte adhesion and macromolecular permeability in the mesentery of the rat. the increase in permeability was measured as changes in optical density. we found that topical administration of leneotriene b (ltb , x " tool/l) or intravenous injection of interleuldn- (il- , - iu/kg b.w.) and lipopolysaccharide (lps, mg/kg b.w.) resulted in a significant extravasation of fitc-labelled rat serum albumin (fitc-rsa) in venules but not in arterioles. we could correlate the changes in vascular permeability with a locally increased number of rolling and sticking leukocytes in venules. both effects were dose dependently inhibited by different drugs. pentoxlfylline inhibits lps-indueed fitc-rsa extravasation and leukocyte adhesion at a dose of mg/kg b.w., superoxid-dismutase (sod, . iu/kg b.w.) was able to decrease the ltb effect, and the immuumodulating drug leflunomide (hwa ) exerted inhibitory effects on il- -induced permeability at a dose of mg/kg b.w.i.v. the obtained results demonstrate that lps, ltb or il- induced extravasation of fitc-rsa is mediated by activated leukocytes and can be deminished following administration of different drugs. platelet-endothelial cell adhesion molecule-i (pecam-i), a member of the immunoglobulin superfamily, is constitutively expressed at high levels on the endothelial cell surface. in vitro data have suggested that pecam-i functions as a vascular adhesion molecule, specifically in neutrophil transmigration across the endothelium. this current work is the first demonstrating the in vivo role of pecam- in neutrophil migration. blocking antibodies to human pecam- , in which the antibodies are crossreactive with rat pecam- , were able to block the movement of neutrophils into the rat lungs after igg immune complex deposition. furthermore, when human foreskin was transplanted into mice with severe combined immunodeficiency and the site injected with tnf-alpha, anti-pecam-i blocked neutrophil emigration into the dermal interstitium. it has already been established that neutrophil recruitment is dependent upon selectin mediated rolling, followed by firm adherence that is icam- / integrin mediated. these data suggest, for the first time, that a third endothelial adhesion molecule (pecam-i) is involved in the coordinated recruitment of neutrophils in vivo. to test whether trauma causes generalized activation or priming of pmns, cdi adherence receptors were measured with iinmunomonitoring in whole blood after lps stimulation ex vivo. anesthetized (fentanyl) mongrel pigs ( - kg) were subjected to % arterial hemorrhage + soft tissue injury and after liar, resuscitated with all the shed blood + supplemental fluid. blood was collected at hr intervals from unanesthetized animals with indwelling catheters, pmns were counted, and lps was added ( , , , i.tg/ml) ex vivo. after hr incubation at - °c, %cd (+) pmns were determined with fitc-ib and flow cytometry from mean channel fluorescence histograms. ± # p< . vs baseline * p< . vs sham $p< . vs no anesthesia these observations provide direct evidence for time-dependent changes in pmn priming following major injury because cd expression was depressed for at ]east hr after trauma relative to sham but by hr, was enhanced, relative to sham, and because fentanyl anesthesia at hr had a greater effect on cd expression in trauma vs sham. neutrophil (pmn) adhesion to vascular endothelial cells (•c) is a key element in the inflammatory response and tissue injury. inflammatory mediators such as lps (exogenous) and tnf (endogenous) can promote pmn-ec interaction which is believed to be responsible for capillary leakage and subsequent organ injury. however, the mechanism of this injury remains unclear.we hypothesised that the mechanism of tissue injury is due to ec necrosis with release of toxic products and that activated pmn are responsible. human pmn were obtained from healthy donors, separated by density gradient, and activated with lps ( ng/ml), tnf( ng/ml), and lps/tnf( ng/ ng/ml). cultures of the human ec tine(ecv- ) were used as surrogates of the microvasculature, were exposed to either lps, tnf, lps/tnf and pmn activated with lps, tnf, lps/tnf and incubated for , , , and hrs. ec necrosis was assessed by a cr release cytotoxicity assay. pmn activation was assessed by cd lb receptor expression and respiratory burst activity hr _+ . -+ -+ . _+ _+ . _+ _+ . _+ . hr + . _ _+ . _+ _+ _+ " +_ +-- . " lghr - . _+ +_ - " o:fo , " ~ +- . * hr _+ . - -+ +_ * _+ _+ * _+ _+ " data = ec % necrosis mean_+sd stats: student's t-test with significance (*) set at p< . vs control. ( our previous studies have indicated that despite the increased cardiac output and maintenance of tissue perfusion, hepatoceliular dysfunction occurs during early sepsis. nonetheless, it remains unknown whether vascular endothelial cell function (i.e., the release of endothelium-derived relaxing factor/nitric oxide) is depressed under such conditions and, if so, whether endothelial cell dysfunction also occurs at the microcirculatory level. to determine this, rats were subjected to sepsis by cecal ligation and puncture (clp), following which these and corresponding shams received ml/ g bw normal saline. at hr after clp (hyperdynamic sepsis) or sham operation, the thoracic aorta was isolated, cut into rings, and placed in organ chambers. norepinephrine (ne, xi - m) was used to achieve near-maximal contraction. responses for an endothelium-dependeut vasodilator, acetylcholine (ach, via nitric oxide), were determined. in additional studies, the small gut was isolated at hr post-clp. after pre-contraction of blood vessels in the isolated gut with xl m ne, vascular responses to ach ( x m) and an endotheliumindependent vasodiiator, nitroglycerine (ntg, xl - m), were determined. total vascular resistance (tvr, mmhg/mi/min/ g) was then calculated as pressure/ perfusinn rate. ach-induced relaxation (%, n= /group) in the aortic rings were: ach lxl i~s, st-in ~ ~ significantly at hr post-clp (i.e., increased *p(o vs. sham; n- per group. tvr) in the absence of any changes in ntginduced relaxation (fig. a) . thus, the vascular endothelial cell dysfunction observed in the aorta in early sepsis also occurs at the microcirculatory level. introduction: the cytokine-mediated adherence of leulcooytes to vascular endothelium is considered as an early step in the cascade of pathologic reactions culminating in the "systemic inflammatory response syndrome" (sirs); the purpose of this study was to evaluate the influence of interleakin- on leukooyteendothelial cell-interactions and microoirculation in the liver after hemorrhagic shock by means of intravital microscopy. methods: in anesthetized female sprdrats co.w. - g) shook was induced by fractionated withdrawl of arterial blood within rain and maintained for h (map at mm hg, cardiac output % of baseline). rats were adequately resuscitated with % of shed blood and twice the volume in ringer's solution additionally. following h of reperfusinn (map > mm hg, co > % of baseline) the microcirculation in liver lobules was examined by intravital fluorescence microscopy after labelling of leukocytes. continuous administration of il-lra (synergen, boulder, colorado, mg/kg/h) was started at different time points in a randomized and blinded manner. the animals in group p (n= ) received the il-lra as pretreatment beginning min prior to shock induction. in the group t (n= ) the application of il-lm started at the beginning of the reperfusion period with a bolus injection of mg/kg and was followed by continuons administration of mg/kg/h. the control group c (n= ) received equal volumes in nac , %, the sham-operated group s (n= ) was not exposed to shock. results: macrohemodynamics were comparable in all shook groups. the increased percentage of permanendy adherent leukocytes after hemorrhagic shook (s: , % + , %; c: , % _+ , %) was significantly reduced by pretreatment or treatment with il-lra (p: , % -+ , %; p< . , t: , % -+ , %, p< . , anova). temporary adhesion of leukocytes was unaffected by application of il-lra. liver microcirculation measured by volumetric blood flow in liver sinusoids and sinusoidal diameters was impaired after hemorrhagic shock in all groups and was not affected (c: iam /s + um /s, p: llm /s + }am /s, t: ams/s -+ lam /s, s: am /s -+ am /s). di.seu~sinn: the results demonstrate that permanent adherence of leukocytes to endothelium is in part regulated by il- . pathological adherence could be reduced by application of illra, even given at die time of resuscitation. the effect of ll-lm on permanent adhesion is a specific event and might be caused by reduced expression of specific receptors on sinusoidal endothelial cens and leukocytes. objectives of the study. the adhesion of activated neutrophils (pmn) to endothelial ceils (ec) and the concomitant production of reactive oxygen metabolites (rom) initiates organ damage after trauma, sepsis, shock and organ reperfusion. aien of this study was to investigate the effect on adhesion and rom production of the highly water-soluble, membrane-permeable and physiological ascorbic acid (asc). materials and methods. adhesion of pmn to nylon fiber (cell count) and simultaneous rom production (chemiluminescence-cl-response) were measured up to retool/ asc as well as adhesion, rom production and ec damage (lllln-release from labeled ec) of endotoxin-activated pmn to cultered ec moanlayers. in an in vivo animal model (sheep with lung lymph fistulas) the effect of asc ( g/kg bw bolus, followed by . g/ kg-h infusion) on the endotoxin-induced ( . ixg/kg bw) neutropenia (cell count), lung capillary permeability damage (lung lymph protein clearance) and rom production of neutrophils (zymosan-induced cl response) was measured. results. asc scavenged rom dose-dependently during adhesion of pmn to nylon fiber (p< . at mmol/l asc), adhesion itself was unchanged. during the activated pmn/ec interaction asc scavenged rom (p< . at mmol/l asc) and reduced the adhesion dose-dependently (p< . at mmol/l asc); ec damage was also reduced (p< . at retool/ asc). in the in rive model asc increased the endotoxin-induced blood pmn decrease (p< . ), decreased the protein clearance (p< . ) as well as the zymosan-induced rom production (p< . ), indicating the asc-mediated reduction of adhesion, rom production and lung tissue damage processes. conclusions. by in vitro and in rive experiments ascorbic acid reduced the adhesion-and rom production-initiated tissue damage. therefore, i.v. administration of ascorbic acid is recommended for oxidative stress-associated states after trauma, sepsis, shock and organ reperfusion. for neut rophi l-accumulat ion and activation. we investigated the influence of or to the activation and the expression of lecam-i and cdiib,cdi on neutrophils and lymphocytes. methods: from blood samples (n= ) all white blood cells (wbc) and neutrophils (nc) were isolated and cultured. or were produced via the xanthine oxidase/hypoxanthine system. after , , , , and minutes a giemsa-staining to determine the granulation of neutrophils (n: normal, r : reduced ) and a facs-analysis with monoclonal antibodies detecting cdiib,cdi and lecam-i was performed. results: under the influence of or a degranulation of neutrophils starting at min was observed in wbc-cultures (n/r: min / , min / , min / , min / , min / ). these data were confirmed in the dot-plots of facs-analysis. only in wbc-cultures or induced a significant increase of lecam-i expression on neutrophils up to min followed by a decrease to normal values at min. lecam-i on lymphocytes disappeared totally during the observed period. cdllb,cdl -expression was not altered. conclusion:increased lecam-i expression on neutrophils due to or could enhance the 'rolling' of neutrophils along the endothelium which is a prerequisite for neutrophil sticking and migration. further or are able to activate neutrophils without endothelium. these changes seem to be mediated by other wbc. introduction. multiple organ failure (mof) has been hypothesized to be the result of an excessive uncontrolled autedestructive inflammatory response. since the complement system is an important mediator and initiator of the inflammatory response, interruption of this cascade could theoretically lead to an attenuation of mof. in order to test this hypothesis we evaluated the response of c -delicient mice in a model of zymesan indt~ed mof. materials and methods. c -deficient b d /oid and c -sufficient b d /new mice were used in this study. on day all mice received an intraperitoneal injection with zymosan suspended in paraffin in a dose of mg/g body weight. between day and , biological parameters (temperature, body weight and clinical condition) were measured daily and mortality was monitored. clinical condition was assessed by blindly grading the degree of lethargy, conjunctivitis, diarrhea, and ruffled fur of each mouse on a two point scale (maximum score= ). on day all surviving mice were sacrificed and relative organ weights of lungs, liver, spleen and kidneys (relative organ weight= (organ weight/body weight)x ) wore calculated. earlier experiments with our model have shown a good correlation between histological organ damage and relative organ weights. statistical analysis of biological parameter was performed using the koziol curve analysis. analysis was divided in an acute phase (day - ) and a late phase (day - ). relative organ weights were analyzed using wilcoxon's test and mortality rate using fischor's exact test. results. all zymosan injected mice showed a typical triphesic illness. deterioration of the clinical condition as indicated by the symptom score and the decrease in temperature and body weight in the acute phase were all significantly lass severe in c deficient mice (all p< . ). in the late phase no differences could be noticed in the courses of biological parameters. overall mortality was / ( %) in c deficient mice and / ( %) jn c sufficient mice (p= . ), a difference mainly due to a difference in the acute phase. organ damage assessed as the relative organ weights did not show any statistical differences for any organ between both strains. conclusion. complement factor c appears to play an important role in the acute hyperdynamic septic response in this model but deficiency of c could not prevent organ damage in the late mof phase. this suggests that other factors could be more important in the development of the inflammatory response leading to mof. proinflammatory cytokines are thought to play a critical role in the pathophysiology of multiple organ failure (mof). in mice, zymosan-lnduced generalized inflammation (ztgi) leads to mof. therefore we performed a sequential study into plasma levels of, and macrophage production capacity for, four cytokines during the development of mof in the zigi model. male young-adult c bl/ mice received zymosan ( mg/g body weight) intraperitoneally. groups of animals were killed after , , , and h and subsequently at each day until day . plasma was collected and peritoneal macrophages were isolated and cultured overnight with or without lipopolysaccharide (lps). interleukin -ct, and - (il-lc~,~,), and tumour necrosis factor-o~ (tnf-c were measured in plasma and culture fluid by means of a ria (detection limit . ng/ml). interleukin- (il~) levels were assayed using the b hybddoma cell proliferation assay. zymosan induces a three-phase disease in mice. after an acute phase the animals recover. around day , they start to develop clinical signs which resemble mof. plasma tnf-~ peaked within h after zymosan injection and disappeared within h. from day onwards, tnf levels started to rise again. plasma il- behaved almost similarly in the acute phase, but in the mof phase plasma il- remained low. no circulating il- could be detected at any time point. macrophage lps-stimulated production of il-lcq il- ~ and tnf--c~ was suppressed immediately after zymosan injection. production of il- and tnf-~ was normalized within h, while production of il-lc~ remained lower than that in macrophages from untreated control mice. only at day did production of il-i~ reach control values. il- production was higher than control values from day onwards. il production was similar to that of ili-il the production of tnf-ct was strongly elevated between days and and again during days to . the development of mof-like symptoms during zlgi in mice is accompanied by increased plasma levels of tnf-ct without enhanced il- or il- . also, the ability of macrophages to produce excessive amounts of il- and tnf--~, as well as the suppressed capacity to produce il-lcq could be important mechanisms in the pathophysiology of mof. when conjugated to an asialoglycoprotein, dna and oligonucleotides are specifically taken up by the hepatocytes via the asialoglyccprotein receptor which is unique to the liver. human asialoglycoprotein (~ -acid, asgp) was derivatized with low molecular weight poly(l)lysine(pll) and complexed with antisense dna's (as) complementary to the ' region of the il- gpl receptor. the antisense were '-agtttagggatgagg- ' (asl), '-atcttcatcttctgaat- ' (as ), '-aagtgaatgattaaaacact- ' (as ), '-aaacctttataggcg- ' (as ), and '-cgttctacaactgcaacgt- ' (as ). using hepg , the biological effects of these antisense complexes on the high affinity il- receptor were evaluated by scatchard analysis, cellular proliferation, and acute phase protein expression by radioimmunoprecipitation and two dimensional gel electrophoresis. scatchard analysis demonstrated that high affinity receptor expression was inhibited by incubation of cells with asgp-pll-asi for h. underivatized asl was less effective and the complex, asgp-pll-as , had minimal effects on high affinity binding. when the cells were treated with the conjugates and stimulated with il- (i units) asgp-pll-asi alone showed a dose dependent ( .i- . ~m) inhibition of ss fibrinogen synthesis. two dimensional gel electrophoresis showed that expression of other acute phase proteins was also blocked. these results indicate that the targeted delivery of antisense molecules via conjugates recognized by the asialoglycoprotein receptor can block the cytokine stimulated acute phase protein response in hepatocytes, this approach may be relevant to the therapeutic management of patients with severe injury and sepsis. it has been established that immune cells are able to express neuropeptide genes and to release products that were considered to be of neuroendocrine origin. we have shown that proenkephalin (penk), a neuropeptide encoding gene, is expressed in lymphoid cells in culture. to study the physiological significance of these observations we have used the model of experimental endotoxemia. in this model, a disease state is induced by bacterial lipopolysaccharide (lps), that activates the immune system, the adrenocortical axis and the nervous system. we found that the expression of penkmrna is markedly enhanced in vivo immediately after lps injection both in the adrenal glands and in the lymph nodes. in situ hybridization analysis combined with immunohisto-chemistry indicated that the induced penk expression is confined to macrephages within the lymph nodes and chromaffin cells in the adrenal medulla. furthermore, this expression in lymph nodes is modulated by ligands of the adrenergic system. our results strongly support the notion that immune derived opioids participate in the bidirectional communication between the nervous and immune systems. of neurology hadassah university hospital, jerusalem , israel. objectives of the study: multiple-organ-failure is recognized as the most severe, and often lethal, complication after multiple trauma. however there is no adeqate animal model available. our goal was to develop an animal model, in which reproducable irreversible failure of parenchymal organs is achieved in the late phase after insults in the early phase (trauma). materials and methods: l female merino-sheep were included (mean weight: kg). day : hemorrhagic shock (mean arterial pressure (map) mmhg for hrs.), closed femoral nailing (ao-technique), day - : bolusinjection of endotoxin (et) ( , ~tg/kgbw) und zymosan-activated plasma (zap) ( ml) every hrs., day - : observation. bronchoalveolar lavage (bal): day , , . the course of representative parameters of organ function was documented: cocardiac output (i/min), svr -systemic vascular resistence (dyn ~ s cm- ), pap -putm.art.pressure (mmhg), pap -arterial oxygen pressure (mmhg), bill -bilirubin (;xmov ), crci -creatinin clearence (ml/min) statistics: data as means+sem, *significant from baseline (wileoxon test; p< ) results: baseline day day day day heart: co , _+ , , _+ , , _+ , , _+ , * , _+ , * svr _+ + _+ +_ " +- " lung: pap , _- , , _+ , " , +- , " , + , " , +- , ' pap , + , , +- , , _+ , , +- , , +_ , * liver: bill , _+ , , _+ , ' , _+ , ' , _+ , " , _+ , " kidney:crcl , +_ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , _+ , , + , , + , histologic specimens showed all signs of fulminant mof. combination of hemorrhagic shock, femoral nailing, et und zap (insults in the early phase) lead to an irreversible organ failure in the late phase. prostaglandin e (pge) levels are elevated by trauma, shock or sepsis and can profoundly affect the immune response. pge is produced by many cell types including fibroblasts, macrophages, monoeytes, follicular dendritic cells, and epithelial cells and is induced by il-i, bacterial lps, components of the complement cascade, tnf, il- and crosslinking of surface fc receptors for igg, iga and ige. our research has shown that pge inhibits b cell activation (specifically enlargement, class ii ~c and fc~ rii expression), proliferation, igm and igg responses, t cell proliferation, and il- synthesis in the mouse model. in contrast, pge greatly promotes class switching to ige,the isotype responsible for type i allergic hypersensitivity. thus, our model mirrors th~ general immunosuppression and elevated ige titers of the trauma or sepsis patient. pge increases the number of cells secreting ige and iggl, acts on surface igm positive b cells, synergizes with il- and lp$ to induce preswitch germline transcripts, and induces more rapid expression of mature vdj~ mp~a than in eontro~ pge intracellular signalling occurs through cyclic adenosine monophosphate (camp) levels and can be mimicked by camp-inducing agents and blocl~ed by an inhibitor of campdependent protein kinase a. pge action requires de novo protein synthesis and candidate pge-inducible regulatory proteins have been identified by d gel eleetrophoresis. thus, pge inhibits a number of immune mechanisms while promoting ige production. a deeper understanding of pge immune regulation may lead to more effective treatment of immune perturbations as sequelae of trauma, shock or sepsis. during infrarenai aortic surgery mesetueric traction (re.t.) results in prostacyclin (pgi:) release and consecutively in hemodynamic disturbances (decreased systemic vascular resisteace, mean arterial pressure; increased cardiac output, heartrate). these symptomes are bypassed by cyclooxygenase inhibition. hemodynamic symptoms vanish after - rain even without cyclooxygenase inhibition although pgi levels remain elevated. to study the endocrine vasopressor system in a prospective double blinded protocol, we investigated patients undergoing major abdominal surgery as compared to ibuprofen ( rag, i.v.) pretreated (ibu) patients. the surgeon applied m.t. in a uniform fashion. we chose a general anesthesia combined with a supplemental thoracic epidural anesthesia. at the points in time , , , , , , , rain after and before (to) mesentzrie traction we determined the plasma concentrations (pc) of -keto-pgf~o~pr~, epinephrine, norepinephrine, dopamine, renin, aldosterone, adh and cortisol. pc of -k-pgf~,tp~, peaked minutes after m.t. ( _+ , ibu: _+ , to: +i ng/l) and declined monotonously over h ( +_ , ibu: _+ ng/ ). catecholamine pc "s did not exceed the reference range during the observation period. reninpc peaked after rain ( _+ , ibu: + , to: -+ /~u/ml); aldosteronc also presented a maximum after rain ( + , ibu: -+ , to: +- pg/ml), whereas cortisol demonstrated irrespectively of circadian rhythms a maximum h after m.t. ( +_ , ibu: -+ , to: +_ ~g/ ). adh pc peaked min after m.t. ( + , ibu: -+ , to: +_ pg/ml) and showed analogously to -k-pgft~j~ pc a monotone decline over the observation period. our data demonstrate a counteractive reaction to pgiz mediated vasodilation via adh secretion. the second regulative is the renin-angiotensin-aldosterone system (raas), which is activated min after m.t., the aldosterone pc does not paratlel the cortisol pc, which peaked post operafionem in both groups, probably due to the end of anaesthesia. a regulative release of catecholamines could not be documented. the activation of adh and raas after mt is not a hormonal response primaryly related to surgical trauma and/or stress but a counterregulation to systemic vasoditafion induced by prostacyclin. although adh and raas support systemic circulation, angiotensin and vasopressin may compromise local organ blood flow (e.g. splancimic vascular bed). insfitut f. klin. chemic, anaesthesiologie ~, chirurgie l*, univ. ulm, elm, expression of c-fos protein in rat brain following occlusion of superior mesenterie artery. takanobu there is general agreement that neurologic abnormalities are seen in sepsis. the aim of this study is to examine what effect does the brain receive in case of sma occlusion by immunohistochemistry using antibody to c-fos, an immediate early gene, which is recently recognized as a genetic marker of activated neurons. moreover, we investigated the correlation between c-fos induction in the brain and plasma endotoxiu level. rats of them received sma clipping and others wee used as control. control and treated rats at , , , hours were perfused and fixed. the brain were sectioned at pm and stained by abc method using c-fos antibody. plasma endotoxin level of rats were measured at , , , , hours after the treatment by chromogenic limulus method. immunohistochemical study showed scarcely no immunoreactivity in control rat brain. in treated rat brain, the significant expression of c-los was detected in specific nuclei including the habenula, some hypothalamie nuclei, amygdala, locus ceruleus and nucleus tractus solitarii. such immunoreactivities were increased in time curse, which well corresponded plasma endotoxin levels. the mean plasma endotoxin level of , , , , hours after the treatment were . ± . , . _- - . , . _+ . , . ± . and . ± . pg/ml, respectively. the results indicate that limbic and hypothalamic-brainstem systems are involved in sma occlusion, and suggest that such neuronal actival.jon may precede the elevation of plasma endotoxin icy.el. systemic vascular resistance and increased cardiac output accompanied presumingly by a increased pulmonary shunt (qs/qt). this response is induced by prostacyclin (pgi ). we examined oxygen transport after traction on the mesentery root and the transpulmonary prostacyclin levels in a prospective placebo controlled study with intravenous ibuprofen. methods: with approval of the human [nvestigadon review board we studied patients in a prospective, randomized double-blinded protocol who were scheduled for major abdominal surgery. ibuprofen ( mg i.v.) or a placebo equivalent was administered minutes before skin incision. pulmonary artery thermodilution and radial artery catheters were placed after induction of anesthesia. mt was applied in a uniform fashion. baseline values preceded the incision of the peritoneum (to). fulther assessments followed , , , , . tile plasma concentrations (pc) of -keto-pgft, (stable metabolite of pgi ) were determined in arterial and mixed venous blood by radioimmunoassay. at all points in time we measured arterial and mixed venous blood gases. qs/qt was calculated by standard formula. data are given as median (p < . placebo vs. [ibuprofen] [ ] mmhg (*p< . i). these changes were accompanied by a marked increase of -keto-pgf~ pc up to rain after mt in arterial and mixed venous blood of untreated patients with a peak of *[ ] ng/l tl (*p< . ol). there was no difference between arterial and mixed venous pc. ibuprofen pretreated patients (n=zr) demonstrated stabile qs/qt and pao while -keto-pgf~ pc remained within the normal range. discussion: our data clearly indicate that mesenteric traction response includes a critical rise in qs/qt followed by significant decrease of paov stable oxygen transport determinants following cyclooxygenase inhibition signify an action mediated by prostacyclin. an indicative transpulmonary gradient for -keto-pgft~ was not detectable. a splanchnic vascular source for pgi release seems to be likely, but could not be proved by our current data. department of anesthesiology, cliu. chemistry * and surgery*; university clinics uim, prittwitzstral]e , ulm, germany it is unclear whether injuries like bums, in general, directly result in alterations of cell-mediated immunity that, in turn, promote endotoxic and bacterial translocation or, alternatively, whether these conditions allow increased bacterial invasion that, in turn, inhibits cmi. aim: to determine whether infectious challenge, as clp alone or combined with ti causes further immune abnormalities in the days following clp. study plan: on day , two groups of n= week old aj mice were subjected to either a % scold burn (ti), or were untreated (c) n= . on day , mice (ti+clp) and mice (clp) were subjected to clp. the two other groups (ti and c) were untreated. at days , and after thermal injury splenocytes (sp) were harvested and cultured with cona for an assay of il- and adherent splenocytes (as) were cultured with lps for il- , tnf, il- and pge . results: either ti + clp or clp alone result in significantly decreased secretion of all cytokines tested. in the ti group almost every cytokine production determined was elevated in comparison to ti + clp and prosmcyclin (pgi ) has been implicated in the pathophysiology of septic shock. however, pgi~'s role in the inflammatory response to sepsis is not well-defined. the purpose of this study was to identify which acute septic events are mediated by pgi during graded bacteremia. methods: eleven ~nesrhetized, hemodynamically monitored adult swine were infused iv with aeromonas h. ( /ml) at rates increased incrementally from . to . mi/kg/hr over hours. animals were studied in two groups: septic control (sc), graded bacteremia only (n= ); pga (n= ), graded bacteremta plus anti-pgiz antibody, ml/hr iv, beginning at hours. mean systemic (map) and pulmonary arterial (pap) pressures and arterial po , mmhg, cardiac index (ci), l/min/m , oxygen delivery index (do i) and consumption index (vozi), ml/min/m , and oxygen extraction (er), %, )latelet aggregometry (plt), %max., plasma pg -keto f alpha ; in the first instance~ peak values of lt ~ after i~ hrs post infarction were times higher than in the controls and excess leucocyte infiltration was noted at the infarction zone. in second instance two levels of lt b led to weak infiltration of the infarction zone by leucocytes. a. mo~e~o, in~.~p~siolo~,d~t.e~.cardiolo~,bogotsolets , ~ev , ukrmne systemic lesion$of erythron in traumatic disease and possibilities of their regulation by opioid peptides. redkin y. v., fominih s. g. using clinical ( patients) and experimental material( rats and dogs) we revealed general regularities of erythron lesions after hard mechanical trauma of various genesis as well as some mechanisms of development of posttraumatic anemia and possibilities of its correction with preparations of opioid peptides. the condition of central and peripheral compartments of erythron was studied with unified morphologic, immunogematological, biochemical and radiological methods. it was revealed that irrespective of the experimental animal species (dogs, rats) or in clinical experiments (patients) and irrespective of the injuring factor type (skeletal trauma, craniocerebral trauma, loss of blood) in erythron can be observed one-directed unspecific reaction realized by the considerable lowering of hemoglobin concentration, erythrocytes number and hematocrit. in the initial period ( - days) in the system of erythron prevail processes of distraction and elimination of er~zthrocytes relatively to the general production of stimulated erythropoiesis. the primary alterating factor is the prolonged intensification of peroxydation of membrane iipids of erythrocytes with simultaneous lowering of reserves of reduced glutathione. the distraction of erythrocytes is supported by the developing phenomena of autoallergization of organism that becomes apparent by the appearance of sensitized t cells and antierythrocyte antibodies. the intensified production of erythropoietin rules to the realization of he program of fetal and terminal (reserved) erythropoiesis. failure of erythropoiesis function is supported by disturbances of the processes of the injuring of cell metabolic apparatus. using of dalargin ( microgram per kilogram of body mass intrap'eritoneally within days after the trauma) showed the precise pharmacotherapeutic effect revealed by the diminishing of anemia of experimental rats, more . fiberbronohoscopic procedures are known to produce "peep-like" effects and to increase pulmonary artery (pa) resistance [ ] . peep can affect rv function by reducing preload and ejection fraction (ef) [ ] . since changes of rv function during bronchoscopy in septic patients are not reported, we measured rv parameters before, during and after fiberoptic bronchoalveolar lavage (bal). method: this -year-old patient (apache-ii: ) developed a hyperdynanlic septic state due to staphylococcus aureus (blood culture). we inserted a "fast response" thermistor pa-catheter (baxter-edwards) to evaluate rv performance [ ] . the therapeutic procedure included volume replacement, vasopressors (dopamine , dobutamine gg/kg/min. iv) and analgosedatior/. before bronchoscopy (olympus bf- , od= mm) the patient received pancmonium for muscle relaxation. ventilation was not changed during the procedure (endotracheal tube: id= ram, bennett a, pressure controlled mode, pm~x= mbar, peep= mbar, i:e=i:i, fio = . ). we measured rv enddiastolic volume (edv), stroke volume (sv), ef, heart rate (hr), cardiac index (ci) and mean pa pressure (mpap gerlach h, gerlach m, clauss m, falke kj renal hypoxia and/or ischemia initiates the development of a deteriorated medullary perfusion based on fibrin deposition in the peritubular capillaries, vasoconstriction, and perivascular edema, which is followed by a swelling of the tubular epithelial ceils, intraluminal tubular obstruction, and a backleak of fluid through the injured tubules into the renal interstitium, finally leading to an acute tubular necrosis (atn) [ ], clinically diagnosed as acute renal failure (arf). one important pathway for induction of enhanced vascular procoagulant activity and permeability is based on the synthesis and expression of macrophage-derived cytokines, which bind to specific endothelial cell surface receptors. we recently described the identification and purification .of a new , dalton polypeptide, which is synthesized and expressed by murine macrophages after stimulation with lipopolysaccharide, and exerts procoagulant activity on cultured endothelial cells [ ] . in the presented study, we demonstrate that the new polypeptid is also synthesized by macrophages under hypoxic conditions. the protein binds to specific receptors, which are expressed by endothelial cells dependent on the environmental oxygen tension. animal studies were performed after approval by the local committee for animal safety; the animals were anesthetized, treated and supervised in accordance with the guidelines of this committee. in contrast to other authors, who performed long-term hypoxia experiments in awake animals, we preferred to implement the studies under anesthesia for ethical reasons, although regulatory functions for ventilation might be influenced. animal studies demonstrated that the intravenous injection of the polypeptide initiates fibrin formation in the peritubular vessels. keeping the animals under hypoxic conditions induces similar effects, which are reduced by a rabbit-antiserum against the new protein. in conclusion, the new polypeptide obviously contributes to the pathogenesis of acute renal failure by tubular necrosis during and after hypoxic events. the use of verapamil as cardioprotective agents for management of patients with acute ischemic/reperfused heart is based on the assumption that the increased intracellular ca+ level is a key factor in causing cell death. our in vitro study was designed to focus on effects of verapamil on the metabolic potential of cardiac slices after reversible ischemia in rats. the material consisted of two main groups : group a (non ischemia/reperfusion group) and group b (ischemia/reperfusion group), each is subdivided into two subgroups (a and b). each subgroup included rat hearts. group aa is the control group, group ab is verapami] added group. group ba is ischemia group without verapamil. group bb is verapamil added group. ischemic cardiac slices were obtained from rats subjected to min. haemorrhage to induce reversible global ischemia. both nonischemic and ischemic cardiac slices were placed in well oxygenated krebs ringer phosphate buffer containing mg% glucose & gm% bovine albumin and incubated in dubnoff shaking water bath for min at °c the results revealed that there was an enhancement in release of free fatty acids (ffa) ( %) and lactate ( %) and in glucose uptake ( %) in group ba as compared with group aa. these metabolic alternations produced by ischemic cardiac slices were reversed by verapamil addition ( ml%) but in group ab verpamil did not alter the release of ffa & lactate from non-ischemic cardiac slices, whereas it inhibited glucose uptake from these slices by %. the improvement of the metabolic intervention of ischemic myocardium indicates that verapamil may be of importance in reducing the extent and severity of acute myocardial ischemic injury in acute haemorrhage. severe endothelial dysfunction occurs following injury to carotid arteries which is characterized by a decreased ability of these arteries to dilate when challenged with ach or a , but not with a direct vasodilator (nano ). this failure to relax to ach and a reflects an inability of endothelium to generate edrf, but relaxation recovers gradually to control values by weeks. exogenous no donors (e.g., c - or spm- ), accelerate the recovery of the injured endothelium in rat carotid arteries. intravenous infusion of an no donor ( p.g/day) with an implanted osmotic pump significantly accelerated the recovery of regenerated endothelium to produce edrf at days. rat carotid artery rings relaxed only + % and + % to gm ach in vehicle treated rats and in inactive no donor treated rats respectively days following injury compared with + % in no donor rats (p< . ). relaxation to gm nan was normal in all groups indicating that the differences in relaxation were not the result of damage to vascular smooth muscle. contraction to l-name ( mm) was markedly reduced by injury, but was protected by no donors (p< . ). thus, exogenous no donors enhance the ability of the endothelium to regenerate and to release edrf in response to endothelium-dependent vasodilators. this may be due to an anti-proliferative and anti-mitogenic effect of no on vascular smooth muscle cells, allowing the endothelium to regenerate without intimal thickening. no also has been shown to inhibit platelet aggregation, and to attenuate neutrophil adherence and activation. the superoxide scavenging effect of no is not the basis for these effects since hsod is inactive in preserving endothelial function in injured arteries. thus, no exerts a variety of cytoprotective effects which may be of importance in protecting against vascular injury. much evidence has now accumulated to show that the excess production of the vasodilator nitric oxide (no) in sepsis is an important contributor to the hypotension and multiorgan failure characteristic of this condition. various cytokines play an important role in this process through their ability to induce the production of one of the enzymes responsible for no synthesis, the inducible no synthase (inos). we have studied the effects of cytokines on the induction of this enzyme both in vitro using vascular smooth muscle cells, and in a murine model of gram-negative sepsis. tn smooth muscle ceils, the cytokines il- , ifnq', and tnf-oc show strong synergy with one another in the production of inos. in order to define the molecular basis for this synergic effect, we have linked the promoter of the inos gene to a "reporter" gene, chloramphenicol acetyl transferase (cat), and transfected these constructs into vascular smooth muscle cells. assays of cat activity reflect the activity of the promoter in this system, and by generating sets of deletion mutants of the promoter sequence we have been able to define the area within the promoter which mediates the synergic effect of these cytokines. in addition to stimufatory effects on inos production, certain cytokines are able to down-regulate the production of inos in vascular smooth muscle cells, and the effects of these counterregulatory cytokines will be discussed. the interaction of these cytokine effects in the whole organism has been studied in a murine model of gramnegative sepsis. widespread induction of inos occurs in this model as assayed by enzyme activity and through use of specific antisera to inos. neutralizing antibodies to tnf-~ and tfn-y are both able to prevent death in this model, but it is only the anti-ifn-y which attenuates the induction of inos assayed in the liver. clearly there is some redundancy in the effects of cytokines on the production of inos in sepsis, and greater understanding of the most important factors in inos production is required in order to target anti-cytokine therapy most appropriately. effects of nitric oxide on hepatocyte metabolism in inflammation. j. stadler, department of surgery, tu mqnchen, frg hepatocellular nitric oxide (no) synthesis is induced by proinflammatory mediators such as tumor necrosis factor, interleukin- and interferon gamma or by bacterial toxins such as lipopolysaccharide. stimulation of the hepatocytes (hc) with a combination of these agents leads to an output of no in quantities which are not seen in any other celltype. it has been demonstrated by various investigators that important effects of these cytokines and bacterial toxins on hc metabolism can be attributed to the action of no. in contrast to other celltypes hc seem to be relatively resistant to suppression of basic metabolic functions such as energy metabolism by no. therefore, cell damage has not been described to a significant extent following exposure to no. however, no does inhibit total protein synthesis. the exact biochemical mechanism of this phenomenon has not been uncovered yet, but it has been demonstrated for some specific proteins that their production is inhibited at a posttransscriptional level. as in many other celltypes cgmp generation is elevated in hc by no through activation of the soluble guanylate cyclase. cyclic gmp may possibly exert a plethora of metabolic functions, but it is interesting to note that most of the cgmp seems to be transported out of the cell. some very specific effects of no on hc metabolism include the inhibition of the glyceraldehyde- -phosphate dehydrogenase (gapdh) and the cytochrome p (cyp) enzymes. inhibition of gapdh activity is mediated through nitrosylation of critical domains of the enzymes by no which enhances auto-adpribosylation. this effect on gapdh activity might be responsible for the inhibition of gluconeogenesis by no, which has been described recently. finally, no-mediated inhibition of cyps may help to explain the suppression of hiotransformation processes which is a characteristic featur,'~ r ~ "~flamed liver. nitric oxide (no) is an endogenous inhibitor of polymorphonuclear leukocyte (pmn) adhesion which limits pmn-endothelial cell interactions under normal conditions. we have previously demonstrated that following ischemia, no production by the vascular endothelinm is dramatically reduced. accordingly, we investigated the effects of no-donors on pmn accumulation and tissue injury following hemorrhagic shock and ischemia. hemorrhagic shock was induced in anesthetized rats by bleeding to mmhg for hours followed by reperfusion. segments of superior mesenteric artery (sma) were isolated and suspended in organ baths. in rats receiving saline sma relaxation to acetylcholine (ach, nm) was reduced by % compared to control sma segments (p< . ) while relaxation to sodium nitrite ( gm) was unaffected. in addition, mesenteric tissue pmn accumulation as determined by myeloperoxidase (mpo) activity was significantly elevated compared to controls (p< . l). interestingly, treatment with the no-donating agent, s-nitroso-n-acetylpenicillamine (snap) significantly preserved sma relaxation (p< . ), attenuated mesenteric mpo (p< . ) activity, and significantly improved survival compared to saline vehicle. in anesthetized, open-chest dogs we investigated the cardioprotective actions of a novel no-donor, spm- (schwarz pharma), following regional myocardial ischemia ( hour) and reperfusion ( . hours) . treatment with spm- ( rim) significantly reduced myocardial necrosis by % (p< . ) compared to an no-deficient analog of spm- , spm- . furthermore, mpo activity within the ischemic-reperfused zone was also significantly (p< . ) reduced following treatment with spm- compared to spm- ( . + . vs. . + . u/ mg tissue). these data strongly suggest that no is a potent inhibitor of pmn-mediated tissue injury following hemorrhagic shock as well as in acute myocardial ischemia-reperfusion injury. overproduction of nitdc oxide (no') may contribute to sepsis-induced hypotension. during septic shock, excess no" is produced by an isoform of nitric oxide synthase (nos) which is induced by inflammatory mediators. nonselective nos inhibitors have been proposed as a new therapeutic approach to treating hypotension in septic shock. we studied the differential hemodynamic effects of n~-methyi-l-arginine (l-nma), a nos inhibitor, in normal canines versus those challenged with endotexin (lps) and compared the activity of this drug across the venous, pulmonary and systemic vascular beds. awake canines were challenged with lps ( mg/kg, n= : mg/kg, n= ; or mg/kg, n= ) and treated with l-nma ( , , , , mg/kg/hr) for hours following a , , or mg/kg loading dose. animals were resuscitated with iv ringers solution ( ml/kg/hr). hemodynamic data were collected at , , , , , and hours using intravascular catheters and radionuclide heart scans and analyzed by anova. in both normal and endotoxemic animals, l-nma at all doses studied similarly increased mean arterial pressure (p= . ), and systemic vascular resistance index (p= .ol) and decreased cardiac index (p= . ) and oxygen delivery index (p= . ). in contrast, the effect of l-nma on mean pulmonary artery pressure, central venous pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance index was greater in lps-challenged canines compared to normal animals (p< . ), but this differential effect on the venous and pulmonary circulation occurred, > hours after lps challenge. l-nma did not significantly increase survival rates or times at any of the doses studied ( , , , or mg/kg/h) in either the low ( mg/kg) or high dose ( mg/kg) lps-challenge groups. a nonsignificant (p> . ) trend toward a beneficial effect on survival ol low dose l-nma ( mg/kg/h) in animals given the mg/kg lps-cha[lenge was not enhanced by increasing the lethality of the model or by administering higher l-nma doses. at the highest l-nma dose used in this study ( mg/kg/h), survival time decreased significantly for both the low and high dose lps-challenge animals (p< . ). this increased mortality was not explained by changes in plasma concentrations of either lps or tnfc~. thus, l-nma did not have a greater effect on the systemic arterial circulation in endotoxemic compared to normal canines. however, in the venous and pulmonary vascular beds, the effect of l-nma increased with time after endotoxin-challenge these data suggest the induction of nos activity by endotoxin in canines may be relatively greater in venous and pulmonary vessels compared to systernic arteries. l-nma, a nonselective nos inhibitor, did not decrease mortality in endoloxemic canines and the highest dose studied was harmful. pulmonary hypertension (ph) and arterial hypoxemia are characteristic features of the adult respiratory distress syndrome (ards). reducing pulmonary vascular pressures may promote the resolution of pulmonary edema. intravenously infused vasodilators lower ph in ards, but, as a result of their general vasodilatatory effects, systemic mean arterial pressure may also decrease. furthermore, blood flow may be increased to non-ventilated or poorly ventilated lung areas resulting in a rise of intrapulmonary shunt, thus causing a further fall in pad . recently, short term inhalation of low concentrations of the gas nitric oxide (no), an endogenous endothelium derived relaxing factor, which is rapidly inactivated in blood by hemoglobin, was reported to decrease ph without causing systemic vasodilation in sheep [ ]. similar changes have been observed in patients with severe ards during repeated short term inhalation of no ( and ppm), which rapidly and selectively decreased the mean pulmonary artery pressure (pap) and, in contrast to intravenously infused prostacyclin, induced a remarkable increase of pad [ ] . this improvement in oxygenation was caused by a redistribution in blood flow away from intrapulmonary shunt areas to normal ventilated lung regions. continuous no inhalation ( - ppm) consistently lowered the pap and augmented the pao /f.o for up to days. no negative side effects were observed during the whole time span examined. in particular methemoglobin levels always remained below . %. following these investigations, it could be shown that these effects may also occur using concentrations in the parts per billion range [ ] , which may reduce possible toxic side effects. however, in the same study it was demonstrated that the dose-response curves for pa and pap have different patterns. whereas pap presented a continuous dose-dependent downward tendency with an eds o of approximately - ppm, the improvement of oxygenation had a maximum at ppm and, at higher doses, drifted back towards the baseline data. the ed~o was estimated at approximately ppb, i.e. more than ten times lower than for the reduction of pap. in conclusion, inhalation of no by patients with severe ards may result in persistent and reproducible decreases in pap associated with an evident improvement in pad , thus allowing reduction of the f.o . no inhalation should be performed using low concentrations which are less toxic, although any possible risks still have to be considered carefully. dose-response studies for the individual patients are recommended urgently. finally, controlled randomized studies are required to demonstrate that additional no inhalation is able to reduce mortality of ards. inhibition of the activity of glyceraldehyd- -phosphate dehydrogenase (gapdh), an enzyme of the glycolysis/gluconeogenetic pathway, through adp-ribosylation is promoted by nitric oxide (no). since no is produced in the septic liver and hypoglycemia is a major problem of late sepsis, it was investigated whether no interferes with gluconeogenesis of hepatocytes. hepatocytes (hc) were isolated from sprague-dawley rats using a collagenase perfusion technique and differential centrifugation. exogenous no was applied by incubation with the no-donors s-nitrosyl-acetylpenicillamine and sodium-nitroprusside. endogenous no synthesis was induced by incubation with cytokines (tnfcq il- , ifnj and lipopolysacchafide (lps). hrs later the incubation medium was changed to a solution containing lactate, ornithine, lysine, ammoniumchloride and glucagon for optimal conditions of gluconeogenesis. after more hrs glucose and nitrite levels were determined spectrophotometrically. gapdh activity was measured by the nadh-dependent conversion of , -diphosphoglycerate to glyceraldehyde- -phosphate. incubation of hc with no-donors led to a concentrationdependent inhibition of gluconeogenesis and gapdh activity. however, gapdh activity was about times more sensitive to the inhibitory effect of exogenous no. incubation of hc with cytokines and lps induced nq synthesis as measured by an increase in nitrite concentrations. endogenously produced no suppressed gluconeogenesis by _+ %. in contrast to exogenously applied no, the effect of endogenous no synthesis was less on gapdh activity resulting in an inhibition of only _+ %. in conclusion, exogenous and endogenous no inhibited gluconeogenesis as well as gapdh activity. however, there was no correlation between the extent of inhibition of these two parameters of hepatocellular glucose metabolism. we have shown that inhibition of hepatocyte (hep) synthesis of nitric oxide (no) potentiates cell injury in a model of acetaminopheninduced oxidative stress and the extent of damage was paralleled by depletion of reduced glutathione (gsh) stores. to clarify the role of no in modulating the redox state of hep, we studied the effect of inhibition of cytokine-mediated no production on hep gsh stores, in a system of isolated rat hep in primary culture, no synthesis was induced (stim) by exposure to il- , tnf, ifn, and lps for hours. , , and ~m of n-monomethyi-l-arginine (nmma), a specific inhibitor of no synthesis, was added. cells incubated in media alone served as controls (cont). the no metabolite (no ); aspartate aminotransferase (ast), an indicator of cell injury; and gsh were assayed. (data presented as mean + sem; n= .) gsh (nmovma orotein) ..~ (nmol/ma orotein) cont . + . + . # stim . + . + stim+ o tzm nmma . + . + . # stim+ ~m nmma . _..+ . * + . # stim+ pm nmma . + . * + . # stim+ )lm nmma . + . * + . # anova , . (* p < . versus stim, # p < . versus stim; anova with neuman-keuls) gsh in cont+ i~m l-nmma was equivalent to that of cont ( . vs. . ). ast release was equivalent in all treatment groups. these data show that inhibition of hep synthesis of no depletes intracellular stores of reduced gsh. we conclude that hepatocyte no production modulates cellular gsh homeostasis and as a result, may be hepatoprotective in oxidative injury. nitric oxide (no) is a modulator of immune response and may be involved in the changes in immune reactivity after major trauma and operations. we investigated no-generation in rat and mice spleen cells (sc) after partial hepatectomy (ph). c bl/ mice and lew rats underwent a % and % ph, respectively. sc were prepared - days after ph and plated at to x ecells per well. after h incubation at °c, no-production was measured as nitrite levels (griess reagent). normal mouse sc did not produce no, neither basal nor in response to lps or con a starting at the second day after ph, we found a substantial production of no. in rats, also sc from control animals were able to generate no; both basal and stimulated no-generation were further enhanced after ph (table, values expressed as mean --se). after shame operation, there was only a modest elevation of noproduction in rat and mouse sc. in first experiments we could demonstrate no-production also in phagocytes from a patient days aider liver partial resection ( . nmol nitrite/ cells) enhanced no-production in macrophages may contribute to the changes of immune reactivity after partial hepatectomy. nitric oxide (no) is recognized as an important mediator in endotoxemia and sepsis. increased synthesis of no has been demonstrated in septic humans and animals, and no inhibitors have been used in the treatment of septic shock. recent reports have, however, suggested that this form of therapy may cause serious organ damage. in the present investigation circulatory and metabolic changes in the liver were studied during treatment with the no-synthase inhibitor n-nitro-l-arginine-methyl ester (l-name) in endotoxemia. methods: juvenile pigs were randomized to one of the following treatment groups: ) encletoxin and l-name, ) endotoxin, ) naci and l-name, ) nach preliminary results from groups (n= ) and (n= ) are presented. catheters for pressure measurement were introduced into the aorta, hepatic and portal veins and ultrasonic transit time flow probes were placed on the hepatic artery and portal vein. a catheter was introduced into the pulmonary artery. endotoxin ( . gg/kg/h) was given as a continous portal infusion over the entire observation period of hrs. l-name ( mg/kg) was given as a bolus after hrs. of endotoxemia. results: endotoxin transiently reduced portal vein flow (pvf) by %* and hepatic artery flow (hal e) by %*, while l-name caused a further and lasting reduction in flow (pvf %, haf %)*. transhepatic (portal-hepatic vein) vascular resistance increased to times baseline value during endotoxemia while l-name caused a further marked increase in resistance to times initial value. portal oxygen saturation (so ) decreased by %* during endotoxemia. l-name caused a reduction in portal so by %*. arterial so was unchanged in both groups. hepatic oxygen uptake was not changed by endotoxin, but was markedly reduced after addition of l-name. endotoxin caused a % reduction in cardiac output (co). the addition of l-name reduced co by a total of %*. *: p < . . conclusion: is the present model of endotoxemia treatment with the nitric oxide synthase inhibitor l-name markedly reduced liver perfusion and portal oxygen supply. this might explain the increased liver damage reported in previous studies using no-inhibitors. the increase in transhepatic resistance found after l-name treatment will tend to cause pooling of blood in the splanchnic veins, resulting in reduced filling of the heart and thus contribute to the observed reduction in cardiac output. institute for surgical research, rikshospitalet, the national hospital, university of oslo, oslo, norway. we have investigated the role of tumour necrosis factor (tnf) and interleukin-i (il-i) in the induction of nitric oxide synthase (nos) by bacterial endotoxin (lipopolysaccharide; lps; mg kg -i i.v.) in vivo. in anaesthetized rats, pretreatment with a monoclonal antibody for tnf (tnfab; mg kg -i s.c., at h prior to lps) or with an il-i receptor antagonist (il-ira; mg/kg bolus and . mg/kg/h infusion) ameliorated the fall in mean arterial blood pressure (map) at - min after lps. for instance, endotoxaemia for min resulted in a fall in map from -+ (control) to -+ mmhg (p< . ; n= ). in contrast, animals pretreated with tnfab or il-ira prior to lps injection maintained significantly higher map at min when compared to lps-control: -+ mmeg (n= ) and -+ mmhg (n= ), respectively (p< . ). three hours of endotoxaemia significantly reduced the contractile effects of noradrenaline (na) in the thoracic aorta ex vivo. the hyporeactivity to na was partially restored by in vitro treatment of the vessels with ng-nitro-l-arginine methyl ester (l-name, min, x - m). pretreatment of rats with tnfab or il-ira significantly (p< . ) prevented the lps-induced hyporeactivity of rat aortic rings ex vivo. l-name did not alter or only slightly enhanced the contractions of aortic rings obtained from tnfab or il-ira treated lps-rats, respectively. at min after lps there was an induction of calcium-independent nos activity in the lung ( . -+ . pmol citrulline/mg/min, n= ), which was attenuated by tnfab and !l-ira by -+ % and -+ %, respectively (n= ; p< . ). thus, the production of both tnf and il-i contributes to the induction of nos by lps in vivo. the protective effect of agents which inhibit the release or action of tnf or il-i in shock may be, in part, due to inhibition of nos induction. neal garrison, md objective: sepsis is often accompanied by organ dysfunction, in part due to impaired microvascular perfusion. recently, nitric oxide (no) has been described as an important mediator of the hemodynamic changes of sepsis, and no synthase (no-s) inhibitors have been advocated for treatment of septic shock, but their visceral microcirculatory effects are inadequately characterized. we postulated that no-s inhibition would exacerbate the impaired organ perfusion of sepsis. methods: six groups ofdecerebrate rats were studied. bacteremia was induced with live e. coli, which consistently increased cardiac output - % above baseline (bl). the no-s inhibitor nm-nitro-larginine methyl ester (l-name, mg/kg iv), prevented this increase and elevated map by - %. in the first groups, total hepatic blood flow (thbf, ml/min by time transit flowmetry) and microvascular perfusion (mi-ibf, ¼ bl by laser doppler flux) were measured. in the other groups, in vivo videomicroscopy was used to observe renal microvascular responses (ila=interlobular artery, aff=afferent arteriole, eff=efferent arteriole; % bl for all). results: data are rains after e. cob. n= - /group. * p< . vs bl by remanova and § p< . vs e. coli alone by anova. ec+l-name -+ - _+ " § - _+ * § - _+ * § - + * - + * § conclusions: l-name administration in controls decreased renal blood flow, indicating no contributes to basal renal tone. bacteremia decreased mtlbf but not thbf, and mi-ibf was further impaired by no-s inhibition. e. coli caused renal preglomemlar, but not postglomerular constriction and reduced flow. l-name exacerbated these e. coli-induced alterations and caused eff constriction. these data indicate that no-s inhibition exacerbates bacteremia-induced impairment of renal and hepatic blood flow, suggesting that no is an importam compensatory dilator mechanism in these organs during sepsis. irf (iron responsive factor) is the central regulatory protein of intracellular iron metabolism able to bind to responsive rna elements (ires) present atthe 'untranslated region (utr) of ferritin mrna and 'utr of transferrin receptor mrna. binding of irf to ires results in repression of ferritin mrna translation and increased stability of transferrin receptor mrna leading to enhancement of transferrin receptor translation. we describe here that either tetrahydrobiopterin dependent stimulation as well as cytokine (ifn-~)/lipopolysaccharidemediated induction of nitric oxide synthase activates irf, which is due to direct interaction of nitric oxide with the iron-sulphur-cluster of irf. this was shown by gene expression studies using a plasmid containing a ferritin ire and a cat indicator box which was transfected into k myelomonocytic cells, which were shown to have a constitutive form of nitric oxide synthase (nos). furthermore, the increased binding of re to irf due to irf activation of irf by nitric oxide was demonstrated by gel shift assays. irf activity was much more increased in cellular extracts from murine macrophages (j ) where a cytokine inducible form of nos has been characterized earlier as compared with irf activity in k cells, where nos was stimulated by increasing the availability of the essential nos cofactor , , , -tetrahydrobiopterin. we then demonstrated that activation of irf by nitric oxide is accompanied by alterations in ferritin translation as checked by metabolic labeling and immunoprecipitation. these results suggest a reasonable mechanism for the regulation of iron disturbances under chronic inflammatory disorders, characterized by increased concentration of immune activation parameters like ifn- or neopterin and low serum iron and hemoglobin concentrations. taken nitric oxide, no, the putative endothelial derived relaxant factor, edrf, has been shown to be a potent inhibitor ofplatelet aggregation in vitro. in vivo evidence however, is scarce. accumulation of platelets in the lungs has been shown to occur during extracorporeal circulation. the aim of the present study was to investigate the effect of inhaled no on this reaction. materials and methods: the animals were divided into two groups, each consisting of pigs. platelets were selectively labelled with luln-oxine. dialysis was instituted via catheters in the femoral vessels. in group , no, ppm, was added to the inhaled gas from the start of dialysis. in group no was not given. the activity over the lungs was followed dynamically with a gamma camera. central hemodynamics was monitored via a swan -ganz catheter. results: the activity was significantly lower in group , from minutes after start of dialysis and onwards, indicating diminished accumulation of platelets in the lungs. parallel to this the hemodynamic response in terms of increased pulmonary artery pressure and pulmonary vascular resistance was blunted in this group conclusion: inhaled no in this model seems to affect pulmonary platelet sequestration. an associated attenuation of the changes in central hemodynamics was also seen. previous studies from our laboratory have demonstrated that vascular contractility decreased in endothelium-intact blood vessel rings in early and late stages of sepsis. although endothelium removal in early sepsis restored vascular contraction, the depressed smooth muscle contractility observed in late sepsis was not restored by endothelium removal. this indicates that impairment of smooth muscleper se may be responsible for such dysfunction in late sepsis. the aim of this study, therefore, was to determine whether or not smooth muscle-derived nitric oxide (no) plays a role in producing vascular smooth muscle dysfunction during late stages of sepsis. to study this, rats ( - g, n= - /group) were subjected to sepsis by cecal ligation and puncture (clp). septic and shamoperated rats then received rrd/ g bw normal saline. the animals were killed at , , or h post-clp ( h post-clp=early sepsis; - h post-clp=late sepsis), and thoracic aortic rings were prepared for contraction studies using organ chambers. the complete removal of endothelial cells was tested by the absence of any significant acetylcholine-induced vascular relaxation. contractile responses to norepinephrine (ne, to - m) were determined in the aortic rings without intact endothelium. ng-monomethyl-l-arginine (l-nmma, /~m, an inhibitor of no synthase) was then added to the organ chamber and ne-induced peak contraction was determined before and after the addition of l-nmma. the peak contraction (rag/rag tissue, mean_+sem) is shown below: the results indicate that the addition of l-nmma did not significantly affect ne-lnduced peak contraction in endothelium-denuded vessel rings at and h after clp. in contrast, l-nmma administration produces an % increase (p< . ) in peak contraction during late sepsis. therefore, the vascular smooth muscle contractile dysfunction observed at h post-clp is partially due to smooth muscle-derived no over-production. thus, unlike macrophages in which inducible nitric oxide synthase (inos) is observed in early sepsis, the inos in vascular smooth muscle appears prominent only in the late stages of sepsis. in three cases of human septic shock in which ng-monomethyi-l-arginine, (l-nmma) a nitric-oxide-synthase-inhibitor was applied, we isolated three completely different types of pathogens: candida, pseudomonas aeruginose and multiresistant coagulase-negative staphylococci. this observation suggests that endotoxin alone is not the main factor triggering hypotension in septic shock by the nitric oxide pathway. in a -years-old woman in severe septic shock due to a candida and pseudomonas aeruginosa infection complicated by adult-respiratorydistress-syndrome conditions deteriorated despite adequate conventional therapy. in this trial, effects of l-nmma on cytokin-levels were investigated. the study-protocol was approved by the ethical committee of the department of surgery. after two boll of mg of l-nmma, a continuous infusion was installed ( . mg/minute and kg body weight l-nmma). as expected mean arterial blood pressure rose ( to mmhg}, heart rate stayed stable ( + b/rain), systemic vascular resistance increased ( to dyne.sec/cm ), cardiac output decreased ( to . l/rain), and cardiac index declined ( . to . l/min/m }. before and after minutes while the infusion of l-nmma, blood samples for immunological measurements were taken and processed together. pulmonary-shunt-volume was observed before the application of l-nmma, after one hour and after matutes. neopterine increased from . to . ng/ml, tumour-necrosis-factor-a increased from . to . pg/ml and intedeukin- increased from . to . pg/ml. immunoglobulines a, g, and m ( . to . , . to . , . to . g/i), complement factor c- c and c- ( . to . , . to . g/i), alpha-l-antitrypsine ( . to . g/i), c-reactive-protein ( . to . rag/i), interleukin- ( pg/ml) and soluble interleukin- ( to units/ml) did not change significantly. pulmonary-shuntvolume decreased from . % to . % within one hour and to . % after minutes. in septic shock blocking nitric oxide as an intervention at the end of a not ~,et ful!y understood cascade might have important influences on pulmonary-shunt-volume and inter-cell-communication. department of surgery, pharmacy* and immunology**, university hospital of zurich, r~imistrasse , zurich, switzerland we previously reported that hypoferremic cba mice had an increased resistance to salmonella infection, and that injection of ammonium ferric citrate (afc) to these mice led to enhanced infection (ganthier et at. . microbiol.immuno : ) . because nitric oxide (no) is involved in the antimicrobial activity of routine macmphages towards various inttacellular pathogens, we investigated the influence of iron on the bactericidal activity of cba mouse macrophages towards s.typhimurium and on the production and activity of reactive nitrogen intermediates (rni). peritoneal macrophages hum cba mice were cultured in the presence (or not) of afc ,um, ifn-,/ u/ml, lps fig/m/, ngmonomethyl-l--arginine (mmla) ram. nitrite (no -) content of the supematants was determined by a standard griess reaction, and h release was measured by the peroxidese dependant oxidation of phenol red. for intracellular killing, macrophages monolayers were infected, and, at various intervals, lysed by triton x- , and surviving bacteria enumerated by colony counting on agar. for in vivo experiments, mice were infected ip with . ml of a suspension of . ~" s.typhimurium, strain c , and injected with aminoguanidine (ag) mg/ml in saline. our results show that the rn[ inhibitor ag strongly accelerates the mortality of infected mice, the survival rate decreasing from % in the control group to % in the treated group, days after challenge. correlatively the rni inhibitor mmla induces in vitro a decrease in the rate of bacterial killing, fxom % to %, in macrophages triggered with ifn-? + lps. the cultivation of macrophages in the presence of afc leads to a decreased no -accumulation, . nmole/well v.s. nmole/well. conversely h production is enhanced from nmole/well up to , nmole/well. nevertheless, macrophages cultivated in the presence of afc exhibit an increased tale of intracellular killing, % in iron exposed macrophages v.s, % in control macrophages. when triggered with ifn-~, alone, macrophages have a reduced antibacterial activity ( % v.s. %) whereas the addition of afc to these macrophagas restores an elevated ( %) rate of killing. in conclusion, the results show that bactericidal activity of cba macrophages towards s.typhimurium depends on the production of no by these macrophages ; but they also demonstrate that no is not the only reactive species involved in the intracellular kil/ing of s.thyphimurium ; indeed afc which strongly inhibits rni production, stimulates h release by these macrophages and increase their bactericidal activity in vitro. nevertheless afc may promote bacterial growth in vivo. crssa. unit de microbiologie. bp . la tronche cedex france. henning jahr, ulrike noack, karin braun the large amounts of no produced by the inducible no synthase in rat macrophages have direct antimicrobial effects, but inhibit the activation of the lymphocyte-dependent host defense system. the aim of this study was to investigate if complement activation influences no-generation. spleen cells from lew rats were incubated at °in tcm- / % fcs, with or without additional rat serum. after h, nitrite (end product from no metabolism) was measured by oriess reagent. in rat spleen cell preparations, most of the no is produced by macrophages. complement activation in vivo was carried out by i.v. injections of u cobra venom factor/kg b.w. at days and . significantly higher (p<o.o ) lps-stimulated no-generation was found in spleen cells prepared at day ( . - . nmol nitrite/ cells, n= ) compared to spleen cells from non-treated animals ( . ± . nmol, n= ) complement activation was effective also in vitro. when incubated in % zymosan-activated rat serum, both basal and lps-stimulated noproduction were enhanced in spleen cells (table, values increased production of nitric oxide (no) is associated with sepsis, however, the effect of no inhibition on survival during sepsis is unclear. we examined the effect of no inhibition on host's ability to eliminate bacteria and survival in mice sepsis model. sixty female balb/c mice were injected with e.coli ( qbody) into peritoneal cavity. the treated group received n-ultro-l-arginine-methyl-ester (l-name), an inhibitor of nos, one hour before bacterial challenge. thirty mice were observed for survival after e.coli challenge and the other mice were sacrificed at hours. blood was obtained by cardiac puncture and peritoneal lavage fluid (plf), liver and lung were harvested. the number of peritoneal exudative cell (pec) was counted and colony forming units (cfld of bacteria in the tissues, blood, and plf were also determined. in addition, pec was cultured in vitro with or without lipopolysaecharide (lps). tnf levels in the blood, plf, and supematants of cultured pec were measured by l bioassay. survival rate (%) qrql/,p n hr hr dav control (normal saline . ml/body i.p.) n (l-name mg/kg i. administration of l-name before e.coli injection increased the number of bacteria in plf and tnf level in plasma, the result suggests that nos inhibitor may depress the host's ability to kill the injected bacteria and that it may induce greater systemic tnf production. we conclude that nos inhibitor is detrimental to animals in sepsis. the hypothesis that sod prevents reperfusion injury to the liver by protecting the endogenous endothelium derived vascular relaxing factor (no) from being inactivated by oxygen free radicals should be investigated. male wistar rats were subjected to min of partial liver ischemia ( %) and min of consecutive reperfusion in situ. some rats were pretreated with the no synthase inhibitor nitro-l-arginin (nla: i mg/kg). sod, when used, was given as mn-containing preparation at a dose of u. i.v. i min prior to ischemia. results (sod/ nla+sod/ ni~,, respectively): bile flow (~i/g/min) : . ± . "#/ . ± . / . ± . . alt (u/ ) • ± ~#/ ± / ± . gldh (u/l): . ± . e#/ . ± . #/ . ± . . in absence of nla, sod enhanced postischemic bile flow and reduced leakage of alt and gldh into the plasma, while the effects of sod disappeared, when endogenous ~synthesis was inhibited by nla. nla had no ~ffect on untreated animals submitted to the same protocol. these results may suggest, that oxygen free radicals interfe~:e with the endogenous vasodilator no and that the benefit of sod can be attribuated in large part to a protection of no during reperfusion. nitric oxide (no) reduces pulmonary vascular resistance and increases oxygenation by inhalation in ards patients [ ] . animal studies on the endogeneous no production proved that no is exhaled after synthesis in the respiratory tract [ ] . with approval by the hospital ethics committee, we studied healthy volunteers and ventilated patients by measurement of inand exhaled no by no/no -chemiluminescence in segments of the upper respiratory tract. we found that no is synthesized predominantly in the nose and in the upper nasopharynx, leading to inspiratory tracheal no concentrations of . - . parts per million in non-smoking volunteers; data during mask ventilation per nose were as follows: non . . . . , parts per million (ppm) no, mean, n = ; ~ p < . (t-test) between smokers and non-smokers; p < . (t-test) between in-and expiration. about % of no is resorbe.d by the lung, and the exhaled no -in contrast to former presumptions -is the remaining part of the autoinhaled no. intubated and ventilated patients are deprived of no autoinhalation, and the exhaled no in the trachea decreases more than % {o. ppm before intubation vs. . ppm after intubation, ~, < . ), whereas the nasal no concentration increases by cumulation. hence, low-dose no inhalation in ards patients might be considered as a no replacement, especially since the tracheal no concentrations we measured in volunteers are similar to those which could be demonstrated to be effective for ards in former studies [ ] . the data demonstrate that no is synthesized in the nose, and inhaled and resorbed by the lung. this phenomenon of no autoinhalation, which is reduced in smokers and in ventilated patients, does possibly contribute to the regulation of the ventilation-perfusion ratio in the lung. kikuchi , yoshihiro inoue , masao yoshida critical care and emergency center, and department of bacteriology, iwate medical university. nitric oxide (no) is produced by macrophages and vascular endothelial cells. it is thought to be the true form of endotheliumderived relaxing factor, and to be involved in the fall of blood pressure during septic shock. we have reported previously that endotoxin (lps), tnf-c~ and il- contribute to the occurrence of septic shock (circ shock : ; . the present study investigated the in vitro effects of lps, tnf-o~, il- and ifn-'i on the production of no by macrophages. peritoneal macrophages were cultured with lps, il- , tnf-~ and ifn-¥. in culture with lps, no was produced in a dose-dependent manner, and the production was suppressed by a no production inhibitor, l-nmma. ifn-y, il- and tnf-c~ used alone did not promote the production of no, but helped lps to facilitate no production. a combination of il- and tnf-c( enhanced lps-facilitated no production to a greater extent than il- or tnf-c~ alone. the above results suggest that these cytokines are involved in endotoxin shock through the mechanisms that facilitate no production. - uchimaru, morioka . japan. t. yolk , , i. ioannidis , w.j. kox and h. de groot objectives: nitric oxide (no.) is known to play an important role in neurotransmission, vasoregulation, and bactericidal as well as tumoricidal cellular defense systems. by means of no-donating agents we studied the mechanism of no-mediated cytotoxicity against rat liver microvascular endothelial cells. materials and methods: -morphoiinosydnonimine-n-ethylcarbamide (sin-l) and sodium nitroprusside (snp) were used as no. donators, ldh release and trypan blue exclusion were applied to indicate cell viability. results: sin- ( mm), which releases both no. and o -., caused a time-dependent cytoreduction of % and % after and hrs, respectively. this effect was not inhibited by superoxide dismutase (sod), which removes --to form h and . in contrast, the addition of catalase (cat), which removes h to form h and , diminished the cytotoxic effect ot sin- to %, equivalent to high concentrations of snp ( mm), which solely releases no.. in addition, the amount of h formed by mm sin- equaled the amount ot enzymaticany produced h by mu/l glucose oxidase (god). whereas god in this concentration and snp in low concentration ( mm) alone were not toxic to endothelial cells, the combination caused an % reduction of viability, comparable to the effect observed with sin- ( mm) alone. moreover, toxicity mediated by high concentrations of snp ( mm and ram) was reduced by % under hypoxic conditions indicating synergism with no-and . conclusions: we conclude, that no.-induced toxicity against endothelial cells is enhanced slightly in the presence of oxygen and is not due to an interaction with -. however, toxicity increases dramatically in the presence of h . this may possibly occur either by a chemical formation of more potent reactive hydroxyl radicals or by independent actions on different cellular targets. although it is becoming increasingly clear that nitric oxide (no) is associated with otxan dysfunctions in septic patients, little is known as to die kinetics of no production in these patients to clarify these kinetics, we have investegated serum arid monocyte associated no in septic patients. five patients who had undergone gastrointestinal surgeries mid were complicated postoperatively with severe sepsis served as the subjects in this study (sgroup), using twelve healthy volunteers as a control group (c group). serum no and no levels were measul*d sliectrophotometricallymonocyte cultures were done for itrs with or without lps+ifn-t stimulation mid no and no levels in the supernat,'utts were also measured spectrophotometrically. furthermore,using an no selective electrode,time course of the lps+ifn-t induced no production by monocytes was studied. l) serum no levels in s group were slightly lfigher than dmse in c group,bnt there were no significoatt differences between the two. )both no levels in the supematmlts of monocytes cultured with lps+ifn-t mid no , no levels ill lhe supernatants of monocytes cultured without lps+ifn-y were significantly higher in s group. further,the time required for the no production by enltnred monoeytes was siglfificantly shorter also in s groap. conclusions l)in severe septic patients, monocyte no productions wei~ not only primed, but also activated concomitantly, suggesting that these monocyte activations m'e strongly associated with organ dysfunctions in sepsis. )based on the restdts of serum no nteasuremeuts, it can be deduced that no p~'oduced by monocytes in septic patients affects tissues and org~s ioeoregiomflly. objectives of the study: nitric oxide (no) is an important messenger which accounts for a wide spectrum of physiological and pathophysiological processes, e.g. mediating vasodilation in endoloxin shock investigating the signal lransducfion pathways involved in the regulation of the inducible nitric oxide synthase (inos), we report the involvement of phosphatidylcholinespecific phospholipase c (pc-plc) and proteinkinase c (pkc). materials and methods: no-production was induced in the murine macrophage cell line j with lipopolysaccharide (lps) [lljg/ml] and interferon ;f (ifny) [ u/ml]. after hours of incubation no-release was determined as nitrite (no ) by using a colorimetric assay based on the griess-reaetion. results: preincubation of cells with the pkc-inhibitors staurosporine (stp), chelerythrine, bisindolylmaleimide (bim) and d , that recently has been identified as a selective inhibitor of pc-plc, diminished significantly lpsand ]fnt-induced no -production (p<o, ). although we observed no toxic effect on cell viability, no -production was related to protein concentrations to exclude any inhibitory effect on celt growth. celts preincubated with stp [lo nm] released % less no in response to lps and ifn,[ compared to control cells cultured without inhibitor. chelerythrine [ }jm] and bim [ioijm] reduced the no -formation by % and %, respectively. interestingly, the most potent inhibitor of no-production turned out to be the xanthate d cells pretreated with d [ ~g/mt] released % less no than stimulated controls the inhibitory effect on no production decreased the later the inhibitore were added after stimulation; e.g. bim added and hours after stimulation reduced no -production only by % and %, respectively. accordingly, inqs activity present in stimulated cell lysates supplemented with l-arginine and co-factors was not suppressed by the inhibitors tested. conclusions: our findings suggest, that the induction of inos but not its activity is a pkc and particularly pc-plc dependent process. dr. k tschaikowsky, institut for anaesthesiologie, universital erlangen--nqrnberg, krankenhausstr , erlangen interleukin- (il- ) affects nearly every cell type by increasing the expression of a variety of genes associated with the promotion of inflammatory processes. these include upregulation of cyclooxygenase and nitric acid synthases. the il- ri transmits a signal(s) through the cytoplasmic domain which is structurally related to the fruit fly toll protein. we have recently cloned the promotor most proximal to the ' utr of the human il- ri gene. the genomic sequences reveal a lack of tata and caat boxes but rather a considerable ( %) gc rich region. the translation of the type i il- r appears under a significant suppression and may limit the biological activities of il- by low level of expression. on the other hand, the type ii il- r, lacking a significant cytoplasmic domain, does not transmit a signal and acts as a decoy receptor preventing the binding to the type i receptor. there are several approaches to reducing il- activity; inhibition of il- converting enzyme which cleaves pro-il-l[ , anti-il- ri, the il-i receptor antagonist (il- ra) and soluble (extracellular) il- ri and il- rii. il- ra is structurally related to il- and binds at °c to the il- ri with near equal affinity as that of bona fide il-i; however, il- ra does not transduce a signal. il- ra has been given to humans in pharmacologic levels (mean plasma levels of gg/ml) without evidence of agonist activity. in addition, there has been no affect on normal homeostatic parameters, suggesting that il-i does not play a role in health. in healthy humans given intravenous endotoxin, il-ira reduced endotoxin-associated neutrophilia by % and completely reversed endoloxin-iuduced immunosuppression, il-tra is produced naturally and is elevated in the circulation in several diseases. in a variety of diseases, plasma levels of il- ra are in -fold molar excess to those of il-i [ . it is unclear whether these endogenous levels of il- ra are sufficient to block il- activity in disease. a single injection of ]l- or ifna in humans does not induce il- but rather high levels of il- ra ( ng/ml). prof.dr.l.a. aarden interleukin (il ) is a multifunctionai cytokine with a central role in host defense mechanisms and consequently in inflammation. il is thought to be involved in the pathogenesis of various diseases. therefore, specific inhibitors could have therapeutic value. a human-mouse chimeric monoclonal antibody to il has been applied in a phasei clinical trial in patients with multiple myeloma and in primate models of sepsis. no toxicity was observed and the most remarkable outcome of this study was the build up in the circulation of il -anti-il complexes, suggesting that plasma il measurements represent a gross underestimation of il production in the patient. until now no natural antagonists of il have been described. the biological activities of il results from binding to a lowaffinity il -receptor (il r). the il /il r complex induces disulfide-linked homodimerization of the signal transducing receptor component, gp . studies on the structure-function relation of il revealed that disruption of the gpl -interaction site on il gives rise to a mutant il that, by virtue of its intact binding to the il r, acts as a potent antagonist on human hepatocytes and on human b cells. in vivo studies using this molecule will be initiated in the near future. the evolution of infla~ation involves a dynamic series of cellular events controlled by specific signals which are important to the initiation, maintenance, and final resolution of the inflammatory response. the various phases of inflammation are influenced via the expression and subsequent regulation of a number of key mediators which play a predominant role during each particular stage of the developing lesion. for example, the initial elicitation of blood born leukocytes to on inflamed area is a complex system that is dependent upon the expression of early response cytokineso these proximal mediators, including both interleukin-i (il-i) and tumor necroisis factor (tnf), are important in the initiation phase by activating both immune and non-immune cells and establishing a series of cytokine networks, thus, the above proximal mediators can stimulate endothelial cells, epithelial cells, smooth muscle cells, and fibroblasts to generate more distal cytokines. these latter cytokines include interleukin- (il- ), macrophage inflammatory protein-i (mip-i), and monocyte cbemoattractant protein-i (mcp-i). the importance of the above chemukines can be found in the role they play in leukocyte elicitation, as well as wound repair. numerous investigations have shown the diverse cellular sources of il- and the ability of il- to elicit neutrophils in vitro at pm to nm concentrations, however, recent studies have sho%~ an additional role for il- during the resolution phase of the inflammatory process. using corneal pocket animal models of angiogenesis/neovascularization, il- was found to be a potent angiogenic factor at concentrations ranging from - ng/ml. sequential fluorescein angiograms demonstrated that il- induced neovascularization by days, which regressed by weeks. in further analyses, both conditioned media recovered from either inflamed human heumatoid synovial tissue macrophages or lps-stimulated peripheral blood monocytes were found to possess potent angiogenic activity, which was effectively blocked by neutralizing antibodies directed against human il- . in addition, an il- antisense nligomunclentide blocked the expression of a functionally active angiogenic factor from lps treated monocytes. the above data demonstrate that il- has multifumctional activities during the initiation, maintenance, and resolution of a local inflammatory response. inhibits specific t-cell responses to soluble protein antigens and alloantigens. the proliferative responses of th , thl and th cd ÷ t-cell clones and cytokine production by these t-cell subsets are equally well inhibited. the inhibitory effects of il- are indirect and related to inhibition of antigen-presenting capacity and accessory function of the antigen-presenting cells (apc). however, il- also directly inhibits t-cell proli/eration induced by cross]inked anti-cd or anti-cd mabs (e.g. in the absence of professional apc), by specifically inhibiting il- gene transcription and il- protein production. il- also inhibits the production of the pro-inflammatory cytokines il-l-a, ~, il- , and tnf-a and the chemokines il- and mip-i-u, which are strong chemo attractants for neutrophils and macrophage, respectively. in contrast, il- enhances the production of the il- receptor antagonist, a cytokine with anti-inflammatory activity. il-l produced by monocytes downregulates class ii mhc expression and il- production by these cells in an autoregulatory fashion. collectively, these in vitro data indicate that il- is a powerful suppressor factor for immune-and inflammatory responses and therefore may have potential clinical utility as an anti-inflammatory agent. this notion is supported by recent studies which indicated that il- also prevents lethal lps-induced toxic shock in mice. five of the chamekines (hip-i~,era~tes. ip-io and il ) also chemoattraet t lymphocytes, while others act on mast cells. we have studied the effaces of these chemokines on t cell subsets. il preferentially chemoattracts uns~imulated t cells. raises ~ttracte resting as well as activated cd and cd memory t cells. ip- chemoattracts only preactivated (not resting) cd or cd t cells. hip-l~ preferentially chemoattracts gd t calla, while hip- more readily attracts the cd t call subset. the chemoklnes and ip-io were also sho~rn to promote the adherence of ~he same subsets of anti-cd activated t cells to ili activated human umbilical vein endothelial cells (hitvec). this was not associated with a~y i~crease in the number of lymphocyte adhesion molecules, bu~ could be inhibited by neutralizing monoclonal antibodies re lfa-i and vla- . these chemokines also rapidly increased ~ha adhesion of resting t l~phoeytes to plates coated wi~h integrlns (i-cam or v-cam) or matrix proteins such as f~bronectln. this induction of adhesion began wiehln ', peaked by hr and was completed in hr. this suggests that chemoklnee rapldly increase the binding affinity of adhesion prote~ns on t cells. we also recently observed ~hat mcaf/mcpi and rantes chemoattract unatimulated mast calls. furthermore, igs actlvared mast calls were chemoattraeted by mcaf, ra~tes, pf and mip.i~. however. ~he chemoklnee did not induce mast cells ~o release histamines. presumably, chemokines as regulators of the adhesion, migration and homing of all kinds of leukocytes participate in many types of inflammatory diseases. natural killer cell stimulatory factor or interleukin- (il- ) is an heterodimerie cytokine formed by two covalently linked glycosylated chains of kd and kd. il- was originally purified from the supermatant fluids of ebv-transformed human b ly~phobiastoid cell lines. however, in addition to b cells, phagocytic cells, i.e. monocytes, macrophages, and neutrophils, have been identified as the major physiological producers of il- . phagocytic cells produce il- in response to bacteria, bacterial products such as lps, and intracellular parasites. the cell types on which il- exert biological activity are t and nk cells. the major direct biological function of il- on these cell types are the induction of cytokine production, primarily ifn-y, the enhancement of a generation of cytotoxic cells, and a mitogenic effect on antlgen-activated lymphocytes. in part thromgh its ability to induce ifn-y production, il- , produced in response to infections, represents an important functional link between effector cells of innate resistance, phagocytic cells and nk cells, and effector cells of adaptiye resistance, t and b lymphocytes. the ability of il- to induce ifn-y production from circulating. nk cells and at least a proportion of t cells determines a rapid, antigen-independet production of ifn-y during infections. ifn-y acts as a potent enhancer of phagocytic and bacteriocidal activity of phagocytic cells, participating early in infection to activate some of the inflammatory mechanisms that represent the first innate resistance against infection. this antigem-independet activation of phagocytic cells that involves, in addition to il- , other monocyte derived cytokines such as tnf and il-l, has been shown to be important in experimental animals for the resistance against infection by microorganisms such as limteria monocytogens and toxoplasma gondii. in addition to this role, early in infection in the antigen-independet phagocytic cell activation, il- has a major effect in the ensuing antigenspecific admptive immune response by facilitating the generation of t helper type (th-i) response and suppressing a th- response. the presence of il- during antigen stimulation in vitro using human peripheral blood lymphocytes, or both in vivo and in vitro in experimental animals, induces generation of th-i cells producing ifn-y and il- , and inhibits the generation of th- cells producing il- . il- induces a direct differentiative effect on th-cells, priming them for high ifn-y production. ~is priming effect is stable and maintained even when t cell clones are cultured for extended periods in the absence of il- , however, il- needs to be present during the first few days after stimulation with antigen or mitogen and established th clones are resistant to the priming effect of ifn-y. unlike the generation of high ifn-y producing clones, the il- -mediated inhibition of il- producing cells in probably due to selective mechanisms, which may include a selective mitegenic effect of il- for thl cells and an inhibitory effect of ifn-y on th cell proliferation. in several experimental systems, it has been shown that the enhancing effect of il- on th-i responses is dependent on production of if~-y and on the presence of nk cells, possibly needed for the early production of ifn-y. the importance of phagocytic cells and nk cells in determining the characteristics of the th response during antigenic stimulation indicated that the mechanisms of innate resistance have a determining influence on the subsequent antigen-specific immune response: il- appears to have a key role in mediating the interaction between phagocytic cells. nk cells, and t lympocytes in these proccessem. trinchieri, g. , interleukin- and its role in the generation of t e cells, imm~ol. on peripheral blood monocyte/macrophages, il- behaves like il- in a variety of assays, and shows both similar and contrasting, activties with either il- or ifn-y. il- reduces inflammatory monokine and il- production. it reduces the pyrogen-induced expression of tissue factor (herbert et el, , febs lett. , ) . it mpregulates manmose receptor and ~c class ii expression, while reducing cdi expression. il- produces morphological changes (extensive cell processes, aggregation, giant cell formation) which have previously been observed with il- . it inhibits niv-i production (montaner et el, , i. exp. mad. , ) , and interferes with hiv-induced cell fusion. the activities of il- and il- differ on t-ly•ocyte and large granular lymphocyte population. in particular il- does not exhibit the suppressive effects of il- on thl-type-helper functions (ifny production) and cytotoxic functions (perforin production). data will be presented showing that il- and il-l share a common receptor on a nu~er of cell types, but not on t-lympocytes (see also zmrawski st el. , embo j. . - ), explaining both thai common and divergent activities. the levels of il- ~a in activated peripheral blood lymphocytes are greater than or equivalent to those of il- mp~ja and the two ml{nas are expressed by different t lympocyte population: in particular, t cytotoxic lymphocytes express markedly higher levels of il- ~rna. in vivo, il- may thus be contributing, significantly to some of the activites previously ascribed to il- il- . recently, we cloned the human cdna encoding interleukin- (il- ). human il- is a non-glycosylated protein of aa with a molecular mass (mr) of kd and has biological activities on monocytes and b cells, il- , like il- , strongly enhanced the expression of class ii mhc antigens on monocytes and induced expression of cd (fc~rii). furthermore, il- , like il- and il~ , inhibited the production of pro-inflammatory cytokines il- , ]l- , tnfo~ and chemokines miplc~ and tl- by lps activated monocytes. both il- and il- enhanced the production of il-lra by monocytes. in contrast, il- lacked the t cell stimulating activities of il- . the responses of monocytes to il- and il- were not additive or synergistic, supporting the hypothesis that il- and il- receptors are complex and share a common component which is important for signal transduction, taken together, these data indicate that il- , il~ and il- have important anti-inflammatory activities on human monocytes. in addition, these results indicate that il- is unique in that it can modify inflammatory reactions without stimulating (as does il- ) or inhibiting (as does il- ) t cell responses. transforming growth factor beta i (tgf-fll) belongs to a family of proteins that have potent immunoregulatory properties ranging ftom effects on the growth and dfflerentiafion of primitive stem cells to the differentiated functions of immune system effector cells. tgf-i~i is synthesized as a large secretory precursor polypeptide of amino acids that is inactive until processed to a disulfide linked homodimeric molecule of t amino acids each. recently it has been found that tgf-[~i can have autocrine as well as paracrine effects on the immune system indicating that immune cells can activate the inactive secreted form of tgi~-~i. in addition, tgf-i~i has differential intraceuular effects on cell surface receptor modulation, tyrosine phosphorylation and cytokine gene transcription as well as cell mediated cytotoxicity. the systemic administration of tgf- has proven beneficial in a variety of animal models such as septic shock, allograft rejection and experimental forms of autoimmunity including collagen induced arthritis and experimental autoimmune encephalomyelitis. moreover the increased levels of tgf-ill and other tgf- isoforms found in several disease states associated with immunosuppression such as different forms of malignancy, chronic degenerative diseases and aids implicate the involvement of tgt~-i~ in the pathogenesis of some diseases. hopefully, well designed clinical trials will define the potential roles of the tgf-[ family of proteins in the treatment of diseases of man. patient development of systemic inflammatory response syndrome (sis) after severe trauma is accompanied by a wide range of immune aberrations and altered cytokine production. in particular, t lymphocyte proliferation and ifn, t production is suppressed while monocyte (mo) tnfc~, il- , pge and tgf~ production is massively increased concomitant to decreased antigen presenting capacity. recently, two new cytokines, il- and il- , have been characterized as critical in regulation of mo tnfa and il- , as well as in induction of t lymphocyte proliferation and ifn production. in this study, peripheral blood leukocytes (pbl) from severe trauma patients (injury severity score > ) were analyzed for their il- levels, their in vitro proliferation to mitogen (pha) and their response after il- addition. since il- produced either by mo or by t lymphocytes can depress m~ antigen presenting capacity, inhibit t cell ifn,/production and directly diminish t cell proliferation, it might be suggested that immunosuppressed patients' mo and/or t lymphocytes would have increased il- levels. increased patient il- production might also be resulting from the high levels of tnfa a known stimulator of il- . conversely, since il- augments mo antigenpresenting capacity, thl induction and proliferation, post-trauma leukocytes might be il- deficient. pbl of trauma patients were compared to normals' pbl, either unstimulated or ptta induced, and their levels of il- found to be dramatically and significantly reduced. patients' isolated m~, either stimulated with the bacterial cell wall analogue, mdp, or unstimulated, also had depressed il- production concomitant to elevated tnfa production when compared to normals' mo. mechanisms for the depressed patients' mo il- were explored. increases in tgf[ may have partially contributed to the patients' depressed il- level, but elevated pge had no effect. addition of il- to patients' pbl significantly increased their mitogen responses. these data imply that sis is characterized by disruption in the interactions between mci and t lymphocytes so that patients' m~i produce excesses of some mediators (tnfa, il- , pge ) and a dearth of other monokines (il- , il-io). t lymphocytes are not activated and, therefore, unable to function in both immune defense and monocyte regulation. it is known that lge receptor-mediated or ca-ionophore-induced activation of mouse bone marrow-derived mast cells ( mmc) may result in the production of different cytokines including the interleukins (il) , , , and as well as gm-csf and tnf-a. in the present study we analyzed the effects of exogeneously applied pro-inflammatory cytokines (il- , l- , tnf-c as well as various mast cell growth factors (il- , il- , il- , il- , ngf, kl (kit ligand)) on cytokine production in primary mouse bmmc using a standard activation protocol (lxl bmmc/ml; ll.um ionomycin; - h). the actixdties of bmmc supernatants were assessed in specific biological (il- , il- il- , l- ) and/or elisa assays (il- , il- ). here we show that homogeneous populations of bmmc (> %alcian blue+/safranln-; in vitro age: weeks) generated in the presence of recombinant (r) rail- from normal balb/c mice produced modest amounts of l- and low or undetectable levels of il- , - , and - after induction with lp.m ionomycin only. however, a dramatic increase ( -to -fold) of these cytokine activities was noted, when in addition to ionomycin also human ( ) rll-la was provided during the induction period. this il- effect was dose dependent with a maximgm at - u/ml hrll-la and specific, as pre-incubation (lh) of bmmc with ng/ml hrll- receptor antagonist abolished the action of u/ml hrll-lcc similar effects were noted with hrll-lg or rurll-lb (lng/ml, respectively), but not with rhll- or rmtnf-~. both mrll- and hrll- substantially enhanced ionomycin-induced l- production of bmmc in the absence or presence of il- . il- significantly enhanced il- and il- production while decreasing il- activities to abont - % of control levels, when il-i was provided in the presence of il-l/ionomycin. a monoclonal anti-nfil-t antibody (ascites : ) abrogated the effects of mrll- . other mast cell-active cy~okines (] ,- , il- , l- , ngf, or kl) added to ionomycia-or l- /ionomycin-treated bmmc had no major effects on cytokine production. il- and il-i did not induce significant cytokine release in the absence of ionomycin suggesting tlmt cadependent signalling was required. at doses of " m, dexamethasone, corticosterone, or hydrocortisone almost completely abolished ionomycin/il- /ll- induced cytokine production. the inducer cocktails per se did not interfere with the cytokine bio-assays. in case of il- inducibility of this cytokine in bmmc was confirmed at the mrna level by northern blot analysis. hence our data show that activated mast cells are a source of il- previously recognized as a product of th type lymphocytes only. moreover, our study reveals novel functional roles for i-l-i, il- , and ghicecorticoids in the regulation of cytoldne production in mast ceils. accumulating data suggests that cytokines, peptides involved in regulation of both physiological and pathological immunological responses, predominantly are produced at the local site of antigen stimulation. a new method was used to detect cytokine-producing cells in haman tissue at the protein level. single-cell production of different httman cytokines, ilia, ill [ , illra, il , il , il , il , il , ils, ill , gm-csf, tnfa, ifn and tgf[ . , was identified by indirect immunohistochemical staining procedures and use of carefully selected cytokine-specific mab's. frozen sections were fixed with % paraformaldehyde and permeabilized by . % saponin treatment, eluting cholesterol from the membranes. the intracellular presence of all cytokines except ill, illra (late) and tfg[ _ , could be demonstrated by a characteristic perinuclear configuration in producer cells. in addition, the immunoreactivity extended over a large extracellular area encompassing the producer cell. a localization of the cytokine to the golgi-organelle was established by use of two culour staining including a haman golgi complex specific mab. this staining pattern was only evident in producer cells because injection of recombinant human cytgkines into the tissue caused a membraneous and extracellular staining pattern. both the extra-and the intracellular types of staining reaction could, however, be blocked by preincubating the cytokine specific mab with pure human interleukins. oxygen radicals (or) directly induce lipid peroxidation, indirectly they trigger adhesion and activation of pmn leukocytes. we investigated whether or also lead to a release of acute-phase response cytokins such as tnf-alpha, il-i beta or il- in whole blood cultures to maintain the induced inflammatory reaction. methods: blood samples from healthy volunteers (n= ) were incubated at °c. or were produced by the xanthine oxidase (xo)/ hypoxanthine (hx) system. after , , , , and minutes plasma levels of tnf-alpha, il-i beta and il- were determined with elisa kits. results: under the influence of or tnf-alpha plasma levels increased from , pg/ml at min to pg/ml, pg/ml, pg/ml after , and min. il-ibeta ( , pg/ml, , pg/ml, , pg/ml, pg/ml and pg/ml after , , , and min) and il- ( , pg/ml, l,lpg/ml, , pg/ml, pg/ml and , pg/ml after , , , and min) plasma levels were increased min later than tnf-alpha. summary: these data suggest that or do not only play an important role in initial accumulation and activation of pmn leukocytes but also lead to a stimulation of monocytes to produce the acute phase reaction cytokins tnf-alpha, il-i beta and il- to maintain and strengthen the inflammatory reaction. department of general surgery, steinhsvelstr. , ulm, germany jan k. horn md, greg a. hamon md, robert h. mulloy md, greg chen bs, rebecca chow bs, and christof birkenmaier md. transforming growth factor-i~l (tgf- ) is released from inflammatory ceils following injury and in sepsis. in vitro experiments have confirmed that low concentrations of tgf- ( . - . ng/ml) are chemoattractive for monocytes, whereas higher levels of tgf- (> . ng/ml) potentiate production of the immunedepressive prostaglandin e . other investigators have shown that tgf-] can cause the appearance of cd (fc immunoglobulin receptor) on monocytes exposed to ng/ml of tgf-[~i for hours. monocytes also express on their surface a glycoprotein that binds complexes of lipopolysaceharide (lps) and lpsbinding protein (lbp). such binding is associated with generation of proinflammatory cytokines such as tumor necrosis factor alpha. we have shown that cd is depressed in septic patients and therefore we hypothesized that tgf- could account for the down-regulation of cd observed in these individuals. we incubated normal human monocytes with platelet-derived tgf-[ for and hours at °c and examined ceils for cd and cd expression using flow cytometry after immunnfluoreseent staining with appropriate monoclonal antibodies. monocytes were selected on the by usual criteria for size and granularity. non-viable ceils were excluded with the use of propidium iodide. two populations of monocytes could be found afcer incubation at °c alone. one displaying high density of cd had increased fluorescence over the homogeneous expression of cd in cells maintained at °c (baseline). the other population displayed decreased cd expression relative to the baseline cells. tgf-i~i ( - ng/ml) caused a shift of ceils from the high density into the low density cd population. this trend was observed within hours of incubation and was complete by hours. we observed a net decrease in cd expression f % for all subjects studied (p< . vs controls). phorbol myristate acetate ( ng/ml) also caused down-regulation of cd to a similar degree as tfg-i~i. we also confirmed that monocytes could be induced to express cd after incubation with tgf- ( ng/ml) for hours. these studies demonstrate that monocytes incubated with immunodepressive levels of regulation of cd by tgf- deplete their surface expression of cd while generating cd . this down-regulation of cd by tgf- correlates with our clinical observations of lower cd expression on monocytes obtained from septic patients. for over years, activated t lymphocytes have been considered to be the cellular source of mif. we recently isolated and cloned the murine homolog of mif after identifying the specific secretion of this protein by lpsstimulated pituitary cells in vitro and in vivo. however, further experiments showed that mif protein is detectable both in t-cell deficient (nude) and hypophyseetomized mice, suggesting that yet additional cell types may produce mif in vivo. since monocytes/macrophages are a major source of the cytokines that appear in response to lps administration, we examined the possibility that mif also is expressed in cells of the monocyte/macrophage lineage. we found that mif is expressed constitutively in the murine macrophage-line raw . and in thioglycollate-elicited peritoneal macrophages. significant amounts of mif mrna (rt-pcr) and protein (western blotting) were observed in cell lysates. in raw . cells, mif secretion was induced by as little as pg/ml of lps (e.coli l:b ), peaked at ng/ml, but was not detectable at lps concentrations > txg/ml. similar data were obtained with elicited macrophages, but higher lps concentrations were required, unless the cells had been preincubated with ifn . production of mif by lps-stimulated (l ng/ml) macrophages peaked at hr. expression ofmif mrna and tnf mrna by lps-stimulated raw . macrophages was investigated by rt-pcr. as expected tnf mrna expression increased over the range of lps concentrations ( pg/ml to p_g/ml). in contrast, levels of mif mrna correlated inversely with lps concentration. by competitive pcr, mif mrna was observed to increase approximately -fold after lps induction ( pg/ml). mif secretion also was induced by tnfoc ( ng/ml) and ifn? ( iu/ml), but not by il- and il- (up to ng/ml). lps and ifn had additive effects in inducing mif secretion. in separate experiments, macrophages stimulated with recombinant mouse mif ( gg/ml) were found to secrete bioactive tnf~ (> pg/ml by l cytotoxicity). we conclude that the macrophage is an important albeit overlooked cellular source of mif in vivo. mif secretion is induced by lps, tnfc~ and ifn?. mif also stimulates macrophages to secrete tnf. taken together with previous observations that anti-mif antibody protects against lethal endotoxemia, these data implicate mif as a critical mediator of inflammation and septic shock. inflammation is characterized by an exacerbation of proinflammatory cytokine production. cytokines such as il- , il- , and tgf , have been identified as anti-inflammatory mediators thanks to their ability to down regulate the production of il- , il- , il- , tnfc~ by activated monocytes / macrophages. however, other cells, including polymorphonuclear cells (pmn) do contribute to the release of pro-inflammatory cytokines. we investigated the capacity of the so-called anti-inflammatory cytokines to control the release of il- by activated neutrophils. human pmn were purified following glucose-dextran sedimentation and ficoli-hypaque centrifugation. the cells were cultured at °c for h in the absence or presence of lipopolysaccharide (lps) or tnfa. il- release was measured in the supernatants using a specific elisa. among tested cytokines, il- was the most efficient inhibitor of il- production by lps-activated pmn. il- was also active, whereas no down regulation was noticed with tgfp~i. when tnfa was used as a triggering agent, none of the cytokine could prevent il- production. northern analysis are under investigation to precise the level of the il- -and il- -induced inhibition of il- production by pmn. our data illustrate that il- and il- possess the capacity to down regulate the production of il- by both monocytes and pmn, whereas tgfb has a more limited inhibitory activity. ciliary neurotrophic factor (cntf), a member of the il- superfamily, has recently been shown to promote axonal growth and neuronal healing. cntf production is also increased during neuronal and muscle damage, associated with soft tissue injury or trauma. we postulated that production of cntf may explain the loss of skeletal muscm protein that occurs in inflammation. female, wistar ( - gm) rats received either or pg/kg bw s.c. injections of recombinant rat cntf for seven days, or received sham injections and were freely-fed. additional animals were pretreated with mg/kg ibuprofen lp prior to pg/kg bw cntf. rats treated with ,ug/kg bw cntf lost . _+ . gms bw as compared to freely-fed controls which gained . _+ . gms (p<o. by anova and lsd), and ibuprofen treatment had no effect on cntf-induced weight loss (- . _+ . ). animals pair fed to the high dose cntf gained body weight ( . -+ . ), although weight gain was less than seen in freely-fed controls. rats treated with pg/kg bw had reduced body weight gain (+ . +_ . gin). food intake was also reduced by % in pg/kg cntf (from . +_ . gm/day to . _+ . gm/day; p<o. ) and was also unaffected by prior ibuprofen treatment ( . +- . gm/day). despite the loss in body weight noted in the high dose cntf animals, there was no appreciable hepatic acute phase response, since liver weight ( . + , gms vs. . _+ . gins), total protein ( . +- . gms/l vs . +- . gins/l) and albumin ( . + . gms/l vs. . +_ . gms/l) were not different between cntf and freely fed animals. we conclude that cntf causes anorexia, and increases body weight loss in excess of the associated anorexia. unlike the cachexia associated with il- and tnf infusions, which is associated with an acute phase response, cntf acts predominantly on food intake and carcass weight through a prostaglandin-independent mechanism and has only minimal acute phase inducing properties, n. joseph espat, md. university of florida, department of surgery, j-box , gainesville, fl. . of cytokines by neurotrophic factors, the neuroendocrine system and phenotiazines. cytokines, including tnf and il- , have a pathogenetic role in various diseases related to infection and inflammation. the action and/or production of cytokines can be regulated by drugs or endogenous mechanisms that involve the cetral nervous system (cns) we found that the antipsychotic chlorpromazine (cpz) potently inhibits tnf production and protects mice against endotoxic shock. cpz also inhibits brain tnf production in mice intracerebrally injected with endotoxin, whereas cpz analogs that do not cross the blood-brain barrier inhibit only perypheral, not brain, tnf. tnf production and susceptibility to the toxicity of endotoxin, tnf and il- are increased in adrenalectomized mice, indicating that endogenous corticosterone (cs) controls cytokine production and toxicity, in a feedback fashion since endotoxin and cytokines increase serum cs. increased tnf production was also observed in mice where the hypothalamus-pituitary-adrenal axis was blocked by chronic administration of dexamethasone, following a two-day washout. administration of cytokines acting through the gp signal transd,uction protein, including il- and ciliary neurotrophic factor, cntf potentiated il-l-induced elevation of cs. il- and cntf also induced hepatic acute-phase proteins. thus il- and cntf might have antiinflammatory activity, by potentiating the feedback responses of the neuroendocrine axis. these data indicate how complex can be the interregulatory relationships between the brain and the immune system, how they can be used to pharmacomodulate cytokine action and how their disregulation might exacerbate il- -and tnf-mediated pathologies. lipopolysaccharide (lps) constitutes a well established activator of monocytes/ macrophages (mizi) and murine b lymphocytes. the hydrophobic part of lps, termed lipid a, represents the endotoxic principle of lps. we now demonstrate that lps is also capable of inducing proliferation of human t cells at a dose of to pg/ml. the specificity of this stimulation was analysed by the following experiments: i) the synthetic hexaacyl escherichia coiltype lipid a (compound ) also stimulated human t cells; ii) the synthetic tetraacyl lipid a precursor (compound ) or the phosphono-oxyethyl analogue pe- , structures known to antagonize lps-induced monokine production in human mz, also inhibited lpsinduced t-cell proliferation. the t-cell proliferation expressed the following features: i) cd ÷-as welt as cd ÷ t cells proliferate in response to lps, ii) limiting dilution analyses reveal that the frequency of responding cells was between / to / cells; iii) purified t cells alone cannot be stimulated by lps, but need the help of monocytes. this help cannot be replaced by b cells or fixed monocytes. furthermore, for activation a direct cell-to-cell contact between t cells and monocyte is neccessary; iv) t cells stimulated with lps express mrna for il- and ifnf, but not for il- or il- (determined by pcr). in supernatants, ifnf was detectable (elisa); v) lps-activated cd ÷ as well as cd + t cells express cd , the high affinity il- receptor. our results indicate that in contrast to previous reports human t cells respond to lps with il- receptor expression, lymphokine production, and proliferation. the reactive cells appear to belong to the t, cell type, the finding that human t cells can be activated by lps is of important relevance for the understanding of the pathomechanisms of infections by gramnegative bacteria. this may lead to new strategies for the therapy of sepsis. we have recently shown that human eosinophils produce mrna for interleukin (il)- when stimulated with calcium ionophore (eur. j. immunol. ( ), ). we now present evidence that human eosinophils contain preformed il- protein although they do not express mrna for il- as measured by rt-pcr. il- protein expression was determined using specific anti-human il- monoclonal antibodies by western blotting, facs analysis and immunohistochemistry. moreover, preformed il- was re/eased into supernatant by % pure eosinophils after priming with gm-csf or il- and subsequent -min stimulation with paf, rantes, ionomycin or pma, however not with il- or il- , as measured by elisa. this observation implies that activation of protein kinase c and/or intracellular calcium mobilization are necessary events for il- release in human eosinophils. the determined amounts of preformed il- protein was higher in patients with asthma compared to normal individuals suggesting a role for eosinonhi! derived il- in asthma. since the eosinopnit is the ,,r~:=z~mmant cell in the asthmatic airways, we determined il- concentrations in bronchoaiveolar lavage (bal. ~ids from normal !i~.~ijvtduals and asthmatic patients. indeed, il- concentrations in bals from both groups were similar to those seen in the supernatants released by activated eosinophils. the role for il- in asthma remains to be determined. based on a well established rat model named activity-induced ulceration (asu) or activity based anorexia (aba), we have developed a rat model for chronic stress. male rats were exposed to a feeding schedule in order to reduce body weight by - % within days. while one group of rats was kept sedentary, the other had access to a running wheel. food restricted rats allowed to exercise developed highly increased activity as compared to ad libitum fed rats in wheels (ca. versus kin/day). they developed elevated plasma corticosterone levels ( _+ gg/dl) at their circadian peak, increased adrenal weight and decreased thymus and spleen weight as compared to control rats and weight matched sedentary rats, establishing this paradigm as a model of chronic stress. no differences in plasma acth were seen among the various groups, suggesting increased sensitivity of the adrenal glands to acth. the effect of chronic stress accompanied by hypercorticism on baseline and endotoxin-induced cytokine levels was studied in this model. under baseline conditions,splenic il- a was suppressed in both food-restricted groups. this was more pronounced in rats with access to a running wheel. il- and tnf activity in plasma was not affected. after administration of .tg/kg lipopolysaccharide (lps), tnf activity in plasma was suppressed by food restriction but there were no differences between sedentary or exercising rats. in addition, no differences were found among groups for corticosterone, spleen il-lc~ and plasma il- activity. we conclude, that the food restriction-induced hyperactive rat model is a useful model for studies on the effects of chronic stress. in this model, under basal conditions il-le~ in tissues may be subject to downregulation by glucocorticoids, whereas after lps-stimulation of cytokine production only tnf activity is regulated by fast acting feedback loop between cytokines and the hypothalamo-pituitary-adrenal axis (hpa-axis). this is supported by strong correlations between plasma tnf activity and corticosterone in stressed rats. cytokine antagonists modulate cytokine actions and it appears that a balance between production of cytokines and cytokine antagonists is important to control of host responses. recent observations show that during myocardial infarction there is an increase in circulating cytokines such as tumor necrosis factor (tnf) and interleukin (il- ). we tested the idea that compensatory increases in cytokine antagonists likewise occur and investigated changes in plasma concentrations of tnf and interleukin i (il- ) and those of their specific antagonists interleukin- receptor antagonist (il- ra) and soluble tumor necrosis factor receptor type i (s tnf r-i). we also measured plasma concentrations of ~-melanocyte-stimulating hormone (~-msh), an endogenous neuropeptide that occurs in pituitary, brain, skin, gut and other tissues. when administered to laboratory animals, this peptide has potent antiinflammatory and antipyretic activity, perhaps by mimicking an endogenous modulatory influence on cytokine actions. samples were obtained from patients with acute myocardial infarction at presentation in the coronary unit, every three hours for hours, and daily thereafter until discharge. we found elevations in the plasma cytokines il- and tnf only in a proportion of subjects whereas cytokine antagonists c~-msh, il-lra, and stnfr were elevated in all patients, o~-msh was elevated at presentation but it decreased progressively in successive tests, reaching normal values within hr whereas stnfr and l-lra peaked at - hr or later. there were significant correlations between plasma concentrations of cytokine antagonists and enzymes released from injured myocardium, including creatine kinase (ck), aspartate serum transferase (ast), and lactate dehydrogenase (ldh). the data show that cytokine antagonists increase in the circulation of patients with acute myocardial infarction likely to modulate prninflammatory effects of cytokines. objects of the study: interleukin- (il- ) is a multifunctionai cytokine known to be involved in important homeostatic processes. il- levels are increased in many pathological situations, and correlates with disease activity and patient outcome. to exert its effect il- binds to its receptor on the membrane of its target cell. this receptor is also present in a soluble form in plasma and in urine. in this study we quantitatively measured the availability of soluble il- receptor (sll- r) in biological fluids in healthy volunteers. materials and methods: blood, urine, cerebrospinal fluid (csf), and synovial fluid (sf) are obtained from healthy volunteers, sil- r and il- are measured using elisa's. both elisa's are tested for interference of sil- r mid il- . the effect of sll- r in the il- bio-assay (b ) is tested. results: baseline levels are (mean + sd): . -+ . ng/ml in serum, . -+ . ng/ml in urine, . _+ . ng/ml in csf and . + . ng/ml in sf. there is no interference of sll- r in the il- elisa or bio-assay and no interference of l- in the sil- r elisa. conclusions: in all investigated biological fluids sll- r can be found. these data provide baseline values for investigations concerning pathological situations. both elisa's described are useful tools to do these investigations. trauma-associated immune aberrations coincide with augmented release of immunoregulatory and proinflammatory cytokines. the present study examines the effect of thermal trauma on the capacity for specific (receptormediated) response of lymphoid cells to interleukin (il ) and to turnout necrosis factor ~x (tnfc . methods. bum patients (n= , -> % total body surface area) were studied weekly up to days post-injury. the limulus amoebocyte lysate (lal) test was used to measure plasma endotoxin levels. the percentage of il ~-and tnfcz-binding t(cd ) lymphocytes was assessed by flow cytometry analysis. levels of il receptor antagonist (il lra) in patients' plasma and cultures of peripheral blood ceils (pbc) were determined by immunoassay. results. plasma endotoxin concentrations were significantly (p< . ) increased up to weeks post-bum (means . + in non-surviving and . + . u/ml in surviving patients vs < u/ml in the control). within weeks of bum, the percentage oft ceils expressing receptors for tnfa and il [~ constitutively was elevated (by - fold). in contrast, the capacity for de novo receptor expression by activated pbc was reduced. serum levels of il ira were significantly increased (range . - x j pg/ml vs < . x j pg/ml in the control). in all patients, high concentrations of il lm were released spontaneously in unstimulated cultures of adherent ceils (range - x - pg/ml vs - x j pg/ml in the control). however, its secretion was decreased in lps-stimulated parallel preparations. conclusions. in the bum patient, susceptibility to the immunoregulatory effect of tnfcz and tl ~ may be modulated by infection-related products. alterations in the capacity for receptor expression and secretion of l lra may affect il -regulated biological responses including specific immune reactions. while studies suggest that il- is an important lymphokine involved in cell-mediated immunity, little is known about this mediator's role in hem-induced immunesuppression. our aims, therefore, were to determine: i) if il- contributes to depressed t-cell responses seen following hem; and ) how other agents, known to play a role in hem, effect il- release. to study this, c h/hen mice were bled to and maintained at a map of mmhg for h and then adequately resuscitated. mice were killed h post-hem to obtain splenic t-cells (nylon-wool purified). il- 's immunosuppressant role was demonstrated by the ability of monoclenal antibody (mab) to il- to markedly improve the t-cell proliferative response [ . #g the marked increase in capacity of t-cells from hem mice to produce il- was significantly reduced by treatment with either ibu or mabs. since ibu, tgf-~, as well as il- are all reported to directly/indirectly influence prostanoid synthesis, this implies that eicosanoids play a major role in inducing il- release by t-cells following hem which depresses t-cell function. the mechanisms underlying immunosuppression induced by thermal injury and alcohol ingestion are in part due to cytokine dysregulatinn. il- down-regulates production of eytokines by maerophages and may be an important regulator of the initiation of the immune response. il- has also been demonstrated to inhibit the production of no by macrophages. this study examined the alterations in eytokine production and effect of inhibition of no production on immunologic function in a routine thermal injury model. methods: balb/c mice (n= ) were randomized to groups: saline-sham(ns-sham), alcohol-sham(etoh-sham), ns-bum, etoh-bum. animals received % etoh or ns daily for days by gavage. a % full thickness bum was induced hrs after the last dose of etoh or ns. animals were resuscitated, then sacrificed days post bum. splenic lymphocytes were cultured for days with lps, and lps with two concentrations of n-monomethyl-l-arginine, a nitric oxide inhibitor (l-nmma . ug/ml, ug/ml). splenocyte production of il- , interferon-gamma, il- , pge were measured, and lymphocyte proliferative response examined. results: il- production was significantly suppressed in thermal injury. exogenous l-nmma normalized the suppression of .- in a dose-dependent manner, indicating nitric oxide may modulate il- and interferon-gamma production in thermal injury. il- production is normal in etoh-burn animals. conclusion: il- and interferon-gamma production is altered in this murine thermal injury model, and may contribute to this injury-induced immunosuppression. inhibition of no synthesis normalizes il- production and should be investigated further as an immanomodalator in thermal injury. surgery, infection and inflammation results in the production of pro-inflammatory cytokines which mediate metabolic and immunologic host responses. the aim of this study was to characterise the elaboration of cytokine release following a variety of surgical procedures. twenty one patients undergoing elective intermediate, hip, knee and major gastrointestinal surgery were studied. levels of interleukin- (i - ), interleukin- (i - ), the interleukin- receptor antagonist (i - ra) and the acute phase c-reactive protein (crp) were measured in bloods drawn , , , , , , and hours following operation. a portion of the results are shown (mean -+ sem). + -+ _+ one and two factor anova; *p< . , #p< . , §p< . , ¶p< . , for differences between groups i - was not detected at any time point. both ii-ira and i - increased after surgery. maximum responses occurred following major git and hip surgery, minimal responses were seen after intermediate and knee surgery. ii-ira levels increased within two hours and remained elevated for hours; the b-ira increase was a thousand fold greater than the rise in i - levels. i - levels increased up to hours after surgery. crp levels reflected maximum ii-ira and i - levels (r =. , p< . and r =. , p< . respectively). high ii- ra and i - levels reflect major surgery, however the ii-ira response is more rapid and of greater magnitude. the strong i - ra correlation with crp may indicate that this regulatory cytokine is itself a mediator of host responses to surgery. dept. of surgery, meath/adelaide hospitals, heytesbury st., dublin , ireland. change of il- and soluble il- receptor levels after surgery s. hisano, k. sakamoto, s. mita, t. ishiko, m. ogawa [objectives] under surgical stress, il- plays a main role in producing acute phase proteins and contributes to host defense mechanism. soluble il- receptor (sll- r) is considered to be agonistic to il- , unlike other soluble type receptors of cytokines. here we measured il- and sll- r levels in the serum and drain fluid from surgical field in order to investigate the changes of il- and sll- r after surgery and their origins. [materials and methods] serum and drain fluid samples from cases ( of esophagectomy and of gastrectomy ) were serially collected before and after surgery. il- and sll- r levels were measured by elisa. [results] ( ) serum il- : all cases reached the maximum level on pod-l, more precisely - hours after operation. ( ) il- in the drain : maximal il- levels in the drain were recognized - hours after operation, at almost the same time as serum il- . furthermore the il- values in the drain were much higher, about times, than those in serum. ( ) sll- r in the serum : all cases reached minimum levels - hours after operation and recovered to the preoperative levels a few days later (decrease ratio : . + . ~,, range : - ~'). ( ) sll- r in the drain : sll- r levels in the drain showed almost the same value and change as serum sll- r. [conclusions] ( ) il- is produced from the cells gathering around operative fields whereas sll- r is considered to be produced in the cells which do not gather around the operative fields. ( ) there may be a mechanism that down-regulates sll- r in the early stage of surgery. [objectives] il- plays an important role in host defense in the early stage after surgery. in the present study, we examined changes in il- concentration after major thoracoabdominal surgery and elucidated the effect of surgical trauma and factors influencing postoperative elevation of serum il- . [materials and methods] thirty-eight patients undergoing elective surgery of the thoracoabdomen were classified into groups according to the location of the operation. bloods and drain fluids were serially obtained and samples were frozen until measured, keukocytes were simultaneously collected for northern blot analysis. concentration of il- was measured by elisa and il- mrna was detected by northern blotting after total rna was extracted by the acid guanidium phenol chloroform method. [results] ( ) serum il- levels reached the maximum concentration on the st postoperative day in all patients. ( ) the il- peak was significantly correlated with surgical trauma as defined by the operation length and the volume of blood loss during operation (r= . , p< . , r= . , p< . , respectively). ( ) the peak concentration of serum il- in patients undergoing esophagectomy was significantly higher than in those undergoing pancreaticoduodenectomy (p< . ), despite a similar degree of surgical trauma. ( ) peak l- concentration observed in a patient who underwent esophagectomy was about fold greater in the drain fluid of thorax than in the peripheral blood. ( ) il- mrna was demonstrated in leukocytes from thoracic and abdominal exudate at , and hours after surgery. in contrast, il- mrna could not be detected in leukocytes from the peripheral blood. [conclusion] il- is mainly produced in the operative field and subsequently enter the peripheral blood to induce cytokinemia. the operation length, volume of blood loss and thoracotomy are factors influencing the concentration of cytokine in the blood. zaragoza spain age may be an important factor influencing the function of immunocompeteut cells releasing cytokines after both accidental and surgical trauma the aim of the present paper is to ascertain if patients (pts) over years old show a different serum level cytokine pattern than pts under after a standard surgical procedure considered as a "medium strength trauma". patients and methods: pts( females males)with gallstone disease were perspectively studied, pts were allotted in two groups: gr.a: pts under years(mean age: . +- )gr.b: pts over years(mean age: . _+ ). all pts underwent cholecystectomy and cholangiography. pts in gr.a and pts in gr. b underwent common duct exploration. spbintercctomy was performed in each group. on the day of surgery (pre) and on the st and th postoperative day(leo, po) : percentages of cd , cd , cd , cd and cd cells we measured by means of flow cytometry using moab. and levels of il- , il- , il- and tnf "in vivo" by elisa using moab. results: ere: cd % was . _+ in gr.a and . objectives of the study. after surgery for esophageal cancer multiple organ damage has been reported to be caused by polymorphonuclear leukocyte (pmn)-mediated injury. we measured serum granulocyte colony-stimulating factor (g-csf) and interleukin (il- ) levels to determine a role of g-csf and il- in pmn function after surgery for esophageal cancer. materials and methods. peripheral pmn counts, peripheral pmn chemiluminescence, serum g-csf levels, and serum il- levels were measured before and after surgery in patients with esophageal cancer (ec), and patients of gastric cancer (gc). esophagectomy with thoracotomy and laparotomy were performed for patients with ec, while subtotal gastrectomy with laparotomy were performed for patients with gc. results. peripheral pmn counts (p< . ) and peripheral pmn chemiluminescence (p< . ) of patients with ec were significantly decreased compared to those of patients with gc at and hours after surgery. serum g-csf levels of patients with ec were significantly (p< . ) increased compared to those of patients with gc at and hours after surgery. serum il- levels of patients with ec were significantly (p< . ) increased compared to those of patients with gc at , and hours after surgery. significant inverse correlations (p< . l) between peripheral pmn count and serum g-csf and il- levels were seen at hours after surgery. conclusion. these results suggest that many circulating pmns, which are excessively activated by g-csf and il- , may adhere to the endotherial cells and then migrate into the tissues, and cause multiple organ damage after surgery for esophageal cancer. immunnogical changes in patients with severe brain trauma receive increasing attention since morbidity and mortality ere still high. interleukin- (il- ) was previously detected in the cerebrospinal fluid (csf) during different pathologies of the nervous system ( , , ). in our study we monitored il- and nerve growth factor (ngf) production in the csf after human brain trauma. since astrocytes within the brain constitute one of the major cell type contributing to the inflammatory response through the release of cytokines and other factors after injury, we investigated the functional relationship of il- and ngf on a single cell niveau using cultured astrocytes. methods csf was obtained from patients with severe brain injury (glasgow coma score (gcs) < and ct abnormatities or gcs < over hours) after implantation of intraventricular icp monitoring device for therapeutic purpose and collected over hours csf and serum. il- and ngf were assayed by elisa. astrocytes were isolated from neonatal mouse brain as described ( ) . ngf production by cultured astrocytes was measured by elisa in the presence of csf, il- and il- antibody. astrocyte migration was tested in a chemstaxis chamber. results head trauma patients were included in this study (approved by the university hospital medical ethics board) and the csf was obtained through intraventricular catheters. high levels of il- were detected in the csf of these patients when compared to serum during the first days after brain trauma. furthermore ngf could be found inside the intracerebral compartment. csf containing high levels of il- could stimulate ngf production in cultured astrocytes. this effect could be [nhibited partially by il- antibodies, purified il- exposed to cultured astrocytes in vitro, stimulated the migratory activity of these cells in a dose response fashion. il- was found in the csf of brain injured patients, suggesting a role for this cytokine in the pathophysiology of brain injury. since astrocytes are involved in maintaining the homeostasis of the brain, we further investigated the possible role o il- on astrocyte functions, il- promoted ngf production in vivo and in vitro, thus contributing to neuronal cell survival and regeneration. furthermore il- stimulated astrocyte migration in a dose response fashion, potentially contributing to astrocytosis following brain injury and inflammation, these results show that il- represents a key cytokine in traumatic human brain injury with possible systemic effects, which are at preserlt under investigation. we studied a) the role of tnf and b) the therapeutic effect of a mab to tnf with regard to haemorrhagic shock (hs) related ,pathophysiologic alterations and mortality in rats. method: a prolonged hs was induced by bleeding to a blood pressure of - mmhg for pin followed by reinfusion of shed blood (sb) and resuscitation with two times of sb volume of ringer's lactate over rain. animals received a bolus dose ( mg/kg) of tnf mab (celltech, berkshire, uk) at min after resuscitation (tn ). the control group (n = ) was treated similar to the tn group but received ringer's lactate (con). results: at min the prolonged hs resulted in a metabolic acidosis indicated by a significant decrease of blood ph ( . + . ), hco -( . ___ . mm), and base excess (- . + . ram) values with pco ( . + . mmhg) and po ( . + . mmhg) in the tn with no difference to the con group. immediately after resuscitation ( min) plasma endotoxin levels were found to be increased in both groups ( . + . in tn vs . _ . pg/ml in con group) . prior to the treatment with tnf mab ( min) there was also no difference between plasma tnf levels of the two groups ( . + . in tn vs + . pg/ml in con group). treatment with the tnf mab at rain post-hs improved the hour survival rate to . % as compared to . % in the control group. macropathologic evaluations revealed frequency of intestinal bleeding in oniy animals in the tn vs in the con group. no bleeding in the kidneys was found in the tn but in rats in the con group. the significant increase in lung wet weight observed in non-survivors in the con (n = ) was prevented in animals which died in the tn (n = ) group (( . +_ . vs . +_ . g/kg). conclusion: our data suggest that tnf formation induced by hs in rats is an important mediator for pathophysiologic alterations leading to multi organ failure and lethality. antibodies to tnf might be a useful agent in the treatment of haemorrhagic shock related disorders. -+ n=ll*$ -+ n= _+ n= * * p< . vs baseline :~p< . no anesthesia vs anesthesia thus ) tnf production increased - fold by - hrs following trauma in unstimulated blood, but was reduced or not changed after lps stimulation, so circulating leukocytes are probably not an important source of tnf post trauma; ) anticd had no obvious effect on tnf production in unstimulated or lps stimulated blood, relative to vehicle, which suggests that the protective mechanism of anticd does not involve tnf suppression; ) fentanyl anesthesia at hrs following trauma unexpectedly decreased lps-evoked tnf production, which suggests that anesthesia alone can influence an inflammatory response. proinflamrnato~ cytokines have been shown to play a signific~t role in the pathogenesis of sepsis, which is a very common occurrence in born injury. tnfa is infrequently detected in the blood of burned patients, the ability to detect the shed receptors of stnfg has not been determined. serial serum mmples from burn patients were collected from the time of admission until death from septic shock. these samples were analyzed using an enzyme-linked immunosorbent assay (elisa) for stnfr, l-ira, tnf-a, and il-ib. the patients ranged in age from to yeas of age. the percentages of bum ranged from % - %. cytokine concenlrntions vmled from patient to padent irrespective of bum size. tnfa levels were consistentiy in the range of pgjml - pg/ml. peaks in the tnfa values were above pg/ml and were also associated with a peak in the stnfr levels. these levels began at < , pghnl within the in,st ins of injury and gradually increased with time. clinically. ti~ appearance of eytoklnes was independent of positive wound, blood, or respiratory cultures however peak values in tnfa and stnfr were ~ialed with a fluid requirnmenl levels of il-i ra were also elevated independent of clinical findings as well as extent of injury. in pl there is a significant corresponding peak in il-trn (> ~ /ml) at the same time as t/~:a and stnfr levels. we aimed to characterise the pattern of secretion of interleukin- beta l-ii ), intefleukin- (il- ) and tumour necrosis factor alpha (tnfa) in multiply injured patients and to relate these results to their clinical condition and outcome. two hourly blood samples were taken from ten patients from the time of injury until hours. cytokine levels were measured using sandwich enzyme-linked immunosorbent assays (elisas). injury severity scores (iss) were calculated and haemorrhage was assessed from the blood transfusion requirement over the hours. patients' ages ranged from to years. iss varied from to and transfusion requirement from to units. five patients died after the study period. ] ,- was raised in / patients (max level , pg/ml) but was unrelated to condition or outcome. / showed a rise in il- b (max level pg/ml) which was negatively correlated to iss (i=- . , p< . ). tnfa was raised in / (max level pg/ml). peak tnfc~ was positively correlated with iss ( = . , p< . ) and haemorrhage (i= . but p< . ). il-ib and tnfa production was mutually exclusive. there was no common cytokine profile for these patients. unlike elective surgery there was no correlation between peak ,- and severity of injury: tissue damage may not be the stimulus for the cytokine response to multiple injury. periods of ischemia or hypoxia produce endothelial damage in peripheral organs. tumor necrosis factor-alpha (tnf) plays a central role for regulation of endothelial physiology during septic events, taking influence on vascular permeability and coagulant activity [ ] . animal experiments demonstrated a synergism between hypoxia and septic shock on letality, leading to the hypothesis that low oxygen tension leads to enhanced sensitivity of target cells for tnf [ ] . radioligand binding studies with ~ odid-tnf on cultured human endothelial cells were performed after incubation in several environmental oxygen tensions (pc ) for hours. data were achieved by nonlinear regression of an idealized saturation curve according to the equation: b = n " k./( + k,); b = totally bound tnf; k,: association constant (concentration for half-maximal binding); n: number of binding sites per cell. p_o o (mm h¢i): _k, (nm}: n (molecules/cell): - . ± . _+ - . ± . + - , ± . -+ - . + . -+ presented are calculated values on the idealized curve + % percentiles. hypoxia induces enhanced binding of tnf to specific receptors on the endothelial cell surface in a time-and dose-dependent manner by a mechanism, which is not dependent on oxygen radicals, as shown by additional protocols with radical-scavenging drugs. with respect to former findings about a correlation between growth and tnf receptor affinity [ ] , these data lead to the hypothesis that enhanced tnf binding during hypoxia is due to a biochemical conversion of the receptor protein from the low affinity to the high affinity state, possibly by posttranslational phosphorylation of the binding protein by intracel)ular kinases. the proposed involvement of tnf-dependent pathways in pathogenesis of organ dysfunction and multiple organ failure after hypoxia/ischemia may provide a basis for understanding the initiation of hypoxic vascular injury, as manifested by increased permeability and prothrombotic tendency, and, thus, merits further attention. the levels of activity of circulating cytokines (ill, il- and tnf-alpha) which are believed to play important regulatory role in response to trauma are determined (by hioassays and respective anti-cytokine antibodies) in mice and rats subjected to scald injury ion c, see, ° v bsa, ld ) and ( c, see, ~ b ~^)~ , respectively. biphasic increase of cytokine activity was noted in mice: initial increase of il-i and il- , - hr following injury and of try activity hr after scald, followed by elevated levels of il-i and il- at hr, with tendency of decrease of activity at later time points. increased activity of tnf was noted hr following injury, in rats, initial, short-lived increase of il-i and tnf activity was detected lhr following injury, folowed by increase on days i and postburn. il- increase peaked - hr after scalding and levels remained elevated - days following injury. similar kinetics of appearance of proinflammatory cytokines (il-i and tnf-alpha) both in lethal and ncnlethal injury concomitant with differential profile of circulating il- activity (early,short-lived increase and later slow decrease of activity in lethal burn injury) with late persistent high levels of activity in nonlethai injury demonstrated in the present study highlight the need for investigation the relationship of these cytokines in burn-injury induced inflammation. zikica jovicic,lnstitute for medical research, mma,crnotravska , belgrade~yu. asadullah k ( ), woiciechowsky c ( ), liebenthai c ( ), doecke wd ( ), volk hd ( ), vogel s ( ), v. baehr r ( ); depts. of med. immunology ( ) and neurosurgery ( ) , medical school (char#d), humboldt university berlin, frg in patients after polytrauma or major abdominal surgery a hyperinflammatory phase seems to be followed by the development of a phase of monocyte inactivation. the latter is charaeterised by a decrease of monocytic hla-dr expression and a shift to anti-inflammatory cytokine production. as shown, by us and others, this phenomenon indicates severe immunodepression with a high risk of infection. however, the mechanisms leading to monocyte inactivation in the above mentioned syndromes may be multiple. to elucidate the influence of a selective, sterile trauma to the central nervous system (cns) on immune reactivity the neurosurgieal patient is an interesting model. initially, patients who developed a systemic inflammatory response syndrome following neurosurgery were analysed. in all of them a marked decrease of monocytic hla-dr expression was observed soon after the operation. these results suggest that neurosurgery alone can induce immunodepression and lead us to conduct a prospective study, in which we closely monitored l patients undergoing neurosurgery from the first preoperative day until at least day after the operation. hla-dr expression was decreased hi all patients to various extent only hours after surgery. in one patient only we found a persistently reduced hla-dr expression and this was the only patient to develop sepsis syndrome. this suggests that a prolonged, postoperatively decreased hla-dr expression is predictive of infection following cns trauma. in order to assess, whether a decrease of hla-dr expression was associated with a preceding inflammatory response, local cytokine release in the cns was compared with systemic cytokine release. for this purpose, paired samples of earebrospinal fluid (csf) from a vantricle drainage and peripheral blood plasma were obtained. in the csf extremely elevated futerleakin (il)- levels, peaking already a few hours after the operation were found. in plasma, by eontrast, il- ( and tnf-alpha) was detectable not until days later and only if infection was present. the antiinflammatory ili-ra, on the other hand, was also present in csf but peaked after il- and was detectable in peripheral plasma too. we believe there is an association between the inflammatory response in the cns and the following depression of hla-dr expression on peripheral blood monocytes. our results suggest that even a sterile cns-trauma by itself may contribute to general immunodepressinn leading to septic complications. the aim of this study was to evaluate the effect of haemorrhagic shock (hs) a) on total capacity of the host, and b) the circulating blood cells to produce tnf immediately after bleeding. in vivo studies: baboons were subjected to a limited oxygen deficit ( - ml/kg) hypotension phase (mean arterial pressure = map of - mmhg for - hours followed by adequate resuscitation). rats subjected to hs (map of - mmhg for rain followed by reinfusion of shed blood and fluid resuscitation) were challenged with endotoxin ( ~g/kg i.v.) at the end of shock (rhs group). the control group (rco) received the same dose of endotoxin as rhs group but without prior bleeding. in vitro studies: whole blood (wb) obtained from both baboons and rats before and at the end of hs were incubated with endotoxin ( ng/ml) for hrs at °c. results: at min post-lps challenge we found significantly higher plasma tnf levels in rats that were subjected to hs prior to the endotoxin challenge as compared to the control group ( _+ vs + pg/ml) . after hs the tpc was significantly decreased in in vitro stimulated cbc of both rats ( + post-hs vs + ng tnf/ml pre-hs) and baboons ( ± post-hs vs ± pg tnf/ml pre-hs). in contrast, the il- productive capacity was increased in baboons cbc (not yet analysed in rats) stimulated at the end of hs ( ± pre-vs ±_ pg il- /ml post-hs). conclusion: from our data we suggest that despite of down regulation of the cbc to produce tnf the overall tpc is enhanced at the early stage of i-is. with regard to the related literature (chaudry's group) it can be assumed that among the macrophage/monocyte populations, as the main source only the kupffer cells (kc) exhibit enhanced tnf production capacity following haemorrhage. the mechanisms of down/up regulation of cytokine response of cbc and/or kc following hs remain to be examined. d. eg~er, s. geuenich °, c. dertzlin~er °, e. schmitt*, r. mailhammer, h ehrenreich #, p. drrmer, and l. h mer gsf-instimt fox experimentelle h~znatologie, °medizinische kliulk iii, klinikum groghadern, munich, *institut for immunologic, johannes gutenberg universit/it, malnz, and #psychiatrische k/in& der georg-aagust-universi~t, grttingen, germany. it has been shown previously (ehranreich et al., , new biol. : ) that mouse bone marrow-derived mast cells (bmmc) synthesize and secrete endothelin- (et-i) and express eta-type endothelin receptors (eta). so far, however, no functions of et- /et a in bmmc have been described. in the present study we investigated the effect of exogeneously administered et- on the release of histamine, serotonin, and leukotriene c (ltc ) by primary mouse bmmc (in vitro age: weeks) caltured with different recombinant mttrine cytokines (interleukin (il- ) and/or kit ligand (kl) in the presence or absence of il ) for two weeks prior to activation. et- ( x - to lxl - m) induced an extremely rapid (_<lmin) and dose-dependent release of histamine and serotonin (up to % and % of total mediator content, respectively, comparable to ige/ag-indueed mediator release) from bmmc cultured with il- and il- . only when cultured in the additional presence of il- rather than in medium containing kl or kl plus il- alone, bmmc released histamine and serotoaln upon challenge with et- .furthermore, et- stimulated ltc biosynthesis up to -fold in bmmc cultured in the presence of il- . in contrast, the peptide was without major effect on ltc biosynthesis in bmmc culturd without il- . the release of histamine and sereotonin was not altered if bmmc were preincubated for i h with il- prior to activation with et-i, suggesting that a differentiation process rather than a functional priming effect had been initiated by ]l- . et- ( " m) -induced histamine and serotouln release from bmmc was inhibited by an eta-specific antagonist (cyclic id-asp-pro-d-val-leu-d-tel ) in a dose-dependent manner, with a complete inhibition observed at an antagonist concentration of - m. crude peritoneal cells (containing - % serosal mast cells) obtained from normal balb/c-mice released % histamine upon challenge with et- ( - m; rain). taken together, these resu/ts demonstrate that et- can directly function as a histamine and serotohin secretagogue and as a stimulator of ltc production in mast cells. il- appears to be involved in the differentiation of immature mast cell prec~trsors towards an et-l-reactive functional phenotype. when inflammatory reactions are advanced, type ii phospholipase a (type ii pla ) is produced in high levels by various cells at the site of inflammation. cytokines such as tnf-a and il-i activate type ii pla and promote the production of eicosanoid, which is one of the mechanisms by which they enhance the inflammatory reaction. in the present study, the blood levels of type ii pea , endotoxin, tnf-c~, il- and il- were determined in patients with sepsis to examine the relationship between these levels and the patients' pathological conditions. the levels of type ii pla and tnf-a in these patients were . ± . ng/ml and . ± . pg/ml, respectively, the two parameters being significantly correlated (r = . , p = . ). there were also a significant correlation between the level of type ii pla an il- (r = . , p = . ). there was no significant correlation between the level of type ii pla and il- . these in vivo findings suggest that tnf-a may be involved in the production of type ii pla . a. filzmaver, g. reisbach, e. schmitt °, r. mailhammer, and l. hiittner. gsf-iustitut ff~r experimentelle h~imatologie, munich, and °iustitut fttr immunelone , johannes gutenberg universit~t, mainz, germany the product of c-kit, a transmembrane tyrosin ldnase receptor, and a corresponding kit ligand (kl) are critically involved in the control of different hemopoietic cell lineages including the proliferation, maturation, migration, and function of mast cells. it has been reported previously that interleukin (il)- down-regulates kit receptors in human primary myeloid leukemic cells and in a human mast celt line (sinaber et al. , j. immunol. : ) . transforming growth factor (tgf) gl, was also found to down-modulate c-kit mrna and kit receptor proteins in human aml blasts, a mechanism probabely contributing to the anti-proliferative effect of tgfih on kl-stimulated aml ceils in vitro (de vos et at. , cancer res. : ) . in porcine endothelial cells transfected with a retroviral construct carrying the human (hu) e-kit gena, exogenous hu kl transiently down-regulated kit receptors (blume-jeusen et al. , embo j : ) . in the light of these previous findings we analyzed the effects of these exogenously applied cytokines (il- , tgfgl, kl) on kit receptor expression and kl-mediated proliferation and chemotactic migration of primary mouse bone marrow-derived mast cells (bmmc) (in vitro age: weeks). our results show that in bmmc cultures initiated with recombinant (r) marine (mu) il- the additional presence of rmull- for or days did not change the expression of kit protein (assessed by facs analysis with the anti-mouse c-kit antibody ack- ) nor kl-mediated proliferation or chemotaxis. in contrast, il- syeergistically increased kl-stimulated growth of bmmc in a short-term proliferation assay (mtt-tes . pre-incubation of bmmc with rhutgfl~ ( . , . , or . ng/ml) for h had no effect on kit receptor expression, although tgffil at concentrations of . - . ng/ml completely suppressed the proliferative action of kl on these ceils. similar anti-proliferative effects of tgfg were observed in various factor-dependent mast cell lines stimulated with different mast cell growth factors (il- , i,- , il- , and/or il- ). moreover, pre-incuhation ( h) of bmmc with tgf-gl (> pg/ml) significantly enhanced spontaneous undirected cell movement (chemokinesis) and synergistically increased il- -or kl-induced chemetaxis. when bmmc were preancuhated with rmukl ( ng/ml) for , . or days, a transient down-modulation of kit receptors with a maximum effect on day was demonstrated by facs analysis and correlated well with a decreased chemotactic response of these cells. in conclusion our results show that neither il- nor tgfi affect expression of kit receptors in primary murine bmmc. it is reasonable to suggest that c-kit expression is controlled in a cell type-specific manner.interestingly, tgfgl is obviously able to dissect the proliferative from the migrational signal transducted by kl in these cells. objectives of the study: antisense strategies using dna-otigonucleofides (odn) to modulate the cytokine response are presently under investigation. odn are thought to act very specifically with little or no relevant negative side effects. we now report that odn unspeeifically protect wehi cells from tnf-mediated cytolysis. material and methods: wehi subclone ceils ( x ), that are highly sensitive to the cytolytic activity of tnf, were grown on -well culture plates in rpm medium. after hours, phosphorothioate(ps)and partially ps-modified-odn as well as phesphodiester-odn ( - bp) were added ( . , and pm). four hours after incubation with odn, ce(i lysis was induced by recombinant murina tnf. after hours the plates were washed and stained with crystal violet cell lysis was determined by reading the absorbance (abs) at nm. results: wehi ceils incubated with tnf ( - ng/ml) were completely lysed after hours ( % abs). interestingly, wehi cells incubated with tnf and odn resisted complete lysis, eg cells incubated with . ng/ml tnf and jm odn showed still % of the absorbance observed in control ceils without tnf ( % abs). the protective effect of odn started at . pm, reached a maximum at ,um, and diminished at jm. with increasing amounts of tnf the protective effect of qdn decreased and no protection was detectable at ng tnf per ml conclusions: dna-oligonucleotides were found to unspecifically inhibit tnf-induced cytolysis. we hypothesize, that this protective effect of qdn results from an inhibition of the binding of tnf to its receptor, or from interference of odn with the subsequent signal transduction mechanisms. as a consequence, to discriminate the specific effect of odn in biologic systems, several control odn should be used. secondly, whether dna released by degradation of tumor cells or leukocytes can significantly impair tumor-and immune-defense mechanisms merits further investigation dr. med. michael meisner, institut for anaesthesiologie der universitat erlangen-nqmberg, krankenhausstral~e , d- erlangen. in this study we investigated the involvement of serine protease and free radical generation in the systemic release of tumor necrosis factor-alpha (tnf) and interieukin i(il- ), in the sepsis model of lipopolysaccharide (lps, mg/kg i.p.) induced hepatitis in galactosamine (gain, rag/mouse, i.p.) sensitized mice. treatment of gain-sensitized mice with lps (gain/lps) led to dramatic increase in serum cytokine (tnf and il-i) ievels and transaminase activity at hr and hr respectively. pretreatment of serine protease inhibitor, c~jantitrypsin (a j-at, mg/kg i.p.), rains prior to gain/lps treatment, fully protected the animals against the hepatotoxic challenge with significantly reduced serum tnf and il- levels. in order to block and scavenge superoxide generation, the mice were pretreated with xanthine oxidase inhibitor, allopurinol (al, x mg/kg i.p.) and pyran polymer-conjugated superoxide dismutase (sod, x unit/mouse i.v) r spectively. pretreatment with al and sod ( and hr prior to gain/lps) prevented gain/lps hepatitis and blocked lps induced released of tnf and il- into serum of the mice. the protective agents like cq-at or al/sod did not protect the mice against th~ hpp~totoxi£ ch~llpn-e indllee b'~ th~ recombinant mmlse tnf-o' ( . ~/rno~e j.p.) ~d oi~lps ~ caln-.~dlfa%aed mlce. it-l cett~aged la tnf (x/gain treated mjde was not detectable in animals pretreated with oq-at or al/sod. our study suggests that a serine protease sensitive to cq-antitrypsin is responsible in regulating tnf release, possibly by proteolytic cleavage of a tnf-precursor or membrane bound tnf. in addition our evidence suggest that the balance of extracellular protease/antiprotease activity may be regulated by free radical generation, possible superoxide anion, resulting in inactivation of the antiprotease. il- release may be subsequent to tnf release. objective: during sepsis one can observe a dramatically impaired production of proinflammatory cytokines like the tumor necrosis factor alpha (tnf-a), interleukin i-alpha (il-la), intedeukin i-beta (il-i&) and interferon gamma (if~) upon in vitro stimulation of circulating cells. however there is also evidence of a decreased ability to produce cytokines in other immuno-deficient states. in this study we compared the capacity to secrete proinflammatory cytokines upon in vitro stimulation of patients in severe sepsis and patients with malignant tumors. methods: heparinized blood samples of ten patients ( + years) in severe sepsis (sepsis score > according to e}ebute and stoner) were drawn at onset of disease, from fifteen patients with solid growing carcinoma ( + years) blood was drawn at diagnosis prior to any therapy. controls were obtained from fifteen healthy volunteers. pl of whole blood were incubated either with / of a standard medium or with pl of a standard medium and pl of phytohemagglutinin (pha) a potent mitogen. after an incubation period of hours plasma concentrations of tnf-a, il-la, il- and if-~ were determined by elisa. comments: our results suggest that down-regulation of cytokine secretion or of cell responsiveness to non-specific mitogens during sepsis has occurred. we observe a similar phenomenon for the group of carcinoma patients vs control significant for stimulated tnf-a and stimulated if-t. sustained immunological interactions between tumorcells and cytokine producing cells could effect responsiveness of the latter, a general increased immuno-tolerant state in patients with carcinoma has to be discussed. however we found significant differences between sepsis and cancer concerning the in vitro capacity of responsable cells to produce il-la and il-i#. the dramatically decrease of the ability to produce il-i upon in vitro stimulation could be more sensitive for a septic state than stimulated tnf-a or if- ,. objective: tumor necrosis factor alpha (tnf-a) has been implicated as a central mediator of sepsis and its sequelae. increased systemic levels of this cytoklne seem to be correlated with severity of sepsis and outcome. however mechanism of action and metabolism of tnf-g are not fully understood. in most studies blood samples for tnf-a determinations are obtained either by peripheral venipuncture, a central venous catheter or by an indwelling arterial catheter. very often blood samples are taken in different manners within the same study. in this study we measured circulating tnf-a and the amount of tnf-a released upon in vitro stimulation in arterial and central venous blood. methods: heparlnized arterial and central venous blood samples of ten patients ( males, females, mean age +_ ) with severe sepsis (sepsis score > , elebute and stoner} were drawn on day , , , , and of disease. blood was immediately placed on ice and processed within hour. pl of whole blood were incubated with pl rpmi-medium supplemented with antibiotics and l-glutamlne or with pl of rpmi-medium and pl phytohemagglutinin (pha) a potent mitogen. after an incubation period of hours samples were centrifuged and plasma was harvested and stored at - ° celsius before assessment of tnf-a concentration by elisa. statistical analysis was performed with the paired student-t-test. results: we found a significant difference (p < , ) for circulating mean arterial tnf-a concentration ( pg/ml _+ sem} and central venous tnf-a ( pg/ml +_ sem). upon in vitro stimulation there was also a significant difference (p < , ) between released arterial tnf-~' { pg/ml _+ sem) and venous tnf-a ( pg/ml +_ semi. conclusions: these results are difficult to interprete but could reflect the influence of pao and sao on tnf a release. it could also be the result of different concentrations of tnf-o release influencing factors like for example endotoxin, interferon-f or prostaglandin. a possible pulmonary and/or a hepatic metabolism of tnf-n and tnf-a producing cells cannot be ruled out. however for better interpretations of tnf-a release in septic states it is necessary to use either arterial or venous blood samples. early inflammatory processes following trauma and/or infections were found to be associated with the secretion of high amounts of proinflammatory cytokines. besides intedeukin-t (il- ), tumor necrosis factor-a (tnf-c and interleukin- (il- ) the multifunctional cytokine intedeukin- (il- ) was described to be a central regulatory element of the primary cellular and humeral defence reaction. the previously described close temporal correlation of pathologically elevated il- -concentrations and the extracellulary release of lysosomal enzymes from activated pelymorphnuclear neutrophils suggests, that il- may be a potential substrate of these preteases. the serine preteases elastase (ec . . . ) and cathepsin g (ec . . . ) derived from the azurophilic granules were assumed to be mainly involved in unspecific proteolysis at sites of inflammation by cleavage of structural as well as soluble proteins at random sites, if the inhibitory potential is decreased. the possible proteolytic activity of elastase and cathepsin g toward the proinflammatory cytokine interleukin- (il- ) was investigated. the addition of purified neutrephil elastase and cathepsin g to recombinant human il- leads to a rapid sequential degradation in vitro. at least two intermediate products could be detected by silver staining and western blotting following protein separation under reducing conditions. the serine protease inhibitor g-anitrypsin was shown to prevent the proteolytical degradation of intedeukin- . furthermore the loss of the biological activity of both, recombinant and natural human il- , was demonstrated by determination of the capacity of protease-treated il- to stimulate hybddoma growth ( td bioassay). these data suggest a possible downregulation of pathologically elevated il- levels by proteolytic activity of extracellulary released enzymes at sites of inflammation. the aim of the study was to compare circulating levels of three cytokines -il- , il- , _- -between critically ill subjects who developed gram-negative sepsis and who did not. materials and methods: the patient population consisted of patients admitted to an intensive cars unit, with different underlying diseases. sepsis diagnosis was given according to pre-estabilished cdteda. nineteen cases were enrolled in sepsis group, twenty in control group. serum sampling was collected in sterile tubes at study entry and every three days until study dismissal. serum concentrations of il- , _- and il- were measured using commercially available test kits, based on the dual immunometric sandwich principle. results: the causative patogens of sepsis were: pseudomonas aeruginosa, acinetobacter, eseherichia co~i, serratia marceseens, proteus mirobilis and citrobacter freundl the time of observation was equal to days, for a total of four tests performed (to, tl, t , t ). i .- was not detected in any samples. the serological profiles of the two cytokines .- and _- were similar; augmented levels were found at study entry and throughout the observation period, peaking at t and decreasing at t . however, in patients with sepsis, il- and _- concentrations were significantly higher in respect to control group. conclusion: our observations shown that in icu patients increased il- and il- release may be induced by cdtical illness; however, in subjects in which sepsis occurred, il- and il- production appears more significantly elevated, suggesting a role of il- and _- in the pathophysiology of sepsis. the fact that ii. objective: to check whether continuous veno-venous haemofiltration (cvvh) could remove the cytokines, namely tumour necrosis factor alpha (tnfc and interleukin (il- ) from the circulation of critically ill patients with sepsis ad multiple organ failure (mof). setting: the intensive therapy unit of the medical school teaching hospital. patients: nine critically ill patients with sepsis and mof treated with cvvh. methods: blood samples were collected before the cvvh had been started. then, blood and ultrafiltrate samples were collected simultaneously after hours and every hour. tnfct and il- levels were measured using the bioassays with cell lines wehi- ci and td , respectively. other data were recorded from the patient notes and intensive therapy unit charts. results: no measurable concentrations of tnfct were detected in either blood or ultrafiltrate samples. il- was found in all the patients' plasma samples and five patients' ( . %) ultrafiltrate samples. the il- blood level ranged from . to . u/ml (mean . , sd . ). the il- level in positive ultrafiltrate samples ranged from . to . u/ml (mean . , sd . ). conclusions: our preliminary results suggest that il- is present in bloodstream of septic patients. we assume we could not detect tnfa in any sample because we usually started observations when septic state had developed. cvvh could extract cytokines from the circulating blood. it remains under discussion, whether that extraction may be beneficial to patients with mof. the pattern of some significant cytokines tnf, il- and il- and their pharmacomodulation were evaluated in an experimental model of polimicrobial sepsis induced in cd- mice by cecal ligation and puncture (clp) in order to understand their roles. this model of sepsis, which resembles the clinical situation of bowel perforation, was also compared with that induced by administration of pure endotoxin (lps). tnf was detectable in serum and tissues during the first h with a peak h after clp at a significantly lower level than after lps. il- was measurable in serum only after h, significantly increased in spleen and liver after and h and in mesenteric lymphonodes from to h after clp compared with shammice. il- was significantly increased in serum throughout the first h after clp. pretreatment with dexamethasone (dex), ibuprofen (ibu) and nitro-l-arginine (n-arg) significantly reduced the survival time while chlorpromazine (cpz) and tnf did not affect it. only the antibiotics and pentoxifylline (ptx) significantly increased the survival in clp. however cpz and dex protected from lps-mor~ality. in conclusion, by inhibiting tnf with dex, cpz, ptx a reduced, unchanged and increased survival time was observed and by increasing tnf with ibu and tnf administration the survival was decreased or unchanged respectively suggesting that the modulation of this cytokine does not seem to play a significant role in clp unlike lps_ moreover the negative effects of ibu and n-arg suggest an important and protective role by prostaglandins and no in clp. to gain more insigths on the contribution of tnf~, il-i~ and if to lps toxicity, we explored the time-course of the cytokine production in ealb/c mice given different doses, from the lethal (= ld ) to the sublethal (= / ld ) of three different lps (e.coli oiii:b and :b ; p.aeruginosa r ) endowed with different degree of toxicity cytokines were measured in serum and organs with specific elisas up to i h after lps administration. results demonstrate that i) circulating and organ levels of tnf~ do not reflect lps toxicity. in fact, the lethal dose of lps :b induced as much tnf~ as the sublethal dose of lps :b ; furthermore, lps r , whose cytokine inducing capability is far lower than that of lps from e.coli, induced higher tnf~ levels at the sublethal than at the lethal dose. in addition, policlonal anti tnf ab, that were able to protect mice from e.coli lps induced mortality, failed in mice treated with lps r ) circulating il-i~ levels are generally low and increase significantly only in muribond animals. on the contrary, in spleen and lung very high levels of il-i~ are persistent from i to h post lps administration moreover, the treatment with mgr of neutralizing policlonal anti il-i~ ab, did not modify survival in lps challenged mice. ) circulating and organ levels of if are proportional to the dose and degree of toxicity of all the administered lps even if lps r was again a less efficient cytokine inducer than lps from e.coli. csa is an immunos~ppressive drug, able to inhibit gene expression for many cytokines, including if . to study the effect of cytokines modulation on lps toxicity, csa was administered to mice twice at the oral dose of i mg/kg before the challenge with lps. mice were monitored in terms of mortality and tnf~, il-i~ and if production. together with the total ablation of if , the strong reduction of tnfu and unmodified il-i~ levels, a significant increase of lps toxicity was also observed. these results suggest the hypothesis that the numerous factors that jointly mediate lps toxic effects, can also be protective, the final outcome depending on their relative ratio rather than on the absolute amount interleukin- (il- ) mediates the septic shock syndrome and affects intestinal secretion in vitro. we studied the intestinal production of il-t and its effects on diarrhea during endotoxic shock. cd- mice were randomized to mg/kg e.coli :b lps or saline infusion (i.p. or i.v.). diarrhea invariably occurred following lps infusion. mice were sacrificed at , ', lh, . h, h, h, h, and h ( mice/group/time-point). the small bowel was compressed and the intestinal contents were weighed and expressed per g sb weight. the small (sb) and large bowels (lb) were eventually frozen, weighed, and homogenized for either cytosolic protein or total rna. il-i~ (cell-associated agonist) was measured with a radioimmunoassay specific for mouse il-l~ (detection limit pg/ml) and expressed as ng/g weight + sem (lowest detectable amount ng/gwt). northern analysis of total rna and in sfu hybridization of paraformaldehyde-fixed frozen tissue were done with [ ~- p]-iabeled mouse il-lc~ cdna probes. only sb had il-i~ constitutively present ( . + . ng/gwt). lps i.p. or i.v. induced elevation of il-lc¢ in both organs in a biphasic pattern; lps i.v. induced -fold more il-i~ than lps i.p. following lps i.p., il-i~ in sb was . + . ng/gwt at lh, reached maximal levels at . h ( . -+ . ng/gw-i) and returned to baseline at h. saline controls maintained their constitutive il-i~ levels. sb had fold more il- ¢ than lb and identical kinetics, but lb showed a clearer doseresponse. northern analysis of sb-total rna showed induction of il-i~ mrna by lps in correlation with il-lc¢ kinetics. il-i~ mrna producing cells were mononuclear cells in the lamina propda and epithelial cells at the bottom of the crypts of ueberkuhn. mucus and fluid were increased in the small bowel post-lps in correlation with intestinal il-lc~ kinetics (r = . ). separate mice were pretreated with saline i.p. orthe il- receptor antagonist (irap, mg/kg bolus i.p.) and were challenged rain later with . mg/kg lps i.p. or saline i.p. specific blockade of il- by irap decreased intestinal secretion at h and h post-lps challenge (p<_. . , student's-t-test). these data indicate that local (intrinsic) intestinal il-i~ mediates sepsis-induced intestinal changes. inflammatory cytokines initiate the host response to endotoxemia, causing severe physiological and hemodynamic changes which may lead to septic shock. among the regulatory systems that play an important rote in controlling host inflammatory responses is the pituitary. it has been known for many years for example, that hypophysectomized animals are extremely sensitive to lps lethality. while investigating the possibility that protective, pituitary mediators might explain this phenomenon, we identified the cytoldne mif to be a specific secretory product produced by pituitary cells in vitro and in vivo after lps challenge. analysis of serum mif levels in control, t-cell deficient (nude), and hypophysectomized mice revealed that pituitary-derived mif contributes significantly to the rise in serum mif that occurs after lps administration. of note, pituitary mif content ( . % of total pituitary protein) and peak serum mif levels ( - ng/ml) were determined to be within the range observed for other pituitary hormones that are released after pituitary stimulation. to investigate a possible beneficial role for mif in septic shock, we co-injected mice with purified, recombinant murine mif (rmif) together with lps ( mg/kg). surprisingly, rmif markedly potentiated lps lethality compared to control mice that were injected with lps alone ( % vs. %, p = . ). to confirm these results, mice were treated with anti-rmif antibody prior to injection of a high dose of lps ( . mg/kg). anti-rmif antibody fully protected mice against lps lethality, increasing survival from % to % (p = . ). serum levels of tnf,~, the first cytokinc that appears in the circulation after lps challenge, were reduced by . _+ . % in anti-rmif-treated mice. we conclude that pituitary derived mif contributes significantly to circulating mif in the post-acute response in endotoxemia and may act in concert with other pituitary mediators to regulate both pro-and antiinflammatory effects. moreover, mif may play a critical regulatory role in the systemic host response in septic shock. our results suggest that anti-rmif antibody might be of potential therapeutic use in the treatment of septic shock. although anti-interleukin- (il- ) antibodies and il- receptor antagonist have been shown to improve survival in animal models of endotoxemia and abrogate the lethal effects of tnf, the presence of il- in the serum does not correlate well with outcome. we hypothesized that this may be because il- acts mainly in a paracrine fashion and is metabolized before it diffuses into the circulation. methods: we measured the il-i~ mrna expression with the differential reverse transcription polymerase chain reaction (rt-pcr) using g-actin as internal standard in the peritoneal macrophages and lung tissue in normal controls and mice after cecal ligation and puncture (clp). clp resembles human intra-abdominal sepsis in that it is characterized by very slight elevations of serum il- levels. results: il-lg mrna levels after clp are expressed as % of normal (mean+sem, n= in several experimental models of infection exacerbation of disease was observed, when infected animals were depleted of tuajor necrosis factor (tnf). after sublethal cecal ligation and puncture (clp) leading to peritonitis and sepsis the survival of mice also critically depends on tnf as demonstrated in earlier studies, when clp-treated mice injected with anti-tnf antibody died, whereas mice injected with a control antibody survived after clp (echtenacher et al. , j. inununol. : ) . from a panel of different cell types (macrophages, neutrophils, t lymphocytes, natural killer cells, mast cells) able to produce tnf upon activation~ the mast cell is apparantly the only one capable of storing in cytoplasmic granules preformed tnf-ct which is rapidly released following challenge. in the present study-we analyzed serum tnf after lps injections as well as the outcome of clp in severely mast cell deficient mutant mice (wav v) as compared to syngeaeic wild-type littermates (+/+). we proposed that concentrations and/or kinetics of serum tnf should be different between wavv mutants and wild-type mice, if mast cell-derived tnf significantly contributes to the rise in serum tnf levels following systemic stimulation with endotoxin. although similar levels of increased tnf were detected in the sera of both genotypes after and hours of lps injection ( btg/ . ml / mouse i. p.), mast ceil-deficient mice indeed showed decreased serum tnf levels iron after injection amounting to only to % of the concentrations observed in the corresponding sera of normal wildtype mice. in the clp model of septic peritonitis we found that mast celldeficient mutant mice were dramatically more sensitive to clp than syngeneic normal mice resulting in % mortality in w/w v versus % mortality in +/+ mice . days after initiation of clp. further experiments with w/w v mutants selectively reconstituted with cultured bone marrow-derived mast cells from normal syngeneic wild-type mice and the use of an antibody specifically blocking the action of tnf tn vivo should clarify a potential protective function of mast cells in this model of septic peritonitis. interleukin- (il- ) inhibits cytokine production, including tumor necrosis factor (tnf), by lipopolysaccharide (lps)-aetivated maerophages. we recently observed that lps injection (e.coli :b , gg ip) into balb/c mice induces the rapid release of circulating il- ( ± u/ml at min). blocking endogenous il- using monocional antibody (jes - a , mg, h before lps) resulted in a massive increase in tnf production ( ± in lps+anti-il- treated mice vs ± ng/ml in lps alone, p< . , n= to mice per group) and an enhanced lps-induccd lethality ( % vs % in anti-il- +lps or lps alone respectively, p= . , n= mice per group). irrelevant igg rat monoclonal antibody (lo-dnp) did not influence neither tnf production nor lethality associated with endotoxin shock. this led us to study the production of il- during human septicemia. plasma samples were obtained from patients with gramnegative (gns, n= ) or gram-positive septicemia (gps, n= ) and from healthy volunteers. among these patients, suffered from septic shock at the time of sampling. il- levels were measured by elisa (detection limit: i pghrd). we found that patients ( %) had increased il- plasma levels (range to pg/nd). patients with gps had il- levels similar to the ones observed in gns (median: vs . pg/m, respectively). patients with septic shock had higher il- values (median: pg/ml) than septicemic patients without shock ( pg/ml, p= . ). no il- was detected in plasma from healthy volunteers. we conclude that il- is produced daring human septicemia. our experimental data suggest that il- might be involved in the control of the inflammatory response induced by bacterial products. dr arnand marchant, immunology department, hopital erasme, route de lennik, brussels, belgium. to provide information about the role of tnf in sepsis and mods we measured tnf and stnfr-i levels in septic patients and investigated if there is a relation between plasma concentration of these molecules and the severity of sepsis evaluated by two scores (apache i and sss). patients and melhods: septic patients fullfilling sepsis criteria of american college of chest physician and society of critical care medicine were studied. tnf-cc and stnfr-i ( kda) were measured by enzyme immuneassays (norms values = + pg/ml and . _+ a ng/ml respectively). results: the mean tnf and stnfr-i values for each patient (mean+sd) were + pg/ml and . + . ng/ml respectively. these values are approximately seven and ten times greater than those observed in normal healthy volunteers (p< . ). mean tnf concentrations for each patient were significantly greater in non survivors ( + vs _+ pg/ml p< . ); stnfr-i levels also were greater in this group, but the difference was not statistically significant ( . + . vs . _+ . ng/ml). plasma tnf and stnfr-i concentrations were significantly correlated (r = . p< . ). mean tnf levels were significantly correlated with apache ii (r = . p< . ) and sss (r = . p<o. ); stnfr-i levels were likewise correlated with both scores (r = . p< . and r = . p< . respectively). tnf and stnfqgi levels increase with the number of dysfuctional organs; in particular tnf and stnfr-i increase when hemodynamics deteriorate and kidney failure ensues. conclusions: the correlations between tnf and stnfr-i levels and sepsis severity scores suggests that tnf is involved in sepsis and may influence the occurrence of mods and finally clinical outcome. tnf and stnfr-i are in fact especially increased when mods occurs. in particular their concentrations are elevated when cardiovascular system and kidney failure ensue, suggesting that tnf can have a direct role in hemodynamic derangements caused by sepsis and that kidneys are involved in tnf and stnfr-i excretion. lif is a pleiotropic cytokine that has been implicated in the pathogenesis of sepsis in animal models. we conducted a prospective study in septic patients to correlate lif plasma levels with patient's clinical and biological data (among them il- ). plasma was drawn daily from day one to .ten and lif presence was determined with a specific elisa and with the dai,a bioassay (sensitivity of pg/ml and ngml respectively). risk factor associated wftt~ with elevated lif plasma level was determined by an univariate analysis. a multivariate stepwise logistic regression analysis was subsequently performed with a bmdp statistical software. lif was detected with the elisa and with the bioassay in and out of the patients, respectively. lif peak plasma levels were statistically associated with high creatmin levels, temperature and il- . multivariate regression analysis showed that high serum creatinin level was the major independent risk factor associated with elevated lifplasma levels. this correlation was also found for il- . peak plasma levels of both lif and il- correlated inversely with patients survival duration. cox's analysis for plasma levels of lif > pg/ml yelded a hazard ratio of [exp ( . )= . ]. our study indicates that lif levels were associated with clinical and biological parameters of illness severity and significantly increased (cut-off value pg/mi) in patients with fatal outcome. current consensus exists about the central role of tumor necrosis factor (tnf) alpha in initiating the systemic inflammatory response syndrome (sirs). a correlation with sirs has inconsistently been found. tnf effects its pleiotropic reactions upon two distinct cellular receptors. soluble extracel]ular fragments of the human kda tnf receptor (stnfri) and the kda receptor (stnfrii) are detectable in the circulation. the kinetics of these endogenously produced tnf-inhibitors were measured to evaluate their role in patients with sirs. fourteen patients of an operative icu were included with the diagnossis of sirs (mean apache ii score: points). serial blood samples were obtained within h after diagnosis of sirs, every hrs for the first hrs and every hrs thereafter until patients died or recovered. soluble tnfri and stnfrii were assayed by an enzymed-linked immunological binding assay. soluble tnfri and ii could be detected in all samples with a significantly higher level (p<o,o ) compared to healthy controls (normal value: tnfrh , ng/ml; tnfrii: , ng/ml). the serum concentration of tnfri ( , ng/ml) as well as tnfrii ( , ng/ml) were significantly higher in nonsurvivors (n= ) compared to survivors ( , and , ng/ml; n= ) at the onset of sirs and during the course of the inflammation response (p< , ). a positive correlation exists between both receptors (r- , ; p < , ). increasing levels and maximal values of stnfri ( ng/ml) and i ( ng/mi) were detected only in patients who died. the serum concentrations of patients who recovered did not change and are remaining at the initial level. tnf alpha bioactivity was detected in out of patients. no significant correlation exists between the concentration of both receptors and tnf alpha as well as the apache ii score at the onset of sirs. elevated serum concentration of stnfri and are found in patients with sirs. these naturally occuring antagonists reflect the inflammatory process. the measurement of soluble tnf receptor levels may be useful in monitorina sirs and in the prediction of outcome. - is given to patients with advanced melanoma or renal carcinoma. however, this therapy is accompanied by severe side effects, including the vascular leak syndrome (vls) that closely resembles septic shock. to investigate the involvement of cytokines and phospholipase a z in the pathogenesis of the vls we collected serial plasma samples from patients during the first hours after administration of il- . in these patients we monitored temperature, blood pressure and heart rate and assessed levels of the cytokines tnf, il- and il- using immuno assays. in these plasma samples we also measured phospholipase a activity using an enzyme activity assay, since this enzyme is beleived to play a major role in the generation of lipid mediators. we demonstrate that during il- therapy the cytokines tnf, il- , and il- are produced and that the release of these cytokines is followed by an induction of phospholipase az activity in the plasma of these patients, we further discuss the role of these mediators in the development of the vascular leak syndrome observed in patients receiving il- . objectives of the study: sepsis caused by candida albicans (ca) is no longer a clinical rarity but a common consequence of immunosuppression and surgery, and is associated with high mortality. tumor necrosis faetor-c¢ (tnf-<~), interlcukin-lg (il-lg) and interleukin- (il- ) are thought to play an important role in the pathogenesis of the sepsis syndrome. we therefore studied the in vitro production of tnf-<x, il-ib and il- by human peripheral blood mononuclear cells (pbmc) stimulated by ca compared to stimulation by bacterial lipopolysaccharide (lps). materials and methods: pbmc were isolated from venous blood of healthy volunteers and cultured at a concentration of . • ~ eells/ml in culture medium with a dose-range of either heat-killed ca or lps. supernatants were harvested after hours. using elisa, tnf-c~, il-ib and il- concentrations were measured. ca was isolated from a patient with ca sepsis and cultured under sterile conditions. results: ca and lps stimulate the production of tnf-~t, il- ] and il- by human pbmc. we observed a dose-dependent synthesis of these three cytokines in human pbmc. tnf-c¢, il-ib and il- in ng/ml as mean _+ standard error. ca/ml . . ( ) we constructed a single-chain fv-fragment (sc-fv) from the variable domains of a neutralizing antibody to human tumornecrosisfactor-alpha (tnf) because sc-fv should have some advantages in vivo. the sc-fv has a similar affinity ( , x - m) as the fab-fragment ( , x - m) but bind the antigen with a eightfold lower avidity compared to the parental mab ( , x - ). the parental mab as well as its fragments can compete the binding of rhutnf to both tnf-receptors. this was shown by competitive binding to the cell line hl- and to immobilized rtnf-receptors. in the nutralization assay on the cell line, l , the sc-fv can neutralize tnf but in comparison to the mab or its fabfragment, the capacity was three-fold lower as expected from the molar ratio of the dissociation constants. the in rive-neutralizing capacity was tested in a mice receiving toxic dose of rhutnf. the sc-fv showed a -fold lower neutralizing capacity in comparison with the fab-fragment. this could be explained in different manners: i) partial instability of scfv at c, ii) shorter half-life because sc-fv but not fab-fragments are eliminated via kidney, iii) elimination of tnf-immunocomplexes may be improved by opsonization mechanisms which requires some structures of the constant region (as in fab or mab). in summary, despite the encouraging in vitro experiments, the in vivo data suggest that sc-fv are not the right strategy for neutralizing tnf in vivo. tnf production in endotoxin non-responder mice, effect of a glucocorticoid antagonist g. iazgtr jr, e. duda, j. ol~th, e. husztik, g. iazar glucocorticoids inhibit lipopolysaccharide (lps)-induced tnf production and tnf can stimulate pituitary adrenocorticotropin secretion, resulting in the release of corticosterone. earlier studies ( ) reveales that the glucocorticoid antagonist ru , nufepristone, sensitizes both endotoxin responder and nonresponder, c h/hej, mice to endotoxin lethality. we have also shown that the glucocorticoid antagonist ru sensitizes endotoxin-tolerant (endotoxin-pretreated) and normal mice to the lethal effect of septic and endotoxin shock. on this basis, we set out to study the influence of ru on tnf production induced by endotoxin in endotoxin responder and non-responder mice. one and hrs following lps injection, ru significantly increased the tnf concentration in the serum, liver and spleen of treated animals as compared with the control and methylprednisolonetreated groups. in tissue cultures, ru induced the tnf synthesis of myeloid cells and increased the tnf production of genetically modified hela cells, which synthesize tnf constitutively. normal and tumor cell cultures exhibited an increased sensitivity toward tnf in the presence of ru . however, the same dose of lps did not induce tnf production in the serum, liver and spleen of endotoxin non-responder mice and this was not influenced by concomitant ru treatment. these studies suggest that ru aggravates lps lethality via factors other than tnf in endotoxin non-responder, c h/hej mice. the cytokine response to a novel exnacellular mitogenic factor, mf, produced by the group a streptococci (gas), and to the streptococcal pyrogenic exotoxins (spe) a and b, was determined by in vitro stimulation of peripheral blood mononuclear cells (pbmc) obtained from healthy blood donors. the induction and kinetics of different cytokines was studied at single-cell level using cytokine specific monoclonal antibodies and intracellular immunofluorescent staining. all three mitogens induced a massive ifny and tnfi response in - % of the pbmc after - hours of cell stimulation. in contrast, il and tnfc~ containing cells was only detected in - % of the pbmc. the induction ofil , il , il , and ill , was weak or completely absent. thus, the response indicates activation of th cells. however, illc~, illl , illra and il , were consistently found and gradually produced, peaking at hems in approximately - % of the pbmc. mf induced an equally extensive cytokine as well as proliferative inducing capacity, as did spea and speb, which suggests that also mf is a superantigen. a marked inter-individual variation could be noted between lymphocytes isolated from different individuals, both in the toxin induced proliferation and cytokine induction. this may be one explanation for the varying clinical severity noted in patients after infection with clonal gas strains. introduction -tumour necrosis factor (tnf) is released by mononuclear cells in response to inflammation and sepsis. it has been implicated as a possible mediator in inflammatory bowel disease (ibd) but its pathogenic role remains uncertain. this study assessed the relationship between tnfct and disease activity by measuring plasma and faecal tnf concelnmtions in an experimcntai model of ibd. methodologo' -colitis was induced in male wistar rats by intmcolonic instillation of rag , , -trinitrobenzenesulphunic acid in . ml % ethanol (n= ). control animals received an isovohlmetric instillation of normal saline (n= ). faecal pellets were collected before induction of colitis (day ) and throughout the experiment. after days the colon was excised, ueighed and the colon macroscopic score (cms) assessed plasma tnf (ptnf) samples were assayed by bioassay and elisa. faecal samples were vortcxed in water and the supernatant removed for estimation of protein and faecal tnf (itnf) content (elisa). there is a significant increase in itnf on day -#p= alld the total ftnf measured during the study correlatcs with the cms oll day -p= . there is no correlation between ftnf and ptnf. conclusions -therc is evidence of coloific tnf excretion by macroscopically normal animals and following induction of colitis there is increased faecal tnf which correlates with disease actmty. there is no significant elevation in bioactive or imnmnoreactive plasma tnf in colitie animals this data would suggest that faecal tnf is a marker of colonic inflamrnatiort and serial tnf assessment inay be useful as an indicator &severity in ibd. to study the effect of in-vivo hypoxia/reoxygenation on cytokine elaboration by routine peritoneal macrophages. materials and methods: adult male cba mice ( - g) were primed intraperitoneauy with either lipopolysaccharide (lps) ug]anlmal or saline. five days later, the animals were subjected to hypoxia ( % ) for , followed by of normoxia. harvested peritoneal macrophages were plated in-vitro, culture supernatants were collected at , , and and assayed for tumor necrosis factor (tnf), prostaglandin e (pge ) and nitric oxide (no). control animals underwent the same procedures, but were maintained in normoxia ( %o disease , berlin, germany the precise mechanisms of reactivation of latent human cytomegalovirus (cmv) infection are still unknown. apart from the permissive effect of diminished cellular immunity there is evidence of a cytokine mediated cmv reactivation as it is known for other systemic virus infections (e.g. hiv). we found that tumor necrosis factor-alpha (tnf) -in contrast to all other cytokines tested -can stimulate the activity of the cmv-ie-enhancer/promoter region in the human monocytic cell line, hl . we wondered whether our in vitro results were actually reflected by the incidence of cmv reactivation in diseases which go together with high tnfalpha levels. cellular immunodeficiency as well as at least temporarily increased tnf levels are known to occur in septic disease. we tested for the presence of cmv infection in peripheral blood mononuclear cells (pbmnc) by means of h centrifugation culture, immunocytological detection of different cmv antigens (apaap-technique), and pcr technique (cmv-ie dna). in striking contrast to healthy controls almost all examined septic patients were positive, irrespective of the method for cmv-ddtection applied, including the less sensitive immunocytology. follow-up studies showed that cmv-antigen positive pbmnc ceased to be detectable in patients with good outcome once septicaemia had been overcome. to further back up our hypothesis, we looked for a coincidence of enhanced tnf-alpha serum levels and cmv antigenaemia (immunocytology) in some other diseases which are known to have either enhanced tnf serum levels or increased incidence of active cmv infection and found the majority of patients with b-cell chronic lymphocytic leukemia, liver cirrhosis, and common variable immunodeficiency to be positive for these two parameters. we now wondered whether, apart from cmv reactivation, tnf-alpha could also cause cellular immunodeficiency this way promoting cmv replication and spreading and eventually causing cmv disease. in summary, we were able to show that a diminished cellular immune response results from/n vitro or in vivo methylprednisolone (mps) is used to suppress both inflammatory and immune responses. il- receptor antagonist (il-lra) and tnf binding protein (tnfbp) are naturally occuring anti-cytokine proteins, possibly modulating inflammatory and immunological responses. to define mps modulation of cytokine and anticytokine responses, we examined effects of mps on il-lra production and tnfbp generation as well as il-i~ and tnfa production by human peripheral blood mononuclear cells (pbmc) stimulated with lipopolysaccharide (lps). pbmc were purified from the blood of healthy volunteers, then incubated with lps ( ng/ml) supplemented with different concentrations of mps ( , pg/ml, mg/ml). after hrs incubation, the supernatants were collected for rias of secreted cytokines. the cell lysates obtained by cycles of freeze-thaw, were also collected for r ias of cell-associated cytokines. both the supernatant for secreted cytokines and the cell lysates for the cell-associated cytokines were subjected to rias for il-i~, tnfa, il- ra, and tnfbp-i (tnfsrp ). il-la, il- ra, and tnfbp were produced mainly as cell-associated forms in response to lps, whereas most tnfa was secreted into the supernatant of lps-stimulated pbmc. mps supplement resulted in reduction of il-la, il-lra, and tnfa production. il-la production was reduced up to . + . %( mg/ml) by mps in a dose dependent fashion, whereas about % decrease in tnfc, and il-lra production was observed at both high and low dose mps supplement. however, total tnfbp generation was not reduced significantly by mps supplement. furthermore, tnfbp secretion was increased times more in the supernatant of lps-stimulated pbmc with gg/ml of mps. these data suggest that mps could effectively block tnf activity by both reducing its production and up-regulating tnfbp generation and that mps works as an anti-inflammatory drug as well as an immunosuppressant by modulating cytokine and anticytokine responses. in severe gram-negative sepsis, excess of proinflammatory cytokines is associated with increased morbidity and the mortality. we have found that immunocytes possess functional -adrenergic receptors (~-ar) which, when activated, down regulate the lipopolysaccharide (lps) induced gene expression and subsequent secretion of tnf-~ in vitro. in the present study, we used a lethal endotoxic model in mice to test the hypothesis that -ar stimulation will down regulate the gene expression thus decreasing the circulatory levels of proinftammatory cytokines and improve the survivals in severe endotoxicosis. the animals (iso group) were injected times with ! -ar agohist isoproterenol ( . mg/kg i.m. and . mg/kg s.c.) , and hours prior to a lethal dose of lps injection ( mg/kg i.p.). control group (ctl) received same volume of saline at the same times before the lps insult. at the appropriate time points after lps injection animals were sacrificed and venous blood was collected from the inferior vena cava. the plasma levels of tnf-cc and il-loc were determined by elisa. in the mortality study, each grou the data showed that isoproterenol significantly decreased the mortality and the circulatory levels of tnf-c~ and il-lcc (fig. ) . these data suggest that -ar activation of immunocytes down regulates cytokine gene expression, decreasing circulatory eytokine levels thus reducing endotoxicosis mortality. these results provide a new pharmacological approach to reduce the excess of proinflammatory cytokines and mortality in sepsis. introduction: cytokines released from monocytic cells are thought to play an important role in the pathophysiology of sepsis. during the last few years several investigations have been performed aimed at modulating this mediator response. in the present investigation using a full blood model we have studied the effect of a standard immune globulin and an antitipopolysaccharide (lps) immune globulin preparation and a monoclonal anti-lps antibody in modulating the endotoxin induced cytokine response. methods: citrated blood from healthy human donors was incubated at °c in rotating polystyrene tubes. samples were taken before addition of x ng/l e. col± endotoxin and after hours. plasma was assayed for the cytokines minor necrosis factor alpha (tnf-~) and interleukin- (il- ) using elisa methods. the eodotoxin concentration was assayed by lal and end-point chromogenic substrate technique. the blood was preincubated with standard immune globuline (human igg from pooled plasma, gammagardr, baxter) or with an anti-lps immune glubuline (human anti-lps igg obtained by screening of blood donors, novo nordisk) in the concentrations of mg/ml or mg/ml or with the monoclonal lipid a igm antibody ha- a for ten minutes before the endotoxin was added. results: two hours after endotoxin addition markedly elevated tnf-~ and il- values were found.in the plasma. cytokine values at hours: tnf-ec pg/ml (mean) and l- pg/ml (mean). preincubalion with mg/ml standard immune globulins reduced il- values by % (mean) while there were no effects on tnf-c~ values at hours. a slight reduction in il- values was also found with the lower concentration, mg/ml, but this was not statistically significant. preincubation with anti-lps immune globulins had no effect on il- nor on tnf-cc values. preincubation with the monoclottal lipid a igm antibody ha- a in variable concentrations had no effect on cytokine release in this model. in this full blood in vitro model standard immune globuline reduced endotoxin induced l- release while tnf-cc values were unchanged.the anti-lps immune glubuline preparation and the monoclonal lipid a igm antibody ha- a had no effect on the il- or tnf-ct release. the effect of anti-tnf treatment in severe haemorrhagic/traumatic shock was investigated in a conscious rabbit model. the jugular vein (for administration of substances and blood withdrawal) and right femoral artery (for measurement of bp) were cannulated and an aortic thermistor probe inserted into the left; femoral artery for the measurement of cardiac output (co). the following day, upto % of the estimated blood volume was withdrawn over - rain, to reduce bp to - mmttg and co by / mad withheld for rain. shed blood ( %) was then reinfused followed by lactate solution to give a total potential dreulat%ag fluid volume of %. zymoeen activated plasma ( , gg/ml) was given rain prior to haemorrhage and during blood r~n%eion, all ~,~ir, ak were killed at h and o~gane removed for histology. rabbita received either monoclonal antirabbit tnf (r , rat igg , mgkg i.e. n= ) or emine (nffi ), rain prior to haemorrhage. the cardiovascular and biochemical changes during the haemorrhage and hypotensive phase (is. haemorrhagic stimulus) were similar in both groups. upon reinfusion, haematccrit and white cell count remained sigutfia~utly (p< . ) higher in saline compared to r -treated animals, indicating a relative haemoconcentration (i,e. reduced circulating volume) in saline animals. the lettkocytosis persisted in the saline animals upto h. plasma glucose, lactate and asparteto .m~-o transferase all rose similarly in both gorups but plasma ¢rea~!~+-e levels were markedly (p< . ) higher in ealine ve r animals at and h indicative of kidney damage, using a macro and micro. pathological scoring system, major organ damage was seen in the lung, liver and kidney which was significantly (p< . ) attenuated in r treated animals. in the hmg and liver, this was primarily due to a reduced bleeding and pmn infiltrate and to an additional maintenance of tubular integri~:y in the kidney. hence, in tlais model anti-tnf treatment markedly reduced the biochemical and histological indices of severe ,, ~gan damage during liaemorrhage and ranerfn~ion. thermal injuries and systemic bacterial sepsis produce a wasting diathesis with anorexia and marked loss of lean tissue and body fat. endogenously produced cytokines, including interleukin- (il- ), are thought to mediate many beneficial as well as pathologic host changes that occur during burn injury and infection. to evaluate whether bluckade of il- in vivo would affect survival and attenuate the anorexia and cachex[a associated with a thermal injury and chronic fulminant gram negative infection, sprague-dawley rats were studied. anesthetized rats were divided in groups, implanted with alzet r minipumps and randomized to receive the following treatment for days:i: gg/kgbw/min of il-lcc; ii: ~tg/kgbw/min of il- receptor antagonist (il-ira); iii: buffered vehicle. the animals were subjected to a % bsa, full thickness scald burn and the wounds then infected with + cfu/ml pseudomonas aeruginosa. eight additional rats were anesthetized, but were not burned, and served as healthy controls. . il-hx reduced food intake transiently but was otherwise without effect however, il-lra significantly attenuated weight loss over the first days and improved food intake between days and . we conclude that blockade of il- after a thermal injury with superimposed infection does not adversly affect the progression of the disease, but does attenuate the anorexia and weight loss associated with this model. these data indicate that il-i receptor blockade may offer a means to minimize the morbidity associated with catabolic illness. tumor necrosis factor (tnf) and its downstream induced mediators have pivotal roles in the pathogenesis of sepsis and septic shock. the suppressive effect of pentoxyfillin (ptx) on tnf production may be of clinical importance. when peripheral white blood ceils were stimulated with either lps or staphylococcus aureus, pentoxyfillin inhibited tnf production. in contrast, no inhibitory effect was observed on the induction of il- . ptx inhibited not only the tnf production of monocytes but also the tnf secretion of both granulocytes, and unseparated whole blood. the facs analysis revealed that the expression of cd antigen on monocytes was not influenced by pentoxyfillin. the in vitro tnf and il- producing capacity in septic patients were higher than in the control group, but decreased on subsequent days especially in fatal cases. administration of ptx ( mg/day) in septic patients resulted in tnf and il- productions similar to those found in control donors. it also subsequently led to an improvement of the clinical status. a further improvement in apache score could be achieved by administration of pentaglobin ° (biotest)( ml/kg/day ). the prevention of lpsinduced in vitro tnf and il- production by pentaglobin ° could be demonstrated in in vitro experiments involving the use of whole blood rather than purified lymphocytes, very probably because of the presence of lps binding protein in the plasma. the level of soluble icam- in sera of septic patients was significantly higher ( - ng/ml) than in normal individuals ( - ng/ml), but it decreased following the ptx and pentaglobin ° therapy. it is presumed that ptx and pentaglobin ° can antagonize eytokine production at different levels, resulting synergistic action being beneficial in the treatment of sepsis. albert szent-gy rgyi medical university, institute of microbiology, szeged, hungary h- ddm t. . e~i~im~/tii, septic sh ~ '. tnf alfa/pge, and somatostatln lands ji., alvarez j., gram m., llanos k., alcalde j., sanchez ja., balibr~d jl. taurine, a semi-essential sulphur-containing t:~-amian acid, promotes neutrophil phagocytic activit ' against yeasts and enhances intracellular killing of e.coli. paradoxically it protects against hypochlorous acidmediated biomembmne oxidatio~ and abrogates the pyrogenic effects of intracerebral endotoxin. it is therefore possible that taurine mediates some of these effects by modulating the cytokine cascade. aim to assess the cytekine responses in a rat model of intraperitoneal sepsis, pretreated with supplenmntary taurine, by measuring tnf and il- concentrations. methodology female wistar rats (wt - g) (n- per group) were prefed with % tanrine, . % glyciuc ( in tap water) or tap water (tw) for days prior to caecal ligation aud puncture (clp). normothermia was maintained intraoperatively and the animals received . % saline subcutaneously ( mls/ g) post-procedure. animals were venosected by direct cardiac puncture at or hours post-operation and the blood placed in endotoxin-free tubes. centrifilgation and storage of plasma at - °c was completed within hours. tnf and il- were measured using wehi and b bioassays respectively. results (means ± sem) bioactivc tnf concentrations were not significantly different between clp or sham groups. however plasma il- estimation revealed a statistically significant reduction at hours in tanrine-treated animals compared to glycino and tw controls ( objective: to evaluate the effects of allogeneic blood transfusion, thermal injury and bacterial garage on interteukin (il- ), tumor necrosis factor alpha (tnf) production and host mortality and to study if the administration of thymopentth (thy) could affect these events. materials and methods: balb/c mice were transfused with allogeneic blood (from c h/hej mice) and treated daily with thy (i mg/kg)(t+thy) . control animals were transfused but not treated (t). after days systemic blood was harvested to determine the circulating levels of il and tnf. a second group was treated with thy for days and then received a gavage wide lxl escherichia coli and a % burn injury (bg+thy). one hour post-bum, blood was collected to measure cytokins. control animals received the same treatment but thy (bg). a third group was transfused, treated with thy for days and then received gavage and burn (tbg+thy). one hour post-burn, blood was collected to measure cytokins. control animals received the same treatment but thy (tbg). all treated and control groups had mice/group. in separate groups (n= /group), receiving the same treatments, mortality was observed for days post-burn or transfusion. the production and release of oxygen radicals by phagocytic leukomytee is one of the most relevant and important functions of these substances in biology. when neutrophilic granulocytes or certain macrophages phagocytize they produce super oxide and hydrogen peroxide and form secondary products of these activated species. all of these substances are released in to the phagosome. it has been appreciated since that the amount of oxygen consumed by phagocytes in producing free radicals is prodigious. what has not been totally appreciated is the significant contribution this consumption contributes to total body oxygen consumption. our understanding of increased oxygen consumption following sepsis is compounded by a paradox of increased cardiac index and a narrow av difference. it was mclean in a study reported in that showed an increase in cardiac index and a narrowing of the avo z difference in humans following sepsis. other studies documented similar changes in humans and it has recently been speculated that increasing o~ delivery might have a favorable impact on outcome. at least three different explanations have been put forward as to why there are possible alterations in energy metabolism during sepsis. these include decreases in oxygen supply, peripheral shunts and direct action o~ cellular mediators on o~ delivery, a provocative review by hodgkiss and nark in shewed that in experimental animals sepsis did not cause any evidence of bioenergatic failure in muscle i liver, heart or brain tissue. they further showed that the increase in serum lactate is mot necessarily due to cellular hypoxia. they conclude that cellular hypoxia and defects in energy producing metabolites are not the cause of metabolic abnormalities in sepsis. we set out on a series of experiments to try to explain the paradox in cellular metabolism and whether or not white cells might contribute to total body oxygen consumption during sepsis. the first set of experiments involved growing rat cardiac myocytes on tissue culture. pyruvate was added to the medium as substrata and physiologic levels of peroxide were also added simultaneously, carbon labeled co~ production was measured as was nucleotides and degradation products from the cell. the peroxide induced a significant inhibition of pyruvate dehydrogenase. in addition, there was a loss of cellular atp and a corresponding rise in the release of inosine and adenine from the cell. we concluded from this first sst of experiments that physiologic levels of peroxide are a potent inhibitor of pyruvate dehydrogenase in isolated cardiac mitochendria as well as the cultured myocyte. we further showed that pyruvate dehydrogenase inhibition blocks the aerobic oxidation of glucose and leads te adenine nucleotide metabolism with adenosine and inosine release from the cell. other enzymes within the tca cycle did not appear to be specifically blocked by peroxide. this would explain the increase in lactate and the ability of the cell to continue to make high energy phosphate by entry of metabolites in to other entry points of the tca cycle, the second set of experimbnts was designed to estimate the magnitude of whole body reactive oxygen generation via nadph oxidase following granuloeyte activation invivo. using a guinea pig model baseline oxygen consumption was determined. ~iaphenyl iodinium (dpi) was used as a specific inhibitor of granulocyte nadph oxidase. animals were divided into two groups; those that received dpi and those that served as control, all animals were then injected with phorbcl myristate acetate (pma) intravenously. pma is a potent stimulus for granulocyte activation and subsequent reactive oxygen generation. whole body oxygen consumption measurements were then repeated after the p~la injection. in addition, arterial blood gas amalysis was performed, circulating neutrophils were collected and assayed for their ability to generate hydrogen peroxide and the r~ght lung was removed for wet and dry weight measurement. total body oxygen consumption increased by percent after pma injection. arterial oxygen tension fell significantly in the control animal. neutrophil hydrogen peroxide generation rate doubled and lung water in the untreated animals increased by percent. in this animal model we could show that granulocyte activation substantially increases whole body oxygen consumption to approximately percent of control values. the nadph oxidase inhibitor, dpi, decreases granulocyte hydrogen peroxide generation invivo and prevents the pulmonary injury induced by pma. using this animal modal it is possible to transpose this to the human septic state. if we assume there are , neutrophils per cubic millimeter of blood, a kg man would have ~ . xi u circulating neutrophils. when activated ixl ~ neutrophils generate one nanemole of hydrogen peroxide per minute. t~erefore, the circulating neutrophil pool could generate - . xi nanomoles of hydrogen peroxide per minute. this corresponds to an oxygen consumption of - . ml/ojmin by the circulating neutrophil pool alone. this does not take into account the production of oxygen by macrophages or the amount of oxygen consumed to produce nitric oxide. manipulation of oxygen delivery in human sepsis may or may not be beneficial. irshad h. chaudry, ping wang, and alfred ayala life threatening blood loss, due to soft tissue and bony injuries, is a frequent complication in trauma victims. although numerous organs and cells are adversely affected by hemorrhage, the focus here will be to discuss whether or not there are any differential alterations in splenic and hepatic immune functions. in particular, m~ antigen presentation (ap) and associated processes will be described since one of the important functions of the m is to activate resting t-cell lymphocytes by processing and presenting foreign antigens in a mhc class ii-restricted fashion. studies have shown that splenic m and kupffer cell (kc) ap was significantly depressed following hemorrhagic shock and remained so for at least h alter resuscitation. the presentation of antigenic fragments associated with mhc class ii antigen itself was not decreased following hemorrhage, but the catabolism of antigens in antigen-presenting cells was decreased. this is likely due to a significant loss of cellular atp. although m ap was depressed in splenic, as well as kc, only kc showed an enhanced capacity to produce inflammatory cytokines, il- , il- , and tnf. this difference in response between kc and splenic md may be due to differences in the microenvironment in which these cell populations are found, as well as potential differences in the effects that hemorrhage has on the environment from which these cells are obtained. splenic m from hemorrhage-resuscitated mice exhibited a significantly reduced cytotoxic response, whereas kc showed an enhanced cytotuxic capacity. the increased kc cytotoxicity is probably mediated through the increased expression of cell-associated tnf and the release of reactive nitrogen. the enhanced production of reactive nitrogen may play an important role in the clearance of microbes translocated from the gut following hemorrhage. however, excessive release of reactive nitrogen by kc may have deleterious effects on the adjacent hepatncytes. such an effect could, in part, explain the reduction in active hepatocellular function, which is seen following hemorrhage-resuscitation. thus, hemorrhage induces differential effects on splenic and kc m populations; it decreases splenic m but increases kc capacity to mount a cytotoxic response. the depressed splenic md and kc ap was, however, significantly improved by posttreatment of animals with atp-mgcia, chloroquine, diltiazem or interferon-'/. these agents also decreased the susceptibility to sepsis following hemorrhage. thus, the use of atp-mgci~, dfltiazem, chloroquine or interferon- offers new therapeutic modalities in the treatment of immunosuppression and for decreasing the susceptibility to sepsis, which is observed following severe blood loss. the production of macrophages from bone marrow precursor cells is a dynamic and highly regulated process. the differentiation of myeloid lineage-restricted progenitor cells is initially controlled by interleukin- , which drives the progenitors along a maturation pathway that leads to their response to specific lineagerestricted colony-stimulating factors(csfs) we have previously hypothesized that thermal injury can initiate a self perpetuating cycle of production of defective immune cells: thermal injury can initially affect circulating immune cells. then these cells, by unbalanced production of colony stimulating factors and other mediators, can cause a derangement of hematopoiesis resulting in an abnormal production profile of tnf, il-i, and il- and cytotoxic activity of bone marrow derived cells. the results of our studies so far have supported parts of this hypothesis. il- and il- +m-csf treatments increased the production of tnf in burn day macrophages and progenitor cells compared to normal cells. il- +m-csf+il- increased the production of il- by burn progenitor cells compared to normal macrophagee. preliminary results for the ratios of tnf/~ actin mrna indicate that il- +m-csf increased the mrna for tnf in the -day macrophages derived from burned animals compared to macrophages derived from normal animals. ratios of il- /~ actin mrna indicated that il- , il- +m-csf, and m-csf increased the il- ~rna in progenitor cells from burn animals compared to progenitor cells from normal animals. these preliminary results support our hypothesis that bone marrow derived macrophages and progenitor cells from burned animals act differently compared to cells from unburned animals regarding the production of inflanunatory cytokines. more specifically, the results suggest that the different cell types are regulated in different ways by cytokines, and cells from burned animals are regulated differently than cells from unburned animals. it i,~ to ~ssume that the translneatinn is due to a ixx~h,v functioning ~astroiutestlnal surface pro|ection system, which leads to an unacceptably high load ¢ln the imrsunc dcfcncc system, partlcul~ly the local system in the gastrointestinal wall, leading tu exh~ustiou of ihi~ system. tlae g&~lrointesliual i]'ac( can be regal'deal a.s a t~ servojf of appr m ~ separating i~ eucayotic ceils of the hosl ttom l ~ bacterial culls. in the human body the the myriad of cndngan¢nts micrix)rganistns, exogenous itl,~ttdittg micro~ganisms altd taxies m-'e sepia"areal li'otll lhe rest of the body by a simple epithclhd layer. the barrier function is heavily tlcpcnding tm =~ proleclive layer cmtsisting ie. surl~:emts, nluclts, probiotic bacteria, and ,~ub~tances with strong antioxid~lt, antipfotease al~d other i~rotective eft'ecru, the surfaet~ml htycr consists at tile besl if i(.) bimolecular layers, fl is thus very iltil~, the epilhelial layer is renewed every hours , and tile tanuwer of the mucus is ~so fa,~t, all attdphy of die epithelial layei induced by g&sttointestinal st~'vation does also include the mu~usprndocing cells, gnhlet cells, which leaduhg lu slmnage aad luwer quality of gi mucus, altered viscoelas,jc properties and reduced protection, ]~'obioiic bactcrla keeps the ppm's low, produce nutrients for the intestinal mllcosa, eliminates tuxia~ and stimulates the local immune system, the gl surface is conslanlly under hc wv wearing by ingested bacteria and their enzymes, ingested substaucas, chefftie,'ds at~d toxins. 'll~e n~tective flora is reduced in disease, by stress and by cm'clcss antibiotic therapy. wc have made attempts tn recondition the i,,.astroiniesli!l~d. tnucosa by rcstlpply of surfactants or sttrfactanfliko glyc~lipids, gels with pseudomuein [until.oil, and probiotl¢ laetobaeilli. by supply of glycolipids we have bt:cn able m prevent and heal intlammatory and tlleerallve injuries (and io p)'cveut microbe transhteatkln) in uppe~' and lower (. u'acl, this c~al be fu~'ther augmentented by shnultaueos supply el' a p.~uedomucin,likc gel like pectin. ()at contain~ one hundred times more ot membrane lipid$ th~a =nay other food, much of fiber, ~spceially watcrsnlnhlc betaglucaal~, at~d has an close to ideal amino acid cornpo~ition, <')at, termented by species-specific lactobacilli, has a strol~ ability to prevent local inflammatory and ulcerative chunges,transh)cadnn and sepsis in experimeut~d attimals mid to pl~ven~ revert mof in ba,nan.~.lt seems us, that it the mucos~lnucus/probiotic bacterial filnclinns cat'= %' restated by mucosa reconditioning, even in severely sick iudividuals) the hx:~d iuuuuue ~y,~teme will be capable tu pr~)tec! the ix~y ag~lls~ sepsis ~nd mof. the impaired immune response associated with multiple system organ failure (msof) has been most widely studied following surgery for inflammatory disease and trauma. the majority of late deaths following trauma are due to infection and msof. not all patients with multiple organ failure have concomitant infection present, yet most have been septic at some time in their hospital course. their generalized inflammatory condition often persists whether or not organisms have been recovered. immune failure probably precedes msof with or without overt infection and indeed may perpetuate such widespread sepsis. macrophage tumor necrosis factor-alpha (tnf) production is thought to represent an important pathogenic mechanism by which this is mediated. cecal ligation and puncture (clp) is a clinically relevant murine model of intra-abdominal infection and sepsis. serum tnf and endotoxin levels, and peritoneal macrophage tnf production are only slightly elevated in this model even in endotoxin sensitive animals. mortality in this model, therefore, does not appear to be attributed to overwhelming endotoxemia and/or tnf production. it has therefore been postulated that tnf and other cytokines may act in a paracrine fashion to cause local injury. tnf messenger rna (mrna) expression was therefore measured and found to be increased in the lung and liver following clp. a different pattern of expression was seen after endotoxin administration, characterized by a more rapid rise and fall, and enhanced tnf mrna expression in the spleen as well. route of spread of infection as well as the type of stimulus may determine the organ specific cytokine response. these data support the concept of locally produced tnf as a contributing factor in tissue damage and multiple organ failure during sepsis. the estimation of histamine's role in sirs changed over the years based on increased knowledge in shock pathogenesis, evidence later found to be faulty, and the discovery of other, more fashionable mediators. over the decades, the prevailing view has been that histamine is a noxious mediator contributing to the fatal outcome of shock. the analysis of experimental data on exogenously administered, endogenously released and/or newly formed histamine in septic/endotoxic shock suggests that histamine contributes to the early cardiovascular changes via hi-receptor vasoconstriction thus excerbating (directly and indirectly) the effects of catecholamines. in the later phase of septic shock (low out-put, high resistance states), however, it can be assumed that histamine exerts strong vasodilator and positive inotropic effects via h -receptors. these effects are considered beneficial in counteracting or attenuating the effects of sympathetic responses of catecholamines and other mediators. thus, a blockade of the early reaction with hi-antagonists and a stimulation of the h -receptors by h -agonists are worthwhile therapeutic approaches. shock produc~s ~ij alterations, an encrgy crisis and eventual c~ll damage, however, shock in itse|f do~ not lead freqoenfly to r~mote organ damage. in animal ~xpcrhnents and clinical expariez:ces in korea and vietnam, shock i~r s¢ was not associated with lung damage, renal failure or ards. the same is true with g.l bleeding. however, when shock is due to trauma or associated with tlssus injmy, then organ malfunction m~d damage is frequent. shock is bclleved to increase the frequency of infection, but clinical evidcnc~ for this is scant. hemonhsgio shock akme is an unusual o~orrenee dinica[ly. immune dysfolletion dons occur witl~ experhnental hypovolemic shock and in pailcnts with hypotcnsion or after receiving blood ~ansfosions. tbc most significant factor affecting reoorrcnce of resented ca,lorectal liver mclastasis was hypotensivc episodes during operation. blood transfosions depress immune function, improve transplant ~raft survival and increase ttll'rmr rec~r'tcnos ill co[eli and head and nc~k cancers. in experimental hemorrhagic shock, we found decreased response of [ymphocytes to mitogens, el:clad mixed lymphocyte reactilln and i[,- decreased. othe~.x hsvc found decreased macrophage and t and b ¢¢lt function, deci~ased re,ease of/l~i, increased poe v depressed macrophagc antigen presanlatiota, increased ien y, decreased il- , and , and shared mscrophags funclion with loss nr f and c b r~ccpto~s. this is inhibited by chlornqoine, ibuprofen, dihiazem, and atp. shock may activate ncutrophils contributing to ilappitlg in cspillarics, no refluw, increased adhesion, cytotoxicity and organ damage. this may be related to decreased clearance of bacteria after shock. t~lls shock, hypotcnsion and decreased microcirculatory blued flow initiate or set the stage for immune dysfmtction. they, along with tissue injury trigger inflammatory cascades. this also contributes to immunologic dysfonctitm, which is associated with increased lufoction. thus altered bh,od flow and mediator cascades are bolh involved, the question now is can wc rapidly improve microcirculatory blood flow, and dg'masa inflsrmnatory fosponss, which is also necessary for survival the effe~ of ~nterferon ~amma @n wour~ healing was ewaluated ~n a routine mo~el. ~mma ~n~erferon we g~ven in doses of ~ . to ~ , u~%$ synchronous with ereatio~ of a pa~splnal woumd then daily for is ~lays. ~mteet~on ~amma impaired tensile strength a% all ~oses relative to control. m zphology suggested ~reas~ ¢oll~gen deposition and r~du~-~ neovag~ulaeit¥ ~n t~eat~ animals, interferon ~amma was a so ~valuated in a murine mo~el of cecal llgatlon and punneure. one hundred to ,s uni~ vere ~iv.n following ~nju~ an~ than daily. interferon qamma was associated with inco:ea~ed mortalit~ and earlier death a~/a~n ~n a dose dependant manner (p< , ). afmlnistra~ion the proinfiammatory cytokines tumor necrosis factor-c~ (tnf-c , interleukin- (il-ii ), interleukin- (il- ), and interleukin- (il- ) have been implicated in the pathogenesis of the multiple organ dysfunction syndrome (mods) following shock and trauma. these mediators which are released in high concentrations by activated macrophages, endothelial cells, and connective tissue cells cause a systemic inflammatory response syndrome (sirs), thus leading to a shock-like state and tissue destruction. recently, a number of proteins have been characterized in in vitro and in vivo studies demonstrating potent anti-inflammatory properties. these latter cytokines include interleukin- (il- ), interleukin- (il= ), transforming growth factor- (tgf-j ), and the newly sequenced interleukin- (il-i ). they are considered antiinflammatory, since in vitro studies using purified macrophage cultures or whole blood assays revealed an inhibitory effect of these antmnfiammatory cytokines on ~he synthesis and release of tnf-cl and il-u . in addition, they reduced the severity of disease and reduce plasma levels of tnf-c~ and il-ii when administered to animals with infection or inflammation. furthermore, naturally occurring substances have been described that specifically neutralize the bioactivity of il- b and tnf-a. the il- receptor antagonist (il-i ra) is related structurally to il-i and binds to the same cell-surface receptors, but does not stimulate the cell. in animal models ore. cob-induced shock, inflammatory bowel disease, and peritonitis, injection of il-lra significantly reduced the severity of disease. the cytotoxicity of tnf-c~ can be inhibited through two types of soluble tnf receptors (stnfr) type i (p ) and type ii (p ). these stnfrs are proteolytic cleavage products of the cell-bound tnfreceptors. when given to baboons to combat e. coil-induced shock, soluble receptm's to the tnf type [ receptor decreased the severi~ of the shock-like state. it has been well accepted that shock and severe injury result in an increased release of proinflammatory cytokines with a high incidence of sirs and mods. our studies investigating plasma levels of anti-inflammatory mediators (il- , il-lra, stnfrs) in patients after severe injury further suggest that shock and injury lead to an activation of anti-inflammatory processes with altered plasma levels of these mediators. however, while plasma levels of il- and l-lra were significantly increased in trauma patients compared to healthy volunteers, stnfrs did not differ from control samples. thus, shock and severe injury result in different activation patterns of anti-inflammatory processes. m,l. rodrick, boston, b~usa following severe thermal injury significant suppression of the immune response has been demonstrsfed. these changes are associated with increased susceptibility not only to co,on human pathogens, but to organisms not normally pathogenic in the uncompromlsed host. early observations included prolonged graft rejection and skin test anergy in patients following burn injury. work from our laboratory and that of numerous others has shown that the~e is a profound £mmunoeuppresslon following severe thermal injury. i~mune deficiency has been identified in these patients hyz ii lack cf t nell responses to mitogens, ) early decreases in total t and helper t cells in the peripheral bloo~ } lack of response to tetanus toxoid i~uniza~io~ in spite of increased non-speoifi~ i~k~unoglobulin praduction and ) severe and prolongei deficiency of interleukin- (il- ) prcductlon by peripheral blood mononuclear cells (pbmo). this il- deficiency could be an underlyin~ cause of all the afo~ementloned immune defects by failing to activate both helper and suppressor t cell functions. mo~a recent work has focused on the molecular mechanisms of this il- deficiency end shown that the defect lies post-transcrlptionally since mrna for il- is also depressed following thermal injury. we have also investigated the potential of a defect in ii- receptor status on peripheral blood mononuclear uolls from patients fqllowing burn injury and in a murine model. in both oases no decrease in il- r was found either by phenotypic markers or by funational assays. another hallmark of thermal injury is hyperao~ivatlon of proinflammatory ~ytok~ne secretion, which may play a significant role in multiple organ failure following burn injury. therapy o~ major burn injury may reasonably be aimed, therefore, at up-regulating t cell ~unction and down-regulating hyperactive secretion of proieflaam~ntory cytokines. the majority of patients dying of bums succumb to sepsis which coincides with dysfunction in the specific and non-specific host defences. generally, concepts relating to the mechanism(s) of specific immune failure in thermal trauma imply that inhibition of t (cd +) cell responses is imposed by the injury or infection-related factors. however, the same factors elicit strong biological reactions within the lymphoid compartment. recent evidence indicates that systemic activation is inherent in the burn patient. to establish the relation of molecular and cellular events to the development of post-bum anergy we examined the state of and the capacity for t cell activation with regard to: ) occurrence of activation-induced cell death (aicd), ) activation-related phenotypic and functional_ diversity in the pool of peripheral cd + t cells. initially, (up to days post-bum), peripheral blood lympliocytes from severely injured (> % total body surface area) patients exhibited high levels of constitutive expression of surface receptor for ]l (cd ) and spontaneous blastogenesis. the presence of activation-related t cellproducts in bum plasma was also apparent. subsequent impairment of the t cell receptor (tcr)-regulated t cell responses in vitro was accompanied by significantly increased dna fragmentation that is associated with cell death by the mode of apoptosis. using molecular markers we established that flesh peripheral blood ceils from immunosuppressed patients also contain large numbers of apoptotic cells. fluctuations in the number of viable (pi-) peripheral blood lymphocytes involved primarily cd +/cd ro+ (memory) subset of t ceils. the above observations suggest that thermal trauma-associated t cell anergy develops through aicd, a phenomenon commonly associated with the tolerogenic activity of bacterial superantigens. persistence of staphylococcal infections in the burn patient may support this assumption. response following trauma jane shelby, ph.d. the immune system is integrated with other physiologic systems, and is exquisitely sensitive to changes in nervous and endocrine systems changes following traumatic stress challenge. the immune, nervous and endocrine systems interact via both direct and indirect pathways which utilize neuro and endocrine hormones, neurotransmitters, neurepeptides and immune cell products. it is now known that the immune system may be affected by all of the neuroendocrine products produced during a stress response, with evidence for innervation of iymphoid organs, lymphoid cell receptors for neuroendocdne products, and leukocyte production of chemicals which are virtually identical to certain neuroendocdne peptides (acth, endorphins). trauma induced alterations in the equilibrium of various neuropeptides and neuroendocdne hormones have a significant impact on immune response potential, affecting control of proliferation, differentiation and function of immune cells. for example, the neurohormone melatonin is thought to be a natural antagonist to counteract glucocorticeid associated immunosuppression resulting from stressful challenges, such as surgery and trauma, plasma melatonin levels are known to be significantly reduced in burn patients. the administration of exogenous me[atonin improved cellular immune response following burn injury in an animal model. melatonin was also shown to have in vivo cytokine regulatory activity, increasing the potential for il- secretion and downregulating excessive il- and ifn~ in burn injured, stress susceptible mice. the regulatory interactions between the immune, nervous and endocrine systems provide mechanistic pathways for trauma associated immune dysfunction. increased knowledge of these interactions will enhance the potential for the design of novei clinical interventions to improve immune response and decrease the risk for infection in trauma and surgical patients. . animals receiving e were given a single dose daily of either . g/kg of e in a % solution by garage (ge), or . g/kg of sterile ive in saline. four hours following the last dose, bum animals were subjected to a % body surface area bum injury to their dorsum. twentyfour hours following injury, the animals were sacrificed and spleen cells were harvested for assessment of lymphocyte function. splenocytes were prepared by mincing the spleen, followed by incubation on glass petri dishes to remove adherent macrophages. non-adherent cells were then tested for proliferative response to t-cell mitogen concanavalin a (con a) and b-cell mitogen lipopolysaccharide (lps). data were analyzed by anova. results: chronic alcohol exposure and burn injury independently inhibit lymphocyte response to con a but not to lps. the combination of e plus bum injury, however, pmfouedly decreases this response to both con a and lps as outlined in the this data clearly identifies the synergistic impairment of immune function produced by ethanol and bum injury. it is furthermore apparent that ibis effect is gut mediated and that gastrointestinal exposure to alcohol is necessary to produce this effect. further studies will work to identify cellular and subcellular mechanisms to explain this effect. in experimental animal studies and investigations on human volunteers endotoxin infusion is mgulary accompanied by the release of the cytokine tumor necrosis factor a (tnf-~) determined by elisa technique. in patients with menigococcal sepsis also elevated tnf-a values have been found using a functional assay. we have studied the role of tnf-et in surgical icu patients with sepsis. using functional technique, we were not able to detect tnf-~ activities in the patient plasmas. when this cytokine, however, was determined by immunochemicai technique (el sa) elevated tnf-e~ values where frequently oberserved. in order to further elucidate these observations, we studied shedding of tnf receptors in the patients. in these studies, we noticed that shedding of tnf receptors oecured regulary in the patients. at the time of diagnosis, soluble tnf receptor p and p were both - fold higher than values found in plasma samples obtained prior to die diagnosis of sepsis. we also observed that the sepsis patients revealed higher maximum values of p and p during the icu stay compared to values found in surgical icu patients without sepsis. these observations indicate that soluble tnf receptors are available in sufficient amounts to bind tnf-ot which is released in surgical patients developing sepsis. this mechanism may explain why functional tnf-c~ was not detected in the patients. institute for surgical research, rikshospitalet, the national hospital, university of oslo, oslo, norway. decker, d., sch ndorf, m., bidlingrnaier, f., hirner, a., yon rfcker, a. the advantage oflaparoscopic cholecystectomy over conventional open surgical approaches in the treatment of symptomatic cholelithiasis has been shown convincingly by clinical studies. in order to facilitate comparisons of different surgical approaches, we evaluated the cell biological characteristics of tissue trauma by measuring changes in various cell surface markers on leukocytes and eytokines in plasma as a possible means to assess tissue trauma in choleeystectomy. patients recruited into our study had experienced at least one typical bifiary colic, had ultrasound-proven cholelithiasis (stages -ii according to me sherry), were - years old, and presented for elective choleeysteetomy. patients could choose between laparoscopic and conventional eholeeystectomy after being informed about the advantages and disadvantages of each procedure. cell surface markers on leukoeytes were determined using whole blood techniques with the help of commercially available fluorescent monocloml antibodies and flow cytometry. shed cell surface markers in plasma and cytoldnes were measured with the help of sandwich-elisa kits. blood samples were drawn h before surgery, immediately before incision (after anaesthesia), h and h after incision. seventeen cell surface markers were examined on different cell populations and cellular subsets in laparoscopic and open-surgery patients. three soluble cell surface markers and six cytokines were monitored. by statistical analyses (multivariate regression analysis, student's t test, wilcoxommann-whituey's rank sum test) the six markers/cytekines that best distinguished open surgical from laparoscopic procedurea were determined. these were . the interleuldn- receptor and im soluble form (cd /scd ); . the activation antigen fd- and its soluble form (cd /scd ), a member of the nerve-growth-factor receptor family; . the cd ro epitope which characterizes t memory ceils; . the trausferrin receptor cd ; . the soluble adhesion molecule icam- ; and . the cytokines interieukin- and interleuldn- . on the basis of these results, a tissue trauma activation (tta) index was calculated by combining the marker/cytoldne measurements by simple multiplication. anaesthesia and pre-ineision maneuvers did not significantly change cell marker or cytokine levels in either surgical approach as compared to h before surgery. h after incision the tra index in open cholecystectomy showed a distinct - fold increase, whereas in laparoseopic surgery a mere - fold increase was noted. h after incision, the tra-index returned to near pre-surgery levels. in conclusion, our results demonstrate that changes in cell surface markers and cytokines can help evaluate the magnitude of tissue trauma in diffei'ent surgical approaches. the relationship between lymphocyte subpopulation changes after thermal injury and the increased susceptibility of burned patients to infection is unclear. in this study, we have attempted to correlate such subpopulation changes with the presence of infection in burned patients. peripberal blood from patients was monitored for lymphocyte subpopulation changes three times weekly for three weeks postburn and weekly thereafter for three additional weeks. mean bum size was . % (range %- %) of total body surface and mean age was years. infection was diagnosed by carefully defined clinical and laboratory criteria and its presence or absence noted each time blood was drawn. samples taken when patients had wound infection, bacteremia, or pneumonia were compared with samples taken in the absence of systemic infection. whole blood samples were stained with four monoclonal antibodies, the red blood cells lysed and the leukocytes fixed and analyzed by flow cytometry. for each patient sample, the proportion of lymphocytes falling within the light scatter gates was determined as the percentage of cells negative for cd and most strongly positive for cd . this percentage was used to correct each sample for the presence of debris or nonlymphocytic cells. the proportion of cd and cd positive cells was slightly greatc~ in the samples from infected patients, while the proportion of b cells (cd +) was unchanged and nk (cd +) cells were decreased by ahnos[ % compared to sampie~ li'om uuiuleclcd patients. the percentage of cells positive for cdilb (c~ integrin) decreased sharply and cd ro (memory cells) decreased slightly in samples from infected patients while the expression of the lymphocyte homing receptor and cd were unchanged. cd (il receptor) and cd (early activation marker) were significantly increased in the samples from the infected patients while hladr was unchanged. these changes in lymphocyte phenotype correlate with the presence of infection. if they closely precede or occur during the early development of infection they may be valuable clues to the mechanism of susceptibility following thermal injury. trauma patients are subjected to an immediate massive impact on their host defense integrity due to the combined effect of tissue trauma, shock and endotoxemia. cytoldnes are playing a crucial role within the course of an impaired cell mediated immune response (cmi) resulting from a disruption of intact m%/tcell interaction. the current study was undertaken to further elucidate the mechanisms of dysfimctional cmi following major burn and mechanical trauma -via comparative analysis of mrna expression and protein release. the major regulatory levels for different cytokines were determined in mitogen, respectively lps stimulated peripheral blood mononuclear cell (pbmc) cultures of trauma patients on consecutive days ( ) t, , , and post injury. we analyzed the cumulative data for interleukin- beta (il-i[ ), il- , il- as well as tumor necrosis factor alpha (tnf-~) and saw a considerable impairment of the protein release in the stimulated pbmc cultures until d post-trauma and recovery thereafter. *p < . , ** p < . vs control comparing the autoradiographies of the specific cytokine mrna expression with the protein release in the supernatants, we saw a good correlation between mrna signal intensity and protein synthesis for il- and ,- , suggesting that for these cytokines the main regulatory mechanisms are located at the pre-/transcriptional level. for the other cytokines investigated one has to suppose posttranseriptional mechanisms. the analysis of our data clearly indicates a severe impairment of forward regulatory immune mechanisms following trauma. most likely the regulatory mechanisms, that are involved are greatly different among the cytokines investigated. it may be concluded, that depressed cmi responses post-trauma are partly due to an impaired pro-inflammatory cytokine production. the severity of the injury (iss) correlated with the development at multiple organ failure (mof-score; r= . ). the levels of mediators and markers of the inflammatory response were generally higher in the more severely injured group (iss> , n= ). i - , - , g-csf, fpa, and c a -levels differed significantly (p< . ) between the iss-groups (>-< iss ) at the time of admission, whereas on day tnfa, c a, - , and ealpi showed significant differences. beyond the first week, major differences were restricted to pge and c a. the formation of two groups with respect to later multiple organ failure (mof < ; mof > n= ) yielded similar results. leukocyte-facs analysis revealed significant differences mainly in the cd (monocytes), cd /cd (i - r + t-cells), and cd /cd (th calls) populations. summarizing our findings we were able to detect some alterations in the surface antigens of immunocompetent cells. the inflammato d response, however, seemed to be more pronounced and correlates wi~ the further clinical course. using an experimental bum model in rodents, we have demonstrated that administration of a full thickness, scald burn involving % or more of the total body surface area (tbsa) elicits systemic responses which are characterized by numerous alterations in t-ceu function (i.e., lymphokine production and contact hypersensitivity (ch) responses) plus an enhanced susceptibility to bacterial infection. in the present study we questioned whether the apparent systemic effects mediated by large burns would be elicited as site-specific alterations in immune function following administration of small area burn trauma ( % tbsa). following a % tbsa burn, ch responses to contact sensitizing antigens were found to be altered. the depression in ch responses could be induced independent of the site used for topical skin sensitization. following a % tbsa thermal injury, development of ch responses were affected in a site-specific manner. immunization of % tbsa thermally injured mice in a site near the position of the burn resulted in depressed responsiveness, whereas immunization through a contralateral site resulted in responses that displayed both the intensity and kinetics of a ch response equivalent to sham-bumed mice. similar systemic and site-limited changes in lymphokine production were observed with % and % tbsa thermal injuries, respectively. a % tbsa injury affected the lymphokine producing potential of all cells regardless of which lymphoid tissue the cells were isolated from. the effect of a % tbsa burn was significant but site-specific. thus, ceils from lymph nodes receiving drainage from thermally injured tissue were specifically affected, whereas lymphokine production by cells from lymphoid organs receiving drainage from unaffected skin was normal. it was concluded that modulation of lymphokine production and cellular immune responses may be a normal consequence of burntrauma regardless of the size of the burn. changes in immune competence can be mediated either regionally or systemically in direct proportion to the area of skin exposed to the burn injury. this work is supported by phs grant gm and the office of navy research n - -j- . division of cell biology and immunology, department of pathology, university of utah school of medicine, salt lake city, ut . post spleneetomy septic sequelae may be fatal, but the mechanisms remain unclear. the objectives ef this study were to assess the mortality from concomitant splen-'etomy and ]~eritoneal bacterial challenge and to elucidate the local cetkdar responses. cd- mice were randomised to receive laparotomy and sham splenectomy (l) or splenectomy (s) with simultaneous ca'-cal ligation and "):mcture and the survival patterns assessed. subsequently, cd- mice were randomised into control (c), l or s groups and peritoneal cells studied at hours for bacterial phagocytosis and killi:~g, superoxide ( -) and tumour necrosis factor (tnf) production and macrophage activation vsing mac-i(cd- b) receptor in~.ensity expressed es mean channel of fluorescence (mcf). these resides indicate that sf!enectomy predisposes to nrortal~ty from bacterial sepsis ia the early pos~ operative period compared to sham operated animals. failure ~f p'.acrophages to kill bacteria in the splenectomv group '~:cured in t?~e absence of impairment of oxygen freeradical or tnf pred:~ctien. the macrovh~ge ac!ivotion marker mac- was significantly reduced in both l and s groups and impaired phagocytosis of bacteria oceured in both operative groups compared to controls. laparotomy a!one reduces macrophage activity in terms of surface re:eptor mac- expression and !ingestive capacity. splenectomy however s~gnificantiy ~mpairs r-acrophage-wediated l~,acterial killing and this qefect rttav co~tribut~ sig~ifjcav'ly to th-~ dissemination of local infection and to n':ortalit). depts of haem~ tology & surgery, beaumont hosoital, dub!in ,eire. introduction: loss of cell membrane integrity appears to be a common pathway of injury to tissues subjected to high-voltage electrical shock. the cell membrane is the most heat labile structure in the cell, and is also the most vulnerable to externally-imposed electrical forces. skeletal muscle and nerve cells are particularly susceptible to electroporation by clinically relevant electric fields. restoration of membrane integrity is essential for cell survival in victims of electrical shock. we have studied the effect of non-ionic triblock copolymers ( poloxamer class) on the transport properties of isolated rat skeletal muscle cells following electroporation-induced membrane disruption. - mm long adult skeletal muscle fibers were isolated by enzymatic digestion from the rat flexor digitorium brevus and maintained under standard culture conditions. they were loaded with the calcein-am dye and placed in a ,c chamber for recording by real-time video confocal microscopy. the cells were subjected to msec, v/era, a field pulses with a low duty cycle to allow thermal relaxation. peak temperature rise was , .c. the uye content of the cell was monitored in real time. experiments were carried out in calcium-free phosphate buffered saline, with mm mg%. experiments were repeated with mm neutral dextran ( the aim of the present paper is to ascertain if thuracotomy induces a different pattern of variations of cytokines, immunocompetent cells and antibodies from laparotomy in the early postoperative period. patients ( males females,mean age: . _+ ) with gallstone disease and with non neoplastic pulmonary disease were studied. none of these patients received blood transfusion, biological response modifiers, radiotherapy or surgery for at least months before being included in our study. anaesthetic procedures were similar in all patients and none were matnourished. on the day of surgery and on the st and th postoperative days (pre, lpo, po) percentages of cd , cd , cd , cds, cdi were measured by means of flow cytometry using moab., and levels of ig a, lgg, igm, ige. by nephelometry cytokine levels in peripheral blood(il- , il- , il- , il- , tnf) were measured in pts. of each group by means of elisa using moab. _r. esults:variations of il- and il- were not s.s.. il- increased but differences between groups were not statistically significant (s.s). il-i decreased on po and increased on po in both groups but were only s.s. in the th.g., and therefore, the differences between groups were s.s (p< . ).tnf decreased in the l.g. and increased in the th.g. on the po, the difference was s.s(p< . ); on po, tnf decreased in the l.g. and decreased in the th.g. but these variations were not s.s. cell percentages decreased an lpo and increased on po, except for %cd cell that increased on lpo and decreased on po ,in both groups of pts. differences were not s.s. ig a, igm decreased and ige increased in both groups (p< . i), but differences between them were not s.s. in contrast, igg decreased on po (p< . ) and increased on po in both groups, but the decrease iu the th.g. was greater than in the l.g. twenty male children,aged from six months to years,admitted for elective inguinal operation were studied. the operations were performed under balanced combined anaesthesia (fentanyl,thiopemtone,vecuronium, % nitrous oxide in oxygen) and blood samples were collected before flunitrazepam premedication,after anaesthesia, and hours after anaesthesia. cells from the wound were collected with cellstick sponge which was removed from the wound or hours after anaesthesia. the study was approved by the local ethical committee. the percentage of neutrophils was increased and that of lymphocytes was decreased in perpheral blood after the operation.the values in the wound were close to the values found in peripheral blood. the percentage of t-lymphocytes (cd ) and helper-t-cells (cd ) decreased in peripheral blood being lower in the wound than in peripheral blood after the operation. the percentage of t-eytotoxic cells (cd ) also decreased in peripheral blood and was similar to that in the wound. b-lymphocyte (cd ) percentage was increased in pe~pheral blood after the operation and was higher than in the wound. the percentage of activated t-cells (cd +hla-dr-positive cells) in peripheral blood increased while that of natural killer cells (cd +cd +leu -pos) was increased just after anaesthesia being decreased at g and hours after the operation. spontaneous lymphocyte proliferative responses didn't change while phytohemagglutinin a and concavalin a induced responses were decreased in peripheral blood samples hours after the operation with recovery at hours.pokeweed mitogen induced lymphocyte proliferative responses were decreased at hours (p<o. ) and hours after the operation we previously reported that plasma ige increased after traumatic injury. in this study, we measured plasma ige ievels in trauma patients on hospital admission and x weekly in the intensive care unit to evaluate ige kinetics. patient characteristics were: mean age -+ years ( m, f), mean injury severity score (iss) + , sepsis ( patients), sepsis syndrome ( patients), ards ( patients), renal failure ( patients). ige increased in patients ( %). the mean increase was ng/ml (range to ng/ml; % ci was to ng/ml). increase in plasma ige was significantly greater in patients with sepsis syndrome (p= . ) and renal failure (p< . ). although mean plasma ige was higher with ards, pneumonia, hepatic dysfunction, and shock, these differences were not significant (p> . ). plasma ige increase was not related to severity of injury by iss score (p = . ). the mean day to highest ige was . -+ . . the day sepsis was first observed preceded the day of highest ige by . + . days. there was a significant association between the day of sepsis onset and the day of highest ige (p= . ). eight of nine patients with sepsis syndrome had > % increase in plasma ige from admission. one patient's ige levels were normal ( - ng/ml) for days and then increased to ng/ml over the next days, after onset of sepsis syndrome. changes in ige plasma levels may reflect the action of cytokines, such as il- , which concurrently regulate production of ige and il- receptor antagonist in a response to sepsis. sepsis remains a leading cause of late mortality in trauma and hs. although hs-induced bacterial translocation is supposed to be the major cause of sepsis and mof, depression of the res increases susceptibility to infection after injury. the purposes of this study were: a) to evaluate the res in the lung, spleen and liver after hs and subsequent hypertonic saline (hsl) treatment, and b) to document the patterns of phagocytic activity in these organs during hrs. adult male wistar rats ( +_ gin) were submitted to hs (sbp tort) and after t hr (shock i hr) and hrs (shock hrs) hsl (nac . %, . ml/kg) treatment, e. coli (i ) was injected into the portal vein ~tci (n_> ). twenty minutes later, the lungs, spleen and liver were harvested and scintilographic counts obtained. data is depicted as mean_%+sem * p< . , ~" p< . and statistical analysis was performed by analysis of variance and wilcoxon tests. one hr after treatment, lung uptake was increased and liver and spleen uptake were reduced compared to sham. twenty four hrs after treatment, all organs, except lung uptake, returned to normal values. radioautographic histological analysis revealed radiolabeled particles inside phagocytic cells of all organs. we conclude that pulmonary phagocytic activity increases after hr of hs hsl reatment, diminishing by hrs although still above normal values. in contrast, res suppression occurs in liver and spleen after hr hs hsl treatment, returning to normal values by hrs. these results may explain lung complications and immunosuppression after trauma. infusion of endotoxin as well as major surgery is followed by lymphopenia in peripheral blood. the purpose of this study was to investigate to which tissues the lymphocytes are redistributed in response to endotoxaemia and major surgery. in addition changes in lymphocyte subpopulations and expression of mecii was measured. lymphocytes were isolated from peripheral blood of rabbits, labelled with indium-tropolene and reinjected intravenously into the rabbits, i rabbits received an infusion of escherichia coli endotoxin ~g/kg, while i rabbits were subjected to a major sham operation and i rabbits served as a control group. the redistribution of lymphocytes were imaged with af gamma camera, and calculated with an interfaces computer before, and , and hours after major surgery or infusion of endotoxin or saline. interleukin-l~ and serum cortisol were measured. in addition we followed cd , cd , cdlla/b, cdis, cd , cd , mhcii and cd /cd ratio. following endotoxaemia interleukin-lf~ increased significantly, following endotoxaemia as well as major surgery serum cortisol increased significantly. following major surgery as well as endotoxaemia there was significant lomphocytepenia in peripheral blood with a decreased cd /cd ratio while the cd positive subpopulation increased. in addition there was a decrease in the expression of mhcii on the lymphocytes peripheral blood. the radioactivity of the lymphatic tissue in and around the intestine increased to % of initial values following endotoxaemia and to % following major surgery. the results indicate that endotoxaemia as well as major surgery induces redistribution of lymphocytes from peripheral blood to lymphatic tissue. among the lymphocytes staying in peripheral blood there was a decreased expression of mhcii and a relative decrease in cd cells compared to cd positive lymphocytes. in order to analyze the effects of immune suppressive substances on expression of mrna of interleukin- (il- ) and interleukin- reeeptor(il- r), this study was carried out. twenty male rabbits with comminuted fracture were used in the study. ten ml blood were taken at , i, , , days after injury. the sera were tested for the effects on lymphocyte blastogenesis and induction of il- stimulated by concanavalin a(con a): the sera from the rabbits days after injury were analyzed with sds-page gel eleetrophoresis, and divided into three groups by ultrafiltration (ufpi ttk, kd,milipore; centricon- , kd,amicon), that are less than kd, between i and kd, and more than kd. each group of the substances also was tested for the expression of il- and il- r by the dot blot hybridization. the results showed that: i) all sera from the rabbits after injury had significant suppression on lymphocyte proliferation and secretion of il- by the con a-stimulated splenocyte in mice; ) the sera from the rabbits days after injury had more profound suppression than other injured sera; ) there was a marked band at about kd in sera from the rabbits days after injury, but nothing at the same position in normal sera analyzed with electrophoresis; ) the substance with molecular weight of about iokd had more obvious suppressive action on expression of mrna of il- and il- r than other groups substances, of which molecular weights are more than kd. it is concluded that: i) the sera from the injured rabbits can reduce immune response; ) there is kind of substance, of which molecular weight is about kd, it is probable the main factor involved in the pathogenesie of postinjury suppression immune; } the substance can depress the expression of mrna of both il- and il- r. research institute of surgery daping, chongqing, p. r. china acute ethanol uptake prior to injury modulates monocyte tnfo~, production and mononuclear cell apoptosis. g. szabo, b. verma, p. mandrekar, d. catalano monocytes (mo) have been shown to contribute to immunosuppression after both major injury and alcohol consumption. we reported that acute ethanol exposure of m( results in decreased antigen presentation, induces tgf- and pge while inhibiting inflammatory monokine production. we also showed that post-trauma immunosuppression is mediated by hyper-elevated mo tnfc~ and il- . consequently, here we investigated rnonokine production in trauma patients (n= ) who had elevated (>o.lmg/dl) or had no blood alcohol level (n=t ) at the time of emergency room admission. none of the patients had chronic alcohol use history. met tnfc~ production from trauma patients with prior alcohol uptake was undetectable during days - post-injury in contrast to patients without alcohol exposure. furthermore, decreased tnf~x levels were found in alcoholic patients' mci after mdp or ifny + mdp induction. however, mcl tnfc~ levels during the - days post injury period became higher in alcoholic trauma patients. furthermore, over days post-injury, alcoholic trauma patients showed significantly elevated mci tnfo~ production after adherence isolation, mdp, or ifn+mdp stimulation compared to patients without alcohol. these results suggest that acute ethanol uptake prior to injury decreases tnf(x inducibility in the early post-trauma period, but these patients' mo produce hyper-elevated tnfa levels later post-injury, thereby prolonging their cytokine shock risk. tnf ng/ml - days post-injury days post injury stimulus ale. pt. pt . . . . immunosuppression might also be increased by the elevated apoptotic activity found in trauma patients' mononuclear ceils, which was even greater in alcoholic trauma patients' cells. in non-alcoholic trauma patients' preactivated mo, in vitro acute ethanol ( - mm) exposure resulted in a significant down-regulation of tnfc~ (p< . ) and il- (p< . ) production. in contrast, in vitro ethanol exposure increased the production of inhibitory monokine, tgfi]. these results provide both in vivo and in vitro evidence for the effect of acute ethanol exposure increasing immunosuppression and cytokine shock. the 'systemic inflammatory response syndrome' (sirs) with consecutive septic multi-organ dysfunction represents the major cause of late death following major mechanical and burn trauma. systemic hyperinflammation and concurrent depression of cell mediated immune response (cmi) render the traumatized host anergic, resulting in profound susceptibility to opportunistic infection. monooytes/macrophages (mo) play a central role within the host defense system in developing and manifesting states of injury, shock and sepsis. the mechanistic scrutiny of the synthesis patterns of crucial cccytokines appears to be a helpful tool to further analyse mo behaviour in the compromised individual. the objective of this study was to further dissect the characteristics of cytokine regulation in pbmc under stressful conditions, via analysis of the expression of cd + receptor, the proinflammatory mediator il- , the macrophage activating factor ifn- ,, and neopterin (npt) a metabolite of activated mo. we investigated pbmc's on consecutive days , , , and after mechanical trauma of and after bum trauma of patients (mean age ~ years; mean iss ± pts). in trauma patients we saw a massive increase of pha induced neopterin synthesis compared to controls. however, when discriminating the npt levels in the supernatants for the amount of mo stimulated, the npt output of the individual cell was lower compared to mo of nontraumatized individuals. interestingly there was a contrary coarse in the cumulative protein release patterns of il- and ifn- in mechanical versus burn trauma patients. wheras in burn patients ifn-y was decreased significantly ( + u/ml) compared to controls ( + u/ml) as well as mechanical trauma ( + u/ml). il- showed a significant suppression following mechanical trauma ( + u/ml) vs control ( + u/ml) and bum patients. the rt~,na signal intensity for beth eytokines was in concurrence with the protein release in more than % of the individual patients investigated. from these data we can conclude that the inadequate low npt synthesis predominantly in bum patients appears to be a sign of cellular immaturity and is probably partly due to low t-cell ifno t signals. in addition we could state that the quality of trauma is apparently responsible for the different synthesis patterns of ]l- and ifn-q,. it has been postulated that bacterial invasion or endotoxemia are necessary for cytokine production following burn injury. we studied the organ distribution and kinetics pattern of il-fc~ (cell-associated il- agonist) in eutrophic rats subjected to either % tbsa cutaneous scald injury (bi), muscle scald injury of equivalent % tbsa (mbi), sham muscle bum (resection of skin only, up to % tbsa) (smbi), and sham cutaneous burn (sbi), followed by saline resuscitation ( mukg i.p.). separate rats were infused with mg/kg e.coli :b lps or saline lv. unmanipulated rats were baseline normal controls. liver, lung, spleen, ileum, thymus, kidney, skin, and plasma were harvested at various time-points within the first h. tissues were frozen, weighed, homogenized, the homogenates centrifuged and the supernates assayed with a radioimmunoassay specific for rat il-l(z (detection limit pg/rnl). il-lc~ was expressed as ng/g weight + sem (lowest detectable amount . ng/gwt). il-lo~ was constitutively present only in the skin ( + . ng/gwt). cutaneous burn and sham cutaneous bum induced biphasic elevations of il-lcc in the liver and lung only, with maximal levels at . h (in the liver, bi = . _+ . ng/gwt, sbi = . + . ng/gwt, p _< . ; in the lung, bi = . + . ng/gwt, sbi = . + . ng/gwt, p -< . ). of note, both bi and sbi rats had detectable il-i~ in the liver at timepoint already ( min real-time). these levels increased in parallel until min and became eventually different by log at - . h. all other organs as well as plasma were below detection limits. muscle burn injury and sham muscle burn (skin resection) induced similar elevations of il- ~ in the liver at lh, indistinguishable from each other and from cutaneous burn. in contrast, lps challenge induced dramatic elevation of il-t~ in all organs tested except for the kidney; the spleen was the most responsive organ to lps-induced il-lo~ production. these data indicate that thermal or mechanical injuries induce very early and organ specific production of il- c~ in vivo by mechanisms other than endotoxemia. injury-induced complement and platelet activation may be involved as well as the neuro-endocrine axis, which may explain the low levels of il-lo~ induction observed in all rats at the very early time-points. trauma services, massachusetts general hospital, and department of surgery, harvard medical school. fruit, st, boston, ma . j. f. schmand *#, a. ayala* and i. h. chaudry* studies indicate that i.v. infusion of the colloid hes in normal animals does not adversely affect non-specific immunity. it remains unknown, however, if lies affects cell mediated, specific immune functions after trauma and hemorrhage (hem). to study this, non-heparinized c h/hen mice underwent midline laparotomy to induce trauma and were then bled to and maintained at a bp of mmi-ig for rain. the animals were then resuscitated with either times (x) the shed blood vohune as lactated ringer's solution (lrs) or x lrs + lx % lies. sham mice were neither hemorrhaged nor resuscitated. at or hours post hem serum, peritoneal (pm~) and splenic macrophages (sm~) were obtained. bioassayes were employed to assess the levels of ii-l, il- ( alternatively pmqb showed no differences in il- release between all groups at and h, while sm~ from the lrs + hen group showed a depression at h. tnf production by pm~ was depressed in all groups at h and remained so in the lrs + hes group at h. sm~b showed decreased tnf release values in both hem groups at and h. in summary, the levels of inflammatory cytokines (particularly the values of circulating il- ) after trauma/hem are positively influenced by the administration of hes. this might be due to a protective effect on pmqb and sm~, but also on other cytokine producing cells, e.g. kupffer ceils. we conclude that hes is not only a safe, but also beneficial agent in the resuscitation of patients atler trauma/bemorrhagic shock. this study investigated endotoxemia and consecutlve immune response in patients with multiple trauma (median injury severity score = , ). blood samples.were collected shortly after injury and after , , , , s and l days. endotoxin was measured with limulus-amebocyte lysate test and the specific antibody content (sac) against endotoxins of the classes igg, igm and lga by elisa-technique. five antigens were used: lipopolysaccaride (lps) of e.coli (ec), lipid a of e.coli (la), lps of pseudomonas aerog. (pa), lps of vibrin cholerae (vc) and cx-hemolysin of staphylococcus anreus (oth). a nephelometer indicated the total concentrations of igg, igm and iga. differences were checked with wilcoxon-test and p< , s was considered significant. cross-reactivity was calculated with rank correlation coefficients. results: endotoxemia peaked shortly after injury ( - h) at , eki/ml (median), decreased thereafter to , eh/ml at day s and remained on this level. sac oflgmclass increased to all endotoxins and peaked at day revealing the lfighest level to la followed by pa (= % of la-sac), ec (= % of la-sac) and vc (= % of la-sac). lga antibodies increased as well but only slightly and not significant (exception: sac to la was elevated significantly at day ). igg antibodies increased similar to iga class only slightly and again only sac to la was significantly higher at day and . however sac to (xh of all ig-classes remained continuously on the same level troughout the observation time. correlation analysis revealed strong cross-reactivity (r> , ; p< , ) most often between antibodies of igm-elass ( %) followed by igaclass ( %) and lgg class ( %]. conclusions: multiple trauma is associated with temporary endotoxemia. endotoxins probably translocated from the gut cause specific increase of anti endotoxin antibodies in blood of the igm-class. endotoxins cause no increase of antibodies to gramposilave bacteria. igm antibodies are most unspecific. during cardio-pulmonary bypass, as well as postoperatively, high levels of endotoxin, interleukin- (ii- ) and c-reactive protein (crp) were measured in patients. i female and male, ageing from to with a median age of . blood sampling was done preoperatively, immediately after induction of anaesthesia, after thoracotomy, after cannulation of the aorta and right atrium after the first half of the reperfusion phase, after closure of the thorax, and hours after the operation and then every morning until the th postoperative day. blood was drawn into heparinized tubes (i iu/ml) which were free of endotoxin. crp levels were determined through the use of the behring nephelometer. - levels were measured by using commercially-available elisa test. the endotoxin level was determined by a chromogenic modification of the limulus amebocyte test. the statistical analysis was done using the wilcoxon ranks test and correlation analysis. a significant increase {p . ) in endotoxin plasma occurred during surgery, culminating in a peak (median value of . eu/m!) during reperfusicn. plasma levels of endotoxin continued to be slightly raised till the th day after surgery, whereas those of interleukin- rose at the end of the operation and were at their highest hours later (median value of . pg/ml). crp levels were also high postoperatively with a median value of mg/l, and were markedly raised on day ( mg/l). a definite, statistically significant correlation between the plasma levels of endotoxin and - during the operation was establisthed (p . ), leading us to conclude that the endotoxin liberated during cardiac surgery acts as the main trigger in the releasing of - , and thus induces the postoperative acute phase reaction. there was no evidence of a correlation between crp and endotoxin or - plasma levels. impaired immune function is well described following trauma and hemorrhagic shock (hs). prior studies have utilized peripheral blood or spleen cells to index immune function following hs. however, changes in mucosal immunity are not weii characterized in this setting. gut origin sepsis is thought to be an important cause of organ failure and death following trauma. a rodent model was utilized to allow comparison of mucosal-associated immune function vs, systemic compartments after hs. fischer rates underwent hs (map ± mm hg) for minutes followed by resuscitation with shed blood and lr. sham animals were instrumented only. rat tears were collected at and hours following hs for quantitation of slga by ria. animals were sacrificed at hours and spleen (spl), peripheral lymph nodes (pln), and mesenteric lymph nodes (mln) harvested for cell population analysis using flow cytometry and mitogen stimulation analysis. cell marker expression analysis revealed no changes in t or b ceil populations following hs. mitogen mucosal immune function appears relatively spared following hs. the mechanism(s) for this variability in immune function requires further investigation. we have found that transplantation of bone marrow in a hind-limb graft to syngeneic lethally irradiated recipient is followed not only by rapid repopulafion but also overpopulation of bone marrow cavities. the question arises whether this unexpected phenomenon could be the result of stimulation of stem cells by factors (cytokines) released from surgical wound at the site of anastomosis of graft with recipient. aim of the study was to investigate which tissues damaged during the procedure of limb transplantation may be a potential source of humoral factors accelerating in vivo bone marrow proliferation. methods. experiments were carried out on lew rats in groups. in group i, the hind limb was transplanted orthotopically to a syngeneic recipient; in group ii, sham operation was performed; in group iii, a four-cm long cutaneous wound was made on the dorsum; in group iv, limb skin was harvested, fragmented and implanted into peritoneal cavity; in group v, bm from femur and tibia was implanted intraperitoneally. bm, lymphoid tissues and blood were sampled and days later for cell concentration and phenotype evaluation. results. the yield of nucleated cells from tibia was on day in the control . + . , in group . + . , in group ii . + . , in group iii . + . , in group iv . _+ . , in group v . _+ . x ( ). the evident increase in bmc yield in all groups continued until day . increase in weight and total cell count of spleen and mesenteric lymph nodes in all but group iii was also found. no differences in percentage of maturing erythroid cells, but higher of mature myeloid cells and lower of lymphocytes were observed. conclusions. trauma of skin, muscles, and bone brought about an increase in bone marrow cellularity and acceleration of maturation of myeloid lineage. transplantation of bm ceils alone did not produce this effect. transplantation of bm in limb graft is a good model for studies of natural factors reaulatin~ bm hemormesis. this study sought to determine a relationship, if any, between the degree of hypochclesterolemia upon trauma patients' admission and their subsequent outcome. all blunt and penetrating trauma patients admitted to a level i facility from through , and who had serum cholesterol assayed during the first hrs were retrospectively studied for development of death or significant organ dysfunction. the mantel-kaenzel chisquared test was used to determine significance of data at the p< . level. results: trauma patients were admitted during the four-year period who had serum cholesterol assays performed in the first hrs. patients had cholesterol levels less than mg/dl; of these ( . %) died, ( . %) developed ards, ( . %) developed acute renal failure, and ( . %) developed multisystem organ dysfunction; hypocholesterolemia in these patients was not due to liver injury or massive fluid administration. the risk of death was times greater and risk of multi-organ failure times greater in this group than in those with a normal serum cholesterol (>if mg/dl; patients; p< . ). conclusions: admission serum cholesterol level in the trauma patient serves as a powerful marker for those at risk of subsequent organ failure or death. hypocholesterolemia in this setting may result from organ hypoperfusion and humeral mediator release. lung tissue contains many immunocompetent cells. resection, therefore, is expected to activate extensively inflammatory mediators such as pmn-elastase, pmstanoids and pteridines. in a prospective clinical study we compared patients (pts) undergoing either thomcotomy with or without lung tissue msectioh and tboracoscopic lung resection concerning activation of inflammatory response. material & methods: group a pts (n= ) had thoraantomy but no lung tissue injury; group b pts (n=ls) had thoracotomy and lung tissue resection due to benign diseases; group c (n= ) represents group b tissue resection but using a thomcoscopic procedure. the following parameters were determined pre-, peri-, and postoperatively: elastase and crp as indicators of activation of pmn-leukocytes and injury severity; prostacyclin (pgi ) and thromboxane (txa~) as parameters of lung endothelial response; prostaglandin f ~ (pgf~) and pgm representing pulmonaly metabolic activity; pge a and neopterin as proof of macmphage activation. statistics were performed using analysis of variance for repeated measures. results: group b pts revealed postoperatively an increase in crp (p< . ) indicating a higher injury severity in comparison to the thoracoscopic procedure (c). both, controls (a) and group c pts did not show pmn-activation, whereas group b demonstrated a reversible increase in elastase. surgical trauma caused in all groups a release of pgi z and txa which was more pronounced in c (p< . ) and most in b (p< . ). similar results were found for pge~ and pgf =. there was no activation of maerophages since neopterin did not increase. apparently, metabolic lung function was not impaired because there was no marked rise in pgm except in b (p< . vs. c). discussion: our results demonstrate that lung tissue injury aggravates the mediator release induced by thoracic traum. these mediators among others are able to increase capillary pressure and hence lung edema formation. impairment of lung function, however, seems dependent on the extent of the liberation. therefore, the maximal release reactions occured in group b and c after lung tissue resection, whereas the controls showed the highest levels immediately after the incision. we conclude that thoracoscopic procedures are superior in reducing the resection trauma per se and hence might prevent severe mediamr-induced (pulmonary/systemic) sequelae. in a prospective study we investigated patients using radiochemical method according to sch~dlich (s) and photometric method according to hoffmann (h). serum of severly traumatized patients was withdrawn directly after admission at our emergency room and in narrow time intervals during first hours after trauma. follow up control samples were taken daily until day ten. whereas no elevated pla-ca was found during first hours, a peak was regularly observed around day four. there was high correlation between pla-ca and iss (r= . , p<o.o ) except patients suffering from thoracic trauma, thoracic trauma {tt) provoked similar gons-score-and pla-ca-values compared to multiple trauma (mt) despite significantly lower iss: pla-ca (h) mt . + . tt , +_ , n.s. pla-ca(s) mt . +_ . tt . _+ . n.s. goris mt . - . tt . _+ . n.s. iss mt - tt - p< . we found delayed elevation of pla-ca after severe trauma, however detection of delayed pla-ca in the serum of traumatized patients cannot give reliable information about the exact role of pla in the inflammatory reaction after trauma as latest results show that pla is secreted early but bound at lipophilic sites of vascular membranes. hern~mdez m j, amiguet ja, monreal ji, vid~n jr, jim nez f j, l pez-vivanco g acute phase reactant proteins increment in serum of patients with traumatisms and inflammation has been previously reported. alpha- antitrypsin (aat), alpha- macroglobulin (amg) and ceruloplasmin (cp) are evaluated in the following of patients, males and females (mean age: years), with compound fractures. % of them were located in tibia and fibula. intercurrent infection developed in patients and internal fixation rejection in one. measurements were made by radial immunodiffusion on days , , , , , and . a control group of healthy volunteers was also evaluated. aat and cp showed increased values from day which kept elevated untill the end of the study. amg elevated from day . when infection developed, aat and cp values were even higher whereas amg values decreased. fixation rejection caused aat, amg and cp increment. aat and cp increment in non complicated fractures might be due to accompanying inflamation, by means of cytokines release and aprps hepatic synthesis induction. therefore, increment is higher when infection or rejection develop. amg behaviour at early stages of evolution is secondary to hiperconsumption, considering mean life shortening after proteases ligation. amg modifications in fixation rejection remain obscure. aprps increment modulates inflammation and bony callus formation by means their antyprotease and antioxidant properties. clinically, aprps might be useful parameters in determining complications onset in fractures evolution. hemorrhagic shock (hs) is a common complication of trauma, as well as some major surgical procedures. the alteration of the immune system by hs is thought to contribute to the increased septic morbidity and mortality seen in these patients. multiple mediators are released following hs. il- , il- , tnf, pge and tgf-b have all been implicated in these immune system changes. in vitro, pge causes many of the immune system changes following hs, yet the time course of pge release has not been well deliniated. the aim of this study was to determine the time course of pge release by peritoneal and splenic macrophages following hs. c h/hen mice were bled to a mean bp of + mm hg for minutes. the animals were resuscitated with the shed blood and normal saline. control animals were cannalated, but blood was not withdrawn. the animals were sacrificed at , , , , and hours following hs. peritoneal and splenic macrophages were harvested from each animal and cultured with lps for hours. the supernatants were collected and frozen until assayed. pge was assayed using an elisa (cayman chemical). results are shown below for the peritoneal macrophages: pge release by peritoneal macrophages was significantly elevated at , and hours over control. it was maximal at hours, but by hours it had started to decline. splenic macrophage pge release was much more variable. (data not shown.) there was less consistency between time points and no clear trend was seen. in conclusion, pge is significantly elevated at hours following hs, and reaches a peak at hours. pge release may be responsible for the immune system changes seen in the first few days following hs. splenic and peritoneal macrophages respond differently in their release of pge following hs; which may be due to differences in their milieu. there is an obvious association between the altered immunocompetence of patients following traumatic injury of various types and the increased riskto develop complications. the present investigation was undertaken in order to analyze the value of both neopterin (n) and c-reactive protein (crp) in monitoring disease course in patients with multiple trauma. we were interested to compare nconcentrations as marker of t-cell/macrophage activation with crp levels as indicator of the inflammatory acute-phase response daily serum concentrations(n and crp) were measured in patients ( male, female, mean age . ), admitted to our icu following serious trauma (mean iss= ) and in control subjects. the clinical course of each patient was evaluated with apacheii score according to knaus. mean stay in icu was . (range - ). patients didn't develop organ failure(nof-group), patients survived, developing mof (s,mof-group), patients died with mof (ns, mofgroup). three patients(one s and two ns) showed signs of septicemia and septic shock. the serum samples were measured for neopterin (immu-test-ria, henning-berlin) and for crp (immunoturbidimetric method) -at the university hospital for internal medicine, innsbruck, austria. the highest crp levels were measured h after trauma, but they were not accompanied by significant increase in n-values. we found significantly elevated n-concentrations from the days - . n and crp levels showed a parallel release peaks on the days - and the values discriminated significantly among the three outcome groups(the second crp peak is lower in comparison to the first posttrauma peak). by the ns-group we found constant and parallel increasing crp and n levels, reaching extremly high values - h and preceding clinical signs of mof and sepsis. the values increased dramatically before death. the serum levels by all control subjects were upper the normal limit for n and crp.. the parallel occured peak changes in n and crp concentrations showed a significant correlation with clinical status, using a disease activity score (apac h eli). our findings suggest that both-cellular and humoral mediated immune mechanisms are activated after multiple trauma and that simultaneous determination of n-crp may be of advantage as diagnostic and prognostic parameter in polytrauma-patient monitoring panel. it is apparent, that measurement of very high levels may be of value as a srong indicator in developing of mof or septic complications and thus offer the possibility for earlier therapeutic intervention. the modification of t-cell/macrophage and acute-phase responses may be potentially useful in the treatment of icu patients, resuscitated after severe trauma, and suggest that n-crp may be relevant indicator for testing experimental immunomodulating therapies. although several in vitro studies suggested the catalytic action of iron in oxygen free radical generation, few data are available concerning iron-metabolism following ischemia-reperfusion injury and hemorrhage in vivo. aim of the present studies was to evaluate iron metabolism following mild and severe hemorrhage in the presence and absence of intraperituneal hematoma. methods. male lewis rats ( g) divided in groups (observation time hrs): a: mild hemorrhage by sequential blood sampling ( . ml each)( , , , , , , , , hrs). b: a with hemoperitoneum (hp)( ml/ g), c: hemorrhagic shock: blood withdrawal of ml/ g over min and resuscitation with ringer's lactate ( x shed blood) and isogenic donor blood; d: c with hp. parameters: serum iron ([g/dl], ferrozin-method); fe labeling of erythrocytas (application of ci fe i.a. into a donor rat, days later bleeding of the rat and injection intraperitoneally in experimental rat; plasma transferrin ([g/ml], ria). t-tests and mann whitney. data are expressed as mean + sem. results. compared to baseline, mild and severe hemorrhage caused a significant increase in serum iron at and hrs, respectively ( + vs. + ; +_ vs. +_ ). hp reduced this increase ( +_ vs. + ; + vs. +- , p<. ). i-ip significantly increased hemoglobin between to hrs in mild ( . +_. vs. . +. ) and severe hemorrhage ( . +. vs. . +. ). in mild and severe hemorrhage comparable maximal resorption ( fe labeled erythrocytes in circulating blood) of intraperitoneal hematoma occured at hrs (mild: +_ vs. severe: +- counts/rain). hp increased survival-rate following hemorrhagic shock (no hp: / ; hp: / ). in mild hemorrhage no alterations of plasma transferrin concentrations. in shock group without hp, there was at hrs a significant higher transferrin level than with hp alone ( . +_. vs. . + . ). in conclusion, hemoperitoneum with hemorrhage prevents increase in plasma iron levels by increasing hemoglobin through resorption of erythrocytes and thereby suppressing iron mobilization from endogenous iron resources, e.g. liver. this suggests that intraperitoneal hematoma not necessarily promotes iron-mediated oxygen free radical production, especially since survival in these groups was improved. increased transfarrin levels in group c at the end of the experiment suggest increased iron turnover which was not observed in shock groups associated with hemoperitoneum. primary immune response to thymus-dependent (srbc) and thymus-independent (vi-polysaccharide) antigens was determined during days after cct. antigenic challenge was made on day i, , or . number of spleen plaque forming cells (pfc) and serum haemagglutinin (ha) titre were studied on day after immunization. cct stimulated immune response to t-dependent, but not to t-independent antigen. enhanced response was noted when srbs were given in posttraumatic day i, it was higher than preceding one after injection on day and reached a maximum when antigen was presented on day after trauma (pfc number . times exceeded the level of immunized, but nontraumatized rats). the rise of pfc number in spleen correlated with increased ha level. thymectomy had been performed days before cct completely abolished posttraumatio stimulation of immune response to t-dependent antigen. standard thoracotomy also enhanced humoral response when srbc were administered on day after the operation. thymus trauma modeled by pincett squeezing of its right lobe and performed at the same time with thoracotomy fully abrogated as well as thymectomy stimulation of immune reaction. thus, different experimental chest traumas are able to increase antibody production via thymus-dependent mechanisms. endothelin is a amino acid peptide produced by ischemic or injured endothelial cells. in vitro and in animal studies, et is also a potent constrictor for renal mesangial and coronary vessels, a negative cardiac inotrope and an endocrine regulator. our lab has shown that et is an agonist for monocyte production of interleukins i, & , prostaglandin e (pge ) , and substances which trigger superoxide production. systemic et levels increase in hypoperfused and septic patients, and et may be yet another important cytokine in critical illness. but while et has been shown to be a potent vasoconstrictor in healthy dogs, systemic vascular resistance does not increase in critically ill patients with high et levels. (we hypothesize that this might be due to pgez-mediated vasodilation predominating over et-mediated vasoconstriction.) we next asked what happened to systemic et levels in patients with major burns (> %.) ten hemodynamically stable patients resuscitated by a modified parkland formula to a urine output > cc's per hour had et levels drawn on admission, at i, , , and hrs. et levels were measured by radioimmunoassay. mean levels were elevated at ± pg/ml at all time points versus levels in healthy controls of ± . in summary, systemic et levels increase significantly in patients with major burns. et may be yet another cytokine playing a significant role in the immune, inflammatory and multiorgan dysfunction observed with major burns. restoration processes in an organism after ischemic damage are realized through ~n~lammatory mechanisms~ the intensity of which is significantly defined by blood levels of neuropeptides. myocardial infarction (mi) was chosen for studyin these processes since it eradicates the influence of infectious factc~rs. dogs~ in whom mi underwent different forms o¢ healer, g; bhn~ed ~h~t during the acute phase of the disease there was a characteristic rise of ne!~ropeptides in the blood. these neuropeptides had nociceptive and antinociceptive effects. particularly substance p and -endorphins triggered off the development of compensatory and adaptive mechanisms and defined the intensity of inflammatory reaction at the zone of ischem~t: damage-notable fall in substance p levels after an ~nitial increase, while the ~-endorphins stayed high was an important condition for non complicated healing of mi. on the other hand high levels of substance p with low ~-endorphin concentrations lead to increased infiltration o~ neutrophils into the infarction zone and weakened the activity of synthetic processes~ thereby leading to left ventricular aneurysm. at the same time low intitial levels of substance p slowed down the development of necrotic processes which lead to delay in refunctioning of the heart and complicated the healing process. thus, regulation of the levels of neuropeptides in the blood in trauma forms a perspective method of its treatment. of laparascopic versus open choleocystectomy c. schinkel, s. zimmer, v. lange, d. fuchs, e. faist the impairment of immune function due to surgical trauma may be followed by deleterious septic sequelae. compared to open abdominal surgical procedures (lap), laparaseopic surgery (lsc) is associated with a decrease in hospital stay and in accelerated patient recover. the aim of the study was to evaluate the sensitivity of the immune sermn parameters of il- , saa and neopterin, the percentage of cd + cells, the in-vitro il- synthesis after mitogen stimulation and lymphocyte proliferation, in order to purposefully discriminate differences in the severity of trauma. we investigated the blood of patients with cholecystolithiasis undergoing either laparascopic ( ) or open (i ) cholecystectomy on consecutive perioperative days - , , and . there was no significant difference between the two groups concerning age and sex. patients with clinical signs of acute cholecystitis were excluded from the study. operation time and hospital stay were obviously longer in lap patients ( versus minutes, versus days) compared to the lsc group. concerning the unspecific acute phase reaction we could show no difference in the increment of senun amyoid a (saa) synthesis in the lsc group (d-i + lng/ml, d + ng/ml) versus lap group (d- + ng/ml, d + ng/ml), while in serum il- levels we saw a less steep increment in the lsc group ( -fold from d- to d ) compared to the lap group ( -fold from d- to d ). the analysis of cd + receptor expression and serum neopterin did not reveal any difference between the groups. lymphocyte function showed an impairment of proliferation to antigen stimulation in lap (d - : . + . cpm, d : . + . cpm) compared to the lsc group (d -h . + . cpm, d h . + . cpm). in both groups il- synthesis was decreased post-operatively. our data indicate that laparascopic cholecystectomy reusults in a less distinct unspecific acute phase reaction post-trauma compared to that following lap. neopterin serum levels and cd receptor expression show that these parameters apparently are less useful markers to detect differences of surgical trauma severity while it appears that the impact of lap is reflected most impressively on the lymphocyte compartment. trauma alters the host resistance of organism and is accompained by appearence of excgenic and endogenic proteins in the body. to understand the molecular mechanisms of host resistans disorders in trauma, as a first step, the genetic regulatory mechanisms of immune response after antigen injection has been studed. the appearence of specific protein factors ( - and kda), in the nucleus of rat splenic and brain cells, accordingly, was shown after immunization with sheep erythrocytes. the stimulatory effect of these factors on the il- mrna and il- production was detected. the nucleotide sequences of the human il- gene regulatory region bounding by the splenic nuclear proteins were determined between + - b.p. the il- trans-factors shows the affinity to splenic and thymic lymphocytes in vitro. thus, the antigen causes the appearence of specific protein factors in the cells,which act on the gene level,stimulate il- production and the host resistance. these results cause the next step of experiments using the same model, but after trauma. these investigations will let us verify the hypothesis that the protein il- gene trans-factors may play a definite role in the decrease of the cell immune responce after trauma. confronted with the routine procedure of prophylactic treatment of candidates for surgery in a rural african hospital, we initiated studies on the fre'quency of post-surgical malaria. in tanzania non-pregnant patients from rural areas were followed. of preoperative patients % had a parasitaemia and those maintaining it showed no increase or complaints. nine percent of patients without detectable parasitaemia before surgery came down afterwards and one-third had malaria-like complaints. spinal and general anaesthesia were equally applied in these last patients. in burkina faso we studied patients of which % had a parasitaemia on admission and % had postoperative malaria. half of the surgical patients came from rural areas, whilst only % of those with malaria lived in the city (with much less exposure and immunity). % underwent major surgery and % minor. bloodtransfusions ( % with parasites) never evoked a parasitaemia in recipients. post-surgical malaria is thus a reality in about % of the adult cases, both in east and west africa. surgery evokes a cascade of factors, varying from cortison to interleukines and acute phase proteins; immune responses may temporarily be suppressed. clinical attacks of malaria in otherwise immunes could be evoked by one of these factors. though malaria can easily be cured, the differential diagnosis is difficult because of post-surgery fevers; we found that % was treated without justified indication. the involvement of "student-doctors" a. this study examines glucose uptake and hexose monophosphate (i~ip) shunt activity in normal human peripheral lymphocytes and polymorphonuclear leukocytes (pmn). glucose uptake was determined by measurir,g the uptake of tritiated deoxyglucose, a non-metabolized glucose analogue. adsorption of co derived from [i- c] glucose was used to determine knp shunt activity. in vitro assays were carried out in hormone concentrations approximating normal and elevated trauma blood levels. (normal -cortisol . ~g/ml, glucagon #g/m , epinephrine ~g/ml, insulin t~u/ml; traumaeortisol . ~g/ml, glucagon /*g/ml, epinephrine ~g/ml, insulin ~ij/ml. analysis of twenty subjects showed a reduction of ° ~mp shunt activity by lymphoeytes and a ] % reduction in glucose uptake by p~n in normal vs. trauma hontc,nes p < . . lymphocyte glucose uptake was also reduced by trauma hormones p~ . . it ha~ be.ea~ suggested thgt idiopatno pulmonary fibrous (y.pf) [s a consequence of severe alveolar epithelial injury and is associated with an nveolar irnammamry reactio~ and the presence f.neutr phils. there~bre, neutr pk~ chemoattra~ant~ are probably important in the genegs oft.he infial lesions of ipf. the obse,"wson that stimulated macrophages are or~n histologically promin~t in fibmfio [-~gs ~.nd am capable of p~oducmg a v~dery f flbrogenic pep'ides also a~gues for their role ~n the pathogenic prc~e~ oflpf. the observation that stimume~ maerophages ere often histologica[iy prominent in fibrotio lungs and ~re ~pable of producing a varie~, offibroge.~e peptide~ also argues for tkek role in the pathogenic process, therefore, we ha-~e tested the potentn for iater!eukln- (i ..- ) and mo~tocyte chemotacde pop, de (x¢cp- ) to induce neutro~hil ~d mononuclear phagocyte accumuhdon in lungs of pafient~ with pulmonary .~r~idosis and i~f. brenet~o.alveolar lavabo (bal) fluids from ipf and sar~qidosis patient were conexntratea by reversed-phase chromatography, ~d ii. arid mcp-i asso.~ed by ells& ehemotaxis mad enzyme-reieasing ~ssas's on msnocyte~ and neatrophiis. elisa revealed significenfly elevated b al-eoneentrations o£mcp-i ( . ng]mg aibumm) in purisms with p~monary sarcoidodis artd in ipf ( . ng!mg) in comparises to . normal individuals ( . ng/mg) and to patients w~th obreic bronentis (cb) (~, rig/rag). similarly, chemota*dc ac~a~' for monocles (mcp- e.qu/va]ent) was strongly increased in sareoidosis ( . ngjmg) as well as ~n f pag,nts ( . ng/mg). norra.al indlvidu~s and cb patiants hzd a . or -fold lower ~cn%i~y, re~peefively. patients with ipf and sarcoidosi~ also h~l eievated il- ievei~ ( . and . rig/rag, respe~veiy; nomzls: . rig/rag; cb: . ng/mg) mad nvatropmi ohemotax~ ( . ~'~d . nnmg, res!z~ztiveiy; aormals: . ng,'mg; cb: l ngmg). these data suggest that increased ievels of born mcp. ~d il- may be oharacted~tie for ~arcoidosis or ipf_ it appears iikely that both ehernoattraetants ~ontribute to the influx ofmonocytes and neutrophils into the pulmonary alveoius and interstit~um in these dlsea~es. we have recently shown that the combined administration of noninjurious doses of lps and paf in the rat produce ards-like lung injury characterized by neutrophil adhesion to lung capillary venules, neutrophil accumulation in lung parenchyma, pulmonary edema, and increased protein and neutrophil count in bal fluid. this new paradigm of lung injury was associated with elevated serum tnfc~ and pretreatment with anti tnfa mab dose-dependently prevented these responses. also, the combined administration of lps and paf induced lung mrna levels of tnfe~ ( fold vs. lps or paf alone), ll-lg ( fold), kc ( fold) and il- . taken together, these data suggest that this new paradigm of lung injury is cytokinemediated and that lps/paf in vivo can functionally couple to the activation of gone expression of a multi-cytokine network system, all of which may be involved in the pathogenesis of ards. materials and methods. the sheep model included hemorrhagic shock and closed femoral nailing at day , hourly injections of e. coli endotoxin and zymosan-activated autologous plasma at clays - and further observation and measurements at days - . from venous blood and bronchoalveolar lavage(bal)fluid of ten merino sheep (mean weight kg) neutrophil counts ( e pmn/ml blood or epithelial lining fluid-elf-), the elf/ plasma ratio of albumin (r), and the zymosan-induced (stim) and non-induced (spont) chemiluminescence response (cl) of blood ( e cpm/ , pmn), and of blood-and bal-isolated pmn ( e cpm/ , pmn) were measured. for statistical calculations the wilcoxon test was used. data of the changes in polymorphonucleur leukocyte (pivinl) metabolism have been suggested to play a pivotal part in the post-traumatic systemic inflammatory response syndrome. the underlying cellular mechanisms which control this response are not yet completely understood. since the 'ca + second messenger'-system has been shown to be involved in regulation of pmnl-'respiratory burst', we investigated changes in pmnl-ca z÷ regulation in relation to oxygen free radical mediated injury. methods. in polytranmatized patients (mean injury severity score = ) arterial and venous blood samples during days. daily evaluation of horowitz-quotiant (po /fio ), plasma lactate (mg/dl) and body temperature ( results. body temperature peaked at day and (day : +. ; day : . +. ). plasma lactate was significantly increased at day l ( + ) and day ( . + ). hurowitz-quotient (day : + ) was low at day ( + ) and day to ( + )(p<. ). at day a substantial rise in venous pmnl-superoxide production (day : . +_. , day : . +. , day : . +_. ), oecured with significant increase in plasma lipid peroxidation (day : . + . ; day : . + . ). pivin~-myeloperoxidase activity was high at day ( . +--. ) and then continuously declined (day : . +. ). plasma antiexidant activity (glutathione pemxidase) was reduced by % at day (day : . +. ; day : . +_. ; day : . +. ). whereas basal ca + concentration remained unchanged (day : +_ , day : +_ ), fmlp-stimulated cytosolic ca + mobilization increased at day (day : + , day : , day : + ). conclusion. the present study in polytraumatized patients shows, that seven days after injury the agonist-induced pmnl ca + mobilization is significantly enhanced. at the same time, pmnl-oxygen free radical release and phagocytotic activity, systemic fever response and lactate concentrations were maximal. these observations were accompanied by post-tranmatic respiratory failure and in some patients by clinical signs of multiple organ failure. preliminary data from an ongoing study using hes-and dextran-infusions in these patients show attenuation of this inflammatory response. stefan rose, m.d., trauma surgery, univ. of saarland, homburg/saar donnelly sc, haslett c, dransfield i, robertson ce, grant is, carter c, ross ja, tedder tf. dept's of respiratory medicine, accident & emergency, intensive care, surgery, university of edinburgh, scotland and dept. tumor immunology, dana farber cancer institute, boston. the selectins are a family of adhesion molecules (l-selectin, e-selectin, pselectin), all of whom are implicated in inflammatory cell transendothelial migration. they, as a family can be proteolytieally cleaved from their parent cell and exist in a soluble form within the circulation. ards is a disease state in whic neutrophils and neutrophil transendotheliat migration have been implicated. in this study we wished to investigate whether the levels of these circulating soluble receptors from patients at-risk of ards at initial hospital presentation, correlated with subsequent ards progression. eighty-two patients were enrolled (pancreatitis (n= ), perforated bowel (n= ), and multiple trauma (n= )), of whom progressed to ards. assays for soluble l,p & e-selectin were performed on collected plasma samples via a sandwich elisa. (ns = not significant, **** = p<o. ) we have found a highly significant inverse correlation between a low circulating soluble l-selectin (and not soluble e & p-selectin) and subsequent ards. these results further our understanding of neutrophilendothelial interactions in the early stages of ards pathogenesis and offer the promise of sl-selectin in combination with other markers of inflammatory events being used to identify individuals at particularly high risk of ards progression on initial hospital presentation. it has been suggested that polymorphonuclear leukocytes aggregate in the lung capillaries of patients developing the adult respiratory distress syndrome (ards) and account for the endothelial damage while releasing toxic metabo-iites such as o.a. free oxygen radicals. among many antioxidants which have been investigated in in vitro systems and in animal models, n-acetylcysteine (nac) has been established to be useful as a free radical scavenger in vivo. to assess the influence of n-acetylcysteine (nac) on the activation of neutrophils in patients undergoing cardiopulmonary bypass (cpb) surgery with extracorporeal circulation (ecc), we evaluated the plasma levels of elastase and myeloperoxidase (mpo) throughout the operation and up to hours after surgery. four hours after surgery also a bronchoalveolar lavage was performed. a spectrophotometric method was used for the detection of plasma elastase activity and mpo levels were measured using a radioimmunoassay. we found that pretreatment with intravenous nac prevented the increase in elastase activity ( _+ pmol/i vs _+ ; p - . ), but not the release of neutrophil related mediators ( . _+ . ng/i vs . _+ . ; p= . ). besides, nac had the capability to prevent the enhancement of neutrophil numbers in lavage fluid as is normally seen during cpb ( . + . % vs . _+ . ; p = . ). although not significant, nac prevented also the increase in elastase levels in lavage fluid ( . + . pmol/i vs . + . ; p = . ). it is concluded that nac is able to protect against the inactivation of a -proteinase inhibitor, the main inhibitor of elastase activity, and that nac interferes with adhesion and migration of neutrophils. therefore nac may be useful in the prevention of tissue damage. this study is supported by inpharzam belgium. sodium nitroprnsside (snp) has previously been shown to attenuate the neutrophil induced lung injury associated with limb ischaemia and repeffusion. glyceryl trinitrate (gtn), already widely used in aortic surgery, also increases nitric oxide but has a less marked splanchnic "steal" effect. we examined the effect of gtn on lung injury, neutrophil infiltration and activation in a model of aortic occlusion ( rain) and repeffusion ( min). sprague dawley rats were randomized into: control (n=i ); ischaemia repeffusion (ir) (n= ); and ir treated with gtn ( ug/kg/min) during repeffusion (n= ). myeloperoxidase activity (mpo) measured pulmonary neutrophil influx. pulmonary endothelial permeability was measured by wet to dry weight ratio (w/d), broncboalveolar lavage protein (bal) and neutrophil counts (bal pmn). neutrophil superoxide release (mean channel fluorescence mcf) was measured by flow cytometry in a further ir v gtn experiment (n= per group). control _+t "* _+ _+ ** bal pmn/mm l+- " + # _~ *p< . , #p< . v control/gtn;**p< . v ir. students t test the significant increase in mpo activity produced by ir was attenuated by gtn. the increase in pulmonary microvascular leakage after reperfusion was also prevented by gtn. neutrophil superoxide release increased significantly from . + . to . _+ . mcf after minutes repeffusion (p<. ). this increase in superoxide was prevented in the gtn treated group. these results indicate that gtn inhibits neutropbil superoxide release during limb reperfusion, thus preventing pulmonary vascular leakage and neutrophil infiltration. these data suggest that the beneficial effects of gtn in aortic surgery may be due in part to a protective effect onpulmonary microvasculature. department of surgery, beaumont hospital, dublin , ireland. lipton adult respiratory distress syndrome (ards) is marked by increased vascular permeability of the lung to white blood ceils (wbc). indeed, influx of wbc into the lung is believed to be the central mechanism in acute lung injury of ards. evidence is developing that the neuropeptide c~-melanocyte stimulating hormone (c~-msh), a proopiomelanocortin derivative, inhibits inflammatory reactions in animai models of inflammatory responses in humans. to test the influence of a-msh on experimental ards, the peptide was administered to rats after intratraeheal infusion of endotoxin (s. typhosa, #g in . ml saline). three groups (n= each) received: intratracheai infusion of endotoxin plus ip injections of o~-msh ( ~tg in . ml saline) at , , and hr post-endotoxin treatment; intratracheal endotoxin infusion plus saline injections; control intratracheal saline infusion plus saline injections. the bal data showed overall differences among groups (f , = . , p<. ), o~-msh treatment inhibited endotoxin-induced wbc migration into the pulmonary tree (p<. ). circulating wbc counts were markedly lower in both groups given endoroxin than in the control group (p<. ), but there was no difference in wbc count between these two endotoxin-treated groups. the results indicate that c~-msh can reduce wbc migration in experimental lung injury. in further experiments we tested the hypothesis that c~-msh, administered alone or in combination with an inhibitor of gram-negative bacterial growth, increases survival in a model of peritonitis/endotoxemia/septie shock. cecal ligation and puncture were performed under sodium pemobarbital anesthesia ( mg/kg, i.p.) in female balb/c mice ( - g) that were then randomly assigned ( - mice per group) to receive at time and hr later: control saline thjectioas (i.p.), injections of ~-msh ( ~tg), gentamicin sulfate (i mg/kg), or both ~-msh and gentamicin. one ml of normal saline was given s.c. to each animal for fluid replacement. both ix-msh and gentamicin treatments administered singly improved survival; when given in combination survival was even greater these findings suggest that the anticytokine ot -msh molecule might be useful for treatment of systemic inflammation, perhaps particularly when used in combination with agents that inhibit bacterial growth. previous studies showed a close relationship between xanthine oxidase activation, membrane damage and postischemic cardio-respiratory failure following aortic clamping and reperfusion. aim of the present study was to evaluate alterations of polymorphonuclear leukocyte (pmnl)-metabolism and signal lransduction systems during ischemia/reperfusion induced by aortic clamping in man. methods, in patients ( female, + years) with elective reconstruction of infrarenal aortic anearysms, arterial (a) and venous (v) blood samples were obtained before clamping and declamping, and min after declamping. arterial pla concentrations were higher than venous ( + vs. + ). while cytosolic basal pmnl ca + concenlxation was not altered at the end of ischemia (v: . + ; a: _+ ) and during reperfusion (v: + ; a: + ), fmlp-stimulated cytosolic ca + mobilization showed a significant arterial increase as compared to venous ( _+ vs. + , p < . ). these presented data indicate that the reperfusion syndrome after infrarenal aortic clamping is characterized by ) pulmonary membrane damage possibly due to pmnl-degranulation, ) activation of pmnl-superoxide radical production with release of activated pmnl in arterial circulation, and ) a significant arterial increase of pmnl cytosolic ca + mobilization after fmlp-stimulation parallel to pmnl-activation. in conclusion, ischemia/reperfusion in man induces pulmonary damage and activation of pmnl superoxide production possibly due to an altered pmnl-ca + messenger system by inflammatory mediators (e,g. ii- , tnf, paf). the septic lung diseases (i.e. ards) generally show distinct alveolar damage and surfactant disturbances. it is thought that alveolar macrophages are involved in specific release products like h and cytokines like tnf. in this pathway the type ii alveolar epithelial cell (p cell) is not only an important target, but as recently shown it is also capable of producing h . the aim of this study was to investigate the influence of endotoxin on h release of p cells. we obtained p cells from lungs of female wistar rats and investigated the effect of lipopolysaccharid (lps) on h release of fresh isolated cells and on cells cultured for days in a fibronectin matrix. furthermore we conditioned isolated alveolar macrophages for hours with p.g/ml lps and tested the conditioned medium (mcm) on cultured p cells. p cells h ex vivo were _> % pure, _> % vital and had an basal h release of . _+ . nmol h per hour and million cells. adding p.g/ml lps to the incubation medium the h release decreases slightly but significantly to . _+ . nmol. adding . p.g/ml phorbol myristate acetate (pma) to the basal incubation medium the h release increased -fold to . _+ nmol. pma induced h release decreased to . + . nmol after addition of p.g/ml lps. after culture days the p cells were _> % pure and showed a pma inducible h release of . _+ . nmol addition of p.g/ml lps had the inverse effect as on freshly isolated cells as it increased the h release up to . _+ . nmol. addition of mcm to cultured p cells increases pma-stimulated h release to . +_ . nmol. the release decreased to . _+ . nmol when an murine anti-tnf-alpha antibody was added. vitality of cultured cells was > % in all experiments. the results show that lps has an direct effect on p cells cultured on fibronectin. we conclude that the observed additional stimulatory effects of mcm seems to depend on tnf-alpha. the induction of h release of p cells could be important for generating internal oxidative stress in p cells before external oxygen radicals exceed. the produced h did not necessarily damage p ceils, but it can effect surfactant metabolism, especially when extracellular h release of alveolar macrophages following an immune response is increasing. introduction: primary stabilization of femoral shaft fractures in patients with multiple trauma is beneficial. however, in patients with associated lung contusion we have found an increased incidence of ards, apparently associated with primary reamed femnral nailing (rfn). previous animal studies revealed, that perioperative disturbances of lung ftmetion appear to be related to the reaming procedure, ix~ssibly due to pulmonary embolizafion of bone marrow fat. in a prospective clinical analysis we compared effects of intrameduuary nailing with and withont reaming on parameters known to be related to ards-pathoganesis. in order to gain further insight into the role of endotoxin and cytokines in the pathogenesis of the adult respiratory distress syndrome (ards), we enrolled patients with severe lung injury after sepsis ( ) or polytrauma ( ) and obtained multiple blood samples ( days) for endotoxin, tumor necrosis factor e (tnfa), interleukin (il- ) and interleukin (il- ) determination. to evaluate the cytokine releasing capacity of the blood, plasma concentrations of tnfe, il-l and il- were also determined after the "in vitro" stimulation of the whole blood samples with lipopolysaccharide (lps, . ng/ml) for hours at c (stimulated values). the difference among stimulated cytokines levels and the basal plasma concentrations were defined as "delta values", an expression of the cytokine releasing capacity of the blood. the pao /fiao quotient was used as an index of the severity of lung injury (sli). the endotoxin plasma level was significantly higher in patients with sli < ( . ± . eu/ml, mean values ± sem) versus the patients with a sli > ( . ± . eu/ml, p<o. ). the basal plasma concentration of ll- also correlates with the sli index (p<o.o ). the delta tnfe and delta il- values were s~gnificantly decreased in patients with a severe lung injury. compared with the survivors (n: ), the deceased patients (n= ) showed higher endotoxin level, a reduced tnfa and il- releasing capacity of the blood and higher basal il- levels. we can conclude that endotoxemia, high il- plasma level and a decreased capacity of the blood to release tnfa an il- under endotoxin stimulation associates with the severity of lung injury. [objectives] experimental and clinical findings implicate the involvement of inflammatory cytokines in the pathogenesis of the decreased oxygenation in the lung after major surgery, though the mechanism remains unclear. in the present study, we elucidated the involvement of il- in the pathogenesis of lung injury defined by deterioration of pulmonary oxygenation after esophagectomy. [materials and methods] seventeen patients underwent subtotal esophagectomy through a right thoracotomy. in all patients, tbe alveolar-arterial oxygen tension difference (aado ) was measured everyday and bronchoalveolar lavage fluid (balf) samples were obtained from a single segment ($ or $ ) of the right and left lung through a bronchoscope on days l, , and days after surgery. they were then examined for cell analysis, measurement of cytokines by elisa, and measurement of neutrnphil elastase (ne) by elisa. [results] aado unexceptionally deteriorated postoperatively and the mean aado in patients reached the maximum (mean ± sem; _+ mmhg) on the rd postoperative day. the mean concentrations of il- , ne and neutrophil count in balf also increased postoperatively and reached their maximum level ( + pg/ml, -+ gg/l, and ± x cells/ml, respectively) on the rd postoperative day. these increases in balf were recognized in both the right and left lung. a highly significant correlation was observed between il- and ne levels in balf (r= . , p= . ). also, significant correlations between aado and the neutropbil count, and the concentration of ne or l- were observed. in contrast to il- , neither il- , il- nor tnfa was detected in balf. [conclusion] major surgical trauma such as esophagectomy may induce recruitment of neutrophils to the lung and cause lung injury. il- increased in the lung is an important mediator of neutrophil recruitment and activation in the lung. phorbol myristate acetate (pma) is commonly used to cause edema and other tissue damages in the lung. lung injuries induced by the administration of pma has been shown to be mediated mainly by neutrophils. neutrophils recruited to the lower respiratory tract may damage lung tissues by releasing reactive oxygen species, neutral proteases and lysosomal enzymes. the present study was conducted to investigate whether c~tocopherol, entrapped in dipalmitoylphosphatidylcholine liposomes and delivered directly to the lung, could counteract some of the pma-induced lung injuries. plain liposomes or c~tocopherol-containing liposomes ( mg c~-tocopherol/kgbody wt.) were instilled into the lungs of rats h prior to pma exposure ( pg/kg, intratracheally) and treated rats were killed h later. lungs of control animals exposed to pma developed increases in lung weight and lipid peroxidation as well as decreases in lung angiotensin converting enzyme (ace) and alkaline phosphatase (akp) activities. pma treatment also caused an increase in myeloperoxidase (mpo) activity in the lung, suggestive of neutrophi] infiltration. pretreatment of pma-treated rats with plain liposomes had no effect on pma-induced injuries. in contrast, pretreatment of rats with liposomal c~-tocopherol, h prior to pma administration, resulted in a significant elevation of pulmonary a-tocopherol concentration, accompanied by a concomitant reduction in mpo activity and reversal of pmainduced changes in lung edema, lipid peroxidation, ace and akp activities. these results appear to demonstrate that the intratracheal administration of a liposome-associated lipophilic antioxidant, such as a-tocopherol, can significantly ameliorate the toxic effects of reactive oxygen species, released from pmastimulated pulmonary target cells and infiltrating neutrophils. jk wojcik, g palasiewicz, w roszkowski immunology department,institute of tuberculosis and lung diseases~ warszawa, poland, m~larhospital, eskilstuna, sweden. introduction:the critical point in neutrophil migration to the alveolar space in the course of ards is the attachment between giyeoproteins of neotrophil membranes(sialyl lewis x carbohydrate epitope containing u-l-fucose) and lectin domains of endothelial p and e selectins (gmp- ,elam-i). a potential beneficial therapeutic strategy may be designep to suppress neutrophil recruitment to the lungs by preventing their rolling and attachment to the pulmonary endothelial cells. objeclive:to investigate if tz-l-fueose prevent experiments pulmonary hypertension in ards as effective as metylpredniselone. methods:only healthy rabbits (n- ) weighing .d- . kg oaselinepao> kpa and mean pulmonary arterial pressure (mpap)<i. kpa were included in this study. anaesthesia was induced with thiopental - mg/kg bw and "blind" jntubation was performed. a f swan ganz catheter was introduced via the left jugular vein into the pulmonary artery. pma, as was used in our experiments activates neutrophils and produces acute respiratory failure with pulmonary hypertension and pulmonary edema. eight rabbits serving as control animals received pma ug/kg bw iv only. sixteen other animals were divided into two groups receiving either ~-l-fucose mg iv or metylprednisolone mg iv min before pma admininstration. results:after pma administration notable physiological changes including marked increase in mpap( . -+o.~ kpe ..lere found. the increase of npap was observed to be completely blocked in both groups of animals which received ~-l-fucose or metylprednisolone. conclusion:in aur rabbit model ards cz-l-fucose pretreatment prevents pulmonary hypertension after pma administration. the effect is comparable with high dose metylprednisolone. the possible explanation is that g-l-fueose molecules block iectin domains of gnp- or elam-i preventing the adhesion of the neutrophils to the pulmonary endotheliom. bartens c, elmadfa i, steltzer h, fischer m, druml w introduction: various micronutrients and vitamins are particulary effective in modulating immune functions and host defense. the nutritive ant±oxidants vitamin c, e and b-carotene, as well as selenium lower the burden of reactive free radicals and protect the structural integrity of cells and tissues of the immune system, as well as other systems in the body. certain cells of the immune system like polymorphonuclear leucocytes (pmn's) use free radicals as a weapon to destroy invading pathogens. these reactive molecules, when released into the surrounding area, mediate lipid peroxidation and tissue injury. there is growing evidence that pmn's are activated in vivo by complement or immune complexes in disorders such as ards. the respiratory host defense mechanisms of patients with adult respiratory distress syndrome (ards) may be defective. the aim of this study was ta evaluate the status of the free radical scavengers and their activity in ards and to investigate the respiratory burst of ards patients. methods: seven ards patients ( sepsis, trauma) with an fie of . + .( , a peep of . ± . , and a murray score of . ± . were included in this study. healthy adults served as controls. superoxide anion production in granulocytes was measured photometrically, and the hydrogen peroxides by fluorimetric assay. vitamin a, e, and g-carotene concentrations were assessed by hplc, and plasma vitamin c photometrically. plasma selenium was determined by dectrothermal aas. plasma lipid peroxidation pruducts, expressed as malondialdehyde (mda), were determined by thiobarbituric acid assay and hplc. results: mda-plasma (/xmol/l) . ~: . * . ± . *= < . , **=p< . condusion: ards patients showed significantly decreased plasma concentrations of vitamin c, e and g-carotene, as well as selenium. these nutritive ant±oxidants are consumed during increased oxidative stress. mda, a final product of lipid peroxidation, is increased. however, a difference in rates of release of hydrogen peroxides and superoxide-anion of pmn could not be detected. therefore, oxygen radical accumulation is more likely a result of excessive inspiratory oxygen concentrations (f.io ), pro-oxidant drugs, and a high settlement of pmn in the lungs, and not an increased release of free radicals of the single pmn. kd glycoprotein secreted by the alveolar type ii cells. recent study showed that sp-a exists in the sera from normal healthy adults and that the significantly elevated serum sp-a levels were observed in the patients with interstitial pneumonia and pulmonary alveolar proteinosis. these findings means there may be a mechanism that the sp-a produced in the alveoli escapes into the bloodstream. here we examined the serum sp-a levels in the patients with critical illness including sepsis and ards. ]clinical subjects & methods] a total of serum samples were collected from patients hospitalized in the division of critical care medicine(icu), sappom medical college hospital. serum sp-a levels were measured by an enzyme-linked immunosorbent assay using monoclonal antibodies to human sp-a. ]results] there was no significant difference between the septic (n= ) and non-septic (n= ) patients. patients with ards (n= , . + . ng/ml) and with respiratory disease other than ards (n= , . +- . ng/ml) showed significantly higher levels of serum sp-a than those with non-respiratory disease (n= , . _+ . ng/ml). as to the ards patients, it was likely that the serum sp-a levels were getting higher in their clinical courses. however, there was no significant correlation between the serum sp-a levels and the pa%/fio ratio. ]discussion] at the present time, the exact mechanism of the escape of sp-a into the bloodstream remain to be unclear. our results may suggested that there was some relation between this leakage of sp-a and the alveolar-capillary permeability because of the higher sp-a levels observed in the ards patients. however it is also likely that higher serum sp-a level represents the proliferation of alveolar type ii cells as the regeneration of damaged lung. further studies are now being done. neutrophils contain a number of enzymes within intracellular granules,potentially damagingto lung tissue.release of these enzymes into the lung tissue from the sequestred activated neutrophils is felt to play significant role in lung injury in the course of aros. using -hours acute animal model of aros the activity of cathepsins,beta-glucuronidase and acid phosphatase was determined in the lung tissue. results of this research were compared with neutrophil proteases activity in serum and broncho-alveolar lavage.also hemodynamic,respiratory and biochemical investigations were performed before beginning of experiment,and in a two-hours time intervals of its duration.after hours was determined total and free activity of cathepsins,beta-glucuronidase and acid phosphatase in full homogenate of the lung tissue,mitochondriallysosomal fraction and the final supernatant. in the course of our experiment we observed an increase ( .i- . %) both total and free activity of neutrophil proteases in all fractions of the lung tissue.generally accepted current pharmacological treatment of aros only attenuated this increase but never caused reversion to the level before beginning of our investigations. the presence of aros was histologically proved.an activity of acid phosphatase in serum and the lung tissue fractions was compared with histochemical pictures of the lung. results of our research indicate that neutrophil proteases are a very important mediators in aros and they are a cause of the lung injury. in addition neutrophil-derived proteases can amplify the inflamatory process by enzymatitally activating of many other mediators and they also may to increase an oxidant induced injury by imparing of antioxidant defenses. oepartment of general surgery, sk~odowskiej a - ~ia~ystok, poland, tel/fax + . in vitro studies demonstrated that paf activates polymorplionuclear leukocyte (pmn) - ipoxygenase, but the generation of leukotrienes (lts) is critically dependent on exogenous arachidunic acid (aa) disposal (f. grimminger et at., mol. pharmacol. : , ) . we investigated the features of paf-evoked lt synthesis in a model of pulmonary microvascular leukostasis, in the presence and absence of intravascular n- -and n- -prescursor fatty acid supply. human neutrophils were infused into isolated, ventilated and perfused rabbit lungs to achieve microvascular sequestration of ligand-responsive leukecytes. leukotrienes (lt) and hydroxyeicosatetra(penta)enoic acids (het(p)e) were quantified by itplc techniques. intravascular application of paf ( um) or arachidonic acid (aa;ioum) provoked the generation of limited quantities of -series lts and -hete (total sum of - ipoxygenade products rd. and rd. pmol/ml.; both in pmn-preloaded and non-preloaded lungs). combined administration of pat r and aa caused amplification of - ipoxygenase product formation with predominance of cysteinyl-lt synthesis both in lungs without (total sum rd. pmol/ml) and, much more strikingly, with pro-application of neutrophils (total sum rd. pmofml). eicosapentaeooic acid ( um) elicited exclusive generation of -series lts and -hepe (total sum rd. pmol/mi). dual stimulation with paf and epa provoked amplification of epa-derived - ipoxygenase product formation, again with predominance of cysteinyl-lts, in lungs without (total sum rd. pmul/ml) and in particular in those with preceding microvascular pmn entrapment (total sum rd. pmol/ml). we conclude that the paf-evoked - ipoxygenase product formation in the neutrophil-harbouring lung capillary bed is critically dependent on intravascular precursor fatty acid supply, with epa representing the preferred substrate as compared to aa. pmn-related transcellular eicosanoid synthesis is suggested to underly the predominant generation of cysteinyl-lts. these findings may be relevant for lipid mediator profiles provoked by infusion of n- -versus n- enriched lipid emulsions in diseases with pmn-related inflammators events. adult respiratory distress syndrome (ards) involves damage to the alveolar epithelium and microvascular endothelium. products released from neutrophils (pmn) are thought to be among the chief causes of this damage, while the role of mononuclear cells (mnc) is uncertain. we studied patients at risk of or with acute ards. we measured the concentration of myeloperoxidase (mpo) and elastase (el) within circulating pmn as an index of pmn activation, elastin degradation products (edp) in the plasma as an index of tissue damage, as well as the cytotoxici~y of pmn and mnc to endothelial cells (ec) in vitro. cells and plasma were prepared from venous blood of healthy controls; or systemic arterial blood of patients on ventilators in intensive care but not at risk of ards; at risk of ards because of sepsis; at risk because of multiple transfusion/major trauma; or with acute ards. lung injury, multi-organ failure and apache h scores were recorded. to measure cytotoxicity, human umbilical vein ec were labelled with cr- , incubated with either pmn or mnc for hours, and the supernatant counted. the adherence of the pmn and the mnc to the ec was also measured. standard assays were used to measure mpo and el in the pmn, mad edp in the plasma. the mnc cytotoxicity did not differ between the groups. the pmn cytotoxicity was higher in the transfusion/trauma patients compared to each other group, which did not differ from each other. there was no correlation between cytotoxicity and adherence for any group. the mpo and the el concentrations were significantly decreased in the pmn from each of the patient groups, including the patient controls, compared to healthy controls. the edp were only increased in patients at risk of or with ards. thus pmn degrannlation occurred in patients not at risk of ards, but tissue damage as measured by increased edp only occurred in patients with or at risk of ards, suggesting that factors additional to pmn activation and degranulation are required for the progression to ards. there was no correlation between the parameters measured and the indices of disease activity, or outcome. these measures of pmn and mnc activation and function are not of value as prognostic indicators in patients with or at risk of ards. the liver is made up of several different cell types which subserve distinct functions in vivo. in addition to the different functions of the distinct cell types, it is now evident that even within the population of hepatocytes substantial functional heterogeneity exists. this heterogeneity occurs in a very organized fashion in the normal liver based upon the position of the hepatocyte in the acinus. although it has been proposed that the acinar heterogeneity of hepatocytes arises from migration of immature hepatocytes from the periportal region to the perivenous region where they become senescent and die, many of the heterogeneous responses can be accutely reversed by reversal of the oxygen gradient via retrograde perfusion. under normal conditions in which the acinus is exposed to unidirectional flow, the periportal hepatocytes are exposed to relatively high levels of oxygen, substrates and hormones. as these substances are extracted along the aeinus their concentration decreases leaving relatively low concentrations for the perivenous hepatocytes. in the normal liver, the heterogeneity of response is attenuated by extensive communication via gap junctions. the major liver gap junctions are made up of hexamers of connexin (cx ) which forms channels between cells capable of pas.~ing any molecule smaller than d. coupling is sufficient to allow diffusion of molecules such as atp or camp from one hepatocyte into > adjacent hepatocytes within seconds. during stress conditions such as endotoxemia or zymozan inflammation, expression of cx is markedly decreased while the secondary gap junction protein cx is either unchanged or even increased. while cx readily effects electrical coupling, molecules > d pass only very slowly. this would result in restriciton of transmission of moecules the size of atp or camp. since inhibition of gap junctions also attentuates metabolic response to hormone or nerve stimulation, it is evident that modulation of hepatocyte hetereogeneity by gap junctions must be considered in determining the mechanisms of metabolic alterations during stress. already minor haemorrhage decreases portal venous blood supply to the fiver and the reduction in portal blood flow becomes more pronounced with more profound btood loss. severe hacmorrhagic hypovolemia also reduces hepatic arterial blood supply which, however, is maintained over a vide range of haemorthage. the net effect of blood loss is a reduction in liver oxygee supply and this reduction is in proportion to the vulume iossed. however, oxygen supply to the liver exceeds the demands of the normal liver and this is the ca~ stilt following reduction of % of blood volume. the situation in sepsis is more complicated. po~l venous supply to the liver is redur.~i fairly early following normovolemic sepsis while hepatic arterial blood supply is maintained at le,~t initialiy, oxygen saturation might be maintained in arterial blood but may also be slightly reduced during sepsis, oxygen saturation of portal venous blood is significantly reduced during sepsis due to increased extraction of the intestines. therefore oxygea delivery to the liver during sepsis becomes sigalfkzntly reduced. at the s,~ne time and for mai.v.ly unknown reasons the need for oxygen becomes significantly increased in the ~-~ptic liver. as a consequence liver oxygen consumption becomes flow dependent and the liver is likely to suffer from ischemia during septic conditions. $ although liver failure is well recognized in sepsis, it is generally thought to be a late complication following pulmonary and renal failure. jaundice, hypoglycemia, encephalopathy and bleeding secondary to low levels of liver-synthesizing clotting factors are, however, signs of rather severe end-stage hepatic failure. furthermore, elevated liver enzymes (sgot and sgpt) represent hepatucyte damage and not hepatocellular dysfunction. in view of this, a more sensitive indicator of hepatic function is desirable in order to detect early hepatic abnormality. in this respect, indocyanine green (icg) is a tricarbocyanine dye that possesses several properties which makes it particularly valuable inthe assessment ofhepatic function. this dye is bound m albumin and is cleared exclusively by the liver through an energydependent membrane transport process and is nontoxic at lower doses. we propose that maximal velocity (vm~,) of icg clearance is a valuable measure of active hepatocellular function, since the total concentration of functioning receptors is directly proportional to vm~. we have utilized a fiber optic catheter and an in vivo hemoreflectometar to continuously measure the administered icg in vivo and consequently determine its clearance without the need of blood sampling. using this technique, we have found that in the early stages of sepsis (i.e., and h following cecal ligation and puncture), the vm~ and kinetic constant (k=) of icg clearance was significantly depressed. it should be noted that at this stage of sepsis, there was no elevation in serum enzyme levels. furthermore, hepatic blood flow and cardiac output increased at the above mentioned time points. thus, the extremely early depression in active hepatocellular function in sepsis, despite the increased hepatic blood flow and cardiac output, may form the basis for cellular dysfunctions leading to multiple organ failure during sepsis. additional studies indicated that following hemorrhage, active hepatocellular function was markedly depressed. this returned to prehemorrhage levels after ringers lactate resuscitation, however, this function was not maintained and decreased significantly after fluid resuscitation. nevertheless, the depressed active hepatocelinlar function following hemorrhage was markedly improved by post-treatment of animals with either atp-mgci , peutoxifylline or diltiazem. thus, the use of icg clearance provides an early sensitive indicator of hepatic abnormality during sepsis and following hemorrhage and this method should be used, not only experimentally, but also in the clinical arena for the early detection of hepatocellular abnormality. although multiple organ dysfunction syndrome (mods) remains a major cause of mortality and morbidity in intensive care units, very little is known about the mechanisms that precipitate its development. since an episode of inadequate tissue oxygenation is considered to be the trigger for mods, we have proposed that a primary localized injury such as ischemia/reperfusion may be sufficient to cause a change of gene expression of remote and apparently unaffected organs. such modulation of remote organ gene expression may decrease the organ's tolerance to a subsequent stress contributing to the development of mofs. to test this hypothesis, rats were subjected to hepatic regional ischemia by clamping the blood flow (hepatic artery and portal venous inflow) of the left and median liver lobes. intestinal congestion was prevented by allowing flow through the smaller right and caudate lobes. after minutes of ischemia, the clamp was removed and the blood flow restored. the animals were allowed to recover for , and hours. kidneys were removed, total rna was isolated and poly(a) ÷ selected by affinity chromatography on oligo(dt) columns. message was in vitro translated using rabbit reticulocyte iysates in the presence of radioactive amino acids. the gene products (radiolabeled polypeptides) were fractionated by two dimensional gel electrophoresis, and visualized by fluorography. analyses of the two dimensional fluorograms indicate that there is a dramatic change in the electrophoretic pattern of in vitro translated products in samples corresponding to kidneys obtained after minutes of hepatic ischemia and hours of reperfusion with respect to kidney samples obtained after sham operation or from control rats. the latter were not subjected to any surgical manipulation. these studies suggest that the gene expression of the kidneys is specifically modified after a remote organ injury (hepatic ischemia/reperfusion). we speculate that this change of gene expression in kidneys after an indirect injury may be part of the early events leading to the development of mods. a priming event, e.g. local ischemia, in combination with a second insult, e.g. sepsis, may amplify a host's response and lead to multiple organ failure. to better understand the mechanisms involved in the pathophysiology, male fischer rats were subjected to min of hepatic ischemia followed by reperfusion (rp) and injection of . mg/kg salmonella enteritidis endotoxin (et) at min of rp. et injection potentiated the postischemic liver injury as indicated by histopathology and an increase of plasma alt activities from + u/l (i/rp only) to + u/l at h rp. inhibition of kupffer cells (kc) with gadolinium chloride ( mg/kg) attenuated liver injury in this model by %, however, monoclonal antibodies (cl , wt ) directed against adhesion molecules ( integrins, cd ) on neutrophils had no effect on the injury despite the substantial accumulation of neutrophils in the liver at that time ( + pmns/ hpf; baseline: + ). isolation of kc and neutrophils from the postischemic liver indicated a -fold increase of the spontaneous superoxide formation only in the kc fractions [ . + . nmol o -/h/ %elts (kc ); . _+ . (kca) ] at h rp compared to control cells. in addition, stimulation with phorbol ester or opsonized zymosan revealed a substantial priming of kc for reactive oxygen formation. in contrast to the short-term experiments ( h), the antibody wt ( mg/kg) attenuated liver injury by % at h of rp and improved survival. conclusion: liver injury during the early rp phase is mediated mainly by kc generating excessive amounts of reactive oxygen while neutrophils are primarily responsible for organ damage during the later rp period. (es- and gm- ) tumor necrosis factors (tnf) are cytokines which are cytotoxic towards some tumors in vivo and certain tumor lines in vitro. moreover, these polypeptides are powerful immunomodulators and have been found to be distal mediators in several models of septic shock and septic organ failure. one of the best-characterized experimental systems is the hepatitis caused by lps or tnf in galactosamine (galn)-sensitized mice. here we describe a cell culture system, in which the direct toxicity of tnf towards mouse hepatocytes was examined. the toxicity of tnf, as determined by ldh-release or formazan-formation, was dose-and time-dependent. the threshold of toxicity was ng/ml, which corresponds to serum concentrations found in mice after lpsinjection. toxicity was only observed in hepatocytes sensitized with transcriptional inhibiters such as galn, actinomycin d (actd) or cxamanitin. sensitization was neither observed with different translational inhibitors nor with various other metabolic inlaibitors or toxins. inhibitors of protein synthesis or protein processing such as cycloheximide, puromycin, tunicamycin and ricin protected actdsensitized hepatocytes from tnf-induced cytotoxicity. tnf induced apoptotic changes and dna-fragmentation in sensitized hepatocytes which is in line with the above findings that cell death is dependent on protein synthesis. thus tnf may be a trigger of programmed cell death during inflammatory organ damage. with the purpose of studying the role of complement activation in tissue injury after ischaemia and reperfusion we blocked the complement cascade in a model of rat liver isehaemia and reperfusion, either by administration of soluble human complement receptor type (scri), mg/kg iv after vascular occlusion (n= ) or by depleting the complement system using cobra venom factor (cvf), . mg im, and hours before ischaemia (n= ). non-ischaemic rats (n= ) and ischaemic non-treated rats (n= ) were used as controls. the experimental procedure consists of the temporary interruption of arterial and portal blood flow to the left lateral and medial lobes of the liver during minutes, followed by reperfusion, recording the liver blood flow and haemoglobin saturation with a laser doppler flowmeter and photometer during one hour after declamping; alt levels were assayed and immunoperoxidase stainings for c and c were performed. there were statistically significant differences between the experimental ~roups and the untreated ischaemic control group in terms of post-isehaemic blood flow (p< . ) and haemoglobin saturation (p< . ). c and c were present in the endothelium of the ischaemic control group. no deposits of c or c were found in the cvf group. few c and no c were found in scri treated rats. these results show that the effect of reperfusion injury in the rat liver is ameliorated either by depleting complement with cvf or by regulating complement activation with scri. hepatic dysfunction, a major cause of mortality following hemorrhagic shock, has not yet been well characterized. the present study was designed to assess the effects of liver blood flow and cytokine levels on hepatic function following resuscitation from severe hemorrhagic shock in normal and cin-hotic rats. methods: aftor pentobarbltal anesthesia, control and cirrhotic sprague-dawley rats were subjected to severe hemorrhage to reduce their systolic blood pressure to + mm hg. this level of hypotension was maintained until the skeletal muscle transmembrane potential (era) depolarized by %.; the animals were then resuscitated with ringer's lactate solution in three times the volume of the shed blood. serial blood samples for tumor necrosis factor (tnf) determination (a modified flow-cytomeuic wehi cell bioassay) were obtained at baseline, during hemorrhage and following resuscitation. liver blood flow measurements by low dose galactose clearance (glc) and functional bepatocyte mass (fhm; defared as galactose elimination capacity [gec] from the zero order portion of the plasma disappearance curve following an intravenous galactose bolus [ mg/kg], divided by liver weight) were measured before shock and after resuscitation. results: higher survival rates (p < . ) were observed in control as compared with cirrhotic rats. shock produced a significant reduction in gec (to < . ); fhm ( < . ); and liver blood flow (p < . ) in normal and cirrhotic rats. decreases in gec and fi-im were greater (p < . ) in cirrhotic rots. tnf levels were higher (p < . ) in cirrhotic rats at baseline and during induction of shock. pre gap junctions provide pathways for metabolic signals between cells. in the liver, the majority of gap junctions are composed of connexin (cx ) polypeptide subunits, and are regulated by gluconeogenic hormones. since sepsis and other inflammatory states alter hepatic glucoregulatory control, we have evaluated the contribution of gap junctional conductance to the metabolic dysregulation in the liver. an acute inflammation was induced in rats by injection with e. coli endotoxin (lps lmg/kg). northern blot/hybridization analysis of total rna isolated from livers after endotoxin injection show a decrease in the steady state transcript levels of cx to % of sham controls. immunostaining of liver sections using anti-cx revealed punctate fluorescent staining on the plasma membrane at regions of call-cell contact in saline injected animals, whereas, staining was only observed in cytoplasmic vesicles hrs after animals were treated with lps, suggesting the internalization of cx without replacement on the cell surface. the staining was quantitated and expressed as % of pixels above threshold. at hr post injection . % ofpixels exceeded threshold, compared to . % in sham controls. functional gap junctional communication was assessed by dye coupling using lucifer yellow in an isolated perfused liver under intravital fluorescence microscopy. dye diffusion was markedly decreased hr after endotoxin injection. this suggests that decreased metabolic coupling after lps injection results from decreased gap junction abundance. the present data suggest that metabolic dysregulation during sepsis may arise in part from changes in intercellular communication caused by a decrease in gap junctional expression and communication. given the marked metabolic heterogeneity of hepatocytes with respect to acinar location, metabolic signaling via gap junctions most likely serves to moderate this heterogeneity, contributing to a coordinated metabolic response. altered cellular ca ÷ regulation might be a critical step in organ dysfunction during sepsis and ischemia/reperfusion events. the aim of the present study was to evaluate hepato-ceuular ca ÷ regulation in isehemiah'eperfusion after hemorrhage and to assess effectiveness of tnfc~-monoclonal antibody (tnfo~-moab). methods. male sprague-dawley rats ( g, n>_ /group; pentobarbital mg/kg) with hemorrhage for rain at mm hg. reperfusion by ringer's lactate ( x maximal bleed out/ min) and % of citrated shed blood. tnfcz-moab (tn , ceutech, mg/kg in . % nac ) infused during flrst min of reperfusion. at baseline, end of ischemia and min of reperfusion, hepatecyte isolation by liver collagenase perfusion. " hepatocyte incubation ( mg w.w./ml) with caci ( . + + + mbq/ml) for rain (ca influx [slope, /mini; ca uptake [nmol ca /mg protein]) w/ and w/o epinephrine (epi, nm). hepatecyte resuspension in radioisotope-free medium and farther incubation (exchangeable ca + (ca +ex) [nmol ca +/mg protein]; ca + membrane flux [nmol ca +/mg protein'min]). during incubation, aliquots ( ~tl) were centrifuged through oil/lanthanum gradient and acivity measured by scintillation counting. statistics: anova. mean + sem. results. hepatocyte ca +ex and membrane ca + flux were significantly increased at both, the end of ischemia ( . +. ; . +. ) and reperfusion ( . +. ; . +. ), as compared to sham-operated animals ( . +_. ; . +. )( <. ). tnfc~-moab treatment significantly prevented reperfusion-induced increase of ca +ex ( +. ) and membrane ca + flux ( . +. )(p<. ). fast ca + influx was significantly increased by epinephrine in hepatecytes from sham-operated rats ( . +. vs. epi: . +. , p< . ). this hormone effect was not observed in isehemia ( . +. , epi: . !-_. ) or reperfusion (untreated: . +. , epi: . +. ; tnft~-moab: . _+. , epi: . +. ). conclusion. the present study clearly demonstrated hepato-cellular ca + overload in ischemia and reperfusion as a result of hemorrhagic shock. analysis of membrane ca + fluxes and hormone ca + mobilization suggests disturbances of membrane ca + transport mechanisms, e.g. through ca +-atpases. reperfusion-induced oxygen free radical generation which affect exchange kinetics of cellular ca + buffering compartments might also be operative. prevention by tnfct-moab indicates the pivotal role of tnf as an early inflammatory mediator of hepatocellular alterations in signal transduetion mechanisms and cellular homeostasis. although the precise mechanism has not yet been elucidated, bacterial translocation and endotoxin absorption have been frequently shown after burn, and have been postulated to be one of the underlying processes of sepsis. the purpose of the current study is to define the hemodynamic response of the liver to endotoxin release in burns, in correlation to bacterial translocation. twelve female minipigs, weighing - kg, underwent a laparotomy & transition time ultrasonic flow probes were positioned on the portal vein, the common hepatic artery, and the superior mesenteric artery. . fr catheters were inserted in the superior mesenteric vein and the left hepatic vein. a jejunostomy was also performed. after five days all animals were anaesthetized and randomized to receive % of tbs a third degree burn. eighteen hours after burn. gg/kg e. coli lps was intravenously administered over rain. ali animals were studied for additional hours and then sacrificed. several recent data suggest that in severe injuries, such as shock state, the gradual activation of kupffer cells and the excessive release of destructive and immunosuppresive products from macrophages may contribute to the development of "multiple organ failure". in in vivo experiments in mice, the effect of kupffer cell phagocytosis blockade on the correlation between the tissue distribution of lps, endotoxin sensitivity and lps-induced tnf production was investigated. to depress the activity of the kupffer cells, gadolinium chloride (gdc ) or carrageenan was used. th~e studies indicate the dissociation of tissue localisation of cr jllabelled endotoxin and endotoxin lethalithy. both gdc and carrageenan depressed kupffer cell activity, but endotoxin sensitivity was enhanced only by carragenan treatment. however, there was a close correlation between the sensitivity to lps and lps-induced tnf production as measured in the serum, since lpsinduced tnf production was enhanced only by carrageenan treatment. on the other hand, gdc pretreatment significantly increased tnf production in the spleen. these results support our earlier findings that gdc -indueed kupffer cell phagocytosis blockade leads to activation of the spleen, and may explain some of the immunological effects of gdc . inositol(l, , ) triphosphate (ip ) has been proposed as a second messenger for calcium mobilization. the addition of ip at low concentration has been shown to cause calcium release from intracellular microsomal store in rat hepatocytes. the effects of sepsis on the ip binding from microsomal fraction of rat hepatocytes during sepsis were investigated. sepsis was induced by cecal ligation & puncture (clp). control rats were sham-operated. three microsomal fractions (rough, intermediate and smooth) were isolated from rat liver. study of ip receptor binding was performed with tridium label ip . the results shewed that the ip binding was significantly depressed by - % (p< . ) during late sepsis ( hrs after clp), but not in early sepsis ( hrs after clp). the ip binding depression during late sepsis was most significant on rough and intermediate endoplasmic reticulum (p< . ), but not on smooth subfraction. since ip binding plays an important role in the regulation of intracellular calcium homeostasis in hepatocytes, an impairment in the calcium release due to depressed ip binding on smooth and intermediate endoplasmic reticulum during late sepsis may have a pathophysiological significance in contributing to the development of altered hepatic metabolism during septic shock. septic organ failure is currently recognized as an overactivation of the nonspecific immune system by bacterial stimuli giving rise to proinflammatory mediators. little is known about the mechanisms of the resulting cellular injury. here, a synergism is described between tnf as a major mediator of septic organ injury released by macrophages and hydrogen peroxide (h ) as a representative of reactive oxygen species as formed by e.g. neutrophils. rat hepatocytes are only slightly sensitive to either agent alone. when treated with a conbination of tnf and h# a stronq synergistic toxicity was found, especially w~e~ tnf-treatment preceeded challenge with h~o~. we have recently described a coculture model bfzrat liver macrophaqes and hepatocytes where lps induces hepatocyte cell death partially mediated by macrophage tnf release. when h was also employed in fhis more complex cellular system a similar synergism was found: the ecc~ of lps was consecutive patients with liver cirrhosis admitted to the department of surgery over a year period from january to december were studied for their complement profiles in relation to other parameters of liver function, the aim of the study was to determine if a direct correlation existed between low complement levels and end stage liver cirrhosis. cirrhotic patients were divided into child's a, b and c categories using child's classification. complement levels (c , c ) were measured and functional assay for complement (ch ) were performed in each of these groupings in addition to normal blood donor controls. these results show that the qualitative c , c and the functional chs complement assays have good predictive values in assessing deteriorating liver function• in particular, the functional assay for complement (ch ) showed marked impairment in child's c patients (p< . ) confirming the impaired immunological status of these patients. sera from this group of patients (child's c) were titrated with pig red blood cells (rbcs) in a haemolytic assay. the results showed that there were significantly less haemolysis of pig rbcs in these patients (p= . ) as compared to the controls. this findings strongly support an impaired immunological status in child's c liver cirrhosis and may explain the high incidence of sepsis as a terminal event in these patients. aim:kupffer cells(kc) have an importamt play to cause hepatocellular injury in sepsis, because these cells release many kinds of substances. we reported that oxygem radicals released by kcs stimulated by lipopolysaccharide (lps) caused hepatocellular injury. aim of this study is to investigate the relationship between imtracellmlar calcium(ca) concentration of cultured rat kcs stimulated by lps and release of oxygen radicals, and effect of prostaglandin e~ (pge~) on imtracellular ca concentration. production of acute phase proteins (c-reactive protein, crp, transferrin, tf) and £erritin (f) in rat hepatocytes (hps) and its dependence on extracellular matrix components were studied. hps isolated from the liver by collagenase perfusion were cultured at ~o per . ml medium fi +dmem ( : ) with % fetal calf serum for days on uncoated or type i collagen coated plastic surface or in the presence of dextrane sulphate in the medium. hps were stimulated by conditioned medium (gm) from i~ia-p or e. coli lps preineubated human blood mononuclear cells. production of crp, tf and f by hps was detected by elisa. it was found that both cms decreased tf synthesis in hps by - % (p<o.os). the level of f synthesis didn't change or only slightly decreased. the addition of cms led to the enhancement of crp synthesis more than . times. the most reproducible results were obtained when plastics had been coated with collagen. dextran sulphate markedly increased crp synthesis. thus using this model of an acute phase reaction in vitro we found the enhancement of crp synthesis and the decrease of tf synthesis. our data correspond with nublished materials on the acute phase in vivo and point to relevance of the proposed model. metabolism of hepatocytes under traumatic illness has not been sufficiently investigated. therefore we have applied absorption and fluorescent cytophotometry techniques to study the content of rna, glycogen and its fractions in hepatocytes of patients with severe mechanical trauma, both with and without endointoxication at various stages. for these purposes slides were prepared from the repeated aspiration biopsy material according to special techniques (kudryavtseva et al., ) . slides were stained by gallocyanin-chromalum to measure rna or underwent fluorescent pas-reaction to measure glycogen and its fractions (kudryavtseva et al., (kudryavtseva et al., , the ability of metabolites derived from the xanthine-xanthine oxidase system to inhibit mitochondrial function was examined using freshly isolated rat liver mitochondria. under uncoupled conditions, mitochondria exposed to free radicals exhibited a significant decrease in consumption supported by nad+-iinked substrates, but showed almost no change in consumption in the presence of succinate and ascorbate. the activity of electron transfer complex i (nadh oxidase and nadh-cytochrome c oxidoreductase) and the energy-dependent reduction of nad+ by succinate were unaltered by oxidative stress. exposure to free radicals also had an uncoupling effect at all three coupling sites. the degree of mitochondrial swelling was closely correlated with the inhibition of state oxidation of site i substrates and with the increase in state oxidation of succinate. the immunosuppressive agent cyclosporin a (cya) completely prevented the mitochondrial damage induced by oxygen free radicals (swelling, ca + release, sucrose trapping, uncoupling, and selective inhibition of the mitochondrial respiration of site i substrates). the same protective effect was found when ca + cycling was prevented, either by chelating ca + with egta or by inhibiting ca + re-uptake with ruthenium red. these findings suggest that the deleterious effect of free radicals on mitochondria in the present experimental system was triggered by the cya-sensitive and ca ÷-dependent membrane transition, and not by direct impairment of the mitochondrial inner membrane enzymes. correspondence should be addressed to: naoshi takeyama the aim of this study was to clarify the critical role of reduced glutathione (gsh) on the progression of lipopolysaccharide (lps)induced liver damage of mouse. the conditions of gsh-depletion and -richness were produced by intraperitoneal administration of buthionine sulfoximine (bso), a specific inhibitor of gsh synthetase, and of gsh-monoethyl ester (gsh-me), respectively. gsh-me, which was esterified the caboxyl group of the glycine residue, is readily transported into cells and is hydrolyzed intracellularly; this leads to greatly increased the cytosolic and mitochondrial levels of gsh. bso and gsh-me were administered intraperitoneally mmol/kg and mmollkg, respectively, and lps ( mg/kg) given h later. hepatocytes were isolated by in situ perfusion of the liver with collagenase h after lps injection. the degree of hydrogen peroxide (h ) synthesis and mitochondrial membrane potential were measured by flow cytometry using fluorescence probe dichrolofluorescein diacetate and tetrametyl rhodamine ethyl ester, respectively. the degree of mitochondria membrane permeability transition (mmp) was assessed by [ ]sucrose entrapment. we found that lps treatment results in a decrease in hepatic gsh level and mitochondrial membrane potential, and an increase in h synthesis and mmp. lps administration to bsq-pretreated mouse worsened at[ these parameters. in contrast, gsh-me pretreatment ameliorates. all together, gsh may acts an important role in cellular defence against lps-mediated liver damage, and mmp may result in the decrease in mitochondrial membrane potential. it has been shown, up to now, that disturbances of enzymatic processes in the cell organella are the basic factor of the changes taking place during endotoxin shock it has been observed that lysosomes are biochemically changed as result of the effect of lipopotysacharides of gram negative endotoxic bacteria. the purpose of the experiment was: .evaluation nfthe course of the ees due to the biochemic changes .determination of the influence of the ees on the activity of lysosomal enzymes in liver cell .deterrmnatian of the influence of h and d on the activity of some lysosomal enzymes in liver cell during ees material and method: examinations ware carried out on dogs. the shock was evoked by i.v. administration of endotoxin e.coli. the dogs were divided into groups: icontrols, i[ -dogs with untreated shock, iii-dogs in shock treated with h, ivdogs in shock treated with d, v -dogs in shock treated with h and d. the following parameters were determined: .activity of acid phosphatase in the venous blood serum. - .total and free activity of acid phosphatase and catepsins in the full liver cell homogenate, in mitochondrial-and-lysosomal fraction, and in the superuatunt (all after hours of the experiment). conclusions . essential increase of activity of lysosomal enzymes was observed in the ees. . increased activity of lysosomal hydrolases in the liver cell homogenate corresponds, as a result of the endotoxin effect, with increased enzymatic activity in the peripherial blood. extensive investigations from our laboratory of the pathophysiology of hepatic no-flow ischemia ( min) -reperfusion injury demonstrated substantial kupffer cell activation with reactive oxygen formation during the first few hours of reperfusion as indicated by increases in plasma glutathione disulfide (gssg) levels in vivo (am. j. physiol. : g , ) and enhanced superoxide formation by kupffer cells (kc) isolated from the postischemic livers (free radic. res. commun. : , ) . the early kc-induced injury initiated the later, primarily neutrophilmediated reperfusion injury (faseb j. : , ). to test whether or not similar mechanisms are operative during hepatic ischemia induced by hemorrhagic shock, male fischer rats ( - g) were subjected to rain of hemorrhage (mean arterial pressure mm hg) followed by resuscitation (rs) (reinfusion of shed blood). hepatic atp levels declined from . + . txmol/g to . _+ . ( min shock) indicating severe ischemia, and recovered to . -- . at min rs. to test for potential oxidant stress during rs, plasma gssg conc. were measured. although gssg levels increased by % compared to baseline levels ( . !-_ . i.tm), there was no significant difference to shamoperated controls. spontaneous superoxide formation of isolated kc was . + . nmol o -/min/ ecells (kc ) and . + . (kc ) in controls and did not change significantly after shock and rain rs. addition of phorbol ester or opsonized zymosan to isolated kc did not indicate a priming of these cells. conclusion: in striking contrast to our previous findings with hepatic no-flow ischemia, there is no evidence for a significant kc activation after min of hemorrhagic shock and up to rain of resuscitation. objectives-this study investigates morphometric changes in kc nltrastmcture which might account for this diminution in phagacytosis. materials and methods -three groups of wistar rats were studied: control, sham-operated [sham] and bile duct ligated [edl] . after weeks animals were sacrificed and livers were "perfusion fixed" with % glntaraldehyde and processed for transmission electron microscopy and image analysis. results -in the the bdl group kupffer cell numbers were greatly increased. biliary ductular proliferation was evident and sinusoidal spaces were compromised. eleven nuclear and cytoplasmic parameters were measured and statistically significant results are summarised in the results: ascorbic acid levels were slightly elevated after the hs and returned to basal values after rain. glutathione concentrations were increased significantly after the hs and the gsh levels kept rising continuously to as much as -fold of basal levels at the end of min. mda showed no significant variation before and after the hemorrhagic shock. plasma concentrations of ratine, teucine, isoleucine, phenylalanine, proline, threonine and serine showed significant increase over basal levels during the whole ischemic period. glutamic acid was slightly elevated at the onset of hs and remained the same for the rest of ischemic period. hydroxyproline was significantly below the basal value at the mid-point of ischemic period. alanine, glycine, histidine and aspartate did not change significantly throughout experimental time course. conclusions: ( ) oxidative stress might not be severe in the systemic hemorrhagic shock for pigs since no significant variations were observed for ascorbic acid and mda ( ) the increase of gsh might be that it was released from hepatocytes when the animal was under systemic ischemia. ( ) celzain amino acids might be acting as transmitters in the event of ischemia. however, fm"lher investigations are needed to clarify the detailed mechanism in regard with antioxidants and amino acids. dr. fang-ku p'eng taichung veterans general hospital talchung, taiwan , r.o.c. jia shi yong, huang zhi oiang and men xian jun. in patients underi~ent major hepatic surgery,obstructive jaundice has been implicated with fnoreased susceptibility to sepsis and liver failure. jaundice was said to he associated with derangement of iamune function and result in expression of pr,:.inflar...aatory cytoki~es that cause hepatooellular damage. this study is ~.o investigate the effects ,.,t lip,~polysaccharide(lps)rats. jaundice were produced in healthy ~istar rats of either sex weighing - m~ by common hi l~ duet l igation(bl)l).seven days post l igation, rats were given lps( .gg. ) . rag/kg intraperitoneally. at the end ,:,f l,gand hours after lp$ ehanllenge, liver were removed and prepared for forzen sections immediately. i)emonstration of inf in liver parenchyna were performed by method of abu i~munohistochemistry using r~onoolonal antibody against tnf, leve of mrna for tnf ~ere measured by in-situ hybridization using biotin-labeled edna probe. results sho'~ed that tnf stained granules appeared in kup~'fer eell~ and polymorphonuclear leukocytes(pnnl,but not in hepatoeytes nor endothelial eel is. they ~'ere located within cytoplasms and peaked at - hours after lps ohal lenge. there was vocomitant tnfmrna expression but peaked earlier hour post lps challenge. tnfmrna vcere detected notably in necrotic area and barely in bdl rats ~ithout lps challenge. it is therefore postulated that production of tnf by inflammatory effeetor cells-kupffer cell and phn in site, in the obstructive jaundice rats during sepsis may atribute to the hepatocellular damage. it also provide evidence for the beneficial effects of early release of biliary obstruction. in the present study, an animal model of a c in wlstar rats was developed by tigatlng the common bite duct and injecting d. mt solution of e. goli % b, (g× ' efm/mt) into the bite duct. the mortality rate was ~ at h after aoc. at , , , h after aoc, kcs were isotated and cultured atone or cocuttured with hepatocytes to evaluate the modulation effect of kgs on hepatoeyte protein synthesis. the results showed that tactodehydrogenase leakage was increased progressively as the injured k~ function and structure developed. tnf and il-i tn the supernatant were detected with the peak values at h after aoc. at h after aoc, ~-teueine incorporation was obviousty decreased in the normal hepatocytes eocuttured with stimulated kcs compared to the uormai hepatocyte cultured group (p< . ), but it was slgnificantiy increased in the group cocultured with normal kcs. in the a c group, 'h-teuclne ineorporatien was decreased progressively in the injured hepatoeytes cocuttured with stimulatedkgs and it was markedly elevated when cocuttured wlthnormat kcs at h after a c (p< . og). it is concluded that the impaired hepatocyte proterin synthesis was directly mediated hy the stimulated kc function during aoc. such a mechanism possibly may be involved in the patho ensis of hepatic dysfunction and m f following h . " the project supported by nsfc. in the past few years it has become evident that cytokines are implicated in various pathophysiological mechanisms. therefore measurement of cytokines and their potential inhibitors in biological fluids may be helpful in diagnosing and monitoring of diseases. however, dependent on the type of assay used investigations performed in different laboratories have often yielded conflicting results. in order to assess reliability and reproducibility of cytokine measurements two comparative studies for the determination of cytokines in biological fluids were launched by several investigators interested in this field: one national austrian ~tudy and one european study in the context of the european workshop for rheumatnlogy research. serum and synovial fluid samples were distributed by the organisers, and participants had to measure one or several of the following cytokines in all samples: il- , il- , l- , i , tnf-alpha, ifn-gamma, gm-csf, and the soluble receptors for il- and tnf; both commercially available immunoassays and home-made assays were allowed. so far, the main conclusions emerging from these preliminary studies are: ( ) the same immurzoassay (elisa) yielded comparable results in different laboratories; ( ) immunoassays from different manufactureres usually measured the highest concentrations in the same samples, yielded similar relative values but disparate absolute values; ( ) assays for soluble receptors yielded less discrepant results; ( ) some assays seem to be more suitable for measuring cytokines in biological fluids than others. the mean retrieval of exogenous recombinant human cytokines was approximately % for most cytokines tested. however, it must be borne in mind that natural and recombinant cytokines may behave differently in immunoassays. this raises the question as to the necessity of setting up international standards for all cytokines. possible interferences by serum components such as (lipo)proteins, complement, rheumatoid factors, etc., which may either decrease assay sensitivity or yield false positive results, must also be considered. in addition, natural cytokine binding proteins (e.g. soluble receptors) might interfere with cytokine determination in immunoassays. the problem of immunoassays versus bioassays has not yet been approached, but is without any doubt worth indepth investigation. thus, these studies are a promising first approach to deal with the difficulties of cytokine analysis in biological samples, and it is hoped that they will help to overcome some of the major methodological problems in the near future. tumor necrosis factor (tnf) is a pleiotropic cytokine which plays a key role in a number of immunologically mediated disorders like septicemia or cachexia. tnf receptors are found on the surface of a variety of cells, where they provide molecular signals for the cytokine effect. there exist two types of soluble tnf receptors (stnf-rs), tnf-r p and tnf-r p . these stnf-rs can compete with the cell surface receptors and block their activity. the expression on and shedding from the cell surface of stnf-rs is enhanced by interferon gamma. increased concentrations of stnf-rs can be found in patients with infectious as well as malignant disorders. in patients undergoing immune stimulatory therapy with interleukin- and interferon alpha a simultaneous increase of tnf and its soluble receptors can be seen. in patients with hiv infection a strong correlation exists between the levels of stnf-rs and markers of immune activation like neopterin or beta- -microglobulin. likewise patients with hematological disorders show elevated stnf-r levels. patients with weight loss have higher concentrations than patients with stable weight. the final value of stnf-rs within the complex network of cytokines is not yet clear. however, there exist striking parallels between infectious and malignant disorders pointing to a key role of endogenous immune activation. biochemicatly, d-erythro-neopterin derives from guanosine triphosphate. in vitro studies show that large amounts of neopterin are produced by human monocytes/macrophages stimulated with interferon-j (ifn-j). neopterin is biologically stable, and its halflife in the blood seems to solely depend on renal excretion. specimen for neopterin determination can be stored without special precautions. increased concentrations of neopterin have been described in body fluids of patients suffering from diseases which are apparently associated with an activated cellular immune response and with enhanced endogenous formation of ifn-~', e.g,, ) increasing neopterin levels predict rejection episodes in allograft recipients ) virus infections induce increased neopterin concentrations, and the degree of neopterin elevation predicts prognosis in these patients which is particularly true in hiv- infection ) in autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis neopterin levels reflect activity of the disease ) increased neopterin concentrations in patients suffering from certain types of cancer indicate poor prognosis. significant associations between changes of neopterin and decrease of hemoglobin as well as the development of weight loss and cachexia, e.g., in cancer patients and in patients with hiv- infection, support the concept that endogenously formed cytokines such as ifn-~" and tumor necrosis factor-~( are involved in the pathogenesis of such symptoms. in conclusion, neopterin monitoring is a sensitive tool to detect the activation status of the cell-mediated immune system in vivo. repair and healing or perpetuation of acute inflammation is characterized by a complex network of interacting cellular and humoral defence mechanisms. of the numerous inflammatory mediators/effectors investigated hitherto, the proteolydc lysosomal enzyme pmn elastase has turned out to be highly destructive when released extracellularly thus contributing considm:ably to organ dysfunctions in severe posttraumatic and postoperative courses. besides various cytokines, elastase in complex with its main antagonist c¢ -proteinase inhibitor (a pi) is also supposed to induce the shedding of intercellular adhesion molecules from inflammatory cells (pmns, monocytes/macrophages, endothelial cells). these soluble adhesion molecules may modulate the inflammatory process in many different ways, e.g. via acting as chemotaxins, blocking neutrophil activation or competing with the membrane-bound forms in cell-cell adhesion. thus, measuring circulating or local levels of elastase-a pi and soluble adhesion molecules (icam, e-selectin,-pselectin, l-selectin) may be a helpful tool in judging the severity of an acute inflammatory process. in several clinical studies on surgical patients suffering from multiple trauma and/or sepsis we could demonstrate that the measurement of these parameters in consecutive plasma samples and local body fluids was highly valuable for early diagnosis and prognosis of multiple organ failure. prof. dr. m./ochum, institut fdr klinischechemie und biochemie, lmu miinchen, nufibaumstrage , m nchen, germany procalaitonin (proct) a aa peptide is dramatically increased in the blood of patients with various sepsis and infections. the increase begins as soon as hours after the andoto:edn release and readied maximal level with a to b-fold increase h after li~ edrmrdstration. prcc, alcitorfin response was temporally different from these of tnf~ and ii- , that reached peak levels at h and h respectively. at the opposite of eytokine (tnfcz, ild, j, is), proct is a very stable molecule. the half iife of proct in ~he blood is surprising if we consider the half llfe (about nine mirtute) of mature ¢alcitonin (co. we have found that it is due to the binding of proct with a protein on the n-termktal part. thin complex of about daltons is unable to cross the kidney and the c_n barriers and the half life is at least elghteen hours. this long half llfe is very useful in the evaluation of a sepsis. a very sensitive and specific sandwich in'ununoassay has been developped. the results cart be delivered in two hours. at time, we know that in the healthy adults, the values are less thau . ng/ml. it is also clear that proct is not increased ~n patients wlth inflammatory dleeasea without lnfectlon. for instance, proct is not signlffcat vely increased in purpura rhumatom, arthritis, crohn's disease, rectocolitis, also in various cancer patients with inflammatory components. am other interesting finding, is the absence of increase or a very low increase in the viral infections. at the opp site, in all the patients with bacterial sepsis or in the malaria pat/ants, progt was dramatically increased, from i to fold. p~oct can be useful to the follow up of patients with sepsis. actually, we don't know the origin of this proct production, in the united states, will also be discussed. the septest portion of this study will eventually enroll over patients tentatively diagnosed as septic. the results of septest will be compared with commonly accepted symptoms and criteria associated with sepsis in order to determine the clinical utility of this endotoxin assay. preclinical results of patients and normals be presented as well as data on the time course of endotoxemia and clinical outcome of selected septic patients. preparation of dna libraries clifford w. schweinfest, ph.d. a fundamental tool of the molecular biologist today is the ability to work with purified dnas representing genes of interest with respect to the investigator's field of study. originally applied almost years ago to the genetic dissection of simple organisms such as viruses and bacteria, molecfllar cloning was rapidly applied to study the more complex genetics of the mammalian cell. today, virtually any study of cell physiology which depends upon specific gene expression is approachable using the tools of the molecular biologist. therefore, stress induced gene expression (such as the heat shock gene, hsp ) or the regulation of the nitric oxide synthetase gene or the induction of cytokines and growth factors as a result of trauma or injury lend themselves to investigation at the level of the gene. during these workshops, we will discuss the means by which cdnas and genes are isolated, amplified and identified. we will discuss the strategies and methods for cloning cdnas and genomic dnas, for organizing such cloned libraries, for finding specific genes and for characterizing those genes. this speaker will focus on the techniques and considerations involved in the synthesis of cdna libraries. topics include rna isolation, mrna quality, reverse transcription, choice of cloning vectors and library quality. genomic dna library synthesis will also be discussed with respect to the vector/host systems available and applications which are specific to genomic dna. finally, polymerase chain reaction (pcr) will be discussed briefly with regard to its impact on dna cloning. the identification of the genes or gene products that have a role in cellular processes is fundamental to our understanding of genetic control and methodologies to achieve this aim are currently available. all levels of the various signal transduction pathways can b~ molecularly analyzed to define the mechanism by which critical steps in each pathway are achieved. the questions that are unresolved in each area of investigation serve to direct the scientist towards analyses of gene products or gene regulation of the gene itself. thus, selection of the type of library (genomic or cdna) to be used is dependent upon the specific goals of each investigator. to facilitate resolution of this question, an overview of the uses for the different types of libraries will be presented. at least four methodologies are currently available for screening a library, which are dependent upon specific interaction between nucleic acids, nucleic acids and proteins, antibodies and antigens or between different proteins. the use and advantages of each of these methodologies will be discussed along with a description of probe preparation. sequence methodologies required to begin characterization of gene clones will be presented. hopefully, the participants in the workshop will help define areas of emphasis and allow time for directed interaction to discuss specific applications based upon their own experimental systems. alterations of physiological conditions, such as those occurring after shock and sepsis, induce changes in gene expression of cells composing the major organ systems. the challenge is to detect and characterize these changes in geae expression and relate them to the injury. the development of cloning techniques has emerged as the methodology of choice. changes in gene expression are usually characterized by variations in the concentration of cellular messages because synthesis of the final product "the polypoptide" is usually proportional to the concentration of mrna. due to the rapid regulation of gene expression the cellular concentration of messages changes very quickly. this is commonly referred to as steady-state levels, a balance between transcription and degradation. steady-state levels of mrna can be detected in a single cell (in situ hybridization) or in total rna isolated from cells or organs and separated in agarose gels (northern blots). although analysis of mrna steady-state levels are very useful, they do not provide information about the mechanisms that regulate gene expression. changes in gene expression primarily occur at the level of transcription; characterization of the rna species being synthesized at a given time is performed by the nuclear run-off technique. when there is no a priori information about the gene that may be regulated after a particular situation such as sepsis, the total pool of messages present in cells at given time can be characterized by a combination of in vitro translation of the cellular messages and fractionation of the in vitro translated products by two dimensional gel electrophoresis. such approach permits the visualization of the general pattern of gene expression, a "finger print", of the physiologic state. in summary, researchers now have access to a great variety of techniques to identify and characterize genes expressed in response to a physiological condition that may be utilized as "molecular tools" to study the organism's responses to shock and sepsis. the acute phase proteins are a set of plasma proteins with greatly increased plasma concentrations during acute inflammations and after tissue trauma, e.g. after major surgery. the proteins counteract the source of injury, facilitate clearance of infectious particles by phagocytes, assist immune responses and initiate wound healing. the corresponding genes are expressed in liver hepatocytes and regulated by the inflammatory mediators interleukin and interleukin (ill, il ). class acute phase genes are mainly controlled by ill and by combinations of ill plus il ; class genes mainly by ii, . the human c-reactive protein(crp), serum amyloid a(saa) and complement c genes will be discussed as examples of class genes, and rat c~ macroglobulin as a prototypical class gene. both classes of genes use different types of ¢ytokine response elements in their promoter-proximal transcription control regions; class genes use the transcription factor nf-il or c/ebp as the key factor to mediate cytokine responsiveness; class genes use a different, so far unidentified factor to achieve responsiveness to il . ongoing efforts to purify this factor, called the il -response factor (il -rf), from rat liver nuclear protein extracts will be described. the il -rf apparently mediates the effects of il in a broad range of cell types, including b lymphocytes and other hematopoietic cells. it is therefore likely to be of equal general importance for gene regulation by il as nf-il . the importance of transcription factors as potential targets for novel bioactive substances and possibly therapeutic agents will be discussed with the help of several recent examples. new methods for altering the germ lines of mice provide powerful tools for understanding the roles of individual genes in normal and pathological processes, and for reproducing specific genetic mutations that result in congenital disease. three approaches will be discussed. conventional transgeulc mice are frequently constructed using artificial transgenes that express genes from a promoter other than the normal gene promoter. this paradigm is used to produce very high levels of a gene product, for example, with a viral promoter, or to attempt to regulate gene expression using an inducible promoter. alternatively, normal promoter sequences can be hooked to a gene whose expression is lethal to the cell (e.g., diptheria toxin a chain) to ablate all cells expressing that gene. another approach uses an intact gene with its normal regulatory sequences. here, an elevated level of the gene product is delivered from the correct cells in the correct tissues at the correct developmental stages or in response to natural signals. this approach has been refered to as "genetic pharmacology," and provides a precise delivery of the gene product to the target. however, to be most effective, the transgene should contain arl regulatory sequences as welt as the entire genomic segment containing gene coding regions. the introduction of conventional transgenes is limited to roughly kilobases, while genes containing all regulatory sequences frequently stretch over dozens or even hundreds of kilobases. to overcome this problem, procedures have been developed recently to introduce yeast artificial chromosomes (yacs) into mouse embryonic stem (es) cells. yacs can include over mb of human dna, large enough to encompass the largest known human genes. es cells are also useful for targeted gene deletions and mutations. homologous recombination can be targeted to any known gene in es cells. when these modified cells are injected into a mouse blastocyst, they can be incorporated into all tissues of the resulting mouse, including germ cells, so subsequent generations will pass the genetic modification as an inherited trait. assessment of the effects of a null allele on development can provide valuable insights into its normal role. ultimately, these technologies may be adapted to human cells -not for embryonic intervention, but to provide modified stem cells for various tissues (e.g., gut, eye, hematopoietic system) which could then be applied to somatic therapies. with major illness/injury that respirswy faihne fi'equently followed sepsis, tilney el al nse, d the term "soqueutial syste~ failure" for patients with renal failure after solmir of ruptured abdominal aortic ~aeurysms, i then reviewed our experiences after inju~ and oporstion and suggested that multiple, progsesslve or sequential systems or organ failure was a syndrome to be reckoned with in the, 's. eiseman et al then wrote about "multiple organ failure", especially with liver failure. polk el m found that renmte orgau failure often signalled occult anita-abdominal infection. fry et al ampbasized the role of uncontrolled infection in organ failure, border et ai described metabolic alterations with mof and used the term multiplesystems organ feilmo (msof). other early conltibutots to our knowledge of mof include faist, trunkey and miller, marshall and dimic&, cassone, catlleo, meakins and marshall, (}otis et at., mater and many others. mof or msof were used eommoifly. cerra coined the terms "post-trsumatic septic sfndromc" and "hyper metabolism otgau failure complex", and border et al, used lhe ex ~ression "gut origin seplic states" to illdioate important eurrem aspects of abe gt.'nerlc problem of organ failure and death, other terms include acute organ-system failure, multiple organ injury syndrome, post-traumatic multi-system organ failure nod post-~aumatic organ system infection s~dmmc (fi~sis), i bdieve the latin "maltiple organ failure" is clean, neat and says it all, now there is a proposal for a new set of torminolugios -mods and sirs. will they be helpful in the study and esro of patients? our speakers in this session will review thcsa proposals and the evidence as we strlvo for eoasensns. it has been well demonstrated that the administration of pro-inflammatory cytokines, and especially tumor necrosis factor (tnf) can result in a picture similar to septic shock with secondary multiple organ failure. it is also clear that tissue hypoxia can lead to organ damage. we believe that it is the interaction between the two phenomenons that can lead to mof. on the one hand, the inflammatory response is amplified in the presence of hypoxia. on the other hand, the release of the mediators of sepsis can increase tbe oxygen demand ef the tissues, alter their oxygen extraction and decrease myocardial contractility, and the combination of these elements accounts for the development of septic shock. this hypothesis is supported by two lines of evidence. first, mof is usually preceded by an episode of acute circulatory failure (even though frank circulatory shock may not be evident). second, recent experimental and clinical studies indicated that immunotherapy (especially antibodies to tnf) is particularly effective in the most severe forms of sepsis, associated with circulatory shock. hence, an effective way to prevent mof may be a combination of aggressive cardiovascular management and immunotherapy. development of the multiple organ dysfunction syndrome (mods) in the critically ill follows an heterogeneous group of stimuli including infection, sterile inflammmion, extensive tissue injury, ischemia, intoxication with a variety of substances, and immune system activation. whether the resulting physiologic abnormalities reflect a common pathologic process, or are simply a non-specific manifestation of tissue injury is unknown. moreover, the lack of clearly-defined functional criteria for the characterization of the syndrome on the one hand, and of reliable biochemical markers of its evolution on the other, has made attempts to define its epidemiology and natural history difficult. using a numeric scoring system to quanfimte the clinical severity of mods, we demonstrated that, although mods is more common in patients who have significant infection at the time of icu admission, a much stronger correlation is evident between the severity of mods and the subsequent development of nosocomial icu-acquired infection. furthermore the severity of mods correlates strongly with the severity of the clinical septic response, and with the degree of immunologic compromise evident on delayed type hypersensitivity skin testing. to determine the relative importance of the initial stimulus, and the host response to that stimulus, to the subsequent emergence of mods, we undertook a matched cohort study of critically ill patients admitted to the icu with infection, matched by age, sex, and apache ii score to uninfected controls. organ dysfunction scores were higher in patients admitted with infection, but were also significantly associated with the expression of a septic response at the time of icu admission, independent of the presence of infection. by stepwise regression analysis, the magnitude of the septic response was the most powerful predictor of the severity of mods in both infected and uninfected patients. these data suggest a model of mods in which a stimulus (eg infection) and the host response to that stimulus (eg the septic response) result in a state of altered systemic homeostasis (manifested in this example by immunologic dysfunction). moreover they suggest that the principle determinant of the emergence of mods is the response of the host, rather than the nature of the stimulus, and are consistent with the hypothesis that a stereotypie systemic response to an heterogeneous group of injurious stimuli underlies the pathogenesis of mods. arthur e. baue, m.d, ever since the attorapt build the tower ef babel, as desclibcd in the old testament of the biblc, it has been difficult to got agreement o;x common definitions or language, although mof has served well, there will always he now classifications proposed with good reasons for them, thus mods and sirs are not the final oxpressinns in the lexico~aphic sweepstakes. attcmpts to develop standard animal shock and scpsis models (hemorrhage, endotoxin, foes[ pellets, cecal ligation and puncture, e. colt hlf sioi to evaluate therapy have net been suoca.ssf~. clinical syndromes of mof, sepsis, sepsis syndrome and athers have not been aeacpte.d by all. our problem is that we arc tryittg tu d¢ffino a non-emily. mof or mods or sirs is net a disease or oven a syndrome. it is a series of complications of injury, disease and intensiva care which loads to death for many patients in intensive care units, it is not a fixed entity, but an ewilving picture. we have lumped (ugethet for therapy and definition a number of diseases and problems according to clinical manifestatieos rather than the eause of ihe problem, the search for unified mechanisms has not bean successful. will we benefit oleo from a more precise classification and definition of a non-outjty, a hodgu-podge of human disorders which have charsmeristic.s and manifestations of tissue injury, inflammation and infactian? re.hi clinical trials of potential "magle ballets" suggest that we should go in a different direction--instead of lumpors, we should be splitters, to seek effective therapy, we must fucus on specific disorders such as trauma, specific infections, inflammatory disease and chronic or acute organ damage (copd -renal failure, etc.), i will say more aboet this later ha the me.ethag. thcre is cue potentially important pert of the mods proposal, and that would be do~mcntation of organ dysfunction before fsiiure occurs and before tile need for external supporl dovelope. this could lead to hatter methods of preventing organ failure. preveution is ultimately the only answer to organ failure, m mof, mods and sirs. have wo reached a consensus?--only that we arc dealing wilh a diffl~x:lt probtolr looking for solutlons. acute lung injury (ali) and its most severe form, acute respiratory distress syndrome (ards) characterized by severe hypoxemia, diffuse infiltration of both lungs, a reduction of compliance and a wedgepresure lower than mm hare related to direct or indirect injury. when aliresults from direct injury (toxic agents, lung contusion, pneumonia), the lesions of epithelial barrier and the activation of lung macrophages are the first events leading to the release of inflammatory mediators wh:ch are responsible for alteration of the membranar permeability and for invasion of the alveoli by fluids, proteins and cells. an inflammatory reaction develops, with injury to endothelial cells, adhesion of polymorpbonuclear leucocytes (pmn) and the release in blood stream of intlammatory mediators dispersing the inflammatory reaction to other organs and tissues. the failure of lung function also results into hypoxia in other organs, leading to tissular ischemia, triggering an inflammatory reaction leading to organ dysfunction. frequent complications of direct lung injury are septic pneumonia with endotoxin release, phagocytes activation and cytokine production disseminating inflammation. by this way, direct lung injury can be at the origin of the multiple organ dysfunction syndrome (mods), the frequence of which having been estimated to % and is increased when all has occured in patients alreadypresenting an organ dysfunction (immunodepresslon, cancer...). when ali results from redirect or extrathoraclc injury (trauma, infections, hypovolemic shock, acute pancreatitis...), inflammatory mediators and micro-aggregates released in particular organs or tissues reach the lung via the blood and lymph streams, are filtered in the organ or trapped in the lung capillaries, and are responsible for a local inflammatory reactaon (endothelial cell activation, pmn trapping and adhesion, platelet aggregation, release of mediators). sepsis acts by the way of endotoxiu and sequential eytokines release (tnf, ill,...) while trauma with important blood loss acts especially by the way of hypoperfusionreperfusion phenomena leading to a disseminatedinflammatory reaction and to a possible bacterial transloeation when intestinal hypopeffnsion is present. in these conditions of indirect injury, all (or ards) is a iocal early (often the first) manifestation of a general phenomenon of altered membrane permeability and inflammatory reaction, easily and rapidly recognized by its clin~cai signs. the iung is one of the numerous organs participating to the mods, in these conditions, the mortality rate is high, reaching more than % when sepsis is present or when at least organs are implicated in mods. by direct or redirect injury, lung is so a target organ for mods and injured lung can be the cause of mods or simply a participant to this syndrome. jorge cervts-navarro main determinants for brain dysfunction are breakdown of the blood-brainbarrier and raise of intracranial pressure (icp), in second place decrease of systemic blood pressure, disorders of blood coagulation and respiratory function. the blood-brain-barrier of cerebral blood vessels can be opened by stroke, cerebral trauma, inflammation, convulsions, acute hypertension and changes in the blood osmolarity. the consequence is brain oedema, increase of lop and decrease of the perfusion pressure. a close correlation between intraventricular pressure and the fate of patients with severe brain injuries has been established. regional cbf values of to ml/ g/min are reflected in isoelectric eeg, and values about t ml/ g/min, result in loss of somatosensory evoked potentials. for ionic pump failure the threshold has been determined by values of about ml/ g/min and is reflected in massive release of intracellular potassium. in stroke and in brain trauma when the oedematogenous condition is initially localized the tissue pressure variance within and between the hemispheres lead to tentorial and falciform herniations are the common cause of death even before the critical threshold of intracranial pressure is reached. the increase of the icp over the level of the perfusion pressure leads to the arrest of the cbf. if this persists {or periods exceeding seconds of global brain ischemia loss of conciousness and developing seizures appear. if it exceeds min irreversible injuries of the brain appear. following cerebral ischemia and after severe head injury a tendency to increased coagulation can be detected. vascular occlusion may develop either as a result of local thrombus formation or from emboli caused by circulating platelet aggregates. the formation of microthrombi is triggered by the plateletactivating factor a mediator in central nervous injury also responsible for aggravation of posttraumatic brain edema. acute hemorrhagic leucoencephalitis and brain purpura are known to arise as complications of acute viral infections and following gram-negative septicaemia. institute of neuropathology, free university of berlin, hindenburgdamm , berlin, germany undoubtedly, attempts to quantify as objectively as possible the degree of dysfunction of the various organs is very valuable. however, cardiovascular failure has a peculiar place in the context of sepsis. the development of acute circulatory failure (shock) is of paramount importance as a cause rather than as a consequence of organ failure. it is therefore essential to clearly separate patients with and without circulatory failure. once this has been done, attempts to list the cardiovascular system among the other systems have been unconvincing. in a number of studies, cardiovascular complications are assimilated to a low systemic vascular resistance (svr), but since svr is basically the ratio of blood pressure over cardiac output, and since hypotension is already included in the definition of shock, then a low svr is basically equivalent to a high cardiac output, which is a characteristic rather than an ominous complication of severe sepsis. development of a low cardiac output unresponsive to fluids is usually a terminal event. it is not advisable to list other problems such as severe arrhythmias, myocardial infarction or tamponade as complications of severe sepsis. host defense dysfunction following trauma, shock and sepsis e. faist, g. f. babcock * major accidental, burn and operative injury often precipitates a profound multicentric immunologic depression that is believed to predispose patients to become anergic and thus to develop towards a higb probability of infection. anergy or a lack of immunologic reactivity stands for a total elimination of skin test reactivity and recall antigen responses in the inununocompromised patient. anergy following overwhelming trauma or major septic conditions results from a massive impairment of cell mediated immunity (cmi) together with a whole body malignant inflammationiike state. we and others have demonstrated clearly that the skeration of cmi following trauma is mainly due to the disruption of intact monocyte (moo) / t-cell interaction. within this phenomenon we see a shift of the cell ratio in the compartment of peripheral blood mononuclear cells (pbmc) with a considerable increase of prostaglandin e synthesizing m~ and a simultaneous decrease of functionally competent cd + and cd + lymphocytes. t-cell dysfunction in states of profound stress is characterized by impaired synthesis of two crucial lymphokines -interleukin- (il- ) and gamma-interferon (y-ifn). the inability to produce adequate amounts of il- , most likely attributable to alterations in the transmission of signals from the cell membrane to the nucleus, results in incomplete proliferative t-cell responses to antigenic stimuli, while a lack of ?-ifn results in inadequate m~ antigen processing and presentation. the role of the two functionally distinct t-helper subsets, t-helper- (thl) secreting principally il- and ?-ifn and t-helper- (th ) acting principally in inducing antibody formation with a secretion of il- , il- , il- and tnf-[ has still to be established within the context of major trauma. antibody formation to common protein antigens is impaired, the predominant finding is a shift from igm to igg synthesis. although excessive secretion of prninflammatory cytokines (il-u , tnf-c~, il- , il- ) has been considered to be deleterious for the host in states of major inflammation and infection, in-vitro and whole blood investigation of me function has clearly revealed that there is initially a marked suppression of moo from septic patients to synthesize and secrete proinflammatory cytokines to endotoxin. this probably will result in immunodeficiency of traumatized as well as septic patients, since these cytokines in low concentrations are involved in the upregulation of the essential humoral and cellular immune functions. abnormalities of pmn function noted after serious injury have been interpreted by some investigators as signs of unresponsiveness of this cell population, others have demonstrated signs of pmn byperactivation. latest findings revealed that there is a clear pmn dysfunction in circulating blood: % of all pmn's in this compartment show downregulated or non existent ~-integrins within hours posttrauma -these cells do not phagocytose, have a reduced respiratory burst and appear to be completely degranulated. restoration of these cell functions within days post-trauma is significantly correlated to survival of traumatized patients. other reports however stress increased expression of cr + receptors (cdll/cd complex) on circulating pmn's, increasing the ability of these cells to adhere to intercellular adhesion molecules, thus contributing to play a major role in inducing the pulmonary capillary leakage. our knowledge about the perturbation of host defenses associated with serious injury and sepsis is continuously increasing and represents the precondition for the design of effective therapeutic measures to prevent and counteract the resistance to invading microorganisms. dept. of surgery, klinikum grosshadern, ludwig-maximilians-university, munich, germany. * dept. of surgery, university of cincinnati, cincinnati, ohio, usa lg thijs~ ce n~ck sepsis is the most common cause of acute disseminated intravascular coagulation (dic) and coagulation disorders as well as abnormalities of fibrinolysis are common in septic patients. some clinical and experimental studies indicate that dic is a pathogenetic factor for the development of multiple organ failure. endotoxin and various mediators (tnf, il-i) enhance tissue factor and decrease expression of thrombomodulin on endothelial cells in vitro. also, tpa activity is suppressed and release of pai-i is stimulated. in such a way the endothelial surface becomes procoagulant whereas fibrinolysis is inhibited. following administration of endotoxin to normal volunteers levels of prothrombin fragments (fi+ ) and thrombin-antithrombin (tat) complexes increase, indicating thrombin generation. also the fibrinolytic system is activated as evidenced by a rise of levels of tpa and plasmin-antiplasmin (pap) complexes but this is counteracted by a subsequent release of pai-i. in severely ill septic patients levels of tat complexes are increased and concentrations of the natural inhibitors of coagulation (at iii, protein c) are usually decreased. also, tpa levels snd pap complexes as well as concentrations of pai-i are elevated. the severity of many of these alterations is related to mortality. thus, both coagulation and fibrinolysis are activated in sepsis, but not in a balanced way, thereby promoting coagulation. one of the hallmsxk pathological alterations associated with sepsis is the development of microvascular thrombosis, an entity ~lmre~erizod by microvas~tlar plugbing with leukoeyies (predominately nentrophils) and fibrin deposits. preranably, ischemia remlt~g fibm ve~-'ttlac ow,.luwion contributes sisni.ficantly to end orgen darnaje and consequent dysfatlctlon. p, er~t srldies haw focused pmdominately on the role of adhesion molecules in the pathogenesis of neu~ophil sequestration during infection and s~sis. this preparation will review the mechanisms underlying intravak-'v.ler i~brin deposition and its contribution to organ injury. the normal endothelial cell sure is generally conddered o be anticos~am. this state is maintained by two major anticoag~lam molecules on the cell so,ace: hepax'an su,lfale and thmmbomodulin. studies performed over the past decade have do~mentod a general shii~ towards a procoa~qtlant staw during gram negative hffeodon, aft e~| mediated mainly by changes in the endothalial cell surface. antt-tf antibodies have been shown to be pro~ective during l~'ml endotexemia. in summary, ~erova~'~ler fibrin deposition, in ~rt mediated by ~rcgulation of cellular tf, is a consistemt patholo~cal flndin~ during sepsis and contributes to organ injury. strategies designed to abrogate this event may n~nimjze the magnitude of erg~ dysftm~on. n, v, christou md phd, department of surgery, megill university, montreal, quebec, canada interactions between immune calls and the endothelium vie adhesion molecules serve to modulate immune cell traffic between the blood strum and the extrmvascular space, these families of molecules acting in a cascade and closely integrated with the oytoklna network, blood coagulation and the complement system, are responsible for the homing of leukocytes to areas of inflammation and the realrculatlon of tymphocytes. there are three types of immune ceils that must exit the blood stream into the extravascular space: lymphocytes ; polymorphonuclear leukocytes; and non-lymphocyta mononuclaar cells (monooytes, basophlls, aoslncphils). b lymphocytes exit the blood stream and recircu}ate mostly via the high endothelial venule (hev) in lymphatic tissue, rarely, in chronic }nfectlon=, they may recirqulate vie hev in non-lymphoi:t tissue. t-lymphocyte recircutation on the other hand can occur via hev in lymphoid tissue, as well as, the endothalium of the skin, returning to peripheral lymph nodes via the lymphatic channels. lymphocyte recirculation is the mechanism which allows ¢ontaot between the immune repertoire and pathogens, and homing delivers these cells to the appropriate environment for activation and for effeotor function, pmns exit the blood stream through endotbelium in close proximity to the site of inflammation after appropriate endothelial membrane receptor expression. they must reach the site of pathogen tnveslon quickly in order to be effective. their exudation to the inflammatory site can be modulated by their intravascular pdmlng, which results from appropriate receptor expression. because endotoxin leak from the gut has been postulated as an important trigger mechanism for the systemic inflammatory response syndrome seen after serious injury, the immunologic and metabolic effects of bacterial endotoxin infusion into normal volunteers can be expected to shed considerable light on the validity of this hypothesis. we and ethers have used tbis model to show that endotoxin causes a temporary paralysis in the ability of circulating monocytes to prudce the proinflammatory cytokines interleukin-i (il-i) and tnf-a. endotoxin, however, causes increased production of pge by the same cell population. endotoxin infusion causes significant suppression of circulating t-cell numbers and a profound suppression in the ability of the circulating t-cell population to proliferate and to produce interle~in- (il- ) upon in vitro stimulation. after endotoxin circulating t-cells are also more sensitive to the inhibitory action of exogenous pge . administration of cyclooxygenase inhibitors at the time of endotoxin infusion largely abrogates the effect of endetexin on t-cell proliferation and il- production. endotoxin infusion also causes the release of increased levels of circulating catabolic hormones including cortisol. administration of cortisol alone or cortisol along with endetowin to volunteers has allowed dissection of cortisol effects from those of endotoxin itself. cortisol infusion alone causes a diminution in the circulating t-cell population but the remaining ceils continue to produce il- after appropriate stimulation. cortisol infused along with endotoxin blocks the overshoot in monocyte proinflammatory cytokine production seen - hours after endetoxin infusion. at present, one may conclude that administration of sublethal doses of bacterial endetoxin to human volusteers produces alterations in cytokime production and tlymphocyte activation which are both similar and dissimilar to those seen following serious injury. hemodynamic support is based first on intravenous fluids and second on vasoactive agents. colloids are usually preferred to crystalloids, for their more rapid hemodynamic effects and their lesser passage in the interstitial space. in the presence of hypotension, the pharmacological profile of dopamine makes it the first agent of choice. it is only when high doses of dopamine are insufficient to restore a sufficient tissue perfusion pressure that norepinephrine should be added. even when cardiac output is not decreased, a dobutamine infusion is often indicated to counteract the myocardial depression, prevent vasoconstriction, and increase oxygen delivery to the tissues. the benefit derived from the administration of "renal" doses of dopamine is doubtful, but stimulation of dopaminergic receptors may increase blood flow also to the gut. in any case, none of these catecholamines has been shown to significantly improve the oxygen extraction capabilities of the tissues. agents with antiinflammatory properties but also with some vasodilating properties, such as n-acetylcysteine, prostaglandin el or pentoxifylline represent more attractive options to increase oxygen extraction. cardiovascular support should aim not only at the restoration of a sufficient arterial pressure but also at the maintenance of an optimal oxygen delivery to the cells. it should thus be guided also by measurements of cardiac output, mixed venous oxygen saturation and oxygen extraction, and indexes of cellular hypoxia, such as blood lactate levels, gastric intramucosal ph or vanearterial pc gradients. supranorma[ delivery contributes to the prevention of tissue hypoxia tissue hypoxia is considered to be the common final pathway in the pathogenesis of multipte systems organ failure. it may directly contribute to cellular injury and organ dysfunction as well as enhance further mediator activation and release by a positive feed back mechanism. prevention of tissue hypoxia, is therefore, one of the most important aims in the supportive therapy of critically ill patients, especially in those with sepsis and septic shock. mismatch of cellular o= supply and demand in these patients may resuit from the impairment of the cardiocircu[atory system on all levels. . myocardial depression with a drop in delivery (do~) . redistribution of blood flow between the different organ systems . inadequate nutritive blood flow due to tissue edema and endothelial damage (gic, leucocyte swelling etc.) these pathological changes may go along with increased metabolic needs. cellular and organ supply may therefore be inadequately matched with cellular needs in patients with normal and even supral normal doz. hyperdynamic circulation is often present in adequately volume resusucitated patients. it is most likely that one of the bodys main compensatory mechanisms would maintain cellular o= supply in the face of increased metabolic needs and impaired oz extraction capabillities. this pathophysiology may explain the findings in several clinical investigations that patients with normal or even supranormal doz can have signs of inadequate regional tissue oxygenation. it is also consistent with the results of different studies which demonstrated that the achievement of supranormal doz levels, either spontanuously or due to adequate supportive therapy, resuits in better patient outcome. any attempt to prevent or treat tissue hypoxia in these patients, however, has to take into account the effects of therapy not only on global dgz but especially on regional and microcirculatory blood flow. r. rossaint, d. pappert, k. lewandowski, h. gedach, k. slama, k.j. falke klinik for anaesthesiologie und operative intensivmedizin, ukrv, freie universit §t berlin, germany important contributory factors to the high mortality of severe acute respiratory distress syndrome lards) are the aggressive therapies required, such as mechanical ventilation with high inspiratory oxygen concentrations and airway pressures. as specific therapies for reducing or preventing the general inflammatory reaction of the lung resulting in severe hypoxemia is unknown, today's therapy is limited to procedures which predominantly support or maintain pulmonary function, i.e. pressure limited ventilation with peep and permissive hypercapnea, avoiding or treatment of fluid overloading, and positional maneuvers. extracorporeal lung assist combined with low frequency positive pressure ventilation has been recommended, when conventional therapy fails. today, extracorporeal gas exchange may be carried out using a system internally coated with covalently bound heparin. this allows for a lower level of systemic heparinzation reducing the risk of severe hemorrhagic complications of extracorporeal respiratory support. from april to august patients, aged from months to years, were transferred to our intensive care unit (icu) for treatment of severe ards. all fulfilled at least the slow entry criteria of the u.s. national ecmo study. due to hypoxemia patients required veno-venous extracorporeal membrane oxygenation (ecmo) immediately after transfer to our icu. the other patients were first treated with pressure controlled mechanical ventilation, permissive hypercapnea, prone position, and dehydration, if necessary. in out of these patients, in which the gas exchange did not improve in the following days, veno-venous ecmo with heparin-coated systems was additionally performed. heparin was given to achieve a partial thrombin time between - s and an activated clotting time between - s. if surgery was performed during ecmo, heparin infusion was interrupted. no severe bleeding complications related to anticoagulation for the extracorporeal bypass could be observed, however, in some patients, after three weeks of ecmo thrombi in the drainage cannula were observed. a problem of of membrane leakage shortened the life span of the membrane lungs to a mean of about four days. in the conventionally treated group % survived and in the additionally with ecmo treated group % survived, representing a % survival rate in patients whose risk of death is considered more than %. on the basis of these experiences, we conclude that the described strategy, including veno-venous ecmo with heparin-coeted systems, may improve the survival in patients suffering from severe ards. abnormally high skeletal muscle po in septic patients and its normalization during recovery: evidence against tissue hypoxia but for impaired oxygen metabolism of skeletal muscle? p. boekstegers, k. werdan department of medicine i, gro hadern university hospital, munich, germany a pathological oxygen uptake supply dependence was suggested to indicate tissue hypoxia in sepsis-a hypothesis which is discussed controversially. because the detection of reduced oxygen transport to tissue and &tissue hypoxia would have important implications for therapy, skeletal muscle oxygenation was studied in patients with sepsis. intermittent and continuous determination of skeletal muscle po by polarographic needle or catheter probes provided no evidence for skeletal muscle hypoxia even in severe stage of sepsis (boekstegers et al., crit care med ) . in contrast, mean skeletal muscle po was found to be abnormally high in patients with sepsis ( _+ , mmhg, n= ) compared to patients with limited infection ( , + , mmhg, p< . , n= ) , to patients with cardiogenic shock ( , + , mmhg, p< . , n=ls) and to healthy subjects ( , _+ , mmhg, p< . , n= ). furthermore, serial measurements in patients with sepsis showed that skeletal muscle po was higher ( , _+ , mmhg) on days with severe sepsis than on days with intermediate state ( , _+ mmhg) and than on days without sepsis ( , _+ , i mmhg) . thus, a decrease of abnormally high skeletal muscle po was related to improvement of sepsis. this was also demonstrated by comparing the decrease of abnormally high skeletal muscle po with the decrease of apache ii score or elebute score as well as interleukin- serum levels in a separate study (boekstegers et el., shock, in press). in summary, our data provide no evidence for skeletal muscle hypoxia in patients with sepsis but support the assumption &impaired oxygen metabolism in severe sepsis. neutropnlic emigration from the vascular space into the extracellular matrix is important for the response to tissue injury or contamination by providing a large recruitable pool of tissue-based phagocytes. the consequences of neutrophil exposure to intravaseular chemoattractants, likely relevant for il- and c a in sepsis, trauma, and in burn injury, are suppression of neutrophil attachment to endothelial cells and matrix proteins. it is probable that proteoglycan-bound attractants are of considerable biologic relevance, and may result in enhancement of responses to subsequently encountered cytokines. in the presence of connective tissue proteins expressing integrin-specific binding ligands, neutrophils respond to tnf-cq gm-csf and other cytokines by producing large amounts of hydrogen peroxide. this response is likely important in the digestion of contaminated or injured tissue by facilitating activity of neutrnphil granular proteases and inactivating plasma anti-proteases. this matrix-dependent oxidative response is important in defining potential novel targets for therapeutic intervention. the response appears to involve signalling by integrin-linked tyrosine kinases. the net effect of matrix protein injury through this mechanism is enhancement of the fibrotic response which underlies much of the prolonged ventilator dependence of patients with the adult respiratory distress syndrome. this adherence dependent response has also been implicated in direct hepatocyte injury, and may represent an early component of the syndrome of multisystem organ failure. study purpose: in this patient (pat.) population with a considerable sepsis morbidity and mortality, parameters proposed for sepsis assessment (elebute sepsis score [ele], sirs) were investigated with regard to their use in the early classification of pop. pat. at risk for developing sepsis. patients and methods: in a previous observational study on consecutive pat. after elective open-heart surgery, we had determined ele daily for at least pop. days (in pat. with a longer stay: until icu discharge). after publication of the newly proposed sirs definition, these criteria were retrospectively calculated and compared to ele. results: on the total of n = patient-days, both ele and sirs showed significant (p< . ) correlations with parameters reflecting the general and sepsis-related severity of the pop. clinical course. compared to sirs, the ele correlations were better (icu mortality: . vs. . ; icu treatment days: , vs. . ; days on mechanical ventilation: , vs. . ; days with vasopressor requirement: . vs. . ; number of microbiological findings: . vs. . ), the optimal classification criteria for the mainly sepsis-related outcome gave maximal youden indices of . for ele (ele >_ on >_ days, accuracy: %) compared to . for sirs (sirs present on > days, accuracy: %). accordingly, ele roc curve areas for both overall ( . ) as well as sepsis-related prognostic evaluation ( . ) were significantly (p< , ) larger compared to sirs ( . and . , resp.), this higher overall accuracy of the ele criterion was primary due to a more valid assessment already on the first and second pop. day, where sirs still had a high false positive classification rate ( % and %, compared to % and %, resp.). conclusion: in the early postoperative course after cardiac surgery, the sirs definition displayed a high false-positive classification rate (low specificity) for subsequent sepsis-related mortality compared to better classification results obtained by the elebute sepsis score. from the departments of medicine i and of "cardiac surgery, grosshadern university hospital, marchioninistr. , d- munich, frg. correlation between physiological and immunological parameters in critically ill septic patients. ma rogy, h oldenburg, r trousdale, s coyle, l moldawer, sf lowry a relationship between physiological parameters of severe sepsis and immunological function has not been established. in an effort to assess such a relationship we prospectively evaluated nine severely ill septic patients. physiological risk was assessed by the apache iii score , while one component of immunologic function was evaluated by peripheral blood mononuclear cells (pbmc) eytokine production after in vitro lps stimulation . four of the nine patients died. apache iii scores at h were lower in survivors (s) than in non-survivors (ns), ( -+ vs -+ p< . ), while apache iii scores at admission were not significant different between s and ns ( -+ vs -+ ). down regulation of cytokine production by pbmc upon lps stimulation was a transient event in s. while s demonstrated an fold increase of tnf-a bioactivity with[r~ hours, ns did not demonstrate any increase at all. a similar pattern was demonstrated for il- [ and il- immunoactivity. tnf was measured by wehi bioactivity, il- [~ and il- immunoactivity were determined by elisa. the sensitivity was pg/ml for tnf, pg/ml for il-ll and pg/ml for il- , respectively. in conclusion, both physiological as well as immunological functions of severe critically ill septic patients demonstrate predictive value for ultimate survival. while patients biological status seems to be more predictable by apache iii at day , p< . , the pattern of cytokine production by pbmc upon lps stimulation over the first h might be a reliable predictor as well. introduction: therapy of sepsis and its sequelae depends largely on its early recognition. many studies have investigated the change of certain mediators during sepsis and their potential to predict multiple organ failure and outcome. it was the objective of this study to investigate whether the onset of sepsis can be predicted by alterations of levels of interleukin- (il- ), tumour-necrosis-factor (tnf), pmn-elastase and c-reactive protein (crp). materials and methods: over a one year period, polytraumatized patients were prospectively studied (mean age y, % male, iss ). serum and edta-plasma samples were taken in h intervalls until the patient left the icu. il- , tnf, elastase, and crp were determined immunologically. sepsis was defined according to the criteria of 'systemic sepsis' (veterans" administration study, ) with at least of clinical signs: ( ) tachycar-dia> /min, ( ) temperature > , °c, ( ) blood pressure < mmhg, ( ) mechanical ventilation, ( ) leukocytosis > . /ml, ( ) thrombocytopenia < . /ml and ( ) presence of an obvious septic focus. clinical parameters, sepsis severity and serum levels were documented on a daily basis, beginning on day after trauma. results: of patients developed a systemic sepsis ( . %), and died. all mediator levels were elevated under septic conditions. the clinical severity of sepsis correlated well with the respective levels of mediators. in patients, who developed a sepsis the following day, il- ( vs. ng/l; p= . ), crp ( vs. mg/l; p= . ) and tnf ( vs. ng/l; p= . ) were significantly increased as compared to those patients who remained non-septic. elastase levels were considerably elevated but did not reach the level of significance. we conclude that il- , tnf and crp appear to be sensitive markers for prediction of septic complications in polytraumatized patients. objectives of the study: the assessment of liver function in polytraumatized patients who are at risk of developing mof is too inaccurate and late by using conventional biochemical parameters. methats: the injury severity of the patients (n= ) was determined by the injury severity score (iss). lidocaine is given at a dose of mg/kgbw over rain. i.v. and is metabolized in the liver by a cytochrome p- mechanism to monoethylglycinexylidide (megx). the metabolite is measured by a fluorescence polarization immunoassay. serial determinations of the test were performed between the ~t and the ~ day after trauma and were compared with other liver function tests (bilimbin, gldh, alt, ast). the systemic inflammatory response syndrome (sirs) is still a challenge concerning early diagnosis, therapy and prognosis. therefore, evaluation of inflammatory and disease activity becomes more important. c-reactive protein (crp) is a well established acute phase protein in chronic inflammatory diseases. recent reports suggest an induction of crp by interteukin- (il- ), a cytokine involved in the mediator cascade of sirs. on the other hand, tumornecmsisfactor alpha (tnfcx) is a very early released mediator in sirs removed very rapidly from circulation. in addition, soluble tnf receptors (stnfr~ , stnfr ) are released into circulation in the acute phase response. this study examines the kinetics of five acute phase proteins (crp, il- , tnfot, stnfr , stnfr ) in patients suffering from sirs. eighteen patients entered the study after diagnosis of sirs. blood samples were drawn every six hours during the first two days and every twelve hours thereafter. crp was measured in an routine turbimetric assay. il- was detected in an biological assay using the/l- dependent -cell line / . detection of tnfc~ was performed in an elisa system using a monoclonal antibody" for tnfo~. soluble tnf receptors were also measured by elisa. crp levels were elevated (> mg/l) in all patients and at all time points. crp values did neither differ significantly in patients with ( ± mg/l) or without ( a: ) multiple organ failure (mof) nor in survivors ( ± ) or non-survivors ( :t: ). in contrast, l- was elevated in patients wilh mof (mean pg/ml, range - pg/ml). il- levels correlated especially with lung dysfunction. tnf(x levels were consistently elevated in patients with mof. crp, il- and tnfoc did not correlate with each other. in contrast, levels for both stnfr showed a positive correlation (r= . ). patients could be divided into two groups by values for stnfr~ and stnfr : the group with higher soluble tnf receptor levels showed increasing values combined with a poor prognosis. the group with lower levels of soluble tnf receptor consisted of patients surviving mof or without mof. in conclusion, crp does not monitor the course of sirs adequately. in contrast, il- correlates with mof and episodes of high disease activity. high stnfr levels may indicate poor prognosis. klinik f r an/isthesiologie and operative intensivmedizin der cau kiel, schwanenweg , kiei, germany. ch. waydhas, md; d. nast-kolb, ivid; m. jochum, phi); l. schweiberer, mi) objective: to evaluate the irfflarranatory response after different types of orthopedic operations and compare them with the systemic effects of accidental trauma of varying severity. patients: in consecutive patients with multiple injuries (iss . ) the inflammatory response to trauma was prospectively studied. the patients were divided into groups according to their iss points. additionally, the alterations after secondary operations (> hr) were determined (msteosynthesis of the femur (n= ), pelvic girdle (n=ll) and spine (n= ), facial reconstruction (n= ), smaller osteosynthesis (n= ) and others (n= )). methods: specific and unspecific parameters of the inflammatory response were determined in the trauma patients every h, beginning on admission of the patient to the emergency room for a period of hr, and in the operative patients on the morning of the operation, at the end of the procedure and every hr during the first two days. results: lactate, neutrophil elastase, heart rate, po /fio -ratio, and other parameters discriminated significantly between the injury severity groups during the first hr (kruskal-wallis-test, p<. ). the degree of postoperative changes differed significantly (kmskal-wallis-test, p<. ) between the types of operations for lactate, heart rate, po /fio -ratio, nitrogen excretion and showed a strong discriminating tendency for neutrophil elastase and c-reactive protein. the extent of changes were highest after operations of the pelvic girdle, followed by procedures on the femur, spine, smaller bones, and the facial region. the postoperative changes after osteosynthesis of the femur or pelvis were comparable to the alterations noticed after smaller (iss to ) or moderate (iss to ) accidental trauma for neutrophil elastuse, heart rate, po /fio -ratio and parameters of the coagulation system. conclusions: there is a considerable inflammatory response to operative procedures that varies with the type of surgery. large operations cause changes in the body homeostasis that resemble those after multiple injuries. it remains to be established whether the inflammatory sequelae of surgical trauma are additive to the changes caused by accidental trauma. objective of the study: we retrospectively compared characteristics of elderly patients (~ years) and yeunger patients admitted to a surgical {sicu) and a medical intensive care unit (micu). we further studied the relations between advancing age, chronic disease, sepsis, organ system failure (osf) and mortality in the elderly group. material and methods: during a -year period, patients were consecutively admitted into the icu; and during a -year period, patients were consecutively admitted to t~mich. criteria for chronic disease, sepsis, osfsi.e. cardiovascular (cf), pulmonary (pf), renal (rf), neurological (nf), haematological (hf), hepatic (lf), and gastrointestinal failure (gf)-were derived from the literature. results: patients from the sicu and~cu were similar in age, number of osf, and length of stay. however, when compared to sicu patients, micu patients had more cf (p<o.o ), sepsis (p<o.o ), and mortality rate ( % vs. ii~, p<o.ool). in contrast, sicu patients had more hp and nf, and prior chronic disease (all, p<o.o ). of the total group of , patients, there were ( %) patients years of age or older. elderly and younger patients had comparable length of stay in the icj, but elderly patients had significantly more chronic disease, sepsis, and number of osf (all, p<o.o ). all osfs, except hf and nf, were more ~o~mon i~ mdeljl, eompard to you-ger patients. ~he mortality is also higher in elderly patients ( % vs. % in younger patients). after multiple logistic regression, only number of osf increased mortality by a factor of . ( % confidence limits, . - . ), age did not increased [odds ratio . (i. i.i )], while admission to the sicu reduced risk of death by a factor of . ( . - . ). conclusions: based on these results, we conclude that age does not have any impact on icu outcome in the elderly. the only prognostic factor is the extent of acute disease, as measured by the number of osf. hence, prevention of oaf may influence outcome in elderly patients with critical illness. the lower risk of death in sicupatients may be explained by the large proportion of postoperative elective patients with relative mild chronic disease, and the lower incidence of sepsis. department of surgery, free university hospital, de boelelaan , ~v amsterdam, the netherlands. septic shock and low output syndrome h.miyakawa, t.noguchi, s.hattori, a. mizutani, m. mori and n.honda objectives: cytckines are thought to cause the acute phase reactions under several critical conditions. we had investigated the relationships between cytokines network which included il- , l- ,acth and cortisol,and the outcome of the patients with septic shock or low output syndrome (los). materials and methods: in the septic group and los group,nine and four patients were enrolled respectively. furthermore, the patients in the septic group were divided into two groups,survival (n= ) and non-survival group (n= ).tn these patients,ll- , l- ,acth and cortisol had been measured every day after diagnosis of septic shock or los.the total number of measurements were points in survival septic group, l l points in non-survival septic group and points in los group.statistical analysis was used student's t-test to compare the mean of each group,and the changes were reported as clinicat significant if p< . . results: il- levels in non-survival septic group were higher than in both survival septic and los group.ll- levels in non-survival septic group were more significant than in both survival and los group.otherwise,there were no differences with respect to acth and cortisol among three groups. conclusions: we assumed that los would make several organs dysfunction as well as septic shock. but our results showed septic shock, especially non-survival,had different cytokins network mechanism for organs failure from los. lasson ,~, g/ ransson j, jijnsson k. eady diagnosis of complications after trauma is imperative to decrease morbidity and mortality. for this purpose an easy, cheap and fast diagnostic method is needed. the aim of this study was to analyse if complications after surgical trauma of various extent could be diagnosed earlier using preoperative or daily postoperative measurements of various plasma proteins than by using climcal signs of complications. material and methods: two acute phase proteins (c-reactive protein and antichymotrypsin), lbur main plasma protease inhibitors (alpha- -maeroglobulin, c estemse inhibitor, antithrombin ill and alpha- -antiplasmin) and one collagen precursor (procollagen iii peptide) were measured preoperatively and then once dally for days postoperatively. for the plasma protease inhibitors immunorcactive as well as functional levels were measured. haemoglbin, albumin and the white blood cell count were also measured. measurements were done preoperatively in patients and continued postoperatively in patients, % of the patients were operated on for malignancy. resulls: preoperative plasma c-reactive protein levels were higher in patients developing postoperative complications. this discrimination increased when plasma was sequentially analysed postoperatively, when a remaining high level ora second increase in plasma levels depicted a complication - days earlier than clinical signs. high levels were seen both in patients developing local as well as in patients developing general complications. there was no clear correlation between plasma protease inhibitory levels and complications, neither pre-nor postoperatively. procollagen iii paptide levels were slightly (but not significantly) higher postoperatively in patients developing complications. contusions: the acute phase response, especially concerning c-reactive protein, predicts postoperative complications better than both plasma protease inhibitors or collagen precursors. preoperative plasma c-reactive protein levels indicate the risk of postoperative complications, while daily postoperative measurements more readily depicts a complication, usually preceeding the clinical signs of complication by - days. dept. of surgery m'alm general hospital, s- i malmr, sweden. mof is a major threat to the extensive burned patients and associated with a high mortality rate. the role of endotoxemia in the pathogenesis of mof in burned patients remains controversial. in this study, we examined the relationship of plasma endotoxin levels to development of mof, and outcome in patients with thermal injury. methods: a prospective cohort study of patients admitted with burns covering more than per cent of body surface area was undertaken. circulating endotoxin concentrations were measured by modified limulus amebocyte lysate assay in serial samples of plasma. results: out of burned patients developed mof according to multiple criteria. the plasma endotoxin concentrations of patients with mof were . -- . eu/ml, significantly higher than that of patients without mof ( . - . eu/ml) on , , and days postburn (p< . -- . ). significantly more incidence of positive endotoxin test (>_ . eu/ml) was found in patients who developed mof as compared to that of non-mof during the observation period (p< . ). as the mean endotoxin levels increased, the prevalence of mof and death also increased (see table below), persistent endotoxemia carried a poor prognosis. conclusions: the present investigation provide further evidence that endotoxemia in severely burned patients commonly occur. cimulating endotoxin has also been found to be strongly associated with development of mof and mortality following major burn injury. multiple hemostatic changes occur in sepsis mad multiple organ failure (mof). to evaluate the role of platelcts in patients with sepsis and mof, we examined changes in surface glyeoproteins on circulating platelets of t patients with suspected sepsis and mof. the severity of sepsis and mof was assessed by eiebute and apache i scoring system, respectively.using flow cytometric techniques and platelets specific monoclonal antibodies, platelet surface expression of fibrinogen receptor on gpiib-iiia, ofvon willebrand receptor gpib, and of granula glycoproteins (thrombospondin, gmp- , and gp ) was measured. receptor density of gpiib-illa mad gpib on circulating platelets was not affected by sepsis or mof. in septic patients surface expression of activated fibrinogen receptor (libs expression) was significantly elevated (p< . ) and correlated well with severity of disease (f . ). no significant change in surface expression ofthrombospondin, gmp- or gp was noted in septic patients. in contrast, degranulation ofgraanle glycoproteins was significantly elevated in mof (! < . ) that correlated well with severity of mof (gmp- , r= . ; thrombospondin, r= . ).we speculate, that platelets in sepsis circulate in a hyperaggregable (fibrinogen receptor activation ) but still reversible state that results in increased risk of microthrombotic events. in the course of the disease, irreversible platelet degranulation might occur and may play an important role in development of mof. abdominal sepsis is still associated with high morbidity and mortality. the present study aimed at evaluating patients with abdominal sepsis treated at our surgical intensive care unit during a -year period with the aim of identifying potential prognostic factors, bacteriological cultures, diagnostic procedures, treatment and outcome. during the period - i patients with abdominal sepsis were treated at the icu at our university hospital. patients were women and men with a mean age of ( - ) years. in cases, the abdominal sepsis occurred as a postoperative complication. the patients were scored according to apache ii and bacteriological cultures and the occurrence of organ failure were noted. the patients were hospitalized in median for (- ) days out of which (- ) in the intensive care unit. out of patients ( %) died in median after ( - ) days. the primary cause of mortality was multiple organ failure ( / ; %). apache ii scoring could not predict a fatal outcome. abdominal bacterial cultures were dominated by bacteria of enteric origin ( %) and in % cultures grew multiple bacteria. patients bad organ failure and multiple organ failure. / patients ( %) had abdominal sepsis due to diffuse peritonitis despite a morphologically intact gastrointestinal tract and the absence of localized abscess formation. mortality in this group was significantly higher as was the percentage of positive blood cultures and the occurrence of multiple organ failure. abdominal sepsis is still associated with a high mortality, predominantly caused by multiple organ failure. abdominal culture findings are dominated by bacteria of enteric origin. in about / of patients with severe abdominal sepsis a diffuse peritonitis with intact gastrointestinal tract without localized abscess formation was found. in this group the mortality was increased as well as the risk of developing multiple organ failure. during the period from january to september patients, mean age + years were referred to our department of resuscitologywith the diagnosis of eclampsia. all the patients were delivered by cesarian section and were mechanically ventilated for . _+ . days. diagnosis of sepsis was confirmed in cases by clinical and microbiological methods. patients were divided in two groups: lnon septic patients, -patients with sepsis, the control group consisted of patients after cesarian section without symptoms of eclampsia or infection. we determined plasma concentrations of immunoglobulins a,g,m(a,g,m), complement factors (c ,c ), alphal-antitrypsin (aat), trausferrin (trf) and albumin (alb) using beckman (usa) analyzer,protein concentration, using kone (finland) analyzer. a(mg/dl) g(mg/dl) m(mg/dl) c (mg/dl) c (mg/dl) k +- + _+ + +- -+ " -+ * _+ " -+ ' _+ " +_ '* -+ ** -+ "* -+ "* _+ " in a prospective study we investigated serum of severly traumatized patients withdrawn directly after admission at our hospital (tr i). follow up controls were taken daily until day ten after trauma (tr ii). two control groups were performed: serum of healthy volunteers (co, n = ) was investigated as. well as serum of patients undergoing elective herniotomy (n= ) hours before (op i) and hours after operation (op ii). serum bactericidal index (sbi) was determined using a hemolytic e.coli strain :k :h . / suspension with a final concentration of - cfu were incubated with l oopl serum. after overnight incubation sbi was calculated according a special formula. results: co . _+ . opi . _+ . opii . _+ . * tri . _+ . "* trii . + . ** (*:p< . ; **:p<o. ) sbi represents a simple and reproducible method to detect immunobiological alterations after trauma and elective surgery. patients undergoing elective surgery showed slight but significant diminuation of sbi h after operation. deterioration of sbi was observed in serum of traumatized patients directly withdrawn after admission at our hospital. ten days after trauma significant improvement of sbi was found. further investigations have to be done to proof sensitivity and prospectivity of this simple but reliable test. a sepsis like syndrome (sls) occurs in i % of our patients following cardiac surgery. sls is characterized by a severe decrease in systemic vascular resistance requiring the use of vasopressors to maintain adequate hemodynamics in the presence of negative blood cultures. in order to determine whether preoperative factors predict the occurrence sls we retrospectively studied patients with sls (group i: age . ~ . years); they were compared to control patients (group : age ± . years). treatment of sls consisted of aggressive fluid replacement and norepinephrine infusion. rydrocortisone ( mg/ hrs) was given on the first day. antibiotics were switched prophylactic to cover gramnegative bacteria in pts. preoperatively pts in group revealed a significantly lower cardiac index ( . ± i/min/m ) compared to group ( . ± . i/min/m ; p < . ) higher left atrial pressure (group i: . ~ . mmhg; group : . ~ . mmhg; p < . ) and lower ejection fraction (group i: . z . %; group . ± . %; p < . ). bypass time, minimum and mean blood pressure on bypass and aortic clamp time were not different between the groups. immediately postoperatively (pop), the white blood count was elevated (group i: , ± , /ui; group : , ~ , /ui; p < . ) and core temperature hours pop was higher (group i: . . °c; group : . ~ . °c; p < . ). serum lactate was already elevated on arrival on the icu pop (group i: , z . mmol/l, group : . ~ . mmol/l) but dropped within hours (p < . ). icu stay (group i: . ! . ; group : . ± . days; p < . ) and mortality over months (group i: . %; group : . %; p < . ) were significant higher in group i. sls is observed more frequently in patients with preoperative cardiac congestion and results in longer icu stay and higher mortality. although intraoperative hemodynamics are similar in both groups, the white blood count and serum lactate levels suggest an intraoperative cause for sls. further investigations will focus on possible intraoperative causes of sls. the objectives of the study were to estimate the problem of stress ulcers in critically ill patients and to compare ranitidine and omeprazole to determine their efficacy in the prophylaxis of stress ulcers. patients who were admitted to the intensive care units between january and july ' with polytrauma, sepsis or those requiring ventilatory support for more than hours were selected for the study. the patients were randomized into groups to receive ranitidine, omeprazole or a placebo. the changes in gastric ph were monitored hourly and the patients underwent an upper gi endoscopy hours after the start of the study to look for stress ulcers and hemorrhage. the drugs were withdrawn one week after the start of the study. of the patients selected for the study, had undergone cardiac surgery, had polytrauma and had sepsis. the change in average pre and post drug gastric ph was + . in the omeprazole group, + . in the ranitidine group and -). in the placebo group (p < . ). endoscopic evidence of stress ulcers was seen in % of patients not on prophylaxis, . % of those on omeprazole and . % of those on ranitidine. while all the patients in the placebo group who had stress ulcers showed endoscopic evidence of hemorrhage, % of the patients with ulcers in the ranitidine group and none of the patients with ulcers in the omeprazole group showed hemorrhage (p < . ). in critically ill patients the incidence of stress ulceration is high. an alkaline gastric ph is protective against stress ulcers. omeprazole when used for prophylaxis against stress ulcers in critically ill patients or those on short term ventilation will reduce the incidence of formation and hemorrhage from stress ulcers. the early and accurate diagnosis of sepsis is of key importance for critically ill patients survival. many studies have shown that tumor necrosis factor ~x (tnf ~) and interleukin- (il- ) are mediators of the inflammatory response in sepsis. bacterial antigens interact also with antigen specific t cell receptors and the activation of t ceils takes place. activated t cells release soluble interteuldn- receptors (sil- r). the aim of this study was to evaluate: the significance oftnf c~, il- and sll- r in the diagnosis of bacterial sepsis and to evaluate the correlation of clinical and laboratory parameters with serum levels of tnf ~x, il- and sll- r. we examined patients with clinical signs of sepsis treated in the intensive care units of university medical centre ljubljana. venous blood was drawn from each patient within hours after the first clinical signs of sepsis. clinical data (body temperature, blood pressure), laboratory dam (peripheral white blood cell count with differential, platelet count, c-reactive protein), and quantitative blood cultures were recorded. serum levels of tnf c~, ,- and sil- r were measured in septic patients and in adult healthy controls. tnf ct, il- and sil- r serum levels were measured by commercially available ria and elisa (amersharn and eurogenetics) kits. the differences in serttm levels of tnf ~, il- and sil- r between healthy control and patients and correlation between clinical and laboratory parameters were calculated. we found that only sll- r serum levels were significantly (p< . , student t test) increased in patients in comparison with healthy controls. of all indicators of sepsis that we compared, only hypotension was significantly correlated with tnf ~x levels and leukocytosis with ] ,- levels. we conclude that only the increased serum sil- r levels were predictive of bacterial sepsis within hours after the first septic signs. tnf c~ and il- levels were not significantly increased at that time in lifts small group of patients. in order to create high precision prognostic system for patients with sepsis and septic shock we have made prospective and retrospective analis of cases of sepsis. patients were included in this analis according bone's criterions of sepsis. comparing with apache-h, we have excluded such phisiologic variables as:temperature,na+ ,k+ ,}it, ph,which had a little influence on prognos of illness. we have added the other, more important variables: biilirubin, plateles,pti. we took into account: the seat arrangement, methods of respiratory support, comorbid conditions as: caneer, diabets,obersity. in general new score has headings: -physiologic variables, -age, -seat arrangement, -chronic comorbid conditions, -methods of respiratory support. roc -analis have showed a greater precision of our score, compared with apache-ii score. there is significant difference between the roc-curve of apache-ii scare. the k.p.tit~v.,i.e.gurmanchuk. objectives of the study. sepsis is a severe complication of the local infection, th e fever and the systemic inflammatory response syndrome may take place in such a case as manifistations of the inflammation induced by bacteria. the systemic fever observed in infection is known to develop due to the action of certain cytoldnes. other systemic manffistation of inflammation are the production of acute phase reactants, acute phase proteins, the activation of the complement system. ivratertals and methods. we observed children with light and children with severe course(l- class of serionuess) of the sepsis. the ftmetional activity of the complement system (ch , level of c -c , factors b told d, c a), level of c-reactive protein (crp} and tumor necrosis factor (tnf) were investigated, results. the level of crp was increased in the children with more severe class of the septic process in both group ( %- st and ioo%- nd}( with light and hard eours of disese) of patients. parameters of the complement system -the activity of cl, c , c components, activity of b and d factors-were increased in the seram of children with light course of sepsis. in children with severe course of sepsis these parameters were signffieantty decreased, especially in the group of chiidrellwith higer level of crp. we found the negative correlation of the tnp-alfa concentration with the functional activity of classical pathway components (cl~ ) and the positive onewith the funfional activity of the alternative pathway factors b-and d of the complement system. conclusions. thus, in children with different course of sepsis certain changes in levels and functional activity of an acute phase o[ inflammation proteins -crp and the complement system ones -&ire characteristic. the relationship between the tnf-alfa level and the activity of classical and alternative pathways proteins indicates on its role in the complement proteins genes expression. schr der j, braun j, rennekampff ha, schr der dw various alterations of the immune response are known in trauma, but the course will not be complicated by multiple organ dysfunction syndrome (mods) in all patients. phenotyping of cells offers a rapid system of evaluation certain aspects of the immune response. different subsets of lymphocytes and neutrophils were determined to evaluate their prognostic role in developement of mods. in trauma patients with an injury severity score (iss) > (mean iss = ; mean age years) lymphocyte and neutrophil phenotypes cd (t-cells), cd (t-helper cells), cd (t-suppressor cells), ratio cd /cd , cd b (receptor for cr ) and cd (fcriii) were measured on day , , , , and post trauma. the expression of class ii histocompatibility antigen (hladr) on monocytes (hladr+ cd ) and il -receptors on t-helper cells (cd /cd were determined as well. the percentage of cells was monitored by immunofluorescence using monoclonal antibodies and three color cytometry. the percentage of hladr+ cd were significantly lower an day , , and in patients who developed mods (p< , ) compared to patients without mods and a healthy control (p<o,o ). the expression of il receptors on cd was significantly different only on day . no differences could be measured in lymphocyte phenotypes cd , , and cd /cd -ratio as well as in expression of cd b and cd on neutrophils. class ii histocompatibility antigen (hladr) on monocytes offers the best ability to reflect cellular immunosuppression in trauma. this parameter allows the best differentiation of patients with and without mods. we retrospectively studied the relative importance of age, prior chronic disease, sepsis and organ system failure (osf) to determine outcome in critically ill patients with acute renal failure (arf). arf was defined as serum creatinine > /zmol/i, a twofold creatinine rise in prior renal insufficiency or the need of acute renal replacement therapy. definitions for prior chronic disease and other osfs -i.e. cardiovascular (cf), pulmonary (pf), neurological (nf), haematological (hf), hepatic (lf), and gastrointestinal failure (gf)-were derived from the literature and described previously. of the consecutively admitted patients to a surgical and a medical intensive care unit during -ye r period, ( %) had arf. arf mortality was %. ninety-eight percent had other osf. overall, cf, pf, gf, and nf was significantly more common in nonsurvivors than in survivors (all, p<o, ). although both the number of osf before and after arf was higher in nonsurvivors than in survivors (p< . ), the number of osf before was higher compared to after arf in both groups of patients (p< . ). furthermore, age, cf and pf before the ontset of arf, nf thereafter, and renal replacement therapy were related to mortality (all, p< . ). however, prior chronic disease was not related to mortality and chronic renal insufficiency was inversely related to outcome (p< . ). after multiple logistic regression, advancing age, cardiopulrnonary failure and sepsis before arf, and nf after arf remained significant. these results show the high prevalence of arf in critically ill patients and that arf rarely occurs alone. the prognosis of arf in critically ill patients is poor, especially if associated with advancing age, additional osf, particularly cardiopulmonary failure and sepsis before arf, and nf after arf. hence, prevention of cardiopulmonary and sepsis before the outset of arf may influence outcome in arf in patients with critical illness. the search cominnes for a magic bullet ta help critically ill petienta, bat recent elini ',.ml rials of agents that showed ixomise in animal studies raise questions about such trials. expcrlmemai uvidan~ :in anlmats and human volanteet~ for concepts, mechanisms and treatment of inju~ ur illness can be substentlal, l~rauasive and exciting but the positive effects of potential therapy suggested by such animal and ctinieal research may be difficult to prove in sick patients. efficacy of a new txeatment can be difficult to prove became elinie.al situations, hi spi~e of important biologic phenomena, are v~iable and conrplex. there is redundancy and overlap of mediators ~d problems of timing of therapy. a majt~r cause of this dilemtns is not with the trials or hypotheses, but rather the promem of the cause or the causability of the human dise~.se that is trebled. this is/hu "causa nets" or '*specific cause" as described by stehbens, when prevention or tre.atmcnt is based em the sauna nero, extinetiem of the disease is ix~ssible as with saul/ pox. only elimination of the cause wl cure the disease. careful animal studit~s evaluate single pcrturbmiuns for survival or other changes. an ldso preparation may be infiuancad aignificantly by a ~mall clangs which may be insignific~lt ht pstiants, most human experiments ate carried out in normal volunleers with a single porlurbation, such as a low-level, non-lethal dose of a substance. such studies are huportant in defining mechanisms attd mediators of disease, in our world of injm'ed, operated, infected and inflslned patients, there are many diseases, mof is not one of lhem. it isn't even a syndrume, it is the final pathway for a number of diseaaes~ each of which has a cause. mecormock believes thal a "multi-causal" etiology is a euphemism for ignoranc# or a synonym fo~ unknown etiology. admission iv sn icu, a high apache seer% the sepsis syndrome, mof, muds, or sirs and having predictors indicating potential mortality, are not diseases. the inmpors are getting negative results in trials of agents on eiek or septic icu patients and aru now becoming splitters, dafining subgaoups at higher risk for death. such an approach may produce positive results if the diseases are identified and the treatmeul is specific for them, a major challenge in deterraintng the efficacy of new therapies for sepsis nnd shock is identifying patients whose e#temtc inflammatory response is appropriate from those in whom the mediator| are contributing to end organ system damage end death, traditional and recently revised categorical patient descriptions such as sepsis syndrome, sepsis syndrome with shock, multiple organ system failure, or the recently proposed systemic inflammatory response syndrome (sirs) may not be sufilcient since they identify individuals at varying levels of risk for short term mortality, the efficacy of new lmmunotherapy may be directly related to the patient's severity end risk of mortality at entry to the study. we recently reported (jama ; : z - ~ ) a comprehensive risk assessment approach for patients with sepsis syndrome, a common eategarlcal description used as an entry eriterlon for many trials. by screening s database of , recent admissions to hospitals in the united states and western europe, we identified , patients who met sepsis syndrome criteria but were not enrolled tn clinical trinh, we then developed a survival model end severlty assessment method to estimate their g.day mortality risk. k..ente physiologic abnormalities were the most important prognostic factors ( % of total chl square) influencing outcome. the specific disease resulting in ice admission and the days the patient spent in the hospital and icu before qualification were independent risks, as were age and a clinical history of cirrhosis. the predictive model was cross-validated within the original , patients with a receiver d_perator characteristics (roc) area of . and in two independent databases, the first independent database contained hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome (roc= . ); in the second, the placebo patients withtn the recently completed phase ill e~aluatlan of il- ra (rocffi . ). in all databases the risk model was able to accurately risk stratify patients throughout the range of risks that varled from a very low % to a very hlglt %. by drawing on the ready avatlabillty of large clinically aeuurate, current databases and using the power of modern statistical techniques to model the bodfs response to sepsis, we are able to produce very aeettrate pre-treatment risk estimates, these prospectively defined and continuous risk estimates reduce reliance on multiple subgroups and data dredging that can compromise a stady's integrity. they cart provide a nnlform method for patient description across clinical trials of different attempts at immmlotherapy. risk calculations can also be useful in developing entry criteria for phase ii evaluations in order to initially test efficacy on a limited number of high risk patients, fonowing sueeessinl completion of a definitive trial, the risk estimates can be used to develop specific |ndlcattons for s drug's use and can monitor the impact of both new and multiple compounds on patient outrome, when dealing with therapeutic trials for the treatment of sepsis, there are ways of checking the comparability of the groups (placebo and treated groups) -to use several description items such as age, sex, preexisting disease, number and nature of organ failures, physiology score, such as saps il ( ) -to use a model for risk of death either from a score (apache ii, lii, ( ) saps ii) or directly (mpm ii system ( )) before using the model for risk of death in septic patients, is it mandatory to validate it (by calibration, i.e. goodness of fit, and discrin'dnation, i.e., roc curves) first on a data base using the same definition for sepsis as in the trial and secondly on the placebo group of the trial ? or is it better to use a specific model for each trial ? the general models usually do uot fit for septic patients. there are methods to make them fit : either to add variables to the original score (model for sepsis using the apache iii system ( )) or to customize the model. for saps ii the customization is applied to the equation regression, using the same saps ii score. for mpm i each component of the model can be customized. several remarks : only one model is published to be applied at the icu entry ( mpm ii ) before any therapy. -most of the published scores are calculated from the lsl icu day. applying these scores to the let day of sepsis could have a very different significance. -is the accp classification of sepsis useful at the bedside to select oatients ? ( the pathophysiology of sepsis involves a dynamic interaction between the host and the infecting microorganism(s). a multitude of biochemical and hemodynamic interactions occur which function in concert to determine the ultimate outcome of the septic episode. the complexities of the septic process preclude outcome analysis by in vitro systems or computer models, animal studies have become indispensable in evaluating new therapeutic agents in the treatment of sepsis. these studies provide valuable information on safety, pharmacokinetics, relative efficacy and dosing strategies for potential therapeutic agents in the treatment of sepsis. there are three basic types of animal models: ( ) toxicity models with injection of bacterial endotoxin or exotoxins; ( ) live or killed bacterial challenge models; ( ) actual infection models. all models employ some form of external manipulation under controlled conditions to induce sepsis and to analyze potential therapeutic efficacy. these experimental requirements may limit the ability of animal models to accurately predict the clinical value of new agents in human sepsis. four major end points are analyzed in the various animal models: ( ) hemodynamic parameters; ( ) modulation of host-derived inflammatory mediators; ( ) resolution of end organ injury; or ( ) lethality. each animal model has certain advantages and limitations. species-specific differences in physiologic and immunologic features make it difficult to directly extrapolate the results of animal experiments into clinical medicine. while no ideal animal model exists, consistent benefit of a new immunotherapeutic agent in multiple animal systems provides the most compelling preclinical evidence of its therapeutic potential in septic patients. consensus-assisted development of a study protocol on sepsis: an important difference from previous randomized trials there have been several, and perhaps too many metaanalyses of cliuical trials on surgical infections, but their results have only rarely been incorporated into the design of new randomized trials in sepsis. metaanalysis is retrospective. it seems more important to analyse and to criticize the design of tria/s before they are ongoing. incorporation of that into development of a study protocol is the aim of the following procedure: the time-schedule of about two years should include further cell culture and animal experiments after the first successful studies showing effectiveness. exhaustive evidence for a dose-dependent cost-banefit and near complete explanations of the pathomechanism should not be awaited for development of the protocol of the clinical study. however, a discussion forum of experts should be performed in a recently published, almost perfect trial in order to see the frontiers of the present research in cell and molecular biology, clinical pharmacology, statistics and decision making. this should be followed by a metaanalysis of at least study designs on sepsis with methods of formalized medical decision making (decision tree). clinical algorithms -developed by objective methods including nominal group processes -should be developed to standardize any concomitant treatment in the centers considered for a multinentre trial. the latter is usually necessary in the field of sepsis. finally, a pilot study should be performed to demonstrate not only feasability, but to learn about all possible types of interventions which modify endpoints as response variables. especially mortality is not free from such effects. the time for the individual phases of this consensus-assisted process of protocol development have to be shortened by their temporal hiterloeldug. due to the fast discovery of new chemical factors in sirs it wilt otherwise be impossible to come up with results of randomized trials which are fascinating enough to be incorporated in daily routine treatment. severity scoring systems are intended to provide a population-based estimate for the risk of an unwanted outcome resulting from some disease process. in the area of infections and the "septic" response, this has routinely been defined as death. for anti-infective trials, there has been a reasonable correlation of severity (apache ll) with outcome measured as persistent or recurrent infection, but this is not as robust as the association with mortality. it is expected that non-lethal failure would not immediately correlate with disturbed physiology: the basis for antiinfective failure depends on a variety of factors not measured in severity scoring, such as type of infecting organisms, density and susceptibility to administered antimicrobia[s, and anatomic features of infection (e.g., pancreatic). severity scoring is important in differentiating these "categorical" variables from continuous (physiologic) variables. there are, additionally, a series of problems related to the cause of death in relation to severity scoring. in those tdals in which cause of death is analyzed, high severity scores did not routinely predict death as an immediate sequelae of sepsis/septic shock. many of the predicted deaths occurred remotely of progressive background diseases. other important problems with severity scoring have to do with lead-time bias: hew long patients were ill before entry into the study. statistical techniques for condensing various categorical and continuous variables, as well as factoring in information requiring the pharmacodynamics of agents which affect outcome, are being developed to further refine deviation from predictive equations as an outcome measure. stepwise logistic regression analysis has identified the presence of shock, intm-abdominal or unknown source of infection, hospital acquired infection, age greater than years, neutropenia and inappropriate antimicmbial therapy as independent variables associated with increased mortality in sepsis. maldistribution or" these variables is a concern in targe randomized clinical studies. it should be noted that only the selection of antimicrobiai therapy could be addre.~'sed and altered at the time of enrollment in a sepsis clinics] trial. inappropriate antimicrobial therapy has been noted in %- % of septic patients. well designed, randomized sepsis trials do not assure the absence of imbalance between treatment and control groups with regard to inappropriate antibiotic therapy, especially with subgroup analysis. statistical manipulation to correct for any imbalance is appropriate but avoiding imbalance is ideal. selection of antibiotics in septic patients requires such considerations as clinical setting (history, physical examination and underlying disease), appropriate laboratory tests (such as gram stain), identification of source and associated bacterial flora, antibiotic susceptibility patterns for that hospital and likelihood of resistant organisms. determination of inappropriate antibiotic therapy is made retrospectively after culture results are available. in some circunmtances the organism and antibiotic sensitivities cannot be predicted, while in others it can. leibovici et al identified hospital acquired infection, antibiotic treatment before a bacteremic episode, endotracheal intubetion and thermal trauma as independent variables which predicted isolation of a multiresistant organism. the same authors developed a predictive index for resistant organisms, which when compared to prescriptions of attending physicians, improved antibiotic selection in critically ill patients. including a standard antibiotic regimen for all septic patients in a clinical trial is impractical. there is too much interhopsital variability in flora and antibiotic susceptibility. in addition, the aggressive broad spectrum coverage necessary for some patients is inappropriate for others. a protocol which guides a prescribing physician through a logical chain of reasoning might improve antibiotic selection in critically ill patients and could be included in the design of a clinical trial in sepsis. although this approach might minimize potential for maldistribution of inappropriate antimierobial therapy, it would likely create multiple problem areas. will the patient's physicians agree to the protocol choice? what is the availability of speciftc antibiotics at a participating hospital? what is the aplpiieability of study results in typical clinical situations? if there is agreement that thin is an appropriate antibiotic protocol, should it not be used in all seriously ill septic patients in the hospital? in other conditions such as ards, the success of protocol therapy is dependent upon measurable goals such as pao and highest plateau pressure, while measurable goals are not as clear in choosing antibiotics. based on the above confounding issues, a complex and extensive algorithm covering many potential possibilities of error and specific antibiotics seems impractical; however, an algorithm focusing on three to four major common errors in antibiotic selection and dealing with classes of antibiotics is plausible for inclusion in sepsis clinical trials. in this session we will attempt to outline the methodology of such a future study, emphasizing the immense difficulties involved in its proper conduction including: design, selection of patients, surgical considerations, supportive treatment, the "human factor" and ~nd points. only a close cooperation between a few dedicated surgeons, obsessively studying a large number of well selected and stratified patients over years, could make such a study possible. algorithmis have frequently been mistaken for the graphic format in which they are presented. however, an algorithm is neither a flow chart nor a list of instructions; it is a step-by-step approach to solving a problem. likewise, a clinical algorithm is a step-by-step approach to solving a clinical problem. cas are deterministic, which does not mean that they are rigid. they are practical rather than mathematical algorithms, that tan be used only with clinical judgment, and must be tailored to each patient. there are a number of types of, or uses for, cas that can improve sepsis management, including: diagnostic or severity scorm cas, a management ca for managing sepsis constructed according to recently published standards for use in teaching research protocol algorithms that must be used to collect data or guide implementation of a clinical trial aimed at validating one or more dicisions in the management ca; finally, protocol-style cas drawn from the management ca and should be validated using matching outcome studies. organisational problems peculiar to multicentre trials the organisation of any randomised clinical trial is fraught with difficulties, and that of a multicentre trial particularly so. there are problems associated not only with the principles on which the investigation is based but also with the detailed organisation and analysis. are all the participants truly unbiased about the relative merits of the regimens being studied? is like being compared with like -are all the end points and the standards for measuring them clearly defined so that they cannot be misunderstood? are all eligible patients being studied, and their results reported? is truly informed consent being sought that will satisfy not only the patient's right to choose what happens to him, but also the law of the land? and, finally, how can the participants be sure that the trial will be stopped at the right time, to ensure that no treatment is given to any patient that might be harmful? these questions may seem insoluble, but until we tackle them we shall never be certain. dr.m. ev~s, scar~mu~ hospital, scarborough, nonhyo~s~ y ql, u.k. increasing knowledge of the pathogenesis of sepsis and septic shock has led to the development of many new therapies and technologies capable of preventing, blocking or even reversing the deleterious cycle of events. recent results of subsequent multicenter trials testing some novel therapeutic drugs, however, did not confirm the promising sometimes overwhelming effects obtained experimentally. it is postulated that this is largely due to inappropriate design and conduct of multicenter trials as currently performed. one of the shortcomings emphasized in this paper is the "treatment mix" problem. multicenter trials in sepsis are performed because no single center is able to recruit the necessary number of eligible subjects within a reasonable time. each single center (icu) has its own individual policy which cannot be standardized for the trial (treatment mix). even if we ascribe that each icu did the "best" for their patients, it is highly probable that the outcome differs between the icus. this translates to the effect of the new therapy under investigation. ]t is therefore worthwhile to consider that icus must first demonstrate a certain standard based on the patients' outcome (audit) before becoming accepted as a participating center. this prerequisite ensures comparable quality between participating centers, led to the reduction of "noise level" and increases the probability of positive study results. the riyadh-icu program based on standard mortality ratios is recommended as an audit instrument. during the last decade most clinical trials of potential therapeutic agents in systemic sepsis have failed to demonstrate benefit from the drug under study. although in many instances it is entirely possible that the agent in question does not have clinical efficacy, an equally plausible explanation for the multitude of negative results is that the studies were improperly designed and thus could not show therapeutic benefit, if it existed. problems which have been identified in these various trials include inappropriate or unrealistic definitions of response to the drug; inadequate sample size, with attendant insufficient statistical power to demonstrate a difference, if it existed; insufficient standardization of customary therapeutic maneuvers in septic patients; imprecise criteria for patient entry into the study, which creates unacceptable inhomogeneity between control and treatment groups and invites unjustified post-study subgroup analysis; the lack of a formal sequential monitoring procedure for interim data analysis, which could potentially affect patient safety; and a primary analysis of study results that excludes protocol deviants and is not according to intent-to-treat. these and other problems have impacted upon the validity of the various trials conducted to date and may well have prevented the resolution of controversies surrounding the use of certain agents in the treatment of septic patients. the complexity of bacterially-induced septic shock involves a cascade of events that evolve over time, beginning with the proliferation of offending organisms and followed by the release of toxic mediators from the bacteria. endotoxins [e.g. lipopolysaccharides) from gram-negative bacteria initiate septic shock by precipitating a systemic inflammatory response syndrome (sirs) through release of a broad spectrum of hostderived mediators. over the last century, hundreds of these endogenous mediators have been proposed to serve as pathophysiological substances in this "alphabet soup" of cytokines, eieosanoids, biogenic amines, kinins, peptides, ions and hormones. an evaluation of the literature on septic shock leaves the investigator with a sense that, although many pieces of the septic shock puzzle have been presented, no clue was provided to indicate how these pieces fit together, in an attempt to assess objectively the causal role of individual mediators, we recently completed a collective meta-analysis of mediators that were individually reviewed and subjected to koch-dale analysis of causality by distinguished authorities in the field ( ). in summary, our attempt analyze available evidence to support a cause-and-effect relationship for putative mediators of septic shock revealed that only eight of the mediators analyzed could be strongly inferred as playing a causal role in septic shock. evidence supported the involvement of endotoxln, endorphins, complement, interleukins, tumor necrosis factor, eieosanoids, platelet activating factor and calcium. other mediators either lacked adequate supportive evidence or were not conclusively involved. posttraumatic outcome may be reduced by an amplified stress response mediated by neural and humoral stimuli. the classical hormonal catabolic response is predominantly mediated directly or indirectly by neural stimuli, while most changes in inflammatory responses such as leukocytosis, acute phase proteins and changes immunofunction are mediated by humoral mediators. clinical experience from controlled studies suggest afferent neural blockade and modification of stress response to improve organ function and postoperative outcome, and limited experimental studies also suggest neural blockade to be of beneficial value in shock states. of special value may be the improved gastro-intestinal motility after neural (visceral) blockade. no outcome studies are available from patients with major truma, multiple organ failure or sepsis, conditions where humorai mediators may be more important to modify than neurally mediated responses. future studies should investigate the clinical outcome effect of combined neural and humoral mediated blockade, as well as the potential role of an initial neural blockade in elective trauma (first hit) to improve the metabolic scene and outcome if a postoperative complication (second hit) should occur. neutrophil elastase is the predominant protease of the human neutrophil. this enzyme, and a variety of other enzymes, including neutrophil collagenase, are released by activated neutrophils in the setting of high concentrations of reactive oxygen metabolites. in addition, in this extracellular environment, the normal antiprotease defense mechanisms of the organism may have been severely inactivated oxidatively especially along capillary endothelial cells. accordingly, release of neutrophil elastase which mediates inflammation and degrades most extracellular matrix proteins, including elastin, fibronectin and many forms of collagen, may contribute to tissue injury and organ failure in a variety of diseases ranging in severity and acuity from pulmonary emphysema to the adult respiratory distress syndrome (ards). as a result, significant efforts by the pharmaceutical industry have been directed not only toward the development of human neutrophil elastase inhibitors, but also toward their characterization in a variety of animal models of neutrophil mediated diseases, and their evaluation as potential therapeutics for the treatment of a variety of human clinical conditions. data from animal models of organ injury and failure along with data collected from a series of patients at risk for ards and with ards will be presented and discussed as a rationale for inhibition of neutrophil elastase. parameters that need to be monitored to obtain success in future clinical studies will also be presented in this context. have turned out to initiate and maintain organ dysfunctions in severe posttraumatic and postoperative courses. such proteolysis-induced disorders are especially rendered possible by the concurrently arising consumption of inhibitory regulators (e.g. a vproteinase inhibitor=a pi, antithrombin iii=at iii) via cofnplex formation and/of proteolytic/oxidative inactivation. besides the well-known destructive potency against protein substrates, proteinases such as elastase or thrombin (active or in complex with the serpin inhibitors ~ pi or at iii) are also supposed to increase the inflammatory reaction by inducing cytokine release or shedding of soiuble adhesion molecules from various inflammatory cells (pmns, monocytes/macrophages, endothelial cells). those cell-derived mediators may provoke further cell activation through an autocrine/paracrine loop thus increasing significantly the proteinase burden at the inflammatory focus. therefore, this noxious circle might be interrupted by a convenient proteinase inhibitor therapy to ameliorate the inflammatory process. to verify this hypothesis, high dosis of at iii (mean plasma levels up to %) were applied in first controlled randomized studies on surgical patients suffering from multiple trauma or severe sepsis. in control patients we could clearly demonstrate the sequential appearance of proteinase/serpin-complexes (fa pi, tat), cytokines (il- , il- ), and soluble intercellular adh sion molecules (icam, elan, p-selectin) in the circulation. these factors turned out to be a helpful tool for early diagnosis and prognosis of forthcoming organ dysfunctions. interestingly, m at iii-treated patients a significantly reduced release/production of inflammatory mediators became obvious concomitant with the improved clinical course in comparision to an increasing deterioration in control patients. soluble mediators of inflammation are cytokines (e.g. il- , il- and tnfe) as well as breakdown products of complement proteins (e.g. c a and terminal complement complex). therefore, attenuation of both, release and generation of these synergistically functioning mediators together with stimulation of release of antagonists including soluble forms of receptors are potentially beneficial in all kind of inflammatory diseases. intravenous immunoglobulins (ivigs) are known to have an anti-inflammatory effect in humans (nih consensus conference on wig, ) . the mechanism of action becomes more and more clear. in single cells stimulated by anti-cd mab wig was able to down-regulate production of il- , il- , ifn% and tnfj~ significantly. igg coated solid-phase stimulates release from monocytes of interleukin- receptor antagonist (il-lra) but not of il- ; this observation is very much in contrast to the effect of endotoxin in the same in vitro system. furthermore, naturally occurring anti-cytokine antibodies can be demonstrated in apparently healthy individuals and in wig prepared from plasma pools. some of these antibodies can be detected by antigen/antibody reactions in fluid phase (anti-ll-le, anti-il- ), some only by solid-phase detection systems (anti-ll- , anti-ifn% anti-tnfc . infusion of wig to patients suffering from inflammatory disorders have resulted in a decrease in il- in circulation. during infusion wig might induce an acute but transient rise of tnfo~, il- , and il- . self limitiation of this process might be due to demonstrable instant release of il- ra and soluble tnfo~ receptors. in vitro ivig has also been shown to attenuate complement activation via the classical pathway. furthermore, acid haemolysis of erythrocytes in paroxysmal nocturnal haemoglobinuria could partially be prevented by ivig. ivig was able to attenuate forssman shock in guinea pigs. we have seen a patient with congenitally elevated turnover of alternative pathway of complement who repeatedly showed an increase of haemolytic titres after administration of ivig. thus, wigs apparently have multiple potencies including attenuation of soluble mediators of inflammation and might therefore be of benefit in trauma, shock, and sepsis. significance of sinusoidal liuing cells and of humoral factors on hepatic function following sepsis and major surgery hirata k, katsuramaki t, yamaguchi h, mukaiya m, yamashiro k. regeneration of the liver after hepatic necrosis or partial removal has been extensively studied, but uncontrolled mechanisms to irreversible hepatic failure following sepsis or major surgery of liver or with hepatic dysfunction have so far not been well documented. we suggested the importance of the intrasinusoidal aggregation between sinusoidal lining cells and intrasinusoidal running ceils in the mechanisms of hepatocyte dysfunction. thus, the purposes of this study was to investigate the changes in each sinusoidal lining cell during this process and the effect of cytokine on hepatocyte under various oxygenation. [ materials and methods ] ( ) clinical study : thirty two patients with histologically proved malignant tumor underwent major hepatectomy were devided in two groups, i_e. the cirrhotic liver group and the non-cirrhotic [aver group. most of the former were the patients with hepatocellular carcinoma and most of the latter were the patients with metastatic carcinoma of colorectal cancer. five patients were complicated septic conditions with hepatic failure. following operation in each patient, a verous blood sample was taken for measurement of serum il- , il- , tnf and c-reactive protein concentration. and hepatic biopsies were sometimes undergone in patients with anomalous hepatic function. ( ) experimental study : kupffer ceils, sinsoidal endothelial cells and hepatocytes were separated from mouse ( c hhen ) liver. and also polymorphonuclear cells and platelets were purified from blood and peritoneal macrophages were from peritoneal cavity of mouse. co-cultures between or among these cells with iipopolysaccharide were performed. cytokine concentrations in media and hepatocytic function were compared. [ results and conclusion ] our findings in above experiments demonstrated the cleanly different concept for the mechanism of hepatocyte dysfunction following sepsis or major surgery. namely, the effect of hepatoeytie function by cytokines or superioxide were significantly affected under low oxygenation, but not significant under good oxygenation. hirata m.d.,nishi ,hokkaido,japan $ immune complexes as .mediators of sepsis and immune dyafumcffon laa k horn, chxistof birkenmaier, and greg h mon departmen~ of surgery, san frandsco general hospital, urdversr , of calif(~rrda, san frandsco. immune complexes (ic) a;:e commonly found circulating in parians during infection and sepsis; and following traumm, bums, and massive l~ensfusion. clearance of c occurs by phago~'tmsis of esll-bou_nd or opsonized p~tlcles. monocyte activation du~jng phmgocytos/s could lead ~o release of cytokilies ieletexiot~ to the hosh to examine tb/s phenomenon, we formed insoluble ic by precipitating iow-endotoxin bovine serun~ albumin (bsa) with rabbit ant/-bsa igg. we have ~town that these ic are ingested by monocytes and concomitantly stimv/ate re~pizatory bu~t activity measuxed by assay of in%racellul~ peroxldaffon. we have shown that ic ingesffon produces signlqcant el,era,lore in the monoey~e phenotype. spedacally, cdi is down-regu/ated, along wl~ cd and cd . thus responsiveness to lipopolysacchmdde ( ) a~xd i=m~unoglobulin fe st~mu/mtlon is reduced. in cert,+rest, the complement rote.p tot cdc is u~-regulamd, indicaling mcremsed re~ponalx=~ness to opsonized pat,rotes, we examined monocyte superna~n~s for production of hzmor necrosis factor alpha (tnfg) following ic stimulation and showed that ic are capable of provoking ~elaase of hrmaunl)reac~ve tni~. j[c also increase mono=yte produchon of prnstaglandin e . in summary, ~/~ese results demonstrate lhmt ic are capable of indudng production of ¢ytokines and the imrau-nosuppressive prostaglandin pge . ic also allez ~he surface expression of important receptors involved in actlvaffon by lp~ and phagocyiosis. thus, ic aze competent for indud/on of the mepl/e s! otlse. by examining m n cyte phenotypms, it may be possible to d~mrmkne extent ohn'u~u~e complex activation and predict immune depression iu criffcally ill pa~ents. a great deal of experimental work has focused on preventing and/or treating sepsis and organ failure following injury. many of these strategies have tried to attack mediator substances released during the systemic inflammatory response following injury. sugermann has demonstrated the improvement of pulmonary function, but not eappillary leak using [buprofen in the porcine model. in a clinical trial, faist demonstrated the effectiveness of indomethacine in amelierating the post trauma of cellular amenity using in vitro parameters. morbidity and mortality, however, were not different between control and treatment groups. baue und chaudry have suggested that atp magnesium chloride may have protective effect in renal failure um kupfer cell dysfunction seen after shock. pentoxiphyllin has been found to be effective in improving tissue oxygenation and oxygen consumption following hemorrhage, and there may be promise for this drug in the ischemia reperfusion injury. monoclonal antibodies against endothxin and inflammatory mediators seemed promising at first glance; however, preliminiary clinical data of the treatment of sepsis with either ha-ia or e monoelonoal antibodies against bacterial cell wall have been disappointing. initial studies with il-i receptor antagonist also appeared encouraging, but no difference was seen in the most recent trial. currently studies are ongoing with monoclonal antibodies to tumor necrosis factor which may have more efficacy given the fact that it is a macrophage mediator released by endotoxin. although we seem closer to understanding and preventing the problems of sepsis and organg failure after trauma, we must continue to appreciate the complex interrelationships and delicate balances inherent in the host defense system. overzealous attempts at restoring immunity in the absence of understanding pathophysiology may be just as dangerous at post-traumatic immlmospremsion. severe acute pancreatitis was caused by different etiologic factors, but once pancreatic tissues were infected, patients show a similar pattern of aggravation and develop organ failure. remarkable elevation of serum il- was unexceptionally observed in patients with severe acute pancreatitis. the serum levels were more than pg/ml (normal: less than pg/ml) during the first one or two days after onset. there was a significant correlation between the peak serum il- level and the number of organs showing failure (r= . ). tnf-a production by isolated peritoneal macrophages following lipopolysaccharide (lps) stimulation was significantly increased in cerulein-induced pancreatitis rats. serum tnf-a activity was elevated following intraperitoneal administration of lps as the septic challenge both in pancreatitis rats and in control rats, being significantly higher in the former (p< . ). histological findings and liver function tests revealed that lps induced more severe liver damage in pancreatitis rats than in control rats. these results indicate that increased tnf-a production by peritoneal macrophages in acute pancreatitis augmented lps-induced liver injury. organ failure in severe acute pancreatitis could be caused, at least in part, by increased cytokine production. it is clear now, that in mods, organ injury is not directly due to exogenous factors, such as bacteria or toxins, but instead is largely a consequence of the host's own endogenously produced mediators. there is an extensive body of literature on the inhibition of mediator production, release and action in different cascade systems by glucocorticoids. they can serve as a host protection against overactive defense reactions if used adequately. a new understanding of the regulation of cytokine synthesis, especially tnf, may lead to an insight of the conflicting findings between the benefits of glucocorticoid therapy in animals and its current failure in recent clinical trials. glucocorticoid shares its role with other novel therapeutic approaches also shown to be successful only in experimental settings. a mete-analysis of steroids in sepsis, however, revealed a beneficial effect in the subgroup of patients with gram-negative infections. there is now a series of arguments to reevaluate the indication for steroid thera-py and/or prophylaxis in mods and sepsis. honjo i- - , kumamoto , japan in septic shock j. briegel, m. halter, h. forst, w. kellermaun, m. bittl, k. peter imrodnetlea and methods: hydrocortisone (hc) at an infusion rate similar to the maximal secretory rate of cortisol in man improves hemodynamics in human septic shock ( ). we hypothesized that the hc-induced hypercortisolemia prevents a harmful overshoot of immune reactions. to test this hypothesis we prospectively investigated patients admitted to the icu in refractory septic shock. after resuscitation (mechanical ventilation, fluid resuscitation, titration of vasopressors, and initiation of antimicrobial therapy) hc was started with a loading dose of mg/ rain, followed by a continuous infusion ( mggh). with hemodynamic improvement (dopamine < gg/kg/min) the infusion rate nfhc was tapered over a period of days. phospbolipase a (pla ), c-reactive protein (crp), and elastase-proteinase inhibitor complex (e-pi) were deierminated daily. results: according to our previous results hemodynamics improved during hc infusien. after days dopamine requirements decreased to less than gg&g/min in all patients. this corresponded to an attenuation of the systemic inflammatory response syndrome (sirs) indicated by the abrogation of fever and the decrease in heart rate and inflammatory mediators. pla activity and e-pi concentrations decreased to near normal values and crp concentrations decreased as well. after cessation of hc infusion (between day and ) a reinforcement nfthe sirs was observed despite cortisol levels within the normal range. this was first indicated by e-pi, followed by fever, increases in heart rate, crp, pla , and finally by the relapse of septic shock in four patients on days , , and o. a second infusion of hc again resulted in shock reversal and in a decrease in pla , crp, and e-pi in the patients under study. discussion: there is growing evidence that the endogenous steroid hc and proinflammatory cytokines integrate a complex immunoregulatory feec~ack circuit. the elaboration of tnf, il- , il- , and il- is attenuated by- rag hc prior to endotoxin challenge in humans ( , ) . cytokines like tnf, il- , il- , and il- are potent proinflammatory signals for acute reactants (--, clip), neutrophil degranulation (--, e-pi), and pla synthesis and secretion. our data provide evidence that hc at an infusion rate similar to the maximal secretory rate of cortisol in man attenuates the systemic inflammatory response in human septic shock. to evaluate the feasibility of a nigh-dose regimen of antithrombin iii (at iii) treatment in patients with multiple injuries regarding blood levels of antithrombin iii and undesired side effcts and to analyse effects of the initibitortherapy on the systemic inflammatory response. patients and methods: patients with an iss nf more than points who could be treated with at iii administration within rain after trauma were randomized to receive either at iii or placebo. at iii was given to reach an antithrombin iii inhibitory capacity in plasma of % by using the following calculation: at iii to administer = ( % -at iii measured) x body weight. at iii was given every six hours for a period nf hours and on the th day. patients were followed up throughout their stay in the icu but at least days. in this abstract the data of the first patients are included. results: the patients' median injury severity score was points with a median age of years. the patients were equally distributed between verum and placebo groups with respact to age , iss, prehospital treatment, blood pressure, hemoglobin and at nmevel on admission, and time from the accident until the test solution was given. the patients of the at iii group received , units of the inhibitor on average during the first days. with our regimen, the at iii levels could be kept between % and % of normal, whereas control patients an at hi concentration of % to % was observed. patients with at ni treatment required less red blood cells bur received the same amount of ffp and fluids. there were no differences with respect to platelet count, partial thromboplastin time, l~rothrombin time and prothrombim. we did not observe bleeding disorders or any other side effect with peak concetrations of up to % of normal. white blood count, pmn--elastase, interleukin and and c-reactive protein tended to be lower in the at iii group. there were no differences with respect to renal and hepatic function parameters but the duration od mechanical ventilation was shorter in the at ii group ( . vs. . days) conclusions: we conclude that our treatment protocol (a) was able to restore at iil levels to the desired range of %, (b) did not lead to coagulation disorders, (c) did not increase transfusion requirements, (d) did not reveal other undesired side effects, and (e) showed a tendency towards reduced posttranmatic inflammation and mechanical ventilation requirements department of trauma surgery, essen, germany antithrombin-lll (at-ill) acts as an inhibitor of thrombin, further proteases and the alternative pathway of the complement system. inhibiting thrombin, at-ill works as a functional antagonist of paf~ therefore, in state of hypevolemic-traumatic shock, continuous supranormal serum -and tissue -concentrations of at-ill may be efficient to reduce the local posttraumatic reactions resulting from complement and pmn-activation. patients with severe multiple trauma ( treatment [at-ill] -- controls [c]) were investigated. study cdteda were age > and < years, injury severity (iss) > points and glasgow-coma-scale > points; randomization and treatment has to be started within hours after trauma. permission for the clinical study was given by the local ethic committee. bradykinin (bk) and related kinins are potent inflammatory peptides which possess the ability to induce, vasodilation, increased vascular permeability and hyperalgesia. cp- , a novel homodimer bk antagonist has previously been shown to increase survival in rat and rabbit models of lethal endotoxin shock and is now in clinical trials for sepsis. we have now evaluated the effect of cp- in other models of inflammation. male rats were precannulated with a catheter in the carotid artery. h later bk was injected ia and the pain score ranked from (no responses) to (vocalization). cp- at . umoles/kg completely inhibited the pain responses for a period of . - h. cp- at . umoles/kg s.c. was also found to inhibit the increase in paw volume and hyperalgesia induced in rats over a - h period by an intraplantar injection of . % carrageenan. the abdominal constriction response o an intraperitoneal injection of kaolin was inhibited in a dose-dependent manner by cp- . when ul of . % formalin was injected into the paw of a mouse a characteristic licking response was observed which was biphasic in nature. cp- significantly inhibited both the first ( - min) and second ( - min) phase responses. ]n a rat burn model, where the hind paw is immersed in water at °c for sec the increase in paw volume was significantly reduced by pretreatment with cp- , . umoles/kg s.c. finally cerebrai edema was induced in rats by applying cold (- °c for sec) to the dural surface following a craniectomy. cp- at . umoles/kg s.c. produced a significant reduction in the amount of edema compared with sham controls h later. these data suggest that bk is an important mediator of inflammation and hyperalgesia and that the bradykinin antagonist, cp- , may be useful in the treatment of such inflammatory, hyperalgesic disorders. partial hepatectomy in humans is associated with a considerable morbidity due to hemodynamic and metabolic derangements, which increase the risk for organ failure and mortality. we hypothesized that endotoxemia may play a pivotal role in these complications. we therefore, investigated whether peri-operative infusion of rbpi , a recombinant protein of the human neutrophil bpi with bactericidal and endotoxin-binding capacity, could prevent postoperative derangements following partial hepatectomy. male wistar rats ( - g.) received a % liver resection (phx) or a sham operation (sh), and a continuous intravenous infusion of either . mg/kg/hr rbpi (phx-bpi, n= ; sh-bpi, n= ) or the (iso-electric, iso-kd) control protein thaumatin (phx-con, n= ; sh-con, n- ). various parameters were measured h after the resection or sham operation. mean arterial pressure, cardiac output and heart rate were significantly decreased in phx-con rats compared with sh rats, which effects were not observed in phx rats treated with rbpi . blood ph was significantly decreased in the phx-eon group, whereas the leucocyte count, hematocrite and il- levels were significantly increased compared to sham levels. in the phx-bpi group, these parameters were restored to near sham levels. in vitro experiments with rat plasma and human mononuclear cells (mncs) revealed that plasma of phx-con rats is highly capable of activating mncs, accompanied by the release of cytokines. this activation is attenuated with phx-bpi plasma. in vitro added acd or polymyxin b was able to reduce the activation by phx-con rat plasma to the levels of phx-bpi rats thus, these data suggest that systemic endctoxemia, possibly of gut origin, is a major cause of postoperative hemodynamic and metabolic derangements following phx and that rbpizz can prevent these changes. more recently we reported a transient appearance of both endotoxin and tnf in the circulation of rats subjected to the haemorrhagic shock (hs) already at - rain. similar to bpi, recombinant bpi was found to bind lps and inhibit tnf formation in vitro. the aim of this study was to investigate the effects of rbpi (kindly provided by xoma corporation, berkeley, ca) against haemorrhage related endotoxemia and mortality in rats. method: a prolonged hs was induced by blood withdrawal to a mean arterial pressure of - mmhg for rain followed by reinfusion of shed blood (sb) and resuscitation with two times of sb volume of ringer's lactate over rain. rbplg. was administered at a total dose of mg/kg i.v. ( . mg/kg at the -eginning followed by two doses of . mg/kg each at end of shock and the end of resuscitation). the control group was treated similar to the bpi group but received thaumatin as a protein control preparation at the same dose as rbpi . results: imrffe?diately after resuscitation ( min) the detected plasma endotoxin levels in the control group (mean = , range = - pg/ml) were almost neutralized by rbpi treatment (mean = , range = - pg/ml) . plasma tnf levyis were not significantly influenced by rbpi treatment at the two time points and min of experiment (means: and in bpi vs , pg/ml in the control group). the -hour survival rate was improved from / ( . %) in the control to / ( %). conclusion: these data suggest that haemorrhagic shock may lead to bacterial translocation and/or transient endotoxemia with concomitant cytokine formation that may play an important role in the pathogenesis after shock and trauma, rbpi might be a useful therapeutic agent against endogenous bacterfal/endotoxin related disorders in hemorrhagic shock. morbidity and mortality after hypoxia of the vital organs had been correlated to the production of oxygen radicle which is mediated by xanthine oxidase activity, in this study we have evaluated the survival rate after allopurinol. rabbits weighed + grams divided into two groups. group i included tabbits were treated with allopurinol mg/kg for seven days before induction of haemorrhage. group ii as a control included rabbits. all rabbits were subjected to % arterial blood loss through the central ear artery for one hour then resusciatation was done by the heparinized withdrawn blood through a marginal ear vein. during the experiment blood pressure and heart rate were monitored through the central ear artery. also uric acid, lactic acid, glutathione activity were estimated. animal survival was followed for days. postmortem vital organ histochemistry and histopathology examinations were done. in group i the survival after three days was out of while in group ii it was two out of . our conc|usion, allopurinol had increased the survival in aiiopurinol pretreated rabbits which may indicate the value of allopurinol premedication for patient prepared for elective bloody surgical intervention . h receptor antagonists are commonly used for stress ulcer prophylaxis, but their actions on the septic response are largely unknown, in an experimental model, pigs were first anesthetized, then injured with joules of energy to the posterior thigh, then hemorrhaged - % of their blood volume. after i hr of shock, all the shed blood plus x the hemorrhage volume as lactated ringers was infused. following resuscitation, ranitidine ( . mg/kg iv twice daily) or saline placebo was begun. the treatment group was randomly assigned in a blinded fashion. after hrs, a septic challenge was administered ( bg/kg of e. coil endotoxin (lps)). serial gastroscopy, gastric ph, hemodynamics, abg's, physiologic dead space ventilation, leukocyte counts, and tumor necrosis factor (tnf) levels were recorded for min. baseline values and units were cardiac index _+ ml/min/kg (ci), arterial po + mmhg(pao ), base excess . -+ meq (be), physiologic dead space fraction +_ % (pds), and tnf . + . units/ml. baseline gastric ph was . -+ . and . _+ . in the placebo and ranitidine groups, respectively. the gastritis following hemorrhage was marginally attenuated in the ranitidine group. following lps infusion the following were obtained: ci pao * be* gastric* pds* peak* rain rain rain ph min tnf ranitidine _+ _+ - . ± . bum injury results in hypermetabolism, fever and nitrogen wasting. endotoxin (lps) has been proposed to mediate these effects, either directly or via activation of macrophages to produce cytokines such as interleukin- (ii- ). this study was designed to clarify the role of lps and - in the metabolic response to bum injury. twenty-five burn patients ( -+ %; + % ft bsa burn; _+ years old) were studied serially for three weeks post bum. patients underwent partitional calorimetry to assess metabolic rate and compartmented heat loss. nitrogen was assayed using chemiluminescence. lps and i - were measured with limulus amebocyte lysate assay and elisa. patients were excluded if they suffered smoke inhalation, showed any sign of sepsis or failed to rapidly meet their nutritional needs via the enteral route. ten patients received intravenous polymixin b ( , u/kg/day to bind lps). these patients did not differ for the remainder. all patients were hypermetabolic and febrile in proportion to the size of their bum wound but were not endotoxemic ( . +_ . pg/ml; normal < pg/ml). i - did demonstrate a significant correlation with cole temperature (tr~ = . + . ogi - , p= . ) and with nitrogen excretion (nou t = - . - . ogi - + . tr, p= . ). administration of polymixin b had no effect on metabolic rate, temperature or i - levels but did reduce nitrogen excretion resulting in more positive nitrogen balance ( .t grn/day vs. - . gm/day, p= . ). although bum injury does not produce an obligatory endotoxemia, i - does appear to play a role in the fever and nitrogen wasting seen with such injuries. the effect ofpolymixin b on nitrogen excretion suggests that lps may play a role either locally or in the portal system. introduction: there is substantial evidence that release of inflammatory mediators by activated kupffer cells contribute to the course of a systemic inflammatory process, e.g. after shock or lrauma. besides the systemic effects of mediators such as tnf, paf or interleukines, local actions on hepatic microvasculature and hepatic inflammatory response have to be considered. our aim was to assess the role of tnf and paf by blocking their effects using anti-tnf monoclonal antibody, pentoxifylline and a paf antagonist. methnds: in anesthetized sprd-rats, hemorrhagic shock was induced by withdrawl of arterial blood within rain and shock state was hold for h at a map of mm hg (cardiac output of %). following adequate resuscitation with % of shed blood and twice of this volume as ringer's solntion, animals recovered to map > mm hg and co > %. hepatic microcirculation and sinusoidal leukocyte-endothelium interactions were examined by intravital epi-fluorescence microscopy at , , or hours after resuscitation. in a blinded fashion, a rat-specific monoclonal anti-tnf antibody [ mg/kg, celltech, uk) , pentoxffylline (ptx, mg/kg, hoechst, d), and a paf antagonist (web , boehringer, ingh., d) were given either as pretreatment or at the time of resuscitation (n= - group bolla. k*., duchateau, j., hajos, gy., mbzes, t., hern~di, f. prevention of temporary/secondary immune deficiencies or reduction of their severity and/or duration as well as the reduction of the perifocal inflammatory processes belong to the rational targets of posttraumatic/pedsurgical medication. such a targeted medication can result in less frequently occurring nosocomial infections, and in reducing the duration of the intensive care and convalescence period. the results of in vitro studies performed with the amino acid sequence - of thymopoietin, i.e., with thymocartin in whole blood and peripheral mono-nuclear celi(pbnc) cultures clearly show some characteristic effects of this immunomodulator. preincubation with the tetrapeptide significantly (p<o.ol) and concentration-dependent reduced the endotoxin(lps)-induced tnfalfa production from , to about pglml, but did not abolish it. the inhibition of the lps( . ug/ml)-induced tnf production occured already in presence of , pg peptide/ml and peaked at the concentration of , ng/ml. higher concentrations did not increase this effect. in contrast to the other two small thymic peptides (tp- and tp- ), thymocartin did not enhanced the pwm-induced pge production in pbmc cultures up to a concentration of ng/ml, inclusive. the selection of thymocartin (tp- ) for perisurgical medication and/or for treatment of trauma-induced temporary immune depression has been strongly supported also by targeted animal experiments. thus, mortality of about % registered in mice infected with pseudomonas aeruginosa after bum injury could be reduced with the tetrapeptide treatment to a level which did not differ significantly from that of the infected non-burned controls. moreover, observations gathered first of all with the inflammatory model of air poach/croton oil grenuloma (selye) clearly showed, that a very definite, antiexudative effect can be achieved with this thymic peptide. as to this effect, thymocartin has been confirmed, e.g., to be equipotent with locally administered fluocinolone acetonide and/or s.c. injected prednisolone. the interim results of two explorative double-blind clinical studies (involving more than patients after polytrauma and hip-fracture untill now, respectively) correspond to the expectations. the treatment significantly reduced the occurence of nosocomial infections, the days spend in intensive care and on antibiotics as well as it shortened the bed-out time and reduced the additional medication. objective of this prospective randomized study was to further delineate the mechanisms leading to these alterations and to investigate the effects of immunomodulatory intervention. patients and methods: patients (pts) formed control group a. group b pts received x mg indomethacin (indo) from the first (dl) to the fourth postoperative day (d ) intravenously to block prostaglandin e induced suppression of cmi response as well as mg thymopentin (tp- ) subcutaneously preop., on d and d to augment cmi reactivity. in vitro investigations preoperatively, on dl and d included measurements of the percentage of cd + t-helper (th) cells, pbytohemagglutinin (pha)induced synthesis of interleukin (il)- as one cytokine primarily produced by thl-cells, and pha-induced synthesis of il- as one cytokine primarily produced by th -cells. delayed type hypersensitivity (dth) skin response to an antigen skin test battery and specific antibody (ab) production following tetanus vaccination preoperatively and on d were used as in vivo tests for thl-and th -induced immune response respectively. results: postoperatively, group a pts showed a persistent significant reduction of cd + th cells, il- /il- ratio, and dth skin response as compared to baseline values (bl), while ab production increased (p< . vs.bl). in group b pts no change in cd + th cells, il- /il- ratio, or dth skin response was observed (p< . vs.group a), and postoperative ab production increased significantly (n.s. vs. group a). conclusions: .these results clearly indicate a significant suppression of th induced cmi response, while th induced response remains normal following ohs. .these alterations may gain clinical significance whenever a postoperative infection requires a th response and may explain the susceptibility to opportunistic microorganisms observed in pts after ohs. the aim of this study was to find out whether the establishment of administration of thymostimulin (tp-i) in jaundiced and anergic rats would return the rats to the state of immunocompetence. material and methods. male wistar rats weighing - g were injected with haemocyanin (klh). all rats with a positive response were included in the study and we evalu ated the t cell subpopulations and il- . they underwent laparotomy and the common duct was ligated and divided. those rats whic become jaundiced and anergic one week after the operation, were divided in two groups: control group ( objective of study. the goal of this study was to prove the necessity of thymus derived immunomodulators treatment in acute period of infantine sepsis, materials and methods. immune status was investigated in o infants. clinical conditions of children were defined by syndrome of multiple polyorgan]c insufficiency. the heaviness nf condition was estimated as the sum of points according to efforts needed to restore of basic living functions -respiration, hemodynamjcs, hemocoagulatlon, metabolism, functions of liver and kidneys. it was expressed in form of clinic condition classes from to . results.it was found that in % of infants with - classes of heaviness immunode[iciency took place simultaneously with ii and iii stages of hemocoagulattve syndrome. amounts of t cells and t helpers were decreased more then times, ratio th/ts was reduced to . or lower. concentration of lgg and igawas reduced almost a hull in comparison to control. phagocytic and metabolic activities nf neutrophils were depressed. complement system state was changed: the functional activity of the alternative pathway factors b, d and the level or c a subcomponent were increased but the level of c , c ,, c and c components of the classic pathway were decreased. during the development of coagnlopathy the direct correlation between chso, levels of plasminogen and antithrombine iii was found. in greater extent the function of immune system was disodered in accordance with point metabolic violations and hemocoagulative disturbances considered as disseminated inmtravaseular clotting syndrome on ii or ili stages. conclusions. the rehabilitation of the immune system functions was promoted by taetivine and thymaline in doses of i- mcg/kg per day and mg/kg per day accordingly during a week in children with - classes el heaviness. aiter - days tactivine had advantage. when eoagulopathy took place thynaaljne promoted restoration of ( - )-~-d-glucan (bgc) is a major cell wall compornent of pathogenic fungi and shows many immunopharmacological activities on experimental animals. lps is also derived from gram-negative bacteria and have in~ttnomodulating activities on immune systems positively or negatively. because of difficulty to cure contaminating lps from bgc preparations, it is very hard to evaluate the exact activities of bgc. in this study, we compared the immunological activities of lps ans highly purified bgc on murine system. materials and methods: c h/hen or c h/hej mice, to wkolds of both sexes were used through experiments. highly purified ( - )-{ -d-glucan (gurdran; bgc)was courteous gift from seikagaku kogyo co. tokyo, japan and resolved in endotoxin-free ultra-pure water. escherichia cell lps was purchased from sigma chemicals, usa. mitogenic activities of bgc or lps on splenic cells were measured by mit dye assay. in vitro activation of peritoneal exudate macrophage (pen) have moniotored by phagocytosis and intraphagocytic killing of pseudomonas aeruginosa (z~b- . induction of cytokine productions from pem or spleen cells induced by bgc or lps were detected by cytotoxic assay. results and (bnclnsions: i ) in vitro cultures of pem with bgc have induced enhanced phagocytic and bactecidal activities in c h/hen and c h/hej mice, whereas lps only induced such activities in c h/hen mice. most effective dose of bgc was ug/ml. ) bgc-dependent proliferative response of c h/hen splenic cells was not detected under the culture condition used. ) induction of tnf~ prodction was apparently observed in bgc-stimulated c h/hej pd cultures, but not in lps stimulated one. these findings indicate that activation mechanisms of pr and splenic cells by bgc are different from that by lps. to investigate the bsc-induced p~ activation, intracellular signaling pathways of p~ by bgc-stimulation are under consideration. yamagami k, uedono y, kawakami k, kitazawa y and tanaka t according to the latest reports of use of il- in a burned-sepsis model, the dose was too high to adjust for human therapy. adoptive transfer of l~ymphokine-activated killer (lak) cells has been demonstrated as a means of enhancing therapy in malignant tumors. we therefore attempt to use lak therapy on burned-infected mice instead of il- . under anesthesia, -weekold male c h-hej mice were subjected to a % scald or sham burn and then resuscitated. sham burned mice served as controls. scald burn mice were subjected to peritonitis by intraperitoneal innoculation of organisms of p. aeruginosa hr after burn. burned-infected-mice were divided into two groups. one group had no further treatment, and the other group received lak cells ( x ) intraperitonelly after septic challenge. the mice were scored for survival daily. on day after burn, using moabs dual-color flow cytometry, we studied lymphocyte expression in mice with use of blood and spleen. simultaneousely we studied the alteration of il- and il- in their serum using immunoassy kits. sham burned animals had no mortality. the mortality of the lak-treated mice was significantly reduced when compared with that of the burned-infected mice. the most consistent changes observed were depressions in percentages of thyl, positive cells and a remarkable depression of nk cells in spleen. after lak cell treatment, those two percentages of cells significantly increased. all the data of assay of ill and [l were not detected on sham burn mice serum. due to burn and septic challenge the levels of illand il (n= ) were raised to . _+ . and _+ pg/ml, while the levels in lak treated mice were reduced to . _+ . and _+ pg/ml, respectively. the results reported here demonstrate that lak therapy is able to improve cell-mediated immunity in burned-infected mice. this is associated with a significantly improved survival rate, since ill has been demonstrated to mediate immune and inflammatory responses. also a cause effect relationship between elevated endetoxin levels and increases of [l has been recently established. the aim of our present study was to investigate the effect of parenteral indomethacin on the immune system of patients under major operations. our study included operated patients, of which received mg indomethacin before and , and days after surgery (group a) and patients received no antiinflammatory therapy (group b). we measured total t-cells helper (cd ), suppressor (cd ), nk-cells and interleukin- and tnf production by pha or endodoxin (lps) stimulated peripheral blood mononuclear cells at day and , and days after operation. in group a we detected a significant (p< . ) increase in cd /cd ratio on day while no differences were ~oted in nk-cells or cytokine production in both groups (table ) . it seems, therefore, that parenterai indomethacin may have a benefitial effect on the immune system of patients under major operations by increasing the t-helper /t-suppressor cell ratio while having no effect on the production of cytokines by peripheral blood mononuclear cells. this study was undertaken td dete~nnine the role of prostaglandin synthesis inhibitor on survival post traulna sepsis. analysis of the effects of prostaglandin synthesis inhibitor on survival of four groups of mice each were made after laparatomy and intravenous administration of live e.coli. post trauma sepsis, group a received no treatment; group b received antibiotics im; group c received prostaglandin synthesis inhibitor im and group d received both antibiotics and prostaglandin synthesis inhibitor im. survival time was longest in group treated with prostaglandin synthesis inhibitor and antibiotics post trauma sepsis. the singular use of either antibiotic or prostaglandin synthesis inhibitor did not alter the outcome on survival. mortality rate was lowest in the group treated with combined prostaglandin synthesis inhibitor and antibiotics. use of this combination showed a reduction in bacterial growth in peritoneal and blood samples, mild morphologic changes secondary to sepsis in the heart, lungs, liver, kidney and stomach and marked enhancement of mean level of activity. the study indicates that addition of prostaglandin synthesis inhibitor in treatment of trauma-sepsis has clear beneficial effects. interferon-? (ifn-y) is a potent immunostimulant which has been shown to be detrimental when administered during septic shock. blockade of this cytokine however is beneficial during the acute septic response. the aim of this study was to evaluate the cellular effects of this cytokine and its blocking monoclonal antibody (moab) in lethal sepsis following injury. female cd- mice were randomized into two groups: septic=lps vs injury=hind limb amputation (hla vs igg. nstats= anova=p< . vs lgg ifn-y was detrimental when given to control septic animals. however its blocking moab was protective (p< . ). conversely ifn-y was proteetive in injured septic animals compared with anti-ifn-? (p< . ). these findings demonstrate that the immune stimulant ifn-? has therapeutic potential in the immunosuppressed injured host predisposed to sepsis, while blockade of this cytokine is required for protection in the septic host with a normal immune response. dept of surgery, rcsi, beaumont hospital, dublin , ireland. oxidants play a role in physiology. the potential noxious oxidant biochemistry is restrained by chemically distinct antioxidants. these antioxidants, which may reside in different cellular compartments, can act synergistically. in normal physiology an oxidant/antioxidant bai&nce exists. unbalance in favour of the oxidants is called oxidative stress. oxidative stress has been implicated in many pathologies including lung diseases(e.g, doxorubicin induced cardiotoxicity), ischemia/reperfnsion damage and central nervous system trauma. transition metals such as iron are involved in the early events leading to oxidative damage in these pathologies. this has been underlined by the finding that postischemic cns pathology closely resembles that caused by a chemical oxidative insult (e.g. iron microinjection). moreover, a protective effect of oxygen-radical scavening agents or compounds that inhibit lipid peroxidation (antioxidants) in brain ischemia/trauma is apparent. some known drugs (e.g. anti-arrhythmics or histamine h -antagonists may act as non-specific antioxidants. howe~er, recently, interesting new membrancespecific antioxidants (e.g. -aminosterdids) have been designed. subt&e effects on iron redox chemistry contributes to the potent antioxidant activity of these aminosteroids. since a few years, one area that greeted enthusimastlcally in clinical medicine is that of reoxygenatlon injury or ischemia-repeffusion, a phenomenon accepted to make a majo:" contribution to organ dysfunction in trauma, shock and sepsis through the formation o( oxygenated free radical species. however, thei detection in vivo always remains a difficult challenge. efforts have been made recently to directly establish the formation of free radicals in biological samples as complex as blood, plasma or tissue with the use of electron spin resonance (esr) spectroscopy. using spin trapping agents, the presence of reactive carbon-and oxygen-centered radicals has been demonstrated in animals blood submitted to heart, renal and intestinal ischemia-repeffusion or to liver transplantation. recently, the in vivo formation of free radicals in the cerebra; extracellnlar fluid during cerebral isehemia-repeffusion has been assessed by the spin trapping technique coupled to brain microdialysis. esr investigations have also been conducted to detect endotoxin-induced free radical generation in rat or baboon liver and oxygen free radicals (ofr), produced both at intra-and extra-cellular levels, seem to play a major role in the pathophysiology of tissue injury and organ dysfunction in sepsis, through induction of lipid pemxidation in cell membranes. oxidative damage can result both to an ofr-overpmduction or to a depletion of endogenous antioxidant defenses, which are represented by scavenger enzymes (e.g. sod), hydrosoluble and liposoluble antioxidants (e.g. ascorbate, vitamin e), and other mechanisms such as metal-ion sequestration. in animal models, oxidative damage has been proved by detection of increased levels of lipoperoxidative products, and a depletion of antioxidant defenses was found both in plasma and tissues. in the few clinical studies a similar results have been reported, and oxidative damage appears to correlate with dic, with organ dysfunction and with red blood cell deformability. in a group of critically ill septic patients we found increased levels of conjugated dienes (cd) (bioproducts of lipoperoxidation) and decreased plasma levels of alpha-tocopherol and coenzyme qlo (coqi )(endogenous liposoluble antioxidants). a relationship between cd and uric acid (p< . ) was found, may be related to xantine-dehydmgenase to xantine-oxidase conversion. antioxidant depletion is due both to overconsumption and to a nutritional deficiency, even if a reduced synthesis can also be present. in fact one more relationship between coqi and plasma cholesterol (p< . ) demonstrates the commun hepatic biosynthetic defect. is there any role for antioxidative therapy in sepsis? can it achives a significant improvement in the septic course, organ dysfunction, and final outcome? several antioxidant drugs, have been evaluated in experimental and clinical sepsis: scavenger enzymes, natural antioxidants, alloporinol, -aminosteroids or lazaroids, have been proved to reduce lipopemxidative damage, to protect organ dysfunction, and in some cases to improve survival. several questions must be addressed in evaluating safety and utility of antioxidative therapy. more specific and standardized methods must be applied to detect and quantify the lipoperoxidative damage. antioxidant drags must act selectively on ofr-production, without interference with other than that are beneficial for the organism. antioxidants must be able to achive in adequate amount the tissue or cellular compartment where their action is required. many antioxidants have also a pro-oxidative effect which can he detrimental in some conditions. the timing of administration, the dosage used and the association wih others antioxidant drugs must be defined. nutrition plays an important role as antioxidative therapy, since it supplies all compounds needed to maintain adequately levels of endogenous antioxidant or to support their synthesis. thiobarbituric acid reactive substances (tbars) concentration in serum has been determined in a large population of healthy subjects and in patients suffering acute hepatitis and chronic cases of hepatitis c, as well as several other processes. the correlation with different physiological and clinical parameters in these populations is also presented. treatment with interferon of the chronic active hepatitis c patients, x u three times a week during two months, led in those patients whose sgpt activity normalized in serum, to a concomitant decrease in serum tbars content. the possible theoretical involvement of peroxidation and antioxidants in this beneficial effect of i~terferon in hepatitis c patients is discussed. the results presented confirm the value of tbars as laboratory test in the management of disease and as a useful tool for the study of pathogenic and/or therapeutic mechanisms. -hydroxyalkenals are among the different substances measured by the tbars assay. these compounds show several biological effects that have been demonstrated mainly in different experimental models. we have studied the capacity of different tissues to conjugate these compounds patients surviving the initial subarachnoid hemorrhage (sah) from a ruptured in~raeranial aneurysm are prone to develop cerebra] ischemia from vasospasm which is associated with significant morbidity and mortality. among the many treatments that have been prol~osed to treat this condition, none has been shown to be satisfactorily effective. recently, a new drug, namely the -aminosteroid tirilazadmesylats, has been studied in a large, prospective, multicentor trial for its effectiveness to improve the outcome of patients with aneurysma! said. the study was conducted in europe and australia in neurosurgical centers and included patients. all patients received presently accepted standard treatment, including nimodipine. patients were randomized to four different groups: placebo and groups of tirilazad in escalating dosage ( . - mg/kg/day). the clinical outcome was compared for these groups and cerebral a~giography was performed in % of patients on day - follovang sah, to study the effect f'the dflf~ off cerebral vasospasm. the study reached its planned endpoint months ago. preliminary results ~how a significant improvement with regardto mortality in those patients receiving the highest tirilazad dose as compared to placebo and the two lower dose groups. additional beneficial effects were seen in the rag/day groups with regard to the occurence of symptomatic vasospasm and good clinical outcome. although the final analysis of all data is still pending, these results suggest that tirilazad-mesylate could represent a major improvement for the treatment of patients with sail. experimentally lipidperoxidation products (lpo) are increased in acute pancreatitis (ap) due to oxygen radicals (or). the purpose of this clinical study was to determine the antioxidant status and lpo in patients suffering from ap and to evaluate the effect of antioxidant treatment with sodium selenite (se) thus improving the function of the se dependant glutathione peroxidase which is the major detoxifying system for or. materials and methods: in z patients sufferin s from severe ap (c-reactlve protein > me/l) we determined on day and day after admission the lpo ma!ondialdehyd (mda), conjugated dishes (cd), reduced (gsr) and oxidized (gssg) glutathione, the vitamins a,c,e and se. moreover the patients were evaluated clinically using the ranson and the apache ii score. i patients were randomly treated with ug/day of se for days. results: all patients suffered from a severe depletion of antioxidants,especially a low concentration of se (only / of normal). thereby the increase in lpo correlated with the clinical course. during se treatment lpo decreased and the levels of antioxidant vitamins improved. se had no influence on leth-slity the lenl or the chan in rs or ap ii. background: since reperfusion injury occurs when oxygen is reintroduced into ischemic tissue, the ideal timing for administration of therapeutic compounds aimed at ameliorating oxygen radical mediated injury is at the time of initial fluid resuscitation. currently used colloid or crystalloid preparations do not provide optimal, or even significant, anti-oxidant protection. systemic iron chelation affords protection against the iron catalyzed components of oxygen and lipid radical mediated tissue injury. the conjugate resulting from chemical attachment of the clinically approved iron chelator, deferoxamine (dfo, desferal ®, ciba), to hydroxyethyl starch (hes) represents a novel approach to colloid based fluid resuscitation. hes-dfo contains % hes and % chemically bound dfo. the polymer-drug conjugate has a lower molecular weight than that of hes in order to allow more rapid excretion. results: preclinical and initial clinical trials indicate that hes-dfo is well tolerated, even at high doses. in animal studies, fluid resuscitation with hes-dfo does not significantly improve central hemodynamic recovery beyond that observed with hes, but hes-dfo seems to afford better protection of microcirculation in organs at risk (lung, liver and gut), possibly by decreasing neutrophil sequestration. in a burn model, total fluid requirements are lower and oxygen utilization higher in hes-dfo treated animals compared to hes controls, suggesting decreased vascular leak and improved tissue perfusion. conclusion: hes-dfo represents a means by which potent antioxidant protection can be administered at resuscitation. iron has been suggested to play a pivotal role in oxygen flee radical mediated tissue injury. in vitro experiments indicated its critical role as a katalyst in hydroxyl free radical generation fenton-reaction). since iron chelator deferoxamine administered in shock alone demonstrated severe side effects, a hydroxyethylstarch (hes)daferoxamine (dfo)-conjugute was used to modulate oxygen free radical injury during the ischemia/reperfi~ion syndrome induced by hemorrhagic shock. methods. female lewis rats ( - g, n> ; pentobarbital anesthesia mgjkg), in hemorrhagic shock ( the aim of the study was to elucidate ( ) whether the generation of or would affect lung and kidneys as primary shock organs in the very early phase of sepsis and ( ) whether dfo-hes could prevent this tissue damage. methods: in rats sepsis was induced by cecal ligation puncture (clp) peritonitis. the animals were randomly assessed to groups: one group was treated with ml dfo-hes ( mg/kg iv), the other rats received solely ml of the carrier starch solution. , , , and min after induction of sepsis respectively, the animals were sacrificed, the organs collected, and tissue contents of glutathione (gsh), malondialdehyde (mda), myeloperoxidase (mpo) and conjugated dienes (cd) determined. plasma samples were obtained for analyses of endotoxin (chromogenic lal test). blood pressure (map) was measured via a carotid artery catheter. results: clp caused sepsis with high (> . eu/ml) endotoxin levels. map in both groups decreased slightly but significantly during sepsis regardless any treatment. in the lungs mpo concentration was increased (p< . ) in the lies group already min after sepsis induction. concomitantly, tissue gsh level decreased and lipid peroxidation was pronounced as shown by elevated mda and cd levels. dfo-hes diminished tissue pmn accumulation and mpo concentration. moreover, at each time point lung mda and cd levels were lower (p< . ). histomorphological examination showed marked micro-atelectases, destruction of the alveolar septa, and splicing of the basal membranes in the lies group. in contrast, in dfo-hes treated rats the alveoli remained well-ventiiated and only some enlarged reticular fibers without splicing were observed. almost similar results were found for the kidneys. mpo levels differed neither within nor between both groups. the slight decrease in gsh levels seen after min in the dfo-hes group seems to demonstrate an oxidative stress to a lesser degree. the most impressive effect of iron chelation, however, was revealed by the lipid peroxidation products. at each time point, mda and cd levels were lower (p< . ) compared to the hes group. light and electron microscopic examination disclosed tubulotoxic and mitochondriat damages while dfo-hes lxeatment prevented that alterations. conclusion: both the biochemical and histological results of this study reveal an early and remarkable generation of or in peritonitis-induced sepsis. thereby, these or obviously cause pulmonary and renal tissue damages, intravenous application of dfo-hes may, however, benefit by preventing early lipid peroxidation of the tissue. the proteolytic irreversible conversion of xanthine dehydrogenase (xd) to xanthine oxidase (xo) is triggered by calcium flux. the aim of our study is to clarify ~he link between intracellular ca + levels and xo activity determined by uric acid release, and to evaluate the efficacy of verapamil, on the generation of hydrogen peroxide associated with reperfusion by assaying lactate & pyruva~e release and the levels of cytosolic free nad /nadh ratio. experimental protocol consisted of :(a) non ischemic/reperfused experiment in which normal cardiac slices of rats were perfusated with oxygenated kreb's ringer phosphate buffer containing glucose ( mg%) and bovine albumine ( gm%) for min at °c.it composed of groups, group aa (control group), and groups ab & ac (perfusate supplemented with verapamil in the dose of loo& mi% respectively). (b) ischemic reperfused experiment in which ischemic cardiac slices were obtained from rats subjected to min ~aemorrhage.lt was also divided into two groups; group ba and bb (verapam~/ mi% added to perfusate}. verapamil stimulated uric acid release from normal rat cardiac slices were % in group ab and % in group ac(dose related). rates of uric acid release is enhanced by verapamil in group bb. moreover, rates of uric acid release in groups ac & bb are insignificant. in verapmil added groups (group ab, ac & bb), increase uric acid release is associated with an enhancement in pyrurate release and with increase levels of cytosolic free nad+/nadh ratio, although it is not evident ~ ischemic group (group ba).it is concluded that the conversion of xd to xo is calcium independent. eicosanoids like thromboxane a , leukotriene b and leukotriene c are known as promoters of initial inflammatory reactions. we investigated whether oxygen radicals (or) are able to induce a release of these eicosanoids in whole blood. blood from healthy volunteers was incubated with xanthine oxidase/hypoxanthine to generate oxygen radicals. after , , , and minutes plasma levels of thromboxane b (txb ), leukotriene b (ltb ) and leukotriene c (ltc ) were determined via elisa technique. another volunteer had taken mg aspirin one day before taking the blood sample (no ). results: txb plasma levels increased from pg/ml at min to pg/ml, pg/ml, pg/ml and pg/ml at , , and min (p< , ) . ltb and ltc plasma levels showed an increase during the first few minutes (ltb : min: llpg/ml, min: pg/ml; ltc : min: pg/ml, min: pg/ml (p< , )) followed by a decrease to normal values at min. in the sample no the cyclooxigenase-pathway was completely inhibited, the txb plasma-levels did not alter at all, whereas ltb and ltc -plasma levels weren't affected. opallogeneic blood transfusion jane shelby, ph.d., and edward w, nelson, m.d, there have been numerous investigations dudng the last two decades examining the effect of surgery, anesthesia, blood loss and transfusion on vadous immune parameters in humans and animal models. there appears to be concurrence among several well controlled studies that transfusion of whole blood (containing leukocytes), has regulatory effects on immune ceil function which include decreased cell mediated immune response, and inhibition of il- secretion. these effects occur following transfusion alone and in con.cart with the distinct immune effects of surgery, trauma and anesthesla, the clinical consequences of this immune modulation by transfusion include decreased allogeneic response to transplanted organs, which has been exploited clinicelly in renal transplant patients. additionally, there is evidence for a strong association with increased risk for infection in transfused patients following surgical procedures. aiiogeneio blood transfusions have been shown to inhibit cellular anti.bacterial mechanisms, causing increased susceptibility to bacterial pathogens, in humans and in animal models. there is also concern that allog~neic transfusion may adversely affect cancer patients, resulting in decreased disease-free survival. several stategies have been proposed to minimize the adverse effects of blood transfusion. there is evidence that the risk of immune mediated infectious complications associated with transfusion may be greatly minimized wlth the use of autologous blood and leukocyte free allogeneic blood.products in surgical and trauma patients, it also appears that the inhibition of cellular immune response and il- productiorl following atlogeneic blood transfusion may be mediated by increased prostaglandin e secretion, and that immune response may be preserved in allogeneio whole blood transfused subjects receiving c lc~oxygenase inhibitors such as ibuprofen. among these are various alterations in immune function. efforts have therefore been made to utilize alternatives to homologous transfusions. these include the use of autologous predonation, supplemental iron therapy, and recombinant human erythropoietin. although initially considered innocuous, these therapies are now recognized to have potential deliterious immune sequelae. erythropoietin, by its ability to lower serum iron levels, can impair both lymphocyte and nk cell activity. autologous donation impairs nk cell function. finally, supplemental iron therapy can stimulate bacterial growth and increase the rate of infectious complications. this talk will present a discussion of these factors as well as a weighting of their importance. r.l rutan, rn;bsn, shriners burns institute and the university of texas medical branch, galveston tx, usa the serious sequelae of homologous blood transfusions have resulted in vigorous efforts at identifying alternate therapies for correcting red blood cell (rbc) deficits. erythropoietin (epo) was hypothesized to exist in the early th century, however the protein was not isolaled until . the human gene was identified and cloned in , which permitted the production of epo through recombinant techniques. the earliest clinical trials were performed in anemic end-stage renal failure palients on hemodialysis. treated patients experienced increases in erythropoiesis with normalization of hematocrit and hemoglobin levels, cessation of lrans-fusion requirements and improvement in general wellbeing. these studies, however, identified side effects of epo treatment such as hypertension, seizures and ee deficiency. volunteer trials have established that the hypertension is not a direct pressor effect but rather the result of abnormally rapid increases in red cell mass in the face of the incompetent volume-controlling mechanisms of the end stage renal failure patient. lower doses of epo and the subsequent gradual increases in red cell mass are associated with significantly lower incidences of hypertensive complications of epo therapy. likewise, seizure activity is not the result of a direct epileptogenie effect but parallels the incidence of hyper-tensive-related sequelae during high.dose epo treatment. in cross-over designed studies, pre-existing iron deficiency has been demonstrated to decrease or negate stimulated erythropoiesis but effective-hess can be restored with appropriate fe supplementation. exogenous epo is effective whether given by iv or sq routes and dose response curves do not vary with route of administration. increases in rbc mass are directly related to the dose of epo, both in amount and frequency of administration although there is a - day time lag between the first epo dose and laboratory indications of its action (i.e. increase in the number of reticulceytes in peripheral wood). epo is currently labelled for use in the treatment of anemias associated with end-stage renal disease and aids. however, its use in the surgical population has been explored because of its unique direct dose-response, epo has been used to effectively increase the blood harvest amounls in autologous pre-donation, significantly increase hematocrils in children following thermal trauma and successfully increase red blood cell mass following essential surgical procedures in patients with religious aversion to transfusion. by blood transfusion in colorectal cancer surgery mm heiss md, ch delanoff md, r stets md, j hofinann, e faist md, kw jauch md, fw schildberg md allogeneic blood transfusions are associated with an increased risk for postoperative infections in colorectal surgery when compared with autologous blood transfusions. attribution of this effect to immunomodulation was suspected in our previous study (lancet ; : - ) . task of the recent investigations was to analyze which specific effector systems were affected in-vivo by this transfusion-associated modulation. for global in-viva assessment of cell-mediated immunity (cmi) multiple recall skin-reactions were applied prior and post-operative. the specific humoral immune mechanisms were investigated by applying tetanus-toxoid one day preoperatively and deterimnating the quantitative igg-response. for indication of macrophage stimulation in-vivo tnf-levels were determinated by bioassay. dth-responses were significantly suppressed (p< . ) in patients receiving allogeneic blood (n= ) or operated without blood transfusions (n= ). dthresponses were not suppressed and tendentiously increased in patients with autologous blood transfusions (n= ). in contrast, specific igg-levels increased sigmficantly (p< . ) in patients receiving allogeneie blood (from . + . to . _+ . ie/ml) whereas in patients receiving autologous blood a smaller increase (from . + . to . + . ; p= . ) was observed. tnflevels demonstrated a similar pattern with a higher increase in patients receiving allogeneic transfusions (l . + . to . + . u/ml) compared to those patients with autologous blood ( . + . to . + . ). in conclusion these data indicate that allogeneic blood transfusions lead to a remarkable macrophage/rhs stimulation. this is corroborated by the boostered humoral igg-response which was initiated before onset of surgical trauma and blood transfusion. concerning cmi this caused a substancial suppression probably due to a stimulated secretion of immunosuppressive monokines. objective: firstly, to analyse the concentrations of the cytokines tumor necrosis factor (tnc), interleukin- (il-i), interleukin- (il- ) and coagulatioo/fibrinolysis parameters in postoperatively retrieved blood from a surgical area, secondly to characterize the correspanding cytokine patters in the patients and thirdly to study cytokine concentrations in the initial portion of drainage blood from a surgical area. materials and methods: blood retrieval was performed in a closed-loop system without anticoagulant during - hours after surgery in patients undergoing arthroplasty ( hips and knee). kf, il- , it- , thrembin-antithrombin complexes (tac) and antithrombin (at) ~ere determined in shed blood. patient plasma tn v, il-i and il- concentrations ~ere analysed at the beginnlqg and end of the - hour blood retrieval period. in a separate study ( hip arthroplasties) f~f, il-i and il- ~ere determined in the initial portion of drainage blood. cytekine analyses ~re performed usiog ipmuooassays. an omidolytic method was used for at determinaf.ion and tac was analysed by elisa. n~n-poram~tric tests was used for the statistical comparison. results: the patient plasma il- coocemtratiems rose from a median value of to pg/ml, p<o. , during the blood ret.rieval period. in c was detectable in patients, range: - pg/ml. il-i was not detectable in the patients. in retrieved blood tag was > mg/ml in all samples (ref:< . mg/ml) and at was . - . units/ml (ref:o. - . ) . the il- concentrations in retrieved blood was > pg/ml in all samples. tn v or il-i was not detectable. in the separate study, (n= ), characterlzing eytokine content in the initial portiere of drainage blood, in= (range: - pg/ml) and il-i (range: - pg/ml) ~re present in all samples but ii- (range:o- pg/ml) was detectable in o.qly one semple. conclusion: theses findings indicate that hypereoagulability and hic~ ccrcentratioos are present in retrieved blood. the cytokine pattern in the initial portion of blood from a surgical area differed from these observed in retrieved blood and in the systemic circulation. to identify the role of both autologous and homologous blood on postoperative infections in elective cancer surgery. materials and methods: patients with colo-rectal cancer submitted to curative elective surgery were prospectively studied. on hospital admission the following nutritional measurements were assessed: serum level of albumin, cholinesterase, delayed hypersensivity response , total lymphocyte count and weight loss, as were age and sex, duration of operation , operative blood loss, amount and type of blood given, pathological dukes' stage of the disease and the attending surgeon were also recorded. results : eighty-four patients ( . %) were perioperatively transfused. thirty-six ( . %) patients were given autologous blood , while ( . %) received homologous blood. no patients received both autologous and homologous blood. twenty eight ( . %) patients developed postoperative infections. non transfused patients had a . % infection rate , those receiving autologous blood had a . % infection rate, whi]e in the homologous blood group the infection rate was . % (p < . ). univariate analysis showed that infections were significantly related to operative blood loss (p< . ), length of operation (p< . ) blood transfusion (p< . ) and attending surgeon (p< . ) . multivariate analysis identified homologous blood transfusion as the only variable related to the occurrence of postoperative infections , while the other variables failed to reach statistical significance. blood transfusion (bt) remains an essential life-saving treatment for surgical patients. however, besides the beneficial short-term impacts, negative longer-term effects are observed, which include various alterations in the immune responsiveness. in surgical patients these alterations may contribute to the increased risk for infections and cancer recurrence. since relatively few data demonstrate immunologic changes occurring in other lymphoid compartments than blood after bt, we studied the effect of et on the frequency and responsiveness of immune cells in bone marrow (bm), spleen (spl) and blood (b) in a rat model. normovalemic, month old rats were transfused intravenously with syngeneic heparinized venous blood ( x ml, every other day), and , and days after the last transfusion bm cells ( leh is an experimental oxygen-carrying resuscitation fluid. since leh is cleared from the circulation primarily by the mps, its effect on the development of sepsis and the nature of its relationship with the mps remain a major concern. preliminary in vivo data from our laboratory failed to show any leh effect on the hemodynamic and hematologic responses to endotoxin lipopolysaccharide (lps) in the rat. in contrast, leh exacerbated the lps-induced tnfa production and early mortality. the exacerbation of early mortality by leh was attenuated by pretreatment with the tnfu synthesis inhibitor rolipram. ex vivo, peritoneal macrophages from rats treated with leh and lps have shown increased il-lg mrna signal as compared to lps alone. also, leh increased tnftx production by peritoneal macrophages in response to lps stimulation in vitro. additionally, recent pilot studies indicate that leh attenuates pma-induced superoxide production from rat peritoneal macrophages and that leh augments fmlp-induced migration of human monocytes. taken together, these data strongly support possible interactions of leh with the mps and therefore the nature of such interactions should be further explored. over the last decade, we have developed liposome encapsulated hemoglobin (leh) as an artificial oxygen carrying fluid, or blood substitute. our efforts have focused on studies to define the safety and efficacy of this resuscitative solutions. leh consists of distearoyl phosphatidylcholine, cholesterol, dimyristoyl phosphatidylglyeerol, and alpha tocopherol in a : : . : . mole ratio and can encapsulate hemoglobins of different origin (bovine, human, recombinant human). leh is fabricated using hydrodynamic shear to create an average particle size of . microns. leh can be lyophilized using disaccharides and stabilized in the dry state and easily reconstituted before administration. histopathology and clinical chemistries indicate that leh rapidly accumulates in tissue resident macrophages in small animals injected in the tail vein, principai y in the liver and spleen. the consequences of accumulation in the reticuloendothelial system are manifest by transient increases in liver transaminases (ast, alt), bilirubin, and bun over - hours with no change in biliary function (ggt, ap) . clearance through the liver and spleen is observed over the course of - -weeks. more recent attention has been focused on secondary consequences of leh administration especially with regard to inflammatory eytokines. leh does not elicit expression of tumor necrosis factor in vivo and in isolated macrophage cultures, but does result in a transient increase in serum il- . we have also examined the interaction of leh with lps in vitro macrophage culture to further understand how this blood substitute may effect the immune system. we have labeled leh with technetium- m ( mtc) to study the biodistribution of leh non-invasively in anesthetized rabbits. rabbits were infused with a % topload of leh ( mg of phospholipid, . g of hemoglobin per kg of body weight) and imaged continuously with a gamma camera. at hours, images were again acquired. animals were then sacrificed and tissue counts obtained, images revealed an initial rapid uptake bythe liver, % at minutes and % by hours. the spleen accumulated activity at a slower rate, % at minutes and % at hours. at hours, autopsy biodistribution studies revealed that approximately . % of the dose is in the blood pool, . % in liver, . % in spleen, . % in lungs, . % in muscle and . % in urine, with trace levels in kidney, brain and heart (< °/o). in a hypovolemic model, rats were % or % exchange transfused with mtc-leh. in the % exchange model, mtc-leh was rapidly taken up by the liver and spleen with minimal activity in the circulation at hours. with the % exchange, % of the leh was in circulation at hours. the interaction of leh with platelets labeled with indium- was also studied. after infusion of leh, the labeled platelets rapidly moved from the circulation to the lungs and liver. over the next minutes, the platelets gradually returned to circulation. this effect was not seen with iiposomes of the same lipid composition but containing no hemoglobin. non-invasive imaging is proving to be a very useful tool for the investigation of leh. the need for a safe, efficacious and commercially viable blood substitute is unequivocal. of the several strategies pursued to invent an adequate blood substitute, liposome entrapped hemoglobin (leh) has been already established as a leading possibility. major advances in liposome technology have already resulted in liposome preparations compatible with clinical use for drug delivery. recent technological advances made by the u.s. naval research laboratories resulted in the capacity to entrap hemoglobin into liposomes in a way which secludes hemoglobin from interacting freely with biological systems. the leh produced has already been tested in in vivo systems and was foun.d to be well tolerated. moreover, the leh originally produced as a solution can be transformed into a lyophilized form which can be reconstituted and delivered as a fresh solution. while important milestones in leh development for a practical blood substitute have been achieved, several issues remain to be explored. most notably, the long term consequences of leh on host defense mechanisms and, in particular, immune cell function. in addition, it is important to understand more fully the metabolic fate and repercussions of leh delivered at clinically relevant dose/schedule regimens. finally, while leh is a highly promising strategy for a blood substitute, the present formulations consist of human hemoglobin derived from human blood, to improve the safety profile, a recombinant preparation for liposome entrapment will be much desired, aa-ginine, a semi-essendai dietary amino acid, possesses several unique and potentially pharmacologic properties. argirdun is a potent secretagogue for pituitary growth hormone and prolacfin and for pancreatic insulin and glueagon; it modulates host protein metabolism by increasing nkmgen retention and enhancing wound collagen synthesis. it also is a potent t call function regulator. ait of these effects coupled with its relative lack of toxicity and safety make it an a~antive nulritionai pharmacologic agem (t). rodents fed supplemeutal arginine exhibit increased thymsc weight which is due to increased numbers of thymic lymphocytes present in the gland. thymic lymphocytes from animals fed supplemental ar~e demonstrate increased blastogenesis in response to coma. and pha ( ) . peripheral blood lymphocytes from humans given supplemental arginine also have heightened mitogunic responses to mitogen or antigens ( ) . in postsurgery padents supplemental arginine abrogates or diminishes the deleterious effects of trauma on lymphocyte responsiveness and restores peripheral blood lymphocyte responses much faster than observed in controls. overall host immunity is also enhanced by arginine. allograft rejection is enhanced and septic animals survive longer when given supplemental arginine ( ) . tumor bearing urginine-supplemented animals have decreased tumor growth and enhanced survival (i). lastly, asgmine can induce t cell maturation and t cell mediated responses in athyrnic nude mice. arginine also has remarkable effects on host nitrogen metabolism post-injury. in increases nitrogen retention in healthy human volunteers and in surgical patients. this beneficial effect on overall nitrogen metabolism is accompanied by a unique effect on the healing wound. supp]emental arginine increases wound collagen synthesis which also translates into increased wound breaking strength ( ) . arginine has no effect ou epithelialization. douglas w. wilmom, m.d. boston, ma gintamine is the most abundant amino acid in the body, but it has long been considered a nonessential amino aeid because it is synthesized in many tissues. fohov~g st,~'vation~ injury or infection, skeletal muscle pmteln inoresses its net tale of degradation and releases amino acids into the blunds~mm at an aocelerared rate. app~o)~mately one-third of the amino nitmgea is ghitamine, which is metabolized by the kidney where it parth:~pates in acid-base homeostasis, is the primly ~ for lymphocytes, mac~optmgcs and untexocyms, and contm'butcs to the synthesis of giumth~une. olmamine degrades slowly while in ~olu~ou, especially at usual room teml~mtums. because giulamine was considered nonessential, it has beer absent r'om nil intravenous and most gluts.mine should be considered a cendittona]ly essential nutrient for individuals with serious ilinesses, uspccially those confoanded by infcctinn and inflammation. over the uc~:t - years, glutamine will be incorgorated into most feeding formulas designed for patients with critical illness. o]~ga- pufa there continues to much interest in the application of the mega- pufa in clinical nutrition. the basic principle has been that the mega- pufa will displace arachidunic acid and result in a decrease in eic san id production. in addition these changes in pufa will after the physical characteristics of the membrane including flujdity, receptor function and transmembrane signals. animal studies have shown that there is omega- incorporation with continuou~ enteral feeding both in control and endotoxic animals within days. this includes the liver, spleen, circulating and alveolar marc phages and the lung. this incorporation resuls in significant changes in the eicosan id production including pgf and ket -pgflalpha. there is improvement in the cardio-vascular reep nse of these animals with ~ecreamed lactic acidosis and improved cardiac contractility. as well there is improved immune function with improved t cell response to mit gens. the ~ of a mumber of pharmacological agents blocking cicosanoid production can enhance the cell effects of mega- pufa. clinical studies using short term entsral nutrition with mega- either alone or with other enteral supplements in a number of clinical settings have shown significant mesa- incorporation and decreased eicosan id production. these positive results must be discussed with the additional evidence that long term omega- supplementation decrease eic san id production but als induce a state of immune suppression that is capable of increasing transplant sunvival. these ng te~ inune effects may benefit clinical conditions including rheumatoid arthritis and cr hn' disease early enteral nutrition instituted i~mediately afte~ injury will decrease the entry of bacteria into the intestinal wall and decrease the number of bacteria that translocate into the portal blood. these reductions are associated with & decreased catabolic response, decreased plasma cortisnl levels, end decreased vma excretion in the urine and prevention of mueosal atrophy. sdecific nutrients also affect the transloeation process. addition of arginlne to the diet significantly improves the ability to kill translocated organisms. however. translooetion across the gastrointestinal barrier is not affected. in contrast, glutamine diminishes the rate of translooation across the imtestinal barrier and also improves killing of the beetarla that do translooate. the omega fatty acids in the form of fish oil slightly decrease the rate of translocation but more significantly increase the ability of the animal to kill translo~ated organisms, all three dietary additives, i.e. argini~e, glu=amine and fish nil. significantly improve survival, hut adding glyoine or medium chain triglyeeridem do not, combinations of srginine and glutamlns, glutamine and fish oil, and fish ell end arginine each improve survival, and to a greater degree than a combination of all three. these studies add further evidence that translocation is an important determinant of survival after injury, early feeding with immunonutrlent enriched dices will improve survival and dsarease transloeation to varying degrees, depending upon the nutrients provided. objectives: we studied effects of supplementing a commercial enteral diet, impact r (imp, sander nutr lnc), with fiber (imp/fib) or alanyl-glutamine (imp/ag, exogenous glutamine (gln) gms/l) on influencing the incidence of bt to mesenteric lymph nodes (mln) in burned mice. fiber has been shown to improve gi integrity under certain stress/treatment conditions. the dipeptide ag is a water-stable source of gln, which is a specific fuel for many cells including enterocytes. traumacal (trcal), a high-protein, high-fat enteral diet (mead johnson iuc), was also studied, as well as rodent chow (harlan teklad inc), which contains very high protein & fiber. methods: anesthetized cf- mice aged - wks received % tbsa fullthickness dorsal burns & were resuscitated with cc ip saline. diets were allowed ad lib; caloric intakes were comparable in all gps except fasted gp (fast hrs, chow hrs). at hrs postburn mln were sterily removed, homogenized and plated on heart brain infusion agar; cfu/g mln tissue were determined. bt was analyzed by fishers exact test, cfu/g by anova-bonferroni. * p< . , ** p< . compared to imp and burn-fast gps. background. infectious complications following trauma, major operation, or critical illness adversely affect hospital cost and length of stay (los). some key nutrients have been shown to possess immune enhancing properties. this multicenter trial was conducted to determine if early administration of an enteral formula supplemented with arginine, dietary nucleotides and fish oil can decrease los and infectious complications in icu patients. methods. this was a prospective, randomized, double-blind study of adult icu patients who required enteral feeding for > days. patients entered the study within hr of the event, were stratified by age and disease, and were randomized to receive either the supplemented formula (impact®) or the conventional formula (osmolite ® hn). feedings were initiated at full strength and advanced to at least ml/hr by hr after event. results. both groups tolerated administration of formula well. for patients fed > days, the median los was % shorter (p=o.ol) for the--supplemented group ( days) compared to the conventional group ( days). the incidence of most infectious complications was lower in the supplemented group, but this difference reached significance only for urinary tract infections (p=o.o ). the supplemented group had a significantly shorter los from onset of infectious complication until discharge for patients with pneumonia ( vs. days) and skin/soft tissue infection ( vs. days). conclusions. administration of the supplemented formula was safe and well tolerated. when fed > days, it reduced the incidence of most infectious complications, and significantly reduced los. materials and methods: twenty-seven patients were randomised into groups ( n= each) to receive either a standard enteral formula, the same formula enriched with arginine, rna and omega fatty acids (enriched group) or isonitrogen, isocaloric parenteral nutrition. early enteral nutrition was started within hours following surgery ( ml/hour). it was progressively increased reaching a full regimen on day . on hospital admission and on post-operative day and , the following parameters were assessed: serum level of transferrin , albumin , prealbumin, retiool binding protein (rbp), cholinesterase. delayed hypersensitivity response, igg, igm, iga, lymphocyte subsets and monocyte phagocytosis ability were evaluated on admission and on post-operative day , , . the three groups were comparable for sex, age, cancer stage, type and duration of surgery, intra-operative blood loss and amount of blood transfused . in all groups a significant drop in all the nutritional and immunological parameters was observed on postoperative day . comparing post-operative day versus day a significant increase of prealbumin (p< . ) and rbp (p< . ) was found only in the enriched group. with respect to immunological variables an increased phagocytosis ability (p< . ) and a significant recovery in delayed hypersensitivity response (p< . ) was observed only in the enriched group. conclusions : these data are suggestive for a more effective post-operative recovery of both. nutritional and immunological status in cancer patients fed with enriched enteral formula. gastrointestinal intolerance was equivalent ( % in each group) and laboratory screening confirmed that both diets were safe. when analyzing clinical outcome for all patients, there were no significant differences in septic complications (immun-aid = % vs vivonex ten = %), mean mof score (immun-aid = l.b vs vivonex ten = . ), or mortality (immun-aid % vs vivonex ten = %) . kowever, when analyzing the subgroup of patients with severe injury (iss or ati _> ), patients receiving immun-aid appeared to have fewer septic complications ( % vs %) and their mean mof was significantly lower ( . _+ . vs . + . , p = . , student's t-test) . these preliminary data indicate that immun-aid is tolerated well when aggressively delivered immediately postinjury. the ultimate affect on clinical outcome appears ~avorable for immun-aid, but needs to be confirmed in larger patient groups. kemp?n, m., neumann, h.a., he i[michh b: as both increased, normal and reduced phagocytic capabilities of polymorphonuclear leukocytes (pmn) and monocytes in acute batterial infections have been reported, the role of phagocytes in patients with severe sepsis is less clear.we examined pmn and monocytes from patients in septic shock and heailhy votunteers for phagocytic function. phagocytosis was determined by flow cytometry (facscan) and was measured by the ability of pmn and monocytes to phagocytose e.coli marked with fluorescent antibodies. a septic shock was defined by the presence of a ~ource of i, nfoctiqn with a known bacteriology, distinct signs of a systemic response and defined minimum scores in icu scoring systems indicating the presence of a multiple organ failure. additionally we examined how phagocytosis is influenced when a new enteral diet formulation containing substrates suggested to improve immune function or arginine, one of its major compononts, is added in vitro in defined concentrations and incubated for minutes. pmn (p{o, ) and monocytes (p<o, ) of the septic patients showed a significantly enhanced phagocytosis compared tolhe phagocytes of the healthy group. the incubation with the enteral diet in vitro was followed by a higher dose-related rate of phagocytosis, especially in the healthy group, that was not statistically significant. after addition of l-argintne we atso observed an iqcrease in phagocytosis, that was lower than in the group with the complete diet. using a modern immunefluorescence-cytometric essay we founfl an improved phagocytic function in septic shosk. there are signs for an influence of nutrient substrates on phagocytosis which seems to be complex and should be further investigated. arg and gln were lower in the %-bcaa vs %-bcaa group; arg was related directly to arg dose and inversely to bcaa dose (p<o.o for all). clearances of bcaa increased with increasing bcaa dose (p<o.o ); arg and gln clearances were directly related to the bcaa clearances (rz=o. , p<o.o i). relationships between arg, gln and other aa seem to be ruled by patterns involving specific intracellular aa transport systems. regulation of arg and gln clearances through bcaa administration may be related to an increased flux of aa into synthetic processes. intestinal segments from rats immunized by infection with the nematode trichinella spiruus undergo intestinal anaphylaxis or type i hypersensitivity when challenged in vitro with parasite antigen. immunized rats exposed to t-radiation ( gy) and sustained on rat chow,fail to fully express type i hypersensitivity up to days post irradiation (dpi). we hypothesized that enteral nutritional support immediately following irradiation may be effective in preserving mucosal immune responsiveness or in reducing the recovery time after radiation-induced injury. rats were infected with x t.spiralis larvae. thirty to fifty days later rats received gy t-radiation from a co source as total abdominal irradiation (tai). immediately following tai, rats were fed an elemental amino acid diet (eaad) and at various dpi sacrificed and tested in ussing chambers for local anaphylaxis, expressed as antigen-induced ci secretion. the normal ci secretory response to antigenic challenge which is suppressed after irradiation,was restored by dpi when rats were placed on the eaad. antigen-induced c[ secretion is dependent on the interaction o~ antigen with specific ige antibodies on the surface o mucosal mast cells and their subsequent degranulation. mast cell-derived -ht,histamine and pg, together effect ci secretion.in irradiated rats on rat chow,the failure to respond to antigenic challenge appears to be associated with the destruction of mast cells. they are undetectable with standard staining procedures and mucosal histamine levels are drastically reduced. also,el secretion can be induced by direct stimulation of epithelium with cr secrctagogues and circulating ige levels are normal. despite a more rapid recovery of immune responsiveness in irradiated rats receiving eaad,mast cells were not restored. we conclude that the eaad contributes to an adaptation that supports the expression of local anaphylaxis in the absence of mast cells. total parenteral nutrition (pn) and bowel rest may influence the host response to infection. this study examined the different host response to infection in parenterally and enterally fed animals. forty-three rats were divided into pn group and total enteral nutrition (en) group. they received identically constituted isocaloric isonitxogenous diets for seven days. animals were then challenged intraperitoneauy with xl(y escherichia coli and survival were observed. in other experiments, they were sacrificed before and two hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and peritoneal exudative cells (pec) were harvested and cultured in vitro for hours with and without lipopolysaccharide (lps). colony f(m, ning units of bacteria (cfu-b) in the peritoncal lavaged fluid (plf) were determined and tnf in the plf, serum and pec culture supernal,ants were measured by l bioassay. twenty-fonr hour survival rate in en group was significantly greater than that in pn group ( % vs %). the data suggest that local immune responses of pn-treated animals may be depressed with consequent disturbance in the clearance of bacteria. this may lead to a greater systemic cytokine response and resulting in a poor survival after bacterial challenge in pn group. the effects of intragastfic tube feeding of diets enriched with m- polyunsaturated fatty acids (pufa) from safflower oil (so) or (o- pufa from menhaden oil (mo) on eicosanoid production, and onthe membrane phospholipid fatty acid composition were investigated in a severe acute septic shock model. the percent calories from fat maintained at % in the diets was adjusted to provide % each of saturated, monounsaturated, and pufa using olive oil and palm oil as filler fats. after feeding for days, lipopolysaccharide (lps, mg/ g) was injected through the tail vein. the percent of animals surviving in the mo group was % ( / ), and did not differ significantly compared to % ( / ) in the so group. the plasma concentrations of tnf ct for the groups of animals fed so ( . + . ng/ml) and those fed mo ( . + . ) did not differ significantly. the levels of prostaglandin(pg)e , -keto-pgflc~ and tumor necrosis factor-ct (tnf-c were determined min after lps injection. the fatty composition (relative mole%) of the liver was determined before (lps-) and h after the lps administration (lps+). the data (mean_+sd; n= ) are as follows. group these data indicate that a marked reduction in the plasma levels of poe and -keto-pgflct for rats fed mo diet was associated with a reduction in aa which was displaced by epa in the membrane phospholipids. further, in these rats, we observed that there was a . % reduction in the percent of epa following lps challenge compared to the basal levels. however, for the group of rats maintained on so diet, the liver membrane phospholipid fatty acid composition before and after lps administration was unaltered. these finding suggest that although a reduction in aa was associated with a decrease in the production of pro inflammatory eicosanoids after days of continuous mo feeding, there was no marked effect on the survival following lps challenge. animal models have been used to examine the effects of various nutrients and nutrient combinations upon the immune system. we studied the effects of standard and specialized enteral formulations on the response of mice to infectious challenge with listeria monocytogenes, influenza a or candida albicans in order to test the efficacy of specialized ingredients. cf- outhred female mice ( - g) were fed purina # chow, commercially available osmolite hn ®, perative ® or impact*. mortality and tissue burden of pathogen were examined during the d period following induced infection. the results indicate that there were no differences between the groups fed the liquid formulas with regards to mean survival time or % survivors in these models of infection. examination of spleens in the groups challenged with l. monocytogenes and kidneys in the groups challenged with c. albicans revealed no differences in tissue burden of pathogenic organisms. alterations in the length of pre-feeding from to days prior to infection did not affect these results. these data demonstrate that, contrary to previous reports, the use of specialized nutrients did not improve resistance to disease in mice challenged with l. monocytogenese, influenza a or c. albicans as compared with mice fed osmolite hn. animals fed standard chow tended to be more resistant to infectious disease than those fed the liquid formulas perhaps due to the form of diet or complexity of ingredients. the results indicate that these animal models of infectious challenge may be of limited use to distinguish effects of modified nutrient composition of enteral formulas. laboratories the beneficial effects of sesame oil (ses) have been attributed to the presence ofsesamin, a non-fat constituent which is claimed to iultibit a- desaturase activity. we investigated the effects of ad libidum feeding of ses enriched diet on fatty acid composition of phospholipids from plasma, liver, on eicosanoid production, and on the protective effects in mice after cecal ligation and puncture (clp) and compared with safflower oil (so) diets. olive and palm otis were added as filler fats to the so diet to maintain the ratios of saturated, and unsaturated fatty acids similar to ses diet. thus, while the total fat remained at wt%, the only difference between the two diets is the presence ofsesamin in ses diet. the animals were fed for weeks. the incorporation of dihomo-y-linolealc acid (dgla: : o)- ) in the phospholipids from plasma and from the liver for the group of mice fed so diet ranged between - % compared to the undetectable levels for those fed so diet. there were no significant differences in the incorporation of other fatty acids either in plasma or in the cell membranes between the two groups. following an intraperitoneal administration oflps ( p.g/kg body wt), the plasma levels of both pge , and txb , were significantly decreased (p< . ) by nearly % for the group of animals maintained on ses diet compared to those maintained on so diet. these findings suggest that sesamin inhibited the release of arachidonic acid (aa) which upon accumulation is retroconverted to dgla which could reflect a modest increase in the content of dgla. failure to decrease the formation of aa could mean that the effects of sesamin on chain elongation process may be after aa is formed, and that sesamin may not inhibit a- desaturase activity. on the other hand, our data suggest that sesamin present in sesame oil inhibited the activity of cyclooxygenase which converts aa to its metabolites), or alternatively could block the activity of phosphalipase a (pla ) (which releases aa from membrane phospholipids) as is evident from a marked decrease in eicosanoid production. the percentage of animals surviving after cecal ligation and puncture in rite group of mice fed ses diet was % ( / ) which was markedly higher (p< . ) compared to only % ( / ) for the so group. increase in survival in the group of mice fed ses diet was associated with nearly % reduction in the production of tnf in response to lps i.p. challenge, for ses group compared to so fed animals. our data suggest that sesamin, present in sesame oil, decreased the production tnf~, inhibited the activity ofpla and consequently offered a significant protection against clp. thus sesamin or sesame oil appear to be novel antiinflammatory agents which are present naturally in many edible products. [dept. surgery, ~e. deasoness hosp.,harvard medical school, boston, usa] stress causes alterations in the homeostasis of an organism with major changes in various organs, lifespans of cells, protein turnovers, metabolic pathways of activation or stimulation, energy mobilization, etc. punctual changes have been described in several organs and various cell types of the nervous, endocrine and immune systems. many stored or newly synthesized proteins are released to the bloodstream to be transported to target organs or to be disposed of. as stress alters protein synthesis and requirements in the targets, the bloodstream is a useful system for monitoring the relevant changes. we present here the pattern of newly synthesized or released serum proteins in c bl/ mice that have been stressed by immobilization. the proteins have been labelled with ssmethionine in vivo and the study was performed by two dimensional gel electrophoresis based on the method originally described by o'farrel. the electrophoretic run was carried out in an isodalt apparatus. a molecular dynamics laser scanner and the kepler image analysis system (lsb, rockville, usa) were used for modelling the radiofluorographic images. the radiofluorographic images of the gels from serum samples obtained from mice injected with i mci of ss-methionine reveal about protein spots, from which a small fraction -about are altered in both qualitative and quantitative manner. the major changes are in the range of to . d. the analysis displays a highly reproducible pattern, where clear differences between stressed and non-stressed conditions are shown. differences between patterns attributed to chronic vs. acute stress will be presented. patients with severe trauma or major surgery are known to acquire alterations in neutrophil functions which contribute to their enhanced susceptibility towards microbial infections. we analyzed neutrophil functions from fourty patients admitted for major surgery days and days preoperatively and on the ist and th postoperative days (study-days i, , , and ) in a randomized placebo-controlled double-blind study. patients were divided into two groups, one ~eceived days preoperatively an enteral nutrition enriched with omega- fatty acids, arginiee, and rna (impact), the other an isocaloric, not enriched control nutrition (placebo). meutrophils were isolated from the peripheral blood and stimulated with the ca-ionophor a ( . pm). the capacity of the respective neutrophils to generate leukotrienes was analyzed by rp-hplc. neutrophils from impact group generated significantly higher amounts of ltb (mean values . ng/l x i~ cells) compared to the placebo group ( . ng) at study-day [p, . ). in contrast, the capacity of neutrophils to produce ltb was not significantly different in both patients populations at study-days and . the omega-oxidation of ltb to its biologically less active metabolites oh-ltb and cooh-ltb was not significantly different in both groups. however, neutrophils from group f patients generate more ltc at study-day (p( / ). the capacity of the patients'neutrophils to generate reactive oxygen radicals upon stimulation with fmlp, pma or the caionopbore a exhibited patient dependent differences but no correlations to the repective nutritional supplementation as was measured by luminol dependent ohemiluminescense= these data indicate that an enteral nutrition enriched in omega- fatty acids lead to alterations in distinct parameters of neutrophil functions. clinical patient characteristics and mean caloric intake were similar between the two groups. both formula were tolerated well and the incidence of diarrhea was low. the number of infectious and wound complications as well as the apache ii score was evaluated for the two study groups. although the number of complications in the group supplemented with arginine, rna and omega- fatty acids was lower no significant difference in the occurance of infectious and wound complications has been observed between the two groups. however, the apache ii score indicated a significantly improved clinical outcome in patients with supplemented diet. in conclusion, early enteral nutrition with an arginine, omega- fatty acids and rna supplemented diet helps to recover more rapidly after surgical total parenteral nutrition (tpn} is associated with intestinal atrophy and dysfunction attributed to the absence of the non-essential amino acid glutamine in current parenteral nutrition solutions. in this animal study with male wistar-rats we tested the hypothesis that glutamine-dipeptide supplementation during tpn for days would restore small bowel atrophy and tpn induced dysfunction. a conventional tpn solution ( kcai/kg bw) was compared to an isocaloric and isonitrogenous tpn ( , g n/animal/d) supplemented with alanin-glutamin (ala-gin) dipeptide ( , g n derived from ala-gin = % gin-n). an enteral fed cqntrol group was included. mucosal thickness, villous height and architecture, absorption of water and glucose as well as dissacharidase activity of maltase and alkaline phosphatase were evaluated. total parenteral nutrition in rats causes villous atrophy, a significantly reduced absorption rate and a decreased activity of villous enzymes compared to an enteral fed control (p<o, ). addition of ala-gin to parenteral nutrition solutions prevents intestinal atrophy and restores functional alterations with a significantly increased rate of water and glucose absorption as well as a higher dissacharidase activity compared to the standard tpn group (p< , ). there was no significant difference found between the enteral fed control and the dipeptide supplemented animals concerning intestinal structure and absorption, the enzyme activity was significantly decreased in the ala-gin supplemented group compared to the enteral fed control (p< , ). in this rat model supplementation of parentera] nutrition solutions with ala-gin dipeptide restores tpn induced intestinal atrophy and dysfunction. boston. ~ usa injury, infection and major o ~'ations s~nulate a variety of factors whi~ initiate the body's response to th~ st~..sses. 'i"hese reactions are m~liated by a cbmage ia the neta'al hormonal, eac.ranmemt, by the elaboration of eytokines and tl~ougb the stimu/ation of other inflammatory mediators. this eatabolio setting zesulis in body protein loss, which g-taduai y erodes both fimetianal and stm~ tissue. wiu _b the normally nom'ished individual can withslzod "d~ response for a brief period of time, ircolonged eatabollsm l~ associated with ~,nmunosuppmssion, poor wound healing, and proioagcd convalescence. surgeons have rej ed on intraveaous or eater~ feedings to ~everse this process. a va~ety of data now indicates that it is extremely di~edt to replete protein-containing tissue d~g the eataholie state of illness; the umutt response to hypercaloise feedings in this setting is the incxeased accretion of body fat md water. administration of gxow~ ho~moae ~cesults i.a n shift of the body's oxidative machinery to fat rather than eazbohydmte utiq~afic~; ¢oncomitaatiy, protein synthesis is stimulated. this metabolic state may have clinical utility in p~e.n.ts who need to heal large wotmds, in those who need to gain strength in order to be w~ed ore veatilatory support, or those patients who ~ve mulfiorgan failure and nee~ to ealaaace protein syatsesis to in.suze recovery. als are now in progress to dcterm~e the benefit of growth hormone in these and other disease state.s, rn the fature, the increased use of growth hormone, will occur;, this and other growth factors will serve to su~ po~ the host and shorten convalesceace following catabolic diseases. our objective was to study effects of pre-trauma growth hormone (gh) treatment on liver and skeletal muscle metabolism in a trauma model in piglets. twenty-four piglets were randomized to three treatment groups; one group was pretreated with gh iu daily three days before the experiment (gh- ), another group treated with gh ie at the start of the surgical procedure (gh- ) and one group served as untreated controls (con). they underwent a standardized surgical procedure to place sampling cathethers in the portal, hepatic and femoral veins and doppler flow probes around the portal vein, the hepatic and the femoral arteries. all pigs recieved a primed constant infusion of u- c-glutamine. substrate fluxes were measured one (lh) and five ( b) hours after termination of the surgery. nitrogen excretion was significantly decreased in the gh treated animals (gh- : . + . mg/kg, gh-i: . +_. . mg/kg, con: . +- . mg/kg, p= . ). in the hindieg, there was reduced net glutamine efflux due to decreased absolute glutamine release (gh- : . + . gmol/min at lh and - . + . in.tool/rain at h, gh-i: - . + . i.tmol/min at lh and - . + . pmol/min at h, con: - . +_ . g mol/min at lh and - . + . /amol/min at h, p= . , p= . ), whereas the absolute uptake of glutamine in hindleg was unchanged (p= . ). glucose uptake in the hindleg was decreased (p= . ). net glutamine uptake in liver was attenuated (p= . at h), whereas net glutamate release from liver was increased (p= . ). thus, pre-trauma treatment with gh improved nitrogen economy, attenuated net glutamine loss from hindieg due to decreased absolute release, and attenuated hindleg glucose uptake. liver net glutanaine uptake was decerased and net glutamate release increased. patients with major abdominal surgery exhibit a considerable catabolic response with negative nitrogen balance and protein breakdown, which may have detrimental effects on outcome. we investigated the effects recombinant human growth hormone on substrate metabolism in parenterally fed patients. metabolic healthy patients were randomized to receive either placebo or hgh in a dosage of , ; , or , i.u. per kg bw. substrate oxidation rate, energy expenditure as well as short life proteins were measured daily. six patients were excluded from analysis as drop outs, due to surgical complications. we could find a dose-dependend effect of growth hormone on resting energy expenditure, carbohydrate oxidation, fat and proteine oxidation. with increasing growth hormone resting energy expenditure increased from . calories per kg body weight to . calories. this was mainly due to an increased carbohydrate and fat oxidation, while proteine oxidation decreased. this was in accordance with a decreased urea.production rate and an improvement in cumulative nitrogene balance, which increased from minus . to plus . g n / days. in consequence short life proteins were also increased. the only negative side effect was an increased blood glucose concentration in some of the patients, making insuline administration mandatory in patients. our results are in accordance with other studies showing improvement of nitrogen balance, maintainance of lean body mass and muscular strength. if growth hormone administration may have any impact on morbidity, mortality and length of hospital stay in these patients it should be evaluated in a larger number of patients. in patient after liver transplantation (oltx) the effect of recombinant human growth hormone (rhgh) on protein metabolism and hormonal changes was studied. patients and methods: the underlying disease in all patients was end stage liver cirrhosis, non of the patients included in the study was suffering from malignancies. the patients were randomly allocated to receive either u of rhgh bid (sc) or no alternative medication. the study period lasted days. from daily hrs udne collection urinary nitrogen loss and daily loss of urea were determined. body compostion analysis (bca, bioimpedance, akern-ltaly) was performed preoperativly and at the postoperative days and to evaluate changes in body water and body cell mass (bcm). the effect on resting energy expenditure (ree) was analysed using indirekt calorimetry wrhin the same intervalls (metabolic monitor, datex). blood levels of gh, igf and igf , igfbp were measured daily during the study period, on day a hour profile of gh was.performed. samples were collected each minutes. results: cumulative udnary nitrogen and urea loss were not signifcantly different for the whole study period but for the first study days. bia indicated for the rhgh-group a loss of bcm to a lesser extent than for the controls (n.s.), changes in bodywater where similar for both groups. ree changes (kcal/kg bcm) were not significantly different for the two groups. blood levels of gh and igf differed significantly between the groups for the whole study period, but not igf and igfbp- . the circadian rhythm of endogenous gh-excretion had not been altered by gh, but absolute levels of gh were increased. conclusion: during the first days after oltx we could proof the protein sparing effect of gh treatment. although the differences between the two groups were not significantly different for the whole study period the results showed on all days a less catabolic situation for the rhgh treated patients. to possibly improve protein balance after major abdominal surgery we studied the effects of gh on protein metabolism after ltx. excluding malignant diseases, candidates for ltx were randomized to either postoperatively receive the usual treatment (co=control group, n= , age range - yr, bmi . + . kg/m ) or for days additional gh ( x i.u.s.c.) (gh group, n= , - yr, . + . kg/m ). metabolic studies (calorimetry and lsc-leucine infusion) were performed (test a) and days (test b) after surgery. tracer analysis was done by gas chromatography-mass spectrometry. during the -week study clinical parameters did not differ significantly between groups; however, there was a tendency for increased glucose levels, insulin need, and energy expenditure at the time of test b in the gh group. leucine oxidation (x+se) during test a;b was + ; + (co) and + ; ± (gh) pmol/kg ffm/h (n.s.). protein breakdown was ± ; + (co) and + ; + (gh) pmol/kg ffm/h (n.s.). nonoxidative-leuine disposal was ± ; + (co) and ± ; + (gh) pmol/kg ffm/h (p< . for the rise in the gh group). tracer data were supported by cumulative urea nitrogen excretion (days - : gh + vs co ± g; p< . ). we conclude that after major abdominal surgery gh lowers nitrogen excretion by increasing total body protein synthesis. it is not known which organs contribute to this effect. in several investigations it has been shown that the protein saving effect of recombinant human growth hormone (rhgh) in the postoperative state is accompanied by raised igf- levels in plasma. it was concluded that the anabolic effects of rhgh were probably, at least in part, mediated by igf- . this study was aimed at detecting the efficacy of igf-i on modulation of the protein metabolism in the catabolic state. patients and methodes: patients (both sexes, age: - years, bmi - kg/m ) with major upper gastrointestinal surgery (gastrectomy or partial gastrectomy) received ug rhlgf- /kg body weight/twice daily or placebo during treatment days beginning on the first postoperative day in a double-blind, randomized study. all patients received hypocaloric and hyponitrogenous total parenteral nutrition ( g chng, o. g aa/kg) troughout the whole study period. cumulated nitrogen balance, -methyl-histidin exretion in urine as well as serum-igf- levels have been determined. the two tailed wilcoxon test was used for statistical analysis results: first results will be presented previous studies have suggested that growth hormone (gh) potentiates various activities of leukecytes. however, it is not clear whether gh can improve survival of animals with gram-negative sepsis. we investigated the effects of gh on host response to infection in septic mice model. methods balb]c mice were randomized to groups (n= /gronp): gh-high ( + mg/kg/day), gh-iow ( a mg/kg/day) or control (saline). following subcutaneous treatment (every hours for days) with gh or saline, mice were challenged i.p. with e.coli (lxl /body). survival rate was recorded every hours. in the next experiment, gh-high and control animals were sacrificed hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and the peritoneal exudative cells (pec) were harvested and counted. colony forming units (cfu) of bacteria in the peritoneal lavaged fluid (plf), liver, lung and blood were determined. pec were cultured in vitro for hours with lipopolymccharide ( p.g/ml in normotensive adults growth hormone (gh) rises when clonidine challenge is performed. recently evidence was shown for gh to accelerate wound healing. while gh secretion patterns are inconstant the gh-dependant insulin like growth factor (igf- ) and the insulin like growth factor binding protein (igfbp- ) reflect the integrated gh secretion over days. since we administer clonidine to patients with acute alcohol abuse we determined plasma levels of igf- and igfbp- . materials and methods: patients sheduled for esophagus resection were investigated once they had given written informed consent. patients showed acute alcohol abuse and were treated with clonidine postoperatively• patients with no history of acute alcohol abuse served as controls. besides liver enzymes igf- and igfbp- were determined. results: both groups had a comparable hepatic capacity of synthesis with decreased cholinesterase levels as to be expected after a major operation. regression analysis of igf- and igfbp- levels showed no differences between the groups. discussion: igf- and igfbp- plasma levels are not increased in normotensive patients who are treated with clonidine for prevention of postoperative alcohol withdrawl syndrom. further studies are required to discriminate whether our results are due to impaired postoperative liver function or if clonidine has not any impact on the gh-igf-axis in patients with alcohol abuse. recent studies have revealed that igf-i has several immanoregulatory roles. however, little is known about its effects on septic animals. we tested whether igf-i could increase the survival o f mice challenged intraperitoneally (i.p.) with e. coli. m~thqd$ balb/c mice received either high dose igf-i (n= , mg/kg/day), low dose igf-i (n= , . mg/kg/day) or saline ( = ) every eight hours subcutaneously for six days. animals were then challenged i.p. with lx e. coli. survival was observed every two hours. in the other experiment, mice that received high dose igf-i or saline were sacrificed four hours after bacterial challenge. peritoneal cavity was lavaged with ml saline and the peritoneal exudative ceils (pec) were harvested and counted. colony forming units (cfu) of bacteria in the peritoneal lavaged fluid (plf), liver, lung and blood were determined. in addition, pec were cultured/n vitro for hours with lipopolysaccharide ( ).tg/ml). tumor necrosis factor (tnf) in the supernatants of pec culture, plf and serum were measured by l bioassay. results igf-i improved the survival rate at a dose of mg/kg/day. severe chronic neutropenia (scn) is a disorder characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (kostmann-syndrome; scn) or regular cyclic fluctuations in the number of blood neutrophils with a median absolute neutrophil count (anc) of less than /~tl (cyclic neutropenia). patients suffering from scn have an impaired acute inflammatory response to injury and an increased susceptibility to infections, i.e. bacterial or fungal infections, resulting in chronic oral inflammation, severe pneumonia, abscess formation and bacteraemia. we have treated patients ( scn, cyclic neutropenia) with r-methug-csf (filgrastim). thirty of patients with scn and all cyclic neutropenia patients responded to this treatment with an increase of the median anc to greater than /~tl. the dose of r-methug-csf needed to achieve and maintain the response varied between . and ~tg/kg/d. long-term treatment did not exhaust myelopoiesis: the anc remained stable after up to years of treatment and antibodies to r-methug-csf were not detected. the increase of anc was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment, and reduction of hospitalizations. no severe bacterial infections occurred in any of the r-rnethug-csf responders during longterm treatment. severe adverse events, most likely due to the underlying disease, included the development of mds/leukemia in two patients, and osteopenia/osteoporosis in patients. these results demonstrate the beneficial effects of r-methug-csf treatment in severe chronic neutropenia patients. the newborn is predisposed to mortality during infections due in large part to developmentally immature host defenses. recently cytokines have been identified that regulate the development of these defenses. one such cytokine is specific for neutrophils and is termed granulocyte colony stimulating factor (g-csf). in the studies to be discussed, we have attempted to impact hematopoiesis in the fetus using exogenous rhg-csf delivered through the pregnant dam. our rationale was that an enhanced myeloid system may result from such in utero treatment leading to, perhaps, enhanced protection to microbial insult. rhg-csf crossed the placenta and reached peak fetal serum concentrations hours after administration. these levels were -fold lower than the levels detected in the adult dams serum. white blood cell counts were elevated approximately - -fold over control newborn blood. this increase was due to circulating numbers of neutrophils. the marrows from these pups were hyperplastic consisting of predominately immature and mature neutrophilic cells. no changes were seen in the thymus or livers. pups born to mothers treated with rhg-csf since day of gestation (parturition in rodents occurs on approximately day ) survived a lethal challenge of group b- hemolytic streptococcus. in contrast their untreated yet infected counterparts did not survive. recent clinical developments have led to trials of rhg-csf in certain neutropenic states including cyclic and chronic neutropenia. we have identified several of these patients who were pregnant during treatment with rhg-csf. biologically and anfigenically identifiable rhg-csf was detected at increased levels in the cord serum of these neonates. we will discuss our findings with these patients in light of our animal model of neonatal myeloid development. we have previously demonstrated decreased g-csf production and g-csf mrna expression from activated mononuclear cells from newboms compared to adults (cairo, pediatr res : , ) . we have also recently observed that administration of a single dose of rhg-cse to one-day-old newborn rats induced significant neatrophilia, while administration for days induced neulrophilia and increased the bone marrow (bm) neutrophil storage and progenitor pools (cairo, blood : , cairo, pediatr res : , ) . we embarked on a phase i trial exploring the safety, pharmacokinetics, and biological efficacy of g-csf in newborns with presumed sepsis. infants < hrs old with a diagnosis of presumed sepsis were stratified into three groups: very preterm ( - wk), preterm ( - wk), and term (> wk) and randomized to receive either a placebo or , , and gg/kg/qd or and p.g/kg/bid of rhg-csf infused by pump over hour for consecutive days. cbcs were obtained at , , , , and hrs. tibial bone marrow aspirations were performed hrs after study entry and differential counts and cfu-gm pools were determined. c bi expression was determined at and hrs after rhg-csf, and g-csf pharmacokinetics were performed after the first dose of rhg-csf utilizing a sandwich elisa. a significant increase in the anc was observed at , and hrs following administration of both and ~tg/kg/d of rhg-csf. the maximum increase in the anc occurred hrs after and ~tg/kg/d ( - %) (p< . ) and ( % -+ %) (p< . ), respectively. there was a significant dose-dapendeat increase in the bm neutrophil storage pool ( _+ % vs. + %) (p< . ) (placebo vs. ~tg/kg/d). there was no significant difference in the nantrophil proliferative pool. an increase in cfu-gm and cfu-gemm was seen at all doses tested, compared to placebo ( . _+ . vs. -+ ) (colonies/l(p cells/plate). c bi expression was significantly increased hrs after bg/kg/d of rhg-csf ( + % vs. +- %) (p< . ). peak serum g-csf levels occurred at hrs and were dosedependent. the half-life of rhg-cse was . + . hrs. most importantly, there was no observed toxicity from g-csf in all patients studied. of patients were on ventilators prior to administration of rhg-csf and there was no increase in pulmonary toxicity. these preliminary data suggest that rhg-csf is well tolerated at all gestational ages in newborns with presumed sepsis. a multi-center phase ii/iii randomized double-blindad placebo controlled trial is required to determine the efficacy of rhg-csf in this clinical setting. we investigated the effects of recombinant canine granulocyte-colony stimulating factor (g-csf) on survival, cardiopulmonary function, serum endotoxin levels and tumor necrosis factor (tnf) levels in a canine model of lethal bacterial septic shock (clinical research. : , ) . methods: awake ylo beagles had serial cardiopulmonary and laboratory studies before and for up to days after intraperitoneal placement of an e. celi infected clot. nine days before and daily until days after clot placement, animals received high (n= ) or low dose (n= ) g-csf or protein control (n= ) subcutaneously. results: survival in high dose g-csf animals ( / ) was significantly improved compared to low dose ( ) and controls ( ) (p< . wilcoxon). high dose g-csf also improved cardiovascular function evidenced by a higher mean left ventricular ejection fraction (day after clot, p< . ) and mean arterial pressure (day , p< , ) compared to low dose and controls. high dose rcg-csf increased (p< . ) peripheral neutrophil numbers both before and after clot implantation ( hours to days) compared to low dose and controls. in addition, high dose rcg-csf produced a more rapid (p< . ) rise (day ) and fall (day ) in alveolar neutrophils determined by bronchoalveolar lavage compared to low dose and controls. lastly, high dose rcg-csf decreased serum endotoxin ( to h, p< . ) and tumor necrosis factor (tnf, h, p< . ) levels compared to low dose and controls. discussion: these data suggest that therapy with g-csf sufficient to increase peripheral neutrophil numbers during peritonitis and septic shock may augment host defense and endotoxin clearance, reduce cytokine levels (tnf) and improve cardiovascular function and survival. the use of g-csf in sepsis prophylaxis in neutropenic patients is well established and has been ascribed to accelerated recovery in granulccyte counts. here, an additional sepsis-prophylactic property could be demonstrated in healthy volunteers: eleven volunteers were employed in a sinqle-btind, controlled study and were given uq g-csf or saline placebo via subcutaneous injection. blood was withdrawn immediately before and or hours later. lps-inducible tnf, il- , stnf-r p and il-lra were assessed in the supernatant of whole blood incubations stimulated with ug/ml lps from salmonella abortus equi. similarly to previous animal studies, lps-inducible tnf was attenuated by about % hrs. after treatment. the same was true of il-lb. in contrast, lps-inducible stnf-r p which was indetectable in blood incubations from untreated donors increased dramatically hrs. after g-csf treatment. il-lra found after lps challenge was increased tenfold by g-csf treatment. it is concluded that g-csf treatment switches peripheral leukocytes to an antiinflammatery state characterized by an attenuation of il-i and tnf releasing capacity and an augmentation of the release of cytokine antagonists. this findinq minht offer a novel concept in septic shock prophylaxis. objective.the aim of the study was to investigate the effect of recombinant human g-csf (rhg-csf) on survival, bone marrow neutrophil myelopoiesis, neutrophil counts, levels of bacteria and some important sepsis mediators in a model of rat abdominal sepsis. lethal peritonitis was induced with a mm coecal perforation (cp) in male wistar rats. rhg-csf was administered as /.tg/kg iv every h, first dose at sepsis induction. bone marrow neutrophi] progenitors were determined as blast colonies, cfu-gm and cfu-g. neutrophils and bacteria were determined in peripheral blood and peritoneal fluid. lps, tnf, endothelin and lactate were measured in blood from femoral vein. mortality rates were registered with g-csf treatment starting either or days before or hours after cp. results. mortality was reduced from % to about % with rhg-csf intervention and there was no difference between the pretreatment and treatment groups. bone marrow blast colonies were not influenced while neutrophil myelopoiesis was augmented at the stages of cfu-gm and cfu-g. neutrophils in blood and peritoneal cavity were enhanced and numbers of bacteria in the same compartments were substantially reduced. circulating lps, tnf, endothelin and lactate were attenuated the first hours after cp. neutrophil myelopoiesis is augmented with increased number of neutrophils in blood and peritoneal cavity, resulting in enhanced clearance of pathogens. lps, tnf, endothelin and lactate are suppressed the first hours during sepsis course. a. wendel, j. barsig, g. tiegs gm-csf stimulates the proliferation and differentiation of granulocytic and monocytic progenitor cells. in addition the hemopoietic cytokine activates the inflammatory response in mature leukocytes. the priming effect of gm-csf towards lipopolysaccharide (lps)-induced cytokine production in vitro has been described, but little is known about proinflammatory gm-csf effects in vivo. we detected gm-csf in plasma of lps-challenged mice with kinetics similar to tnf, reaching peak levels h after lps administration. gm-csf pretreatment ( ~tg/kg i.v.) enhanced mortality in mice challenged by a sublethal dose of lps. plasma levels of tumor necrosis factor (tnf) and interleukin- (il- ) were significantly enhanced. a monoclonal antibody, which neutralizes gm-csf bioactivity, rendered mice less sensitive towards lethal lps-challenge. tnf-and il- -tevels were reduced in these mice compared to control animals without antibody treatment. in addition, severalfold potentiation of lps-induced cytokine release by gm-csf was observed in vitro in murine bone marrow cell cultures. these data demonstrate the proinflammatory capacity of gm-csf and suggest that the hemopoietic cytokine plays also a role as an endogenous modulator of lps toxicity. immune dysfunction, developing in the wake of multiple trauma, overwhelming infection and other forms of critical surgical illnes% is associated with increased infections, morbidity and mortality. the mechanisms responsible for alterations in immune regulation are incompletely understood but monocyte appear to play a central role. polymorphonuclear leukocytes (pmn) are known to play a central role in the inflammatory response of the host toward invading microrganisms. reports of defects in all the aspeots of pmn function have been accumulated in recent years. the possible role of gm-csf in modifing the state of immuno suppression detected in severe intraabdominal infected pt~. inspite of surgical appropriate procedures and in reducing the expected mortality is investigated. the safety of rh-gm-csf administration in sepsis is also evaluated. a double blind randomized study is proposed. this study include icu patients who do not exhibit signs of shock and/or ards, with clinical signs and symptoms of abdominal infection. immunodepressed patients-aids, chronic chemotherapy or chronic steroid administration do not partecipate to the study. patients will receive rgm-csf (l~g/kg/day) or placebo in hs. continuous infusion for days. safetyandefyieacy will be assessed till to day . the apache ii score is adopted for risk stratification of patients because it is reliable and validated, objective and composed of information that is indipendent of diagnostic criteria. patient's entry criteria is apache ii > (score corresponds to expected mortality rate of %).in this protocol the surgeons report the judgement of the efficacy of surgical procedure to remove or not the focus of infection. objectives: infections and subsequent septic responses remain the leading cause of death among surgical intensive care (sicu) patients despite tmprovetaunts in supportive care and brond-epectrum antibiotics. usually invading bacteria are efficiently cleared by neutrophil granulocytes. however, during sepsis various neatrophil dysfunctions have been demonstrated, leading to impaired host defense. granulocyte colony-stimulating factor (g-csf) induces a sustained increase in circulating neutrophils and enhances various noutrophil functions. it was the purpose of the present study, to evaluate the safety and efficacy of g-csf (filgrastim) in sicu patients at risk of sepsis. materiel a.d methods: the study was designed as an open-label phase-ll study of filgrastim. ten consecutive slcu patients, with a therapeutic interveotion score greater than , were included in the study. filgrastim was given by daily continuous intravenous infusion for days or discharge from the sicu. apache ll-score, multiple-organ-failure (mof) score, definitions of infections, sepsis, systemic inflammatory response syndrome (sirs), and acute respiratory failure were applied daily. a response to filgrastinl th_erapy was defined as an improvement in disease severity quantified by a decrease of > apache i score points on day after onset of treatment. results: none of the patients developed a sepsis or mof later on and no patient died during hospitalization. specific postoperative complications occured in one patient ~jth a leekage of the oesophagou-gastric anastomosis after oesophageus resection. at study entry the leucocytes amounted to . + . /~tl (mean + sem) and reached a level of . +_ . /tal at day after onset offilgrastim therapy. the apache ii score initally was + . (mean + sem) and as an indicator of filgrastim response a decrease of points ~dthin days oceured in out ot patients. filgrastim was well tolerated, side effects were not noted. growth of solid tumors might be modulated by the activity of inflammatory and/or immune effector cells of undefined specificity. in this study patients undergoing surgical treatment for gastric (n= ) or colorectal (n= ) cancers were evaluated for endogenous serum levels of granulocyte colony-stimulatingfactor (g-csf) during a pre-and postoperative time period. from the same blood specimens mononuelcar cells (mnc) were prepared. the release of ifn-%, and il- , which are secreted by thl cells, were stimulated in vitro by pha during a cell culture period up to hours. the patients were further classified for their immunreactivity by responses in dth skin testing to seven different antigens (e.g. tetanus toxoid, ppd, diphtheria toxin, trichophyton, streptococcus, candida and proteus antigens). dth testing has been repeated in each patient two remarkable results were obtained. the serum levels of endogenous g-cse showed a biphasic increase with maximum values of pg/ml (preoperative < pg/ml) on day and day to after surgical treatment. similar patterns of g-csf production were found in both groups of patients with gastric or colorectal cancers. high serum levels of g-csf were significantly (p < , ) correlated with infectious complications in patients whh gastric cancer (n= / ). secondly patients could be arranged into two groups according to an anergic (n= ) or normergi¢ (n = ) responsiveness in dth testing. the frequency of anergi¢ responsiveness was similar in both patients with gastric (n= / ) or colorectal (n= / ) cancers. interestingly we found a significant correlation (p < , ) between low serum levels of g-csf and anergy during the postoperative period in both groups. stimulation of mncs from anergic patients (n= ) within the pre-and postoperative period resulted in reduced mean values (about %) for ifn-ff release (preoperative means llo pg/nfl), if compared to patients with normergic dth (n= , preoperative means pg/ml). similar, but less significant results were obtained for il- secretion. our results confirm a correlation between infectious complications and g-csf in the postoperative period, however elevated levels were also found in some patients without any signs of infections. more interestingly there might be an association between cytokine (c~csf, ifn-% and il- ) release and dth, which is known to be mediated by activated thl calls. to recognize anergic dth as a possible higher risk in the postoperative outcome of cancer patients extended periods of observation are needed. objectives of the study effects of recombinant huraan granulocyte colony-stimulating factor(rhc-csf)a galnst severe septic infections were investigated by its single use or by its corn b{nation with cephera antibiotlcs.we examined its effects on the mortality,and circulating blood neutrophyis counts and functlons,such as phagocytic activity and h production using the rat severe septic model. rats were subcutaneously administsrd rhc~csf(s orl o ~ g/k~ body wt)after on set of peritonitis brought about by cecal ]igation and one puncture withe -gaug e needle once a day for three days.in addjtlon,cefmetazol na(cmz)( m$/k bo dy wt)was injected intrarnustularly to the rats tv~ce a day for three days. cirehlatlng blood neutrophyls counts were determoned electronically with a hem ocytometer,and blood smears stained with may~runwaldm.qlemsa~taln. neutrophyls functions in vltro,such as phagocytic activity and h producti on using the rat severe septic model was analyzvd by automated flow cytometri c single cell-analysis methods. the reortallty rate after weeks was significantly decreased by administratlon of rh~-csf(p< , ).ln addjtion,a combination therapy of rhg-csf wlte cephern ant~biotics(cmz)showed a significantly survive] advantage and the rate had b een reached . %. nextly,treatn%ent wlth rhg-csf(s ~ $/k body wt)increased the nuzaber of the peripheral blood neutrophjls slgn[fieantly(p< . ). iv~oreover,functions of neutrophlis which were phagocytic activity and h p roduction were remarkably enhanced by admlnlstratlon of rhg-cs~( ~ /ks b ody wt) (p< .( ). these findings suggest that combination therapy of rhcrcsf with cephern antib iotlcs(cmz)is an efficient regime against severe infectlons.and the increased ne utrophils counts and enhanced neutrophiis functions were played a important ro le about the survival advantage. granulocyte macrophage colony-stimulating factor (gm-csf) is a haematopoietic growth factor active on neutrophils and macrophages. leukopenia often occurs following renal transplantation and can be associated with infection and/or the myelosuppressive effect of azathioprine. aim: we report the use of gm-csf in renal allograft recipients with leukopenia. nonglycosylated recombinant gm-csf was obtained from e. coli transvected by human gm-csf gene. m~terial ~,nd methods : written informed consent was obtained from all patients. patients were suffering from toxic neutropenia (neutrophils < /mm ) with medullar hypocellularity on bone marrow aspiration, or leukopenia (neutrophils < /ram ) with cytomegalovirus infection requiring ganciclovir administtation. gm-csf was given subcutaneously at a dally dose of to mcg/kg/day, according to renal function. results : in all cases, neutrophil counts returned to normal levels within to days. in most of them, spectacular correction was observed within hours, with a single injection. adverse events due to gm-csf at this dose were mild and easily managed ( cases of bone pain treated with paracetamol). one acute rejection episode was observed after correction of leukopenia. conclusion : on the basis of this study, it appears that gm-csf at a dose below mcg/kg/day is an effective treatment for renal transplant recipients with leukopenia associated with cmv infection or toxic neutropenia. department of nephrology, , rue de s~vres, hopital necker, paris, france. changes in serum g-csf and il- after surgical intervention hitoshi toda , atsuo murata , hidewaki nakagawa , takesada mori , nariaki matsuura osaka university medical school, osaka, wakayama medical school, wakayama, japan we measured serum immunoreactive interleukin (il- ) and granulocyte colony-stimulating factor (g-csf) levels of the patients undergoing major thoraco-abdominal surgery for esophageal cancer. serum samples were collected from eight patients on the day before surgery, at the time of operation, and thereafter at suitable intervals for one week. il- and g-csf were measured by means of enzyme linked immunoassay. the normal range of serum ]l- was less than pg/ml and g-csf less than pg/ml. values between groups were compared with linear regression analysis. both serum g-csf and il- levels reached their maximal levels at the first postoperative day and decreased thereafter. the correlation between g-csf (y) and il- (x) was y= . x+ . (r= . , n= , p< . ), showing a significant correlation. in the case who suffered from aspiration pneumonia and ards at the second postoperative day, the peak level of il- was pg/ml and g-csf pg/ml respectively. the estimated value of g-csf was pg/mi by the regression equation. this means the real g-cse level was less than half of the estimated value. it suggests that low responsiveness of g-csf is one of the reason of immunodeficient state after the major surgery, neutrophils from injured patients ingest and kill bacteria less efficiently as compared to those of healthy individuals, probably reflecting the suppression in respiratoly burst which occurs after severe trauma. one of the main mechanisms of killing bacteria by neutrophil granulocytes is production of oxygen radicals (respiratory burst). granulocyte colony-stimulating factor (g-csf), a kilodalton cytokine, leads to a sustained, dose-dependent increase in circulating neutrophils. thus, it was investigated whether filgrastim (recombinant human granulocyte colony-stimulating factor, rhg-csf) therapy fits for prophylaxis of sepsis in postoperative/posttraumatic patients, and whether, besides an expected increase in neutrophil count, filgrastim would also augment neutrophil function. material and methods: this study was designed as an open label, prospective phase ii study of filgrastim and performed in a surgical intensive care unit (sicu) (university hospital). postoperative/post-traumatic patients with a therapeutic intervention scoring system (tiss) score greater than were treated with filgrastim ( . - l.tg/kg/day) for prophylaxis of sepsis on days or until discharge from the sicu. production of oxygen radicals can be quantified by analysis of fmlp-and zymosan-induced chemiluminescence. neutrophil oxygen radical production was tested by fmlp-and zymosan-induced chemiluminescence by the polymorphonuclear cells (pmn) of these patients in multiple blood samples over a period of up to days. results: none of the patients treated with filgrastim for prophylaxis of sepsis developed sepsis. in vitro fmlp-induced ( - reel/l) neutrophil oxygen radical production was significantly increased under therapy with filgrastim by a maximum of % +- % ( % - %) compared to pretreatment values of %. tapering of filgrastim resulted in a reduction of fmlp-induced neutrophil oxygen radical production within hours. in contrast, zymosan-induced neutrophil oxygen radical production was not affected by filgrastim treatment. conclusions: besides its quantitative effect on neutrophil counts enhanced neutrophil function, documented here as increased fmlp-induced oxygen radical production, may account for the beneficial effect of filgrastim for prophylaxis of sepsis in posttraumatic/post-operative patients. granulocyte colony stimulating factor (g-csf) and granulocytemacrophage colony stimulating factor (gm-csf) have been recently introduced in the treatment of chemotherapy-induced neutropenia. effects of these csfs on cellular immune system were evaluated in neutropenic gynecological cancer patients during chemotherapy. g-csf and gm-csf were equally able to induce a rapid recovery of white cell count within one or two days. g-csf treatment resulted in a significantly higher concentration of leukocytes measured in the peripheral blood although by gm-csf a sufficient effect was achieved (p< . ). before initiation of csf treatment urinary neopterin was similar in both groups of patients ( +/- and +/- lamol/mol creatinine for gm-csf and g-csf respectively expressed as mean +/-one sd). in g-csf treated patient only a marginal induction of neopterin was observed. on day the mean value was about % above the basal level (p< . ). on the other hand gm-csf treated patients were characterized by a pronounced increase in urinary neopterin levels. in comparison with the basal level a more than fold induction was noted and the difference between g-csf and gm-csf was highly significant (p< . ). this effect was confirmed in vitro by investigating the effects of these csfs on interferon-gamma mediated pathways in thp- human myelomonocytic cells. results suggest activation of immune effector cells by gm-csf which may help the organism to overcome infections. however, activated macrophages produce several growth factors which may increase malignant proliferation, and augmented neopterin production as sign of macrophage activation has also been associated with poor prognosis m several malignancies. more data are therefore necessary to clarify whether csf mediated immune activation is beneficial or deleterious for cancer patients but considering our results caution in applying csfs in oncology seems advised. from a historical perspective, the development of humoral immunity to bacterial endotoxin has assumed a prominent position in the spectrum of therapeutic approaches which have been explored for the treatment of gram negative septic shock. predicated upon the fact that rough strains of bacteria manifest lps containing exclusively conserved structural features common to lps from all gram negatives, specific antibodies were elicited which conveyed cross protective immunity in experimental models of bacteremia and endotoxemia. such studies culminated in a well-conducted, randomized, double-blind placebo-controlled clinical trial using passively administered human polyclonal antiserum to treat patients with suspected gram negative sepsis. the efficacy of treatment established in that trial spurred efforts to develop monoclonai reagents which, to date, have not been uniformly successful in reproducing those earlier studies with polyclonai antibodies. nevertheless, the numerous successes which have been documented in experimental models of endotoxemia continue to foster promise for this immunotherapeutie approach. several recent studies with human polyclonalimrnunoglobulin preparations containing antibodies reactive with lps and lipid a have yielded promising results in treatment of patients with sepsis. in addition, the recent development of an antiidiotypic monoclonal antibody which reflects an internal image of a kdo specific monoclonal antibody has provided an alternative experimental approach to generate anti-lps antibody. immunization of mice with the antiidiotype provides significant protection against subsequent lps lethality consistent with the development of circulating immunoglobulin specific for lps. thus, the use of polyclonal immunoglobulins contrives to provide an alternative and potentially cost effective method for the treatment of endotoxin shock. supported by r a and pot ca . john holaday, anne fortier, shawn green, glenn swartz, john madsen, carol naey, and jan dijkstra entremed, inc.. rockville, md, . at the time of diagnosis, the signs and symptoms of septic shock are an indication that the systemic inflammatory response is well underway; thus, it has been argued that the endotoxin "cat is out of the bag", and that subsequent passive immunization may be too late to achieve therapeutic benefit. our approach has been to evaluate active immunization as a prophylax~s against sepsis. mice were inoculated twice (two weeks apart) with liposomes containing dmpc[i. ], dmpg[ . ], cholesterol [ . ] , and monophosphoryl lipid a [ - gg/txmole phospholipid] by several routes (i.p., i.m.), and serum was collected - days after each inoculation. after a single injection, highest tilers of ab were produced in mice inoculated i.p., but mice inoculated by all routes produced anti-lipid a ab. following the second injection. ab levels were roughly equivalent in mice inoculated by all routes, regardless of lipid a concentration. mice vaccinated i.p. with liposomes containing , or gg lipid a were treated with cyclophosphamide to produce neutroperda and then challenged with e. cole in an infection model of gram negative sepsis. the lds for control (liposomes with no lipid a) mice was x bacteria; ld for mice vaccinated with p.g was x ( -fold increase in resistance) and with ~tg was x bacteria ( -laid increase in resistance). mice vaccinated as before were also treated with actinomyein d to increase sensitivity to lps (salmonella minnesota) challenge in an endotoxemia model of grain negative sepsis. the ld for control (liposomes with no lipid a) mice was ng lps; the ld for gg lipid a was rig lps ( -fold increase in resistance) and for xg was ng lps ( -fold increase in resistance). mice were similarly vaccinated and challenged with an aggressive gram negative pathogen, francfsella tularensis. the ld of franciseua in normal mice or mice inoculated with liposomes without lipid a was - bacteria. in contrast, mice vaccinated with liposomal lipid a ( ggl survived challenges as high as , bacteria, ( logs of protection). the impressive protective capacity of this vaccine did not correlate with ab liter in any of the sepsis models, nor did it correlate with classic nonspeeific events, such as macrophage activation. maerophages harvested from the peritoneum of mice vaccinated and protected against sequelae of gram negative infections did not spontaneously kill the bacteria in vitro, but could be activated by ifn-y for antimicrobial activity equivalent to that of macrophages from unt#eated mice. research is underway to defme the protective mechanism(s) activated by this liposomal-lipid a vaccine. intervention by monophosphoryl lipid a in septic shock jon a. rudbach, ribi immunochem research, inc., hamilton, montana, usa monophosphoryl lipid a (mla), the clinical form of which is called mpl®-immunostimulant, has been tested extensively as an intervenient material in septic shock. mla is protective when given to experimental animals prior to a live microbial challenge or challenge with lethal doses of microbial products or certain cytokines. this is shown with gram negative and gram positive bacteria, gram negative bacterial endotoxins, and gram positive bacterial exotoxins. furthermore, animals treated with a regimen of mla which results in a refractory state to a lethal dose of gram negative bacterial endotoxin concomitantly display increased resistance to a live bacterial challenge. thus, both endotoxin tolerance and nonspeciflc resistance to infection can be manifested simultaneously. also, prophylactic doses of mla do not interfere with other therapies given subsequently; an additive or a synergistic protective effect can be demonstrated with certain combinatorial treatment regimens, such as mla followed by antiendotoxin monoclonal antibodies. the preclinical studies were extended to human trials wherein the safety of agonistic doses of mla was verified. furthermore, when mla was administered to human volunteers hr before challenge with a pharmacologically active dose of reference endotoxin, febrile, cardiac, tnf, il- , and il- responses were all decreased significantly as compared with the responses of subjects pretreated with a control solution and challenged with endotoxin. human trials with mla are being extended into patient cohorts which have high probabilities of developing septic shock; this will expand the safety base and establish clinical efficacy for mpl®-immunostimulant. a considerable body of in vitro evidence supports the concept that the effects of lps on cells of the immune/inflammatory systems are controlled by interactions of lps with cd . to evaluate if blocking lps-cd interactions has potential as a therapeutic in septic shock we have evaluated the effect of anti-cdi monoclonal antibody (mab) on lps-induced cytokine production and physiologic changes in an experimental model of endotoxin shock performed in cynomolgus monkeys. a novel model has been established where animals were treated with interferongamma for three days prior to infusion of highly purified lps over an eight hour period. in this model lps challenge resulted in marked release of eytokines in the blood, substantial hemodynamic changes, release of liver enzymes and alteration in lung permeability observed over a hour period. to evaluate the effect of treatment with anti-cd mab, animals were given either nothing, an isotype control or anti-cd mab ( mg/kg) rains, prior to the beginning of the lps infusion. evaluation of physiologic changes including mean arterial blood pressure and cardiac output, quantitative analysis of eytoldne levels including tnfct, il- , i,- , il- and il- , and liver enzymes during a hour period revealed that treatment with anti-cd mab markedly attenuated all parameters of injury including decreased mean arterial blood pressure, increased cytnkine levels and the release of liver enzymes observed in animals given the isotype control mab or those not treated. administration of anti-cd mab to interferon-gamma treated animals not challenged with lps did not induce any detectable physiologic changes or increases in cytoldnes. these studies suggest that strategies to block lps-cd interactions will have utility in diseases such as septic shock or ards where lps plays a central role in initiating injury. preclinical studies with recombinant bactericidal/permeability increasing proteins (rbpi and rbpi ). p.w. "frown, dept. of preclinical science, xoma corporation, berkeley, california, usa. bactericidal/permeability increasing protein (bpi), from neutrophils, binds to and neutralizes lipopolysaccharide (lps); it also specifically kills gram-negative bacteria (gnb). these properties, which reside in the n-terminal half of the molecule, indicate potential therapeutic application in the treatment of gram-negative sepsis. the gene for human bpi has been cloned and recombinant holoprotein (rbpi) and a kd n-terminal fragment (rbpi; ) have been produced in sufficient quantities for preclinical studies. both rbpi and rbpi bind to lipid a and neutralize the biological activities of lps derived from a variety of organisms, rbpi has equivalent antibacterial activity to bpi against rough gnb but is up to x more potent than bpi vs. serum-resistant and smooth gnb. rbpi and rbpi compete with lps-binding protein (lbp) for binding to lps under physiological conditions. consequently, both rbpi and rbpi block the cd -dependent lpsinduced synthesis of the cytokines tnf, il- , el- and il- in vitro. rbpi has also been shown to inhibit the lps-induced synthesis of reactive metabolites, endothelial adhesion molecules and the procoagulant molecule tissue factor. in animals, rbpi has been reported to increase survival of endotoxin-challenged rats and mice, to inhibit the dermal schwartzman reaction in rabbits and to increase survival of neutropenic rats with pseudomonas bacteremia, rbpi increases survival and decreases cytokine production in endotoxin challenged mice and rats. it normalizes lps-induced changes in hemodynamic, pulmonary and/or metabolic parameters in lps-induced rats, rabbits and pigs. treatment with rbpi also increases survival and decreases cytokine production in bacterial challenge models in rats and mice. rbpi was not toxic to rats after daily consecutive i.v. doses of mg/kg. this combination of properties indicate that recombinant bpi may be useful in the treatment of sepsis. phase i/ii clinical trials of rbpi have begun. the discovery of lps binding protein (lbp) and subsequent identification of cd as a receptor for lps or lps-lbp complexes has resulted in a new understanding o£ how lps responsive ceils are stimulated. cd is found either as a glycosylphosphatidyl-inositol (gpi)-anehored membrane glycoprotein (mcd ) of myeloid cells or as a soluble serum protein (scd ) lacking the gpi-anchor. binding of lps to mcd triggers cell activation while binding of lps-scd complexes to cells such as endothelial or epithelial cells that normally do not express mcd activates these cells. these pathways are shown in schematic form below. ~di mcd plays a crucial role in presentation of lps to additional membrane components that make up a functional lps receptor. an immediate consequence of engagement of this functional receptor is protein tyrosine phosphorylation. the molecular mechanisms leading to these events will be discussed. understanding of these pathways will lead to the development of new therapeutic approaches to controlling host responses to lps. pretreatmen t posttreatment (before or after tnf peak) d) with different antibody dosages: mg/kg --- . mg/kg pretreatment with anti-tnfab prevented death in most model situations (except peritonitis), but also posttreatment up to h after sepsis induction was successful in the few studies performed. there is additional evidence that low-dose tnfab is partially effective. especially baboon anti-tnfab studies provided many insights into the pathophysiological sequences of sepsis induction, due to crossreactivity with human reagents. those events include the cytokine sequence with tnf-dependent il-i, il- , or il- , but also il-lra or stnf receptor release. granulocyte as well as endothelial cell activation were shown to be partly tnf related, and the procoagulatory response was influenced by anti-tnf treatment. from many animal studies the concept that tnf plays a pivotal role in sepsis is clearly evident and therefore anti-tnf therapy is a major candidate tbr clinical studies. the beneficial or harmful effects of tnf-mediated inflammatory responses depend on the clinical context. decreasing exaggerated tnf-mediated inflammatory responses may be useful in some patients with organ failure. tnfr:fc (immunex, seattle, wa) is a recombinant human protein composed of two identical extracellular p tnf receptors linked by the fc region of iggl. it neutralizes tnf with an affinity for tnf<z of - m and has a t / of • h in normal humans. methods: normal volunteers were randomized to receive either tnfr:fc vehicle (n= ), or low dose (ld) tnfr:fc ( mg/m iv, n= ), or high dose (hd) tnfr:fc ( mg/m iv, n= ) infused over rain prior to endotoxin (e) (escherichia coil : ; ng/kg iv) administration. plasma cytokines were measured using elisa and tnf bioactiv'dy. systemic hemodynamics were evaluated with indwelling arterial and pulmonary artery catheters and radionuclide heart scans and compared before and after fluid loading in subjects given vehicle with hd tnfr:fc. results: endotoxin-related symptoms were unchanged after ld or hd. peak temperature occurred at a later time point ( - h) in subjects given tnfr:fc compared to vehicle ( h) (p=. ). at h, h (post fluid load ), and h, subjects given vehicle developed increased cardiac index and heart rate and decreased systemic vascular resistance index (all p=. ). hd tnfr:fc did not alter this hyperdynamic cardiovascular response. ld and hd inhibited the e-induced teukopenta at i h post endotoxin (p<. ) and later leukocytosis (p< . ). peak tnf bioactivity in subjects given vehicle was + pg/ml and < pg/ml in the ld or hd tnfr:fc groups (p<. ). two immunoassays for tnf were performed because the detection of receptor bound tnf varies with elisa. tnf (biosource) was decreased in ld vs vehicle or hd (p=. ) whereas tnf (r&d systems) was increased after hd or ld vs vehicle (p<. ). decreased levels of il- (p=. t), granulocyte colony stimulating factor (p=. ), and il- receptor antagonist (p=. ) were found after ld or hd vs vehicle. il- levels were lower after ld vs vehicle or hd (p=. ). il- levels were similar among subjects given vehicle, ld, and hd tnfr:fc. conclusions: ld and hd tnfr:fc delayed the febrile response to e but did not alter the early hyperdynamic cardiac response. this suggests that mediators other than tnf play an important role in the initial cardiovascular response to e in humans. tnfr:fc attenuated the release of some e and tnf-induced cytokines. ti~e antiinflammatory responses of tnfr:fc may be useful in some patients with disease processes resulting from excessive tnf-mediated inflammatory responses. the biosynthesis of tnf within macrophages is regulated both at the transcriptional and the translational levels. the ' flanking region of the tnf gene contains several transcriptional control elements, including two kb enhancers similar to those of immunoglobulin genes and a "y box" similar to that of the mhc class ii promoter. these elements are critical for the enhancement of transcription noted after stimulation of macrophages with lps. despite these and other elements, transcriptional regulation alone accounts neither for the absence of tnf protein during normal homeostasis nor the profound increasein tnf production following stimulation with lps or other secretagogues. the translation of tnf mrna into protein is also tightly regulated via mechanisms involving the octameric "ttatttat" motif present in the 'untranslated region of tnf, human inducible no synthase, and several other cytokine genes. this region not only destabilizes mrna, but also confers a translational blockade so that tnf protein is not normally synthesized despite leaky basal transcription. lps stimulation releases translational blockade and, together with enhanced trancriptional rate, accounts for significantly increased tnf secretion. opportunities for inhibition of tnf production are available at each of these two levels. agents which increase intracellular camp (pentoxif¥ ine, amrinone) inhibit accumulation of tnf mrna; in contrast, corticosteroids act primarily at the level of translation, inhibiting lps induced translational activation. understanding the regulation of tnf biosynthesis may assist in clinical strategies designed to regulate tnf secretion. the serine protease thrombin is formed by enzymatic conversion from its proenzyme form after coagulation activation and may enhance the inflammatory response in various ways. in the last step of the coagulation cascade, thrombin cleaves its substrate fibrinogen, thus forming fibrin. the fibrin clot may prevent phagocytosis of bacteria and promote local bacterial growth. thrombin can also stimulate a specific th.rombin receptor that exists on a variety of cells. for example, minute amounts of thrombin ma), stimulate platelets to develop tissue factor and boost the activation of more thrombin, thus initiating a positive feedback loop. other cellular effects of thrombin receptor stimulation include increase in intracellular calcium of platelets and monocytes, contraction of smooth muscle cells, increase in endothelial permeability, thromboxane generation by neutrophils and lymphocytes, pulmonary vasoconstriction, and enhanced cytokine production. animal experiments have been conducted with a variety of thrombin inhibitors including heparin, antithrombin ili, hiradin, and hirudin-like peptides. an alternative approach is the inhibition of the coagulation cascade at an earlier point in the cascades, or administration of the anticoagulant enzyme protein c work from our own group in a porcine model of lipopolysaccharide-(lps)-induced shock with disseminated intravascular coagulation has shown that prelreatment with recombinant desulfatohirudin (r-h) or with a preformed complex of human donor antithrombin iii with heparin or post treatment with r-h are able to block the degradation of fibrinogen and the formation of fibrin monomer. in addition, after pretreatment with r-h it was found that lps-induced lung injury was reduced. since both natural hirudin as well as r-h were well tolerated by healthy volunteers, adminislration of r-h may be a promising therapeutic approach in patients with sepsis and sirs. corticosteroids have been used in the management of various shock syndroms including sepsis. the data concerning the effects of this therapy is, however, conflicting and in large prospective studies, the use of early administration of high doses of corticosteroids have been found to give no beneficial effects in patients with sepsis. we have particularly been engaged in studies on possible effects of corticosteroids on the plasma cascade systems and on the mediator release from leukocytes. in in vitro studies, high doses of methylprednisolone were found to facilitate endotoxin induced generation of plasma kallikrein. furthermore, plasma prekallikrein and kallikrein inhibitor values decreased together with formation of kallikrein-c inhibitor complexes ( ). in this in vitro plasma model we also found that methylpredoisolone alone in doses of mg/ml induced contact activation with the formation of kallikrein-c inhibitor complexes. methylprednisolone was also found to have an additive effect on endotoxine induced decreases in kallikrein inhibitor functions. in the same experimental model on endotoxemia methylprednisoione was found to give an additive effect on activation of the initial part of the complement cascade ( ) . activation of the terminal part of complement, however, was inhibited by the same dose of methylprednisolone. addition of methylprednisolone alone to plasma was also found to activate the initial part of complement. using a full blood model, we studied the effect of methylpredoisolone in modulating the endotoxin induced cytokine response. when ng/l e. coli endotoxin was added to citrated blood from healthy human donors preinkubation with gg/ml methylprednisolone significantly reduced the release of tumor necrosis factor et ( %) and interleukin- ( % ) at two hours after exposure to endotoxin. in conclusion, these studies show that corticosteroids might facilitate contact activation of plasma and reduce the function of major protease inhibitors. furthermore, we also observed that this drag in in vitro conditions facilitated activation of complement. on the other hand, corticosteroids were found to reduce endotoxin induced cytokine release from leukocytes in whole blood. these studies also showed a dose dependence of the effects of corticosteroids on endotoxin induced cellular and cascade system activation. different predisposing conditions like extensive trauma, infection or pancreatitis result in a remarkably similar inflammatory response. although thls inflammatory response primarily aims at the removal of devitalized tissues, destruction of bacteria and reestablishment of the integrity of host tissues, it may potentially become unregulated and generalized and thereby producing deleterious effects to vital organs or the body" as a whole. cytokines play an important role in the development of the systemic inflammatory response. most of their biological effects, however, are not directly mediated but exerted through other mediator systems. when the inflammatory response results in the formation of capillary leak syndrome and refractory hypotension, the unregulated activation of complement and contact systems appears to be the cause. both systems are almost exclusively regulated by c - nhibitor. am unbalanced degradation of the inhibitor protein was found to be associated with the onset of capillary leakage in various conditions such as bone marrow transplantation, severe burns, and septic shock. these observations suggest a relative deficiency of biologically active c - nhibitor in these septic shock like syndromes. therapeutic intervention studies were initiated using high doses of c - nhibitor concentrate. first results are promising, as in most patients the administration of the drug was followed by a quick and marked improvement of the patient's hemodynamics. whether the administration of c - nhibitor alone or in combination with other drugs is also sufficient to improve long-time survival has to be investigated in double-blind, placebocontrolled studies. salutary effect of human soluble complement receptor type- in models of adult respiratory distress syndrome g. feuerstein, m. dimartino, and *r. rabinovici, smithkline beecham pharmaceuticals, king of prussia, pa, usa, and *jefferson medical college, philadelphia, pa, usa adult respiratory distress syndrome (ards) is a severe pulmonary insufficiency syndrome associated with diverse diseases and injuries. ards is believed to be the consequence of a massive acute inflammatory reaction consisting of activated neutrophils infiltration into the lung. neutrophil activation is likely the result of multiple factors of which complement is believed to play a major role. a potent complement regulatory system in the form of the complement receptor type- (cr- ) exists on many cells where protection against complement injury is provided by inhibition of both the alternative and classical pathways for c /c convertase formation. we have recently purified the human recombinant cr- in a truncated form (brl , tp-io, scr- ) and tested this soluble protein for protective effects in several models of ards. specifically, we have used the following rat models: ) endotoxin-induced ards in paf primed animals; ) .- induced ards; ) thermal injury ( % body surface)-induced ards; ) acid aspiration-induced ards. ards-like features included edema (increase in lung wet weight and water content), neutrophil accumulation (histological inspection and myeloperoxidase assay) and increase in cells and protein in the bronchoalveolar lavage (bad. scr- , - mg/kg, i,v., given as prophylactic (and in some cases, therapeutic) treatment significantly inhibited edema formation and leukocyte infiltration and, in some cases (e.g., endotoxin/paf or il- ), virtually completely. these comprehensive studies strongly support the therapeutic potential of scr- in ards due to diverse injuries. the xanthine derivative pentoxifylline (ptx) and several analogs of ptx have been evaluated for their protective effect in various animal models of septic shock. data from these in vivo studies demonstrate that ( ) ptx suppresses lps-induced tnf release from activated macrophages; ( ) ptx prevents tnf-induced pmn activation; ( ) ptx attenuates lps-or tnfinduced acute lung injury as evidenced by prevention of increased pulmonary vascular permeability and detoriation of gas exchange; ( ) ptx exerts its .protective effects even when administered following initiation of sepsis. the sum of these actions suggest that administration of ptx in sepsis may have therapeutic potential. hans hoffmann md, dept. of surgery, klinikum grosshadern, ludwig-maximilians-universit~.t, marchioninjstrasse , d- m nchen, germany. pentoxifylline [pof] and related xanthins are drugs of known haemorrheologieal activity and widely used clinically. recently, new pharmacological aspects of these established drugs could be demonstrated. it was found that pof selectively inhibits the formation of tnf but not il- most likely by causing accumulation of intraceliular camp via inhibiting phosphodiestersse activity, and, secondly, by inducing prostacyclin in different cell types. furthermore, pof is able to counteract tnf-mediated adherence of neutrophils to vascular endothelium and to inhibit fmlp-indueed respiratory burst in neutrophils. we and others have, therefore, studied its effect in different animal models. it was found that pof protected from increased pulmonary vascular permeability and sequestration of neutrophils into the lung in different animal models of acute lung injury. moreover, in pigs with induced faecal peritonitis the drug improved haemodyrmmle variables as well as pulmonary compliance and reduced the number of pulmonary neutrophila and lymphocytes. consequently, as a general outcome, pof could be found to improve survival in different models of haemorrhagie and endotoxie shock. the protective effect of pof was dose-dependent and observed even when pof was given up to hours after endotoxin. in order to evaluate these pharmacological effects of pof in humans, we studied pof under controlled conditions of endotoxlnemia in volunteers. we found that pof selectively inhibits the lps-indueed endogenous formation of tnf without affecting il- and il- . moreover, pof counteracts the lps-indueed initial leukocytopenia by interfering with the adherence of neutrophils in the microvasculature. meanwhile the inhibition of endogenous formation of tnf by pof could be demonstrated under different clinical conditions of acute and chronic cytokine release syndromes, {okt first-dose reaction, cancer-or tuberculosis-induced cachexla}. it appears worthwile and promising to investigate wether pof exhibits beneficial effects also in septic patients. objectives: to determine the specific role of paf in both lethal primate bacteremia and nonlethal human endotoxemia. materials and methods: two double-blinded placebo controlled studies were performed. first, ten baboons ( . +. kg), were randomized to a control group receiving ° cfu/kg of intravenously administered e. co/i (n= ) and a treatment group (n = ), pretreated with . mg/kg of paf receptor antagonist ro - two hours prior to e. co/i infusion. in a second study, ten healthy male volunteers were randomized to a control group receiving ng/kg of intravenously administered endotoxin (lps) (n= ) and a treatment group (n= ) pretreated with mg of ro - eighteen hours prior to lps administration. physiologic parameters and cytokine levels were measured continuously in both studies for hours. results: baboons pretreated with the paf antagonist had improved oxygenation ( + mm hg v -+ in controls, p < . ) and creatinine clearance hours post e.coli ( . + . ml/min v . _+ . in controls, p < . ). similarly, volunteers pretreated with the paf antagonist experienced fewer symptoms, including rigors and myalgias at hour post lps. this was in concert with a diminished peak cortisol ( +_ mmot/l v +- mmol/l in controls, p < . ), epinephrine secretion ( + nmol/l v + nmol/l in controls, p < . ). hemodynamics and circulating tnfa levels (data not shown) were unaffected in either study by prior paf antagonism. concluslons: paf influences some components of the multi-organ failure syndrome in lethal gram negative sepsis and the counter-regulatory hormonal system in human endotoxemia through tnf-independent mechanisms. paf antagonists may serve as adjuncts to cytokine blockade in the treatment of gram negative sepsis. the mediator role of platelet-activating factor in gramnegative septic shock pierre g. braquet, david hosford and matyas koltai institut henri beaufour, le plessis robinson, france considerable evidence has been accumulated to support the concept that a paf/cytokine autogenerated feedback network is responsible for priming and amplification of inflammatory mediator release in septic shock. cytokines, such as tnf~x, il- and other interleukins interact with paf which then amplifies cytokine production, therefore, paf may be the principle mediator in endotoxin shock. a single factor identified as tnf is suggested to play a pivotal role in the fatal phase of septic shock. presumably excess tnf release is the result of amplification process primarily triggered by paf. one may assume that the high tnf concentration in the blood of 'non survivors' is the consequence rather than the cause of cell death. the dubious results of clinical trials with anti-tnf antibodies and il- ra, a naturally occurring il- antagonist protein, have risen debate around the exceptional role of cytokines in the pathomechanism of septic shock or systemic inflammatory response syndrome (sirs) induced by gramnegative microorganisms. there are similar problems with the interpretation of the results obtained in clinical trials of monoclonal igm antibodies against e. coli endotoxin, ha- a and e . future studies will answer the question as to the effectivity of inefficiency of this treatment. perhaps when the plasma concentrations of lps and cytokines exceed a critical level, treatment fails to save the patients life. with regard the causal role of lps in septic shock, the putative role of bacterial porins may have to be taken into consideration. the marked release of paf induced by endotoxin leading to excess txa production may be responsible for the microvascular failure and death in septic shock. antagonists of paf markedly protect against the release of txa , and may interrupt the vicious circle of amplification process. no produced by the inducible no synthase plays a pivotal role in causing vascular paralysis in lps-induced sirs. to explore the relationship of paf to no synthesis will provide better understanding of the pathomechanism of septic shock. several paf antagonists, including bn , have undergone phase ii and phase iii clinical trials. the strategy in the treatment of sirs, however, remains multifactorial, since little is known about the sirs caused by microorganisms other than gram-negative bacteria. evidence has begun to accumulate which suggests that in sepsis excess production of lps and cytokines can lead to uncontrolled production of inos and that this might in part explain the severe unresponsive hypotension seen in some septic patients. a number of strategies have been explored in an attempt to limit excess no production. a favourite target has been competitive inhibition of nos by arginine analogues such as l-nmma. in animals, some investigators have shown that the haemodynamic effects of lps challenge can be attenuated by l-nmma, but there is a narrow toxic-therapeutic ratio. in a model of live e. cell sepsis, we have been unable to reproduce these findings. localisation of no production by immunohistochemistry suggests that no production is compartmentalised, and more subtle methods of regulation may be required if this approach is to have clinical valuc. anti-adhesion molecule strategies ch wortel, repligen corporation, one kendall square, building , cambridge, ma , usa. the neutrophil has been implicated as a pivotal player in the pathogenesis of multiple organ dysfunction. an important first step in the process of neutrophilmediated organ injury involves the binding of neutrophils to endothelial ceils. this process is largely regulated by complementary adhesion molecules, some of which are present constitutively on the cell surface and others that can be upregulated in response to chemotactic and pro-inflammatory stimuli. several different adhesion molecules have been described. l-selec tin is expressed on the plasma membrane of neutrophils and is shed from the surface early in the inflammatory process. it is therefore thought to mediate the initial interactions with endothelial cells. e-selectin and p-selectin are endothelial adhesion molecules. e-selectin is not constitutively expressed but is upregulated by inflammatory mediators, particularly il- and tnf. p-selectin is present in the weibel-palade bodies within the endothelial cytoplasm and can be upregulated rapidly in response to thrombin, histamine, and oxidants. all selectins recognize oligosaccharides, particularly sialylated lewis x antigen. this carbohydrate moiety is expressed on many proteins, including the selectins themselves. the leukocyte integrins are glycoproteins expressed on the neutrophil surface and in the cytoplasmic granules. integrins consist of a common beta or cluster differentiation (cd)i chain covalently linked to one of three different alpha chains (cd a, cd lb, cd lc) and exist on the cell surface as three distinct heterodimers. cd l a/cdi is expressed on all leukocytes, whereas cd l b/ cd and cd lc/cd are restricted to cells of myeloid origin. cd i/cd interacts with intracellular adhesion molecule- (icam- ), its ligand on endothelial cells. icam- is a member of the immunoglobulin family of adhesion molecules. it is constitutively expressed on endothelial cells and can be upregulated by cytokines. the potential for monoclonal antibodies to adhesion proteins to reduce vascular and tissue damage has been studied in alarge number of experimental models. protective effects have been observed in a wide variety of inflammatory, immune, and ischemia-reperfusion injuries such as arthritis, bums, endotoxic shock, bacterial meningitis, autoimmune diabetes, nerve degeneration, allograft rejection, allergic asthma, acute lung inflammation, skin lesions, and ischemia-reperfusion models of the intestine, myocardium, lung, skeletal muscle, and central nervous system. protective effects have also been observed in animals resuscitated following hemorrhagic shock. since modulating the function of adhesion molecules may temporarily leave the host without effective defense machinery, safety evaluations are of utmost importance in evaluating this therapeutic approach. treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial ingolf schedel, ursula dreikhausen; birgit nentwig; marion hockenschnteder, dirk rauthmann, salim balikcioglu, rolf coldewey, helmuth deicher, md endotoxin may play a major role in the pathogenesls of muitiorgan failure in the context of the toxic process in septicemia induced by gram-negative pathogens. the hypothesis which has led to a prospective clinical study consisted in the idea of inhibiting the biological effects ofendotoxin during the early phase of septic process, and thereby attampting to attain a positive effect on the clinical course of the disease. -objecave: to evaluate the effectiveness ofa polyclonal immunoglobulln (ig) preparation containing igg, lgm, and iga as an adjunctive therapy for septic shock. -desigru prospective, randomized clinical trial. patients: fifty-five patients w~th septic shock were randomly allocated to two groups according to criteria of septic shock. -intervention: one group of patients (n = ) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacteria endotoxin) during the first days after inciosion in the study. the other randomized group (n = ) did not receive any immunogiobulin preparation. -measuremems and main resmts: during the period of < wks after the beginning of clinically apparent septic shock, death related to the septic process occurred in one ( %) of patients who received immunoglobulln. by comparison, nine ( %) of control group patients died during this period (p <. ). within the first hrs after onset of the clinically apparent septie process, significaptly increased activity of circulating endotoxin and simultaneously decreased specifie igg serum titers to lipid a were detected in the group of nonsurvivors. the rationale for the use of polyvalent intravenous immunogiobulins (ivig) to treat severe infections stems from in vitro and animal studies documenting that high-dose igg enhance opsonization and phagocytosis of pathogenic bacteria. moreover, recent clinical studies have shown that in septic patients the phagocytic function of circulating polymorphonuclear neutrophils (pmn) is defective; the degree of such impairment correlates to the severity of the septic state, the beneficial effect of administering high dose igo in septic patients can be two-fold: i) ivig provides large quantities of antibodies against invading pathogens; the igg bound to the pathogens can opsonize their phagocytosis; ) the opsonization of phagocytosis by exogenously administred polyvalent igo would be of special importance in those patients who present a significant defect of their phagocytic function, when they are challanged by a large bacterial invasion. a prospective, randomized, double-blind study was carried out comparing the administration of ivig (sandoglobulin@) vs, paeebo (human albumin) in severely septic surgical patients, only patients with gepis score >_ (meaning a mortality risk > %) were accepted into this protocol. patients were randomized to receive . g/kg of ivig or placebo on day (when they reached sepsis score> ), repeated on day + and + . at the beginning of icu treatment, the two groups of patients were similar for severity of sepsis, age, concomitant disease, type of surgical procedures, antra and perioperative procedures, antibiotic administration. the results of the study indicated a significantly reduced mortality in patients with severe surgical sepsis treated with ivig as compared to placebo control patients (mortality: % vs, % respectively; p< , ). in conclusion, the results of our study in patients with severe surgical sepsis were the following: ) ivig plus multimodal treatment of sepsis, including antibiotics, reduce mortality significantly', ) the reduction of mortality seems to be due to a decreased incidence of lethal septic shock. despite substantial clinical research, the avallable data regarding the effectiveness of supplemental immunoglobulin (ig) treatment in sepsis in adult patients do not yet allow definitive conclusions. in view of the persistently high sepsis mortality there is a need to continue clinical investxqations regarding supplemental sepsis treatmen~ in general, as well as concerning ig administration in particular. we present and discuss the protocol of the ongoing ,,score-based-immuneglobulin therapy of sepsis (sbits)" study. the protocol (theoret surg ( ) - ) of this multicenter, randomized, prospective and double-blind trfal relies on the results of an observational trial on i.v. igg treatment in patients with sepsis and septic shock (infection ~ ) - ), carried out as a prerequisite for the present trial. using microcomputer-based bedside routine score monitoring, we regard quantitative measures of severity of disease and sepsis: only patients with a certain degree of both severity of disease (apache ii score - ) and severity of sepsis (elebute sepsis score - ) will be included. by observing these previously validated inclusion criteria, this trial snould iqentify a priori and include patients with potentially optimal response to therapy, consisting o~ either placebo ( .i % albumin) or polyglobin n" - ml ( . g)/kg on day and ml ( . g)/kg on day i. with an anticipatedpopulation size of patients the study should comply with the statlstical requirements (estimated mortality: %, with a % reduction in -day mortality in the treatment groupl to prove or disprove the question of igg effectiveness in sepsis in terms of improved prognosis. up to november , more than patients had been included; patient enrollment will be finished in . previous studies have demonstrated rhll-i ra, a naturally occurring antagonist of il- , increases survival in animal models of andotoxemia and eschehchia coli bacteremia and attenuates the decrease in mean arterial pressure resulting from challenge with both gram-negative and gram-positive bacteria. previously, in patients, rhll-lra was demonstrated to increase survival in patients with sepsis syndrome and septic shock in a dose-dependent manner. methods: a randomized, double-blind, placebo-controlled, malticenter, clinical trial enrolled patients at academic medical centers in europe aad north america. eligible patients received either placebo (vehicle) or rhil-lra (anakinra) . or . mg/kg/hr by continuous intravenous infusion for hours. the presence of organ dysfunction (i.e., ards, dic, renal, and hepatic) at study entry was determined prospectively by a clinical evaluation committee using definitions which were developed a-priori. survival time was evaluated over days utilizing a linear dose-response model, assuming a log-normal distribution. results: patients had one or more sepsis-induced organ dysfunction(s) at study entry. a dose-related increase in survival time was observed with rhll-lra compared to placebo in patients with ards, dic, and renal dysfunction (p --< . endotoxin infusion releases platelet-activating factor (paf), a potent phospholipid mediator which leads to an autocatalytic amplification of cytokine release. bn (ginkgolide b), a natural paf receptor antagonist, has provided significant protection against sepsis in different animal models• a randomized, placebo-controlled, double blind, multicenter trial on efficacy (mortality at d ) and tolerance of bn ( iv infusion of mg x /day over days) in severe sepsis has enrolled pts. the day mortality rate was % for the placebo group and % for the bn group (p = . ). the efficacy of bn was greater in pts with gram-negative sepsis: the -day mortality rate was % for the placebo group and % for the bn group (p = . ). bn also reduced mortality among pts with gram-negative septic shock (mortality was % for placebo vs % for bn ; p = . ). using statistical adjusments for pronostic factors, the relative risk of death of the bn group was . ( . - . , % confidence interval; p = . ). this risk corresponds to an adjusted reduction in mortality of % for pts receiving bn . no differences in mortality rates were found between the placebo and the bn groups in the absence of gram-negative sepsis• there were no differences in adverse events between the placebo and the bn groups. bn is a safe and promising treatment for patients with severe gram-negative sepsis. a confirming study, focused on gram negative sepsis, is in progress. v~ lliam a. kanus m.d. and the rhll-lra it has been traditional within the field of infection and sepsis to think in terms of specific indications for drugs based on the type of infecting organisms, advances in antibiotic therapy now control or ltnflt the growth of bacteria. the majority of deaths are now caused by either an initial overwhelming response to infection or subsequent multiple organ system failure attributed, in part, to the effects of intrinsic biologic responses of the host. type of organism, therefore, may not be as critical as determining the exact severity of the host's severity or risk of death from infection. we also know that both the relative benefit of a new treatment across groups and its absolute benefit for an individual patient will vary with their risk in a predictable fashion. we recently iuve~iguted the relationship between one measure of host response, the acute risk of death as prospectively estimated by u comprehensive risk mode[ for -day mortality (jamb. ; : , - ) , by its retrospective application to the results from the phase in evaluation of recombinant human intcrlenkin- receptor antagonist (rhll. ira). we found that there was a significant interaction between the patient's predicted risk of mortality at the time of entry to the study and the ability of rhil-lra to prolong survival time (x = . , p [] . , log.normal) for all patients in the trial• survival benefit began st approximately % baseline risk of -day mortality. for the $ patients with a predicted risk > %, there was a % reduction (p= , $ log normal). when we examined the variation in patients above and below the % risk level with hazard functions, i.e., their daily risk of death during the study period, we found that placebo patients with < % risk had lltile acute daffy risk during the hlltial two days follawh~g study entry and this risk was little affected by rhil-lra, in contrast, patients with > % risk had high daily mortality risks during the tuttlal two days that high dose rhtl-lro substantially reduced. these results are compatible with our current understanding of outcome from sepsis and the proposed mechanism of action o£ immunotherapy, the earliest deaths from sop sis are secondary to an immediate inflammatory response followed closely by deaths secondary to multiple organ system failure, later deaths (after days) are not as closely related to the acute effeete of the inflammatory cascade. because of the timing and action of most proposed tmmunotherapy, they may be capable of preventing mortality primarily in these initial two phases. in this study, an independent predicted risk of mortality reflected this mortality pattern ned illustrated the potential benefit of immtmotherapy. use of a predicted risk of mortality in the design and analysis of clinical trials could improve our understanding of the clinical benefit of these new therapeutic approaches. the systemic inflammatory response syndrome (sirs) is a term recently proposed to describe patients with systemic inflammatory responses to insults such as infections (sepsis), trauma, burns, pancreatitis, and other initiating events. patients with sirs may have similar activation of inflammatory mediators and similar outcomes independent of the initiating event. these outcomes include organ dysfunction and failure, shock, and death. challenges to the successful conduct of clinical trials in sirs include the complexity of illness in these patients and the important--but limited--clinical benefits of novel compounds that may be limited to selected patient subsets. addressing these challenges will require new tools and approaches. these will include more sensitive and appropriate endpoints, and the use of methods such as baseline risk adjustment, to allow detection of drug risk interactions not captured adequately by categorical definitions, such as sepsis syndrome. on the basis of supportive preclinical and phase i safety studies, we have initiated phase ii clinical trials of a novel bradykinin antagonist, cp- , in four sirs subcategofies: sepsis, multiple trauma, burns, and pancreatitis. each of these studies is designed to measure the effect of cp- on mortality, organ dysfunction and failure, and activation of mediators. in addition to investigating rates of organ failure using standard definitions--a new endpoint--a continuous summary measure of organ dysfunction (the acute physiology score of apache tm iii) is being used to quantify the degree of organ dysfunction and the speed and pattern of recovery of physiologic stability. in the sepsis study, another new approach--a study specific risk model based on the apache ill database--has been developed which will be used to assign a pre-treatment baseline risk to each patient enrolled. the primary outcome variable will be risk adjusted survival time to days. this type of risk-adjusted analysis may allow for more efficient and powerful trials and more accurate and useful indications for use. study purpose: in post-cardiac surgical patients (pat.) at risk for sepsis, the efficacy of early i.v. immunoglobulin (ig) treatment was compared to a matching historical control (con.) population. postoperative risk assessment: using apache ii scores lap) (first postoperative [pop.] day) in a pilot study phase, we were able to differentiate between the large population ( . %) of pop. low-risk pat. (ap< ; mortality: %) and the small groups of pop. pat. at risk lap= - ) and high risk lap_ ) with a significantly higher mortality ( % and %, mainly due to sepsis). subsequently, among consecutive pop. pat. we prospectively identified and treated these pat. iq treatment reqimens: first study period (n = ): (gg (psomaglobin n a, tropon biologische pr~parate, cologne, frg, day : ml/kg, day : ml/kg). second study period (n= ): iggma (pentaglobin r, biotest, dreieich, frg, ml/kg on days to ). results: ig pat. and con. were comparable in demographic data, operation characteristics and baseline disease severity lap and elebute sepsis scores). in contrast to con. (risk: n= , high-risk: n- ), the ig pat. showed a marked improvement in disease severity (fall in ap), especially in the high-risk group (igg, n= : p<o. ; iggma, n= : p: . ). in this group, ig led to higher (p< . ) response rates, defined as an ap score decrease -> within four days (igg: %, iggma: %; con.: %), and reduction in mortality (igg: %, iggma: %; con.: %), statistically significant (p< . ) for ig treatment as a whole (igg and iggma). conclusion: given the good comparability of the study groups, our results indicate, despite the non-randomized design, that early supplemental ig treatment can improve disease severity and may improve prognosis in prospectively apache ii score-identified high-risk patients after cardiac surgery. objective. elevated plasma levels of endothelin (et) have been demonstrated in both experimental and human sepsis. et has been proposed as a sepsis mediator leading to vasoconstriction with tissue hypoperfusion and organ failure. the aim of the study was to determine the effects of sepsis treatment with volume resuscitation, antibiotics and the anti-lps monoclonal antibody es® on big et and active, aminoacids et (et ) in rat abdominal sepsis. methods. lethal peritonitis was induced with a mm coecal perforation (cp) in male wistar rats. plasma levels of big et and et were determined with amersham tm endothelin rias , and h after sepsis induction. experimental groups: . cp control, . volume replacement (vr); , % saline ml/kg/h continous iv infusion started after h, . antibiotic; imipenem mg/kg iv after h, . e ®; mg/kg iv after h, . vr + imipenem + es® after h. results. high concentrations of both big et and et could be demonstrated after h and lasting for h after cp. neither volume replacement nor imipenem did influence the elevated plasma et. e ® significantly reduced et both , and h after sepsis induction, but did not reduce big et. when es® was combined with vr and imipenem, reduction of et was the same as for e ® alone. these results strongly suggest that bacteria and hypovolemia per se are not decisive stimuli for et production during sepsis. e ® reduces circulating lps and tnf which is the probable mechanism of the suppressed et synthesis. the unaltered big et fraction after e ® treatment indicates conversion of big et to et as the site of action responsible for reduced et . conclusion. lethal peritonitis in the rat is followed by elevated plasma levels of big et and et . e ® anti-lps antibody significantly reduces plasma et while volume resuscitation and antibiotics failed to do the same. es® did not reduce plasma big et. pmx treatment on severe endotoxemia with multiple organ failure was safety and effect in prognosis, and sepsis related parameters. it was certified that reduction of plasma endotoxin was effective in severe endotoxemia. a. lechleuthner,s. aymaz, g. grass, c. stosch, s. dimmeler, m. nagelschmidt, e. neugebauer. ii. dept. surgery, university of cologne, germany. introduction: the cardiovascular therapy of hypodynarnic shock states is a challenging problem. in clinical as well as experimental studies beneficial functions of a new hg-agonist bu-e- in congestive heart failure has been demonstrated aumann, ). therefore, we investigated the effect of bu-e- in hypodynamic shock in pigs. materials and methods: pigs (deutsches hausschwein, pitrain, [ ] [ ] [ ] [ ] [ ] [ ] were anesthesized with fentanyl/dormicum, ventilated (n :o = : ) and cardiovascular parameters were monitored with a complete icu-eqnipment. the hypodynamic model was established in a pilot study ( animals) to evaluate the effective concentration of bue- in healthy and endotoxin (lps)-treated animals. endotoxic shock was induced by continous infusion of ~g lps/kgkg/h ( :b , fa. difco). the hypodynamic state was defined as a decrease of cardiac output by % of steady state levels. a wedge pressure of - mmhg was kept constant by volume resucitation during the experiment. in a subsequent randomized controlled trial (rtc) groups with animals per group were studied. the groups were treated as follows: group i, lps and , % nac ; group ii, lps and bu-e- ( #g/kgkg/h); group iii, famotidine (h -blocker) pretreatment ( mg/kgkg), lps and bu-e- . results: the pilot study in healthy pigs revealed, that bu-e- had positive inotropic effects. these effects were inhibited by the h antagonist famotidin. bu-e- however had no beneficial effects in the hypodynamic phase of endotoxic shock in the rct. cardiac index (ci) and the oxygen delivery (do ) were not significantly influenced by bu-e- application (group i versus group ii). bu-e- did not ameliorate the negative inotropic effect measuring left ventricular stroke work (lvsw) in hypodynamic shock phases. on the contrary, bu-e- led to a further significant decrease of lvsw (p < , ). famotidin pretreatment did not affect the response (group iii versus group ii). conclusion: in hypodynamic shock states the h -agonism seemed to have no beneficial effect under these experimental conditions. receptor down regulation or changes of signal transduction under septic conditions may be responsible. cellular studies may help to identify these mechanisms. objectives. antithrombin iii inactivation of proccagulant proteases is so far the only inhibitory therapeutic approach to disseminated intravascutar coagulation (dic). we therefore set out to investigate whether cll substitution reduces coagulation activation in an endotoxin induced rabbit dic model. materials and methods. male rabbits chbb:hm(spf) were randomty assigned to one of the following groups. group k : naci . % (control without endotoxin, n= ). group e : endotoxin tjg kg " bolus i.v. + naci . % (control with endotoxin, n= ). group c : endotoxin pg kg - bolus i.v. + cll u kg - bolus + u kg " h "~ i,v. (treatment group, n= ). all animals were anesthetized and mechanically ventilated. blood samples were drawn prior to endotoxin administration (m ) and after (m ) and rain. (m ). thereafter, lung and liver tissue samples were taken intravitatly in a standardized fashion for h&e microscopic fibrin quantification using a triple score (fibs). from all blood samples the prothrombin time (pt), activated partial thromboplastin time (aptt), fibrin monomers (fm), and d-dimers (dd) were measured. for statistical significance of differences between the groups anovas and the wilcoxon test (fibs) were performed. results. fibs for lung/liver were significantly different (p< . ) between group e (lung , liver ) and c (lung , liver ) (group k : lung , liver ). , a synthetic serine proteinase inhibitor, has an anticoagulant activity in the absence of" antithrobim iii. gabexate has been reported to be useful in the treatment of disseminated intravascular coaguiation due to neoplastic diseases. in this study, we investigated gabexate therapy for the treatment of dic due to sepsis in the postoperative critical patients. materials and methods: from july to june , patients in the surgical intensive care unit met the criteria of dic or pre-dic. eleven were male and four were female with the mean age of . years. all these patients suffered from some complication of operations which led to the development of sepsis. foy was administered at the rate of mg/kg/hr untii the coagulation profile retumed to normal or the patient died. the coagulation parameters were monitored before and on the st, rd, th and th day. results: fourteen of these fifteen patients died despite transient improvement of the coagulation parameters in five patients. these patients suffered from sepsis resulting from surgical complications which could not be well controlled. the only survival was a case of recurrent intrahepatic duct stone with biliary tract infection complicated with sepsis and dic. after choledocholithotomy and the use of foy, the patient recovered gradually. conclusion: dic is a late manifestation of sepsis in the critical surgical patients. the most important thing is to eradicate the cause of sepsis. if the underlying septic focus cannot be controlled, dic will persist despite the use of gabexate mesilate. emergency surgery, taipei veterans general hospital, taipei, taiwan. there are main types of bradykinin (bk) receptor, namely bk~ and bk z. the bk receptor is constitutive. the bk receptor is also constitutive but in the majority of cases is inducible and involved in chronic inflammatory syndromes such as sepsis, hyperalgesia and airways hyperreactivty in animals. the mechanism(s) involved in the upregulation of the bk receptor is unclear, however a variety of agents including lps, e coil and ill are particularly efficacious in vitro and in vivo. ill and bradykinin acting at their respective receptors are believed to be involved in sirs/sepsis. we have investigated the effect of antagonists at ill (antril), bk (bradycor [cp- ]),bk~ (cp- ) and bkz/bk (cp- ) receptors on the de novo generation of bk~ receptors (reflected by hypotensive responses to a bk agonist) in the lps-treated ( ug iv) rabbit. in lps treated rabbits hypotensive responses to bk~ but not bk agonists increased with time and at time min appeared maximally induced. constant iv infusions of cp- blocked bk but not bk~ and cp- bk~ but not bk responses. cp- ,cp- +cp- and antril+cp- blocked both bk and bk~ responses. antril alone had no effect on bk or bk~ responses. within - min after stopping the infusions of antagonists the responses to bk~ and bk z agonists were the same as those in nonantagonist infused rabbits. these results indicate, at least in the lps-treated rabbit, that neither bk ,bk ~ or ill receptors alone or in combination, are involved in the de novo generation of bk receptors. in vitro studies demonstrated that beth bradycor and cp- (but not antril) were antagonists at both bk z and bk~ receptors. if both bk z and bk receptors are significantly involved in chronic inflammatory situations in man such as sirs/sepsis then the rationale for the use of compounds such as bradycor or cp- is clear. infection is a major cause of or contributor for morbidity and mortality in liver transplant recipients. effectiveness of prophylactic and therapeutic protocols is important for the success of liver transplantation ( olt ). sdd is used as prophylaxis for reduction of infection caused by gram negative or fungal microorganisms. between september and july olt's in patients were performed at our department. the actuarial -year patient survival is %. infection prophylaxis is started with sdd and ciprofloxacin once the patient is accepted as an olt candidate. perioperatively metronidazol, tobramycin and cefotaxim, postoperatively cotrimoxazol are prescribed additionally. the table shows pneumonia, peritonitis, major wound and urinary tract infection are common nosocomial infections following severe injury. in a series of severely injured patients from the university of louisville hospital, pneumonia was the most common infection followed by peritonitis, intra-abdominal abscess formation and burn wound infection. pneumonia is actually the leading cause of death from nosocomial infection. these are defined as occurring from to hours after hospital admission. this definition has important implications for antibiotic therapy because the likely pathogens and their respective sensitivities are different for community acquired pneumonia. the diagnosis of nosocomial pneumonia is difficult following major injury as many patients will have pre-existing fever, leukocytosis, tachypnea, and chest x-ray changes. reliance on sputum gram stain and culture is important and best obtained by a bronchoalveolar lavage or protected specimen brush during bronchoscopy. predisposing risk factors include severe head injury, emergent intubation and shock, and such patients have been shown to benefit by early tracheostomy. staph aureus has been the most common pathogen isolated from the sputum and the remainder gram-negative organisms with pseudomonas aeruginosa, and klebsiella pneumonia predominating. bacteria recovered by site as well as by intensive care unit is published in the six month antibiogram which also includes recent antibiotic sensitivities. this aids in empiric antibiotic selection against such nosocomial organisms. in a series of severely injured patients (iss - ), mean temp. was . f, leukocytosis was k, pan was , fin was . , and peep was . at the time of diagnosis (ards excluded). there was marked reduction in class ii histocompatibility antigen (hla-dr) density on peripheral and bal monocyte/macrophages which recovered over time with resolution of pneumonia. immune suppression occurred prior to development of pneumonia, was especially localized to the infected tissue, but recovered with clinical improvement. specific immune modulation targeted to pulmonary white cells may hasten clinical recovery and minimize pulmonary dysfunction. -clinical experience j. tnllemar amphntericin b remains the drug of choice for many systemic fungal infections. its advantages include a broad spectrum of activity and intravenous administration. the major disadvantages of amphoterlcin b is its severe side-effects, especially the nephrotoxicity. to decrease the toxic side..cffccts various liposomal amphoteficin b formulations have been produced. it was found that these liposemal formulations were as effective as amphotericin b but in contrast had a low incidence of toxicity. at present there are three ~different variations of lipid formulations under assessment: amphotericin b lipid complex (ablc), amphotericin b coloidal dispersion (abcd) or true liposomes. the ablc has a ribbon like structure. it has been shown to have a reduced toxicity and an efficacy ranging from being as effective to four times less effective that conventional amphotericin b. regarding abcd the particles have a disk-like structure with a diameter of around t am and a thickness of nm. the ami-fungal efficacy is - times less than that of conventional amphotedcin b. both ablc and abcd are presently investigated in phase ii/iii studies in the us. ambiseme is currently the only commefieally available true lipesome. ambiseme is a spherical small unilamellar lipesome with a diameter less than nm with a mutina ld of > mg/kg. it has been used in dosages up to mg/kg/day in compassionate based studies with good tolerability. the mycological efficacy range from a % response rate for invasive candida infections to % response rate for aspergillosis. ambisomc have been evaluated as anti-fungal prophylaxis in randomized trials in bone marrow (bmt) and liver transplant (ltx) recipients. it was well tolerated. in bmt recipients the incidence of proven fungal infections was % among placebo treated patients compared to % for the ambisome treated patients (ns). in ltx recipients ambisome prophylaxis was effective, significantly reducing the incidence of deep fungal infections from % to % ill placebo and ambisome treated patients respectively (p< . ). prospective randomized trials comparing these various amphotericin b preparations with conventional amphotericin b is needed to determine their future place in the therapeutical arsenal. two patlentgroups ere particularly at risk to develop serious cmv disease: cmv seronegative transplant recipients of seroposltlva donors and those patlants treated for rejection with anti t-ceil preparations, we have evaluated the value of prophylactic anti-cmv immunoglobulin (cytotect", biotest pbarma gmbh, dreieich, frg) administration in high risk heart and kidney transplant recipients, in a double blind placebo controlled study kidney transplant recipients, treated for biopsy proved re)action with rabbit atg, received globullntplacebo infusions. the preparatlons were given i,v, in a dose of mg/kg at day , , , , and after the initiation of anti = rejection therapy, passive immunization completely prevented cmv related death, although it did not reduce th~ incidence of cmv isolation, viraemia or disease, this effect was mainly observed in cmv saronegativa recipients of a serop sitive donorktdney. seroposltive recipients did not benefit from treatment and seronegatlve recipients of a seronegetlye donor were not et risk for cmv infection at e!l. in a open study the incidence of cmv infection and disease was evaluated in consecutive i~eart sllograft recipients. sixty-five patients were cmv seronagatlve and they all received passive immunlzation according to the dosage schedule used in the kidney patients, but starting on the day of transplantation, this scheme resulted in median snti-cmv igg titers of elisa units during months. cmv infection occurred in / ~eronegetlve and in / seropositive recipients (n,s,), in ssronegetive donor-recipients pairs the incidence was significantly lower ( / ] , the passively immunized seronegstive recipients of e seroposltlve donorheart showed comparable incidence of cmv infection f t ) vs the seropositive recipients. primary infection more often resulted in disease than secondary infection ( v / ), but no difference in incidence of disease ( vs / ) or severity in symptoms was noted between the immunoglobulln treated serone(]ative patients and the seropositiva recipients. apparently passive immunization induces anti-cmv immunity which crossly resembles naturally acquired resistance. abdulkadirov k.,chebotkevich v., moiseev s. the incidence of infection is still high in patients underwent bmt. this complication is the major cause of mortality if it is not recognized and treated promptly and properly. our data showed that from patients with different types of leucemia after autologous and allogenzc bmt had the episodes of fever. in the ma i ority of these episodes the bacterial etiolog$ gram negative bacflli and gram positive cocci) can be proved. on the other hand, in % of the fever cases we detected also viral respiratory (corona-, adeno-, rs-and other) infection. our previous investigations showed that even in healthy persons the viral infection has influence on antibacterial immunity, in the cases of model experimental reaction in volunteers we found the decrease of delayed hypersensitivity - days after intranasal inoculation of influenza virus a (h n - ) to bacterial (staphylococcal, streptococcal and pneumococcal) and ~iycoplasma pneumoniae antigens in the leucocyte migration inhibition test. these results showed that respiratory viruses may be the important pathogenic factor in the development of bacterial infection in posttransplanted period. we consider the constant control of latent and visual respiratory viral infection in bmt patients to be very important. ficcb the ~ter£~li of the nation~l institute of trad/~atoloqy in budapest . consecutive cases of revision hip grafting were carried out arthroplasties wlth hemoloquous bone between the years and . in the same period of time pri~ total hlp replacen~nts were performed under i entieal technical conditions. the average septic rate for the 'total hip althroplasties was less than %. in the selected i cases the septic rate was % indicating the role of bone grafting° homografts were prepared by deep freezing~ it .is recognized that the cells of the hl~grafts become destroyed by the ium~unological, response of the host~ and the patients develop ~ti-hl~, ar~tib'o~ies. the dead ~trix, however, has a bone-inducing capacity that stimulates host osteoblasts to recolonize the *i~/trix which serves as scaffolding. the sequence of events favours the infections. for this reason, beside preventive perioperative systemic ant/biotic treatment, local ~ntibioties were also applied in the form of antibiotic-//npregnated cement. the role of age and the .immune status of the patients .is discussed.. the purpose of this study is to evaluate the rate of toxemia in patients with acute panereatitis and to find this coudition to the activation of cascade systems that are encountered in the subsequent complications of the disease. we studied a series of patients with acute pancreatitis, the severeness of which was evaluated by the ranson's criteria and the apach-ii scoring system. all of them were considered to have severe acute puncreatitis. the determination of toxemia was made using the limulus test (lal test). we also determined the levels of the third (c ) and fourth (c ) complement components as weu as the coagulation factors, iibrinolysis faeters and kimns by serial measurements. the severity of the disease was serially determined by the apach-ii scoring system. it was found that complement activation ( which was also assessed using a graphically illustrated method by a aggregometer ) was followed by an increase of morbitity and mortality .we also detected that toxemia (positive lal-test) was closely correlated with complement activation and more of the ranson's criteria. a clear relation existed between the number of ranson's signs and the enmplieations' rate ( "= - . , p < . ). the documentation of toxemia and the complement activation cannot predict the kind and the severity of complications. the study of coagulation, fibrinolysis and kinms systems didn't reveal any results with statistical significance. necrotizing pancreatitis still represents a life-threatenthg disease. infectious complications dominate among the causes of death. differences in the individual immune response could possibly explain different clinical courses even in patients with comparable pancreatic morphology. to explore the inflammatory response in acute pancreatitis, the following investigation was performed. methods: peripheral-venous blood was withdrawn on admission and furthermore twice weekly in as yet patients with acute pancreatitis and tested for the parameters mentioned below. in parallel, polymorphounciear granaiocytes were isolated using density gradient centrifugation and assessed for superoxide anion and hydroxyl radical producing capacity using electron spin resonance techniques. results: total leukocyte cotmt and total lymphocyte count did neither reflect the clinical course nor predict complications. this comes tree also for serum igg, igm, iga, c , c , crp, alpha-l-antitrypsin and neopterth as well as for plasma il-la, il-ib, il- ra, il- , il- r, il- r, tnf-ct, tnf-~r (p ) and icam- . in contrast, pmn-elastase, il- and il- closely correlated to the clinical course. isolated pmn's in vitro capacity to produce oxygen radicals depended on the respective radical species and was slightly elevated (superoxide anions) or decreased (hydroxyl radicals), respectively. patients with a cd +/cd + ratio below i were seen at risk of developing septic complications. in contrast, a percentage of monocytes of % or more among total mononuclear cells indicated an uncomplicated course, in general. conclusions: the immune status of the individual patient may significantly influence the course of acute pancreatitis. the cytokine pattern in peripheral blood is very complex and most parameters are of little use for the clinician. the pmn-elastase, il- and il- , however, closely correlate to the clinical course and may prove valuable for follow-up. the cd +/cd + ratio was found the best predictor of septic complications, but it failed in non-septic patients. a percentage of % or more of monocytes among total mononuclear ceils indicated a rather mild course. the reduced ability of the pmns to produce hydroxyl radicals may help to explain the frequent development of septic complications in severe necmtizing pancreatitis. peroxidation of membrane lipids contributes to ceil injury in pancreatitis. overwhelming release of toxic metabolites by infiltrating neutrophils is regarded a major pathogenetic factor, too. as yet little is known about the mechanisms by which oxidative stress and leukocytes damage pancreatic cells. the present study examines (i) the susceptibility of pancreatic acinar cells to attacks by oxidants and leukocytes and ( ) the potential of antioxidants to prevent such damage in order to better understand the cellular mechanisms of pancreatic injury in inflammatory states. methods: freshly isolated rat pancreatic acinar ceils were exposed to a model system of oxidative stress consisting of mu/ml xanthine oxidase (xod), mm hypoxanthine (hx), mm fec and mm edta. in a second set of experiments, acinar cells were exposed to excess autologous neutrophils or neutrophils obtained from patients with acute pancreatitis. neutrophils were stimulated by zymosan a, pma, and il- . cell viability was assessed by both cellular uptake of trypan blue (tb) and by release of ldh. results: the xod/hx system caused a time-dependent acinar cell injury. this injury was effectively prevented by catalase (cat) and gfutathione peroxidase (gpx). in comrast, superoxide dismutase (sod) enhanced cell injury. addition of both sod and cat abolished the damage seen with sod alone. the non-enzymatic scavengers mannitol, dmso, dmtu and the iron chelator deferoxamine were not protective and at a higher concentration even accelerated cell decline. the newly developed antioxidants of the lazaroid type effectively prevented oxidative acinar cell damage. stimulated neutrophils, both autologous and heterologous, did not damage healthy acinar cells but had even protective effects. conclusion: pancreatic acinar ceils are very susceptible to oxidative injury. a combination of catalase and sod prevented cell damage effectively. sod when given alone may rather damage than protect aelnar cells when h is generated in concentrations overwhelming the capacity of endogenous catalase. therapeutic approaches to pancreatic disease using antioxidants should, therefore, include combinations of protective substances. the lazaroids seem to be candidates for clinical use as antioxidants in pancreatitis. the results argue against direct toxic effects of stimulated neutrophils to pancreatic acinar cells. are ch~act~z~ by the presence of a polymicrobial flora, the pmtotyi~ cffthese inf~ons is secend~,y bacterial pedtonitlw, whereby a pathololoeal process in the ~trointesfimd tract r~ful~ in tim disrup~on ofi~ inteffrlty and ¢ollseqtlent sptl]nge of inte~.i,o~.l gontents into the peritoneal c~iry. the ensuing infection invariably contains a mixtm~ of gt~m negative enteric bacilli, gram positive b~eria and anaerobe& experimental and clinical =t~ies have de~ed the eantrlbution of each of th¢~ components to ti~ ovemu virulence of these in~ons, gram negative enteri~ such as f.veher~chla coil ere endowed with a virulent l~l~x~lyse~haride ptill~ly t~sponsible for lethality, by contrast, bacteroldes sl~cles, which rarely c~se death, prornot~ abscess fonllation, a uniqm~ capsul~ polyseccluu'ide, particularly on b.j~ogiljs slrai~, oontributes to tjtis erect, several mecltanims have bccn pml~ed whereby or~ microorganism mi~t interact with its microbial ~net to augment the overall virulence of a r~xed im~edan. these include: l) provision of nutrients by one apexes which stimulates the growth of its ~opathoge& ) inhibition of host deletes by one of the migroorganisms so that the other microbes might persist and exert their virulence, ) the trant~ of vim.©n~e traits between ~renr~a.,dsms and ) the ~.mizatian d the mi~oe~vironmental con~tion$ by one d the baetez'isl pa#, so that the other might persist. exampl~ for each of these m~banisms imv~ been provided by experimental ttudies i~stigating e.co!l-b.p~flls synergistic in~ra~ons. byproducts ofg.coli metabolim l~¢ovide essential short ebath fatty acids £~ optimal b,frosili~ ga'owth. fm-ther, oxygen ¢ons~tmption by kcelt lowers oxygen tension end redox potantial to levels eomlucive to b#a#lts gro~h. coawr~ely, b,~agtlis rolea~s proteases and fatty acids wl~¢h impair pl'tsgocy~¢ ~lt rmctlon tnd permit f-..¢oli proliferation and expression of its intrinsic virulent. in summaxy, interactions among the separate microbial cemponents of mixed infections heighten the overall virttienee of these lafectiot~, this knowledge provides ~r rationale for targetting of antibiotic therapy against the knowa eantributors of these synergistic pro~¢sses, intraabdominal abscess formation and the macrophage william g. cheadle, m.d., department of surgery, university of louisville school of medicine, louisville, ky inflammation of the peritoneal cavity following bacterial contamination has been classified into primary, secondary and tertiary, the last two relating to bacteria originating from the gastrointestinal lumen. the natural history of such infection is either resolution without clinical sequelae, which is uncommon, abscess formation, or generalized peritonitis, which occurs as a result of failure of peritoneal host defenses. early clearance of microorganisms by peritoneal fluid circulation and filtration througti subdiaphragmatic lymphatics into the thoracic duct and systemic circulation occurs as well. simultaneously peritoneal macrophages and the omentum approach the area of inflammation and lead to neutrophil influx and abscess formation adjacent to the affected viscus. we have found a shift in peritoneal macrophage function from antigen presentation to proinflarnmatory cytokine production that occurs early after experimental peritonitis produced by cecal ligation and puncture. this is also reflected by reduced class ii histocompatibility antigen expression on peripheral blood mononuclear cells and peritoneal macrophages. this is accempauied by an influx of both neutrophils and macrophages into the peritoneum and subsequent abscess formation. interestingly, there is little serum endotoxin or tnf seen in this model despite tnf mrna expression in peritoneal macrophages. we believe this model is more clinically relevant than other models of endotoxemia or bacteremia in which different patterns of cytokine expression are seen. newer agents aimed at reduction of systemic manifestations of sepsis originating from intra-abdominal infection such as monoclonal antibodies against cytokines or il- receptor antagonists may need to be directed against remote organ macrophage populations while preserving peritoneal macrophage function. inflammation is a complex process involving microcirculatory changes, extravasation of fluid and a cellular influx in the affected body area. in our communication, we will only consider the regulation of the cellular infiltrate which plays a major role in the defense of the peritoneum against microbial invasion. until recently, it was thought that the influx of leukocytes in the abdomen was induced by bacterial products, local humeral factors and secretions of resident macrophages. there is now increasing evidence that this view is too simplistic. many other cell types present in the abdominal cavity or composing the peritoneal membrane (mast-cells, mesothelial cells, fibroblasts) are able to release or secrete vasoactive or chemotactic substances such as histamine, prostagtandines, or cytokines. they are most likely to play a role in the regulation of intraperitoneal inflammatory reactions. the emigration of leukocytes towards the abdominal cavity is also modulated by a previous contact with gram negative bacteria. in the rat, this intriguing phenomenon is long lasting, cannot be transferred by serum and seems independent from t lymphocytes. the clinical relevance of these various regulating mechanisms has still to be determined. kinnaert paul, h pital erasme, route de lennik , bruxelles belgium generalized response in secondary peritonitis the clinical course of an intraabdominal infection may depend on a variety of variables including the capacity of host defense mechanisms and the degree of the inflammatory response. if local defense mechanisms fail to restrict the inflammation to the abdominal cavity a generalized inflammatory reponse will result. in a first stage generalized signs of a local inflammation become detectable whereas the second stage comprises the overwhelming systemic inflammatory response. the extent of this systemic response determines the outcome. sometimes it may appear to be unrelated to the severity of the intraperitoneal findings. the activation of plasma systems and cellular elements leads to a fast release of cytokines, inflammatory mediators and other substances. these parameters precisely reflect the degree of the generalized response. inflammation of the peritoneum causes significant morbidity. objektives: to test the hypothesis that peritoneal mesothelial cells play a role in regulating inflammatory responses within the peritoneal cavity, we examined neutrophil-chemotactic activity (interleukin ) and monocyte-chemotactic cytokine (mcp) release by sytokine-etimulated mesothelial cells. confluent human peritoneal mesothelial cells were exposed to varying concentrations of phorbolmyristate-acetate (pma) and the cytokines tumorneerosis factor a (tnf a) and interleukin i~ (il-i~). the supernatant was examined for il- by elisa and for mcp by investigating the ehemotactic activity for isolated human monocytes. mesothelial cells express low levels of il and monocyte chemotactic activity when cultured. these activies were significantly increased ( -fold) after stimulation with either tnf a or il-i~. additionally macrophage inflammatory protein was detected. these observations provide a probably important mechanism whereby peritoneal mesothelial cells respond to imflammatory stimuli released during peritonitis and how leucocyte recruitment by liberation of chemotactic cytokines is regulated. the perioperative course of lps, tnfa and il- in patients with bacteriologic proven abdominal infection (intraabdominal abscess , diffuse peritonitis , pancreatic necrosis , pancreatic abscess ) was followed prospectively and evaluated for possible correlation with septic state and organ function. methods: patients were studied in a to hours period during their first surgical intervention because of intraabdominal infection. all were monitored for their cardiovascular, respiratory, hepatic and renal function. plasma samples for lps. tnfa and il- determination were drawn preoperatively, intraoperatively, and until h postoperatively in regular intervals (min /pat), results: preoperative apache ii was in median (rain , max ). patients fulfilled the criteria of sirs. of them were in septic shock.there was a significant correlation between preoperative tnfa and apache ii (p= , i, spearman coefficient). preoperative cardiovascular (systol. rr< mmhg) and respiratory (pao < mm hg) dysfunction were associated with significantly elevated tnfa (cardial: p= , i, wilcoxon; pulmonal: p= , ) and il- (cardial: p= , ; pulmonal: p= . ) overall, lps, tnfa and il- values varied considerably during the observation period. however, tnfa was markedly higher in patients with sirs and septic shock (group a: n= i , mean pg/ml) than in those who did not fulfill these criteria (group b; n= , mean pg/ml; p= , i, wilcoxon). il- was significantly higher in group a (mean pg/ml) than in group b (mean pg/ml; p= , o i wilcoxon). conclusion: perioperative tnfa and il- were shown to correlate significantly with preoperative organ function, apache ii and the severity of sepsis. these results could help to define patients that might benefit from further therapeutic strategies, e.g. antibody administration. department of surgery, university vienna, akh wien, wahringer gurtel - , wien. aim of the study: the purpose of this pilot study was to establish and to prove a standardized reproducible animal model of intraperitoneal sepsis induced by e.coli-endotoxinaemia in lew.lw-rats in order to investigate early immunoserological responses to find a mediator based evaluating system of peritonitis sepsis. materials and methods: in lew. lw-rats, diffuse peritonitis was induced by intraperitoneal injection of a mixture of e.coli (khu +) and autogenous haemoglobin solution. in the control animal group (n= ) an intraperitoneally injection of physiological saline solution was done. blood samples were obtained by heart puncture after hours. stastistieal calculations were performed on a personal computer with the spss programm vers. . (correlation with pearson's r, mann-whitney-u-test, descriptives statistics, discriminant analysis). results: in contrast to the sham treated rats, the peritonitis animals showed significant differences in the concentrations of endotoxin, interferon-gamma (wn-y), the pteridin derivate biopterin and serum pla -activities [endotoxin range from . eu/i, sd= . to . eu/ , sd- . (p < ), ifn-¥ levels, range from . pg/ml, sd- . , to pg/ml, sd= (p < . ), circulating pla -activities range from . , sd= . to . u/ , sd= . (p < . ) and biopterin range from . nmol/l sd= . to . nmol/l, sd= . (p < . )]. for the peritonitis group we found strong correlations between the degree of endotoxinaemia to elevated levels of ifn-'~ (rp = . , p < . ) and bioptefin synthesis (rv= . , p < . ). the increase of ifn-t levels was correlated to the regulatory synthesis of biopterin (r = p < . .. p • , . . ) and to the pla -actwtues (rp = . , p < . ). the biopterin synthes~s correlates slightly with the pla -actn,ities (rp= : . ; p < . ). using the para, meters of endotoxin, ifn-y levels, biopterin and the pla~ -activities only, the statistical procedure of the linear discriminant analysis makes it possible, to distinguish between non-septic animals and septic animals correctly at a rate of %. anaerobes were found in . %, anaerobes were isolated in . %. there were aerobic and anaerobic associations in . % and microflora was not found in . % of the cases. express method of anaerobes discovering let to receive information on - days early than in generally accepted nethods. intraaotal transfusion of oxygenate blood and laser irradiation of blood reduces the duration of anaerobic sow, disminishes intoxication and accelerate the patients recovery. patients with abdominal sepsis are subject to long periods of hospitalization and high associated morbidity and mortality rates. this category of patients is thus consuming extensive facilities and costs. as the age-related outcome of abdominal sepsis is not fully known, the aim of the present study was to investigate abdominal sepsis in the elderly. out of patients with abdominal sepsis treated at the surgical intensive care unit during a -year period, ( %) had an age of years or more. were women and were men, a sex distribution not differing with patients younger than years. the patients were scored according to apache ii and septic severity score (sss) upon arrival to the intensive care unit. bacterial cultures, the occurrence of organ failure, hospitalization and outcome was noted. in median two operations were performed for both "younger and elderly" patients. the median time of hospitalization in the elderly was (- ) days including in median days in the icu. figures in patients less than years of age were comparable ( (- ) days out of which in median days in the icu). apache ii and sss-scores did not significantly differ ( . vs and . vs . , respectively), between the groups. neither did the incidence of organ failure differ ( / vs / ). however, the incidence of multiple organ failure was significantly lower in elderly patients ( / vs / (p < . )). the mortality rate, however, did not differ between the groups ( / vs / ). in conclusion, severe abdominal sepsis in the elderly was not associated with an increase in mortality, incidence of organ failure or hospital stay. with the help of light transmissional scanning electron microscopy morphology of erythrosytes of peripheric blood was studied in patients with different stages of diffuse peritonitis before and after intravascu!ar irradiation of blood with heliun-neon laser. peritoneal morphology was investigated in patients who died from peritonitis, it was established that in all phases of peritonitis occured stomatocytoric and echinocytoric transformation of erythrocytes which progressed simultaneously with increase of intoxication. it combined with strongly pronounced vessels variability of microcirculatory peritoneal bed which displaied by erythrocytes aggregation, stasis and microtrombogenesis. in intravascular laser irradiation of blood number of erythrocytes which underwent to stomatocytoric and echinooytorie transformation was lower than in patients without laser irradiation. it indicated that the intravascular irradiation of blood with helium-neon laser can prevent development of severe alterations of rheological property of blood and consequently variability of microcirlatory peritoneal bed in patients with diffuse peritonitis. abdominal sepsis is still associated with high morbidity and mortality rates, frequenfly caused by multiple organ failure. it has been reported that changes in capillary permeability play a role in the pathogenesis of multiple organ failure. the present study aimed at evaluating the influence of intraabdominal sepsis induced by cekal ligation and puncture on capillary permeability in multiple organs and tissues. adult male sprague-dawley rats were subjected to laparotomy with separation of the cekum (sham operation) or induction of intraabdominal sepsis by cekal ligation and puneatre (n-- in each group). at , , , , and hours (n= /timepoint), the animals were evaluated concerning mortality and capillary permeability as determined by the passage of : i-labelled albumin from capillaries to the peritoneum, the proximal and distal small intestine, cekum, colon, spleen, kidneys, lungs. the mortality rate in rats with intraabdominal sepsis was % both at and hours. capillary permeability in the peritoneum, cekum, colon and kidneys significantly increased from hours and on in rats with intraabdominal sepsis. in septic animals, capillary permeability in the lungs and spleen increased from hours and on and in the proximal and distal small intestine from hours and on. different types of alterations in capillary permeability seem to appear: ) a temporary short increase e.g. in the proximal small intestine and spleen; ) a temporary longer increase e.g. in the colon and kidneys; ) a persisting increase e.g. in the peritoneum, cekum, distal small intestine and lungs. we conclude that experimentally induced intraabdominal sepsis induces early alterations in capillary permeability in multiple organs and tissues. such changes may contribute to explain the development of sepsis-induced multiple organ failure. despite a number of significant advances in the care of burn and non-burn traumatic injury, infection and sepsis remain major causes of morbidity and mortality. the severe immunosuppresslon often seen in patients with severe trauma or large burns may predispose these patients to life threatening infections. included among the many immune alterations are changes in the functional capabilities of neutrophlls (pmns). we have examined the expression of the p integrins (cd l a, b,c/cd ), and the fc'?r (cd , cd , and cd ), as well as several functional parameters, on pmns from thermal and non-thermal traumatic injury, pmns were obtained from patients sustaining severe trauma (initial apache ii score > ) or thermal injury (> ~ total body surface area, % full thickness), and healthy controls. the expression of cd b and c and to a lesser degree cdi a was significantly reduced on pmns. the expression of cd and cd but not cd was also significantly reduced. pmns displaying this reduction in receptor expression have a significantly reduced ability to phagocytose bacteria and undergo the oxidative metabolic burst response. thermal and traumatic injury result in global reduction in the expression of integrins and for which may lead to decreased functional capabilities, these abnormalities may in turn account at least in part for the increased rate of infection in these patlems, institute, dept. of surgery, ~ ethesda ave, cincinnalt, oh, usa, - s b, antibiotic-phagocytic cell interactions: their effect on endotoxin release. c g c-emmet , dep[baeteriolog.z, univer_sitv of glasgow, scotlan~_d increasingly it is recognised that pathogenic bacteria are capable of surviving intracellularly within phagocytic cells in addition to their capacity to produce disease whilst in the extracellular milieu. as well as providing protection from certain antibiotics which fail to penetrate the phagocyte, such intraceltular bacteria may be transported from the initial site of infection to a distant more vulnerable body site wherein they may proliferate. it is also known that some antibiotics are capable of becoming concentrated within phagocytic cells mid displaying bioactivity therein. such bioactivity might be responsible for the release of endotoxia #orn gram-negative bacteria which when liberated from the celt could ~gger the cytokine cascade. anfib,.'otic-induced damage to the ultrastructure of bacteria can also occur when the target bacteria are exposed to low (sub-mic) concentrations of certain drugs. such bacteria may present quite altered surface components m host-defense cells as well as releasing biologically active ceil wall components such as endotoxin. the nature of these interactions at the cellular level as well as the consequences for the host will be discussed. new jersey medical school: umd, newark, nj a technique of physiologic state classification has been developed based on the m~itlvariable analysis of patient derived data sets of seventeen physiologic variables. these multivariable data sets obtained from critically ill patients requiring intensive care, were aormallsed by the mean and the standard deviation of recoverin~ trauma patients who were not critically ill, the resulting normalized seventeen variable sets were then clustered. seven independent data groupings were developed. the normal stress response hyperdynamic state seen post-trauma and in compensated sepsis (a stets)/ metabolic insufficiency seen in septic decompsnsation (b stste}; early (c,) and late (e ) respiratory insufficiency associated with ards; cardlogenlc dscompensation (n state); post-trauma hyvolemla without shock (r stats). the stats closest to a new patient's values allows patient classifi atlon with regard to his previous physiologic state. classifying observations f~om patients who lived or died who fell into these physiologic states enables a probability of death (p death) to be obtalned. utilizing this criteria for the staging of severity in recent trauma patients the physiologic states accurately and significantly predicted the likelihood that the patient had an increased circulating level of the eytoklnes tnf and il- . the probability of death (p death) as well as the cytoklne levels appear to be a function of the physiologic b state with the highest levels being seen in the b state of metabolic insufficiency and the c~ state of oombined respiratory and metabolic insqffioienoy characteristic of septlc ards. the increase in the magnltude of metabolic abnormalities associated with the transition from non-sepsls to septic a, septic b, or septic c z states was associated with an increasing probability of death (p denth)(mean a state =. , mean b state = . , mean ~ state = . ). the accuraay of this estimate was prospectively analyzed in this group of m~itlple patients of whom % had sepsis and % had ssptlo ards. the survivors had a mean p death of . and the deaths had a mean p death of . . the severity of post-trauma sepsis can be quantified by probability analysis and stra~ifie~ by physiologic state. serologic tests have not been extensively tes'~ed in surgical patients but seem to be of limited value. we use nystatin as the main form of chemoprophyhxis. patients "~'ith signs of infection who do not rapidly improve with antibacterial therapy are candidates for anti-funsal therapy, amphoteradn b remains the first llne of therapy although combination therapy '~'ith flueonazole is use;l with increasing freque~;c)', the recovery of c~dida from an antra-abdominal site represents a challenging problem, anti~ngal therapy in such patients depends on the underlying disease, the nature of the infected material and overall patient risk. role of neural stimuli and pain principles and practice of anesthesiology effect of combined prednisolone, epidural analgesia and indomethacin on the systemic response after colonic surgery arginine: biochemistry, physiology and therapeutic irnplications immunosfimulatory effects of arginine in normal and injured rats arginine stimulates lymphocyte immune response in heahhy humans rote of arginine in trauma, sepsis and immunity arginine enhances wound healing in humans if labrecque t, gv campion t, and the rhll-lra phase i//sepsis syndrome study group the cleveland clinic foundation a murine-anti-human tnf-monoclonal antibody known as cb was the first anti-tnf mab which was studied in a phase ii multinational trial in the treatment of patients with severe sepsis.this was an open-label, dose-escalation trial consisting of patients who were enrolled into one of four treatment groups: ( ) . mg/kg of anti-tnf mab, ( ) . mg/kg, ( ) mg/kg or ( ) . mg/kg at study entry and the second dose hours later. the small sample size in each group (n= ) precludes detailed statistical inference in this study. nonetheless, a considerable amount of useful information was obtained from this investigation. irst, this study demonstrated the clinical feasibility of specific anticytoldne therapy in septic patients. second, the measurement systemic levels of tnf proved to be an elusive target; interleukin- may prove to be a more useful indicator of cytokine activation. third, immunologic reactions including tnf: anti-tnf mab immune complexes and human anti-routine antibodies were frequently found in these patients. despite their apparent lack of overt toxicity in this study, these immunologic reactions may complicate this form of anticytokine therapy. additionally, the potential benefits of anti-tnf mab therapy occur within the first hours of therapeutic administration in these septic patients. infecting organisms differ in their potential to induce tnf in vitro and these differences correlate with circulating tnf levels observed in septic patients. rapid methods to define those patients most likely to respond to anticytokine therapy are needed to determine the ultimate therapeutic potential of these agents in clinical medicine. wherry, j., abraham e., wunderink r., silverman h., perl t., nasraway s., levy h., bone r., wenzel r., balk r., allred r., pennington j. and the tnfa mab sepsis study group.tnfa mab (bay x ) is a murine monoclonal antibody raised against human tumor necrosis factor. tnf~ mab has been shown to reduce morbidity and mortality in animal models of septic shock and has been safely administered to septic and non septic patients.to evaluate the efficacy and safety of tnf~ mab in patients with sepsis syndrome, a prospective, multicentered, double-blind, placebo-controlled trial was conducted in hospitals in north america. patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single intravenous infusion either of mg/kg tnf~ mab, . mg/kg tnf~ mab or placebo ( . % human albumin).patients received standard aggressive medical/surgical care during the day post dosing period.the three treatment arms were well balanced with respect to demographics, apache ii score and other parameters. for all infused sepsis syndrome patients, those who received tnf~ mab had slightly reduced day all cause mortality compared to placebo. among shock patients there was a more pronounced trend towards efficacy at day post dosing with lower mortality rates in both active treatment arms. among nonshock patients tn~ mab did not appear beneficial. the initial clinical experience with a chimeric anti-tnf monoclonal antibody, ca , was undertaken in septic patients. the objectives of the study were to determine the safety, pharmacokinetics and effects on cytokine levels of ca . as a single infusion or in combination with ha- a in septic patients. the study was conducted with the intent to progress to an efficacy trial based on the information collected.the trial was conducted in three stages. stage was an open label trial in which groups of patients each with the clinical diagnosis of sepsis received ascending doses of ca ( . , , , mg/kg). stage was a randomized, double blind study in which patients received a single dose of ha- a ( mg) and placebo or one of doses of ca ( , , mg/kg). stage was a randomized, double blind study in which patients received a single dose of placebo or one of doses of ca ( . , , mg/kg). in addition to usual laboratory tests, the following assays were performed: chimeric anti-tnf concentration, anti-chimeric antibody, endotoxin, tnf, il- , and il- levels.a total of patients were enrolled from clinical sites ( in stage , in stage and in stage ). primary analyses were performed on patients in stage and . there were patients who received ca exclusively and patients received placebo. administration of ca was well tolerated at doses up to mg/kg. no patient discontinued treatment due to adverse events. human anti-chimeric antibody responses were positive in % ( / ) of evaluated patients. mean cma × and auc increased proportionally with increasing doses of ca . the mean half-life was - hrs ( - hrs). a dose related decrease in tnf concentration was observed hr post infusion of ca . tnf is considered to be one of the central endogenous mediators for the inili'ation of the pathophysiological changes in patients with sepsis and septic shock. high tnf levels were demonstrated to correlate with patient outcome. blocking or neutralising tnf with specific antibodies was effective in preventing death in some animal modets of sepsis. in a placebo controlled prospective randomized study we tested the mur~ne derived antibody mak f. it is a f(ab') fragment. the fragment rather the complete antibody was selected in order to reduce the potential immunogenicity and to facilitate tissue penetration. patients with severe sepsis or septic shdck were enrolied in the study, three different doses of mak f or placebo were administered ( , ; , and i mg/kg) over a perid of hours in random order. the patients were evaluated for side effects, hemodynamics, organ dysfunction, cytokines (il , il and tnf), and outcome. at this time only an interim analysis of patients is available i indicating that mak f in all dosage groups resulted in a decrease in il . this contrasted to a further in crease of il in the placebo patients. no serious side effects have been reported so far. a more detailed analysis on all patients in the study will be presented and discussed.$ s staubach,k.h., otto, v., kooistra,a,, rosenfeid,j.a., bruch, h.p., univ. lfibeek, germany once endotoxinemia occurs in sepsis a vieieus cycle with translocation of et can be established. increasing the clearance capacity for et would therapeutically be the ulimate aim. we developed a new et on-line adsorption (ad) system in whole blood by means of polymyxin b (pb) coupled eovalently to a matrix (acrylic particles) via a atom-chain spacer. the detoxification capacity was ug[et/ml column material. the biocompatbility resulted in ~ platelet recovery. the column contained ml of admaterial and was sterilized by high steam autoclave, anticoagulation was achieved by heparine . iu/h in the inflowline after bolus injection of . iu. hp was performed on pigs at a rate of ml/min by means of a roller-pump until the animals succumbed (h). animals served as controls (c). serum et levels rose from . pg/ml to , pg/ml after hours in the c and from . pg/ml only to pg/ml in the h group after hours whieh was highly significant. survival time could be extrended from to min. results are listed in the following l. blinzler, p. zaar, m. leier, r. b( rger, d. heuser clinic of anaesthesiology , city hospital nuremberg, germany sepsis and multiple organ failure (mof) are still related with poor prognosis inspire of pharmacological and technical progress. impressed by revealing reports about blood purification the continuous veno-venous hemofiltration (cvvh) was used as supporting treatment beside the critical cam basic therapy of mof. from to consecutive patients were treated by cwh. mof was caused by hemolrhagic-traumatic noxa in °, and by septic-toxic event in %. all patients required mechanical ventilation (fio > , ) . ° showed hyperdynamic shock. % had renal and % hepatic failure. medium appache ii score amounted to , points. cvvh was performed in postdilution mode with a polyamide membrane (fh ) and high volume exchange ( l/die). anticoagulation was done with heparin. hemofiltration in mof was installed, when critical cam basic therapy including adequate respiratory and hemodynamic management, pamnteral nutrition, antibiotic treatment, etc., failed to stabilize organ functions. during consequent application of cvvh most of these patients showed improvement of their clinical course. pulmonary stabilization was seen in %, hemodynamic in % and renal in % of the cases. % of the patients survived and were discharged from hospital. of non-survivors ( %) died because of fatal mof within h after admission to icu. patients with early application of cvvh in mof showed a better survival rate.mediators of mof, i.e. products of the complement cascade measured in blood and nitrafiltrate by elisa, were partially removed by cvvh. the testing ultrafiltrate by hplc demonstrated decreasing spikes ofpolypeptides during hemofiltration. mof seems to be generated by cascade-activation of immune competent cells and plasmatic mediators (e.g. bmdykinin, eicosanoides, cytokines, anaphylatoxins, etc.). therapeutic approaches aim to inactivate or eliminate single substances. cwh with high-flux membranes in combination with high-volume exchange allows elimination of many mediators with different molecular weight and therefore may contribute to improve the prognosis of mof. other significant advantages of this teqalnique like adequate nutrition, optimized fluid balance and control of body temperature should not be negicctod. introductioni pseudomonas (p) aeruginosa has to be considered an important pathogen of nosocomial pneumonia and septic organ failure. the lung seems to be the predominant target organ for the pore-forming p. aeruginosa cytotoxin, thus inducing microvascular injury. with respect to therapeutical consequences, the potential protective effects of paf-antagonist (web ), cyelooxygenase inhibitor (diclofenac) and specific and unspecific antibodies on cytotoxin-induced pulmonary vascular reaction and mediator release were studied in the isolated perfused rabbit lung. methods: cytotoxin ( p_g/ml) was administered into the perfusion fluid in all groups, either in the absence of inhibitors (n= ), or after pretreatment with web ( xl -gm, n= ), or diclofenac ( #g/ml, n- ). furthermore, the application of specific antitoxin (mg/ml, n= ) was tested in comparison with the unspecific immunoglobulins (venimmun®, behring, . mg/ml) (n= ) and the combination of immunogiobulins, web and diclofenac (n= ). six experiments without toxin served as controls. the arterial pressure mad the weight gain as an indicator of edema formation were continuously monitored during the three hour peffusion phase. arachidonic-ucid metabolites, as well as lactate dehydrogenase (ldh) and k + concentrations were determined at rain intervals. results: cytotoxin caused a gradual increase in pulmonary arterial pressure, reaching a maximum value of . times higher than the control, starting after min and a delayed onset of edema formation resulting in a mean weight gain of g after min. this was paralleled by a significant increase in prostacyclin generation and a continuous release of k + and ldh. thromboxane synthesis exceeded about times that of controls in the toxin treated lungs. pretreatment with web or diclofenac significantly attenuated the pressure response and edema formation evoked by cytotoxin. the addition of the unspecific immunognbulin preparation alone induced a transient pressure increase within the first minutes, but mean values remained below those of the cytotoxin group in the continuing observation period. mmost complete inhibition of the pressure reaction, the edema formation and the metabolic alterations was achieved mainly by the combination of immunoglobulin, web and diclofenac and to lesser extend by the specific toxin antibody. conclusion: the current results point towards the crucial role of paf and aa-metabolites as mediators of cytotoxin induced microvascular injury. the systemic or local application of cytotoxin antibodies or even unspecific immunoglobolins in combination with paf-antagonist and diclofenac appears to be a promising therapeutic approach in the case of infection with cytotoxin-preducing strains. cytokines have long been shown to be of particular importance in the metabolic derangements occurring in lps-induced shock. recent studies strongly imply the involvement of platelet aggregating factor (paf) in the pathogenesis of gram-negative bacterial sepsis. an autocatalytic feedback network has been postulated to exist between paf and tumor necrosis factor (tnf), a key cytokine involved in septic metabolic cascade, leading to an uncontrolled amplification of inflammatory mediator release. we have previously shown that st ( -n,n,n trimethylammonium-(r)- -isovaleroyloxy-butanoic acid z- -( -chlorphtalidiliden) ethyl ester bromide) was quite effective in inhibiting the "in vitro" binding of h-paf (ki= . x - m) to rabbit platelets. the present study shows that pretreatment of c bl/ mice with st , administered by different routes, dose-dependently and significantly reduces the lethality induced by endotoxin (e.coli :b injected at mg/kg intraperitoneally). very interestingly, st administered at the same doses as above (i.e. . , . , and mg/kg body weight) results to be significantly effective in reducing the endotoxin-induced release of serum tnf. the reported dual activity of st (i.e. paf antagonism and decreased circulating tnf levels) may turn out to be greatly beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of tnf and paf such as septic shock. introduction: recently, we reported that prophylactic whole body hyperthermia ( . °c) induces heat shock protein ('asp) and increases smvival - fold in a mouse endotoxin model (am. j. physiol. in press). other investigators reported that prophylactic pharmacologic induction of hsp- by sodium arsenite improves survival in a rat sepsis model (abstract a am. rev. resp. dis. vol. , ) . the effects of heat are complex and in addition to formation of lisp- include release of cytokines, changes in cellular ph etc. thus, the protective mechanisms of heat may differ from those due to pharmacologically induced . the purpose of this study was to compare the protection of heat vs the protection of pharmacologically induced hsp- in a mouse endotoxin model to determine if different protective mechanisms were likely to be involved.. i%'lethods: both sodium arsenite ( mg/kg) and ethanol ( ~ of % ethanol) caused marked induction of hsp- in lung, gut, kidney, and liver, which was comparable to heat-induced hsp- . female nd mice weighing - gms were pretreated with arsenite or alcohol hours prior to challenge with escherichia coli endotoxin (-ld ) and survival was compared to control mice. results: survival at hrs. for arsenite treated and alcohol treated mice was % and % respectively and was statistically different from the % survival for control mice. (p< . ) (n= mice per group). however, at days post endotoxin, there were no differences in survival in the groups, i.e., ~ % survival for all groups. in contrast, the protective effect of hyperthermia remains present at days, i.e., ~ % survival vs % survival control. conclusion: the protective effect of heat is probably due to other factors such as the effect of hyperthermia to release il-lc~ and is not due solely to hsp- formation. it was the aim of the study to examine whether bacteria play a causative role in the pathogenesis of anastomotic insufficiency following gastrectomy in man.the study was carried out in form of a prospective, randemised, double-blind, multicenter trial. primary endpoints were the rate of anastomotic insufficiencies, infectious-and uncomplicated postoperative courses. all pat. received a periop, i.v. prophylaxis with cefotaxim. identical numbered vial either contained placebo or polymyxin b, tobramycin, vancomycin and amphotericin b . the vials were administered x per day from the day be ~ fore the operation until the th postop, day. insufficiencies were detected by gastrographin swallow and recorded by x-ray on day postop.. evaluation was carried out on an "intention to treat'basis. statistical analysis was done with the pearson's chi square and fisher's exact tests~ results: interim analysis was carried out in / after pat. had been recruited. along with a significant reduction of s.aureus and enterobacteria there was a reduction in the rate of anastomotic insufficiency of the esophago-jejunostomy from . % in the placebo-group to . % in the treatment group. the difference was not yet significant. the rate of nosocomial infections (e.g. respiratory tract infection and uti) were significantly reduced from . % in the placebo-group to . % in the treatment-group (p ~ . ;fisher's exact test). in march final results with more than patients will be presented for the first time. (= po < mm hg, b s-creatinin > mg%). respiratory insufficiency was the most frequent systemic complication followed by sepsis and respiratory insufficiency. etiology of pancreatitis and initial serum increase of pancreatic enzymes predicted neither complications nor outcome. only of deaths occurred during the st week, all other deaths occurred late (after - weeks), generally as the consequence of septic complications and multi-organ failure. high levels of crp were correlated with a compliacted course and a fatal outcome. although same cytokines (e.g. -- ) were found increased in severe disease, the predictive value of these markers was not better than the combination of ctinical scores (ranson, imrie, apache ii) with gt or crp. conclusions: intensive care medicine can often control the inital shock situation in severe pancreatitis. thus. only % of deaths today occur eady in the course of the disease, whereas this percentage varied between - % just years ago. nowadays, most deaths are caused by late septic complications and multi-organ failure. ranson-and ct-scores as well as serum crp predict a course with systemic complications; they are less helpful for prediction of sepsis and late mortality. it is doubtful whether measurements of cytokines will help to better predict the late outcome. as yet, only careful and continuous monitoring of patients (e.g. by apache scores) may help to early identify those who develop septic complications and multi-organ failure. the classic description of severe acute pancreatitis has hinged upon the release of large volumes of activated enzymes into the peritoneal cavity and thertce the lymphatics and blood stream. these activated enzymes escape from the pancreas due to disruption of cells with associated ischaemia and occasional infarction of tissue. for to years it has been postulated that the bocly's defence system to activated pancreatic enzymes required supplementation iu the form of anti-protease support either in the vascular space or in the peritoneal cavity. all controlled studies have shown that this is either impracftcal or unnecessary.hore recently release of a large number of cytokines from monocytes, macrophages and neutrophils have been considered to be harmful to the body and various agent~ which oppose the action of tnf alpha, paf and similar cytokines are being examined in experimental anim~is and certain clinical trials, it has clearly been shown that higher levels of cytokines are released in the patients with objectively graded severe acute pancreatitis than in those with milder disease. we now seem to be moving into an exciting phase of potentially beneficial therapy in acute pancreatitis which has had no specific effective therapy through studies utilising aprotinin, gabexate mesilate and fresh frozen plasma. inflammation cascades may play a role in the pathogenesis of acute pancreatitis. to evaluate the status of the cellular immune system we examined serum concentrations of immune activation markers in patients with acute pancreatitis ( males, females; median age: years, range: - years). concentrations of neopterin, serum soluble tumor necrosis factor receptor (stnf-r) and serum soluble intercellular adhesion molecule type (slcam- ) were determined using immunoassays (henning, bender, t cell sciences). / had increased concentrations of stnf-r compared to the th percentile obtained in healthy controls (> . ng/ml), and / patients had increased neopterin (> . nmol/i), / presented with elevated slcam- (> u/i). all patients with increased neopterin also had increased stnf-r, patients had concentrations of all three markers outside the normal range. there existed a significant correlation between neopterin and stnf-r (rs = . , p < . ). weak associations between age and stnf-r (rs= . , p=o. ) or neopterin (rs= . , p = . ) were also found. our results demonstrate activation of the cell-mediated immune system taking place in a sub-group of patients with acute pancreatitis. the finding of increased neopterin and stnf-r levels implies that activated monocytes/macrophages are involved in the pathogenesis of the disease. further data are necessary to evaluate potential associations between changes of marker concent-rations and the course of the disease. pancreatic injury after heart surgery was reported as soon as ( , ) and characterized by increased serum or urine amylase levels (in about % of patients) in the fi~t postoperafi.'ve days. this pancreatic injury, which sometimes led to acute pancreatitis, was atreaay at~buted to inappropriate perfusion of this organ. in the ffs, studies were published dealing with pancreatic suffering alter heart surgery, in large series of patients, concluding ~n~at panc~a~c injury (with a low incidence of pancreatifis) is more common than previously recognized and is a potential source of complication after camliac surgery ( , , ) . in a recent study ( ), evidence of pancreatic cellular injury was found in out of patients undergoing cardiac surgery, with out of these patients presenting abdominal signs or symptoms and developing severe pancreafitis. this injury was associated w~th preoperative renal insufficiency, valve surgery, ~..stoperalive hytxxension, calcium administered periopuratively and length of bypass. we studied patients submitted to cardiopulmunary bypass (cpb) for heart surgery and used the measurement of un:~sin, pancreatic iso-amylase and lipase in plasma for biochemical characterization of pancreatic cellular injury. blood samples were obtained before surgery, directly aller surgery (return to inte~ve care unit), hours alter surgery and in the folfowing days alter surgery (days , , , and ). computed tomography scan of pancreas was performed in patients presenting hi~ levels of amylase on day . we measured abnormal levels of trypsin and pancteatic iso-amylase in % of patients and observed simultaneous releases of these enzymes, the fi,'st one in the hours after surgery and the second more intense from day and pa~icularly on day after smgery. this second release was concomitant with abnormal levels of llpase. these biochemical observations were accompanied by radiological and clinical signs of pancreatic injury in about % of our patients : pancrealic abnormalities were revealed by scan in patients and acute pancreatitis in i patient. more pronounced pancreatic suffering was observed in patients undergoing valve replacement than in patients undergoing coronam-anrtic bypass grafm~g. analysis of trypsin and pare're, tic so-amylase are sw.cific of pancreatic cellular injury and their simultaneous ir~rease in plasma alter cpb in our padents confirms the presence of an exocrine pancreatic injury. the presence of a simultaneous peak of lipase mcaezse~ the specificity of overt pancreatic injtu diagnosis. the precise cause of th/s injury could he related to hypoperfnsion leading to ischemic injury of foe splancbnic area, pancreas being largely sensible to hypoperfnsion ( ). this hypoperfosion could he responsible for the ftmt release of pancrealac enzymes observed in our patients and would contribute to the deterioration of other organs leading to an inflammatory reaction developing in the following days and responsible for the second release of pancreatic enzymes observed in our patients. patients with necrotizing pancreatitis show a heigh rate of pulmonary, renal and septic complications, whereas the course in acute interstitial pancreatitis is generally very mild. we have prospectively analysed the value of endotoxin, interleukin- (il- ) and transferrin in compare with c-reactive protein(crp) for the early assessment of the severity of acute pancreatitis. patients aud methods: the values of endotoxin(measured by limulus-lysate-test), ii- (elisa), transferrin and crp (nephelometry) were analysed daily along the first i days of hospitalisation by patients with acute pancreatitis admitted to our hospital from / to / . it was judged whether the patients have either interstitial (aip) (n= ) or necrotizing (anp) (n=lg) pancreatitis. patients with anp have died during the course of pancreatitis (mortality= . %). results: -severity o~ pancreatitis: signifcant differences (p<o. , mann-whitney test) could be calculated between aip and anp for endotoxin, il- , transferrin and crp during the i days of monitoring. -mortality: except of il- on days , , and after ad-mission there were no significant differences between the values of analysed parameters in patients who survived and those values in patients who died. -organ failure: the patients with pulmonary, renal or multiorgan failure have significantly heigher values of endotoxin, il- and crp along the i days of monitoring in compare with those patients without an organ failure. conclusions: endotoxin, il- and transferrin, an important endotoxin carrier, are promising parameters to differentiate between the severe and mild form of pancreatitis comparable with crp. this parameters may be helpfull in the early clinical assessment of patients with acute panereatitis. the determination of cytokines may elucidate the pathophysiologic mechanisms that produce early systemic complications in acute interstitial (i) or necrotizing (n) pancreatitis (ap). the appearence of respiratory insufficiency (ri) is used to appraise the early systemic complications and is compared to the results of cytokine blood levels. in a prospective clinical trial from / - / , patients with ap were recruited and blood samples taken for cytokine determination with commercial elisa-kits. the differentiation between i (n= ) and n (n=l ) ap was made through ct-scan in all and laparotomy for drainage and necrosectomy in patients. the etiology of ap was gallstones in , alcohol abuse in , hyperlipidemia in and other or unknown causes in patients.five of patients with nap died early (n=l) or of late septic complications. none died of iap.the peak of cytnkine level in the first three days of hospitalisation was used for calculation. ri was diagnosed in the first week of hospitalisation, if oxygenmask or iutubation for at least days was nescessary to treat arterial hypoxemia. for statistical analysis u-test of wilcoxon, mann and whitney was applicated.the il- concentration in blood reached up to pg/ml in the first days depending on the severity of ap and dropped to almost zero in the next days, independently of the clinical course. the differentiation of i-versus nap, using a cutoff-line of pg/ml was correct in patients ( %, sensitivity (se): %= specificity (sp): %, (z: , ). high levels of il- over pg/ml correlated well with the prognosis ifri in the first week (accuracy: %, se: %, sp: %, c~: , ). the blood levels of il- reached a maximum of pg/ml in the first days, depending on the severity of ap, and showed a correlation to the clinical course in the following days. the peak of l,- blood levels indicated correctly the severity of ap in out of patients using a cut offtevel of pglml (accuracy: %, se: %, sp: %, ~: , ). there was no correlation between cytokine blood levels and mortality, also there seemed to be no correlation between the levels of il- and il- . in the bloodsamples of five patients with i-or nap no c~-tnf was detectable.the blood levels of il- , and to a lesser extent of [l- , can predict the severity and early systemic complications of ap in men. the excessive rise of cytokines can be explained by the stimulation of immunological cells ( macrophages, lymphocytes and endothelial cells) in the course of ap. objectives: in an opossum model, ligation of the sphincter of oddi or separate ligation of the bile and the pancreatic duct together leads to severe haemorrhagic pancreatffis while single ligation of the pancreatic duct causes only an exocdne atrophy. since bo has been discussed to be a contdbutor t¢, res dysfunction, this may depdve the organism of a potent defensive mechanism thus promoting the course of pancreatitis. the present study wa,,; carded out tc develop a new method for measuring dynamic liver res func.. tion and to test the hypothesis that bo causes a res dysfunction. material & methods: opossums were randomly placed in three groups. all received a central venous line. after midline laparotomy, a specially designe tourniquet was placed around the common hepatic duct above its junction with the pancreatic duct (group a, n= ), around the pancreatic duct (group b, n= ) or around both ducts (group c, n= ). after one week, the tourniquets were closed. using a scintillation camera, the liver uptake of nanocoll, a mtcalbumin colloid with a diameter of nm, was measured before, , and days after the obstruction. the curves were analysed by a computer and two parameters (r, s) were calculated using natural logarithmic regression. as a common measure for res function, the corrected granulopexic index (a) wa,,; determined, after day , the pancreas of each opossum was searched for necrosis by morphometdc methods. results: all animals survived till day . the opossums in groups a & had a macro-and microscopic normal pancreas, while those in group c showed a severe hemorrhagic pancreatitis. the granuinpexic index showed a significan~ change to the worse starting at day in group a & b (p<o, ) and at day it~ group c (p< ,ol). at day , res function in group c was significantly worse than that in group a & b (p< , ). the regression parameter r showed no significant change in groups a & b, but a highly significant decrease in group c starting at day (p< . ), thus showing a dysfunction of the hepatic res. conclusions: obstruction of the hepatic or pancreatic duct alone does no{ result in immediate dysfunction of the hepatic res, while obstruction of beth ducts does. because only ligation of both ducts is followed by a severe hereof.. rhagic pancreatitis, res dysfunction could be an important factor in the pathogenesis of pancreatitis and resulting organ failure.logarithmic regressinrl has proven to be a valuable tool to analyse dynamic hepatic res function. (b ) in lewis rats weighing - g. there were five groups: group a (n= ) were untreated controls; group b (n= ) were given isotonic saline intraperitoneally and observed for hours; group c (n= ) ml x e. coli intraperitoneally and observed for hours; group d (n= ) were given ml x e. coli and observed for hours; group e (n= ) ml x i e. coli and observed for hours, the rats were than killed, the spleens were removed and heparinised blood taken for immunological tests. total t-ceils, helper t-ceils, suppressor t-cells, monocytes, and the interleukin receptor were determined by monoclonal antibodies, indirect immunfluorescence, and flow cytometry (facs analyser ). statistical analysis was by the t test on rank transformed data.in group b (isotonic saline) the total t-ceils increased in the blood (p= , ) and spleen (p= , )com pared with the untreated rats (group a), in the groups with peritonitis (c, d, and e) we found highly significant rises in suppressor t-cells in the blood and spleen (both p< , ) compared with the non-infected control groups a and b. this increase was significantly higher in group d than in groups c and e. as well as other alterations, we found a uniform increase in the number of t suppressor ceils in our model of acute peritonitis that was both time and dose dependent, department of surgery, university vienna, akh wien, w~hringer gurtel - , wien. d~'na~'aics of som~ l~mnunologic indices in children with abdo;~tinal shock v.z.i~ioskalenko, s.f.vesiol$,t.v.p~bina serum (iga,:~i,g, circulating imaune co!~plexes, co:apleaentary serum activity, antimesothelialvisceral and parietal antibodies) and cellular (i-l~q~hocytes, ~s/th,b-lyaphoeytes,i nlaunoleukosis to aesothelial allergens; spontaneous blast cell transformation to phytohemaaglutinin and .nesoth<-~lial ~,togen; phagooftic neutrophil activity) im:~une indices v.'ere studied in children operated v:ith symi~to'as of abdo~ainal shock. ,'~!-~ of them had appendicnlar( - ocalized jo-diffuse, -~eneralized) and -hemoperitoni-~is (dull abdominal trau;na with injayy of 'the spleen- , the spleen and liver-q), flo patients tjere operated on for co~iplete iieus (~-intussnsc.sption, -com:lissural ileus). he follo~'~ing serum factors: cireula:;ing im~aune complexes and ~).esothelial antibodies are the aost i~portant ~ar~ers of the abdominal shock course. :yith the progress of the process the indices increase irresponsive of t.l~e cha±.aeter of pathology. in case of ileus regress and hemoperitonotis an abrupt drop in ~he titer of anti~aesothelial antibodies is noted. in bacterial peritonitis a high ~iter of anti:aesothelial parietal antibodies in great dilutions ("+++","++++"-q ; ) persisted even in the period of clinical recovery. cellular factors cham'acterize dfnaaics of the abdominal shock coulees less specifically llast cell transfor~aation and phagocyue neut~ophil activit can inderectly characterize transition of shock f~orn reversible into irreversible phases. the past so years have brought a number of major advances in burn care. the initial advance was the discovery that burn victims required large volumes of resuscitation fluid in the initial hours to maintain hsmodynamic stability, this was followed hy the dsvelopmsnt of topical antimicrohlal agents to prevent end treat infections. next, was the reporting that early excision of burn wounds, with autografting of the excised wounds was possible.finally, was the identification of the importance of aggrsssive nutritional support for the hypermstabolic burn patient.these advances have markedly increaesd survival rates for given burn mimes, s~ch that burns which would previously have been considered to be aniformly fetal, are now readily survivable.thsre remain two unsolved problems in burn care, which are limiting survivability cf burn patients.the first ie ths treatment of inhalation injury. ths sscond is how to obtain coverage of ths maaaivsly burned patient, who has limited skin graft donor sites available.this ssssion will focus on the new treatments being developed to obtain permanent coverage of burn wounds.these include the use of various tcplcal growth £aotore which can speed the rate of reepithelialization of wounds, both the beneficial and dstrimental effects of using cultured karatinooyte preparations, to obtain in excess of one squats meter of a pseudoskin from a single fifteen square centimeter biopsy of unburned skin, will be discussed, finally, the used for artificlal dermal preparations will be discussed. integumentary wound healing consists of simultaneous epithelializalion and contraction. not long ago, it was thought that healing proceeds at an optimum fixed rate and could only be delayed. the recent explosion in molecular biology and recombinant gene techniques have produced information on the biological activity of compounds previously believed to be biologically inert. many current attempts to modulate the rate of wound healing center on the topical application of various growth factors produced by integumentary cells or agents designed to modulate growth factor expression or response. epidermal growth factor (egf), plateiet derived growth factor (pdgf), transforming growth factor (tgf) and fibroblast growth factor (fgf) have been demonstrated, both in vitro and in vivo, to stimulate the proliferation and diferentiation of their designated cells types. egf and pdgf have been clearly demonstraled to increase the rate of wound closure in partial and full thickness wounds. pdgf also has demonstrated efficacy in the closure of recalcitrant pressure sores, whereas tgf increases the tensile strength of incisiona[ wounds and fgf stimulates angiogenesis. it appears that epidermal keratinocyte migration during wound healing depends on integrin-mediated interactions with compounds and ceils extracellular matrix. additionally, the activities of extracellular glycoproteins such as fibronectin, fibrinogen, laminin and thrombospondin are coordinated by multiple integrins with specific distributions and binding affinities. currently, agents which incorporate specific protein sequences essential for the interaction of the glycoproteins with the cells of the extracellular matrix are being investigated. it is has been clearly established that the rate and nature of wound healing can be influenced by the application of various agents and that sufficient quantities of these agents can be manufactured. the future challenge is to develop techniques to now the objective evaluation of the clinical efficacy of these various agents and to employ the appropriate agents in a cost-effective manner. transplantation; and ) the immune status/manipulation of the host.multiple interactive variables will determine the effect of employing allogeneic cells and tissue in wound coverage design and a batter understanding of the dynamics of the wound-graft microenvironment will facilitate the dove opment of clinicauy beneficial graft composites. cadaver allograft skin (cas) is the "gold standard" for wound coverage, but has limitations including varied availability & quality, immunogenicity leading to rejection, & potential for disease transmission. our development of a temporary living skin replacement (tlsr) addresses these issues; the tlsr consists of highly screened human neonatal fibroblasts (hf) cultured in biobrane a, a bilayer dressing consisting of nylon mesh laminated to a thin silicone membrane which controls water-vapor transmission. studies in our lab indicated that "fresw ~ tlsr grafts reproducibly close full-thickness wounds in mice & perform better than bb controls. we studied wound adherence & structural/molecular properties of fresh & cryopreserved (cryo) tlsr. methods: tlsrs were prepared by seeding /co hf in bb nylon mesh in dmem. hf quickly attached to the nylon mesh & were allowed to proliferate - wks. fibroblast mitochondrial activity was assayed by mtt assay. matrix proteins were identified by immunostaining, mrnas for specific growth factors were identified by reverse-transcription polymerase chain reaction amplification, & quantitated by gel scans. bb structure was studied by scanning electron microscopy & stretching measurements pro/post cryo. grafts were cryo'd in % dmso, quick-thawed & sutured onto x cm excised full-thickness dorsal wounds on athymic mice. "fresh" grafts were similarly placed. controls grafts were cas and aeellular bb. adherence was quantitated by a device which peeled grafts from wounds at intervals following placement, using a serve motor and a strain gauge. results: postcryo, storage and subsequent thawing tile tlsrs maintained > % cell viability by the mtt assay, indicating continued mitochondrial activity, and bb structure & stretchability were maintained. multiple matrix proteins secreted and deposited in the bb nylon mesh (types l/iii collagen, decorin, fibroneetin) were identified by specific immunostaining. growth factor mrnas in the tlsrs (afgf, bfgf, kgf, tgf~,p~,) were present in - , x higher levels in fresh/cryo tlsrs than in adult hcs. grafts adhered to wounds on mice through days of followup. histologic exams on days - showed excellent vascular ingrowth and minimal inflammation. adherence of tlsrs to wounds was >cas adherence. burn wound coverage in the massively burned patient remains a difficult problem. although cultured keratinocytes have been utilized for burn wound coverage, their impact on the patient with burns greater than % total body surface area has not been spectacular, with poor graft take and unstable epithelium.current investigations have been directed toward dermal replacement beneath either very thin split-thickness autografts (stag) or utilizing cultured keratinocytes. current products include: collagen dermal replacement with thin stag (burke, et al). collagen dermal replacement with cultured keratinocytes and fibroblasts (boyce, et ai). allograft dermis with cultured keratinocytes (cnno, et al). allograft dermis with thin stag (life cell). polyglactin acid mesh and neonatal human fibroblasts with thin stag (hansbrnngh, et al).investigations regarding culture media, use of growth factors, topical nutrients and antibiotics, and melanocytes for pigmentation as well as safety and efficacy are needed before any of the current products become viable options for coverage of the massively burned patient. the~ is a growing world-wide problem with the ujc of cadaver tissues and ocgans bae, au~ of the tren~m~s~km of dilemma such a; cmutzfeldt.jukob disease and iiiv as we ] as ready availability of urdform lis~ue~. on dec~mt~r , , the fda assumed control of as tissue bar~s in the uldtod st=tea in an attempt to bflng ~s difficult problem of dise~s~ transmission under ¢onlrol. in europe, ~om¢ of the governments are consldofll~ a c~mplcte bat) on the use of cadaverlc fissu~s such as ddn, 'this |ncroam in regulation of cadavefle ~s,quct will incmar¢ the difficulty of obtain~g and dlslflbulmg them. however, thc nc~ for these tissues contlnue~ m incrcaso, we will discuss ~'l¢ solulion to this important pmbl~n: tissue engineering. tlssu~ engineering is an in~rdisdpllnary field that applies pdnclplc~ of angin~edng and die life sclcnce~ reward the development of ~olok~¢al sub~dtute,~ ih= mslom, maintain, or improve tissue function, " ssuc ongln~cdng can provide ~ho nccassary tlssuoa for wound repair ~d ibe assuranoe fl'~t the lissuos are d.ls¢~¢ free. in addition, a ds~uo-cng~ne~n~l wound covering will bo u~lvemally acceptable and evntlublc as "off g~o shell", consis~t products, them are several approaches to restating thls function in a large wound, 'l'nosc i~elud~ tmmcdiete long term coverage, short t=nn coverage, uandtl~el coverage and compost= dssu¢ coverage, "flssuo onglncrcd wound coverings that meet those vaflous ne,.cds will he r~vlowod.cllni~:sl and experimental d~la in venous ulcer, dlabctl¢ ulcers, prossur~ ulcers and bum wounds wgj be mvlcw~, a~ welt as new approacl~s u~ csrtilag¢, bone, liver and bone marrow it~suos. c oomplon, k nadirs, w press, g wetland, j fallen iv, shrtners burns institute and massachusetts general hospital, boston, ma~schusetts, usa the clinical "take" rate o? cultured epithelial autografts (cea) has been observed to increase with transplantation to allodermls, but the reasons for the improved clinical performance have not yet been defined. the aim of this study was to determine the biological impact of normal human dermis on cea differentiation and maturation, biopsies of cea transplanted to engrafted and de-opldermlzed human homograft dermis have been compared to nopsles of cea transplanted to granulation tissue in tullthickness burn wound beds on the same patient, each patient serving as hls or her own control. paired test and control biopstes from six patients have acquired from as early as one week postgrafting to as late as years postgrafting (one patient) and analyzed histopathologlcally, ultrastructurally and immunoh[stochemloally, results demonstrate more rapid normalization of differentiation markers (e,g., involucfln, fllaggrln, cytokeratln profiles) in the cea transplanted to allodermls compared to their corresponding controls by in all patients, the proliferation rate within the basal layer ot the epidermis as determined by ki- (proliferation-associated antigen) is seen to norh~altze more quickly in the cea transplanted to allodermls in every case, persistence of allodermal matrix can be dooumented in all patients by elastic tlssue-trichrome stain, allowing visualization of the dermal elastin network. the popu;atlon densities ot intraepldarmal langerhans cells are conslstently and signlflcantly higher in cea transplanted to ,allodermls, possibly reflectlng an immunologlcal reaction to the underlying allogenlc tissue. overall, these preliminary results indicate that transplantation to a normal human dermal matrix accelerates the maturation of cea-deflved epidermis, wound closure continues to be a major problem in patients who have sustained a major thermal injury, cultured epidermal autografts (cea) have been utilized extensively since when galllco et el reported theh'use in two brothers with greater than % total body surface area burn. unfortunately, cea take rate varies widely and the resultant skin coverage is often fragile and the cosmetic results are less than optimal however the overall take rate and durability of the coverase can be markedly improved by using nn allodermls base as the recipient bed. a review of cea applications performed by physicians using cultured outologens epithelium obtained from blusurfaoe teclmology, inc. shows a marked discrepancy in the results obtained utilizing different methods of wound bed preparation. tgf-b is an important modulator coordinating complex physiological events associated with growth and development. it is assumed that tgf-b is also involved in the well-coordinated process of cutaneous wound healing by regulating proliferation, differentiation, chemotaxis and matrix deposition. the purpose of our study was to analyze the spatial and temporal pattern of tgf-b expression during granulation tissue formation in patients with accidanutl surgical trauma (monotraumata mid polytraumata) and bum wounds. after debridement (day ), the full thickness wounds were covered with epigard, a synthetic dressing until day . after this time the granulated wounds were closed by transplantation of mesh graft. biopsies of the wound center were taken from patients at the beginning of surgical treatment (day ) and after , , and days. cryosections were stained with antibodies against tgf-fi s using the apaap technique and -for standard histology -with hematoxylin-eosin. for identification of the cell type expressing tgf- , double staining immunofluorescence experiments were conducted using antibodies specific for monocytes/macrophages, polymorphoanclear neutropkils and fibroblasts. the results showed a characteristic pattern of tgf-t~ distribution during wound development. tgf-fi appearence was mainly cell-associated znd the absolute and relative number of cells that were positive increased with lime. infiltrating cells and developing blood vessels were most prominently stained; epithelial and t-cells showed no immuno-reactivity. a delay of emergence for tgf-b during the time course could be seen in one patient group. this might reflect various regulation patterns depending on the type and severity of injury.( ) pharmatec gmbh, frankfurt ( ) institut fiir immonologie and serologic, heidelberg ( immune cells extravasating specifically in skin recognize and eliminate the invading antigens (bacteria, viruses, etc.) either in situ or transport them to regional lymph nodes. they also participate in the process of skin wound healing. cells which traffic through the skin can be harvested from efferent lymph drained from a given area of skin. the type of migrating cells changes after trauma, heating and infection. we have developed a method for collection of human afferent lymph in lower limbs. the method allows obtaining immune cells from normal and injured skin and their characterization. aim of the study was to characterize skin immune cells in situ and in skin lymph with use of immunohistological methods (staining, facs). results. group , cells migrating through skin: + % t lymphocytes (cd ), + % langerhans and dendritic cells (cdla, hla dr, s ), + % cd , + % cd , no b cells (cd , ), % cd r (memory cells), + % il r. approximately % cells possessed cdlla and antigens. cd lc was expressed only on large cells. the frequency of all phenotypes was different from the blood populations. group , cells in skin: langerhans cells were found only in epidermis, cd , and , cd r , rb, ila/ cells around venules, cd (macrophages) uniformly dispersed, no il r and b cells. hla dr positive were endothelial and some dispersed mononuclear cells. group , one, three and thirty days after surgical wound (simple varicous vein extirpation): high density of epidermal langerhans cells, hla dr positive keratinocytes and all endothelial ceils, few il r cells, perivenular infiltrates of cd , r but less cd cells, high density of cdlla/ cells. classic staining of isolated and in situ located ccl!s with mgg or he did not allow to follow kinetics of changes. conclusions. this study presents the first in the literature quantitative data of immune cell traffic through normal and injured human skin. in the controlled release of biological response modifiers for soft tissue regeneration. alan s. rudolph, helmut speilberg, mariam monshipouri, and florence rollwagen, and barry j. spargo. we have employed lipid microstructures as controlled release vehicles for the delivery of growth factors in wound repair. traditional liposomes as well as novel lipid based microcylinders have been examined for their in vitro kinetics of the release of transforming growth factor beta (tgf-b). in vitro reiease has been examined by setting up models with examine the physical release of iodinated tgf-b as well as a cell based bioassay (based on the ht bioassay). the hollow lipid microcylinders ( microns in length and i micron in diameter) show an initial burst ( - ng) followed be zero order kinetics which result in the release of approximately i ng tgf/day. this release behavior can be modified by temperature based on the phase behavior of the lipid bilayer which comprises the microcylinder.we have also examined the cellular response to lipid microcylinders applied in vivo. the lipid microcylinders are mixed in agarose and implanted as a composite hydrogel block under the flank of a mouse. the blocks are removed , , and days following implant and the cells analyzed by facs sorter analysis. the observed pattern of ceil recruitment to the blocks mimics that seen in a local inflammatory response. cell surface phenotype studies included the determination of cd and cd , mac-l, and ig bearing cells. we have also begun to examine the change in cell surface phenotype and kinetics of recruitment following the inclusion of tgf-beta in the lipid microcylinders.center for biomolecular science and engineering, code , naval research laboratory, washington, dc. - . expression pattern of heat shock proteins in acute, good healing and chronic human wound tissue. abstract: wound healing is a complex biologic process that is well characterized at the histological level, but its molecular regulation is poorly understood. after clot formation, inflammatory cells are rapidly drawn into the wound, followed by migration of fibroblasts and epithelial cells that divide and repopulate the wound area. during the last decade peptide growth factors and cytokine are thought to play a key role in initiating and sustaining the phase of tissue repair. these factors which are released from different cells appear to initiate the cascade of events that lead to healing. different studys described the rapid activation of a family of proteins,named heat shock proteins (hsp) in differnt tissue that were exposed to various forms of stress (heat, toxic agents, mechanical). in this context hsp's have the ability to regulate protein folding and assembly, to transport proteins across cytoplasm and membranes, to disrupt protein complexes, to stabilize, degrade and regulate the synthesis of proteins and to take part in dna replication and repair. we now attempted to find out if hsp-gene activation is also involved in injury and wound healing, which likewise resemble a stress situation for cells. therefore we collected tissue samples during operation and single biopsies from chronic wounds (decubitus for example) and granulation tissue. after rna preparation from these samples we used rna-pcr and nothern analysis to study the expression of objectives of the study chronic, non-healing cutaneous tflcers are a challenging clinical and socioeconomic problem. several animal studies have shown that cytukines (e.g. egf, pdgf, fgf, tgfb) accelerate the healing process and tissue repair in general. results from first clinical trials indicate a promising value of cytokines in the treatment of chronic non-healing diabetic and venous ulcers. recent reports in the literature indicate that the biological activity of the solution of platlet derived wound healing formula (pdwt~) released from c~-granules (mainly pdgf & tgfi~) is greater than the activity of the recombiant single factors like e.g. pdgf-bb (robson, lancet ) . the aim of our study was to determine whether a correlation exits between the concentration of tgfi~ & pdgf and the time course of wound healing. materials and methods pdwhf was prepared from ml of auto]ogous patient blood and diluted with a special buffer to a final concentration of ng/ml g-thromboglobulin. the concentrations of pdgf and tgfg were determined by elisa-tests developed in our laboratory. patients with chronic non-healing ulcers have been evaluated alter treatment by topical application of pdwhf. pdfg and tgff~ concentrations of the topical solution were measured and two patient groups formed for analysis the time course of wound healing was regularly and meticulously documented and evaluated by photography and casting. the time from initiation of treatment instil o wound volume reduction to go of the origional size (t %) was noted• results: healing of extensive burn wounds can be accelerated by grafting cultured autologous or allogeneic keratinocytes. the stimulation of granulation tissue formation and reepithelialization is presumably based on growth factors and cytokines released by keratinocytes. we wanted to prove this hypothesis by investigating the bfgf expression during wound development, bfgf is mainly described as an angiogenic protein with mitogenic activity on various mesodermal and ectodermal cell types pointing to its stimulating potential in wound heating. in the present study we compared the pattern of human bfgf m-rna expression and the localization of bfgf protein during the first days of wound healing. biopsies were taken from juvenile human bum patients, immediately after wound debridemerit mad on day after transplantation of cultured allografts. biopsies were snap frozen and cryosected. the pattern of bfgf expression was assessed by in situ hybridization of the bfgf m-rna with a digoxigenin-labelled antisense-rna and the parallel detection of the mature protein with an anfi-bfgf monoclonal antibody. our study revealed typical patterns of bfgf-m-rna-expression and intense bfgfprotein deposition during granulation tissue formation and reepithelialjzation of healing bum wounds. 'it, is known that major thermal injuries cause early impairment of wound healing followed by decreased influx of granuiocytes st. the site of injury. the role of granuiocytes in the process of wound healing is not ~"~ "" elucidated, it is now assumed that they are not merely phagocytic cells but active participants in ~n~*' ~.,.,a+~o~: processes secreting_ a number of various cvt-;kines, in order to investigate the effect of there is accumulating evidence that neuropeptides could be involved in the pathogenesis of several inflammatory reactions. vasocactive intestinal polypeptide (vip) and substance p (sp) have been detected by immunohistochemistry in normal as well as inflammed skin mostly in perivascular and periglandular location. both vip and sp are involved in vasodilatation, mast cell degranulation and irnmunomodulation.we determined the influence of sp and vip on the proliferation of lymphocytes in patients with psoriasis and healthy individuals. peripheral blood t-lymphocytes of psoriatics and healthy controls were isolated by density gradient centrifugation and passage over nylon wool. cell enrichment was controlled by facs analysis, lx t-lymphocytes were then incubated alone or in coculture with x irradiated autologous lymphocytes in culture medium containing - mol/i sp or vip. cell proliferation was measured semiquanfitatively by tdr uptake in a betacounter. significance was tested by the wilcoxon signed-rank test.our results show that sp and vip exert only an effect on unstirnulated t-cells. in healthy individuals but not in patients with psoriasis sp increases significantly proliferation of t-cells. vip, however stimulates significantly the blastogenesis of t-lymphocytes only in psoriatics.our results confirm the psychoneuroimmunologic component in inflammatory reactions and vip and sp could be partially implicated in their pathogenetic mechanisms. moreover psoriatic lymphocytes show an altered reaction to sp and vip. this might be due to a preexisting (genetic?) or more likely to an epiphenomenal receptor defect. the adhesive interactions between endothelial cells and circulating ~enkocytes in shock and innammatory vondltions is mediated by several distinct families of ce -surface determinants. of particular importance are the leukocyte integrins cdib / cdlla-c. in this study monoclonal antibodies to two of the u chains (cdlla & cdiib) and the common [~ chain (cdib) have been used to investigate leukocyte-dependent and leukocyte-independent plasma leakage in tee skin of rabbite. plasma leakage was measured as the local accumulation of t si-hsa over a rain period, the chemotac~c peptide imlp ( . . ng) and bradykinin were used to induce cell.dependent and cell- ndependent leakage respectively, the antibodies used were . e (cdis), nri (cdlla) and antibody (cdllb). ]ntradermal in~ections of bradyklnin and ~dlp both caused a dose dependent increase in plasma extravasatien ( .~. ffi . p.l to . z b.bttl and . ,- . ~ to . z . d respectively. . e ( . - . mf,/k~ iv) caused a dose dependent inhibition of imlp-induced but not bradyldnin.inducecl plasma exudation. at . mk/kg, the plasma leakage was completely inhibited, antibody nr produced similar results, treatment with antibody did not cause inhibition o£ plasma leakage due to either tnedi~tor. in vitro, the irmnune system ex~nination in persons with bone, chest and abdominal traumatic injury (i group . patients without infectious coz~lications and group - patients with wound infections development) was carried out. to restore found immunity disorders and host defense to infection patients of the group were treated with thymalin-the biologically active peptides prepared from bovine thymus. the examination on t~e i- days after injury revealed a considerable decrease of lymphocytes, ed ",$d ~ and cd cells amo~it in the blood, cd /cd ratio and indexes of let~ocyte migration inhibition test in both groups of patients. the imm~lity disorders recovered to norm on the - days in pateents of+the i group. but stable ~eple$ion of cd and cd cells amount, lower cd /cd ratio and indexes of leukocyte migration inhibition test in patients of the group were observed~ besides that, these persons showed higher cd cells amount and ig level in the blood. after thymalin therapy valid ii~rovement of inun~e status was discovered. also good clinical effect of immunotherapy and best wo~id healing observed in % of cases. these results allow us to propose that the thymus involution and the reduction of cell-mediated immunity responsiveness with disturbances of immu_uoregulatio~ on the level of restriction of activated cd tho cells play the most important role in the pathogenesis of wound infections development in persons with traumatic injury.dept. of immunology, military-nedical academy, lebedeva str. , , st.petersburg, russia a severe impairment of neutrophil (pmn) function often occurs following severe thermal or non-thermal traumatic injury. our laboratory has previously reported that following severe burn or non-burn traumatic injury the expression of the p integrlns (cd a,b,c/cd ) and the fw receptors (cd , and cd ) were significantly decreased on pmns, in this study, the effects of gm and g-csf on the expression of the f~ r and the ~ integrln family on pmns were examined, pmns were obtained from severe trauma (initial apache ii score ;z ) or thermal injury (> ~; total body surface area, > ~ full thickness) and incubated /n v/tro with gm or g-csf. the j integrins or fcyr were detected with monoclonal antibodies and flow cytometry. gm end g-csf induced a sllght increase in the percentage of pmns expressing cd lb, cd , and cd while gm bur not c-csf induced an increase in the percentage expressing cdi a, cd lc, and cd , gm-csf and to a lesser extent g-csf induced an increase in the density ( , fold) of the ~ integrlns on pmns from normal, burn, and trauma patients, these data suggest that cytoklne modulation with csfs could have a role clinically in certain situations. institute, dept. of surgery, bethesda ave, cincinnati, oh, usa, - . funl~al infections after solid organ transplantatlon(sot) lewis flint, md and ed,~-afd e. etheredge, me) dept. of surgery tullrte univ. school of medicine new orleans. louisiana infections contribute to increased gra loss and mortaliw following sot. pr~isposing facton include diabetes, hepatitis, leukopenia, cc.¢xistem infection, and intense, especially triple drug, immunosuppression. funga] infections occur ~s isolated conditions in % and in association with bacterial infection(l %), viral infection( */.), and combined infections(it%), candida sp. is the most common fungus recovered but aspecgillus, coccidiodies, cryptococcus, histoplasma, mueor~ ghizopus, tinea, and toruiop~is s?. also are pathogens. clinical syndromes vary among orga.aizms or may be variable with a single p~tthogen, for ~ample, with aggressive immunosuppression, candlda my be localized esophagitis or cystitis or systemically iavaslve with an associated high mortality. aspergilius presents ~ a diffuse pneumonia while cryptococcus causes pulmonary and centrad nervons sy'stem infection, clinical examination, ct scanning and aggressive sampling for c'ultures a.s wall as serologic tests contribute to diagnosis. empiric the~py is ind',cated where there is a high level of suspicion. preventlon of ca.adlda izfection is ~ci~itated by early remov-a. of central }ants, ca~hetess and stents as well as by the use of oral nystatin. amphotericin ]~ remains the drug of choice for treatment of in.save fungd infection, surgical resection of infectious loci in the lung and brain is indicated in selected patients. the main problems of diagnosis in lower respirator-), tract infection are the differentation of infection from colonization or contamination, and the isolation of a reliable and true pathogen. expectorated sputum may be unreliable in pneumonia, because of contamination by oropharyngeal flora. although blood cultures may be negative, they provide a precise diagnosis and should be obtained in all pneumonias. other more invasive procedures are transtracheal needle aspiration, fibrobronchoscopic techniques including protected specimen brush and bronchoalveolar lavage with quantitative culturing and cytological analysis, transthoracic needle aspiration, thoracoscopy -guided biopsy and open lung biopsy. recently m. e -ebiary, a. torres et al, reported quantitative cultures of endotracheal aspirates for the diagnosis of ventilator-associated pneumonia offering reliable results in these patients and should be further investigated. any invasive procedure in a severely ill patient should be carefully directed weighing the risks as well as the benefits, whilst taking the underlying diseases and expected survival into consideration. -current therapeutic approach is based mainly on monotherapy with broad spectrum antibiotics. combination therapy is apparently indicated only in p. aeruginosa infections and severe s. aureus pneumonia. graft infection can lead to fulminant graft failure or rapid progressive cirrhosis. for prevention of graft infection immunoprophylaxis, i,e. administration of human polyclonal anti hbs hypedmmunoglobutin (hig), starting in the anhepatic phase during operation, has proved to be at least partially succesful when performed on a long term basis.from a total of olt in adult patients olt were performed for hbsag positive liver disease (cirrhosis n= , fulminant liver failure n= , retransplantation n= ) in pat. all pat. received . u hig in the anhepatic phase and . u/per day for the first week. a small group of pat. received hig only for i week (short term immunoprophylaxis), in all other pat. hig is administered on a long term basis to keep anti hbs serum levels above uii or until graft infection occurs (long term immunoprophylaxis);one-year survival rates are % in pat. who were transplanted for fulminant hepatitis, % in pat. with cirrhosis and long term prophylaxis, and % ir~ pat. with short term prophylaxis. all fatalities were related to hbv graft infection. the total rate of graft infection was % under short term prophylaxis and was independent from preoperative hbv dna status, under long term prophylaxis graft infection occurad in % in pat, negative for hbv dna. in hbv dna positive pat. infection rate was %, the total rate of reinfection for all pat. with long term prophylaxis was %the results of liver transplantation in hbsag positive pat. are comparable to other indications, graft infection with hepatitis b virus ist the major risk factor for these patients. under long term therapy with hig the rate of graft infection can be significantly reduced. the crucial cellular element for mods-mof: monocyi'f_./m acrophaoe ronald v. meier, m,d., f.a,c,s. the severely :injured or crldcally ill surgical patient is at high risk for immune dysfunction. a major consequence of this immune dysfunction is multiple organ dysfunction and failure leading to death, the underlying etiology is now recognized to be an uncontrolled, unfocused, disseminated activation of the host normally protective inflammatory. ,, cascades.. the resultant "mahgnant' systemic" inflan'a'natlon produces d~ffuso multiple organ bystander injury !eading to progressive organ dysfunction and failure. systemic malignant inflammation involves diffuse actlvatton of all components of the humoral and cellular inflammatory host response. of these various components, the macropha~e is the crucial central cellular element. the tissue fixed macrophage is ideally located diffusely throughout the various organs injured to orchestrate the inflammatory process. the macrophage is long-lived and highly metabolic, the macrophage regulates both the extent and the dissemination of the inflammatory processes. the macrophage is an exu'emely active c¢ capable of producing and releasing not only directly eytotoxlc agents, s irnil~, to the neutrophil, including oxidants and numerous proteases out also the multitude of other cytokines and initiators of the interacting inflammatory cascades. the macrophage is the central source for ehemotactic agents (il- , ltb , c a) for neutrophils and other inflammatory cells, production of vasoaetive arachidonie acid metabolites (tx, pgi , poe, lt's), complement components (c a, csa), thrombotic agents (pca, tx), metabolic and physiologic modulators (il, , il- or tnf), and immunosuppressivc agents (poe , il- ). these products of the macrophage are highly effective in enhancing and augmenting the inflammatory response. disseminated activation otthe macrophage is critical to the induction of the long-term diffuse activation of inflammation necessary to induce multiple organ injury and failure. our ability to elucidate the molecular mechanisms that control the macrophage will lead to our ability to conu'ol the maerophage response and prevent mods-mof.flarborview medical center, - th ave za- , seattle, wa usa key: cord- -o hr mox authors: nan title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: o hr mox nan rationale: expiratory muscles has recently been stated as the «neglected component» in mechanically ventilated patient. several authors stated these muscles importance in cough capacity, contractile efficiency of the diaphragm or reduction of hyperinflation. however, few studies reported potential factors leading to expiratory muscle weakness and its importance on weaning success or survival after mechanical ventilation. patients and methods: this study is a secondary analysis of our previously described cohort of patients ventilated for at least h assessed for respiratory muscles function. maximal expiratory pressure (mep) measurement was carried out during spontaneous breathing trial using a manometer with an unidirectional valve. mep diagnostic accuracy to predict icu-aw (icu acquired weakness), weaning success and sursvival within days were assessed using expiratory muscle strength as absolute values (cmh o), as %predicted values and as %lower limit of normal. results: due to the paucity of data reporting threshold value for expiratory muscle weakness, we considered our median value ( cmh o (iqr )) as the threshold value for expiratory muscle weakness group (mep ≤ cmh o) and normal expiratory muscle group (mep > cmh o). patients with low mep received more catecholamines (p = . ) and a higher duration of mechanical ventilation (p = . ). inversely, higher body mass index was associated with higher mep. patients with low mep presented more icu-aw compared to normal mep patients ( % vs. %; p = . ). no other outcomes were different between groups. mep was statistically able to predict icu-aw but area under (auc) receiving operating curves showed weak predictive ability (auc: . ( % ic . - . ; p < . ) for a threshold value ≤ cmh o. expiratory muscle weakness was unable to predict critical outcomes when adjusting mep to the %predicted or lower limit of normal. discussion: possible explanation is that contrary to inspiratory muscle weakness, cough inefficacy after weaning from mechanical ventilation could be managed with cough supplementation techniques (i.e. mechanical in-exsufflation). conclusion: in our cohort, mep was not associated with mechanical ventilation weaning or death. despite our results, different clinical techniques for quantifying expiratory muscle weakness may provide more beneficial results. compliance with ethics regulations: yes rationale: venoarterial extracorporeal membrane oxygenation (va-ecmo) is used to support tissue perfusion during extracorporeal cardiopulmonary resuscitation (e-cpr). shock, resuscitation and the extracorporeal circuit may trigger a capillary leakage and a vasoplegic shock. currently, in these situations, high doses of norepinephrine (ne) are required. because high ne doses may have significant cardiovascular side effects, alternative options to support arterial blood pressure are needed. in recent years, several approaches to decrease the administration of high ne doses have been tested, one of them is the administration of vasopressin (avp). randomized trials have shown that avp infusion increases arterial pressure and systemic vascular resistance, decreases catecholamine requirements in patients with or at high risk of vasoplegic syndrome and attenuates vascular dysfunction. currently, no data are available for the study of the effects of avp in shock state in post refractory cardiac arrest. patients and methods: pigs were randomized into two groups, in order to receive avp or ne. a refractory cardiac arrest of ischemic origin was surgically created and va-ecmo was started after a min period of cardio-pulmonary resuscitation. then, resuscitation lasted h in each randomization group. the evolution of the consequences of the shock was evaluated by lactatemia and microcirculation (sdf and nirs) at baseline hour, h (when ecmo starts), h and h . renal and hepatic functions were assessed. results: experimental conditions were met for animals (avp, n = ; ne, n = ). the groups were comparable on the shock impact and its severity. no significant differences were found between populations for ecmo flow and map. there was a significant difference on fluid volume resuscitation amount ( [ . - . ] ml in the ne group versus ml in the avp group, p < . ) (fig. ). no significant difference between the ne and avp groups for lactate clearance between h and h ( . [− . to . ]% vs . [ . - . ]%, p = . ). we did not find any significant for sublingual microcirculation indices and nirs values. renal and liver function evolution were similar in the two groups during the protocol. conclusion: avp administration in refractory cardiac arrest resuscitated by va-ecmo when compared to ne is associated with less fluid volume for similar global and regional hemodynamic effects. compliance with ethics regulations: yes. patients and methods: a single-center prospective study. patients younger than months with severe bronchiolitis and supported by niv or hfnc were included. niv/hfnc was discontinued according to the local practices and no protocol existed. exceptt the principal investigator, the attending team was blinded to the study. weaning failure was defined as the need to reinstate niv/hfnc in the h after discontinuation. ethical approval was not necessary for this study in accordance with the french data protection autority methodology reference number mr- . results: a total of patients (median age days, ( %) males) were included. respectively, ( %) and patients ( %) were supported by niv and hfnc at admission (fig. ) . regarding the mode of niv, a bilevel mode was used in patients ( %) (fig. ). in patients supported by hfnc, the ventilatory support was discontinued progressively by decreasing air flow in patients ( %) while it was stopped abruptly in ( %). in patients supported by niv, the respiratory support was stopped abruptly in ( %) of them while hfnc was used as a weaning method for ( %) patients. a total of ( %) patients experienced a weaning failure. patients supported by niv/ hfnc who experienced a prompt weaning had a lower pediatric intensive care unit (picu) length of stay as compared to patients in whom hfnc was used as a weaning method ( ± h versus ± h, p = . ). however, the hospital length of stay was similar according to the weaning method ( ± days versus ± days for prompt and progressive methods respectively, p = . ). the duration of the weaning process did not differ according to the bed-availability in picu. in patients with severe bronchiolitis, a prompt weaning from niv/hfnc was associated with a lower length of stay in picu. however, the hospital length of stay was similar according to the weaning method. we suggest that a prompt weaning should be preferred in order to reduce the risk of picu related complications. compliance with ethics regulations: yes. information and incitation to open a twitter account and to follow critical care journal feeds) or group (control group). ict were interrogated on their recent medical literature knowledge at and month on trials published in pre-selected journals. results: during the study period, on the french ict contacted, agree to participate: were already on twitter, were randomized to twitter incitation and to control group. at month, there were who answered electronic questionnaire. self-declaration of article knowledge was not different between groups (p = . ). knowledge of primary outcome of each trial was not significantly better in groups (p = . ). in per-protocol analysis of ict on twitter or not, knowledge of article and primary outcome were also not significantly different (respectively p = . and p = . ). short incitation to open a twitter account and follow major medical journals with specific focus on cardiac arrest did not improve knowledge of medical literature by intensive care trainees at month. further trials are needed to better imply intensive care trainees in scientific medical literature. compliance with ethics regulations: yes. - . ] ; p = . ) as independently associated with in-hospital mortality ( fig. ). discussion: triple therapy is the recommended first-line treatment of caps. however, herein, it was not significantly associated with better survival in critically ill, thrombotic aps patients. for the subgroup of "definite/probable caps" patients, double and triple regimens were associated with survival. but the bivariable analyses including the day- saps ii showed that survival was linked to in-icu anticoagulation and corticosteroids-not ivig or plasmapheresis. our findings indicate that corticosteroids should probably be added to in-icu anticoagulation to treat "definite/probable caps". frequent fever and elevated c-reactive protein in all thrombotic aps patients suggest a marked inflammatory state that could explain corticosteroid efficacy. neither plasmapheresis nor ivig impacted the prognosis of "definite/ probable caps", but that finding could be explained by a lack of power compared to caps registry data. conclusion: in-icu anticoagulation was the only aps-specific treatment independently associated with survival for all patients. doublebut not triple-therapy was independently associated with better survival of "definite/probable caps" patients. in these patients, double therapy should be used as first-line therapy while the role of triple therapy requires further evaluation. compliance with ethics regulations: yes. motor deficiency ( %) ( %) ( %) . cognitive impairment ( %) ( %) ( %) . intra-individual relationships between Δpdi and tfdi for mechanically ventilated (mv) patients (a) and healthy subjects (c). relationships between Δpdi and tfdi when breathing cycles were averaged for all participants during each condition for mv patients (b) and healthy subjects (d). − %: initial settings minus % inspiratory help, + %: initial settings plus % more inspiratory help, pep : zero positive end-expiratory pressure, sbt: spontaneous breathing trial. healthy subjects performed spontaneousbreathing (sb) and ventilation against inspiratory threshold at , , , and % of maximal inspiratorypressure (mip) groups. airway closure occurrence increased with bmi ( %, % and %, p = . ). when present, airway opening pressure was . cmh o ( . - . ) and similar between the groups. with increasing bmi, total peep increased from . to . cmh o between groups (p = . ). all values of esophageal pressure increased with bmi. endexpiratory esophageal pressure was strongly correlated with bmi (rho = . , p < . ), as illustrated in fig. . consequently end-expiratory transpulmonary pressure decreased from − . to − . cm h o with increasing bmi (p = . ). the ratio of eelv to predicted functional residual capacity was negatively correlated with end-expiratory pressure (rho = − . , p = . ), but not with bmi. driving pressure and elastance of the respiratory system, chest wall and lung were similar across all ranges of bmi. likewise, eelv was similar between groups. conclusion: in ards, increasing bmi is associated with increased occurrence of airway closure and increased values of esophageal pressure. conversely, chest wall elastance is not influenced by bmi, as well as lung elastance. including bmi in interpreting respiratory mechanics in ards patients can provide additional information for the clinical management. compliance with ethics regulations: yes. rationale: low tidal volume is the cornerstone of protective ventilation inthe initial phase of ards ( ) . whether such low tidal volume can still be achieved when the patient is allowed to breathe spontaneously under pressure support ventilation (psv) is unknown. in moderate-tosevere ards patients receiving neuromuscular blockade, we assessed the tidal volume and its potential association with the outcome during the "transition period" following neuromuscular blockade. patients and methods: retrospective observational study in two university intensive care units. patients fulfilling moderate-to-severe ards criteria less than h after intubation and receiving neuromuscular blockers were included upon entry in the "transition period". we defined the "transition period" as the h following neuromuscular blockers cessation. ventilatory and hemodynamic parameters were recorded every h during the "transition period". primary outcome was the association between mean tidal volume under pressure support ventilation (psv) during the "transition period" and the -day mortality after adjustment for confounding factors. data are reported as median [ st- rd quartile] or number (percentage). results: one hundred nine patients were included, with a pao /fio ratio of mmhg at intubation and mmhg at inclusion and a sofa score at [ . - ] . patients had been ventilated days [ - . ] before inclusion. during the "transition period", patients ( . %) were switched to psv. the median duration of psv was h . the mean tidal volume under psv was significantly lower in survivors than in non survivors at day ( . ml/kg [ . - . ] vs. . ml/kg [ . - . ] respectively, p = . ). by multivariate analysis (cox proportional hazards regression model), mean tidal volume during psv remained independently associated with the -day mortality after adjusting for sofa score and immunosuppression. patients with a mean tidal volume above ml/kg under psv during the "transition period" had a lower cumulative probability of survival at day as compared with others (log rank test, p = . ) (fig. ) . conclusion: in patients with moderate-to-severe ards, a higher tidal volume under psv within the h following neuromuscular blockers cessation is independently associated with the -day mortality.compliance with ethics regulations: yes. kaplan-meier estimate of the cumulative probability of survival according to the mean tidal volume (vt)-lower of higher than ml/ kg-under pressure support ventilation (psv) during the "transition period" transfusion is associated with adverse events, and equipoise remains on the optimal transfusion strategy in oncologic patients in surgical setting. patients and methods: this is a retrospective, single center study. all adults admitted to the intensive care unit (icu) after oncologic surgery from january to december were eligible. the following types of surgery for cancer or metastasis resection with a high risk of bleeding were eligible: thoracic, abdominal, neurosurgery, gynecologic, urologic, otorhinolaryngology or spinal surgery. the primary outcome was a composite outcome including post-operative complications (respiratory, cardiac, renal, thromboembolic, infectious and/or hemorrhagic) and/or hospital mortality. results: of the patients included, patients ( . %) had anemia (based on the who definition: hemoglobin level - . g/dl for female; hemoglobin level - . g/dl for male), patients ( %) had moderate anemia (hemoglobin level: - . g/dl) and patients ( . %) severe anemia (hemoglobin level < g/dl). fifty-six patients ( . %) received at least one rbc transfusion during their hospital stay. patients exposed to moderate and severe anemia required more often renal replacement therapy (rrt) for acute kidney injury (aki) ( . % vs. . %; p = . ), had more surgery-related infections ( . % vs. . %; p = . ). patients who received rbc had more often aki with rrt ( . % vs. . %; p < . ), thromboembolic events ( . % vs. . %; p = . ), sepsis ( . % vs. . %; p = . ), pneumonia ( . % vs. . %; p = . ), surgical site infections ( . % vs. . ; p < . ) and second surgery for infection ( % vs. . %; p = . ). the multivariate analysis found an association between moderate and severe anemia (moderate anemia: or . [ . - . ] ; severe anemia: or . [ . - . ]; p = . ) and severe post-operative complications (fig. a) . there was also an association between rbc transfusion and severe post-operative complications ]; p < . ) (fig. b) . conclusion: anemia was frequent in oncologic surgical patients. anemia, including moderate anemia, was independently associated to patient outcomes; however, rbc transfusion also negatively impacts on patients' prognosis. our study highlights the need for further research to identify the optimal hemoglobin threshold for rbc transfusion in surgical oncologic patients. compliance with ethics regulations: yes. rationale: right ventricular (rv) failure is a common complication in moderate to severe acute respiratory distress syndrome (ards). rv failure is exacerbated by hypercapnic acidosis and overdistension induced by mechanical ventilation. veno-venous extracorporeal co removal (ecco r) might allow ultraprotective mechanical ventilation strategy with a low tidal volume (vt) and plateau pressure (pplat). this study investigated if ecco r therapy could have beneficial effects on rv function. patients and methods: this prospective monocentric pilot study was conducted in a french icu from january to march . patients with moderate to severe ards with pao /fio ratio between to mmhg were enrolled. ventilation parameters, arterial blood gases, echocardiographic parameters performed by transthoracic echocardiography (tte), low-flow ecco r system operational characteristics, outcomes and adverse events were collected during the protocol. primary end point was evolution of rv echocardiographic parameters with ultraprotective ventilation strategy at ml/kg pbw during the -h following the start of ecco r. results: eighteen patients were included. efficacy of ecco r allowed an ultraprotective strategy in all patients. we observed a significant improvement of rv systolic function parameters assessed by tte (fig. ). tricuspid annular plane systolic excursion (tapse) increased significantly under ultraprotective ventilation compared to baseline (from . to . mm; p < . ). systolic excursion velocity (s') also increased after -day protocol (from . m/s to . m/s; p < . ). a significant improvement of aortic velocity time integral (vtiao) under ultraprotective ventilation settings was observed. there were no significant differences in the values of systolic pulmonary arterial pressure (spap). when patients were separated in two groups according to baseline paco level above or under mmhg, we showed the deleterious effect of hypercapnia on rv function, and observed in both groups a beneficial impact of an ultraprotective ventilation strategy on tapse. no severe adverse events directly related to ecco r were observed in our small cohort. conclusion: the low-flow ecco r allows ultraprotective ventilation strategy and improve rv function in moderate to severe ards patients. similarly to prone positioning, ecco r could become a strategy that enables to reconcile lung protective approach with rv protective approach in ards patients. large-scale clinical studies, including patients with severe rv dysfunction, will be required to confirm these results and to assess the overall benefits, in particular the best timing of beginning ecco r in ards patients. compliance with ethics regulations: yes. rationale: bronchoalveolar lavage (bal) is usually deemed to allow the diagnosis of a large array of pulmonary diseases and is usually considered as well tolerated in intensive care unit (icu) patients. however, recent data suggest that the diagnostic yield of bal could be rather low ( ) , and may question its innocuity ( ) . the present study aimed at assessing the benefit-to-risk balance of bal in icu patients. patients and methods: the study was approved by the appropriate ethics committee and registered with clinicaltrials.gov (nct ). in icus, from april to october , we prospectively collected adverse events (ae) during or within h after bal and assessed the bal input for decision-making in consecutive adult patients. aes were categorized in grades of increasing severity. the occurrence of a clinical ae at least of grade , i.e. sufficiently severe to need therapeutic action (s), including modification (s) in respiratory support, defined poor bal tolerance. the bal input for decision-making was declared satisfactory if it allowed to interrupt or initiate one or several treatments. results: we included bal in patients (age yrs ; female gender: [ . %]; simplified acute physiology score ii: ; immunosuppression [ . %], chronic pulmonary disease [ / ( . %)]). bal was performed either in non-intubated patients receiving standard o therapy (n = [ . %]), or noninvasive ventilation (n = [ . %]), or high-flow nasal cannula o therapy ( [ . %]), or in patients under invasive mechanical ventilation (n = [ . %]). a total of aes were observed in ( . %) patients. sixty-seven ( . %) patients reached the grade of ae or higher. the main predictor of poor bal tolerance identified by logistic regression was the association of a bal performed by a non-experienced physician (non-pulmonologist, or intensivist with less than years in the specialty or less than bal performed) in non-intubated patients (or: . [ % confidence interval . - . ] ; p < . ). ordinal regression also showed that when bal was performed by a non-experienced physician in a non-intubated patient, this was associated with an increased risk of ae of any grade (or: . [ . - . ]). a satisfactory bal input for decision-making was observed in ( . %) cases and was not predictable using logistic regression. conclusion: adverse events related to bal in icu patients are frequent, and sometimes serious. our findings call for an extreme caution when envisaging a bal in icu patients and for a mandatory accompaniment of the less experienced physicians. compliance with ethics regulations: yes. meningitis is a rare complication of critically ill patients with severe pneumococcal community-acquired pneumonia paul jaubert, julien charpentier, jean-daniel chiche, frédéric pene, alain cariou, guillaume savary, marine paul, jean-paul mira, mathieu jozwiak cochin, paris, france; mignot, versailles, france correspondence: paul jaubert (paul.jaubert@gmail.com) ann. intensive care , (suppl ): rationale: severe pneumococcal community-acquired pneumonia (pcap) is a frequent infection requiring intensive care unit (icu) admission. pneumococcal meningitis associated with pcap has been reported and could worsen the prognosis of patients. however, this complication is difficult to predict and lumbar puncture is not systematically performed, regardless the severity of pcap. thus, we investigated the characteristics of patients with pcap associated with pneumococcal meningitis. patients and methods: we retrospectively included all patients admitted for pcap in our icu between (inception of our electronic medical sheet) and the end of . community-acquired pneumonia was defined according to the criteria of the american thoracic society. we excluded all patients admitted in icu with initial suspicion of meningitis. variables regarding epidemiology, clinical and microbiological characteristics, management and prognosis of these patients were collected and analyzed. results: among the patients admitted for pcap ( ± years old, saps ii ± , % of men), % of the patients required mechanical ventilation and % vasopressors infusion. the icu mortality was %. s. pneumoniae was documented by a positive antigen test in % of the patient and/or by a positive sputum smear, tracheal aspirate or distal protected airway specimen in % of the patients, and/or by pleural aspirate in % of the patients and/or by positive blood culture in % (n = ) of the patients. a lumbar puncture was performed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia, with a median delay of h [interquartile range: after the onset of antibiotherapy. alllumbar punctures (n = ) were performed for neurological signs: % of coma, % of confusion and % of seizures. when a lumbar puncture was performed, meningitis was diagnosed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia (p < . ). the icu mortality ( % vs. %, respectively), age ( ± vs. ± years old, respectively), saps ii ( ± vs. ± , respectively) or icu length of stay ( ± vs. ± days, respectively) were not different between patients with and without meningitis (each p = ns). conclusion: meningitis is a rare complication of pcap and is more frequent in patients with bacteriemia. suprisingly, meningitis is not associated with higher icu mortality. further analyses are ongoing to identify independent risk factors of meningitis in patients with pcap. compliance with ethics regulations: yes. rationale: shock is the clinical expression of a circulatory failure that results in inadequate cellular oxygen utilization. whereas the host response to septic shock has been extensively described, knowledge of the pathogenesis of non-septic shocks remains limited. we aimed to characterize the systemic host response in shock related to non-septic conditions (nssh) as compared with septic shock (ssh). patients and methods: we performed a prospective study in two intensive care units (icus) in patients admitted for ssh (n = ) or nssh (n = ). immune responses were determined upon icu admission by measuring plasma biomarkers reflecting host response pathways implicated in the pathogenesis of critical illness (in ssh and nssh patients), and by applying genome-wide blood mrna expression profiling (in ssh and nssh patients). results: compared with nssh, patients with ssh had more chronic comorbidities, greater disease severity (apache iv score vs. , p < . ) and worse outcomes resulting in higher mortality rates up to one year after icu admission ( . % vs. . %, p < . ). plasma biomarker analysis revealed severely disturbed host responses in both ssh and nssh patients. however, ssh patients displayed more prominent inflammatory responses, endothelial cell activation, loss of vascular integrity and a more pro-coagulant state relative to nssh patients. blood leukocyte genomic responses were more than % common between ssh and nssh patients relative to health (fig. a) , comprising overexpression of innate pro-and anti-inflammatory pathways, and underexpression of lymphocyte and antigen-presentation gene sets. direct comparison of ssh to nssh patients matched for severity (fig. b) showed overexpression of genes involved in mitochondrial dysfunction and specific metabolic pathways, and underexpression of lymphocyte, nf-κb and cytokine pathways. conclusion: patients with ssh and nssh present with largely similar host response aberrations at icu admission; however, patients with septic shock show more dysregulated inflammatory and vascular host responses, as well as specific leukocyte transcriptome alterations consistent with greatermetabolic reprogrammingand more severe immune suppression. compliance with ethics regulations: yes. rationale: aki is associated with short and long term mortality and morbidity. although recovery has been demonstrated to be associated with outcome of critically ill patients, interpretation of available data is limited by time dependent nature of recovery and by competing risks. our objective was to describe renal recovery, pattern of recovery according to adqi definitions and risk factor of this later. monocenter retrospective cohort study. adult patients admitted in our icu from july to december were included. aki was defined according to kdigo criteria and recovery according to adqi definition. incidence of recovery at each time point was depicted using competing risk survival analysis. risk of transition between aki and no-aki was assessed by a semi-markov model. last, a trajectoire analysis was performed to depict most frequent recovery patterns. results are reported as n (%) or median (iqr). results: patients were included with a median age of ( - ). median sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] . at icu admission, patients ( . %) had an aki stage , patients ( . %) an aki stage and patients ( . %) an aki stage . according to adqi criteria, aki was defined as rapidly reversed in patients ( . % of aki patients), persistent aki in patients ( . %) and as acute kidney disease (akd) in patients ( . %), remaining patients couldn't be classified (n = ). risk of recovery was of % per day until day then % per day (fig. a) . fine and gray model, taking into account death as competing risk, identified risk factors negatively associated with renal recovery, namely sofa score (shr = . per point; % ic = [ . - . ]), preexisting hypertension (shr = . ; % ic = [ . - . ]) and aki severity (stage vs. stage shr = . ; % ic = [ . - . ]). risk of de novo aki was maximal during the first days and ranged from to % per day. trajectoire model identified clusters of patients ( fig. b) , closely associated with patients' outcome: a) low patients' severity and no or mild aki (n = ; hospital mortality: %); b) moderate to severe aki but little associated organ dysfunction (n = , hospital mortality: . %); c) severe aki and multiple organ failure (n = ; hospital mortality: . %). conclusion: this study, assessing aki recovery patterns, is the first to our knowledge using adqi definition. despite the high rate of early recovery and of rapidly reversed aki, up to % of aki patients had not recovered at day and could therefore be classified has having akd. compliance with ethics regulations: yes. rationale: sepsis is the most frequent cause of acute kidney injury (aki). the "acute disease quality initiative workgroup" recently proposed new definitions for aki, classifying it as transient or persistent. we aimed to determine the incidence, attributable mortality and host response characteristics of transient and persistent aki in patients with sepsis. patients and methods: we performed a prospective observational study comprising consecutive admissions for sepsis in intensive care units (icus) in the netherlands, stratified according to the presence and evolution of aki. attributable mortality fraction (excess risk for dying with persistent aki relative to transient aki) was determined using a logistic regression model adjusting for confounding variables. in a subset of sepsis patients, plasma biomarkers indicative of major pathways involved in sepsis pathogenesis were measured. in a second subset of patients, whole-genome blood-leukocyte transcriptomes were analyzed. results: sepsis patients were included. aki occurred in . % (n = ), of which . % (n = ) was transient and . % (n = ) persistent. patients with persistent aki had higher disease severity scores on admission than patients with transient aki or without aki and more frequently had severe (injury of failure) rifle aki-stages on admission (n = , . %) than transient aki patients (n = , . %, p < . ). persistent aki, but not transient aki, was associated with increased mortality by day- (adjusted or . , % ci . - . ; p = . ) ( figure) and up to -year (adjusted or . , % ci . - . ;p = . ). the attributable mortality of persistent relative to transient aki by day- was . % ( % ci . - . %). persistent aki was associated with enhanced and sustained inflammatory and procoagulant responses during the first days, and a more severe loss of vascular integrity compared with transient aki. baseline blood gene expression showed minimal differences with respect to the presence or evolution of aki. conclusion: persistent aki is associated with higher sepsis severity, sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient aki, and independently contributes to sepsis mortality. compliance with ethics regulations: yes. rationale: to address the paucity of data on the epidemiology of patients admitted to intensive care units (icus) with in-hospital cardiac arrest (ihca), we examined key features, mortality and trends in mortality in a large cohort of patients admitted in french icus over the past years. patients and methods: from to database of the collège des utilisateurs de bases de données en réanimation (cub-réa), we determined temporal trends in the characteristics of ihca, patients' outcomes and predictors of icu mortality. results: of the icu admissions, ( . %) were cardiac arrests and were ihca ( . %). during the study period, the age of ihca patients increased by . years (p = . ) and patients presented more comorbidities (chronic heart disease, chronic kidney disease and cancer). patients were also more critically ill over the period as reflected by the increase of saps-ii by . % (p < . ). paradoxically, in-hospital management became lighter through the time with reduced respiratory support (p < . ), renal support (p < . ) and use of vasoactive drugs (p < . ). crude in-icu mortality decreased from % to . % over the past eighteen years (p < . ), fig. rationale: in surgery, prophylaxis antibiotic aims at preventing the occurrence of post-operative infections. for adults, it is currently recommended to only use prophylactic antibiotic therapy during the time of the intervention. but in pediatric cardiac surgery, there is no consensus around the optimal duration of use of antibiotic prophylaxis. the protocol was modified in in the icu and its time reduced to h. we aimed to determine whether h of post-sternotomy antibiotic prophylaxis was not less effective than h treatment to help prevent care-associated infections. patients and methods: after agreement of the ethics committee of our institution, we performed a retrospective non inferiority study, with an inferiority margin to %. the primary objective is to compare the incidence of care-related infections between a second-generation cephalosporin (c g) antibiotic prophylaxis during h and a -h protocols. the secondary objectives are to determine the infection's incidence, to identify the risk factors for nosocomial infections and to compare the incidence of multidrug-resistant infections. results: between january and july , children underwent cardiac surgeries with sternal opening. received h of c g antibiotic prophylaxis and received h of c g treatment. five previously infected children have been excluded. both groups were demographically and surgically similar. the median age was months (range a few hours of life to . years old) and the median weight was . kg. in the intent-to-treat analysis, incidence of care-related infections is at . % in the c g- h group and . % in the c g- h group. a multivariate analysis shows that the shorter -h time antibiotic prophylaxis is not inferior regarding infection prevention compared to h of antibiotic prophylaxis, p = . . as in the per protocole analysis, the c g- h group rate was . % and . % for the g g- h group. conclusion: it demonstrates that shortening the antibiotic prophylaxis treatment time to h does not affect or increase the rate of infections after a pediatric sternotomy surgery compared to -h protocole. prophylaxis in pediatric cardiac surgery should be short-lived. a multicenter prospective study would allow a consensus and confirm this decision. compliance with ethics regulations: yes. rationale: the use of "big data" is getting increasingly popular in the medical field, especially in intensive care where large amounts of data are continuously generated. however, big data can be misleading when essential clinical data are missing. the adequate adjustment for potential confounding factors (e.g., severity of respiratory distress) should be the key procedure in the big data analyses; however, it is challenging to capture the clinical severity within large electronic databases. bronchiolitis is one main reason for admission to pediatric intensive care unit (picu). the modified wood's clinical asthma score (mwcas) is widely used to assess the severity of bronchiolitis. the objective of the study is to build an automated mwcas (a-mwcas) to continuously assess the severity of respiratory distress in critically ill children. this retrospective study included all infants < years old with a clinical diagnosis of bronchiolitis, ventilated with non-invasive neurally adjusted ventilatory assist, in a canadian picu, between october and june . we developed an algorithm, using python . , which was directly connected to the electronic medical record. the components of the score were collected using structured query language (sql) queries and processed to derive the a-mwcas. for validation, the a-mwcas score was compared to the mwcas manually computed by a clinical expert (m-mwcas) . results: sixty-four infants were included in the study, for which of a-mwcas and m-mwcas were generated respectively. the cohen's kappa coefficient was applied to estimate the agreement between the two scores which was . ( % confidence interval) ( table ) which corresponds to . % of complete agreement. . % of the a-mwcas scores were within ± . of the m-mwcas. the kappa coefficient for the each score component were: . for the oxygen saturation, . for the expiratory wheezing, . for the inspiratory breath sounds, . for the use of accessories muscles and . for the mental status, respectively. discussion: the largest discrepancy was observed in the mental status, which clinical evaluation is relatively subjective and varies among care team members (doctor, nurse, respiratory therapist…). the automated score likely decreases this variability by consistently using the same source (respiratory therapist), but its validity should be confirmed in a prospective study. the a-mwcas provides a valid estimation of the mwcas that is fast and robust. after external prospective validation, it may help to add some clinical sense within large electronic databases, with improved assessment of the respiratory distress. compliance with ethics regulations: yes. rationale: in paediatric intensive care units (picu), survival rates have dramatically improved. this has been accompanied by increased morbidity, including psychological morbidity. these new impairments, that can affect the survivors and their families have been conceptualized under the frame of post-intensive care syndrome (pics) and picsfamily. the aim of this study was to explore the experience of critically ill children parent's during the stay in picu, and its impact on the family. patients and methods: we planned a prospective, single centre study for months. we collected qualitative written data from parents whose child had been admitted to the picu for the first time, for at least two nights. results: fifty-seven questionnaires were analysed from thirty-seven admissions. picu admissions were mostly unplanned. among parents % experienced very painful memories during admission and % have feared for their child's life. during the stay, noise has bothered % of parents, and many have described difficulties to rest at night. % had the sensation that their child was suffering, mostly from pain, tiredness, anxiety or fear. during picu stay, % of parents had to stop working, and siblings schooling was impacted in % of cases, % of parents considered themselves to be useful for their child and % have participated to nursing care. more than % were satisfied about information given and communication, % appreciated empathy and support from care givers. parents received support from family, friends, and also from other parents of hospitalized children. parents expressed relief ( %) and serenity ( %) to leave picu, % of them were in demand to meet picu staff again after discharge. conclusion: picu parent's experience is tough, and the impact on family is clear. these are known risks factors for pics. on a very positive note, parents seemed to be satisfied by family-centred care, and were able to preserve their parental role. however, there is still room for improvement of practices. compliance with ethics regulations: yes. the gut has been suspected to be involved in multiple organs dysfunction syndrome (mods) in the intensive care unit (icu). studies suggested a link between gastrointestinal dysfunction (gid) and outcomes. but these studies included very few patients and most of them were retrospective. patients and methods: this study is a secondary analysis of data from a previous study that included patients from french icus. gid is defined as the association of vomiting and constipation or diarrhea during the first week after icu admission. patients included were treated with vasopressors and mechanical ventilation. the first goal was to determine if gid is a risk factor of -day mortality in this population. secondary goals were to assess the impact of gid on nosocomial infections. results: among included patients, ( . %) had gid. by day- , ( %) of the patients with gid and ( %) of the patients without gid had died (odds ratio . [ . - . ]; p = . ). multivariable regression model did not show any association between gastrointestinal dysfunction and increased risk of -day mortality in patients (odds ratio . [ . - . ], p = . ). gastrointestinal dysfunction was strongly associated with other secondary outcomes ( table ). patients with gid had longer ventilation duration, icu length of stay and hospital length of stay. they also had more nosocomial infections, in particularly ventilator-associated pneumonia. this association still existed in a multivariable regression model for prediction of nosocomial infection including the same variables than the previous model (odds ratio . [ . - . ], p = . ). no association with day- mortality was observed. conclusion: gastrointestinal dysfunction was not a risk factor of day- mortality but was associated with an increased risk of nosocomial infection and an increased length of stay. this study is observational and no causality link can be done. however, our data suggest further studies on strategies aimed to limit gid. compliance with ethics regulations: yes. rationale: acute cholangitis (ac), a bacterial infection related to an obstruction of the biliary tree, may be responsible for life-threatening organ failure. however, little is known about the outcome and the predictive factors of mortality of critically ill patients admitted in icu for acute cholangitis. we aimed to describe characteristics of patients admitted in icu for ac and to analyze predictive factors of in-hospital mortality including the time to biliary drainage procedure. patients and methods: retrospective study of all cases of acute cholangitis admitted in french icus ( tertiary hospitals and non-ter- [ . ; . ] µg/l. % of patients (n = ) have positive blood culture, mostly gram negative bacilli ( %) and % producing extended spectrum beta lactamase enterobacteriaecae. at icu admission, persisting obstruction was frequent ( %) and therapeutic endoscopic retrograde cholangiopancreatography was performed in % of them. in a multivariable analysis, at icu admission, several factors were significantly associated with in-hospital mortality: sofa score (or = . [ % ic . ; . ] by point, p = . ), arterial lactate (or = . [ . ; . ] by mmol/l, p < . ), total serum bilirubin (or = . [ . ; . ] by umol/l, p < . ), obstruction nonrelated to gallstones (p < . ) and ac complications (liver abcess and/or pancreatitis) (or = . [ . ; . ] p = . ). in addition, time > h between icu admission and biliary drainage was associated to in-hospital mortality (adjusted or = . [ . ; . ] p = . ). conclusion: acute cholangitis is responsible for high mortality in icu. organ failure severity, causes and local complications of cholangitis are predictive factors of mortality as well as delayed biliary drainage. compliance with ethics regulations: yes. the united kingdom) were included (n = ). predictors of one-year mortality were retrospectively screened and tested on a single center training cohort. a predictive score was developed and tested on an independent multicenter cohort. results: four independent pre-transplantation risk factors were associated with one-year mortality after transplantation in the training cohort: age ≥ years (or = . , % ci = . - . , p = . ), pre-transplantation arterial lactate level ≥ mml/l (or = . , % ci = . - . , p = . ), mechanical ventilation with pao / fio ≤ mmhg (or = . , % ci = . - . , p = . ) and pretransplantation leukocyte count ≤ g/l (or = . , % ci = . - . , p = . ). a simplified version of the model was derived by assigning point to each risk factor: the transplantation for aclf- model (tam) score. a cut-off at points distinguished a high-risk group (score > ) from a low-risk group (score ≤ ) with one-year survival of . % vs. . % respectively (p < . ). the model and its simplified version were validated on the independent multicenter cohort. there was a significant difference between the high-risk and low-risk group with one-year survival of % vs. . % respectively (p < . ). conclusion: liver transplantation can be an effective treatment for critically ill cirrhotic patients with hepatic and extra hepatic organ failure provided patients are carefully selected and that they are transplanted at the optimal time in the intensive care. the tam score can help stratify post-transplantation survival and assist clinicians in the transplantation decision-making process at the bedside of aclf- patients. compliance with ethics regulations: yes. rationale: trans-thoracic echocardiography (tte) is commonly used in the initial management of patients with shock in icu. there is little published evidence for any mortality benefit. we compared the effect of echocardiography protocol versus standard care for survival and clinical outcomes. patients and methods: this randomized controlled trial included selected shocked patients (systolic blood pressure < mm hg and signs of organ hypoperfusion) randomized to early tte plus standard care versus standard care without tte. the primary outcome measure was survivalto days. secondary outcome measures included initial treatment and vasopressor weaning. results: consecutive subjects with circulatory shock (low systolic arterial blood pressure (sap) and signs of organ hypoperfusion) at the time of icu admission are included in the study. in the tte group: fluid prescription during the first h was significantly lower rationale: both the negative prognostic value and reversibility of left ventricular (lv) diastolic dysfunction in septic patients remain debated. the excess of mortality in septic shock patients with hyperdynamic profile has only been reported by small-size studies. accordingly, the primary objective of the prodiasys study was to assess the impact of lv diastolic dysfunction (and its severity) and of lv hyperkinesia echocardiographically identified during the initial phase of septic shock on -day survival. the secondary objective was to assess the potential link between lv diastolic dysfunction, cumulative water balance (on day ), and outcome. patients and methods: this was a multicenter, prospective, observational, cohort study. patients older than years hospitalized in icu for septic shock (sepsis- definition) were eligible. exclusion criteria were administration of inotropes, severe left valvular disease, constrictive pericarditis and moribund patients. in each patient, echocardiography was first performed within h after the diagnosis of septic shock and then daily until day , after vasopressor discontinuation, at icu discharge and on day or at hospital discharge, whichever occurred first. vital and biological parameters usually monitored for septic shock management were collected at each echocardiographic assessment. vital status was collected on day . associations between lv diastolic dysfunction or lv hyperkinesia and day- mortality were analyzed using a chi test. adjusted analyses were performed using logistic regression models, including variables known to be linked with the prognosis of septic shock (e.g., severity scores, delay of antibiotherapy). the relationship between the grade (i to iii) of lv diastolic dysfunction and -day survival were analyzed using a logistic regression model. the relationship between the presence of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model adjusted on the body weight on admission. the relationship between the grade of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model. diaphragm dysfunction and weaning induced pulmonary edema are two frequent causes of weaning failure but their coexistence and interaction have been poorly investigated. we hypothesized that diaphragm dysfunction may not induce a sufficient decrease in intra-thoracic pressure to increase venous return and generate a weaning induced pulmonary edema. we therefore investigated whether weaning induced pulmonary edema and diaphragm dysfunction are or not associated and evaluated the effect of diaphragm dysfunction on cardiac function and lung aeration during a spontaneous breathing trial (sbt). patients and methods: patients with readiness to wean criteria who had failed a first sbt were eligible. before and after a second sbt, diaphragm function was assessed by measuring the change in tracheal pressure induced by a bilateral phrenic nerve stimulation (ptr, stim), cardiac function (cardiac output, systolic pulmonary arterial pressure) was evaluated with echocardiography and lung aeration was estimated from the lung ultrasound score (lus). plasma protein concentration and hemoglobin were also sampled before and after the sbt. diaphragm dysfunction was defined by ptr, stim < − cmh o and weaning induced pulmonary edema was diagnosed in case of sbt failure associated with ) increase in plasma protein concentration or hemoglobin > % during the spontaneous breathing trial and/or ) early (e) over late peak diastolic velocity ratio > . or e over peak diastolic velocity ratio > . . results: fifty-three patients were included and / ( %) failed the sbt. diaphragm dysfunction was present in / ( %) of patients with weaning induced pulmonary edema, in / ( %) patients with sbt success and in / ( %) patients with other causes of sbt failure (p < . ). during the sbt, diaphragm dysfunction induced a significant increase in systolic pulmonary arterial pressure but no change in cardiac output. patients with diaphragm dysfunction had a higher lus as compared to their counterparts ( ± vs. ± , respectively, p < . ). conclusion: diaphragm dysfunction induces a loss of lung recruitment and a significant increase in systolic pulmonary arterial pressure during the sbt. coexistence of diaphragm dysfunction and weaning induced pulmonary edema is common in case of sbt failure but weaning induced pulmonary edema appears more likely to be involved than diaphragm dysfunction. compliance with ethics regulations: yes. rationale: diaphragmatic weakness in the intensive care unit (icu) is associated with poor outcome. prolonged mechanical ventilation is associated either with a decrease (atrophy) or an increase (supposed injury) in diaphragmatic thickness, both associated with prolonged weaning. shear wave elastography is a non-invasive technique that measures diaphragm shear modulus (sm), a surrogate of its mechanical properties. the aim of this study was to describe the diaphragm shear modulus during the icu stay and to describe its relation with diaphragm thickness. patients and methods: this prospective and monocentric study included all consecutive critically ill patients. ultrasound examination of the diaphragm (aixplorer; supersonic-imagine, aix-en-provence, france) was obtained by two investigatorsevery other day until icu discharge. demographics, diaphragm thickness, sm and outcomes were collected. a mixed model regression was used to study the relation between sm and diaphragm thickness. results: we enrolled patients from december st to june st, being invasively mechanically ventilated during the stay. diaphragm ultrasound evaluation was feasible in / ( %) patients. the duration of mechanical ventilation during the icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days with [ ] [ ] [ ] [ ] [ ] days spent on controlled mechanical ventilation. sm was . ± . kpa and diaphragm end-expiratory thickness was . ± . cm upon icu admission. increase and decrease ≥ % during icu stay occured in and percent of the patients respectively for diaphragmatic thickness, and in and percent of the patients respectively for diaphragmatic sm. diaphragm thickness over time was inversely correlated with diaphragm sm and with time spent under mechanical ventilation (table) . diaphragm sm over time was correlated with time spent under pressure support ventilation or under spontaneous breathing (compared to controlled ventilation) and with time spent under deep sedation. diaphragm sm was inversely correlated with age, sepsis, exposition to steroids (table) . no association was found between diaphragm sm and outcomes. discussion: our results are in line with the myotrauma concept, suggesting alteration in diaphragm mechanical properties associated with increased diaphragm thickness in critically ill patients. we hypothesize that this observation most likely reflects muscle injury and tissue infiltration with edema and inflammatory cells. conclusion: shear wave ultrasound elastography suggests that in critically ill patients, the increase in diaphragmatic mass is associated with an alteration in diaphragm mechanical properties as measured by sm. compliance with ethics regulations: yes. rationale: diaphragm dysfunction and intensive care unit (icu) acquired weakness (icu-aw) are associated with poor outcomes in the icu but their long term impact on prognosis and health-related quality of life (hrqol) is poorly established. this study sought to determine whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and icu-aw has a particular impact on two-year survival and hrqol. patients and methods: we used a previous cohort study conducted in our institution to follow up mechanically ventilated patients in whom diaphragm and limb muscle functions were investigated at the time of liberation from mechanical ventilation. diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation < cmh o and icu-acquired weakness was defined by medical research council (mrc) score < . hrqol was evaluated with the sf- questionnaire. results: sixty-nine of the patients enrolled in the original study were included in the survival analysis and were interviewed. overall two-year survival was % ( / ): % ( / ) in patients with diaphragm dysfunction, % ( / ) in patients without diaphragm dysfunction, % ( / ) in patients with icu-acquired weakness and % ( / ) in patients without icu-acquired weakness. patients with concomitant diaphragm dysfunction and icu-acquired weakness had a poorer outcome with a -year survival rate of % ( / ) compared to patients without diaphragm function and icu-acquired weakness ( % ( / ) (p < . )). hrqol was not influenced by the presence of icu-acquired weakness, diaphragm dysfunction or their coexistence. conclusion: icu-acquired weakness but not diaphragm dysfunction has a strong negative impact on two-year survival of critically ill patients. the presence of diaphragm dysfunction appears more likely to be a determinant of early prognosis and does not appear to have a significant impact on long-term survival. compliance with ethics regulations: yes. rationale: influenza can lead to severe condition with acute respiratory failure and acute respiratory distress syndrome due to a massive pulmonary inflammatory in response to the viral invasion. lung bacteriobiota has been described to be associated with pulmonary inflammation in chronic respiratory diseases such as chronic obstructive pulmonary disease or cystic fibrosis. lung mycobiota has been poorly investigated despite the well-known role for fungi in numerous respiratory diseases. the aim of our study was to assess the prognostic value of lung bacteriobiota and mycobiota among critically ill influenza patients. patients and methods: we prospectively included influenza patients admitted to icu. sputum were stored a - °c. bacterial and fungal dna were extracted thanks to qiaamp ® powerfecal ® pro dna kit. s rrna gene v -v regions and its regions were amplified by pcr and sequenced on illumina miseq ® . taxonomic assignation was obtained by dada pipeline and microbiota analysis were performed according to day- mortality by the mean of phyloseq package on r . . software. results: thirty-nine patients were admitted to icu for influenza with sputa available and finally dna samples available after extraction. bacteriobiota alpha diversity was significantly lower among non-survivors than survivors when expressed by the mean of shannon index, simpson index or evenness (respectively p = . , p = . , p = . ). area under the curve to predict day- mortality was . , ci [ . ; . ] for shannon index, . ci [ . ; . ] for simpson index and . ci [ . ; . ] for evenness. β-diversity analysis also demonstrated significant differences between survivors and non-survivors (adjusted permutational multivariate anova, p = . ). nonsurvivors had a higher abundance of staphylococcus, haemophilus, streptococcus and moraxella. none of the fungal alpha-diversity index nor beta-diversity were significantively different between survivors and non-survivors. non-survivors had a higher proportion of candida albicans and malassezia but not of aspergillus. conclusion: the lung bacteriobiota profile, but not the mycobiota one, of critically ill influenza patients is associated with day- mortality and may be used to identify subjects with a poor prognosis at the time of admission. compliance with ethics regulations: yes. that takes into account the interaction between multiple cellular pathways. the pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. results: patients ( severe and moderate influenza patients) and healthy control subjects were included in the study. severe influenza was associated with upregulation in several neutrophilrelated pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (net) formation. the degree of upregulation in neutrophil-related pathways was significantly higher in severely infected patients compared to moderately infected patients. severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation, cd + t-cell co-stimulation, cd + t cell and natural killer (nk) cells effector functions. apoptosis pathways were also downregulated in severe influenza patients compared to moderate and healthy controls. conclusion: these findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection. compliance with ethics regulations: yes. rationale: herpesviridae reactivation among non-immunocompromised critically ill patients is associated with impaired prognosis, especially during acute respiratory distress syndrome (ards). however, few is known about herpes simplex virus (hsv) and cytomegalovirus (cmv) reactivation occurring in patients with severe ards under venovenous extracorporeal membrane oxygenation (ecmo). we tried to determine the frequency of herpesviridae reactivation and its impact on patients'prognosis during ecmo for severe ards. patients and methods: we conducted an observational, retrospective study in a medical icu (ards and ecmo referee center) between and . patients with a severe ards requiring a venovenous ecmo for days or more were included. hsv and/or cmv reactivation occurring after ecmo insertion was screened for these patients. patients with immunosuppression, antiviral therapy against hsv and/ or cmv prior to inclusion, or hsv/cmv reactivation known at the time of ecmo insertion were excluded. hsv reactivation was defined by a positive qualitative throat sample (virocult ® ) pcr or positive bronchoalveolar lavage (bal) pcr. cmv reactivation was defined by a positive quantitative blood or bal pcr. results: during a five-year period, non-immunocompromised patients with a severe ards necessitating a veno-venous ecmo were included. sixty-seven ( %) experienced hsv and/or cmv reactivation during ecmo course ( viral co-infection, hsv alone and cmv alone). hsv reactivation occurred earlier than cmv after the beginning of mv ( ( - ) vs. ( - ) days; p < . ) and after ecmo implementation ( ( - ) vs. ( - ) days; p < . ). in univariate analysis, hsv/cmv reactivation was associated with a longer duration of mechanical ventilation ( ( - . ) vs. . ( - ) days; p < . ), a longer duration of . ) vs. ( - ) days;p < . ), and a prolonged vs. ( - ) days; p < . ) and hospital stay ( ( - . ) vs. ( - ) days; p < . ). however, in multivariate analysis, viral reactivation remained associated with prolonged mv only. when comparing patients having cmv (alone or combined with hsv) vs. hsv reactivation alone, cmv positive patients had a longer mechanical ventilation duration and fewer ventilator-free days at day- and a longer icu and hospital length of stay. conclusion: herpesviridae reactivation is frequent among patients with sevre ards under veno-venous ecmo and is associated with a longer duration of mechanical ventilation. cmv seems to have a proper negative role on pulmonary fiunction as compared to hsv alone. hsv and cmv deserve to be researched in severe ards patients under ecmo. compliance with ethics regulations: yes. charlotte vandueren , benjamin zuber , eve garrigues , antoine gros , nicolas epaillard , guillaume voiriot , yacine tandjaoui rationale: respiratory syncytial virus (rsv) is a common cause of pediatric bronchiolitis and influenza-like illness in adults. its involvement in severe infections in adults remains unclear. the captif study aimed at comparing characteristics and prognosis of icu patients infected with rsv and influenza, assuming that, based on the limited evidence, the mortality of rsv infection would be lower than the influenza related one. patients and methods: multicenter franco-belgian retrospective study. adults admitted to icus between /nov/ and / apr/ with respiratory rsv infection were included and matched : to influenza patients on center and icu admission date. patients' characteristics, clinical presentation, and outcome were compared between groups using univariate and multivariable analyses. results: we report here the results for the first cases among included patients. mean age was . ( . ) years and saps- score was ( ), not different between groups. compared to influenza patients, rsv patients more frequently had chronic respiratory failure ( % vs %, p < . ) or immune suppression ( vs %, p = . ). frequencies of cardiac, renal and hepatic chronic diseases were similar. almost all patients had respiratory symptoms (> %), extrarespiratory symptoms were more frequent in influenza patients ( vs %, = . ). rsv patients more frequently had bronchospasm ( vs %, p = . ). clinical presentation such as ards ( %), shock ( %) and pulmonary coinfection ( %) were similar, however sofa score was higher in rsv patients ( . ( . ) vs . ( ), p = . ). the p/f ratio was around mmhg in both groups, paco was higher in rsv patients ( vs mmhg, < . ). respiratory assistance at diagnosis tended to differ (p = . ), rsv patients receiving more non invasive ventilation ( vs %) and less high flow oxygen therapy ( vs %) but invasive ventilation was required similarly ( vs %). during icu stay, ards was more frequent in rsv patients ( vs %, p = . ), accordingly prone position ( . vs . %) and ecmo ( . vs . %) were more frequently needed. length of mechanical ventilation ( days ( - ) ) and icu los ( days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ) were not different. icu mortality was similar in rsv and influenza patients ( . % and . %), the multivariate analysis did not find an association between type of virus and mortality. conclusion: rsv infection is frequent in adult icu patients. it presents more frequently than influenza as an acute on chronic respiratory failure with bronchospasm. despite difference in case mix and clinical presentation, vrs severity and burden appear similar to influenza justifying effort to prevent and treat it. compliance with ethics regulations: yes. rationale: mortality in acute stroke patients requiring mechanical ventilation ranges from to % at year. studies evaluating indicators of outcome in these patients have limitations, including singlecenter, retrospective designs and no adjustment for withholding/ withdrawal of life-sustaining treatments (wlst). our objective was to identify factors associated with -year survival in acute stroke patients requiring mechanical ventilation. patients and methods: retrospective analysis of a prospective multicenter database between and . icu stroke patients entered in the database and requiring mechanical ventilation within h were included. were excluded patients with stroke of traumatic origin, subdural hematoma or venous cerebral thrombosis. factors associated with -year survival were identified using a cox model stratified on inclusion center, adjusted on wflst occurring during the first h. data are presented as median [q -q ] or percentages. cox model results are presented as hazard ratios (hr) and % confidence intervals (ci). results: we identified patients from icus, aged [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] years and % males. on admission, the glasgow coma score (gcs) was [ ] [ ] [ ] [ ] [ ] [ ] and the saps score was . types of strokes were ischemic ( %), hemorrhagic ( %) and subarachnoid hemorrhage (sah) ( %). ischemic stroke patients received thrombolysis or thromboaspiration in / ( %) cases, and hemorrhagic stroke/ sah patients received neurosurgery or embolization in / ( %) cases. reasons for endotracheal intubation were coma ( %), acute respiratory failure ( %), seizures ( %), cardiac arrest ( %) and elective procedure ( %). sixty-five ( %) patients received a decision of wflst in the first h. one-year survival year was %. variables independently associated with -year survival were stroke type (ischemic as reference, hemorrhagic hr . (fig. ) . inclusion period ( inclusion period ( - inclusion period ( / inclusion period ( - inclusion period ( / inclusion period ( - or having a stroke unit on site was not associated with -year survival. conclusion: in acute stroke patients requiring mechanical ventilation, the reason for intubation and the opportunity to receive a specific stroke therapy are independently associated with long-term survival. these variables should be integrated in the decision process regarding initiation of mv in acute stroke patients. compliance with ethics regulations: yes. rationale: international guidelines recommend targeted temperature management (ttm) between ° and °c for out-of-hospital cardiac arrest (ca) patients. however, it is unknown if this treatment is effective whatever the severity of the insult. we aimed to examine the association between ttm and long-term neurological outcome according to the risk evaluated at time of admission in intensive care unit (icu) using a dedicated and validated score. patients and methods: we used data prospectively collected in the sudden death expert center (sdec) registry (great paris area, france) between may and december and in the resuscitation outcome consortium-continuous chest compression (roc-ccc) between june and may . we used a modified version of the cardiac arrest hospital prognosis (mcahp) score to assess the risk of poor outcome at icu admission in each of datasets. we finally studied the association between ttm use and long-term neurological prognosis according to mcahp score at icu admission divided into tertiles of severity in each of the datasets. results: there were patients analyzed in the french dataset and in the north-american dataset. the mcahp identified categories: low risk (score < points, % of unfavourable outcome), medium risk ( ≤ score < , % of unfavourable outcome) and high-risk group (score > , % of unfavourable outcome). according to the mcahp score at icu admission, ttm was associated with a better long-term neurological prognosis in patients with low risk (aor = . [ . - . rationale: acute ischaemic stroke is associated with a high risk of mortality, morbidity and healthcare-related costs. over the last decades new treatments, such as thrombolysis and thrombectomy, have been introduced. because of their further improvement, complications have been decreasing. this also led to extending indications for treatment to patients who were previously not eligible. the impact of this evolution on long-term outcome and cost-effectiveness has mainly been assessed in clinical trials and simulation studies. patients and methods: this single-centre retrospective study included patients treated for stroke between january and february . functional outcome at days was assessed by the modified rankin scale (mrs). cost data were retrieved from individual invoices of patients. undiscounted total healthcare costs were calculated for the index hospital stay, capped at days. contribution of cost categories to total costs was analysed. mrs at days was used as a proxy for utilities to define quality-adjusted life years (qalys). multivariate analysis was done for gender, age, charlson comorbidity index, pre-stroke mrs, stroke severity (nihss) and treatment modality (thrombectomy, thrombolysis, thrombectomy + thrombolysis, no intervention). incremental cost-effectiveness ratios (icers), associated to each treatment modality, were calculated. results: no intervention was done in patients ( . %). patients ( . %) required thrombolysis, ( . %) thrombectomy and ( . %) the combination. total costs were mean , eur ) . hospitalisation costs (mean , eur, iqr - , ) represented % of total costs, compared with drug costs ( eur, iqr - ), procedural costs ( eur, iqr - ), honoraria ( eur, iqr - ), lab ( eur, iqr - ) and imaging ( eur, iqr - ). mean total costs differed between treatment modalities: , (iqr - , ) eur for no intervention, , ) eur for thrombolysis, , (iqr , ) eur for thrombectomy and , (iqr , ) eur for the combination (p < . ). drivers for total costs were treatment modality (p < . ) and nihss-stroke severity (p < . ). utility scores were . rationale: emergency endotracheal intubation (eti) in the intensive care unit (icu) often concerns hypoxemic patients with hemodynamic instability. a cardiovascular collapse (cvc) after eti is a life-threatening complication. french guidelines suggested systematic fluid loading prior to eti. our study aimed to predict cvc after eti, while using echocardiography, and to evaluate the impact of fluid loading. patients and methods: a prospective study of consecutive intubations was performed from june to november in three icus. patients were selected if mean blood pressure measurements ≥ mmhg before eti. cvc was defined as mean blood pressure < mmhg within min following eti. four echocardiographic examinations were performed: - min before and - min after eti (or when a cvc occurred); -after passive leg raising; - h following eti. patients were classified as fluid responders when the left ventricular outflow tract velocity-time integral increased by at least % compared with baseline. results: echocardiographic examinations were performed. cvc occurred in / procedures ( %). in cvc group, mean dose of diprivan, used for fast sequence induction, was higher ( . ± mg/kg vs . ± . mg/kg, p = . ). in the cvc group, fluid responsiveness was considered in % patients and left ventricular (lv) systolic dysfunction %. lv diastolic dysfunction did not concern any patient in the cvc group. systolic blood pressure (sbp) < mmhg was the sole independent risk factor for cvc occurrence in multivariate analysis: or . ci % . - . , p = . . fluid responsiveness independent risk factors for cvc patients was sbp < mmhg (or . , ci % . rationale: the autonomic nervous system is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of autonomic nervous system activity and a relation between hrv and outcome has been proposed in various types of patients. we attempted to evaluate the best determinants of such variation in survival prediction using a physiological data-warehousing program (reastoc clinicaltrials identifier nct ). patients and methods: physiological tracings were recorded at hz from the standard monitoring system (intelliview philips mp ) using the synapse software (ltsi inserm umr ), for a h period, during the h following icu admission. all measurements were recorded while patients were laying in bed, with the head at ° and without any medical intervention. physiological data were associated with metadata collection by a dedicated research assistant. hrv was derived using kubios hrv, in either temporal ( (sdnn), (rmssd) and triangular index (ti)), frequency ( (lf), (hf)), non-linear domains (poincaré plotting) and entropy. results: consecutive patients were recorded between may and april . a lower lf/hf (< . ) and sd /sd (< . ) ratios on admission were associated with a higher icu mortality. multivariate analysis enabled to develop a mortality predictive model (bicus) associating spo /fio and hrv parameters (lf/hf and shannon entropy) with an auc = . (p < . ) for a bicus value > (fig. ) . conclusion: hrv measured on admission enables to predict prognosis in the icu, independently of the admission diagnosis, treatment and mv requirements. bicus may help predict prognosis on a real time basis, using parameters derived from standard routine monitoring. compliance with ethics regulations: yes. rationale: stroke, in the context of type diabetes (t d) is associated with a worse outcome than in non-diabetic conditions, reflected by an increased ischemic volume and more intracerebral hemorrhage. an unbalanced diet is one of major risk for developing t d. we aimed at creating a reproducible mouse model of stroke in impaired glucose tolerance condition induced by high fat diet. patients and methods: adult c bl mice ( male and female) were fed for months with either high fat diet (hfd, % lipids, % proteins, % carbohydrates) or a normal diet (nd, . % lipids, . % proteins, . % carbohydrates) . we used a model of middle cerebral artery occlusion (mcao) by a monofilament for min. oral glucose tolerance test and insulin tolerance test were used for evaluating the pre-diabetic state. mice were euthanized h after reperfusion. systemic inflammation, cerebral infarct volume and hemorrhagic transformation were determined. results: hfd was associated with an increased glycaemia following the oral glucose tolerance test. plasma leptinlevels in stroke conditions were significantly higher in hfd vs nd group. the hfd group presented a significant increase of infarct volume (hfd: . ± . mm vs nd: . ± . mm p = . ) and hemorrhagic transformation (hfd: . ± . vs nd: . ± . p = . ) (fig. ) compared to nd group. discussion: in humans, one of the mechanisms leading to insulin resistance is low-grade inflammation. hfd increases gut permeability, which leads microbiota dysbiosis, thereby promoting metabolic endotoxaemia and a low-grade inflammation state. experimental mouse models available for diabetes studies use leptin receptor deficient mice which develop t d or destruction of pancreatic beta cells by streptozotocine injection (t d). studies using diet-induced insulin resistance models generally feed the mice for weeks or more. however, metabolic disorders could appear earlier such as increase inflammatory markers. in our model, a short exposition to hfd ( weeks) leads to an increase of the pro-inflammatory markers as plasma leptin and a more severe stroke status (infarct and hemorrhagic transformation). conclusion: two months of hfd in adult mice altered hyperglycemia control. this metabolic disorder was associated with significantly higher leptin production, increased infarct volume and hemorrhagic complications than in normal-fed mice. this new model is particularly relevant to study stroke under pre-diabetic conditions induced by hfd. compliance with ethics regulations: yes. eight weeks of hfd increase ischemic volume and hemorrhagic transformation. (a)-infarct volume (v) h after reperfusion, all value are mean ± sem, hfd: v = . ± . mm , n = , nd: v = . ± . mm , n = , *p = . (b)-hemorrhage transformation (ht) score h after mcao. all value are mean ± sem hfd: ht score = . ± . , n = , nd: ht score = . +/+ . , n = *p = . rationale: cardiac arrest (ca), as massive ischemia reperfusion (ir), is an universal health issue. medication taken at the time of the ca could have prognosis consequences. no medication has proven its benefit on ca prognosis. pharmacological pre-or postconditioning aims to reduce ir injury but with disappointing results. metformin (met) is a worldwide-prescribed antidiabetic drug, and several clinical reports plead for a potential protective effect in various settings of sterile and non sterile inflammation, including ir. our hypothesis is that met act as a preconditioning drug against ca-induced ir. patients and methods: retrospective single academic medical center survival study (french west indies) on resuscitated ca in icu (institutional ethical committee approval). data were extracted from medical charts, pmsi, and laboratory dbsynergy ™ software. anonymized data were entered on a excel ™ and transferred to ibm ® -spss ® software (v . . . ) for analysis. univariate study (chi- , fisher exact tests, student-t test, mann-whitney u-test if required) was followed by a multivariate model (odd ratio or and % ic: kaplan-meier estimator and non parametric logrank test-mantel cox model). assuming an overall in-hospital mortality for ca in icu of % with an expected mortality decrease of % by met, the number of patients to be included is . results: the inclusion period was to , with included patients ( diabetic patients among whom took met). the d mortality was % in met+ patients (n = ) versus % in nomet patients (n = ), p < . . comparing alive (n = ) versus deceased (n = ) at d in univariate then multivariate analysis, asystole on the first ekg, number of iterative cardiac arrest,sofa, no-flow, lactate, low-flow and sapsii appear as independent criteria associated with d mortality.conversely, met intake showed up as a protective criterion (or . , ci . - . ). the survival curve, including strata of low-flow duration at the cut-off min, is reported on the fig. . among diabetic patients (n = ), the mortality of patients in the met+ (n = ) was % versus % in the nomet (n = ), p = . . conclusion: in diabetic patients suffering of massive ir related to resuscitated ca, a current treatment by met is associated with a better survival. these results support a protective effect of met and are important to initiate prospective evaluations, because of millions diabetic people around the world and the potential benefit of met. the potential benefit in non diabetic patients and in sterile as well as non sterile inflammation should be addressed. compliance with ethics regulations: yes. rationale: during systemic inflammation, the accumulation of misfolded proteins in the endoplasmic reticulum (er) induces er stress (ers). in animal models, the inhibition of ers reduces inflammatory response and organ failure. cardiopulmonary bypass (cpb) induces a significant systemic inflammatory response but ers expression has never been described in cardiac surgery patients. our objective was to describe the variations of the glucose related protein of kda (grp ), the final effector of the ers, during cpb. patients and methods: we conducted a prospective monocenter study including patients undergoing cardiac surgery with cpb. two samples (paxgene ® tube + edta tube) were taken at three times: before cpb, h after the end of cpb (h -cpb) and h after (h -cpb). after rna isolation and reverse transcription, we performed a quantitative polymerase chain reaction to evaluate the expression of gene encoding for grp and determined the plasma level of grp using enzyme-linked immunosorbent assay. our main objective was to study the variation of grp between pre-cpb and h -cpb samples. our secondary objectives were to evaluate the association of ers with morbi-mortality: organ failure at h (catecholamines and/or invasive ventilation and/or acute renal failure), troponinemia and pao /fio ratio (lung damage control). fig. ). we found an inverse correlation between grp plasma level and troponinemia at h (r = − . ; % ci[− . ; − . ]; p = . ) and a correlation between the pao /fio ratio and grp plasma level at h (r = . ; % ci[ . ; . ]; p = . ). we showed a significant relationship between the variation in plasma concentration of grp and post-operative organ failure after cpb. further studies are needed to better understand the molecular mechanisms of ers in acute inflammatory organ failure in humans. compliance with ethics regulations: yes. patients and methods: in a retrospective monocentric study ( / - / ) conducted in cardio-vascular surgical intensive care unit (icu) in henri mondor teaching hospital, all consecutive adult patients who underwent peripheral va-ecmo were included, with exclusion of those dying in the first h. diagnosis of acute mesenteric ischemia was performed using digestive endoscopy, abdominal ct-scan or fist-line laparotomy. significative results in the univariate analysis were analyzed in a multivariate analysis using logistic regression. results: va-ecmo were implanted. median age was ( - ) years and median . va-ecmo was implanted after a cardiotomy in % of the cases and for a medical reason in % of the cases including % of refractory cardiac arrest. patients characteristics are reported in the table. acute mesenteric ischemia was suspected in patients, with a delay of ( - ) days after ecmo implantation. digestive endoscopy was performed in patients, ctscan in five patients and first-line laparotomy in three patients. acute mesenteric ischemia was confirmed in patients, i.e. an incidence of %. laparotomy was performed in six of the patients, two having a stage i colitis ischemitis with stable conditions and being considered too severe to undergo futile surgery. overall mortality was %. all the patients with acute mesenteric ischemia died in the icu. independent risk factors of developing acute mesenteric ischemia were renal replacement therapy , p = . )) and onset of a second shock state within the first days of icu stay (or . ( % ic . - . , p = . )). conversely, early enteral nutrition was negatively associated with acute mesenteric ischemia (or . ( % ic . - . ), p . ). conclusion: acute mesenteric ischemia is a relatively frequent condition among patients under va-ecmo for cardiogenic shock. its extremely poor prognosis requires low threshold of suspicion. compliance with ethics regulations: yes. ( ). it allows the computation of trans-pulmonary pressure ( ) and can be used to set positive end-expiratory pressure (peep) ( . ) . prone position(pp) can reduce mortality in patients with acute respiratory distress syndrome (ards), but peep selection in pp is controversial. in human ards end-expiratory pes at zero flow (peept,es) was not different between supine (sp) and pp at same peep ( ). as no study measured ppl in sp and pp in ards we aimed at comparing peept,es and end-expiratory ppl at zero flow (peept,ppl) in this condition. our hypothesis was that peept,es was close to dorsal peept,ppl (peept,ppldorsal) in sp and to ventral peept,ppl (peept,pplventral) in pp. in eight female pigs of kgs intubated, sedated, paralyzed and mechanically ventilated, ards was induced by repeated saline lavage until pao /fio < mmhg under fio and peep cmh o. pes was measured by nutrivent catheter. ppl was measured by custom-made pouch sensors inserted surgically into the right anterior and posterior sixth intercostal space. ppl sensors were filled with air. after ards induction animals were randomly assigned to sp or pp. in each position, a recruitment manoeuver was performed and peep decreased from to cmh o by steps of cmh o lasting min each, then the animals were crossed over into the alternate position where the same procedure was done. at the end of each step nonstressed volume and correct position (baydur maneuver) were determined for pes and ppl sensors, then a -s end-expiratory occlusion was performed and pes and ppl recorded. linear mixed model was used to compare the value of pes and ppl at each peep and position. results: box-and-whisker plots of pes and ppl in sp and pp are shown in fig. . there is marked dorsal-to-ventral gradient in ppl at each peep in sp, which is reverted in pp at peep and only. there was no interaction between pressures and peep or position. with increasing peep pes increased significantly from peep in sp and pp. peept,pplventral was significantly lower than peept,es in sp but not in pp. (medtronic) , carescape (ge)) were set in pressure support cmh o, peep cmh o, fio % and equipped with the same double limb ventilator circuit (intersurgical) without any humidification device. asl bench model was set with inspiratory/expiratory resistance (r) and compliance (c) combinations: r / -c , r / -c and r / -c mimicking normal, ards and copd conditions, respectively ( ) . inspiratory effort generated by asl consisted of consecutive breaths obtained from the esophageal pressure in a real patient at the time of a spontaneous breathing trial. for each icu ventilator and rc combination, two steps were performed: in the first, atc was not activated and ventilator attached to asl without ett (atc-ett-); in the second, atc was set on at % compensation for an ett mm id and such an ett (shiley hi contour, covidien) joined icu ventilator to asl (atc+ ett+). the null hypothesis is that vtatc+ ett+ minus vtatc-ett-is . primary end point was the breath by breath paired difference betwen atc+ ett+ and atc-ett-. it was tested to zero for each ventilator in each rc condition. results: median vt was ml. table displays mean (± sd) difference in vt (ml) between atc+ ett+ and atc-ett-: a negative value means that atc under delivers and a positive value that atc over delivers vt for a given patient's inspiratory effort and rc. in four ventilators (c , s , elisa and ) atc almost systematically under delivered vt. in several instances under compensation was greater than % median vt. by contrast atc performed better with the other three ventilators (evita xl, v and carescape ). conclusion: atc tended to under deliver vt. furthermore, there were marked differences between icu ventilators the clinician should be aware of when using the atc option. compliance with ethics regulations: na. rationale: during the last decades, identification of factors associated with ventilation-induced lung injury has led to improved survival in patients with ards. the mechanical power of ventilation is the total energy transmitted from the ventilator to the respiratory system per unit of time and comprises three different components: elastic related to peep, elastic related to tidal volume and resistive. this integrative variable has been recently proposed as an useful predictor of ventilationinduced lung injury and death among ventilated patients. our goal was to determine the respective impact of the total mechanical power and its three components on the outcome of patients with ards. patients and methods: we performed a post hoc analysis of a randomized, controlled study of patients with ards with a pao /fio ratio < . themechanical power at inclusion and averaged on the first days after inclusion (total and its three different components) was computed according to the following equation: powerrs (j/ min) = . respiratory rate tidal volume [peep ( ) + ½ driving pressure ( ) + (peak pressure-plateau pressure) ( )], where the ( ), ( ) and ( ) parts correspond respectively to the elastic related to peep, elastic related to tidal volume and resistive components. the association between each of these four types of mechanical power evaluated during the first days after inclusion and mortality at d was assessed one after the other through multiple logistic regression, allowing control for potential confounding variables at inclusion (age, igs score without age, group of randomization, pao /fio , arterial ph). results: data from patients were analyzed, among which ( . %) died before d . there was no difference concerning the mechanical power at inclusion between survivors and non survivors (either total or its three components). among the four different types of mechanical power tested during the first days after inclusion, the elastic component related to tidal volume was the only one that was independently associated with mortality at d (or . ; % ci . - . ; p = . ) (figure) . conclusion: our study shows that only the elastic component of the mechanical power related to tidal volume independently predicted mortality at d among patients with ards, whereas the total mechanical power, its elastic component related to peep and its resistive component did not. further studies are needed to better define how the mechanical power of ventilation could be useful to synthetize the risk of ventilation-induced lung injury. compliance with ethics regulations: yes. probability of death at d as a factor of mean value (on d -d ) of the elastic component related to tidal volume of the mechanical power. to examine the effect of early-stage mechanical ventilation (mv) on diaphragmatic contractility. in the nd step, if a diaphragmatic dysfunction was detected, we assessed its influence on the weaning from ventilator. patients and methods: we measured prospectively the ultrasounddiaphragmatic thickening fraction (dtf) between groups: a study group versus a control group (n = for each). the study group included all adult patients receiving mv, in whom, the dtf was measured within a minimum of h and a maximum of days of mv. for the control group, were enrolled after their approval for participation, adult volunteers in spontaneous ventilation (sv). patients with factors affecting the diaphragmatic contractility (neuromuscular disease, severe obesity, and neuromuscular blockers…) were excluded. the ultrasound measurements were obtained at the zone of apposition of the right hemithorax. teleinspiratory and telexpiratory diameters (tid/ ted) were taken on the medio-axillary lines: posterior, median and anterior. the dtf was calculated as following: dtf = (tid-ted/ted) x . at the st step, the dtfs were compared and at the nd step: the relationship between dtf and weaning was analysed. results: our groups were comparable in corpulence and co morbidities. the sv group was younger ( vs. years, p < . ) with a predominant female composition. the diaphragmatic exploration concluded that in the mv group, the mean tid tended to be higher but without significant difference ( . + versus . + mm, p = . ), the mean ted was significantly higher ( . + versus . + . mm, p = . ) and dtf was significantly lower ( . + . % versus + . %, p = . ). the ventilation mode had no effect on dtf ( . + % for control volume vs. . + % for psv mode, p = . ). fourteen among ventilated patients had a successful weaning with a mean duration of days. a negative correlation was found close to significance between dtf and weaning duration (rho = − . and p = . ). a dtf value > % wasassociated with weaning success (or = , % ci = [ . - . ] and p = . ) with sensitivity = . %, specificity = %, ppv = % and npv = %. conclusion: the diaphragmatic contractile function was altered from the first days of mv. weaning duration seemed to be negatively correlated with dtf, and a dtf at the first days of mv greater than % was predictive of weaning success. compliance with ethics regulations: yes. rationale: mechanical ventilation is a life-saving treatment that is however associated with lung injury and/or diaphragm dysfunction. the optimal ventilator settings to provide lung protective ventilation while maintaining safe diaphragm activity are difficult to determine. a noninvasive and bedside evaluation of the diaphragm activity could be helpful in this context. the present study investigated whether changes in diaphragm shear modulus (i.e. stiffness, Δsmdi) assessed by ultrasound shear wave elastography (swe) may be used as a surrogate of changes in transdiaphragmatic pressure (Δpdi) in mechanically ventilated patients. patients and methods: patients had to be ventilated for at least h without contraindications for the placement of an oeso-gastric catheter. pdi was monitored continuously and smdi was measured at the zone of apposition of the right hemi-diaphragm, at hz sampling rate. measurements were performed twice under initial ventilator settings and at the end of a weaning trial. pearson correlation coefficients (r) were computed to determine within-individual correlations between pdi and smdi and changes in pdi and in smdi occurring between initial ventilator settings and the end of the sbt were compared by a paired test. results: twenty-five patients were enrolled and displayed a significant correlation between Δsmdi and Δpdi (mean r = . , range = . - . , all p < . ) (fig. a ). compared to their counterparts, patients with significant within correlations had a lower respiratory rate ( . ± . vs . ± . breath/min. respectively; p < . ) and a significant increase in Δsmdi ( . ± . kpa vs . ± . kpa. p < . ) between initial ventilator settings and the sbt. patients without Δsmdi-Δpdi correlation only displayed an increase in Δpdi ( . ± . vs . ± . cmh o, p < . ) at the end of the sbt with no concomitant significant increase in Δsmdi ( . ± . kpa vs . ± . kpa, p > . ). (fig. b) . conclusion: smdi obtained by swe appears as a promising technique to assess diaphragm activity in mechanically ventilated patients but technological improvements are necessary to increase swe sampling rate before enabling its generalization in the icu. compliance with ethics regulations: yes. rationale: end-inspiratory (eip) and end-expiratory (eep) pauses are commonly used during volume assist control ventilation to assess plateau pressure and total positive end-expiratory pressure (peeptot). they can also be used during assisted ventilation (av) for muscle pressure assessment. it requires ventilators able to perform eip during av. plateau pressure (pplat) usually increases in av during eip due to "hidden" inspiratory effort. pressure muscular index (pmi) is equal to pplat minus the sum of peeptot (measured during an eep) and set pressure support (ps); it theoretically reflects patient's effort without esophageal pressure (pes) monitoring. pes is the gold standard method to assess inspiratory muscle pressure (pmus, difference of pes drop at neural end-inspiration and correction factor for chest wall elastance and tidal volume). we aimed to illustrate the feasibility of measuring pmi using a standard icu ventilator at the bedside and study the correlation between pmus and pmi. patients and methods: measurements were recorded in icu patients. pes was measured using an nasogastric probe (equipped with an esophageal balloon) inserted for advanced monitoring (severe acute respiratory distress syndrome-ards) or for a study protocol (difficult weaning after copd exacerbation). recorded eip, eep and pes were used for post hoc analyses. results reported as ranges and median [iqr] . correlation between pmus and pmi tested with spearman correlation test. results: out of eip and eep duos could be analyzed ( -esophageal spasm/ -calibration error). ventilator mode was pressure support ventilation (ps - cmh o). cmh o, pmus = . [ . - . ] cmh o, pmi = . [ . - . ]. for all recordings, spearman r coefficient between pmus and pmi was . (p = . ). conclusion: muscular effort can be assessed in av using eip and eep using icu ventilators. however, recordings can be influenced by expiratory muscles contraction. patient's ability to follow directions during the maneuvers is an important factor to obtain reliable values. there seem to be a correlation in our small sample between muscular pressure assessed without and with pes. compliance with ethics regulations: yes. rationale: severe pneumonia can culminate in acute respiratory distress syndrome (ards). an uncontrolled inflammatory response is a key feature favoring transition towards ards. however, the underlying mechanisms remain poorly understood. in this context, the contribution of "innate t cells" (itc) -a family of non-peptide reactive t cells comprising nkt cells, mucosal associated invariant t (mait) cells and γδt cells-has never been explored. itc have emerged as key players in orchestration of the host response during infections and inflammation processes. for these reasons, these cells are already seen as potential therapeutic targets in other medical fields (especially oncology). here, we hypothesized that a tight regulation of their functions could be paramount to control the inflammatory response and to prevent ards development. patients and methods: to explore this, we combined a murinemodel of influenza a virus (iav) infection mimicking ardssymptoms and a clinical study recruiting patients admitted in icu for severe pneumonia. using flow-cytometry approaches, we investigated ( ) the abundance and dynamics of itc in various compartments, ( ) their pattern of activation/regulation markers (respectively cd and pd- ) and ( ) their cytokine production. results: during experimental iav pneumonia, itc were transiently recruited into the airways. unlike γδt and nkt, mait cells phenotype was largely changed, displaying a progressive cd overexpression and increased il- a production. during the resolution phase, up to % of pulmonary maits expressed pd- (versus < % in controls), which can suggest emergence of regulatory functions. last, using gene-targeted mice, we suggested that mait cells confer a protective effect during pneumonia. in the ongoing clinical study, the proportion of circulating mait cells in patients was markedly decreased compared to controls ( . ± . % versus . ± . % of t cells), but not for nkt or γδt cells. notably, some patients with severe ards presented detectable levels of maits in their respiratory fluids. in addition, circulating mait cells in patients overexpressed cd and pd- ( . % and % respectively), but with a reduced proportion able to produce il- and ifnγ, compared to healthy controls. lastly, proportion of activated (cd +) mait cells significantly decreased with clinical improvement. conclusion: this translational approach combining in vivo animal experiments and clinical samples with ex vivo experiments indicates a preferential modulation in mait cells functions during severe pneumonia. these data justify an in-depth analysis of mait cells activation mechanisms and functions in this context, in order to further explore a potential use as a disease-progression marker and -in a long term perspective-as a potential therapeutic target. compliance with ethics regulations: yes. representative flow-cytometry dot-plots of mait cells labelling using fluorophore-conjugated mr tetramers loaded with -op-ru from lungs of an infected mouse (a) and blood sample of a patient with pneumonia (b). c: frequency of mait cells, proportion of cd and pd- + mait cells in bronchoalveolar lavage during experimental murine pneumonia. d: blood frequency of mait cells in patients with pneumonia compared with healthy controls (as % of total t cells) rationale: immune paralysis following hyperinflammatory states increases the risk of secondary infections and death. reversing t-cells exhaustion using recombinant il or immune checkpoints inhibitors may improve the prognosis of patients with sepsis admitted to the icu. however, there is an unmet need to better characterize the state of t-cells exhaustion in these patients, its reproducibility and its correlation with the outcomes before implementing immunotherapy in the therapeutic armamentarium against sepsis. patients and methods: prospective observational cohort study performed in two tertiary-care icus in a university hospital. peripheral blood mononuclear cells were collected at day in adult patients with sepsis admitted to the icu. the level of cd + and cd + t-cells exhaustion was quantified using multi-color flux cytometry targeting the following exhaustion markers: pd- , b and cd . cd + regulatory t-cells (cd + cd + cd hi cd lo cells) were also assessed. results: the patients included in the study could be split in five clusters according to their dominant pattern of exhaustion markers on cd + t-cell (i.e. no markers, pd- +, b +, b + cd + and b + pd- +) and independently of their underlying morbidities. no patients harbored a fully exhausted triple-positive pattern. by multivariate analysis, saps gravity score at day (p = . ), a dominant b and/or pd- cd + pattern (p = . ) and lung sepsis (p = . ) where associated with the risk of death at day , whereas hemoglobin level was associated with survival (p = . ). no cd + or cd + exhaustion pattern independently predicted the risk of secondary infections. neither the level of cd + regulatory t-cells nor the dominant cd + exhaustion pattern was associated with the outcomes. rationale: there is growing use of multiplex polymerase chain reaction (mpcr) for respiratory virus testing in patients with communityacquired pneumonia (cap). data on one-year outcomes in patients with severe cap of bacterial, viral and unidentified etiology are scarce. patients and methods: a single-center retrospective study was performed in intensive care unit (icu) patients with known one-year survival status who had undergone respiratory virus testing for cap by mpcr. one year after icu admission, mortality rates and functional status were compared in patients with cap of bacterial, viral or unidentified etiology. results: there were ( . %) patients in the bacterial group, ( . %) in the viral group and ( . %) with unidentified etiology. one-year mortality was . % (n = / ), % (n = / ) and . % (n = / ), respectively (p = . ). in multivariate analysis, one-year mortality was higher in the bacterial group than in the viral group (hr . , % ic . - . , p = . ), had a trend to be higher in the bacterial group compared to the unidentified etiology group (hr . , % ic . - . , p = . ) and was not different between the viral and unidentified etiology groups (hr . , % ic . - . , p = . ). severe dyspnea (mmrc score = or death), major adverse respiratory events (new homecare ventilatory support or death) and severe autonomy deficiencies (adl katz score ≤ ordeath) were observed in / ( . %), / ( . %) and / ( . %) patients, respectively, with no difference between groups. conclusion: cap of bacterial origin was associated with a poorer prognosis than viral or unidentified etiology. impaired functional status was observed in a substantial proportion at one-year, irrespective of the causative microorganisms involved. compliance with ethics regulations: yes. interest of unyvero multiplex pcr (curetis) for bal rapid microbiologic and antibiotic susceptibility documentations in immunocompromised patients under antibiotic therapy jean-luc baudel , jacques tankovic , redouane dahoumane , salah gallah , laurent benzerara , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet rationale: our aim was to evaluate the interest of the unyvero rapid ( . h) multiplex pcr assay (performed on bronchoalveolar lavage [bal] samples) for the management of immunocompromised patients already treated with antibiotics and diagnosed with pneumonia (according to clinical and radiological findings). we thus performed an observational study that compared the results (and the length of time to obtain them) of routine microbiological evaluation and unyvero assay. patients and methods: from july to january and from april to august , we examined bal samples from immunocompromised patients (coming from hematology, oncology, hepatology, gastroenterology, internal medicine, and neurology units) diagnosed with pneumonia (based on clinical and radiological findings), and already receiving antibiotic treatment. the following data were collected: age, gender, saps score, lung ct scan ( %) or x-ray ( %) results, duration and content of prior antibiotic therapy, direct examination, culture, antibiogram and unyvero results, secondary confirmation of pneumonia or not, possible changes in antibiotic therapy that could have been made after obtention of unyvero results. informed consent was obtained from all patients. results: bal samples were analyzed in immunocompromised patients (m/f ratio . , saps . ± . ) mostly with hematologic ( %) or oncologic ( %) diseases. the patients received either corticosteroids ( %), or chemotherapy ( %), or immunotherapy ( %). % of the patients were under mechanical ventilation, % under optiflow. % presented a shock, % had aplasia or neutropenia, % were allografted, % were autografted. the duration of prior antibiotic therapy at the time of bal were . ± . days. direct examination was positive in . % of the cases, culture (both above and under the classical threshold of cfu/ml) in %, unyvero in . %. a retrospective analysis of all the cases confirmed the initial diagnosis of pneumonia in only % of the cases. compared to culture, the sensitivity of unyvero was %, its specificity %. unyvero could permit to rapidly deescalate antibiotic therapy in % of the cases and to rapidly stop it in %. the unyvero assay on bal samples is useful in this specific population for rapid obtention of microbiological results and also for confirmation of the negativity of cultures and thus permits a better management of antibiotic therapy, leading to a reduction of antibiotic resistance selection pressure in the icu. compliance with ethics regulations: yes. do not underestimate rsv pneumonia among critically ill patients erwan begot , suzanne champion , charline sazio , benjamin clouzeau , alexandre boyer , hoang-nam bui , marie-edith lafon , camille ciccone , julia dina , didier gruson , renaud prével chu bordeaux, medical intensive care unit, bordeaux, france; chu bordeaux, virology laboratory, bordeaux, france; national reference center for measles mumps and rubella, chu de caen, caen, france correspondence: erwan begot (erwan.begot@chu-bordeaux.fr) ann. intensive care , (suppl ):f- rationale: respiratory syncitial virus (rsv) is a well-known cause of respiratory failure among neonates but its pathogenicity in adults is now emerging as a potential cause of viral pneumonia. data are limited with conflicting results regarding rsv pneumonia severity in adults. data are lacking about critically ill rsv patients' characteristics and outcomes. the aim of this study is to compare rsv patients' characteristics, care and outcomes to influenza patients' ones. patients and methods: patients diagnosed with rsv and influenza pneumonia admitted to our medical icu were included. data were retrospectively recorded. quantitative data are expressed by median and interquartile range and compared by use of mann-whitney test. qualitative data are expressed by number and percentages and compared by use of fischer exact t-test. rsv strains were prospectively collected. results: eighteen critically ill patients with rsv pneumonia and with influenza pneumonia were included. rsv and influenza patients had the same characteristics at admission except for age (respectively yo [ ; ] and acute respiratory distress syndrome rates (respectively / ( %) vs / ( %), p = . ). they received similar treatment as suggested by oro-tracheal intubation rates (respectively / ( %) vs / ( %), p: . ) and antibiotics prescription (respectively / ( %) vs / ( %), p: . ). rsv and influenza patients also had the same rates of bacterial co-infections ( / ( %) vs ( %), p: . ). invasive aspergillosis remained a rare event but also occurred among rsv patients ( / ( %) vs / ( %), p: . ). acute coronary syndromes were as frequent in both groups (respectively / ( %) vs / ( %), p = . ). day- mortality was similar between rsv and influenza patients (respectively / ( %) rationale: respiratory distress from seawater drowning is commonly considered multifactorial. etiologies are debatable and include heart failure, infection and acute respiratory distress syndrome (ards). documented bacterial infections seems mostly related to the site of drowning. data in this regard are scarce with prospective studies lacking. the objective of our study was to describe prospectively the characteristics and determinants of respiratory distress from seawater drowning. patients and methods: all patients admitted for seawater drowning to seven intensive care units (icu) on the french riviera in the summers of and were prospectively included. recorded data included clinical features on examination, personal history, chest x-rays, echocardiography and biological results obtained within the first h. a paired student's t-test was used to study statistical differences between quantitative variables on admission and during early evaluation (i.e. first h). results: forty-eight patients were admitted to seven centers of which ( %) were diagnosed as having ards, ( %) early pneumonia and ( %) acute cardiogenic pulmonary edema. twenty-one ( %) respiratory samples were collected but bacterial culture was positive in only cases. multidrug-resistant bacteria were not observed, and amoxicillin-clavulanate as first-line treatment was effective in all cases. echocardiography performed in ( %) patients was normal and unable to identify specific patient profiles. the median clinical pulmonary infection score (cpis) on admission was (iqr, - ) and decreased rapidly and significantly (p < . ) within h to (iqr, - ) (fig. ) . conclusion: data from this multicenter cohort suggest that respiratory distress following seawater drowning can mimic bacterial pneumonia during the first h with subsequent rapid clinical improvement in patients admitted to the icu. probabilistic antibacterial therapy should therefore be limited to the most severe patients. isolate ards is often the only etiology found and is resolutive within h. this prospective cohort is the largest of its kind and gives a better insight into the limited impact of cardiogenic and infectious processes on sea drowning-related respiratory distress. compliance with ethics regulations: yes. rationale: patients treated with "extracorporeal membrane oxygenation" (ecmo) are at a higher risk of developing nosocomial infections and they are consequently often treated with beta-lactams. french guidelines recommend obtaining beta-lactam trough concentrations above four times the minimal inhibitory concentration (mic) of the causative bacteria. the ecmo device may alter the pharmacokinetics of these medications, which may result in underexposure to beta-lactam antibiotics. patients and methods: this observational, prospective, multicenter, case-control study was performed in the intensive care units of two tertiary care hospitals in france. ecmo patients with sepsis treated with piperacillin-tazobactam were enrolled. control patients were matched according to sofa score and creatinine clearance. the pharmacokinetics of piperacillin was described based on a population pharmacokinetic model, allowing to calculate the time spent above × the mic breakpoint for pseudomonas aeruginosa susceptibility after the first dose and at steady state between two piperacillin infusions. results: forty-two patients were included. the median age was years [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the sofa score was [ ] [ ] [ ] [ ] [ ] [ ] , and median creatinine clearance was ml/min . there was no significant difference in the time above x mic in patients treated with ecmo and controls during the first administration (p = . ) and at steady state (p = . ). there was no significant difference between the trough at steady state (p = . ), with / patients ( %) exhibiting concentrations of piperacillin lower than x mic. ecmo support was not associated with a steady state trough concentration below x mic (or = . [ . - . ], p = . ). the only variable independently associated with this risk was a creatinine clearance ≥ ml/min, (or = . [ . - . ], p = . ). conclusion: ecmo support has no significant impact on piperacillin exposure. intensive care unit patients with sepsis are, however, frequently underexposed with piperacillin, which suggest that therapeutic drug monitoring should be strongly recommended for severe infections. impact of a visual support dedicated to prognosis of patients on symptoms of stress of family members rationale: family members commonly have inaccurate expectations of patient's prognosis. adding to classic oral information a visual support, depicting day by day the evolution of the condition of the patient, improves the concordance in prognosis estimate between physicians and family members. the objective of this study was to evaluate the impact of this support on symptoms of anxiety/depression of family members. patients and methods: we conducted a bi-center prospective beforeafter study. all consecutive patients admitted in the two icus were eligible. in the before period ( months), family members received classic oral information. in the after period ( months) , in addition to classic oral information, the visual support ( fig. ) was available for family members in the patient's room from the day of admission until discharge from the icu. at day and from admission, symptoms of anxiety/depression of referent family member were evaluated by hospital anxiety and depression scale (hads). results: patients and their referent family members were included ( in period before and after). characteristics of patients of the two groups were similar regarding age, reason for admission, saps ii at admission and sofa score at day . also characteristics of referent family members were comparable in terms of age, sex ratio, type of relationship with the patient and number of visits since admission. at day , total had score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group before without the support and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after with the support (p = . ). the prevalence of symptoms of anxiety (had-a score > ) and depression (had-d score > ) was similar in the two groups (respectively . % and . % in the group before, and . % and . % in the group after (ns)). at day , total had score was in the group before [ - ] and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after (p = . ). by multivariate analysis the following factors were significantly associated with total had score > at day : age of patient ]), number of visits of referent ) and previous or current treatment of referent for anxiety or depression . ]). conclusion: in this study, the use of a visual support dedicated to prognosis of patients did not modify the level of stress of family members. compliance with ethics regulations: yes. rationale: the use of sedation and opioids at the end of life is a topic of considerable ethical debate. incidence of discomfort during the end-of-life of icu patients and impact of sedation on discomfort are poorly known. patients and methods: post-hoc analysis of an observational prospective multicenter study comparing terminal weaning vs. immediate extubation for end-of-life in icu patients, aimed at assessing the incidence of discomfort events according to levels of sedation. discomforts including gasps, significant bronchial obstruction or high behavioral pain scale score, were prospectively assessed by nurses from mechanical ventilation withdrawal until death. level of sedation was assessed using the richmond agitation sedation scale (rass). results: among the patients included in the original study, ( %) experienced discomfort after mechanical ventilation withdrawal. patients with discomfort received lower doses of midazolam and equivalent morphine, and less frequently had deep sedation (rass - ) than patients without discomfort ( % vs %, p < . ). after multivariate logistic regression, immediate extubation was the only factor associated with discomfort whereas deep sedation and administrations of vasoactive drugs were two factors independently associated with no discomfort. death occurred less rapidly in patient with discomfort than in those without discomfort ( . h [ . - . ] vs . [ . - . ], p < . ) (figure) . long-term evaluation of psychological disorders in family members of dead patients did not differ between those with discomfort and the others. discussion: despite the theoretically expected anticipatory titrated doses of opioids and benzodiazepines to alleviate any discomfort after withdrawal of mechanical ventilation, half of the patients did not receive sedation or opiate when the decision to withdraw mechanical ventilation was taken. a major point that could interfere with the continuous deep sedation practice until death is the fear of potentially hastening death, and there is much controversy regarding its proper use in end-of-life care. conclusion: discomfort was frequent during end-of-life of icu patients and was mainly associated with terminal extubation and less profound sedation. compliance with ethics regulations: yes. rationale: bereavement in intensive care unit (icu) is associated with psychiatric disorders on relatives called post-intensive care syndrome family (pics-f). no isolated intervention (such as condolence letter) has shown a positive effect on these disorders, despite a well acceptance by relatives. we thought that a more integrated bereavement program should be considered. the goal of this study is to evaluate a combined psychologist-physician post-death meeting (pdm) in a bereavement program to evaluate needs and adhesion of relatives, and the effect on symptoms of anxiety and depression. patients and methods: monocentric, prospective study focused on relatives of patient admitted > h and deceased in icu. during patient's stay, relatives' presence was allowed on a h-basis and they could meet a clinician psychologist. formal meeting between relatives and the staff was realized at patient's admission and after important decision-making treatment. two weeks after patient's death, the psychologist called relatives to offer emotional support and to invite to a pdm. pdm occurs weeks after patient's death with the psychologist and the physician in charge of the patient. the objectives of the meeting were to provide emotional support, to answer medical question, and to detect symptoms of anxiety and/or depression with the hospital anxiety and depression scale (hads). we hypothesized that pmd would be able to alleviate pics-f at months. we aimed to enroll families to detect a % lowering of hads. results: the rate of pdm acceptance was lower than expected. after inclusions, only relatives accepted the pdm, whereas the phone call was well perceived ( %). main association with acceptance of pmd was a short duration of icu stay ( . days [ - . ] vs . days [ . - . ] p = . ) and icu admission for acute respiratory failure ( . % vs . %, p = . ) ( table ) . we found no relation between the number of in icu meeting (psychologist of medical staff) and pmd acceptance. for relatives who accept pmd we found a high proportion of symptoms of anxiety and depression ( % and %) with a hads at . [ - . ] (median, iqr). no evaluation was performed at months. conclusion: post death contact appears well perceived by relatives but pmd quite useless. this result may be explained by the inclusion of only late death (> h) where psychologist and medical staff had the opportunity to support relatives. further study should focus on early death (< h). compliance with ethics regulations: yes. rationale: pediatric intensivists frequently question themselves on the issue of limitation or termination of life-sustaining treatments (llst) carried out on children. such a decision comes under the claeys-leonetti law which forbids doctors from applying unreasonable treatment however, every so often, parents oppose themselves to a collegial llst decision that the medical and paramedical team had taken. such cases can even end up in court. in order to sort out this problem, this study focused on the factors that underlie the disagreement and the solution brought forward by pediatricians whenever parents demand to persue treatments although considered as unreasonable obstinacy. patients and methods: we carried out a qualitative study involving three multipurpose pediatric critical care unit. all pediatricians operating within these units were contacted. those who volonteered were met individually for a semi-directed interview. every interview was recorded and entitled to a complete hand-written retranscription. the interviews were analysed following the phenomenological interpretive analysis method and were subject to dual listing. results: pediatricians out of took part in the study. / claimed they would increase treatments or carry out cardiopulmonary resuscitation acts if asked to do so by parents, even if this went against the initial collegial decision. / claimed they would persue treatments although not beyond the current level. / said they would oppose themselves to parents concerning blood transfusion for comfort reasons. several key factors were identified as leading a doctor to the non-application of a llst decision: the certainty regarding the child's death on a short or mid-term basis ( / ), the litigiousness risk ( / ), the apprehension of mediatic pressure ( / ), the fear of a violent reaction from parents ( / ), other self-interest positions within the medical team ( / ), empathy towards parents ( / ), the uncertainty concerning the neurological prognosis ( / ), the lapse of time needed to fully accept the application in force of a decision ( / ). pediatricians out of admitted their own-suffering when confronted to the situation. conclusion: this study points out that pediatricians tend to follow parents' position when confronted to parental opposition. in such situations, pediatricians go against their own decision in order to safeguard the parental alliance even if it leads to unreasonable obstinacy, thus conflicting with medical deontological code obligations. compliance with ethics regulations: yes. rationale: end-of-life management strategies are clearly a worldwide issue of major importance that intensivists have to deal with on a daily basis. advance directives may be the solution sought to guide physicians to take such difficult decisions. yet, health care directives are not legislated in tunisia. the objective of this project was to draw a general descriptive overview to assess patients' wishes in tunisia. patients and methods: data were collected from a -item-questionnaire based on the french intensive care society's form for advance directives which was filled by people of general population in tunisia, including doctors and paramedics, from may to mid-september . all people included were or older and well informed of the form's utility. results: a total of participants were included. the mean age was . ± . years with extremes of and and a sex ratio of . . fourty-one ( . %) were either doctors or nurses and ( %) did suffer from a severe medical condition. among all the participants, ( . %) thought that end-of-life decisions were up to the doctor. for the rest, they willingly chose to be hospitalized in an icu, to undergo cardiopulmonary rescuscitation and to have ventilation support with orotracheal intubation or tracheostomy respectively in ( . %), ( . %) and ( . %) of the cases. only ( . %) refused temporary dialysis. when asked about sequelae they can live with, participants accepted hemiplegia in . % and paraplegia in . % of the cases. on the contrary, ( . %) refused to live in permanent coma and ( . %) disagreed to undergo tracheostomy and ventilation for life. moreover, ( . %) found that serious un aesthetic sequelae was a fatal consequence they could not survive. as well, only ( . %) consented to live with deep intellectual deficiency. regarding palliative care, ( . %) participants wished to be profoundly sedated until death, ( . %) prefered to die home over ( . %) in hospital. sixtytwo ( . %) desired to see a representative of their religion. furthermore, ( %) were for organ donnation. gender, being a health care professional and age under versus equal or over were not significant in dependent factors (p > . ). conclusion: it is our duty ashealth care professionals to spread advance directives awareness and education. nevertheless, the law should keep the pace with ethics evolution. compliance with ethics regulations: yes. rationale: adapted organ support techniques are needed to enhance reliability of preclinical animal experiments in the intensive care setting (guillon, annals of intensive care- ). a few renal replacement therapy (rrt) models have already been developed in rats, mostly hemodialysis in chronic kidney disease models or hemofiltration techniques in sepsis experiments. mounting evidence from clinical (gaudry, nejm- ) and histopathological studies suggest that rrt for acute kidney injury (aki) could impair renal recovery by acting as a 'second hit' leading to a maladaptive repair of tubular epithelium. we aimed to study this hypothesis in a hemodialysis model in rats with septic aki. patients and methods: on day , sprague-dawley rats were injected with lipopolysaccharide or placebo (nacl . %) intraperitoneally. on day , anesthetized rats underwent femoral artery catheterization for hemodynamic parameters monitoring. at the same time, one femoral vein and one carotid artery were catheterized for arterio-venous sterile extracorporeal circulation with or without passing through a miniature sterile polyester sulfone hemodialyzer ( cm surface, kda pores, microkros ® ) filled with dialyzate liquid in the outer compartment (table ) . vessels were ligated after the procedure and rats allowed to awaken. on day , rats were sacrificed. results: all rats injected with lipopolysaccharides o :b mg/kg survived at day . anesthesia was much challenging: ketamine + xylazine and tiletamine-zolazepam + xylazine required induction and maintenance intraperitoneal injections. these medications induced important hemodynamic parameters fluctuations and high mortality. isoflurane gas inhalation enabled better stability, less hypothermia and quick awakening. adequate temperature was controlled with a heating pad during the procedure and an incubator after. supine position was maintained. the whole circuit was anticoagulated with ml of heparinized saline ui/ml, since clots occurred in the absence of anticoagulation and bleeding when higher dosing was used. circuit (< . ml including dialyzer) was filled with saline solution before initiation, and total restitution of blood at the end of the experiment prevented any blood transfusion requirement. hematocrit was determined at beginning ( %) and end of experiment ( %). a peristaltic pump provided a blood flow rate of . ml/min, (higher rate was not tolerated) for h. of note, rats who underwent sham procedure (vessels ligature only) survived and did not display aki. circulation of a counterflow dialysate in the dialyzer is planned but has not been performed yet. conclusion: this hemodialysis system for rats is feasible at a reasonable price and might help research involving rrt in either ckd or aki. compliance with ethics regulations: yes. there were no significant relationship between rri and past medical history or severity score. we observed a significant negative correlation between rri and diastolic arterial pressure (p = . ) and heart rate (p = . ) as it could be expected by rri formula. an increased rri was associated with higher potassium (p = . ) and higher creatinine levels (p = . ). although not significant, we found a higher rate of subsequent rrt in the high rri group ( % vs %, p = . ). over the first days, fluid balance was significantly different between groups ( ml vs - ml respectively for low and high rri group, p = . ). since standard of care were similar, this suggests different fluid volume status between the two groups. in the low rri group, the cause of aki could predominantly be prerenal since positive fluid balance was not explained by more severe aki with refractory oliguria as shown by the low rrt rate. nevertheless, we did not observed any relationship between rri and the evolution of serum urea or creatinine levels, nor with the presumed aetiology of aki. conclusion: when focussing on the first rri measurement once stage aki was reached, rri ≤ . seems to be in favour of prerenal and transient renal dysfunction even if this is not supported by creatinine serum evolution. compliance with ethics regulations: yes. rationale: critically ill patients are at higher risk of bleeding but also dialysis filter clotting (inflammatory state). intermittent hemodialysis with calcium-free citrate-containing ( . mmol/l) dialysate (cafcit-ihd) recently emerged as a new safe and simple alternative to continuous renal replacement therapy allowing heparin-free extended dialysis sessions (> h). in this study, we aimed to answer to two issues still unresolved: (i) can citrate contained in the dialysate accumulate and lead to citrate intoxication in patients with liver disorders, and (ii) can citrate be avoided using citrate-and calcium-free dialysate (ccf-ihd)? patients and methods: monocentric retrospective study. among the sessions performed with cafcit-ihd, the ihd sessions ( critically ill patients) with citrate measurement available before and after the dialysis filter were reviewed. estimation of the liver clearance was performed using the picco lemon ® system (pulsion). in addition, sessions performed using ccf-ihd were reviewed. results: all the patients had liver disorders (post-liver transplantation period n = ; cirrhosis with child > a ). among the eighteen cafcit-ihd patients, fifteen ( %) and six ( %) received mechanical ventilation or vasopressive drugs, respectively. the median time of the dialysis session was h [ ] [ ] [ ] [ ] , with hourly ultrafiltration rate of ml (one premature termination not related to dysfunctional catheter). in all patients, ionized calcium (ica) decreased below . mmol/l after the filter, whereas post-filter calcium reinjection according to ionic dialysance led to a stable pre-filter (i.e. patient) ica. median citrate concentrations were all below . mmol/l after the filter (minimal concentration to obtain anticoagulation mmol/l) and all except one below the normal value (< µmol/l) before the filter. during all the sessions, ionized to total calcium ratio was below . and the strong ionized gap decreased. when available (n = ), no correlation could be identified between serum citrate concentration and liver clearance. last, in ccf-ihd sessions performed in critically ill patients, no premature termination occurred (median time of the sessions h) and post-filter ica also decreased below . mmol/l. no citrate accumulation could be identified in critically ill patients (even with liver disorders) and receiving extended dialysis sessions ( h or more) using calcium-free citrate containing-ihd. interestingly, we demonstrated that citrate is not required to obtain optimal regional anticoagulation (i.e. post-filter ica < . mmol/l), and a citrate-and calcium-free dialysate could be a safe alternative. compliance with ethics regulations: yes. rationale: ventilator induced diaphragmatic dysfunction is highly prevalent in adult critical care and associated with worse outcomes. specificities in pediatric respiratory physiology suggest that critically ill children may be at high risk of developing this complication, but no study has described the evolution of diaphragmatic function in critically ill children undergoing mechanical ventilation. this study aims to validate a method to quantify diaphragmatic function in mechanically ventilated children. in this prospective single-center observational study, children between week and years old intubated for elective ent surgery and without pre-existing neuromuscular disease or recent muscle paralysis were recruited. immediately after intubation, diaphragmatic function was evaluated using brief airway occlusion maneuvers during which airway pressure at the endotracheal tube (paw) and electrical activity of the diaphragm (eadi) were simultaneously measured for consecutive spontaneous breaths, while the endotracheal tube was occluded with a specific valve. occlusion maneuvers were repeated times. in order to account for central respiratory drive and sedation use, we recorded the neuromechanical efficiency ratio (nme, paw/eadi), in addition to the maximal inspiratory force (mif). in order to determine the optimal measure of nme during an occlusion, the variability over the three occlusion maneuvers of different variables (first breath, last breath, breath with maximal paw deflection, breath with maximal nme value, and median nme value) was assessed using coefficients of variation and repeatability coefficients. results: patients had a median age of . years (interquartile range . - . ), a median weight of kg ( - ), and were male ( %). the median evolution of paw, eadi, and nme ratio over the occluded breaths are represented on fig. . nme values corresponding to the last breath and the breath with maximal paw deflection were the least variable, with median coefficient of variation of % and % and repeatability coefficients of . and . , respectively. conclusion: brief airway occlusions can be used to assess diaphragmatic function in intubated children through both mif and nme ratio, and the latter should ideally be computed on the last breath or the breath with the largest pressure deflection to improve repeatability and decrease variation. compliance with ethics regulations: yes. epidemiology is poorly understood due to the rare use of validated diagnostic tools. the main objective of the study was to determine, by systematically calculating the wat- score, the incidence of ws in our surgical picu. the secondary objective was to analyze the risk factors, consequences and management modalities of ws. patients and methods: following institutional review board approval, we conducted a prospective monocentric study between july and january . all consecutive mechanically ventilated children admitted in our surgical picu with sedation/analgesia by continuous intra-venous (iv) benzodiazepines (bzd) and/or opioids for at least h were included. as soon as sedation was decreased and during h following their total discontinuation, wat- score was assessed twice a day. ws was defined by a wat- score > . the search for risk factors and consequences associated with ws was performed by univariate analysis (mann-whitney and chi test). ethical standards were satisfied and the lack of opposition from patients and their parents was systematically checked. results: the incidence of ws was % among the patients of our cohort including % of children admitted postoperatively and % after severe traumatic brain injury (tbi). significant results are reported in table . our results show that even for sedation time less than days, children could develop ws ( / patients). on the other hand, age, severity (pelod score), number of previous surgeries and severe tbi were not associated with ws. our study also demonstrated that cessation of sedation and prevention of ws was not uniform in our unit. the high incidence of withdrawal syndrome in our study, even in children sedated for less than days, and its consequences require thinking about prevention. we suggest a systematic monitoring of the occurrence of this adverse event using a validated score, from days of continuous iv sedation/analgesia. compliance with ethics regulations: yes. rationale: severe traumatic brain injury (tbi) is a major healthcare problem. amplitude and duration of intracranial hypertension is highly associated with patient outcome. the intracranial pressure (icp) is therefore one key parameter to monitor in the acute phase. when icp is monitored with an external ventricular drain, the pressure recorded by the monitor does not always correspond to the real icp, depending on the status (open/closed) of the -way tap. misleading values could therefore be sent to the patient medical record. our hypothesis is that a machine-learning algorithm will be able to identify automatically and in real time the reliable and non-reliable values of the icp signal. we retrospectively studied pediatric patients having an external ventricular drain between july and july , in a single pediatric intensive care unit. the icp signals were extracted from a high-frequency database ( hz) and pre-processed adequately. to train the algorithms, an annotated database was manually created with two classes: reliable icp vs. non-reliable icp (drain system opened to allow cerebrospinal fluid removal). eleven signal characteristics were compared between the two classes (mann-whitney test), and significantly differing variables were tested in the algorithms. we compared the performance of two machine-learning algorithms: the k-nearest neighbors (knn) and the support vector machine (svm). using -fold cross-validation method, % of the data was used to train the algorithms and % was used for testing. the best classifier was further validated by simulating a real-time icp analysis, using a s sliding-window approach with % overlap. the study was approved by the localresearch ethics committee. results: sixteen patients were included in the study. the training database created from patients, contained segments (of s duration) per class and per patient. eight signal variables were identified and kept to define the segments. the knn algorithm, with k = , led to the best performance, with a mean of % (mean ± sd: % ± . %). the knn was then visually validated on icp signals from the remaining two patients ( figure) . by simulating a real-time icp extraction, our algorithm was able to efficiently identify the reliable icp segments, and to display a mean value only for valid segments. university hospital picu (paris). all consecutive children ( month- years) admitted for acute encephalitis were included and diagnosis was confirmed using the consensus conference criteria's. data regarding clinical, biological and radiological presentations were collected as well as data on the therapeutics used and outcomes at discharge and at the last medical consultation. results: patients were included with a mean age of . years (range . to years old). infectious causes were identified in % (n = ), autoimmune causes in % (n = ) and acute demyelinating encephalomyelitis in % (n = ) of cases. etiology remained undetermined in % of cases (n = ). the most common pathogens were, in order of frequency, influenzae virus, mycoplasma pneumoniae and epstein-bar virus. the main clinical features were fever ( % n = ); epileptic seizures ( % n = ) and coma ( % n = ). regarding therapeutics, % of patients required mechanical ventilation and % of patients required hemodynamic support. % received corticosteroids, % intravenous immunoglobulins and % plasmatic exchanges. the use of these specific treatments was heterogeneous, especially in infectious and undetermined encephalitis, where respectively % and % received boluses of corticoids. the mean length of stay in picu was . days (range - days). the mortality rate was % and the overall rate of sequelae at discharge was % and % at distance, with % considered as severe (gose-ped score > ). the use of mechanical ventilation and young age at diagnosis were risk factors associated with poor prognosis at discharge. the etiology of acute encephalitis remains indeterminate in more than % cases with a clear predominance of infectious causes when an etiology is found. this is a severe pathology responsible for significant mortality and morbidity requiring long-term follow-up. compliance with ethics regulations: yes. rationale: preserving neurological outcome of children under extracorporeal membrane oxygenation (ecmo) remains challenging. acute brain injury (abi) is a frequent complication of ecmo that could be prevented by continuous neuromonitoring. cerebral near infrared spectroscopy (nirs) is routinely used for detecting cerebral complications of cardiac surgery. in adults and infants under prolonged ecmo, cerebral hypoxia is associated with poor neurological outcome. the aim of this study was to assess the value of an impaired cerebral oxygenation on mortality and occurrence of an abi in children under ecmo. patients and methods: children under years old were included in this observational retrospective monocentric study if they needed veno-venous (v-v) or veno-arterial (v-a) ecmo for respiratory and/ or circulatory failure and had concomittant nirs monitoring. cerebral desaturation was defined as a rsco value under % or under % from the baseline; cerebral hyperoxia was defined as a rsco value above %. proportion of time in cerebral desaturation and hyperoxia were recorded. neurological lesions were identified on imaging (mri or scan) by blinded radiologist and classified as major or minor. abi was defined as any hemorragic or ischemic lesion on cerebral imaging, including brain death. results: patients were included. ecmo duration was [ ; ] days. the mortality rate was ( . %), and the proportion of abi was ( %) including brain deaths, ( . %) major lesions, and ( . %) minor lesions. mean rsco was ± % in the right hemisphere, and ± % in the left hemisphere. there was no significant difference in cerebral hypoxia between survivors and non survivors, and between patients with and without an abi. cerebral hyperoxia was associated with a better survival (p = . in the right hemisphere, and p = . in the left hemisphere). in v-v ecmo and at the right conclusion: in our study, cerebral hypoxia was not associated with poor neurological outcome, but cerebral hyperoxia seems to be protective especially in v-v ecmo. this is the first study assessing the value of cerebral oxymetry in all age ranges pediatric ecmo. in this population, multimodal monitoring might be better than nirs alone to predict neurological impairment. further prospective studies are needed to assess first the feasibility, then the impact of such a monitoring. compliance with ethics regulations: yes. cerebral autoregulation impairment is associated with acute neurological events during pediatric extracorporeal membrane rationale: children supported by extracorporeal membrane oxygenation (ecmo) present a high risk of adverse neurological complications. as some animal studies have shown, cerebral autoregulation (ca) impairment after exposure to ecmo, may be a key factor. our main objective was to investigate the feasibility of ca continuous monitoring during ecmo treatment. the second objective was to analyze the relationship between ca impairment and neurological outcome. patients and methods: an observational prospective study including children treated by ecmo in centers was conducted. a correlation coefficient between the variations of regional cerebral oxygen saturation (rsco ) and the variations of mean arterial blood pressure(map) was calculated as an index of ca (cerebral oxygenation reactivity index, cox) during ecmo. a cox > . was considered as indicative for dysautoregulation. cox values were averaged inside mmhg-map bins, allowing determining optimal map (mapopt) and lower (lla) and upper (ula) limits of autoregulation in -h periods. neurological outcome was assessed by the onset of an acute neurologic event (ane) defined by occurrence of hemorrhagic or ischemic stroke and/ or clinical or electrical seizure and/or brain death during the ecmo treatment. rationale: myocardial ischemia reperfusion (ir) injury is the leading cause of perioperative morbi-mortality. protective effect of pharmacologic preconditioning such as anesthetic preconditioning (apc) with sevoflurane (sev) has been widely demonstrated in animal and human models. apc seems to protect myocardial cells from apoptosis, a programmed process of cell death tightly controlled by bcl- family proteins. however, the involved mechanisms in apc have yet to be characterized. we hypothesized that apc protects against myocardial apoptotic cell death by regulating bcl- anti-apoptotic members. to study the sev-induced apc mechanisms against myocardial ir, we used a validated in vitro model reproducing ir injury. rat cardiomyoblast cells h c were cultivated in . % o hypoxia in the presence of ischemia-mimicking medium. after min of ischemia, the reperfusion injuries are induced by replacing the culture medium with a krebs-henseleit normoxic medium for min. apc was performed by adding sev directly into the culture medium at an initial concentration of mm, prior to ischemia, for min. we then used another preconditioning agent, metformin (met), to explore the same signaling pathways. apoptotic cell death was measured by caspase activity assay and western blotting (expression of cleaved caspase ) under ir and apc conditions. results: our model faithfully reproduced the protective effect of apc which results in a significant decreased apoptosis under ir ( % reduction of the caspase enzymatic activity, correlated with a decrease of caspase cleavage). we showed that sev induces overexpression of the anti-apoptotic protein bcl-xl, which is responsible for the protective effect of apc. furthermore, these observations were confirmed in vivo in mouse heart lysates. we demonstrated that bcl-xl overexpression was due to the activation of the protein kinase akt. interestingly, we were able to show that preconditioning with met reproduces the protective effect of sev by inducing an akt-dependent bcl-xl overexpression. indeed, sev and met, which are both complex inhibitors of mitochondrial respiratory chain, seem to share a common reactive oxygenated species-dependent protective mechanism responsible for bcl-xl protein regulation. rationale: despite early endovascular treatment with successful recanalization, % of acute ischemic stroke (ais) patients experience a poor functional outcome after a large vessel occlusion. sepsis is frequent at the acute phase of stroke and is associated with poorer short and long term outcomes. we aimed to investigate the cerebral consequences of sepsis after recanalized ais and explore possible mechanisms involved. patients and methods: male c bl mice were randomly assigned to a x factorial plan to one of the following groups: ) a -minute middle cerebral artery (t-mcao) transient occlusion under inhaled general anesthesia, followed min after recanalization by intraperitoneal (i.p.) sepsis (lps, µg/g diluted in µl of nacl . %), (tmcao/ lps group); ) t-mcao followed by i.p. placebo ( µl of nacl . %) (tmcao/placebo group); ) sham operation (cervicotomy without carotid catheterization) followed by i.p. lps. (sham/lps group); ) sham operation followed by i.p. placebo, (sham/placebo group). in all groups, animals received subcutaneous fluid resuscitation ( µl nacl . %) immediately after the procedure and h later. twenty-four hours after recanalization, animals were scored for sepsis features and neurological deficit (on the modified neurological severity scale), (mnss) before sacrifice. the primary outcome measurement was a composite of death and hemorrhagic transformation at h. secondary outcome measurements included neurological deficit, sepsis features, neutrophil activation reflected by plasmatic myeloperoxydase (mpo) levels, stroke volume, and microglial activation in brain parenchyma (infarct core, perilesional area, controlateral hemisphere). results: t-mcao/lps animals had higher mnss ( . fold, p = . ) and sepsis ( fold, p = . ) scores at h with increased plasma mpo levels at h ( . fold, p < . ) and h ( . fold, p < . ), as well as, lower temperature ( . °c reduction, p = . ) and glycemia ( . g/l reduction, p = . ) as compared to tmcao/placebo animals. t-mcao/lps animals had a higher risk of unfavorable outcome at h ( -group comparison: p = . ; x analysis: t-mcao/lps, / − %vs. t-mcao/placebo / - %-, p < . ), whereas stroke volumes were not significantly different between groups. detailed results are presented in table . compared to t-mcao/placebo group, t-mcao/ lps animals had . fold increase (p = . ) in the mean number of microglial cells in the hemisphere controlateral to t-mcao, whereas no significant difference was observed in infarct core or peri-infarct parenchyma. conclusion: early sepsis after experimental ais worsens outcome and neurological deficit, without impacting stroke volume. early sepsisinduced systemic activation of neutrophils and increased microglial activation in the hemisphere contralateral to ischemia may have an important role on neurological outcomes observed in this setting. compliance with ethics regulations: yes. rationale: extracellular vesicles (evs) regulate diverse cellular and biological processes via facilitating intercellular cross-talk. several studies have suggested an association between lung injury and the generation of evs derived from platelets, neutrophils, monocytes, lymphocytes, red blood cells, endothelial cells, and epithelial cells. every year more than , patients require cardiac surgery with cardiopulmonary bypass (cpb). this cpb allows a substitution of the heart pump function and an oxygenation of the blood permitting a stop of the mechanical ventilation (mv). stopping mv during cpb is responsible for lung damage, leading to postoperative systemic inflammation while maintaining mv with positive expiratory pressure (peep) diminished the occurrence of atelectasis and the postoperative inflammatory response. in addition, this surgery is marked by immune dysfunction, leading to real immunosuppression of patients in postoperative care. a link between pulmonary injury and postoperative immunosuppression has been established, however, the mechanisms underlying this association are not fully known and evs may have a role in this post-operative immunosuppression. the purpose of this study is to investigate whether lung injury induced during cardiac surgery with cpb lead to the emergence of evs. the effect of mv during cpb on the production of these evs has also been studied. patients and methods: patients were prospectively divided into two groups: without mv during cpb and dead space mv with positive end-expiratory pressure during cpb. pao (arterial oxygen tension)/ fio (inspired oxygen fraction) ratio, biological markers of lung injury (cxcl , ccl , tnf-α, il- β, il- , rage, il- ) and blood cell count were collected before, h and days after surgery. the quantification of plasma evs was performed using turnable resistive pulse sensing and characterization of evs was performed using flow cytometry before, h and days after surgery. rationale: the benefit of prone positioning (pp) during moderate to severe acute respiratory distress syndrome (ards) may be related to its impact on the inflammatory response to ventilator-induced lung injuries. [ c]-pk is a positron emission tomography (pet) radiotracer that allows the non-invasive quantification of macrophages. we aimed to evaluate the effects of pp on [ c]-pk lung uptake in animals with experimental ards. patients and methods: experimental ards (by hydrochloric acid) was induced in pigs in supine position (sp), to obtain a pao / fio < mmhg. animals were under general anesthesia, neuromuscular blockade, and ventilated with a ml kg − tidal volume, and cmh o of positive end-expiratory pressure (peep). immediately after experimental ards, animals were randomized to be prone positioned, or to remain in sp. pet and computerized tomography (ct) were acquired h after randomization (h ). [ c]-pk uptake was measured on the whole lungs, and by dividing the lungs into regions or slices-of-interest (soi) along the ventro-dorsal axis, and was quantified by the standardized uptake value (suv), corrected for lung tissue density. results: pp was performed in animals, and sp in . after ards induction, pao /fio was [iqr, [ . - . ] in sp animals (p = . ). in pp animals, [ c]-pk suv was significantly lower in ventral soi, compared to sp, and significantly increased in dorsal soi ( fig. , *: p < . between groups in a given soi). in univariate analysis, [ c]-pk regional suv was positively associated with regional ct-measured peep-related increase in gas volume, and negatively with peep-related lung recruitment, but not with regional tidal volume. conclusion: during experimental ards, pp redistributed lung macrophage recruitment estimated by [ c]-pk uptake from ventral lung regions to dorsal regions, without affecting global macrophage influx. the intensity of macrophage recruitment was associated with peep-related lung inflation. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) is a pleiomorphic disease characterized by a severe respiratory failure associated with an increased mortality. nowadays, predicting clinical outcome of patients suffering from ards remains difficult. therefore, identifying new biomarkers to predict patient outcome, to evaluate response to therapy and to identify new potential pathways of interest are highly needed. exosomes are extracellular vesicles involved in cell-cell communication by transferring micrornas (mirnas) from donor to recipient cells. thus, exosomal mirnas can significantly affect biological pathways within recipient cells resulting in alterations of cellular function and the development of a pathological state. as biomarkers are highly needed in the particular field of ards, we realized a monocentric and prospective study to identify a new potential biomarker of interest. therefore, a prospective plasma sampling at the diagnosis of moderate to severe ards according to the definition of "berlin" has been performed. we analysed mirna content of exosomes from plasma ards patients compared to healthy subjects (hs) in order to identify new potential predictive biomarkers in ards. during one-year period, patients hospitalized in the icu of chu sart tilman suffering from infectious moderate-to-severe ards have been included. the ethical committee review boards of the hospital approved the research protocol (b , ref: / ), and informed consents were obtained. exosomes were isolated from plasma samples of ards patients and hs with standard ultracentrifugation protocol. exosomal mirna content was analyzed using small rna sequencing method, and diseases/biological processes associated to altered mirs were determined by bioinformatic analysis. results: for the first time, exosomal mirna expression modifications were studied in patients with moderate-to-severe infectious ards. we identified a new signature statistically significant composed of three up-regulated mirnas (mir- , mir- a and mir- ) and one downregulated (mir-let- b). conclusion: we identified potential biomarkers for ards from plasma exosomes. our findings may thus lead to predict ards outcome but also a better understanding about the roles of these mirs in the pathogenesis of ards and thus open new avenues for therapeutic approaches. in particular, exploit and develop the pro-fibrotic pathway induced by down-expression of mir-let- b. but also confirm in the future the current interest about mir- in its ability to restore pulmonary integrity after trauma. compliance with ethics regulations: yes. rationale: diabetic ketoacidosis (dka) is a life-threatening emergency. microvascular hyporeactivity was reported in these patients and was completely reversibly when ph was corrected with treatment: aggressive rehydration, electrolyte replacement and insulin therapy ( ) . red blood cell (rbc), a component of the microcirculation, showed alterations oftheir shape in diabetic patients ( ) but no data were available concerning the time course of the rbc deformability during treatment for dka. we aimed to assess the rbc deformability during dka treatment in icu patients. patients and methods: after approval by the ethics committee, rbcs deformability was assessed, in all icu patients admitted for dka and without infection, by ektacytometry technique (laser-assisted optical rotational red cell analyzer-lorrca): at icu admission, + h, + h and at the end of the icu stay ( - h). elongation index (ei) was defined as (l − w)/(l + w), where l is the length and w is the width. at °c, ei values were determined in the function of shear stress (ss) in a range of . - pa, based upon the laser diffraction pattern changes. a higher ei indicates greater rbc deformation. rbc deformability from patients with dka was compared at icu admission to healthy volunteers (v) and to diabetic patients followed in consultation (d). we also studied the evolution of deformability during treatment. results: icu dka patients compared to d and v were studied. as expected, glycemia and glycated hemoglobin were significantly higher in dka compared to d (respectively: glycemia: ( - ) vs ( - ) mg/dl and . % ( . - . ) vs . ( . - . ); all p < . ). dka patients received ( - ) ml of fluids and . ui/ kg bw ( . - . ) of insulin during their first h of icu stay. rbcs deformability from dka patients was significantly more altered at icu admission compared to others groups ( fig. ) and these alterations persists despite treatment. no correlations were observed between these alterations and quantity of fluids or insulin received, glycemia, glycated hemoglobin, ph, natremia, age or length of diabetes history. conclusion: in contrast of reversible microvascular hyporeactivity, rbc deformability from dka patients was already altered at icu admission and remains altered despite treatment. these alterations could contribute to the blood flow abnormalities observed in these patients. compliance with ethics regulations: yes. rationale: sepsis remains the first cause of acute circulatory failure in the emergency department (ed). standardized fluid resuscitation may not be adapted in certain patients, especially those with early sepsisinduced cardiac dysfunction in whom excessive fluid administration could be deleterious. information on early hemodynamic profile of septic patients in the ed are scarce. accordingly, we aimed at describing hemodynamic profiles encountered in septic patients assessed shortly after their ed admission using focused echocardiography. patients and methods: we prospectively enrolled adult patients with sepsis (qsofa score ≥ ) from january to july in the ed (nct ). focused echocardiography were performed by emergency physicians previously trained to ecmu level. each patient was evaluated according to a standardized protocol based on a limited number of simple binary clinical questions. investigators interpreted on-line the echocardiographic examination, determined the hemodynamic profile based on simple yet robust criteria (hypovolemia, left ventricular [lv] or right ventricular [rv] failure, vasoplegia with hyperdynamic state, tamponade, severe mitral or aortic regurgitation, or apparently normal profile), and recorded any substantial change in planned therapeutic management (surviving sepsis campaign ). data were digitally stored and validated off-line by an expert in critical care echocardiography. results: focused echocardiography were performed in patients (mean age: ± years; men: %; source of infection: pulmonary %, urinary %, abdominal %) after a median fluid loading of ml (iqr: - ml). according to sepsis- definition, patients had sepsis and sustained septic shock. mean sofa score was . ± . (hemodynamic failure %, respiratory failure %, renal failure %), mean lactate reached . ± . mmol/l, icu admission involved % of patients and overall -day mortality reached %. hemodynamic profile was hypovolemia in patients ( %), vasoplegia in patients ( %), cardiac failure in patients ( %) (lv failure: n = ; rv failure: n = ) and without relevant hemodynamic abnormality in patients ( %). ongoing therapy was altered based on early echocardiographic assessment in % of cases. mortality rate was not significantly different between groups (p = . ). conclusion: although hypovolemia was predominantly identified in patients presenting to the ed with sepsis during hemodynamic assessment, early ventricular dysfunction involved one-quarter of patients. these results suggest that early focused echocardiographic assessment promises to help the front-line physician tailoring the therapeutic management of septic patients in ed, especially regarding fluid resuscitation. compliance with ethics regulations: yes. right ventricular failure in septic shock characterization, incidence and impact on fluid-responsiveness guillaume geri , amélie prigent , xavier repessé , marine goudelin , gwenael prat , bruno evrard , cyril charron , philippe vignon , antoine vieillard-baron ambroise paré hospital, boulogne-billancourt, france; ambroise paré hospital, medical icu, aphp, boulogne-billancourt, france; chu limoges, limoges, france; chu brest, brest, france correspondence: guillaume geri (guillaume.geri@aphp.fr) ann. intensive care , (suppl ):f- rationale: right ventricular (rv) failure was defined by rv dilatation with systemic congestion. tricuspid annular plane systolic excursion (tapse) could be of limited value. we report the incidence of rv failure in patients with septic shock, its potential impact on the response to fluids, as well as tapse values. patients and methods: ancillary study of the hemopred prospective multicenter study including patients under mechanical ventilation with circulatory failure. with septic shock were analyzed. patients were classified in groups based on central venous pressure (cvp) and rv size (rv/lv end-diastolic area, eda). in group , patients had no rv dilatation (rv/lveda < . ). in group , patients had rv dilatation (rv/ lveda ≥ . ) with a cvp < mmhg (no venous congestion). rv failure was defined in group by rv dilatation and a cvp ≥ mmhg. passive leg raising (plr) was performed. results: % of patients were in group , % in group and % in group . in group and , rv/lv eda was higher than in group , . [ . ; . ] versus . [ . ; . ]. cvp was [ ; . ] mmhg in group . a correlation between rv size and cvp was only observed in group . higher rv size was associated with a lower response to plr (figure) . a large overlap of tapse values was observed between the groups. . % of patients with rv failure had an abnormal tapse. conclusion: rv failure is frequent in septic shock and alters fluid responsiveness. tapse was not accurate enough to diagnose rv failure. compliance with ethics regulations: yes. rationale: weaning-induced pulmonary oedema (wipo) is a leading cause of weaning failure in high-risk patients (heart failure, copd, obesity). we hypothesized that hypervolemia associated with positive fluid balance facilitates wipo in high-risk patients. patients and methods: in this prospective, observational, singlecenter study, patients with copd and/or heart failure with reduced ejection fraction (< %) were studied. exclusion criteria were nonsinus rhythm, severe mitral valve disease and inability to obtain adequate echocardiographic views. echocardiography was performed immediately before and during spontaneous breathing trial (sbt, -min t-tube). patients who failed sbt were treated according to echocardiographic results before undergoing a second sbt. fluid balance and body weight were collected at each sbt. shows interesting performance to predict fluid responsiveness in spontaneously breathing patients. nevertheless, measurement sites of inferior vena cava (ivc) diameters remain controversial for that purpose. the aim of the study was to test the accuracy of different measurement sites of civc to predict fluid responsiveness in spontaneously breathingpatients. this study is a post hoc analysis of two prospective cohorts. we included spontaneously breathing patients without mechanical ventilation presenting with sepsis-related acute circulatory failure and considered for volume expansion (ve). we assessed hemodynamic status at baseline and after a fluid challenge (fc) induced by a min-infusion of ml-gelatin %. the ivc diameters were measured off-line with ultrasonography using the bi-dimensional mode on a subcostal long-axis view. the civc was calculated as [ (expiratory-inspiratory)/expiratory] diameters during standardized (civc-st) and unstandardized breathing (civc-ns) conditions. breathing standardization consisted of a deep inspiration with concomitant control of buccal pressures and passive exhalation. patients were referred to be responders to fc (i.e. fluid responsive) when the stroke volume increased by ≥ %. results: among the patients included in the study, ( %) were responders to fc. the accuracy of civc-st and civc-ns before fc to predict fluid responsiveness differed significantly by measurement sites (interaction p value < . and < . , respectively). measuring ivc diameters cm from the junction of the ivc and the right atrium provided the best accuracy to predict fluid responsiveness ( fig. ). at cm caudal to the right atrium, civc-st was significantly better than civcns to predict fluid responsiveness: area under roc curve . ( % ci . - . ) versus . ( % ci . - . ), p < . . at cm, a civcst ≥ % and a civc-ns ≥ % predicted fluid responsiveness with sensitivity of % and %, and specificity of % and %, respectively. conclusion: accuracy of civc to predict fluid responsiveness in spontaneously breathing patients depends on both measurement sites of ivc diameters and breathing conditions. measuring ivc diameters during a standardized inspiration maneuver at cm caudal to the right atrium is the most relevant mean to optimize civc performance to guide ve. compliance with ethics regulations: yes. rationale: intermittent hemodialysis (ihd) is increasingly used in patients admitted to intensive care unit (icu) with acute kidney injury (aki) requiring renal replacement therapy (rrt). however, this technique is associated with nearly % of episodes of perdialytic hemodynamic instability (hi), a common cause of increased morbidity and mortality. at the same time, trans-thoracic echocardiography (tte) has become widely used in intensive care units and is now one of the hemodynamic monitoring methods used daily in the icu setting. patients and methods: search for one or more pre-dialysis tte criteria predictive of perdialytic hi, defined by a systolic blood pressure (sbp) lesser than mmhg or a suddain decrease in sbp of more than mmhg. prospective, observational study of standard care in a medical icu. collection of demographic, clinical and pre-dialysis echocardiographic data from included patients. results: twenty-five patients with a total of sessions of ihd between november and november were included in the study. tte was performed for each patient before each ihd session. hi occurred in hemodialysis sessions. in univariate analysis, the existence of prior heart disease ( % vs %, p = . ), a greater diameter of the left atrium ( . vs . cm, p = . ), a lower cardiac output ( . vs . l/min, p = . ), a right dysfunction assessed by lowered tapse and s-wave ( vs mm, p < . and . vs . cm/s, p = . , respectively) and an increase in paps ( vs mmhg, p = . ) were significantly associated with the occurrence of perdialytic hi (fig. rationale: several transthoracic echocardiography (tte) parameters of left (lv) and right ventricular (rv) systolic function are available. we compared the ability of these different parameters to track changes in lv or rv systolic function and to detect lv or rv systolic dysfunction in critically-ill patients. in patients ( mechanically ventilated and with atrial fibrillation), tte examinations were performed before and after i) infusion of -ml of saline (n = ), ii) changes in norepinephrine (n = ), iii) or in dobutamine (n = ) dosage. for the lv systolic function, we compared the mitral annular plane systolic excursion (mapse), the systolic (s') peak velocity of the lateral mitral annulus and the global longitudinal strain (glslv) to the lv ejection fraction (lvef), considered as the gold standard. for the rv systolic function, we compared the tricuspid annular plane systolic excursion (tapse), the systolic peak (s) velocity of the tricuspid annulus and the global longitudinal strain (glsrv) to the rv fractional area change (fac), considered as the gold standard. results: after pooling all values, lvef ( ± % at baseline) was better correlated to glslv (r = . ) than to mapse (r = . ) and s' wave (r = . ) (each p < . ). the concordance rate between changes (in %) in lvef and in the other parameters of lv systolic function was % for glslv, % for mapse and % for s' wave. both mapse and s' wave could not reliably detect moderate ( % ≤ lvef ≤ %) or severe (lvef < %) lv dysfunction. conversely, a glslv > − % predicted moderate lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %) and a glslv > − . % predicted severe lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). after pooling all values, fac ( ± % at baseline) was better correlated to glsrv (r = . ) than to tapse (r = . ) and s wave (r = . ) (each p < . ). the concordance rate between changes (in %) in fac and in the other parameters of rv systolic function was % for glsrv, % for tapse and % for s wave.both tapse and s wave could detect rv dysfunction (fac ≤ %) with moderate reliability only. conversely, a glsrv > − % detected rv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). in critically-ill patients, glslv and glsrv seem to be the best tte parameters of lv and rv systolic function. enrolments are still ongoing, which may allow further analysis. compliance with ethics regulations: yes. rationale: passive leg raising (plr), pulse pressure variation (ppv), and the -second end-expiratory occlusion test (eexpo) are frequently used to assess preload responsiveness. however, there are conditions in which they are not valid or feasible, which may preclude their applicability in the daily clinical practice. the aim of this study was to estimate the prevalence of such conditions in critically ill patients with acute circulatory failure. between january and april , all patients of a -bed medical icu were daily screened and those with acute circulatory failure, defined by norepinephrine infusion or fluid therapy > l during the previous h, were included. in each of them, we screened the criteria of validity/feasibility of ppv, plr and eexpo. results: eighty-four patients ( % with septic shock, % with cardiogenic shock, % with hypovolemic shock, % with non-septic vasoplegic shock) were enrolled in the study. among them, norepinephrine infusion was ongoing at the time of enrolment in % of the patients whilst % were under mechanical ventilation, and % with acute respiratory distress syndrome. plr was not applicable in % of cases. this was mainly due to venous compression stocking ( % of cases), intra-abdominal hypertension ( % of cases), and either an absence of cardiac output monitoring or impossibility to perform echocardiography ( % of cases). among the intubated patients, ppv was applicable in % of cases, including cases with high ppv under conditions generating false negatives (low tidal volume or lung compliance) or low ppv values under conditions generating false positives (spontaneous breathing, cardiac arrythmias). however, ppv was not interpretable in % of cases. this was mainly due to low tidal volume ventilation ( % of cases), spontaneous breathing activity ( % of cases), while the remaining non-interpretable cases ( %) had more than one reason. in the intubated patients, eexpo was not applicable in % of cases. this was due to impossibility for patients to sustain a -s hold of mechanical ventilation in % of cases, and either an absence of cardiac output monitoring or the impossibility to perform echocardiography in % of cases. plr and eexpo were both valid and feasible in % of the patients, and the three tests were all feasible in only % of patients. rationale: comorbid association between chronic respiratory diseases and sleep apnea syndrome (sas) revealed frequent with systematic search in icu following icu stay. this association carries prognosis impact depending whether specific treatment is implemented or not. nosas and stop bang scores are proposed for screening of sas in general population. the aim of the present study is to report the prevalence of sas in icu patients admitted for hypercapnic respiratory failure and compare association of nosas and stop bang score with sas severity. the study was conducted between january and september . patients consecutively admitted in the icu for hypercapnic respiratory failure had calculation of a no sas and stop bang scores at admission. in survivors nocturnal polygraphic records was performed to weeks following icu discharge. the association between the number of apnea-hypopnea episodes, bmi, and clinical variables suggestive of sas, was tested by poisson regression model. results: during the study-period, patients (mean age: ± years, ph . ± . , paco ± ) were admitted for hypercapnic respiratory failure. non invasive ventilation was used in % and death occurred in six patients. polygraphic records were performed in ( lost to follow-up) mean apnea-hypopnea index was ± with a minimum of and a maximum of . poisson logistic regression showed that no sas (p = . ) but not stop bang (p = . ) was associated with the level of apnea-hypopnea index. rationale: patients with severe acute exacerbations of chronic obstructive pulmonary disease (copd) may benefit from high-flow nasal oxygen regarding its physiological effects and good tolerance. bronchodilator vibrating mesh nebulization through high-flow nasal oxygen circuit has been described to induce similar effect to standard facial mask jet nebulization in stable copd patients. we aim to evaluate whether vibrating mesh nebulization of salbutamol through highflow nasal oxygen circuit is efficient in unstable patients with copd. patients and methods: we conducted a monocenter non-randomized physiological prospective cross-over study, between january and september , including icu patients with severe acute exacerbation of copd and respiratory acidosis treated by salbutamol nebulization. spirometry and airway resistances records were performed after a -h wash-out period without bronchodilator, before and after vibrating mesh nebulization of mg salbutamol through high-flow nasal oxygen circuit. the primary endpoint was forced expiratory volume in s after salbutamol nebulization. secondary endpoints included other spirometry parameters, clinical parameters, dyspnea assessed by a borg scale. results: fourteen consecutive patients were included, forced expiratory volume in s increased significantly after salbutamol nebulization through high-flow nasal oxygen ( ± ml, p = . ), as well as forced vital capacity ( ml ± , p = . ). airway resistances were not significantly changed after nebulization (− . ± . , p = . ) as well as peak expiratory flow (+ ml ± , p = . ). no difference was observed on borg scale (p = . ) and respiratory rate (p = . ) after salbutamol nebulization, while heart rate increased significantly (p = . ). discussion: salbutamol nebulization using vibrating mesh nebuliser placed on high-flow nasal oxygen circuit induces a significant but moderate bronchodilation in patients with severe acute exacerbation of copd. moreover, improvement of forced vital capacity after salbutamol nebulization suggests a reduction of dynamic hyperinflation. conclusion: salbutamol vibrating mesh nebulization through highflow nasal oxygen circuit increases significantly forced expiratory volume in s. compliance with ethics regulations: yes. t-piece versus sub-therapeutic pressure support for weaning from invasive mechanical ventilation in patients with chronic obstructive pulmonary disease: a comparative prospective study amira jamoussi, fatma jarraya, samia ayed, takoua merhabene, jalila ben khelil, mohamed besbes abderrahmen mami hospital, tunis, tunisia correspondence: amira jamoussi (dr.amira.jamoussi@gmail.com) ann. intensive care , (suppl ):f- rationale: the best weaning strategy for patients with chronic obstructive pulmonary disease (copd) remains unknown. the spontaneous breathing trial (sbt) represents a crucial step of weaning, but the choice between the t-piece (sv-tube) or the sub-therapeutic setting of the level of pressure support without positive expiratory pressure (psv) is still a matter of debate. we aimed to compare the success of extubation between two groups of copd patients according to the sbt type (vs-tube vs psv). patients and methods: it was a prospective and comparative study, from april to march , at the abderrahmen mami hospital's intensive care unit (icu). copd patients who underwent invasive mechanical ventilation (mv) for at least h and met the criteria for weaning were included and randomized to sv-tube or psv. a multivariate analysis was performed to determine the association between the sbt modality and the success of extubation (no re-intubation during the h following extubation). results: during the two years' study, patients were included. the mean age was ± years, the sex-ratio was . . weaning process was simple in patients ( %), difficult in patients ( %) and prolonged in patients ( %). fifteen and patients were respectively randomized to the sv-tube and psv groups. the mean duration of mv before randomization was comparable between the groups (sv-tube . ± . days vs psv . ± . days, p = . ). mean weaning time (days) was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the sv-tube group and . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the psv group. the mean total mv duration (days) was higher in the sv-tube group than in the psv group ( . vs . , p = . ). the number of re-intubated patients within h following extubation was higher in the psv group ( / vs / , p = . ) as well as the overall reintubation rate ( . % vs %, p = . ). in multivariate analysis, the sbt's trial was independently associated to the success of extubation (or = . , ic [ . - . ], p = . ) in favor of sv-tube' modality. the median length of stay in intensive care was days [ ; ]. the mortality was higher in the psv group ( / vs / , p = . ). extubation failure was a factor associated with mortality (or = . , ci [ . , . ], p = . ). conclusion: ventilation weaning was easy in % of intubated copd patients. sv-tube as sbt modality was associated to success of extubation in patients with copd. mortality in intensive care was significantly higher in re-intubated patients. compliance with ethics regulations: yes. rationale: non-invasive ventilation has become the mainstay in hypercapnic respiratory failure. delaying intubation and invasive ventilation is associated with a worse outcome in these patients. although a predictive score of niv failure has been validated for hypoxemic respiratory failure no such score exists in hypercapnic respiratory failure. the aim of our study is to compare the performance of two scores in the predictive niv failure hypercapnic respiratory failure. patients and methods: consecutive patients admitted between january and july for hypercapnic respiratory failure, were included. hacor score and rox score were calculated in each patient at admission. in patients ventilated non-invasively, the outcome (niv success or failure) was noted. the area under curve (auc) and operative characteristics were computed for both scores. results: during the study-period, out of patients admitted for hypercapnic respiratory failure received niv as the primary ventilatory mode. these patients were mainly men ( / ), had a mean age of . ± years and had the following pulmonary disease: copd exacerbation . %, obesity-hypoventilation syndrome . %, bronchiectasis . %, and other diseases: . %. niv failure occurred in patients ( . %) and icu mortality in . %. mean hacor score and rox score were . ± . and . ± , respectively. the auc under roc was higher for hacor than rox ( . and . respectively) ( fig. ). the hacor score (cut-off ) had a sensitivity of . and specificity of . . conclusion: hacor score seems more accurate in predicting niv failure in hypercapnic respiratory failure. further prospective validation is needed. compliance with ethics regulations: na. rationale: published data on outcomes in respiratory weaning centers are limited and seem to depend on the organisation of healthcare systems and patient case-mix. the weaning center of our university hospital (post intensive care rehabilitation unit) admits for weaning and rehabilitation patients from medical and surgical intensive care units without severe neurological pathologies. the aim of this study was to describe patient's characteristics and outcome (weaning outcomes and survival) and to compare in subgroups according to the initial medical, surgical or cardiac surgical context. patients and methods: we conducted a monocentric retrospective observational study between / / and / / . «successful outcome» was defined by the association of survival and weaning from invasive ventilation. factors associated with evolution were investigated by uni-and multivariate analysis. survival after discharge was analysed according to the initial context and according to the type of ventilation at discharge. results: among patients included, ( . %) had a successful outcome with high use of non-invasive ventilation (niv) ( %). respiratory history (p = . ), female gender (p < . ), igs score at admission to the srpr (p = . ) and non-cardiac surgical setting (p < . ) were associated with an adverse course. the -month survival rate was % in discharged patients. the outcome was not different in the tree subgroups. niv rate at discharge was high in the subgroup of cardiac surgery patients. a multidisciplinary and personalised approach by a specialized weaning unit can provide a successful service model for patients who require liberation from prolonged invasive mechanical ventilation. compliance with ethics regulations: yes. rationale: high-dose insulin euglycemic therapy (hiet) is recommended as first line therapy for calcium channel blockers (ccbs) poisoning because of its inotropic effect. our first objective was to study its hemodynamic impact. we performed a retrospective cohort study of all consecutive patients admitted for ccbs poisoning treated with hiet, in one icu at the university hospital of lille between january and july . the hemodynamic impact was studied through mean arterial pressure (map), vasoactive-inotropic score (vis) and map/vis ratio during the h following hiet initiation. metabolic parameters were also collected. results: patients admitted for ccbs poisoning. patients treated with hiet in icu ( patients without circulatory shock, patients with shock after hiet and patients with shock at baseline before hiet). among shocked patients at baseline (n = ), no hemodynamic improvement was found except an increased map/vis ratio at h (p < . ). on the contrary, an initial worsening of vis ( [ rationale: ketamine is used in the induction and maintenance of general anesthesia. recently, there were concerns regarding its liver toxicity. we conducted a study to investigate the link between ketamine use and liver dysfunction (ld) in intensive care unit (icu) patients. patients and methods: data were extracted from the [anonymized] study, a randomized controlled trial designed to evaluate the effect of cisatracurium on -day mortality rate in moderate and severe acute respiratory distress syndrome (ards) patients. the main endpoint was the occurrence of a ld defined as a total serum bilirubin superior or equal to micromol/l. a matched case-control cohort was created: cases, receiving at least day of continuous ketamine infusion, were paired for with controls according to treatment with cisatracurium, hepatic and cardiovascular sofa sub-score, total serum bilirubin level at the time of inclusion, age, sex, ards from septic origin, shock anytime after inclusion. an analysis was also made on the whole cohort comparing the patients receiving at least day of continuous ketamine infusion to all patients who did not fulfill this criterion. results: cases were identified and matched to controls. in the ketamine group, the median ketamine duration was ( - ) days, and median total cumulative dose . ( . - . ) g. the occurrence of ld was higher in the ketamine group than in the matched control group ( . % versus . %, p = . , fig. ). the hazard ratio (hr) for ld in the ketamine group was . ( % ci . - . , p = . ). there was an increased risk of ld of . % per day of exposure to ketamine (hr . , % ci . - . p = . ) and of . % per gram of ketamine infused (hr . , % ci . - . , p = . ), with a risk starting to be statistically significant after days and gr. in multivariate analysis on the whole cohort, ketamine exposure (hr . , % ci . - . , p = . ), cumulative dose in gram (hr: . , % ic: . - . , p = . ) and ketamine exposure in days (hr: . , % ic: . - . , p < . ) remained independent risk factors for ld occurrence. conclusion: ketamine use in critically ill patients treated for ards is associated to a higher risk of liver dysfunction, assessed by total serum bilirubin. this risk is dose-dependent and increases with duration of treatment. the prescription of high doses or prolonged treatment with ketamine should probably be avoided in critically ill patients. compliance with ethics regulations: yes. rationale: ciguatera is one of the most common cases of marine poisoning associated with fish consumption in the world. the incidence of this intoxication is largely unreported. in martinique, the incidence of this intoxication seems constantly increasing. during the last years, numerous cases of large collective poisonings have been reported in martinique, especially during summer. the spectrum of clinical manifestations is large including gastrointestinal, neurological andcardiovascular symptoms. ciguatoxin, the toxin responsible for ciguatera fish poisoning is considered as a sodium channel agonist with cholinergic and adrenergic activity. it is rarely fatal and management of poisoned patients is essentially based on supportive care. the objective of this study was to describe the clinical characteristics and complications of ciguatera poisoning in martinique, focusing on the cardiovascular ones. observational, retrospective, single-center study covering six-year period from october to september , including all patients admitted to the emergency department of the university hospital of martinique (chu), and all patients who were declared to the regional health agency (ars) for ciguatera intoxication. results: one hundred and forty-nine patients ( ) who were ciguatera-affected were included. the incidence rate found was to be . cases per . patient-years in martinique over the period. about % of patients had gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; % neurological disorders and % cardiovascular symptoms including, bradycardia, hypotension and interventricular block. ingestion of carangue fish was related to a major risk of chronic signs. conclusion: the incidence of ciguatera in martinique is increasing, with . cases/ . patient-years. the clinical presentation is defined mainly by digestive signs, followed by peripheral neurological disorders and cardiovascular symptoms. ciguatera fish poisoning in martinique presents similar clinical presentation to that of the other caribbean islands. there is no specific treatment. acute ciguatera poisoning is responsible for significant cardiovascular complications. physicians should be aware of the potential cardiovascular risk of ciguatera poisoning. compliance with ethics regulations: yes. rationale: pesticides have represented the most incriminated products in severe acute poisonings, in the developing countries, due to the availability of these products. organophosphate poisoning accounts for million poisonings/year worldwide. organophosphate (op) pesticides are used mainly as insecticides in agriculture. the moroccan anti-poison and pharmacovigilance centrer shows that op poisoning are responsible for % of all poisonings combined. the aim of our study: epidemiological, clinical, management and prognostic factors. patients and methods: a retrospective study was conducted on patients with op poisoning admitted to our nine-bed medical intensive care unit between january and december . inclusion criteria were: all patients over years of age and the exlusion criteria were: pesticide poisoning other than op, alcohol poisoning, drug poisoning, scorpionic poisoning and snake bites. statistical analysis was performed with spss software. results: forty patients were admitted for acute op poisoning. in morocco, organophosphores are available over-the-counter in several forms: rodentocides, malathion, cockroach trap, baygon insecticide ( fig. ). the average age was years with a female prévalence of . %. the intoxications were mostly intentional ( %). the symptomatology was determined by the three syndromes: central syndrome in %, muscarinic syndrome in %, nicotinic syndrome in %. rhythm disorders in %, and cardiovascular collapse in %. the symptomatic treatment was applied to all patients, antidotic treatment was administered in % of patients. the average length of hospitalization was days. conclusion: acute op poisoning is a real public health problem. its associated symptomatic treatment (respiratory and neurological resuscitation) and antidotic treatment. the mortality remains high in our context, therefore, we must attach great importance to the prevention. compliance with ethics regulations: yes. ( ). over an -month period, health officials in guadeloupe and martinique reported more than . such cases. assault of these brown algae represents not only an environmental and economic disaster, but also a threat for human health. after h on seashore, large amounts of toxic gas are produced by matter decomposition, including hydrogen sulfide (h s) and ammoniac (nh ). the acute effects on humans after exposure to high concentrations of h s are well described and of increasing severity with concentration, leading to potentially fatal hypoxic pulmonary, neurological and cardiovascular injuries (table ) ; however, the association of long-term exposure to sargassum and health events is unknown. although less documented, long term exposures may result in conjunctiva and upper airways irritation, headaches, vestibular syndrome, memory loss, and modification of learning abilities. in the absence of any available antidote, management of h s intoxication relies on supportive care and prevention using individual protection. the objective of this study was to evaluate the clinical characteristics and consequences of long-term exposure to sargassum among the local population. we conducted a prospective observational cohort study including all patients admitted to the emergency department at the university hospital of martinique from march to december due to exposure to sargassum. patients were managed according to the protocol established by the research group on sargassum in martinique. we assessed the patients exposure to sargassum and air pollutants using monitor located near of the patient's residence. demographics and clinical data (including cardiovascular, neurological and respiratory events) were collected. data are presented as mean ± sd or %.comparisons were performed using univariate analysis. results: in months, patients were included (age: ± years, m/ w, past history: hypertension (n = ), diabetes (n = ), asthma ( ). patients arrived with referral letter from their general practitioner ( %) and presented headaches ( %), developed gastrointestinal disturbances ( %), dizziness ( %), skin lesions ( %), cough ( %) and conjunctivitis ( %). not all patients were clinically symptomatic. in the patients presented in june ( %), symptoms more frequently occurred in the workplace or at home (p < . ). initial lung function tests were normal ( %). three patients were admitted in intensive care unit. conclusion: our study indicates that the magnitude of health effects following long-term exposure to sargassum may be larger than previously recognized. efforts to limit long-term exposure are mandatory. compliance with ethics regulations: yes. rationale: liver consequences of out-of-hospital cardiac arrest (ohca) have been poorly studied. the aim of this study was to describe the characteristics of ohca-induced acute liver dysfunction and its association with outcomes. we analyzed all consecutive ohca patients admitted to two academic centers between and . patients treated with vitamin k antagonist were not included. acute hepatocellular insufficiency (ahi), liver failure (lf) and hypoxic hepatitis (hh) were defined as a prothrombin (pt) ratio < %, a hepatic sofa sub-score > and an increase in transaminases > times the normal values, respectively. indocyanine green (icg) clearance was used as the reference measure of liver function in a subset of patients. multivariate logistic regression was used to identify potential risk factors for day mortality. rationale: neuron-specific-enolase (nse) is commonly used as a biomarker reflecting the extent of brain injury in different settings. in post-cardiac arrest patients, previous clinical studies reported that an increase in nse was predictive of a poor outcome but did not specifically focused on neurological outcome. in this prospective study, we aimed to determine the nse performance for prediction of severe brain damage in post-cardiac arrest patients. patients and methods: all consecutive patients admitted in our icu after cardiac arrest between january and february that were still comatose at h and had at least one measurement of serum nse were included. blood samples for nse measurement were serially collected at (h ) and h (h ) after cardiac arrest and serum nse levels were measured within h. we used the following criteria for the definition of severe brain damage (primary endpoint): cerebral performance categories (cpc) or level at discharge, brain death or withdrawal of life-sustaining treatments (wlst) based on neurological status. we also assessed the predictive value of serum nse using allcause mortality as a secondary endpoint. results: during the study period, patients were available for the analysis. they were mostly male ( . %), with an age of . years. among these patients, ( . %) had a good neurologic outcome (cpc - ) and patients were classified as having a severe brain damage ( wlst based on neurological status, brain deaths and survivors with . in univariate analysis, patients with severe brain damage less frequently received bystander cpr, had longer duration of no-flow, less initial shockable rhythm, more post-resuscitation shock and higher nse values: mean at h were . versus . ; and . versus . at h (p < . ). nse levels at h and h were strong predictors of severe brain damage (auc of . and . respectively, figure ) and also predicted all-cause mortality (auc of . and . respectively). to predict severe brain damage with % specificity, best nse cutoff values at h and h were . and . µg/l, with a sensitivity of . and . % respectively. conclusion: a high serum nse measured at h and h after cardiac arrest accurately predicted severe brain damage with a high specificity. our results support the use of nse for neuroprognostication after cardiac arrest, in combination with other predictors. compliance with ethics regulations: yes. rationale: the psychological care of patients, their relatives and of healthcare workers is a major issue in the intensive care unit (icu). psychologists may provide emotional support during trying times. the intervention of a psychologist may alleviate long term mental health issues such as post-traumatic stress disorder. the main objective of our study was to describe the availability of psychologists in french-speaking icus. patients and methods: internet survey conducted between march and may using surveymonkey (san mateo, usa). survey consisting of questions sent to subscribers of the srlf mailing list via mailchimp software (atlanta, usa). frequencies and percentages were determined for categorical variables and median and interquartile range for continuous variables. the icus with or without psychologist were compared using nonparametric fisher exact test. stata used (lakeway drive, te, usa). results: responses were obtained from unique icus in france (n = ), belgium (n = ), switzerland (n = ), algeria (n = ), morocco (n = ) and tunisia (n = ). ( %) icus were part of public hospitals, ( %) of private facilities. ( %) icus cared for adult patients, ( %) for children. the median number of beds was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ( %) icus were open to visitors / , ( %), to visitors > h/day and ( %) to visitors < h/day. psychological consults were established in ( %) wards ( icus did not answer). pediatric icus employed more psychologists than adult icus (p = . ). comparison of icus based on the presence or not of a psychologist appears in table . in icus where a consulting psychologist is available, their effective availability is . [ . - ] full time equivalent. consults are delivered to: patients ( %), families ( %) or healthcare workers ( %). out of the icus without a psychological consult, responders from ( . %) icus believe that a psychological consult is undesirable. out of the icus without psychological consult, ( %) responders cannot obtain a psychological consult, whatever the circumstances, ( %) can require an outside psychological consult when needed, while ( %) can require assistance from a psychologist working in another unit (several answers possible for each respondent). conclusion: psychologists consult in only half of adult icus but in almost all pediatric icus. % of icus are unable to provide a psychological consult. psychological consults are delivered in similar proportions to patients, their family and to a lesser extent to healthcare workers. responders from . % icus without an established psychological consult believe that the availability of a psychologist is undesirable. compliance with ethics regulations: na. rationale: comfort of patients in intensive care unit (icu) is now a real concern for the healthcare teams. perceived patient discomfort assessment is a daily practice for our staff. the primary objective of our study was to assess whether the overall discomfort score reported by patients hospitalized in a separate intermediate care unit differs from that reported by patients hospitalized in icu. a tailored multicomponent program consisting of assessment of icu-related self-perceived discomforts with a -item questionnaire, immediate and monthly feedback to healthcare teams and site-specific tailored interventions, was applied in our department, located in a general hospital, and comprising a -bed icu and a separate -bed intermediate care unit rationale: the transition period surrounding the discharge from icu to hospital ward is a critical period in the course of the patient. handoff of complex patients is at high risk for communication failures between providers, inaccurate cares and icu readmission. a transition program including a post icu follow-up has been proposed to improve handoff quality. post icu consults by icu team represent, also, an opportunity for improving feedback on the quality of icu cares. the goal of the present study is to assess the feasibility and the impact of a systematic early post-icu consult (epicuc) program on handoff quality in a bed mixed icu. patients and methods: before the development of the epicuc program, standardized handoffs were already applied including identified day and hour of discharge and both verbally communicate and written medical and nurse information for receiving team. from st march to th october , all patients who were discharged to the ward of our hospital were candidates for epicuc. epicuc were performed by icu staff (at least one icu physician) within the days following discharge. the epicuc consisted of a face-to-face discussion with the receiver team to assess the accuracy, completeness and understanding of passing information and of a patient visit. a standardized form was used for collecting data. the impact of epicuc on handoff quality was assessed by the number of communication failures and the number of patients in whom epicuc resulted in a management change. personal feeling of epicuc providers on its usefulness was assessed by a - rating scale. results: among the candidates for epicuc, were dead and already discharged alive from hospital at epicuc time. epicuc were performed in patients ( %) within ± days after icu discharge. epicuc ( %) were performed by both, nurse and icu physician. ( %) patients and receiver teams ( %) were available at epi-cuc time. epicuc duration was ± min. a communication failure was identified in epicuc ( %), either a rectification of passing information (n = ; %) and/or a change in patient management (n = ; %). the usefulness of the epicuc was rated at ± and ± by icu physicians and nurses, respectively. conclusion: the time spent for epicuc appears reasonable. epi-cuc identified a communication failure in one-third of handoffs and allowed care readjustment in one quarter of patients. factors associated with handoff failures will be presented during the congress. compliance with ethics regulations: yes. rationale: surviving a critical illness is a challenging condition for patients and relatives. the psychological aspects are directly affected by physical status and performance. patients can feel depressed or anxious facing difficulties during recovery time. the aim of this study was to correlate patients' perceptions of his health status and his clinical performance measured after icu discharge. patients and methods: this is a prospective pilot study of an icu follow-up clinic conducted in a single center from january to july . this clinic is multidisciplinary and includes two visits at and months after icu discharge. patients with more than days of icu los were eligible. all patients at and -m visit were evaluated with sf- , mwt, mrc and time-up-and-go test. we conducted an analysis comparing clinical performance data and qualitative data between and months after icu discharge. the investigation included patients who had at least days of icu length of stay. patients attended the consult at -m and patients attended the consult both times. the median age (iqr) was ( - ) and % were men. %, % and % of patients had medical, scheduled surgical and emergency surgical admission causes respectively, with median (iqr) saps iii score ( - ). %, % and % of patients had sepsis, delirium and mechanical ventilation as a support. the physical status was progressively increased overtime likewise the physical capacity assessed by sf- score with p-value . between and -m. however, no significant difference between the subjective dimension of sf- , which analyses the perception of the patient about his physical capacity, assessed at -m and at -m was demonstrated (p . ). in this pilot-phase of following a cohort of critically ill patients, the natural physical improvement does not seem to change the patient's perception of their performances. this paradigm rouses a different perspective that should take into account when setting up rehabilitation programs. compliance with ethics regulations: yes. post-traumatic stress disorder after discharge from an acute medical unit basma lahmer , naoufel madani , , jihane belayachi , , redouane abouqal rationale: post-traumatic stress disorder (ptsd) occurs after exposure to a traumatic event and comprises of symptoms of repeated re-experiencing of the said event, avoidance of reminders, emotional numbing and persistent hyperarousal. in individuals exposed to "medical stress", various studies found evidence of ptsd occurring after the onset, diagnosis, or treatment of physical illness. our study aims to determine ptsd's risk factors in patients of an acute medical unit (amu) after their discharge. patients and methods: it was a prospective, analytical study conducted over a period of months at an acute medical unit. we collected sociodemographic and clinical data, patients' medical history, and evaluated the symptoms of anxiety and depression during their stay using the hospital anxiety and depression scale (hads). the prevalence of severe ptsd symptoms was assessed with the impact of events scale-revised (ies-r) at weeks and months using a cutoff of . associations between ptsd as evaluated by ies-r at months and patients' characteristics, including hads scores at admission were investigated using unadjusted linear regression, for univariate and multivariate regression analysis. statistical analyses were carried out using spss for windows (spss, inc., chicago, il, usa). we included patients in our study with a mean age of . ± . . in our population, . % of patients scored higher than a ies-r cutoff at weeks compared to . % at months. the mean hads-anxiety score is . ± and that of the hads-depression score is . ± . . on one hand, higher hads-anxiety score during the stay in the amu was linked to higher ies-r scores at months β: rationale: objective of critical care includes restoration of functional capacities. prompt identification of muscle acquired weakness (icu-aw) is crucial to target efficient rehabilitation. in published literature, data of quadriceps strength (qs) cannot be compared because of insufficient standardization of measurement protocols. we recently validated a highly standardized protocol of qs measurement. in order to build basic and comparable knowledge and to identify the weakest patients, this study aimed to describe qs of critically ill (ci) patients during their short-term evolution, and to compare them to surgical (s) and healthy (h) subjects. patients and methods: this observational study included ci patients who spent at least days in icu, patients scheduled for elective colorectal surgery (s) and young healthy volunteers (h). maximal isometric qs was assessed using a handheld dynamometer (microfet ® ) and expressed in newton/kg (n/kg). dominant leg was tested in supine position using a highly standardized procedure. ci and s patients were tested at t (as soon as collaborative in icu) and month after discharge (m rationale: the post intensive care syndrome (pics) gathers various disabilities, associated with a substantial healthcare use. however, patients' comorbidities and active medical conditions prior to intensive care unit (icu) admission may partly drive healthcare use after icu discharge. to delineate the relative contribution of critical illness and pics per se to post-critical illness increased healthcare use, as opposed to pre-existing comorbidities, we conducted a population-based evaluation of patients' healthcare use trajectories. patients and methods: using discharge databases in a . -million-people region in france, we retrieved, over three years, all adult patients admitted in icu for septic shock or acute respiratory distress syndrome (ards), intubated at least days and discharged alive from hospital. healthcare use (days spent in healthcare facilities) was analyzed two years before and two years after icu admission. healthcare trajectories were next explored at individual level: patients were assembled according to their individual pre-icu healthcare use trajectory by clusterization with the k-means method. results: eight-hundred and eighty-two ( ) patients were included. median duration of mechanical ventilation was days (interquartile ranges [iqr] ; ), mean saps was , and median hospital length of stay was days (iqr ; ). prior to icu admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. however, clusterization of individual according to pre-icu healthcare trajectories identified patients with elevated and increasing healthcare use (n = ), and two main groups with low (n = ) or no (n = ) pre-icu healthcare use. patients with high healthcare use had significantly more comorbidities than those with low healthcare use. in icu, however, saps , duration of mechanical ventilation and length of stay were not different across the groups. interestingly, analysis of post-icu healthcare trajectories for each group revealed that patients with low or no pre-icu healthcare (which represented % of the population) switched to a persistent and elevated healthcare use during the two years post-icu. conclusion: for % of ards/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to icu, to a sustained higher healthcare recourse two-years after icu discharge. this underpins the hypothesis of long-term critical illness and pics-related quantifiable consequences in healthcare use, measurable at a population level. compliance with ethics regulations: yes. ( ) to describe the pre-hospital grading protocol developed by the northern french alps emergency network (trenau) for children, ( ) to evaluate its quality to detect the most severe trauma patients and ( ) to assess the accuracy of this procedure to perform an adequate triage. patients and methods: our regional trauma system included hospitals categorized as level i, ii or iii pediatric trauma centers. eachpatient was graded a, b or c by an emergency physician, according to the seriousness of their injuries at presentation on scene. the triage was performed according to this grading and the categorization of centers. this study is a registry analysis of an -year period ( to ). results: a total of children (mean age years, % were boys) with severe trauma were included in the cohort. fifty-seven, % and % of patients were admitted to a level i, ii and iii, respectively. road accident was the main mechanism of injury ( % of patients). thirtysix percent of patients had a severe trauma, defined as an injury severity score (iss) higher than . one quarter of patients had at least severe lesions and one-third of patients had a trauma brain injury. the pre-hospital gradation was closely related with injury severity score (iss) and intra-hospital mortality rate. the triage protocol had a sensitivity of % and a specificity of % to predict adequate admission of patients with iss more than . using a specific trauma score (including occurrence of death, an admission in intensive care unit and the need for urgent surgery), sensitivity and specificity reached and %, respectively. fourty-six percent of patients were not graded at the scene (non-graded group). undertriage rate was significantly reduced in the graded group compared with the non-graded group, ( % versus %), without significant modification of the overtriage rate ( % versus %). overall, mortality at discharge from hospital was %, but % in grade a patients. conclusion: implementation of a regional pediatric trauma system with a specific pre-hospital triage procedure was effective in detecting severe pediatric trauma patients and in lowering the rate of prehospital undertriage. compliance with ethics regulations: yes. rationale: critically ill children suffer from pathophysiological changes, leading to large between-subject variability in drug clearance. since piperacillin is eliminated mainly via the kidney, changes in renal function go along with a modified elimination, and possible subtherapeutic or toxic drug concentrations. we aimed to determine the most accurate glomerular filtration rate (gfr) estimation formula for assessing piperacillin clearance in critically-ill children. patients and methods: all children hospitalized in pediatric intensive care unit and receiving piperacillin were included. piperacillin was quantified by high performance liquid chromatography. pharmacokinetics were described using the non-linear mixed effect modeling software monolix. in the initial pharmacokinetics model, gfr was estimated according to the schwartz formula. in the study, gfr was estimated with additional formulas, developed with plasma creatinine and/or cystatin c. biases, precisions, spearman's rank correlation coefficient and normalized prediction distribution error (npde) were used to assess the models. results: we included children with a median (range) postnatal age of . ( . - ) years, body weight of . ( . - ) kg and estimated gfr according to the schwartz formula of . ( - ) ml min- . . m . piperacillin concentrations were best predicted with the model using the creatinine clearance. the correlations were most accurate: r = . between the population-predicted and the observed concentrations, r = . and r = . for the npde versus population-predicted concentrations and time, respectively. concerning the individual predicted concentrations, bias and precision were respectively − . mg l − and . mg l − . gfr estimations based on serum creatinine were higher than those based on cystatin c (p = . ). conclusion: in summary, the -h creatinine clearance is the best predictor of piperacillin clearance and this could be investigated for drugs with renal elimination. as a whole, literature and our findings strongly suggest using creatinine clearance to also estimate gfr in critically ill children. the gap between the gfr estimations is large depending on the formulas, with higher estimations with equations based on serum creatinine. compliance with ethics regulations: yes. rationale: acute pancreatitis (ap) incidence have increased dramatically over the past years. new guidelines in were recently published in order to standardize the definition and management of ap. the aim of this study is to describe the management of children that were diagnosed with ap from the pediatric intensive care unit (picu) in two french hospitals. patients and methods: this retrospective cohort study included children aged under years old, who were admitted to the picu of robert-debré hospital and trousseau from to with a discharge diagnosis of ap. data collected included management, severity and outcomes. we have also obtained data on clinical, biological and radiological presentation. results: sixty patients were included, the median age was years ( - ) and % had a co-morbidity mainly hematologic ( / ). most of the ap were moderate ( %) or severe ( %). hemodynamic failure was the main reason for picu admission requiring a median fluid resuscitation ml/kg complemented by a median intravenous fluid therapy of ml/kg/h ( - ) during the first h. twenty patients ( %) required mechanical ventilation. fasting has been instituted in patients ( %) for a median of days ( - ), whereas patients ( %) received parenteral nutrition, only patients ( %) received enteral nutrition. antibiotic therapy was given to patients ( %) including % for curative therapy. the median length of stay in picu was days ( ) ( ) ( ) ( ) ( ) . the mortality rate was %. conclusion: this is the first french study which precisely described the management of patients with ap in picu. it highlighted the differences withthe new international guidelines. this study could improve the management of pa in picu and open research perspectives. compliance with ethics regulations: yes. rationale: apheresis and therapeutic plasma exchange (tpe) for children diseases has been poorly investigated in mostly small-uncontrolled studies. the purpose of this study is to describe indications and safety of tpe in children. patients and methods: in this single center and retrospective study, we included patients who underwent tpe with an age < years old in the pediatric center of necker-enfants-malades hospital from january to december . data were retrospectively collected in an electronic case report form via a web-based data collection system. results: patients with a median age of . years [range . ; . ] were selected. they achieved a total number of procedures. indications were antibody-mediated rejection (n = ; %) or desensitization therapy (n = ; %) for solid organ or hematopoietic transplantations; microangiopathy (n = ; %); renal diseases (n = ; %) and pediatric inflammatory diseases (n = ; %); or hyperviscosity syndrome (n = ; %). each patient had an average of procedures for the first session [range ; ] with a median volume of ml [range ; ml] corresponding to a median (rang) total plasma volume (tpv) equivalent of . l/m [ . - . ]. within days since the beginning of sessions, patients ( %) present a total of adverse events (aes) potentially related to tpe. there was a median (range) of aes/patients [ - ]. there was no association between aes and diseases, severity of patients, venous access, plasma substitute and body weight. few of aes (n = for patients) were potentially life-threatening and concerned mostly critically ill children. allergic reactions represented only aes for patients (grade i n = ; grade ii n = ; grade iii n = ). at the months endpoint, ( %) patients died and ( %) patients had severe persistent disease. no death had been related to the tpe process. we describe one of the largest retrospective pediatric cohort updated to the last international recommendations. tpe in children is performed for specific and potentially refractory disease. it is feasible without a major risk of life threatening adverse events. compliance with ethics regulations: yes. yacine benhocine university hospital nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):f- rationale: although analysis of literature data shows that implantable chamber catheters (iccs) are less at risk of infectious complications than other central venous catheters, these complications can be serious, which may differ from ongoing treatments such as chemotherapy, and may lead to the removal of the implanted device. the literature on preventing these infections is quite disparate, as practices. purpose: to evaluate the incidence of infections, to identify responsible germs and to measure the impact of preventive measures. patients and methods: prospective, descriptive, mono-centric study, from january to january . all patients under the age of who have benefited from an implantable chamber catheter, whose insertion procedure is as follows: local anesthesia, surgical asepsis (polyvidone iodine) in an operating room, double disinfection, no antibiotic prophylaxis, routes used: subclavian ( %), internal jugular ( %) by anatomic registration. the main criteria of judgment are: the incidence of local and general infections, their time of onset, responsible microorganisms. statistical analysis used the statistical package for the social sciences software. results: patients were included, the average incidence density of early infection is . / day-catheters. the time of onset of infection is essentially between the nd and rd week post-exposure, of which % is general infection. ablation involved % of infected catheters. the causative organisms are mainly gram-positive cocci ( . %), gram-negative bacilli are less involved ( . %), with a significant number of candida infections ( %). discussion: higher incidence of data from the literature. to remedy this requires the implementation of additional hygiene measures: antiseptic showers preoperatively, chlorhexidine??, and practice changes: echo guidance, antibiotic prophylaxis or locks? second generation catheters? our practices are disparate especially since the recommendations specifically concerning the prevention of infectious risk associated with internationally published iccs are rare. conclusion: at the end of this work, our perspectives are to: update the procedure, highlight risk factors on which it is possible to act, the adhesion of the different staff to the protocols. compliance with ethics regulations: yes. rationale: the sepsis and septic shock pediatric guidelines advise to treat patients using care bundles. in the first hour, the «resuscitation bundle» contains an appropriate fluid resuscitation, a broad-spectrum antibiotics administration after blood cultures, and initiation of inotrope if needed. the objectives were to evaluate the resuscitation bundle compliance in a cohort of septic children with cardiovascular dysfunction, and to analyze the effect on severity and outcome in pediatric intensive care unit (picu). patients and methods: retrospective analysis of the diabact iii study. this study analyzed the care course of children with severe community-acquired bacterial infection, hospitalized in picus in france's west departments, between august and january . children with severe sepsis and cardiovascular dysfunction were retrospectively included. results: we included children of whom ( . %) had compliant bundled care. the severity scores at picu's admission were similar between groups (p = . for the prism score and . for the pelod ). there was the same proportion of fluid-refractory shock (p = . ), mechanical ventilation (p = . ), neurological dysfunction (p = . ) and cardiac arrest (p = . ). in the «resuscitation bundle compliant» group, . % died versus . % in the other group (p = . ). we highlighted a severity bias: the sickest patients were more likely to receive compliant bundled care. conclusion: in our cohort, the resuscitation bundle's compliance was low. we did not show some effect on morbidity nor mortality. however, this study helps understand the factors associated with resuscitation bundle's compliance. rationale: nosocomial infections with extended-spectrum β-lactamase (esbl) producing gram-negative bacilli (gnb) are an important cause of hospital morbidity and mortality. the objective of this study was to determine the incidence and risk factors of nosocomial esbl-producing gnb infections in a paediatric intensive care unit (picu). patients and methods: a prospective surveillance study was performed from january through march in a picu. all patients hospitalized for more than h were included. centers for disease control and prevention criteria were applied for the diagnosis of nosocomial infection. results: during the study period, patients (median age: ± days) were included. the average length of stay was ± days with a total of , days of hospitalization. newborns accounted for . % of patients. sixty-two per cent of patients were colonized with multi drug resistant gram-negative rods, on admission or during their stay in the picu. one hundred and nineteen bacterial infectious episodes were registered ( . / patient days). one hundred infectious episodes were caused by a gnb and ( . %) by esbls producing gnb with an incidence of . / patient days (bloodstream infections: episodes, ventilator acquired pneumonia: episodes). esbls producing gnb infection had a specific incidence of . per catheter-days, and . per mechanical ventilation-days. fifty-nine percent of patients infected with esbls producing gnb had a prior digestive colonization with a multidrug-resistant gnb. forty-one episodes ( %) occurred in patients with central venous catheters. klebsiella pneumoniae was the most frequently isolated bacteria ( . %). mortality in the esbls producing gnb group was high ( . %). associated factors of nosocomial esbls producing gnb infection were mechanical vrntilation (p < . ), central venous catheterization (p < . ) and colonization with multiple drug-resistant gram-negative bacteria (p < . ). conclusion: nosocomial esbl-producing gnb infection had an incidence of . per patient days in our unit and seems to increase the mortality rate. factors associated with this infection were identified. marie lemerle , aline schmidt , valérie thepot-seegers , achille kouatchet , valérie moal , mélina raimbault , corentin orvain , jean-francois augusto , julien demiselle chu angers, médecine intensive réanimation, angers, france; chu angers, maladie du sang, angers, france; chu angers-ico, angers, france; chu angers, pharmacie, angers, france; chu angers, labora-toire de biochimie, angers, france; chu angers, néphrologie dialyse transplantation, angers, france correspondence: marie lemerle (marielemerle@yahoo.fr) ann. intensive care , (suppl ):f- rationale: acute kidney injury (aki) is associated with high morbidity and mortality in the setting of tumor lysis syndrome (tls). thus, strategies aimed at preventing aki occurrence represent a major goal to improve prognosis of patients with tls. the role of hyperphosphatemia as a risk factor of tls has been poorly analyzed. the aim of this study was to study the association between hyperphosphatemia and aki, and to determine whether a cut-off value of phosphatemia or phosphatemia's variation was associated with aki development during tls. patients and methods: in this retrospective and monocentric study, we included all patients with tls and whithout aki at admission, admitted to hematology, nephrology and intensive care units of the university hospital of angers between / / and / / . results: one hundred and thirty tls episodes were identified in patients. aki developed during episodes of tls ( %). hospital mortality was much higher in aki patients ( . % versus . %, p = . ). phosphate maximal values ( . ± . versus . ± . ) and ldh maximal values ( . ± . versus . ± . ) were higher in tls with aki, before aki occurrence (p = . and p = . , respectively). we found no association between the other biological parameters of tls and aki (serum calcium, uric acid and potassium). after adjustment for cofounders, there was a strong association between a rise in phosphate level of . mmol/l (hr . ic % [ . - . ], p < . ), exposure to platinum salts (hr . ic % [ . - . ], p = . ) and increasing maximal ldh value (hr per ui/l increase . ic % [ . - . ], p = . ) with aki. conclusion: this study highlights the utmost importance of serum phosphate in the setting of tls: phosphate is an early relevant biomarker for the risk of aki development. further studies are needed to assess whether aggressive prophylactic treatment to control serum phosphate concentration, such as renal replacement therapy before aki onset, constitutes a valuable approach. compliance with ethics regulations: yes. retrospective cohort of patients admitted to the medical icu of university affiliated hospital after carts treatment between august and august . results: of the patients treated by carts in the haematology department, ( %) were subsequently admitted to icu. median age was [ . - . ] years, and ( . %) were female. carts were indicated for r/r lymphoma. the median time between carts injection and icu admission was [ . - . ] days. all patients had cytokine release syndrome (crs), and ( . %) developed car-related encephalopathy syndrome (cres). median sofa score and saps were [ - . ] and [ . - . ], respectively. four ( . %) patients had hypotension treated by fluid bolus (n = ) or vasopressors (n = ), and ( . %) had acuterespiratory failure requiring oxygen therapy (n = ) or mechanical ventilation (n = ). six ( . %) patients had neurological symptoms (impaired consciousness n = , confusion n = , transient aphasia n = ), of whom one developed refractory convulsive status epilepticus afterwards. all patients received broad spectrum antibiotics, of whom ( . %) had documented infections. six ( . %) patients received interleukin- inhibitor (single dose n = , multiple doses n = ), and ( . %) received intravenous dexamethasone. one patient died in the icu from septic shock. median icu and hospital length of stays were [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and [ . - . ] days, respectively. two ( . %) patients died from relapsing malignancy before hospital discharge. three months after icu admission, four ( . %) patients were alive in complete remission. conclusion: more than % of patients treated with carts required icu admission for the management of a crs or a cres. early icu admission, close collaboration between haematologists and intensivists, and prompt administration of appropriate therapy (il- inhibitor and/or dexamethasone) and supportive care resulted in a good prognosis. compliance with ethics regulations: yes. rationale: tisagenlecleucel (ctl ) is a chimeric antigen receptor t cell therapy that reprograms autologous t cells to target cd + leukemia cells, approved in the us since august and in the eu since august for children and young adult (< years old) with relapsed/refractory b-cell acute lymphoblastic leukemia (b-all). this study reports the experience of picu management of ctl toxicity in patients treated in robert-debré university hospitals. patients and methods: all patients (age < years old) treated by tisagenlecleucel infusions between march , and september , , included in sponsored-clinical trials or treated within the french compassionate program or with the commercial product, were retrospectively analyzed. results: twenty-four patients were infused and patients ( %) were managed in picu for stays. ( stays: n = and stays: n = ). median age at picu admission was . years old [ . ; . ] with a median delay after car-t cells infusions of days [ . ; ] . the median length of stay in picu was days [ . ; ] with a max at days. cytokine release syndrome (crs) was the main indication of picu hospitalization ( . %, n = ) with grade (n = ) and grade (n = ) according to american society for transplantation and cellular therapy (astct) consensus grading system and treated by corticosteroid (n = . ) and tocilizumab (n = , only one infusion). norepinephrine was the only vasopressor used. the median vaso-inotrope score (vis) for grade was [ . ; . ] with a maximum at . neurologic toxicity was observed in patients with a grade (status epilepticus) and grade (focal edema on neuroimaging with depressed level of consciousness) according to immune effector cell-associated neurotoxicity syndrome (icans) grading system from astct consensus. the status epilepticus was managed with anti-epileptic drugs without mechanical ventilation. the focal edema was related to hhv and toxoplasmosis encephalitis. evolution was positive with foscavir and ganciclovir and days of mechanical ventilation. one patient was hospitalized for septic shock secondary to gram-negative central line bloodstream infection in aplasia, with a vis score at . evolution was favorable with antibiotics and central line removal. no death in picu from severe tisagenlecleucel toxicity was observed since the beginning of the car-t cells program. conclusion: toxicity profile of tisagenlecleucel required frequent and early picu hospitalization after infusions for severe crs and icans management. compliance with ethics regulations: yes. rationale: car-t cell (chimeric antigen receptor t) therapy is a promising treatment in refractory acute lymphoid leukemia (all) and diffuse large b cell lymphoma (dlbcl). the main complication consists in a cytokine release syndrome (crs) leading to an inflammatory state that can be very severe with life-threatening organ failure. neurological toxicity is also reported. we aim to describe car-t cells-related complications in icu patients. patients and methods: this is a single-center prospective study conducted between july and august . all the patients who have received car-t cells and who required icu admission were included. crs grading was defined according to the most recent classification of the asbmt and neurological toxicity was assessed with the cartox scale. each admission is considered independent and therefore corresponds to one patient. results: admissions, representing patients ( men and women), were considered. the median age was years . twothirds of the patients have been diagnosed with dlbcl (n = , %) and one-third with all (n = , %), months [ - ] ago. they had received lines [ ] [ ] of chemotherapy and had a high tumor burden ( % of lymphomas classified stage iv). the majority of the patients was admitted because of hemodynamic failure (n = , %) or respiratory failure (n = , %), days [ ] [ ] [ ] [ ] [ ] after car-t cells infusion. sofa at admission was [ ] [ ] [ ] [ ] [ ] . all the patients presented at least one complication ( figure) , the most common being crs (n = , %) with a median grade of [ ] [ ] . neurological toxicity was reported in ( %) patients (worst grade at [ ] [ ] [ ] ). documented bacterial infection involved % of the patients and consisted in catheter-related infections for half of the cases. in the icu patients were managed with fluid resuscitation (n = , %) during the first day, vasopressors (n = , %) and broad spectrum antibiotics ( %). a single patient required mechanical ventilation and two patients underwent dialysis. tocilizumab (anti-il receptor) was given to patients ( % of crs) in a median time of . h [ . - . ] after icu admission. patients ( %) received corticosteroids. the median icu length of stay was . days [ ] [ ] [ ] [ ] . patients ( %) died in the icu and hospital mortality was %. the -fluorouracil ( -fu)-induced hyperammonemic encephalopathy is a rare but serious -fu adverse drug reaction, which could require the admission of patients in intensive care unit (icu). given the paucity of data regarding this -fu adverse drug reaction, we performed a retrospective national survey from the french pharmacovigilance database to better characterize -fu-induced hyperammonemic encephalopathy and its management. patients and methods: since the inception of the french pharmacovigilance database, we identified all patients that experienced -fu-induced encephalopathy. variables regarding epidemiology, characteristics, management and prognosis of these patients were collected and analyzed. results: from from to years-old, % of women) were included. overall mortality was % (n = ) and % (n = ) of patients were admitted in icu. the -fu-induced hyperammonemic encephalopathy started [ ] [ ] [ ] [ ] days after the onset of -fu infusion. the most common neurological disorders were consciousness impairment, confusion and seizures. abnormalities in ct scan, mri, electroencephalogram and lumbar puncture were found in %, %, % and % of the whole population respectively, similar in icu and non-icu patients. ammonemia was dosed in % of the whole population and in % of icu patients. hyperammonemia tended to be higher in icu than in non-icu patients ( [ - ] vs. [ - ] µmol/l, respectively, p = ns) and in patients with the lowest glasgow outcome scale, but was not different between survivors and non-survivors. among icu patients, % required mechanical ventilation and % anti-epileptic drugs administration. besides -fu discontinuation, lactulose intake, renal replacement therapy or ammonium chelators were used to decrease hyperammonemia in %, % and % of patients respectively. a complete neurological recovery was observed in up to % of icu and non-icu patients within a delay of [ - ] days. a dihydropyrimidine deshydrogenase (dpd) deficiency was found in % of tested patients. a -fu rechallenge was considered in % (n = ) of patients with complete neurological recovery, including a patient with a partial dpd deficiency, within a delay of [ - ] days after recovery. a -fu-induced hyperammonemic encephalopathy relapse was observed in % of patients with -fu rechallenge. no relapse was observed when -fu rechallenge was performed with a decreased -fu dosage. conclusion: we report the first national survey and the largest cohort of patients with -fu-induced hyperammonemic encephalopathy so far. this serious -fu adverse drug reaction must be known by intensivists, since more than half of patients are admitted in icu and specific treatments are available. compliance with ethics regulations: yes. immune related adverse events: a retrospective look into the future of oncology in the intensive care unit adrien joseph , annabelle stoclin , antoine vieillard-baron , guillaume geri , jean-marie michot rationale: immune checkpoint inhibitors (ici) represent a paradigmatic shift in oncology. with their new position as a mainstay in cancer treatment, new toxicities called immune related adverse events (iraes) have emerged. patients and methods: retrospective study including patients admitted in the icu within days after treatment with an ici in french hospitals. patients were classified into groups according to the reason for admission: irae, intercurrent adverse event (intae) or event related to tumor progression (tumprog). results: patients were admitted during the course of an ici treatment, including irae, intae and tumprog, with a significant increase between (n = ) and (n = patients, p for trend < . ). irae included pneumonitis, colitis, diabetes complications, hypophysitis, nephritis, myocarditis and cardiac disorders, hepatitis or allergic reaction and meningitis. the immune related nature of the complication was known before admission in only ( %) cases. mean age was (± ) years and % had a performance status of - . primary tumors were melanomas ( , %), non-small cell lung cancers ( , %) , urothelial carcinomas ( , %) and hodgkin lymphomas ( , %) . ici at the time of admission included anti-ctla ( , %), anti-pd /pdl ( , %) and anti-ctla /anti-pd combination in ( %) patients. mean duration of stay in the icu was . (± ) days. three patients required vasopressor therapy alone, with mechanical ventilation and one with extracorporeal membrane oxygenation. three patients required non-invasive ventilation and renal replacement therapy alone. six required only endocrine or electrolytic equilibration and others did not receive any form of organ support. icu mortality was %. compared with other admissions, anti-ctla or anti-ctla /anti-pd combination treatments were associated with irae diagnosis (or = . [ . - . ] , p = . for anti-ctla and . [ . - . ] for anti-ctla /anti-pd , p = . ) and so was the diagnosis of melanoma ( . [ . - . ] , p = . ). there was no difference in terms of icu and post-icu survival between irae (median post-icu survival months [ -na]), intae ( . [ . -na]) and ). six patients admitted for an irae were rechallenged with the same ici after icu discharge and achieved complete response. conclusion: we conducted the first study describing patients admitted in the icu for iraes. their specific and heterogeneous profile, along with the expected increase in the number of admissions, underlines the need for an in-depth knowledge for icu physicians in order to take part in the multidisciplinary care required by these patients. compliance with ethics regulations: yes. rationale: patients with advanced-stage non-small-cell lung cancer have high mortality rates in the intensive care unit (icu). in this context, acute respiratory failure due to cancer involvement is the worst situation. in the last two decades, targeted therapies have changed the prognostic of patients with lung cancer outside the icu. unlike cytotoxic chemotherapy, the fast efficacy of targeted therapies led some intensivists to use them as rescue therapy for icu patients. we sought to investigate the outcomes of patients with lung cancer involvement responsible for acute respiratory failure and who received tyrosine kinase inhibitor during icu stay. patients and methods: we performed a national multicentric retrospective study with the participation of the grrroh (groupe de recherche en réanimation respiratoire en onco-hématologie). all patients with non-small-cell lung cancer admitted to the icu for acute respiratory failure between and were included in the study if a tyrosine kinase inhibitor was initiated during icu stay. cases were identified using hospital-pharmacies records. we collected demographic and clinical data in icu charts. vital status was assessed at the time of study completion (august ). the primary outcome was overall survival days after icu admission. results: twenty-nine patients (age: ± years old) admitted to a total of icus throughout france were included. seventeen patients ( %) were nonsmoker. the most frequent histological type was adenocarcinoma (n = , %) and a majority had metastatic cancer (n = , %). epithelial growth factor receptor mutation was the most common oncologic driver identified (n = , %). during the icu stay, ( %) patients required invasive mechanical ventilation, ( %) catecholamine infusion, ( %) renal replacement therapy and one ( %) extracorporeal membrane oxygenation. in addition to tyrosine kinase inhibitor, ( %) patients received steroids (beyond . mg/kg/day) and ( %) cytotoxic chemotherapy during icu stay. seventeen patients ( %) were discharged alive from icu and ( %) were still alive after days (see kaplan-meier curve figure) . moreover, patients ( %) were alive one year after icu discharge. conclusion: despite a small sample size this study showed that, in the context of lung cancer involvement responsible for acute respiratory failure, the use of tyrosine kinase inhibitor should not be refrained in patients with severe condition in icu. compliance with ethics regulations: yes. rationale: acute respiratory failure is the leading reason for intensive care unit (icu) admission in immunocompromised patients and the need for invasive mechanical ventilation has become a major clinical end-point in randomized controlled trials (rct). however, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. this study explores how this outcome varies across icus. patients and methods: hierarchical models and permutation procedures for testing multiple random effects were applied on both data from observational cohort (the trial-oh study: patients, icus) and randomized controlled trial (the high trial: patients, icus) to characterize icu variation in intubation risk across centers. results: the crude intubation rate varied across icus from % to % in the observational cohort and from to % in the rct. this center effect on the mean icu intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p-value = . , median or . [ . - . ]; rct: p-value: . , median or . [ . - . ]). two icu-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to icu admission) and could partly explain this center effect. in the rct that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. conclusion: invasive mechanical ventilation has become an important endpoint in immunocompromised patients with acute respiratory failure. however, we found significant variation in intubation risk across icu in both an observational cohort and a randomized controlled trial. our results highlight the need to take into account center effect in analysis because it could be an important confounder. reasons for heterogeneity are various (case-mix differences, center practices). this gives opportunities to future improvement in care management and study design. compliance with ethics regulations: yes. rationale: influenza virus (iv) infection is a major cause of ards that has been the focus of attention since the pandemic h n (h n pdm ) iv. although iv-mediated damage of the airway has beenextensively studied emphasizing specificity compared to other causes of ards, the impact of iv infection on the prognosis of ards patients, compared to the other causes of ards, has been few assessed. patients and methods: systematic detection of iv in times of epidemic using rt-pcr in respiratory specimen is routine practice in our icu along with prospective data collection of patients admitted to our icu for ards with pao /fio ratio ≤ mmhg. all patients received lung-protective ventilation, the sequential organ failure assessment (sofa) score was calculated on the first days of mechanical ventilation. the primary endpoint compared the -day survival from the diagnosis of ards between patients with and without iv infection. results: from october, to may, , patients (pts) [median saps ii score = ( - ); age years ( - ); pao / fio ≤ mmhg, n = ( %)] were admitted to our icu for ards with pao /fio ratio ≤ mm/hg, including pts ( %) with iv infection (h n pdm iv a, n = ; h n a virus, n = ; b virus, n = ; associated bacteria, n = ). other main causes of ards were bacterial pneumonia without iv ( %), aspiration ( %), non-pulmonary sepsis ( %). ( %) received prone positioning, and ( %) extra-corporeal membrane oxygenation. the overall mortality rate at day- for the entire population was % ( pts ( %) with iv infection versus pts ( %) without iv infection, p = . ). kaplan-meier survival curves showed that survival was significantly higher in patients with iv infection than in those without iv infection. iv infection remained independently associated with a better prognosis at day- when entered as dichotomous variable (iv infection, yes/no) (adjusted hazard ratio (hr) = . , % ci . - . , p = . ) and when iv infection only was distinguished from other causes of ards including mixed infection iv plus bacteria (adjusted hr = . , % ci . - . , p = . ). of note, within the first days of mechanical ventilation, non-pulmonary sofa scores were significantly lower in iv patients although similar pulmonary sofa scores. conclusion: our results suggest that patients with iv related ards have less severe non-pulmonary organ dysfunctions than those with ards from other and a lower mortality at day- despite similar ards severity. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) remains frequent in intensive care unit (icu) with % to % mortality. according to joint theater trauma system, ards occurs among % of war casualties: direct lung trauma, blast lesions, burn, massive transfusion and systemic inflammatory response syndrome lead to ards development. however, there is no data reporting ards among french evacuated casualties from forward environment. our study's aim is to describe ards incidence and its severity concerning medical evacuations from war theater. patients and methods: this is an observational retrospective multicentric study analyzing all evacuated patient from war theater and admitted in icu. all patients developing ards according to berlin definition have been included. study has been approved by local ethic committee. primary study endpoint was ards developing. second study endpoints were ards severity, duration of invasive ventilation, ards treatments, icu length of stay and mortality. results: patients have been admitted in icu between and . have been excluded. a total of patients have been analyzed. % (n = ) were military aged ( - ) years. % (n = ) developed ards. we found % (n = ) war casualties, % (n = ) trauma not related to war and % (n = ) medical patients. among severe trauma, median iss was ( - ), ais thorax ( ) ( ) ( ) , and % benefited from surgery on forward environment and % (n = ) received massive transfusion. % (n = ) suffered from mild ards, % (n = ) moderate ards and % (n = ) severe ards. evacuation time was ( - ) h. at admission in icu, pao /fio ratio was ( - ) (fig. ). all patients were intubated. ards treatments used were curarization ( %, n = ), prone position ( %, n = ), inhaled nitric oxide (noi) ( %, n = ), almitrine ( %, n = ) and extracorporeal life support (ecls) ( %, n = ). invasive ventilation duration was ( - ) days, length of stay ( - ) days, and -month mortality % (n = ). conclusion: according to our study, ards among french evacuated patients from war theaters remains frequent: it occurs on % among icu admitted patients. % suffer from severe ards with % global mortality. those datas are consistent with us studies. also, we wonder if we must adapt our treatment capacities on forward environment for the most severe patients. in us army, a specialized team (acute lung rescue team) is trained to care the most hypoxemic war casualties with more treatment options as noi, ecls. compliance with ethics regulations: yes. rationale : we recently reported that septic shock patients with pneumonia exhibit a high risk of icu-acquired pneumonia, suggesting that a primary pulmonary insult may drive profound alterations in lung defence towards secondary infections ( ) . given their importance in lung immune surveillance, alveolar macrophages (am) are likely to play a pivotal role in this setting. the objective of this experimental study is to address the impact of primary pulmonary or non-pulmonary infectious insults on lung immunity. patients and methods: we established relevant double-hit experimental models that mimic common clinical situations. c bl/ j mice were first subjected either to polymicrobial peritonitis induced by caecal ligation and puncture (clp), or to bacterial pneumonia induced by intra-tracheal instillation of staphylococcus aureus or escherichia coli. respective control mice were subjected to sham laparotomy or intratracheal instillation of phosphate-buffered saline. seven days later, mice that survived the primary insult were subjected to intra-tracheal instillation of pseudomonas aeruginosa (pao strain). we assessed survival and pulmonary bacterial clearance of post-septic animals subjected to p. aeruginosa pneumonia, as well as the distribution and functional changes in alveolar macrophages. results: when compared to sham-operated mice, post-clp animals exhibited increased susceptibility to secondary p. aeruginosa pneumonia as demonstrated by defective lung bacterial clearance and increased mortality rate ( % vs. %, p < . ). in contrast, all postpneumonia mice survived and even exhibited improved bacterial clearance as compared to their control counterparts. when addressing whole-lung immune cell distribution at the time of second hit (day ), amounts of am were decreased in post-clp mice while preserved or even increased in post-pneumonia mice. antigen-presenting functions of am appeared similar in all conditions. percentages of apoptotic (annexinv + ) and necrotic ( -aad + ) am were comparable at day and day after the first hit. interestingly, both ly c high and ly c low monocytes were sustainably increased in the lungs of post-clp mice, while only transiently expanded following pneumonia, suggesting that differences in am counts could be related to modulated turnover from precursor monocytes. conclusion: using clinically relevant double-hit experimental models, a primary pulmonary infection conferred resistance to secondary bacterial pneumonia. ongoing investigations are aimed at addressing the antibacterial am functions, as well as the turnover-driving mechanisms.compliance with ethics regulations: yes. rationale: little is known on the role of exit-site signs in predicting intravascular catheter infections. the current study aimed to describe the association between local signs at the exit-site and catheter-related bloodstream infection (crbsi), which factors substantially influenced local signs and which clinical conditions may predict crb-sis if inflammation at insertion site is present. patients and methods: we used individual data from multicenter randomized-controlled trials in intensive care units (icus) that evaluated various prevention strategies regarding colonization and crbsi in central venous and arterial catheters. we used univariate and multivariate logistic regression stratifying by center in order to identify variables associated with redness, pain, non-purulent discharge, purulent discharge and ≥ local sign and subsequently evaluate the association between crbsi and local signs. moreover, weevaluated the role of thedifferent local signs for developing crbsi in subgroups of clinically relevant conditions. results: a total of patients, , catheters ( , catheterdays) and crbsi ( . %) from icus withdescribed local signs were included. redness, pain, non-purulent discharge, purulent discharge and ≥ local signs at removal were observed in ( . %), ( . %), ( . %), ( . %) and ( . %) episodes, respectively. the sensitivity of ≥ local sign for crbsi was by . %, whereas the highest specificities were observed for pain ( . %) and purulent discharge ( . %). positive predictive value (ppv) was low for redness ( %), pain ( %), non-purulent discharge ( %) and ≥ local sign ( %), but increased for purulent discharge ( . %). negative predictive values were high for all local signs. after adjusting on confounders, crbsi was associated with redness, non-purulent discharge, purulent discharge and ≥ local sign (fig. ). conditions independently associated with ≥ local sign were age ≤ years old (or . , % ci . - . , p < . ), sofa score (sofa < or . , % ci . - . , p < . ), non-immunosuppression (or . , % ci . - . , p < . ), catheter maintenance > days (or . , % ci . - . , p < . ) and insertion site (or for subclavian site . , % ci . - . , p < . ). however, the presence of ≥ local sign was more predictive for crbsi in the first days of catheter maintenance (or . , % ci . - . vs. > catheter-days or . , % ci . - . , p heterogeneity = . ). conclusion: this post hoc analysis showed that local signs were related to crbsis in the icu. local signs were independently associated with specific patient's and catheter's conditions. in the first days of catheter maintenance, local signs were predictive for crbsi. compliance with ethics regulations: yes. rationale: pneumococcal meningitis (pm) is the leading cause of bacterial meningitis in adult patients requiring icu admission and is associated with a high case fatality rate (cfr), ranging from to more than % ( ) ( ) ( ) . patients with pm may develop sepsis or septic shock that may impact management and outcomes. we aim to describe the epidemiology and outcomes of pm associated with sepsis in adult patients in france. we analysed the occurrence of pm with sepsis from to in adult patients, using the national french hospital database pmsi (programme de médicalisation des systèmes d'information). for all analyses, only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for sepsis (either a code for organ failure or a procedure code for organ support). data recorded included comorbidities ( ), characteristics of the hospital stay, severity of the patients including major intracranial complications and characteristics of the infection. costs and endpoints were determined at the end of all the hospital stays related to the first admission for pm with sepsis. standardized incidence, hospital mortality, and cfr were estimated. temporal trends were assessed using cochran armitage tests of trends and linear trend analyses. results: a total of pm with sepsis aged ≥ years were hospitalized in france during - . the incidence of pm decreased from . to . per m inhabitants (p < . ) (fig. ) . most of them came from home ( %), were admitted in an academic institution ( %) and benefited from icu ( %). their median age was [ ; ] years. twothird of them had at least one comorbidity. the initial neurological presentations included coma ( %), focal signs ( %), seizures ( %) and brain stem involvements ( %). the saps ii score was [ ; ] points. the main neurological complications were cerebrovascular complications ( %), cerebral abscess ( %) and hydrocephaly ( %). pm was associated with pneumococcal septicaemia or pneumococcal pneumonia in % and % of cases respectively. the length of icu and hospital stays were [ ; ] and [ ; ] days respectively and only icu length of stay decreased over time (p < . ). the prognosis was poor since only . % of the patients were discharged to home. indeed, . % of them died and % were transferred to rehabilitation units. no temporal trends could be observed for these outcomes. the average hospital costs per case were , € [ . ; . ] . conclusion: pm with sepsis in adult in france remained a real burden associated with a high mortality rate, and disability. compliance with ethics regulations: na. rationale: mucormycosis is an emerging fungal infection, especially in patients with hematological malignancies. although this infection may lead to multi organ failure, no study has been dedicated to critically ill patients with hematological malignancy. the primary objective was to assess outcome in this setting. the secondary objective was to assess prognostic factors. patients and methods: this retrospective cohort study was performed in icus. critically ill adult patients with hematological malignancies and mucormycosis were included between and . mucormycosiswas classified as "probable"or "proven" regarding eortc criteria. variables are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: twenty-six patients were included with a median age of years [iqr, . acute leukemia was the most frequent underlying disease (n = , %). nine patients ( %) were allogeneic stem cell transplantation (sct) recipients. nineteen patients ( %) had neutropenia and patients ( %) had received steroids. the main reason for admission was acute respiratory failure (n = , %) followed by shock (n = , %). the median sofa score at admission was [iqr, - ] points. only patients ( %) had received prior anti-fungal prophylaxis effective against mucorales. mucormycosis was "proven" in patients and "probable" in patients. diagnosis was made by histopathologic examination in patients, direct microscopy or culture in , and polymerase chain reaction in . rhizopus and mucor were the most frequent documented species. seven patients ( %) had concurrent aspergillus infection. mucormycosis was diagnosed day [− to + ] after icu admission. ten patients ( %) had pulmonary involvement whereas five patients ( %) had rhino-cerebral involvement. infection was disseminated in eight patients ( %). twenty-two patients ( %) were treated with liposomal amphotericin b. twelve patients ( %) received antifungal combination including posaconazole in . eight patients ( %) underwent curative surgery. multiple organ failure was frequent, patients ( %) requiring invasive mechanical ventilation (imv), ( %) vasopressors, and ( %) renal replacement therapy. icu and hospital mortality rates were % and %, respectively. only two patients were alive at day . three variables were associated with mortality in a cox model including allogeneic sct . ]; figure), sofa score (hr . [ % ic . - . ]) and dual therapy (hr . [ % ic . - . ]) (fig. ) . conclusion: mucormycosis is associated with a high mortality rate in patients with hematological malignancies, especially in allogeneic sct recipients. futility of icu management in these patients is to be considered and strategies aiming to improve these patients' outcome are urgently needed. compliance with ethics regulations: yes. rationale: sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. several mediators, alone or in combination, were proposed to characterize individual response, but none was proven to have good external validity. the aim of this work was to establish whether some combinations are linked to clinical phenotypes in patients with presumed sepsis, using the data collected in the captain multicenter cohort which methods and first results were previously published (parlato, icm ). patients and methods: patients were prospectively included at the time of sepsis criteria, ( %) of whom with a secondary confirmed infection. community acquired pneumonia was causal in % of infections. saps score = points [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , age = years , male sex = %. patients were followed for more than days, in whom usual icu clinical and biological parameters were collected, as well as plasma biomarkers and leucocyte associated rnas. patients were clinically classified according to their acute severity (sofa score, serum lactate), confirmed initial infection, outcome (secondary infection occurrence, icu survival). non-supervised principal component analysis of the maximal values of biomarkers assessed on first days of sepsis, and varimax rotation technique of the selected components using sas software. results: patients, med sofa day = pts, med serum lactates day = . meq/l, bacterial infection = ( %), enterobacteriaceae infection = ( %), vap and/or bacteremia after day = ( %), alive at icu d/c = ( %). five components explain % of the variance of the biomarkers. the first component ( % of the variance) was not linked to the clinical predetermined phenotypes. the second component ( % of the variance) was principally made of hla-dr rna, cd rna and cx cr rna, and linked to a lower initial severity (r = − . , p = . ), a less frequent confirmation of initial infection (p = . ), a lower occurrence of pneumonia or bacteremia (p = . ) or death (p = . ). conclusion: in our cohort, using non supervised analysis, we could separate a biomarker association linked to lower initial severity, lower rate of a bacterial cause to sepsis, and better outcome. the markers found are among those which are regularly considered as describers of the peripheral alteration of the immune system observed during sepsis (pachot, ccm ; friggeri, cc ; peronnet icm ) . compliance with ethics regulations: yes. ( ) compared a standard of care to a procalcitonin (pct) oriented use of antimicrobials for sepsis in icus. serial blood samples were biobanked in / icus ( / patients enrolled for pro-adrenomedullin (proadm) and pct concentrations). patients and methods: the aim of the study was to evaluate the respective impact of serial pct and proadm measurements in predicting relapse or superinfection and death on day *. relapse was defined as the growth of one or more of the initial causative bacterial strains (i.e., same genus, species) from a second sample taken from the same infection site at h or more after stopping of antibiotics, combined with clinical signs or symptoms of infection. superinfection was defined as the isolation from the same or another site of one or more pathogens different from that identified during the first infectious episode, together with clinical signs or symptoms of infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] points at amission, medical admission: ( %), immunocompromised: ( %), on mechanical ventilation ( %), pct and proadm at inclusion were [ . - . ] ng/ml and . [ . - . ] nm/l respectively. ( %) patients developed a first episode of recurrence or supereinfection after a median delay of days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ( %) died before d . the hr maximization process proposed an optimal cut point of ng/ml for pct and nm/l for pro adm to predict d death. in the multivariate cox model, both pct and proadm were associated with death but not with relapse or superinfection (table ) . conclusion: conclusion: both serial measurements of pct and proadm are independent predictors of death in patients treated for sepsis in icu. our study confirmed the use of nm/l as a good prognosis cut point for proadm. . compliance with ethics regulations: yes. rationale: the performance of serum ( - )-β-d-glucan (bdg) and its evolution to predict the occurrence of invasive fungal infection (ifi) in a high risk non immunocompromized population remains to be determined ( ). in a post hoc analysis of the empiricus randomized clinical trial ( ), we aimed to assess the prognostic value of repeated measures of bdg on the occurrence of invasive fungal infections. patients and methods: non-neutropenic, non-transplanted, critically ill patients with icu-acquired sepsis, multiple candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between july and february in french icus were included. bdg were collected in icu at day , , , and after inclusion. a value time of more than pg/ ml, pg/ml and an increase by more than % from the previous measurement (threshold of measurement error) were assessed at baseline and overtime. for that purpose, we conducted cause specific hazard models with death as a competing risk. we also planned subgroup analyses on the placebo and the micafungin groups. cumulative risk (cumrisk) of ifi at day were derived from models. [ . ; . ] ). neither a bdg > pg/ml, nor an increase by % of bdg over time were associated with the occurrence of ifi. similar results were found in the placebo subgroup. conclusion: among high risk patients, a first measurement of bdg over pg/ml was highly associated with the occurrence of ifi. neither a cut-off of pg/ml, nor repeated measurements of bdg over time seemed to be useful to predict the occurrence of ifi. the cumulative risk of ifi in the placebo group if bdg > pg/ml is . % questioning about the potential interest of empirical therapy in this subgroup. compliance with ethics regulations: yes. rationale: since the sepsis- conference, the distinction between sepsis and septic shock is based on blood lactate value. septic shock may be encountered in the pre-hospital setting. in order to reduce the mortality, the precocity of treatments implementation has been emphasized, particularly early antibiotic administration. prior antibiotic administration, and blood culture drawing must be performed. the aim of this survey was to clarify the capabilities of french prehospital emergency service (pems) to measure blood lactate and to draw blood culture prior to hospital admission for septic shock. patients and methods: we performed an electronic survey of auto-questions addressed to the deputy chair of the french pems in . results: sixty pems ( %) participated in the survey. twenty-five percent are able to measure blood lactate and % are able to draw blood culture in the prehospital setting. ninety-five percent declared lactate measurement is helpful in assessing severity. ninety percent claimed that the lactate value influences the hospital facility, emergency department vs. intensive care unit. twenty-eight percent believe that the impossibility to draw blood culture precludes prehospital antibiotic administration. sixty-three percent estimate that a protocol for septic shock management would be beneficial. conclusion: few french pems are able to measure lactate and draw blood culture in the prehospital setting. the impact of blood lactate measurement and blood culture drawing by pems on septic shock outcome requires further studies. compliance with ethics regulations: yes. rationale: head injury is a common cause of morbidity and mortality in the first four decades of life, accounting for approximately , annual hospital admissions in the united kingdom. the majority of patients recover without intervention, however some may develop a long-term disability or even die. the early detection of pathology is therefore absolutely critical in determining patients' prognosis, helping to provide appropriate timely management. the national institute for health and care excellence (nice) adult head injury guidelines, recommend that head injuries with specific risk factors should have a ct scan within h of risk factors being identified. furthermore the provisional report should be made available within h of the scan. this audit assessed the compliance of staff to the nice adult head injury guidelines. patients and methods: the previous adult ct head scans, requested due to head injury, from the emergency department (ed) at london north west healthcare nhs trust were analysed for compliance to the nice guidelines. the standards measured were: ( ) time from request of scan to completion of scan should be within h; ( ) time from completion of scan to publication of provisional report should be within h. the locally agreed target for both standards was %. results: on review of the ct scans, ( %) were completed within h of request. from the scans ( %) not completed within the hour, were due to porter unavailability, due to an uncooperative patient and the remaining reasons were not clear from documentation. following completion of the scan, scans ( %) were provisionally reported within h. conclusion: this study highlighted a good compliance by hospital staff in ensuring patients with head injuries are managed appropriately, following detection of risk factors indicating a ct head scan. having said that, the locally agreed targets were just short of being met. one factor resulting in delayed scans was porter availability. an intervention recently introduced is the use of the "e-portering" application, which will endeavour to save time for referrers requesting porters and allow patient tracking. it is also worth educating porters, via email bulletins, on the importance of priority scans, such as ct head following injury. furthermore, the findings of the audit were relayed to the radiology department to help improve reporting times and to the ed to re-emphasize prompt requesting of ct head scans when clinically indicated. compliance with ethics regulations: yes. rationale: continuous insufflation of oxygen (cio) performed with specific endotracheal tube during cardiopulmonary resuscitation (cpr) is as effective as intermittent ventilation on endotracheal tube. experimental data suggest that cio improves the efficacy of external cardiac massage and reduces gastric dilatation. as endotracheal intubation is a cause of cpr interruption and requires skilled staff, a specific device has been developed to perform cio without intubation. this device has been implemented progressively in our fire department since . we evaluated this practice. patients and methods: longitudinal study comparing the patients with out-of-hospital cardiac arrest managed by our fire department with cio or bag-valve ventilation between january and april . patients who received mechanical chest compression were excluded. the main outcome was hospital survival. secondary outcomes were the return of spontaneous circulation (rosc) and cpr quality. univariate and multivariate analysis was performed in the whole cohort and in the sub-groups of patient with shockable and non-shockable rhythms to take into account factors associated with survival (shockable rhythm, witness, age). results: among the patients included, have been ventilated with cio and with valve-bag. the mortality was similar in the two groups (cio: . % valve-bag: . % p . ). mortality and rosc were not associated with cio in the multivariate analysis (odds ratio or . %-confidence interval ci [ . - . ] and . [ . - . ], respectively). cpr quality was better with cio than with valve-bag regarding cpr fraction (ratio of duration of chest compressions on total duration of cpr, versus % p < . ) and adequacy to the guidelines of the rhythm and depth of chest compressions ( % vs % p < . and % vs % p < . , respectively). in both subgroups of patients, cpr quality was still better with cio than with valve-bag. in the subgroup of patients with shockable rhythm, univariate analysis showed a lower mortality among the patients with cio than among the patients with valve-bag ( . % vs . % p < . ) but this difference was not confirmed by the multivariate analysis (or . ci [ . - . ], p . ). conclusion: cio without intubation is associated with an improvement of cpr quality but neither with mortality nor return of spontaneous circulation in case of out-of-hospital cardiac arrest. compliance with ethics regulations: yes. rationale: cardiovascular accidents are a leading cause of death. a cardiopulmonary resuscitation (cpr) of quality has well shown that can reduce the mortality; despite this, survival rate has not changed significantly during last years. the aim of this study is to test a new wearable glove to provide lay people with instructions during out-ofhospital cpr. patients and methods: we performed a blinded, controlled trial on an electronic mannequin ambuman to test the performance of adult volunteers, non-healthcare professionals performing a simulated cpr both, without and with glove, following the glove instructions. the group without glove, also called "no-glove" is intended as control group. each compression performed on the electronic mannequin ambuman was recorded by a connected laptop computer, drawing a depth frequency curve over the time. primary outcome was to compare the accuracy of the two simulated cpr sessions in terms of depth and frequency of chest compressions performed by the same lay volunteers. secondary outcome was to compare the decay of performance and percentage of time in which the candidate performed accurate cpr. finally, the participants were asked if the glove was useful for cpr maneuvers. the difference between the two groups in regard to change in chest compression depth over time due to fatigue, defined as decay were also analyzed. results: chest compressions were included: in control group, in glove group (table ) . mean depth of compression in the control group was . mm versus . mm in the glove-group (p = . ). compressions with an appropriate depth were not statistically different ( . % vs . %, p = . ). mean frequency of compressions in the group with glove was . rpm vs . rpm in the control group (p < . ). the percentage of compression cycles with an appropriate rate (> rpm) was . % in the group with the glove versus % in the control group, with an observed difference of . % between the two groups, which was statistically significant (p < . ,ci = %). a mean reduction over time of compressions depth of . mm (sd . ) was observed in the control group versus a mean reduction of . mm in the group wearing the glove (sd . ), but this mean difference in the decay of compressions delivery was not statistically significant (f-ratio = . , ss = . , df = , ms = . , p = . ). conclusion: the visual and acoustic feedbacks provided by the device were useful in dictating the correct rhythm for non-healthcare professionals, translating in a significantly more accurate cpr. compliance with ethics regulations: yes. rationale: neuroprognostication after cardiac arrest (ca) is a crucial issue and current guidelines recommend delayed multimodal approach. we aimed to describe reasons for death in a prospective cohort of ca patients and evaluate the diagnostic accuracy of early combined neurological prognostication tools such as automated pupillometry (ap), continuous amplitude electroencephalography (aeeg) and cardiac arrest hospital prognosis (cahp) score performed h after return of spontaneous circulation (rosc). we set up a monocentric prospective cohort of adult ca patients admitted in icu after sustained rosc and collected data according to utstein style recommendations. reasons for death were described under recently proposed classification: withdrawal of life-sustaining therapies (wlst) for neurological reasons, wlst due to comorbidities, refractory shock or recurrence of sudden ca or respiratory failure. for patients who kept abnormal neurologic state after rosc with glasgow coma scale < , we analysed accuracy of early neuroprognostication tools (ap, aeeg and cahp score) to predict poor neurological outcome, i.e. cerebral performance category (cpc) > at hospital discharge. results: patients were admitted after sustained rosc from ca during the period ( . . to . . ). in-hospital mortality was %. neurological wlst was the first reason for death ( %). exhaustive early neuroprognostication with ap, aeeg and cahp score was available for patients. among them, poor neurological outcome at hospital discharge (cpc > ) was observed for patients ( % (fig. ) . this strategy would falsely misclassificate % of patients in a good neurologic outcome category. other survivors ( %) should then be investigated with further classical delayed neuroprognostication tools. compliance with ethics regulations: yes. rationale: management delay is one of the determining factors in the assessment of emergency department quality of care. asking for a specialized advice seems to increase the time of delay. our study aimed at measuring the delays in obtaining specialized advice and identify their major causes. patients and methods: we conducted a prospective study over the period of month. we included all adult patients presenting to the emergency department who required specialized advice. data of all patients was collected. waiting times and influencing factors were studied. results: a total of patients were included. the main reason for calling for a specialized advice was to ask for a department transfer in % of cases. the time of the day when specialized advice was solicited (n (%)): in the morning ( ); in the afternoon ( ); in the evening ( ). the main solicited specialties were (n (%)): visceral surgery ( ), trauma medicine ( ), cardiology ( ), urology ( ), and pulmonology ( ). the average waiting time between calling for and getting the specialized advice was ± min. seventy-five percent of the specialized advice was obtained within h. the causes of the delay were (n (%)): physician busy in the operating room ( ), unreachable physician ( ), physician in the outpatient clinics ( ). the impact of the waiting time was (n (%)): conflict ( ), worsening patient state ( ). the average time between calling for the specialized advice and reaching a management decision was ± min. conclusion: the increasing length of stay of patients in the ed is strongly correlated to the delay in obtaining specialized advice. the implementation of a strategy to reduce the waiting time is necessary to avoid overcrowding the emergency departments and provide optimal care. compliance with ethics regulations: yes. rationale: hypnoanalgesia has been used since few years to reduce icu-patients physical and psychological discomfort during invasive procedures. however, feasibility of overall well-being management of intubated patients with hypnosis has not been described. patients and methods: we report here the hypnotic accompaniment of a -year old patient without significant medical history hospitalized in our icu for a severe gbs during months. the gbs was diagnosed by electrophysiological study and immunologic markers. patient had nearly complete paralysis of all extremities, but no facial or bulbar muscles. he received mechanical ventilation during days, including weaning time. tracheotomy was performed at day . sedative drugs were stopped days after intubation. hypnosis sessions were startedvery early after intubation by one of our trained intensivist. eight hypnotic sessions of hypnoanalgesia or hypnotherapy were performed after approval of the patient and his parents. time distribution is reported in fig. . first and second sessions were performed in order to induce relaxation and reduce anxiety. following sessions were dedicated to: ) decrease pain intensity (initially neuropathic, then induced by physiotherapy), ) attenuate the negative perception of paralysis, ) reduce the discomfort of tracheotomy ) promote the belief in healing ) facilitate swallowing exercises. furthermore the patient was quickly trained to use self-hypnosis in order to dissociate him from pain, anxiety and icu pollutions. results: feasibility of hypnosis was judged satisfactory by the operating physician, despite mechanical ventilation. after extubation, final debriefing with the patient indicates that the most efficient sessions were those focused on anxiety disorders (using the suggestion of a safe place) and suggestions of mobility (using a mangas metaphor). the patient reported very positive perception of hypnosis use. he explained that self-hypnosis was effective to reduce many discomfort. he used it frequently (generally twice a day) for a puff of anxiety or before enoxaparin injection. our observation suggests that hypnosis seems feasible in icu-awake patients and may be an interesting way to improve their icu lived experience in combination with validated measures. further investigations are needed to evaluate its effects on post-traumaticstress disorder. compliance with ethics regulations: yes. rationale: there is little medical reference for hypnosis in the intensive care field. closed specialties such as anesthesia, emergency medicine can help and refer to hypnosis for certain technical procedures. objective: to propose landmarks for a successful implementation of hypnosis by intensivists within the intensive care unit. patients and methods: this monocentric prospective observational study was performed from february to june in the -bed medical icu of brest university hospital. collected data were: characteristics of patients and hypnosis sessions performed, demographic data, physiological parameters (heart and respiratory rates) and objective and subjective evaluation of hypnosis sessions quality. results: patients were included (mean age . ± years, saps ii . ± points). hypnosis sessions were performed, of which / under mechanical ventilation. patterns of hypnosis sessions were: anxiety/comfort ( %), during a technical procedure ( %): toe, cvc placement, thoracic drainage, upper digestive or bronchial endoscopy), initiation of noninvasive ventilation or before intubation. most of time, the hypnotic trance was permitted by formal hypnosis techniques with travel and nature themes suggestion. efficacy was qualitatively assessed and rated as "total effectiveness" for % of sessions. qualitative evaluation by hypnotherapist, technical operator and observers was respectively . ± . , . ± . and ± / . heart rate decreased from ± to ± bpm and respiratory rate/min decreased from ± to . ± rpm during sessions. discussion: after a meeting, the healthcare team carried out a brainstorming to propose hypnosis in our unit. several difficulties were observed to explain implementation failures such as: finding competent patient, respiratory assistance, difficult communication, noisy environment, many nursing care, unexpected emergencies, etc.…). this experience allowed writing a vademecum to perform hypnosis in intensive care. our aims are to get more trained caregivers and to integrate hypnosis during our postresuscitation consultation, especially for post-traumatic stress. conclusion: hypnotic tools can facilitate technical procedures and improve patients' and caregivers' quality of life within the icu. compliance with ethics regulations: yes. effect of a musical intervention during central venous catheterization in an intensive care unit: the music cat prospective randomized pilot study sophie jacquier, brice sauvage, gregoire muller, thierry boulain, mai-anh nay chr, orléans, france correspondence: sophie jacquier (sophie.jacquier@chr-orleans.fr) ann. intensive care , (suppl ):f- rationale: evaluate the effect of a musical intervention on patient anxiety during a central venous access or a dialysis catheter implantation in an intensive care unit. patients and methods: the music cat study was a prospective, single-centre, controlled, open-label, two-arm randomized trial, conducted from february to february . central venous catheterization with musical intervention was compared to standard care, i.e., the usual procedure of central venous catheterization without listening to music. eligible patients had to be able to hear, understand explanations and consent. randomisation was stratified according to ventilation type (mechanical ventilation or not) and catheter site (superior vena cava or femoral vein). the music care ® (paris, france) application was used to make the patients listen to music through headphones. each patient chose his/her musical topic on a digital tablet, just before the catheterization. the primary outcome was the change in anxiety visual analogic scale (vas) between the beginning and the end of the catheterization procedure (t -tf anxiety vas). secondary outcomes included the patient's pain vas at the end of the procedure (tf pain vas). results: patients were included in the standard care group versus in the musical intervention group. main reasons for admission were the need of central catheter for chemotherapy ( , %), and sepsis and/or shock in both groups ( , %). catheters were inserted in the internal jugular vein in most cases ( , %) and about one-third were tunnelled in both groups. there was no between-group difference regarding median t -tf anxiety vas: [iqr:− to ] in the standard care group versus − [− to ] in the music intervention group (p = . ) (fig. ) , with no significant interaction between the variables of stratification or the operator experience and the intervention. the median tf pain vas was not statistically different between groups: [ to . ] in standard care group and [ to ] in music intervention group (p = . ), with no significant interaction between the variables of stratification or the operator experience and the intervention. conclusion: in this first randomized pilot study of musical intervention for central venous catheterization in awake patients in the intensive care unit, the musical intervention did not reduce patients' anxiety as compared to usual care. as the study may have been underpowered, larger size trials are needed. compliance with ethics regulations: yes. rationale: sleep is markedly altered in icu-patients under mechanical ventilation and may be due to noise, light, patient-care activities, patient-ventilator asynchronies, or the result of acute brain dysfunction induced by sedative drugs. to our knowledge, sleep has never been studied at icu admission before any sedation. our study aimed at assessing sleep quality of non-intubated sedation-free patients admitted to icu for acute respiratory failure. patients and methods: observational study performed in a single centre of a teaching hospital. patients admitted to icu for acute respiratory failure (respiratory rate ≥ breaths/min and pao / fio < mm hg under high-flow nasal oxygen) could be enrolled. patients with hypercapnia, central nervous disease, intubated early after admission and those with a do-not-intubate order were excluded. sleep was evaluated by complete polysomnography (psg) that started in the afternoon following admission and was continuously performed until the next morning. results: over a -year period patients were screened and patients were included. among them, patients were excluded for the following reasons: patient was intubated shortly after psg initiation, psg was lost, and eeg recordings ( %) were stopped before midnight (electrodes turned off or loss of signal). therefore, patients in whom psg was complete during the nocturnal period were retained in the analysis ( rationale: convulsive status epilepticus (cse) is a common neurological emergency associated with high mortality and morbidity rates. there are strong experimental data suggesting a potential impact of secondary brain insults (sbi) on outcome after cse. however, there is no clinical proof to support this hypothesis. our objective was to evaluate the association between sbi (mean arterial blood pressure, arterial partial pressure of carbon dioxide, arterial partial pressure of oxygen, temperature, natremia, and glycemia) at day and neurological outcomes days after cse. patients and methods: this was a post hoc analysis of the hyber-natus multicenter open-label clinical trial randomized critically ill patients with cse requiring mechanical ventilation to either therapeutic hypothermia ( - °c for h) plus standard care or standard care alone. patients still alive at day after inclusion were enrolled from march to january in french medico-surgical icus. the primary outcome was favourable outcome days after cse defined as a glasgow outcome scale score of . results: median age was of years . a previous history of epilepsy was noted in ( %) patients. most episodes ( / , %) occurred out-of-hospital, and ( %) were witnessed from their onset. cse was refractory in ( %) patients and total seizure duration was min ( - ). a favorable -day outcome occurred in ( %) patients. maximal glycemia value and hyperglycemia > . mmol/l at day were the only sbi variables associated with outcome in univariate analysis. by multivariate analysis, age > years (or, . ; % ic, . - . ; p = . ), refractory cse (or, . ; % ic, . - . ; p = . ), and primary brain insult (or, . ; % ic, . - . ; p = . ) were associated with an increased risk of poor outcome, and a bystander-witnessed onset of cse (or, . ; % ic, . - . ; p = . ) was associated with a decreased risk of poor outcome. conclusion: in our population, secondary brain insults were not associated with outcome in critically ill patients with convulsive status epilepticus; whereas age, bystander-witnessed onset of status epilepticus, refractory status epilepticus and primary brain insult were identified as strong predictors of -day functional impairment. further studies are warranted to confirm our findings. compliance with ethics regulations: yes. rationale: acute stroke (as) is a leading cause of morbidity and mortality worldwide. however, data on the prognosis andfunctional outcome of patients with as requiring icu management is limited. our purpose was to identify factors associated with good outcome (defined by a modified rankin score (mrs) of - ) months after icu admission. patients and methods: retrospective cohort of patients admitted to the medical icu of a university-affiliated hospital between january and december and coded for acute stroke using the icd- criteria. patients with traumatic stroke and isolated subarachnoid hemorrhage were excluded. results: we identified patients. median age was [ . - ] years and ( . %) were males. main reasons for icu admission were coma ( %), hemodynamic instability ( . %), acute respiratory failure ( %), and cardiac arrest ( . %). glasgow coma score at icu admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and points. types of stroke were hemorrhagic in ( . %) patients and ischemic in ( . %). mechanical ventilation was required in patients ( . %). seizures occurred in . % of the patients and convulsive status epilepticus in . %. pneumonia was diagnosed in ( . %) patients (aspiration pneumonia n = , ventilator associated pneumonia n = ). thrombolysis or thromboaspiration were performed in ( %) patients with ischemic stroke. surgical evacuation of expanding hematoma was performed in ( . %) patients, ( . %) had craniectomy, and ( . %) had external shunt for hydrocephalus. icu and hospital mortality were . % and %, respectively. six months after icu admission, ( . %) patients had a good outcome (mrs - ), ( . %) had significant disability (mrs - ), and ( . %) were deceased (lost follow-up n = , . %). on multivariable analysis, age (or . per year ( . - . ), p = . ), saps (or . per point ( . - . ), p = . ), and hemorrhagic stroke (or . ( . - . ), p = . ) reduced the likelihood of good outcome (mrs - ) months after icu admission. conclusion: in our study, prognosis of acute stroke requiring icu admission was poor and a good functional outcome occurred in less than % of the patients at months. age, severity at icu admission, and type of stroke predicted outcome. compliance with ethics regulations: yes. rationale: in intensive care units, severe spontaneous hemorrhagic brain injuries have a poor prognosis for mortality and functional outcomes. affected patients face particular ethical issues regarding the difficulty of anticipating their eventual recovery. in this context, prognostic scores can help clinicians in patients/relatives counseling and therapeutic decisions. the previous reviews pointed out many prognostic tools for intracranial hemorrhage and subarachnoid hemorrhage but did not focus on injuries explicitly severe nor assessed the methodological limitations of the models. our systematic review aimed to assess methodologically prognostic tools for functional outcomes in severe spontaneous haemorrhagic brain, with particular attention to their clinical utilities. patients and methods: following prisma recommendations, we queried medline, embase, web of science, and the cochrane by february , . we included multivariate prognostic models explicitly developed or validated on adults with severe intracranial or subarachnoid haemorrhage. we evaluated the articles following the charms recommendations (checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies) and the tri-pod statements (transparent reporting of a multivariable prediction model for individual prognosis. results: our review confirmed the multiple publications of prognostic scores, as we found articles aiming to develop or validate prognostic tools. relying on guidelines, we discarded articles due to the lack of prognostic capacities, validation, or predictor selection. articles developed and validated a prognostic tool and externally validated existing models (fig. ) . no score was of good methodological quality in intracranial hemorrhage. we highlighted two prognostic scores in subarachnoid hemorrhages: the sahit predicting unfavorable outcome or mortality at months and the fresh predicting unfavorable outcome at months. conclusion: although prognostic studies on haemorrhagic brain injuries abound in the literature, they generally lack of methodological robustness or show incomplete reporting. with the numerous published scores, we believe that it is time to stop developing new scores. ongoing validation, recalibration, and impact studies would keep improving existing good tools. the use of "patient-centered" approaches could also enhance them, and be more appropriate to inform patients and families about their long-term potential recovery. these considerations should drive future research in the modern era of neurocritical care prognosis. compliance with ethics regulations: na. rationale: respiratory pattern analysis by a visual examination is an important part of clinical assessment but is dependent on caregiver expertise and is subjective. furthermore, there is no easy medical device used in picu to measure tidal volume (vt) and minute ventilation (mv) in spontaneous breathing patients. the clinical research unit in critical care of chusj and ets have developed a non-invasive computerized d video analyzing system (retract system) to detect and perform a video analysis of respiratory status in children. the aim of this study is to test the reliability of the retract system to monitor respiratory distress in critically ill children. the retract system is detailed in reference . in summary, cameras reproduce in d the thorax and abdomen of a subject. the respiratory status (respiratory rate (rr), tidal volume (vt), minute ventilation (mv)) assessed by the retract system was compared on a bench test (high-fidelity mannequin) and in critically ill children, to the ventilator measurements and clinician expert evaluation (gold standard). bland-altman plots were used for comparison. results: we observed a significant agreement, on mannequin, between retract system and gold standard method in estimating vt, rr and mv, i.e. % of the paired differences were within the limits of agreement in bland-altman plots, as illustrated in fig. . in critically ill children (n = ), the correlation between the pairs of measures was also high (r > . , p < . ) and thecoefficient of determination with a high fit ( . < r < . , p < . ). for good correlation, the retract system needed to have a visual access to thorax and abdomen in a quiet subject. the retract system measurements of vt, rr and mv for respiratory distress monitoring in patients seems reliable. more testing are required to validate this method in usual practice and to develop the retractions signs video analysis. compliance with ethics regulations: yes. rationale: severe bronchiolitis requires hospitalization in paediatric intensive care unit (picu). non-invasive ventilation (niv) has been demonstrated to treat them since twenty years, its use is well defined but there is no consensus for the weaning. this study evaluated the application of a nurse-driven niv weaning protocol in hospitalized infants with severe bronchiolitis and verified its safety. this was a retrospective monocentric study in a picu of robert debré hospital-paris, france. in the epidemic period of bronchiolitis between and , all patients under one year old with severe bronchiolitis and requiring niv were included. two groups were compared: one group using the nurse-driven niv weaning protocol and one group without using this protocol. occurrences of complications, duration of ventilatory support and length of stay (los) in picu and total los were compared. results: patients were included in the study, in the no-protocol group, and in the protocol group. the nurse-driven protocol was using at the rate of % (n = / in the protocol group (p = . ). picu los were . days [ ] [ ] [ ] in the no-protocol group versus days [ - . ] in the protocol group (p = . ), hospital los was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the no-protocol group versus days [ ] [ ] [ ] [ ] [ ] [ ] in the protocol group (p = . ) (fig. ) . the use of this first nurse-driven niv weaning protocol was feasible and simple with a very good application rate. its utilization was safe. the occurrence of complications did not increase by the use of this protocol. it would allow an optimal niv weaning without prolonging the ventilatory support duration nor picu los or hospital los. the professional practices appeared to be coordinated and the nurses appeared to be more autonomous. compliance with ethics regulations: yes. no-protocol and protocol groups comparison: cpap duration ( ), ventilatory support duration ( ), picu los ( ), hospital los ( ) rationale: first-line management of severe acute bronchiolitis in infants is mainly based on non-invasive ventilation (niv) and high-flow nasal cannula (hfnc) therapy. however, pediatric data regarding weaning from niv/hfnc are lacking. this study aims to identify the weaning practices from niv/hfnc in children with severe bronchiolitis. the weaniv-survey is a cross-sectional survey. a questionnaire was sent to french-speaking physicians with key roles in pediatric intensive care units. results: a total of % ( / ) of french university hospital were represented in the study. only % of pediatric centers used a protocol for weaning from niv/hfnc and nurses were considered as key-actors of the weaning process for half of participants. continuous positive airway pressure (cpap) was the mode of ventilation mainly used as the first-line therapy in clinical practice. the main criteriaconsidered toinitiate weaning process were: noor slight respiratory distress, a fio < %, a respiratory rate < /min and no significant apnea. three strategies to discontinue niv/hfnc were identified: /gradual decrease of ventilatory parameters (pressure or flow), /abrupt discontinuation and /gradual increase in off-ventilation time. abrupt weaning strategy was the most commonly used, no matter the mode of ventilation. a significant level of respiratory distress, the presence of apneas, an increase in oxygen requirement, and a respiratory rate > / min were identified as weaning failure criteria by most pediatric intensive care physicians. conclusion: in most centers, the weaning process does not follow any protocol. abrupt weaning seems to be commonly used as weaning strategy in children with severe bronchiolitis supported by niv/hfnc. based on the study findings, we suggest that criteria for weaning initiation and for weaning failure must be defined and weaning protocols generated. compliance with ethics regulations: yes. complications secondary to prone positioning occured for patients ( . %). conclusion: this first study, which evaluate prone positioning efficacy in severe p-ards shows evidence that prone positioning improves oxygenation parameters and survival rate. these results highlight the necessity to develop a multicentric prospective randomized study to confirm these conclusions. compliance with ethics regulations: yes. ( vs ) and vasoactive-inotropic score (vis) ( vs ) were significantly higher in the non-survivor group. cannulation was veno-venous ( %) or veno-arterial ( %) and patients ( %) were finally not initiated on ecmo. we observed an increase of patients cannulated in our picu over time (fig. ). there was no significant difference in mortality between patients transported on ecmo after cannulation in our picu and those who were transported to be cannulated in a referral ecmo center. the median time between the decision and the cannulation was . h and the median time taken in charge by picu transport team was approximately h. these periods were not significantly different between cannulation on site or in an ecmo center and between survivors and not-survivors. conclusion: in our study, multiple organ dysfunction, particularly hematologic and acuterenal failures, seems to be a risk factor of mortality. the delay between decision and management is similar whatever the cannulation site. specific ecmo mobile team and picu transport team seem to be essential, fast and trained to transfer these patients. it would be interesting to compare our cohort with children requiring ecmo already hospitalized in a referral ecmo center. compliance with ethics regulations: yes. rationale: life expectancy in patients with metastatic breast cancer (mbc) has substantially improved over the last decade. life threatening complications result from advanced diseases, infection and treatment-related toxicity. only few studies have assessed outcomes in this setting. we performed a hospital-wide study to investigate how icu resources are needed in patients with mbc. patients and methods: all patients with mbc managed at our hospital between and were retrospectively included. the primary outcome was overall survival (os). factors associated with icu mortality were identified using a multivariable cox proportional hazard model with sensitivity analysis. results are expressed as median [interquartile ranges] unless stated otherwise. results: among the patients managed at our hospital, ( %, including male) were admitted to the icu ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patients per year). age was [ - ] years. patients were receiving their nd [ st- rd] line of treatment and had [ ] [ ] metastatic sites. sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . main reason for icu admission was sepsis (n = , %), acute respiratory failure (n = , %), coma (n = , %) and metabolic disorder (n = , %). invasive mechanical ventilation was required for patients ( %) and renal replacement therapy for ( %). sixteen ( %) patients died in icu. following icu discharge, median os was . months ( % ci [ . - . ]) and / ( . %) patients died within months. an antineoplastic treatment was resumed for / ( %) patients alive after icu discharge. factors independently associated with mortality were performance status ≥ (hr . , % ic [ . - . ] ) and sofa score at day (hr . per point, % ic [ . - . ] ). after sensitivity analysis, the number of treatment lines at icu admission was not associated with mortality. conclusion: icu admission is required in the course of the mbc disease for % of the patients. determinants of short term outcomes rely on performance status and disease severity but not on the characteristics of the underlying disease. ongoing analyses will assess whether icu survivors reach life expectancy of patients never admitted to the icu. compliance with ethics regulations: yes. hubert gheerbrant , jean-françois timsit , nicolas terzi , stephane ruckly , mathieu laramas , matteo giaj levra , emmanuelle jacquet , loic falque , denis moro-sibilot , anne-claire toffart chu grenoble alpes, grenoble, france; aphp, paris, france; outcom-erea, bobigny, france correspondence: hubert gheerbrant (hgheerbrant@chu-grenoble.fr) ann. intensive care , (suppl ):p- rationale: the prognosis of critically ill cancer patients admitted in intensive care unit (icu), remains an issue. our objective was to assess the factors associated with -and -month survival of icu cancer survivors. patients and methods: based on the french outcomerea ™ database, we included solid cancer patients discharged alive, between december and november , from the medical icu of the university hospital in grenoble, france. patient characteristics and outcome at and months following icu discharge were extracted from available database. results: of the cancer patients with unscheduled admissions, ( %) were discharged alive from icu. the main primary cancer sites were digestive ( %) and thoracic ( %). the -and -month mortality rates were % and %, respectively. factors independently associated with -month mortality included ecog performance status (ecog-ps) of [ ] [ ] . . - . ). interestingly, cancer chemotherapy prior to icu admission was independently associated with lower -month mortality (or, . ; % ic: . - . ). among patients with an ecog-ps - at admission, % (n = ) and % (n = ) displayed an ecog-ps - at and months, respectively. at months, ( %) patients received anticancer treatment, ( %) were given exclusive palliative care. discussion: factors associated with -month mortality are almost the same as those known to be associated with icu mortality. we highlighted that most patients recovered an ecog-ps of - at and months, in particular those with a good ecog-ps at icu admission, and could benefit from an anticancer treatment following icu discharge. conclusion: these results should be taken into account when deciding upon icu admission. it is of paramount importance to have an evaluation of both patient's general condition and anticancer treatment opportunities following icu discharge. compliance with ethics regulations: yes. rationale: the decision to urgently initiate medical anti-cancer treatment in cancer patients admitted to intensive care unit for cancerrelated organ failure is an issue. we currently lack criteria to select patients who may benefit from the treatment initiation. the purpose of our exploratory study was therefore to evaluate the characteristics of patients whose medical anti-cancer treatment is initiated in icu and to identify prognostic factors for in-hospital mortality. in these patients. patients and methods: we analyzed retrospectively, over a period of years ( / / to / / ), cancer patients over -year old admitted to our icu bordet and in whose anti-cancer medicaltreatment was initiated during in-icu stay. to identify prognostic factors for in-hospital mortality, we carried out a multivariate analysis of the factors influencing this mortality, considered as a binary. we also analyzed the long term survival of patients alive after their hospital stay (from the day of going out of hospital). results: overall, patients were included, men ( %) and women ( %), with a median age of years ( - ). of these, patients ( %) had a solid tumor and ( %) had a hematological tumor. in-icu mortality is % ( % ci - %) and in-hospital mortality % ( % ci - %). the prognostic factors for in-hospital mortality were age (mean vs in those who survived), the sofa score (median vs ), the saps ii score (mean vs ), the charlson score (mean vs. . ), the number of organ failure (mean . vs . ) and the presence of a therapeutic limitation (ntbr stated within h: % vs %). survival at year of patients who survived the hospital stay was % and median survival time was estimated to be . year ( % ci . - . ). in patients with a solid tumor, -year survival was % and % in those with a hematological tumor (p < . ). conclusion: we observed, in selected cancer patients admitted to the icu for a cancer-related complication, that the initiation of an anti-cancer medical treatment is feasible and can lead to interesting results, particularly in patients with a hematological tumor. compliance with ethics regulations: yes. rationale: considerable progress in the management of onco-hematology (oh) malignancies led to an increase in the number of patients proposed for intensive care unit (icu) admission. several guidelines offer decision models for icu transfer of these patients. we aimed to describe prognosis, adequacy of icu admission and denial in oncohematology patients. we included all oh patients proposed for icu admission in a tunisian medical icu, between january and july . from an admission proposal registry, were collected patient underlying condition, functional status, malignancy and predicted prognosis, acute critical illness and its reversibility, adequacy of icu rationale: cancer patients frequently need intensive care support for a life-threatening condition due to the underlying neoplasm or an adverse therapy-related event. however, there are poor data on their characteristics and outcomes in the intensive care setting. the aim of the present study was to describe clinical characteristics and to identify factors associated with in-icu mortality in critically ill cancer patients. patients and methods: it is a retrospective study conducted in the medical icu of farhat hached teaching hospital between january and december . all cancer patients with complete records were included. baseline characteristics, clinical parameters, severity of illness, primary tumor location and outcomes were collected. univariate and multivariate regression analyses were carried out to identify factors independently associated to poor prognosis. rationale: prognostic impact of underlying malignancy seems limited in most studies assessing outcome of critically ill cancer patients [ ] . however, only limited number of characteristics, namely disease progression status and preexisting stem cell transplantation, were usually assessed [ ] . primary objective of this study was to assess influence of hematological malignancy aggressiveness on hospital outcome. secondary objective was to assess influence hematological malignancy aggressiveness on type of infection. patients and methods: post-hoc analysis of prospective multicenter cohort performed in hospitals in france and belgium and including critically ill adults with underlying hematological malignancy admitted in icu from jan to may . a cox model was used to adjust for confounding variables then a propensity score matching on characteristics associated with underlying malignancy aggressiveness was performed. results: of the included patients, ( . %) had low grade malignancy (lg), the most frequent being myeloma (n = ), chronic lymphocytic leukemia (n = ), and myelodysplasia (n = ). patients with lg malignancy were older, underwent more frequently autologous stem cell transplantation (sct) and had less frequently altered performans status. they had more severe organ failure at icu admission (sofa score [ ] [ ] [ ] [ ] [ ] [ ] vs. [ ] [ ] [ ] [ ] [ ] [ ] , p = . ). before adjustment, mortality was % (n = ) and . % (n = ) respectively in patients with and without lg malignancy (p = . ). after adjustment for confounder using a cox model, a higher mortality was associated with nonlow grade malignancy (or . ; % ic . - . ). a propensity score then allowed a : matching upon variable associated with malignancy aggressiveness. after matching unadjusted mortality was % (n = ) in patients with lg malignancy and . % (n = ) in patients with high grade malignancy (p = . ) (figure) . in the matched cohort and after adjustment for confounder, high grade malignancies were associated with lower mortality (or . ; % ic . - . ). risk of fungal infection was unchanged by underlying malignancy before adjustment ( % vs. . % of patients with and without lg malignancy; p = . ) or after adjustment (hr . ; % ic . - . ). conclusion: despite anti-cancer advances, aggressiveness of hematological malignancies is associated with overall icu outcome. lowgrade malignancies displaying a better prognosis than non-low grade. aggressiveness of the underlying malignancy is not associated with risk of fungal infection. compliance with ethics regulations: yes. rationale: guillain-barré syndrome is the most common cause of acute flaccid paralysis and is associated with pulmonary embolism due to the mobility limitation. the aim of this study is to describe the incidence, the severity of pulmonory embolism in patients admitted to an intensive care unit (icu) for guillain-barre syndrome (gbs). patients and methods: twenty-eight adults patients with confirmed diagnosis of gbs were admitted to the icu in our university hospital center over a -year period and they were all included. prevalence, risk factors and course of vte were analyzed in icu patients with various forms and severity of gbs. results: during the study period, adult gbs patients were included. five ( . %) developped pulmonary embolism. the mean age was . ± . years and the sex ratio was . . the comparaison betewen the groups with and without pe showed that factors associated with the development of this complication were: respiratory failure requiring mecanical ventilation (p = . ), infectious complications (p < . ), blood pressure lability (p = . ), the delay of icu admission (p = . ), the delay to treatment initiation (p = . ), the sofa score (p = . ) and the presence of quadriplegia (p = . ). conclusion: pulmonary embolism is a frequent complication in patients with gbs. factors associated with this complication were: respiratory failure requiring mecanical ventilation, infectious complications, the delay of icu admission, the delay to treatment initiation, a high sofa score and the presence of quadriplegia. preventive measures in this category of patients have to be improved. rationale: acute respiratory distress syndrome (ards) is a life-threatening pathology associated with very high morbidity and mortality ( - %) in intensive care units (icu) and with even higher mortality among the severly burned patients worldwide ( à %). the aim of our study was to describe in tunisia burn patients with ards and to identify prognosis factors. patients and methods: we conducted a descriptive retrospective study between - - to - - , in burns icu, in ben arous, in tunisia. all burns who presented an ards, according to the berlin definition, during their stay in the icu, were included. when clinical or gasometric data was uncomplete, these patients were excluded. results: during the study period, patients were admitted to our burn unit including ventilated patients. fifty patients presented an ards: fifteen patients were excluded for lack of information, and patients were retained. the sex ratio was . . patients had a mean age of ± years, an average burned area of % ± %, an average unit of burn skin score (ubs score) of ± and an average sequential organ failure assessment score (sofa score) of . none of the patients had a history of cardiovascular or pulmonary diseases. the average time of onset of ards was ± days. ards was mild in case, moderate in and severe in . the etiology of ards was pulmonary in cases ( %) and extra-pulmonary in ( %). the pulmonary ards had as cause pneumonia isolated in patients, an isolated pulmonary burn in patients and a combination of pneumonia and lung burns in patients. extra-pulmonary ards were all due to sepsis and mainly to bacteremia. septic shock was associated with ards in patients ( %). the treatment was a conventional treatment based on protective ventilation, curarization and prone positioning in addition to the etiological treatment. the average length of stay in icu was days and mortality was % in these patients. conclusion: mortality from ards in burns in tunisia, is important especially in those with pulmonary burns as well as those with sepsis. the introduction of new treatments, such as extracorporeal membrane oxygenation, remains essential to improve the prognosis of burn patients. compliance with ethics regulations: yes. rationale: aspiration pneumonia (ap) is common in intensive care unit (icu). the incidence of ap among adults hospitalized with pneumonia ranges between and . %. usually one or more risk factors are identified to be involved in ap. the aim of this study was to determine the risk factors and predictors of mortality on patients with ap. patients and methods: we retrospectively included patients aged more than years and who were hospitalized in our icu for ap. patients were excluded if they had history of tuberculosis, if they have bronchiectasis or metastatic brain tumor. results: a total of patients were included. history of diabetes, hypertension, epilepsy and ischemic stroke were found respectively in . %, . %, . %, and . % of cases. the reason of icu admission were coma ( %), acute respiratory failure ( %), poisoning ( %) and cardiac arrest ( %). the incidence of acute respiratory distress syndrome (ards) was %. the most common organism isolated was staphylococcus aureus ( cases). risk factors for ap were epilepsy ( %), swallowing disorders ( %), ischemic stroke ( %), copd ( %) and degenerative neurological disease ( %). the mortality rate was . %. the median duration of mechanical ventilation was days [iqr - ]. in multivariate logistic regression analysis; saps ii score (or = . , % ic [ . - . ], p = . ) and ards (or = . , % ic [ . - . ], p = . ) were independently associated with mortality. conclusion: risk factors for aspiration pneumonia were epilepsy, swallowing disorders and ischemic stroke. ards and saps ii score were independent predictive factors of mortality. compliance with ethics regulations: yes. undetermined. the aim of this study was to evaluate the impact of hyperoxia on morbidity and mortality. patients and methods: this was a prospective study performed in the icu of abderrahmen mami hospital during a -month period. all patients admitted in icu during the study-period were included. those who didn't need oxygen therapy or in end of life stage were excluded. arterial blood gases were analyzed daily and each day with at least one value of oxygen arterial saturation (sao ) > % was considered as a day with hyperoxia. for each patient included, the number of times and days spent in hyperoxia was recorded as well as complications during the icu stay and the outcome. results: during the study-period, patients were included but only were eligible. mean age was ± years. acute on chronic respiratory failure was the most frequent reason of admission ( %). non-invasive ventilation was required for % of patients and invasive mechanical ventilation was necessary in % of cases. overall mortality was %. hyperoxia was observed in % of cases, with an average of ± times during the icu stay and ± days. a statistically significant association was observed between a long duration of hyperoxia and the occurrence of ventilator acquired pneumonia (p < - ), ventilator acquired bronchitis (p = . ), acute respiratory distress syndrome (p < - ), atelectasis (p < - ), septic shock (p < - ), rythm disorders (p = . ), reintubation (p < - ) and tracheostomy (p = . ). on multivariate analysis, independent factors of mortality were: simplified acute physiology score ii, cardiac failure, need for invasive mechanical ventilation and septic shock. hyperoxia was not independently associated with mortality. conclusion: hyperoxia is frequent in icu. it is significantly associated with icu complications but not independently associated with mortality. compliance with ethics regulations: yes. experience of the practice of prone position in patientswith acute respiratory distress syndrome in intensive care (chu oran) nabil ghomari, soumia benbernou, djebli houria faculté de medecine d'oran, oran, algeria correspondence: nabil ghomari (nabilghomari@hotmail.fr) ann. intensive care , (suppl ):p- rationale: mechanical ventilation (mv) in the prone position (pp) and low tidal volume have become recommendations with a high level of scientific evidence in recent years. the pp has been practiced for years in the chu oran emergency resuscitation service. we wanted to report the service experience in the practice of pp in patients with ards. patients and methods: retrospective study performed in patients with severe hypoxia ards with spo < % under fio > % or pao /fio < during the period march to december . results: patients received ventilation in pp. ards was secondary to thoracic trauma in % of patients, septic shock in % and aspiration pneumonitis in %. analysis of the success factors and improvement of oxygenation found that lobar ards, the delay < h and a duration of pp ≥ h were statistically significant. conclusion: the pp must be integrated into the arsenal of care of the patients in ards especially in our country where we do not have all the therapeutic options. compliance with ethics regulations: yes. julien goutay, nicolas cousin, thibault duburcq, erika parmentier-decrucq chu de lille, pôle de réanimation, hôpital salengro, lille, france correspondence: julien goutay (julien.goutay@gmail.com) ann. intensive care , (suppl ):p- rationale: in veno-venous extracorporeal membrane oxygenation (vv-ecmo) therapy, blood flow is the main determinant of arterial oxygenation and should be - ml/kg/min in adults. this flow rate is determined by several factors including the size of the inflow cannula. the impact on clinical outcomes of arterial cannula's size in veno-arterial ecmo (va-ecmo) has already been studied, and showed no difference for survival to discharge, weaning success rate and initial flow rate between a small cannula group and a larger one. our first objective was to describe the impact of inlet cannula size on the assistance flow rate in patients treated with vv-ecmo. secondary objectives were to analyze its impact on ecmo weaning, mechanical ventilation characteristics and mortality. patients and methods: we retrospectively reviewed all cases of respiratory failure treated with vv-ecmo admitted in the medical intensive care unit (icu) of lille's teaching hospital from january st, through march st, . inlet cannula size was collected and divided into two groups: the "small cannula" group had inlet cannula less than or equal to fr, while "large cannula" were larger than fr. primary endpoint was the initial flow rate according to the inlet cannula size, and its changes during the first h of assistance. secondary endpoints were the analysis of predictive factors associated with the choice of a larger inlet cannula, and the impact of its size on clinical outcomes such as successful ecmo weaning. results: patients treated with vv-ecmo were admitted in our hospital. eleven ( %) were cannulated with a large inlet device. mean initial ecmo flow rate was statistically higher in the "large cannula" group than in the "small cannula" one: . l/min (± . ) versus . (± . ) respectively, p < . . the difference was also significant during the first h of assistance. we found no difference between the two groups on clinical outcomes such as ecmo weaning time. in univariate analysis, weight was heavier in the "large cannula" group [ (± ) kg] than "small cannula" [ (± )], p < . . conclusion: ecmo initial flow rate was higher in a "large inlet cannula" group (internal diameter more than fr) compared with a "small cannula" group. we found no correlation with cannula-related haemorrhagic or thrombotic complications. inlet cannula size did not influence ecmo weaning, and duration time, but this may be a lack of statistical power. further prospective studies should confirm this results. compliance with ethics regulations: yes. rationale: burn patients are at risk of multidrug-resistant (mdr) bacterial infections with high mortality rate. therefore, monitoring the emergence of mdr pathogens in these vulnerable patients is important. this study aimed to assess digestive colonization with carbapenemase-producing gram-negative bacilli (cp-gnb) in patients admitted to the burn intensive care unit. patients and methods: our study was prospective and conducted over a one-year period (january to december ). every admitted patient was subjected to the screening. a double swab set was used to collect rectal swab specimens. one swab was used for mdr screening by disk diffusion method on selective media; the other for multiplex real-time pcr (cepheid's genexpert ® ) allowing detection of the most common carbapenemase-encoding genes (ceg) (blaoxa- , blakpc, blandm, blavim and blaimp). results: among the studied patients, ( . %) were detected positive at admission for cp-gnb by the genexpert ® carba-r assay. eleven patients, initially not colonized, acquired positive faecal carriage subsequently during their hospital stay. forty-two colonized patients ( . %) developed cp-gnb infection during their hospitalization. the ceg blandm quantitatively dominated by far with detections; either alone ( cases) or associated with other ceg ( cases). the second most frequent gene was blaoxa- . it was detected alone eight times and in association with other ceg times. forty-three patients carried blavim gene, usually in association with other ceg ( %). however, only one patient carried blakpc gene. the parallel screening by classical microbiology methods (disk diffusion on selective media) detected the presence of cp-gnb in all molecular positive samples. conclusion: our study describes the characterization of carbapenemase in burn patients and highlights their alarming spread. this emphasizes the importance of an active surveillance program by early detection of cp-gnb carriers and an isolation policy to limit the mdr infections expansion. compliance with ethics regulations: yes. rationale: invasive fungal infections are increasingly observed in the icus especially in burn units. inthe absence of simple and accessible techniques for early microbiological diagnosis, the use of antifungal treatment is increasing. little is known about the extent of the problem of antifungal prescription in burn icus. we aimed to evaluate the antifungal prescription in major burn patients. patients and methods: during the study period ( - ), all prescriptions of antifungals were analysed. analysis concerned demographics, clinical circumstances, as well as the basis of antifungal prescribing (targeted vs. empiric). among the patients admitted in this period, patients were treated with antifungals (sex ratio: . ; mean age: ± years, with low associated comorbidity). the tbsa was . % [ . - . ], ubs was [ . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . most of the patients ( . %) were transferred from another hospital structure within ± h. antifungal treatment was started at the average of the seventh day post wound injury, more often on an empiric basis. sofa score at the beginning of the treatment was ± . . lymphopenia was present in % and thrombopenia was present in %. index of colonisation was positif only in cases. the average candida score was . ± . . microbiological results were tardily collected, within weeks, in %. fungal urine infections were found in cases. candidemia and catheter-related infections were considered only in cases. the risk factors of fungal infection as described in literature were found in most of the patients including mechanical ventilation ( . %), length period of stay ( days [ . - . ]), central venous line ( %), severe sepsis or septic shock ( %), large-spectrum antibiotherapy for more than days ( %). conclusion: the management of antifungal infections in major burn patients is still challenging. antifungal prescription is based on clinical presumption. the empirical prescription reflects the lack of efficient laboratory support and late microbiological results prompting physicians to rely on clinical informations. the management of fungal infections is based on the improvement of mycological investigations. compliance with ethics regulations: na. rationale: invasive candidiasis is a widespread and alarming infection in intensive care units (icu) patients. its diagnosis is often difficult because of the lack of specificity of clinical signs and the low sensitivity of blood cultures. while the candida albicans species remain the most common cause of bloodstream infections, non-albicans are emerging. these infections are serious, associated with high mortality rate and requiring early diagnosis and appropriate treatment. in tunisia, few data are available. we aimed to determine the epidemiological profile of a series of candidemia in icu, the risk factors associated with the occurrence of candidemia and to describe the modalities of the mycological diagnosis of candidemia and their etiological profile. patients and methods: a retrospective longitudinal descriptive study conducted in the parasitology-mycology laboratory with the collaboration of the medical icu of la rabta hospital-tunis over a -year period from january , to december , . all hospitalized icu patients with at least one candida-positive blood culture were included. results: forty-three patients among hospitalized patients during the study period had at least one candidemia infection. the main risk factors for development of candidemia infection include invasive procedures, a prior use of antibiotics and parenteral nutrition. c. albicans was the most common species, detected in . % of patients. nonalbicans candida species were prominent ( . %), represented by c parapsilosis, followed by c. tropicalis and c. krusei then c. glabrata and finally c. lusitaniae. all the isolates tested were sensitive to the common antifungal agents. the mortality rate of our patients was high ( . %), and the detection of the albicans species in blood cultures was the only prognostic factor identified (or = . [ . - . ], p = . ). conclusion: candidemia in the medical icu patients is common and is associated with high mortality rate. despite the progress of biological tools, the diagnosis is difficult and needs to take into account the risk factors of the patients as well as scores based on clinical and microbiological parameters. a better identification of risk patients may help to early initiate empirical antifungal treatment. compliance with ethics regulations: yes. necrotizing soft-tissue infections in the intensive care unit: a retrospective hospital-based study kais regaieg, sabrine nakaa, arnaud mailloux, madjid boukari, johana cohen, dany goldgran-toledano groupe hospitalier intercommunal le raincy-montfermeil, montfermeil, france correspondence: kais regaieg (kais.regaieg@gmail.com) ann. intensive care , (suppl ):p- rationale: the objective of our study is to describe the epidemiological and clinical characteristics of necrotizing soft-tissue infections (nsti) and to improve therapeutic management. we conducted a retrospective observational study that included patients admitted in the intensive care unit (icu) of general hospital between september and aout with a primary or secondary diagnosis of nsti. we collected demographic and clinical data, cultured pathogens, lengths of stay, and in-icu mortality. results: during the study period, a total of patients admitted to the icu were diagnosed with nsti ( . % of the total number of patients). the mean of age was years. the sex ratio (m/w) was . . ten patients ( %) were directly admitted to the icu, others were transferred from medical or surgical wards. the mean of saps ii was . ( . ). the main indication to admission in icu was shock ( %). the most common comorbidity was diabetes ( %). the other co-morbidities associated with nsti were cardiovascular diseases ( %), obesity ( %) and carelessness ( %). the sites most commonly affected were extremities in patients ( %) and abdomen/ano-genital in patients ( %). in icu, a total of patients ( %) were mechanically ventilated [ (median duration: . days ( . )], patients ( %) were given vasopressors, and patients ( %) underwent renal-remplacement. all patients underwent one or more chirurgical intervention. patients ( %) underwent radical necrosectomy. in cases, an amputation was necessary. polymicrobian infection was seen in patients ( %). in patients ( %), we used vacuum assited closure therapy, which in patients was followed by definitive reconstruction by split skin grafts. the mortality in icu was %. the mean stay in icu was days . the mean duration of hospitalization of the patients who survived was days ( - ). on the basis of a univariate analysis, higher saps ii score and lactate levels were associated with increased mortality (p < . ). conclusion: ntsi is rare in icu but it's a life-threatening and disabling disease with a high mortality requiring a multidisciplinary management. early diagnosis and adequate treatment are necessary to improve clinical outcome and must be known by everyone. more studies are needed to estimate the interest and delay of new strategies such as negative pressure therapy. compliance with ethics regulations: yes. rationale: nosocomial infections remain a major cause of mortality and morbidity in burn patients. providing information about the main causative bacterial agents and determination of their susceptibility to antibiotics may improve empiric therapy and early detection of emerging antimicrobial resistance. the aim of our study was to investigate the species distribution and antibiotic susceptibility of isolated strains from a burn intensive care unit (icu). patients and methods: this study was performed retrospectively on all bacteriological samples taken from the burn icu at the trauma and burn center in tunisia during a seven year period (from january to december ). all isolated microorganisms were identified on the basis of standard microbiological techniques. antibiotic susceptibility testing was carried out by the agar disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, the most frequent identified species were pseudomonas aeruginosa ( . %), staphylococcus aureus ( %), klebsiella pneumoniae ( . %) and acinetobacter baumannii ( %). these strains have been mainly isolated from blood cultures ( %) and skin samples ( . %). pseudomonas aeruginosa resistance to ceftazidime increased from . % in to . % in and resistance to imipenem and ciprofloxacin was . % and . %, respectively. four strains were resistant to colistin. rationale: community-acquired peritonitis is a heterogeneous condition characterized by peritoneum inflammation in response to a bacteria injury. the aim of our study is to describe the epidemiological, clinical, bacteriological, etiological, therapeutic characteristics of community peritonitis, and to evaluate the prognostic factors. patients and methods: this is a retrospective descriptive and analytical study spanning three years (between january and december ) involving cases of community peritonitis, hospitalized in the surgical emergency resuscitation department p ibn rochd casablanca university hospital. our study included adult patients with community-acquired peritonitis who underwent medical and surgical management. the studied parameters are the demographic data, the clinical and paraclinical signs, the care taken and the evolution of the patients. the study showed that the mean age was . ± . years, with a sex ratio of . . patients medical history included tobacco ( . %), extra-abdominal signs [hemodynamic failure ( %), renal failure (n = , %), hematological disorders (n = , %) and respiratory disorders (n = , %)]. therapeutic management was based on perioperative resuscitation, treatment of organ failure, probabilistic antibiotic therapy and median laparotomy surgery. the main etiologies of community peritonitis were: digestive perforation ( . %), purulent effusion ( %), intestinal necrosis ( . %), cholecystitis ( . %). intraoperative bacteriological specimens yielded the following bacteriological profile: predominance of ngb ( . %) dominated by e. coli ( . %) followed by klebsiella pneumoniae and enterobacter cloacae ( . %) the mean hospital stay was . ± . days. the mortality rate was . %. conclusion: improvement in the prognosis of community-acquired peritonitis can only be achieved by constant assessment of very early diagnosis and initiation of appropriate resuscitation and antibiotic therapy associated with a complete surgery carefully codified according to guidelines. compliance with ethics regulations: yes. rationale: klebsiella pneumoniae carbapenemase (kpc)-producing bacteria are a group of emerging highly drug-resistant gram-negative bacilli causing infections associated with significant morbidity and mortality. the aim of our study is to point out the incidence of bloodstream infections (bsi) caused by kpc in icu patients, its clinical presentation and course. patients and methods: we conducted a retrospective descriptive study. all patients hospitalized in the icu of our hospital who developed bsi caused by kpc from january , to december , were included. results: during the study period, patients were included. the mean age was . ± . years ranging from to years. sex ratio (m/f) was . trauma was the major cause of hospitalization in cases ( %). the most common past medical diseases were arterial hypertension in patients ( %). length of hospital stay prior to icu admission was ± . days. at infection onset, mean saps ii was ± . , mean sofa was . ± . and mean apache ii was . ± . . during icu hospitalization, all patients required invasive mechanical ventilation during . ± . days, had a central venous catheter (cvc) and an indwelling urinary catheter in place, patients ( . %) had tracheotomy, ( %) underwent surgery, ( %) presented acute kidney failure and ( %) needed hemodialysis. before the isolation of kpc, all patients presented infections. antibiotics prescript were: colistin in patients ( %), carbapenems in patients ( %), amoxicillin/clavulanic acid in patients ( %), cephalosporins in patients ( %), fluoroquinolones in patients ( %), tigecycline in patients ( %), aminosids in patients ( %), rifampicin in patients ( %), fosfomycin in patients ( %), glycopeptides in patients ( %). the delay for kpc-bsi onset was . ± . days. the most common infection sources responsible of kpc-bsi were: cvc in patients ( %) and pneumonia in patients ( %). kpc infection was responsible of septic shock in patients ( %). resistance rates were: gentamycin ( %), amikacin ( %), colistin ( %), fosfomycin ( %) and tigecycline ( %). antibiotics used to treat kpc bloodstream infection were resumed in table . the mean length of icu stay was . ± . days. out of the included patients, patients died (the mortality rate was %). death was related to kpc infection in patients. conclusion: the high prevalence of kpc-bsi in icu patients dictates the importance of implementation of infection control measures and strict antibiotic policies. compliance with ethics regulations: not applicable. we identified episodes of nosocomial infections in patients, representing a cumulative incidence rate of . per exposed patients. the incidence density was . infections per days of hospitalization. the prevalence of pneumonia was . %, followed by urinary tract infections . %, central venous catheterization infections . %, bacteriemia . %, meningitis . % and surgical site infections . %. the incidence rate of intubation-related pneumonia was . / day of exposure. the incidence rate of bladder-related urinary tract infection was . / day of exposure. the incidence rate of positive culture of the central venous catheter was . / day of exposure. the incidence rate of bacteremia related to stay was . / day of exposure. the mortality rate was . % with a significant difference between infected and uninfected patients (p = . ). microorganisms were gram negative bacteria in % of cases. conclusion: epidemiological surveillance of healthcare-associated infections is needed to establish prevention plans. compliance with ethics regulations: not applicable. in the prehospital setting, early identification of septic shock (ss) with high risk of mortality is essential to guide hospital orientation (emergency department (ed) or intensive care unit (icu)) prior to early treatment initiation. in this context, the severity assessment is most of the time restricted to clinical tools. in this study, we describe the association between prehospital shock index (si) and mortality at day of patients with ss initially cared for in the prehospital setting by a mobile intensive care unit (micu in this study, we reported an association between prehospital si and mortality of patients with prehospital ss. a si > . is a simple tool to assess severity and to optimize prehospital triage between ed and icu of patients with ss initially cared for in the prehospital setting by a micu. the association of si with biomarkers may be helpful to improve the screening for ss and decision making of ss in the prehospital setting. compliance with ethics regulations: yes. the failure rate and complications were comparable between the groups, but the ultrasound-guided internal jugular catheter appears to be faster to insert and requires fewer punctures, so it could be an alternative to the femoral one in emergency situations. rationale: neuromyelitis optica (nmo) is a rare but severe disease. the prognosis of treated nmo attacks remains unclear. we evaluated our practice, the early evolution and the prognosis of nmo patients. patients and methods: an observational study was performed on patients with nmo attacks presenting with visual or medullar symptoms admitted for plasma exchange (pe) therapy from january to august . treatment efficiency was defined as a negative shift of the visual or motor disability score (edss). nonparametric mann-whitney and fisher exact tests were used for statistical analysis as required. results: twenty-four patients had pe sessions. characteristics of the cohort are described in table . ( . %) died from complications of nmo attacks. treatment had an effect in ( . %) patients. the shift in the ambulatory and visual edss was respectively − . + . and − . + . . the non-survivor patients had all aqp antibodies (p < . ). residual edss was higher in the non-survivor group ( . + . vs . + . , p < . ). pulse steroids were administered in ( %) patient in the non-survivor group vs ( %) patients in the survivor group (p < . ). twelve ( %) patients previously given pulse steroid therapy responded to pe. discussion: we assessed the handling of nmo attacks and identified our flaws. we concluded that pulse steroid therapy should not be withheld or replaced by lower dosage. we also need to find a way to make attacks identified by physicians earlier to shorten the delay between its onset and patient's admission in a specialized care unit. we observed that the mean improvement is modest during the early phase of our treatment. but a modest improvement in the edss can have a great impact in the patient's quality of life and even survival. conclusion: nmo attacks remain a threatening disease despite aggressive treatment. shortening the delay of treatment and ensure adequate pulse steroid therapy coupled to pe could be a way to improve the prognosis. compliance with ethics regulations: yes. rationale: acute kidney injury in trauma patients is a problem that has been little studied in the intensive care unit (icu). its occurrence has been shown to be associated with high morbidity and mortality. we aim to determine the outcome of icu trauma patients with acute kidney injury (aki), including the incidence of death in the icu, of nonreversible renal impairment and icu complications. patients and methods: this is a prospective study, conducted in the department of emergencies and icu, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of mortality and poor outcome were identified using univariate and then multivariate analysis. results: one hundred and fifty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. the overall mortality of patients with post-traumatic aki was . % ( patients) with a mean icu lengh of stay (los) at ± days and of days on ventilator at ± . eight patients ( . %) needed renal replacement therapy and thirty-four had non-reversible renal impairement ( %). during icu stay, eight patients ( %) were diagnosed with pulmonary embolism. on univariate analysis, the following variables were associated to mortality in patients with post-tramatic aki including; age, hemodynamic instability on the day of diagnosis and bilirubin levels on the day of aki diagnosis. besides, according to our analysis, the use of renal replacement therapy and the non-reversibility of renal impairment during icu stay were also associated to icu mortality. among these factors, the non-reversibility of renal impairment in the icu was a predictor of mortality on multivariate analysis (p = . , or = , . in this cohort, the following variables were predictive of non-reversible renal impairment during icu stay; including age (with a best cut-off of years old), medical history of hypertension, higher iss and diuretics' administration. on multivariate analysis, the age (p = . , or = . , ci . - . ) and use of diuretics (p = . , or = , ci . - ) were associated to non-reversible aki in the icu. conclusion: our study confirms that post-traumatic aki in the icu is associated to high morbidity and mortality. the identification of outcome predictors could be valuable to guide the management of aki. compliance with ethics regulations: yes. rationale: the occurrence of acute kidney injury (aki) in trauma patients is a problem that has been little studied to date. its presence has been shown to be associated with an increased risk of morbidity and mortality in affected individuals. to determine the incidence of post-traumatic aki and identify its predictive risk factors that could be eventually prevented. patients and methods: this is a -month long prospective cohortstudy, conducted in the department of emergencies and intensive care unit (icu) of a university hospital, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of aki were identified using univariate and then multivariate analysis. results: one hundred thirty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. on univariate analysis, older age and medical history of diabetes or hypertension were predictors of aki. injury assessment found traumatic brain injury (ais > ), glasgow (gcs) on admission, and the diagnosis of fat embolism to be associated to post-traumatic aki. moreover, hemodynamic instability on admission and during icu stay, shock-index on admission, the amount of fluid administered the use of vasoactive drugs, sepsis, hyperbilirubinemia, p/f ratio and acute respiratory distress syndrome (ards) were also associated to post-traumatic aki. among these factors, ards (p = . , or = , ci - ), fat embolism (p = . , or = , ci . ) without preload-dependence, and were unclassified. multivariate analysis (using variables collected prior to hypotension) identified the following variables as risk factors for the occurrence of hypotension associated with preload-dependence: preload-dependence before hypotension (odds ratio = . , p < . ), fluid removal rate by crrt (or = . per increase in sd, p < . ), and lactate levels (or = . per increase in sd, p < . ). in this single center study, preload dependence-associated hypotension was slightly more frequent than hypotension without preload dependence in icu patients undergoing crrt. testing for preload dependence to adjust fluid removal could help prevent hypotension incidence during crrt. rationale: few studies report the relation between functionnal brain alterations during and after icu stay and abnormalities of cbf displayed on tcd. using vti as hemodynamic parameter is unusual for evaluation of cbf. the purpose of this preliminary study was to compare the values of vti of healthy controls (c) versus icu (p) with usual parameters (i.e. diastolic (vd) and mean velocities (vm), resistance (ir) and pulsatility index (ip)). rationale: accurate diagnosis of the level of consciousness is a challenge and different states such as coma, vegetative state (vs) or minimally conscious state (mcs) are often confused while they convey meaningful prognostic information. this distinction rely on the coma recovery scale-revised (crs-r) gold-standard. however, this clinical scale is imperfect since unresponsive patients can exhibit genuine signs of consciousness using advance neuroimaging techniques. expanding the range of behaviors indexing consciousness at bedside is thus of decisive importance. patients and methods: we designed and proposed a new clinical sign of mcs, the habituation to auditory startle reflex (asr), based on the blink response to repeated sounds: either inhibition of the automatic asr response (extinguishable) or nohabituation (inextinguishable response). we prospectively tested this new sing in patients suffering from disorders of consciousness after severe brain injury and first compared its diagnostic performances with the current gold-standard (crs-r) using standard discrimination metrics (auc, sensitivity, specificity, likelihood ratios) and their % confidence interval. we then investigated the correlates of this new sign on two validated neuroimaging diagnostic procedures (multivariate eeg-based classification of the state of consciousness and fdg-pet metabolic index of the best preserved hemisphere) using an anova with the state of consciousness and the asr response as independent variable. rationale: although continuous electroencephalography (ceeg) is commonly recommended in neurocritical care patients, implementation of this monitoring in routine is facing the need for a specific training of professionals. we evaluated the effectiveness of a training program for the basic interpretation of ceeg to critical care staffs in a prospective multicentre study. patients and methods: after completion of a pre-test, participants (physicians and nurses) recruited in french intensive care units (icu) received a face-to-face eeg learning course, followed by additional e-learning sessions at day- (post-course), day- , day- and day- , based on training tests followed by illustrated and commented answers. each test was designed in order to evaluate knowledge and skills through correct recognition of predefined eeg sequences covering the most common normal and abnormal patterns. the primary objective was to achieve a success rate of more than % of correct answers at day- in at least % of participants. results: among participants, ( . %) completed the full training program and of these ( . %) full-training participants achieved at least % of correct answers at day- . paired comparisons between scores obtained at each evaluation demonstrated a statistically significant increase over time. at day , rates of correct answers were greater than % for all predefined usual eeg sequences, excepted for the recognition of periodic and burst-suppression patterns and reactivity, which were identified in only . % ( % ci . - . ) and . % ( . - . ) and . ( . - . ) tests, respectively. discussion: this multicentric prospective study, which evaluated a training program for the basics of electroencephalography offered to critical care teams, provides interesting information about the training process and its impact on learners according to their different characteristics. we believe that participants reflect the heterogeneity of the various use of ceeg in the critical care setting. participants came from university and non-university icus, and whereas some of them used to monitor patients with ceeg, others were in an implementation process when the last monitored neurocritical care patients with intermittent eeg. in accordance with previous studies, we focused to the entire medical and nursing icu staffs. conclusion: a -months training program aiming to teach the basic interpretation of continuous eeg in the intensive care units was associated with a significant attrition in participation over time. however, participants who received the full training program were capable to accurately recognize the vast majority of eeg patterns that are encountered in critically ill patients. compliance with ethics regulations: yes. mourad goulmane oran hospital and university center, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann. intensive care , (suppl ):p- rationale: cerebral venous thrombosis (cvt) is a rare but very serious disease with various clinical and etiological aspects. unlike ischemic arterial accidents, epidemiological studies are limited. the aim of our work was to study the clinical, etiological and evolutionary features of cvt in the algerian population from a sample of patients. patients and methods: this is a retrospective observational study conducted in the neurology department of the chu d'oran between january and december . in a clinical context suggestive of cvt, the diagnosis of certainty was provided by brain mri coupled with mra. all subjects benefited from a complete etiological assessment. the anticoagulant treatment was based on the low molecular weight heparin relayed by the anti-vitamin k. the duration of the follow-up was months. results: the mean age was . ± . years, the sex ratio was ( f/ h), the onset was subacute in % of cases. the main early signs were headache ( . %), visual disturbances ( %), epileptic seizures ( . %) and motor deficit ( . %). thrombosis predominated in the upper sagittal sinus and lateral sinuses; parenchymal lesions were associated in / of the cases. gynecologic obstetric causes were by far the most frequent. the evolution was favorable in . % of the cases. discussion: cvt is characterized by its clinical polymorphism, its predominance in young women, and its most often favorable evolution. the causes are multiple and often intricate requiring the realization of a systematic etiological assessment even if the cause seems obvious. the treatment of choice remains early anticoagulation, based on heparinotherapy even in case of hemorrhagic softening. the characteristics of cvt in the algerian population are distinguished by a high frequency of gynecological obstetric causes. awareness campaigns for women of childbearing age are useful. compliance with ethics regulations: not applicable. rationale: the ct-dragon score was developed to predict longterm functional outcome after acute stroke in the anterior circulation treated by thrombolysis. its implementation in clinical practice is hampered by the plethora of variables included. in addition, the score has not been validated in important subgroups such as stroke patients undergoing thrombectomy. given these limitations, the current study was designed to evaluate the use of a simplified score based on machine learning, as a possible alternative. this single-centre retrospective study included patients treated for stroke, in the anterior and posterior cerebral circulation, between - and - . at days, favourable (modified rankin scale (mrs): - ) and miserable outcome (mrs: - ) were predicted by ct-dragon. machine learning selected the aim was to describe the adherence rates to gold guidelines in critically ill copd patients and to identify predictors of low adherence. patients and methods: a prospective cohort study conducted from december to april in a -bed medical intensive care unit of farhat hached hospital. all adult patients admitted for aecopd during the period of the study were included. demographic and clinical data were recorded. adherence to gold was evaluated. univariate and multivariate regression analyses were carried out to identify factors independently associated to non-adherence to gold guidelines. results: seventy-seven patients were recruited. patients' characteristics were : mean age, . ± years; male ( . %); median duration of the disease, [ - ] years; mmrc scale ≥ , ( . %); health insurance coverage rate, ( %); pulmonologist follow up, ( , %); frequent exacerbator (≥ exacerbations in the last year), ( . %); median exacerbations episodes, [ ] [ ] [ ] . long-term oxygen use and home mechanical ventilation were respectively used in ( . %) and ( . %). eight ( . %), ( . %) and ( . %) belonged to copd groups b, c and d, respectively. pharmacological treatment included: saba-ics combination, ( . %), laba-ics, ( . %), laba-lama, ( . %) and lama-laba-ics, ( . %). overall adherence to gold guidelines treatment recommendations for the different stages of copd was ( . %). two patients ( . %) were over treated and ( . %) were undertreated. inappropriate treatment rate was ( %) in gold b, ( . %) in gold c and ( . %) in gold d. univariate analysis identified two factors associated with non-adherence to gold : the absence of pulmonologist follow-up ( % vs. . %; p = . ) and the low income ( . % vs. . %; p = . ). in multivariate analysis only the lack of pulmonologist follow-up was identified as an independent risk factor associated with gold guidelines discrepancies (or, ; % ci [ . - . ]; p = . ). there is a lack of adherence to gold guideline treatment recommendations in tunisian copd patients. this may lead to severe exacerbations. discrepancies were due to the poor access of severe copd patients to an appropriate pulmonologist follow-up. compliance with ethics regulations: yes. the operating theaters concerned were: the otolaryngology block, ophthalmology, vascular and thoracic surgery, and gynecological surgery. all patients over years of age were enrolled using the clinical parameters of difficult intubation (arne score > ), which will benefit from orotracheal intubation. the main judgment criteria were: first-pass success rate, intubation time, which is defined as the time between inserting the slide into the patient's mouth and obtaining the capnography curve, the cormack-lehane score and the pogo score (percentage of opening of the glottis). statistical analysis used spss software. results: a total of patients were included. no cases of failure with this device were observed, the duration of intubation was on average . s (only cases required more than min). the cormack-lehane score and involved patients ( . %), and the pogo score greater than % involved patients ( . %). one case required the features of the simplified score. discrimination, calibration and misclassification of both models were tested. results: % had proximal anterior stroke, % proximal posterior stroke and % lacunar infarcts in either circulation. in % no thrombus was objectivated. % of patients were treated with thrombectomy, % received thrombolysis and % underwent both thrombolysis and thrombectomy. % only received anti-platelet therapy. the area under the receiver-operating-characteristic curve (auc-roc) for ct-dragon was . ( % ci . - . ) for favourable and . ( % ci . - . ) for miserable outcome. r ofct-dragon was . and . for favourable (lack of fit, p = . ) and miserable (lack of fit, p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with ct-dragon. selection of predictors from the ct-dragon was done by logistic regression, bootstrap forest and decision tree analysis. nih stroke scale, pre-stroke mrs and age were identified as the strongest contributors to favourable and miserable outcome, and included in the simplified score. auc-roc was . ( ci% . - . ) and . ( ci% . - . ) for the prediction of favourable and miserable outcome respectively. r was . and . for the prediction of favourable (lack of fit p = . ) and miserable (lack of fit p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with the simplified score. the simplified score had better discriminative power than ct-dragon for both outcomes (both p < . ). the ct-dragon score revealed acceptable discrimination in our cohort of both anterior and posterior circulation strokes, receiving a variety of treatment modalities. the simplified score had a better discrimination, while maintaining comparable and good specificity and misclassification rate for miserable outcome. the simplified score needs further validation in a prospective, multi-centre study. compliance with ethics regulations: yes. rationale: the gold report represents a major revision to gold strategy guidelines. it brings new recommendations regarding diagnosis, severity assessment, and both pharmacologic and non-pharmacologic treatment of copd. however, adherence to evidence-based therapeutic guidelines is often poor in low-income developing countries and represents a significant barrier to optimal management. the setting up of an lma-fastrach (desaturation). a case of glottic edema has been noted. discussion: this study shows a very high success rate with this technique ( . % in the first trial and . % in the second trial), in the context of a predictable difficult intubation. the video-airtraq allows a very good visualization of laryngeal structures, a shortening of the duration of intubation, and is rarely responsible for immediate or secondary complications. all the data in the literature go in the same direction. conclusion: at the end of this work, our perspectives are to update the difficult intubation procedure, integrating the video-airtraq into our algorithm, as well as into our difficult intubation trolley. to take into consideration the cost of this device to eventually generalize it to all our structures. compliance with ethics regulations: yes. ) and beds of continuous monitoring. the activity of the cp is organized in a medical visit in the morning and in conducting projects in the afternoon. the activity is presented using a -years balance sheet results: the activity of pharmaceutical interventions (pi) or answers to requests from teams is shown in table . the solicitations doubled the second year. the cp is involved in the conduct of internal or polar projects (set up of cooperative sedation, nutrition…), the good use of health products (relay iv/po, infusion, crushed tablets and compatibility with gastric probe, drug incompatibilities, proton pump inhibitors…), the efficiency of the drug circuit (link with the pharmacy, reflection on the improvement of the circuit, regular meetings with nurses), medico-economic analysis of health products spending and the formalization of actions by protocolisation. he is also very involved in clinical research: patient screening, clinical study setup: blipic study (beta-lactam's dosing in pneumonia in icu in patients treated by continuous renal replacement therapy; clinicaltrials nct ) or in candiarea project (invasive infections to candida and preemptive treatment guided by biomarkers; in progress). a satisfaction survey submitted at months to nurses ( answers/ ) or to doctors/ residents ( / ) reported cp competence in the accompaniment of teams (> %) [in medico-economical, contribution of knowledge, vigilance reflex…], relevance of information transmitted (> %) [administration of drugs, dosage adjustments, …] and his relationship adapted to the units (> %) [communication, availability] . the development of clinical pharmacy in icu involves mastery of the specificities of icu by the cp, requiring a learning period and relationships adapted to clinical situations and teams. many health products projects specific to critical care are coordinated by the cp and made possible by medical and paramedical involvement. the cp appears as a vector of good use both in medical (reasoned prescription) and paramedical (good practices) with increasing solicitation of teams since his arrival. this reception has been facilitated by an innovative approach of clinical pharmacy deployment in our icu on an impulse of the clinical pole compliance with ethics regulations: yes. predicting models such as the news has been developed in the emergency department, but it has only been fewly evaluated in the icu. heart rate variability (hrv) reflects the autonomic nervous system response in various pathological situations and may vary according to patients' physiological status. the rox index, which reflects the acute respiratory failure severity, seems to be a good predictor of high-flow nasal canula failure. the aim of this study was to evaluate the potential value of news, hrv and irox (inversed rox) as poor outcome predictors, using artificial intelligence and machine learning. a retrospective analysis of a prospective datawarehousing project (reastoc clinicaltrials identifier nct ) on icu patients who did not require invasive ventilation. physiological parameters were collected on admission, within a -h delay. news, hrv (in time, frequency, and non-linear domains), and irox were computed and integrated into the prediction model. analysis was performed using medcalc and matlab machine-learning work-package. results: one hundred and twelve patients were included. patients who died in the icu (n = ) had highest news as compared with icu survivors ( . [ . - . ] vs. . [ . - . ] respectively; p = . ). the irox was higher ( . [ . - . ] vs. . [ . - . ], p = . ) and most hrv parameters also depicted higher values for icu survivors. considering a composite icu prognostic outcome parameter (mortality and/or need for any form of respiratory assistance and/or an icu los > median los), there was also a difference for news, hrv and irox (p < . ). the best value to predict icu mortality for news was (auc = . , p = . ), irox > . (auc = . , p = . ) and hrv (shannon entropy) > . (auc = . , p = . ). the best model to predict the need fo respiratory assistance combines irox and hrv (sd /sd ; auc = . , p = . ). adding shannon entropy on this model predicts either the need for respiratory assistance and icu survival (respectively auc . , p = . and auc . , p = . ). in icu spontaneously breathing patients, news, irox and hrv are different in between survivors and patients who died. the best model to predict the need for respiratory assistance combines irox and hrv (sd /sd ). compliance with ethics regulations: yes. rationale: sepsis is known for its important mortality in critically ill patients. the last guidelines defined sepsis as life threatening organ dysfunction. it rejected the concept of systemic inflammatory response syndrome (sirs) associated to suspected or confirmed infection, and considered the concept of dysregulated response to infection. actual guidelines recommend the quick sequential organ failure assessment score (qsofa) to identify patients with sepsis especially when outside intensive care unit. thus, outcomes have mainly to judge the value of sirs in the sepsis- era. the purpose of our study was to compare whereas qsofa score or the sirs criterion are superior to predict in-hospital mortality, shock and mechanical ventilation use in sepsis. our study includes patients in whom the sepsis- definition is met. therefore, this inclusion was retrospectively performed throughout emergency department (ed) admission cases for clinically suspected infection. we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. death occurs in . % of patients, sepstic shock in % and the use of mechanical ventilation in . %. qsofa ≥ has a significant association with in-hospital mortality (p < . ) but not sirs ≥ ( . ). neither qsofa ≥ nor sirs ≥ has association with the use of mechanical ventilation (p = . vs. p = ). whereas, both have a significant association for prediction of septic shock. the absolute sensitivity and negative predictive value in our study can be explained by the small size of our sample. this needs confirmation with literature data about the fact that sirs criterion are superior in term of sensitivity and npv than qsofa to predict septic shock. despite the weak odds ratio (or) of sirs before that of qsofa and the poor specificity and positive predictive value (ppv), we can conclude that sirs according to its sensitivity and npv, seems to persist useful in the sepsis- era as a reliable prognostic tool in the ed. this may need more large studies for confirmation. conclusion: despite sirs has no significant association with mortality in sepsis, it has largely higher sensitivity and superior npv to predict septic shock than qsofa in ed. compliance with ethics regulations: yes. our study aimed to determine the predictive factors of mortality in our patients. retrospective study over years in the intensive care unit of the hospital august. all patients with septic shock were included. a p value < . was considered significant. results: patients were collected. the age ranged from to years old. the average duration of hospitalization in pre-intensive care was days. the reasons for admission: (febrile respiratory distress: % of cases, polytrauma: % and % for sepsis), the most frequent infections: pulmonary ( %) and blood ( %). % received prior antibiotic therapy and % were immunocompromised. the overall mortality was %. the analytical study of the data shows that the age, the length of stay before admission in intensive care and that in intensive care, fever, hypothermia, slimming, hypotension, collapse, failures (respiratory, hematological, renal, hepatic and neurological) and the use of catecholamines are correlated with mortality, whereas sex, chest pain, tachycardia or bradycardia and mottling are not predictive of mortality. conclusion: despite improved techniques for the diagnosis and treatment of patients with septic shock, mortality remains high, especially in the presence of certain risk factors, hence the value of prevention in immunocompromised patients and the reduction in their length of stay in a hospital setting. compliance with ethics regulations: yes. conclusion: p. mirabilis is among the leading bacteria responsible for nosocomial infections in icu. they are emerging highly drug resistant pathogens whose incidence is rapidly increasing in icu. so that, it early identification with in vitro testing is of paramount importance to the success of infectioncontrol efforts. compliance with ethics regulations: not applicable. rationale: influenza is a potential lethal disease causing dozens of thousands excess deaths per year both in europe and in the united states. besides hygiene procedures, vaccination is a cornerstone of influenza prevention and guidelines recommend for vaccination among health workers (hw), especially if they are in close contact with frail people. despite these recommendations, the vaccination coverage is low among health workers both in europe and in the us. the relevance of a mandatory vaccination for health workers is currently a hot topic but data are scarce regarding intensive care unit health workers' opinion. patients and methods: health workers from medical, surgical and polyvalent icus received a link to the electronic record of the survey. results: among the icus, icu health workers (hw) (medical: and paramedical: ) were questioned. three hundred and forty-one icu ( %) answered, ( %) medical health workers (mhw) and ( %) paramedical health workers (phw) (p < . ). among mhw / ( %) were vaccinated vs only / ( %) phw (p < . ). discrepancies exist between medical and paramedical icu health workers' opinions and beliefs about vaccination for influenza and its acceptance. medical health workers were more prone to consider influenza as a potentially lethal disease occurring not only among frail people but also in healthy people, to consider the vaccine efficient and safe. to agree with "vaccination for influenza is mostly related with gain for pharmaceutical industry" (or: [ . - ] ) and to disagree with "the risk of guillain-barré syndrome is higher after an episode of influenza than after vaccination for influenza" (or: . [ . - ] ) were independently associated to the disagreement with a mandatory vaccination for icu hw. conclusion: vaccination for influenza should be strongly recommended as a tool of individual protection for icu health workers as for general population. as confidence in vaccine efficacy and concerns about vaccine side-effects impact the vaccination rate, objective information should be provided to icu health workers about the efficacy and the side effects of vaccination for influenza. compliance with ethics regulations: yes. rationale: intra-abdominal infections are a major cause of morbidity and mortality. sfar recommendations on this topic were published in february . the purpose of this work was to evaluate whether our antibiotic therapy was adequate for these recommendations and whether they were adapted to our unit. the secondary objectives were to look for different risk factors for mortality, to evaluate the impact of inappropriate antibiotic therapy, to evaluate the relevance of carbapenem prescription. this is a single-center retrospective observational study of secondary peritonitis in the tourcoing intensive care unit. for each peritonitis, the epidemiological data and the co-morbidities of the patients were collected. bacteriology and anti-infectious therapies were described to determine the rates of adaptation of our antibiotic therapy and that recommended by sfar. the adequacy of our treatments to the recommendations was also quantifiable. the description of the stay, the occurrence of a death was specified. results: peritonitis were included. the rate of adaptation of the sfar antibiotic therapy was %. the rate of adaptation of our antibiotic therapy was % and its adequacy rate of %. the main differences in prescriptions concerned over-prescription of antifungals, molecule against gram positive bacillus and a sub-prescription of aminoglycosides and beta-lactams, in particular carbapenems. the different mortality risk factors found were sofa score > (or . % ci . - . ), the charlson score > (or . % ci . - . ), the hollow organ perforation (or . % ci . - . ). a comparison of the appropriate or not antibiotic groups did not reveal a significant difference in mortality, number of surgical revision and length of stay. in % of nosocomial peritonitis, antibiotic therapy with carbapenem was recommended. after recovery of microbiological data, it was only necessary for . % of cases. conclusion: our work showed a low rate of compliance with sfar recommendations. these recommendations are applicable to our service by providing a particular reflection for fungal infections. our study does not show a correlation between mortality and inadequate antibiotic therapy, surgery remaining the major treatment. compliance with ethics regulations:yes. rationale: acinetobacter baumannii is a gram-negative opportunistic bacteria that has gained several drug resistance mechanisms over the last decades. analysis of a. baumanii's resistance profile helps to establish a prompt control and a prevention program. the aim of this study was to evaluate the epidemiology and antimicrobial resistance of a. baumannii isolates in a trauma and burn center in tunisia. patients and methods: retrospectively, we studied all strains of acinetobacter baumannii isolated over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with the disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sir-system. minimum inhibitory concentration (mic) of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, non-repetitive strains of acinetobacter baumannii were isolated representing . % of all isolates, % of gram-negative bacilli (gnb) and . % of non-fermenting gnb. in our center, infections due to a. baumannii were endemic with epidemic peaks. a. baumannii was mainly isolated from burn intensive care unit ( %) and anesthesiology department ( . %). the most frequent sites of isolation were blood cultures ( . %), catheters ( %), respiratory specimens ( . %) and skin samples ( % sampling duration is also reduced, improving workflow. evaluators consider that bronchosampler rationalizes the cumbersome sampling process and that the closed system design reduces the risk of losing sample or sample contamination. the set-up, the suction capacity, the sampling quality and quantity have all been evaluated better or far better than that usually observed with usual sampling techniques and devices. finally, ( %) of users prefer bronchosampler to commonly used method. conclusion: this satisfaction survey shows that with its simple but revolutionary design, bronchosampler brings a real effective benefit in sampling procedure enabling the clinician to perform it alone, and ( %) of the survey evaluators consider that bronchosampler should replace their current practice. compliance with ethics regulations: yes. rationale: the possibility of having a sensitive, specific and prognostic biological marker for bacterial infections is a considerable challenge. a step was taken with the discovery of pracalcitonin. patients and methods: this is a prospective observational cohort study of patients in the medical resuscitation department of the university hospital of casablanca during the -month period, including patients in whom the pct was dosed. the data collected allowed us to form two groups according to the pct value: pct+ group with pct > ng/ml and pct− group with pct < ng/ml. the statistical analysis of these different data was carried out using epi info software version . . . results: % of our patients had a bacterial infection and % did not have one. we also distinguished community infections ( % of i+ patients) and nosocomial infections ( % of i+ patients). we found that the highest rates of pct were in nosocomial infections and the lowest pct rates were found in community-acquired infections. then, in each type of organ involvement we tried to vary the pct thresholds to . - and ng/ml in order to find the best threshold for which pct allowed to diagnose bacterial infection, justifying our choice of departure. we concluded that the best pct cut-off value in general was ng/ml, because it gave us the best sensitivity/specificity ratio ( % and % respectively) with a positive predictive value of % and a negative predictive value of %. the link between pct and bacterial infection was moderate (yule q-factor at . ). by analyzing the different therapeutic aspects, we showed that % of our patients had been treated with atb before the pct assay and that the broadest spectrum antibiotics available to our service were used in patients with pct levels the highest. finally, concerning the evolution, the higher the rate of pct, the higher the death rate, especially since % of patients with pct > ng/ml died. conclusion: procalcitonin is considered to be one of the best markers of systemic bacterial infection. indeed, its elevation is earlier than that of crp and its specificity is better compared to il- and il- . the rate of procalcitonin remains low in the presence of viral infection. procalcitonin is also a prognostic marker, its elevation is correlated with the severity of the infection, and its decrease is a good indicator of the effectiveness of antibiotic therapy. compliance with ethics regulations: not applicable. rationale: due to induction immunosuppression infection is the most common cause of mortality within the first year after lung transplantation (ltx). the management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. we sent by email a survey to ltx centers around the world dealing with daily clinical vignettes concerning perioperative antibiotic therapy. we considered perioperative period as the period of the transplant surgery (per operative) and the postsurgery time before any infection occurrence (postoperative). after general questions on local practices, we asked each center for colonization definition and their diagnostic methods for microbial screening in recipients and donors. the clinical cases were related to specific issues concerning the management of antibiotic therapy in different clinical situations, including no prior colonization, prior colonization with sensitive or multi-drug resistant (mdr) microorganisms including prior colonization with mdr bacteria not sensitive to beta-lactams. the invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center between june and september . we received a total of responses from countries, mostly from western europe (n = ) and the usa (n = ), (fig. ) . systematic screening for bronchial colonization before ltx was mostly performed with sputum samples ( %), regardless of the underlying lung disease. definition of colonization was very heterogeneous and the delay between the last bacterial isolation in pre-transplant and the ltx to consider if the therapy should target these bacteria varied between week and more than year. in recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin/tazobactam, cefepime, ceftazidime, carbapenems) were reported in % of the centers, and antibiotics with activity against methicillin-resistant staphylococcus aureus (mainly vancomycin) were reported in % of the centers. for these recipients, the duration of antibiotics reported was days ( %) or less ( %) or stopped when cultures of donor and recipients were reported negatives ( %). in recipients with pre-transplant colonization, antibiotics were adapted to the susceptibility of the most resistant strain isolated in pre-transplant samples and given for at least days ( %). conclusion: practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. the antibiotic duration reported was longer for colonized recipients. compliance with ethics regulations: not applicable. the vancomycin was therefore considered as justified or not and appropriate or not. occurrence of nephrotoxicity and supratherapeutic exposure in this study group was compared to critically ill children control group. results: thirty one children receiving vancomycin lines of treatment whose ( %) observed a risk of acute kidney injury (aki) (n = ) and an aki (n = ) during the vancomycin treatment period were included. there was a trend to inversed relationship between plasmatic concentrations of vancomycin and estimated creatinine clearance (r = . ). seven patients observed a nephrotoxicity related to vancomycin, they had a higher plasmatic concentration of vancomycin (p = . ). seven patients ( %) had a supratherapeutic exposure to vancomycin. nephrotoxicity and supratherapeutic exposure were higher in children with or combined liver-kidney transplantation than in comparative critically ill children group. we found blood stream infection due to the central catheter and blood stream infections probably due to the central catheter. one hundred thirtyfive bacteria were identified of which ( %) were staphylococcus coagulase negative. nineteen ( %) lines of vancomycin were appropriate and ( %) were justified. conclusion: vancomycin could have been avoided in one third of children with liver or combined liver-kidney transplantation during the early phase of postoperative stage. vancomycin is associated with a risk of both nephrotoxicity and supratherapeuric exposure. vancomycin should be used with caution, appropriate indications and dosing in this vulnerable population. compliance with ethics regulations: yes. rationale: early bacterial infection is a major and severe complication occurring within the first month after pediatric liver transplantation (lt). the rise of antimicrobial resistance, especially extended-spectrum beta lactamase producing enterobacteriaceae (esbl-pe), is henceforth a concern for these patients. this study aimed to assess the epidemiology of early bacterial infections, including those caused by multidrugresistant (mdr) pathogens, and to identify the risk factors for infection. rationale: the number of cancer patients admitted to emergencies is clearly increasing and digestive oncology is the leading cause of consultation. the aim of this work is to identify the epidemiological factors, the therapeutic modalities as well as the predictive factors of mortality and to compare them with the data of the literature. patients and methods: patients admitted to visceral emergencies for an urgent syndrome revealing or complicating a primary or secondary digestive cancer, and who required immediatemedical and/or surgical intervention and who had stayed at the surgical resuscitation level in our hospital center for a duration of years. several data were entered on excel and analyzed using the spss version software.-epidemiological, concerning age and sex; -clinics including risk factors, history, general condition of the patient and clinical examination data; -para-clinical, interesting biological assessments, and morphological examinations-medical and surgical therapeutics; -postoperative follow-up-treatment results. the three most frequent sites were rated in order of increasing frequency: colo-rectum ( %), pancreas ( %), and stomach ( %). the age group most found was age over years with % of cases, % of patients had under years. this series includes men and women with a sex ratio of , . the installation method was mostly gradual with % of cases. our patients have consulted for urgent clinical presentations mainly occlusive syndrome noted in % of patients. abdominal ct was the first examination performed, followed by abdominal ultrasonography in % and %, respectively. the therapeutic management was medico-surgical. the surgery done in % of patients, % for palliative indication: % were operated for an ostomy discharge, % for a digestive bypass, % for a palliative resection and % for a stoma feeding. postoperative outcomes were % morbidity and % mortality. the main cause of death was septic shock in % of cases, thanks to multivariate statistical analysis three factors were deduced significantly related to mortality: the asa score: p = . ; or = . ; ic: [ . ; . icu and hospital mortality rates were % (n = ) and . % (n = ), respectively. ten patients were alive months after with a median rankin score at [ - ]. more than half of the patients without stupor had a favorable neurological outcome (fig. ) . in univariate analysis, mechanical ventilation and stupor were correlated with mortality, whereas dic and apl were not. by multivariate analysis stupor was the only factor significantly associated with a higher mortality (hr: . [ . - . ] ). conclusion: intracranial hemorrhage is associated with a high mortality rate in al patients, stupor at the onset of intracranial bleeding being independently associated with poor outcome. up to one third of patients will nevertheless survive and experience a favorable neurological outcome. compliance with ethics regulations: yes. neurological outcome assessing by modified rankin scale according to stupor or coma at intracranial hemorrhage diagnosis (blank reflect missing data) rationale: sinusoidal obstruction syndrome (sos, previously known as veno-occlusive disease) is a complication of high dose chemotherapy, frequently occurring during bone marrow transplantation (bmt). severe sos is associated with a high mortality rate, related to multi-organ failure (mof). defibrotide being the only available option for prevention and treatment. prognosis of patients with sos requiring intensive care unit (icu) admission remains unknown. the primary objective was to assess the outcome of these patients. secondary objective was to assess risk factors associated with hospital mortality. patients and methods: retrospective study conducted between january and july in french icus. critically ill adult patients with sos (according to ebmt classification) who received defibrotide were included. results are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: seventy-one patients were included with a median age of years . underlying hematologic diseases were acute myeloid leukemia ( %), lymphoma ( %),myelodysplasia/myeloproliferative neoplasm ( %) or acute lymphoid leukemia ( %). sos occurred during myeloablative allogeneic bmt ( %), reduced conditioning allogeneic bmt ( %), autologous bmt ( %) or chemotherapy ( %, including gemtuzumab ozogamycin in patients). median sofa score at icu admission was ]. ebmt prognostic score was often "very severe" ( %). main reasons for icu admission were respiratory failure (n = ), acute renal injury (n = ), shock (n = ), liver failure (n = ), coma (n = ) and monitoring (n = ). median bilirubin level at icu admission was µmol/l [iqr - ] and platelets count g/l . mechanical ventilation (mv), vasopressors, and renal replacement therapy (rrt) were required in % (n = ), % (n = ) and % (n = ) of patients, respectively. sixteen patients receiving defibrotide experienced bleeding events. icu and hospital mortality rates were % and % respectively, mainly related to organ dysfunction. in univariate analysis, delayed defibrotide initiation, bilirubin level, organ supports, sofa, and ebmt scores were associated with hospital mortality. cox model identified older age (hr . , % ci . - . ), mv (hr . , % ci . - . ), rrt (hr . , % ci . - . ), as associated with mortality. prophylactic defibrotide was correlated with a better outcome (hr . , % ci . - . ). similar results were observed after adjustment for center effect. conclusion: when organ support is required, icu management is associated with high mortality. organ support (namely rrt and mv) and older age were associated with poor outcome. prophylactic defibrotide was associated with survival either due to selection process or to efficacy in this setting. additional studies are needed to confirm these results. compliance with ethics regulations: yes. rationale: prognosis of critically ill immunocompromised patients (ciip) has improved over time. neutropenia is common and is found in one third of these patients. prognostic impact of neutropenia remains controversial and little data focus on ciip admitted in a context of acute respiratory failure (arf). primary objective was to assess prognostic impact of neutropenia on outcome of these patients. secondary objective was to assess etiology of arf according to neutropenia. patients and methods: retrospective analysis of prospective multicenter multinational dataset. adults immunocompromized patients with arf were included. adjusted analyses included ( ) a hierarchical model with center as random effect; ( ) propensity score (ps) matched cohort; and ( ) adjusted analysis in the matched cohort. results: overall, patients were included in this study. median age was [iqr - ] and patients ( . %) were of female gender. median sofa score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ps was [ ] [ ] [ ] [ ] . main immune defect were hematological malignancy in patients ( %), solid tumor in ( %), systemic disease in ( . %), and other immunosuppressive drugs in ( %). neutropenia at admission was observed in patients ( %). initial oxygenation strategy was oxygen in patients ( %), high flow nasal oxygen in ( %), non-invasive ventilation in ( %) and invasive mechanical ventilation in ( %). before adjustment, hospital mortality was significantly higher in neutropenic patients ( % vs. % in non-neutropenic patients; p = . ). after adjustment for confounder in a mixed model, neutropenia was no longer associated with outcome (or . , % ci . - . ). after ps matching, neutropenic and non-neutropenic patients were compared. hospital mortality was similar in both groups ( % vs. % respectively; p = . ). after adjustment for variables associated with mortality, neutropenia was not associated with hospital mortality (or . , % ci . - . ). arf etiologies were distributed similarly in both neutropenic and non-neutropenic patients (fig. ) , main etiologies being bacterial pneumonia ( % vs. %), invasive fungal infection ( % vs. %), pneumocystis jiroveci pneumonia ( % vs. . %), and undetermined etiology ( % vs. %) (p = . ). conclusion: neutropenia at icu admission is not associated with hospital mortality in this cohort of ciip admitted for arf. surprisingly, arf etiology did not differ despite the multiplicity of observed immune defects. compliance with ethics regulations: yes. rationale: hepatic dysfunction (hd) is commonly observed in patients with hematologic malignancies and associated with an increased mortality in allogeneic hematopoietic stem cell transplantation patients. we aimed to assess incidence, risk factors and prognostic impact of hd in a large multicenter cohort study of critically ill patients with hematologic malignancies. patients and methods: this research was a post hoc analysis of a franco-belgian multicenter prospective study assessing the prognosis of patients with hematologic malignancies admitted to intensive care unit (icu) between january and may . hd was defined as serum total bilirubin ≥ µmol/l at icu admission. for patients with hd, a review of medical hospital records was performed by an expert panel to assess management of hd by attending physicians. results: among the patients with hematologic malignancies admitted to icu, were included in the study, mainly patients with non-hodgkin lymphoma ( . %) or acute myeloid leukemia ( . %). hd at icu admission occurred in patients ( . %). factors independently associated with hd were the use of cyclosporine (or = . , % ci . - . , p < . ) and antimicrobial treatment (or = . , % ci . - . , p = . ) before icu admission, abdominal symptoms at icu admission (or = . , % ci . - . , p < . ), ascites (or = . , % ci . - . , p = . ), hepatic charlson comorbidity (or = . , % ci . - . , p = . ), increased creatinine at icu admission (or = . , % ci - . , p = . ), neutropenia (or = . , % ci . - . , p = . ) and myeloma (or = . , % ci . - . , p = . ). hospital mortality was . % and . % in patients with hd and patients with no hd respectively (p < . ). hd appeared as an independent factor of hospital mortality after adjustment with other organ failure (oradj = . , % ci . - . , p = . ). factors independently associated with hospital mortality among patients with hd at icu admission are reported in table . etiologic diagnoses for hd by physicians were undetermined for patients ( . %) including ( . %) for whom the existence of hd has not even been mentioned in the medical record. investigations were performed in % and only % of patients received a specific treatment for hd. conclusion: hd at icu admission is common, underestimated, poorly investigated, and impairs outcome in critically ill patients with hematologic malignancies. hd should be considered and managed as other organ dysfunctions. it raises the importance of an early severity assessment of hd and a development of diagnosis strategies to get therapeutic options, in close collaboration between hematologists and intensivists. compliance with ethics regulations: yes. rationale: acute respiratory failure (arf) is the main cause for admission to the icu for patients with hematological malignancies (hm). viral pneumonia is poorly described in this population. respiratory viruses pcr is a rapid and sensitive diagnostic tool. thoracic ct allows to guide the diagnosis but is also poorly described. the primary objective was to describe ct features suggesting viral pathogenicity. secondaryobjectives were to assess risk factors associated with the use of invasive mechanical ventilation (imv) and icu mortality. rationale: high-dose methotrexate (hd-mtx) is commonly used in the treatment of solid tumours and hematological malignancies. severe toxicities are frequent, leading to organ dysfunction, multiple organ failure and death. outcome of these patients when critical illness occurs is poorly studied. this study aims to describe mtx-induced toxicities and to assess outcome in critically ill patients. in this retrospective study conducted in the icu of one university hospital between january and december , all the patients who were given hd-mtx (single dose greater than mg/m ) in the icu were included. results are presented as median [interquartile range] and number (percent). results: patients ( men and women) aged years [ - ], were included. b-cell lymphoma had been diagnosed in patients (burkitt, n = ; diffuse large b cell lymphoma with cns (central nervous system) involvement, n = ; primary cns lymphoma, n = ) and t-cell lymphoma in two patients. patients were mainly admitted for coma (n = ; %) or acute kidney injury (n = ; %). mtx was administered at a median dose of . g [ - ] . fourteen patients had concomitant medication interacting with mtx. median mtx clearance was days [ ] [ ] . frequent mtx-related complication were mucositis (n = , %), diarrhea (n = , %) or hepatic failure (n = , %). during icu stay, patients experienced acute kidney injury (kdigo stage . [ ] [ ] ). two patients received carboxypeptidase and three underwent dialysis. overall, patients ( %) required mechanical ventilation, ( %) vasopressors. hospital mortality was % (n = ). cox model identified mtx concentration h after administration higher than . µmol/l as associated with hospital mortality (hr . , % ci . - . ) (fig. ) . conclusion: to our knowledge this is the first study assessing characteristics and outcome of critically ill patients receiving hd-mtx. mtx concentration at h was associated with hospital mortality. despite underlying malignancy, icu support of these patients was associated with a meaningful survival. compliance with ethics regulations: yes. rationale: high-dose methotrexate ( g/m ; hdmtx) is the cornerstone of chemotherapy in acute lymphoblastic leukemia (all) and several high-grade non-hodgkin lymphoma (hnhl). despite standardized prevention, acute kidney injury (aki) and other life-threatening complications still occur. given the cost of glucarpidase, an enzyme that metabolizes mtx in few minutes, and the complexity of hematological patients admitted to the icu, a better comprehensive view of the factors that predict hdmtx toxicity, as well as the role of glucarpidase as rescue therapy in patients with organ failure, is mandatory. patients and methods: retrospective monocenter study including all the adult patients referred for all or hnhl in a french university hospital, and who received hdmtx. aki was defined according to the kdigo classification. univariate analysis (fischer exact or mann-withney tests) followed by multivariate analysis (stepwise logistic regression) were used to identify before hdmtx the clinical and biological predictive factors of aki. outcomes following glucarpidase were also addressed. results: from dec- to sept- , patients received hdmtx (median dose g/m ; all n = , hnhl n = ), totalizing hdmtx pulses. sixty-nine patients ( . %) developed aki after a median time of days (stage n = , stage n = , stage n = including one requiring dialysis in the first week). by multivariate analysis, only age, body mass index and a diagnosis of all were significantly and independently associated with the risk to develop aki. mtx exposure (maximal serum concentration at h - ) was also associated with aki (auc . , p < . ). glucarpidase was used in patients ( %) that differed by a higher age and bmi, and a lower basal egfr. glucarpidase was followed by a rapid renal improvement but serum creatinine did not return to baseline ( vs. micromol/l). thirty patients with aki or delayed mtx elimination did not receive glucarpidase but none required renal replacement therapy and egfr was only slightly but not significantly reduced at the end of follow-up. extra-renal adverse-events (rbc and platelets transfusions, neutropenia, hepatitis, severe diarrhea, mucitis) were more frequent in patients that developed aki. eighteen patients were admitted to the icu, including and that required mechanical ventilation or vasopressor drugs, respectively. conclusion: few actionable factors predict the development of aki after hdmtx, suggesting additional genetic factors. aki was reversed by glucarpidase but progression toward ckd was the rule. further studies will have to identify patients that will actually beneficiate from glucarpidase. compliance with ethics regulations: yes. khaoula ben ismail, sana khedher, ameni khaled, nassereddine foudhaili, mohamed salem usi digestif-service de gastroenterologie-eps charles nicolles.tunis-tunisie., tunisia, tunisia correspondence: khaoula ben ismail (khaoula @hotmail.fr) ann. intensive care , (suppl ):p- rationale: infection is common and accounts for major morbidity and mortality in cirrhosis. patients with cirrhosis are immunocompromised and have increased susceptibility to develop spontaneous bacterial infections, hospital-acquired infections, and a variety of infections from uncommon pathogens. we aimed to evaluate the impact of infection on hepatic encephalopathy. patients and methods: this is a prospective study, conducted over a period of years from january to december . consecutive patients with approved decompensated cirrhosis admitted to our department are included. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the impact of infection on hepatic encephalopathy. results: a total of patients diagnosed with decompensated cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome ( % of cases), digestive bleeding ( % of cases), fever ( % of cases), and encephalopathy ( % of cases). patients with infection seemed to have a high incidence of hepatic encephalopathy with % versus % when the patients are none infections. the results also showed that in those with hepatic encephalopathy, an effective antibiotic treatment accelerates significantly wakefulness under h with a rate of % vs. % (p < . ) . in addition, the infection does not influence mortality or length of stay compared to other complications such as digestive bleeding. conclusion: we found that infection caused more episodic hepatic encephalopathy than other complication and an effective antibiotherapy accelerate wakefulness. compliance with ethics regulations: yes. rationale: hepatic encephalopathy (he) is a common cause of hospitalization in patients with cirrhosis. pharmacologic treatment for acute (overt) he has remained the same for decades. to compare polyethylene glycol electrolyte solution (peg) and lactulose treatments in patients with cirrhosis admitted to the hospital for he. we hypothesized that rapid catharsis of the gut using peg may resolve he more effectively than lactulose. patients and methods: this is a prospective study, conducted over a period of years. from janury to december , we have been interested in cirrhotic patients with hepatic encephalopathy. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the difference beteween peg and lactulose in the treatement of hepatic encephalopathy. results: a total of patients diagnosed with decompation of cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the hospitalization reasons were: edematous-ascitic syndrome in %, gastro-intestinal bleeding %, fever in %, and encephalopathy was present in % of cases. a total of patients were randomized to each treatment arm. baseline clinical features at admission were similar in the groups. twelve of patients in the standard therapy arm ( %) had an improvement of or more in hesa score, thus meeting the primary outcome measure, compared with of evaluated patients receiving peg ( %) (p < . ). the mean ± sd hesa score at h for patients receiving standard therapy changed from . ± . to . ± . compared with a change from . ± . to . ± . for the peg-treated groups (p = . ). the median time for he resolution was days for standard therapy and day for peg (p = . ). adverse events were uncommon, and none wasdefinitely study related. conclusion: we found that peg led to more rapid he resolution than standard therapy, suggesting that peg may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute he. compliance with ethics regulations: yes. acute pancreatitis and pregnancy janati adnane, lina berrada obstetric intensive care unit, casablanca, morocco correspondence: janati adnane (adnanejanati@gmail.com) ann. intensive care , (suppl ):p- rationale: the association of acute pancreatitis and pregnancy is rare but not negligible, it often cause a diagnostic problem given the gravidal context that can lead to serious repercussions. the objective of our study is to assess the particularities in the diagnosis, management and prognosis of acute pancreatitis during pregnancy patients and methods: this is a retrospective study about cases of acute pancreatitis occurred during pregnancy over a -year period ( - ) at the obstetric intensive care unit of the meriem maternity hospital in the chu ibn rochd casablanca. a retrospective analysis of the medical files of these patients was carried out, considering epidemiological and etiological criteria, the treatments administered and maternal/fetal fate. we found cases during this period, with an incidence of / . the average age of onset was years, % of cases occurred in the rd trimester. epigastric pain and vomiting were the common symptomatology. ultrasound showed biliary lithiasis in % of cases with increased pancreas size in % of cases. maternal mortality was zero. uncomplicated benign forms are the most common ( %). severe hypokalemia was found in % of patients. neonatal morbidity was marked by six premature deliveries. among them, a newborn died at day- of life discussion: the association of acute pancreatitis and pregnancy is rare, more frequent during the rd trimester, it mainly affects the young woman. lithiasic biliary pathology remains by far the most frequent etiology. the diagnosis is clinical most often represented by epigastralgia with vomiting and biological via lipasemia and amylasemia dosage. uncomplicated benign forms are the most common. hydroelectrolytic disorders are often found. abdominal ultrasound allows the etiological diagnosis. the treatment is above all symptomatic whose objective is the digestive rest, the correction of the hydroelectrolyte disorders but first of all relieve the pain. conclusion: acute pancreatitis is a rare event in pregnant women, but can have a maternal and fetal prognosis. it must be systematically evoked in front of the acute abdominal pains of the pregnant woman because the confirmation of the diagnosis is easy and the maternal results depend mainly on therapeutic management. prematurity remains the predominant factor in neonatal morbidity. compliance with ethics regulations: not applicable. rationale: aclf is a clinical concept defined in patients with chronic liver disease who presented organ failure(s) secondary to an acute decompensated event. liver transplantation in this indication showed good results in selected patients. the aim of this prospective study was to evaluate the outcome and the factors associated with a favorable selection to liver transplantation in this population. patients and methods: all consecutive patients admitted to the icu with cirrhosis and aclf, were recruited. patient with age < years or with fulminant hepatitis were excluded. results: between july and february , cirrhotic patients were admitted to icu. mean age was . ± . years ( . % male). cirrhosis was due to alcohol in . % of the patients. aclf grading at admission was: . % aclf (n = ), . % aclf (n = ), . % aclf (n = ), and . % aclf (n = ). of the patients, . % (n = ) were considered to be eligible for a transplant project and were assessed for liver transplantation. the main reasons were alcohol abuse ( . %, n = ), death within days after admission ( . %, n = ) and rapid improvement of the liver disease. of the eligible patients, % were transplanted with a mean time between admission to icu and liver transplantation of . ± . days. twelve patients died on the waiting list ( % of the listed patients), mainly of septic shock. among those who were assessed for liver transplantation but not listed (n = ), . % died before the listing (n = ) and . % were not listed because of severe comorbidities (n = ). the global mortality rate was . % (n = ). the and days rate mortality were respectively . % and . %. the overall -month patient survival was respectively % and % in the transplant and non-transplant group (p < . ) for the entire cohort. among eligible patients, factors associated with the absence of liver transplantation, in the multivariate analyses, were mechanical ventilation (hr . , % ci rationale: body composition is known to be a prognostic factor in cirrhotic patients. however, the link between this and the prognosis of patients in intensive care unit (icu) is unknown. the computed tomography offer accurate estimations of muscle mass by analysing a cross-section usually going through the third lumbar vertebrae. this retrospective study aimed to assess the feasibility of body composition (bc) analysis in cirrhotic patients with septic shock, using computed tomography (ct) and evaluate the impact of bc (muscle mass, subcutaneous and visceral fat) on outcome. patients and methods: this retrospective study included cirrhotic patients with septic shock hospitalized in icu who underwent an abdomino pelvic ct scan within h of admission. we collected the surface areas of muscle mass and adipose tissue on the ct scans. we compared bc data with mortality and with the number of organ failures. the average age was years . the average child and meld scores were respectively . [ - ] and . . the prevalence of sarcopenia was %. it was not associated with a higher mortality rate at day (p = . ) or with a higher number of organ failures at day (p = . ). we observed a higher subcutaneous adiposity index in patients who died at day (p = . ) and in patients with renal insufficiency at admission (p = . ). there was a trend (p = . ) towards more visceral fat in patients who died in icu. the assessment by ct of body composition reveal evaluation of bc using ct is feasible and reproducible and may constitute a promising tool to evaluate in cirrhosis critically ill patients. visceral fat mass seems associated with poor outcome in cirrhotic patients with septic shock compliance with ethics regulations: yes. rachid jabi, mohammed bouziane chu mohammed vi, oujda, morocco correspondence: rachid jabi (jabirachid@gmail.com) ann. intensive care , (suppl ):p- rationale: the infection of the necrosis constitutes a pejorative element in the management of the necrotico-haemorrhagic pancreatitis, in the absence of the drainage the mortality approaches %. the morbidity and mortality of surgery can be avoided with minimally invasive treatments. purpose: to compare the morbidity and mortality of the two groups of post-ercp pancreatitis and the other etiologies. patients and methods: a retrospective study over years between and and a comparison between pancreatitis secondary to post-ercp and other etiologies of pancreatitis. a p value of . is considered significant. the surgical treatment used in cases of superinfection post ercp against seven cases of other etiologies of pancreatitis. high mortality in post-ercp pancreatic arm % vs. % (p = . ). high morbidity in the operated group % vs. % (p = . ) represented mainly digestive haemorrhages. duration of stay was significantly longer in the operated group vs. days (p = . ). thrombocytopenia and beta-lactamase-producing enterobacteria have further complicated management in the post-ercp infected pancreatitis arm. the antibiotic resistance of infected pancreatitis in post-ercp patients is . % for ciprofloxacin, . % for imipenem and % for amikacin. conclusion: pancreatitis the most common adverse effect of ercp with significant morbidity and mortality. the collaboration between the intensive care unit gastroenterologist and the surgeon improves management since the risk factors are mainly related to the patient and can not be modified. compliance with ethics regulations: yes. gautier nitel, aghiles hamroun, anne bignon, gilles lebuffe chru lille, lille, france correspondence: gautier nitel (gautier.nitel@gmail.com) ann. intensive care , (suppl ):p- rationale: liver transplantation (lt) has been recently experiencing an expansion of its indications, allowing patients with potentially more co-morbidities to access to transplantation. in our era of graft shortage, we should focus on the identification of the best lt candidates. the aim of our work is to study the determinants of early morbidity and mortality after lt from three angles: occurrence of a major cardiovascular event (mace) or acute renal failure (kdigo stage - aki) in the first days postoperative, and death in the year following lt. retrospective study investigating the occurrence of mace or aki (kdigo - ) within days post-operative and mortality at year after lt, including patients who received a first lt between january and december in our center. analysis of risk factors by a multivariate step-by-step analysis. statistical significance for p < . . data presented in odds ratio (or) rationale: infectious complications are frequently reported in critically ill patients supported by veno-arterial extracorporeal membrane oxygenation (va-ecmo) for refractory cardiogenic shock, but their diagnosis is challenging. no study has specifically studied bloodstream infection (bsi) in this population and some recommendations suggest performing systematic blood culture (bc). in our unit, systematic bc are daily sampled. we investigated the interest of systematic bc to detect bsi under va-ecmo. patients and methods: in a retrospective analysis ( - ), and after exclusion of patients dying within h, all adult patients from cardio-vascular intensive care unit supported by va-ecmo were included. systematic daily and "on demand" bc (at the physician's discretion) performed from va-ecmo implantation to days after withdrawal were analyzed. bsi was defined as at least one bc positive to a pathogen (except for contaminants bsi which required at least two positive bc with the same bacteria in h). multivariable logistic regression was performed to identify risk factors for positivity of systematic bc. rationale: fungal infections are constantly increasing in hospitals. indeed, the increase in these infections and especially candida yeast infections is almost parallel to the increase in the widespread use of a wide range of implanted medical devices such as catheters. for this reason, we have been investigating, isolating and identifying candida yeast colonizing vascular catheters and studying the epidemiological and clinical characteristics of patients with colonized catheters. patients and methods: it is a prospective, transversal study conducted at the intensive care and neurosurgery services of the sétif university hospital, evaluating the fungal colonization of vascular catheters. these are collected from hospitalized patients for a period of months. a culture of the distal end of the catheter is performed directly after its ablation. the results obtained showed that among the samples taken, six are colonized by the yeasts, the incidence is %. six yeast of candida spp were isolated, % of them were candida albicans species, . % candida parapsilosis and . % were candida glabrata. conclusion: it appears that colonization of catheters occurs most frequently in patients with the following characteristics: extreme ages of life, male sex, antibiotic therapy and length of hospitalization or prolonged catheterization. compliance with ethics regulations: yes. rationale: the threat of emergent extensively drug-resistant bacteria (exdr) dissemination worldwide is real. it has become a global public health issue. in fact, glycopeptides-resistant enterococcus faecium (gre) and carbapenemase-producing enterobacteriaceae (cpe) are the lead microorganisms in the high resistant bacteria category. the aim of our study was to characterize the molecular mechanisms and to determinate the antimicrobial susceptibility profiles of gre and cpe isolated from burn patients. patients and methods: prospectively, we studied all cpe and gre strains isolated from burn patients between january and december . all isolated microorganisms were identified on the basis of conventional microbiological techniques. antibiotic susceptibility testing was carried out by the agar disc diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. molecular characterization was performed by multiplex real-time pcr (cepheid, genexpert ® ) allowing detection of the most prevalent carbapenemase encoding genes (blavim, blandm, blaimp, (blaoxa- and blakpc) as well as the genes vana and vanb of gre. results: during the study period, exdr were isolated from burn patients. the most frequent sites of isolation were blood cultures ( %) and skin samples ( . %). cpe represented . % of isolated exdr ( strains). among them, the most frequently identified species was klebsiella pneumoniae ( . %) followed by enterobacter cloacae ( %). twenty-four cpe ( . %) expressed the blandm gene. the blaoxa- gene was found in strains ( . %) and ten strains ( . %) carried both genes. of the cpe, . % revealed ertapenem mic > mg/l whereas most strains were susceptible to imipinem and meropenem with . % and . % of susceptibility, respectively. the antibiotics showing the highest resistance rates were cefotaxime ( . %), piperacillin-tazobactam ( . %), ciprofloxacin ( . %) and amikacin ( . %). the most active agents were colistin and fosfomycin with . % of resistance for each. seven strains of gre were isolated ( . % of exdr). all of them expressed the vana gene, with vancomycin mic > mg/l. however, teicoplanin mics ranged from to mg/l. all gre strains were beta-lactam resistant and highly resistant to aminosides. linezolid and tigecycline were the only active antibiotics. the dissemination of these extensively drug-resistant bacteria must be contained by implementation of strict isolation methods and better hygienic procedures in order to limit their economical and health consequences. compliance with ethics regulations: yes. rationale: stenotrophomonas maltophilia has emerged as an important pathogen that induces nosocomial infections. it is a non-fermentative, gram-negative bacillus that causes severe infectious diseases, particularly bacteremia in the hospital setting. morbidity and mortality due to stenotrophomonas maltophilia seems to be high, particularly in critically ill patient. the aim of this study was to describe the clinical features, management and outcome of patients with stenotrophomonas maltophilia infections. patients and methods: this was a retrospective analysis of prospectively collected data of patients hospitalized in intensive care unit (icu) between january and december . collected data were: age, gender, comorbidities, severity scores on admission, prior infections, use of antibiotics, use of invasive devices (urinary tract catheter, or mechanical ventilation), microbiological data, and antimicrobial therapy and outcome. results: during the study period, patients with stenotrophomonas maltophilia infection were included, with a mean age of ± years. the simplified acute physiology score ii and acute physiology and chronic health evaluation ii on admission were respectively ± and ± . bacteremia caused by stenotrophomonas maltophilia was observed in patients ( %) and ventilator acquired pneumonia in two patients ( %). twenty four episodes were classified as primary bacteraemia and only one as secondary bacteraemia due to urinary infection. four patients ( %) developed septic shock. mean sofa on the day of stenotrophomonas maltophilia infection was ± . prior antibiotic use was observed in % including an antipseudomonal agent in % of cases. infection due to stenotrophomonas maltophilia was considered in cases. empiric antibiotic therapy was administered to patients ( %) and had included an appropriate agent in only five cases ( %). after adapting antibiotics, monotherapy was the choice for six ( %) patients while a combination of two antibiotics was indicated in the others ( %). the most used antibiotic was the colistin in episodes ( %). intensive care mortality was %. univariate comparison between dead and survivors showed a significant difference in prior nosocomial infection and respiratory comorbidities. no independent risk factor of mortality was found in multivariate analysis. rationale: thrombocytopenia is a frequent disorder in critically ill patients, and several studies have reported its correlation with poor prognosis. considering the major role of platelets in hemostasis, a significant drop in platelet count is an alarming sign in septic patients. the aim of this study was to show the relationship between thrombocytopenia and platelet level changes and mortality in septic patients. patients with criteria for septic shock (based on the third international consensus definitions for sepsis and septic shock) at admission or at any time during hospitalization were included in a prospective study conducted for a period of months (january -august , ) in a medical surgical intensive care unit. patients hospitalized for less than h were excluded. thrombocytopenia was defined as a platelet count less than . /mm , and recovery was defined as returning to levels more than . /mm after presenting thrombocytopenia. we assessed the platelet count during the hospitalization and its outcomes. we included patients. the mean ± sd age was . ± . years. sex ratio was . . thrombocytopenia during sepsis (group ) was found in patients ( %) with a mortality rate at %. the mortality rate among patients not showing thrombocytopenia (group ) was significantly lower % (p = . ). the receiver operating characteristic showed that in (group ), a drop in the platelet count (from admission to septic shock day) more than % was associated with poor outcome (sensibility = %, specificity = %, auc = . ). among the (group ), % showed recovered platelet counts. the mortality was significantly higher in the patients with uncovered thrombocytopenia ( % vs. %, p = . ). conclusion: thrombocytopenia was shown to be an indicatorof poor prognosis in our study. in addition, drops of > % and failure to recover the platelet counts were further determinants of unfavorable outcomes. compliance with ethics regulations: yes. mehdi gaddas , sarra dhraief , karim mechri , imen jami , amenallah messaadi , lamia thabet rationale: pseudomonas aeruginosa is known as an opportunistic pathogen frequently causing serious infections. multidrug resistance in this bacterium is increasing worldwide and poses a major problem in the treatment of infections due to this microorganism. analysis of resistance profile to antibiotics of p. aeruginosa helps to establish a prompt control and prevention program. the aim of this study was to evaluate epidemiological profile and antimicrobial resistance of p. aeruginosa isolates in a trauma and burn center. patients and methods: retrospectively, we studied all p. aeruginosa isolates over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with disk diffusion method and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sirsystem. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during study period, non-repetitive strains of p. aeruginosa were isolated, representing % of all isolates. in our center, infections due to p. aeruginosa were endemic with epidemic peaks. p. aeruginosa was mainly isolated from burn intensive care unit ( . %) and anesthesiology department ( . %). the most frequent sites of isolation were skin samples ( . %), blood cultures ( . %), catheters ( . %) and urines ( . %). the survey of antibiotic susceptibility showed high percentage of resistance to the different antibiotics: . % of strains were resistant to ceftazidime, % to ticarcillin, . % to pipercaillin-tazobactam, % to imipenem, . % to ciprofloxacin and % to gentamicin. resistance to colistin was rare. it concerned only four strains, isolated from burn patients. the survey of antibiotic susceptibility evolution have shown a global increase of resistance to commonly prescribed antibiotics between and : from % to . % to imipenem, from . to . % to ticarcillin-clavulanate, from . % to % to ceftazidime and from . to % to gentamicin. whereas ciprofloxacin resistance rate have decreased from . to %. antibiotic resistant strains were mainly isolated from burn intensive care unit, with % of resistance to imipenem and . % to ceftazidime. the dissemination of multidrug-resistant strains of p. aeruginosa in our center must be contained by the implementation of strict isolation methods and better hygienic procedures. compliance with ethics regulations: yes. acinetobacter baumanii: therapeutic impasse sabah benhamza, mohamed lazraq, abdelhak bensaid, youssef miloudi, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: acinetobacter baumanii (ab) is frequently responsible for nosocomial infection in the intensive care units, and its resistance to antibiotics continues to increase. the objective of our study is to determine the epidemiological profile and antibiotic sensitivity of isolated bacteria in the intensive care unit august , in order to optimize the probabilistic antibiotherapy of bacteremia in intensive care. patients and methods: this is a retrospective study performed in the intensive care unit of the hospital august , , spread over a period of years from january to january . results: the incidence of ab infection in our department was . % for all patients admitted to intensive care. the average age was years ± , male predominance (sex ratio . ). the average time to onset of infection was days. during the study period, ab strains were isolated, % of which were pulmonary, % blood, and % urinary. resistance to c g reached % in , % in and % in . for imipenem resistance was % in , % in , % in . for amikacin, resistance was % in , % in , and % in . for fluoroquinolones resistance was % in , % in and % in . cotrimoxazole resistance was around % in the last years conclusion: the resistance of ab to antibiotics has reached very alarming levels, especially for carbapenems. this requires resuscitators to change their antibiotic prescription behavior and to invest in the prevention of nosocomial infections. compliance with ethics regulations: yes. this is a prospective observational study conducted at the ed during the period of year. data of all patients admitted with suspected infection of any cause were collected. poor outcomes were defined as death and transfer to an icu within h. results: during the study period, a total of patients with a mean age of ± were included. % were male. within h of management in the ed, % of patients were transferred to the icu and % died. independent predictors of icu-transfer and death included low systolic blood pressure, fever and tachycardia. a prediction model containing these independent predictors had a good predictive accuracy with an area under the curve of . ( % ci . - . ). sensitivity was %, specificity %, positive predictive value % and negative predictive value %. conclusion: assessing readily available clinical variables at arrival to the ed can aid in predicting poor outcomes. [ ] [ ] [ ] [ ] [ ] [ ] . the most common co-morbidities were chronic respiratory failure (crf, n = ) and hypertension (n = ). respiratory distress (n = ) and coma (n = ) were the major indications for iv. us diaphragmatic exploration was performed at a median delay of iv at days [ ] [ ] [ ] [ ] [ ] [ ] . % of patients received sedation and . % received neuromuscular blockers. the ventilator mode was control volume in patients via endotracheal tube (n = ) and tracheostomy cannula (n = ). no major incident was detected during the turning of patients. both tid and ted decreased from the sp to the pp (fig. ) : tid (mm) ( in sp vs. . in pp, p = . ), ted (mm) ( . in sp vs. in pp, p = . ). the observed dtf was lower in the pp but without significance ( . vs. . %, p = . ). no difference was showed when the comparison between sp-dtf and pp-dtf was adjusted on the ventilator mode, obesity, neuromuscular blockers and crf. the positioning in pp in ventilated patients reduces both tele-inspiratory and tele-expiratory diameters of the diaphragm but not altered its contractile function. compliance with ethics regulations: yes. significance was considered at p < . . results: results are presented in the table below. discussion: nebuliser type influences the efficiency of aerosol delivery, with the vmn delivering a significantly higher % aerosol dose than the jn at the two circuit positions (p = . on inspiratory limb; p = . at the dry side of humidifier). in agreement with previous reports using bias flow, for both nebulisers, the location within the circuit has a significant effect, with the nebuliser on the dry side of the humidifier delivering more aerosol than on the inspiratory limb (p = . for vmn; p = . for jn). conclusion: for a mechanically ventilated adult tracheotomy patient, the type of nebuliser and the location of the nebuliser within the circuit influences aerosol delivery. rationale: automatic tube compensation (atc) is a mode available in most icu ventilators. it compensates for the resistive pressure into endotracheal tube/tracheostomy canula by continuously providing a pressure assistance based on internal diameter of a new endotracheal tube/tracheostomy tube. its use in icu is unclear. we designed a survey to further explore this. patients and methods: the survey was endorsed by the acute respiratory failure section and the clinicaltrials group of the european society of intensive care medicine (esicm). the pool was sent out via an email on june to the esicm members worldwide. the following closed questions were: country, years in icu, kind of icu, kind of hospitals, kind of respirators, atc use (never, always or in some patients), reasons to or not to use atc, ventilatory mode in which atc was used. the database was frozen on august st after two reminders. we used the gross national income per capita (usd) provided by the world bank to transform the respondent's country into a geographical-economical variable with levels: high-europe, high-noneurope and middle ( ) . atc use was coded as yes or no. the primary end-point was atc rate of use and the hypothesis was that less than % of the respondents do use it. variables were expressed as counts. groups were compared by chi square test. a logistic regression analysis was performed to explore the contributing factors to atc use. we received responses without any doublons, of which six were empty, from countries. four-hundred and nine respondents used atc always or in some patients ( % atc rate of use). this rate was not different between economical-geographical regions, icu, hospitals and years in icu. for those respondents who did not use atc the reasons were: atc mode not available in icu ventilators ( . %), atc not helpful mode ( . %), atc not known ( . %) and atc provides too much pressure assistance ( . %). for those respondents who used atc the reasons were: helpful in weaning ( . %), set by default ( . %) and physiological benefit ( . %). they used atc during spontaneous breathing trial ( . %), with any assisted mode ( . %) and with specific modes ( . %). we found no risk factor for atc use in the logistic regression model (fig. ) . the atc rate of use was unexpectedly high in this survey. this may result from respondents selection bias or from an a priori underestimation of its use. compliance with ethics regulations: yes. rationale: during pressure support ventilation (psv), adjusting the level of assistance mainly aims at maintaining the patient's respiratory effort within a normal range. however, respiratory effort measurement is impeded in clinical routine by the need of esophageal pressure recording. in this study, we evaluated the accuracy of assessing the respiratory effort from the flow and airway pressure signals using several machine learning algorithms based on the equation of motion of the respiratory system. patients and methods: using the asl simulator (ingmar medical) connected to a pb ventilator (medtronic) set in psv, we simulated a massive number of different respiratory cycles. each simulated cycle represented a unique combination of compliance and resistance of the respiratory system, duration and intensity of the muscle pressure (pmus), positive end-expiratory pressure (peep) and pressure support levels. using least squares regression methods, the flow waveform was fitted according to the equation of motion of the respiratory system to determine the compliance and resistance of the respiratory system, and the pmus. the hypothesis used (alone or in combination) to constrain the system were: linearity of pmus at the onset of the inspiratory effort, nullity of pmus at the end of insufflation, and nullity of pmus during expiration. thus, nine methods were built and tested. calculated and actual peak pmus values were compared using the bland-altman method. the nine methods of pmus assessment were evaluated using different simulated cycles. by limiting the analysis to selected cycles with a predefined applicability criterion (intrinsic peep less than cmh o), a limited inspiratory effort (peak pmus less than cmh o) and a high quality of fitting (r > . ), the method using the three hypothesis together to constrain the system was characterized by a bias of . cmh o and limits of agreement of - . and . cmh o. however, when widening the analysis to all the simulated conditions, no method allowed an accurate estimation of the peak pmus : the best one exhibited a bias of - . cmh o and limits of agreement of − . and . cmh o. conclusion: among the nine machine learning methods tested, some provided an accurate estimate of the respiratory effort in selected cycles but none allowed such accuracy across all simulated conditions. this incites to assess automated methods using a more complex physiological and physical model. compliance with ethics regulations: not applicable. rationale: there is a growing interest in esophageal pressure monitoring in mechanically ventilated patients. esophageal pressure can be measured with a specific nasogastric catheter equipped with esophageal balloon and connected to a pressure transducer. it is used as a surrogate for pleural pressure and may be considered as a corner stone in advanced care of ventilated patients to better assess lung and chest wall mechanics and easily detect patient-ventilator asynchronies. however, this promising technique is still seldom used in clinical practice. trained icu nurses may perform oesophageal pressure measurements which may help facilitate its implementation in the usual patient care. this study aimed at assessing whether a specific educational program to train nurses to perform esophageal pressure monitoring allowed reliable measurements. this was a prospective monocenter study performed in an academic icu. written informed consent was obtained from the nurses before inclusion in the study. the specific educational program consisted of a -min online theoretical course, a -h group theoretical teaching and a -min simulation training on a mannequin. then each participating nurse performed three esophageal pressure measurements (using nutrivent ® catheters and an icu monitor connected to arterial line pressure transducers system) on three different mechanically ventilated paralysed patients under supervision. a knowledge assessment was performed with a short written mcq test. the skill evaluation was by two trained experts. concretely the trained nurses performed an esophageal pressure measurement without assistance. their ability to control the esophageal balloon position by an occlusion test, to measure the inspiratory and expiratory airway and transpulmonary pressures and to calculate of respiratory system, lung and chest wall compliances was assessed at the bedside using a standardized evaluation form. we present here the preliminary results of the first nine included nurses. the written knowledge assessment was considered as rationale: several modalities of ventilatory support have been proposed to gradually withdraw patients from mechanical ventilation. we conducted this study to compare t-piece and pressure support ventilation (psv) ( cmh and peep ) in the process of weaning of mechanical ventilation in burns. patients and methods: it was a prospective randomized trial in burn icu in tunisia during months. mechanically ventilated patients who met standard weaning criteria were included [ ] . patients were randomized into two groups: group under t-piece and group under psv. duration of the test: - min. the tolerance of the vs test should be judged on clinical criteria. stopping the test if occurred: agitation, tachypnea > cycles/ min, tachycardia > / min, spo < %. successful withdrawal was defined as the ability to maintain spontaneous respiration for h after extubation. results: thirty patients were included, randomized into two groups. the mean age was ± years with a ratio sex of . the average tbsa was ± %. the cause of mechanical ventilation was essentially a face neck burned ( %). the following table shows the weaning outcome of both modalities. eighty percent of succeeded extubation for both groups (n = / ). the cause of failure of extubation was secretion retention and clutter in majority of cases followed by neurological and cardiac distress. the duration of mechanical ventilation does not influence the outcome of the weaning test (p < . ), with a mean of duration of ± days. conclusion: our study did not show any difference between the two weaning modalities in the matter of outcome of extubation. the choice of weaning test of mechanical ventilation is to be judged by the clinician according of the state of his patient. compliance with ethics regulations: not applicable. rationale: when expiratory tidal flow does not go up after increasing expiratory driving pressure expiratory flow limitation (efl) occurs. it is thought that efl heralds airway closure (ac). we investigated the role of chest wall elastance (ecw) in both efl and ac in acute respiratory distress syndrome (ards) patients. our hypothesis was that the lower the ecw to lung elastance (el) ratio the higher the likelihood of efl and ac. patients and methods: twenty-five moderate to severe ards patients were prospectively included in two centers. mechanical ventilation was delivered in volume-controlled mode with tidal volume ml/kg predicted body weight at positive end-expiratory pressure cmh o in semi-recumbent position. airway (paw) and esophageal (pes) pressures and flow were continuously recorded during min by a data logger (biopac ). then, end-expiratory and end-inspiratory occlusions were performed for s, then respiratory system was slowly inflated at constant flow. finally, patient was allowed to breathe out freely to atmosphere by using a three-way stop lock by-passing expiratory valve. ac and airway opening pressure (aop) were determined according to chen et al. ( ) . efl was assessed by the atmospheric method ( ) . dynamic elastance of chest wall (edyn,cw) and lung (edyn,l) were obtained from least square linear regression method over consecutive breaths. static elastance (est,cw and est,l) were determined by classic formulas and also by taking into account aop (est,cw_aop and est,l_aop, respectively). the performance of ecw/el ratio to predict efl and ac was assessed by the area under receiver operating characteristic (aucroc) curve. results: efl was observed in patients ( %) and ac in ( %). median aop was . cmh o ( % ci . - . ) . aucrocs for ecw/el ratios to detect efl and ac are shown in table . edyn,cw/edyn,l ratio was better to detect efl than est,cw/est,l ratio with edyn,cw/edyn,l ≤ . % sensitivity and % specificity. correction for aop made the performance of est,cw/est,l ratio as good as that of the edyn ratio. ac was poorly predicted by edyn and est ratios but its prediction greatly improved with aop correction. however, with the est,cw/ est,l_aop the critical ratio was . (sensitivity %, specificity %) and . (sensitivity and specificity %) for predicting efl and ac, respectively. conclusion: efl and ac are frequent in ards at peep cmh o. edyn,cw/edyn,l ratio lower than best predicted efl occurrence. once ac is taken into account est,cw/est,l ratio greater than accurately predicts ac. efl and ac are two distinct phenomena. compliance with ethics regulations: yes. rationale: anesthesia outside the operatingroom (aoor) in a pediatric environment was giving increasingly increasing indications and a lot of progress because of its interest in carrying out diagnostic and/or therapeutic explorations: % of the acts of anesthesia are performed outside the operating room. the objective of our study is: to clarify the importance and the frequency of the practice of the ahbo, to define its particularities, as well as an evaluation of the ratio: benefit/risk in order to reduce the morbidity and mortality. patients and methods: we report in this study the experience of the service of the resuscitation mother-child on the gestures of aoor. this is a prospective observational study, spread over a period of months: from / / to / / , dealing with acts performed for endoscopic digestive and bronchial procedures, cures in dermatology and radiotherapy, and medical imaging (ct and mri). results: of the procedures performed: were performed for ct, for mri, for arteriography and for endoscopic digestive procedures, for bronchoscopies, for radiotherapy treatments, for laser treatments in dermatology. anesthesia techniques use intravenous induction in % of cases using: hypnotics (propofol, midazolam, ketamine), morphine (remifentanyl, fentanyl), inhalation induction in % of cases (sevoflurane, halothane) and curare for cases of bronchoscopy (rocuronium). this anesthesia was marked by the occurrence of accidents in order of frequency: cardiac in % of cases (tachycardia, hypotension and rhythm disorders), and then respiratory in % of cases. the most serious accidents were admitted in reality and are represented by cases, of which required an intubation (bronchoscopy), a case of cardiorespiratory arrest recovered, cases of severe hypoxia associated with bradycardia and which required the ventilation with the mask (radiotherapy), and cases of bronchospasm requiring the deepening of the anesthesia (absence of tci). a good knowledge of the patient and the intervention, and difficulties specific to each specialty is necessary, as well as a preanesthetic consultation. the aoor must obey the same safety rules as in the operating theater and that in terms of: equipment, monitoring (integrate the capnograph to respiratory monitoring whenever deep sedation and when the continuous control of vas is difficult), anesthetic technique (tcbi) and post-procedure wakefulness management that must meet the same requirements as the sspi, especially for prolonged sedation. compliance with ethics regulations: yes. umbilical vein catheterization through wharton's jelly: a possibility for a fast and safe way to deliver treatments in the delivery room? suzanne borrhomée hôpital rené dubos, france correspondence: suzanne borrhomée (suzanne.borrhomee@gmail. com) ann. intensive care , (suppl ):p- rationale: a fast and safe venous access can be a critical issue in the delivery room during neonatal cardiopulmonary resuscitation, or before endotracheal intubation. here, we describe a new method to inject drugs using the umbilical vein, directly punctured through wharton's jelly. this method was performed in newborns between november and may . umbilical vein was identified and punctured easily and a reflux was obtained in all patients. the first step was antisepsis, and then the umbilical vein was punctured. the puncture was made approximately to cm above the navel. after checking for blood reflux, the nurse injected the treatment. the cannula was left in the vein during the injection and removed as soon as the intervention was over (intubation was performed, or the heart rate had increased). results: here, we report ten cases of emergency injection in the delivery room using this method: -four cases of cardiopulmonary resuscitation using this method to deliver epinephrine. cardiac massage was performed on all patients.-six cases of intubations in the delivery room using this method to administer the premedication. in all patients, the umbilical vein was identified easily. the equipment was the one usually used for venous injection in our unit and was manipulated and handled with ease. venous access was obtained in a matter of seconds, and blood reflux was observed in all patients. the treatments were efficient in all but two patients, which was imputable to the method in one patient. discussion: although this method has been known in our nicu for several years, there has been no publication regarding this method in neonates. inserting an umbilical vein catheter in the delivery room has been validated for resuscitation but this technique is lengthy and requires some sterility conditions that makes it even longer, and thus non-fitting for an emergency tracheal intubation. our method is fast and can be performed easily with no specific training. the whole manipulation procedure, from the beginning of the puncture to the end of the flush-out takes to s. we only identified few specific risks related to this method, mostly infectious, and the risk of drug diffusion. we describe a new route for administration of drugs in the delivery room that was successfully used in nine neonates. umbilical vein needle catheterization is not only safe and efficient, but is also fast and easy to perform without any special training. compliance with ethics regulations: yes. rationale: liver transplantation (lt) is the only option for children with end stage liver disease. recent advances in surgical procedure and immunosuppression have permitted a better patient and long term graft survival. however, acute cellular rejection remains a frequent complication occuring in to % of the cases according to different studies. it is more likely to occur during the first weeks post lt. many predictive factors of acute rejection have been described in litterature and results differ from one study to another. pediatric studies regarding this topic are few. the aim of this work is to study acute cellular rejection prevalence in the days following lt and to determine predictive factors. rationale: sedation practices for pediatric magnetic resonance imaging (mri) are highly heterogenous. the main challenge is to keep children immobile while being alone in a traumatizing environment for a long time. clinicians have to ensure hemodynamic and respiratory stability in this isolated environment while minimizing sedation neurologic adverse effects. in this series, we report the potential usefulness, feasibility, efficacy and safety of dexmedetomidine sedation for pediatric mri. patients and methods: a single center retrospective review of six children sedated with dexmedetomidine for mri in an emergency context. all children were hospitalized in the pediatric intensive care unit of a university hospital at the time of mri. results: data on six patients aged months to years is reported. five patients received dexmedetomidine by intravenous route (bolus of - µg/kg over min, followed by a continuous infusion of µg/ kg/h). one child received dexmedetomidine by intranasal route ( µg/ kg with atomization device). one child experienced bradycardia that did not require any intervention. very few movements were recorded during the mris for which images were rated as good quality. conclusion: dexmedetomidine seems a promisingly useful sedation agent for pediatric mri, thanks to its efficient sedative properties and good tolerability without respiratory compromise. compliance with ethics regulations: yes. rationale: computational models, or virtual patients, could be used to teach cardiorespiratory physiology and ventilation, determine optimal ventilation management as well as forecast the effect of various ventilatory support strategies. currently, there is no virtual patient specifically designed for modelling children cardiorespiratory system. thus, our research team has developed a cardiorespiratory simulator for children called "simulresp©". according to summers et al., the quality of a physiologic model is evaluated by three specific criteria: qualitatively, which relates to the model's ability to provide directionally appropriate predictions; quantitatively in steady states and in dynamics, which is the ability of the model to provide accurate predictions in steady state situations as well as dynamic transitions. the purpose of this study was to evaluate the quality ofsimulresp© according to these criteria. this study consisted in a prospective evaluation of the simulresp©'s predictions with simulated healthy subjects. the tests were performed with patients from to years old ( , , , , , years), with different characteristics; gender (m, f) and weight ( th, th and th percentile). blood gas values (ph, pco , po and spo ) were simulated for several virtual healthy patients with different characteristics. this study was conducted for both spontaneously breathing and mechanically ventilated patients. simulresp©'s quality and reliability were evaluated in terms of accuracy, robustness, repeatability and reproducibility. results: simulresp©'s validation procedures are ongoing. we intend simulresp© to be accurate when simulating healthy spontaneously breathing patients. but we hypothezised that simulresp© would not be able to simulate accurate blood gas values of mechanically ventilated patients conclusion: simulresp© is a promising computational model that will serve to perform calibration and validation procedures of clinical decision support systems and help clinican to determine optimal respiratory support strategies at bedside. further calibration procedures are yet required. compliance with ethics regulations: yes. the isthmic surgical tracheostomy, which was performed in the operating room by otolaryngologist under general anesthesia. the cutaneous incision was transversal in all cases.the choice of the cannula was adapted to the age, and the decanulation was carried out according to the evolution of the underlying disease. complications associated with tracheotomy are diverse, and common complications are such as careassociated pneumonia ( . %), tracheostomy tube obstruction ( . %), accidental decannulation ( . %), pneumothorax ( . %) and cases of tracheal stenosis ( . %). the mortality rate amounted to . %, where in most cases was due to the poor prognosis of the underlying diseases. the main factors of evolution are the patient's previous condition, cranial trauma, guillain-barré syndrome, tracheostomy time, prolonged tracheal intubation and the presence of complications. conclusion: regardless of the indication, the tracheotomy is an act of survival whose usefulness and effectiveness are certain. rationale: aspiration pneumonia (ap) is a frequently suspected complication of drug overdose requiring mechanical ventilation (mv) and admission to intensive care unit (icu). in the absence of reliable biomarkers for distinguishing between aspiration pneumonia and aspiration pneumonitis, antibiotic therapy is frequently prescribed. latest studies suggest that a care protocol could better select patients requiring antibiotic therapy. the objective was to determine the impact of a care protocol on the antibiotic prescription among patient admitted to icu for toxic coma with mv. we conducted a prospective observational cohort study in four icu. we included all patients admitted for toxic coma with mv. in the university-affiliated icu, a care protocol was applied. in the three others icu, physicians declared that they did not follow formalized conduct within the service and did as usual. results: we included patients in care protocol group and in control group. the mean saps ii was . (± . ) with a mean glasgow coma scale score at . (± . ) before intubation. within the total population, patients ( %) had a pulmonary bacteriologic sample (pbs), mostly because purulent tracheobronchial aspirate and new infiltrates on the chest x-ray (respectively . % and . % of the population with a bacteriological sample). among the patients with a bacteriological sample, ( %) were culture positive. the incidence of probabilistic antibiotherapy did not differ between the care protocol group (n = ) and the control group (n = ) . there was no difference for the incidence of pbs ( in each group). the others secondary outcomes did not differ either (table ) . conclusion: our study does not show that a care protocol allows a reduction of antibiotic prescription among patient admitted to icu for toxic coma with mv. our incidence of antibiotic prescription is lower than the previous studies. the absence of difference can be explain by two reasons: some of the physicians of the control group had been trained in the university-affiliated icu in the last years and may follow a management approach similar to that of the control group; despite our precautions, the existence of the study could have modify the practices in the control group. compliance with ethics regulations: yes. rationale: pancreatic surgery is associated with high morbidity, mostly due to infectious complications, so that many centers introduce post-operative antibiotics for all patients. such systematic prescriptions are not consensual and often rely on local practices. the aims of the study were to describe the occurrence of surgical site infection (ssi) and the antibiotic (atb) prescription after pancreatic surgery, and to determine the risk factors of post-operative surgical site infection, in order to better define the clinical indications for the prescription of antibiotics after major pancreatic surgery. patients and methods: all patients undergoing a scheduled major pancreatic surgery from january to november were included in the study. patients were classified in four groups according to the occurrence of a surgical site infection and to the post-operative antibiotic prescription as follows (ssi+/atb+; ssi-/atb+; ssi+/atb-, ssi-/ atb-). in addition, risk factors (fever and pre-operative biliary prosthesis) associated with the occurrence of a surgical site infection and with the antibiotic prescription, were analyzed using a logistic regression model. results: data from patients ( pancreaticoduodenectomies and splenopancreatectomies) were analyzed and classified as presented in the table. thirty patients ( . %) experienced a surgical site infection and ( . %) received post-operative antibiotics. we did not find any difference on post-operative antibiotic prescriptions ( . % versus . %, p = . ) between patients who developed a surgical site infection and those who did not. amongst the patients who were not prescribed antibiotics post-operatively, ( . %) did not develop a surgical site infection while ( . %) did. in-icu mortality did not differ between infected and non-infected patients ( versus %, p = . ). post-operative fever was different between ssi+ and ssi-( . versus . %, p < . ), while the prevalence of pre-operative biliary prosthesis was similar ( . versus . %, p = . ). amongst patients who did not develop a surgical site infection, antibiotic prescription was not associated with fever (p = ), but associated with a higher prevalence of preoperative biliary prosthesis ( . versus . %, p = . ). conclusion: non-systematic antibiotic prescription after major pancreatic surgery allowed to appropriately spare antibiotics in ( %) patients at the cost of under prescription in ( . %) patients. these results suggest that systematic post-operative antibiotic prescription could be excessive. fever appears to be a relevant clinical sign for individual-based prescription, whereas the presence of a biliary prosthesis does not. compliance with ethics regulations: yes. ( , ) . however, there is little evidence to support those recommendations ( ) . we aimed to describe care paths of pm with sepsis in french hospitals and to assess outcomes depending on their hospital trajectory. we conducted a retrospective analysis of the french medico administrative (pmsi) database of consecutive patients with pm and sepsis admitted to french hospitals, between and . only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for organ failure or a procedure code for organ support. hospital trajectories were determined from the first admission to death or discharge, taking into account all potential transfers. costs and endpoints were determined at the end of patients' trajectories. five groups of patients were defined, according to care pathways: direct icu admission ( sticu); secondary icu admission, after initial admission to another unit including wards (ward ndicu) rationale: new-onset atrial fibrillation (af) is a common complication in patients with sepsis and is associated with increased mortality and morbidity rates. this condition results from a complex chain of events in response to infection, involving immunologic, humoral and cellular process and sympathetic overactivity. landiolol, the new injectable beta-blocker, with high beta selectivity and minimal impact on arterial blood pressure, may have beneficial effects in such a context. in this study, we aimed to investigate whether landiolol decrease the newonset of atrial fibrillation in a mice model of endotoxin-induced sepsis. patients and methods: thirty c bl/ male mice were randomly allocated to the following groups: sham (administration of µl of isotonic saline intraperitoneally-ip), septic (administration of µl of isotonic saline with mg/kg of lipopolysaccharide-lps-of e. coli o :b ip) and septic + landiolol (administration of isotonic saline with mg/kg of lps and, two hours later mg/kg of landiolol ip). four hours later, an attempt of af occurrence was triggered by a transesophageal electric pacing at fixed rate (as previously reported) in all mice previously anesthetized by isoflurane %. ekg was continuously recorded. results: ten mice per group (mean weight: ± g) have been included and analyzed. among the sham group the mean heart rate was at bpm versus bpm in the septic group. among the septic + landiolol group the mean heart rate was at bpm (p < , ). after transesophageal stimulation, none mice in the sham group had af, seven mice ( %) in the septic group had an af, and mice ( %) in the septic + landiolol group had an af. landiolol decreased the incidence of new-onset, sepsis-induced atrial fibrillation in mice (p = . ). conclusion: landiolol seems to have a protective effect against sepsis-induced af in mice. however, the mechanisms, including sympathetic activation and inflammasome pathways, should be investigated before drawn definitive conclusion regarding to efficiency of landiolol to prevent new-onset af during sepsis. compliance with ethics regulations: yes. - mg/l at or h, proportion of patients with a vancomycin serum concentration < mg/l, previously associated with resistance emergence and assessment of mortality and test of cure. results: a serum vancomycin concentration between - mg/l was reported in out of included patients ( %). a serum vancomycin concentration < ml/l and > mg/l were reported in patients ( %) and patients ( %), respectively. vancomycin serum concentrations during follow-up are shown in fig. . in multivariate regression analysis, a longer time between admission and initiation of vancomycin was the only parameter associated with a serum vancomycin out of this target, while acute kidney injury (aki) was associated with a lower incidence of subtherapeutic concentration. acute kidney injury rate was significantly higher in patients with a serum vancomycin concentration > mg/l. discussion: an adequate therapeutic target of serum vancomycin concentration was reached in % patients with nearly % < mg/l, which was similar to previous studies. aki and rrt requirement were higher in patients with serum vancomycin concentration > mg/l, whereas it is hardly to know whether it is a cause or a consequence. conclusion: these findings highlight the importance of a larger loading dose, vancomycin monitoring and measured creatinin clearance to improve vancomycin dosing protocol. compliance with ethics regulations: yes. rationale: suicide is a global phenomenon and one of the leading causes of death in the world. tunisia ranks second in the suicide rate in the maghreb, with . cases of suicide per , inhabitants. the aim of this study was to reconstruct the state of suicidal subjects before the act in order to identify their psychiatric profile. patients and methods: a -year prospective observational singlecenter ( -bed intensive care unit) study including all patients hospitalized for suicide attempt (sa). psychiatric evaluation of patients and contact with their families were done before intensive care unit discharge. results: seventy-one patients were enrolled with female predominance (sex ratio . ). mean age was ± years. familial or personal history of mental illness were found in ( %) and cases ( %) respectively. personal mental disorders were depression ( %), bipolar disorder ( %), schizophrenia ( %) and border line personality disorder ( %). twenty-five per cent had prior sa. sixty-three per cent were single, % married and % divorced. the common methods of suicide included drug ( %), chloralose ( %) and pesticide ( %) poisoning. mean igs ii and apache ii scores were ± and ± respectively. on admission, % of all patients were in coma, % had shock and % developed aspiration pneumonia. mechanically ventilation was done in % of all cases with mean duration of days. the mean length of stay in intensive care unit was days. mortality rate was %. psychiatric evaluation and contact with families deduced that the main precipitating factors for suicide were traumatic events. in fact: relationship problems (familial, marital or breakups), school failure and mourning were found in %, % and % of all cases respectively. reactional sa accounted for %. rationale: poisoning is a worldwide problem, associated with high morbidity and moratlity. in tunisia, the rate of fatal poisoning has been increasing in the last years, with emergence of new toxic substances. regardless of the toxic, fatal poisining is considered as a non natural death, that requires medico-legal investigation, to assess whether it is suicidial, crimnal or accidental death. this study aimes to determine the epidemiological characteristics of the cases of fatal poisoning in south, to identify the toxics used in oder to deduce the preventive measures. patients and methods: we conducted a retrospective study of all cases of fatal poisoning recorded in the forensic department of habib bourguiba university hospital in sfax, tunisia, over a -years period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . results: during the study period, cases of fatal poisoning were autopsied. the number of victims recorded per year varied between and cases with an average of cases per year. the average age was years with extrems ranging from months to years. nearly half ( . %) were younger than years. a male predominance was noted with a sex-ratio of . . the majority of victims were single, loweducated and from rural origin. personal antecedent of psychiatric pathology was found in . % of cases. psychotic disorders (schizophrenia) and depression were the most common pathologies. in our study we noticed that death occured every weekday without significant difference between days. however, the frequency of fatal poisoning was slightly higher in cold seassons ( . %). in . % of cases, victims were found dead at home. accidental fatal poisoning was the most common ( %). no criminal cases have been observed. we noted a male predominance in accidental forms and a female predominance in suicidal forms. carbon monoxide poisoning was the most common ( cases) followed by the organophosphorus poisoning which was noted in cases. conclusion: decreasing the mortality rate from poison ingestion requires increasing public awareness about poisons and improving emergency service equipment and health personnel training. compliance with ethics regulations: yes. severe acute poisoning by organophosphate pesticides: report of cases at the oran hospital and university center mourad goulmane hospital and university center of oran, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann.intensive care , (suppl ):p- rationale: organophosphate pesticides are synthetic organic pesticides widely used in agriculture mainly as an insecticide, nemacid or acaricide. these are the agricultural products, the most incriminated in poisoning in our context. the objective of this work was to determine the clinical, paraclinical, and progressive characteristics of this poisoning in a resuscitation environment. patients and methods: retrospective study of cases admitted to intensive care (january -december ). inclusion criteria were clinical, para-clinical, therapeutic and progressive. results: cases were identified: women and men, mean age = . ± years. the suicide attempt was the main reason for the intoxication ( cases). the glasgow coma score averaged ± . the central syndrome was present in % of our patients, followed by muscarinic syndrome % and nicotinic syndrome in % of cases. therapeutic management consisted of mechanical ventilation in % of cases, the use of vasoactive drugs in % of cases and the administration of antidotal treatment in % of cases. the overall mortality was . %. conclusion: organophosphate pesticides intoxication is a real health problem in algeria. it is a serious condition dominated by the respiratory and neurological distress that causes most deaths. it concerns in our context especially young women who ingest the product for the purpose of autolysis. the diagnosis is based on the clinical and dosage of cholinesterase activity in the plasma. treatment combines symptomatic measures that rely primarily on respiratory and neurological resuscitation to antidotal treatment. the clinical course in this type of intoxication is generally favorable under treatment with regression of signs in a few days. mortality is high in our context, so it should be considered a diagnostic and therapeutic emergency. the commercial availability of these products is worrisome, justifying the use of a broad prevention program to inform the public and authorities of the danger of organophosphate pesticides compliance with ethics regulations: not applicable. . the clinical examination revealed that five patients met the criteria for serious intoxication with the following signs: coma in four patients requiring the use of mechanical ventilation, seizures (n = ), rhabdomyolysis (n = ), shock (n = ), toxic takotsubo (n = ) and hepatocellular failure (n = ) leading to patient's death. the use of mechanical ventilation was necessary in patients. the analysis of the severity factors did not show a statistically significant association between severity, age (p = . ), sex (p = ) and chronic consumption of psychoactive substances (p = . ). on the other hand, we did not find a statistically significant association between serious intoxication, the number of tablets ingested (p = . ), the apacheii score (p = . ) and the average length of stay (p = . ). conclusion: ecstasy acute poisoning is becoming more common in our country and can potentially be very serious regardless of age, sex, medical history or number of tablets ingested. on the other hand, the concentration of nmda could be the only factor to be taken into consideration upon admission. compliance with ethics regulations: yes. quarter of early trauma-related mortality, in some series. early identification of poor outcome predictors could be valuable to guide the most appropriate care. we aim to determine factors associated to mortality in patients with severe non-penetrating chest trauma admitted to the icu. patients and methods: this is a prospective cohort study, including all patients with isolated severe blunt chest trauma (abbreviated injury scale ais > ) admitted to the intensive care unit of a university hospital, over a one-year period. the primary objective was to analyse risk factors associated to death and poor outcome using univariate and multivariate analysis. results: one hundred-thirty patients were admitted to the icu for blunt chest trauma among them were diagnosed with severe isolated chest trauma and were included. the mean age was at ± , mean iss at ± and mean tts at ± . twenty-eight ( %) patients were diagnosed with acute respiratory distress syndrome, ( %) with post-traumatic acute kidney injury and fourteen ( %) with post-traumatic pulmonary embolism. the mean length of icu stay (los) was at ± days and mean number of days on ventilator was at ± days. thirty-two ( %) patients underwent elective tracheostomy for prolonged intubation. thirty-seven patients ( %) developed infections, among them thirty ( %) were diagnosed with pulmonary infection and seven ( %) with non-thoracic infections. overall mortality had an incidence of . % ( patients rationale: early hyperglycaemia in traumatic brain injury (tbi) is a part of the stress response. it is an important indicator of severity and a reliable predictor of prognosis. we aimed to describe the epidemiological, clinical and paraclinical characteristics and to assess the prognostic impact of this hyperglycaemia on the tbi. we conducted a retrospective study in the intensive care unit (icu) of our hospital between and . were included all patients with tbi and blood glucose > mmol/l at the first h post-trauma. results: during the study period, patients were hospitalized in our icu with tbi. early hyperglycemia (> mmol / l) was found in patients ( . %). in univariate analysis, glycaemia > . mmol/l (= mg/dl) at admission was significantly associated with mortality (p = . ). we observed that glycaemia > . mmol/l at h , > . mmol/l at h , > . mmol/l at h and > . mmol/l at h was significantly associated with mortality (p = . ; p < . ; p = . and p = . , respectively). the risk factors significantly associated with mortality were age > years (p < . ), saps ii > (p < . ), initial shock (p < . ), glasgow coma scale (gcs) < / (p < . ), coma period > days (p = . ). the ct scan lesions statistically associated with mortality were: subdural hematoma (p < . ), cerebral oedema (p < . ), intra cerebral haemorrhage (p = . ), cortical contusion (p = . ), contusion of cerebral trunk (p = . ), contusion of the corpus callosum (p = . ), thalamus contusion (p = . ). in multivariate analysis, independent risk factors statistically associated with mortality were age > years old (or = . ic [ . - . ]; (p = . )), glycaemia > . mmol/l at admission (or = . ic [ . - . ]; (p = . )),gcs < / (or = . ic [ . - . ]; p < . ), intracerebral hematoma (or = . ic [ . - . ]; p = . ). we recommend a mandatory control of the blood glucose levels during a tbi with a target between . and . mmol/l in the acute phase. compliance with ethics regulations: not applicable. the fat embolism syndrome (fes) is a set of clinical, biological and radiological signs resulting in the obstruction of microcirculation by micro-droplets of insoluble fats.the clinical signs of the fes are not very specific, the diagnosis is difficult and the risk of misunderstanding this syndrome is very real.the fes appears after a trauma, often few days later. however, it sometimes occurs without previous trauma; and it is particularly difficult to recognize in these cases. the aim of this work is to define the epidemiological profile, the clinical and para-clinical features of this syndrome and its therapeutic management. rationale: sedative and analgesic treatment administered to critically ill patients with mechanical ventilation need to beregularly assessed to ovoid complications of oversedation mainly in elderly patients. our objective is to evaluate our sedation practice in the elderlyin our unit patients and methods: it was a prospective observational study, including elderly patients over years of age without acute brain injury requiring sedation more than h of hospitalization in the intensive care unit of our university hospital between april and december . thirty patients were included. the aged was . years, the sex ratio was . . respiratory distress was the most common reason for hospitalization %. the most accepted diagnoses were the decompensation of copd in % of cases and septic shock in % of cases. the saps ii averaged ± points, sofa averaged ± . points. renal failure was found in patients ( %), hepatic impairment was noted in patients ( %), hypoproteinemia was marked in patients ( %). midazolam was used in % of patients. it was in combination with fentanyl in % of cases and remifentanyl in % of cases. the median ramsay score . ± . on the first day of sedation and . ± . on the second day of sedation. the median rass scale was − . ± . on the first day of sedation and − . ± . on the second day of sedation. the median bps scale . ± . on the first day of sedation and . ± . on the second day of sedation. the mean wake up time was ± , days. neuromyopathy of resuscitation was suspected in seven patients ( %), withdrawal syndrome was observed in two patients ( %) and acute cognitive dysfunction in two patients ( %). the median duration of sedation was . days ± . days, the median duration of mechanical ventilation was . ± . days, the median length of stay was . ± . days. ventilator-associated pneumonia was diagnosis among % of patients. the mortality in intensive care was %. conclusion: sedation analgesia in the elderly person should be adapted according to age, ideal weight and renal and hepatic function by decreasing the initial doses. it should be evaluated by the recommended scores by setting a sedation objective according to the pathology. compliance with ethics regulations: not applicable. rationale: more than original articles are newly indexed in pub-med every day. journal club (jc) is one way to cope with this abyssal amount of medical information. we aimed at ( ) describing journals and articles analyzed during our jc sessions ( ), reporting the proportion of published articles being analyzed during jc sessions and ( ) assessing the clinical impact on our daily practices for each journal. patients and methods: a retrospective analysis of prospectively collected data over a -year period from to in a universityaffiliated icu. jc sessions were scheduled weekly and participants were free to choose and expose orally an article recently published in any medical journal (general, icu or non-icu specialized). clinical impact of a journal was retrospectively and independently assessed by two attending intensivists (dc, hm) and was defined by the ratio of articles considered as having a direct impact on our daily practices over the number of articles of the same journal read during the same period. results: from august to august , jc sessions were held and articles-mostly original (n = / ; %)-from journals were analyzed, accounting for . % of the articles ( . % of the original articles) referenced in pubmed during the same period. median number of articles exposed per session was [ ] [ ] [ ] [ ] . median number of doctors attending each session was [ ] [ ] [ ] (attendings: [ ] [ ] , fellows: [ ] [ ] , residents: [ ] [ ] ). general, icu and non-icu specialized journals accounted for %, % and % of the exposed articles, respectively. most of the reported articles dealt with intensive care (n = , %) especially infectious diseases (n = / ; %), hemodynamics (n = / ; %) or icu-organization (n = / ; %). compared to general and non-icu specialized journals, the proportion of read-over-published articles was higher for icu-specialized journals ( . % vs. . % vs. . %, respectively; p < . ). among original articles, only ( . %) [interventional (n = / ; %); observational (n = / ; %) studies] were considered as having a clinical impact on our daily practices. compared to icu and non-icu specialized journals, general journals had a higher clinical impact ( . % vs. . % vs. . %, respectively; p = . ). data regarding the most read general, icu and non-icu specialized journals are detailed in table . in a french university-affiliated icu with regular jc sessions, the proportion of read-over-published articles and the clinical impact of medical journals appear minor. in the ocean of medical literature, general medical journals appear more worth reading by intensivists than icu-specialized journals. compliance with ethics regulations: yes. rationale: the world's population is aging and the and over's age group is growing fast (+ . % per year). this aging population is impacting intensive care units with exponential rates of elderly patients ( . % in , % in ) , associated with significant mortality (from % to %). the evolution and the prognostic factors of these elderly patients in intensive care are therefore a public health issue for optimal management. patients and methods: we included all patients aged and over who were operated and admitted to surgical resuscitation in our center, with a duration of stay greater than h, from april to july . the data collected were: general characteristics of this population, mortality in intensive care, at day and at months and the prognostic factors guiding their evolution in intensive care and at months. results: of the patients included in our study, mortality was . % in intensive care, . % at day and . % at months. the prognostic factors in the intensive care unit were the average dose of noradrenaline at day (threshold at . mg/h), the sofa score at day (threshold at points) and the igs score (threshold at points). the prognostic factors at months were ventilatory autonomy on day (spontaneous ventilation, non-invasive ventilation, invasive ventilation), the reason for admission to intensive care (acute respiratory distress or septic shock) and the fragility score (clinical failure scale with a threshold at ). conclusion: the mortality of patients aged and over is influenced by prognostic factors easily obtained daily at patient's bed. these prognostic factors could be an aid for the resuscitation teams to evaluate the relevance of the care undertaken in elderly or even very elderly patients admitted in an acute situation. compliance with ethics regulations: not applicable. assessing patient safety culture perception in the intensive care unit in tunisia oussama jaoued, chaoueh sabrina, sik ali habiba, wael chemli, gharbi rim, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: in tunisia health care system, patient safety has become a priority of quality assessment. the aim of our study was to describe the safety culture perception of the intensive care unit staff. patients and methods: the safety attitude questionnaire (saq-icu) was distributed to all intensive care unit staff by email. the questionnaire explores safety culture domains: "team work", "safety climate", "job satisfaction", "stress recognition", "perception of the hospital and intensive care unit management" and "work condition". results: eighty participants responded to the questionnaire, % of them were women. participants were doctors in . %. the coordination between physicians and nurses was very good only in %. thirtynine participants thought that the workload was high and % like their work. medical errors are handled appropriately in % of cases and it was difficult to discuss errors in % of cases. the hospital is a good place to work in % of participants, % of participants were less effective at work when there were tired. the hospital did a good effort of training new personal in % of cases. the number of medical staff was lower than expected in % of cases. half of participants would feel safe being treated as patients in their respective units. all domains explored by saq-icu could be improved according to attendants. conclusion: safety culture perception among intensive care unit staff had several deficiencies, mainly the working conditions, the ignorance of medical error reporting procedures and the lack of communication. rationale: the simplified acute physiology score ii (saps ii) is an icu scoring system used to predict the mortality risk in patients presenting at the icu. however the majority of critically ill patients present initially at the ed and their transfer to the icu may be delayed for hours. therefore, the ability to accurately assess mortality risk at ed may have a great impact. the purpose of this study was to evaluate the performance of saps ii in predicting early and late mortality in ed patients. patients and methods: this prospective study was conducted at the ed during a -month period. data for adult ed patients were evaluated. saps ii score was used to predict early and late mortality rates at -h and -day respectively. discrimination was evaluated by calculating the area under the receiver operating characteristic curve (auroc). results: during the study period patients were enrolled. the mean age was ± years, % of the patients were men. the mean saps ii was . the early mortality rate was % and late mortality rate was %. saps ii was efficient in predicting early mortality, with an auroc of . ( % ci . - . ). however, it demonstrated no value in predicting late mortality with an auroc of . ( % ci . - . ) conclusion: in this study, saps ii score was accurate in predicting early mortality, however this tool appears less suitable for predicting late mortality. compliance with ethics regulations: yes. oussama jaoued, chaoueh sabrina, sik ali habiba, yosri ben ali, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: the aging of the population increased the number of hospitalizations in icu. the aim of our study was to determine the impact of hospitalization of patients over the age of on morbi-mortality and consumption of care (omega score). patients and methods: this is a retrospective study carried out in the icu in the hospital of taher sfar in mahdia over a period of years. all patients hospitalized in the icu were included in this study. two groups of patients were individualized: g : patients over years old, g : patients under years old. results: during the study period, patients ( < years old and ≥ years old) with a mean age ± years and with a mean sapsii ± were included. the common reason for hospitalization was acute respiratory failure in % of cases. comparing the two groups, the severity score sapsii was higher among patients older than years ( ± vs ± , p < . ). the use of mechanical ventilation was more common in the first group ( % vs. %, p < . ). the incidence of nosocomial infections was similar in both groups ( % in the group g and % in group g , p = . ) and the use of renal replacement therapy was also similar in tow groups ( % in the g group and % in the g group, p = . ). the duration of mechanical ventilation and length of stay were similar between the two groups. workload evaluated by the omega score was higher in the first group ( rationale: icu outcome depends on quality of pre-icu care. we aimed to assess the chain of care of deteriorating ward patients (dwp), through evaluation of preadmission severity and delays before admission, and association with outcome. patients and methods: retrospective observational study in a single center ( beds general hospital) for year-may th of to . all adult patients admitted in the icu from the wards were included, except for scheduled surgery, or unexpected event in the operative theater. preadmission severity was assessed through levels of national early warning score (news ): group with news inferior to , group with news between and , and group with news superior to . these scores were established from vital signs during the h before icu admission. patterns of patients, including sofa and saps , knaus index, charlson comorbidity score, cause of admission and technics used in the icu, length of stay in the icu and in the hospital, limitations of life-supporting care, and mortality at and days after icu stay. satistical analysis was performed through chi and fisher tests on qualitative parameters, and with kruskal-wallis, student and mann-whitney tests for quantitave data. results: sixty-eight patients were studied: in group , in group and in group . most patients (all except ) had not respiratory rate monitoring before icu admission. icu mortality was associated with rising preadmission severity (group : . %; group : . %; group : . %). base patterns (charlson comorbidity score, knaus index) did not differ between the groups, and . % of patients presented with sepsis. main causes of admission were respiratory ( . %), hemodynamic ( %) or neurologic ( . %) failures. all patients admitted after cardiac arrest resuscitation ( patients) belonged to group . acute severity scores (sofa and saps ) followed preadmission severity. limitation or withdrawing of life support in the icu was higher in group ( . %) than in groups ( %) and ( . %) . median delay between first news equal or superior to and icu admission was h, and h between news equal or superior to . diffrences in delays were not associated with outcome. discussion: our study outlines weaknesses in the chain of care of dwp. emphasis should be put on respiratory rate monitoring and better assessment of severity. rationale: access to critical care is controversial in older patients for reasons: lack of available icu-beds and speculation on induced costs. in contrast, admission of young patients aged or under is infrequently questioned even though they develop catastrophic multiple-organ failure requiring full care. in addition, emotive reaction triggered in staff by these patients often represents a heavy psychological burden when icu-stay is < h. information on the epidemiology, clinical information and induced costs regarding such patients is lacking. patients and methods: this study retrospectively assessed the records of patients aged or under, and admitted from january to august . cost-related expenses charged to care-payers were obtained from our medical information department. data (number, percentages or medians) were reported and discussed by comparison with those of nonagenarians during the same period. results: of , icu-admissions, were aged or under ( %), of whom ( . %) died within the icu, with ( %) dying within h of admission despite full intensive care. the latter represent our study population ( . % of the screened population). the median age was . years , male gender was prevalent ( %). half the patients (n = , %) were referred from the emergency department, ( . %) from hematology, from oncology ( . %), from medical intermediate care units ( . %), and one from digestive surgery ( . %). the first diagnosis at admission was septic shock (n = , . %), followed by post-anoxic encephalopathy (n = , . %), coma (n = , . %), acute respiratory failure (n = , . %) and cardiogenic shock (n = , . %). sapsii was . all patients were ventilated and infused norepinephrine. two patients underwent ecmo, and others mars. mean (± sem) retribution per stay was , ± €, and mean retribution per "day of stay" €. discussion: full care of these icu-patients, with early mortality has a financial impact similar to that of nonagenarians at , ± , €; the cost per "day of stay" is therefore on average % higher than that of nonagerians (mean length of stay: . days), and, in our experience, % higher than that of average patients. conclusion: icu-patients aged or under represent a small percentage of admissions and display half our overall mortality: one third of them die within h of admission with a not insignificant financial impact for cost-payers. septic shock is the first cause of referral, followed by unexpected cardiac arrest. compliance with ethics regulations: yes. rationale: severity scores in patients with sepsis are useful for triaging and predicting mortality. mortality in emergency department sepsis (meds) score is validated in patients with sepsis in the emergency department. curb- is validated in patients with communityacquired pneumonia but not in sepsis. curb- is a simple bedside tool that has many common elements with new sepsis identification score-q sofa. the study aimed to assess the accuracy of curb- score in predicting icu admittance and mortality compared to meds score. patients and methods: this prospective study was conducted at the ed during a -month period. we enrolled all adult patients with sepsis admitted to the ed. meds and the curb- scores were calculated at admission. patients were studied using curb- score and their icu admission and in-hospital mortality were ascertained. results: a total of patients were enrolled. the mean age was ± years. % of the patients were men. % of patients had a curb- score ≥ points with a mean meds score of %. among these patients, % were admitted to icu and % died. the curb- score,was efficient in predicting both icu admittance and in-hospital mortality with an auroc of . ( % ci . - . ) and . ( % ci . - . ), respectively. conclusion: a higher curb- score was correlated with higher rates of icu admittance and mortality in patients with sepsis due to any cause. compliance with ethics regulations: yes. abderrahim achouri, hadil mhadhbi, khedija zaouche, hamida maghraoui, radhia boubaker, kamel majed university hospital center rabta of tunis, tunis, tunisia correspondence: abderrahim achouri (achouryabderrahim@gmail. com) ann. intensive care , (suppl ):p- rationale: sepsis is a major cause of mortality. in other hand, preexistent chronic diseases seem to worsen outcomes among critically ill patients. the acknowledgement of this fact may motivate studies in this type of situations in order to improve survival in sepsis. on that purpose, our study tried to check the impact of chronic pre-existent illnesses on outcomes in this type of emergency patients. patients and methods: we have included patients in whom the sepsis- definition was met throughout emergency department admission cases for infection. in this study, considered outcomes were in-hospital mortality, shock occurence and the use of mechanical ventilation. results: we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. cormorbidities were: insulin dependent diabetes mellitus in . % of patients, non insulin dependent diabetes mellitus in . %, chronic obstructive lung disease in . %, chronic renal failure in . % with % in chronic replacement therapy from total patients, coronary artery disease in . %, with stent in . % and . % with aortic coronary graft from total patients, arterial hypertension in %, chronic heart failure in . %, atrial fibrillation in . %,. death occurs in . % of total patients, septic shock in % and the use of mechanical ventilation in . %. we did not find any association between comorbidity and the use of mechanical ventilation, but association with in-hospital mortality was found in pre-existent coronary artery disease (p = . ) and in patients with coronary artery stent (p = . ). odds ratio (or) was respectively . ( % ic = [ . - . ]) and . ( % ic = [ . - . ] ). we found significant association between chronic heart failure and shock (p = . ) with or = . ( % ic = [ . - . ] ). discussion: the small size of our sample may enlimit the contibution of other comorbidities on outcomes in sepsis such chronic renal failure, especially with renal replacement therapy and diabetes mellitus. whereas, we can conclude that cardiac diseases have the most important impact on outcomes in sepsis. outcomes in sepsis can be affected by comorbidities, especially cardiac diseases. therefore, that needs large studies to check it. compliance with ethics regulations: yes. micafungin population pk analysis in critically ill patients receiving continuous veno-venous hemofiltration or continuous veno-venous hemodiafiltration nicolas garbez , litaty mbatchi , steven c. wallis , laurent muller , jeffrey lipman , jason a. roberts , jean-yves lefrant , claire roger chu nîmes, nîmes, france; university of queensland, brisbane, australia correspondence: nicolas garbez (nicolas.garbez@umontpellier.fr) ann. intensive care , (suppl ):p- rationale: to compare the population pharmacokinetics (pk) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (cvvh, ml/kg/h) to those receiving equidoses of hemodiafiltration (cvvhdf, ml/kg/h + ml/kg/h). critically ill patients in septic shock undergoing continuous renal replacement therapy (crrt) and receiving mg micafungin once daily were eligible for inclusion. total micafungin plasma concentrations were analyzed using pmetrics ® . probability of target attainment (pta) was calculated from monte carlo simulations using -hour area under curve/minimum inhibitory concentration (auc - /mic) cut-offs (c. parapsilosis), (all candida species) and (c. non parapsilosis). daily dosing regimens of , and mg were simulated for the first days of treatment. results: eight patients were included in the study. micafungin concentrations were best described by a two-compartmental pk model. no covariate, including crrt modality (cvvh and cvvhdf), was retained in the final model, confirmed by internal validation. the mean parameter estimates (standarddeviation) were . ( . ) l/h for clearance, . ( . ) l for the volume of the central compartment, . ( . ) /h and . ( . ) /h for rate constants. the standard mg daily dosing was unable to reach % of pta for all candida species except c. albicans on the second day of therapy (fig. ) . conclusion: there was no difference in micafungin pk between equidoses of cvvh and cvvhdf. a dose escalation to mg is suggested to achieve the pk/pd target of candida species with mics exceeding . mg/l in this population. these "off-label" dosing regimens should be further investigated in clinical trials knowing the favourable toxicity profile and the post-antifungal effect of micafungin in order to ensure efficacy and to prevent the emergence of resistance due to an inadequate initial antifungal dosing regimen. compliance with ethics regulations: yes. rationale: sepsis is an important cause of morbidity and mortality in hospitalized patients. recognizing and responding to patients who experience clinical deterioration remains challenging in daily practice. our purpose was to assess the ability of the quick sequential organ failure assessment (qsofa) score to identify, among patients reviewed by an intensivist, those at risk of adverse outcomes. patients and methods: retrospective cohort of patients with suspected infection reviewed by an intensivist in a university-affiliated hospital between january and june . outcomes of interest were hospital mortality and a combined criterion of hospital mortality or icu stay of days or more. results: during the study period, patients were reviewed by an intensivist, of whom ( . %) had suspected infection according to the sepsis- criteria. at the time of review, ( . %) patients with suspected infection were qsofa positive (≥ ) and ( . %) were qsofa negative ( - ). following the review, ( . %) patients were admitted to the icu, among whom ( . %) had a prolonged stay (≥ days). in-hospital mortality was . %, and . % of the patients met the combined criterion of in-hospital mortality or prolonged icu stay. qsofa positive patients required more frequently mechanical ventilation ( . % vs. . %, p = . ) and vasopressor support ( . % vs. . %, p < . ) than qsofa negative patients. moreover, qsofa positive patients had higher hospital mortality than qsofa negative patients ( . % vs. . %, p = . ). for the prediction of in-hospital mortality, a positive qsofa had a predictive positive value (ppv) of %, and a negative predictive value (npv) of %. for the prediction of in-hospital mortality or prolonged icu stay, a positive qsofa had a ppv of % and a npv of %. conclusion: hospitalized patients with suspected infection for whom a review by an intensivist was requested, are at high risk of hospital mortality. although the accuracy of qsofa for identifying patients at risk of adverse outcomes is limited, its integration in a multimodal risk assessment approach may help distinguish the subset of patients who will benefit from an escalation of care. compliance with ethicsregulations: yes. rationale: according to the sepsis- consensus, sepsis is identified as an increase of at least points in the sepsis-related organ failure assessment (sofa) score in patients who presented infection. the quick sofa or qsofa is considered as a predictive tool of sepsis and mortality when it is equal to points or more. systemic inflammatory response syndrome (sirs) criteria are of limited utility because of their low sensitivity. hyperlactatemia, as known is a determinant of tissue hypoperfusion. our objective was to evaluate the prognostic value of sofa > , sirs > , qsofa > and lactate level > mmol/l in infected patients. nine-month prospective cohort study. patients aged years or older who had a proven or suspected infection were included. sofa score, sris criteria, sofa q and lactate levels were determined within the first h of infection. the primary endpoint was hospital mortality at days. the predictive power of the studied parameters was determined using using the area under the receiver operating characteristic curve (auroc). results: a cohort of cases was studied with mean age at . years. bacterial pneumonia was the most common infection site ( %). in the first h of onset of infection the medians [iqr - ] of the sofa, sris, and sofa scores and lactate levels were respectively [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] , [ - ] and . [ . - . ] . the progression to severe septic status was observed in patients ( %) and norepinephrine was introduced in cases. median length of stay was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and mortality was %. overall, the accuracy in predicting mortality of the studied parameters was poor. an increase of sofa score by at least points had greater accuracy with auroc = . [ . - . ], sensitivity = % and specificity = %. conclusion: in infected patients, the sofa score had greater prognostic accuracy than the sirs criteria, the qsofa score or the lactate level. these results suggest that sirs, qsofa, and high lactate level may be useful in screening for sepsis, but this utility is limited in predicting mortality. compliance with ethics regulations: yes. rationale: quick sequential organ failure assessement (qsofa) has been validated for patients with presumed sepsis and others in general emergency department (ed) population. however, it has not been validated in specific subgroups of patients with a high mortality. the aim of this study is to evaluate the ability of qscore to predict prognosis in patients with decompensated liver cirrhosis. patients and methods: this is a retrospective study, conducted over a period of years from january to december . consecutive patients with decompensated cirrhosis, admitted in our department are included. data of all patients were collected and the qsofa score was calculated at admission. the main study endpoints were length of stay, complications and in-hospital mortality. results: a total of patients diagnosed with decompensated cirrhosis were enrolled. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome in % of cases, digestive haemorrhage ( % of cases), fevers ( % of cases), and hepatic encephalopathy was present in % of cases. the mean duration of stay was days ± . in-hospital mortality rate was % and mean score qsofa was . .the qsofa score was significantly correlated with length of stay (p = . ) and complications(p = . ) but not with in-hospital mortality (p = . ). conclusion: the qsofa score was not useful for predicting in hospital mortality in patients with decompensated liver cirrhosis but it was significantly correlated to the length of stay and complications. compliance with ethics regulations: yes. angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study clara vigneron , aldéric lécluse , thomas ronzière , sonia alamowitch , olivier fain , nicolas javaud médecine interne, centre de référence associé sur les angioedèmes à kinines (créak), hôpital saint-antoine, aphp, paris, france; neurologie, chu angers, angers, france; neurologie, chu pontchaillou, rennes, france; neurologie, hôpital saint-antoine, aphp, paris, france; urgences, centre de référence associé sur les angioedèmes à kinines (créak), hôpital louis mourier, aphp, colombes, france correspondence: clara vigneron (claravigneron@hotmail.fr) ann. intensive care , (suppl ):p- rationale: bradykinin-mediated angioedema is a complication associated with thrombolysis for acute ischemic stroke. risk factors are unknow and management is discussed. the aim of this study was to clarify risk factors associated with bradykinin-mediated angioedema after thrombolysis for acute ischemic stroke. patients and methods: in a case-control study conducted at a french reference center for bradykinin angioedema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angioedema, were compared to controls treated with thrombolysis treatment without angioedema. two matched control subjects were analyzed for each case. results: thrombolysis-related angioedema were matched to control subjects. the sites of attacks following thrombolysis for ischemic stroke mainly included tongue ( / , %) and lips ( / , %). the upper airways were involved in ( %) cases. three patients required mechanical ventilation. patients with bradykinin-mediated angioedema were more frequently women ( ( %) vs. ( %); p = . ), had higher frequency of prior ischemic stroke ( ( %) vs ( %); p = . ), hypertension ( ( %) vs. ( %); p = . ), were more frequently treated with angiotensinconverting enzyme inhibitor ( ( %) vs. ( %); p < . ) and were more frequently hospitalized in intensive care unit ( ( %) vs. ( %); p = . ). in multivariate analysis, factors associated with thrombolysisrelated angioedema were female sex (odds ratio [or], . ; % confident interval [ci], . - . ; p = . ) and treatment with angiotensin-converting enzyme inhibitors ([or], . ; % [ci], . - . ; p < . ). discussion: because of theretrospective case-control design and the lack of the total number of thrombolysis for ischemic stroke, the incidence of this complication could not be evaluated in our study. previous studies reported an incidence of . to . % of angioedema in patients treated with a thrombolytic therapy for acute ischemic stroke. our case-control study permits for the first time to analyse more cases to evaluate associated risk factors of this rare complication. conclusion: this case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykininangioedema associated with thrombolysis for ischemic stroke. compliance with ethics regulations: yes. rationale: patients with inflammatory bowel disease (ibd), frequently treated by immunosuppressive drugs, are more susceptible to be admitted to the intensive care unit (icu). however, outcome and predictive factors of mortality are little known. therefore, we aimed to assess the outcome and prognostic factors for critically ill ibd patients. patients and methods: we retrospectively studied data of consecutive ibd (i.e. crohn's disease and ulcerative colitis) patients admitted in icus between and . in-icu and one-year mortalities were estimated and predictive factors of in-icu mortality were identified by univariate and multivariate analysis. results: seventy-six patients (male: %, median age: . [ . - . ] years, charlson index: [ . - . ]) entered the study. ibd type was largely represented by crohn's disease ( . %) and its localization was mostly extensive: l ( . % of crohn's disease) or e ( % of ulcerative colitis) according to the montreal classification. twenty-seven patients ( . %) were treated with corticosteroids and ( %) with immunosuppressive therapy (azathioprine: . % and anti-tnfα: %). reasons for admission were shock/sepsis ( . %) and acute respiratory failure ( . %). icu diagnoses were infection ( %), ibd flare-up ( . %) or both ( . %), and pulmonary embolism ( . %). at admission, sofa score was [ . - . ] and . fifty-three patients ( . %) required mechanical ventilation, ( . %) vasoactive drugs, and ( . %) renal replacement therapy. twenty-three patients underwent emergency surgery ( . %) and six urgent endoscopic treatment ( . %). in-icu and one-year mortality rate were . % and . %, respectively. prognostic factors of in-icu mortality were sofa score (hr . , % ci [ . - . ], p < . ) and azathioprine treatment before icu admission (hr . , % ci [ . - . ], p < . ) (fig. ) . previous immunosuppressive treatment with anti-tnf did not alter the prognosis and even the type of ibd. conclusion: our study showed that more than % of ibd critically ill patients were discharged alive from the icu and a majority of them survived after one-year ( . %). we also found that sofa score and previous azathioprine immunosuppressive treatment worsened icu outcome. higher severity of the acute event affected short-term prognosis and should be taken into account for best icu triage and management. intensivists should pay particular attention to patients treated by azathioprine. compliance with ethics regulations: yes. fig. outcome of ibd patients admitted to the icu according to precious treatment with azathioprine status all aps patients with any new thrombotic manifestation(s) admitted to icus. results: one hundred and thirty-four patients (male/female ratio: . ; mean age at admission: . ± . years), who experienced caps episodes, required icu admission. the numbers of definite, probable or no-caps episodes (fig. ) , respectively, were: ( . %), ( . %) and ( . %). no histopathological proof of microvascular thrombosis was the most frequent reason for not being classified as definite caps. overall, / ( . %) episodes were fatal, with comparable rates for definite/probable caps and no caps ( % vs. . % respectively, p = . ). the kaplan-meier curve of estimated probability of survival showed no between-group survival difference (log-rank test p = . ). discussion: our results suggest that the caps criteria do not sufficiently encompass all the parameters responsible for thrombotic aps patients' disease severity in the icu. the absence of items referring to organ dysfunction/failure in the caps criteria probably limited their ability to predict mortality. albeit useful for the retrospective classification and comparison of patients, the caps criteria may be too stringent and not yet ready-to-use for the management of icu patients. for physicians outside expert aps centres, the absence of caps criteria could be misleading and lead to rejection of the diagnosis for near-caps patients, thereby preventing them from receiving the appropriate aggressive treatment they indeed require. we think that, when confronted with a critically-ill thrombotic aps patient, caps criteria should be interpreted with caution and should not be the only elements taken into account to decide the intensity of the therapeutic management. rationale: % of resuscitation patients develop anemia during their stay, it can worsen the prognosis, prolong the length of stay and lead to transfusions that can be the cause of complications. the objective of our work is to specify the incidence of anemia in our unit, its etiologies and its therapeutic management. patients and methods: we conducted a descriptive and analytical retrospective study within the surgical emergency resuscitation department of ibn rochd university hospital of casablanca, over a period of years from to . we included all anemic patients. statistical analysis was performed with spss statistics . p < . was considered significant. results: we included patients with an estimated incidence of %, the average age was years, the sex ratio h / f was . . % of admissions were for traumatic pathology and % postoperative digestive surgery. % had hypotension at admission and the mean temperature was . % .the onset of anemia and its depth were related to length of stay with . % of patients who were anemic beyond the th day of hospitalization with a hemoglobin level that became < . g / dl beyond the th day. % of the patients had a normochromic normocytic anemia becoming microcytic with the lengthening of the duration of stay. ferritinemia dosed in % of patients and was normal. % of our patients had exclusive parenteral nutrition while % had an enteral / parenteral combination. % were transfused in red blood cells (rbc) and % of patients were transfused more than once. % received between and rbc units. in patients who received transfusion episodes costing euros, the transfusion was inappropriate. the total cost of the transfusion was estimated at around , euros. % were supplemented with oral iron with an increase in hemoglobin in % of them. % of the patients came out of the intensive care unit with a hemoglobin level < g/dl/l. the mortality rate of our patients was % with as predictive factors in multivariate analysis, hyperthermia, coagulopathy, the transfusion appears as a factor of good prognosis. the prevention of blood spoliation and the fight against inflammation and nosocomial infection remain the pillars of the management of anemia in intensive care but in view of our results and the protective role of transfusion it would be interesting to see again the transfusion thresholds in our context. compliance with ethics regulations: yes. (fig. ). discussion: we described a series of patients with severe acute viral myopericarditises associated with anti-rnapol autoantibodies, an association that has never been reported previously. the fortuitous association of these autoantibodies with acute myopericarditis is highly unlikely. acute myocarditis is a very rare disease with a reported incidence of / , inhabitants. anti-rnapol -antibody detection is also very rare: . % positive tests (including the patients in this series) out of samples during a -year period in our immunology laboratory. this % proportion of patients with proven influenza-virus infections suggest that such severe infections could trigger anti-rnapol autoantibody production. however, influenza is a common disease and anti-rnapol autoantibodies are very rare. furthermore, no anti-rnapol autoantibodies were detected in the patients with severe influenza-related ards. last, anti-rnapol autoantibodies remained detectable several months after the viral infection had been cured. conclusion: this previously unknown association between severe acute viral myopericarditis and anti-rnapol autoantibodies is probably not fortuitous. anti-rnapol antibody detection in acute myopericarditis patients could imply individual susceptibility to severe viral infection. further studies are needed to investigate the pathophysiological mechanisms involved in this entity and potential specific therapeutic strategies. fig. relative frequencies of digestive manifestations in critically ill tma patients rationale: arrhythmia-induced cardiomyopathy has been recognized for several decades, but most severe forms, i.e. cardiogenic shock and refractory cardiogenic shock requiring mechanical circulatory support, were rarely described in adults. in this retrospective study, we described patients admitted in our tertiary care center for non-ischemic acute cardiac dysfunction (or worsening of previously known cardiac dysfunction) and recent onset supraventricular arrhythmia who developed cardiogenic shock requiring veno-arterial ecmo (va-ecmo). results: in a years period, patients had va-ecmo for acute non ischemic cardiac dysfunction and recent onset supraventricular arrhythmia (table ). fourteen ( %) patients had known nonischemic cardiomyopathy and ( %) known paroxystic atrial fibrillation. cardiogenic shock was the first manifestation of the disease in patients. atrial fibrillation was the main cause of arrythmia ( % of cases). at ecmo implantation, sofa score was [ - ], inotropic score , lvef % [ - ] and lactate level was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mmol/l. twelve patients had sustained successful reduction after amiodarone and/or electric shock, all were weaned from ecmo and survived without transplantation nor long term assist device. among the patients with failure of reduction, underwent an atrio-ventricular ablation while on ecmo and had atrial tachycardia ablation; all were weaned from ecmo and survived. among the remaining patients without reduction and without ablation procedure, only the patients who were bridged to heart transplantation or left ventricular assist device survived. in univariate analysis, factors associated with unfavorable outcome were previously known heart disease, heart rate, renal replacement therapy, nt-probnp level, failure of rhythm reduction after amiodarone load and/or electric shock. among the patients who recovered and survived ( with successful reduction and with successful ablation), lvef increased from [ - ]% before ecmo implantation to [ - ]% at long term follow-up. discussion: this is the largest cohort of arrhythmia induced cardiomyopathies on va-ecmo and the first description of atrio-ventricular node ablation with favorable outcome in this setting. conclusion: arrhythmia induced cardiomyopathy is probably underrecognized and should be considered in any patient with nonischemic acute cardiac dysfunction and recent onset supraventricular arrhythmia. recovery is possible in the most severely ill patients on va-ecmo, even with severe left ventricular dilation. aggressive rate control by av-node ablation may be warranted in case of failure of reduction, and may allow recovery and favorable outcome. compliance with ethics regulations: yes. rationale: diagnosis of sepsis is a major challenge in intensive care units and is associated with a high morbidity and mortality. sepsis identification is even more difficult in patients with extracorporeal membrane oxygenation (ecmo) because of many confounding factors. the primary objective was to study the ability of c-reactive protein (crp) and procalcitonin (pct) values measured at ecmo support initiation (day ) to predict the occurrence of early sepsis in patients undergoing venoarterial ecmo (va-ecmo) or venovenous ecmo (vv-ecmo). the secondary objectives were to study the association between these biomarkers and mortality rate during ecmo support and in-hospital mortality rate. furthermore, we investigated the relationship between early sepsis and mortality. patients and methods: we performed a retrospective, monocentric study in the cardiovascular intensive care unit of the university hospitals of lille, france. between november , and december , , we included patients over years old, who underwent an ecmo support for a medical or surgical indication, and for whom biomarkers (crp and pct) levels were available for at least the first days of admission. biomarkers and blood cultures were daily assessed for the first ecmo support days. early sepsis was defined by sepsis diagnosis in the first days after circulatory assistance initiation. in-hospital mortality rate was censored at days. after univariate analysis, a cox multivariate regression model was used to assess if the association between biomarkers levels and early sepsis or mortality rate was independent. a kaplan-meier survival plot was used to describe the association between early sepsis and mortality. results: among patients included, underwent va-ecmo and underwent vv-ecmo. an early sepsis diagnosis was made in . % of va-ecmo patients and in % of vv-ecmo patients. pct and crp levels on day were significantly associated with early sepsis diagnosis (fig. rationale: fluids are one of the most prescribed drug in intensive care, particularly among patient with circulatory failure. yet, very little is known about their pharmacodynamic properties and this topic has been left largely unexplored. several factors may impact the haemodynamic efficacy of fluids among which the infusion rate. the aim of this study was to investigate the influence of the rate of fluid administration on the fluid pharmacodynamics, in particular by studying mean systemic pressure (pms). we conducted a prospective observational study in patients with septic shock to compare two volume expansion strategies. a fluid bolus, ml of normal saline were administered and several haemodynamic variables were recorded continuously: cardiac output (co), arterial pressure (ap), mean systemic pressure (pms, estimated from ci, pvc and map). infusion rate was left at the discretion of the attending physician. a "slow" and a "fast" groups were determined based on the median of the infusion duration. fluids effect was measured by the area under the curve (auc), maximal effect (emax) and time to maximal effect (tmax) for each haemodynamic variable. the effects of fluid on psm disappeared in one hour on average. compared to patients of the "slow" group, those of the "fast" group had a shorter tmax and a higher emax for pms (p = . and . respectively). the auc for pms was identical between group, while in case of similar effect of infusion rates, it should be larger in the "slow" group. regarding co, tmax was also shorter in the "fast" than in the "slow" group (p = . ). the decreasing slope from maximal effect was comparable between groups, for pms as for co. the effect of a ml fluid bolus with normal saline in septic shock patients vanished within one hour. a faster infusion rate increased the maximal and total effect of the fluid bolus and shortened the delay to reach the maximal effect. rationale: significant hypotension following spinal anesthesia is a common issue in everyday clinical practice. toavoid this potentially harming situation, an empirical fluid administration is usually performed before the procedure. inferior vena cava (ivc) ultrasound has been demonstrated effective in guiding fluid therapy in critical care patients. the purpose of this study was to evaluate the ivc ultrasound guided volemic status optimization in order to decrease post-spinal hypotension rate. patients and methods: in this prospective, controlled, randomised study, consecutive patients were recruited and patients were randomly assigned to a control group, consisting of pre-anesthesia empirical fluid administration (itt), an ivc ultrasound group in which fluid management was based on an ivc ultrasound evaluation, and a passive leg raising test (plrt) group in which volume optimization was performed following the above mentioned test. primary outcome was the hypotension rate reduction after spinal anaesthesia following fluid optimization therapy between the groups. secondary outcomes were the total fluid amount administered, the total vasoactive drug amount used and the time needed to realize the whole anaesthetic procedure in all three groups. results: % reduction in hypotension rate ( % ci - %, p = . ) was observed between the echocardiography group and the control group, and there was a reduction of hypotension rate by % (ci % - %, p = . ) between the echocardiography group and the plrt group. the total fluid amount administered was significantly greater in the ultrasound group than in the control group ( ml; sd ml, versus ml; sd ml, p = . ). the total amine consumption was % in control group, % in ivc group and % in plrt group. an increased of total study time was observed for the echocardiography group min (sd min) in comparison with the control group min (sd min) and ptlr group min (sd min), (p < . ). the study showed a faint but positive trend toward the use of ivc-ultrasound to identify patients in spontaneous breathing needing fluid optimization before spinal anesthesia compliance with ethics regulations: yes. rationale: we performed a systematic review and a meta-analysis of studies investigating the ability of the end-expiratory occlusion (eexpo) test to predict preload responsiveness, through the changes in cardiac output (co) or its surrogates, in adult patients. this meta-analysis was prospectively registered on prospero (crd- ). we screened pubmed, embase and cochrane database to identify all original articles published between and evaluating the ability of the eexpo test to predict a significant increase in co or surrogate, compared to the one induced by a subsequent volume expansion or by passive leg raising (plr). the meta-analysis determined the pooled area under the receiver operating characteristics curve (auroc) of eexpo testinduced changes in co to detect preload responsiveness, as well as pooled sensitivity and specificity and the best diagnostic threshold. subgroup analysis and sensitivity analysis were planned to investigate potential sources of heterogeneity. results: thirteen studies ( patients) were identified and included in the analysis. nine studies were performed in the intensive care unit and four in the operating room. preload responsiveness was defined according to co changes induced by fluid administration in studies (fluid-induced increase in co ≥ % or ≥ %) and according to co changes induced by plr in one study. the duration of the respiratory hold ranged between and s. for the eexpo test-induced changes in co, the pooled sensitivity and specificity were [ - ]% and [ - ]%, respectively, while the pooled auroc curve was . ± . (fig. ) . the corresponding best diagnostic threshold was . ± . %. when changes in co were monitored through pulse contour analysis compared to other methods the accuracy of the test was significantly higher ( ( ). continuing (decrease to % of peak level) or modification (decrease < %) of antibiotic therapy was guided by a serum pct assay from the third day of treatmentand every h until antibiotic was stopped. this last was stopped when pct levels had decreased of % from the initial value. results: a total of patients had been diagnosed as sepsis (n = , %) and septic shoc (n = , %). mean age was years ± . an average ubs and absi score of % and . the average length of stay in icu was days. patients were assigned into two groups: group a (favorable evolution, n = ); group b (unfavorable evolution, n = ). the therapeutic attitude according to the kinetics of the pct are presented in the table . we found a significant difference between patients with unfavorable evolution compared to those with a favorable evolution (in whom we stopped antibiotics) (p < . ), in terms of hemodynamic state, pct concentration and renal clearance. pctguided antibiotic treatment has been proven to significantly reduce length of antibiotic therapy in our patients. the average duration of antibiotic was . ± days. conclusion: pct measurement may help with the decision to initiate antibiotic therapy in low risk acuity of infection and allows more judicious antibiotic use by reducing antibiotic exposure. compliance with ethics regulations: not applicable. rationale: reducing the risk of severe hypoxemia during endotracheal-intubation (eti) is a major concern in intensive care unit but little attention was paid to co variations during this period. we conducted a prospective observational study to describe transcutaneous co (ptcco ) throughout intubation in patients who received preoxygenation with standardoxygen therapy (sot), non-invasive ventilation (niv), or high flow nasal cannula oxygen therapy (hfncot). patients and methods: patients over years undergoing eti in icu were continuously monitored for ptcco during intubation and the following h under mechanical ventilation (mv). haemodynamics and respiratory parameters were also recorded as well as arterial partial pressure of co (paco ) to evaluate reliability of the transcutaneous measure. results: two hundred and two patients were included in the study. we found a strong correlation between ptcco recorded at preoxygenation and the last paco available before intubation (r = . , p < . ). in % of patients ptcco values recorded at initiation of mv were out of - mmhg ranges. ptcco recorded at eti, at initiation of mv, min and h of mv were significantly higher than ptcco during preoxygenation (p < . by anova). variations of ptcco were significantly different according to the preoxygenation method (p < . for interaction in anova). lastly, a decrease in ptcco higher than mmhg within half an hour after the beginning of mv was independently associated with postintubation hypotension (pih) (odds ratio = . , % confident interval . - . , p = . ). conclusion: ptcco is a valuable tool to record paco variation in patients requiring invasive mechanical ventilation and could be useful to prevent pih. compliance with ethics regulations: yes. rationale: intubation in intensive care unit (icu) is a critical procedure which leads to serious adverse event in to % of cases. several recent trials were conducted to help physicians to choose medications, devices and modality of intubation. especially, videolaryngoscope (vl) led to several publications in the last few years, with increasing tools marketed and spread use (difficult airway management, routineintubation). we designed an online survey to take a picture of intubation process and devices availability in france. toolbox. it was positioned as a first line laryngoscope for every intubation in critically ill patients to reinforce the vl skill training. present study was performed using prospectively collected data from a continuous quality improvement database about airway management in a -beds french teaching hospital medical icu. all consecutive intubation procedure performed with vl from september to june were included. "first attempt success" group and "first attempt failure" group were compared by univariate and multivariate analysis in order to analyze the first attempt intubation success rate according to the level of operators' expertise, identify factors associated with first pass intubation failure and describe the intubation related complications. results: we enrolled consecutive endotracheal intubations. overall first attempt success rate was ( %). comorbidities, junior operator, the presence of cardiac arrest and coma were associated with a lower first attempt success rate. the first attempt success rate was less than % in novice operators ( - previous experiences with vl, independently of airway expertise with direct laryngoscopies) and % in expert operators (greater than previous experiences with vl) (fig. rationale: tracheostomy in intensive care unit (icu) has many advantages. but only patient comfort and shorter icu and hospital stay were demonstrated. the timing of this procedure is still debated. the aim of this study was to determine the impact of early tracheostomy on prognosis. we performed a retrospective study in a medical icu ( beds unit) from january to november . the technique of tracheostomy was exclusively surgical in the operating room made by the surgeon. the primary endpoint was mortality in icu. the secondary outcomes were post-tracheostomy incidence of ventilator acquired pneumonia, duration of mechanical ventilation and length of stay in icu. these criteria were assessed in relation to timing of the tracheostomy defined as early when performed before day of mechanical ventilation. results: forty-two patients were enrolled during the study period. mean age of patients was ± years. median length of stay in icu was of days. mortality rate was of %. comparing the two groups, early vs late tracheostomy, no difference was found with respect to mortality ( % vs. %, p = . ), vap occurrence ( % vs. %, p = . ), post-tracheostomy duration of mechanical ventilation ( ± d vs. ± d, p = . ), or length of stay in icu ( ± d vs. ± d, p = . ). in multivariate analysis, the only factor independently related to mortality was the sofa score patient on tracheostomy day with p = . and or = . (ci % [ . - . ] ). conclusion: tracheostomy in the intensive care unit remains a justified alternative despite the discordant data in the literature. in our study, the delay of the procedure didn't interfere with the evolution. however, the patient severity as attested by sofa score at the day of tracheostomy, was the only independent prognostic factor. those results should be confirmed by other large prospective studies. compliance with ethics regulations: not applicable. sabah benhamza, mohamed lazraq, youssef miloudi, abdelhak bensaid, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: many unknowns remain as to the place of tracheostomy in intensive care. reluctance to perform a tracheotomy is numerous, especially when pre-exists chronic respiratory failure, but some data suggest benefits. we report in this work our experience in tracheotomy in the intensive care unit of the august hospital, casablanca. patients and methods: this is a retrospective descreptive study over years (january to january ) including all patients that have been tracheostomized in the intensive care unit of the august hospital . results: during the study period, patients were tracheostomized with a prevalence of . % in years, the predominance was male (sex ratio . ). the average age was ± years old. the indication for tracheostomy was prolonged ventilation in % of cases, extubation failure in % of cases, and intubation failure in % of cases. tracheostomy was performed on average on the th day of intubation. all patients were tracheostomized in the operating room by ent surgeons. the main complications attributable to tracheotomy were hemorrhage of the tracheostomy orifice in patients ( %) immediately resumed, cases of subcutaneous emphysema ( %), case of pneumothorax ( %), cases of orifice infection ( %). no patient died of a tracheostomy related cause. the tracheotomy in intensive care is still a subject of debate especially concerning the time of its realization. however it seems to reduce the duration of mechanical ventilation, facilitates the care and also the ventilatory weaning. compliance with ethics regulations: yes. rationale: hfnco is a frequently used device providing heated and humidified high flow oxygen with several advantages: decreased work of breathing, decreased dead space, increased end expiratory lung volume (eelv), more stable fio . the increase in eelv is relying of the positive expiratory effect generated by the device. the level of generated pep seems however to largely depend on whether the mouth is open or not. this study was aimed to assess the impact of mouth opening on eelv increase induced by hfnco using electric impedance tomography. patients and methods: the following hfnco trial was proposed to healthy subjects who used hfnco on a regular basis for patients care. oxygen flow was set successively during min periods at , and l/min (optiflowtm; fisher & paykel healthcare, auckland, nz). these three conditions were tested in semi recumbent and supine position chosen at random. measurement started in supine position with no flow (baseline) and each period was separated from the following by a wash out period on min during which the subject could breath normally with no supplemental oxygen. electric impedance tomography (pulmovista ® , dräger medical gmbh, lündbeck, germany) was performed applying a electrodes belt placed between the th and th intercostal space, including a reference electrode located on the abdomen. as no spirometer was used, the data of eelv computed on the eit device were expressed as percentage of variation of the value measured in supine or semi recumbent position with no flow. demographic data were expressed as median and extreme values. comparisons were performed using u mann whitney test. [ . - . ] accepted to participate to the study. when subjects received hfnco with open mouth (whatever position) no modification of eelv was observed (table ) . conversely, a significant increase in eelv was noted with closed mouth, whatever position. in the semi recumbent position the increase in eelv was even more important with l/min. conclusion: electrical impedance tomography illustrates the impact of mouth closure on eelv increase among healthy subjects receiving hfnco. compliance with ethics regulations: yes. rationale: in stable copd patients, nasal high flow oxygen (nhf) use can be associated with reduction in respiratory rate (rr) and minute ventilation (mv). in thesepatients, paco remains stable or decreases under nhf. this suggests a possible dead space reduction related to a washout effect of nhf. the aim of this study was to assess the physiological effects of nhf in hypercapnic patients with acute copd exacerbation. patients and methods: crossover study in hypercapnic patients suffering from acute copd exacerbation and treated with intermittent non-invasive ventilation (niv). nhf l/min or standard oxygenotherapy (stand o ) were randomly administered during h between niv treatments. rr, tidal volumes (vt), mv and corrected mv (cormv = mv x paco / ) variations were recorded during the last min of each study period using a respiratory inductive plethysmography vest. blood gas analysis was performed at the end of each oxygen administration period. visual analogic dyspnea score (vas) quoted from to was assessed by the patient after and min. results given as median [iqr] . wilcoxon tests were used to compare data between stand o and nhf. results: twelve patients were included and data could be recorded in ( (fig. ). dyspnea scores were not different between the modalities. conclusion: in case of acute copd exacerbation, using nhf between niv treatments was associated with paco and rr decrease. mv concomitantly decreased suggesting a deadspace volume reduction related to a washout effect of nhf. corrected mv decreased in all the patients except one. these results suggest that nhf could be used to deliver oxygen between niv treatments to copd patients suffering from acute exacerbation and could contribute reducing paco . compliance with ethics regulations: yes. rationale: the role of atypical micro-organisms in acute exacerbation of chronic obstructive pulmonary disease (copd) that require mechanical ventilation is poorly none. the aim of this study was to determine the role of atypical pathogens in severe acute exacerbation of copd. patients and methods: in this prospective study we included all patients admitted for acute exacerbation of copd requiring mechanical ventilation. atypical pathogens (chlamydophila pneumoniae and mycoplasma pneumoniae) were searched by serological diagnosis and by culture of sputum samples. in this study we included patients aged ± years. sixty-eight percent of sputum culture were considered significant. six cultures were positive with different microorganisms. neither chlamydophila pneumoniae nor mycoplasma pneumoniae were found. the prevalence of chlamydophila pneumoniae was . % (positive igg serum). the demographic characteristics was similar between patients with and without positive culture. the rate of noninvasive ventilation (niv) failure was % in positive serology group versus % in negative serology group (p = . ). the mortality was similar in both groups. in multivariate logistic regression analysis only positive serology (or = . ; % ic [ . - . ], p = . ) was an independent factor of niv failure. conclusion: a positive serology of chlamydophila pneumoniae was a predictive factor of niv failure without an impact on the morbidity and mortality of copd patient treated with mechanical ventilation. compliance with ethics regulations: yes. rationale: emergency departments (ed) receive a growing up number of patients with acute exacerbation of chronic obstructive pulmonary disease (copd) .non-invasive ventilation (niv) could be a good alternative to achieve a respiratory support, avoiding as much as possible the complications of invasive ventilation. the study aimed to assess the clinical outcomes of using niv in acute exacerbation of copd at ed and to identify whether clinical variables present at admission are predictive of niv failure. we conducted a prospective study conducted at the ed over a period of one year. data of all patients admitted for acute exacerbation of copd for all causes and requiring non-invasive ventilation were collected. niv failure was defined as need for endotracheal intubation or death. results: during the study period, a total of patients with a mean age of years (± ) were included. acute exacerbation of copd was due to bronchitis in %, to pneumonia in % of cases. % of patients had no apparent etiology of acute exacerbation of copd. bilevel positive airway pressure was performed on all patients, during a mean period of h (± ). clinical niv success was observed in patients ( %). the predictors of niv failure were advanced age, tachycardia, and hypercapnia. conclusion: the efficiency of niv in the management of acute exacerbations of copd at ed is well documented. this is further supported by our study which showed a clinical success in % of patients with acute exacerbation of copd. compliance with ethics regulations: yes. rationale: non invasive ventilation (niv) is often performed in elderly patients with acute respiratory failure (arf) at emergency department (ed). this technique may be subject to many difficulties, due to the presence of frequent co-morbidities. the aim of this study was to identify the predictive factors of niv failure in elderly patients with arf at ed. patients and methods: this was a retrospective study conducted at ed on year and months including patients aged more than years and who required the use of niv for an arf. all data were collected and analyzed using the spss software. patients were divided into two groups: niv failure and niv success. niv failure was defined by inhospital mortality, requirement of intubation or hospitalization at intensive care unit. results: during the study period, a total of elderly patients that required niv for arf were included. median age was years (min = , max = ) and sex ratio was . . the median charlson index was (min = , max = ). the etiological diagnoses of arf were acute decompensation of chronic obstructive pulmonary disease ( %), acute heart failure ( %), pneumonia ( %) and pulmonary embolism ( %). the arf was hypercapnic in % of cases and nonhypercapnic in %. niv failure concerned %. predictive factors of niv failure were clinical signs of right heart dysfunction (p < . ), c reactive protein (p = . ), initial ph (p = . ) and kidney dysfunction (p < . ). conclusion: in our study, niv failure in elderly patients with arf at ed was influenced by clinical signs of right heart dysfunction, c reactive protein, initial ph and kidney dysfunction. these clinical and biological factors could be useful to identify the most critical elderly patients and to better guide therapeutic decisions. compliance with ethics regulations: yes. rationale: the interest of ecco r in the management of very severe acute asthma exacerbations is still unclear. since it could help to control respiratory acidosis and /or to limit dynamic hyperinflation, its clinical benefits are uncertain, even in mechanically ventilated patients. the rexecor observatory is a prospective ecco r cohort in the great paris area. tencases of severe asthma treated by ecco r were retrospectively reviewed. mainly, arterial blood gases (abg), duration of ecco r and imv were collected and in-icu mortality were assessed. data are reported as median (iqr). results: ten patients ( men, age: (ic: - ) years, bmi: . (ic: . - . ) kg/m , fev- : . (ic: . - . ) l, ( (ic: - ) %), saps : . (ic: . - . ) points) were included. one patient suffered from cardiac arrest before admission and one had pneumothorax at icu admission. nine patients were under imv (started on the day of admission for ). before ecco r, patients received systemic corticosteroids, paralyzing agents, epinephrine and salbutamol. two patients suffered from pneumonia. ecco r was started (ic: - . ) days after intubation. venous vascular access was achieved via the right internal jugular route in patients and via the femoral route in . the hemolung device was used in patients, the ila activve in and the prismalung in . abg before and after day of ecco r are reported in table . duration of ecco r was (ic: . - ) days and patients were weaned from imv under ecco r. for the remaining patients, duration of imv after ecco r was (ic: - . ) days. icu stay was . (ic: - . ) days. the only one niv patient was not intubated. ecco r as stopped in patients because of complications (one hemolysis, one internal bleeding and one membrane clotting). one patient died in icu after limitation of life-sustaining therapy decision. we report a preferential use of ecco r in imv patients, contrasting with a marginal use in only one niv patient to prevent intubation. the mortality rate was low, in line with previous case series of severe acute asthma with ecmo or ecco r support. more studies are needed ( ) to better delineate the pathophysiological benefits of ecco r in asthma patients and ( ) to confirm strong clinical benefits. compliance with ethics regulations: not applicable. rationale: acute exacerbations of chronic obstructive pulmonary disease (aecopd) are the most important events characterizing respiratory illness progression. their management often needs noninvasive or invasive ventilation (iv). data of literature confirm that the mortality of aecopd requiring iv is high but are discordant about prognostic factors. the aim of our study was to describe the epidemiologic and clinical features of patients admitted for aecopd requiring iv, the treatment and the evolution in intensive care unit in order to deduce the independent factors of mortality. patients and methods: a -year retrospective analytic observational single-center study including patients hospitalized for aecopd requiring iv. results: fifty-eight patients were enrolled. mean age was ± years with sex-ratio of . . eighty one percent were smokers and % were classified gold stage . history of intensive care hospitalization and prior iv were found in % and % of all cases respectively. mean apache ii score was ± . the predominant precipitating factor for aecopd was respiratory tract infection ( % of all cases). twenty two percent of all patients presented septic shock. iv was initiated on admission in % of all cases and after noninvasive ventilation failure in % of all cases. forty-eight per cent of all patients developed septic shock as evolutionary complication. mortality rate was %. in univariate analysis: male gender (p = . ), duration of respiratory disease progression (p = . ), annual exacerbations frequency (p < − ), gold stage (p = . ), prior iv (p < − ), duration of symptoms before hospitalization (p = . ), apache ii score (p = . ), ph (p = . ), shock on admission (p = . ) and septic shock as evolutionary complication (p = . ) were predictors of mortality in our study. besides; shock on admission (p = . ) and as evolutionary complication (p = . ) were the two independent prognostic factors in multivariate analysis. conclusion: vital and functional prognosis of aecopd requiring iv depends on the severity of the underlying respiratory illness, the severity of the exacerbation and the quality of an early management. this emphasizes the importance of controlling modifiable risk factors including smoking cessation, basic treatment improvement and early appropriate treatment of these exacerbations. compliance with ethics regulations: yes. medical background, biological parameters, death-rate and outcome of patients have been compared. results: in total, patients have been included in the "hlh" population. death-rate in intensive care unit was % in the "hlh" group compared to % in the "not hlh" group (p = . ). we used more extrarenal cleansing in the "hlh" group ( % vs. %, p < . ), the duration of assisted ventilation was longer ( . days vs. . days, p < . ), as well as the duration of extrarenal cleansing ( . days vs. . days, p < . ) and those of amines ( . days vs. . days, p = . ). the average time of hospitalization was significantly longer in the "hlh" group ( . days vs. . days, p < . ). the secondary hlh to sepsis in intensive care unit, not well known and understudied, seems to have a different profile and a more serious outcome but no change in death-ratehas been found considering the pairing with the sofa. further studies are needed to plan a better therapeutic strategy within this population. compliance with ethics regulations: not applicable. serum and peritoneal exudate concentrations after high doses of ß-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study lisa leon, philippe guerci, elise pape, nathalie thilly, amandine luc, adeline germain, anne-lise butin-druoton, marie-reine losser, julien birckener, julien scala bertola, emmanuel novy chru nancy, vandoeuvre les nancy, france correspondence: lisa leon (lisaleon @gmail.com) ann. intensive care , (suppl ):p- rationale: critically ill patients with severe intra-abdominal infections (iais) requiring urgent surgery may undergo several pharmacokinetic alterations that can lead to ß-lactam under dosage. the aim of this study is to measure serum and peritoneal exudate concentrations of ß-lactams after high doses and optimal administration schemes. patients and methods: this observational prospective study included critically ill patients with suspicion of iai who required surgery and a ß-lactam antibiotic as empirical therapy. serum and peritoneal exudate concentrations were measured during surgery and after a h steady-state period. the pharmacokinetic/pharmacodynamic (pk/ pd) target was to obtain ß-lactam concentrations of % ƒt> x mic (minimum inhibitory concentration) based on a worst-case scenario (highest ecoff value) before bacterial documentation (a priori) and redefined on the mic of the isolated bacteria (a posteriori). results: forty-eight patients were included with a median [iqr] age of [ - ] and a saps ii score of . septic shock occurred in % of cases. the main diagnosis was secondary nosocomial peritonitis. piperacillin/tazobactam was the most administered ß-lactam antibiotic ( %). prior to bacterial documentation, patients ( . %) achieved the a priori pk/pd target. iai was documented in patients ( %). enterobacteriaceae were the most isolated bacteria. based on the mic (n = ) of isolated bacteria, % of the patients achieved the pk/pd target ( % ƒt> xmic). in the fig. we presented serum ß-lactams pk/pd target attainment and observed total concentrations of piperacillin-tazobactam at each timepoint in serum and peritoneal exudate. in critically ill patients with severe iais, high doses of ß-lactams ensured % ƒt> xmic in % of critically ill patients with severe iais within the first h. a personalized ß-lactam therapeutic scheme with a pk/pd target based on local ecology should be warranted. compliance with ethics regulations: yes. rationale: intensive care unit acquired bloodstream infections (icu-bsi) are frequent, and associated with high morbidity and mortality rates. the objective of our study was to describe the epidemiology and the prognosis of icu-bsi in our icu (cayenne general hospital). secondary objectives were to search for factors associated to icu-bsi caused by esbl-pe, and those associated with mortality at days. patients and methods: we retrospectively studied icu-bsi in the medical-surgical intensive care unit of the cayenne general hospital, during months (january to june ). we assessed survival at days from the diagnosis of icu-bsi. results: icu-bsi was diagnosed in . % of admissions giving a density incidence of . icu-bsi/ days. the median delay to the first rationale: necrotizing soft tissue infections (nsti) are a heterogenous group of severe infections. among them, group a streptococcal (gas) infection represent a subgroup that could benefit from specific therapies targeting the toxinic pathway, such as intravenous immunoglobulins or clindamycin. nevertheless, previous trials evaluating these treatments suffered from a low rate of gas infection among the study population. early identification of patients at high risk of gas infection would allow for assessing targeted treatment strategies. patients and methods: we conducted a secondary analysis of a previously published cohort of patients admitted to our tertiary center for surgically proven nsti between and . admission characteristics and microbiological documentation based on surgical samples, blood cultures or subcutaneous puncture were recorded. we compared patients with a documented gas infection to all other patients regarding admission characteristics. a generalized linear regression model was used to identify admission characteristics associated with a subsequent documentation of gas infection. results: among patients, ( %) had a gas infection, which was monomicrobial in ( %) cases. admission characteristics associated with gas infections by univariate analysis were nsaid treatment before admission ( ( . %) for gas infections vs ( . %) for others, p = . ) and leukocytosis as a continuous variable ( , /mm [ , - , ] vs. , [ - , ], p = . ). those inversely correlated with gas infections were immunodeficiency ( ( %) vs. ( . %), p = . ), and an abdominoperineal topography ( ( . %) vs. ( . %), p > . ). after multivariate analysis only immunodeficiency (or = . [ . - . ], p = . ) and an abdominoperineal infection (or = . [ . - . ], p = . ) remained associated with the absence of gas infection. using these criteria allowed for identifying subgroups of patients with increased likelihood of gas infections: from % overall (n = ) to % for non-abdominoperineal infections (n = ), % for patients without immunodeficiency (n = ) and % for both non abdominoperineal infections in patients without immunodeficiency (n = ). a sensitivity analysis for monomicrobial gas infections yielded similar results with the addition of younger age and non-nosocomial infections as predictors. conclusion: upon admission, the absence of immunodeficiency and of an abdominoperineal infection in nsti patients were covariables associated with gas infection. compliance with ethics regulations: yes. rationale: sickle-cell disease is the most common genetic disorder in the world. a complication of this disease is the acute chest syndrome (acs) which is associated with a high risk of death. respiratory tract infections are often mixed up and the introduction of betalactam antibiotics is recommended. glomerular hyperfiltration is common and responsible of a high risk of underdosing. this study compares cefotaxim continuous infusion to intermittent bolus in adult patients with acs. patients and methods: this observational retrospective monocentric study included acs admitted in intensive care unit and treated by cefotaxim with at least one plasmatic dosing between may and august . results: thirty patients received bolus administration while the others received continuous infusion. we observed patients ( %) and patients ( %) with a cefotaxim trough level ≥ mg/l in the bolus and continuous group, respectively (p < . ). the median residual concentration was mg/l [ - ] and . mg/l [ . - . ] in the bolus and continuous group, respectively (p < . ). there was no toxic effect induced by overdosing of cefotaxim. conclusion: compared to intermittent bolus infusion, continuous cefotaxim administration maximizes the pharmacokinetics parameters by obtaining a plasmatic concentration times above the minimal inhibitory concentration of usual germs associated with acs. continuous infusion of time-dependant antibiotics seems to decrease the risk of underdosing in patients with sickle cell disease. compliance with ethics regulations: not applicable. (n = , %), followed by esophageal varices rupture (n = , %), ulcer bleeding (n = , %) and diverticular hemorrhage (n = , %). infectious diseases were diagnosed in three patients ( %), including one clostridium colitis, one erosive gastritis with helicobacter pylori and one esophageal candidiasis. conclusion: gib is associated with a high mortality rate in immunocompromised patients, especially in patients with hematological malignancies. specific malignant lesions were the main etiology and may be difficult to treat. comparison with critically ill non-immunocompromised patients with gib will help physicians to provide specific therapeutic strategies in this population. compliance with ethics regulations: yes. risk factors for delayed defecation and impact on outcome in critically ill patients: a multicenter prospective non-interventional study benoît painvin ,* , arnaud gacouin , antoine roquilly , claire dahyot-fizelier , sigsimond lasocki , chloe rousseau , denis frasca , philippe seguin anesthésie-réanimation/chu rennes, rennes, france; réanimation médicale/chu rennes, rennes, france; réanimation chirurgicale/ chu nantes, nantes, france; réanimation chirurgicale/chu poitiers, poitiers, france; anesthésie-réanimation/chu angers, angers, france; centre investigation clinique/chu rennes, rennes, france; anesthésie-réanimation/chu poitiers, poitiers, france; réanimation chirurgicale/chu rennes, rennes, france correspondence: benoît painvin (painvinbe@gmail.com) ann. intensive care , (suppl ):p- rationale: delayed defecation is very common in intensive care units (icu) and it increases length of mechanical ventilation (mv), icu length of stay (los) and possibly mortality. the objective of this prospective multicenter study was to determine risks factors for constipation in icu and to evaluate their impact on mortality. patients and methods: it was a prospective multicenter non-interventional trial performed in university icus in france from january to october . all patients ≥ years old who had an expected los of days and mechanically ventilated for at least days were eligible. defecation was defined as the time of the first stool passage. results: patients were included in the analysis. a stool passage was observed in % of the patients during their icu stay with a mean delay of ± days. in multivariate analysis, risk factors for delayed passage of stool were non-invasive ventilation use and time spent under invasive ventilation whereas alcoholism, laxative treatment (before and after icu admission) and nutrition ≤ h favoured passage of stool (table ) . no relations between constipation and mortality were found. conclusion: we highlighted new and important independent factors for constipation in critically ill patients leading to a better prevention of this phenomenon.. compliance with ethics regulations: yes. rationale: community peritonitis is a frequent medical-surgical emergency of the adult, acquired by the patient in a non-hospital setting. careful multidisciplinary care is essential, involving surgeons, anesthetists, microbiologists and radiologists. the objective of our study is to determine the bacteriological aspects of intra-abdominal sepsis, to describe their sensitivity profiles and to propose treatment regimens for the management of community peritonitis. we conducted a descriptive retrospective study spanning a period of two years from january to january involving cases of community abdominal sepsis operated in the operating room of surgical emergencies of our hospital. we included in our study adult patients admitted for suspected or confirmed abdominal sepsis who had undergone bacteriological examinations on the abdominal collections. samples taken are sent directly to the bacteriology laboratory for bacteriological analysis of the results. the studies showed the mean age is . years old, with a sex ratio of . . we found positive results mainly of peritoneal origin with a percentage of . % peritonitis, dominate by intestinal peritonitis . % followed by the appendicular origin . % then peritonitis by perforation of ulcer. the most incriminated organism in intraabdominal sepsis is e. coli with a percentage of . % of the total germs found, followed by streptococcus spp . %, enterococci . %, non-fermenting bgn composed mainly of pseudomonas aeruginosa . %, staphylococci . % and acinetobacter baumanii . %. note also the presence of bacteroides fragilis is %. e. coli had a very low sensitivity profile for amoxicillin/clavulanic acid ( . %), unlike ceftriaxone, gentamicin, amikacin and ertapenem, which had a sensitivity of . %, respectively. . %, %, . %. conclusion: knowledge of the bacterial ecology of intraabdominal sepsis is important in the choice of probabilistic antibiotherapy, pending bacteriological findings. no data are yet available about nutritional management and risk of malnutrition in tunisian medical intensive care units (icu). the purpose of this study was to describe nutritional management in medical intensive care patients and to evaluate the risk of malnutrition. patients and methods: we conducted a prospective observational cross-sectional study in medical icus all around the tunisian country on the th september . all participant units received a questionary form about routine nutritional management and data of all patients hospitalized in icu on the study day. collected data were: demographic characteristics, reason for admission, severity scores and subjective evaluation of nutritional status on admission, type and volume of nutritional support on the study day and the day before, nutritional status, nutric score and biological data on the study day, reasons for nutritional interruption and other supports prescribed. results: thirteen icu all around tunisia participated to the study. no icu had a nutrition team and only one had a written nutrition protocol. four icus evaluated systematically the nutritional status on admission. all icus were aware and practiced early enteral nutrition in patients unable to maintain oral intake with a systematic supplementation of oligoelements and minerals. neither target energy nor protein intake were calculated. on the study day, patients were hospitalized with an occupation rate of %. mean age was ± years. mean body mass index was ± and % of patients were judged well nourished. enteral nutrition support was prescribed on admission in % of cases with a mean caloric intake of ± kcal/day. the mean caloric target on the study day was ± kcal/day with a mean caloric intake of ± kcal/day and a mean caloric gap of ± kcal/day. the mean nutric score and body mass index on the study day were ± and ± respectively. twenty patients were judged malnourished by the nutric score and twenty two by clinical evaluation. a good correlation was found between nutric score and clinical evaluation of nutritional status (k = . ). conclusion: tunisian icus don't have nutrition team or nutritional written protocol. early enteral feeding and supplementation is common. a good correlation exists between nutric score and clinical nutrition status evaluation. compliance with ethics regulations: yes. rationale: whether more intensive glycemic control (gc) is beneficial or harmful forcritically ill patient has been debated over the last decades. gc has been shown hard to achieve safely and effectively in intensive care. the associated increased hypoglycemia and glycemic variability is associated with worsened outcomes. however, modelbased risk-based dosing approach have recently shown potential benefits, improving significantly gc safety and performances. the stochastic targeted (star) gc framework is a model-based controller using a unique risk-based dosing approach. star identifies modelbased patient-specific insulin sensitivity and assesses its potential variability over the next hours. these predictions are used to assess hypoglycemic risks associated with a specific insulin and/or nutrition intervention to reach a specific target band. this study analyzes preliminary clinical trial results of star in a belgian icu compared to the local standard protocol (sp). the mean age in our series was . years with a male predominance (sex ratio = . ). the main revealing symptoms were epigastralgia, weight loss and vomiting. subtotal gastrectomy was performed in . % of cases and total gastrectomy in . % of cases. curative resection could only be performed in . % of cases. operative mortality was . % and morbidity was . %. the main factor influencing operative mortality was age greater than years. in univariate analysis the main prognostic factors; tumor size, degree of parietal invasion, presence of ganglionic invasion, presence of more than ganglia invaded, presence of metastases, locally advanced tumor, tumor stage and curative nature of resection. patient-related factors such as age associated blemishes and biological factors have a significant influence on the patient's prognosis. the prognosis of gastrectomies, although it has improved overall, remains mediocre. the only way to improve the prognosis remains the early diagnosis with an effective surgical management and the introduction of an adapted resuscitation. compliance with ethics regulations: yes. efficacy of multiple second line agents in refractory status epilepticus in a pediatric intensive care unit lea savary, claire le reun chu tours, tours, france correspondence: lea savary (lea.savary@hotmail.com) ann. intensive care , (suppl ):p- rationale: convulsive status epilepticus (cse) is the most common neurological emergency in children. refractory status epilepticus (rse) occurs whenseizures are not controlled with first-and secondline agents. in adults, rse requires pharmacological induced coma. in pediatric patients, association of second line treatment is often used to avoid general anesthesia although there is currently no data on the efficacy of this association. we performed a monocentric retrospective study to assess the efficacy of multiple second line agents in pediatric rse. all children admitted to clocheville hospital (tours) between january and december with a diagnosis of rse were included. our population was divided into two groups: need of general anesthesia (midazolam+) or not (midazolam-). results: children were included ( in group midazolam+, in group midazolam−) during the study period. among the patients with multiple second line agents, % did not need general anesthesia (n = ). in group midazolam+, cse was % longer in patients treated with multiple second line agents ( rationale: drowning is an acute respiratory failure resulting from immersion or submersion in a liquid. patients and methods: we report cases of drowning collated in the pediatric reanimation department during a period from to . the aim of our retrospective study was to analyze and compare the different epidemiological, clinical, parcalinical, therapeutic and evolutionary of drowning in our study. results: our study contains boys and girls, with a sex ratio (m/f) of , in an age between months and years. for cases studied, no one was classified stage i, . % classified stage ii, % stage iii, and . % stage iv. all cases collected by ou service were victim of accidental drowning, . % were secondary to the lack of parental supervision. among cases, had respiratory complications, cases of hydroelectrolytic disorders, case with infectious complications, cases of neurological and cases of cardiac or hypothermic complication. in our study, cases recovered well and cases died. the survival of the drowned person depends on the speed and efficiency of the intervention, which in thefirst place is prehospital, thus ensuring the first actions at the scene of the accident, which will have repercussions on the hospital care. this has an equal share in the improvement of the victim's prognosis. compliance with ethics regulations: not applicable. epidemiology of severe pediatric trauma following winter sport accidents in the northern french alps emilien maisonneuve , nadia roumeliotis , pierre bouzat , guillaume mortamet chu grenoble, grenoble, france; chu sainte-justine, montréal, canada correspondence: emilien maisonneuve (emilienmaisonneuve@orange. fr) ann. intensive care , (suppl ):p- rationale: this study describes the epidemiology of severe injuries related to winter sports (skiing, snowboarding and sledding) in children, and assesses potential preventive actions. we did a single-center retrospective study in our pediatric intensive care unit in the french alps. we include all patients less than years old, admitted to the intensive care unit following a skiing, snowboarding or sledding accident from to . results: we included patients (mean age . years and % were male); of which ( %), ( %) and ( %) had skiing, snowboarding and sledding accidents, respectively. the average iss (injury severity score) was . the major lesions were head (n = patients, %) and intra-abdominal (n = patients, %) injuries. compared to skiing and snowboarding, sledding accidents affected younger children ( vs. years, p < . ); most of whom did not wear a helmet ( % vs. %, p < . ). severity scores were similar amongst winter sports (iss = for skiing, for snowboarding and for sledding accident, p = . ). rationale: best strategies for the management of severe pediatric traumatic brain injury (tbi) are still not clearly established and wide variations among professional practices have been reported in the literature. unfortunately, these variations in practice have an impact on the patient's outcome. the objectives of this work were to assess the adequacy of professional practices to the guidelines for the management of severe head injury and to assess the level of agreement of respondents in the absence of guideline. patients and methods: a practice survey was conducted in frenchspeaking hospitals in canada, belgium, switzerland and france from april st to june th, . the survey was conducted as a progressive clinical case with questions based on guidelines and the literature from to . the questions related to the assessment and management of tbi during the acute and intensive care phase. results: seventy-eight questionnaires were included. the adherence to guidelines was good, with items out of obtaining an adherence rate of more than % regardless of the annual number of tbi managed by the centre. there was strong agreement among clinicians on the intracranial pressure (pic) (> %) and cerebral perfusion pressure (> %) thresholds used according to age. guidelines for indication of pic monitoring were almost perfectly followed in the case of glasgow score < and abnormal brain ct scan (n = , %). on the other hand, the natremia and glycemia thresholds and the role of transcranial doppler were not consistent. strong adherence to recent recommendations was achieved: seizure prophylaxis with levitracetam (n = / , %) and capnia threshold (n = , %). assessment of o pressure in brain tissue (n = , %) and autoregulation (n = ; %) was not a common practice. conclusion: overall, practices for the management of tbi appear to be standardised. variations persist in areas where there is a lack of literature and guidelines in paediatrics, so clinicians seem to refer to adult guidelines. compliance with ethics regulations: yes. choubeila guetteche chu constantine, constantine, algeria correspondence: choubeila guetteche (cguetteche@gmail.com) ann. intensive care , (suppl ):p- rationale: ingesting a coin cell is a common household accident in children, which can have serious consequences. the goal is to determine prognostic factors to improve management and reduce complications. patients and methods: we conducted a retrospective study including children under admitted in pediatric intensive care between january and may for ingestion of button cells, with epidemiological, clinical and paraclinical data collection. results: twenty-six children boys ( %), and girls ( %) were included, with an average age of months ( - ), increased incidence in recent years. clinical signs indicative were dysphasia with hyper-sialorrhea in cases, cervical pain in one case, respiratory distress in one case, the cell was located in the upper third of the esophagus in cases, third average in cases, third inferior in cases, the mean time before extraction was h. complications: cases of mediastinitis, cases of oesotracheal fistula, a case of perforation. conclusion: the young age of the child, the diameter of the battery, and especially the time of care are risk factors for the occurrence of complications, the prevention passes through the education of the general public and creation of channel of taking into account fast charge. compliance with ethics regulations: not applicable. yacine benhocine university hospital center nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):p- rationale: inhalation of foreign bodies is a common and serious accident in children, especially between and years old. at this age, children use their mouth to explore their environment. asphyxia is the immediate risk and respiratory sequelae may appear secondarily. the severity of this incident has been considerably reduced due to the progress of the instrumentation and anesthesia which condition the smooth running of the therapeutic act. aim: to evaluate the anesthetic modalities of the extraction of the foreign bodies of the airways in children, in order to optimize our care with a maximum of security. a prospective, mono-centric, descriptive study from january to november of patients treated for inhalation of foreign bodies in the airways. study population wasdefined by: age, sex, hospitalization context, physical and radiological examination data, anestheticmanagement. results: the average age of the patients was . months, the male predominated ( %), and the hospitalization context was polymorphic. general anesthesia was necessary in all cases, sevoflurane mainly for narcosis; the combination of an opioid in . % of cases and a curare in . %. spontaneous ventilation is desirable, but % was manually broken down intermittently between extraction attempts. cases of desaturation, bronchospasm, bradycardia, and pneumothorax have been reported. . % had a good evolution. discussion: the results of the epidemiological data are consistent with those of the literature. the penetration syndrome is very revealing. the chest x-ray is the key examination, the diagnosis is often based on indirect signs. in case of asphyxia by foreign body enclosed above or between the vocal cords, laryngoscopy and oxygenation is the first step to perform. in other cases, a rigid bronchoscopy is performed under general anesthesia; inhalation induction with sevoflurane is the technique of choice for many experienced authors. controlled ventilation is used in the majority of cases because spontaneous ventilation is not often not possible. the heterogeneity of anesthetic practices accounts for the multiplicity of clinical situations. conclusion: the inhalation of a foreign body is a diagnostic and therapeutic emergency. extraction of the foreign body takes place under general anesthesia, which is difficult and at risk. compliance with ethics regulations: yes. non-invasive neurally adjusted ventilatory assist (nava) in infants with bronchiolitis: a retrospective cohort study alex lepage-farrell, sally al omar, atsushi kawaguchi, sandrine essouri, philippe jouvet, guillaume emeriaud chu sainte justine, université de montréal, montréal, canada correspondence: alex lepage-farrell (alex.lepage-farrell@umontreal.ca) ann. intensive care , (suppl ):p- rationale: bronchiolitis is one main reason for admission to pediatric intensive care unit. most infants are successfully managed with nasal cpap or high-flow nasal cannula, but about a third of these patients are not sufficiently supported and require an alternative support. non-invasive neurally adjusted ventilatory assist (niv-nava) improves patient-ventilator interactions and could therefore improve the effectiveness of non-invasive support. our hypothesis is that niv-nava is feasible in infants with bronchiolitis and that it reduces the respiratory effort. patients and methods: we retrospectively studied all patients under years of age with a clinical diagnosis of bronchiolitis ventilated with niv-nava in our pediatric intensive care unit, between october and june . patients characteristics, respiratory and physiologic parameters, including diaphragmatic electrical activity (edi) were extracted from an electronic medical database (data collected every s). respiratory effort was estimated using the modified wood clinical score for asthma (mwcas) and the inspiratory peak edi, and -h periods before and after niv-nava initiation were compared (wilcoxon rank test). the study was approved by the local research ethics committee. results: during the study period, patients were admitted with bronchiolitis; infants ( boys) with a median ( th- th percentile) age of ( - ) days were treated with niv-nava after a failure of other non-invasive support methods, and all were included. twentyfive subjects ( %) had at least one comorbidity. the interfaces used were predominantly face masks ( %). the maximum ventilatory settings were nava level of . ( . - . ), peep of ( - ) cmh o, fio of % ( - ) and maximal pressure of ( - ) cmh o. total duration of non-invasive ventilation was ( - ) hours, including ( - ) hours in niv-nava. as detailed in the table , mwcas significantly decreased after niv-nava initiation, from . ( . - . ) to . ( . - . ), p < . . a decrease in inspiratory peak edi was also observed, which was particularly clinically relevant in infants with high baseline edi (> mcv). capillary blood ph and pco also significantly improved after niv-nava introduction. six patients ( %) needed escalation to endotracheal intubation. conclusion: this study confirms the feasibility of niv-nava in infants with bronchiolitis after failure of first line non-invasive support, with a low failure rate. niv-nava initiation was followed by a decrease in respiratory effort and an improvement in blood gases. this observational study supports the needs for prospective interventional trial. compliance with ethics regulations: yes. rationale: the use of blood transfusion is frequent in pediatric intensive care units and has increased significantly since . considered as therapeutic, it requires an assessment of the benefit / risk balance before making the transfusion decision. the aim of our study is to describe the transfusion practices in the pediatric resuscitation department of the ehs canastel, algeria. patients and methods: a retrospective observational study over a -month period from january of any blood transfusion performed in hospitalized patients, in the pediatric intensive care unit. we studied : the age, the sex, the history of blood transfusion, the indication of transfusion, the haemodynamic and respiratory parameters, the transfusional accidents, the length of stay in intensive care, the evolution after a blood transfusion. results: these included transfusion patients out of hospitalizations during the -month period, mean age was months.all patients had no transfusion history, % of patients had their anemia admission and % developed it during their stay. the reason for hospitalization was respiratory distress in %, convulsive condition in %, polytrauma in %, and head trauma in %. the indication of the transfusion was placed on a hb inferior or equal to g / dl in % of cases, in % on an hb superior to g / dl in addition to the clinical criteria of intolerance to anemia; in % of the cases no clinical or biological criteria found, the nature of the blood products was of the red cell in % of the cases and of the plasma concentrate in / of the cases and pfc in %. % received a+, % of a-, % of b+, % of o+ and % of o-. % of the patients had a transfusion-like reaction at min after the start of the transfusion; % of the patients were under artificial ventilation and % were under hemodynamic support, % under diuretic.the average length of stay was days; the favorable outcome was % of the patients after the transfusion with an increase in the hb level beginning, % of the patients had complications of their pathology and the death in % of the cases. conclusion: current transfusion practices in children often do not reflect the implementation of our current knowledge of the need for transfusion. hence the need to review the protocols and practice other transfusion alternatives to avoid complications and improve the quality of care. compliance with ethics regulations: not applicable. rationale: bacterial multi drug resistance is medical actuality nowadays, because of its morbidity and mortality especially in intensive care, it constitutes a real problem in our hospitals. we conducted a retrospective descriptive study, to identify bacterial drug resistance profile of patients with cross infections in the department of intensive care in august hospital. this study included patients hospitalized between st january and st december . the data was collected from medical records of this unit as from the register of the bacteriology service of ibn rochd university hospital. results: patients were hospitalized in the resuscitation service, of which had nosocomial infection, an incidence of . %. the mean age of the patients was years with male predominance (sex ratio . ), the average stay in intensive care was days. the site of infection was pulmonary in % of cases, blood in % of cases, urinary in % of cases, central catheter in %, neuro-meningeal in . % of cases. the germs isolated were: acinetobacter baumanii in . % of cases, pseudomonas aeroginosa in . % of cases, klebsiella pneumonia in . % of cases, enterococcus feacalis in . % of cases, e.coli in . % of cases and staphylococcus aureus in % of cases. acinteobacter baumanii showed resistance rates of up to % for the impenem and % for amikacin. regarding pseudomonas, it was resistant to impenem in % of cases and in % of cases to amikacin. compared to klebsiella, resistance to imipenem was % and % for amikacin. the mortality rate of infected patients was % conclusion: in the light of this work, we found that important emergence of multidrug resistance bacteria in intensive care unit is related to not only the immunocompomised state of patients but also to daily bad practices of health professionals such as the misuse of antibiotics. compliance with ethics regulations: yes. overnight culture of escherichia coli, klebsiella pneumoniae, staphylococcus aureus and pseudomonas aeruginosa, was also sequenced. results: twenty-four samples and the pc were analyzed. amplicon sequence analyses found similar results with the two primer pairs in % of cases. cultured pathogen was found in % ( / ) for human primer pair and in % ( / ) for earth primer pair. for each eta, ngs revealed bacteria unknown as pathogen globally identified as oropharyngeal flora in conventional microbiology (table ) . alpha diversity decreased for all vap patients overtime, average shannon . ( ; . ) versus ( . ; . ), and was higher in upper respiratory tract (os) versus lower respiratory tract (eta): average shannon . ( . ; . ) vs. . ( . ; . ) (ns). conclusion: this pilot study highlights the impact of s rdna amplification procedures (especially oligonucleotide sequences) used on the results in microbiome research. concordance between ngs and bacterial culture, as well as similar evolution of the alpha diversity than previously described ( ), enables us to validate our methodology using the "gut primers" pair f- r. these findings allow furthers major studies on the pulmonary microbiome of icu ventilated patients including comparison according to the occurrence of a vap or not. compliance with ethics regulations: yes. rationale: in the field of intensive care only few studies have explored bacterial microbiota whereas virome remained hardly considered. it appears essential to describe both evolution in mechanically-ventilated patients to improve the pathophysiological understanding of ventilator-associated pneumonia (vap) development. to date no study had been simultaneously conducted on lower respiratory tract with a single nucleic acid extraction before metagenomics analysis of bacterial microbiota and virome. we conducted a preliminary study to validate our methodology based on a common automated extraction of nucleic acids. patients and methods: twelve mechanically ventilated patients were selected: five who developped (vap) and seven controls (c) who did not. endotracheal aspirate (eta) were collected between intubation and day (or dvap for vap patients). conventional bacterial microbiology and multiplex respiratory viruses pcr were also performed. total nucleic acids were extracted using nuclisens easymag extractor. for the bacterial microbiota, region v of the s rrna genes was amplified. for the virome, the nextera dna xt kit (illumina) and rna seq trio kit (nugen) protocols were used to prepare viral dna and rna libraries. libraries underwent paired-end sequencing on the illumina miseq (bacteria) or nextseq- (virus) platform. after bioinformatics analysis we compared the performance of metagenomics analysis with conventional bacterial culture and other common viral detection methods. results: for culturable bacteria, concordance between conventional microbiology and sequencing was found in % ( / table . our preliminary results confirm the feasability of exploring both bacterial microbiota and virome on the same sample using a common extraction method. data from metagenomics were highly concordant with conventionnal detection methods for known pathogenic viruses and bacteria in lower tract respiratory sample and enables identification of other microorganisms. this is the first step for a large cohort study that aims to compare evolution of global lung microbiome in patients at risk of vap and assess how bacteria and virus interplay. compliance with ethics regulations: yes. references . clancy department of medical and toxicological critical care, lariboisière hospital one microorganism was isolated in . % and two in . % of cases. the main isolated microorganism were enterobacteriaceae in . % of patients. they were esbl-producers in . % of cases. initial antibiotic therapy was appropriate in . % of cases. factors independently associated with esbl-pe as the causative microorganism of icu-bsi were esbl-pe carriage prior to icu-bsi the sensitivity of esbl-pe carriage to predict esbl-pe as the causative microorganism of icu-bsi was . %, and specificity was . %. mortality at days was . % in the general population in multivariable analysis, there was no parameter which was independently associated to mortality at day from the occurrence of icu-bsi. conclusion: icu-bsi complicates . % of admission to icu and was associated with % in-hospital mortality assessing and applying individualized treatment for group a streptococcal necrotizing soft-tissue infection is possible service de réanimation médicale intensive care decompressive craniectomy in traumatic brain injury: about cases karama bouchaala sex ratio of . . the mean (sd) length of stay in icu was . ± . days. the mean glasgow coma score (gcs) (sd) was . ± . and gcs ≤ in . %. sofa score > was found in patients ( . %) and sapsii score ≥ in patients ( . %). the cerebral ctscan at admission showed acute subdural hematoma (asdh) in ( . %), cerebral oedema ( . %) and cerebral contusions ( %) teaching: fresenius medical care; patent or product inventor: gml czech republic banydeen rishika: no conflict of interest baptiste amandine: no conflict of interest baptiste olivier: no conflict of interest barbar saber davide: no disclosure barbier françois: no disclosure barbierlouise: trainings, teaching: ethicon, astellas; invitation to national or international congresses: sandoz, astellas barnerias christine: no disclosure baron aurore: no disclosure baron elodie: no conflict of interest barr att -due andreas: no disclosure barrau stephanie: no disclosure barraud damien: no disclosure barraud helene: no disclosure barrois brigitte: no conflict of interest baruchel andré: no disclosure bastide marie anaïs: no conflict of interest baudel jean-luc: no conflict of interest baudin florent: invitation to national or international congresses: dr baudin has received speaking fees from maquet critical care (epnv teaching: drager; invitation to national or international congresses: msd; hill rom beganton frankie: no conflict of interest begot erwan: no disclosure beinse guillaume: research support/scientific studies: association pour la recherche contre le cancer ion and fresenius kabi bensaid abdelhak: no disclosure bensardi fatimazahra: no disclosure benyamina mourad: no disclosure benzerara laurent: patent or product inventor: aphp benzerdjeb nazim: research support/scientific studies: amarape, icap; consultancy, expert: alphasights, msd; trainings, teaching: msd beqiri erta: no disclosure bÉranger agathe: no conflict of interest berard emilie: no conflict of interest berdai adnane: no disclosure berger patrick: no disclosure bernal william: no disclosure bernardin gilles: no disclosure berrada lina: no conflict of interest berthaud romain: no conflict of interest berthet guillaume: no conflict of interest berti enora: no conflict of interest bertoli sarah: no disclosure bertrand pierre-marie no conflict of interest besbes lamia: no disclosure besbes mohamed: no conflict of interest besch camille: invitation to national or international congresses: abbvie no conflict of interest boisseau chloé: no disclosure boissel nicolas: no disclosure boissier florence: no conflict of interest boivin alexandra: no conflict of interest bonacorsi stéphane: no conflict of interest bongiovanni filippo: no conflict of interest bonnardel eline: no conflict of interest bonnefoy-cudraz eric: no disclosure bonnet sixtine: no conflict of interest bonnevie tristan: research support/scientific studies invitation to national or international congresses: fresenius kabi and fresenius medi-calcare bucur petru: no disclosure buetti niccolo: research support/scientific studies: swiss national science foundation research grant and bangerter rhyner foundation supporting my postdoc bui hoang-nam: no disclosure burelli gabrielle: no conflict of interest burgel pierre-régis: no disclosure burghi g: no conflict of interest bustarret olivier: no conflict of interest butin-druoton anne-lise: invitation to national or international congresses expert: astra-zeneca; invitation to national or international congresses expert: hamilton medical; invitation to national or international congresses: hamilton medical chemli wael: no conflict of interest chenouard alexis: no conflict of interest cherkab rachid: no conflict of interest chevret sylvie: no disclosure chhun stephanie: no conflict of interest chiche jean-daniel: no disclosure chicoisneau maxence: no conflict of interest chlilek abdelaziz: no disclosure chocron richard: consultancy, expert: aspen chommeloux juliette: no conflict of interest chomton maryline: no conflict of interest chosidow olivier: no disclosure chouchana laurent expert: biotest; invitation to national or international congresses: sanofi research support/scientific studies: fresenius medical care; consultancy, expert: fresenius medical care; invitation to national or international congresses: xenios novalung, heilbronn, germany dachraoui fahmi: no disclosure dahoumane redouane: no conflict of interest dahyot-fizelier claire: no disclosure daix thomas: no conflict of interest daly foued: no conflict of interest damonti lauro: no conflict of interest dantan etienne: no conflict of interest darmon michaël: research support/scientific studies: msd no disclosure das vincent: no disclosure daubin cedric: no conflict of interest daubin delphine: no conflict of interest daudon michel: no disclosure daufresne pierre: no conflict of interest dauger stéphane: no conflict of interest daviet florence: invitation to national or international congresses: sandosz de courson hugues: no conflict of interest de jong audrey: trainings, teaching: baxter, medtronic; invitation to national or international congresses teaching: cardiosleep delhaes laurence: no disclosure delignette marie-charlotte: no conflict of interest dellamonica jean: trainings, teaching: medtronic; invitation to national or international congresses: msd, general electrics delpierre clément: no conflict of interest delville marianne: no conflict of interest demailly zoé: research support/scientific studies: srlf demarest elsa: no disclosure demaret pierre: no conflict of interest demiselle julien: no conflict of interest demondion pierre: no conflict of interest demoule alexandre: research support/scientific studies: drager, philips; consultancy, expert: baxter, respinor, lungpacer; trainings, teaching: fisher & paykel, hamilton, baxter; invitation to national or international congresses: fisher & paykel denis manon: no conflict ofinterest depeyre fanny: invitation to national or international congresses: pfizer deplante yvon: no conflict of interest dequin pierre-françois: research support/scientific studies: medimmune combioxin ferring pharmaceuticals a/s asahi kasei pharma america corporation derauglaudre lucie: no conflict of interest derbel karim: no disclosure derkaoui ali: no disclosure dervin krystel: no conflict of interest desaive thomas: no conflict of interest desguerre isabelle: research support/scientific studies: ptc inc, avexis; consultancy, expert: avexis, ptc inc, biogene; trainings, teaching: roche, ptc inc, avexis; invitation to national or international congresses: sarepta, biogen, avexis, biomarin desnos cyrielle: no conflict of interest desroys du roure françois: no conflict of interest detollenaere charles: no conflict of interest devaquet jérôme: invitation to national or international congresses expert: lungpacer; invitation to national or international congresses: lungpacer dreyfuss didier: research support/scientific studies: grant from french ministry of health drouot xavier: no disclosure du cheyron damien: no conflict of interest dubÉ bruno-pierre: consultancy, expert: novartis, gsk dubert marie: no conflict of interest dubost baptiste: no conflict of interest dubost jean-louis: no conflict of interest duburcq thibault: no conflict of interest duchemann boris: consultancy, expert: bms, msd, roche; invitation to national or international congresses no conflict of interest frÉrou aurélien: no conflict of interest fritz caroline: no disclosure fromentin mélanie: research support/scientific studies: msd; invitation to national or international congresses: msd frouin antoine: no conflict of interest frugier alexandre: no disclosure gaboriau louise: no conflict of interest gaci rostane: invitation to national or international congresses: bard gacouin arnaud: no disclosure gaddas mehdi: no conflict of interest gaillard arnaud: trainings, teaching: zoll medical gaimard sophie: no conflict of interest gainnier marc: no conflict of interest galbois arnaud: no conflict of interest galerneau louis-marie: invitation to national or international congresses: agir À domicile galicier lionel: consultancy, expert: novartis, eusapharma; trainings, teaching: baxalta, pfizer; invitation to national or international congresses no conflict of interest ichaÏ philippe: no conflict of interest imen sioud: no conflict of interest ioos vincent: no disclosure iserin franck: no disclosure issa nahema: no conflict of interest jaber samir: consultancy, expert: drager, fisher-paykel; medtronic; baxter xenios fresenius; invitation to national or international congresses: drager no conflict of interest jacq gwenaëlle: no conflict of interest jacquet emmanuelle: research support/scientific studies: unicancer (esme and storm studies invitation to national or international congresses: pfizer université laval-qc-ca labbe vincent: no disclosure labro laura: no disclosure lacaille florence: no conflict of interest lacampagne alain: no disclosure lacan claire: no conflict of interest lacherade jean-claude: no conflict of interest ladjemi maha-zohra: no conflict of interest lafon charles: no conflict of interest lafon marie-edith: no disclosure lafon thomas: no conflict of interest lagache laurie: invitation to national or international congresses advertising documents: philips; trainings, teaching: novartis, gsk, astra zeneca, boeringher; invitation to national or international congresses: chiesi, astra zeneca, sos oxygene, novartis, boeringher lamoth frédéric: consultancy, expert: gilead, msd, basilea; invitation to national or international congresses: msd expert: norgine; trainings, teaching: fujifilm, boston scientific lebreton guillaume: no disclosure lebrun-vignes benedicte: research support/ scientific studies: novartis; consultancy, expert: ansm lebuffe gilles: no disclosure leclerc maxime: no conflictof interest lÉcluse aldéric: research support/scientific studies: pgrx avc study; consultancy, expert: bms-pfizer, boerhinger ingelheim, bayer; invitation to national or international congresses: bms-pfizer, boerhinger ingelheim ledoux didier: no disclosure lefebvre francois: no conflict of interest macloughlin ronan: research support/scientific studies: aerogen ltd no conflict of interest mari arnaud: no conflict of interest marie damien: no conflict of interest marijon eloi: no disclosure mariotte eric: consultancy, expert: sanofi-aventis marjanovic nicolas: no disclosure marjanovic zora: no disclosure maroni arielle: no conflict of interest marot benoit: no conflict of interest marque sophie: no conflict of interest marti teaching: zambon, chiesi; invitation to national or international congresses no conflict of interest matusik elodie: no conflict of interest mauchien benedicte: no conflict of interest maury eric: research support/scientific studies: doran international, drager; trainings, teaching: vygon maxime virginie: no conflict of interest mayaux julien: invitation to national or international congresses stock shareholder: tanderev; patent or product inventor: tanderev mercat alain: research support/scientific studies: fisher-paykel, general electric; consultancy, expert: faron pharmaceuticals no disclosure merhabene takoua: no conflict of interest merle jean-claude: no disclosure mesotten dieter: no conflict of interest messaadi amenallah: no conflict of interest messika jonathan: invitation to national or international congresses: cslbehring; fisher&paykel metaxa victoria: no disclosure metogo mbengono junette arlette: no conflict of interest meunier anne: no conflict of interest meurice jean-claude: no disclosure meybeck agnes: consultancy, expert: janssen, gilead; invitation to national or international congresses teaching: msd no conflict of interest morimont philippe: no conflict of interest moro-sibilot denis: no disclosure mortamet guillaume: no conflict of interest mosbah nabil: no conflict of interest moschietto sebastien: no conflict of interest moucadel virginie: research support/scientific studies: biomérieux moulaire rigollet valérie: no disclosure mouliade charlotte: no conflict of interest moulin florence: no disclosure mounir yousfi: no conflict of interest mourabit karima: no disclosure mourvillier bruno: trainings, teaching: msd research support/scientific studies: aerogen; advertising documents: aerogen; patent or product inventor: aerogen musiari michele: no conflict of interest n'guyen quang-thang: no conflict of interest n'guyen tran: no disclosure nabil mosbah: no disclosure naccache lionel: no disclosure naimi skander: no conflict of interest nakaa sabrine: no disclosure nallet-amate megan: no conflict of interest natalis eloïse: no disclosure naudin jérôme: invitation to national or international congresses: novartis nay mai-anh: no conflict of interest nemlaghi safaa: no conflict of interest neofytos dionysios: research support/scientific studies: msd; consultancy, expert: msd, gilead, pfizer; invitation to national or international congresses: gilead, pfizer nesseler nicolas: no conflict of interest neviere remi: no disclosure nguyen alexandre: no disclosure nguyen khoa thao: no conflict of interest nicolau-travers marie-laure: no disclosure niÉrat marie cécile: no conflict of interest nieszkowska ania: no disclosure nigeon olivier: no conflict of interest nitel gautier: no conflict of interest nodea elena madalina: no conflict of interest noel marine: no conflict of interest nogier marie-béatrice: no disclosure noorah zaid: no disclosure nouira wiem: no conflict of interest noumeir rita: stock shareholder: softmedical noury norbert: no conflict of interest novy emmanuel: research support/scientific studies: msd; invitation to national or international congresses: pfizer expert: air liquide medical system ollivier veronique: no conflict of interest onimus thierry: no conflict of interest oppenheimer anne: invitation to national or international congresses: gedeon richter orkisz maciej: no conflict of interest orliaguet gilles: research support/scientific studies research support/scientific studies: oxynov; patent or product inventor: oxynov patrier juliette: no conflict of interest paugam catherine: no disclosure paul marine: no conflict of interest paul-bellon rachel: no disclosure paulo nicolas: no conflict of interest pavot arthur: invitation to national or international congresses: fresenius medical care france pehlivan jonathan: no conflict of interest peigne vincent: invitation to national or international congresses: air liquide pÉju edwige: no conflict of interest pene frédéric: consultancy, expert: alexion pÉpin-lehalleur adrien: invitation to national or international congresses: chiesi pere morgane: no conflict of interest pereira bruno: no disclosure perez didier: no disclosure perez pierre: no disclosure perez yonatan: no conflict of interest perier françois: no disclosure perin nicolas: no conflict of interest biomerieux robin emmanuel: no conflict of interest robin nicolas: no disclosure robineau olivier: no disclosure roch antoine: no disclosure roche anne: no conflict of interest roger claire: consultancy, expert: pfizer, fre-senius medical care; invitation to national or international congresses: msd,pfizer rolle amélie: no conflict of interest rondeau eric: no disclosure ronziÈre thomas: no disclosure roquilly antoine: no disclosure rosselli sylvène: no disclosure rouby jean-jacques: no disclosure rouis sana: no conflict of interest rouleau stéphane: no conflict of interest roulet sylvie: no disclosure roulland charlotte: no disclosure roumeliotis nadia: no conflict of interest rousse natacha: no disclosure rousseau anne-françoise: invitation to national or international congresses no disclosure sagnier anne: no disclosure saillard colombe: trainings,teaching: amgen, novartis; invitation to national or international congresses no conflict of interest schmidt aline: no disclosure schmidt matthieu: consultancy no disclosure schultz marcus: no conflict of interest schwebel carole: invitation to national or international congresses: pfizer scicluna brendon: no disclosure sculier jean-paul: no conflict of interest see perrine: no conflict of interest seghboyan jean-marie: no disclosure seguin amelie: no conflict of interest seguin philippe: consultancy, expert: lfb; invitation to national or international congresses: astellas sejourne caroline: no conflict of interest sellami walid: no conflict of interest sendid boualem: research support/scientific studies: allfun project, fp european commission; invitation to national or international congresses: pfizer senhadji lahcen: no conflict of interest serbouti rita: research support/scientific studies: fresenius medical care; consultancy, expert: fresenius medical care; trainings, teaching: fresenius medical care; invitation to national or international congresses: fresenius medical care serfaty lawrence: no disclosure sÉrie mathieu: no conflict of interest shaw geoffrey m.: no conflict of interest shi rui: no conflict of interest shimi abdelkrim: no disclosure shojaei maryam: no disclosure si-tahar mustapha: consultancy, expert: cynbiose respiratory; stock shareholder: cynbiose respiratory siami shidasp: no conflict of interest silva daniel: research support/scientific studies: fresenius medical care france; consultancy, expert: fresenius medical care france; invitation to national or international congresses: xenios novalung, heilbronn no conflict of interest sirault bruno: no disclosure sirodot michel: no disclosure slama michel: no disclosure slim amine: no disclosure smielewski peter: no disclosure soares marcio: stock shareholder: epimed solutions teaching: gilead; invitation to national or international congresses: pfizer spagnoletti marco: no conflict of interest steckelmacher claire: no disclosure stockx luc: research support/scientific studies: phenox, medtronic; consultancy no conflict of interest voiriot guillaume: research support/scientific studies: biomérieux, sos oxygène, janssen; consultancy, expert: biomérieux; invitation to national or international congresses: biomérieux von kietzell matthias: invitation to national or international congresses expert: aguettant; invitation to national or international congresses: vifor yacoubi wejden: no conflict of interest yager hélène: no conflict of interest yahya yosra: no conflict of interest yakini khalid: no disclosure yakouben karima: no disclosure yonis hodane: invitation to national or international congresses: lvl medical et pfizer younan romy: no conflict of interest youssoufa atika: no disclosure zacharia mahi: no disclosure zafrani lara: research support/scientific studies: jazz pharmaceuticals zambon olivier: no disclosure zaouak nadia: no conflict of interest zaouche khedija: no conflict of interest zarrougui wafa: no conflict of interest ze minkande jacqueline: no disclosure zeghdoud dalila: no disclosure zerbib yoann: no conflict of interest zerhouni amel: no conflict of interest zerhouni amine: no conflict of interest zerimech farid: no conflict of interest zerouali khalid: no disclosure zheng yi: no conflict of interest zimmerli stefan: research support/scientific studies: msd, pfizer, gilead; consultancy, expert: msd, pfizer; trainings, teaching: gilead; invitation to national or international congresses springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations farhat hached hospital, sousse, tunisia; yassminet regional hospital, ben arous, tunisia; habib bougatfa regional hospital, bizerte, tunisia; larabta hospital, tunis, tunisia; carthagene private hospital, tunis, tunisia; regional hospital of zaghouan, zaghouan, tunisia; regional hospital of tozeur, tozeur, tunisia; habib thameur hospital, tunis, tunisia correspondence: samia ayed (samia.ayed@yahoo.fr) ann. intensive care , (suppl ):p- geoffroy hariri, kyann hodjat-panah, laurene blum, jean-rémi lavillegrand, idriss razach, naike bige, jean-luc baudel, bertrand guidet, eric maury, hafid ait-oufella médecine intensive-réanimation, hôpital saint-antoine, paris, france correspondence: geoffroy hariri (geoffroyhariri@hotmail.com) ann. intensive care , (suppl ):p- rationale: hemolytic anemia (ha) is a common condition in intensive care unit but its diagnosis remains challenging. free hemoglobin (and heme) degradation leads to co release that can bind to hemoglobin to form carboxyhemoglobin (hbco). we hypothesized that hbco concentration could be used as a reliable diagnosis tool for ha. patients and methods: we performed a monocentric retrospective study in a -bed intensive care unit at st antoine hospital, paris, between and . all patients hospitalized for ha with arterial hbco dosage at admission were included. arterial hbco was measured in routine in our department with an il system ph/ blood gas analyzer. demographic and biological data were collected. a group control of patients with non-hemolytic anemia (hb < g/ dl) (nha) was also included. finally, we analyzed patients outcome according to hbco changes during icu stay. results: between and , patients with ha were included. nha patients were included in the control group. patients with ha were younger than patients with nha ( [ ; ] vs. [ ; ] years old, p = . ) but admission sofa was not different between groups ( [ ; ] , vs. [ ; ] , p = ns). among patients with ha, % had thrombotic microangiopathy, % had autoimmune hemolytic anemia and % had sickle cell disease. at icu admission, ha patients had higher hbco level than patients with nha ( . [ . ; . ] vs. . [ . ; . ] %; p < . ). hbco was a reliable biomarker of hemolysis (auc . ( . ; . ) p < . ). an hbco level threshold at . % identify hemolysis with a sensitivity ( - ) % and a specificity ( - ) %. in ha group, hbco was negatively correlated to hb level (r = . ; p < . ). in ha patients, changes of hbco level during icu management were associated with outcome, decreasing in survivors ( . [ ; . ] vs. . [ . ; . ] ; p = . ) but not in non-survivors ( . [ . ; . ] vs. . [ . ; . ] %; p = . ). conclusion: carboxyhemoglobin is a reliable diagnosis and prognosis biomarker for hemolytic anemia in icu compliance with ethics regulations: yes. rationale: thrombocytopenia is the most commonly hemostatic disorder encountered in intensive care, present in to % of patients. the mortality associated with this thrombocytopenia, the numerous pathological contexts associated with resuscitation and the lack of a recommended management strategy led to the establishment of these guidelines. the aim of our study was to determine the incidence, causes and risk factors associated with the occurrence of thrombocytopenia, as well as the impact of thrombocytopenia on the mortality and length of stay in the icu ibn medical resuscitation unit. rochd de casablanca, over a period of months. patients and methods: this was a prospective study, carried out in the medical resuscitation department of ibn rochd university hospital in casablanca over a period of months. there were two groups: ''sick'' group with thrombocytopenia with a platelets count < , / mm , and a ''control'' group without thrombocytopenia. patients with previous platelet disorders, hematologic malignancies, and patients undergoing chemotherapy were excluded. of the patients included, episodes of thrombocytopenia were identified, anoverall incidence of . %. sepsis was incriminated times ( . %), followed by ards in patients ( . %), massive filling in patients ( . %), disseminated intravascular coagulation in patients ( . %), and massive transfusion in patients ( . %). the drug origin was incriminated in patients ( . %). it was due to quinolones and imipenem. the mortality rate was deaths ( . %) which was inversely proportional to the lowest platelet count in the thrombocytopenia group, compared to deaths ( %) in the control group. the mean duration of stay in the thrombocytopenia group was ± days with extremes ranging from to days. conclusion: thrombocytopenia was a common abnormality in the intensive care system, it occured in many pathological situations and was a factor of morbidity and excess mortality. the most common etiology in this study was sepsis. the diagnostic and therapeutic approach depended on the particular clinical context in which thrombocytopenia occurs. its onset may constitute a hematological emergency, particularly when there is a major mucocutaneous and / or visceral hemorrhagic syndrome, which necessitates a rapid etiological diagnosis, and the establishment of an effective treatment, both symptomatic and specific. compliance with ethics regulations: not applicable. marc pineton de chambrun , romaric larcher , frédéric pene , laurent argaud , alexandre demoule , rémi coudroy , elie azoulay , yacine tandjaoui-lambiotte , stanislas faguer , alain combes , charles-edouard luyt , zahir amoura sorbonne université, aphp, hôpital la pitié-salpêtrière, institut de cardiométabolisme et nutrition (ican), service de médecine intensive-réanimation, paris, paris, france; rationale: catastrophic antiphospholipid syndrome (caps), the most severe manifestation of antiphospholipid syndrome (aps), is characterised by simultaneous thromboses in multiple organs. diagnosing caps can be challenging but its early recognition and management is crucial for a favourable outcome. this study was undertaken to evaluate the frequencies, distributions and ability to predict mortality of "definite/probable" or "no-caps" categories of thrombotic aps patients requiring admission to the intensive care unit (icu rationale: septic acute kidney injury (s-aki) is a frequent complication in critically ill patients and is associated with high morbidity and mortality. it is well known that chronic kidney disease increases the risk of pulmonary embolism (pe), but few studies have investigated the relationship between acute kidney injury (aki) and pe occurrence in septic patients. the aim of this study is to determine whether patients with aki are at increased risk of developing pe. patients and methods: were included, in a prospective study conducted over months (january -june , ) in a medical surgical intensive care unit, all the patients older than years with septic shock at admission or during hospitalization. two groups were compared: patients with kidney injury (aki+ group) and patients without kidney injury (aki− group). we studied the occurrence of pe in these two groups. results: we included patients. the mean (sd) age was . ( ± ) years. sex ratio was . . thirty one ( . %) patients developed pe. the occurrence of pe was significantly higher in (aki + group) [ patients ( %) vs. patients ( %); p = . ]. the incidence of pe according to kidney injury severity was patients ( %) kdigo i, patients ( %) kdigo ii, patients ( %) kdigo iii. in the aki+ group, pe was significantly associated with increased sofa score at admission ( points vs. points; p = . ), lower platelets count ( , vs. , ; p = . ), higher lacatatemia at septic shock day [ . vs. . mmol/l; p = . ] and higher c reactive protein level [ mg/l vs. mg/l; p = . ]. in a multivariate analysis the pe risk factors in (aki+ group) were thrombopenia (odds ratio = . ; ci [ . - . ], p = . ) and c-reactive protein value (odds ratio = . ; ci[ . - . ], p = . ). discussion: the increased risk for pe with aki may be due to endothelial involvement, vascular injury and the related changes found in procoagulant proteins (increased levels of fibrinogen, factor vii, factor viii, von willebrand factor, and plasminogen activator inhibitor- ). in our study, lower platelet and higher c reactive protein level were found in patients with pe, suggesting the participation of disseminated intravascular coagulation. these factors may contribute to increase pe risk. conclusion: the risk of pe is higher in septic patients with aki than in those with normal kidney function. therefore, because of paucity of evidence, larger studies are needed to understand pe pathway in septic aki and to establish efficient prophylaxis protocols. compliance with ethics regulations: yes. and of these patients ( . %) required intensive care. the lasted were males ( %) and a majority ( %) were younger than years of age. in intensive care patients, only ( . %) had nosocomial infection, majority were community acquired infections ( . %) with ( %) pneumoniae, ( . %) profound abscess, pyelonephritis ( . %), ( %) meningitidis. patients( %) required mechanical ventilation for days ( % ci - ), length of stay in icu was days ( % ci - ) and mortality rate was %. conclusion: hmkp infections lead young patients in intensive care unit in one third of case with a majority of pneumoniae requiring mechanical ventilation and with a high rate of mortality. furthers studies are needed to investigate the role of this particular strain in severity. compliance with ethics regulations: yes. rationale: infections secondary to snakebite occur in a number of patients, and are potentially life-threatening. bothrops lanceolatus bites in martinique average thirty cases per year and may result in severe thrombotic and infectious complications. we aimed to investigate the infectious complications related to bothrops lanceolatus bite. patients and methods: a retrospective single-center observational study over seven years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) was carried out, including all patients admitted to the hospital due to bothrops lanceolatus bite. clinical and biological data were reported using the dx care, x-plore et cyberlab softwares of the emergency medicine and analyzed. one hundred and seventy snake-bitten patients ( males and females) were included. thirty-nine patients ( %) presented grade or envenoming. twenty patients ( %) developed wound infections. the isolated bacteria were aeromonas hydrophila ( cases), morganella morganii ( cases), group a streptococuss, and group b streptococcus (one case each). patients were treated empirically with third-generation cephalosporin (or amoxicillin/clavulanate), aminoglycoside and metronidazole combinations. outcome was favorable. the main factor significantly associated with the occurrence of infection following snakebite was the severity of envenoming (p < . ). our findings clearly point towards the frequent onset of infectious complications in b. lanceolatusbitten patients presenting with grade and envenoming. conclusion: infectious bite-related complications of bothrops lanceolatus account for approximately % of the cases, with a strong predominance for grade iii and iv. thus, based on the bacteria identified in the wounds; we suggest that empiric antibiotic therapy including third-generation cephalosporin should be administered to those patients on hospital admission. compliance with ethics regulations: yes. rationale: endocrine abnormalities have been reported with varying frequencies, following traumatic brain injury (tbi). few studies have examined the clinical features and outcomes of isolated acute thyrotropic hormone deficiencies after tbi. theaim of the study was to evaluate the early changes in thyrotropic hormone levels after traumatic brain injury (tbi) and to evaluate whether hormone changes are related to outcome patients and methods: we conducted a months long prospective cohort, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). blood samples for basal hormone values of thyroid-stimulating hormone (tsh) and free thyroxine (ft ) were obtained on days , , and . tsh serum concentrations were considered normal at > . mu/l; ft at > pmol/l. a thyrotropic insufficiency was defined as low ft and low tsh plasma levels. all patients were screened with a brain mri. patients were also monitored for neurological deterioration, including cognitive decline, convulsive seizures, increase in cerebral edema and brain herniation that were simultaneous to the diagnosis. results: during our study period's, trauma patients were admitted to our icu and met the inclusion criteria. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . of the patients a thyrotropic insufficiency was diagnosed in patients ( %) during the first days. the median delay to thyrotropic insufficiency diagnosis was days. in three of ( %), the thyrotropic insufficiency was nonrecovering during the patient's icu stay and was transient for the rest. none of the patients with acute thyrotropic insufficiency had direct hypothalamic or pituitary lesions on the brain mri. factors associated to the occurrence of acute thyrotropic insufficiency were: the ais of the head ( . ± . vs. ± . , p = . ), cerebral contusions ( % vs. %, p = . ), subarachnoid haemorrhage ( % vs. %, p = . ) and subdural haematoma ( % vs. %, p = . ). thyrotropic insufficiency was associated to neurological deterioration (p = . ) on the day of diagnosis but did not affect icu mortality ( % vs. %, p = . ). in this study, low pituitary-thyrotropic axis hormone levels were found in the acute phase of tbi and were associated to neurological deterioration but with no perceived effect on icu mortality. compliance with ethics regulations: yes. rationale: acute diabetes insipidus following head injury and its effect on patients outcome have not been sufficiently evaluated in large prospective studies. the aim of this study was to determine the incidence of acute cdi, delay of onset predictive factors and its impact on tbi patients. we conducted a prospective cohort, including all patients admitted to icu with moderate to severe tbi, defined as a glasgow coma scale (gcs) below twelve. for each tbi patient plasma sodium was measured daily, and if abnormally high, urine specific gravity and osmolality were measured. cdi was diagnosed using the seckl and dunger criteria. acute cdi was defined as cdi diagnosed in the first week following injury. all patients were screened with a brain mri. results: during our study's period, trauma patients were admitted to our icu, presented with moderate to severe tbi and were included. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . twenty-three percents ( patients) of the patients developed hypernatremia and % ( patients) were diagnosed with acute cdi. in of ( %), the cdi was nonrecovering. the median delay to develop transient cdi was h and for non-recoviring cdi was h (p = . ). none of the patients with acute cdi had direct hypothalamic or pituitary lesions. factors associated to the occurrence of acute cdi were: younger age ( ± vs ± , p = . ), neuro-surgery ( % vs. %, p < . ), hemorrhagic shock ( % vs. %), p < . ), cerebral edema ( % vs. %), p < . ), and fractures to the base of the skull ( % vs. %, p = . ). patients who developed cdi had a significantly higher mortality than those who did not ( of ( %) vs. of ( %), p < . ). there were no difference in terms of mortality between non-recovering and transient cdi ( % vs. %, p = . ), similarly the onset of cdi did not affect mortality ( h vs. h, p = . ). patients with acute cdi had poor glasgow outcome scale ( ± . vs. . ± . , p < . ) and longer icu los ( ± vs. ± , p = . ). conclusion: acute cdi is associated with higher mortality and poor outcome. therefore it is essential to diagnose and treat it promptly and correctly. compliance with ethics regulations: yes. acute glucocorticoid deficiency following traumatic brain injury mariem dlela, rania ammar zayani, abir bouattour, najeh baccouche, mounir bouaziz habib bourguiba hospital, sfax, tunisia correspondence: mariem dlela (mariem @gmail.com) ann. intensive care , (suppl ):p- rationale: published data demonstrates that long-term hypopituitarism could be common after traumatic brain injury (tbi).however, few studies focused on radiological, clinical, and repetitive endocrine assessment in the acute phase. the aim of the study was to evaluate the early changes in the adrenal axis following (tbi) and to evaluate whether hormone changes affect patient's outcome. we conducted a prospective study, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). each patient underwent sequential measurement of plasma cortisol (pc) on days , , and after tbi. we defined adrenal insufficiency as pc less than ng/ml. patients who received glucocorticosteroid therapy were excluded. outcome was measured by incidence of death, and glasgow outcome scale (gos) on day thirty. souhila sadat, dalila zeghdoud, dalila bougdal, kamel guenane ehs salim zemirli, alger, algeria correspondence: souhila sadat (sadatsouhila@hotmail.fr) ann. intensive care , (suppl ):p- rationale: the renewed interest in the pathophysiology of severe traumatic brain injury (tcg), allowed the understanding of the pathophysiological mechanisms leading to neuronal death.the non-invasive, easy, patient-based technical dtc allows evaluation of cerebral blood flow. purpose of the study: to determine the contribution of transcranial doppler (dtp) in the prevention of post-traumatic ischemia. patients and methods: a monocentric, observational, prospective study over a period of years, including tcg in the monitoring of cerebral blood flow (dsc) was provided by the dtc. we collected the following data: age, gender, lesion mechanism, lesion association, glasgow score at admission, time to perform the initial scan, time to perform the initial doppler, various abnormalities found at the initial dtp, the analysis of the level of map according to each situation of cerebral blood flow, the proposed therapies, the time to obtain a correct dtc. ( %), the statistical analysis showed no difference between the delay in setting up a hypohemia and the presence of a correct cerebral blood flow (p = . ), the statistical analysis of the map in the dtc group hypohemia compared to the correct dtc group objectified the absence significant difference between the two groups. the realization of dtp allowed therapeutic prioritization, the introduction of norepinephrine was in % of cases, osmotherapy in % of cases, optimization of sedation in . % of cases, the introduction of penthotal in . % of cases and the completion of decompressive in . % of cases. statistical analysis of mortality showed a significant difference in mortality (p = . ) in the hypohemic dtc group compared with the correct doppler . conclusion: ttc is an essential monitoring tool of cerebral hemodynamics, which may in prove the neurologic outiome of tcg. compliance with ethics regulations: yes. rationale: hyponatremia is a frequent electrolyte disturbance in hospitalized patients. it is particularly common in brain-injured patients with significantly elevated morbidity and mortality. the aim was to study the prevalence of hyponatremia in the acute phase of post-traumatic cerebral aggression, its degree of severity, its predictive factors as well as its prognostic impact in the population of post-traumatic brain injury. patients and methods: this is a retrospective study, carried out over a period of years about all traumatized head patients who developed hyponatremia during the first h of their stay. the descriptive part treated all patients who developed hyponatremia by detailing its different stages of severity.the analytical part treated the patients who developed a hypo-osmolar hyponatremia with a threshold of mmol/l retained to define the severity. during the study period, the incidence of hyponatremia in head trauma patients was . %. the occurrence of hyponatremia was associated only with the occurrence of early seizures (p = . ).severe hyponatraemia was associated with paroxysmal occurrence (p = . ), mass effect (p = . ), and hemostasis disorders. the multivariate study revealed that severe hyponatremia was associated with the glasgow score (p < . ) and pupillary changes (p = . ). on the other hand, it is the initial variation in serum sodium that was associated with both the severity of the initial neurological examination; glasgow (p < . ), saps (p = . ), pts (p = . ) and prism scores (p = . ), haemodynamic instability (p = . ) and neurovegetative disorders (p = . ). lesional features have also been found.regarding the prognosis, the occurrence of initial hyponatremia had a protective effect: a more favorable gos score p = . and a lower mortality (p = . ). a poor neurologic prognosis as well as a high mortality were associated with the most severe hyponatraemia and particularly with the initial variation of the sodium level (p = . ;). the mortality was . %. it was also particularly related to the initial change in sodium levels (p < . , . ). we concluded that there is no association between post traumatic early hyponatremia and the severity of the initial clinical presentation. however, the depth of hyponatremia and especially the initial change in sodium levels have been associated with more severe clinical pictures and a more limited prognosis. compliance with ethics regulations: yes. rationale: post-traumatic epilepsy (pte) is one of the complications described in the aftermath of headtrauma. its incidence is variable in the literature because of its clinical polymorphism. objectives of the study was to analyze the epidemiological profile (clinico-biological, radiological, therapeutic and evolutionary) of the patients having presented pte and to determine the risk factors for this pathology by comparing them with the rest of the traumatized brain patients. patients and methods: our study was retrospective. it was conducted in the intensive care unit (icu) of our university hospital between and . were included in our study all patients admitted to the service with brain injury and a glycaemia above mmol/l during the first h post-trauma. results: the incidence of pte was . %. ( among ) the average age was . ± . years. the sex ratio was . . the average of gcs was . ± . . three ( . %) patients had initial motor impairment. seizures were observed in ( . %) patients during the first h of hospitalization. the mean delay of occurrence of pte was ± . months. pte was diagnosed before the end of the first post-traumatic year in patients ( % of cases). the most commonly observed brain lesions were cortical brain contusions ( rationale: electrolytic disorders are common in neuro-resuscitation, especially dysnatremias and dyskalemias. hyponatremias are the most frequent, including the main etiologies: the syndrome of inappropriate secretion of antidiuretic hormone (siadh) and the "cerebral salt wasting" syndrome (csw). diabetes insipude of central origin secondary to a lack of dha secretion is the second most common disorder. patients and methods: it is a prospective study, analysing all the brains injured admitted to the a intensive care unit of chu hassan in fez, morocco. study spread over a -month period from / / to / / . the objective of the study is to detect the most frequent hydro-electrolytic disorders and to evaluate the therapeutic effectiveness of the service protocols. results: all these brains injured have caused he disorders over a period of time varying between d and d : * cases of hyponatremia ( %)/ cases of hypernatremia ( %), * cases of hypokaliemia ( %)/ cases of hyperkaliemia ( %), * cases of hyperchloremia, or %/ cases of hypochloremia ( %). * cases of diabetes insipidus, or . %. * cases without he disorder ( . %). the treatment for these disorders was: *for hypona; it reached mmol/l, initially corrected by a -hour water restriction, followed by an increase in the basic ration and furosemide boluses according to the ecv, even sodium loads for a single case of salt loss syndrome, while the main etiology remains the siadh. *for hyperna, it has reached mmol/l, evaluated by the extracellular volume, corrected by enteral tap water after calculation of the hydric deficit. if hperna is associated with polyuria greater than cc/kg/h; we speak of: *insipude diabetes, with polyuria up to cc/kg/h, compensated with potassium-containing solutions and blood ionogram monitored every h. desmopressin was used in titration, by bolus of . µg, with a diuresis objective between and . ml/kg/h. *for hypokalemia, up to . g/dl, observed mainly in the acute phase of brain aggression, corrected by increase in br for a k between . and g/l, and by potassium loads if k below . g/l. the evolution: deaths or . % ( cases of uncorrected diabetes insipidus), the restriction of disorders were corrected. conclusion: a knowledge of the hydroelectrolytic disorders encountered in this context is essential, as well as the implementation of a diagnostic and therapeutic protocol, which will reduce the time required to correct these disorders. compliance with ethics regulations: yes. . ] u/h). however, workload was increased under star ( vs. measurements per day), as expected from measurement interval difference between star ( -hourly) and the sp ( -hourly). conclusion: this unique patient-specific risk-based dosing approach gc framework was successful in controlling all patients safely and effectively. these preliminary results are encouraging and show gc can be achieved safely and effectively at lower target bands. in turns, these improved gc outcomes could improve patient outcomes. compliance with ethics regulations: yes. rationale: although its incidence has declined in recent years, gastric cancer remains common worldwide and is the leading cause of gastrectomy. his treatment is mainly surgical, but his prognosis remains poor. many studies on survival and prognostic factors have been carried out in foreign series. patients and methods: this is a retrospective study covering a period of three years from january to december interesting patients who had a gastrectomy and hospitalized in emergency resuscitation department surgical uhc ibnou rochd from casablanca. the statistical analysis of the different clinical, paraclinical and therapeutic data was carried out thanks to an exploitation sheet. rationale: gram-negative bloodstream infections (gnbsi) require timely appropriate antimicrobial therapy in intensive care units (icu) patients. conventional techniques usually take - h for antimicrobial susceptibility testing (ast). innovative approaches (accelerate pheno ™ system) provide pathogen identification in ~ h and ast including minimal inhibitory concentrations (mics) in ~ h. we report, in icu patients with gnbsi, results of implementation of the accelerate pheno ™ in our laboratory. we prospectively screened all gnbsi episodes reported in adult icu patients between september and september . to allow integration into the laboratory workflow, the accelerate pheno ™ was run on blood bottles positive before am (day ), in parallel with routine procedures: maldi-tof identification after short incubation on solid media (day ), β lacta (bio-rad ® ) test (day ) and disk diffusion method for ast (day+ ). for each episode, antimicrobial regimen was reassessed by a multidisciplinary team of bacteriologists, infectious diseases and icu physicians by the end of day . we measured: (i) concordance of accelerate pheno ™ results with conventional techniques, (ii) number of antibiotic adaptations on day and (iii) number of patients within the therapeutic range (free fraction over x mic and below concentration at risk of adverse events), based on real-time measurement of beta-lactams concentrations. results: of patients reported with gnbsi over the study period, were included. mean age was of ± . years, / were males. main sources of gnbsi were pulmonary (n = ) and digestive (n = ). bacterial identification of the accelerate pheno ™ was concordant with standard techniques in ( %): enterobacteriacae (n = ), pseudomonas aeruginosa (n = ). overall categorical agreement for ast was of % ( errors including very major errors). by the end of day , the antibiotic regimen was de-escalated in ( %) patients, which was appropriate in ( %). in cases, de-escalation was possible, but not fulfilled by icu physicians. twenty patients had beta-lactams concentrations measurements: were in the therapeutic range, below and over. conclusion: accelerate pheno ™ provided rapid and accurate results for most microorganisms isolated in blood cultures of icu patients with gnbsi. however, in a laboratory with routine maldi-tof early identification and β lacta test performed on day , the impact on early adaptation of the antibiotic regimen was evident in around patient over . compliance with ethics regulations: not applicable. jean-luc baudel , jacques tankovic , redouane dahoumane , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet service bactériologie, hôpital saint-antoine, paris, france; service réanimation médicale, hôpital saint-antoine, paris, france correspondence: jean-luc baudel (jean-luc.baudel@aphp.fr) ann. intensive care , (suppl ):p- rationale: evaluation of the accurateness of the accelerate phenotest bc kit for rapid analysis ( . h for microorganism identification and additional hours for antibiotic susceptibility testing) of positive blood cultures from icu and hematology patients. patients and methods: from february to august , we included patients from the icu and hematology units with positive blood cultures. the following informations were collected : gender, age, duration of prior antibiotherapy, source of the infection, results obtained by conventional microbiological methods and by phenotest (data obtained and time to obtention of results). informed consent was obtained from all patients. results: blood cultures were analyzed in patients (m/f ratio . , age . ±, from the icu and from hematology). % of the patients were receiving antibiotics at the time of blood culture collection (mean duration : . days). the source of infection was unknown in % of cases, urinary in %, catheter-related in %, ascites in %, pneumonia in %. in cases ( %), there was a perfect match between phenotest and conventional results (identification and antibiotic susceptibility testing). in cases ( %), the bacterium responsible was not present in the phenotest panel. in cases ( %), phenotest identification was correct, but some discrepancies were observed regarding antibiogram. in cases ( %) phenotest identification was again correct but no antibiogram was available. in cases ( %), where two bacteria were present, phenotest could not identify one of them. in cases, phenotest did not provide bacterial identification because too few bacteria were present in the blood culture bottle. conclusion: the phenotest panel covered % of the bacteria implicated in this study. when the bacterium responsible was present in the panel, the results given by the phenotest correlated in % of cases with those of conventional methods. some rare discrepancies were observed regarding antibiotic susceptibility testing that have to be analyzed further. in the remaining % of cases, where too few bacteria or two different bacteria were present in the blood culture bottle, technical limitations did not permit to correctly identify microorganism(s) present or to obtain an antibiogram. compliance with ethics regulations: yes. mélanie fromentin, antoine bridier-nahmias, constance vuillard, jean-damien ricard, damien roux inserm umr iame infection antimicrobials modelling evolution, paris, france correspondence: mélanie fromentin (mel.fromentin@wanadoo.fr) ann. intensive care , (suppl ):p- rationale: studying human lower respiratory tract microbiota by using ngs (new generation sequencing) method is complex because of many unexpected biases due to dna extraction and amplification procedures. lung microbiota evolution under mechanical ventilation evolution may be highly informative to evaluate the actual risk of vap (ventilator-associated pneumonia) development. before starting a large study on the lung microbiome of ventilated icu patients, a methodological study was mandatory. patients and methods: five control and three vap patients were selected. endotrachealaspirate (eta) and oropharyngeal swab (os) were collected at icu admission for control patients and, days before and on the day of vap diagnosis for vap patients. after automated extraction of total dna, hypervariable region v of the s rdna genes was amplified with two different pairs of primers f- r: oligonucleotides from the earth microbiome project (earth primer pair) and from the gut microbiome project (gut primer pair), followed by sequencing on illumina miseq plateform. after bioinformatics analysis with mothur ® software, we compared the performance of ngs alongsideconventional bacterial culture. differences in alpha diversity (microbial diversity in a sample), expressed as the shannon index, across respiratory tract site (upper or lower) and across time (before and at vap time) has been investigated. a positive control (pc), rationale: colistin is used as a last-line treatment to combat multidrug-resistant (mdr) gram-negative bacilli (gnb). worryingly, colistin resistance in klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumannii is increasingly reported worldwide. we hereby report the prevalence of colistin resistance among gnb isolated from burn patients in tunisia. the study was carried out on strains of gnb isolated from microbiological samples of burn patients hospitalized in the intensive care unit between october and december . identification was performed by conventional methods. antimicrobial susceptibility was tested by disk diffusion method and the results were interpreted according to ca-sfm guidelines. minimum inhibitory concentration (mic) of colistin was determined using the eucast broth micro-dilution method (umic, biocentric ® ) results: pseudomonas aeruginosa was the most frequently isolated bacteria ( strains), followed by acinetobacter baumannii ( strains) and klebsiella pneumoniae ( strains). the most common sites of isolation were blood cultures ( %), catheters ( %) and skin samples ( %). most of p. aeruginosa isolates were multidrug-resistant with high levels of resistance to imipenem ( . %), ceftazidime ( %) and ciprofloxacin ( . %). however, all of them were susceptible to colistin. in fact, mics of colistin against all p.aeruginosa isolates were less than or equal to . mg/l. a. baumannii strains had high resistance rates to beta-lactams : % to ceftazidime and % to imipenem. only one strain was resistant to colistin with a mic equal to mg/l. all k. pneumoniae isolates were resistant to extended-spectrum cephalosporins. one third of these strains were resistant to imipenem and more than half ( . %) were resistant to amikacin. two strains were resistant to colistin with high mics (> mg/l). both were carbapenemase-producers, carrying oxa- and ndm carbapenemase encoding genes. conclusion: these data suggest that colistin-resistant or pan-drug resistant gnb clinical isolates are still relatively rare. however, they have important global public health implications because of the therapeutic problems they present, especially for vulnerable populations such as severely burned patients. hence the need to test colistin regularly in the laboratory and to set up a monitoring program for mdr pathogens. compliance with ethics regulations: yes. rationale: descending necrotizing mediastinitis (dnm) are medicosurgical emergencies whose forecast is closely related to the precocity of the therapeutic assumption. the purpose of our work is to profile these patients as well as the therapeutic and evolutionary aspects. patients and methods: retrospective study over years in the intensive care unit of the hospital august. all patients with dnm on cervicofacial cellulitis were included. results: cases were collected, % of cellulitis, incidence of . patients / year. average age , sex ratio of . . smoking, chronic alcoholism and diabetes are the most common antecedents. the favoring factors were: (poor dental conditions: % of cases, non steroidien anti-inflammatory drugs: %, diabetes: %). in % of cases the front door was dental. average time taken to take care of days. c-reactive protein and procalcitonin were positive in all patients. in % the chest x-ray was normal. all patients received tri-antibiotic therapy. intubation were difficult in all patients, we used nasofibroscope in % of cases and a rescue tracheotomy in one patient. only one patient had a cervico-thoracic surgical approach; for all the others she was cervical alone. streptococcus was the most isolated germ. the complications were (septic shock: %, ards: %). the average hospital stay was days with a mortality rate of %. conclusion: dnms are poorly prognostic. the best treatment remains prevention by better management of dental abscesses and tonsillar phlegmons. rationale: the initial, empirical antibiotic therapy of ventilator-associated pneumonia (vap) is often based on timing of its occurrence in relation to the onset of mechanical ventilation. this is due to reported differences between causal pathogens associated with early-onset (e-vap < - days of mechanical ventilation) compared to late-onset vap (l-vap ≥ - days of mv). e-vap is most often reported to be due to antibiotic-sensitive pathogens while l-vap is frequently attributed to antibiotic-resistant pathogens. however, there is emerging evidence that the isolated microorganisms may be similar regardless of onset time. the aim of our study was to compare the clinical outcomes of critically ill patients developing e-vap and l-vap and to compare the causative pathogens of the two groups. patients and methods: all the patients with the diagnosis of vap admitted between january and december were retrospectively included. vap was suspected on the basis of clinical and chest x-ray findings. the identification of the causative organisms was performed with endotracheal aspirate (eta) cultures. results: ninety patients developed vap. e-vap was observed in patients ( , %), whereas patients ( , %) developed l-vap. among patients with early-onset vap, % received antibiotics prior to the development of pneumonia, compared to % with late-onset vap (p = . ). otherwise, no differences (sociodemographic factors, antecedents, severity score, length of stay, length of mv) between the two groups were observed. the most common pathogens associated with e-vap were enterobacter species ( . %), pseudomonas aeruginosa ( . %) and oxacillin-resistant staphylococcus aureus (orsa , %). enterobacter species ( . %), acinetobacter baumannii ( . %) and pseudomonas aeruginosa ( %) were the most common pathogens associated with l-vap. no difference was noted in the contribution of multidrug resistant bacteria mdr ( % vs. %). hospital mortality was significantly greater for patients with l-vap caused by mdr ( %) compared to patients with e-vap ( %) (p = . ). conclusion: this classification is no longer helpful for empirical antibiotic therapy, since both early-onset and late-onset vap were caused by mdr bacteria. this justifies the need of intensive care unit-specific knowledge of causal agents associated with vap to reduce the rate of administration of inadequate antimicrobial therapy. compliance with ethicsregulations: yes. key: cord- -ak pq authors: nan title: th european congress of intensive care medicine athens - greece, october – , abstracts date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: ak pq nan objectives: evaluate the levels of tnf, il- and pai-i in different moments of the ards and the possible relationships among them. methods: septic patients with ards were studied. also significant differences for: tnf, pai-i and il- in septic patients and both evaluations of ards with control gropup; pai- between septics and nd evaluation in ards, and between the ist and nd evaluation in ards; il- between septics and both evaluations in ards; and il-~ in both evaluations in ards patients in relation to mortality. conclusions: i) elevations of tnf, pai-i and il- , with clinical signs, are suggestive of infection; ) the persistent and progressive elevation of pai-i with any clinical criteria may suggest evolution to ards; ) due to its own kynetics, il- takes part later in the acute phase, its levels being related to the magnitude of the injury in the tissues. objectives: the influence of long-term volume therapy with different solutions on plasma levels of circulating adhesion molecules was studied. methods: according to a randomized sequence, patients with sepsis secondary to major surgery exclusively received either hydroxyethylstarch solution ( % hes, mean molecular weight (mw) , daltons, degree of substitution (ds) . ) or human albumin % (ha) for volume therapy for days. plasma levels of circulating (soluble) adhesion molecules (endothelial leukocyte adhesion melecule- [selam -i] , intercellular adhesion molecule- [sicam -i] , vascular cell adhesion molecule- [svcam -i] , and p-selectin ) were serially measured on the day of admission to the intensive care unit (='baseline ' value) and during the next days. results: selam-i, sicam-i, and svcam-i plasma levels were markedly higher than normal at baseline in both groups. in the hes-patients, selam-j decreased to normal range, whereas it further increased in the ha-group (from • to • during the study period, sicam-i and svcam-i plasma levels remained unchanged in the hes-patients, but further increased in the ha-group (from • to , • sgmp- increased significatly only in the ha-group ( • to • only pao /fio was significantly correlated to plasma levels of adhesion molecules. conclusions: sepsis is associated with markedly elevated plasma levels of adhesion molecules indicating endothelial activation or damage. by long-term volume therapy with hes, these levels remained unchanged or even decreased, whereas volume therapy with human albumin did not have any beneficial effects on soluble adhesion. central venous catheters are frequently used in the care of the critically ill patient. the incidence of catheter related sepsis varies in the literature. we investigated the occurrence of contamination and sepsis compared to results of the epic study as part of quality assesment in our intensive care unit. from january until august all removed central venous catheters were examined for microbiological culture. the patients who showed signs of sepsis were also registered. the results of the contaminated catheters and septic patients were compared with results from the epic study. during the month period , patients were hospitalized on our intensive care unit. central venous catheters were examined for microbiological culture. specimens appeared to be possitive ( %). patients showed clinical signs of sepsis. the incidence of sepsis due to contaminated central venous catheters was / ( %). the incidence of sepsis due to the presence of all central venous lines was / ( %). the microorganisms responsible for the sepsis syndrom were : stapylococcus aureus (n= ), escherichia colt (n= ), others (n= ). in the epic study the percentage for sepsis on the icu was . % for the netherlands and . % for europe. despite a high number of positive culture from removed intravascular lines, a low percentage of sepsis was seen compared to results of the epic study. we recommend routine bacteriological culture of all removed central venous lines and recommend to look at colonization and sepsis due to intravascular lines as a measure of quality control in the intensive care unit. objectives: prognostic assessment of simplified acute physiology score (saps) in granulocytopenie patients with septic shock (ss). methods: the medical records of admissions to an intensive care unit (icu) of granuloeytopenic patients with ss are reviewed. fiftytwo patients had haematological malignancies. seven patients had aplastie anaemia. patients were categorised as survivors (discharged from icl and non-survivors (died in the icu). saps index was calculated for patients daily during their stay in icu. all patients were severe granulocytopenic (total white cell count less than , ] ] ). results: five patients ( , %) were discharged from icu. fifty-four patients died in icu. non-survivors had saps on admission higher than survivors ( . + . and . + . , respectively, p< , , mann-whitney u test). no patient with a saps greater than survived. mortality among the patients with saps from to was , %o. the evolution of ss was rapid. the mean stay in icu among non-survivors was only hours. an analysis of the saps index on admission of non-survivors showed an inverse correlation with the duration of their stay in icu (r=- , , p= . ). all survivors recovered from granulocytopenia. they had normal white cell counts at the time of discharge from icu. there was inverse correlation in survivors between saps and white cell counts, when these parameters were evaluated daily. however, the saps index alone cannot be considered to be on individual predictor factor of mortality. patients who had failure of the malignancy to respond to chemotherapy and who had persistent granuloeytopenia died in icu despite saps index on admission and recovery from ss. conclusion: saps index greater than , failure of the malignancy to respond to chemotherapy and persistent leueopenia all point to a poor outcome of granulocytopenie patients with ss. introduction: antipyretics sometimes are used for fever control in febrile neutropenic patients with hematological malignancies(hm). we observed a dramatic fall of blood pressure(bp) and development of septic shock(ss) in some of the patients who received antipyretics. aim: to clarify can antipyretics provoke ss in neutropenic patients with infection. methods: retrospective review of medicat records of neutropenic(wbc < , / )patients with hm, admitted to the intensive care unit for ss, was performed. there was selected group of patients receiving antipyretics shortly before a fall of bp. results: there was a definite causal relationship between receiving antipyretics and fall of bp in from patients. all patients had fever due to infection and had normal level of bp before receiving antipyretics. hypotension developed within minutes up to , hours after administration of antipyretics. three patients received , g of metamisol and one , g ofparacetamol per os. in all cases we observed dramatic diaphoresis and the temperature fall to subnormal level ( . + . ~ accompanied'by hypotension. but in - hours the fever was coming back without blood pressure elevation. the fluid replacement was controlled by central venous or wedge pressures. there were required + ml colloid and cristalloid solutions for volume loading. in spite of fluid administration the hypotension persisted and all patients required inotropic therapy. only one patient survived and is alive now. conclusion: it seems to us that our data offer to state that antipyretics administration can initiate ss in febrile neutropeuic patients with infection. objectives: to assess the agreement between cardiac output (co) measured by odm t and by other methods used in icu patients. methods: we prospectively studied adu t patients requiring hemodynamic monitoring with a pulmonary artery catheter. an esophageal doppler monitor provided measurements of co (odm), stroke volume and flow time (ft) used as an indirect evaluation of patient's volume status. patient hemodynamic status was evaluated by a modified fast response pulmonary artery catheter (baxter health care corporation, santa ana, ca), allowing co measurements by thermodilution "d) and an evaluation of right ventricular ejection fraction and end diastolic volume (rvef and rv-edv). in the last six patients co was measured by transthoracic echocardiography (echo) and oxygen consumption was measured by a deltatrack ii metabolic monitor (datex) allowing co calculation according to the fick formula (fick). the agreement between methods measuring co and their reproducibility, were evaluated by bland and altman analysis. results: agreement between co measurements is expressed as bias (d) and % limits of agreement (l of a = d_+ sd . td-fick - . - . to . fick-echo . - . to . there was no correlation between ft and rv-edv. conclusions: although co measurements by odmil had the best reproducibility, the limits of agreement between the four methods tested were unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of co measurement in the icu. phd, a. paltzev, v.bajbikov, b.dobryakov d.sc., a.ostanin phd, o.leplifia phd, h.chernykh phd munieip. hosp. n l, n ; inst. of clin. immunol., novosibirsk, russia objectivies: efficiency of native cytokines used in the treatment of patients with severe surgical infections has been studied. methods: for two years patients were treated with cytokine mixture (ssp) obtained by arterio-venous perfusion of swine spleen and contained the following cytokines: il- , il- , il- , tnfa, ifny, gm-csf. results: ssp intravenous infusions were shown to accompany with mortality decrease from . % to . % in patients with abscessed pneumonia and lung abscesses and from % to % if disease course was complicated with sepsis. in patients with purulent peritonitis and sepsis efficiency of ssp was decreased due to endotoxieosis. thus, we used adoptive immunotherapy with mnc activated in vitro with ssp or recombinant il- . intravenous infusions of such cells resulted in transformation of a pathologic process from destructive into productive one. moreover, clinical manifestations of sepsis were controlled in % and mortality was decreased from % to %. conclusions: the use of eytokines themselves as well as cytokine-treated lymphoeytes permits to control the disease and leads to the mortnlity decrease owing to stimulation of host defence mechanisms. background: although red blood cell transfusions (rbct) are used to increase oxygen availability in septic patients, several lines of evidence suggest that rbct may actually worsen tissue hypoxia. thus, rbct may negatively influence outcome of septic patients. objectives: to determine the association of ) rbct ; ) number of units transfused; and ) mean age of the units transfused on the first day of transfusion with mortality of critically ill septic patients. methods: we prospectively identified patients who met strict criteria for sepsis syndrome (ss) seen in the icu of st. paul's hospital from to and excluded patients who died in the first days after the onset of sepsis. we recorded clinical characteristics, multiple system organ failure score, and apache ii at onset of sepsis. then, we retrospectively recorded the total number and age of rbc units transfused during the first days after onset of sepsis. overall -day mortality was %. results: the main results are shown in the table. the mortality of patients who received rbct was nearly double the mortality of those who did not receive rbct even after adjusting for severity of illness using apache ii. objectives: gastric mucosal acidosis is frequently observed in patients with sepsis. the aim of this study was to determine whether volume infusion using pentaspan| decreases abnormal gastric mucosal pco (pico ) in patients who have sepsis syndrome (ss) who have already been resuscitated using clinical endpoints. methods: we prospectively identified patients who met strict criteria for ss, had a pulmonary artery catheter and a gastric tonometer in place, and pico > mmhg. pentaspan| ( ml) was infused in rain. measurements of hemodynamics, hemoglobin, arterial lactate, blood gas analysis, and pico were performed before and repeated miff and hr after pentaspun| infusion. we calculated the pico -arterial pco' difference (pico -paco ) and phi (using henderson-hasselbach equation). anova was used to assess statistical significance. results: all patients werereceiving adrenergie drugs. map was : : mmhg and lactate . : : . mmol/l. pentaspan| increased ci by % (p< . ) but did not change pico ( and increase m oxygen o* wery were simimny achieved in both groups. nevertheless, epinephrine was associated with a lactic acidosis and increased laetate/pyruvatemia ratio (l/p) that evoke a dysoxia rather than a metabolic effect. an higher gastric mucosal pco in the ep group compared to nor-rob suggests the hypothesis of an anaerobic production of co in favor of a splanchnic hypoxia. in both group, arterial ketone body ratio that reflects hepatic mitochondrial redox state, compared to a control group without shock was decreased but increased between and hours after restoration of arterial pressure. the association norepinephrine-dobutamine seems to be better for splanehnic circulation than epinephrine and should be used for dopamine resistant septic shock. moreover, the increase in arterial pressure with nor-dob improved gastric mueosal ph and hepatic mitochondrial redox state and argue to reconsider arterial pressure as a significant goal for resuscitation in septic shock. conclusion: significantly higher malondialdehyde and ghitathione levels and glutathione-peroxidase activity in group ns at the end of icu stay were related to mortality these findings indicate an increased generation of free oxygen radicals together with increased anfioxidant activity in this group and sapport the employment of antioxidant interventions in critically ill patients. oblecfives: to determine the role of nitric oxide (no) in the mechanism of septic shock induced by isolated limb perfuslen with recombinant tnfcr methods: we have measured tnfr~ and metebo~ites of no in patients with signs ot septic shock following treatment with isolated limb perfusion for nonresectable soft tissue tumors and melanomas of a limb. perfuslen was carried out with melphalan (burroughs wellcome) and recombinant tnfcr (boehringer). tnfc~ was determined by specific radiometric assay (medgenix diagnostics), nitrate and nitrite were measured with a modification of the guess reaction ~. results: results are shown in the table. conclusions: during isolated limb pedusion with recombinant tnf~ very high levels of tnfcr were measured in arterial blood in patients. they all showed signs of severe sepsis syndrome with shock from vasodilafion, probably due to leak of recombinant tnft~ from the peduslen circuit to the systemic circulation. tnfc~-induced vasodilation was not accompanied by a rise in serum no-metsbolites. our findings do not confirm the widely accepted theory, mainly based on animal experiments, that genera• of no is the key pathogenefic mechanism in septic vasodilafion , nor that tnfrt invariably induces forreafion of no. the precise mechanism of shock in these patients remains to be elucidated. references: . moshage h, kok b, huizenga jr, jansen plm nitrite and nitrate determinaiions in plasma: a critical evaluation. clin chem : / . . moncada s, higgs a. the l-argioine-nitrio oxide pathway. n engl j med ; : - ec is a commonly used for prolonged, stable animal anesthesia. noting that the hypotension after iv lps was attenuated by ec, we hypothesized ec also protects against lps toxicity. sprague-dawley rats received ip saline (s), thiobutabarbita mg/kg (tb), or varied doses of ec, followed hours later by bolus mg/kg iv lps. -day survival is shown below: group: s tb ec( . gmikgi ec( .sgm/kg) ec(i. gm/kg) alive (n) t ~ total (n) s s "signiflcant;y different from all other groups, p< . s / rats given lps followed hours later by ec ( . gm/kg) also died. additional rats were treated with s (n= ) or gm/kg ec (n= ) followed by mg/kg lps, then sacrificed at hours. blood glucose (bg, mg/dl),.hematocrit (hct), leukocyte count (wsc/mm~ platelet count (pltxl ~/mm ), bicarbonate (hco, mg/dl), gross bowel hemorrhage (bh, - scale) and lung myeioperoxidase activity (mpo, ~vmirvgm wet lung) are shown below ( we conclude that ec reduces the lethality and multiple organ toxit;~ty of lps. its diverse effects suggest asite of activity upstream from the cytokine cascade. these results are important for studies of lps which may use ec anesthesia and may have potential in the therapy of septic shock. [zo = hz impedance (z; {dyn.sec.cm " }); zl = first harmonic z; zc = characteristic z; z ph. = t'trst harmonic phase angle {radians}; f, #, * at least p < . between fio . and . , fio . and fio . &no - . _+ . - . _+ . # - . + . m - . + . * - . + . * - . + . * - . _+ . * in hyperoxia, compared to dogs at the same q, minipigs had a higher ppa ( + rnmhg versus + mmhg; p < . ). hypoxia increased (ppa-ppao) at all levels of q by an average of mmi-ig in minipigs and mmhg in dogs. inhaled no inhibited hypoxia-induced (ppao-ppa)/q changes in both species. conclusions: we conclude ~ that the minipig is an animal model of elevated pulmonary vascular resistance and impedance, and ~ that hypoxia-induced alterations in pvz spectrum are due to changes of resistance in small arteries. objectives: ) to determine the toxicity of ng-monomethyi-larginine (nma) administered by intravenous bolus to patients with refractory septic shock. ) to investigate the biologic activity of nitric oxide synthase inhibitors in septic shock. methods: from august to january , thirteen patients with vasopressor refractory septic shock received nma intravenously in escalating doses from to mg/kg. results: no hepatic, renal, gastrointestinal, or hematologic toxicity was observed at doses of nma as high as mg/kg. significant biological activity was observed at all dose levels consisting of increased blood pressure (systolic blood pressure from . mm hg + . to . _+ . s.e.m., p= . , systemic vascular resistance ( + to + dyne.sec/ cm s, p=. ), and a decrease in vasopressor requirements. the magnitude and duration of these effect were dose dependent. decreased cardiac output ( . _+ . to . _+ . i/min p=. ) and increased pulmonary artery pressure ( . _+ . to . _+ . mm hg; p=. ) were also observed. no significant effects on heart rate, pulmonary capillary wedge pressure, or central venous pressure were observed. four of patients survived for more than days, patients died of cancer complications (all patients had maintained blood pressure for h on nma) and patients died of complication attributable to septic shock (mods, ards, dic, refractory hypotension), and patient was unevaluable. conclusions: no adverse clinical effects have been observed in patients receiving bolus doses of nma as high as mg/kg. the increased pulmonary artery pressures observed in septic shock patients is further augmented by nma and may limit the dose which can be administered by intravenous bolus. other schedules of drug dosing may attenuate this effect. glucose-insulin-potassium (gik) solutions have been shown to improve cardiac contractility and increase oxygen availability in experimental and clinical settings of septic shock. several mechanisms have been proposed to explain these effects including a direct improvemeut of the energy balance by glucose, a direct influence of insulin on cardiac performance or an increase in intravascular volume due to the hyperosmolarity of the solution. to explore the role of hyperosmolapity, we compared the effects of gik to those of a isoosmolar hypertonic saliue solutiou in endotoxin shock in dogs. methods : the study included mongrel dogs ( • pentobarbitalanesthetized aud mechanically ventilated with air. thirty minutes after the intravenotls administration of mg/kg of e. coli endotoxin, the dogs were randomized to receive a ml/kg infusion in rain of a hypertonic ( mosm]l) solution iucludiug either a mixture of glucose % with u insulin and meq kcl/l (glk-group ) or hydroxyethyl starch . % in naci . % (hes-group ). in each dog, a . % saline infi~sion was continued to maintain the puhnonary arlery occluded pressure at baseline level. hemodynamic, blood gas aualysis and laboratory data were collecled at baseline and miu, rain, rain, and nunutes later.. results : eudotoxin administration was followed by a fall in mean arterial pressure (map) aud cardiac index (ci) and a rise in blood lactate levels. resuscitation with either gik or hes hypertoaic solutions resulted in similm increases in map, ci, oxygen delivery and left ventricular stroke index (table ) . we conclude that during resuscitation from endotoxic shock the use of gik solutions is not superior to hypertouic hes solutions. the higher blood lactate levels observed in the dogs receiving gik can be attributed to the glucose metabolism. , for group , for group ) were drawn and immediately analysed at ~ using the abl radiometer for po , pco and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the ps at ph= . , pco = mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood, as was the ps "in vivo" (i.e. the ps at the patient's value of ph, pcoz and temperature), using siggaard-andersen's algorithm. the data were compared by the one-way anova test and by the t-test for paired and unpaired samples. results: the mean resulting values (in mmhg) with the statistical differences are shown in table i. in addition, the time series analysis shows the mean ps~st values as statistically below the psin vivo" in the septic patients while the opposite is shown for the cardiac patients. no differences in the time analysis are demonstrated for the second group. a possible clinical significance may be drawn from these different behaviours. objectives:toxemia degree and humoral immunity condition have been studied in patients aged from to with progressive course of sepsis and polyorganic insufficience. methods: such toxemia and humoral immunity findings as lencositlcindex of toxication (lii), level of oligopeptides of the middle molecular mass registered at the wave length of nm(mmi) & nm (mm ), distribution index (id), immunoglobulins a,m,g, concentration of circulating immunocomplexes (cici & cic ) and also some clinical and biochemical findings on the , , day after the operation serve as criteria for treatment effect. results: it was founded that in intensive therapy and detoxication, level of lii is successively decreased from . ~ . to . +. on the -th day after the operation. true decrease of the level mm from . ~. to . +. un & optimal density and increase of distribution index from . to . are argued. conclusions: in studlng the dynamics of the immunoglobulin's spectrum and the true increase of immunoglobulin g level from . +. g/i to i . +. g/i on the -th day after the operation simultaneously with the decrease of cic from . ~ to . ~ . (p . ) were founded. some stages of the investigation true increase of lymphocytes from . + . % to . + . % was noted and it appeared to be a favourable prognosis finding for disease outcome. high correlation dependence between bacillus-and segmentonuclear neutrophils and immunoglobullns g & m (r=. -. in p<. ) was discovered and it also showed positive dynamics of the course of the disease. a year old male patient was admitted to the icu with severe paraquat poisoning. treatment consisted of gastic lavage and oral administration of fullers earth. because of very high plasma levels hemodialysis together with charcoal hemoperfusion was started within one hour after admission. this treatment was further continued by continuous veno-venous hemofiltration in order to remove the circulating paraquat and also circulating cytokines. nevertheless patient s condition worsened necessitating artificial. ventilation and hemodynamic support. patient died hours after admission of acute multiple organ failure due to paraquat poisoning. serum levels of paraquat were determined by colorimetric method (table) . levels of interleukin (il ) and (il ), tumor necrosis factor (tnf-alpha), interleukin i receptor antagonist (il ra) were determined both in plasma and ultrafiltrate ( q~!ectives : evaluate in critically ill patients the effects of tow-dose dopamine on gastric mucosal blood flow (gmbf) using laser-doppler flowmetry, a continuous non invasive method of assessing microcirculation. methods : patients requiring both mechanical ventilation and pulmonary artery catheterization for multiple trauma (n= ), ards (n= ) and pancreatitis (n=l) were included. in each patient, the laser-doppler (ld) probe was inserted through a naso-gastric tube. the ld signal is proportional to the number of red blood cells moving in the measuring volume and the mean velocity of these cells. when the ld signal was satisfactory, an aspiration was created into a catheter which was fixed in parallel to the ld probe, to maintain the tip of the probe against the gastric wall at the site of measurement. data (systemic hemodynamic parameters and gmbf) were obtained at the end of a rain resting period (baseline), then min after dopamine ( mcg/kg/min) infusion, and finally rain after the end of dopamine infusion (recovery gmbf _+ (perfusion units) gmbf ~a% vs baseline) * p < . vs "baseline" and "recovery". conclusions : ) despite a slight increase in co (+ %), the dramatical increase in gmbf (+ %) with dopamine, strongly suggests a selective vasodilator effect of low-dose dopamine on gasaic mucosal perfusion. ) laser-doppler flowmetry appears a promising method to assess gastric microcircalation in critically ill patients. increasing evidence suggests that the activation of inos is the final common pathway for vasodilation in human sepsis associated with endotoxic shock. activation of the cellular immune system induces the excessive release of the pteridines neopterin (n) and , -dihydroneopterin (nh ) by human macrophages/monocytes. besides the well established diagnostic value of pteridines in several inflammatory diseases, it is speculated that these substances per se exhibit biochemical functions. thus we hypothesize that pteridines can modulate inos gene expression in vascular smooth muscle cells (vsmc) in vilro. cdtured rat aortic vsmc from female wistar kyoto rats were incubated with n ( pm), nh ( ilm), lipopolysaccharide (lps, ~g/ml), and interferone-~/(ifn-~/, u/ml) for h, respectively, inos gene expression was measured by competitive reverse transcription polymerase chain reaction. the results are summarized in the table. the present study demonstxates a neopterin induced increase in inos mrna expression at the transcriptional level in vsmc. while coincuhation of cells with n + lps resulted in an additive effect on inos gene expression, n + ifn- seem to have a more than additive effect nh did not alter inos mrna synthesis, but it suppresses the lps as well as the ifn-yinduced augmentation of inos gene expression. we speculate that this pteridine-mediated modulation of inos gene expression is involved in the regulation of the vascular tone in endotoxic septic shock. the relationship of sepsis and coagulation abnormalities is well known, mainly in severe sepsis and septic shock. still farther, the extreme expression of hemostasis abnormalities (disseminated intravascular coagulation) in sepsis, has been extensively described. we studied the changes in several coagulation and fibrinolysis markers in septic patients, trying to correlate them with the evolution of the sepsis phenomenon, with an emphasis in its early stages, where therapeutic intervention might be more drastic. in patients, with sepsis, with severe sepsis and with septic shock, as well as in healthy volunteers (control group) we measured : platelet (ptl), coagulation markers [fxii, fvii, fviii, fvw, fibrinogen (fibr) we conclude that all parts of the coagulation system are gradually changed during the evolution of sepsis phenomenon , even in the earliest stage of sepsis. the expression of an inducible nitric oxide (no) synthase (inos) plays a major role in the pathophysiology of septic shock (ss). inhibition of inos could therefore be of therapeutic value. however, such an inhibition has been shown to be detrimental, increasing tissue anoxia (and end-organ damage), possibly through the simultaneous blockade of constitutive nos (cnos). thus, selective inhibition of inos might be more suitable. we evaluated the effects of l-canavanine (can), a more potent inhibitor of inos than cnos, in an animal model of ss. method: in anesthetized rats, catheters were placed in the femoral vein and artery. rats were given an iv bolus of lipopolysaccharide (lps, mg/kg), at baseline (to). after h (t ), rats received at random an infusion of either can ( mg/kg/h; can group, n=l ) or an equivalent volume of . % naci ( cc/kg/h; nac group, n= ), giyen over h (t -t ). a third group (sham group, n= ) received . % nac in place of lps, and then was treated like the nac group. mean blood pressure (mbp), blood lactate and nitrates (no ) were measured each h. glucose, creatinine and asat were also measured in rats (n= in each group). the can _+ * + "t . + . "~ . +_ . "t + " + " *p< . can vs naci ?p< . vs sham can suppressed the hypotension, reduced the hypoglycemia and hyperlactatemia, and attenuated the biological signs of renal and hepatic dysfunction induced by endotoxemia. these effects were associated with a lesser elevation of blood no , confirming a partial inhibition of inos. conclusion: l-canavanine attenuates the hemodynamic and metabolic consequences of endotoxemia in the rat. these effects may be related to a partial inhibition of inos. they contrast with the deleterious effects described with non selective inhibitors of nos. l-canavanine could become a new tool for the treatment of septic shock. rocalc tonin :marker of sepsis, ii~flammaiiur% t~ boifi .cheval*~ jf.timsit*, m.assicot**, b.misset*,/.carlet*, c.bohuon** saint joseph heap, paris**biochemistry institut g roussy, villejuif, ce bi~)l~i~ttectives_: high serum levels of procalcitoaln (proct) have been shown to be ~ss-ocinted with bacterial infection. however, few data exist about the ability of proct to differenciate septic shock and shock from other origin in which an activation of intlmmamtory mediators has been also demonstrated. methods: thirteen patients with bacterial septic shock (ss), patients with non septic shock (nss), patients with bacterial infection without shock ( nf) and icu patients without shock and without infection (control) were compared for proct levels at dayl, , , , . patients were classified blindly and independently fi'om proct results. twelve patients were excluded because any classification was impossible due to mixed pathology. proct was measured with ebemoluminescenee (brahms diagnostica-berlin). results: dayl, proct levels are significantly different between the four groups. dayl proct levels are correlated with saps (p= . ), infection ( . +_ vs _+ ,p= . ), shock ( _+ vs +.- ,p= . ), death at day ( _+ vs _+ ,p= . ). when shock and infection are introduced in multifactor &nov& only infection remains correlated with day proct levels ( = . ) in patients with shock, dayl proct levels are correlated with saps, infection and death at day , but not with arterial lactate levels (p= . ), white blood calls (p= . ) or fever (p= . ). proct levels remain higher i~i septic shock patients at day , and ( figure) . i c edpsion: procalcitonin levels in the first three days of shock are differen[" between septic and non septic shock patients. in patients with diseases known to induce acute an inflammatory process, procaldtonin seems to be a marker o~ infection. obiectives-to evaluate the effect of endotoxic shock on the distribution of blood flow between the mucosal and the muscular layer of the intestinal wall. methods: in fasted pigs, mean aortic pressure (map, mm hg), cardiac output (co, ml/min-kg),superior mesenteric artery flow (q sma, ml/min.kg), and phi, where measured before (control) and after i.v. endotoxin ( gg/kg). the blood flow to the mucosal and the muscular layer was measured in regions (proximal jejunum (pj), mid-small intestine (mi) and terminal ileum (ti)) by colored microspheres, using adjacent samples in each region. the muscular layer was separated from the mucosa by blunt dissection, and the flow determined independently in each layer. results: endotoxin with fluid resuscitation induced the expected decrease in map ( . _+ . vs . -+ . , p< . ), and phi ( . !-_ . vs . _+ . , p< . ), with a constant co ( _+ vs _+ , p= . ) and qst, aa ( . _+ . vs . _+ . , p= . ). the results of regional pertusion are presented in the table. (flow in ml/rain g of tissue; mean _+ sem ; * p< . vs control by two-way anova) conclusions-these data indicate that the mucosal flow increased during septic shock. they suggest that a decrease in phi may be due to hypoper~usion of the muscular layer or to metabolic alterations within the mucosa, despite a % increase in flow. acute increase in wbc count (from a mean of lo.oo mm a to o /mm~), between the rd and the th day of therapy. there was a decline of the wbc count to an average of about . mm a after decreasing the daily dose of the medication to mcg there was no increase in tile absolute number of the eosinophils during the whole course of the medication. there was a slight decrease in the c complement between . to . g/i. normal values . to . g/i there was no change in c values. conclusions : an early increase in wbc count was observed ( rd day) without subsequent increase in the number of immature types from bone marrow, probably due to the mobilization of wbc from the periphery and this increase was dose dependent. there was a slight decrease in c fraction of complement, probably due to the consumption of this fraction in the process of opsonization. no adverse effects of the medication were observed, during the treatment with the above dose. these data sugest that cm csf may be a useful complement to tile main antimlcrobial treat,nent ~ of septic [cu patients. objectives: as part of a large multicentric, placebo-controlled, randomized clinical trial investigating the effects of interleukin- receptor antagonist (ii-lra) in the treatment of severe sepsis and septic shock, this substudy evaluated in dem.il the acute hemodynamic effects of ii-lra in patients who were invasively monitored. methods: in a total of evaluable patients in whom vasoactive support was little altered, hemodynamic measurements were performed at baseline (twice), and i hour, h, h, h, h, and h after the administration of mg/kg (n= ) or mg/kg (n= ) of i - ra or the corresponding placebo (n = ). / patients ( %) were treated with adrenergie agents and / ( %) with mechanical ventilation. data were analyzed by a kruskal-wallis test. results: during the study, there was no significant difference with time or between groups in arterial pressure, cardiac filling pressures, cardiac index or left ventricular stroke work (figure). burmester, "~ man and h. djonlagic medical university (internal medicine, "cardiology, *'microbiology) and "**southern city hospital, lfibeck, germany obiectives: evaluation of the incidence of bacteremia and sepsis in patients with nontyphoidal salmonella (s.) infections, specification of risk factors, need of icu treatment, clinical course, and mortality in the group of the patients who developed septic complications. methods: data of all patients with microbiologically proven s. infections hospitalized in the medical university of lobeck and in the southern city hospital of l beck from to . results: within the observation period s. was isolated from the stool cultures of patients. in patients (g m, f, median age yrs) s. could be detected in blood cultures ( s. enteritidis, s. typhimurium). in addition, in of these patients s. was also isolated from other specimens (urine, liquor, and tissue fluids derived from abscess punctures). in all patients with positive blood cultures the clinical course of s, infection was complicated: ? patients developed mof (acute renal failure, ards, hemodynamic instability, dic) and required icu treatment for at least up to days, of the patients died. the predisposing disorders in the patients with s. bacteremia were (n=): aids ( ), immunosuppressive drugs ( ), chronic alcoholism ( ), malignancies ( ), none ( ). septic complications in patients with nontyphoidal s, infections are relatively rare (in this study < % of all hospitalized patients with microbiologically proven salmonellosis) but severe (mortality of approx. %). patients at risk for a complicated clinical course are predominantly those with predisposing disorders but occasionally also patients without evidence for an underlying disease. age (yr) + + death (n) duration of shock (h) + + noradrenaline (rag/h) , _+ + temperature (~ , + , + pvr (dynxsecxcm - ) + + co (ljmin) , _+ , , + , lactate (mmol/l) + , , + interleukin- (pg/ml) _+ + interleukin- (pg/ml) , _+ , , + , tnf-alpha (pg/ml) , + , + neopterin (nmol/l) , + , + crp (rag/l) _+ +_ pro-ct (ng/ml) , + , , + there was no positive correlation between serum lactate levels, degree of shock, hypoxemia and pro-ct positivity. pts with septic shock of bacterial origin entirely developed hyperprocalcitoninemia, whereas pts with cardiogenic shock, who expired within h did not. however, in late cardiogenic shock (> h) all pts developed fever of unknown origin and consecutive hyperprocalcitoninemia. these data suggest bacterial inflammation and/or mucosal translocation of bacterial products in pts with prolonged cardiogenic shock. the use of a loading dose of quinine ( . mg/kg base in h) is recommended in previously untreated patients (pts) with sfm, particularly in multi-drug resistance areas. this protocol is difficult to validate, since the viability of microorganisms is not assessed routinely in parasitology laboratories. objectives: to examine the evolution of parasite viability during the early phase of therapy of sfm. methods: from / to / , pts with sfm (who ) treated with iv quinine for less than h were included prospectively. blood samples were collected at o, , , , , and h viability was assessed by culturing parasitized red blood cells in the presence of h-hypoxanthine, and radioactivity was determined at h by scintillation counting. viability was expressed as the percentage of radioactivity compared to the initial sample. plasma quinine was determined by liquid chromatography. tile ratio plasma quinine (pmol/ )xlo /icso for quinine (nmo]/]) was called the parasiticida/ index. results: pts were included, • saps . -+ . . the initial parasitemia was t. + . %. complications of malaria were coma ( pts), shock ( pts), renal failure ( pts) and acute lung injury ( pts). all strains were sensitive to quinine (icso -- nmol/ ). in pts who were not given a loading dose, parasite viability increased by and %, with concomitantly low quinine levels ( and #mow] at h); pt died. in pts that received a loading dose (serum quinine at h = . -- . ~mol/]) a marked decrease of parasite viability (by +_ % at h) was shown. viability was inversely correlated with plasma quinine (r=. , p-.o ) and parasiticidal index (r=. , p-.o ). conclusions: even with fully sensitive strains, the use of a loading dose of quinine seems warranted in severe falciparum malaria in order to reach rapidly adequate plasma quinine ]evels, necessary to inhibit significantly parasite viability. l nkka, e ruokonell j takala. critical care research program, department of intensive care, kuopio univ hospital, finland objective: to determine the incidence of positive blood cultures, their microbial subgroups and to evaluate the outcome of icu patients with different bacleremias. material and methods: we analysed all positive blood cultures in consecutive admission to a university hospital icu in - and the icu and hospital survival of the bacteremia patients. during these years patients had positive blood cultures that were considered as clinically relevant, excluding colonizations or contanfinations. results: patients with positive blood cultures had an icu survival of . % (vs. , % in all icu patients) and six month survival of . % (vs. . % in all icu patients). the most common bacteria were enterobacteriaceae ( , %), staphylococcus aureus ( , %) , coagulase negative staphylococci ( . %), pseudomonas ( . %) and slieptococci ( . %). obiectives: to evaluate prognostic factors and mortality in consecutive patients (pts) with hiv infection and septic shock. methods: from - to - , records of consecutivepts with septic shock (crit care med , : - ) admitted to the icu were reviewed retrospectively. results: among pts with septic shock admitted during the study period, had hiv infection- of whom had aids-(gr. i) and were hiv-negative (gr. ill. ten gr. ii pts ( %) were irnmunosuppressed because of neoplastic or immune dlsease. mechanica] ventilation was required in % gr. i and % gr. ii pts in gr . i pts ( %) a multivariate analysis demonstrated that hiv infection and sap i were independently predictive of death in pts with septic shock. ~onclusions: evidence of increased mortality, number of organ failures and higher severity scores (saps i does not take into account immunosuppression) is demonstrated in hi v-positive pts, infection with hiv appears to be an independent prognostic factor in pts with septic shock. the frequency of opportunistic infections (often responsible for delayed diagnosis and treatment) may contribute to the poor prognosis in this population. obiectives: to determine interleukin (il)-i levels in plasma of patients with sepsis and septic shock. to analyze the relationship between plasma il- and the proinflammatory mediators, tumor necrosis factor-aifa (tnf) and il- , the underlying severity of the disease and the evolution of patients with sepsis. methods: we studied critically ill patients ( men, women; - years old) in three diferents groups. group i: patients without evidence of infection, group i : patients with sepsis and with septic shock (group iii). we measured plasma il-lo, tnf and il- levels in the first hours of diagnosis. severity of illness was estimated with the acute physiology and chronic health evaluation (apache ii) scoring sytem. results: plasma levels of il- were higher in group iii (median, pg/ml; range, - pg/ml) than in group ii (median, pg/ml; range, - pg/ml; p <. ) and group i (median, pg/ml; range, - pg/ml; p <. ). median il- concentrations did not differ among patients who survived (median pg/ml; range, - pg/ml) and those who died during the overall follow-up period ( days) (median, ; range, - pg/ml); but patients who died in short-term (< hours) with catecholamine-refractory hypotension showed the highest concentrations of il-io (median, pg/ml; range, - pg/ml). in patients with bacteriemia ( %), levels of il- were higher (median, pg/ml; range, - pg/ml) than in those with negative blood culture (median, , pg/ml; range - . pg/ml; p< . ). there was a good correlation between plasma il-io concentration and levels of tnf (r= . ; p < . ) and il- (r= . ; p < . ). the correlation between levels of il- and the apache ii score was significant only in the septic shock group (r= . ; p <. ). conclusions: in septic shock, il-io and proinflammatory citokines are released in high concentrations. the significant correlation observed in patients with septic shock between il- levels and apache ii, short-term death and bacteriemia can possibly be explained by the massive inflammatory response in septic shock with fulminant course. intensive care department -calmette hospital - lille -france. in septic shock, inadequate splanchnic blood flow may play a prominent role in the pathogenesis of multiple organ failure. measurement of gastric phi has been propose to evaluate tissue oxygenation in splanchnic organs. objectives: to compare gastric phi values with hepatic icg clearance, an index of liver blood flow and function ; to determine if one of these two methods could be proposed to assess the entire splanctmic peffusion in septic shock. methods : patients (age : • years ; saps ii : • were prospectively investigated (septic shock : bone criteria). following parameters were collected during hours : systemic hemodynamic parameters (swan ganz catheter a h -ref computer -baxter lab.), calculated systemic oxygen transport (do ), oxygen consumption (vo ) by indirect calorimetry (deltatrac datex lab.), gastric intramucosal pco (pco ss) and phi (trip -ngs catheter -tonometrics lab.) and plasma disappearance rate of icg (pdr dye) (femoral artery fiberoptic/thermistor catheter , cold z computer -pulsian medizintechnik, germany). correlations were performed using a linear regression. elevated in all days with the highest value in second and third days of treatment. nonsurvivors had higher values of these parameters than survivors but differences did not reach statistical significance. another trend of changes were observed in selectin p (gmp- ) concentration. in all patients concentrations measured were elevated but in survivors after not significant decrease this parameter in second day another one had simmilar values. in patients who died we noted significant decrease in third day (p < . ) whereafter prominent increase, significant after seventh day, in comparison to third day value and value in survivors group. icam- concentrations in all patients reached high levels and in nonsurvivors after four day of treatment significant increase in comparison to survivors we found. conclusions: multiple trauma complicated with sepsis induce rapid elevation of concentrations of il- , il- and increased expressior of adhession molecules (selectin e, p, icam- ) measure of icam- and selectin p concentration determine lung injury severity and prognosis as to health and life. (clp) .pathophysiology of cip is unclear, but changes in regional bloodflow may be a ~ignificant factor. nerve blood flow (nbf)is reduced in rat models of hemorrhagic shock (g),but no information is available in sepsis. we studied the comparative effect of acute endotoxemic shock {etx)& h on perfusion of rat sciatic nerve. methods: male sprague-dawley rats were anesthetized with pentobarbital (ip), instrumented with a tracheostomy, carotid arterial & venous catheters and mechanically ventilated (fi = . ). the left sciatic nerve was surgically exposed. monitored variables included: a) mean arterial pressure (map,mmhg) ,b) nbf (ml/ o g/min) by laser doppler flow meter,c) nerve internal arterial diameter (id ~ m) by video image shearing and splitting method. after stable baseline measurements were obtained, acute hypotension was induced by randomly assigning the rats to etx ( . b , difco) in saline at mg/kg or h. both interventions produced % reduction in map within min., which recovered to baseline values spontaneously in etx group, & by reinfusion of heparinized withdrawn blood in m. data were analyzed by linear regression, two-way repeated measures analysis of variance followed by bonferroni-t method. experimental stages were:( )baseline, ( ) mid-point of map reduction; ( ) nadir of hypotension, ( )midpoint of map recovery, & ( ) after stable recovery of map. both etx & h induced shock result in similar reduction in nbf consistent with lack of autoregulation in peripheral nerve vessels independent of etiology. since cip is primarily associated with sepsis, it is not likely that acute reduction in nbf alone causes cip. direct & indirect neurotoxic effects of mediators of sepsis need to be evaluated. .':_.~::::o o:oc ., objectives : evaluate the relationship between il- , a cytokine which inhibits tnf, production and protects mice from endotoxin toxicity, and the other proinflammatory cylokines, tnf~, il and ils in severe sepsis and septic shock. methods : twenty-eight icu patients ( m, f, mean age + y) were studied as soon as they developped a severe sepsis (n = ) or a septic shock episode (n= ) as defined by a conference consensus in ( ). tnf~, il , il s and il- plasma levels were measured by immuno-radiometrie assays from medgenix (fleurus, belgium). lc mean and range. results : the comparisons between cytokine levels in severe sepsis versus septic shock were made using the logarithm of the value in order to normalize the distribution of data, and student test. il- plasma levels were higher in patients with septic shock than in patients in severe sepsis. there was a significant correlation (p < . ) between il- and tnf a (r= . ), il- and il~ (r = . ) and il- and il s (r = . ) as well as between il- and apache n score (r= . ). patients who died (n = ) had il- levels higher than patients who survived but this difference was not statistically significant ( pg/ml vs . pg/ml; p> . ). conclusions : during severe sepsis and sepsis shock, il- seems at least to follow the same evolution (increase in plasmatic level) with the severity of sepsis as the other cytokines. reference : ( ) crit care med ; : - . objectives: to evaluate the effects of steroids on hemodynamics and mortality in septic patients with konwn levels of cortisol concentration. methods: retrospectively we analyzed data ofpatients with documented septic shock who received steroids after assessment of adrenal function. in all patients hemodynamic parameters as well as the necessary vasoactive medication were assessed, before and hours after corticosteroid medication. immediately before administration of corticosteroids adrenal function was evaluated with cortisol levels before and after synthetic corticotropin ( . mg). finally we studied mortality. we defined a positive respons on corticosteroids as an elevation of map of at least mmhg and/or a decrease in the necessary vasoactive medication of at least % within hours. adrenal insufficiency was defined as a cortisol level after stimulation of less than nmol/l. results: of patients were found to respond to steroid medication, did not. mean cortisol levels before and after corticotropin were • and • nmol/l in the responder group (rg) and • and • nmol/l in the non responder group (nrg). in the rg out of ( %) were found to have an adrenal insufficiency, in the nrg out of ( %). in the rg -weeks mortality was . % (l out of ), the overall mortality % ( out of ). mortality in the nrg was % ( out of ) (p < . ) and % ( out of ) (p < . ) respectively. conclusions: in patients in septic shock there is a beneficial effect of steroids in case of adrenal insufficiency, but also in a subgroup with normal adrenal f{unction. obiectives: intercellular adhesion is a critical step in the accumulation of leukocytes. postischemic cardiac lymph has the capacity to stimulate icam-i. in the coronary microcirculation neutrophils can be trapped and in many cases obstruct capillaries, previously we found that troponin t (s-tnt) a marker for myocardial iechemia, was increased in septic patients. the aim of the study was to follow slcam- and s-tnt levels continuously starting at the beginning of sepsis. methods: patients were ingluded in this institutionally approved study after relatives had given their informed consent. all patients were included within hrs following the beginning of sepsis. blood was drawn every hrs in the first ;~ hrs, after hrs, followed once per day for days. s-tnt, icam- , elam (elisa's, boehringer mannheim inc, r&d systems ltd.) arterial and venous blood gases were determined, an ecg and a complete hemedynamir measurement including cardiac output were obtained. all patients received adequate volume and catecholamine therapy (norepinephrine, dopamine, dobutamine; median (range) . ( . - . ), . ( . - ), . ( . - . ) pg/kg/min, respectively). statistical analysis: wileoxon signed rank-sum test. . ( . - . ) . patients had s-tnt levels > . pg/l. of these died, whereas only of patients died with s-tnt values < . pg/l (p= . ). all patients that died had elevated sjcam- levels ( ilg/l:cut-off ) whereas in the survivor group only % had elevated icam- levels (p= , ). conclusions: increased slcam- and s-tnt levels were found during early sepsis in the majority of patients, a high sicam- and s-tnt value was associated with a higher mortality. the research of the noninvasive haemodynamic monitoring accelerated recently all over the world. the aim of our study was to test whether the changes of the haemodynamk parameters measured by impedance cardiography (icg) were corresponded to clinical changes in septic patients. investigations were performed on critically ill postoperative septic patients (their multiple organ failure score was - /with icg monitor. in cases the investigation~ were performed in septic shock. the measured parameters were: heart rate (hr), mean arterial pressure (map), cardiac output (co), peripherial resistance (svr),preejection period (pep), and ventricular ejection time (vet). these parameters were measured during - hours in every minutes, depending on the patients cl~tnical condition. results: at the septic patients the hr and the co ]~reased. in septic shock the co was significantly higher the svr lower than in the septic group. in the hr there was no difference between the two groups. in septic shock noradrenalin influenced more effectively the measured parameters than dobutamin. conclusion: the trend of the measured icg parameters correlated with the clinical changes of septic patient's state. the noninvasive haemodynamic monitoring by impedance cardiography helps the planning and leading the adequate intensive therapy of these critically ill septic patients. to evaluate the development of sirs, sepsis and septic shock in hospitalized patients with fever, a prospective study was performed on patients using previously defined criteria. methods: normotensive patients with fever (temperature > . ~ axillary), admitted to the department of internal medicine were evaluated for the existence of sirs during the first three days of the study and sepsis at inclusion. during a follow-up period of days the patients were daily evaluated for the development of sepsis or septic shock. results: most patients ( %) had or developed sirs within the first three days, patients ( %) did not. sepsis was present in % at inclusion. in patients with sirs, % did not progress to sepsis or septic shock, % progressed to sepsis (mean interval . • . days), and patient (< %) directly progressed from sirs to septic shock. in patients with sepsis, % progressed to septic shock (mean interval . • . days). sepsis was preceded by sirs in %. septic shock was preceded by sepsis in % and by sirs in %. conclusions: % of patients with fever in an internal medicine department develop sirs, or sepsis. furthermore, progression from sirs to sepsis or septic shock is poorly predicted by fever or sirs. nevertheless, all patients with septic shock were preceded bysirs or sepsis. taken together, this may indicate a severity hierarchy of the syndromes. however, fever, sirs and sepsis are relatively poor indicators of development of septic shock. this supports further research on additional predictors of septic shock. b. m.manuylov, v.b.skobelsky (moscow) in recent years sodium hypochlorite (sh) has been successfully used to eliminate pyo-septic complications. moreover, the mechanism of the sh effect on the immune system has not been sufficiently studied. the aim of the present investigation was to study the mechanism of sh effect in inflammatory pulmonary diseases. patients with double pneumonia were subjected to the evaluation. sh in the concentration of mg/l in the volume of - m / hours was administered by drop infusion into the central vein. to evaluate one of the defence systems the leukocytes activity by the chemoluminescence technique was studied. in all the patients baseline secondary immunodeficiency which was indicated by the decrease in the luminescence level was established. even hour after the sh administration the leukocytes activation exp-ressed by the enhancement of their chemoluminescence . - times was observed. this supports the available findings that accumulation and liberation of the oxygen active forms (ol'oh, ' , h ) are accompanied by the increased phagocytosis, i,e. the signs of "the oxydation explosion" testify to the favourable sh effect on the course of inflammation processes. the use of sh permitted to decrease the percentage of lethality in double pneumonia by % in the intensive care unit over the year. at the same time, excessive activation of free radical oxygen may be a damaging factor. therefore, precise individual control over the choice of concentration, dosage and the preparation administration rate is required. prospective, double-blind, placebo-controlled, trial of atiii substitution in sepsis r. a. balk objective: pilot study to evaluate the efficacy and safety of atiii substimtion therapy in patients with sepsis. efficacy assessed using change in mortality or organ failure/dysfunction. adult patients meeting a definition of sepsis and cared for in a tertiary care academic medical center in chicago were identified and prospectively randomied to receive either atiii (kybernin p) or placebo in a double-blind treatment protocol. all other therapy and patient management were under the direction of the patient's attending physician. all patient's were followed for days and the organ dysfunction/failure were scored using published scoring systems (jordan et al crit. care med. , goris et al arch. surg. , kuaus et al ann. surg. colldusions:wha~ we met the shomaeker objectiv% the mortality and the pro~os[s were i~ttc*. those criteria were obtained with file tradititmal t~ctor likr doht~mme, hut c.~vh ~,as ca in~aertam measure. they ac~s smxergically in the optimizatic~l of the fell vmtrictdar work index, tad fimdameatally cavh seox~s to have an impo.aat role in the better respiratory ev-altmtioa, leaving yet the possibility to coltrol the flui& r althou~l eomproved it's not aec~pt~xl file importmlce h* the diminution, of the sepsis modiat~lrs llke fnt and il- with h~wmotiltrafi(al, stopphlg the evolution to nmltiorganic failure mid de~easethe mortality. with ours clhlicals results, we could saythat cavii in multiol~atlie disfut~oa septic patieats, se~r~ to be an c xilna] supoa or troatmeat maesure. of anaesthesia and intensive therapy, medical university of prcs, p~csf hungary. objectives: since some biological effects of bacterial endotoxin require an interaction between the lps molecule and a serum factor(s), we hypothesized that lps-induced no production and cgmp accumulation in vascular smooth muscle cells (vsmc), a mechanism ~thought to underlie cardiovascular collapse associated with septic shock, is modulated by serum factor(s). methods: cultured vsmc from rat aorta were challenged with e. coli lps for - hours either in the presence or absence of fetal calf serum (fbs), and no production was monitored by radioimmunoassay determination of cgmp content of hci extracts. results: in the absence of serum, o ng/ml lps was required to increase cgmp levels, whereas the presence of % fbs shifted the lps concentration curve i times to the left. similarly to fbs, human serum also potentiated lps-induced cgmp accumulation. in contrast to lps, serum had no effect on cgmp accumulation elicited by sodium nitroprusside, a no releasing agent, suggesting that the sensitivity of vsmc to generate cgmp in response to exogenous no is not modulated by serum. heat inactivation (> ~ min) but not removal of small molecules (< , d) from the serum by dialysis, reduced the potentiation of cgmp accumulation by serum. time course studied indicated that serum is required within the first min of lps exposure to increase cgmp levels. to investigate whether the effect of serum is specific for lps, we treated the cells with increasing concentration of interleukin -~ (il-i). % fbs shifted the il-iinduced cgmp responses five times to the left. conclusions: our study suggests that lower concentrations of e. cell lps and il-i require a heat labile macromolecule in the serum in order to elicit no production. this factor is present in the human serum and it may play a potentially important role during no synthesis induction in vsmc. objective: to evaluate the factors of acquisition and the outcome of methicillin resistant staphylococcus aureus (mrsa) bacteremia in an intensive care unit (icu). methods: all patients in which bacterermia due to staphylococcus aureus developed > hours following admission to our icu, during a year period ( january through january ) were reviewed. patients (pts) were included, mean age , y (sd , ), saps , (sd , ), mac cabe ( and ) %, mortality directly due to sepsis %. pts had mrsa bacteremia and methicillin susceptible staph. aureus (mssa) . both groups were compared using the chi square (with correction of yates), fisher's exact, student's t or wilcoxon test. results: there was no statistically significant difference between mrssa and mssa regarding at age ( , + , vs , + , ) , saps ( , + , vs , + , ), use of vancomycin ( % vs %), mechanical ventilation ( % vs %), number of days (d) before the drawing of the first positive blood culture (median d, range - d vs median d, range - d). more mrsa than mssa pts had previous use of nonsteroidal anti-inflammatory drugs (nsaid) ( % vs % p< , ), central venous catheter infection due to staph.aureus ( , % vs % p< , ), but previous use of antibiotics was not significantly different ( , % vs %). the outcome of the bacteremic pts was not statistically different: saps at the first day of bacteremia ( , +_. , vs , + , ), severe sepsis and septic shock ( % vs %), persistence of the bacteremia ( % vs %), mortality directly due to bacteremia ( % vs %). conclusion: previous use of nsaid, infection of venous central catheter are more frequently associated with mrsa bacteremia. thus, similar to others studies (hershow infect control hosp epidemio ; : - ) , these results do not indicate that mrsa is associated with increased virulence. objectives: to closer definition of mosf formation mechanismes in nosocomial sepsis (ns) the complex clinicobiochemical, microbiological, immunological, functional exaroination of cases with ns had been done. methods: examination of cellular and humoral immunity, nonspecific immunologic reactivity, systemic and hepatic circulation, microbiological examination of blood,electro-and echocardiography, sonography and computer tomography of chest and abdomen organs were obligatory. autopsy findings of dead cases had been analized. results: in cases ( , %) opportunistic pathogen microscopic flora ( staphylococcus anreus,staphylococcus epidermidis, staphylococcus saprophyticus) had been found out in blood inoculations. in cases ( %) side by side with destructive process in lungs the bacterial endo-and myocarditis with blood circulation failure had been determined.in cases ( %) simultanious lesion of three organs (heart,lungs,liver) had been found. morphologic examinations of dead cases ( %) internal revealed involvement of them in mosf-syndrome.hyperplasia of adenohypophysis;sclerosis of adrenal glands cortical layer;perivascular brain oedema,paralysis of brain capillaries and plasmorrhagia, cerebral thrombosis and cerebral abscess,necrobiosis of epithelium tubules of the kidney,pletora of hepar, fatty and granular degeneration of hepatocytes had been found.atrophy of white pulp and hyperplasia of red pulp, supress of lymphoid tissue, plethora and formation of infarctious had been found in spleen. mentioned changes in spleen were indispensable in ns. conclusion: in ns spleen can not secure it functions to support and appropriate detoxication potencial of organism,elimination of microbes,toxines,antoallergenes. insolvency of immunological link of antimicrobic defence is the starting mechanism of mosf developmentin ns. %neviere, jl. chagnon, b. vallet, d. mathieu, n lebleu, f. wattel ] ept of intensive care, hop calmette, lille, france ~everal studies have described tiypoperfusion of intestine during sepsis. owever, it is unknow whether the mesenteric blood flow is associated with nucosal hypoperfusion. additionally, the effects of resuscitation on the ntestinal microcirculation remain controversial. bjectives : to describe the effects of endotoxin in a porcine model during ~hock and resuscitation. ~ethods : ten pigs ( kg) were anesthetized and instrumented for "neasurement of cardiovascular variables. gastric and gut oxygenation vere assessed by intra-mucosal ph and microvascular laser doppler lowmetry. after baseline data collection, a minute intravenous infusion )f escherichia colt (serotype h , sigma, st. louis, mo) was begun ~t a rate of pg/kg. an infusion of either saline at . ml/kg/min (group ; n= ) or saline and dobutamine at a rate of pg/kg/min (group ii; n= ) vas begun mn after the end of the endotoxin infusion. tesults : to td t ~ fl w fluid ioadin,q alone sfyras d, k perreas, e douzinas, k spanou, m pitaridis and c roussos critical care dpt, evangelismos hosp., athens univ, school of medicine. obiectives: much controversy exists concerning the beneficial effects of cvvh on sepsis. we studied the effects of cvvh application on septic patients with reference to the following parameters: i) survival rate ii) cytokines' removal and iii) timing of cwh onset. methods: patients with sepsis (criteria according to accp/sccm, ) underwent cvvh as soon as they developed renal failure or dysfunction (urinary output< ml/ h, cr> . mg/dl and bun> mgd'dl ). specimens were collected: blood samples before cvvh and therafter both blood and ultrafiltrate (uf) samples on , and hours. cytokines tnfa, i - and ii- were measured by the immunoassay method in all specimens (uf and plasma -p) and sieving coefficient ([uf]/[p]) and h solute mass transfer of tnf and i - were calculated (v h x [uf] ). the apache ii score before cvvh onset, the duration of icu stay and the timing of cwh application related to the sepsis onset in days (ta) were recorded.with respect the mortality two groups were formed, i.e. group a (survivors) and group b (non-survivors) . the morbidity period in days of those septic patients who died in the past year and were not subjected to cwh (group c) was compared to that of group b. results: group a included pts and group b pts with mean+sd age ( _+ vs _+ , ns) and apache scores( _+ vs -+ . , ns). the mean ta-+ sd was . + vs -+ , p< . . the mean_+se morbidity period of group b vs group c was _+ vs _+ . p< . . the mean values of cytokines are presented in the following figures. the sieving coefficient for tnf was . and for i - was . . the solute mass tranfer was -fold the actual plasma content at a given time. . o conclusions: i) early application of cvvh seems to favourably affect the outcome of septic patients, ii) cytokine plasma levels do not decrease although cytokine removal is substantial, iii) it seems that cwh application in sepsis of any stage helps to buy time for further treatment. the most commonly monitored variables in shock stages idclude : arterial pressure, heart rate, central venous pressure, pulmonary artery wedge pressure and cardiac index. with vigorous therapy it is possible to bring these values back into the normal range in both survivors and nonsurvivors. therapeutic goal in septic shock stages is to maximize the values of cardiac index, delivery (do ) and consumption (c ). objectives: the main purpose of this article is to determine the relationship betwee~ delivery an consumption as a sign of hypoxia. fifteen patitents with septic shock were treated with intention to maximize the value of ci,d and v . we compared the levels of these parameters between the survivors and nonsurvivors and found no significant differences after hours. high levels of do and v may not guarantee against tissue hypoxia in early stage of septic shock. zjar~iic, dj janjic, lj. gvozdenovic, a.komareevic. t.petrovic, &marjanovic, institute of surgery, novi sad, yugoslavia objectives: evaluation and mutual comparison of clinical signs, laboratory data and microbiological monitoring in the patients with burn sepsis. method: retrospective analysis of the recorded data of all burn patients treated in our department between january and december . specially attentions were given to data considering wound infection, positive haemocultures, positive urinocultures and characteristics of septic state. results: out of patient there were ( , ~) adults and ( , ( ~) children. almost two thirds of the patients ( - , ~) were males. the predominantly cause ( , ~) of children's burns was scalding b~y hot liquids and flame burns ~ , ~) in adult patients. the most frequdntly species isolated from surface swat~ were pseudomonas aeruginosa ( " in adult patients) and staphyloccocus epidermidis ( , % in children). in only five patients ( , ~ the haenmcultures were positive -pseudomonas aeruginosa was isolated in three and staphyloccocus aureus in two patients. urine infection was diagnosed in , % of all patients. the treatment protocol included use of imipenem and polyvalent pseudomonas vaccine again~ pseudomonas aeruginosa and vancomycin and aminoglycosides against staphylococcus aureus. total mortality rate in this group of burned patients was , ~, but the mortality rate caused of sepsis was low (i %) . conclusions: early detection of any signs of wound infection and symptoms of septic state is a foundation for prevention and treatment of burn sepsis. the burn sepsis could be reliable detected by continuously monitoring the patient's status and by systematic microbacteriological monitoring of the burned patients. hyperdynamic vasoplegic septic shock p.f. laterre, p. goffette, j. roeseler, j.p, fauville, a. poncelet, p. lonneux, m.s. l~eynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. splanchnic ischemia is described as a common feature of septic shock and could determine the development of msof. therapy such as noradrenaline (na) aiming at improving blood pressure is expected to worsen splanchnic ischemia by its vasoconstrictive effect and subsequent reduction in intestinal blood flow. ob[ective: evaluate the effect of na on splanchnic blood flow. material and method : in a patient admitted for variceal bleeding, ards and sepsis with positive blood culture, a fiberoptie catheter was positionned in the portal vein after recanalisation of its portosystemic stent shunt. blood pressure (bp-mmhg) , ci, svr, do (vigilance ~ baxter), v (indirect colorimetry), arterial, mixed venous and portal vein blood gases, phi were determined before (to) and during (t ) na infusion ( , to , hcg/kg/min.) . changes in splanchnic flow were assessed by changes in portal oxygen saturation (sp ) and arterio-portal oxygen saturation gradient (sao, -spoe laterre, ,lp. pedgrim, th. dugernier, v. delrue, ph. hantson, p. mahieu, m.s. reynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. aim of the study : prospective determination of plasma levels of in patients with ss and their correlation with the type of microorganism and outcome. material and methods : in patients (pts) with ss and severe sepsis, plasma levels of tnfti, ill-b, il and il were determined every hours for days and on day after fulfilling the criteria of ss and severe sepsis. results : in pts, sepsis was caused by a gram (-) microorganism, in pts by a gram (+) and in pts no microorganism was identified. there were survivors ( %) (s) and non-survivors ( %) (ns) . cytokines profiles and levels were not different between gram (+) and gram (-) sepsis. ill-b levels were seldom elevated whatever the group studied. tnfot and il- were significantly higher in ns than in s ( objective: to evaluate the effects on the nitric oxide synthase inhibitor l-n~ hcl ( c ) on myocardial performance in human septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion >_ .i ]tg/kg/min with a map _< mmhg. cardiovascular support was limited to na _+ dobutamine (db), c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t = ); and at the end of treatment (t = ) with c . conclusions: c can restore systemic vascular tone in patients with septic shock enabling na therapy to be reduced and/or removed. the ci tends to fall whilst lv performance is sustained over time. c is a novel vasoacfive agent for the treatment of septic shock, which is undergoing further clinical evaluation. laterre, f. thys, e. danse, j.p. pelgrim, e. florence, z roeseler, m.s. r eynaert. dept, of intensive care, st. luc univ, hospital, brussels, belgium. therapy aiming at improving blood pressure and cardiac index in septic shock (ss) might have deleterious effects on regional blood flow. objectives : compare the influence of volume loading (vl), dobutamine (dobu) and noradrenaline (na) on sushepatic oxygen saturation (shoe) and svoe-sho, gradient in treated ss. material and methods : in patients with ss, ci (thermodilution) , doe, svo,. sho,, svoe-sho e gradient and lactate (l) were determined before (to) and after (t ); vl, dobu and na. results: in patients with treated ss, tests were performed (vl n= ; dobu n= ; na n= method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion ~> . ~g/kg/min with a map _< mmhg. cardiovascular support was limited to na + dobutamine (db), c was administered for up to h at a fixed dose-rate of either i, . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at h from the start of treatment (t = ); and at the end of treatment (t - ) with c . conclusions: c is a novel vasoactive agent that can sustain map in patients with septic shock, enabling na support to he reduced and/or removed. there is a tendency for the ci to fall during treatment, which may be reflex in response to the increase in systemic vascular tone. c is a promising new therapy for septic shock, which will now be evaluated in a randomised, placebo-controlled safety and efficacy study. k. guntupalli objective: to evaluate the acute effects of the nitric oxide synthase inhibitor l-n~ hc ( c ) on selected indices of organ function in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . [xg/kg/ min with a map _< mmirlg. cardiovascular support was limited to na + dobutamine. c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. indices of organ function were assessed at baseline (t = ); at the end of treatment (t = ); and h after treatment (t = ) with c . results. -median values (* assessment made at h or when c discontinued). conclusions: there was no appareut dose-dependent adverse effect on these indices of organ function either during or after exposure to c . the plmelet count tended to fall whilst creadnine appeared to increase over time in all dose cohorts. this novel and promising therapy for septic shock will now be evaluated in a randomised, placebo-controlled safety and efficacy sludy. pharmacokinetics of c in patients with septic shock preliminary results z. hussein, b. jordan, c. fook-sheung, k. guntupalli objective: to evaluate the pharmacokinetics of the nitric oxide synthase inhibitor l-n~ hc ( cg ) given by continuous infusion for h in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . ~tg/kg/min with a map _< mmhg. cardiovascular support was limited to na • dobutamine. c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. plasma was collected from each patient over a h period and analysed for c . pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental pharmacokinetic analysis. results: the (cm~ -maximum plasma concentration; auc -area under curve; cl -plasma clearance; v,, s -steady state volume of distribution; t'/ -plasma elimination halflife). conclusion: the pharmacokinetics of c in patients with septic shock are dose-independent at infusion rates up to . mg/kg/h. at higher rates, clearance of c decreases without any marked change in volume of distribution. c metabolism may be partially saturable at dose-rates above . mg/kg/h. obiectives: investigate the effect of the no synthase inhibitor, l-nt-methylarginine hc ( c ) on the haemodynamics and survival rate in a conscious mouse model of endotoxin shock. methods: female cd- mice ( - g) were instrumented under gaseous anaesthesia (isofluorane, %) and connected to a swivel tether system for continuous monitoring of blood pressure and drug administration. results: after h recovery, endotoxin administration (e. col• :b , - . mgkg - i.v.) elevated the plasma concentration of nitrite/nitrate (nox) and caused a progressive fall in mean arterial pressure (map) from + to + mmhg (n= , p< . ) at h, with a survival rate at h, h and h of %, % and % respectively. c administered as a h continuous infusion ( mgkg-th -t i.v., n= ), h after endotoxin, inhibited the elevation of plasma nox and attenuated the fall in map from + to + mmhg (n= ) at h, with an improved survival rate at h, h and h of %, % and % respectively. conclusions: this study suggests that overproduction of no is involved in the hypotension and mortality characteristic of septic shock. inhibition of no synthase using c represents a novel and promising treatment for septic shock. cultures of e.coli ( , %) and candida( , %) were olso received from autopsy material of children;p.aeruginosa,unspored anaerobes,proteus sp.,s.aureus,b.pneumonia were found in the few cases. in adults the spectrum of bacterioflora was mo~ re limited speaking about the number of species and cultures. in generalized forms of bacterial pyo-septic pathology a wider specific spectrum of causative agents was revealed usua fly with associations. e.coli and k.pneumonia played the leading role in children as well as in adults. in general,k.pneumonia ( , %cultures) and common e.coli( , %)prevailed according to the date of microbiological investigations of authopsy material in pyo-septfc pathology in . objectives: .in spite of all clinical exertion sepsis is still the reason for high clinica! lethality. this study is characterizing the group of patients which survived a septi~ shock. methods: during a period of months all surgical patients on icu were registrated prospectively, more than parameters for each of them were documented'daily in a paradox file. results (see table ): of patients fulfilled the criterion of a septic shock (r. bone, ) , of them died at the lth day, while the surviving group of patients stayed almost days at icu. obiectives: to compare the effects of and % pentastarch solutions to a human albumin solution on oxygen delivery (do ) in septic patients. methods: this stud}, included septic patients with fever (t > ~ tachycardia flqr > /rain), tachypnea (rr > /min) or mechanical ventilation, leukocytosis (wbc> /mm ) or leukopcnla (wbc< ()/mm ) and a clinical source of infection, who required a fluid challenge. in each patient the pulmonary arterial occlusion pressure (paop) was < mmhg. patients were randomized to receive ml of % albunun (n:i ), hydroxyethyl starch (hes -mw /d.s. . ) % (n: ) or t % (n=i ); patients were also treated with adrenergic agents. results cardiac index (c ) increased significantly only in % lies (table) hemoglobin (hb) decreased significantly at min in the same group. there was not significant change in oxygen delivery ( do ). baseline ci alb . :: . (l'min/m ) hes % . = . hes % . polyneuropathy of the critically ill (pci ) is a well recognized complication, acquired in the course of severe illness. we undertook a prospective study, to estimate the severity, extension and time of onset of pci in a selected group of patient with established septic shock ( bone's criteria ). all patients received inotropic circulatory support and were mechanically ventilated. none received relaxants or aminoglycosides. pci was diagnose<by clinical investigation and by emg, and repeated weekly ( axonal degeneration ). after days ( day = onset of septic shock ) in % of the patients pci was demonstrable. after days % of the patients had pci. there was a strong correlation between pci and other mof and between pci and encephalopathy ( eeg ). we conclude that i. pci is a common complication after septic shock. . pci develops early in the course of illness ( % after days ). . pci can be considered as a part of mof, suggesting a common pathogenesis. objectives: we addressed two questions: ) can serial measurements of vapco and avph also reflect the onset of tissue hypoxia during endotoxemia? ) are whole body changes in vapco and avph associated with parallel changes in regional circulation? methods: in anesthetized, mechanically ventilated dogs exhaled gases were sampled for determination of oxygen consumption (vo ). a catheter was positioned into the pericardial cavity to induce cardiac tamponade. ultrasonic flow probes were placed around superior mesenteric, left renal and left femoral arteries, and the corresponding veins were cannulated. group l served as control (n= ), group (n-- ) received mg/kg of endotoxin. thirty min later, tamponade was induced to gradually reduce do . results: systemic do crit was higher ( . _+ . vs . + . ml/kg.min, p < . ) and critical oxygen extraction ratio (o ererit) was lower ( . +_ . vs . +_ . %, p< . ) in the endotoxie than in the control group. meslenteric and femoral do crit were higher in the endotoxic than in the control group ( . _+ . vs . _+ . mlll g tissue.min and . _+ . vs . _+ . ml/min, respectively, both p< . ). regional o ercrit were lower in we endotoxic than in the control group (mesenteric: . _+ . vs .i_+ . %, renal: . + . vs . -+ . % and femorah . -+ . vs . _+ . %, all p< . ). vapco and avph followed a similar pattern in both groups, increasing slightly before do crit was reached, but dramatically wh,en do fell below do crit. in the presence like in the absence of endotoxin, systemic and regional do crit calculated from vo , from vapco , or from avph were similar; do crit was also significantly higher in the mesenteric and the femoral beds of the endotoxic than the control dogs. systemic and regional do crit could be calculated from the blood lactate levels only in the control group. conclusions: during an acute reduction in blood flow i) vapco and avph can reflect hypoxic threshold in the presence like in the absence of endotoxemia. ) alterations in organ oxygen extraction capabilities induced by endotoxin can be reflected by regional changes in vapco and avph. objectives: enhanced nitric oxide (no) release has been incriminated in the vasodilation and myocardial depression characterizing septic shock, but the administration of no blockers has yielded equivocal results. the present study explored the systemic and regional effects of a no donor linsidomine (sin-i) during endotoxic shock. methods: anesthetized dogs received endotoxin ( mg/kg iv), followed min later by a saline infusion to keep cardiac filling pressures constant. oxygen uptake (vo ) was derived from the expired gas analysis. regional blood flow was measured by an ultrasonic flowmeter (transonic). results: the control endotoxie group (n= ) maintained low arterial pressure and systemic vascular resistance. the dogs receiving a continuous infusion of , , ~ug/kg.min of sin- starting min following initial fluid resuscitation (each dose for h), had a higher cardiac index ( . -+ . vs . _+ . l/min.kg, p< . ) and lower systemic and pulmonary vascular resistance than the control group ( -+ vs -+ and -+ vs -+ dyne.sec/cm , respectively, both p< . ). arterial pressure and pulmonary artery pressure were not influenced. sin- significantly increased the mesenteric blood flow from -+ to + % of baseline levels and renal blood flow from -+ to -+ % (both p< . ) but did not influence femoral blood flow. the relative blood flow was increased in the mesenteric bed (at all doses), and reduced in the femoral bed (at highest dose). systemic oxygen delivery, vo , oxygen extraction and blood lactate levels had similar course in the two groups. conclusions: in fluid-resuscitated endotoxic shock dogs, the no donor sin- increased cardiac index without deleterious effects on arterial pressure, and increased splanchnic blood fl w. objectives: sepsis syndrome is associated with the release of a variety of inflammatory mediators, such as interleukins, tumor necrosis factor and platelet-activating factor (paf). administration of paf, a naturally occuring phospolipid, to laboratory animals has been demonstrated to resullt in pathological changes that closely resemble those found in sepsis. in addition, paf antagonists of various origins have been demonstrated to attenuate cardiovascular collaps and to protect against lethality in endotoxemia. in the present study the efficacy and safety of the paf-antagonist tcv- g was investigated in sepsis syndrome patients. in addition, the putative inflammatory parameters tumor necrosis factor (tnf), interleukin il) - il- , and soluble (s) e-selectin were measured in both tcv- and placebo treated patients. metho.~a randomized, double-biind, multi-center study was undertaken to compare the safety and efficacy of intravenously administered tcv versus placebo (takeda chemical industries ltd., osaka, japan). tcv- was used as add-on to conventional therapy in the treatment of patients with severe sepsis and septic shock ( . mg/kg body weight intravenously over hrs, twice a day for one week). day mortality was registered, as well as vital signs, laboratory parameters, hemodynamic parameters, apache ii score and mof score. plasma samples for the determination of inflammatory parameters were collected twice a day for one week. the study was approved by each institutional review board and written informed consent was obtained for each patient. results: a total of patients were included in the study. one patient had to be excluded as a result of protocol violation of the remaining patients patients were randomised to receive tcv- and to be treated with placebo. there were no significant differences between the treatment group with respect to age. gender, and apache i~ score on admission. however, admission levels of il- and il- , considered to reflect severity of disease, tended to be higher in tcv treated patients: . . vs . ng/ml for il- (p. ) and . vs . ng/ml for il- (p. ) in tcv- and placebo treated patients, respectively. a remarkable difference in survival, however not significant, was observed at day i.e. the end of tcv treatment (mortality: out of in the tcv group and out of patients in the placebo group). the inc;dence ui ~-,~verse events, 'n both treatment groups were comparable. plasma il- and plasma il- levels tended to decrease more rapidly in tcv treated patients compared to controls (p=. and p=. , for il- and /l- respectively) conclusions: tcv- is safe as add-on treatment in sepsis syndrome patients. the data presented indicate that tcv- may enhance survival of sepsis syndrome which will be assessed in a phase ill study. objective: oxidation of lipids by free oxygen radicals playes an important role in sepsis. an important source of oxygen radicals is the respiratory burst of phagocytic leukocytes, especially~ polymorphonuclear leukocytes. clinically the hallmark of sepsis is the capillary leak, which is mediated in part by oxyradicals. the adult respiratory distress syndrom (ands} represents the most studied capillary leak phenomenon in sepsis. methods: in ii patients (df,~m, aged - y.) with verified septicemia had been included in this study. beginning from day oxidisable lipidautoantibodies (club), ~opterin and crp were determined in the patients serum and compared against the apache ii score during the days - . patients, f and m died @u= ring their stay at the icu, of them in less than h~urs: after admission. at the begin surviving patients showed olab values between - %, non-survivors between - %, com= pared to neopterin values of - m~ol/l in survivors and - ~mol/l in non-survivors. apache ii score didn t show any difference. during the following days olab sbowed an in= crease in survivors, while in non-survivors olab stayed equal or showed a decrease. no difference between both groups was found in neopterin, crp and apache ii score. as result we conclude, tbat lipidperoxidation playes an important role during septicemia. olab as a marker of this process are predictive for the outcome of patients. obiectives : to evaluate the influence of cardiopulmonary bypass ongastrointestinal transit. meth~xls; gastrocoecal transit time (gtt) in consecutive children on day after uncomplicated open heart surgery was compared to gtt in children after closed heart thoracic surgery and to healthy controls. gtt was measured by hydrogen breath testing, using lactulose (o, g/kg in a % aequous solution) as nonabsorbable marker. exspiratory hydrogen content was measured using a electrochemical system (stimotron). patients in both groups had continuous infusion of morphine and midazolam and were comparable in respect to catecholamine dose. children with a history of toddler's diarrhoea and children with elevated central venous pressure were excluded. results: gastrocoecal transit was delayed in all patients after cpb, no transit was achieved within minutes in / . after closed heart surgery gtt was delayed (+- ) min vs. (+- ) compared to controls, but transit was achieved in all aptients within rain. mean dopamine dose was , mcg/kgmin after cpb and , meg after closed heart surgery.. conclusions: after uncomplicated cpb gastmcoecal transit is extremely delayed. the degree of delay is not explained neither by the use of analgetic and sedative drugs neither by the use of catecholamines. factors directly related to cpb (e.g. low flow perfusion, hypothe,mia) may be responsible. these findings are of limited clinical relevance in ancomplicated cases. in critically ill patients delayed enteral feeding may contribute to infectious complications. studies of therapentic measures to accelerate gastrointestinal transit therefore are warranted. neonatal ecmo -czech experience. nekvasil r., penkova z, vasek l., plier p., bobula a novotna e., pavlicek v., hnilicka m. nicu and ecmo center brno and dept. pediatric surge ', children's hospital brno, czech republic. introduction. in spite of the fact that neonatal ecmo has been gradually considered a standard method of solving uncontrollable respiratol t failure in newborns in most countries of the western europe, the introduction of this sophisticated method in countries of the former communist block meets a lot of problem. material methods. in the course of two years, only newborns, b.w. - g, were reffered to neonatal ecmo because of uncontrollable respiratow failure. at the admission the average values of oxygenation index were + , and aado , -+ , kpa. results. newborns ( %) died shortly alter" admission or during transport without possibity to further is newborns ( , %) were treated using high-frequency ventilation (hfo or hfjv), one for conspicuous airway resistance paradoxically with low-frequency ippb. all ventilated newborns survived. ecmo was applied in newborns ( , %) and of them survived the mortality rate of group mentioned was %. conclusion. the fact that in the czech republic ( mil. population with natality rate of about . newborns/year) only small part of patients was reffered to neonatal ecmo has a number of causes. the most important are: unacquaintance of prognostic and indication criteria at forwarding workplaces and the aversion of neonatologist to all new.therapeutic interventions. last but not least, a negative role is also played by current change of health service systems when, under the influence of health-service insurance companies a newborn in serious condition given only a standard intensive care in primary and secondary nicu is literally "the golden calf", and therefore these workplaces either do not send him or send him too iate ~o an ecmo center. stndy aim: urfactant, which is being applied into the lungs for treatment of respiratory distress syndrome, can reach the circulatory blood system by absorption. it refinances local fimctiun of macrophages and lymphocytes and increases the accumulation of nentrophils into the hmgs this eunld influence the local acute phase reactiml in the hmgs after surfactant application. "ilia aim of the stud), was to investigate the influence of oatural and artificial surfactaat onto the acute phase reaction and the blood elottiog system. material :and methods: a) measurement of tnf-a, - , ltb and thromboxane b release in whole blood: each of . ml hepariaised blood of healthy adult volunteers was iucubated lbr hears with eillier ill ug/ml lps, mg/ml b&,ine smfactant (alveulhct/themae), rag/nil artificial surfactant (exosurf/wellcome), og lps + i mg/ml bovine surfactant or i ug lps + i mghal artificial sorfactant, tleparinised bhx-,d without additions was used for controls. ' e concentration of e)lokines and eicosanoids ".van measured semiquantilatively by eijsa or eia (dimmva/hamburg) after ceatrifagalion, b) measurement of platelet aggregation: each of . ml haparinised hltxxl of healthy adult vohmteers was inculmled lbr hours with eilher aghnl i,ps, i mg/ml bovine surfactant (alveafact/thomae), i mg/ml artificial snrlhctant (exosurf/wellcotne), it} ug lps + i mghnl bovine snrfactant or ug lps + i mg/ml artificial surfaetant, tlepminised blood withont additions was nsed for controls. platelet aggregation in whole blood was measured by impedance in the aggregometer (g~nstaedt). c) measurement of the dotting activity: citrated bleed of healthy adult w~lunlccrs was mixed with difl'ereul couccalrations of imvine or artificial snrfactant fad then prolhrombiu tiaras and imrlial thrmnlx~plaslia filues were ineasnrcd. for measurement of the prokoagulatioo acfivily the reagent in the qnick test was replaced by surfaclant. results: dependmlt on the dose both surfactants stimulated the release of - but not or tnf-a io wlmle blood. "illere was no suppression of the lps-indaeed eytokine-release. both surfaclants did not directly influence the extrinsic blood coagulation system, while both activated the inniasie activity dependant on the dose. platelat aggregatiun was slightly stimulated by bovine snrfactunt and strongly inhibited by by artificial surthctant. in comhinafion with . ~ both factors showed no difft.'renca to lps ahme.'fhe reltu.tse of eiconasnid~." was stimolated more by artificial surfactant then by bovine surfilctant with regard to the cyehmxygelmse (thromboxsne b ) and the lipooxygenase (lencotrieae b ) pathways. conclusion: we cooclude: ) i:lovine as well as artificial surfaelant stimulate the cellular inmnn]e response. ) bovine as well as artificial surfnctant activate the intrinsic ctmgnlation cascade. ) bovine surlilctant stimulates platelet aggregation, artificial sar-fijctant inhibits platelet aggregation.. introduction: although the use of modem noninvasive methods like measurement of tope , tcpco or san leeds to an carly infonnation about pathologic alterations of the gas exdmage of ventilated patients, these methods cannot replace invasive bloodgas analysis. a new noninvasive method to monitor the capillary gas exchange is the reflection spectrophotometry. to record reflection spectra with a ldgh sensitivity on the surface of tissue we eonstnmted a special mierolightgnide photospectronmter (empito). this spectrometer enables the investigation of local helerogenities of llbo and lb content, capillary flow rate and oxygen uptake rate. aim of the study: ) to compare the sousitivity and specifity ofthe empilo with other non-invasive method~ of monitoring the gas exchange in neonatal intensive care patients. ) to investigate the possibility of obtainiug infonnations about the local nptake and the venous as well as arterial satnration. patients and methods:we investigaled non-selected patients of oar pediatric intensive care unit. for coulinnons monitoring we conslracted a special sappert to fix file end nf the microlightguide+ during the investigation tope , tcpco and san were measured by standard methods. "fo investigate the local tisslm oxygen uptake we recorded spectres within minutes by moving the lightgnide over an described area of the skin of the patient. 'lhe reselting i(gx) l ibo vahms were sorted by a software package. on the assumption that the low values correspond to the tibo value of the veaons ends of the capillaries and the high values to those of the arterial ends we ) it is possible to gel infonnations about the local o -uptake and arterial saturation ia the peripheral tissue by photoslg'ctroscopy. ) in combination with noninvasive pl i-measorement it seems possible to reduce withdrawal of blood for invasivn bhmd gas analysis. objectives:improve ventilation,tissue oxygenation and acid base balance among extremly low birth weightand premature infants. methods: fourteen cases were s~udied,their gestational age ranged from( - )ws.continnous positive air way pressure was applied to six cases at peep level from ( - )cm h o through nasal pronge,(group i),the other cases were managed as routine,(group ii).blood gases, tcpo ,tcco ,resp.rate,depth and pattern were monitored for assessment of tissue oxygenation and ventilation, results: our rasults showed that early application of cpap improve ventilation among ( . %)of cases,while ( . %)of cases need imv.the cases of group ii need imv among ( %)of the studied cases during the second or the third day of life. conclusions:-this preliminary study showed the import-............ ance of early application of cpap before the onset of respiratory distress syndrom to improve spontaneous ve ventilation,tissue oxygenation and to gecrease the risk of intubation. comparative assessment of pediatric intensive care; a national multicenfre siudy. reinoud j.b.j. gemkc, gouke j. bonsel , the dutch picasso (pediatric intensive care assessment of outcome) study group. twilbelmina children's hospital and utrecht university, utrecht department of clinical epidemiology, academic medical center, : amsterdam, the netherlands the performance of all ( ) pediatric intensive care units (icus) in the netherlands ( tertairy and non-tertiary) was analyzed in an open prospective muiticenter study. effectiveness of care was defined as the ratio of observed to prism-score derived expected mortality aenee, standardized mortality rate). efficiency was determined by objective criteria (mortality risk > % or administration of at least icu-dependent therapy)'. consecutive admissions aged < years old were included. overall, observed and expected mortality were in good agreement (p > . ). between hospitals, crude mortality showed wide variations (mean . %, range - %). however, in each center, observed and expected mortality were similar (mean ratio . , range . - . ). in tertiary care centres, severity of illness corrected mortality in high-risk patients was less than in non-tertiary care centres; paradoxically, in low-risk patients the opposite was found. probably the large proportion of low-risk tertiary care patients suffering from severe, incurable chronic disease, explains the higher mortality in this group. this indicates that simultaneous assessment of circumstances of dying and of long term morbidity in similar future studies is imperative. the average proportion of efficient icu days was %, however large variations between units were found (range: - %). in conclusion differences in mortality rates among pediatric icus were explained by differences in severity of illness. high efficiency rates in combination with adequate effectiveness, found in several centres suggest that admission and discharge decisions might be improved by a better selection of high risk patients requiring icu-dependent therapies, especially in less efficient centres. objectives: previously published studies showed that serum lactate levels correlated with outcome of severe ill adult, 'we hypothesized that critically ill newborns are often incurred hypopeffusion manifested by elevated lactate levels. these initial blood lactate levels should be related to nicu outcome. design: prospective study with ethical comfnittee approval. setting: the -bed neonatal intensive care unit of a university hospital material and method: a total of consecutive outbem newborns admitted to nlod from , . to ., . were enrolled to the study. babies who died or were discharged from the unit within hours of treatment were excluded from the study, mean birth weight was g (+/- r), mean gestatational age was weeks (+/- . wks), mean age at the admission was h (+/- hi. multiple (~_ j organ system failure occurred jn . % of babies at the admission./~tertal lactates were measure/at the admission, among - hour and - hour of n[c'lj therapy. outcome was defined as a mortality and length of nicu stay. results" survival rate was . %, mean length of nicu stay for survivors was . days (+/- . day). we found high lactate levels at the admission in . % babies (~ . % with levels above . retool/i). the mean arterial lactate concentrations for nonsurvivors were signiftcahtly higher than for survivors durin~ consecutive da~ as follows: objectives: the purpose of our research was to analyze the frequency of bronchial asthma (b.a.) exacerbations in pregnant women and health status of infants. methods: the research was based on the epidemiological investigation and prolonged observation of pregnant women with b.a. during the gestation period. remission of b.a. before the pregnancy in excess of years was recorded in patients ( . %), patients ( . %) reported a - year remission and patients ( . %) had a remission lasting less than months before they became pregnant. results: seven patients ( . %) developed medium attacks in the second half of pregnancy, four patients ( . %) experienced light attacks of b.a. asthma attacks were most frequently caused by acute respiratory diseases and stress factors. in two cases with grave manifestation of b.a., the pregnancy ended in abortion within the first - weeks due to the frequent and heavy choking attacks. to fight b.a. attacks, five patients used adrenomimetics (salbutamol, becotid) in sprays, six women were administered theophyllinum and salbutamol in the form of tablets during - weeks. a significant portion of pregnant women with b.a. ( %) exhibited frequent complications during pregnancy (toxemia, late gestosis, threat of miscarriage). our findings prove that babies born from women with b.a. of domestic and pollen origin had a low body weight ( - gr), functional immaturity and chronic antenatal and intranatal hypoxia twice as often as the infants born from healthy women without allergic background. conclusions: preventive treatment of women with b.a. prior to pregnancy is required to maintain a stable remission of the disease, which is a key to having healthy children delivered by mothers suffering from b.a. introduction. intracerebral hemorrhage (ich) is a common event in human prematudty, affecting about % of newborns weighing below g who are born before weeks of gestation, however, little is known about the pathogenesis of ich with exception of the prematurity of the brain itself, (birth) trauma, and asphyxia. the postischemic production of oxygen free radicals (ofr) dudng reoxygenation as a cause of brain damage has been demonstrated in animal research. since almost all preventive antioxidant activity of plasma is associated with ceruloplasmin and transferdn we investigated the association of such iron-oxidizing resp. iron-binding proteins and ich. we could demonstrate significantly reduced levels of both, iron-oxidizing and iron-binding proteins, in premature asphyxiated newboms pdor to development of ich. an increase of suparoxide after hypoxia in the presence of iron ions facilitates the formation ofthe highly reactive hydroxyl radicals. our data support the theory that ich may be caused by ofr, which can damage any sensitive tissue including growing endothelial cells. the estimation of transferrin-saturation and measurement of ceruleplesmin levels might help to identify an infant at dsk before the onset of ich. with the new medos | hia-vad | cardiac assist system the missing tool in the armamentarium of cardiac surgeons is available in two pediatric sizes: i -ml and -ml pump volume. the right sided pumps are % smaller for biventricular use. between february and may we implanted this assist system in children. the indications and demographics are indicated in the following table (left ventricular assist device-lvad, right vad-rvad univentricular vad-uvad, post cardiotomy cardiac failure-pcf, dilated cardiomyopathy-cmr bland white garland syndrome-bwg, tetralogy of fallot-tof, hypoplastic left heart syndrome-hlhs). objectives: evaluate tile effeci'of inhaled nitric oxide (no) as puhnona] t vasodilating agent ill tile posloperalivc period after correclion of congenital heart defects in infant. patient n.l: kg, lnonlhs, down syndrome undenvcnl rep~fir of atrioventricular septal defect (avsd). after surgery the puhnonary arlcry pressure (pap) slowly rose to tile syslemic dcspilc tnaximal eonvcnlional fllerapy (fentanyl mcg/kg/h, hypocapnia of mmhg and metabolic alcalinization). no was delivered into tile inspiratory branch of!be breathing circuit at ppm, and the gas aoalyser for no and no (polylron dmger) were situated at the espiratory branch, a rapid dccrcasc of pap io i/ of systemic was obtained with a dramalic improvement. no was continued at ppm for six days and the baby was exlnbated if! days after surgery and discharged from the icu days after. patient n. : . kg, monlhs, onderwen! repair of avsd. the day after surgery the systemic oxygen salnralion was % wilh a pap at % of systemic. two hours of c wenlional therapy failed o improve ihc patient and no administration was slarled at ppm. so dramatically incrcased to %, but the pap dropped only to % of syslemic. nevertheless ihe clinical conditions improved and the no administration could be reduced at ppm in the following days. she was extubaled days after surgery and discharged from the icu days after. patient n. : kg, 'ears. underwen| hearl tral~splantalion for congenital heart disease with moderate hypoplasia of pulmonary arlcrics. at the end of cardiopulmonary bypass the transpnlnlonary al~erio-venoas gradient yeas higher than mnfflg and we speculaled !hat w'ls due to a degree of puhnonary vasocostrictiont. the nsnal dose of no was otilised, however no significant modilicalion of pulmonary pressure or systemic oxygen saluralion was noled, and after h no was discontinned. tile palienl was carried io the icu with maximal inotropic support, extubated after d;b's and disclmrged from the icu after days. in all patient no major adverse effect relaled to no admilfistration ",','as holed. conclusion: in our experience no ms a pulmonary vasodilaling agent is effective and easily adjustable to tile palienls requiemenls, however its use remains limited ill those palienl ill whoin tile alnonll! of fixed inlllllojliify vascular resistance is predominanl. we report the use of ecmo support in two unusual cases of severe tracheal disruption in which it had become impossible to achieve adequate ventilation. case : severe tracheal laceration due to aspiration of a share forelan bodv: a previously healthy month old toddler was referred for ecmo following aspiration of a porcelain foreign body (with razor sharp edges) which had become embedded in the right mainstem bronchus with massive extrusion of air. this was removed on veno-arteda[ ecmo support, as the patient was unventilatable prior to bronchoscopy due to ongoing airieak. ecmg was continued after bronchoscopy to permit airway healing without the presence of an endotracheal tube. unfortunately, an extensive pulmonary haemorrhage on day of ecmo necessited re-exploration of the airway. this revealed a posterior tracheal tear from the cricoid to the middle of the right lower lobe. following repair the patient was left on ecmo support together with high frequency oscillation ventilation (hfov), the latter being used to minimise potential aideak and maximise alveoli recruitment. ecmo was weaned after days ( hours) -the patient was extubated weeks later. case : tracheal wound dehiscence due to seosls -tracheal transelant on ecmo: a month old infant with a c[inically significant congenital long segment tracheal stenosis and left pulmonary artery sling underwent resection of the stenosis, followed by primary reanastomosis. this was complicated, days later, by severe mediastinitis and complete dehiscence of the anastomosis. an autologous pericardial patch was used to repair this, however, the tracheal wound again dehisced days later making mechanical ventilation impossible. in view of ongoing sepsis and a severely disrupted trachea ecmo was the only possible form of support. following resolution of the local sepsis ( days) a definitive procedure in the form of a tracheal homograft (transplant) was undertaken on ecmo. the patient was managed on ecmo and hfov for a further days, the hfov being used to optimize rapid lung inflation. unfortunately this patient died months after weaning from ecmo due to complete disintegration of the homograft, which was not deemed reparable. conclusions: ) ecmo can be used in the acute management of oxygenation when there is major airway disruption making mechanical ventilation impossible. ) hfov was a useful adjunct in aiding recruitment of lung volume on ecmo in these two patients. backoreund: persistent pulmonary hypertension of the newborn (pphn) consists of a heterogenous group of diseases ranging from transient reversibte pulmonary hypertension to fixed primary malformations of the lung (primary pulmonary dyspfasia-ppd). inhaled nitric oxide (ino), a selective pulmonary vasodilator, has been proposed as a treatment for severe pphn. obiective and methods: ino was administered to near term neonates with severe persistent pphn, oxygenation index > and echocardiogrephic evidence of pulmonary hypertension, in order to further determine the clinical role of ino in the treatment of pphn. the response to ino was also analysed retrospectively to examine whether this could be of diagnostic value in differentiating at an early stage patients with reversible from fixed causes of pphn results: twenty one of the patients studied responded to the initial trial of no ( ppm x minutes), as defined by a greater than percent improvement in pad as well as a fall in the el to < . these patients were continued on ino therapy, with patterns of response emerging: pattern babies (n= ) continued to show a sustained response to ino and were successfully weaned from it within days -all survived. pattern babies (n= ) failed to sustain their response to ino over hours, as definded by a rise in the el > . six survived, five with ecmo. pattern babies (n= ) had a sustained dependence on ino for - weeks. all three died and lung histology revealed severe primary pulmonary dysplasia (ppd). patients with ppd (pattern ) not only required ino for longer periods of time than did the sustained responders (pattern ), but also required significantly higher doses of ino we report on the air transport of paediatric intensive care patients. these transports fall into three categories: ) retrieval of critically ill neonates and paediatdc patients referred for either ecmo or inhaled nitric oxide (ino) (n = ). one patient was transferred on ind. mean transfer time . hours (se + . hrs). ) long distance international transport using chartered aircraft (n = ). the indications for these transfers included both urgent retrievals for cardiac surgery and semi-elective transfer of stable patients back to their referring unit following treatment in tertiary centres. mean transfer time . hours (se + . hrs) ) long distance international transport using commercial aircraft (n = ). indications for transfer were either semi-elective retrieval for tertiary treatment or the return of stable chronically ventilated patients to their referring hospitals. mean transfer time hours (se _+ .fhrs, longest hrs). the transport team consisted of a paediatric intensive care doctor of at least registrar grade and a registered sick chidrens nurse with intensive care experience. the administrative components of the transfer (ambulances, airlines, customs) were managed in collaboration with companies specializing in air ambulance transfers. outcome: all the patients were safely transported to their destination without mortality or morbidity. complications durino transfer ir~lv~; ) patient complications -semielective endotracheal tube change and central access needed in the only patient brought to the commercial aircraft by the referring hospital (all others retrieved directly from referral hospital), seizure in patient with known encephalopathy, severe cyanotic spells in patient with fallots tetralogy who was retrieved for urgent surgery for this indication ) mechanical compfications -ventilator failure, incubator battery failure, oxygen regulator failure -all occurred with equipment sent from referral hospital, this was unfamiliar and unchecked by our transport team -it was not the decision of the transfer team to use this equipment on this single occassion. ) administrative complications -confiscation of incubator battery by airport security police, excessive delay by custom officials ( hours) in the airport. the incidence of such problems were felt to be low and unpredictable. in conclusion: mechanically ventilated paediatric patients can be safely transported on both chartered and commercial airlines. these transports are best accomplished by trained intensive care medical and nursing staff with the backing of an air ambulance organization competent in arranging the necessary administrative details. it is essential to use your own equipment and to retrieve the patient _directly from the referrin(] hospital to minimise ootential complications. our experience with anaesthesia for paediatric electromyography _w_._pla_ti_k_a_n_o_v, r.eousseff, k.pavlova, d.marinova dpts. of anaesthesiology and int. care and clinika] neurophysiology, med. university, pleven, bulgaria ~)_b_j#~ti_v~. to t~st a " heavv sedation " regimen of anaest-es~a for the purpose of paediatric electromyography d#s~gil~ non-randomized,non-blinded human trial in the seting of an uriiversity hospetal. _m_a_t_eri_a_is_a_nd_ m_e_th_od_s_. children,asa i-if,median age years,range - who undervent eleetrcmyography required anaesthesia. they recieved low-dose ketamine + i~iazepam or midazolam via musculary route( children,age - yrs,ketamine , mg/kg, diazepam - mg total dose ) or per os ( children,ketamine - mg/kg,diazepam , mg/kg or midazclam , - , mg/kg ) _resu_l_t_s. - minutes after medication a state of heavy sedation with weak spontaneos and stimuli-provoked movements was achieved in all children, that lasted - minutes and allowed adequate needle emg and nerve conduction investigation. children recieved additional , - , vol.% halothane during the placement of the needle. non -invasive blood pressure , breath and heart sounds and hb sad by pulse oxymetry were monitored.none of the older children disclosed memories of pain when asked after they regained adequate verbal contact.no complicationes were observed. antenatal maternal steroids reduce the risk of periventricular-intraventricular hemorrhage in very premature neonates treated with natural surfactants. i.apostolidou, c.papagaroufalis, g.touloumi, m.xanthou, n.kalpoyannis a' and b" neonatal icu "ag. sophia" children" s hosp. athens, greece. dept of hygiene and epidemiology, athens university, greece. obiectives: the aim of the study was to evaluate the association of periventricular-intraventricular hemorrhage (p-ivh) in surfactanl treated premature neonates with pre-and postnatal variables. methods: the population of the study was neonates admitted during the years to , with gestational age _< weeks and severe respiratory distress syndrome (rds) (mechanical ventilation and arterialalveolar oxygen tension ratio (ajapo ) < . ), who received rescue therapy of at least two doses of natural surfactants (alveofact or curosurf) and examined with ultrasound and/or autopsy for the presence of p-ivh (papile's classification). the examined factors in each neonate were the following: gestational age, birth weight, sex, multiple pregnancy, antenatal maternal steroids (complete and incomplete course of betamethasone), a/apo before the administration of the st dose of surfeclant, delivery, apgar score at min, type of surfactant, pneumothorax and patent ductus arteriosus. the statistical methods used were x and one-way analyses of variance followed by logistic regression medels, results: the incidence ot p-ivh was . %. three factors were found to have an independent relation to p-ivh (final logistic regression model): gestalional age, a/apo before surfactant administration, and antenatal administration of maternal steroids (complete and incomplete courses). for every weeks of lower gestational age the neonates had an almost doubled associated risk of p-ivh (or: . , % c : . , . ). for every . on average decrease of a/apo before surfactant administration the risk of p-ivh in the neonates was . times higher ( % ci: . , . ). the neonates whose mothers received antenatally steroids had only one tenth of the risk of p-ivh of the neonates whose mothers had not (or: . , % ci: . , . ). conclusions: our results suggest that the antenatal administration of maternal steroids, even less than hours before delivery, reduce the risk of pqvh in very premature neonates treated with natural surfactants, whereas the small gestational age and the lung immaturity still remain the main risk factors tor the development of p-ivh. we analysed retrospectively the management of ( boys, girls) accidental ingestions of foreign bodies in children (mean age : . years, range : months- years). no child had ingested more than foreign object. the majority of the ingested foreign bodies were : coins (n : ), toy parts (n : ), jewellery (n : ), batteries (n : ), "sharp" materials such as needles and pins (n : ), "large" amounts of food (n : ). impaction of food occurs more frequently in children after oesophageal reconstruction in cases of oesophageal atresia. although according to literature "coca-cola" is reported to be effective, this was not seen in our experience. / patients had minor transient symptoms at the moment of ingestion, such as retrosternal pain. only children experienced severe manifestations (cyanosis, dysphagia). in these children, endoscopy revealed oesophageal and gastric erosions. children were seen at the emergency ward within a few hours after the accident ( mean : hours, range min. - hours). chest and/or abdominal x-ray was performed as first-line investigation ( / objects were radio-opaque), and revealed an (unexpected) oeeophageal impaction in children. in / the foreign body was in the stomach. batteries, sharp objects and objects trapped in the oesophagus were removed, either by endoscopy or by magnet-extraction whenever possible. the outcome of the patients was excellent. no complications were observed. extraction is recommended in symptomatic patients, and whenever the foreign body is trapped in the oesophagus, or if the foreign object is "sharp" or a battery. objectives: two strategies were used for management of malignant diphtheria in children aged from . to years. methods: protocol n consisted of intravenous administration of diphtheria antitoxic serum, prednisolone ( mg/kg bw/day), plasmapheresis and supportive care. protocol n included the use of antitoxic serum against the background of high-dose dexasone ( - mg/kg bw/day), hemocarioperfusion and a preventive use (before the clinical manifestation of myocardial damage) of inotropic medications, inhibitors of angiotensin-converting enzyme and pentoxyphylline. each of protocols included the monitoring of serum toxin (diphtherin) levels. results: the group of patients treated according to the protocol n consisted of children with malignant diphtheria, of them with severe malignant diphtheria (grade and ). all patients exhibited the circulation of toxin during at least three days after the start of treatment. all patients with severe grade of disease demonstrated heavy cardiovascular disturbances associated with malignant diphtheria. of the children in the group died seven. the children of the second group were treated according to the protocol n . out of total of patients of this group. patients had severe malignant diphtheria. in all children a significant reduction in serum toxin level was revealed after hemocarboperfusion. in all but one case the satisfactory control of cardiovascular function on was achieved. of children admitted to the trial survived, one child with malignant diphtheria of grade and congenital filbroelastosys of the left ventriculum died. the severity of neurological complications was similar in each of groups. conclusions: the use of hemocarboperfusion, high-dose dexasone and early prevention of heart failure as a adjunct to the standart treatment has been shown to be of benefit in the management of malignant diphtheria. t. schaible, i. reiss, j. m er, l. gortner med. university of lqbeck, children's hospital, kahlhorststr. - , l~beck, germany surfactant therapy seems a promising approach for the treatment of the biochemical and biophysical abnormalities of the pulmonary surfactant system in severe ards. patients and methods: over a months period non-neonatal pediatric ards patients (age - months) in a "pre-ecmo"-situation (oi over h) were treated with bovine surfactant (alveofact| the underlying conditions-of ards were pneumonia ( ), sepsis ( ), immunosuppression ( ), near drowning ( ), neurogenous ards ( ). a total of - mg/kg b.w. was applied in several fractions. before surfactant therapy, we first tried different ventilation (best peep-finding, inversed i/e-ratio, hfo-ventilation) while monitoring the pulmonary mechanics. for hemodynamic stabilisation both norepinephrine and epoprostenol were used to optimize pulmonary perfusion for max. hrs. if there was no improvement of the oi by at least , further treatment with surfactant was initiated. in addition to surfactant all patients received a treatment with dexamethasone of mg/kg in doses. patients with no benefit (oi remained unchanged or increased within the max. - hrs) were taken on ecmo. results: nine patients improved within hours after surfactant therapy: the oi decreased from a level of (mean, range - ) before our treatment to a level of (mean, range - ) thereafter. in patients we were able to continue the positive effects of our treatment and they could be weaned of the respirator within - days. the other patients got worse despite respiratory improvement, they suffered of multiorgan failure of more than organ systems. the last patient did not benefit from surfactant, he had to be put on ecmo, but died because of a complication (hemopericard)after days. the autopsy of the ecmo-patient showed a pulmonary fibrosis, but the other death were not due to pulmonary failure. conclusion: a different sequential ards treatment integrating surfactant therapy can reduce the number of patients requiring ecmo. but ecmo as a therapeutic tool should be available in centers involved in ards treatment. l.blindl, t.p.le, h.weinzheimer, centre for paediatrics, university of bonn, germany selective reduction of elevated pulmonary vascular resistance by inhaled prostacycliu (pgi) has been reported in adults with acute lung injury, neonates with persistent pulmonary hypertension and in one infant with idiopathic pulmonary hypertension. we report on the effect of aerosolized prostacyclin in two children with secondary pulmonary hypertension. patient : in a boy with down's syndrome an avsd had been surgically corrected at month of age. at , yr of age a catheter examination revealed a pulmonary vascular resistance of % of systemic vascular resistance in room air and at an fin of . . prostacyclin ( . mcg/ml) was administered with a jet nebulizer at an fin of . . pvr declined to . systemic vascular resistance and returned to baseline after stopping pgi-inhalation. subsequent intravenous infusion ( ng/kg rain) had to be stopped after minutes because of systemic arterial hypotension. patient : a month old male infant with bronchopulmonary dysplasia developed suprasystemic right ventricular pressure inspire of therapy with oxygen and nifedipin. while he was spontaneously breathing % oxygen via face mask pao was mmhg, arterial ph was . . systolic arterial pressure was mmhg, a rv-ra gradient of mmhg was measured by cw-doppler. while fio was maintained aerosolized prostacyclin was administered over minutes. rv-ra gradient was mmhg, systemic blood pressure mmhg, pao mmhg. two hours later nitric oxide ( ppm) was inhaled at an fio of ( , . rv-ra gradient declined from to mmhg, systemic systolic blood pressure remained stable at mlnhg. discussion: sporadic experience shows that aerosolized prostacyclin selectively reduces elevated pulmonary vascular resistance in some patients. in patient the poor response to inhaled pgi compared to inhaled nitric oxide may be explained by the fact that the action of pgi is not independent from endothelial function, limiting it's effect in severe vascular disease. during the last two years ( - ), infants weighing less than gr. admitted to our referral unit. thirty four of them ( %) survived, ( % of infants weighing - g and % of infants weighing - gr survived) for the years - - the survival of these infants was % and for the years - - , % (p< . ). we analyzed the perinatal and neonatal factors influencing the outcome of these infants. the comparison among neonatal survivors ( ) to neonatal deaths ( ) shows: gestational age: . w ( ) to . w ( ) (s). birth weight: . g ( ) to . ( ) (s). apgar score: , ( ) to . ( ) (ns). presentation and mode of delivery: breech presentation is associated with higher incidence of neonatal deaths. i.v.h. (at the age of weeks): no one of the survival infants had evidence of i.v.h. respiratory problems: intubation, at the admittance of the infants . ",,( ) to % ( ) (s) use of surfactant: % ( ) to % ( ). bpd observed in % of the babies and only one was dependent on oxygen at home. antenatal betamethasone was given in % of the mothers. in conclusion: ) a great improvement in the survival rate observed in these infants the last years in our unit. ) factors with positive effect are increasing gestational age and birth weight, the absence of i.v.h. and the use of surfactant. the breech presentation and the severe respiratory problems increase the incidence of death. animal experiments demonstrated, that brain temperature determines the amount of neuronal damage caused by hypoxia and that mild hypothermia may have a protective effect. until now there is no method described and evaluated to measure brain temperature in neonatal intensive care units. we non-invasively measured brain temperature analogues, nasopharyngeal (tnasoph) and zero-heat-flux temperature (zht) at the temple whereby under zero heat flux surface temperature represents deep head and thus brain temperature. the aim of our study was to investigate the practicability of the method, the relationship of the two brain temperature analogues to rectal temperature (trect) and their dependence on insulation, thermal environment, body activity and time course. we investigated healthy preterms less then weeks postnatal age (gestational age +_ . wks; x + sd, weight +_ g) in an incubator. tnasoph was measured by a thermistor within a feeding tube, advanced to the nasopharynx, zht temple by a thermistor and a heat flux transducers both covered by an insulating pad, and trect thermal environment was characterised by operant temperature (tair . . + twall . ). body activity was video taped. measurements were performed during the following interventions: i/ insulation increased by turning the temple with sensors onto the mattress ( rain). ii) insulation increased by a cap ( min), iii) min after its removal, iiii) increased operant temperature by . + . ~ ( min). results: seven children with ea had a gasless abdomen, the endoscopic procedure excluded ( ) or diagnosticated an upper pouch fistula ( ). in patients who suspected "h" fistula ( ) broncoscopy has strong advocated method to make diagnosis and established cervical approach. from july newborns with ea and lower pouch tef received a selective transtracheal incannulation. we were not able to proceed just in case with congenital subglottie stenosis. in these patients we provided gastric drainage by radiopaque and flexible - french catheter. the knowledge of the precise anatomic position of tef consent to adjust the tip of the endotracheal tube in order to achieve best ventilation. the presence of the catheter through the fistula helps the surgeon to identify, it quickly. no complications were correlated to the procedure and no babies had early pneumonia. alimentary continuity was achieved in all patients ( primary anastomosis, resections of tef, oesophagocoloplasty and died with gastrooesofagostomy). the late mortality . % ( ) was only directly related to the severity of associated malformations. conclusion: the advantages of this technical approach are unquestionable for the anaesthesiologist and the surgeon. in our experienc e the procedure improves perioperative management of babies and appears to be safe. relation between cytokines, prethrombotic markers and endotelial injury markers in children with septic shock objectives: to establish the relationship between cytokines (tnf, il- , il- ) prethrombotic markers (d.d., pcam) and endothelial injury markers (tm, uwf) in pediatric patients with sepsis and bacteriemia without shock, and patients with septic shock. design and methods: prospective study, children ( months- years) were admitted in our picu in with the following diagnosis: bacteriemia ( ) sepsis ( ) and septic shock ( ) according to jacob's r f criteria. measurements: il- , il- , tnf, tm, vnf, d.d. pcam and routine laboratory data on admision, , , hours and on discharge. the prism (pediatric risk of mortality score) was also recorded. results and conclusions: two patients in the septic shock group died. significant differences were found between non-shock and septic shock patients in relation to tm, dd, pcam, il- , il- and tne high levels of tnf and il- are closely associated with the severity of septic shock with purpura in children. low levels of pcam on admission were associated with severe shock. who underwent open hea~nt surgery, hypervotaemia with or without oliguria was the most frequent reason to start pd ( %). in patients pd lasted less then one week and there were no complications; in patients it lasted - days (one child had a peritonitis). instillation of dialysis fluid into the peritoneal cavity was associated with a significant increase in central venous pressure. there were no significant changes in cardiac output or arterial oxygeu saturation. in all patients pd dhnjnished fluid overload or improved the metabolic status. patients ( %) survived the postoperative course and all had complete reintegration of renal function. conclusion: pd is a useful method to treat the fluid overload and acute renal failure in paediatric patients following open heart surgery with file effects of little importance on the cardiovascular fimction. obieetives: with the marketing of computerised systems for lung function testing in newborns, there has been an increasing interest in clinical approaches. percentile curves of pulmonary parameters permit an appropriate and clinically useful interpretation. however, the manual evaluation of the results using different curves is an impractical technique. therefoi'e a computer programme was developed. methods: the percentiles ( %, %, ~ %, %) of the most important pulmonary parameters were determined non-parametrically in weight-classes. for the calculation we have taken results of our own as well as other laboratories using a meta-analysis of reference studies. in all, individual data of - healthy newborns ageing between - days were collated. using these percentiles, for every parameter in relation to the body-weight the cumulative distribution was calculated approximately using piecewise linear and exponential functions. as shown in the figure the results of computing are represented numerically as well as graphically and can be included in the patient report. conelusions: clinic~d experiences with the programme have shown that representation of all measured parameters on standardised % scales allows an easy interpretation at first sight and improves the detection of pathologic patterns in the parameters. ")supported by bmft, fp "risikoneugeborene" prism (pediatric risk of mortality) score is a well known, already validated scoring system that quantifies severity of illness based on routinely clinical and laboratory variables measuring physiological instability. once computed the score by summing up the weights corresponding to the most abnormal value recorded during the first hours, the overall risk of mortality can be predicted by using the coefficients estimated by a logistic regression where prism score is the main independent variable. (pollack mm et al, -pediatric risk of mortality (prism) score. crit. care med. ; : - . to assess the applicability and validity of prism in the italian setting we launched out a prospective data collection in a sample of pediatric icus. measures of calibration (goodness of fit statistics) and discrimination (receiver operating characteristics and area under the roc curve) are planned to be adopted in the cohort of patients recruited during year period. as the validation study started on july , data collection is still on going and validation analyses will be carried out on july . up to now centers recruited cases. at present, characteristics of the sample recruited are the following: most of the patients were male ( %); the mean age is years with % of patiens having less than days; more than half were medical cases ( %) admitted from emergency room or from hospital floor ( %); % cases were admitted with an organ failure while % to be intensively monitored. icu-mortality was l %. the paper will present final results of calibration and discrimination analyses that will be carried out in the whole sample and across subgroups known to differ in terms of clinical relevance and prognosis. if calibration and discrimination assessment will produce not satisfactoty findings, a customization of the current coefficients will be made allowing a formal comparision of previous and new parameters. jf riera-faneao, m wells, j lipman. baragwanath intensive care unit, university of the witwatarsrand, south africa. [background the prism score is designed to assess the likelihood of death in ipaediatdc icu patients, using only acute physiological disturbances, age and [operative status to predict mortality. there is no evaluation of chronic health status, [including malnutrition. this may significantly affect its ability to accurately predict outcome in a population where malnutdtion is common. aim to determine the influence of nutritional insufficiency, as indicated by a low weight-for-age on outcome prediction by prism. patients & methods we analysed prism, weight and demographic data co ected prospectively from consecutive paediatdc icu admissions over a year pedod. a proportional weight (pwt) was calculated as a percentage from the th centile of the who weight-for-age growth charts. the pwt was compared for survivors and nonsurvivors, and mortality compared for pwt categodes nho wellcome classification). multivariate statistical techniques were used to identity associations with non-survival and to develop a modified logistic regression equation including a measure of i nutdtional status. receiver operating characteristic (roc) analysis was performed including and excluding patients with low pwt for the odginal and modified equations. results non-survivors had a lower weight than survivors ( . kg and . kg medians p = ) a lower pwt ( % and % medians p = . " . the incidence of malnutdtion , in our icu population was %. the mortality of manoudshed patients was' significantly increased (p = . ), with a good correlation with the degree of malnutrition. the accuracy of prism was significantly improved when malnourished patients were excluded from the analysis (roc value increased from . to . ). ! logistic regression and discriminant analysis identified a significant association between prism, pwt and outcome; age and operative status were not significantly related to mortality. the use of a modified equation including the raw prism score, pwt category and age can significantly improve the discriminatory power (az dm/elopmental sample . , az validation sample . ). the modified formula is: legit = - . + . *prism score - . *age + . *weight category, where the probability of mortality is exp(iog/t)/ + exp(iogio. discussion although we can improve the prediction of mortality by a modified or recelibrated formula, this still does not compare with the reference prism population. the need for validation of the score itself, in the association with outcome of the acute physiological variables themselves, is thus apparent. we conclude that while the odginal prism formula can be improved significantly, a modification of the basic variables in this and other third wodd populations may be essential. a high incidence of malnutrition is an independent risk factor of mortality, and an important cause of the poor discriminatory performance of prism. in order to improve the accuracy of prism, nutritional status should be taken into account. objectives: to assess the value of inhaled no to differentiate between pulmonary vascular constriction or fixed anatomical obstruction. methods: we assessed the response to ppm inhaled no in patients( m, f, median age . months, range day to years) with signs of increased pulmonary vascular resistance, there were pre and postoperative patients. patients were divided into responders(+) or non-responders(-). a positive response was defined as a % reduction in pulmonary arterial pressure and pulmonary vascular resistance(pvr) or in the presence of a left to right shunt, a fall in pvr accompanied by increasing pulmonary blood flow. left atrioventricular valve atresia + mustard pat: pulmonary atresia vsd: ventricular septal defect asd: atrial septal defect pda: patent ductus arteriosus tapvc: total anomalous pulmonary venous connection the responders( / ) were characterised by left to right shunts or pulmonary venous hypertension( / ). patient# was weaned from ecmo with inhaled no. patient# , without congenital heart disease, underwent a lung biopsy which confirmed reversible pulmonary vascular changes. patient# had a pulmonary hypertensive crisis which responded to no. all non-responders( / ) had evidence of anatomic obstruction to pulmonary blood flow (# , , )or a low pvr(# ) on subsequent cardiac catheterisation. in patient # , lung biopsy confirmed severe obliterative vascular disease. conclusions: inhaled no appears to be an effective pulmonary vasodilator. a failed response may be evidence of either irreversible pulmonary vascular disease or a residual anatomical obstruction which may be surgically remediable in the postoperative cardiac patient. therefore, inhalation of no may be a useful diagnostic test to differentiate between fixed anatomical obstruction and reversible vasoconstriction. results: during these years, the incidence of sdra was . % of the total of admissions. the most common etiology was meningococcic septic shock. since , there is a decrease of its incidence. (from % to %) and an increase of pneumonia and immtmodeficiencies. mean age of our patients was , years ( % males, % females), total mortality by sdra was % and there is an increase up to % since mean time of stay of the dead was , days and , days those who survived. although during the late years we offer in the picu a better attendance quality to the patients with sdra and the mean stay is longer, both for those who die and for those who survive, mortality of patients with sdra have increased. the incidence of sdra secondary to the septic shock of a meningococcic etiology have decreased. on the contrary, the sdra secondary to infections by opportunistic germs in patients with congenital inmmunodeficiencies or acquired immuodeficiencies have a tendency to increase. in our series, this change of aetiology is the responsible for the increase in mortality. hospital infantil unlversitario "virgen de roclo". sevilla. espalqa aims:to assess the incidence, etiology, clinical course, sequelae and mortality of the patients admitted to a paedfiatic intensive care unit with the diagnosis of severe traumatism. material and method: cases of severe traumatism in children admitted to our icu in the period from january to june were reviewed. age of patient ranged from months to years, % were males. in our series, % of cases suffered traumatism due to a traffic collision and % had a fall from a considerable height. only in one case was traumatism due to violence to the child. we assessed the first assistance received in % of cases: where was it performed, interval of time since the accident, and steps taken. these data were also studied in relation to the latter evolution. results: % of our patients suffered cranioencephalic traumadsm (ct); in % it was an isolated picture and in % of cases was associated to other lesions. there was participation of thoracic and/or abdominal organs in % of cases. % of cases presented important maxillofacial involvement. only one case presented serious cervical medullar lesion. mortality in our series was . %. in . % important sequelae remained. all of these patients presented tepas on admission equal or lower than . % of those with traumatises had slight sequelae. . % of the total evolve towards healing. a polytraumatized child is a patient that benefits considerably of it admission in a paedriatic !cu. the rapidity in receiving first aid and its quality are essential to avoid sequelae and to make mortality decrease. after unilateral lungtransplantation % of the patients develop a lung failure with decrease of perfusion and increase of pulmonary blood pressure in the transplantated lung. the improvement of perfusion is an importent task in the postoperative period. case report: a year old girl with idiopathic pulmonary fibrosis received a left sided single lung transplantation. during the early postoperative period occured a higtter demand of oxygen and an increasment of the pulmonary vascular resistence in the left lung. the pulmonary ventilation and perfusion scintigraphy indicated in comparison with the right lung a reduced perfusion of only % in spite of a ventilation of % of the transplanted lung. to improve the perfusion of the transplant we administrated per inhalation prostacyclin in a maximal dose of ng/kg/min. the arterial blood pressure decreased but the perfusion continued nearly at the same level. during the following administration of ppm no in the respiratory air we achieved a significant reduction of the respiration pressure f~m to nun h and of the pulmonary arterial pressure. the perfusion in the transplanted lung increased to ca/of the total pulmonary perfusion. after days of administration with no we were able to withdraw the axtifical respiration without any following complications. conclusions: the perfusion of transplanted lungs is a major proble_r~ in the postoperative period. this case demonstrated the advantage of no towards the inhalativ application of prostacyclin. no showed a significant improvement of perfusion in the transplanted lung of a year old girl. results: a total of children with ards were treated with bovine surfactant (alveofact| cases were evalable. the median age was . years (range weeks to , years). in six cases ards was associated with pneumonia, in two cases with lung hemorrhage; in one case isolated ards followed hemihepatectomy. the first surfactant application was performed with a median latency of clays (range - days) after first symptoms of ards witha median doseof mg/ kg (range - mg/kg). in patients doses of surfactant were applied. during the hour before therapy, the median pao / fio -ratio was - . within min. after application of exogenous surfactant the pao / fio -ratio increased to with successive decrease over a period of hours to . accordingly, an increase in pao and oxygen saturation and (less significant) a decrease in ventilation parameters could be observed. analysis of broncho-alveolar lavage before surfactant application in children receiving repeated doses revealed in most examined cases either clear surfactant deficiency or pathological function. of treated patients survived ( of the , respectively). of the surfactant doses were applied in the surviving patients.conclusions: the application of exogenous surfactant in children with ards caused a significant increase in oxygenation, which declined over a period of - hours. the effect often could repeatedly reproduced, in one case after applications. the increase in oxygenation often allowed the reduction of fio and/or the inspiratory pressure. no side effects were observed after exogenous surfactant application.in many cases the application of surfactant wag too late after first symptoms of disease (median latency days). ards mostly due to pneumonia seemed to respond to surfactant therapy less well or not at all. permanent junctional reciprocating tachycardia (pjrt) is the most common incesant supraventricular tachycardia (svt) in children. it is usually drug resistant and its onset in early life has been associated with dilated eardiomyopathy. we report our clinical experience with patients detected antenatally and another diagnosed at months of age. method.diagnosis: negative p waves were detected in leads ii,iii and f, p'r > rp" and there was not warm-up at tachycardia onset.clinical records, ekg,x-rays, echo and holter were reviewed. ep studies were undertaken only with therapeutic purposes. results. in a year period patients under y of age fullfilled diagnostic criteria; were detected prenatally ( - weeks) and one was diagnosed at age mo. the fetuses had intermitent svt during gestation. all of them had pjrt in the first month of life at rates between and bpm. they were admitted to the icu but did not develop signs of heart failure. they were controlled with digoxine (d); d and quinidine; d and propafenone in to days. one was in sinus rhytm until age y; he then showed persistent pjrt over % of the day on repeated holters and underwent successful radiofrecuency catheter ablation (rfca).the other two patients showed initially a lowering of tachycardia rate followed by sinus rhytm for over % of the day (follow-up ran and y). the mo. old infant was admitted to the icu in severe cardiac failure. echocardiogram showed marked systolic dysfunction (shortening fraction %) treatment with digoxine, amiodarone and propafenone were unsuccessful despite lowering heart rate to ; rfca was performed at m. of age with restoration of sinus rhytm and rapid recovery of contractility. all patients were given atp at admission with transient ( to see) recovery of sinus rhytm. ff,s clinical course of pjrt is variable. atp is useful only as a diagnostic tool. initial treatment with digoxine + amiodarone or propafenone is adviced. rfca is a very useful therapeutic modality and can also be performed in young infants twelve patients ( %) died. these were meningitis, head injury, sub-arachnoid bleeds, status epileptieus, leukaemie, drowning, and multiple trauma. calculated from the a admission day p edialric risk of mortality score (prism), the probability of death (p) ranged from - %. of the deaths, i were predicted by prism analysis except for the leukaemie patient (p i%) who died from haematological complications following chemotherapy. two children predicted to die (p % & %) survived. the median length of stay was days (range - days). patlents( %) received ventilatn~ support and patienta( %) were transferred to specialist units ( neurosciences, liver, cardiac, bums). this data supports the view that many paediatric patients are being adequately treated in a dgh icu. meningitis and other neurological illness caused the majority of deaths and respiratory problems caused most admissions. most deaths ( of ) occurred within a few hours of admission. ectopic junctional tachycardia (ejt) is one of the most dangerous arrhythmias in the postoperative setting of congenital heart defects since it does not respond to antiarrhythmics or defibrilation. the object of this presentation is to report on two patients who presented f_jt in the early postoperative period and developed intense congestive heart failure which could be controlled after treatment with moderate topical hypothermia. two patients, m and y, diagnosed of atdoventficular septal defect and tetralogy of fallot developed intense heart failure in the early postoperative period. taehyeardia rate was and bpm. medical drug therapy included weaning from vasoactive drugs, iv digitalization and iv amiodarone treatment. there was not response. they were both surfaced cooled by placing plastic bags filled with cold water over the patient's chest and abdomen. temperature was monitored to obtain a central temperature of ~ there was a gradual decrease in heart rate in the following hours ( - bpm) paralel to the degree of surface cooling and clinical course estabilized.both recovered normal sinus rhytm in to hours. there were not significant arrhytmias after the procedure and postop, was uneventful. conclusions. moderate hypothermia is a very useful manuever for the treatment of drug resistant ejt. since it lacks side effects of other antiarrthymics we beleave it should be the treatment of choice for the treatment of ejt in the postoperative patient. present understanding of the pathogenesis of sepsis, based on the theory of systemic inflammatory reaction, has risen new interest in the more invasive methods of treatment, like plasmapheresis, leucapheresis and exchange transfusion (et). obiectives: evaluate the effect of et in the treatment of neonatal sepsis. material and methods: from september to december , a prospective study was carried out, where the severest cases of bacteriologically proven neonatal sepsis (n= ) were treated with et. in total newborns were treated for culture positive sepsis in the intensive care unit during this study period. diagnosis of sepsis was based on the clinical criteria of suspected neonatal sepsis, used by mc harris et al., laboratory data and positive blood culture. newborns with severe congenital malformations were excluded. et was carried out with fresh (less than hours old) adsol-conserved erythrocytes, from which buffy coat had been removed, and same donors plasma, using a slow continuous two-site technique. the mean volume of et was . ml/kg. the effect of et was assessed as a change in the score for acute neonatal physiology (snap), general treatment results were compared with a historical control group of newborns, treated for culture-positive sepsis in the same icu during the first eight months in . students ttest and chi-square test were used in statistical analysis of the data. results: with the use of el a significant decrease in mortality was achieved: death of cases during the study period, compared to deaths among the controls (p< . ). no baby, receiving et, died. the incidence of severe complications did not differ in the two groups. the snap-score showed quick improvement by the first post-transfusion day (p<o. ) and the effect persisted during the five following days. conclusions: we conclude, that the use of et in the treatment of critical cases may help to lower the mortality of neonatal sepsis. it provides a quick improvement in the clinical condition of septic neonates. the granulocyte-colony stimulating factor (g-csf) is largely employed in granulocytopenic patients. experimental studies have' demonstrated the effectiveness and safety of the therapeutic use, nevertheless the human employ is reported almost exclusively in neoplastic patients submitted to chemotherapy and in patients with fungal or pseudomona~ spp infections. the authors report the data concerning three non granulocytopenic children: in the first, o girl years old, affected by pseudomomm aerug/n~a pyeionephritis, the antibiotic therapy was not tolerated in consequence of renal and hepatic failure. the second patient, an infant months old, has been treated with salbactam-ampiciilin, ceftriaxone and chioramphenicol because of haemepldlw iafluem~ meningitis; a late neurological aggravation required the antibiotic therapy recommencement the last, a years old insulin dependent diabetic boy, was affected by cared/do spp systemic infection; the antifungnl therapy w~ not practicable in consequence of renal and hepatic involvement in all the g-csf was administred subcutaneously at the'dose of $ u for days. a significant increase of granulocytes was ever noted already after the second administration until hours after the last dose. clinical signs, fever and biochemical values are promptly influenced positively and all patients are restored to health. no side affects were noted. the granulocyte colony stimulating factor, at indicated doses, can prove of great help in critical patients, in who the antibiotic or antifangal therapies can result toxye or cannot be tolerated. the ~reptococcas p~, among the gram pmltlve~ represents the main causative organism of bacterial meningitis in children, with the majority of deaths occurring within hours of admission, the third generation cepohlosporim were indicated as antibiotic of first choice, and some literature reports have demonstrated no significant dlffereuces in dinical course of patients treated with ce~rlaxoae and of those treated with ampieibin and chlornmphenicol. the authors report the ease of on infant, male, months old, submitted to a neurosurgical interventiol after days the infant became febrile and lethargic and a bacterial meningitis by ~trepmcecctz ~ was diagnosed, in spite of he was given the eoftriaxone therapy.. an amelioration was found only when a systemic treatment with vaucomyein was added. after days an intrathecal administration of vancomyein m~day was started: the norbmlization of the spinal fluid profile was uoted two days later and the infant receve~d progressively. the follow-up after eight months doem't evidentiate motosensorini sequelae-the individuation' of ~cscc~ pmmmsm/ae strains heta-loctam antibiotics resistant requires alternative therapeutic regimens: the k~terity quead vitam and quoad valetudinem of these infections justifies an intrathecal therapy, especially failing o prompt answer to the systemic treatment objectives: to evaluate the incidence of the burnout (bo) of the staff in a picu in a university hospital. the bo is a syndrome charactedzed by many factors like emotional stress, lack of personality and reduced work ability. this syndrome represents a kind of abnormal response in the working habitat, above all, where psychological and personal characters are mostly involved. the symptoms of bo are represented by demoralisation, demotivation, incapability, boredom, isolation up to organic disturbances, like migraine, insomnia, dizziness and gastrointestinal disturbances. the major incidence of this syndrome was found in the hospital staff, especially among the nurses, working in an atmospher of high emotional dsk, just like in an intensive care unit. methods: from january ' till april ' , all the staff of the picu of the a. gemelli hospital of rome, underwent a test to evaluate the bo. the test used was taken from the book "bumout: from tedium to personal growth", by pines and aronson. twenty seven people were studied ( females, males)i out of which doctors, residents and nurses. it was considered sign!ficant as mild bo, a score between - and as severe, the score of bo >. . results: subjects ( %) resulted positive for bo, out of which were females ( %) and were males ( %). the subjects with mild bo were / : was a doctor, residents and nurses. the subjects with severe bo were / , out of which resident and nurses. conclusion: the results obtained show that bo is a condition well represented in the staff of our picu. the category most at dsk seem to be the nurses ( subjects), as well as residents ( subjects), as in literature, which shows a major incidence of the syndrome in younger subjects and having a limited partecipation of functional decision. the results obtained obliged us to start a programme of serial controls so that the subjects most exposed can have a necessary psychological support to react adequately to this condition. the term systemic inflammatory response syndrome (sirs) was adopted by the consensus conference to denote a type of systemic response to severe infection or otherinsults in critically ill patients. when sirs occurs from infection it is called sepsis. sepsis occurs more frequently in persons with perexisting illness or severe trauma. there has been tremendous advances in prophylaxis, diagnosis, and treatment of sepsis. a comprehensive model of the disease progression from sirs to mods should be developed giving priority to severity of illness scoring system and other predictive methods. some recommendations for future clinical trials include: trials should not start with humans. before proceeding to human trials, animal studies should indicate an acceptable risk/benefit ratio. appropriate patient populations must be defined and treatment protocols should be standardized. full and rapid reporting of all results should be mandatory and a central repository of published and unpublished study results could be helpful. accrual at each center should be of sufficient size, and should include the number of patients accrued, mortality rates, and patient characteristics. pivotal trial should be preceded by sufficient pilot or phase ii studies. correct drug dosage and usage should be delineated in pilot studies. large, multicenter, trials should be used to enhance the unversality of trial results. analyses should be planned a priori. definitions for the target population should be explicit, reproducible, and include illness severity scores. outcomes should be relevant reproducible and include both measures of benefit and harm. mods and its reversal should be considered as an endpoint. quality of life should also be considered as an endpoint. the estimators of overall treatment effects should be controlled for base-line prognostic factors and subgroup anaiysis should only be used for hypothesis generation and not to modify the conclusoin of the trial. economic analysis should be included as part of clinical design. evaluatin of source control should be a critical component of any study. standardized clinical mediator assays should be pursued. placebo patients in clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of sirs, evidence based medicine should be used to evaluate the validity of clinical. introduction: use of inhaled nitric oxide (no) as a modulator for optimizing ventilation-perfusion or lowering pulmonary artery pressure is becoming increasingly common. no is a free radical but little toxicological research has been published. clearance of nebulized mtc-dtpa is known to be, a sensitive indicator for early function impaimaent of the alveolocapillary barrier. we investigated whether exposure to no increased clearance of ~tc-dtpa from the lung. methods: three groups of white sealand rabbits (bw . kg) were anesthetized, tracheotomized and paralyzed. groups were ventilated for six hours at pressure regulated volume control, set to deliver ml/kg with a frequency of /rain, i/e ratio = : and peep = cm hzo using a modified servo ventilator (siemens, solna, sweden) with computerized no delivery system. gas mixture per group was either / or / [no (ppm) / fioz]. after six hours of ventilation in these groups and immediately after anesthesia in group (control), ~tc-dtpa was nebulized into the inspiratory line of the breathing circuit and administered as a fine aerosol. gamma counting was measured for minutes, monoexponential curves were fitted to the data and the clearance half-time (t was calculated. the t~/ mean • sd of the different groups were: t~a (mean -sd) h"e,i witl~ arf : di.ff:erent kinds, aged .q-ore mon't.hes to [ gears o : (bodi weight .~rom ., to kg), is presen .... "ed ( i,,~u::trl:e i:ibstraclive d:lse~se... ~ .ards'- ; :~,;,,arf o~ ::entral genes:i s .- , ,~ :inc lud ing men ingeenceph it :is- ~ reye ' s ~yrtdro~e-..#~,bri~:ln pes~.re~nimatior~ disease.." ). int:lrl~]. pa-. "iiulle'i,~s ariel regymes o+ l;mv,l;i"t"v were cle'l'.ermllled by ba- 'i~ier was. about . tuber,, dopamin tiara-:. t.io; was ~.".,,'.r:~r~led. cmv,cppv d~.!"~tion raniled -~rom f to dayns.,~ < .-:in , "t -irl lo;and> davs'-in 'l~atierr~{s i'i"ai s:ltiol~ o ; patterers to imv, simv modee was per.r:)rmed, ~herl pif:' decrease.d to - ml~ar, fi ~ecreased to , . lind less with a = /,,. i:lesq.lts:{ in pat:i.ents e{ group :l, who were tre,~d.ed w&th f'f'v, teoph :i. : . l:i.r~ (is- .mg/kg/day), g lucecdr t icostei~oids ( .... :~;mg/kg/day), when r exceeded in , -.];, times normal va i tea the e aqes/,'!:l"oln ~j,, ite :i.~;::.!;, ~ml"lrj), it was possible 't'(' ce 'e~ e aad]t:..~rom ! . '.' i', to !..'; , - , mml-lg in ~}.. :~.[~ houi,!; ~d'l(:i to ru:}l",g'd!~l:i. e i::h,:~e,'~c['el';i.stil obieetives : this chapter will describe what is knovca of the psychlogical responses of infant and children to hospiuiisation and attendant procedures. the factors which may modify these responses will he discussed and important considemtiorts will be outlined for optimal anaesthetic management and postoperative period of infants and children which will minimised the rise of emotional upset. methods : in this paper the autors will discttssed the probl of: . health children (asa i, ii) facing single uncomplicated surgical elective procedures . various abnormal situations including neurotic children, children facing repeted operations, chronically ill, buaaes and tsaumatically impired ones . unfortunate young patient facing and often expoclting fatal outcome from le "ul'ukaemia, tumors, cystic fibroses or otheq" disease. : management of each child must vary greatly, ifi general the phases of emotional conditioning include home and preadmissiun preparation, admitiun preoperated and operative care and postoperative period. the authors would be happy if the child passes all stages without any trauma which could be prolonged in the future life. introduction ino is used to selectively reduce pulmonary vascular resistan(~e. we applied ino in the postoperative intensive care of patients with pulmonary hypertension and the risk of right ventricular failure after surgical correction of a congenital cardiac defect. methods - ppm no were added to the ventilatory gas mixture using a specially designed equipment (messer-griesheim, germany/austria). indications for application included pulmonary artery pressure > % systemic pressure, critically depressed right, ventricular function or an oxygenation index > . assessment of n oefficiacy consisted of on-off-on measurements according to the clinical stability of the patient including hemodynamic parameters, pulmonary gas exchange, continuous monitoring of ventitatory function and transesophageal echocardiography of the right heart. results in situations ( patients, age days- , years), ino was applied - h postoperatively. oxygenation was improved in situations from _+ to + mmhg pc ; pulmonary pressure was reduced in situations from -* % to _+ % of systemic pressure. in situations, no reduction of pulmonary pressure was present, but measurement of cardiac output or echocardiographic analysis indicated an improvement of right ventricular function (right ventricular stroke volume + -* %, cardiac output + -* %). in situations (immediately postoperativ with suprasystemic pulmonary artery pressures [n= ], multi-organ-failure [n= ]), no response to ino could be determined. conclusions for a special group of patients, the selective reduction of pulmonary vascular resistance by ino has become an important part of postoperative therapy. using this selective afterload reduction, postoperatively depressed right ventricular function can be improved. this effect of ino seems to be the most important one in the postoperative period. thus, ino appears justified to be appfleo when impaired right ventdcular function could be improved even when pulmonary artery pressure is not raised or remains unchanged. obiectives : premature infant are exposed to danger of apaea due to anaesthesia during their tirst months of life. it is yet unknown whether prematurity is corelated to any other kind of reslgratory disorder due to anaesthesia within the tirst year of life. methods : we theretbre researched retrospectively for respiratory disorders in all infants under months of life belonging to asa group . they all had been anaesthetised in . in our clinic for the following surgical reasons: ingvinal haemia, umbilical haemia, hydrocelae testis and phymosis. results : in cases we tbund: lafingospasm during induction in anaesthesia ( , %), bronchospasm during induction in anaesthesia ( , %), impaired intubation ( , ~ postanaesthetic laringospasm ( , %), supposed aspiration ( , %),postanaesthetic inspiratory stridor ( , %), postinductional inngoedema ( , %), death after months in consequative of infection pneumonie ( , %), none of these disorders was correlated the prematurity, infants suffered of post anaesthetic apnea, of them had premature medical history. concludions : prematurity does not enhance the risk of respiratory disorders due to anaesthesia within the first year of life, except the danger of postanaesthetic almea needs spetial cosideration. it could be demonstrated that aepgi lowers pulmonary vascular resistance and indirectly improves cardiac function. this effect seemed to be selective, and was comparable to ino in the doses we have examined. therefore, aepgi could represent a clinically useful alternate to inc. however, further research is necessary to work up the benefits of either therapeutic strategy. objectives: heat and moisture exchange filtem (hme) are used as artificial noses for intubated patients to prevent tracheo-bronchial or pulmonary damage resulting from dry and cold inspired gases. furthermore they are used for the prevention of bacterial contamination of the anesthetic apparatus by the patient's exspired air. so they are considered as a time-and money-saving device in anesthesia. filters are mounted directly on the tracheal tube, where they collect a large fraction of the heat and moisture of the exspired air, adding this to the subsequent inspired breath. the effective performance depends on the water-and bacteria-retention capacity of the filter. this study evaluates the efficiency of four different filters under clinical conditions. methods: four different types of filters ( dar hygrobac, gibeck humidvent, medisize hygrevent and pall bb ) were investigated dudng mechanical ventilation over a pedod of hours. minipigs with hemorrhagic shock were intubated and ventilated for days in an animal intensive care unit (icu). after hours of mechanical ventilation the filter was randomly replaced maintaining the individual ventilatory conditions. the weight of the filter was determined before use and after removal after hours. the airway pressure was monitored online to record changes during use. tracheal secretions and both sides of the filter were microbiolologically tested to see whether bacteria of the animal's respiratory system could be found on the patient's side of the filter or if they even would have penetrated the barrier. results and discussion: over a pedod of hours of types of filters showed an increase in weight of + % and airway pressure. bactedal celonisation ccured in nearly all fillers ( of ) on the patient's side, whereas only three of four types of filters showed identical bacterial colonisation on both sides. the only filter that did not show bacterial penetration, increase in weight or airway pressure was the pall-hme, a condensation humidifier without hygroscopic salts for moisture retention. with respect to our data one should use a condensation humidifier if airway conditions should remain stable dudng mechanical ventilation and desinfection of the anesthetic apparatus should be avoided after each patient. aim: to assess the clinical uses of, and experiences with, the hayek oscillator. this is a non-invasive device capable ef delivering not only continuous negative pressure (cnp) but also external oscillatory ventilation around a negative baseline (eov-nb) using an external cuirass. this type of ventilation avoids the need for intubation and intermittent positive pressure ventilation (ippv) and facilitates weaning in ventilator dependent patients. patients and methods: patients in respiratory failure, age range weeks to years in a total of patient episodes were treated using either cnp or eov-nb mode. duration of treatment varied from hours to days. indications for use ef the device were: ) to facilitate weaning from ippv ) prevent reintubation of patients following unsuccessful extubation, and ) avoid intubation and ippv altogether using the hayek oscillator as the on[y means of respiratory support. results: there was an increase in pao :fio ratio after cnp and eov-nb (p < . , and p= . respectively, wilcoxon signed rank test). patients who were in respiratory failure with hypercapnia showed a statistically significant reduction in paco both with eov-nb and cnp (p= . and p= . respectively) but the magnitude of change was individually greater in the patients who were treated with eov-nb. all patients, however, showed a fall in respiratory rate (p< . ) after the application of the cuirass in cnp mode. there was no physiological deterioration related to the application of external extrathoracic negative pressure in either cnp or eov-nb modes. conclusion: the improvement in pao :fio , the fall in paco and respiratory rate were indicators of an improvement in ventilation. the proposed mechanisms include improvement in frc, recruitment of additional alveolar units, and improvement in secretion clearance resulting in reduction in the work of breathing. meek to ~ month of the lifo,the bemodyuanicfacls were defined uitb the help of tetropolar reography method!. the excretion of !he catbocholauines fcfi] mith the urine gas detertend by taylor ll,laoorsy ~ iacg/dayl. hsaltl in the hypercuagulation stage of bic we deflorteeed the acliuutiun of the tbrubio and plasiin syaet~ mitb the increase of the inhihitnrs, in this case we registered in full uahe dot this process coabined uitb the dayl~ excreliou with lho urine epinopbr ne e], nor~pinopbr no tel and dophanine io], lbat shod the inlensificatiou of the s~nthosis prnoe-s~es and the release of ea in blood fron hissue deport the actffat on of the svnpathadrenui systen ]sfisl assisted to furl the b?perd~nanical rosins of the eircuidion and increase the ,icrocirculatinn, the klinicai sings of the insufissieutly of the circulalion have not defined,that has been associated the conpensatury character uf the ehan~es of ~ and heludy~enic status, t~e uun~u|p-lion ceugulupatby bus been donoustraled in the hypocougulatien stage ~bat man xauifosted b the exhaust of lhe confulalion nod oessel-platel heuostasis, the consuxptton of cnnpononts tbronbln ,plnstin, kallek~eiu-kinln s~slots and the forniration eat in fell canoe clot uas accoqaued bs docrea,e of fl,nfl,o, the products of the xotabolisx of c~ and the activation of xonoaninoxydasu. the decrease of the extoll'on g and the exhaust deport co indicahd about t!e ]ou fund/anal reserve of ~fl~. it was one of the lain reason of ~bo heiod~uanic disbroed iheat insnfissient]~] and the uicrncireulaflion lintestinal codeme with the low effectife periferal flow] and nul[iplay organ failure,the distrued deport of sos mitb throubocytupenin no; be one of the nechanisn the dislrood of uessej-plalol heioshasis, the correlation bolueeo changes of boiostosis c~ and circulation ore reguired aduinistration nedidns, thai reslore the love s of c~ in the blood, prevent uulliplay organ failure and hetorrnge in children with sepsis, ~b~ectives: multi-measured correlative analysis of the most number of non-invasive indices of the cardiorespiratory system function was made to determine the structure of their interrelation and the ways of their adequate and effective correction. hethods: spiremetry, capno~raphy, oxygenography, indirect fick method at recurrent respiration, plethysmography, integral rheography -in all indices were used. the received data were processed on a computer by a standard package of statistical bmdp programs. results: women with ~h-gestosis (i group) and somatically healthy pregnant women (ii group) were studied. cluster analysis has shown that the rate of the mean correlation connection between ventilation indices was % in the ist group and % in the iind group; gaseous metabolism - % and %, respectively; central hemodynamics was ~ in both groups. conclusion: cluster interpretation allowed to suggest that an increase of the rate of the mean correlation connection between the indices was characteristic of effective adaptation as the system was multi-component and well-regulated. on the contrary, the increase of the rate of strong correlation connection between the indices reveals the rigidity of the system and the tensity of adaptation mschaniams, i.e. the proximity to decompensation. it follows from this that in cases of eph-gestgsis, the reliability of regulating ventilation and gaseous metabolism decreases. seve/e hypoxemia in non intubated patients represents a major contraindicafion to fiberoptic bronehoscopy (fob) and bronehoalveolar levage (bal), but these procedures are often required for a correct diagnosis of the causative agent of pneumonia. aim of this investigation was to veaify the safety and efficacy of bronehoseopic procedures during pressure support ventilation administered through facial mask (fm-psv). five intensive care patients, all immunoeompromised, ( males and females; mean age . • were enrolled in the study. all patients presented criteria for pneumonia with pao /fio ratio ~ and were responders to fm-psv. fob and bal were performed afte~ topical anesthesia with fm-psv ( ps = em h ; peep = emh ; trigger = -lemh ) continuously admires" tered ( ' before fob fio = . ; during fob, fio = and for ' alter fob, fio = . ). pao /fio ratio as well as saturation (sat) did not show signifteative changes during the procodure (fig.l) . no complication was observed and hemodynamic conditions were stable for all patients. cmv, pnenmoeystiis ( ), legionella and mycobaetermm tuberculosis were identified from bal allowmg a prompt and targeted therapy. we concluded that mask psv can represent an excellea~ technique to pexform fob and bal in severely hypoxemic patients without deterioration of gas exchanges and avoiding endotraoheal intubation. intensive care unit, hospital general of albacete, albacet~ spain. objective: to analyze the current incidence and epidemiology of total parenteral nutrition (tpn) among critically ill patients placed on mechanical ventilation. design: prospective observational study. setting: medical intensive care unit in a tertiary hospital. patients: a total of consecutive l'ritically ill patients with non-coronary related disease needing mechanical ventilation admitted in our icu during a months period. measurements: data of sex, age, diagnosis, and outcome were recorded. severity of illness and therapeutic effort in the first hours were measured using acute physiology score and chronic health evaluation (apache ii) and therapeutic intervention scoring system (ties). r~ults: mechanically ventilated patients, male and female, were studied. only ten patients needed tpn and their main diagnoses were: five cases of multiple organ failure secondary to pneumonia ( ), ards ( ) and septic shock ( ); two eases of acute panereatitis; and one mesenteric throngmsis, one status epilepticas, and one ,prolonged cholinergic crisis b~ suicidal organophnsphate insecticide subcutaneous injection. no statistically significant differences between both tpn and non-tpn groups were found: objectives: evaluate the efficacy of prone position in ards and determine its importance in the therapeutic algorithm. methods: consecutive patients with severe ards (murray-score > , ; pao / fit < mmhg; male, female, mean age years) were conventionally ventilated (pcv, peep - mbar, i:e=i:i, ppeak < mbar). if after hours pulmonary function did not improve patients were placed in prone position. change from prone to supine position was done every hours. beside ultimate survival, parameters investigated were aado , pao /fio , and venous admixture (qs/qt). results: during the first hours in prone position of patients showed a significant decrease in qs/qt ( . % vs. . %) and aado ( vs. mmhg), and an increase in pao /fio ( vs. mmttg). changes were most pronounced in patients with high qs/qt, and in patients with an onset of ards less than hours before first application of prone position. after an average of position changes ( to ) of patients could be weaned from the ventilator. patient could leave tile hospital. i the later course letality was primarily determined by additional organ failures and by the severity of the underlying disease. negative side effects were minor, including slight cardio-vascular depression and increase in p~co , and never posed a limitation to continuation of prone position. especially in patients with septic shock skin lesions in exposed areas could not always be prevented, prone position could easily be combined with all ventilation modes and with all intensive care interventions. also immediately after major surgery and in patients with open packing prone position was possible. conclusions: in this investigation prone position proved to be an efficient and safe method in the treatment of severe ards. patients with a pronounced ventilation/ perfusion mismatch and patients in the early stages of ards appear to profit most from prone position. though the immediate effect on oxygenation is striking, still more the % of all patients die from multi organ failure and underlying diseases. a proposed therapeutic algorithm for ards is as follows: if under conservative ventilation (pcv, peep < mbar, ppeak < mbar) pulmonary function does not improve within - hours prone position should be applied. when after - position changes no lasting effect can be achieved further ventilation modes (e.g. pc-irv, aprv, no, etc.) should be used in addition to prone position. standard intensive care principles, such as fluid restriction and optimization of circulation, apply also to patients in prone position. objectives: nitric oxide reacts with superoxide to form peroxynitrite, an extremely reactive and toxic species. we quantified the presence nitrotyrosine, the stable product of the interaction ' of peroxynitrite with tyrosine residues in the lungs of pediatric patients that died with respiratory distress syndrome (rds). methods: paraffin embedded lung sections, obtained at autopsy, were incubated with a polyclonal antibody raised against nitretyrosine, followed by a secondary fluorescent antibody. alveolar structure-associated fluorescence was quantified using existing methods. results: tissue sections from patients who died with rds exhibited significant specific immunostaining which was uniformly distributed across the blood-gas barrier. in contrast only background levels of fluorescence were seen in the lungs of patients who died from non-pulmonary causes. intense staining was also seen in the lungs of rats that breathed % for h, a condition known to result in rds-type illness; no immunostaining was observed in air-breathing rats. conclusions: significant levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. peroxynitrite may be contributing to the pathology of rds by damaging key components of the alveolar epithelium including the pulmonary surfactant system. mechanical ventilation time was prolonged ,g • days in patients with ardsvs , _+ l, days in control . mean staylcuwas lg _+ ,g days in the ards group vs , • , days in control group postoperative mortality rate was % in ards patients vs , % in those without respiratory failure. -ards incidence in liver transplantation is low ( , % in our sene) but it causes high mortality ( %) page, gas ventilation of the perfluorocarbon-f'dled lung, supports gas exchange and circulation in small animals (< kg) with lung disease. we hypothesized that large animals could be supported by page without adverse effects on bemodynamics. we first elucidated the determinants of gas exchange in normal sheep, and applied them to a model of adult respkatory distress syndrome (ards). methods: using the ventilator settings determined to be optimal in our pilot study (fio of . , peep of cm h , imv of bpm, it of %, and tv of ml/kg), sheep weighing . ~ . ) kg had lung injury induced by instilling ml/kg of . n hc into the trachea. ten minutes after injury, sheep with pao < ton" were randomized to continue gas ventilation (control, n= ) or to institute page (n= ). page was instituted by instilling . l of unoxygenated pefflubron into the trachea and resuming gas ventilation at the previous settings. abg's were drawn at baseline, minutes after injury, minutes after injury, and then every minutes for hours. objectives: inhaled nitric oxide (no) can improve oxygenation and decrease mean pulmonary artery pressure (papm) in hypoxemic patients with ards. in severe hypoxemic copd patients, it is not known whether inhaled no can exert a similar effect on hemodynamics and gas exchange. therefore, we investigated die response of inhaled no in hypoxemic copd patients and the results compared with those obtained in a group of ards patients. methods: ten copd patients (age _+ y;fev~ . _+ . l) and ards patients (age _+ ; lis . _+ . ) mechanically ventilated were studied. hemodynamic parameters were measured using a swan ganz catheter. arterial and mixed venous blood gas determinations, sao , svo , hb and methb were measured (abl ,osm ). mean intratracheal concentrations of no and no were continuously monitored using a chemiluminescence analyzer (nox ) . during the study the ventilatory pattern and fioz were kept constant. the protocol was for ards group: basalt, no loppm, basal~; copd group: basalz, no lo ppm, no ppm, no ppm and basal . after a steady state of rain hemodynamic and gas exchange measurements were performed. a positive noresponse was defined as a % increment in pao . results: papm was similar in both groups and decreased significantly after no (ards, basal . _+ . mmhg, no . + . mmhg, p < . ) (copd, basal . _+ . mmhg, no- . _+ . nrmhg, p< . ). all other hemodynamic variables remained unchanged after no. basal oxygenation was higher in copd group (paojfio _+ mmhg) vs ards group (paojfio _+ mmhg)(p< . ). after no- , pao increased ( _+ mmhg to _+ mmhg, p< . ) and qs/qt decreased ( + % to _+ %, p< . ) only in ards group. in both groups, significant correlations between basal papm and inhaled no-induced decrease in papm were found. inhaled no-induced increase in pao /fio was not correlated with basal paoflfio . no responders were / ( %) in ards group and / ( %) in copd group (p< . ). conclusions. in hypoxemic ards and copd patients, inhaled no decreased mean pulmonary artery pressure. however, oxygenation only ameliorated in ards group because die number of responders to inhaled no were higher in ards group and this effect seems not to be related to the basal hypoxemia. these results might be explained by the v/q abnormalities present in copd patients. grant fis / . objectives: it has been recently reported that expired con slope as a function of time is modulated by total respiratory system resistance (rrs) in critically ill patients (chest ; : - ) . in this study, we analyze the relative contribution of disease (dis), endotracheal tube resistance (rtube), airway resistance (rmin), additional resistance (~rrs), autopeep (peepi) and dylmmic/static elastance (ed/es) to the co elimination in different clinical conditions. methods: we have studied adult patients ( controls, acute respiratory failure, severe ards and copd) mechalfically ventilated (servo and c, siemens) without peep. we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. objectives: alveolar ejection volume (van) can be defined as the fraction of tidal volume (vt) with minimal dead space (vd) contamination. according to the classical paradigm: limvd_~ [vco /vt] =facoz, vco vs vt relationship tends asyntotically to a constant slope when approaches end-tidal volume. we have defined van as the volume that defines this relationship until a limit of % variation. methods: six subjects with normal respiratory mechanics were studied during anesthesia for minor surgery. two subjects, otherwise normals but having high values of total resistance and dynamic compliance, were also studied. capnograms were recorded in steady-state at levels of vt ( . , . and . l) and four levels of peep ( , , and cmh objectives: patients with ards presented lung abnormalities which originate an increase in airway resistance (rmin), in additional resistance (~rrs) and in static elastance (ers). application of peep further increases ~rrs. capnographic indexes reflect lung ventilation]per fusion inhomogeneities. in these conditions, the effects of peep on lung mechanics could be better understood by simultaneous measurement of capnographic indexes. methods: we studied groups of subjects. n: normal subjects scheduled for minor surgery; arf: critically ill patients with mild acute respiratory failure; ards: patients with early ards (< h). we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. respiratory system mechanics was assessed by constant end-inspiratory and end-expiratory occlusions technique. at equal tidal volmne ( . l) a peep level of , , and cmh was applied in all patients. we calculated ers (cmh /l), rmin, c~rrs (cmh /l/s) and autopeep. capnographic indexes were alveolar ejection volume (vae)/vt ratio and expired co slope beyond vae (sipco in contrast to synthetic surfactant natural suffactants (alveofact| are able to inhibit pmn-activation. after incubation of activated neutrophils with surfactant, l-selectin expression is decreased. these effects depends on which preparation is used. we conclude, that natural surfactant (aveofact| can perhaps influence early recruitment (,,rolling") of pmn in patients with respiratory failure like ards. with ards hormann cb, baum m, putensen c, knapp r, lingnau w, putz g . clinic for anesthesia and general lntensiv care medicine, university of lnnsbruck, anichstrabe , innsbruck objectives: in thoracic ct scans of patients with severe ards atelectasis and pleural effusion can be found in the dependent lung regions. by rotating these patients from left lateral position to right lateral position a redistribution of the ct densities, a recruitment of atelectasis and therefore an improvement of gasexchange is possible within a few days ( , ). the objective of this study was to find out the mechanism of alveolar recruitment during lateral positioning by ct scanning in left and right lateral position. methodes: after approvel by the local institutional reviewboard we investigated ventilated patients with severe ards (entry criterias: murray score > , ) in the ct scann of the university hospital. after a stabilisation period of minutes in supine position a thoracic ct scan slice cm above diaphragm was taken. then two different positions of the patients were studied in a randomized order: a) degree of left lateral position, b) degree of right lateral position. each lateral position was held for minutes. at the end of each of these periods a thoracic ct scan slice cm above diaphragm was taken. quantitative analysis of ct scan data was based on the frequency distribution of the ct numbers. to quantify the alveolar recruitment during lateral positioning by means of ct scan we defined compartments within the lungs: a) normaly inflated lung, b) poorly inflated lung, c) noninflated lung ( = atelectases) ( ). results: independant of the side of lateral positioning (l) in the non-dependent upper lung a significant increase of the normaly inflated compartment (s: %; l: %) as well as a significant decrease of the noninflated compartment (s: %, l: %) was observed in comparison to supine position (s). in the dependant lower lung the normaly inflated compartment decreased significantly (s: %, l: %) whereas the noninflated compartment increased significantly (s: %, l: %). throughout the whole studyperiode we did not observe any significant change regarding gasexchange and hemodynamic parameters. conclusions: in lateral position the non-dependent upper lung is decompressed. therefore a significant recruitment of atelectases is observed in the upper lung within minutes. on the other hand the dependent lung is compressed by the weight of the upper lung and the mediastinum. a great amount of the alveoli of the dependant lung collapse in this short time intervall. therefore the net effect of recruitment of one positioning maneuver is very small. when positioning patients one should be aware, that the patient is kept in each lateral position long enough to clean up the atelectases in the non-dependant lung and short enough to compress less lung tissue in the dependant lung. objective: to analyze effects of low-dose no inhalation ia patients with severe aeut~ respiratory distress syndrome (ards) over five days. methods: we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who required no inhalation with a dose of ppm for at least days. entry criteria for no injaalafioa were murray score >i . aud pat/fie < nun hg with peep >~ em i~o for at least hours. all patients were sedated, intubated and mechanicauy vantil~ed with volume assist-control ventilation, and had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) to measure cardiac output (by thermodilufion) and relevant intravaseular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and endotraeheal tube and flow was adjusted to obtain ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endouacheal tube by the chemiluminiscence method (nox , see-seres, france). metahemoglobinemia levels were mesured daily. no inhalation was manteined if paojfio ~ improved at least % and was stopped when the change in pao /fio ~ was below % or when the patient presented a paojf > mm hg a~er minutes without no inhalation. every day we made an on-off test to determine if no inhalation improved pao /fio ~. statistics: analysis of vmiance. data: mean + standard deviation. results: the mean age was . +_ . years and mean lung injury score was . • . . mortality was % ( / ), metahemoglobinemia . • . %, and no concentrations zero. paojf~o always improved significantly al~er ppm no inhalation (see :~ conclusions: reintubation in salf-extubated patients strongly depends on the type of meehamcal venfilatory support: the probability of needing a reintabation ff ese occurs during fult vontilatory support is higher than ff ese occurs during weaning. these data suggest that some patients may remain under weaning from mechanical ventilation for unnecessarily prolonged periods of time. objective: the aim of this study was to evaluate the acute effects on gas exehonge and hemodynamics due to positional changes from supine (sp) to prone (pp) in patients with severe acute respiratory distress syndrome (ards). methods: nine intubated, sedated, paralyzed and mechanically ventilated patients with severe ards were prospectively studied. all had a murray score > . , and a pao /f~o < with peep ~ cm h for at least h. all patients had indwelling arterial catheters in the pulmonary artery as well as in the radial or femoral artery in order to measure cardiac output (by thermodilution) mad relevont pressures, and to withdraw blood samples. arterial blood gases and hemodynamie parameters were measured first in sp, and then in pp after minutes of stabilization. vontilatoly parameters remaing unchanged during all the study. statistical analysis was done by the non parametric wdeoxon test. data are expressed as mean ~= sd. results: there were men and women with a mean age of . years ( - ) and mortality was % ( / ). main results are shown below: objective: to describe and compare a new method for obtaining p-v loops (p-vcv) by using a two-way collins valve (twv) with thosu obtained by the supersyringe method (p-vss). methodology: we prospectively studied patients who had an aeute lung injury and were intubated, sedated and paralyzed, and mechanieany ventilated. we performed the p-vev loops and p-vss loops in random order, and the static inflation pressure was limited to emh with both methods. pressure (p) was measured at the airway opening by means of a differential p transducer, and volume was obtained from flow (measured with a pneumotacograph) integration. the p-vse method has already been described (h~trf a,et al.bepr ; : - ) . the p-vev method consists in the following: the inlet of a twv is connected to the ventilator's y-piece, and both outlets are couneeted to the endotraeheal tube by means of an additional y-piece; one of this outlets has a one-way rudolph valve in order to allow inspiration but not expiration during the inflation maneuver. changing the twv tap position allows basal ventilation or progressiveinflation of the respiratory system. this maneuver is as follows: during an end-expiratory occlusion, the ventilatory settings are adjusted to deliver a ml v r with a respiratory rate of /min and i/e ratio : ; at the same time the twv tap is ehonged in order to divert flow through the one-way valve. inflation then begins alter releasing the expiratory oonlusion. pressure and flow signals were digitized and acquired by a computer for subsequent data analysis. we analyzed the following parameters: inflation compllonee ( objective: to analyze the variables which eventually may differentiate ards patients who do and do not respond to low doses of inhaled no. we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who were treated with no ( ppm). the onta'y criteria for no inhalation were murray score >/ . and paojfo z < mm fig and peep >/ cm i~o for at least hours. all patients were sedated, intubated and mechanically ventilated with volume assist-control ventilation. tidal volume was between and ml&g, with constant inspiratory flow, respiratory rate was - /rain, and i/e ratio between : to : . all patients had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) in order to measure cardiac output (by thermodiintion) and relevant intravascular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and ondotracheal tube, and flow was adjusted to obi~a ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endotracheal tube by the chemilumiinscenee method (nox , see-seres, france). metahemogtobinemia levels were measured daily. we considered a response to no inhalation when an improvement in paoz/fo above % was observed after the inhalation of ppm no (group r) . when the cha~age in paojfi z was below % it was considered a lack of response (group non-r small airways functional abnormalities have been recognized as a common feature of lung pathology. however peripheral airways contribute relatively little (~ %) resistance to flow and there disturbances can not be adequately estimated by conventional measurements of respiratory mechanics. the purpose of the study was to evaluate the relationship between raw and small airways conductance following weaning from ventilator methods. patients (age: - years; males) with no serious complications al~er mitral or multiple valves replacements and with more than hrs on mechanical ventilation have been enrolled in this study. the modified flow interrupter technique (ptg "gould" with fleish head # ; differential pressure transducer pm- -tc "statham" w amplifier "kistler ") and flow-volume recording of forced expiration (fleish head # ) have been applied before surgery and following operation on mechanical ventilation (my), after extubation (t:xtijb), on ( nay) and ( day) days. airways specific conductance (sg aw) has been calculated as a mean of - consequent measurements in each patient at each stage. the sac was estimated by max expiratory flow at and % of vc on - f-v curves (mef .~ , mef ) all the data were statistically analyzed with t-test introduction : noninvasive ventilation (niv) reduces the need for endotracheal intubation, the length of stay in icu and the mortality rate in acute exacerbation of copd. however, some patients failed to be ventilated with niv. .objectives...; to further delineate patients who failed to be ventilated with niv and to obtain predicted factors of failure. patients : a cohort of patients ( • years) presenting with acute exacerbation of copd (fevi: • ml, paco : • , ph: . • . ) and nonmvasively ventilated (pressure support through a full-face mask) between april and may twenty-seven ( %) were successfully ventilated with niv (discharged alive without the need for endotracheal intubation) while ( %) failed, requiring endotracheal intubation. .methods : patients successfully ventilated and those who failed were compared according to respiratory and nonrespiratory variables univariate analysis (wilcoxon rank-sum test and fisher-exact test) was performed to select variables included in a multivariate analysis by stepwise logistic regression. results : underlying disease assessed by the simplified acute physiologic score ( • vs • , p = . ), creatinine serum concentration ( • vs • gm/l, p = . ), blood urea nitrogen (bun : • vs mm/l, p = . ), age ( • vs • , p = . ) were higher and encephalopathy ( vs %, p = . ) more frequent in patients who failed. multivariate analysis showed that encephalopathic patients (or (odd ratio) = , p = . ) older than years (or = , p = . ) and presenting with bun >_ mmyl (or = , p = . ) failed to be ventilated with niv. variables related to the respiratory" status (i.e. paco , pao , fev ) were unable to predict tile failure of niv. conclusion : copd patients older than years, presenting with acute exacerbation, encephalopathy and bun > ram/l, should be carefully monitored because of high probability of failure with niv. methods:from february to december we studied pa_ timnts, males and females(mean age +/- ); of the se had emphysema,lo chronic bronchitis, dilatative car diomyopatia,with tracheostomy and emphysema.mean pac at admission in icu was +/- mmhg,while when weaningbegan, +/- .mean autopeep was cmh ( - ).all patients were ventilated in crpv as long as four hours to calculate st tic and dynamic cmpliance and autopeep.then the ventila tion was continued with psv+cpap(peep cmh objectives: analysis of the incidence of neurogenic pulmonary edema (npe) in a population of headtrauma patients with acute respiratory failure (arf). npe can occur after a central nervous system insult. differential diagnosis: cardiogenic pulmonary edema and other forms of non eardiogenic pulmonary edema. true incidence and pathophysiohigy remain poorly defined, however the role of catecholamines seems undeniable. early onset npe (within h after trauma) is characterised by hypoxemia, transient pulmonary hypertension and bilateral central fluffy infiltrates on chestx-ray. characteristics of cardiogenic edema or pneumonia are absent. late onset npe, (beyond hours after trauma), is more insidious. the clinical and radiographic picture has to clear within to hours. ( ) methods: all headtrauma patients admitted from january to december , in a nearotrauma icu setting were retrospectively analyzed for arf with as sole criterinm a pao -fio ratio < . results: neurotrauma patients were admitted during . patients ( %) presented with severe head injury (gcs< ), patients ( . %) with moderate (gcs - ) and patients ( . %) with minor head injury (gcs - ). overall mortulity was . % early (within h. after trauma) and delayed onset respiratory incidents were distinguished, counting for ( . %), respectively patients ( . %), patients ( . %) had early and late respiratory complications. early respiratory insufficiency was caused in patients ( . %) by aspiration, in patients ( . %) by lung contusion, in patient ( . %) by fat embolism and in patients ( %) by npe. in the late onset group patients ( . %) presented with pneumonia, ( . %) with fat embolism and ( . %) with npe. the npe group, patients, presented as follows: patients ( . %) developed early npe, and ( . %) delayed onset npe. patients ( %) died within the first days after admission, showing high mortality. gcs was less than in patients ( . %), indicating severity of head injuries. conclusions: high incidence of arf with various etiology ( , ~ was found in this population. in about % of all admitted hcadtrauma patients ( , % of arf) npe was causing attetial hypoxemia. occurrence of npe seems to be related to the severity of the brain injury and thus to outcome. these data call for extreme vigilance in respect of the insidious occurrence of npe. were included if recovering from respiratory failure and if in the opinion of the primary physician were ready for extubation. patients were excluded if undergoing compassionate withdrawal of support or had tracheostomies. the attending physicians were blinded to the measurements. included patients were placed on pressure support (ps) of em h with demand-flow continuous positive airway pressure (cpap) cm h . after a minimum of minutes on the above sehiogs: gastric intramucosai pc'o , abg, and a p . were measured. the padents were then disconnected from the ventilator for a period of one minute and the patients" respiratory rate and minute ventilation were measured using a wrights respirometer to calculate the frequency to tidal volume ratio (f/vt). patients were then extubated. extubafion failure was defined as the inability to maintain spontaneous ventilation for hours for any reason. results: twenty patients met criteria and were studied over one month period in october . six of the twenty patients ( %) failed weaning. the mean and standard deviation is outlined in failure . +/- . . +/- . . +/- . . +/- . comparison between roc areas shows phi and p . to each show a statistically significant difference from an area of . (p<o. ). the area at which the test has no discriminative value. this is not the case for either the integrative index or the f/vt ratio. the differences between areas for each curve is not statistically significant. the area's for each roc curve is shown in table #' . results. of the newborns referred to us for ecmo-therapy developed barotrauma, of the required ecmo and one of the three other patients who did not recieve ecmo-therapy died. to determine the correlation between the risk factor barotrauma and the severity of the pulmonary situation, we determined the oxygenation index of each patient referred to us for ecmo-therapy . the table demonstrates , d- giessen, frg. inhalation of nitric oxide (no) and aerosulizatiun of prostaglandin (pg) i: have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with acute respiratory distress syndrome (ards). we directly compared these two modes of transbronchial vasodilator therapy in ards patients mechanically ventilated for - h (mean murray lung injury score [ ] . + . ). patients were randomized to receive either first no and then pgi (n= ), or vice versa (n= ), with an intermediate baseline period. each drug was titrated individually to find the lowest effective dose for maximum improvement of arterial oxygenation. gas exchange variables, including data from the multiple inert gas elimination technique (miget), and hemodymmaics under application of no/pgi were compared to pro-and past-challenge values. no (mean dose . + . ppm) increased the mean oxygenation index (pao /fio ) from + to + mmi-ig (p < . ) and reduced the shunt-flow from . + . to . : . % (p < . ). aernselized pgi (mean dose . + . " ng/kg rain) augmented pao /fio from + to + mmhg (p < . ), and decreased shunt from . + . to . + . % (p < . ). the miget analysis showed predominant redistribution of blood-flow from shunt areas to regions with normal ventilation-perfusion ratios in response to both agents. in patients, both no and pgi caused an increase in pao /fio by at least rnmhg. two further patients displayed a corresponding improvement of arterial oxygenation in response to either no or pgiz. the mean pulmonary artery pressure decreased from . : . to . : . mmhg in response to no, and from . : . to . : . mmhg (p < . ) in response to pgi . cardiac output, systemic arterial pressure, and right and left heart filling pressures were not affected by either agent. we r that individually titrated doses of inhaled no and aerosolized pgi~ effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to weu-ventilated regions with nearly identical efficacy profiles. obieetives: the use of extraeorporeal bypass systems for oxygenation and co -removal is performed in patients with acute respiratory distress syndrome (ards) to reduce mortality and to improve restitution of pulmonary functions. high-dose heparin -commonly used in such patients to prevent thrombotic complications -might cause incurable bleadings as a major risk. this lead to the development of heparinized bypass systems; results of animal and first clinical studies proposed that such systems might run with low-dose heparin or even without any systemic anticoagulation. methods: since , patients with severe ards were treated with extracorporeal lung assist (ela) using heparin-coated systems (type maxima, medtronic, carmeda coating) in our icu. they received a moderate systemic heparinization. standard clotting assays (act, aptt, tt, ptt, at-ill, fbg, fsp) as well as special tests (tat, r~-tg, pf , pal-l, d-dimers, protein c, cl-inhibitor) were performed. results: covalent heparin-eoating of the ela-systems combined with lowdose heparinization could not prevent major changes in coagulation: ) in mean, platelets dropped from /nl to /nl within h after onset of ela. ) tat levels were already elevated before ela start ( ug/]) and demonstrated an additional peak h after onset of ela (up to ug/[). ) in parallel, there was a transient peak of pai-i levels (from to au/ml} h after onset of ela. ) in mean, fibrinogen levels dropped from to mg/ ml within h after onset of ela. ) in mean, cl-inhibitor levels dropped significantly from % to % after onset of ela and reached the initial levels within h. ) after membrane change, there were significant changes for c -inhibitor, fibrin-d-dimers and tt. ) global clotting tests such as aptt, ptt and tt were within normal range. conclusions: patients with severe ards develop a prethrombotic state already before they get connected to the ela bypass system. after onset of ela, they experience additional involvement of procoagulant, anticoagulant, fibrinolytic, and complement systems. in parallel to laboratory findings, clinical data suggest that the use of heparin-coated systems with accompanying systemic low-dose heparinization does not avoid thrombembolic and hemorrhagic complications in tong-term ela patients. thus, at the present, higher dosed individually adjusted heparin treatment has to be recommended. thereby, standard clotting monitoring is not sufficient. objective: poor muscle performance contributes to prolonged dependence on mechanical ventilation. longitudinal data on muscle function in icu patients is scarce. we evaluated changes in inspiratory and peripheral muscle performance during prolonged intensive care in patients with acute respiratory failure. methods: patients requiring intensive care for more than one week were studied. maximum inspiratory pressure (pimax) was measured twice a week for a maximum of three weeks. handgrip power (dynamometer) and subjective fatigue (keldet score) were obtained in survivors only. one measurement was done on the date of extubation. pimax pressure was obtained by occluding the airway for seconds or at least five inspiratory breath attempts. obiectives -measurement of peep-induced changes in lung volume helps to assess respiratory mechanics in acute lung injury (ali). we evaluated the accuracy and stability of a new respiratory inductive plethysmograph (rip), in the measurement of peep induced changes in end-expiratory lung volume (eelv) and tidal volume (vt) against volume reference, pneumotachograph (pnt), methods -two hours periods of basal ventilation and stepwise increases and reductions of peep ( - - - - cm h ) were recorded in patients with all. in addition, the new rip device (respitrace plus tm) was compared to an older rip (respigraph tm, nims, fl, usa) to determine its thermal stability using cold and warm devices and a ventilated lung model. results -the difference between the new rip and pnt in the measurement of vt was - _+ mi (x _+ se) or a - . _+ . % error. increasing peep from to cm h induced a + ml change in eelv. a difference of + ml ( . % of max. eelv change) (ns) was found between rip and pnt eelv readings. during controlled ventilation with constant settings the mean change in eelv was _+ ml/ min (fig.i) . validation of calibration showed a mean error of -+ . % after rain. the new rip had a higher drift when cold (cold + ml/ min vs warm _+ ml/ min), whereas the old rip was thermally stable (cold - + ml/ rain vs warm i + ml/ min). trauma icu, hospital traumatologia y rehabilitacidn. vall d'rebron. barcelona. spain. recent data suggest that the proportion of patients with relevant discrepancies between two jugular bulb (jb) oxygen saturation (sjo ) values is higher than suspected. objectives: determine the incidence, the significance and the pro nosis value of those differences,if they exist,in severe head injured-patients. material and methods: severe head-injured patients, coma glasgow scale (gcs) , with diffuse brain injury according to marshall criteria in the first ct scan, icp recorded, with an interval from accident-double jb monitoring < than hours, were studied. data from bilateral sjo were obtained simultaneously, every hours. discrepancies were considered significant, when differences in sjo were > %. no chan es in treatment protocol (hyperventilation, man• etc) were carried out due to this study. results: men and women were studied, aged • yrs. at arrival at hospital, gcs were < in and ) in to. the incidence of high icp() mmhg) were sz at the entry. the mean therapy index level required to control lop was ~l all patients required vasopressor therapy to maintain upp over ds mmhg. in patients a s.s f swan-ganz fiberoptic catheter was used to obtain a continuous recording of sjo . in the others , sj were intermittently controhed.the mean time of monitoring were d. • days. ten patients died within this period. a total of . blood samples were analized. at arrival, sjo discrepancies were found in patients, b %. at hours, the incidence were lower, / , . %. at th day, were h/ , z and at day , when the catheters were retired, ii[ , z showed discrepancies. the ct showed new injuries in g z of patients with differences > ~ in sd values throughout treatment period. none of those were considered for neurosurgical treatment. no correlation was found between iop and sjo values and sjo differences. conclusions: the incidence of discrepancies between sjo was higher than expected in severe head-injured patients. these situation could reflect disturbances between demands. when differences are known, and those lend to change, the ct scan, nearly always, will show new injuries. platelet-activating factor (paf) is an inflamatory mediator implicated in the pathogenesis of bronchial asthma and acute respiratory distress syndrome (ards). its inhalation in healthy subjects produces transient bronchoconstriction and mild ventilation-perfusion mismatch, together with peripheral leukopenia as a result of intrapulmonary neutrophil (pmn) sequestration. likewise our group has shown in healthy subjects and asthmatic patients that aaibutamol (s) inhibits both pulmonary and systemic effects of paf, suggesting that s may inhibit paf-induced venoconstriction in pulmonary microoirculation. the aim of the present study was to investigate if s inhalation decreases pmn by lung sequestration induced by paf. we studied healthy, non-atop• nonsmoking subjects ( m/ f, + yr), which were pre-treated with s ( ,ug) or placebo, with a randomized, double-blind, crossover, design, before paf ( ,ug) inhalation. we measured the respiratory system resistance (rrs) by forced oscillation, arterial btood gases and both total white cell and pmn count every min over a min. period. simultaneously, we recorded continuously the lung dynamics of inm-neutrophil and tc m-erythrocytes activity, with a gammacamara. after placebo, paf inhalation decreased white cells (from to x /l), and pmn(from to _+ x /l), and increased aapo (from . _+ . to . + . mmhg, p<o. ) and rrs(from . . to . . cmh .s.i q ) (p < . each). the fall in total white cell count correlated with the intrapulmonary pmn retention (r = . , p < . ). by contrast, after s, paf did not induce any change in white ceil count (from to + x /i), pmn count (from to x /i), aapo (from . to . + . mmhg), and rrs (from . . to . . cmh .s.i ). compared with placebo, after s there was a lower ~lln-pmn lung activity ( . . vs . . cts/mci/pixel, p<o. ), lower intrapulmonary pmn retention ( . . vs . . %, p=o, ), and a faster washout ( . . vs . . s ~, p= , ). our results indicate that s inhibits paf-induced intrapulmonary pmn sequestration, being consistent with the hypothesis that s may offset the venoconstriction of pulmonary microcirculadon caused by this mediator. supported inpiratory muscle fatigue with failure of force generation as def'med by a tensiontime index (tti)> . - . has been shown to occur in normal volunteers and in stable copd patients with a specific imposed breathing pattern. its role, however, in hypercapnic respiratory failure is less certain. we studied failed weaning trials in copd patients in which breathing pattern, tension-time index (tti) of inspimtory muscles, dynamic peepi, dynamic lung elastance, lung resistance, and arterial paco and ph were measured at the beginning and end of a t-piece weaning trial. in addition, the change in esophageal pressure during a mueller maneuver (apes max) was measured. a weaning trail has been prospectively defined to have failed if one of the following criteria was met: a rise in pco > mmhg from baseline accompanied by a fall in ph< . ; a respiratory frequency (f) > /min; excessive accessory inspiratory muscle recruitment; and a marked increase in dyspnea. values are expressed as mean • se. weaning failure was characterized by a more rapid, shallow breathing pattern, worsened mechanics, hypercapnia and respiratory acidemia despite an unchanged tri and pes max. we conclude that in this setting hypercapnic respiratory failure is not a consequence of inspiratory muscle fatigue. rather the adopted breathing strategy and resultant hypercapnia may represent an adaptation to forestall the onset of muscle fatigue. concerning the investigated elf-par~eters, no stadstically signhqcant differences were detected between the pgi and the control group. histopathologlcal changes occured in both groups and consisted in rare focal flaaaning f tracheal epithelium with loss of cilia and slight inflammatory cell infiltration, as well as slight swelling of alveolar typo pneumoeytes. sections of generation , and from bronchial tree were free of pathological changes. conclusion: alter h inhalation of p~ji no signs of respiratory-lract tissue damage caused by the aerosol could be detected. the minor pathological findings in the trachea are most likely due to mechanical irritation by bronchoscopy, changes of the alveolar epithelium are known for long-term mechanical ventilation . objectives: the aim of this study was to evaluate of efficiacy of ganglion stetlate blockade in patients with respiratory failure. methods: two groups of patients were investigated: group i (n = ) trauma patients with acute lung injury (ali), group if (n = ) patients with asthmatic status. in all cases continuous mandatory ventilation (cmv) was used with bennett ae. in both groups bilateral ganglion stellate blockade with antero-lateral approach was performed, using . % marcain. the following parameters were analysed: pao , sao , paco~, pip and c~t~t. results: in trauma patients with aij after bilateral ganglion stellate blockade short -lived and slight improvement of pao and sao , decrease of pacoz and pir and increase of static compliance of respiratory system were found. in second group bilateral ganglion stellate blockade interrupted the asthmatic status and significant statistical improvement of parameters of oxygenation, ventilation and respiratory system mechanics were observed. conclusions: we suggest that the bilateral ganglion stellate blockade is a very useful method in treatment of patients with obstructive respiratory insufficiency. the aim of the study was to analyse whether there exists serum and urine electrolyte disorder in patients(pts.) with acute respiratory insufficiency(ari). the study included t pts. with ari (pao : , @ , kpa. paco : , i- , kpa, ph: ~: , , hco : , :~ , mmol/ , sao : , ~- , %) who were hospitally treated due to pneumonia( pts.),emboly of the pulmonary artery( pts.) and severe attack of bronchial asthma ( pts). among tham there were ( , %) males and ( , %) females, average age , ~: , years, otherwise previously healthy. electrolyte concentracions were measured at the onset of the disease in serum and urine collected during hours (sodium-na,potassium-k, chlorine-c , calcium-ca,magnesium-mgand phosphorus-p). the measured serum and urine electrolyte concentrations were compared with respective referent values (rv). by serum electrolyte analysis, the following average velues were obtained: na:l o, the object of our investigation was a group of pts with massive pneumonias, males ( . %), females ( . %),mean age yrs.thirteen ( %) of them were smokers, ( %) nonsmokers. only pt ( . %) had pre-existing chronic respiratory disease, and ( . %) were admitted for the first lime,with no previous respiratory anamnesis. diagnose was based on anamnestic data of productive cough in pts( . %),physicaly ~onchial breathing in i~s ( . %),white cell count onder x /l in pts( . %). radiographicly, bilateral massive homogeneous shadows were found in pts ( . %), onilateral in pts( . %),pleural effusion in pts ( . %). abnormal renal function was found in pts ( . %). sputum culture was positive in pts ( %): slr.pneumoniae, str.pyogenes, pse'udomonas aerug, in , , cases respectively. all patients had remarcable hypoxernia (pao range from , to , kpa) without hypercalmea. all patients needed oxygenotherapy together with antibiotics and other .symptomatic therapy. nineteen pts had anaelioration of general condition and normalization of blood gas analyses, while pts with the lowest hypoxcmia died.in conclusion, massive pneumonias are frequently followed by respiratory insufficiency which is one of the markers of pneumonia severity. as existing hypoxemia complicates the course of the disease,prolonges the recovery, makes therapy more complexe and may be cause of death , frequent blood gas measurement is recomanded. we studied the effects of bosentan (bos), an eta and etb receptor antagonist, to examine if endogenous et mediates pulmonary hypertension in anesthetized and ventilated dogs with acute lung injury due to oleic acid (oa). the gradient between pulmonary artery pressure (ppa) and occluded ppa (ppao), and gas exchange (evaluated by arterial blood gases and sf intrapulmonary shunt) were measured at controlled flow. in dogs (treatment), data were collected at baseline, during long injury (obtained rain after intravenous administration of oa . ml/kg), and again after bos ( mg/kg intravenously). in dogs (pretreatment), data were obtained at baseline, after bos and then after oa. in treated dogs, oa increased (ppa-ppao, mmhg, table, means + sem, * p < . vs base) and deteriorated gas exchange. after oa, bos did not affect pulmonary vascular tone nor gas exchange. in pretreated dogs, bos had no effect on baseline pulmonary vascular tone but prevented the increase in (ppa-ppao) after oa. the deterioration in gas exchange after oa was not influenced by bos pretreatment. objectives: the alveolar tension is measured by the application of the alveolar air equation in which the arterial pco is used or by the simplified form of this equation in which the respiratory exchange ratio is taken at the value of . . the purpose of this study was to estimate the effective alveolar tension (pao eff) during spontaneous breathing with a new bedside technique which is simple non-invasive in normal subjects and patients with chronic bronchitis-emphysema. we also compared these values with the ideal alveolar po (pao (i)), measured from the alveolar air equation in which paco was substituted by the effective alveolar pco (paco eff) and with the alveolar po measured from the simplified alveolar air equation (pa ). this study is complemantary to previous work for the estimation of paco eff. methods: the subjects breathed quietly through the equipment assembly (mouthpiece monitoring ring, fleisch transducer head) connected to a pneumotachograph and a fast response and co analyzer. the method is a computerised calculation of the effective alveolar po quite similar to that of paco eff, obtained from the simultaneously recorded at the mouth expiratory flow, and co concentration versus time curves. results: the results showed a mean difference (pao eff-pa (i)) of - . kpa in normal subjects and - , in patients. the mean of the difference (pao eff-paq ) and (pad (i]-pao z) was much greater than . in all subjects. the limits of agreement for the difference (paozeff-pa (i))were - . to . kpa in normal subjects and - . to . in patients, while those for the differences (pao eff-pad ) and (pao (i)-pad ) were very large ( > - . to > . ) in all subjects. conclusions: the effective alveolar po is very close to the ideal one in normal subjects, tn patients pao eff may excessively deviate from pa (i) due to the observed significant difference between the alveolar/tidal volume ratio for o and that for co . the alveolar po measured from the simplified alveolar air equation (pao ) differed substantially from pao eff and pad (i) in all subjects. the essential role of glucoprotein hormone erythropoietin is to control red cell production. hypoxemia, reduced blood -carrying capacity and increased affinity of hemoglobin for are the primary stimuli for erythropoietin production. both anemia and hypoxemia induce rapidly erythropoietin secretion. kidney erythropoietin rna levels correlate inversely with hematocrit and directly with plasma erythropoietin level. similarly, hypoxemia increases kidney erythropoietin rna and plasma erythropoietin. the effect of hyperoxemia (pa >lo mmhg) on erythropoietin secretion isn't very well understood. the purpose of this study was first to evaluate the erythropoietin secretion in patients with acute respiratory failure and second to determine the effect of hyperoxemia on erythropoietin secretion in patients with and without anemia. sixteen patients with acute or acute on chronic respiratory failure needed mechanical ventilation were included in this study. these patient were divided in two groups. the patient who developed anemia were included in group i and the patients without anemia in group i . erythropoietin was estimated in venous blood in three stages. the first sample was taken during hypoxemia, the second during hyperoxemia and third during normoxemia. all the patients had high erythropoietin level during the hypoxemia period (mean value • mu/ml). during hyperoxemia etythropoietin levels were reduced in both groups ( mean value . + . mu/ml in group i, . • mu/ml in group ii). in normoxemia stage, erythropoietin increased again in anemic patients, and decreased more in the patients of group i . we conclude that hyperroxemia inhibit erythropoietin secretion in spite of anemia and tow arterial oxygen content. hyperoxemia may be a factor of the insisted anemia in with oxygen treated icu patients. the purpose of this study was to determine the relationship between clinical features of acute lung injury (all) and parameters like total proteins, total and individual phospholipids, the presence of paf, and acetylhydrolase activity in bal of mechanically ventillated patients. acetylhydrolase catalyses the cleavage of acetyl-group from the second position of the glycerylether backbone of paf, leading to its inactivation. mechanically ventillated patients were divided to three groups. group i includes patients without all; group ii, comprisespatients with moderate degree all, ( . <g-i < . ); and group iii comprises patients with severe ards (all score > . ). broncoalveolar lavage (bal) was obtained after infusion of normal saline at ~ to intubated patients and cooled immediately. cells were removed after mild centrifugation ( x g, min, oc). aliquots from the supernatant were used for total protein, phospholipid and paf analysis and determination. acetylhydrolase activity was assessed after incubation of bal with h-paf labelled on the acetyl group. released label was measured by liquid scintillation counter in the supernatant after trichloroacetic acid precipitation of the non-reacted substrate. kinetic characteristics of the enzymes were also studied. total phospholipids appear reduced in bal of patients with all, while total proteins increase. these factors appear to correlate with the severity of all. paf was not present in bal samples pretreatad with equal volume of % acetic acid to denaturate acetylhydrolase. detection limit for paf under our experimental conditions: pg paf/ml bal. instead, acetylhydrolase activity was detected in amounts increasing with the total protein content. background: intubated patients without lung injury or impaired breathing control normally display an inspiratory peak flow of below l/s. the aim of our study was to investigate the inspiratory peak flow generated by patients with acute respiratory insufficiency (ari). we had to take into account that both an inspiratory pressure support (ips) and the resistance of the endotracheal tube considerably influence the flow pattern generated by the patient. patients and methods: to investigate the non-influenced flow pattern we developed a new ventilatory mode which automatically compensates for the flow-dependent resistance of the endotracheal tube (automatic tube compensation, atc). furthermore, the mode maintains a constant tracheal pressure in inspiration and expiratio n . consequently, the measured flow pattern exactly corresponds to the flow pattern generated by the patient except that the ventilator modified for this mode (evita, driiger liibeck, germany) was not able to deliver a gas flow of more than l]s. we have investigated patients with ari arising from different reasons. results: the inspiratory peak flow measured in the atc-mode was . l/s _+ . l/s. the maximal deliverable flow of l/s was obtained in of patients. the figure shows the flow pattern under atc and ips in [~s] oi:) one of these patients. conclusions: patients with ari display a highly increased inspiratory peak flow. ventilators used for spontaneous breathing should therefore be able to deliver a gas flow of more than l/s. an overproduction of no and reactive oxygen species (ros) has been demonstratred in septic shock. ros and nitric oxide (.no) are free radicals which are known to react together leading to peroxynitrite anions that can decompose to form nitrogen dioxide (no ) and hydroxyl radical (oh~ thus, no has been reported to have a dual effect on lipid peroxidation (prooxydant via the peroxinitrite or antioxidant via the chelation of ros). in the present study we have investigated in different models the in vitro and in vivo action of no on lipid peroxidation. copper-induced ldl oxidation was used as an in vitro model of lipid peroxidation. ldl ( ~g apob/ml) was incubated with cu + ( , ~tm) in presence or absence of no donor (sodium nitroprussiate or glutathione-no) from to ~m. oxidation of ldl was monitored continuously with conjugated diene formation ( nm) and hydroxy nonenal accumulation (hne). exogenous no prevents in a dose dependent maner the progress of copperinduced oxidation. ischaemia-reperfusion injury (i/r), characterized by an overproduction of ros, is used as an in vivo model. anaesthetized rats were submitted to hour renal isehaemia following by hours of reperfusion. sham operated rats (sop) were used as control. lipid peroxidation was evaluated by measuring the hne accumulated in rat kidneys in presence or absence of l-arginine or d-arginine infusion. l-arginine, but not darginine, enhances hne accumulation in i/r but not in sop (< . nmol/g tissue in sop versus . nmol/g tissue in i/r), showing that in this experimental conditions, no produced from l-arginine, enhances the toxicity of ros. this study shows that the pro-or antioxydant effects of no are different in vivo and in vitro and could be driven by environemental conditions such as ph, relative concentration of no and ros, ferryl species...these conditions are impaired in circulatory shock. methods:" the diagnostic and therapeutic approach was standardized so that data collected over a -year period were comparable. a progressive deterioration of clinical conditions and/or pulmonary gas exchanges was considered as indication for my. variables potentially predicting the need for hv were derived from clinical and arterial gas data, extrapulmonary diseases, use of drugs, chest x-ray and ecg abnormalities. results: rv, performed with external and/or internal ventilators, was necessary in patients ( %). at the hospital admission, pac was higher and ph was lower in patients requiring rv ( pneumomediastinum, pneumothorax, ateleetasis and myocardial infarction are rarely seen in bronchial asthma. these complications occur as a result of the severe asthma.the aim of our retrospective study was to analyse the complications seen in acute asthma attacks. during the years through , patients were admitted to hospital in acute asthma episode. there were ( , %) pts with complications; mean age of yrs; females ( %). clinical history, ecg and chest radiogr~hs were analysed. the mean duration of bronchial asthma was yrs (range from months to yrs), all patients were atopics. there were four ex-smokem and one smoker. the worsening of asthma symptoms begun two days before the admission (range from to days). on ecg all patients had tschycardia. rightward shift of the qrs axis and st-t changes indicative of right ventrieutur strain were found in three pts. these were the transient fmdings that improved after curing the acute asthma attack. non-q myocardial infarction oeeured in one patlent and resulted from the hypoxaemia of asthma. hyperinfl~ion was the usual finding on the chest radiograpk pneumomediastinum and subcutaneous emphysema were apparent in five pts and required no additional treatment unilateral pneumothoraccs were present in two pts and needed eontimous intrapleural drainage; one of these patienst died in eardiorespiratory insufficiency. ateleetasis of right upper lobe was present in one patient. it oceured due to inspissated secretions and needed no additional treatment all these patients, except one who died, improved on lreaanent with oxygcr~ steroids, beta-two agonists, theophylline and antibiotics. in conclusion, complications occur in acute asthma episodes as a result of the severe asthma mediastir,*l emphysema and atelectasis are not serious complications. pneumothorax and myocardial infarction are very serious life-treatening complications and always have to i:m considered in taati~ts with sev~ asthma. acute bronchial asthmatic episodes represent one of the most common respiratory mnergendes, its maximmum expression "status asthmatiens" is one entity of low incidence, still it is a risk to the physical integrity of the patient. during a total of patients with diagnosis of status asthmabcas were hospitalized. out of these palients six had a near-fatsl asthma and they were subjected to a complex examination. near-fatal asthma was defined as either respiratory arrest or acute asttuua with paco greater than , kpa and/or an altered state of consciousness. mean age was , -d: , yrs, four male and two female sex. at presentation two patients suffered from coma, others were confused. they exh'bited severe dystmoes, diffieul~ speaking, used accessory muscles of respiration, increased whee~tg while two cases had silent chest on auscultation. cyanosis indicated a very severe asthma attack in all six patients. mean respiratory rate was ~ /min and puts rate .d: bts/imn. arterial blood gases revealed a pao of , ~ , kpa, paco of , • kpa and ph of , -+- , . area-careful evaluation they received conventional therapy (immediately continuous oxygen, impelled nebulization with high doses of betatwo agonists and ipmtropium bromide, intmvanous st~oids and theophylline). in two eases signs and symptoms of deteriorating airflow and respiratory muscle fatigue determined the need for mechanical ventilation. out of six near-fatal attacks aggressive lrealanent was suscessfull in four patients and fatal in two eases. one patient admittcxl in coma died in severe hypoxae~a upon one hour and one mechanicaly ventilated died from cardiac arrhythmia. life-threatening attacks in asthmatics in our group developed gradual worsening despite neatment which r symptoms in most other patients. one patient had "brittle asthma", other long-standing acute episodes ireated with systemic steroids. conclusions: idantitiechon of fatality prone subjects may lead to fttrther muetion of seveze episodes. respiratory affest and coma upon admission, severe dyspnoca with silent chest on ausouhation, oyanusis and use of accessory muscles of respiration constitute the basic cfinieal picture. hypoxasmia must be immediately eon'ected.the patients and physicians should be able to assess the severity of asthma, a major factor in near-fatal and fatal asthma attacks. objectives :our purpose was to asses if the evolution of patients with a adult respiratory distress syndrome (ards) ,shows any relation to the pulmonary or systemic origin of the disease and whether or not there were differences in the frequency of the syndrome in both groups. methods : randomized prospective study in multidisciplinary icu. one hundred and sixteen patients with a high risk developing ards were distributed into two groups. one was named systemic origin group(so) and the other pulmonary origth group (po).ai patients only showed one cause (pulmonary or systemic) with potential risk of ards.the patient's hemodynamic and respiratory status was evaluated every hours the first day and every hours the second and third day. at the end of hours the patients were diagnosed as ards or non-ards. measurements and main results : of the total patients, were finally included in the so group and in the po group.patients in so group and po group had comparable ages (p<. ).peep in both groups was comparable (=. ) at the mmnent of admission to the study. there were no statistically significant differences for cardiac index and systemic vascular resistances. the pulmonary vascular resistances (pvr) showed significant differences at h.(p<. ) and h. (p<. ).the oxygen comsumption (vo) in patients of the so group showed statistically significant differences at h. (p<. ) with respect to initial values.fifteen cases of ards ( . %) in the so group and twenty five cases ( . %) in the po group were identified. the time of onset of ards was _+ hours in the so group and + b hours in the po group.the final outcome was very similar th both groups : mortality of % in the so group versus % in the pc group. conclusions : the pathogenesis of ards depends on whether the lesion is originated at or outside the lung. the po group showed a sborter thne of onset of ards, a faster and more severe increase of pulmonary shunt and a higher percentage of patients developing ards compared with patients of the so group.the so group showed a higher and faster increase in puhnonary resitances tbat po group and a decrease th oxygen comsumption earlier and more severe than in the po group. these data thus seem to show that there could be two mechanisms involved in the genesis of ards depending on the cause. the fact that the ards genesis is shorter in the cases of pulmonary etiology with faster impairment of pulmonary shunt, and a slower increase in pulmonary resistances in this pulmonary group, would indicate that the underlying mechanisms responsible for the hypoxemia are different to those which thitiate the increase in pulmonary resistances. finally, the exclusive inapairinent of oxygen consumption, which appears earlier than the onset of ards in the systemic origth group, could show the generalized character of the process in this group. perfusion of prostacyclin (pgi ) to treat pulmonary hypertension in adult respiratory distress syndrome (ards) worse pulmonary gas exchange due to a marked impairement of ventilation/perfusion mismatch. recently has been shown that if prostacyclin is given by aerosol instead of intravenous the net effect is an improvement of arterial oxigenation due to a redistribution of blood flow to well ventilated areas. objectives: to asses the effects of inhaled proatacyclin on pulmonary haemodynamics and gas exchange in patients with severe ards. methods : two patients with severe ards (murray score > ) recived inhaled pgi at - ng.kg.min " using an ultrasonic nebulizer. haemodynamic measurements, arterial and mixed venous blood gas analysis were performed before and after rain of pgi inhalation. results: short-terro p~i inhalation improved pulmonary g-~ e-'~hange in both patients. arterial oxygen partial pressure (pao ) increased from to mmhg in patient and from to in patient , the ratio pao to the fraction of inspired oxygen increased from to (patient ) and from to (patient ). venous admixture decreased from % to % and from % to % in patient and respectively. mean pulmonary artery pressure decreased slightly from to mmhg in patient and from to mmhg in patient . no effects on systemic haemodynamics were observed in any patient. conclusions: pgi inhalation improves gas exchange and produces selective pulmonary vaaodilation, thus can be an alternative therapy for the treatment of pulmonary hypertension and hypexemia in patients with severe respiratory falllure. methods: we treated ards-patients (age yr ( - ) mean, range) during - . the lowest pao /fio -ratio was ( - ), the worst murray score . ( . - . ), icu-stay ( - ) days and hospital mortality %. the costs of intensive care were calculated according to intensivity of patient care as assessed by tiss-scoring (therapeutic intervention scoring system). the more intensive the care, the higher are the costs. costs per year of life saved (=life-year" in us $) were compaired by other medical treatments ( - ). it is assumed that the mean expected length of remaining life in ards-survivors after intensive care is years. treatment life-year ($) ' bone marrow transplantation (acute leukemia) lowering cholesterol using iovastatin treating hypertension using nifedipine heart transplantation intensive care of ards-patients conclusions: intensive care of patients with severe ards is highly more cost-effective as compared with many other routinely used medical treatment strategies, the usually good recovery and the reasonable quality of life in survivors justifies investments to care of these patients ( ). there is a close correlation between these two methods of measuring evlw. however there is an underestimation of . % in this kind of pulmonary edema ( oleie acid induced ) with the double dilution method. although the size of the sample is small, in normal lungs there appear not to be this underestimation. the effect of peep on evlw has been studied with contradictory results, probably as a consequence oft differences in methods of measuring evlw, variations in the type and severity of lung injury, and different timings of peep application. objective= ) to analyse the effect of different levels of peep ( , and omh ) on evlw during hpe; ) to establish whether increases in intrathoracic pressure due to high peep levels can obstruct lymphatic drainage. material and methodet hpe was provoked in groups of dogs by inflating a foley catheter in left auricular to a pressure of - r~uhg. peep levels of , i or m~hg were applied. resultst objective: to assess the effect on extravascular lung water (evlw) of the application of peep and the reduction of vt in an oleic acid pulmonary edema model in pigs, using three ventila~ary strategies. material and methods: twelve adolescent pigs (weighing over kg) were randomly divided in three gmups immediately alter infusing via a central vein . ml/kg of oleic acid to produce a permeability pulmonary edema. the ventilatory parameters for each group were as follows: group i (n= ) : vt: - ml/kg; zeep. group :(n= ) : vt: - ml/kg; peep: cm h . group :(n= ) : vt: - ml/kg; peep: emil . (resulting in permissive hypereapnla) after a four-hour period of ventilation the animals were killed and the lungs excised to calculate gravimetrically the extravascular lung water using a standardized procedure ( hemoglobin content method ). ill evlw (ml/kg) group obiective: in the postoperative period, maintenance of adeguate arterial oxygen tension is a major problem in morbidly obese patients probably because of a large reduction in functional residual capacity (frc). the aim of this study was to evaluate the effects of peep on respiratory mechamcs and gas exchange in this kind of patients. methods: in nine postoperative mechanically ventilated morbidly obese patients (bmi> kg/m ) we partitioned the total respiratory system mechanics into its lung ( ) and chest wall (w) components using the airway occlusion technique associated with the esophageal balloon, during constant flow inflation (jap ; : ) . at three different levels of peep ( , , cmh ) we measured: compliance (cst), airway (rim) and "additional" (dr) resistance, frc and gas exchange. obiectives. to describe the use of prone position in our icu we analyzed the clinical records of all patients admitted in - , selecting adult patients with arf defined as: intubation and pao /fio < mmhg plus an fio > . or peep> cm i . results. patients met the arf criteria: of them ( . %) underwent prone positioning (p+). prone position use began in the early phase of arf ( . • days from the beginning, range - , median ). out of p+ pts were treated with controlled ventilation (cppv or pcv), while were on assisted ventilation (simv+ps) and on spontaneous breathing (cpap). only pts were awake when turned prone, while pts required adjuncts of sedation to tolerate the change of position. the duration of prone positioning was variable (average lenght . • h, range . - h). only minor side effects were observed (eyelids and facial edema, chest and facial pressure bruises). we consider responders (r+) those patients presenting at least . mmhg increase in pao /fio : / patients ( . %.) were responders when first pruned. the pao /fio changes induced by prone position are reported in the figure. pao /fio increased when patients were pruned (*p< . ) and remained higher than baseline values when returning supine(*p< . ). paco remained unchanged. prone positioning was used at least twice in / ( conclusions. this retrospective analysis confirms that prone positioning improves oxtgenation in the majorib' of arf patients. altough we have no available criteria to discriminate in advance r+ from r-pts, we now routinely consider the use of prone position in the treatment of severe arf. palo a, otivei m*, galbusera c, veronesi r, sala gallini g, zanierato m, iotti g, braschi a.servizio anest. e rianim. i, *laboratorio biotecnologie e tecnologie biomediche irccs s. matteo, pavia, italy inhaled no can improve arterial oxygenation and reduce pulmonary hypertension in ards patients; little information is, however, available about the dose-response curves. methods seven ards patients (lis . +. ) submitted to mechanical ventilation randomly received inhaled no doses in increasing or decreasing sequence: . , , , , , and ppm. reference measurements were obtained before and after the entire period of no inhalation. hemodynamic parameters and blood gases were measured after min in each condition. cmv was administered under sedation and paralysis, with constant ventilation, peep (lol-_ cmh ) and fit (. +. ). the changes in vt and fit due to the no ( ppm in n ) injection in the ventilator external circuit were compensated for. results . the dose of . ppm, ineffective on papm, significantly improved oxygenation. the increase of pat and the decrease of q'va/q' and papm were nearly maximal at - ppm. no deterioration of arterial oxygenation was observed at no doses as high as ppm. co exchange was not influenced by no inhalation. systemic hemodynamic variables did not change throughout the study. these results suggest that a concentration around ppm is adequate for obtaining maximum effects on hypoxemia and pulmonary hypertension in patients with ards. low-dose inhaled nitric oxide (no) induces redistribution of pulmonary perfusion in patients with severe ards and causes improvement of oxygenation [ ] . however, addition of exogenous lowdose no in the inspiratory gas mixture might be only a replacement of missing atmospheric no ( - ppb) in hospital central-supplied medical air. [ ] we have realised nitric oxide measurements in ten healthy volunteers, ( smokers and non-smokers) breathing with a mouthpiece and occluded nostrils through a ventilator circuit, with separation of inhaled and exhaled gases by a valve. no concentration was measured with a double-chamber chemiluminometer (environnement sa, france) and with charcoal/silicate purified compressed air. there was no nitric oxide detectable in the inspirat ry limb of the ventilator. unfiltered central supply medical air contained : - ppb of no and - ppb of no , whereas central supplied oxygen was no/no free. samples were taken after equilibration periods of minutes, with increasing fit levels of . , . and . for subsequent minutes periods; paired values were recorded every s. the mean no value was . ppb (sd . ) and n o significant differences were found for different fit levels both in smokers and non-smokers. these data suggest that the no concentration of pulmonary origin in the exhaled air of' healthy volunteers is probably lower than that reported by other authors [ ] and that, previously reported, differences between smokers and non-smokers are not always striking [ ] . we suggest the use of activated charcoal/silicate filters for clinical trials in order to achieve standard conditions. [ objective: to compare efficacy and safety of two doses of salbutamol. methods: sixteen adults who had severe acute a~hma were randomly assigned to receive either rag (n= ) or rag (n= ) of nebulized sulbutamol. both groups were similar with respect to age, duration of a~hma, duration of attack before arrival at the hospital and severity of a~hma according to baseline measurements (table) . evaluation was performed , , and rain after the start of nebulization. results: compared with mg regimen, mg regimen resulted in the same improvement in peak-flow and fischl index (figure). the changes in heart rate, respiratory rate and pace did not differ significantly between both groups. the incidence of side effects, which included tremor, palpitations, cardiac arrythmlas and other symptoms, was not sj~ificanfly different in the two populations. conclusion:the results of this study suggest that nebulization of ng of salbutamol is not more effective than rag in the initial treatment of acute severe asthma in adult patients. the prognostic factors of neutropenic patients admitted to the icu remain poorly known. the aim of this study was to determine the respective weight of underlying malignancy and organ system failures on the outcome of these patients. patients and methods: the charts of neutropenic patients (wbc < /mm and/or pmn < /ram ), admitted to the icu between and , were retrospectively reviewed. the characteristics of the neoplastic disease (h~emopathy or solid tumor, tumoral evolution, duration of cancer disease and of neutropenia), the mac cabe's score, the organ system (respiratory, hemodynamic, renal, neurologic, hepatic) failures and the severity scores (saps, saps ii ,osf) were registred within the st day in the icu. when discharged from the icu, the patients were classified as alive or dead. results: fifty-seven patients ( . %) had a h~ematologic malignancy, and ( . %) a solid tumor. fifty-nine of the patients died ( . %); the mortality rate did not differ between both groups ( . and % respectively, p = . ). with univariate analysis, none of the tumoral features is linked to the prognosis; only the respiratory (p < - ) and cardiovascular (p < - ) failures, and the number of organ system failures (p < - ) are associated to the risk of death. the saps (p < - ) and saps ii scores (p < - ) were higher in patients who died. with multivariate analysis (logistic regression), only the respiratory failure is correlated to the risk of death (p = - ); neither the features of the underlying malignancy (p > . ), nor the duration of neutropenia before admission in icu (p = . ), nor the severity scores figs ii: p = . ) are linked to the outcome. conclusions: the tumoral characteristics do not modify the prognosis after admission to the icu. they should not influence the decision to admit or refuse a cancer patient in the icu. respiratory failure at icu admission has the predominent weight on the risk of death in the icu. patients with respiratory acidosis due to asthma occasionally require levels of mechanical ventilation that place them at risk for barotrauma. a few case reports have described the use of an extra-corporeal membrane oxygenator(ecmo) circuit as an alternative means of co removal. generally, this has been used for short periods of time (< h) without serious complications and with low blood flows through the extra-corporeal circuit. we report a case of refractory asthma who could not tolerate even small-volume breaths from a mechanical ventilator due to severe bilateral airleak. ecmo therapy was initiated at the referring hospital prior to helicoptor transport. high blood flows were used ( % of the patient's cardiac output), sufficient to achieve both co removal and oxygenation. satisfactory gas-exchanged was accomplished (pco = - mmhg) with nearly total lung rest for a prolonged period ( h). however, the long ecmo duration was associated with two severe complica-ti ns: ) bilateral hemothoraces due to anticoagu!ation in the extra-corporeal circuit, and ) prolonged weakness as a result of neuromuscular blockade for six days. the patient was discharged from the hospital in good condition. we present the respiratory and hemodynamic features of this case aw well as the potential complications of ecmo therapy in asthma. objectives: parameters derived from tidal expiratory flow ~e) and volume (vt) can be used to detect airflow obstruction in copd patients who might be unable to perform forced spirometry (e.g., icu). however, indices such as ave/v t and at/re are highly variable (thorax, : ; ) . methods: we investigated whether the standardized for v m effective time (teff~) of a tidal breath, which is derived by asimple mathematical procedure (teff,= j'vdt/vt ), is a more reproducible and sensitive detector of airways obstruction, we studied nine normal subjects ( male, -+ yr) and copd patients ( male, -+ yr) in the seated position, with a noseclip on. they breathed quietly, through a pneumotashograph to measure flow (v). volume was obtained by numerical integration of thellow signal. each subject had an initial - min trial run, in order to become accustomed to the apparatus and procedure. when regular breathing had been achieved, all breaths over a min time interval were recorded. the mean value of six consecutive breaths (ers criteria) for each subject was used for analysis under the condition that within session variation of tidal volume (vt) was < %. lung function tests were: in normals (mean-sd), fevl%pred = • fevl/fvc%= -+ % , and in copd patients, fev~%pred= __. and fevi/fvc%= --. %. results: values are shown as mean-..+-sd in the following a su~ve~ os literature sources p~oves that t~aditlona], i.e. medicinal medication and physiothe~apeutic methods os t~eatment often p~ove to be insufficientl~ effective both currently and in the ~emote future. the goal of this study was to investigate the efficacy os t~eatment of b~onchial asti~ma patients by means os speleo-and artificial sp~ay therapy. speleotherapy t~eatment was conducted in the conditions os mic~oclimate os salt mine in solotvino hospital. a~tis sp~ay the-~apy was conducted by means os a self-made device. ou~ method is based on the p~inci-~ le os using the majo~ facto~ of speleo-he~apy -highly dispe~sed sp~ay s sodium chloride. the obtained ~esults ~e~e analyzed in five g~adations. at the end os the speleothe~apy improvement and considerable improvement was observed in , ~ os patients; inconsiderable improvement -in , ~ os patients. having evaluated the e~s os t~eatment using a~tis sp~ay therapy the indices a~e , h and , ~ ~espectively. remote ~esults of t~eatment a~e an important index os t~eatment, the ~esult os ~hich ~e~e studied by means s a ~uestionnaive-method. patients ~ho had been t~eated by speleothe~apy mo~e f~eguently ~e-po~ted a ~elapse in disease ust afte~ the course o~ t~eatment ( , h). ho~eve~, in a ]ate~ phase the ~emission ~ould last ]on-~e~ (s months in , ~ os patients, till one yea~ in ~ ~). in , ~ os patients who passed the co~se os a~tificial sp~ay therapy a ~elapse was ~egiste~ed immediately as the co~se os t~eatment. then thei~ condition stabilized ~hile in , ~ os patients a period os ~emission lasted s ha]s a yea~. , ~ of patients dida't ~epo~t a ~elapse of the disease du~in~ one yea~. evangelismos hospital, critical care department, athens, greece method#: mechanically ventilated patients ( copd, ards, other pulmonary diseases) were studied in two phases: ) during the acute phase of respiratory failure; ) during recovery - days later. we measured mip and monitored the pattern of breathing while the patients were breathing spontaneously through the respirator (pressure support mode with - cmh ) until either the point they were unable to sustain spontaneous breathing (sb) any longer (phase ) or for two hours when they could sustain sb indefinitely (phase ). subsequently the patients were sedated, paralyzed and mechanically ventilated. then we simulated the pattern of sb at the end of the sb trial by manipulating the variables of the ventilator and assessed respiratory mechanics b y the end-inspiratory and end-expiratory occlusion technique. . during recovery, a combination of reduced inspiratory load and increased venfilatory capability makes a patient previously unable to sustain sb to breathe spontaneously. . inspiratory load is reduced during recovery, mainly because both intrinsic peep and breathing frequency are diminished. obiectives: although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (bal) fluid (balf) of patients with the adult (acute) respiratory distress syndrome (ards), the pethogenesis of ards is largely unknown. leukemia inhibitory factor (lif), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated balf of patients from different patient groups. methods: lif was measured in balf by means of a specific and sensitive elisa (detection limit pg/ml)in balf (lavage of x ml in the right middle lobe). results: lif was not detected in the balf of healthy control patients and in only one ( pg/ml) out of patients at risk for ards (after cadiopulmonary bypass surgery) who underwent bal h after the end of the extracorporeal circulation. high and detectable levels were found in the unconcentrated balf of out of patients with full-blown ards ( + , mean + sem, range - pg/ml). there was a good correlation between the level of lif in the balf and a number of markers of inflammation: neutrophils/ml (r: . , p= . ), albumin ( r: . , p= . ) and protein level (r: . , p= . ). conclusions:the biological role of lif in these balfs is not readily explained by its currently known actions and it is unkwon whether lif contributes to or is a response to local tissue damage. our results indicate that this cytokine with lots of interesting _functions is a pert of the inflammatory cytokine cascade in ards. background and obiective : we recently demonstrated that cisapride -a new prokinetic drug -enhanced enteral feeding in a heter genoas group of ventilated icu patients by significantly accelerating their gastric clearance (crit care meal, ; : - ) . it remains unknown, however, whether certain subgroups of patients might benefit more from adding cisapfide to their enteral nutrition regimen than others. patients with chronic obstructive pulmonary disease (copd) might represent such a subgroup since their illness and its specific treatment put them at risk for gastric emptying disorders. design and setting : prospective, consecutive sample study in an adult medical intensive care unit in a university hospital. patients : mechanically ventilated and hemodynamically stable copd patients. interventions : gastric emptying was evaluated by bedside scintigraphy and expressed as the time at which % of a tcg~-labelled test meal was eliminated from the stomach (t / ). baseline data (do) were recorded after enteral nutrition reached to ml daily. scintigraphic measurements were repeated days after cisapride ( ml orally, q.i.d) had been added to this regimen (d ). patients were considered cisapride responders when gastric clearance improved by more than % from baseline. results : normal values for the test meal and for scintigraphic acquisitions obtained in the supine position were found to be + min. in healthy volunteers (crit care med, ; : - ) . five patients responded to cisapride (t / : + rain vs. + min at do and d , respectively) and five did not (t / : + min vs. _+ rain at do and d , respectively). in contrast with non-responders, all five responders had clinically significant maldigestion at baseline (excessive (> ml) gastric residues, vomiting (> times/day and abdominal distension) which disappeared in of them after the administration of cisapride. conclusion : copd patients who tolerate enteral nutrition well have basal gastric emptying times which are comparable with those of healthy volunteers and are not influenced by cisapride. however, cisapride treatment provides both scintigraphic and clinical improvement in those copd patients who exhibit clinically obvious gastric emptying disorders. cernv v., dostal p., zivny p., zabka l. dept. of anesth. and critical care, charles university, faculty hospital, i-irade~ kralove , czech republic objective: the aim of the study was to evaluate the effect of early entera nutrition started within hours of injury on the incidence of multiple orgar failure (mof) in trauma patients requiring vantilatory support. methods: after institutional approval patients were enrolled in the study enteral feeding was begun within hours of injury in trauma patients (en group) admitted to icu. nasuenteric tube was placed as soon as possible after admission into the distal duodenum under endoscopy. additional parenteral nutrition was used to meet patients energy and protein requirements. the control group (pn) consisted of patients fed during this period paretuerally. severity score apache ii, trauma score, cumulative balance of nitrogen (g), incidence of mof (three and more organs) and length of ventilatury support (days) were calculated. values are expressed as mean + sd. results: tab introduction : parenteral nutrition (pn) is an important aspect in the optimal treatment of patients on gastroenterology or intensive care. the aim of this bi-center study in patients has been to assess tolerence and efficacy of a new protein-lipid mixture for pn from a simple preparation. patients and m~hods : patients were selected in two hospitals (tenon and saint-lazare, paris) and were divided into two groups : group a (gastroenterology~ l short bowel syndrome) and group b (intensive care, surgical patients). all patients likely to require pig for a period of days (group a) or days (group b) were studied. the pn regimens administered were the following : combination with g of mct/lct fat emulsion end , g of nitrogen, in liter end glucose requirements were met by imfizsion of l liter of glucose - % via a "y " connection. lipid thus provided % of the non introgen calories. total daily calorie intake was to ] kced. this study monitored, before and at the end of infusions, the sennn albumin (alb), preaiburtun (prealb), triglycendes (tg), cholesterol (cs), and the serum ammotransferases (sgot and sgpt) end alkaline phosphatase (alp) activities. statistical significances were calculated using the wilcoxon-tost. introduction: many cu patients present a catabolic illness in response to inflammation and infection, characterized by a rapid loss in skeletal-muscle mass despite optimal nutritional support. growth hormone (gh) is responsible for a rise of lipolysis, enhancing the energetic balance, and of protein synthesis. recombinant human gh (rhgh) is nowaday available for clinical use, but its cost is very high. therefore, rhgh should only be prescribed to icu patients when its efficacy can reasonably be anticipated (ie. when the patients are catabolic or stressed, but in order to avoid overprescription for unstressed patients and for those who are overly catabolic). hence, we, as others, recently demonstrated that rhgh had no favorable effect in highly stressed icu patients. objective: to detect on a clinical basis, low (ls), mild (ms) and severe stress (ss) states in icu patients and validate this clinical judgement by objective metabolic mesurements, in order to select early those icu patients potentially able to benefit from rhgh therapy. methods: consecutive icu patients were prospectively stratified as ls, ms and ss by two experienced icu senior consultants (temperature; agitation; heart rate; arterial blood pressure; presence of an infection; respiratory rate; exogenous catecholamines). anabolic (insulin, igf- , gh) and catabolic (cortisol, ghicagon) hormones, and nitrogen balance were determined for each patient within hours after admission in the icu. metabolic and clinical data were then compared. the clinical stress states determined by icu physicians correlate with an objective metabolic assessment. therefore, the patients who will more likely benefit from adjuvant rhgh therapy can be detected simply and early. a prospective study on rhgh therapy in ms icu patients is in progress. berger mm md , chiolero r md , pannatier a phd , berger l , cayeux c , voirol p , hurni m md . surgical icu, pharmacy, and cardiac surgery, chu vaudois, ch-iotl lausanne, switzerland objective. nutrition of the compromised cardiac surgical patient is challenging. numerous factors influence the gastrointestinal (gi) absorption function, among which gut perfusion, which depends largely on the systemic hemodynamic status. patients in hemodynamic failure are prone to organ failure, and may benefit from an early jejunal feeding. the study was designed to assess the absorption function after cardiac surgery in patients with adequate and altered hemodynamic status, using paracetamol as tracer of gi absorption. methods. after cardiac surgery, patients, aged _+ years (mean_+sd) were assigned to groups (anaesthesia: fentanyl gg/kg + midazolam): group (n= ): reference group, with normal hemodynamic status, easy recovery. group ('n= ): patients in low output syndrome, cardiac index < . i/m on day (d ) after surgery, requiring prolonged intensive care, mechanical ventilation + nutritional support. paracetamol g, was given intragastrically on d + d : plasma levels measured (h.p.l.c), at administration (to), t - - - - - and rain. hemodynamic status assessed with pulmonary artery catheter. healthy subjects served as controls. results. compared to healthy controls, absorption was strongly reduced on d in all patients (no difference between groups). on d , peak paracetamol level was significantly lower in group (low cardiac output): in group the area under the curve on d and d were similar. there was a large inter-patient variability, reflecting the hemodynamic status. conclusion. gi absorption was decreased on d in all patients, and reverted to normal between d and d in case of normal cardiac function, but not in case of low output syndrome. the decrease on d can be attributed to fentanyl, known to slow down the gi transit. in patients with cardiac failure, correction of altered absorption was correlated with the hemodynamic status, suggesting that gi absorption is dependent on adequate splanchnic perfusion. the aim of the work was to define specific significance and evaluate efficiency of enteral component of infusion therapy in the intensive care of gastroenterotogic patients of surgical profile with pyo-septic complecations. there were used the methods of radial diagnostics and polyelectrography; the laboratory control on oxygen-transporting function, volumetric and hemodynamic state, changes in metabolic, hormonal and immunologic status was conducted. from january, [ till november, there was carried out the randomized study of patients with general purulent peritonitis; among them persons constituted the control group and -the main one. in the main g~oup the intestinal lavage, enterosorption, enteral introduction of nutrient solutions with gradual turn to enteral nutrition by equalized mixture "ovolaet" were started from the first hours after operation. the data obtained allowed to define the specifity of the program of artificial medical nutrition in the group of examined patients, based on necessity of individual selection of media for enteral introduction depending on the stages of intestinal insufficiency syndrome. it was shown that inclusion of enteral component into the program of infusion therapy during early periods stabilized circulation in the regime of moderate hyperdynamia, considerably decreases the deficiency of circulating blood volume, normalizes the values of oxygen transport, consumption an}d extraction, provides the optimal level of mycardial adaptive possibilities without tension of its compensatory functions and pulmonary circulation overload. due to combined application of parenteral and enteral nutrition the metabolic processes are shifted towards anabolism. this is supported by decrease to normal values in the contents of blood aggresive hormones (acth,hydrocortisone) and increase in somatotrophic hormone. the complete parenteral-andenteral nutrition influences positively on restoration of cellular and tumoral immunity, activates the factors of organism nonspecific protection and recovery from immunodepression, prevents the development of immunodeficiency. impact tm vs control. s atkinson, n maynard, r grover, e sieffert, r mason, m smithies, d bihari departments of surgery and intensive care, guy's hospital, london, u.k objectives: comparison of the effect of an immunonutrient enteral feed versus a control on the outcome of a mixed intensive care unit (icu) population. methods: admissions to this multidisciplinary adu)t icu thought likely to stay more than three days and with tube access to the gi tract ~r randomised to receive either impact tm, a feed with supplemental arginine, dietary nucleotides and omega- fatty acids, or an isocaloric and isonitrogenous control feed. study end points included mortality and icu stay. approval was obtained from the hospital ethics committee. rosults: patients were entered into the trial. the two groups were well matched for age, sex, and admission apache ii with an overall mean admission risk of death of . (std. dev. -+ . ). on an intention to treat basis, there was a no significant difference in icu mortality, icu stay or standardised mortality ratio (s.m.r.) between the two groups (see table) . similarly, there were no differences after stratification for patients receiving or more litres of feed. conclusion: there is no evidence of an effect of impact@, an enteral immunonutrient feed, on pre-determined end-points (icu mortality, icu stay or standardised mortality ratio) in a mixed intensive care unit population over that of an isocaloric, isonitrogenous control feed. objeeflves: evaluate changes of blood laatate levels according to patient medical status after cvvhd initj,~ion using dialysate solution containing lactate. method: review of medioal records of consecutive patients ~eated by cvvhd (dialysate solution hmnosol lg , hospal,uk, lactate concentration retool/l). date obtained hr before and - hrs at~er cvvhd initiation were analysed. results: all data are presented as mean + sem. in one patient, pre end post filter lactate levds were measured during standard cvvhd setting (blood flow ml/mlu, dialysate solution flow i /hr), and approximate daily lactate flux into the patient was calculated to be as high as mmol/d. lactate leveh measured after cvvhd initiation increased significenfly compared to baseline levels ( . + . axtd . + . ,respectively; p< . ,paired t-test). when patiente with increased basal lactete (~- ) were compared to paliente with normal basal values (n= ), no difference in laotete increase was fmmd (p= . , manova). patiente with severe liver dysfunction ( points in mop scomlg, n= ) had higher basal laotate levels than patiente with normal or slightly abnormal liver teste ( or point in mof scoring, n=ll), rite values being . + . and . + . , respectively (p< . , student t-test). increase in blood lactate did not differ between these two groups after cvvhd was stetted (p= . , manova). in pafiente with invasive hemedynamio mo~, no oorrelation batween changes in lactate levels and eitlm" changes in oxygen ddivery (t =o.ol; p--o. ) or oxygen consumption (reversed fie, k) (r -q).o ;p-- . ) were found after cvvhd initiation. conclusion: blood lactate increases on cvvhd with dialysate soh~on rich in lactate. this increase is predominantly caused by influx of lactate into the blood via the filter end does not seem to depend on the liver fimotion and/or oxygen metabolism changes. objectives: the study was designed in order to determine the effect on plasmatic proteins, of two types of aminoacids solutions of parenteral nutrition (pn) adapted to stress, having different concentration of branched chain aminoacids (bcaa), when applying to politraumatized critical patients. methods: a prospective study was performed using a randomized double blind design of polytraumafized patients, split in two groups of ten patients each, with mean ages of _+ an -+ years. due to their condition, all patients required p.n. for at least days. both groups were subjected to isocalorie and isonitrogenous solutions ( ci/kg/ day and . g of nitrogen/ks/day), varying only in the concentration of bcaa; solution a having a % concentration and solution b %. blood samples determinations during days , , , after the beginning of treatment with p.n. were total proteins., albumin, trandferrine, protein binding retinol; prealbumine and fibronectine. the anova test (one and two way) was used to compare the values between the two groups. results: the administration of solution a, showed statistically significant increases in the determinations of the values of protein binding retino] (p < . ) and prealbumin (p < . ). no significant increases were observed in the values of total protein, albumin, transferrine and fibronectin. solution b produced statistically significant increases only in the values of total proteins (p < . ). the remaining proteins did not changed from their control values during the whole period of pn administration. comparing both groups, no statistically significant differences were observed related to the type of diet. nevertheless, differences were found in total proteins, albumin, protein binding retinoi, fibronectin (p< . ) and prealbumin (p < . ) in relation to the time course of pn therapy. only the albumin values showed significant differences (p < . ) when considering the interaction of both the type of diet and the time course of pn. conclusions: . solutions of pn adapted to stress, can maintain the control values of slow turnover proteins and improve the values of rapid turnover proteins. . no significant differences on plasma proteins were found between the two solutions having % or % concentration of branched chain aminoaeids. &determination of rapid turnover proteins does not seems useful for discriminating different solutions of bcaa during pn. obiectives; the hormonal changes in the post-traumatic situation often leads to an elevated blood glucose and a negative nitrogen balance. to reduce the elevated glucose production by aminoacids the apprication of xylitol may be an alternative energy source. in a double-blind randomized study we investigated the effects of a xylitol/glucose solution (group a: aminoacids g/i; glucose/xylito g/ g/l) on metabolism and particularly on pancreatic and liver enzymes compared to a glucose based nutrition solution regimen (group b: aminoacids g/i; glucose g/i). methods: the clinical trial was carried out after the approval by the local ethical committee on patients with severe brain injury. there was no difference in body mass index bmi (group a: . +/- . kg/m and group b: . +/- . kg/m=), age, and sex. daily individual energy expenditure was measured by indirect calorimetry (deltetrac "~). nutrition was started - hours after trauma or surgery with carbohydrates and aminoacids. fat was added h after nutrition had started. to analyze the effects on pancreatic and liver enzymes we investigated the following parameters for days: blood gtucose, serum lipase, serum amylase, asat, alat, ~gt, ap, and serum cholinesterase (che). results: due to the daily indirect calorimetric measurements energy requirements were satisfied. there was no difference in blood glucose concentration and cumulative nitrogen balance between the two groups. neither were there any significant changes in asat, alat, ap, and che for days in both groups. serum tipase steadily rose to lull in group a and . lull in group b, respectively. conclusions: there was no measurable influence of either nutrition solution on liver enzymes. the xylitol/glucose nutrition regimen does not have any advantage over the glucose based nutrition solution concerning blood glucose level or nitrogen balance. the elevation of serum lipase to a -fold level in either group needs further investigation on trauma patients. the effects of fat emulsions in lung function, particularly in lungdamaged patients, have been attributed to alterations in pulmonary vascular tone caused by eicosanoid production modificatione. as the eicosanoid production may depend on the fatty acid profiles of the intravenous fat emulsion, haemodynamic, pulmonary gas exchange and plasma levels of prostanoids were investigated in acute respiratory distress syndrome (ards) patients, during different intravenous lipid emulsions (providing different prostanoid precursors). we studied in a randomized double-blind design groups (n= each) with ards. group i (lct) received a fat emulsion with long chain triglycerids (lct- %), group ii (mct) an emulsion containing a mixture of medium and long chain triglycerids (mct/lct / - %) and group iii placebo (control), during h ( mg/kg/min each). we measured before, at the end of h infusion, and h after the end of the infusion: lipaemia, arterial and venous blood gases, pulmonary and systemic haemodynamics, and plasmatic levels (arterial and in mixed venous sample) of eicosanoids (txb=, -keto pgf~,, and ltb ). at the end of the fat emulsion, groups (i and il) to , • to , • mmol/i), the paoz/fio z remained unchanged in the three groups; no changes in intrapulmonary shunt (qs/qt) were shown; neither in the mean pulmonary artery pressure. in contrast, only in the lct group: cardiac output and oxygen consumption increased significantly ( . % and %) (p< . ). eicosanoids were increased at baseline compared to reference values (p< , ). a decrease (p<o, l in the arterio-venous difference of the vasodilatador prostanoid ( -keto pgf~=) was shown in lct group. our results indicate that fat emulsions in ards patient do not influence pulmonary gas exchange, provided that the perfusion rate were keept at mg/kg/min. the present study was designed to evaluate the metabolic changes of a carbohydrate-based diet versus a fat-based diet on oxidation rate of substrates and energy muscle metabolism in patients with an acute exacerbation of chronic obstructive lung disease. patients were mechanically ventilated with a volume-cycled respirator. after an overnight fast, patients were randomnly treated with a continuous enteral feeding over a nasogastrie tube with a carbohydrate/fat ratio of / in group i (n= ) , and a carbohydrate/fat ratio of / in group i] (n = ) during consecutive days. indirect calorimetry was set at baseline and hours later the enteral feeding was started. muscular quadriceps biopsy was performed on baseline and on day of enteral feeding. urine was collected during hours and was used to measure h urea nitrogen production. the caloric intake was set according to the measured resting energy expenditure. respiratory gas exchange rate were measured using a computerized open-circuit indirect calorimeter. quadficeps femoral muscle samples were obtained by muscular biopsy after local anesthesia. analyses of glycogen, glucose -phosphate, lactate, phosphocreatine and adenosine triphosphate (atp) and enzymes (glycogen synthase and glycogen phosphorylase) were determined. after h of nutrition patients in group i showed an increase in carbohydrate oxidation (from . % to . %, p= . ), and in group ii a decrease in protein oxidation (from % to %, p= . ). after days of enteral feeding a tendency to increase in glycogen concentration (group i, p= . ; and group ii,p= . ) was observed. while patients in group i showed a tendency (p= . ) to decrease glycogen phosphorylase, patients in group ii maintained these enzymatic levels. the increased in glycogen was correlated in group li with degradation enzyme (p = . ). in group i, the pao /fio ratio increased after days of treatment (from . to . ; p= . ), but no changes in days of mechanically ventilation, length of stay in icu, or mortality rate was evidenced between groups. it is concluded that the oxidation rate of substrates used for energy production varies according to the caloric sources administered. with nutritional therapy muscle glycogen concentration increases in both diets, with different enzymatic influence. more studies are warranted to further assess the clinical implications of the different pathophysiologic behavior of the two diets. under certain experimental and human conditions (radiation and/or thermal injury) the gi mucosa is unable to perform this protective function and could play an important role in the pathophysiology of the syndrome of multiple organ failure (smof). the objective of the present multicenter study was to know the gi mucosal permeability in critically ill patients and the relationship with their outcome. the method used to assess the integrity of the gi mucosal barrier measured mucosal permeability to various hydrophilic compounds. specifically, we measured the urinary excretion ratio (uer) of two sugars (lactulose and mannitol) that had been previously administered through a nasogastric tube. urinary excretion rate was measured in healthy humans (control) and in patients admitted to the intensive care unit (icu) at days , and . the apache ii of the patients studied was _+ . there was an increase of uer in the critically ill patients compared with controls (o. _+ . vs . _+ . ) (p< . ). in contrast, no changes in uer between days , and were observed ( . -+ . . significant changes were also established in the different groups: major and minor surgery, general and epidural anaesthesia , transfused and non transfused patients except for iron and ferritin plasma levels which didn't change significantly in patients who had received blood. a positive significant correlation was established between crp and ferritin (r= . ) for patients under general anaesthesia, but not on epidural, regardless of the type of surgery. conclusions: iron and transferrin plasma levels fell acutely in surgical patients while ferritin and crp rose. transfusion implied an acute iron load.the established correlation between cpr and ferritin in patients on general anaesthesia suggests that ferritin behave as an acute phase reactant in that setting, while epidural anaesthesia may ameliorate the inflammatory response. objectives: to analize the effect of gastrointestinal complicacions (gic) related to the enteral nutrition (en) in the real volume of diet administered to icu adult patients. a prospective multicenter study was designed (comgine study) in wich en application, gic definition and his management were defined by collaborative consensus.patients treated with en in one month pedod were included. in each case, daily volume of diet prescribed (pv) and administered (av) was recorded and the volume ratio calculated (vr=pvxl /av). patients were divided for days of en according to the presence (group ) or absence (group ) of gic (abdominal distension, increase of gastdc residuals,vomits or regurgitation, diarrhea,constipation and bronchoaspiration). differences between groups were analized by anova and mann-whitney u test with p< . for statistical significance. (vr%) group (vr%) tolerance to the enteral nutrition (en) has been related to the severity of illness in icu patients. the aim of this study was to evaluate this relationship. methods. a prospective, multicenter, study was performed (comgine study) in wich en application and related gastrointestinal complications (gic) were defined by collaborative consensus. adult icu patients treated with en in one month pedod were included. gic were classified as: ) abdominal distension (abd), ) increase of gastdc residuals (igr), ) vomits (vom), ) diet regurgitation (reg), ) diarrhea (dia) and ) constipation (con). patients were divided in two groups: group a: patients with gic dudng their evolution. group b: patients without gic. differences between groups were analized for apache ii admission score or evolutive variables ( carbon dioxide production is a major determent of work of breathing. increase in co production during nutritional support may precipitate ventilatory failure and difficulty in weaning from mechanical ventilation. in the present study, co output was calculated while passive mechanically ventilated patient were fed with different amount of calories and different proportion of protein, carbohydrate and fat. four clinical stable and mechanically ventilated patients were studied. carbon dioxide was calculated while patients were paralyzed, sedated and mechanically ventilated. six nutritional regimens were used: a) no calories, b) t gr glucose/ h, c) calories equal to rest energy expenditure in special formula with low carbohydrates and high fat (pulmocare) d) calories equal to rest energy expenditure in standard formula (nutdson) e) calories double to rest energy expenditure in standard formula (nutrison) and f) calories equal to rest energy expenditure parenterel (tpn). carbon dioxide output was low while no calories and/or only gr/ h glucose was provided, the mean values of vco output were _+_ and !-_ ml/min respectively. there was no difference in vco output between with low carbohydrates and high fat regimen and standard regimen, mean values were t . -+ and _+ respectively.the high calories regimen and tpn resulted in higher vco output, mean values _+ and • respectively. we conclude that the special with low carbohydrates and high fat regimen did not reduce vco output, in the contrary, high calories intake as well as tpn increased vco output under tested conditions. klouche k., cristol j.p., vela c., canaud b., b raud j.j. m tabolic intensive care unit and nephrology department. lapeyronie hospital. montpeuier france. predictive factors for rhabdomyolysis (rh) -induced acute renal failure (arf) were studied in a retrospective study from january to january . patients (pts) (male: , female:lo; mean age: + y.o.) were admitted with rh defined as cpk> iu/ . etiologies were: traumatic and ischaemic , infectious , toxic , excess activity . factors studied were: simplified acute physiologic score (saps: . + . ), organ systemic failure (osf: . _-!- . ), diagnosis delay (d: +_ h), clinical parameters (sepsis, dehydration), blood chemistry data (cpk, bun, creatinine, potassium, phosphorus, calcium, proteins, hematocrit) and urinary ph. severity of rh was estimated by ward score determined according to phosphorus, albumin, potassium, cpk, dehydration and sepsis. urea appearance rate (uar) and creatinine index (ci*) were determined over a hours period. arf was observed in pts. in non-arf and arf groups respectively, saps ( . _+ . vs . + . ), deshydratation ( vs ), sepsis ( vs ), phosphorus ( . + . vs . -+ . ), calcium ( . + . vs . _+ . ), ward score ( _+ . vs . + . ) were significantly different. however, no significance was observed in uar ( -+ vs -+ ) and ci ( _+ vs _+ ). patients required hemodialysis (hd) ( : sessions) and remained dialysis free. only osf ( . _+ . vs . -+ . ), ward score ( . _-/- . vs . _+ . ) and ci ( +_ vs -+ ) appeared significantly higher in pts requiring hd. pts died from associated disease. all patients suffering from arf recovered a normal renal function. we confwmed that an elevated ward score (over ) is a good predictive index of arf. in addition we found that ci is a severity factor for arf requiring hd. thus, patients suffering for rh with elevated ward score and ci, have a fair chance of dialysis and should be treated more intensively. * ci (expressed in mg/kg) = (car + feces creatinine) / weight. where car: creatinine appearance rate; feces cr~t..= mean plasmatic creatinine x . . tr~er k., cetin t.e., tugtekin i., georgieff m., ensinger h. universit~tsklinik flir an~sthesiologie, uim, germany introduction: endogenous as well as exogenous adrenergic agonists have a profound effect on carbohydrate metabolism in human critical illness. in this study the effects of noradrenaline (nor) and dobutamine (dob) on carbohydrate metabolism during a hr infusion were investigated. methods: after approval by the local ethic committee healthy volunteers were studied. hepatic glucose production (hgp [mg/kg/min]), using , -d glucose as stable isotope tracer, as well as plasma concentrations of glucose (glc [mmol/i]) and lactate (lac [mmol/i]) were measured prior and during infusion of nor ( . pg/kg/min) and dob ( pg/kg/min). blood samples were drawn before and during the agonist infusion. results: no major changes in insulin and gtucagon plasma concentrations could be found during the study period. ::i:::: :iiiii~ ~ i ::i: ~:: : :: i:ii. mean-+sd are shown. # p< . , anova for repeated measurments. conclusions: the effect of nor on hgp and glc were smaller as compared to adrenaline (i) with a similar time course. in contrast to the effects of adrenaline and nor, dob had a different effect on carbohydrate metabolism: a decrease in hcp and glc, which is uncommon for a / -adrenoceptor agonist. since hgp is an energy consuming process that might deteriorate hepatic oxygen balance in critical illness, the differential effects of adrenergic agonists may be of importance and need further clarification. the nutritional insufficiency often accompanies post-operative hypercaloric states, inanition, serious infections and weakening chronic illnesses. that is why the early nutritional support, sufficient and appropriate for each individual base, is a fundamental component of intensive care unit as an indispensable factor for recovery. per this reason, our unit, developed a software for the implementation and nutritional control of t~e assisted patients. this software is incorporated is an expert system called ~i~su, designed and developed by the computational division of our unit. this system arrives to inferred diagnoses such as : respiratory, hepatic, renal(with and without dialysis) dysfunctions, pancreatitis, ards, decrease of consciousness, diabetes. according to these data objectives: to compare the effect of short term enteral feeding versus parenteral nutrition, when a isonitrogenous and isocaloric feeding solution is administered by either mute. methods: in a prospective controlled clinical trial patients were studied; all exhibited moderate degree of malnutrition, normal liver and kidneys, and a functi ning gastrointestinal tract. the patients were randomized to receive a free amino acid and small peptide diet ( patients) or an isonitrogenous isocaloric parenteral support (tpn) ( patients) (total energy: kcal, nitrogen: . g, carbohydrates: g, fat: g, n/non protein calories: / ) at least for days. results: there were no significant changes in anthropometric parameters within either group. nitrogen equilibrium was aqhieved by day in the tpn group and by day in the enteral group ( . % of the enterally fed patients and % of the tpn patients maintained in positive balance the day of the study). there were no significant changes in serum albumin within either group. serum level of transferrin reached a significant increase in both groups (p= . ). thyroxine-binding prealbnmin rose significantly in both groups as well (p= . and . respectively). statistically significant rises in lymphocyte counts (p= . and . respectively), in levels of c (p= . and . ) respectively), iga (p= . ), igg (p= . and . respectively) and igm (p= . ) occurred in either treatment group. there was a high incidence of negative skin tests at the start of the study in the enteral group ( . %) and the tpn group ( %). by the end of the study the incidence of negative responsiveness was . % and . % respectively. despite maintenance of similar glucose levels in both groups, tpn led to significantly higher serum insulin levels. the serum insulin increased almost linearly over the study period and eventually prevented fat mobilization and lipolysis, so that free fatty acid levels had fallen significantly. a significant elevation of the liver enzymes over the study period occurred in . % of the tpn group, but not in the enterany fed patients. conclusions: the present findings provide no evidence that enteral diets containing free amino acids and small peptides, as their nitrogen sources, are in any way inferior to isonitrogenous isoealoric regimes parenterally given. aim: the aim of this study is to describe and explore the expectations of the functions of the critical care nurse to enable the formulation of guidelines for the scope of practice for the critical care nurse with a south african context, methods: phase i was to determine the expectations of the critical care nurse, the nursing service managers and the doctors with regard to the functions of the critical care nurse. a focus group interview was held with a group of experts in the field of critical care. the results were used to compile a questionnaire. this questionnaire was sent to the critical care nurses, the nursing service managers and the doctors in south africa for completion. from these results the functions of the critical care nurse were determined. phase ii was to formulate guidelines for the scope of practice for the critical care nurse within a south african context. through usage of the date (phase i) the scope of practice was formulated. guidelines were formulated for the practise, education and research regarding the limitations of the professional-ethical authoration and the implementation of the scope of practice for the critical care nurse. objectives : high output gastric aspirates arc occasionally observed during fasting in critically ill paticnts, preventing any attempt of feeding via the enteral route. although these patients are often said to suffer from "gastroparesia", the motor correlates of this condition arc lurgcly unknown. in this stud?', wc recorded the gastrointestinal motility of critically ill patients with abundant (> ml/ hours) fasting gastric aspirates. methods : antral ( sites separated each other from . cm), duodenal ( site) and jejunal ( site) contractions were recorded simultaneously by ~eans of a multihimen tube assembly positioned trader fluoroscopic control (perfused catheter technique). tracings from prolonged recordings were obtained on a multichannel recorder ( a recorder, hewlett-packard) then anal) ,ed visually, with a special attention for the following abnormalities which are characteristic of intcstinal pseudoobstmctiou: l) absence or aberrant propagation of the migrating motor complex (mmc), ) presence of bursts (> min) of nonpropagated phasic pressure and ) presence of sustained (> min) uncnardinate pressure activity. patients with a volume of gastric aspirates of • (sd) [median ml/ hrs were investigated for - [median minutes. results : only one patient had no detectable motor abnormality. mmcs were either absent (n= ) or migrated abnormally (retrograde propagation : n= ; retrograde and stationnary : n= ) in pts. bursts of nonpropagated phasic pressure activity were present in the duodenum in pts and sustained uncoordinate pressure activity was found in pts. additional abnormalities included episodes of prominent pyloric activity. (n=l) and sustained antral pressure activity (n= }. conclusion : critically ill patients with large volume of gastric aspirates have manometric evidence of intestinal pseudoobstruction. prokinetic therapy in these patients should thus focus not only on enhancing gastric motility, but also on restoring a normal propagative contractile activity in the intestine. this prospective, open-label, randomized placebo-controlled study included patients with hypokalemia in whom rapid potassium replacement ( meq kci in h) was performed: patients received mg sulfate ( g in hours) and patients received a corresponding saline infusion. measurements were made at time , + , + and + hours results: k levels increased more in mg treated patients than in the patients who received saline infusion at time and h (p < . -students-newman-keuls). (table ). introduction. dual lumen uaso-gastrojcjunal tubes are a major ads'ance in nutritional therapy of mechanically ventilated critically ill patients since the " authorizc jejunal feeding with concurrent gastric decompression, there,, reducing the risk for aspiration. unfortunately, placcmem of these tubes in the jejunum regularly dictates to resort to endoscopy in order to facilitate pyloric intubation. recently, the remarkable gastrokinetic properties of the well known macrolide antibiotic er}lhromycin have been demonstrated in gastroparetic critically ill patients . aim. in the presem stu~,, we evaluated the feasibility of placing dual lumen naso-gastrojcjunal feeding tubes at the bedside without endoscopy, using edthromycin to help iranspy'loric migration of the tube under fluoroscopic control. methnd each patient admitted in our icu during a months period and requiring artificial ventilation and enteral nutrition for a period of at least days was included in the study.. after inserting the tube (stayput| sandoz, usa) in the gastric anmnn, e.rythromycin ( rag) was aduunistored intravenously, to help fluoroscopic positioning of the tube into the jejunum. the total duration of the procedure (from nasal intabatiun to jejunal placement), as well as the duration of ftuoroscopy were recorded in each patient. results. patients (male/female : / : mean age : . + . years; mean apacbell score : .t • . ) wore enrolled into the study.the procedure was performed within the dab,s following institution of mechanical ventilation. jejunal access was obtained in all patients without resort to enduscopy in , • . min.(total duration of the procedure). mean duration of fluoroscopy was . + . rain. conclusion. we conclude that placement of dual lmnen naso-gastrojejunal tubes can be obtained in mechanically ventilated critically ill patients without resort to endoscopy., provided that e rythromycin is used as gastrokinetic agent to help pyloric intubation. the following ad and dis parameters were considered in all patients: -mid arm circumference, triceps skinfold thickness, serum transferrin, albumine and lymphoeites and urinary creatinine/height index. patients whose results were bellow % of normal values in or more of the above criteria were considered undernourished (und).statistical analysis was performed using % analysis.statistical significance was established at p<o.o . results: a total of patients( female, male) -with a mortality rate (~) of , % -were studied, aged -+ years and a median ]enght of stay of days. -nourished (nou) at ad and at dis - ; ~ %; -nou at ad and und at dis - ; ) , % ; -und at ad and und at dis - ; ~ . %; -und at ad and nou at dis - ; ~ , %. we observed a p< . when we compared groups and (p= . ), and groups and (p= . ). variation in nutritional status and longht of stay: -nou at ad and nou at dis = > median lenght of stay days; und at ad and und at dis = > median lengbt of stay days; nutritional status and age at admission: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) nutritional status and age at discharge: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) we observed a p<o. when we compared groups and (p=o. ) and groups and (p = . ) conclusion: such study permits to conclude that most of our patients ( . %), staying in icu for more than days, were und, namely the elder. we observed that this kind ef patient had a longer median length of stay in icu, associated with higher mortality rate. in conclusion, the nutritional management is an essential element in suportive care of critical)y ill patients. ohiectives: sirs is associated with hypercataholisnl and resistance to nutritional support, despite raised circu&ting levels of growth hormone and insulin. serum igf- levels however are low; thercti~re rhigf-i administration might produce nsefnl anabolic effects. the pharmacokinetics of exogenously administration rhlge-i in such patients are likely to differ from that seen in the less seriously ill due to changes in circulating blood volume, increased capillary permeability, poor nutritional stares, and alterations in binding proteins. the ol jective of this study was to determine the clearance, apparent vohnne (if distribution (vd), time to peak concentration (tmax) and elimination half-like (tia) of a single subctkaneous il~ieetion of rhlgf-i in patients with sirs on the intensive care unit (icu). methods: icu patients with sirs were entered into the study, which had been approved by the ethics comjnittee. in each patient baseline hlood samples for circulating gf-i were obtained over a hour period, prior to il!iection of p.g/kg of rhlgf- subcutaneously. a further l samples were taken fi'om each subject over the next hours. circulating ige-i was measured in serum at each time point by radioimmtme assay, and the area under the curve tbllowing administration of rhlgf-i was derived tbr individual patients fixm~ baseline a~!justed igf-i levels. clearance values were caietdated by dividing the administered dose of rh[ge-[ by the total area under the etnve. vd and tv were calculated by regression analysis of the terminal part nf the log sertnn concentration time profiles. results: results are expressed as median (range). age ( - ) years, apache ii score ( - ), and length of icu stay ( - ) days. baseiine circulating igf- levels were low ( < - ) ng/ml reaching a peak of only ( < - ) ng/ml. of the patients had basal levels predmnhaantly below the inwel-limit of detection of the assay, and showed no appreciable rise in serum igf-[ levels tbllowing rhigf-i injection. parmacokinetic variables could not therefi)re be determined in these two patients. following rhlgf-i injection in the remaining patients tmax was at ( - ) hours, clearance was ( - ) ml/min, vd was . ( . - . ) l/kg, and tia . ( . - . ) honrs. conchlsions: there was marked patient wu-iability in response to rhlgf-i administration. vd was similar to that seen in poshq~erative maior surgery patients ( . vs . l/kg), but clearance was greater ( vs ml/min), tmax earlier ( vs hours) and t~a shorter ( . vs i . homts). if riaigp-i is to be administered to dtically ill patients the dose should he nlodified m the light of these findings. baekgronnd: acute bacterial endoearditis continues to be a condition with high morbidity and mortality. the majority of patients are treated with high dose antibiotics, but a patient group requires surgical treatment. methods and results: from january to march , patients underwent surgery for acute bacterial endocarditis: had native valve endocarditis and had prosthetic valve endocarditis. there were men and women. streptococcus viridans was the predominant infecting agent in native ~alve endocarditis and staphylococcus epidermidis in prosthetic valve endocarditis. progressive congestive failure, uncontrolled sepsis and peripheral emboli were the most common indication for surgery. although the mitral valve is more commonly involved in acute bacterial endocarditis, the aortic valve most often requires surgical inlervetion. the postoperative bleeding in the no-aprotinin group was + cc and in the aprotinin was :t: (p < , ). the mortality in icu was , %, the staphyloccocical endoearditis mortality was , % and the no-staphyloccocical endocarditis mortality was , % (p< , ). conclusions: the early surgery is indicated if endocarditis has no response with medical treatment. the mortality of staphyloceocical endoearditis involving left valves was higher than caused by other infecting agents. aprotinin treatment improved prosta#andin metabolism and preserved pletelet function during open heart surgery and could be useful in this type of interventions. urgent surgery had a high mortality ( %). selective digestive decontamination (sdd) has increasingly become the subject of critical discussion sine~ the development of multiresistant organisms has become an issue. moreover, a selection of gram-positive pathogens must also be taken into account when using the sdd regimen, which is primarily directed at the gramnegative bacterial specumn, with the methicillin-resistant staphylococcus aureus strains (mrsa) being of particular importance. the objective of our study was to determine the extent to which colonization with mrsa strains is promoted by sdd. method: patients (ventilation period > days) were randomized and allocated to the sdd group (n= ) or the control group (n= ). in their general intensive care theraw, there were no differences between the groups. the sdd regimen consisted of the four times daily administration of rag polymi~ mg tobramycin and mg amphotericin b in the nesc, mnoth and stomach. systemic prophylactic ~dmini~/rution of antibiotics was not part of the sdd regimen. smears were taken from the nose and the rectum twice wceldy and from the pharynx and trachea once wceldy, and tested for mrsa. further samples were taken as clinically reqnircr results: smears were examined in the sdd group. mrsa strains were detected in samples ( . %) from patients, and in patients they were detected for a period of up to weeks. the positive smears were districted as follows: tracheal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal ( . %). severe mrsa-induced infections were observed in patients (infection rate . % of the colonized sdd patients). smears were examined in the control group. ivlrsa swains were r in samples ( . %) from patients, but only repeatedly over a period of up to days in patients. the po~tive snmars were distributed as follows: traclmal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal / ( . %). there were no mrsa infections in the control group. conclusion: the data collected support the view that the use of sdd promotes a selection and persistence of mrsa strains. longer-term colonization with mrsa and sovere systemic inf~ons were only found in the sdd group. although the clinical and epidemiological impact of resistance develol~ng when sdd is applied ~maine unclear, this question should be given close scrutiny. tazobactam/piperacillin (taz/p p) is a new broad spectrum antibiotic, in which the acylaminopenicillin piperaeillin is protected by the betatactamase inhibitor tazobactam from hydrolization by bacterial enzymes. taz/pip has shown to possess a high antibacterial activity against almost all clinically relevant bacteria and is a registered drug in germany. obiectives: purpose of this investigation was to evaluate, whether faz/pip . g is suited for efficient antibacterial monotherapy of severe infections and what influence dosage frequency reveals on clinical efficacy. methods: hospitalized patients have been documented in this multicenter trial during a year period. as this investigation should reflect the usual clinical treatment, the only criteria for enrolment were the typical signs of infection as e.g. temperature > ~ leucocytosis or an isolated pathogen. exclusion criteria did not exist and the patients were treated in accordance to the severeness of infection, underlying diseases, risk factors etc. with taz/pip . g t.i.d, or b.i.d. results: patients suffered in most cases from infections of the lower respiratory tract (n= ), followed by intraabdominal (n= ) and skin and soft tissue infections (n= ). % of the lrtis wvre nosocomial acquired and in % the treatment was conducted as monotherapy. in % the lrti was treated with taz/pip b.i.d, and in % t.i.d. pseudomonas spp. (n= ) and staph..aureus (n= ) were the most isolated pathogens pretrcatment. the clinical response rates (cured/improved) after treatment with taz/pip . g b.i.d, and t.i.d, were % and % respectively. results for intraabdominal-and skin and soft tissue infections will be presented. conclusions: in hospitalized patients with severe infections successful treatment with taz/pip in monotherapy is possible. in this population a reduction of the dosage frequency to . g b.i.d, revealed equivalent clinical response rates. objectives. retrospective evaluation of cases of severe generalized tetanus (sgt), treated in our icu the last years. we review cases of sgt ( m, f), mean age . years. in eases the entry site of c.tetanus was a skin laceration, in case it proved to be the external genitalia, while in the rest no portal of entry could be determined. in the first cases incubation period was short ( - days) and so was the period of onset ( - days). all patients needed mechanical ventilation (range - days), initally through an orotracheal tube,and later through a tracheostomy, performed • days after admission. clinical manifestations of sgt included muscle rigidity and i generalized spasms, persisting for up to weeks in the most severe cases. significant autonomic nervous system dysfunction was present in cases occurring - days after the admission and following the time course of generalized spasm. besides general supportive measures, specific treatment included passive +active immunization, penicillin g, magnesium sulphate and sedation in a variety of regimens. neuromuscular blockade was required in cases. nosocomial infections occurred in eases, with sepsis and mof in one. average stay in the icu was - days. one patient died with severe septic complications and one was discharged with severe disability due to anoxaemie ancephalopathy, after a cardiac arrest on admission. ~ disinfectant in suspension test, without presence of organic load, disinfectants showed efficacy on lm. in the carrier test, in the presence of organic load, out of examined disinfectants did not exposed efficacy on lm. the results of examinations clearly showed that evaluation of disinfectant's efficacy partly depend on the used test method. antun basi , intensive care unit, kb firule split spin~ideva ! jugoslavia bacteremia and sepsis are frequent complications encouuntered in severe icu patients.microorganism identification with hemoculture presents the basis for adequate and successful antibiotic treatment.in many patients damage and vulnerability of the peripheral veins presents an obstacle for obtaining the blood culture from the central venous (cv) catheter sample could be also used. material and methods blood cultures were perfomed in lo patients on blood samples simultaneously obtained from the peripheral vein and cv catheter three times in a -hour period.criteria for the suspected bacteremia were body temperature above c and leucocytosis above ioooo leucocytes/dl. the site for venipuncture and the cv catheter stopcock port were cleansed with povidon iodine.after the initial ml of blood were discarded,lo ml were used for the blood culture.standard laboratory technique for blood cultures was used. results and discussion in ( %) patients hemocultures was negative at both sites,whereas in the remaining ( %) they were positive.for twentyone ( ~ of the positive patients the same results were obtained at both sites (peripheral vein and cv catheter),whereas in ( . %) patients the blood culture were positive only for the cv catheter samples.the cv catheters were in place for less than days in patients and for more than days in patients.from patients with positive blood culture from the cv catheter,one patient had the catheter for three days,whereas the other had the catheter from - o days. we neither found significant differences in hemodynamic dates : objectives: , to count and evaluate bacteria isolated from endotracheal (et) suctiori samples (with and without saline). . to establish the exogenous source(s) of pathogens isolated from carer's hands and the equipment involved in sampling in order to reduce the incidence of contamination and infection. method~: this prospective study included consecutive ventilated patients ( male and female, _ + yr; apache ii score -+ ) over a period of months. et aspirated samples with and without saline were taken daily from day of intubation until pathogen~ were presented in counts of _> per ml. at the same time, samples from both carer's hands were taken before and after et suction and a swab from the ventilator tube. results: the overall length of intubation varied between to days. bacterial transfer between staff and patients was noted in % of patients until day of intubation. there was no significant correlation between severity score and appearance of colonization. the incidence of pneumonia in studied patients was % with an overall mortality rate of %. acinetobacter anitratas (no ), staphylococcus aureus (no. ), klebsiella pna~moniae (no. ) and pscudomonas aeruginosa (no. ) isolates predominated in all our specimens. we noticed increased resistance to most antibiotics with the exception of imipenem for gram (-) bacteria and vancornycin for gram (+) bacteria. conclusions: i. tracheobronchial colonization appears directly in the maiority of intubated patients. . there is a close relationship between the microflora of personnel, patients and equipment. . bacteria transfer was noted both to and from patients. . strict hand disinfection policy remains an important measure for the proper care of mechanically ventilated patients to reduce respiratory infections. nnseeomial pneumonia is the most common nnsocomiai infection in the icu-settiag, reported in up to % of patients admitted to the icu following surgery. it is associated with significant mortality that ranges from ~ to %. enteric gram-negative bacilli have been implicated in % to % of ventilntor-associated pneumonias and pseudomonas aeruginosa accounts for % to % of these pneumonias. importantly, epidemics of/ - actamnse-pruducing enterobacter spp or klebsiella spp that are resistant to extended spectrum cephalosporins or penicillins, pose serious obstacles to effective antibiotic choices. carbapenems provide in ~tro activity against a wide range of enterobacteriaceaeand other gramnegative aerobic bacteria, except steaotrophomonns maltophilia. in vitro meropcnem is more active against pseudomonas spp than imipanem (especially p. aeruginosa and p. cepacia), imipenem and meropenem are effective against more than % of strains responsible for nnsocomial infections. all major pathogens associated with lrti are usually covered by the carbapenems, exceptions are pathogens involved in so-called atypical pneuomouia like mycoplasma, chlamydia and legionella. carbapenems are highly stable in the presence of most chromsomal and plasmid-mediated blactumases and usually offer a postantibiotie effect lasting for three hours against most of the enterubacteriaceae. reeent studies comparing imipenem/cilastatin with other ~-lactams and fluoroquinolones in severe lrti in icu patients resulted in favourable clinical cure rates and good tolerance, but development of resistance in p. aeruginosa and ;. aureus during treatment were of some concern. meropenem offers the advantage of greater stability against enzymatic degradation, so no concomitant administration of an enzyme inhibitor is necessary, and meropenem appears to be associated with a lower risk of seizures, particularly when used at high doses. results from studies with meropenem in lrti, especially in critically ill patients with acute exacerbations of chronic bronchitis, demonstrated excellent cure rates and better gastrointestinal tolerance of this new carbapenem. both earbapenems are effective candidates for use as empiric monotherapy in nosucominl infections of critically ill patients. qbl~ctives a favourable effect of iv immunoglobulins in septic surgical patients has been reported, but not sufficiently validated. we conducted this study on trauma patients to: i) investigate the effect of ivig on septic complications and il) quantify this effect by means of serum bactericidai activity (sba) assessment and iii) to explore the effect of temperature increase (from to ~ c) on the sba methods: twenty trauma patierits matched on admission for age, sex, inju~ severity score and glasgow coma scale, were allocated to receive either wig (ivig group; i patients) or equal volumes of human albumin % (control group; patients). wig (sandoglobulin) was administered in a total dose of g/kg divided in a four time regimen on days , , and post-admission. three blood collections were performe& before the first dose (day ) and hours after the third and the fourth dose (days and respectively). complement, lgg fractions, the sba at ~ and at o c and clinical parameters were recorded. results-similar lgg and igg] serum levels were found in groups ivig and control on day ( +_ vs • ns and + vs + , ns), whereas they were significantly higher (p< ) in the v g group on days ( _+_ vs + , p< ) and ( _+ vs +i , p< . ). the various complement-fractions increased in both groups without inter-group differences the mean (• sbas ( ~ c) at rain in ivig group vs control group were: - _+ vs - • ns for day , _+ vs - _+ p< for day and _+ vs - + p< for day . the mean (+sd) sbas ( ~ c) at rain presented a significant improvement over those of ~ c but for the control group remained negative a~d were respectively as following: -~ • vs - + , ns for day , +_ vs - _+ , p< . for day and _+ vs - _+ , p< . for day . the increase of temperature induced a -fold improvement of sba in iv g group and -fold ofcontrol-~oup positive blood cultures, and the product of the infectious episodes number multiplied by days of occurence, were significantly lower (p< ) in the ivig group than in the control ( vs , and vs , respectively). conclusions: our study shows a significantly favourable effect of ivig administration on septic complications and on sba of trauma patients. the increase of temperature results in a significant improvement of sba of patients that received ivig, which theoretically means a farther prevention of infection in the febrile state. pharmaceutical microbiology, university of bonn, meckanheimer aune , d- bonn, germany infectious diseases in intensive care patients are common in comparison to patients on other wards and out-patients. the main difference is that intensive care patients are much more sensitive even to less virulent bacteria. thus, the spectrum of infecting organisms is different. strains often regarded as pathogens with low virulence cause serious infections in these patients. strains such as serratia, however, have intrinsic resistance to most commonly used agents such as rd generation eephalosporins. furthermore, the common pathogens like staphylococci, psoudomonas aeruginosu, enterocneei and gram-negative bacteria, enterobacteriaeceae as well as the non-fermenters are less sensitive if isolated from intensive care patients. it is difficult to generalize on intensive care units as different patient groups are in different icus aud there are great changes from one hospital to another and from one country to another. if we take s. aurens strains from one study from the'overall resistance in intensive care units towards oftoxacin was %, whereas in other hospital wards the percentage of resistance was . %, in out-patients, however, only .$ %. the same trend was true for entercnecus faecnlis, coagulase-negntive staphylococci, and other bacteria as well as other drugs. one most striking difference was found with klebsialla pneumoniae and gantamycin resistance, which was $ times higher in intensive care units as compared with outpatients, whereas in the same species no difference was to be seen with the resistance towards carbapenems. however, differences between countries seem to be even more striking, as example gantamycin resistance and staph. anrens is given. the extreme difference is more than fold. thus, it is evident that there is a general trend towards higher resistance in intensive care units, but no generalizatiouis possible. therefore, surveillance studies in intensive care units are needed and the antibiotic policy has to be adapted to the specific needs of the unit. in the icu setting the most potent antimicrobial agents are required to address problem organisms including those resistant to penicillins, cephalosporins and aminoglycosides. carbapanems would appear to present a useful option in this setting. objectives of this study was the evaluation of systemic candid• in postoperative cardiac surgery patients (pts) with prolonged icu stay. methods: out of postoperative adults pts of mean age . + . years old, with a mean icu stay of . _+ . days, following an open heart surgery from july to april , pts ( %) remained in icu for more than days because of severe perioperative complications. patients were included in the protocol if they had clinical signs of infection or sepsis, and fungi isolated in blood culture or in culture from at least three different sites. the patients who developed systemic candidiasis received iv fluconazole ( mg/day) ( patients) or amphotericin-b for at least four weeks, and then they were closely monitored. results: out of postoperative pts with prolonged jcu stay, pts ( . %) developed systemic candid• usually after the th postoperative day. they were males and females of mean age +_ . years old. this group of pts had prolonged bypass and aortic cross-clamp time compared to control group ( min vs , and vs min). all these pts received inotropes per• (mean value= . ). during their icu stay, pts developed sepsis of bacterial origin, while the other two severe infection, and received antibiotic regimens for prolonged period. the patients were submitted to mechanical ventilation for a median period of days. the median icu and hospital stay was and days respectively. all pts have been improved and finally negative cultures were obtained. conclusions: . a significant percentage of patients who remained in the postoperative icu for more than days developed systemic candidiasis. . all patients who developed systemic candidiasis had received antibiotics because of sepsis or severe infection, for prolonged period. . fluconazole seems to be a very good alternative to amphotericin-b. . fluconazole is a safe antifungal agent with few side effects. botulism is the most severe and an odd food poisoning. although it is more commonly related to preserved meat derivatives, preserved fish and vegetables are also responsible for a number of cases. obiectives: to evaluate four familiar outbreaks of botulism . methods: we study the patients that were admitted in our hospital because of botulism from may to february . results: the thirteen pacients involved had a previous history of home preserved beans ingestion. after a -hours incubation period, gastrointestinal symptoms (abdominal pain, vomits, constipation) appeared and lead them to hospital consultation in the th to th day after ingestion. two patients died (acute respiratory failure before admission), seven were admitted in icu, two in ward and two of them were discharged from emergency room. clinical symptoms and the previous history of the ingestion established the diagnosis, that was emg confirmed. in all cases, symptoms were consistent with b-toxin botulism. b-toxin was isolated in serum and food proceeding from the third outbreak, and the serum was negative in the other ones. neurological symptoms were predominant: midriasis ( %), dry mouth ( %), dysfagia ( %), asthenia ( %), palpebral ptosis ( %), accomodation paralisis ( %) and urinary retention ( %). muscle weakness lead to acute respiratory failure in three patients (one of them required mechanical ventilation). four patiens developed infections (respiratory, urinary and phlebitis). both died patients and one another presented severe hypertension. all admitted patients were treated with polivalent anti-toxin. the two patients who underwent a more severe muscle weakness received also guanidine hydrochloride, with no answer in one case and provoquing a cholinergic crisis in the other one. icu length of stay was days. at hospital discharge, patients continued symptomatic, mainly with dry mouth, disfagia and impaired vision. conclusions: although botulism is a serious illness, the pronostic seems favorable if treatment and support measures are avaible. usually neurological symptoms we predominant and at discharge some of them could still persist. the arrow "hands-off" (aho) thermodilution catheter (tc) is completely shielded during balloon testing, preparation, and the insertion procedure. in order to assess the value of the aho thermodilution catheter in the prevention of systemic infections associated with pulmonary artery catheterization (siapa), we conducted a randomized prospective study over an -month period. methods : the patients (pts) were randomly assigned to two groups : group i for a standard tc customarily used in the department, versus group for the aho thermodilution catheter. the diagnosis of siapa was determined on the basis of a positive culture of tc and bacteremia with the same organism, with out any other nearby focus, in association with regression or disappearance of the clinical signs of infection after removal of the thermodilution catheter. results ( objectives: the mortality rate (mr) of tb requiring mechanical ventilation (mv) is high ( - %). the aim of the study was to evaluate mr, associated factors, and prognostic significance of mv and hemodynamic disorders from tb in icu in patients with tb. methods: clinical parameters on admission, and complications in icu were related by univariate analysis to icu, hospital, and month outcome. patients required mv; were immunocompromised (ic) including hiv. tb was pleuropulmonary in , disseminated in and meningeal in . results: mr was % in icu, % in hospital and % at month. / ( %) < . mortality was associated with a high saps score, initial shock, mv and nosocomial septicemia. the mr dramatically increased when ards occurred during illness, despite the lack of correlation between mr and initial po /fio ratio or initial murray score. the site of infection did not influence the mr. surprisingly, the mean therapy delay was shorter for non survivors. mr was not related to ic status, nor hivstatus, but was only related to previous steroid therapy. conclusion: mr of tb requiring icu is high ( % at month). need for mv increased mortality ( % vs %). general severity and respiratory dysfunction seem to be major prognostic factors in icu rather than tb per se or than therapy delay. in spite of the improvement in the prognosis of pneumococcal meningitis (pm) with third generation cephalosporins (tgc), this infection still presents a great mortality which could be increased with the appearance of antibiotic resistant streptococcus pneumoniae. objectives: to asses intensive care mortality and morbidity of pm and to define patients (pts) at risk of complicated evolution. patients and methods: a retrospective evaluation of pm cases (all diagnosed by csf culture) admitted in our icu from january tit march . in all pts we analized: demographic data, underlying disease, apache ii score, clinical symtomps, treatment, complications and outcome. statistical analysis was done using bmdp sofware package. results:a total f pts were studied, males; mean age , _+ ( - ); apache ii score , + , ; glasgow coma scale (gcs) at admission , _+ , ; ( %) pts suffer from cronic pathology; ( %) pts diabetes mellitus (dm), ( , %) pts had had a previous cranial traumatism. in cases the source of infection was otic and also in ( %) episodes of pm there were bacteriemia. in out of ( %) pts that ct was performed no radiologic abnormalities were shown, of them presented cerebral oedema and pts a cerebral abscess. twenty-eight percent presented seixures, % hemiparesia, , % respiratory failure, , % shock, i % renal failure, , % multiple organ failure (mof). as for treatment refers , % pts recieved only penicillin, , % pts only tcg, , % pts tcg followed by penicillin and , % pts tcg+vancomycin. seventy-five percelat of pts recieved corticosteroids and , % vasoaetive drugs. the mean icu stay was , : days ( - ). twelve ( , %) pts died, two of them presented pm relapse (resistant streptococcus pneumoniae) and another two pts developed neurological sequelae. factors associated statistically with bad prognosis were dm, the use of vasoactive drugs, shock, mof, the apache ii score at admission, the gcs at the and hours from admission in the icu but not the gcs at admission. didn't resulted statistiealy signifcative age, previous eronie pathology, seizures, baeteriemia, renal failure and coagulation disorders. conclusions: mortality was high and associated to apache ii score at admission, to gcs at and hours after admission, shock, vasoaetive drugs and mof. objectives:the aim of the study was to analyse some of significant immunologycai changes in surgical patients,requiring intensive health care,and to determinate the possibility for evaluation,dynamical examination and importance of immunologycal problems for treatment. methodes:the study concerns a number of patients with expanded surgical intervention or serious postoperative complications.the results has been carried out with fiowcytometryc analyses of lymphocytic suhpopulations and routins methods for investigation of humeral immunity.the"panel" for evaluation of (} immunologycal parameters has been offered:t-calls total/cd +/;t-helper/cd +/;t-supressor/cd +/ th/ts ratio;b-cells/cd +/;naturai kilier/nk/cells;skin test for cellular immune function;phagocytic and oxidative activity;serum levels of immunogiobulins-g ,a,m;protease inhibitors;c-reactive protein.all patients have been studied during suffering and after surgical procedures dynamicaly. results:there have been estimated significant changes in immunologycal parameters especially:decrease of t-cells: cd +mean= . %/ . %- . %/and cd +mean= . %/ % - . %/;inverted th/ts ratio ,mean=o. / . - , /;reduced or negative skin teste;reduced phagocytic and oxidative activity before septic complications. conclusions:dynamical examination of immunologycal parameters shows,that the prolonged t-total,t-helper lymphocytopenia with functional deficience of ceils-mediated immunity correlates with the stage of clinical condition of the patients and has prognostic importance.it's clear,that immunologycal monitoring gives a possibility for immunecorrection. patients (pts) with the human tmunodeficiency virus (hiv) infection have a decreased immune response and are particularly susceptible to infectious endocarditis (ie). the aim of our study was to analyze the prevalence of ie, its clinical and therapeutic implications in a hiv population we prospectively studied pts, . % ( / -group ie+) with ie during the clinical course of this disease. we analyzed the following parameters: age, gender, race, type of hiv, cdc classification, number of t and t type cell population and its ratio, therapeutic with azt, type and number of opportunist infections (inf, mycobacteriosis (mb), neoplasm's (nee) the echocardiographic parameters were lv internal diastolic and systolic diameters, lv percentage of fractional shortening, interventricular and posterior wall thickness, the degree of valvular regurgitations and the presence of pericardial effusion. el was located at the mv in . %, tv in . %, av in % and pv in . ~ and was multiple in . %. hiv el+ pts had larger lv diameters and more frequent significant valvular regurgitations ( % tr, pe %, mortality %). these two groups differed significantly in the following clinical parameters: the typical symptoms were watery diarrhea, high fever, tachycardia,luekocytopenia and oligouria within th postoperative days. the patients with mrsa enterocolitis had positive mrsa culture from the many materials except feces.mesa strains frequently had coagulase type ,enterotoxin a and toxic shock syndrome toxin- .eight of patients had postoperative organ failure.most of the mrsa strains in japan were similar in coagulase type to our hospital and our department.all of mesa strains were susceptible to vancomycin and arbekacin,tbough most of them showed resistant to many other antibiotics.we have employed guidelines for therapies such as oral or enteral administration of vancomycin and correction of the hemodynamics for dehydration and circulatory failure due to diarrhea from .futhermore we have placed colonized or infected patients in private room,worn gown and mask,and carefully washed our hands from . these countermeasures for prevention of nosocomial infections after significantly reduced the incidence of mrsa enterocolitis. conclusions:earlier diagnosis and treatment, and distric prophylactic measureres against mrsa infections are very important. -- cdo ivda leptespiresls affects all the organs with widespread hemorrhage that is more prominent in skin, mucosa, skeletat muscles, liver and kidneys. lung involvement is usually mild and less common. suli, it is very uncommon acute respiratory failure to be the pr sontirlg symptom. a case with leptosplrosl..,s which was presenting with acute respiratory failure is described. a year-old man admitted to icu becauso of fever, myaigla, aevere c~, hemopty~s. his blood gases showed: pao : mmhg with fio : . , pco : mmhg, ph: . , hco : mecl chest x-ray film demonstrated diffuse bilateral alveolar pattern occupying beth lung / ). trarmamlnase, bllllrubln, ~ and esr were elevated, wbc was . mm , platelet: . ram , hematesrlt: %, hemoglobin: .sgrldl=. there was no clinical or ecttlographlc evidence of left heart failure.patient fulfilled the criteria for diagnosis ards he was found to have an ~lutinatlon tlter for leptoq~lral antigens(indirect he~lutlnatlon atomy, ilia} very high ( / , negative<ill ) and iglm antibodies also very high (elisa, a= . , negative< . ) strongly suggesting leptospirosls. treatment with tetracycline and non-tnvaslve mechanical ventilation by nasal mask were started. pre~jre support mode and cpap was usod. the following days the clinical picture,the oxygenation and the chest x-ray of the patients were improved, and patient dl~herged from the icu. the control of leptosplremlc phase as well as his good cooperation during nipsv contributed to rapid recovery and excellent outcome in hiv infections, pneumonias (pnm), mainly due to pne~ mocystis carinii (pc) have an outstanding place in pu ! monary complications. the aim of this work was to compare two group> of patients admitted with pnm in our icu during the same period ( - ): group a, patients hiv+, and group b, patients hiv-. apache ii was identical in the groups (p=ns). group a required more often mechanical ventilation (p= ,o ), had a higher p(a-a)o (p= , ) and metabolic acidosis was more frequent (p= , ). regarding laboratorial parameters group a had a lower no. of linfocytes (p= , ), a higher ldh (p= , ) and a more marked hypoalbuminemia (p=o, ). mortality was higer in group a ( , %) than in group b ( , %), (p= , ). analysing the a group patients, we found no significant differences between alive and deceased patients, with exception for albuminemia, which was lower in the deceased patients (p= , ). in conclusion, the hiv+ patient's pnm have a more agres sive behavior when compared with community acquired hiv-patient's pnm. the prognosis was not influenced by the apache ii. perhaps other parameters such as p(a-a)o , metabolic acidosis, linfocytes, ldh and albumin shoud be more evaluated as possible predictive indices. some prognostic factors, usually accepted as predictive in the analysis of hiv+ patients do not seem to be worth in the late stages of aids, mainly when they reqquire intensive care. intensive care unit, onassis cardiac surgery center, athens, greece. objectives of this study was the comparison of two different antibiotic regimens as prophylaxis in cardiac surgery patients. methods: in a prospective randomised comparative study, two different forms of antibiotic regimens were investigated : a single dose of cefuroxime (zinacef, gr) (group a) given during the induction of anaesthesia, versus a four days combination of amoxiculine (amoxil, gr tid) plus netilmicin (netromycin, mg bid) (group b). a total of patients (pts) ( males and females, of mean age . + . years old) were included in the study over a period of one year; in group a and in the group b. patients were checked for the occurrence of infection during the first postoperative month. results: the total rate of infection in cardiac surgery pts was . %; . % in group a and . % in group b (p=ns). pts ( . %) developed infection following cabg, pts ( . %) following valve replacement and pts ( . %) after other cardiac surgery. they were males ( . %) and females ( . %). endocarditis has occurred . % in group a and . % in group b. severe wound infection was recorded in . % in group a and in . % in group b. one case of sepsis ( . %) in group a and in group b ( . %). respiratory infection occurred in pts of group a ( . %) and in pts of group b ( . %). two cases of urinary tract infection was in group a and one in group b. catheterrelated infection was occurred in ( . %) in group a and ( . %) pts in group b. pts ( . %) had fever of unclear aetiology in group b. conclusions: there was no statistically significant difference regarding the rate of infection in both groups. a single dose administration of cefuroxime is accordingly just as effective as a four days regimen of amoxicilline plus netiimicin. legionella pneumophila is a common bacteria of the environment, and it is an agent responsible for severe community acquired pneumonia (cap). we analyzed the patients with lpp admitted in our icu during the last years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . they represented . % of cap. seven patients were males and female, with mean age . + . years. tiss was . + . and apache ii . + . . all, but patient, were under mechanical yen tilation (mv) during a mean period of . • (min-l, max- ) days. two pneumonias occurred beyond the season, while patients had an epidemiological history. only patient had no risk factor. in all the others tobacco smoking and alcohol abuse was quite frequent. diagnosis was based on serologic test and culture or direct fluorescent antibody staining of bronchial secretions. seven patients had a multisystemic disease with hepatic dysfunction in , renal failure in (due to rhabdomy~ lysis in ). one patient had a prosthetic valve endocarditis and another developped ards. nosocomial septicaemie occurred in patients. mortality rate was %. deceased patients had initially higher apache ii, (a-a) , and lower natriemia. comparing lpp with the other cap (n= ), both submitted to mv, mortality rate was similar ( , % versus . %). in conclusion lpp can occur all over the year. there was a high incidence of severe complications and outcome was similar to the other cap when requiring mv. prospective specimen brash (psb) with culture > cfu cfu/ml. broncho-alv~lat lavage (bal) ~= c'fu/rnl or positive blood culture. were excluded for rapture of treatment ; were analysed (shift with oral antibiotic : ; prohibited antibiotics associations : ; resistant germ : ). clinical data : age , • , ; saps • , ; mac cabe i : , % -ii : , % -iii : , . , % of the patients were intubated and under mechanical ventilation. the pneumoaiae were : primitive in ( , %), copd ( , %), aspiration pneumonia ( , %). germs were isolated (psb , bal , blood culture ) : s. pneumoniac ( , %), h. influeazae ( , %), sttep~:occns ( , %), saar ns ( , %), enterobaetdrindr ( , %), mosexella catarrhalis ( , %), othem . / ( , %) were sensitive to freatment. the ltentment was mg/kg/d of ampiclllin and mg/kg/d of sulbactam in continuous iv adminisu'ation during at least days. clinical eff~ienev : success ( %), failures ( %) with superinfeetion , worsening or relapse , dead , side effects . there was no difference between etiologies : primiti~;e~ , %, copd , %, aspiration pneamoniae , %. the bacteriological effieieacy was evaluated only for patients with eradication ( , %), eradication but super~ection ( , %) : with pseadomoaas a&ogiuosa , eater~ac~ ; beeteriological failure ( , %). in conclusion, the aasor ampicillin -sulbactam is effective for the i~eatment of severe acquired community pneumonise. objectives : to assess the efficacy of chlorhexidine (cl) gel or suspension applied in the nose and in the op for the prevention of the tmcheobronchial colonization. methods : thirty-seven patients expected to be intubated for > h were randomized to received topical application oga cl suspension ( %) qshrs, a cl gel ( %) q hrs or a placebo. in addition all vpts received a nasal and a op spray ( %) of either cl or placebo administrated according to the same schedule. semi-quantitative cultures of the anterior nares, the oropharynx (op) and the trachea were obtained on admission and once a day until extubation (just before the next application). the results were assessed according to the following criteria: success = no acquisition of gnb in the trachea ; failure = acquisition of gnb in the trachea. acquisition was defined by a follow-up culture positive for a gnb not present in the trachea on admission. results : success failure nosocomialpneumonia overall morality clsusp. placebo clgel placebo n= n= n= n= / / / * / / / / * / / / / / / / / / i *p = , byfisher'sexacttest conclusions : these results suggest that topical cl gel administered q hrs may prevent tracheal colonization by gnb. f. daumal*, m. daumal**, c. plot**, v. vurmmen ~ e.colpurt**, b. manonry** * hygiene hospitali&e, ** service de r enmmtion, * service des admissiens-urgeuces centre hospitalier g- ndral - saint-quentin -france obiectives: evaluate the nosocemial risk due to peripheral venous inserted short catheters, and the quality of care. patients-methods: the intensive tare unit (i.c.u.) is a beds unit. the prospective study includes all the patients comn~ in from / / to / / . the recruitemont uses an evaluation schedule of local clinical signs. the nurses aimed to create this evaluation data which includes the place of entry site, the duration of catheterization and the cause ot withdrawal. only patients staying longer than days in the i.c.u. are accounted for. the diagnosis of uosoenmial infection is assured by the physician taking care of the patient and by the hospital epidemiologist on the next signs: evident pus at the catheter entry site, positive culture of the strain, with or without the same pathogen in the blood sla'uam,the patient having no other distant source of infection. analyses were performed on epi/nfo. results: the occurrence of nosoeomjal inthrtions: i abcess and bacteremia during the first part of the study lent the medical staff to modify the protocol of insertion end survey of the device. so we analysed different periods: period ( / / to / / ) and period ( / / to / / ) for all .e peripheral catheters inserted in the i.c.u. period , % , % en infection due to peripheral venous device is a daily threat. the severity of some clinical situations requiring admission in icu proves it. the motivation of nurses for rigid adherence to established protocol, the daily survey of the entry site, the withdrawal of the peripheral catheter every hours aimed to reduce significantly the local signs of inflammation end infection of peripheral catheters inserted inside the i.c.u. objectives: to investigate the use of a new metabolic monitoring device for different ips levels by comparing oxygen consumption (vo ) to measurements of the mechanical work of breathing (web) and p . . methods: the study was approved by the institutiotml ethics committee. eight patients were investigated during weaning after prolonged mechanical ventilation ( - days) for various diagnoses when the clinical physician judged the patient to be ready fur weainag. ips was setto , , , mbar far rain periods each. all patients had a peep between - mbar.. respiratory frequency (f), tidal volume (tv), minute ventilation (ve) were read from the ventilator display ( ae, puritan bennett, carlsbad, usa). flow and airway pressure were measured at the endotracheal tube site. esophageal pressure was measured using an esophageal balloon catheter (fa. ruesch, frg). web was determined as the area subtended by the pleural-pressure-vohime curve. p . was determined by using standard occlusion technique and graphical analysis of the airway pressure tracing. vo and vco were measured using the pb metabolic monitor (puritan bennett, carlsbad, usa) connected to the pb ae ventilator. all data are given as mean• deviation for each ips level. comparison between the different ips levels was performed using anova for repeated measurements. significance was considered at p< . , compared to ips mbar. results: the values for breathing pattern, web, p . , vo and vco are given in the table for the different ips levels; significance is indicated by ~. objectives: fluidized beds are often used in the management of critically ill mechanically ventilated patients. critically ill patients are increasingly colonized with resistent pathogens [ie: p. aeruginosa, methicillinresistent s. aureus (mrsa), extended spectrum i~-iactamase producing enterobacteriaceae ] that can ultimately cause nosocomial infection. methods: we prospectively monitored bacterial colonization of mechanically ventilated patients and of the fluidized bed (clinitron) inwhich they were treated. multiple samples for quantitative bacterial cultures were taken from oropharynx, trachea, feces and bedsores. samples of ceramic beads from the bed were also taken both during and after patient stay (after bed operation in the absence of patient). re,~ults: episodes in consecutive patients (mean age: . years) were analyzed. all had bedsores and/or urinary catheters and fecal incontinence, patients had nosocomial pneumonia, had urinary tract infection [ with extended spectrum imactamase producing k/ebsie//a pneumoniae (ki~lse)], one had positive blood cultures with mrsa, and one patient had a ki~lse found in high concentrations ( - s cfu/ml) in occasions in feces. patients were heavily colonized: the , samples from ceramic beads showed no growth or became sterile without any sterilisation procedure (even in one case of presence of kf~lse) during the patient stay. conclusions: fluidized beds do not put patients at high risk of acquiring nosocomin pathogens, and cross-contamination between patients seems unlikely, even when multiple resistent organisms were initially present. the recommandation from some manufacturers to undergo extensive sterilization of fluidized beds after use does not seem warranted, at least with the bed used in this study. ant. koutsoukou, a, tahmitzi, p. kithreotis, m. koutonlidou, k. stavrakaki, kainis e, g. vlahogiorgos and e. eliopoulos icu-centre for respiratory failure -chest diseases hospital of athens. the cost-effectiveness issue is becoming vital in modern medicine and may lead to moral dilemmas since sometimes certain groups of patients may not have access to highly specialised modalifies. objective: our study compared the mean daily cost for antimicrobial medication in copd patients treated in icu versus all other patients in the context of relevant epidemiological, prognostic and outcome data. methods: age, sex apache ii score, length of icu stay (los) and in -icu fatality were retrieved from the files of all icu admissions over . mean daily cost for antimicrobial therapy per patient (dcat) was estimated. these variables were statistically compared between copd and non-copd patients. significance was assumed at p< . results: of the total admissions were fully evaluable. of them ( %) were copd patients. data (m---sd) results for statistical test are given in table i . copd patients were significantly older spent more time in the icu and presented with significantly higher apache ii scores. outcome and dcat were comparable in the two groups. objectives: the use of heat and moisture exchangers (hmes) during long term mechanical ventilation (mv) is increasing. in icu patients, they are routinely changed every day, according to the recommendations of the manufacturers, but the clinical basis for such a daily practice is lacking. we therefore prospectively assessed whether changing hmes (dar hygrobac, spa, mirandola, italy) every h only would affect their clinical and bacteriological efficiency. methods: two consecutive groups of patients requiring mv for > h were compared: group = hme replaced every day, n= episodes of mv in patients; group = hme changed every h, n= episodes in patients. tubings were not changed in the same patient during the whole length of ventilatory support. diagnosis of nosocomial pneumonia (np) was based on a positive quantitative culture (~ cfu/ml) of a protected specimen brush in patients with clinical signs of pneumonia. quantitative cultures of pharynx, trachea and y-cannector were performed every h. results: the groups were similar in terms of age, indication for and overall duration of mv ( +_ . vs +_ days, p= . ), and severity of illness (saps: --- . vs . +_ . , p= . ). the maximal values for peak airway pressure were identical in both groups ( . -+ . vs . • cmh , p= . ). obstruction of the tracheal tube was observed in only one instance in a group patient who had tracheal bleeding. circuit colonization was very rare, and of low grade in both groups. the level of patient colonization and the type of organisms were identical in both groups. more importantly, the incidence of np was the same ( / vs / , p= . ), as was duration of mv before the occurence of pneumonia ( • vs . +_ . , p= . ) and overall mortality rate ( vs , p= . ). conclusions: the clinical efficiency of this hme does not seem altered after days of use. indeed, replacing this hme every h only neither affect circuit and patient bacterial colonization nor the incidence of np. therefore, substantial savings could be obtained changing hmes every other day only. obiectives: to evaluate the usefulness of different paraclinical investigations for the diagnosis and prognosis of acute viral encephalitis in icu patients. methods: we reviewed patients (pts) admitted to our icu from july to december with the diagnosis of acute viral encephalitis. all were in coma and were initially treated as presumed herpes simplex virus (hsv) encephalitis. the causative agents were: hsv ( cases), herpes zoster varicellae ( ), measle ( ), rabies ( ), unidentified ( ). eleven pts survived and three presented neurologic sequelae. twelve pts were investigated by mri, and eleven also by spect and multi-modality eps. including brainstem auditory eps (baeps). these investigations were obtained as soon as possible following admission and were repeated during icu stay when possible. the clinical outcome was noted. results: six pts ( / ) had an abnormal mri. among them, pts made a complete recovery, in comparison with / pts with a normal mri. in one hsv infected patient, mri remained normal despite clinical deterioration and bad outcome. when repeated, mri became abnormal in cases (with poor outcome in one) and was improved in one. spect was found abnormal in / pts (among them, pts had thus a normal mr/). the correlation regarding the topography of brain lesions was poor between mri and spect. the findings of spect could not be correlated with a poor outcome. the baeps confmned in % of the pts the clinical diagnosis of brainstem involvement. changes in visual and somatosensory eps were mild in all the pts and were not helpful for the prognosis. eps were otherwise interesting for the follow-up of the coma in these sedated and ventilated pts. conclusions: the value of mri and eps for the diagnosis of acute viral encephalitis is of limited interest. spect seems to show early modifications, even in pts with a normal mri, but this test is poorly specific and does not correlate with mri changes when present. concerning the prognosis, larger studies should probably confmn that a normal mri could usually result in a good outcome. this serie illustrates also that hsv encephalitis could be demonstrated only in a small number of cases and that the prognosis of non hsv encephalitis is not easily assessed. objectives: to study the influence of gram (-) bacterial lung infections on liver function i~ mv icu pts. pts and methods: we studied pts, # ( , %), ( , %). hean age: , • years ( - ). mean stay in icu: , • days ( - ). they were divided in groups: a( pts) who did not suffer from pneumonia and b ( pts) who developed a gram(-) bacterial pneumonia. both groups were consisted of pts with same age, sex and disease distribution and same systemic failures. we measured sgot, sgpt, total bilirubin(tb), direct bilirubin (db), alk.phosphatase (al.ph.), v-gt and albumin (alb.) times: on days o, and of the pneumonia for group b and respectively for g~oup a. conclusions: ) in elderly intubated pts of an icu, kp is isolated more frequently than in icu pts< years (p<o, ). ) the frequency of isolation of kp in icu pts during - was - %, but now ( - ) kp becomes more and more rare ( - %) and is isolated especially in elderly pts. ) its sensibility to antibiotics remains always the same. ) the prognosis of np in our study was independent from age (p<o, ), sex, presence of bacteremia (p< , ) and type of invading microorganism. gram neg bacteria and renal failure (rf) from aminoglycoside toxicity are common and serious complications in critically ill patients. the aim of this prospective, pilot study was to compare the safety and adequancy of the endotrecheal (et) vs the intravenous (iv) administration of aminoglycosides. were measured in the plasma and the bronchial secretions at and hours after the iv (bolus) or the et (nebulized) administration of mg of gm in seven criticcally ill patients ( with established renal failure). safety was defined as peak and trough plasma gm levels _< than and ijg/ml respectively and adequancy as gm levels in bronchial secretions _> , ijg/ml. results: gentamicin was administered by the et and iv routes in and separate sessions respectively. a total of samples were assayed, in bronchial secretions (bs) and in serum. the et route resulted in higher gm levels in the bronchial secretions compared to the iv route ( , + , vs , _+ , pg/ml respectively, p = ns ). adequate bronchial gm levels were achieved in % of patients after et administration, compared to % after iv aaministretion. the blood levels of gm were significahtly lower after the et vs the iv route ( , + , vs , • , pg/ml respectively, p _< . ). the et administration resulted in toxic bronchia~ gm levels in % of the specimens. % of these samples were from patients with renal failure, however toxic blood levels were reached in only % of these. gentamicin seems to be a safe and adequate alternative route of treatment for the lrti. however, in patients with renal failure the et administration of the aminoglycosides should also be modified and continuously monitored. in order to evaluate the pathogenic role of anaerobes in nosocomial pneumonia (np), we investigated the systemic humoral response in patients who developed a np with anaerobic bacteria, especially prevotella species. methods: blood samples from groups of patients were tested. group i: patients with a np in which prevotella spp. was isolated from protected specimen brush (psb), group ih a control group of patients with a np without anaerobic bacteria, group ill: a control group of patients with dental stumps but without pulmonary infection, group iv: a control group of healthy voluntary people with prevotella spp. isolated from the dental plaque. an elisa was used to evaluate the total antibodies level against a mixture of four prevotella strains and a western-blot method was done to identify the antigenic proteins. results: data are expressed as means .+ sd. the antibody levels in patients of group i ( • was statistically higher (p=o.o ) than in the control groups (respectively: + , _+ , _+ ). using western-blot method, the intensity of the response was roughly superposable to levels obtained by elisa and the profiles were different according to the prevotella species. the occurence of a np with anaerobic bacteria (prevotella species) isolated from psb leads to an antibody response which seems specific of the prevotella species isolated. fever is common in the intensive care unit, but is not always related to an infection. we sought to define the epidemiology of febrile patients in a general medical/surgical icu. methods: we prospectively analysed the source of fever (t > . ~ c) in all adult patients admitted for >- hours in the icu during a two month period. these patients were studied for consecutive days. and werc classified in groups according to the evidence of infection (center for disease control criteria) after complete evaluation: documented infection: cdc criteria + isolation of pathogen (d); possible infectron: cdc criteria without isolation of pathogen (p); unlikely infection: patients who did nol meet the cdc criteria (u). results: of a total of patients studied, dec'eloped fever ( %). including (after complete evaluation) d, p and u palients. both the highest temperature in tile first day of fever and the maximal temperature were higher in d than in u ( . • versus . • and . -~ . ~ versus . - . , respectively p= . and p= . ). most common sources of infection in d were the lungs in patients ( %) and urina .ry tract in ( %). of these patients had positive blood cultures ( %). the overall mortality was % ( % in d, % in p and % in u. differences ns). antibiotics were given in % of d, % of p and % of u ( patients). in p there was a non significant lower mortality." in patients who received antibiotics ( / ( %) versus / ( %) patients, respectively). conclusions: in febrile icu patients both the highest first day" temperaturc and maximal temperature are significantly higher in infected than in non infected patients, but the differences are too small to be useful clinicall). mortality rate is not significantly influenced either by the presence of an infection or by the administration of antibiotics, obiective: retrospective study to determine the influence of candida infection on icu outcome. methods: patieet with a stay of more than days in inteaasive care were screened for candida infection. patients were treated with antifungal therapy due to either an increased antigen titre of -> : or clinical evidence of candida colonization. serological candida-antigens (ramco, pastorex) and antibody titres (hemagglutination, lgg-, igm-elisa) were examined routinely. seroconversion was defined as a threefold increase of antibody titre or a titre of : or higher. results: the median length of stay was (ranging from to ) days, the mean apache ii score on admission was (+_ . sd) points. of patients patients died ( . %). in the group treated with antifungnls ( patients) patients died ( . %). although of the patients only ( . %) developed a candida infection as defined above the mortality in the group that showed signs of infection was significantly higher ( . % vs. . %, p < . [chi-square-test]). in patients an antigen concentration-> : was measured. seroconversion was found in patients. the most common fungus was candida albicans ( . %). furtberm re, candida glabrata was found in . %. most of the patients were treated with x mg fluconazole ( patients). in patients therapy was changed to amphotericin b/flucytosine. in patients therapy was started with amphotericine b and flucytosine. in patients a threefold decrease of candida antigen titre was found. patients showed a decrease of candida antibody titre. conclusions: meticulous screening for eandida infection seems to be necessary since the number of patients with fatal outcome is significantly higher in the group with signs of fungal infections and thus requires immediate antifungal treatment. objective: early diagnosis of patients with ventilator-associated pneumonia (vap), and subsequent identification of causative microorganism, and selection of the appropriate therapy are critical important points that affect morbidity and mortality. the results of the quantitative bacterial cultures are not available for at least hours, while a two hours period, since the specimen are obtained is enough to know the gram stain results. the aim of this study is to determine the usefulness of gram stain in specimens obtained by bronchoaiveelar lavage (bal), through the bronchoscope. material and methods: we studied patients ( males and females, age + ) with suspected ventilator-associated pneumonia. the bal gram stain was considered positive when the specimen after a centrifugation at rpm for min revealed: i) more than leukocytes per optic field, ii) squamous epithelial cell less than percent and iii) one or more microorganisms per optic field on magnification. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap and patients did not. in cases the bal specimens (quantitative bacterial cultures) established the diagnosis of vap in the remaining three patients the vap diagnosis was established by other procedures (blood or pleural fluid culture, clinical outcome, autopsy). apache fl score in patients with vap was , -+ , , while in patients without vap was , + , . there was a significantly higher incidence of vap in patients who had i) coma (gcs < ) and ii) been receiving neuromuscular blockade (p< . ) . the sensitivity of the gram stain for vap diagnosis was %, the specificity , %, the positive predictive value %, and the negative predictive value , %. conclusion: our data indicate that the gram stain of bal specimens is useful for the early diagnosis of vap and the subsequent administration of the appropriate treatment. the role of anaerobes in mechanically ventilated patients with pneumonia (mvp) have been poorly investigated aim of the study : analyse the prevalence of anaerobic isolation in mvp. methods : between october and february all suspected mvp were investigated using protected specimen brush (psb) technique. brushes were rapidly transported in shaedler broth to laboratory. a special care was tooken for anaerobic isolation. results : among the psb performed for suspected mvp ( nosocomial and community-acquired pneumonia), yielded at least one micro-organism (positive psb : %). of positive psb demonstrated only aerobic bacteria and ( %) yielded with anaerobes. in out patients, anaerobes were associated with aerobic bacteria. anaerobes were mostly isolated in nosocomial pneumonia ( / positive psb). strains of anaerobes were isolated. prevotella species represent out these strains ( %) the most frequent anaerobic species were prevotella oralis ( ) p. intermedia ( ) and p. buccae ( ). comments:using adequate methods, anaerobic bacteria are frequently isolated in mvp. it could be off importance to take in account anaerobes in the choice of empirical antibiotic therapy in mvp. objectives: the majority of patients with multiple trauma are considered immunocompromised. the aim of this study was to identify risk factors of pneumonia in mechanically ventilated patients with multiple trauma or after surgery. methods: in this prospective study we studied multi-trauma patients (mean age + years, apache ii . + ), admitted to a general intensive care unit (icu). all patients were intubated and mechanically ventilated. we were considered that a patient had ventilator associated pneumonia (vap) when the specimens of bronchoalveolar lavage (bal) or protected specimen brush (psi?,), ebb'ned through the bronchoscope, had one or more microorganisms in concentrations greater than and cfu/ml respectively. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap, and patients didn't. in the bivariate analysis, the glasgow coma scale (gcs)< (x = . , p< . ), the administration of neuromuscular blockade (x = . , p< . ), the duration of mechanical ventilation to be greater than days (x = . , p< . ), the flail chest (x = . , p< . ), the parenteral nutrition (x = . , p< . ), the ards (x = . , p< . ), the abbreviated injury scale (ais) of more than for thorax (:,: = . , p< . ), the pneumothorax (x = . , p< . ) were statistically significant related to development of vap. in multivariate regression analysis, using the stepwise technique, three of the seventeen studied factors showed to have an indepantent association with the development of vap:the administration of neuromuscular blockade (f: . , p< . ), flail chest (f: . , p= . ), and gcs (< ) (f: . , p= . ). conclusions: in patients admitted to icu for multiple trauma or major surgery, the administration of neuromuscular blockade, the flail chest, and the gcs (< ), in the population under study, were the indepedent risk factors for vap. mof is a sereous complication of differem states: infection, sterile inflamation, extensive fissure injure, intoxication, ets. there is close correlation between extension of mof and death, developement of nasocomial infection. immunologic disfunction. in order to prgnose probability of risk of mof development among the patients with sepsis and septic shock, we achived an eqation, allowing to recive a coeficient, closely connected with this probabiliti. we have used retrospective analisis of cases of sepsis. diagnosis of sepsis was based according to bone's criterions of sepsis. mof was assessed as disfunction of or more systems according to bone's classification of mof. having used correlation analisis we have estimated factors which have had high correlation coeficient with the probability of development of mof. there were: apache-ii score points, evidenceof septic shock, endocrinopathy. with the help of multyple regression analisis we acheved next equation: y= , + , x~ + , x + , x , were x i-apache-ii score points, x -evidence of septic shock, x -endocrinopathy. the explanatory power of this quation was evidenced by roc of . , se (v - . introduction: the presence of liver dysfunction in the process of multiple organ failure is associated with an adverse outcome, particularly when it becomes progressive to liver failure. disturbances of liver function may occur early and their detection may be of significant importance for the further development of organ failure. routinely used liver function tests appear to be inconsistent indicators of hepatic damage. in this study, we used p_lasma disappearance rate (pdr) of indocyanin-green dye (icg) as an early estimate of liver function. methods: we serially evaluated pdr and routine liver function tests (serum bilirubin, sgot, sgpt), as well as acute phase and non-acute phase proteins (crp, transferrin) in patients during the first week after trauma or the onset of sepsis. patients: group : (n = ) multiple trauma iss > , group : (n = ): abdominal sepsis, acute necrotizing pancreatitis (anp) grade iii. patients were selected on the basis of clin cal estimates that these patients would require continued icu observation. pdr was determined by means of a fiberoptic catheter and a computerized system (cold z- , pulsion), which permits repeated bedside measurements. the initial values of pdr, serum bilirubin and transaminases were not significantly different in trauma, sepsis and anp. in trauma patients pdr improved during the first week. in patients with sepsis and anp pdr remained low and worsened with time. the decrease in pdr preceeded an increase in biochemical liver function tests in these patients. + . &-_ ( - ) discussion: routinely available blood tests of liver function are usually altered several days after injury. however, they are generally non-specific indicators and they are influenced by extrahepatic factors. pdr seems to be useful to evaluate impaired liver function early after the onset of sepsis and trauma. objectives: to study frequency of organ system failure (osf) and it's influence on outcome in granulocytopenic patients with hematological malignancies and septic shock(ss). materials and method: retrospective review of medical records of granulocytopenie(wbc< , xl ) patients with hematological malignancies and ss, who were admitted to the intensive care unit (icu). frequency of osf before and after ss was analysed. the patisnts were categorised on survival and non-survival. results: signs of osf were observed in . % of patients before ss and in all patients after ss. only patients presented with hypotension refractory to inotropic therapy. nevertheless there was a significant increase of frequency of acute respiratory failure (arf), acute renal failure (arenf) and liver injury (li) after ss occurred(showed on the figure). only frequency of organ failure before and after objectives: statusmetria allows to define the effective level of oxygen status and accordance to it means of carbon dioxide and elec-trolyte in critical care. the conception of syndrome int~ive care (sic) is exhausted itself and invariable outcomes of sic of multiergan system failure (mosf) confirms that. therefore, an alternative to sic should be advanced. methods: efficlenoy of treatment has been asscsaed in patients with mosf using value of metabolic rate and ability of an organism to cover it by oxygen and substrate supply. oxygen pulse (op) and index of efficacy of oxygen transport (ieto ) was monitored. ~lt~.lntenaive care is considered to be homeostasis-securing therapy (hst) if energostructure deficit is eliminated and necessary for recovery regeneration rate is .restored. op in patients with mosf was . mt-m " , and le,~ and ie'i~ w~ . units in sic. we managed to maintain op of . - . ml.m " and ieto of . - . units in hst. patients from with mosf survived in sic and patients from survived in hst. efficiency of hst appeared to be two times as much as efficiency of sic. cr of homeostasia-se-'uring therapy is advancing. the conception provides restoration of regeneration rate due to effective then in sic elimination of en=gostructure deficit. the conception may be a basis of new technology for treatment of mosf. helen f goode phd, nigel r webster phd. anaesthesia & intensive care, university of aberdeen, ab zd, uk. objectives: xanthine dehydmgenase is converted under conditions of ischemia, reperfusion and endothelial damage to xanthine oxidase, with superoxide anion as a co-product of its catalytic activity. multiorgan dysfunction syndrome is associated with splanchnic vasoconstriction resulting in significant and prolonged gut ischaemia. aggressive volume resuscitation with prompt restoration of blood flow results in reperfusion of the tissue and is likely to cause xanthine oxidase-mediated release of oxygen-derived radicals. this study investigates xanthine oxidase activation and oxygen-derived free radical-mediated damage in such patients. methods: fourteen consecutive patients on itu who met established criteria for septic shock and secondary organ dysfunction were studied. serum xanthine oxidase activity was measured using oxidation of a chromagen in a dual enzyme system and plasma malondialdehyde was measured using a specific spectrephctometdc assay. apache ii scores, blood pressure, svr, cardiac output and day survival were also recorded. biochemical data were compared with results from healthy subjects. results: xanthine oxidase activity was . + . units/i in patients (mean :t: sem) and . + . units/i in controls (p<o. , mann whitney u test), and was highest in the patients who survived (p< . ). malondialdehyde concentrations were elevated ( . • . prnol/i compared with . • . pmol/i in controls, p< . ). xanthine oxidase activity did not relate to apache score or any of the cardiovascular parameters recorded, and was not influenced by the degree of organ dysfunction. conclusions: patients with sepsis and secondary organ dysfunction have xanthine oxidase activation and evidence of free radical damage. the finding that activity was highest in those patients who survived suggests that reperfusion was incomplete in patients who died, with decreased tissue xanthine oxidase ~tash out' into the circulation. influence objective : evaluation of the feasibility of measuring the intragastrie partial pr~sure of carbon dioxide (pco ) using a chemilumin~nt optode and fibre~ptics originally developed for intrav~cular blood gas monitorlng(p ) methods the pco electrode w~ calibrated i~-vitro according to the m~ufaeturers instructions the sensor w~ then stripped of its outer c~ing and threaded down the pile tube of a g~ c enema e (gt) so ha he ens ng portion sat well within the balloon. the modified gt was inserted n~og~trically after induction of anesthesia in ten patients undergoing c~diopuimonary byp~s throughout results: according to the datas of integral rheography % of patients were revealed to have hypodynamic type of blood circulation (cardiac output was decreased on - % and general peripheral resistance increased on - %). it was effective to use complamin (xantinoli nicotinas) in the complex therapy of su~h patients. the dosage was - mg/kg during - days. as a result of such therapy was also the oliguric stage shortening (ac n ).in , % of the cases unsatisfactory datas of central hemodynamic,combined with high (more than cm h ) venous pressure,lung oedema.then nanipruss ( , - , mkg/kg/min) was succesfutly used in complex with routine therapy.in the patients with low cardiac output and low general peripheral resistance mesaton ( , - , mg/kg) and dopamine ( - mkg/kg/min) were effective.change for the worse in the hemodynamics datas, inspire of therapy during - days,was prognostically unfavourable. conclusions:we consider early diagnostic of hemodynamic disorders and adequate correction of them is one of the most important factors, determined the outcome and prognosis in arf patients. obiective: to evaluate the results of renal replacement therapy (rrt) in surgical icu patients with acute renal failure (arf). arf in icu patients is associated with high mortality rates. we investigated the relation between mortality and organ failure in different categories of surgical icu patients receiving renal replacement therapy (rrt) for arf. methods: the records of surgical icu patients with arf requiring rri-(haemodialysis or cavhd) were examined. five different patient categories were defined; .ruptured aneurysm of the abdominal aorta (raaa) n = .elective vascular surgery (evs) n = .abdominal sepsis n - .trauma n = .others ( e.g. malignancy, obstetric emergencies) n- seven organ systems (cns,circulatory,respiratory,hepatic,renal,digestive,haematologic) were scored for possible failure using the mof score. results: mortality was as follows: all patients % , group % , group % , group % , group % , group % . mortality increased with the number of failing organ systems; mortality for all patients with > failing organsysterns was % the only exception being the subgroup of trauma patients where mortality under these circumstances was o% conclusions: mortality in surgical icu patients receiving rrt for arf is high. no significant difference in mortality is found between raaa and evs. mortality increases with the number of failing organ systems. the subgroup trauma patients shows a lower mortality compared to the group as a whole, even with > failing organ systems. to look for the most accurate scoring system to measure the severity of the complications occuring in the early phase ( first day) of kidney transplantation and to asses their prognostic value. methods: in our retrospective study we applied the apache li and the goris scoring system for the kidney recipients who developed multiple organ failure (mof) as a consequence of their pulmonary and. cardiovascular complications following kidney transplantation. we evaluated the recipients the distribution of the women and men ( % ~ % ) was the same as in the kidney recipients. applying the apache ii system most of the patients had their score between and , and the function of , or organs were affected at the time of the onset of mof. the apache ii system gave adequeate information about the disturbance of the function of other organs beside the kidney failure even at the time of the transplantation. the scores and the number of the affected organs correlated with the condition of the patients in the goris scoring system but not as sensitively as in the apache ii scoring system. conclusions: both the goris and the apache ii scoring system can be applied to measure the severity of the multiple organ failure occuring during the early phase of kidney transplantation. however the apache ii system is more suitable to follow not only the stateof the patients at the time of the admission but also the changes occuring in their condition during the complication. v.v.erofeev, v.v.ivleva scientific research institute for general reanimatulogy russian amsci, moscow, russia objectives: the analysis of ssc and results of their treatment in patients following critical states showed the necessity of developing a combined antibacterial therapy. methods: according to the protocol patients ( - years old) with combined trauma and massive hemorrhagy following vast aml traumatic operations were examined. microflora's composition and resistence to up-to-date antibiotics was studied using the anaiyser iems reader by "labsisteme"(finland). general clinical, bacteriological, immunological indices, as weil as the duration of the treatment and recovering rate served as criteria of the combined antibacterial therapy effectiveness. results: it was proved expedient to administer antibiotics in staphylococcus infection in the following combinations: riphampizin with fluoroquinolones; i-ii degeneration, cephalosporins with aminoglycosides; cephalosporins with fluoroquinolones. in case of singling out the exciters of the euterobacteriaceae family, including the pseudomonas aereginosa, -fluoroquinolones combined with modern amynoglycosides; fluuroquinolones with ureidopenicillines; ureidopenicillines with amynoglycosides; amynoglycosides with the ii-iii generation cephalosporins; cephalosporins with fluoroquinolones. in severe ssc caused by combined infection (including anaerobes) clindamicin with modern amynoglycosides was prescribed. conclusion: the combined antibacterial therapy allows: ) to increase the effect on microbic agents and the efficacy of treatment in combined infections; ) to lessen the possibility of the exciters'resistence to antibiotics; ) to prevent the development of superinfection: ) to decrease the doses of medicine and its toxic effect. objectives: two methods of blood volume measurement in a group of critically ill patients were compared to investigate the practical possibilities of a new easy to use method based on carbon monoxide (co) uptake. methods: all patients had multi-organ failure and haemodynamic monitoring with a swan-ganz catheter. mean apache ii score was ( - ). when indicated, patients had blood volume measurements simultaneously based on the techniques of, i) dilution of ~cr labelled red cells, and ii) inhalation of carbon monoxide gas with measurement of the rise of carboxyhaemoglobin produced. the co was administered via a newly designed, ventilator driven, fully closed circle system ensuring co retention and co removal with automatic addition of oxygen to m}ttch patient uptake. a portable computer performed all necessary calculations. results: volumes obtained by co uptake were compared with the "gold standard" radiolabelling method. mean blood volume determined by the co method was ml ( - ml) compared with ml( - ml) with slcr labelled red cells (r= . ). regression analysis produced an intercept at ml. the slope of the regression line was . ( . - . , % confidence limits). discussion: the co method produces volumes in excess of the radiolabelling method. there appears to be a systematic error, and one possible explanation is co binding to substances other than haemoglobin. conclusion: the co method is easier to use than radiolabelling and of the lower cost, since cohb measurement only is required. aceuraey is sufficient for clinical use and our preliminary findings suggest this system will meet the requirements. objectives: this study was conducted to determine the role of nitric oxide (no) in the pathophysiologic alterations and multiple organ damage, and the possible effects of " " " (l-n -monomethyl-l-arglnlne nmma) on hemodynamics and mortality in rats caused by a prolonged hypovolemic insult. methods: a prolonged hemorrhagic shock ( - mmhg for rain) was induced in anesthetized rats followed by adequate resuscitation. l-nmma was administered intravenously at doses of . mg/kg or . mg/kg at the end of resuscitation. results: infusion of . mg/kg l-nmma diminished the fall in mean arterial pressure, significantly increased the cardiac index (ci) and stroke volume (sv), together with remarkable protection from multiple organ damage compared to the controls. the h survival rate was significantly improved from . % in the control group to . % in the treatment group (p< . ). in contrast, the high dose of . mg/kg l-nmma resulted in a strong blood pressure response but a marked reduction in ci and sv concomitant with an increased total peripheral resistance index within the observation period, and caused severe damage to various organs at h after treatment. in addition, marked elevation in both endotoxin and tnf levels were observed in animals subjected to shock insult. conclusions: these results suggest that no induced by hemorrhagic shock in rats is an important mediator for pathophysiologic alterations associating with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. thus, regulation of no generation and use of no inhibitors might provide new aspects in the treatment of hemorrhage related disorders, and the use of l-nmma would be either deleterious or salutary in a dose dependent manner. (hebert, chest- ) . the purpose of this study was to assess the risk factors for hepatic dysfunction in mosf. methods: patients have been hospitalized in our icu from january to may . , ( %) with mosf. among mosf pati~ts, ( %) have had hepatic dysfunction defined according to hebert (bilirubin ~ ttmop , chest ). thirty six of these patients acquired hepatic dysfunction after admission in the icu. these patients were compared with mosf patients without hepatic dysfunction selected blindly. chrorfic diseases, severity scores, eanse of admission, clinico-biologieal and hemodyunrrfic parameters, use of vesopressors, use of hepaiotoxic drugs, use of nutritional support and mortality were compared for hepatic failare and non hepatic failure groups.twenty nine patients had postmortem hepatic histologic examination, results: univaciate analysis: only parameters with p _< . are pre~nted. including these paramet~'rs in a multivariate analysis, anly c~hosis and vascular surgery remain independent risk factors for hepatic dysfunction. in particular, pao /fio , arterial lactate, do were not different between the two groups, some de~'ee of histological abnormalities was found in all liver samples, despite a normal bilirubin level in % of the cases conclusions: in our patients, conu'ary to previous studies, hypoxic and hemody~anfic parameters were not independent risk factors for hepatic dysfantion. this might be due to the inadequacy of the usual biologic definition of hepatic dysfunction as well as to the poor sensitivity of general hamodynamic parameters. critical states of various origin are complicated with the mldtiorgan farm (moi~ oceuzr~ce. due to their and functional features the lungs become the primmy damage target in various critical.states. ard that occurs in such states is associated with pulmonary edema development because of capillary permeability increase mediated by humeral and cenular responses to amag/~ factors exposure. r nmst be emphasized that mediators and effecto~rs of this respo~e affect not only puknonary capillaries, but other organs capiu~es as wellenhancing their permeability. orsans edema is a conmm~ finding at the autopsy of patients died from mof.clinical and radiolosial findings allow to have a diagnosis of pulmonmy edema before ~mi!ar lesions in other organs occm. additionally, there are some techniques that permit quantitative assessment of pulmonary edema flv.id (evlw) volume. in conclusion, we suggest that evlw changes in .dyn~rmcs in patients with mof are considered as a critical state severity measure which reflects indirectly the edema in other organs. objectives: we compared three different dialysis membranes to find out whether or not there were differences between their clearance characteristics on substances such as inuline, creatinine, urea, and phosphate to be eliminated in acute renal failure (arf). moreover, if a loss of clearance did occur we were interested in whether this was due to heparinization and a high production of the thrombine-anti-thrombine-complex (tat). methods: we carried out a randomized controlled study on consecutive critically ill patients presenting with arf, most of them in association with multi-organ failure, to be treated by continuous pump-driven arterio-venous renal replacement therapy on continuous low-dose heparinization. three different types of high-flux filter membranes (f tm [fresenius] , ct tm [baxter] , and filtra tm [hospal]) were assessed. each filter was changed intentionally after a hours" use. together the data of filters were evaluated, each at three different times (immediately after its onset [ hi, after h, and after h). the clearances of creatinine, urea, phosphate, and inuline were measured. results: there were some significant differences in clearance characteristics of inuline, creatinine, urea and phosphate between the filters (p< , ) showing the f tm membrane excelling filtra mand ct tm the more. the loss of inuline clearance ( mi/min/m ) after h, however, was insignificant for all filter types. a continuous low-dose heparinization scheme was applied without any relevant prolongation of the aptt. even lower losses were noted for the clearances of creatinine, urea, and phosphate. we found the tat-producfion increased after h (p< , ), but it did not rise any further. conclusions: as we could demonstrate in our study the clearance data of different types of filter membranes applied during continuous renal replacement therapy do show significant differences. on the other side, no relevant loss of clearance occurs during a hours" period indicating a high efficiency over time. to consider commercial aspects as well it shows that inexpensive conventional filter membranes can successfully be applied even for a longer renal replacement period, if needed. a retrospective study was performed on patients with acute renal failure (arf). we analysed survival in continuous (cd) and intermittent dialysis (hi)). mean age of the patients was years (y), patients ( % ) were < y, patients ( %) were >= y. the incidence of dialysed arf in our mixed intensive care departement is %/admission/y. statistics: fischer's exact test, mann-whitney-u test. efioloev: the contribution sepsis, cardiac failure and aminnglycosidcs was respectively %, % and %. treatment: cavh (cd) or cvvh (cd) was used in patients ( %), hemedialysis (hd) was used in patients ( %). data: mean apache scores were the same for cd and hd ( for both groups), patients treated with continuous dialysis techniques had significantly (p<o, ) more need for ventilation ( % vs %), elevated bilirubin ( % vs %) and a higher vasopresser need ( % vs %@ than patients treated with hemedialysis. there was a trend towards more sepsis ( % vs %; p= . ) mad coaguiation disorders ( % vs %; p= . ) in cd. taere were sign/ficantly more younger patients (< y) treated with cd ( % vs %, p< .os). mean apache score was significantly lower in patiants< y than as patienta>= y ( vs ; p< . ). patients< y had significantly (i}< . ) more coagulation disorders ( % vs %) and elevated bilirabin ( % vs %). there was no significant difference in vasopressur need and ventihatio~ between age groups. outcome:. hi) had a better sr compared to cd ( % vs ~ p< . ). patiants>= y had a comparable sr vs patients< y ( ") */e vs %; p----a.s.). tha global survival rate (sr) was % ( patients). conclusions : diaiysed arf has a well known lowsurvival rate ( %): hc~raedialysed patients had a better survival rate than patients treated with continuous dialysis. this can be explained by the fact that the latter were in a worse condition considering organ failure (more vantilatian, elevated bflirubin and need for vasepressurs), apache score couldn't illustrate that. patient~ y with arf have the same survival rate as patients< y: although patients >=- y have a higher apache score they have less organ faille. the avacbe score is not a good oredictor of survival in p with organ failure. departments of surgery and intensive care, guy's hospital, london, u.g-obiectives: a randomised controlled trial of a management protocol utilising the regular measurement of gastric intramucosal ph (phim) to control the administration of dopexamine. methods: patients admitted to a multidisciplinary teaching hospital intensive care unit (icu) undergoing insertion of a pulmonary artery catheter were managed according to a resuscitation protocol. randomisation was to either the protocol alone or to insertion of a nasogastric tonometer and subsequent management guided by phim. phim < . initiated volume and inotrope resuscitation and, if unsuccessful in elevating phim, dopexamine was commenced. approval was obtained from the hospital ethics committee. results: patients were considered for analysis and the two groups were well matched for age and sex. overall, there was a high hospital mortality of . %. there was no difference in icu or hospital mortality between the two groups (see table) . objectives: to compare cardiac output (co) measurements between continuous termodilution (cco) by thermal wire on pulmonary artery catheter (cco/svo vigilance. baxter critical care), and co measurement using a trans-esophageal doppler (dco) ultrasound system (odm ii, abbott laboratories), in the immediate postoperative period of cardiac surgery. methods: patients undergoing myocardial revascularization were monitored with cco by a swan-ganz catheter and an intra-esophageal dco probe, after induction of anesthesia. exclusion criteria were: aortic valve disfunction, previous valvular surgery esophageal disease, absense of sinus cardiac rhythm, and need of ventricular or intraaortic assistance. hemodynamic parameters, co by both cco and dco, svo . sao , diuresis, pha, and hemoglobin were repeatedly registered during the first hours after surgery, as the patients were kept under sedation and mechanical ventilation. results were compared using the method described by bland and altman. results: measurements of co were obtained, ranging . objectives: a decreased tissue oxygen delivery is responsible for a higher morbi-mortality rate among surgical patients; this diminished oxygen delivery/consumption rate (dojvo ) may origin the lactic acidosis observed in the gastrointestinal tract, reported in patients undergoing hypothermic cardiopulmonary extra corporeal surgery, and can be registered by tonometry as result of the gastric mucose ph. the purpose of this study is to evaluate the reliability of the intramucosal ph (phi) measurement by a nasogastric catheter as indicator of the do /vo > its co> relation to other parameters of do /vo disturbance, and with postoperative complications and clinical course. methods: patients ( male, female) undergoing cardiac surgical procedures were included ( myocardiai revascularizations, valvular substitutions, constrictive pericarditis). mean age was + years, mean weight _+ kg. a nasogastric probe (trie tonometrics) was placed after anesthesia induction; phi values were registered in the postoperative period ( ', ', ", ' and h after surgery end). the corresponding hemodynamic parameters, venous oxygen saturation (svo ), diuresis and arterial ph (pha) were also recorded. results: phi values ranged . to . (mean . ( . ); the mean values of clinical evolution were: extubation time, _+ hr.; discharge from postoperative care unit, - hr.; and hospital total postoperative time, _+ . days. complications registered were: perioperative acute myocardial infarctions, cases of respiratory insufficiency, occlusion of coronary bypass, an ease of hyperamilasemia. all patients with severe complications needing specific treatment showed either a low phi value, or a considerable descent in comparison with the initial register. statistic correlation between low phi and presence of complications was found; the low significance (p > . ) degree may be due to the low population size. conclusions: phi measurement in cardiac surgery patients is a non invasive, uncomplicated method for prediction of doz/vo disturbances, thus reflecting risk of increased major complications, and may precede changes in other usual indicators (svo , pha, cardiac output, ...). work-in-progress with a greater population size may offer more significant results. references: ( ) gutidrrez g: lancet ; : - . ( ) landow i: acta anaesthesiol scand ; : - . the haemoglobin-level (hb) is besides the arterial oxygen saturation and the cardiac index one of the relevant parameters of oxygen supply to the tissue. in contrast to otherwise healthy patients, there is no agreement on tile so-called transfusion-trigger in critically ill patients. in i?ont of this background the question arises, whether and to what extent blood transfusion in critically ill patients improves oxygen supply io tile tissue. this study was performed in critically ill/septic patients in the postoperative period alier an inlcclive/scptie revision operation of the hip or knee joint. on cardiac/seplic reasons monitoring consisted beside other measures of a pulmonary arlery catheter and of an indwelling arterial line li~r measurering/calculating standard haem~dynamic as well as systentic oxygen parameters. the indication for blood transfusion was given by hb together with the cliuical slatus of thc patienl (asa-scorc and multiple organ dysfunction (moi))). statistical analysis w~ks performed by mann-whitney-u-test. by fisher's exact-test and by wii.coxon-test: statistical significance was set with p< . . according tu the pretransfusion value of hb and of lactate (lac) palicnts ;,,'ere divided into groups as follows: a: hb< and b: >sg/dl: i: ac< . and ii: > .smm. in either group blood transfusion results in zt significant increase in hb (a: . _+ . to . + . g/dl; b: .(~ . tt, . + . g/dl; i: . -+ . to . -+ . jdl; i : . -+ . to . + . g/dl). wlailc, however, haemodynamic parameters do not difl)r significantly from each other before and alter blood transfusion, oxygen delivery (do, -ml/min x m-') increases significantly hi either group studied (a: -+ to -+ ; b: + to + ; : -+ to -+ ; i : -+ to -+ ), in contrast oxygen consumption (vo~ -ml/min x m e) does not change significantly in either group (a: i -+ to -+ ; b: -+ to -+ ; i: -+ tu -+ ; : -+ to +_ ); oxygen exlraction ratio decreases. this study in critically ill/septic patients demonstrates, that in this group of patients studied blood transfusion at a base-line-value of > . -+ . g/dl expectedly rises do~, however, it does not improve vo=; even not in septic patients with elevated lac-values. paclitaxel in a new anticancer agent, extract from the bark of the yew tree (taxus brevifolia), employed against breast and ovarian cancers resistant to chemotherapy. it promotes the polymerization of tubuline, and disrupts the normal microtubule dynamics. hematologic toxicity, hypersensitivity reactions (bronchospasm, urticaria and hypotension), and peripheral neuropathy are the main reported toxic effects. cardiac side effects are rare: atrioventricular blocks of higher degree are reported in . % of patients; congestive cardiotoxicity was discussed only in one trial in patients treated with paclitaxel and doxorubicin. we describe the history of a -years-old worn an with a breast cancer, diagnosed in , initial staging t nim , treated with mastectomy, axillary lymphadenectomy, andchemotherapy with a cumulative dose of anthracyclines of mg/m until august . the patient complained of dyspnea and severe hypotension immediately after an intravenous infusion of mg paclitaxel, given over hour for the treatment of bilateral, malignant pleural effusion. at echocardiography die left ventricular ejection fraction was reduced to %. she died days later because of a severe cardiac low output with hepatic and renal failure; an impressive hepatic cytolysis was observed. the post mortem examination confirmed the dilatation of the cardiac cavities, especially of the right ventricle, bilateral pleural fluid, and ascites. the histology was suggestive for a cardiomyopathy secondary to anthracyclines. the electron microscopy revealed a deposition of an unusual pathological pigment in the myocytes; subsarcolemmal deposition or membranous were absent. we hypothesize that paclitaxel was the cause of a major hypersensitivity reaction with shock and severe hepatic cytolysis, worsening the myocardial damage induced by anthracyclines. the possibility that a low doge of paclitaxel could directly increase anthracyclines cardiotoxicity -as decribed in the medical literature -will be discussed. objectives: activated endothelial cells release soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selectin (selam- ). sicam- , svcam- , selam- , and inflammatory cytokines were determined. methods: sicam- , svcam- , and selam- were determined by elisa. tnf-a, il- , and il- were also measured by elisa. endotoxin was measured by an endotoxin-specific endospecy test after pretreatment of new pea method. results: the sicam- and s vcam-i levels were significantly higher in the septic multiple organ failure (mof) and sepsis groups than in the non-septic mof group. the selam- level was slightly higher in the septic mof group than in the sepsis withut mof group and non-septic mof group. the increases of soluble adhesion molecules were not in agreement with changes of plasma endotoxin level. levels of soluble adhesion molecules were correlated with the levels of plasma tnf-a and il- , but the level of il- . discussion and conclusion: the slcam- and svcam- levels in septic patients closely reflected the severity of the pathophysiological conditon. it was possible that the release of sluble adhesion molecules were not stimulated by plasma endotoxin, but endotoxin in the local infectious region. tnf-c~ and il- also were suggested to be involved in the release of these soluble adhesion molecules. obiectives: cardiopulmonary bypass (cpb) surgery is associated with a systemic inflammatory response attributable to the release of various inflammatory mediators and the activation of complement or coagulofibrinolytic system. in addition, adhesion molecules, such as icam- , elam- , and vcam- , appear to be of central importance in the inflammatory process following cpb surgery. we previously reported the effects of a synthetic protease inhibitor, fut- , reduced release of inflammatory cytokines (tnf, il-lg, il- ), activation of complement (c a, c a) or coagulofibrinolytic system (tat, pic, fpa) and protected platelet function (gpib, gpiib/llla) following cpb surgery. methods: in this study, we analyzed fut- on soluble adhesion molecules following cpb surgery. patients undergoing cpb surgery were divided into two groups, group a consisted of patients who received omg of fut- in priming solution, followed by a continuous infusion at mg/kg/hr during cpb in addition to initial heparin dose of mg/kg. group b, a control group, included patients who were injected with heparin only. the plasma slcam- , selam- , and svcam- concentration was measured by elisa. results: every soluble adhesion molecules decreased during cpb in both groups, and rose after cpb. selam- and slcam- reached their peaks on hours after cpb and on pod respectively in both groups, but they remained lower in group a (selam-i: . + . vs. . • ng/ml, p< . , slcam-i: • vs. • ng/ml, p< . ), svcam- , in both groups, remained lower than preoperative levels, but did much lower in group a. conclusions: fut- reduced adhesion molecules and suggested to be the effect on postoperative organ dysfunction. in the last few :,'ears the conditions of treatment in continuous hemofiltration/hemodiafiltration were discussed controversially. a significant removal of tnf-alpha and il-i could be demonstrated in cvvhd. the aim of our study was to investigate the elimination of tnf-alpha, l- , il- , il- , s-cd- and ifn-gamma in cvvh by measurement in plasma and hemofiltrate of critically ill patients with an acute renal failure. the patients of our study were treated with a continuous veno-venous-hemofiltration (polysulfone-filter, blood flow: - ml/h, filtration rate ml/h). the samples, hemofiltrate and plasma, were taken one hour after the start of treatment. the patients suffered from septic shock ( ), the so called hepatorenal s~aldrome ( ) and a severe pancreatitis ( ). the cytokine concentrations were measured with elisa-method. in contrast to elevated concentrations in plasma for tnf-alpha ( cases), scd ( cases), il- (l case) and il- ( cases), hemofiltrates contained no activities. only il- was removed in significant amounts with even higher levels in hemofiltrate than in plasma. this phenomenon was described so far for tnf-alpha and il- and may be due to the absence of metabolic properties (possibily enz~natic) in hemofiltrate. it can be shown, that tnfalpha, il- , il- could not be eliminated in cvvh with a filtration rate to ml/h. in contrast to findings of other investigators with a higher filtration rate (> ml/h), we found no significant concentrations of tnf-alpha and il in hemofiltrate. we conclude, that for a significant removal of important cytokines higher filtration rates (> ml/h) are necessary. objectives: multiple organ dysfunction syndrome including liver and renal impairment is a fatal complication in patients with the diagnosis of sever sepsis. this study focused to the effects of removing toxic substances from inflamnatory tissue by hemodiafiltration. ~ ethods: eleven patients were admitted to the icu in emergency center and met the criteria of systemic inflammatory response syndrome in association with infection. all patients developed liver and renal dysfunction and were treated by hemodiafiltration with high flux membranes (fb-u:nipro). the hemodiafiltration were performed times using nafamostat mesilate as an anticoagulant in hours with l of substitution fluid (hf-b:fuso). the serdm levels of endotoxin, cytokines, endothelin-i (et-]), human neutrophil elastase ~ -proteinase inhibitor complex (hne-pi), fibronectin (fn), lactate, and amino acids were measured before and after the hemodiafiltration. the hemodiafiltration would be effective to renal dysfunction by reducing endothelin and beneficial to tissue metabolism represented in fisher's ratio, but might be harmful to respiratory function by activating neutropila in patients of severe sepsss. background : intermittent hd may be poorly tolerated in the early phase of arf in hemodynamically unstable patients (pts). this technic may fail to achieve steady state urea low levels in hypercatabolic pts. method : nt = consecutive pts treated with hd; n = consecutive pts treated with cvvhf. hemodynamic unstability is defined by arterial hypotension and requirement of inotropie support despite adequate filling. rate of change in urea (u), ereatinin (cr), k + , ph were computed from a linear regression .analysis of data vs time in each treatment group during the first days of application of the two technics (anova). dally worst values were recorded. results : hd-group : apach% score = _+ ; mean number of organ system failure (osf) = . -+ ; mean blood pressure (mbp) = • mmhg (first day of application of hd). cvvhf-group : apachen score : + ; osf = -+ ; mbp = + mmhg (first day of application of cwhf discussion : during the first days of application of hd/cvvhf, u and cr decreased much more rapidly in the cwhf-group. k* and ph were maintained within normal range in the two groups. initial mbp which was much lower in the cwhf-group significantly improved during the application of cvvhf while mbp remained unchanged in the hd-group. conclusion : despite higher severity of disease in cvvhf group (apachen score, osf, lower initial mbp), we obtained a better performanco with cvvhf regarding the decrease of u and cr and the improvement of mbp. in relation to the different and continuous renal replacement techniques, the continuous venovenous one is the alternative method to continuous arteriovenous for critical patients with acute renal failure (arf). we present you our experience with cvvh in patients with mof. in our intensive care unit (icu) patients with mof were treated with cvvh in the period between january in to march in . the mean (• age of our patient population was , • years, being % male and % female the whole patient population was with mof iust at the moment the technique was accomplished; % was in mechanical ventilation, % needed vasopressor support and % required both of them (mechanical ventilation and vasopressor support) apache ii score mean of the patient population was , ~: , (range - ) and ati of them were with arf oligoanudc. technique: cvvh was accomplished using a single-d~al iumen catheter, ptaced in either a temoral or subclavian vein by the stand ard seld{nger technique. pol{sultone hemofitiers were also used, and the extracerporeal circuit used standard arterial-venous blcod tubing. blood flow and hence oltrafiltration pressure, within the circuit was generated by a roller blood pump. the modulus has a roller pump, a pressure transducer connected in an arterious and venous line, such as an air-transducer which is adapted to a drip-chamber in the return way. the replacement used was a peritoneal dialysis solution. medicine , st. george's hospital medical school, london. england. hepatic sinusoidal endothelium shows a major inflammatory response in porcine sepsis that can be attenuated by the administration of dopexamine hydrochloride. dopexamine is a beta and dopaminergic receptor agonist. the specific beta adrenoceptor antagonist ici has been shown to reduce the protective effects of dopexamine. we investigated the effect of this antagonist on hepatic ultrastructure in porcine sepsis. six pigs ( - kg) divided into groups were anaesthetised and intubated. cardiac output and portal blood flow were measured using standard techniques. the groups were; placebo, (peritonitis induced); blocker, (peritonitis induced and pg/kg ici bolus infused then given hourly). caecal content was aspirated and peritonitis induced. colloid was infused to maintain pawp at - mm hg for eight hours the animals culled, hepatic tissue removed and prepared for electron microscopy. in the placebo group hepatic endothelium was swollen and the sinusoids occluded by wbc. but in the ici blocker group, much of the sinusoidal endothelium was absent and there where large extra sinusoidal spaces among the hepatocytes. an assessment of the two groups showed worse hepatic architecture in the blocker group. the b antagonist blocked any protective effect of endogenous beta adrenoceptor agonist (adrenaline) on hepatic endothelium in porcine sepsis. george's hospital medical school, london. england. dopexamine hydr chloride, a beta and dopaminergic receptor agonist reduces hepatic damage in porcine sepsis. we tested dopexamine's effect on cerebral oedema. the beta adrenoceptor antagonist ici was infused to block any protective effect of dopexamine. nine anaesthetised pigs ( - kg) were randomised into groups; placebo, (peritonitis induced); dopexamine, (peritonitis induced and ~tg/kgdar of dopexamine infused); blocker, (as in dopexamine group but in addition pg/kg ici bolus given then infused at that rate hourly). caecal peritoneum was induced and colloid infused to maintain pawp at - mmhg for eight hours when the animals were culled, cerebral tissue removed, prepared for electron microscopy and digitisation. digitisation of the area of oedema surrounding the blood vessel and expressed as a percentage of the micrograph. . _+ . , dopexamine . + . ", blocker . + . . data expressed as mean + sd. significance p< . . * dopexamine compared to placebo and blocker. in the dopexamine group the area of tissue oedema was significantly lower than either the placebo or blocker groups. there were no significant differences between the placebo or blocker groups. the antagonist completely blocked the protective effect of the drug on cerebral oedema in porcine sepsis. beta adrenoceptor stimulation is protective of cerebral oedema in porcine sepsis. objectives: the hemodynamie~ of hepatic circulation during multiple organ failure (mof) have not been suffleienly studied. we investigated liver hemodynamics in two subgroups of patients with mof, those with either liver or lungs as the main organ of involvement. methods: three groups of patients were created: i) mof-hepatic involvement (mof-hi) ( patients) with bilirubin > . mg/dl and lung injury score < . , it) mof-ards ( patients) with respective values < . and > , iii) patients with head injury with respective values < and < , served as group control. all patients were in haemodynamieally stable state with an oxygen delivery index > ml/min/m prior to measurements. two swan-ganz catheters 'were inserted, one in the hepatic veins and one in pulmonary artery and the following measurements were determined: the hepatic vein free pressure (hvfp), the hepatic vein wedge pressure (hvwp), cvp, paop and co. the gradient of hvwp-hvfp represents liver perfusion pressures. by injecting contrast media at dose of iml/lokg with the balloon inflated to achieve sinusoidai image, the hepatic blood flow (hbf) was concluded by the time in seconds of media removal after balloon deflation. results: the co, cwp and cvp were comparable to all three groups. namely, for mof-hi, mof-ards and control groups the mean (+sd) value of co was . _+ . vs . _+ . (ns) and . _+ . respectively, of the paop was . +_ . vs +: (ns) and . + . respectively and of the cvp was .+. . vs . + . (ns) and . respectively. in contrast the two mof groups were different after the cut-offinclusion criteria ie the mean (+sd) value for bilirubin was . + . vs . + . ( < . ) and . _+ . respectively and lung injury score was . objectives: oxygen delivery (do ) and oxygen consumption (vo ) are increasingly monitored parameters in the icu. there still remain controversies about an oxygen supply dependency in critical illness particularly with respect to vo determination by either indirect calorimetry (vo m) or tick calculation (vo c). the purpose of this study was to investigate the changes in vo m and vo c following do increase. methods: the relatives of critically ill patients (mean age years, mean apache ii , mean mof-score ) gave their written informed consent to participate in this institutionally approved, prospective study. do was increased by fluid loading (hydroxyethylstarch %: mean volmne ml, mean duration of infusion min) and catecholamine support (dobutamine: mean dose , ~g/kg/min). changes in vo m and v c were recorded sinmltaneously before, during and following interventions. calorimetry was obtained with the metabolic monitor integrated in the ventilator (puritan bennett, carlsbad, ca adaptive endocrine response of organism to septic shock consisting in activation of the production of adrenal hormons, renin -angiotensin -aldosterone system (raas) and other hormonal systems has an influence over microvascular changes in these states and for development of multiple organ failure (mof). in patients with peritonitis of different origins ( nonsurvivors and survivors) were followed the changes in cortisol level and raas by radioimmunological methods and many variables for evaluation of respiratory, renal, hepatic function, coagulation etc. as a signs of mof. it was observed significant increase of the level of cortisol ( +_ , nmol/ i), aldosterone ( , • , nmol/i). by factorial statistical analysis we found significantly high correlations between hormonal changes and respiratory function (for example r=- , , p < , between cortisol and pao ; r = , , p < , between cortisol and d (a-v) ; olso renin -cao r=- , , p < , , renin d ~,vl o r = , , p < , ). such significant correlations was found and for raas with respiratory, renal function, byproducts of arachidonic acid thromboxan b and p fla, soluble fibrine degradation products etc. these correlations between the degree of endocrine changes and multiple organ failure in patients with septic shock produced by peritonitis suggest that their effects upon peripheral vascular resistance and constriction of the splanchnic, splenic, renal and other organ vasculatures are not always with physiologic expediency and there are perhaps the possibilities of therapeutic influence. intredu~on : dopexamlne has previously been shown to control hyperkalaemia ia patients with acdto renal failure (arf), however effects on the subsequent course of art are undomunente~ ob_iectlv~ : to evaluate clinical progress in patients with acute renal failure (arf) in an intensive care unit (icu) with regard to biochemical control, need for -and time to -dialysis, and outcome in patients receiving dopexamine. m~ods : consecutive patients meeting standard criteria for diagnosis of arf were included in the study. full cardiovas~dar, biechemical and intervention/outcome details were recorded. dopex.~min~ was infilsed at a dose of pg/kg/min in conjunction with a regimen of inotropir support and blood volume optimization. resn]~ : following the intzoduetion of dopc',~mine ilrinr vohlmes increased slightly over the next hrs fzom + ml/ hrs to + ml/ hrs (ns). data expres,uxl as mean + sem. three patients ( %) became polyuric with urine output > ml/hr within days and did not need dialysis. in the remaining patients the time to dialysis (to correct acid-base deficits or volume overload) was . + . days. serum potassium levels were well controlled. day or immediate pre-dialysis levels were . + . mmol/l compared with pre-lreatment . + . mmol/l overall mortality in this series was / ( %). duration of acute dialysis in survivors with renal recovery was . +_ . days. patients ( %) progressed into chronic renal failure and needed continuing renal replacement therapy. no adverse cardiovascular altects were seen at this low dopoxami~ dose although its competitive inhibition to adrenergic reuptake mechanisms meant that doses of pressor agents could often be reduced. : dopcx:~minr nsed in conjunction with inotropic support and blood volume oplimitntion, can safely postpone, or even avoid, the necessity for acute haemodialysis in icu patients. no evidence of tachyphylaxis to the effect on serum potassium levels was seen over the duration of the study. hen'era m., suarez g., dagn d., varela a., ramos j., garoia jm, aragdm c, jurado l, medina a. icu. hospital regional. malaga. spain. objective: to evaluate the haemodinamic tolerance to the veno-venous continuous hemefiltration (vvchf) system in patients with systemic inflammatory response sindrome (sirs), and the possible beneficial effect of this technique on the haemodinamics in these patients. material: patient admitted to the icu, with diagnosis of sirs and monitored with a pulmonary artery catheter at the beginning of wchf. we performed a complete haemodinamic study to all these patients (cardiac output, vascular resistanoss, ph and co in arterial and mixed venous blood samples, saturation of pulmonary mixed venous blood, do and vo calculations and temperature) and determined the respiratory mechanics (compliance and pao /fie relatinship) before starting the procedure, after minutes operating with the ultraflltrate branch closed (without filtered fluid production), afler and minutes of zero fluid balance bemofiltration and after minutes of filtration with negative balanos adjusted to the patients conditions. for the statistical analisis we have performed the anova test over the mentioned variables. results: we have not detected statisticaly significant differences of the analyzed variables before the beginning after operating the pun'@ for minutes without filtered fluid production and after minutes of zero fluid balance hf. only temperature shows a meaningful decrease in time. objectives: among many organs, playing the important role in pathogenesis of multiple organ failure, the particular place is taken by the intestine. ~ethods: the study was carried out in dogs !~n"~h pi was modelled by severe operative trauma (ot). the dcm was estimated by the indices values of work time (wt), contraction frequency (cf), mean amplitude of contractions (~ac) and motility index (mi) measured by method of tensography. "sl", created on the basis of sorbit and sodium lactate ( mosm/l), was injected in the dose of .o ml/ kg into v. cephalica antebrachii after hrs of ot. the results of the present study are the evidence of "sl" stimulative action on dcm and are experimental ground for "sl" using in complex therapy of pi in clinic. with splanchnic venous blood pc p.f. laterre p. goffette, j.p. fauville, a. poncelet, p. loneux, m.s. reynaert. intensive care unit, st. luc univ. hospital, brussels, belgium. determination of gastric intramucosal ph (phi) by gastric tonometry using the henderson-hasselback equation is expected to allow the detection of splanchnic ischemia in critically ill patients. because of bicarbonate concentration and acidbase balance influences on the calculation of phi, it has been proposed to use arterio-gastric pco,_ gradient [p(gast-a)co,] to assess splanchnic perfusion. htpothesis : pcoz in the gastric mucosa is in equilibrium with intraluminal co z and with co, in the blood leaving the stomach (mesenteric and portal blood). objective: mesure pco; and ph in portal vein blood and compare its value with pco and phi obtained simultaneously by gastric tonometry. material and method : in a patient ( y.), a fiberoptic catheter (baxter r) was positionned in the portal vein after transhepatic stent shunt repermeabilisation. hemodynamic parameters, do, (vigilance n baxter), gastric co and phi (tonometrics baxter) and portal blood gas were determined at regular intervals. results : sets of data were obtained and are expressed in mean + sd. gastric pco z was , + compared to , + . mmhg for portal pco . phi was . +._ , vs . +._o, for portal ph. no correlation was found for these parameters. p (gast-a) c was . + mm hg vs + . mm hg for p (portal-a) coz (no correlation). there was a good correlation between do e and p (portal-a) co z (r = , ) [figure] but no correlation with p (gast-a) c . obiectives: desaturation is a common finding during haemodialysis (hd). pulmonary oedema might be one cause for impaired gas exchange ( ). the aim of this study was to quantitate the amount of extravascular lung water (evlw) and gasexchange in chronic renal failure patients during and after a regular hemodialysis session. methods: chronic renal failure patients without symptoms or diagnosis of cardiac or respiratory disease were studied at the start (i), at the end (ii) and two hours after (iii) a regular bicarbonate hemodialysis session. the double-indicator dilution method, with indocyanine green and the stable isotope h as tracers, was used to measure evlw ( ). arterial bloodgases and endtidal co were registered. evlw data was compared to a group of renal healthy patients ( ). dcp n evlw, ml -pao , mmhg h~o +, nmol/l control group - -- l _+ "* -+ _+ crfgroup ii -+ ~ +- ns -+ "(" iii +- t _+ ns -+ t ** p < . dcp i from dcp , t p < . dcp li or i from dcp i, :~ p < . dcp ii from dcp i the evlw at the start of dialysis was larger in the crf group than in the control group. the evlw decreased significantly to a level not different from the control group in response to the reduction in weight after hd. pao~ was normal at the start of hd and showed a nun-signficant reduction after hd. paco ( . + . kpa) and etco ( . + . kpa) were unchanged while h o+ decreased and bicarbonate increased significantly. conclusions: the elevated level of evlw at the start of hd did not impair gasexchange. the decrease in evlw did not inhibit the decrease in pao . the reduction in h + followed by a fall in alveolar vantilation is the most plausible cause for the decrease in pao in bicarbonate dialysis. . prezant lung ; : - . . wallin j appl physio ; : - . a. dona~ d. battis& l col~ r danieli, d. achill~ l viglienz;~ c. giov-anaini, p. piaropao~ oblectives: to verify if intraoperative modifications of mtramucosal gastric ph (phi) below the normal lowest value . , can be predictive for important complications, as perforation, sepsis, mof or death. methocls: we have considered patients who andenvent major abdominal surgery. all patients received the same drugs in pre-anaesthasia, the same type of anaesthesia (balanced anaesthesia) and the same treatment with h -bloekers. after the induction of anaesthesia a gastric tonometer was positioned and a catheter was positioned in the radial artery. during the operation, every minutes, the following parameters were measured at the same time: phi, arterial ph (pha), blood lactate, mean arterial pressure. in follow up we considered death and complications happened during the hospital stay, in relation to intraoperative phi falls below . . results: among the patients, had a drop of phi below . during surgery. in three of them this fall was a single episode and happened within the first hour after the begiluting of the operation. after that phi rose to nomml values until the end of the operation these patients had a normal post-operative period, without complications, the other patients had a fall of phi during the demolitive manoeuvres. two paticots of them died. the first had a lowest phi= . and the second . . the first one ~zs operated on for hepatic istiecitoma, suffered a complete del'dseenco of the surgical wound on the th day after operation and died on the th day, the second one was operated on for a hepatic carcinoma had an intraoperative haemorrhage and died ~vo hours after the end of the operation. the other patients with a fall of phi had a lowest phi= . . . . . . . respectively.the first patient,operated onfor sigmoid carcinoma, underwent on a second operation for a transmural necrosis of the colic segment on the th day; the second one, operated for carcinoma of the right colon, had a cardiac ischelnia on the th pest-operative day and a dehiscence of the surgical wound on the th day: the third one, operated on for a sigmoid carcinoma, had melena in h post~ operative da b, and finally the fonrth patient, operated on for carcinoma of the tight colon, suffered a fistula of the surgical enteral anastomosis.all these patients were discharged alive from the hospital. the other patients, who had not reductions of phi ditring the operation, had a normal pest-operative period, without complications. conclusion: phi was able to predict the arising of some complications, probably due to intraoperative ischemic events. we can say that gastric tenometry, for its low invasivi.ty, can be included among the intraoperative monitoring in patients that tmdenvent on major abdominal surgery. (ttd),t"ea~rrerj.~ of hours duraticn. all l:atients nm.'-~ms_(~lly va~ ated in eantrol wcde ard_ la':'ad a a,~m--ganz catheter, with optic fibers for contirums mmsuremmt of svo mic studies were performed, c~e before the hegir~ of hd, c~e rain after the ~, ~ne at the middle, ~ne rain before lhe erd ard one rain after the erd of hd. paired t test ~as used far slatistical eval~ti~n. results: daring i~d there was a significant'reductton (p<o.~) of: c~tr~ venc~s eres~.re ( ve)emm to . ~ ~, ) ~arn'~w capil~ ~f~e pressure (i<~p) fr~n to ~mg hg, ) i~ from to . mmg hg. ~here was also a less pmnameed bat also-slatistics/ly significant r~ucticn (p<o. ) of: i) s~o~ from to patients undergoing surgical reconstruction of the aorta due to anenrysms of its abdominal part may develop transient and sometimes sustained episodes of dysoxia despite the conventional appeoreneas of being adequately resuscitated. indirect masurement of gastric mussel ph (phi) is being widely evaluated as a minimally invasive and sensitive means of assessing the adequaey of tissue oxygenation in these circumstances. the duration end degree of gastric intramucosal acidosis are related to the risk developing injured gastrointestinal tract end its putative consequences, i.e. translceation, cytokine release, organ dysfunction end failure, sepsis end death. measurement of phi is obtained indirectly by measuring pc in the lumen of the stomach with a silicone balloon tonometer (tonometrics, inc., worcester, ma, usa) and the bicarbonate concentration in arlz,,rial blood, end substituting these two values in the henderson-hasselbalch equation. objectives: to evaluate whether perioperative phi changes are predictive of complications end outcome end how they compare to standard haemodyuamic and oxygen trensport parameters. methods: patients ( males and female) urtderwent surgical replacement of abdominal aortic anonrysm with the aortic simple or bifurcated grail. patients were operated on eleetively, had an emergency surgery for raptured enentysm. haemodynamic, arterial ph and bicarbonate concentration measurements were taken before and after induction of anaesthesia, after cross-clamping and declamping of the aorta end at admission to itu. phi calculations ware done at the sime time except before induction, as tonometers were inserted after patient had been asleep. we used pulmonary utilizing a computer billing survey as well as hospital service transfer data from a month period ( / - / ), all obstetric patients that were transferred to the med/surg icu were identified, as well as their diagnoses and procedures. twenty-eight obstetric patients were transferred to the med/surg icu, compared to , deliveries occurring during that time period for a . % rate. the following procedural indications for icu transfer occured: insertions of endotracheal tubes, arterial catheterizations, temporary tracheostumy, and venous catheter. the following medical diagnoses were found: hypertensive/eclamptic episodes, hypotensive episodes, pulmonary embolism, mitral stenosis, and coagulation deficiency. there were four episodes of respiratory failure ( %). the historical rates of respiratory failure from the medical literature seen at a university hospital ore higher than those at our community hospital despite comparable icu transfer rates for critically ill ob patients. objectives: to evaluate the usefulness of several isss used in order to predict risk of death (rd). design: prospective data collection for months in a multidisciplinary -bed icu. methods: data from consecutive patients admitted to the icu from / / to / / were studied. all the necessary informations were stored in a computer using special software for every day computation of three isss (saps, saps ii, apache ii) and of the rd predicted by saps ii, mpm , mpm and odin. data from days of hospitalisation were used for comparative evaluation of isss and rd, while sensitivity and specificity in death prediction (cut off point of rd = %) were evaluated from data collected during the day of admission (saps ii, rpm , odin) or after hrs (mpm ). agreement between rd predictions was evaluated by bland and altman analysis. results:our results were the following: objectives: a) to create and validate software specially designed for the collection of demographic data and estimation of illness severity and predicted rd and b) to provide data necessary for the evaluation of the effectiveness and the efficiency of our icu. design: prospective data collection in a multidisciplinary -bed icu. methods: prospective data on specific physiological variables, selected demographic characteristics, comorbidity and the reason for icu admission were recorded every day for consecutive patients admitted to the icu from / / to / / . data were entered into a portable computer using specially designed software allowing the calculation of usual illness severity scoring systems (isss) and the corresponding predicted rd. results: we studied men and women, with a mean age of years. we conclude that, although observed mortality was higher than predicted rd, this difference was not statistically significant. the fact that the sd of predicted rd was too large, limits the usefulness of isss predictions for a comparative evaluation of different icus. objectives :the importance of objective evaluation of patients prognosis at their admission to an emergency department is clear. the aim of this study was to appreciate the prognosis of patients with the simplified acute physiology score ii (saps ii), and correlate this score to the prognosis and orientations of patients. methods : the score which is a reduced form of saps ii was calculated from clinical variables and laboratory items for patients. sensibili}y (se), specificity (sp) and accuracy (ac) were calculated to evaluate the performances of saps i . thresholds were calculated with the youden's test (se+sp- ). results : patients were admitted in the intensive care unit (icu)and patients in medical units; patients died. the saps ii was higher in patients which died than the survivors ( , + , vs. , + , , p< , ; respectively), the best threshold was , se was de %, sp was %, the ac was / . thus for patients admitted in icu than in medical unit ( , : : , vs. , + , , p< , ; respectively); the best threshold was , se was %, the sp was %, the ac was %. conclusions : these preliminary results suggest that saps ii can be used to determine the short term prognosis and the destination of patients seen in an emergency department. design: data was collected on all admissions over a six month period. all patients had a screening hiv elisa test. confirmatory ifa tests, western blot and flow cytometry were performed on hiv positive patients. the institutional ethics committee considered the major clinical impact of the study sufficient cause to waive the patient's right to informed consent, icu staff and patients were blinded to hiv results. following discharge patients were given the option of being advised of their hiv status. setting: the study was conducted in a bedded surgical icu at a tertiary care teaching hospital. patients, participants: all patients admitted during the period in question were included. interventions: "all patients were treated according to standard icu protocols. there were no interventions. results: most patients were admitted following trauma. there were no patients with aids, hiv positive and hiv negative patients. with respect to the latter two groups, the mean age and sex distribution was similar, there was a significant difference in organ failure ( % versus %, p < . ) and septic shock ( % versus %, p , : ) but no difference in icu/hosp[tal mortality or duration of icu/hospital stay. flow cytometry changes in hiv positive patients were consistent with the quiescent phase of hiv infection. conclusion: while morbidity is higher in hiv positive patients, there is no difference in mortality. hiv status should, therefore, not be an exclusion criterion for icu admission in this patient population. , n= ) and january-march (period , n= ) were studied. interventions: a resident micu team led by a trained intensivist took over the medical care from the primary physicians when the patients were admitted to the micu. the intensivist also vetted micu admissions and decided on micu discharge. in addition, there was a resident respiratory therapist to attend to vendlatory care during office hours. after office hours, the care of the micu was delegated to the on-call team on a rotational basis among the medical departments. results: the patients in the two groups were similar with respect to age, sex, race, source of admission and apache scores. the icu and hospital mortalities decreased from . % to . % (p=ns) and . % and . % (p=ns) respectively in period . the mean icu and hospital stay was also decreased from . __+ . to . + . days (p=ns) and . __+ to . • . days (p=ns) respectively. the improved micu length of stay for survivors in period was statistically significant ( . • . days vs . • . days = . ). there was no significant differences in the vse of peritoneal dialysis ( . % vs . %) and mechanical ventilation ( . % vs . %). however, utilisation of intra-arterial lines and pulmonary artery catheters increased from % in both to . % and . % respectively in period . conclusion: the duration of critical illness was reduced in period . hence, we believe that the closed |cu which was staffed by an intensivist and had the services of a respiratory therapist was beneficial for the care of the critically ill. the intensivist, was also more likely to utilise invasive monitoring. in the absence of liver transplantation, intensive care for patients with acute hepatic decompensation arising from alcoholic liver disease (ald) is indicated only for those who are likely to benefit from conventional means of organ support. we have attempted to elucidate potential risk factors and the efficacy of organ support in relation both to hospital outcome and icu costs so as to allow the earlier identification of relatively futile intensive care in this group of patients. methods: over a period of one year, ald patients ( males; females; median age years, median apache ii score ; hospital mortality %)with severe complications ( [ %] with bleeding oesophageal varices, [ %] with hepatorenel failure, [ %] with respiratory failure, [ %] with septic shock, and [ %] others) were studied in our liver icu. organ system failure, daily therapeutic interventions and icu costs were assessed using a patient management system (riyadh intensive care program). results: whilst survivors had a significantly lower admission apache ii score compared with non survivors (medians and , p< . ), or more organ systems in failure in the first hours of icu admission was associated with a % ( ) mortality. mortality was also related to child's grading and the numbers of organs supported. of the patients who received more than one form of organ support only one survived. organs supported mortality a (n= ) % none / ; % b (n= ) . % one / ; % c (n= ) . % two or more / ; % the icu costs for the patients were only s but s ( %, patient days) was utilised by the patients who died, giving an effective cost per survivor (ecps) of s . although the cost of treating the patients with or more organ systems in failure on the day of admission was s ( % of the budget) the ecps was s . conclusion patients with ald who have or more organ systems in failure early in their icu course have a poor prognosis and in the absence of liver transplantation, traditional strategies of organ support are ineffective. this begs the question whether such costly care is appropriate as although the ecps in this sub group is comparable with other patient groups with multiple organ failure, their outcome is considerably worse. objectives: to evaluate the economic impact to the healthcare sector of using dopexamine hydrochloride infusions to deliberately increase perioperative oxygen delivery in high-risk patients. methods: effectiveness data were obtained from a controlled clinical trial in which surgical patients were randomly assigned to either a control group (n = to receive best standard optimal fluid resuscitation perioperatively, or a protocol group (n = ) to receive, in addition, an infusion of dopexamine hydrochloride to increase the perioperative oxygen delivery index to greater than ml/min per square metre. resources consumed by patients during treatment were recorded prospectively and costs of resources at / prices were obtained retrospectively. cost-effectiveness ratios were estimated by dividing the total cost for each treatment group by the total number of patients in each group and by the clinical outcome of mortality days postoperatively. results: in the protocol group, there was a % reduction in mortality days postoperatively (p = . ), a significant reduction in the number of complications (p = . ) and a reduction in length of stay in the icu and surgical ward. the average cost per protocol patient to achieve a . % survival rate days postoperatively was s , , resulting in an average cost of s , per surviving protocol patient. the average cost of a control patient was s , to achieve a . % survival rate days postoperatively, resulting in an average cost of s , per surviving control patient. the use of dopexamine to deliberately increase oxygen delivery perioperatively generated a cost saving to the nhs of s , per patient together with a % reduction in mortality at days postoperatively. hence, the cost per surviving protocol patient was s . less than the cost of a surviving control patient. conclusion: the additional cost of dopexamine in protocol patients was offset by a lower incidence of complications and a shorter stay in the icu and on the surgical ward. hence, increasing oxygen delivery perioperatively in high-risk surgical patients saves both money and lives. objective: although king's college criteria are widely used, indication and timing for liver transplantation in acute liver failure is still far from certain. long-latency sensory evoked potentials -a proven measure of metabolic brain dysfunction (grimm et al. lancet ; : - ; madl et al. lancet ; : - ) -are markedly affected in patients with acute liver failure. serial sensory evoked potential recording should provide very useful information for the management of patients with acute liver failure. methods: recordings of standard bilateral sensory evoked potentials were performed in patients with acute liver failure. findings were focused on cortical n peak -a stable negative deflection occuring • ms after median nerve stimulation in healthy subjects, which can be recorded by skull electrodes over the sensory cortex. results: nine patients recovered spontaneously, patients were referred to emergency liver transplantation, and patients died. in all patients who recovered spontaneously, n peak was detectable between and ms. all patients who were referred to liver transplantation and of patients who died, developed a loss of a prior detectable n peak during the course of acute liver failure. objective: to determine high risk arid low risk patient groups in a medical intensive care unit regarding short term and long term outcome. methods: data on all admissions of the year were collected prospectively. according to their mode of admission patients were classified as admissions by the physician staffed ambulance service (as), admissions through the emergency department (ed)i referrals from non-intensive care wards (ni), and secondary referrals from other hospitals (oth). outcome was assessed in terms of in-unit mortality, in-hospital mortality, and long time mortality. patient groups were compared using the \ -test. life table analysis were per{ormed by kaplan-meier method comparing patient groups by log-rank test. the software spss for windows . . was used for statistical calculations. results: in-unit mortality: / patients ( . %) --oth . % > as . %> ni . % > ed . %; p = . . in-hospital mortality: / patients ( . %) --oth . % > ni . % > as . % > ed . %; p = , . mean survival time in days after discharge: as < ni < oth < ed ; p = . . conclusions: despite an excess in-unit mortality of secondary referrals from other hospitals the iongtime course of this special patient group is not different to others. solsuam, j, marrugat*, g, mirs, j, nolla, a, vazqu~z-sanchez, l alvamz, ~ioio s xndioina i~siw. ir~itate l(~icipal da l~sti~isn l~di~*, ~ospits dal objective: to study the influence of modifiable variables (complications derived from therapeutic activities) on the prognosis of ~atients admitted to the icu indapemently on thn severity of illnsss. patients am methods: between january asd ]lay data from , patients over years of aqe who retained in the icu for mare than hours ~ere pr~pectively regiatered. a cohort st~ly with follo~-~ nf patients durin~ ~eir stey in the hospital was deni~.el in all patients, reasons for a~issien, principal diagnosis sad severity of illn~s moasared by the saps scare vare recorded. fastens affecting patients' outcome that my be proventsd or modified included technical :omplisafioss, heapital-acqnired infections and in~pro~riate therapeutic decisions. a logistic regression model was used to assess the relative risk (l~} for in-heapital mortality adjusted for each variable. results: ic~ mortality ~s . % and in-hospitul mortality . %. patients who died showed a higher spas score then survivors ( , ~ i ,i). after adjusting hy severity of illness, co~;licetices that statistically increased the risk of in-hospital death were septic shock secomery to hoapitul-acqdired infection ( ~ . ; % el, . to . ), pmo~othor~x related to mocasnical ventilation (@ . ; % cl, . to . ) and delay in the insertion of a fln~-quidod catheter (ii~ . ; % ic, i.i to . ). col~lusien: registration of complicaticas derived from therapeutic activities is a valuable tool far quality central in the icu. g, ~i~ , j.l mle~ma, j, ~amqat*, j..~lla, a, vazquez-saltemz, f, alvamz , servioia de nndicina l~siu. i~stitutu ~icipal de ln~sti~acidn ~ i:a*, hospital dsl objective: to dstsr~ine the incidence of self-extebatien and its effect on ~ortality. patients and ]~etheds: betveen january and april , all i~tiente in whom selfextubatien w~s registered were inclnded in a prospective study. patients were divided into @nee who needed r~intabatinn within hoers and those who did not. in all patients, dsmoqraphie and ciinical data were recorded as well as icii mortality, in-hoapital mrtality and severity of illness according to saps score. eta were analyzed usi~ the cbj-square test for cathgorical verinbls, the analysis of varianc~ (anva) for aontinuc~ ~ria~les and a leqi tic regression anal~is to estimate the relative risk (iiii) for mortality as result of celt-nxtt~ation after adjusting for severity of illness. results: a total of intnmtsd patients amre stndied. self-extu~atien occurred in ( . %) patients and . % required reintuhot~pn. when a co,arise was made between patients who did not required reint@atinn and patien~.s who did, statistically significant differences in eqe ( . v_s . years, p = .~ ), ~verity of illness ( . ~ . spas score, p = . ), dia~isstia category ( s. % v_s . % of patients with res~iratury conditiono, p = , } and mean length of stay ( , ~ , days~ p = . ) were fo~m, a~ter ad~sti~ for severity, patients with self-ext@atinn who did not reqnired reintalatien showed a . iir for mortality ( % ci, .i to . ) as co~arod with patients in when self-ext@ation did mot occur. conclnsien: self-~extamtice that does not require reint@ation is associated with a isamr in-hospital natality probably dt~ to a prolonged period of weaming. patients' admissions to ices am often delayed doe to the shortage of beds available. @ile amaltieq icu admission, these patients are treated in observation nits of @e emergency services which bare ,either tile structure nor the trained ~reomenl that are available in leb~. objective: to daterdno the effect on the patient's proqusis of a delay in tile admission to the icu when criteria for icij admission are fulfilled. ~terials and methods: between jme am l?ece~ber all patients who fulfilled criteria to be almittod to the ic who for waste~r reason retained in tile observation unit for more than hours were included in a prospective stedy. in all patients, des~raphic end clinical dabs amre recorded as well as severity of illness aencrdi~j to saps score. a cesucontrol dasi~ was eend with a total ss~ln of , patients who suffered no delay is admission to icii over a period of years. data wen analyzed using the chl.-squ~re test (to aeons the association hetwenn in-patienty mortality end categorical vari~lns) and a maltipln logistic reqression model to sstimta odds ratio for) for in-hospital mortality as result of delay in icy admission as compared with early ad~issi| after adjusting for severity of illness end use of assisted mchenical ventilation. ~ &ults: a total of patients remained in the observation nit for more than hours with a del w in igd admission of . _+ . hoers. assisted mechanical ventilation was requited in % of patients and only monitericatien in %. itsse patients were cspared with ntients from the tet~l sample ratchod by age, sp~ score and rennoss of admission. in-hospital mortality for cases warn % as compared with . % for controls (p = s). after adjamtilg fen spas, age and mobamioal ventihtien, no statistically significant differences between both ~renpa were foam, altho~b there was a tendency towards a higher mortality amen@ patients with delay in icu admission (or = . ; % ci, , to , ). conclnnien: ~se findings suggest that prognosis of critically-ill patients is no worse as a result of admission to the loll being deln~d for borers. all data appropriate for the calculation of the apache ii score (aps) together wi'th other specific cardiac details relevant to these .patients were collected daily, verified and enter~ into a computer database. results: patients were studied. six patients died and five of thee underwent cardiac surgery. the mean aps was for survivors and t for non-survivors (p < . ). the mortality ratio was . and the major markers of mortality were apache ![ score, presence of chronic ill health, mean duration of ventiiation, mean length of icu stay and need for emergen~ surgery. sixteen percent ( ) of icu bed days were occupied by % of patients (non-sarvivors) which resulted in cancellation of cardiac sot#cat sessions in momhs. conclusions: this study concludes that apache t could be used as an audit tool in a cardiac surgical icu and demonstrates the severe compromis~don of cardiac surgical throughput by a few non-survivors, organ to determine the number of organ failure free days (offd) in a cohort of survivors and non-survivors with sepsis syndrome followed over a day period. ) to determine sample size requirements for clinical trials utilizing a increase in the number of organ failure free days as the primary outcome as opposed to mortality. methods: beginning december through to april , patients who met inclusion criteria of the "cardiopulmonary effects of ibuprofen in sepsis syndrome" and who did not have hiv/aids. brain death or moribund state were prospectively identified. presence or absence of failure of organ systems (pulmonary, cvs, renal, hepatic, gi, hematologic, & cns) was recorded daily until death or until days. a score of one was assigned to each organ system free of organ failure in patients still alive, ie, maximum daily off score= , maximum day off scorn= , sample size estimations were performed for variable detectable differences in off scores (delta). alpha was set at . (two-sided), with n/group = [(z a +z b ) o conclusions: a clinically relevant increase in off days may be detected with as small a sample size as to patients per group. this represents a significantly smaller sample size than needed to detect a change in mortality from % to % ( % relative risk reduction) where the n/group= . scoring patients in this manner prevents a lethal inte~entien from providing an improved organ failure score. in addition, an intervention that prolongs survival must also provide greater organ failure free days in order to be counted by this scoring method. survival as an outcome provides no information about the quality of that survival. off days provides a measurement of burden of illness. interventions which lessens this burden may be just as valuable as those that decrease mortality by providing a measure of the quality of survival and by decreasing costs of care. they may also prove to be an accurate surrogate marker of mortality. the advantage of this approach is that the event rote is much higher and sample size requirements are subsequently smaller. this would mean that clinical trials can be completed faster and at lower cost. outcomes such as mortality could then be assessed at a later date utilizing recta-analysis. we suggest that the use of off days is a valid outcome measure that may be utilized in clihieal trials of sepsis syndrome. the icu is perceived by many as being a stressful environment for both patients and staff. stress has been defined in three ways: a stimulus producing a particular response; the physiological and psychological response to a stimulus; an interaction butwom an individual and their environment. stress is currently thought to be a dynamic system of stimulus and. response which takes into account the individual's perception of the stimulus and their ability to respond effectively. stress may, therefore, be positive and allow personal development but an individual unable to respond effectively to a stimulus will experience negative effects or strain. critical illness is an intense stimulus to which the body needs to respond effectively. physiological responses are vital and most of intensive care involves supporting these. alternatively, blocking them, for instance with atom(date, increases mortality. psyehological responses are also vital but often poorly appreciated because of communication problems. many of the problems patients experience in an icu are evidence of psychological strain. this can be exhibited in various ways, for instance, anxiety, depression, passivity and confusion. dealing with critically ill patients is perceived as stressful. we recently studied occupational stress in our icu. most aspects of intensive care were not generally perceived as stressful indicating a self-selectien of icu staff. the most stressful aspects of icu work for nursing staff were the structure of the organization and career opportunities. medical and nursing staff had different stressors and different coping strategies. support for occupational stress, therefore, should focus on the individual and concentrate on information and communication. atmosphere, and especially at intensive care units, we face up to daily decision making. in most cases these are taken on the basis of personal opinion and the processing of a very limited amount of information. rising need to optimize the results of medical attendance becomes necessary to set structured system of d@cision making in which ethical basis have a sp@dial significance in view of next considerations: -we live into a pluralist society in which the importance of values is different. -most persons consider health as the first value only in the event of illness. -medical resources available are limited, whereas medical, attendance demand from population increases in a way many people consider it unlimited. in consequence, it becomes necessary to set up priorities in patients treatment. ehtical basis that rule decision making are essentially these ones: i. beneficence: to provide the patient that is being treated the highest profit. . non maleficence: it is our first duty to avoid hurting or damaging the patient."primum non nocere" . autonomy: in every particular medical attendance, the patient has ability to decide by himself. . justice: as equity: to provide the same treatment for those who have the same pathology, ignoring another factors such as age, sex or race. severe application of these principles can cause difficulty, which resolution requires a systematization of decision making. ( - ) . the lenght of stay between survivors and non survivors didn "t show statistical significance (p = . ). the mean aiii score when considering all admissions was , ( - ) . the initial score between survivors and non survivors showed ststistical difference ( . vs . ) respectively (p < . ). univariate logistic regresion analysis demostrated a % increment in death probability for every points augmentation in the aiii score with a sensitlbity of . % and specificity of . %, the roc curve showed that the best cut off point for death prediction was points with a sensitivity of . % and specificity of . %. if a patient is classified as high risk (> ) the bayesian analysis showed a . probability of death and for one class(fed as low risk (< ) a death probability < %. conclusions: the first day aiii score in this population showed to be a good discriminator between survivors and non survivors, and the risk of death augments as the aiii does. in this population an aiii score > points is asociated with a greater risk of death. using the aiii score in conjuntion with the clinical judgement will help clinicians reducing uncertainty in the every day decision making and better predict outcome, the results from this study should been taken with caution because the data were obtained from a small sample. objective: the quality of life has been considered a "uniquely personal perception" resulting from a mixture of health related factors and social circumstances [t. m. gill, jama , : ] . the aim of this study was to evaluate two measures of pqol in intensive care unit (icu) admitted patients. patients and methods: during icu stay and six-months after hospital discharge, co-operative icu admitted patients were directly interviewed about their pqol. we administered ftrstly the uniscale (pqolu) [sage et al crit. care med. , : - ] and then a step verbal scale (pqolv): best, good, fair, poor, worst. of the studied patients, at the first interview, were able to use both scales, but ( . %) understood only the verbal one. at the second interview, patients were not able to answer, used both scales and only pqolv. statistical analysis was performed using wilcoxon signed ranks, spearman rank correlation, student's t and chi square tests. results: of all cardiac surgery pts, pts ( . %) died in icu. they were males ( . %) and females ( . %). their mean age was (+ ) years and mean ef was . (+ . ). nineteen pts ( %) had low (< . ) preoperative ef. mortality was . % in the coronary artery bypass grafting (cabg) group (n= ) and . % in the valve replacement (vr) group (n= ). in the cabg +vr group, mortality was . % (n= ), and . % in the remaining pts (n= ). cardiogenic shock was the sole cause of death in pts ( %), septic shock in pts, whereas sepsis in combination with ards in pts, sepsis and stroke in two pts. in addition, pts died from cerebrovascular accidents, one from ards and one from pulmonary embolism. the pts who died in the icu had a significantly longer bypass and aortic cross clamp time and received more blood transfusions (p< . ) than a matched control group that survived to icu discharge. the duration of mechanical ventilation and length of icu stay were greater in the pts who died in the icu than in the control group. conclusions: . although cardiogenic shock is the main cause of death ( %)in cardiac surgery pts, sepsis and cerebrovascular accident are relatively frequent causes. . patients who died in the icu had longer bypass and aortic cross clamp time and received more transfusions, compared with the control group. . although renal or hepatic failure contributed to death in some pts, they were not the primary cause of death in any patient. objectives: evaluate the acute and follow-up outcome of patients (pts) treated with primary ptca (without prior thrombolysis) in acute myocardial infarction (ami) after and up to hours after onset of typical thoracic pain ("late" primary-ptca). methods and patients characteristics: from / to / consecutive pts with ami were treated by primary ptca in the wuppertal heart center pts ( , %) were admitted to our hospital > hours and < hours after symptom onset with ongoing chest pain and typical ecg-changes.mean age was years ( - ). pts were male, four female. % had an anterior wall myocardial infarction, % suffered an inferior/postero-lateral wall myocardial infarction.two pts were in cardiogenic shock at admission. singlevessel-disease was documented in . %, multi-vessel-disease in . %. average time of onset of pain to recanalisation was min ( - ). angiography revealed timi-flow in . % of the pts, timi-flow i in . %, timi-flow ii in . %. average follow-up (fu) period was months ( - months). timi iii lv-ef ~ -day major late re-late flow p.i.* aeute/fu mortality bleeds infarction mortality . % %/ % . % . % . % % early mortality occured in the two pts, who were in cardiogenic shock at admission no pt required emergency coronary artery bypass grafting.restenosis > % was seen in % of the pts. conclusions: "late" primary ptca achieves a favourable high recanalisation rate of about % (timi ill-flow) in our study group. additionally, there seems to be a trend for lv-ef improvement in follow-up. early high mortality is influenced by the patients admitted in cardiogenic shock. there might be a trend for increased major bleeding complications. objective: to assess the validity of saps ii (new simplified acute physiology score), comparing it with the previous version, (saps), in a sample of patients recruited by giviti, a network of icu's representative of the italian icu system methods: measures of calibration (goodness-of-fit statistics) and discrimination (receiver operating characteristics curve and area under the curve) were adopted in the whole sample and across subgroups differing in relevant prognostic characteristics. of the patients recruited during one month period, a total of patients were included in this study. for the purpose of the comparison of the two scores, patients with less than years, or having cardiac surgery or staying in the icu less than hours were excluded. vital status at icu discharge in the whole sample and at hospital discharge in half cases wher adopted as outcome measure. re$ ~: saps ii fits the data equally well compared to the older version (goodness-of-fit p= . and in the new and old versions, respectively) but its performance is somewhat better in terms of capability to distinguish patients who live from patients who die (areas under the curve . and . , respectively). furthermore, saps ii is better in terms of uniformity of fit across relevant subgroups, although substantial over prediction of mortality was observed in trauma patients and in patients admitted without organ failure to be intensively monitored. saps ii performed very wet] also in the subsample where hospital mortality was the dependent variable.satisfactory measures of calibration (goodness-of-fit p-- . ) and discrimination (receiver operating characteristics area= . ) were observed. c nr saps ii, a multipurpose scoring system developed in an international study, retains its validity in this independent sample of patients recruited in a large network of italian icus. although it has shown a good performance when adopted to predict icu and hospital mortality in the entire sample, further investigations are warranted. the observed over prediction of mortality in a few subgroups indeed call for a through assessment of the impact of confounders and biases on model performance when saps ii is adopted in samples that do not reflect the "average" icu patient. objectives: ) assess the effectiveness in a group of intensive care units by means of a quality performance index (qpi); ) assess the efficiency by means of a resource use index (rui); ) evaluate the performance of individual icus with respect to both indices (clinical and economical) while controlling for severity of illness. critical from ucis in catalonia patients alearic islands have been included in the study. inhospital mortality and weighted hospital lenght-of-stay (los) have been considered the outcome variables. severity of illness has been measured with the mpm ii at admission. in each icu, expected mortality has been obtained adding the probabilities of dying for its patients. expected los has been estimated adjusting a second order polynomial to the severity of illness. performance indices have been obtained by dividing the observed by the expected outcomes. re~ult~: the overall qpi was . and it ranged from . to . in the icus. the overall rui was and it ranged l~ont . to . . there was not a trade-offpattern between clinical performance and resource use. objectives: teaching hospitals often provide [cu care across a variety of specialized services. overall, this approach appears to result in the best risk adjusted survival rates, but at the highest cost (critical care medicine ; : - ): recently, there has been increasing focus on markers of overall hospital performance. however, in large teaching institutions, such markers may fail to detect intra-institntional variation at a large tertiary care medical center. methods: first intensive care unit (icu) day, acute physiology and chronic health evaluation iii (apache iii) and active therapeutic intervention scoring system (tiss) data were collected on random admissions to specialty icus with beds (range - ) between february i and december l, . post-operative solid organ transplant recipients were excluded. units included general medical, general surgical, and trauma, neurosurgery, cardio-thoracic surgery, and coronary care units. data were analyzed for risk adjusted outcomes: icu and hospital mortality and length ef stay (los); risk of requiring active cu treatment; and icu readmissinn using apache iii risk prediction models. results: the study icus cared for a diverse group of patients. mean apache iii scores ranged from . - . ; predicted risk of hospital death ranged from . - . %. standardized mortality ratios ranged from . to . with icus performing significantly better and performing worse than predicted (p< , ). los ratios and icu readmission rates ranged from . to . (ns) and . to . % respectively. patients predicted at low risk of requiring active icu treatment ranged from , to . % conclusions: there was wide variation in the mean level of patient severity between icus. after controlling for this severity, outcomes also varied widely. no clear pattern of overall institutional performance was evident. these data suggest that efforts to assess performance, improve quality, and maximize efficiency must be focused within individual units. programmatic evaluation of outcome allows for focused review of the processes of care contributing to good outcome (best practices) and where to focus ongoing quality improvement and cost reduction activities. background and method : we compared icu mortality in different age groups presenting with the same severity of disease. we assessed severity of illness by the physiological day -apache~ (physio-aa) score (thus excluding the age related points). for each of the following physio-a n score intervals ( - ; - ; - ; - ; > ) , we compared tcu mortality within age intervals (< ; - ; - ; - ; - ; > years - , - , - ) . in these groups mortality may be twice higher in the > years patients than in the _< years. mortality does not vary with age in low (physio a n = - ) and high (physio a n = > ) risk groups. in the low risk group, mortality is low in all the age intervals because of the begninity of illness. in the high risk group, extreme severity of disease probably blunts the impact of age and leads to high mortality rates in all age intervals. introduction: to access the actual social/clinical outcome of the patients who undenvent intensive care therapy oct) is rather difficult, quality of lilr is not easih.' defined and ohserver subjectivity is a prime factor in the evaluation. mortality ratio after discharge must be established and its causes understood. obieetives: the propose of this stud)-is to look into the mortality ratio that occurred on a series of patients that undorwent ict at our unit from of the ~iew point of severity of the original illness and the diagnostic groups. material and methods: during the period of one )-ear ( ), patients were treated at the unit, of them died, and ~ere not matched in our series because os incumpletc records. thirteen patients died in hospital after their reference to other departments, twelve patients were lost after discharge. thus. at the end. only patients were evaluated on the fu. the, were classified into the follov ng three groups: acute medical, elective surge d and acute and emergency postoperative. the patients were seen at , and months after discharge. the, were evaluated in accordance to their abili~, to being self supported in their daily life and capecity to fully return and hold to their pre~ ous jobs. apache scores were evaluated for each of the three groups and correlated to the icu dead, hospital dead, and mortality after hospital discharge, spss package was used for statistical analysis. remlts/conclasions: data shows that / patients died after discharge from the hospital, of ~itch nine died in the first three months. seventy-eight per cent of the patients were fully self supported in their daily life and % showed some kind of handicap. fosty-nine per cent of the patients wore on retirement either due to age or some form of chronic disease, when admilled to our unit. thirty-two peg cent had not been able to return to work, because the" were incapacitated on discharge. only % had return to their fully jobs but the period of the stu~, is not enough for all of them to be fully physically recovered. preliminmy statistical analysis shows us significant differences among groups. the aim of the present study is to compare the prognostic performance of five general severity indices ou coronary patienta and to find out if a proper ntatistical hundling of these indices could provide better results in these patients. methods: saps ii, mpm ii (mpm ii i mpmp ii ), apach ii end gaprik were evaluated o~ patients with acute myocardial infurction admitted to intensive care units from catulunye. calibration and discrimination were calculated for each index. calibration was calculated by th bosmer-lemeshow test. discrimination was evaluated by the area under the relative operating characteristic (roc)curve. if a model did not show a good performance it was customized using multiple logistic regression. finally, tworeduced models were developed, one fro~ the mpm series (mpm ii cor) and one from the group apache-saps (sapsiicor).their performances were again evaluated. results: discrimination was high enough for all models. neverthelees, oelibration of apache ii, saps ii and mpm was not satisfactory. thus,mpm ii , saps ii and gaprik were customized for coronary patients using the logits of both models, and obtaining good calibrations. mpm ii , and apache-saps were adapted and reduced to (mpm ii cor) end to variables (sapsiicor), respectively . both models showed better oalibrutions end discriminations than the original models. conolusion| models developed for multidisciplinary patients show a good discrimination when applied on aoronar i patients, but some needed customization in order to improve calibration. the number of variables of the principal model can be reduced (even to or variables) without loosing prognostic accuracy. objective: to compare the ability of two methods to predict outcome for intensive care patients. methods: we included consecutive intensive therapy unit (itu) admissions with an itu stay> hrs in a month prospective study (exclusion criteria: burn injury and age < yrs). data were couectsd applying the criteria described by the developers [ , ] . the definition of coma (mpm ii) was modified and the best assessment within in's, rather than the admission score, was used. statistical analysis included classification tables and receiver operaung characteristics (roc) curves to assess discriminative power, and lemeshaw-hosmer statistics and calibration curves to test accuracy of prediction. results~ average abe was yrs (ranse: - ) with a male:female ratio of . : . the actual hospital mortality was . %, mean predicted death rates were . % (mpmz ii) and . % (ap hi). non-survivors had siguitlcanfly higher predicted risks than survivors applying both methods (p< . l, t-test). the total correct classification rates (tccr) for apache iii were bett~r for all decision criteria applied (tccr, decision criterion %: apache ]/i . %, mpm ii . %). the area under the roc curve was . (ap iii) and . (mpm ii) confirming the better discrimination of apache ill. accuracy of risk prediction was similar for both models (ap nl ~ - , mpm b ;( - , lemeslmw-hosmer). showing some fluctuation, calibration curves lay close to the ideal line for predicted risks -< % with increasing deviation for higher risk groups (s. figure) . apache iii underestimated the risks of hospital death for almost all risk groups (curve above diagonal), whereas considerable overestimation for predicted risks > % ceenred with mpm~ii. objective: to assess the goodness-of-fit of the apache iii model for british itu patients. methods: we prospectively studied a cohort of adult patients consecutively admitted to a medical-surgical itu over a period of months. patients with burn injury, age < yrs and itu stay < hrs were excluded. using a eomputerlsed database, we routinely recorded hrs apache ill scores. predicted risks of hospital death were computed by critical audit ltd, london. accuracy of risk prediefion was assessed by hosmer-lemeshaw chi square (;( ) statistics and calibration curves [ ]. discrimination was tested employing classification tables and receiver operating characteristics curves (roc). restths: the mean age of the male and female patients was yrs (range: - yrs). of these patients, % were medical admissions, % were admired after emergency and % after elective surgery. the observed hospital mortality was . %, the overall mean predicted death rate was . %. mean predicted risks were siguifieanfiy greater for nonsurvivors ( . %o) than for survivors ( . %, p< . l, t-test). apache iii showed good calibration (z -~ , lemeshaw-hosmer). however, the calibration curve lay above the diagonal for almost all risk groups reflecting the tendency to underestimate actual mortality (s. figure) . the best total correct classification rate (tccr) was . % (decision criterion: %). the area under the roc curve was . % confirming the good discriminative ability of the model. objectives: the aim of this study is to point out the discrepancies between needs and actual treatment of less severely ili patients admitted in italian intensive cam units (icus) requiring only intensive monitoring, and verify the substantial likelihood of data comparing those collected from a national short term study with a regional long ternl use. ~: less severely ill patients ("observed patients") were only monitored; they did not require intubation, even if for a short period (less than houm) or major cardioeiranlatory supports, and were neurologically normal. epidemiologieal national data were obtained from giviti group (gruppo italiano valutazione interventi in terapia intensiva); this cohort study, collected patients, in two months in summer in all over italy. regional data were echieved in a three years entlection ( -i ) in lombardia' icus from archidia group (arehivio diagnostieo), including patients. mortality, severity score, diagnostic category and some typical intensive procedures were analysed and compared in both studies. patients' disgunstie categories were defined as surgical, medical and trauma, according to the main diagnosis and the presence/absence of surgical procedures. rr observed patients account for . % and % of all icu's patients respectively in national and regional data. very tow mortality rate was found in national data ( . %) and extremely low mortality in regional data ( . %). in both studies mortality, s.a.p.s. and length of stay were much lowor in "observed patients" than in general icu's population (mortality: . % and . %; .a.p.s. score: . and ; iength of stay: % and ). homologous distribution of patients in the two studies was noted for what concern their diagnostic category, aside from a slight prevalence of tranmatised patients in the giviti study. in the two groups the surgical patients were respectively % vs. %, medical patients were % vs. % and traumatised were % vs. %. % of "observed patients" in national study and % in the regional did not received any intensive procedure. only a minority of these patients availed haemodynamie eonu'ol with swan-ganz or renal haemofiltration. conclusions: these results underline that about one fourth patients admitted in italian icus benefit an oversized slructure i, relation to the real needs of their pathology. in hot more than % did non received any advanced treatment and mortality and s.a.p.s. score were substantially lower respect to general population. the results obtained from these two studies are similar, suggesting an uniform distribution of the case mix in italy, even if a different recruitment period and a different gengraphieal distribution were used. some discrepancies in the two studies were found in the diagnostic categories moreover regarding the tranmatised patients ( % vs. %); this can be explained from the seasonal (summer) characteristic of the national study. mutuality, yet very low, is different in the two groups, but these data do not allow any definite explanation. finally these epidemiologieal survey suggest need of further studies settling more strict criteria of admission in icu. this study aims to evaluate patients outcome, quality of care and effectivity of therapy in our intensive care unit. the main goal was to indentify factors that the most influence that outcome. during . the authors collected data of patients outcome and predictor variables. overall mortality rate was , %. the most common causes of death were infection. the diagnosis of sistemic inflammatory response syndrome (sirs) and multiple organ dysfunction syndrome (muds) significantly correlate with death ( %). average length of stay was . days ~. % patients died in the first ten hosiptal days and only % after days. age was directly correlated with death % of dead were older then sixty years. an analysis of physiological variables showed that serum levels of gl~cose ( %) and natrium ( %) were in optimal physiological values. serum proteins ( %) and haemoglobin ( %) levels were inversely related to death. multivariate showed that alveolo-arterio difference in content was the most informative of all mortality predictors (mean value , mmhg in % patients io>mrnhg). factor that most influence the patients outcome was infection (sepsis) and muds. use of predictive indicators of outcome in critically ill patients may help to assess treatment regimens and to compare patient groups. acute physiology and chronic health evaluation (apache if) score (crit. care had. ; : - ) and the sepsis score of elebute and stoner (br. h surg. ; : - ) have been used, objectives: to compare sepsis score and apache ii score in predicting outcome of critically ill patients. methods: overall survival during the past years for patients in our icu was calculated = % (prior probability). the outcome of patients who were admitted to our icu for > hours was observed. apache ii score on admission, patient predicted risk of death (apache ii risk) and the sepsis score on the first day of antibiotic course were prospectively recorded. discriminant function analysis of the scores in relation to outcome was performed. results: apache ii and sepsis scores in the survivors were significantly lower than in those who died ( . i . v~s . • . and . • v's . • . respectively p < . ). correct prediction of outcome by each score is shown in discussion and conclusions: although both scores have been previously evaluated in predicting outcome of icu patients, studies of the sepsis score were conducted in small numbers of patients or involved additional measurements not routinely available. this study demonstrates that the sepsis score alone or in combination with apache ii score is more effective than apache ii score in predicting outcome. objective to test the hypothesis that resuscitation titrated against gastric intramucosal ph (phi) improves survival in critically ill patients as suggested by gutierrez et al~. method emergency admissions to the intensive care unit were randomized into control and intervention groups. in the control group phi was measured at , and h while in the intervention group phi measurements were made hourly for h. both groups were managed according to the same guidelines to achieve the following targets: mean arterial pressure > mmhg, systolic arterial pressure > mmhg, urine output > . /ml/kg, haemoglobin > g/dl, blood glucose < mmol/ , arterial oxygen saturation > % and correction of uncompensated respiratory acidosis. if the phi was < . after achieving these targets, or after maximal therapy to achieve the targets, patients in the intervention group were given fluid to ensure an adequate cardiac preload and then dobutamine at then mcg/kg/h, titrated against phi. this additional therapy was continued until h after entry into the study. in each year patients were subdivided in two series with random selection, so that the st series contained abeat / and the nd / of the patients. the st series of all the years constituted the devdoping data set and the nd series the validation data set. with data of the st series ( patients), we created the predictive model, using stepwise logistic regression (bmdp, usa). each patient has been evaluated in die st, th, th and th day, calculating for each lime the apache ii score (for a total of records), independent variables were, besides time and apache ii of the time ( michaloudia g,, melissaki a., alexias g., gogafi c., kolotoura a., krimpeni g., pamouktaoglou f, filias n. objectives: to determine the medical staff's attitude towards various ethical issues methods : between january and february , anonymous questionnaires were sent to intensive care units, all over greece. results : questionnaires ( , %) were replied and returned back. of them , % were answered by male and , % by female. the doctors replied in the following rate : , % aged up to , % aged between and , % aged over . questions were answered and were divided into main topics, as following: . admission criteria: limited bed availability was the main cause for refusing admission in , % of icu's. , % evaluated each case's viability and only , % used some prognostic score system. , % of icu's accepted all cases and a significant percentage ( %) gave in to pressure coming from their colleagues ( , % female and , % male). . informing the patient/relatives: only , % was willing to tell the whole truth, while , % had given selective information.. in the case of iatrogenic incident, , % withheld it, because either they feared legal implications ( , %), or lost of trust ( , %). doctors are asking consent from the patient and/or his family, in order to include him/her in research protocols, in a rate of , %, while only , % found informed consent necessary for the proposed treatment procedure. . withdrawal of therapy/dnr orders/organ donation: , % were willing to withdraw complex treatment in patients with short life expectancy, except of administi'ating intravenous fluids, feeding and analgesics. in , % such a decis~n was unanimous, while the percentage of those carrying it out was , % ( , % female, , % male). in case of brain stem death , % ( , % female, , % male) withdrew any life support. , % would like therapy withdrawal to be legally established, while only , % would perform euthanasia, if there was substantial legal cover. for these cases, relatives' consent was considered to be necessary from a percentage of only , %. , % considered organ donation to be a necessary proposal, while , % refused to ask the patients' relatives for an organ donation, either because they didn't have the psychological strength for it ( , %), or because they doubted the procedures' objectivity ( , %). note: in greece, icu beds are less than % from the total number of hospital beds available. only a percentage of - % of these admissions comes from the same hospital, with a potentially direct evaluation. usually an icu doctor has to be informed through the telephone. finally, employment conditions in greece are such that any changes of the medical and nursing staffare limited. conclusions: the mathematical model we found has been validated also in the second series and the discrimination capability increases with time. using this model we can evaluate the probability of survive at every, time. its application at different times permits a better evaluation of haemodinamically instable patient trend. introduction: the feasibility to assess pulmonary capillary pressure (pcap) offers the opportunity to determine the longitudinal distribution of pulmonary vascular resistance (pvr). the purpose of this study was to measure pcap and to calculate pvr to determine whether relevant shifts in the distribution of pvr could be expected after routine cardiac surgery. methods: the study population consisted of consecutively admitted patients after cardiac surgery. surgical procedures included coronary artery bypass graft (cabg) (n= ) and mitral valve replacement (mvr) (n=t ). pcap was estimated by analysis of the pressure decay tracing after pulmonary artery occlusion. after estimation of pcap precapillary (ra) and postcapillary resistance (rv) was calculated. a complete set of hemodynamic variables was obtained at hour and at hours after operation. results: there were no significant hemodynamic changes during the first hours after surgery. the mvr group maintained pulmonary hypertension and higher levels of pcap. ra/rv, reflecting the longitudinal distribution of resistances, remained unchanged. however, rv predominated ra during the postoperative period in both groups. objectives: evaluation of the influence of long-term continuous i.v. administration of the ace-inhibitor enalaprilat on regulators of circulatory homeostasis. methods: t trauma and sepsis patients randomly received either . mg/h (group i, n= ) or . mg/h (group , n= ) of enalaprilat i.v. or saline solution (control, n= ) as placebo for days. plasma levels of endothelin- (et), atrial natriuretic peptide (anp), renin, vasopressin, angiotensin-ii, and catecholamines were measured before injection of enalaprilat (='baseline' values) and during the next days. results: except for et, plasma levels of all vasoactive substances exceeded normal range at baseline. angiotensin-ii significantly decreased during enalaprilat infusion ( . mg/h: from . • to . • pg/ml; . mg/h: . • to . • whereas it remained significantly elevated in the untreated control patients. vasopressin increased only in the control group (p< . ) and decreased after . mg/h of enalaprilat. et remained almostunchanged in group , whereas et increased significantly in the control patients (from . • to .t• on the th day). catecholamine plasma levels (epinephrine, norepinephrine) markedly increased in the control group (p< . ), but they did not change significantly throughout the study period in both enalaprilat groups. conclusions: continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat beneficially influenced systemic and local vasoactive regulators of the circulation, which are normally increased in the critically ill. thus patients at risk of (micro-) circulatory abnormalities may profit from enalaprilat infusion. objectives: to determine the time taken for hemodynamic and gas exchange variables to a reach stady-state after a change from supine to trendelenburg position (trp). methods: we prospectively studied adult patients with severe sepsis or septic shock requiring hemodynamic monitoring. usual cardiorespiratory parameters were measured at baseline, min after the patient was placed in a trp and again min after the return to a supine position. a fiberoptic pulmonary artery catheter (svo~ oximetrix, abbott) allowing continuous svo monitoring wa~used. during the protocol we also continuously measured sao~ by pulse oximetry and vco~ and vo by monitoring partial concentration of o and co ir~ inspiratory and expiratory gases (deltatrac metabolic monitor, datex). therefore, we were able to monitor cardiac output variations by dividing vo~ with arteriovenous difference according to the fick equation (co-fick). results: no significant difference in hemodynamic status was observed min after the patients were placed in trp. despite the fact that no significant change was observed in co and vo~ estimated by thermodilution, co-fick had a tendency to dedrease continuously in trp and then to return to its initial value when patients regained supine position. respiratory gas analysis showed a small but persistent continuous increase in vco without a similar trend in vo values. conclusions: we conclude that no significant hemodynamic effect was detected in our patients after min in trp. evaluation of vo from respiratory gases analysis after a change in body's position should be interpreted with caution, since the patient may not yet have reached a stady-state after rain. since vo did not change, vco~ increase was probably due to position related changes in-pulmonary gas exchange and not to a change in patient's metabolic status. objectives: to determine whether changes in svo and/or other hemodynamic parameters during weaning trials could be used to predict successful weaning. methods: we prospectively studied adult patients with a history or clinical evidence of cardiovascular dysfunction, who were unable to tolerate spontaneous breathing (sb) for hours. for all these patients right heart catheterisation was considered necessary in order to detect hemodynamic alterations during weaning. a fiberoptic pulmonary artery catheter (svo ximetrix, abbott) allowing continuous svo monitoring was sod. hemodynamic status was evaluated ~t baseline and after one hour of spontaneous breathing through a t-piece. patients were assigned to one of two groups depending on whether they tolerated sb for hours. data were analysed by analysis of variance and unpaired student's t-test we also used multiple linear regression analysis to determine which hemodynamic variables were correlated with the magnitude of svo~ change and multiple discriminant analysis to determine if asy of the above variables were associated with toleration of sb for hours and/or successful weaning (s-w). (j physiol ; ." - ) . we tested the hypothesis that the ventilatory stimulation by dead space (vd) loading and % co inhalation is accompanied by a proportionate cardiovascular change. methods: six healthy subjects, mean age, year, performed three incremental exercise tests in a randomized order: ) inspiring air without vd (air control, ac); ) inspiring air with vd of ml (avd); ) inspiring % co ; % oxygen, balance nitrogen. the ventilatory responses were examined at matched heart rate (hr) equivalent to % peak hr. results: ventilation (vi) was significantly greater (p< . ) during the avd and co tests than during the ac test at the same work rates. end-tidal co (petco ) and estimated arterial co (paco ) were significantly greater (p< . ) at w and w. oxygen saturation was significantly lower (p< . ) during the avd test than during the ac and % co exerdse. at matched hrequivalent to % peak hr, vi was significantly greater (p< . ) during the avd and % co tests than during the ac exerdse ( l, l, and /). conclusion: we conclude that the increase in xri and petco due to vd loading and % co inhalation is not associated with an acceleration in hr. sup.ported by mrc (canada). objeetlve: the production of large amounts of oxygen radicals from the onset of ~en may be responsible, st least in part, for peroxidative damage to myocardial tissue. the aim of this study was to evaluate the time dependence of plasma tbars in patients with am] receiving thrombolytie therapy (tt). patients and m~hods: filiy eight patients admitted in icu ( men and women; mean age . - . years) rec~ving systemic tt for possible am] were ~died. all patients received recorabinant haman tissue-type plasminogen activator (r-tpa). the mean time fi'om the onset of symptoms and the be~nning of tt was . - . hours. peripheral veao~s blood samples were obtained fi'om each patient before and serially after tt ( , , and hours). tbars levels woe determined by using a spectrophotometrie technique. rq~r fusion was identified by the timing of ereatine phosphate kkmse (cpk) peak (< hours). table i list the variation of plasma eoneenlrations of tbars (mean -sd) in groups (a,b, and c) as a function of time from the beginning of tr. co,arisen oftbe time cuncentzatiens reveal a difference p<o. between group ami (a and b) versus group c. the between-groups (a-c) comparison showed significant differences (p<~). ) at , and hours fi-om de begin~g of'it. comparison ofthe , and hours eonocnlratiens did not reveafl any difference becween n~ (group b) and angor (group c). condmien: we have observed a maintenance of high level of tbars in reperfused patients enly. these results suggest that the increase of tbars levels may be due to phospholipid derangament of reperfused myocytes. objective: to detemline if tbars levels may be an early index reflecting peroxidative damage in ami patients. patients and methods: by using a spectrophotometric teclmiqtm, based on a modificatien oftbe buege and aust method, tbars levels ware determined in healthy subjects (group i) , patients with several risk factors of ischaemic cardiopathy (group if) and icu patients with possible aim ( were confirmed ami (group ma) and were angor (group iiib)). peripheral blood was obtained at the time of the icu admission in the group i . electrecardiographic data and eehocardiographic wall motion were used to identify ami location (anterior, inferoposterinr and indeterminate). statistical analysis was made with a standard statistical package (rsigma, horus hardware). , h , s, , h statistically significative increase of ' ix~e/ea.ee x~* tbars levels (p< . ) only in pstients with con/tuned ami (group ilia) . no differences were found between the rest of the groups. the figure shows the relationship between the tbars values and the time from the onset of the aim's symptoms. conclusion: we have found that in am/patients the tbars levels can be used as an early index reflecting peroxidative damage occurring to ischemie tissues. perioperative risk in patients with ischemic heart disease. the protective role of diltiazem. lg. hatziantoniou, p. tassiopoulos, c. fakiolas, ! g. foussas~ m. lycourinas perioperatlve morbidity and mortality are mainly of cardiac origin, particularly among elderly patients (pts) ~ith ischemic heart disease. we performed a randomized trial, in order to investigate the possible protective activity of diltiazem (d). methods: pts (aged zo• with a history of coronary insufficiency were subjected to major urological operations. they were randomized to two groups: group i ( pts) -p:ithout d and group ii ( pts) -d ~as administered . mg/kg iv bolus hours prior to anesthesia and . mg/kg/h upon the end of operation and for at least hours post-operatively. iv was substituted by oval administration of x mg starting the next day and for the rest of hospital stay. all pts underwent daily clinical, electrocardiographic and laboratory (ck-mb) control. results: are shown in the following interactions between the heart-lung unit and a cardiac assist device are the crucial issues for successful outcome of patients under mechanical circulatory support. several factors have been indicated and we can diffrentiate between anatomical and hemodynamic interactions. especially right heart failure and pulmonary hypertension have been proven to limit left ventricutar assist device (lvad) performance. in order to study the effects of right heart failure (rhf) and pulmonary hypertension (pht) on mechanical circulatory support, we designed an experimental study in dogs and combined in six groups left heart failure (lhf) and rhf and pht, respectively. in the control group we induced lhf with subsequent occlusions of lad and cx followed by reperfusion: in the next group we supported with an lvad during minutes starting minutes after cx occlusion (group if). in the next group we added right ventricular ischemia by occluding the rca simultaneously to the cx (group iii). these both groups we repeated only with pre-existing acute pht induced by the injection of o fm glass beads (groups vi and v). a last group was similar to group v (lhf and rhf and pht), but instead of a lvad, we used bvad support. in i and v no animal survived the second perfusion period ( hours). in ii and iii (no pht), all dogs survived in stable conditions. in iv (lvf, pht), % survived, the remainder died of incomplete recovery. in vi with bvad, only % survived. in iii and v, during occlusion of the rca, the right ventricle stopped contracting and right atrial pressure and mean pulmonary pressure equalized. this lead to a significant drop in inflow on the left heart side, which still provided sufficient lvad performance in case of absent pht (iii) and lead to death due to "low lvad output" syndrome in v. this "low lvad output" snydrome could be partly overcome by bvad support. we conclude that heart-lung interactions play a major role in lvad performance. by optimizing the perioperative management, they all can be overcome, except the occurrence of alveolar leakage syndrome. obiectives : we propose a new approach of transmural pulmtmary artery occlusion pressure (paoptm), in presence ef peep, from the folluwing hypothesis : if respiratory swings of paop are compared to those of alveolar pressure (apalv = plateau pressure -total peep), an index of transmission of airway pressures to pulmonary vessels is obtained (i t = apaop/apalv). the value of the product of it by peep can be substracted from end-expiratery paop (paopee) to obtain a calculated paoptm (paoptrnc). thus paoftmc = paopee -(apaop/apalv x peep). methods : we tested this hypothesis in patients by comparing paopee, paoptmc, and paopnadir obtained within the first seconds after disconnection from the ventilator, value of reference of paoptm in absence of intrinsic peep (peepi). at zeep, peepi was absent in patients (group a) but present in others (group b). patients were studied under the peep level chosen by the attending physician-(gr a : +_ ; gr b : _+ cmh ). results : l. gr a : paopee ( _+ mmhg) differed (p < - ) from paopnadir ( • mmhg) and paoptmc ( _+ mrahg). gr b : paopee, paopnadir, paoptmc differed between themselves ( " - , + , + mmhg respectively). . good correlatkm (r - (i. ) and agreement between paopnadir and paoptm were found in gr a, while there was no agreement in gr b (bland and altman analysis). . lung compliance (v t/bpah,) correlated well with i t in both groups (r - . ), suggesting that our hypt)thesis was strtmg even in patients with peepi. conclusions : paoptm under peep ventilation can be obtained, even in patients with peepi, from parameters easily measured at the bedside. introduction: cardiopulmonary bypass (cpb) may cause ischemia in several organ systems like the heart, brain and kidneys. reactive oxygen species (ros) are formed by subsequent reperfusion and stimulation of neutrophils by cpb. ros are harmful to biological systems e.g. cellular membranes, enzymes~ dna. many natural antioxidant systems protect against the effect of ros. in patients undergoing cabg we evaluated the production of ros by total plasma antioxidant status (tas) and lipid peroxidation measured by lipofuscin flip). methods: tas (randox, uk) and concentrations ofllp (tsuchida et al.) were measured in consecutive patients undergoing cabg. all the patients had a normal serum creatinine clearance (> ml/min). serum samples were obtained a) before operation, b) after removal of the aortic crossclamp, c) at admission to the icu, d) hours after operation, e) hours after operation. results: tas was significantly decreased after removal of the aortic crosselamp ( b, c and d lower than a), followed by a subsequent significant increase of lip ( c and d higher than b). the levels of tas and lip returned to baseline hours after operation. methods: patients with preoperative lvef< % undergoing coronary artery bypass grafting were studied. after surgery, a f femoral artery catheter was inserted and connoted to a fiberoptic monitoring system (cold z- t; pulsion medizintechnik, germany); this allows, with a double-indicator dilution technique, the calculation of cardiac index (ci,l/min/m ), intrathoracic bood volume (itbv,ml/m ), pulmonary blood volume (pbv,ml/m ) and extravascular lung water (evlw,ml/kg). with a f pulmonary artery catheter, wedge (w,nunhg) and central venous pressure (cvp,mmhg) were measured, while extraction ratio (o exr,%) and oxygen delivery (do ,ml/min/m ) was calculed. peak inspiratory pressure (pawp,cmh ) and mean airway pressure (mawp,cmh ) were measured with a varflex flow transducer (bicore,sensormedics,us). the patients were studied after minutes (to) of volume controlled standard ratio ventilation (vc), and after minutes (ti) of stabilisation period of pcirv ( % inspiratory time, % pause). vt,ve and total peep were held constant in every mode of ventilation. +_ . " *'p < , versus to conclusions: these data show that pcirv : is a safe ventilatory support also in cardiac patients with impaired ventricular function, and monitoring of itbv is more reliable to measure and optimise circulatory volume status, than w and cvp. c.ledeki-,g.rldisis,s.karotzai,c.micheilidis,m.agioutantb, g.beltapaulos. objeolivee:to evaluate the influence of lvswl on the well known correlation of sr and svo . paw eight patients ( melee end females) were included in this study regerdlen of the icu ~h"niseion couse. all paints were ,'~theta~ with e fiboroptir pulmonary artery catheter connected with an oxymetfir (r)~ so /co abbot computer.for any pulmonary artery catheter insertion, two pain= of sr and svo were obtained, one dudng inserlion and one during taking the catheter out. for any pair obtained, we eleo collected the deta concemig with the pedient's hemodynamir and oxygenation end we calculated the lvswi. were significantly (p<o. ) higher in group i. conclusion: breathing room air, the less hypoxemic patients had a rather satidactory do and tissue oxygenation (pro ) because they had properly adapted their ci. the absence of this mechanism (right heart impairement ?) in the hypoxemic patients, in spite of higher blood ne and e, was responsible for the poor do and pro . objectives: acute massive pulmonary embolism (pe) increases pulmonary artery pressure (pap) and dght ventdcular aftedoad, which may lead to dght ventdcular failure. inhaled nitdc oxide (no) selectively dilates pulmonary vessels. thus, inhaled no may be of potential therapeutic value in the management of the acute phase of pe. methods: following institutional approval, ten piglets (body weight + kg) were anaesthetised (midazolam/piritramide) and ventilated using a modified servo ventilator (siemens elema, sweden; fio . ). the following variables were obtained: systolic pap (spap), mean pap (mpap), diastolic pap (dpap), mean artedal pressure (map), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), cardiac output (co), and artedal (pao ) and mixed venous (pvo ) oxygen saturation. pulmonary vascular resistance (pvr) was calculated. to induce pe, pm microspheres (sephadex g coarse, pharmacia biotech, freiburg, germany) were injected in an amount sufficient to increase mpap to mmhg initially. rain after embolisation when haemodynamics were in a steady state (control ), inhaled no was administered. further measurements were taken min after ppm no (no ), min after ppm no (no ), and min after discontinuation of no administration (control ). the administration of inhaled no resulted in a significant decrease in spap, mpap, and pvr. the cessation of no inhalation led to a complete return to pretreatment control values (table) . co, map, cvp, pcwp, pao?, and pv~ remained unchan no administration. objectivss:evsluate the yield of recombinant tissue plasminogen activater(rt-pa, actiiyse ~ oehringer ingelheim) as a thrombolytic agent ie pulmonary embolism ie .kr~auma patients. methods: in five patients with diagnosed pulmonary embolism(blood gases, chest x-ray, echocardiography, perlesion lung scans) were given rag of actij.yse as ~ hrs infusion, followed by heparin~single j. ihjaction snd iefusion ie doses - j./kg/day).the effectiveness of rt-pg thrembo].ytic sctier~ was svaluated im . . hrs(blood gases) amd on the third dayafter t~eat-,ment(~chocardiography and lung scan). results: three hrs after actilyse was given we observed significant clinical imprevemeet,confirmed by elevation of pao and sao in dlood.echocardiegr~m on the third day showed regression of pulmonary hypertension and lung scans showed % improvement in total lung perfusien. except slight bleeding from the site of injection nc~ more thromboiytic complicatioos were observed. conclusiens: actilyse used in five hrauma patients with pulmonary embol.ism was a very effsctive and safe thrombolytic agerlt, inducing rapid and evident clinical improvement. intermittent positive pressure ventilation ( ppv) by increasing pleural pressure, decreases the pressure gradients for systemic venous return and left ventricular (lv) ejection. we have previously shown that when inspiration is synchronized with systole using synchfjv in patients with severe cardiomyopathy, that cardiac output (co) was increased relative to both ippv and non-synchronized hfjv ( ). however, it is not known if similar effects could be realized in ventilatordependent patients with lesser degrees of lv dysfunction and fluid overload. we thus compared synci-ifjv to ippv in stable patients following coronary artery bypas grafting. methods: normothermic who were stable (< % variance/h.) were studied following admission to the sicu. heart rate (hr), mean arterial (pa), pulmonary artery occlusion pressure(ppao), co by continuous thermodilutiun (vigilance, baxter, usa), mixed venous saturation (svoz) and arterial blood gases (abg) were measured after rain. of each step. ippv was simv adjusted for a rate, tidal volume and fit to insure both normal abg and a peak airway pressure < cm h,o. syncfifjv was delivered by a hfjv ventilator (acutronic) during systole with ventilator parameters adjusted to optimize abg. protocol: patients received three ippv runs (ippvi. , ) with synchfjv runs interposed (hfjvz ). statistics: anova for repeat measures and paired t-test were used to compareruns and demonstrate variability. results:no significant difference in any of the measured hemodynamic variables were seen among the ippv and synchfjv runs (table) . post hoc separation of patients by preoperative ejection fraction (ef; ef > % ; n= and < %; n= ) did not alter these results. back~ound: in man, vascular endothelium-bound ace is expressed in concentrations greater than x that in serum and is believed to be the site of synthesis of circulating angioteusin il it is unclear whether ace inlubitors interact similarly with ace in different vascular beds. coronary vessels possess all the components of the renin-angiotensin system, including ace which may be involved in normalcardiac homeostasis, as well as in the pathogenesis of various cardiomyopathies. obiecfive: to develop a method for assaying the interaction of ace inkibitors with coronary endothelium-bunnd ace in man, methods: ace a~aty was meas~ed in five patients undergoing cabg surgery, from the transeuronary hydrolysis of the synthetic ace substrate h-bpap. trace mnou~ of ~fi-bpap ( gci) were injec~d as a bolus in the root of the aorta and simultaneously blood was withdrawn from a coronary sinus catheter into a syringe containing protease inhibitors which prevented the convession of umeaet~ ai-i-bpap by blood ace. the sample was later centrifuged to separate cells from plasma and the radioactivities due to formed product (~rl-bphe) and total sh were astimated in a [b-counter. two additional such determinations of ace activity were perform~ the second in the presence of . pg/kg e (coinjected with ~-i-bpap) and the third ten minutes after e. results: all subjects were hemodynamically stable throughout the course of the there were no noticeable hemodynamic effects of e. control transcorunary metabolism of~-bpap averaged g -a: %, in agreement with previously reported data. in the presence of e, % metabolism of ~-bpap was reduced to • reflecting a • inhibition of normal ace activity. ten minutes after e, ~ri-bfap metabolism had partially recovered to :l: %, representing a -a: % inhibition of control ace activity. from this data, the dissociation constant of e for coronary ace in vivo was estimated as . x " sec "l. conclusions: we have demonstrated the feasibility of repeated, reproducible measures of coronary endothelium-bound ace activity and of its inhibition by e. this procedure is safe and can be used to study the role of ace in normal cardiac function and in card pathologies. objectives. primary pulmonary hypertension (pph) is a progressive fatal disease of unlmown origin, with median life expectancy of less than three years after diagnosis. the responsiveness of pulmonary hypertension to a variety of vasodilator agents led to the speculation that, concomitant with vascular renmdelling processes, persistent vasoconstriction is an important feature of the disease. long term use of ca-channel blockers and intravenous pgiz may improve mortality in certain populations of pph patients, but both of these treatments lack selectivity for tire lung vasculature. the aim of this study was to test the efficacy of aerosolised prostacyclin and its stable analogue, [loprost for selective pulmonary vasodilatation in pph. methods: in three patients with pph, we compared aerosolisation of prostaglandin iz (pgi ) and iloprost to a battery of vasodilatory agents (diltiazem, nifedipin, inhaled nitric oxide, intravenous pgiz). results: nebulisation of pgi and iloprost tumed out to be most favourable for achieving effective and selective pulmonary vasodilatation. pulmonary vascular resistance decreased from + to -+ dyn*s*cm (p< . ) and pulmonary artery pressure from . + . to + . mmhg (p < . ), cardiac output increased from . + . to . _+ . i/rain (p < . ), mixed venous oxygen saturation from . _+ . to . + . % (p < . ) and arterial oxygen saturation from . + . to . _+ . % (mean _+ sem of trials in patients). -month iloprost nebulisation in one patient ( gg/day in six aerosol doses) demonstrated sustained efficacy of the vasodilator r~men. conclusion: aerosolation of pgi or its stable analogue may offer as new strategy for selective pulmonary vasodilatation in pph. endothelial adhesion molecules may play an important role in the pathogenesis of myocardial cell damage, and may contribute to the progression of heart failure. we measured the plasma soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selecfin (selam- ) levels in patients with acute myocardial infarction admitted within hours after onset. peripheral venous plasma-samples were collected at the time of admission, , , , , and hours after onset. plasma soluble adhesion molecule concentrations were determined by elisa. patients were divided into groups as follows: group ; killip's class (k) and without thrombolytie therapy, group ; k and with thrombolytic therapy and group ; k and . both plasma sicam- and svcam- concentrations in group and were elevated rapidly and significantly and maintained at a high level during the first days. plasma selam- level did not change in any of the groups. these results suggest that the adhesion molecules icam- and vcam- may play a role in the pathogenesis of myocardial reperfusion injury and may indicate its severity in myocardial infarction. objectives: nitric oxide (no) is known to exert cytotoxic and negative inotropic effects on cardiomyocytes. no synthase activity has been reported to be increased in infarcted area in animal model of myocardial infarction. these findings suggest that no may be an important regulator for myocardial damage and cardiac function after myocardial infarction. we measured plasma no no -(nox) levels and estimated serial changes in acute phase of myocardial infarction. methods: subjects were patients admitted within hours after onset. venous blood samples were collected at -hour intervals on the first day, -bour intervals on the nd day and -hour intervals on the rd day and th days after onset. plasma nox concentrations were determined by griess method. results: the time course of the plasma nox levels (mea~+sem) displayed a tendency to gradually increase and to make a biphasic pattern with two peaks about hours and - days after onset (basal level; . _+ . , first peak; . !-_ . , second peak; . + . ram/l). plasma nox concentration was not influenced by the thrombolytic therapy, and nox values at the time of hours after onset were significantly correlated with maximal plasma creatine kinase level (r= . , p< . ). the levels of plasma nox in the early stage of myocardial infarction (from admission to the th day after onset) did not correlate significantly with the hemodynamic parameters (left ventricular ejection fraction, pulmonary capillary wedge pressure). conclusion: the early and late increase in no production after myocardial infarction may be implicated in the deterioration of myocardial contractility and induction of myocardial damage in the early phase of myocardial infarction. range - ) fullfilling the high risk criteria of shoemaker (colectomy , gastrectomy , pancreaticoduodenectomy , others ). patients were admitted to the icu preoperatively. arterial and pulmonary artery catheters were inserted and hemodynamics and oxygen transport were measured at admission and after stabilization to predetermined physiological end points. patients were considered stable when ci > . l/min/m , pcwp > mmhg, hb > g/l, sat >. . objectives: evaluate the acute effects of , mg ipratropium bromide and , mg fenoterol (ibf) inhaled dose on pulmonary function in nonsmocers (nb:m) and smocers (s) with sever (new york heart association class ii-iii), stabile congestive heart failure(chf) and healthy subjects. methods: pulmonary function tests were performed < h postprandial. the tests consisted el arterial blood gas aspiration followed by routine spirometry and pletismography, and single-breath gas analysis. after performance of these maneuvers, the patients was administred puffs-ipratropium bromide ( , rag) and fenoterol ( , rag). for , h, spirometry was repeated. results: in resting, pulmonary abnormalities observer in the s group were more severe then abnormalities observere in the nsm group. after treatment with ibf the improvement in pulmonary function was even more marked in patients who had smoked. the mean changes by forced expiratory volume in second(eevt) was , % (p< , t) improvement and , % (p< ,ob), forced expiratory flow betwen % and % of the forced vital capacity (fef . ) was , % (p< , ) and , % (p< , ) and maxamal voluntary ventilation (mw) was , % (p< , ) and , % (p<o, ) improvement. the mean changes in normal subjects were mild (fev increased by , %,fef - by , % and mvv by , %). we observed no adverse heamodinamie conseevence and no arrthytmogenicity. conclusion." in patients with chf the airway response to ibf is highly significant. further study is needed to determine whether therapy with ibf will load to improvement quality of life in patients with chf with dearly documented venti/atory defects. compared with unilateral ima grafts, usage of bilateral ima grafts in cabg patients causes greater thoracic trauma and further reduces blood supply to the sternum and intercostal muscles. these effects may be associated with increased postoperative respiratory complications obiectives: to study the effects of bilateral ima grafts on postoperative respiratory morbidity in cabg patients. methods: two groups of patients undergoing cabg were prospectively studied: group (n= ) received both imas as grafts and group (n= ) received only the left ima. the two groups were matched for age, smoking habits, total number of grafts and preoperative ejection fraction. pao /fio ratio was measured in all patients in the icu, at , , minutes on mechanical ventilation (mv), at , , minutes after extubation (ex) and on postoperative day (pod) . in addition, radiografic scores of atelectasis and pleural effusion were assessed postoperatively. results: group had significantly longer bypass ( _+ vs + . p< , ) and aortic cross clamp time ( +- vs + , p= , ). pao /fi ratio was significantly higher in group only at minutes after extubation (table) . there was no difference in the incidence or severity of atelectasis or pleural effusion between the two groups. the duration of mv was longer in group ( +_ vs _+ , p= , ), but the length of icu stay and hospitalization were similar. there was one case of pneumothorax in group and one case of pulmonary infection in each group. after extubation m[n min min min* rain min pod ' _+ _+ + -+ - -+ _+ _+ _+ _+ -+ _+ _+ -+ mean_+sd, *p=o, o conclusions: compared with unilateral ima grafts, the usage of bilateral ima grafts in cabg patients is not associated with increased postoperative respiratory morbidity. the diagnosis of rv ischaemia is difficult in the critical care setting. the purpose of this study was to determine the ability of rv endomyocardial and interstitial ph electrodes to detect rv ischaemia in an animal model of rv infarction produced by fight coronary artery ligation. we hypothesized that changes in transmural and interstitial ph would accompany the induced tissue hypoperfusion. rv interstitial (phint) and transmural endomyocardial ph (phendo) were measured in adult anaesthetized pigs before and serially after coronary ligation. phendo and phint fell progressively and significantly following coronary occlusion. this was accompanied by ischaemic ekg changes. the absolute and relative rates of change were greater for phendo compared to phint, particularly after minutes of ischaemia, ph was unchanged in control experiments when the electrode was placed within the fight atrial or ventricular chambers, as well as when coronary ligation was not performed. these data suggest that rv myocardial ph measurements reflect coronary ligation induced rv ischaemia, ph recorded from an electrode placed against the rv endomyocardial wall via a central vein was as useful as an interstitial measurement that required a thoracotomy. this newly described technique may be helpful in clinical settings where differentiation between ischaemic and nonisehaemic causes of rv dysfunction is important. centre. depts of cardiac surgery and anesthesiology, university of bari, italy. lung injury secondary to cardiopulmonary bypass (cpb) is well recognized. nevertheless, mechanical respiratory changes after cpb have been poorly investigated. aim of the study was to evaluate the effects of cpb on respiratory mechanics. elastance of the lung (est l), chest wall (est cw), and total respiratory system (est rs) were measured in patients without previous pulmonary disease undergoing elective cardiac surgery. there were males and females; no pleurotomy was done. cpb was carried out with membrane oxygenator. mean cpb and cross clamping times were _. and • min. flow (pneumothacograph), airway opening and esophageal pressures (pressure transducers and esophageal balloon) were measured on patients sedated and paralysed. measurements were obtained before sternotomy, at the end of cpb after chest closure, four and seven hours later. est rs, est l and est cw, were measured by occluding the airways and the end of a tidal breath. before end cpb- h after h after stemotomy closed chest cpb cpb estrs (cmh /l) . + . . - . " . _+ . * . - . * est cw " . _+ . . • . + . . -+ . est l " . -- . . - . " . -_ . " . _+ . " x + sd. * p < . : anova vs "before sternotomy". our data show that cpb induces increase in est l, whereas est cw remains unchanged despite sternotomy. impairment in est l after cpb evolves within the first hours and stabilizes hours later. during the clinical course of human imunodeficiency virus infection (hiv), patients (lots) can develop congestive and dilated cardiomyopathy syndrome (dcm). the aim of our study was to analyze the prevalence of dcm among an hiv population, its clinical and echocardiographic changes under a long term follow-up and therapy with an ace-inhibitor agent (captopril). we prospectively studied pts, % ( / ) developed dcm during the follow-up study. among this group % ( / pts) were in class i and ii and % ( / pts) in class iii and iv of the nyha classification. we divided this population in a acei+ ( pts) and acei-( pts), according to the administration of captopril. we analyzed the following parameters: age, gender, race, ivda, type of hiv, cdc classification, number of t and t type cell population and its t /t ratio, therapeutic with acei, type and number of opportunist infections, mycobacteriosis and neoplasm's. we analyzed several echocardiographic parameters, which included the initial (i), final (f) and variation (a) of the lv internal diastolic (lvdd/mm) and systolic (lvsdimm) diameters, lv % of fractional shortening (lv%fs/%), ivs and posterior wall thickness and lv mass (lvm/g). the two groups differed significantly in the following parameters: left ventricular functional indices of patients (pts) with iscjhemic dilated cardiomyopathy (idcm) have a critical value in terms of clinical prognosis of this disease. three-dimensional echocardiography ( -de) is a recently developed method that gives a better evaluation of lv morphology and function. the purpose of our prospective study was to assess the clinical applicability of this new -de method in a population with ischemic dcm diagnosis and calculate its lv indices of global and regional function. we studied a group of idcm pts, mean age _+ yrs, % male gender, using a combined -de tee approach. all pts were in class ill/iv of the nyha classification. first, ekg gated images were acquired through a mechanical pullback of the tee probe, and each set of data was transferred to a conventional ibm-pc system using a dedicated -de software. computer processing and analysis of the tee images led to a -de reconstruction matrix and off-line calculation of several lv global and regional indices. in all idcm lots the lv cavity was clearly reconstructed and end-systole and diastole in several orthogonat projections, out in multiple planes and its function quantitated using -de derived indices. mean values of -de lvesv= -+ ml, lvedv= _+ ml, lvstv= _+ ml and lvef= -+ % were obtained. for all these -de parameters, good correlations were observed with -de lv measurements obtained through biplane tee analysis of the lv cavity (r>. ; p<. ) as well as regional analysis of sequential -de cut planes. conclusion: in our group of patients with the diagnosis of ischemic dilated cardiomyopathy, this new -de method could be applied. our results show that this method allows a better assessment of the lv morphology and spatial geometry, with the calculation of global and regional indices with critical clinical and prognostic value in this particular cardiovascular pathology. simultaneous left atrial (la) and left ventricle (lv) inflow analysis assessed by pulsed doppler tee illustrate the loading conditions and reflect the hemodynamics of the left heart. we performed a prospective tee pulsed doppler study with recordings of the transmitral lv filling and pulmonary venous (pv) flow drainage in a group of patients with dilated cardiomyopathy (dcm). a group of dcm patients, mean age _+ yrs, % male were studied. this population was divided according to tee severe lv dysfunction (group slvd+ % pts; group slvd- % pts) in each pt we measured the peak velocities (vel/m/sec) and time velocity integrals (vti/m) of the transmitral early (e) and late (a) filing waves, the vel and vti of the pv systolic (s), diastolic (d) and atrial contraction (c) reversal flows. -de tee evaluation of the lved, lves, lvst volumes and lvef were obtained. we calculated other parameters, such as e/a, s/d and a/c ratios and the sum of c+a vel, that refelect la systolic function and lv compliance. + -_ . simultaneous and quantitative analytical approach of the pulmonary venous and transmitral flows and ventricular volumes improve the non invasive assessment and understanding of left ventricular diastolic function and cardiac performance in dilated cardiomyopathy patients. objectives : to assess the hemodynamic effects of fluid loading (fl) in acute circulatory failure (acf) due to acute massive pulmonary embolism. methods : hemodynamic measurements (fast-response thermistor pulmonary artery catheter) were performed at baseline (baseline) and after a rapid fluid loading with (fl ) and (fl ) ml of dextl'an (rhemacrodex| in patients free of previous cardiopulmonary disease ( • yrs) with acf (ci < . l/rain/m ) due to angiographicalty proven mpe (miller score > ) . results : are expressed as mean _+ sem and compared by anova. a significant negative correlation (r = . ) was observed between baseline rvedv[ and the effects of fl on ci. such correlation was not observed between baseline rap and the fl induced increased in ci. conclusion : fusibmificantly increases ci in acf due to mpe. however, the simultaneous decrease of arterial content due to hemodilution, limits the benefits expected from improved ci on peripheral oxygenation. obiective: to examine the hemodynamic effects of external positive endexpiratory pressure (peep) on right ventricular (rv) function in acute respiratory failure (arf) patients. methods: incremental levels of peep ( - - - cmh ) were applied and rv hemodynamics were studied by a swan-ganz catheter with a fast response thermistor for right ventrieular ejection fraction (rvef) measurement in mechanically ventilated arf patients (lis = . ~- . sd). according to the response to peep , two groups of patients were defined: group a ( pts.) with unchanged or increased rv end diastolic volume index (rvedvi) and group b (h pts) with decreased rvedvi. results: in the whole sample cardiac index (ci) and stroke index (sj) decreased at all levels of peep, while rvedvi , rv end systolic volume index (rvesvi) and rvef remained anchange d. at zeep the hemodynamic parameters of the two groups did not differ. in group a, ci decreased at peep , rvef decreased at peep (~ . %)~ rvesvi increased only at peep (+ . %) and rvedv[ reded unchanged. in group b, ci and rvedvi started to decrease at peep , 'rvesvi decreased only at peep (- . %), anf rvef was unchanged. individual behaviors of the hemodynamic parameters at the levels& peep were studied. rvedvi and ci were significantly correlated in out of:l patients in group b, and in no patient of group a. on the contrary, mpap and rvesvi were significantly correlated in out of patients in group a, and in no patient of group b. the slope of the relationship between rvedvi and rv stroke work index (rvswi) expresses rv myocardial performance. this relationship was significant (no change in rv contractitity)in patients of group b and in patients of group a. in some patients of group a, increments of peep shifted the rvswi/rvedvi ratio rightward inthe plot (rv function decrease). conclusions: in arf patients peep causes more often a preload decrease with unclmnged rv conctraetility. on the contrary, the finding of increased rv volumes during the application of peep is related to a decrease in rv myocardial performance. thus, these data suggest that application of peep might be considered as a stress test to assess rv function. right introduction: after heart transplant (ht), the right ventricle can be subject to an acute pressure overload, especially in cases where there is a preexisting severe pulmonary hypertension. this provokes right ventricular failure and, occasionally, circulatory collapse in intensive care unit. desire the advances that have been made in systems for preserving the donor heart and in post-surgical management, we have failed in our attempts to totally avoid this problem. the right ventricular function, although it usually remains within tolerable limits in these patients during the post surgery period, represents a factor which limits the results achievable in clinical transplant programmes. objectives: to determine the maximum tolerance of the right ventricle (mxtrv) when faced with acute pressure overload. to study the function of both ventricles of the healthy heart (donor) when faced with different degrees of pulmonary hypertension. to detect possible interactions between the ventricles in the absence of the pericardium to approximate the experimental model to the clinical model of ht. materials and methods: the pulmonary artery is progressively constrained in an experimental model until biventricniar failure is detected. this experiment is performed in two diffferent situations: with and without pericardial integrity. results: when pericardial integrity is maintained the mxtrv faced with a pressure overload is . + . nun hg. when this pressure is exceeded there is a circulatory collapse with a sharp fall in the cardiac output and in the aortic pressure. however, when pericardectomy is performed (model similar to ht), only • . nun hg is tolerated (p < . ). conclusions: with the pericardium open, as in heart transplant, the maximum pressure that the right ventricle can support is significantly less than with the pericardium closed. the pericardium has a positive effect in protecting the systolic ventricular interaction. it is, therefore, advisable to close the pericardium after heart transplant. jb prrez-bernal, a ordrfiez, a. heroandez, jm borrego, map camacho, c cruz, mac s~nchez, j monterrubio, c garcia, e. gonz~lez. hospital uulversitario " virgen del rocio ". sevilla. espaiqa. introduction: nowadays cardiomyoplasty isused incases of cardiac insufficiency as an alternative to cardiac transplant. after surgery the patients show a noteable improvement with the aid of this "biological circulatory assistance". some researchers suspect that the improvement could also be due to the formation of new blood vessels from the muscle that wraps the heart, nourishing the ischemic myocardium. objectives: our cardiovascular research group has proposed as an objective, the detection of any possible myocardial neovascularization through the muscle used for cardiomyoplasty. in the case that there are new blood vessels to the diseased myocardium through the wide dorsal muscle in which it is wrapped and which aids it mechanically, it would be possible to confirm the worldng hypothesis that cardiomyoplasty not only improves the cardiocirculatory funcfinn mechanically but also by facilitating a better blood flow to the ischemic myocardium. materials and methods: the cardiomyoplasty technique is described using an experimental model of myocardial ischemia. the vascular cast is achieved by injecting methacrylate simulataneously into both the coronary tree and the wide dorsal muscle, in five experiments the connections between the coronary vascular system and the vascular structure of the wide dorsal muscle are demonstrated, conclusions: we have demonstrated that cardiomyoplasty, as well as improving ventricular function, favours the revascularization of the myocardium. cardiomyoplasty could be indicated for cases of ischemic cardiopathy in patients in whom it is not possible to perform direct revacularization using conventional methods. a the therapeutic cardiological manouevres necessary in cases of ischeima reperfusion have increased considerably: fibrinolysis, transluminal angioplasty, coronary revascnlarization surgery and cardiac transplant. the appearance of a specific pathology ht acute reperfusion has been related to free oxygen radicals (for) generated by oxidative damage. objectives: to evaluate the appearance of for during a conti-olled process of ischemia-reperfusion in an experimental biological model and compare it with that in clinical cases. materials and methods: transitory cardiac ischemia was performed in five rabbits by reversible surgical ligation of the descending anterior coronary artery. after minutes coronary reperfusion was performed. blood samples were taken in the basal situation, at the end of ischemia and at , and minutes after the start of reperfusion. malondialdehyde (mda) was measured to evaluate the degree of lipid peroxidation (oxidative damage to the membrane). in ten patients undergoing conventional cardiac surgery the production of for was measured after aortic clamping. results: we observed that after minutes of reperfusion there was a highly significant increase (p < . ) in the mda values (mean = . /zmols/l). these returned to basal levels after and minutes of reperfusion. conclusions: an "explosion" of oxygen free radicals was detected very quicldy, just a few minutes after post-ischemia reperfusion. thus, if antioxidant agents are to be used to reduce the toxic effects of the for, these will ordy have a therapeutic effect if they are administered in the early phases of reperfusion. introduction: aortic connterpulsation is a ventricular assistance widely used in intensive care units in patients with cardiogenic shock as a provisional ventricular assistance. paraaortic or external aortic counterpnlsation is been investigated as a definitive veutricular assistance in those cases of terminal congestive heart failure and when heart transplantation is counterindicated. aims: to assess the haemodynamic effects of an aortomyoplasty in a biological model of congestive heart failure. material and method: as specimens, we used "large white" pigs. mean weight was kg. after the administration of conventional anaesthesia, dissection of the ladssimns dorsi muscle was performed on the samples at the laboratory of experimental surgery of our hospital. then we performed a thoracotomy at the level of the fourth intercostal space to reach the thoracic aorta. the aorta is dissecated centimetres from the exit of the subclavia and it is wrapped by the dissecated muscle. a cardiomyostimulator is provided in order to allow the synchronization between the diastole and the muscle contraction. the model of heart failure was provoked using verapamil plus propanolol i.v.. results: a significant increase of the aortic diastolic pressures and a significant decrease of the left ventricle telediastolic pressures were observed. this improvement in the parameters (dpti/tti) implies an increase of the coronary perfusion in a model of heart failure. conclusions: using the external aortic counterpulsation, the aortomyoplasty improves the coronary perfnsion and the heart efficiency in patients with heart failure in whom no conventional therapeutic action is possible. the permanent character of the paraaortic counterpulsation is it main advantage. the appearance of specific pathologies as a resuk of myocardial reperfasion has been related to the oxidative damage secondary to the release of oxygen derived free radicals (ofr). during the myocardial ischemia induced during heart surgery with extraeorporeal circulation, severalsubproducts of the oxygen are produced that shall cause toxic effects after the reperfusion which could be counteracted by the physiological antioxidant systems and/or provided by the medication. aims: to asses the ofr during heart surgery. to check whether an antioxidant treatment administered in the preoperative period make decrease the levels of ofr before and after the myocardial reperfusion and to verify whether its administration have any beneficial effect on the intra and extraoperative management. material and method: the study comprehends patients studied as two groups of individuals each (a and b). all patients underwent conventional heart surgery of valvniar substitmion or myocardial revaseularization. group a patients were administered rag/ hours of vitamin e (tocopherol acetate) hours prior to the intervention as antioxidant treatment. group b patient were not administered vitamin e. we assessed the quantity of malondialdehido (mda) to assess the degree of lipidic peroxidation or oxidative damage of the membrane during the myocardial ischemia and nm after the reperfusion. conclusion: patients who underwent heart surgery and were treated with tecopherol acetate in the preoperative period presented levels of rlo significantly lower than those who were not administered the drug, both during the intraoperative period and after myocardial reperfusion. we detected in these patients a need for antiarrhythmicals and pharmacoiogical support with catecholaminas, although not significant, both in the introaperative period and the immediate postoperative period. recommendations for the treatment of pulmonary embolism (pe) in the presence of right atrial thrombus (at) are conflicting. because of a significantly higher mortality rate due to fulminam or recurrent pe, there is a necessity to treat patients (pts) with mobile type a thrombi compared to pts with adherent type b thrombi. therapeutic strategies include anticoagulation, thrombolysis (t) or surgical thrombembolectomy. combination thrombolysis (cot), predominantly used for the treatment of acute myocardial infarction proved to prevent reocclusion of the infarct related artery at a comparable rate of hemorrhagia. benefit has been related to the alteration of hemostatic proteins by non-fibrinspecific thrombolytic s. administration of cot in pe has been performed sporadically. in the present case, a -year old male with no history of prior cardiovascular disease developed acute dyspnea which was related to pe in the presence of deep vein thrombosis of the left femoral vein. therapeutic anticoagulation was installed for a couple of days until there were several bouts of deterioration. biplane transesophageal echocardiography (tee) was performed and revealed a large, wormlike, hypermobile thrombus within the right atrium. computer tomography (ct) of the chest detected a saddle embolus in the bifurcation of the pulmonary tmnk almost occluding the entire left pulmonary artery (pa) and parts of the right pat consisted of mg frontloaded rt-pa and the subsequent continuous administration of urokinase in a dosis of . u/hr for hrs followed by therapeutic anticoagulation. symptoms, blood gases and ecg improved steadily during infusion, no adverse effects, i.e. minor or major hemorragia were registered. follow-up ct promptly after termination of t showed almost complete resolution of the saddle embelus, whereas tee showed complete dissolution of the at. ' finally, the patient was switched to oral anticoagulants and had an uneventful clinical course until he was discharged. conclusion: in the present case, cot was effective for the treatment of a complicated pe without any adverse effect. introduction: nowadays we can assist hearts with problems of insufficiency by techniques other than transplant. many researchers believe that the best way of assisting insufficient heart muscle is with another muscle from the patient. this technique of ventficular assistance is known as cardiomyoplasty. we describe the surgical technique of cardiomyoplasty using a biological model. the transformed skeletal muscle is transferred to the thoracic cavity where it wraps the heart and assists it. the choice and preparation of this muscle is currently under investigation. our group has focussed on the development of protocols for electrical stimulation to transform a skeletal muscle into a muscle which resists fatigue and which is functionally similar to the myocardium. we detect the optimum time at which this muscle has been transformed, by studying the transmembrane action potentials using intracellular electrodes. when the action potential of the trained muscle behaves like cardiac muscle we consider it ready for cardiomyoplasty. conclusions: cardiomyoplasty is an alternative surgical technique to cardiac transplant, which has a great future in the treatment of patients with advanced cardiac insufficiency. we describe methodology which, by intracellular techniques, allows selection of the optimum moment of transformation of a skeletal muscle trained to perform,like cardiac muscle, without suffering fatigue. purulent pericarditis is a rare disease. its treatment associate systemic antibiotics and drainage of the pericardium. we report a ease of purulent constrictive pericarditis in which intraperieardial fibrinolysis was use. a years old patient admitted in our icu for a constrictive pericarditis as a complication of a purulent pericarditis diagnosed seventeen days before. he had also an aehalasia and the o'esogastric endoscopy had found an oesophageal neoplasm. a fistula was not seen, indeed pericardial of flora was the same that oropharyngeal. hemodynamie and echographic study had confirmed a constrictive pericarditis. because of the poor state of the patient an intraperieardial fibrinolysis was prescribed ( . ui of streptokinase on days , , , ). fluid drainage was improved and cardiac output was also improved (day : . .min "i, day : . l.min'l). no change ofhemostasis was noted. a pericardeetomy and an oesophagectomy were performed after days of evolution. eighteen months latter the patient was still alive. intraperieardial fibrinolysis seems an interesting therapeutic way if rapidly prescribed in the purulent pericarditis course. the decrease in the systolic pressure following a mechanical breath, termed ddown (delta down), has been shown to be a sensitive indicator of preload ( , ) . however, the clinical use of this method necessitates the introduction of a short apnea. we have therefore developed a respiratory systolic variation test (rsvt) which obviates the need for apnea. the test is based on the delivery of successive breaths of increasing magnitude ( , , , and ml/kg). a line of best fit is drawn between the minimal systolic values (one after each breath) and the downslope calculated as the decrease in blond pressure for each increase in airway pressure ( mmhg / cmh ). in mechanically ventilated patients the rsvt was performed during controlled mechanical ventilation under sedation. the test was repeated after the administration of ml/kg of plasma expander. the initial mean downslope of the rsvt was -. + . mmhg/cmh . following volume loading the downslope decreased to -. + . (ns). at the same time, cardiac output (co) increased by . + . l/min (p<. ), end-diastolic area (determined by tee) increased from . + . to . + . cm (ns), and paop increased from + to + mmhg ( p < . ). the preinfusion downslope value of the rsvt correlated significantly with the increase in the co (r = . ) and the eda (r = . ). methods: an expert system has been constructed running on a multimedia computer with the two objectives in mind, viz training of inexperienced staff, and protocol guidance with treatment regimes for all staff. the system is based on experience gained from two previous systems, the one for dealing with acid-base and electrolyte problems in icu patients; the second for stabilisation of patients with heart rate and blood pressure abnormalities. the training section takes the form of a stage-by-stage account of the insertion of the pac and displays of correct waveforms, coupled with indications of possible incorrect placements, and guidance when failing to achieve the perfect positioning. the treatment protocol section extends an existing protocol for correcting abnormalities in heart-rate and blood-pressure, and now takes account of all the indices as measured by the pac. the system will suggest treatment to correct such things as abnormal wedge pressures concomitant with parameter values throughout the rest of the cardiovascular system. the type of patient eg post-operative cardiothoracic or i. c. u. trauma, will be taken into account when recognising abnormal parameter values and when prescribing treatment. results: a working system which will be improved by the finetuning being carried out. the results and lessons learnt will be presented at the conference. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion ~ . g/kg/ rain with a map --< mmhg. cardiovascular support was limited to na + dobutamine (db). c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t - ); and at the end of treatment (t - ) with c . conclusions: c does not appear to increase mpap or worsen pulmonary gas exchange in patients with septic shock, when given by infusion for up to h. c is a novel vasoactive agent for the treatment of septic shock which will now he evaluated in a randomised, placebo-controlled safety and efficacy study. objectives : to compare cardiac output (q) data obtained for thermal indicators in pulmonary artery (qtpa) and aorta (qtao) and for the stable isotope hzo in aorta (q v~ o) with indocyanine green (icg) in aorta (qicg) as reference. methods : an indicator solution of ice cold h ( . ml), h ( . ml) and icg ( mg) was injected as bolus via the injection port of a swan-ganz catheter. qlco and qzmo was measured using a dual optical system (penn lab instruments, philadephia, pa, usa). qtpa and qtao was measured using a in contrast to the recoveries of thermal indicator in pa and h in aorta the :~covery of thermal indicator in aorta was significantly increased in group ii (n= boluses) over group i (n= boluses) ( . <- . vs. . +- . , p= . ). conclusions: the "overrecovery" of thermal indicator in aorta is in agreement with " biscks deconvolution study (i) and results in erroneous values for q. the most pausible explanation is the distortion of the thermal curve caused by the slow response time of the thermal detection instrument as shown by ganz ( ) objectives: to compare data obtained with the double indicator dilution method using indocyanine green (icg) and the stable isotope h for the estimation of extravascular lung water (evlw hzo) to gravimetriu lungwater data (evlwg~). methods: an indicator solution oflcg ( rag) and h ( . ml) was injected as bolus via the injection port of a swan-ganz catheter. dilution curves for icg and zh was registered in aorta with a dual optical system (penn lab instruments, philadephia, pa, usa). cardiac output and mean tranist time was measured for both tracers (qico, tlco, q n o, t o) ( ). data analysis: evlwg~av was reference for evlwzhzo calculated as q hzo times the difference in mean transit time between t nzo and rico (atm n). as reference for atzn o evlwg~,v was divided by q~cg to obtain atg~,. a reference distribution volume for h was calculated as the sum of central blood volume and evlwg=v. boluses were administrated in a group (i) of anaesthetized pulmonary healthy sheep while q was altered. another boluses were administrated in a group (ii) of anaesthetized sheep with stable oleic acid induced pulmonary oedema. evlwg~v measurement was performed postmortem. results: for boluses h parameters were not significantly different from their respective reference parameter: at vao . +_ . s vs. atg~, . + . s, evlwzh o -+ ml vs. evlwg~,~ + ml. in group i the ratio between hzo parameters and respective reference parameters (n= ) were independent of qlco from . to . l/min. obiectives: to assess the thermo dye method using indocyanine green (icg) and thermal indicator for the estimation of lung water (evlwt). methods: ice cold indicator solution of icg ( mg) in water ( ml the aim of the study was to assess left and right ventricular function in the early postoperative period after orthotopic heart transplantation to elaborate therapeutic approaches of heart function abnormalities correction. mathefial and methods. haemodynamic monitoring data of twenty one patients ( men, women ) age from to were studied. cardiac output, pulmonary artery, right atrium and pulmonary wedged pressure were measured with swan-gans catheter. central haemodynamic indices were calculated with the help of computer-based monitoring system. relations of ventricular stroke work index to it's end-diastolic pressure were used for ventficular function assessment. results. in most cases right ventricular disfunction was the main problem. isolated fight ventficular failure with high pulmonary vascular resistance (pvr) was observed in % ( pts), without high pvr-in % opts) and with left ventricular failure-in % ( pts). one of the most important reasons for fight ventricular failure was the time of heart ischemia more than min, which is of great importance in the ease of distance harvesting. the most effective treatment for cardiac failure was combination of dobutamine with i oprotherenol, atrial pacing and vasodilatators in case of right ventfieular disfunction. all cases with isolated right ventricular failure were treated sucsessfully. biventricular heart failure was a sighn of bad prognosis and the reason of death in cases. conclusion. right ventfieular disfunetion is the main problem during transplanted heart adaptation in the early postoperative period. optimal therapeutic management of cardiac disfunction includes infusion of dobutamine in combination with isoprotherenol, atrial pacing and vasodilatators. cardiology-department of clinical centre-kragujevac institution for occupational health "zastava"-kragujevac, sr yugoslavia the aim of the investigate is analisis five years survives patients with a.i.m.in dependence of locality and risk-factors. we ana~sed- ~-pat~e~ts ( males and woman), average , years. for statistic evaluation we used life-table slstem in oder to estimate prognostic determinants. patients with respkatory muscle paralysis may benefit from respiratory assistance by abdomino-diaphragmatie pneumatic belt. we used a non invasive technique, m-mode sonography, to assess the effect of this device on diaphragmatic excursion. we measured the amplitude of right diaphragm motion in seven patients with duehenne muscular dysl~ophy in supine position with various thoracic posture ( ~ ~ ~ without and during pneumatic belt respiratory assistance. without respiratory assistance, the thoracic posture had no significant consequence on the amplitude of diapttragm motion, either in quiet or deep breathing. the pneumatic belt increased the diaphragm motion amplitude from . +__ . mm to . +_ . ram (p = . ) at ~ tilt angle, and from . + . mm to . + . mm (p = . ) at " tilt angle. the tidal volume increased from + to + rut a * tilt angle, and from + to + ml at * tilt angle (p = . ). two patients could not bear the horizontal position ( ' tilt). in the five other patients, the pneumatic belt increased but not significantly the amplitude of diaphragm motion ( . + . mm to . + . ram). after an overnight respiratory assistance, pao increased from . +_. . to + . mmhg ( = . ), sao increased from . + . % to . +_. % (p = . ), and paco decreased from + . to . +_. mmhg (p = . ) according to the ventilatory pattern result, m-mode sonography allows to measure non invasively the improvement of diaphragm kinetics obtained by pneumatic belt respiratory assistance, and may be helpful for its adjustment. objective: to study the effect of flow triggering (flow sensitivity and l/min) vs pressure triggering (-lcmh ) on inspiratory effort during pressure support ventilation (psv) and assited/controlled mode (a/c) in stable copd patients non-invasively ventilated with a full face mask. methods: the patients were studied during randomized min. runs using a bird st ventilator at zero peep (zeep). trigger values for pressure (-lcmh ) and flow ( l/rain) were the lowest allowed by this ventilator. the transdiaphragmatic pressure time product per breath (ptpdi), dynamic intrinsic peep (peepi,dyn), maximal airway pressure drop during inspiration (apaw) andl ventilatory variables (ti,te,ttot,rr,vt and minute ventilation) were measured. results: no major problems due to airleaks or to auto-triggeriffg phenomena were observed in the patients, so that all of them were able to perform all the protocol runs. minute ventilation and respiratory pattern were not different using the two triggering systems. the ptpdi was significantly higher during both psv ( . + . cmh: x sec) and a/c ( . + . ) with pressure triggering, as respect to psv ( . + . , p< . ) and a/c ( . + . , p< . ) with flow triggering ( l!m). no differences were observed between and l/min flow triggers. apaw was also significantly larger during pressure triggering; peepi,dyn was reduced during flow triggering being . + . cmh (psv flow trigger) vs . + . (psv pressure trigger) and . +_ . (a/c flow trigger) vs'f~ +l (atc pressure trigger). conclusions: in stable copd patients non-invasively ventilated, flow triggering reduces the respiratory effort during both psv and aic mode as compared to pressure triggering. this may be partly due to a decrease in peepi,dyn using a flow-by system. objective. cardiac output is higher during alternating ventilation (av) (i.e. differential ventilation of the lungs with a phase shift of half a ventilatory cycle) than during synchronous ventilation (sv) of both lungs . we verified the hypothesis that the higher cardiac output depended on a lower central venous pressure and intrathoracic pressure, due to a lower mean lung volume, which we attributed to part of the expansion of the inflated lung at the expense of the expiring, opposite lung . we studied this interaction between the lungs during one-sided inflation, which we called cross-talk. method. in anaesthetized and paralyzed piglets we applied short periods ( s) of one-sided ventilation ( breaths per rain, bpm), while the other lung was open to the ambient air. the air flow into the non-ventilated lung during expiration of the ventilated lung was integrated to volume. we studied -to-r and r-to-i cross-talk at ventilatory rates of , and bpm. the amount of cross-talk was the volume displacement in the non-ventilated lung. results. during bpm the r-to-i crosstalk was _+ . % (mean +__ sd) of the tidal volume to the right lung and the -to-r crosstalk _ . % of the left tidal volume. both values increased at bpm to _ . % (p < . ) and _ . % (p < . ) respectively. the values at bpm were in between., conclusion. we concluded that the lower mean lung volume and lower thoracic expansion during av compared to sv depends on partial expansion of the inflated lung into the non-inflated lung, resulting in a lower mean intrathoracic pressure as the main reason for the higher cardiac output during av. obiective: natural surfactant given for rds in premature infants leads to a rapid improvement in oxygenation, but lung compliance did not improve in most studies. however, acute effects on lung mechanics during and immediately after surfactant administration have not been studied before. methods: a total of administrations of bovine surfactant in recommended doses was given via a small catheter into the distal endotracheal tube either as a bolus (n = ) or as a slow infusion (n = ) in infants with established rds. static compliance (c), resistance (r) and time constant (tc = cxr) of the lung were measured every minutes with a lung function cart (sensormedics ) without interrupting ventilation. infants receiving synthetic surfactant were studied as controls. results: after surfactant as a bolus or during infusion c first decreased but then increased, whereas r increased immediately with great fluctuations but did not return to baseline. this pattern was more pronounced in infusion than in bolus administration. change of c and r varied greatly in the individual case, maximum c was > %, maximum r > % of baseline value. retreatment was followed by an increase in r in all patients, but c increased only in the one who was responder. patients receiving synthetic surfactant had no change of c or r and were non-responders. ob~i ctives= acute lung injury (ali} sometimes induces severe hypoxernla which may be refractory to conventional modes of mechanical ventilation (mv). the elm of this study was to observe some cardio-pulmonary effects of an alternative method of ventilatory management of severe ali. five patients with severe ali (murray scores > ) requiring mv were studied. protocol inclusion was considered when a control-mode of mv (with a pzo~=l. and a peep level < cme=o} was not able to get either a p.ojf=o= ratio > or a s.o= > %. patients were sedated, paralyzed, and a ventilator (serve c) was used for pressuz'e-control ventilation (pcv). fio= was maintained at . and peep removed. continuous gas flow ( • ml/kg] was humidified and jet delivered through a tube ( ram id, ml capacity, . ml/cm h=o compllancel ended in a nozzle ( . mm is) attached to the endotracheal tube connector. a thermodilution flcw-dlrected catheter was inserted in pulmonary artery. following variables were recorded minutes before and after protocol started: tidal volume (vt), minute ventilation (vz), intratracheal pressures (p~w), wedge pulmonary artery pressure (wp), central venous pressure (cvp), mean arterial pressure (map), cardiac index (ci), arterial and mixed venous oxyhemoglobin saturation (sao=, svoa) , oxygen delivery (do~) , oxygen consumption (vo ) , intrapulmonary shunting (q./qt) , and oxygen extraction ratio (ero). this observation suggests that hfpv could allow to ventilate at lower fin and improve blood oxygenation during the acute phase after inhalation injury reducing toxicity risk related to high fin . further studies are necessary to confima these results and evaluate the possible implications on mortality alter smoke inhalation and for other icu pts. objectives: to design a system for volume controlled high frequency ventilation (hfv) and to estimate the dependence of the tidal volume (vt) on frequency (f) in normocapnic ventilation in rats at frequencies - hz. methods: a new system for volume controlled hfv was devised consisting of the generator of the constant flow during inspirium and the constant pressure during expirium. the ventilator allows ventilation at frequencies - hz with the relative inspiratory time (ti) . - . . the airway pressure was measured at the proximal port of tracheostomic cannula , at the same site inspiratory and expiratory flow was measured using modified lilly-type of pressure-differential flow sensor. non-linearity of flow sensor was compensated on line by derived equation based on calibration at static and dynamic conditions. flow and pressure data were evaluated on line using original software. value of the positive end expiratory pressure (peep) was serve-regulated by analogous feed-back. in animal experiments white wistar rats ( - g) narcotized with ketamine/xylazine with cannulated carotid and femoral arteries were kept at the rectal temperature ~ the arterial pressure was monitored. after traeheotomy the metal cannula ( mm [.d.) was inserted, animals were curarized and ventilated at the following condition: peep = . kpa, ti = . . the dead space of ventilator including canula was . ml. the initial frequency was hz and rain after each change of the ventitatory regimen the blood gases analysis was performed. the frequency was changed according to the following schedule : hz--> hz--> hz--> hz--> hz--> hz--~ hz--> hz. vt for each frequency was regulated to maintain normocapnie ventilation with arterial pco = + mm hg. the arterial po was always above mm hg. results: for normocapnie ventilation in rats the following tidal volumes vt [ ml/kg] were found : vt = . --+ . ml/kg for ft = hz, vt = . + . mukg for fz = hz, vt = . +_ . ml/kg forf = hz, vm = . + . ml/kg forf = hz andvmt= . + . mukg for fs = hz (presented as mean values _+ s.d., n = ). the regression analysis using the mean values resulted in the equation for normocapnic vt in rats in our experiments : vtn = . * f-e. . conclusions: the described system allowing ventilation in a wide frequency range - hz with accurate measurements of airway pressures and vt might be useful for optimisation of artificial ventilation in new-barns with different lung pathologies. supported by grants iga mz cr nr - and gacr nr . s intensive care unit. university. hospital of south manchester, uk. methods: measurements were conducted on ventilated patients (puritan bennett ac with metabolic monitor pb set to measure end tidal co ). all measurements were repeated with the patient stabilised at cm. cm and cm peep. inclusion criteria were: ) haemedynamic stab(l( .ty for hr; ) pulmonad" anon" flotation catheter in situ: ) volume control ventilation with plateau of . s: ) fio ~ > . to maintain pao~. > kpa with em peep: ) qs/ot > %; ) pao /fio ratio < . measured variab!es included: r minute volume: plateau ainvay pressure: applied and intrinsic peep: fractional end tidal co ; arterial and mixed venous blood gases and hacmod).ttamic variables. results: statistical analysis was performed using repeated measures anova. significant decreases in cardiac index (ch p< . ), compliance (p<t). ) and o,'gcn deliver, index (do , p< . ) occurred with increasing peep (table ) . no other variable showed any significant change. methods : all consecutive patients orally intubated in the micu between january to april were studied. etts were positioned according to the reference marks mentioned above (measurements from upper incisors). the position of the ett tip in relation to the carina was measured on the chest radiograph done with the patient's head in neutral position. results : a total of men and women were studied (n= ). the mean distance of ett tip to carina was . cm. using the reference markings, cases ( . %) had the ett tip < cm from the carina and cases ( . %) > cm. one case resulted in an endobronchial intubation. the mean height of all patients were cm ( - ) for males and cm ( - ) for females. of the patients with ett tip < cm from carina, the mean height was cm and cm respectively. ~ onclusion : adopting the above quoted reference marks did not result in ideal positioning of the ett in a significant proportion of cases ( . %). we postulate that [s because our asian population is generally shorter than those in previous studies. objectives: to measure the changes of pulmonary mechanics before and after tracheostomy in patients with prolonged mechanical ventilation and to determine factors that predict the outcome of liberation from mechanical ventilation. design: prospective. setting: respiratory intensive care unit (ricu) in a tertiary hospital. patients: twenty patients with chronic lung disease requiring long-term mechanical ventilation. tracheostomy is indicated for further care. intervention: tracheostomy. measurements and results: pulmonary mechanics including respiratory rate (rr), tidal volume (vt), peak inspiratory pressure (pip), intrinsic positive end ex~ piratory pressure (peepi), lung compliance (cld), mean airway resistance (rawm), work of breathing (wob), pressure time product (ptp) by bicore cp- pulmonary monitor were recorded hours before and after tracheotomy. ventilator setting parameters remained the same during surgical intervention and were also recorded for comparison. generally, the mechanics including pir wob, raw~x and ptp showed improvment after tracheostomy. but only pip was significantly reduced (pre . _+ . to post . _+ . , p < . ). changes of wobp showed significant correlation with pre-operation rr, minute volume (mv), wobp, and peep(. changes of raw m were also significantly correlated with pre-operation peep, vt, and raw m. the patients were divided into two groups according to their outcome after two week follow-up. group included eight patients who were completely weaned from ventilator; group included twelve patients who still remained ventilator-dependent or were mortality. there was no difference in age, duration of mechanical ventilation, pro, post or changes of several lung mechanics between the groups of patients. pre-tracheostomy peep i and cld showed significant difference between these two groups ( . _+ . vs . + . in peepi; . _+ . vs . _+ . in cld, p < . ). pre-tracheostomy ventilator setting in mode of assist/control also showed significant higher percentage in group ( % % in group vs . % in group ). conclusion: in prolonged mechanical ventilation patients with chronic lung disease, tracheostomy will significantly improve pip and slightly reduce wobp, raw m and ptr patients who used pressure support mode before tracheostomy had better underlying lung conditions (lower lung compliance and auto-peep) will have better chance to wean from mechanical ventilation. forty-eight infants with congenital diaphragmatic hernia presenting within the first hours of life, who underwent surgical rapair,were analysed prospectively in order to produce a reliable inde x of severity of disease that would reliably predict eventual outcome. there were survivors and deaths in this series (mortality %).using arterialpco values measured hours after surgical repairand correlating them with an index of mechanical ventilation,we have been able to clearly define two groups of diaphragmatic hernia based on their response to hyperventilation. the first group, with co retention and severe preductal shunting,was unresponsive to hyperventilation with high rates and pressures the mortality was %. the second group responded well to hyperventilation and demonstrated reversable ductal shunting only. survival in this group was %. arterial co accurately reflects the degree of lung development in this disease and separates those patients with severe pulmonary hypoplasia where the outcome is invariably fatal, from those with a well developed contralateral lung where there is excellent potential for survival. respiratory failure unit, dpt medicine, univ. thessaloniki, thessaloniki, greece the variability of arterial blood gases (po , pc ) and the ph (abg) was examined in stable icu patients, few hours before a successful weaning from the ventilator. all patients were lightly sedated and the ventgatory conti~ons were pressure support (ps) for and ps plus intermitted mantatory ventilation in ii. [n each patient, speciments of abg were measured at min intervals during a - study period. at the same time with abg the arterial blood pressure (bp), the heart rate (cf), the tidal volume (tv) and the respiratory rate (n r were measured. for all the patients, the mean coefficient of variation (c) was . percent for po , . percent for pco and . percent for hco . the average sd for ph was . , the corresponding c for systolic bp, diastolic bp, cf, tv, rf were . , . , . , . , . percent. we conclude that the spontaneous variability of arterial blood gases in icu patients is not substantial ~hen they have stable the heamodynamic and the ventilatory parameters. deptx?fa'aaesthesioiogy and reanimation, rhe sechenov medical academy, moscow, russia objective: ~he prevention and treatment of hypoxia in the critical patiems. methods: i~fusions of perphtoran -a blood substitute with gas-transporting fimclion based on perphtorhydrocarbon -in patients with acute hypovolemia, microcirculatory distnrbance~ tissue gas exchange and metabolism; pulmonary iavage in ; iongterm extrapulmonary oxigenation with tleoroearboa oxygenator in combination whb ~trafiltra!ion, hemosorption and hemodialysis -in patients. results: pe~htoran increases blood volume, co,sv, decreases svr, improves capillary blood flow, increases the blood oxygen capacity, tissue oxygen tension, del, vo by improving the rheologic properties of blood and plasma, normalizes ext., prevents and eliminates fat embolisation and ards. decreases the need for blood transfusions and infusions of plasma expanders by . - . limes. alveolar venti!ation-perfusion ratio remains unchanged with its increased effective utilization. there was no surfactant destruction during lavage. extrapulmonary oxygenation of small volumes of venous blood eliminates venous destruction and then arterial hypoxia and increases pulmonary oxygenation. the use of lluorocarbon cxygenators during hemosorption and hcmodialysis provides the atraumatic and iongterm oxygenation of arterial blood and increases elimination of co which prevents the development of hypoxic complications. conclusions: perphtoran and fluorocarb~n oxygenators are effective in the correction of hypoxia in the criticat patients. objeqtives: to determine if there are differences in oxygen consumption (vo ) during weaning from mechanical ventilation (during total ventilatory support and spontaneous ventilation with cpap), and to compare different predictive parameters of weaning in predicting success of weaning. methods; prospective study in critically ill patients treated with mechanical ventilation for at least h, who fulfilled at least of standard weaning criteria (vt> ml/kg; respiratory frecuency (f) < ; pimax > cm h ; pao /fio > ). baseline measurements: t, vt, p . , pimax, f/vt, p . *(f/vt), p . /pimax. study protocol: measurement of vo , vco (medgraphics), vt, f, ve, and arterial blood gases during total ventilatory support (cmv), and after and minutes of spontaneous ventilation with cpap cm h . the weaning trial was stopped, failure to wean diagnosed, and mv resumed it a patient presented significant tachypnea, tachycardia, bradycardia, cardiac rythm disturbances, hypertension, hypotension, hypoxemia or hypercapnia. results: four patients did not complete the weaning trial, were extubatad, and of them had to be reintubated before h, being considered also weaning failures. during cmv, vo /kg was . + . ml/kg/min, and . _+ . mlo- /kg/min after ' on cpap cm h (p < , ). of patients ( %) with standard criteria were extubated, while only of ( %) with criteria (p< , ). next objectives: compare the extent and distribution of lung injury in dogs preinjured with oleic acid (oa) and ventilated with high tpp and adequate peep in the prone and supine position. methods: lung injury was induced with oa ( . - . ml/kg) in anesthetized, paralyzed, and intubated dogs (n= ) during volume controlled ventilation: rate= /min, peep= cmh , ti/ttot= . , fio = . , vt= ml/kg. animals were rotated during the oa infusion and the following minute stabilization period to assure uniform injury. in the supine position, peep was set - cmh above the lower inflection point (as determined by the pressure-volume curve), and vt was set to obtain a tpp of cmh : animals were ventilated in either the prone (n= ) or supine (n= ) position for four hours. pulmonary artery occlusion pressure was maintained constant ( - mmhg) with saline infusion. at the end of the protocol the lungs were removed and divided by template into dependent (d) and nondependent (nd) sections for wet weight/dry weight (v~n/dw) and grading of nstologic lung injury (hli; scale - ). oseillatron | is a pneumatic device that generates high frequency, oscillation by means of a reciprocating system in the form of a membrane. it generates sinusoidai wave form at ( to ( cycles/rain. the system does not deliver gas but must be adapted to the proximal respiratory, circuit of a conventional ventilator, resulting in ci-ifo. it was developed to enhance intrapnlmona~ diffusion during mechanical ventilation and to mobilise endebronchial secretions. methods. we measured arterial blood gases and haemedynamics during a first period of conventional ventilation (cppv) followed by. two rain periods of chfo (sequences : ( and ) c/rain : group l, n = l: and c/rain : group , n = ). measurements were made at the end of each period. cardiac output was measured using thermedilution method: flu and peep were kept unchanged throughout the study. intrinsic peep was also evaluated by, means of an occlusive valve. results. pa is not significantly modified during chfo at or c/rain. paco is slightly decreased at c/rain (p = .( ). however, intrinsic peep remains unchanged. there is no sequential effect (gr. l vs gr. ). there is no more effect of chfo for patieets who are at a flu higher than . (n = ). no changes in haemodynurmcs are observed except a slight increase in central venous pressure (cvp) during ci-ifo (p < .ol). obiectives: to examine the effects of inspiratory muscles unloading on neuromuscular output at controlled levels of chemical stimuli. methods: the ventilatory response to co was examined in ten normal subjects using rebreathing method. ventilation ~) and respiratory muscle pressure output (pmus) at the same end-tidal partial pressure of co (petco~) were compared with and without combined flow and volumeproportional pressure assist in two protocols (a and b). protocol a (n = ): two levels of assist were studied; flow assist (fa) of cmh /i/sec and volume assist (va) of cmh /i (assist ), and fa of cmh /i/sec and va of cmh /i (assist ). all conditions were applied randomly. v~, tidal volume (vt) and breathing frequency (f) were measured breath by breath and plotted as a function of petco~. protocol b: in subjects, in addition to above measurements, esophageal (pes) and gastric (pg) pressures were measured and the time courses of transdiaphragmatic pressure (pdi) and pmus were calculated. one level of assist (assist ) was studied in this protocol. results: in both protocols inspiratory muscle unloading did not change the f response to c%. compared to control, with assist v t response was displaced upwards; at petco of mmhg v t was increased significantly by . + . i and . + . i in protocol a with assist end , respectively, and by . _+ . i in protocol b with assist (p< . ). ~/~ responses showed similar changes as vtresponses. in both protocols the slope of v~ response (s did not change significantly with unloading. at low petco~ ( mmhg), pdi and pmus waveforms did not differ with and without assist. with unloading, at high petco ( mmhg), pdi and pmus at the end of neural inspiration decreased by . -+ . % and . + . %, respectively, from control values. neither change was significant (p> . ). by theoretical analysis we estimated the expected changes in vt and ~/~ when the levels of assist used in both protocols were applied in the absence of : any change in neural output response to co z. the predicted response was similar to that observed, indicating that the small difference in pdi and pmus between control and unloading runs was due to intrinsic properties of respiratory muscles end respiratory system. conclusions: these results suggest that when chemical stimulus is controlled, respiratory motor output is not downregulated with unloading. the determinants of the response of the respiratory output to inspiratory flow rates (v~) were examined in awake normal subjects. subjects were connected to a volume-cycle ventilator in the assist/control mode and v~ was increased in steps from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. in six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (protocol a) and in subjects the effects of airway anesthesia (upper and lower airways, protocol b) on the response of respiratory output to varying v~ were studied. in protocol b, in order to calculate muscle pressure during inspiration (pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. independent of conditions studied breathing frequency increased . significantly and end-tidal concentration of c% decreased as v~ increased. the response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas and airway anesthesia. with and without airway anesthesia (protocol ) neural inspiratory and expiratory time and neural duty cycle, estimated from pmus waveform, decreased significantly as v~ increased. at all conditions studied the rate of change in airway pressure prior to triggering the ventilator tended to increase as v~ increased. the changes in timing and drive were nearly complete within the first two breaths after transition with no evidence of adaptation during a given ~/~ period. we conclude that v~ exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate and airway anesthesia. the response most likely is neu~'al in origin, mediated through receptors not accessible to anesthesia such as those located in chest wall or below the airway mucosa. it has been shown, in mechanically ventilated awake normal humans, that increasing inspiratory flow rate (~/~) exerts an excitatory effect on respiratory output. it is not known if this effect persists during sleep. to test this seven normal adults were studied during wakefulness and nrem sleep. subjects were connected through a nose-mask to a volume-cycled ventilator in the assist/control mode and ~/t was increased in steps ( - breaths each) from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. forty-one trials during nrem sleep and during wakefulness were analyzed. both during sleep and wakefulness minute ventilation increased and total breath duration (ttot) decreased significantly in a graded and reversible manner as ~' increased. these changes were complete in the first breath after v{ transition. the response was significantly less during sleep than during wakefulness (p< . ); at i/min ttot, expressed as % of that at i/rain, was . +_ . % during sleep and . +_ . % during wakefulness. during wakefulness, at i/min, the rate of change in airway pressure prior to triggering the ventilator, an index of respiratory drive, was % of that at i/min (p< . ). the corresponding value during sleep, was % (p> . ). in four sleeping subjects the increase in v~ was sustained for . - min. there was no evidence for adaptation of the response; tro t, averaged over the last three breaths, did not differ from that obtained when vj was sustained for only - breaths. we conclude that ) vt exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism and ) the gain of this reflex is attenuated by sleep. chest radiographs is a common complementary technique for patients in critical care units, with a low cost and easily available. however, it has certain well-known limits in diagnosis, the most important derived from the low quality of some pictures. in this paper we make a general review of some new technical approaches developed for improving the quality of the images, and so incrensing the diagnostic value of conventional radiology. we begin deaeng with the correct positioning of the patient, trough the filtering techniques, the synchronization of radiology and ventilation, and we make reference to the new computerized systems for digital image processing. conclusions: the portable radiographic system is a device that probably with maintain for many years in critical care units as a basic non-invasive diagnostic tool. but we need an increase in the efficiency of it, applying means as simple as a correct positioning of the patient, or the use of fitlers or synchronizers. thus we should improve the general standards of portable radiography. "are circular circuits safe? quantifying undelivered tidal volume in pediatrics patients". objectives: to evaluate the overall influence of internal compliance of circular circuits on delivered tidad volume (vt). methods: we studied prospectively asa i pediatrics patients ( to yr. old) scheduled for elective general surgery. mechanical ventilation was supplied by an ohmeda excel (circular circuit). the internal compliance of the circuit (cc)-anesthesia machine plus external circuit-was determined by the supersyringe method: corrugated dar tubes of mm. id and . m. long (children < kg), and a corrugated dar set of mm. id and . m. long (children > kg) were respectively used for ccl an cc values of . and . ml/cm h . a vtof mlg/kg and respiratory frequency was adjusted for an end-tidal co (etpco ) between mmhg. tidal volumes (measured by spirometry) and airway pressure (paw) data were recorded every ten minutes. volumes and thorax-lung compliances were calculated as follows: (vt delivered = vtadjusted-vol compressible, being vol. compressible = co x ppeak (aw). apparent compliance (ca) = vt adjusted/pplateau(aw), and true compliance (ct) = =vt delivered/pplatean(aw)). comparative statistics were separately designed between calculated compliance data and tidal volumes on a paired sample ~test basis. results: calculated values for volumes and thorax-lung compliances were: conclusions: due to the elevated internal compliance of the circular circuit there is a remarkable dilference between adjusted and delivered vt: mean undelivered vt was . % and reached as high as . %. teere is also a significative error in calculating true thorax-lung compliance: its overestimation can be as high as . %. circular circuits are considered safe and cost-saving for anesthetical practice. nevertheless we conclude that anesthetists should bearin mind vt losses when using circular circuits, due to compressible volume. tracheal stenosis is one of the most serious complications of patients submitted to prolonged endotracheal intubation, in which the decrease in inner diameter of upper airway makes it very difficult to achieve a correct ventilation. objectives: compare the results of applying high frequency jet ventilation (hfjv) to some of these patients with conventional controlled ventilation (cmv). methods: we used a prototype of high frequency jet ventilator (santiago- ) developed in our university, and we developed a tracheal tube in wich we modified the distal tip (conic tip). we applied this system to two patients which were initially ventilated in the operating room with usuai controlled mecanical ventilation (cmv) following the standards of our department, and then intubated with the special endotracheal tube and ventilated with hfjv. results: we could verify a proper ventilation of both patients with cmv and hfjv. during hfjv, the airway pressures were lower than those recorded during cmv. a lower airway pressure prevents lesions due to high pressures. conclusions: hfjv is a good method of ventilation for patients with significative stenosis of the trachea, not only during surgical procedures, but also during ventilation for long periods in critically patients. the ventilatory setting is pressure support mode. the pressure level and fit were kept constant during h/d. arterial blood gas, wbc count, and mean bp was checked according to the schedule: '(immediately before h/d), ', ', ', ', ', '. respiratory drive (represented by poa), tidal volume(ti) and minute ventilation(ve) were continuously recorded by pulmonary mechanics monitor (bicore cp- ). the mean value of the breaths minutes before blood sampling were used to represent the ventilatory status of that period. anova test is used for comparison between groups. for poa, hierarchical cluster method is applied to divide the cases into two groups of similar change. conclusions: our data suggest that pl is very useful, non invasive and low-expensive emergenc e support for arf, expecially in the elderly with severe chronic pulmonary disease and relative controindications to eti. pl seems to be an effective alternative when it is not immediatly possible to perform etl. the multiple inert gas elimination technique (miget) can be used to assess the effects of any given mode of mechanical ventilation on the pulmonary and systemic factors determining arterial po and pco> however, a potential problem in mechanically ventilated patients is that the l mixing box (mb- l) placed in series in the expiratory side of the circuit of the ventilator to sample mixed expired gas may provoke substantial discrepancies between the tidal votume set in the ventilator and the effective tidal volume delivered to the patient, due to the increase in the compression volume (vc) of the circuit. the effects of the mb- l on the v c were compared with those produced by a new l mixing box (mb- l) specifically designed to produce adequate gas mixing and to prevent loss of the two most soluble gases (ether and acetone) used in the miget. at any given peak cycling pressure (p~ak, cm h~o), the v c (ml) provoked by the mb- l was substantially higher (vc= . *ppeak) than that provoked by the new mb- l (vc= . *ppeak). at a ppeak = cm h ~ the v c were ml (mb- l) and m{ (mb- l), respectively (p< . ). in a group of subjects ( m/ f, _+ years), for each of six the gases used in the miget, the regression line between the mixed expired partial pressures simultaneously obtained from mb- l and mb- l fell on the identity line. it is concluded that the new mb- l allows adequate assessment of the effect of different modalities of mechanical ventilatory support on pulmonary gas exchange, with less potential for gas compression and thus hypoventilation. objectives evaluate the influence of different pressure support ventilation (psv) levels on cardiovascular and respiratory funcion in icu polytrauma patients. metbed&we studied polytrauma icu patients , who were in weaning process , after long term mechanical ventilation for acute respiratory failure . mean age ( - ) yrs . they all were connected to servo ventilators siemens c , and all were in stable condition , without sedation , inotropes or diuretics. the hemodynamic studies were done with continuous svo , swan ganz catheter (oximetrix, abbott). they all were in spontanuous mode (spent) with cm h cpap for at least one hour. we turned them to psv with inspiratory assistance (psv cm h ) and after rain we applied psv cm h , and after min psv cm h . hemodynamlo and respiratory measurements were done before and after the application of insiratory assistance. the results were statistically analyzed with anova. resets . respiratory variables . no significant changes in minute volume (ve). tidal volume (vt) and mean airway pressure (mpaw) increased statistically significant (p< . ) . respiratory rate (rr) decreased significantly (p< . ) . blood gase showed no difference . cardiovascular variables. cardiac output (co) decreased ns , heart rate (hr) had no change , central venous pressure (cvp) , mean pulmonary artery pressure (mpap) , pulmonary capillary wedge pressure (pcwp) , increased ns , oxygen delivery (do ) decreased ns, oxygen consumption (vo ) decreased ns. conclusions. psv is a very useful respiratory mode helping patients to be weaned from long term mechanical ventilation . it has beneficial effects on respiratory function and oxygen consumption without affecting seriously the hemodynamic parameters, possibly due to a decrease of the work of breathing. a. michalopoulos, a. anthi, k. rellos, j. kriaras, s. geroulanos intensive care unit, onassis cardiac center, athens. objectives of this study was to examine the effect of different levels of peep on postoperative svo and pvo values in a group of patients, following open heart surgery. methods: upon transfer to icu, patients ( males and females) of mean age _-+ years, were randomly assigned to receive (n= ), (n= ), or cm of peep (n= ). there were no statistically significant differences in demographic data or preoperative respiratory status among the three groups. all patients were ventilated on the assist control mode with a tidal volume of ml/kg. the fraction of inspired oxygen (fio ) was adjusted to keep a pao around mmhg. mixed venous po and svo were measured at min, and hours after application of mechanical ventilation in the icu, just before extubation (be), half hour after extubation (ae), and at hours post-extubation. differences at each study time were analysed by anova. results: mean svo and pvo values among the three groups, for all study intervals, are presented in the table. conclusion: we found no differences (p=ns) in tissue oxygenation (expressed by svo and pvo ) among the three groups, at any study interval, in the early postoperative course of patients following open heart surgery. intrinsic peep (peepi), and high elastance and resistance increase inspiratory work load in copd. cpap reduces work of breathing by counterbalancing peepi. pav provides flow (fa) and volume (va) assistance proportionally to patient resistance and elastance and inspiratory effort. we studied the effects of partitioned support (cpap-fa-va) on breathing pattern and inspiratory effort in five copd patients on pav compared to spontaneous ventilation (sv) and full support (fs: cpap+fa+va). flow, volume, minute ventilation (ve) respiratory rate (rr), inspiratory swing in esophageal pressure (apes), and its integral per breath (pti/b) and per minute (pti/m) were measured. objectives: to evaluate airway pressure fluctuation (apf) during spontaneous breathing in a high compliance cpap system. methods: the cpap system consisted of two l weighted balloons in a wedge shaped holder. ventilating gas flowed from one balloon through a low resistance one way valve into a tracheal tube (ett) provided with a pycor co sensor to monitor rebreathing. the ett was connected to a piston drive mechanical lung. expired gas flowed through a low resistance valve into a second weighted balloon, from where it was exhausted through a peep valve connected in parallel with the second weighted balloon. we evaluated system performance at v r from to ml, at rr from to bpm, while closely monitoring cpap airway pressure swings. at v v of and ml the rr was limited to bpm. for comparison we explored aps of a one l balloon cpap system, the cpap mode of the puritan bennett , and siemens ventilators, when connected to a healthy adult volunteer breathing through an ett. results: the compliance (cpl.) of one l balloon system was linear over a range from . to . l, with a cpl. of . l/em h .the cpl. of the l balloon ( . l/em h ) was linear between a volume of and . l. apf of the weighted balloon system was under em h at all v r (except at a v r of ml aps was . em h ), while the apf in the l balloon was up to em h . apf witli human volunteers with the two commercially available ventilators in the cpap mode was about cm h ; while under identical conditions apf in the l balloon system was . emhzo; and in the two l balloon system was below lcm h . conelusions: cpap using the two balloon system exhibits lower airway pressure fluctuations than a single balloon system; and is substantially lower than found in the two commercially available ventilators when used in the cpap mode. objective: to perform independent lung ventilation (ilv) with individual tidal volume (vt) set at a value generating a plateau airway pressure (pplat) < crnh~o and to evaluate the usefulness of the continuous monitoring of endtidal co (etco ) as a guide to titrate individual lung vt during ilv and for the weaning from ilv. methods: in seven patients, ilv was performed with ttvo ventilators set with the same fio: and respiratory rate. each lung was ventilated with a vt that developed a pplat < cmh~o. this setting led to a lower vt on pathological lung (pl). vt was increased in pl following etco~ and paco -etco variations. ilv was discontinuated when etco~., vt and statical compliance (cst) were similar in both lungs. results: one hour after starting ilv (ti), pl mean vt was significantly lower than in normal lungs (nl) ( + ml vs + ml, p< ) two individual behaviours were observed on tl in pl: four patients presented low etco: (range - mmhg)and normal pacoz (range - mmhg), while three patients had normal etco (range - mmhg) with high pac (range - mmhg). one hour before stopping ilv (t ), vt, etc and paco were the same in each lung. the pao /fio: ratio improved in all patients from the beginning ofllv cst of pl was + % of the normal lungs' cst on ti and improved to . + % ofnl's cst on t (p< . vs conclusions: setting vt of pl to a value not overcoming a pplat threshold does not impair oxygenation and is helpful in avoiding barotraumatism. measurements of differential etco and of the differential paco -etco gradient can be used to titrate vt allocation during ilv and as a guide for the weaning from ilv. total respiratory resistance in mechanically ventilated patients exceeds values obtained in normal subjects, due to the added and highly flow dependent resistance of the endotracheal tube (rett). this can adversely effect the efficacy of pressure regulated modes of assisted ventilation, such as pressure support (psv) and proportional assist ventilation (pav). recent work demonstrates that the influence of rett during psv can be overcome by using tracheal (ptr) rather than airway opening (pao) pressure to regulate the pressure applied (intensive care med :$ , ) . the purpose of this study was to see if this approach would also be effective during pav. flow, volume, pao, ptr, and transdiaphragmatic pressure (pdi) were measured in intubated patients in which either pao or ptt were used to regulate the pressure applied during pav where volume assistance was varied from to % of respiratory elastance. representative results (mean + se) are shown below. compared to spontaneous breathing (pav %), pav increased tidal volume (vt) while reducing respiratory rate (rr) so that minute ventilation ('~e) also rose. this was associated with a reduction in inspiratory effort, as reflected by a decrease in the pressure-time integral ( [ p) of pes and pdi both per minute and per liter ~re. the effects on breathing pattern were similar for pao and ptr regulated pav. in contrast, the reduction in inspiratory effort was always greater for ptr regulated pav. in conclusion, the volume assistance provided by pav is more effective when ptr rather than pao is used to regulate the pressure applied. pav methods: retrospective data analysis of adult patients with normal pulmonary function before operation and uneventful course following coronary artery bypass graft surgery over an month period. we compared assist/controlled mandatory ventilation (s-cmv, patients), synchronized intermittent mandatory ventilation with inspiratory pressure support (s-imv/psv, patients) and biphasic positive airway pressure ventilation (bipap, patients). results: patients ventilated with bipap had a significantly shorter mean duration of intubation ( . h, p< . ) than patients treated with s-imv/-psv ( . h) and s-cmv ( . hi. with s-cmv . % of the patients required single or multiple doses of midazolam but only . % in the s-imv-/psv group and . % in the btpap group. the mean total amount of midazolam of these patients was significantly higher in the s-cmv group ( . mg) than in the s-imv/psv group ( . mg, p< . ) and in the bipap group ( . mg, p< . ). the consumption of pethidine and piritramide did not differ between s-cmv and s-imv/psv but was significantly lower during bipap (p< . ). after extubation the paco patients was highest in the s-cmv group. conclusion: ventilatory support with bipap reduces the consumption of analgesics and sedatives and duration of intubation. unrestricted spontaneous breathing as well as fully ventilatory support allow adequate adaptation to the patients requirements. bipap seems to be an alternative to s-cmv and sqmv/psv ventilation not only in patients with severe ards but also in short term ventilated patients. _objectitives: after end-inspiratory airway occlusion we examined the ensuing gradual decrease in tracheal pressure (ptr) with the following equations proposed by bates et al. and hildebrandt: pv = p'v e'~cccl~ +pst, rs (bates) [ ] where p'tr is tracheal pressure immediately after occlusion, to= is occlusion time, "r is viscoelastic time constant of respiratory system, and p t is static elastic recoil pressure of respiratory system. p~(t) = h -h log t (hildebrandt) [ ] where h~ and h are parameters depending on lung volume, and initial time is s for analytical reasons. materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecuronium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pressure was measured in the trachea. flow was measured with a pneumotachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a frequency of hz and processed on a pc. the influence of the cardiac artifacts during the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean (+ sd) coefficient of correlation using eq. was , -+ . , and using eq. was . + . . the values ofz~ (eq. ), however, decreased with increasing the tidal volume (vt) according to the following equation: "~ = . - . v t, similary, the values of h~ and h increased with increasing v t according to the following functions: h~ = . + v i and h = . + . v t. conclusions: the behaviour of "% of eq. suggests that the linear viscoelastic model is not sufficient to further describe the mechanical properties of the respiratory system over the vt range ( - ml/kg) in ventilated patients. infect this model predicts that "c is constant and independent of tidal volume. on the other hand the plastoelastic model is not sufficient to further describe the mechanical properties of the respiratory system. in fact "r obtained by fitting an exponential for data of eq. , is determined by the time of endinspiratory airway occlusion. obiectives: according to the viscoelastic model, the viscoelastic pressure of the respiratory system pv=rs during lung inflation with constant flow e~ is t/ r wh t lsms ira tlmeand r given by:pv~c.~ = d~( -'e-~ )[ ] ere " ' p" tory " and "r are resistance and time constant of viscoelastic unit. in the past, the viscoaletic constants were determinated by performing a series of occlusions at different lung volumes, or a sedes of occlusions at a fixed lung volume achieved with various inflation flows. in the present study we have developed a new method for determining "c and r which requires a single constant flow inflation. our method is based on determination of pv~r, during a single breath constant flow inflation, and of z during the ensuing end-inspiratory airway occiusion. dudng the occlusion the tracheal pressure p~, declines according the following function: ptr = p'lr e " too= " z + e~t.r= [ ] where p'~r is tracheal pressure immediately after occlusion, toc c is occlusion time, p,i.rs is static elastic recoil pressure of respiratory system, and ~ is viscoelastic time constant. we first determinated "~ by analyzing the time-course of ptr according to eq and next determining r according to eq. , using the expedmental values of p,i=~, ~ and ti, as well as "~ obtained with eq. . materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecurenium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pres-sure was measured in the trachea. flow was measured with a pneumniachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a fi'equency of hz and processed on a pc. the influence of the cardiac artifacts dudng the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean coefficient of correlation with eq. was . . with v t of ml/kg, the mean values (+ sd) of ': and r of the subjects amounted to . • . s and . • . cmh i "~ s. with the traditional multi breath method the corresponding values were . + . s and . _+ . cmh i " s, respectively. with the t-test the difference between new and traditional "~ was statistically significant, between new and traditional r was not significant. conclusions: with the single breath method it is possible to compute ': and r . the mean values of r with v t of nd/kg, however, was slighuy different than those obtained with the traditional multi breath method. the application of modem principles of respiratory care and mechanical ventilation in icus has resulted in increased survival of critically ill individuals with neuromuscular, skeletal and irrevers~le pulmonary diseases. in these chronically ill individunts mechanical ventilation, long term therapy (ltot) and continuous home care is considered a chronic life supporltng technique that can not be withdrawn after their discharge from an icu. the aim of this study was to present the results of a rehabilitation programme and home care that runs in our ward. twenw three patients were referred to our clinic f~om icus during - . a specific rehabilitation programme designed according to individual's needs was performed. patients that benefitted from this programme were grouped into the following disorders. ) post tb respiratow failure ( %) ) neuromuscular diseases, ( %) } undiagnosed sas { %) ) cope) ( %) ( patients had a overlap syndrom). the programme consists of : ) assessment and mechanical support ff needed of the respiratonj system with non invasive methods (nasal or via tracheostomy). ) group and individual respiratory therapy ) mobilization ) nutritional support ) educational classes for the members of the family. three from the patients passed away (during the year), are under nippv during night with or without supply, pts recieve ltot. conclusion: the development of a programme for chronically ill individuals in especially designed wards in hospitals and the overall care at home is considered necessary at least in hospitals with icus. a rehabilitation programme and home care permits the fast but safe discharge of these patients from units of acute medicine that the cost of treatment is high and besides permits beds that are invaluable. we considered that the rehabilitation prod'amine and home care in our ward is the first performed in greek chronically ill pts and even though there is no special administxative support we think that the results are quite saltsfactory. objective: we postulated that the product of the respiratory frequency (f) and the ratio of inspiratory pressure (ip) to maximal inspiratory pressure (mip) would predict the weaning outcome in deeompensated copd patients better than either variable alone or other indices previously proposed. methods: in decompensated copd patients with difficult weaning, we measured, daily, respiratory mechanics data both during mechanical ventilation and after ten minutes of spontaneous breathing. then we calculated weaning indices reported in literature and some new integrated indices. according to the results of the discriminant analysis, we considered the integrative index crop (acronym of compliance, rate, oxygenation and pressure), the rapid shallow breathing index f/vt, the load/capacity ratio ip/mip, and the following new index: f x ip/mip. we used receiver-operatingcharacteristic (roc) analysis by calculating the area under the curve considered as the overall probability of correct classification. results: main results are reported in the following objective: to evaluate the reliability of some indices of endurance in predicting the weaning outcome of decompensated copd patients. methods: in decompensated copd patients with difficult weaning from mechanical ventilation (mv) we measured, daily, blood gas analysis, ventilatory and airway pressure pattern during mv, breathing pattern (frequency (f) and tidal, volume (v~)), inspiratory pressure (ip), and maximal ip (mip) during spontaneous breathing (sb). thereafter we calculated the following weaning indices: crop (compliance * mip * (pao /pao ) / f), flvt, ip/mip. data obtained the day at which the patient was considered ready for a trial of sb on clinical grounds but weaning failed (wf) and those obtained the day of the successful weaning (ws) were compared statistically through the wilcoxon rank-sum pair analysis. in order to quantify the predictive accuracy for each index with respect to successful weaning we calculated sensitivity, specificity, and diagnostic accuracy according with the standard formulas. methods : five patients ( + yrs) suffering from ards (lung injury score > . ) for hours or less entered into the study. irv (volume controlled, decelerating flow, % inspiratory pause, lie = / ) was compared to conventional ventilation (cv) (volume controlled, constant flow, no inspiratory pause, iie= / ). these two modes were applied for hours in a randomized order, with the same levels of total peep (peept = peep + peepi), tidal volume ( . • . ml/kg), respiratory rate ( • "bpm) mad fit ( • %). measurements (respiratory mechanics, hemodynamics, arterial and mixed venous blood gases) were performed after , , and hours of application of each mode. rvsuils : are expressed as mean + sem and compared by anova. backeround and methods: periodic breathing (pb) is characterized by repetitive cyclic variation in minute ventilation. pb is considewxl to be provoked by an instability in the respiratory control. inintubated, spontaneously breathing patients conventional modes of pressure support ventilation, i.e., triggered inspiratory pressure support ps), do not allow patients to breathe with theirinherent breathing pattern. therefore, pb, if existing, will appear mainiy after extubation. since our new mode of pressure support ventilation" automatic tube compensation" (atc) continuonsly corrects for the flow-dependent tube resistance during insnmdon and expiration ("electronic" extubatim), it pemaits patients to maintain their own inherent breathing pattern. then, ff necessary, tracheal pressure can be additionally supported by volume-proportioead and/or by flow-proportional pressure support (proportional assist ventilation, pav). (~as~: we report the case of a -year-old male patient who was intubated due to acute respiratory insufficiency after acute myocardial infarction with left ventricular dysfunction. during ips of mbar the patient showed a regular breathing pattem which became periodic during atc. in addition, proportional assist ventilation of mbar/l increased periodic breathing in such a way that the typical cheyne-stokes breathing pattem occurred (see figure) . baqkground: the hering-breuer reflex (hbr) is characterized by an inhibition of inspiration during lung inflation. this response has been recognized as an important vagally mediated mechanism for regulating the rate and depth of respiration in newborn mammals. in adult man the hbr is considered to be active only at lung volumes well above functional residual capacity, i.e., at tidal volumes above ml. assessment of the hbr requires specialized methods such as single breath or multiple occlusion technique. methods; in the presence of desynchronization between ventilator and patient, which frequently occurs during triggered inspiratory pressure support ventilation (ips)(see figure) , prolongation of the interval between inspiratory efforts (indicated by negative deflection of the esophageal pressure) due to lung inflation exposes an active hbr. we examined the occurrence of hbr in intubated critically ill patients. strength of hbr was assessed by the formula: prolongation [%] = ((inspiratory interval of interest -preceding inspiratory interval)/preceding inspiratory interval) * ( . rr of patients examined showed moderate to severe desynchronization. in of these patients a (re)activation of the hbr was found. the strength of hbr amounted to + %. there was a significant correlation between tidal volume and strength of hbr. in contrast to previous reports, an active hbr was shown during lung inflation well below ml. b pck~round: triggered inspiratory pressure support ventilation (ips) is commonly used to support inspiration in intubated spontaneously breathing patients. despite its usefulness ips shows some disadvantages which can be deleterious in crificauy ill patients: -additional work of breathing to be performed by the patient due to the flow-dependent tube resistance -desynchronization between patient and ventilator due to inherent triggering failures of the ips mode suppression of the patient's inherent breathing pattern -inability to predict successful extubation in difficult-to-wean patients methods: based on the known flow-dependent tube resistance our new mode "automatic tube compensation" (atc) compensates for the pressure drop across the endotracheal tube ("electronic" extubation). then, if necessary, tracheal pressure can be supported by volume-proportional pressure support (vpps) and/or by flow-proportional pressure support (fpps). results: hitherto, we have examined patients after open-heart surgery and patients with acute respiratory insufficiency (ari) or ards using atc with/without vpps/fpps. preliminary results suggest that the new mode avoids additional work of breathing due to accurate compensation of the pressure drop across the endotracheal tube during in-/expiration prevents desynchronization between patient and ventilator allows patients to breathe with their inherent breathing pattern accurately predicts the outcome of extubation even in difficult-to-wean patients due to "electronic" extubation conclusions: the new mode atc with/without vpps/fpps allows to support ventilation in a more physiologic manner and overcomes the disadvantages of conventional modes of pressure support in intubated patients. backgound: cheyne-stokes respiration (cs) is characterized by regula]; recurring periods of hyperpnea and apnea. in normal subjects, cs may occur after hyperventilation, after arrival in high altitude, or during sleep. it has also been observed in patients with prolonged circulation time due to congestive heart failure, as well as in some neurological patients. there is no report about the influence of sedative drugs on periodic breathing (pb) and cs. methods: in intubated patients conventional modes of pressure support do not allow patients to breathe with their inherent breathing pattem. therefore, periodic breathing and cs are rarely seen. since our new mode of pressure support ventilation "automatic tube compensation" (atc) continuously corrects for the flow-dependent tube resistance during inspiration and expiration ("electronic" extubation) it permits patients to maintain their own inherent breathing pattem even if pathological, e.g., periodic. results: using this new mode of pressure support ventilation, periodic breathing was unmasked in of intubated patients, of which showed cs. in of these patients the occurrence of cs was linked to impaired left ventricular function with increased circulation time. normal left ventricular and neurologic function was found in the remaining patients. in of these patients cs disappeared after intravenous administration of the benzo-diazepine antagonist flumazenil (figure). consequently, in this patient cs was induced by benzodiazepine sedation. objecti',~s: in contrast to conventional rhodes for pressure supported spontaneous breathing, our newly developed ventilatow mode ,,automatic tube compensation" (atc) completely compensates for the flow-depandant pressure drop tlpm-r across endotracheal ttlbe (ett). in the atc mode, the ventilator supplies a flow v' in order to maintain a constant tracheal pressure p~,,~. to this end, pk,,= has to be oontinuousiy determined. since continued measurement of p,,~ by introducing a catheter via the ett is not reliable, we opted for its continuous calculation socordng to the following equation: p~ = p,,, -aperr, pw being the continuously measured airway pressure. this also requires the continual measurement .of flow v' to calculata apm-r using the non-fineer approximation: aport = kvv' + k .w. the constant tube coefficients k~ and k are mathematically determined by mesns of a least-squares-fit procadum based on laboratory investigations. tracheal secretions, however, reduca the omss-saction of the ett. consequently, ~ values of ki end k are changed rendering the p~,ch calculations inaccurate. therefore, k and ~ have to be pedodcally updated to ensure an a~urete monitoring of pn,~ and a complete tube compensation under atc at any time. background: one of the first steps in weaning patients from controlled mechanical ventilation is to stop muscle relaxation and to reduce sedation. it can take several hours, however, until the patient is able to trigger the ventilator and to breathe spontaneously. during this period, many patients display a sudden increase in peak airway pressure of up to %. patients and methods: to investigate the reason for this potentially dangerous effect, we continuously measured lung and chest wall mechanics in post-operatively ventilated patients. lung mechanics (airway resistance and lung compliance) was measured using the esophageal balloon technique as described in [ ] . chest wall mechanics (tissue resistance and chest wall compliance) was calculated from lung mechanics and total respiratory system mechanics as described in [ ] . results: we found a decrease of chest wall compliance (cw) to be the main reason for episodes of sudden airway pressure increase while lung compliance (cl) remained unchanged. the decrease of c w can be inter- gil cano a, san pedro jm ~, sandar d, herntndez . , carrizosa f, , herrero a. emergency and intensive care department, hospital of jerez, spain objective: ) to determine the incidence of hypoteasion (h) associated with emergency intabatian of mechanical ventilation, and ) to establish its relauonship with respiratory mechanics (rm) and arterial blood gases. mechanical ventilation performed in the emergency room, in a prospective eans~eative manner, were evaluated. data collected included patient demographics, diagnoses, blood pressure and arterial blood gas levels before and at~er intabatian, and p_m, including calculated pulmonary end-inspiratory volume above functional residual capacity (veic) and calculated dynamic hypetinflatien (dhc). all patients received midazolen and awaanrinm to facilitate tracheal intubatien and rm measurement. hypotension was defined as a decrease in systolic pressure higher than mmhg or an absolute decrease in systolic blood pressure below to mhg within hour of intabatian. patients were excluded because met at least one of the following exclusion criteria: preexisting shock or h ( ), cardiac arrest ( ) . there weren't any association between peepi or other airway pressures (paw) and h, but calculated pulmonary volitmes had tendency to be larger in patients with h (p < . ). high paco before lrasheal intubatian ( . - mmhg) with a quickly decrease alter starting mechanical ventilation was a usual finding (p < . ) in patients who developed h. paw. ) thexe was a good relatienship between h and high arterial paco before traqueal intahatian and its fast "washing" with mechanical ventilation. ) because cao patients had the highest incidence of h, controned mechanicel hypoventilatien driven by paco changes and pulmonary volumes monitoring instead paw, should be attempted in these patients to avoid this cemplication after tracheal intubatiert. introduction: the endotracheal tube (ett) and demand valve devices cause an added work of breathing (wobadd), which is the work necessary to overcome the resistive load of the ett and the breathing circuit ( ). application of ips has been shown to partly compensate this added work ( ). since tbe amount of wobadd is flow dependent, a fixed ips is not adequate to completly compensate the wobadd ( ). therefore, atc has been developed as a new form of assisted spontaneous breathing ( ), which provides a flow-dependent pressure support. thereby, it theoretically should compensate all the wobadd due to the tube. the purpose of this study was to evaluate the reduction of wobadd with ips and atc for different ett. methods: a mechanical lung model (ls , dr*alger, liibeck, frg) was used to generate a constant spontaneous breathing pattern. the ls was connected to an artificial trachea (at, cm long, mm id). the at was intubated with three different tubes of . , . , . mm id and connected to an evita ventilator modified to provide atc as an option (dfager, liibeck, frg). flow and airway pressure were measured between the y-piece and the ett for four different modes of ventilation: cpap, ips of and cm i and atc all with a peep of cm h . the tracheal pressure (ptrach) was measured in the at. total wobadd was calculated as the area subtended by the ptrach-volume curve below peep. results: the results for total wobadd in nd/ are shown in the figure for the three different ett: breath/mln, s=success, f=failur% *~p<. , **-p< , ns = non significant, f versus s neveltheless, in / patients, invasive ventilation was necessary in mean . _+ hours after beginning of fmpsv. there was no significant difference between the two groups (success, failure) in following parameters : sex, age, previous histoly, medical treatment, saps & , clinical signs (rr, spo , heart rate, blood pressure, glasgow score...), radiological and echocardiographic findings and standard biological parameters. only two parameters were related with failure : .a low value of pac on admission until the patients were intubated. . an increased level of cpk in relation with an acute myocardial infarction ( / cases in the failure group, vs / cases in the success group, x~(with continuity correction) : p<. ). conclusion : fmpsv is a noninvasive, safe, rapidly effective method of treatment in acpe, which may avoid tracheal intubation. further studies are necessary to precise if association of arf and low paco (< mmhg) and/er acute myocardial infarction represents an indication of immediate invasive ventilation. introduction: since the added work of breathing (wobadd) imposed by the endotracheal tube (ets and the breathing circuit is regarded as an important contribution to the total work of breathing, considerable effort has been tmdettaken to compensate for this added work. ips has been fotmd to decrease the wobadd imposed by different ventilators ( , ). because of the flow dependent pressure drop across the etf the tracheal pressure (ptr) should be measured to estimate the total imposed wobadd (wobtut) ( , ). the aim of this study was to assess the circuit imposed work (wobcirc) and wobtot (including ett) for different demand valve ventilators during cpap and/ps. methods: a mechanical lung model (ls , driiger, lfibeck, frg) generated a constant spontaneuus breathing pattern. the ls was connected to an artificial trachea (at), intubated with an . nun et]', end connected to one of four ventilators (servo c and servo , siemens,-elema, sweden; evita , driiges, liibeck, frg; pb ae, puritan bennett, carlsbad, usa). three different modes of ventilator settings were tested (cpap, ips and mbar; trigger set at maximal sensitivity, peep always mbar). flow and airway pressure (paw) were measured between the y-piece and the etr; tracheal pressure (ptr) was measured in the at. wobtot was calculated as the area under the ptr-volume curve below peep, wobcirc was calculated as the area under the paw-volume curve below peep. results: in the foti g., patroniti n., cereda m., sparacino me., giacemini m., pesenti a. inst.of anesth.and intensive care-univ.of milan -sgh monza i aim of the study was to assess cpl,rs measurement obtained by the airway occlusion method during psv. we therefore studied paralyzed cppv ventilated ali patients (lung injury score = . • that were weaned to psv. we performed end inspiratory and end expiratory airway occlusions using the hold function of the ventilator (siemens serve c), first during cppv and then within the th psv hour. airway pressure and flow signals were recorded (cpi bicore) for subsequent analysis. an airway pressure plateau was defined as a flow tracing in which airway pressure was stable for at least . sec. end inspiratory (pel,rsi) and end expiratory (pel,rse) recoil pressures were then measured as the mean airway pressure during plateaus. cpl,rs was computed as tv/ (pel,rsi-pel,rse i) cpl,rs can be adequately estimated during psv using the airway occlusion method; ) during psv inspiratory plateaus are longer than the expiratory ones; ) the length of plateaus is negatively affected by the respiratory drive. foti g., de marchi l., *tagliabue m., gilardi p., giacomini m., sparacino me., pesenti a. inst.of anesth.and intensive care,-univ.of milan *dept.of radiology-sgh monza i we retrospectively compared ct scan and gas exchange findings between a group of patients successfully weaned from vcv to psv (group s = ii patients) and a group who failed the weaning (group f = patients). we selected ali patients (lis= . • in vcv mode who had available a chest ct scan performed within days from the weaning trial. a psv trial was began as soon as the patient reached hemodynamic stability and a pao > mmhg, irrespective of fie (peep < cmh ). maximum psv level was < (pel,rs-peep) measured during vcv, where pel,rs was the respiratory system elastic recoil pressure at end inspiration. psv ventilation was considered successful if a respiratory rate < bpm, an increase in fie lower than . compared to vcv, a pace increase < % of vcv value and hemodynamic stability were maintained during the next hours of psv. if any of these conditions was not met the trial was declared a failure. interdisciplinary critical care unit, regional hospital lugano-ch *surgical critical care unit, university hospital, geneva-ch objective: to assess the degree of correlation of cardiac output measured by thoracic electrical bioimpedance and thermodilution in mechanically ventilated patients with different levels of positive end-expiratory pressure (peep). methods: prospective study with ventilated patients, after head injury and with postoperative sepsis, with normal cardiac output: simultaneous determination of cardiac output by thermodilution and thoracic electrical bioimpedance performed with different levels of peep ( - - cm h ). results: cardiac output measured by thermodilution during sequential increment of peep did not vary: . + . for peep , . + . for peep and . + . l/rain for peep . simultaneously the bioimpedance device recorded a significant increase in cardiac output from . + . for peep to . + . l/mi for peep . (p < , ). conclusion: cardiac output measured by bioimpedance cannot replace the invasive thermodilution methods of cardiac measurement output during mechanical ventilation with peep. we also isolated a subset (h) of patients who had been hypercapnic (paco > mmhg) for at least days (range to days) before the end of cv. the psv trial was started as soon as pao was > mmhg, irrespective of fie and with peep < cmh and the psv level had to be < (pplateau-peep) as measured during cv. pace , pha, base excess (be) were collected before discontinuation of cv and on the ist day of psv: ) . ) weaning is more difficult in pts with head injury(p<o, ) and iss> (p<o,ol), in elderly(p<o, ) and in pts who need fi > , (p<o, ) and peep>io cm h (p<o, ). ) pts with iss> need longer duration of mv (p<o,ol). ) the mortality rate is higher in pts with iss> (p<o,o ), with head injury (p<o,ol) and in elderly (p<o, ). ) paradoxally, compliance was found to be higher in pts> years than in pts< years (p<o, ). s. crotti, p.pelosi, d.mascheroni, m.cerisara, a.lissoni, l.gattinoni. istituto di anestesia e rianimazione -irccs, milano, italia. obiectives. we investigated by ct scan the effects of extrinsic peep (peepe) on lung inflation, tidal volume distribution and regional compliance in sedated, paralyzed chronic obstructive pulmonary disease (copd) patients with dynamic hyperinflation (peep• methods. two ct section (end expiration, end inspiration) were obtained at lung base level in patients (individual analysis for each of the eight lungs) at peepe levels: peepe = cmh (zeep) and peepe amounting to %, % and % of the peep• at zeep ( . • cmh ). tidal volume was kept constant ( • . ml/kg). each lung section was divided into zones equally spaced along the vertical axis: upper (the most ventral), middle and lower (the most dorsal) zone. for each zone we computed: gas volume at end expiration (gase) and at end inspiration (gas• tidal volume (dgas=gasi-gase) and compliance (cpl=dgas/dp;.dp=plateau pressureactual peep• we also computed the lung inflation as the entire ct section gas volume at end expiration (total gase). results. at each peep level both gase and gas• were higher in the upper than in the lower zone ( we cone!ude that in copd patients with dynamic hyperinflation only the application of peepe higher than peepi produces a further increase of lung inflation, decreasing cpl of the upper zone (the more expanded one) probably by stretching phenomena, and causing dgas redistribution from the non dependent to the dependent lung zones. i. ravagnan, p. vicardi, f. valenza, d. tubiolo. p. pelosi l. gattinoni. st . anestesia e rianimazione, universita' di milano, ospedale maggiore -irccs, italy objectives: to investigate the effects of peep and ps on respiratory. pattern and inspiratory effort during ps ventilation in patients with acute lung injury or acute exacerbation of chronic lung disease. methods: pts with acute (a) (paco = • mmhg, pao /pao = . • and pts with chronic (c)(paco = • mmhg, pao /pao = . : . ) lung disease were studied in ps ventilation during the weaning phase. measuring airway pressure, esophageal pressure and gas flow we computed respiratory rate (ril bpm), tidal volume (tv, ml) and pressure time product (ptp, cmh *s/min), which is an index of oxygen muscle consumption. measurements were collected, after rain of stabilization, at and cmh ps and at two different peep levels ( and cndd conclusions: during psv: ) breathing pattern and ptp are different between a and c; ) in both groups peep does not modify breathing pattern; ) peep reduces ptp in c but not in a; ) ps modifies breathing pattern and reduces ptp in c but not in a. to test the performance of a new heat and moisture exchanger (hme): twistair, baxter. this is a hydrophobic-hydrophilic hme without hygroscopic salts. method: we evaluated the hme performance with a previously described method (i); it consists of a "lung simulator" connected to a mechanical ventilator and a flow divider, with a dry and a wet thermal probe inserted into inspiratory and expiratory limbs. on average ps level changes were associate( with opposed changes in both p . and rr. changes in p . were remarkable, homogeneous and highly significant (p<. ), while changes in rr were less pronounced, inhomogeneous and less significant (p<. ). it seems therefore that p . is a better index than rr for estimating a change in load for the respiratory muscles. recently, the lsf method has been described as an interesitng alternative to conventional tecniques used to measure total respiratory mechanics, providing, over these latter, advantages such as no need for hold maneuvers and no need for particular flow patterns. data on the reliability of the lsf method, however, are still few. methods. sets of measurements were obtained in each of ards patients, paralyzed and ventilated in cmv with constant inspiratory flow and an end-inspiratory pause equal to % of ttot. the lsf method provided data for total compliance (ctotlsf) and total resistance (rtotlsf) by multiple linear regression analysis of airway pressure, flow and volume change, applied over the entire breath. the lsf measurements were automatic and continuous, and each value used for analysis was the average of consecutive cycles. conventional measurements of dynamic.compliance (cdyn), quasistatic compliance (cqs), minimum inspiratory resistance (rmin) and maximum inspiratory resistance (rmax) were obtained by the constant flow, end-inspiratory occlusion method, each value being the average of measuremts. ctotlsf was compared with cdyn and cqs, while rtotlsf was compared with rmin and rmax. results. ctotlsf showed a high correlation both with cdyn (cdyn=. .ctotlsf+l. , r =. ), and with cqs (cqs =. .ctotlsf + . , r =. ). the average difference between ctotlsf and cqs, yet, was much lower (+. + . ml/cmh ) than the one between ctotlsf and cdyn (+ . + . ml/cmh ). rtotlsf correlated much better with rmax (rmax=. *rtotlso+. , r =. ) than with rmin (rmin =. .rtotlsf +. . , r =. ). the average difference between rtotlsf and rmin was + . + . cmh / /s, while the one between rtotlsf and rmax was +. + . , confirming the better agreement between rtotlsf and rrnax. conclusion.the agreement between rtotlsf and rmax suggests that rtotlsf takes into account both the airway and the tissue components of resistance, unlike rmin which only expresses airway resistance. the agreement between ctotlsf and cqs indicates that ctotlsf expresses the pure elastic components of the respiratory system. in the paralyzed patient, the expiratory time constant (rce) of the unit represented by total respiratory system and ventilator can be calculated from the slope of the expiratory flow-volume curve. recently it has been suggested that an estimate of this slope is provided by the ve/v'epeak ratio, ve being the exaled tidal volume and v'epeak the peak expiratory flow.the reliability of this method is still little known. methods. sets of measurements were obtained in mechanically ventilated ards patients during paralysis and cmv. measurements of ventilator expiratory resistance (rext) and of total respiratory mechanics were performed in order to calculate these reference measurements for ve/v'epeak: rcdyn=(rmin+rext)ocdyn, rcstat=(rmax+rext)ocqs, rclsf=(rlsf+rext)~ cdyn (dynamic compliance), cqs (quasistatic compliance), rmin (minimum inspiratory resistance), rmax (maximum inspiratory resistance) were obtained by the constant flow, end-inspiratory occlusion method. clsf and rlsf respectively corresponded to measurements of total respiratory system compliance and resistance by the least squares fitting method. ve/v'epeak showed a high correlation with all reference measurements, rcdyn (ve/v'epeak= . orcdyn-. , r =. ), rcstat (ve/v'epeak = . rcstat -. , r = . ), and especially rclsf (see fig the static pressure volume curve of the respiratory system (p/vst) provides valuable information, but the extensive data analysis prevents its use in clinical routine. dynamic p/vcurves are simpler to record. the objective of this study was to develop an automated method to obtain quasi-static p/v-curves (p/vqs) during low flow inflation as well as to measure resistance. preliminary tests were done in normal subjects and subjects with varying degree of lung disease. methods: a computer/ventilator interface (cvl) was constructed for control of a servo ventilator c during an automatic sequence: a) a normal breath, b) a prolonged expiration at zero peep, c) a low flow inflation of a predetermined volume, d) analysis of ventilator pressure and flow. pressure was corrected for tube resistance. airway resistance was calculated from a) and used to derive p/vqs from c). as reference, p/vst was obtained by the occlusion method. results: in non-obstructive diseases the method performed well at volume and pressure controlled ventilation. static and quasistatic compliance were virtually identical. p/vqs clearly reflected the lower inflection point and, when present, the upper inflection point (uip). in some patients uip was more evident in p/vqs, especially at an increased inflation flow rate. in obstructive diseases, the method for subtraction of resistive pressure was inadequate. conclusions: the system for automated computer controlled studies of lung mechanics based on a standard ventilator provides comprehensive information. differences between p/vst and p/vqs imply that the latter reflects also other factors than p/vst that contribute to impedance at hyperdistension. the clinical significance of the two curves remains to be shown. obiective: to evaluate the effect of combined high frequency jet ventilation (chfjv) in patients with severe respiratory insufficiency (sri). methods: in a retrospective study of the period - we analyzed patients suffering from sri who were refractory to conventional mechanical ventilation and were treated with combined high-frequency jet ventilation (chfjv). refractory to conventional mechanical ventilation was defined as a pao /fio < , despite maximal ventilator settings: peep > cm hz , fit > . . a total of patients matched these criteria, males and females with a median age of ( - ) years. seventeen suffered from severe trauma. chfjv was started following a median period of ( - ) days of conventional mechanical ventilation. prior to chfjv ventilation parameters expressed as median were the following: fit . , pao /fio , peep cm h peak airway pressure (pap) cm h . chfjv consisted of high frequency jet ventilation with a frequency of to breaths/minute, driving pressure of . to . arm, and inspiration time of to percent, superimposed on the whole cycle of conventional mechanical ventilation with a frequency of l to breaths/minute and tidal volumes of to ml. results: following two days of chfjv of patients showed an improvement of ventilatory parameters; peep could be reduced to < cm h in patients, the pap was decreased with > cm h:o in patients, fio could be reduced to < . in patients and finally the median pao /fio ratio changed from to . during chfjv patients died, of respiratory failure and due to multiple organ failure, died within two days of chfjv. the median duration of chfjv in survivors and nonsurvivors was days in both groups. conclusions: our data show that with chfjv in the majority of patients with sri who are refractory to conventional mechanical ventilatior" the ventilatory parameters can be improved. backeround and obiectives: although ventilation with peep above the inflection point (pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions, it carries the risk of hyperinflating the lungs. in the present study we set out to develop a new strategy to recruit the lung during ventilation with small vt, while maintaining peep levels as low as possible. we hypothesized that if the lung was recruited with a sustained inflation (si) to total lung capacity, recruitment would be maintained as long as the peep level was higher than the critical closing pressure of the lung, as observed on the deflation limb of the pv curve (ajrccm ; ( ) :a ). the purpose of this study was to examine the hypothesis that a strategy using si and a peep<pinf would induce less lung injury during small tidal ventilation than ventilation at the same low peep level without using a recmitment strategy in a model of respiratory distress syndrome. methods: we used a randomized protocol with groups to ventilate nonperfused, lavaged rat lungs with small vt ( to ml/kg) for hours and studied the effect on compliance and lung injury. group : peep>ping group : peep<pin f with an si, inflation to on h over sec, to recruit volume; group : peep<pinf without si; group : control group, lungs were inflated at peep<pin f, but not ventilated. results: in group and group static compliance did not change after ventilation (table) . in group static compliance fell significantly. group showed significant changes in the pv curve, which were less severe than in group . results from morphological examination are pending but preliminary results showed less lung injury in group , compared to group . conclusions: small tidal ventilation following a recruitment manoeuvre in a model of respiratory distress syndrome allows ventilation on the deflation limb of the pv curve at a peep below pinf. this strategy ( ) minimizes lung injury as well as, or better than using peep above pint" and ( ) ensures a lower peep to minimize the detrimental consequences of high lung volume ventilation. i~peep>pin~ _objectives-this report is presenting the results of the clinical study for using eeg examination as a method of the evaluation of patients ability for weaning. methods: the study inclljqles eeg examinations with fourier spectral analysis' of patients ~vith respiratory insufficiency and prolonged control mechanical ventilation (cmv). all patients have had a-rhythm of eeg before weaning. we have followed respiratory rate, tidal volume, respiratory pa{tern, end-tidal co and blood gases during weaning. results: patients had invariable eeg activity or short -waves period (till one hour). the weaning of this patients was fast arid sucsessful. other patients have had a decreasing of a-activity, an appearence of -waves for an hour and more, a short episodes of a-and e-activity. after that this patients had gas exchange and respiratory disorders with regression of the weaning right up to cmv. conclusion: eeg could be used as a method of the evaluation of patients ability for weaning from cmv. some eeg signs shows the overstrain of compensatory systems before the change to the worse of gas exchange and respiratory pattern. s. elatrous, p. aslanian, d. touchard, d. corsi, h. lorino, l. brochard. medical intensive care unit, inserm u , hopital henri mender, cr~teil, france. in vitro comparison of flow triggering (ft) systems demonstrated advantages compared to pressure triggering (pt) systems for some ventilators (puritan bennett ) but not others (siemens serve ). we studied the two types of systems in two groups of patients mechanically assisted with pressure support ventilation ( + cmh ). in the first group (pb ) the effort of breathing, assessed by the esophageal pressure time index, was significantly lower with the ft than with the pt ( + cmh .s/min - vs + , p< . ). by contrast no significant difference appeared in the second group (serve ), as predicted by the bench study despite marked interindividual differences ( + cmh .s/min - vs + , p = . ). we conclude that ) rigorously performed bench studies can predict in vivo effects, ) mild advantages can be found for the new triggering systems on some ventilators. objectives: pressore-volume curves (pv) of the respiratory system is of interest for the determination static compliance (cs , lower (lip) and upper (uip) inflection points which indicate zones of airway recruitment and overdistension. this study aimed to compare an "automated low flow inflation" method (alfi) to the reference occlusion (oc) method. the ability of the former method to identify cst, lip and uip was tested in icu patients. me,otis: ( arf and ards) sedated paralysed patients were studied using a serve c ventilator linked to a computer which automatically forced the ventilator to insufflate at a low constant flow a velum up to - ml or a maximum paw of cm h (alfi). the quasistatic elastic pressure (pel,qs was obtained by subtraction of the resistive pressure of tubing and patient and related to volume for calculation of compliance cqst. for oc tidal volumes (v from up to - ml were followed by a s post-inspiratury pause for determination of static pal (pel,st) in relation to volume. compliance was defined from the linear part of the p/v curves. lip and uip were defined from the consistent deviation of p/v data from extrapolated the linear part. ~,~ i~: in ards, mean cst was . + . and cqst . + . ml/cm h (us), lipst . + . and lipqst . + . cm h (us), uipst . + . and uipqst . + ~ cm h (us). nosocomial pneumonias (np) are frequent and often unsuspected during ards (bell, ! ). in the present study, we evaluated prospectively the onset of np during severe ards (group b of the european study). patients and methods: the charts of patients with severe ards have been prospectively recorded. a plugged telescopic catheter (ptc) specimen has been systematically performed every hours, for quantitative bacteriological analysis. the diagnosis of np was defined by a number > colony forming units / ml. results: for the patients studied, the mean saps score (+ sd) was +_ , the initial pao /fio ratio was -&-_ , the duration of mechanical ventilation (mv) was + days. the mean delay before the onset of the first np was . + . days ( - ), and the mean pao /fio ratio was +- . respiratory symptoms (purulent aspirates, new pulmonary infiltrates, or gazometric changes) were present in % of the patients studied. alteration of gas exchange was present in of the patients ( np) . a new pulmonary infiltrate was present in only np ( %). an increase of fever was noted in patients, an increase of leukocytosis > % in patients, an increase of volume and purulence of sputum in of the patients with np. the degree ofgazometric worsening (pao /fio before np minus pao /fio during np) during the first episode of np was + mmhg. excluding the bacteriological criteria of np, the number of criterias of np present was in / patients, ( / ), ( / ) or ( / ). two patients only had a pulmonary colonization (ptc: < cfu / ml) before the first episode of np. the incidence of np is high ( %) during severe ards. the first episode occurs in average:at the th day, and is the cause of a severe hypoxemia (pao /fio ) . the onset of a np may contribute to the high mortality rate observed in our patients ( %). each worsening of hypoxemia during severe ards should induce to suspect a np. respiratory system during mechanical ventilation. the me~hod quantifies the dissipative energy consumption of the respiratory system in terms of energy loss aek, inefficiency ~k~ and respiratory dissipative resistance rk~ over a given partition of the tidal volume. the method can be applied in intensive care units with no interference to ventilatory support. it allows for monitoring the combined effects of inhomogeneities, non-linearities and visco-elastic effects, that are subject to change in the respiratory system. the method is studied on pigs~ in the presence of a log-dose response curve of methacholine (mch) induced disease. in healthy pigs~ we find a mean value of energy loss, ae, of . • j/l, a mean value of inefflency, ~ of . ~= . and a mean value of resistance, ~, of . • cm h s/ . the respiratory resistance, rk, shows a variation over the partition of tidal volume with armax ---- . • . cm h s/l. during methacholine provocation~ ae rises more than five-fold up to . • j/l~ doubles to . • and t~ increases to a maximum of • cm h s/l, with armax : . • . cm h s/ . the variation in rk becomes more pronounced with higher doses of methacholine. methods: ards patients were prospectively studied. initially they were ventilated in the amv (assist mechanical ventilation) mode with the settings prescribed by their primary physician. after stabilization, ventilatory gas exchange and hemodynamic variables were determined. patients were then ventilated in the mrv (mandatory rate ventilation) mode with breaths as the target rate. in mrv the target rate is set and the ventilator autoregulates the pressure support level delivered ~o achieve this rate. after stabilization, the measurements done on amv were repeated. finally, patients were sedated and paralyzed and ventilated in cmv (control mechanical ventilation) with the ventilatory variables they had during mrv. measurements done in amv and mrv were repeated and respiratory mechanics were assessed with the constant flow end inspiratory occlusion method. results: two groups were recognized based on their response to mrv. tn group patients responded to mrv by decreasing their v and increasing the t/t t ratio. ve, vo , and aado decreased while paco increased and tda vo ume and co remained unchanged. on the contrary, in group v, vr and ve increased; ppeak and trr t remained unchanged, paco~ decreased while vo and aado increased with constant co, the pressure support level needed to achieve the target rate was much lower in group than in group ( , -+ . vs . _+ . ). obiectives : in the newly developed mode of ventilatory support ,,automatic tube compensation" (atc) the ventilator compensates for the flow-dependent pressure drop across the endetracheat tube (ett) thus allowing ,,e]ectronic extubation". the aim of the study is to investigate whether healthy subjects perceive atc in inspiration (atc-in) and in expiration (atc-in-ex) and whether atc provides an increase in subjective comfort compared with the conventional assisted spontaneous breathing mode (asb). methods : healthy volunteers (no preceding lung disease, non-smokers, male, - years)breathed spontaneously through an uncut ett of . mm id via a mouthpiece. the ett was connected with a prototype ventilator evita modified by the manufacturer (drfiger, lebeck) for atc. flow and airway pressure were measured at the outer end of the ett. three ventilatory modes, ( ) asb ( mbarover mbar peep), ( ) atcin, ( ) atc-in-ex were selected in random order. immediately following the transition from one mode to another the volunteers answered by hand sign how they perceived the new mode compared with the preceding mode: ,,better" (+ ), ,,equal" ( ) or ,,worse" (- ). inspiration and expiration were investigated separately by presenting mode transitions (in total; including ,,placebo" transitions). results : the difference between atc and conventional asb is perceived in inspiration and in expiration. atc is positively judged; asb is nega ively judged. the diagrams show mean values _+ sd of five volunteers investigated up to now. the new mode atc is perceived as an increase in subjective comfort. our explanation is that atc preserves the natural breathing pattern better than conventional asb. objectives: to determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest. to correlate the results with indices of cerebral oxygenation and the levels of several vasoactive hormones in the jugular bulb. methods: in comatose patients after cardiac arrest we measured the pulsatility index (pi) of the medial cerebral artery by transcranial doppler sonography. the pi is a reliable indicator of cerebral vascular resistance. we also sampled blood from the jugular bulb and measured cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate and cgmp. the first measurement was done within hours after cardiac arrest and repeated , , , , and hours later. results: we studied patients, females, mean age , + , years. the pi decreased s!gnificantly between th~ first and the last measurement from . _+ . to . + . (p = . ). cerebral oxygen extraction ratio decreased also from . + . to . + . (.p = . ). endothelin levels were high, but didn't change during the studied period. nitrate levels varied in a wide range, but didn't change significantly. however, cgmp levels increased significantly from very low levels in the first measurement to very high levels hours later, rasp. . pmol/ml (median; th . - th . ) and . pmol/ml (median; th . - th . ) (p = . ). eighteen and hours after the first measurement we found a strong correlation between pi and cerebral oxygen extraction ratio ( r = . , p = . and r = . , p = . ). we.also found hours after the first measurement a significant correlation between pi and cgmp levels ( r = . , p = . ). we found no correlation between pi and endothelin or nitrate levels. conclusion.~; our results show a high cerebral vascular resistance in the first few hours after cardiac arrest, gradually decreasing during the next hours. this is accompanied by an initially high cerebral oxygen extraction ratio and low cgmp levels, suggesting that the cerebral vascular resistance is induced by active vasoconstriction because of insufficient cgmp levels, leading to a decrease in cerebral blood flow and a compensatory ~ncrease in cerebral oxygen extraction. objectives: sudden cardiac arrest is a major cause of mortality in western countries accounting for over half of all cardiovascular deaths. in most cases the mechanism of death is prolonged cardio-circulatory arrest due to ver:tricular fibrillation (vf) preceding final asystole. recurrent syncopes due to idiopathic vf with good neurological prognosis have been reported in patients with and without cardiac etiology ( , ). in the past measurements of cerebral hemodynamics have been repeatedly done in humans during cpr, but until today no studies of cerebral blood flow velocity (cbfv) have been reported during controlled cardiac arrest in humans not under-going cpr. it was the purpose of our study to evaluate the acute hemodynamic effects of untreated vf on cbfv. methods: after approval by the local university ethics comittee, five male patients aged - years without evidence of cerebral disease were investigated during vf while undergoing implantation of a pacer cardioverter defibrillator system (model d; medtronic| a standard anaesthetic regimen was used (propofol, fentanyl). after implantation of the automated cardiac defibrillator vf was induced by electrical countershock to test effective sensing, pacing, and defibrillation. to measure cerebral blood flow velocities (cbfvmca) the doppler probe was placed above the zygomatic arch between the lateral margin of the orbit and the ear and directed towards the m segment of the middle cerebral artery (mca). results: a total of phases of vf were investigated. duration of vf ranged from to seconds, with cbfvmc a (mean_+sd, cm sec - ) flow pattern changing from pulsatile to laminar flow immediately after onset of vf. conclusions: the underlying mechanism of the laminar cerebral blood flow observed during vf in our patients is uncertain, but it may provide insight into the prognosis of patients with idiopathic vf. theoretically, the laminar cerebral blood flow observed in our pulseless patients may provide a substantial amount of cerebral perfusion even during clinical cardiocirculatory arrest objective: to investigate whether the intensive care nursing staff can inflate more accurately a specific air volume with the laerdal resuscitation bag when they receive feedback after each inflation about the delivered volume compared to no feedback. method: icu nurses were asked to inflate a testlung model times with a specific air volume ( ml, ,ml or ml) under three different conditions (normal, decreased compliance and increased resistance) without and with feedback. we measured the mean absolute difference from the specific airvolume after each ten inflations. results: the largest absolute difference was found when icu nurses inflated ml ( ml). the mean inflated volume for this group was ml. when the icu nurses had to inflate ml the mean absolute volume difference was ml with a mean inflated volume of ml. inflating ml produced an absolute volume difference of ml with an mean inflated volume of ml. the absolute volume difference decreased when the compliance of the testlung was decreased and even more when the resistance of the used endotracheal tube was increased. when the icu nursing staff received volume feedback after each inflation the mean absolute volume difference was reduced between the ml and ml for all specific air volumes. % of the last inflations with feedback were significantly smaller than ml from the specific air volume (p < . ). conclusion: the majority of nurses overinflated the specific air volumes. the largest over inflation occurred when ml and the smallest when inflating ml. when nurses were provided with volume feedback the performed significantly better. we concluded that icu nurses are not able to inflate a specific air volume with the laerdal resuscitation bag without receiving volume feedback. feedback is desirable in order to reduce the volume trauma. objectives: a pro_found impairment in systolic and diastolic myocardial function following successful cardiopulmonary resuscitation (cpr) has been demonstrated by using langerdorff method in rats. in the present study we have investigated post resuscitation myocardial dysfunction in a porcine model of cpr. methods: ventricular fibrillation (vf) was electrically induced by alternating current applied to the ep{cardium of the right ventricle in domestic pigs. following rain of untreated vf, precordial compression and mechanical ventilation was initiated and maintained for min. electrical defibrillation was then attempted and of animals were successfully resuscitated. results: following successful cardiac resuscitation, stroke volume index (svi) decreased from prearrest value of . ml/kg to . ml/kg (p< . ), and left ventricular stroke work index (lvswi) from . to . mmhg,ml/kg (p< . ). both svi and lvswi remained depressed for another hours. these decreases were associated with increases in heart rate from bpm to bpm (p< . ). no significant changes from baseline in mean arterial pressure, mean pulmonary pressure, right atrial pressure and pulmonary artery wedge pressure were observed. prehospital resuscitation efforts c. k ppel. g. fahron, h. lufft, a. kruger, c. th(jrk, f. bertschat, f. martens dept, of nephrology add medical intensive care, virchow-klinikum, humboldt-universit~t, d- bedin, germany obiective: the success rate of prehospital resuscitation in patients with cardiocirculatory arrest in an emergency medical system (ems) may reach - % depending on the time of calling the ems, the distance to cover by the emergency ambulance and the training of the emergency physician and his staff. in the berlin ems, which is associated with the berlin fire brigade, the time between alarm and arrival at the scene ranges from - min, mean min. resuscftation is based on the advanced cardiac life support (acls) according to the guidelines of the american heart association. if resuscitation efforts fail to restore circulation, they are terminated after - min, depending on duration of cardiocirculatory arrest, pre-existing disease, age, absence of an even transient response to cpr. however, there is a lack of practical criteria for termination of cpr in individual decision making. patients: we report cases of prehospital cpr with primary asystolia terminated after - rain of frustraneous cpr efforts including highdose epinephrine and dopamine. results: after termination of cpr, the ecg monitor remained connected and showed permanent asystolia in all patients while the emergency physician completed his records. spontaneous resumption of respiration and circulation was observed in these patients after - min and cpr efforts were immediately resumed, nevertheless, of the patients died at the scene, while could be hospitalized with stable circulation. one of them died hours after admission to the icu, the other survived for weeks in a vegetative state. spontaneous resumption of circulation and respiration is most likely due to the development of extreme hypercapnia and acidosis, which -at least in some patients -seems to be a stronger stimulant of the circulatory and respiratory brainstem centers than cpr with high-dose catecholamines, conclusion: because of the legal and ethical implications of this rare phenomenon, emergency physicians should continue ecg monitoring for at least rain. after termination of cpr efforts. pulmonary artery catheterezation is used for patient's monitoring [ ]. we reported our results on such monitoring in [f.coaobbeb,r.fe enb~-kap~monorm~, ,n ,p. - ] .however not all of the received criteria assessments meet demands that are necessary for early diagnosis of critical states. here we report the data on po ,pco (mm rg),so ,ph levels in femoral [af) and pulmonary (ap) arteries blood, as well as on summary gas pressure (sgp) calculated from pe=(po +pco ) in mm hg in ap blood. these data were derived from:i) subjects free of cardiovascular pathology according to catheterization data during their spontaneous air breathing (n group in ap blood appears to be a measure of adequacy ratio between pc and sgp in ap blood during air breathing; partly its characteristics and variations ranges are presented earlier [ j. in control group it is equal to , • mm hg. tests on sgp neither exclude nor substitute conventional (pc and pco ) tests, but rather include them as a part choosing only additive characteristic -pressure. they appear to be a part of general system of human metabolism regulation by pressure (arterial,venous,intracardiac, tissue,liquor,onco-osmotic,etc ietraabdeminal pressure produces perturbations of cardiac, pulmonary, and renal physiology. this most often occurs fonowing eeliotomy for peritonitis or intestinal obstruction; bowel edema and distention prevent wound closure without unacceptable compromise of blood pressure or pulmonary compliance. a variety of temporizing measures have been reported for managing wounds that cannot be closed: ) using towel clips to reapproximate skin only, )i sewing silastic, marlex or other prosthetic grafts to the fascia to "enlarge" the peritoneal cavity, ) using loosely tied retention sutures for partial closure, ) simply packing the wound without attempts at c~osure. these techniques either traumatize the abdominal wall (complicating definitive closure), expose the bowel to damage, or allow excessive loss of fluid and heat. since we have evolved a suturelees technique which permits the abdomen to be partially closed in a quick, safe, sterile, sealed, atraumatic fashion -while providin! decompression of unphysiologic intraabdominal pressure. methods: whenever possible omentum is interposed between bowel and the open incision. viscera are covered by a layer of sterile, non-reactive plastic, placed deep to the fascia and extending we~t beneath the edges. sump tubes are placed above the plastic and covered in turn by two layers of an adhesive plastic drape which sticks to the skin and seals the wound in all directions, the patients remain intubated and paralyzed. results: we have used this technique in a total of patients, four of whom suffered from compartment syndrome. all of the latter were males and ranged in age from to . all four showed immediate physiologic improvement. all four incisions were eventually closed without complication. one compartment syndrome patient died t days later of multiple organ failure. there were no complications related to the closure technique in any of the patients. conclusions; . selected patients with abdominal compartment syndrome will benefit from decompression using this temporary sutureless technique. the technique a) is quick, safe, sterile, sealed, and atraumatic, b) minimizes loss of fluid and heat, c) facilitates eventual definitive abdomina| closure. although m. brunner m. mitllncr objectives: to determine incidence and predisposing factors for cardiac arrest occurring during the first hours after open heart surgery. methods: the study included patients who, following open heart surgery, had adequate cardiac function and in whom cardiac arrest was not anticipated. all data were prospectively recorded and analyzed. results: from / through / , pts underwent open heart surgery at our hospital. of th~se, pts ( %) (age _+ yrs) had a cardiac arrest during the first hours after transfer to icu. they were operated on for coronary artery bypass grafting (cabg) ( pts), valve replacement (vr) ( pts), cabg and vr ( pts) and aortic aneurysm ( pt). the preoperative ejection fraction was _+ % whereas bypass and aortic cross-clamp time were + and + rain, respectively. prior to arrest, they had a cardiac index of . _+ . l/min/m and were receiving . + inotropes. arrythmias leading to cardiac arrest were ventricular tachycardia/fibrilation ( pts) and bradyarrythmia ( pts). closed-chest cpr was initially performed on all pts and was followed by open-chest cpr in pts. eighteen pts ( %) survived to icu discharge. causes of arrest included perioperative myocardial infarct (t pts, %), tamponade ( pts, %), rupture of the proximal vein gra& anastomosis ( pt, %), graft occlusion ( pts, %); no cause was found in pts ( %). conclusions: postoperative cardiac arrest in stable cardiac surgery pts is relatively infrequent (- % incidence) and is associated with a high survival rate following successful cpr. perioperative myocardial infarct is the most common predisposing factor. group ~deptof anaesthesia and intensive care, semmelweis univ. medical school, buda military hospital intensive care unit, budapest background: when a cardiac arrest occurs in-hospital, the outcome can be improved by a higher quality of basic life support provided by the witnessing health care workers until the code team arrives. this basic life ~pport (bls) should include the best available method for airway management as well. since not all medical staff are ready for carrying out endatracheal intnbation, we investigated the effieacy of the use of different airway management methods during bls. methods: we have investigated the efficacy of airway management of doctors and nurses from different hospital wards: internal medicine, department of surgery, trauma, urology and gynaecolagy. comparing the bag-valve-mask, laryngeal mask and the endotracheal intubafion, we have measured the following parameters: time needs for correct application (sec.), number of incorrect applications (out of ten trial), efficacy of artificial ventilation provided by the device. we used a computerised als trainer manikin for the evaluation of the performance. total performance score was created after the measurement between - . after the first screening we held a x hours training. doctors and nurses were trained for the endotracheal intubation (group it , t ) , doctors and nurses were trained to use the laryngeal mask (group lm , lm ) . all respondent were trained to use the bag-valve-mask device. day, month and month after the training we have carried out retention study using the same method. results: we have found that the efficacy of the artificial ventilation using the above mentioned devices were poor before the training. the average after-training performance scores of the groups are presented in the table below. (bls) should be initiated by the witnessing health care professional. the cpr study introduced a multi level code system, which means bls included sophisticated airway management, early defibrillation and early epinephrine administration provided before the code team arrives. our previous studies confirmed a poor level of cpr performance and a high demand for cpr training among health care professionals. method: we established a cpr training course centre, where doctors and nurses are being trained for in-huspital basic and advanced life support. x hours of training were held. after the theoretical introduction a step-by-step training method ws used for trainees to be familiar with all sequences of basic and advanced life support. then we synthetised all separated sequences. afterwards, a r e play of rescue groups was taken in simulated situations. we also trained the multi level alarm system fur the in-hospital resuscitations. after the training all respondents had to sit for examination. the quality of performance was scored and compared to our previous results. semi-structured interviews were carried out before and aider the training among all respondents to collect information about the course. results: we have found a remarkably high interest among doctors and nurses in our cpr training courses. it was very important to use proper equipment for the training: audio-visual training facilities, computerised als trainer manikin, manual and automatic defibrillator units. the evaluation of the examination held immediately a~er the training course showed a significant higher quality of performance than before the training. the self.-eonfidence of the trainees for initiating and carrying out resuscitation had increased. their overall feeling about the course was positive and % responded the course "very useful". . % of doctors and . % of nurses claimed fur regular training facilities with als trainers, conclusion: the cpr training for health care werkers is mandatory including the training of sophisticated airway management and use of elad~l~ills~tt~r wlaa ~en ~r a~ti~atir ~nel r rm~a'*h*nr m~thnd for training will improve the efficacy, the satisfaction of trainees, therefore their compliance for further co-operation will also increase. s objectives: the effect of reinfusion in emergency surgery and gynecology. methods: we had an experience of autologous blood transfusion in patients whom was produce t an emergency surgical or gynecological interventions in occasion with break tubal pregnancies ( . %), penetrating abdominal wounds with injuries of mesenterial vessels ( . %), injuries of the liver ( . %), blunt abdominal trauma with lien ruption ( . %). in . % patients had the previous somatic pathology. blood loss volume was - ml, & the reihfuside blood volume was - ml, consisting - % of blood loss. it was needn't to fransuse donor blood in . % in further but - ml of contanined erythrocytes were frasfused for supporting of hb concentration on the g/l ( g/dl) rate at the other patients with isovolemie hemodiluttion. results: the arterial blood pressure fast stabilisation on the perfusion level had noted after reinfusion, excluding the case, when the volume of reinfused blood had conisted just % of blood loss at the patient with massive blood loss. complications have noted in two cases. one patient with slash wound, injury of arteria gastrica dextra and total blood loss of ml, has an episode of asystoly, dic (disseminated intravascular coagulation) syndrome, acute renal failure, and acute pancreatitis that we haven't connected to reinfusion. all the complications were successfully corrected and at thirty first day patient with subcapsular wound of the lien that has happened days before complicated with external rupture of the capsull & massive intraabdominal bleeding, has the hemolytical shock, dic syndrome, acute renal failure developed after reinfusion. he was died. all another have no complications. posthemorrhagic anemia had corrected rapidly than in case when hemorrange corrected exclusively by donor blood. conclusions: we consider that simplicity, accessibility, high effectiveness, quite well further results of blood reinfusion, except the case of blood reinfusing that was for time-expired out of blood vessels (more than days in our case) will promote to the wide spreading of this method, especially in emergency surgery, in massive injuries, & in disarters, all the cases of insufficiently of time for selection of lot of donor blood. objectives: study of a reaction of the oardioreepiratory system of pregnant women to i/v microperfusion of clophelinum which is known to eliminate hemodynsmic and endocrine nociceptive reactions and can be used for treating hypertensive syndrome in pregnancy and labor. methods: the following non-invasive methods were used: capnography, spirometry, oxygenography, indirect fick principle based on the circle breathing, plethysmography and integral rheography~ functional indices of cardiorespiratory function were evaluated. results: pregnant women with ~h-gestosis were examined before and after i/v infusion of i ml of . % clophelin solution, . mg/kg/hour. before the treatment intensification of carbohydrate metabolism, hyperventilation with moderate hypooapnia and complete respiratory compensation of metabolic acidosis~ increased alveolar ventilation, decreased alveolar volume, predomination of perfusion over ventilation, hypokinetio type of circulation with dominated load by peripheral vascular resistance to the blood flow was observed in this group of patients. microperfusion of clophelin imp~-oved the ventilation/perfusion ratio, ventilatory and gaseous exchange efficiency, resulted in a decrease of congestion in the pulmonary circulation, possibly owing to a decrease of peripheral vascular resistance by %, of the heart rate by io. %, of the oardial output index by . %. conclusionm: the resulted type of circulation with a decreased load on the heart both by resistance and volume allowed to improve the cardioreepiratory system function in pregnant patients. objectives: the injury severity score is a measure of severity of anatomic injuries. iss is a sum of squares of the highest degrees of the abbreviated injury scale (ais) for each of three most severity injured regions. the purpose of the study is to establish correlation between the iss values and mortality rate in older, polytraumatized patients. methods and results: iss was determined for patients. the mean iss value was . + . while the median value was . minor injuries were present in ( %) patients with iss less than , while ( %) patients with iss more than had severe injuries. increased mortality of the older patients was noted in the range - . all patients older than died while % of patients below yrs of age survived, indicationg correlation between iss and mortality rate in polytraumatized patients above yrs of age. conclusions: this mode of evaluating severity of injuries may help in triage, determining appropriate level of care and as an indicator of future outcome of polytraumatized patients. objectives : tissue hypoxia is a non exclusive cause of hyperlactatemia. other serious medical situations induce hyperlactatemia. therefore, lactatemia could be a non specific indicator of severity in patients admitted in emergency unit. the aims of this study were to examine the correlations between lactatemia with the short term survival course prognosis and the unit of hospitalisation; intensive care unit (icu) or medicine unit, in patients admitted in our emergency department. methods -lactatemia was measured as soon as the admittance, in arterial blood sample of patients which needed arterial blond gas. sixty-one patients were included during months. to assess the statistical performances of lactatemia, sensitivity (se), specificity (sp) and accuracy (ac) were calculated for the threshold determined by the youden's test (se+sp- ). results : fifteen patients were admitted in icu and in a medical unit. fifteen patients died. a group of patients had a lactatemia up to mmol.l" . in this group of patients, had acidocetosis, had asthma, had cerebral vascular ischemia, had neoplasia, had cardiogenic shock, was epileptic, had congestive heart failure, had acute respiratory failure, had septicaemia, had hyperosmolar status finally had medicinal intoxication. lactatemia was significantly higher in non survivor than survivor ( . • vs. . + . , p<o.oool, respectively), the cut point of lactatemia was . mmoll" se was %, sp was % and the accuracy was %. on the other hand lactatemia was higher in patients admitted in icu than in medical unit ( . + . vs. . • p<o. , respectively). conclusions : this preliminary results suggest that lactatemia is a good indicator of the short term survival course in patients admitted in an emergency unit. furthermore, hyperlaotemia is present in several pathology seen in emergency. objective: to determine the pattern of injury, total peripheral white cell, neutrophil, and lymphocyte responses, and the outcome of trauma patients who are leucopaenic on admission to the icu. design: prospective, descriptive study of consecutive admissions over months. setting: a -bed surgical intensive care in a teaching hospital. patients: thirty consecutive adults admitted to the icu following trauma. leucopaenia was defined as a total peripheral white cell count of < x , neulropaenia < x , and lymphopaenia < . x ~ cells per litre. measurement and results: the total peripheral white cell count was documented daily and the neurtophil and lymphocyte counts and differential percentages on days , , and . the incidence of leucopaenia was significanfiy higher in patients with gunshot wounds (p < . ) and hollow visceral intra-abdominal injury (p < . ). eight ( %) patients died. no significant differences were found in the initial mean total white cell, neutrophil, or lymphocyte counts nor in the differential percentages between survivors and non-survivors. the total peripheral white cell count increased significantly in survivors compared to those who died (p < . ) and significant differences were found in absolute neutrophil counts (p < . ) and differential percentages (p < . ) on days and . no significant differences were found in lymphocyte counts or differential percentages. conclusions: there is a signficant association between leucopaenia, neutrepaenia, and intra-abdominal hollow visceral injury and peritoneal contamination. survival is related significantly to resolution of these white cell deficiencies. these findings suggest a possible role of granulocyte colony stimulating factor in the trauma patient with intra-abdominal infection and persistent neutropaenia. amelioration of organization emergency care team in order to improve caring for urgent cases. objectives: emergency care team (ect), as integral part of health, respectively as activity of primary health protection care all acute difficult conditions which vitaly danger patients and distressed. the aim of our investigations was to indicate on the possibilities of amelioration of organization ect in order to improve caring for urgent cases. methods: in our investigations we used epidemiologicai and statistical metods all informations and matherials from terrain ects. results: the number of traumatized in traffic accidents etc. have a epidemic character. it is well known that . % traumatized died in first two hours. ect isn't enough qualified to care a traumatized on the place of accident and during transport. because that medical personnel must have an education with solid qualities. conclusions: . besides a physician specialized (vii --+ vii -~ viii gradus) in urgent medicine, it's necessary to introduce two ( ) medical technicians instead of one as is existing now ( ~ ). .the medical technicians can drive cars and one of them always, drives the ambulance car ("b" category). .the technicians have been specially educated for urgent cases (iv ~ v ~ vi). . such a new team structure should be more capable in professional sense. .we can see an importance of team-work in ects. . such teams should also be more economic in comparison with existing one. . we think, that on the general medical studies need to include a new discipline-urgent medicine! objectives: to detoxicate an organism since we have used biological sorbents: isolated from liver and spleen of human or animal cells or tissue fragments. methods: cellular dialysis ( dialyses) in patients with an acute hepatic insufficiency poisoning by hepatotropic poisons: cc , dichloethane, mushrooms -were conducted using "artificial kidney" apparatus, by means of arteriovenous shunt, formed at forearm with disposable dialyzers. hepatocytes suspension was poured into dializing circuit of dialyzer at - mg of cells per i kg of patients weight. dialysis was performed during - hrs. patients with purulent-septic states were treated as for hemoperfusion through prepared sorptional column: . ml of hemosorbent and . ml of fragmented spleen or hepatocytes suspension with the help of roller pump with the rate of - ml/min, during - min. average volume of hemoperfusion made . . conclusions: in all cases we used both native and cryopreserved biomaterial. analysis of the dynamics of clinical, biochemical, scintigraphic and us-investigastions allows to conclude that application of cellular-sorptional method of detoxication enable to prolong life and reduce lethal outcome in some severe category of patients with endotoxicosis. after infusion of diazepam ( . mg/kg),thiopentone ( mg/ kg) and vecuronium (lmg/kg),patient was intubated and mechanical ventilation was adjusted to mantain normoca= pnia. ct scan showed left parieto-occipital hypodensity with brain swelling. after admission in neurological icu,dexamethasone ( mg/ kg/die),mannitol ( .smg/kg) and diphenylydantoin ( mg/ kg/die) were administred. two hours later neurological status of the patien~ was normal and she was extubated. the risks of stereotactie radiosnkgety are related to: hemorrhgge during the latency interval;transient radia= tion effects;permanent radiatio~einduced complications; radiation induced neoplasia. no epilepsy is reported in pts with avm and no seizure before radiosurgery. in c nclusion, epilepsy can be a posmib~e delayed eompli c~t~n, ~fe~r rgdi surgery for cerebral avm. serum potassium deficiency is a frequently reported finding in the time course of acute myocardial infarction (ami). if this is also correct for patients with ami undergoing primary percutaneous transluminal coronary angioplasty (ptca) is unknown.for that reason we analysed in patients ( m., f., + y.) serum potassium concentrations on ad ,mission and directly after ptca.the reference intervall for potassium in our clinical laboratory is , - , mmol/l. although more than % of the patients with ami undergoing ptca showed normal potassium serum concentrations on admission a measurable decrease of potassium could be found in % of patients ( ) after ptca.therefore for the majority of patients with ami potassium supplementation prior to ptca can be justified to avoid electrolyte disturbances as a possible trigger factor for cardiac arrhythmias in the setting of ami and acute reperfusion due to primary ptca. objectives: diagnostic procedures are very important in the management of abdominal injures in trauma. the aim of this paper is to present our experience with peritoneal lavage as diagnostic procedure in abdominal injury. methods: we analyzed patients to whom peritoneal lavage was applied in the surgical emergency from st of january till st of december . results; in this four years period there were abdominal injures. there were blunt injures. among them in patients peritoneal lavage was applied. results were positive in patients and negative in patients. false positive finding were in patients and false negative in two patients. in patients with positive lavage there were more than , /mm red blood cells, more than , /mm white blood cells and the level of amylase was up to u/i. the gall, urine and stool were positive as well. in patients with negative lavage there were less than , /mm red blood cells, less than /mm white blood ceils and amylase were negative. conclusion: peritoneal lavage is useful and important diagnostic procedure in the management of abdominal injures in trauma. our experience with urgent surgical management of the acute gastric and duodenal bleeding s.se en md, z.milo~evi md, *s.srdi md, k.sar ev md. clinic for abdominal and endocrine surgery, institute for surgery; *clinic for cardiology, institute for cardiovascular diseases; school for medicine novi sad, university of novi sad, yugoslavia objectives: acute gastric and duodenal bleeding are very common complication of gastric and duodenal ulcer. the aim of this paper is to present efficiency of our surgical management of these acute conditions. methods: in this paper results of surgical management of patients with acute gastric and duodenal bleeding, treated in our clinic from the st of january till st of december , are presented. results: among operated patients there were females ( . %) and males ( . %). there were patients ( . %) with gastric bleeding and patients ( . %) with duodenal bleeding. bleeding from gastric ulcer were treated with the following methods: excision of ulcer with suture in patients ( . %), ulcer suture in patients ( . %), billroth i in patients ( . %) and billroth ii in patients ( . %). heinecke-mikulicz-weinberger pyloroplastica was the most frequently used in the treatment of the duodenal ulcer bleeding. bilateral truncal vagotomy was done in patients ( %), duodenotomy with ulcer suture was done in three patients ( . %) and three patients underwent billroth ii operation. we had three complicationsduodenal dehiscence in pyloroplasty. there were no lethal complications. conclusions: based on our own experience we conclude that acute bleeding from gastric and duodenal ulcer can be safely managed with urgent and modern operative techniques. dept. of anaesthesiology. emergency center of serbia, belgrade, srj b ectives and methods: cardiac contusion was evaluated by serial determination of cpk-mb fraction and co using non-invasive doppler technique in patients with blunt trauma of the chest. results: miooardial contusion was diagnosed in ( %) patients, while in ( %) it appeared unaffected. cpk-mb of % and more in comparison to total cpkwas . + , % in patients, and , + , % in pts (p< . ).c of . + . l/min in patients with cardiac contusion, measured hrs after admission at the latest, was significantly lower than in group of patients with co of . + . l/min (p< . ). conclusions: co values were significantly lower in patients with cardiac contusion and correlated with pathological values of cpk-mb fraction. objectives: extracorporal plasmophoresis (pph) was implemented by non-stop method in patients with obstructive jaundice. methods: changes of serotonin (s) and histamine (n) in arterial (ab) and venous (vb) blood were investigated before and after one-time session of pph. s and h in blood serum were determined with fluoremetric method. results: before pph the average s contents in ab and vb did not differ. after one-time pph session s in the blood outflowing lungs was % lower than in the blood inflowing. hours after extracorporal detoxication implemented the indices kept the same level. similar dynamics after pph was observed in h. before the session h contens was equal both in the blood inflowing and in the blood outflowing lunge. after pph h contents in ab was % lower compared to the vb and did not change for hours. conclusions: dynamics of changes of biogene amines shows that under the influence of pph there takes place not only mechanical removal of their surpluses together with plasm, but there sharply grows inactivating role of lungs towards ba substances, which is confirmed by reduction of their concentration in the blood outflowing lungs. this effect is probably connected with the "deplasmation" of the lung cellular elements. simultaneously lungs' cells are freed not only from plasm but from toxic adsorbents on their surface. as a result the lung cells activate absorption of the surplus number of amines from the vessel channel. it is not excluded that s inactivation is due to growing activity of monoaminooxidase resulting in deminishing of intoxication. acute pulmonary embolism: thrombolytic therapy or pulmonary embolectomy? i.lodiena md, phd, s.shevchenko md, pphd., medical university, kharkov, ukraine objectives: pulmonary embolism (pe) remains a challenging problem for diagnosis and management for the emergency physician. the aim of this work is to identify the best treatment for massive pulmonary thromboembolism. methods: during recent years patients with symptomatic acute serious pe were reffered to our observations. selective pulmonary arteriography confirmed this diagnosis in all cases. ( . %) underwent urgent surgery, of them ( . %) with cardiogenic shock and ( . %) with massive pulmonary embolism. patients ( . %) underwent thrombolytic therapy. results: in the patients who received thrombolytic therapy successful results were achieved in cases ( . %), in ( . %) patients subsequent pulmonary embolectomy was performed. mortality rate was ( . %) in the patients who underwent pulmonary embolectomy after unsuccessful thrombolytic therapy and ( %) in the patients with cardiogenic shock and massive pe. lower extremity deep venous thrombosis caused pe in % patients. pe mortality rate is repoted to be %, but all patients with cardiogenic shock and massive pe died. this very high mortality rate related to the clinical status of the patients whose condition became worse despite intensive treatment. conclusions: the results of this study show that in most cases thrombolytic therapy is an effective rapid method of treating pe. however, surgical treatment is preferable when the patients reveal adverse effects to drug therapy, when medical therapy is unsuccessful or when the patients are seriously ill with reccurent cardiac arrest. high-quality pulmonary angiography remains the most accurate and reliable means of diagnosing pe. this prospective study was conducted to investigate the serum thyroid hormone levels in traumatized critical ill patients. serum thyroid stimulating hormene(tsh),total thyroxine(tr ),free thyroxine(ft ),total tri-iodothyronine(tr ),free tri-iodothyronine (ff ) levels were measured within hr.of intensive care unit admission(first day) in multiple tratmmtized male patients(injury severity score higher than ). in fifth day the same hormone levels were repeated. tsh,et ,ft ,tr and ft levels were determined by radioimmueoassay(ria). the levels of 'i~sh,xt ,fr ,et and ft in survivors and nonsurvivors were compared with first and fifth days (table) . in conclusion, we are convinced that there was a high correlation between low ser~n thyroid hormone levels and mortality, serum thyroid hormone levels are prognostic value in traumatized critical ill patients. objectives: glucagon improves myokardium contractility, intensifies kidney blood flow, stops bronchospasm ( ), these were the reasons of investigating its effect on hemodynamics and metabolism in hypovolemic shock expermentally and in clinic. methods : in experiments on white rats with traumatic shock glucagon (novo nordisk) was injected intraperitoneally in dose rocg/kg. patients with hypovolemic shock (trauma, hemorrage) were injected glucagon intravenously in dose mg on the background of infusion therapy. results : glucagon hightened recovery indexes of glucose in rats and patients with shock, whereas in groups without glucagon hyperglycemia developed. rats with glucagon injection had double times urea content than the norm ( , + , mmol& norm - , + , mmol/i ), whereas rats without glucagon had urea content , + , mmol/ ( p < , ). osmolarity of blood plasma in rats having glucagon injections was , + , mosm/kg h , without the drug - , + , mosm/kg h ( p < , ), ldh activity - , + . and , + , ( p < , ) mcmol cec- accordingly. lethality in the group of rats without glucagon was % /n= /, with glucagon - (n = ). in patients with hypovolemic shock in minutes after glucagon administration stroke volume increased to % (sv), miocardium contractility -to % (mc), peripheral resistance of vessels ( vr ) decreased to %. in - , hrs sv increased to %, mc-to %, pvr -decreased to %. conclusion : the study provides the evidence that glucagon has an anti-shock effect, improves hemodynamics and metabolism indexes in cases of hypovolemic shock. reference : picazo j. glucagon in acute medicine : pharmacological, clinical and therapeutic implications (norwell, mass:kluwer publishing, ), p. n, vasina (t) ,n.sebbota hph ( ). dept; of acute endotoxicosis, n.v. s~lifosovslay scientific research institute of ermergency ltealth care, boscow, lk'ussia (i}. institute for problems of cryobiology and cryouledicine of the national academy of sciences of the f/maine, kl'k r-key, [ maine ( ), objectives: the investigation of isolated hepatocytes using's efficacy in patients with acute hepatic fai lln-e. methods: native and crioconsrved allo-and xeno-!mmatocztes fixed on semi;ermeable ~mbr~s were used. results: the artificial supporting system with isolated hepatocttes as metabolic ~its was. ap-plied in patients. during tl~ treatmen~ with this cytotherapz an improvement of clinic state and biochemical rates were observed even inthe first we~s. for instance, the kncreasing of glutamin acid's level in blood up to normal value and decreasing of ammontes -concentration from i ~ mmol/l down to # mol/l were discovered. ~ae diminution of ence,%halo;athy was noted too. general lethality was' equal z, there of i z concerned acute hepatic failure (/k~). conclusions: the using of sum~rting hepatic system is able to cope the ~nenomenon of ~i~. objectives: fat embolism (ee) is an important and insufficiently studied problem of the intensive care medicine. fe is clinically diagnosed in % and morphologically in - % of the victims with severe multiple skeletal injury that is accompanied by the shock. methods: during the last years patients with the cerebropulmonary form of fe were treated in the icu. the prognosis of the probability of fe development was done using the computer system "cite-prognosis" in which the triss-method, dynamic and statistical prognosis of the injury outcome~ and the values of the most severe injury in points were realized. the treatment consisted of the surgical stabilization of the fractures with the authors' design of the rod apparatus in the acute period, long-term mechanical ventilation with peep via tracheostomy, complex fluid therapy using perfluorochemical emulsions (pe), and electrochemically active solution of na hypochlorite (snh) via the central vein. results: the treatment of patients with fe gave a good result that was manifested by the complete regression of psychoneurologic and respiratory disorders. conclusions~taking into account the prognostic data~ it is necessary to provide early complex of intensive care to the polytraumatized patients. it includes the surgical stabilization of fractures, fluid therapy using pe and snh~ early long-term mechanical ventilation. dr. alexandr e. poladko, station of medical aid. kiev ukraine. objectives: the reason of investigation is to prove the necessity of beginning of the intravenous infusion of nitroglycerin before the hospitalisation. methods: from january i to june protocols of treatment myocardial infarction patients in kiev medical aid station. results: the results of treatment are better if infusion began early or prolonged during hospitalisation. conclusions: there were patients with acute myocardial infarction treated before hospital by the cardiological groups. patients were treated with the early infusion of nitroglycerin and without. the results of treatment were: in the group with infusion: mortality in the first hours % the full disappear of pain % in the group without infusions mortality in the first hours % the full disappear of pain % that's why our opinion is that infusion of n. is necessary in the treatment of the patients with myocardial infarction from the first minutes of illness. dr. gennady d. kyrzhner, station of medical aid, kiev, ukraine. object: looking for safe medication which is good for the treatment of arterial hypertension and is simple for use. we inspected the effect of prazosin in the conditions of the cail during the year. method: we used mg prazosin tablets sub lingua and measured blood pressure ones during hours. the parameters were registrated in protocol. result." one hundred patients took part in investigation. the middle age of patients was . the reason of hypertension was not taken into consideration. in two hours after beginning of the treatment we caught the reliable lowering of blood pressure in % of patients. the general condition of patients became better in - min. it was only one accident of complication during the treatment -the orthostatic hypoter~sion, conclusion: prazosin hydrochloride in the dose mg sub lingua is safe and simple for use in the urgent situations. objectives: hypomagnesemia is frequently observed in severely burned patients during the early period after injury. increased urinary excretion is insufficient to explain the magnitude of the magnesium (mg) depletion. the possibility of exudative cutaneous mg losses has been proposed, but not yet demonstrated. the study aimed at measuring the mg content of the cutaneous exudates and urine during the first week after major burns. methods: patients, aged _+ years (mean _+ sd), and burnt _+ % of body surface, were studied from day (d ) to d . serum samples were collected at do, serum and urine from d to d , and on dio, d , d . cutaneous exudates were extracted from the textiles surrounding the patients, collected over h periods from d to d , using bidistilled acidified water. mg supplements ( . to mmol/ h) were prescribed from d to dio according to the severity of hypomg (serum mg < . mmol/i). results: mg serum levels decreased below reference ranges in patients between d and d , and normalised thereafter during supplementation. urinary mg excretion was increased in patients, mean excretion being . _+ . mmol/ h until d . mean daily mg cutaneous losses, were mmol/ h, i.e. mmo; in days. large inter-& intra-patient variability: the daily exudative losses ranged from to mmol/ h. conclusions: the mean daily mg cutaneous losses after burns were larger than the urinary losses, and equivalent to the recommended intakes for mg; the addition of the exudative and urinary losses largely explained the increased mg requirements after burns. complex immunologic alterations occur following thermal injury. the activation and consumption of the complement and dotting systems are suggested to play an important role in the development of the capillary leak syndrome, tn burned patients, a generalized inflammatory reaction as well as the impairment of the host defense are considered to be the major reasons for complications, such as sepsis and multiple organ failure. in a pig model we investigated a possible protective effect of cl-inhibitor (berinert, behring). before conducting the animal experiments the human cl-inhibitor concentrate was analyzed for its inhibitory capacity on purified pig cls and its pharmacoldnetic behaviour in pigs (t / ,id ). pigs received anesthesia and analgesia and arterial, venous and pulmonary (swan ganz) katheters were placed into the carotis and jugular veins. the pigs were scalded for seconds with ~ hot water to achieve a % tbs partial-thickness burn. blood samples were taken prior and after surgery as well as , minutes, , , and every further hours after thermal trauma. two control groups (each n= ) included animals which were either scalded or not scalded and treated only by resuscitation of ringers lactat solution. besides various parameters blood samples were analyzed for complement. the pigs (n= ) received c -inhibitor concentrate at an initial dose of u/kg body weight either immediately or hours after thermal trauma (n- ), followed by three further applications (of reduced amounts) every hours. the clinical outcome as indicated by vital parameters and as well as demonstrated by reduced edema and inflammatory tissue destruction suggested a protective effect of cl-inhibitor. complement analysis revealed a faster recovery of the alternative and classical pathway activities in cl-inhibitor treated pigs as compared to the control group but only if the regulator was given immediately after thermal trauma. from these results a protective function of c -inhibitor on thermal trauma can be assumed. objectives: the aim of study was to characterise the pattern of secretion of interleukin- (il- ) and tumor necrosis factor alpha (tnf alpha) in multiply injured or not injured critically ill patients and to relate these results to their outcome. methods: blood samples of multiply injured ( ( ) ( ) ( ) il- (nis) ( ) ( ) ( ) il- (nin) ( ) ( ) ( ) conclusions: this data suggest tnf alpha is a better prognostic marker in patients with multiple injury, than in critically ill patients without injury. il- is not significantly higher in nonsurvivors of both groups. sepsis is associated with an increased production of nitric oxide (no), as reflected by a rise in plasma levels of nitrites (no ) and nitrates (no ). severe bum injury is associated with similar symptoms of inflammation like hypotension, high cardiac output low vascular resistance and increased vascular permeability so that an increased no production may be involved. the present study included patients admitted to the intensive care unit of the burn center of brussels (age : - years; burned surfaee area - %), and control (non-septic) patients hospitalized in the neurological rehabilitation unit of the erasme hospital (age - years). the patients in both groups were fed enterally with to kcal/kg/day of a standard solution. in the burn group, daring the study period, patients were mechanically ventilated, required vasopressor (dopamine) therapy, and received antibiotics; patients were discharged alive from the intensive care unit, and no patient died during the study period. plasma was sampled for no /no determinations (griess reaction) daily from day to day (n=ll) or to discharge (day , n= ; day , n= ) in the burn group, and once the control group. in the burn group, no /no levels were elevated at day ( _+ #moles/i), reached a maximal value on day ( - p.moles/l) and progressively decreased to day (fig). these values were higher than in the control group ( . :t: . #moles/l, all differences p< . ). however, no correlation was found between the plasma no /no levels and the age of the patient or the total burned surface area; burned patients who became infected tended to have higher plasma no /no levels than those who did not ( + vs - #moles/i, ns). the present study indicates that burn noa/noa (llmol**/l) injury is associated with increasedloo] [__ ] ~ no /no plasma levels, which are ao so consistent with an enhanced no pro- o duction, ao obiectives:urapidil has been recommanded for therapy of hypotension in neurosurgical patients, because it was found not to increase intracranial pressure in patients with compromised intracranial dynamics ( ). in contrast several authors reported an increase of icp after urapidil administration in patients with head injury ( ). our study was designed to determin the influence of urapidil on mean lumbar cerebrospinal fluid pressure (csfp) in awake humans with uncompromised intracranial compliance. methods: after approval by the local university ethics comittee, six volunteers (asa , male, female) were studied in the lateral decubitusposition with the vertebral column positioned horizontally. a gauge needle was inserted into the lumbar subarachnoid space at level l /l and connected to a trancducer (mx | medex inc.) for csfp measurements. the volunteers were advised to keep respiratory rate and etco constant. after a resting period of minutes basline measurements were performed including csfp, cvp, map, hr, etco (cardiocap | datex). then the volunteers were given urapidil . mg/kg over a period of minute. minutes later measurements were repeated. results: statistics: wilcoxon signed rank test, p< . significant; values: mean_+sd, si = mmhg. - _ " _+ * _+ * - _+ " _+ csfp: cerebrospinal fluid pressure, cpp: mean cerebral perfusion pressure. conclusions: during normoventilation urapidil leads to a decrease in map parallel by an increase in csfp and therefore in icp, most likley mediated by an autoregulatory dilatation of cerebral vessels. if this cerebrovascular response is suppressed by hyperventilation, no increase in icp is found despite a uredipil induced drop in map ( ). after longterm hyperventilation cerebralbloodflow is normalized. this might be the reason why the drop in bloodpressure following urapidil administration again led to an increase in icp ( background and objectives: the intestine is one of the most sensitive tissues to ischemia-reperfusion injury. reperfusion of the intestine is often associated with increase in mucosal permeability and ulceration. d(-)-iactate is produced by indigenous bacteria found in the gastrointestinal tract and mammals do not possess the enzyme systems to rapidly metabolize it. the present study was designed to determine the kinetics of plasma d(-)-iactate alteration in rats paused by acute intestinal ischemia-reperfusion injury. methods: following the anesthesia, the superior mesentcric artery (sma) was exposed and it was occluded by a micro-bulldog clamp applied at its origin from the aorta. after min of occlusion, the arterial clamp was removed and the supply area of the sma was allowed to be reperfused ( h). plasma d(-)lactate levels were measured by an enzymatic spectrophotometric assay. the endotoxin content of plasma sample was assayed by the limulus amebocyte lysate test with a kinetic modification of the test kit procedure. results: intestinal ischemia for min resulted in a significant increase in d(-)-lactate levels within the portal vein as compared to sham-operated animals. plasma d(-)-lactate levels had a tendency to further increase after reperfusion up to h. it was showed that significant elevation of endotoxin concentrations in portal vein was alread~r detected at the end of -min ischemia, reaching peak at . h post-reperfusion and decreasing gradually throughout the study period. at the end of ischemia, marked mncosai damaged such as edema, hemorrhage and necrosis was observed. there was evidence of injury to ti, e muscuiaris propria together with diffuse mucosal damage and destruction following reperfusion, particular at h postreperfusion. in addition, penetration of bacteria was commonly found in the intestinal wall at various time points following ischemia/reperfusion injury. conclusions: these data suggest that acute intestinal ischemia is associated with permeability change of mucosal barrier resulting in increased plasma d(-)qactate, which is also remarkably influenced by subsequent reperfusion. plasma d(-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult. objective: to assess the clinical usefulness of two methods of intracranial pressatre (icp) monitoring: intraparonquimatous recording (icpc) and epidural recording (icpe), versus intraventricular icp (icpv) as a gold standard. we prospectively studied patients with severe head injury (glasgow coma score < ) admitted to our icu between fobmaly and december . icpv was monitored in all pativrats by means of a multipzffolated catheter connected to a water coinnm. six of patients were additionally icpc monitored by a fiber optic transducer (comma r~), and seven of patients were icpe monitored by a couplvd fluid system (plastimedr). icpc was placed homolatetal to the focal, lesion m two cases and contralateral in three; icpe was placed homolateral to the focal lesiou in two cases and contralateral in three. all three systems were calibrated at the ear level. stali~cs: correlation coefficient and lineal regression were done between icpe and icpv, and between icpe and icpv with the hourly p~rs of values obtained dttting assistontial period. results: of the six icpc -icpv studied pa~onts, we observed a correlation coef~cieut r = . (p < . ) with a regres~on line y = . + . x. four of ~hx lcpc -icpv patients had r > . when correlaliou eoet~dent was obtained indixddually. of the seven icpe -]cpv studied patients, we observed a cortelafiau ooeffioiont r = . (p < . ) with a regression line y = . + . x. corralalmu eoetfieiont was inwer than . in all seven patients. corrdation eoelfieients for levals of icpv > man hg, > mm hg and > tuna hg with icpe showed r = . , r = . and r = . respectively; and with icpe r = . , r = . and r = . . the obtained values did not change during the study. conclusdns: in our study icpe was considered a good type of icp monitoring. /cpe signiticantly infravalorates icp values. we observed a good correlatinn between icpc and icpv values in patients with high inttacramal presanre. objective: midazolam is a benzodiazepine agonist widely used for sedation in emergency medicine. few studies in animals and humans point to a direct analgesic effect of midazolam probably mediated by spinal antinociceptive receptors and/or peripheral benzodiazepine receptors ( , ). in our experience in the berlin emergency medical system (unpublished results) with anecdotal cases of extreme chest pain due to binge drinking but no evidence of acute myocardial infarction or extreme abdominal pain due to peritonitis, acute intermittent porphyria, peutz-jeghers syndrome or testicular torsion, we found that small doses of midazolam ( - mg i.v.) were much more effective in relieving pain than repeated administration of high doses of buprenorphine or morphine, which may be associated with a considerable respiratory depressant effect. the dose of midazolam required for pain relief in these patients is non-narcotic and allowed further communication on the character and localization of' the residual pain, which might be very important for the further diagnostic procedure. patients: ten patients with abdominal pain due to acute gastrointestinal bleeding, suspected pancreatitis, suspected acute porphyria, and chest pain with no evidence of acute myocardial infarction received first-line midazolam i.v. at an initial dose of mg and were asked how it affected the intensity and character of pain. results: at the chosen dose of midazolam ( - mg), all patients were responsive to detailed questioning on basic orientation, the character, intensity and localization of the pain, and medical history. none of the patients required an additional opiate. all patients stated that the pain was tolerable after midazolam alone. conclusion: our preliminary clinical observations suggest that low-dose midazolam might be an alternative to opiates in extreme pain of presumably visceral odgin. objectives: it is known that severe head injury in elderly patients is associated with higher mortality than in younger patients. it remains however to be clarified whether the preinjury pathology which is frequent among these patients, affects the outcome. methods: in an attempt to investigate this hypothesis, patients aged over years suffering from head injury, with glasgow coma scale (gcs) of or less, were studied retrospectively. twenty-six patients ( . %) had preinjury pathology i.e. diabetes mellitus, arterial hypertension, heart failure, alcoholism, parkinson's disease etc. (group a) and fifty-three ( . %) did not (group b). the following data were recorded: mortality in the i.c.u., duration of hospitalisation, incidence of infective complications and neurologic status at discharge. results: groups were comparable in terms of mean gcs ( . vs. . ) and median age ( . vs. ). the incidence of brain pathology in the two groups was the following: epidural haematoma . % vs. . %, acute subdural! haematoma . % vs. . %, intracerebral haematoma . % vs. . %, subarachnoid haemorrhage . % vs. . %, diffuse haemorrhage . % vs. . %, contusion . % vs. . % and non-visible pathology (normal ct) . % vs. . %. unilateral pupilary dilatation was found to be . % in group a and , % in group b. the mortality during hospitalisation in the i.c.u. was almost the same: % iu group a and . % in group b patients. however, group a patients had significantly more infective complications, required longer hospitalisation and had lower gcs at discharge. conclusions: the results show that the existence of preinjury pathology does not seem to affect the short-term outcome of elderly patients with severe head injury. it has however an impact on morbidity and perhaps long-term survival of these patients. the assessment of clinical development in intensive care patients with severe head injury still remains a problem. to optimize the monitoring of intracraniel prassure (icp) we rautlr~dly implant an eplduml measuring device in our hospital. the aim of this study was to prove the correlation of the icp-values with ct findings and clinical development. during a month period ( - r the icp was monitored in p~,tients ( male, female) with severe head injury by an eplclural measuring device (epldyn~/$plegelberg| the mean age was . years ( - ). the glasgow coma scale at admission was . ( - ). in all cases the device was placed wfihln the first hours after admission. the tcp was compared with physical examination, radioidglcal or intraoperatlve findings and cunlca! outcome. the average time of measuring was . days ( - ) . the traatment depended on the !cp values recorded. rising icp-valuea ~ed to radlologlcal c ntra!s by ct-scan. in case an intracranlai hemorrhage was detected and drained. the overall survival rate was . %. showed a complete resolutl n, in other . % psychological residuals like decreased mentatlon, in . % sensomotorlc residuals like cerebral nerve dysfunction and aphasia, and . % of the injured remained in a comatous status. in % of our cases the measured values correlated with clinical course and management. in cases ( . %) we observed a displacement of the icp-pevice. there was no icp induced infecllon. istituto di anestesiologia e rianimazione, universit& ,,la sapienza", rome, italy * istituto superiore di sanit& -servizio di epidemiologia e biostatistica, rome, italy objectives: acute renal failure (arf) can be a severe complication of trauma. the current incidence of post-traumatic arf is associated with high mortality . identification of risk factors and prevention of this complication could improve the outcome of trauma patients. methods: one hundred fifty three consecutive trauma patients (age . _+ . , injury severity score . + . ) admitted to icu were studied. incidence of arf was . % ( / ). arf was defined as persisteat plasma creatinine > mg/dl with or without oligoanuria . arf was defined as early when occurring within the first hours (earf) and late when the onset was after the first four days (larf). results: earf occurred in patients while larf developed in patients. age, iss, and incidence of rhabdomyolysis and acute respiratory failure were not different in the two groups. an higher incidence of multiple organ failure (mof) and sepsis ( . % for both) were observed in larf group, when compared to earf ( % and % respectively). abdominal trauma was more frequent in earf group ( % vs %). the gs for earf and larf were respectively _+ . and _+ . while in the group who not developed arf (narf) the gs was . • conclusions: gs score difference seems suggestive and can be that an abnormal cerebral activity (hipofisary hormones?) may play a crucial role on onset of arf in these patients. moreover the frequency of acute respiratory failure in the group of arf was higher ( . versus . ) than narf group. the early ipoxia in the early phase of trauma, then, may be another crucial point for development organ failure. these are preliminary data. a more exact statistical analysis must be perform to have definitive conclusions. to compare the active compression-decompression cardiopulmonary resuscitation (acd-cpr) with the standard cardiopulmonary resuscitation (s-cpr) in out of hospital cardiac arrest patients. is a controlled, randomized study. two groups of patients with cardiac arrest out of the hospitalwere formed. group i, (acd-cpr) and group ii (s-cpr). for the acd-cpr groupweusedthecardiopumpdeviceofambulnternational. asfortherest, the erc ( ) algorithms for acls were followed. the utstein style (for out of hospitat cardiac errest) was used for listing and evaluating all cases of the study. the cpr was contucted by the crew and the doctors of our mobile intensive care units (micu). we studied consequitive patients ( in group i) and ( in .group ii). demographics pre-cpr characteristics (e.g. ecg form of cardiac arrest) and procedures (eg bystanders or second tiers crew cpr, defibrillation, drugs) were quite similar for both groups. the mean arrival time of micu was min. in group i we recorded r.o.s.c. (return of spontaneous circulation) , %, death %, continuation of cpr efforts , %. while in group ii, %, %, and , % respectively (recorded percentage until the admission to the hospital). no significant difference was found in anyofthe short term outcome parameters. no complications related to the acd-cpr technique, were noted. not any significant difference between the two methods was proven (from this small evaluated sample). the results of previous clinical studies are controversial (i) . more sophisticated studies proved the superiority, in a certain number of parameters (e.g pressures, flow, etc) of the new technique although there are many difficulties for establishing clinical results. in the pre-hospital setting that is related to many parameters (speed of the intervention, effectiveness of bystanders cpr, education ofparamedics, etc.)the evaluation is even harder. the superiority ofthe acd-cpr can be proven when it is performed in almost times increased number of studied patients as w~ll as improvement of the technique could lead us to more established results. objectives; infectious morbidity is the major cause of mortality after burn injury, and is due to multiple factors. trace elements (te), which are involved in both humeral and cellular immunity, exhibit severely altered status after burns. te supplementation has been shown to be associated with increased leukocyte counts and shortened hospital stay. the trial aimed at studying the immune responses in severely burnt patients receiving normal te supplies or early large supplements. methods: patients, aged _+ yrs (mean_+sd), with burns covering + % of body surface were studied from day (d ) to d post-injury, were randomised in groups (g): g -control receiving recommended te supplies + placebo; g -receiving in addition large supplements of cu, se and zn from d to d . enteral nutrition was started within hours of injury in all patients. immunological parameters: peripheral leukocyte counts, proliferation of mononuclear cells to mitogens, cell surface molecule expression, and neutrophil chemotaxis at d and d . infectious episodes and micro-organisms were monitored until d . results: the patients' characteristics were similar g & g . the total leukocyte counts were higher in g between d and d , due to increased neutrophils (significant from d to d ). total cd + and cdlg+ cells did not differ, whereas cd + (monocytes) were significantly increased at d . proliferation to mitogens was significantly depressed in all patients. chimiotactism was not altered. the number of infectious episodes was significantly decreased in g with a mean of . _+ . infections during the first days versus . _+ . in the control group (p < . ). conclusions: the large te supplements for days was associated with a significant decrease of the number of infectious episodes. supplementation was associated with increases in total leukocyte, monoeyte and neutrophit numbers. further studies are required to determine the precise mechanism underlying the improved immune defences. objectives: evaluate the efficiency of local adsorption (la) with the use of carbon adsorbents in case of severe burns in expertment and clinic. methods: experimental studies on la were performed on a model of % body surface area iiib-iv burn in rats. a burn eschar was excised on the rd day after burn, the wounds were dressed with the gauze bandages (control) or with adsorptive dressings (la), dressings were regularly changed. clinical investigations were carried out in the course treatment of patients with severe thermal and radiation ilia-iv burn. in the dynamics of bum disease some indices of proteometabolism and intoyacation criteria were evaluated. results: the experiments have demonstrated that the application of la after early excision of a burn eschar exerts a pronounced normalizing effect on a protein electrophoregram and the activity of proteases and their inhibitors in burned tissues preserving vitality. thus, by the th day after burn infliction the activity of cathepsin d in injm'ed muscles is times lower under an adsorptive dressing than under a gauze bandage (control) (p< , ), the activity of trypsin-like proteases is . - . times lower and the antitryptie activity does not differ significantly from the normal level. the cytotoxicity of extracts of burned tissues after the adsorptive dressing application fn vivo and adsorption in vitro is - % and - %, respectively, of the toxicity of control extracts. a similar normalizing effect of la is ok~rved for an intact muscular tissue and blood serum. the dectron-spin-resonance studies have demonstrated that la allows to normalize antitoxic activity of liver and functional activity of kidneys. the application of la in the treatment of patients with severe burns have been shown to localize a region of irreversible tissue changes, accelerate rejection of a burn eschar, attenuate an endogenous intoxication level and, as a result, shorten the time for grafting of a burn wound and accelerate wound heating. conclusions: proceeding from the obtained results, we can consider la as an effective method of localization of a region of irreversible tissue changes as well as of correction of local and general metabolism failures and overcoming burn autointoxication during burn disease. c de deyne, t vandekerckhove*, j. decruyenaere, b. vaganee, v vandewalle*, f colardyn depts of intensive care and neurosurgery*-university hospital gent-belgium. jugular bulb oximetry is the first bedside available cerebral monitoring technique providing an estimation of the adequacy of cerebral perfusion. its routine use in all patients suffering from severe head injury admitted to our ic unit enabled an extensive analysis of all very early cerebral perfusion data in order to evaluate the incidence of abnormal sjo~ data (and their possible causes) in this very eady period after traumatic insult and to search for possible implications as to the emergency management. these very early data were defined as the first hours icu data and icu admission had to occur within h of traumatic insult. over the last years, pts with severe head injury (gcs< ) were monitored by jugular bulb oximetry, starting immediately after their arrival at the icu (mean of . h after trauma, range between - h). in a total of pts (= . %), jugular bulb desaturatiens (< %) were noticed during this early h period. in pts (= %), jugular bulb saturations higher than % were observed, whereas pts (= . %) revealed no abnormal sjo data ( - %) during these first h. concerning the periods with too low jugular bulb saturations (n: ), we found the following correlation ; in pts (= . %) cerebral perfusion pressure (cpp) was below mmng, in pts (= . %) paco~ was below mmhg and finally in pts (= %) we found primary intracranial hypertension. for the high jugular saturations (n: ) we found a primary intracraniaf hypertension in f pts (= %), and a pace level above mmhg in pts (= %). in all patients we could restore jugular bulb saturation within normal range ( - %) with the correct!on of the presumed causative factor. we can conclude that ultra early jugular bulb saturation data revealed a high incidence of abnormal values, with a predominance of jugular bulb desaturations, confirming once again the high incidence of disturbed and too low cerebral perfusion within the first hours after severe head injury. these jugular bulb desaturations were especially correlated to systemic causes, as a too low cpp (caused in the vast majority by primary map insufficiency, and not by intracranial hypertension) and hyperventilation were the major causes of the desaturation periods. as jugular bulb desaturatione are known to be significantly correlated to a worse neurological outcome after severe head injury, one might improve outcome by an emergency management avoiding these possible causes of jugular desaturation. therefore, extreme attention should be paid to the maintenance of an adequate mean arterial blood pressure (above mmhg?) even duhng the few time spent at the emergency department. one should be as attentive to the maintenance of normoventilation during this very early period of admission and hyperventilation without any knowledge of icp or sjo should be abandonned. recently, indomethacine has been proposed for the treatment of therapy refractory intracranial hypertension in pts suffedng from severe head injury ( ). indomethacine, a cyclo-oxygenase inhibitor, gives rise to a significant fall in cerebral blood flow by inducing cerebral vasoconstriction. therefore, its use could result in a drastic lowering of the intraeranial pressure (;cp) in pts suffering from intracranial hypertension secondary to cerebral hyperaemia and in whom the use of other cerebral vasoconstrictive drugs (barbiturates or hyperventilation) appears insufficient to control icp. for the last months, we included the use of indomethacine in our therapeutic flow chart for severe head injury management. pts revealing intracranial hypertension (icp> mmhg) and cerebral hyperaemia (sjo~> %) and in whom icp was not efficiently controlled by the combined use of hyperventilation and barbiturates were given indomethacine in a trial to control icp. a total of head injured pts received treatment for intracranial hypertension over the last months. six of them met the criteria set for the administration of indomethacine. in pts, no decrease in icp or in sjo was observed and both pts died due to therapy refractory intracranial hypertension. in the other pts, a significant fall in icp and in sjo was observed shortly after indomethacine administration. in pts we observed a catastrophic fall of sjo= even below %, indicating an extreme cerebral vasoconstriction with the possible risk of inducing cerebral ischaemia. in one of the pts, icp remained under control without further administration of indomethadne, but he died days later in multiple organ failure. the other pts, needed multiple indomethacine administrations (for pt even during consecutive days) to finally control icp. in all pts, icp was finally controlled, but only pt survived. both other pts died from systemic causes (multiple organ failure in pt, massive gut infarction in the other tat, possibly due to the systemic vasoconsttictive effects of the indomethacine administration). in conclusion, indornethacine might have a role in the treatment of intraoranial hypertension, especially when caused by cerebral hyperaemia. we observed however a poor final outcome and a threatening high incidence of systemic events (multiple organ failure, gut infarction) in those pts receiving indomethacine for icp control. therefore, indomethacine in the treatment of intracranial hypertension should be reevaluated in controlled study settings, before its routine use can be considered. untill recently, intracranial hypertension (ich) in pts suffering from severe head injury was managed in a staircase approach, with csf drainage as first therapeutic step, mannitol as second step, hyperventilation as third step, and finally, barbiturates as the last rescue step for therapy refractory ich. this staircase approach for the treatment of tch was only guided by the intracraniat pressure, and not by other parameters such as e.g. the actual state of cerebral perfusion of the concerned pt. jugular bulb oximetry provides us with the first, bedside and continuous available, estimation of cerebral perfueion. its implementation in a rigourous flow chart, based on as well icp-as jugular bulb oximetry-data might result in an altered strategy for ich management. we adopted a '~ugular bulb saturation (sjo~)-guided approach" for ich management in consecutive pts, suffering from severe head injury (gcs< ). we maintained csf drainage as first therapeutic step, but the decision for the second step was guided by sjo information. pts revealing ich and sjo=values above %, were treated with hyperventilation, and did not receive mannitol. if ich persisted, barbiturates were added as a third step. on the other hand, pts with ich and sjo= vales less than %, received mannitol administration as second step. hyperventilation and/or barbiturates were only added if ich persisted and if no cerebral hypoperfusion was discerned (sjo=> %). our objectives were to prospectively analyze this new therapeuticstrategy, as compared to the formerly used staircase approach of ich. we managed pts with ich, with an overall mortality of . % due to therapy refractory ich. all pts received standard primary care with head elevation, full sedation and normovenfilation. fer pts, csf drainage alone was sufficient to control ice of the remaining pts, pts received mannitol and pts were hyperventilated as second approach. in the third line, pts were managed with barbiturates, with mannitol and pts with hyperventilation. finally, barbiturates were used as the final rescue in pts. these results reveal a less frequent use of mannitol as only pts received mannitol, compared to the pts that would have received mannitol using the former staircase approach. hyperventilalien was used much earlier in the treatment course, as lots were already hyperventilated in the second line approach, were this was formerly exclusively reserved for the third line approach. finally, also barbiturates were used much eadier ( pts received barbiturates as third approach). we may therefore conclude to a important change in the management of ich, induced by a sjo -guided flowchart. however, future studies will have to elucidate if this new strategy for the intensive care management of severe head injury will also result in an improved outcome. obsectives: in a first series of experimental brain injury we investigated the course of brain po , icp and cerebral blood flow after traumatic brain injury (tbi), whilst accordingly there are very few data available and the mechanisms leading to secondary brain damage are poorly understood. methods: in piglets ( days old, , - kg) of either sex we produced a moderate brain injury ( , arm., msec.) using a lateral fluid percussion {fp) device. complete measurements were made before and min. after brain trauma and after , and hours including blood gases, cardiac output (htermodilution), heart rate, eeg, laser doppler flow probe (ldf} and icp values (camino), brain temp., po by a clake type oxygen electrode (licox) and coloured microspheres for regional blood flow. results: immediately after the trauma a typical "cushing"response to the icp peak up to mm hg being highly significant (before mean i mm hg, range - mm hg) could be observed: mean arterial blood pressure rose from appr. mm hg to ii mm hg for - min. in two animals this was followed by an ischemic period lasting min. accordingly icp values gradually returned to starting measures within hours; in the ischemic animals they remained at a level of about mm hg.-no secondary increase of icp could be observed, once icp dropped to starting values within hours. cerebral blood flow (ldf) fell from mean values being i before trauma to appr. zero and recovered to around . brain po started at mean values of mm hg (range - mm hg) and fell to around zero depending upon the severity of the ischemic reaction. on average values of mm hg were reached over the time course. conclusions: with our fp trauma model we can reproduce the well known "cushing"-response after brain injury; secondary icp elevations cannot be achieved, although local edema is observed. direct brain po measurement seems to be a very sensitive variable for detection of cerebral ischemia and anticipates eventually following icp elevations by far. pulmonary aspiration s,traoaras. v. sgountzos, p. agouridakis, m eforakopoulou, e. ioannidou. intensive care unit (tcu) of "kat" hospital, athens, greece ob!e=ives: the reported mortality rate after pulmonary aspiration is variable in several series. the purpose of this study was to find out the influence of preexisting disease or situation on morbidity and mortality of intensive care unit (icu) patients with pulmonary aspiration. methods: patients who were treated in icu and had pulmonary aspiration, were studied, entrance's criteria in the study, all of them obliged, were: ) suction of gastric contents from trachea during intubation, ) presense of a predisposing factor, e.g. coma. ) recent hypoxaemia or new infiltrates in xray. preexisting disease was recorded and correlated with complications and outcome. patients with glasgow coma scale , because of cerebral injury, and patients who died within days from cause other than aspiration, were excluded from the study. method of statistical analysis: chi-square test, results: one hundred forty five patients were studied. the trauma patients were and the non trauma patients . from the trauma patients, had cerebral injury and were polytreumatized without cerebral damage. from the non trauma patients, had malignant neoplasms, neurological diseases in terminal stage, old age, drug overdose, and several diseases. eighty seven from trauma patients ( %) and from non trauma patients ( %) manifested several complications (pneumonia, ards, etc), so there was no statistical difference in complications' frequency between the groups (p> , ). the severity of complications was also proportional in the groups. eighteen deaths were recorded in the trauma patients (mortality %). only deaths correlated directly or indirectly with the aspiration ( %). in non trauma patients, deaths were recorded ( %). twelve deaths were recorded in patients with neoplasms, deaths in patients with neurological diseases, deaths in aged patients, death in drug overdose patients, and death in patients with several diseases, the mortality difference in trauma and non trauma patients was statistically significant (p< , ). in patients with drug overdose the mortality was significantly lower from the other non trauma patients and the difference was statistically significant (p< , ). conclusion: the preexisting disease or situation plays a major role in the outcome of the patients with pulmonary aspiration. the mortality of patients with aspiration seems to be caused by severe preexisting situations rather, that lead to death, than from the pulmonary aspiration per se, which may be a final happening in a predetermined course. obiectives; the purpose of this study was to compare fluconazole and amfotericin-b in the treatment of fungal infections in severe trauma patients. methods: thirty five severe trauma patients who were treated in intensive care unit (icu), were studied prospectively. they all developed fungal infections, prooved with blood positive cultures and at least one of the following: fever, positive urine or bronchial secretions cultures, infiltrates in xrays. the patients were separated randomly in groups. the patients of group a ( patients) received fluconazole rag/day for days. and the patients of group ( patients) amfotericin-b rag/day for also days. compaiison's criteria were the clinical responce to treatment (fever etc), the fungal elimination (blood and other cultures), the relapses of the disease, the side effects of drug, and the outcome of the patients. as method of statistical analysis was used the chi-square test. results: nine patients from of the group a ( %), and from of the group b ( %), presented remission of fever (patients of group b had better clinical responce than patients of group a, and the difference was statistically significant, p< , ). all the patients before treatment had positive for fungi blood cultures. after days of treatment, patients of group a and none of group b had positive cultures. eight patients (from who had positive cultures of bronchial secretions before treatment) of group a. and (from ) of group . had positive cuttures of bronchial secretions after days of treatment, so positive bronchial secretions were fewer in group b than in group a, but this difference wasn't statistically significant, (p< , and p> , ): ten patients (from ) of group a and patients (from ) of group b had positive urine cultures, after days of treatment (positive urine cultures were fewer in group b than in group a and this difference was statistically significant. (p< , ). two patients of group a and none of group b had a relapse of fungal disease. in group a, no side effects were obsepced, while in group b were observed only minor side effects (small increase of serum creatinine in patients, chills and fever during infusion in patients, and hypokalemia in patients). three patients of group a and patient of group b died, because of sepsis. conclusion: amfotericin-b (even i~ short regimen of days), is superior to fluconazole in the clinical and laboratory responce and also in the relapse of fungal disease, fluconazole is superior to amfotericin-b as it has no side effects. ob!ectives: flail chest after thoracic trauma is a serious injury. it is controversial if flail chest by itself orthe concomitant intrathoracic injuries e.g. pulmonary contusion, is the cause of the reported significant morbidity and mortality. in this study we searched the influence of concomitant thoracic injuries in the course and outcome of patients with flail chest. methods: eighty five patients with flail chest after isolated chest injuries were studied, for the purpose of analysis, we separated the patients into groups, patients with isolated flail chest were included in group a, patients with flail chest and hemo-pneumothorax in group b, patients with flail chest and pulmonary contusion in group c, and patients with flail chest and hemo-pneumothorax and pulmonary contusion in group d. complications from the chest, duration of mechanical ventilation and mortality were compared in the groups. statistical comparison of results belween groups was made using chi-square and t-studend tests. results: the patients were . all patients received mechanical ventilation, twenty eight patients were ihcluded in group a, in group b, in group c. and in group d. seventy three patients manifested complications from the chest, especially pulmonary infections. there was no statistical difference among the groups as to number of complications ( twenty four patients had chest complications in group a, in group b, in group c, and in group d. p> , }. the duration of mechanical ventilation was not statistically different among the groups (the mean duration was , days in group a, , in group b, , in group c, and , in group d, p> , ). there was also no statistical difference in mortality among the groups (six patients died in group a. in group b, in group c, and in group d, p> , ). conclusion: flail chest by itself is a serious thoracic damage with many complications, regardless of the presense of other thoracic injuries, which don't contribute to greater morbidity and mortality. the present study investigated the correlation between blood lactate mortality and organ failure in trauma patients admitting between december , and july , in the icu. road traffic accidents were the most common cause of trauma in this studded population. brain damage was the main cause of mortality .nevertheless, of patients died from sepsis and multiple organ failure without significant brain damage and these deaths were potentially preventable. respiratory failure was the most common complication and was developed in ( %) of survivors and in ( %) of non survivors .we noted low fncidence of renal failure may be do to the early and aggressive ittv'asive hemodynamic monitoring and cardiopulmonary support. as part of our routine case protocol serial blood lactate levels were measured in each patient at least times a day until the valses returned within the normal range or until death. we analysed the blood lactate levels on admission, the highest value and the number of days until the first normal value (<l.smeq/i). initial lactate and highest lactate levels were significantly higher in patients with than without organ failure.( . vs . , . vs . meq/l, p< . )the duration of hyperlactemia also was higher in the patients with organ complications. ( . vs . days, p< . ). both initial lactate and highest lactate levels were higher in the non survivors than in the survivors.( . vs . , . vs . meq/l, p< . ) the present study demonstrated that not only the degree but also the duration of hyperlactemia can be related to the development of posttraumatic complications. serial blood lactate measurements are reliable indicators of morbidity and mortality following trauma. s current evidence suggest that peep only affects intracrenisl pressure (zcp)when it interferes with systemic arterial pressure, although the effects of peep over cerebral oxygenation remains unknown. objective: determine the effects of peep over icp and cerebral metabolism measured by sj , kjdo and ceo in severe head injured patients. meterial ~ methgds: patients with glasgow coma scale l at arrival, with difusse brain injury in the first gt, according to marshall criteria,lop and jo monitored, under analgesia and sedation, normoventilated with zeep, without mannitol treatment in the previous hours, normal x ray chest and within the first hours from injury, were considered candidates. peep value where increased fro~ zero to cmh , in three different steps, each one with min of duration. all date were analized on line, pmax p'p ..... p.._, from the ventilator, systemlc haemodynem]c data, cerebra perfuslon pressure (cpp), icp and sjo , in the case of hemodynamic deterioration, during the study, ppc ommhg, extra-volume were administered. if persistence, dopamine were begun or increased dosage. if no good response were obtained, patients were retired from the study. results. patients were candidates, of them were exc;uded due to haemodynamic instability, k total of completed all steps and were e~amined, men and women, age ! . yrs. at hospite; arrival, glasgow were < in patients, and > in the rest . patients mmhg at the beginning. zeep ob/ectives. critically ill patients are transpoded to an intensive care unit(icu), under conditions, which have not been systematically evaluated. therefore, we set suite investigate transportation and admission condition of these patients to our department. methods. we studied patients( females), aged (mean-..+-sd) . _ . yrs, which were consecutively (from august to march ) admitted to the icu, through the greek national emergency transporta~on service. apache ii severity score upon admission was . -+ . (range - ). the following data were evaluated: ) number of medical departments, where health care was provided until final admission to the icu, ) ambulance transportation conditions, ) catheters and tubes inserted before admission, ) vital signs upon admission ) information provided by referring physician (scored on a to scale: history, electrocardiogram, chest x-ray, laboratory data, drug therapy already administered), ) comparison of the state of the patient described by referring physicians, to the actual state u pen admission. resu/ts. one to four medical departments had provided health care before the palient was admitted the icu ( : . %, : . %, : . %, : %). thirty/ ( . %) patients were escorted by a physician. twenty-six/ ( . %) were transported on oxyge n, fio (mean__.sd): -+ %, pao : . -+ . mmhg. five of the remaining , for whom no oxygen was provided, had pao : . -+ mmhg. twelve/ ( . %) were intubated and ventilated during transportation. thirtyfour/ had a peripheral venous line, / had an arterial line, / had a nasogastdc tube, / had a urinary catheter. eleven/ were sedated and / were paralysed. three/ were on inotropes. vital signs upon admission were: arterial blood pressure, systolic . -+ mmhg, diastolic -+ mmhg, heart rate -+ bpm, temperature . -+ cc. patient information score was --. . . the actual state upon admission was found substantially different, as compared to the description of the referring physician, in / ( . %) patients. conclusions. we conclude that several aspects of the greek national emergency transportation service to an icu should be reevaluated and further improved, i. e. ventilatory support, adequacy of information provided and accuracy of prior description of the patient's state. a new perspective must be applied for critically ill patients transportation since . % of the patients were evaluated and treated in more than one, medical departments, mostly primary care, before they were finally admitted to our icu. dclhb is a human derived hemoglobin molecule that has been cross-linked to stabilize and permit heat pasteurization to remove residual proteins and inactivate viruses. dclhb is mixed with a lactated electrolyte solution to yield a total hemoglobin concentration of log/dl objective: to present an overview of four recently completed clinical safety studies of dclhb in the u.s. and europe, and to discuss the properties, actions and potential indications for dclhb. method: patient populations in the four studies included males and females ranging in age from to years. dosing ranged from mglkg to mg/kg. the controlled randomized safety studies were conducted in chronic renal failure patients, surgical patients undergoing total hip replacement or abdominal aorta repair and in hemorrhagic hypovolemic shock patients. these very diverse patient populations allowed safety evaluation of the product in patients who were generally elderly, often hypertensive with some degree of cardiovascular disease, and receiving medications for treatment of other conditions. results: over patients received dclhb in the four:studies. no product related sarious adverse events occurred during the clinical trials. conclusion: results from phase itll safety studies of dclhb in patients undergoing chronic renal dialysis, abdominal aorta repair, or total hip replacement and in patients in hemorrhagic hypovolemic shock, indicate that the product was well tolerated in these distinct populations. although these studies were designed to evaluate safety, the data suggest clinical benefit. follow-up efficacy trials are indicated. prehospital emergency services represent the extension of emergency care into the community and constitutes the manpower, communications, transportations and facilities used to provide care for patients outside hospital. one of the main points of the system is how to decide the hospitalization of patients and what kind of facilities to provide : emergency medical service, fire brigade, locat general praclitionner or ambulance officers. objectives : to realize guidelines for using the prehospital emergency medical service in case of patient'calls outside hospital. methods : from st june to july , all the calls for emergency care were analysed using a questionnaire of items (origin of the call, responses to the questions of an emergency practitionner, kind of emergency service provided and the issue of the patient). after taking account of the appropriatness of the decision, statistical method used was a logistic regression. results : calls were analysed. the criteria, for prehospital emergency medical service using, given by the logistic regression were as following : existence of a call for emergency, thoracic pain, dyspnea, seizures, cyanosis, drug intoxication, fall of the patient, fracture, age, the state of consciousness and the neurologic reactivity. the minimal and maximal predictive values of the model given by the logistic regression are respectively % and %. the performance of the model is %. conclusion : it seems possible to help medical decision of emergency medicine by using only some easy criteria and a predictive model. (italy) objective: to evaluate the incidence of blunt carotideal injury (bci) in patients admitted to our icu after head injury. methods: we reviewed the medical records of all patients diagnosed to have a bci. at admission, the severity of trauma was assessed either with glasgow coma scale (gcs) and with ct scan. bci was demostrated by doppler ultrasography (us) and by angiography (ang). results:since may to april , patients were admitted to our icu with bci ( m, f, age + ). a history of direct trauma was present in patients. admission gcs was in all patients, and was associated with hemiparesis in of them; the last became paretic hours thereafter. two patients had concomitant injuries (a homoiateral clavicular and a controlateral zygomatic fracture, respectively). the initial ct scan was negative in every patient, and showed signs of ischemia after a variable timespan ( - days) after the onset of the symptoms. the bci was diagnosed with us and ang, which demonstrated a thrombosis of the internal carotid artery (ic). in two patients, an intimai dissection was also present. three patients were treated with heparin associated with antiaggregating agents and were discharged alive. the last patient was referred to our icu after the development of a massive hemispheric infarction, and died three days after the admission. at necropsy, the ic thrombosis was associated to an extensive homolateral extra and intracranial venous thrombosis. conclusions:the presence of focal neurological signs despite a negative ct scan should address the diagnosis toward a bci, thus implementing the diagnostic workup with us and/or ang. tab i: distribution of l~tients (%) in the groups the outcome were monitorett results were sabmitted to statistical analysis using a continence table x in z test. res.cl~s: of patients were submitted to thrombolysts and died. the higher incidence of bracb, ar~lhmias (ii degree gg p t e and av block. i degree av block. avsb . <ii. sinus arrest) that requited the insertion of avsc . <cl temporar~ pace-maker was recorded in group a b vs c . ns in % of the cas ~. the rapid recognition of life tab li:;~ test. threatening conditions suggests the monitoring of v r-lead r b' in the course of inferior ami. the authors report their own expirience in application of ringer lact.(rl)and , %nacl/ %dextran . methods:in polytraumatized patients with developed hae morrhagic shock,injures of the chest(qg)and abdomen(q ) prevalid.replacement of the volume loss egan in institutions of general medicine,frequently by rl and dextran or haemaccel.after receiving necessary medical aid,polytraumatized patients wer transported to mma by helicopter,continuing replacing of circulation volume by the same solution. results:average quantities of the solution dministered ~o the injured wer~ - ml.a group of the inoured which,after the admission to mma was resuscitated by adml nistration of the , %nacl/ %dextran @(groupii)( -sml/kg observed to the final surgical management,had statistically higher map(increase of % in relation to admission), cvp(average increase of , cmh~o),diuresis(averagely omi after min.),better gas ~nalyses and acid-base status in relation to the group which was administered only rl(groupi)(increase of the map of q %,average increase c~ of cvp , cmh and average diuresis oml after omin). total quantity of the administered solutions was significantly smaller in the groupii( ml: ml).the only ob served complication was hyperhatr~f~a::and~moderat~hyper osmolerity of plasma which disappeared within hours. the quantity of replaced blodd was considerably smaller in the groupii(qooofnl: ooml).in the group i interstitial pulmonary oedema was observed in two patients(qo%),while: in the group ii no complication was observed.coagulation i disorder and hypotension were not recorded because of the fast infusion of hypertonic/hyperoncotic solution in the groupil as the infusion of , %nacl/ %dextran lasted minutes. w.scherzer(l~,k.lechner( ),r.simon( ). ll)dept.anaesthesiology,trauma hospital,vienna-meidlin !( )neurotraum.rehabilitation center,vienna-meidling both austrian workers'compensation board,vienna,austria what we usually call"unconcious" means only that the patient is not able to interact in any kind of way.experiences in intensive care medicine (robinson, ) ,in general anaesthesia (bennet, ) and with evoked potentials show,that unconcious patients are not automatically unhble to process and recall information.this implicates a challenge to start the efforts to restore the traumatica-!ly desintegrated brain function as early as possible in the acute phase ia (zieger, ) .we present a method to ~repare the patient for the rehabilitation goals of the postacute phase ib,the phase of stabilisation ii and of rehabilitation iii within one concept. to achieve sensory stimulation in phase la we use: attempt at some kind of dialogue by speaking to and tou-ching the patient,to make him experience his body limits, ~acio-oral therapy by ice application,tast and smell pro vocations and trials of feeding,early adaption to circadian rhythm and guiding the patient in every-day-life-ac-tivities e.g.:in the brushing of teeth,washing etc. to achieve motor stimulation and orientation in terms of ~-ace,time and gravity in phase la we use: avoidance of perceptual impairment as produced by air-:sack-beds or habituation to supine position,using method~ according to affolter( ) ,basal stimulation (bienstein, ) , bobath-therapy( ) and facilitation of a physiological moving pattern(pnf)according to knott( ) . conclusions: by integrating all these measures in the ~herapy and nursing even in the acute phase la one prei ares the comatose patient for multisensory stimulation nd motor training and all other rehabilitation activities in the following phases of therapy. s objectives." measurement of cardiac output (co) and stroke volume (sv) requires insertion of a central venous catheter and is associated with a considerable risk for complications. non-invasive methods for determination of hemodynamic parameters have been introduced recently. one of these methods is the aortic modelflow program, which provides co and sv continously using a three-element windkessel model. the aim of the study was to evaluate the accuracy of the aortic modelflow program in critically ill patients. methods: patients (mean age: ) admitted to the emergency department after cardiopuimonary resuscitation (n=ll) and for myocardial infaction (n= ), acute congestive heart failure (n= ) and anaphylactic shock (n=l) were included to the study protocol. after stabilization all patients received a swan-ganz catheter (baxter~; edwards swan-g-anz) via a central vein. co and sv were measured by the use of a cardiac output catheter and injection of rrd ice-cold glucose % non-invasive cardiac output measurement was done by using the continuous cardiac output software package modelflow (tno; portapres| results: overall, paired measurements were used for the evaluation of the accuracy of non-invasive obstained sv and co. mean values, standard deviation and range of co and sv evaluated by invasive and non-invasive methods are summarized in the aortic modelflow provides reliable hemodynamic data in critically ill patients. it may be a useful alternative due to its non-invasive approach and continous measurement. objectives: to determine the feasability and accuracy of a rapid urine screening test (triage tm, merck-diagnostika) in an emergency department. methods: prospective analysis of the triage tm testkit (tt) in patients admitted because of suspected drug abuse during an observational period of months. the tt is a eompetitve immunoassay which gives qualitative results within i minutes for methadone, benzodiazepines, cocaine, amphetamine, opiates, barbiturates and cannabis. urine samples were analysed with the tt and compared to the results of a enzyme-lihked tmmuno-assay (el.a) in our labratory (gold standard). results: during the study patients were enrolled, in of these patients substance abuse was proven by tt and verified by eia. we recorded no false positive or false negative results for benzodiazepines, barbiturates, opiates, cocaine and cannabis. two results were false positive and one false negative for methadone; one result was false negative for amphetamines. the triage-testldt had an overall sensitivity of . and specificity of . . conclusions: the triage tm testkit seems to be a a useful rapid test device in addition to quantitative tests for drugs of abuse in an emergency department. objectives: the purpose of this study was to evaluate the influence of several factors of the renin-angiotensin-aldosterone system on blood pressure response in patients with hypertensive crises. methods: patients with systolic blood pressure > rorohg and diastolic blood pressure > nunllg were included into the study. prior to treatment blood samples for determination of plasma renin activity (pra), angiotensin converting enzyme (ace), angiotensin ii (ang ii) and aldosterone (aldo) were collected. all patients received rog enalaprilat intravenously. success of treatroent was defined as a reduction of systolic blood pressure below mmi-ig and diastolic blood pressure below mmi-ig within minutes after start of treatment. results: patients were included in our study, ( %) patients responded successfully to treatment. mean arterial pressure decreased in responders by . mmhg and in non-respenders by . mmhg (p< . ). responders and non-respenders differed signii'icantly concerning pra (p= . ), ace (p= . ) and ang ii (p= . ). . . the extent of blood pressure reduction correlated positively with the pretreatment pra and ang ii concentrations (correlation coefficient for pra: r= . ; ang ii: r= . ). conclusion: our data confirm that in patients with hypertensive crises blood pressure response to ace inhibition is mainly determined by circulatory pra, ace and ang ii. as the extent of blood pressure reduction correlates with pra, ace-inhibitors in patients with suspected high renin status cannot be recommended, as excessive blood pressure reduction, which carries a considerable risk for further organ damage, may occur. f. staikowsky, n. grillon, f.pevirieri, c.jedrecy, c. zanker, f. michard, a. haft medical emergency department. hospital bichat, paris epidemiology of acute intentional self medications-poisoning (smp) in france is especially known by data of poison control centei,s and intensive care units (icu). the purpose of this study is pro~,ided characteristics of this problem in a med for adults. method: july to june , files of patients consulting to the ed for smp have been retrospectively analyzed. results: patients, women and men, . + years old (range - ) have been admitted for episodes of smp ( % of all consultations) whose relapses during the period of study. psychiatric disorders, drug addiction or hiv patients was found for respectively . %, . % and , % of patients. the interval of time between the ingestion and emergency consultation was noted for % of smp ( + min, ranges - ). the involved products name was known in totality in % of cases with an average number by episode of . + drugs (ranges - ). the most often, ( %) or ( %) different products were interfered. the nonbarbiturate psychotropic drugs accounted for . % of the products (benzodiazepines %, antidepressants . %, neuroleptics %, carbamates . %, imidazopyridines . %, cyclqpyrrol nes . %). analgesics and nonsteroidal antiinflammatories represented . % of all drugs, anticonvulsants . %, cardiovascular drugs %, antiinfective agents . %, drugs against cough . %, muscle relaxants . % and antihistamines h . %. the benzodiaz pines were present in episodes, alone in episodes. in . % of cases, there was a simultaneous intoxication with alcohol. the processing consisted of gastric lavage in . % of cases, activated charcoal in . % of cases, flumazenil in . % of cases, naloxone and acetylcysteine in . % of cases; orotracheal intubation was performed in patients. admission in hospital was effective for patients, in medical ward (n = ), psychiatry (n = ) or icu (n = ); no fatal case was recorded. conelusion: smp to ed are often benign. the benzodiaz pines are the most often incriminated but the new anxiolytics and hypnotics (imidazopyridines and cyclopyrrolones) take a growing place. the latsion burn center of athens. its planning constructive and functional refinements j. ioannovich, a. petalas-vourekus, d~ serbetis, h. carsin a bed burns unit is under construction following a donation to the general hospital of athens. the plan of the unit, covering a surface of approximately . m is based on the principle of three identical bed satelites which may function totally independent from each other. in the center of the unit the common facilities are installed, like operation theatres, storage rooms etc. this new modification in the plan of a burn unit is presented in this paper. the advantages from the fucntional, administrative and medical point of view are discussed. tiffs anisotropic conduodon could favour the ocenrence of a circular movement of the impulse that leads to tachyeardias by reentry. purposes of this work were to study, with the help of epicardial mapping, the influence of a trieyclie antidepressant, clomipramine (c), on the conduction velocity longitudinal (vl) and transverse (vt) to myocardial fiber orientation and on anisotropy (a = ratio vl/vt), and their modificutions by the sodium bicarbonate ( ). method: a plaque of electrodes, positioned on the left anterior ventricular wall of anesthetized dogs, allowed to deliver, thanks to central electrodes, programmed electrical stimulations inducing vcuttienlar complexes, and to collect them. each entailed unipolar dectrogram was processed by a computer system that drew the isochrones and a map of activation allowing the calculation of v. the c was infused ( . mg/kg/min iv) during rain; at t , dogs received the b until the retuni of qrs to its initial value fro). a lengthening of qrs of at least % of its value at to was demanded before the administration of b. results: dog was excluded because of an.~nsufficient prolongation of qrs before the administration of b. all values (map : mean arterial pressure, i-ir : heart rate, qrs andqt intervals, v) differed significatively ( < . ) compared to values control fro)except qrs at t . the b ( + ml/kg; ranges . and . ml/kg) modified no studied dements outside of the ( }rs. to ti t t t t t a , + , , + , , + , , + , , + , , + , , +- ,~ conclusion : the c slowed v l and v t without modify the anisotropy. the b did not modify the v of~conduction while the qrs prolongation was corrected. the c acts as a class i antiarrythmie drug on the inward sodium current during the phase of action potential; the gap junctions have shown to be important in the conduction and an action on the gap junctions such as a modulation of the junctional resistivity, can not be rule out. is the doctor a heroe ? p. t.schies~.he, t. bauer, m. seyr dept. of anaesthesiology and intensive care, aokh krems, austria objectives: helicopter emergency services (hes) are getting popular more and more. the results concerning outcome are encouraging. however, some recent accidents with dead or badly wounded hescrew-members have shown the relatively high risk for the crews. therefore we were interested to eval ate the motivation of physicians to participate in a hes. this survey was designed to investigate current concerns about safety and motivation of doctors on emergency call. methods: a questionnaire was sent to doctors of the austrian emergency system. the survey consisted of multiple choice questions and subjective scoring tables from (--full agreement) to (=disagreement). overall, "/. of the active emergency physicians participated in the survey. results: . % of the doctors assume the system is basically safe, experienced doctors tended to have less trust in safety. only % would not hesitate to go into action by dark. . % stdctly refuse night flights to accidents outdoors. although defibrillations are assumed to be safe dudng flight, only % would do it. . % of the doctors would rather stop flying. the most common reasons for ,uitting were wish of family and fear of an accident. . % conclusioq: short transportation times help to avoid trauma related stress, pain and shock-induced organ complications. therefore the physiologic and economic advantages of hes are undebatable. however, the survey data indicate a considerable concern about safety of the medical personal in a hes. crash landings within less than years with deadcases and badly wounded crew members in a small country like austda make desire for safe flying conditions understandable. obiectives: to evaluate the clinical usefulness of trachlight. methods: trachlight is a new device facilitating endotracheal intubation. a stylet with a lightprobe is inserted into the endotracheal tube. intubation is guided by the light glowing through the neck tissues, thus rendering direct laryngoscopy unnecessary. intubation using trachlight was studied in patients (age - years). the indication for intubation was elective surgery in patients (asa i-ii) and emergency intubation in patients. in the elective patients, anaesthesia was induced with thiopentone supplemented with fentanyl, and intubation was facilitated with vecuronium. the cause for intubation in the emergency patients was dyspnea in , cardiac arrest in , trauma in, and unconsciousness due to drug overdose or seizures in patients. intubation was facilitated with medication in patients. results: of the elective patients, ( %) were successfully intubated. six patients ( %) needed two attempts before successful intubation. the duration of intubation exceeded seconds in patients ( %). of the emergency patients, ( %) were successfully intubated. six patients ( %) needed two attempts, and the duration of intubation was more than seconds in patients ( %). in % of all patients, intubation was assessed as easy. no or insufficient glow, prolonging intubation or necessitating two attempts, was noted in patients ( %). oesophageal intubation occurred in patients. conclusions: trachlight may be a valuable adjunct for intubation in varoius settings provided that adequate training is provided. a learning curve was found to exist. objectives: to compare enoxaparin and standard heparin in cavhd and calculate the value of laboratory controls in the treaanent. patients and methods: twenty patients needing dialysis for acute renal failure participated in the study. the main exclusion criteria were massive bleeding or a thrombocyte level < x e /i. in each treatment the same type (av- , fresenius ag, germany) of a polysulfone capillary haemofilter was used. the study scheme consisted of two consecutive four-day cavhd treatments, one course for each type of heparin. the order of heparin administration was counterbalanced between patients. the standard heparin was given as a continuous infusion aiming at an activated coagulation time between and s. the initial enoxaparin dose was rag every :th hour intravenously, but was modified by any signs of coagulation in the dialysis blood lines or bleeding complications. results: the dialysis treatment was adequate in both treatment modes, with mean blood urea levels . and . mmol/l respectively (ns). the bleeding complications were moderate and similar in both treatment modes. the mean life-span of haemofilter using enoxaparin as an anticoagulant was some longer than using heparin ( . + . h versus . + h, ns). the mean aptt-levcl during heparin treatment was s and during enoxaparin treatment s (ref. - s). the mean daily dose of heparin was nag, that of enoxaparin lg mg. the mean anti-xa activities were . u/mi and . u/mi, respectively, reflecting a better bioavallability of enoxaparin. conclusions: both anticoagniation modes were equally effective and well tolerated. the amount of enoxaparin needed for a proper anticoagulation was, however, less than half of that of standard heparin. the changes in aptt level were too slight to make its use possible in controliing the dose of enoxaparin. the use of enoxaparin seems to be rather safe in cavhd even without laboratory controls. the adv~ucea in the management of computerized data of an intensive care unit have been petalled to the clinical advauces and the increasing sophistication of methods of diagnosis fop the clinical application an therapy. this has led our unit to design and develop a computational system called timbu which is used to help physicians assist patients. among its various uses, this system has a software for the hemodynsmic control of a critic patient. this program was carried out to get as fast as possible the hemodynamic data of the patients in an intensive care unit. as an example, we can mention that when we load data obtained through direct measurement from the monitors and the lab, the program calculates parameters that guide, intelligently, to the diagnosis and therapeutic behaviour of the hemodynamic problem through screen messages. the validation of this program in the unit of intensive care has demonstrated that its use allows a more efficient handling of the patient with serious hemodynamics and respiratory disorders. ohieetlve: traema is a heterogeneotm 'disease' that ecatr~ a~"o~s all age ~oupe with v~ying degrees of severity. this imerogeneity has made the di~e, trmma, diflkaflt to r the ehn of this stady wa~ to assr the fitaen of saps in ibis popeleties. methode: in order to compute the ~ probability, a model derived from logistic regression w~ developed. meam'e of calibration (goodaess-of-fit stetislj.r and di~'riminafion (roc ou~e) were adopted in developmm~ and validetlon set randomly taken from a database of pts eeeseemivety admitted in icu (arohidia). ~ witho= salm, p~ yom~ am is yam, with los ~horter thma hotam wore exr fa'om thi~ mmly~ir thi~ model v~s then evahmed on the ~per ~mbgro~ (i.e., trmma pts). if'it did t~t fit the data well ~, new model wm developed rer the logit only on trm=~apm. reims: data were availabte for pts during aperiod of three .y~m , treama pts were . %), teats of calibration iadioaled probability model did mot provide m adequate refle~on of the mortality ezperieace in pm with ireutae, being the observed mortality lower flma the expected (figm'o). a aew model was then variable. this oastomized model fit~ the de~t of trmara pts very well (g =- a p> . ; roc = , ). the di:lferencea between the two modele were evident. conclusion: this ltudy shows that mortality in iramna pts is over wcfe~d when ~se~ed by menm of saps. however the r mode! meets high standmcd in terms of calibration mid dil~'iminat'~o~ ']"he advaatage of ~imd models meaas the colleotion of the ~ set of variables for all pm admitted in icu e~einat the ase of diasma specific ~oring syatex~. ("sl"): effects on cardiovascular and hemostasis systems (cvs, hss) a.oborin~ph, ~.~yndiuk~ph, b.kondratsky ~pt. of'""su~gery and transfusiology, research institute of hematology, lvov, ukraine objectives: great interest has been shown recently in the use of hoss for the initial resuscitation of hypovolemic shock. methods: the study was carried out in dogs -~h hs was induced by jet momentary hemorrhage (h) from a. femoralls (the bloodloss volume made . + . ml/kg). the treatment was begun after .u+o. hrs of h. "sl", created on the basis of-sorblt and natrium lactate ( mosm/l) was injected into v. femofalls at the dose of io. ml/kg. results: it is established that before treatmen-~rterial blood and central venous pressures (abp, cvp) diminished to . mm hg and - . + . cm h (p .o ), while heart rate (hr)-increased to . + . per min (p<.o ). by this the indices of ~latelet counts (pic) and plasma fibrinogen (pf) lowered by . % (p<.i) and . % (p~. ), while fibrin degradation products (fdp) enlarged by . % (p~ . ). after - min of treatment termination abp and cvp increased to . + . mmhg and . +o. cm h (p<.o ), and ~[r diminished to t . + . per min (p>. ). at the same time the indtces of pic and pf enlarged by . % and . % (p>.i), while fdp diminished by . % (p>.i). one of dogs survived. life duration of the other dogs was . + . hrs. conclusions: the obtained data are ~he evidence of normalizing influence of "sl" on cvs and hss, and allow to recommend it as a mean of initial resuscitation of hs in clinic. oblectives: we prospectively studied icu patients with severe head injury (hi), which cerebral lesions monitorized with sjo through opljcal fiber and the cerebral flux with tcd. methods: since january until june , we collected ht admitted to the icu, and of them monitorized with optical fiber in the right jugular bulb and tcd. all patients needed mechanical ventilation related to gcs <__ , with ct in admission (classifing lesions according to marshall and al.) . we related the final results to the evolution of sjo and tcd, with other monitorizing methods like gcs, ct and icp. ~sults: conclusions: in patients with gcs _< , sjo is useful to evaluate the evolution towards vegetative state, still more in cases with ct type ii in admission and higher apache ill. elevation of icp implies an evolutive nsk to brain death and data of tcd is a good indicator of brain death, the complete monitorization of these patients can improve the therapeutic control of this neurologic problem, , ( m, f) , (m. age: + years), divided in two groups (a and b) under specific criteria(tremor and/or fever during admission in i.c.u., or not). the injury severity score was > in all studied patients. tbe group a ( m, ") had no tremor and/or fever on admisskm, while em group b (tin, the above criteria were ix)sitive. bhx~d samplings were taken - hours after accident and - rain. after admisskm in i.c.u. micro-eli~ method was used for measuring cytokinc-levcls. statistic analysis was performed by studcnt-t test. as control group, healthy people were examined. _resu!_ts-il-lct, il-ii~, il- and tnf-tt levels were similar to control group levels in both groups a and b. i!,- and g-csf levels were found increased in both groups (p< jxjl), while il- levels were statistically significant comparing to group a. in con_tin_skin, during immediate post raumatic period,proinflamatory cylokines il-i~, il-i~ and tnf.-ct, produced in an earlier stage than ,. , cannot be detected,whereas .- was increased significantly, especially in group b. g-csf was fimnd in increawal levels in both gr(mps, without statistically significant difference between gnmps a and i|. objectives-l~valantc proteolitic activity, disorders in" eariy, period after combined trauma and p(~.ssibilit, i' of their correction by injection of proteo[ysis inhibitors contrycal and s-fto~:nracil in combination with driving an isotonic snlu~ion of sodlum chloride and polig[ucine. methods: biochemicai studies of proteolitic activity in dogs with limited deep burn and acute bloodloss, . result:s: in case of deep % burn, cornplicated by bloodshed the of blood grows at - times. it; is the restdt of the pancreas glandischemi demage, caused by the centralised circulation of blood and intensifies the deviations of haemodiaamics and albumin exchange. the degree of endogene intoxication by mean mofecular peptides which are the products of albumin decay reses to %, and % in hours. in hours after the trauma the-process is accompanied b ! , % lower inhibitory activity of blood, where as at the peak of the trauma it was , ~ higher. that proves the nnfavuurahle process of the shock in case a combined trauma. conclusion: the vein injection of 'proteolysis inhihitotz cnntrycal and -fforuraei[ in cumbination with driving an isotonic solution of sodium chloride and p.dligh]cine to refill lhe loss of blood helps to lower at times the profeolitic activity of blood. but it still remains above the initial level. the degree of endogene intoxication lowers at times; [ emodinamics aml albumin exchange stahilised. objectives: nimodipine, a known calcium antagonist, has been shown to dispose a beneficial effect on patients with subarachnoid hemorrhage, but its efficacy on traumatic or spontaneous intracerebral hematoma has not been justified. therefore, we studied the effect of nimodipine on the histopathological changes following an experimental intracerebral haematoma in rabbits. methods: twenty-three new zealand albin rabbits of both sexes, weighing - , kgr and at age of - months were anesthetized and a small burr hold in the left parietal aerea was carried out under aseptic conditions. the dura was opened and . ml (this volume assuring a normal incranial pressure after kaufman ) of autologous blood was injected into a depth of mm via a needle of . mm bore. the wound was closed and the animals were left to recover. nimodipine, of , mg/kgr of by weight per day was given via a nasogastric tube to fifteen animals for a period of time of fifteen days (group b). six rabbits were given water and served as control (group a). both groups of animals weie sacrified on the fifteenth day, their brains were removed and immersed into % formalin solution. tissue sections of ~ were embedded into paraphin and stained with haematoxyline and eosin, mason and gfap stain for gliac cells. results: two animals died after the surgical procedure, because they developed large intracerebral bematoma. no animal developed neurological deficit except one of group a which manifested a right side hemiparesis. the results of the bistopathological changes are the following: i) the mean -+ sd diameter of the lesions in the group a was --. ~t while that of group b was + ~t (p< , ) ii) secondary ischaemic neural tissue changes, characterized by the extravasatlon of red cells, the presence of haemosiderin-containing macrophages and signs of low grade inflammation zpredominated in the specimens of group a and were totaly absent from those of group b. iii) a ring of gliac hyperplasia and a low grade local fibrosis was found, encircling the lesions in the specimens of group a in contrast to those of group b. conclusions: nimodipine when administered in rabbits following the development of a non increasing the icp experimental intracerebral haematoma, prevents the extention and the severity of the lesion. objectives: to study the efficacy and side effects of adding intramuscular clonidine (clophelinum) to analgesic regimen in early management of patients with serious burn injury. methods: pts with - % bsa second to third degree flame burns (respiratory tact injury excluded) to yrs of age were randomised to study (n= ) and control (n= ) groups. burn shock was treated with hypertonic saline -bicarbonate solutions ( mmol/l na +) ml/kg/%bsa for the first hours and ml/kg/%bsa for second day. analgesia in control group for the first hours was provided by regular hourly intramuscular administration of mg of morphine sulphate and mg of analgesic -antipyretic analgin with mg of diphenhydramine (dimedrol). from the rd day regular administration of morphine was finished. in the study group ixg of clonidine was added -hourly for hours and dose of morphine halved. vas, verbal rating scale for sedation (vrs, - ), sleeping time, spo , hr, bp, diuresis, vomiting and other complications were comparatively evaluated during patients' stay in icu. results: addition of ~g of intramuscular clonidine daily allowed to achieve better analgesia and sedation with halved consumption of morphine. mean vrs in study group for the first days was . - . vs . - . in control group with twice longer sleeping time. there was significantly less tachycardia in study group; dynamics of bp for the first hours did not differ considerably; later, there, was tendency for hypotension in study group without adverse effects on diuresis or other indices of tissue perfusion. because of high incidence of chronic ethanol abuse among study population pts of control group suffered from psychomotor agitation or delirium, probably as a sign of alcohol withdrawal syndrome (aws). this made regular evaluation of vas impossible. in the study group only pt showed sign of aws. mean vas score was in . - . range for first postburn days. pts appeared excessively drowsy due to clonidine, but it had no adverse effect on their overall clinical course. mean spo values in study group were in - % range, among controls - %; vomiting was absent in. cionidine group vs cases among controls conclusions: clonidine could be a valuable addition to analgesic -sedative regimen in burns, especially for prevention of aws and deserves further study in this regard. hemodialysis -hemoflltration modifications and/or intratracheal gas insuflation have been recently used for blood gas exchange in several models of respiratory failure. objectives: evaluate the combination of cavh-m and igi for respiratory support in experimental acute lung injury. methods: five mongrel dogs ( -+ kgr) were mechanically ventilated inroom air, paralysed, heparinized, connected with a cavh-m system (diafilter- polysulphone membrane) and remained stable for one hour (pao~= . • peco = -+ mmhg, ph= . -+ . , bp= -+ mmhg and pap= -+ mmhg). all was induced two hours after oleic acid infusion ( . ml/kgr) into the pulmonary artery (poo~= . _+ -p< . , paco~- . _+ -p< . , ph= . -+ . -p< . , bp= -+ -p=ns, and pap= _+ -p< . ). fio % for the next minutes did not significantly altered the b ood gas abnormalities. afterwards, pure oxygen applied simultaneously a) through the inlet of the filtrate's compartment of the hemofilter ( l/min) while filtrate and gas were removed from the outlet port (bypass flow ml/min) b) through a thin intratracheal catheter positioned cm above the carina ( l/min). the fio given through the ventilator readjusted to %. results replacement fluids/filtrate during the next four hours were not exceed . l/hour, whilst the blood gases and pressures were improved as follow: cavh-inlet:pao.= . objective. to compare the changes in humoral immunity in trauma patients following massive transfusion of autologous and homologous blood. methods. we studied randomised clinical groups of patients each containing patients with trauma and operation of large arterial vessels. the amount of autologous or homologous blood transfused to the patients was exceeding ml, while the patients in the control group did not recieve blood or blood products. results. we recorded most pronounced and characteristic changes on the -st and on the -th day in the group of patients recieving homologous blood transfusion, i.e. decreased amount of igg,iga,igm,c and c fractions of the complement system, haptoglobin and significant and sustained rise of circulating immune complexes up to the end of the study period. in the control group of patients the decrease was weaker and lasted only during the -st post-operative day; the dynamics of the circulating immune complexes level were almost the same as in the first group of patients. in the group of patients recieving autologous blood transfusion, the parameter values did not change significantly from preexisting levels after the -st day, while on the -th and on the -th day showed a tendency towards aslight rise. conclusions. autologous blood has a favourable effect upon humoral immunity and should be the transfusion medium of choice in cases where autologous blood reinfusion is technically possible. ivan petkov, m.d., rumen farashev, m.d. and dimitar terziiski, m. d. medicine, military medical academy, g. sofiiski str., sofia, bulgaria objective. the amount of blood lost during trauma and operation could hardly be forseen and donor blood supplies are not always available in sufficient amounts. rare blood group types and/or unexpected haemorrhage pose a great challenge to the transfusion therapy and the methods of intraoperative autologous blood transfusion. methods. we report a case of a -year old male patient with extremely massive intraabdominal haemorrhage ( m( blood loss ) during an abdominal aorta reconstruction following a traumatic injury of the abdominal aorta. we achieved a successful reinfusion of ml of autologous blood using an original autotransfusion system developed by us ( pat. no / . . ) . results and conclusions. the autotogous blood in the case reported here was the only and the most suitable transfusion medium for the rapid intraoperative compensation of the acute haemorrhage and the favourable outcome of the patient. the post-operative period was smooth and no significant disorders in the clinical course as well as in the laboratory tests ( morphological,biochemical,coagulation and immunological) were recorded. there were no complications during the postoperative period despite the fact that the amount of blood reinfused to the patient was slightly exceeding his own volume of circulating blood. objective. the haemoglobin concentration and the perfusion pressure value could not be the only criteria for the early signs of tissue and organ dysfunction. because of this, we employed the extensive monitoring of oxygen transport during severe trauma in order to. achieve dynamic evaluation of physiologic compensatory mechanisms and to assess the efficacy of intensive care management. methods. we conducted a prospective controlled trial on the blood oxygenation, oxygen transport and tissue perfusion during the first days after the trauma in patients with polytrauma. we used a swan -ganz pulmonary artery catheter (beckton -dickinson, u.s.a.), deseret cardiac output computer (medical inc., u.s.a.) and hewlett -packard monitor (hewlett -packard, germany) to measure and calculate all the parameter values. the severity of the injury was assessed using the apache ii score system. all the patients had scores over . results. the results show a significant decrease in the arterial blood oxygen content and in the arterio-venous difference, as well as an increase in alveolo-arterial oxygen difference and in the transpulmonary right-to-left shunt. the tissue oxygen supply and the tissue oxygen consumption reveal a tendency towards a decrease below the physiologic minimum of adeqate values. the erythrocyte current velocity and the ratio between oxygen transport and erythrocyte current velocity also decrease inspite of the optimal blood rheology. conclusions. the dynamics in the parameters values are most pronounced between the -nd and the -th hr after trauma, which predisposes patients to the risk of developing stable hypoxemia and characterizes this period as the most critical for tissue metabolism and organ dysfunction. posttraumatic changes in immune mechanisms in lung compartment in trauma were analyzed in ao and da inbred strains of rats which differ in their immunological reactivity: the former being low responder and lat-~er hiperresponsive. methods: the levels of tnf-alpha activity in the supernatants of cultured lung lobes and dynamics of cells migration from tissue explants in h lung cultures were assessed in ao and da rats subject ted to severe burn trauma. results: increased levels of tnf activity ( + pg/ml compared to + . pg/ml in control) were found od day following trauma in lung sups of ao rats while no changes in the levels of activity of this cytokine were found in lung-sups od da rats more pronounced extent and dynamics of cell emigration were noted in da rats, while almost unchanged in ao rats sharp rise in pmn percentages h following trauma ( - % compared to rare pmns in control), followed by increase in lymphocyte numbers at later time points among lung cell emigrants was detected in ao rats. slower but persistent increase ( %, h following trauma and % and % on days and after trauma infliction, respectively) in pmn numbers among da lung cell emigrants was detected, which appeared to be activated, as judged by their nbt reduction capacity. increased percentages of peripheral blood pmns and increased state of leukocyte aggregation/adhesion were detected in both strains, but different levels of plasma tnf: increased levels in ao rats on days and following trauma, and initially but persistently high levels of plasma tnf alpha in da rats ( - fold higher compared to initial levels in ao rats). conclusions:different patterns of local (lung) and systemic changes in cell numbers and cytokine levels implicate differential posttraumatic migratory capacity of pmns vs. lymphocytes in lungs in ao and da rats. early diagnosis of acute intestinal ischemia by color doppler sonography e. danse, b.van beers, p.goffette, f.hammer,aav.dardenne, f.thys, p-f.laterre, m,s. reynaert, .lpringot dept of radiology (profb.maldague) and dept of intensive care ( prof m,s.reynaert), st.luc univ.hospital, brussels, belgium ob emergeny medical squad service is the most important segment in the process of saving the people, in the cases of mass accidents, like industrial accidents caused by the: explosion, fire, chemical poisoning, traffic accident, elemental catastrophes and the war. because of that, each emergency medical squad service needs to have in its motor-pool vehicle for the mass accidents/ for provoding at least people, wounded as well as the people became ill/. objectives: presentation of such special vehicle, produced by "zastava-kamioni" and it's medical-technical equipment. methods: descriptive and comparative analysis of the medical and technical characteristics, based on the actual norms/din, , iso , yus.../ results: on the base of doctrinaired requirements of the emergency medical squad in the case of mass accidents, our researches resulted in the following medical and technical characteristics -the vehicles for mass accidents are gvw/with a payload off cca - t, with the fixed, closed body, type: universal van, -technical equipment aggregates, stretches, anti-fire device, equipment for pitching the tent and for maintaing technical conditions of the work -medical equipment: linen bags with complete sets of bandage material, means for the reanimation and immobilization, for the infusion, medical instruments and remedies as well as the tent for lodging at least wounded and sik people. in federal republic yugoslavia, it was proposed such vehicles for the emergency medical squad needs. conclusion: we suggest to introduce this vehicle in the production range of the ambulance vehicles for saving, especially in the circles where can occur serious accidents. introduction : carbon monoxide (co) poisoning commonly generates central nervous system abnormalities though an important cardiac morbidity and mortality must be considered. long-term exposure to co with cohb levels < % may be more dangerous than short-term levels of - %. we report a case of an adolescent who after prolonged exposure to co developed a severe reversible cardiac dysfunction with low levels of bloed cohe c a.ase history : a year old boy was found comatose at home. his mother in the neighbouring bathroom died severn hours earlier of what was later proven to be a co intoxication. on arrival the gcs was / and the patient was breathing spontaneously. a postictal status with eventual postanoxic encephalopathy was suspected. a coh'b level of % was objectivated. the cardiorespiratory situation quickly deteriorated requiring mechanical ventilation. chest x-ray showed diffuse bilateral patchy infiltrates. ecg revealed signs of ischemia. severe left ventricular dysfunction was evidenced by pulmonary artery catheterisation and echecardiography and later by isotopic angiography (lvef %). treatment was intensified with inotropic support, intta-aortic balloon counterpulsation and oxygen therapy. the clinical course was further complicated by a crush syndrome and renal failure. the patient's condition gradually improved and he fully recovered without any residual lesions (lwf %) conclusion : even after prolonged exposure cohb levels can be misleadingly low. high tissue levels of accumulated co can be associated with coma and fulminant cardiorespiratory failure requiring advanced life support facilities. introduction : both neuroleptics (nlp) and tricyclic antidepressive agents (tca) can induce arrhythmias, prolongation of the qt segment and the pr interval and hypotension. we report a case illustrating that combined overdose of these agents increases the toxicity of each compound and the risk for adverse cardiac events. .c, gse history : a year old male ingested mg doxepin (sinequanr), a tca and mg prothipendyl (dominalr), a potent nlp in an attempted suicide. upon arrival in the emergency department the patient was unconscious (gcs / ), breathing superficially, and presenting signs of recent vomiting. physical examination revealed a taehycardia of b.p.m., an arterial blood pressure of / mmh g. ecg showed a brood qrs complex tachycardia. a chest x-ray revealed the presence of an aspiration pneumonia. laboratory investigation demonstrated increased levels of crcatine phosphokinase, lactate dehydrogenase and aspartate transaminase ; hyperglycemia and leucocytosis were present. the plasma concentrations of doxepin and prothipendyl were respectively gg/l (toxic level #g/l) and i.tg/l (no reference). treatment consisted of mechanical ventilation, gaslric lavage and administration of activated charcoal and iv fluids and antibiotics. a hemodynamically well tolerated veatricular tachycardia developed / h later. nahco ( meq/ h) was administrated inducing an ectopic atrial tachycardia with a normal qrs complex and prolonged qt. h after admission a normal sinus rhythm was present; the prolongation of the qt segment persisted for days. the patient fully recovered. conclusion : the treatment with nahco~, alkalizing the blood and thus increasing the protein binding of the tricyclic antidepressant molecule, can readily correct the potentially life-threatening cardiac arrhythmias and therefore should be part of the routine treatment of combined tca-nlp overdose. ob/ectives: the development of diabetes insipidus (di) in patients with brain injury is a known negative prognostic sign. the aim of this study was to investigate whether this is also a reliable early prognostic sign of brain death. methods: this is a retrospective study of patients treated" during a two year period ( - - to - - ) in our i.c.u who meeted the following criteria: ( ) coma score _< gcs within the first hours, ( ) positive brain ct scan on admission classified according to marshall's diagnostic classification (classes - ), ( ) normal renal function during the entire icu stay. for the definition of di were used the usual di criteria plus hypematriaemia (serum na" >_ meq/l). survival was defined up to the th postadmission day. conclusions: according to the findings of this study, the development of diabetes insipidus in brain injured patients seems to be a highly specific index for brain death (positive predictive value = . ). however, further prospective studies are needed for the definitive evaluation of these findings in such patients. emergency care in italy, despite all efforts, is still lacking a nationwide organized prehospital care system and, until today, there are only different regional solutions. the majority of these realities imply rather simple ambulance first-aid services without attending emergency physicians and without resuscitation equipment. the emergency medical service (ems) system in falconara m., italy, was implemented in august by a collaboration between the school of anesthesiology and intensive care of the university of ancona and the, already existing, volunteer rescuer organisation "yellow cross". according to the guidelines pubblished in [ ] the pre-existing equipment of the volunteers was completed with type a ambulances and special equiped motorcar (patient monitor, defibrillator) for ambulance indipendent physician transpur[. a special data collecting schedule was created to memorise every emergency intervention in a computerised data-base. the intraining members of the school of anesthesiology and intensive care provide hour ready intervention. in this report the authors describe their experience concerning primary firstaid medical interventions. for a preliminary evaluation we considered, retrospectively, consecutive emergency interventions in the time period from novembre , to april , . the emergency physicians treated male ( %) and female ( %) patients, patients died before hospital admission and patients ( %) were treated at home by the ambulance indipendent physician and did not need any further medical treatment. in the same time period year earlier (november to april ) without attending physician the volunteer rescuers transferred all first-aid interventions to near-by hospitals. we conclude that the presence of an attending, iudipendently motorised physician in emergency interventions is essential for the establishment of precise priorities and may be helpful to reduce hospital admissions by ambulance intervention, though reducing primary" health care costs. we have developed the method of liquor filtration which allows to purify the cerebrospinal liquor from blood and its decay products in the subarachnoid bloodstroke. the hemipermeable dialysis membrane was used as a filter, which lets only in water, electrolytes and substances with small molecular weight. the liquor filtration was used for the treatment of patients with the subarachnoid bloodstrokes of different etiology. the perfusion of liquor was performed at the rate ml/min in the recirculatory mode. its duration was - min depending on the bloodstroke intensity. the filtration makes possible the most completely purifying of the hemorragic liquor, the reducing of the content of blood ceils and its decay products - times as less. the monitoring of the patient's state during the perfusion didn't revealed the departure from the norm of the main vital part. the liquor filtration technique compares favo-~ rsbly with the routine method of cleaning by the absence of toxical effect of heterogenous solutions on the central nervous system. the filtrstion of the cerebrospinal liquor in the subarachnoid bloodstroke sllows to provide the the early cleaning of liqour, the regression of meningeal syndrome and to improve the patient's state of health. e tabli~mczr bd ~ of rei~idnal medical first-aid zhoulittoing, ed., tan zi, m.d. dept. of sargery, the first teaching t[ospitat, yejin-l)a-l)ao, wuhan fltlna objectives: the medical first-aid is the most important task of the public hc atth department. in general, single hospital model couldn't fatty, effective ly rescue mony severe patients who need mergant treatment in the scene. bub establishing the medical first-aid network, the severe patients can be given the most timely und the most scientific emergent treatment. so that, the suc cessfut rate of the saving wilt be greatly increased. methods..; our hospital is a general big hospital. through developing and cons tructlng for more than ten years, the medical first-aid network distributed art over the area under our jurisdiction has been set up. it consists of thr ee units: the medical first-aid unib center comartd and mnagment unit, co m~nlcation and tiaison unit. the principle of the network operation is with oat having to far to mergoncy, specialized emergency and the best merge acy. results: the results of the network operation were notable. cmpari~ the to tat successful rate of the saving ( . ~), the successful rate of saving tra ma ( .~), the suscessfut rate of saving shock ( .~) and the successful rate of cardioputmonary resuscitation ( . ~) daring the three years after t he network operated with these before ( . ~), ( ]. ~), ( . ~) and ( ft. ~), the successful rates after operating were remrk~iy higher ( p<i).o ). conctusions~ the above results showed estabiishmnt and mena emont of region at medical first-aid network had very si~nificont action during mergentty s avin the severe patients. moreover, the regi~at medical first-aid network atso take an important part in prevention and health protection of the mass. objectives: se related mortality is due to the occurrence of both rv and lv dysfunction evoking cardiogenic shock and pulmonary edema (f. abroug, intensive care med ; s. nouira. chest ) . prospective evaluation of scorpion antivenon (sav), the only available specific treatment, is lacking. the aim of this study is to assess the effects of sav on the basis of a case-control study. methods:among consecutive victims of se presenting to the emergency department, were managed using sav (group sav+). these patients were matched to envenomated patients who did not receive sav (group sav- chest injuries are the cause of death in % of trauma fatalities and a major contributing factor in an additional %. pneumothorax is a major complication of chest injuries and can be initially overlooked bringing to additional morbidity and mortality especially in patients who require mechanical ventilation. the real incidence of pneumothorax in severe blunt chest trauma hasn't yet been established, as many pneumothorax can be missed on the initial chest x-ray (cxr) and computed tomography (ct) has not been routinely used. to evaluate the incidence of pneumothorax in patients with severe blunt chest trauma. methods: a prospective study. from january to december , all trauma patients with one of the followings conditions: fractures of four or more ribs, signs of lung contusion on the initial cxr or presenting a severe hypoxemia on admission (pao /fio < ) in the absence of pre-existing pathologies, were evaluated by initial cxr and subsequently submitted routinely to a ct. results: severe trauma patients were considered. of them, presenting a severe hypoxemia on admission, had no evidence of major chest trauma (ais< ). hypoxemia was the consequence of severe trauma in other districts; these patients were therefore excluded. patients with severe thoracic trauma (ais>= ) were admitted into the study. the mean iss was . ( - ). thirty-six patients required artificial ventilation for at least hours during the icu slay. three of them, who had a tension pneumothorax, were submitted to an emergency thoracic decompression on the field by the emergency helicopter team. in cases pneumothorax was diagnosed an the initial cxr more patients had a pnx which was identified only on the ct. in cases a large pnx with lung collapse was missed on the cxr. in our group of severe blunt trauma patients, % ( / ) presented a pnx that required the insertion of a thoracic drainage. only one third ( / ) of the pneumothorax could be recognised on the initial cxr, while other were decompressed before performing the cxr. as many as % of the cases of clinically significant pnx were missed on the cxr, and a ct performed soon after admission allowed an early diagnosis bringing to changes in the treatment. (as the patients were mechanically ventilated a chest tube was inserted in all these cases). in cases, the initial cxr overlooked a huge tended pnx which was the cause of hemodynamie instability. conclusion: in patients with severe blunt chest trauma even large pnx can be missed on the initial cxr. moreover due to the non compliant compressible lung, a % pneumothorax which can be recegnised only on a ct, can bring to high intrapleural pressure altering eardiopulmonary function. n. andoeli , .~osid, m.zesevid, m.risovid, d.stepi , d.djokid b~rga~yc~qterclinicalcaqterafserbia, belgrade cb~ctives:~lis study ~ the use of ~rq]ofol earbired with k~t~ine (aq a~sjgh~ic s@~qt widn inirjrsic armlgesic pro~mities) or with fsqtmtyl,with psrtial azgmsis an hgenxlyn-a~ic ~ durirg ~ ~ re:~ver~ f~m ~ in hxh ~ of ~ti~. ~: yali~mial and ~bod: a~it p~tie~ts a~ i-ii were included in ibis shxly. patients were rsrd]nly dieided in two ~ns. all d~tie~ts ~me given - prcpofol bolus doses (o, ~gkg) for ird~iqn of ~. ~ia ~s m~sjn~ with an infusion ~ ~ropafol. as sdflitianal were given fan-i~l (o, n]g) ~tely before ~ anj trad~e~ irfojoation followad by feasted bolus of o,i mg in ~ro o l.patients in gr~ o received i~ (an initial bolus dose of rg slowly intcavax~ rd mg as infusion over ~ rain) .infusions of pro~fol or imcpofol with kg~mine ~ stopfsj - rain ]:~o~ extuhation.arterial blood ~ (sistolic arterial blood preassu-re~zap,mean ~rterial blood pr~,d~lic arterial preassure-[zp a~ h~art rate-~) ~ m~ before induction of a~ io, snd rain aftem ~ intutation. results: arterial blood preasstre ~s decreases duri~ irn~ction of sn~wd~sia in hy~ ~n~s,tnt mare in th~ ~ who r~eived fsqtanyl.~ere w~s statisticslly sifnific~ntly difemerme dmir~ m~ of an~ia. arterial blood r~easatre and heart rate were stable in the t-..e~min -~a ~. all th~,fl-e keta'nire grcqo hsd e~rly :~e~y time. ctrmlusi~s: ~e ombiretion of protxfol wilh keta/ne for irduorion a~d ~ of sn~sd~esis w~s yell accept~ by p~tierfcs anj coald he ~ as an alterrstive ~o ccnva~icrsl a~es -d~sia. objectives : assess the relation between cytokine or endotoxin release and indices of splanchnic malperfasion after hemorragic shock in multiple trauma patients. ]~r study was approved by the local ethical committee. trauma patients admitted to the emergency room who met the entrance criteria of more than hour map < mmhg or use of vasoactive agents or blood lactates > mmol/ were selected for study. a nasogastric tonometer (tonometrics, inc, plastimed, france) and a swan ganz catheter were placed on admission. phi, lactates, hemodynamics, plasma cytokine and endotoxin concentrations were measured on admission and at . , , , hrs. an immunoradiometric assay was used to determine plasma concentrations of il (n< . ng/ml) and tnfc~ (n< pg/ml). plasma endotoxin concentrations were measured using a chromogenic limulus assay (n< . eu/ml)( endotoxine unit= pg). results : severe multiple trauma patients (age = _+ yrs, iss = -!-_ , saps = +'~, mean-+sd) were studied. they received + packed red cells during the first h. mean duration of collapsus before inclusion was . _+ . hrs. death occm'red in ~tients. ~ pglml, *: ng/ml, etox : endotoxin(eu/ml), lact: lactate (retool/l) a significant correlation between initial il level and saps was observed. in the early post-injury period phi, sao , svo , vo were significantly associated with ;il release (p< . at ho, h , h ). later a significant correlation existed between lactates and ii (h , h ). a peak of tnf was detected at and hrs. it was associated with low phi and low arterial ph of the early post-injury period (p< . iat ho, h , h ,h , h ) and with high lactate levels of later period (_>h ). only the late release of endotoxins (i{ ) was correlated significantly with initial !oxygea-delivered parameters. iconclusion : there was a marked increase in il in the early phase of trauma . i and tnf release after major trauma iwith hemorragic shock is associated with splanchnic malperfusion, as assess by the ivery low values of phi. lactates seem to be a later indice. toxic effects are a well-known complication of an overdosage of prescription theophylline. what is less known is that over-the-counter (otc) asthma medications contain theophylline, and that in some cases this might cause toxic effects. a case seen by us involved toxic effects from theophylline in an otc medication and to date is the only published case in the english literaturet the rationale for this study was to delineate the otc products containing theophylline from whatever data sources available. hyperthermia frequently occurs in intensive care treated patients and intentional application of whole body hyperthermia together with chemotherapy is a therapeutical access to treatment of malignant disorders. anaesthetic support is required in either condition. due to the marked decrease in systemic vascular resistance seen in hyperthermia an additional vasodilatory effect of the anaesthetic is unwanted. the vascular effects of anaesthetics in hypertherm organisms is not known in detail. therefore, we performed an experimental study to detect the effects of inhalational anaesthetics in whole body hyperthermia. in sprague-dawley-rats katheters were inserted into trachea, jugular vein, and carotid artery. for continuous monitoring of cardiac output a flow probe was placed around the aortic arch. the rats were mechanically ventilated with different concentrations of inhalational agents in oxygen. we compared the effects of enflurane, isoflurane, and halothane in stepwise increased body temperature by submerging in a temperature controlled water bath. results: isoflurane lowers arterial pressure more than halothane or enflurane. the inhalational anaesthetics lower the cardiac output similarily and independently of temperature. isoflurane decreases systemic vascular resistance independently of core temperature and the decreasing effect of halothane on the resistance is completely abolished in hyperthermia. conclusions: the influence of hyperthermia on the systemic vascular resistance is dangerous. this allows no additional effect of the anaesthetic management. in spite of the vasodilating effect of inhalational agents in normotherm subjects, this effect is abolished in hypertherms using halothane. the condition of management of analgosedation in hyperthermia is different from normothermia. objectives: to evaluate a bedside computer processed cerebral function monitor for assessment of brain wave activity when clinical/visual clues are not present. methods: ten icu patients undergoing neuromuscular blockade monitored with the aspect brain wave monitor from january to june , . results: time to onset and depth of sedation were readily apparent to icu physicians not specifically trained in eeg reading. objectives: to determine whether non-depolarising neuromuscular blockade reduces oxygen consumption (vo ) in sedated, apnoeic patients. methods: haemedynamic. metabolic and oxygen transport variables were determined in sedated, apnoeic patients with severe acute lung injury. all patients were ventilated using a puritan-bennett ae ventilator with integrated metabolic monitor. inclusion criteria were; ) stable cardiorespirator s" status; ) systemic and pulmonary artery catheters already in situ; ) inspired oxygen < %. patients were sedated with midazolam or propofol to abolish response to verbal stimuli, and sufficient morphine or alfentanil to abolish all spontaneous respiratory efforts. following baseline measurements, neuromuscular blockade was induced with intravenous vecuronium, ug/kg, followed by an infusion of ug/kg/h to maintain the train-of-four ratio at . a further four sets of measured and calculated variables were obtained at min intervals. results: statistical analysis was by repeated measures anova. there were no significant changes in any variable over time. the changes in calculated oxygen consumption (vo fick) , and measured oxygen consumption (vo gas), and in energy expenditure (ee), are shown in the table. objetive: to study the effects on coronary hemodyrtamics and myocardiai metabolism of administering propofol during postoperation sedation of patients with normal coronary circulation and good ventricular function undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mi~-a/ valvular cardiac surgery were selected, with an ejection fraction greater than . and normal coronary circulation. for postoperation sedation propofol was administered in . mg/kg i.v. bolus, followed by a . mg/kgth perfusion. all data were registered before administering propofol and after minutes, the patients being hemodynamically stable and a rectal temperature of _+ . -~ systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabofic variables were measured. results: the patients studied were about years old, and the average period of aortic cross-clamp was . min. the adminstering of propofol caused a decrease in the coronary blood flow (- %), great curonary vein flow (- %), myocardial oxygen consumption (- %), regional myocardial oxygen constanption (- %), myocardial oxygen extraction (- %), regional myocardial ooxygen extraction (- %), while coronary vascular resistances and global coronary vascular resistances did not change. oxygen saturation increased in the coronary sinus (+ %) as well as in the great cardiac vein (+ %). in no patient were significant changes suggestive of myocardial ischemia objectified. there was also found a decrease in systolic (- %), diastolic (- %) and mean (- %) arterial pressure, systemic vascular resistance (- %), and cardiac output (- %). conclusions: in accordance with the clinical conditions of this study, the administering of propofol is not likely to cause changes in coronary autoregulation, oxygenation and myocardial metabolism. obietive: analyse the effects of . % "end tidal" isoflurane (sedative dosage) on the metabolism and coronary hemodynamics during the postoperation period of patients undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mitral valvular cardiac surgery, with an ejection fraction greater than . and normal coronary anatomy, were selected. after the surgical operation, . "end tidal" isoflurane was administered for postoperadon sedation. the determination of variables to be studied was carried out before and minutes after administering isoflurane, die patients being hemodynamically stable and a rectal temperature of _+ . -+c. systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabolic variables were measured. results: the average age of the patients studied was -+ . years. during surgical operation the period of aortic cross-clamp was . _+ . rain. the administering of isoflurane was followed by a statistically significant drop in coronary perfusion pressure (- %), coronary vascular resistance (- %), regional coronary vascular resistance (- %), regional myocardial oxygen consumption (- %), regional myocardial oxygen extraction (- %) and accompanied by a significant rise in oxygen saturation in the coronary sinus (+ %) and in the great cardiac vein (+ %). myocardial oxygen consumption, myocardial exu'action of lactate and regional myocardial lactate extraction did not change. in no patient were enzyme or electrocardiograph changes objectified. systolic (- %), diastolic (- %), mean (- % ) arterial pressure, and systemic vascular resistances (- %) decreased, while cardiac output did not. discussion: the administering of . % "end ddal" isoflurane, in the clinical conditions of this study, produced a decrease in systemic arterial pressure due to a reduction of systemic vascular resistance without deteriorate cardiac output. at coronary circulation level, has and effect on coronary autoregulation but had no effect on oxygenation and myocardial metabolism. the idea of tiva implies the realisation of major anesthesia components (los of consciousness, neurovegetative inhibition, analgesia, myorelaxatiou, providing the adequate gas-exchange) through i.v. introduction of drugs exclasively. aim: providing for the main tiva components with minimal side effects of the drugs used, taking into consideration the patients characteristics and the surgery specific character. methods: anaesthesias have been conducted in patients aged years ( females, males), undergoing planned and urgent operations with the pathology of lower, extremities, perinaeum, small pelvis, hypogastrium and with reserved spontaneus respiration against a background of % insnffladon through mask. operations lasted from . - . h. anaesthesia adequacy was assested by constant monitoring: "cardiocap" (nibr hr, rr, sao , t), through glykhaemia level and mimicry reactions. standart premedicatioo of m-cholinolytics ( . mg/kg) and h -blockers ( . mg/kg) on the operational table was sumplemented by administration of . - . mg/kg of lidocaine, . . mkg/kg of clonidine, . - . mg/kg of pentamidine by the tachifilaxia method. the premedication adequacy was assessed through haemodynamics characteristics. sedation: . - . mg/kg of droperidoi, .l- . mglkg of diazepam and analgesia: - mkg/kg of phentanyl, . -- . mg/kg of ketamine were introduced fractionally according to indications. infusion rate of ringer-lactat solution was - ml/kg/h and depended on the intraoperational blood loss volume and on the patients preoperational condition. the duration of postoperative analgesia was registered. results: clinical assessment of analgesia according to this techniques allowed to decrease the anaigetics dosage to the subauaesthetic levels. smooth stabilisation of haemodynamics (bp) at proper age norms in patients with the initial hypertension by the -th min. of anaesthesia as well as the absence of its increase in response to the additional introduction of anaesthetic have been achieved. (hr) had no abrupt changes and remained in the range of - per rain. adequate external breathing: decrease (rr) by - per rain., with sao increase from % to - %. hypoventilation was avoided by respirate ventilator. according to unauthentic data the glykhaemia level had been lowered by -t % to the end of the operation with the initial moderate hyperglykhaemia of up to mmol/l the cutaneous covering grew warm and got pink colouring. no mimicry reactions. in the postoperative period patients were in the superficial sleep state ( - ) and analgesia lasted - b. there were no complications due to anaesthesia. conclusion: combined using of bz, opiates, neuroleptics potentiate the i.v. anaesthetics effects allowing lowering of each tiva component dosage and, as a consequence avoiding their negative influence on respiratory and heart vascular systems. complex application of adrenergetics (therapeutic doses of cionidine and pentamini with using of taehfilaxy effects) permitted to provide for analgetic and neurovegetative components of general anaesthesia under subanacsthetic doses of tiva main components, and manifestation of hyperdynamic reactions of haemodynamics decreased while using of lidocaine -the economicai activity of heart-vascular system. good level of muscle relaxation was achieved allowing for widening of surgical intervention extent without respirator ventilators and inhalation anaesthetics application. anaesthesia is easily controlled due to fractional introduction of drugs with quick recovery of cns functions after anaesthesia. postanaesthetic analgesia is increased while concurrent opiates doses are decreased. absence of marced haemodynamic, endocrine and metabolic reactions during the operation and after it resulted in shortening the period of patients staying in hospital. a yo white man was admitted to hospital for dyspnea and a productive cough. he had cabg in past, but no recent cardiac ischemia. physical exam: decreased breath sounds over right lung. chest xray: consolidation of right lung. admission medications included diltiazem, furosemide (both were continued) and trazodone (which was discontinued). admission ecg: sinus rhythm, qt . /qtc . sec, with st and t wave abnormalities similar to prior tracings. he required intubation and mechanical ventilation for progressive hypoventilation and hypoxemia. between icu days and he received haloperidol, - mg/d (cumulative dose rag) for agitation and delirium. icu day : qt . /qtc . sec. icu day : for better control of delirium, trazodone " mg q hs was added. icu day : he developed frequent nonsustained ventdcular ectopy. icu day : qt . /qtc . sec, pha . , paco mm hg, pao mm hg, k . meq/l, mg . meq/l. later in icu day the patient had brief episodes of torsades de pointes, each responding to precordial thump, and finally rhythm stabilized with i.v. lidocaine and magnesium. haloperidor and trazodone were discontinued. ecg was unchanged and myocardial infarction was ruled out. next day, icu day : qt . /qtc . sec. torsades de pointes, a form of ventricular tachycardia characterized by a twisting qrs axis, is commonly associated with qt prolongation. haloperidol is used frequently in icu for control of agitation and delirium, with reported doses up to mg/day. over past decade, cases of torsades de pointes with prolonged qt related to haloperidol have been reported. trazodone may also prolong qt and cause ventricular arrhythmias, especially in patients with pre-existing cardiac disease. in this patient, trazodone likely exacerbated qt prolongation from halopeddol leading to torsades de pointes. critical care physicians must be aware of this interaction. it is imperative to follow the qt interval for patients receiving halopeddol, especially when another drug also known to prolong qt is added. one must consider discontinuing the drug when qt/qtc becomes prolonged. objectives: analgesics and intravenous anesthetic drugs are routinely used in critically fll patients, who often suffer from a secondary impairment of the immune system. previous in vitro studies have demonstrated inhibitory effects of these drugs on polymorpho nuclear cells (pmn). the potentially important role of endothelial cells (ec), however, was not investigated, since suitable test systems were not available until recently. therefore a physiologically more relevant in vitro migration assay through cultured human endothelial cell monolayers (ecm) we established. using this assay system, the comparative effects of fenlanyl, sufentanil, propofol and the known pmn inhibitor thiopontal were tested. methods: human umbilical vein endothelial cells (huvec) were isolated and cultured on microporous membranes (cyclopererm) until an ecm was grown. pmn from male and female volunteers were separated by standard procedures. ecm and pmn were preincubated with clinically relevant concentratious of thiopental ( m), propofol ( p_g/ml), the solvent of propoful (intralipid), fentanyl ( ng/ml) and sufentanil (sng/ml). after preincubatiun (ecm minutes, pmn minutes) with the reslx~tive drug, leukocyte migration towards the chemoatfractant fmlp ( o - m) was measured in a two chamber well system for hours. the migration rate of untreated (untr.) and treated (treat.) pmn through untreated and treated ecm were determined. as a control untreated pmn and untreated ecm were used. results are given as means from independent duplicate determinations and expressed as a percentage of control (table) . statistical analysis was done with student's t-test. results: clinical concentrations of fentanyl, sufentanil and prupofol showed similar inhibitor~ effects as the known pivin inhibitor thit e ). % conclusions: for the first time we could show that analgesics and anesthetics exert their inhibitory effects not only on pmn, but mainly on the interaction of pmn with endothelial cells. moreover, we could shmv a significant suppressive effect of the opinids fentanyl and sufentanil on both ec and pmn. the known inhibitory effect of thiopental obtained in ec-free test systems were also confirmed in our physiologically more relevant assay system. objectives: to investigate when and how sedation is used in a consecutive cohort of patients admitted in a large sample of italian intensive care units (icus), gathered in a network named giviti, representative of the italian icus system. methods; the study called for a recruitment period of one month, from january to february , , data collection included age and other demographic variables, acute diagnostic broad profiles, severity of illness scores, treatments, lenght of stay and vital status at icu discharge. as concerned sedation, each patient was observed until discharge or for a maximum period of seven days. information on all the drugs used for analgesia/sedation, the route and modalities of administration, the timing, dosages and purpose of the administration have been recorded. results: the study involved the cooperation of icus, of which enrolled at least one case. the total sample included patients. overall, . % of patients analyzed (t / ) received at least one prescription of sedative during their stay. globally, at least one sedative drug was prescribed to these patients in days in icu. although over drugs were reported to be used, pharmacological principles accounted alone for % of all prescriptions. opioids were actually used in % of prescriptions; propofol in % and benzodiazepine in . %. as regards the way of administration, intravenous administration was applied in % of cases and, followed by intramuscular in . %. moreover, non-steroidal anti-inflammatory drugs (nsald) were used in % of patients and neuromuscular blockade agents (nmba) in %. detailed analysis on certain subgroups (surgical, trauma, ventilated patients etc.) have been also carried out in order to describe the practice of sedation in these peculiar subgroups. findings will be widely discussed during the presentation. conclusions: these results should be interpreted keeping in mind how peculiar is the intensive care setting compared to many other less complex settings of hospital care. in conclusion we thought it was important to present the data currently available in the most neutral form, to start moving in a direction which will enable us -by means of more specific and detailed studies, and with the cooperation and involvement of all those participating in the project -to shed light on one of the many aspects of medical practice in the field of intensive care which deserve closer attention. introduction: the aged run perilously high risks in cardiac surgery: among others, of haemodynamic fluctuations, respiratory depresskm and organ failure. response to anaesthetics is a crucial determinant for post<)perative complications, none the less being reintubation due to mechanical ventilation difficulties which increase morbidity, mortality and intensive cdre unit (icu) stay. objective: we wanted to assess our a,aesthesia window (selection, and a view of the induction -extubation period) for predicting safe and swift awaking, thus: icu dismissal for the aged. methods: in , selected patients (pts) (> y, f) followed a regular elective cardiac surgery protocol (propofol given at precisely designated time intervals). upon cu arrival, they were subjected to an admission protocol. our predictive criteria for early extubation at h included: a) alertness and ready response to commands; b) adequate gag reflex and sufficient protection for respirak)ry tract; c) pao > mmhg with flu < . ; d) stable ph> . with spontaneous respiration; d) stable haemodynamics without dysrhythmias; e) adequate perfusion and diuresis (> .(i ml/kg/h); f) mediastinal bfeeding< ml/h for at least h; g) normothermia (core temp> ~ and no shivering). subsequent reintubation was for: ) rr> /min; ) spontancx)us ventilation for rain with paco > mmhg; ) pao < mmhg with fio > . ; ) ph> . ; ) heart rate>] bm; and/or ) non mental alertness; and ) other medical disorders, after which adequate weaning therapy was necessary. then, successful weaning after h was considered: ) spontaneous breathing without any forrn of mechanical assistance; ) stability in haemodynamics; and ) elimination of fever threat. results: pts ( %) were extubated at h without complication; other pts ( %) at h but had to be reintubated because they were hypoxic and began weaning therapy; finally, they were all re-extubated by h. only pts ( %) proved problematic. conclusion: a,aesthesia wimhlw options (selectkm, extubation, reintubation and weaning) predicted quick (times propofol administration) and safe (rigid criteria) extubation ( %= h and %= h), exempting pts with developed post-operative complications ( %=extubation< h) unrelated to al~aesthesia window or icu protocol. dismissal and recovery then became an abbreviated question of time. fifisetll p, domeneg~i ~, sforzini i., veronesi i~, maconi a.g. *, breg~ massone p.p h [] ic+pca request conclusions:using e~aprenorphine, a synthetic,long-acting, ago-antagemist opinid drug as analgesic, in the major surgery we obtained the best clinic results with association of conttheus infusion of haft dose drug with bohts of pca in the first - hours and just pca in the secmad day after surgery when the patient is less sleepy. in this way we dent have a great sav~g of suppled drug but the major well-belng of patient without ~erious side-effects and quick mobilization; the dosage used don't compromise a good awake of patient: all patients are sleepy but ready for answer, no allueinatian, bradipnea but not less than b/m without ipoxia. also the patient proffered this kind of truit meut than the traditional at demand. the ward staff feel it useful] and rehabl~ the negative feed-back technology of the electronic infuser system makes possible to use it safe in the ward with high drug's concentration too. the infusion rate of low dose of drug assure a continuative analgesic covering ~n the first postoperative periad; the pca mode involves the patient him-self in the managemenl of therapy and enables him to choose the best way to confront the dll~icuity of postoperative period without call medical stall using pca-device we have had no probicm~ no accident. analgesia during extracorporeal shook wave lithot ripsy a .levit, b.grinbezg regional hospital, ekaterinbu~g, russia b~ectives: our task was to compare ~he analgetic effect of norphin and tramel. methods: study was made of two groups of uro-li~patients aged - . group a ( patients) received baprenorphine hydrochloride (norphin) at dosages of #. • mg/kg. group b ( patients) received tramadel hydrochloride (t~aasl) st dosages of . z . mg/kg. before the procedure diazepam was administrated i.v. ( . ! . mg/kg). blood saturation (spoz), hemodynamics incides (bp, hr,sv,co,sap,svr) were examined and the patients' subjective assessments of snsesthesis quality were analyzed. the hospital ethics committee approved the investigation. results: when using norphin hr increased by . % on the onset of the procedure while sap and sv decreased by .%% and . %, respectively (p< . ). however, there were no reliable co chsnges. spoz ~educed by @. % (p< . ) and remained lower than the initial one after the procedure was oyez. when administrating tramsl min. after ste~ting the procedure sap and svr increased by ~ . % and . % respectively. sv and co decreased insignificantly. nine patients in group b saffeting some dlscomfo~t needed additional tm~msl in~ection. in the course of the whole p~oced~e spo, was constant and was highez than that in ~he case of nozphin (p<o. ). conclusion: respiratory suppression by no~phin can limit its use in case of lithotzip@y while the advantages of tremsl a~e: lack of dyspnoe and good contact with the patti-b_ the role of uncommon agents of antinociception, placed epidurally, in the control of pain transmission in the spinal cord is well documented. somatostatin as an inhibitory agent is found in the dorsal horn of the gray matter of spinal cord. the effects of somatostatin is similar to the opiates if injected into the epidural space (ref. i, , , ) . the aim of the present study is to present the clinical effect of above mentioned palliative therapy in the case of cancer and non cancer pain. informed consent had been obtained from every patient before treatment was initiated under the legalisation of the local ethics committee. using the permanent epidural catheter and continuous infusion pump, we administer somatostatin in the dose of up to microgram per hour for one up to three days. the patients paln feeling was evaluated using a vas (visual analogue scale). we found that the opiate resistant pain level decreased by %. the rest pain could be controlled by pereral opiate analgetics or by combination of somatostatin and an opiate plus a local anaesthetic agent epidurally. theoretically, it seems that epidural administration of somatostatin and local anaesthetic agent is useful in the control of acute pancreatic pain and systemic effect of somatostatin is beneficial in the treatment of acute pancreatitis. few studies have been performed in the critically ill (ci) and because of the complex pharmacodynamic and pharmacokinetic changes that occur, it is difficult to predict accurately drug responses and interactions in individual patients. midazolam (m) is a watersoluble benzodiazepine with a rapid onset and short duration of action in normal individuals; however its metabolism is decreased in the ci. critical care physicians every day experience suggest that among the ci there is a different pattern of response to m; here it is hypothized that such a response could be due to different metabolic behaviours of ci. m (i.v.infusion rate - rag/h) and antipyrine ( rag p.o.) were infused to ci with ( patients -group ) and without ( patientsgroup ) endotracheal intubation. blood samples were collected at fixed times during and after m infusion. total urine nitrogen and antipyrine elimination half-life demonstrated different metabolic characteristics in group chypermetabolizer") as compared to group chypometabolizer"). results follow. the results of our study are preliminary and more kinetic data in critically ill patients are needed to statistically confirm our approach of "hypometabolizer" and "hypermetabolizer". objectives: some clinieai and experimental studies suggest that propofol decreases myocardial contractility in coronary artery bypass grafting (cabg) patients. the intrinsic negative inotropic action of the drug may be independent from changes of preload and afterload, whereas the myocardial depression induced by propofol may depend on changes in ca ++ ious availability. aim of this study was to verify the hemodynamic effects of propofoi in a group of cabg patients with uneompromised contractile function and to minimize myocardial depression, during induction of anesthesia, choosing to associate calcium chloride (cac ) in an other group and to define its role in producing this effect. methods: fourty patients, randomly divided in two groups ( pts a and pts b), undergone elective cabg, were enrolled in this study. anesthesia was induced by senior anesthetist in both groups by means of fentanyl mg• kg < in ", pancuronium . mg x kg - and propofol mg • kg - in ". a blind investigator administered via another venous way at same speed ( ") saline in patients of group a and mg x kg - cac in patients of group b. hemodynamic data (heart rate hr, mean arterial pressure map, mean pulmonary artery pressure pap, pulmonary capillary wedge pressure pcwp, central venous pressure cvp, cardiac index ci, stroke volume index svi, systemic and pulmonary vascular resistances indexed svri and pvri) were obtained at baseline (to), ' after anesthesia induction (t ) and " after tracheal intubation (t ). results: hr decreased moderately in both groups (p = ns). map decreased as well, more markeatly in group a at ti and t . this trend was statistical significant (p < . ) in both groups. pap, pcwp and cvp unchanged following induction in any of two groups. ci decreased in group a (p < . ) dramatically dropping at t , while in group b it showed a negligible decrease at t (p = ns) and value similar to baseline at t . svri and pvri did not exhibit statistically significant changes. conclusions: the use of propofol as a starter of anesthesia in cabg patients allows to reduce total dose of fentanyi, dramatically reducing post-operative intubation time. propofol-fentanyl association prevented the hyperdynamic response to stress (i. e. laryngoscopy, intubation) but severely depressed ci and svi. cac simoultaneous administration effectively minimized the negative inotropic effect of propofol. moreover no unwanted side-effects due to cac were observed. diseoordinated labor activity (dla) is one of most serious in obstetric pathology.medication sleep effect to a woman in birth is of limitation of pathologic impulsation from the central nervous system, but it does not influence processes resulting in and supporting dla on the organ level. constant discoordinated uterine contractions during medication sleep (ms) imerease disturbances of uterine blood flow, organ hepoxemia connected with hyperergia of vascular wall and myometrium to catecholamines, that reduces efficiency of anesthesiologic protection. we applied hexoprenalin in complex with ms to primaparas. efficiency control was being accomlished through hysterograms, grade scale of analgetic effect where hemodynamics reaction to pain, significance of emotional reactions and their vegetative manifestations before and during ms were registered, and also through hydrocortisone level in plasma before and during ms. the examined women's average duration of ms was hours more than in control and made hours, though their average labor duration and in control was the same and made hours. % of the examined women experienced independant labor, as for the control group -only %. supplementary methods of anesthesia were required in % in control,that increased medicamentous depression of the fetus, but for the examined group -only in %. the examinees's newborns experienced favourable terminations, in control newborns were in state of light rate asphixia. analgetic effect was complete in control just in i %, and of examinees -in %. on the women's hysterogrnms before ms discoordinated contractions were registered on the background of increased tonus. during ms in control similar uterine contractions were constantly registered, but for the examinees they were not marked at all or had the proper character. the examinees' hydrocortisone level was reduced for % and in control only for %. the study has allowed to make a conclusion that hexoprenalin applications in complex with ms in case of dla make anesthesiologic care safer and more effective, promote simultaneous removal of patholgic processes in the central nervous system and uterus, which lead to dla development. objectives: the aim of report is to present a clinical study results for the evaluation of anesthesia for a patients in unconscious states by eeg examination: methods: the study was conducted on patients after a severe abdominal operations on stomach and intestine and on one patient after traumaticat exarticulation of upper extremity. all patients have different unconscious state levels from somnolence to coma ]. also thay hav~ had respiratory insufficiency and control mandatory ventilation have been used. we were used intrave,~ous injections of morphine hydrochloride from initial dose of mg. than we were increased the dose to mg i.v. by drops with an accompanying eeg monitoring and fourier spectral analysis. initially all patients have had -rhythm with slow and a-activity. an c~-activity index have been lower than %. results: after anesthesia the o-and a-activity have disappeared. the or-activity index have increased to %. also we have noted decreasing of the unconscious state levels to a possibility of a verbal contacts ( - points gcs). conclusion: the quality of anesthesia could be evaluated by eeg monitoring. a regaining consciousness afte~ the injections of high doses of morphine, probably, may be a result of an opiate deficiency (full or partial). anesthesia with the following drugs: clonidine, l-arginine, l-n-arginine-methyl-ester (l-name), and their combinations. tail-flick latency (tfl) was determined at time zero and min after each treatment. clonidine (i- ~g/mouse) prolonged tfl in a dose-dependent manner. at a clonidine concentration of gg/mouse, tfl increased . -fold compared to time zero. l-arginine increased tfl at a high concentration (i gg/mouse). l-name suppressed tfl . -fold compared to time zero at a concentration of gg/mouse. conclusion: we have found that no is involved in clonidine spinal analgesia. studies are currently being undertaken to assess the effect of combination treatment of the above drugs on clonidine supraspinal analgesia. objectives: hemodynamic changes ussualy accompany laryngoscopy and tracheal intubation.the aim of this prospective study vas tu present the effectivness sufentanil in preventing reflex circulatory respone of laryngoscopy and tracheal intubation and provides stable hemodynamio condition for induction of balanced anaesthesia. methods: adult asa i-ii patients sheduled for elective surgery.they were allocated randomly and divided into two groups:fifteen patients received single bolus of placebo prior to laryngoscopy.and tracheal intubation. anaesthesia induction was then performed with thiopental (smg/kg) and atracurium ( , mg/kg), followed by neurolept anaesthesia. mean arterial preassure (map) and heart rate (hr) were measured before, during and min after intubation. althought ecg was recorded at the same time intervals. results: the groups were compared with regard to the changes in arterial blood pressure,heart rate and electrocardiogram. mean arterial preassure and heart rate were incresed significantly during and after laryngoscopy and tracheal intubation in control group but remained unohange the baselin values in the group who received sufentanil. control group ecg suggested more changes than sufentanil group. conclusions: the results indicated that , mg/kg sufentanil for anaesthesia induction reducing the pressor response to laryngoscopy and tracheal intubation. obiective: the aim of this experimental study was to evaluate morphologically the influence of anesthesia in liver as well as in isolated hepatocytes (hc). methods: a total of female swine ( - kg) were used as liver donors and were randomly assigned to one of two groups regarding anesthesia protocol: group a (n= ): induction with intravenous sodium thiopental in a dose of mg/kg, group b (n= ): propophol in a dose of mg/kg for induction'and mg/kg/h for maintainance of general anesthesia. both groups were under the same preanesthetic regimen (diazepam, ketalar and atropin) and received standarised doses of fentanyl and pancuronium during anesthesia. in beth groups total hepatectomy was performed and the liver was perfused with - it of cold ( oc) university of wisconsin solution for a period of hours before hepatocyte isolation. liver tissue samples were fixed in formalin for the morphological study and stained with hematoxylin-eosin and pas. for hc isolation collagenase solution (type v, sigma, c- , . mg/ml) was infused via portal vein and the liver was incubated at oc for rain. cells were filtered and then washed in cold hanks' solution. isolated hc were fixed and prepared for staining or simply cryopreserved (- oc). results: histology was completed in / experiments ( in group a and in group b). mononuclear infiltration (halothane type injury) was found in all specimens ( / ). focal zonal necrosis and acidophilic bodies were found in specimens from group a ( / and / respectively) while portal inflammation with piece meal necrosis was found in one specimen from group b ( / ). smears of hepatocytes -beth formalin fixed and cryopreserved at - oc -were stained with hematoxylin-eosin and showed morphologically intact hepatocytes. conclusion: pre[imineq~' study of our material reveals mote frequent livet injury in the thiopental group, but this finding has yet to be established by increasing the number of observations. objectives: in this paper we present our experience and point out the importance of sedation of those patients who suffered severe head injuries/contusic cerebri with signs of decelebration/and who were put on ventilatory machine to obtain better mechanical ventilation in neurosurgical intensive care unit of emergency center in belgrade. methods: patients were treated from jan. till dec. results: in patients we successed to reduce agitation and decelebration. conclusions: the major demand of sedation in neurosurgical patients are that the patient should be calm, comfortable and painless. references we compared three analogous groups of patients in each, with orthopedic operations on lower extremities. in each group we applied different kind of analgesia: first group rece-ned local anesthetic ( ml . ~ bupivacaine) when analgesia was first demanded; second group received ml fentanyl via peridurai catheter when analgesia was first demanded, and third group received m] fentanyi intravenously on demand for analgesia. we used visual analog scale (vas) for estimation of pain intensity and success of applied therapy. statistical data analysis was performed using student's t-test. tha best vas had group in which local anesthetic was applied periduraly. second was the group with periduraly applied fentanyl, and third was the group with intravenously applied fentanyl the longest duration of the effect of analgesia ~/as in the second group. there were no adverse effects and complications, apart from mild sedation in the third group. for orthopedic operations on lower extremities, application of peridural catheter for anesthesia and successful postoperative analgesia with local anesthetic, or opioid analgesics is acceptable. background and obiective : tympanic temperature measurement (ttm) is a relatively new procedure which provides accurate estimates of core temperature in stable postoperative patients and in patients admitted to the emergency ward. however, experience with this technique in hemodynamically unstable adult icu patients is limited. design : prospective study with patients serving as their own control. se:ttijlg : adult medico-surgical icu in a tertiary care hospital. patients : consecutively enrolled patients with thermodilution catheters in place and without contraindieation for rectal temperature measurement and without hypothermia (core temperature < ~ interventions : tympanic temperature, measured by a commercialized tympanic thermometer (genius a first temp) was compared with pulmonary artery (pat) and rectal temperature (rt). within minutes, core temperature was assessed in each patient by the same trained individual using the three techniques in random order. measurements and main results : mean bias (ix~ and its variability (sdr of method comparison pairs were calculated using the methods comparison analysis as described by bland and alunan (lancet, ; i : - objective: to measure the prevalence of pressure sores on the intensive care unit and the effect of risk calculation on pressure score prevalence and pressure score severity. method:in during a period of months a series of prevalence studies was carried out on the sicu to investigate how many patient days with pressure sores were taken care for by the icu nursing staff, what kind of preventive interventions were done and what the patient risk was on developing a pressure score. results: on average there was a prevalence of pressure sores on the buttocks of . % on the short stay unit and . % on the long stay unit; preventive interventions increased when the pressure score was visible for the nurse and the majority of patients had a high risk or extra high risk for developing pressure sores according the pressure score risk calculator. as a result of these findings the nursing management decided in that nurses had to complete daily on every patient the pressure score risk assessment in order to be able to take adequate preventive interventions. when the results of the two studies were compared, the most important results were that: ) there is no indication of a reduction in patient days with pressure sores (short stay unit: %, long stay unit: %); ) there is a reduction in severity of pressure sores (grade iv decreased from . % to . %) because adequate preventive measurements are initiated by icu nurses in an earlier stage. possible explanations for the increase of patient days with pressure sores on the long stay unit are that the average pressure score risk score was increased from . to . and the mean frequency of nursing patients on alternate sides decreased from . to . times each day. conclusion: daily assessment of the individual patient risk on developing pressure sores does not decrease development but reduces the severity of the developed pressure sores. method: the conventional woundcare method of patients with an open abdomen is to change frequently the saline soaked ribbon gauze pads ( - times each day). this method is labour intensive for the itu nursing staff and rather uncomfortable for the patient. problems that often occur are: insufficient hygiene, frequent nursing interventions, a progressive risk for deterioration of the skin and underlying tissues, difficult to measure abdominal output and in case of bowel fistulas enteral feeding is hardly possible. in using the new method, stomahesive is applied on the skin surrounding the wound. a large size of surgical film dressing, opsite | is applied over the abdomen. two or more foley ~ catheters ch are inserted through an opening in the surgical filmdressing. the application of several lateral openings in the catheters is advised. the drains are held firmly in place between two layers of sterile opsite | "flexigrid ~'' x with the so called bookend method and are connected to a low vacuum suction system ( - kph) results: we studied the frequency of dressings changes on patients in the itu. in total they had days with an open abdomen. during this period there were dressing changes. this means one dressing change every days. further advantages of the new method are; more hygiene in patient care, no maceration and irritation of the skin, nursing on alternate sides is possible, output can be measured, in case of bowl fistula, enteral feeding is possible and an abdominal lavage is possible on the sicu by opening the opsite | conclusion: this new method of woundcare management is more patient friendly, prevents several nursing complications and decreases the work load for the nursing staff. objective: to investigate the interaction between the ventilator and the closed suction system related to possible induced negative pressure by this sytem. method: we studied in a testlung model what the effect was of the different ventilators (evita: dr~iger; servo c: siemens), ventilation modes ppv, simv) and ventilator settings (tv, trigger level, frequency, peep level) on the induced negative pressure by the closed suction system during suctioning. results: when using the evita the magnitude of the negative pressure increased when the ventilation frequency and tv decreased.. the largest negative pressure (- cm h ) was produced with a tv of ml and a frequency of /min in the ippv mode with trigger level on - cm h and a peep level of + cm h . the servo c showed a complete different pattern. the largest negative pressures were measured when no trigger level was set ( cm h ), the induced negative pressure was not depended on the tv or ventilation frequency but more depending on the ventilator mode. the simv mode produced the smallest negative pressures ( - cm h ) and the ippv mode the largest ( - cm h ). conclusion: the effectiveness of the closed suction system is very much depending on the kind of ventilator, ventilator mode and ventilator setting that is used. if the interaction with the used ventilator is not known by the icu nurse this piece of equipment can cause damage to the patient by inducing large negative pressure in the comprimised lung and there fore creating the possibility of alveolar collaps and atelectasis or oedema. introduction : ethical problems are daily and disturbing preoccupations for the icu staff. objectives : improving ethical management in icu by creation of an intelprofessional group of ethical reflexion ( iger ). methods : existing was evaluated by a preliminary formulated series of questions sended to the whole staff (q , n = , items) after two training sessions (laws, deontology, professional values, culture, norms of quality) followed by persons ( %) and directed by an external chairman, satisfaction and needs of the staff were evaluated by a second series of questions (q , n = , items). at the issue, iger was created. results : q : responders ( %). law's misinformation : to %, disagreement for limitation of intensive cares : %, hope to improve collective decisions and creation of iger : % q : responders ( %) : satisfied by the training sessions : %, non satisfied : %, want to continue the project : %, refuse : %. iger was constitute by physicians, nurses, secretary, dietetic (n = ). the first working theme was {< therapeutic's withholding and withdrawing decisions in icu ~>. four subgroups of iger's members (having access to an ethical library) worked independautly and submitted their reflexions in a tdmestrial plenary session of iger in the presence of an external chairman, allowing a synthesis. at the issue a report was writted to be used as a reference for bedside and individual decisions. conclusions : constitution of iger seems to improve ethical management in icu. the first result of iger is that it is now possible to began collectively a reflexion concerning therapeutic's withholding and withdrawing in icu. the work is going on and further subjects will be studied. objectives: ) to compare the value of heat-moisture exchangers with bacterial filters (hmef) and without bacterial filters (hme) in the prevention of colonization of ventilator tubing and ventilator-associated respiratory infections. ) to asses the temperature and relative humidity of inspired all using both types of heat-moisture exchangers. methods: mechanically ventilated patients were randomized, to either hmef or hme. endotraeheal aspirates, pharyngeal swabs and samples from tubing were collected for bacterial cultures on the st, nd day mechanically ventilation and weekly thereafter. temperature and relative humidity were measured in patients ( hmef and hme) h and h after placing the hme or the hmef. results: both groups were comparable as regards age, mechanical ventilation period, severity score (saps ii), leukocyte count, and number of patients with prior antibiotic treatment. from the hmef group, ( %) ventilator tubing yielded microorganisms in, at least, one sample as compared to ( %) of the hme group; p=ns. the incidence of respiratory infection was similar in both groups ( % vs %, p:ns, for hmef and hme respectively). among the bacterial species isolated from ventilator tubing in the hmef group, ( %) were not isolated from pharyngeal swabs. a similar ratio was shown in the hme group ( / , %). both heat-moisture exchangers were efficacious in keeping a good relative humidity of inspired air ( % • vs % • .%; p=ns, for hmef and hme respectively). relative humidity was significantly higher after h of mechanical ventilation in the hme group as compared to hme group ( . % • vs . % • %; p= . ). conclusions: both types of heat-moisture exchangers have the same effect on the prevention of colonization of ventilator tubing. similar relative humidities are achieved when using either type of heat-moisture exchanger. results: tumor and nontumer enhrgements of the thyroidea were present in ~ of the operated, surgicel adrenal disease in io!, hyperplssle or persthyroid gland tumor in ~ end endocrine pancreatic tumors in %. in the intensive oere unit, these patients wore screened by noninwsive monitoring in ~ of cases: and invasive monitoring was applied in % of ceses.the basic noninvesive methods included: electrocardiogram with standard end precerdial leeds, percutaneous eutomotlc measurement of systolic, diastolic and mean arterial pressure, measurement of hourly diuresis and body temperature, frequency, hearing capacity and rhythm of one s own breathbng bs well as pulse oxymetry. a special plece in monitoring and control of vital parameters in postoperative period belonged to the nurse, thoroughly trained for enelysis end interpretation of the observed parameters which would be discussed in the paper. it has been believed that the leader sits at the pinnacle of power. over the years, this has proven to produce frustruation and anguish instead of the expected results. leaders have not been able to produce the changes they know are essential to their organization's survival with this command-and-control paradigm. through literature reviews and evaluating leadership styles, one can clearly see the most effective form is that of empowering people to a new level of performance -not ordering it. changing the leadership paradigm to a manner/style that has been shown to be effective and one of people empowerment shifts the focus to personal responsibility for performance. removing obstae}es~ stimulating self-directed actions, and determining focus and direction are just a few elements used to create the successful environment of empowerment. with increasing pressure in the health care arena, it becomes critical that a leader's job is to get the people to be responsible for their own performance. developing ownership, creating an environment where people want to be responsible, being a mentor or coach, and learning faster while encouraging others to do so demonstrates the commitment to effective leadership. this presentation will illustrate the critical components that are achieved when every person in the institution is empowered to perform at a level that is directed toward positive, effective results. herrera m. (md) . icu. hospital regional. malaga. spain. the systems of veno-vanous continuous haemofiltration (wchf) have a high cost and a limited life span. in an attempt of lengthening their mean life it has been proposed to accomplish programmed washes of the ~-stems. this practice supposes an increase in nursing workload. in order to evaluate the real efficiency of this practice we have accomplished this study. material: prospective randomized study of all the filters of vvchf used during the last year in our icu. we have determined two groups of filters, in the first (group a) we accomplished washed in a programmed way, and in the other (group b) only when the alarms of the system suggested a clotting of the filter. for the statistical analysis we used the kaplan-meier test for survival analysis. results: we have studied a total of patient submitted to wchf during the last year. we used a total of filters with this results. objectives. sounding out the nurses about the need to inform patients" relatives and the rigth kind of such information, like a preliminary approach to an information cuality assessment, methods: we inquired all the nurses of the intensive care unit of an regional hospital by an semiestructurated questionary which included personal data: age, sex, contractual relation, professional experience.., and opinion data: do you think to inform relatives is a nurse task?. which of the next informafions do you think is more important?, please, write others topics about information you think are relevant. we process the data on epi-info estatistical program and use x test to compare the results. results" from nurses of staff refused to flu the quetionary, and were not available. of the remaining, %were v~men and % men. the mean age were . % had an svable contract and ( eventual, the mean professional experience were of years and % worked in the unit since more than years. the % answered that offer information to relatives is part of the nurse activities. we did not find differences with nurses who answered negatively comparing by sex, age, contractual relation or proffesional experience. the three information topics found out like more important were: ) to inform about patient mood. ) to inform about happenings from the last visit. ) to inform about dressing instrument required by the patient, nurses who answered negatively think that to inform is a doctors task or that nurses are not competent. conclusion~ intensive care unit teams (nurses, doctors and auxiliar personnel) should get accord on who and how to inform relatives, we consider the nurses' role on information as unquestionable. objective: investigate the respiratory and cardiovascular response after discontinuing oxygen therapy durir~ intr~/]o~pital transport. desiqn: fifty-one patients ( male and female, aged + , and , , years respectively, ~+sym) being on therapy were studied prospectively in two consecutive intrahospital transports. oxygen therapy was continued in the first transport while the second one was performed as usually, i,e, without . during transport each patient was monitored by pulse oxymeter and holter whereas arterlal blood gases were tested just before a~xl aft~-trar~portation. results: compared to daseline, pa and sa were signif~canthy decreased in the case of oxygen discontinuation (p< , i). paco was significantly inur~ds~i only in the subgroup of patients with obstructive lun[ disease (p< , ) . heart rate increased in all phases of the transport when administratlon was discontinued. blood pressure remained stable in either case. the percentage of supraventricu!ar extrasysto!es, ectopic v~r[hicui~r contractions and st-s ~ment depression was progressively increasing and became very high at the end of transport in the case of therapy discontinuation. other arrhythmias did not change significantly. conclusion: discontinuation of oxygen therapy during intrahospital transport causes severe drop of pao and sa , increases the heart rate and contributes to the appearance of arrhythmias which were not present before. methods:for evaluation of the functional state of brain the complex of methods was used,whieh included electro encephalngraphy ( brain mapping ), rheoencephalography, tetrapolar transtorax rheography. for the estimation of humoral status the level of histamine and serotonine, products of free-radical oxidation,enzimatic markers of ishemic damage of brain and of endogenous intoxication was investigated. results: patients with encephalopathies after resuscitation were observed.asystolia was as a result of:shock, trauma, asphyxia,poisonings,appiication of drugs, eclamp sia,injury of the heart,diseases of fhe cardiac vessels. all patients with postasystolic syndrome entranced in comafose condition.in the group (reconvalescents) the depth of coma by glasgo~ pittsburg"s scale was , +- , . the duration of coma was from rain. to hour,average , +- ,sh.ln the group (the deads) the depth of come was , +- , .the artificial lung ventilation was used in all patients:in the group , +- , days,in the ~ , +- , days.apallish syndrome developed in cases,in patients diagnozed <<brain death~. the th degree encephalopathy (coma) was found to be associated with disorganized eeg-pattern with predomi nant alpha-( group) and slow ( group) activity. the relative power of delta-and theta-ranges was about - per cent.the patients with apallich syndrome demonstrated greatly elevated theta-range power, that of beta -range was essentially decreased. the degree of disturbances of circulation in the both groups was different.cardiac index (ci) and stroke index (si) in the group decreased on , % and , z, in the -on , % and (; , %.general peripheral resistance (gpr) increased in the group on , %,in the -on (; , %.in the group brain blood flow was increased, in the -decreased on , n.in the group there was the normotonic type of reg-curve,in the -atonic or hypotonic type (without reaction on pharmacologic influ ence).disturbances of permeability of cellular membranes (enhanced free-radical oxidation with an increase in di enic conjugates on and n) and vascular ones (an increase of serotonin concentration on and %, hi stamine content on and %) resulted in hyperfermentia (an increase of concentration of creaune phosphoki nase in the group on %,in the - %.the level of middle molecules (mm) increased in the group on , %, in the -on , %,of polyamines (p) (spermidin,spermin,putrescin).coefficient of correlation between mm and p was , . immediate correction of neurocyte metabolism is impossible due to marked brain oedemaswelling,severe dis ordes of cerebral circulation, disturbances of membrane permeability.thus,the following treatment algorythm might be advisable: . protective inhibition of brain and reduction of its energy requirements. . recovery of cell and vascular membrane fuoctions. .recovery of blood circulatiom .oxygenation of nervous tissue and drainage of brain disintegration products.in patientshbo carried out. .active methods of detoxication (homo-and enterosorption). .correction of cerebral metabolism. . dehydrative therapy must be very cautious. conclusion: the activation of energetic metabolism in neurocytes must be carred out only under neurophysiolngical control and after definite preparation. ( ). the clinical estimation of acute cerebral failure carried out by olasgo-pittsburg"s classification of coma. we studied such groups of patients: poisoning co ( ), asystolia ( ), eclampsia ( ), acute renal failure ( ), control group ( ). methods: electroeneephalngraphy (brain mapping) was fulfilled by means of encephalograph <,medicor ~ in monopolar channels. the estimation of eeg patterns by zhirmunskaya method ( ) was carried out. there were analyzed and changes of eegb by results of rapid transformation furie after rhythmical photostimulation(phts) , , , hz. we studied also the figures of absolute and relative power in such diapason : delta ( - hz), theta ( - hz), alpha ( - hz), betal( - hz), beta ( hz and more). results: all eeo changes were divided into following types: -organized ( , groups); iii -asynehronic ( group); iv -disorganized with prevalence of alpha-waves ( , , groups); v -disorganized with prevalence of delta-and theta activity ( , , ; , groups) akkording to our model of hormonal-metabolic disbalance in pregnancy , one of the main reason of destosis is hypoergos , reesults in endotoxemia and neuro-endokrine disregulation. so, stady of central nervous system function give us the information about adaptation processes. the aim of our work is to study the degree of neurologikal deficit in destosis when olifen and lipin were used. there were studied pregnants with different severe forms of gestosis. the degree of neurologikal deficit was valued by datas of neurologikal status . eeg with ,~brain mappinng~, , electrikal resistance of the skin. the komplex inteensive therapy with applikation of olifen and lipin allowed to improve the patient,s condition , decrease the degree of neurolodikal deficit and mortality . kostenko v.phd,kabanko t.,phd,galalu s.md,beliavtseva n. ,shramenko k. phd intensive care department,donetsk medical university, donetsk, ukraine plasmapheresis (pph),as other extracorporal methods of detoxicatin,has a great importance in contemporary medicine. the role of pph is special,because of its simplicity, effectiveness, atraumatic.we incalcated pph in obstetrical clinic. there are rough changes in agregate condition of blood in more of pregnants.these changes lead to disturbances of central,organ and peripheral hemodynamic.the therapeutic effect of pph is due to influence on agregate condition of blood. we considered that application of pph is very effective in pregnants with:bronchial asthma, severe forms of diabet, psorias, gestosis, allergic diseases. we used the membrane pph in pregnants: apparatus-,,hemos-pf>,, plasmofllter pmf- ,with effective area- cm,the volume of extracorporal contour- ml.such pph has no the ~ agressive effect,,, as in cases of application another extracorporal methods. this method was incalcated in our practice recently, so results will be reported in further publications. ( ). post-operative cerebral neoplasm ( ), post-operative subdural hematoma ( ). icp was monitored via a catheter inserted in the lateral ventricle and values were continuously digitally recorded by means of a bedside computer data acquisition system (maclab). the fiberoptic tracheobroucosenpe, which guided the procedure, was passed between the nasotracheal tube and the trachea in order to avoid hypoventilalion. the patients had stable baseline hemodynaimcs. propofol infusion and fentanyl boli were administered to mantain stable mean arterial pressure values. peak (mean(sd)) icp duping the minutes pre-ciaglia procedure (baseline values) were compared with values during ciaglia procedure, and the minutes p st-ciaglia procedure. data were compared with repeated measures anova. results: ciaglia procedure duration was (mean(sd)) ( ) objectives: transient global amnesia (tga) is a syndrome caracterized by impairment of short-term memory, inability to form new memories, retrograde amnesia and repetitive queries, without other neurological signs and symptoms. the pathophysiology of tga is unknown; thromboembolic, epileptic, migrainous and metabolic mechanisms have been suggested. to address some of these issues, we undertook a study of cases of tga in whom we examined clinical, laboratory data, electroencephalogram, ct of the head, ultrasonography ecodoppler. methods: patients were included in this study: men and women. the mean age was years. all cases underwent a standard clinical examination, electrocardiogram, routinary humoral tests and x-ray, electroencephalogram (eeg), ct scan of the head, ultrasonography ecodoppler. results': the mean duration of amnesia was h. m. +/- h. m. hypertension was found in patients ( %), ischemic heart disease in patients ( %), hypercholesterolemia in patients ( %), hypertrigliceridemia in patients ( %), smoking in patients ( %), atrial fibrillation in patient ( %), history of epilepsy in patient ( %), migraine history was not recorded. ct scans of the head showed multiple small deep infarcts in patients ( %), a single hypodense lesion in patients ( %). in patients electroencephalogram was normal ( %), in patients there were widespread nonspecific electrical changes ( %), in patients there were focal nonspecific eeg abnormalities ( %). conclusion: in our study tga was more common in women ( %). we showed a prevalence of hypertension, hypercholesterolemia and cerebral infarcts compared to normal controls. we have demonstrated a higher incidence of nonspecific electrical changes in tga of lower length, while ischemic lesions in ct of the head were more frequent in tga of greater length. these data seem to be in agreement with the hypothesis that tga is a heterogeneous clinical syndrome, consisting of pure, epileptic, and ischemic types. however we did not find any correlation useful in discriminating pure from associated tga forms. from our study it is tempting to speculate that pure tga is a rare event, underlying still unknown mechanisms wich differ from ischemic, epileptic, migraineous causes. objectives: aneurysmal subarachnoid haemorrhage (sah) is special condition increasing intracranial pressure (icp) in various ways. at the other hand cerebral vasospasm and related delayed ischaemic deficit (did) could answer for the poor outcome. triple h therapy seems today a basic option to prevent did, but it may increase the icp worsening the altered intracranial pressure condition and thereby the cerebral perfusion pressure (cpp). is there any way to individualise the triple h therapy when it is necessary? methods: between sept. march thirty-seven patients with intracranial aneurysms were operated on within hours following sah. five patients were in hunt-hess iv at admission. all patients received triple h therapy in a preventive fashion following surgery and were monitored by daily transcranial doppler ultrasonography (tcd). icp and cpp was measured in twenty-four cases. twenty-two of them received lumbar liquor drainage (lld) and nineteen were administered induced hypertension. the other group was treated by basic triple h therapy. results: in group with monitored icp the outcome was twenty-one excellent, one poor, two died (one of them died from extracranial decease). in the other group four had excellent, six moderate, two poor outcome, and one died. conclusion: according to our recent observation the patients can be divided into two groups of therapy. in group i, the patients with elevated tcd values and either low or high icp reacted to lld. we are concerned that haemodilution and slight hypervolaemia should dominate in the triple h therapy. in group ii patients having high icp with tcd and/or symptomatic vasospasm should be managed by the induced hypertensionhypervolaemia dominated therapy focusing on cpp (icp) and focal neurological signs. air emboli were detected in lo% (n= ) of natients undergoing coronary srtery bypass craftin~ (cabg). central nervous system ~ysfunction occured in ~$ of the nstients with air embnli and in none of those ~ithhout air embo!i. hvtothermia is the classic form of oro-tect~on used dur~nc ~"~" " ~ ~ ca~.,~modu] :r, on~_,_. bj/oass. the surf~eon sho,;,ed thorough!~: evecnnte air from the heart, but the onesthesio!o[[ist can signifieamt!y influence the outcome by emt!oyin ~ methods to detect and treat air emboli. the changes in head rate are primarily due to alterations of autonomic tone. the heart rate variability (hrv), that express the degree of heart rate fluctuation around the mean heart rate, reflects somehow the condition of central nervous system. hrv may be measured by a number of techniques. short-term time-domain variables of hrv are reflect generally the vegal activity. in this study the changes in hrv variables of patients with brain damage, and in addition the changes in hrv measurements in comparison with the clinical evolution were evaluated. eight patient with brain damage and six normal individuals as control group were studied. a elecrocardiographer with availability of computation the sequence of beat-to-beat intervals for one minute was used. the following variables of hrv were measured: ) standard deviation (sd) of beat to beat r-r interval differences that reflects the respiratory control, )the maximum/minimum (max/rain) interval that reflect variability related to baroreflex and thermoregulation and ) the coel~cient of variation (cv), the results are shown in the in the patients with brain death and in vegetate state there were virtually no hrv. increased hrv pattern was found with clinical improvement, the changes of hrv precede of the changes of gcs, we conclude that time-domain hrv could reflects the degree of brain damage, it is good prognostic index of the brain damage and may change earlier than the gcs. objectives: cerebral co vasoreactivity is an important determinant of cerebral blood flow (cbf) and has been shown to be of prognostic value in head trauma (acta anaesthesiol. scand. ; : - ) . we wondered whether co vasoreactivity could be selectively altered in one hemisphere in comatose patients. methods: patients ( m/ f, age - yrs, glasgow - ) in coma due an acute brain lesion (trauma, hemorrhage, or infection) were studied. cbf was measured bilaterally using jugular thermodilution at paco , , , and mmhg by increasing pico with mechanical ventilation kept constant. normal co vasoreactivity was defined as an increase in cbf of at least i ml/min. g per mmhg paco . results: patients had normal co vasoreactivity bilaterally, patients had altered co vasoreactivity at both sides, and patients had a normal response at one side (left or right) with an altered response on the other side (dght or left). for the patients left cbf was in mean ! ml/min. g lower than right cbf (figure methods: following institutional approval piglets (body weight :tl . ) were anaesthetized by % fluothane. a catheter was placed in the right femoral artery for blood pressure monitoring and a fiberoptic catheter (oxymetncs- abbott) was advanced via the right internal jugular vein to the jugular bulb for sjo determinations. another catheter with a balloon on the tip was advanced in the right atrium via the right femoral vein. a mean arterial pressure (bp) at mmhg was achieved by appropriate balloon inflation for rain and two groups were cleated: i) the hypoxemic group by respirator disconnection (*) and it) the hyperoxemic group by fio =l on respirator (o). samples were obtained at time ( ), ' min at hypoperfusion ( ) arid at reperfijsion at ' ( ), ' ( ) and ' ( ). pao , pjo and oxidative brain stress evaluation was performed from jugular bulb blood. the latter included: i) no synthase (nos) and xanthine oxidase (xo) activities by a method based on the oxidation of scopoletin detected fluorometrically, it) no levels estimated as onoo-by luminol enhanced chemiluminescence in the presence of ~tm hydrogen peroxide (h ). resul'~s: the mean pao was mmt-ig for group i and methods: we retrospectively reviewed all upper gi-endoscopies, performed in the period january -july in patients ( men and women) admitted at the icu's of our hospital. results: it concerned surgical, medical, eardiological and neurological patients with a mean age of . yrs (range: - ). in %, the endoscopy was performed at the icu and in % at the endoscopy department. in % of the cases, the endoscopy was primarily diagnostic, of which % was performed for localization of upper gi blood loss. in % the endoscopy was primarily thempentic, of which % was performed for placement of a duodenal feeding canula. location of the upper gi bleeding was: variees ( %), duodenal ulcer ( %), oesophagitis ( %), gastric ulcer ( %), others ( %) and none ( %). as coincidental findings were noted: cesophagitis ( %), gastritis ( %), gastric deer ( %), duodenal ulcer ( %), duodenitis ( %), oesophageal ulcer ( %) and others ( %). conclusions: there were marked differences in indications and findings of endoscopy at the different icu's. these differences reflect an admission bias and differences in populations and treatment preferences. compared with cardiological and neurological icu's, substantially more endoscopies were performed at surgical and medical icu's. in a considerable number of cases, no source of upper gi blood loss could be found endoscopicaiiy. when upper gi blood loss was the icu admission diagnosis, the main cause was needing varices, which could be controlled endoscopically in the vast majority of cases. when upper gi blood loss was ndt the icu admission diagnosis, peigie ulcer and oesophagifis were the main causes of bleeding. because of the considerable number of coincidental almom~adities found at endoscopy, there is still room for debate whether antacid medication and/or motility stimulating agents should be given prophylactically at icu's. many studies have shown that blood lactate levels in survivors and nonsmvivors of traumatic and septic shock are significantly different. the degree of multiple organ failure is related to the duration of lactic acidosis ( ). the aim of this study was to evaluate blood lactate level as a prognostic marker of high risk postoperative patients who may benefit from invasive hemodynamic monitoring and aggressive fluids administration and early inotropic support based on oxygen transport parameters. methods: patients undergoing elective long term vascular and abdominal surgery (asa i-bi) were studied. blood lactate levels were measured after icu admission. in the case of blood lactate level above mmoltl, measurement was repeated every hours for hours or until normaiisation (blood lactate level less than mmol/ ). type of surgery, length of surgery, amount of fluids delivered intraoperatively and postoperatively, hemoglobin levels, hemodynamic variables, diuresis, postoperative complications, length of icu stay and clinical outcome were recorded. because no attempts were made to randomisr therapy or change our standard therapy protocol institutional approval was not required. rebuts: the frequency of postoperative complications was , % and mortafity was , % in a group of patients with blood lactate level less than , mmol/l (n = ). frequency of complications ( , %) was significantly increased in a group of patients with blood lactate levels , - mmol/l (n = ), mortality was , %. mortality ( %) and frequency of complications ( %) were significantly increased in a group of patients with blood lactate levels above mmol/l (n = ). conclusion: blood lactate levels can serve as early marker of high risk postoperalivr patients and may predict increased risk of postoperative complications mad ~e death. objective.~: investigated practicability and clinical value of the routine measurement of hepatic venous oxygen saturation (shvo ) after major liver surgery, as shvo is considered an indirect parameter for splanchthc and hepatic blood flow. methods: consecutive patients were included in this study after liver resections for primary or secondary liver tumors. patients suffered from liver cirrhosis (childs a). immediately after post-operative admission on the icu a pa-catheter ,was inserted under fluoroscopy via the right jugular internal vein into the hepatic vein contralateral to the resection area. hepatic venous and arterial blood samples were drawn every two hours. shvo was correlated to the clinical course, macro hemedynamics, abgs aug other established lab parameters. results: in out of attempts the catheter could be placed correctly. in four cases after right hemihepatectomy the left hepatic vein could not be intubated due to a dorso-lateral tilting of the left liver. this is also reflected in a significantly longer time of fluoroscopy for catheterization of the left hepatic vein ( . _+ % rain vs. . + . rain; p < . ). the procedure requires a total of between and minutes. relevant clinical complications were not observed except for short term supraventricular arrhythmias during passage of the catheter through the right atrium. hemodynamics and pulmonary function could be considered normal in all individuals at time of measurement. shvo showed a span from . % to . % with a mean of . % -+ . %. the following statistically significant findings could be obtained: (a) patients with liver cirrhosis showed a significantly lower shvq than patients without ( . % • . % vs. . % • . %; p < . ). (b) a negative correlation between shvo immediately after operation and the duration of intraoperative hepatic vascular occlusion could be observed (r = - . ; p < . ). this correlation could also be seen for the first post-operative hours (r = - . ; p < . ). (c) a negative correlation between shvo and the difference between arterial and hepatic venous lactate levels was found (r = - . ; p < . ). conclusions: the routine measurement of shvo appears to be a promising extension of post-operative monitoring after major liver surgery. it is a safe method easily feasible on any major surgical icu though relatively time consuming. a further validation of this method is necessary in larger studies. therapeutic recommendations on the basis of shvo findings cannot be given yet. methods: in cases after major liver resection, in which abnormally low readings of shvo suggested an impaired hepatic blood flow, pgi was applied at a dose rate of ng/kg/min. as shvo can be considered an indirect parameter for hepatic blood flow, the effect of pgi infusion on shvo was measured. moreover, the changes of macro hemodynamics and pulmonary function were monitored. results: before the application of pgi z mean shvo for all patients .was . % ( - - - ). in three cases without major structural alteration of the remaining liver tissue the continuous intravenous administration of pgi lead to a sustained increase of shvo z to an average of . % ( . - , ). the postoperative course in these three cases was uneventful. in two cases with compensated liver cirrhosis after hepatitis c no change in shvoz under pgi infusion could be observed. both patients died and days respectively after operation in protracted liver failure. side effects of pgi included a slight decrease of systemic and pulmonary vascular resistances. consequently map decreased by up to % as did intrapuimonary right-left shunt increase. in none of the observed patients did these side effects posed a limitation of continuous application of pgi z. conclusions: in patients without structural alteration of the liver the systemic application of prostacyclin at a dose rate of ng/kg/min could significantly increase an abnormally low hepatic venous oxygen saturation after major liver resections, tn two cases of severe liver cirrhosis a similar increase could not be observed. after first clinical investigations and with the results of recent studies in animal further controlled clinical studies of prostacyclin in the postoperative management after liver surgery appear justified. any delay in gastric emptying can promote micro-aspiration and give rise to ventilator associated nosoarnnial pneumonia. h -receptor antagonists have been suspected of promoting pneumonia by changing the gastric ph. in a few tri',ds on humans ranitidine was noted to delay gastric emptying. the aim of this prospective, randomised, blinded study was to evaluate in a ventilated icu population if there was a difference between cimetidine (c) and ranitidine (r) on the gastric filling index (gfi conclusion: in this population there was no difference in gfi between c and r; however the age and creatinine were significantly different and could have favoured the c group. also the very long t/ could have hidden smaller differences between c and r as has been described in volunteers. between april , and april , , patients with severe acute pancreatitis were admitted to participating hospitals. patients were entered into the study if severe acute pancreatitis was indicated, on admission, by multiple laboratory criteria (imrie score >_ ) and/or computed tomography criteria (balthazar grade d or e). patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination (norfloxacin, colistin, amphotericin; selective decontamination group). all patients received furl supportive treatment, and surveillance cultures were taken in both groups. results: fifty patients were assigned to the selective decontamination group and were assigned to the control group. there were deaths in the control group ( %), compared with deaths ( %) in the selective decontamination group. (adjusted for imrie score and balthazar grade: p = . ). this difference was mainly caused by a reduction of late mortality (> weeks) due to significant reduction of gram-negative panreatic infection (p = . ). the average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < . ). failure of selective decontamination to prevent secondary gram-negative pancreatic infection with subsequent death was seen in only three patients ( %) and transient gramnegative pancreatic infection was seen in one ( %). in both groups of patients, all gram-negative aerobic pancreatic infection was preceded by colonization of the digestive tract by the same bacteria. reduction of gram-negative colonization of the digestive tract, preventing subsequent pancreatic infection by means of selective decontamination, significantly reduces morbidity and mortality in patients with severe acute necrotizing pancreatitis. ieco by sodium hypochlorite (nacio) infusion is considered to be a model of microsomal oxidation in liver on cytochrome p- . active c provides oxidation of toxic metabolic products in the blood and exfused during plasmapheresis plasma, and also hydrophobic to hydrofilic transformation of substanses. sterile nacio in necessery concentrations was obtained by electrolysis of saline ( , - , % naci solution) in electrochemical set e~io- (russin,moscow). methods: . the nacio in concentration ragfl ( - ml/ h ) was administred into central veins in patients with extensive peritonitis and endotoxicosis - /t. erytrocytes resistance to nacio, circulating blood volume glycemia and hemostasis were initially estimated. . after plasmapheresis exfused toxic plasma was mixed with nacio conccantration of i mg/t in : ratio in sterile "hemacons".the effectiveness of plasma detoxication and possibility of its reinfusion were evaluated by determination of albumin effective concentration (eca g/l), the concanlration of medium molecular oligopeptides (mm , ) and other biochemical tests (bilimbin, creatinine, carbomide and so on). results: . the intravenous administration of nac excels detoxicative effect of hemosortion by - % provides effictive presentation of protein components and blood cells and improves the transport function of albumin by %. . the return of exfused plasma after its purification ieco was - %. only the remaning - % of deficient plasma were compensated by fresh cryoplasma and albumin solutions. ischemic hepatitis (ih) is a severe complication in critically ill patients. acute circulatory failure of multiple etiology can lead to splachnic hypoperfusion and cause acute and reversible anoxic damage. over a period of mos pts, m and f, mean age + . yrs developed liver disease compatible with ih. eight pts had a documented hypotensive episode (six pts with septic shock and two hypovolemic shock), while cardiogenic pulmonary edema in the absence of hypotension was responsible for ih in the remaining four pts. all the pts had a rapid striking elevation of ast, &lt and ldh with equally rapid resolution of these parameters to near normal wimin days (mean . ). the mean peak level of ast, alt and ldh was iu/l (range to ), iu/l (range to ) and iu/l (range to ) respectively. serum total bilirubin levels rose transiently with a moan t:eak level of . mg/dl (range . to . ), while altered coagulation paran-,ete's (pt> . times normal) was observed in four pts and clinically significant coagulopathy with fibrin degradation products occurred in one pt ( . %). renal impairment (cr> . mg/dl) was manifest in all pts; six pts developed non-oliguric renal failure ( %) while two pts required hemodialysis. ten lots required vasoconstrictor inotropes [dobutamine (range - pg/kg/min) and dopamine (range - pg/kg/min), while replacement of circulatory blood volume was performed in two pts with hypovolemic shock. eight lots expired ( . %), but none died as a direct result of hepatic damage. the mortality rate was higher among pts with concurrent renal failure ( %). it is concluded that: ) ih is not uncommon complication in the icu with the prognosis depending on the underlying disease. ) clinically significant coagulopathy is uncommon complication of ih. ) titration of inotropes is required to obtain optimal cardiac output support and subsequently liver blood flow. it is difficult to ascertain the perfusion of free flaps such as jejunal loops after surgery. objectives: to assess ischaemia as evidenced by intramural ph of jejunal free flaps used for reconstructive surgery following total pharyngolaryngectomy. methods: the sigmoid ph tonometer ( tonometrics inc.,usa ) was used to monitor intramural ph of the jejunal free microvascular flaps ( phig ) in patients who underwent total pharyngolaryngectomy. a standard general anaesthetic was given and all patients were admitted to the icu for controlled ventilation and monitoring. all had similar postoperative care. phig was measured pre, post-revascularization of the flap and on icu admission, , and hours postrevascularization. objectives: to classificate the wide spectrum of itc of anp into distinct pathophysiological patterns according to presentation and course. patients (pts) and methods: pts, ~( , %), ( , %) were admitted in the icu because of anp and acute respiratory failure(arf), ilean age: , • years. hean stay in icu: , • days. pts were operated, of them twice. hean value of ranson's scale: , • ( - ). we analyzed hemodynamic measurements,arterial blood gases(abg), x-ray findings(xrf), ct-scans and operative records. results: patterns of pleuropulmonary complications were identified: a)early hypoxia without xrf - pts. b)early ards with typical xrf - pts( died), c)early arf with xrf(atelectasis,infiltrates)- pts( died). d)late ards with typical xrf- pts( died), e)pleural effusions in various combinations with the above patterns - pts. overall mortality rate: / = , %. conclusions: l)frequent x-rays and abg are important for the classification of itc of anp. )even though patterns of classification in anp are not clearly distinguishable,they facilitate an anticipatory management. )deterioration of abg and xrf indicates that preventive measures for arf must be intensified and agressive surgical therapy is required. )delay of surgical therapy is related to worse prognosis(p<o, ) and prolonged hospitalisation time(p<o,ol). in the contrary, the early timing of the operation before infection and extrapancreatic necrosis is essential for a better prognosis (p<o, ). objectives: the development of cholestasis during intensive care treatment is allied with an inferior prognosis. this study investigates the sensivity, specification and also the positive and negative forecast of patients survival -exemplary for bilirubine. methods: during a period of months all surgical patients on icu were registrated prospectively (n = ). for documentation of disease development a standard foldcrform based on a computer-data-system was used. the results of this kind of documentation showed aapprax. , m!ll. of single patient informatioas. results: of patients didn't suffer from liver disease or have any operation on liver or bile tract. of them have had a normal scale of bilimbine in the postoperative period, a higher scale of bilirabine was regisu'atcd by patients. at a ,,cut-off" of rag% (total-bilirubine) the sensitivity was , , specivity , , positive predicive level , , negative predictive level , for survival criteria of a patient. the max. reached level of bilirubine, also the daily increase turned out almost the same results as they were found for other parameters nf cholcstasis like ap or gamma-gt. objective: the aim of this experimental protocol was to evaluate the morphological and functional parameters of isolated pig liver grafts, perfused in an extracorporeal liver support system. methods: the system consists of the graft liver, a membrane oxygenator (oxygenation surface . cm z, flow= itlmin), a heater, a centrifuge pump and a fluid reservoir. twenty pig livers, mean weight gr (min , max gr) were obtained and after a mean cold ischemia time of min were perfused fo} a mean of . h (min . , max h). perfusion solution consisted of r/l and hemacell. inflow to the graft liver was performed through the portal vein at a mean pressure of ( - ) mmhg at ~ while outflow was secured through the suprahepatic inferior vena cava. during perfusion the following parameters were evaluated through pre-and posthepatic hourly (to-t ) sampling: po , " + + " pco , ph, hco -, na , k , ca , osmolality, glucose, lactate, ast, alt, alp, u bilirubin and coagulation factors i, v and viii. biopsies were obtained periodicallty. b_p_~: results were as follows: mean ph fell from . at t o to . at t while mean output po fell from at t o to at t . mean output ast values increased from at t o to > at t while mean output alp values increased from . at t o to at t . mean output k + values increased from . at t o to > at t . histology revealed lesions of ischemic necrosis, more prominent after t . conclusion: results show that the isolated liver graft presents satisfactory function and morphology at least for a five hour perfusion period in the described extracorporeal circuit. correction of ph contributed to an increase in bile flow. between and the practice of transplantation has changed drasticaily in switzerland -besides kidneys also hearts, heart and lung, lung, iiver and pancreas transplantation has started in several centers. major information efforts have been made, organ exchange rules were set up and a national coordination center was initiated. the aim of this retrospective single center study was to assess the influence of transplantation on organ donation. in the past eleven years organs were donated from potential donors i single, multi organ donations) analysis of refusal was evaluated categorized into medical and/or familiar reasons. the number of potential donors increased from ( ) ,to ( ) with a concomitant drastic reduction of donations from % in to % in ; amounting to a net unchanged number of donations over the last years ( = ; = ) . the import and export of donor organs was balanced since the introduction of the national coordination center. in contrast multi organ donation increased from % in to % in despite of the more stringeant selection criteria, in conc]usion the introduction of a full range of transplantation procedures at several new university programs and the increase of multi organ donation has not had the forecasted impact on organ donation despite a sustained informative and promotional campaign, objective: monitoring hepatic venous oxygen saturation (svho ) provides online information about hepatic-splanchnic oxygen supply-demand ratio [ ]. previously, x~ reported hepatic venous catheterization in patients undergoing orthotopic liver traru~lantation (olt) [ ] . in the present study, we assessed the effects of nitroglycerin (ng), a vasudilator that affects the venous capacitance vessels more than arterial vessels and prostaeyclin (pgi , flolan r~, wellcome, uk), an arterial and splanchnic vasodilator on hemodynamies and hepatic venous oxygen saturation (svho ) in human liver transplantation. methods: with institutional approval and informed consent, consecutive patients, mean age - -_ years, were studied following olt. postoperatively, fiberoptic pulmonary artery catheter was inserted into the right hepatic vein. timed infusions of ng at a rate of . gg/kg/min and pgi at ng/kg/min were initiated for a rain period. each sequence was followed by baseline therapy for rain. results are expressed as mean=tsd. statistical analysis was performed using friedman's-two-way-anova-test, significance was accepted at p< , . results: ng at . gg/kg/min induced a decrease of mean arterial pressure (map) ( _ [baseline] vs. + mmhg) and pulmonary artery wedge pressure (pcwp) ( j: [baseline] vs. : mmhg). cardiac index (ci) ( - vs. + l/rain/m ), oxygen delivery index (do i) ( -+ vs. + mgnfin) and svho ( _~ vs. -l-_ %) were decreased (p< . ). pgi at ng/kg/min induced a reduction in map ( • nm~. _g) and pcwp ( + mmhg). ci ( _+ l/rain/m ), do i ( : ml/min) and svhoz ( + %) were increased (!o< . ). vasedilatation induced by ng decreased systemic oxygen supply and impaired splanclmie oxygenation. pgi increased systemic oxygen delivery in parallel with svho , suggesting a corresponding improvement of hepatic-splanchnic okygenation. thus, if vasedilator therapy is indicated in th orient receiving liver grafting, pgi appears to be advantageous. however, due to its platelct aggregation inhibiting properties, the usefulness and safety of pgi in olt patients has still to be determined. objectives: to analyze the effect of steroid treatment given to donor on the early function of transplanted kidney. methods: from january, until now donors were involved into this prospective study. every other donor was treated with mg/kg solu-medrol one hour before organ retrieval. according to the steroid treatment of the donor the recipients were divided into two groups: group -steroid pretreatment goup (y~= ), and group -control group (n= ). the donors and the recipients were treated using the same kidney transplantation protocol onl~r the adults, and the first cadaver kidney transplanted patients were involved into the study. the daily routine parameters were analyzed pre-and intraoperafive, and on the - th, th and th postoperative days. results: we could not show any clinically important differences between the two groups in respect of donor parameters. preoperative, the patients in group had slightly lower ereatinin level ( -+ g.,non vs. -+ gmol/ ) which persisted into the early postoperative phase. the values of the other examined pre-and intmoperativc parameters were almost the same. during the first postoperative days the patients in group i needed less diuretics (furosemide and renal dose of dopamine) and their sodium excretion was closer to the physiological range than in group . the other parameters did not differ significantly. the less furosemide need in group ! pe~isted to the end of the first month. conclusions: according to our data the steroid treatment of the donors improves the early function of the transplanted kidney in some respects. to prove the real benefit of the donor steroid treatment needs more data and further analysis. objectives: severe infections may compromize the outcome of liver transplantation..determination of new parameters may increase the knowledge of pathophysiologic mechanisms and may lead to changes in postoperative therapeutic management of patients at risk. methods: between august and september , patients with transplants were monitored for cytokines and extracellular matrix pammeters on a daily basis. serious infections (n= ) included microbiologic evidence and more than secondary organ failures. patients with cholangitis (n=ll) or uneventful postoperative course (n= ) referred as control groups. results: -year patient survival was . % ( / ): patients died due to serious infections, while died for other reasons. mean bilimbin, stnf-rii-, ifn- -, il- -, il- -, il- -, laminin-and neopterin levels were significantly elevated in patients with serious infections compared with patients experiencing mild cholangitis or with an uneventful postoperative course. a further increase of all parameters was observed in patients who subsequently died; tnf-ri/: _+ pg/ml vs • pg/ml; ifn- : _+ pg/ml vs . -+ . pg/ml; il- : -+ pg/ml vs -+ pg/ml; il- : -+ pg/ml vs _+ pg/ml; il- : _+ pg/ml vs • pg/ml; laminin: -+ ng/ml vs -+ ng/ml; neopterin: _+ nmol/ vs _+ nmolb for non surviving vs-surviving patients. a significant decrease of sialic acid yeas observed in patients with serious infections; and a further decrease occurred in patients who subsequently died: -+ mg/l vs • mg/ . conclusions: the increase or decrease of various cytokines and extracellular matrix parameters may be indicative for severity of infectiolx routine monitoring of these parameters may improve current diagnostic tools and poss~ly lead to changes in therapeutic management of patients at ~k. objectives: evaluation of the cytokine network after liver transplantation may give some insight in pathophysiologic mechanisms of rejection and may lead to detection of patients at high risk. methods: patients with transplants were monitored for various cytokines on a daily basis between august and september . rejection was assessed by histology in combination with clinical signs of rejection and laboratory investigations. results: during the first postoperative month, patients ( . %) developed rejection; patients were successfully treated with methylprednisolone (steroid-sensible rejection), while further patients required additional treatment with fk or okt (steroid-resistant rejection). patients subsequently developed chronic rejection. mean levels of various cytokines and extracellular matrix parameters including tnf-rii, ifn- , il-ib, il- r, il- , il- , il- , hyaluronic acid and neopterin were significantly higher in patients with steroid-resistant than in patients with steroid-sensible rejection. a further increase of some parameters was observed in patients who subsequently developed chronic rejection; bilirubin: . -+ . mg/dl vs . -+ . rag/all; tnf-rii: -+ pg/ml vs _+ pg/ml; il- : +- pg/ml vs -+ pg/ml; neopterin _+ nmol/ vs -+ nmol/ ; hyaluronic acid: _+ ~tg/l vs _+ ~tg/l for patients with chronic versus patients with acute steroid-resistant ~ejection. sialic acid levels decreased in patients with acute steroidresistant rejection; and a further decrease was observed in patients who tieveloped chronic rejection: _+ mg/l vs _+ mg/ . ~onclusions: various cytokines and extraeeuular matrix parameters were indicative of severity of rejction. the extensive increase of bilirubin, tnf-ii, il- , hyaluronic acid and neopterin may indicate subsequent chronic ection. monitoring of these parameters may, therefore, lead to changes in immunologic management after liver transplantation. background : combined kidney and pancreatic transplantation is being performed with increasing frequency in patients with diabetes mellitus and renal failure, as it offers more chances of success and better results than kidney transplantation alone. mycotic arterial aneurysm constitutes a devastating complication following pancreatic transplantation. all cases of mycotic arterial aneurysms have been however reported with exocrine pancreatic drainage into the gastrointestinal tract. intervention : we describe a series of consecutive whole kidney-pancreas transplantation performed at the university of geneva hospitals ( beds) between december and may . exocrine pancreatic drainage into the bladder (epdb) was performed to improve early detection of rejection episodes. epdb was hypothesized to reduce the risk of contamination from the gastrointestinal tract and the subsequent possible occurrence of potentially fatal infectious complication. in all patients the dual transplantation was performed through a median incision according to the procedure described by nghiem. results : two out of the patients who received kidney-pancreatic transplant developed arterial mycotic aneurysms and days following surgery. aneurysms developed at the site of the arterial anastomosis used to rearterialize the homograft. both patients had peritonitis caused by candida albicans requiring surgical drainage and intravenous antifungal therapy. rupture with hemorragic shock occured in both patients leading to graft removal in one patient, and three episodes of lffetreateniug hemorragic shock followed by graft failure and removal days after transplantation in the other. conclusion : arterial mycotic aneurysm constitutes an early, lifetreatening complication of kidney-pancreatic transplantation; it mandates graft removal. although exocrine pancreatic drainage into the bladder consitutes a definitive advantage for caller diagnosis of graft rejection, it does not eliminate the risk for retrograde colonization and subsequent severe infection in our experience. s. bocharov, i. teterina, regional clinical hospital, irkutsk, russia acute profound loss of blood can result from the very different injuries and hepato-pancreato-duodenai operations enter such a rank. ill-timed and inadeguate correction of operation hemorrage is one of the reasons for postoperation complications, including polyorganic insufficiency. the pathogenesis seems to be very complex. in early stages of bleeding the liquid enters the vessel bed, followed by hypoproteinosis and hematocrit fall. however, as decompensation develops, the fluid leaves the vessel system in the result of increasing postcapillary resistance and lowering col-ioidnooncotic blood pressure (cop). the resulting hypovolemia causes primarily acute disturbance of central hemodynamics and then of microcirculations and transcapillary exchange. central hemodynamic failure after acute loss of blood manifests itself through cardiac output lowering and capillary blood flow deceleration. taking into consideration, that % is critical value for cpv loss and for cev it is %, we consider arising the level of cop to the immediate task. cop raising allows to normalize transcapillary exchange, which we assess through cop and mcp (mean capilary pressure) gradient. the next task is to make up for globular volume till homeostasis providing level. considerable attention is given to catabolism inhibition and maximum possible enegry provision. control over high proteolitic activity of blood and callicreinkinin system activity implies direct proteases inhibitors. reologic, membrane stabilizing, antihypoxanthine and anticoagulant therapies are obligatory. virehow clinic, dept. of surgery, humboldt university berlin, germany regarding a high mortality up to % of fulminant hepatic failure orthotopic liver transplantation seems to be the only promising therapeutic approach in many cases. this study shows experiences from a transplantation center. between june and april patients suffering fulminant hepatic failure were admitted to our surgical intensive care unit all patients showed severe liver dysfunction with grade ii to iv encephalopathy. after a period of diagnostics and conservative treatment ranging from few hours to days (mean . days) we reported of these patients as possible organ recipients to eurotransplant. all of these patients were transplanted within hours, ( %) of them even within hours. the principal aetiologies were hepatitis b ( ), hepatitis c ( ), nanb hepatitis ( ), mushroom poisoning (amanita phalloides ). after transplantation patients suffered from initial-non-function and underwent re-transplantation. the one-year-survival rate was %, patients died within months after transplantation due to various reasons. patients were not referred for liver transplantation. of them never met transplantation criteria, improved by conventional therapy and could finally be discharged from hospital. the known reasons for liver failure in this group were mushroom poisoning ( ), paracetamol intoxication ( ) and fulminant hepatitis a ( ). patients suffering from fulminant hepatitis ( ) or intoxication ( ) were excluded from emergency liver transplantation for various contraindications. of these patients ( %) died despite conventional intensive care. we don't know if some of the patients in the transplantation group would have survived without transplantation, because whenever we decided on transplantation we could perform the operation within hours. but the good survival rate in the transplantation group ( %) the % recovery rate in the group, where there was no transplant-indication in our opinion and the fatal outcome ( % mortality) in patients with contraindications are an encouraging proof of a successful therapeutic strategy in acute liver failure. these results are based on a close cooperation between experienced transplant surgeons, hepatologists and intensive care doctors, using sophisticated laboratory and imaging techniques in a specialized center. introduction: during brain death patients suffer from multiple endocrinologic disturbances. one of the most important are those related with thyroidal axis. it is well described the euthyroid sick syndrome whose more frequent pattern consist of decreased triiodothyronine (t ), increased reverse t (rt ) with normal levels of tetraiodothyronine ( " ) and tsh, this lacking in " " levels lead to a change from aerobic to anaerobic metabolism which results in tissular damage. objective: .to study thyroidal pattern in brain death patients potential organ donors. .to avoid organ impairment by administration of t . .to study the hemodynamic and hormonal changes after the administration of t in these patients. material and methods:population: brain death patients of any etiology potential organ donors admitted to the intensive care unit. patients were classified in hemodynamically stable (group ) and unstable (group ). group received a bolus of . p.gr/kg. and a perfusion at a dose of - . p.gr]h of t . hormonal assays: total t (tt ), total " (tt ), tsh. fxee t (ft ), free " (ft ) and rt were determine at the moment of clinical brain death ( hrs) and in group two these assays were repeted at hours , and . results: patients ( male) with a mean age of years (range to yrs.) were studied. the clinical brain death was confirm later with other explorations (eeg, doppler). there were patients in group ( , %) and patients in group ( , %). hormonal pattern: at the moment of brain death tt was normal in cases ( , %) and decreased in i ( , %); tt was normal in patients ( , %) and decreased in ( , %); ft was normal in cases (i , %), decreased in ( , %); fl' was normal in patients ( , %) , decreased in ( , %) .rt was normal in cases ( , %) and increased in cases ( , %). there were no statistically significant differences in hormonal pattern between the two groups. only t levels at hours , and were significant in group . in the cases with ft decreased, the tt was normal in ( %) and decreased in ( %), tt was decreased in ( , %) and normal in ( , %), tsh was decreased in i ( , %), normal in ( , %) and increased in i( , %) and ft decreased in ( , %) and normal in ( , %) and rt was normal in ( , %) and increased in ( , %). there were no statistically significant differences in cardiac index, vascular resistances and pulmonary shunt before and after the administration ef t . conclusions: . the hormonal pattern most often find in brain death patients was: normal tt , decreased tt , normal tsh, decreased ft , normal fr and normal rt . . there were discrepancies in the values of ft and tt . there were no statistically significant differences in hemodynamic and pulmonary parameters. objectives: magnetic resonance angiographie (mra), a non-invasive procedure, provides flow-related information additionly to the anatomy of the vascular system. measurement of signal intensity and edge detection of vessel structures permits to calculate blood flow velocity and vascular diameters. we examined whether cerebral hemodynamic changes by altering the arterial pressure of carbon dioxid (pace ) could be detected by mra. methods: following institutional approval and informed consent, mechanically ventilated patients without elevated intracraltial pressure underwent mra with defined periods of hyper-, hypo-and normoventilation (pace : , , mmhg; arterial blood gas probes; avl). mra was performed with a . tesla magnetom (vision, siemens). two different mra techniques were used: a conventional time-of-flight- d-angiography (tr: ms; te: ms; fl: deg; slab: mm) for vessel diameter detection and a flash- d-gradient-echo-sequence (tr: ms; te: ms; fl: dog) for measurements of blood flow velocity. an axial view parallel to the ac-pc-iine (anteriorposterior-commissur-line) was used for repeated imaging of identical regions of interest toi) of the proximal part of the internal carotid (ica) and middle cerebral artery (mca) as well as of peripheral branches of the mca and the posterior cerebral artery (pca). results: changes of pace correlated with changing signal intensities, whereby under hyperventilation a decrease of , % (p . ) and under hypoventilation an increase of . % (p . ) was observed compared with normoventilation. blood pressures were stable throughout the whole study period, pace dependent changes in vessel diameters were more pronounced in peripheral branches of mca and pca. a change from normo-to hyperventilation produced a decrease in proximal vessel diameter of - . % (p _< . ) and in peripheral diameter of - . % (p _< , ). a change from normo-to hypoventilation produced an increase in proximal diameter of + . % (p < . ) and of + . % (p -< . ) in peripheral diameter. conclusions: pace related changes of cerebral vessel diameter can be easily detected by mra without injecting a contrast agent. the results confirm that co -reactivity is more pronounced in peripheral cerebral vessels, which are subjected to greater changes in diameter than major basal arteries. hyperventilation leads to a decrease and hypoventilation to an increase in signal intensity thus reflecting the corresponding changes in blood flow velocity, intensive care unit (icu) of "kat" hospital, athens, greece, ob!ective$; the value of bronchoscopy in pulmonary atelectasis of icu patients is under question the presence of an air bronchogram sign in xrays, which is considered as evidence of central bronchus patency, is referred in several studies as a negative criterion for bronchoscopy, whereas its absence as a positive one. it is also referred that air bronchogram sign correlates with delayed resolution of atelectasis, probably because of obstruction of many periferal airways (not central). the purpose of this prospective study was the evaluation of the air bronchogram sign on frontal chest film as a negative criterion for bronchoscopy and as criterion of delayed resolution of atetectasis, methods: icu patients with atelectasis were studied prospectively. they underwent bronchoscopy, bronchoscopic findings, presense of air bronchogram sign, and outcome of atelectasis were recorded, correlations were made, between: ) bronchoscopic potency of airways and air bronchogram sign } resolution time of atelectasis and broncoscopic potency of airways. ) resolution time'of atelectasis and air bronchogram sign, methods of statistical analysis were the t-student test and the chi square test, results:the patients were , men women , seventeen patients had atelectasis of whole lung, of upper lobe, and of lower lobe. ten patients had atelectasis in right and in left lung. eight from patients had air bronchogram sign in x-ray, there was no statistical correlation between air bronchogram sign and bronchoscopic potency of airways [ from patients with air bronchogram sign ( %) and from without air bronchogram sign ( %), had bronchoscopic potency of airways, p> . ], resolution time of atelectasis didn't correlate statistically with bronchoscopic potency of airways (mean resolution time in patients with bronchoscopic potency , days and in bronchoscopically closed bronchi , days, p> , ). there was also not a statistical correlation between resolution time of atelectasis and air bronchogram sign (mean resolution time in patients with air bronchogram sign , days, and without air bronchogram sign , days. p> ). conclusion~i; the presense of an air bronchogram sign in x-ray of icu patients with atelectasis, does not coexist obligatorily with bronchoscopic patency of airways and cannot be used as a negative criterion for bronchoscopy, neither as a criterion of delayed resolution of atelectasis. th. wertgen chest sonography (cs) is routinely used in our department to examine icu patients with clinical symptoms of pulmonary embolism, pneumonia, pleural effusion or unclear chest pain. we perform cs with a sector transducer ( . mhz) and a linear transducer ( . mhz) using acuson xp/ c. the sonographic signs of pulmonary embolism and infarction are most well demarcated, mainly wedge shaped and triangular pleural based lesions, more roughly structured, observed with a hyperechoic reflex in the center corresponding to the bronchitic (fig. ) . pneumonia is characterized by homogenously hypoechoic, wedge shaped parenchymal lesions, containing air or fluid bronchograms; they move with respiration (fig. ) . pleural effusions are spaces of various echogenicities, from anechoic to homogeneously echogenic, which may contain floating strands or complex septa, located between visceral and parietal pleuras (fig. ) . from march to april we did examinations by cs in icu patients ( male, female; age from - ). patients examinations pulmonary embolism pneumonia pleural effusion us-guided thoracic punctions were performed in patients. in two patients we found pneumonia or pleural effusion caused by a lung carcinoma. another two patients showed a normal cs (diagnosis: inflammation of the gall bladder, inflammation of the myocardium). conclusion: cs is a very useful method for icu patients with chest diseases. it takes less time and is less expensive than ctand sometimes of a higher diagnostic value than x-ray. last but not least cs is invaluable for the icu patient, because the examination is done save and quickly at bed side and the results of cs are very helpful in diagnoses and treatment. results : inter-observer reliability was evaluated as an % concordance. results of the tee classification were : class : n = ( %) ; class : n = ( %) ; class : n = ( %) ; class : n = ( %) class : n = ( %). therapeutic implications of tee in class patients were : cardiac surgery in patients (two cases of acute mitral regurgitation, two valvular abscesses and one hematoma compressing the left atrium), discontinuation of peep in one ventilated patient with an atrial septal defect, weaning of mechanical ventilation in one patient with an atrial septal defect, prescription of antimicrobial therapy in patients with endocarditis and prescription of anticoagulant therapy in patients with left atrial thrombus. the only noteworthy complication was a case of spontaneously resolving supraventrieular tachycardia. conclusion : tee is safe and well tolerated, and is useful in the management of icu patients with shock, unexplained and severe hypoxemia or suspected endecarditis. the aim of this study was to determine whether ultrasound guidance can help interns to improve the results of jugular vein access in icu. methods : in a prospective and randomized study, we compared, in patients admitted to the icu, an ultrasound-guided method (ultrasound group : patients) with an external landmark guided technique (control group : patients). all jugular vein accesses were performed by young interns with an experience of < procedures. results : internal jugular cannulatian vein was aci~ieved in all patients in the ultrasound group and in patients ( p.cent) in the control group (p < . ). average access time was longer in the control group ( • sec. vs • see. ; p = . ) and puncture of the carotid artery occurred in patients in each group (p = . ). patients ( p.cent) in the ultrasound group and patients ( p.cent) ia the control group (p < . ) were cannulated in rain. or less. the cannula was therefore unabie to be inserted within minutes in patients in the control group, with failure of eannulation in of these patients ( p.cent). failure was due to thrombosis (n = ), small calibre of the internal jugular vein (< ram) (n = ), abnormal vascular relations (n = ) or cervical irridation (n = ). among the primary failures of cannulation, an internal jugular vein catheter was able to be inserted in cases by an experienced physician on the side initially selected and with ultrasound guidance in cases. the catheter was inserted into the contralateral internal jugular vein under ultrasound guidance in the remaining cases. jugular cannulation was obtained at the first attempt in p.cent in the control group and p.cent in the ultrasound group. conclusion : ultrasound guidance improved the success rate of jugular vein cannulation by inexperienced operators in icu patients. when the internal jugular vein has not been successfully eannulated within minutes by the external landmark guided technique, the authors recommend the use of the ultrasound guidance. in the majority of cases right atrial or ventricular thrombi represent pulmonary emboli in transit. these may be fatal in patients (pts) treated conservatively with anticoagulation only. in literature the incidence of right heart thrombi in pts with proven pulmonary embolism (pe) is said to be in the range of - %. extremely mobile, long, worm-shaped masses in the right heart cavities carry an especially high early thrombus-related mortality rate which ranges from - %. current therapeutic strategies favour fibrinolytic therapy with consecutive anticoagulation. we report five cases ( male, i female, - years) of right heart and pulmonary thromboembolism. in these pts diagnosis and regression of thromboemboli following systemic intravenous lysis therapy with recombinant tissue-type plasminogen activator (rt-pa) was documented by transesophageal echocardiography (tee). a submassive pe occured in pts, a massive pe in pts. one patient (pt) had a cardiac arrest. in all cases tee clearly identified the extensive thrombns formation in the right-sided cavities of the heart and in the central pulmonary artery in cases. all pts were treated with mg rt-pa, pts in a front-loaded regimen over minutes, pt over minutes, and, due to the life threatening situation, in one case a bolus injection as ultima ratio was performed with no intracerebral bleeding complication. regression of thromboembolic masses after fibrinolytic therapy was demonstrated by transthoracic and transesophageal echocardingraphy after to hours. all pts survived and were put on coumadine, pt developed an intracerebral bleeding with persistent hemiplegia. conclusions: the use of thrombolytic therapy is highly efficacious for the therapy of pts with pe and concomitant right or ventricular thrombus formation. transthoracic and especially transesophageal echocardiography are powerful bed-side diagnostic tools for the immediate diagnosis and follow-up of successful treatment in this life-threatening condition. although widely used, catheterisation of the femoral vein in the groin using "landmark" technique is frequently complicated by accidental arterial puncture. suboptimal hygiene and patient discomfort are also associated with this technique. with regard to these last two factors cannulation of the femoral vein - cm below the inguinal ligament would seem an attractive alternative. as "landmark" technique is not possible for the cannulation of the femoral vein in this part of the thigh, ultrasound was used to locate the vessel and the results of this technique were evaluated. methods: a portable compact ultrasound device (site rite,dymax corp.) featuring a . mhz transducer (ultrasound depth - cm) fitted with a needle guide and a cm screen was used by residents with no previous experience in ultrasound guided cannulation. patients consisted of a surgical icu population. results: in patients catheters were introduced.in cases more than one ( - ) attempt was made and in patients the procedure was unsuccesfull due to the fact that the vessel was situated out of reach of the ultrasound (vessel depth > - cm), during the procedures one accidental arterial punction was registered. the catheters remained in situ for a mean of days (range - ) and were used for volume suppletion, medication, parenteral nutrition and haemodialysis.co-ionisation rates compared to those of subclavian catheters in our icu. in the first patients cases of asymptomatic thrombosis of the femoral vein were seer on ct-scans performed for other indications, in the following patients duplex scanning performed after removal of the catheter yielded another cases of asymptomatic femoral vein thrombosis. conclusions: ultrasound guided femoral vein catheterisation - cm below the inguinal ligament is a safe and simple technique that can easily be performed by residents without prior experience. the incidence and impact of thrombo-embolic complications associated with this technique are still subject to further investigation. objectives: to estimate the cost of antibiotherapy (ab-cost) in a multidisciplinary -bed greek icu and to correlate ab-cost with total cost of drugs and consumables and with patient's outcome, severity of illness and type of admission. methods: prospective data from consecutive patients admitted to the icu from / / to / / were studied. a tick chart was designed to record all drugs, materials and consumables regularly used for icu patients, but did not include low price drugs and consumables, which are provided from hospital's pharmacy as stock and were included in a fixed icu cost calculated for a month period. the chart also contained demographic details and data necessary for the calculation of several illness severity scoring systems. obiectives: over years evaluate the necessary efforts and expenses to implement a cis in the routine of a -bed stcu. methods: in june a commercially available, unix-based cis was installed on a -bed surgical icu. the goal was a paperless documentation at the bedside. after more than years clinical experience two aspects were investigated: what effort is necessary to install and support a cis, and what is the benefit for patients and personnel on the icu? results: the installation and support of a full-fledged cis requires a considerable effort: (a) the conceptual framework for the cis has to be defined. this includes the definition of documentation standards, as well as nursing and therapeutic standards, which is the essential basis for the configuration of any cis. (b) configuring a cis, i.e. "fine-tuning" it to the user's specific needs, is always a laborious task. moreover, constant maintenance is necessary. these tasks require the following personnel: experienced health care professionals for defining the conceptual framework, - trained health care professionals for configuration, system administrator. on a single icu ( - beds) these are not considered full-time jobs. (c) training is best done employing the "train-the-trainers" approach. (d) beside the necessary amount of man power and money to install and purchase a cis, administrative and mis support is needed, especially when interfaces to the hospital and laboratory information systems have to be set up. in general, a cis needs the commitment of all people involved. without a really professional approach with a longterm goal any major cis can turn into an unnecessary but inevitable night mare. after years clinical use and a thorough implementation of a cis on a major sicu it can be said that full-fledged cis offers an opportunity to dramatically improve the working environment on an icu. moreover, it adds to patient safety, quality of care and cost efficiency in one of the most advanced and expensive areas of medicine. conclusion: a major investment in man power and money is necessary to install and maintain a full-fledged cis. a sincere professional commitment to the goals of a cis is necessary. in exchange, a well configured and well maintained cis dramatically improves the quality of therapy and care on the icu. even return of investment and financial profitability of a cis seem feasible todayl from the clinical perspective it appears that the users themselves are the central determinant whether a cis makes a dream come tree or turns into a night mare. objectives: to establish a relationship between the activities of the staff and the occurrence of auditory alarms on the i. c.u. ard to evaluate confusion between auditory alarms. methods: laboratory based studies which investigated aspects of confusion between alarms in current use on the i. c. u. the observational studies were conducted over an month period and examined the frequency and duration of alarms together with the concurrent activites being undertaken by staff on the unit. the laboratory based studies showed that there were enduring confusions between the alarms on various items of medical equipment, for example a ventilator alarm and an e. c. g. monitor alarm. the results of the observation studies demonstrated that alarms are activated when specific activities are being undertaken by staff. sounds could be used in future recommendations for alarms on medical equipment. suggestions are also discussed for improving and rationalising auditory warnings in the i. c. u. obiectives: we investigated inferior petrosal sinus (ips), the lowest affluent to jugular bulb (jb), as a possible source of contamination of samples in jb for monitoring oxyhemogiobin saturation (sjbo ). pulling back the catheter the oxyhemoglobin saturation usually rises indicating extracerebral contamination (jakobs en met al: j cereb blood flow metab ; : ). methods: the study was carried out on patients undergoing ips sampling to differentiate cushing disease from ectopic acth syndrome and to lateralize any resulting pituitary lesion. we studied the value of oxyhemogiobkn saturation high in jb (sjbo ), at ips (sipso ) and at mid jugular vein ( th cervical vertebra) (smj ) bilaterally. results: we found significant differences between right sjbo and both right sipso (p= . ) and right smjo ( p= , ) and between left sjbo and both left sipso (p= . ) and left smjo (p= . ) we did not fred any difference bilaterally. objectives: we studied various methods of receiving and editing of clinical datas in critically ill patients (different ethiology). patients were investigated in regional intensive care center. methods : the following datas were studied : anamnesis, status praesens objectivus ( organs and systems ) ,. clinical and biochemical markers of critical condition , datas of eeg ,rheography . the medical information complex contained : channel electroencephalograph, -channel roencephalograph, ad-converter ( analog inputs, bit resolution, k hz), ibm dx , software includes set of routines for spectral eeg analysis, eeg-mapping, correlative analysis, and brain bloodstream reg-monitoring (written in turbo pascal . ), expert programs for estimation objective and humoral patient status (written in clipper . ) and statistics. there were used following programme-language instruments : borland c++ . , nantucket clipper . , ca-clipper tools ii. as the methods of statistical processing of dates were used: t-students criterion , fisher criterion, methods of correlation analisis, calculation of the regression levels, dispersion analysis, results : there was created the optimal structure of hard and sofware complex of search steady objective regularity in dynamic of critically ill patients condition. conclusion : the created system allowed to value effectiveness of intensive care and give us new opportunities in study pathogenesis of systems disorders in critical condition . over a five year period a patient data management system has been installed which allows individualised patient data to be accurately collected. using this data a costing system has been developed which ascribes costs thus: . direct costs -drugs, fluids, consumables, interventions. these are ascribed to individual patients, according to data collected from the pdms. . indirect costs -energy, depreciation, admm costs, maintenance etc. these are summed for the year and ascribed as an overhead per patient day. n.b staffcusts contain art element of both cost types the aim is to make as many costs as possibie 'direct', hence 'activity costs' have been calculated winch comprise staff time, drugs and consumables -these are direct costs. these costs of patient care are then searnlessly integrated into the financial and budget management of the icu environment. it was found that by calculating costs in this manner % of the total cost of icu are captured within the 'direct' element, and so are able to be ascribed to individual patients. this is much more accurate than simply dividing the total costs of ~cu by the number of patient days. temporal costs (variations during patient stay) and cross sectional costs (cost differences between admitting specialities) were also noted with interest. results of the initial analysis of data captured by the system will be presented. little is known about the resource costs (not simply cash costs) of icu. even less is known about individual patient costs, with previous estimates of these costs varying widely. however, if cost effectiveness studies are to be undertaken accurate calculation of individual, group and total icu cost is an essential, prerequisite, which, via this system of costing, is now achievable. information about intensive care of cancer patients is limited in the literature, despite the increasing use of such facilities in oncology over the two last decades. in order to determine if and how critical care facilities can be used specifically for these patients, we performed a world-wide inquiry in anticancer centers selecting the hospitals by using the international directory of cancer institutes and organizations. we mailed a questionnaire to centers and we received responses ( . %). there was at least one uncological (i.e. with > % of cancer patients) icu in (% % an -year old woman with graves disease presents with sore throat, vomiting, diarrhea, sinus tachycardia at /minute and a temperature of ~ several weeks before, treatment with propylthiouraeil had been stopped (rash and fever) and replaced by methimazole and ledide prior to a minor surgery. however, both drugs were discontinued by the patient two weeks before admission. shortly after arrival in hospital, patient's condition progressed to respiratory failure (upper airway edema), delirium and shock requiring icu admission, intubation and resuscitation with fluids and vasopressors. white blood count was /mm ~ with neutrophils. patient's hemodynamic data showed initial hyperdynamic profile followed by low output state with decreased sv ( %) (n - %) and cardiac index ( , ) (n , - ). echocardiogram confirmed cardiac chambers dilation as previously described in thyroid storm. lithium carbonate, corticosteroids, antibiotics and beta-blocker perfusion were given. plasmapheresis was started. free t& (n= , - pmo/l) went from , to , after the first two pheresis. after a remarkable clinical recovery, sub-total thyroideetomy was done i days after admission. in life-threatening thyroid storm, plasmapheresis is a very effective therapy when anti-thyroid drugs are counterindicated. purpose: to compare the reliability of prognostic indexes in crhically iu patients admitted in an intesive care unit (icu) who had acute renal failure (arfi and were treated with different dialytic techniques. material and methods: patients were included in a prospective study from june to november . patients presented arf defined by creatinin serum leve(s greater than pmol/l and previous normal levels. patients were divided in three groups. group i (control) : patients with arf who did not receive substitutive techniques. group ih patients under intermittent hemodialysis (hd) or peritoneal dialysis (pd). group ii : patients under continuous hemodiafiltrstion (hf). the statistical analysis was chi-square test and analysis of variance. results: the table shows the results we obtained, we did not find any significant difference betwen the two groups of patients undergoing dialysis. d(fferences were observed only between group i and the other groups as shown below. we did not find any significant association between the theoretical mortality predicted and the observed mortality according to saps in the three groups. due to exposure to a wide variety of unpleasant stimuli, for example, tracheal suctioning, venipuneture and physiotherapy, most pataents admitted to the icu will require some form of sedation. this review will describe the suggested properties of an ideal sedative agent for use in the icu and review the current limitations of some of the available agents from this perspactive. methods used to quantify the level of sedation, such as the ramsay score, glasgow coma score, newcastle sedation score and visual analogue scores, and their deficiencies will be examined. consideration will be given to defining the optimal level of sedation and the circumstances under which sedation might be varied over the icu course will be discussed. preliminary results from an ongoing study examining the role of light versus heavy sedation and ischaemia in a cardiac surgical icu population will be presented. the pharmacceconomics of icu sedation will be briefly addressed. finally, the role that sedation may play in increasing morbidity, pastieuiarly nosocomial pneumonia, in the icu will be discussed. objectives : therapy cost(tc) in icu patients is a substantial component of total hospital care cost. estimation of tc during this year, partitioning to various groups of drugs used and attempt to minimise it, were considered practically useful. methods : in collaboration with the hospital pharmacy we were able to have a complete report of au drugs used for icu patients (including enteral and parenteral nutrition). mean apache ii severity score upon admission was . and mean length of tcu stay was . days. price per drug unit and cost per group of drugs were also available drugs were divided into two groups: antibiotics ( ) cardiovascular drugs ( ), gastrointestinal system drugs ( ), enteral and parenteral nutrition ( ), respiratory system drugs ( ), sedative, analgesics and paralysing agents ( ), parenteral solutions with electrolytes, vitamins and trace elements ( ), anti-inflammatory agents ( ), protein substitutes and immunomodulation agents ( ), anticoagulative agents ( ). antibiotics were further subdivided into those "freely" prescribed (a) and those whose prescription and administration requires filling of a relevant form (b). results : !) tc for icu patients/day was . drs ($ ). total tc/patient was . drs ($ . . ). ii) partitioning total tc per group of drugs reveals : ( ) %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %. t ) concerning antibiotics which consist the major cost component, group a and group b contributed by . % and . % to the total icu tc respectively. group b were administered to . % of all icu patients. conclusions : i) for the above studied patient population antibiotics consist almost half of total tc followed by protein substitutes and immunomodulation agents. ii) if tc control could be attempted in the icu, prescription of beth groups must be reviewed. appropriate treatment should be prescribed and readily provided to any patient. clinical significance of routine protein substitution, currently controversial, should be re-evaluated. new antibiotics (third & fourth generation cephalosporins, quinolones, carbaponems) should be prescribed on the basis of strict diagnostic procedures using modern technology available. rationalisetion of antibiotic therapy will lead to cost control, redistribution of icu expenses and substantial contribution to infection policy in our country. objectives: i -to investigate the clinic efficiency of the monitoring of the rso cerebral, in relationship to the stroke prevention, in patient undergoing carotid surgery. -to determinate the variations of the rso during the different surgical and anesthetic procedures in these patients methods: ten patients undergoing carotid endarterectomy. precise neurological exploration previously to the surgery and in the immediate postoperative period. angiography evaluation to the extend of carotid artery disease. invasive blood pressure, ecg, pulse-oximetry ( pso ) and rso were collected previousty to the induction of anesthesia. the premedication was administered intravenously -midazolam ( mcgr/kg) and fentanyl (i rncgr/kg) -. thiopental ( mg/kg),fentanyl ( mcgr/kg) and atracnrium ( , mg/kg) have been used for induction of anesthesia. co te is monitoring al~er the orotraqueal intubation ! the anesthetic maintenance is accomplished with lsofluorane ( , - , %) and bolus of atracurium and fentanyh the surgical procedure is standard (without arterial shunt during the carotid cross-clamping). we register each minutes: blood pressure, cardiac frequency, pso , co te and rso . the rso cerebral variate in relation with: the anesthetic induction, blood ~ressure, co te, cross-ulampping carotid and with the modifications of the head position. the maximum decrease of rso cerebral was in relation with the :ross-clampping carotid ( minimal value: ). no patient had neurologic complications and postoperative stroke after carotid endarterectomy were not observed. objectives: there are more than anesthesia in chelyabinsk emergency hospital every year. to % patients of it emergency anesthesia is applied. more than patients have ishemie heart disease (ihd), hypertansion (hp) and previos miocardial infarction (pmi). more than % of all patients are old patients (op). the resalts deep noninvasive bioimpedance monitoring (nbm) in surgical patients have been studied by us. methods: our nbm system "kentavr" includes parameters of cardiac and vessels function. it is realised by monitors in operation theatres and computer network. moreover we are able to examine surgery patients before anesthesia and perioperatively by using special computers system for cardiovascular reflex control by fast fourie transform (fft) of parameters simultaneously. results: pathients extremly needed peryoperative monitoring of hemodinamics. from these patients more % had stroke volume (sv) less than ml, n -co less than . /mim/m , % -ejection fraction (ef) less than n and % -puls bioimpedans microvessels (pbm) less than morn. patient had intensive care in special department. out of died. comparing with survived with these patients before operation hr was larger, sv, co,ef, pbm and puls bioimpedance aortha was smaller. much more of these patients were with ihd, pmi, hd, op. even with survived patients these parameters decreased the towards the end of operation. surgery patients had different variability of basic hemodinamical parameters with common tendency to increase power amplitude in low frequency by fft. conclusions: using of bioimpedanee noninvasive parameters allows to have criteria for corrections (infusies, vasodilatators, inotrops and others) and then us the final goal, to have more sucssesful surgery. with survived patients was perioperatively and postoperatively care more intensive. obiectives: the aim of the study was to compare the phi with the hemodynamically derived tissue oxygenation indexes as: oxygen delivery (do ), oxygen consumption (vo ), cardiac index (el), and arteriovenous difference in oxygen [(a-v)do ]. methods: patients ( males and females) with major trauma or major abdominal surgery were studied. on admission, a nasogastric tube allowing phi measurement was introduced and a pulmonary artery catheter was inserted for optimal hemodynamic management. each phi measurement was accompanied with a complete hemodynamic study comprising systemic and pulmonary artery pressures, blood gases, and cardiac output measurements with the thermodilution method. derived parameters vo , do , ci, (a-v)do were measured according to the standard formula. hemodynamic parameters were opt• as soon as possible with fluids, inotrepes, and vasopressors according to repetitive hemodynamic measurements. all patients were under mechanical ventilation. after hemodynamic stabilisation phi and hemodynamic measurements were repeated every eight hours, during a -hour study period. a total number of measurements were obtained and compared. statistics: results are presented as means + sd, correlations were performed between phi and the hemodynamically derived oxygenation parameters. a p< . value was considered as significant. results: mean values were phi= . + . , do = + , vo = + , c. = . + . , (a-v)do = . + . . no correlation was found between phi and do , phi and vo , phi and c.i, phi and (a-v)do . on the contrary in patients phi remained below . for more than hours despite adequate hemodynamically derived tissue oxygenation parameters. mortality in this group of patients was very high ( %). conclusion: no correlation was found between phi and the hemodynamically derived tissue oxygenation parameters our data suggest that phi is a better oxygenation indicator than the hemodynamically derived tissue oxygenation parameters, because it is closely related to the patient's outcome. objectives: the pathogenesis of septic shock and multiorgan failure is believed to be related to tissue hypoxia of the gastrointestinal tract. therefore new monitoring techniques, preferably organ specific, are required to establish the adequacy of tissue oxygenation. peep is used to reduce pulmonary shunt volume and improve blood oxygenation, but is accused to impair splanchnic perfusion. we studied mucosal oxygenation and perfusion on the capillary level in the stomach and the duodenum. methods: we used the erlangen microlightguide spectrophotometer (empho ll) together with a specifically designed fibre probe (bodenseewerk ger~tetechnik, berlingen) in combination with a standard gastroscope. measurements were performed on ventilated, traumatized patients (ages - years), with no evidence of shock or severe infection, after informed consent was obtained from the relatives. all patients were hemodynamically stable without inotropic support. an area of cm was analysed in the gastric corpus, the antrum and in the duodenum. in three patients we simultaneously measured the muc sal blood flow using a laser doppler flowmeter ( objectives: to investigate the influence of hb-o affinity in the monitoring of svo~ during improvement of cardiac index (ci) in cardiogenic shock. design: to state whether changes in svo: were associated in changes in actual pso (p~ ) and standard p~ (ps st) consecutive measurements of artero-venous bga, before an.d after therapy-induced changes in ci, were evaluated in patients (mean age -* y) suffering from cardiogenie shock, all under mechanical ventilation in psv modality. methods: together the hemodynamic measures, m~xed venous samples were analysed at ~ c using the abl radiometer for po , pco: and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the p~ at ph= . , pco:= mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood as was the ps "in vivo" (i.e. the pso at the patient's value of ph, pco and temperature), using siggaard-andersen's computerizated algorithm. mean time between paired measurements was . -* . houm. the data were compared by anova test for linear regression and t-test for paired samples. results: a dose linear relationship was found between svo and oxygen extraction ratio (oer), r= . ,p= . . the improvement of ci ( . -* . to . + . l/min/m , p< . ) induced a significant increase in svo~ ( . -* . to . • . %, p<. ). a significant decrease in p ( . • . to . • . mmhg, p< . ) without any significant change in p~ st ( . • . to . • . mmhg, p=ns) was also found. these data show that either oer or the shift to the left of the oxygen dissociation curve account for increase in svo occurring with restoration of systemic blood flow. the program is intended to help the intensive care unit interne providing him with a practical tool when making decisions concerning patients in a critical condition. in his daily practice in intensive care unit, in this case the interne of the unit, uses this program for each patient as follows: on the first stage of data collection he should complete the following modules: ( )personal data ( )patient's pathology ( ) laboratory and~ monitor lug data ( )drugs prescribed or toxic elements ingested. in this way, the system allows optionally the consult with a computerized data base about the drugs prescribed, standardized parameters and techinques performed by the central laboratory. ( )reference to an antibiotics guide regarding becterian sensitivety in our unit, whitch ee checked every six month ( ) access to de questionnaired apache ii to load up new data. ( ) statistcs about patient's admission and discharge. results: once all data collection is finished the system performs the followin duties: ( )detailed drugs interactions, including toxic elements ( )diagnosis starting from the clinical, laboratory and monitoring data. in some cases, it also establishes therapeutic strategies, e.g. a coagulopathy ( ) give the l~narmacological incompatibilities between the drugs p~escribed and %he diagnosis established, and ( )perform dosage adjustments based upon the personal and pathological data. objeatve: to assess the power of diseri~,~ion ofa multiperpose severity score (sai~) when applied to subgroups ofpatieals (pta) according to their lemg~ of ~ay (los) in icu. design: in order to compute the saps probability, a model derived fi~m legible regression was developed. meaumree of calibration (goodmem..of.fit statistics) end discrimination (roc cm've and relative area under the cm've) were adopted in develotammtul asd validation set. the whole databue was ~ati~ed in five gronps reeked on los as follows: los = days, los = - days, los = - da~, los = - days, los > day~. area under the carve (auc) was ud~ninted for each ro~. s~ing: imlimlcus. patents: of ~ pts comec~ively admired ~ a period of three yeet~ ( ) ( ) ( ) , a total of was i~leded in this study. pts without saps, p~ yolmger them yearn, p~ with los shorter ~ hom'~ were excluded from this maly~is. iaterventinns: nose mema'onm~ end result: the logistic model developed gave good remits in terns of calibration md discrimin~on, both in developmental set (do.s g : . , p > . ; auc = . i- . ) and in validation ~t (g.o.g g : . , p > . ; auc = . ..+ . ). auc of each grottp showed a loss in di~zimination (i.e., prediaton) closely related with los, being . i- . in pts with los = days el . ~. ia tm with los > da~ (figure). following the present guidelines of integral management, in order to achieve optimization of sanitary resources and better use of facilities, we feel that the setting up of objetives is a key factor in the continuous process of improvement of quality care. postsurgical intensive care services maintain an interdepent relationship with other hospital services. within the general plan of the hospital it's of the utmost importance to delegate autonomy to the various depertments and service units in determining and achieving objetives. it's also necessary to establish mechanism for coordination of the activities in order to assure the succes of the program. the objetives cannot be improvised, they must be carried out in a specific manner in the following stages: .-analysis of the present situation (starting point). where are we?. defining objetives and making explicit the activities and methods to achieve them is to anticipate the future; it is of the utmost importance to comunicate said plans to all whom affect by encouraging them to attain the desired results. in the present paper we intend to show the guidelines to follow in carrying out a course of objetives. introduction:we presents results related to the quality of life (qol)of critical patients, from paeec project data. material and methods: the paeec project is a multicentre study define the type of patients cared for in spanish icus, and the therapeutic activity provided. ninety-five icus from spain are taking part. this study analyzes the qol of critical patients prior to their icu admission.for the evaluation of qol a questionnaire designed by our team for critical patients was used, with items grouped in sub-scales: physiological functions ( items); functional capacity ( items) and subjective aspects ( items). qol is classified in levels: normality ( points); slight deterioration ( - points);moderate deterioration ( - points); significant deterioration (>i points). the we present results related to therapeutic activity in critical patients and their age, from the paeec project. material and methods: the paeec project is a multicentre study to define the type of patients in spanish icus, and the therapeutic activity provided. ninetyfive icus from spain are participating. this study analyzes therapeutic activity in the first hours as evaluated by tiss, and related factors. results: the sample was , patients, sge . ~ . years. severity by apache ii system was . • points. the tiss score was . • points, distributed as follows: i (<i points): %; ii (i - points): %; iii ( - points): %; iv (> points): %.there is a positive correlation between the level of therapeutic activity and severity by apache ii (r = . , p < . ), and a very weak but negative correlation between tiss and age (r = - . , p < . ), so that an increase in age corresponds to a lower level of therapeutic activity.patients the multivariate analysis of the relationship between tiss and age took into account: severity, existence of previous history, need for mechanical ventilation, size of hospital, diagnosis and mortality. it indicated that there continued to be a relationship between therapeutic activity and age, so that as age increased, therapeutic activity diminished. conclusions: therapeutic activity performed on critical patients is less in the oldest patients, in whom excessively aggressive procedures are limited. a relational data base management system in the icu. c. kotsavassiloglou*, d.matamis, g. dadoudis, j. kioumis, d. riggos. icu dep., g. papanicolaou gen. hosp., exohl, thessaloniki, and * a' neurological clinic of aristotelian university, thessaloniki, greece. objectives: the introduction of the information technology in the i. c. u seems to be unavoidable because of the large amount of produced data and the need for their systematic analysis. such an information system should be a) easy to use, b) friendly to the user, c) powerful and d) modular. on that basis, we created a patient data management system (pdms) according to the expectations of the medical staff of an eighteen bed multidisciplinary icu. methods: we selected paradox for windows v . for the implementation of a relational data base because this program meets the above mentioned criteria. informations regarding the patients include a) demographic data, b) previous medical history, c)diseases upon admission, d)complications during hospitalization and e) outcome data. the diseases' registration consists of items classified in categories upon the principal system affected. specific informations about the need and duration of mechanical ventilation, nutrition, renal replacement, right heart catheterization and icp monitoring are also available. an extension was added concerning icu infections and related informations about antibiotic-resistant pathogens. all icu pathogens can be matched to their resistance or sensitivity and cost of antibiotics. the program can perform queries and various statistical analyses based on complex criteria. new modules can be added later according to the future needs and remarks of the users. results: the program was well accepted by the medical staff and patients were registered as a test. the first analysis of the data related a) observed mortality versus the apache ii predicted mortality, b) mortality according to the age, gender, pathology aud duration of icu stay and c) pathology upon admission and icu related complications. conclusions: the long term use of this pdms can be an efficacious research tool. it can be used in retrospective or prospective studies by addition of necessary modules. the first data analysis revealed the iack of an international diseases' classification system. the development of a worldwide common classification system is essential for the compatibility of the data analysis among various icus. this will allow the realization of multicenter trials on a large scale. s. nanas= n. sphiris, a. precates, a. lymberis, m. pirounaki, and ch. roussos dept. of critical care, university of athens, athens, greece the complexity of the cases submitted to an icu, the variety of underline disease, tbe severity, as well as the large number of substances administered to each patient constitute obvious the need of support with an easy available dss. this system will assure the safety of the administered treatment will help to adjust the dose according to the situation of each patient and it will screen for possible interaction and incompatibilities between the administered drugs. the goal of the present effort is the design and development of a software system acting as a decision support tool to physicians of icu. the application is organised around a relation database management system (rdbms) that consist of: a) all available substances ( . ), b) all generic names of medications available in our country for each substance, c) incompatibilities ( . cases) and d) interactions with other substances ( . cases). the following figure shows the structure of the rdbms. y ta~ortato~ [ c~rs using the stored parameters for each patient the dose and the rate of administration of selected substances will be possible to calculate. the continuous monitoring of the treatment for each patient supports the medical staff to make the necessary changes of the prescriptions. the application is currently developing in wireless pen based computer systems which place patients at the centre of "islands of information" located throughout icu. in conclusion this dss is a powerful and useful tool for icu staff because it provides without additionai work to the routine of daily practice, the currently available information for each order concerning drug interaction and incompatibilities as well as treatment monitoring is to obsea~ among critically ill pfdieats, stdjdivided following the diagn~s at the adn~ssio~ the diffmeax:es in the ~ and oxyplx~efic l~mmems bawe~ strvwors [s] and non sumvors ins] and to test the pc~'bih'ty to have soar survival criteria, as earliest as tx~able. method~ :we made a ~ study on consexa~e ~ilically ill paliffas, subdivided in series following the diastases at the admission: medical pafiea~ ( s and ns), surgical patients ( s and ns), a~d poliwauntas ( s and ns). follow up was done at d,.ays from the admission in ice. all the patienls were ramitored with a ~ c~eter and laeno:lymmi. "c and o .x.xyphorefic txuamaers va:~e couected at fin~es (t): at fiae ~draission (t ), at x~ars from t (t ), at (f ), (y ), (t ), % (t ) and horus from t cf ). in~,h ~ies, for ~y ~ a all the lin'~ n~an and sandaid d~viation was ~ tx~h for s and for ns. th~ betw~ s and ns tl~ roeaas of ~h porarneter ~e ccmpared tt~ng t-lest and p < . w~ considered ska~ significant in each series in the t wheae the mast significative diffemx:as ~goeamd bet~en s and ns, we made a txedictive criterion, asamting as predictive indices for stnvival the i:r values, higher or lower than flae treans of the ~rar~ers of au flae patients, axx)rdhlg to those ones t~iatistically diff~'e~ betw~m s and ns. fhmlly xse co:weatxt onaong the series the nrametees of the st~rs with the analysis of variance, to daserve the lxjsable differealt irea~ of sty hflices, following the diagn~s of admission: :nedkal, angical patient or poll~tam results: we c~ld not find ~ predictive criterion for politraonaas, perhaps ixx:ause of the few ntanber of l~fients. for high ri~ saw~cal patieras the following criterion at t has a sensitivi .ly of ~ ,and a ~ecificity of . %: sv > . nffmin/n~, map> mmhg, pmap< nmalqg cvp<i nunhg will nmah& lvswi> g m/m , sxo > ~ do > mlhnin/m , o er< %. for lx~dical l~tienls at t the following criteric~a has a ser~tivi.ty of % and a ~zificity of . ~ cvp< . mn~g, sao > %, s,g) > ~ vo i< ml/nfin/m , o er< %, shunt< % survlvops' data of the series ~ signitic~atly differenl~ both for the t~mody~nic a~ for fl~e ox rphomfic lxlmn~s; moreover we ~ that the vatt~ of hemodynamic mad ox.~ho~tic indices were higher in politrautms. conclus'ions: acx~ording to the fftffe~mt patho!o~es, the ~ rnelabo~c needs are diffeten~ so that it is juslified to mash ~ the~alceutic goals, following the type oflmthology. hen~ we foru~d for high ~k mrgical pmka~ and for medical patier~s assme, ff mllslied, a good prognosis while, if n [ ntljsfled~ the plinsliclioil ofdl~tth is no[ g(ioct finally, ab~ high iis~ supgical palieaats, according to what other atmhors say, txatws sh ~'n~ers ' therapeutic goalsvvould seem inadeqt~te, bec~jse they need a gear physiologic and themtx~ic elth~ in rdation to the rretabolic needs. figure ) . thus, the smaller european nations had a greater participation than ~e larger ones, with the exception of norway. a similar result was evidenced for contributions to intensive care medicine (figure ). these findings can be explained by different submission policies and language banners. however, there was no significant correlation with the gross national product of each country. conclusion: we conclude that the smaller european countries generally contribute more to international intensive care journals than the larger ones. objectives: to evaluate the agreement between a new and three old methods measuring ctp and to assess their reproducibility. methods: we studied patients ventilated with a siemens c respirator. we measured ctp by dividing the tidal volume with the increase in airway pressure (paw), either with the respirator setting used (ca) or with a fixed setting (cf). by modifing the inspiratory time (ti) without changing inspiratory flow, we were able to deliver two series of inflations ( , ,... ml) before and after curarisation of the patient. the same volumes were also inflated in paralysed patients with a super syringe. at the end of each inflation a plateau of sec was performed and paw was recorded. the above three sets of pressure-volume (pv) points were used to reconstruct the corresponding pv-curves (( , c , c the new method for ctp measurement without a super-syringe had the best reproducibility in paralysed patients and gave similar results without curarisation in the majority of them. however, agreement between the methods tested was unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of ctp measurement in icu patients. m kunert, r.sorgenicht, l.scheuble, k.emmerich, h.g ker med.clinic b (dept.of cardiology) i heart center of wuppertal/university witten-herdecke,germany objective to determine the accuracy of activated partial thromboplastin time (apl-l) and activated clotting time (act) studies when samples are drawn through heparinized central venous catheters (cvc). methods a total sample of paired act/p't-/" values was analysed in patients ( m., f., + y.) for monitoring heparin therapy.all patients had a cvc (certofix trio,braun,frg) in the internal jugular vein receiving a continous infusion of . u heparin via the central catheter.act (hr-act, hemotec,usa) and ap'i-f (neothromtin, behring,frg) samples were drawn from the cvc using the double syringe technique (removing and discarding ml blood before drawing the sample). these blood samples were compared to act/ap'cf blood samples obtained by venipuncture (v.fem.) at the same time, act values were analysed directly in the intensive care unit (icu),api-i samples were measured in the hospital laboratory within minutes. results ac-i -~ pi-f~ cact/~pi r = , ) cvc samples + + . v.femoralis samples " + + p-value n.s. n.s. conclusion there is no difference in heparin anticoagulation studies drawn from heparinized central venous catheters compared to those obtained by femoral venipuncture,withdrawing ml blood prior to obtaining the blood specimen is a safe way for eliminating heparin contamination.not only the aptt test but also the act test is a useful method for heparin anticoagulation assessment in the icu. objectives: evaluation of the delicate balance between filter-coagulation and patient-hemorrhage using heparin as anticoagulant in continuous renal replacement procedures. methods: from january through august , we studied filter surviva[ and hemorrhagic complications during filter periods in critically d[ patients, treated with continuous arterio-venous hemo(dia)filtration, with special emphasis on the heparin dose, concurrent use of coumarins, systemic activated partial thromboplastin tirne(aptr), platelet count, mean arterial bloodpressure and the type of filter used. results: filters ( %) were disconnected because of coagulation. mean survival of multiflow an filters was twofold shorter compared to survival of fh gambm filters. a total of hemorrhagic complications occurred of which three patients died at aptt values of respectively , and seconds. after adjustment for mean arterial bloodpressure, platelet count and the type of the filter, the risk for filter-coagulation decreased % (relative risk . , %c . - . ) for each ten seconds increase in aptt. the risk for patient-hemorrhage increased % (relative risk . , %ci . - . ) at an aptt-increase of ten seconds. the occurrence of filter-coagulation and patienthemorrhage was not correlated with the administered dose of heparin. concurrent use of cournarines had a positive effect on filter-survival, without increasing the overall incidence rate of patient-hemorrhage. conclusions: the systemic apt]" is a good predictor of the risk for filtercoagulation and patient-hemorrhage. heparine therapy seems optimal at an aptt between and seconds, although one should realize that fatal hemorrhagic complications still can occur. objectives: the alterations in vascular tone which are primarily regulated by adreno-sympathetic tone(ast) are compensatory responses in hemorrhagic patients. this study was designed to evaluate the correlation between vascular tone and ast in patients with hemorrhage, methods: the vascular tone was expressed by volume elastic modulus (ev) that is defined as; ev = ap/(av/v) (ap; the arterial pulse pressure, av/v; the volume change ratio). ev was measured using a non-invasive transmittance infrared photoelectric plethysmography (tipp) and a volume oscillometric sphygmomanometer . we prospectively studied patients with hemorrhage. the initial ev measurement was performed on arrival and repeated for a hours duration. as a parameters of ast, serum concentrations of adrenalin (ad), noradrenalin (nor), plasma renin activity(pra) were measured simultaneously. we analyzed the correlation of ev and conventional parameters to ast by multivariate statistical analysis. results: ev values at transmural pressure mmhg on admission and hours later were respectively . + . mmhg, . +_ . mmhg (mean + sd). systolic pressure(pas) and serum hormones on arrival and hours later were respectively, pas; . _+ . , + . mmhg, ad; . _+ . , . _+ . ng/ml, nor; . _+ . , . + . ng/ml, pra; . _+ . , . _+ . ng/ml/hr. the ev values correlated significantly with ad (r= . , p= . , n= ), nor (r= . , p= . , n= ), pra (r= . , p= . , n= ). by multivariate statistical analysis, ev correlated more significantly with ad and nor and pra (p= . ) than the conventional parameters such as pas, heart rate and pulse pressure. conclusions: the alterations of ev correlates closely with ast. the compensatory mechanism in hemorrhagic patients can be detected noninvasively by ev monitoring. obiectives and method: autologous oxygenator blood was processed at the end of cardiopulmonary bypass (cpb) by either hemofiltration (hf , , m , fresenius) or by cell washing with a onntinous autologous transfusion system (cats, fresenius). prospectively the blood of patients for each group was processed and then retransfused intravenously to the patient. besides, volume and time requirements, standard hematologic chemistry, coagulation and complement activation were measured. results (mean values for oxygenator blood at the end of cpb, and results of concentrate after processing by filtration or washing): both processing techniques show excellent hemoconcentration of the diluted cpb blood with a good transfusion effect for the patient. filtration retains all plasma proteins and large molecular weight plasma bound waste products. in contrast, cell washing with cats significantly depletes plasma proteins and waste products. the newely developped cats machine gives eonsisinnt laboratory result in a fully automatic continuous processing mode. in conclusion, both filtration and washing are effective for processing cpb blood. filtra tion yields a highly concentrated whole blood, whereas cats washing produces a high quality autologous erythrocyte concentrate. soluble fibrin has during the last years gained interest as a marker for the activation of the coagulation in connection with various clinical conditions, e.g. disseminated intravascular coagulation, deep venous thrombosis and myocardial infarction. elevated levels of soluble fibrin in plasma can be detected by the chromogenic assay coaset fibrin monomer, relying on the ability of fibrin to enhance the tpa-catalyzed conversion of plasminogen to ,plasmin. using this test, it has been shown that the level of soluble fibrin can be correlated to severeness of illness in critically ill intensive care unit patients. a revision of the coaset fibrin monomer kit has now been made and the new product, coatest soluble fibrin, is considerably more convenient to handle and gives higher resolution at low fibrin levels. the test is performed by the addition of a buffer dilution of the plasma sample to a microstrip well containing the colyophilized mixture of tpa, plasminogen and the plasmin specific cbromogenic substrate s- . the reaction is allowed to proceed at,. room temperature for minutes before discontinuation. the absorbance at nm, measured in a microplate reader, is proportional to the content of soluble fibrin in the sample. the assay is carefully standardized and calibration curves are provided in the kit. the convenient and rapid assay procedure makes the coatest soluble fibrin test well suited for single test analysis in acute situations. objectives : blood coagulation abnormalities have been reported in the systemic blood of patients with cerebral lesions. the physiopathology of such events is not yet completely understood. we compare the coagulation profile of blood from the right jugular bulb with systemic blood of patients with head injury. methods: we studied patients, who were admitted to our neurosurgical intensive care unit between january and march with head injury and no other associated pathology (age - yrs), a glasgow coma score <= g, no abnormality in baseline coagulation profile and no history of coagulopaties. the patients did not undergo angiography. a one-way gauge certofix catheter was inserted through the right internal jugular vein up to the jugular bulb. an identical catheter was inserted through a subclavian vein. blood was sampled from either catheter (a=atrial; j=jugular) - hours after trauma (t ) and t hours later (t the inddence dpontolx'rative thmmhi~e and haumord~gic complieatiom were assessed in padents treated with indobefen, heparin calcine caeca), low mollecolar weight heparin (lmwh) (f.nosheparin) and undergoing hemodiludun, blood predeposhing, intra mad postoperative blood saving. ]'he indolmfon tempota~.norks platelet aggregation through ,,elective inhibition of the cyclatygenasis and thus atacbldonicadd( ).tbe n'mimum effect occurs after hours from the fast administration and is still present after hours. ~- patients, mean age --- yrs., weight --- kg were studied. ( . %) were male and ( . %) female. onderwent hip prosthesis ( previously plate and screw removal) hip revim'un ( stem, cop and stem + cop), tutal knee prosthesis, in the st anaesthesidogy depl from - to - - . as for antithromboembolic ptephylam, apart from hemodihitiun pts were with treated indobufen ndo), with heparin ealdum caeca) and with low mo!lecular weight hepam (lwr, ). as the slightest clinical and/or imtmmental suspidon of deep vein thrombosis (dv'i') or polmonary umbolism(pe), a phlebogram or sdndgram were respectively carried out. -the inddence of homologom transhisiom was significandy lower (p= . l) in the padeats treated with indobufen ( . ) compared .'ith heca ( . %). the con~gency table shows statistical signifleance for the use of heca in patients with vein deficiency in the lower limbs, past dvr and/or pe, coronary heart disease (cdh'), while there is no correlation for renal, cardiac or liver defidency, obesity, systemic hypertemion, atrhythmy, diabetes, chronic bronchitis and rheumatoid arthritis. by comparing the postoperative cumplications with the risk factors, there ks a highly significant correlation (p= . l) between cdh and thrombotic and humord~agic complieatiom (pe, death, he~atoma, die use of hum_ologous blood). thee data show that hep~in, preferred in patients with c'dh, roost likely for leagal-tuedical reasons, did not have the de~'ed effect. conclusions -the stastisfical aar~ais shows ~nifieanfly different efflea~ (pro . ) between the therapies (see table) : it can be seen that in patients undergoing autotramfusiun and hemedihidon, indobufen produo~ a lower incidence of haemotrhagic complieatiens compared to heca and lmwh and is more effective in the prevention d ~c complications at clinical e~idence. the duration of i~toperadve hospital stay is signi~cantlylonger for patients transfused with homologous red ceils and treated with hec, .a ( . -+ . days) and lmwh ( . +- a days) compared with indo(ll. _+ a days). one of the main causes for postoperative complications in major orthopaedic surgery is postopemtive bleeding with local effects in the operation site (hematomata, pain and delayed mobilization) and/or systemic and subsequent cardiodrculamry repercussions that are sometimes severe. the aim of this study is to assess the possibility to apply a new system of monitoring, control and saving postopemtive blood loss from the drainage. the bt recovery dideco (marandola, modena-italy) ~ used since it is the only apparatus capable of doing this. the apparatus consists of a pressure transducer, adjustable from - a + mmhg, which activates a peristaltic pump connected m drainage robes. the bt recovery display shows hourly bleeding in the first hours, total bleeding, time passed since the start of monito~g and subsequent salvage and the aspimtioo pressure on the drainage robes; the latter is inserted at - mmhg and then modified according to bleeding/minute, g bt recovery also has an alarm that sounds automatically if.' blood loss is more than ml/hour; air is in the circuit; the batteries are running low. materials and methods: pts were studied ( m and ~), aged . -+ .lyears, basal hemoglobin . -+ (range . - . )g/all, treated from st january, to mst december, in the st service of anesthesia and intensive care unit of our hospital. the patients underwent the following surgical treatment: total hip revision ( pts), cup revision (~ipts), stem revision ( pts), total knee revision ( pts). the average dumtion of the operations was -+ min. intranpemtive monitoring and blood salvage was applied to all patients. genera! anesthesia was used on pts. and integrated (epidural analgesia + light general) on the remaining t . anttthromboembolic prophylaxis consisted of external pressure bandage, isovolemic hemodilution with iodobufen in ( . %)pts., calalc heparin in ( . %)pts., low molecular weight heparin in ( . %)pts.; pt did not give a predepoalt of blood, gave unit, pts units, pts units, pts units. the data obtained was statistically analysed using contingency tables and anova. results: average intmop salvage was -+ ml, average postop salvage was -+ mi the average intra+postop +- ml. average postop loss was -+ ml. the global incidence of postop complications was: h~natomata . %, dvt . %, pulmonary thromboembolism , , myocardiac ischemia . %, acute myocardic infarction . %, respiratory deflciecy . %, arrhythmia %, cystitis . % there were nn complications in . % of pts. postop bleeding over ml in under minutes (with bleeding alarm activation) occurred in pts ( . %). this sta~tically correlates only with the type of operation performed (more frequently in total hip revision p= . ) and with a significant decrease (p~ . ) in the pruthrombic activity detected about hours after the operation. this bleeding, also made the alarm sound, calling the attention of staff who could act accordingly, by making the drainage pressure positive and incre~sthg the tension of the external pressure bandage. conclusions postop monitoring, control and blood loss salvage combined with predepoalting and intmop salvage has enabled allogenic transfusions in % of cases to be avoided in operations with high postop blood loss like hip or knee revision. the usefulness of the system can be seen by the fact that in the patients with so much bleeding to set off the alarm, there was no significant difference in the incidence of allotransfusions and complications. references )borghi b., bassi a., de simone n., laguardia am., fonnaro g. an injury of the brain may result in various disorders of hemostasis caused by the release of • into the circulation through a damaged blood-brain bar tier. disseminated intravascular coagulation(dic) is one of these disorders. it is a freguent but relatively rare ly diagnosed complication of subaraohnoidal haemorrhage. the aim of this study was to evaluate some parameters of both blood coagulation and fibrynolisis in patients with sah.in addition one wanted to find out wh~ther potential changes correlated with the pa• condition in the acute phase of sah and whether they influenced the course of this disease. patients with sah were studied. in of them sah was due to closed eraniocerebral injury and in the rema ining resulted from vascular malformation. the following parameters were evaluated:the prothrombine time,the activated partial thromboplastin time, the thrombine time,level of factor v,fibrinogen degrada tion products and fibrin monomers. the results let us show the presence of oic in patients with closed craniocerebral injury and in with vas. cular malformation despite the lack of clinical symptoms the tests in posttraumatic patients and in patients from second group showed incomplete dic.on admission patients with such changes in measured parameters were in poor condition.the course of the disease and the effe cts of treatment were also worse in these patients. the results showed ihal in patients with sah complex disorders of both coagulation and fibrynolisis occur, and they depend on clinical condition of the patient. they also influence the course of the disease. methods : charts of all patients admitted with d.i.c. over a ten year period ( - ) were reviewed. diagnosis of dic was based on the association of fibrinogen < g/ -platelets < / -fpd > ~tg/ml in the hours of the admission. results : patients -mean age + y -saps +_ -gestanional age _+ weeks -the two first conditions associated with d.i.c. were placental abruption ( %) and preeclampsia or eclampsia ( , %). bleeding episode was present in pts ( %) and surgical treatment has always been necessary. pts ( %) were given packed red ceils ( + u) and fresh frozen plasma ( + u). patients were given platelets packs. heparin was never administered. pts required mechanical ventilation and two patients hemodialysis. all the patients survived. correction of prothrombin time (p.t.) and fibrinogen (f) was quick (p.t. at t h ~ % -f at t h , + , g/i). but platelets count remained low (plat. at t h + / ) -no difference was observed in patients who received platelets. conclusion : prognosis of critically ill o.p. is good. blood loss is the main complication. correction of hypovolemia and anemia with concomitant surgical treatment are essential. the administration of coagulation factors or platelets is still under discussion. objectives: to evaluate the effects of antithrombin iii i at-iii) and a protease inhibitor, gabexate mesilate foy), on the coagulation and fibrinolysis in disseminated intravascular coagulation (dic). methods: after the approval of our institution and consent from patient's family, patients with a dic score ( , japan) more than points (dic or having a risk for dic) entered this study. they were randomly divided into two groups, foy (i- mg/kg/h for days or more) treated group and no foy group, each of patients. platelet count (plt), fibrinogen (fen), at-iii fibrin degradation product (fdp), d-dimer (do), fibrin monomer (fm), thrombin-antithrombin complex (tat), plasmin-plasmin inhibitor complex (pic), and prothrombin time ratio (ptr) were measured before the start of treatment (at admission) and i, , and days after the admission. at-iii at units for days was administered if the at-iii at admission was less than %. finally the patients were divided into four groups: group a, foy (+) and the at-iii ~ %; group b, foy (+) and the at-iii < %" group c, foy (-) and the at-iii %; group d, foy (~) anffthe at-iii < %, each of patients, to match the patients for backsrounds. all parameters, dic score and survival rate in a month following treatment were compared among the four groups. results: the at-iii and plt from day to were significantly higher in groups a and c than in groups b and d. the fdp, dd, tat, and pic after treatment decreased significantly from the baselines in groups a and c but not in groups b and d. the fgn and fm were not significantly different among the four groups. the ptr decreased in groups c and d but increased in group b. the dic score decreased significantly in groups a and c than in groups b and d. survival rates were %, %, % and % in groups a, b, c and d, respectively, although not significantly different. conclusions: in patients with dic or a risk for dic, foy had no expected effects but at-iii had suppressive effects on the coagulation and fibrinolysis mechanisms. a prognostic factor ? carbon monoxyde intoxication is a classical complication of inhalation injury. carbon monoxyda is also physiologically produced during the heme metabolism: heme is conversed to bi]irubin by the hemeoxygenase which is an intracellular stress protein. icu patients (pts) were studied prospectively for apache ii score and carboxyhemnglobin (hbco) arterial level to assess if hbco level could be correlated with the severity of the pts. objective: to evaluate a new technique of non-surgical tracheotomy. patients: adults, mean age years and children, mean age months ( me.- yrs). method: through a needle inserted in the trachea, a guide wire is retmgradely pushed out of the mouth and attached to a special device formed by a flexible plastic cone with pointed metal tip joined to an armoured tracheal cannula. this device is then pulled back through the oral cavity, larynx and trachea, and outwards across the neck wall by applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the operator's other hand. when the cone and / of the eannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. results: endoscopic control facilitates and improves the safety of all manoeuvres. the pointed cone easily pierces the tissues, and the cannula is extracted without difficulty since it has the same outer diameter as the cone. tissue adherence around the cannula is absolute thus preventing local inflammation. the time in apnea required for dilation and cannula placement does not exceed see., and it is well tolerated because within safety limits in patients hyperventilated with oxygen. only one case of bleeding occured in a patient on dialysis with severe coagulopathy. autoptic findings in subjects who died due to progression of primary disease showed a very regular stoma with an almost complete lack of hematic and flogistie infiltration in recent tracheotomies. .conclusions: translaryngeal tracheotomy (tlt), by virtue of its greater inherent safety and lower tissue trauma than percutaneous techniques, can also be carded out in infants and children, a severe test bench for any tracbeotomy technique. further specific indications are recently stemotomized patients, since tlt is associated with a low rate of infection, and short term tracheotomies after laryngeal surgery, to prevent obstructive complications. references: fantoni a., translaryngeal tracheotomy, apice, ed. gullo, trieste, , . background: inhalation of no has been shown to reverse hypoxic pulmonary vasoconstriction , to reduce pulmonary pressure in pulmonary hypertension of different origin and to improve gas exchange. in putmoflary embolism, pulmonary hypertension is caused by mechanical vascutar obstruction and by reactive vasoconstriction. the effects of inhaled no in putmonary embofism has been partiatly studied' the purpose of this study was to investigate and determine the effects of no inhalation on pulmonary hemodinamica and gas exchange in a hypoxic canine model of pulmonary embolism. methods: two groups of adult mongrel dogs were studied: group (control} dogs and group (no inhaled) dogs. both groups were anestesized with tiopental, mechanically normoventilated with an hypoxjc mixture of and n~ (f[q , ) and instrumented (swang-ganz catheter, femoral artery catheter) pulmonary embolism (pe) was induced by fisher's method s. no inhalation ( ppm) in group was started rain. pdor to pe and kept constant throughout the experiment. no inhaled concentration was analyzecf by chemiluminiscence technique. pulmonary artery pressure (pap), central venous pressure and sistemic arterial pressure were continuosly recorded. cardiac output, artedat po~ (pan ) and mixed venous po~ were measured in both groups under hypo)dr conditions, before pe and , , and rain. after pe. pulmonary vascular resistance (pvr) and gas exchange (pao fio:~ ratio), were calculate using standard formulas. data were process and analyzed with non pararnetdc test, and reported as mean -so and statistical significance was considered if p < , . : no produced an increase in arterial oxigenation (pao /fio~ ratio) and reduced pap before pe induction in group . after pe we found no significant difference with .respect to the time eour.se of pap, pvr and gas exchange between beth groups throughout the experiment. probably, the severe mechanical obstruction produced in pulmonary embolism masked the small effects of no inhaled. obiectives: blood volume measurement would be useful in critically ill patient management if it were easy to perform. this is not the ease and current methods are based on radiolabelled red cell dilution. inhalation and uptake of a known mass of carbon monoxide (co) gas and measurement of earboxyhaemoglobin increase can give results accurate enough for clinical use. this requires a rebreathing system providing oxygenation and carbon dioxide removal, yet complete retention of all carbon monoxide administer&l, and so most authors hand ventilate with a bag and waters soda-lime canister, adding oxygen as necessary. we aim to popularise this method by; i)design of an automatic co administration system driven by the itu ventilator and ii)writing of software for a portable computer to perform all necessary calculations method: we show the computer is use estimating the co dose required and later estimating the blood volume. we also show the new gas administration system. this is a fully closed circle attached to a "bag in bottle", driven by the ventilator. the novel feature is the mechanism by winch driving gas (set to % ) spills automatically into the circle, balancing o uptake by the patient, yet allowing no co loss. conclusions: this equipment is easy to use, reduces human error and allows optimum ventilator settings to remain. the operator merely administers the volume of co determined by the computer and takes blood on two occasions. carboxyhaemoglobin measurement is easy to perform, thus there is a cost saving also. with our modifications use of this technique may potentially become more widespread, the video demonstrates the method in use in our itu. - ( %) underwent conventional surgical therapeutics. " ( %) with resection of tracheal stenosis with end-to-end anastomosis(rts). i ( %) with broncoscopic dilatation. one patient died and the others still have stable patency(sp) without continued treatment. - ( , %) have received endoscopic laser ablation with or without calibration tubes. of them ( , %) are receiving continued endotracheal treatment until now. ( , %) have sp wihout continued treatment. -i ( , %) endoscopic laser therapeutic case turned to rts and is having sp. conclusion: conventional surgical aproach has been progressively replaced in our hospital by endoscopic laser ablation and silicone calibration tubes. this study suggests that these technics are effective and could be the elective treatment for iatrogenic stenosis. obiectives: hemorrhagic disorders due to thrombocytopenia and thrombocyiopathia remain one of the most serious complications during long-term extracorporeal membrane oxygenation (ecmo) in patients with severe acute respiratory distress ~drome (ards). in the presented study, nitric oxide (no), kwown as a potent endogenous platelet antiadhesive, disaggregating and antiaggregating compound, was evaluated for its possible antagonistic effect on platelet trapping when added to the gas compartment of membrane oxygenators (mo). meti~ods: two parallel separated extracorporeal circuits, consisting of heparin bonded hollow fiber oxygenators (minimax, medtronic, carmeda eioactive surface), tubing systems, low pressure reservoirs, and roller pumps were prepared. for each measurement, a pair of circuits was simultaneously filled blood from the same volunteer. low-heparinized fresh warm blood was obtained from four healthy volunteers, who had no drugs for at least two weeks. the gas inlets of both oxygenators received dry gas ( % oxxygen, % carbon dioxide, % nitrogen); gaseous no ( ppm) was added to the gas of one of the oxygenators (no-mo), whereas the other one (mo) was used as control. after minutes no gas was switched off, so that the no-mo received no more no, and no was added to the gas inlet of the membrane, which had no no before_ to assure iutracircnit volume stability, drawn blood for measurements was replaced with saline, and platelet counts were corrected for dilution by hemoglobin values. the mean of four platelet counts (coulter counter) of each timepoint (start, , , , , , , , and minutes) was used for statistical analysis (paired sample t-test). results: in the no-mo platelets remained at + , % (percentage of baseline value, mean -+ sd) until min. in contrast, platelets of the mo continuously decreased after start and were significantly lower after minutes ( , + , % vs _+ , %(p< . ); min. , -+ , %vs , _+ , %(p< . ); min. , _+ , % ( p < . ). after switching of no gas to the mo, further decrease of plateleta was stopped and platelets remained at , +_ , % until termination of circulation. platelets of the former no-mo decreased slightly after cessation of no gas to , _+ , %. conclusions: these data indicate that gaseous no significantly attenuates platelet trapping in hollow fiber oxygenators, when added to the gas compartment. this might be a new therapeutical approach for membrane oxygenator induced thrombocytopenia during long-term ecmd. objectives: nitric oxide (no) plays a pivotal role in regulation of vascular hemostasis. several studies elucidated the antiadhesive, antiaggregating, and disaggregating properties of endothelially synthesized no to platelets. additionally, agonist-induced no production in platelets by the l-arginine-no pathway was found as a negative feedback mechanism after platelet activation. although noplatelet interactions were intensively studied by several investigators, no data exist, about changes in platelet surface molecule expression in no-modulated platelets measured by flow cytometry using monoclonal antibodies (moabs). methods: p-selectin (alpha-granule-membrane protein, gmp- , cd p) and glycoproteiu (gp , lysosomal protein, cd ) are expressed only after platelet activation and degranulation. activation was quantified in thrombin ( . u/ml) and adp ( . ram) stimulated platelet rich plasma samples (prp). blood was obtained from healthy volunteers (n= ), who had no drugs for at least days. for evahiation of no-modulated activation, the spontaneously noreleasing compound sin-i ( . mm) ( -morpholino-syndonimin-hydrochlorid) was added in parallel prepared samples prior to the addition of agonist. platelet surface molecule expression was evaluated with moabs directed against cd a (gpilbliia, fibrinogen-receptor, phycoerythrin(pe)-conjugated), cd p (fitcconjugated), and cd (fitc). only cd a-positive signals were gated in sideangled light scatter, and assayed for activation marker expression (defined as percent of gated population). results: basal p-selectin expression was . + . %, and increased to . _+ . % after thrembin-activation, and to . + . % in adp-stimulated samples. addition of sin- attenuated p-selectin expression to . - - % in thrombin (p<. , two-tailed paired t-test), and . + . % (p<. ) in adpactivated platelets. basal gp expression was . _+ . % and increased to . + . % in thrombin, and to . _+ . % in adp-stimulated samples. with sin-l, gp expression decreased to _+ . % (p<. ) in thrombin, and . : . (p . ) in adp-stimulated samples. conclusions: these data implicate, that no leads to a significantly reduced activation of surface molecule expression in thrombin and adp-stimulated platelets. in addition, flow cytometry might be a useful tool for studying modulation of platelet activation by no or no-releasing compounds. introduction: acute cadmium poisoning is very rare. on initial presentation may mimic metal-fume fever, but acute inhalation cadmium toxicity may produce fatal chemical pneumonitis. case report: we present a case of acute fatal respiratory failure secondary to cadmium-fume irthalation. a year old patient was trasferred from another hospital with acute respiratory failure presumably due to pneumonia. the last days before he had had commom cold symptoms. he had been cutting with a welder during one hour without any respiratory protective measure. three hours after exposure he developed progressive dispnea and was admitted to hospital. with presumtive diagnosis of respiratory infection, antibiotics were begun, however be failed to improve. all microbiological studies were negative. chest x-ray showed bilateral diffuse infiltrates. on seventh day he needed intubation and mechanical ventilation and on th he was admitted to our icu. antibiotics were stopped and new microbiological studies were performed including brochoalveolar lavage and virologic studies. all results were negative. he developed progressive hipoxemia and hipercapmia and finally, multiorganic disfunction syndrome. he died days after exposure. the metal he had been working with was a % cadmium alleation. blood cadmilam concentration days after exposure was . mcg cd/g cr, and urine cadmium concentration was . mcg/l. on postmortem examination, tissue cadmium concentrations were: blood ng/ml, liver ng/g, kidney ng/g and lung ng/g. these values confirm that cadmium was the cause of the fatal respiratory illness in this patient. conclusion: this case evidences the considerable hazard of acute poisoning after inhalation of eadmium-fume and stresses the need of appropiated safety measures against metal-fume poisoning. aim : lactic acidosis is considered the hallmark of cyanide poisonirig. however, the relationship between plasma lactate and blood cyanide levels has not been determined. the aim of this study was to determine the significance of plasma lactate concentration (plc) during the course of cyanide poisonings. methods : the patients were included according to the clinical suspicion of pure cyanide poisoning at the time of presentation. fire victims were excluded. serial blood samples were collected before and after intravenous hydroxocobalamin (hoco). blood cyanide concentration (bcc) was measured colorimetrically. plc was measured enzymatically. results : patients were studied. on admission, plc ranged from . to mmol/l, and bcc from . to gmol/l. mean systolic blood pressure was • mm hg, mean arterial ph . • . , mean anion gap was . + . mmol/l and mean pao . • . kpa. three patients died. before antidotal treatment, there was a significant correlation between plc and arterial ph (p = . ), anion gap (p = . ) and bcc (p = . ) but not with heart rate, pao , paco and blood glucose, or blood pressure. during the whole course of the poisoning, a plc _> retool/ was a sensitive and specific indicator of a blood cyanide concentration > ~tmol/ . sustained catecholamine administration reduces the correlation coefficient. conclusion : baseline measurement of plc allows assessment of severity of acute cyanide poisoning. thereafter, plc may be used to assess the adequacy of antidotal treatment, more especially in patients not requiring sustained infusion of catecholamines. aim: the aim of this case report was [o study the correlation between the plasma lactate levels and several clinical, biological, and toxicological parameters serially measured during the course of a cyanide poisoning treated with a high dose of hydroxocobalamin. a -year-old male ingested potassium cyanide leading to cardiac arrest. cpr was performed prior to hospital arrival where the patient received g hydroxocobalamin. sbp rapidly returned to normal allowing withdrawal of epinephrine. the patient remained comatose and died from brain injury days after the ingestion. methods plasma lactate and blood cyanide levels were measured serially. blood cyanide levels were measured using a colorimetric method.~ plasma lactate levels were measured using an enzymatic method. for correlation spearman rank correlation test was used. results. initial plasma lactate and blood cyanide levels were mmol/l and gmol/l, respectively. there was no overall correlation between sbp and either blood cyanide or plasma lactate levels. similarly, there was no overall correlation between arterialvenous oxygen saturation difference with either blood cyanide or plasma lactate levels. in contrast there was a strong correlation between blood cyanide and plasma lactate levels (r= . , p< . ). the time-course of the blood cyanide concentrations was described by a mono-exponentiai decay (r = . ) with a blood half-life of . h. similarly, the time-course of plasma lactate levels was described by a mono-exponential decay (r = . ) with a blood half-life of . h. discussion. in this case of acute human poisoning, sbp was a much poorer indicator of continuing cyanide effect both before and after antidotal treatment, than was lactate production. this suggests a potential clinical role for following serial plasma lactate levels as a marker of the evolution of cyanide toxicity. aim : cyanide (cn) poisoning in fire victims is frequent and rapidly fatal. in a prospective study we tried to assess the clinical tolerance of a high dose of hydroxocobalamin (hoco) administered at the scene of the fire in fire victims suspected of cn poisoning. methods : inclusion criteria : soot in mouth or sputum ~ any degree of neurological impairment. exclusion criteria : children, pregnant women, burns of total surface body area > %, multiple trauma. protocol desigrl following examination and the collection of a blood sample in dry heparin, a g dose of hoco ( g in case of cardiovascular collapse) was administered intravenously over min. the systolic blood pressure was monitored before and after the administration of hoco, and one hour later. results : there were females and males. the mean blood cn concentration was • pmol/ . the mean blood carbon monoxide was . • . mmol/ . nineteen fire victims eventually died. among the non-cn-intoxicated patients (blood cn < ~mol/ ), there was no significant change in arterial blood pressure. in the cn-intoxicated patients (blood cn > gmol/ ) a significant increase in blood pressure was observed both immediately (p < . ) and hour later (p < . ) after the admistration of hoco. no allergic reactions were observed. conclusions : in fire victims with cyanide poisoning, the administration of a high dose of hydroxocobalamin was associated with an improvement in systolic blood pressure. hydroxocobalamin is well tolerated in fire victims without cn poisoning. objectives: tricyclic antidepressant (tca) overdose can lead to serious complications including cardiac arrhythmias [ ] . because of the known risk of early deterioration and the implication for management, emergent evaluation is essential. we determined the diagnostic usefulness of the electrocardiogram (ecg) in tca poisoning. methods: retrospective study of all patients with tca intoxication (pos. ,toxicology screening in urine and/or pos. history) in a -beduniversity hospital from through . the severity was graded with mild= no symptoms or agitation; medium= disorientation, somnolence, tachycardia, or convulsions; and sever~ coma, significant arrhythmias or death. we analysed the first ecg after admission with a special emphasis on qrs-and qtc-intervals and the terminal ms frontal plane qrs-vector (tqrs), which, was reported to lie typically between + and * + + • the best correlation with severity grade was found with qrs-and qtc-duration (p= . ), the tca-dose (p= . ) and hf (p= . ); tqrs did not correlate. patients died ( . %). conclusion: qrs-and qtc-prolongation in the admission ecg, and the reported dose of ingested drugs are useful predictors for severity of poisoning due to tricyclic antidepressants. we did not find additional benefit in determining the terminal ms frontal plane qrs-vector. objectives: since treatment of amphetamine poisoning is usually symptomatic and often associated with a fatal outcome, a search for specific drugs to help the amphetamine-intoxicated victim is sorely needed. methods: we report a case of a suicidal ingestion of large amounts of the amphetamine-derivative , -methylenedioxy-ethamphetamine (mdea) and heroin (diacetylmorphine) and present the hypothesis that the two drugs produce opposing clinical effects. results: a year old caucasian male was admitted to the emergency ward because of acute-onset confusion. at presentation, he was agitated and showed increased muscular rigidity. he had taken tablets of "eve" (mdea, approx. g) and g of "smack" (heroin) by oral route approximately h before admission. because of rapidly progressive tachypnea and exhaustion, the patient was intubated and ventilated. the serum concentration of "eve" on admission was ng/ml (lethal range - ng/ml). trace amounts of cocaine and substantial amounts of heroin ( ngtml; mean value in heroin-related deaths: ng/ml) were also found in the serum. the patient was successfully weaned from the ventilator by day and recovered without persistent neurobehavioral disturbance. despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. amphetamines in general, and mdea in particular, have opposite clinical effects to heroin or diacetylmorphine. none of these were however present in the case presented despite the high ingested doses and the serum levels in the lethal range. conclusions: the fascinating fact that, apart from the respiratory depression, none of the clinical signs reported after massive overdose with these two drugs were present, might be attributed to the opposite pharmacological effects of mdea and heroin. we believe that the patient unwittingly saved his own life by the oral coingestion of both mdea and heroin. our clinical data raise an interesting point about the pharmacological treatment of acute poisoning with amphetaminederivatives. introduction: the acute attack of aip still carries a significant risk of mortality of around %. a succesful outcome depends on early diagnosis, removal of pricipitating factors and provision of intensive supportive therapy. objectives: twenty one patients ( females, male) with documented aip were seen over a -year period in the university hospital. patient was in clinical remission and were with the acute attack of aip, among them with respiratory paralysis were required artificial lung ventilation and -assistant ventilation with peee pathologic treatment during the attack was normosany, adenil, androgenes, glueosa, riboxin parenteral and enteral nutrition via nasogastric tube. symtomatic treatment -pethidine, propranoton, antibiotics, bronchoscopia. methods: intermittent phasmapheresis was performed on patients. the following measurements were peformed: level of porphobilinogen (pbg) in the wire and delta-aminolevulinic acid in the blood. hematological and routine chemical evaluations, hepatic, hemodynamic and respiratory function. results: after plasmapheresis the median pbg excretion (normal range - mkg per/ kgr creatinine) fill from mkg on admission . mkg, then on - day raise to mkg and then during treatment with normosong and prasmapheresis lowest level was . mgk. fatalities occured in two females during attacks with proforma cerebral involvement and patients attained clinical remission. conclusion: after therapy with plasmapheresis normosong we found that there was consistently reduce the urinary excretion of pbg and shortening the duration of the acute attack. objectives: pigs has been reported to present with a higher pulmonary arterial pressure (ppa) and stronger pulmonary vascular reactivity than many other species, including man. aim of the present study was to compare pulmonary vascular impedance (pvz) before and after embolisation in weight-matched adult dogs and minipigs. methods: we investigated pvz spectra in anaesthetized and ventilated (fio . ) minipigs and dogs. after baseline measurements the animals were embolised with autologous blood clots to reach a ppa above mmhg. results: flow ( and ppa matched pvz data (mean-+sem) are shown in the table. [zo = hz impedance (z; {dyn.sec_em- }); zl = first harmonic z; zc = characteristic z; z phase = first harmonic phase a@e {radians}; fmin = frequency of pvz the first m{n~mam; *, f p at least < . between dog and minipig, and before v~. after embolisation respectively]. before case report: a -yr-o]d woman affected by legs recurrent thmmbophlebitis, was admired in medmine department for tach.~pnea, chest pain, tachycardia and cyanosis. before starting two-dimensional transesophageal echocardiography (tee) to confirm the suspicion of pulmonary embolism, she suddenly had ventricular fibrillation. resuscitation and defibrillation were readily performed. when sinus rhythm was reinstituted she was in superficial coma with preserved corneal and light reflexes: right hemiplegia, poor perfusion and h~posphygrma of the left arm. tee showed dilation of rigth ventricle (rv), incomplete occlusion of pulmonary arter~ (pal at it~ hifurcation, severe tigth-to-left shunt through a patent foramen ovate, paradoxical embolism with incomplete occlusion of left subclavian artery mechanically ventilated with vt= ml, rr= /mm, fio =l, the patient had ph= . , pao = mmhg and paco = . systemic bp was / mmhg and hr= b/min with low dose epinephrine ( . g/kg/min) a thrombolytic infusion (rtpa: mg/ h) through a peripheral vein was started tee imaging and clinical status hours later were unmodified. a new rtpa infusion was performed through the pulmonary hole of a swan-ganz catheter with the tip close to the embolus. one hour later pa pressure decreased from / mmhg to / mmhg, etco increased from to mmhg and sao improved from % to % three days later the parietal, spontaneously breathing and with normalized tee scans of rv and pa, was transferred to rehabilitation service to perform physical therapy. conclusions: massive pulmonary embolism in a patient with patent foremen ovale, paradoxical embolism and refractory hypoxaemia was unaffected by systemic rtpa infusion, while intrapulmonary rtpa administration dramatically improved gas-exchange, hemodinamics and the general conditions of the patient. the presence of a large rigth-to-left _atrial shunt and the rapid rtpa metabolism could likely explain the effectiveness of its intrapulmonary administration in front of failure of systemic thrombolysis. introduction. cardiogenic shock during massive pulmonary embolism (blpe) is due to an acute increase of right ventricle (rv) afterload and possibly rv ischemia causing a failure of rv pump function. the rec~;mmended therapeutic strategies are: xoiume augmentation ~n ~rder m }ncrease rv pre-h~ad, adrenergic drugs to increase t'ontractillly and maybe coronary perfusion, fibrinolytic drugs to delermine clot lysis. there have been several reports of noradrenaline (na) as a useful drug in this setting for its sluing ~z, but also ~, properties. case report.an obese },ears old woman was transferred to our icu for tetanus. she was given the usual antibiotic and immunoglobuline therapy. l'wo thoracic epidural catheters were put in place at different levels and replenished with marcaine qid. a continous infusion of sedation (diazepam § was started together with mechanical ventilation. curarization ~,as given occasionally. fraxiparine . /die was used for prophylaxis of thrombotic disease, on day th at . a.m. she started to be hypoxic (sa %), tach ,tardic l l(i b/rain.), her blood pressure(rp) dropped frum norma~ values to r mm/hg, the central venous pressure (cvp) raised [rom lb to mm/hg and the end tidal co was mm/hg lower than one hour before. the physical examination of the chest revealed a clear bilateral ventilation and the chest x-ray was normal apart from an elevation of the :tiaphragm as compared to the previous. an e.c.g. showed sinus tachycardia, right bundle branch block and a possible inferior necrosis (which was already present on admission). a trans-thoracic echozardiography was performed which showed "an acute overload of the right centricle wilh remarkable dilatation. tricuspidal regurgitation ++. paradoxical movement of septum. small left ventricle with normal wall kinetics". the cardiac enzymes were later shown to be normal. an acute massive pulmonary embolization was assumed m be present.. a bolus of streptokinase x i(i u. was given fonowed by a continous infusion . two liters of colloids were also given in a sh~rt time, two hours later the patient was still deeply hypotensive, hypoxemic and anurir(bp / mm/hg, cvs mm/hg, spo %) despite a cominnus infusion of dobutamine fag/kg/min and adrenaline . ~tg/kg/min. at this stage a bolus of aoradrenaline ,g was given followed by a cnntinous infusion of . !*g/kg/min. an immediate improvement of the hemodynamics was noticed and one hour later the bp was / mmhg, the cvp mm/hg, the sao % and a brisk diuresis started. the hemodynamics kept stable and weaning from vasoactive drugs was achieved within two days. one month iater the patient was discharged home in good conditions.. con c i u sio n.ne administration may help to restore rv coronary flow and ;~ump function during mpe. aeute putmonary t~omboembo~sm [ffe) cou be mamfeslated with either respiratory or cardiovascular syndromes or both. the arm of the study was to establish leading respn'atory symptoms, frequency and form of the roendganographic (rig) changes as well as blood gas disturbance degree in acute pte with dommam respiratory disease appearance. the study includes retrospeotive analysis of i pte patients (pts), males (average age , yrs) and .q females (average age , yrs). they were admitted at university, olinie" with suspection ofpleuropnlmonary disease, including pte. final diagnosis of pte was based o~ evident risk factors in , % of the eases (deep venous thrombosis, surgery, trauma, imobilisation, malignancy ere), acceptable clinical, rtg, sdntigraphic and laboratory findings, as well as deep veins examination by dopple~-sonographie and radioisotopic -~enogmphy. respiratory symptoms appeared in all cases: sudden pleural pain ( %), dyspnea ( %), hemoptysis ( %), cough ( %) with association of two or more symptoms in %. chest xrays findings were abnormal in % with diaphragmal elevation ( , ~ lung opaeilies ( , %), atelectasis ( , %), plemal effusion ( , %), main pulmonary brancah asimetry ( , ~ oligemia ( %), heart shadow changes ( , %) and pulmonary arteries "cut off' ( , %). the association of two or more abnormalities was found in , % while normal chest x-rot was found in ~ of the cases. hypoxemia with pao < , kpa was found in , % followed with hypocapnia and respiratory alealosis in , % in , % of the gas exchage analysis were within normal limits. among cardiovascular symptoms short syn~cpa appeared in i , %, ecg changes-st q t type in "~ , %. results show high frequency of positive ~g findings in pte pts that is opposite to oppinion that chest x-ray in acute fie is the most ofran normal. leading symptoms are pleural pain and dyspnea, while hemoptysis were found in a half of the study group. blood gas changes were present in two thirds of the cases. kakkar, in his classic work ,clearly demonstrated the efficiency of low doses of heparin in prevention of deep vein thrombosis (lancet : , ) .after this first study the application of heparin prophylaxis became more and more diffused until to be considered a routine in many surgical departement.actually application of blood saving technique induces postoperative hemodilution effect. in that condition prophylaxis routinely applied seems a nonsense and can be at risk for postoperative hemorrhage. methods: to analize this problem we compared patients arrived in our intensive care unit (i.c.u.) in. : (group a) with arrived in : (group b) .every patient was operated for major abdominal surgery.in each one we considered the hemoglobin (hb) value,hematocrit(hct), and coagulation pattern (c.p.) at the arrive in i.c.u. and hours later. the patients was also divided in those receiving heparin prophylaxis (i) from not treated patients (ii) results:the application of blood saving technique clearly appears from the hb and hct level wich have a mean value of , +/- , (hb) and +/- (hct) in group a while in group b mean value are , -/- , (hb) and +/- (hct).patients of group a (ii) are the only one where a pathologycal c.p. with statistical significance has been demonstrated.in this goup we got four cases of evidence of venous thrombosis and one of pulmonary embolism.in patients of group b(i) we encontered the incidence of two cases of severe hemorrhage despite the absence of statistical significance in c.p.modifications. oxygen desaturation during broncho-alveolar lavage: role of oxygen saturation monitoring in prevention of acute respiratory insufficiency g. galluccio, b. valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the broncho-alveolar iavage is a diagnostic procedure employed in interstitial diseases of the lung. it requests the introduction through the working channel of a fiberoptic bronchoscope, after occlusion of a segmentary bronchus, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove cells and proteins from elf (endoalveolar lining fluid), which is related to interstitial medium. bronchoalveolar lavage induces deep effects on pulmonary function: -lowering of the alveolar surface of exchange; -shunt effect, depending on the perfusion of non-ventilated districts; -increased pulmonary arterial pressure, due to hypoxic vasoconstriction; -decrease of lung compliance. in this report the authors present the result of oxygen saturation monitoring in a group of patients with interstitial lung disease, who underwent diagnostic broncho-alveolar lavage. in most patients with severe interstitial involvement, the lavage performed without supplement of oxygen induced a severe fall in the oxygen saturation during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. in patients without thickening of interstitium, in whom the lavage was performed in order to obtain material for bacterial or cytologic examination, no modification of oxygen saturation was observed in standard procedure. as conclusion the authors strongly reccomend monitoring oxygen saturation in patients with radiologic evidence of interstitial involvement also in patients with no evidence of dyspnoea. g. galluccio, b.valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the treatment of choice in patients with alveolar proteinosis consists of pulmonary lavage. this procedure requests the introduction, through the working channel of a fiberoptic bronchoscope, segment by segment, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove the proteins deposited in the alveolar spaces. the method is very similar to that used in bronchoalveolar iavage, a diagnostic procedure used to obtain cells and substances from elf (endoalveolar lining fluid), which is related to interstitial medium. as known, bronchoalveolar lavage induces oxygen desaturation, because of shunt effect. understandably, one lung lavage has remarkably more deep effects on pulmonary function than bronchoalveolar lavage, for the amount of fluid introduced, the length of the procedure and the conditions of controlaterai lung. in this report the authors present the result of oxygen saturation monitoring in a patient who underwent pulmonary lavage for alveolar proteinosis. in the lavage performed without supplement of oxygen a severe fall in the oxygen saturation was observed during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. as conclusion the authors strongly reccomend the subministration of supplementary oxygen in pulmonary lavages, also in patients with excellent respiratory conditions. a. b. dublisky prof., m. r. isaakjan ass., v. a. zasukha, s. m. vinichuk prof., v. p. tserty ass. prof., chair of anaesthesiology, resuccitation and medicine of catastrophes, neurology of ukrainian state medical university, kiev, ukraine. objectives: detection of plasmophoresis's influence of results in treatment of ishemic insult. methods: we ve investigate patients with ishemic insult, treated with reverse plasmopheresis in complex treatment. after primary infusive therapy we took ml of patients' blood and separated it within min with rotation frequensy of /rain. after separation of erythrocytes from plasma, the latter has been returned to patients. we made - procedures during - days. hemoglobin, hematokrit, time of blood coagulation were determinated. the brain blood flow in internal carotid arteries, regional volum brain blood flow and total brain biood flow were evaluated with tetrapotar chest rheography and tetrapolar rheoencephalography. obtained date were comparised with control group after traditional treatment. results: it was found that after reverse plasmopheresis the hemoglobin and hematokrit levels decreased significantly in studied patients' plasma (from + . g/l to _+ . g/ and from + . % to _+ . % respectively). the time of blood coagulation by lee-white has increased by - . times (up to - rain). the level of brain blood flow has been increased significantly after reverse plasmopheresis in comparison with control group. the following tests of brain blood flow have been increased: a) the total volume brain blood flow from . + . ml/min to . _+ . ml/min (p < . ); b) the regional brain blood flow from . _+ . ml/min to . + . ml/min (p < . ); c) the brain blood flow in internal carotid arteries from . _+ . ml/min to . + . ml/min (p < . ). conclusions: the use of reverse plasmopheresis in complex treatment of patients with ishemic insult aiiows to improve rheological blood patterns, helps to increase volume brain blood flow. it results in quicer reparation of neurological functions. objectives: a prospective evaluation of the efficacy of continuous infusion of verapamil in reducing the incidence of postoperative atrial fibrillation after pulmonary surgery. methods: a total of consecutive patients, on verapamil, on placebo was included after lobectomy or pneumouectomy. a loading bolus of verapamil ( mg over minutes) was followed by a rapid loading infusion ( . mg/min) for minutes and finally a maintenance infusion ( . rag/rain) for hours. results: a mean plasma level of verapamil of ng/ml was obtained only after more than hours. atrial fibrillation occurred in five out of patients who tolerated the verapamil infusion, and in out of patients on placebo (p = . ). verapamil infusion was not tolerated in patients because of hypotension or a heart rate of less than /min, within hours of the start of the therapy. when atrial fibrillation occurred, the ventricular response, mean _+ sd, was not significantly slower during verapamil infusion ( + ) compared to placebo ( + ). conclusions: because of its frequent side effects and the only modest efficacy verapamil should not be considered for prophylactic therapy of atrial fibrillation after pulmonary surgery, and is probably not a good first choice for slowing the heart rate in case of rapid ventricular response once atrial fibrillation has occurred in these patients. results: study of haemostasis in these patients has showed deep disturbances of blood coagulation. fibrogen level has reduced to . + . g/l, fibrinogen and/or fibrine degradation products concentration have enhanced to . _+ . g/l, monofibrin soluble complex concentration to . -+ . g/l, blood plasmin level was enhanced to . + . mmol/ , plasminogen proactivator level was also enhanced to . + . ram, plateletes aggregation has decreased to %. after plasmopheresis aggregation was decreased in . times. it has been connected with decrease of fibrin and/or fibrinogen degradation products level and level plasmin in . times, and plasminogtnt activator level in . times. at the same time we have observed increase in total antifibrinalitic activity of blood in . times. activity of activators plasmine and plasminogene proactivators has decreased in . times and in the same time activity of activation inhibitors and antiplasmines has increased in times. conclusions: plasmapheresis leads to considerable improvement of a general condition and reduction of the haemorrhagic syndrom's sings (controlling of gastrointestinal haemorrage, reduction of intensity of subcutaneons haematoma). evaluation of continuous cardiac output (cc ) monitoring based on thermodilution technique in critically ill patients. methods: cardiac output (co) was monitored continuously using a modified pulmonary artery (pa) catheter, on which a heating filament is located and by which energy is transmitted to the circulating blood. a microprocessor calculated co by a new algorithm. standard bolus thermodilution technique ( ml of ice-cold saline solution) was used to compare cc with intermittent bolus cardiac output (ic ) measurements. the following subgroups were prospectively studied: i. heart rate (hr) > beats/min, . cardiac output > i/min . cardiac output < . i/min, . rectal temperature > . ~ and . pa catheter was inserted for more than days. results: a total of pairs of ic and cc measurements were obtained from the patients. bias (ico measurement minus cc measurement) of all measurements were . • i/min and the % confidence limits (mean difference• were - . / . i/min. also in the subgroups, cc measurement agreed closely with ico measurement (c > i/min: bias= . • i/min; co < . i/min: bias=- . • i/mln). elevated temperature and prolonged lay-days of the pa catheter did influence agreement of cc measurement with ic measurement neither (> ~ bias= . • i/min). conclusions: monitoring of cc using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise also in the critically ill when compared with "standard" intermittent bolus thermodilution technique. this method enhances our armamentarium for more intensive monitoring of these patients under various circumstances. background: the number of patients who need coronary artery surgery was) grows every year. most of these surgical operations are with extrar eircuiation (ecc). since january , this surgery is made without ecc in selected patients in our hospital. this technique is exceptional in spain. this type of surgery has proved useful in patients requiring revascularization of the left anterior descending, eireunflex or right coronary artery (not for grafting the pos~tefio~r descending branch}. blethods and results: since , patients aged to years (mean years) underwent cas without ecc. the mortality in programmed surgery was %. no patient was reexplored for hemorrhage. the mean values of some clinics parameters v~ere: a) blood requeriments: units per patient, b) need of mechanical ~entilation: i , hours, c) postoperative bleeding: cc, d) days at icui , . we used the student % t test or fisber~s exact test to compare these results with the mean values of surgery with ecc: a) blood requeriments per patient (p< , ), b) need of mechanical ventilation: hours (p< , ), c) postoperative bleeding: cc (p< , ), d) days at icu: (p< , ), e) programmed surgery mortality: % (p< , ). conclusion: our limited experience shows that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated pathology and in jehova's witness. the need of mechanical ventilation, days at icu, blood requeriments and morbi-mortality were fewer than surgery with ecc. to study the hemodynamic and antiarrhythmic influence of ace-inhibitor enalapril in acute myocardial infarction (mi). methods: holter ecg monitoring, heart rate variability analysis, echocardiography ( and l days after beginning of the treatment), stress-echocardiography and stress ecg ( - -th day after the onset of mi). enalapril was included into the treatment of pts with mi (study group), with normal or increased blood pressure, from the -st day of the disease. the data were compared with pts treated without enalapril (control group). results: silent ischemia during stress-test was registered in pts of the study group and of control group, the arrhythmia episodes during stress test -in and pts and episodes of silent nocturnal isehemia -in and pts correspondingly. enalapril importantly attenuated the hypertensi~re re~aetioh % stress test. in pts of the study group the number of perifocal hypokinesis zones decreased; in the control group it didn't change. the quantity of ventricular extrasystoles in the patients of the study group decreased by %; the heart rate variability indices improved as well; in the control group the character of ventrieulir arrhythmias, heart rate and its va]~i~bili%y didn't change significantly. conclusions: the inclusion of enalapril into the treatment of mi is a useful t ol to improve hemodynamie parameters and decrease the incidence of ventricular arrhythmias. objectives: to study left ventricular (lv) systolic function in the patients with acute myocardial infarction (ami) before and after peroral captopril test. methods: the original echocardiographic parameter of lv contractility, "coefficient of effective systolic function" (cesf), was proposed in the study. cesf is calculated from lv stroke volume (sv), obtained from doppler aortic flow in lv outflow tract and lv end-diastolic diameter (edd): cesf =sv/edd. the study included patients with ami, who had local lv dyskinesia and global lv systolic dysfunction (ef< %). besides cesf, the ejection fraction was calculated before and after administration of mg eaptopril (on the fifth day of ami) by methods of bullet and simpson. results: the dynamics of these parameters, as well as heart rate (hr) and mean blood pressure (bp), is shown in the tabte. before cal~topril ef (bullet) . • . ef (simpson) . introduction: the cold system is a monitoring system for measurement of right (copa) and left (coart) ventricular cardiac output, cardiac function index (cfi), fight ventricular ejection fraction crvef), fight ventricular cnddiastolic volume (rvedv), intrathoracic blood volume (!tbv), global enddiastolic volume (gedv), lung water (etv) and excretory liver function (pdr). patients and methods: pts have been monitored by the cold system. above mentioned parameters are measured by thermal dye dilution and a fiheroptic femoral artery catheter. copa, rvef and rvedv measurements additionally were compared to measurements by the baxter explorer. :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ;;;k;;;;i cov (%) explorer ! ! [ gedv, itbv and pdr showed a significant decrease dufing the first - h after the operation, cfi and rvef si~canfly improved after k wheras etv showed a i~ in the early postoperative phase and fell to normal ranges at h. comparison of cold/explorer m~ements sb wed good correlations. discussion: concerning m ~toring of ri,ght ventric~ar function cold and explorer can he seen as equal. rvef gives an ar report about the performance of the right ventricle without use o f echocardiography. measuring itbv and gedv ~ improve ~gement and con~ol of th.e volume status, monitoring etv helps preventing lung edema. pdr shows good corre|ati n to liver blood chemistry and is bedside avai|ab|e. thus the cold system offers additional parameters for comprehensive m~nitofing of pts. ~e~ ~c surgery. obiectives: to evaluate the influence of an a!'~ered cardiac function on the cardiovascular response to the increase in oxygen demand induced by an increase in core temperature. methods: this preliminary study included adult critica!ly ill patients monitored by arterial and pulmonary artery catheters in whom thermodilution cardiac index {ci) and arteria! and mixed-vef)ous blood gases measurements could be obtained before and after an acute change in core temperature of at least . ~ (max rain apartl the patients were separated in two groups according to their cardiac function: patients had an impaired cardiac function as defined by a history of cardiac disease and an ejection fraction below % and patients had normal cardiac function. results: individual data are shown in the figure. in contrast to the control group (continuous line) in which c! increased without changes in oxygen extraction ( er), the q er in patients with impaired cardiac function (dottled line) increased without changes in ci. conclusions: the increase in oxygen demand associated with changes in temperature is met by an increase in c! in patients with unaltered cardiac function and in an increase in o er in patients with altered cardiac function. temperature should be taken into account in the assessment of the adequacy of cardiac output in patients with impaired cardiac function. objectives: to define the hemedynamic and metabolic response to physical therapy(pt) in relation to the type/level of sedation and the cardiac status in icu patients. methods: we studied mechanically ventilated icu patients ( • years) in stable hemodynamic status (no change in vasoactive treatment for at least hours), separated in groups: group = deep sedation, cardiac dysfunction required dobutamine (n= )r group = deep sedation (barbiturates), unaltered cardiac function (h=lo), group = moderate sedation, altered cardiac function (h= ) and group = moderate sedation, unaltered cardiac function (n= ). complete hemodynamic data, arterial and mixed venous blood gases, respiratory gas analysis (metabolic cart ccm, medgraphics) were obtained at baseline ( x) and twice (q. min) during leg mobilization. data were analyzed by anova. calcium channel blockers were used in complex preoperative preparation of hypertensive surgical patients. patients were allotted to groups based on their hemodynamic profile: hypokinetic: ejection fraction (ef)< . , patients; eukinetic (ef> . ),i patients and hyperkinetic (ef> . ),i patients. the most noticable change in hemodynamics was in the hypokinetic group: ef and cardiac output (co) were significantly decreased (p< . ) while systolic arterial pressure (sap) (p< . ) and peripheral resistance (pr) (p< . ) were elevated. the results showed that in hypokinetic patients on nifedipine ef (p< . t) stroke volume (sv) (p< . l) and co (p< . ) were increased while pr(p< . t), sap(p< . ) and diastolic arterial pressure(p< . ) were decreased. eukinetic type patients also showed an increase in ef,albiet to a lesser extent,than in the hypokinetic group. increased sv and co(p< . ) were observed in eukinetic patients though this was to a lesser extent than in the hyperkinetic group. in the hyperkinetic group of patients nifedipine had no effect on the aforementioned parameters except for a decrease in sap(p< . i). nifedipine increased ef in all hypokinetic patients. comparative results show that isoptin was less effective than nifedipine in decreasing peripl~eral vascular resistance and had a depressive effect on the myocardium. it can be concluded that the action of calcium channel blockers normalizing the circulation in the hypertensive surgical patient depends on: the condition of myocardium, the patients hemodynamic profile and their pharmacological properties. they were most effective in the hypokinetic group. zalo/nthinos e., daniil z. zakynthinos s., armaganidis a., kotanidou a., nikolaou ch..,roussos ch. critical care department, university of.athens, evangelismos hospital, athens, greece. introduction : surgical is the optimal treatrnent for ioculated effusions and the preferable procedure when multiple bands are seen in the pericardial sac by echo. patients : palients, post cardiac surgery, uremic ( men, women) with large pericardial effusion and clinical or echocardiographic findings of tamponade or both. these particular patients displayed numerous linear echo-dense bands and s~'ands crossing the pericardial space (in one of them a ioculated effusion compressed the left ventricule). one had aptt increased, four were mechanically ventilated. technklue : a fr polyurethane catheter with end and multiple side holes over ga needle was echo-guided to the ideal site (fluid abundant and closest to the transducer). the catheter was attached to a close system with a heimlich valve for continuous drainage (pneumothorax kit). subcostal entry was selected in one patient and chest wall in five. the patient's position was changed every hour at least. (we believe that the small changes in the position of the catheter and the mechanical breaking of the bands in relation with the movement of the heart assist the pericardial fluid to remove). results : in all cases only a small quantity of fluid was withdrawn in the first minutes( - ml) with some clinical and echo-findings improvement. the fluid was bloody or serosanuginous with high protein content (ht= % ,protein , gr/dl) in all cases. in first hours the mean volume of fluid removed was ml ( to ml). in that period echo showed no residual fluid. the catheter remained within the pericardium to days .. no complications are mentioned. conclusion : cardiac tamponade due to hemorrhagic high protein pericardial effusion in uremic and postcardiac surgery patients,, as it is revealed by echo dense bands, can be faced by -d echo guided perieardiocentesis. a -fr polyurethane catheter with multiple side holes, attached to a heimlich valve was effective to evacuate the pericardial fluid. no catheter was occluded though heparin infusions were not used. multiple changes of the patient's position may be fundamental. this -d echo guided pericardiocentesis performed in in~nsive care unit seems to be useful , safe and quick technique. determining the best inotropic drug represents a very serious problems. the use of more selective and potential inotropic and vasodilatative drugs does not always lead to improvement of hemodynamic parameters in patients with low cardiac output syndrome. this paper presents patients with acbp who need an inotropie support after extracorporeal circulation in first hours. the patients were divided into dobutamin et dopamine groups. the heart rate (hr). mean sistemic arterial pressure [map), central venous pressure (cvp). and termodilution cardiac index (ci) were measured. the measurements were without using inotropic drugs, and then using them after rain, min, and finally with one hour rate, within first hours. the statistical analysis shows that both drugs lead to an increase in hr in the first hour of the application. the final effect of dobutamine is no change in hr, whereas the effect of dopanime is very significant increase in hr. thus. an absence of taehyeardie response selects the dobutamine as a better choice. backeround: pulmonary vascular eadothelium possesses major metabolic functions, which when altered contribute to the development of serious pathologies such as ards. one such function is the conversion of angiotensin i to angiotensin ii, catalyzed by angiotensin converting enzyme (ace), located on the luminal surface of the endothelial cells. ace activity has been extensively studied in animals in vivo, by means of indicator-dilution techniques, providing: i) under toxic conditions, an early index of lung injury, and it) under normal conditions, estimations of dynamically perfused capillary surface area (pcsa). objectives: to validate the use of these techniques in matt: i) for pulmonary endothelial function assessment, and it) for pcsa estimation. methods: ace activity was estimated in ten adult haman volunteers, with no pulmonary medical history and normal pulmonary artery pressures, undergoing cardiac catheterization for coronary artery disease assessment. single-pass traspulmonary hydrolysis of the specific ace substrate hbenzoyl-phe-ala-pro (bpap; p.ci) was measured by means of indicatordilution techniques, and expressed as %metabolism (%m) and v=-hi( -m). bpap was injected as a bolus i) into a main pulmonary artery, and it) inside the right atrium, to assess ace activity in one and both lungs. we also calculated a,~,/i~, an index of pcsa. pulmonary plasma flow (fv) was determined by thermodilution. fp in one lung was estimated as . xf v. results: similar values of %m ( . + . vs . • and v ( . • vs . • were observed in both and one lung respectively. a~k~ decreased from • ml/min (both ltmgs) to :~ (one lung). conclusions: i) pulmonary endothelial ace activity and thus pulmonary endothelial function may be assessed in humans by means of indicator-dilution techniques, it) our data denote homogeneous pulmonary capillary ace coneentratious and capillary transit times in both haman lungs, iii) the % reduction of a=~/k~ in one lung suggests that this procedure can be used to quantify pcsa in man. (supported by the fonds de la recherche en saute du quebec and the national health system of greece). objective: verify whether antioxidant activity is higher in reperfused than in no-reflow myocardium after i.v. thrombolysis for acute myocardial infarction (ami). methods: patients with ami were included. blood for estimation of catalase (cat), glutathione peroxidase (gpx) and mn-superoxide dismutase (sod) was drawn before initiation of i. the mechanism of myocardial cell defence against free radicals is probably identical in both reperfusion and no-reflow phenomena. therefore, antioxidants cannot be used as reperfusion markers. objectives_ to evaluate the precipitating factors of hypothermic phrenic nerve injury following cabg with lima. methods: fifty two consecutive patients ( females), with a mean age of + (mean +sd) years were studied. during the ischemic arrest time topical hypothermia was obtained in al~ patients wffh ice slush and no cardiac insulation pad was used. all patients received a lima graft, with or whithout additional vein grafts. supramaximai, bilateral phrenic nerve stimulation was performed percutaneously preoperatively and whithin hours postoperatively. square wave stimuli of . msec duration were applied at the posterior border of the sternomastoid muscle. the compound muscle action potential of the diaphragm was recorded, using surface electrodes on the anterior chest wall. the time interval from the application of stimulus to the onset of diaphragmatic activity, phrenic nerve conduction time (pnct), was measured. values exceeding . msec were considered as abnormal. besults: preoperatively, all patients had normal (mean+sd) pnct, . • msec for the left nerve and . • mseo for the right nerve. on the first postoperative day, right pnct was normal in atl patients ( . • msec) , whereas left pnct was normal in patients ( . • msec) and abnormal in patients (incidence . %). in patients the left phrenic nerve was inexcitable and in patient left pnct was prolonged ( . msec). comparing patients with normal and abnormal pnct there was no difference in age, gender, number of grafts used, aortic cross-clamp and bypass time. however, patients with abnormal pnct had a lower preoperative ejection fraction ( • vs • p= . ). moreover, in all of them lima was dissected from its origin ligating all upper arterial branches, which provide the blood supply to the left phrenic nerve, whereas in those with normal pnct the small vessels originating from the upper to cm of lima were preserved (p= . ). conclusiojel~ a hypoperfused left phrenic nerve seems to be more susceptible to hypothermic injury during cabg with a lima conduit. objectives: to test if necessary interventions on systemic vascular resistance (svr) along with preset pump flew (q) during cpb could adversely affect autoregulatory response and cause vo shifts. methods: we studied males ( - yrs) who underwent cpb for cardiac surgery. at o oesophageal temperature - c we set pump flow at . i.m~ .min - . when map was higher than mmhg we calculated vo by using fick equation. then we infused sodium nitropruaside (sn) to control map at - mmhg for min and we calculated vq . without changing the sn infusion rate we set q at . i.m' .min " . ten min later we measured vo . we took vo changes into consideration if greater than %. statistical analysis using students-t-test for paired data and analysis of variance was used as appropriate. results: depending on the biphasic vo response to sn infusion during low and high q we classified pts in four groups (table). i. vo increases with sn and increases further during high q unmasking hypoperfusion and supply dependency. ii. vo increases with sn but the addition of high q results in systemic shunt. iii. vo increase during high q proves that vasodilatation can turn flow insufficient. iv. vo does not change with any intervention. the small number of pts and the wide standard deviation did not allow any statistical significance. conclusions: cpb is an interesting model for the behavior of microcirculation. intervention on svr and q can improve or impair effective regional oxygen delivery, resulting in either better perfusion or systemic shunt. vo monitoring seems necessary during cpb. preoperative cardiovascular optimization (opt) to ci > . l/min/m , _< paop < mm hg,and svri __< mmhg/ll/min/m decreases cardiac events (events) and mortality (mort) in peripheral vascular surgery patients (pvs). objectives: to determine if opt to the same endpeints decreases events in patients undergoing abdominal aortic aneurysm repair (aaar) and to study the r predictive value in pvs patients. methods: aaar patients and pvs patients were admitted to the s cu monitored with e pa and arterial catheters and treated to achieve opt. patients underwent surgery independent of success of opt data included demograph cs, incremental risk factors, laboratory and hemodynamic data pre, intra, a~nd postoperatively events, and mort. events included arrhythmias requiring treatment or prolonging the sicu stay > hours, a st depression > !mm or t wave inversion, an acute mr defined by a new q wave > . sec or cpk-mb > %. results are presented as means _ -. sd. opt was achieved in of ( %) and in of ( %) in the pvs and aaar group, respectively. events did nat differ between groups of ( , %) and of ( , %) in the pvs and aaar group, respectively (p>o. ). mort was of ( %) and of ( . %) in the pvs and aaar group, respectively (p > . ), while there was no difference in endpoints of opt between patients with and with.out events in the aaar group, there was a significant difference in ci between patients with and without events in the pvs group. of note, of ( %) patients who developed events in the pvs group had a ci < . in contrast to of ( %)in the aaar group. the positive and negative predictive value were % and % in the pvs and % and % in the aaar group. conciusione: f. the endpoints of opt used for pvs patients cannot be ~sed to reduce events in aaar patients; . pvs patients who have net achieved opt are at extraordinary risk of perioperative events; . preoperative card ovascu ar opt in aaar patients makes no difference in cardiac related events, background : comparison of the right and left filling pressures (cvp/pcwp ratio) is considered as a useful diagnostic clue : the normal ratio is _< . ; ratio >_ . may suggest right ventricul~ infarction while equalization of the cvp and pewp is a classic sign of tamponade ( ). however after cardiac surgery, many conditions (diastolic dysfunction, pulmonary hypertension, positive pressure ventilation) are susceptible to modify the '*normal" cvp/pcwp ratio. material and method : we determined cvp/pewp ratio in consecutive patients (pts) after uncomplicated cardiac surgery ( coronary artery bypass grafts; valvular replacements) measurements were made before and after tracheal axtubation. results :cardiac index : . _+ . /minlm~; laotate: + rag/i; cvp range : - rnmhg; pewp range : - mmhg. mean cvp/pcwp ratio before extubation is . ( % confidence imerval : . - . ) and after extubation, . ( % confidence interval : . -. . ), (ns, paired t-test). in % of the pts, cvp was higher than pewp. there are no correlation between the cvp/pcwp ratio and c! before (r = - . ) and after extubation (r = - . ) nor between the cvp/pcwp ratio and mean pulmonary arterial pressure (mpap), before (r = . ) and after extubation (r = - . ), discussion : cardiac performance is adequate according to ci and lactate. however the cvp/pcwp ratio is markedly higher than the "normal" (_< . ) ratio. this difference is not related to mechanical ventilation because the ratio is similar before and after extubation, nor to pulmonary hypetaension because of absence of any correlation with mpap, post-cpb diastolic dysfunction of the right ventricle could be an alternative explanation. in this group of pts, increased cvp/pewp is not associated with any impairment of cardiac performance (absence of correlation with ci), conclusions : cvp/pcwp ratio as high as within a large range of cvp ( - mmhg) and pcwp ( - mmhg) may still be considered as normal after cardiac surgery. this emphasizes the limitations of the hemodynamic monitoring after cardiac surgery (in comparison with echographic technics). careful analysis of the morphology of the cvp and right ventricular pressure curves (x descent, y descent, dip-plateau) is mandatory rather than relying on the quantitative assessment alone. reference : ( ) ntensive care.-university hospital -m~laga (spaink introduction. fibrinolitic treatment (ft) permits the treatment of acute myocardial infarction (ami) addressing the etiology, thereby eading to mproved ventncular function and a marked reduction m mortality. the main clinical oroblem is the reduced time of application. delay in hospitalization, which can be from to minutes, is potentially the most avoidable delay. method. to reduce delays in hospitalization, the following was carried out in two chases. audit: analysis of the time lapse from onset of symptoms to start of ft. showed that during "(he period june to december , patients with chest paros were treated within a eriod varying from minutes to hours from onset of symtoms. ages ranged from to (average , ), oelng males and females. they were glved initial ecgs to determine st mcreases suggesting ami. median t~me for this orocedure was l m.. potentia ami patients were then admitted to the coronary unit, [)atients, under age with no contraindications received ft the median time apse from admission to corona-y care and administration of ft was minutes ( . ), -he total median delay was minutes ~ -i h. min,~ delays n start of this procedure are grouped as follows: extra-hosdita delays (from onset of symtoms to arrival at hospital) diagnostic delays (from hospital arrival to ecg). treatment delays (from diagnosis to ft). objectives: protocol of procedure to implement a fast-track method. a protoco was drawn up with the object of reducing diagnostic delays to -i minutes and treatment delays to less than i minutes results. following rmplementatlon of this protocol in january , fts were glven, with an over all average delay of minutes. this fast-track method did not reveal any inappropnate ft or any increase m complications, conclusions: detailed study of the various times taken for diagnosis ane treatment of ami patients, showed up weaknesses in the system and improvements througn the protocol based on performence orocedures which led to a % reduction in the start of ft background: the importance of the early use of thrombo!ytic agents in acute myocardial infarction (ami) is based in the better remaining ventrictjlar function and smaller mortality rate because of the greater reperfusion and sma!ler infarction size, therefore, it is very impodant to apply this treatment to the maximum number of patients without thrombolytic contraindicati n, and within the minimun period of time. the "thrombolytic fast track" implementation allows to optimize the time to administrate thrombelytic agents avoiding multiple delays~ methodology: we anal!ze the application of thromboly c agents to patients with suspect of ami from the begin!ng of september until the end of february . in this time there are two different periods, during the first months thrombolytic agent were admin!strated at intensive care unit (icu), and during the second period we carried out a protocol of quick detection and thrombolysis therapy in susceptible patients at the emergency room in order to reduce the time to treatment. ma!n results are shown in the faffewins de ay h=hours m=minutes the implementation of the fast track does not need supplementary personal or equipment but a protocelized approach and training of the personal involved the main problem detected was the usual attendance overload of the emergency department that makes difficult to follow many structurated actions. conclusions: pratocqlized changes in the management of ami can significantly reduce the detay in the administration ef thrombolytic agents. it is not necessary to eomplet the procedure iq the emergency department, as the use of bolus schedules allows to begin the treatment in this area and to transfer the patient to icu afterwards. elective cardiac surgery. b calvet, f ryckwaert, p trinh duc, p colson. anesthesia -reanimation, hopital arnaud de villeneuve, montpellier, france. obhectives: the study was aimed at analysing the incidence of renal dysfunction following cardiac surgery and its prognosis (acute renal failure, post-operative morbidity and mortality). methods: two hundred and thirty seven patients (aged from to ) were consecutively operated on for elective cardiac surgery and retrospectively included in the study. patients with preoperative infections and operated on in emergency were excluded. each patient had preoperative invasive cardiac investigation with angiography and calculated ejection fraction (ef). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest management were similar in all patients. general body temperature was reduced to - ~ c. renal dysfunction was defined as a % increase from baseline of serum creatinine. demographic data, asa, treatments, pre-operative creaunine level, cpb and clamping (axc) times, intra and postoperative use of inotrope, serum lactate level before surgery, at the end of cpb, at the time of admission in intensive care unit (icu) and on post operative day one and apache score were compared in patients with or without renal dysfunction using anova test for repeated mesures and x when appropriate. data are expressed as mean +__sd. p value less than . was considered statistically significant. results: thirtytwo patients ( , %) suffered from renal dysfunction. age, serum lactate level at the end of cpb, at admission in icu, at pod and apache level at admission in icu, intra-operative use of inotropes were statistically different in patients with or without renal dysfunction (p< , ). mortality rate was statistically different in patients with or without renal dysfunction(~, , % and %, respectively, p= , ). incidence of acute renal failure following renal dysfunction was , % ( patients required hemodialysis). conclusions: although our cdteria for defining renal dysfunction were very sensitive, the incidence of renal dysfunction following elective cardiac surgery was lower than communly accepted in the litterature ( ). however renal dysfunction appeared significantly associated with a poor prognosis. reference: -settergren g, ohqvist g current opinion in anaesthesiology , : - r ; , tzelepis, g. , , late complications were observed in % of cannulations: local infection in (i, %), catheter displacement by the patient in cases ( , %), catheter displacement during nursing care in ( , %) and malfunction in cases ( , %). conclusions: central venous catheterizations are followed by immediate and late complications in almost the same percentage acute poisoning with amphetamines (mdea) and heroin: antagonistic effects between the two drugs methods: after institutional approval and informed consent, selected patients ( _+ years) undergoing peripheral vascular surgery (n= ) or carotid endarterectomy (n= ) were investigated. patients included had either documented cad (n= ) or two or more (n= ) dsk factors (age > years, smoking, diabetes meltitus, hypertension, hypercholesterolaemia > mg/dl). -lead ecg recordings were carded out preoperatively, on ardval in the postanaesthetic care unit, and h, h, h, and h postoperatively. ecg recordings were analysed by an independent blinded cardiologist for signs of pmi (new st segment depression > . mv and/or new t inversion). in addition results: of the patients investigated developed ecg-documented pmi, % occurdng in the immediate postoperative phase. troponin i levels > . ng/ml were found in of these patients thus, comparing a cardiac troponin i cut-off level of ng/ml with intermittent -lead ecg recordings, we found a sensitivity of % and a specificity of % methods: demographic, clinical and ecg data were analyzed. . % of patients were male; . % female. cad was the most common underlying cardiac disease ( . %) and . % underwent open heart surgery. % received proeainamide for supraventricular and % for ven~cular arrhythmias. % received a loading dose. maintenance was provided by iv route in . % and by po in . % ( . %sr end . % ir). . % of patients were obese right ventricular function following cardiopulmonary bypass: is important the mode of myocardial protection we underwent this study in order to examine its safety and usefulness in pts with trustable coronary conditions (unstable angina ua the mean age for group a was • years, for group b • years, and for group c • years. a history of previous myocardial infarction was present in pts of group a, in of group b and in of group c. three pts in group a, in group b and in group c had previous coronary artery bypass grafting. the median time between the onset of symptoms and a was days ( - ) for group a we used a continuous fixed intravenous a infusion at a dose of the sn was % in groups a and b, % in c, and sp % for group a, (fixed defects included) and % for groups b and c. there was no difference of side effects among groups: chest pain (i pt -group a, pts -group b, and pts -group c), transient hypotension ( pt -group c), headache ( pts, group c), dyspnea ( pt -group a), while st depression was seen in pts of group b and in pts in group c. the rate of a infusion was decreased to /kgr/min in one group b pt due to development of chest pain s five year follow up of humoral immunity in paced patients athens polyclinic hospital, department of cardiology athens, greece author index a abiad ch bertschat, e betbes blanch, l del nogal saez e -meneza nolla, j. nolla-salas pilz~ u puig de la bellacasa e scarpa, n. van de wetering objectives: only % of patients suffering from acute guillain-barr@ syndrome (gbs) respond promptly to established therapies like plasma exchange or intravenous immunoglobulines. in contrast to serum, cerebrospinal fluid (csf) of gbs and ctdp patients contains enriched portions of antiexcitatory factors(i) and cytokines ( ) able to induce pronounced conduction block ( ). to reduce or remove such pathologic factors we introduced a technique with direct access to the subarachnoid space. methods: with informed consent we lumbally inserted g catheters in gbs-and cidp -patients under sterile conditions. some of them had not responded very well to established therapies. - ml of csf were withdrawn and retransfused by a bidirectional pump (flofors) after passing newly developed filters (pall). daily filtrations with several cycles were performed ( - ml) over one week. results: the gbs patients improved after days (median) for one grade (according to the gbs-scale from the gbs study group) . the ventilator dependent patients were weaned after days (median). patients not at all treated before ( / ) responded better than patients that had been pretreated ( / ) with plasmaexchange or intravenous immunoglobulines. / cidp patients drew benefit from treatment, stabilized iongterm. conclusions: csf-filtration is a relatively save and well tolerated additional procedure. the costs are considerably lower ( / ) than those for plasmaexchange or intravenous immunoglobulines. references:( )wsrz aet al: csf and serum from patients with inflammatory polyradiculopathy have opposite effects on sodium channels. muscle nerve ( ) . ( ) clinical observations were made in patients admitted to the clinic. they were in coma associated with acute alcohol intoxication.standard evaluations (ecg-monitoring, electrocardiography, neuromonitoring, studies of acid-alkali condition, biochemical and toxicologic investigation of blood and urine) prior to and following the treatment conducted were undertaken in all the patients.to correct irreversible impairement of functions twofold laser blood irradiation by means of alok- apparatus, the exposure within minutes, was carried out.the data obtained confirm more rapid coma withdrawal of the patients, reconstruction of the heart and central nervous system electrophysiologic indeces, reliable reduction in complications compared with the control group. objective: to know the actual incidence of the critical illness polyneuropathy(cip). setting: fourteen intensive/critical care unit beds, in bed university hospital, covering . inhabitants (majority rural area). the icu patients are medical, surgical and coronary, excluded the neurotrauma and neurosurgical. design: a conseculive and prospective study. all the patients admitted during three months, from january lth to march th , were eligible (patients with admittance diagnosis of polyneuropathy were excluded ). methods: patients with apache ii score > , at the admission and six days after admissions were included into the study protocol. diagnosis of sepsis, mof, and all the drugs administered days before were recorded. a complete neurological exam, by a neurologist, in absence of ssdatives and muscles reliant ( th, ~ and th days after icu admittance) was made. we evaluated the nerve and muscles function with and electromyography study in all patients, at same days. in some paeents with cip we performed a nerve biopsy. results: from patients ( apache ii score: . ) admitted in the icu, ( . %) enter the study protocol. seven ( , %) had an axonal polyneuropathy(cip), three very severe. only four of the patients with cip had pathologic clinical exam. apache ii score: cip vs non-cip was . vs . . the incidence of cip by diagnosis (cip/diagnosis) was: sepsis, / and mof, / . conclusions: . -we think that it is necessary to define the "critically ill" for some score, before designing a study to know the incidence of this syndrome. . -we think that the incidence of the cip is lower that the latest papers say. objectives:acute pancreatitis(ap)is becoming a more important problem among the elderly as the population ages. the increasing presence of gallstone disease,as well as the use of certain drugs,may also contribute to the occurrence of pancreatitis. methods:all patients(> years)admitted to our medical department over an eight year period were included.pancreatitis was confirmed by biochemical tests and imaging techniques.scores were developed using ranson's criteria and a multiple organ system failure(mosf)index . overall, patients were evaluated; ( %)had pancreatitis of unknown etiology . results:( )patients with pancreatitis of ~nlqnown etiology were sicker and had greater morbidity( % vs %),mortality( % vs %),and longer hospital stays than p~tierf~ with pancreatitis of known cause.( )the best predicto~of severity and outcome was the mosf index and not ranson's criteria;the higher the score,the greater the associated disease,the worse the outcome.( )curlously,no difference existed in associated medical conditions between patierts withknown and ur ~own causes of pancreatitis. conclusions:greater organ dysfunction exists in patients with pancreatitis of unknown etiology, even though age and associated medical conditions do not differ . the application of the total enteral nutrition in the burns disease has minimized the complication rate and consequently increased the survival rate of children and adults. time of initiation, composition, duration and way of administration are very important in obtaining the optimum beneficial effect from the treatment and diminishing the complication rate and side effects. the above features will be discussed in view of our experience in cases. ta buckle?,, ra freebalm, c gomersall g joynt, r young. tg short. department of anaesthesia and intensive cm+e, prince of wales hospital. the chinese university of hong kong, shatin, hong kong introduction: gastric mucosal ph (phi) monitoring has been proposed as a relatively noninvasive index of the adequacy of aerobic metabolism in the gut. to examine the accuracy of gastric intramucosal pit measurements as a function of time and as a function of the catheter itself to determine whether the measurement error between catheters is clinically acceptable. patients with a gastric tonometer (trip tm, tonometrics, worcester. ma) insitu for > days were studied. following informed consent two new tonometers were inserted equidistantly & correct position was confirmed radiographically. measurements of intramucosal gastric ph were then performed over a hr period. eight -ten measurements were made in each of ten critically ill patients.percent differences between the two new catheters were . % ie at ph . _+ . ( % limits) and between old & new catheters were . %, ie ph j _+ . ( % limits). conclusions: the results suggest that the function of the tonometer deteriorates over time and that the absolute values of phi m~ not ~ufficiently accurate. however as a trend monitor phi may be useful in the clinical setting. despite a continuous decline both in li'equency and severity of gastro-intestinal stress-lesion/-bleeding (gisb) due to both improvement in preclinical support and in intensive care medicine, patients with cerebral lesion are still considered at high risk for developing gis . therefore the question arises, whether m> specific (}lsb-prophylaxis besides general and neurological intensive care, specific pharlnaeothcrapy or even the combination of two specific drugs reveals any protective efli~ct on frequency and severity of gisb.this pntspcclive randomized study has been perfornted in patients snfrering t'rttna head-injury/cerebral lesion and with a glasgow-coma-scale on admission (gcs:,)of < . according to randomization the patients have been grouped as tbllows: h analgesia/sedation (n= ); ih analgesiajsedation plus pirenzepine mg/day (n= ); .[ih anatgcsia/sedalkm plus sncraltate x [ g/day (n= ); iv: analgesidsedatkm plus pirenzcpine mghlay plus sucralfate x e/day (n= ). slalislical analysis has been performed by chl:*tt~sl. rank correlatinn and unpaired t-test; statistical significance has been set with p < . . / patients ( . %) developed gisb. although the mean gcs~-value (x -+ sd) did not reach significance between patients with and without gisb ( . + . vs . -+ . ). a significant inverse correlation between gcs:, and the incidence of gtsb (rs~ = . ) has been shown. the frequency of gisb among the groups is as follows: h . %; lh . %; llh . %; iv: . % (ch -~ = . ; not signilicant). no gisb-induced blood translusion or mortality, respectively, could be demonstrated. survival rate between the groups did not differ significantly (chi-" = . ; p= . ) and reached an overall-value of . %.drug-specific glsb-prophylaxis -administered either as monotherapy (pirenzepine, sueralfate) or in combination of these two specific-drugs -reveals no additional significant influence on the incidence of gisb in patients with cerebral lesion compared to no specific prophylaxis besides the general trauma-/disease-specific intensive care measures. critical care dpt, evangelismos hospital, athens university scho~" of medicine objectives: the correlation of longterm presence of nasogastric tube (ngt) to gastroesophageal reflux (ger) is still in question. in case of positive correlation, peg should represent an alternative to tube feeding in patients unable to be fed orally. therefore, we investigated: i) the correlation between ng and ger and ii) the effect of peg on ger. methods: a -h esophageal ph-metry was performed in patients in recumbent position at ~ who had a ngt for more than days and were on sucralfate for gastric mucosal protection. the tip of the ph-probe was lied cm over the esophagogasttie junction, confirmed by x-rays. patients who presented a percentage of ger-total (i.e. with a ph less or more than ) (ger-t) more than %, underwent ~t peg. the presence of a creseent-notch on the esophagogastric junction persisting on inspiration and the grade os endoseopic and histologic esophagitis (scale= - ) was noted. two ph-metrles repeated on h and on days post-peg were compared to the pre-peg one, with the followin~ parameters taken in consideration: i) % ger-t, ii) number of ger-total per hour (no/h ger-t) and iii) the duration that ph was less than (tph< ). in case ot ger persistence at the ph-metry on ?th day post-peg (group ii) another endoscopy was performed, while patients with reduced ger (group i) were considered as esophagifis-free.results: out of patients presented a ger-t> %. eleven out of group i group (n= ) i ( objectives: the aim of the present study was to compare the performance of a specially modified version of a photo-and magnetoacoustic (pa/ma) gas analyzer (br~)el & kjaer, denmark) with a conventional quadrupole mass spectrometer (ms) (innovision, denmark) in inert gas rebreathing (rb) tests such as determination of functional residual capacity (frc), pulmonary capillary blood flow (pcbf) and lung tissue volume (vtc). methods : from simultaneous readings of inert gas concentrations with the ms and the pa/ma analyzer during rb experiments a comparison was made of the pcbf, vtc and frc values. the rb tests were performed during rest and exercise ( , and w) in ten healthy subjects. results: the differences (mean +/-sd) between simultaneous estimates of rebreathing parameters were the following (pa/ma -ms) for pooled data, pcbf: . +/- . i/min, vtc: - +/- ml and frc: . +/- . liters. conclusions: smell but significant differences were found between the estimates of pcbf, vtc and frc using the ms and pa/ma, respectively. reference: p. clemensen, p. christensen, p. norsk, and j. gr~nlund. a modified photo-and magnetoacoustic multigas analyzer aplied in gas exchange measurements. j appl physiol ; : - . objectives: because transcranial doppler (tcd) has been proposed to explore cerebral co vasoreactivity in brain injury (stroke ; : - ), we compared this technique with the kety-schmidt reference method to assess cerebral vasoreactivity in comatose patients. methods: mechanically ventilated patients (age - yrs, glasgow - ) in coma due to acute brain injury were investigated during stepwise changes in paco ( , , , and mmhg) by increasing inspired pco . middle cerebral artery velocity (vm) was measured by tcd. after insertion of a catheter in the ipsilateral jugular bulb, cerebral blood flow (cbf) was determined by the kety-schmidt method, using the inhalation of % n through the inspiratory line of the ventilator. for each patient a cerebral co~ vasoreactivity index was calculated as the slope of linear relationship between vm or cbf and paco . objectives: after cardiac surgery the fluid shill, between interstitial and intravasal space may be marked. this is due either to the intraoperative volume loading by the extracorporeal circulation or the increased postoperative diuresis. therefore, infusion of a large amount &fluids is necessary during the first postoperative hours. it still remains unclear which of the substances at disposal is the best for this purpose. aim of the present study was to compare the different fluids with special regard to postoperative bleeding and rheological behaviour. methods: patients undergoing cabg-surgery were investigated and randomizedly distributed to three different groups of postoperative volume replacement to stabilize the mean arterial pressure at mm hg. . ringer's solution, . . % gelatine solution, . % hydroxyaethylstarch (mean m.w. . ). we evaluated the following parameters within intervals of min: arterial and central venous pressure, heart rate, postoperative bleeding, urinary output, volume replacement. results: there was no statistically significant difference between the groups with regard to urinary output and bleeding. in spite of larger amounts of fluids necessary in the ringer treated group patients of this group showed symptoms of hypovolemia. hematocrit was increased in the ringer patients. this was statistically significant. introduction: pulmonary wedge pressure (pcwp) and central venous pressure (cvp) are frequently used as parameters for cardiac preload, although it is known that both are poorly correlated to the cardiac index (ci). it has been claimed that intrathoracic blood volume (itbv) measured with the thermal dye dilution method reflects cardiac preload better than pcwp and cvp. we studied the correlation between itbv and ci in a mixed population of critically ill patients. methods: in consecutive patients ( sepsis/sirs, acute heart failure, ards, transjugular intrahepatic portosystemic shunt) monitored with a pulmonary artery catheter, itbv was measured on regular intervals using the pulsion cold z- system (pulsion, munich, germany). ci, pcwp, and cvp were recorded simultaneously. results: a total of ol measurements was made. pcwp and cvp did not correlate to ci, nor did apcwp or acvp correlate to aci. itbv was correlated to ci in a non-linear fashion (f - , df = , p < . , (figure) ). aitbv was correlated to ac in a linear fashion (r = . , f = , df = , p < .o ). a rapid and efficient circulatory support system may save a patient in cardiogenic shock. left heart bypass with percutaneous and transseptal placement of the aspiration canuia simplifies the circuit and avoids the need for an oxygenator. we assessed this preclinical set-up in anaesthetized pigs using a centrifugal pump with a f arterial catheter and a f left atrial aspiration line. animals were supported for two hours at a mean flow of . liter ( ' rpm), a mean hematocrit of % and low heparinisetion (act double baseline). hemodynamic and laboratory samples were taken at baseline (a), minutes (b), one hour ( pulmonary hypertension (ph) usually involves obliteration and loss of functional pulmonary microvasculature. the microvaseular endothelium normally acts as a major metabolic organ, converting angiotensin i to angiotensin ii via the angiotensin-converting ectoenzyme (ace). it is unknown whether the loss of functional vasculature and altered pulmonary blood flow seen in ph will affect lung ace metabolic activity. we therefore estimated pulmonary vascular ace activity in patients with ph of various causes: primary; post atrial septal defect closure (asd); chronic thromboembolic (te); anorexigen; iv drugs; collagen disease. single-pass transpulmonary hydrolysis of the specific ace substrate h-benzoyl-pbe-ala-pro (bpap) was measured and expressed as % metabolism (%me . we also calculated an index of peffused functional capillary surface area (amax/km). all patients with ph had an abnormality of %met or amax/km, or both. as compared to control humans (mean %met = . % _+ . % s.d.), the mean %met in ph patients was . % _+ %. the %met in ph patients correlated inversely with cardiac output (r= . ), possibly reflecting more complete bpap hydrolysis with longer pulmonary transit times. amax/km was markedly decreased in ph ( + ml/min) as compared to controls ( _+ ml]min), consistent with a significant loss of functional capillary surface area. patients with collagen disease, asd and anorexigen-induced ph had the most marked abnormalities. in conclusion, patients with pulmonary hypertension have decreased pulmonary endothelial angiotensin converting enzyme activity, likely due to a loss of functional or perfused pulmonary microvaseulature. supported by the funds de la recherche en same du quebec and the national health system of greece. objective: to investigate adrenocortical function in patients with ruptured aneurysm of the abdominal aorta (raaa). studies investigating adrenocortical insufficiency in critically ill patients report an incidence ranging from % to less than %. this may in part be explained by difference in methods used (single cortisol measurement vs short acth stimulation test) and populations studied (heterogenous groups of patients with great individual variation in underlying disease as well as duration and severity of illness). methods: we investigated the adrenocortical function in patients with (raaa).a short acth stimulation test (synacthen test; ug - acth iv) was performed at hrs within hrs of admission. plasma cortisol was measured before (cort basal) and after stimulation (cort stim). a plasma cortisol level > . umol\l before or after stimulation was considered normal, severity of illness was assessed using apache ii. results: of the patients investigated died and survived. mean cort basal in nonsurvivors was significantly (p< .o ) higher than in survivors; . (range . - . ) vs . (range . - , ). this difference between nonsurvivors and survivors was also present for cort stim but lacked significance; . (range . - . ) vs . (range . - . ). while patients showed a cort basal < . , no cort stim < . was found. there was no significant difference in mean age or apache ii score between survivors and nonsurvivors; vs and vs . conclusions: single plasma cortisol levels were inadequate to assess the adrenocortical function in the patients studied, judged by a short acth stimulation test, our investigation in patients with raaa showed no adrenocortical insufficiency. mortality in raaa is associated with elevated plasma cortisol levels. obiectives: mortality in acute myocardial infarction (ami) prinicipally depends on hemedynamic impairment. thus, patients (pts) with elevated pulmonary wedge pressure (pwp) present high in-hospital mortality. however, the complete right heart catheterization is laborious, so the central venous pressure (cvp) alone is frequently used to assess the severity of ami. the accuracy of cvp in estimating pts with ami was tested in this retrospective study. methods: pts. aged + years, admitted to our ccu from to with their first ami, were inctuded in this study. all had undergone right heart catheterization because of overt or suspected heart failure. swan-ganz catheters ( f, cm, abbott, il, usa) had been used, every treatment had been temporarily interrupted l h before the calheferization. based on ecg findings the pts were retrospectively divided into groups. in group a we included pts with anterior ami, in group b, pts with inferior ami, and in group c, pts with inferior and right ventricular ami. the initial values of cvp and pwp were considered for the linear regression of the pwp variable on cvp and p< . was accepted as statistically significant.results: in g~oup a, the cvp and pwp vaiues were + mmhg and _+ mmhg respectively. despite the signifanf correlation (p< . ) between the two variables, it was not possible fo predict the exact value of pwp based on cvp value, pts ( %) presented cvp> mrnhg and of these ( %) had pwp_> mmhg. in group , the cvp was _+ mmhg and the pwp, _+ mmhg. significant correlation (p< . ) between the two variables also existed, however it was impossible to predict the pwp value. pts ( %) had cvp> mmhg but only of these ( %) had pwp> mmhg, similar was the relation between cvp and pwp in group c (p< . ). cvp averaged + mmhg, and pwp, _+ mmhg. pts ( %) had cvp> mmhg and from these ( %) presented pwp> mmhg,conclusions: a single measurement of cvp in ami does not ensure an accurate assessment of pwp. because every pt with ami needs optimal values of pwp in order to prevent pulmonary congestion or manifestations of low preload, the significance of complete right heart catheterization becomes apparent. in patients (pts) with advanced hf the need and the prognosis for heart transplantation (ht) can be predicted from vo= max. indirect measure of functional capacity with the six-minute walk test can also predict smvival in moderate hf. to predict vos max from indirect astinmtions of functional capadty such as - ~q~/, pulmonary and heart function tests, and to assess the prediddve value of the above parameters in hf pts survival. we evaluated pts (age + yeats nyha class: ii, hi, iv) with hf for pit. they underwent a pmgmmive exercise test on cycle ergometer for vo max determination, a -mw, a right heart catheterization and a spirometry and dlco estimation. introduction: brain death causes myocardial impairment by mechanisms that are not well understood yet. the aim of this work was to assess the echocardiographic features found in these patients from the clinical onset of brain death to somatic death, methods: seven brain dead patients were studied (patients" relatives refused to allow them to be used as donors). mean age was . ( - ) years old. four of the patients were female, none of the patients had any history of cardiac disease. transthoracic echocardiogram (echo) and electrocardiogram (ecg) were obtained at the onset of clinical brain death and were repeated every hours until somatic death. we we detected severe diffuse hypokinesia (ef< %) in patients and mild hypokinesia in others (ef - %). systolic function was strictly normal in only patients. corrected qt interval (qtc) in ecg was . _+ . msec (normal range - msec) just before somatic death (b). conclusion: in patients with brain death we observed a significant increase of left ventricular mass due mainly to ivs "hypertrophy" without any important change in the dimensions of the left ventricle. to our knowledge, this finding has never been reported before and its importantance in heart transplantations may be of particular interest. predict right ventricular outcome. l. jacquet, r. dion, p. noirhomme. m. van dijck. m. goenen cardiothoracic intensive care unit, st-luc univ. hospital(ucl) we have registred: heart rate (hr), blood pressure (bp), pulmonary artery pressures (pap), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), pulmonary and systemic vascular resistances (pvr, svr), right ventricle end-diastolic end end-systolic volume (redv, resv), right ejection fraction (ref), right sistolyc ventricular work (rsvw) and cardiac output (co) using a thermodilution thechnique and a microprocessor (model ref- ; baxter-edwards laboratory); duration of cpb and aortic clamping, and the requirements of haemodynamic support after cpb.results: in the c group an increase post-cpb of the fc ( + . + . , p < . ) was produced without significantly changes in the redv, resv, ref, rsvw neither co. in the w group, hr increased from . + . to . + . (p < . ); redv was reduced from . -+ to . _+ . (p < . ); resv was reduced from • . to + . (p < . ). there were not changes in the other haemodynamyc parameters. there was a trend (no significantly) to an increase of ref in the w group ( . + . |• . ) compared with the c"group ( • . ($ . • . ) post-cpb. the need for haemodynamic support was similar in both groups.conclusions: the warm, continuous, anterograde-retrogade myocardial protection has obtained a decrease of preload, hr, and a trend to an increase in the ref, making an improvement in the right ventricular global performance when is compared with the classic form of cold myocardial protection. objective: to evaluate the effect of dobutamine on gastric mucosal ph (phi) after coronaly artery bypass surgery. design: prospective study in a university hospital intensive care unit (icu). subjects: elective cardiac surgery patients. interventions: dobutamine was infused at ug/kg/min for hours immediately after admission to the icu. hemodynamics were measured every minute periods until hours and again hours after stopping dobutamine. results: there were no significant differences in mean gastric phi between the groups but mean phi decreased in both groups during the study period. oxygen delivery and consumption both increased during dobutamine infusion but decreased to the control group level after stopping the dobutamine infusion. lactate levels did not change. baseline objectives: the aim of the study was to evaluate the usefulness of a low dobutamine dose in conjunction with intraaortic balloon pumping and mechanical ventilation in cardiogenic shock. we studied patients . -+ t . years of age suffered of post infarction cardiogenic shock characterized by a systolic arterial pressure< mmhg, urine output< ml/h and mental confusion or purpueral signs of low output, non responded to dobutamine infusion up to pg/kg/min. all patients underwent mechanical assistance by the intra-aortic balloon pump (iabp). five patients were additionally placed on mechanical ventilation due to blood gases disturbances. the end points in our study were: reversion of cardiogenic shock, improvement of patients survival or both on the th post infarction day and months later. results: three patients refused iabp treatment and / survived on the th day. on the th day / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p < . ). on the th month / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p< . ). conclusions: in conclusion, the combined use of mechanical ventilation and iabp assistance in severe cardiogenic shock might improve survival. obiectives: the study was aimed at analysing predictive factors of swan ganz pulmonary catheter (pc) requiremen t during elective cardiac surgery according to the need of sustained inotropic support after surgery. methods: three hundred patients (aged from to ; females and males)were consecutively operated on for elective coronary artery bypass surgery (cabg, n= ), valvular replacement (vr, n= ), combination of both (vr-cabg, n= ), or others (n= ) and retrospectively included in the study. each patient had preoperative invasive cardiac investigation with calculated ejection fraction (ee). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest managements were similar in all patients. pc requirement was estimated from the need of either dobutamine, adrenaline, dopamine or enoximone use during the first hours after cardiac surgery. demographic data, asa and nyha classifications, preoperative ef and treatments, type of surgery, cpb and aortic cross clamping (axc) times, and postoperative incidence of complications were compared in patients with or without inotropic support using either student's t test or x with continuity correction when appropriate. results: seventy hree patients ( . %) required inotropic support after surgery. axc .and cpb times, mean stay in icu were significantly longer in patients with inotropie support (p< . ). type of surgery, preoperative ef, and nyha classification are the first significant factors related to inotropic support (p< . ). most patients operated on for double-vr or vr=cabg required inotropic support ( and %, respectively). postoperative mortality was higher in patients receiving inotropic support ( , % vs , % 'overall mortality, p= . ). conclusions: since pc insertion is most.often justified because inotropes are required, these results suggest that elective rather than routine systemic pc insertion could be helped by considering several but selected preoperative factors. background: cardiovascular depression due to anaesthesia, old age and major gastrointestinal surgery is becoming an increasingly frequent challenge .to the anaesthesia-surgory team. deliberate preoperative manipulation of haemodynamics and oxygen transport parametres towards prede~t~mined optimal values may prove to be effective "in reducing morbidity ~nd mortality in high risk surgical patients,. a new concept of using conlimaous perioperative measurement of cardiac'output to obtain and maintain supranormal oxygen delivery (do i) is presented. methods: continuous measurement of cardiac output is a relatively new form of on-line monitoring, in which trains of impulses are emitted from a thermal filament mounted on a pulmonary artery catheter. computer software recognizes patterns generated by minute changes in blood temperature and ealoalates cardiac output every - seconds. cardiac output and mixed venous blood oxygen saturation are displayed graphically on line. in tins tm study cardiac output was measured continuously by vigilance cardiac outpu t compl/ter (baxter). preoperative haemodynamic optimization was performed with the goal of increa- sing do i to at least ml/min/m accordfing to shoemaker's algorithm . this was.done by infusing colloids (albumin or hydroxy ethyl starch (haes-steril| until the desired do was reached. infusion was stopped if cardiac output ceased to increase with infusion, if there were signs of pulmonary oedema or if wedge pressure reached mmhg. vasoactive or inotropic drugs were infused if the desired do was not reached by infusion alone. anaesthetic technique included continuous thoracic epidural and isoflourane anaesthesia. expected mol:bidity and mortality rates were calculated by the "possum" score aasing preoperative clinical and paradinical estimates of organ function as well as surgery characteristics . materials: asa group ill-iv patients with a mean age of years (range - ) and a mean weight of kg (range - )) scheduled for major abdominal surgery were included. results: patients were excluded because do i could not be raised at all. mean do i was increased from ml/min/m (range - ) to ml/min/m (range - ). mean volume of preoperativdy infused colloid was ml (range - ). during surgery ml (range ) of colloid was infused. mean length of surgery was minutes (range - ). mean blood loss was ml (range ). expected mortality and morbidity rates ("possum") were % and %, respectively, whereas patient follow up upon discharge or at death revealed mortality and morbidity rates of % and %, respectively. conclusion: based on experience from the present study, continuous measurement of cardiac output has proved to be a valuable tool for perioperative optimization of do in asa group ili and iv patients during major surgery. however further studies including a greater number of patients are necessary to confirm the promising preliminary findings. we studied the hemodyn~c effects of three different combinations of positiv inotropic .agents, vasodilators, diuretics and av-filtration (av) in patients (pts) with severe left heart faille (left veutrieul x filling pressure (lvfp) > mmhg) due to acute myocardial infarction. hemodynamic measurements (intravascular pressures (lvfp), thermodilution (cardiac index (ci)) were made before (control) and after each therapy. in furosemide (f) + d butamin (d) + nitroglycerin (ni) reduced lvfp and a small increase of ci occurred. in of these pts :(group a) nitroprusside (hip) instead of ni increased ci significantly, in the other pts adding of amrinone (a) resulted in a pronounced increase of ci. group c (n= ): the combination of ni and av reduced lvfp but did not increase ci which was achieved by av+d+ni. in order to optimize the treatment of acute heart failure a combination of inotropic agents, vasodilators, diuretics and av-filtration should he used guided by hemodynamic monitoring. arias jr, miragaya d, sandard, san pedro dm ~, herndndez d, valenzuela . objectives: to evaluate the variation in nomdrenaline (na) plasma concentrations in patients with acute myocardial infarction (am ) after thrombolytic therapy with noniltvasive reperfusion criteria (clinical, electrocardiographic and enzymatic), in relation to infarct size and location.methods: consecutive patiens with ami, from october , to february , , admitted within hours alter onset of symptoms, undergone successfull systemic thrombolysis. of them were anterior (group a) and inferior (group b) . noradrenaline plasma levels at (na ), (na ) and (na ) minutes after admission were compared with ck-peak plasma levels by linear regression. differences were tested for significance by student-t-test for paired and unpaired values. na plasma concentration was measured by high-presssure liquid chromatography. p< ns . ns means -sem (normal limit for our laboratory: na < / pg/ml; ck < u/i ) conclusions: . the na plasma levels at admission (nai) are more increased in anterior than inferior amis, probably in relation to infarct size. . the decrease in na is more evidence in amis with anterior location. . this decrease is probably due to the major efficacy of thrombolytic therapy in amis with anterior location. arias jd, miragaya (group b) , probably due to certain degree of t~cg'rfueion. . there is not significant variation in na in conventional treated ami (group c). v.suchanov, a.levit, p.trofimov, icu, regional hospital, ekaterinburg, russiaobjectives: our task was to improve the technique of preservation of platelet rich plasma. methods: patients scheduled for multiple cardiac valve replacement in were divided into two groups: group i ( patients) -without pp; group ii ( patients) -pp was performed preoperatively. the first pp was made ten days and the second - days before the operation. prp was preserved by cryoconservation. our technique of cryoconservation is distinguished by the speed of freezing ( - ~ and absence of dmso. this made it possible to preserve % functionally active platelets during days. the prp was transfused back after heparin neutralization. the hospital ethics committee approved the investigation.results: the blood loss through the st p. o. d. was significantly greatest in the group i ( _+ ml) and all the patients required transfusion of the donor blood ( + ml) whereas the blood loss in group ii was +_ ml and olny patients required the donor blood. the number of platelets on the st p.o.d, was _+ . /l (group i) and + . /l (group ii), p < . .conclusions: our technique of prp cryoconservation makes it possible to avoid the crystallization phase during freezing of prr thus the infusion of prp may improve hemostasis after open heart surgery and limit the use of the donor blood. in-hospital outcome of women suffering an ami is generally considered worse than that of men, but it is still debated whether female sex is per sea negative prognostic factor or is merely associated with other negative determinants of prognosis. the purpose of the present study is to evaluate the independence of the association between female sex and mortality (in the patients of the swiss centers) and in the patients randomized in the isis- trail mortality rate in women was . % ( / ) compared to . % ( / ) in men; in switzerland: in-hospital mortality for women was . % ( / ), for men . % ( / ).the table shows the results of isis- in terms of odds ratios and their % confidence intervals either after unadjusted analysis or after adjustment for age, known to be the major confounding variable when prognosis of women after myocardial infarction is considered, and for all the available clinical and epidemiological characteristics collected at trial entry: these observations suggest that there is a small but independent effect of female sex on short-term mortality after acute myocardial infarction. ( ) and bubble ( ) oxygenators a, ere used. anaesthesia was balanced and pts were extubated to hrs after cpb. pts were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that time qs/qt was calculate( according to )be standard shunt equation. after the sgc had been removed, an estimated shunt was calculated. measurements of qs/qt were performed: before induction of anaesthesia ( ), after induction of anaesthesia (i[), mins after cpb (iii) (iv) and (v) hrs afiter cpb, rains after extubation (vi), hrs after cpb (v[ ) and on the nd, rd, th, th and tb postoperative day (pd) (viii, x, x, xi, xi , respectively). analysis of data was performed by two-way analysis of variance, p < . being regard as significant.results: the figure shows the values for qs/qt expressed as means + sd. there was a significant increase in qs/qt above b~setine throughoul the whole investigated period except on the th pd. qs/qt reached maximum at rains after extubation (vi). objectives: many stndies have shown advantages of membrane oxygenalors over ubbie type oxygenators. the aim of this study was to evaluate the influence of x 'genator type on pulmonary shunt (as/at) after coronary surgery. methods: patients (pts) gave their informed consent to the study which was approved by the university ttuman research committee. pts were divided into two groups: a (n = ) with a membrane o~genator and a (n = ) with a bubble oxygenalor used during cardiopulmonary bypass (cpb). ths were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that tfme os/ot was calculated according to the standard shunt equation. alter the sgc had been removed, an estimated shunt was calculated..measurements of os/qt were performed: betore induction of anaesthesia (i), mins after extubation ( ), hrs alter cpb ( ) and on the nd, rd, th, th and th postoperative day (iv, v, vi, vii> viii, respectively). analysis of data was performed by one-way analysis of variance, p < . being regarded as significant.results: the figure shows the values for qs/qt expressed as means _+ sd. os/qt was significantly greater at rains after extubation (ii) in a group. the difl'ereuce between the two groups was no more significant from hrs after cpb (iii) to the end of the investigated period. ! i * p < a. s betw~n ~o~ conclusions: membrane ox 'genation during cpb is accomplished by reduction in blood cellular destruction and less alteration in blood. the results of our study show the influence of oxygenator type on value of qs/ot only after extubation ( to hrs after cpb). the difference in qs/qt disappeared his after cpb and since that time the oxygenator type had no influence on qs/qt. it may be of particular importance in patients with severe forms of cardiopulmonary disease who are at risk of higher postoperative morbidity and mortality. objectives: hypomagnesemia has been reported with a variable prevalence ( to % ) in icu patients. magnesium deficiency can induce a number of climcal symptoms (primarily cardiovascular and neuropsychiatric) but can also be clinically silent ( - % are asymptomadc), methods: we measured whole blood ionized magnesium (lmg++) in patients on admission to the icu, using a nova electrolyte analyzer (nova biomedical), containing an img++ electrode. blood was collected in syringes with dry heparin (radiometer qs ). normal range of img++ was found between . - . mmot/l (healthy volunteers). results: for the entire population, we found a % prevalence ( / ) of hypomagnesemia (figure ) . among the surgical patients, the prevalence was highest after cardiac surgery ( %) and after thoracic surgery ( %) and was lowest after neurosurgery ( %). hypomagnesemia was also common in patients after liver transplantation (lvtx) or with hepatic failure ( % for both groups). conclusion: our findings confirm that hypomagnesemia is common in acutely ill patients, especially in those after cardiothoracic surgery or those with liver disease. nevertheless. it is difficult to define the associated factors with sufficient specificity, so that measurements of img++ are warranted to diagnose hypomagnesemia. hepariu influences platelet function and may lead to thrombocytopenia called heparin-associated thrombocytopenia (hat) regardless of the dose and route of administration. additinnal venous and/or arterial thrombosis may lead to life-threatening complications. the incidence of so-calied heparin-associated thrombocytopenia and thrombosis (hatt) ranges between i- %. hatt is confirmed by a heparin induced platelet activation assay (hipa). results: from / to / consecutive patients of our icu were reviewed retrospectively. all patients were treated with heparim the incidence of hatt was % ( ). in all cases diagnosis was proven by a positive hipa. / patients died. in / hatt could be confirmed before severe thromboembolic complications occured. / patients developed a deep vein thrombosis (dvt), / dvt and pulmonary embolism (pe), / dvt, pe and arterial thrombosis (at) and / a dvt, pe~ at and a sinus thrombosis. conclusion: the incidence of hatt in a r series of pts. is %. presence of thrombocytopenia and thrombosis of the great 'vessels is associated with a significant mortality ( / ). computed tom graphy (ct) and transthoracic/transesophageal echocardiography (tte/tee) are important tools in diagnosing and monitoring the extent of cenlrai venous and arterial thrombosis. a. cabral md, m. shahla md c. meneses-oliveira md and jl vincenl md.phd. department of intensive care. erasme university hospital, brussels, belgium objective: to determine extreme hemodynanuc patterns in cardiogenic shock. although ~.~xdiogenic shock is characterized by a low cardiac index (ci), high systemic w~,scular resistance index (svri), and high cardiac filling pressures, some patients may develop art atypical pattern. we reviewed the hemodyuamic pattern of patients with cardiogenic shock, as defined by an initial ct below . l/rain/m: in the presence of myocardial dysfimction attributed to ischemic heart disease (n= ), heart failure (n= ), valvulopathy (n= ) or recent cardiac surgery (n= ). after exclusion of patients with concurrently suspected/documented infection, this study included patients, of whom ( . %) survived. treatment of shock included dopamine (n= ), dobutamine (n= ), norepinephrine (n= ) and epinephrine (n= ). patients with arterial hypertension (ah) and initially law plasnla renin activity (pra) had been studied. in all patient changes of arterial pressure (ap) after single administration of enap was studied. nypotensive reaction wiht deereasin e of average ap about - mm hg ayter single drug administration observed only in patients. ezap monotherapy accomplished during one week with mg daily dose. hypotensive effect observed in patients including ones which were susceptible to single enap administration. after that first stage of therapy all patints began to combinate enap with hypothyazid in dose of mg per day~ after week of treatment such drugs combination lead to veritable ap lowering in addition patients. in the remaining resistant to such drug combination patients was add corinfar in daily dose of mg. this new drug combination permits to lower ap in patients. subsequent discontinuation of enap administration to such patients aid not connected with increasing of again.therefore the most of the patients with ah and law pra( , %)did not susceptible to enap therapy and enap and hypothyazid combination. on the contrary-combination of corinfar with hipothyazid was effective in % patients with ah and low pra. methods: in patients with cardiogenic shock due to ischemic heart disease (n= ), heart failure (n= ) and valvulopathy (n= ), hemod aamic data including measures of intravascular pressures, cardiac output and mixed venous gases were collected at regular times intervals, at least times a da?. all measurements were obtamed in a relative steady state and in the absence of severe anemia or hypoxemia. treatment of shock included dobutamine (n= ), dopamine (n= ), norepinephrine (n=i ) and epinephrine (n= objective: based on our previous studies of the function of isolated liver grafts, this experimental protocol aims at developing a novel extracorporeal liver support circuit, with an incorporated pig liver. methods:the graft liver was obtained from pigs weighing - kg. under general anesthesia the aqimals underwent total hepatectomy,following cannulation of the portal vein, the infrarenal aorta and the infrahapatic vena cava and peffusion wit h it of heparinised r/l solution at ~ the circuit consisted of the graft liver connected to a fluid reservoir and a centrifuge pump. ten healthy pigs weighing - kgr were connected to the circuit as follows: the rt carotid artery was connected to the portal vein of the graft and the rt jugular vein was connected to the fluid reservoir, through the centrifuge pump. the fluid reservoir collected the outflow from the graft's suprahepatic inferior vena cava. the cystic duct of the graft was ligated and the bile.duct cannulated for bile collection and measurement. bridges were adapted to the circuit to bypass the graft liver when necessary, in cases of by pass blood perfusing the graft was oxygenated through a bubble oxygenator. mean total priming volume of the circuit was ml. temperature was maintained at ~ and portal vein pressure at ( - ) mmhg. the flow was . - . ml/gr of graft liver mass per minute. observation period was hours (t ). results: results of the hemadynamic and metabolic monitoring of the recipients [map (t = mmhg , t = mmhg), hr (t = , t = ), rap (t = mmhg , t = mmhg), pap (t = mmhg, t = mmhg), pcwp (t = mmhg, t = ~mhg), svr (t = dyn'sec/cm ' , t = dyn'seclcm~ pvr (t = dyn.sec/cm o, t = dyn.sec/cm ,'~), co (t = . t/min, t = . t/min), do (t = ml/min, t = . ml/min), vo (t = ml/min, t = ml/min), o er (t = . %, t = . % ), ph (to= . , t = . ), po (t = mmhg, t = mmhg), pco (t = mmhg, t = mmhg), pvo (t = mmhg, t = mmhg), svo (t = %, t = %), be, na, k, ca ++, lactate, osmolality, ast, alt, pt, aptt, revealed hemodynamic and metabolic stability of the animal. consumption, co production and tissue oxygenation of the graft were also studied. conclusion; the described circuit proved to be safe and well tolerated by healthy animals but its value for temporary liver support is currently being estimated, in a surgically induced experimental fulminant hepatic failure modal. introduction: prosthetic materials like silikone, dacron, teflon e.tc. produce auto immune responses and may even trigger clinical syndromes like scleroderma, sjogren, sle el.c. in our study we followed the evolution of humorial immunity parametrs for up to five years in a cohort of paced pts with implanted metallic and silicone materials. method: paced pts (mean age +- yrs) without clinical or laboratory findings of malignancy or immune disorders were included. we measured the immunoglobulins, the complement, the auto antibodies and the proteins involved in inflammatory reactions every months. the initial and final mean values are shown in the obiectives: hsp, a systemic leucocytoclastic vasculitis and anaphylactoid purpura can be accompanied by abdominal pain and life-threatening intestinal bleeding. recently we could disclose, that these patients develop severe fxiii-deficiency and immense haemorrhagic oedema of the intestinal wall. by the following case report we will demonstrate and discuss the importance of fxiiideficiency for pathogenesis, therapy and outcome in hsp. case report: a year old man developed typical skin manifestations of hsp following an episode of severe (biliary ?) pancreatitis and percutaneous draining of a pancreatic pseudocyst. two days later he had a paralytic "ileus with immense hemorrhagic wall-oedema and massive dilatation of the small bowel. he got fever up to . ~ and developed severe gastrointestinal haemorrhage (blood transfusions necessary). the coagulation data disclosed a severe fxhi-deficiency (activity %), whereas quickvalues, platelet count and atiii-level were found to be within the normal range. elastase was markedly elevated. substitution of fxiii to normal levels leeds to the cessation of bleeding symptoms and abdominal pain, later resulting in a restitutio ad integrum. conclusions: hsp with intestinal involvement is a life-threatening vasculitis, in which careful and frequent examinations of the coagulation system, especially of fxiii are necessary. detailed analysis of the coagulation data suggest, that the severe fxiiideficiency is due to a specific degradation by proteolytic enzymes (like elastase) as well as consumption within the immense haemorrhagic oedema of the intestinal wall. knowing these facts, even most severe cases of hsp with intestinal involvement can be successfully treated by substitution of fxih. a -year-old woman presented a year history of occasional self-limited episodes of weakness, generalized edema and o!!~aria. the immunologic testing showed no~nnai levels of complements, clq inhibitor, and serum chemistry values, between or during a attack, she was not treated. she was a~mitted to the hospital with symptoms including nausea, vomiting, weakness and ol!guria. on examination, the patient presented facial and g~neralized edema. the systolic blood pressure was mm hg, pulse beats/mir~ute, hematocrit . , seln~n protein /i, and se~um albumin q/l. an leg-kappa pa[apfotein was demostrated ( . g/l) and urine was neaative for puotein. c~'stalloid and colloid don't increased the blaod pressure but resulted in anasarca, with a total of ii lit[as of in~ravenous fluids. therapy wink flozen plasma, . units of clq inhibitor, cortlcosteroids, annihistwnines and antifibrinolytic agents was uns~iccessfull. the a~minist~ation of dopamine, norepineph~ne and epinephrine was inefective. the patient died at the bores, only a few cases have been reported, all had igg paraprotein, the pathophysio!o~] is urd~no~n% but is possible that the paraprotein may be zesponsib!e for the increased capillary pe~leabilityo despite efforts to res~scinate the patients during an acute attack, the syndrome is often fatal. the variable course of systemic uapiliary leak syndrome and the unpredictability and self-limited nature of attacks cloud assessment of therapeutic inte~-vention. the purpose of the present work is to provide some information about the nursing care and results from our experience in continous arteriovenus hemofiltration (cavh).cavh is an extracorporeal technique, especially applicable in the critically ill patients, for disturbances, and for the control of azotemia.we used this method in critically ill patients men and women ages from - who had sepsis -arf congestive heart failure postoperative multiple organ failure and polytrauma .this method was applied to these patients from to hours. % of the patients recovered completely their kidney function, % improved their kidney function and % died.we concluded therefore that this method was very effective for the critically ill patients to whom it was applied, but it requires excellent and continuous nursing care; under the above mentioned circumstances the method works effectivelly. an animal model with rats undergoing a dialysis procedure was designed to test the hypothesis that recovery from ischemic acute renal failure (airf) may be affected by the type of membrane used in hemodialysis. male sprague dawley rats were allocated to groups: in group i, (n= ) airf was inducted by bilateral renal artery clamping for rain. group h (n= ) rats underwent a sham procedure. in each group, rats were dialyzed twice ( th and th day) with either a cuprophan (cupro), a hemophan (hemo) or a pan (an ) minidialyscr or stayed nondialyzed (no hi)). renal function was monitored daily by measuring urea and creatinine values and by two single shot inulin clearances on the days following dialysis. additionally hemolytical activity of complement was determined. inulin clearance on day was reduced significantly but there was no difference in the degree of decrement in glomular filtration rate (gfr) between dialyzed and undialyzed rats, nor between the dialyzed animals with different membranes (gfr: no hi): . _+ . ; cupro: . _+ . ; hemo: . _+ . ; an : . _+ . ). the evaluation of renal function by day nine revealed significant recovery for all airf-groups compared to day (p< . ), irrespective of wether they underwent dialysis or not, or the type of dialysis membrane. complement activation could be detected in all dialyzed groups but no statistical differences between the animal groups dialyzed with different membranes were noticed. our findings refute the hypothesis that in airf exposure to complement-activating cellulosic membranes impairs the recovery of renal function in rats. changes patients: patients who underwent first cadaver kidney transplantation in our unit between january and december in were involved. the recipients were divided into groups: group i." non functioning graft (n= ); group ii: delayed graft function (n= ), group ili: good graft function (n= ). the grouping criteria were: a/haemodialysis in the fii~t postoperative days, b/diuresis in the i st postoperative day, c,' scram crcatininc difference between the st postoperative day and the preoperative level. all of the parameters were involved into the exarainatio, which we measllre in our every, day practice. results: the preoperative haematocrit level differed significantly between group i. ( . ) and croup ii. and iii. ( . and . , p< . ). intmo! emtive significant differences were found between the different groups in systolic blood pressure (group i. hgrmn, group ii. hgnnn, group iii. hgmm, p< . ), mean arterial pressure (group i. hgmm, vs. group ii. hgnun p< . , vs. group iii. hgmm p< . ), and pulse-amplitude and rate-pressure product too. the second warm ishaemic time in group iii. was significantly shorter than in the other two groups (group iii. inin. vs. group ii. rain. p< . , vs. group i. rain. p< . !). the rejection rate was higher in the first days in the patients with non-functioning grafts (group i. % and group ii. % vs. group iii. %) . the other examined parameters have not differed significantly. conclusion: according to our results the success of the kidney transplantation is mnitifactorial. the most important factors of this relationship are: the perioperative fluid-balance, the maintenance of adequate perfusion blood pressure during the operation, good surgical technique and immunological problems.